Cobalt-catalyzed regioselective synthesis of pyrrolidinone derivatives by reductive coupling of nitriles and acrylamides

Article abstract of DOI:10.1021/ja9088296

(Chemical Equation Presented) A convenient and highly regioselective method for the synthesis of 5-methylenepyrrolidinone derivatives from various nitriles and acrylamides via a cobalt-catalyzed reductive coupling reaction is described. A possible mechani

Full text of DOI:10.1021/ja9088296

Published on Web 12/03/2009
Cobalt-Catalyzed Regioselective Synthesis of Pyrrolidinone Derivatives by
Reductive Coupling of Nitriles and Acrylamides
Ying-Chieh Wong, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
Received October 16, 2009; E-mail: chcheng@mx.nthu.edu.tw
Table 1. Results of Cobalt-Catalyzed Reductive Coupling of
Transition-metal-catalyzed regioselective reductive coupling
(RRC) of two organic π components into various new products
has emerged as a powerful method for organic synthesis.1 Alkyne/
alkyne,2a alkyne/alkene,2b-l alkyne/carbonyl,2m-r alkyne/imine,2s
alkene/imine,2t alkene/alkene,2a alkene/carbonyl,2b and diene/
carbonyl2q RRC reactions catalyzed by ruthenium, rhodium, nickel,
and palladium complexes have been reported. The reactions are
generally highly atom- and step-economical.3
Nitriles and Acrylamidesa
Cobalt complexes have also been employed as catalysts in RRC
reactions. In this context, Druliner and Blackstone reported a
stoichiometric cobalt-promoted tail-to-tail coupling of acrylonitrile
to give adiponitrile.4 We also found a series of cobalt-catalyzed
reductive coupling reactions of alkynes and activated alkenes,5a,b
reductive dimerization of conjugated alkenes and head-to-tail
dimerization of vinyl arenes,5c and intermolecular reductive [3 +
2] cycloaddition of allenes and enones.5d In 2007, Hilt and
Treutwein described an intermolecular cobalt-catalyzed Alder-ene
reaction of alkynes with alkenes to form highly substituted 1,4-
dienes.6 To date, the most commonly employed π components
include alkynes, alkenes, dienes, allenes, aldehydes, imines, and
allylic halides. Our continued interest in metal-catalyzed RRC of
two π components7 prompted us to explore the coupling reaction
of nitriles with acrylamides. Herein we report a cobalt-catalyzed
regioselective synthesis of pyrrolidinones from intermolecular
reductive coupling of nitriles and acrylamides in one pot. It is
interesting to note that the pyrrolidinone group is an important core
in various natural products and biologically active compounds.8
We have previously reported the cobalt-catalyzed RRC reaction
of two π components by employing zinc as a reducing agent and
water as a proton source.5 During the course of our investigation
of RRC reactions, we noticed that nitrile and acrylamide readily
formed pyrrolidinone derivatives. Thus, treatment of 2-phenylac-
etonitrile (1a) with N-benzylacrylamide (2a) in the presence of
Co(dppe)I2, Zn, ZnI2, and water at 80 °C for 12 h gave pyrrolidinone
derivative 3a in 91% isolated yield with excellent regioselectivity
a Unless otherwise mentioned, all reactions were carried out using
nitrile 1 (5.0 mmol), acrylamide 2 (1.0 mmol), Co(dppe)I2 (0.100
mmol), Zn (1.50 mmol), ZnI2 (0.200 mmol), and H2O (1.0 mmol) at 80
°C for 12 h. b Isolated yields.
reductive coupling reaction also works with N-phenyl- and N-alkyl-
substituted acrylamides. Accordingly, the reaction of 2e with 1a
afforded 3e in 58% yield (entry 5). Similarly, N-alkyl-substituted
acrylamides 2f-h reacted well with 1a to produce substituted
pyrrolidinones in good to excellent yields (entries 6-8). Acryla-
mides 2i and 2j having methyl and propyl substitution at the
R-carbon also worked smoothly with 1a, providing 3i and 3j in 66
and 59% yield, respectively (entries 9 and 10).
