# Patent

## Title
Process for producing cyano substituted arene boranes and compounds

## Abstract

A process for producing cyano substituted arene boranes is described. The compounds are useful intermediates to pharmaceutical compounds using the cyano group as a reactant.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application relies for priority on U.S. provisional application Ser. No. 60/689,161, filed Jun. 9, 2005.


STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was supported in part by National Institutes of Health, National Institute of General Medical Sciences Grant No. R01 GM63188-01. The U.S. government has certain rights in this invention.


BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a process for producing a cyano ring-substituted arene or heteroarene borane which comprises reacting a ring-substituted cyano arene or heteroarene with an HB or B—B organic compound in the presence of a catalytically effective amount of an iridium complex with three or more substituents, excluding hydrogen, bonded to the iridium and an organic ligand, which is at least in part bonded to the iridium, to form the ring-substituted cyano substituted arene or heteroarene borane.
(2) Description of Related Art
Alkyl and arylboronic esters and acids are versatile alkyl and aryl transfer reagents in organic chemistry wherein the boron serves as a “mask” for a broad range of heteroatoms and functional groups. Some of the most remarkable and broadly used applications of organoboron chemistry are catalytic cross-coupling reactions of C—B and C—X (X═Cl, Br, or I) groups which yield new C—C bonds as shown below.




In the pharmaceutical industry, organoboron complexes are key building blocks for drug manufacturing, versatile reagents for high-throughput parallel synthesis in drug discovery, and exhibit some useful and unique biological activities.

Arylboronate esters and the corresponding acids are presently prepared by reacting Grignard reagents generated from halogenated aromatics and magnesium metal with alkyl borate reagents. A related method involves the reaction of alkyllithium reagents with aromatic halides or arenas to generate lithium reagents which are subsequently reacted with alkyl borates. Moreover, introduction of the Bpin group using other methods, such as Miyaura's cross-coupling reactions of alkoxydiboron reagents and aryl halides, are inconvenient because access to the 2-halogenated compounds is extremely limited (Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510). Significant limitations of the current technologies include: (1) the reactions are run typically in ethereal solvents, (2) halogenated aromatics must be synthesized from hydrocarbon feedstocks, (3) for large-scale synthesis, unreacted chlorinated aromatic starting materials and biaryl byproducts can create significant environmental hazards and pose waste disposal problems, (4) in some instances attempted product isolation has resulted in explosions attributed to unreacted lithium and magnesium intermediates, (5) Grignard and organolithium reagents can be incompatible with a range of common functional groups including esters, amides, bromides, chlorides, iodides, alcohols, acids, and the like, and (6) cryogenic cooling is sometimes required to prevent side reactions.
Aromatic hydrocarbons are fundamental chemical building blocks, and their reactivity is a cornerstone of organic chemistry. Their utility derives largely from the regiochemical fidelity embodied in electrophilic aromatic substitutions (Taylor, R., Electrophilic Aromatic Substitution; John Wiley and Sons: New York, 1990). While steric effects can influence electrophilic aromatic substitution, electronic effects typically dominate. For electrophilic aromatic substitution (EAS) reactions, substituents on aromatic rings fall into two classes: ortho, para directors and meta directors. When directing groups are positioned to work in concert, regioselectivity can be complete as in the classic example of nitration at the 3-postion of 4-bromobenzonitrile (Scheme 1, electronically preferred product, FG=NO2) (Schopff, M., Ber. 1890, 23, 3435-3440). For most disubstituted benzenes, EAS does not usually offer well-defined regiochemical outcomes. For example, two of the three possible arrangements of directing groups in 1,4-substituted benzenes give poor regioselectivity as shown in Scheme 1.




For the functionalization at positions meta to ortho, para directors and/or ortho to meta directors, alternate methods to electrophilic aromatic substitutions are required. In the case of certain meta directing substituents, directed ortho metalation (DoM) constitutes a powerful method for functionalization at the adjacent positions, provided that the substituent is a sufficiently strong directed metalation group (DMG) (Whisler, M. C., MacNeil, S.; Snieckus, V.; Beak, P., Angew. Chem. Int. Edit. 2004, 43, 2206-2225). For disubstituted benzenes, the regioselectivity of DoM depends on the positions of the substituents and their ranking in the DMG hierarchy. 1,3-Subsituted benzenes can often be derivatized selectively at the 2-position because DMG's can act in concert to direct metalation.

In contrast, DMG's can compete in 1,2- and 1,4-substituted benzenes. Therefore high regioselectivities are typically realized when there is a substantial difference in relative DMG powers. For example, while DoM protocols can be effective for functionalizing ortho to cyano groups in simple aromatic nitriles,(Kristensen, J.; Lysen, M., Vedso, P., Begtrup, M., Org. Lett. 2001, 3, 1435-1437; (b) Pletnev, A. A.; Tian, Q. O., Larock, R. C., J. Org. Chem. 2002, 67, 9276-9287) the presence of other groups can subvert the selectivity. Sometimes the regiochemical outcome is unexpected. For instance, competitive 2,5-dilithiation of 4-bromobenzonitrile occurs with LDA (Lulinski, S., Serwatowski, J., J. Org. Chem. 2003, 68, 9384-9388) and deprotonation at the 3-position has been reported with the hindered phosphazene base, P4-t-Bu, (Imahori, T., Kondo, Y., J. Am. Chem. Soc. 2003, 125, 8082-8083) even though the DMG ranking of CN is greater than Br. In fact, there are no documented transformations of 4-bromobenzonitrile that are selective for the 2-position. Moreover, examples of functionalization at the 2-position in other 4-substituted benzonitriles are limited, and there are no general approaches toward this end (Wang, C et al., J. Org. Chem. 1998, 63, 9956-9959; Kim, B. H., et al. J. Chem. Soc.-Perkin Trans. 1 2001, 2035-2039; and Sonoda, M., S., Bull. Chem. Soc. Jpn. 1997, 70, 3117-3128). This is unfortunate because aryl nitrites have a rich chemistry, and are particularly useful entries into heterocyclic systems (Meyers, A. I., et al., The Chemistry of the Cyano Group. In the Chemistry of the Functional Groups; Patai, S. et al., Eds. Wiley & Sons: New York, 1970; Chapter 8; Fatiadi, A. J., In Supplement C: The Chemistry of the Triple-bonded Functional Groups; Patai, S., et al Eds. Wiley & Sons: New York, 1983; Chapter 26).
An alternate strategy for functionalizing benzonitriles that can potentially complement electrophilic aromatic substitutions and DoM's is to differentiate positions based on steric effects (Scheme 1). Since the first report by Ittel and co-workers in 1976, (Ittel, S. D. et al., J. Am. Chem. Soc. 1976, 98, 6073-6075) there have been several reports of transition metal mediated C—H activations where steric, not electronic, effects are the overriding factors in regioselection. More recently, significant progress has been made in coupling C—H activation with subsequent transformations of the nascent M-C bond to design new catalytic processes (Goldberg, K. I. et al., Activation and Functionalization of C—H Bonds. American Chemical Society: Washington, D.C. 2004). Since 1999, we,(Iverson, C. N., et al., J. Am. Chem. Soc. 1999, 121, 7696-7697; Cho, J.-Y et al., J. Am. Chem. Soc. 2000, 122, 12868-12869; Cho, J. Y., et al Science 2002, 295, 305-308; Maleczka, R. E., Jr. et al, J. Am. Chem. Soc. 2003, 125, 7792-7793; Chotana, G. A. et al., J. Am. Chem. Soc. 2005, 127, 10539-10544; Tse, M. K. et al., Org. Lett. 2001, 3, 2831-2833; Holmes, D. et al., Org. Lett. 2006, 8, 1407-1410; and Shi, F. et al., Org. Lett. 2006, 8, 1411-1414); and others, (Ishiyama, T. et al., J. Am. Chem. Soc. 2002, 124, 390-391; Ishiyama, T. et al., Angew. Chem. Int. Edit. 2002, 41, 3056-3058; Takagi, J et al., Tetrahedron Lett. 2002, 43, 5649-5651; Ishiyama, T. et al., Chem. Commun. 2003, 2924-2925; Ishiyama, T. et al., Adv. Synth. Catal. 2003, 345, 1103-1106; and Mertins, K. et al., J. Mol. Catal. A: Chem. 2004, 207, 21-25) have been particularly interested in utilizing Ir-catalyzed borylations of arenes to tap the unique regioselectivities available to sterically directed C—H activations.
In light of the above limitations of the current processes for producing cyano substituted arene boronate esters and acids, there remains a need for a synthetic route to synthesizing boronate esters and acids that does not have the limitations of the current processes.
Objects
It is an object of the present invention to provide a process for synthesizing cyano substituted arene or heteroarene boranes. A further object of the present invention is to provide a process for synthesizing ring-substituted cyano boranes by metal catalyzed activations of C—H bonds in arenes or heteroarenes and B—H or B—B bonds in boron reagents to produce novel B—C bonds. These and other objects of the present invention will become increasingly apparent with reference to the following drawings and preferred embodiments.
SUMMARY OF THE INVENTION
This application incorporates by reference in its entirety the disclosure in relation to the catalysts and organic ligands of U.S. Pat. No. 6,878,830.
The present invention relates to a process for producing a cyano substituted arene borane which comprises: reacting a ring-substituted cyano arene, wherein arene is 4, 5 or 6 carbon atoms and optionally is heterocyclic with an HB or B—B organic compound, in the presence of a catalytically effective amount of an iridium complex with three or more substituents, excluding hydrogen, bonded to the iridium with an organic ligand in the complex to form the cyano substituted ring-substituted arene borane.
The present invention also relates to a process for producing a di or tri ring-substituted cyano substituted arene borane which comprises: reacting a di or tri ring-substituted cyano arene, wherein arene is 4, 5 or 6 carbon atoms and optionally heterocyclic, with an HB or B—B organic compound in the presence of a catalytically effective amount of an iridium complex with three or more substituents, excluding hydrogen, bonded to the iridium and a dipyridyl organic ligand, in a molar ratio of complex to ligand between about 1 to 3 and 1 to 1, wherein the ligand is at least in part bonded to the iridium, to form the di or tri ring-substituted cyano substituted arene borane.
The present invention also relates to a cyano substituted arene borane ring compound comprising 4, 5 or 6 carbon atoms in the ring, which is optionally fused with aromatic rings and which is optionally heterocyclic, wherein there is at least one ring substituent other than hydrogen selected from the group consisting of halo other than fluoro, alkyl, alkoxy, thioalkyl, amino, alkyl acyl, alkyl aminoacyl, trifluoro methyl, substituted aryl, organosilane, organoborane, organostannane and phosphorous each typically containing 1 to 8 carbon atoms except for the halo group. Preferably the arene ring is a benzene ring.
The present invention also relates to a process for producing a ring-substituted arene borane which comprises: reacting a ring-substituted arene containing one to five substituents of which one or more is a cyano group, and wherein the arene is 4, 5 or 6 carbon atoms and optionally heterocyclic and including polycyclic rings with an HB or B—B organic compound, in the presence of a catalytically effective amount of an iridium complex with three or substituents, excluding hydrogen, bonded to the iridium, and a nitrogen substituent organic ligand, in a molar ratio of complex to ligand between about 1 to 3 and 1 to 1, wherein the ligand is at least in part bonded to the iridium, to form a ring-substituted arene borane containing two to six substituents at least one of which is cyano group. Preferably the borane moiety is ortho to a cyano group in the ring-substituted arene borane produced. Preferably the nitrogen organic ligand is selected from the group consisting of:




wherein R are each selected from the group consisting of hydrogen, linear alkyl containing 1 to 8 carbon atoms, branched alkyl containing 1 to 8 carbons, and a carbon in a cyclic structure, Y is a carbon, oxygen, nitrogen, or sulfur containing moiety, and G is a heteroatom containing group, multiple atom chain, or multiple atom ring. Preferably the nitrogen organic ligand is selected from the group consisting of:





wherein R are each selected from the group consisting of hydrogen, linear alkyl containing 1 to 8 carbon atoms, branched alkyl containing 1 to 8 carbons, and a carbon in a cyclic structure. Preferably the nitrogen organic ligand is selected from the group consisting of:





wherein R are each selected from the group consisting of hydrogen, linear alkyl containing 1 to 8 carbon atoms, branched alkyl containing 1 to 8 carbons, and a carbon in a cyclic structure, Y is a carbon, oxygen, nitrogen, or sulfur containing moiety, and Z is a carbon, oxygen, nitrogen, sulfur, or boron containing moiety or a multiple atom chain containing a carbon, oxygen, nitrogen, sulfur, or boron containing moiety.

Preferably the HB or B—B organic compound is HBPin or B2Pin2. Still further, the present invention relates to the process wherein the complex is an iridium complex of [Ir(OMe)(COD)]2, where COD is 1,5-cyclooctadiene complexed with 4,4′-di-t-butyl-2,2′-bipyridine (dtbpy).
Preferably a benzonitrite of the formula:




wherein BPin is





and Z is selected from the group consisting of —Cl, Br, —I, —CH3, —OMe, —SMe —NMe2, —CO2Me, NHAc and CF3 moieties.

