Suzuki-Miyaura coupling of aryl carbamates, carbonates, and sulfamates

Article abstract of DOI:10.1021/ja906477r

(Chemical Equation Presented) The first Suzuki-Miyaura cross-couplings of carbamates, carbonates, and sulfamates is described. The method provides a powerful means of using simple derivatives of phenol as precursors to polysubstituted aromatic compounds, as exemplified by a concise synthesis of the anti-inflammatory drug flurbiprofen.

Full text of DOI:10.1021/ja906477r

Published on Web 11/20/2009
Suzuki-Miyaura Coupling of Aryl Carbamates, Carbonates, and Sulfamates
Kyle W. Quasdorf, Michelle Riener, Krastina V. Petrova, and Neil K. Garg*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095
Received May 7, 2009; E-mail: neilgarg@chem.ucla.edu
Table 1. Cross-Coupling of Aryl Carbamates and Carbonates with
Arylboronic Acid 2a or 2ba
Transition-metal-catalyzed cross-coupling reactions continue to
play a vital role in modern synthetic chemistry.1 Although cross-
couplings of aryl halides and triflates are most common, recent studies
have demonstrated the successful cross-coupling of simple and
affordable phenolic derivatives. In 2008, notable achievements in this
area include the Suzuki-Miyaura coupling of electron-deficient aryl
methyl ethers by Chatani,2 and the Suzuki-Miyaura coupling of aryl
pivalates,3 which was reported simultaneously by our group4a and the
group of Shi.4b A conceptual advantage of these technologies in
comparison with methodologies involving halides and sulfonates is
the potential to direct the installation of other functional groups onto
an aromatic ring prior to cross-coupling (Figure 1). In practice,
however, the ability to use methyl ethers (R ) Me) and pivalates
[R ) -C(O)CMe3] in this sense is somewhat limited.5 In view of the
importance of polyfunctionalized aromatics in medicine, ligands for
catalysis, and materials chemistry, we sought to address this problem.
In this communication, we describe the first Suzuki-Miyaura couplings
of aryl carbamates, carbonates, and sulfamates. Moreover, we disclose
a concise synthesis of the anti-inflammatory drug flurbiprofen (1)6
using this methodology.
Figure 1. Approach to polysubstituted aromatics such as flurbiprofen.
Of the potential phenolic derivatives to be studied, aryl carbamates
and sulfamates were considered ideal because of their ready availability
and pronounced stability under a variety of reaction conditions.
Furthermore, these substrates can be used to direct the installation of
functional groups at both the ortho and para positions (via ortho
lithiation chemistry pioneered by Snieckus7 and electrophilic aromatic
substitution,8 respectively). Although Ni-catalyzed Kumada couplings
of these substrates have been documented,7b,9 cross-coupling under
milder, more attractive Suzuki-Miyaura conditions has not been
reported. Notably, the oxidative addition of a metal into the aryl C-O
bond of an aryl carbamate or sulfamate presents a considerable challenge.
Despite this difficulty, we have found that Suzuki-Miyaura coupling
of aryl carbamates with arylboronic acids proceeds in the presence of
NiCl2(PCy3)2, K3PO4, and heat, with toluene as the solvent (Table 1).
The fact that NiCl2(PCy3)2 could be used to facilitate the desired
transformation is advantageous,10 as this readily available complex
shows marked stability toward air and water and can be used on the
benchtop rather than in a glovebox.11 The carbamate derivative of
1-naphthol could be converted to the desired biaryl product at 110 °C
with 5 mol % Ni complex (entry 1). However, the yield improved
substantially when the reaction was carried out at higher temperatures
with increased catalyst loading (entry 2). 2-Naphthol derivatives could
also be coupled under these conditions (entries 3 and 4). In addition,
the reaction was tolerant of an electron-withdrawing group (-CO2Me,
entry 4) and an electron-donating group (-OMe, entry 5) on the
a Conditions: NiCl2(PCy3)2 (10 mol %), ArB(OH)2 (4 equiv), K3PO4
(7.2 equiv), toluene (0.3 M), 130 °C, 24 h. b Conditions: NiCl2(PCy3)2
(5 mol %), ArB(OH)2 (2.5 equiv), K3PO4 (4.5 equiv), toluene (0.3 M),
110 °C, 24 h. c Isolated yields.
naphthyl ring. The corresponding reactions of nonfused aryl carbamates
proved to be more challenging. Nonetheless, carbamates derived from
phenol and p-methoxyphenol could be converted to the corresponding
cross-coupled products, albeit in modest yields (entries 6 and 7). Aryl
tert-butylcarbonates were also deemed to be suitable cross-coupling
partners (entries 8-10). Interestingly, the carbonate congener of
2-naphthol delivered the cross-coupled product in significantly higher
yield than the corresponding carbamate (entry 9 vs entry 3).
As shown in Table 2, aryl sulfamates serve as superior coupling
partners in the Ni-catalyzed Suzuki-Miyaura reaction. Both naphthyl
and nonfused aromatic substrates could be converted to biaryl products
in excellent yield (entries 1-11 and 14-17). Electron-withdrawing
(entries 2 and 9) and electron-donating groups were tolerated (entries
3, 10, and 11). In addition to substrates with methyl substituents at
the para, meta, and ortho positions (entries 5-7), a sterically congested
2,6-disubstituted substrate also participated in the desired cross-coupling
process (entry 8). A heteroaromatic sulfamate (entry 12) and a vinyl
sulfamate (entry 13) proved to be competent substrates. Finally, a range
of ortho-substituted sulfamates, prepared by ortho lithiation/function-
