Facile synthesis of acyl sulfonamides from carboxyic acids using the Mukaiyama reagent

Article abstract of DOI:10.1016/j.tetlet.2018.12.030

A fast and convenient method using the Mukaiyama reagent was developed to prepare acyl sulfonamides from carboxylic acids and sulfonamides. This methodology is effective for a range of acids and sulfonamides proceeding in moderate to good yields with the

Full text of DOI:10.1016/j.tetlet.2018.12.030

Accepted Manuscript
Facile Synthesis of Acyl Sulfonamides from Carboxyic Acids using the Mu-
kaiyama Reagent
Ling Chen, Guanglin Luo
PII:
S0040-4039(18)31471-0
https://doi.org/10.1016/j.tetlet.2018.12.030
TETL 50493
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 October 2018
7 December 2018
13 December 2018
Please cite this article as: Chen, L., Luo, G., Facile Synthesis of Acyl Sulfonamides from Carboxyic Acids using
the Mukaiyama Reagent, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.030
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Facile Synthesis of Acyl Sulfonamides from
Carboxylic Acids using the Mukaiyama
Reagent
Leave this area blank for abstract info.
Ling Chen* and Guanglin Luo
O
N+
Cl
O
O
I-
O
O
O
S
R1
N
R2
+
S
H2N
R2
H
R1
OH
DMAP/TEA
CH2Cl2
R1,R2: Aryl, Heteroaryl, Alkyl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Facile Synthesis of Acyl Sulfonamides from Carboxyic Acids using the Mukaiyama
Reagent
Ling Chen and Guanglin Luo
Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A fast and convenient method using the Mukaiyama reagent was developed to prepare acyl
sulfonamides from carboxylic acids and sulfonamides. This methodology is effective for a range
of acids and sulfonamides proceeding in moderate to good yields with the majority of reactions
complete within one hour under the optimized condition.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Acyl sulfonamides
Mukaiyama reagent
Carboxylic acids coupling
Coupling with sulfonamides
Acylsulfonamides synthesis
———
 Corresponding author. Tel.: +01-609-252-7582; e-mail: ling.chen1@bms.com

