FUNCTIONALIZING ORGANIC COMPOUNDS

Field of the Invention

The present invention relates to the field of reactive organometallic adducts for making functionalized organic compounds.

Background of the Invention

Organometallic reagents are of increasing importance in organic chemistry especially for the synthesis of pharmaceutical drugs as well as organic materials. Since organomagnesium and organolithium reagents possess an unnecessary high reactivity, organic chemists focused during the last decades on more selective organometallic reagents such as zinc, silicon, tin and boron derived compounds in order to achieve higher tolerance towards a wide range of functional groups.

Among the latter, organoboron compounds have proven to be of distinguished usefulness in transition-metal catalyzed reactions. In particular, the use of organoboranes in the Pd-catalyzed Suzuki-Miyaura cross-couplings has emerged as highly practical straightforward C-C-bond formation. This reaction has been frequently applied in academic institutions and industry. Organoboron compounds such as boronic acids, boronic esters and, in particular, organotrifluoroborates have been found to have a relatively high tolerance towards functional groups and improved thermal stability. However, the direct synthesis of such compounds has been difficult, has had a low atom-economy and has required transition-metal catalyzed C-H-activation reactions. Thermal instability at ambient temperatures has remained an issue.

Moreover, the reactivity and selectivity of such organoboron compounds for the synthesis of functionalized organic compounds is currently not sufficient to reduce or eliminate costly and time-consuming purification of the resulting products. Therefore, there continues to be a need for direct, practical and inexpensive synthesis of organoborates via metalation reactions to facilitate the synthesis of functionalized organic compounds, particularly synthesis via cross-coupling reactions.

The present invention addresses this and other problems as further described below. Summary of the Invention

The present invention relates to metallic amidoborate adducts for making metalated compounds that enable a direct, practical and inexpensive functionalization of organic compounds. The metallic amidoborate adducts comprise at least one metallic cation or cationic complex and an anion comprising the moiety represented by formula (I):

(R ¹ ) ₂ N - B(R ² ) ₃ (I)

wherein

each R ¹ independently represents Z ¹ (Z ^1A ) _P - , wherein each Z ¹ and Z ^1A independently represents a carbon atom or a silicon atom and each p independently represents the integer 2 or 3 and

each R ² independently represents a fluorine atom or Z ² (Z ^2A - , wherein each Z ² independently represents a carbon atom, nitrogen atom or a silicon atom, each Z ^2A represents a hydrogen atom, a carbon atom or a silicon atom, and "k" is a positive integer equal to the valence of Z ² minus 1, wherein at least one, preferably two, and more preferably three, of the R ² substituents is/are Z ² (Z ^2A -.

The present invention also relates to a process for making metallic amidoborate adducts comprising reacting:

(A) at least one metal amide base comprising a moiety represented by formula (II):

(R ^X ) ₂ N - Met (II)

with

(B) at least one borane compound comprising a moiety represented by

formula (III):

B(R ² ) ₃ (III),

wherein R ¹ and R ² have the same meaning as defined above and Met represents at least one metallic cation or cationic complex.

The present invention also relates to methods for making a metalated organic compound comprising reacting (A) at least one organic compound with

(B) at least one of the above described metallic amidoborate adducts to form a metalated organic compound and metalated organic compounds obtainable by such methods.

Further encompassed are metalated organic compounds represented by formula

(IV):

Q(B(R ² ) ₃ · Met) _w (IV) wherein

each Q independently represents an organic compound comprising at least two carbon atoms,

each R ² and Met has the same meaning as defined above and in the detailed description of this invention, and

w represents an integer having a value of at least 1.

Furthermore, the present invention relates to methods for functionalizing organic compounds comprising reacting at least one metalated organic compound according to this invention with at least one compound comprising at least one atom, or group of atoms, that is electrophilic relative to the metalated position(s).

Further details regarding the present invention are presented in the following detailed description of the invention.

Brief description of the drawings

Fig. 1 shows the mass spectrometric analysis spectrum of a metalated 2-chloro- pyridyltrialkylborate prepared according to Example 8 of the present invention in dry tetrahydrofuran (THF) which was not previously exposed to hydrolytic conditions.

Fig. 2 shows the mass spectrometric analysis spectrum of the metalated 2- chloropyridyltrialkylborate of Fig. 1 after treating the metalated 2- chloropyridyltrialkylborate with water (50 vol%) at 25°C for one hour. Detailed Description of the Invention

Definitions of terms used herein

The abbreviations used herein are defined in the following table:

When "p" of Z ¹ (Z ^1A ) _P - is 2, this moiety has a valence of 2 and may, for example, be represented -Z ¹ (Z ^1A ) _p -. When "p" of Z ¹ (Z ^1A ) _p - represents 3, this moiety has a valence of 1.

The term "metalated" means that the compound that is the subject of this adjective is bonded, coordinated or complexed with Met.

Unless stated otherwise, the expression "hetero atoms" as used herein preferably refers to the atoms N, O, S, and P.

Preferred anions and starting materials

In the anions and metal amide bases used to make the metallic amidoborate adducts of the present invention, each R ¹ independently represents a moiety represented by the formula Z ¹ (Z ^1A ) _P - , wherein each Z ¹ and Z ^1A independently represents a carbon atom or a silicon atom and each p independently represents the integer 2 or 3. When Z ¹ is a silicon atom, Z ^1A is preferably a carbon atom. When each Z ^1A is a silicon atom, Z ¹ is preferably a carbon atom. In a preferred embodiment, Z ¹ (Z ^1A )p-, more preferably R ¹ , contains bonds selected solely from C-C bonds and C- Si bonds.

R ¹ is preferably represented by the formula (R ³ )3 _-p - Z ¹ (Z ^1A ) _P -, wherein each R ³ is independently selected from H, a methyl group, an alkyl group such as a C2-8 alkyl group, a cycloalkyl group such as a C _5- i ₀ cycloalkyl group, an aryl group such as a C _5- io aryl group, an aralkyl group such as a Ce-is aralkyl group, or a silyl group which is preferably mono-, di- or tri-substituted with a methyl group an alkyl group such as a C _2- 8 alkyl group, a cycloalkyl group such as a C _5- i ₀ cycloalkyl group, an aryl group such as a Cs-io aryl group, an aralkyl group such as a Ce-is aralkyl group or, when each R ¹ is represented by the formula (R ³ )3 _-p - Z ¹ (Z ^1A ) _P - and p represents 2, the R ³ groups of each R ¹ together form one multivalent group covalently bonded to each Z ¹ group to form a ring structure comprising the nitrogen atom displayed in the moiety represented by formula (I) above, wherein the multivalent group comprises two or more carbon atoms and, optionally, one or more nitrogen, oxygen, or sulfur atoms.

