Biaryl sulfonamides from O-acetyl amidoximes: 1,2,4-Oxadiazole cyclization under acidic conditions

Article abstract of DOI:10.1002/jhet.603

A series of 4-cyanobenzenesulfonamides (1a-h) was converted to the corresponding O-acetylated amidoximes (2a-h). The reaction of 1a was exemplarily investigated with respect to the formation of a byproduct, which was identified as 1,2,4-oxadiazole derivative 3a. This observation led to the development of an improved procedure for the preparation of 2a-h. Compounds 2 could be transformed to 1,2,4-oxadiazoles 3a-h in high yields and purity upon heating in acetic acid.

Full text of DOI:10.1002/jhet.603

March 2011
Biaryl Sulfonamides from O-Acetyl Amidoximes: 1,2,4-
Oxadiazole Cyclization under Acidic Conditions
407
a
Stefan Dosa, Jorg Daniels, and Michael Gutschow *
b
a
¨
¨
aPharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany
bInstitute of Inorganic Chemistry, University of Bonn, 53121 Bonn, Germany
*E-mail: guetschow@uni-bonn.de
Received April 27, 2010
DOI 10.1002/jhet.603
Published online 21 January 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of 4-cyanobenzenesulfonamides (1a–h) was converted to the corresponding O-acetylated
amidoximes (2a–h). The reaction of 1a was exemplarily investigated with respect to the formation of a
byproduct, which was identified as 1,2,4-oxadiazole derivative 3a. This observation led to the develop-
ment of an improved procedure for the preparation of 2a–h. Compounds 2 could be transformed to
1,2,4-oxadiazoles 3a–h in high yields and purity upon heating in acetic acid.
J. Heterocyclic Chem., 48, 407 (2011).
INTRODUCTION
The typical synthetic route to 1,2,4-oxadiazoles
includes the O-acylation of easily accessible amidox-
imes [17], followed by their intramolecular condensa-
tion. For the first step, acid chlorides [18], esters [19],
or symmetrical anhydrides [15] have been used, or car-
boxylic acids have been coupled to amidoximes in the
presence of CDI, DCC, EDC, or BOP-Cl [20,21]. The
1,2,4-oxadiazoles were then obtained after thermal con-
densation of the O-acylated amidoxime precursors [22].
Numerous conditions for the dehydration step have been
published, mostly involving heating in solvents such as
DMF [23,24], diglyme [20], pyridine [15], or water
[25]. Sodium acetate-catalyzed cyclodehydration was
performed to produce series of enantiopure 1,2,4-oxadia-
zole-containing, Fmoc-protected b3- and a-amino acids
[26,27]. Cyclization could also proceed at room temper-
ature, provided the presence of a strong basic reagent
like TBAF [28]. Direct cyclization has also been
reported, for example when reacting benzamidoxime
with succinic anhydride under solvent-free conditions
[29] or with acyl chlorides in pyridine [30]. However,
da Costa Leite et al. heated aryl amidoximes in acetic
acid as solvent and observed a product mixture of 3,5-
bis(aryl)-1,2,4-oxadiazoles and 3-aryl-5-methyl-1,2,4-
oxadiazoles [31].
The 1,2,4-oxadiazole heterocycle has been found in a
large number of compounds which display biological ac-
tivity. Among a series of 5-alkyl-1,2,4-oxadiazol-3-yl-
benzenesulfonamides, a 5-n-pentyl derivative was a par-
ticularly potent b3 adrenergic receptor agonist [1]. The
1,2,4-oxadiazole moiety has been incorporated in selec-
tive SH2 inhibitors of tyrosine kinase ZAP-70 [2], novel
5-HT3 antagonists [3], and histamine H3 receptor antag-
onists [4].
Because of their increased hydrolytic stability, oxadia-
zoles are often considered as ester bioisosteres in drug
discovery research. For example, replacement of the
methyl esters in arecoline or azabicyclo derivatives by
3- and 5-methyl-1,2,4-oxadiazole resulted in potent mus-
carinic agonists [5,6]. As benzodiazepine-receptor
ligands, oxadiazoles have also been found to be meta-
bolically stable alternatives to esters [7–9], and oxadia-
zoles related to disoxaril with antirhinoviral activity
were identified [10]. The use of 1,2,4-oxadiazoles as
amide mimetics has frequently been reported, for exam-
ple to improve the in vivo efficacy of benzodiazepine re-
ceptor ligands [11] and to develop new inhibitors of pal-
mitoyl-CoA oxidation [12]. The carboxamide-oxadiazole
replacement led to A2B-selective xanthine-based adeno-
sine receptor antagonist [13] and to rimonabant-related
CB1 cannabinoid-receptor antagonists [14]. Moreover,
1,2,4-oxadiazoles have been reported as dipeptido-
mimetics and successfully used in the design of pseudo-
peptides as l- and d-opioid and NK1 receptor ligands
[15,16].
RESULTS AND DISCUSSION
In the course of our studies related to the inhibition
of serine proteases, we have designed benzamidines con-
taining a sulfonamide structure as amide bioisostere
C
V
2011 HeteroCorporation

408
S. Dosa, J. Daniels, and M. Gu¨tschow
Vol 48
Scheme 1. Conditions: (i) H2NOH ꢀ HCl, DIPEA, EtOH, 87ꢁC, 1 h; (ii) Ac2O (3 equiv), AcOH, room temperature, 1 h.
with strong hydrogen bonding donor–acceptor properties
[32,33]. To take advantage of the preference of trypsin-
like enzymes for arginine, the benzamidine substructure
was chosen as a well-known arginine mimetic [34,35].
