Nickel/Lewis acid-catalyzed cyanoesterification and cyanocarbamoylation of alkynes

Article abstract of DOI:10.1021/ja102346v

Cyanoformates and cyanoformamides are found to add across alkynes by nickel/Lewis acid (LA) cooperative catalysis to give β-cyano-substituted acrylates and acrylamides, respectively, in highly stereoselective and regioselective manners. The resulting adducts serve as versatile synthetic building blocks through chemoselective transformations of the ester, amide, and cyano groups as demonstrated by the synthesis of typical structures ofβ-cyano ester, β-amino nitrile, β-lactam, disubstituted maleic anhydride, and β-aminobutyric acid. The related reactions of cyanoformate thioester and benzoyl cyanide, on the other hand, are found to add across alkynes with decarbonylation in the presence of a palladium/LA catalyst.

Full text of DOI:10.1021/ja102346v

Published on Web 07/07/2010
Nickel/Lewis Acid-Catalyzed Cyanoesterification and
Cyanocarbamoylation of Alkynes
Yasuhiro Hirata,† Akira Yada,† Eiji Morita,† Yoshiaki Nakao,*,† Tamejiro Hiyama,*,†,|
Masato Ohashi,‡,§ and Sensuke Ogoshi§
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto 615-8510, Japan, Center for Atomic and Molecular Technologies, Osaka UniVersity,
Suita, Osaka 565-0871, Japan, and Department of Applied Chemistry, Faculty of Engineering,
Osaka UniVersity, Osaka 565-0871, Japan
Received March 20, 2010; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp;
thiyama@kc.chuo-u.ac.jp
Abstract: Cyanoformates and cyanoformamides are found to add across alkynes by nickel/Lewis acid
(LA) cooperative catalysis to give ꢀ-cyano-substituted acrylates and acrylamides, respectively, in highly
stereoselective and regioselective manners. The resulting adducts serve as versatile synthetic building
blocks through chemoselective transformations of the ester, amide, and cyano groups as demonstrated by
the synthesis of typical structures of ꢀ-cyano ester, ꢀ-amino nitrile, γ-lactam, disubstituted maleic anhydride,
and γ-aminobutyric acid. The related reactions of cyanoformate thioester and benzoyl cyanide, on the
other hand, are found to add across alkynes with decarbonylation in the presence of a palladium/LA catalyst.
transition metals through oxidative addition4 or the formation of
silylisonitrile complexes,5 which is relatively feasible due presum-
Introduction
The vicinal difunctionalization of alkynes with carbonaceous
groups has gained much interest in organic synthesis, mainly
because the transformation allows simultaneous construction of two
different C-C bonds. In particular, transition-metal-catalyzed
cleavage of C-C bonds followed by insertion of unsaturated bonds
should be of great synthetic potential because there is no need for
prefunctionalization and no formation of byproduct.1-3 Whereas
the initial developments of this class of transformations depend
heavily on the release of ring-strain in three-1 or four-membered2
compounds, much attention has been paid to reactions involving
the cleavage of strain-free C-C bonds.3 In this regard, we and
others have been interested in the cleavage of C-CN bonds by
ably to a kinetically favorable interaction of a cyano group with a
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D. Tetrahedron Lett. 1973, 14, 3433. (b) Shair, M. D.; Yoon, T. Y.;
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118, 9509. (c) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio, K.; Kitagaki, S.;
Ueda, K.; Akai, S.; Fujioka, H. J. Am. Chem. Soc. 2001, 123, 3214. (d)
Nair, V.; Pillai, A. N.; Menon, R. S.; Suresh, E. Org. Lett. 2005, 7, 1189.
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† Kyoto University.
‡ Center for Atomic and Molecular Technologies, Osaka University.
§ Department of Applied Chemistry, Faculty of Engineering, Osaka
University.
| Present address: Research & Development Initiative, Chuo University,
1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan.
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10070 J. AM. CHEM. SOC. 2010, 132, 10070–10077
10.1021/ja102346v  2010 American Chemical Society

Cyanoesterification and Cyanocarbamoylation of Alkynes
A R T I C L E S
transition metal through η1- or η2-coordination6 and a resultant
highly stable metal-CN bond7 as a thermodynamic driving force.
