Conjugated diene-assisted allylic C-H bond activation: Cationic Rh(I)-catalyzed syntheses of polysubstituted tetrahydropyrroles, tetrahydrofurans, and cyclopentanes from Ene-2-dienes

Article abstract of DOI:10.1021/ja100409b

C-H activation followed by addition to alkenes is challenging in the current C-H activation/functionalization field. We report herein an unprecedented diene-assisted transition-metal-catalyzed activation of allylic C-H bonds and their subsequent insertion

Full text of DOI:10.1021/ja100409b

Published on Web 03/16/2010
Conjugated Diene-Assisted Allylic C-H Bond Activation: Cationic
Rh(I)-Catalyzed Syntheses of Polysubstituted Tetrahydropyrroles,
Tetrahydrofurans, and Cyclopentanes from Ene-2-Dienes
Qian Li and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular Engineering,
Peking UniVersity, Beijing 100871, China
Received January 16, 2010; E-mail: yuzx@pku.edu.cn
Selective C-H functionalization represents one of the most
efficient and straightforward methods for accessing complex
molecules from ubiquitous C-H groups.1 Among various C-H
activation/C-C bond-forming reactions, the addition of C-H bonds
across multiple bonds such as alkenes and alkynes is particularly
appealing in light of atom- and step-economy considerations.2 In
comparison with the addition of aromatic C-H bonds to multiple
bonds, the addition of aliphatic C-H bonds to multiple bonds is
more challenging because of the inertness of aliphatic C-H bonds
and problems with site selectivity. Thus, many efforts have been
directed to the activation of C-H bonds adjacent to heteroatoms
or double bonds.3 However, only limited examples of catalytic
additions of allylic C-H bonds to alkynes and allenes have been
reported.4-6 In particular, catalytic addition of allylic C-H bonds
to alkenes has not been forthcoming.
There are several reasons that may account for this lack of
reactivity. First, the addition of allylic C-H bonds to alkenes
requires preferential activation of an allylic C-H bond in the
presence of several similar ones (the chemoselectivity challenge).7
Second, the addition of allylic C-H bonds to alkynes and allenes
forms C(sp2)-C(sp3) bonds via easier reductive elimination,
whereas the addition of allylic C-H bonds to alkenes involves a
more difficult reductive elimination step to form C(sp3)-C(sp3)
bonds (the reactivity challenge).8 Moreover, this reaction might be
further challenged by issues of diastereoselectivity. Herein, we
report a new strategy to meet these challenges by employing
conjugated diene-assisted allylic C-H activation and the addition
of the generated allyl-Rh-H complex to the alkene moiety of the
conjugated diene (Scheme 1).
insertion transition state, which would lead to the type-II [4 + 2]
reaction pathway, complex A prefers an allylic C-H activation
pathway to generate allyl-Rh-H complex B, which, after alkene
insertion and reductive elimination, affords product 2 exclusively
(Scheme 1). Highly chemoselective C-H activation was achieved
in this reaction, as only the allylic C-H bond of the ene component
was activated. Good diastereoselectivity was observed, as only one
diastereoisomer with both vinyl groups in a cis configuration was
obtained. The importance of the diene in this C-H activation/alkene
insertion reaction was demonstrated by the lack of reactivity showed
by ene-ene substrate 4 lacking the diene moiety (Scheme 1). We
also found that substrates with different tether lengths failed to give
the desired products (Scheme 1, X ) NTs, n ) 0 or 2), implying
that there are likely to be geometric and conformational require-
ments in this diene-assisted allylic C-H bond activation/alkene
insertion process.
Since the above allylic C-H activation/diene interception
reaction can generate five-membered rings with two vinyl substit-
Table 1. Rh(I)-Catalyzed Cycloaddition via C-H Activation
Scheme 1. Conjugated Diene-Assisted Rh(I)-Catalyzed Allylic C-H
Addition to Alkenes
We discovered this reaction serendipitously during our attempts
to develop a Rh-catalyzed intramolecular type-II Diels-Alder
(D-A) reaction (Scheme 1).9 The reaction of nitrogen-tethered ene-
2-diene substrate 1a (Table 1) in the presence of a Rh(I) catalyst
(generated from RhCl(PPh3)3 and AgSbF6) underwent cyclization
to form substituted tetrahydropyrrole 2a10 rather than the [4 + 2]
product 3. We propose that intermediate A, a Rh complex
coordinated by both diene and ene, is generated in this reaction.
However, because of the ring strain associated with the alkene-
9
4542 J. AM. CHEM. SOC. 2010, 132, 4542–4543
10.1021/ja100409b  2010 American Chemical Society

