TiCl4-promoted direct N-acylation of sulfonamide with carboxylic ester

Article abstract of DOI:10.1016/j.tetlet.2010.08.092

Several Lewis acids were investigated as promoters in the intermolecular or intramolecular direct N-acylation reaction of sulfonamides using carboxylic ester as an acylating agent. TiCl₄ was found to possess the highest activity and enhanced efficiently sulfonamide to form N-acylsulfonamides under optimized conditions. This method provides a novel approach to make N-acylsulfonamides from ester via an easy work-up procedure.

Full text of DOI:10.1016/j.tetlet.2010.08.092

Tetrahedron Letters 51 (2010) 5834–5837
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
TiCl4-promoted direct N-acylation of sulfonamide with carboxylic ester
Shaomin Fu a, Xiaoyan Lian a, Tongmei Ma a, Wenhua Chen b, Meifang Zheng a, Wei Zeng a,
⇑
a School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510640, PR China
b School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2010
Revised 20 August 2010
Accepted 31 August 2010
Available online 6 September 2010
Several Lewis acids were investigated as promoters in the intermolecular or intramolecular direct N-acyl-
ation reaction of sulfonamides using carboxylic ester as an acylating agent. TiCl4 was found to possess the
highest activity and enhanced efficiently sulfonamide to form N-acylsulfonamides under optimized
conditions. This method provides a novel approach to make N-acylsulfonamides from ester via an easy
work-up procedure.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Acylation
Lewis acid
N-Acylsulfonamide
Carboxylic ester
Acylating agents
Many bioactive natural products and medical molecules consist
of N-acylsulfonamide (NAS) structural motifs. For instance, several
recently developed drugs, including an inhibitor of human aspara-
gine synthetase,1 a therapeutic agent for Alzheimer’s disease,2 and
a hepatitis C virus NS3 protease inhibitor3 are all derived from NAS
precursors. In addition to being used as carboxylic acid bioisostere
because of suitable acidity (pKa = 4–5),4 NAS functional group is
also incorporated in organocatalysts and plays an important coop-
erative catalytic role in certain enantioselective asymmetric reac-
tions.5 Moreover, the family of acylsulfonamides was also
employed as a ‘‘safety-catch” linker for efficient chemical protein
synthesis in solid-phase reaction.1,6
Generally, N-acylsulfonamide derivatives are prepared via
direct condensation of a carboxylic acid with a sulfonamide using
carbodiimides (EDCꢀHCl or DCC) or N,N0-carbonyldiimidazole
(CDI) as coupling agents.7 Of course, more reactive carboxylic
anhydrides and acid chlorides are also used in the presence of a
base or an acid.8 An alternative synthetic approach starting from
sulfonyl chloride and carboxylic amides in basic reaction condition
can afford N-acylsulfonamide product.9 Recently, sulfonyl isocya-
nate or N-acylbenzotriazoles were used as acylating agents under
basic conditions.10 Moreover, the preparation of acylsulfonamide
from aryl halide and sulfonamide catalyzed by Pd (II) and Mo(CO)6
under microwave irradiation was also reported.11 Recently Chan
found Rh (II) could catalyze intermolecular oxidative sulfamidation
of aldehyde to form N-sulfonylcarboxamide by using PhI(OCOtBu)2
as an oxidant.12 Although most of the methods provide various
approaches to make N-acylsulfonamide starting from parent sul-
fonamide and acylating agents such as acyl chlorides or anhydrides
or carboxylic acid, no studies have reported the direct N-acylation
Table 1
Catalyst screening for N-acylation from p-toluene sulfonamine and ethyl acetatea
Me
SO2NH
2 + CH3COOC2H5
2a
1a
Lewis acid (1.5 equiv.)
