Nickel-catalyzed regioselective hydroalkynylation of styrenes: Improved catalyst system, reaction scope, and mechanism

Article abstract of DOI:10.1021/ol802475h

(Chemical Equation Presented) Addition of the sp-C H bond of triisopropylsilylacelylene to the carbon-carbon double bonds of styrenes bearing functional groups proceeded efficiently at room temperature in the presence of 3 mol % of Ni(cod)₂ wit

Full text of DOI:10.1021/ol802475h

ORGANIC
LETTERS
2009
Vol. 11, No. 3
523-526
Nickel-Catalyzed Regioselective
Hydroalkynylation of Styrenes: Improved
Catalyst System, Reaction Scope, and
Mechanism
Masamichi Shirakura and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
suginome@sbchem.kyoto-u.ac.jp
Received October 27, 2008
ABSTRACT
Addition of the sp-C-H bond of triisopropylsilylacetylene to the carbon-carbon double bonds of styrenes bearing functional groups proceeded
efficiently at room temperature in the presence of 3 mol % of Ni(cod)2 with a PMePh2 ligand. Use of 2-deuteriotriisopropylsilylacetylene in the
hydroalkynylation of styrenes resulted in regioselective incorporation of deuterium into the ꢀ-positions of recovered styrenes, along with its
regioselective introduction into the product’s methyl group.
Catalytic C-H functionalization has attracted much attention
because of its high efficiency and the easy availability of
starting materials.1 The sp-C-H bond of a terminal alkyne
has been the primary target for catalytic activation. Particular
attention has focused on the addition of the alkyne C-H
bond across carbon-carbon multiple bonds, which serves
as a convenient method for the synthesis of functionalized
alkynes. Much effort has been devoted to the addition to
the C-C triple bond in the presence of transition-metal
complexes, leading to the development of a variety of
methods for homodimerization2 of terminal alkynes and
cross-dimerization,2c,3 i.e., addition of one terminal alkyne
to a different alkyne. In contrast to carbon-carbon triple
bonds, CdC bonds hardly undergo the addition unless they
are sufficiently activated by ring strain or cumulation. Thus,
while use of cyclopropene,4 norbornadiene,5 and allenes6 has
been reported, hydroalkynylation to less reactive CdC bonds
has not been achieved except for some limited examples in
ruthenium-catalyzed codimerization of terminal alkynes with
1,3-dienes, in which the positions of the CdC bonds in the
product are difficult to predict.7 We recently reported room-
(3) (a) Akita, M.; Yasuda, H.; Nakamura, A. Bull. Chem. Soc. Jpn. 1984,
57, 480. (b) Trost, B. M.; McIntosh, M. C. Tetrahedron Lett. 1997, 38,
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Y.; Inoue, Y. Org. Lett. 2007, 9, 2919. (l) Nishimura, T.; Guo, X.-X.;
Ohnishi, K.; Hayashi, T. AdV. Synth. Catal. 2007, 349, 2669.
(1) (a) Dyker, G., Ed. Handbook of C-H Transformations; Wiley-VCH:
Weinheim, Germany, 2005. (b) Kakiuchi, F.; Murai, S. In ActiVation of
UnreactiVe Bonds and Organic Synthesis; Murai, S., Ed.; Springer: Berlin,
Heidelberg, 1999; p 48. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731. (d) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949.
(2) (a) Singer, H.; Wilkinson, G. J. Chem. Soc. A 1968, 849. For a
review, see: (b) Bustelo, E.; Dixneuf, P. H. In Handbook of C-H Trans-
formations; Dyker, G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; p 62.
(c) Trost, B. M.; Chan, C.; Ruhter, G. J. Am. Chem. Soc. 1987, 109, 3486.
For homodimerization of terminal alkynes using Ni/trialkylphosphine, see:
(d) Ogoshi, S.; Ueta, M.; Oka, M.; Kurosawa, H. Chem. Commun. 2004,
2732.
(4) Yin, J.; Chisholm, J. D. Chem. Commun. 2006, 632.
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(b) Yamaguchi, M.; Omata, K.; Hirama, M. Tetrahedron Lett. 1994, 35,
5689. (c) Bruyere, D.; Grigg, R.; Hinsley, J.; Hussain, R. K.; Korn, S.; De
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(d) Rubin, M.; Markov, J.; Chuprakov, S.; Wink, D. J.; Gevorgyan, V. J.
Org. Chem. 2003, 68, 6251.
10.1021/ol802475h CCC: $40.75
Published on Web 01/14/2009
2009 American Chemical Society

