Pharmacophoric 2-hydroxyalkyl benzenesulfonamide: A single-step synthesis from benzenesulfonamide via hemiaminal

Article abstract of DOI:10.1016/j.ejmech.2006.09.021

ortho-Acylation attempt of benzenesulfonamide afforded the corresponding hemiaminal as major product. The in situ reduction of the reaction mixture, reported herein, directly provided 2-hydroxyalkyl benzenesulfonamide, an important pharmacophoric element

Full text of DOI:10.1016/j.ejmech.2006.09.021

European Journal of Medicinal Chemistry 42 (2007) 456e462
http://www.elsevier.com/locate/ejmech
Original article
Pharmacophoric 2-hydroxyalkyl benzenesulfonamide: A single-step
synthesis from benzenesulfonamide via hemiaminal*
a
a
a
a
Sunil K. Singh a, , S. Shivaramakrishna , V. Saibaba , K. Srinivas Rao , K. Ravi Ganesh ,
*
R. Vasudev b, P. Praveen Kumar b, J. Moses Babu b, K. Vyas b, Y. Koteswar Rao a, J. Iqbal a,
*
a Discovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India
b Analytical Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 19 May 2006; received in revised form 10 July 2006; accepted 21 September 2006
Available online 13 November 2006
Abstract
ortho-Acylation attempt of benzenesulfonamide afforded the corresponding hemiaminal as major product. The in situ reduction of the
reaction mixture, reported herein, directly provided 2-hydroxyalkyl benzenesulfonamide, an important pharmacophoric element for designing
drug-like scaffolds. Its application is demonstrated through designing a novel series of 1,5-diarylpyrazoles for cyclooxygenase-2 (COX-2)
inhibition.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Benzenesulfonamides; Benzisothiazoles; Hemiaminalecarbonyl mixture; 2-Hydroxyalkyl benzenesulfonamide
1. Introduction
sulfonamide which on further reduction would afford the
desired functionality. Though many 2-hydroxyalkyl benzene-
sulfonamides have been synthesized by reacting the ortho-
metalated intermediates with aldehyde and ketone [11,12], it
was practically too difficult for us to get the desired quantity
of 2-hydroxymethyl or hydroxyethyl derivatives using this
method because of extremely poor yield (5e10%). Thus, we
attempted the ortho-formylation of 4-halo N1-tert-butyl benze-
nesulfonamides 1aeb. But, the reaction failed to give the
desired products. The major products isolated in these exper-
iments were identified to be 2-tert-butyl-3-hydroxy-5-halo-
2,3-dihydro-1,2-benzisothiazole-1,1-dioxides 2aeb (Scheme
1). Literature also supported the formation of cyclic products
during ortho-formylation/acylation reactions [13,14]. Pasteris
had extensively used similar cyclic hemiaminals obtained after
trapping the dianion with HCO2Et or DMF during herbicidal
research [15,16]. Even with our trials to negotiate with reac-
tion conditions, we could increase the quantity of the ortho-
formylated product to a maximum of w13%. The literature
also revealed the isomerization of these ortho-formylated
products to corresponding hemiaminals [17,18]. However,
Benzenesulfonamide moiety is an integral part of many
drugs and drug-like scaffolds [1e3]. We needed 2-hydrox-
yalkyl benzenesulfonamides 4 and 12, the important starting
materials, in large quantities, for the structureeactivity rela-
tionship (SAR) study during the search of cyclooxygenase-2
(COX-2) inhibitors as anti-inflammatory agents [4e6]. Syn-
thetically, these materials could be obtained from correspond-
ing 2-methyl benzenesulfonamides [7], by the ring opening of
saccharin derivatives [8] or, by Lombardino’s ortho-metalation
of corresponding sulfonamides [9,10]. Though the first two
methods appeared simple, much chemistry was required for
generating the starting materials with desired substitution.
Therefore, we conceived the n-BuLi induced ortho-metalation
of compounds 1 and 7 to introduce an acyl group adjacent to
*
DRL publication no. 388-C.
* Corresponding authors. Tel.: þ91 40 2304 5439; fax: þ91 40 2304 5438/
5007 (S.K.S).