Toluene, 110 oC, 12 h
Me
SO2NHCOCH3
3a
Entry
Catalyst
Yieldb (%)
1
2
3
AlCl3
FeCl3
TiCl4
No reaction
<5
53
4
5
6
7
8
9
10
11
12
13
Cu(OAc)2ꢀH2O
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
Fe2O3
MgO
FeCl2ꢀ4H2O
ZrCl4
MnCl2ꢀ4H2O
ZnCl2
CuCl
CdCl2ꢀ2.5H2O
NiCl2ꢀ6H2O
a
Reaction conditions: p-toluene sulfonamide (2 mmol), ethylacetate (4 mmol),
Lewis acid (1.5 equiv), toluene, (4.5 mL), the reaction was carried out at 110 °C for
12 h in sealed tube.
⇑
Corresponding author. Tel.: +86 020 13570415118; fax: +86 020 22236337.
E-mail address: zengwei@scut.edu.cn (W. Zeng).
b
Isolated yield after purification.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.092

S. Fu et al. / Tetrahedron Letters 51 (2010) 5834–5837
5835
Table 2
of sulfonamides with unreactive carboxylic ester. Accordingly, we
present here an alternative preparation method for N-acylsulfona-
mide by using carboxylic ester as acylating agents in the presence
of Lewis acid catalyst.
The effect of solvent, reaction time, and temperature on the TiCl4-catalyzed
N-acylation of p-toluene sulfonamide (1a) with ethyl acetate (2a)a
Entry
Reaction time (h)
Temp (°C)
Solvent
Yieldb (%)
Optimal conditions for this transformation were first deter-
mined by systematically investigating the Lewis acid catalysts,
reaction solvents, reaction time, reaction temperature, and the
catalyst/substrate ratio. Initially, the N-acylation reaction of the
readily available p-toluene sulfonamide 1a (2 mmol) with ethyl
acetate 2a (4 mmol) was carried out in toluene by using various
kinds of Lewis acid promoters (1.5 equiv, 3 mmol) such as AlCl3,
FeCl3, TiCl4, ZrCl4, MgO, etc., at 110 °C for 12 h in a sealed tube
(Table 1). Gratifyingly, we quickly found TiCl4 was an only pro-
moter for the N-acylation of sulfonamide with ethyl acetate in
53% yield (Table 1, entry 3), and basically other Lewis acids didn’t
work. Notably, no product was observed when the reaction was
carried out in the absence of TiCl4 even after 48 h. Inspired by these
positive results, we further investigated other reaction conditions
to define the reaction parameters (Table 2). To find the best sol-
vent, the N-acylation of p-toluene sulfonamide (1a) with ethyl ace-
tate (2a) was carried out for 12 h in different solvents such as
CH3CN, CCl4, ClCH2CH2Cl, Cl2CHCHCl2, toluene, dioxane, etc. We
1
2
3
4
5
6
7
8
9
12
12
12
12
18
24
18
18
18
18
18
18
70
110
110
110
115
115
90
100
120
140
115
115
CHCl3
Toluene
DCEe
TCEf
TCE
TCE
TCE
TCE
TCE
34
53
60
64
76
65
Trace
62
69
10
11
12
TCE
TCE
TCE
Decomp.
53c
72d
a
Reaction conditions: p-toluene sulfonamide (2 mmol), ethyl acetate (4 mmol),
Lewis acid (1.5 equiv), solvent (4.5 mL), the reaction was carried out at the given
temperature in a sealed tube.
b
Isolated yield after purification.
1.0 equiv of TiCl4 used.
2.0 equiv of TiCl4 used.
DCE: 1,2-dichloroethane.
c
d
e
f
TCE: 1,1,2,2-tetrachloroethane.
