Rhodium-catalyzed cross-coupling reaction of arylboronates and diazoesters and tandem alkylation reaction for the synthesis of quaternary r,r-heterodiaryl carboxylic esters

Article abstract of DOI:10.1021/ol2022577

A rhodium-catalyzed one-pot three-component coupling reaction was developed for the synthesis of quaternary α,α-heterodiaryl carboxylic esters. This reaction involves cross-coupling of the arylrhodium(I) complexes with R-aryldiazoacetates to form oxa-π-al

Full text of DOI:10.1021/ol2022577

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5370–5373
Rhodium-Catalyzed Cross-Coupling
Reaction of Arylboronates and
Diazoesters and Tandem Alkylation
Reaction for the Synthesis of Quaternary
r,r-Heterodiaryl Carboxylic Esters
Yuk-Tai Tsoi, Zhongyuan Zhou, and Wing-Yiu Yu*
State Key Laboratory for Chirosciences and Open Laboratory of Chirotechnology of the
Institute of Molecular Technology for Drug Discovery and Synthesis, Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong
bcwyyu@inet.polyu.edu.hk
Received August 19, 2011
ABSTRACT
A rhodium-catalyzed one-pot three-component coupling reaction was developed for the synthesis of quaternary R,R-heterodiaryl carboxylic
esters. This reaction involves cross-coupling of the arylrhodium(I) complexes with R-aryldiazoacetates to form oxa-π-allylrhodium complexes.
With KOtBu and alkyl halides, tandem alkylation of the allyl complex occurs to form a quaternary stereocenter at the carbenic carbon.
Advances in transition metal catalyzed cross-coupling
reactions have led to the development of highly efficient
transformations such as SuzukiÀMiyaura reactions,1a
BuchwaldÀHartwig aminations,1b and HeckÀMizoroki
reactions.1c Underlying these transformations is the effec-
tive coupling of organotransition metal complexes with
nucleophilic organoborons, amines, and alkenes/alkynes.
The use of diazo compounds as coupling partners for
catalytic cross-coupling reactions is attracting current
interest.2 Pioneered by Van Vranken and co-workers, the
research groups of Wang and Barluenga have developed a
highly efficient Pd-catalyzed coupling of aryl halides with
carbenoid reagents to afford highly substituted alkenes.3
Recently, our group also achieved a highly stereoselective
oxidative cross-coupling of arylboronic acids with diazoa-
cetates to produce (E)-1,2-diarylacrylates with dioxygen as
the sole oxidant.4a Mechanistically, migratory carbene
insertion into the PdÀC bond is involved in these carbe-
noid coupling reactions.5 Despite the apparent successes,
(3) For examples of Pd-catalyzed carbenoid-mediated cross-coupling
reactions for CdC bond formation, see: (a) Zhou, L.; Ye, F.; Ma, J.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2011, 50, 3510. (b) Zhou, L.;
Liu, Y.; Zhang, Y.; Wang, J. Chem. Commun. 2011, 47, 3622. (c)
(1) (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004;
Vol. 1, pp 41À124. (b) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.;
ꢀ
Barluenga, J.; Florentino, L.; Aznar, F.; Valdes, C. Org. Lett. 2011,
13, 510. (d) Peng, C.; Yan, G.; Wang, Y.; Jiang, Y.; Zhang, Y.; Wang, J.
Synthesis 2010, 24, 4154. (e) Zhao, X.; Wu, G.; Yan, C.; Lu, K.; Li, H.;
Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 5580. (f) Zhao, X.; Jing, J.; Lu,
K.; Zhang, Y.; Wang, J. Chem. Commun. 2010, 46, 1724. (g) Barluenga,
€
Wiley-VCH: Weinheim, 2004; Vol. 2, pp 699À760. (c) Brase, S.; de
Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp
217À316.
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J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Adv. Synth. Catal. 2010,
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352, 3235. (h) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C.
Chem.;Eur. J. 2010, 16, 12801. (i) Barluenga, J.; Escribano, M.; Aznar,
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(2) For reviews, see: (a) Franssen, N. M. G.; Walters, A. J. C.; Reek,
J. N. H.; de Bruin, B. Catal. Soc. Technol. 2011, 1, 153. (b) Zhang, Y.;
Wang, J. Eur. J. Org. Chem. 2011, 1015. (c) Jellema, E.; Jongerius, A. L.;
Reek, J. N. H.; de Bruin, B. Chem. Soc. Rev. 2010, 39, 1706.
F.; Valdes, C. Angew. Chem., Int. Ed. 2010, 49, 6856. (j) Kudirka, R.;
Devine, S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew. Chem., Int.
Ed. 2009, 48, 3677. (k) Devine, S. K. J.; Van Vranken, D. L. Org. Lett.
2008, 10, 1909.
r
10.1021/ol2022577
Published on Web 09/06/2011
2011 American Chemical Society