Thus, we were interested in a straightforward synthesis
of a library of benzamidines from carbonitriles, which
includes the formation of amidoximes, their O-acetyla-
tion and final reduction. These three steps were analyzed
with respect to side products to develop a one-pot proce-
dure to benzamidines. The first two steps were com-
bined and the representative sulfonamide-containing
nitrile 1a was reacted with hydroxylamine hydrochloride
and N,N-diisopropylethylamine (DIPEA) in refluxing
ethanol. The crude product was directly dissolved in
acetic acid [36] and treated with acetic anhydride
(Scheme 1). Monitoring the reaction by TLC, a second
product with unexpected low polarity was observed. The
byproduct was separated from the desired O-acetylated
substance 2a by column chromatography and was then
recrystallized. NMR spectroscopy showed a downfield
shift of the methyl protons of 0.54 ppm and an upfield
shift of the methyl carbon of 7.7 ppm, relative to the
signals of 2a. The NH2 resonance and the N¼¼CAN car-
bon signal at 155.6 ppm disappeared, whereas a new
signal at 178.1 ppm was observed. Finally, the structure
was confirmed by X-ray crystallography [37] to be the
dehydrated 1,2,4-oxadiazole 3a (Fig. 1, Table 1).
reaction time nor by operating at higher temperatures,
which even led to decomposition. Therefore, suitable
conditions should be established to (i) convert O-acety-
lated amidoximes 2 to corresponding 1,2,4-oxadiazoles
3 and (ii) produce the benzamidine precursors 2 free of
heterocyclic impurities. The corresponding reactions are
depicted in Scheme 2.
Upon reaction with different amines, in dichlorome-
thane and the presence of pyridine [38], the commer-
cially available 4-cyanobenzenesulfonyl chloride was
converted to eight cyano-substituted sulfonamides 1a–h
(Table 2). The corresponding O-acetylated amidoximes
2a–h were obtained in good yields (Table 2) by a proce-
dure combining the reaction with hydroxylamine and
the O-acetylation. When performing the acetylation at
room temperature using three equivalents of acetic anhy-
dride and acetonitrile as the solvent, instead of acetic
Table 1
Crystallographic data of 3a.
Empirical formula
Formula weight
Temperature
C
16H15N3O3S
329.37
163(2) K
˚
0.71073 A
Triclinic, P-1
Wavelength
Crystal system,
space group
Unit cell dimensions
ꢁ
˚
a ¼ 11.7210(3) A; a ¼ 105.463(2)
ꢁ
˚
b ¼ 11.9411(2) A; b ¼ 98.7490(10)
ꢁ
˚
The cyclodehydration of O-acylated amidoximes at
room temperature in the absence of a base has not been
described in literature yet. It was not possible to com-
plete the dehydration of 2a, neither by increasing the
c ¼ 16.9507(5) A; c ¼ 92.208(2)
3
˚
Volume
2252.16(10) A
Z, Calculated density
Absorption coefficient
F(000)
6, 1.457 Mg/m3
0.235 mmꢂ1
1032
Crystal size
y range for data
collection
0.42 mm ꢀ 0.33 mm ꢀ 0.19 mm
2.34–27.48ꢁ
Limiting indices
Reflections
collected/unique
Completeness to y
Absorption correction
Max. and min.
h, k, l ꢂ15/15, ꢂ15/15, ꢂ22/2
40076/10139 [R(int) ¼ 0.0399]
98.1% (ymax ¼ 27.48ꢁ)
Semi-empirical from equivalents
0.9567 and 0.9078
transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
Largest diff. peak and hole
Full-matrix least-squares on F2
10139/0/628
0.996
R1 ¼ 0.0360, xR2 ¼ 0.0882
R1 ¼ 0.0563, xR2 ¼ 0.0956
0.265 and ꢂ0.569 e/Aꢂ3
Figure 1. Molecular plot of 3a showing the atom-labeling scheme and
displacement ellipsoids at 30% probability level for the non-H atoms.
H atoms are depicted as small circles of arbitrary radii [37].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Biaryl Sulfonamides from O-Acetyl Amidoximes: 1,2,4-Oxadiazole
Cyclization under Acidic Conditions
409
Scheme 2. Conditions: (i) pyridine, CH2Cl2, room temperature, 24 h; (ii) H2NOH ꢀ HCl, DIPEA, EtOH, 87ꢁC, 1 h; (iii) Ac2O (3 equiv), MeCN,
room temperature, 1 h; (iv) AcOH, 80ꢁC, 6 h.
acid, no heterocyclized byproducts were observed. The
series of O-acetylated amidoximes 2 will be used for
further transformation to benzamidines to become part
of a library of potential serine protease inhibitors. Their
biological evaluation is in progress and will be reported
in due course.
are useful methods for the introduction of heterocyclic
biphenyl-analogous building blocks in the design of bio-
active compounds, for example, inhibitors of cysteine
cathepsins [39].
EXPERIMENTAL
The final 1,2,4-oxadiazoles 3a–h were prepared from
2a–h in acetic acid at 80ꢁC (Table 2). Crystallization
from ethyl acetate/hexane afforded the products in
excellent purity. When compared with the initial experi-
ment noted above, this procedure resulted in a complete
conversion and yields of >78%. The use of purified ma-
terial 2 in the cyclodehydration step seems favorable for
the desired course of the reaction. An exemplary com-
pound, 2a, was cyclized in acetic acid at 120ꢁC. This
time, the product formation was completed after 1 h and
the product, 3a, was obtained in the same yield (80%)
after recrystallization. The structural elucidation for 3a–
Solvents and reagents were obtained from Acros (Geel, Bel-
gium), Fluka (Taufkirchen, Germany), Merck-Schuchardt
(Hohenbrunn, Germany) or Sigma (Steinheim, Germany).
Thin-layer chromatography was carried out on Merck alumi-
num sheets, silica gel 60 F254. Preparative column chromatog-
raphy was performed on Merck silica gel 60, 70–230 mesh.
Melting points were determined on a Bu¨chi 510 melting point
1
apparatus and are uncorrected. H- and 13C-NMR spectra were
acquired on a Bruker Avance DRX 500 spectrometer operating
at 500 MHz for 1H and 125 MHz for 13C. Chemical shifts d
are given in ppm referring to the signal center using the sol-
vent peak for reference: DMSO-d6 2.49 ppm/39.7 ppm. The
NMR signals were assigned by 1H, 13C correlation spectra
(HMQC, HMBC) using standard pulse sequences. Elemental
analyses were carried out with a Vario EL apparatus.