Table 3
TiCl4-catalyzed N-acylation of sulfonamines with carboxylic ester15
O
O
O O
TiCl4 (1.5 equiv.) / TCE
R3
R1 SO2NH2
S
R1
NH
R2
R2
O
+
115 ~ 160 oC
45~ 97% yield
1
2
3
Entry
1
Sulfonamide
Carboxylic ester
Time (h)
Product16
Yielda (%)
76
O
S
O
S
O
H
Me
NH2
1a
Me
N C Me
3a
O
CH3CO2Et 2a
18
30
55
48
36
24
24
24
24
24
O
O
O
O
H
Cl
S
O
O
S
NH
Cl
Br
S
O
O
S
N C Me
2
3
CH3CO2Et 2a
CH3CO2Et 2a
CH3CO2Et 2a
CH3CO2Et 2a
CH3CO2Et 2a
CH3CO2Et 2b
CH3CO2tBu 2c
CH3CO2 tBu 2d
81
2
1b
3b
O
H
Br
NH2
1c
N C Me
77
3c
O
O
O
O
O
H
O2N
MeO
S
O
O
S
NH2
1d
O N
2
S
O
O
S
N C Me
3d
4
48
O
H
5
30 (54b)
70
NH2
1e
MeO
H
N
Me
C
O
O
3e
O
O
S
O
H
NH
S
N C Me
6
2
1f
3f
O
O
O
O
S
O
H
Me
Me
Me
Me
NH2
1a
Me
Me
Me
Me
S
O
O
S
N C Me
3a
7
69
O
O
S
O
H
NH2
1a
N C Me
3a
8
56
O
O
S
O
O
S
O
H
NH2
1a
N C Me
3a
9
72
O
O
S
O
O
S
Me
O
C
Me
Me
H
N
CHCO2Et
2e
51c
NH2
1a
10
Me
O
O
3g
(continued on next page)

5836
S. Fu et al. / Tetrahedron Letters 51 (2010) 5834–5837
Table 3 (continued)
Entry
Sulfonamide
Carboxylic ester
Time (h)
24
Product16
Yielda (%)
97d
O
S
O
S
O
C
3h
H
CO2Et
2f
Me
N
Me
NH2
1a
11
12
13
14
O
O
O
S
O
S
O
H
N
3i
Me
Cl
CO2Et
2g
Me
Me
Me
Cl
C
24
24
24
55d
46d
45d
Me
Me
Me
NH2
1a
O
O
O
S
O
O
H
CO2Et
2h
S
N C
NH2
1a
3j
O
O
O
S
O
O
H
CO2Et
Me
S
N C
3k
NH2
1a
2i
N
N
O
O
O
S
O
SO2NH2
NH
C
O
15
16
—
48
82
1g
CO2Et
3l
O
S
O
H
CO2Et
2f
24
24
94d
63
Me
N C
CH3SO2NH2 1h
3m
O
O
S
O
H
N
3n
Me
NH
C Me
17
CH3CO2Et 2a
O
1i
a
Isolated yields, average of two runs.
1.5 equiv N(C2H5)3 was added, 30% sulfonamine remains unreacted.
3 equiv ethyl isobutyrate was added.
b
c
d
The reaction was carried out at 160 °C.
found the non-polar solvent Cl2CHCHCl2 was superior to CHCl3,
ClCH2CH2Cl, and toluene (Table 2, entries 1–4, see Supplementary
data for complete details). Based on this results, and we further
investigated the effect of the amount of catalysts, reaction temper-
ature, and reaction time on the transformation. After an extended
reaction time (from 12 to 18 h), treatment of p-toluene sulfon-
amide and ester in tetrachloroethane at elevated temperature
(115 °C) provided the desired N-acylation product in up to 76%
yield (Table 2, entry 5). Increasing the amount of catalyst loading
from 1.0 to 1.5 equiv. resulted in higher conversion and yield (from
53% to 76%) (Table 2, entries 11 and 5). On the other hand the yield
decreased to a certain extent when the catalyst loading is up to
2.0 equiv. (see Table 2, entries 5 and 12). In addition, a longer reac-
tion time (>18 h) and higher reaction temperature (>120 °C) led to
tedious work-up and lower yield (Table 2, entries 6, 9, and 10).
