Synthesis and cross-coupling of sulfonamidomethyltrifluoroborates

Article abstract of DOI:10.1021/ol200202g

Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to acc

Full text of DOI:10.1021/ol200202g

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1694–1697
Synthesis and Cross-Coupling of
Sulfonamidomethyltrifluoroborates
ꢀ
Gary A. Molander,* Nicolas Fleury-Bregeot, and Marie-Aude Hiebel
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received January 22, 2011
ABSTRACT
Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing
the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to access such structurally interesting
motifs.
Sulfonamides represent a very large and important class
of drugs that can be used as antibacterials, diuretics,
anticonvulsants, and hypoglycemic, anticancer, and anti-
viral agents.1 Among them, arylsulfonamides are the most
studied, but arylmethylsulfonamides also constitute an
important class of compounds, showing potent activities
in several therapeutic areas.2 These compounds are com-
monly synthesized by reacting sulfonyl chlorides and
arylmethanamines.3 This method, which has proven to
be efficient, is nevertheless hampered by the handling and
storageofrequisitesulfonyl chlorideseachand every timea
new sulfonamidomethyl target is required.4 More recently,
reactions starting from sulfonic acids or sulfonate esters
have been reported.5 Other alternative synthetic methods
are reductive aminations of aldehydes with sulfonamides,6
reduction of N-sulfonylimines,7 or the reaction between amines
and alcohols.8 The latter is usually catalyzed by transition
metal complexes via homogeneous catalysis or more recently
via heterogeneous catalysis (Scheme 1, routes a and b).
Interestingly, the synthesis of sulfonamidomethyl com-
pounds based on a cross-coupling strategy between an aryl
(1) (a) Drews, J. Science 2000, 287, 1960. (b) Navia, M. A. Science
2000, 288, 2132. (c) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.;
Supuran, C. T. Curr. Med. Chem. 2003, 10, 925. (d) Banerjee, M.;
Poddar, A.; Mitra, G.; Surolia, A.; Owa, T.; Bhattacharyya, B.
J. Med. Chem. 2005, 48, 547. (e) Cole, D. C.; Lennox, W. J.; Lombardi,
S.; Ellingboe, J. W.; Bernotas, R. C.; Tawa, G. J.; Mazandarani, H.;
Smith, D. L.; Zhang, G.; Coupet, J.; Schechter, L. E. J. Med. Chem.
2005, 48, 353. (f) Koehler, N. K. U.; Yang, C.-Y.; Varady, J.; Lu, Y.; Wu,
X.; Liu, M.; Yin, D.; Bartels, M.; Xu, B.; Roller, P. P.; Long, Y.; Li, P.;
Kattah, M.; Cohn, M. L.; Moran, K.; Tilley, E.; Richert, J. R.; Wang, S.
J. Med. Chem. 2004, 47, 4989. (g) Natarajan, A.; Guo, Y.; Harbinski, F.;
Fan, Y.-H.; Chen, H.; Luus, L.; Diercks, J.; Aktas, H.; Chorev, M.;
Halperin, J. A. J. Med. Chem. 2004, 47, 4979.
(4) (a) Caddick, S.; Wilden, J. D.; Wadman, S. J.; Bush, H. D.; Judd,
D. B. Org. Lett. 2002, 4, 2549. (b) Caddick, S.; Hamza, D.; Wadman,
S. J.; Wilden, J. D. Org. Lett. 2002, 4, 1775.
(5) (a) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004,
126, 1024. (b) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron
Lett. 2007, 48, 2185. (c) De Luca, L.; Giacomelli, G. J. Org. Chem. 2008,
73, 3967.
(6) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(7) (a) Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. E. Org.
Lett. 2000, 2, 3921. (b) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan,
D. W. Angew. Chem., Int. Ed. 2007, 46, 8050.
(2) (a) Nirogi, R. V. S.; Daulatabad, A. V.; Parandhama, G.;
Mohammad, S.; Sastri, K. R.; Shinde, A. K.; Dubey, P. K. Bioorg.
Med. Chem. Lett. 2010, 20, 4440. (b) Holmes, C. P.; Li, X.; Pan, Y.; Xu,
C.; Bhandari, A.; Moody, C. M.; Miguel, J. A.; Ferla, S. W.; Nuria de
Francisco, M.; Frederick, B. T.; Zhou, S.; Macher, N.; Jang, L.; Irvine,
J. D.; Grove, J. R. Bioorg. Med. Chem. Lett. 2005, 15, 4336. (c) Shen, Y.;
Liu, J.; Estiu, G.; Isin, B.; Ahn, Y.-Y.; Lee, D.-S.; Kapatral, V.; Wiest,
O.; Oltvai, Z. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 1082. (d) Bladh,
(8) (a) Haniti, M.; Hamid, S. A.; Liana Allen, C.; Lamb, G. W.;
Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J.
J. Am. Chem. Soc. 2009, 131, 1766. (b) Da Costa, A. P.; Viciano, M.;
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H.; Henriksson, K.; Hulikal, V.; Lepisto, M. WO 2006/046914 A1. (e)
Miller, T.; Witter, D. J.; Belvedere, S. WO 2005/034880 A2. (f) Sun, D.;
Perkins, E. L.; Tugendreich, S. WO 03/043578 A2.
(3) Sulfur-Containing Reagents. In Handbook of Reagents for
Organic Synthesis; Paquette, L. A., Eds.; Wiley & Sons Ltd.: Chichester,
U.K., 2009.
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r
10.1021/ol200202g
Published on Web 03/02/2011
2011 American Chemical Society

