COMPOUNDS

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. provisional patent application serial no. 61/545,570, filed October 10, 201 1, the entire contents of which are hereby incorporated by reference.

GOVERNMENT SUPPORT

The invention was made in part with United States Government support under grants DE-FE0002474 awarded by the Department of Energy. The United States

Government has certain rights in the invention.

FIELD OF THE INVENTION

The invention pertains to the field of chemical synthesis. More particularly, the invention pertains to methods for the N-alkylation of polycyclic guanidine compounds using dialkylcarbonates.

BACKGROUND

Highly basic bicyclic and tricyclic guanidine compounds have found applications as reagents and catalysts in the field of organic synthesis and as polymer additives.

N-methyl Triazabicyclo[4.4.0] dec-9-ene (MTBD) is of interest as a catalyst to replace potentially toxic tin compounds in polyurethane systems. k .A> .

N N

^{C H} 3 MTBD

A recent publication (Macromolecules 2012, 45, 2249-2256) demonstrates that MTBD is a potential replacement for tin catalysts used in polyurethane chemistry, and that it is a more efficient catalyst than currently used amine catalysts such as DABCO and DBU. Unfortunately, a major drawback of MTBD as a catalyst is its high cost relative to other amine catalysts that it might replace. Thus, even though MTBD has superior catalytic activity in some systems, its high cost relative to other base catalysts may outweigh its advantages. Currently MTBD seems to be available only in small quantities and at high prices (>$50/g).

A patent application (WO/2011/079041) also owned by Novomer discloses a novel and highly efficient route to make TBD (Triazabicyclo [4.4.0] ' dec-9-ene) at large scale which is the typical precursor to MTBD. Alkylation of this material to provide MTBD and related analogs remains challenging at large scale. The few examples reported in the literature generally rely on deprotonation with a strong base such as sodium hydride followed by treatment with alkyl iodide. Such methods are unsuitable for large scale production of MTBD since NaH is reactive and difficult to handle and methyl iodide is highly toxic.

As such, there remains a need for methods to alkylate TBD and related cyclic guanidines without the use of toxic and reactive materials and under conditions amenable to large scale production. Among other things, the present invention provides such methods.

It has recently been shown by Meier et al. (Green Chem., 2012, 14, 1728-1735) that TBD is an effective catalyst for the synthesis of alkyl carbonates by transcarbonation in the presence of alcohols:

(reproduced from Green Chem. 2012, 14, p 1729)

This reference reports the step of heating TBD in the presence of dialkylcarbonates and thus shares certain features of the invention described hereinbelow. In the Meier paper, the result of this step is the formation of new alkyl carbonate products while the TBD remains unchanged. This result makes the present invention all the more unexpected since the result of the present invention— efficient alkylation of the TBD upon heating with dialkylcarbonate— is unexpected in light of the known literature.

SUMMARY OF THE INVENTION

The present invention encompasses among other things, the recognition that dialkylcarbonates are preferred reagents for the mono-N-alkylation of polycyclic guanidines.

DEFINITIONS Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, 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; Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

Certain compounds of the present invention can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. Thus, inventive compounds and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain embodiments, mixtures of enantiomers or

diastereomers are provided.

Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.

As used herein, the term "isomers" includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. For instance, a stereoisomer may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as

"stereochemically enriched." Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer, and may also be referred to as "optically enriched." "Optically enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33 :2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds

(McGraw-Hill, NY, 1962); 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).

The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I). The term "aliphatic" or "aliphatic group", as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-30 carbon atoms. In certain embodiments, aliphatic groups contain 1-12 carbon atoms. In certain embodiments, aliphatic groups contain 1-8 carbon atoms. In certain embodiments, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-5 carbon atoms. In some embodiments, aliphatic groups contain 1^1 carbon atoms. In some embodiments, aliphatic groups contain 1-3 carbon atoms. In some embodiments, aliphatic groups contain 1-2 carbon atoms.

Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term "unsaturated", as used herein, means that a moiety has one or more double or triple bonds.

