Palladium-catalyzed homocoupling reactions between two Csp3-Csp3 centers

Article abstract of DOI:10.1021/ol0258536

(Matrix Presented) A novel palladium-catalyzed coupling reaction between two Csp³-Csp³ centers has been investigated. This protocol is initiated by the oxidative addition of an α-halo carbonyl compound to a palladium(0) species, followed by the double transmetalation. The key dialkyl palladium intermediate undergoes reductive elimination to form the desired coupling product.

Full text of DOI:10.1021/ol0258536

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2285-2288
Palladium-Catalyzed Homocoupling
Reactions between Two Csp3−Csp3
Centers
Aiwen Lei and Xumu Zhang*
Department of Chemistry, 152 DaVey Laboratory, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received March 11, 2002 (Revised Manuscript Received May 29, 2002)
ABSTRACT
A novel palladium-catalyzed coupling reaction between two Csp3−Csp3 centers has been investigated. This protocol is initiated by the oxidative
addition of an r-halo carbonyl compound to a palladium(0) species, followed by the double transmetalation. The key dialkyl palladium intermediate
undergoes reductive elimination to form the desired coupling product.
During the last several decades, palladium-catalyzed carbon-
carbon bond formations have been extensively studied for
organic synthesis.1 Generally, these reactions involve the
oxidative addition of a RX to a Pd(0) species as the initial
step, followed by transmetalation and reductive elimination.
However, most coupling reactions reported involve at least
one sp- or sp2-hybridized carbon. The coupling reactions
between two sp3-hybridized carbon centers are rare.2 The
possible reasons are that the oxidative addition of a sp3-alkyl
halide to a palladium species is slow and the competitive
â-H elimination of the alkyl-Pd-X is fast.3
Development of coupling reactions between two sp3-
hybridized carbon centers bearing a â-H atom remains a great
challenge in organic synthesis. Knochel et al. have developed
an efficient Ni-catalyzed cross-coupling reaction of primary
alkyl iodides and organozinc reagents in the presence of an
assisting functional group2c,2f or cocatalysts.2a,e Fu’s group
reported the highly efficient palladium-catalyzed cross-
coupling reactions of alkyl bromides bearing â-H atoms using
PCy3 as the ligand.2b
Recently, we have developed a novel double transmeta-
lation process that introduces two R groups from RM onto
a palladium center (Scheme 1).4 The reactions were initiated
by the oxidative addition of R-halo carbonyl compounds and
(1) (a) Tsuji, J. Transition Metal Reagents and Catalysts: InnoVations
in Organic Synthesis; Wiley: Chichester, U.K., 2000. (b) Cornils, B.;
Hermann, W. A. Applied Homogeneous Catalysis with Organometallic
Compounds; Wiley: Weinheim, Germany, 1999. (c) Diederich, F.; Stang,
P. J. Metal-catalyzed Crosscoupling Reaction; Wiley-VCH: New York,
1998. (d) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis;
Wiley-VCH: New York, 1998. (e) Farina, V. ComprehensiVe Organome-
tallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, U.K., 1995; Vol. 12, pp 161-240. (f) Leong, W. W.;
Larock, R. C. In ComprehensiVe Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, U.K., 1995;
Vol. 12, pp 131-160. (g) Grigg, R.; Sridharan, V. ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: Oxford, U.K., 1995; Vol. 12, pp 299-321. (h) Tsuji, J.
Palladium Reagents and Catalysts: InnoVation in Organic Synthesis; John
Wiley: Chichester, 1995. (i) Collman, J. P.; Hegedus, L. S.; Norton, J. R.;
Finke, R. G. Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA, 1987.
(2) (a) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79-85. (b)
Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem. Soc.
2001, 12, 10099-10100. (c) Giovannini, R.; Stu¨demann, T.; Devasagayaraj,
A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-3553. (d)
Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020. (e)
Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew. Chem. 1998,
110, 2512-2515. Angew. Chem., Int. Ed. 1998, 37, 2387-2390. (f)
Devasagayaraj, A.; Stu¨demann, T.; Knochel, P. Angew. Chem. 1995, 107,
2952-2954; Angew. Chem., Int. Ed. Engl. 1995, 34, 2723-2725. (g)
Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691-
694. (h) Nakajima, R.; Morita, K.; Hara, T. Bull. Chem. Soc. Jpn. 1981,
54, 3599-3600.
(3) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. ReV. 2000, 100, 3187-
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10.1021/ol0258536 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/19/2002