These elemental reactions have been applied to catalytic transfor-
mations of nitriles including isomerization,8 decarbonylation,9
decyanation,10 silylation,11 and cross-coupling12 reactions. Taking
advantage of the particular ability of nickel to activate various
C-CN bonds, we, on the other hand, reported the nickel-catalyzed
addition reaction of nitriles across alkynes, namely the carbocya-
nation reaction, as a new entry in the class of transformations.13
More recently, we disclosed that the use of Lewis acid (LA)
cocatalysts allowed the scope of nitriles to expand significantly to
include even alkyl cyanides to give a wide variety of (Z)-alkyl-
substituted acrylonitriles highly stereo- and regioselectively14
probably through the promotion of both oxidative addition15 and
reductive elimination16 of C-CN bonds.
transformation with these particular nitriles allows simultaneous
installation of both carbonyl and cyanofunctionalities. The inter-
molecular addition reaction of benzoyl cyanide across arylacety-
lenes was first reported using a palladium catalyst.17 Unfortunately,
the scope of this reaction is severely limited, since its mechanism
involves benzoylation of the terminal alkyne followed by hydro-
cyanation of the resulting alkynyl ketones and isomerization of
the double bond. More recently, palladium catalysis has been found
to be effective for the activation of C-CN bonds of cyanoformates
and cyanoformamides, allowing the intermolecular cyanoesterifi-
cation of norbornene18 and the intramolecular cyanocarbamoylation
of alkynes and alkenes,19 respectively. Independently, we have also
been interested in such difunctionalization by the nickel catalysis
and have developed the intermolecular cyanoesterification of 1,2-
dienes.20 Nevertheless, a general scope of these transformations
has remained unexplored, and its successful realization is highly
desired as a new synthetic tool for introducing two different
functional groups at a vicinal position with defined stereochemistry.
We report herein nickel/LA-catalyzed regio- and stereoselective
cyanoesterification and cyanocarbamoylation reactions of alkynes
to give ꢀ-cyano-substituted acrylate esters and acrylamides.
Subsequent transformations of the two functional groups thus
introduced are demonstrated to readily afford a range of useful
building blocks such as ꢀ-cyano ester, ꢀ-amino nitrile, γ-lactam,
disubstituted maleic anhydride, and γ-aminobutyric acid. Also
described briefly is that related reactions of cyanoformate thioesters
and cyanoketones with alkynes are accompanied by decarbonyla-
tion and are more efficiently catalyzed by palladium/LA.
Cyanoketones, cyanoformates, and cyanoformamides are attrac-
tive substrates for the carbocyanation reactions, in view that the
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Results and Discussion
Nickel/BAr3-Catalyzed Cyanoesterification of Alkynes. We
first examined the reaction of ethyl cyanoformate (1a) with
4-octyne (2a) at 100 °C in the presence of a nickel catalyst
along with various ligands (Table 1). Two ligands PMe2Ph and
PMe3, effective for the cyanoesterification of 1,2-dienes20 and
arylcyanation of alkynes,13 were completely ineffective (entries
1 and 2). On the other hand, electron-deficient triarylphosphine
ligands such as P(4-CF3-C6H4)3 and P[3,5-(CF3)2-C6H3]3 gave
a small amount of desired adduct 3aa (entries 3 and 4), whereas
neutral PPh3 and electron-donating P(4-MeO-C6H4)3 showed
no trace amount of 3aa. These observations prompted us to
examine the effect of LA cocatalysts in assisting the activation
of the C-CN bond of 1a by a nickel(0) species coordinated by
the less electron-donating phosphines. Of organoboron LA
compounds examined with P[3,5-(CF3)2-C6H3]3 as a ligand
(entries 7 and 8), B(C6F5)3 was found to be dramatically
effective, giving 3aa in 64% yield as estimated by GC (entry
8). The reaction proceeded even at 35 °C giving a higher yield
of 3aa (entry 9). A further increase in yield was observed using
20 mol % of the ligand, and the reaction with a 1 mmol scale
´
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9
J. AM. CHEM. SOC. VOL. 132, NO. 29, 2010 10071

A R T I C L E S
Hirata et al.
Table 1. Cyanoesterification of 4-Octyne (2a) with Ethyl
Cyanoformate (1a)a
adduct 3 or 3′, respectively, and regenerating nickel(0) and a
BAr3 adduct of 1. The cyano group rather than the ester carbonyl
is considered to coordinate to the borane LAs throughout the
catalytic cycle, making the cyano group less nucleophilic and
reluctant to undergo the migratory insertion step. The borane
LA could also interact with the triarylphosphine ligand to assist
the ligand exchange step (e.q. 4 to 6 in Scheme 1).22 However,
the stoichiometric reaction of the triarylboranes with P[3,5-
(CF3)2-C6H3]3 monitored by 31P NMR showed no significant
shift of the original signal of the free triarylphosphine due
presumably to the steric bulk and/or the electron-withdrawing
nature of the aryl group that makes the phosphorus atom less
Lewis basic, whereas that with PPh3 showed formation of white
precipitates ascribed probably to a Ar3B-PPh3 complex.23 On
the basis of these observations, we conclude that such effect of
the borane LA may not be operative in our system especially
in the presence of Lewis basic cyano and alkoxycarbonyl
functionalities in a higher amount.
