FLUOROALKYLATION REAGENTS AND USES THEREOF

RELATED APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S.

provisional patent application, U.S. S.N. 61/987,251, filed May 1, 2014, which is incorporated herein by reference.

BACKGROUND OF INVENTION

[0002] Fluorinated organic compounds are used as pharmaceuticals and

agrochemicals, in part due to their favorable pharmacological properties such as increased metabolic stability (see, for example, Miiller et al., Science 2007, 317, 1881-1886; and Jeschke, P. ChemBioChem 2004, 5, 570-589). In particular, small fluoroalkyl groups such as the -CF ₃ and -CF ₂ CF ₃ groups are widely used in materials and medicinal chemistry because of their unique chemical and electronic properties. Fluorinated organic compounds also find applications as tracers in positron emission tomography using the isotope 18 F (Lasne, et al. In Contrast Agents II, 2002; Vol. 222, pp 201-258). While fluorinated organic compounds are useful, fluorine has the highest electronegativity, the highest oxidation potential, and the smallest anionic radius of all elements, each of which complicates carbon-fluorine bond formation when compared to other carbon-heteroatom bond formations (see, for example, Chambers, R.D., Fluorine in organic chemistry. Oxford: New York, 2004; and Furuya et al. Curr. Opin. Drug Discov. Devel. 2008, 11, 803-819). Based on these challenges to the formation of carbon-fluorine bonds, numerous chemical methods have been developed to introduce fluoroalkyl groups. Examples of reagents developed for nucleophilic

trifluoromethylation include the Ruppert Prakash reagent (TMSCF ₃ ) and trifluoromethylator reagents (which generate an active "CF Cu" species), while reagents developed for radical trifluoromethylation include the Langlois (NaSO ₂ CF ) and the Baran reagents (Zn(SO ₂ CF ) ₂ ). Exemplary electrophilic trifluoromethylation reagents include the Umemoto and Togni reagents.

Umemoto Reagent Togni Reagent [0003] Fluoroalkyl iodides, in particular trifluoromethyl iodide, are inexpensive sources of fluoroalkyl fragments that are useful functional groups for a variety of

applications. However, the synthetic utility of the two early homologues trifluoromethyl and pentafluoroethyl iodide is diminished because they are gases. Gases are generally less safe to handle than liquids and often more cumbersome to employ in the laboratory, especially when performing reactions on millimolar scale; and stock solutions can often not be stored without variation of the titer.

SUMMARY OF INVENTION

[0004] The present invention provides compounds, reagents, systems, reaction mixtures, compositions, kits, and methods for fluoroalkylating an organic compound.

[0005] The present disclosure is at least partially based on the discovery that Lewis base complexes of fluoroalkyl iodides possess advantageous properties when compared to free fluoroalkyl iodides. Various Lewis bases are disclosed herein for forming adducts with the fluoroalkyl iodides; these include, but are not limited to, amine bases, guanidine bases, sulfides, sulfoxides, heterocycles, and heteroarenes. As is demonstrated herein, halogen bonded complexes of fluoroalkyl iodides possess comparable reactivity to the parent fluoroalkyl iodides, enabling them to serve as replacements for these inconvenient and difficult- to-handle reagents in a wide variety of applications.

[0006] One aspect of the present invention provides compounds of Formula (I):

wherein:

is a halogen bond;

R ¹ is unsubstituted C _1-3 fluoroalkyl;

D is N(R ² ) ₃ , ((R ² ) ₂ N) ₂ C=NR ² , O=S(R ² ) ₂ , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;

each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and

y is 1 or 2. Exemplary compounds of Formula (I) include compounds of formula:

CH3 H CH3 H

,N . N l-CF, .N^ _/ N l-CF ₂ CF ₃

H ₃ C

H ₃ C CH3 H3C CH ₃

(CH ₃ ) ₂ S=0--I-CF ₃ , (CH ₃ ) ₂ S=0--I-CF ₂ CF ₃ ,

H3C-N N-CH3 H3C-N N-CH3

i i ί ί

I I

CF ₃ CF ₃ F3CF2C CF2CF3

[0008] In another aspect, the present invention provides methods of fluoroalkylating an organic compound, the method comprising contacting a compound of Formula (I) with an organic compound of formula:

(a-1) (a-2) (a-3) (a-4) (a-5) (a-6) (a-7) wherein:

each instance of R 7', R 8°, R 9", R 10 , R 11 , R 12 , and R 1 ¹ 3 ^J are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R 7 , R 11 or R 13 groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring; under suitable conditions, to form a fluoroalkylated organic compound of formula:

_R f R* R1 R1 R1 R ^{1 0H Rl} r° ^H

(b-1) (b-2) (b-3) (b-4) (b-5) (b-6) (b-7).

[0009] In another aspect, the present invention further provides methods of preparing a compound of Formula (I), reaction mixtures comprising a compound of Formula (I), compositions comprising a compound D and a fluoroalkyl iodide of formula I-R ¹ , and kits comprising a compound of Formula (I).

[0010] The details of one or more embodiments of the invention are set forth herein.

Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Examples, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 shows DFT calculation results demonstrating the orbital character of the three iodine lone pairs of trifluoromethyl iodide (CF ₃ I). Shown are the two p-type and the s-type iodine lone pairs in CF ₃ I.

[0012] Figure 2 shows DFT calculation results depicting the natural bond orbitals

(NBO) of trifluoromethyl iodide (CF ₃ I).

[0013] Figure 3 shows an electrostatic potential map of trifluoromethyl iodide (CF ₃ I) in Hartrees at the 0.001 electrons Bohr- isodensity surface highlighting the σ-hole region.

[0014] Figures 4A-4E show the optimized conformation for several key compounds and their trifluoromethyl iodide (CF ₃ I) adducts as determined using DFT calculations (for details of calculations, see Examples). Figure 4A shows the optimized conformation of trifluoromethyl iodide (CF ₃ I). Figure 4B shows the optimized conformation of

tetramethylethylenediamine (TMEDA). Figure 4C shows the optimized conformation of 1,1,3,3-tetramethylguanidine (TMG). Figure 4D shows the optimized conformation of the bis-trifluoromethyl iodide (CF ₃ I) adduct of tetramethylethylenediamine (TMEDA). Figure 4E shows the optimized conformation of the trifluoromethyl iodide (CF ₃ I) adduct of 1,1,3,3- tetramethylguanidine (TMG). [0015] Figure 5 shows the X-ray structure of TMEDA ^» 2CF I, the experimentally measured and calculated N-I distance, and the calculated interaction energy per CF I molecule.

[0016] Figure 6 shows the calculated interaction energy and N-I distance for

TMG'CF ₃ I.

[0017] Figures 7A-7B show the release of CG3I from various halogen bonded adducts. Figure 7 A shows the weight loss (mol ) for CF ₃ I-TMG and CF ₃ I-2DMSO. Figure 7B shows the weight loss (mol ) for CF ₃ I-3CH ₃ CN, CF ₃ I-3CHC1 ₃ and CF ₃ I-3TMG and CF ₃ I-3DMSO.

[0018] Figure 8 show formation of a 1:1 adduct (maximum in the plot at %(DMSO) = 0.5).

DEFINITIONS

[0019] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH

Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic

Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0020] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. "Racemic" refers to a compound in which the percent by weight of one enantiomer is equal to the percent by weight of the other enantiomer.

[0021] The terms "enantiomerically enriched," "enantiomerically pure" and "non- racemic," as used interchangeably herein, refer to a compound in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer compared to a control mixture of the racemic composition (e.g., greater than 1: 1 by weight). For example, an enantiomerically enriched enantiomer, means a compound having greater than 50% by weight of one enantiomer relative to the other enantiomer, e.g., at least 75% by weight, or at least 80% by weight. In some embodiments, the enrichment can be much greater than 80% by weight, providing a "substantially enantiomerically enriched," "substantially

enantiomerically pure" or a "substantially non-racemic" compound, which refers to a compound with at least 85% by weight of one enantiomer relative to other enantiomer, e.g., at least 90% by weight, or at least 95% by weight.

[0022] Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ah, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0023] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or ¹⁴ C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0024] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "Ci_6 alkyl" is intended to encompass, C _1; C ₂ , C ₃ ,

C ₄ , C ₅ , C ₆ , Ci_6, Ci_5, Cn, Ci_ ₃ , Ci_2, C ₂ -6, C ₂ _5, C-2-A, C ₂ _3, C ₃ _ ₆ , C ₃ _ ₅ , C ₃ ^, C4_ ₆ , C4--5, and C5-6 alkyl.

[0025] The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C^o alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C^ alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C^ alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C^ alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci_6 alkyl"). In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("Q-5 alkyl"). In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C^ alkyl"). In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("Ci_ ₃ alkyl"). In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C^ alkyl"). In certain embodiments, an alkyl group has 1 carbon atom ("Q alkyl"). In certain embodiments, an alkyl group has 2 to 6 carbon atoms ("C ₂ -6 alkyl"). Examples of Ci_6 alkyl groups include methyl (CO, ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C ₄ ), sec-butyl (C ₄ ), iso-butyl (C ₄ ), n-pentyl (C ₅ ), 3-pentanyl (C ₅ ), amyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butanyl (C ₅ ), tertiary amyl (C ₅ ), and n-hexyl (C ₆ ). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted C^o alkyl (e.g., -CH ₃ ). In certain embodiments, the alkyl group is a substituted C o alkyl.

[0026] The term "haloalkyl" is a substituted alkyl group as described herein wherein one or more of the hydrogen atoms are independently replaced by halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("Ci- ₈ haloalkyl"). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("Ci-6 haloalkyl"). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("Ci^ haloalkyl"). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("Ci- ₃ haloalkyl"). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("Ci- ₂ haloalkyl"). Examples of haloalkyl groups include -CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , - CC1 ₃ , -CFCI2, -CF2CI, and the like.

[0027] The term "fluoroalkyl" refers to a haloalkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by fluoro. A "substituted fluoroalkyl group" refers to an alkyl group as defined herein comprising fluoro substituent(s) and one or more additional different substituent(s). An "unsubstituted fluoroalkyl group" refers to an alkyl group as defined herein comprising only fluoro substituent(s).

[0028] "Perhaloalkyl" is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a "perchloro alkyl" group.

[0029] The term "heteroalkyl" refers to an alkyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroCi-io alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4

heteroatoms within the parent chain ("heteroCi-g alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4

heteroatoms within the parent chain ("heteroCi-8 alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4

heteroatoms within the parent chain ("heteroCi- _? alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms within the parent chain ("heteroCi-6 alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-s alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain ("heteroCi^ alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-s alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroC^ alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroC ₂ -6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted

heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.

[0030] The term "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C ₂ -8 alkenyl"). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms ("C ₂ _ ₇ alkenyl"). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms ("C ₂ -6 alkenyl"). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms ("C ₂ _5 alkenyl"). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms ("C ₂ _4 alkenyl"). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C ₂ _3 alkenyl"). In certain embodiments, an alkenyl group has 2 carbon atoms ("C ₂ alkenyl"). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C ₂ - alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1- butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and the like. Examples of C ₂ _6 alkenyl groups include the aforementioned C ₂ ^ alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a

"substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C ₂ _io alkenyl. In certain embodiments, the alkenyl group is a substituted C ₂ _io alkenyl.

[0031] The term "heteroalkenyl" refers to an alkenyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC^io alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ _9 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ _g alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ _7 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms within the parent chain ("heteroC ₂ _6 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2

heteroatoms within the parent chain ("heteroC ₂ _5 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC ₂ ^ alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC ₂ -3 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC ₂ _6 alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is

independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC^io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC^io alkenyl.

[0032] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C^io alkynyl"). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C ₂ _9 alkynyl"). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C ₂ _g alkynyl"). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C ₂ _ ₇ alkynyl"). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C ₂ _6 alkynyl"). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C ₂ _5 alkynyl"). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C ₂ ^ alkynyl"). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C ₂ _ ₃ alkynyl"). In certain embodiments, an alkynyl group has 2 carbon atoms ("C ₂ alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C ₂ _ alkynyl groups include, without limitation, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and the like.

Examples of C ₂ _6 alkenyl groups include the aforementioned C ₂ ^ alkynyl groups as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl include heptynyl (C ₇ ), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C ₂ _ ₁₀ alkynyl. In certain embodiments, the alkynyl group is a substituted C ₂ _ ₁₀ alkynyl.

[0033] The term "heteroalkynyl" refers to an alkynyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ -io alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ -9 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ -8 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC ₂ - ₇ alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms within the parent chain ("heteroC ₂ -6 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC ₂ -5 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain ("heteroC ₂ ^ alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC ₂ -3 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC ₂ -6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC ₂ -io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC ₂ -io alkynyl.

[0034] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3_ ₁₄ carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ('¾_ ₁₀ carbocyclyl"). In certain embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms ("C3_9 carbocyclyl"). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3_8 carbocyclyl"). In certain

embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ('¾_ ₇ carbocyclyl"). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ('¾_ ₆ carbocyclyl"). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl"). Exemplary C ₃ _ ₆ carbocyclyl groups include, without limitation, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), and the like. Exemplary C ₃ _g carbocyclyl groups include, without limitation, the aforementioned C ₃ _ ₆ carbocyclyl groups as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (Cg), and the like. Exemplary C ₃ _ ₁₀ carbocyclyl groups include, without limitation, the

aforementioned C ₃ _g carbocyclyl groups as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-lH-indenyl (C ₉ ), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C ₁₀ ), and the like. In certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro-fused ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon- carbon double or triple bonds. Exemplary fused bicyclic systems include, but are not limited to, decalin (cis or trans decalin). Exemplary fused tricyclic systems include, but are not limited to, fluorenyl. Exemplary spiro-fused bicyclic systems include, but are not limited to, spiropentane. Exemplary bridged bicyclic systems include, but are not limited to, norbornane, norbornene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[3.2.1]octane, and bicyclo[2.2.1]heptan-2-one. Exemplary bridged tricyclic systems include, but are not limited to adamantane. "Carbocyclyl" includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted

carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C ₃ _ ₁₄ carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C ₃ _ ₁₄ carbocyclyl.

[0035] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. In certain embodiments, the heterocyclyl group is either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro-fused ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")) and can be saturated or can contain one or more carbon- carbon double or triple bonds. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0036] In certain embodiments, a heterocyclyl group is a 5-10 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5-6 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0037] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,

dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,

dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4- b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7- dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3- dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetra- hydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1 ,2,3,4-tetrahydro-l ,6- naphthyridinyl, and the like.

[0038] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C -u aryl"). In certain embodiments, an aryl group has 6 ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms ("C ₁₄ aryl"; e.g., anthracenyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce- ₁₄ aryl. In certain embodiments, the aryl group is a substituted Ce_ ₁₄ aryl.

[0039] "Aralkyl" or "arylalkyl" is a subset of "alkyl" and refers to an alkyl group, as described herein, substituted by one or more aryl groups, as described herein, wherein the point of attachment is on the alkyl moiety.

[0040] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0041] In certain embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In certain embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In certain embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently

unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5- 14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0042] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary

5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary

6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,

benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0043] "Heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group, as described herein, substituted by one or more heteroaryl groups, as described herein, wherein the point of attachment is on the alkyl moiety.

[0044] The term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.

[0045] The term "saturated" refers to a ring moiety that does not contain a double or triple bond, i.e. , the ring contains all single bonds.

