Nickel/AlMe2Cl-catalysed carbocyanation of alkynes using arylacetonitriles

Article abstract of DOI:10.1039/b907290j

Nickel/Lewis acid dual catalysis was found to effect the carbocyanation reaction of alkynes using arylacetonitriles, giving a range of triply substituted acrylonitriles; the reaction of optically active α-phenylpropionitrile suggested a reaction mechanism

Full text of DOI:10.1039/b907290j

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Nickel/AlMe2Cl-catalysed carbocyanation of alkynes using
arylacetonitrileswz
Akira Yada, Tomoya Yukawa, Yoshiaki Nakao* and Tamejiro Hiyama*
Received (in Cambridge, UK) 14th April 2009, Accepted 5th May 2009
First published as an Advance Article on the web 26th May 2009
DOI: 10.1039/b907290j
Nickel/Lewis acid dual catalysis was found to effect the carbo-
cyanation reaction of alkynes using arylacetonitriles, giving a
range of triply substituted acrylonitriles; the reaction of optically
active a-phenylpropionitrile suggested a reaction mechanism
that involves oxidative addition of a C–CN bond with retention
of its absolute configuration.
cyanides with substituents on the phenyl ring, and found that a
range of functional groups, such as chloro, acetal and ester
moieties, were compatible with both electron-rich nickel(0)
and LA catalysis, with the C–CN bonds being activated
exclusively to give various (Z)-3-arylmethyl-2,3-dipropylacrylo-
nitriles (entries 2–8). Naphthyl and heteroaryl derivatives
also participated in the reaction (entries 9–12). Notably, no
N-protecting group was necessary for pyrrole (1k) and indole
(1l) substrates (entries 11–12). Even the sterically hindered
C–CN bond of diphenylacetonitrile (1m) was activated to give
the corresponding adduct with a tertiary carbon, albeit in a
low yield (entry 13).
The stereoselective synthesis of polysubstituted alkenes has
been a major subject in organic synthesis.1 To this end, we2
and others3 have demonstrated the carbocyanation reaction4
of alkynes as a new entry to stereochemically well-defined
and atom economical protocols for the synthesis of tri- or
disubstituted acrylonitriles, versatile synthetic intermediates
for polysubstituted alkenes. While we have recently disclosed
that the use of Lewis acid (LA) cocatalysts significantly
promotes the carbocyanation reaction of alkynes to allow
the addition of acetonitrile, the attempted addition of
propionitrile resulted in a low yield of the corresponding
ethylcyanation product due to b-hydride elimination.2d In this
communication, we report the carbocyanation reaction of
alkynes with arylacetonitriles to give a wide variety of
tri- and disubstituted acrylonitriles with a functional group
regio- and stereoselectively (eqn (1)).
The scope of alkynes with benzyl cyanide (1a) is shown in
Table 2. As a symmetrical alkyne, 1,4-bis(trimethylsilyl)-2-
butyne (2b) participated in the benzylcyanation reaction to
afford 3ab in 93% yield in an exclusive cis-fashion (entry 1),
whereas the addition reaction across diphenylacetylene (2c)
gave a mixture of stereoisomers (entry 2). The stereochemistry
of (Z)-3ac was unambiguously confirmed by X-ray crystallo-
graphy (Fig. 1).z Internal unsymmetrical alkynes with sterically
biased substituents reacted with modest to excellent regio- and
stereoselectivities (entries 3–6). While the regioselectivity
across 2-pentyne (2d) was modest because of small steric
differences in the substituents (entry 3), 4,4-dimethyl-2-pentyne
(2e), 1-phenyl-1-propyne (2f) and trimethyl(1-propynyl)silane
(2g) all reacted regioselectively to afford an isomer with a lager
substituent at the cyano-substituted carbon as a major product
(entries 3, 5 and 6).6
ð1Þ
To gain a mechanistic insight, (S)-a-phenylpropionitrile
[(S)-1n]7 of 85% ee was reacted with 2a under slightly modified
conditions using Ni(cod)2 (20 mol%), 2-(2,4,6-i-Pr3–C6H2)–
C6H4–PCy2 (L2, 40 mol%),5 and AlMe2Cl (20 mol%)
(eqn (2)). The corresponding adduct, (S)-3na, of 41% ee was
obtained in 22% yield, the absolute configuration being
determined based on the reported optical rotation of
(R)-2-phenyl-3-hexanone8 after oxidative cleavage of the
double bond. Also obtained were hydrocyanation product 4,
styrene 5 and hydrocinnamonitrile 6 in 35, 44 and 3% yields,
respectively, as estimated by GC. Recovered 1n showed 80%
ee, suggesting that background racemization of 1n under these
conditions appears to be slower than the carbocyanation
event. We also confirmed that no further racemization of
3na took place under the present conditions. Accordingly,
these results clearly suggest the mechanism shown in
Scheme 1, which should start with oxidative addition of a
C–CN bond with retention of configuration through the LA
adduct of Z2-nitrile nickel species A4g to give B.9 The oxidative
addition of acetonitrile to nickel(0) has also been suggested to
proceed in a similar manner by theoretical calculations.10 This
Initially, we examined the reaction of benzyl cyanide
(1a, 1.0 mmol) with 4-octyne (2a, 1.0 mmol) in toluene in
5
the presence of Ni(cod)2 (2 mol%), 2-Mes–C6H4–PCy2 (L1,
4 mol%), and AlMe2Cl (8 mol%) as a Lewis acid, an optimized
set of catalysts for the reaction of propionitrile.2d The reaction
proceeded smoothly at 35 1C to afford the corresponding
cis-benzylcyanation product, 3aa, in 90% yield after 8 h
(entry 1 of Table 1). We further studied the scope of benzyl
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan.
E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp,
thiyama@z06.mbox.media.kyoto-u.ac.jp; Fax: +81 75 383 2445;
Tel: +81 75 383 2446
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chemistry.
Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: General
experimental information, spectral data and crystallographic data
(excluding structure factors) for the structure of (Z)-3ac. CCDC
727199. For crystallographic data in CIF or other electronic format,
see DOI: 10.1039/b907290j
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3931–3933 | 3931