Alkenylnickel intermediate 8 seems to be favored kinetically
since migration of the alkoxycarbonyl group to a less hindered
carbon of the coordinating alkyne in 6 would proceed in a
manner similar to the arylcyanation of alkynes.24 With silyl-
substituted alkynes, on the other hand, the alkoxycarbonyl group
could interact with the silyl group through the carbonyl oxygen
to direct coordination of the silylalkynes as depicted in 5′ to
result in the exclusive formation of 3′ The ratios of 3:3′ were
constant during the course of the reaction with silyl-substituted
alkynes, suggesting both that 3′ should be a kinetic product and
irreversibility of the reductive elimination step.
The synthetic versatility of the cyanoesterification products
is demonstrated by the transformations shown in Scheme 2.
Protodesilylation of 3′ae followed by reduction of the remaining
double bond gave ꢀ-cyano ester 9. Upon treatment of 9 with
NaBH4 in the presence of CoCl2,25 γ-lactam 10 was obtained,
whereas hydrolysis of the ester group26 in 9 and the subsequent
Curtius rearrangement27 afforded N-Boc-protected ꢀ-cyano
amide 11, a potential precursor for ꢀ-amino acid derivatives.
Treatment of 3aa with a base gave 12 (eq 1). Because
disubstituted maleic anhydrides such as 12 are found in some
biologically active natural products such as chaetomellic acid
A anhydride,28 the present synthetic scheme would be applicable
to access this class of compounds,29 starting with readily
available cyanoformate esters and internal alkynes.
entry
ligand (mol %)
LA
solvent
temp (°C) yield (%)b
1
2
3
4
5
6
7
8
9
PMe3 (10)
PMe2Ph (10)
P[3,5-(CF3)2-C6H3]3 (10) none
none
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
0
0
4
4
0
0
P(4-CF3-C6H4)3 (10)
PPh3 (10)
none
none
none
P(4-MeO-C6H4)3 (10)
P[3,5-(CF3)2-C6H3]3 (10) BPh3
100 35
100 64
35 74
P[3,5-(CF3)2-C6H3]3 (10) B(C6F5)3 toluene
P[3,5-(CF3)2-C6H3]3 (10) B(C6F5)3 toluene
10 P[3,5-(CF3)2-C6H3]3 (20) B(C6F5)3 toluene
11 P[3,5-(CF3)2-C6H3]3 (20) B(C6F5)3 1,4-dioxane
12 P[3,5-(CF3)2-C6H3]3 (20) B(C6F5)3 DMF
13 P[3,5-(CF3)2-C6H3]3 (10) AlMe3
14 P[3,5-(CF3)2-C6H3]3 (10) AlMe2Cl toluene
35 83 (80)c
35 42
35
100
100
0
0
0
toluene
a All the reactions were carried out using 1a (0.20 mmol), 2a (0.20
mmol), Ni(cod)2 (10.0 µmol), a ligand (20 or 40 µmol), and a LA (40
µmol) in toluene (0.133 mL). b GC yields as determined using tridecane
as an internal standard. c Isolated yield with a 1.00 mmol scale.
for 24 h gave 3aa in 80% yield after isolation (entry 10). The
use of more polar solvents such as 1,4-dioxane and DMF was
not effective, because they could act as a Lewis base to
coordinate to highly Lewis acidic B(C6F5)3 to retard the LA
cocatalysis (entries 11 and 12). Organoaluminum LAs were
ineffective (entries 13 and 14).