General procedure for the synthesis 4-cyanobenzenesul-
fonamides (1a–1h). A mixture of 4-cyanobenzenesulfonyl
chloride (605 mg, 3 mmol), amine (3.3 mmol) and pyridine
1
h was based on elemental analysis, H- and 13C-NMR
data. Signals of both oxadiazole carbons, C-3 and C-5,
appeared about 11 ppm downfield shifted, compared
with the corresponding carbons in compounds 2. Oxa-
diazole cyclizations, including the one presented herein,
Table 2
Conversion of 4-cyanobenzenesulfonamides to O-acetylated amidoximes and corresponding 1,2,4-oxadiazoles.
O-Acetyl-
amidoxime
R1
R2
n
Nitrile
Yield (%)a
Yield (%)a,b
1,2,4-Oxadiazole
Yield (%)a
H
H
H
OMe
OMe
H
1
1
1
1
0
0
0
0
1a
1b
1c
1d
1e
1f
71
97
67
46
45
75
92
88
2a
2b
2c
2d
2e
2f
83
77
77
91
92
75
74
95
3a
3b
3c
3d
3e
3f
80
94
84
79
87
85
90
88
OMe
H
OMe
H
OMe
H
OMe
H
OMe
OMe
1g
1h
2g
2h
3g
3h
a Yields after recrystallization.
b No formation of 1,2,4-oxadiazole, monitored by TLC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

410
S. Dosa, J. Daniels, and M. Gu¨tschow
Vol 48
(736 mg, 9.3 mmol) was stirred for 24 h at room temperature
in dry dichloromethane (10 mL). The solvent was removed
under reduced pressure, acetic acid (1 mL) was added and the
oily residue was purified by flash-column chromatography
(dichloromethane). The product was obtained after
recrystallization.
N-Benzyl-4-cyanobenzenesulfonamide (1a). Using benzyl-
amine (354 mg, 3.3 mmol) as the amine component, the prod-
uct 1a was obtained following the general procedure after
recrystallization from ethanol/water. Yield 580 mg (71%). Col-
orless solid, mp 138–140ꢁC, ref. 40, 141–142ꢁC; 1H-NMR
(DMSO-d6): d 4.04 (s, 2H, CH2), 7.17–7.27 (m, 5H, phenyl-
H), 7.90 (d, 2H, J ¼ 8.8 Hz, phenyl-H), 8.01 (d, 2H, J ¼ 8.8
Hz, phenyl-H), 8.45 (s, 1H, NH); 13C-NMR (DMSO-d6): d
46.3 (CH2), 114.8 (Cq), 117.9 (CN), 127.4 (3ꢀ CH, Ph), 127.8
(2ꢀ CH, Ph), 128.4 (2ꢀ CH, Ph), 133.4 (2ꢀ CH, Ph), 137.3
(Cq), 145.2 (Cq).
4-Cyano-N-(4-methoxybenzyl)benzenesulfonamide (1b). Using
4-methoxybenzylamine (453 mg, 3.3 mmol), the product 1b
was obtained following the general procedure after recrystalli-
zation from toluene. Yield 880 mg (97%). Colorless solid, mp
128–131ꢁC; 1H-NMR (DMSO-d6): d 3.70 (s, 3H, CH3), 4.00
(s, 2H, CH2), 6.78 (d, 2H, J ¼ 8.6 Hz, phenyl-H), 7.08 (d, 2H,
J ¼ 8.8 Hz, phenyl-H), 7.87 (d, 2H, J ¼ 8.5 Hz, phenyl-H),
8.00 (d, 2H, J ¼ 8.5 Hz, phenyl-H), 8.35 (s, 1H, NH); 13C-
NMR (DMSO-d6, APT): d 45.9 (CH2), 55.2 (CH3), 113.8 (2ꢀ
CH, Ph), 114.7 (Cq), 117.9 (CN), 127.3 (2ꢀ CH, Ph), 129.1
(Cq), 129.2 (2ꢀ CH, Ph), 133.4 (2ꢀ CH, Ph), 145.3 (Cq),
158.7 (Cq). Anal. Calcd. for C15H14N2O3S: C, 59.59%; H,
4.67%; N, 9.27%. Found C, 59.71%; H, 4.70%; N, 9.18%.
4-Cyano-N-(3-methoxybenzyl)benzenesulfonamide (1c). Using
3-methoxybenzylamine (453 mg, 3.3 mmol), the product 1c
was obtained after recrystallization from toluene. Yield 610
mg (67%). Colorless needles, mp 124–127ꢁC; 1H-NMR
(DMSO-d6): d 3.67 (s, 3H, CH3), 4.03 (s, 2H, CH2), 6.71 (dd,
1H, J ¼ 1.9 Hz, J ¼ 1.9 Hz, phenyl-H), 6.74–6.77 (m, 2H,
phenyl-H), 7.15 (dd, 1H, J ¼ 7.9 Hz, J ¼ 7.9 Hz, phenyl-H),
7.88 (d, 2H, J ¼ 8.2 Hz, phenyl-H), 8.00 (d, 2H, J ¼ 8.5 Hz,
phenyl-H), 8.44 (s, 1H, NH); 13C-NMR (DMSO-d6, APT): d
46.2 (CH2), 55.1 (CH3), 112.9, 113.3 (2ꢀ CH, Ph), 114.8 (Cq),
117.9 (CN), 119.9, 129.4, 127.3, 133.3 (6ꢀ CH, Ph), 138.8
(Cq), 145.2 (Cq), 159.3 (Cq). Anal. Calcd. for C15H14N2O3S:
C, 59.59%; H, 4.67%; N, 9.27%. Found C, 59.61%; H, 4.72%;
N, 9.12%.
hexane. Yield 349 mg (45%). White powder, mp 110–111ꢁC;
1H-NMR (DMSO-d6): d 7.03–7.09 (m, 3H, phenyl-H), 7.24
(dd, 2H, J ¼ 8.7 Hz, J ¼ 7.6 Hz, phenyl-H), 7.88 (d, 2H, J ¼
8.8 Hz, phenyl-H), 8.02 (d, 2H, J ¼ 8.9Hz, phenyl-H), 10.49
(s, 1H, NH); 13C-NMR (DMSO-d6, APT): d 115.5 (Cq), 117.7
(CN), 120.8, 124.8, 127.5, 129.4, 133.6 (9ꢀ CH, Ph), 137.1
(Cq), 143.7 (Cq). Anal. Calcd. for C13H10N2O2S: C, 60.45%;
H, 3.90%; N, 10.85%. Found C, 59.87%; H, 3.83%; N,
10.49%.
