Cyanation of arenes via iridium-catalyzed borylation

Article abstract of DOI:10.1021/ja104442v

We report a method to conduct one-pot meta cyanation of arenes by iridium-catalyzed C-H borylation and copper-mediated cyanation of the resulting arylboronate esters. This process relies on a method to conduct the cyanation of arylboronic esters, and conditions for this new transformation are reported. Conditions for the copper-mediated cyanation of arylboronic acids are also reported. By the resulting sequence of borylation and cyanation, 1,3-disubstituted and 1,2,3-trisubstituted arenes and heteroarenes containing halide, ketone, ester, amide, and protected alcohol functionalities are converted to the corresponding meta-substituted aryl nitriles. The utility of this methodology is demonstrated through the conversion of a protected 2,6-disubstituted phenol to 4-cyano-2,6-dimethylphenol, which is an intermediate in the synthesis of the pharmaceutical etravirine. The utility of the method is further demonstrated by the conversion of 3-chloro-5-methylbenzonitrile, produced through the one-pot C-H borylation and cyanation sequence, to the corresponding 3,5-disubstituted aldehydes, ketones, amides, carboxylic acids, tetrazoles, and benzylamines.

Full text of DOI:10.1021/ja104442v

Published on Web 08/02/2010
Cyanation of Arenes via Iridium-Catalyzed Borylation
Carl W. Liskey, Xuebin Liao, and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Matthews AVenue, Urbana, Illinois 61801-3602
Received May 22, 2010; E-mail: jhartwig@illinois.edu
regioselectivity would result from the steric effects that control the
Abstract: We report a method to conduct one-pot meta cyanation
C-H borylation process (Scheme C). We describe such a cyanation
of arenes by iridium-catalyzed C-H borylation and copper-
of arenes by C-H borylation and copper-mediated conversion of
mediated cyanation of the resulting arylboronate esters. This
process relies on a method to conduct the cyanation of arylboronic
esters, and conditions for this new transformation are reported.
Conditions for the copper-mediated cyanation of arylboronic acids
are also reported. By the resulting sequence of borylation and
cyanation, 1,3-disubstituted and 1,2,3-trisubstituted arenes and
heteroarenes containing halide, ketone, ester, amide, and pro-
the intermediate arylboronate ester to the corresponding aryl nitrile.
The selectivity of this undirected C-H cyanation process comple-
ments that from conventional halogenation followed by cyanation
of the resulting aryl halide. The utility of our new process extends
beyond the synthesis of aromatic nitriles because aromatic nitriles
are readily converted to the corresponding aldehydes, ketones,
amides, carboxylic acids, and benzylamines.13
tected alcohol functionalities are converted to the corresponding
A C-H cyanation based on arene borylation requires the
meta-substituted aryl nitriles. The utility of this methodology is
conversion of arylboronate esters to aromatic nitriles. To identify
demonstrated through the conversion of a protected 2,6-disub-
conditions for this transformation, a series of copper reagents and
stituted phenol to 4-cyano-2,6-dimethylphenol, which is an inter-
cyanide sources were tested. The reaction of the pinacol ester of
mediate in the synthesis of the pharmaceutical etravirine. The
3,5-dimethylphenylboronic acid (1) with Zn(CN)2 in the presence
utility of the method is further demonstrated by the conversion of
