Asymmetric intramolecular arylcyanation of unactivated olefins via C-CN bond activation

Article abstract of DOI:10.1021/ja805094j

The enantioselective, intramolecular arylcyanation of unactivated olefins via C-CN bond activation has been accomplished using a Ni(0) catalyst and BPh₃ co-catalyst. High enantioselectivities are achieved using TangPHOS as a chiral ligand. This method allows the generation of two new C-C bonds and one new quaternary carbon stereogenic center in a single synthetic step, converting readily available benzonitrile substrates into 1,1-disubstituted indanes in 49-85% yield and 92-97% ee. Copyright

Full text of DOI:10.1021/ja805094j

Published on Web 08/30/2008
Asymmetric Intramolecular Arylcyanation of Unactivated Olefins via C-CN
Bond Activation
Mary P. Watson and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received July 2, 2008; E-mail: jacobsen@chemistry.harvard.edu
Scheme 1. Representative Chiral Ligands Screened in the
Asymmetric Arylcyanation Reaction
The development of transition metal-catalyzed transformations
involving C-C bond activation is an emerging area in organic
synthesis.1 Methods where C-C bond activation is coupled with
alkene insertion hold the potential to establish two new C-C bonds
and up to two new stereogenic centers in a single operation. In
this context, Nakao and Hiyama have disclosed that aryl nitriles
can be activated and the resulting fragments can be added across
alkynes2 and strained alkenes such as norbonene3 using nickel(0)
catalysis.4 Inspired by these important studies, we have explored
the arylcyanation of unactivated olefins via C-CN bond activation.
We disclose here the identification of catalytic asymmetric intramo-
lecular olefin arylcyanations, providing indanes with quaternary
carbon stereogenic centers from readily available benzonitrile
precursors in good yields and high enantioselectivities.5,6
Initial studies focused on identifying reaction conditions for in-
tramolecular olefin arylcyanation in a racemic manifold. Treatment
of monosubstituted olefin 1a to the conditions reported for alkyne
arylcyanation (eq 1)2 led only to partial olefin isomerization. In contrast,
1,1-disubstituted olefin 1b underwent arylcyanation under the same
conditions to afford indane 2b in 21% yield. Systematic investigation
led to identification of solvent, phosphine ligand, and particularly added
Lewis acid as important reaction parameters, and indane 2b was
generated in high yield under the optimal conditions (eq 2).7
of 1b might be suppressed by using a different Ni0 source. Indeed,
use of NiCl2 ·DME and Zn as the Ni0 source14 and increasing the
ratio of TangPHOS to Ni led to minimized olefin isomerization
and provided indane 2b in 81% yield and 95% ee (eq 3).15 Of the
large number of boron- and aluminum-centered Lewis acids
examined, BPh3 afforded highest enantioselectivities.
Investigation of the scope of the arylcyanation reaction revealed
that this methodology provides access to a range of substituted indane
structures in highly enantioenriched form (Table 1). Substrates bearing
varying substitution on the benzonitrile (R1, entries 2 and 3) and on
the alkene (R2, entries 4-8) all underwent cyclization with consistently
high ee’s (92-96%). However, attainment of useful product yields
from substrates bearing sterically demanding or electron-deficient
alkene substituents necessitated elevated catalyst loadings (10 mol%
NiCl2 ·DME, 18 mol % TangPHOS, 20 mol % BPh3, and 20 mol%
Zn) and extended reaction times.
Fused pyrrole 2j was generated in 97% ee from the corresponding
homoallylic pyrrole-2-carbonitrile (entry 9), demonstrating the ap-
plicability of this method to heteroaromatic frameworks. While
benzopyran 2k could be accessed in 77% ee (entry 10), treatment of
the analogous allylic ether under similar reaction conditions failed to
provide the desired cyclization product 2l. In fact, introduction of the
same allylic ether to the arylcyanation of substrate 1b led to complete
catalyst inhibition and no detectable formation of indane 2b. These
observations are consistent with formation of an inactive π-allyl-nickel
complex upon the addition of the electron-rich catalyst to allylic ethers.
With an effective racemic method in hand, we evaluated a variety
of chiral ligands for their potential in the asymmetric arylcyanation
of benzonitrile 1b (Scheme 1). Whereas achiral monophosphine
ligands provided high reaction rates and yields in the formation of
product 2b, reactions using representative chiral monophosphines
were generally low-yielding and displayed poor enantioselectivity.
Bidentate ligands such as (R,R)-Me-BPE,8 (R,R)-BozPHOS,9 (R)-
i-Pr-PHOX,10 and (S,S,R,R)-TangPHOS11 proved more promising,
affording 2b in moderate to high enantioselectivities.
Highest ee’s were achieved using TangPHOS as the chiral ligand,
but product was generated in very low yield.12 Examination of the
crude reaction mixture revealed olefin isomerization of substrate