4-Cyano-N-(4-methoxyphenyl)benzenesulfonamide (1f). Using
p-anisidine (406 mg, 3.3 mmol), the product 1f was obtained
following the general procedure after recrystallization from tol-
uene. Yield 650 mg (75%). White powder, mp 148–149ꢁC,
ref. 41, 188–191ꢁC; 1H-NMR (DMSO-d6): d 3.66 (s, 3H,
CH3), 6.81 (d, 2H, J ¼ 9.2 Hz, phenyl-H), 6.95 (d, 2H, J ¼
9.2 Hz, phenyl-H), 7.81 (d, 2H, J ¼ 8.5 Hz, phenyl-H), 8.01
(d, 2H, J ¼ 8.8 Hz, phenyl-H), 10.13 (s, 1H, NH); 13C-NMR
(DMSO-d6, APT): d 55.3 (CH3), 114.6 (2ꢀ CH, Ph), 115.3
(Cq), 117.2 (CN), 124.1, 127.6 (4ꢀ CH, Ph), 129.4 (Cq), 133.5
(2ꢀ CH, Ph), 143.7 (Cq), 157.1 (Cq). Anal. Calcd. for
C14H12N2O3S: C, 58.32%; H, 4.20%; N, 9.72%. Found C,
58.48%; H, 4.32%; N, 9.65%.
4-Cyano-N-(3-methoxyphenyl)benzenesulfonamide (1g). Using
m-anisidine (406 mg, 3.3 mmol), the product 1g was obtained
following the general procedure after recrystallization from tol-
uene. Yield 800 mg (92%). Yellow crystals, mp 99–103ꢁC;
1H-NMR (DMSO-d6): d 3.66 (s, 3H, CH3), 6.61–6.67 (m, 3H,
phenyl-H), 7.13 (dd, 1H, J ¼ 8.6 Hz, J ¼ 8.4 Hz, phenyl-H),
7.90 (d, 2H, J ¼ 8.9 Hz, phenyl-H), 8.03 (d, 2H, J ¼ 8.8 Hz,
phenyl-H), 10.50 (s, 1H, NH); 13C-NMR (DMSO-d6, APT): d
55.2 (CH3), 106.4, 109.9, 112.5 (3ꢀ CH, Ph), 115.5 (Cq),
117.7 (CN), 127.6, 130.3, 133.6 (5ꢀ CH, Ph), 138.4 (Cq),
143.6 (Cq), 159.9 (Cq). Anal. Calcd. for C14H12N2O3S: C,
58.32%; H, 4.20%; N, 9.72%. Found C, 58.49%; H, 4.25%; N,
9.58%.
4-Cyano-N-(3,4-dimethoxyphenyl)benzenesulfonamide (1h).
Using 4-aminoveratrole (505 mg, 3.3 mmol), the product 1h
was obtained following the general procedure after recrystalli-
zation from toluene. Yield 730 mg (76%). Dark pink crystals,
mp 135–140ꢁC; 1H-NMR (DMSO-d6): d 3.63, 3.66 (each s,
6H, CH3), 6.53 (dd, 1H, J ¼ 8.7 Hz, J ¼ 2.2 Hz, phenyl-H),
6.66 (d, 1H, J ¼ 2.5 Hz, phenyl-H), 6.80 (d, 1H, J ¼ 8.5 Hz,
phenyl-H), 7.84 (d, 2H, J ¼ 8.8 Hz, phenyl-H), 8.02 (d, 2H, J
¼ 8.9 Hz, phenyl-H), 10.13 (s, 1H, NH); 13C-NMR (DMSO-
d6, APT): d 55.6, 55.87 (CH3), 107.1, 112.2, 114.3 (3ꢀ CH,
Ph), 115.3 (Cq), 117.7 (CN), 127.6 (2ꢀ CH, Ph), 129.8 (Cq),
133.5 (2ꢀ CH, Ph), 143.6 (Cq), 146.1 (Cq), 149.0 (Cq). Anal.
Calcd. for C15H14N2O4S: C, 56.59%; H, 4.43%; N, 8.80%.
Found C, 56.89%; H, 4.51%; N, 8.69%.
4-Cyano-N-(3,4-dimethoxybenzyl)benzenesulfonamide (1d).
Using 3,4-dimethoxybenzylamine (552 mg, 3.3 mmol), the product
1d was obtained following the general procedure after recrystalliza-
tion from ethyl acetate/toluene. Yield 460 mg (46%). Pink solid,
1
mp 171–175ꢁC; H-NMR (DMSO-d6): d 3.64, 3.69 (each s, 6H,
CH3), 3.98 (s, 2H, CH2), 6.67 (dd, 1H, J ¼ 8.2 Hz, J ¼ 1.9 Hz,
phenyl-H), 6.72 (d, 1H, J ¼ 1.9 Hz, phenyl-H), 6.77 (d, 1H, J ¼
8.2 Hz, phenyl-H), 7.86 (d, 2H, J ¼ 8.8 Hz, phenyl-H), 7.98 (d,
2H, J ¼ 8.8 Hz, phenyl-H), 8.35 (s, 1H, NH); 13C-NMR (DMSO-
d6, APT): d 46.2 (CH2), 55.5, 55.7 (CH3), 111.7, 111.8 (2ꢀ CH,
Ph), 114.7 (Cq), 117.9 (CN), 120.2, 127.4 (3ꢀ CH, Ph), 129.5
(Cq), 133.3 (2ꢀ CH, Ph), 145.3 (Cq), 148.2 (Cq), 148.7 (Cq). Anal.