center, we envisioned that the new Csp3-Csp3 coupling
reaction can offer some advantages compared with the classic
carbon-carbon coupling reactions.
Scheme 1
The reaction of benzyl zinc bromide formed from the
benzylmagnesium bromide and ZnBr2, PdCl2(rac-BINAP)
and methyl R-bromophenylacetate in THF was carried out.
Moderate yield (55%) was obtained for this Csp3-Csp3
homocoupling reaction. After screening different R-halo
carbonyl compounds, we found that desyl chloride was an
excellent reagent to initiate the oxidative addition and
facilitate the isomerization from a C-bound palladium enolate
to an O-bound palladium enolate. Double transmetalation
of the organozinc reagents and the reductive elimination
yielded Csp3-Csp3 homocoupling products. The results of
these homocoupling reactions with different benzyl zinc
reagents are shown in Table 1. Moderate to excellent yields
have been achieved for many organozinc reagents. The
results with R-methylbenzyl zinc bromide (Table 1, entries
13 and 14) were encouraging since it showed that the system
could tolerate â-H atoms.
followed by an isomerization to an O-bound palladium
enolate. In this paper, we report our strategy to construct a
Csp3-Csp3 bond through this double transmetalation pro-
cess.5 Since a Csp3-Pd-Csp3 intermediate can form from
the double transmetalation of a Csp3-M to a palladium(II)
Table 1. Homocoupling Reations Involving the sp3-Hybridized
Carbon-Palladium Bond via Double Transmetalationa
Under the optimized conditions, we have explored the
coupling reaction of two sp3-hybridized carbon centers
bearing â-H atoms. Moderate yields were obtained (Scheme
2). In one case, low yield (35%) was observed, and this
Scheme 2
problem still needs to be addressed. Presumably, â-H
elimination remains a key competitive side-reaction, and in
this case it is responsible for the low yield while the higher
yield obtained from the other reaction may be due to the
presence of heteroatoms.2c,f
To examine the influence of the â-hydrogen in the Csp3-
Csp3 coupling reaction, we explored the coupling reaction
of 2-methyl-2-phenylpropylmagnesium chloride in the pres-
ence of ZnCl2. The high yield obtained under our coupling
conditions indicated that the reductive elimination between
two alkyl Csp3-Csp3 centers without â-H atoms could
proceed smoothly (Scheme 3).
a Method A: Reactions were performed using 0.25 mmol of methyl
R-bromophenyl acetate, 0.025 mmol of PdCl2(rac-BINAP), and 0.7 mmol
of zinc reagent at room temperature for 16 h. Method B: reactions were
performed using 0.25 mmol of desyl bromide, 0.025 mmol of PdCl2(rac-
BINAP), and 0.7 mmol of zinc reagent at 60 °C. The reactions were done
when desyl bromide had been completely consumed from TLC. Method
C: It is the same as Method B except desyl chloride was used instead of
desyl bromide. Method D: it is the same as method C except room
temperature was used. b Isolated yields. c 42% conversion. d 20% conver-
sion. e 100% conversion in 4 h.
Scheme 3
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Org. Lett., Vol. 4, No. 14, 2002