E-mail address: sunilkumarsingh@drreddys.com (S.K. Singh).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.09.021

S.K. Singh et al. / European Journal of Medicinal Chemistry 42 (2007) 456e462
457
O
O
O
O
O
O
O
O
S
S
S
S
N
a, b
N
d
N
H
H
R
N
+
X
H
R
X
X
X
R
OH
OH
2
O
4
1
3
a, c
O
e
R = H
X= F, Cl
R = H,Me, Et, CF3, Ar
O
O
O
O
O
S
S
S
N
N
N
H
H
H
+
F
HOH2C
X
HO2C
X
O
5
O
4a-b
6a-b
Scheme 1. Reagents and conditions: (a) n-BuLi (2.10 equiv.), THF, ꢀ78 ꢁC, 0.5 h. (b) R ¼ H (DMF or HCO2C2H5), R ¼ CH3 [(CH3CO)2O or CH3CO2Et),
R ¼ C2H5 (C2H5CO2C2H5], R ¼ CF3 (CF3CO)2O or CF3CO2Et), R ¼ Ar (ArCO2Me) (1.50 equiv.). (c) (C2H5CO)2O (1.50 equiv.), ꢀ78 ꢁC for 3e4 h followed
by ambient temperature, 12 h. (d) NaBH4 or LiBH4 (0.5 equiv.), 0e30 ꢁC, 0.5 h. (e) For the mixture of 2 and 3 (R ¼ H), NaOH or NaH (1.0 equiv.), 0e30 ꢁC, 0.5 h.
the cyclic hemiaminal being in equilibrium with the carbonyl
isomer has been reported to undergo condensation reactions
[17]. But, to the best of our knowledge, the reductive opening
of this hemiaminal to 2-hydroxyalkyl benzenesulfonamides 4
and 12 (R ¼ H, Me, Et, CF3) has not been disclosed so far.
Therefore, we report herein a highly efficient scalable sin-
gle-step synthesis of 2-hydroxyalkyl benzenesulfonamides 4
and 12, the useful components of drug research, from benze-
nesulfonamide via in situ reduction of hemiaminalecarbonyl
mixture, and its application in designing COX-2 inhibitors.
product, (Z )-propionic acid 1-(2-tert-butylsulfamoyl-5-fluoro-
phenyl)-propenyl ester 5. Apart from the spectroscopic evi-
dences, the structure of compound 5 was assigned by the
X-ray diffraction studies (Fig. 1). Possibly, this product was
formed via 2-propanoyl derivative 3d when the carbanion
generated on its a-carbon was stabilized by N-Li co-ordina-
tion and the resulting cis-enolate got further O-acylated. An
electrophilic quenching with (CF3CO)2O exclusively afforded
ortho-trifluoroacetyl product 3e while CF3CO2Et gave a 40:60
mixture of 2e and 3e. But, the ortho-acylation with the esters
of aromatic acids exclusively afforded the corresponding 2-
benzoyl benzenesulfonamides 3feg [13].
2. Results and discussion
We also studied the effect of same electrophiles on N-ethyl
benzenesulfonamide 7 (Scheme 2 and Table 1). While the ratio
of the hemiaminalecarbonyl products in ortho-formylation
and trifluoroacylation reaction remained almost same during
DMF or HCO2Et and (CF3CO)2O or CF3CO2Et quenching,
the ortho-acetylation attempt exclusively afforded an elimina-
tion product 10 with Ac2O, and a mixture of 10 (50%) and 11
(30%) with EtOAc. However, the ortho-acylation with esters
of aromatic acids exclusively afforded the corresponding 2-
benzoyl benzenesulfonamides 9ced. In none of these cases
we could isolate the product accounting ortho-directing effect
of 4-fluoro/chloro groups.
Isothiazoles and their benzo derivatives are known to un-
dergo ring cleavage [8]. The mode of cleavage is either via
SeN or CeN bond fission, and depends on the reaction
condition [19]. The stable benzisothiazoles 2 and 8 which
could not completely isomerize even after heating, were re-
acted with a range of reagents, such as NaBH4, LiAlH4,
LiBH4, NaH and NaOH under different reaction conditions.
To our delight, NaBH4 and LiBH4 exclusively afforded the
corresponding 2-hydroxyalkyl benzenesulfonamides 4ae
b and 12aeb from the respective mixture of 2aeb and
3aeb, and 8aeb and 9aeb in very high yield (w84%) at
room temperature (Table 2). While the ring cleavage of
2aeb and 8a also occurred with the use of NaOH and
NaH at slightly higher temperature, there was no effect of
LiAlH4 even after heating for several hours.
The ortho-lithiation of N1-(tert-butyl)-4-fluoro benzenesul-
fonamide 1a using 2.1 equiv. of n-BuLi in dry THF at ꢀ78 ꢁC
followed by an electrophilic quenching with 1.5 equiv. of dry
DMF or HCO2Et afforded a non-separable mixture (w87:13)
of 2-tert-butyl-3-hydroxy-5-fluoro-2,3-dihydro-1,2-benziso-
thiazole-1,1-dioxide 2a and N1-(tert-butyl)-4-fluoro-2-formyl
benzenesulfonamide 3a (Scheme 1). However, this mixture
left behind crystals of pure product 2a when dissolved in ethyl
acetate and kept at room temperature for slow evaporation.