In one embodiment, the multivalent group covalently bonded to each Z ¹ group is a divalent alkylene group, such as a C2-3 alkylene group, which is optionally substituted with one or more methyl groups, alkyl groups such as C2-8 alkyl groups, cycloalkyl groups such as Cs-io cycloalkyl groups, aryl groups such as Cs-io aryl groups, aralkyl groups such as Ce-is aralkyl groups, or silyl groups mono-, di- or tri- substituted with a methyl group or an alkyl group, such as a C2-8 alkyl group. In a preferred embodiment, the multivalent group is ethylene, propylene or isopropylene, more preferably propylene.

Each Z ^1A of R ¹ is preferably independently a methyl group, an alkyl group, such as a C2-8 alkyl group, a cycloalkyl group, such as a Cs-io cycloalkyl group, an aryl group, such as a Cs-io aryl group, an aralkyl group, such as a Ce-is aralkyl group, or a silyl group tri-substituted with a methyl group or an alkyl group, such as a C2-8 alkyl group. In a preferred embodiment, each Z ^1A group is a methyl group.

In a particularly preferred embodiment, each and every Z ^1A and R ³ of R ¹ represents a methyl group. When Z ¹ is a carbon atom, R ³ is preferably a hydrogen atom, so that R ¹ preferably represents zPr, for example. When Z ¹ is a silicon atom, R ³ is preferably a methyl group, so that R ¹ preferably represents a trimethylsilyl group, for example.

In the anions and the borane compounds used to make the metallic amidoborate adducts of the present invention, each R ² independently represents a fluorine atom or Z ² (Z ^2A )k-, wherein each Z ² independently represents a carbon atom, nitrogen atom or a silicon atom, each Z ^2A represents a hydrogen atom, a fluorine atom, a carbon atom or a silicon atom, and "k" represents an integer equal to the valence of Z ² minus 1, wherein at least one, preferably two, and more preferably three, of the R ² substituents is/are Z ² (Z ^2A ) _k -.

In a preferred embodiment, each Z ² (Z ^2A )k- independently represents

Z ² (Z ^2A (R ^2A ) ₃ ) _k -, wherein Z ² and "k" have the same meaning as in Z ² (Z ^2A ) _k -, Z ^2A represents a carbon or silicon atom, and each R ^2A independently represents an hydrogen atom, a fluorine atom, a carbon atom, a nitrogen atom, or silicon atom. In

2 2A 2A 2 2A 2

one embondiment, Z (Z (R ) ₃ )k-, Z (Z and/or R , contains bonds selected solely from C-C bonds, C-N bonds and C-Si bonds.

In a further preferred embodiment, at least one, preferably two, and most preferably three, Z ² (Z ^2A - independently represent(s) a methyl group; an alkyl group, such as a C2-8 alkyl group; a cycloalkyl group, such as a Cs-io cycloalkyl group; an aryl group, such as a Cs-io aryl group; an aralkyl group, such as a Ce-is aralkyl group; a silyl group; -N(R ⁴ )2 wherein each R ⁴ independently represents -C(Z ^3A ) ₃ , wherein Z ^3A represents a hydrogen atom, a carbon atom or a silicon atom or the two R ⁴ groups are j oined to each other to form a divalent group attached to the nitrogen atom of -N(R ⁴ ) ₂ to form a nitrogen-containing ring structure, wherein the divalent group preferably comprises two or more carbon atoms and, optionally, one or more hetero atoms preferably selected from nitrogen atoms, oxygen atoms, sulfur atoms, or silicon atoms, wherein the R ² and R ⁴ groups may optionally be substituted with one or more methyl groups, alkyl groups such as C2-8 alkyl groups; cycloalkyl groups such as Cs-io cycloalkyl groups; aryl groups such as Cs-io aryl groups; aralkyl groups such as Ce-is aralkyl groups; silyl groups and/or fluorine atoms. Each R ⁴ preferably independently represents any one of the R ¹ and R ² groups as previously defined other than -N(R ⁴ )2. In a preferred embodiment, no more than one R ² substituent is a fluorine atom. In a more preferred embodiment, none of the R ² substituents is a fluorine atom. In an even more preferred embodiment, no more than two, more preferably no more than one, and even more preferably none, of the R ² substituents are halogen atoms.

In a preferred embodiment, at least one, preferably at least two, and more preferably at least three, R ² substituent(s) represent Me, Et, zPr, nBu, sBu, tBu, c- hexyl, Ph, HMDS, -Nz ^' Pr ₂ , N-pyrrolidyl, and N-piperidinyl, which may optionally be substituted with one or more fluorine atoms. The N-pyrrolidyl, and N-piperidinyl may also be optionally substituted with one or more groups comprising one or more carbon atoms and, optionally, one or more hetero atoms preferably selected from nitrogen atoms, oxygen atoms, sulfur atoms, or silicon atoms, such as Me, methoxy, methoxymethylene, Et, ethoxy, ethoxyethylene, zPr, «Bu, sBu, tBu, ohexyl, Ph, HMDS, and -Nz ^' Pr ₂ . Particularly preferred R ² substituents are those having at least 2 carbon atoms up to 6, more preferably up to 4, carbon atoms. The R ² substituents are preferably alkyl groups, such as Et and sBu.

In another preferred embodiment, all the hydrogen atoms of R ² are replaced by fluorine atoms. In a particularly preferred embodiment, R ² is an aryl ring, more preferably a phenyl ring, fully substituted by fluorine atoms (e.g., -CeF ₅ ).

Met is preferably selected from the group consisting of Li, MgX, Na, ZnX, CaX, A1X ₂ , MnX _q , FeX _r , CuX _s , LaX ₂ or ZrX ₃ , or a mixture thereof, wherein X represents CI, Br or I and p, q, and r represent the number of "X" atoms. The number of "X" atoms is less than the valence of the metal atom with which it is associated, so that the metal complex has a positive (i.e., cationic) charge. Each of the values of "q", "r", and "s" are therefore an integer that is equal to the valence of the corresponding metal atom Mn, Fe and Cu, respectively, minus 1. The value of "q" and "r" is therefore preferably 1 or 2 and the value of "s" is therefore preferably zero or 1, the selection of each depending on the valence of Mn, Fe and Cu, respectively. MgCl is preferred.

In addition to Met, other metals, such as Li, and metal complexes, such as LiCl, may be present with the metal amide base and the metalated compounds made with those bases. When LiCl is present, MgCl is preferably present as well.