[0046] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g. , alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0047] As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as described herein, are, in certain embodiments, optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., "substituted" or

"unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or

"unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0048] Exemplary carbon atom substituents include, but are not limited to, halogen, -

CN, -N0 ₂ , -N ₃ , -S0 ₂ H, -S0 ₃ H, -OH, -OR^, -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X , - N(OR ^cc )R ^bb , -SH, -SR^, -SSR ^CC , -C(=0)R ^aa , -C0 ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO^, - OC(=0)R ^aa , -OCOzR^, -C(=0)N(R ^bb ) ₂ , -OC(=0)N(R ^bb ) ₂ , -NR ^bb C(=0)R ^aa , -NR^CO^, - NR ^bb C(=0)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , - C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=0)NR ^bb S0 ₂ R ^aa , - NR ^bb S0 ₂ R ^aa , -S0 ₂ N(R ^bb ) ₂ , -S0 ₂ R ^aa , -SC^OR^, -OSO^, -S(=0)R ^aa , -OS(=0)R ^aa , - Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=0)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=0)SR ^aa , -OC(=0)SR ^aa , -SC(=0)OR ^aa , -SC(=0)R ^aa , -P(=0) ₂ R ^aa , -OP(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , - OP(=0)(R ^aa ) ₂ , -OP(=0)(OR ^cc ) ₂ , -P(=0) ₂ N(R ^bb ) ₂ , -OP(=0) ₂ N(R ^bb ) ₂ , -P(=0)(NR ^bb ) ₂ , - OP(=0)(NR ^bb ) ₂ , -NR ^bb P(=0)(OR ^cc ) ₂ , -NR ^bb P(=0)(NR ^bb ) ₂ , -P(R ^CC ) ₂ , -P(R ^CC ) ₃ , -OP(R ^cc ) ₂ , - OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR^OR^), Ci_i ₀ alkyl, Ci_i ₀ perhaloalkyl, C ₂ _ ₁₀ alkenyl, C ₂ _io alkynyl, Cno heteroalkyl, C ₂ _ ₁₀ heteroalkenyl, C^ioheteroalkynyl, C ₃ _ ₁₄ carbocyclyl, 3- 14 membered heterocyclyl, Ce_ ₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=0)R ^aa , =NNR ^bb C(=0)OR ^aa , =NNR ^bb S(=0) ₂ R ^aa , =NR ^bb , or =NOR ^cc ; each instance of R^ is, independently, selected from Ci-w alkyl, Cno perhaloalkyl, C ₂ _io alkenyl, C ₂ _ ₁₀ alkynyl, Cno heteroalkyl, C ₂ _ ₁₀ heteroalkenyl, C^ioheteroalkynyl, C ₃ _ ₁₄ carbocyclyl, 3-14 membered heterocyclyl, C ₆ -i ₄ aryl, and 5-14 membered heteroaryl, or two R^ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

each instance of R ^bb is, independently, selected from hydrogen, -OH, -OR ³ *, - N(R ^CC ) ₂ , -CN, -C(=0)R ^aa , -C(=0)N(R ^cc ) ₂ , -C0 ₂ R ^aa , -SO^, -C(=NR ^cc )OR ^aa , - C(=NR ^CC )N(R ^CC ) ₂ , -S0 ₂ N(R ^cc ) ₂ , -S0 ₂ R ^cc , -S0 ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^CC ) ₂ , -C(=0)SR ^cc , - C(=S)SR ^CC , -P(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , -P(=0) ₂ N(R ^cc ) ₂ , -P(=0)(NR ^cc ) ₂ , d_ ₁₀ alkyl, C _H0 perhaloalkyl, C ₂ _io alkenyl, C ₂ _io alkynyl, C^o heteroalkyl, C ₂ _io heteroalkenyl, C ₂ ioheteroalkynyl, C ₃ _ ₁₄ carbocyclyl, 3-14 membered heterocyclyl, C ₆ -i ₄ aryl, and 5-14 membered heteroaryl, or two R ^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

each instance of R ^cc is, independently, selected from hydrogen, C^o alkyl, Cno perhaloalkyl, C ₂ _io alkenyl, C ₂ _io alkynyl, C^o heteroalkyl, C ₂ _io heteroalkenyl, C ₂

1 ₀ heteroalkynyl, C ₃ _ ₁₄ carbocyclyl, 3-14 membered heterocyclyl, C ₆ -i ₄ aryl, and 5-14 membered heteroaryl, or two R ^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

each instance of R ^dd is, independently, selected from halogen, -CN, -N0 ₂ , -N ₃ , - S0 ₂ H, -S0 ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N(R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X , -N(OR ^ee )R ^ff , -SH, -SR ^ee , - SSR ^ee , -C(=0)R ^ee , -C0 ₂ H, -C0 ₂ R ^ee , -OC(=0)R ^ee , -OC0 ₂ R ^ee , -C(=0)N(R ^ff ) ₂ , - OC(=0)N(R ^ff ) ₂ , -NR ^ff C(=0)R ^ee , -NR ^ff C0 ₂ R ^ee , -NR ^ff C(=0)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , - OC(=NR ^ff )R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , - NR ^ff C(=NR ^ff )N(R ^ff ) ₂ ,-NR ^ff S0 ₂ R ^ee , -S0 ₂ N(R ^ff ) ₂ , -S0 ₂ R ^ee , -S0 ₂ OR ^ee , -OS0 ₂ R ^ee , -S(=0)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R") ₂ , -C(=0)SR ^ee , -C(=S)SR ^ee , -SC(=S)SR ^ee , -P(=0) ₂ R ^ee , - P(=0)(R ^ee ) ₂ , -OP(=0)(R ^ee ) ₂ , -OP(=0)(OR ^ee ) ₂ , d_ ₆ alkyl, d_ ₆ perhaloalkyl, C ₂ _ ₆ alkenyl, C _{2 6} alkynyl, d_ ₆ heteroalkyl, C ₂ _ ₆ heteroalkenyl, C ₂ _ ₆ heteroalkynyl, C ₃ _ ₁₀ carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents can be joined to form =0 or =S;

each instance of R ^ee is, independently, selected from d_ ₆ alkyl, d_ ₆ perhaloalkyl, C _{2 6} alkenyl, C ₂ _ ₆ alkynyl, d_ ₆ heteroalkyl, C ₂ _ ₆ heteroalkenyl, C ₂ _ ₆ heteroalkynyl, C ₃ _io carbocyclyl, C ₆ -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

each instance of R ff is, independently, selected from hydrogen, d_ ₆ alkyl, d_ ₆ perhaloalkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, d_ ₆ heteroalkyl, C ₂ _ ₆ heteroalkenyl, C ₂

6heteroalkynyl, C ₃ _ ₁₀ carbocyclyl, 3-10 membered heterocyclyl, C ₆ -io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; and

each instance of R ^gg is, independently, halogen, -CN, -N0 ₂ , -N ₃ , -S0 ₂ H, -S0 ₃ H, - OH, -Od_ ₆ alkyl, -ON(d_ ₆ alkyl) ₂ , -N(d_ ₆ alkyl) ₂ , -N(d_ ₆ alkyl) ₃ ⁺ X- -NH(d_ ₆ alkyl) ₂ ⁺ X ^~ -NH ₂ (d- ₆ alkyl) ⁺ X ^~ -NH ₃ ⁺ X ^~ -N(Od_ ₆ alky CCi-e alkyl), -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -Sd-6 alkyl, -SS(Ci_6 alkyl), -C(=0)(Ci_6 alkyl), -C0 ₂ H, -C0 ₂ (Ci_ ₆ alkyl), -OC(=0)(Ci_6 alkyl), -OC0 ₂ (Ci_ ₆ alkyl), -C(=0)NH ₂ , -C(=0)N(Ci_ ₆ alkyl) ₂ , - OC(=0)NH(Ci_6 alkyl), -NHC(=0)( Ci_e alkyl), -N(Ci_e alkyl)C(=0)( Ci_6 alkyl), - NHC0 ₂ (Ci_6 alkyl), -NHC(=0)N(Ci_6 alkyl) ₂ , -NHC(=0)NH(Ci_6 alkyl), -NHC(=0)NH ₂ , - C(=NH)0(Ci^ alk l),-OC(=NH)(Ci_6 alkyl), -OC(=NH)Od_ ₆ alkyl, -C(=NH)N(Ci_ ₆ alkyl) ₂ , -C(=NH)NH(d_ ₆ alkyl), -C(=NH)NH ₂ , -OC(=NH)N(Ci_ ₆ alkyl) ₂ , -OC(NH)NH(d_ ₆ alkyl), -OC(NH)NH ₂ , -NHC(NH)N(Ci_ ₆ alkyl) ₂ , -NHC(=NH)NH ₂ , -NHS0 ₂ (Ci_ ₆ alkyl), - S0 ₂ N(d_ ₆ alkyl) ₂ , -S0 ₂ NH(C^ alkyl), -S0 ₂ NH ₂ ,-S0 ₂ d^ alkyl, -S0 ₂ 0d_ ₆ alkyl, - OS0 ₂ Ci^ alkyl, -SOd_ ₆ alkyl, -Si(Ci_6 alkyl) ₃ , -OSi(d_ ₆ alkyl) ₃ -C(=S)N(Ci_6 alkyl) ₂ , C(=S)NH(Ci_6 alkyl), C(=S)NH ₂ , -C(=0)S(Ci_ ₆ alkyl), -C(=S)SCi_ ₆ alkyl, -SC(=S)SCi_ ₆ alkyl, -P(=0) ₂ (C^ alkyl), -P(=0)(d_ ₆ alkyl) ₂ , -OP(=0)(d ₆ alkyl) ₂ , -OP(=0)(Od ₆ alkyl) ₂ , d_ ₆ alkyl, d_ ₆ perhaloalkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, d_ ₆ heteroalkyl, C ₂ _ ₆ heteroalkenyl, C ₂ _ ₆ heteroalkynyl, C ₃ _ ₁₀ carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ^gg substituents can be joined to form =0 or =S; wherein X is a counterion.

[0049] In certain embodiments, one or more carbon atom substituents are selected from the group consisting of halogen, -CN, -N0 ₂ , -N ₃ , -S0 ₂ H, -SO3H, -OH, -OR ^aa , - N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=0)R ^aa , -C0 ₂ H, -CHO, -CO^, -OC(=0)R ^aa , -OCO^, - C(=0)N(R ^bb ) ₂ , -OC(=0)N(R ^bb ) ₂ , -NR ^bb C(=0)R ^aa , -NR ^bb C0 ₂ R ^aa , -NR ^bb C(=0)N(R ^bb ) ₂ - C(=0)NR ^bb S0 ₂ R ^aa , -NR^SO^, -S0 ₂ N(R ^bb ) ₂ , -S0 ₂ R ^aa , -S(=0)R ^aa , _ ₁₀ alkyl, Ci -10 perhaloalkyl, C ₂ _ ₁₀ alkenyl, C ₂ _ ₁₀ alkynyl, d-io heteroalkyl, C ₂ _io heteroalkenyl, C ₂

1 ₀ heteroalkynyl, C ₃ _ ₁₄ carbocyclyl, 3-14 membered heterocyclyl, C ₆ -i ₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups.

[0050] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro,

-CI), bromine (bromo, -Br), or iodine (iodo, -I).

[0051] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -OR^, -N(R ^CC ) ₂ , -CN, - C(=0)R ^aa , -C(=0)N(R ^cc ) ₂ , -CO^, -S0 ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , - C(=NR ^CC )N(R ^CC ) ₂ , -S0 ₂ N(R ^cc ) ₂ , -S0 ₂ R ^cc , -S0 ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^CC ) ₂ , -C(=0)SR ^cc , - C(=S)SR ^CC , -P(=0) ₂ R ^aa , -P(=0)(R ^aa ) ₂ , -P(=0) ₂ N(R ^cc ) ₂ , -P(=0)(NR ^cc ) ₂ , Cue alkyl, C e perhaloalkyl, C ₂ _io alkenyl, C ₂ _io alkynyl, C^o heteroalkyl, C ₂ _io heteroalkenyl, C ₂ _io heteroalkynyl, C ₃ _io carbocyclyl, 3-14 membered heterocyclyl, Ce_ ₁₄ aryl, and 5-14 membered heteroaryl, or two R ^cc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R^, R ^bb , R ^cc and R ^dd are as defined above. [0052] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR ^aa , -N(R ^CC ) ₂ , -C(=0)R ^aa , - C(=0)N(R ^cc ) ₂ , -COzR^, -S0 ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^CC )N(R ^CC ) ₂ , - S0 ₂ N(R ^cc ) ₂ , -S0 ₂ R ^cc , -S0 ₂ OR ^cc , -SOR^, -C(=S)N(R ^CC ) ₂ , -C(=0)SR ^cc , -C(=S)SR ^CC , Ci_i ₀ alkyl (e.g., alkyl, aralkyl, heteroaralkyl), C ₂ _io alkenyl, C ₂ _io alkynyl, C^o heteroalkyl, C ₂ _io heteroalkenyl, C ₂ _ ₁₀ heteroalkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce_ ₁₄ aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R ³ , R ^bb , R ^cc and R ^dd are as described herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W.

Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0053] For example, nitrogen protecting groups such as amide groups (e.g., -

C(=0)R ^aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide,

picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p- phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (Ν'- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.

[0054] Nitrogen protecting groups such as carbamate groups (e.g., -C(=0)OR ^aa ) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-i-butyl-[9-( 10,10-dioxo-l 0, 10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-i-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), l-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1— (3,5— di— i— butylphenyl)-l-methylethyl carbamate (i-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, i-butyl carbamate (BOC), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1- isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), /?-nitobenzyl carbamate, p- bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4- methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1, 1- dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)- 6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, i-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1, 1-dimethylpropynyl carbamate, di(2- pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p '-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-l- cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1- methyl-l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1- methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, /?-(phenylazo)benzyl carbamate, 2,4,6-tri-i-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6- trimethylbenzyl carbamate.

[0055] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=0) ₂ R ^aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,- trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0056] Other nitrogen protecting groups include, but are not limited to,

phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'- phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N- 2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l, 1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl] amine (MMTr), N-9-phenylfluorenylamine (PhF), N- 2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2- picolylamino N'-oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Ν,Ν'- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0057] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=0)SR ^aa , -C(=0)R ^aa , - COzR^, -C(=0)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=0)R ^aa , - S0 ₂ R ^aa , -Si(R ^aa ) ₃ , -P(R ^cc ) ₂ , -P(R ^CC ) ₃ , -Ρ(=0)^, -P(=0)(R ^aa ) ₂ , -P(=0)(OR ^cc ) ₂ , - P(=0) ₂ N(R ^bb ) ₂ , and -P(=0)(NR ^bb ) ₂ , wherein R ^m , R ^bb , and R ^cc are as described herein.

Oxygen protecting groups are well known in the art and include those described in detail in

Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0058] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,

(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), /?- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), i-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzo furan-2-yl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-l-benzyloxyethyl, 1- methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, i-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), /?-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p- halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3- methyl-2-picolyl N-oxido, diphenylmethyl, p,p '-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, /7-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"- tris(benzoyloxyphenyl)methyl, 3-(imidazol-l-yl)bis(4',4"-dimethoxyphenyl)methyl, 1 , 1- bis(4-methoxyphenyl)- -pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl- 10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, i-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,

diphenylmethylsilyl (DPMS), i-butylmethoxyphenylsilyl (TBMPS), formate,

benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifhioroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate

(levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, i-butyl carbonate (BOC), /?-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(l, l,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl

N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate,

dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0059] In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=0)SR ^aa , -C(=0)R ^aa , -CO^, - C(=0)N(R ) ₂ , -C(=NR )R ^aa , -C(=NR )OR ^aa , -C(=NR )N(R ) ₂ , -S(=0)R ^aa , -SO^, - Si(R ^aa ) ₃ -P(R ^CC ) ₂ , -P(R ^CC ) ₃ , -Ρ(=0)^, -P(=0)(R ^aa ) ₂ , -P(=0)(OR ^cc ) ₂ , -P(=0) ₂ N(R ^bb ) ₂ , and - P(=0)(NR ^bb ) ₂ , wherein R ^aa , R ^bb , and R ^cc are as described herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0060] These and other exemplary substituents are described in more detail in the

Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0061] The term "Lewis acid" refers to a species as defined by IUPAC, that is "a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base." Exemplary Lewis acids include, without limitation, boron trifluoride, aluminum trichloride, tin tetrachloride, titanium tetrachloride, and iron tribromide.

[0062] The term "Lewis base" refers to a species as defined by IUPAC, that is "a molecular entity (and the corresponding chemical species) that is able to provide a pair of electrons and thus capable of coordination to a Lewis acid, thereby producing a Lewis adduct" Exemplary Lewis bases include, without limitation, anions, amines, imines, ethers, thioethers, alkenes, alkynes, or carbonyl groups.

[0063] The term "halogen bond" as defined by IUPAC refers to a bond occurring when "there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity." As used herein, a dashed line drawn between a Lewis base or electron donor group (D) and a halogen X (e.g., fluorine, chlorine, bromine, or iodine) which is attached to an organic compound R represents a halogen bond, for example:

D X— R

In such a complex, the D group may be referred to as a "halogen bond acceptor" while X may be referred to as a "halogen bond donor." As described by IUPAC, a typical halogen-bonded complex may have one or more of the following non-limiting features:

1. The interatomic distance between X and the appropriate nucleophilic atom of D tends to be less than the sum of the van der Waals radii.

2. The length of the R-X covalent bond usually increases relative to the unbonded R-X. 3. The angle D— X-R tends to be close to 180°, i.e. , the halogen bond acceptor D approaches X along the extension of the X-R bond.

4. The halogen bond strength decreases as the electronegativity of X increases, and the electron withdrawing ability of R decreases.

5. The forces involved in the formation of the halogen bond are primarily electrostatic, but polarization, charge transfer, and dispersion contributions all play a role. The relative roles of the different forces may vary from one case to the other.