of CsF or KOH with 1.5 equiv of added Cu(OAc)2, which has
3-chloro-5-methylbenzonitrile, produced through the one-pot C-H
commonly been employed in Chan-Lam coupling reactions,
borylation and cyanation sequence, to the corresponding 3,5-
generated the corresponding benzonitrile product in less than 10%
disubstituted aldehydes, ketones, amides, carboxylic acids, tet-
yield. However, this reaction with 1.5 equiv of copper(II) nitrate
razoles, and benzylamines.
in place of copper acetate formed the product in 64% yield after
12 h at 100 °C (eq 1).
Aromatic and heteroaromatic nitriles are in dyes, herbicides,
pharmaceuticals, and natural products.1 Such nitriles have been formed
by the Rosenmund-von Braun2 or Sandmeyer3 reaction involving
stoichiometric copper(I) cyanide and aryl halides or diazonium salts,
respectively, or with palladium-1,4 or copper-catalyzed5 reactions of
cyanide with aryl halides (Scheme 1A). Palladium-catalyzed, copper-
Variation of the reaction conditions showed that the copper and
mediated reactions of arylboronic acids with benzylthiocyanate6 and
cyanide source, additive, and solvent all have a large effect on the
oxidative cyanations of azoles with hypervalent iodine reagents7 have
outcome of the cyanation of arylboronates. Copper(II) nitrate was
also been reported recently. A few palladium-catalyzed cyanations of
the only copper complex we found to promote this reaction in yields
arenes that contain a directing group (Scheme 1B)8 or of heteroarenes
that have an acidic C-H bond have been reported recently,9 but a
method to conduct cyanations of arenes that lack a functional group
at the point of reaction or at a position to direct the C-H bond cleavage
are unknown.
above 40%.14 Reactions of 1 with Cu(NO3)2 and acetone cyano-
hydrin or Zn(CN)2 as the cyanide source in the presence of CsF or
KOH occurred in 60-68% yield, but reactions with K4[Fe(CN)6],
NaCN, TsCN, and CuCN as the cyanide source gave less than 5%
yield of the aromatic nitrile. A fluoride or hydroxide base was needed,
presumably to activate the arylboronate ester by generating an inter-
mediate borate. Reactions conducted in a solvent combination of
MeOH and water generated the product in higher yields than those
conducted in other polar solvents, such as DMSO, DMF, or t-BuOH
(43-55%). The major side products of these reactions resulted from
protodeborylation, coupling with the aqueous methanol solvent to form
phenol and anisole, and homocoupling to form biaryls.
Scheme 1
With the conditions just described for the cyanation of arylbo-
ronate esters, we developed a one-pot sequence to convert 1,3-
disubstituted or 1,2,3-trisubstituted arenes and heteroarenes to
aromatic and heteroaromatic nitriles (Table 1). The borylation of
1,3-disubstituted arenes in the presence of bis(pinacolato)diboron
(B2pin2), [Ir(cod)OMe]2, and di-tert-butylbipyridine (dtbpy) in THF
at 80 °C over 18 h produced arylboronate esters, which were
converted to the aromatic nitriles by evaporation of the volatile
materials, dissolution of the residue in MeOH, addition of
We envisioned a method for the cyanation of arenes that exploits
the iridium-catalyzed borylation of arenes.10-12 The discovery of
a method to convert an arylboronate ester to an aryl nitrile, in
conjunction with the iridium-catalyzed borylation of C-H bonds,
would create a new route to aromatic nitriles in which the
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J. AM. CHEM. SOC. 2010, 132, 11389–11391 11389