Catalysts

The present invention provides a catalytic composition comprising an iridium complex with three or more substituents, excluding hydrogen, bonded to the iridium. In a further embodiment, the present invention provides a catalytic composition comprising an iridium complex with three or more substituents, excluding hydrogen, bonded to the iridium and an organic ligand selected from the group consisting of a phosphorus organic ligand, or a nitrogen organic ligand such as an organic amine, an imine, a nitrogen heterocycle, and an ether in a molar ratio between about 1 to 3 and 1 to 1, wherein the ligand is at least in part bonded to the iridium complex.
In an embodiment of the catalytic composition, the iridium complex is selected from the group consisting of (Cp*)Ir(H)2(Me3P), (Cp*)Ir(H)(BPin)(Me3P), (CP*)Ir(H)(C6H5)(Me3P), (Ind)Ir(COD), (MesH)Ir(BPin)(B(OR)2), ((R1)3P)3Ir(B(OR2)2)3, (R1)2P)2Ir(BPin)3, [((R1)2P)3Ir((R2O)2B)3]2, ((R1)3P)4Ir(BPin), ((R1)2P)2Ir(BPin)3, (MesH)Ir(BPin)3, IrCI(COD), [IrCI(COD)]2, and [Ir(OMe)(COD)]2. In the foregoing, CP* is 1,2,3,4,5-methylcyclopentadienyl, BPin is pinacolborane, Me is methyl, H is hydrogen, P is phosphorus, Ind is indenyl, COD is 1,5-cyclooctadiene, and MesH is mesitylene. Further R, R1, and R2 are each selected from the group consisting of hydrogen, linear or branched alkyl containing 1 to 8 carbons, aryl, and a carbon in a cyclic structure.
The catalytic composition also can include an iridium complex of the formula: (BY)n—Ir-(ligand)m with three or more n and m substituents, excluding hydrogen, bonded to the iridium BY is a boron moiety and the ligand is selected from the group consisting of a phosphorus organic ligand, an organic amine, an imine, a nitrogen heterocycle, and an ether wherein the ligand is at least in part bonded to the iridium.



DETAILED DESCRIPTION OF THE DRAWINGS
FIG. 1 is a gHMBC spectrum of the borylation products of 4-chlorobenzonitrile.
FIG. 2 is a gHMBC spectrum of the borylation products of 4-bromobenzonitrile.
FIG. 3 is a gHMBC spectrum of the borylation product of 4-iodobenzonitrile.
FIG. 4 is a gHMBC spectrum of the borylation products of 4-methoxybenzonitrile.
FIG. 5 is a gHMBC spectrum of the borylation products of 4-thiomethylbenzonitrile.
FIG. 6 is a gHMBC spectrum of the borylation product of 4-dimethylaminobenzonitrile.
FIG. 7 is a gHMBC spectrum of the borylation product of methyl 4-cyanobenzoate.
FIG. 8 is a gHMBC spectrum of the borylation product of 4′-cyanoacetanilide.
FIG. 9 is a gHMBC spectrum of the borylation products of 1,5-dimethyl-2-pyrrolecarbonitrile.
FIG. 10 is a gHMBC spectrum of the borylation products of 5-methyl-2-furonitrile.



DESCRIPTION OF PREFERRED EMBODIMENTS
All patents, patent applications, provisional patent applications, government publications, government regulations, and literature references cited in this specification are hereby incorporated herein by reference in their entirety. In case of conflict, the present description, including definitions, will control.
Ir-catalyzed borylations of 4-substituted benzonitriles are described hereinafter. In contrast to electrophilic aromatic substitutions and directed ortho metalations, C—H activation/borylation enables functionalization at the 2-position, adjacent to the cyano group, when the 4-subsitutent is larger than cyano. When an excess of borane reagent is used, diborylation can be achieved with a single regioisomer being formed in certain cases. Extension of sterically directed borylation to cyano substituted, 5- and 6-membered ring heterocycles is also described.
Borylation ortho to nitrile groups should be possible for appropriate substrates since the cyano group is only slightly larger than fluoride. Initial attempts to borylate benzonitriles with pinacolborane (HBPin) using Ir phosphine systems at elevated temperatures gave complex mixtures due to competitive reduction of the nitrile. These catalysts can provide a lower temperature; however, other catalysts were available. More active Ir catalysts developed by Hartwig, Ishiyama, and Miyaura (Ishiyama, T., et al., J. Am. Chem. Soc. 2002, 124, 390-391) overcome this problem. These Ir dipyridyl catalysts operate at room temperature, and examples have been reported showing that the nitrile group is compatible with the borylation conditions. However, data are available for only three substrates, none of which addressed the regiochemical hypothesis. The following results show borylations ortho to cyano groups of benzonitriles.
Results
Borylations of 4-substituted benzonitriles were examined. As most substrates were poorly soluble in saturated hydrocarbons, borylations were typically carried out in tetrahydrofuran (THF) solvent using the catalyst constituted from a 1:2 ratio of [Ir(OMe)(COD)]2 (COD=1,5-cyclooctadiene) and 4,4′-di-t-butyl-2,2′-bipyridine (dtbpy) as indicated in Scheme 2. The results for monoborylation reactions are given in Table 1. The reaction times roughly correspond to relative reactivities and yields are for isolated products with respect to the limiting reagent. Either HBPin or B2Pin2 can be used with shorter reaction times required for the latter reagent. Diborylation can be significant when the benzonitrile is the limiting reagent. For these substrates, a benzonitrile: borane reagent ratio of 4:1 was used to minimize diborylation.




For 4-halobenzonitriles, the extent of borylation at the 3-position (isomer 2) diminishes in the order F>Cl>Br>I. This trend is consistent with the ordering of steric energies for substituents on a benzene ring F<CN<Cl<Br<I. However, the regioselectivities are also consistent with the thermodynamic ordering of ortho-C—H acidities F>CN>Cl from the literature (Stratakis, M. et al., J. Org. Chem. 1996, 61, 3145-3150; and Krizan, T. D. et al., J. Am. Chem. Soc. 1983, 105, 6155-6157). Thus, rationalization of the regiochemical outcome is shackled with the age-old dilemma of definitively separating steric and electronic effects. Nevertheless, a compelling case can be made for steric directing effects as outlined below.







TABLE 1







Regioselectivities for borylation of 4-benzonitriles.a












Entry
Z
Borane (equiv)
Time (h)
% yieldb
%1:%2c
















 1
F
HBPin (0.25)
8
71
11:89
(8:92)


 2
Cl
HBPin (0.25)
36
76
80:20
(81:19)


 3
Br
HBPin (0.25)
48
73
95:5
(97:3)


 4
I
B2Pin2 (1.0)
40
70
>99:1
(>99:1)


 5d
CH3
HBPin (0.25)
72
64
94:6
(92:8)


 6
OMe
HBPin (0.25)
24
65
67:33
(67:33)e


 7f
SMe
B2Pin2 (0.25)
18
55
90:10
(87:13)e


 8d
NMe2
B2Pin2 (1.0)
72
58
>99:1
(>99:1)


 9
CO2Me
B2Pin2 (0.8)
48
65
>99:1
(>99:1)


10g
NHAc
B2Pin2 (1.6)
18
62
>99:1
(>99:1)


11h
CF3
HBPin (1.1)
24
68
>99:1
(>99:1)





aUnless otherwise noted, all reactions were run in THF solution at 25° C. with [Ir] = 3 mol %.


bYields are for isolated products based on the limiting reagent.


cThe major isomer was assigned by NMR and ratios were determined from crude reaction mixtures by GC integration. Isomer ratios for isolated products are in parentheses.


d[Ir] = 6 mol %.


eIsomer ratio was determined from NMR integration.


fReaction run at 80° C.


g[Ir] = 8 mol %.


hReaction run in n-hexane.






There are several approaches for evaluating steric efffects (White, D. P. et al., J. Org. Chem. 1999, 7707-7716). Following a course recommended by Ingold, (Ingold, C. K., J. Chem. Soc. 1932, 1032) Taft developed a parameter, Es, to account for steric effects on hyrolysis and esterification rates of o-benzoate esters (Taft, R. W. J., J. Am. Chem. Soc. 1952, 74, 3120-3128). It was later shown that Es values could be quantitatively related to van der Waals radii, (Charlton, D., J. Am. Chem. Soc. 1969, 91, 615-618) and values have been calculated for substituents absent in Taft's original work (Kutter, E. et al., J. Med. Chem. 1969, 12, 647-652). Dubois later revised Taft's definition, introducing the Taft-Dubois steric paramater, E′s (Macphee, J. A. et al., Tetrahedron 1978, 34, 3553-3562). Despite their demonstrated utility, Es and E′s values are nonetheless empirical and the database of values is still limited. Alternatively, the energy difference between equatorial and axial conformers of monosubstituted cyclohexanes (the A value) has been invoked as a measure of steric effects (Winstein, S. et al., J. Am. Chem. Soc. 1955, 77, 5562-5578). Although the equatorial site is indeed favored from a steric standpoint, cyclohexane conformational energies are not immune to electronic effects. Hence, A values are poor predictors of steric differences for electronically disparate substituents. For our purposes, although there is no E′s value in the literature for CN, the Es value that is typically quoted places CN between F and Cl, which seems reasonable (Hansch, C. et al., Exploring QSAR: Hydrophobic Electronic, and Steric Constants; American Chemical Society: Washington, D.C., 1995; p. 227). Unfortunately, the value does not appear in the primary literature that is cited. A values are of little help as the value for CN is lower than that of F, (Jensen, F. R. et al., J. Am. Chem. Soc. 1969, 91, 344-351) and general agreement between A and Es values is poor.
Calculations of steric energies have been addressed using modern computational methods. We felt that a good, albeit crude, model for our purposes was that employed by Fujita and co-workers for evaluating the steric effects in the acid-catalyzed hydrolysis of o-benzamides (Sotomatsu, T. et al., J. Comput. Chem. 1991, 12, 135-138; and Sotomatsu, T. et al., J. Org. Chem. 1989, 54, 4443-4448). In essence, their approach involves calculating the difference in enthalpies for 2-substituted toluenes and tert-butylbenzenes relative to toluene and tert-butylbenzene to extract steric enthalpies, denoted as DDHs(Z), for substituents Z, relative to hydrogen. For consistency, the dihedral angles for the methyl and tert-butyl groups were constrained as shown in Chart 1. Since CN and other substituents in Table 1 were not included in the previous report, we recalculated the series (AM1 calculations were carried out on an SGI Origin 3400 supercomputer using SPARTAN SGI Version 5.1.3, Wavefunction, Inc., Irvine, Calif.). Table 2 lists these DDHs(Z) values along with calculated and experimental ratios of 2- and 3-borylated benzonitriles.











TABLE 2







Calculated steric enthalpies (ΔΔHs) for o-benzene


substituents Z and isomer ratios for borylation.










Z
ΔΔHs(Z) kcal · mol−1
%1:%2 calc
%1:%2 observed













H
0
—
—


CN
3.211
—
—


F
1.535
 6:94
   8:92


Cl
4.133
 83:17
   81:19


Br
5.405
98:2
  97:3


I
7.759
>99:1  
>99:1


CH3
5.532
98:2
  92:8


OMe
2.013
 31:69
   67:33


SMe
3.682
 66:34
   87:13


NMe2
5.039
96:4
>99:1


CO2Me
4.856
94:6
>99:1


NHAc
5.166
96:4
>99:1


CF3
8.845
>99:1  
>99:1









Agreement between the calculated and experimental isomer ratios is surprisingly good. The halide data correlates best, while selectivities for CO2Me, NMe2, and NHAc substituents are better than the calculated values. To gauge whether aromatic borylation is likely to be more sensitive to steric effects, it is instructive to consider putative transition states for acid-catalyzed hydrolysis of an o-benzamide (A) and Ir-catalyzed C—H activation (B) in Chart 2.





First, transition state A more closely resembles the steric model in Chart 1 from which DDHs(Z) values are calculated. Moreover, transition state B should be more sensitive to the sterics of Z because an Ir—C bond ultimately forms ortho to Z, whereas attack by the less hindered water molecule is one carbon removed in transition state A.
The poorest agreement between calculated and observed isomer ratios in Table 2 is for Z=OMe, where the borylation is favored at the more hindered position. Although this could simply result from inherent deficiencies in the model, there is reason to believe electronic effects contribute to the regioselectivity. Specifically, while borylation of benzonitrile gives a nearly statistical 2.15:1 ratio of meta to para isomers, anisole borylation favors the meta isomer 4:1. After taking statistics into account, this corresponds to a 2:1 preference for meta vs. para borylation. Given that CN and OMe groups are nearly isosteric, the identical 2:1 preference for borylation meta to OMe may have electronic origins.
To strengthen what is a circumstantial case for sterics overriding electronics in borylations of 4-benzonitriles, we turned to 1,3-disubsituted CN and F benzenes, where C—H bonds flanked by 0-2 ortho hydrogens are present. Under DoM conditions, 1,3-dicyano and 1,3-difluorbenzene are known to react selectively at the 2-position as shown in Scheme 3 (Krizan, T. D. et al., J. Org. Chem. 1982, 47, 2681-2682; and Bennetau, B. et al., Tetrahedron 1993, 49, 10843-10854). If selectivities of Ir catalyzed borylations of CN and F substituted arenes are sterically directed, the propensity for borylation in the 1,3-disubstituted benzenes should follow the order 5->4->2-. As indicated in Scheme 3, this is indeed the case. Furthermore, only 1,3-difluorobenzene exhibits significant borylation at the 2-position, consistent with the lower steric requirement for F relative to CN. Murai has invoked CN to Ru Π-bonding to account for selective C—H activation ortho to CN (Kakiuchi, F. et al., Chem. Lett. 1999, 1083-1084). However, from the data in Scheme 3, the borylation ortho to H vs. CN is favored by a factor of 5.7 in the present system. Thus, sterically directed regioselectivity is the only satisfactory explanation for the regiochemistry in these borylations. Based on these results and the data in Table 2, we favor steric directing effects to account for the selectivities in Table 1.