Calcd. for C16H16N2O4S: C, 57.82%; H, 4.85%; N, 8.43%. Found
C, 57.99%; H, 4.86%; N, 8.34%.
Conversion of 1a to a mixture of 2a and 3a. A mixture of
N-benzyl-4-cyanobenzenesulfonamide 1a (545 mg, 2 mmol),
hydroxylamine-hydrochloride (278 mg, 4 mmol) and DIPEA
(517 mg, 4.08 mmol) in dry ethanol (17 mL) was refluxed for
1 h. The solvent was removed and the oily residue was dis-
solved in acetic acid (8 mL). After addition of acetic anhy-
dride (613 mg, 6 mmol), the solution was stirred for 1 h at
room temperature. The solvent was evaporated under reduced
pressure and the crude product was purified by column chro-
matography (ethyl acetate/petroleum ether ¼ 2:1) to obtain 2a
(598 mg, 86%) and 3a (46 mg, 7%). Compound 3a was
recrystallized from ethyl acetate/hexane.
4-Cyano-N-phenyl-benzenesulfonamide (1e). Using aniline
(307 mg, 3.3 mmol), the product 1e was obtained following
the general procedure after recrystallization from ethyl acetate/
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Biaryl Sulfonamides from O-Acetyl Amidoximes: 1,2,4-Oxadiazole
Cyclization under Acidic Conditions
411
53.06%; H, 5.20%; N, 10.31%. Found C, 53.00%; H, 5.29%;
N, 10.05%.
General procedure for the synthesis of N-acetoxy-benzi-
midamides (2a–2h). A mixture of hydroxylamine-hydrochlor-
ide (2 equiv) and the 4-cyanobenzenesulfonamide (1 equiv)
was refluxed in ethanol (25 mL) in the presence of DIPEA (2
equiv) for 1 h. Afterward, the solvent was removed in vacuo.
The residue was dissolved in acetonitrile (20 mL), and acetic
anhydride (3 equiv) was added. After 1 h, the solvent was
evaporated, and the N-acetoxy-benzimidamide was isolated af-
ter recrystallization from ethyl acetate/hexane as a colorless
solid.
N-Acetoxy-4-(N0-benzylsulfamoyl)benzimidamide (2a). Foll-
owing the general procedure, product 2a was afforded from 1a
(429 mg, 1.58 mmol). Yield 455 mg (83%). White solid, mp
168–170ꢁC; 1H-NMR (DMSO-d6): d 2.15 (s, 3H, CH3), 4.00
(s, 2H, CH2), 6.95 (s, 2H, NH2), 7.20–7.30 (m, 5H, phenyl-H),
7.86 (d, J ¼ 8.8 Hz, 2H, phenyl-H), 7.89 (d, J ¼ 8.8 Hz, 2H,
phenyl-H), 8.23 (s, 1H, NH); 13C-NMR (DMSO-d6, APT): d
19.9 (CH3), 46.3 (CH2), 126.7, 127.3, 127.7, 127.7, 128.4 (9ꢀ
CH), 135.4 (Cq), 137.7 (Cq), 142.5 (Cq), 155.6 (N¼¼CAN),
168.5 (CO). Anal. Calcd. for C16H17N3O4S: C, 55.32%; H,
4.93%; N, 12.10%. Found C, 55.03%; H, 5.28%; N, 11.71%.
N-Acetoxy-4-(N0-(4-methoxybenzyl)sulfamoyl)benzimida-
mide (2b). Following the general procedure, product 2b was
afforded from 1b (756 mg, 2.5 mmol). Yield 727 mg (77%).
Colorless solid, mp 165–166ꢁC; 1H-NMR (DMSO-d6): d 2.14
(s, 3H, CH3), 3.70 (s, 3H, OCH3), 3.92 (s, 2H, CH2), 6.82 (d,
J ¼ 8.9 Hz, 2H, phenyl-H), 6.94 (s, 2H, NH2), 7.13 (d, J ¼
8.6 Hz, 2H, phenyl-H), 7.83 (d, J ¼ 8.8 Hz, 2H, phenyl-H),
7.88 (d, J ¼ 8.9 Hz, 2H, phenyl-H), 8.13 (s, 1H, NH); 13C-
NMR (DMSO-d6, APT): d 19.9 (CH3), 45.8 (CH2), 55.2
(OCH3), 113.8, 126.6, 127.6, 129.1 (8ꢀ CH, Ph), 129.4 (Cq),
135.3 (Cq), 142.5 (Cq), 155.6 (N¼¼CAN), 158.6 (Cq), 168.4
(CO). Anal. Calcd. for C17H19N3O5S: C, 54.10%; H, 5.07%;
N, 11.13%. Found C, 53.97%; H, 5.13%; N, 11.07%.
N-Acetoxy-4-(N0-phenylsulfamoyl)benzimidamide (2e). Fol-
lowing the general procedure, product 2e was afforded from
1e (280 mg, 1.08 mmol). Yield 333 mg (92%). Colorless nee-
dles, mp 166–167ꢁC; 1H-NMR (DMSO-d6): d 2.12 (s, 3H,
CH3), 6.91 (s, 2H, NH2), 7.02 (tt, 1H, J ¼ 7.4 Hz, J ¼ 1.0 Hz,
phenyl-H), 7.01–7.11 (m, 2H, phenyl-H), 7.22 (dd, 2H, J ¼
7.6 Hz, J ¼ 8.5 Hz, phenyl-H), 7.80, (d, J ¼ 8.9 Hz, 2H, phe-
nyl-H), 7.84 (d, 2H, J ¼ 8.5 Hz, phenyl-H), 10.33 (s, 1H,
NH); 13C-NMR (DMSO-d6, APT): d 19.9 (CH3), 120.4, 124.4,
126.9, 127.8, 129.3 (9ꢀ CH, Ph), 135.9 (Cq), 137.6 (Cq),
141.3 (Cq), 155.5 (N¼¼CAN), 168.4 (CO). Anal. Calcd. for
C15H15N3O4S: C, 54.04%; H, 4.54%; N, 12.60%. Found C,
54.01%; H, 4.57%; N, 12.37%.