The structure of compound 2a was confirmed by X-ray
diffraction studies (Fig. 1). The reported event of thermal
isomerization [17,18] was checked by recording the 1H
NMR (DMSO-d6) of this non-separable mixture of 2a and
3a (w87:13) at 30, 60 and 90 ꢁC. The content of product 3a
in the mixture was found to increase with rise in temperature,
but went up to only w33% at 90 ꢁC.
The ratio of these two products was found to depend on the
nature of the electrophiles. It was neither affected by the
quantity of the reagents nor by the reaction temperature
(Table 1). An electrophilic quenching of the ortho-lithiated in-
termediate with Ac2O exclusively afforded the 2-acetylated
product 3c whereas quenching with EtOAc afforded a mixture
of 2c and 3c (w30:70). While the quenching of ortho-lithi-
ated intermediate with EtCO2Et afforded
a
mixture
(w44:56) of benzisothiazole 2d and 2-propanoyl derivative
3d, treatment with (EtCO)2O exclusively afforded a different

458
S.K. Singh et al. / European Journal of Medicinal Chemistry 42 (2007) 456e462
Fig. 1. Crystal structure of compounds 2a and 5.
The effect of groups (R ¼ H, Me, Et, CF3) at position-3 of
The ineffectiveness of LiAlH4 indicated that the reducing
agents generating alkaline solution during aqueous work-up,
e.g. NaBH4 and LiBH4 were necessary for this conversion.
Conversion of benzisothiazoles 2aeb and 8a to corresponding
2-hydroxymethyl benzenesulfonamides 4aeb and 12a with
NaH and NaOH under heating condition occurred due to Can-
nizzaro disproportionation [20]. This fact became more clear
when oxidation products, sulfamoyl benzoic acids 6aeb and
13 (w32%) [9] were isolated in these cases apart from alco-
hols 4aeb and 12a (w40%) in contrast to an exclusive forma-
tion of 4aeb (w82%) during NaBH4 and LiBH4 reaction.
To demonstrate the utility of this single-step transformation
in drug discovery, the tert-butyl group of 2-hydroxyalkyl ben-
zenesulfonamide 4a was removed by an azeotropic distillation
using catalytic amount of p-toluenesulfonic acid in refluxing
toluene and the resulting benzenesulfonamide 14 was trans-
formed to the desired phenylhydrazine 15 by refluxing with
benzisothiazole 2 and 8 was found to be very significant
during reduction. While the reduction of 2aeb, e and
8aeb (R ¼ H, CF3) was observed to be very facile, the methyl
derivative 2c required longer reaction time, more quantity of
reducing agent and high temperature for completion. The ethyl
derivative 2d was found to be quite inert even under drastic
conditions. Therefore, on optimization, 2-hydroxymethyl,
2-(1-hydroxyethyl) and 2-(2,2,2-trifluoro-1-hydroxyethyl)
benzenesulfonamides were prepared in very high yield by in
situ reduction of the corresponding mixture of hemiaminale
carbonyl products whereas 2-(1-hydroxypropyl) and 2-(hy-
droxyphenylmethyl) benzenesulfonamides were prepared by
reducing the corresponding 2-acyl or 2-benzoyl derivatives.
Though not important at this stage, the asymmetric reduction
has also been recently taken up to obtain optically pure 2-hy-
droxyalkyl benzenesulfonamides.
Table 1
Ratio of benzisothiazole and O-acylated product during ortho-metalation reaction of 1 and 7a
Substrate
X
R
Reagent
Overall yield (%)
Products (relative %)b
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
F
H
DMF
HCO2Et
78
75
80
82
74
76
68c
65
71
70
75
78
76
75
80
76
78
77
2a (87)
2a (86)
2b (85)
2b (87)
2c (2)
3a (13)
3a (14)
3b (15)
3b (13)
3c (98)
F
H
Cl
Cl
F
H
DMF
HCO2Et
H
CH3
(CH3CO)2O
CH3CO2Et
F
CH3
C2H5
2c (30)
c
3c (70)
c
F
(C2H5CO)2O
C2H5CO2C2H5
(CF3CO)2O
CF3CO2Et
F
C2H5
CF3
2d (44)
2e (3)
3d (56)
3e (97)
3e (60)
3f (98)
3g (96)
9a (14)
9a (12)
9b (98)
9b (55)
9c (97)
9d (98)
F
F
CF3
4-FeC6H4e
2e (40)
2f (2)
F
4-FeC6H4eCO2Me
4-NO2eC6H4eCO2Me
DMF
1g
7a
7a
7b
7b
7c
7d
a
F
4-NO2eC6H4e
H
2g (4)
8a (86)
8a (88)
8b (2)
8b (45)
8c (3)
Cl
Cl
Cl
Cl
Cl
Cl
H
CF3
HCO2Et
(CF3CO)2O
CF3CO2Et
CF3
4-FeC6H4e
4-NO2eC6H4e
4-FeC6H4eCO2Me
4-NO2eC6H4eCO2Me
8d (2)
Schemes 1 and 2.