With the optimized reaction conditions in hand, a variety of
substrates were surveyed to explore the scope of the reaction (Ta-
ble 3). It was observed that electronic effects from aromatic ring
substituents play a key role in N-acylation of sulfonamides, benze-
nesulfamide with electron withdrawing group such as chloro, bro-
mo and nitro at the para position requires longer reaction time
(30–55 h) for the best yield (Table 3, entries 2–4), and total conver-
sion of substrate with electron donating group such as Me- was
achieved in a shorter reaction time of 18–24 h (monitored by
TLC) (Table 3, entries 1 and 6). But for the substrate 1e, Sulfon-
amide with a methoxy substituent gave poor yield (30%) at first,
then we think the formation of oxonium salt from anisole segment
of benzenesulfamide and HCl13 might lead to low reactivity, so
1.5 equiv. of N (C2H5)3 was introduced to the reaction system for
neutralizing HCl, and the corresponding yield raised from 30% to
54% (Table 3, entry 5). Increasing the steric hindrance of substitute
group (R2) from carboxylic ester led to a substantial decrease in
product yield (Table 3, entries 1 and 10), while decreasing the
steric hindrance of alkoxyl group (R3) from carboxylic ester led
to improved N-acylation yield (Table 3, entries 8 and 9).
Moreover, several examples illustrated that aromatic and aro-
matic heterocyclic carboxylic ester with electron-withdrawing or
electron-donating group could react smoothly with sulfamide to
afford the corresponding N-acylsulfonamides in 45–97% yields (Ta-
ble 3, entries 11–14), and changing the substrate from an aryl sul-
fonamide to an alkyl sulfonamide such as methanesulfonamide
also gave the desired acylated product (Table 3, entry 16). Also,
the N-acylation reaction of N-substituted p-toluene sulfonamide
and ethyl acetate gave a 63% yield of N-phenylacetamide instead
of the desired N,N-disubstituted sulfonamide (Table 3, entry 17).
Moreover, TiCl4 can also efficiently catalyze 2-sulfamoyl-benzoic
acid ethyl ester to form saccharin (3l) (Table 3, entry 15) via intra-
molecular N-acylation in 82% yield at 115 °C (see Supplementary
data about the single-crystal X-ray diffraction data of 3l), and
unexpected dehydration reaction proceeded to afford 20% yield
of dehydrated compound (3o) except saccharin (44% yield) at high-
er reaction temperature (160 °C, Scheme 1).14
In conclusion, we have demonstrated TiCl4-catalyzed direct
intermolecular or intramolecular N-acylation of sulfonamide with
carboxylic ester for the first time. Importantly, the transformation
was extended to the use of carboxylic ester as an acylating agent.
Our current efforts are centred on TiCl4-catalyzed dehydration of
sulfonamides, and we will report our studies in due course.
O
S
2
O
S
O
S
O
NH
TiCl (1.5 equiv.)
4
N
+
2
o
NH
160 C, TCE, 24 h
CO Et
CO Et
2
2
3o
1g
3l
44% yield
O
20% yield
Scheme 1. TiCl4-promoted dehydration of 2-sulfamoyl-benzoic acid ethyl ester.

S. Fu et al. / Tetrahedron Letters 51 (2010) 5834–5837
5837
5. (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84–96; (b) Bellis, E.; Vasilatou, K.; Kokotos, G. Synthesis
2005, 2407.
Acknowledgments
The financial support for this work from the Program for New
Century Excellent Talents in University by Ministry of Education
(Grant No. NCET-10-0371) and the Fundamental Research Funds
for the Central Universities (Grant No. 2009ZM0262) is gratefully
acknowledged.
6. Mende, F.; Seitz, O. Angew. Chem., Int. Ed. 2007, 46, 4577.
7. (a) Pelletier, J. C.; Hesson, D. P. Synlett 1995, 1141; (b) Drummond, J. T.;
Johnson, G. Tetrahedron Lett. 1988, 29, 1653; (c) Go, A.; Kudo, S.; Takahashi, T.;
Higure, R. Jpn. Pat. 06172323.