With the optimized conditions in hand, we next studied the scope
of alkynes using nitrile 1a (Table 2). The reaction with 1,4-
bis(trimethylsilyl)-2-butyne (2b) yielded highly functionalized
allylsilane 3ab stereoselectively in 75% yield (entry 1). The
stereochemistry of 3ab was confirmed by NOE observed between
the two allylic methylenes in 3ab. Whereas 4-methyl-2-pentyne
(2c) gave a mixture of regioisomers (entry 2), 4,4-dimethyl-2-
pentyne (2d) gave single adduct 3ad with complete regioselectivity
(entry 3). This regioselectivity is identical to that observed for the
carbocyanation reactions of alkynes with other nitriles:13,14 isomers
having a larger substituent at the cyano-substituted carbon were
produced preferentially. On the other hand, alkynes with a silyl
terminus 2e-2j proceeded highly stereoselectively but with op-
posite regioselectivity using BPh3 as a LA in 1,4-dioxane instead
of B(C6F5)3 in toluene (entries 4-10). It is worth noting that internal
double bond, silylether, ester, and imide functionalities were
tolerated under the present Ni/LA catalysis (entries 7-10). The
use of B(C6F5)3 for the reaction of 1a with 2e in toluene resulted
in 17% yield of 3ae. Methyl cyanoformate (1b) also added across
2f in a moderate yield under similar conditions (entry 6). The
reactions with other alkynes such as 1-phenylpropyne (<30% of
adducts), methyl 2-butynoate, and terminal alkynes (trimerization
and/or oligiomerization of the alkynes) as well as simple 1-alkenes
(no reaction) were all futile.
The synthetic potential of the cyanoesterification is also
demonstrated by the formal synthesis of pregabalin, an anti-
convulsant drug used for the treatment of neuropathic pain
(Scheme 3).30,31 Protodesilylation of 3′bf followed by enanti-
oselective conjugate reduction of the R,ꢀ-unsaturated ester
moiety with polymethylhydrosiloxane (PMHS) in the presence
of a chiral Cu/(R)-binap catalyst32 afforded ꢀ-cyano ester 14 of
80% ee, which was hydrolyzed without loss of the %ee to give
synthetic precursor 15 for pregabalin.31a
Nickel/BPh3-Catalyzed Cyanocarbamoylation of Alkynes. We
next turned our attention to the reactions of cyanoformamides
with alkynes. We again surveyed nickel/LA catalysts for the
reaction of N,N-dimethylcyanoformamide (16a) with 4-octyne
(2a) (Table 3). Of various combinations of Ni(cod)2, a ligand,
The cyanoesterification reaction likely proceeds through a
plausible catalytic cycle shown in Scheme 1. The cycle should
be initiated by the oxidative addition of C-CN bonds of
cyanoformate esters,21 whose CN group coordinates to BAr3 to
give 4. After the phosphine ligand in 4 is replaced by an alkyne
to give 5 or 6, the alkoxycarbonyl group migrates to the
coordinating alkyne to give rise to 7 or 8, which then undergoes
reductive elimination followed by transfer of BAr3 to 1, giving
9
10072 J. AM. CHEM. SOC. VOL. 132, NO. 29, 2010

Cyanoesterification and Cyanocarbamoylation of Alkynes
A R T I C L E S
Table 2. Nickel/BAr3-Catalyzed Cyanoesterification of Alkynesa
a All the reactions were carried out using 1a (1.00 mmol), an alkyne (1.00 mmol), Ni(cod)2 (50 µmol), a ligand (0.100 or 0.20 mmol), and a LA
(0.20 mmol) in toluene or dioxane (0.67 mL). b Isolated yield. c Estimated by 1H NMR analysis of a crude product. d Methyl cyanoformate (1b) was
e
1
used instead of 1a. Estimated by H NMR analysis of an isolated product.
and a LA examined, electron-donating and sterically bulky
ligands with BPh3 as a LA catalyst gave ꢀ-cyano-substituted
acrylamide 17aa with yields better than those including tri-
arylphosphines (entries 1-5 vs entries 11-13). A catalyst
derived from Ni(cod)2 (5 mol %), PCyPh2 (10 mol %), and BPh3
(15 mol %) was found indeed optimum to give 17aa in 93%
isolated yield (entry 5). The use of other LAs such as B(C6F5)3
and AlMe3 completely retarded the reaction (entries 6 and 7),
whereas only a trace amount of 17aa was obtained in the
absence of a LA catalyst (entry 8). A less polar solvent such as
1,4-dioxane did not affect the reaction, while highly Lewis basic
DMF retarded the reaction (entries 9 and 10). The catalysts
suitable for cyanoesterification were not effective (entries 12
and 13). No trace amount of the adduct was obtained with
Pd(PPh3)4, a catalyst of choice for the intramolecular cyano-
carbamoylation of alkynes.19
Cyanoformamides derived from N-methylbenzylamine (16b)
and morpholine (16c) also added across 2a in good yields under
the optimized conditions (entries 1 and 2 of Table 4). The
reaction of 16a with 4-methyl-2-pentyne (2c) gave 17ac in a
(21) (a) Bianchini, C.; Masi, D.; Meli, A.; Sabat, M. Organometallics 1986,
5, 1670. (b) Nishihara, Y.; Miyasaka, M.; Inoue, Y.; Yamaguchi, T.;
Kojima, M.; Takagi, K. Organometallics 2007, 26, 4054.