Additional features of the reactions in Table 1 merit comment. First, the 2-borylated products for entries 2-11 are new compounds. In fact, 4-F-2-BPinC6H3CN is the only previously reported 2,4-benzonitrile with boron at the 2-position to the best of our knowledge (Blackaby, W. P. et al., U.S. Patent Publication No. 20040192692). Moreover, introduction of the BPin group using other methods, such as Miyaura's cross-coupling reactions of alkoxydiboron reagents and aryl halides, are inconvenient because access to the 2-halogenated compounds is extremely limited (Ishiyama, T. et al., J. Org. Chem. 1995, 60, 7508-7510). Entries 8-10 highlight the complementary nature of sterically directed borylations to DoM protocols, where hydrogens ortho to amine, ester, and amide groups react preferentially (Clayden, J. et al., Tetrahedron Lett. 2003, 44, 3059-3062; and Jaroch, S. et al., Bioorg. Med. Chem. Lett. 2002, 12, 2561-2564). Thus, aromatic borylation provides the most general approach to elaborating the 2 positions of 4-substituted benzonitriles. Lastly, it should be noted that entries 7 and 10 are the first examples of functional group tolerance for SMe and NHAc substituents, respectively.
The regioselectivities in Table 2 are not necessarily limited to disubstituted benzenes. In addition to diborylation of 4-benzonitriles (vide infra), we also note that 4-bromo-2-fluorobenzonitrile is borylated according to Eq 1, affording a 5:95 ratio of 5- and 6-borylated products. This is a particularly attractive reaction because 1,2-benzisoxazoles and other heterocycles can be obtained by substitution of fluoride followed by ring-forming condensation with the cyano group (Cui, J. R. et al., Bioorg. Med. Chem. Lett. 2002, 12, 2925-2930). Similarly, borylation of 3,4-dichlorobenzonitrile yields the 5- and 6-borylated isomers in a 20:80 ratio. For both substrates, the selectivity for borylation ortho to CN vs. halide is virtually identical to that for the corresponding 4-halobenzonitriles in Table 1.




In order to avoid diborylation, excess arene was used for several entries in Table 1. We were curious as to how efficiently the diborylated products could be formed and whether compounds with isomeric purities sufficiently high as to be synthetically useful could be obtained. The reactions were typically run in THF with a 4:1 ratio of HBPin to arene at twice the catalyst loading for monoborylation. The results are given in Table 3.







TABLE 3







Diborylations of 4-benzonitriles.a










% yield,



Z
time
Productsb













F
92, 24 h










 


OMe
81,48 hc










 


Cl
82, 48 h










 









CN
71,20 hd






 


CF3
83, 36 h









aUnless otherwise noted, all reactions were run in THF solution at 25° C. with 4.0 eq HBPin and [Ir] = 6 mol %.


bIsomer distribution determined GC-FID. Calculated values are shown in parentheses. For Z = OMe and Cl, the 3,5-diborylation product are calculated as 7% and 2% of the isomer mixture.


cReaction run at 60° C.


dIsolated as a single isomer after recrystallization from a 93:7 mixture of 2,5- and 2,6-borylated isomers.






Unlike the situation for 4-bromo-2-fluorobenzonitrile and 3,4-dichlorobenzonitrile, the observed distribution of isomers is much different than a simple extrapolation of selectivities from Table 1 predicts Isomer distributions for diborylation where the BPin group does not affect selectivity were calculated as follows. For 4-chlorobenzonitrile, borylation ortho to CN vs. Cl is favored by a factor of 4, giving the 2-borylated isomer as the major product. In the second boryaltion, selectivity ortho to CN is lowered by half because there are two H's ortho to Cl and only one H ortho to CN in the monoborylated product. Applying analogous arugments to the other monoborylated isomer, the percentages of 2,6-,2,5-, and 3,5-diborylated isomers can be calculated as 54%, 44% and 2%, respectively. Isomer ratios for the other substrates in Table 3 were calculated similarly. In all cases the extent of 2,5-diborylation is significantly higher than expected, except for Z=CF3 where borylation ortho to CF3 is likely prohibitive. The data suggest that the BPin group has a directing role. To answer this question, we examined the regioselectivity for PhBPin borylation in THF under similar reaction conditions (Eq 2). The reaction was examined at low conversion to avoid skewing the data by borylation of m-C6H4(BPin)2. The experiment in Eq 2 was performed through the reaction of benzene with 1.2 equivalents of HBPin in the presence of Ir catalyst. The first equivalent of borane generates the PhBPin in situ and the remaining 0.2 equivalents give the diborylated isomers. The para to meta ratio is 1.8:1, significantly greater than the 1:2 statistical ratio. This translates to a 3.6:1 selectivity for para vs. meta borylation after statistical corrections. While we are reluctant to speculate on the origins of this selectivity, BPin clearly has a para directing effect that likely contributes to the regioselectivities in Table 3. Lastly, it should be noted that single isomers of diborylated products can readily be obtained for Z=CN, or CF3.




We have also examined a limited number of heteroaromatic compounds to assess whether the regioselectivities found for arenes will translate to other substrates (Scheme 4). Borylation of 1,5-dimethyl-2-pyrrolecarbonitrile (3a) gives an 85:15 ratio of the regioisomers 4a and 5a with the major isomer 4a arising from borylation adjacent to the cyano group. Similarly, 5-methyl-2-furonitrile (3b) borylates predominantly at the 3-position to also give an 85:15 ratio of borylated isomers 4b and 5b. Borylation of 2-bromo-5-cyanothiophene was unsuccessful. Since the steric interactions between adjacent positions diminish as aromatic rings contract, the decline in selectivity for the 5-membered heterocycles is not surprising. Two isomeric cyanopyridines were also examined. 5-bromo-2-cyanopyridine undergoes borylation to afford an isomer mixture. While borylation ortho to CN accounts for the major product, the degree of borylation ortho to Br is substantially higher than that found for 4-bromobenzonitrile. Somewhat surprisingly, 2-bromo-5-cyanopyridine gave no borylation products. Since halogen substituted aromatic heterocycles tend to be more reactive than their carbocyclic counterparts, side reactions that deactivate catalytically active species are more likely.




Conclusions

In summary, the steric directing effects that govern the regioselectivities in Ir catalyzed borylations of aromatic and heteroaromatic compounds enable functionalization of C—H bonds adjacent to cyano groups, when these positions are the least hindered sites in the substrate. The regioselectivities for borylations complement those found in electrophilic aromatic substitutions and DoM's, and several relatively simple borylated products have been prepared for the first time. Diborylations of 4-benzonitriles favor para-disposed BPin groups when borylation at the 5-position is possible. Similar trends in regioselectivities can be extended to borylations of heteroaromatic nitriles, the substrate scope is narrower and the regioselectivity is poorer than for carbocyclic aromatic substrates. Regioselectivities were improved by modifying the Ir ligands, as well as sterically differentiating other aromatic substituents.
Methods:
Pinacolborane (HBPin) and bis(η4-1,5-cyclooctadiene)-di-μ-methoxy-diiridium(I) {Ir(OMe)(COD)}2 were prepared per literature procedures (Knochel, P.; Davidson, J.; Tucker, C. E., J. Org. Chem. 1992, 57, 3482-3485 and Uson, R.; Oro, L. A., Inorg. Synth. 1985, 23, 126-130). Bis(pinacolato)diboron (B2Pin2) was purchased from Callery Chemical Company and was used without purification. Tris(dibenzylidineacetone)dipalladium(0) (Pd2dba3) was purchased from Strem. 4,4′-Di-t-butyl-2,2′-bipyridine (dtbpy), tricyclohexylphosphine, and potassium acetate were purchased from Aldrich. 1-Bromo-3,5-difluorobenzene, 2-bromo-1,3-difluorobenzene, 1-bromo-2,4-difluorobenzene, and 4-iodobenzonitrile were purchased from Alfa Aesar. 4-Bromobenzonitrile and 4-methoxybenzonitrile were purchased from Lancaster Synthesis. 2-Bromo-4-methylbenzonitrile was purchased from Trans World Chemicals. 5-Bromo-2-cyanopyridine and 2-bromo-5-cyanopyridine were purchased from Matrix Scientific. All other benzonitriles were purchased from Aldrich. All substrates were purified before use. Solid substrates were sublimed under vacuum. 5-Methyl-2-furonitrile and 5-bromothiophene-2-carbonitrile were passed through activated alumina. 1,4-Dioxane and n-hexane were refluxed over sodium, distilled, and degassed. Tetrahydrofuran was used from a dry still packed with activated alumina. Silica gel was purchased from EM Science (230-400 Mesh).
Unless otherwise specified, all reactions were carried out at 25° C. in 20 mL vials in a glove box under a nitrogen atmosphere. All reactions were monitored by a Varian CP-3800 GC-FID (column type: WCOT Fused silica 30 m×0.25 mm ID coating CP-SIL 8 CB). GC-FID method: 70° C., 2 min.; 20° C./min, 9 min.; 250° C., 20 min.; 1.8 mL/min flow rate. All reported yields are for isolated materials.
1H and 13C NMR spectra were recorded on a Varian Inova-300 (300.11 and 75.47 MHz respectively), Varian VXR-500, or Varian Unity-500-plus spectrometer (499.74 and 125.67 MHz respectively) and referenced to residual solvent signals. 11B spectra were recorded on a Varian VXR-300 operating at 96.29 MHz and were referenced to neat BF3.Et2O as the external standard. 19F spectra were recorded on a Varian Inova-300 operating at 282.36 MHz and were referenced to neat CFCl3 as the external standard. All coupling constants are apparent J values measured at the indicated field strengths. All 1-dimensional NOE experiments were obtained using the Varian implementation of the DPFGSE-NOE experiment (hereafter termed NOESY1D). All 2-dimensional experiments were run using z-axis pulse field gradients. Elemental analyses were performed at Michigan State University using a Perkin Elmer Series II 2400 CHNS/O Analyzer. GC-MS data were obtained using a Varian Saturn 2200 GC/MS (column type: WCOT Fused silica 30 m×0.25 mm ID coating CP-SIL 8 CB). High-resolution mass spectra were obtained at the Michigan State University Mass Spectrometry Service Center with a JOEL-AX505 mass spectrometer (resolution 7000). Melting points were measured on a MEL-TEMP® capillary melting apparatus and are uncorrected.
General Procedure
Substrates which gave a significant amount of both isomers were borylated employing an excess of benzonitrile to minimize diborylation (General procedure A), otherwise, excess borane was employed (General procedure B). Unless otherwise specified, all reactions were run in THF solutions at 25° C. with 3 mol % [Ir]. The major isomer for the borylation of 4-methylbenzonitrile was identified by preparing an authentic sample using a slightly modified literature procedure. The regioisomers in all other cases were assigned by NMR spectroscopy (13C for substrates which have fluorine, while gHMBC and NOESY1D were used for substrates without fluorine). Ratios of the major versus minor isomer were determined from the crude reaction mixtures. Yields are based on the limiting reagent.
General Procedure A (Borane as Limiting Reactant):
In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with {Ir(OMe)(COD)}2 (5.0 mg, 0.0075 mmol, 3 mol % Ir), 4,4′-di-t-butyl-2,2′-bipyridine (dtbpy) (4.0 mg, 0.015 mmol, 3 mol %), and pinacolborane (HBPin) (73 μL, 64 mg, 0.5 mmol, 1 equivalent). These reagents were dissolved in 2 mL of THF, the corresponding benzonitrile (2 mmol, 4 equivalents) was added, and the mixture was stirred at room temperature until the reaction was judged complete by GC-FID. Solvent was removed under reduced pressure. The crude material was dissolved in CH2Cl2 and passed through a plug of silica gel to remove metal byproducts. Kugelrohr distillation gave analytically pure samples.
General Procedure B (Benzonitrile as Limiting Reactant):
In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with {Ir(OMe)(COD)}2 (10 mg, 0.015 mmol, 3 mol % Ir), dtbpy (8.1 mg, 0.03 mmole, 3 mol %), and excess HBPin or B2Pin2 (1.1 to 3.2 equivalents of boron). These reagents were dissolved in 3 mL of THF, the corresponding benzonitrile (1 mmol, 1 equivalent) was added, and the mixture was stirred at room temperature until the reaction was judged complete by GC-FID. Solvent was removed under reduced pressure. The crude material was dissolved in CH2Cl2 and passed through a plug of silica gel to furnish the desired borylated product.
General Procedure C (Diborylation):
In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with {Ir(OMe)(COD)}2 (20 mg, 0.03 mmol, 6 mol % Ir), dtbpy (16.1 mg, 0.06 mmol, 6 mol %), and excess HBPin (4 equivalent of boron). These reagents were dissolved in 3 mL of THF, the corresponding benzonitrile (1 mmol, 1 equivalent) was added, and the mixture was stirred at room temperature until the reaction was judged complete by GC-FID. Solvent was removed under reduced pressure. The crude material was dissolved in CH2Cl2 and passed through a plug of silica gel to furnish the desired borylated product.
Regioisomer Assignment by NMR Spectroscopy:




From gHMBC NMR experiments, the two regioisomers for the borylation of 4-substituted benzonitriles can be distinguished unambiguously as in FIGS. 1 to 10. In isomer A, carbon atoms represented as C1 and C4 on the benzene ring, as well as C7 (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C3 is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (3JC-H), which can be observed using gHMBC spectroscopy. In the gHMBC spectrum, carbon atoms C1 and C7 should show one cross peak each to proton Hc, whereas carbon atom C4 should show two cross peaks to protons Ha and Hb. Therefore the resulting number of cross peaks for C1, C4, and C7 should be 1, 2, and 1, respectively.
In Isomer B, carbon atoms represented as C1′, C4′, on the benzene ring, as well as C7′ (nitrile carbon) are the three quaternary carbon atoms in the 100-170 ppm region (quaternary carbon C2′ is typically not observed due to broadening from and coupling with boron). These three quaternary carbon atoms should show cross peaks due to long range H—C couplings (3JC-H). In the gHMBC spectrum, carbon atoms C1′ and C7′ should show two cross peaks each, to protons Hd and He, whereas carbon atom C4′ should show only one cross peak to proton Hf. Therefore the resulting number of cross peaks for C1′, C4′, and C7′ should be 2, 1, and 2, respectively. Hence isomers A and B can be unambiguously assigned from gHMBC data.
For isomer A, with proton Hc unambiguously assigned by gHMBC, Ha and Hb can be assigned from their multiplicities. Proton Ha appears as a doublet, coupled to proton Hb with J≈2-3 Hz. Proton Hb appears as a doublet of doublets due to coupling to protons Ha and Hc. Carbon atoms C2, C6, and C5 were then assigned from the correlations in the gHMQC spectra. Carbon atom C7 (nitrile carbon) usually appears around δ 119. Depending on the substituent, carbon atom C1 was usually found shifted downfield around δ 130-170 (except in 4-iodobenzonitrile for which it appears around δ 100). Carbon atom C4 is shifted upfield, and was usually found around δ 100-115. Similarly, all the carbons of isomer B can be assigned.
In the five membered heterocycles, the 4JH-H coupling was used together with gHMBC and NOESY1D spectroscopy to identify the major isomer. Regioisomers in the fluorine containing benzonitriles were assigned by 13C spectroscopy (with the help of the fact that the boron bearing carbon is not observed due to broadening from and coupling with boron). In the case of 1,3-dicyanobenzene, 1H NMR spectroscopy was employed to assign the major and minor isomers.
Experimental Details and Spectroscopic Data
EXAMPLE 1
Borylation of 4-fluorobenzonitrile




General procedure A was applied to 4-fluorobenzonitrile (242 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 8 h. The ratio of the two isomers in the crude reaction mixture by GC was 11:89. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (88.5 mg, 72%) as a white solid. The ratio of the two isomers in the isolated product by GC was 8:92. 13C NMR spectroscopy was used to assign the major isomer as 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 8.04 (dd, 4JH-F=5.4 Hz, J=2.2 Hz, 1H, Hd), 7.7 (ddd, J=8.5, 2.2 Hz, 4JH-F=4.9 Hz, 1H, He), 7.1 (t, J=8.5 Hz, 1H, Hf), 1.32 (br s, 12H), (minor isomer) 7.67 (dd, J=8.8 Hz, 4JH-F=4.9 Hz, 1H, Hc), 7.52 (dd, 3JH-F=8.5 Hz, J=2.9 Hz, 1H, Ha), 7.17 (dt, J=8.3, 2.9 Hz, 1H, Hb) 1.34 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 169.0 (d, 1JC-F=261.3 Hz, C1′), 141.6 (d, 3JC-F=9.6 Hz, C3′), 137.0 (d, 3JC-F=10.5 Hz, C5′), 117.9 (nitrile C7′), 116.7 (d, 2JC-F=25.6 Hz, C6′), 108.2 (d, 4JC-F=3.8 Hz, C4′), 84.5 (C8′), 24.7 (C9′), (minor isomer) 164.2 (d, 1JC-F=257.1 Hz, C1), 135.9 (d, 3JC-F=8.8 Hz, C5), 122.8 (d, 2JC-F=21.0 Hz, C2), 118.5 (d, 2JC-F=22.2 Hz, C6), 118.1 (nitrile C7), 113.1 (C4), 85.1 (C8), 24.7 (C9); 11B NMR (CDCl3, 96 MHz): δ 29.92; 19F NMR (CDCl3, 282 MHz): δ (major isomer) −92.62 (m), (minor isomer) −104.84 (m); FT-IR (neat): 3076, 2982, 2934, 2231, 1608, 1487, 1429, 1412, 1373, 1350, 1236, 1143, 1070, 964, 852, 835, 571 cm−1; LRMS (% rel. int.): m/e (major isomer) 247 M+ (26), 232 (100), 205 (12), 188 (20), (minor isomer) 247 M+ (29), 232 (97), 206 (100), 189 (74), 148 (97), 121 (25); Anal. Cacld for C13H15BFNO2: C, 63.20; H, 6.12; N, 5.67. Found: C, 63.52; H, 6.20; N, 5.56. HRMS Calcd for C13H15BFNO2: 247.1180. Found: 247.1171.
EXAMPLE 2
Borylation of 4-chlorobenzonitrile




General procedure A was applied to 4-chlorobenzonitrile (550.3 mg, 4 mmol) and HBPin (145 μL, 128 mg, 1 mmol) with a reaction time of 36 h. The ratio of the two isomers in the crude reaction mixture by GC was 80:20. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (200 mg, 76%) as a white solid. The ratio of the two isomers in the isolated product by GC was 81:19. gHMBC spectroscopy (FIG. 1) was used to assign the major isomer as 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 300 MHz): δ (major isomer) 7.80 (d, J=2.2 Hz, 1H, Ha), 7.57 (d, J=8.3 Hz, 1H, Hc), 7.45 (dd, J=8.3, 2.2 Hz, 1H, Hb), 1.33 (br s, 12H), (minor isomer) 7.94 (d, J=2.2 Hz, 1H, Hd), 7.56 (dd, J=8.3, 2.2 Hz, 1H, He), 7.41 (d, J=8.3 Hz, 1H, Hf), 1.32 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ (major isomer) 138.5 (C1), 135.8 (C2), 134.5 (C5), 131.2 (C6), 118.0 (nitrile C7), 115.3 (C4), 85.0 (C8), 24.6 (C9), (minor isomer) 144.5 (C1′), 140.1 (C3′), 134.6 (C5′), 130.2 (C6′), 117.8 (nitrile C7′), 110.2 (C4′), 84.7 (C8′), 24.6 (C9′); 11B NMR (CDCl3, 96 MHz): δ 29.59; FT-IR (neat): 2982, 2228, 1587, 1554, 1479, 1402, 1373, 1333, 1271, 1215, 1169, 1144, 1103, 1065, 1042, 965, 870, 847, 831 cm−1; LRMS (% rel. int.): m/e (major isomer) 263 M+ (24), 248 (65), 222 (100), 205 (31), 164(32), 137 (11), (minor isomer) 263 M+ (1), 248 (27), 228 (100), 186 (60), 164 (15), 142 (6); Anal. Calcd for C13H15BClNO2: C, 59.25; H, 5.74; N, 5.32. Found: C, 58.90; H, 5.74; N, 5.10.
EXAMPLE 3
Borylation of 4-Bromobenzonitrile




General procedure A was applied to 4-bromobenzonitrile (364.1 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 48 h. The ratio of the two isomers in the crude reaction mixture by GC was 95:5. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (112 mg, 73%) as a white solid. The ratio of the two isomers in the isolated product by GC was 97:3. gHMBC spectroscopy (FIG. 2) was used to assign the major isomer as 4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.97 (d, J=2.0 Hz, 1H, Ha), 7.62 (dd, J=8.3, 2.0 Hz, 1H, Hb), 7.50 (d, J=8.3 Hz, 1H, Hc), 1.33 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 138.8 (C2), 134.5 (C5), 134.2 (C6), 127.1 (C1), 118.1 (nitrile C7), 115.8 (C4), 85.0 (C8), 24.7 (C9); 11B NMR (CDCl3, 96 MHz): δ 29.92; FT-IR (neat): 2980, 2228, 1582, 1551, 1480, 1416, 1399, 1373, 1335, 1271, 1144, 1084, 1069, 963, 862, 841, 763, 673 cm−1; LRMS (% rel. int.): m/e (major isomer) 307 M+ (16), 292 (51), 266 (100), 251 (45), 228 (17), 170 (15); Anal. Calcd for C13H15BBrNO2: C, 50.70; H, 4.91; N, 4.55. Found: C, 50.29; H, 4.75; N, 4.57. HRMS Calcd for C13H15BBrNO2: 307.0379. Found: 307.0376.
EXAMPLE 4
Borylation of 4-Iodobenzonitrile




General procedure B was applied to 4-iodobenzonitrile (229.1 mg, 1 mmol, 1 equivalent) and B2Pin2 (254.0 mg, 1 mmol, 2 equivalents of boron) with a reaction time of 40 h. Only one isomer was observed in crude reaction mixture by GC and by 1H NMR spectroscopy. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford the single pure isomer (255 mg, 71%) as a white solid, mp 77-79° C. gHMBC spectroscopy (FIG. 3) was used to assign the single isomer as 4-iodo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, J=2.0 Hz, 1H, Ha), 7.85 (dd, J=8.3, 2.0 Hz, 1H, Hb), 7.36 (d, J=8.3 Hz, 1H, Hc), 1.34 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ 144.6 (C2), 140.1 (C6), 134.3 (C5), 118.3 (nitrile C7), 116.3 (C4), 99.8 (C1), 85.1 (C8), 24.7 (C9); 11B NMR (CDCl3, 96 MHz): δ 29.77; FT-IR (neat): 2980, 2228, 1576, 1545, 1480, 1414, 1395, 1374, 1335, 1271, 1140, 1071, 963, 859, 839, 826, 673 cm−1; LRMS (% rel. int.): m/e 355 M+ (42), 340 (75), 314 (100), 297 (72), 256 (77), 228 (11); Anal. Calcd for C13H15BINO2: C, 43.99; H, 4.26; N, 3.95. Found: C, 44.17; H, 4.44; N, 3.88.
EXAMPLE 5
Borylation of 4-methylbenzonitrile




General procedure A was applied to 4-methylbenzonitrile (468.6 mg, 4 mmol) and HBPin (145 μL, 128 mg, 1 mmol) using 6 mol % [Ir] with a reaction time of 72 h. The ratio of the two isomers in the crude reaction mixture by GC was 94:6. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (156 mg, 64%) as colorless oil which solidified on standing. The ratio of the two isomers in the isolated product by GC was 92:8. The major isomer was assigned as 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile by the NOESY1D spectrum and by preparing an authentic sample using a slightly modified literature procedure (Miyaura, N., et al., Tetrahedron 2001, 57, 9813-9816). 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.67 (br s, 1H, Ha), 7.57 (d, J=7.9 Hz, 1H, Hb or Hc), 7.30 (d, J=7.9 Hz, 1H, Hb or Hc), 2.38(s, 3H), 1.36 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 142.2 (C1), 136.5, 133.4, 131.8 (C2, C5 and C6), 119.2 (nitrile C7), 114.2 (C4), 84.7 (C8), 24.8 (C9), 21.5 (C10); 11B NMR (CDCl3, 96 MHz): δ 30.36; FT-IR (neat): 2980, 2932, 2226, 1603, 1491, 1447, 1408, 1391, 1381, 1373, 1346, 1265, 1213, 1140, 1069, 965, 853, 828, 675, 661 cm−1; LRMS (% rel. int.): m/e 243 M+ (46), 228 (70), 202 (100), 185 (52), 144 (92), 117 (25); Anal. Calcd for C14H18BNO2: C, 69.17; H, 7.46; N, 5.76. Found: C, 68.74; H, 7.64; N, 5.62. HRMS Calcd for C14H18BNO2: 243.1431. Found: 243.1425.
Preparation of an Authentic Sample of 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile
In a glove box, a 100 mL schlenk flask, equipped with a magnetic stirring bar, was charged with Pd2(dba)3 (13.8 mg, 0.015 mmol, 3 mol % Pd) and tricyclohexylphosphine (PCy3, 20.2 mg, 0.072 mmol, 7.2 mol %). Dioxane (6 mL) was added and the resulting mixture was stirred for 30 minutes at room temperature. B2Pin2 (280 mg, 1.1 mmol), KOAc (147 mg, 1.5 mmol), and 2-bromo-4-methylbenzonitrile (196 mg, 1 mmol) were added successively. The schlenk flask was brought to a schlenk line. A condenser was attached, and the flask was flushed with nitrogen. The reaction mixture was stirred at 80° C. for 12 h. The mixture was treated with water (5 mL), and the product was extracted with ether, washed with brine, and dried over MgSO4. Kugelrohr distillation furnished the desired product (151 mg, 62%) as a colorless oil. Its spectral data matched the major isomer obtained from the catalytic borylation of 4-methylbenzonitrile described earlier.
EXAMPLE 6
Borylation of 4-methoxylbenzonitrile




General procedure A was applied to 4-methoxybenzonitrile (266.3 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 24 h. The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was 67:33. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (84 mg, 65%) as a colorless oil. The ratio of the two isomers in the isolated product by 1H NMR spectroscopy was 67:33. The NOESY1D and gHMBC spectra (FIG. 4) were used to assign the major isomer as 4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.59 (d, J=8.5 Hz, 1H, Hc), 7.31 (d, J=2.9 Hz, 1H, Ha), 6.97 (dd, J=8.5, 2.9 Hz, 1H, Hb), 3.84 (s, 3H), 1.35 (br s, 12H), (minor isomer) 7.93 (d, J=2.4 Hz, 1H, Hd), 7.65 (dd, J=8.8, 2.4 Hz, 1H, He), 6.87 (d, J=8.8 Hz, 1H, Hf), 3.85 (s, 3H), 1.32 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 161.7 (C1), 135.3 (C5), 120.6 (C2), 119.3 (nitrile C7), 117.0 (C6), 108.8 (C4), 84.8 (C8), 55.5 (C10), 24.73 (C9), (minor isomer) 166.9 (C1′), 140.9 (C3′), 136.6 (C5′), 119.2 (nitrile C7′), 110.7 (C6′), 103.6 (C4′), 84.1 (C8′), 55.5 (C10′), 24.7 (C9′); 11B NMR (CDCl3, 96 MHz): δ 30.50; FT-IR (neat): 2980, 2942, 2842, 2224, 1601, 1493, 1466, 1449, 1424, 1412, 1373, 1345, 1271, 1238, 1144, 1060, 1030, 965, 853, 830 cm−1; LRMS (% rel. int.): m/e 259 M+ (100), 244 (61), 232 (9), 216 (73), 201 (65), 186 (25), 174 (20), 160 (79); HRMS Calcd for C14H18BNO3: 259.1380. Found: 259.1383.
EXAMPLE 7
Borylation of 4-thiometylbenzonitrile