The terms "cycloaliphatic", "carbocycle", or "carbocyclic", used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or bicyclic ring systems, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3-6 carbons. The terms "cycloaliphatic", "carbocycle" or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring. In certain embodiments, the term "3- to 8-membered carbocycle" refers to a 3 - to 8- membered saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, the terms "3- to 14-membered carbocycle" and "C _3-14 carbocycle" refer to a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 7- to 14-membered saturated or partially unsaturated polycyclic carbocyclic ring. In certain embodiments, the term "C ₃ _2o carbocycle" refers to a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 7- to 20-membered saturated or partially unsaturated polycyclic carbocyclic ring.

The term "alkyl," as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Unless otherwise specified, alkyl groups contain 1-12 carbon atoms. In certain embodiments, alkyl groups contain 1-8 carbon atoms. In certain embodiments, alkyl groups contain 1-6 carbon atoms. In some embodiments, alkyl groups contain 1-5 carbon atoms. In some embodiments, alkyl groups contain 1^1 carbon atoms. In certain embodiments, alkyl groups contain 1-3 carbon atoms. In some embodiments, alkyl groups contain 1-2 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n- hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.

The term "alkenyl," as used herein, denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Unless otherwise specified, alkenyl groups contain 2-12 carbon atoms. In certain embodiments, alkenyl groups contain 2-8 carbon atoms. In certain embodiments, alkenyl groups contain 2-6 carbon atoms. In some embodiments, alkenyl groups contain 2-5 carbon atoms. In some embodiments, alkenyl groups contain 2-4 carbon atoms. In some embodiments, alkenyl groups contain 2-3 carbon atoms. In some embodiments, alkenyl groups contain 2 carbon atoms.

Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.

The term "alkynyl," as used herein, refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Unless otherwise specified, alkynyl groups contain 2-12 carbon atoms. In certain embodiments, alkynyl groups contain 2-8 carbon atoms. In certain embodiments, alkynyl groups contain 2-6 carbon atoms. In some embodiments, alkynyl groups contain 2-5 carbon atoms. In some embodiments, alkynyl groups contain 2-\ carbon atoms. In some embodiments, alkynyl groups contain 2-3 carbon atoms. In some embodiments, alkynyl groups contain 2 carbon atoms.

Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and polycyclic ring systems having a total of five to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to twelve ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like. In certain embodiments, the terms "6- to 10-membered aryl" and 'Όβ-ιο aryl" refer to a phenyl or an 8- to 10-membered polycyclic aryl ring. In certain embodiments, the term "6- to 12-membered aryl" refers to a phenyl or an 8- to 12-membered polycyclic aryl ring. In certain embodiments, the term "C ₆ -i ₄ aryl" refers to a phenyl or an 8- to 14- membered polycyclic aryl ring.

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term

"heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring",

"heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. In certain embodiments, the term "5- to 10-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, the term "5- to 12-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 12-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl), or ⁺ NR (as in N-substituted pyrrolidinyl). In some embodiments, the term "3- to 7-membered heterocyclic" refers to a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the term "3- to 8- membered heterocycle" refers to a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the term "3- to 12-membered heterocyclic" refers to a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the term "3- to 14-membered heterocycle" refers to a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 14- membered saturated or partially unsaturated polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,

pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, 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 aryl or heteroaryl moieties, as herein defined.

One of ordinary skill in the art will appreciate that the synthetic methods, as described herein, may utilize a variety of protecting groups. By the term "protecting group," as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is masked or blocked, permitting, if desired, a reaction to be carried out selectively at another reactive site in a multifunctional compound. In some embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group is preferably selectively removable by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms a separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group will preferably have a minimum of additional functionality to avoid further sites of reaction. By way of non-limiting example, hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), ?-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), -methoxybenzyloxymethyl (PMBM), (4- methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), ?-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- methanobenzofuran-2-yl, 1-ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1- methoxyethyl, 1 -methyl- 1-benzyloxy ethyl, 1 -methyl- l-benzyloxy-2-fluoroethyl, 2,2,2- trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, ?-butyl, allyl, / chlorophenyl, / methoxyphenyl, 2,4-dinitrophenyl, benzyl, / methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, -nitrobenzyl, -halobenzyl, 2,6-dichlorobenzyl, -cyanobenzyl, p- phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p '- dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tn(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)-l'-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), ?-butylmethoxyphenylsilyl (TBMPS), formate,

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

(levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, -phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9- fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl -nitrophenyl carbonate, alkyl benzyl carbonate, alkyl / methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl / nitrobenzyl carbonate, alkyl 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, (is)-2-methyl-2-butenoate, o- (methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkyl Ν,Ν,Ν',Ν'- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate,

dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). Exemplary protecting groups are detailed herein, however, it will be appreciated that the present disclosure is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present disclosure. Additionally, a variety of protecting groups are described by Greene and Wuts (infra).