temperature hydroalkynylation of CdC bonds of 1,3-dienes
and styrenes.8 It was essential to use a Ni/PBu3 catalyst
with triisopropylsilylacetylene, whose bulkiness retards its
homodimerization.3k The catalyst system was particularly
effective for hydroalkynylation of 1,3-dienes, allowing highly
regioselective formation of various 1,4-enynes. However,
hydroalkynylation of styrene derivatives with the Ni/PBu3
catalyst still encountered difficulty in reacting styrenes having
no electron-withdrawing groups. For instance, in the presence
of the Ni/PBu3 catalyst, styrene afforded <20% yield of
hydroalkynylation product under the reaction conditions,
while reaction of p-ethoxycarbonylstyrene afforded 94%
yield under the same reaction conditions. In this communica-
tion, we describe a modified catalyst system for the hy-
droalkynylation of styrene derivatives, including electron-
rich derivatives. The mechanism of the reaction is also
discussed on the basis of deuterium-labeled experiments.
Hydroalkynylation of unsubstituted styrene has been
reexamined with a variety of tertiary phosphine ligands
(Table 1). Use of PBu3 resulted in the formation of 3a in
required (entry 8). In the presence of the bidentate ligand
DPPE (1,2-bis(diphenylphosphino)ethane), only the alkyne
dimerization reaction proceeded, with no formation of
hydroalkynylation product (entry 9).
Taking PMePh2 as the best-yielding ligand, hydroalkyny-
lation of various styrenes (2a-k) was carried out at room
temperature in the presence of 3-5 mol % of Ni(cod)2/
PMePh2 (Ni/P ) 1/4) catalyst (Table 2). Styrene afforded
Table 2. Scope of the Nickel-Catalyzed Hydroalkynylation of
Styrenesa
Table 1. Ligand Screening of Ni Catalysta
entry
ligand
T (°C)
% yield of 3ab
% yield of 4b
1
2
3
4
5
6
7
8c
9
PBu3
PMe3
80
80
80
80
80
80
rt
12
36
52
80
trace
0
87 (88)
86
11
21
28
14
42
38
11
15
66
PMe2Ph
PMePh2
PCyPh2
PPh3
PMePh2
PEtPh2
DPPE
rt
rt
0
a Acetylene 1 (1.0 mmol), styrene (3.0 mmol), Ni(cod)2 (0.1 mmol),
and phosphine ligand (0.40 mmol for entries 1-8, 0.20 mmol for entry 9)
were reacted in toluene (1.0 M) for 3 h at the temperature indicated in the
b
table. 1H NMR yield. Isolated yield in parentheses. c 8 h.
only 12% yield at 80 °C (entry 1). PMe3 resulted in improved
yield for 3a (entry 2). It was remarkable to observe the
significant increase in yields by using PMe2Ph and PMePh2:
the latter afforded 80% yield of the product 3a (entries 3
and 4). In sharp contrast, no product was obtained with PPh3
or PCyPh2, although the latter has electronic properties
similar to those of PMePh2 (entries 5 and 6). Using PMePh2
as a ligand, the reaction proceeded at room temperature in
better yield than the reaction at 80 °C (entry 7). It should be
noted that no regioisomer was formed in the catalytic
reaction. PEtPh2 showed almost the same catalytic activity
as PMePh2, although a slightly longer reaction time was
a Reactions were performed with an excess (3.0 equiv) of styrenes on
a 0.3 mmol scale in toluene (2.0 M) in the presence of Ni(cod)2 (3.0-5.0
mol %) with PMePh2 (P/Ni ratio ) 4/1). b Isolated yields. c 5 mol % of Ni
catalyst. d The reaction were performed with an excess (1.2-1.5 equiv) of
styrenes under otherwise identical reaction conditions. See the Supporting
Information for details.
(7) Mitsudo, T.; Nakagawa, Y.; Watanabe, K.; Hori, Y.; Misawa, H.;
Watanabe, H.; Watanabe, Y. J. Org. Chem. 1985, 50, 565.
the hydroalkynylation product 3a in 86% yield under these
reaction conditions (entry 1). In addition to styrene 2b having
(8) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410.
524
Org. Lett., Vol. 11, No. 3, 2009