N-Acetoxy-4-(N0-(4-methoxyphenyl)sulfamoyl)benzimidamide
(2f). Following the general procedure, product 2f was afforded
from 1f (625 mg, 2.17 mmol). Yield 590 mg (75%). White
1
crystalline solid, mp 150–152ꢁC; H-NMR (DMSO-d6): d 2.12
(s, 3H, CH3), 3.66 (s, 3H, OCH3), 6.80 (d, J ¼ 9.2 Hz, 2H,
phenyl-H), 6.91 (s, 2H, NH2), 6.97 (d, J ¼ 9.2 Hz, 2H, phe-
nyl-H), 7.72 (d, J ¼ 8.6 Hz, 2H phenyl-H), 7.83 (d, J ¼ 8.8
Hz, 2H, phenyl-H), 9.96 (s, 1H, NH); 13C-NMR (DMSO-d6,
APT): d 19.9 (CH3), 55.3 (OCH3), 114.5, 123.8, 126.9, 127.7
(8ꢀ CH, Ph), 129.9 (Cq), 135.7 (Cq), 141.2 (Cq), 155.5
(N¼¼CAN), 156.8 (Cq), 168.4 (CO). Anal. Calcd. for
C16H17N3O5S: C, 52.88%; H, 4.72%; N, 11.56%. Found C,
52.67%; H, 4.79%; N, 11.38%.
N-Acetoxy-4-(N0-(3-methoxyphenyl)sulfamoyl)benzimidamide
(2g). Following the general procedure, product 2g was
afforded from 1g (641 mg, 2.22 mmol). Yield 600 mg (74%).
1
White solid, mp 120–121ꢁC; H-NMR (DMSO-d6): d 2.12 (s,
3H, CH3), 3.65 (s, 3H, CH3), 6.60 (ddd, J ¼ 8.5 Hz, J ¼ 2.4
Hz, J ¼ 0.6 Hz, 1H, phenyl-H), 6.65–6.67 (m, 2H, phenyl-H),
6.91 (s, 2H, NH2), 7.12 (dd, J ¼ 8.5 Hz, J ¼ 8.5 Hz, 1H, phe-
nyl-H), 7.82 (d, J ¼ 8.5 Hz, 2H, phenyl-H), 7.85 (d, J ¼ 8.8
Hz, 2H, phenyl-H), 10.35 (s, 1H, NH); 13C-NMR (DMSO-d6,
APT): d 19.9 (CH3), 55.1 (OCH3), 106.0, 109.4, 112.2, 126.9,
127.8, 130.2 (8ꢀ CH, Ph), 136.0 (Cq), 138.8 (Cq), 141.2 (Cq),
155.5 (N¼¼CAN), 159.8 (Cq), 168.4 (CO). Anal. Calcd. for
C16H17N3O5S: C, 52.88%; H, 4.72%; N, 11.56%. Found C,
52.48%; H, 4.75%; N, 11.40%.
N-Acetoxy-4-(N0-(3-methoxybenzyl)sulfamoyl)benzimida-
mide (2c). Following the general procedure, product 2c was
afforded from 1c (346 mg, 1.14 mmol). Yield 333 mg (77%).
1
White solid, mp 118–120ꢁC; H-NMR (DMSO-d6): d 2.14 (s,
3H, CH3), 3.68 (s, 3H, OCH3), 3.98 (s, 2H, CH2), 6.77–6.81
(m, 3H, phenyl-H), 6.94 (s, 2H, NH2), (7.18 (dd, J ¼ 7.6 Hz,
J ¼ 8.8 Hz, 1H, phenyl-H), 7.85 (d, J ¼ 8.5 Hz, 2H, phenyl-
H), 7.89 (d, J ¼ 8.6 Hz, 2H, phenyl-H), 8.22 (s, 1H, NH);
13C-NMR (DMSO-d6, APT): d 19.9 (CH3), 46.2 (CH2), 55.1
(OCH3), 112.9, 113.1, 119.8, 126.7, 127.7, 129.5 (8ꢀ CH, Ph),
135.4 (Cq), 129.2 (Cq), 142.5 (Cq), 155.5 (N¼¼CAN), 159.4
(Cq), 168.5 (CO). Anal. Calcd. for C17H19N3O5S: C, 54.10%;
H, 5.07%; N, 11.13%. Found C, 54.06%; H, 5.16%; N,
10.89%.
N-Acetoxy-4-(N0-(3,4-dimethoxyphenyl)sulfamoyl)benzimi-
damide (2h). Following the general procedure, product 2h was
afforded from 1h (430 mg, 1.35 mmol). Yield 504 mg (95%).
1
White crystalline solid, mp 116–118ꢁC; H-NMR (DMSO-d6):
d 2.12 (s, 3H, CH3), 3.63 (each s, 6H, OCH3), 6.54 (dd, J ¼
8.5 Hz, J ¼ 2.5 Hz, 1H, phenyl-H), 6.69 (d, J ¼ 2.2 Hz, 1H,
phenyl-H), 6.79 (d, J ¼ 8.5 Hz, 1H, phenyl-H), 6.91 (s, 2H,
NH2), 7.76 (d, J ¼ 8.5 Hz, 2H, phenyl-H), 7.84 (d, J ¼ 8.5
Hz, 2H, phenyl-H), 9.97 (s, 1H, NH); 13C-NMR (DMSO-d6,
APT): d 19.9 (CH3), 55.6, 55.7 (OCH3), 106.9, 112.3, 113.9,
127.0, 127.7 (7ꢀ CH, Ph), 130.4 (Cq), 135.8 (Cq), 141.2 (Cq),
146.4 (Cq), 149.0 (Cq), 155.5 (N¼¼CAN), 168.4 (CO). Anal.
Calcd. for C17H19N3O6S: C, 51.90%; H, 4.87%; N, 10.68%.
Found C, 50.73%; H, 5.17%; N, 10.38%.
General procedure for the preparation of 1,2,4-oxadia-
zoles (3a–3h). Compound 2 was stirred in acetic acid (15 mL)
for 6 h at 80ꢁC. The solvent was removed under reduced pres-
sure, and the corresponding 1,2,4-oxaziazole was obtained af-
ter recrystallization from ethyl acetate/hexane.
