Unification of anion relay chemistry with the Takeda and Hiyama cross-coupling reactions: Identification of an effective silicon-based transfer agent

Article abstract of DOI:10.1021/ja2120103

The unification of Anion Relay Chemistry (ARC) with the Takeda and Hiyama palladium-mediated cross-coupling processes to provide aryl-aryl, alkenyl-aryl, and alkenyl-alkenyl coupled products by exploiting a common silicon-based transfer agent has been achieved. These results provide a practical solution for intermolecular cross-coupling of organolithium reagents without the problematic lithium-halogen exchange and/or undesired homocoupling that has kept organolithium cross-couplings from achieving the same level of utility asother palladium-mediated methods (e.g., Suzuki organoboron, Negishi organozinc, Stille organotin, Kumada organomagnesium, etc.).

Full text of DOI:10.1021/ja2120103

Communication
pubs.acs.org/JACS
Unification of Anion Relay Chemistry with the Takeda and Hiyama
Cross-Coupling Reactions: Identification of an Effective Silicon-Based
Transfer Agent
Amos B. Smith, III,* Adam T. Hoye, Dionicio Martinez-Solorio, Won-Suk Kim,† and Rongbiao Tong‡
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19128, United States
S
* Supporting Information
Scheme 1. Silicon-Mediated Reaction Pathways
ABSTRACT: The unification of Anion Relay Chemistry
(ARC) with the Takeda and Hiyama palladium-mediated
cross-coupling processes to provide aryl−aryl, alkenyl−
aryl, and alkenyl−alkenyl coupled products by exploiting a
common silicon-based transfer agent has been achieved.
These results provide a practical solution for intermo-
lecular cross-coupling of organolithium reagents without
the problematic lithium−halogen exchange and/or un-
desired homocoupling that has kept organolithium cross-
couplings from achieving the same level of utility as
other palladium-mediated methods (e.g., Suzuki organo-
boron, Negishi organozinc, Stille organotin, Kumada organo-
magnesium, etc.).
ross-coupling reactions (CCRs) of organometallic/main-
group reagents with organic halides, which permit facile
C
respectively, alkylation products (3; pathway A) or ARC/CCR
adducts (4; pathway B), the latter process requiring 3 mol %
Pd(PPh3)4.11
construction of a wide variety of carbon−carbon bonds, con-
stitute one of the most important reaction types discovered and
developed over the past 50 years. As such, CCRs have evolved
into the mainstay of modern drug development, complex
molecule synthesis, and material science programs. Early in the
annals of CCRs (cf. 1974), Murahashi and co-workers reported
the palladium-catalyzed cross-coupling of readily available
organolithium compounds with aryl halides.1 Although it is a
highly atom-efficient process, limitations of the Murahashi CCR
include the required use of preformed arylpalladium complexes
and/or extremely slow addition of the aryllithiums in order to
limit formation of homocoupled products resulting from rapid
lithium−halogen exchange prior to the Pd-catalyzed C−C
bond-formation event. Thus, CCRs that intrinsically avoid homo-
coupling (i.e., use of Suzuki organoboron,2 Stille organotin,3
Negishi organozinc,4 and Hiyama5/Denmark6 organosilicon
reagents) have gained in popularity and now are the gold
standards of CCR methods despite the requirement in many
cases of an additional synthetic manipulation and possible
isolation of a suitable nucleophilic coupling partner, the latter
frequently accessed via the corresponding organolithium species.
In connection with the evolution of Anion Relay Chemistry
(ARC),7 we recently demonstrated that 1-oxa-2-silacyclopen-
tene 1 is a competent alternative substrate for accessing the
type-II ARC manifold,8 now recognized to entail an alkoxide
intermediate,9 via addition of an alkyl- or aryllithium (Scheme 1).
Subsequent addition of a polar solvent such as hexamethyl-
phosphoramide (HMPA) triggers a “Brook-like” rearrangement10−12
that in the presence of an alkyl or aryl halide furnishes,
To document the concept of common reactive intermediates
between known silicon-mediated processes (Scheme 1), we
demonstrate in Table 1 that identical biaryl cross-coupling
products 4 can be accessed via either the aforementioned ARC/
CCR pathway or the Takeda pathway,10 employing different
starting materials. Following the ARC precedent, addition of an
initiating nucleophile (MeLi) to 1 followed by exposure to CuI
in a polar solvent (HMPA) leads to Si−C bond cleavage.