The present cobalt-catalyzed reductive coupling reaction was
successfully extended to various substituted phenylacetonitriles
1b-e. Thus, electron-donating 4-methoxyphenylacetonitrile (1b)
reacted well with 2a to afford the corresponding cyclized product
3k in 78% yield (entry 11). In a similar manner, the reaction of
4-chloro- and 4-fluorophenylacetonitriles 1c and 1d with 2a gave
pyrrolidinones 3l and 3m in 71 and 83% yield, respectively (entries
12 and 13). 2-Naphthylacetonitrile (1e) underwent reductive cy-
clization with 2a to afford 3n in 81% yield (entry 14). Similarly,
both 2- and 3-thienylacetonitriles 1f and 1g reacted smoothly with
2a to provide the expected pyrrolidinone derivatives 3o and 3p in
(Table 1, entry 1). Product 3a was characterized by its 1H and 13
C
NMR and mass spectroscopic data. The E stereochemistry of
product 3a was further confirmed by nuclear Overhauser effect
(NOE) experiments. To the best of our knowledge, no catalytic
reaction using either nitrile or acrylamide as a π component for
reductive coupling has been reported previously. It is noteworthy
that an intramolecular reductive coupling of nitriles with alkenes
using Cp2ZrCl2/n-BuLi as the reducing agent to give cyclic ketones
has been reported by Mori et al.9
Under similar reaction conditions, various N-substituted acry-
lamides reacted smoothly with 1a to give the corresponding
substituted pyrrolidinones. Thus, N-3-arylpropyl acrylamides 2b and
2c underwent reductive cyclization with 1a to give 3b and 3c in
84 and 80% yield, respectively (entries 2 and 3). Similarly, the
coupling of N-thienylmethyl acrylamide 2d with 1a afforded the
corresponding pyrrolidinone 3d in 64% yield (entry 4). The
9
18252 J. AM. CHEM. SOC. 2009, 131, 18252–18253
10.1021/ja9088296  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
coupling of nitrile and acrylamide followed by keto-amide
cyclization and dehydration in one pot. Further detailed investiga-
tions of the mechanism, the substrate scope, and the application of
this methodology in natural product synthesis are in progress.
Acknowledgment. We thank the National Science Council of
the Republic of China (NSC-96-2113-M-007-020MY3) for support
of this research.
Supporting Information Available: General experimental proce-
dures, characterization details, and crystallographic data (CIF) for 3b
and 3h. This material is available free of charge via the Internet at
http://pubs.acs.org.
79 and 61% yield, respectively (entries 15 and 16). Alkyl nitriles
also worked well for this reaction. Thus, propionitrile (1h) and
butyronitrile (1i) nicely underwent cyclization with 2a to give 3q
and 3r in 78 and 83% yield, respectively (entries 17 and 18).
Under similar reaction conditions, acetonitrile also effectively
reacted with 2a in a highly regioselective manner to provide
pyrrolidinone 3s in 90% yield (eq 1): Very interestingly, reductive
References
(1) (a) Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (b) Ikeda, S. Acc. Chem.
Res. 2000, 33, 511. (c) Song, M.; Montgomery, J. Tetrahedron 2005, 61,
11440. (d) Ng, S.-S.; Jamison, T. F. Tetrahedron 2005, 61, 11405. (e) Jang,
H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653. (f) Moslin, R. M.;
Moslin, K. M.; Jamison, T. F. Chem. Commun. 2007, 4441. (g) Rayabarapu,
D. K.; Cheng, C.-H. Acc. Chem. Res. 2007, 40, 971. (h) Jeganmohan, M.;
Cheng, C.-H. Chem.sEur. J. 2008, 14, 10876.
(2) (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (b) Ho, C.-Y.;
Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782. (c) Ng, S.-S.; Ho,
C.-Y.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 11513. (d) Takimoto,
M.; Kajima, Y.; Sato, Y.; Mori, M. J. Org. Chem. 2005, 70, 8605. (e) Ng,
S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 7320. (f) Hratchian,
H. P.; Chowdhury, S. K.; Gutierrez-Garcia, V. M.; Amarasinghe, K. K. D.;
Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23,
4636. (g) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. J. Am. Chem. Soc.
2005, 127, 201. (h) Shirakawa, E.; Yamamoto, Y.; Nakao, S.; Oda, T.;
Tsuchimoto, T.; Hiyama, T. Angew. Chem., Int. Ed. 2004, 43, 3448. (i)
Yi, C. S.; Lee, D. W.; Chen, Y. Organometallics 1999, 18, 2043. (j) Ikeda,
S.; Yamamoto, H.; Kondo, K.; Sato, Y. Organometallics 1995, 14, 5015.
(k) Ikeda, S.; Cui, D. M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712. (l)
Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903. (m) Zhao, L.; Lu, X.; Xu, W.
J. Org. Chem. 2005, 70, 4059. (n) Sato, Y.; Takimoto, M.; Hayashi, K.;
Katsuhara, T.; Takagi, K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771.
