Cobalt-catalyzed addition of azoles to alkynes

Article abstract of DOI:10.1021/ol101777x

A ternary catalytic system consisting of a cobalt salt, a diphosphine ligand, and a Grignard reagent promotes syn-addition of an azole C(2)-H bond across an unactivated internal alkyne with high chemo-, regio-, and stereoselectivities under mild conditions. Mechanistic experiments suggest that the reaction involves oxidative addition of the oxazolyl C-H bond to the cobalt center, alkyne insertion into the Co-H bond, and reductive elimination of the resulting diorganocobalt species.

Full text of DOI:10.1021/ol101777x

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4180-4183
Cobalt-Catalyzed Addition of Azoles to
Alkynes
Zhenhua Ding and Naohiko Yoshikai*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link, Singapore 637371
nyoshikai@ntu.edu.sg
Received July 30, 2010
ABSTRACT
A ternary catalytic system consisting of a cobalt salt, a diphosphine ligand, and a Grignard reagent promotes syn-addition of an azole C(2)-H
bond across an unactivated internal alkyne with high chemo-, regio-, and stereoselectivities under mild conditions. Mechanistic experiments
suggest that the reaction involves oxidative addition of the oxazolyl C-H bond to the cobalt center, alkyne insertion into the Co-H bond, and
reductive elimination of the resulting diorganocobalt species.
Aromatic heterocycles represent ubiquitous structural motifs
found in a broad range of functional molecules including
pharmaceuticals and photo- and electroactive materials.
Consequently, the development of efficient preparative
methods for densely functionalized heteroarenes has attracted
considerable attention from synthetic chemists. In this
context, C-C bond-forming reactions through activation of
heteroaromatic C-H bonds are particularly attractive.1 While
rhodium has been among the most versatile metals for such
transformations,1a its lighter homologue, cobalt, has rarely
been exploited for catalytic elaboration of heteroaromatic2
and aromatic3 C-H bonds regardless of its attractiveness
because of its much lower cost.4 Here we report that a cobalt
complex serves as an efficient catalyst for activation of a
C(2)-H bond of an azole derivative followed by insertion
of an unactivated internal alkyne.5 The reaction occurs under
mild conditions to afford a trisubstituted olefin with excellent
cis-stereoselectivity and makes a useful addition to the
rapidly expanding repertoire of methods for direct function-
alization of azole heterocycles.6-12
Our study began with the reaction of benzoxazole 1a and
4-octyne 2a.7a,b Screening of catalysts generated from cobalt
(4) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087–4109.
(5) For cobalt-catalyzed addition of organometallic reagents to alkynes,
see: (a) Yasui, H.; Nishikawa, T.; Yorimitsu, H.; Oshima, H. Bull. Chem.
Soc. Jpn. 2006, 79, 1271-1274. (b) Murakami, K.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2009, 11, 2373–2375.
(1) Recent reviews on CH bond functionalization: (a) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. ReV. 2010, 110, 624–655. (b) Lyons,
T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147–1169. (c) Ackermann,
L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9827.
(d) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2009, 48, 5094–5115. (e) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–
3039. (f) Alberico, D.; Scott, M. E.; Lautens, M. M. Chem. ReV. 2007,
107, 174–238. (g) Godula, K.; Sames, D. Science 2006, 312, 67–72. (h)
Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077–1101.
(2) Truong, T.; Alvarado, J.; Tran, L. D.; Daugulis, O. Org. Lett. 2010,
12, 1200–1203.
(6) For examples of arylation, see: (a) Pisva-Art, S.; Satoh, T.;
Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
467–473. (b) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman,
J. A. Org. Lett. 2004, 6, 35–38. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2007, 129, 12404–12405. (d) Ackermann, L.; Althammer, A.; Fenner,
S. Angew. Chem., Int. Ed. 2009, 48, 201–204. (e) Canivet, J.; Yamaguchi,
J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733–1736. (f) Hachiya, H.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737–1740. (g) Hachiya, H.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202–
(3) (a) Murahashi, S. J. Am. Chem. Soc. 1955, 77, 6403–6404. (b)
Murahashi, S.; Horiie, S. J. Am. Chem. Soc. 1956, 78, 4816–4817. (c)
Halbritter, G.; Knoch, F.; Wolski, A.; Kisch, H. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1603–1605. (d) Funk, J. K.; Yennawar, H.; Sen, A. HelV.
Chim. Acta 2006, 89, 1687–1695. (e) Gao, K.; Lee, P.-S.; Fujita, T.;
Yoshikai, N. J. Am. Chem. Soc. DOI: 10.1021/ja106814p.
2205
.
(7) Alkenylation with alkynes: (a) Nakao, Y.; Kanyiva, K. S.; Oda, S.;
Hiyama, T. J. Am. Chem. Soc. 2006, 128, 8146–8147. (b) Kanyiva, K. S.;
Nakao, Y.; Hiyama, T. Heterocycles 2007, 72, 677–680. (c) Mukai, T.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 6410–6413
.
10.1021/ol101777x  2010 American Chemical Society
Published on Web 08/24/2010