As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH ₂ )o-4R°; -(CH ₂ )o- ₄ 0R°; -0-(CH ₂ )o- ₄ C(0)OR°; -(CH ₂ )o^CH(OR ⁰ ) ₂ ; -(CH ₂ ) ₀ ^SR°; -(CH ₂ ) ₀ - ₄ Ph, which may be substituted with R° ; which may be substituted with R° ; -CH=CHPh, which may be substituted with R°; -N0 ₂ ; -CN; -N ₃ ; -(CH ₂ ) _C N(R ⁰ ) ₂ ; -(CH ₂ ) ₀ ^N(R ^O )C(O)R°; - N(R°)C(S)R°; -(CH ₂ )o^N(R°)C(0)NR° ₂ ; -N(R°)C(S)NR° ₂ ; -(CH ₂ ) ₀ ^N(R°)C(O)OR°; - N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR° ₂ ; -N(R°)N(R°)C(0)OR°; -(CH ₂ ) ₀ - ₄ C(O)R°; -C(S)R°; -(CH ₂ )o^C(0)OR°; -(CH ₂ ) ₀ _ ₄ C(O)N(R ^o ) ₂ ; -(CH ₂ ) _C C(0)SR ⁰ ; -(CH ₂ y

4C(0)OSiR° ₃ ; -(CH ₂ ) _C OC(0)R ⁰ ; -OC(0)(CH ₂ ) ₀ - ₄ SR- SC(S)SR°; -(CH ₂ ) _C SC(0)R ⁰ ; - (CH ₂ )o- ₄ C(0)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -SC(S)SR°, -(CH ₂ ) ₀ - ₄ OC(O)NR° ₂ ; - C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH ₂ C(0)R°; -C(NOR°)R°; -(CH ₂ ) ₀ ^SSR°; - (CH^SCC .R ⁰ ; -(CH ₂ )o_ ₄ S(0) ₂ OR°; -(CH ₂ ) ₀ ^OS(O) ₂ R°; -S(0) ₂ NR° ₂ ; -(CH ₂ y ₄ S(0)R°; -N(R°)S(0) ₂ NR° ₂ ; -N(R°)S(0) ₂ R°; -N(OR°)R°; -C( H)NR° ₂ ; -P(0) ₂ R°; - P(0)R° ₂ ; -OP(0)R° ₂ ; -OP(0)(OR°) ₂ ; SiR° ₃ ; -(Ci^ straight or branched alkylene)0-

N(R°) ₂ ; or -(Ci- ₄ straight or branched alkylene)C(0)0-N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, Ci-8 aliphatic, -CH ₂ Ph, -0(CH ₂ )o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH ₂ y ₂ R ^e , -(haloR*), -(CH ₂ y ₂ OH, -(CH ₂ y ₂ OR ^e , -(CH ₂ y ₂ CH(OR') ₂ ; -

O(haloR'), -CN, -N ₃ , -(CH ₂ y ₂ C(0)R ^e , -(CH ₂ y ₂ C(0)OH, -(CH ₂ y ₂ C(0)OR ^e , -(CH ₂ y ₄ C(0)N(R°) ₂ ; -(CH ₂ ) ₀ - ₂ SR ^e , -(CH ₂ ) ₀ - ₂ SH, -(CH ₂ ) ₀ - ₂ NH ₂ , -(CH ₂ ) ₀ - ₂ NHR ^e , -(CH ₂ ) ₀ - ₂ NR" ₂ , -N0 ₂ , -SiR's, -OSiR's, -C(0)SR ^e -(C _1-4 straight or branched

alkylene)C(0)OR", or -SSR" wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH ₂ Ph, -0(CH ₂ )o_iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S. Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR ^* ₂ , =NNHC(0)R ^* ,