N-Acetoxy-4-(N0-(3,4-dimethoxybenzyl)sulfamoyl)benzimi-
damide (2d). Following the general procedure, product 2d was
afforded from 1d (341 mg, 1.03 mmol). Yield 380 mg (91%).
1
White solid, mp 137–138ꢁC; H-NMR (DMSO-d6): d 2.14 (s,
3H, CH3), 3.65, 3.69 (each s, 6H, OCH3), 3.93 (s, 2H, CH2),
6.72 (dd, J ¼ 8.2 Hz, J ¼ 1.9 Hz, 1H, phenyl-H), 6.76 (d, J ¼
1.9 Hz, 1H, phenyl-H), 6.81 (d, J ¼ 8.2 Hz, 1H, phenyl-H),
6.93 (s, 2H, NH2), 7.83 (d, J ¼ 8.9 Hz, 2H, phenyl-H), 7.88
(d, J ¼ 8.5 Hz, 2H, phenyl-H), 8.13 (s, 1H, NH); 13C-NMR
(DMSO-d6, APT): d 19.9 (CH3), 46.2 (CH2), 55.5, 55.7
(OCH3), 111.7, 111.8, 120.0, 126.7, 127.6 (7ꢀ CH, Ph), 129.8
(Cq), 135.4 (Cq), 142.6 (Cq), 148.2 (Cq), 148.7 (Cq), 155.5
(N¼¼CAN), 168.5 (CO). Anal. Calcd. for C18H21N3O6S: C,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

412
S. Dosa, J. Daniels, and M. Gu¨tschow
Vol 48
Hz, 2H, phenyl-H), 7.91 (d, J ¼ 8.8 Hz, 2H, phenyl-H), 8.13
(d, J ¼ 8.8 Hz, 2H, phenyl-H), 10.38 (s, 1H, NH); 13C-NMR
(DMSO-d6, APT): d 12.2 (CH3), 120.6, 124.6, 127.8, 128.0,
129.4 (9ꢀ CH, Ph), 130.3 (Cq), 137.5 (Cq), 142.1 (Cq), 166.8
(N¼¼CAN), 178.2 (N¼¼CAO). Anal. Calcd. for C15H13N3O3S:
C, 57.13%; H, 4.16%; N, 13.33%. Found C, 57.22%; H,
4.28%; N, 13.09%.
N-Benzyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzenesulfona-
mide (3a). Following the general procedure, compound 3a
was prepared from 2a (348 mg, 1.0 mmol). Yield 263 mg
1
(80%). Colorless solid, mp 158–159ꢁC; H-NMR (DMSO-d6):
d 2.69 (s, 3H, CH3), 4.04 (s, 2H, CH2), 7.17–7.28 (m, 5H, phe-
nyl-H), 7.94 (d, 2H, J ¼ 8.6 Hz, phenyl-H), 8.14 (d, J ¼ 8.5
Hz, 2H, phenyl-H), 8.32 (s, 1H, NH); 13C-NMR (DMSO-d6,
APT): d 12.2 (CH3), 46.3 (CH2), 127.3, 127.5, 127.7, 127.8,
128.3 (9ꢀ CH, Ph), 129.7 (Cq), 137.6 (Cq), 143.5 (Cq), 166.9
(N¼¼CAN), 178.1 (N¼¼CAO). Anal. Calcd. for C16H15N3O3S:
C, 58.34%; H, 4.59%; N, 12.76%. Found C, 58.41%; H,
4.75%; N, 13.01%.
N-(4-Methoxybenzyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)ben-
zenesulfonamide (3b). Following the general procedure, com-
pound 3b was prepared from 2b (377 mg, 1.0 mmol). Yield
338 mg (94%). Colorless solid, mp 152–153ꢁC; 1H-NMR
(DMSO-d6): d 2.69 (s, 3H, CH3), 3.67 (s, 3H, OCH3), 3.96 (d,
J ¼ 6.3 Hz, 2H, CH2), 6.79 (d, J ¼ 8.5 Hz, 2H, phenyl-H),
7.12 (d, J ¼ 8.5 Hz, 2H, phenyl-H), 7.92 (d, J ¼ 8.9 Hz, 2H,
phenyl-H), 8.14 (d, J ¼ 8.9 Hz, 2H, phenyl-H), 8.22 (t, J ¼
6.3 Hz, 1H, NH); 13C-NMR (DMSO-d6, APT): d 12.2 (CH3),
45.9 (CH2), 55.2 (OCH3), 113.8, 127.5, 127.8, 129.1 (8ꢀ CH,
Ph), 129.4 (Cq), 129.7 (Cq), 143.5 (Cq), 158.6 (Cq), 166.9
(N¼¼CAN), 178.1 (OAC¼¼N). Anal. Calcd. for C17H17N3O4S:
C, 56.81%; H, 4.77%; N, 11.69%. Found C, 56.83%; H,
4.77%; N, 11.49%.
N-(3-Methoxybenzyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)ben-
zenesulfonamide (3c). Following the general procedure, com-
pound 3c was prepared from 2c (199 mg, 527 lmol). Yield
160 mg (84%). Colorless solid, mp 152–154ꢁC; 1H-NMR
(DMSO-d6): d 2.69 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 4.03 (d,
J ¼ 6.0 Hz, 2H, CH2), 6.73–6.80 (m, 3H, phenyl-H), 7.15
(ddd, J ¼ 7.6 Hz, J ¼ 7.6 Hz, J ¼ 1.0 Hz, 1H, phenyl-H),
7.93 (d, J ¼ 8.6 Hz, 2H, phenyl-H), 8.12 (d, J ¼ 8.5 Hz, 2H,
phenyl-H), 8.31 (t, J ¼ 6.0 Hz, 1H, NH); 13C-NMR (DMSO-
d6, APT): d 12.2 (CH3), 46.2 (CH2), 55.1 (OCH3), 112.9,
113.1, 119.9, 127.5, 127.8, 129.4 (8ꢀ CH, Ph), 129.7 (Cq),
139.1 (Cq), 143.5 (Cq), 159.3 (Cq), 166.9 (N¼¼CAN), 178.1
(N¼¼CAO). Anal. Calcd. for C17H17N3O4S: C, 56.81%; H,
4.77%; N, 11.69%. Found C, 56.70%; H, 4.78%; N, 11.39%.