Particularly preferred metal amide bases of Formula (II) for making the amidoborate bases according to the invention described herein include: Li or MgX or Na or

CaX or AIX ₂ or

MnX-|/ ₂ or FeX-|/ ₂ or Na, Li, K, MgX

CuX ₀ /i or LaX ₂ or (with or without LiCI)

ZrX ₃

(with and without LiCI) H, alkyl, aryl, heteroaryl, alkenyl

R1 = H, alkyl, aryl, heteroaryl,

alkenyl, cycloalkyl

Specific examples of suitable metal amides include lithium diisopropylamide, magnesium chloride diisopropylamide, tmpLi, tmpMgCl LiCl, LiHMDS,

CIMgHMDS, and

\ ^{1 1} /

N

I I

Li or MgCI Li or MgCI or ZnCI Na, Li, K, MgCI

(with and without LiCI) (with and without LiCI)

diisopropylamide hexamethyldisilazide

2,2,6,6-tetramethylpiperidyl

The above metal amides are either commercially available or may be prepared by the skilled chemist without undue effort. The metal amides tmpMgCl LiCl, LiHMDS and zPr ₂ NLi are commercially available from sources such as Sigma Aldrich and Acros Organics. The following table provides examples of citations describing procedures for making additional metal amides. The citations are incorporated herein by reference for their relevant disclosure.

Metal Amide Citation

"Carbene generation by a-elimination with lithium 2,2,6,6- tetramethylpiperidide: l-ethoxy-2-p-tolylcyclopropane",

tmpLi

ORGANIC SYNTHESES (1978), 58, No pp. given. Publisher:

(John Wiley&Sons, Inc., )

"Silylamino-substituted Grignard compounds",

(HMDS)MgCl

ANGEWANDTE CHEMIE (1963), 75, (1), 95

"New mixed Li/Mg/Zn Amides for the Chemoselective

zPr ₂ NMgCl LiCl Metallation of Arenes and Heteroarenes", EUR. J. ORG.

CHEM. (2009), 1781-1795

"Magnesium amide bases and amido-Grignards. 1. Ortho zPr ₂ NMgX magnesiation", JOURNAL OF THE AMERICAN CHEMICAL

SOCIETY (1989), 111, (20), 8016-18

Particularly preferred borane compounds of Formula (III) for making the

amidoborate bases according to the invention described herein include:

R = H, alkyl, aryl, heteroaryl, R = H, halogen, alkyl, aryl, heteroaryl,

alkenyl, cycloalkyl alkenyl, cycloalkyl,

R = H, halogen, alkyl, aryl, heteroaryl, R = H, halogen, alkyl, aryl, heteroaryl, alkenyl, cycloalkyl, alkenyl, cycloalkyl,

Specific examples of suitable borane compounds include BMe ₃ (la), BEt ₃ (lb),

BzPr ₃ (lc), B«Bu3 (Id), BsBu ₃ (le), B^Bu ₃ (If), BcHex ₃ (lg), BPh ₃ (lh), B(C ₆ F ₅ ) ₃ (li),

2) ₃ (lj), FB(HMDS) ₂ (lk), and

R = Me, Et, iPr, sBu, tBu, nBu, cycHex, Ph

The above borane compounds are either commercially available or may be prepared by the skilled chemist without undue effort. The following table provides examples of citations to procedures for making additional metal amides. The citations below are incorporated herein by reference for their relevant disclosure.

The metal amidoborate base obtained by reacting the metal amide and the borane compound preferably have a decomposition temperature greater than 30°C.

Preferred process conditions for making the metal amidoborate bases

The reaction between the metal amide and the borane compound is preferably conducted at a temperature in the range from 25°C up to, but not including, the decomposition temperature of the reactant having the lowest decomposition temperature.

The reaction is generally conducted under the exclusion of oxygen or air in an inert nonprotic solvent under an inert atmosphere, such as argon gas, until conversion of at least one starting material is complete. Suitable inert nonprotic solvents include, but are not limited to, cyclic ethers, such as THF and Me-THF, aliphatic ethers, such as dimethoxyethane, toluene, benzene, dimethylsulfoxide, dimethylformamide, dichloromethane, tetrachloromethane, hexachloromethane, and acetonitrile. The cyclic and aliphatic ethers are preferred. THF and Me-THF are particularly preferred solvents.

This reaction should be carried out in the substantial absence of protic solvents, such as water. The reaction vessel, reactants and solvent should be dried or distilled before use to ensure that water is not present during the reaction.

Preparation of metalated organic compounds using the metal amidoborate bases

The metal amidoborate bases described above may be reacted with a substrate to form a metalated organic compound. The substrate is an organic compound having at least one C-H bond. The organic compound preferably comprises at least one ring comprising at least one carbon atom having at least one C-H bond and, optionally, one or more hetero atoms as ring members. The ring may be substituted or unsubstituted, saturated or unsaturated, carbocyclic or heterocyclic ring or ring structure. The ring structure may comprise multiple rings that may be fused or non-fused.

The rings and ring systems preferably comprise unsaturated rings. The unsaturated rings are preferably carbocyclic or heterocyclic aryl or aralkyl rings. The carbocyclic aromatic ring is preferably optionally substituted Ph, more preferably substituted Ph. The carbocyclic aromatic ring system is preferably a naphthalene ring system. The heterocyclic and carbocyclic aryl or aralkyl rings are further described below.

When the ring or ring system is substituted, the substituents are preferably halogen atoms F, CI, Br, or I), nitro groups, sulfoxy groups, ether groups, thioether groups, and ester groups, methyl groups, alkyl goups, an alkyl group such as a C2-8 alkyl group, a cycloalkyl group such as a Cs-io cycloalkyl group, an aryl group such as a Cs-io aryl group, an aralkyl group such as a C6-is aralkyl group, or a silyl group which is preferably mono-, di- or tri-substituted with a methyl group an alkyl group such as a C2-8 alkyl group, a cycloalkyl group such as a Cs-io cycloalkyl group, an aryl group such as a Cs-io aryl group, and an aralkyl group such as a C6-is aralkyl group.

In a preferred embodiment, each substituent independently represents an electronegative group, such as a halogen atom or an aromatic ring or ring system. The halogen atoms are preferably selected from F, CI, Br and I. The ring preferably comprises 1, 2, or 3 hetero atoms as ring members. The hetero atoms are preferably selected from N, S, and O. The ring preferably comprises at least one nitrogen atom as a ring-member. Examples include the organic compounds used as substrates in the examples which follow.

The reaction conditions, such as solvent and temperature conditions, are substantially the same as those used to prepare the metal amidoborate bases.

The reaction is conducted at a temperature in the ranges previously specified for making the metal amidoborate bases, except that the decomposition temperature below which the reaction should be conducted is now the decomposition temperature of the metal amidoborate base or the metalated organic compound, whichever is lower. The decomposition temperature is often greater than the lowest decomposition temperature for making the metal amidoborate bases. It is preferably at least 30°C, more preferably at least 40°C, so that the reaction may preferably be conducted at room temperature (25°C).