a
Table 3. Hydroalkynylation of p-Ethoxycarbonylstyrene with Deuterated Triisopropylsilylacetylene 1-d1
3b
recovered 2b
entry
ligand
x
y
% catalyst loading time/h % conversionb % yieldc % Dc R-D:ꢀ-Dc,d % yieldc % Dc R-D/ꢀ-Dc,d
1
2
3
4
PMePh2
PBu3
PMePh2 1.2
PBu3 1.2
1
1
10
10
1
10
10
3
4
24
3
>95
>95
45
99
90
44
37
49
31
95
1:>99
2:98
1:99
92
89
55
58
3
6
34
70
3:97
2:98
3:97
3:97
1
3
9
38
103
1:99
c
a See the Supporting Information for the experimental details. b Conversion of 1-d1 (entries 1 and 2) or 2b (entries 3 and 4). Determined by H NMR.
Determined by H NMR.
1
d
2
electron-withdrawing substituents at the p-position (entry 3),
responsible for the observed moderate (49% D) deuterium
incorporation into the product 3b. A similar deuterium
incorporation into both product and starting material was
observed in nickel-catalyzed hydrocyanation of styrenes, in
which reductive elimination was proposed as the rate-
determining step.9 Our observation strongly suggests that our
hydroalkynylation system also proceeds through the rate-
determining reductive elimination step. This assumption is
also supported by reaction of 1-d1 with 2b in the presence
of PBu3 as a ligand, resulting in less deuterium incorporation
into product 3b with more D-incorporation into styrene 2b
(entry 2). This result also suggests that the observed higher
catalytic activity of PMePh2-based catalyst may be attributed
to more facile reductive elimination than PBu3-based one.
A more pronounced difference in deuterium incorporation
between PMePh2 and PBu3 was observed, when reactions
of a small excess of 1-d1 with 2b were stopped before going
to completion (38-45% conversion of 2b) (entries 3 and
4). In both reactions, we observed high deuterium incorpo-
ratin to the product because less H-D exchanges in 1-d1
would take place under the modified reaction conditions. The
two ligands showed quite different profiles of the deuterium
incorporation into the starting styrene. Much more H-D
exhange in 2b (70%) was observed for the PBu3-based
catalyst than the PMePh2-based one (34%), suggesting again
that the latter facilitated the reductive elimination step.
those having electron-donating p-substituents such as meth-
oxy and methyl groups afforded the corresponding hy-
droalkynylation products in high yields (entries 5 and 7). In
spite of using the low-valent nickel catalyst, the p-chloro
group of 2e survived with these reaction conditions (entry
8). It should be noted that carbonyl groups, which could have
undergone the alkynylation, were tolerable (entries 9 and 10).
Moreover, m-ethynyl-substituted styrene underwent the hy-
droalkynylation at the CdC bond, with minor formation of
the product in which the triple bond underwent the hy-
droalkynylation (entry 11). The hydroalkynylation could also
be applied to o-substituted styrenes. o-Methylstyrene and
o-divinylbenzene afforded the corresponding products in
moderate yields (entries 12 and 13). In the reaction of
divinylbenzene, no double addition product was detectable
in the reaction mixture. The 1-naphthyl derivative, in contrast,
showed high reactivity, resulting in the formation of hy-
droalkynylation product in high yield (entry 14). Instead of
using excess styrenes, use of a small excess (1.2-1.5 equiv)
of the silylacetylene also afforded good yields (entries 2, 4,
6, and 15).
In a previous report on the nickel-catalyzed hydroalky-
nylation of 1,3-dienes, we proposed a reaction mechanism
involving the formation of (alkynyl)(hydride)nickel species,
the H-Ni bond of which undergoes insertion of the CdC
bond in a highly regioselective manner. To obtain insight
into the reaction mechanism of the present reaction, we
carried out the hydroalkynylation with 2-deuterio-labeled
triisopropylsilylacetylene.
Deuterium incorporation into the vinyl group was also
observed in the reaction of p-methoxystyrene (2c), which
gave very little hydroalkynylation product 3c (<5% conver-
sion) (Scheme 1). 50% deuterium incorporation into the
ꢀ-position of p-methoxystyrene (2c) was observed after 7 h
at room temperature.
Triisopropylsilylacetylene-d1 (1-d1) was reacted with 10
equiv of styrene 2b in the presence of Ni/PMePh2 catalyst
at room temperature (Table 3, entry 1). The reaction was
complete after 4 h, giving hydroalkynylation product 3b and
recovered 2b in 99% and 92% yields, respectively. In 3b,
deuterium was incorporated exclusively at the ꢀ-position (R/ꢀ
These results suggest that the present hydroalkynylation
involves a reversible insertion-ꢀ-hydride elimination step
(Scheme 2). Oxidative addition of the sp-C-H bond of
silylacetylene to the Ni(0) species gives intermediate A,
whose Ni-H bond undergoes regioselective insertion of the
1
2
) 1:>99) as judged by H and H NMR. It should be
remarked that deuterium incorporation was also observed in
the recovered styrene 2b albeit in low deuterium content (3%
D). This H-D exchange in the starting material may be
(9) Casalnuovo, A. L.; RajanBabu, T. V.; Ayers, T. A.; Warren, T. H.
J. Am. Chem. Soc. 1994, 116, 9869.
Org. Lett., Vol. 11, No. 3, 2009
525