1
Acyl sulfonamide is an increasingly utilized motif that has been
explored in many therapeutic areas of medicinal chemistry in
recent years.1 There are commonly known syntheses of acyl
sulfonamides that include reacting acid chlorides/acid anhydrides
with sulfonamides, the use of coupling reagents such as EDC∙HCl,
benzotriazole, and CDI to activate acids that react with
sulfonamides in one pot.2 However, the coupling step can be slow,
often requiring an overnight reaction. Additionally, conversion
from an acid to an acid chloride adds an extra step, and can be
challenging if the acid substrates contain a basic amine or an acid-
sensitive moiety. Another approach to the preparation of acyl
sulfonamides is to employ transition metal-catalyzed
carbonylation chemistry. Under microwave irradiation, various
aryl and heteroaryl iodides/bromides can be carbonylated by CO
released from Mo(CO)6, followed by reaction of the intermediate
with sulfonamides to afford the acyl sulfonamides in moderate to
good yields.3 Recently, the scope of acyl sulfonamide synthesis
was expanded by reacting carboxylic acids with sulfonyl azides
catalyzed by Co2(CO)6.4 However, many sulfonyl azides are not
readily available. During our research, we required an efficient
method to prepare different types of acyl sulfonamides. Because
of the abundance of commercially-available carboxylic acids and
sulfonamides, we focused on further improving the
acid/sulfonamide coupling strategy for the synthesis of acyl
sulfonamides. More specifically, we were interested in employing
the Mukaiyama reagent (2-chloro-1-methylpyridinium iodide,
CMPI) since it has been widely used to activate carboxylic acids
to construct lactams, macrolactones and other moieties but, to the
best of our knowledge, has not been used in the synthesis of acyl
sulfonamides.5 Herein, we report that CMPI is a very good
coupling reagent that generally gives improved reaction yields and
times, relative to some of the previously described methods, for
the formation of acyl sulfonamides from various acids and
sulfonamides in one pot.
Benzoic acid (1a) and methanesulfonamide (1b) were used for
the model studies, as shown in Scheme 1. The initial reaction
conditions used a 2:1 ratio of methanesulfonamide and benzoic
acid with DMAP as a catalyst in CH2Cl2 (0.3 M). The suspension
was stirred for 5 minutes, 2 equivalents of Et3N were added to the
reaction mixture and stirring continued at room temperature.
Some heat generation was observed6 and the suspension became
clear, with precipitates appearing later. The reaction was worked
up after 1 hour to give a 72% HPLC yield7 of 3a (Entry 1).
Allowing the reaction to stir overnight improved the yield only
marginally to 79%. Next, the effect of different solvents on the
reaction was examined. In THF, after 1 h the reaction proceeded
to ~41% conversion to the desired product while after 16 h, ~ 62%
of the desired product had formed with 18% of the benzoic acid
remaining, as determined by HPLC (Entry 2). The use of