8. (a) MacDonald, F. E.; Danishefsky, S. J. J. Org. Chem. 1992, 57, 7001; (b) Richita,
M. A.; Slough, G. A. Tetrahedron Lett. 1993, 34, 6821; (c) Reddy, C. R.; Mahipal,
B.; Yaragorla, S. R. Tetrahedron Lett. 2007, 48, 7528; (d) Massah, A. R.; Asadi, B.;
Hoseinpour, M.; Molseghi, A.; Kalbasi, R. J.; Naghash, H. J. Tetrahedron 2009, 65,
7696.
The authors are grateful to Professor Yuanfu Deng for the X-ray
single-crystal analysis.
9. Ellis, D. Tetrahedron: Asymmetry 2001, 12, 1589.
10. (a) Katritzky, A. R.; Hoffmann, S.; Sukuki, K. ARKIVOC 2004, xii, 14; (b) Manabe,
S.; Sugioka, T.; Ito, Y. Tetrahedron Lett. 2007, 48, 787.
Supplementary data
11. Wu, X.; Rönn, R.; Gossas, T.; Larhed, M. J. Org. Chem. 2005, 70, 3094.
12. Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem. Soc. 2007, 129, 14106.
13. Buswell, A. M.; Rodebush, W. H.; Roy, M. F. J. Am. Chem. Soc. 1938, 60, 2528.
14. For this substrate, an unexpected dehydration reaction proceeded to afford 20%
yield of 2-(ethoxycarbonyl) benzenesulfanenitrile (3o) at higher reaction
temperature (160 °C) (see Scheme 1).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.092.
References and notes
15. General experimental procedure for N-acylation of sulfonamide with carboxylic
ester: sulfonamide (2 mmol), carboxylic ester (4 mmol), and Cl2CHCHCl2
(4.5 mL) were combined in a pressure tube equipped with a stir bar. The
mixture was stirred at 50 °C for about 10 min, then TiCl4 (3.0 mmol) was added
and the reaction mixture was heated to 115 °C for the given time (see Table 3).
After completion of the reaction (monitored by TLC), the reaction mixture was
diluted with 10 mL of H2O to remove the excess TiCl4, then filtered, and
extracted with EtOAc (3 ꢁ 15 mL), the combined organic layers were dried over
anhydrous Na2SO4, then the solvent was evaporated in vacuo, and the crude
compound was purified by flash column chromatography (silica gel,
petroleum/ethyl acetate, 2:1) to afford the corresponding N-acyl sulfonamine.
16. All the products except compound 3o are known compounds and are also
identified using 1H NMR, LRMS, IR, and mp by comparison with previously
reported data (see Supplementary data for complete details).
1. Koroniak, L.; Ciustea, M.; Gutierrez, J. A.; Richards, N. G. J. Org. Lett. 2003, 5,
2033.
2. Hasegawa, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 423.
3. (a) Lee, Y. K.; Bernstein, P. R.; Adams, E. J.; Brown, F. J.; Cronk, L. A.; Hebbel, K.
C.; Vacek, E. P.; Krell, R. D.; Snyder, D. W. J. Med. Chem. 1990, 33, 2437; (b)
Allegretti, M.; Bertini, R.; Cesta, C. M.; Bizzarri, C.; Di Bitondo, R.; Di Cioccio, V.;
Galliera, E.; Berdini, V.; Topai, A.; Zampella, G.; Russo, V.; Di Bello, N.; Nano, G.;
Nicolini, L.; Locati, M.; Fantucci, P.; Florio, S.; Colotta, F. J. Med. Chem. 2005, 48,
4312; (c) Huang, S.; Connolly, P. J.; Lin, R.; Emanuel, S.; Middleton, S. A. Bioorg.
Med. Chem. Lett. 2006, 16, 3639; (d) Rönn, R.; Sabnis, Y. A.; Gossas, T.; Åkerblom,
E.; Danielson, U. H.; Hallberg, A.; Johansson, A. Bioorg. Med. Chem. Lett. 2006, 14,
544.
4. King, J. F. Acidity. In The Chemistry of Sulfonic Acids, Ester and Their Derivatives;
Patai, S., Rappoport, Z., Eds.; John Wiley and Sons: Chichester, 1991; pp 251–
259.