Scheme 1. Mechanistic Hypothesis
these coupling reactions are limited to CdC bond forma-
tion due to spontaneous β-hydride elimination of organo-
palladium species that precludes its further functiona-
lization (Scheme 1). Notably, Wang and co-workers
developed a protocol that successfully intercepted the orga-
nopalladium by transmetalation with copper-acetylides to
furnish two separate CÀC σ-bonds at the carbenic carbon.6
To examine the synthetic application of the diazo cou-
pling reactions, we pursued an alternative reaction mani-
fold based on Rh catalysis. Being a d8 metal center, Rh(I) is
isoelectronic with Pd(II). Thus, we hypothesized that
organorhodium(I) would couple with R-diazoacetates.
Migratory carbene insertion should afford an oxa-π-
allylrhodium(I) complex, which would be tenable for
further functionalization (Scheme 1). Here we present the
successful development of a Rh-catalyzed one-pot three-
component coupling reaction with two CÀC σ-bonds
being formed at the carbenic carbon to afford quaternary
R,R-heterodiaryl carboxylic acid esters using arylboro-
nates, R-diazoacetates, and alkyl halides as reagents. Qua-
ternary R,R-diaryl carbonyl compounds are common
scaffolds in medicinal products such as disopyramide
(Norpace),7a methadone (Dolophine),7b loperamide
(Imodium),7c and proadifen (SKF525-A).7d
Initially, we set out to test the coupling reaction of R-
diazoacetate with arylrhodium(I) complexes derived in
situ from arylboronic acids and [Rh(cod)OH]2. When
4-chlorophenyldiazoacetate (1a, 0.2 mmol) was treated
with phenylboronic acid (0.6 mmol) and [Rh(cod)OH]2
(3 mol % Rh) in a 1,4-dioxaneÀwater (10:1 v/v) mixture,
2-(4-chlorophenyl)-2-phenylacetate (5a) was obtained in
95% yield. The 5a formation can be rationalized by the
coupling of the phenylrhodium(I) complex with R-phenyl-
diazoacetate to produce an oxa-π-allylrhodium(I) species
via migratory carbene insertion. The subsequent protona-
tion of the oxa-π-allylrhodium complex should afford 5a
as product. Indeed, oxa-π-allylrhodium(I) complexes are
known toundergo aldol reactions withaldehydes.8 Thus, it
appeared to us that a one-pot three-component cross-
coupling reaction would be possible through further
functionalization of the putative oxa-π-allylrhodium com-
plex with some electrophiles. After some screening, we
were gratified that treating 1a (0.2 mmol) with phenyl-
boronic acid pinacol ester (2a, 0.6 mmol), benzyl bromide
(3a, 0.6 mmol), KOtBu (0.4 mmol), and [Rh(cod)Cl]2 (3
mol % Rh) in diethyl ether at 40 °C for 5 h furnished the
coupled product 4a in 59% yield (Table 1, entry 2).
However, when phenylboronic acid was utilized as the aryl
source, 5a was produced exclusively without any 4a for-
mation (entry 3). Notably, no 4a and 5a formation was
observed in the absence of the Rh catalyst (entry 14).
Employing other boronic acid esters or solvents (e.g.,
toluene, acetone, DMF, THF, and dioxane) failed to give
better results (entries 4À10). After several attempts, 4a was
eventually obtained in up to 86% yield with [Rh(cod)OH]2
as catalyst and methyl tert-butyl ether (MTBE) as solvent
(entry 1). In this work, we found that Rh(PPh3)3Cl and
(4) (a) Tsoi, Y.-T.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett.
2010, 12, 4506. (b) Yu, W.-Y.; Tsoi, Y.-T.; Zhou, Z.; Chan, A. S. C. Org.
Lett. 2009, 11, 469. (c) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan,
A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 604. For related studies on
carboradicals and nitrenes as coupling partners, see:Chan, C.-W.; Zhou,
Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926. (d) Ng, K.-H.;
Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010, 132, 12862. (e) Yu,
W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S. C. Org. Lett. 2009, 11, 3174. (f)
Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan, A. S. C. J. Am.
Chem. Soc. 2008, 130, 3304. (g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M.
J. Am. Chem. Soc. 2006, 128, 9048.
(5) For examples ofmigratoryinsertionofpalladium-carbenes, see:(a)
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Albeniz, A. C.; Espinet, P.; Perez-Mateo, A.; Nova, A.; Ujaque, G.
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Organometallics 2006, 25, 1293. (b) Albeniz, A. C.; Espinet, P.; Manrique,
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R.; Perez-Mateo, A. Chem.;Eur. J. 2005, 11, 1565. (c) Sole, D.;
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Vallverdu, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. Organometallics
2004, 23, 1438.
(6) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010,
132, 13590.
(8) Example of stoichiometric reaction of oxa-π-allylrhodium(I) com-
plexes with aldehydes: (a) Slough, G. A.; Bergman, R. G.; Heathcock,
C. H. J. Am. Chem. Soc. 1989, 111, 938. For catalytic examples of oxa-π-
allylrhodium(I) complexes with aldehydes, see:(b) Cauble, D. F.; Gipson,
J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110. (c) Yoshida, K.;
Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 10984. (d)
Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122,
4528.
(7) (a) Skokie, J. W. C.; Deerfield, H. W. S. U.S. Patent 3,225,054,
1965. (b) Schultz, E. M.; Robb, C. M.; Sprague, J. M. J. Am. Chem. Soc.
1947, 69, 2454. (c) Stokbroekx, R. A.; Vandenberk, J.; Van Heertum, A.
H. M. T.; van Laar, G. M. L. W.; Van der Aa, M. J. M. C.; Van Bever,
W. F. M.; Janssen, P. A. J. J. Med. Chem. 1973, 16, 782. (d) Lu, M. C.;
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1987, 30, 273.
Org. Lett., Vol. 13, No. 19, 2011
5371

