Hydroheteroarylation of alkynes under mild nickel catalysis

Article abstract of DOI:10.1021/ja0623459

Nickel complexes having a bulky tri(sec-alkyl)phosphine ligand catalyze hydroheteroarylation of alkynes at 35 °C. Selective activation of an Ar-H bond over an Ar-CN bond of N-protected 3-cyanoindoles is achieved by a proper choice of ligand and/or an N-protecting group. The catalysis is applicable to a diverse range of heteroarenes to afford cis-hydroheteroarylation products in highly chemo- and stereoselective manners. Excellent regioselectivity is observed with unsymmetrical alkynes to give the corresponding heteroaryl-substituted ethenes having a larger substituent trans to an aryl group. Copyright

Full text of DOI:10.1021/ja0623459

Published on Web 06/07/2006
Hydroheteroarylation of Alkynes under Mild Nickel Catalysis
Yoshiaki Nakao,* Kyalo Stephen Kanyiva, Shinichi Oda, and Tamejiro Hiyama*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 615-8510, Japan
Received April 6, 2006; E-mail: nakao@npc05.kuic.kyoto-u.ac.jp; thiyama@npc05.kuic.kyoto-u.ac.jp
We report herein nickel-catalyzed activation of an Ar-H bond1
Table 1. Nickel-Catalyzed Reactions of 3-Cyanoindoles with
4-Octyne (2a)a
of N-protected 3-cyanoindoles followed by addition reaction across
alkynes to give 4 (eq 1), demonstrating divergent nickel catalysis2
directed by a ligand and/or an N-protecting group. The observed
catalysis has been extended to a wide range of heteroarenes and
alkynes to give various heteroaryl-substituted ethenes highly
chemo-, stereo-, and regioselectively under mild conditions.
time
(h)
conv. of
yield of
yield of
entry
1
ligand
1 (%)b
3 (%)c
4 (%)c
1
2
1a
1a
1b
1b
1b
PMe3
PCyp3
PMe3
PCyp3
PCyp3
18
18
30
18
96
86
57
69
>95
>95
68 (3aa)
3 (3aa)
<3 (3ba)
<3 (3ba)
<3 (3ba)
6 (4aa)
16 (4aa)d
35 (4ba)
95 (4ba)
88 (4ba)
3
4e
5e,f
a Reactions were carried out using 1 (1.0 mmol), 2a (1.0 mmol), Ni(cod)2
(0.10 mmol), and a ligand (PMe3, 0.20 mmol; PCyp3, 0.10 mmol) in toluene
(2.5 mL) at 100 °C. b Based on recovered 1. c Isolated yields. d E:Z ) 91:
9. e The reaction was carried out at 35 °C. f Ni(cod)2 (0.010 mmol) and
PCyp3 (0.010 mmol) were used.
Scheme 1. Plausible Mechanism
As we have recently disclosed,2a,b the reaction of 3-cyano-1-
methoxycarbonylindole (1a) with 4-octyne (2a) in the presence of
Ni/PMe3 catalyst in toluene at 100 °C gave the arylcyanation
product 3aa in 68% yield after 18 h (entry 1 of Table 1). We also
isolated a small amount (6%) of (E)-3-cyano-1-methoxycarbonyl-
2-(4-octen-4-yl)indole (4aa), which should be derived from the
insertion of the alkyne into the Ar-H bond at the C-2 position of
1a. On the other hand, the identical reaction but with tricyclopen-
tylphosphine (PCyp3) as a ligand instead of PMe3 gave 4aa in 16%
yield together with 3% of 3aa, the activation of the Ar-CN bond
being preceded by that of the Ar-H bond (entry 2). With 3-cyano-
1-methylindole (1b), the corresponding hydroarylation product 4ba
became dominant even under the Ni/PMe3 catalysis (entry 3),3 and
the catalysis was found to be effective even at 35 °C by using PCyp3
as a ligand to afford 4ba in 95% yield.4 It is worth noting that the
bond to be actiVated is controllable by choosing a ligand and/or
an N-protecting group to induce a different catalysis of nickel. Use
of 1 mol % of the catalyst still worked well to give 4ba in 88%
yield, although the reaction took 96 h for completion (entry 5).