The reaction proceeds rapidly, so that the reaction time may be less than one hour, preferably less than half an hour, when conducting the reaction as a batch. The amidoborate bases zPr ₂ NBEt ₃ MgCl LiCl, zPr ₂ NBEt ₃ MgCl and zPr ₂ NBsBu ₃ MgCl were found to be particularly suitable.

The result is a substitution of the metalated borate on the substrate which may be represented by formula (IV):

Q(B(R ² ) ₃ · Met) _w (IV)

wherein each Q independently represents a substrate as defined above covalently bonded to each boron atom via a C-B bond, R ² and Met have the same meanings as defined above, and w represents an integer having a value of at least 1. The value of w is preferably not greater than 3, more preferably not greater than 2, and even more preferably 1.

In a preferred embodiment, Q comprises 5 to 7 ring members, more preferably 6 ring members, not including atoms in a fused ring system outside each heterocyclic ring Q. The ring members preferably comprise at least four carbon atoms. The ring members preferably comprise up to three, more preferably up to two, and yet more preferably one, nitrogen atom. The heterocyclic ring may comprise other hetero atoms, such as oxygen or sulfur atoms. The heterocyclic ring preferably comprises solely carbon atoms and one or more nitrogen atoms.

When the substrate has a structure that allows for determining regioselectivity of the substitution, the substitution may be regioselective. Regioselectivity may be determined when, for example, at least one heterocyclic ring has at least one nonreactive electronegative substituent, such as a halogen atom or an aromatic ring, and/or at least one heterocyclic ring is part of a fused ring system. The

regioselectivity is preferably at least greater than 95: 1, more preferably at least greater than 99: 1, based on GC-analysis of iodolyzed reaction aliquots relative to the total yield of metalated organic compound.

Compounds 5a to 5w in Tables 2A to 2D of Example 4 below are illustrative examples of metalated organic compounds prepared according to this invention.

Preparation of functionalized compounds using the metalated organic compounds

Various types of reactions, such as Pd-catalyzed cross-couplings, copper- catalyzed acylation and allylation reactions, may be conducted using the metalated organic compounds described above. Regioselectivity achieved in preparing the metalated organic compounds is generally reflected in the functionalized compounds made with the metalated organic compounds.

To functionalize the metalated organoborate compound, the metalated organoborate compound is reacted with an electrophile, E ⁺ , which is a compound comprising an electrophilic atom or group with respect to the nucleophilic organoborate. Electrophilic atom such as CI, Br, and I, are preferred. The compound may, for example, be X ₂ , wherein X represents CI, Br, or I.

In a preferred embodiment, the electrophile, E, is an organic compound having a halogen or a nucleophilic leaving group substituent. Each nucleophilic leaving group is preferably selected from the group consisting

of -OS(0) ₂ -R ^A , -N=N-R ^B , -OP(0)(OR ^c ) ₂ , -OC(0)R ^D , -SR ^E , and -N(R ^F ) ₃ R ^G , wherein R ^A , R ^c , R ^D , R ^E , and R ^F each independently represents an hydrocarbyl group or a fluorocarbyl group, wherein the hydrocarbyl or fluorocarbyl group preferably has

B G

from 1 up to 10, preferably up to 7, carbon atoms, and R and R each represent BF ₄ . Preferred hydrocarbyl groups include methyl, branched-chain and straight-chain aliphatic hydrocarbons such as ethyl, propyl, isopropyl, w-butyl, sec -butyl and /-butyl, and aromatic hydrocarbons such as phenyl and benzyl. Preferred fluorocarbyl groups include -(CF ₂ ) _m CF ₃ , wherein "m" represents an integer in the range from zero to 4 and fluorinated aryl groups, such as fluorinated benzyl groups.

Preferred nucleophilic leaving groups include triflates (-OS(0) ₂ CF ₃ ); mesylates (-OS(0) ₂ CH ₃ ); nonaflates (-OS(0)2(CF ₂ )3CF ₃ ); tosylates (-OS(0) ₂ C ₆ H5CH ₃ );

diazonium salts such as ArN ₂ BF ₄ , wherein Ar represents an aryl group such as phenyl, benzyl, tolyl, xylyl, or naphthyl; acetate; pivalate; thiomethyl; and thioaryl, such as thiobenzyl.

Preferred organic compounds may be represented by formula (V):

R ⁵ L _j (V)

wherein

R ⁵ represents an organic residue comprising one or more carbon atoms and, optionally, one or more hetero atoms;

L represents CI, Br, I, or a nucleophilic leaving group; and

"j" represents an integer in the range from 1 up to 10, preferably up to 4, more preferably up to 2, and even more preferably up to 1.

The organic residue, R ⁵ , preferably does not comprise protonated hetero atoms such as, for example, OH, NH, or SH and preferably comprises one or more cyclic groups and/or one or more aliphatic groups.

The cyclic groups may comprise carbocyclic groups, such as cycloalkyl groups and aryl groups, and heterocyclic groups, such as heteroaryl groups and partially or fully saturated heterocyclic compounds. Preferred cyclic groups have at least 4, more preferably at least 5, and even more preferably at least 6, up to 20, more preferably up to 15, and even more preferably up to 10, carbon atoms and optionally from 1 preferably up to a number of hetero atoms equal to the number of carbon atoms in the cyclic group. The heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S. The cyclic group may comprise a monocyclic or polycyclic ring system. The polycyclic ring system may comprise fused ring systems, bridged ring systems and rings having one atom in common. Preferred carbocyclic groups are aryl cycloalkyl groups,and cycloalkenyl groups, such as phenyl groups, napththalene rings, cyclohexyl groups, cyclohexenyl groups, cyclopentyl groups, cyclopentenyl groups, etc.

Preferred heterocyclic groups include heteroaryl groups having 5, 6, or 7 ring members and 1, 2, or 3 hetero atoms. Examples of heterocyclic groups containing one or more nitrogen atoms as ring members include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, isoxazolyl, furazanyl, pyridinyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, morpholinyl or mo holino, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalizinyl, naphthyridinyl, carbazolyl, phenazinyl, phenanthradinyl, acridinyl, phenothiazinyl, perimidinyl, phenanthrolinyl, and phenoxazinyl. Examples of oxygen-containing heterocyclic groups other than those previously mentioned among nitrogen atom-containing heterocyclic groups include furyl, pyranyl, isobenzofuranyl, chromenyl, chromanyl, iaochromanyl, and xanthenyl.