6. The analysis of the electron density topology usually shows a bond path connecting D and X and a bond critical point between D and X (a "bond path" and a "bond critical point" are defined as "within the topological electron distribution theory, the line resulting from the addition of two gradient paths of the electron density function emanating from the bond critical point located between each two neighbouring atomic basins" and "within the topological electron distribution theory, a (3, -1) critical point (the point of the gradient field of the electron density within a given neutral configuration in which Vp(r, ) = 0) which is a local maximum in two directions and is a local minimum in the third, i.e. a saddle point in the three directions").

7. The infrared absorption and Raman scattering observables of both R-X and Y are affected by halogen bond formation; new vibrational modes associated with the formation of the X-R bond are also observed.

8. The UV-vis absorption bands of the halogen bond donor usually shift to shorter

wavelengths.

9. The D— X halogen bond usually affects the nuclear magnetic resonance (NMR) observables (e.g., chemical shift values) of nuclei in both X-R and D, both in solution and in the solid state.

10. The binding energies of the peaks associated with X with the X-ray photoelectron spectrum (XPS) of the complex shift to lower energies relative to unbonded X.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0064] Trifluoromethyl iodide has been used for the trifluoromethylation of

(hetero)arenes, olefins, thiols, enolates, boronic acids, aryl iodides, and aldehydes. Despite its potential synthetic utility and low cost, routine use by synthetic and medicinal chemists has been challenged by the fact that it is a gas under typical laboratory conditions (boiling point of -22.5 °C). Likewise, pentafluoroethyl iodide, another useful fluoroalkyl building block, is a gas under these conditions (boiling point of 12- 13 °C). The handling process of such reagents is impractical, time consuming, and can lead to errors in the quantitive dispensing of small quantities when compared to the other more conveniently handled reagents mentioned above. While the aforementioned reagents are easier to handle than trifluoromethyl iodide, they suffer from additional issues such as high cost, poor atom economy, and narrow scope of reactivity.

[0065] This disclosure represents the first application of the concept of halogen bonding for the preparation of reagents for synthetic organic chemistry. Halogen bonding has only recently been defined by IUPAC, but the phenomenon has long been appreciated and taken advantage of in several applications such as molecular recognition. Halogen bonding has received relatively little attention from synthetic organic chemists when compared to other non-covalent interactions such as hydrogen bonding.

[0066] The present disclosure demonstrates that Lewis base complexes of fluoroalkyl iodides are complexes that possess advantageous properties when compared to free fluoroalkyl iodides. For example, trifluoromethyl iodide and 1, 1,3,3-tetramethylguanidine (TMG) form a 1 : 1 adduct that is liquid at 23 °C, and can be dispensed accurately with a syringe. A 30 g batch of TMG*CF I adduct stored in a glass vial with a Teflon sure seal at 0 °C in a refrigerator showed no signs of decomposition, loss in content of CF ₃ I, or pressure build-up over two months. Likewise, the TMG*CF ₃ CF ₂ I reagent can be readily prepared and is a liquid. Furthermore, sulfoxide complexes such as the dimethyl sulfoxide adducts of CF I and CF CF ₂ I can be prepared and used in a fashion analogous to the TMG adducts. In addition to the aforementioned reagents, the present application also discloses amine, heterocycle, and heteroarene complexes of fluoroalkyl iodides. In certain instances, these complexes are amorphous or crystalline solids (e.g. , tetramethylethylenediamine ^» (CF ₃ I) ₂ ), which offers additional handling benefits. As is demonstrated herein, halogen bonded complexes of fluoroalkyl iodides possess comparable reactivity to parent fluoroalkyl iodides, enabling them to serve as replacements for these inconvenient and difficult-to-handle reagents in a wide variety of applications.

[0067] The present invention provides compounds, reagents, systems, reaction mixtures, compositions, kits, and methods for fluoroalkylating an organic compound. [0068] In one aspect, the present invention is directed to a compound of the Formula

(I):

D--(i-R ¹ ) _y

(I)

wherein:

is a halogen bond;

R ¹ is unsubstituted C _1-3 fluoroalkyl;

D is N(R ² ) ₃ , ((R ² ) ₂ N) ₂ C=NR ² , 0=S(R ² ) ₂ , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;

each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and

y is 1 or 2.

R ¹ and y

[0069] As is generally described herein, R ¹ is unsubstituted C _1-3 fluoroalkyl. In certain embodiments, R ¹ is -CF ₃ . In certain embodiments, R ¹ is -CHF ₂ . In certain embodiments, R ¹ is -CH ₂ F. In certain embodiments, R ¹ is -CF ₂ CF ₃ . In certain embodiments, R ¹ is -CF ₂ CHF ₂ . In certain embodiments, R ¹ is -CF ₂ CH ₂ F. In certain embodiments, R ¹ is - CHFCF ₃ . In certain embodiments, R ¹ is -CHFCHF ₂ . In certain embodiments, R ¹ is - CHFCH ₂ F. In certain embodiments, R ¹ is -CF(CF ₃ ) ₂ . In certain embodiments, R ¹ is - CH(CF ₃ ) ₂ . In certain embodiments, R ¹ is -CF ₂ CF ₂ CF ₃ .

[0070] As is generally described herein, y is 1 or 2. In certain embodiments, y is 1. In certain embodiments, y is 2.

D, R ² , R ⁴ , and z

[0071] As is generally described herein, D is N(R ² ) ₃ , ((R ² ) ₂ N) ₂ C=NR ² , 0=S(R ² ) ₂ , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.

[0072] As is generally described herein, each instance of R ² is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0073] In certain embodiments, D is N(R ² ) ₃ ; and one instance of R ² is hydrogen. In

2 2

certain embodiments, D is N(R ) ₃ ; and two instances of R are hydrogen.

[0074] In certain embodiments, D is N(R ² ) ₃ ; and at least one instance of R ² is substituted or unsubstituted alkyl. In certain embodiments, D is N(R ) ₃ ; and at least one

2 2 instance of R is substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is N(R ) ₃ ; and at least one instance of R is unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In

2 2

certain embodiments, D is N(R ) ₃ ; and at least one instance of R is branched C _1-6 alkyl (e.g. ,

2 2 isopropyl, isobutyl, or i-butyl). In certain embodiments, D is N(R ) ₃ ; and two instances of R are independently substituted or unsubstituted alkyl. In certain embodiments, D is N(R ) ₃ ; and two instances of R are independently substituted or unsubstituted C _1-6 alkyl. In certain

2 2

embodiments, D is N(R ) ₃ ; and two instances of R are independently unsubstituted Ci_6 alkyl

2 2

(e.g. , methyl, ethyl, or propyl). In certain embodiments, D is N(R ) ₃ ; and two instances of R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl). In certain

2 2

embodiments, D is N(R ) ₃ ; and all three instances of R are independently substituted or

2 2 unsubstituted alkyl. In certain embodiments, D is N(R ) ₃ ; and all three instances of R are independently substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is N(R ) ₃ ; and all three instances of R are independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or

2 2

propyl). In certain embodiments, D is N(R ) ₃ ; and all three instances of R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0075] In certain embodiments, D is N(R ² ) ₃ ; and at least one instance of R ² is substituted or unsubstituted carbocyclyl. In certain embodiments, D is N(R ) ₃ ; and at least one instance of R is substituted or unsubstituted 3-6 membered carbocyclyl. In certain

2 2

embodiments, D is N(R ) ₃ ; and at least one instance of R is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain

2 2

embodiments, D is N(R ) ₃ ; and at least one instance of R is monosubstituted 3-6 membered carbocyclyl.

[0076] In certain embodiments, D is N(R ² ) ₃ ; and at least one instance of R ² is substituted or unsubstituted heterocyclyl. In certain embodiments, D is N(R ) ₃ ; and at least one instance of R is substituted or unsubstituted 3-6 membered heterocyclyl. In certain 2 2

embodiments, D is N(R ) ₃ ; and at least one instance of R is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments,

2 2

D is N(R ) ₃ ; and at least one instance of R is monosubstituted 3-6 membered heterocyclyl.

[0077] In certain embodiments, D is N(R ² ) ₃ ; and at least one instance of R ² is substituted or unsubstituted aryl. In certain embodiments, D is N(R ) ₃ ; and at least one

2 2 instance of R is substituted or unsubstituted phenyl. In certain embodiments, D is N(R ) ₃ ;

2 2 and at least one instance of R is unsubstituted phenyl. In certain embodiments, D is N(R ) ₃ ; and at least one instance of R is monosubstituted phenyl.

[0078] In certain embodiments, D is N(R ² ) ₃ ; and at least one instance of R ² is substituted or unsubstituted heteroaryl. In certain embodiments, D is N(R ) ₃ ; and at least one instance of R is substituted or unsubstituted 5-6 membered heteroaryl. In certain

2 2

embodiments, D is N(R ) ₃ ; and at least one instance of R is unsubstituted 5-6 membered heteroaryl (e.g., imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is

2 2

N(R ) ₃ ; and at least one instance of R is monosubstituted 5-6 membered heteroaryl.

[0079] In certain embodiments, D is N(R ² ) ₃ ; and two R ² groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0080] In certain embodiments, D is a compound of Formula (II):

wherein:

each instance of R ⁴ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R ⁴ groups are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring; and

z is 1-5, inclusive.

[0081] In certain embodiments, all instances of R ⁴ are hydrogen.

[0082] In certain embodiments, D is a compound of Formula (II); and one instance of

R is hydrogen. In certain embodiments, D is a compound of Formula (II); and two instances of R are hydrogen. In certain embodiments, D is a compound of Formula (II); and three instances of R are hydrogen. In certain embodiments, D is a compound of Formula (II); and all four instances of R are hydrogen. [0083] In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (II); and at least one instance of R is methyl. In certain embodiments,

D is a compound of Formula (II); and at least one instance of R is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0084] In certain embodiments, D is a compound of Formula (II); and two instances of R are independently substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (II); and two instances of R are independently substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is a compound of Formula (II); and two instances of R are independently unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (II); and two instances of R are methyl.

In certain embodiments, D is a compound of Formula (II); and two instances of R are independently branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0085] In certain embodiments, D is a compound of Formula (II); and three instances of R are independently substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (II); and three instances of R are independently substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is a compound of Formula (II); and three instances of R are independently unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (II); and three instances of R are methyl.

In certain embodiments, D is a compound of Formula (II); and three instances of R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0086] In certain embodiments, D is a compound of Formula (II); and all four instances of R are independently substituted or unsubstituted alkyl. In certain embodiments,

D is a compound of Formula (II); and all four instances of R are independently substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is a compound of Formula (II); and all four instances of R are independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl).

In certain embodiments, D is a compound of Formula (II); and all four instances of R are methyl. In certain embodiments, D is a compound of Formula (II); and all four instances of

R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl). [0087] In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted 3-6 membered carbocyclyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments, D is a compound of

Formula (II); and at least one instance of R is mono substituted 3-6 membered carbocyclyl.

[0088] In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted heterocyclyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments, D is a compound of Formula

(II); and at least one instance of R is mono substituted 3-6 membered heterocyclyl.

[0089] In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is mono substituted phenyl.

[0090] In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted heteroaryl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is a compound of Formula (II); and at least one instance of R is mono substituted 5-6 membered heteroaryl.

[0091] In certain embodiments, D is a compound of Formula (II); and two R ² groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring. In certain embodiments, D is a compound of Formula (II); and four R groups are joined to

independently form two substituted or unsubstituted heterocyclic or heteroaryl rings. [0092] As is generally described herein, z is 1-5, inclusive. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5.

[0093] In certain embodiments, D is ((R ² ) ₂ N)2C=NR ² ; and one instance of R ² is

2 2 2

hydrogen. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and two instances of R are

2 2 2 hydrogen. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and three instances of R are

2 2 2 hydrogen. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and four instances of R are

2 2 2 hydrogen. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and all five instances of R are hydrogen.

[0094] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and at least one instance of R ²

2 2 is substituted or unsubstituted alkyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D

2 2 2

is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is unsubstituted Ci_6 alkyl (e.g. , methyl,

2 2

ethyl, or propyl). In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of

2 2 2 2

R is methyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0095] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and two instances of R ² are independently substituted or unsubstituted alkyl. In certain embodiments, D is

2 2 2

((R ) ₂ N) ₂ C=NR ; and two instances of R are independently substituted or unsubstituted C _1-6

2 2 2

alkyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and two instances of R are

independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and two instances of R are methyl. In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and two instances of R are independently branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0096] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and three instances of R ² are independently substituted or unsubstituted alkyl. In certain embodiments, D is

2 2 2

((R ) ₂ N) ₂ C=NR ; and three instances of R are independently substituted or unsubstituted C _1-6

2 2 2

alkyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and three instances of R are independently unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and three instances of R are methyl. In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and three instances of R are independently branched Ci-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl). [0097] In certain embodiments, D is ((R ² ) ₂ N)2C=NR ² ; and four instances of R ² are independently substituted or unsubstituted alkyl. In certain embodiments, D is

2 2 2

((R ) ₂ N) ₂ C=NR ; and four instances of R are independently substituted or unsubstituted C _1-6

2 2 2

alkyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and four instances of R are

independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and four instances of R are methyl. In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and four instances of R are independently branched C . 6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0098] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and all five instances of R ² are independently substituted or unsubstituted alkyl. In certain embodiments, D is

2 2 2

((R ) ₂ N) ₂ C=NR ; and all five instances of R are independently substituted or unsubstituted

2 2 2

Ci-6 alkyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and all five instances of R are independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and all five instances of R are methyl. In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and all five instances of R are independently branched Ci-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[0099] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and at least one instance of R ²

2 2 is substituted or unsubstituted carbocyclyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is substituted or unsubstituted 3-6 membered carbocyclyl. In

2 2 2

certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is unsubstituted 3- 6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In

2 2 2

certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is

monosubstituted 3-6 membered carbocyclyl.

[00100] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and at least one instance of R ²

2 2 is substituted or unsubstituted heterocyclyl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is substituted or unsubstituted 3-6 membered heterocyclyl. In

2 2 2

certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is unsubstituted 3- 6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is monosubstituted 3-6 membered heterocyclyl.

[00101] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and at least one instance of R ²

2 2

is substituted or unsubstituted aryl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is substituted or unsubstituted phenyl. In certain embodiments, D is

2 2 2

((R ) ₂ N) ₂ C=NR ; and at least one instance of R is unsubstituted phenyl. In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is monosubstituted phenyl.

[00102] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and at least one instance of R ²

2 2 is substituted or unsubstituted heteroaryl. In certain embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is substituted or unsubstituted 5-6 membered heteroaryl. In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain

2 2 2

embodiments, D is ((R ) ₂ N) ₂ C=NR ; and at least one instance of R is monosubstituted 5-6 membered heteroaryl.

[00103] In certain embodiments, D is ((R ² ) ₂ N) ₂ C=NR ² ; and two R ² groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring. In certain embodiments,

2 2 2

D is ((R ) ₂ N) ₂ C=NR ; and four R groups are joined to independently form two substituted or unsubstituted heterocyclic or heteroaryl rings.

[00104] In certain embodiments, D is 0=S(R ² ) ₂ ; and at least one instance of R ² is substituted or unsubstituted alkyl. In certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is

0 2 2

=S(R ) ₂ ; and at least one instance of R is unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or

2 2

propyl). In certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is methyl. In

2 2

certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is branched C _1-6 alkyl

(e.g. , isopropyl, isobutyl, or i-butyl). In certain embodiments, D is 0=S(R ) ₂ ; and both instances of R are independently substituted or unsubstituted alkyl. In certain embodiments,

2 2

D is 0=S(R ) ₂ ; and both instances of R are independently substituted or unsubstituted C _1-6

2 2

alkyl. In certain embodiments, D is 0=S(R ) ₂ ; and both instances of R are independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is

0 2 2

=S(R ) ₂ ; and both instances of R are independently branched C _1-6 alkyl (e.g. , isopropyl,

2 2 isobutyl, or i-butyl). In certain embodiments, D is 0=S(R ) ₂ ; and both instances of R are methyl.

[00105] In certain embodiments, D is 0=S(R ² ) ₂ ; and at least one instance of R ² is substituted or unsubstituted carbocyclyl. In certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is substituted or unsubstituted 3-6 membered carbocyclyl. In certain 2 2

embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain

2 2

embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is monosubstituted 3-6 membered carbocyclyl.

[00106] In certain embodiments, D is 0=S(R ² ) ₂ ; and at least one instance of R ² is substituted or unsubstituted heterocyclyl. In certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is substituted or unsubstituted 3-6 membered heterocyclyl. In certain

2 2

embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments,

2 2

D is 0=S(R ) ₂ ; and at least one instance of R is monosubstituted 3-6 membered heterocyclyl.

