Oxidative cross-coupling through double transmetallation: Surprisingly high selectivity for palladium-catalyzed cross-coupling of alkylzinc and alkynylstannanes

Article abstract of DOI:10.1021/ja0647351

Two different organometallic reagents now can cross-couple together with the oxidative cross-coupling strategy. Palladium catalyzed oxidative cross-couplings of alkylzinc and alkynylstannane reagents using desyl chloride as the oxidant have been explored, which produce the desired C_sp-C_sp3 cross-coupling product in surprisingly high selectivity and yields. The current catalytic system tolerates the presence of β-H, and the reactions using long chain alkyl zinc reagents gave the cross-coupling product in excellent yields and selectivities. Copyright

Full text of DOI:10.1021/ja0647351

Published on Web 11/04/2006
Oxidative Cross-Coupling through Double Transmetallation: Surprisingly
High Selectivity for Palladium-Catalyzed Cross-Coupling of Alkylzinc and
Alkynylstannanes
Yingsheng Zhao, Haibo Wang, Xiaohui Hou, Yanhe Hu, Aiwen Lei,* Heng Zhang, and Lizheng Zhu
College of Chemistry and Molecular Science, Wuhan UniVersity, Wuhan, 430072, P. R. China
Received July 4, 2006; E-mail: aiwenlei@whu.edu.cn
Scheme 1
Palladium-catalyzed cross-coupling reactions have been the
center of focus for transition metal chemistry during the past three
decades, evolving into one of the most powerful tools for the
construction of carbon-carbon and carbon-heteroatom bonds.1 A
general pathway is illustrated in Scheme 1 for many transition
metals promoted cross-couplings.2 This classic pathway typically
involves three major fundamental unit reactions: (1) oxidative
addition or insertion of the low valent transition metal into the
anion (Figure 1). In order to achieve the oxidative cross-coupling
in Scheme 2, two differentiating metal reagents R1M1 and R2M2
were needed to obtain the desired heterosubstituted intermediate.
electrophilic carbon-heteroatom bond, (2) transmetallation or
displacement of a heteroatom leaving group by the nucleophilic
partners, and finally, (3) reductive elimination to form a new C-C
or C-heteroatom bond. So far, this classic mode has been
extensively studied and widely applied in the coupling of sp- and
sp2-hybridized carbon.3 Cross-coupling has been problematic for
sp3-hybridized carbon bond formation, and the reasons are multi-
faceted: (1) slow oxidative addition (O.A.) of RalkylX, (2) deleterious
â-hydride elimination, and (3) sluggish reductive elimination (R.E.)
Figure 1
Our initial attempts at identifying an appropriate pair of orga-
nometallic reagents are listed in Table 1. The reactions of alkylzinc
(1a) with Si-, Zn-, and B-reagents provided low selectivity for the
desired product. The reactions of alkynylzinc reagent (2a) with
alkylboronic (1b) and alkylsilicate reagent (1c) favored the forma-
tion of diyne (6), in 87% and 63% yield, respectively. We were
very delighted to find that a combination of organozinc 1a and
organotin 2b displayed promising result for the coupling of Csp
involving Csp -carbon centers.4,5 Recently, noteworthy progress has
3
3
3
been achieved in Pd-catalyzed Csp -Csp bond formation using
electron-rich and highly hindered trialkyl phosphines as ligands.6-16
Herein, we introduce something different from the traditional
cross-couplings by bringing two nucleophilic partners together by
a Pd-mediated oxidatiVe cross-coupling mechanism, as depicted in
Scheme 2. Specifically, the new process would involve successive
transmetallation of a divalent palladium species X1-Pd(II)-X2 to
afford the key intermediate R1-Pd(II)-R2. Reductive elimination of
this compound gives rise to the cross-coupled product R1-R2, and
a reduced palladium(0) entity. To achieve this, several hurdles have
to be overcome. First an appropriate system has to be found to
favor the formation of a heterosubstituted intermediate R1-Pd(II)-
R2, in preference to the formation of homosubstituted R1-Pd(II)-
R1 or R2-Pd(II)-R2, which would yield uninspiring homocoupled
product R1-R1 and R2-R2, respectively. The second challenge, in
no small magnitude, is the selection of a suitable oxidizing agent
to render a complete catalytic cycle by converting the Pd(0) species
into a X1Pd(II)X2 to enable the double transmetallation. Toward
this end, an essential requirement must be met: this oxidizing agent
(X1-X2) must not react with either of the organometallic agents,
with or without Pd catalysis. In this communication, we report a
3
and Csp centers, in which cross-coupling product 4 was obtained
in 67% yield in the presence of PdCl2(dppf), while only 26% of
3
3
both homocoupling products of Csp-Csp and Csp -Csp was observed
(Table 1, entry 2).
We then investigated the ligand effect on this oxidative cross-