Not separable on TLC/column chromatography, estimated only by 1H NMR, 13C NMR and HPLC.
A different product 5 was isolated (Fig. 1).
b
c

S.K. Singh et al. / European Journal of Medicinal Chemistry 42 (2007) 456e462
459
O
O
O
O
O
O
S
N
S
S
10
+
N
H
N
+
Me
H
H
Cl
CH2OH
CO2H
Cl
Cl
O
(50 %)
11 (30%)
a, d
12a
13
f
R = H
O
S
O
O
O
O
S
O
O
O
S
S
N
H
N
H
a, c
a, b
N
N
+
R
Cl
Cl
Cl
Cl
R
OH
O
9
H
H
10 (75%)
8
7
e
R= H, CF3, 4-F-C6H4, 4-NO2-C6H4
O
O
S
N
H
OH
Cl
R
12
Scheme 2. Reagents and conditions: (a) n-BuLi (2.10 equiv.), THF, ꢀ78 ꢁC, 0.5 h. (b) R ¼ H (DMF or HCO2C2H5), R ¼ CF3 [(CF3CO)2O or CF3CO2Et)], R ¼ Ar
(ArCO2Me) (1.50 equiv.). (c) (CH3CO)2O (1.50 equiv.). (d) CH3CO2Et (1.50 equiv.), ꢀ78 ꢁC for 3e4 h followed by ambient temperature, 12 h. (e) NaBH4 or
LiBH4 (0.5 equiv.), 0e30 ꢁC, 0.5 h. (f) For the mixture of 8a and 9a (R ¼ H), NaOH or NaH (1.0 equiv.), 0e30 ꢁC, 0.5 h.
anhydrous hydrazine. This phenylhydrazine 15 on coupling
with suitable 1,3-diketones provided novel series of 1,5-diary-
lpyrazoles 16 with modified benzenesulfonamide core suitable
for effective COX-2 inhibition (Scheme 3) [4,6]. A few of
these compounds were found to be highly potent in different
animal models of inflammation [5].
reductive conversion of the hemiaminalecarbonyl mixture to
corresponding 2-hydroxyalkyl benzenesulfonamide. Though
this conversion is limited to smaller groups at position-3 of
benzisothiazole, it still can be used as a simple tool to intro-
duce a highly amenable hydroxylalkyl group adjacent to
sulfonamide for designing many drug-like scaffolds.
3. Conclusion
4. Experimental protocols
In conclusion, we described here the practical variation in
the product formation during ortho-acylation of benzenesulfo-
namides and demonstrated a single-step high yielding
The reactions involving n-BuLi were performed under ar-
gon atmosphere using dry THF. Melting points are uncor-
rected. IR spectra were recorded on PerkineElmer FT-IR
Table 2
In situ conversion of mixture of benzisothiazoles and O-acylated products to 2-hydroxyalkyl benzenesulfonamidesa
Mixture
X
R
Reagent
Solvent
Temp (ꢁC)
Time (h)
Product (% yield)
2a þ 3a
2a þ 3a
2a þ 3a
2a þ 3a
2a þ 3a
2b þ 3b
2b þ 3b
2c þ 3c
2c þ 3c
2d þ 3d
2d þ 3d
2e þ 3e
2e þ 3e
8a þ 9a
8a þ 9a
8b þ 9b
8b þ 9b
a
F
H
NaBH4
NaOH
NaH
THFeH2O
THFeH2O
THF
0e35
60e65
40e50
0e35
0.25
0.50
0.50
0.25
1.50
0.25
0.25
0.50
0.50
3.00
3.00
0.25
0.25
0.25
0.25
0.25
0.25
4a (82)
4a (40)b
4a (38)b
4a (84)
4a (7)c
F
H
F
H
F
H
LiBH4
LiAlH4
NaBH4
LiBH4
NaBH4
LiBH4
NaBH4
LiBH4
NaBH4
LiBH4
NaBH4
LiBH4
NaBH4
LiBH4
THF
THF
F
H
50e60
0e35
0e35
Cl
Cl
F
H
THFeH2O
THF
4b (84)
4b (80)
4c (80)
4c (79)
4d (42)d
4d (45)d
4e (80)
4e (76)
12a (85)
12a (82)
12b (81)
12b (79)
H
CH3
CH3
C2H5
C2H5
CF3
CF3
H
THFeH2O
THF
40e50
40e50
Reflux
Reflux
0e35
F
F
THFeH2O
THF
F
F
THFeH2O
THF
F
0e35
0e35
Cl
Cl
Cl
Cl
THFeH2O
THF
H
0e35
0e35
0e35
CF3
CF3
THFeH2O
THF
Schemes 1and 2.
b
c
d
Yield loss was due to the formation of compound 6.