[00107] In certain embodiments, D is 0=S(R ² ) ₂ ; and at least one instance of R ² is substituted or unsubstituted aryl. In certain embodiments, D is 0=S(R ) ₂ ; and at least one

2 2 instance of R is substituted or unsubstituted phenyl. In certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is unsubstituted phenyl. In certain embodiments, D is

2 2

0=S(R ) ₂ ; and at least one instance of R is monosubstituted phenyl.

[00108] In certain embodiments, D is 0=S(R ² ) ₂ ; and at least one instance of R ² is substituted or unsubstituted heteroaryl. In certain embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is substituted or unsubstituted 5-6 membered heteroaryl. In certain

2 2

embodiments, D is 0=S(R ) ₂ ; and at least one instance of R is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is

2 2

0=S(R ) ₂ ; and at least one instance of R is monosubstituted 5-6 membered heteroaryl.

[00109] In certain embodiments, D is 0=S(R ² ) ₂ ; and two R ² groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[00110] In certain embodiments, D is 0=S(R ² ) ₂ ; and the sulfoxide is a racemic mixture. In certain embodiments, D is 0=S(R ) ₂ ; and the sulfoxide stereochemistry is of the

R-configuration. In certain embodiments, D is 0=S(R ) ₂ ; and the sulfoxide stereochemistry is of the ^-configuration.

[00111] In certain embodiments, D is substituted or unsubstituted heterocyclyl. In certain embodiments, D is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is monosubstituted 3-6 membered heterocyclyl. In certain embodiments, D is substituted or unsubstituted azetidine. In certain embodiments, D is substituted or unsubstituted pyrrolidine. In certain embodiments, D is substituted or unsubstituted piperidine. In certain embodiments, D is substituted or unsubstituted piperazine. In certain embodiments, D is substituted or unsubstituted morpholine.

[00112] In certain embodiments, D is a compound of Formula (III):

wherein:

each instance of R ⁵ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R ⁵ groups are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring; and

m is 0- 12, inclusive

[00113] In certain embodiments, all instances of R ⁵ are hydrogen.

[00114] In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[00115] In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted 3-6 membered carbocyclyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is monosubstituted 3-6 membered carbocyclyl.

[00116] In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted heterocyclyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is monosubstituted 3-6 membered heterocyclyl.

[00117] In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is monosubstituted phenyl.

[00118] In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted heteroaryl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is a compound of Formula (III); and at least one instance of R ⁵ is monosubstituted 5-6 membered heteroaryl.

[00119] As is generally described herein, m is 0- 12, inclusive. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain

embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. In certain embodiments, m is 11. In certain embodiments, m is 12.

[00120] In certain embodiments, D is substituted or unsubstituted heteroaryl. In certain embodiments, D is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is monosubstituted 5-6 membered heteroaryl. In certain embodiments, D is substituted or unsubstituted imidazole. In certain embodiments, D is substituted or unsubstituted thiazole. In certain embodiments, D is substituted or unsubstituted oxazole. In certain embodiments, D is substituted or unsubstituted triazole. In certain embodiments, D is substituted or unsubstituted oxadiazole. In certain embodiments, D is substituted or unsubstituted thiadiazole. In certain embodiments, D is substituted or unsubstituted piperidine. In certain embodiments, D is substituted or unsubstituted pyrimidine. [00121] In certain embodiments, D is a com ound of Formula (IV):

wherein:

each instance of R ⁶ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ^6a , -SR ^6a , or -N(R ^6a ) ₂ , wherein each instance of R ^6a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R ^6a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and

p is 1-5, inclusive.

[00122] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[00123] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted 3-6 membered carbocyclyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is monosubstituted 3-6 membered carbocyclyl.

[00124] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted heterocyclyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is monosubstituted 3-6 membered heterocyclyl.

[00125] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is monosubstituted phenyl.

[00126] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted heteroaryl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is monosubstituted 5-6 membered heteroaryl.

[00127] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is -OR ^6a . In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is hydrogen. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is methyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or t-butyl).

[00128] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted 3-6 membered carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6: is monosubstituted 3-6 membered carbocyclyl.

[00129] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted heterocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6: is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6: is monosubstituted 3-6 membered heterocyclyl.

[00130] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is monosubstituted phenyl.

[00131] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is substituted or unsubstituted heteroaryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6: is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6a is unsubstituted 5-6 membered heteroaryl (e.g., imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain

embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -OR ^6a ; and R ^6: is monosubstituted 5-6 membered heteroaryl.

[00132] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is -SR ^6a . In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is hydrogen. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is methyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[00133] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ⁶ is substituted or unsubstituted 3-6 membered carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ⁶ is monosubstituted 3-6 membered carbocyclyl.

[00134] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted heterocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ⁶ is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ⁶ is monosubstituted 3-6 membered heterocyclyl.

[00135] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is monosubstituted phenyl.

[00136] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is substituted or unsubstituted heteroaryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ⁶ is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is unsubstituted 5-6 membered heteroaryl (e.g., imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain

embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -SR ^6a ; and R ^6a is monosubstituted 5-6 membered heteroaryl.

[00137] In certain embodiments, D is a compound of Formula (IV); and at least one instance of R ⁶ is -N(R ^6a ) ₂ . In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is hydrogen. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is methyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[00138] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is hydrogen. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is independently substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is independently substituted or unsubstituted C _1-6 alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is independently unsubstituted C _1-6 alkyl (e.g. , methyl, ethyl, or propyl). In certain

embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is methyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is independently branched C _1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).

[00139] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted 3-6 membered carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In certain

embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is mono substituted 3-6 membered carbocyclyl.

[00140] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted heterocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is mono substituted 3-6 membered heterocyclyl.

[00141] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is - N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is monosubstituted phenyl.

[00142] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted heteroaryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and at least one instance of R ^6a is monosubstituted 5-6 membered heteroaryl. [00143] In certain embodiments, D is a compound of Formula (IV); at least one instance of R ⁶ is -N(R ^6a ) ₂ ; and both R ^6a groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[00144] As is generally described herein, p is 1-5, inclusive. In certain, embodiments, p is 1. In certain, embodiments, p is 2. In certain, embodiments, p is 3. In certain, embodiments, p is 4. In certain, embodiments, p is 5.

[00145] In certain embodiments, D is tetramethylguanidine (TMG),

tetramethylethylenediamine (TMEDA), l,4-diazabicyclo[2.2.2]octane (DABCO), 4- dimethylaminopyridine (DMAP), or dimethyl sulfoxide (DMSO).

[00146] In certain embodiments, D is not ammonia, trimethylamine, triethylamine, N- methyl piperidine, quinuclidine, pyridine, collidine, tetrahydrothiophene, or dimethyl sulfoxide.

Exemplary compounds of Formula (I)

[00147] Various combinations of certain embodiments of Formula (I) are also contemplated.

[00148] In certain embodiments, a compound described herein is a compound of

Formula (I-a):

^D '- ^R1 (!-»),

wherein D and R ¹ are as described herein.

[00149] In certain embodiments, a compound described herein is a compound of

Formula (I-b):

D--I-CF _{3 (I} . _b)

wherein D is as described herein.

[00150] In certain embodiments, a compound described herein is a compound of

Formula (I-c):

D— - -I— CF ₂ CF _{3 (I} . _C)

wherein D is as described herein. [00151] In certain embodiments, a compound described herein is a compound of

Formula (Il-a):

wherein R ¹ , R ² , R ⁴ , and z are as described herein. In certain embodiments, R ¹ is -CF ₃ . In certain embodiments, R ¹ is -CF ₂ CF ₃ . In certain embodiments, z is 2. In certain embodiments, each instance of R 4 is hydrogen. In certain embodiments, each instance of R 2 is substituted or unsubstituted Ci_6 alkyl. In certain embodiments, each instance of R is methyl. In certain embodiments, R 1 is -CF ₃ or -CF ₂ CF ₃ ; z is 2; and each instance of R 2 is methyl.

[00152] In certain embodiments, a compound described herein is a compound of

Formula (Ill-a):

N' ^N—-I— R ¹

(ill-a),

wherein R ¹ , R ⁵ , and m are as described herein. In certain embodiments, R ¹ is -CF ₃ . In certain embodiments, R ¹ is -CF ₂ CF . In certain embodiments, m is 0. In certain embodiments, each instance of R ⁵ is hydrogen. In certain embodiments, R ¹ is -CF or -CF ₂ CF ; and m is 0.

[00153] In certain embodiments, a compound described herein is a compound of

Formula (IV-a):

wherein R , R , and p are as described herein. In certain embodiments, R is -CF . In certain embodiments, R ¹ is -CF ₂ CF . In certain embodiments, p is 1. In certain embodiments, a compound of Formula (IV-a) is /?ara-substituted. In certain embodiments, R ⁶ is -N(R ^6a ) ₂ . In certain embodiments, each instance of R ^6a is methyl. In certain embodiments, R ¹ is -CF ₃ or -

CF ₂ CF ₃ ; p is 1; R ⁶ is -N(R ^6a ) ₂ ; and each instance of R ^6a is methyl. In certain embodiments, a compound described herein is a compound of

wherein R 1 and R2 are as described herein. In certain embodiments, R 1 is -CF ₃ . In certain embodiments, R 1 is -CF ₂ CF ₃ . In certain embodiments, four instances of R 2 are independently substituted or unsubstituted Ci_6 alkyl; and one instance of R is hydrogen. In certain embodiments, four instances of R 2 are methyl; and one instance of R 2 is hydrogen. In certain embodiments, four instances of R 2 are methyl; one instance of R 2 is hydrogen; and R 1 is -CF or -CF ₂ CF ₃ .

[00155] In certain embodiments, a compound described herein is a compound of

Formula (V-b):

wherein R 1 and R2 are as described herein. In certain embodiments, R 1 is -CF ₃ . In certain embodiments, R 1 is -CF ₂ CF ₃ . In certain embodiments, all four instances of R 2 are methyl. In certain embodiments, all four instances of R 2 are methyl; and R 1 is -CF or -CF ₂ CF .

[00156] In certain embodiments, a compound described herein is a compound of

Formula (Vl-a):

(R ² ) ₂ S=0— -I-R ¹ (Vl-a),

wherein R 1 and R 2 are as described herein. In certain embodiments, the halogen bond is between the O atom of the sulfoxide and the iodine atom of the fluoroalkyl iodide. In certain embodiments, R ¹ is -CF ₃ . In certain embodiments, R ¹ is -CF ₂ CF ₃ . In certain embodiments, each instance of R is independently substituted or unsubstituted Ci_6 alkyl. In certain embodiments, both instances of R 2 are methyl. In certain embodiments, both instances of R 2 are methyl; and R ¹ is -CF or -CF ₂ CF .

[00157] In certain embodiments, a compound of Formula (I) is of formula:

CH ₃ H CH ₃ H

, , _N ^N l-CF ₃ , , ^.Ν N l-CF ₂ CF ₃

H ₃ C ^J H ₃ C ^Α

H3C CH3 H3C CH3 (CH ₃ ) ₂ S=0--I-CF ₃ , (CH ₃ ) ₂ S=0--I-CF ₂ CF ₃ ,

H3C^

H3C-N N-CH3 H ₃ C-N N-CH3

i i ί ί

I I

CF ₃ CF ₃ F ₃ CF ₂ C CF ₂ CF ₃

N J^ N— -1-CF3 N J^ N-

Fluoroalkylation reaction substrates and conditions

[00158] Compounds (e.g., a compound of Formula (I)) useful in a method of fluoroalkylating an organic compound or tautomer thereof are described herein.

[00159] An organic compound useful as a starting material in the methods provided herein is an organic molecule of any molecular weight. In certain embodiments, the molecule is a small organic molecule. In certain embodiments, the small organic molecule includes any molecule having a molecular weight of less than 1000 g/mol. In some embodiments, the organic compound contains a chiral center. In some embodiments, the organic compound is further substituted with one or more functional groups (e.g., alcohols, aldehydes, ketones, esters, alkenes, alkoxy groups, cyano groups, amines, amides, and N-oxides). In some embodiments, the functional groups are unprotected. In some embodiments, the organic compound is a precursor of a pharmaceutical agent. In certain embodiments, the organic compound comprises an acidic group. In certain embodiments, the organic compound is substituted with one or more nucleophilic groups. In certain embodiments, the organic compound is an anion. In certain embodiments, the organic compound is substituted with one or more electrophilic groups.

[00160] As is generally described herein, compounds of Formula (I) are useful in fluoroalkylation reactions, wherein the compounds of Formula (I) serve as a source of an electrophilic fluoroalkyl group. [00161] In certain embodiments, a compound of Formula (I) is contacted with an alkyne of Formula (a-2) in the presence of a base to afford a compound of Formula (b-2):

Formula (I) +

Base or D

R ⁸ = H - R ⁸ = R ¹

(a-2) (b-2)

wherein R 1 is as defined herein, and R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[00162] In certain embodiments, a compound of Formula (I) is contacted with an hydroxy organic compound of Formula (a-3) in the presence of a base to afford a compound of Formula (b-3):

Formula (I) +

(a-3) (b-3)

wherein R ¹ is as defined herein, and R ⁹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[00163] In certain embodiments, a compound of Formula (I) is contacted with a thiol of Formula (a-4) in the presence of a base to afford a compound of Formula (b-4):

Formula (I) +

(a-4) (b-4)

wherein R ¹ is as defined herein, and R ¹⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[00164] In certain embodiments, a compound of Formula (I) is contacted with an amine of Formula (a-7) in the presence of a base to afford a compound of Formula (b-7):

Formula (I) +

R ¹³ Base or D R ¹³

R ¹³ R ¹ R

(a-7) (b-7) wherein R 1 is as defined herein, and R 13 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 13 groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring.

[00165] In certain embodiments, a compound of Formula (I) is contacted with an alkene of Formula (a-1) to afford a compound of Formula (b-1):

(a-1) (b-1)

wherein R 1 is as defined herein, and each R 7 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl ring.

[00166] In certain embodiments, a compound of Formula (I) is contacted with a carbonyl containing compound of Formula (a-5) in the presence of a reducing agent or under metal halogen exchange conditions to afford a compound of Formula (b-5):

Formula (I) +

R

(a-5) (b-5)

wherein R ¹ is as defined herein, and R ¹¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R ¹¹ groups are joined to substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl ring. [00167] In certain embodiments, a compound of Formula (I) is contacted with an aldehyde compound of Formula (a-6) in the presence of a reducing agent or under metal halogen exchange conditions to afford a compound of Formula (b-6):

Formula (I) +

Reducing agent or metal-

R!^OH

halogen exchange

R ¹² R ¹²

(a-6) (b-6)

wherein R is as defined herein, and R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[00168] As described herein, fluoroalkylation of alkenes of Formula (a-1) can generally be accomplished under radical or non-radical conditions, e.g., in the case of nonradical conditions, via addition of R ¹ -! across the double bond, followed by HI elimination,

(b-1 )

[00169] Various isomeric fluorinated products are thus contemplated depending upon the substitution of the alkene and the mode of addition of the compound of Formula (I) to the double bond, e.g., wherein R 7 is a non-hydrogen group, optionally wherein each R 7 is different:

(a-1 -a)

rminal

(a-1-b)

CIS

(a-1-c)

trans

(a-1-d)

monosubstituted

(a-1-e)

trisubstituted

[00170] As described herein, fluoroalkylation of carbonyls of Formula (b-5) or (b-6) can generally be accomplished under reaction conditions wherein an anion is generated. Non- limiting examples of reagents useful for generation of an anionic intermediate include alkali or alkaline earth metals (e.g. , lithium or magnesium metal), an organometal species (e.g. , an organolithium reagent), or an organic reducing agent (e.g., tetrakis(dimethylamino)ethylene (TDAE)), e.g. :

metal-halogen

exchange

I— R ¹ M-R ¹

[00171] In certain embodiments, the reactions described herein further include the use of a solvent. Exemplary solvents include non-polar solvents (e.g. , toluene, dioxane, or benzene) or polar solvents (DMF, THF, MeCN).

[00172] In certain embodiments, the reaction is performed under ambient temperature, pressure, and atmosphere. In certain embodiments, the reaction is performed under an inert atmosphere (e.g., an atmosphere that is substantially free of dioxygen or water). In certain embodiments, the reaction is performed under anhydrous conditions (e.g., in a solvent that is substantially free of water). In certain embodiments, the reaction is heated. In certain embodiments, the reaction is cooled (e.g., -30 °C). In certain embodiments, the reaction is performed at room temperature (e.g. , about 20-25 °C).

[00173] In certain embodiments, the reaction conditions comprise an additional reagent such as a base (e.g. , an alkyl amine base such as triethylamine or an inorganic base such as K2CO3). In certain embodiments, the reaction conditions comprise a radical initiator (e.g. , AIBN) or a photoredox catalyst (e.g. , a ruthenium bipyridine catalyst). In certain

embodiments, the reaction conditions comprise irradiation with visible light. In certain embodiments, the reaction conditions comprise an organic reducing agent (e.g. , TDAE). In certain embodiments, a compound of Formula D serves as a base, and no additional base is added.