Table
using arylacetonitriles
1
Nickel/AlMe2Cl-catalysed carbocyanation of 4-octyne
Table 2 Nickel/AlMe2Cl-catalysed carbocyanation of alkynes using
phenylacetonitrile
Yield
Product(s), yield (%),a
Entry Arylacetonitrile
Temp/1C Time/h Product (%)a
Entry R1, R2
Temp/1C Time/h ratiob
1
2
CH2SiMe3 (2b) 80
70
1
2
3
4
R = H: 1a
Ph: 1b
Cl: 1c
35
35
80
35
8
8
18
8
3aa
3ba
3ca
3da
90
90
74
93
3ab, 93
MeO: 1d
5
1e 35
24
3ea
96
Ph (2c)
80
73
3ac, 86c
6b
7
R = CO2Me: 1f
MeO: 1g
80
35
5
24
3fa
3ga
56
83
3
4
Me, Et (2d)
35
24
8
21
53
3ad, 30ad, 69, 59 : 41
3ae, 30ae, 94, 499 : 1
3af, 30af, 85, 92 : 8
3ag, 30ag, 56, 81 : 19
Me, t-Bu (2e) 35
Me, Ph (2f) 35
Me, SiMe3 (2g) 35
8
80
2
3ha
3ia
85
5
6d
a
b
Isolated yields. Estimated by 1H NMR of the crude product.
1h
c
d
E : Z = 79 : 21 (82 : 18 at 1.5 h). The reaction was carried out
using Ni(cod)2 (10 mol%), L1 (20 mol%), and AlMe2Cl (40 mol%).
9
35
96
85
1i
10
80
35
2
3ja
95
54
1j
11b
10
3ka
1k
12b
35
48
12
3la
69
22
1l
Fig. 1 ORTEP drawing for (Z)-3ac.
13b
100
3ma
1m
be ascribed to b-hydride elimination, and subsequent equili-
brium between E and F followed by re-insertion. Particularly,
the formation of 4, styrene and hydrocinnamonitrile is in
accord with these side reactions. In the case of phenyl
substituted alkynes, D would isomerize to G, possibly through
the conjugate addition of phosphorus ligands13 followed
by reductive elimination to give the trans-adduct. A LA
catalyst is likely to accelerate the primary oxidative addition
step,2d,4f,4g,14 though other elemental steps may also be
facilitated by the coordination of a cyano group to a LA
catalyst.9,15
a
b
Isolated yields. The reaction was carried out using Ni(cod)2
(10 mol%), L1 (20 mol%), and AlMe2Cl (40 mol%).
contrasts with non-stereospecific oxidative addition of benzyl
halides to nickel(0).11 Coordination of alkynes and then
migratory insertion into ArCH2–Ni bonds in B, giving D via
C, followed by reductive elimination from D, would give the
carbocyanation products and regenerate nickel(0) species, with
the absolute configuration being retained during these elemental
steps.12 The partial loss of ee during the addition reaction may
ꢀc
This journal is The Royal Society of Chemistry 2009
3932 | Chem. Commun., 2009, 3931–3933