Table 1. Reaction Optimizationa
Scheme 2. Rh-Catalyzed One-Pot Three-Component Coupling
Reactionsa,b
a The reactions were carried out at a 0.2 mmol scale of limiting
reagent. b Yields were determined by GC/FID using dodecane (0.1
mmol) as internal standard. c The reaction was run for 4 h. d 3 equiv of
base were used. e Methyl tert-butyl ether.
[Rh(dppe)Cl]2 are ineffective catalysts for the three-com-
ponent coupling reaction (entries 12 and 13).
Scheme 2 depicts the scope of the Rh-catalyzed three-
component coupling reaction. Evaluation of some substi-
tuted aryldiazoacetates established that diazoesters bear-
ing electron-donating and -withdrawing substituents are
effective coupling partners for the Rh-catalyzed reaction.
Due to intrinsic reactivity, bromo substituents are not
compatible with the Pd(0)-catalysis. For example, the
Pd(0)-catalyzed coupling of benzyl bromides with 4-bro-
mophenyldiazoacetates afforded the product acrylate in
48% yield.4b In this work, however, the Rh-catalyzed
three-component coupling reaction with 4-bromophenyl-
diazoacetates produced 4c in 84% yield. Moreover, poly-
cyclic aryldiazoacetates would couple effectively to give 4d
and 4e in good yields. Previously, we found that 2-meth-
oxyphenyldiazoacetate was a poor reagent for carbenoid
CÀH functionalization of NH-free indoles with
[(cymene)RuCl2]2 as catalyst, presumably due to coordi-
nation of the ortho-methoxy group.4c In this work, the
analogous Rh-catalyzed reaction afforded 4f in 61% yield.
The substrate scope is further extended to a broad
variety of arylboronates; electron-rich and -poor arylbor-
onates (including pentafluorophenylboronates) are effec-
tive aryl donors, and trimethylsilyl, diphenylamino,
carboxylate, and indole groups are tolerated. While 2-to-
lylboronate would undergo facile coupling with 1a and 3a
a Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), 3 (0.6 mmol),
KOtBu (0.6 mmol), [Rh(cod)OH]2 (2 mol % Rh), MTBE (1 mL), 40 °C
for 4 h. See Supporting Information for experimental details. bIsolated
yield. NMR yield. Methyl 2-(2-methoxyphenyl)-2-phenylacetate was
obtained in 30%. e1a was recovered in 55%. fA 1:1 mixture of diaster-
eomeric products was obtained based on NMR analysis. g5a was
obtained in 8% yield. h5a was obtained in 58% yield.
c
d
to furnish 4n in 76% yield, the analogous reaction with 2,6-
dimethoxylphenylboronate was sluggish due to steric hin-
drance to the transmetalation step, and 4o was obtained in
15% yield. 3-Thiopheneboronate is known to be an effec-
tive substrate for the Rh-catalyzed conjugate addition
(9) Yoshida, K.; Hayashi, T. Heterocycles 2003, 59, 605.
Org. Lett., Vol. 13, No. 19, 2011
5372