A catalytic cycle in Scheme 1 may be suggested that starts with
alkyne-coordinating Ni(0) species A,5 which subsequently under-
goes oxidative addition of an Ar-H bond at the C-2 position to
give alkyne-coordinating Ar-Ni(II)-H intermediate B, since the
reaction proceeds best with heteroarenes having a rather acidic C-H
bond (vide infra) adjacent to a heteroatom and an electron-rich
nickel species as a catalyst.6,7 Hydronickelation8 would give aryl-
Ni(II)-alkenyl intermediate C, which then would undergo reductive
elimination to afford a cis-hydroarylation product 4 and regenerate
Ni(0) species.9 A bulky tri(sec-alkyl)phosphine ligand may retard
requisite η2-coordination of a cyano group10 and/or the subsequent
oxidative addition of the Ar-CN bond in cyano- and alkyne-
coordinating Ni(0) species D due to a steric reason. Electron-
donating substituents on the nitrogen atom would also slow the
rate of the oxidative addition of the Ar-CN bond, making the
hydroarylation catalysis a predominant pathway.2a,b,10b
substituent on nitrogen (entries 1-3). Indoles (1f-1h) having an
electron-withdrawing functional group at the C-3 position all gave
the corresponding hydroarylation products at 35 °C (entries 4-6),
whereas 1-methyl-3-phenylindole (1i) required 100 °C to react with
2a (entry 7). The exclusiVe reaction of the Ar-H bond oVer the
formyl C-H bond of 1g is remarkable in view of the fact that the
latter is also activated to undergo addition across an alkyne under
Ni/PBu3 catalysis.1b Substituted imidazoles (entries 8-11) reacted
exclusively at the C-2 position as well as benzofuran (1n) and
benzothiophene (1o) (entries 12 and 13) eVen in the presence of
an Ar-Cl bond (entry 9) or other acidic C-H bonds (entry 11).
Benzoxazole (1p) and 4,5-dimethylthiazole (1q) also participated
in the reaction (entries 14 and 15). Unsymmetrical internal alkynes,
4-methyl-2-pentyne (2b), and silylacetylenes 2c and 2d all reacted
with 1b in excellent regioselectivities to give the adducts having a
larger substituent trans to the aryl group (entries 16-18).12,13
In conclusion, we have demonstrated a divergent nickel catalysis
on Ar-H versus Ar-CN activation and extended the catalysis to
hydroheteroarylation14 of alkynes under mild conditions. The present
hydroheteroarylation is applicable to a diverse range of heteroarenes
and alkynes to give various heteroaryl-substituted ethenes, versatile
synthetic intermediates and/or targets of pharmaceuticals, natural
products, and materials, highly chemo-, regio-, and stereoselectively,
and thus would be complementary to well-established intermolecular
hydroarylation reactions catalyzed by other transition metals.7,9,15
Studies on the detailed mechanism and potential nickel catalysis
on other C-H functionalizations16,17 will be the subject of our future
work.
The catalysis is found to be effective for a wide range of
heteroarenes (Table 2).11 Methyl indole-3-carboxylates (1c-1e)
reacted with 2a in modest to good yields, irrespective of a
9
8146
J. AM. CHEM. SOC. 2006, 128, 8146-8147
10.1021/ja0623459 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Nickel-Catalyzed Hydroheteroarylation of Alkynesa
(7) For trans-selective hydroarylations of alkynes via electrophilic metalation,
see: (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992. (b) Trost, B. M.; Toste, F. D.; Greenman, K.
J. Am. Chem. Soc. 2003, 125, 4518. (c) Tunge, J. A.; Foresee, L. N.
Organometallics 2005, 24, 6440.
(8) Similar regiochemistry was also reported for hydronickelation of unsym-
metrical alkynes; see entries 16-18 of Table 2 and refs 1b and 1f.