(22) Stapleton, R. L.; Chai, J.; Taylor, N. J.; Collins, S. Organometallics
2006, 25, 2514.
(23) Jacobsen, H.; Berke, H.; Do¨ring, S.; Kehr, G.; Erker, G.; Fro¨hlich,
R.; Meyer, O. Organometallics 1999, 18, 1724.
(24) Ohnishi, Y.-y.; Nakao, Y.; Sato, H.; Sakaki, S.; Nakao, Y.; Hiyama,
T. Organometallic 2009, 28, 2583.
9
J. AM. CHEM. SOC. VOL. 132, NO. 29, 2010 10073

A R T I C L E S
Hirata et al.
Scheme 1. Plausible Mechanism of Cyanoesterification of Alkynes
by Nickel/LA Catalysis
Scheme 3. Formal Synthesis of Pregabalina
a Reagents and Conditions: (a) TBAF, CF3CO2H, THF, 0 °C, 2 h; (b)
CuCl (5 mol %), NaOt-Bu (5 mol %), (R)-BINAP (5 mol %), PMHS,
t-BuOH, toluene, rt, 24 h; (c) Ba(OH)2 ·H2O, MeOH, rt, 4 h.
Table 3. Cyanocarbamoylation of 2a Using
N,N-Dimethylcyanoformamide (16a)a
Scheme 2. Transformations of 3′aea
entry
ligand
LA
solvent
yield (%)b
1
2
3
4
5
6
7
8
PMe3
PCy3
PCy2Ph
Pi-PrPh2
PCyPh2
PCyPh2
PCyPh2
PCyPh2
PCyPh2
PCyPh2
PPh3
P[3,5-(CF3)2-C6H3]3
P[3,5-(CF3)2-C6H3]3
BPh3
BPh3
BPh3
BPh3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
DMF
17
73
89
a Reagents and Conditions: (a) TBAF, CF3CO2H, THF, 0 °C, 1.5 h; (b)
H2, Pd/C (10 mol %), dioxane, rt, 2.5 h; (c) CoCl2, NaBH4, EtOH, 0 °C to
rt, 11 h; (d) Ba(OH)2 ·H2O, MeOH, rt, 4 h, then Ph2P(O)N3, NEt3, t-BuOH,
75 °C, 11 h.
91
BPh3
100 (93)c
B(C6F5)3
AlMe3
none
BPh3
BPh3
BPh3
BPh3
B(C6F5)3
0
0
6
92
14
60
15
12
9
poor yield but as a single isomer with regioselectivity opposite
to that of the cyanoesterification (entry 3, cf. entry 2 of Table
2). Reactions with silyl-substituted alkynes also proceeded with
excellent stereo-, regio-, and chemoselectivities with Pi-PrPh2
as a ligand in a 1,4-dioxane solvent to afford single isomers
(entries 4-9). The observed regioselectivity compares well with
10
11
12
13
toluene
toluene
toluene
a All the reactions were carried out using 16a (0.20 mmol), 2a (0.20
mmol), Ni(cod)2 (10.0 µmol), a ligand (20 µmol), and a LA (30 µmol) in a
solvent (0.40 mL). b GC yields as determined using tetradecane as an
internal standard. c Isolated yield obtained with a 1.00 mmol scale reaction.
(25) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron
Lett. 1969, 10, 4555.
(26) Inoue, K.; Sakai, K. Tetrahedron Lett. 1977, 46, 4063.
(27) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(28) (a) Singh, S. B.; Zink, D. L.; Liesch, J. M.; Goetz, M. A.; Jenkins, R. G.;
Nallinomstead, M.; Silverman, K. C.; Bills, G. F.; Mosley, R. T.; Gibbs,
J. B.; Albersschonberg, G.; Lingham, R. B. Tetrahedron 1993, 49, 5917.
(b) Lingham, R. B.; et al. Appl. Microbiol. Biotechnol. 1993, 40, 370.
(c) Singh, S. B.; Jayasuriya, H.; Silverman, K. C.; Bonfiglio, C. A.;
Williamson, J. M.; Lingham, R. B. Bioorg. Med. Chem. 2000, 8, 571.
(29) For a review for maleic anhydrides in natural products, see: Chen,
X.; Zheng, Y.; Shen, Y. Chem. ReV. 2007, 107, 1777.
those for the cyanoesterification reaction of silyl-substituted
alkynes. The structure of the adducts was assigned based on
NOE experiments of H NMR after desilylation of 17ae.