[00174] In certain embodiments, a compound of the present invention or a compound useful in the methods described herein is immobilized on a solid support. In certain embodiments, a compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (III), (Hl-a), (IV), (IV-a), (V), (V-a), (V-b), (VI), (Vl-a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (b-1), (b- 2), (b-3), (b-4), (b-5), (b-6), or (b-7) is immobilized on a solid support.

Reaction products

[00175] Described herein are methods of making fluoroalkylated organic compounds.

In certain embodiments, the fluoroalkylated organic compounds (e.g., compounds of Formulae (b-l)-(b-7)) are generated from their corresponding precursors (e.g., compounds of Formulae (a-l)-(a-7)) in yields of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100%.

[00176] The reaction conditions described herein are tolerant of many functional groups as well as chiral centers. In certain embodiments, the fluoroalkylated organic compound is further substituted by one or more functional groups, such as aldehydes, ketones, esters, alkenes, alkoxy groups, cyano groups, amines, amides, and N-oxides. In certain embodiments, the fluoroalkylated organic compound contains a chiral center that is derived from the starting material. The stereochemistry at the chiral center may remain substantially unchanged (e.g., little to no racemization or epimerization of the chiral center occurs during the reaction).

[00177] In certain embodiments, the fluoroalkylated organic compound is ¹⁹ F labeled.

In certain embodiments, the labeled organic compound is an imaging agent, such as an MRI imaging agents. In certain embodiments, the labeled organic compound may be used as a probe, such as a biological NMR probes for use in in vivo NMR spectroscopy.

[00178] In certain embodiments, the fluoroalkylated organic compound is 18 F labeled.

In certain embodiments, the 18 F-labeled organic compound is an imaging agent, such as a PET imaging agent.

[00179] In certain embodiments, the fluoroalkylated organic compound is a compound having biological activity. In certain embodiments, the fluoroalkylated organic compound is a compound with pharamacologic activity (i.e., binds to a receptor or enzyme). Methods of preparing the fluoroalkylation reagents

[00180] Fluoroalkylation reagents as described herein (e.g., compounds of Formula

(I)) are generally prepared by contacting a compound of Formula D (e.g.,

tetramethylguanidine, tetramethylethylenediamine, DABCO, DMAP, or DMSO) with a fluoroalkyl iodide of Formula I-R ¹ (e.g., I-CF ₃ or I-CF ₂ CF ₃ ) under conditions suitable to form a compound of Formula (I). The gaseous fluoroalkyl iodide is condensed at low temperatures (e.g., to -78 °C) using a suitable apparatus (e.g., a Schlenk flask). A compound of Formula D is then added to the liquid fluoroalkyl iodide. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1: 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1:2. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 2: 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1:5. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 5: 1. In certain embodiments, the fluoroalkyl iodide is in significant molar excess of D (10-fold or greater). In certain embodiments, D is in significant molar excess of the fluoroalkyl iodide (10-fold or greater). In certain embodiments, the reaction mixture is cooled (e.g., to -78 °C). In certain

embodiments, the reaction mixture includes an additional solvent. In certain embodiments, the reaction mixture does not include additional reagents. The reaction mixture is then warmed to ambient temperature. In certain embodiments, residual fluoroalkyl iodide is removed from the reaction mixture by evaporation. In certain embodiments, the resulting compound of Formula (I) is a solid. In certain embodiments, the resulting compound of Formula (I) is a liquid. In certain embodiments, the resulting compound of Formula (I) is a solution in excess compound of Formula D. In certain embodiments, the compound of Formula (I) is stored at low temperatures (e.g., 0 °C). In certain embodiments, the compound of Formula (I) is stored in a light proof container.

Reaction mixtures and compositions

[00181] The present invention provides reaction mixtures comprising any of the aforementioned reagents and compounds of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (III), (Ill-a), (IV), (IV-a), (V), (V-a), (V-b), (VI), (Vl-a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a- 7), (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), or (b-7). These reaction mixtures include, but are not limited to those used for the preparation of compounds of Formula (I) or wherein a compound of Formula (I) is utilized as a fluoroalkylation reagent.

[00182] The present invention provides compositions comprising compounds of

Formula D and I-R ¹ . In certain embodiments, the composition further comprises a solvent (e.g. , a non-polar or polar organic solvent). In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1 : 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1 :2. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 2: 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1 :5. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 5: 1. In certain embodiments, the fluoroalkyl iodide is in significant molar excess of D (10-fold or greater). In certain embodiments, D is in significant molar excess of the fluoroalkyl iodide (10-fold or greater). In certain

embodiments, the composition further comprises a fluoroalkylation substrate of formula (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), or (a-7).

Kits

[00183] The fluoroalkylation reagents described herein may be provided in a kit. The kit typically includes (a) the fluoroalkylation reagent (e.g., a compound of Formula (I)), and, optionally (b) informational material. The informational material can be descriptive, instructional, or promotional or other material that relates to the methods described herein and/or the use of the compounds for the methods described herein. In certain embodiments, the kit may include additional reagents. In certain embodiments, the kit may include a base (e.g., an alkyl amine base such as triethylamine or an inorganic base such as K ₂ CO ₃ ). In certain embodiments, the kit may include a solvent (e.g. , a non-polar or polar organic solvent). In certain embodiments, the kit may include a radical initiator reagent (e.g. , AIBN). In certain embodiments, the kit may include a photoredox catalyst (e.g., a ruthenium bipyridine catalyst). In certain embodiments, the kit may include an organic reducing agent (e.g. , TDAE)

[00184] The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the fluoroalkylation reagent, molecular weight of the fluoroalkylation reagent, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for using the fluoroalkylation reagent.

[00185] In certain embodiments, the informational material, e.g. , instructions, is provided in printed matter, e.g. , a printed text, drawing, and/or photograph, e.g. , a label or printed sheet. However, the informational material can also be provided in other formats, such as computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g. , a physical address, e-mail address, website, or telephone number, where a user of the kit can obtain substantive information about a fluorination reagent described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

[00186] In certain embodiments, the components of the kit are stored under inert conditions (e.g., under nitrogen or another inert gas such as argon). In certain embodiments, the components of the kit are stored under anhydrous conditions (e.g. , with a desiccant). In certain embodiments, the components are stored in a light blocking container such as an amber vial.

[00187] The fluoroalkylation reagent described herein can be provided in any form, e.g. , liquid, dried, or lyophilized form. Typically the fluoroalkylation reagent described herein is substantially pure and/or sterile. When the fluoroalkylation reagent described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent.

[00188] The kit can include one or more containers for the composition containing the fluoroalkylation reagent described herein. In certain embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or ampule, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial, or ampule that has attached thereto the

informational material in the form of a label. The containers of the kits can be air tight, waterproof (e.g. , impermeable to changes in moisture or evaporation), and/or light-tight. EXAMPLES

[00189] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

Materials and Methods

[00190] All manipulations were performed using oven-dried glassware (130 °C for a minimum of 12 hours) and standard Schlenk techniques under an atmosphere of nitrogen, unless otherwise stated. Previously reported compounds are referenced throughout the Supporting Information to published literature procedures/data. Tetrahydrofuran was distilled from deep purple sodium benzophenone ketyl. Dry DMF and dry DMSO were purchased from Acros Organics. Acetonitrile was dried by distillation over Ρ ₂ 0 ₅ . All deuterated solvents were purchased from Cambridge Isotope Laboratories. Thin layer chromatography (TLC) was performed using EMD TLC plates pre-coated with 250 μιη thickness silica gel 60 F ₂₅₄ plates and visualized by fluorescence quenching under UV light and KMn0 ₄ stain. Flash chromatography was performed using silica gel (230-400 mesh) purchased from Silicycle Inc. NMR spectra were recorded on either a Varian Unity/Inova 600 spectrometer operating at 600 MHz for 1H acquisitions, a Varian Unity/Inova 500 spectrometer operating at 500 MHz and 125 MHz for 1 H and 13 C acquisitions, respectively, or a Varian Mercury 400

spectrometer operating at 375 MHz for ¹⁹ F acquisitions. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. For 1H NMR: CDC1 ₃ , δ 7.26; C ₆ D ₆ , δ 7.16. For ¹³ C NMR: CDC1 ₃ , δ 77.16; C ₆ D ₆ , δ 128.06. Data is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants in Hz;

integration.. High-resolution mass spectra were obtained using an Agilent ESI-TOF (6210) mass spectrometer. Visible light irradiation was carried out using a 90 W, 120 V Sylvana household light bulb that was positioned at about 10 cm from the reaction flask. All substrates were used as received from commercial suppliers, unless otherwise stated. CF I was purchased from Oakwood Chemical, CF CF ₂ I was purchased from Matrix Scientific. Ν,Ν,Ν',Ν'-tetramethylethylenediamine, 1,1,3,3-tetramethylguanidine was purchased from Aldrich and used as received. Care was observed in avoiding contact of Ν,Ν,Ν',Ν'- tetramethylethylenediamine, 1,1,3,3-tetramethylguanidine with ambient atmosphere and the two bases were stored under nitrogen atmosphere once the shipping container was opened. Dry DMSO was purchased from Acros Organics. Ru(bipy) Cl ₂ *3H ₂ 0 was purchased from Strem Chemicals. Silyl enol ether 5 was prepared according to a procedure published byYu et al. ¹

Example 1. Synthesis of Halogen Bonded Adducts

Synthesis of TMG ^» CF ₃ I adduct (SI)

N' ^H

CF ₃ I + jl TMG ^« CF ₃ I

Me ₂ N NMe ₂

S1

[00191] Trifluoromethyl iodide (19.7 g, 0.100 mol, 1.05 eq) was condensed into a

Schlenk flask cooled at -78 °C. (The exact amount of the condensed gas was measured by weighing the empty Schlenk flask and then the sealed Schlenk flask filled with cold CF ₃ I at - 78 °C). 1,1,3,3-Tetramethylguanidine (11.0 g, 12.0 mL, 0.958 mol, 1.00 eq) was then added drop wise at -78 °C. The homogeneous mixture was allowed to warm to 23 °C, under a positive pressure of nitrogen and then the Schlenk flask was sealed. The resulting adduct was obtained in quantitative yield. For prolonged storage, TMG*CF ₃ I (SI) was stored in the dark in a standard refrigerator (0 °C). We have stored TMG*CF I (SI) in a Teflon sealed vial in the dark at 0 °C for 2 months without observing decomposition, pressure build up or loss in content of CF ₃ I as judged by ¹⁹ F NMR and ¹ H NMR. NMR Spectroscopy: ¹ H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 4.83 (br. s., 1 H) 2.29-2.56 (m, 12 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ppm 167.3, 80.2 (q, J _CF =348.1 Hz), 39.0. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C ) 5 ppm -5.6.

Synthesis of 2 DMSO ^» CF ₃ I adduct (S2)

o

CF3I + ς 2 DMSO' CF ₃ l

Me' Me

S2

[00192] Trifluoromethyl iodide (21.7 g, 0.111 mol, 1.00 eq) was condensed into a

Schlenk flask cooled at -78 °C. (The exact amount of the condensed gas was measured by weighing the empty Schlenk flask and then the sealed Schlenk flask filled with CF ₃ I at -78 °C). DMSO (17.3 g, 15.7 mL, 0.221 mol, 2.00 eq) was then added drop wise at -78 °C (some precipitate is observed, which dissolves upon warming). The mixture was allowed to warm up to 23 °C, under a gentle positive pressure of nitrogen and then the Schlenk flask was sealed. The resulting adduct was obtained in quantitative yield. For prolonged storage, 2 DMSOCF ₃ I (S2) was stored in the dark in a standard refrigerator (0 °C). NMR

Spectroscopy: ¹ H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 2.29 (s, 6 H). ¹³ C NMR (126 MHz, CDCI ₃ , 23 °C) δ ppm 78.7 (q, J _CF =343.3 Hz) 40.63. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -7.95.

Synthesis of TMEDA ^» 2 CF ₃ I adduct (S3)

CF3I + Me ₂ N'^'— 'NMe ₂ ^ TMEDA ' 2 CF ₃ I

S3

[00193] A Schlenk flask was charged with Ν,Ν,Ν',Ν'-tetramethylethylenediamine

(250 mg, 2.15, mmol, 1.00 eq). The Schlenk flask was cooled to -78 °C and excess CF ₃ I was condensed into the Schlenk with the aid of a cold finger kept at -78 °C (approximately 10 mL). The cooling bath was removed and the reaction mixture was refluxed at the boiling point of CF ₃ I for 20 minutes. The cold finger was then removed and excess CF ₃ I was removed with a gentle stream of nitrogen. Once all the excess CF ₃ I was removed, TMEDA ^» 2 CF ₃ I (S3) was left as a white solid that was kept in the sealed Schlenk flask (1.09 g, 100%). For prolonged storage, TMEDA ^» 2CF ₃ l (S3) was stored in the dark in a standard refrigerator (0 °C). NMR Spectroscopy: 1H NMR (600 MHz, CDC1 ₃ , 23 °C) δ ppm 2.35 (s, 4 H) 2.20 (s, 12 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ρρηι 78.7 (q, J _CF =347.1 Hz), 57.5, 45.6. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -4.25. Crystallization: Crystals of S3 for X-ray analysis were grown from an acetone solution that was kept at -78 °C.

Synthesis of TMG ^» CF ₃ CF ₂ I adduct (S4)

,H

N

CF ₃ CF ₂ I + jJ «► TMG · CF ₃ CF ₂ I

Me ₂ N NMe ₂

S4

[00194] Pentafluoroethyl iodide (12.3 g, 0.050 mol, 1.0 eq) was condensed into a

Schlenk flask cooled at -78 °C. (The exact amount of the condensed gas was measured by weighing the empty Schlenk and then the sealed Schlenk filled with cold CF ₃ I at -78 °C). 1,1,3,3-Tetramethylguanidine (5.8 g, 6.3 mL, 0.050 mol, 1.0 eq) was then added drop wise at -78 °C. The homogeneous mixture was allowed to warm up to 23 °C, under a gentle positive pressure of nitrogen and then the Schlenk flask was sealed. The resulting adduct was obtained in quantitative yield. For prolonged storage, TMG*CF ₃ CF ₂ l (S4) was stored in the dark in a standard refrigerator (0 °C). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 4.78 (br. s., 1 H) 2.53 (s, 12 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ρρηι 167.4, 117.7 (qt, JcF=284.8, 32.6 Hz), 88.5 (tq, J _CF =315.4, 45.1 Hz) 39.0. ¹⁹ F NMR (376 MHz, CD ₃ CN, 23 °C) δ ppm -70.9, -85.4.

Evaluation of CF3I release from halogen bonded adducts

[00195] The stability of halogen bonded adducts towards loss of CF3I was evaluated as follows:

2.110 g of adduct were weighed into a 4 mL screw cap glass vial with a 1.2 cm diameter. The closed vial was immersed in an ice bath (0 °C) and let equilibrate for 5 minutes. The ice bath and the vial were then put on a balance and the vial was opened to the atmosphere. Weight loss was measured every 2-4 minutes. The results are reported as weight loss (in mol of the initial amount) versus time. Figure 7 A shows the weight loss (mol ) for CF ₃ I-TMG and CF ₃ I-2DMSO. Figure 7B shows the weight loss (mol ) for CF ₃ I-3CH ₃ CN, CF ₃ I-3CHC1 ₃ and CF ₃ I-3TMG and CF ₃ I-3DMSO.

Comparison of CF3I release from TMG, DMSO versus other polar solvents

[00196] The release of CF3I from CHCb and CELCN was compared with CF3I release from

TMG and DMSO. For comparison, mixtures composed of 3 moles of solvents and 1 mole of CF3I were prepared in sealed Schlenk flasks (1 : 1 ratios were not evaluated in the case of CELCN and CHCb due to fast gas release). The weight loss (in mol of initial CF3I) was measured as follows: A 3: 1 mixture of solvent:CF3l (mol/mol) was weighed into a 4 mL screw cap glass vial with a 1.2 cm diameter. The closed vial was immersed in an ice bath (0 °C) and let equilibrate for 5 minutes. The ice bath and the vial were then put on a balance and the vial was opened to the atmosphere. Weight loss was measured every 2-4 minutes. The results are reported as weight loss (in mol of the initial amount) versus time.

Evaluation of binding stoichiometry between DMSO and CF3I

[00197] The binding stoichiometry between DMSO and CF3I was evaluated using a Job plot in CH2CI2 solution. Two 0.1317 M solutions of DMSO and CF3I in CEhCh were prepared. The two solution were mixed to afford solutions with total constant concentration [CF3I+DMSO] = 0.1317 M. Samples were prepared for molar fractions x(DMSO) = 0.00, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90 in screw cap NMR-tubes to avoid loss of CF3I. Trifluorotoluene was added as internal standard to each sample. 19F-NMR for each sample was recorded at 20 °C, measuring the change in chemical shift for the CF3I signal. The data show formation of a 1 : 1 adduct (maximum in the plot at = 0.5) (see Figure 8).