(o) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. (p)
Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998,
120, 4033. (q) Ikeda, S. Angew. Chem., Int. Ed. 2003, 42, 5120. (r) Ni, Y.;
Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743. (s) Patel,
S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364. (t) Yeh, C.-
H.; Korivi, R. P.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47, 4892.
(3) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M. Acc. Chem. Res. 2002, 35,
695. (d) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard,
R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl.
Chem. 2002, 74, 25.
(4) Druliner, J. D.; Blackstone, R. C. J. Organomet. Chem. 1982, 240, 277.
(5) (a) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H. J. Am. Chem. Soc. 2002, 124,
9696. (b) Chang, H.-T.; Jayanth, T. T.; Cheng, C.-H. J. Am. Chem. Soc.
2007, 129, 4166. (c) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H. Tetrahedron
Lett. 2004, 45, 6203. (d) Chang, H.-T.; Jayanth, T. T.; Cheng, C.-H. J. Am.
Chem. Soc. 2007, 129, 12032.
(6) Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8653.
(7) (a) Rayabarapu, D. K.; Sambaiah, T.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2001, 40, 1286. (b) Jayanth, T. T.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2007, 46, 5921. (c) Mannathan, S.; Jeganmohan, M.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2009, 48, 2192. (d) Garcia, P.; Moulin, S.; Miclo,
Y.; Leboeuf, D.; Aubert, C.; Malacria, M. Chem.sEur. J. 2009, 15, 2129.
(8) (a) Murray, W. V.; Lalan, P.; Gill, A.; Addo, M. F.; Lewis, J. M.; Lee,
D. K. H.; Wachter, M. P.; Rampulla, R.; Underwood, D. C. Bioorg. Med.
Chem. Lett. 1993, 369, 785. (b) James, G. D.; Pattendon, G.; Mills, S. D.
Tetrahedron Lett. 1985, 26, 3617. (c) Wu, B.; Kuhen, K.; Nguyen, T. N.;
Ellis, D.; Anaclerio, B.; He, X.; Yang, K.; Karanewsky, D.; Yin, H.; Wolf,
K.; Bieza, K.; Caldwell, J.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
3430. (d) Piracetam, Doxapram, and Cotine are widely used pyrrolidinone
drugs.
coupling of benzonitrile with 2a also proceeded to give linear
product 4, but no further keto-amide cyclization step occurred.10
Thus, it is necessary for the nitrile to possess R-protons in order
for the cyclization and dehydration to proceed.
The mechanism of the present reductive coupling cyclization is
intriguing in view of the ability of the catalyst to assemble the two
π components (nitrile and acrylamide) in a highly regio- and
stereoselective manner (Scheme 1). The catalytic cycle is likely
initiated by the reduction of Co(II) to Co(I) by zinc dust. This is
followed by the chemoselective cyclometalation of Co(I) with nitrile
and acrylamide to form cobaltaazacyclopentene intermediate A.
Protonation of A followed by hydrolysis gives intermediate B and
a Co(III) species. The Co(III) species is reduced by zinc to
regenerate the active Co(I) species for the next cycle.11 Intermediate
B further undergoes keto-amide cyclization10 and elimination of
water to give the final pyrrolidinone derivative 3a. Such a
metalloazacyclopentene species has been proposed as a key
intermediate in the RRC reactions catalyzed by nickel complexes.2s,t
The formation of cobaltaazacyclopentene A by the assembly of two
π components is generally regioselective, with the carbon atom
having an electron-withdrawing functionality near the metal
center.5,7 This mechanism explains the regioselectivity of the present
reductive coupling product. In the catalytic reaction, ZnI2 probably
acts as a Lewis acid to remove a halide from the Co(I) center,
assisting the coordination of the nitrile and acrylamide to the metal
center. In addition, it can also activate the keto group in B, assisting
in the cyclization of B to give the final product 3.
(9) Mori, M.; Uesaka, N.; Shibasaki, M. Chem. Commun. 1990, 1222.
(10) (a) Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. Tetrahedron Lett. 1995,
36, 1193. Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996,
61, 5013.
(11) Fillon, H.; Gosmini, C.; Perichon, J. J. Am. Chem. Soc. 2003, 125, 3867.
In conclusion, we have successfully developed a novel method
for the synthesis of pyrrolidinones via cobalt-catalyzed reductive
JA9088296
9
J. AM. CHEM. SOC. VOL. 131, NO. 51, 2009 18253