Table 1. Preparation of Sulfonamidomethyltrifluoroborates
Scheme 1. Possible Disconnections To Access the Arylsulfona-
midomethyl Moiety
halide and a sulfonamidomethyl coupling partner has not
yet been reported. This new disconnection offers an inter-
esting and complementary alternative to existing synthetic
routes by allowing the rapid and convenient introduction
of a wide range of substituents and also allows enhanced
efficiency in the introduction of chemical diversity
(Scheme 1, route c).
The Suzuki-Miyaura reaction is one of the most effi-
cient and widely used C-C bond-forming reactions.9 Our
research group has been involved in the synthesis and use
of organotrifluoroborate salts as replacement coupling
partners for boronic acids, boronate esters, or organo-
boranes.10 Indeed, organotrifluoroborates offer numerous
beneficial features such as being air and moisture stable
salts that are easy to handle and to store. In addition, the
carbon-boron bond remains intact during various chemi-
cal transformations on ancillary functional groups. More-
over, they appear to be very efficient coupling partners in
Suzuki-Miyaura reactions, overcoming many of the
drawbacks encountered with other reagents.11
a Isolated yield. b 2a, Y = K. c 2b, Y = Cs.
in cross-coupling reactions.12 A synthetic route based on
direct nucleophilic substitution of the halide of potassium
halomethyltrifluoroborates proved to be efficient when
using mono- or dialkylamines but failed with amides. In
2010, Hiebel and Molander developed an alternative one-
pot procedure starting from halomethylboronate esters13
and successfully accessed and coupled carboxamidomethyl-
trifluoroborates with aryl- and heteroaryl chlorides.14
In this article we report the synthesis of sulfonamido-
methyl derivatives via a Suzuki-Miyaura cross-coupling
reaction between sulfonamidomethyltrifluoroborates and
aryl and heteroaryl chlorides.
Although the halomethyltrifluoroborate strategy also
failed for the synthesis of sulfonamidomethyltrifluorobo-
rates, even when preforming the anion of the sulfonamide,
the one-pot procedure starting from the chloromethyl
boronate ester 1 gave access to the desired products
2a-p (Table 1).
In continuation of a project based on the synthesis of
functionalized organotrifluoroborates using halomethyl-
trifluoroborates, diverse alkoxymethyl- and aminomethyltri-
fluoroborates have been successfully synthesized and used
(9) (a) Miyaura, N. Metal-Catalyzed Cross-Coupling Reactions;
De Meijere, A., Diederich, F., Eds.; Wiley-WCH: Weinheim, 2004; pp
41-123. (b) Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (c) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(10) (a) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009,
48, 9240. (b) Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug
Discovery Dev. 2009, 12, 811.
(11) (a) For reviews on organotrifluoroborate salts, see:
(a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
(b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (c) Stefani,
H. A.; Cella, R.; Adriano, S. Tetrahedron 2007, 63, 3623. (d) Darses, S.;
Genet, J.-P. Chem. Rev. 2008, 108, 288. For mechanistic details on the
advantages of trifluoroborates over other boron reagents in the Suzuki
reaction, see:(e) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.;
Lloyd-Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49,
5156.
Thus, various sulfonyl chlorides, bearing either electron-
donating or -withdrawing substituents, have been success-
fully used to afford the trifluoroborates with modest to
(12) (a) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031.
(b) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597.
(c) Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem.
2008, 73, 2052. (d) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10,
2135.
(13) For reviews on R-haloboronate esters see: (a) Matteson, D. S.
Chem. Rev. 1989, 89, 1535. (b) Matteson, D. S. Tetrahedron 1989, 45,
1859. (c) Matteson, D. S. Tetrahedron 1998, 54, 10555.
(14) Molander, G. A.; Hiebel, M.-A. Org. Lett. 2010, 12, 4876.
Org. Lett., Vol. 13, No. 7, 2011
1695

