Intramolecular oxycyanation of alkenes by cooperative Pd/BPh3 catalysis

Article abstract of DOI:10.1021/ja301375c

The cooperative catalysis by palladium and triphenylborane effects the intramolecular oxycyanation of alkenes through the cleavage of O-CN bonds and the subsequent insertion of double bonds. The use of 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (Xan

Full text of DOI:10.1021/ja301375c

Communication
pubs.acs.org/JACS
Intramolecular Oxycyanation of Alkenes by Cooperative Pd/BPh3
Catalysis
Dennis C. Koester,† Masato Kobayashi,‡ Daniel B. Werz,† and Yoshiaki Nakao*,‡
†Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannstrasse 2, D-37077 Gottingen,
̈
̈
̈
̈
Germany
‡Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
S
* Supporting Information
such as nickel(0), palladium(0), and platinum(0) through
oxidative addition as a key step in their proposed catalytic
cycles. We have demonstrated that the use of Lewis acid
cocatalysts significantly affects the rate of nickel-catalyzed
carbocyanation reactions,10 possibly by promoting the oxidative
addition of C−CN bonds11 through coordination of a cyano
group to a Lewis acid catalyst in an η1-fashion, which allows the
oxidative addition of C−CN bonds to nickel(0) to proceed
smoothly.12 We envisaged that cooperative catalysis for C−CN
activation may be key to further develop other cyano-
functionalization reactions through the cleavage of unreactive
FG−CN bonds. We therefore focused our attention particularly
on the oxycyanation reaction of unsaturated compounds, which
should be a useful synthetic transformation to access
functionalized nitriles because both oxygen and cyano
functionalities can be installed simultaneously.13 O−CN
bonds of cyanates can be considered strong based on their
bond lengths, which lie between those of O−C single bonds
and OC double bonds.14 Indeed, the catalytic cleavage of
O−CN bonds has never been reported until very recently,15
whereas some nucleophiles are known to react with cyanates
through the cleavage of O−CN bonds in a stepwise manner.16
We report herein that cooperative Pd/BPh3 catalysis allows
chemo- and regioselective intramolecular oxycyanation of
alkenes, a novel entry to cyanofunctionalization reactions, to
proceed for the first time to afford substituted dihydrobenzo-
furans having both a tetra-substituted carbon and cyano
functionality.
To prove the viability of the oxycyanation reaction through
O−CN bond activation by cooperative catalysis, we first
examined the reaction of 1-cyanato-2-(2-methylallyl)benzene
(1a), which is readily available from phenol via O-meth-
allylation followed by the Claisen rearrangement and
subsequent cyanation of the resulting phenolic oxygen.17
After screening several combinations of metal complexes,
ligands, and Lewis acids, we found that the use of Pd2(dba)3 (5
mol % Pd), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos)18 (5 mol %), and BPh3 (10 mol %) allowed the
expected transformation to proceed in a 5-exo-trig manner for
affording 2-(cyanomethyl)-2-methyl-2,3-dihydrobenzofuran
(2a) in 85% yield after 3 h in THF at 50 °C (entry 1 of
Table 1). The Pd/Xantphos catalyst is exceptionally effective
for this reaction; neither Ni(cod)2, the catalyst of choice for the
ABSTRACT: The cooperative catalysis by palladium and
triphenylborane effects the intramolecular oxycyanation of
alkenes through the cleavage of O−CN bonds and the
subsequent insertion of double bonds. The use of 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)
as a ligand for palladium is essential for allowing the
transformation to proceed with high chemo- and
regioselectivity. Variously substituted dihydrobenzofurans
with both a tetra-substituted carbon and cyano function-
ality are accessed by the newly developed methodology.
itriles are an important class of organic compounds,
N
which are found in a number of pharmaceuticals,
agrochemicals, and optoelectronic materials. They also serve
as versatile synthetic intermediates for carboxylic acids, esters,
amides, and amines. Accordingly, the development of novel and
efficient synthetic methods for nitriles has been a major topic in
synthetic organic chemistry.1 Metal-catalyzed cyanation reac-
tions of unsaturated compounds such as alkenes and alkynes to
access a variety of nitriles in highly chemo- and stereoselective
manners have thus gained much interest. Hydrocyanation
typically represents the utility of such cyanation reactions and
has been performed on an industrial scale, as demonstrated in
DuPont’s adiponitrile process.2 In addition to the production of
such bulk chemicals, cyanation reactions should be of great
synthetic potential to access fine chemicals with defined
functionalities and stereochemistry. In particular, metal-
catalyzed cyanofunctionalization reactions, in which both
cyano and other functional groups are installed simultaneously,
have gained increasing attention in the past decade (eq 1).