Scheme 1
.
Reaction of p-Methoxystyrene with Deuterated
Triisopropylsilylacetylene 1-d1
Scheme 3. Desilylation of Hydroalkynylation Product 3k
Treatment of 3k with tetrabutylammonium fluoride in THF
(1.0 M) afforded the desilylated terminal alkyne 5 in 78%
yield. On the other hand, treatment of 3k with tetrabuty-
lammonium triphenylsilyldifluoride10 selectively afforded
allene 6 in 72% yield.
CdC bond of styrenes to give intermediate B. In cases where
no product is formed, the intermediate B reverts to inter-
mediate A through ꢀ-hydride elimination, leaving deuterium
at the ꢀ-position of styrene. In the productive system, the
kinetic barriers for the reductive elimination (forward) and
ꢀ-hydride elimination (backward) from B are comparable,
leading to the formation of the product as well as deuterated
styrene. These results suggest that the reductive elimination
step can be the rate-determining step in the catalytic cycle
and that PMePh2 may lower the barrier for this step.3
The products could be converted to a useful synthetic
intermediate by removal of the TIPS group (Scheme 3).
In summary, we have demonstrated the regioselective
hydroalkynylation of styrenes with a variety of functional
groups using an improved nickel catalyst system with the
PMePh2 ligand. The catalytic cycle may involve reductive
elimination as one of the slowest steps. Further studies on
improvement of the catalyst system, expansion of the reaction
scope, and synthetic applications are now being undertaken
in this laboratory.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan. M. Shirakura acknowledges fellowship sup-
port from JSPS.
Scheme 2
. Plausible Reaction Mechanism of the
Hydroalkynylation of Styrenes
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802475H
(10) Gingras, M. Tetrahedron Lett. 1991, 32, 7381. For use of the reagent
for conversion of alkynylsilanes to terminal alkynes, see: Wright, J. M.;
Jones, G. B. Tetrahedron Lett. 1999, 40, 7605.
526
Org. Lett., Vol. 11, No. 3, 2009