Catalytic allylic alkylation via the cross-dehydrogenative-coupling reaction between allylic sp3 C-H and methylenic sp3 C-H bonds

Article abstract of DOI:10.1021/ja056541b

A catalytic allylic alkylation was developed via the cross-dehydrogenative-coupling reaction of allylic sp³ C-H and methylenic sp³ C-H catalyzed by copper bromide and cobalt chloride in the presence of an oxidizing reagent, t-BuOOH.

Full text of DOI:10.1021/ja056541b

Published on Web 12/07/2005
Catalytic Allylic Alkylation via the Cross-Dehydrogenative-Coupling Reaction
between Allylic sp3 C-H and Methylenic sp3 C-H Bonds
Zhiping Li and Chao-Jun Li*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received September 23, 2005; E-mail: cj.li@McGill.ca
Table 1. Optimization of Reaction Conditions
The palladium-catalyzed allylic alkylation (the Trost-Tsuji
reaction, eq 1) is one of the most important reactions for
constructing C-C bonds in modern organic synthesis.1 The
methodology allows the easy tuning of chemo-, regio-, and
stereoselectivities in complex organic transformations.2 As a general
protocol, a carboxylate (or another leaving group) is required at
the allylic position, which is activated by a palladium catalyst during
the reaction with a pronucleophile.3 In theory, the direct utilization
of an allylic C-H bond rather than an allylic functional group would
avoid the need to synthesize the allylic functional group, thus
leading to increased synthetic efficiency.4 In the pioneering work
using allylic C-H bonds directly to form π-allyl palladium
complexes, Trost and co-workers reported an allylic alkylation from
an allylic sp3 C-H in two steps in the late 1970s.5 However,
because the in situ reoxidation of the reduced Pd(0) into Pd(II) is
difficult, this reaction was stoichiometric with respect to Pd(II),
serving as both the catalyst and the oxidant.
1a
2a
[Cu]a
[Co]a
TBHP
yield
(%)c
entry
(mmol)
(mmol)
(mol %)
(mol %)
(mmol)
1
2
3
4
5
6
7
8
2.5
2.5
1.0
2.5
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
2.5
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
5
5
5
5
10
1
5
1.0
2.0
1.0
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
25
12
6
2.5
5
10
10
10
10
5
10
10
10
36
29
62
71
60
57
60
70
10
trace
10
0
2.5
1.25
2.5 (CuI)
2.5 (CuBr2)
2.5 (CuCl)
9
10
11
12
13
14
15
2.5
2.5
0
10 (CoI2)
10 (CoF2)
Recently, we and others have developed various cross-dehydro-
genative-coupling (CDC) reactions for forming new C-C bonds
by using two different C-H bonds.6 The development of a catalytic
allylic alkylation via a CDC reaction would be quite desirable.
Herein, we report the first catalytic allylic alkylation directly using
allylic sp3 C-H and methylenic sp3 C-H bonds (eq 2).
5
0
5
a CuBr was used, unless otherwise noted. b CoCl2 was used, unless
otherwise noted. c NMR yields using an internal standard.
Scheme 1
To begin our study, we chose cyclohexene and 2,4-pentadione
as the standard substrates to search for potential catalysts and
suitable reaction conditions. When a palladium catalyst was used,
together with a catalytic amount of CuBr and a stoichiometric
amount of tert-butyl hydroperoxide (TBHP),7 the desired product
catalysts, the yield was slightly reduced (Table 1, entry 7 vs 8).
Under the same reaction conditions, CuCl provided results similar
to those obtained with CuBr (Table 1, entry 7 vs 11); however,
CoCl2 gave the best yield of the desired product among the cobalt
catalysts tested (Table 1, entries 12 and 13). Whereas the use of a
cobalt catalyst alone gave the desired product in 10% yield, no
product was obtained with only CuBr as the catalyst (Table 1,
entries 14 and 15).
1
was obtained in 5% yield as shown by the H NMR of the crude
reaction mixture (eq 3). Unfortunately, we were unable to improve
With the optimized reaction conditions established, various
substrates were subjected to the allylic alkylation reactions, and
representative results are shown in Table 2. Various 1,3-dicarbonyl
compounds reacted smoothly with cyclohexene under the standard
reaction conditions. When substituted 1,3-dicarbonyl substrates were
used, the desired quaternary products were obtained with reasonable
yields (Table 2, entries 6-8). Other cyclic alkenes (five-, seven-,
and eight-membered rings) were also transformed into the desired
products when reacted with the diketones. When 1-phenylcyclo-
hexene was reacted with 2,4-pentadione (Table 2, entry 9), the major
product was obtained via the reaction of the less sterically hindered
allylic C-H bond.
the product yield beyond 5%, which indicated that the reaction with
palladium was stoichiometric. After countless failures, we found
that the yield of the desired product8 was improved to 25% by using
a combination of a copper catalyst (CuBr)9 and a cobalt catalyst
(CoCl2)10 (Table 1, entry 1). The product formation was further