These transformations include silylcyanation,3 germylcyana-
tion,4 stannylcyanation,5 borylcyanation,6 carbocyanation,7
thiocyanation,8 and bromocyanation.9
Most cyanofunctionalization reactions rely on the cleavage of
FG−CN bonds by electron-rich late transition metal complexes
Received: February 10, 2012
Published: April 1, 2012
© 2012 American Chemical Society
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Communication
carbocyanation reactions,7 nor other mono- and diphosphanes
give less than 5% yields at most.19 In many cases, decyanation
of the cyanate moiety was observed to mainly give parent
phenols, suggesting that the cleavage of the O−CN bonds may
be relatively facile by the cooperative catalysis compared with
the subsequent insertion of alkenes (vide infra). Among the
aluminum- and boron-based Lewis acids examined, BPh3 was
particularly effective; AlEt3 gave a modest yield and BEt3 and
AlPh3 were futile, whereas the absence of the Lewis acid
cocatalyst showed poor conversion of the cyanates under
otherwise identical conditions.19 Various substituents on the
benzene ring in 1a were compatible with the optimized reaction
conditions to give the corresponding dihydrobenzofurans in
modest to good yields (entries 2−10). Substrates with an
electron-donating substituent at the para-position of the
cyanato group gave better yields than those with an electron-
withdrawing substituent; the latter suffered from decyanation,
presumably owing to reluctant oxypalladation with less
nucleophilic oxygen (vide infra). Nevertheless, the chemo-
selective activation of O−CN bonds over Ar−Br bonds by
palladium catalysis would be worth noting (entry 6).20 An
electron-withdrawing alkoxycarbonyl group at the meta-
position of the cyanato substituent did not affect the
oxycyanation reaction (entry 8). Sterically demanding sub-
stituents at the ortho-position were also tolerated (entries 9 and
10). Different alkyl substituents on the double bond of 1a were
briefly examined to obtain the corresponding dihydrobenzofur-
ans in acceptable yields (entries 11 and 12), whereas simple 1-
cyanato-2-allylbenzene (R1 = R2 = H) gave only a trace amount
of the product (<5% by GC), presumably owing to β-hydride
elimination, which may compete with the desired C−CN bond-
forming reductive elimination (vide infra). Finally, six-
membered ring formation was successfully performed using
Nixantphos as a ligand, whereas Xantphos gave 2m in 10%
yield at most as estimated by GC (entry 13). A slightly larger
bite angle of Nixanthpos (114° vs 111° for Xantphos)18 may be
crucial for the six-membered ring-forming oxypalladation step
(vide infra), although the rationale for its effect is yet to be
investigated.
Table 1. Intramolecular Oxycyanation of Alkenes Catalyzed
by Pd/BPh3
Scheme 1. Plausible Catalytic Cycle
The reaction path is understood in terms of the catalytic
cycle shown in Scheme 1 with 1a. The O−CN bond in 1a
undergoes the oxidative addition to a Pd(0)−Xantphos
complex to give 3, in which the cyano group coordinates to
BPh3, as observed with the oxidative addition of C−CN bonds
to nickel(0) in the presence of Lewis acids.12,21 Syn-
oxypalladation22 takes place in a 5-exo-trig manner to give
a
b
c
Isolated yields based on 1. Run on a 1.0 mmol scale. Run with 5
d
mol % of the Pd/Xantphos catalyst and 10 mol % of BPh3. Run at 50
e
f
°C. Run with Pd[(o-tol)3P]2 instead of Pd2(dba)3. Run at 90 °C.
g
h
i
Run at 100 °C. Run with Nixantphos instead of Xantphos. Run with
j
40 mol % of BPh3. Run on a 0.20 mmol scale.
