overcomes previous failings in the preparation of aryl
sulfonamide boronic acids,7 namely protodeboronation
which was observed in the preparation of the correspond-
ing pyridine boronates.8 We also introduce Ir-catalyzed
borylation reactions (Scheme 6) which allows complemen-
tarity and enhancement of the Suzuki coupling chemistry
to that derived from the DoM-based coupling protocol.
The presented general methodology should be of value for
the construction of biaryl and heterobiaryl sulfonamides
forapplication, especially inthedesignanddevelopment of
medicinal chemistry programs centered on the sulfona-
mide functional group.3a,9
Scheme 2. Synthesis of ortho-Bpin Aryl Sulfonamides
Scheme 1. Synthesis of ortho-Bpin (Het)Aryl Sulfonamides and
One-Pot Process for Bi(Het)Aryl Sulfonamides
conditions followed by i-PrOBpin and MeOBpin quench
smoothly gave the corresponding ortho-Bpin derivatives
8a and 9a respectively in good yields, irrespective of the
borylating reagent. However, once established, i-PrOBpin
was usedowing toits lower cost. The reactionwas explored
in scope with variation of EWG and EDG substitution and
the results are summarized in Scheme 2. While good to
excellent yields were observed for sulfonamides without
ortho and meta substitution (8aÀc, 9aÀc, Scheme 2), steric
hindrance for the latter derivatives played a role in both
regioselectivity and yield (8d and 9dÀi), which could be
ameliorated by switching from i-PrOBpin to the MeOBpin
borylating reagent. For example, using i-PrOBpin the
reaction of 3-chloro-N,N-diethylbenzenesulfonamide 7f
afforded 32% of product 9f while the corresponding
MeOBpin afforded 9f in 83% yield. Similar observations
were made for 3-fluoro-N,N-diethylbenzenesulfonamide
7g (i-PrOBpin: 34% yield by GC/MS; MeOBpin: 78%
yield). In contrast to the expected synergistic effect of
two DMGs in a meta relationship favoring in between
metalation2 (9fÀh, Cl, F, and MeO DMGs), the CF3
group, a known weak DMG, led to alternate ring regiose-
lective borylation to afford products 8d and 9d.13
To initiate the study, we noted the lack of literature on
the preparation of aryl sulfonamide ortho-boronic acid
derivatives by DoMÀborylation protocols.10 To test the
standard procedures, sulfonamides 7b (R2 = H and R1 =
Et) and 7h (R1= Et, R2 = 3-OMe), when subjected to
metalation under n-BuLi/À78 °C/THF conditions fol-
lowed by borylation using B(OMe)3 and B(O-iPr)3 at
several temperatures, resulted in recovery of starting
material or, at best, formation of a low yield of product 9a
by 1H NMR analysis (see Supporting Information (SI) for
details, Table S1). On the assumption that protodeborona-
tion occurred on aqueous workup and with the knowledge
of CÀB compound stability,11 we decided to prepare directly
the Bpin derivatives using MeOBpin and i-PrOBpin.12
In the event, metalation of 6a (R2 = R1 = H)and 7a
(R2 =HandR1 = Et) under standard n-BuLi/À78 °C/THF
The metalationÀborylation of the secondary cumyl
aryl sulfonamide, already recognized as a well-behaved
DMG,6a was explored to provide, after facile post-DoM
TFA-mediated decumylation, primary sulfonamides for
further manipulation which has value in drug design.14
Thus, when compound 10a, prepared conveniently by
reaction of phenyl sulfonyl chlorides with cumylamine
(7) MacNeil S. L. Ph.D. Thesis, 2001, Queen's University, Canada.
(8) Alessi, M.; Larkin, A. L.; Olgivie, K. A.; Green, L. A.; Lai, S.;
Lopez, S.; Snieckus, V. J. Org. Chem. 2007, 72, 1588.
(9) Sulfonamides are generally recalcitrant groups: (a) Shohji, N.;
Kawaji, T.; Okamoto, S. Org. Lett. 2011, 13, 2626. For their CorriuÀ
Kumada cross-coupling excision, see: (b) Milburn, R. R.; Snieckus, V.
Angew. Chem., Int. Ed. 2004, 43, 888. (c) Milburn, R. R.; Snieckus, V.
Angew. Chem., Int. Ed. 2004, 43, 892.
(10) For secondary sulfonamides: (a) Wu, X.; Wan, Y.; Mahalingam,
ꢀ
A. K.; Murugaiah, A. M. S.; Plouffe, B.; Botros, M.; Karlen, A.;
Hallberg, M.; Gallo-Payet, N.; Alterman, M. J. Med. Chem. 2006, 49,
7160. (b) Jia, Z. J.; Wu, Y.; Huang, W.; Goldman, E.; Zhang, P.;
Woolfrey, J.; Wong, P.; Huang, B.; Sinha, U.; Park, G.; Reed, A.;
Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2002, 12,
1651. (c) Su, T.; Wu, Y.; Doughan, B.; Jia, Z. J.; Woolfrey, J.; Huang, B.;
Wong, P.; Park, G.; Sinha, U.; Scarborough, R. M.; Zhu, B.-Y. Bioorg.
Med. Chem. Lett. 2001, 11, 2947. (d) Quan, M. L.; Liauw, A. Y.; Ellis,
C. D.; Pruitt, J. R.; Carini, D. J.; Bostrom, L. L.; Huang, P. P.; Harrison,
K.; Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R. R. J. Med.
Chem. 1999, 42, 2752. (e) For tertiary sulfonamides: Polniaszek, R. P.;
Wang, X.; Thottathil, J.; Denzel, T. Appl. Int. WO 2002/032884, 2002;
Chem. Abstr. 2002, 136, 325535. For other methods, see: (f) Ipso-
borodesilylation: Zhao, Z.; Snieckus, V. Org. Lett. 2005, 7, 2523. (g)
Pd-catalyzed B2pin2 borylation: Cheung, W. S.; Parks, D. J.; Parsons,
W. H.; Patel, S. Player, M. R. Appl. Int. WO 2008/076752, 2008; Chem.
Abstr. 2007, 149, 79605.
(11) (a) Hall, D. G., Ed. Boronic Acids; Wiley-VCH: Weinheim, 2005,
p 14.
(12) For previous syntheses, see: Lin, Q.; Meloni, D.; Pan, Y.; Xia,
M.; Rodgers, J.; Shepard, S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.-Y.;
Liu, P.; Zhou, J. Org. Lett. 2009, 11, 1999. (b) de Meijere, A.; Khlebnikov,
A. F.; Suennemann, H. W.; Frank, D.; Rauch, K.; Yufit, D. S. Eur. J. Org.
Chem. 2010, 17, 3295. Baron, O.; Knochel, P. Angew. Chem., Int. Ed. 2005,
44, 3133.
(13) See also: (a) Macdonald, J. E.; Poindexter, G. S. Tetrahedron
Lett. 1987, 28, 1851. (b) Lulinski, S.; Serwatowski, J. J. Org. Chem. 2003,
68, 9384.
(14) (a) Chen, X.; Zhu, C.-J.; Guo, F.; Qiu, X.-W.; Yang, Y.-C.;
Zhang, S.-Z.; He, M.-L.; Parveen, S.; Jing, C.-J.; Li, Y.; Ma, B. J. Med.
Chem. 2010, 53, 8330. (b) Dragovich, P.; Zhou, Y.; Webber, S. E. U.S.
Patent US 2007/861678; Chem. Abstr. 2008, 149, 246568.
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