C O M M U N I C A T I O N S
uents and a quaternary carbon center with high chemo- and
diastereoselectivity, we set out to explore the substrate scope (Table
1). Importantly, the allylic C-H activation was not limited to allylic
substrates with the C-H bond adjacent to a nitrogen atom.
Cyclization of simple allylic substrates 1b-d proceeded quite well
to give 2b-d as single diastereoisomers. Besides nitrogen-tethered
substrates, carbon- and oxygen-tethered substrates also reacted well,
generating useful cyclopentane (2c and 2d) and tetrahydrofuran (2f)
structures in good yields. C-H activation was not limited to
terminal alkenes, as demonstrated by the successful reactions of
the phenyl- and dimethyl-substituted alkene substrates 2e-g.
Substituents at the internal position of the alkene did not affect the
efficiency (2h and 2i). The present reaction also tolerated substituent
variation at the conjugated diene moiety, as substrates with phenyl,
hydrogen, and butyl at the R4 position underwent smooth cyclization
to give 2j-l, respectively. Substitution at the allylic and homoallylic
positions of the diene was also tolerated, affording heavily
substituted tetrahydropyrrole derivatives (2k-m) in good yields
and diastereoselectivities. However, substrates substituted at the
allylic position of the ene part failed to undergo cyclization even
at elevated temperature (for details, see the Supporting Information).
Two possible paths for the above reaction were considered
(Scheme 2). The reaction is initiated by coordination of the substrate
to Rh to give complex A, which then undergoes conjugated diene-
assisted oxidative addition to the allylic C-H bond to give
intermediate B. Subsequent alkene insertion into the Rh-H bond
would give complex C or D, which would then undergo a
challenging reductive elimination to form the C(sp3)-C(sp3) bond
in the final product (path I). Alternatively, intermediate B could
undergo alkene insertion into the Rh-C bond to give Rh-H
intermediate E, which would deliver the final product via reductive
elimination (path II).4a,c,d
Preliminary studies to elucidate the reaction mechanism were
performed. The allylic deuterium-labeled substrate 1e-D was
subjected to the reaction conditions (Scheme 3). Analysis of the
product revealed that more than one deuterium was incorporated
into the newly formed methyl group and that the tertiary carbon in
2e-D was only 50% deuterated, suggesting that there is hydrogen/
deuterium exchange between the forming methyl group and the
deuterium-labeled methylene group in the substrate during the
reaction process. This observation precludes path II, while path I
is reasonable if reversible allylic C-H activation and alkene
insertion are taken into consideration. This means that ꢀ-hydride
elimination and reductive elimination from C/D to B and then to
A can shift the original hydrogen atoms of the internal alkene to
the allylic position. After equilibrium, the percentages of deuterium
incorporation at both D1 and D2 reach 50%. This D-labeling
experiment suggests that the irreversible C(sp3)-C(sp3) reductive
elimination rather than the C-H activation is the rate-determining
step in the present reaction.2c,11
In conclusion, we have successfully demonstrated the first
example of conjugated diene-assisted transition-metal-catalyzed
activation of an allylic C-H bond and its addition to the alkene of
the conjugated diene moiety in ene-2-diene substrates. This reaction
generates multisubstituted tetrahydropyrroles, tetrahydrofurans, and
cyclopentanes bearing quaternary carbon centers with high chemo-
and diastereoselectivity. A reversible allylic C-H activation/alkene
insertion prior to an irreversible C-C reductive elimination step
has been proposed on the basis of the results of the D-labeling
experiment. Further exploration of the mechanism and the applica-
tion of this new methodology are currently underway.
Acknowledgment. We thank the Natural Science Foundation
of China (20825205-National Science Fund for Distinguished
Young Scholars, 20672005) for financial support.