acetonitrile, a more polar solvent than THF, gave ~65% product
with 6% benzoic acid remaining after 1 h (Entry 3). DMF behaved
similarly to acetonitrile; however, more of the starting benzoic
acid (~13%) remained after 1 h (Entry 4). From these screening
results, CH2Cl2 appeared to be the best non-polar solvent while
acetonitrile was the best polar solvent for conducting the coupling
reaction. Since the reaction profile in CH2Cl2 was much cleaner
than that of acetonitrile, CH2Cl2 was chosen as the standard
solvent. By increasing the amount of Et3N from 2 to 3 equivalents,
the HPLC yield of the reaction was significantly improved to 98%
in 1 hour, with a purified yield of 77% (Entry 5).8 Because of the
acidic nature of the acyl sulfonamide product, an equivalent of
Et3N may be consumed by forming a salt; thus, increasing the
equivalents of the base should help to promote the overall reaction.
Next the ratio of methanesulfonamide and benzoic acid was
adjusted to allow for cases where the sulfonamide is expensive and
would need to be the limiting reagent. Using a 1:1 ratio of
methanesulfonamide and benzoic acid gave a yield of 58% by
HPLC after 1 hour. Allowing the reaction mixture to stir for 16
hours afforded a 67% purified yield of the desired product (Entry
6).
Scheme 1. Method development
N+
Cl
O
O
I-
O
O
O
O
S
+
OH
S
N
H
NH2
DMAP/Et3N
solvent
1a
2a
3a
Entry
2/1
Solvent
Yield of 3 (%)
1 h (16 h)
TEA ( eq)
Ratioa
1
2
2
2
CH2Cl2
THF
72b (79b)
41b (62b)
2
2
3
4
5
6
2
2
2
1
CH3CN
DMF
65b (78b)
57b (73b)
98b, (77c)
58b , (67c)
2
2
3
3
CH2Cl2
CH2Cl2
a 1.2 eq of CMPI, 0.05 eq DMAP, concentration: 0.3 M, rt; bHPLC yield; cPurified yield.

2
Tetrahedron
Table 1. Carboxylic acid scope
O
O
conditions
O
O
O
O
+
S
S
R1
N
R1
OH
NH2
H
1b - k
3b - k
2a
Yield
(%)a
Yield
(%)a
Entry
1
R1
Entry
8
R1
81
72
Cl
N
3b
3i
3j
N
2
3
82
9
78
Cl
3c
N
Cl
73
89
10
58b
Cl
3d
Cl
3k
O
4
5
11
12
75
O
3e
3l
O
91
71
3f
3m
O
6
7
78
78
13
14
77c
36c
CF3
3g
3h
3n
O
O2N
3o
Conditions: 1.2 eq CMPI reagent, 0.05 eq DMAP, 2.0 eq of sulfonamide, 3.0 eq of TEA, CH2Cl2 (0.3 M), rt.
a Purified yield, 1 h reaction time; bPurified by Prep HPLC.
cUsed benzenesulfonamide instead
With optimized reaction conditions in hand, the scope of the
carboxylic acid was explored (1b-k) using methanesulfonamide as
the partner 2a (Table 1). In general, this method was well tolerated
for both electron-donating and electron-withdrawing groups on the
benzoic acids (Entries 1-7). The reactions were often complete
within 15 to 30 minutes; however, these procedures were carried
out for 1 hour in the screening mode. Fused bicyclic carboxylic
acids such as quinoline-3-carboxylic acid (Entry 8) and 1-methyl-
indole-2-carboxylic acid (Entry 9) also participated effectively,
with 72% and 78% purified yield of the desired products
respectively, obtained after 1 hour. The indole analog 3k (Entry
10) was purified by preparative HPLC and isolated in 58% yield.
The primary and secondary aliphatic carboxylic acids (3l, 3m, 3n)