= NHC(0)OR ^* , = NHS(0) ₂ R ^* , =NR ^* , =NOR ^* , -0(C(R ^* ₂ )) ₂ _ ₃ 0-, or -S(C(R ^* ₂ )) ₂ _ ₃ S-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: -0(CR ₂ ) ₂ -3θ-, wherein each independent occurrence of R ^* is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogen, -R", -(haloR"), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR ^e , -NH ₂ , -NHR", -NR' ₂ , or -N0 ₂ , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH ₂ Ph, -O(CH ₂ ) ₀ -iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ^† , -NR ^† ₂ , -C(0)R ^† , -C(0)OR ^† , -C(0)C(0)R ^† , -C(0)CH ₂ C(0)R ^† , - S(0) ₂ R ^† , -S(0) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C( H)NR ^† ₂ , or -N(R ^† )S(0) ₂ R ^† ; wherein each R ^† is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially

unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^† , taken together with their intervening atom(s) form an unsubstituted 3- to 12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R ^† are independently halogen, -R", -(haloR*), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR ^e , -NH ₂ , -NHR", -NR' ₂ , or -N0 ₂ , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) ₀ -iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0^1 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some chemical structures herein, substituents are shown attached to a bond which crosses another bond of a depicted molecule. This means that one or more of the substituents may be attached to the molecule at any available position (usually in place of a hydrogen atom of the parent structure). In cases where an atom of a molecule so substituted has two substitutable positions, two groups may be present on the same atom. When more than one substituent is present, each is defined independently of the others, and each may have a different structure. In cases where the substituent shown crossing a bond of the molecule is -R, this has the same meaning as if the molecule were said to be "optionally substituted" as described in the preceding paragraph. In cases where the substituent is depicted attached to a bond which crosses a bond in a ring, the substituent is to be understood to be optionally present at any substitutable position on the ring whose bond is so crossed. The term dialkylcarbonate as used herein means a carbonate group bearing two optionally substituted aliphatic moieties. The two moieties may be the same or different. For avoidance of doubt, the substituents on the dialkylcarbonate are not limited to alkyl groups per se but also include unsaturated moieties such as allyl and benzyl as well as substituted moieties such as halogenated groups and the like.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present invention provides methods for the N-alkylation of polycyclic guanidine compounds. In certain embodiments the inventive methods comprise the step of contacting a polycyclic guanidine compound with a dialkylcarbonate. In certain embodiments, the method comprises contacting the guanidine compound and the dialkylcarbonate in the absence of an added solvent.

In certain embodiments, the method comprises contacting the guanidine compound and the dialkylcarbonate in the presence of an added solvent. In certain embodiments, the added solvent is selected from the group consisting of hydrocarbons, ethers, esters, nitriles, sulfoxides, amides, chlorinated hydrocarbons and mixtures of two or more of these. In certain embodiments, the solvent comprises an aliphatic hydrocarbon. In certain embodiments, the solvent comprises an aromatic hydrocarbon.

In certain embodiments, where the method comprises contacting the guanidine compound and the dialkylcarbonate in the presence of an added solvent, the solvent is provided in a quantity such that the solvent comprises about 10 to about 90 weight percent of the mixture. In certain embodiments, the solvent comprises from about 20 to about 50 weight percent of the mixture.

In certain embodiments, methods of the present invention further comprise the step of heating the mixture of the polycyclic guanidine compound and the dialkylcarbonate. In certain embodiments, the reaction mixture is heated to between about 40 °C and 200 °C. In certain embodiments, the reaction mixture is heated to between about 50 °C and about 150 °C. In certain embodiments, the reaction mixture is heated to between about 80 °C and about 120 °C. In certain embodiments, methods of the present invention comprise the step of removing volatiles from the mixture of the polycyclic guanidine compound and the dialkylcarbonate as it is heated. In certain embodiments the step of removing volatiles further comprises sweeping the reaction mixture with gas. In certain embodiments, the reaction mixture is swept with an inert gas. In certain embodiments, the inert gas comprises nitrogen, argon, helium, deoxygenated air, or carbon dioxide. In certain embodiments, the step of removing volatiles comprises subjecting the reaction mixture to reduced pressure.

In certain embodiments, the volatiles removed comprise carbon dioxide. In certain embodiments the volatiles removed comprise an alcohol. In certain embodiments, the volatiles removed comprise a mixture of carbon dioxide and an alcohol. In certain embodiments, the alcohol removed is derived from the alkyl group present on the dialkylcarbonate (e.g. ethanol is volatilized if diethyl carbonate is used, methanol if dimethyl carbonate is used and so forth). In certain embodiments, the method comprises the further step of condensing the alcohol and recovering it as a liquid.