salts, ligands, and reducing agents led us to find that the
combination of CoBr2 (10 mol %), bis[(2-diphenylphosphi-
no)phenyl] ether (DPEphos, 10 mol %), and Me3SiCH2MgCl
(100 mol %) serves as an effective ternary catalytic system
to afford the alkenylated product 3aa (E/Z > 99:1) in 75%
yield at 20 °C (Table 1, entry 1). Addition of pyridine (40
decrease. The use of a preformed cobalt-phosphine complex
CoCl2(DPEphos) as the precatalyst gave a similar catalytic
activity (entry 4). While low-valent cobalt complexes are
well-known to catalyze cyclotrimerization of alkynes,13 no
such product was detected in these experiments.
The use of other bidentate phosphine ligands resulted in
much lower yields of 3aa, but dppf was moderately effective
(entries 5-8). Monodentate ligands such as PPh3 were also
ineffective (entry 9). Replacement of Me3SiCH2MgCl with
other Grignard reagents uniformly reduced the product yield,
although neopentylmagnesium bromide was moderately
effective (entries 10-12).14 As for the metal precatalyst,
CoBr2 was the best among other common cobalt salts (e.g.,
CoCl2, CoI2, Co(acac)3), and other metal salts (e.g., Fe, Ni,
Ru, Rh, Pd) were entirely ineffective under otherwise
identical conditions.15
Table 1. Cobalt-Catalyzed Addition of Benzoxazole to
4-Octynea
The present reaction was applicable to a variety of (benz)ox-
azole derivatives, as illustrated in Figure 1. Benzoxazoles
entry
ligand
RMgX (x mol %)
yield (%)b
1
DPEphos
DPEphos
DPEphos
Me3SiCH2MgCl (100)
Me3SiCH2MgCl (100)
Me3SiCH2MgCl (50)
Me3SiCH2MgCl (50)
Me3SiCH2MgCl (50)
Me3SiCH2MgCl (50)
Me3SiCH2MgCl (50)
Me3SiCH2MgCl (50)
Me3SiCH2MgCl (50)
MeMgCl (50)
(75)
(86)
(82)
75
57
2
2
5
7
16
9
2c
3c
4d
5
dppf
dppe
dppp
Xantphos
PPh3
DPEphos
DPEphos
DPEphos
6
7
8
9e
10
11
12
iPrMgBr (50)
tBuCH2MgBr (50)
46
a Reaction was carried out on a 0.3 mmol scale. b GC yield. Values in
parentheses refer to isolated yields. c Pyridine (40 mol %) was added.
d CoCl2(DPEphos) (10 mol %) was used as the precatalyst. e PPh3 (20 mol
%) was used.
mol %) as an additive slightly improved the product yield
to 86% (entry 2). The amount of Me3SiCH2MgCl could be
reduced to 50 mol % without decreasing the catalytic activity
(entry 3), while the reaction became very sluggish with
30-40 mol % of Me3SiCH2MgCl and stopped with further
Figure 1. Scope of azoles. Unless otherwise noted, the reaction
was performed under the conditions described in Table 1, entry 3,
and E/Z ratio of the product was >99/1. For 3da-3ia, 100 mol %
of Me3SiCH2MgCl was used. For 3oa and 3pa, Xantphos (10 mol
%) and toluene were used as the ligand and the solvent, respectively,
and the reaction was performed at 60 °C.
(8) Alkenylation with alkenyl electrophiles: Besselie`ver, F.; Piguel, S.;
Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008, 10, 4029–4032.
(9) Alkynylation: Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed.
2010, 49, 2096–2098, and references cited therein.
(10) Alkylation with olefins: (a) Tan, K. L.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2002, 124, 13964–13965. (b) Tan, K. L.; Park, S.;
Ellman, J. A.; Bergman, R. G. J. Org. Chem. 2004, 69, 7329–7335. (c)
Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 6410–
6413. (d) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. Angew.
Chem., Int. Ed. 2010, 49, 4451–4454.
(13) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005,
4741–4767.
(11) Alkylation with alkyl electrophiles: (a) Ackermann, L.; Barfu¨ser,
S.; Pospech, J. Org. Lett. 2010, 12, 724–726. (b) Mukai, T.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2010, 12, 1360–1363. (c) Vechorkin, O.;
Proust, V.; Hu, X. Angew. Chem., Int. Ed. 2010, 49, 3061–3064.
(12) For examples of cis-hydroheteroarylation of alkynes, see ref 6 and
the following references: (a) Tsukada, N.; Murata, K.; Inoue, Y. Tetrahedron
Lett. 2005, 46, 7515–7517. (b) Kanyiva, K. S.; Nakao, Y.; Hiyama, T.
Angew. Chem., Int. Ed. 2007, 46, 8872–8874. (c) Nakao, Y.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448–2449. (d) Nakao, Y.; Idei,
H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996–15997.
(14) For reactions unique to the combination of a cobalt catalyst and a
silylmethyl Grignard reagent, see: (a) Ikeda, Y.; Nakamura, T.; Yorimitsu,
H.; Oshima, K. J. Am. Chem. Soc. 2001, 124, 6514–6515. (b) Affo, W.;
Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima,
K.; Imamura, Y.; Mizuta, T.; Miyoshi, K. J. Am. Chem. Soc. 2006, 128,
8068–8077. (c) Kobayashi, T.; Ohmiya, H.; Yorimitsu, H.; Oshima, K.
J. Am. Chem. Soc. 2008, 130, 11276–11277.
(15) Ni(0)/P(c-pentyl)3 catalyst has been reported to be effective. See
refs 7a, b.
Org. Lett., Vol. 12, No. 18, 2010
4181