Evaluation of other Lewis bases for the synthesis of halogen bonded adducts with CF3I

[00198] Several Lewis bases were evaluated for their ability to create stable halogen bonded adducts with CF ₃ I. The following procedure was followed. A known amount of Lewis base (250 mg in each case) was weighed in a three necked flask that was cooled to -20 °C. An excess amount of CF ₃ I (approximately 5-10 mL) was condensed in with the aid of a cold finger that was cooled to -78 °C. The reaction mixture was then stirred at the refluxing temperature of CF ₃ I (-22 °C) for 20 minutes and then excess CF ₃ I was evaporated off and the reaction mixture was warmed until +23 °C. As soon as the reaction mixture reached room temperature, a known amount was weighed and analyzed via ¹⁹ F-NMR in the presence of 1- fluoro-3-nitrobenzene. Tested Lewis bases and the results obtained are reported in the table below (Table 1).

Example 2. Reactions with Halogen Bonded Adducts

Synthesis and characterization of (E)-l,l,l-trifluorotridec-2-ene (2)

TMG' CF ₃ I

(15:1 E/Z)

[00199] 1-Dodecene (250 mg, 1.48 mmol, 1.00 eq)was dissolved in CH ₃ CN (3.0 mL).

Ru(bipy) ₃ Cl ₂ ^« 3H ₂ 0 (11.1 mg, 0.015 mmol, 0.01 eq) was added, followed by TMG ^« CF ₃ I (1.38 g, 4.45 mmol, 3.00 eq). The reaction mixture was irradiated at 23 °C for 20 hours with visible light. The reaction mixture was diluted with water (4 mL) and extracted with pentane (3 x 4 mL). The combined pentane extracts where dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by column chromatography (100% pentane) to yield 2 as a colorless oil (291 mg, 83%), as a 15: 1 E/Z mixture of diastereoisomers (R/= 0.90 (pentane)). NMR Spectroscopy: ¹ H NMR (600 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm 6.38 (m, 1 H) 5.53-5.66 (m, 1 H) 2.08-2.20 (m, 2 H) 1.43 (m, 2 H) 1.18-1.36 (m, 14 H) 0.89 (t, J=6.7 Hz, 3 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm 140.8 (d, JCF=6.7 Hz) 117.5-119.0 (q, J _CF =32.6 Hz) 31.9, 31.4, 29.6, 29.5, 29.4, 29.3, 29.0, 28.0, 22.7, 14.1. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm -64.0. Data in agreement with literature.

Synthesis and characterization of 4-chlorophenyl trifluoromethyl sulfide (4)

[00200] 4-Chlorobenzenethiol (250 mg, 1.73 mmol, 1.00 eq) was dissolved in dry

DMF (4 mL). TMG ^« CF ₃ I (700 mg, 2.25 mmol, 1.30 eq) was added at 23 °C and the reaction mixture was stirred for 16 hours at 23 °C under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with pentane (3 x 10 mL). The combined pentane extracts were dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by flash column chromatography (100% pentane) to yield 4 as a colorless oil (310 mg, 84%) (R/ = 0.78 (pentane)). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 7.61 (d, J=8.3 Hz, 2 H) 7.39-7.46 (m, 2 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ppm 137.7, 137.6, 129.8, 129.3 (q, J _CF =309.7) 122.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -42.9. Mass Spectrometry: HRMS (APCI) (m/z): Calcd for [M] ⁺ , 211.9669 . Found, 211.9662. Data in agreement with literature.

Synthesis and characterization of 3,3,3-trifluoro-l-phenylpropan-l-one

[00201] Enolether 5 (100 mg, 0.36 mmol, 1.00 eq) was dissolved in THF (1.8 mL).

Ru(bipy) ₃ Cl ₂ '3H ₂ 0 (1.3 mg, 1.8 μηιοΐ, 0.0050 eq) was added, followed by iPr ₂ NEt (125 μί, 0.720 mmol, 2.00 eq), H ₂ 0 (9.6 μί, 0.53 mmol, 1.48 eq) and 2 DMSOCF ₃ I (1.27 g, 3.60 mmol, 10.0 eq). The reaction mixture was stirred and irradiated with visible light at 23 °C for 20 hours. The reaction mixture was then diluted with 0.5M HC1 (4 mL) and extracted with pentane/Et ₂ 0 1: 1 v/v (3 x 4 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was purified by flash column

chromatography (pentane/CH ₂ Cl ₂ 4: 1 v/v) to yield 6 as a white solid (54 mg, 79%). (the product was found to sublime when drying on high vacuum) (R/= 0.35 (pentane/CH ₂ Cl ₂ 2: 1 v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 7.95 (d, J=7.3 Hz, 2 H) 7.65 (d, J=7.3 Hz, 1 H) 7.52 (d, J=7.8 Hz, 2 H) 3.82 (q, J _CF =10.3 Hz, 2 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) 5 ppm 189.7, 135.8, 134.2, 128.9, 128.3, 124.0 (q, J _CF =276.2 Hz), 42.1 (q, JcF=27.8 Hz). ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -62.1. Data in agreement with literature. ⁴

Synthesis and characterization of compound 2,2,2-trifluoro-l-(naphthalen-l-yl)ethanol

(8)

TDAE = tetrakis(dimet ylamino)ethylene

[00202] 1-Naphthaldehyde 7 (100 mg, 0.64 mmol, 1.00 eq) was dissolved in dry DMF

(2.0 mL) and 2 DMSOCF ₃ I (786 μΐ,, 3.84 mmol, 6.00 eq) was added at 23 °C. The reaction mixture was cooled to -30 °C and tetrakis(dimethylamino)ethylene (923 μί, 3.97 mmol, 6.20 eq) was added drop wise. The reaction mixture was irradiated with visible light while stirring at -30 °C for 2 hours. The reaction mixture was then gently allowed to warm up to 23 °C (the cooling bath was not removed but gently allowed to warm up) and stirred with irradiation over 12 hours. The reaction mixture was diluted with 0.5M HC1 (7 mL) and extracted with Et ₂ 0/pentane 1: 1 v/v (3x5 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was purified via flash column

chromatography (pentane/Et ₂ 0 8: 1) to yield compound 8 (105 mg, 73%) (R/= 0.33

(Pentane/Et ₂ 0 3: 1 v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 8.06 (d, J=8.3 Hz, 1 H) 7.94 (d, J=7.8 Hz, 2 H) 7.86 (d, J=6.8 Hz, 1 H) 7.52 - 7.64 (m, 3 H) 5.88 (q, J _CF =6.3 Hz, 1 H) 2.99 (br. s., 1 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) 5 ppm 133.7, 131.1, 130.2, 130.0, 129.0, 126.9, 126.0, 125.8, 125.2, 124.7 (q, J _CF =283.5 Hz), 122.8, 69.0 (q, JcF=32.6 Hz). ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -76.9. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for [M - H] , 225.0533. Found, 225.0530. Data in agreement with literature. ⁵

Synthesis and characterization of (E)-l,l,l,2,2-pentafluorotetradec-3-ene (9)

TMG' CF ₃ CF ₂ I

(9:1 EIZ)

[00203] 1-Dodecene (250 mg, 1.48 mmol, 1.00 eq) was dissolved in CH ₃ CN (3.0 mL).

Ru(bipy) ₃ Cl ₂ ^« 3H ₂ 0 (11.1 mg, 0.015 mmol, 0.01 eq) was added, followed by TMG ^« CF ₂ CF ₃ I (1.60 g, 4.44 mmol, 3.00 eq). The reaction mixture was irradiated with visible light at 23 °C for 20 hours. The reaction mixture was diluted with water (4 mL) and extracted with pentane (3 x 4 mL). The combined pentane extracts where dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by column chromatography (100% pentane) to yield 9 as a colorless oil (310 mg, 73%) as a 10: 1 EIZ mixture of diastereoisomers (R/= 0.76 (pentane)). NMR Spectroscopy: 1H NMR (600 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm 6.32-6.47 (m, 1 H) 5.57 (dd, J=15.8, 11.7 Hz, 1 H) 2.11-2.23 (m, 2 H) 1.38-1.51 (m, 2 H) 1.18-1.36 (m, 14 H) 0.89 (t, J=7.0 Hz, 7 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) (Major

diastereoisomer) δ ppm 143.1 (t, / _CF =8.6 HZ), 119.0 (qt, / _CF =286.0, 39.3 Hz), 116.5 (t, JcF=23.0 Hz), 112.6 (tq, J _CF =249.3, 38.3 Hz), 32.0, 31.9, 29.6, 29.5, 29.3, 29.0, 27.9, 22.7, 14.1. F NMR (376 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm -85.5, -115.1. Mass Spectrometry: HRMS (APCI) (m/z): Calcd for [M+H] ⁺ , 287.1793. Found, 287.1831.

Synthesis and characterization of 4-chlorophenyl pentafluoroethyl sulfide (10)

[00204] 4-Chlorobenzenethiol (250 mg, 1.73 mmol, 1.00 eq) was dissolved in dry

DMF (4 mL). TMG ^« CF ₂ CF ₃ I (812 mg, 2.25 mmol, 1.30 eq) was added at 23 °C and the reaction mixture was stirred for 16 hours at 23 °C under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with pentane (3 x 10 mL). The combined pentane extracts were dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by flash column chromatography (100% pentane) to yield 4 as a colorless oil (375 mg, 82%) (Rf = 0.62 (pentane)). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 7.61 (d, J=8.8 Hz, 2 H) 7.43 (d, J=8.3 Hz, 2 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ppm 138.3, 138.0, 129.7, 121.2, 120.2 (tq, J _CF =290.6, 40.3 Hz), 118.7 (qt, J _CF =286.7, 36.4 Hz). ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -82.5, -92.0. Mass Spectrometry: HRMS (APCI) (m/z): Calcd for [M] ⁺ , 261.9637. Found, 261.9630.

Summary of Example 2

[00205] To further demonstrate the synthetic utility of TMG*CF ₃ I, we have explored its use as a drop-in replacement for gaseous CF ₃ I described above. TMG*CF ₃ I can be used in Stephenson's photoredox-catalyzed oxidative olefin trifluoromethylation (see (E)- 1,1,1 - trifluorotridec-2-ene (2)). Likewise, thiol trifluoromethylation can be accomplished with TMG*CF ₃ I (see 4-chlorophenyl trifluoromethyl sulphide (4)). In both cases, TMG acts as a base in addition to providing a liquid source of CF ₃ I. In other cases, we found the presence of TMG to be detrimental. For example, TMG*CF I was not a suitable CF I surrogate for the MacMillan trifluoromethylation of enol ethers under photoredox catalysis. ^[llh] However, 2 DMSOCF ₃ I proved effective both in the MacMillan trifluoromethylation, as well as in the TDAE-mediated trifluoromethyl addition to aldehydes (see 3,3,3-trifluoro-l-phenylpropan-l- one (6) and 2,2,2-trifluoro-l-(naphthalen-l-yl)ethanol (8), respectively). The ability of tetramethylguanidine to serve as one electron reductant and/or H-atom donor may explain the differing reactivity of DMSOCF ₃ I and TMG ^» CF ₃ I. We have also found that TMG ^« CF ₃ CF ₂ I is effective for pentafluoroethylation (see (E)- l,l ,l,2,2-pentafluorotetradec-3-ene (9) and 4- chlorophenyl pentafluoroethyl sulfide (10)).

Example 3. DFT Calculations

[00206] Density functional theory (DFT) calculations were performed using

Gaussian09 ⁶ at the Odyssey cluster at Harvard University. Geometry optimizations were carried out using the atomic coordinates of molecular structures created with Gauss View5 and for TMEDA ^» 2 CF I (S3) using the atomic coordinates of the crystal structure as starting points. Basis set I (BS I) includes Stuttgart/Dresden (SDD) quasirelativistic pseudopotentials multielectron-fit wood-boring (MWB) on I (MWB46) with the basis set (4s5p)/[2s3p extended by d-polarization functions (0.289), ⁹ 6-31G(d,p) ¹⁰ on H and 6-311G(d) ⁸ on C, N, F. Geometry optimizations were performed using the B3LYP, ¹¹ ' ¹² ' ¹³ M06-2X, ¹⁴ and &>B97X-D ¹⁵ functionals with the BS I basis set. Natural bond orbitals (NBO) were generated using an isosurface value of 0.01 with B3LYP/BS I. The electrostatic potential of trifluoromethyl iodide is mapped onto the electron density using an isovalue of 0.001 electrons · (a.u.) ^" with GaussView5 for the optimized structure using B3LYP/BS I . Basis set superposition error (BSSE) corrected interaction energies were calculated using the Boys-Bernadi counterpoise technique ¹⁶ for the optimized complex geometries determined with M06-2X/BS I and CL>B97X-D/BS I. Images were generated using Chem3D or Gauss View5.

DFT results for CF ₃ I

DFT results for tetramethylethylenediamine (TMEDA)

DFT results for 1,1,3,3-tetramethylguanidine (TMG)

DFT results for TMEDA ^» 2 CF ₃ I and TMG ^» CF ₃ I

Interaction energies for TMEDA ^» 2 CF ₃ I and TMG ^» CF ₃ I with ωΒ97Χ-ϋ/ BS I and M06-

[00207] C-I bond distances of molecular CF ₃ I are given in parentheses. Energies are calculated using equations (1), (2) and (3). The total energies of all fragments n of a particular complex (TMEDA-2 CF ₃ I or TMG-CF ₃ I) are calculated in the monomer geometry (MG) and in the complex (CG) within both the monomer basis (MB) and the complex basis (CB).

A _C -BSSE _ c-BSSE γη c _\ lit. — - ^C complex ^— Li=l ^c i,MG K )

DFT results for DMSO ^» 2 CF ₃ I

[00208] The Oxygen-bound structure was found to be more stable than the S-bound structure with both (0B97X-D and M06-2X functionals. BSSE-corrected differences in energy between the oxygen-and sulfur-bound structures are as following: -5.22 kcal-mol ¹ (M06-2X) and -4.03 kcal-mol ¹ (coB97X-D).

Interaction energies for DMSO ^» CF3I O-bound with coB97X-D/ BS I and M06-2X/ BS I

[00209] C-I bond distances of molecular CF ₃ I are given in parentheses. Energies are calculated using equations (1), (2) and (3). The total energies of all fragments n of a particular complex are calculated in the monomer geometry (MG) and in the complex (CG) within both the monomer basis (MB) and the complex basis (CB).

AE = E, complex MG (1)

AE BSSE _ pBSSE

comple MG (2)

F ^c CB

CG (3) Example 4. Direct Trifluoromethylation of Arenes

General Procedure

[00210] Arene (0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and

Cu(OAc) ₂ ^» H ₂ 0 (100 mg, 0.500 mmol) were dissolved in glacial acetic acid (2.0 mL). TMG*CF I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated to 90 °C for 24 h. The reaction mixture was diluted with saturated aqueous Na ₂ C0 ₃ (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel.

Benzotrifluoride (1)

1

[00211] Benzene (22.3 μΐ,, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^» H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG'CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and

heated at 90 °C for 24 hours. Ethyl trifluoroacetate (12.0 μΙ_, 0.100 mmol, 0.400 eq) was added

as an internal standard. ¹⁹ F NMR of the crude reaction mixture showed 77% yield of benzotrifluoride 1. The identity of the product was verified by addition of authentic benzotrifluoride to the NMR sample.

l,3,5-Trimethyl-2-(trifluoromethyl)benzene (2)

2

[00212] Mesitylene (34.8 μΐ,, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^» H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG'CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. 4-Fluoronitrobenzene (10.6 μί, 0.100 mmol, 0.400 eq) was added as an internal standard. ¹⁹ F NMR of the crude reaction mixture (AcOH, 23 °C) showed 75% yield of 2 (δ ppm -53.2). The identity of the product was verified by GC/MS, where the major peak (m/z = 188) gave a spectrum identical to that reported in the literature. 17

4-(tert-Butyl)-2-(trifluoromethyl)phenyl acetate (3a) and 4-(tert-butyl)-3- (trifluorometh l)phenyl acetate (3b)

3a 3b

[00213] 4-iert-Butylphenyl acetate (48.0 mg, 0.250 mmol, 1.00 eq), K2S2O8 (270 mg,

1.00 mmol, 4.00 eq) and Οι(ΟΑ ·Η ₂ 0 (100 mg, 0.0500 mmol, 0.200 eq) were dissolved in glacial acetic acid (2.00 mL). TMG'CFsI (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgSCk) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with CFLCL/hexanes (1:7) to afford 30.7 mg (0.118 mmol, 47%) of a mixture of 3a and 3b in a 10: 1 ratio as a colorless oil. We were unable to separate the isomers by chromatography and so the compounds were characterized as a mixture.