Starting material recovered.
No change was observed in the cyclic product 2d. The product 4d was obtained only from the reduction of 3d.

460
S.K. Singh et al. / European Journal of Medicinal Chemistry 42 (2007) 456e462
OH
O
O
S
H2N
O
O
O
O
S
S
N
H2N
H2N
N
c
a
b
4a
R
NHNH2
F
Ar
OH
OH
14
15
16
Scheme 3. Reagents and conditions: (a) PTSA (0.2 equiv.), toluene, reflux, 1.0 h, 87e92%. (b) Anhydrous N2H4 (5.0 equiv.), CH3CN, reflux, 72 h, 69e73%. (c)
Refs. [4e6].
1650 spectrometer. H NMR and 13C NMR experiments were
performed at 200, 400 or 500 MHz Varian Gemini spectrome-
ter using TMS as internal standard. The chemical shifts (d) are
reported in parts per million. Mass spectra were recorded on
HP-5989A spectrometer and the elemental analyses were car-
ried out for C, H, N using PerkineElmer 2400 series II CHN/
O analyzer. The purity of the compounds was determined by
HPLC using ‘‘System 1’’ consisting column Hichrom RPB
(250 mm) and mobile phase 0.01 M KH2PO4/CH3CN
(50:50), and ‘‘System 2’’ comprising column Intersil ODS
3V (250 mm) and mobile phase H2O/CH3CN (50:50) running
115.3 (d, J ¼ 23.9 Hz), 112.3 (d, J ¼ 23.9 Hz), 79.3 (d,
J ¼ 1.9 Hz), 56.9, 54.2, 29.2, 28.9. MS (CI Method) 260
(M þ H)þ, 244, 204. HPLC (System 1) 86.9% 2a and 13.5%
3a; (System 2) 87.2% 2a and 12.6% 3a.
1
4.2. (Z )-Propionic acid 1-(2-tert-butylsulfamoyl-5-
fluorophenyl)-propenyl ester 5
A white solid was obtained in 75% yield when propionic
anhydride was used in the reaction. Mp 146e148 ꢁC. IR
.
(KBr) 3392, 2982, 1759, 1576 cmꢀ1 1H NMR (500 MHz,
at 1.0 mL/min with UV detection at respective lmax
.
CDCl3) d 8.15 (dd, J ¼ 6.6 and 2.4 Hz, 1H), 7.22 (dd,
J ¼ 6.6 and 2.4 Hz, 1H), 7.15e7.10 (m, 1H), 5.75 (q,
J ¼ 6.6 Hz, 1H), 5.20 (bs, 1H), 2.50 (q, J ¼ 6.0 Hz, 2H),
1.77 (d, J ¼ 6.6 Hz, 3H), 1.10 (s, 9H), 1.01 (t, J ¼ 6.0 Hz,
3H). 13C NMR (DMSO-d6) 171.9, 162.8 (d, J ¼ 249.2 Hz),
144.1, 137.7 (d, J ¼ 3.2 Hz), 137.2 (d, J ¼ 9.0 Hz), 131.0 (d,
J ¼ 9.1 Hz), 118.4 (d, J ¼ 23.7 Hz), 117.7, 115.4 (d,
J ¼ 21.5 Hz), 53.6, 29.3, 26.6, 11.4, 8.6. MS (CI Method)
344 (M þ H)þ, 288, 270, 252, 232, 214, 196, 176. HPLC (Sys-
tem 1) 98.4%; (System 2) 97.9%. Anal. (C16H22FNO4S) C:
calcd, 55.96; found, 56.12; H: calcd, 6.46; found, 6.78; N:
calcd, 4.08; found, 4.25.
