Sterically directed functionalization of aromatic C-H bonds: Selective borylation ortho to cyano groups in arenes and heterocycles

Article abstract of DOI:10.1021/ja0428309

Ir-catalyzed borylations of 4-substituted benzonitriles are described. 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, five- and six-membered ring heterocycles is also reported.

Full text of DOI:10.1021/ja0428309

Published on Web 07/12/2005
Sterically Directed Functionalization of Aromatic C-H Bonds:
Selective Borylation Ortho to Cyano Groups in Arenes and
Heterocycles
Ghayoor A. Chotana, Michael A. Rak, and Milton R. Smith, III*
Contribution from the Department of Chemistry, Michigan State UniVersity,
East Lansing, Michigan 48824
Received November 29, 2004; E-mail: smithmil@msu.edu
Abstract: Ir-catalyzed borylations of 4-substituted benzonitriles are described. 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, five- and six-membered ring
heterocycles is also reported.
Introduction
In contrast, DMGs 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
Aromatic hydrocarbons are fundamental chemical building
blocks, and their reactivity is a cornerstone of organic chemistry.
Their utility derives largely from the regiochemical fidelity
1
embodied in electrophilic aromatic substitutions. While steric
4
nitriles, the presence of other groups can subvert the selectivity.
effects can influence electrophilic aromatic substitution, elec-
tronic 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, regioselec-
tivity can be complete as in the classic example of nitration at
the 3-postion of 4-bromobenzonitrile (Scheme 1, electronically
Sometimes the regiochemical outcome is unexpected. For
instance, competitive 2,5-dilithiation of 4-bromobenzonitrile
5
occurs with LDA and deprotonation at the 3-position has been
6
reported with the hindered phosphazene base, P4-t-Bu, even
though the DMG ranking of CN is greater than that of Br. In
fact, there are no documented transformations of 4-bromoben-
7,8
zonitrile that are selective for the 2-position. Moreover,
2
preferred product, FG ) NO2). For most disubstituted benzenes,
examples of functionalization at the 2-position in other 4-sub-
stituted benzonitriles are limited, and there are no general
EAS does not usually offer well-defined regiochemical out-
comes. For example, two of the three possible arrangements of
directing groups in 1,4-substituted benzenes give poor regiose-
lectivity as shown in Scheme 1.
9
approaches toward this end. This is unfortunate because aryl
nitriles have a rich chemistry and are particularly useful entries
10
into heterocyclic systems.
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
An alternate strategy for functionalizing benzonitriles that can
potentially complement electrophilic aromatic substitutions and
DoMs is to differentiate positions based on steric effects
(
4) (a) Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Org. Lett. 2001, 3,
(DoM) constitutes a powerful method for functionalization at
1
435-1437. (b) Pletnev, A. A.; Tian, Q. P.; Larock, R. C. J. Org. Chem.
the adjacent positions, provided that the substituent is a
2002, 67, 9276-9287.
3
(5) Lulinski, S.; Serwatowski, J. J. Org. Chem. 2003, 68, 9384-9388.
sufficiently strong directed metalation group (DMG). For
(
6) Imahori, T.; Kondo, Y. J. Am. Chem. Soc. 2003, 125, 8082-8083.
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 DMGs can act in concert
to direct metalation.
(7) The deprotonation at the 2-position of 4-bromobenzonitrile is cited as an
unpublished result in ref 6.
(
8) Alternatively, the nitrile group could be converted to a DMG, such as an
amide or ester. Subsequent DoM and reformation of the nitrile group could
give 2-substituted nitriles.
9
a,b
(
9) Examples include additions of hindered alkyl radicals and the addition
c
3 6 4
of vinylsilanes to 4-CF C H CN : (a) Wang, C.; Russell, G. A.; Traha-
novsky, W. S. J. Org. Chem. 1998, 63, 9956-9959. (b) Kim, B. H.; Jeon,
I.; Han, T. H.; Park, H. J.; Jun, Y. M. J. Chem. Soc., Perkin Trans. 1 2001,
2035-2039. (c) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull.
Chem. Soc. Jpn. 1997, 70, 3117-3128.
(
1) For an overview see: Taylor, R. Electrophilic Aromatic Substitution; John
Wiley and Sons: New York, 1990.
(
(
2) Schopff, M. Ber. 1890, 23, 3435-3440.
(10) (a) Meyers, A. I.; Sircar, J. C. The Chemistry of the Cyano Group. In The
Chemistry of the Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley
& Sons: New York, 1970; Chapter 8. (b) Fatiadi, A. J. In Supplement C:
The Chemistry of the Triple-bonded Functional Groups; Patai, S., Rap-
poport, Z., Eds.; Wiley & Sons: New York, 1983; Chapter 26.
3) DoM has recently been reviewed within the context of complex induced
proximity effects. See the following article and references therein: Whisler,
M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004,
4
3, 2206-2225.
10.1021/ja0428309 CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 10539-10544
9
10539

A R T I C L E S
Chotana et al.
Scheme 1. Regiochemical Trends in Electrophilic Aromatic Substitution (EAS) for 1,4-Substituted Benzenes
Scheme 2
(
1
Scheme 1). Since the first report by Ittel and co-workers in
976,11 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.12 Since 1999, we and others
13
14
have been particularly interested in utilizing Ir-catalyzed bory-
lations of arenes to tap the unique regioselectivities available
to sterically directed C-H activations. We reasoned that
borylation ortho to nitrile groups should be possible for
appropriate substrates since the cyano group is only slightly
larger than fluoride (vide infra). Our 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. More active Ir catalysts
developed by Hartwig, Ishiyama, and Miyaura overcome this
problem. These Ir dipyridyl catalysts operate at room temper-
ature, and examples have been reported showing that the nitrile
Table 1. Raegioselectivities of 4-substituted Benzonitrile
Borylations
entry
Z
borane (equiv)
time (h)
% yieldb
%1:%2c
1
2
3
F
HBPin (0.25)
HBPin (0.25)
HBPin (0.25)
B2Pin2 (1.0)
HBPin (0.25)
HBPin (0.25)
B2Pin2 (0.25)
B2Pin2 (1.0)
B2Pin2 (0.8)
B2Pin2 (1.6)
HBPin (1.1)
8
36
48
40
72
24
18
72
48
18
24
71
76
73
70
64
65
55
58
65
62
68
11:89 (8:92)
80:20 (81:19)
95:5 (97:3)
>99:1 (>99:1)
94:6 (92:8)
67:33 (67:33)
90:10 (87:13)
>99:1 (>99:1)
>99:1 (>99:1)
>99:1 (>99:1)
>99:1 (>99:1)
Cl
Br
I
CH3
OMe
SMe
NMe2
CO2Me
NHAc
CF3
4
5d
e
6
7
8
9
10
11
f
e
d
g
h
14d,e
group is compatible with the borylation conditions.
However,
data is available for only three substrates, none of which
addressed our regiochemical hypothesis. Herein, we describe
results for the borylations ortho to cyano groups of benzonitriles.
a
Unless otherwise noted, all reactions were run in thf solution at 25 °C
b
with [Ir] ) 3 mol %. Yields are for isolated products based on the limiting
reagent. c The 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. [Ir] ) 6 mol %. Isomer ratio
was determined from NMR integration. Reaction run at 80 °C. [Ir] ) 8
mol %. h Reaction run in n-hexane.
d
e
Results
f
g
We first examined borylations of 4-substituted benzonitriles.
As most substrates were poorly soluble in saturated hydrocar-
bons, borylations were typically carried out in thf solvent using
the catalyst constituted from a 1:2 ratio of [Ir(OMe)(COD)]2
dine (dtbpy) as indicated in Scheme 2. The results for mono-
borylation 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 (vide
infra). However, the regioselectivities are also consistent with
the thermodynamic ordering of o-C-H acidities is F > CN >
(COD ) 1,5-cyclooctadiene) and 4,4′-di-tert-butyl-2,2′-bipyri-
(
(
(
11) Ittel, S. D.; Tolman, C. A.; English, A. D.; Jesson, J. P. J. Am. Chem. Soc.
1
976, 98, 6073-6075.
12) Goldberg, K. I.; Goldman, A. S. ActiVation and Functionalization of C-H
Bonds; American Chemical Society: Washington, DC, 2004.
13) (a) Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc. 1999, 121, 7696-
7
697. (b) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc.
2
000, 122, 12868-12869. (c) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka,
R. E., Jr.; Smith, M. R., III. Science 2002, 295, 305-308. (d) Maleczka,
R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III. J. Am. Chem. Soc. 2003,
1
25, 7792-7793.
(
14) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390-391. (b) Ishiyama, T.;
Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002, 41,
3056-3058. (c) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
N. Tetrahedron Lett. 2002, 43, 5649-5651. (d) Ishiyama, T.; Nobuta, Y.;
Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924-2925. (e)
Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N. AdV.
Synth. Catal. 2003, 345, 1103-1106. (f) Mertins, K.; Zapf, A.; Beller, M.
J. Mol. Catal. A: Chem. 2004, 207, 21-25.
15
Cl from the literature. Thus, rationalization of the regiochemi-
cal outcome is shackled with the age-old dilemma of definitively
10540 J. AM. CHEM. SOC.
9
VOL. 127, NO. 30, 2005

Aromatic Borylation Ortho to CN
A R T I C L E S
separating steric and electronic effects. Nevertheless, a compel-
ling case can be made for steric directing effects as outlined
below.
Chart 1
1
6
There are several approaches for evaluating steric effects.
Following a course recommended by Ingold,17 Taft developed
a parameter, Es, to account for steric effects on hydrolysis and
esterification rates of o-benzoate esters.18 It was later shown
that Es values could be quantitatively related to van der Waals
1
9
radii, and values have been calculated for substituents absent
20
Table 2. Calculated Steric Enthalpies (∆∆H ) for o-Benzene
in Taft’s original work. Dubois later revised Taft’s definition,
introducing the Taft-Dubois steric parameter, E′s.2 Despite
their demonstrated utility, Es and E′s values are nonetheless
empirical, and the database of values is still limited. Alterna-
tively, the energy difference between equatorial and axial
conformers of monosubstituted cyclohexanes (the A value) has
been invoked as a measure of steric effects.22 Although the
equatorial site is indeed favored from a steric standpoint,
cyclohexane conformational energies are not immune to elec-
tronic 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.23 Unfortunately, the value does
s
a
Substituents Z and Isomer Ratios for Borylation
1
1
%1:%2 calcdb
%1:%2 observedc
Z
∆∆H
s
(Z) kcal‚
mol-
H
CN
F
Cl
Br
I
CH3
OMe
SMe
NMe2
CO2Me
NHAc
CF3
0
-
-
-
-
8:92
81:19
97:3
>99:1
92:8
3.211
1.535
4.133
5.405
7.759
5.532
2.013
3.682
5.039
4.856
5.166
8.845
6:94
83:17
98:2
>99:1
98:2
31:69
66:34
96:4
94:6
96:4
>99:1
d
67:33
d
87:13
>99:1
>99:1
>99:1
>99:1
20
a
b
not appear in the primary literature that is cited. A values are
∆∆Hs(Z) values computed according to method in ref 25a. Reference
26. c GC-FID ratios from Table 1. d Isomer ratio was determined by NMR
integration.
2
4
of little help as the value for CN is lower than that of F, and
general agreement between A and Es values is poor.
Chart 2
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. In essence, their approach
involves calculating the difference in enthalpies for 2-substituted
toluenes and tert-butylbenzenes relative respectively, to toluene
and tert-butylbenzene, to extract steric enthalpies, denoted as
2
5
∆
∆Hs(Z), for substituents Z, relative to that of hydrogen. For
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 ∆∆Hs(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.
consistency, the dihedral angles for the methyl and tert-butyl
groups were constrained as shown in Chart 1.2 Since CN and
other substituents in Table 1 were not included in the pre-
vious report, we recalculated the series.26 Table 2 lists these
5a
∆
∆Hs(Z) values along with calculated and experimental ratios
27
of 2- and 3-borylated benzonitriles.
Agreement between the calculated and experimental isomer
ratios is surprisingly good. The halide data correlates best, while
(15) Comparisons to the pK
experimental results to estimate pK
a
of benzonitrile15b can be made by extrapolating
’s for fluoro- and chlorobenzene: (a)
a
Stratakis, M.; Wang, P. G.; Streitwieser, A. J. Org. Chem. 1996, 61, 3145-
3
6
150. (b) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155-
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 regiose-
lectivity. 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
157.
(
16) The following paper provides an excellent overview: White, D. P.; Anthony,
J. C.; Oyefeso, A. O. J. Org. Chem. 1999, 64, 7707-7716.
17) Ingold, C. K. J. Chem. Soc. 1932, 1032.
(
(
(
(
(
18) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 3120-3128.
19) Charton, M. J. Am. Chem. Soc. 1969, 91, 615-618.
20) Kutter, E.; Hansch, C. J. Med. Chem. 1969, 12, 647-52.
21) Macphee, J. A.; Panaye, A.; Dubois, J. E. Tetrahedron 1978, 34, 3553-
3
562.
(
22) Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562-5578.
23) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR: Hydrophobic,
Electronic, and Steric Constants; American Chemical Society: Washington,
DC, 1995; p 227.
(
(
24) Jensen, F. R.; Bushweller, C. H.; Beck, B. H. J. Am. Chem. Soc. 1969, 91,
13b
para borylation. Given that CN and OMe groups are nearly
3
44-351.
(
25) A model for ortho substituent steric effects that correlates strongly with
hydrolysis of o-substituted benzamides has been reported: (a) Sotomatsu,
T.; Murata, Y.; Fujita, T. J. Comput. Chem. 1991, 12, 135-138. (b)
Sotomatsu, T.; Fujita, T. J. Org. Chem. 1989, 54, 4443-4448.
(27) Because the isomer ratios reflect differences in relative rates, values were
s s
calculated using 1:2 ) exp(-[ππH (Z) - ππH (CN)/RT]), T ) values from
Table 1. This should not be expected to reproduce the experimental values;
however, the net trend should be reflected in the data if a steric model is
appropriate.
(26) AM1 calculations were carried out on an SGI Origin 3400 supercomputer
using SPARTAN SGI, version 5.1.3, Wavefunction, Inc.: Irvine, CA.
J. AM. CHEM. SOC.
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VOL. 127, NO. 30, 2005 10541

A R T I C L E S
Scheme 3
Chotana et al.
isosteric, the identical 2:1 preference for borylation meta to OMe
may have electronic origins.
approach to elaborating the 2-positions of 4-substituted ben-
zonitriles. Last, it should be noted that entries 7 and 10 are the
first examples of functional group tolerance for SMe and NHAc
substituents, respectively.
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
The regioselectivities in Table 2 are not necessarily limited
to disubstituted benzenes. In addition to diborylation of 4-sub-
situted 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 het-
erocycles can be obtained by substitution of fluoride followed
by ring-forming condensation with the cyano group.33 Similarly,
borylation of 3,4-dichlorobenzonitrile yields the 5- and 6-bo-
rylated isomers in a 20:80 ratio. For both substrates, the selec-
tivity for borylation ortho to CN vs halide is virtually identical
to that for the corresponding 4-halobenzonitriles in Table 1.
2
8
react selectively at the 2-position as shown in Scheme 3. 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 f 4
f 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 that for CN. Murai has invoked
CN to Ru π-bonding to account for selective C-H activation
2
9
ortho to CN. 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. On the basis of 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.30 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
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.