In certain embodiments the polycyclic guanidine compound and the

dialkylcarbonate are provided in approximately equimolar quantities. In certain embodiments, the polycyclic guanidine compound is contacted with a molar excess of the dialkylcarbonate. In certain embodiments, the polycyclic guanidine compound is contacted with between about 1.1 and about 20 molar equivalents of dialkylcarbonate. In certain embodiments, the polycyclic guanidine compound is contacted with between 1.5 and about 15 molar equivalents of dialkylcarbonate. In certain embodiments, the polycyclic guanidine compound is contacted with between 2 and about 10 molar equivalents of dialkylcarbonate. In certain embodiments, the polycyclic guanidine compound is contacted with between 3 and about 8 molar equivalents of dialkylcarbonate. In certain

embodiments, the polycyclic guanidine compound is contacted with between 2 and about 5 molar equivalents of dialkylcarbonate. In certain embodiments, the polycyclic guanidine compound is contacted with between 5 and about 10 molar equivalents of

dialkylcarbonate. In certain embodiments, the reaction mixture is monitored and the process is allowed to continue until the amount of unalkylated polycyclic guanidine present in the mixture is less than about 5%. In certain embodiments, the process is allowed to continue until the amount of unalkylated polycyclic guanidine present in the mixture is less than about 2%, less than about 1% or less than about 0.5%.

In certain embodiments, the methods of the present invention further comprise isolating the alkylated polycyclic guanidine from the reaction mixture. The isolation may comprise one or more steps. In certain embodiments, one or more of the following steps are performed:

-cooling the reaction mixture;

-filtering the reaction mixture;

-washing the reaction product with water;

-washing the reaction product with one or more organic solvents;

-contacting the reaction product with a drying agent;

-contacting the reaction product an inorganic material (e.g. silica gel, alumina, - diatomaceous earth, activated carbon and the like);

-distilling the product; and

- a combination of any two or more of these.

In certain embodiments, the process of isolating the alkylated polycyclic guanidine comprises distillation. In certain embodiments, excess solvents or dialkylcarbonate are distilled from the product. In other embodiments, the alkylated polycyclic guanidine is distilled from other reaction components or byproducts. In certain embodiments the reaction mixture is washed with a hydrocarbon solvent to dissolve the alkylated polycyclic guanidine. In certain embodiments, where the reaction mixture is washed with a hydrocarbon solvent, the desired alkylated polycyclic guanidine is substantially separated from dialkylated byproducts which do not dissolve in the hydrocarbon. In certain embodiments, the reaction mixture is washed with heptane. In certain embodiments, where the alkylated polycyclic guanidine has been dissolved in heptane, the methods comprise a further step of volatilizing the heptanes from the solution to isolate the desired alkylated polycyclic guanidine. The transformations effected by the methods of the invention conform to the reaction shown in Scheme 1 :

SCHEME 1 Wherein Ri groups are optionally present and, if present, are at each occurrence independently selected from the group consisting of halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, and optionally substituted heteroaryl, and functional groups comprising one or more oxygen, nitrogen, sulfur, phosphorous, or silicon atoms, where two or more Ri groups can optionally be taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more heteroatoms;

n is an integer from 1 to 4 inclusive;

m is an integer from 1 to 4 inclusive; and

R2 groups are independently selected from optionally substituted Ci-20 aliphatic and heteroaliphatic moieties.

In certain embodiments, in reactions of Scheme 1, Ri groups are, at each occurrence, independently selected from the group consisting of halogen, -N0 ₂ , -CN, -Si(R ^y )3, -SR ^y , -S(0)R ^y , -S(0) ₂ R ^y , -NR ^y C(0)R ^y , -OC(0)R ^y , -C0 ₂ R ^y , -NCO, -N ₃ , -OR ^y , -OC(0)N(R ^y ) _2, -N(R ^y ) _2, -NR ^y C(0)R ^y , -NR ^y C(0)OR ^y ; or an optionally substituted radical selected from the group consisting of C _1-20 aliphatic; C _1-20 heteroaliphatic; phenyl; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7-14 carbon saturated, partially unsaturated or aromatic polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 12-membered polycyclic saturated or partially unsaturated heterocycle having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where each occurrence of R ^y is independently -H, or an optionally substituted radical selected from the group consisting of Ci-6 aliphatic, 3- to 7-membered heterocyclic, phenyl, and 8- to 10- membered aryl, and where two or more adjacent R ^d groups can be taken together to form an optionally substituted saturated, partially unsaturated, or aromatic 5- to 12- membered ring containing 0 to 4 heteroatoms.