General procedure A was applied to 4-thiomethylbenzonitrile (298.5 mg, 2 mmol, 2 equivalents) and B2Pin2 (127 mg, 0.5 mmol, 1 equivalent of boron) at 80° C. with a reaction time of 18 h. The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was 90:10. Kugelrohr distillation gave a fraction (155 mg) containing two isomers along with small amount of dtbpy. Passing a CH2Cl2 solution of that fraction through a plug of silica furnished a mixture of two isomeric borylated products (150 mg, 55%) as a white solid. The ratio of the two isomers in the isolated product by 1H NMR spectroscopy was 87:13. The NOESY1D and gHMBC spectra (FIG. 5) were used to assign the major isomer as 4-thiomethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.63 (d, J=2.0 Hz, 1H, Ha), 7.54 (d, J=8.3 Hz, 1H, Hc), 7.27 (dd, J=8.3, 2.0 Hz, 1H, Hb), 2.48 (s, 3H), 1.35 (br s, 12H), (minor isomer) 7.92 (d, J=2.0 Hz, 1H, Hd), 7.56 (dd, J=8.3, 2.0 Hz, 1H, He), 7.14 (d, J=8.3 Hz, 1H, Hf), 2.44 (s, 3H), 1.34 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 144.7 (C1), 133.4 (C5), 132.2 (C2), 127.1 (C6), 119.1 (nitrile C7), 112.4 (C4), 84.8 (C8), 24.7 (C9), 14.61 (C10), (minor isomer) 152.7 (C1′), 139.3 (C3′), 134.1 (C5′), 122.9 (C6′), 119.0 (nitrile C7′), 106.7 (C4′), 84.6 (C8′), 24.7 (C9′), 15.0 (C10′); 11B NMR (CDCl3, 96 MHz): δ 30.27; FT-IR (neat): 2980, 2928, 2224, 1584, 1547, 1483, 1397, 1381, 1373, 1345, 1269, 1213, 1167, 1142, 1107, 1059, 963, 871, 847, 825, 769, 741, 669 cm−1; LRMS (% rel. int.): m/e 275 M+ (100), 260 (26), 232 (41), 217 (46), 202 (9), 190 (10), 175 (54); Anal. Calcd for C14H18BNO2S: C, 61.11; H, 6.59; N, 5.09. Found: C, 61.24; H, 6.95; N, 5.05; HRMS Calcd for C14H18BNO2S: 275.1151. Found: 275.1157.
EXAMPLE 8
Borylation of 4-dimethylaminobenzonitrile




General procedure B was applied to 4-dimethylaminobenzonitrile (146.2 mg, 1 mmol, 1 equivalent) and B2Pin2 (254.0 mg, 1 mmol, 2 equivalents of boron) using 6 mol % [Ir] with a reaction time of 72 h. Only one isomer was observed in the crude reaction mixture by GC and by 1H NMR spectroscopy. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford the single pure isomer (180 mg, 66%) as a white solid, mp 110-111° C. The NOESY1D and gHMBC spectra (FIG. 6) were used to assign the single isomer as 4-dimethylamino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 300 MHz): δ 7.48 (d, J=8.8 Hz, 1H, Hc), 7.04 (d, J=2.9 Hz, 1H, Ha), 6.67 (dd, J=8.8, 2.9 Hz, 1H, Hb), 3.01(s, 6H), 1.35 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ 151.4 (C1), 134.8 (C5), 120.7 (nitrile C7), 118.1 (C2), 113.2 (C6), 102.3 (C4), 84.5 (C8), 39.9 (C10), 24.7 (C9); 11B NMR (CDCl3, 96 MHz): δ 30.5; FT-IR (neat): 2980, 2932, 2815, 2213, 1597, 1553, 1508, 1485, 1429, 1416, 1374, 1337, 1271, 1230, 1169, 1144, 1053, 968, 847, 816 cm−1; LRMS (% rel. int.): m/e 272 M+ (100), 257 (7), 229 (11), 214 (11), 189 (6), 173 (23); Anal. Calcd for C15H21BN2O2: C, 66.2; H, 7.78; N, 10.29. Found: C, 66.54; H, 7.76; N, 10.06.
EXAMPLE 9
Borylation of methyl 4-cyanobenzoate




General procedure B was applied to methyl 4-cyanobenzoate (161.2 mg, 1 mmol, 1 equivalent) and B2Pin2 (203.0 mg, 0.8 mmol, 1.6 equivalents of boron) with a reaction time of 48 h. Only one isomer was observed in the crude reaction mixture by GC and by 1H NMR spectroscopy. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford the single pure isomer (190 mg, 66%) as a white solid, mp 136-137° C. The NOESY1D and gHMBC spectra (FIG. 7) were used to assign the single isomer as methyl 4-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzoate. 1H NMR (CDCl3, 300 MHz): δ 8.49 (d, J=1.7 Hz, 1H, Ha), 8.14 (dd, J=8.1, 1.9 Hz, 1H, Hb), 7.75 (d, J=8.1 Hz, 1H, Hc), 3.93 (s, 3H), 1.37 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ 165.6 (C10), 136.6 (C2), 133.4 (C5), 132.7 (C1), 131.9 (C6), 121.1 (C4), 118.1 (nitrile C7), 85.1 (C8), 52.6 (C11), 24.8 (C9); 11B NMR (CDCl3, 96 MHz): δ 30.1; FT-IR (neat): 2980, 2954, 2230, 1721, 1603, 1487, 1410, 1375, 1337, 1279, 1251, 1144, 1115, 1069, 976, 851, 770, 654 cm−1; LRMS (% rel. int.): m/e 287 M+ (5), 272 (32), 256 (20), 244 (100), 229 (18), 188 (26), 156 (14); Anal. Calcd for C15H18BNO4: C, 62.75; H, 6.32; N, 4.88. Found: C, 62.33; H, 6.26; N, 4.79. HRMS Calcd for C15H18BNO4: 287.1329. Found: 287.1327.
EXAMPLE 10
Borylation of 4′-cyanoacetanilide




General procedure B was applied to 4′-cyanoacetanilide (160.2 mg, 1 mmol, 1 equivalent) and B2Pin2 (406 mg, 1.6 mmol, 3.2 equivalents of boron) using 8 mol % [Ir] with a reaction time of 18 h. One borylated isomer was observed in the crude reaction mixture by GC and by 1H NMR spectroscopy along with a small amount of borylated/reduced (reduction of carbonyl group to CH2) as a side product. Solvent was removed under reduced pressure. Column chromatography (ether, Rf=0.5) gave a mixture of the desired product and pinacol (239 mg). Kugelrohr distillation furnished the desired product (177 mg, 62%) as a white solid, mp 178-180° C. The gHMBC spectrum (FIG. 8) was used to assign the single isomer as 4′-cyano-3′-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)acetanilide. 1H NMR (CDCl3, 500 MHz): δ 7.99 (dd, J=8.3, 2.0 Hz, 1H, Hb), 7.85 (s, 1H, N—H), 7.77 (d, J=2.4 Hz, 1H, Ha), 7.63 (d, J=8.3 Hz, 1H, Hc), 2.18 (s, 3H), 1.32 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ 168.8 (C10), 141.1 (C1), 134.7 (C5), 125.9 (C2), 121.5 (C6), 119 (nitrile C7), 111.6 (C4), 84.8 (C8), 24.7 (C9), 24.6 (C11); 11B NMR (CDCl3, 96 MHz): δ 30.52; FT-IR (neat): 3319, 3104, 2980, 2934, 2225, 1701, 1678, 1601, 1578, 1532, 1497, 1416, 1373, 1344, 1302, 1258, 1140, 1063, 965, 853, 800, 743, 675 cm−1; LRMS (% rel. int.): m/e 286 M+ (100), 271 (18), 253 (32), 244 (89), 228 (68), 201 (42), 187 (68), 158 (13), 144 (58); HRMS Calcd for C15H19BN2O3: 286.1489. Found: 286.1493.
EXAMPLE 11
Borylation of 4-(trifluoromethyl)benzonitrile




General procedure B was applied to 4-(trifluoromethyl)benzonitrile (171.1 mg, 1 mmol, 1 equivalent) and HBPin (175 μL, 154 mg, 1.2 mmol) in n-hexane (3 mL) with a reaction time of 12 h. One monoborylated product and one diborylated product were observed in the crude reaction mixture by GC (90:10). Solvent was removed under reduced pressure. The crude mixture was eluted with CH2Cl2 through a plug of silica gel. Sublimation furnished the desired single monoborylated product (203 mg, 68%) as a white solid, mp 79-80° C. 13C NMR spectroscopy was used to assign the single isomer as 4-(trifluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 500 MHz): δ 8.12 (s, 1H, Ha), 7.81 (d, J=7.8 Hz, 1H, Hb or Hc), 7.76 (d, J=7.8 Hz, 1H, Hb or Hc), 1.38 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ 133.7 (C5), 133.3 (q, 2JC-F=33.2 Hz, C1), 132.5 (q, 3JC-F=2.1 Hz, C2), 127.8 (q, 3JC-F=3.3 Hz, C6), 122.1 (q, 1JC-F=273 Hz, C10), 120.7 (C4), 117.6 (nitrile C7), 85.3 (C8), 24.7 (C9); 11B NMR (CDCl3, 96 MHz): δ 30.03; 19F NMR (CDCl3, 282 MHz): δ −63.4; FT-IR (neat): 2982, 2234, 1613, 1574, 1423, 1354, 1306, 1271, 1175, 1142, 1082, 1065, 965, 878, 849, 675 cm−1; LRMS (% rel. int.): m/e 297 M+ (23), 282 (100), 256 (81), 239 (27), 198 (19), 171 (10); HRMS Calcd for C14H15BF3NO2: 297.1148. Found: 297.1144.
EXAMPLE 12
Borylation of Benzonitrile




General procedure A was applied to benzonitrile (412.5 mg, 4 mmol) and HBPin (145 μL, 128 mg, 1 mmol) with a reaction time of 12 h. The ratio of the three isomers in the crude reaction mixture by GC was 5.7:64.4:29.9. Solvent and excess substrate were removed under reduced pressure. The crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of the three isomeric borylated products (176 mg, 77%) as a white solid. 1H NMR, gCOSY, and gHMBC spectroscopy were used to assign the major isomer as 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile. 1H NMR (CDCl3, 300 MHz): δ (major/meta isomer) 8.07-8.05 (br s, 1H), 7.98 (td, J=7.5, 1.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.44 (dt, J=7.5, 0.7 Hz, 1H), 1.32 (br s, 12H), (minor/para isomer) 7.87-7.84 (m, 2H), 7.62-7.59 (m, 2H), 1.32 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ (major/meta isomer) 138.7, 138.3, 134.3, 128.3, 118.7, 112, 84.4, 24.8, (minor/para isomer) 135, 131, 118.7, 114.4, 84.7, 24.8; 11B NMR (CDCl3, 96 MHz): δ 31.2; FT-IR (neat): 3063, 2980, 2934, 2230, 1603, 1483, 1398, 1360, 1329, 1271, 1143, 1088, 964, 880, 849, 700, 653 cm−1; LRMS (% rel. int.): m/e (major/meta isomer) 229 M+ (11), 230 M+1  (29), 214 (100), 186 (10), 143 (44), (minor/para isomer) 229 M+ (5), 230 M+1  (14), 186 (9), 143 (41); HRMS Calcd for C13H16BNO2: 229.1274. Found: 229.1271.
EXAMPLE 13
Borylation of 2-fluoro-4-bromobenzonitrile




General procedure B was applied to 2-fluoro-4-bromobenzonitrile (200 mg, 1 mmol, 1 equivalent) and HBPin (290 μL, 256 mg, 2 mmol, 2 equivalent) with a reaction time of 9 h. The ratio of the two borylated isomers in the crude reaction mixture by 1H NMR spectroscopy was 95:5. A small amount of diborylated product was also observed. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel. Sublimation afforded a mixture of two isomeric borylated products (278 mg, 85%) as a white solid. The ratio of the two borylated isomers in the isolated product by 1H NMR spectroscopy was 95:5. 1H NMR spectroscopy were used to assign the major isomer as 2-fluoro-4-bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.77 (d, J=1.7 Hz, 1H), 7.44 (dd, 2JH-F=8.3 Hz, J=1.7 Hz, 1H), 1.35 (br s, 12H), (minor isomer) 7.90 (d, 3JH-F=7.5 Hz, 1H), 7.42 (d, 2JH-F=8.5 Hz, 1H), 1.35 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ (major isomer) 163.3 (d, 1JC-F=262.8 Hz, C3), 134.6 (d, 4JC-F=4 Hz, C6), 127.8 (d, 3JC-F=8 Hz, C5), 122 (d, 2JC-F=23 Hz, C4), 112.9 (nitrile, C1), 104.6 (d, 2JC-F=14.1 Hz, C2), 85.4, 24.7; 11B NMR (CDCl3, 96 MHz): δ 29.94; 19F NMR (CDCl3, 282 MHz): δ (major isomer) −103.9 (d, J=7.9 Hz); FT-IR (neat): 3086, 2986, 2934, 2237, 1590, 1557, 1462, 1408, 1375, 1358, 1329, 1140, 972, 985, 880, 843, 742, 665 cm−1; LRMS (% rel. int.): m/e (major isomer) 325 M+ (15), 310 (37), 284 (67), 267 (34), 246 (31), 226 (57); Anal. Calcd for C13H14BBrFNO2: C, 47.90; H, 4.33; N, 4.3. Found: C, 48.15, H, 4.28; N, 4.16.
EXAMPLE 14
Borylation of 3,4-dichlorobenzonitrile