3
In order to investigate the reaction kinetics, an experiment was
worked well with this method, while the tertiary carboxylic acid
carried out in absence of the acid coupling partner. In this
experiment it was shown that the CMPI reagent reacted with
sulfonamide 6 over 1 hour to form 7 with 77% conversion (Scheme
3). Subsequent addition of acid 5 to the reaction mixture did not
result in the formation of the acyl sulfonamide product, suggestive
(3o) afforded lower but acceptable yield (36%).
The scope of the sulfonamides (2b –f) with benzoic acid 1a was
explored next (Table 2). Simple aliphatic sulfonamides (Entry 1,
2) behaved similarly as methanesulfonamide with good isolated
yields. Gratifyingly, aromatic sulfonamides (Entry 3 - 5) also
coupled well to give good yields of the desired products.
of a competitive reaction between the acid and the sulfonamide
11
with CMPI.
Interestingly, the carboxylic acids are activated
significantly faster by the CMPI reagent than are the sulfonamides,
which presumably allows for good conversion to the acyl
sulfonamide product with little to no pyridin-2(1H)-
ylidene)methanesulfonamide-derived side products.
Table 2. Sulfonamide scope
O
O
O
O
conditions
O
O
S
OH
N
R2
+
S
H2N
2b - f
R2
H
Scheme 3. Reaction of sulfonamide 6 with the Mukaiyama
reagent
1a
4b - f
O
O
N
O
a
O
S
S
+
N+
Cl
Yield
Yield
(%)a
Entry
R2
Entry
4
R2
S
S
N
NH2
I-
Br
(%)a
Br
6
7
a: 1.0 mmol CMPI, 1.7 mmol of 6, 0.04 mmol DMAP, 2.5 mmol of TEA,
DCM (0.3 M), rt.
1
83
84
87
4b
Cl
In conclusion, we have described the development of a quick
and efficient preparative procedure to access acyl sulfonamide
derivatives from carboxylic acids using the CMPI reagent. An
excess of sulfonamide (2.0 eq) can be used to drive the reaction to
completion within 1 hour of stirring at room temperature in most
cases. When the sulfonamide is the limiting reagent, a 1:1 ratio of
carboxylic acid to sulfonamide can be used in conjunction with a
longer reaction time to obtain satisfactory yields. This method is
also amenable to large scale synthesis. We were able to routinely
utilize this facile synthesis of acyl sulfonamides in a drug
discovery program focused on the preparation of Nav1.7 inhibitors
that allowed an expedient expansion the SARs in a series of
analogs.12
4e
2
3
89
83
5
Cl
4c
4d
4f
aIsolated yield, 1 h.
To demonstrate the utility of this method, LY573636, an
antitumor agent that possesses an acyl sulfonamide moiety, was
prepared by this method (Scheme 2). LY573636 was obtained in
65% yield (0.6 mmol scale) using the standard reaction
conditions.9 When conducted on a 6 mmol scale, LY573636 was
obtained 76% yield after 1 hour of stirring. Interestingly, 7 was
isolated as a by-product in 15% yield, believed to have arisen from
the CMPI reagent reacting with the sulfonamide (Scheme 3). In
the small scale screening reactions only a few of the couplings
showed a small amount of the corresponding sulfonamide
adduct.10
Acknowledgments
We gratefully acknowledge Drs. Carolyn Dzierba and Nicholas Meanwell for
careful reading of this manuscript and Robert Langish, Linping Wang for
HRMS analysis .
References and Notes
1.
(a) Bowsher, M.; Hiebert, S.; Li, R.; Wang, A. X.; Friborg, J.; Yu,
F.; Hernandez, D.; Wang, Y-K.; Klei, H; Rajamani, R.; Mosure, K;
Knipe, J. O.; Meanwell, N. A.; McPhee, F.; Scola, P. M. Bioorg.
Med. Chem. Lett. 2018, 28, 43. (b) Sun, L.Q.; Mull, E.; Zheng, B.;
D'Andrea, S.; Zhao, Q.; Wang, A. X.; Sin, N.; Venables, B. L.; Sit,
S-Y.; Chen, Y.; Chen, J.; Cocuzza, A.; Bilder, D. M.; Mathur, A.;
Rampulla, R.; Chen, B.C.; Palani, T.; Ganesan, S.; Arunachalam,
P.N.; Falk, P.; Levine, S.; Chen, C.; Friborg, J.; Yu, F.; Hernandez,
D.; Sheaffer, A.K.; Knipe, J.O.; Han, Y. H.; Schartman, R.; Donoso,
M.; Mosure, K.; Sinz, M. W.; Zvyaga, T.; Rajamani, R.; Kish, K.;
Tredup, J.; Klei, H. E.; Gao, Q.; Ng, A.; Mueller, L.; Grasela, D.
M.; Adams, S.; Loy, J.; Levesque, P. C.; Sun, H.; Shi, H.; Sun, L.;
Warner, W.; Li, D.; Zhu, J.; Wang, Y. K.; Fang, H.; Cockett, M. I.;
Meanwell, N. A.; McPhee, F.; Scola, P. M. J. Med. Chem. 2016, 59,
8042; (c) Ammazzalorso, A.; De Filippis, B.; Giampietro, L.;
Amoroso, R.; Chem. Biol. Drug Des. 2017, 90, 1094; (d) DiMauro,
E. F.; Altmann, S.; Berry, L. M,.; Bregman, H.; Chakka, N.; Chu-
Moyer, M.; Bojic, E. F.; Foti, R. S.; Fremeau, R.; Gao, H.;
Gunaydin, H.; Guzman-Perez, A.; Hall, B. E.; Huang, H.; Jarosh,
M.; Kornecook, T.; Lee, J.; Ligutti, J.; Liu, D.; Moyer, B. D.;
Ortuno, D.; Rose, P. E.; Schenkel, L. B.; Taborn, K.; Wang, J.;
Wang, Y.; Yu, V.; Weiss, M. M. J. Med. Chem. 2016, 59, 7818.
Scheme 2. Synthesis of LY573636
Cl
O
O
Cl
O
O
O
a
S
O
N
+
OH
S
H
S
S
NH2
Br
Cl
Cl
Br
5
6
LY573636
O
O
N
S
S
N
Br
7
a: 1.2 eq CMPI, 0.05 eq DMAP, 3.0 eq of TEA, CH2Cl2 (0.3 M), rt.