The aliphatic group preferably comprises at least 2, more preferably at least 3, and even more preferably at least 4, up to 20, more preferably up to 12, and even more preferably up to 8, and even more preferably up to 6, carbon atoms. The aliphatic group may be straight-chained or branched, may comprise one or more heteroatoms representing up to half, more preferably up to one-fourth, the total number of atoms in the aliphatic group, and may comprise one or more unsaturated bonds. The heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S. The unsaturated bonds are preferably double bonds and triple bonds. Preferred aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups. The aliphatic groups are preferably saturated (i.e., do not contain unsaturated bonds).

In a preferred embodiment, the electrophile may be represented by the formula:

R ⁵ -C(Y)-Lj (VI)

wherein R ⁵ , L and "j" have the same meaning, including preferred meanings, as defined above in Formula (V) and Y represents O or S.

Preferred substituents also include fluorine atoms and nonprotic functional groups. The substituents may include halogen atoms that are less electrophilic than the L group(s), nitro groups, sulfoxy groups, ether groups, thioether groups, acyl groups, and ester groups.

Preferred functional group substituents are nitrile, nitro, ester, amide, protected alcohol, protected amine and protected amide. The ester group is preferably represented by the formula -C(0)OR ⁶ , wherein R ⁶ is an organic moiety, which may be selected from a wide range of moieties having at least 1, preferably at least 2, more preferably at least 3, and even more preferably at least 4 up to 15, more preferably up to 10, and even more preferably up to 8, carbon atoms and, optionally, one or more hetero atoms. R ⁶ is preferably selected from a methyl group, an alkyl group, such as a C _2- 8 alkyl group, a cycloalkyl group, such as a C _5- i ₀ cycloalkyl group, an aryl group, such as a Cs-io aryl group, an aralkyl group, such as a Ce-is aralkyl group, or a silyl group tri-substituted with a methyl group or an alkyl group, such as a C2-8 alkyl group.

Protected alcohol, protected amine and protected amide are alcohol, amine and amide groups in which each proton bonded to an oxygen atom or nitrogen atom has been replaced with a group that is less reactive than the proton and yet capable of being removed to permit reactions to take place on the respective groups. Suitable protecting groups for those functionalities are well known in the state of the art. A description of suitable protective groups is provided, for example, in "Protective groups in organic synthesis" T. W. Greene, P. G. M: Wuts, Wiley. An example is TIPS to protect alcoholic and phenolic OH groups.

When the electrophile is X ₂ , the reaction is generally sufficiently

thermodynamically favored to proceed quickly (e.g., at least 70 percent yield within 1 hour) under mild conditions (e.g., at 25°C) without the aid of a catalyst.

When the electrophile, E ⁺ , is not a halogen molecule, but rather an organic compound having a halogen substituent, such as a compound represented by formula (V), it is often desirable to promote the reaction using a catalyst. Catalysts appropriate for conducting nucleophilic-electrophilic cross-coupling, acylation, or allylation are well-known in the organic chemistry literature. Examples include Pd- catalyzed Suzuki cross-coupling and Cu-catalyzed acylation.

In the case of Pd-catalyzed cross-coupling reactions, the Pd is preferably complexed with dba.

Functionalization may be illustrated by the following example:

> 95 % 6a-h: 73-82%

As can be seen from this example, a N-heterocyclic compound is metalated with a metallic amidoborate base described herein to form a metallic organoborate base having a -BR ² ₃ ^» Met group derived from the metallic amidoborate base. When the electrophile E is reacted with the metallic organoborate base, the -BR ² ₃ ^» Met group on the metallic organoborate base is replaced by the electrophile E ⁺ .

Examples of electrophile residues, E, s after attachment to a substrate include:

cross-coupling acylation allylation cross-coupling acylation iodolysis electrophile reaction reaction electrophile reaction _W jth

(Pd-catalyzed) (Cu-catalyzed) (Cu-catalyzed) (Pd-catalyzed) (Cu-catalyzed) iodine In contrast to prior known processes, the method described herein may be used to acylate an organic compound, serving as the substrate, with an aldehyde group in the absence of a transition metal catalyst.

The invention described herein is further described with reference to the following examples. The examples are for illustration only. They are not to be interpreted as restricting the scope of the invention as described herein.

EXAMPLES

In the following examples, the chemical reactions were carried out under argon atmosphere in flame-dried glassware. Syringes which were used to transfer anhydrous solvents or reagents were purged with argon prior to use. THF were continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen.

Diethyl ether was predried over calcium hydride and dried with the solvent

purification system SPS-400-2 from INNOVATIVE TECHNOLOGIES, INC.

(Al ₂ 03,l-3 mm, ICN, Eschwege, Germany). TMPH, liquid acid chlorides and

BF ₃ OEt ₂ were distilled prior to use under argon. Example 1: Procedure for the preparation of (iPr ₂ N)BEt ₃ MgCl LiCl (2k)

At -20 °C, BEt ₃ (50.0 mmol, 4.89 g) was added dropwise to a solution of zPr ₂ NMgCl LiCl (50.0 mmol, 0.94 M in THF, 50.3 mL). After addition, the mixture was allowed to slowly warm to 25°C while continuously stirring the reaction mixture for 30 minutes. Subsequently, zPr ₂ NBEt ₃ MgCl LiCl was titrated at 0°C with benzoic acid and 4-(phenylazo)-diphenylamine affording a concentration of 0.70 M (zPr ₂ N)BEt ₃ MgCl LiCl (2k) in THF.

Example 2: Procedure for the preparation of tmpBEt ₃ *MgCl-LiCl (2b)

At -20 °C, BEt ₃ (50 mmol, 4.89 g) was added dropwise to a solution of tmpMgCl LiCl (50 mmol, 1.1 M in THF, 50 mL). After addition, the mixture was allowed to slowly warm to 25 °C and continuously stirred for 30 min. Subsequently, tmpBEtrMgCl LiCl was efficiently titrated at 0 °C with benzoic acid and 4- (phenylazo)-diphenylamine affording a concentration of 1.0 M tmpBEt ₃ MgCl LiCl (2b) in THF. Example 3: Preparation of additional metal amide derived borate bases

Analogous to Examples 1 and 2, additional metal amide derived borate bases 2a, 2c to 2j, and 21 to 2w were prepared in accordance with Scheme 1.

Scheme 1. Preparation of metal amide derived borate bases:

BR ³ R ⁴ 2

1a-k

(R ² )(R ¹ )N— et (R ² )(R )N— BR ³ R ⁴ ₂ -Met

-20 °C to 25 °C

3a-g 2a -w

R ¹ , R ² = CMe2-(CH ₂ )3-CMe _2i Si(Me ₃ ), / ^' Pr

R ³ , R ⁴ = Me, Et, / ^' Pr, nBu, sBu, fBu, cHex, Ph, N/ ^' Pr ₂ N(SiMe ₃ ) ₂ F Met = Li, MgX, Na, ZnX The designation of variables in Scheme 1 for the metal amide derived borate bases 2a to 2w are independent of the designations for the corresponding variables in the generic description of the invention. The R group and Met designations provided below in Tables 1A and IB correspond to those in Scheme 1.