General procedure B was applied to 3,4-dichlorobenzonitrile (172 mg, 1 mmol, 1 equivalent) and HBPin (218μL, 192 mg, 1.5 mmol, 1.5 equivalent) with a reaction time of 18 h. The ratio of the two borylated isomers in the crude reaction mixture by 1H NMR spectroscopy was 80:20. Solvent was removed under reduced pressure and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of two isomeric borylated products (265 mg, 89%) as a white solid. The ratio of the two borylated isomers in the isolated product by 1H NMR spectroscopy was 81:19. 1H NMR spectroscopy was used to assign the major isomer as 4,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.92 (s, 1H), 7.73 (s, 1H), 1.35 (br s, 12H), (minor isomer) 7.84 (d, J=2 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 1.35 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 137.7, 137.1, 135.8, 134.8, 116.9, 111.3, 85.3, 24.7, (minor isomer) 142.7, 137.6, 135, 134.3, 116.8, 111.3, 85, 24.7; 11B NMR (CDCl3, 96 MHz): δ 29.9; FT-IR (neat): 2982, 2234, 1580, 1535, 1472, 1383, 1342, 1304, 1142, 1084, 964, 910, 850, 669 cm−1; LRMS (% rel. int.): m/e (major isomer) 297 M+ (22), 282 (60), 256 (100), 239 (48), 198 (41), (minor isomer) 297 M+ (1), 282 (28), 262 (100), 220 (80); Anal. Calcd for C13H14BCl2NO2: C, 52.40; H, 4.74; N, 4.70. Found: C, 52.42; H, 4.79; N, 4.55; HRMS Calcd for C13H14BCl2NO2: 297.0495. Found: 297.0500.
EXAMPLE 15
Diborylation of 4-fluorobenzonitrile




General procedure C was applied to 4-fluorobenzonitrile (121.2 mg, 1 mmol, 1 equivalent) and HBPin (580 μL, 512 mg, 4 mmol, 4 equivalent) with a reaction time of 24 h. The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was 54:46. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of two isomeric diborylated products (343 mg, 92%) as a white solid. The ratio of the two diborylated isomers in the isolated product by 1H NMR spectroscopy was 53:47. 1H, 13C NMR and gHMBC spectroscopy were used to assign the major isomer as 4-fuoro-3,5-bis-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 8.1 (d, 4JH-F=4.9 Hz, 2H, Ha), 1.28 (br s, 24H), (minor isomer) 8.04 (d, 4JH-F=5.4 Hz, 1H, Hb), 7.46 (d, 3JH-F=8.8 Hz, 1H, Hc), 1.32 (s, 12H), 1.31 (s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 172 (d, 1JC-F=266 Hz, C1), 143.9 (d, 3JC-F=10.9 Hz, C3), 117. 9 (nitrile C5), 108 (d, 4JC-F=3.6 Hz, C4), 84.4 (C6), 24.7(C7), (minor isomer) 168.1 (d, 1JC-F=261.4 Hz, C1′), 142.6 (d, 3JC-F=8.8 Hz, C3′), 122.6 (d, 2JC-F=23.8 Hz, C6′), 118.1 (nitrile C7′), 112.6 (d, 4JC-F=3.6 Hz, C4′), 85, 84.5, 24.7; 11B NMR (CDCl3, 96 MHz): δ 29.8; 19F NMR (CDCl3, 282 MHz): δ (major isomer) −81.8 (m), (minor isomer) −94.9 (m); FT-IR (neat): 2980, 2934, 2232, 1599, 1497, 1437, 1414, 1373, 1334, 1267, 1215, 1142, 1095, 966, 889, 848, 584 cm−1; LRMS (% rel. int.): m/e (major isomer) 373 M+ (4), 358 (59), 353 (100), 315 (22), 253 (45), (minor isomer) 373 M+ (32), 358 (68), 331 (100), 315 (53), 274 (39); Anal. Calcd for C19H26B2FNO4: C, 61.17; H, 7.03; N, 3.75. Found: C, 61.37,; H, 6.83; N, 3.82.
EXAMPLE 16
Diborylation of 4-methoxybenzonitrile




General procedure C was applied to 4-methoxybenzonitrile (133.2 mg, 1 mmol, 1 equivalent) and HBPin (580 μL, 512 mg, 4 mmol, 4 equivalent) at 60° C. for 48 h. The ratio of the two diborylated isomers in the crude reaction mixture by 1H NMR spectroscopy was 80:20. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of two isomeric diborylated products (310 mg, 81%) as a white solid. The ratio of the two diborylated isomers in the isolated product by 1H NMR spectroscopy was 80:20. 1H NMR and gHMBC spectroscopy were used to assign the major isomer as 4-methoxy-2,5-bis-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile. 1H NMR (C6D6, 500 MHz): δ (major isomer) 8.42 (s, 1H, Ha), 7.36 (s, 1H, Hb), 3.20 (s, 3H), 1.10 (br s, 12H), 1.06 (br s, 12H), (minor isomer) 7.61 (s, 2H, Hc), 3.08 (s, 3H), 1.11 (br s, 12H); 13C NMR {1H} (C6D6, 125 MHz): δ (major isomer) 166.3 (C1), 143.1 (C3), 137.4 (br, C5), 122.1 (br, C2), 119.32 (nitrile, C7), 117.36 (C6), 110.1 (C4), 84.8, 83.8, 24.79, 24.76, (minor isomer) 160.8 (C1′), 123.4 (C2′), 118.6 (nitrile C5′), 114.9 (C4′), 84.6 24.8; 11B NMR (CDCl3, 96 MHz): δ 30.90; FT-IR (neat): 2980, 2936, 2224, 1601, 1503, 1398, 1373, 1337, 1244, 1142, 1094, 964, 858 cm−1; LRMS (% rel. int.): m/e 385 M+ (100), 370 (63), 343 (98), 327 (53), 286 (41); Anal. Calcd for C20H29B2NO5: C, 62.38; H, 7.59; N, 3.64. Found: C, 62.36; H, 7.41; N, 3.69.
EXAMPLE 17
Diborylation of 4-chlorobenzonitrile




General procedure C was applied to 4-chlorobenzonitrile (137.6 mg, 1 mmol, 1 equivalent) and HBPin (580 μL, 512 mg, 4 mmol, 4 equivalent) with a reaction time of 48 h. The ratio of the two diborylated isomers in the crude reaction mixture by GC-FID was 80:20. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of two isomeric diborylated products (320 mg, 82%) as a white solid. The ratio of the two diborylated isomers in the isolated product by GC-FID was 80:20. 1H NMR and gHMBC spectroscopy were used to assign the major isomer as 4-chloro-2,5-bis-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 7.97 (s, 1H, Ha), 7.80 (s, 1H, Hb), 1.35 (br s, 12H), 1.344 (br s, 12H), (minor isomer) 7.83 (s, 2H, Hc), 1.349 (br s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 143.6 (C1), 141.2 (C3), 136.5 (C6), 118.2 (nitrile, C7), 114.8 (C4), 85.1, 84.8, 24.7, (minor isomer) 137.7 (C1′), 137.3 (C2′), 119.7(C4′), 117.6 (nitrile C5′), 85.04,24.7; 11B NMR (CDCl3, 96 MHz): δ 30.25; FT-IR (neat): 2980, 2230, 1591, 1383, 1341, 1269, 1142, 1122, 1088, 962, 855 cm−1; LRMS (% rel. int.): m/e (major isomer) 389 M+ (30), 374 (57), 354 (100), 347 (88), 331 (39), 312 (37), 290 (35), (minor isomer) 389 M+ (36), 374 (64), 348 (23),290 (53), 248 (49), 207 (100); Anal. Calcd for C19H26B2ClNO4: C, 58.59; H, 6.73; N, 3.6. Found: C, 58.27, H, 6.78; N, 3.41; HRMS Calcd for C19H26B2ClNO4: 389.1736. Found: 389.1746.
EXAMPLE 18
Diborylation of 1,4-dicyanobenzene




General procedure C was applied to 1,4-dicyanobenzene (128.2 mg, 1 mmol, 1 equivalent) and HBPin (580 μL, 512 mg, 4 mmol, 4 equivalent) with a reaction time of 20 h. The ratio of the two diborylated isomers in the crude reaction mixture by GC-FID was 93:7. Solvent was removed under reduced pressure. Crystallization from THF/pentane gave the major isomer (270 mg, 71%) as a white solid, mp 242-245° C. 13C NMR spectroscopy were used to assign the major isomer as 2,5-bis-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-1,4-dicyanobenzene. 1H NMR (CDCl3, 500 MHz): δ (major isomer) 8.16 (s, 2H), 1.37 (br s, 24H), (minor isomer) 8.15 (s, 2H), 1.37 (br s, 24H); 13C NMR {1H} (CDCl3, 75 MHz): δ (major isomer) 140.1 (C4, 2C), 135.4 (br, C3, 2C), 120.1 (C2, 2C), 117.4 (nitrile, C1, 2C), 85.4, 24.7; 11B NMR (CDCl3, 96 MHz): δ 30.16; FT-IR (neat): 2984, 2230, 1497, 1416, 1391, 1347, 1287, 1267, 1169, 1140, 1100, 962, 927, 855, 814, 711, 598 cm−1; LRMS (% rel. int.): m/e (major isomer) 380 M+ (35), 365 (69), 339 (100), 322 (69), 281 (46); Anal. Calcd for C20H26B2N2O4: C, 63.21; H, 6.90; N, 7.37. Found: C, 63.39, H, 7.19; N, 7.02.
EXAMPLE 19
Diborylation of 4-(trifluoromethyl)-benzonitrile




General procedure C was applied to 4-(trifluoromethyl)-benzonitrile (171.2 mg, 1 mmol, 1 equivalent) and HBPin (580 μL, 512 mg, 4 mmol, 4 equivalent) with a reaction time of 36 h. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford single diborylated isomer (350 mg, 83%) as a white solid. 13C NMR spectroscopy were used to assign the single isomer as 4-(trifluoromethyl)-2,6-bis-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-benzonitrile. 1H NMR (CDCl3, 300 MHz): δ 8.12 (s, 2H), 1.37 (br s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ 133.9 (q, 3JC-F=3 Hz, C2), 132 (q, 2JC-F=32.2 Hz, C1), 125 (nitrile, C5), 123.3 (q, 1JC-F=273 Hz, CF3), 117.1 (C4), 85.2, 24.7; 11B NMR (CDCl3, 96 MHz): δ 30.14; 19F NMR (CDCl3, 282 MHz): δ −63.3; FT-IR (neat): 2982, 2936, 2234, 1582, 1469, 1431, 1383, 1373, 1334, 1319, 1290, 1269, 1245, 1140, 1080, 966, 883, 846, 690 cm−1; LRMS (% rel. int.): m/e 423 M+ (45), 408 (100), 382 (36), 324 (45), 282 (62); Anal. Calcd for C20H26B2F3NO4: C, 56.78; H, 6.19; N, 3.31. Found: C, 56.81; H, 5.92; N, 3.29; HRMS Calcd for C20H26B2F3NO4: 423.2000. Found: 423.1999.
EXAMPLE 20
Borylation of 1,5-dimethyl-2-pyrrolecarbonitrile




General procedure B was applied to 1,5-dimethyl-2-pyrrolecarbonitrile (240.3 mg, 2 mmol, 1 equivalent) and HBPin (435 μL, 384 mg, 3 mmol, 1.5 equivalents) with a reaction time of 16 h. The ratio of the two isomers in the crude reaction mixture by GC was 85:15. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of two isomeric borylated products (394 mg, 80%) as a white solid. The ratio of the two isomers in the isolated product by GC was 82:18. The NOESY1D and gHMBC spectra (FIG. 9) were used to assign the major isomer as 1,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-2-pyrrolecarbonitrile. 1H NMR (CDCl3, 300 MHz): δ (major isomer) 6.21 (d, 4J=0.7 Hz, 1H, pyrrol ring H), 3.63 (s, 3H, N—CH3), 2.21 (d, 4J=0.7 Hz, 3H, CH3 on pyrrol ring), 1.30 (br s, 12H), (minor isomer) 7.03 (s, 1H, pyrrol ring H), 3.6 (s, 3H, N—CH3), 2.41 (s, 3H, CH3 on pyrrol ring), 1.27 (s, 12H); 13C NMR {1H} (CDCl3, 125 MHz): δ (major isomer) 135.4 (C5), 114 (C4), 113.8 (nitrile C7), 109.6 (C2), 83.0 (C8), 32.0 (C1), 24.3 (C9), 11.8 (C6), (minor isomer) 143.9 (C5′), 125.2 (C3′), 113.7 (nitrile C7′), 103.8 (C2′), 82.6 (C8′), 31.8 (C1′), 24.4 (C9′), 11.9 (C6′); 11B NMR (CDCl3, 96 MHz): δ 32.75; FT-IR (neat): 2980. 2934, 2735, 1561, 1501, 1441, 1408, 1390, 1379, 1371, 1313, 1262, 1187, 1167, 1144, 1111, 1017, 860, 835, 708 cm−1; LRMS (% rel. int.): m/e (major isomer) 246 M+ (100), 231 (19), 203 (12), 189 (16), 160 (13), 146 (20), (minor isomer) 246 M+ (100), 231 (20), 189 (51), 160 (21), 146 (43); Anal. Calcd for C13H19BN2O2: C, 63.44; H, 7.78; N, 11.38. Found: C, 63.34; H, 7.78; N, 11.34.
EXAMPLE 21
Borylation of 5-methyl-2-furonitrile