coupling, and the results were listed in the Supporting Information.
Table 1. The Combination of Different Organometallic Reagents
for Palladium-Catalyzed Oxidative Cross-Couplinga
Pd-catalyzed Csp-Csp oxidative cross-coupling17,18 via the strategy
3
of double transmetallation of organozinc and organotin reagents.
According to the assumption in Scheme 2, the oxidative cross-
coupling would be depended on the proper selection of oxidant
X1-X2. We envisioned that R-halocarbonyl compound, for example,
2-chloro-2-phenylacetophenone (desyl chloride), would be a po-
tential candidate, or its proved ability at promoting the homocou-
a
pling of type Csp-Csp, Csp -Csp , and Csp -Csp .
19-21 The oxidative
2
2
3
3
Reaction condition: The reactants of 1,2, and 3 (the ratio of 2:1.2:1)
was mixed in THF in the presence of 2.5 mol % PdCl2(dppf) in 60 °C.
b The yield was detected by GC in 5 h using naphthalene as the internal
standard. c The reagents were prepared in situ by mixing the corresponding
Grignard reagent and tributyl borate and tetraethyl orthosilicate, respectively.
addition of desyl chloride to Pd(0) species will form O-bounded
Pd enolate chloride.19 Thus the newly formed Pd species will
contain two types of leaving groups: enolate anion and chloride
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J. AM. CHEM. SOC. 2006, 128, 15048-15049
10.1021/ja0647351 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Palladium-Catalyzed Oxidative Cross-Couplinga
3
species produces the Csp-Pd-Csp intermediate. The final reductive
elimination yields the desired cross-coupling product. Theoretically,
3
3
two homocoupled products (Csp -Csp and Csp-Csp) could be
formed at 25% each along with 50% of the heterocoupled product
under a nonselective situation. The observed high selectivity toward
3
Csp-Csp cross-coupling may be a reflection of either the different
rates of transmetallation by the organozinc and organostannanes
with ROPdCl (R ) stilbenyloxy), or the favorable reductive
elimination for the heterosubstituted intermediate (R1PdR2). Pre-
liminary kinetic studies (see Supporting Information) by in situ IR
reveals that the rate of formation of R1-R2 is faster than that of
R1-R1 and R2-R2. In addition, we identified the formation of
ROZnCl (R ) stilbenyloxy), and found that its rate of formation is
almost equal to that of the consumption of desyl chloride and the
formation of cross-coupling product R1-R2 (see Supporting Infor-
mation, this tends to implicate the rate-limiting nature of the
transmetallation step to form R1PdR.2 However, given the multiple
possibilities of Pd(II) species within the reaction system, the
underlying reasons for the selectivity still remain to be elucidated.
In conclusion, useful selectivity can be achieved for palladium
catalyzed oxidative cross-couplings, with the appropriate combina-
tion of organometallic partners. High selectivity and yields for the
a
Reaction condition: The reactants of 1, 2, and 3 (the ratio of 2:1.2:1)
was mixed in THF in the presence of 2.5 mol % pd(dba)2 in 60 °C; isolated
yield.
Scheme 3
3
Csp-Csp cross-coupling were obtained using Pd(dba)2 as the catalyst
precursor. This may present a new mode for carbon-carbon bond
formation. Many aspects regarding other oxidative cross-couplings,
2
3
2
2
3
3
such as the bond formation of Csp -Csp , Csp -Csp , and Csp -Csp
,
others combinations of organometallic reagents, and kinetic studies
of transmetallation and reductive elimination, are under investigation
in our laboratory.
Acknowledgment. This work was support by National Natural
Science Foundation of China (Grant No. 20502020) and the startup
fund from Wuhan University.
Interestingly, the surprisingly high selectivity toward cross-coupling
came from the system using simple Pd(dba)2 as the catalyst
precursor without exogenous phosphine ligands. Using this catalyst,
the desired cross-coupling product 4a was obtained in 87% yield,
while the extent of Csp -Csp homocoupling was less than 1%, and
the Csp-Csp homocoupling was 8% (eq 1).
Supporting Information Available: Ligand effects, kinetic studies,
spectroscopic data, GC-MS, experiments details, and ligand effects.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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3
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3
3
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A possible mechanism for the oxidative cross-coupling is
proposed in Scheme 3. The oxidative addition of desyl chloride to
Pd(0) generates the C-bound Pd enolate chloride, which undergoes
tautomerization into O-bounded Pd enolate chloride. The ensuing
double transmetallation with zinc and tin reagents on the Pd(II)
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