Supporting Information Available: Detailed experimental proce-
dures, compound characterization data, and crystallographic data for
2h (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) (a) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (b) Dick,
A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (c) Godula, K.; Sames,
D. Science 2006, 312, 67. (d) Bergman, R. G. Nature 2007, 446, 391. (e)
Chen, M. S.; White, M. C. Science 2007, 318, 783. (f) Li, B.-J.; Yang,
S.-D.; Shi, Z.-J. Synlett 2008, 949. (g) Chen, X.; Engle, K. M.; Wang,
D. H.; Yu, J.-Q. Angew. Chem., Int. Ed 2009, 48, 5094.
(2) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (b)
Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (c)
Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (d) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. ReV. 2010, 110, 624.
(3) (a) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069. (b) Li, Z.; Bohle, D. S.;
Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (c) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335. (d) Chen, M. S.; White, M. C. J. Am. Chem.
Soc. 2004, 126, 1346. (e) Young, A. J.; White, M. C. J. Am. Chem. Soc.
2008, 130, 14090. (f) Liu, G.; Yin, G.; Wu, L. Angew. Chem., Int. Ed.
2008, 47, 4733.
(4) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 9728. (b)
Ajamian, A.; Gleason, J. L. Org. Lett. 2003, 5, 2409. (c) Brummond, K. M.;
Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2161. (d) Li, W.;
Yuan, W.; Shi, M.; Hernandez, E.; Li, G. Org. Lett. 2010, 12, 64. For an
oxidative coupling, see: (e) Franze´n, J.; Ba¨ckvall, J.-E. J. Am. Chem. Soc.
2003, 125, 6056.
(5) For Alder-ene cycloisomerization reactions, see: (a) Sturla, S. J.; Kabalaeui,
N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1976. (b) Trost,
B. M.; Lautens, M.; Chan, C.; Jebaratnam, D. J.; Muller, T. J. Am. Chem.
Soc. 1991, 113, 636. (c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
2000, 122, 714. (d) Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000,
122, 6490. (e) Fu¨rstner, A.; Majima, K.; Mart´ın, R.; Krause, H.; Kattnig,
E.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 1992.
(6) For the addition of C-H bonds adjacent to heteroatoms to alkenes, see:
(a) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai,
S. J. Am. Chem. Soc. 2001, 123, 10935. (b) Sakaguchi, S.; Kubo, T.; Ishii,
Y. Angew. Chem., Int. Ed. 2001, 40, 2534. (c) Shi, L.; Tu, Y.-Q.; Wang,
M.; Zhang, F.-M.; Fan, C.-A.; Zhao, Y.-M.; Xia, W.-J. J. Am. Chem. Soc.
2005, 127, 10836. (d) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc.
2008, 130, 14940. (e) McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009,
131, 402. (f) Zhang, S.-Y.; Tu, Y.-Q.; Fan, C.-A.; Zhang, F.-M.; Shi, L.
Angew. Chem., Int. Ed. 2009, 48, 8761. For addition to alkynes, see: (g)
Shikanai, D.; Murase, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2009,
131, 3166. (h) Tsuchikama, K.; Kasagawa, M.; Endo, K.; Shibata, T. Org.
Lett. 2009, 11, 1821.
Scheme 2. Two Proposed Reaction Paths
(7) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(8) (a) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525. (b)
Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674. (c) Rudolph,
A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656.
(9) For transition-metal-catalyzed intramolecular type-I D-A reactions, see:
(a) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432. (b)
Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc.
1990, 112, 4965. (c) Gilbertson, S.; DeBoef, B. J. Am. Chem. Soc. 2002,
124, 8784. (d) Aikawa, K.; Akutagawa, S.; Mikami, K. J. Am. Chem. Soc.
2006, 128, 12648, and references therein. For a review of type-II D-A
reactions, see: (e) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem.,
Int. Ed. 2001, 40, 820.
Scheme 3. Deuteration Reaction
(10) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127.
(11) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani,
N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62.
JA100409B
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4543