Palladium-catalyzed cross-coupling of the resultant arylcopper
species then provides 4a−c (entries 1, 3, and 5). Alternatively,
4a−c could be formed via deprotonation of 8 with MeLi and
similar exposure to CuI in HMPA to promote C → O silyl
migration, followed by Pd-catalyzed cross-coupling with the
corresponding aryl iodide (entries 2, 4, and 6). Depending on
the initiating nucleophile and workup conditions, the resulting
silyl ether can be retained to provide a customizable protecting
group in addition to the newly formed C−C bond (entry 7).
In addition to aryl halides, alkenyl halide 9d proved to be a
compatible coupling partner in the process, providing styrene
4d in 45% yield.
On the basis of our initial results with 1-oxa-2-silacyclo-
pentenes,8 we were struck with the similarities between both the
ARC and Takeda alkylation/CCR pathways10 and the reactive
Received: December 23, 2011
Published: February 21, 2012
© 2012 American Chemical Society
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Table 1. Alternate Access to CCR Products 4
Table 2. Initial Attempts To Promote the Intermolecular
CCR over the ARC CCR
a
b
Isolated yields. nd = not detected. 1 (1.2 equiv) and PhLi
c
(1.26 equiv) were used. 1 (2.0 equiv) and PhLi (2.1 equiv) were used.
a
Table 3. Optimization of the Intermolecular CCR
a
b
Isolated yields. PdCl2(dppf) (3 mol %) and PPh3 (6 mol %) were
c
d
used as the catalyst. Pd(PPh3)4 (3 mol %) was used as the catalyst. t-
BuLi was used in place of PhLi as the initiating nucleophile, and HCl
was omitted to preserve the resulting silyl ether.
intermediates of the Hiyama CCR5,6 (Scheme 1, pathway C).
We thus reasoned that we could intersect the latter cross-
coupling reaction manifold via 1-oxa-2-silacyclopentene and
related congeners. Success would provide a valuable and,
ideally, practical method for the direct cross-coupling of
organolithium reagents with aryl and alkenyl halides without
the advent of homocoupling by exploiting a silicon-based
“transfer agent.” To the best of our knowledge, there exists only
a single report in which a silicon-based transfer agent was
utilized to achieve the Pd-catalyzed CCR of aryllithium reagents
to form biaryl products, in which Tamao and co-workers
employed a regioisomeric 1-oxa-2-silaindane.13
a
All reactions were performed on 0.45 mmol scale with 4-iodoanisole
b
as the limiting reagent. Determined by 1H NMR analysis of the crude
mixture of reaction products following aqueous workup and extraction
(Et2O). nd = not detected. PdCl2 (3 mol %), dpca (4 mol %), and
CuI (10 mol %) were premixed for 30 min in THF prior to the
c
We began evaluating this hypothesis by subjecting the
proposed alkoxide intermediate 2 (Scheme 1), derived from the
reaction between PhLi and 1, to conditions similar to those
reported by Hiyama using 4-iodobenzonitrile as the electrophile.5d
As illustrated in Table 2, entry 1, the ARC CCR process was
favored, furnishing 4b as the major product, when the polar
solvent dimethyl sulfoxide (DMSO) was used, consistent with
our previous ARC study using the polar solvent HMPA.8
However, when tetrahydrofuran (THF) was employed as the
solvent, only cross-coupled biaryl 10b was observed (entry 2).
The best results (96%) were observed when 2.1 equiv of PhLi
was employed (entry 3). Taken together, these results support
the unified reaction pathway hypothesis.
To optimize further the reaction conditions, we turned to
4-iodoanisole as the electrophilic coupling partner (Table 3),
which would permit facile analysis of the crude product mixture
by 1H NMR spectroscopy because of the diagnostic methyl aryl
ether signals of the various components. A series of reaction
conditions was explored. Changing the catalyst system to
addition of 4-iodoanisole, after which the PhLi/1 reaction mixture was
introduced via cannula. No 1-oxa-2-silacyclopentene was used in the
reaction; a solution of PhLi in THF was used as a substitute.
d
PdCl2(PPh3)2 and dppp (not shown) led to inconsistent results
with a significant amount of homocoupled 12a. Attempts to
reduce the amount of PhLi needed to consume fully the
starting aryl iodide resulted in 12a with incomplete
consumption of the halide (entry 2). Better conversion of the
aryl iodide occurred when steps a and b were allowed to
proceed for longer times (entry 3). The use of toluene as the
solvent (not shown) led to extremely poor conversion of 9a.