1
The stoichiometric reaction of 16a (0.50 mmol), Ni(cod)2,
PCyPh2 (2 equiv), and BPh3 in benzene gave a new nickel
species showing a signal at δ 32.1 (s) in 31P NMR, which was
assigned to be the signal of trans-(Ph2CyP)2Ni(CONMe2)-
(Ct N-BPh3) (18) (Scheme 4). Evaporation of the solvent in
Vacuo followed by washing of the resulting precipitates with
hexane gave 18 as a pale yellow powder in 80% yield. Single
yellow crystals suitable for X-ray crystallographic analysis were
obtained by recrystallization from hexane and tetrahydrofuran.
The molecular structure of 18 thus obtained clearly indicates
that two equivalent phosphorus ligands coordinate in a trans
geometry to nickel having a carbamoyl and a BPh3-bounded
cyano groups (Figure 1). As expected for the d8 Ni(II)
complexes, the Ni atom in 18 is a square-planar geometry, with
the sum of the angles of L-Ni-L′ (L, L′ ) C1, C2, P1, and
P2) being 358.38°. The Ni-C-N-B linkage is almost linear,
and the Ni-C-N and C-N-B angles (179.7(3) and 172.0(3)°,
respectively) are similar to those reported for [(dippe)Ni(η3-
allyl)(Ct N-BPh3)] (171.05(14) and 175.12(12)°),15b [(dppf)Ni(η3-
1-CH3-C3H4)(Ct N-BEt3)] (175.8(4) and 177.3(5)°),33a and
(30) Silverman, R. B. Angew. Chem., Int. Ed. 2008, 47, 3500.
(31) For examples of catalytic asymmetric synthesis of pregabalin, see:
(a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442. (b) Burk, M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.;
Hoge, G.; Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.;
Mulhern, T. A.; Ramsden, J. A.; Wade, R. A. J. Org. Chem. 2003,
68, 5731. (c) Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219. (d) Hoge,
G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J.
J. Am. Chem. Soc. 2004, 126, 5966. (e) Mita, T.; Sasaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514. (f) Fujimori, I.;
Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.;
Shibasaki, M. Tetrahedron 2007, 63, 5820. (g) Monge, D.; Mart´ın-
´
Zamora, E.; Va´zquez, J.; Alcarazo, M.; Alvarez, E.; Ferna´ndez, R.;
Lassaletta, J. M. Org. Lett. 2007, 15, 2867. (h) Gotoh, H.; Ishikawa,
H.; Hayashi, Y. Org. Lett. 2007, 25, 5307.
(32) For related copper-catalyzed enantioselective conjugate reduction of
R,ꢀ-unsaturated esters, see: (a) Appella, D. H.; Moritani, Y.; Shintani,
R.; Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9473. (b) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem.
Soc. 2004, 126, 8352.
9
10074 J. AM. CHEM. SOC. VOL. 132, NO. 29, 2010

Cyanoesterification and Cyanocarbamoylation of Alkynes
A R T I C L E S
Table 4. Nickel/BPh3-Catalyzed Cyanocarbamoylation of Alkynesa
a All the reactions were carried out using 16 (1.00 mmol), an alkyne (1.00 mmol), Ni(cod)2 (50 µmol), a ligand (100 µmol), and BPh3 (150 µmol) in
a solvent (2.0 mL). b Isolated yield.
Scheme 4. Synthesis and Reactions of trans-(Ph2CyP)2Ni(CONMe2)(Ct N-BPh3) (18)
[Ni(Ct N-B(C6F5)3)4]2- (174.8-178.2 and 174.8-178.2°).33b
The N-B and Ct N bond lengths of 18, 1.607(4) and 1.160(3)
Å, respectively, fall within the respective ranges reported for
well-defined Tm-Ct N-BR3 complexes (1.526-1.614 and
1.135-1.163 Å, where Tm represents transition metals, such
as Ni,15b,33 Fe,34 Ru,35 Mn,36 and Rh37). The oxidative adduct
was consumed upon treatment with five equivalents of 2a in
benzene at 60 °C for 1 h to give a new nickel complex showing
a signal at δ 45.3 ppm (s) in 31P NMR, and cyanocarbamoylation
product 17aa was observed in 40% yield as estimated by GC.
The new nickel species was assigned to be (Ph2CyP)2Ni(4-
octyne) 19 based on the fact that the same set of peaks was
(34) (a) Almeida, S. S. P. R.; da Silva, M. F. C. G.; da Silva, J. J. R. F.;
Pombeiro, A. J. L. J. Chem. Soc., Dalton Trans. 1999, 467. (b) Laing,
M.; Kruger, G.; Du Preez, A. L. J. Organomet. Chem. 1974, 82, C40.