4.1. Mixture of 2-tert-butyl-5-fluoro-1,1-dioxo-2,3-
dihydro-1H-benzo[d]isothiazol-3-ol 2a and N-tert-butyl-
4-fluoro-2-formyl benzenesulfonamide 3a (representative
ortho-acylation)
N1-(tert-Butyl)-4-fluoro benzenesulfonamide 1a (2.0 g,
8.65 mmol) dissolved in dry THF (20 mL) under argon atmo-
sphere, was cooled to ꢀ78 ꢁC and 1.6 M n-BuLi (12.08 mL,
18.12 mmol) was injected. The reaction mixture after agitating
at this temperature for 30 min was brought to ꢀ20 ꢁC for
15 min. It was again cooled to ꢀ78 ꢁC and dry DMF
(0.94 g, 12.98 mmol) was introduced slowly. The reaction
mixture was stirred at this temperature for 4 h and then al-
lowed to stir overnight at ambient temperature. The reaction
mass was poured over ice-cold ammonium chloride solution
and stirred for 5 min. The whole mass was extracted with ethyl
acetate, dried (Na2SO4) and evaporated to get a brownish
gummy mass which was purified by column chromatography
using 230e400 mesh silica-gel and a mixture of ethyl acetate
and petroleum ether (10:90). The colorless viscous mass was
triturated with ethyl acetateepetroleum ether to get a 87:13
mixture of the title compounds (1.7 g, 75%). Mp 102e
4.3. 5-Chloro-2-ethyl-3-methylene-2,3-
dihydrobenzo[d]isothiazole 1,1-dioxide 10
A colorless solid was obtained in 82% yield when acetic
anhydride was used in the reaction of 7. Mp 65e67 ꢁC. IR
(KBr) 3087, 1739, 1688, 1622, 1574 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d 7.70 (d, J ¼ 10.8 Hz, 1H), 7.69 (s, 1H),
7.54 (d, J ¼ 10.8 Hz, 1H), 4.99 (d, J ¼ 3.2 Hz, 1H), 4.53 (d,
J ¼ 3.2 Hz, 1H), 3.72 (q, J ¼ 7.2 Hz, 2H), 1.41 (t,
J ¼ 7.2 Hz, 3H). MS (CI Method) 244 (M þ H)þ, 215. Anal.
(C10H10ClNO2S) C: calcd, 49.28; found, 49.55; H: calcd,
4.14; found, 3.96; N: calcd, 5.75; found, 5.68.
104 ꢁC. IR (KBr) 3440, 2922, 1600 cmꢀ1
.
1H NMR
(200 MHz, DMSO-d6) d 10.68 (s, 1H), 8.05 (d, J ¼ 6.0 Hz,
1H), 7.95 (dd, J ¼ 6.4 and 2.8 Hz, 1H), 7.65e7.58 (m, 3H),
7.45 (dd, J ¼ 6.4 and 2.8 Hz, 1H), 6.95 (d, J ¼ 9.4 Hz, 1H),
6.05 (d, J ¼ 9.4 Hz, 1H), 1.53 (s, 9H), 1.13 (s, 9H). 13C
NMR (DMSO-d6) d 189.9, 164.7 (d, J ¼ 249.6 Hz), 163.8
(d, J ¼ 251.8 Hz), 141.2, 140.3 (d, J ¼ 9.4 Hz), 135.5 (d,
J ¼ 6.8 Hz), 131.9 (d, J ¼ 2.6 Hz), 131.7, 122.8 (d,
J ¼ 9.4 Hz), 120.4 (d, J ¼ 22.3 Hz), 118.3 (d, J ¼ 24.3 Hz),
4.4. N-tert-Butyl-4-fluoro-2-hydroxymethyl
benzenesulfonamide 4a (representative hemiaminale
carbonyl reduction)
After stirring the reaction mixture overnight [ortho-acyla-
tion of N1-(tert-butyl)-4-fluoro benzenesulfonamide 1a leading
to a mixture of 2a and 3a], the whole mass was poured over

S.K. Singh et al. / European Journal of Medicinal Chemistry 42 (2007) 456e462
461
ice-cold ammonium chloride solution and stirred for 5 min.
NaBH4 (0.16 g, 4.32 mmol) was added in three lots and stir-
ring was continued for another 30 min. The whole mass was
extracted with ethyl acetate, dried (Na2SO4) and evaporated
to get a gummy mass which was purified by column chroma-
tography over 230e400 mesh silica-gel using a mixture of
ethyl acetate and petroleum ether (15:85). The colorless vis-
cous mass was triturated with ethyl acetateepetroleum ether
to get a colorless solid of the desired product 4a (1.9 g,
290 (M þ H)þ, 272, 256, 234, 216, 187, 157, 123. HPLC (Sys-
tem 1) 97.5%. Anal. (C13H20FNO3S) C: calcd, 53.96; found,
54.28; H: calcd, 6.97; found, 7.21; N: calcd, 4.84; found, 5.12.
4.8. 2-tert-Butyl-(3RS )-3-ethyl-5-fluoro-1,1-dioxo-2,3-
dihydro-1H-benzo[d]isothiazol-3-ol 2d
A colorless solid was obtained as one of column fraction
(35%) in the above reaction. Mp 105e107 ꢁC. IR (KBr)
.