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Journal of the American Chemical Society
Communication
Angew. Chem., Int. Ed. 2005, 44, 2380. (c) Yamamoto, A.; Ikeda, Y.;
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(alkyl)(cyano)palladium(II) species 4, which reductively
eliminates 2a, and the catalytically active palladium and boron
complexes are regenerated. The Lewis acid catalyst is crucial for
the oxidative addition of O−CN bonds, whereas it has also
been shown to promote C(sp3)−CN bond-forming reductive
elimination from palladium(II) through coordination of a cyano
group to Lewis acid.23 Bidentate phosphorus ligands with a
large bite angle18 can also affect the reductive elimination24 and
oxypalladation steps, although detailed mechanistic studies have
yet to be undertaken for fully understanding the proposed
catalytic cycle with exact structures of the suggested
intermediates and the roles of palladium and the boron Lewis
acid.
In summary, we developed regio- and chemoselective
intramolecular oxycyanation of alkenes by palladium/BPh3
catalysis.25 The transformation allows simultaneous introduc-
tion of a tetra-substituted carbon and cyano group through O−
CN bond activation to give dihydrobenzofurans, which are
often found in biologically active compounds.26 Current efforts
are directed toward further expansion of the substrate scope,27
elucidating the catalytic cycle through characterization of some
of the reaction intermediates, and developing enantioselective
cyclization to access optically active dihydrobenzofuran
derivatives.28
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reactions through the catalytic activation of unreactive O−C bonds,
see: Hoang, G. T.; Reddy, V. J.; Nguyen, H. H. K.; Douglas, C. J.
Angew. Chem., Int. Ed. 2011, 50, 1882.
(14) Kutschabsky, L.; Schrauber, H. Krist. Tech. 1973, 8, 217.
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ASSOCIATED CONTENT
■
S
(16) For a review, see: Putter, R. Angew. Chem., Int. Ed. Engl. 1967, 6,
* Supporting Information
̈
206.
Detailed experimental procedures including spectroscopic and
analytical data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Martin, D.; Bauer, M. Org. Synth. 1983, 61, 35. Caution! All
operations for the synthesis of cyanates must be carried out in a well-
ventilated fume food because cyanogen bromide used for the O-
cyanation of substituted phenols is highly toxic and can generate
hydrogen cyanide upon hydrolysis.
AUTHOR INFORMATION
■
Corresponding Author
yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp
(18) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc.
Chem. Res. 2001, 34, 895.
(19) See Supporting Information for details.
Notes
(20) For similar chemoselectivity with Pd/Au cooperative catalysis,
see: Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc.
2009, 131, 18022.
(21) For C−CN bond activation assisted by BPh3, see ref 10 and
Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 12594.
(22) (a) Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am.
Chem. Soc. 2004, 126, 3036. (b) Hay, M. B.; Wolfe, J. P. J. Am. Chem.
Soc. 2005, 127, 16468. (c) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M.
J. Am. Chem. Soc. 2005, 127, 17778.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Yosuke Miyazaki for measurement of HRMS.
This work has been supported financially by Grants-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” (No. 22105003)
and Young Scientists (A) (No. 21685023) from MEXT and
Takeda Science Foundation. D.C.K. acknowledges the JSPS for
a fellowship for his short-term research stay.
(23) Huang, J.; Haar, C. M.; Nolan, S. P.; Marcone, J. E.; Moloy, K.
G. Organometallics 1999, 18, 297.
(24) (a) Marcone, J. E.; Moloy, K. G. J. Am. Chem. Soc. 1998, 120,
8527. (b) Fujita, K.; Yamashita, M.; Puschmann, F.; Martinez Alvarez-
Falcon, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
9044. (c) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
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(25) For leading references of palladium/Lewis acid cooperative
systems, see: (a) Trost, B. M.; King, S. A.; Schmidt, T. J. Am. Chem.
Soc. 1989, 111, 5902. (b) Tamaru, Y.; Horino, H.; Araki, M.; Tanaka,
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A.; Schaus, S. E. J. Am. Chem. Soc. 2004, 126, 11440. (f) Shen, Q.;
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Y.; Blum, S. A. Acc. Chem. Res. 2011, 44, 603.
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(27) We could not examine the reaction of cyanates derived from
aliphatic alcohols because similar cyanation shown in ref 17 did not
work with aliphatic alcohols.
(28) At present, none of the known optically active bisphosphine
ligands work to give oxycyanation products as the Xantphos backbone
is likely crucial for this reaction.
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