General procedure B was applied to 5-methyl-2-furonitrile (210 uL, 214.2 mg, 2 mmol, 1 equivalent) and HBPin (435 μL, 384 mg, 3 mmol, 1.5 equivalents) with a reaction time of 0.5 h. The ratio of the two isomers in the crude reaction mixture by GC was 85:15. Solvent was removed under reduced pressure, and the crude mixture was eluted with CH2Cl2 through a plug of silica gel to afford a mixture of two isomeric borylated products (456 mg, 97%) as a white solid. The ratio of the two isomers in the isolated product by GC was 90:10. The NOESY1D and gHMBC spectra (FIG. 10) were used to assign the major isomer as 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-2-furonitrile. 1H NMR (CDCl3, 300 MHz): δ (major isomer) 6.23 (d, 4J=1.0 Hz, 1H, furan ring H), 2.29 (d, 4J=1.0 Hz, 3H, CH3 on furan ring), 1.27 (br s, 12H), (minor isomer) 7.12 (s, 1H, furan ring H), 2.46 (s, 3H, CH3 on furan ring), 1.25 (s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ (major isomer) 157.6 (C5), 130.4 (C2), 111.9 (nitrile C1), 111.5 (C4), 84.3 (C7), 24.6 (C8), 13.4 (C6), (minor isomer) 167 (C5′), 127.4 (C3′), 124.1 (C2′), 111.7 (nitrile C1′), 83.8 (C7′), 24.7 (C8′), 14.2 (C6′); 11B NMR (CDCl3, 96 MHz): δ 28.9; FT-IR (neat): 2982, 2934, 1595, 1543, 1446, 1428, 1408, 1392, 1381, 1373, 1335, 1302, 1228, 1169, 1143, 1043, 963, 855, 804, 712 cm−1; LRMS (% rel. int.): m/e (major isomer) 233 M+ (89), 218 (42), 203 (20), 190 (64), 175 (59), 149 (100), 134 (47), (minor isomer) 233 M+ (100), 218 (81), 191 (54), 175 (62), 149 (53), 133 (63); Anal. Calcd for C12H16BNO3: C, 61.84; H, 6.92; N, 6.01. Found: C, 62.25; H, 7.0; N, 5.80.
EXAMPLE 22
Borylation of 5-bromo-2-cyanopyridine




General procedure B was applied to 5-bromo-2-cyanopyridine (183 mg, 1 mmol, 1 equivalent) and HBPin (290 μL, 256 mg, 2 mmol, 2 equivalent) with a reaction time of 18 h. The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was 67:33. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (253.5 mg, 81%) as a white solid. The ratio of the two isomers in the isolated product by 1H NMR spectroscopy was 64:36. 1H NMR and gHMBC spectroscopy were used to assign the major isomer as 5-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-2-cyanopyridine. 1H NMR (CDCl3, 300 MHz): δ (major isomer) 8.76 (d, J=2.4 Hz, 1H, Ha), 8.28 (d, J=2.4 Hz, 1H, Hb), 1.37 (br s, 12H), (minor isomer) 8.76 (s, 1H, Hc), 7.85 (s, 1H, Hd), 1.36 (s, 12H); 13C NMR {1H} (CDCl3, 75 MHz): δ (major isomer) 153.6 (C6), 145.8 (C4), 136.1 (C2), 124.4 (C5), 116.6 (nitrile C1), 85.7 (C7), 24.8 (C8), (minor isomer) 153.1 (C6′), 134.5 (C3′), 131.4 (C2′), 130.1 (C5′), 116.7 (nitrile C1′), 85.6 (C7′), 24.8 (C8′); 11B NMR (CDCl3, 96 MHz): δ 29.5; FT-IR (neat): 3048, 2979, 2244, 1566, 1539, 1416, 1383, 1342, 1318, 1269, 1142, 1069, 1026, 964, 872, 847, 771 cm−1; LRMS (% rel. int.): m/e (major isomer) 308 M+ (41), 310 (M2+ 37), 293 (95), 267 (96), 250 (65), 229 (34), 209 (42), (minor isomer) 308 M+ (7), 293 (33), 267 (17), 229 (100), 187 (91); Anal. Calcd for C12H14BBrN2O2: C, 46.65; H, 4.57; N, 9.07. Found: C, 46.52; H, 4.48; N, 8.761.
EXAMPLE 23
Borylation of 2-Cyano-5-Bromopyridine




In a glove box, a 20 mL scintillation vial equipped with a magnetic stirring bar, was charged with 2,2′-bis[(4S)-4-benzyl-2-oxazoline] (9.6 mg, 0.03 mmol, 3 mol %). Ether (1 mL) was added to the scintillation vial in order to dissolve the ligand. [Ir(OMe)(COD)]2 (10 mg, 0.015 mmol, 3 mol % Ir) was weighed in a test tube. HBPin (218 μL, 192 mg, 1.50 mmol, 1.50 equiv) and ether (1 mL) were added to the [Ir(OMe)(COD)]2 containing test tube. The resulting solution was transferred to the 20 mL scintillation vial. Additional ether (1 mL) was used to wash the test tube and the washings were transferred to the scintillation vial. 2-cyano-5-bromopyridine (183 mg, 1 mmol, 1 equiv) was then added to the scintillation vial and the reaction mixture was stirred at room temperature for 12 h. The ratio of two borylated products at the end of reaction was 92:8 by GC-FID. Kugelrohr distillation gave mixture of monoborylated products as a white solid (263 mg, 85% yield). 1H NMR (CDCl3, 300 MHz): δ (major isomer) 8.76 (d, J=2.4 Hz, 1H, Ha), 8.28 (d, J=2.4 Hz, 1H, Hb), 1.37 (br s, 12 H, CH3 of BPin), (minor isomer) 8.76 (s, 1H, Hc), 7.85 (s, 1H, Hd), 1.36 (s, 12H, CH3 of BPin); 13C NMR {1H} (CDCl3, 75 MHz): δ (major isomer) 153.6 (CH, C6), 145.8 (CH, C4), 136.1 (C, C2), 124.4 (C, C5), 116.6 (C, nitrile C1), 85.7 (C, C7), 24.8 (CH3, C8, CH3 of BPin), (minor isomer) 153.1 (CH, C6′), 134.5 (CH, C3′), 131.4 (C, C2′), 130.1 (C, C5′), 116.7 (C, nitrile C1′), 85.6 (C, C7′), 24.8 (CH3, C8′, CH3 of BPin ); 11B NMR (CDCl3, 96 MHz): δ 29.5; FT-IR (neat) {tilde over (v)}max: 3048, 2979, 2244, 1566, 1539, 1416, 1383, 1342, 1318, 1269, 1142, 1069, 1026, 964, 872, 847, 771 cm−1; GC-MS (EI) m/z (% relative intensity): (major isomer) 308 M+ (41), 310 (M2+ 37), 293 (95), 267 (96), 250 (65), 229 (34), 209 (42), (minor isomer) 308 M+ (7), 293 (33), 267 (17), 229 (100), 187 (91); Anal. Calcd for C12H14BBrN2O2: C, 46.65; H, 4.57; N, 9.07. Found: C, 46.52; H, 4.48; N, 8.761.
EXAMPLE 24
The procedure in Example 23, replacing 2,2′-bis[(4S)-4-benzyl-2-oxazoline] with 2,2′-bis (2-oxazoline) as the ligand, was applied to 2-cyano-5-bromopyridine (183 mg, 1 mmol, 1 equiv) for 6 h. The ratio of two borylated products at the end of reaction was 78:22 by GC-FID. Kugelrohr distillation gave a mixture of monoborylated products as a white solid (242 mg, 78% yield).
EXAMPLE 25
Borylation of 2-Bromo-5-Cyanothiophene




The general procedure in Example 23 was applied to 2-bromo-5-cyanothiophene (111 μL, 188 mg, 1 mmol, 1 equiv) and HBPin (290 μL, 256 mg, 2.00 mmol, 2.00 equiv) with 6% [Ir] catalyst loading for 16 h. Volatile materials were removed on a rotary evaporator. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford the borylated product as a white solid (284 mg, 90% yield, mp 98-100° C.) with >98% isomeric purity by GC-FID. 1H NMR (CDCl3, 500 MHz): δ 7.30 (s, 1H, Ha), 1.30 (br s, 12H, CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz): δ 136.0 (CH), 119.1 (C), 118.8 (C), 113.1 (C), 84.9 (C), 24.7 (CH3, CH3 of BPin); 11B NMR (CDCl3, 96 MHz): δ 28.0; GC-MS (EI) m/z (% relative intensity): M+ 315 (100), 313 (97), 314 (59), 300 (32), 298 (30), 272 (85), 257 (47), 255 (48), 229 (22), 192 (76); Anal. Calcd for C11H13BBrNO2S: C, 42.07; H, 4.17; N, 4.46. Found: C, 42.32; H, 4.11; N, 4.50. It was not possible to borylated this substrate using dtbpy ligand.
EXAMPLE 26
Borylation of 2-Cyano-5-Methylfuran




In a glove box, a 20 mL scintillation vial equipped with a magnetic stirring bar, was charged with 2,2′-bis[(4S)-4-benzyl-2-oxazoline] (9.6 mg, 0.03 mmol, 3 mol %). Ether (1 mL) was added to the scintillation vial in order to dissolve the ligand. [Ir(OMe)(COD)]2 (10 mg, 0.015 mmol, 3 mol % Ir) was weighed in a test tube. HBPin (218 μL, 192 mg, 1.50 mmol, 1.50 equiv) and ether (1 mL) were added to the [Ir(OMe)(COD)]2 containing test tube. The resulting solution was transferred to the 20 mL scintillation vial. Additional ether (1 mL) was used to wash the test tube and the washings were transferred to the scintillation vial. 2-cyano-5-methylfuran (105 μL, 107 mg, 1 mmol, 1 equiv) was added and the mixture was stirred at room temperature for 3 h. Volatile materials were removed on a rotary evaporator. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford the borylated product as a white solid (225 mg, 96% yield) with >99% isomeric purity by 1H NMR. 1H NMR (CDCl3, 300 MHz): δ 6.24 (d, J=1.0 Hz, 1H, Ha), 2.31 (d, J=1.0 Hz, 3 H, CH3), 1.30 (br s, 12H, CH3 of BPin); 13C NMR {1H} (CDCl3, 75 MHz): δ 157.7 (C), 130.5 (C), 112.0 (C), 111.5 (CH), 84.4 (C), 24.7 (CH3, CH3 of BPin), 13.5 (CH3); 11B NMR (CDCl3, 96 MHz): δ 28.9; GC-MS (EI) m/z (% relative intensity): M+1 234 (100), 233 (98), 218 (23), 203 (16), 190 (41), 175 (23).
EXAMPLE 27
Diborylation of 2-Cyanothiophene




In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with {Ir(OMe)(COD)}2 (20 mg, 0.03 mmol, 6 mol % Ir), dtbpy (16.1 mg, 0.06 mmol, 6 mol %), and excess HBPin (4 equivalent of boron). These reagents were dissolved in 3 mL of THF, 2-cyanothiophene (94 μL, 109 mg, 1 mmol, 1 equiv) was added, and the mixture was stirred at room temperature for 1 h. Volatile materials were removed on a rotary evaporator. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford the borylated product as a white solid (317 mg, 88% yield, mp 132-133° C.). 1H NMR (CDCl3, 500 MHz): δ 7.87 (s, 1H, Ha), 1.33 (br s, 12 H, CH3 of BPin), 1.31 (br s, 12H, CH3 of BPin); 13C NMR {1H} (CDCl3, 125 MHz): δ 143.1 (CH), 123.2 (C), 114.3 (C), 84.8 (C), 84.6 (C), 24.8 (CH3, CH3 of BPin), 24.7 (CH3, CH3 of BPin); 11B NMR (CDCl3, 96 MHz); δ 28.6; FT-IR (neat) {tilde over (v)}max: 2980, 2934, 2220, 1532, 1458, 1373, 1319, 1138, 966, 848, 667 cm−1; GC-MS (EI) m/z (% relative intensity): M+1 361 (73), 360 (39), 346 (53), 320 (100), 303 (31); Anal. Calcd for C17H25B2NO4S: C, 56.55; H, 6.98; N, 3.88. Found: C, 56.45; H, 7.16; N, 3.84.
EXAMPLE 28
Diborylation of 3-Cyanothiophene




In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with {Ir(OMe)(COD)}2 (20 mg, 0.03 mmol, 6 mol % Ir), dtbpy (16.1 mg, 0.06 mmol, 6 mol %), and excess HBPin (4 equivalent of boron). These reagents were dissolved in 3 mL of THF, 3-cyanothiophene (91 μL, 109 mg, 1 mmol, 1 equiv) was added, and the mixture was stirred at room temperature for 30 min. Volatile materials were removed on a rotary evaporator. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford the borylated product as a white solid (306 mg, 85% yield). 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 1H, Ha), 1.34 (br s, 12H, CH3 of BPin), 1.31 (br s, 12H, CH3 of BPin); 11B NMR (CDCl3, 96 MHz); δ 28.8.
EXAMPLE 29
Mono borylation of 3-Cyanothiophene
In a glove box, a 20 mL scintillation vial equipped with a magnetic stirring bar, was charged with 2,2′-bis[(4S)-4-benzyl-2-oxazoline]0 (9.6 mg, 0.03 mmol, 3 mol %). Ether (1 mL) was added to the scintillation vial in order to dissolve the ligand. [(Ir(OMe)(COD)]2 (10 mg, 0.015 mmol, 3 mol % Ir) was weighed in a test tube. HBPin (145 μL, 128 mg, 1 mmol, 1 equiv) and ether (1 mL) were added to the [Ir(OMe)(COD)]2 containing test tube. The resulting solution was transferred to the 20 mL scintillation vial. Additional ether (1 mL) was used to wash the test tube and the washings were transferred to the scintillation vial. 3-cyanothiophene (182 μL, 218 mg, 2.00 mmol, 2.00 equiv) was then added to the scintillation vial and the reaction mixture was stirred at room temperature for 1 h. Volatile materials were removed on a rotary evaporator. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford a mixture of borylated isomers (37% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiophene and 63% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiophene). (Note: 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiophene has been prepared by other methods (Christophersen, C. et al., J. Org. Chem. 2003, 68, 9513-9516 and Blackaby, W. P. et al. PCT Int. Appl. WO 2002076983), but never isolated.
2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiphene; 1H NMR (CDCl3, 500 MHz): δ 8.13 (d, J=1.2 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 1.31 (br s, 12H, CH3 of BPin).
2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiphene; 1H NMR (CDCl3, 500 MHz): δ 7.62 (d, J=4.9 Hz, 1H), 7.37 (d, J=4.9 Hz, 1H), 1.34 (br s, 12H, CH3 of BPin).
EXAMPLE 30
The procedure in Example 29 was followed using 2,2′-bis(2-oxazoline) in place 2,2′-bis[(4S)-4-benzyl-2-oxazoline]. The crude material was dissolved in CH2Cl2 and passed through a short plug of silica to afford a mixture of borylated isomers (14% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-4-cyanothiphene and 86% 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-3-cyanothiphene).
The effects of ligand on the regioselectivity for the mono borylation of 3-cyanothiophene is shown below.