1
1b as a major competing pathway.13 Further, H NMR studies of
the reaction of Ni(cod)2 and ligand to form Ni(cod)(TangPHOS)
revealed that all released 1,5-cyclooctadiene had undergone isomer-
ization to 1,3-cyclooctadiene. We reasoned that olefin isomerization
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12594 J. AM. CHEM. SOC. 2008, 130, 12594–12595
10.1021/ja805094j CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Substrate Scope of the Asymmetric Olefin Arylcyanation
migratory insertion leads to generation of the Caryl-Cquat bond, and
reductive elimination then results in formation of the Csp3-CN bond
and regeneration of the Ni(0) catalyst. Because of the significant effect
of olefin substituents on the reaction rate, it seems unlikely that
oxidative addition is rate-determining, but the possibility that olefin-Ni
coordination occurs prior to rate-determining oxidative addition cannot
be excluded. The likelihood that BPh3 remains coordinated to the CN
fragment through the enantioselectivity-determining step is suggested
by the strong dependence of enantioselectivity on the identity of the
Lewis acid co-catalyst.
Reactiona
In summary, highly enantioselective, intramolecular alkene
arylcyanation via C-CN bond activation has been accomplished
using a Ni(0) catalyst and BPh3 co-catalyst. TangPHOS was found
to provide high enantioselectivity in this transformation. Current
efforts directed toward more complete mechanistic studies of this
reaction as well as extension of the substrate scope are ongoing in
our laboratory.
Acknowledgment. This work was supported by the NIGMS
through GM-43214 and a postdoctoral fellowship to M.P.W. We
thank Dr. Yoshiaki Nakao for informing us of his results in the
arylcyanation of alkenes prior to publication.
Supporting Information Available: Complete experimental pro-
cedures, detailed optimization studies, and characterization data for new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; p 97.
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(d) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc 2004, 126, 13904.
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(4) For examples of other Ni-catalyzed carbocyanation reactions, see: (a) Nakao,
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(5) For recent reviews on quaternary carbon formation, see: (a) Douglas, C. J.;
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B. M.; Jiang, C. Synthesis 2006, 369.
a Reactions carried out on 0.6 mmol scale unless noted otherwise.
b Isolated yield after chromatography. c Determined by GC or HPLC
analysis (see Supporting Information). d Reaction carried out on 0.3
mmol scale. e n.d. ) Not determined.
(6) For examples of palladium-catalyzed olefin and allene acylcyanation,
including asymmetric variants, see: (a) Yasui, Y.; Kamisaki, H.; Takemoto,
Y. Org. Lett. 2008, 10, 3303. (b) Kobayashi, Y.; Kamisaki, H.; Takeda,
H.; Yasui, Y.; Yanada, R.; Takemoto, Y. Tetrahedron 2007, 63, 2978. (c)
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K.; Nakajima, K.; Takagi, K. Tetrahedron 2006, 62, 9872. (e) Nakao, Y.;
Hirata, Y.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7420.
(7) Lewis acid co-catalysts have previously been reported to accelerate alkyne
arylcyanation reactions (see ref 2b).
(8) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125.
Scheme 2. Proposed Catalytic Cycle
(9) (a) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B. J. Am. Chem.
Soc. 2003, 125, 14260. (b) Coˆte´, A.; Desrosiers, J.-N.; Boezio, A. A.;
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(12) Other P-stereogenic ligands provided lower enantioselectivity. Details are
included in the Supporting Information.
(13) In contrast, very little olefin isomerization was observed when i-Pr-PHOX
was used. The mass balance was remaining starting material. Efforts to
increase the yield of the reaction catalyzed by PHOX ligands were
unsuccessful. In addition, use of NiCl2 · DME and Zn with i-Pr-PHOX led
to only 22% yield of 2b in 27% ee.
(14) (a) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60,
176. (b) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060.
(15) Excess TangPHOS may be required due to the presence of ZnCl2, which
forms upon reduction of NiCl2 · DME and may bind TangPHOS.
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Organometallics 1999, 18, 297. (b) Garcia, J. J.; Brunkan, N. M.; Jones,
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Garc´ıa, J. J.; Jones, W. D. Organometallics 2008, 27, 3811.
A likely mechanistic scenario for the catalytic arylcyanation is
outlined in Scheme 2. The observed effects of substituents on the
overall reaction rate are consistent with a mechanism involving Lewis
acid coordination to the nitrile, with activation toward oxidative
addition across the Caryl-CN bond by the Ni(0) complex.16 Subsequent
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