Table 1A: Preparation of metal amide derived borate bases 2a to 2i Designation R ¹ R ² R ³ R ⁴ Met

2a -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - Me Me MgCl-LiCl

2b -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - Et Et MgCl-LiCl

2c -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - zPr zPr MgCl-LiCl

2d -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - «Bu «Bu MgCl-LiCl

2e -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - 5Bu sBu MgCl-LiCl

2f -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - /Bu /Bu MgCl-LiCl

2g -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - c-hexyl c-hexyl MgCl-LiCl

2h -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - Ph Ph MgCl-LiCl

2i -SiMe ₃ -SiMe ₃ Et Et Na

Table IB: Preparation of metal amide derived borate bases 2j to 2w

Designation R ¹ R ² R ³ R ⁴ Met

2j zPr zPr Et Et Li

2k zPr zPr Et Et MgCl-LiCl

21 -SiMe ₃ -SiMe ₃ Et Et Li

2m zPr zPr Et Et MgCl ₂ ^« LiCl

2n zPr zPr sBu sBu MgCl-LiCl

2o zPr zPr sBu sBu MgCl

2p -SiMe ₃ -SiMe ₃ Et Et MgCl-LiCl

2q -SiMe ₃ -SiMe ₃ F HMDS MgCl-LiCl

2r -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - -NiPr ₂ -NiPr ₂ MgCl-LiCl

2s -CMe ₂ -(CH ₂ ) ₃ -CMe ₂ - MgCl-LiCl

2t -SiMe ₃ -SiMe ₃ F HMDS Li

2u -SiMe ₃ -SiMe ₃ F HMDS MgCl-LiCl

2v zPr zPr -NiPr ₂ -NiPr ₂ Li

2w zPr zPr -NiPr ₂ -NiPr ₂ MgCl-LiCl

In contrast to the frustrated Lewis pair adducts derived from metal amides and BF ₃ OEt ₂ which are only stable at low temperature (below -20 °C), the borate bases described herein display high stability towards decomposition at room temperature for at least several weeks without loss of reactivity or significant decrease in

concentration.

Example 4: Reactivity of borate bases 2a to 2w In order to investigate the reactivity of the generated borate bases (2a-w),

3-halopyridines (4) were used as test-substrates for regioselective metalation reactions with tmp-derived borate bases affording organoboron compounds of type 5 (Scheme 2).

Scheme 2: Reaction for the determination of the rate of metalation

The results are shown in Tables 2A to 2D. Bases 2a to 2w correspond to the bases 2a to 2w according to Table 1. The variable "X" of Scheme 2 is CI in entries 1- 9 and 13-18. For the remainder of the entries, "X" of Scheme 2 is I. The products in the last column of Tables 2A to 2D were detected using gas chromatography analysis of quenched reaction aliquots.

Table 2 A: Reactivit of the borate bases 2a to 2d

5a tmpBEt

5b

B/PryMgCI LiCI tmpB/ ^' Pr ₃ MgCI LiCI

0.47 25 0.16

2c

5c

5d

Table 2B. Reactivit of the borate bases 2e to 21

5e tmpBfBu

5f

BcHex ₃ MgCILiCI CI

tmpBcHex ₃ MgCILiCI

0.45 25

2g

5g tmpBPh

5h

HMD

5i

5j

BEt ₃ MgCILiCI .Br

/Pr ₂ NBEt ₃ MgCI

11 0.70 25 0.25

2k

5k

5I

Table 2C. Reactivity of the borate bases 2m to 2t

5m

5n

5o

tmpB(F)(HMDS) ₂ MgCILiCI

BF(HMDS) ₂ MgCILiCI 2q 5q ci

tmpB(N/Pr ₂ ) ₃ MgCILiCI

1.07 25 0.25 N B(N/Pr ₂ ) ₃ MgCILiCI

2r

5r

OMe

CI

tmpB-^N I ) MgCI LiCI 0.84 25 0.25 ^" N B(S-Prol) ₃ MgCILiCI

5s

2s

Table 2D. Reactivity of the borate bases 2u to 2w

Br

(/Pr ₂ N) ₄ BMgCILiCI

20 0.78 25 ^" N B(N/ ^" Pr ₂ ) ₃ MgCILiCI

2w

5w

As one can see from Tables 2A to 2D, the 3-halopyridines were metalated in position 4, which indicates the existence of a borate as the reactive metalating species (Tables 2A to 2C, entries 1-15) due to the fact that the magnesiation of 3- halopyridines with tmpMgCl LiCl produces the metallic organoborate species in position 2. However, 3-halopyridines are metalated by tmp-amidoborate magnesium chlorides in position 2 as well (Tables 2C to 2D, entries 16-20).

Example 5: Reactivity of metallic amidoborate adducts with and without LiCl

In addition, the influence of lithium chloride in solution was examined which is generally considered to be an important contributor to the good solubility properties of state of the art metal amide bases. Thus, the borate bases 2n and 2o derived from tri-(sec-butyl)-borane (le) were generated and reacted with 3-chloropyridine (4a) affording metalation in position 4 in both cases with the same reaction rates (Scheme

3).

Scheme 3. Functionalization of N-heterocycles via direct C-H activation using tmp- derived boron bases with and without LiCl.

5o: conv. >90%

These results indicate that lithium chloride additive is dispensable, which is contrary to the expectations of those skilled in this field of chemistry. Example 6: Procedure for the preparation of 4-isoquinolin-l-ylbenzonitrile (6k)

To a solution of isoquinoline (258 mg, 2.0 mmol) in THF (2 mL) in a flame- dried and argon-flushed 25 mL-Schlenk-tube equipped with septum and magnetic stirring bar, zPr ₂ NBEt ₃ MgCl LiCl (2.2 mL, 1.01 M in THF, 2.2 mmol 2k) was added dropwise at 25°C. After stirring for 15 minutes and addition of ZnCl ₂ (0.2 mL, 1 M in THF, 10 mol%), the solution containing the organoborate product was added dropwise at 25°C to a solution of Pd(dba) ₂ (22 mg, 2 mol%), P(2-furyl) ₃ (9 mg, 4 mol%) and 4-bromobenzonitrile (291 mg, 1.6 mmol) in THF (2 mL).