C O M M U N I C A T I O N S
Table 1. Cyanation of Arenes via Iridium-Catalyzed Borylation
Table 2. Conversion of Arylboronic Acids to Benzonitriles
a Yield of isolated product (0.50 mmol scale). b Reaction time was
4 h.
groups located meta to the other substituents. For example,
etravirine (eq 2) is a recently approved drug for the treatment of
HIV that is prepared from 4-cyano-2,6-dimethylphenol.16 By the
one-pot C-H cyanation sequence reported here, a protected 2,6-
dimethylphenol was converted to 4-cyano-2,6-dimethylphenol in
58% isolated yield.17
a Yield of isolated product from the one-pot procedure (0.50 mmol
scale). b Borylation with 0.50 mol % [Ir(cod)OMe]2 and 1.0 mol %
dtbpy. c Reaction performed on 10.0 mmol scale. d Borylation with 1.5
mol % [Ir(cod)OMe]2 and 3.0 mol % dtbpy. e Borylation with 3.0 mol
% [Ir(cod)OMe]2 and 6.0 mol % dtbpy.
Cu(NO3)2 ·3H2O, Zn(CN)2, CsF, and H2O, and heating at 100 °C
for 3-6 h. The reaction sequence occurred with alkyl- and alkoxy-
substituted arenes (entries 1-3). Arenes containing chloride,
bromide, iodide, or fluoride (entries 4-7) afforded the product
without detectable amounts of side product from dehalogenation.
In addition, the reaction occurred with arenes containing alkylcar-
bonyl, aminocarbonyl, alkoxycarbonyl, or protected phenolic hy-
droxyl groups (entries 8-11). Finally, the reaction of 2,6-
disubstituted pyridines produced 4-cyanopyridine products. Reactions
of a variety of protected anilines were also studied, but the
corresponding protected aminobenzontrile products were not gener-
ated under the standard conditions.15
In some cases benzonitriles are the desired final product, but in
many cases they are used as intermediates to generate products
containing functionality resulting from reaction of the cyano group.
The series of reactions shown in Scheme 2 for a prototypical 3,5-
Scheme 2a
The copper-mediated cyanation of arylboron compounds also
occurred with arylboronic acids (Table 2). The reaction of arylbo-
ronic acids with Zn(CN)2 in the presence of Cu(NO3)2 and CsF
formed the aromatic nitriles at lower temperatures and within shorter
times than the reactions of pinacol boronate esters with the same
reagents. Under these conditions, arylboronic acids containing electron-
donating (entries 1 and 2) or electron-withdrawing (entries 3-5) groups
formed benzonitriles in 67-70% yield. This oxidative coupling
provides a method for the preparation of aromatic nitriles that
complements palladium-catalyzed cyanation. For example, the copper-
mediated cyanation of boronic acids containing chloride, bromide, and
iodide formed the corresponding halogenated benzonitriles in good
yield. In addition, sytrenyl and pyridyl boronic acids (entries 8 and 9)
underwent the coupling reaction in moderate yield.
a Reaction conditions: (a) KOH, t-BuOH, 60 °C, 4 h, 94%. (b) AcOH, H2O,
H2SO4, reflux, 5 h, 94%. (c) DIBAL-H, Et2O, 22 °C, 5 h; HCl (10%), 68%.
(d) LiAlH4, Et2O, 22 °C, 5 h, 86%. (e) ZnBr2, NaN3, H2O, i-PrOH, reflux,
30 h; HCl (3 N), 65%. (f) MeMgBr, Et2O, 48 h, reflux; HCl (10%), 74%.
A number of non-nucleoside reverse transcriptase inhibitors that
are potent anti-HIV compounds contain arenes possessing cyano
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C O M M U N I C A T I O N S
Liu, Y.; Chen, Y.; Strine, J.; Phenix, B.; Wallace, D. J.; Chen, C. Y. Org.
Lett. 2004, 6, 3723. (c) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun.
2004, 1388.
disubstituted aromatic nitrile prepared by C-H borylation to form
1,3,5-trisubstituted arene products underscores the versatility of the
cyanation process. As shown, 3-chloro-5-methylbenzonitrile was
converted in a straightforward fashion to the corresponding primary
benzamide, benzoic acid, benzaldehyde, benzylamine, and aromatic
ketone. In addition, this sequence leads to products with a tetrazole,
which can function as bioisosteric replacement for a carboxylic
acid,18 in the mutually meta position of a 1,3-disubstituted arene.
In summary, we have demonstrated the first copper-mediated
oxidative cyanation of arylboronate esters and arylboronic acids
and the use of this procedure to create a route to meta-substituted
benzonitriles containing a variety of functional groups. The
development of other copper-mediated oxidative reactions of
arylboronate esters is in progress.
(5) (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
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2005, 7, 537. (b) Katritzky, A. R.; Scriven, E. F. V.; Majumder, S.; Tu,
H.; Vakulenko, A. V.; Akhmedov, N. G.; Murugan, R. Synthesis 2005,
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Acknowledgment. We thank the NSF (CHE-0910641) for
support of this work, Johnson Mathey for [Ir(cod)OMe]2, and
AllyChem for B2pin2. C.W.L. thanks Abbott Laboratories for a
graduate fellowship.
(13) (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience
Publishers: London, 1970. (b) Larock, R. C. ComprehensiVe Organic
Transformations; Wiley-VCH: New York, 1988.
(14) See the Supporting Information for experimental details, including a table
of parameters tested.
Supporting Information Available: Procedures for the synthesis
and characterization of reaction products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Reactions of other heteroarenes that undergo C-H borylation reactions to
form 2- or 3-borylheteroarenes were conducted under these conditions, but
large amounts of products from homocoupling or protodeborylation of the
pinacol arylboronate esters occurred.
(16) De Clercq, E. AntiViral Res. 2010, 85, 19.
(17) In situ cleavage of the MOM group occurred.
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