A significant increase in the efficiency of the process was
observed when the catalyst system [PdCl2, dpca (11), and CuI]
was premixed for 30 min in THF at room temperature prior to
introduction of the aryl halide, which was followed by
immediate addition of a mixture of PhLi and 1 in THF via
cannula (entry 4). Employing this protocol in conjunction with
the use of 2.0 equiv of transfer agent 1 led to complete
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conversion of 9a with no detectable homocoupled product
(entry 5). However, the use of 1.2 equiv of PhLi did not result
in complete consumption of 4-iodoanisole (entry 6). Impor-
tantly, and as expected, significant homocoupling and catalyst
decomposition was observed in the absence of silicon transfer
agent 1 (entry 7), consistent with Murahashi’s early observations
that constitute the major limitation of known organolithium cross-
coupling processes.1 Additional experimentation identified 1.8
equiv of silicon transfer agent 1 and 1.5 equiv of PhLi as the
optimal amounts for complete consumption of the limiting aryl
iodide while avoiding homocoupling (entry 8).
Table 5. Intermolecular CCR of Alkenyl Halides
Having identified the optimal conditions, the scope of the
Pd-catalyzed CCR of PhLi employing transfer agent 1
with various aryl halides was examined (Table 4). Electron-rich
Table 4. Intermolecular CCR To Form Biaryl Products
a
b
Isolated yields. The crude product mixture was treated with TBAF
in THF to remove the silyl group prior to purification.
a
b
Isolated yields. The reaction was allowed to proceed for 12 h
following cannulation.
vinyl−vinyl couplings between 13f and 9m and between 13g
and (+)-9n to provide dienes 14f and (+)-14g.
and -deficient substrates were well-tolerated in the reaction, as
were a variety of common functional groups (esters, nitriles,
and azaheterocycles), providing the biaryl compounds (10a−g)
in yields of 67−96%. In all cases, siloxane 1 emerged from the
In summary, we have demonstrated that siloxane 1 is a
competent silicon-based “transfer agent” for intermolecular
cross-coupling reactions of aryl and alkenyl organolithium
reagents, in turn confirming our initial hypothesis regarding the
common reaction manifolds of known silicon cross-coupling
processes (e.g., Takeda and Hiyama). Importantly, this
synthetic tactic offers a viable solution to the prohibitive issues
surrounding the cross-coupling of organolithium compounds,
notably lithium−halogen exchange and subsequent homocou-
pling. Studies to determine the effect of the siloxane structure
on reactivity, the possibility of devising a catalytic silicon
transfer agent, and the pursuit of sp3−sp2 and sp3−sp3
couplings continue in our Laboratory.
1
reaction intact, as observed by H NMR analysis of the crude
reaction mixtures. For products possessing polarities similar to
that of silicon transfer agent 1, an oxidative Tamao−Fleming
workup12,14 of the initial reaction mixture was employed to
convert 1 selectively to the corresponding diol, which could be
easily separated by column chromatography.
To extend this protocol further, CCRs using alkenyl
substrates were explored (Table 5). Vinyl halides 9j−l were
competent coupling partners with 13a, generating styrenes
14a−c with retention of the alkene geometry (entries 1, 3, and 5).
Importantly, the roles of the coupling partners could be reversed
by using the corresponding vinyllithium and aryl halide to access
identical coupling products in comparable yields (entries 2, 4, and
6), demonstrating the flexibility offered by this cross-coupling
protocol with respect to the choice of the nucleophilic and electro-
philic components. Geminal and vicinal substitution patterns were
tolerated in the transfer process from silicon, providing coupled
products 14c and 14d. Also noteworthy were the successful
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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(12) Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
17092.
(13) Son, E.-C.; Tsuji, H.; Saeki, T.; Tamao, K. Bull. Chem. Soc. Jpn.
AUTHOR INFORMATION
■
Corresponding Author
smithab@sas.upenn.edu
2006, 79, 492.
(14) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M.
Organometallics 1983, 2, 1694. (b) Fleming, I.; Henning, R.; Plaut, H.
J. Chem. Soc., Chem. Commun. 1984, 29.
Present Addresses
†Department of Chemistry and Nano Science, Ewha Womans
University, Seoul 120-750, Korea.
‡Department of Chemistry, The Hong Kong University of Science
and Technology, Clear Water Bay, Kowloon, Hong Kong.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors dedicate this article to Shun-Ichi Murahashi
(Professor, Okayama University of Science), on the occasion of
his 75th birthday. Financial support was provided by the NIH
through Grant GM-29028. We thank Drs. George Furst and
Jun Gu and Dr. Rakesh Kohli at the University of Pennsylvania
for assistance in obtaining NMR and high-resolution mass
spectra, respectively.
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