In certain embodiments, in reactions of Scheme 1, one or more Ri groups are present and comprise alkyl groups.

In certain embodiments, in reactions of Scheme 1, Ri groups are absent.

In certain embodiments, in reactions of Scheme 1, R2 groups comprise Ci-2 ₀ aliphatic groups. In certain embodiments, R2 groups comprise Ci_io aliphatic groups. In certain embodiments, R2 groups comprise Ci_6 aliphatic groups. In certain embodiments, R2 groups comprise C1-4 aliphatic groups. In certain embodiments, each R2 group is

-CH2CH2CH ₃ . In certain embodiments, each R2 group is -CH2CH ₃ . In certain

embodiments, each R ₂ group is -CH ₃ . In certain embodiments, each R ₂ group is allyl. certain embodiments, each R2 group is benzyl.

In certain embodiments, in reactions of Scheme 1, m and n are each independently 1 or 2. In certain embodiments, m and n are each 2. In certain embodiments, m and n are each 1. In certain embodiments, m is 1 and n is 2. In certain embodiments, m is 2 and n is 1.

In certain embodiments, the polycyclic guanidine is present as a salt. In certain embodiments, the salt comprises carbonate, bicarbonate, a halide, or a sulfonate. In certain embodiments where the polycyclic guanidine is present as a salt, the method comprises contacting the polycyclic guanidine with the dialkylcarbonate in the presence of a base.

It will be recognized by one skilled in the art that the temperature and length of time a reaction is allowed to proceed can be adjusted to maximize the yield of desired products, minimize side-products and most efficiently use laboratory equipment. Based on the teaching and disclosure herein, these modifications and adjustments to the methods presented will be readily apparent to a skilled artisan and the adjustment of these parameters can be a matter of routine experimentation. Such modifications are recognized and specifically encompassed by the scope of the present invention. In certain embodiments, the present invention encompasses a method of manufacturing MTBD, comprising the step of contacting TBD with dimethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBD with a molar excess of dimethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBD and between 3 molar equivalents and 10 molar equivalents of dimethyl carbonate. In certain embodiments, the mixture is heated to a temperature above 50 °C. . In certain embodiments, the mixture is heated to a temperature above about 75 °C. In certain embodiments, the mixture is heated to a temperature of about 90-100 °C. In certain embodiments, the method comprises heating a mixture of TBD with a molar excess of dimethyl carbonate to a temperature of about 90-100 °C, while simultaneously removing volatiles liberated from the mixture. In certain embodiments the method is performed without added solvent. In certain embodiments, the heating and removal of volatiles are continued until substantially all of the TBD has been alkylated. In certain embodiments, the method comprises the further steps of cooling the reaction mixture, and dissolving the product in a hydrocarbon solvent.

In certain embodiments, the present invention encompasses a method of manufacturing ethyl TBD (l-Ethyl-l,4,9-Triazabicyclo[4.4.0]dec-9-ene), comprising the step of contacting TBD with diethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBD with a molar excess of diethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBD and between 3 molar equivalents and 10 molar equivalents of diethyl carbonate. In certain embodiments, the mixture is heated to a temperature above 50 °C. In certain embodiments, the mixture is heated to a temperature above about 75 °C. In certain embodiments, the mixture is heated to a temperature of about 90-100 °C. In certain embodiments, the method comprises heating a mixture of TBD with a molar excess of diethyl carbonate to a temperature of about 90-100 °C, while simultaneously removing volatiles liberated from the mixture. In certain embodiments the method is performed without added solvent. In certain embodiments, the heating and removal of volatiles are continued until substantially all of the TBD has been alkylated. In certain embodiments, the method comprises the further steps of cooling the reaction mixture, and dissolving the product in a hydrocarbon solvent. In certain embodiments, the present invention encompasses a method of manufacturing methyl TBO (l-methyl-l,4, 6-triazabicyclo[3.3.0]oct-4-ene), comprising the step of contacting TBO (1 ,4, 6-triazabicyclo[3.3.0] oct-4-ene) with dimethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBO with a molar excess of dimethyl carbonate. In certain embodiments, the method comprises heating a mixture of TBO and between 3 molar equivalents and 10 molar equivalents of dimethyl carbonate. In certain embodiments, the mixture is heated to a temperature above 50 °C. In certain embodiments, the mixture is heated to a temperature above about 75 °C. In certain embodiments, the mixture is heated to a temperature of about 90-100 °C. In certain embodiments, the method comprises heating a mixture of TBO with a molar excess of dimethyl carbonate to a temperature of about 90-100 °C, while simultaneously removing volatiles liberated from the mixture. In certain embodiments the method is performed without added solvent. In certain embodiments, the heating and removal of volatiles are continued until substantially all of the TBO has been alkylated. In certain embodiments, the method comprises the further steps of cooling the reaction mixture, and dissolving the product in a hydrocarbon solvent.