bearing 5-chloro and 5-methyl substituents underwent addition
reaction to 2a as smoothly as the parent benzoxazole 1a to give
the products 3ba and 3ca in ca. 80% yield. 5-Aryl oxazole
derivatives also participated in the reaction and afforded the
corresponding alkenylated products 3da-3ma in moderate to
excellent yields. The substrates bearing electron-withdrawing
groups such as 4-trifluoromethyl and 2-fluoro groups gave the
products 3ea and 3ga, respectively, in ca. 90% yields. On the
other hand, the reaction became sluggish with a 4-methoxy
group to give the product 3fa in 55% yield. Neither extending
the reaction time nor increasing the reaction temperature
improved the yield. The reaction became even more sluggish
when the substrate bore a chloro or bromo substituent. Thus,
the products 3ha and 3ia were obtained in modest yields. Note
that the C-Cl and C-Br bonds remained entirely intact under
the reaction conditions, and the unreacted starting materials were
recovered. The reaction tolerated the presence of cyano and
amide functional groups and afforded the addition products 3ka
and 3la in 99 and 35% yields, respectively. A thienyl-substituted
oxazole also underwent the reaction albeit with a modest
reactivity (see 3ma).
tivity (E/Z > 99:1). Benzyl ethers and C(sp3)-Cl bonds were
tolerated well (see 3ac and 3kd). Interestingly, the reaction
of 1,4-bis(trimethylsilyl)but-2-yne was accompanied by
desilylation of one of the Me3Si groups and gave the product
3ae in a modest yield. The reaction of an unsymmetrical
aliphatic alkyne required heating to 80 °C and resulted in
regioselective C-C bond formation. While a moderate
regioselectivity of 2:1 was observed for the reaction of
2-hexyne (see 3kf), 4-methyl-2-pent-2-yne and 2,2-dimeth-
yloct-3-yne underwent exclusive C-C bond formation at the
less hindered carbon atoms (see 3gg and 3kh). Arylalkynes
also gave the addition products 3ki and 3kj in good yields,
while terminal alkynes did not participate in the reaction.
In order to gain insight into the reaction mechanism,
several mechanistic experiments were performed. First,
unlike the cobalt-catalyzed carbometalation reactions,5 quench-
ing the reaction of 1a and 2a with D2O did not cause
deuteration of either the product or the recovered starting
material.16 In accordance with this observation, the reaction
of deuterated benzoxazole 1a-d with 2a gave the correspond-
ing deuterated adduct 3aa-d in 43% yield (Scheme 1a). It
An oxadiazole derivative also participated in the reaction
at room temperature and afforded the product 3na in 82%
yield. Furthermore, (benzo)thiazoles underwent addition
reaction to 4-octyne under modified conditions using Xant-
phos instead of DPEphos to afford the products 3oa and 3pa
in good yields. Imidazoles did not participate in the reaction
under the present conditions but underwent decomposition
to unidentifiable products.
Scheme 1. Mechanistic Experiments
Figure 2 summarizes the results of cobalt-catalyzed
addition of (benz)oxazole derivatives to a variety of alkynes.
was notable that the reaction was apparently slower than that
of parent benzoxazole (see Table 1, entry 1). In addition,
the reaction of an equimolar mixture of 1a-d and the oxazole
1k with 2a afforded 3aa-d and 3ka in 80 and 98% yields,
respectively, without causing H/D crossover (Scheme 1b).
These results clearly demonstrate that the aryl group and the
hydrogen (deuterium) atom in the product molecule are
derived from the same reactant molecule. Finally, a competi-
tive reaction of an equimolar mixture of 1a and 1a-d with
2a, which was quenched at an early stage of the reaction,
gave a mixture of 3aa and 3aa-d in 28% yield with a ratio
Figure 2. Scope of alkynes. Unless otherwise noted, the reaction
was performed under the conditions described in Table 1, entry 3,
and the E/Z ratio of the product was >99/1. For 3kd, 3kf, 3gg,
3kh, 3ki, and 3kj, the reaction was performed at 80 °C. For 3ae,
1,4-bis(trimethylsilyl)but-2-yne was used as the alkyne. 3kf is the
major regioisomer (regioselectivity was 2:1).
(16) iPrMgCl is known to deprotonate (benz)oxazoles: (a) Pippel, D. J.;
Mapes, C. M.; Mani, N. S. J. Org. Chem. 2007, 72, 5828–5831. (b) Debaene,
F.; Da Silva, J. A.; Pianowski, Z.; Duran, F. J.; Winssinger, N. Tetrahedron
2007, 63, 6577–6586.
Symmetrical aliphatic alkynes participated smoothly in the
reaction and afforded the addition products 3ab, 3ac, and
3kd in good to excellent yields with excellent stereoselec-
4182
Org. Lett., Vol. 12, No. 18, 2010