optimized by examining various reaction conditions, and the results
are shown in Table 1. The ratio of CuBr and CoCl2 was found to
be important for the reaction (Table 1, entry 1-5). Increasing the
amounts of alkene and TBHP improved the yields of the desired
product (Table 1, entry 6). By decreasing the amounts of the
9
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J. AM. CHEM. SOC. 2006, 128, 56-57
10.1021/ja056541b CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cross-Dehydrogenative-Coupling Reactions of Allylic
C-H and â-Dicarbonyl C-Ha
On the basis of these observations, a tentative mechanism is
proposed in Scheme 1. A π-allyl copper or allyl cobalt complex is
formed via the allylic H-abstraction13 followed by coordination. A
subsequent standard allylic alkylation followed by oxidation
provided the alkylation product and regenerated the catalyst. As
an insight into the mechanism of the reaction, a deuterated
experiment between 8 and 2,4-penadione provided a 1:1 mixture
of 9 and 10 (eq 6), which implies the involvement of an allyl metal
intermediate during the catalytic cycle. However, the exact function
of the combination of a copper catalyst and a cobalt catalyst in the
reaction is not clear at the present stage.
In summary, we have developed a novel catalytic allylic
alkylation via a CDC reaction between allylic sp3 C-H and
methylenic sp3 C-H bonds catalyzed by copper bromide and cobalt
chloride. This novel methodology provides a way to directly use
allylic sp3 C-H bonds for the purpose of C-C bond formation.
The scope, mechanism, and synthetic application of this reaction
are under investigation.
Acknowledgment. We are grateful to the Canada Research
Chair (Tier I) foundation (to C.J.L.), the CFI, NSERC, Merck
Frosst, and McGill University for support of our research.
Supporting Information Available: Representative experimental
procedure and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For representative references, see: (a) Tsuji, J. Transition Metal Reagents
and Catalysts: InnoVations in Organic Synthesis; Wiley: New York, 2000;
Chapter 4, p 109. (b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003,
103, 2921.
(2) Negishi, E.-I., Ed. Handbook of Organopalladium Chemistry for Organic
Synthesis; Wiley-Interscience: New York, 2002.
(3) Kazmaier, U.; Pohlman, M. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Chapter 9, p 531.
(4) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 9728.
(5) Trost, B. M.; Strege, P. E.; Weber, L.; Fullerton, T. J.; Dietsche, T. J. J.
Am. Chem. Soc. 1978, 100, 3407.
(6) (a) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (b) Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2005, 127, 6968. (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 3672. (d) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (e) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(7) CAUTION! Mixing a metal salt and peroxide can cause an explosion.
See: Jones, A. K.; Wilson, T. E.; Nikam, S. S. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley &
Sons: New York, 1995; Vol. 2, p 880.
(8) The other products are mainly the oxidation products of cyclohexene. We
did not find the dialkylation products from the reaction mixture. The
following are representative reviews of catalytic allylic C-H oxidation
with peroxide. Cu: Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58,
845. Co: Iqbal, J.; Mukhopadhyay, M.; Mandal, A. K. Synlett 1997, 876.
(9) For some examples of copper-catalyzed allylic alkylation, see: (a)
Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 10676.
(b) Van Zijl, A. W.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. AdV.
Synth. Catal. 2004, 346, 413. (c) Malda, H.; Van Zijl, A. W.; Arnold, L.
A.; Feringa, B. L. Org. Lett. 2001, 3, 1169.
a Conditions: 0.025 mmol of CuBr, 0.1 mmol of CoCl2, 5.0 mmol of
alkene, 1.0 mmol of 1,3-dicarbonyl compound, and 2.0 mmol of TBHP.
b Isolated yields were based on 1,3-dicarbonyl compounds; the ratio of two
diastereomers is given in parentheses. c At 50 °C.
When cycloheptatriene 4 was reacted with 2,4-pentadione,
tropylacetylacetone 611 was obtained in 41% isolated yield (eq 4).
Interestingly, if cyclopentadiene 5 was used, the major product
obtained was dihydrofuran derivative 712 (eq 5), which was most
likely due to the further transformation of the alkylation product
in situ.
(10) For some examples of cobalt-catalyzed allylic alkylation, see: (a)
Vallribera, A.; Serra, N.; Marquet, J.; Moreno-Manas, M. Tetrahedron
1993, 49, 6451. (b) Hegedus, L. S.; Inoue, Y. J. Am. Chem. Soc. 1982,
104, 4917. (c) Roustan, J. L.; Merour, J. Y.; Houlihan, F. Tetrahedron
Lett. 1979, 20, 3721.
(11) Conrow, K. J. Am. Chem. Soc. 1959, 81, 5461.
(12) Tenaglia, A.; Kammerer, F. Synlett 1996, 576.
(13) Coseri, S.; Ingold, K. U. Org. Lett. 2004, 6, 1641.
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