EXAMPLES

Exam

A mixture of l,4,9-triazabicyclo[4.4.0]dec-9-ene (TBD; lOO.Og, 0.719 mol) and dimethyl carbonate (DMC; 500 mL, 5.9 mol) were charged into a 1L three-necked reaction vessel. The vessel was equipped with a mechanical paddle stirrer, a thermometer, and a six inch long vacuum-jacketed Vigreux column surmounted with a water-cooled distillation apparatus. The otherwise sealed reaction vessel was connected, via the distillation apparatus, to a bubbler to monitor gas evolution. Using a thermostated oil- bath, the charged vessel was carefully warmed to an internal temperature of 97-98°C over about 30 min. During the warming, gas evolution started and eventually solution boiling began. Over the next thirty minutes of the process, steady gas evolution was evident and liquid began to distill out of the reaction mixture; the distillate vapor temperature eventually rose to 70-75°C, then slowly fell. The heating, with concommitant gas evolution and distillation, was continued for a total of seven hours. The reaction mixture was then cooled to ambient temperature, then treated with 25g diatomaceous earth and concentrated in vacuo on a rotary evaporator. Two portions of heptanes (250mL) were sequentially added and distilled off. The residual material was sequentially triturated with three portions of heptanes (350 mL). After each trituration the organic layer was decanted and filtered through a pad of diatomaceous earth. The filtered trituration solutions were combined and concentrated in vacuo on a rotatory evaporator (finally to 40-50°C < 700 torr) to provide the desired product (MTBD) as a pale yellow oil (97.3 g; 88.4%). This material displayed NMR signals consistent with substantially pure product.

Example 2: Preparation of 1-Ethyl-l ,4,9-Triazabicyclo[4.4.0] dec-9-ene

A mixture of l,4,9-triazabicyclo[4.4.0]dec-9-ene (TBD; 5.00g, 35.9 mmol) and diethyl carbonate (DEC; 25 mL, 206.6 mmol), were heated at 130°C under a Dean-Stark trap for ca. 18h. Gas evolution was noted during the heating and a small amount of volatile liquid was collected in the trap. The resultant mixture was concentrated in vacuo on a rotary evaporator to provide a semi-solid mass. This mass was suspended in minimal xylenes and filtered. The solids were washed with a small amount of xylenes. The combined filtrate and wash were concentrated in vacuo to a pale yellow liquid (6.77g). This material displayed NMR signals consistent with the desired product contaminated with xylenes.

Example 3: Preparation of 1-allyl-l ,4,9-Triazabicycio[4.4.0] 'dec-9-ene A sample of l,4,9-triazabicyclo[4.4.0]dec-9-ene (TBD; 5.00g, 35.9 mmol) is treated under the conditions of example 1, except diallyl carbonate is substituted for diethyl carbonate.

Example 4: Preparation of l-methyl-l,4,6-triazabicyclo[3.3.0]oct-4-ene (Methyl TBOyrhe reaction is performed under the conditions of Example 1, substituting 1,4,6- triazabicyclo3.3.0oct-4-ene (TBO) for TBD.

OTHER EMBODIMENTS

The foregoing has been a description of certain non-limiting embodiments of the invention. Accordingly, it is to be understood that the embodiments of the invention herein described are merely illustrative of the application of the principles of the invention. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims, which themselves recite those features regarded as essential to the invention.