of 74:26 (Scheme 1c). Thus, a kinetic isotope effect of ca.
2.8 is indicated for the C-H bond cleavage step.
reagent than required for the reduction of Co(II) to Co(0)
(20 mol %) and the significant influence of the Grignard
reagent on the catalytic activity (see Table 1) suggest possible
involvement of an organocobalt(0)ate species as the reactive
species.23
In summary, we have demonstrated that a cobalt/diphos-
phine/Grignard ternary catalytic system allows alkenylation
of an azole C(2)-H bond with an unactivated internal alkyne
under mild conditions with high chemo-, regio-, and stereo-
selectivities. The catalytic activity of cobalt complexes
toward C-H bonds being rather unexplored,2,3,24 extension
of the present chemistry could lead to cost-effective methods
for the functionalization of other classes of C-H bonds.4
The above experimental results suggest that the present
reaction does not involve either electrophilic metalation17
or deprotonation of the oxazole substrate.18,19 We consider
that the reaction is likely to involve oxidative addition of
the oxazolyl C-H bond to the cobalt center,20,21 insertion
of the alkyne into the Co-H bond in a syn-fashion, and
reductive elimination of the resulting alkenyl(oxazolyl)cobalt
intermediate,7 while other mechanistic possibilities involving
a radical process may not be fully excluded.22 This mech-
anism allows one to rationalize the origin of the regioselec-
tivity observed for the products such as 3gg and 3kh in terms
of the preference of the cobalt center to avoid steric repulsion
during the alkyne insertion step. While the identity of the
catalytically active cobalt species remains elusive at this
stage, the necessity of a larger amount of the Grignard
Acknowledgment. We thank National Research Founda-
tion, Singapore (NRF-RF2009-05 to N.Y.) and Nanyang
Technological University for generous financial support.
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Examples of hydro(hetero)arylation reactions of olefins and alkynes
that involve electrophilic metalation: (a) Ferreira, E. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2003, 125, 9578–9579. (b) Liu, C.; Han, X.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700–3701.
(18) Concerted metalation-deprotonation mechanism for direct arylation
of heteroarenes: Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem.
Soc. 2008, 130, 10848–10849
.
OL101777X
(19) Deprotonation/ring-opening mechanism for direct arylation of
benzoxazole: Sa´nchez, R. S.; Zhuravlev, F. A. J. Am. Chem. Soc. 2007,
129, 5824–5825
.
(23) (a) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 386–
403. (b) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2001, 123, 5374–5375. (c) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.;
Oshima, K. Tetrahedron 2006, 62, 2207–2213.
(20) Lenges, C. P.; Brookhart, M.; Grant, B. E. J. Organomet. Chem.
1997, 528, 199–203
.
(21) (a) Beck, R.; Flo¨rke, U.; Klein, H.-F. Inorg. Chem. 2009, 48, 1416–
1422. (b) Camadanli, S.; Beck, R.; Flo¨rke, U.; Klein, H.-F. Dalton Trans.
(24) (a) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1997, 119,
3165–3166. (b) Lenges, C. P.; White, P. S.; Brookhart, M. J. Am. Chem.
Soc. 1998, 120, 6965–6979. (c) Bolig, A. D.; Brookhart, M. J. Am. Chem.
2008, 5701–5704, and references cited therein
(22) (a) Yorimitsu, H.; Oshima, K. Pure Appl. Chem. 2006, 78, 441–
449. (b) Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81, 1–24.
.
Soc. 2007, 129, 14544–14545
.
Org. Lett., Vol. 12, No. 18, 2010
4183