[00214] R/= 0.35 (CH ₂ Cl ₂ /hexanes 1:7). NMR spectroscopy: ¹ H NMR (400 MHz,

CDC1 ₃ , 23 °C) δ ppm 7.66 (d, / = 8.8 Hz, 1H, minor), 7.64 (d, / = 2.0 Hz, 1H, major), 7.57 (dd, J = 8.4 Hz, 2.0 Hz, 1H, major), 7.43 (d, J = 2.4 Hz, 1H, minor), 7.21 (dd, J = 8.8 Hz, 2.4 Hz, minor), 7.13 (d, ./ = 8.4 Hz, major), 2.32 (s, 3H, major), 2.31 (s, 3H, minor), 1.45 (s, 9H, minor), 1.34 (s, 9H, major). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 169.2, 169.1, 149.2, 148.2, 146.8, 145.6, 130.1, 130.0, 124.5, 123.8, 123.7 (q, J _CF = 5 Hz), 123.2 (q, J _CF = 273 Hz), 122.1 (q, J _CF = 31 Hz), 121.5 (q, J _CF = 8 Hz), 36.4, 34.7, 32.1, 31.2, 29.7, 21.0, 20.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -53.4 (minor), -61.7 (major). Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₁₃ H ₁₅ F ₃ 0 ₂ Na] ⁺ , [M+Na ⁺ ]: 283.0922. Found, 283.0902.

Ethyl 3,4,5-trimethoxy-2-(trifluoromethyl)benzoate (4)

[00215] * Ethyl

3,4,5-trimethoxybenzoate (60.0 mg, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ *H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG'CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexanes (1:7) to afford 44.1 mg (0.143 mmol, 57%) 4 as a colorless oil.

[00216] R/= 0.50 (EtOAc/hexanes 1:3). NMR spectroscopy: 1H NMR (400 MHz,

CDC1 ₃ , 23 °C) δ ppm 6.75 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 168.0, 155.9, 153.0, 144.1, 128.9, 123.1 (q, J _CF = 273Hz), 114.5 (q, J _CF = 31 Hz), 106.9, 62.2, 61.8, 60.9, 56.2, 13.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -56.6. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C1 ₃ H ₁₅ F ₂ 0 ₅ ] ⁺ , [M-F ⁺ ]: 289.0888. Found, 289.0894. 2,4,6-Trimethox -3-(trifluoromethyl)benzonitrile (5)

5

[00217] 2,4,6-Trimethoxybenzonitrile (48.0 mg, 0.250 mmol, 1.00 eq), K2S208 (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexanes (1:3) to afford 39.2 mg (0.150 mmol, 60%) 5 as colorless crystals.

[00218] R/= 0.33 (EtOAc/hexanes 1:3). NMR spectroscopy: 1H NMR (400 MHz,

CDC1 ₃ , 23 °C) δ ppm 6.28 (s, 1H), 4.01 (s, 3H), 3.97 (s, 3H), 3.95 (s, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 165.4, 164.0, 163.5, 122.9 (q, J _CF = 273 Hz), 113.3, 106.0 (q, J _CF = 31 Hz), 91.4, 90.3, 63.4, 56.6, 56.4. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -56.0. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C _n HiiF ₃ N0 ₃ ] ⁺ , [M+H ⁺ ]: 262.0686. Found, 262.0682.

Diethyl 2,5-dimethoxy-3-(trifluoromethyl)terephthalate (6)

[00219] Diethyl 2,5-dimethoxyterephthalate (70.0 mg, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈

(270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 120 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with CH ₂ C1 ₂ to afford 41.0 mg (0.116 mmol, 47%) 6 as a colorless oil.

[00220] R/ = 0.62 (CH ₂ C1 ₂ ). NMR spectroscopy: 1H NMR (400 MHz, CDC1 ₃ , 23 °C) δ ppm 7.53 (s, 1H), 4.43 (q, J = 7.6 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.6 Hz, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 164.8, 164.6, 152.4, 151.5, 127.4, 123.3, 123.0, 122.5 (q, J _CF = 275 Hz), 117.2, 64.3, 62.2, 62.0, 56.7, 14.2, 13.9. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -57.7. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₁₅ H ₁₈ F ₃ 0 ₆ ] ⁺ , [M+H ⁺ ] : 351.1050. Found, 351.1054.

N-(4-ethoxy-3-(trifluoromethyl)phenyl)acetamide (7a) and N-(4-ethoxy-2- (trifluoromethyl)phenyl)acetamide (7b)

[00221] N-(4-ethoxyphenyl)acetamide (45.0 mg, 0.250 mmol, 1.00 eq), TBHP (70% aqueous, 0.140 mL, 1.00 mmol, 4.00 eq) and FeSC mO (14.0 mg, 0.0500 mmol, 0.200 eq) were dissolved in glacial acetic acid (2.00 mL). TMG'CFsI (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 120 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgSCk) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with EtOAc/CH ₂ Cl2 (l :7) to afford 30.9 mg (0.125 mmol, 50%) of a mixture of 7a and 7b in a 1.4: 1 ratio. Further purification by preparative TLC (EtOAc/CHCb 1 :3) afforded pure isomers as colorless solids in quantities sufficient for characterization.

[00222] N-(4-ethoxy-3-(trifluoromethyl)phenyl)acetamide (7a):R/ = 0.37

(EtOAc/CHCl ₃ 1 :3). NMR spectroscopy: 1H NMR (400 MHz, CDC1 ₃ , 23 °C) δ ppm 7.68 (d, J = 8.8 Hz, 1H), 7.58 (bs, 1H), 7.56 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 153.6, 130.3, 125.4, 123.3 (q, JCF = 273 Hz), 119.6, 119.1 (q, J _CF = 31 Hz), 113.6, 110.2, 64.8, 24.2, 14.5. ^iy F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -62.5. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [CnHi ₃ F ₃ N0 ₂ ] ⁺ , [M ]: 248.0893. Found, 248.0895.

[00223] N-(4-ethoxy-2-(trifluoromethyl)phenyl)acetamide (7b): R/= 0.44

(EtOAc/CHC13 1:3). NMR spectroscopy: 1H NMR (400 MHz, CDC1 ₃ , 23 °C) δ ppm 7.85 (d, J = 8.4 Hz, 1H), 7.18 (bs, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 2.18 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 168.6, 156.0, 127.7, 127.5, 123.6 (q, J _CF = 273 Hz), 123.0 (q, J _CF = 29 Hz), 118.1, 112.2, 64.0, 24.2, 14.6. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -61.1. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C _u Hi ₃ F ₃ N0 ₂ ] ⁺ , [M ⁴ ]: 248.0893. Found, 248.0892.

Diethyl 5-methoxy-4-(trifluoromethyl)isophthalate (8a) and diethyl 5-methoxy-2- (trifluoromethyl)isophthalate (8b)

8a 8b

[00224] Diethyl 5-methoxyisophthalate (63.0 mg, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.0500 mmol, 0.200 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (1:9) to afford 46.5 mg (0.125 mmol, 50%) of a mixture of 8a and 8b in a 2.3: 1 ratio. Further purification by preparative TLC (CH^l^exanes 1: 1) afforded pure isomers as colorless oils in quantities sufficient for characterization.

[00225] Diethyl 5-methoxy-4-(trifluoromethyl)isophthalate (8a): R/= 0.33

(CH ₂ Cl ₂ /hexanes 1: 1). NMR spectroscopy: 1H NMR (400 MHz, CDC1 ₃ , 23 °C) δ ppm . 7.72 (s, 1H), 7.68 (s, 1H), 4.41 (q, J = 1.2 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 167.5, 164.6, 158.1, 134.9, 134.8, 122.7 (q, J _CF = 274 Hz), 120.5, 119.3 (q, J _CF = 31 Hz), 114.2, 62.4, 61.9, 56.7, 14.2, 13.9. ^iy F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -58.6. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₁₄ Hi ₅ F ₂ 0 ₅ ] ⁺ , [M-F ⁺ ]: 301.0888. Found, 301.0865.

[00226] Diethyl 5-methoxy-2-(trifluoromethyl)isophthalate (8b):

R/= 0.28 (CH2C12/hexanes 1: 1). NMR spectroscopy: 1H NMR (400 MHz, CDC1 ₃ , 23 °C) δ ppm 7.18 (s, 2H), 4.38 (q, J = 7.2 Hz, 4H), 3.89 (s, 3H), 1.37 (t, J = 7.2 Hz, 6H). ¹³ C NMR

(125 MHz, CDC1 ₃ , 23 °C) δ ppm 167.0, 161.2, 135.4, 123.2 (q, J _CF = 273 Hz), 118.3 (q, J =

31 Hz), 116.3, 62.4, 56.0, 13.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -54.1. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₁₄ Hi ₅ F ₂ 0 ₅ ] ⁺ , [M-F ⁺ ]: 301.0888. Found,

301.0866.

N-(2,4-bis(trifluoromethyl)phenyl)acetamide (9)

[00227] N-(4-(trifluoromethyl)phenyl)acetamide (51.0 mg, 0.250 mmol, 1.00 eq),

K2S208 (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with EtOAc/hexanes 1:3 to afford 32.1 mg (0.119 mmol, 47%) of 9 as a colorless solid.

[00228] R _F = 0.55 (EtOAc/hexanes 1: 1). NMR spectroscopy: 1H NMR (400 MHz,

CDC1 ₃ , 23 °C) δ ppm 8.49 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.54 (bs, 1H), 2.26 (s, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 168.4, 138.5, 130.0, 126.4, 126.1, 123.9, 123.5, 123.3 (q, J _CF = 272 Hz), 123.2 (q, J _CF = 272 Hz), 24.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -61.1 (s, 3F), -62.6 (s, 3F). Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₁₀ H ₈ F ₆ NO] ⁺ , [M+H ⁺ ]: 272.0505. Found, 272.0493. Methyl 2,6-dimethoxy-3-(trifluoromethyl)benzoate (10a) and methyl 2,6-dimethoxy-4- (trifluoromethyl)benzoate (10b)

10a 10b

[00229] Methyl 2,6-dimethoxybenzoate (49.0 mg, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.0500 mmol, 0.200 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ /hexanes (1:2 to 1: 1) to afford 32.4 mg (0.123 mmol, 49%) of a mixture of 10a and 10b in a 3.0: 1 ratio. Further purification by preparative TLC

(EtOAc/hexanes 1:4) afforded pure 10a as a colorless oil and 10b as a colorless solid, in quantities sufficient for characterization.

[00230] Methyl 2,6-dimethoxy-3-(trifluoromethyl)benzoate (10a):R/= 0.22

(EtOAc/hexanes 1:4). NMR spectroscopy: 1H NMR (400 MHz, CDC1 ₃ , 23 °C) δ ppm 7.58 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 165.8, 160.2, 156.7, 129.3, 123.4 (q, J _CF = 272 Hz), 119.2, 116.7 (q, J _CF = 31 Hz), 105.9, 63.4, 56.3, 52.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -60.5. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C _u Hi ₂ F ₃ 0 ₄ ] ⁺ , [M+H ⁺ ]: 265.0682. Found, 265.0674.

[00231] Methyl 2,6-dimethoxy-4-(trifluoromethyl)benzoate (10b): R/= 0.30

(EtOAc/hexanes 1:4). NMR spectroscopy: 1H NMR (400 MHz, CDC13, 23 °C) δ ppm, 6.79 (s, 2H), 3.92 (s, 3H), 3.87 (s, 6H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 165.8, 157.5, 133.2 (q, JcF = 33 Hz), 123.5 (q, J _CF = 273 Hz), 115.9, 101.1, 56.3, 52.6. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -63.1. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C _u HnF ₃ 0 ₄ Na] ⁺ , [M ⁺ ]: 287.0502. Found, 287.0483. Methyl (S)-2-acetamido-3-(4-acetoxy-3-(trifluoromethyl)phenyl)propa noate (11a) and meth l (S)-2-acetamido-3-(4-acetoxy-2-(trifluoromethyl)phenyl)propa noate (lib)

11a li b

[00232] Methyl (S)-2-acetamido-3-(4-acetoxyphenyl)propanoate (70.0 mg, 0.250 mmol, 1.00 eq), K ₂ S2O ₈ (270 mg, 1.00 mmol, 4.00 eq) and Οι(ΟΑ ·Η ₂ 0 (100 mg, 0.0500 mmol, 0.200 eq) were dissolved in glacial acetic acid (2.00 mL). TMG*CF3l (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgSC^) and concentrated in vacuo. The residue was purified by preparative TLC eluting with acetone/hexanes (1: 1) to afford 45.1 mg (0.130 mmol, 52%) of a mixture of 11a and lib in a 1.7: 1 ratio as a white solid. We were unable to separate the isomers by chromatography and so the compounds were characterized as a mixture.

[00233] R _/ = 0.55 (acetone/hexanes 1: 1). NMR spectroscopy: 1H NMR (400 MHz,

CDCb, 23 °C) δ ppm 7.41 (d, J = 8.4 Hz, 1H, minor) 7.37 (s, 1H, major+minor), 7.31 (d, J = 8.0 Hz, 1H, major), 7.24 (d, J = 8.4 Hz, 1H, minor), 7.14 (d, J = 8.0 Hz, 1H), 6.15 (bs, 1H, major+minor), 4.92-4.82 (m, 1H, major+minor), 3.72 (s, 3H, major), 3.67 (s, 3H, minor), 3.30-3.08 (m, 2H, major+minor), 2.31 (s, 3H, major), 2.30 (s, 3H, minor), 1.98 (s, 3H, major), 1.93 (s, 3H, minor). ¹³ C NMR (125 MHz, CDCb, 23 °C) δ ppm 172.0, 171.6, 169.8, 168.9, 168.8, 149.2, 14 5 Hz), 125.1, 124.5, 123.6 (q, 119.7 (q, JcF = 6 Hz), 53.0, 52.9, 52.4, 52.3, 37.0, 34.2, 23.0, 22.9, 21.0, 20.7. 19F NMR (376 MHz, CDCb, 23 °C) δ ppm -59.2 (minor), -61.9 (major). Mass spectrometry: HRMS (APCI) (m/z): Calcd for [CisHnFsNOsf, [M+H ⁺ ]: 348.1053. Found, 348.1057. 5-(trifluoromethyl)pyrimidine-2,4(lH,3H)-dione (12)

1

[00234] Uracil (28.0 mg, 0.250 mmol, 1.00 eq), K2S208 (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^» H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG'CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with water (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 5% MeOH/CH ₂ Cl ₂ to afford 25.5 mg (0.142 mmol, 57%) 12 as a white solid.

[00235] R/ = 0.30 (5% MeOH/CH ₂ Cl ₂ ). NMR spectroscopy: 1H NMR (400 MHz,

CD30D, 23 °C) δ ppm 7.93 (s, 1H), 4.60 (bs, 2H). ¹³ C NMR (125 MHz, CD ₃ OD, 23 °C) δ ppm 162.1, 152.5, 144.8 (q, JCF = 6 Hz), 123.9 (q, J = 269 Hz), 104.8 (q, J _CF = 34 Hz). ¹⁹ F NMR (376 MHz, CD ₃ OD, 23 °C) δ ppm -64.8. Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₅ H ₃ F ₃ N ₂ 0 ₂ ] ⁺ , [M ] : 180.0147. Found, 180.0157.

5-(pentafluoroethyl)pyrimidine-2,4(lH,3H)-dione (13)

13

[00236] Uracil (28.0 mg, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0 ₈ (270 mg, 1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^» H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG*CF CF ₂ I (0.110 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with water (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 5% MeOH/CH ₂ Cl ₂ to afford 37.4 mg (0.142 mmol, 57%) 13 as a white solid.

[00237] R/= 0.32 (5% MeOH/CH ₂ Cl ₂ ). NMR spectroscopy: 1H NMR (400 MHz,

CD ₃ OD, 23 °C) δ ppm 7.90 (s, 1H), 4.59 (bs, 2H). ¹³ C NMR (125 MHz, CD ₃ OD, 23 °C) δ ppm 161.7, 152.4, 146.7 (t, J _CF = 10 Hz), 120.4 (qt, J _CF = 286, 39 Hz), 113.7 (tq, J _CF = 254, 40 Hz), 102.5 (t, JcF = 24 Hz). ¹⁹ F NMR (376 MHz, CD ₃ OD, 23 °C) δ ppm -85.6 (s, 3F), - 114.9 (s, 2F). Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₆ H ₃ F5N ₂ 0 ₂ ] ⁺ , [M ⁺ ]: 230.0115. Found, 230.0117.