Regioselectivity











Ligand








Isolated Yield









53
47
60%


 






37
63
62%


 






14
86
59%









EXAMPLE 31
Mono Borylation of 4-Chlorobenzonitrile
In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with {Ir(OMe)(COD)}2 (5.0 mg, 0.0075 mmol, 3 mol % Ir), 2,2′-bis[(4S)-4-benzyl-2-oxazoline] (4.8 mg, 0.015 mmol, 3 mol %). 4,4′-di-t-butyl-2,2′-bipyridine (dtbpy) (4.0 mg, 0.015 mmol, 3 mol %), and pinacolborane (HBPin) (73 μL, 64 mg, 0.5 mmol, 1 equivalent). These reagents were dissolved in 2 mL of THF, 4-chlorobenzonitrile (275 mg, 2.00 mmol, 4.00 equiv) was added, and the mixture was stirred at room temperature for 48 h. 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile (93%) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)benzonitrile (7%) were formed as a mixture of isomers.
EXAMPLE 32
Borylation of 1,3-dicyanobenzene




General procedure A was applied to 1,3-dicyanobenzene (256.3 mg, 2 mmol) and HBPin (73 μL, 64 mg, 0.5 mmol) with a reaction time of 12 h. The ratio of the two isomers in the crude reaction mixture by 1H NMR spectroscopy was 74:26. Kugelrohr distillation furnished a mixture of the two isomeric borylated products (79 mg, 62%) as a white solid. The ratio of the two isomers in the isolated product by 1H NMR spectroscopy was 77:23. 1H NMR spectroscopy was used to assign the major isomer as 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)-1,3-dicyanobenzene. 1H NMR (CDCl3, 300 MHz): δ (major isomer) 8.24 (d, J=1.7 Hz, 2H, Ha), 7.96 (t, J=1.7 Hz, 1H, Hb), 1.33 (br s, 12H), (minor isomer) 7.99 (d, J=7.8 Hz, 1H, Hc), 7.92 (d, J=1.4 Hz, 1H, He), 7.80 (dd, J=7.8, 1.4 Hz, 1H, Hd), 1.36 (br s, 12H); 13C NMR {1H}(CDCl3, 125 MHz):δ (major, meta isomer) 141.8 (C4, C6), 137.1 (C2), 116.7 (nitrile C7, C8), 113.5 (C1, C3), 85.2 (C9), 24.8 (C10), (minor, ortho isomer) 136.6, 136.1, 134.4, (C3′, C4′, C6′) 118.6, 116.8, 116.7, 115.3, (C1′, C5′, C7′, C8′), 85.5 (C9′), 24.7 (C10′). 11B NMR (CDCl3, 96 MHz): δ 30.03; FT-IR (neat): 3073, 2982, 2237, 1595, 1418, 1398, 1374, 1339, 1233, 1215, 1169, 1144, 1129, 1064, 966, 897, 849, 698 cm−1; LRMS (% rel. int.): m/e 254 M+ (7), 239 (100), 211 (15), 196 (4), 168 (43), 155 (7) Anal. Calcd for C14H15BN2O2: C, 66.18; H, 5.95; N, 11.02. Found: C, 66; H, 6.02; N, 10.81.
While the present invention is described herein with reference to illustrated embodiments, it should be understood that the invention is not limited hereto. Those having ordinary skill in the art and access to the teachings herein will recognize additional modifications and embodiments within the scope thereof. Therefore, the present invention is limited only by the claims attached herein.

## Claims

1. A process for producing a cyano ring-substituted arene borane wherein the arene is selected from the group consisting of pyridine, pyrrole, furan, thiophene and benzene, the process comprising:
reacting a ring-substituted cyano arene with an HB or a B—B organic compound, in the presence of a catalytically effective amount of a catalytic composition comprising an iridium complex and an organic ligand at least in part bonded to the iridium complex, the organic ligand being selected from the group consisting of a phosphorus organic ligand, an organic amine, an imine, and a nitrogen-substituent organic ligand comprising at least one 5- or 6-membered nitrogen heterocycle to form the cyano ring-substituted arene borane;
wherein:
(i) the iridium complex is selected from the group consisting of (Cp*)Ir(H)2(Me3P), (Cp*)Ir(H)(BPin)(Me3P), (CP*)Ir(H)(C6H5)(Me3P), (Ind)Ir(COD), (MesH)Ir(BPin)(B(OR)2), ((R1)3P)3Ir(B(OR2)2)3, (R1)2P)2Ir(BPin)3, [((R1)2P)3Ir((R2O)2B)3]2, ((R1)3P)4Ir(BPin), ((R1)2P)2Ir(BPin)3, (MesH)Ir(BPin)3, IrCl(COD), [IrCl(COD)]2, [Ir(OMe)(COD)]2, and combinations thereof; and
(ii) in the iridium complex, CP* is 1,2,3,4,5-methylcyclopentadienyl, BPin is pinacolborane, Me is methyl, H is hydrogen, P is phosphorus, Ind is indenyl, COD is 1,5-cyclooctadiene, MesH is mesitylene, and R, R1, and R2 are each selected from the group consisting of hydrogen, linear or branched alkyl containing 1 to 8 carbons, aryl, and a carbon in a cyclic structure.

2. A process for producing a di-cyano or tri-cyano ring-substituted arene borane wherein the arene is selected from the group consisting of pyridine, furan, pyrrole, thiophene and benzene, the process comprising:
reacting a di-cyano or tri-cyano ring-substituted arene with an HB or a B—B organic compound in the presence of a catalytically effective amount of a catalytic composition comprising an iridium complex and a dipyridyl organic ligand at least in part bonded to the iridium complex in a molar ratio of iridium complex to dipyridyl organic ligand between 1 to 3 and 1 to 1 to form the di-cyano or tri-cyano ring-substituted arene borane;
wherein:
(i) the iridium complex is selected from the group consisting of (Cp*)Ir(H)2(Me3P), (Cp*)Ir(H)(BPin)(Me3P), (CP*)Ir(H)(C6H5)(Me3P), (Ind)Ir(COD), (MesH)Ir(BPin)(B(OR)2), ((R1)3P)3Ir(B(OR2)2)3, (R1)2P)2Ir(BPin)3, [((R1)2P)3Ir((R2O)2B)3]2, ((R1)3P)4Ir(BPin), ((R1)2P)2Ir(BPin)3, (MesH)Ir(BPin)3, IrCl(COD) [IrCl(COD)]2, [Ir(OMe)(COD)]2, and combinations thereof; and
(ii) in the iridium complex, CP* is 1,2,3,4,5-methylcyclopentadienyl, BPin is pinacolborane, Me is methyl, H is hydrogen, P is phosphorus, Ind is indenyl, COD is 1,5-cyclooctadiene, MesH is mesitylene, and R, R1, and R2 are each selected from the group consisting of hydrogen, linear or branched alkyl containing 1 to 8 carbons, aryl, and a carbon in a cyclic structure.

3. A benzonitrile of the formula:



wherein R is selected from the group consisting of cyano, BPin, halo other than fluoro, alkyl, alkoxy, thioalkyl, amino alkyl, acyl, alkyl aminoacyl, trifluoro methyl, substituted aryl, organosilane, organoborane, organostannane and organophosphorus each containing 1 to 8 carbon atoms except for the halo group.

4. A process for producing a ring-substituted arene borane wherein the arene is selected from the group consisting of pyridine, furan, pyrrole, thiophene and benzene, the process comprising:
reacting a ring-substituted arene having one to five substituents of which one or more is a cyano group, with HBPin or B2Pin2, in the presence of a catalytically effective amount of a catalytic composition comprising an iridium complex and a nitrogen-substituent organic ligand at least in part bonded to the iridium complex to form a ring-substituted arene borane containing two to six substituents at least one of which is a cyano group;
wherein:
(i) the iridium complex is selected from the group consisting of (Cp*)Ir(H)2(Me3P), (Cp*)Ir(H)(BPin)(Me3P), (CP*)Ir(H)(C6H5)(Me3P), (Ind)Ir(COD), (MesH)Ir(BPin)(B(OR)2), ((R1)3P)3Ir(B(OR2)2)3, (R1)2P)2Ir(BPin)3, [((R1)2P)3Ir((R2O)2B)3]2, ((R1)3P)4Ir(BPin), ((R1)2P)2Ir(BPin)3, (MesH)Ir(BPin)3, IrCl(COD) [IrCl(COD)]2, [Ir(OMe)(COD)]2, and combinations thereof; and
(ii) in the iridium complex, CP* is 1,2,3,4,5-methylcyclopentadienyl, BPin is pinacolborane, Me is methyl, H is hydrogen, P is phosphorus, Ind is indenyl, COD is 1,5-cyclooctadiene, MesH is mesitylene, and R, R1, and R2 are each selected from the group consisting of hydrogen, linear or branched alkyl containing 1 to 8 carbons, aryl, and a carbon in a cyclic structure;
(iii) the nitrogen-substituent organic ligand comprises at least one 5- or 6-membered nitrogen heterocycle; and
(iv) the catalytic composition has a molar ratio of the iridium complex to the organic ligand between 1 to 3 and 1 to 1.

5. The process of claim 4 wherein the borane moiety is ortho to a cyano group in the ring-substituted arene borane produced.

6. The process of claim 1 or 4 wherein the nitrogen-substituent organic ligand is selected from the group consisting of:



wherein R are each selected from the group consisting of hydrogen, linear alkyl containing 1 to 8 carbon atoms, branched alkyl containing 1 to 8 carbons, and a carbon in a cyclic structure, Y is a carbon, oxygen, nitrogen, or sulfur containing moiety, and G is a heteroatom containing group, multiple atom chain, or multiple atom ring.

7. The process of claim 1 or 4 wherein the nitrogen-substituent organic ligand is selected from the group consisting of:



wherein R are each selected from the group consisting of hydrogen, linear alkyl containing 1 to 8 carbon atoms, branched alkyl containing 1 to 8 carbons, and a carbon in a cyclic structure.

8. The process of claim 1 or 4 wherein the nitrogen-substituent organic ligand is selected from the group consisting of:



wherein R are each selected from the group consisting of hydrogen, linear alkyl containing 1 to 8 carbon atoms, branched alkyl containing 1 to 8 carbons, and a carbon in a cyclic structure, Y is a carbon, oxygen, nitrogen, or sulfur containing moiety, and Z is a carbon, oxygen, nitrogen, sulfur, or boron containing moiety or a multiple atom chain containing a carbon, oxygen, nitrogen, sulfur, or boron containing moiety.

9. The process of claim 1 or 2 wherein the HB or B—B organic compound is HBPin or B2Pin2.

10. The process of claim 1 or 4 wherein the iridium complex comprises [Ir(OMe)(COD)] and the nitrogen-substituent organic ligand comprises 4,4′-di-t-butyl-2,2′-bipyridine (dtbpy).

11. A benzonitrile of the formula:



wherein BPin is




and Z is selected from the group consisting of —CH3, —OMe, —SMe, —NMe2, —CO2Me, —NHAc, and —CF3 moieties.

12. A 2-cyano-3-borylated-pyridine of the formula:



wherein R is selected from the group consisting of cyano, BPin, halo other than fluoro, alkyl, alkoxy, thioalkyl, amino, alkyl acyl, alkyl aminoacyl, trifluoro methyl, substituted aryl, organosilane, organoborane, organostannane and organophosphorus containing 1 to 8 carbon atoms except for the halo group.

13. A 5-cyano-4-borylated-thiophene of the formula:



wherein R is selected from the group consisting of cyano, BPin, halo other than fluoro, alkyl, alkoxy, thioalkyl, amino, alkyl acyl, alkyl aminoacyl, trifluoro methyl, substituted aryl, organosilane, organoborane, organostannane and organophosphorus containing 1 to 8 carbon atoms except for the halo group.

14. A 2-cyano-3-borylated-furan of the formula:



wherein R is selected from the group consisting of cyano, BPin, halo other than fluoro, alkyl, alkoxy, thioalkyl, amino, alkyl acyl, alkyl aminoacyl, trifluoro methyl, substituted aryl, organosilane, organoborane, organostannane and organophosphorus containing 1 to 8 carbon atoms except for the halo group.

15. A 5-cyano-2,4-di BPin thiophene.

16. A 4-cyano-2,5-di BPin thiophene.

17. The process of claim 1, 2, or 4 wherein the iridium complex is selected from [Ir(OMe)(COD)]2, [IrCl(COD)]2, (Ind)Ir(COD), and combinations thereof.