proved to be effective or lead to full conversion. This might
be explained by the very low solubility of the sulfonamido-
methyltrifluoroborates, which require protic solvents (e.g.,
using the best conditions for amidomethyltrifluoroborates, a
CPME/H2O or THF/H2O mixture led to 9 and 43% con-
version after 24 h, respectively).16 Extensive screening of
solvent, temperature, Pd source, and ligand led to the
following conditions: a 1/1 t-BuOH/H2O solvent mixture,
a temperature of 100 °C, Pd(MeCN)2Cl2 (2 mol %) as the
metal precursor, RuPhos (4 mol %) and Cs2CO3 (3 equiv),
which provided 3b in 78% isolated yield (Table 2, entry 2).
Further optimization showed that replacing the ligand and
the base by XPhos and NaOt-Bu, respectively, increased
the yield to 87%. However, those conditions proved to be
less general and only improved the yields in a few cases
(Table 2).
Table 2. Cross-Coupling of 2a with Aryl Chlorides
To investigate the method further, both electron-rich
(Table 2, entries 1-6) and electron-poor (Table 2, entries
7-12) aryl chlorides were examined. All of these substrates
were found to cross-couple, providing the sulfonamido-
methylated products with yield of 44-95%. A large array
of functional groups was tolerated, although the yields
tended to decrease with delicate substrates such as alde-
hydes or esters (Table 2, entries 10 and 12).
The effects of steric hindrance were tested with mono- or
di-ortho substituted electrophiles (Table 2, entries 3, 4, 5).
The standard conditions proved to be very efficient, as
shown by the good yield (78%) in the reaction of 2-chloro-
5-methoxy-1,3-dimethylbenzene, which is a difficult sub-
strate owing to the presence of two ortho substituents. Yet,
XPhos and NaOt-Bu did not provide full conversion, and
their use resulted in a 48% yield even after increasing the
catalyst loading (Table 2, entry 4). Hindered and electron-
rich 2-chloroanisole was used to perform the reaction on a
larger scale. On a 1 g scale, lowering the catalyst loading to
a Isolated yield. Reaction conditions: 1.0 equiv of aryl chloride, 1.2
equiv of trifluoroborate, 3 equiv of Cs2CO3, L/Pd = 2, t-BuOH/H2O:
1/1, 100 °C, overnight (14-18 h). b Reaction performed with the
cesium trifluoroborate 2b. c XPhos (4 mol %) and NaOt-Bu (3 equiv)
instead of RuPhos and Cs2CO3. d Reaction performed on a 3.13 mmol
scale using 1 mol % of Pd(MeCN)2Cl2, 2 mol % of RuPhos and a 1/1
ratio of trifluoroborate/electrophile. e 4 mol % of Pd(II) and 8 mol %
of ligand used.
Table 3. Cross-Coupling Reaction of 2a with Heteroaryl
Chlorides
good yields. The products are all solids that can be stored
without particular precautions for several weeks until used
in cross-coupling reactions. 2a has been recrystallized, and
an X-ray structure has been obtained (see Supporting
Information). The cesium analog (2b) of the potassium
trifluoroborate 2a has also been prepared by quench-
ing the boronate ester with a solution of cesium
hydrogen fluoride (CsHF2) as described by Matteson
et al.15 to determine whether the nature of the cation
has any influence during the cross-coupling reaction
(Table 1, entry 1).
Once synthesized, the sulfonamidomethyltrifluoroborates
were tested in Suzuki-Miyaura cross-couplings using aryl
chlorides as electrophiles. The conditions were optimized
using the mesitylsulfonamidomethyltrifluoroborate 2a and
4-chloroanisole. Surprisingly, none of the previously re-
ported reaction conditions for aminomethyltrifluoroborates
a Isolated yield. Reaction conditions: 1.0 equiv of aryl chloride, 1.2
equiv of trifluoroborate, 3 equiv of Cs2CO3, RuPhos/Pd = 2, t-BuOH/
H2O: 1/1, 100 °C, overnight (14-18 h). b Obtained using XPhos (4 mol
%) and NaOt-Bu (3 equiv).
(15) Matteson, D. S.; Malakial, D.; Pharazyn, P. S.; Kim, B. J.
Synlett 2006, 20, 3501.
(16) See Supporting Information for more details.
1696
Org. Lett., Vol. 13, No. 7, 2011

