Palladium-catalyzed hydroalkylation of styrenes with organozinc reagents to form carbon - carbon sp3 - sp3 bonds under oxidative conditions

Article abstract of DOI:10.1021/ja908545b

(Chemical Equation Presented) An unconventional route for the formation of sp³-sp³ C-C bonds from various styrenes and an organozinc reagent in a formal alkene hydroalkylation process is detailed. Mechanistically, this process is pro

Full text of DOI:10.1021/ja908545b

Published on Web 11/24/2009
Palladium-Catalyzed Hydroalkylation of Styrenes with Organozinc Reagents
To Form Carbon-Carbon sp3-sp3 Bonds under Oxidative Conditions
Kaveri Balan Urkalan and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-085
Received October 7, 2009; E-mail: sigman@chem.utah.edu
Table 1. Optimization of the Hydroalkylation of 4-Methylstyrene
Metal-catalyzed cross-coupling of simple alkyl electrophiles with
various organometallic reagents has received significant attention
over the last several years because of the extensive synthetic
applications of such a reaction type.1 To initiate the catalysis, a
low-valent metal complex promotes oxidative addition of the
electrophilic compound to access a metal-alkyl intermediate
(Scheme 1).2 The development of these reactions is considered to
be particularly difficult because of the slow rate of oxidative addition
of the alkyl electrophile and the ease with which the resultant
metal-alkyl species undergoes ꢀ-hydride elimination.2 Ni-based
systems have generally overcome these issues,3 but the use of Pd
to affect the coupling of secondary alkyl nucleophiles and electro-
philes is still considered challenging.4 Herein we present an
alterative approach to alkyl-alkyl cross coupling reactions using
a Pd-catalyzed hydroalkylation of styrenes with alkylzinc reagents
wherein a primary-secondary C-C bond is formed.
entry
conditions
% conv.a % 3ab
1c
2
3
4
5
Sn(n-Bu)4 (3 equiv), Cu(OTf)2 (25 mol %), O2
n-BuZnBr (4 equiv), O2
n-BuZnBr (4 equiv), desyl chloride (2 equiv)
n-BuZnBr (4 equiv), BQ (2 equiv)
n-BuZnBr (4 equiv), Zn(OTf)2 (1 equiv),
BQ (4 equiv)
n-BuZnBr (4 equiv), Zn(OTf)2 (1 equiv),
BQ (4 equiv)
n-BuZnBr (4 equiv), Zn(OTf)2 (1 equiv),
BQ (4 equiv)
40
<2
<2
55
80
25
<1
<1
30
70
6d
7e
99
99
97
98
a Measured by GC using an internal standard. b GC yield. c Reaction
performed at 55 °C. d n-BuZnBr made from Rieke zinc. e n-BuZnBr
made using the method of Fu and Huo.11
Scheme 1. Conventional Route and Our Approach to sp3-sp3
Cross-Coupling Reactions
To initiate the investigation, 4-methylstyrene and Bu4Sn were
submitted to the conditions recently reported for the oxidative
diarylation of terminal alkenes using aryl organostannanes.6 We were
excited to observe a 25% GC yield of the hydroalkylation product,
providing proof of concept (Table 1, entry 1). However, we reasoned
that the use of Bu4Sn for further optimization would not be practical
and therefore investigated the use of the analogous alkylzinc reagents,
which are commonly used in Negishi-type cross-coupling reactions.7
Initial screening with commercial n-BuZnBr under aerobic oxidative
conditions did not yield the hydroalkylation product or result in any
consumption of the styrene (entry 2). To the best of our knowledge,
the only example of the use of organozinc reagents in an oxidative
cross-coupling-type reaction was performed with desyl chloride as the
terminal oxidant.8 However, no appreciable hydroalkylation product
was observed under our conditions (entry 3). Benzoquinone (BQ), a
common terminal oxidant in Pd-oxidative catalysis, was next
investigated.9a To our delight, a 30% GC yield of the desired product
was achieved using this oxidant, with incomplete consumption of the
starting material (entry 4). Initial attempts to enhance the reaction
conversion by modifying the reaction conditions did not prove fruitful.
One possible reason for this was the absence of two protons to facilitate
the oxidation of Pd(0) to Pd(II) with BQ, which are not available in
this system. Indeed, addition of Brønsted acids to reactions employing
BQ as the terminal oxidant typically results in rate enhancements.9b
However, since strong Brønsted acids are incompatible with alkylzinc
reagents, Lewis acids were explored, wherein Zn(OTf)2 was found to
Our approach involves using a conjugated alkene to replace the
alkyl halide as the coupling partner, thereby removing the challenge
of slow oxidative addition (Scheme 1). In parallel, we aim to take
advantage of the propensity of unfunctionalized Pd-alkyls to
undergo ꢀ-hydride elimination to access a Pd hydride (B f C)
that could subsequently be trapped by the conjugated alkene to yield
a stabilized Pd-alkyl similar to D. We have recently reported that
this type of process is indeed possible using an aerobic alcohol
oxidation to generate the Pd hydride.5 However, in these reports,
only sp2 coupling partners, generally aryl organometallic reagents,
were successfully added. In the current study, we hypothesized that
the organometallic reagent could act as both the hydride source
and the ultimate coupling partner, along with a styrene derivative
as the alkene. It should be noted that the system must be compatible
with a terminal oxidant to re-form Pd(II).
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18042 J. AM. CHEM. SOC. 2009, 131, 18042–18043
10.1021/ja908545b  2009 American Chemical Society