The reaction solution was stirred for 12 h at 50°C and subsequently diluted with diethyl ether (5 mL). Thereafter, the reaction mixture was quenched with brine (5 mL) and 2 M aqueous NH ₃ (2 mL). The aqueous layer was extracted with EtOAc (3x 10 mL). Subsequently, the combined organic phases were dried over Na2SC>4, the solvent was evaporated under vacuum and the residue was subjected to flash column chromatography (pentane/EtOAc = 9: 1 with 0.5% NEt ₃ ) affording 6k (291 mg, 79%) as a pale yellow solid. Example 7: Functionalization of N-heterocycles using tmp-derived borate bases

In order to demonstrate the synthetic potential of the borate reagents, tmp- derived bases of the type tmpBR ² ₃ · MgCl (type 3) were utilized for the preparation of organoborates via C-H activations and subsequent functionalizations (Scheme 4).

Scheme 4 tmpBR ² ₃ MgCI LiCI (3)

> 95 % 6a-g: 73-82%

The abbreviation E represents the positively charged synthon reacting with the nucleophilic organoborate affording a neutral product. In other words, E ⁺ defines the carbon- or halogen-based electrophile for C-C- or C-Hal-bond forming reactions.

The metallic organoborate bases were reacted with substituted or unsubstituted N-heterocycles generating the corresponding heteroarylborates which subsequently were trapped with various electrophiles (Table 3).

Table 3: Functionalization of N-heterocycles using tmp-derived borate bases

T t Electrophile

Entry Substrate Base Product : Yield (%)

CC) (h) E ⁺

6a" : 77

6b° : 79

6c" : 78

3b 25 0.05 I2 6g ^a : 81 In each of the examples in Table 3, the substrate is reacted with the base in THF to form a metallic organoborate intermediate under the temperature and time conditions specified in Table 3. The metallic organoborate intermediate is then reacted with the electrophile, E, in THF to form the functionalized products 6a to 6g under the following conditions:

[a] Product 6g is obtained via iodolysis of the metallic organoborate intermediate.

[b] Products 6a and 6d are obtained by cross-coupling the metallic organoborate intermediate with ZnC^ (10 mol%) ) at a temperature of 25°C for 10 minutes followed by reacting the product of the cross-coupling reaction with Ar-I (0.8 equiv) in the presence of Pd(dba) ₂ (2 mol%), P(2-furyl) ₃ (4 mol%) at 25°C for 12 hours.

[c] Products 6b and 6f are obtained by acylating the metallic organoborate

intermediate by reacting the metallic organoborate intermediate with ZnC (1 equiv) at a temperature of 25°C for 10 minutes followed by reacting the product of that reaction with CuCN 2LiCl (10 mol%, -40°C, 10 min) and addition of 2-bromobenzoyl chloride (0.8 equiv) at -40°C and slowly warming to 25°C with continuous stirring for 4 hours.

[d] Products 6c and 6e are obtained by allylating the metallic organoborate

intermediate with CuCN 2LiCl (10 mol%) and 3-bromocyclohexene (0.8 equiv) at 25°C for 12 hours.

In comparison to tmp-magnesium bases, the use of trialkylborane and aminoborane derived bases is highly beneficial due to the high reaction rates obtained.

Similarly to isoquinoline, 3-chloropyridine was metalated with various tmp- derived borate bases affording the corresponding substituted pyridylborate derivatives which were further reacted in Pd-catalyzed cross-coupling, acylation or allylation reactions (Table 3, entries 3-7).

Example 8: Functionalization of carbocycles using tmp-derived borate bases

Tmp-derived bases of type 3 were utilized for the preparation of organoborates via C-H activations of carbocyclic compounds and subsequent functionalizations (Scheme 5). Scheme 5

10a- g 11a-g: 75-96%

FG = CN, OMe, CI, F, CF ₃ The metallic organoborate bases were reacted with carbocycles generating the corresponding arylborates which subsequently were trapped with various electrophiles Ar-X (Table 3A).

Table 3A: Functionalization of substituted carbocycles using tmp- BEt ₃ MgCl LiCl

10g g ^a

In each of the examples in Table 3A, the substrate is reacted with the base in THF to form a metallic organoborate intermediate under the temperature and time conditions specified in Table 3A. The metallic organoborate intermediate is then reacted with the electrophile, E, in THF to form the functionalized products lib to llg under the following conditions:

[a] Products 11a to lid and llf to llg were obtained after cross-coupling with ZnCl ₂ (10 mol%), Ar-I (0.8 equiv), Pd(OAc) ₂ (3 mol%), S-Phos (6 mol%), 1 h, 65 °C.

[b] Product lie was obtained after cross-coupling with ZnCl ₂ (10 mol%), Ar-I

(0.8 equiv), Pd(dba) ₂ (3 mol%), P(2-furyl) ₃ (6 mol%), 2 h, 65 °C. S-Phos =

2-Dicyclohexyl-phosphino-2',6'-dimethoxybiphenyl.

Thus, 3-fluorobenzonitrile (10a) was metalated using tmpBEt ₃ MgCl LiCl (2b; 25 °C, 30 min) furnishing after a Suzuki -type cross-coupling (ZnCl ₂ (10 mol%), Pd(OAc) ₂ (3 mol%), S-Phos (6 mol%), 65 °C, 1 h) with ethyl 4-iodobenzoate (12; 0.8 equiv) the functionalized biphenyl 11a in 83% yield (Table 3 A, entry 1). In particular, tmpBEtyMgCl LiCl (2.2 mL, 1.0 M in THF, 2.2 mmol) was added dropwise at 25 °C to a solution of 3-fluorobenzonitrile (10a; 242 mg, 2.0 mmol) in THF (2 mL) in a flame-dried and Argon-flushed Schlenk-tube equipped with septum and magnetic stirring bar. After stirring for 30 min at 25 °C, ZnCl ₂ (0.2 mL, 1 M in THF, 10 mol%), Pd(OAc) ₂ (14 mg, 3 mol%), S-Phos (25 mg, 6 mol%) and ethyl 4-iodobenzoate (12; 441 mg, 1.6 mmol) were added followed by continuously stirring for 1 h at 65 °C. After cooling to 25 °C, the reaction mixture was diluted with Et^O (5 mL) and quenched with sat. NH ₄ C1 (aq.) (5 mL). The aqueous layer was extracted with CH2CI2 (3x 15 mL). The combined organic phases were dried over Na2SC>4 and the solvent was removed under vacuum. Flash column chromatography (pentane-Et20, 95:5) afforded 11a (357 mg, 83%) as a pale yellow solid.