Scheme 1 Plausible mechanism.
Chem., Int. Ed., 2008, 47, 385; (f) Y. Hirata, M. Tanaka, A. Yada,
Y. Nakao and T. Hiyama, Tetrahedron, 2009, in press.
3 (a) K. Nozaki, N. Sato and H. Takaya, J. Org. Chem., 1994, 59,
2679; (b) K. Nozaki, N. Sato and H. Takaya, Bull. Chem. Soc. Jpn.,
1996, 69, 1629; (c) Y. Kobayashi, H. Kamisaki, R. Yanada and
Y. Takemoto, Org. Lett., 2006, 8, 2711; (d) Y. Kobayashi,
H. Kamisaki, H. Takeda, Y. Yasui, R. Yanada and
Y. Takemoto, Tetrahedron, 2007, 63, 2978.
4 For carbocyanation reactions of other unsaturated bonds, see:
(a) Y. Nishihara, Y. Inoue, M. Itazaki and K. Takagi, Org. Lett.,
2005, 7, 2639; (b) Y. Nishihara, Y. Inoue, S. Izawa, M. Miyasaka,
K. Tanemura, K. Nakajima and K. Takagi, Tetrahedron, 2006, 62,
9872; (c) Y. Nakao, A. Yada, J. Satoh, S. Ebata, S. Oda and
T. Hiyama, Chem. Lett., 2006, 35, 790; (d) Y. Nakao, Y. Hirata
and T. Hiyama, J. Am. Chem. Soc., 2006, 128, 7420; (e) Y. Yasui,
H. Kamisaki and Y. Takemoto, Org. Lett., 2008, 10, 3303;
(f) M. P. Watson and E. N. Jacobsen, J. Am. Chem. Soc., 2008,
130, 12594; (g) Y. Nakao, S. Ebata, A. Yada, T. Hiyama,
M. Ikawa and S. Ogoshi, J. Am. Chem. Soc., 2008, 130, 12874.
5 (a) R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461;
(b) H. Tomori, J. M. Fox and S. L. Buchwald, J. Org. Chem., 2000,
65, 5334; (c) X. Huang, K. W. Anderson, D. Zim, L. Jiang,
A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 6653.
6 Terminal alkynes failed to participate in the reaction due to rapid
trimerization and/or oligiomerization.
ð2Þ
In summary, we have demonstrated a nickel/Lewis acid-
catalyzed stereo- and regioselective carbocyanation of alkynes
using arylacetonitriles. Using (S)-a-phenylpropionitrile, the
mechanism of the carbocyanation reaction including the
oxidative addition of C–CN bonds with retention of its
absolute configuration has been elucidated. Current efforts
are directed to the development of a catalyst system for the
carbocyanation reaction of alkynes using alkyl cyanides with a
b-hydrogen, as well as other unsaturated bonds.
The authors are grateful to Professor Masaki Shimizu for X-ray
crystallographic analysis of (Z)-3ac. This work has been supported
financially by a Grant-in-Aid for Creative Scientific Research and
for Priority Areas ‘‘Molecular Theory for Real Systems’’ from
MEXT. A.Y. acknowledges the JSPS for a predoctoral fellowship.
7 Prepared according to the procedure reported by Carreira and
Czekelius using (R,S)-Josiphos, see: (a) C. Czekelius and
E. M. Carreira, Angew. Chem., Int. Ed., 2003, 42, 4793;
(b) C. Czekelius and E. M. Carreira, Angew. Chem., Int. Ed.,
2005, 44, 612.
20
8 [a]D = ꢁ234 (c 0.281 in toluene) for 91% ee of (R)-2-phenyl-3-
hexanone, see: S. Takeuchi, A. Ohira, N. Miyoshi, H. Mashioand
and Y. Ohgo, Tetrahedron: Asymmetry, 1994, 5, 1763.
9 G. Favero, A. Morvillo and A. Turco, J. Organomet. Chem., 1983,
241, 251.
10 T. A. Atesin, T. Li, S. Lachaize, W. W. Brennessel, J. J. Garcı
W. D. Jones, J. Am. Chem. Soc., 2007, 129, 7562.
´
a and
11 J. K. Stille and A. B. Cowell, J. Organomet. Chem., 1977, 124, 253.
12 The migratory insertion of an alkyl group of a transition metal
complexes generally proceeds with retention of its stereochemistry,
see: (a) C. Bird, R. C. Cookson, R. Hudec and R. O. Williams,
J. Chem. Soc., 1963, 410; (b) J. K. Stille and K. S. Y. Lau, Acc.
Chem. Res., 1977, 10, 434.
13 J. M. Huggins and R. G. Bergman, J. Am. Chem. Soc., 1981, 103, 3002.
14 N. M. Brunkan, D. M. Brestensky and W. D. Jones, J. Am. Chem.
Soc., 2004, 126, 3627.
Notes and references
1 A. B. Flynn and W. W. Ogilvie, Chem. Rev., 2007, 107, 4698.
2 (a) Y. Nakao, S. Oda and T. Hiyama, J. Am. Chem. Soc., 2004, 126,
13904; (b) Y. Nakao, S. Oda, A. Yada and T. Hiyama, Tetrahedron,
2006, 62, 7567; (c) Y. Nakao, T. Yukawa, Y. Hirata, S. Oda, J. Satoh
and T. Hiyama, J. Am. Chem. Soc., 2006, 128, 7116; (d) Y. Nakao,
A. Yada, S. Ebata and T. Hiyama, J. Am. Chem. Soc., 2007, 129,
2428; (e) Y. Nakao, Y. Hirata, M. Tanaka and T. Hiyama, Angew.
15 J. Huang, C. M. Haar, S. P. Nolan, J. E. Marcone and
K. G. Moloy, Organometallics, 1999, 18, 297.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3931–3933 | 3933