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
3
1
limited. Entries 8-10 highlight the complementary nature of
sterically directed borylations to DoM protocols, where hydro-
gens ortho to amine, ester, and amide groups react preferen-
3
2
tially. Thus, aromatic borylation provides the most general
34
Table 1 predicts. 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
(
28) (a) Krizan, T. D.; Martin, J. C. J. Org. Chem. 1982, 47, 2681-2682. (b)
Bennetau, B.; Rajarison, F.; Dunogues, J.; Babin, P. Tetrahedron 1993,
4
9, 10843-10854.
(
(
(
(
29) Kakiuchi, F.; Sonoda, M.; Tsujimoto, T.; Chatani, N.; Murai, S. Chem.
Lett. 1999, 1083-1084.
30) Blackaby, W. P.; Goodacre, S. C.; Hallett, D. J.; Jennings, A.; Lewis, R.
T.; Street, L. J.; Wilson, K. U.S. Pat. Appl. 20040192692.
31) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508-
7
510.
(33) Cui, J. R. J.; Araldi, G. L.; Reiner, J. E.; Reddy, K. M.; Kemp, S. J.; Ho,
J. Z.; Siev, D. V.; Mamedova, L.; Gibson, T. S.; Gaudette, J. A.; Minami,
N. K.; Anderson, S. M.; Bradbury, A. E.; Nolan, T. G.; Semple, J. E. Bioorg.
Med. Chem. Lett. 2002, 12, 2925-2930.
32) (a) Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3059-3062. (b)
Jaroch, S.; Holscher, P.; Rehwinkel, H.; Sulzle, D.; Burton, G.; Hillmann,
M.; McDonald, F. M. Bioorg. Med. Chem. Lett. 2002, 12, 2561-2564.
10542 J. AM. CHEM. SOC.
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Aromatic Borylation Ortho to CN
A R T I C L E S
Table 3. Diborylations of 4-substituted Benzonitrilesa
Scheme 4
likely contributes to the regioselectivities in Table 3. Last, 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-meth-
yl-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 five-
membered heterocycles is not surprising. Two isomeric cyano-
pyridines were also examined. 5-Bromo-2-cyanopyridine un-
dergoes 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.
a
Unless otherwise noted, all reactions were run in thf solution at 25 °C
b
with 4.0 equiv of HBPin and [Ir] ) 6 mol %. Isomer distribution
determined GC-FID. Calculated values using the selectivities in Table 1
ref 32) are shown in parentheses. For Z ) OMe and Cl, the 3,5-diborylation
products are calculated respectively as 7% and 2% of the isomer mixture.
Reaction run at 60 °C. Isolated as a single isomer after recrystallization
from a 93:7 mixture of 2,5- and 2,6-borylated isomers.
(
c
d
examined at low conversion to avoid skewing the data by
borylation of m-C6H4(BPin)2.35 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
(
34) 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 borylation, 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 arguments
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.
35) The experiment in eq 2 was performed through the reaction of benzene
with 1.2 equiv of HBPin in thf in the presence of Ir catalyst. The first
equivalent of borane generates PhBPin in situ, and the remaining 0.2 equiv
gives the diborylated isomers.
Conclusions
(
In summary, the steric directing effects that govern the
regioselectivities in Ir-catalyzed borylations of aromatic and
J. AM. CHEM. SOC.
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VOL. 127, NO. 30, 2005 10543

A R T I C L E S
Chotana et al.
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 DoMs, and several relatively simple borylated
products have been prepared for the first time. Diborylations
of 4-substituted benzonitriles favor para-disposed BPin groups
when borylation at the 5-position is possible. While it appears
that 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. We are currently focusing on improving
regioselectivities by modifying the Ir ligands, as well as
sterically differentiating other aromatic substituents.
Acknowledgment. We thank the NSF REU program for a
summer fellowship to M.A.R. and the NIH (GM63188) for their
generous support. We thank Professor Robert E. Maleczka, Jr.
for helpful discussions.
Supporting Information Available: Spectral data for all new
compounds pictured, as well as general experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0428309
10544 J. AM. CHEM. SOC.
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VOL. 127, NO. 30, 2005