In addition to homocoupling of organozinc reagents, we
have also established the homocoupling reaction of organo
boronic acids to form carbon-carbon bonds.4b For example,
the coupling reaction of benzyl boronic acid led to the desired
product in 88% yield in the presence of desyl chloride and
a palladium catalyst (Scheme 4).
Scheme 6
Scheme 4
On the basis of this result, we explored the hydroboration
of alkenes and the coupling reactions to construct carbocyclic
compounds. It is known that organoboranes derived from
hydroboration of alkenes using 9-BBN-H as the reagent can
be used to carry out Csp3-Csp2 and Csp3-Csp3 Suzuki-
coupling reactions.6,2b We wish to extend the scope of this
reaction to examine intramolecular Csp3-Csp3 coupling
reaction with â-H atoms at both ends. Hydroboration of
1,4-dienes using 9-BBN-H produced a key intermediate,
which can be coupled with a palladium catalyst in the
presence of desyl chloride. These one-pot reactions generate
cyclopentane products as shown in Scheme 5. These results
On the basis of our experimental results, we propose that
the oxidative addition of desyl chloride to a palladium center
is the initial step. Double transmetalation leads to a key
dialkylpalladium intermediate, and reductive elimination
forms the coupling product and regenerates the catalyst
(Scheme 6). The intermediate formed from oxidative addition
of desyl chloride to a palladium species contains a pal-
ladium-halide bond and a palladium-carbon bond. Al-
though transmetalation between organometallic reagent and
a palladium-halide bond is well documented, the trans-
metalation between organometallic reagent and a palladium
enolate bond is novel. A carbon anion serving as the leaving
group for transmetalation step is not common. While the
transmetalation is well-known between organometallic re-
agent and a palladium-oxygen bond.1a,c,h Therefore we
propose that the tautomerization of a palladium enolate
between the C-bound and the O-bound palladium enolate is
a key process for our reaction,7 the first transmetalation
occurs between an O-bound palladium enolate and an
organozinc or organoborane reagent, and an alkyl-Pd-X
(X ) halide) intermediate is obtained.8 In the following step,
X (X ) halide) may be displaced in the second transmeta-
lation to form an alkyl-Pd(II)-alkyl species. In contrast to
other palladium-catalyzed coupling reactions, this process
employs desyl chloride as a surrogate to perform the
oxidative addition. Subsequently, the first transmetalation can
form the intermediate alkyl-Pd-X (X ) halide) which can
then undergo a second transmetalation.
Scheme 5
are significant for exploration of the Csp3-Csp3 coupling
reaction. Further modification may inhibit the â-H elimina-
tion process, and a fundamentally useful coupling method
can be generated.
We have achieved some success in performing both inter-
and intramolecular Csp3-Csp3 coupling reactions of sub-
strates bearing â-H atoms. Further efforts will focus on
(4) (a) Lei, A.; Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 1969-
1971. (b) Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525-2528 and
references therein, that discussed the homocoupling reaction between Csp2-
Csp2. (c) Hossain, K. M.; Shibata, T.; Takagi, K. Synlett 2000, 1137-
1138.
(5) Lei, A.; Zhang, X. Abstr. Pap. Am. Chem. Soc. 2001, 222, 67-
ORGN.
(6) (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4544-4568. (b) (b) Johnson, C. R.; Johns, B.
Synlett 1997, 1406-1408. (c) Miyaura, N.; Ishiyama, T.; Sasaki, H.;
Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-
321.
(7) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816-
5817.
(8) We observed the reductive elimination of an alkyl-Pd-X (X )
halide) to form an alkyl-X species in high selectivity. We did not detect
any arylation product from the reductive elimination of an alkyl-Pd-
enolate. This leads us to believe that an alkyl-Pd-enolate intermediate
was not formed in this reaction. A. Lei, X. Zhang, Abstr. Pap. Am. Chem.
Soc. 2001, 222, 602-ORGN.
Org. Lett., Vol. 4, No. 14, 2002
2287

identifying a more efficient ligand that will promote reductive
elimination and inhibit the â-H elimination.
Supporting Information Available: Spectroscopic data
and experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge a generous loan of
precious metals from Johnson Matthey, Inc.
OL0258536
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Org. Lett., Vol. 4, No. 14, 2002