reaction to enones.9 In this work, however, we failed to
obtain the desired coupled product with 3- thiopheneboro-
nate. Yet, when 1a reacted with 3- thiopheneboronate
in a 1,4-dioxaneÀwater (10:1 v/v) mixture, 2-phenyl-
2-(thiophen-3-yl)acetate was formed in 65% yield.
reactive rhodium-carbene complexes II,12 which could un-
dergo migratory carbene insertion to give oxa-π-allylrho-
dium complexes III. As mentioned earlier, protonolysis of
III in aqueous dioxane would produce R,R-diarylacetates.
Scheme 4. Reactivity of Oxa-π-allylrhodium Complex toward
Benzyl Bromide
Scheme 3. A Plausible Mechanism
To probe the role of the oxa-π-allylrhodium in the
second CÀC bond formation, we prepared the oxa-π-ally-
lrhodium complex 6a in situ by reacting [Rh(cod)OMe]2
with 1a and 2a in MTBE. The choice of [Rh(cod)OMe]2 is
to avoid possible protonation of the allylrhodium 6a. We
found that treating 6a with benzyl bromide 3a alone for 2 h
afforded 5a exclusively after workup (i.e., 4a was not
obtained). However, 6a would react with 3a in the presence
of KOtBu (6 equiv) to give 4a in 57% yield (Scheme 4).
Based on these findings, III should apparently exchange
with KOtBu to form a potassium enolate IV,13 which then
reacts with the alkyl halides to establish the quaternary
carbon center. Consistent with this proposal, treating 5a
with KOtBu (3 equiv) and 3a (3 equiv) in MTBE at 40 °C
for 1 h produced 4a in 40% yield.
In summary, [Rh(cod)OH]2 catalyzes the one-pot three-
component coupling of R-aryldiazoesters, arylboronates,
and alkyl halides to form quaternary R,R-heterodiaryl
carboxylic acid esters probably involving migratory car-
bene insertion as one of the principal steps. This reaction
tolerates many commonly encountered functional groups
such as bromo, trifluoromethyl, indole, and esters. This
study demonstrates the versatility of metal-carbene in the
development of highly efficient cascade CÀC bond forma-
tion reactions, which would be useful for creating mole-
cular structures of higher complexity.
Likewise, a range of functionalized alkyl halides would
couple effectively under the Rh-catalyzed conditions. For
example, coupling of the benzyl bromides bearing sulfo-
nylmorpholino and mesityl groups gave 4p (molecular
structure established by X-ray crystallography) and 4q in
76 and 61% yield, respectively. The analogous reaction of
other organohalides including (1-bromoethyl)benzene (4r:
61%), methyl iodide (4s: 79%), and 3,3-dimethylallyl
bromide (4t: 57%) afforded their respective coupling
products in good to moderate yields. Besides alkyl halides,
N-chloromorpholine was found to couple effectively to
afford R-morpholinoacetate 4u, albeit in 25% yield.
The mechanism of the three-component coupling reac-
tion may involve an initial formation of arylrhodium(I)
complex I through transmetalation with the arylboronic
acid ester (Scheme 3). The research groups of Hayashi and
Hartwig already characterized the arylrhodium(I) com-
plexes from the reaction of arylboronic acids with Rh(I)
complexes.10,11 Analogous to the isoelectronic arylpalla-
dium(II) complexes, I shouldreact withdiazoesterstoform
Acknowledgment. We are thankful for the financial
support from the Hong Kong Research Grants Council
(PolyU5038-11P; SEG_01PolyU) and The Area of Excel-
lence Scheme (AoE/P-10-01) administered by the Hong Kong
University Grants Committee. Special thanks is given to Mr.
Chun-Yin Yip (PolyU) for some initial studies.
(10) (a) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2007, 129, 1876. (b) Krug, C.; Hartwig, J. F. Organometallic 2004, 23,
4594. (c) Hayashi, T.; Takahashi, M.; Tanaka, Y.; Ogasawara, M.
J. Am. Chem. Soc. 2002, 124, 5052.
(11) In this work, the putative arylrhodium species I can be trapped
by methyl acrylate to yield 3-phenylpropanoate (58%) and 3,3-diphe-
nylpropanoate (22%).
(12) For an example of an isolable rhodium-carbene complex, see:
Werner, H.; Schwab, P.; Bleuel, E.; Mahr, N.; Steinert, P.; Wolf, J.
Chem.;Eur. J. 1997, 3, 1375.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) It is possible that the allyl exchange with KOtBu would occur via
oxygen-bound rhodium(I) enolate complexes. For an example of oxy-
gen-bound rhodium(I) enolate complexes, see: Slough, G. A.; Bergman,
R. G.; Heathcock, C. H. J. Am. Chem. Soc. 1989, 111, 938.
Org. Lett., Vol. 13, No. 19, 2011
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