(9) For representative examples of cis-hydroarylation of alkynes via oxidative
addition of an Ar-H bond at high temperature or under irradiation, see:
(a) Hong, P.; Cho, B.-R.; Yamazaki, H. Chem. Lett. 1979, 339. (b)
Tokunaga, Y.; Sakakura, T.; Tanaka, M. J. Mol. Catal. 1989, 56, 305. (c)
Aulwurm, U. R.; Melchinger, J. U.; Kisch, H. Organometallics 1995, 14,
3385. (d) Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett.
1995, 681. (e) Satoh, T.; Nishinaka, Y.; Miura, M.; Nomura, M. Chem.
Lett. 1999, 615. (f) Kakiuchi, F.; Sato, T.; Igi, K.; Chatani, N.; Murai, S.
Chem. Lett. 2001, 386. (g) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong,
J.-B.; Jun, C.-H. Org. Lett. 2003, 5, 2759. (h) Kuninobu, Y.; Tokunaga,
Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 202. The
mechanism of cis-hydroarylation of alkynes catalyzed by dinuclear
palladium complexes is unclear. See: (i) Tsukada, N.; Mitsuboshi, T.;
Setoguchi, H.; Inoue, Y. J. Am. Chem. Soc. 2003, 125, 12102.
(10) (a) Garc´ıa, J. J.; Jones, W. D. Organometallics 2000, 19, 5544. (b) Garc´ıa,
J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc. 2002, 124, 9547.
(11) At present, the following (hetero)arenes have failed to participate in the
reaction: 4-(trifluoromethyl)benzonitrile, methyl 4-(trifluoromethyl)ben-
zoate, ethyl 1-methylindole-2-carboxylate, 1-methylpyrrole, 1-methyl
imidazole. Unsubstituted indoles gave a mixture of 2- and 3-alkenylated
products.
(12) A similar reaction of 1g with 2c in the presence of a Ru(H)2(CO)(PPh3)3
catalyst at 115 °C has been reported to give the corresponding adduct as
a mixture of stereoisomers in 42% yield; see ref 9f.
a Unless otherwise noted, all reactions were carried out using a hetero-
arene (1.0 mmol), an alkyne (1.0 mmol), Ni(cod)2 (0.10 mmol), and PCyp3
(0.10 mmol) in toluene (2.5 mL) at 35 °C. b Isolated yields based on the
heteroarene. c The reaction was carried out at 50 °C using 4.0 mmol of 2a.
d The reaction was carried out at 100 °C using 3.0 mmol of 2a. e The reaction
was carried out at 50 °C. f The reaction was carried out at 100 °C using 2.0
mmol of 2d.
(13) Terminal alkynes failed to give the corresponding adducts due to rapid
background oligomerization of alkynes.
(14) For selected examples of related hydroheteroarylations of unsaturated
bonds, see: (a) Hong, P.; Cho, B.-R.; Yamazaki, H. Chem. Lett. 1980,
507. (b) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778.
(c) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc.
1996, 118, 493. (d) Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Org. Lett.
2000, 2, 2927. (e) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2002, 124, 13964. (f) Pittard, K. A.; Lee, J. P.; Cundari, T. R.;
Gunnoe, T. B.; Petersen, J. L. Organometallics 2004, 23, 5514. (g)
Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003, 125, 4720. (h) Ferreira,
E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (i) Youn, S. W.;
Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (j) Liu, C.; Han, X.;
Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700. (k)
Tan, K. L.; Park, S.; Ellman, J. A.; Bergman, R. G. J. Org. Chem. 2004,
69, 7329. (l) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M.
J. Angew. Chem., Int. Ed. 2005, 44, 3125. (m) Tsukada, N.; Murata, K.;
Inoue, Y. Tetrahedron Lett. 2005, 46, 7515.
Acknowledgment. This work has been supported financially
by a Grant-in-Aid for Creative Scientific Research, No. 16GS0209,
and COE Research on “United Approach to New Material Science”
from MEXT.
Supporting Information Available: Detailed experimental pro-
cedures including spectroscopic and analytical data (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For rare examples of stoichiometric and catalytic C-H activation by nickel,
see: (a) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(b) Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem. 1990, 55, 2554. (c)
Brunkan, N. M.; Brestensky, D. M.; Jones, W. D. J. Am. Chem. Soc.