(c) Ginderow, D. Acta Crystallogr., Sect. B 1980, 36, 1950. (d)
Amrhein, P. I.; Lough, A. J.; Morris, R. H. Inorg. Chem. 1996, 35,
4523. (e) Nakazawa, H.; Itazaki, M.; Owaribe, M. Acta Crystallogr.,
Sect. E: Struct. Rep. Online 2005, 61, m1166.
(33) (a) Acosta-Ram´ırez, A.; Mun˜oz-Herna´ndez, M.; Jones, W. D.; Garc´ıa,
J. J. J. Organomet. Chem. 2006, 691, 3895. (b) Zhou, J.; Lancaster,
S. J.; Walker, D. A.; Beck, S.; Thornton-Pett, M.; Bochmann, M.
J. Am. Chem. Soc. 2001, 123, 223.
9
J. AM. CHEM. SOC. VOL. 132, NO. 29, 2010 10075

A R T I C L E S
Hirata et al.
Scheme 6. Transformations of 17cea
a Reagents and Conditions: (a) TBAF, CF3CO2H, THF, 0 °C, 3 h; (b)
H2, Pd/C (10 mol %), dioxane, rt, 5 h; (c) BuLi, THF, -78 °C, 30 min.
lectivity observed with 2c (entry 2 of Table 2 vs entry 3 of
Table 4). Though speculative, a carbamoyl group may also
coordinate reversibly to the borane LA due to its higher Lewis
basicity than an alkoxycarbonyl group to form intermediate
20 in equilibrium, the phosphine ligand being substituted by
an alkyne subsequently to give 21 (path B). Migratory
insertion into the Ni-CN bond at the less hindered carbon
of the alkyne may take place to give alkenylnickel intermedi-
ate 22, which reductively eliminates the adducts. The
insertion of alkynes into Ni-CN bonds was also proposed
in the nickel-catalyzed silylcyanation of ynones,38 and is
energetically feasible (∆E e 10 kcal/mol) based on our
theoretical calculations of the arylcyanation of alkynes.24 The
aminocarbonyl group coordinating to BPh3 is likely reluctant
to undergo the migration in path B due to its plausibly less
nucleophilic nature.
Figure 1. Molecular Structure of 18 with thermal ellipsoids at the 30%
probability level. H atoms are omitted for clarity. Selected bond lengths
[Å] and angles [deg]: Ni-C1 1.893(3), Ni-P1 2.2208(8), Ni-P2 2.2112(8),
Ni-C2 1.898(3), N1-C1 1.160(3), N1-B 1.607(4); C1-Ni-P2 90.60(8),
C2-Ni-P2 87.28(8), C1-Ni-P1 90.10(8), C2-Ni-P1 90.94(8), C1-Ni-C2
173.56(12), Ni-C1-N1 179.7(3), C1-N1-B 172.0(3).
Scheme 5. Plausible Mechanism of Cyanocarbamoylation of
Alkynes by Nickel/LA Catalysis
Cyanocarbamoylation product 17ce was transformed to ꢀ-cyano
ketone 24 through protodesilylation, reduction of the double bond,
and nucleophilic substitution reaction of the morpholinamide group
with an organolithium reagent (Scheme 6).39
Palladium/B(C6F5)3-Catalyzed Decarbonylative Thiocyana-
tion of 2a. We then examined the nickel/LA catalysis using
other nitriles having a carbonyl-CN bond with alkynes. First,
thiocyanoformate 25 was prepared and reacted with 2a in
the presence of Ni(cod)2 (5 mol %), P(4-CF3-C6H4)3 (10 mol
%), and B(C6F5)3 (15 mol %) in toluene at 100 °C. Contrary
to our expectation, cis-thiocyanation product 26 was isolated
in 68% yield after 24 h (eq 3). None of the expected
cyanothioesterification product was formed. The stereochem-
1
istry of 26 was confirmed by NOE experiments of H NMR
after reduction of the cyano group to formyl. Use of a
palladium catalyst instead of nickel improved the yield
significantly, whereas the absence of the LA cocatalyst
retarded the reaction with both the palladium and nickel
catalysts. Whereas thiocyanation of terminal alkynes has
already been achieved with a palladium catalyst solely,40 this
reaction represents the first example of the thiocyanation of
internal alkynes.
observed in the reaction of Ni(cod)2, PCyPh2, and 2a. No
conversion of 18 was observed when the reaction was run at
room temperature for 24 h, suggesting that the coordination of
alkynes could be rate-determining. In addition, 18 served as a
catalyst for the reaction of 16a (0.20 mmol) with 2a (0.20 mmol)
in the presence of added BPh3 (10 mol %) in toluene at 80 °C
to give 17aa in 85% yield after 17 h as estimated by GC (eq
2). These results clearly suggest that 18 is a plausible intermedi-
ate for the cyanocarbamoylation.