4
Tetrahedron
2. (a) Yates, M. H.; Kallman, N. J.; Ley, C. P.; Wei, N. Org. Proc.
HCl (1 mL), water, and brine. The ethyl acetate layer was separated,
dried (Na2SO4), filtered and concentrated. The crude material was
purified by silica gel flash column chromatography eluting with
ethyl acetate in hexane from 0 to 30% to give the desired product
(0.168 g, 65%) as colorless crystals: 1H NMR (499 MHz, CDCl3) δ
7.73 (d, J = 4.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.9
Hz, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.14 (d, J = 4.1 Hz, 1H).
10. For example, in Entry 1 of Table 2 we found the corresponding side
product (~5% by LCMS) mixed in with the desired product after
purification by flash silica gel chromatography.
Res. Dev. 2009, 13, 256. (b) Katritzky, A. R.; Hoffmann, S.; Suzuki,
K. ArkiVoc 2004, xii, 14; (c) Drummond, J. T.; Johnson, G. Tet.
Lett. 1988, 29, 1653. (d) Fu, S.; Lian, X.; Ma, T.; Chen, W.; Zheng,
M.; Zeng. W. Tet. Lett. 2010, 51, 5834.
Wu, X.; Rönn, R.; Gossas, T.; Larhed, M. J. Org. Chem. 2005, 70,
3094.
Fang, Y.; Gu, Z-Y.; Y, J-M.; Ji, S-J. J. Org. Chem. 2018, 83, 9364.
(a) Mukaiyama, T. Angew. Chem., Int. Ed,, Eng. 1979, 18, 707; (b)
Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 13,
1465; (c) Novosjolova, I. Synlett, 2013, 24, 0135.
The observed temperature increase when addition of TEA to the
reaction mixture was probably due to the heat generation of
combination of TEA reacting with acid and acid activation with
CMPI together. The reaction of the activated acid with sulfonamide
seems did not contribute to the heat generation. More details can be
found in the supporting information..
3.
4.
5.
11. 5 was 0.85 mmol so in the end the ratio of this reaction condition
was the optimal condition.
6.
12. (a) Luo, G.; Chen, L.; Easton, A.; Newton, A.; Bourin, C.; Shields,
E.; Mosure, K.; Soars, M.; Knox, R.; Matchett, M.; Pieschl, R.;
Post-Munson, D.; Wang, S.;. Herrington, J.; Graef, J.; Newberry,
K.; Sivarao, D.; Senapati, A.; Bristow, L.; Meanwell, N.A.;
Thompson, L.; Dzierba, C. Manuscript submitted. (b) Wu, Y-J.;
Venables, B.; Guernon, J.; Chen, J.; Sit, S.; Rajamani, R.; Knox, R.;
Matchett, M.; Pieschl, R.; Herrington, J.; Bristow, L.; Meanwell,
N.; Thompson, L.; Dzierba, C. Manuscript submitted.
7.
8.
9.
HPLC yield was roughly estimated with the integration of benzoic
acid, the product and the possible activated acid intermediate. More
details can be found in the supporting information.
LCMS showed that the aqueous layer contained some of the
product. The yield could be higher if multiple back extractions of
the aqueous layer with ethyl acetate were to be performed.
Procedure: DCM (2.0 mL) was added to a 20 mL vial containing
DMAP (3.81 mg, 0.031 mmol), 2-chloro-1-methylpyridin-1-ium
iodide (0.191 g, 0.748 mmol), 2,4-dichlorobenzoic acid (0.119 g,
0.623 mmol), 5-bromothiophene-2-sulfonamide (0.302 g, 1.25
mmol) at rt. After stirring for 5 min, TEA (0.261 ml, 1.869 mmol)
was slowly added to the reaction mixture. The reaction was stirred
at rt for 1 h. The reaction solvent was concentrated under vacuum
and the crude residue was taken up in ethyl acetate, washed with 1N
Supplementary Material
1H NMR and LCMS of compounds in Method Development,
Table 1, Table 2, and Scheme 2.
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Graphical Abstract
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template box below.
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Facile Synthesis of Acyl Sulfonamides from
Carboxylic Acids using the Mukaiyama
Reagent
Leave this area blank for abstract info.
Ling Chen* and Guanglin Luo
O
N+
Cl
O
O
I-
O
O
O
S
R1
N
R2
+
S
H2N
R2
H
R1
OH
DMAP/TEA
CH2Cl2
R1,R2: Aryl, Heteroaryl, Alkyl

Acylsulfonamides were synthesized within 1
hour using Mukaiyama
reagent(CMPI)/DMAP/TEA method at optimal
condition.



Method was efficient with broad scope of
aryl/heteroaryl and alphatic caboxylic acids.
Method tolerated various aliphatic, aryl and
heteroaryl sulfonamides.
Method was simple to operate at room
temperature under atmosphere condition.