Similarly, the substituted arenes lOb-d reacted with 2b (25 °C, 0.5-12 h) affording the corresponding borate which lead after subsequent cross-coupling (ZnCl ₂ (10 mol%), Pd(OAc) ₂ (3 mol%), S-Phos (6 mol%), 65 °C, 1 h) with 12 (0.8 equiv) to the biphenyl derivatives llb-d in 75-95% yield (Table 3A, entries 2-4). For example, tmpBEtyMgCl LiCl (2.2 mL, 1.0 M in THF, 2.2 mmol) was added dropwise at 25 °C to a solution of 3,5-(trifluoromethyl)anisole (10b; 352 mg, 2.0 mmol) in THF (2 mL) in a flame-dried and Argon-flushed Schlenk-tube equipped with septum and magnetic stirring bar. After stirring for 1 h at 25 °C, ZnCl ₂ (0.2 mL, 1 M in THF, 10 mol%), Pd(OAc) ₂ (14 mg, 3 mol%), S-Phos (25 mg, 6 mol%) and ethyl 4-iodobenzoate (12; 441 mg, 1.6 mmol) were added followed by continuously stirring for 1 h at 65 °C. After cooling to 25 °C, the reaction mixture was diluted with ΕΪ2Ο (5 mL) and quenched with sat. NH ₄ C1 (aq.) (5 mL). The aqueous layer was extracted with CH2CI2 (3x 15 mL). The combined organic phases were dried over Na2SC>4 and the solvent was removed under vacuum. Flash column chromatography (pentane-Et20, 9: 1) afforded lib (492 mg, 95%) as a pale yellow solid.

Using the same amidoborate base 2b, 1,3,5-trichlorobenzene (lOe) was metalated at elevated temperature (50 °C, 1 h) providing after cross-coupling (ZnC (10 mol%), Pd(dba) ₂ (2 mol%), P(2-furyl) ₃ (4 mol%), 65 °C, 2 h) with 12 (0.8 equiv) the benzoate lie in 79% yield (Table 3A, entry 5).

Furthermore, disubsituted anisole derivative such as lOf lead after metalation using 2b (25 °C, 0.5 h) followed by cross-coupling (ZnCl ₂ (10 mol%), Pd(OAc) ₂ (3 mol%), S-Phos (6 mol%), 65 °C, 1 h) with 12 (0.8 equiv) to the functionalized anisole llf in 96% yield (Table 3A, entry 6). In particular, tmpBEtyMgCl LiCl (2.2 mL, 1.0 M in THF, 2.2 mmol) was added dropwise at 25 °C to a solution of 3- bis(trifluoromethyl)anisole (lOf; 488 mg, 2.0 mmol) in THF (2 mL) in a flame-dried and Argon-flushed Schlenk-tube equipped with septum and magnetic stirring bar. After stirring for 30 min at 25 °C, ZnCl ₂ (0.2 mL, 1 M in THF, 10 mol%), Pd(OAc) ₂ (14 mg, 3 mol%), S-Phos (25 mg, 6 mol%) and ethyl 4-iodobenzoate (12; 441 mg, 1.6 mmol) were added followed by continuously stirring for 1 h at 65 °C. After cooling to 25 °C, the reaction mixture was diluted with Et^O (5 mL) and quenched with sat. NH ₄ C1 (aq.) (5 mL). The aqueous layer was extracted with CH ₂ CI ₂ (3x 15 mL). The combined organic phases were dried over Na ₂ SC>4 and the solvent was removed under vacuum. Flash column chromatography (pentane-Et^O, 95:5) afforded llf (602 mg, 96%) as a white solid.

Similarly, l-chloro-4-(trifluoromethyl)benzene (lOg) reacted with 2b (25 °C, 12 h) producing the corresponding borate which provided after subsequent cross- coupling with ethyl 4-iodobenzoate (12; 0.8 equiv) the polysubstituted biphenyl llg in 81% yield (Table 3 A, entry 7).

Example 9: Metalation of pyridine with fluorinated borate base

A high reactivity was observed in the metalation of pyridine with the amidoborate base tmpB(C ₆ F ₅ )3 ^» MgCl ^» LiCl according to scheme 5, which led to a substantially complete conversion to the metalated pyridine within 10 minutes at - 40°C. Iodolysis of the metalated pyridine provided 2-iodopyridine (7) in 75 % yield (Scheme 6). Scheme 6. Accelerated metalation of pyridine with

Example 10: Stability of pyridyltrialkylborate towards water

A reaction mixture obtained after reacting 3-chloropyridine with

tmpBEt3 ^» MgCl ^» LiCl in dry THF at 25°C for 15 minutes was observed using mass spectroscopy. The result is shown in Figure 1.

The metalated 3-chloropyridine was stirred in water at 25 °C for 1 h. Thereafter, the reaction mixture was again subjected to mass spectroscopic analysis. The result is shown in Figure 2. Since Figure 2 shows that the organoborate was still present, the organoborate was not hydrolyzed by water. Although not wishing to be bound by theory, this result suggests the existence of an intermediate organoborate of type 8a instead of type 8b as shown in Scheme 7.

Scheme 7: Stability of pyridyltrialkylborate towards water

Example 11: Functionalization of iV-heterocycles using iPr ₂ NBEt ₃ -derived bases

In this example, N-heterocycles such as thiomethylpyrazine and isoquinoline were reacted with iPr ₂ NBEt ₃ · Met bases generating the organoborate intermediates which were subsequently reacted in Suzuki type cross-coupling reactions furnishing the corresponding substituted N-heterocycles 6h-j as shown in Scheme 8a and Table 4.

Scheme 8a

As shown in Scheme 8a, the substrate is reacted with the base to form a metallic organoborate intermediate. The metallic organoborate intermediate is reacted with the electrophile identified in Table 4 to form the respective products by cross-coupling the metallic organoborate intermediate with the Ar-Br electrophile (0.8 equiv) and ZnCl ₂ (10 mol%) in the presence of Pd(OAc) ₂ (3 mol%) and S-Phos (6 mol%) at 50°C for 12 hours. All reactions were conducted in THF. The results are shown in Table 4 below. Table 4: Functionalization of N-heterocycles using iPr ₂ NBEt ₃ -derived bases

6j : 79

Example 12: Extension to providing aldehyde functionality

The scope of reactions with organoborates can be extended to 1,2-addition to aldehyde functions as shown in Scheme 8b without the use of expensive Rh-based or other transition metal catalysts.

Scheme 8b: 1,2-Addition of heteroarylborates to aldehydes

9b: 73%

As can be seen from the above examples, structurally diverse amidoborates (2a- w) can be prepared which react rapidly with a wide range of heterocyclic and carbocyclic compounds to produce metalated borate compounds in high yield and selectivity. The metalated borate compounds can be further functionalized, such as by means of Suzuki -type cross-couplings.

Thus, the metallic amidoborate bases described herein allow for the

regioselective preparation of custom-made bases which are thermally stable, and highly reactive, which may be easily manufactured from inexpensive commercially available starting materials producing hydrolytically stable organoborate

intermediates that react in a wide range of chemical reactions.