C O M M U N I C A T I O N S
enhance the performance of the system with a product GC yield of
70% (entry 5). To further optimize the system, other sources of
n-BuZnBr were evaluated because of the potential of the commercial
sources to contain excess halide ions, which were found to inhibit this
reaction.10 A halide-free n-BuZnBr reagent prepared using Rieke zinc
was found to considerably enhance the yield of the reaction to 97%
(entry 6). Additionally, n-BuZnBr prepared using the method of Fu
and Huo11 again led to an excellent yield of 98% (entry 7); considering
the ease of this route, it was used throughout the remainder of the
study.
alkylzinc reagent was prepared and submitted to the hydroalkylation
reaction conditions (eq 1):
Approximately one D atom was incorporated into the product, as
1
determined by H NMR spectroscopy, which is consistent with the
hydrogen added to the alkene originating from the organozinc reagent.
Interestingly, incorporation of D was observed at both the methyl and
methine positions, indicating that insertion of the alkene occurs from
either side, but the resultant Pd-alkyl species most likely rearranges
via ꢀ-hydride elimination to the more stable π-benzyl intermediate
(D in Scheme 1).
Table 2. Substrate Scope of the Pd-Catalyzed Hydroalkylation of
Styrene Derivativesa
In conclusion, we have described an alternative method for the
formation of sp3-sp3 C-C bonds via cross-coupling, which avoids
the difficulty of oxidative addition of unactivated alkyl halides and
takes advantage of the inherent ease of ꢀ-hydride elimination of
Pd-alkyls. The scope of the process reveals excellent tolerance of
styrene functionalization and the ability to form a quaternary carbon
center. Isotopic-labeling experiments indicate that the hydroalky-
lation process most likely proceeds by initial transmetalation of
the alkylzinc reagent followed by formation of a Pd-H species,
which is trapped by the styrene. An interesting aspect of this process
is that the alkene is formally reduced under oxidative conditions.
Future work will focus on expanding the scope of coupling partners
that can be utilized in this process and development of an
enantioselective variant.
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS RO1 GM3540). We are grateful to
Johnson Matthey for the gift of various Pd salts.
Supporting Information Available: Optimization data, experimen-
tal procedures, and characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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a Yields are average isolated yields of at least two experiments.
The substrate scope of the reaction under the optimized conditions
was then examined (Table 2). First, the nature of the styrene derivative
was explored. Both electron-rich and -poor substituents on the styrene
(3a-f) were tolerated and generally led to high yields. Also, ortho
substitution is allowed, as a 93% yield of 3g was observed. Various
alkylzinc reagents were then explored, including the successful use of
cyclohexylmethylzinc bromide, which contains substitution at the
ꢀ-position (3h). Functionalized organozinc reagents were examined,
wherein an alkyl chloride, a TBDPS-protected alcohol, and an ester-
containing alkylzinc reagent were competent coupling partners (3j-l).
The reaction is not limited to terminal alkenes, as substituted styrenes,
including indene and a ꢀ-methyl styrene derivative, underwent the
hydroalkylation reaction in good yields. Finally, the reaction of a 1,1-
disubstituted styrene proceeded to furnish an all-carbon quaternary
center, albeit in reduced yield. Notably, we did not observe any
constitutional isomers by GC.
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To determine the origin of the hydrogen incorporated into the
product and probe our mechanistic hypothesis, a perdeuterated
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