3424, 2928, 1581 cmꢀ1 1H NMR (200 MHz, DMSO-d6)
82%). Mp 118e120 ꢁC. IR (neat) 3408, 1582, 1449 cmꢀ1
.
1H NMR (200 MHz, CDCl3) d 8.07e8.02 (m, 1H), 7.27 (dd,
J ¼ 6.8 and 2.4 Hz, 1H), 7.08e7.01 (m, 1H), 5.01 (bs, 1H),
4.98 (s, 2H), 3.05 (bs, 1H), 1.22 (s, 9H). 13C NMR (DMSO-
d6) d 163.7 (d, J ¼ 248.3 Hz), 145.2 (d, J ¼ 7.9 Hz), 136.1,
131.1 (d, J ¼ 9.2 Hz), 113.8 (d, J ¼ 23.8 Hz), 113.2 (d,
J ¼ 21.8 Hz), 59.1, 53.5, 29.6. MS (CI Method) 261 (M)þ,
246, 228, 206, 188. HPLC (System 1) 98.4%. Anal.
(C11H16FNO3S) C: calcd, 50.56; found, 50.42; H: calcd,
6.17; found, 6.34; N: calcd, 5.36; found, 5.29.
d 8.20 (d, J ¼ 6.6 Hz, 1H), 7.35e7.25 (m, 2H), 6.80 (bs,
1H), 2.58 (q, J ¼ 7.0 Hz, 2H), 1.14 (s, 9H), 0.88 (t,
J ¼ 7.0 Hz, 3H). MS (CI Method) 290 (M þ H)þ, 272, 232,
216, 176, 123, 109. HPLC (System 2) 98.7%. Anal.
(C13H18FNO3S) C: calcd, 54.34; found, 54.22; H: calcd,
6.31; found, 6.01; N: calcd, 4.87; found, 4.72.
4.9. N-tert-Butyl-4-fluoro-2-(2,2,2-trifluoro-1-
hydroxyethyl) benzenesulfonamide 4e
4.5. N1-(tert-Butyl)-4-chloro-2-hydroxymethyl
benzenesulfonamide 4b
A colorless gummy mass was obtained in w80% yield by
the in situ reduction of a mixture of components 2e and 3e
with NaBH4 or LiBH4 at room temperature. IR (neat) 3288,
A colorless solid was obtained in 84% yield when a mixture
of products 2b and 3b was treated in situ with NaBH4 at room
temperature. Mp 124e126 ꢁC. IR (KBr) 3402, 1585,
2978, 1588, 1478 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d 8.13e8.10 (m, 1H), 8.00e7.88 (m, 1H), 7.57 (dd, J ¼ 6.0
and 1.6 Hz, 1H), 6.18 (m, 1H), 4.62 (bs, 1H), 3.50 (bs, 1H),
1.25 (s, 9H). MS (CI Method) 330 (M þ H)þ, 294, 277, 156.
HPLC (System 1) 97.3%. Anal. (C12H15F4NO3S) C: calcd,
43.77; found, 44.02; H: calcd, 4.59; found, 4.80; N: calcd,
4.25; found, 4.61.
1452 cmꢀ1
. d 8.00 (d,
1H NMR (200 MHz, CDCl3)
J ¼ 6.0 Hz, 1H), 7.32 (d, J ¼ 6.0 Hz, 1H), 7.02 (s, 1H), 5.05
(bs, 1H), 5.00 (d, J ¼ 3.8 Hz, 2H), 2.95 (bs, 1H), 1.20 (s,
9H). MS (CI Method) 278 (M þ H)þ, 260, 208. HPLC (Sys-
tem 1) 98.3%. Anal. (C11H16ClNO3S) C: calcd, 47.56; found,
47.32; H: calcd, 5.81; found, 6.10; N: calcd, 5.04; found, 5.74.
4.10. 4-Chloro-N-ethyl-2-hydroxymethyl
benzenesulfonamide 12a
4.6. N-tert-Butyl-4-fluoro-2-[(1RS )-1-hydroxyethyl)]
benzenesulfonamide 4c
An off-white viscous mass was obtained in w85% yield by
the in situ reduction of a mixture of components 8a and 9a
with NaBH4 or LiBH4 at room temperature. IR (neat) 3375,
.
3324, 1512 cmꢀ1 1H NMR (200 MHz, CDCl3) d 7.88 (d,
A colorless foam was obtained in w80% yield when a mix-
ture of products 2c and 3c was treated in situ with NaBH4ꢀo1r
LiBH4 at 40e50 ꢁC. IR (neat) 3451, 3281, 2976, 1582 cm
.