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17748 J. AM. CHEM. SOC. 2009, 131, 17748–17749
10.1021/ja906477r CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cross-Coupling of Aryl Sulfamatesa
Figure 2. Synthesis of flurbiprofen using orthogonal cross-couplings.
technology presented herein allows for the installation of multiple
functional groups onto an aromatic ring prior to the cross-coupling
event, as demonstrated by a concise synthesis of the anti-
inflammatory drug flurbiprofen.
Acknowledgment. The authors are grateful to the NIH-NIGMS
(R00 GM079922), the University of California, Los Angeles, the
Amgen Scholars Program (undergraduate fellowship to M.R.), and
Boehringer Ingelheim for financial support. We thank Takeru
Furuya (Harvard University), Professor Ritter (Harvard University),
and Professor Snieckus (Queen’s University) for pertinent discus-
sions, the Garcia-Garibay laboratory (UCLA) for access to instru-
mentation, and Dr. John Greaves (UC Irvine) for mass spectra.
Supporting Information Available: Detailed experimental proce-
dures and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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(2) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866.
(3) For reviews, see: (a) Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009,
48, 3565. (b) Goossen, L. J.; Goossen, K.; Stanciu, C. Angew. Chem., Int.
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Chem. Soc. 2008, 130, 14468.
(5) The ortho-directing ability of methyl ethers is modest (see ref 7a and
references therein), whereas ortho substitution of aryl pivalates presents a
considerable challenge.
(6) For pertinent reviews, see: (a) Richy, F.; Rabehnda, V.; Mawet, A.;
Reginster, J.-Y. Int. J. Clin. Pract. 2007, 61, 1396. (b) Kumar, P.; Pathak,
P. K.; Gupta, V. K.; Srivastava, B. K.; Kushwaha, B. S. Asian J. Chem.
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(7) (a) For a review, see: Snieckus, V. Chem. ReV. 1990, 90, 879. (b) For the
use of sulfamates in directed metallation reactions and Kumada couplings,
see: Macklin, T. K.; Snieckus, V. Org. Lett. 2005, 7, 2519.
a Conditions: NiCl2(PCy3)2 (5 mol %), ArB(OH)2 (2.5 equiv), K3PO4
(4.5 equiv), toluene (0.3 M), 110 °C, 24 h. b Isolated yields. c Conditions:
NiCl2(PCy3)2 (10 mol %), ArB(OH)2 (4 equiv), K3PO4 (7.2 equiv),
toluene (0.3 M), 130 °C, 24 h.
alization of phenyl dimethylsulfamate,12 underwent smooth cross-
coupling in excellent yields (entries 14-17).
To further probe the scope and utility of the sulfamate cross-coupling
methodology, a synthesis of the anti-inflammatory drug flurbiprofen6 was
performed (Figure 2). Boronic acid 3, derived from ortho lithiation/
borylation of phenyl dimethylsulfamate,12 was fluorinated using the
conditions described by Furuya and Ritter13 to provide fluorosulfamate
4. Selective iodination of 4 para to the sulfamate furnished 5 in 64% yield.
Notably, both the fluoride and sulfamate of 5 were deemed unreactive
toward Pd(0). As the aryl iodide displayed orthogonal reactivity, we carried
out a site-selective enolate coupling to install the necessary propionate
side chain. Whereas enolate coupling of aryl iodide 5 under Buchwald’s
Pd-based conditions was feasible,14 higher yields of 6 were obtained using
a Ni-catalyzed variant.15 Although the sulfamate was not disturbed in this
process, exposure of 6 to our Ni-catalyzed Suzuki-Miyaura conditions
facilitated the key sulfamate cross-coupling. Acid-mediated hydrolysis
furnished flurbiprofen (1) in 84% yield over the two steps. It should be
emphasized that the aryl fluoride of 6 was chemically inert under our Ni-
catalyzed cross-coupling conditions.16
(8) Arenes that possess an -OC(O)R substituent are well-known to undergo
electrophilic aromatic substitution to predominantly afford para-substituted
products. See: Smith, M. B.; March, J. March’s AdVanced Organic
Chemistry, 6th ed.; Wiley: Hoboken, NJ, 2007; p 668.
(9) (a) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. J. Org.
Chem. 1992, 57, 4066. (b) Dallaire, C.; Kolber, I.; Gingras, M. Org. Synth.
2002, 78, 42. (c) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc.
2009, 131, 9590. (d) Wehn, P. M.; Du Bois, J. Org. Lett. 2005, 7, 4685.
(10) NiCl2(PCy3)2 is now commercially available from Strem Chemicals Inc.
(cat. no. 28-0091) and can be prepared in multigram quantities following
a simple one-step protocol. See: (a) Stone, P. J.; Dori, Z. Inorg. Chim.
Acta 1971, 5, 434. (b) Barnett, K. W. J. Chem. Educ. 1974, 51, 422.
(11) In the presence of excess arylboronic acid, NiCl2(PCy3)2 is thought to
undergo reduction to an active Ni(0) catalyst.
(12) See the Supporting Information for details.
(13) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860.
(14) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(15) Durandetti, M.; Gosmini, C.; Pe´richon, J. Tetrahedron 2007, 63, 1146.
(16) For Ni-catalyzed Kumada and Suzuki-Miyaura couplings of aryl fluorides,
see: (a) Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc. 2005,
127, 17978. (b) Dankwardt, J. W. J. Organomet. Chem. 2005, 690, 932.
(c) Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964.
In summary, we have discovered the first Suzuki-Miyaura
coupling reactions of aryl carbamates, carbonates, and sulfamates.
The method relies on the use of a readily available, air-stable Ni(II)
complex to facilitate the desired transformations. Furthermore, the
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