2004, 126, 3627. (d) Clement, N. D.; Cavell, K. J.; Jones, C.; Elsevier,
C. J. Angew. Chem., Int. Ed. 2004, 43, 1277. (e) Clement, N. D.; Cavell,
K. J. Angew. Chem., Int. Ed. 2004, 43, 3845. (f) Ogoshi, S.; Ueta, M.;
Oka, M.; Kurosawa, H. Chem. Commun. 2004, 2732. (g) Keen, A. L.;
Johnson, S. A. J. Am. Chem. Soc. 2006, 128, 1806.
(15) For hydroarylation of alkynes via the Friedel-Crafts alkenylations, see:
(a) Yamaguchi, M.; Kido, Y.; Hayashi, A.; Hirama, M. Angew. Chem.,
Int. Ed. 1997, 36, 1313. (b) Tsuchimoto, T.; Maeda, T.; Shirakawa, E.;
Kawakami, Y. Chem. Commun. 2000, 1573. (c) Reetz, M. T.; Sommer,
K. Eur. J. Org. Chem. 2003, 3485. (d) Shi, Z.; He, S. J. Org. Chem.
2004, 69, 3669.
(16) For selected recent work on intermolecular transition-metal-catalyzed C-C
bond formation of indoles via C-H activation, see: (a) Sawada, T.; Fuerst,
D. E.; Wood, J. L. Tetrahedron Lett. 2003, 44, 4919. (b) Wang, X.; Lane,
B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (c) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (d) Deprez,
N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 4972.
(17) For selected recent work on intermolecular transition-metal-catalyzed C-C
bond formation of other heteroarenes via C-H activation, see: (a) Pivsa-
Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1998, 71, 4667. (b) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada,
T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc.
2003, 125, 1700. (c) Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607. (d)
Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300. (e) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. J.
Org. Chem. 2005, 70, 3997. (f) Campeau, L.-C.; Rousseaux, S.; Fagnou,
K. J. Am. Chem. Soc. 2005, 127, 18020. (g) Campeau, L.-C.; Parisien,
M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (h) Lewis,
J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed.
2006, 45, 1589.
(2) For ligand-dependent divergent nickel catalysis on the reactions of
benzonitrile with alkynes, see: (a) Nakao, Y.; Oda, S.; Hiyama, T. J.
Am. Chem. Soc. 2004, 126, 13904. (b) Nakao, Y.; Oda, S.; Yada, A.;
Hiyama, T. Tetrahedron, in press. (c) McCormick, M. M.; Duong, H. A.;
Zuo, G.; Louie, J. J. Am. Chem. Soc. 2004, 127, 13904.
(3) A stereochemically unidentified product derived from the insertion of two
molecules of 2a into the Ar-H bond at the C-2 position of 1b was also
obtained in 31% yield.
(4) Other bulky tri(sec-alkyl)phosphines, such as PCy3 and P(i-Pr)3, also gave
comparable results (>90% yield estimated by GC), whereas P(t-Bu)3 and
PPh3 were found totally ineffective for the present hydroarylation.
(5) Preliminary 31P NMR studies show that PCyp3 does not coordinate to the
nickel center of Ni(cod)2 in the absence of an alkyne; see also ref 1f.
(6) The following experiments could suggest that an electrophilic metalation
pathway as a C-H activating step7 would be unlikely. (a) The reaction
of 3-cyano-2-deuterio-1-methylindole (1b-d1) with 2a gave the corre-
sponding deuterated adduct 4ba-d1. (b) The reaction of an equimolar (0.50
mmol) mixture of 1b-d1 and methyl 1-methylindole-3-carboxylate (1c)
with 2a (1.0 mmol) under the identical conditions did not cause
intermolecular deuterium crossover. (c) Nickel(II) complexes, such as Ni-
(acac)2 and NiCl2, failed to catalyze the reaction in the presence or absence
of external bases, such as Et3N and Cs2CO3.
JA0623459
9
J. AM. CHEM. SOC. VOL. 128, NO. 25, 2006 8147