The reaction is understood by the initial oxidative addition of
either the C-CN bond or S-carbonyl bond41 to nickel(0) or
palladium(0) followed by decarbonylation to give an RS-M-CN
Scheme 7. Plausible Mechanism for Decarbonylative
Thiocyanation of 2a
On the basis of these results, a catalytic cycle for the
cyanocarbamoylation reaction is proposed in path A in
Scheme 5, which resembles those for the cyanoesterification.
The only difference between these reactions is the regiose-
9
10076 J. AM. CHEM. SOC. VOL. 132, NO. 29, 2010

Cyanoesterification and Cyanocarbamoylation of Alkynes
A R T I C L E S
Table 5. Decarbonylative Phenylcyanation of 2a Using Benzoyl Cyanide (28)a
product(s), yield (%)b
entry
catalyst
conv. of 28
29
30
31
1c
2
Ni(cod)2
Ni(cod)2
PdCp(π-allyl)
PdCp(π-allyl)
PdCp(π-allyl)
38
40
44
75
100
3
2
0
0
0
3
3
6
15
0
2
0
21
3c
4
22
5d
57 (58)e
a All the reactions were carried out using 28 (0.20 mmol) and 2a (0.20 mmol) in toluene (0.40 mL). b GC yields as determined using tetradecane as
an internal standard. c Run in the absence of BPh3. d Run with PCyPh2 as a ligand instead of PCy2Ph. e Isolated yield obtained with a 1.00 mmol scale
reaction.
intermediate,42 which reductively eliminates a thiocyanation product
after migratory insertion of an alkyne into either the RS-M43 or
M-CN bond38 (Scheme 7).
place through oxidative addition of 28 to palladium(0) followed
by decarbonylation rather than formation of benzonitrile followed
by oxidative addition to palladium(0).
The resulting C-S bond in 26 underwent the Kumada-type
cross-coupling reaction with benzylmagnesium chloride in the
presence of a nickel catalyst44 to give formal benzylcyanation
product 27 in 99% yield (eq 4).
Conclusion
In summary, we have demonstrated that the cyanoesterifica-
tion and cyanocarbamoylation of alkynes proceed by nickel/
LA catalysis in highly stereo- and regioselective manners to
give a range of ꢀ-cyano-substituted acrylates and acrylamides.
These highly functionalized nitrile products are shown to be
versatile synthetic intermediates for γ-aminobutyric acid, ꢀ-ami-
no acid, ꢀ-cyano ketone, and 1,2-dicarboxylic acid derivatives.
We have also briefly shown that similar reactions of cyanofor-
mate thioesters and cyanoketones with alkynes accompany
decarbonylation in the presence of a nickel or palladium/LA
catalyst45 to give thiocyanation and arylcyanation products,
respectively.
Palladium/BAr3-Catalyzed Decarbonylative Phenylcyana-
tion of 2a. Finally, we attempted the benzoylcyanation of 2a. In
the presence of a nickel catalyst without LA, only a small amount
of the expected cis-benzoylcyanation product 29 was observed
(entry 1 of Table 5), along with phenylcyanation product 30 and
benzonitrile (31). Products 30 and 31 should be derived from
decarbonylation of 28.9 Whereas the presence of a LA cocatalyst
was not effective (entry 2), palladium/BPh3 catalysts selectively
gave 30 (entries 4 and 5). Of ligands examined, PCyPh2 was the
best, giving 30 in 58% yield after isolation (entry 5). The reaction
of benzonitrile (31) with 2a under the similar conditions gave 30
in only 20% yield, suggesting that insertion of the alkyne takes
Acknowledgment. This work has been supported financially
by Grants-in-Aid for Creative Scientific Research, Scientific
Research (S), Young Scientists (A), and Priority Area “Molecular
Theory for Real Systems” from JSPS and MEXT, the Kurata
Memorial Hitachi Science and Technology Foundation, and Takeda
Science Foundation. YH and AY acknowledge the JSPS for a
predoctoral fellowship.
Supporting Information Available: Detailed experimental
procedures including spectroscopic and analytical data. Com-
plete ref 28b. This material is available free of charge via the
Internet at http://pubs.acs.org.
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