1H NMR (200 MHz, CDCl3) d 8.03 (d, J ¼ 6.8 Hz, 1H),
7.39e7.20 (m, 2H), 5.69 (q, J ¼ 6.2 Hz, 1H), 4.93 (bs, 1H),
2.80 (bs, 1H), 1.57 (d, J ¼ 6.2 Hz, 3H), 1.25 (s, 9H). MS (CI
Method) 260 (M ꢀ CH3)þ, 242, 216, 201, 185, 168, 159,
123, 109, 101, 95. HPLC (System 1) 97.8%. Anal.
(C12H18FNO3S) C: calcd, 52.35; found, 52.77; H: calcd,
6.59; found, 6.25; N: calcd, 5.09; found, 5.23.
J ¼ 6.8 Hz, 1H), 7.42 (d, J ¼ 6.8 Hz, 1H), 7.08 (s, 1H), 5.10
(d, J ¼ 3.0 Hz, 2H), 4.20 (bt, 1H), 3.76 (q, J ¼ 7.0 Hz, 2H),
2.82 (bs, 1H), 1.15 (t, J ¼ 7.0 Hz, 3H). MS (Electrospray)
250 (M þ H)þ, 232, 197. HPLC (System 1) 98.2%; (System
2) 97.8%. Anal. (C9H12ClNO3S) C: calcd, 43.29; found,
43.35; H: calcd, 4.84; found, 5.02; N: calcd, 5.61; found, 5.27.
4.11. 4-Chloro-N-ethyl-2-(2,2,2-trifluoro-1-
4.7. N-tert-Butyl-4-fluoro-2-[(1RS )-1-hydroxypropyl)]
benzenesulfonamide 4d
hydroxyethyl) benzenesulfonamide 12b
An off-white viscous mass was obtained in w80% yield by
the in situ reduction of a mixture of components 8b and 9b
with NaBH4 or LiBH4 at room temperature. IR (neat) 3372,
A colorless solid was obtained as one of the components in
42% yield when the mixture of products 2d and 3d was in situ
reduced with NaBH4 under reflux. Mp 121e122 ꢁC. IR (neat)
3318, 1505 cmꢀ1 1H NMR (200 MHz, CDCl3) d 7.85 (d,
.
1
3485, 3294, 2982, 1532 cmꢀ1. H NMR (200 MHz, DMSO-
J ¼ 7.0 Hz, 1H), 7.35 (d, J ¼ 7.0 Hz, 1H), 6.98 (s, 1H), 6.05
(m, 1H), 4.90 (bs, 1H), 3.68 (q, J ¼ 6.8 Hz, 2H), 2.96 (bs,
1H), 1.10 (t, J ¼ 6.8 Hz, 3H). MS (Electrospray) 318
(M þ H)þ, 291, 226, 191. HPLC (System 1) 99.0%. Anal.
d6) d 7.95 (d, J ¼ 6.2 Hz, 1H), 7.45e7.20 (m, 2H), 5.35e
5.30 (m, 1H), 5.28 (bs, 1H), 3.35 (bs, 1H), 2.30e1.30 (m,
2H), 1.15 (s, 9H), 0.95 (t, J ¼ 6.4 Hz, 3H). MS (CI Method)

462
S.K. Singh et al. / European Journal of Medicinal Chemistry 42 (2007) 456e462
(C10H11ClF3NO3S) C: calcd, 37.80; found, 37.43; H: calcd,
3.49; found, 3.28; N: calcd, 4.41; found, 4.61.
138, 136, 120, 107, 105, 92. HPLC (System 1) 98.2%; (System
2) 97.8%. Anal. (C7H11N3O3S) C: calcd, 38.70; found, 39.05;
H: calcd, 5.10; found, 5.04; N: calcd, 19.34; found, 19.60.
4.12. Representative preparation of 4-fluoro-2-
hydroxymethyl-1-benzenesulfonamide 14
Acknowledgments
A mixture of p-toluenesulfonic acid (2.92 g, 15.2 mmol)
and N-tert-butyl-4-fluoro-2-hydroxymethyl benzenesulfona-
mide 4a (20.0 g, 76.5 mmol) was refluxed with toluene
(200 mL) using DeaneStark water separator for 1 h. The reac-
tion mixture was brought to room temperature, poured over
ice-water and extracted with ethyl acetate. The combined or-
ganic layer was sequentially washed with 5% aqueous
NaHCO3 and water. The solvent was dried (Na2SO4) and
evaporated to get a viscous mass which on trituration with
ethyl acetateepetroleum ether afforded a colorless solid
(12.0 g, 76%) of the desired compound. Mp 122e124 ꢁC. IR
(KBr) 3607, 3363, 3251, 3106, 1605, 1583, 1448,
The authors sincerely acknowledge the constant support
and encouragement received from Dr. K. Anji Reddy, Chair-
man, DRL.
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4.13. Representative preparation of 4-hydrazino-2-
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1
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