4,6-dimethoxy-5-(trifluoromethyl)pyrimidine (14)

14

[00238] 4,6-Dimethoxypyrimidine (35.0 mg, 0.250 mmol, 1.00 eq), K ₂ S ₂ 0g (270 mg,

1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ I (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by preparative TLC eluting with 10%

EtOAc/hexanes to afford 26.0 mg (0.125 mmol, 50%) 14 as a white solid.

[00239] R/= 0.55 (10% EtOAc/hexanes). NMR spectroscopy: 1H NMR (400 MHz,

CDC1 ₃ , 23 °C) δ ppm 8.48 (s, 1H), 4.05 (s, 6H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 167.9, 158.8, 122.8 (q, J _CF = 273 Hz), 95.5 (q, J _CF = 35 Hz), 55.1. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -56.9. Mass spectrometry: HRMS (APCI) (m/z): Calcd for

[C ₇ H ₇ F ₃ N ₂ 0 ₂ ] ⁺ , [M ⁺ ]: 208.0460. Found, 208.0466. 4,6-dimethoxy-5-(pentafluoroethyl)pyrimidine (15)

15

[00240] 4,6-Dimethoxypyrimidine (35.0 mg, 0.250 mmol, 1.00 eq), K2S208 (270 mg,

1.00 mmol, 4.00 eq) and Cu(OAc) ₂ ^« H ₂ 0 (100 mg, 0.500 mmol, 2.00 eq) were dissolved in glacial acetic acid (2.00 mL). TMG ^« CF ₃ CF ₂ I (0.110 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 90 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by preparative TLC eluting with 10% EtOAc/hexanes to afford 33.1 mg (0.128 mmol, 51%) 15 as a white solid.

[00241] R/= 0.58 (10% EtOAc/hexanes). NMR spectroscopy: 1H NMR (400 MHz,

CDC13, 23 °C) δ ppm 8.47 (s, 1H), 4.01 (s, 6H). ¹³ C NMR (125 MHz, CDC1 ₃ , 23 °C) δ ppm 168.9, 159.2, 119.4 (qt, J _CF = 288, 39 Hz), 112.7 (tq, J _CF = 258, 41 Hz), 93.3 (t, J _CF = 24 Hz), 55.0. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -85.0 (s, 3F), -110.6 (s, 2F). Mass spectrometry: HRMS (APCI) (m/z): Calcd for [C ₈ H ₇ F ₅ N ₂ 0 ₂ ] ⁺ , [M ⁺ ]: 258.0428. Found, 258.0434.

Other Reactions with Halogen Bonded Adducts

Synthesis and characterization of (E)-l,l,l-trifluorotridec-2-ene (17)

17, 83%

{15:1 ez)

[00242] 1-Dodecene (250 mg, 1.48 mmol, 1.00 eq)was dissolved in CH ₃ CN (3.0 mL).

Ru(bipy) ₃ Cl ₂ ^« 3H ₂ 0 (11.1 mg, 0.0150 mmol, 0.0100 eq) was added, followed by TMG ^« CF ₃ I (1.38 g, 4.45 mmol, 3.00 eq). The reaction mixture was irradiated at 23 °C for 20 hours with visible light (see Materials and Methods above about the light source). The reaction mixture was diluted with water (4 mL) and the resulting mixture extracted with pentane (3 x 4 mL). The combined pentane extracts where dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% pentane to yield 17 as a colorless oil (291 mg, 83%), as a 15: 1 EIZ mixture of diastereoisomers.

[00243] R/= 0.90 (pentane). NMR Spectroscopy: 1H NMR (600 MHz, CDC1 ₃ , 23 °C)

(Major diastereoisomer) δ ppm 6.38 (m, 1 H) 5.53-5.66 (m, 1 H) 2.08-2.20 (m, 2 H) 1.43 (m, 2 H) 1.18- 1.36 (m, 14 H) 0.89 (t, J=6.7 Hz, 3 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm 140.8 (d, HZ) 31.9, 31.4, 29.6, 29.5, 29.4, 29.3, 29.0, 28.0, 22.7, 14.1. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer: δ ppm -64.0; minor diastereoisomer: δ ppm -58.1. Data in agreement with literature.

Synthesis and characterization of 4-chlorophenyl trifluoromethyl sulfide (19)

IS 19, 83%

[00244] 4-Chlorobenzenethiol (250 mg, 1.73 mmol, 1.00 eq) was dissolved in dry

DMF (4 mL). TMG ^« CF ₃ I (700 mg, 2.25 mmol, 1.30 eq) was added at 23 °C and the reaction mixture was stirred for 16 hours at 23 °C under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and the resulting mixture extracted with pentane (3 x 10 mL). The combined pentane extracts were dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 100% pentane to yield 19 as a colorless oil (310 mg, 84%).

[00245] R/= 0.78 (pentane). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 7.61 (d, J=8.3 Hz, 2 H) 7.39-7.46 (m, 2 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ppm 137.7, 137.6, 129.8, 129.3 (q, J _CF =309.7 Hz) 122.8. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -42.9. Mass Spectrometry: HRMS (APCI) (m/z): Calcd for [C ₇ H ₄ C1F ₃ S] ⁺ , [M] ⁺ :

211.9669. Found, 211.9662. Data in agreement with literature. Synthesis and characterization of 3,3,3-trifluoro-l-phenylpropan-l-one (21)

20 21 , 79%

[00246] Enolether 20 (100 mg, 0.360 mmol, 1.00 eq) was dissolved in THF (1.8 mL).

Ru(bipy) ₃ Cl ₂ ^« 3H ₂ 0 (1.3 mg, 1.8 μηιοΐ, 0.0050 eq) was added, followed by iPr ₂ NEt (125 μί, 0.720 mmol, 2.00 eq), H ₂ 0 (9.6 μί, 0.53 mmol, 1.48 eq) and 2 DMSOCF ₃ I (1.27 g, 3.60 mmol, 10.0 eq). The reaction mixture was stirred and irradiated with visible light at 23 °C for 20 hours (see Materials and Methods above about the light source). The reaction mixture was then diluted with 0.5M HCl (4 mL) and the resulting mixture extracted with pentane/Et ₂ 0 1: 1 v/v (3 x 4 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent mixture of pentane/CH ₂ Cl ₂ (4: 1 v/v) to yield 21 as a white solid (54 mg, 79%). [the product was found to sublime when dried on high vacuum] .

[00247] R _f = 0.35 (pentane/CH ₂ Cl ₂ 2: 1 v/v). NMR Spectroscopy: ¹ H NMR (500 MHz,

CDC1 ₃ , 23 °C) δ ppm 7.95 (d, J=7.3 Hz, 2 H) 7.65 (d, J=7.3 Hz, 1 H) 7.52 (d, J=7.8 Hz, 2 H) 3.82 (q, J _CF =10.3 Hz, 2 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ppm 189.7, 135.8, 134.2, 128.9, 128.3, 124.0 (q, J _CF =276.2 Hz), 42.1 (q, J _CF =27.8 Hz). ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -62.1. Data in agreement with literature. ⁴

Synthesis and characterization of compound 2,2,2-trifluoro-l-(naphthalen-l-yl)ethanol

(23)

22 23, 73%

[00248] 1-Naphthaldehyde 7 (100 mg, 0.640 mmol, 1.00 eq) was dissolved in dry

DMF (2.0 mL) and 2 DMSOCF ₃ I (786 μΐ,, 3.84 mmol, 6.00 eq) was added at 23 °C. The reaction mixture was cooled to -30 °C and tetrakis(dimethylamino)ethylene (923 μί, 3.97 mmol, 6.20 eq) was added drop wise. The reaction mixture was irradiated with visible light while stirring at -30 °C for 2 hours (see Materials and Methods above about the light source). The reaction mixture was then gently allowed to warm to 23 °C [the cooling bath was not removed but gently allowed to warm] and stirred with irradiation over 12 hours. The reaction mixture was diluted with 0.5M HC1 (7 mL) and the resulting mixture extracted with

Et ₂ 0/pentane 1 : 1 v/v (3 x 5 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ) and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel eluting with a mixture of pentane/Et ₂ 0 (8: 1 v/v) to yield compound 23 (105 mg, 73%).

[00249] R/= 0.33 (Pentane/Et ₂ 0 3: 1 v/v). NMR Spectroscopy: 1H NMR (500 MHz,

CDC13, 23 °C) δ ppm 8.06 (d, J=8.3 Hz, 1 H) 7.94 (d, J=7.8 Hz, 2 H) 7.86 (d, J=6.8 Hz, 1 H) 7.52 - 7.64 (m, 3 H) 5.88 (q, J _CF =6.3 Hz, 1 H) 2.99 (br. s., 1 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) 5 ppm 133.7, 131.1, 130.2, 130.0, 129.0, 126.9, 126.0, 125.8, 125.2, 124.7 (q, J _CF =283.5 Hz), 122.8, 69.0 (q, J _CF =32.6 Hz). ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm - 76.9. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for [C ₁₂ H ₈ F ₃ 0] , [M - H] :

225.0533. Found, 225.0530. Data in agreement with literature. ⁵

Synthesis and characterization of (E)-l,l,l,2,2-pentafluorotetradec-3-ene (24)

TMG*CF ₃ CF ₂ I

16 24, 73%

(9:1 E/Z)

[00250] 1-Dodecene (250 mg, 1.48 mmol, 1.00 eq) was dissolved in CH ₃ CN (3.0 mL).

Ru(bipy) ₃ Cl ₂ '3H ₂ 0 (11.1 mg, 0.0150 mmol, 0.0100 eq) was added, followed by

TMG*CF ₂ CF I (1.60 g, 4.44 mmol, 3.00 eq). The reaction mixture was irradiated with visible light at 23 °C for 20 hours (see Materials and Methods above about the light source). The reaction mixture was diluted with water (4 mL) and the resulting mixture extracted with pentane (3 x 4 mL). The combined pentane extracts where dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% pentane to yield 24 as a colorless oil (310 mg, 73%) as a 10: 1 E/Z mixture of

diastereoisomers.

[00251] R/= 0.76 (pentane). NMR Spectroscopy: 1H NMR (600 MHz, CDC1 ₃ , 23 °C)

(Major diastereoisomer) δ ppm 6.32-6.47 (m, 1 H) 5.57 (dd, J=15.8, 11.7 Hz, 1 H) 2.11-2.23 (m, 2 H) 1.38-1.51 (m, 2 H) 1.18-1.36 (m, 14 H) 0.89 (t, J=7.0 Hz, 7 H). ^1J C NMR (126 MHz, CDC1 ₃ , 23 °C) (Major diastereoisomer) δ ppm 143.1 (t, J _CF =8.6 HZ), 119.0 (qt, JcF=286.0, 39.3 Hz), 116.5 (t, J _CF =23.0 Hz), 112.6 (tq, J _CF =249.3, 38.3 Hz), 32.0, 31.9, 29.6, 29.5, 29.3, 29.0, 27.9, 22.7, 14.1. ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) (Major

diastereoisomer) δ ppm -85.5, -115.1. Mass Spectrometry: HRMS (APCI) (m/z): Calcd for [C ₁₃ H ₂₃ F ₃ ] ⁺ , [M+H] ⁺ : 287.1793. Found, 287.1831.

Synthesis and characterization of 4-chlorophenyl pentafluoroethyl sulfide (25)

25, 63%

[00252] 4-Chlorobenzenethiol (250 mg, 1.73 mmol, 1.00 eq) was dissolved in dry

DMF (4 mL). TMG ^« CF ₂ CF ₃ I (812 mg, 2.25 mmol, 1.30 eq) was added at 23 °C and the reaction mixture was stirred for 16 hours at 23 °C under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and the resulting mixture extracted with pentane (3 x 10 mL). The combined pentane extracts were dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 100% pentane to yield 25 as a colorless oil (375 mg, 82%).

[00253] R _f = 0.62 (pentane). NMR Spectroscopy: 1H NMR (500 MHz, CDC1 ₃ , 23 °C) δ ppm 7.61 (d, J=8.8 Hz, 2 H) 7.43 (d, J=8.3 Hz, 2 H). ¹³ C NMR (126 MHz, CDC1 ₃ , 23 °C) δ ppm 138.3, 138.0, 129.7, 121.2, 120.2 (tq, J _CF =290.6, 40.3 Hz), 118.7 (qt, J _CF =286.7, 36.4 Hz). ¹⁹ F NMR (376 MHz, CDC1 ₃ , 23 °C) δ ppm -82.5, -92.0. Mass Spectrometry: HRMS (APCI) (m/z): Calcd for [C ₈ H ₄ C1F ₅ S] ⁺ , [M] ⁺ : 261.9637. Found, 261.9630.

Summary

[00254] Utilizing liquid TMG*CF I, we were able to rapidly optimize conditions for direct arene trifluoromethylation. We found that electron-neutral to electron-rich arenes could be directly trifluoromethylated when treated with TMG ^» CF ₃ I, K ₂ S ₂ 0 ₈ , and Cu(OAc) ₂ 'H ₂ 0 in acetic acid at 90 °C (Table 17). The reactions are conducted under ambient atmosphere and with no need for rigorously dry conditions or specialized equipment. [00255] The reaction conditions are compatible with common arene substituents, including ethers, esters, nitriles, and amides. The reaction is also effective with highly- substituted arenes and electron-deficient heterocycles. The reagent TMG*CF ₃ CF ₂ l can be substituted for TMG*CF ₃ I to afford pentafluoroethylated products. Positional selectivities are generally modest; generation of mixtures of positional isomers is common for direct arene trifluoromethylations. ^[4 ' ⁵ ' ⁸ ' ^24] Direct arene trifluoromethylation using TMG*CF I is an effective and operationally simple method made possible by the condensed-phase nature of the reagent.

Table 17. Direct perfluoroalkylation of arenes using halogen-bonded reagents."

7a/b, 50% (1 .4: 1 ) ^c ' ^d 8a/b, 58% (2.3: 1 )

65% ⁶ 14, 50% 15, 51 % ^e

a Conditions; 2 equiv. TMG ^« CF ₃ I, 4 equiv. K ₂ S ₂ 0 ₈ , 2 equiv. Cu(OAc) ₂ ^« H ₂ 0, AcOH, 90 °C, 24 h. Isolated yields are shown unless otherwise specified. * indicates site of minor functionalization ^b Yield determined by ¹⁹ F NMR. ^c Reaction conducted at 120 °C. ^d 4 equiv. i-BuOOH and 0.2 equiv. FeS0 ₄ *7H ₂ 0 were utilized instead of K ₂ S ₂ 0g and Cu(OAc) ₂ ^« H ₂ 0. ^e TMG'CF ₃ CF ₂ I was utilized instead of TMG ^« CF ₃ I. Example 5: X-ray Crystallographic Analysis

TMEDA ^» 2 CF ₃ I adduct (CCDC 1033094)

Experimental

[00256] X-Ray quality crystals of TMEDA»2CF ₃ l were grown from an acetone solution kept at -78 °C. A crystal was mounted on a nylon loop using Paratone-N oil, and transferred to a Bruker APEX II CCD diffractometer (Mo _Ka radiation, λ^0.71073 A) equipped with an Oxford Cryosystems nitrogen flow apparatus. The sample was held at 100 K during the experiment. The collection method involved 0.5° scans in ω at 28° in 2Θ. Data integration down to 0.82 A resolution was carried out using SAINT V7.46 A (Bruker diffractometer, 2009) with reflection spot size optimisation. Absorption corrections were made with the program SADABS (Bruker diffractometer, 2009). The structure was solved by the direct methods procedure and refined by least-squares methods again f using SHELXS- 97 and SHELXL-97 (Sheldrick, 2008). Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were allowed to ride on the respective atoms. Restraints on bond lengths and constraints of the atomic displacement parameters on each pair of disorder fragments (SADI and EADP instructions of SHELXL97), as well as the restraints of the atomic displacement parameters (SEVIU/DELU instructions of SHELXL97) if necessary, have been applied for the disorder refinement. Crystal data as well as details of data collection and refinement are summarized in Table 18.

Table 18. Experimental Details.

TMEDA ^» 2 CF ₃ I

Crystal data

Chemical formula C ₈ H ₁₆ N ₂ F ₆ I ₂

M _r 507.93

Crystal system, space group Triclinic, P-l

Temperature (K) 100

a, b, c (A) 6.503 (6), 8.716 (7), 8.726 (7)

, β, γ (°) 61.173 (15), 70.449 (14), 70.350 (14)

V (A3 )399.1 (6)Z 2

Radiation type Mo Ka

Computer programs: APEX2 v2009.3.0 (Bruker-AXS, 2009), SAINT 7.46A (Bruker-AXS, 2009), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), Bruker SHELXTL.

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18.

EQUIVALENTS AND SCOPE

[00257] In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[00258] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g. , in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[00259] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[00260] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.