1 mol % of Pd and 2 mol % of ligand and using a 1/1 tri-
fluoroborate/electrophile ratio afforded the expected pro-
duct 3c with an excellent isolated yield of 91%, emphasizing
the robustness of the method (Table 2, entry 3). The cesium
organotrifluoroborate 2b was also successfully coupled
with 4-chloroanisole in a similar yield, showing that the
presence of both potassium and cesium ions had no effect on
the course of the reaction (Table 2, entry 2).
To expand the array of electrophiles, the potassium mesi-
tylsulfonamidomethyl trifluoroborate 2a was coupled with a
variety of heteroaromatic chlorides (Table 3). RuPhos and
cesium carbonate proved to be the most efficient ligand and
base, respectively, as they afforded the highest yields (Table 3,
entry 2). An array of these substrates was examined including
pyridine, thiophene, and furan derivatives. The resulting
sulfonamidomethylated heteroaromatics 4a-fwere obtained
with good to excellent yields from 62 to 92%, while 5-chloro-
2-furaldehyde coupled with a lower yield.
Table 5. Electrophile Compatibility
entry
X
yielda
95%
1
2
3
4
5
6
Cl
Br
61%
I
55%
OTf
OTs
OMs
95%
70%
33% (46%)b
53%c
a Isolated yield. Reaction conditions: 1.0 equiv of aryl chloride, 1.2
equiv of trifluoroborate, 3 equiv of base, L/Pd = 2, t-BuOH/H2O: 1/1,
100 °C, overnight (14-18 h). b Catalyst loading 5 mol %, ligand 10 mol %.
c K3PO4 used instead of Cs2CO3.
The scope of this method was further demonstrated by using
a variety of arylsulfonamidomethyl potassium trifluoroborates
as coupling substrates with 4-chloroanisole (Table 4). Both
electron-rich and electron-poor arylsulfonamidomethyl
trifluoroborates coupled using the previously defined
conditions with 24-77% yields.
We then proceeded to examine the electrophile compat-
ibility using trifluoroborate 2a (Table 5). The aryl iodide
and aryl bromide gave modest yields; various amounts of
reduced aryls were observed, suggesting that the transme-
talation might be the rate-limiting step. The aryl triflate
showed the same behavior as chlorides as it coupled with
excellent yield (Table 5, entry 4). Phenyl tosylate afforded a
good yield (70%), while the more difficult mesylate gave a
more limited result with a promising yield (53%) after
some modifications of the reaction conditions (Table 5,
entry 6).
Table 4. Variation of the Trifluoroborate Moiety
In conclusion, we have synthesized a variety of potas-
sium arylsulfonamidomethyl trifluoroborates and demon-
strated their suitability as coupling partners in Suzuki-
Miyaura cross-coupling reactions with both aryl and
heteroaryl chlorides. These trifluoroborates can be easily
prepared through a one-pot process from 2-(chloromethyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane, providing a new
means for efficiently accessing a large array of structurally
diverse and significant sulfonamidomethyl-containing
molecules.
Acknowledgment. This research was supported by a
National Priorities Research Program (NRP) grant from
the Qatar National Research Fund (Grant No. 08-035-1-
008) and the NIH (R01 GM-081376). Dr. Rakesh Kohli
(University of Pennsylvania) is acknowledged for obtain-
ing HRMS data. Dr. Patrick Caroll (University of
Pennsylvania) is gratefully acknowledged for performing
the X-ray analysis.
Supporting Information Available. Experimental pro-
cedures, spectral characterization and copies of 1H, 13C,
19F, and 11B NMR spectra for all compounds, and X-ray
crystallographic data for 2a. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Isolated yield. b Conversion measured by 1H NMR.
Org. Lett., Vol. 13, No. 7, 2011
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