N-(3,4-Dimethoxybenzyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)
benzenesulfonamide (3d). Following the general procedure,
compound 3d was prepared from 2d (390 mg, 957 lmol).
Yield 294 mg (79%). Colorless solid, mp 170–171ꢁC; 1H-
NMR (DMSO-d6): d 2.68 (s, 3H, CH3), 3.63, 3.66 (each s, 6H,
OCH3), 3.98 (s, 2H, CH2), 6.71 (dd, J ¼ 8.2 Hz, J ¼ 1.9 Hz,
1H, phenyl-H), 6.75 (d, J ¼ 1.9 Hz, 1H, phenyl-H), 6.78 (d, J
¼ 8.2 Hz, 1H, phenyl-H), 7.91 (d, J ¼ 8.5 Hz, 2H, phenyl-H),
8.12 (d, J ¼ 8.8 Hz, 2H, phenyl-H), 8.22 (s, 1H, NH); 13C-
NMR (DMSO-d6, APT): d 12.2 (CH3), 46.2 (CH2), 55.4, 55.7
(OCH3), 111.7, 111.8, 120.0, 127.5, 127.7 (7ꢀ CH, Ph), 129.6
(Cq), 129.7 (Cq), 143.5 (Cq), 148.2 (Cq), 148.7 (Cq), 166.9
(N¼¼CAN), 178.1 (N¼¼CAO). Anal. Calcd. for C18H19N3O5S:
C, 55.52%; H, 4.92%; N, 10.97%. Found C, 55.34%; H,
5.14%; N, 10.46%.
N-(4-Methoxyphenyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzene-
sulfonamide (3f). Following the general procedure, compound
3f was prepared from 2f (190 mg, 523 lmol). Yield 154 mg
1
(85%). Colorless solid, mp 174–177ꢁC; H-NMR (DMSO-d6):
d 2.66 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 6.80 (d, J ¼ 9.2 Hz,
2H, phenyl-H), 6.97 (d, J ¼ 9.2 Hz, 2H, phenyl-H), 7.83 (d, J
¼ 8.5 Hz, 2H, phenyl-H), 8.12 (d, J ¼ 8.2 Hz, 2H, phenyl-H),
10.01 (s, 1H, NH); 13C-NMR (DMSO-d6, APT): d 12.2 (CH3),
55.3 (OCH3), 114.5, 124.0, 127.8, 127.8 (8ꢀ CH, Ph), 129.8
(Cq), 130.1 (Cq), 142.0 (Cq), 156.9 (Cq), 166.8 (N¼¼CAN),
178.1 (N¼¼CAO). Anal. Calcd. for C16H15N3O4S: C, 55.64%;
H, 4.38%; N, 12.17%. Found C, 55.52%; H, 4.37%; N,
12.06%.
N-(3-Methoxyphenyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzene-
sulfonamide (3g). Following the general procedure, compound
3g was prepared from 2g (406 mg, 1.12 mmol). Yield 350 mg
1
(90%). Colorless solid, mp 162–164ꢁC; H-NMR (DMSO-d6):
d 2.66 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 6.59–6.61 (m, 1H,
phenyl-H), 6.67–6.68 (m, 2H, phenyl-H), 7.12 (dd, J ¼ 8.5
Hz, J ¼ 8.5 Hz, 1H, phenyl-H), 7.93 (d, J ¼ 8.2 Hz, 2H, phe-
nyl-H), 8.14 (d, J ¼ 8.5 Hz, 2H, phenyl-H), 10.40 (s, 1H,
NH); 13C-NMR (DMSO-d6, APT): d 12.2 (CH3), 55.2 (OCH3),
106.2, 109.6, 112.4, 127.8, 128.0, 130.2 (8ꢀ CH, Ph), 130.3
(Cq), 138.7 (Cq), 142.0 (Cq), 159.9 (Cq), 166.7 (N¼¼CAN),
178.1 (N¼¼CAO). Anal. Calcd. for C16H15N3O4S: C, 55.64%;
H, 4.38%; N, 12.17%. Found C, 55.88%; H, 4.38%; N,
12.06%.
4-(5-Methyl-1,2,4-oxadiazol-3-yl)-N-(3,4-dimethoxyphenyl)-
benzenesulfonamide (3h). Following the general procedure,
compound 3h was prepared from 2h (490 mg, 1.25 mmol).
Yield 411 mg (88%). Brown crystals, mp 186–187ꢁC; 1H-
NMR (DMSO-d6): d 2.66 (s, 3H, CH3), 3.62, 3.65 (s, 6H,
OCH3), 6.55 (dd, J ¼ 8.5 Hz, J ¼ 2.5 Hz, 1H, phenyl-H),
6.68 (d, J ¼ 2.2 Hz, 1H, phenyl-H), 6.97 (d, J ¼ 8.9 Hz, 1H,
phenyl-H), 7.86 (d, J ¼ 8.5 Hz, 2H, phenyl-H), 8.13 (d, J ¼
8.9 Hz, 2H, phenyl-H), 10.02 (s, 1H, NH); 13C-NMR (DMSO-
d6, APT): d 12.2 (CH3), 55.6, 55.7 (OCH3), 107.1, 112.2,
114.2, 127.8, 127.9 (7ꢀ CH, Ph), 130.2 (Cq), 130.2 (Cq),
142.0 (Cq), 146.6(Cq), 149.0 (Cq), 166.8 (N¼¼CAN), 178.1
(N¼¼CAO). Anal. Calcd. for C17H17N3O5S: C, 54.39%; H,
4.56%; N, 11.19%. Found C, 54.21%; H, 4.70%; N, 10.99%.
Acknowledgment. This work was supported by the German
Research Foundation, SFB 645. The authors thank Hans-Georg
¨
Hacker for support.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet