Synthesis of 1,2-diazol-4-sulfonamides, 1,2,4- and 1,2,5-oxadiazol-3- sulfonamides, 1,2,3-triazol-4-sulfonamides, and pyrimidine-5-sulfonamides starting from cyanomethanesulfonyl chloride

Article abstract of DOI:10.1007/s00706-006-0536-7

Cyanomethanesulfonyl chloride was reacted with amines yielding cyanomethanesulfonamides which could be transformed into alkoxymethylidene and aminomethylidene derivatives. The reaction of alkoxymethylidene derivatives with phenylhydrazine resulted in the

Full text of DOI:10.1007/s00706-006-0536-7

Monatshefte f€ur Chemie 137, 1321–1347 (2006)
DOI 10.1007/s00706-006-0536-7
Synthesis of 1,2-Diazol-4-sulfonamides,
1,2,4- and 1,2,5-Oxadiazol-3-sulfonamides,
1,2,3-Triazol-4-sulfonamides,
and Pyrimidine-5-sulfonamides starting
from Cyanomethanesulfonyl Chloride
ꢀ
Martin Winterwerber, Rouzita Geiger, and Hans-Hartwig Otto
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
Received March 25, 2006; accepted April 5, 2006
Published online September 22, 2006 # Springer-Verlag 2006
Summary. Cyanomethanesulfonyl chloride was reacted with amines yielding cyanomethanesulfon-
amides which could be transformed into alkoxymethylidene and aminomethylidene derivatives. The
reaction of alkoxymethylidene derivatives with phenylhydrazine resulted in the formation of 5-
aminopyrazol-4-sulfonamides, whereas from cyanomethanesulfonamides via the N-hydroxyamidine
derivatives and their reaction with esters 1,2,4-oxadiazol-3-methanesulfonamides became accessi-
ble. Nitrosation of cyanomethanesulfonamides yielded 2-hydroxyimino derivatives which were then
transformed into 2-hydroxyimino N-hydroxyamidine derivatives, and finally cyclized into 4-amino-
1,2,5-oxadiazol-3-sulfonamides. On the other hand diazotation of cyanomethanesulfonamides gave the
2-arylhydrazono derivatives, which after transformation into N-hydroxyamidine derivatives gave by
reaction with POCl3 5-amino-1,2,3-triazol-4-sulfonamides. Finally, the reaction between cyanomethane-
sulfonamides and formamidinium acetate opened an easy access to 4-aminopyrimidine-5-sulfonamides,
which could be transformed by trialkyl orthoformiates into substituted pyrimidino[4,5-e][1,2,4]thia-
diazine derivatives. All intermediates as well as transformation products of the heterocyclic systems
were isolated and well characterized. Mechanisms were discussed, and the stereochemistry, when
necessary and possible, was elucidated.
Keywords. Cyanomethanesulfonyl chloride; 1,2-Diazol-4-sulfonamides; Oxadiazol-3-sulfonamides;
1,2,3-Triazol-4-sulfonamides; Pyrimidine-5-sulfonamides.
Introduction
Cyanomethanesulfonyl chloride [1] is a highly reactive and unstable compound
whose potency for synthesis is only poorly explored. Some reactions with aromatic
ꢀ
Corresponding author. E-mail: ottohh@pharmazie.uni-greifswald.de

1322
M. Winterwerber et al.
amines and applications in drug research and agriculture chemistry are described
[2], the cycloaddition with enamines yielded thietane 1.1-dioxides [3], and by re-
action with Et3N the sulfene was obtained and used in [4 þ 2] cycloadditions [4].
Some years ago, we decided to start a systematic study of this three-functional
compound, which should allow reactions at the sulfonyl chloride function, at the
methylene group, and at the nitrile function. By a combination of these possibilities
we hoped to be able to synthesize a large number of derivatives, and finally to
develop easy synthetic routes to different types of heterocyclic sulfonamides show-
ing interesting properties. First results are presented. Some other will be published
in a second paper [5].
Results and Discussion
Cyanomethanesulfonyl chloride (1) prepared from chloroacetonitrile by reaction
with Na2SO3 and PCl5=POCl3 [6] reacted with primary or secondary amines yield-
ing the sulfonamides 2b–2m (Scheme 1). All reactions gave satisfactory to excel-
lent yields when they were performed at 0ꢁC by adding the freshly distilled amine
to a solution of 1 in dry(!) Et2O. Reasonable yields of the N-unsubstituted 2a [7]
were obtained when a solution of 1 in AcOEt was dropwise neutralized with a
saturated solution of NH3 in CHCl3. This method seems to us to be more effective
than the described one.
The synthesis of sulfonylureas by reaction of 1 with isoureas or cyanamide [8]
completely failed, and when 2b or 2c in EtOH or acetone were refluxed with
KNCO [9] no products were isolated. Instead, the sulfonylureas 4a and 4b were
obtained (yields ꢂ80%) when the starting material 2b or 2c, BuLi, and the iso-
cyanate were reacted at ꢃ78ꢁC under N2 in THF. We found that this procedure was
Scheme 1

Synthesis of Heterocyclic Sulfonamides
1323
useful not only for the synthesis of the sulfonylureas but even for the acylation of
the sulfonamide nitrogen of 2 with acyl chlorides like methyl or benzyl chlorofor-
mate yielding the hitherto unknown cyanomethanesulfonyl carbamidates. Some
aromatic sulfonyl carbamidates were described and used as agrochemicals [10].
We obtained by this procedure the N-acylated sulfonamides 3a–3p. Compound 3g
was obtained from 2c and acetyl chloride, and 3f was prepared from 2c with ethyl
chlorothioformate.
The IR spectra (KBr) of 2a–2m are characterized by bands at 3300–3200
(NH), two sharp bands at 2980 and 2920 (CH2), a low intensity band at 2260–
2270 (CꢄN), and characteristic bands at 1350 and 1150 cmꢃ1 (SO2). All 1H NMR
spectra show together with the signals caused by the N-substituents a singlet signal
around 4.5 ppm caused by the two methylene protons. IR spectra of the sulfony-
lureas 4a and 4b and of the acylated compounds 3 show an additional carbonyl
band at 1740–1720 cmꢃ1. The spectrum of 3f shows a band at 1675 cmꢃ1 (COSEt),
and that of 3g at 1710 cmꢃ1.
The methylene group of the sulfonamides 2 and 3 enabled a number of con-
densation reactions. Reactions with orthoformates in Ac2O yielded after refluxing
for 2 h the alkoxymethylidene derivatives 5a–5o in good to reasonable yields.
Scheme 2

1324
M. Winterwerber et al.
Compound 5e was obtained from 5d by crystallization from isopropanol. The
aminomethylidene derivatives 6a–6l were accessible either by reaction of the par-
ent alkoxymethylidene derivatives 5 with NH3 in EtOH at 0ꢁC (6e–6g, 6i) or by
reaction of the methylene sulfonamides 2 with formamidinium acetate in refluxing
MeOH (Scheme 2).
As can be seen from the spectroscopic data compounds 5 and 6 were isolated as
single isomers. The IR spectra of these conjugated nitriles show a band at 2210–
2200 cmꢃ1 for the conjugated CꢄN group, and in their 1H NMR spectra one sharp
1
singlet between 7.5 and 8.0 ppm indicates the olefinic proton. In the H NMR
spectra (400 MHz) of some compounds 6 like 6e we found a coupling between
2-H and the protons of the amino group. A definitive decision between (E)- and
(Z)-isomer of three-substituted olefins from their spectroscopic data still remains a
problem. Estimation of the 2-H signal position using increment systems [11] results
only in small differences between (E)- and (Z)-isomer. The same problem arises
3
using the JC,H coupling in the 13C NMR spectra [12]. Significant differences are
found when calculating the energies of the (E)- and (Z)-isomers [13]. In all studied
examples the (E)-isomer was the more stable one. Therefore, we propose that com-
pounds 5 and 6 were obtained as (E)-isomers.
The use of these compounds for the synthesis of heterocyclic sulfonamides was
first demonstrated by the transformation of 5c by the reaction with phenylhydrazine
in EtOH at room temperature yielding the crystalline 1,2-diazol sulfonamide 8b,
yield 70%, from which after hydrolysis by EtONa in EtOH at 50ꢁC and acidifica-
tion 9a was obtained. The first reaction step may be explained as a Michael reac-
tion of the hydrazine to the ꢀ,ꢁ-unsaturated nitrile followed by an elimination of
EtOH and an addition of the amino group to the nitrile function [14]. An identical
product was isolated from the sequence 5b ! 8a ! 9a. The analogous products 9b
and 9c were prepared from 5g and 5f via 8c and 8d with yields of 38 and 55%.
Finally, we transformed 9a by refluxing with formamidinium acetate in n-BuOH
into the bicyclic sulfonamide 10 (Scheme 3).
Transforming the cyanomethanesulfonamides 2 and 3 with H2NOHꢅHCl into
the N-hydroxyamidines 11a–11h opened a comfortable route to the 1,2,4-oxadia-
zol-3-methylsulfonamides. It is essential for the successful reaction, that hydroxy-
lamine is liberated from its salt in an aqueous solution by NaHCO3, and that a
Scheme 3

Synthesis of Heterocyclic Sulfonamides
1325
Scheme 4
solution of the cyanomethanesulfonamide in EtOH is slowly added to that aqueous
solution at room temperature [15] (Scheme 4). The N-hydroxyamidines 11 were
identified by usual spectroscopic and analytical methods. The H–O group gives a
sharp band at 3500 cmꢃ1, the H2N group at 3400 cmꢃ1, and the sulfonamide NH is
1
recorded at 3260 cmꢃ1 in the IR spectra. The H NMR spectra of the derivatives
with R0¼H showed a singlet at ꢂ3.8 ppm from the methylene protons, whereas this
signal was found in the spectra of the other compounds at ꢂ4.4 ppm demonstrating
the effect of the second substituent.
For characterization and for clarifying the reaction possibilities of 11a–11h
we tried a number of reactions with electrophiles, mainly using compound 11b.
O-Silylation with ClSiMe3 in the presence of Et3N was successful. All expected
signals were present in the 1H NMR spectrum of the crude product, but isolation of
the product failed. Reactions with acyl chlorides were successful when done in
THF or HCCl3 at room temperature, and in the presence of Et3N. We obtained the

1326
M. Winterwerber et al.
products 13a, 13d, and 13e from 11b, and 16 from 11h with yields ꢂ80% from
reactions with equivalent amounts of benzoyl chloride, methyl, and benzyl chloro-
formate using this method.
Compound 13b was isolated from the reaction with Ac2O in AcOH at room
temperature, and 13c was prepared by refluxing 11b for 4 h in triethyl orthofor-
mate, yield 60%. When the O-acylated compound 13a was reacted with equivalent
amounts of ethyl, phenyl, and 4-nitrophenyl chloroformate the N-acylated deriva-
tives 17a, 17b, and 17c were isolated as crystalline compounds with yields between
50 and 60%. On the other hand, reactions with esters in EtOH in the presence of
EtONa yielded the 1,2,4-oxadiazol derivatives as is elucidated by the reactions of
11b and 11c with ethyl benzoate yielding 12a and 12b, of 11b with diethyl carbo-
nate to 15, and finally by refluxing of 13b in EtOH with EtONa for 2 h yielding 14
(Scheme 4).
The synthesis of 1,2,4-oxadiazol derivatives is possible either by a 1,3-dipolar
cycloaddition between a nitrile and a nitriloxide [16] or by the long known cycli-
zation of O-acylated amidoximes, which was first described by Tiemann in 1884
[17], but to the best of our knowledge until today none of these methods was used
for the synthesis of such sulfonamide derivatives [18] we described here.
Interesting results were found in reactions of the sulfonamides with N-electro-
philes (Scheme 5). The reaction of 2b, 2c, and 2n [6] with NaNO2 and acid at 0ꢁC
yielded the (E)-oxime derivatives 18a–18c as crystalline, stable compounds. In
analogy to the known synthesis of aminomalononitrile we tried to reduce these
compounds to the hitherto unknown ꢀ-aminosulfonamides 19 but we failed com-
pletely. Whereas ꢀ-aminocarboxylic acids and -phosphonic acids and their deriva-
tives are well known compounds the synthesis of ꢀ-aminosulfonic acids or their
derivatives or other ꢀ-N-substituted sulfonyl compounds seems to be difficult or
not possible [19].
Scheme 5

Synthesis of Heterocyclic Sulfonamides
1327
The reaction of 3 or 4 with diazonium salts in EtOH in the presence of AcONa
enabled the synthesis of the stable hydrazono derivatives 20a–20g as yellow, crys-
talline compounds with yields from 60 to 80%. The reactions must be done at
maximal 0ꢁC, otherwise the mixture becomes red indicating the formation of for-
mazanes. The hydrazone 20h was prepared from 20f by refluxing in a solution of
MeONa in MeOH with 79% yield. It was not accessible by diazotizing of 2c.
It should be mentioned that a CꢄN band was not detected in the IR spectra of
the hydroxyimino compounds 18a–18c, whereas in the IR spectra of the hydrazono
compounds 20a–20h the CꢄN band at 2210 cmꢃ1 was the strongest band of the
spectra.
Nevertheless, the hydroxyimino compounds 18a–18c and the hydrazono com-
pounds 20a–20h allowed a number of interesting transformations. It is long known
that 1,2-dioximes can be dehydrated forming 1,2,5-oxadiazols (furazans) [20, 21],
but there are not many examples described. Therefore, we transformed 18a with
H2NOHꢅHCl in the presence of NaHCO3 in H2O by refluxing for 6 h into the hy-
droxyamidine derivative 21 which by refluxing with EtONa in EtOH or by reaction
with POCl3 gave the 4-amino-1,2,5-oxadiazol sulfonamide 22. When the hydro-
xyamidine 21 was refluxed with HC(OEt)3, and when the crude intermediate 24
was crystallized from CHCl3 the N-formyl derivative 23 was isolated as a crystal-
line compound, yield 80%. Refluxing of 21 in Ac2O ended up with the isolation of
the acetylated 25, and finally, the reaction with methyl chloroformate in THF gave
the N-acylated sulfonamide derivative 26 (Scheme 6).
Formal replacement of the O-atom in 1,2,5-oxadiazols by an N-atom results
in 1,2,3-triazols. This structure is well known, and one of the first examples was
prepared by Dimroth by a reaction between a CH acid with phenyl azide [22].
Another possibility was realized by condensation between a hydrazone and an
oxime [23]. As we had successfully used this method for the synthesis of 1,2,5-
oxadiazols we transferred it to the hydrazono derivatives 20a, 20b, 20e, and 20c.
When they were reacted with H2NOHꢅHCl in the presence of NaHCO3, we ob-
tained the hydroxyimino hydrazono derivatives 27a–27d with yields up to 90%
as crystalline compounds. During this reaction the yellow color of the starting
materials disappeared. Treatment of 27 with POCl3 transformed them into the
Scheme 6

1328
M. Winterwerber et al.
Scheme 7
1,2,3-triazol-4-sulfonamides 28a–28d isolated as crystalline compounds with
high yields (Scheme 7). These derivatives were treated with EtONa at room tem-
perature, whereby the deacylated derivatives 29a–29c were obtained. Acylation
of the amino group was possible by reaction with Ac2O as demonstrated by the
transformation of 28a into 31, or by reaction with ClCOSEt as shown by the
reaction of 29b to 32. Compound 27d was acetylated to the derivative 30, but
it was not possible to transform this into a triazolo derivative. Furthermore,
we have to add that the sulfonylurea derivatives 20f and 20g could not be trans-
formed into the hydroxyimino compounds and thereby not transferred into
aminotriazolsulfonylurea derivatives. Both decomposed completely during the
reaction with H2NOHꢅHCl.
The only sparingly soluble 4-aminopyrimidine-5-sulfonamides 33a–33i were
obtained from the reaction between the parent aminomethylidene compounds 6
and formamidinium acetate, or with higher yields (ꢂ80%) without isolation of
the aminomethylidene compounds by refluxing for 6 h of the cyanomethanesul-
fonamides 2b–2l and an excess of formamidinium acetate in n-BuOH (Scheme 8).
The N-acetyl derivatives 34a–34c were prepared by refluxing of the parent com-
pounds 33 in AcOH=Ac2O. Finally, compounds 33g and 33h were transformed
into the pyrimidinothiadiazine derivatives 36a and 36b by refluxing with triethyl
orthoformate and catalytic amounts of AcOH [24] for 6 h. Compound 35 was

Synthesis of Heterocyclic Sulfonamides
1329
Scheme 8
obtained as a by-product (5%) in the synthesis of 33e from 2g and formamidi-
nium acetate.
Experimental Part
1
Melting points: Linstr€om apparatus; IR spectra (KBr): Perkin-Elmer IR 1310, Beckman IR 4240; H
and 13C NMR spectra: Varian T 60 (1H, 60MHz), Bruker WP 80=90 (1H, 80=90MHz), WM 300, AM
1
400 (300=400 MHz for H, 100.614MHz for 13C), room temperature, internal TMS, values from
80MHz spectra in CDCl3, if not noted otherwise; MS spectra: Finnigan GC MS 4000, MAT 312,
MAT 44S; elemental analyses: Institute of Pharmacy or Chemisches Laboratorium, University of
Freiburg (Germany) or Greifswald (Germany): All compoundsy gave satisfactory elemental analyses;
results agreed with the calculated values within experimental error. Tetrahydrofuran (THF) was stored
over CaCl2 or KOH, then refluxed with Na and benzophenone, and distilled prior to use. Other solvents
were dried=purified according to literature procedures [25]. Thin-layer chromatography (tlc): Pre-
coated silica-gel 60F254 plates (Merck 5549 or 5715). Column chromatography (CC): Silica gel 60
(Merck 7734).
Cyanomethanesulfonyl chloride (1)
See Ref. [1].
Cyanomethanesulfonamide (2a, C2H4N2O2S) [7]
A satd solution of NH3 in CHCl3 was slowly added at 0ꢁC to a solution of 1 (4.2g, 30 mmol) in
100 cm3 AcOEt. After stirring for 2 h at room temperature, the solvent was evaporated in vacuo, the
residue was dissolved in AcOEt, and the solution was washed with a satd NH4Cl solution, dried
(Na2SO4), and evaporated. Crystallization was induced by a few drops of CHCl3, and storing at 0ꢁC
for several hours. Yield 0.9 g (25%); colorless crystals; mp 97–98ꢁC (AcOEt=CHCl3); IR: ꢂꢀ¼ 3300,
y
For simplicity, compounds were named as cyano sulfonamides, ignoring potentially higher-ranking
substituents

1330
M. Winterwerber et al.
3220 (NH2), 2980, 2920 (CH2), 2260 (CN), 1360, 1140 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.41
(s, CH2), 6.7–7.1 (s, NH2) ppm.
General Procedure for the Synthesis of 2
At 0ꢁC, a solution of 1 in 100 cm3 (for 100 mmol) or 20–30 cm3 (for 10 mmol) Et2O was slowly added
to a solution of the amine (freshly distilled!) in 100–500 (50–60) cm3 Et2O. The mixture was stirred
for 2 h at room temperature, the precipitate was separated, and the filtrate was concentrated in vacuo to
the half (only for 100 mmol reactions), washed with H2O, dried (Na2SO4), and evaporated. The residue
was crystallized as noted.
N-Phenylcyanomethanesulfonamide (2b)
See Ref. [6].
N-Benzylcyanomethanesulfonamide (2c, C9H10N2O2S)
From 1 (14 g, 100 mmol) and 21.4g benzylamine (200mmol). Yield 12.6g (60%); mp 49–50ꢁC
(CHCl3=CCl4); IR: ꢂꢀ¼ 3290 (NH), 3090 (CH), 2980, 2930 (CH2), 2265 (CN), 1340, 1150 (SO2)
1
cmꢃ1; H NMR: ꢃ ¼ 3.73 (s, CH2), 4.33 (s, CH2), 5.5–6.0 (s, NH), 7.4 (s, 5 ar H) ppm.
N-(4-Methoxybenzyl)cyanomethanesulfonamide (2d, C10H12N2O3S)
From 1 (1.4g, 10 mmol) and 2.7 g 4-methoxybenzylamine (20mmol). Yield 1.2 g (50%); mp 70ꢁC
(CHCl3=CCl4); IR: ꢂꢀ¼ 3300 (NH), 3010 (CH), 2990, 2930 (CH2), 2270 (CN), 1335, 1145 (SO2)
1
cmꢃ1; H NMR: ꢃ ¼ 3.75 (s, CH2), 3.81 (s, OMe), 4.4 (d, J ¼ 6 Hz, CH2), 5.5 (t, J ¼ 6 Hz, NH),
6.8–7.4 (m, 4 ar H) ppm.
Cyanomethanesulfopiperidide (2e, C7H12N2O2S)
From 1 (1.4g, 10mmol) and 1.7 g piperidine (20mmol). Yield 1.0 g (60%); mp 134ꢁC (CHCl3=CCl4);
1
IR: ꢂꢀ¼ 2980, 2930 (CH2), 2860 (CH), 2260 (CN), 1340, 1160 (SO2) cmꢃ1; H NMR (acetone-d6):
ꢃ ¼ 1.5–1.7, 3.3–3.5 (2m, 10 al H), 4.11 (s, CH2) ppm.
N-(4-Methoxyphenyl)cyanomethanesulfonamide (2f, C9H10N2O3S)
From 1 (1.4g, 10 mmol) and 2.5 g 4-methoxyaniline (20 mmol). Yield 0.45 g (20%); mp 145ꢁC
(CHCl3=CCl4); IR: ꢂꢀ¼ 3200 (NH), 2980, 2930 (CH2), 2830 (CH), 2260 (CN), 1350, 1160 (SO2)
1
cmꢃ1; H NMR: ꢃ ¼ 3.85 (s, Me), 4.05 (s, CH2), 7.0–7.5 (m, 4 ar H), 8.6–8.8 (s, NH) ppm.
N-Propylcyanomethanesulfonamide (2g, C5H10N2O2S)
From 1 (1.4g, 10 mmol) and 1.2 g n-propylamine (20mmol). Purification by Kugelrohr distillation
(180ꢁC=0.1 Torr). Yield 0.7 g (45%); mp 40–45ꢁC; IR: ꢂꢀ¼ 3280 (NH), 2980, 2920 (CH2), 2880 (CH),
1
2250 (CN), 1325, 1140 (SO2) cmꢃ1; H NMR: ꢃ ¼ 1.0 (t, J ¼ 8 Hz, Me), 1.4–1.8 (m, CH2), 3.0–3.4
(q, J ¼ 7 Hz, CH2), 4.42 (s, CH2), 6.6–7.0 (t, NH) ppm.
N-(2-Chlorobenzyl)cyanomethanesulfonamide (2h, C9H9ClN2O2S)
From 1 (7g, 50 mmol) and 14.2g 2-chlorobenzylamine (100 mmol). Yield 2.8 g (23%); colorless
crystals; mp 67ꢁC; IR: ꢂꢀ¼ 3314 (NH), 3061 (CH), 2990, 2940 (CH2), 2258 (CN), 1336, 1141
1
(SO2) cmꢃ1; H NMR: ꢃ ¼ 3.8 (s, CH2), 4.5 (d, J ¼ 6.6 Hz, CH2), 5.7 (t, J ¼ 6.6, NH), 7.2–7.5 (m, 4
ar H) ppm.
N-(4-Chlorobenzyl)cyanomethanesulfonamide (2i, C9H9ClN2O2S)
From 1 (7 g, 50 mmol) and 14.2 g 4-chlorobenzylamine (100 mmol). Yield 4.3 g (35%); color-
less crystals; mp 90ꢁC; IR: ꢂꢀ¼ 3259 (NH), 2977, 2924 (CH2), 2264 (CN), 1343, 1144 (SO2)
cmꢃ1
;
1H NMR: ꢃ ¼ 3.9 (s, CH2), 4.4 (d, J ¼ 6.6 Hz, CH2), 5.7 (t, J ¼ 6.6 Hz, NH), 7.2–7.5
(m, 4 ar H) ppm.

Synthesis of Heterocyclic Sulfonamides
1331
N-(4-Fluorobenzyl)cyanomethanesulfonamide (2k, C9H9FN2O2S)
From 1 (7g, 50 mmol) and 17.5 g 4-fluorobenzylamine (100mmol). Yield 3.0 g (26%); colorless
crystals; mp 99ꢁC; IR: ꢂꢀ¼ 3290 (NH), 2988, 2934 (CH2), 2263 (CN), 1334, 1160 (SO2) cmꢃ1
;
1H NMR (60 MHz): ꢃ ¼ 3.8 (s, CH2), 4.3 (d, J ¼ 6.6 Hz, CH2), 5.7 (t, J ¼ 6.6 Hz, NH), 6.9–7.5 (m,
4 ar H) ppm.
N-(4-Bromophenyl)cyanomethanesulfonamide (2l, C8H7BrN2O2S)
From 1 (7g, 50mmol) and 17.2 g 4-bromoaniline (100 mmol). Yield 8.5g (31%); colorless crystals;
mp 107ꢁC (CHCl3); IR: ꢂꢀ¼ 3300 (NH), 3100 (CH), 2980, 2940 (CH2), 2280 (CN), 1340, 1150 (SO2)
1
cmꢃ1; H NMR: ꢃ ¼ 4.9 (s, CH2), 7.1–7.6 (m, 4 ar H), 10.8 (s, NH) ppm.
N-(3,4-Dimethoxyphenyl)cyanomethanesulfonamide (2m, C10H12N2O4S)
From 1 (3.5g, 25mmol) and 7.6 g 3,4-dimethoxyaniline (50 mmol). Yield 1.3 g (10%); mp 120ꢁC
1
(CHCl3); IR: ꢂꢀ¼ 3243 (NH), 2955, 2914 (CH2), 2258 (CN), 1349, 1150 (SO2) cmꢃ1; H NMR
(acetone-d6): ꢃ ¼ 3.73, 3.75 (2s, 2 Me), 4.8 (s, CH2), 6.7–7.0 (m, 3 ar H), 10.4 (s, NH) ppm.
Cyanomethanesulfomorpholide (2n)
See Ref. [6].
General Procedure for the Synthesis of 3
At ꢃ78ꢁC, BuLi (6.5cm3, 10 mmol) was added to a solution of the cyanomethane-sulfonamide 2
(10 mmol) in 50 cm3 THF. After 10min, a solution of the acyl chloride (10mmol) in 10cm3 THF was
added, and the mixture was stirred for 1 h at ꢃ78ꢁC. After warming to room temperature, the mixture
was hydrolyzed with a satd NaCl solution (100 cm3), the organic layer was separated, dried (MgSO4),
evaporated in vacuo, and the residue was crystallized from MeOH.
N-Methoxycarbonyl-N-phenylcyanomethanesulfonamide (3a, C10H10N2O4S)
From 2b (1.9g, 10 mmol) and 0.95 g methyl chloroformate. Yield 1.8 g (70%); mp 118ꢁC; IR:
ꢂꢀ¼ 3070 (CH), 2980, 2920 (CH2), 2260 (CN), 1730 (CO), 1370, 1180 (SO2) cmꢃ1
;
1H NMR:
ꢃ ¼ 3.77 (s, Me), 4.68 (s, CH2), 7.4 (s, 5 ar H) ppm.
N-Benzyl-N-(methoxycarbonyl)cyanomethanesulfonamide (3b, C11H12N2O4S)
From 2c (2.1g, 10 mmol) and 0.95g methyl chloroformate. Yield 2.2 g (75%); mp 122–123ꢁC; IR:
1
ꢂꢀ¼ 3070, 3020 (CH), 2980, 2920 (CH2), 2260 (CN), 1730 (CO), 1370, 1150 (SO2) cmꢃ1; H NMR
(acetone-d6): ꢃ ¼ 3.83 (s, Me), 4.97, 5.00 (2s, 2 CH2), 7.2–7.5 (s, 5 ar H) ppm.
N-Benzyl-N-(phenoxycarbonyl)cyanomethanesulfonamide (3c, C16H14N2O4S)
From 2c (2.1g, 10 mmol) and 1.56g phenyl chloroformate. Yield 2.7 g (75%); mp 105ꢁC; IR: ꢂꢀ¼ 3030
1
(CH), 2980, 2920 (CH2), 2270 (CN), 1730 (CO), 1380, 1150 (SO2) cmꢃ1; H NMR (acetone-d6):
ꢃ ¼ 5.18 (m, 2 CH2) 7.1–7.6 (m, 10 ar H) ppm.
N-Benzyl-N-(benzyloxycarbonyl)cyanomethanesulfonamide (3d, C17H16N2O4S)
From 2c (2.1g, 10mmol) and 1.8 g benzyl chloroformate. Yield 2.7 g (80%); mp 91ꢁC; IR: ꢂꢀ¼ 3030
1
(CH), 2980, 2920 (CH2), 1740 (CO), 1360, 1160 (SO2) cmꢃ1; H NMR: ꢃ ¼ 4.39, 4.89, 5.25 (3s, 3
CH2), 7.5 (s, 10 ar H) ppm.
N-(Benzyloxycarbonyl)-N-(4-methoxybenzyl)cyanomethanesulfonamide (3e, C18H18N2O5S)
From 2d (2.4g, 10mmol) and 1.8g benzyl chloroformate. Yield 3.0 g (80%); mp 103–104ꢁC; IR:
1
ꢂꢀ¼ 2980, 2920 (CH2), 2250 (CN), 1720 (CO), 1380, 1150 (SO2) cmꢃ1; H NMR: ꢃ ¼ 3.76 (s, Me),
4.35, 4.92, 5.26 (3s, 3 CH2), 6.7–7.4 (m, 9 ar H) ppm.

1332
M. Winterwerber et al.
N-Benzyl-N-(S-ethylthiocarbonyl)cyanomethanesulfonamide (3f, C12H14H2O3S2)
From 2c (2.1 g, 10 mmol) and 1.25 g ethyl chlorothioformate. Yield 2.1 g (70%); mp 103–104ꢁC;
IR: ꢂꢀ¼ 3020 (CH), 2980, 2920 (CH2), 2260 (CN), 1675 (COSEt), 1360, 1180 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 1.3 (t, J ¼ 7.5 Hz, Me), 2.8–3.1 (q, J ¼ 7.5 Hz, CH2), 4.52, 5.08 (2s, 2 CH2), 7.3
(s, 5 ar H) ppm.
N-Acetyl-N-benzylcyanomethanesulfonamide (3g, C11H12N2O3S)
From 2c (2.1g, 10mmol) and 0.79 g acetyl chloride. Purification by CC (AcOEt). Yield 0.5g (20%); IR
1
(Film): ꢂꢀ¼ 2980, 2920 (CH2), 2260 (CN), 1710 (CO), 1370, 1170 (SO2) cmꢃ1; H NMR: ꢃ ¼ 2.34
(s, Me), 4.40, 5.11 (2s, 2 CH2), 7.3 (s, 5 ar H) ppm.
N-(Benzyloxycarbonyl)-N-(4-chlorobenzyl)cyanomethanesulfonamide (3h, C17H15ClN2O4S)
From 2i (2.4g, 10mmol) and 1.8 g benzyl chloroformate. Yield 2.7 g (72%); colorless crystals; mp
90ꢁC; IR: ꢂꢀ¼ 3030 (CH), 2980, 2920 (CH2), 2260 (CN), 1740 (CO), 1360, 1160 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 4.50, 4.95, 5.3 (3s, 3 CH2), 7.2–7.5 (m, 9 ar H) ppm.
N-(Benzyloxycarbonyl)-N-(2-chlorobenzyl)cyanomethanesulfonamide (3i, C17H15ClN2O4S)
From 2h (2.4g, 10 mmol) and 1.8 g benzyl chloroformate. Yield 2.5 g (66%); mp 78ꢁC; IR: ꢂꢀ¼ 3040
(CH), 2985, 2920 (CH2), 2260 (CN), 1750 (CO), 1370, 1150 (SO2) cmꢃ1 1H NMR (90 MHz):
;
ꢃ ¼ 4.50, 5.10, 5.25 (3s, 3 CH2), 7.1–7.45 (m, 9 ar H) ppm.
N-(Benzyloxycarbonyl)-N-(4-fluorobenzyl)cyanomethanesulfonamide (3k, C17H15FN2O4S)
From 2k (2.3g, 10mmol) and 1.8 g benzyl chloroformate. Yield 2.2 g (61%); colorless crystals; mp
1
100ꢁC; IR: ꢂꢀ¼ 3060 (CH), 2985, 2910 (CH2), 2260 (CN), 1760 (CO), 1370, 1150 (SO2) cmꢃ1; H
NMR (90 MHz): ꢃ ¼ 4.40, 4.90, 5.30 (3s, 3 CH2), 6.9–7.5 (m, 9 ar H) ppm.
N-(4-Chlorobenzyl)-N-(methoxycarbonyl)cyanomethanesulfonamide (3l, C11H11ClN2O4S)
From 2i (2.4g, 10 mmol) and 0.95 g methyl chloroformate. Yield 3.0 g (99%); colorless crystals; mp
145ꢁC; IR: ꢂꢀ¼ 2980, 2920 (CH2), 2260 (CN), 1740 (CO), 1370, 1150 (SO2) cmꢃ1; 1H NMR (acetone-
d6): ꢃ ¼ 3.90 (s, Me), 4.90, 5.10 (2s, 2 CH2), 7.4 (s, 4 ar H) ppm.
N-(2-Chlorobenzyl)-N-(methoxycarbonyl)cyanomethanesulfonamide (3m, C11H11ClN2O4S)
From 2h (2.4g, 10 mmol) and 0.95g methyl chloroformate. Yield 0.6 g (20%); colorless crystals; mp
98ꢁC; IR: ꢂꢀ¼ 2980, 2940 (CH2), 2270 (CN), 1750 (CO), 1370, 1150 (SO2) cmꢃ1; 1H NMR (acetone-
d6): ꢃ ¼ 3.90 (s, Me), 5.2 (m, 2 CH2), 7.35 (s, 4 ar H) ppm.
N-(4-Fluorobenzyl)-N-(methoxycarbonyl)cyanomethanesulfonamide (3n, C11H11FN2O4S)
From 2k (2.3g, 10 mmol) and 0.95g methyl chloroformate. Yield 1.6 g (60%); colorless crystals; mp
135ꢁC; IR: ꢂꢀ¼ 2980, 2920 (CH2), 2265 (CN), 1740 (CO), 1370, 1150 (SO2) cmꢃ1; 1H NMR (acetone-
d6): ꢃ ¼ 3.90 (s, Me), 5.0 (m, 2 CH2), 7.0–7.55 (m, 4 ar H) ppm.
N-(4-Bromophenyl)-N-(methoxycarbonyl)cyanomethanesulfonamide (3o, C10H9BrN2O4S)
From 2l (2.8g, 10mmol) and 0.95g methyl chloroformate. Yield 1.85 g (67%); colorless crystals; mp
145ꢁC (MeOH); IR: ꢂꢀ¼ 3000 (CH2), 2940 (Me), 2270 (CN), 1720 (CO), 1370, 1160 (SO2) cmꢃ1; 1H
NMR: ꢃ ¼ 3.75 (s, Me), 4.6 (s, CH2), 7.2–7.7 (m, 4 ar H) ppm.
N-(Benzyloxycarbonyl)-N-(4-bromophenyl)cyanomethanesulfonamide (3p, C16H13BrN2O4S)
From 2l (2.8g, 10mmol) and 1.8 g benzyl chloroformate. Yield 2.0 g (49%); colorless crystals; mp
159ꢁC (MeOH); IR: ꢂꢀ¼ 3093 (CH), 2925, 2993 (CH2), 2265 (CN), 1741 (CO), 1373, 1173 (SO2)
1
cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 5.25, 5.30 (2s, 2 CH2), 7.5 (m, 9 ar H) ppm.

Synthesis of Heterocyclic Sulfonamides
1333
N-Carbamoyl-N-phenylcyanomethanesulfonamide (4a, C9H9N3O3S)
From 2b (1.9g, 10 mmol) and 1.45 g chlorosulfonyl isocyanate. After stirring for 0.5 h at ꢃ78ꢁC the
mixture was hydrolyzed with 2.5 cm3 HCl (36%), washed with a satd NaCl solution, the organic layer
was separated, dried (MgSO4), and evaporated in vacuo. Yield 1.9 g (80%); mp 140–141ꢁC (CHCl3=
CCl4); IR: ꢂꢀ¼ 3440, 3350 (NH2), 3180 (CH), 2980, 2930 (CH2), 2270 (CN), 1730 (CO), 1350, 1170
1
(SO2) cmꢃ1; H NMR: ꢃ ¼ 5.17 (s, CH2), 6.1–6.3 (s, NH2), 7.5 (s, 5 ar H) ppm.
N-Benzyl-N-(phenylcarbamoyl)cyanomethanesulfonamide (4b, C16H15N3O3S)
From 2c (2.1g, 10mmol) and 1.2 g phenyl isocyanate as described for 4a. Yield 2.6 g (78%); mp
147ꢁC (CHCl3=CCl4); IR: ꢂꢀ¼ 3360 (NH), 3060 (CH), 2980, 2910 (CH2), 2270 (CN), 1720 (CO),
1360, 1150 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 3.91, 5.11 (2s, 2 CH2), 7.0–7.5 (m, 10 ar H), 8.4 (s, NH) ppm.
General Procedure for the Synthesis of 5
The trialkyl orthoformate (10 mmol) and the cyanomethanesulfonamide 2 or 3 (10mmol) in 10cm3
Ac2O were refluxed for 2 h, cooled to room temperature, and evaporated in vacuo. The residue was
dissolved in CHCl3, and washed with a NaHCO3 solution. The organic layer was separated, dried
(Na2SO4), and evaporated in vacuo. The residue was purified as noted.
(E)-N-Acetyl-1-cyano-2-methoxy-N-phenylethene-1-sulfonamide (5a, C12H12N2O3S)
From 2b (2.0g, 10mmol) and 1.1 g HC(OMe)3. Yield 1.95g (70%); colorless crystals; mp 122ꢁC
(MeOH); IR: ꢂꢀ¼ 3050, 2980 (CH), 2210 (CN), 1690 (CO), 1610 (C¼C), 1360, 1170 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 1.90 (s, Me), 4.16 (s, OMe), 7.4 (s, 5 ar H), 8.14 (s, 2-H) ppm.
(E)-N-Benzyl-1-cyano-2-ethoxy-N-(methoxycarbonyl)ethane-1-sulfonamide (5b, C14H16N2O5S)
From 3b (2.7g, 10 mmol) and 1.5g HC(OMe)3. Yield ca. 90%; viscous liquid; IR (Film): ꢂꢀ¼ 3060,
2990, 2980 (CH), 2210 (CN), 1720 (CO), 1610 (C¼C), 1370, 1180 (SO2) cmꢃ1; the product was
immediately used for the synthesis of 8a.
(E)-N-Benzyl-N-(benzyloxycarbonyl)-1-cyano-2-ethoxyethene-1-sulfonamide (5c, C20H20N2O5S)
From 3d (3.4g, 10 mmol) and 1.5g HC(OEt)3. Yield ca. 90%; viscous liquid; IR (Film): ꢂꢀ¼ 3060,
1
2990, 2960 (CH), 2210 (CN), 1720 (CO), 1610 (C¼C), 1370, 1170 (SO2) cmꢃ1; H NMR: ꢃ ¼ 1.4
(t, J ¼ 7 Hz, Me), 4.0 (q, J ¼ 7 Hz, CH2), 5.03, 5.24 (2s, 2 CH2), 7.3 (m, 10 ar H), 7.78 (s, 2-H) ppm;
the product was immediately used for the synthesis of 8b.
(E)-N-Benzyl-N-(benzyloxycarbonyl)-1-cyano-2-methoxyethene-1-sulfonamide (5d, C19H18N2O5S)
From 3d (2.0g, 6 mmol) and 1.0 g HC(OMe)3. Yield 0.4g (17%); colorless crystals; mp 84–85ꢁC
(MeOH); IR: ꢂꢀ¼ 3060 (CH), 2210 (CN), 1720 (CO), 1610 (C¼C), 1370, 1170 (SO2) cmꢃ1; 1H NMR:
ꢃ ¼ 3.80 (s, Me), 5.00 (s, NCH2), 5.20 (s, OCH2), 7.2–7.5 (m, 10 ar H), 7.60 (s, 2-H) ppm.
(E)-N-Benzyl-N-(benzyloxycarbonyl)-1-cyano-2-isopropoxyethene-1-sulfonamide
(5e, C21H22N2O5S)
From 5d (2.4g, 6 mmol) by crystallization from i-PrOH. 0.5 g (20%); colorless crystals; mp 75ꢁC; IR:
ꢂꢀ¼ 3060, 2990 (CH), 2210 (CN), 1720 (CO), 1610 (C¼C), 1370, 1170 (SO2) cmꢃ1
;
1H NMR
(60 MHz): ꢃ ¼ 1.25 (d, J ¼ 4.4 Hz, Me), 1.40 (d, J ¼ 4.4 Hz, Me), 4.2 (q, CH), 5.0 (s, NCH2), 5.20
(s, OCH2), 7.40 (s, 10 ar H), 7.90 (s, 2-H) ppm.
(E)-N-(Benzyloxycarbonyl)-N-(4-chlorobenzyl)-1-cyano-2-ethoxyethene-1-sulfonamide
(5f, C20H19ClN2O5S)
From 3h (3.8g, 10 mmol) and 1.5g HC(OEt)3. Yield ca. 90%; viscous liquid; IR (Film): ꢂꢀ¼ 3060,
1
2990, 2960 (CH), 2210 (CN), 1720 (CO), 1610 (C¼C), 1370, 1170 (SO2) cmꢃ1; H NMR: ꢃ ¼ 1.3

1334
M. Winterwerber et al.
(t, J ¼ 7 Hz, Me), 4.1 (q, J ¼ 15.4Hz, CH2), 4.96 (s, NCH2), 5.20 (s, OCH2), 7.2–7.5 (m, 9 ar H), 7.8
(s, 2-H) ppm; the product was immediately used for the synthesis of 8d.
(E)-N-(Benzyloxycarbonyl)-1-cyano-N-(4-fluorobenzyl)-2-ethoxyethene-1-sulfonamide
(5g, C20H19FN2O5S)
From 3k (3.6g, 10 mmol) and 1.5 g HC(OEt)3. Yield ca. 90%; 1H NMR: ꢃ ¼ 1.3 (t, J ¼ 7 Hz, Me), 4.0
(q, J ¼ 15.4Hz, CH2), 4.95 (s, NCH2), 5.20 (s, OCH2), 6.8–7.5 (m, 9 ar H), 7.8 (s, 2-H) ppm; the
product was immediately used for the synthesis of 8c.
(E)-N-(Benzyloxycarbonyl)-N-(2-chlorobenzyl)-1-cyano-2-ethoxyethene-1-sulfonamide
(5h, C20H19ClN2O5S)
From 3i (3.8g, 10mmol) and 1.5 g HC(OEt)3. Yield 3.3 g (74%); colorless crystals; mp 100ꢁC (EtOH);
IR: ꢂꢀ¼ 3060, 2990, 2960 (CH), 2210 (CN), 1720 (CO), 1610 (C¼C), 1370, 1170 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 1.3 (t, J ¼ 7 Hz, Me), 4.1 (q, J ¼ 15.4Hz, CH2), 5.15, 5.25 (2s, NCH2, OCH2),
7.1–7.5 (m, 9 ar H), 7.9 (s, 2-H) ppm; 13C-NMR: ꢃ ¼ 15.11 (Me), 49.12 (NCH2), 69.62 (OCH2),
75.09 (OCH2), 94.6 (C-1), 109.74 (CN), 151.79 (CO), 174.99 (C-2) ppm.
N-(4-Chlorobenzyl)-1-cyano-2-methoxy-N-(methoxycarbonyl)ethene-1-sulfonamide
(5i, C13H13ClN2O5S)
From 3l (3.0g, 10 mmol) and 1.1 g HC(OMe)3. Yield ca. 90%; yellow viscous liquid; IR (Film):
ꢂꢀ¼ 3040, 2960 (CH), 2220 (CN), 1750 (CO), 1610 (C¼C), 1360, 1170 (SO2) cmꢃ1
.
N-(2-Chlorobenzyl)-1-cyano-2-methoxy-N-(methoxycarbonyl)ethene-1-sulfonamide
(5k, C13H13ClN2O5S)
From 3m (3.0g, 10mmol) and 1.1 g HC(OMe)3. Yield ca. 50%; yellow viscous liquid; IR (Film):
ꢂꢀ¼ 3060, 2960 (CH), 2220 (CN), 1740 (CO), 1620 (C¼C), 1380, 1180 (SO2) cmꢃ1
.
(E)-1-Cyano-N-(4-fluorobenzyl)-2-methoxy-N-(methoxycarbonyl)ethene-1-sulfonamide
(5l, C13H13FN2O5S)
From 3n (2.8g, 10mmol) and 1.1 g HC(OMe)3. Yield ca. 80%; yellow viscous liquid; IR (Film):
ꢂꢀ¼ 3040, 2960 (CH), 2210 (CN), 1750 (CO), 1610 (C¼C), 1360, 1170 (SO2) cmꢃ1
.
(E)-N-(Benzyloxycarbonyl)-N-(4-bromophenyl)-1-cyano-2-ethoxyethene-1-sulfonamide
(5m, C19H17BrN2O5S)
From 3p (2.1g, 5 mmol) and 0.75 g HC(OEt)3. Yield 1.2g (52%); mp 147ꢁC (EtOH); IR: ꢂꢀ¼ 3089,
1
3061, 2978 (CH), 2234 (CN), 1737 (CO), 1625 (C¼C), 1377, 1177 (SO2) cmꢃ1; H NMR: ꢃ ¼ 1.4
(t, J ¼ 7.7 Hz, Me), 4.25 (q, J ¼ 15.4Hz, CH2), 5.2 (s, CH2), 7.25 (m, 9 ar H), 8.0 (s, 2-H) ppm.
(E)-N-(Benzyloxycarbonyl)-N-(2-chlorobenzyl)-1-cyano-2-methoxyethene-1-sulfonamide
(5n, C19H17ClN2O5S)
From 4.3 g 5f by crystallization from MeOH. Yield 2.4 g (57%); mp 145ꢁC (MeOH); IR: ꢂꢀ¼ 3047,
2958 (CH), 2228 (CN), 1745 (CO), 1617 (C¼C), 1363, 1177 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 3.9 (s, OMe),
5.15, 5.25 (2s, NCH2, OCH2), 7.1–7.5 (m, 9 ar H), 7.75 (s, 2-H) ppm.
(E)-N-(2-Chlorobenzyl)-1-cyano-2-ethoxy-N-(methoxycarbonyl)ethene-1-sulfonamide
(5o, C14H15ClN2O5S)
From 3.4 g 5k by crystallization from EtOH. Yield 2.0 g (56%); mp 105ꢁC; IR: ꢂꢀ¼ 2980, 2950 (CH),
2220 (CN), 1740 (CO), 1600 (C¼C), 1360, 1170 (SO2) cmꢃ1
;
1H NMR (90 MHz): ꢃ ¼ 1.5
(t, J ¼ 7.55Hz, Me), 3.8 (s, OMe), 4.4 (q, J ¼ 7.55 Hz, OCH2), 5.1 (s, NCH2), 7.2–7.5 (m, 4 ar H),
8.0 (s, 2-H) ppm.

Synthesis of Heterocyclic Sulfonamides
1335
General Procedures for the Synthesis of 6
Method a. The cyanomethanesulfonamide 2 (10 mmol) and formamidinium acetate (1.0g, 10mmol) in
50cm3 BuOH were refluxed for 4–6 h. After cooling to room temperature, the solution was evaporated
in vacuo, and the residue was crystallized from CHCl3.
Method b. The 2-alkoxy-1-cyanoethene-1-sulfonamide 5 (5mmol) was stirred in 300cm3 abs.
EtOH saturated with NH3 at 0ꢁC for 6–10h. Then, the solvent was evaporated in vacuo, and the
residue was crystallized from MeCN.
(E)-2-Amino-N-benzyl-1-cyanoethene-1-sulfonamide (6a, C10H11N3O3S)
From 2c (2.1g), method a. Yield 0.95g (40%); mp 158–159ꢁC; IR: ꢂꢀ¼ 3440, 3300 (NH2), 3070, 3030
1
(CH), 2200 (CN), 1640 (C¼C), 1310, 1160 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 4.2 (d, J ¼ 6 Hz,
CH2), 6.7 (br t, NH), 7.2–8.0 (m, 5 ar H, NH2, 2-H) ppm.
(E)-2-Amino-1-cyano-N-(4-methoxybenzyl)ethene-1-sulfonamide (6b, C11H13N3O3S)
From 2d (2.4g) and 6.0g formamidinium acetate (60 mmol), method a, 30min, 100ꢁC, purification by
CC (AcOEt). Yield0.5 g (20%) (and 1.6 g 33b);mp 151–153ꢁC (AcOEt); IR:ꢂꢀ¼ 3425, 3300, 3260 (NH),
3210, 3005, 2940, 2840 (CH), 2200 (CN), 1655 (C¼C), 1310, 1170 (SO2) cmꢃ1; 1H NMR (acetone-d6):
ꢃ ¼ 3.84 (s, OMe), 4.2 (d, J ¼ 6 Hz, CH2), 6.5–6.6 (t, J ¼ 6 Hz, NH), 6.8–8.0 (m, 4 ar H, NH2, 2-H) ppm.
(E)-2-Amino-N-phenyl-1-cyanoethene-1-sulfonamide (6c, C9H9N3O2S)
From 2b (2.0 g), method a. Yield 0.9 g (40%); mp 156ꢁC (CHCl3); IR: ꢂꢀ¼ 3430, 3280, 3260 (NH2),
3200, 3060 (CH), 2200 (CN), 1650 (C¼C), 1320, 1170 (SO2) cmꢃ1; 1H NMR (DMSO-d6): ꢃ ¼ 7.0–8.5
(m, 5 ar H, NH2, 2-H), 9.8–10.2 (br s, NH) ppm.
(E)-2-Amino-N-(4-chlorobenzyl)-1-cyanoethene-1-sulfonamide (6d, C10H10ClN3O2S)
From 2i (2.4g), method a. Yield 0.9 g (33%); colorless crystals; mp 156ꢁC; IR: ꢂꢀ¼ 3439, 3295 (NH2),
2210 (CN), 1655 (C¼C), 1310, 1165 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.2 (d, J ¼ 6.6 Hz, CH2),
6.8 (t, NH), 7.3–7.95 (m, 4 ar H, NH2, 2-H) ppm.
(E)-2-Amino-N-benzyl-N-(benzyloxycarbonyl)-1-cyanoethene-1-sulfonamide (6e, C18H17N3O4S)
From 5c (2.0g), method b. Yield 0.67g (36%); colorless crystals; mp 155ꢁC; IR: ꢂꢀ¼ 3200 (NH2),
3070, 3030 (CH), 2210 (CN), 1740 (CO), 1620 (C¼C), 1340, 1150 (SO2) cmꢃ1
;
1H NMR
(CDCl3=DMSO-d6, 400 MHz): ꢃ ¼ 4.20 (d, J ¼ 6 Hz, NCH2), 5.20 (s, OCH2), 7.1–7.4 (m, 10 ar H),
7.7 (t, J ¼ 6 Hz, 2-H), 8.1 (d, J ¼ 7.5Hz, 1H, NH2), 10.3 (s, 1H, NH2) ppm.
(E)-2-Amino-N-(benzyloxycarbonyl)-N-(4-chlorobenzyl)-1-cyanoethene-1-sulfonamide
(6f, C18H16ClN3O4S)
From 5f (2.2g), method b. Yield 0.5 g (25%); mp 156ꢁC; IR: ꢂꢀ¼ 3200 (NH2), 3100, 3030 (CH), 2210
(CN), 1720 (CO), 1620 (C¼C), 1340, 1150 (SO2) cmꢃ1
;
1H NMR (CDCl3=DMSO-d6): ꢃ ¼ 4.2
(d, J ¼ 5.5 Hz, CH2), 5.2 (s, CH2), 7.1–7.5 (m, 9 ar H), 8.0 (s, 2-H), 9.8 (s, NH2) ppm.
(E)-2-Amino-N-(benzyloxycarbonyl)-N-(4-fluorobenzyl)-1-cyanoethene-1-sulfonamide
(6g, C18H16FN3O4S)
From 5g (2.1g), method b. Yield 0.5g (24%); mp 150ꢁC; IR: ꢂꢀ¼ 3200 (NH2), 3100, 3030 (CH), 2210
(CN), 1720 (CO), 1620 (C¼C), 1340, 1150 (SO2) cmꢃ1
;
1H NMR (CDCl3=DMSO-d6): ꢃ ¼ 4.2
(d, J ¼ 5.9 Hz, CH2), 5.3 (s, CH2), 7.0–7.5 (m, 9 ar H), 7.9 (s, 2-H), 8.7 (s, NH2) ppm.
(E)-2-Amino-N-(2-chlorobenzyl)-1-cyanoethene-1-sulfonamide (6h, C10H10ClN3O2S)
From 2h (2.4g), method a. Yield 0.5 g (18%); mp 123ꢁC; IR: ꢂꢀ¼ 3440, 3300 (NH2), 3070, 3030 (CH),
2200 (CN), 1640 (C¼C), 1310, 1160 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.3 (d, J ¼ 6.6 Hz, CH2),
6.8 (t, J ¼ 6.6 Hz, NH), 7.2–8.0 (m, 4 ar H, NH2, 2-H) ppm.

1336
M. Winterwerber et al.
(E)-2-Amino-N-(benzyloxycarbonyl)-N-(2-chlorobenzyl)-1-cyanoethene-1-sulfonamide
(6i, C18H16ClN3O4S)
From 5h (2.2 g), method b. Yield 0.5 g (24%); mp 152ꢁC; IR: ꢂꢀ¼ 3200 (NH2), 3100, 3030 (CH),
2210 (CN), 1720 (CO), 1620 (C¼C), 1340, 1150 (SO2) cmꢃ1
;
1H NMR (DMSO-d6): ꢃ ¼ 4.2
(d, J ¼ 4.4 Hz, CH2), 5.3 (s, CH2), 7.2–7.5 (m, 9 ar H), 8.0 (s, 2-H), 8.7 (t, J ¼ 4.4 Hz, 1H, NH2),
11.7 (s, 1H, NH2) ppm.
(E)-2-Amino-N-(4-bromophenyl)-1-cyanoethene-1-sulfonamide (6k, C9H8BrN3O2S)
From 2l (1.4g, 5 mmol) in 50 cm3 MeOH, method a. Yield 0.5g (33%); mp 185ꢁC (CHCl3); IR:
ꢂꢀ¼ 3440 (NH2), 3260 (NH), 2200 (CN), 1650 (C¼C), 1310, 1170 (SO2) cmꢃ1; 1H NMR (DMSO-d6,
300 MHz): ꢃ ¼ 7.0–7.5 (m, 4 ar H), 8.16 (d, J ¼ 11.3Hz, NH2), 10.1 (s, 2-H) ppm; MS (70 eV): m=z
(%) ¼ 303 (31, Mþ), 172 (86, C6H5BrN).
(E)-2-Amino-1-cyano-N-(4-fluorobenzyl)ethene-1-sulfonamide (6l, C10H10FN3O2S)
From 2k (1.1g, 5 mmol) in 50 cm3 MeOH, method a. Yield 0.6 g (47%); mp 140ꢁC; IR: ꢂꢀ¼ 3440
(NH2), 3300 (NH), 2200 (CN), 1650 (C¼C), 1310, 1170 (SO2) cmꢃ1; 1H NMR (DMSO-d6, 300MHz):
ꢃ ¼ 4.0 (s, CH2), 7.1–7.4 (m, 4 ar H), 7.5 (s, 2-H), 8.0 (s, NH2) ppm; MS (70 eV): m=z ¼ 255 (6, Mþ),
124 (100, C7H7FN).
(E)-N-Acetyl-2-amino-N-benzyl-1-cyanoethene-1-sulfonamide (7, C12H13N3O3S)
Compound 6a (1.2g, 5 mmol), 20 cm3 AcOH, and 20cm3 Ac2O were refluxed for 3 h, cooled to room
temperature, and evaporated in vacuo. The residue was dissolved in CHCl3, washed with an AcONa
solution, dried (Na2SO4), and the solvent was evaporated in vacuo. Yield 0.95g (70%); mp 145ꢁC
1
(CHCl3=CCl4); IR: ꢂꢀ¼ 3380, (NH2), 2210 (CN), 1680 (CONH), 1335, 1150 (SO2) cmꢃ1; H NMR
(acetone-d6): ꢃ ¼ 2.33 (s, Me), 5.0 (s, CH2), 7.2–8.2 (m, 5 ar H, NH2, 2-H) ppm.
5-Amino-N-benzyl-N-(methoxycarbonyl)-1-phenylpyrazol-4-sulfonamide (8a, C18H18N4O4S)
Compound 3b (2.7 g, 10 mmol) reacted with HC(OEt)3 (1.5g, 10 mmol) to 5b. The crude product was
dissolved in 30 cm3 EtOH, and with stirring, phenylhydrazine (1.1g, 10 mmol) was slowly added.
After 12 h, the precipitate was separated, H2O was added to the filtrate, and the combined precipitates
were crystallized. Yield 2.7 g (70%); mp 172ꢁC (MeOH); IR: ꢂꢀ¼ 3460, 3360 (NH2), 3050, 2980,
1
2940 (CH), 1720 (CO), 1620 (C¼N), 1350, 1180 (SO2) cmꢃ1; H NMR: ꢃ ¼ 3.78 (s, OMe), 4.9–5.1
(m, CH2, NH2), 7.2–7.5 (m, 10 ar H, 3-H) ppm.
5-Amino-N-benzyl-N-(benzyloxycarbonyl)-1-phenylpyrazol-4-sulfonamide (8b, C24H22N4O4S)
From 5c (4.0g, 10mmol) and 1.1 g phenylhydrazine as described for 8a. Yield 3.3 g (70%); mp 153ꢁC
(MeOH); IR: ꢂꢀ¼ 3450, 3320 (NH2), 3040, 2960 (CH), 1720 (CO), 1620 (C¼N), 1340, 1140 (SO2)
1
cmꢃ1; H NMR: ꢃ ¼ 4.6–4.9 (br s, NH2), 5.03, 5.16 (2s, 2 CH2), 7.2–7.5 (m, 15 ar H, 3-H) ppm.
5-Amino-N-(benzyloxycarbonyl)-N-(4-fluorobenzyl)-1-phenylpyrazol-4-sulfonamide
(8c, C24H21FN4O4S)
From 5g (4.2g, 10mmol) and 1.1 g phenylhydrazine as described for 8a. Yield 3.5 g (73%); mp 140ꢁC
(MeOH); IR: ꢂꢀ¼ 3440, 3320 (NH2), 3040, 2960 (CH), 1720 (CO), 1620 (C¼N), 1340, 1140 (SO2)
1
cmꢃ1; H NMR: ꢃ ¼ 4.8 (br s, NH2), 5.00 (s, NCH2), 5.20 (s, CH2), 6.8–7.8 (m, 14 ar H, 3-H) ppm.
5-Amino-N-(benzyloxycarbonyl)-N-(4-chlorobenzyl)-1-phenylpyrazol-4-sulfonamide
(8d, C24H21ClN4O4S)
From 5f (4.3g, 10mmol) as described for 8a. Yield 1.0 g (20%); mp 120ꢁC (MeOH); IR: ꢂꢀ¼ 3450,
1
3320 (NH2), 3040, 2960 (CH), 1720 (CO), 1620 (C¼N), 1340, 1140 (SO2) cmꢃ1; H NMR: ꢃ ¼ 4.8
(s, NH2), 4.95 (s, NCH2), 5.20 (s, OCH2), 7.1–7.7 (m, 14 ar H, 3-H) ppm.

Synthesis of Heterocyclic Sulfonamides
1337
5-Amino-N-benzyl-1-phenylpyrazol-4-sulfonamide (9a, C16H16N4O2S)
A solution of 200 mg Na in 10 cm3 EtOH was dropwise added to a suspension of 8a (3.8 g, 10 mmol)
in 50cm3 EtOH, the mixture was stirred at 50ꢁC for 1 h, neutralized with HCl (36%), and evaporated
in vacuo. The residue was dissolved in CHCl3, washed with H2O, dried (Na2SO4), and the solvent was
evaporated in vacuo. Yield 2.3 g (70%); mp 147–148ꢁC (MeOH); IR: ꢂꢀ¼ 3470, 3370 (NH2), 3100,
2870 (CH), 1620 (C¼N), 1310, 1160 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 4.2 (s, CH2), 4.5–5.2 (br s, NH, NH2),
7.2–7.7 (m, 10 ar H, 3-H) ppm; MS (70 eV): m=z (%) ¼ 328 (8.0, Mþ), 159 (100, C9H9N3), 106 (41.8,
C7H8N), 91 (71.9, C7H7).
5-Amino-N-(4-fluorobenzyl)-1-phenylpyrazol-4-sulfonamide (9b, C16H15FN4O2S)
From 8c (0.8 g, 1.8 mmol) as described for 9a. Yield 0.2 g (33%); mp 190ꢁC (MeOH); IR: ꢂꢀ¼ 3467,
3376 (NH2), 3110, 2872 (CH), 1622 (C¼N), 1310, 1157 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 4.1 (d, J ¼ 6.6 Hz,
CH2), 5.00 (s, NH2), 5.6 (t, J ¼ 6.7 Hz, NH), 6.8–7.5 (m, 9 ar H), 7.8 (s, 3-H) ppm; MS (70 eV): m=z
(%) ¼ 346 (4, Mþ), 91 (100, C6H5N), 124 (54, C7H7FN).
5-Amino-N-(4-chlorobenzyl)-1-phenylpyrazol-4-sulfonamide (9c, C16H15ClN4O2S)
From 8d (0.5g, 1 mmol) as described for 9a. Yield 0.2g (55%); mp 179ꢁC (MeOH); IR: ꢂꢀ¼ 3463,
3370 (NH2), 3111, 2867 (CH), 1624 (C¼N), 1312, 1161 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 4.1 (d, J ¼ 6.7 Hz,
CH2), 5.0 (s, NH2), 5.8 (t, J ¼ 6.7 Hz, NH), 7.0–7.6 (m, 9 ar H), 7.8 (s, 3-H) ppm.
2-Benzyl-5-phenylpyrazolo[3,4-e][1,2,4]thiadiazine 1,1-dioxide (10, C17H14N4O2S)
Compound 9a (0.65 g, 2 mmol) and formamidinium acetate (0.45 g, 4 mmol) in 30 cm3 BuOH were
refluxed for 2 h, and after cooling to room temperature, the mixture was evaporated in vacuo. The
residue was dissolved in CHCl3, washed with H2O, dried (Na2SO4), and the solvent was evaporated in
vacuo, purification by CC (CHCl3). Yield 70 mg (10%); mp 202–203ꢁC (CHCl3); IR: ꢂꢀ¼ 3115, 2960,
2920 (CH), 1580 (C¼N), 1310, 1170 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 5.03 (s, CH2), 7.2–7.8 (m, 10 ar H,
3-H), 8.10 (s, 7-H) ppm; MS (70 eV): m=z (%) ¼ 338 (8.5, Mþ), 91 (100, C7H7).
2-Amino-N-(4-chlorobenzyl)-2-(hydroxyimino)ethane-1-sulfonamide (11a, C9H12ClN3O3S)
A solution of 2i (2.4g, 10mmol) in 60cm3 EtOH was added dropwise with stirring to a solution of
H2NOHꢅHCl (1.4g, 20 mmol) and NaHCO3 (1.7g, 20 mmol) in 30cm3 H2O, stirring was continued
for 12h, then, the precipitate was separated. Yield 2.2g (80%); colorless crystals; mp 163ꢁC (MeOH);
IR: ꢂꢀ¼ 3500, 3400 (NH2, OH), 3250 (NH), 3080, 2940 (CH), 1660 (C¼N), 1310, 1130 (SO2) cmꢃ1
;
1H NMR (DMSO-d6): ꢃ ¼ 3.8 (s, CH2), 4.2 (d, J ¼ 6.6 Hz, CH2), 5.45 (s, NH2), 7.4 (s, 4 ar H), 7.8
(t, J ¼ 6.6 Hz, NH), 9.5 (s, OH) ppm.
2-Amino-N-benzyl-2-(hydroxyimino)ethane-1-sulfonamide (11b, C9H13N3O3S)
From 2c (2.1g, 10 mmol) as described for 11a. Yield 2.2g (90%); mp 169–170ꢁC (MeOH); IR:
ꢂꢀ¼ 3500, 3400 (NH2, OH), 3280 (NH), 3080, 2940 (CH), 1660 (C¼N), 1310, 1140 (SO2) cmꢃ1
;
1H NMR (DMSO-d6): ꢃ ¼ 3.82 (s, CH2), 4.1 (d, J ¼ 7 Hz, CH2), 5.4–5.6 (s, NH2), 7.3 (s, 5 ar H),
7.6–7.8 (t, J ¼ 7 Hz, NH), 9.5 (s, OH) ppm.
2-Amino-2-(hydroxyimino)-N-phenylethane-1-sulfonamide (11c, C8H11N3O3S)
From 2b (2.0g, 10mmol) as described for 11a. Yield 2.0g (87%); mp 120ꢁC (CH2Cl2=EtOH); IR:
1
ꢂꢀ¼ 3490, 3380 (NH2, OH), 3250 (NH), 2960 (CH), 1660 (C¼N), 1320, 1130 (SO2) cmꢃ1; H NMR
(DMSO-d6): ꢃ ¼ 3.82 (s, CH2), 5.4–5.6 (s, NH2), 7.0–7.4 (m, 5 ar H), 9.5–9.7 (br s, NH, OH) ppm.
2-Amino-2-(hydroxyimino)-N-propylethane-1-sulfonamide (11d, C5H13N3O3S)
From 2g (1.6g, 10 mmol) as described for 11a. Yield 1.7g (90%); mp 130ꢁC (CHCl3); IR: ꢂꢀ¼ 3500,
3380 (NH2, OH), 3280 (NH), 2970, 2920, 2870 (CH), 1660 (C¼N), 1320, 1160 (SO2) cmꢃ1; 1H NMR

1338
M. Winterwerber et al.
(acetone-d6): ꢃ ¼ 0.8–1.0 (t, J ¼ 7 Hz, Me), 1.4–1.6 (m, CH2), 2.9–3.1 (t, J ¼ 7 Hz, CH2), 3.76 (s, CH2),
5.3 (s, NH2), 5.9–6.3 (br s, NH), 8.5–9.0 (br s, OH) ppm.
2-Amino-N-benzyl-N-(benzyloxycarbonyl)-2-(hydroxyimino)ethane-1-sulfonamide
(11e, C17H19N3O5S)
From 3d (0.7g, 2 mmol) as described for 11a. Yield 0.6g (80%); mp 113ꢁC (CHCl3); IR: ꢂꢀ¼ 3500, 3400
1
(NH2, OH), 3080, 3040, 2960 (CH), 1730 (CO), 1670 (C¼N), 1360, 1150 (SO2) cmꢃ1; H NMR
(acetone-d6): ꢃ ¼ 4.27, 4.83 (2s, 2 CH2), 5.3–5.5 (2s, NH2, CH2), 7.3–7.4 (m, 10 ar H), 8.9 (s, OH) ppm.
2-Amino-N-benzyl-2-(hydroxyimino)-N-(methoxycarbonyl)ethane-1-sulfonamide
(11f, C11H15N3O5S)
From 3b (2.6g, 10 mmol) as described for 11a. Yield 2.1 g (70%); mp 110ꢁC (CHCl3); IR: ꢂꢀ¼ 3480,
1
3380 (NH2, OH), 3060, 2940 (CH), 1730 (CO), 1670 (C¼N), 1340, 1140 (SO2) cmꢃ1; H NMR
(acetone-d6): ꢃ ¼ 3.79 (s, Me), 4.28, 4.82 (2s, 2 CH2), 5.2–5.4 (s, NH2), 7.2–7.4 (s, 5 ar H), 8.0–10.0
(s, OH) ppm.
2-Amino-N-benzyl-2-(hydroxyimino)-N-(phenoxycarbonyl)ethane-1-sulfonamide
(11g, C16H17N3O5S)
From 3c (3.3g, 10 mmol) as described for 11a. Yield 2.5 g (70%); mp 163–164ꢁC (CHCl3); IR:
ꢂꢀ¼ 3520, 3400 (NH2, OH), 3060, 2940 (CH), 1720 (CO), 1670 (C¼N), 1360, 1170 (SO2) cmꢃ1
;
1H NMR (acetone-d6): ꢃ ¼ 4.46, 4.98 (2s, 2 CH2), 5.2–6.0 (s, NH2), 7.2–7.6 (m, 10 ar H), 7.8–8.1
(s, OH) ppm.
2-Amino-N-benzyl-N-(S-ethylthiocarbonyl)-2-(hydroxyimino)ethane-1-sulfonamide
(11h, C12H17N3O4S2)
From 3f (3.0g, 10 mmol) as described for 11a. Yield 2.7 g (80%); mp 122ꢁC (MeOH); IR: ꢂꢀ¼ 3480–
1
3380 (NH2, OH), 3020, 2970, 2930 (CH), 1670 (COSEt), 1660 (C¼N), 1340, 1170 (SO2) cmꢃ1; H
NMR (acetone-d6): ꢃ ¼ 1.0–1.3 (t, J ¼ 8 Hz, Me), 2.7–3.0 (q, J ¼ 8 Hz, CH2), 4.33, 5.03 (2s, 2 CH2),
5.1–5.5 (s, NH2), 7.3–7.5 (s, 5 ar H, OH) ppm.
N-Benzyl-5-phenyl-1,2,4-oxadiazol-3-methanesulfonamide (12a, C16H15N3O3S)
A solution of 50 mg Na in 10cm3 EtOH was dropwise added to a mixture of 11b (2.4g, 10mmol) and
ethyl benzoate (1.9g, 10mmol) in 20cm3 EtOH. The mixture was refluxed for 4 h, cooled to room
temperature, neutralized with HCl (36%), and evaporated in vacuo. H2O was added to the residue,
then, it was extracted with THF, the organic layers were dried (MgSO4), and evaporated in vacuo. The
residue was dissolved in CHCl3, and cyclohexane was added until milkiness. After cooling to 0ꢁC for
some h, the precipitate was separated. Yield 1.4g (90%); mp 86ꢁC (MeOH); IR: ꢂꢀ¼ 3340 (NH), 3060,
3030 (CH), 2990, 2940 (CH2), 1610 (C¼N), 1340, 1170 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.2–
4.5 (m, 2 CH2), 5.3–5.5 (t, J ¼ 6 Hz, NH), 7.2–8.2 (m, 10 ar H) ppm.
N,5-Diphenyl-1,2,4-oxadiazol-3-methanesulfonamide (12b, C15H13N3O3S)
From 11c (1.1g, 5 mmol) and ethyl benzoate (0.95 g, 5 mmol) as described for 12a. Yield 1.4 g (90%);
mp 133ꢁC (MeOH); IR: ꢂꢀ¼ 3200 (NH), 3080 (CH), 2990, 2940 (CH2), 1600 (C¼N), 1340, 1150
1
(SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 4.61 (s, CH2), 7.0–8.3 (m, 10 ar H), 9.0 (br s, NH) ppm.
2-Amino-N-benzyl-2-(benzoyloxyimino)ethane-1-sulfonamide (13a, C16H17N3O4S)
Benzoyl chloride (1.4g, 10 mmol) in 10cm3 THF was slowly added with stirring to a solution of 11b
(2.4g, 10mmol) and Et3N (1.0g, 10mmol) in 50 cm3 THF. Stirring was continued for 2 h, the
precipitate (Et3NHþClꢃ) was separated, and the organic phase was extracted with a satd NaCl solution,
dried (Na2SO4), and evaporated in vacuo. Yield 2.7 g (80%); mp 158–160ꢁC (MeOH); IR: ꢂꢀ¼ 3450,
3350 (NH2), 3210 (NH), 3060, 3020, 2980, 2920 (CH), 1730 (CO), 1620 (C¼N), 1320, 1130 (SO2)

Synthesis of Heterocyclic Sulfonamides
1339
cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.06 (s, CH2), 4.3–4.5 (d, J ¼ 6 Hz, CH2), 6.5–7.0 (s, NH2), 6.7–7.0
(t, J ¼ 6 Hz, NH), 7.2–8.2 (m, 10 ar H) ppm.
2-(Acetoxyimino)-2-amino-N-benzylethane-1-sulfonamide (13b, C11H15N3O4S)
Compound 11b (0.5g, 2 mmol) in 20cm3 AcOH and 20cm3 Ac2O was stirred at room temperature for
3 h. Then the mixture was evaporated in vacuo, the residue was dissolved in CHCl3, washed with H2O,
the organic layer was dried (Na2SO4), and evaporated. Yield 0.45g (80%); mp 138–140ꢁC (MeOH);
IR: ꢂꢀ¼ 3480, 3350 (NH2), 3240 (NH), 3040, 2995, 2950 (CH), 1750 (CO), 1640 (C¼N), 1320, 1140
(SO2) cmꢃ1; 1H NMR (DMSO-d6): ꢃ ¼ 2.07 (s, Me), 3.90, 4.18 (2s, 2 CH2), 6.5 (s, NH2), 7.3 (s, 5 ar
H), 7.2–8.2 (s, NH) ppm.
2-Amino-N-benzyl-2-{[(bisethoxy)methoxy]imino}ethane-1-sulfonamide (13c, C14H23N3O5S)
Compound 11b (0.9g, 4 mmol) in 20 cm3 HC(OEt)3 was refluxed for 4 h. After cooling to room
temperature, the mixture was concentrated in vacuo, the residue was dissolved in CHCl3, and after
addition of n-pentane the product was separated. Yield 0.8 g (60%); mp 72ꢁC (toluene); IR: ꢂꢀ¼ 3480,
3380 (NH2), 3260 (NH), 3090, 2990, 2950, 2900 (CH), 1660 (C¼N), 1320, 1150 (SO2) cmꢃ1; 1H NMR
(acetone-d6): ꢃ ¼ 1.0–1.2 (t, J ¼ 7 Hz, 2 Me), 3.5–3.8 (q, J ¼ 7 Hz, 2 CH2), 3.87, 4.35 (2s, 2 CH2),
5.4–5.7 (s, NH2), 6.5–6.8 (s, NH), 7.2–7.5 (m, 5 ar H, CH) ppm.
2-Amino-N-benzyl-2-(methoxycarbonyloxyimino)ethane-1-sulfonamide (13d, C11H15N3O5S)
HC(OMe)3 (0.4g, 4 mmol) in 10 cm3 CHCl3 was dropwise added to a mixture of 11b (0.9g, 4 mmol)
and Et3N (0.4g, 4 mmol) in 10cm3 CHCl3. The mixture was refluxed for 4 h, cooled to room tem-
perature, the precipitate was separated, and the organic solvent was evaporated in vacuo. Yield 0.8 g
(80%); mp 122–123ꢁC (toluene); IR: ꢂꢀ¼ 3480, 3360 (NH2), 3250 (NH), 3015, 2990, 2930 (CH), 1750
(CO), 1310, 1130 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 3.86 (s, OMe), 3.97 (s, CH2), 4.3–4.4 (d, J ¼ 7 Hz, CH2),
5.3–5.7 (s, t, NH2, NH), 7.4–7.5 (s, 5 ar H) ppm.
2-Amino-N-benzyl-2-(benzyloxycarbonyloxyimino)ethane-1-sulfonamide (13e, C17H19N3O5S)
From 11b (2.4g, 10 mmol) and benzyl chloroformate (1.7g, 10mmol) as described for 13a. Yield 3.0 g
(80%); mp 155ꢁC (toluene); IR: ꢂꢀ¼ 3460, 3350 (NH2), 3240 (NH), 1760 (CO), 1630 (C¼N), 1310,
1140 (SO2) cmꢃ1; 1H NMR (DMSO-d6): ꢃ ¼ 3.9 (s, CH2), 4.3 (d, CH2), 5.2 (s, CH2), 6.5–6.7 (s, NH2),
7.4 (m, 10 ar H), 8.6–8.8 (s, NH) ppm.
N-Benzyl-5-methyl-1,2,4-oxadiazol-3-methanesulfonamide (14, C11H13N3O3S)
A solution of 100 mg Na in 10 cm3 EtOH was dropwise added to a suspension of 13b (1.4g, 5 mmol) in
50cm3 EtOH, the mixture was refluxed for 2 h, cooled to room temperature, and evaporated in vacuo.
The residue was dissolved in a few cm3 H2O, neutralized with HCl (36%), and extracted with CHCl3.
The combined organic layers were dried (Na2SO4), and evaporated in vacuo. Yield 1.1 g (80%); mp
74ꢁC (MeOH); IR: ꢂꢀ¼ 3240 (NH), 2940, 2980 (CH2), 1580 (C¼N), 1320, 1140 (SO2) cmꢃ1; 1H NMR:
ꢃ ¼ 2.54 (s, Me), 4.33, 4.3–4.5 (s, d, 2 CH2), 5.2–5.4 (t, J ¼ 7 Hz, NH), 7.4 (s, 5 ar H) ppm.
N-Benzyl-4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-methanesulfonamide (15, C10H11N3O4S)
From 11b (0.5g, 2 mmol) and diethyl carbonate (0.24 g, 2 mmol) as described for 12a. Yield 0.45g
(80%); mp 149ꢁC (CHCl3=cyclohexane); IR: ꢂꢀ¼ 3400, 3360, 3300, (NH), 2980, 2920 (CH2), 1810,
1
1790 (CO), 1600 (C¼N), 1330, 1160 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 4.37 (d, CH2), 4.4
(s, CH2), 7.0–8.5 (s, 5 ar H, 2 NH) ppm.
2-Amino-N-benzyl-2-(benzyloxycarbonyloxyimino)-N-(S-ethylthiocarbonyl)ethane-1-sulfonamide
(16, C20H23N3O6S2)
From 11h (1.65 g, 5 mmol) and benzyl chloroformate (0.85 g, 5 mmol) as described for 13a. Yield 1.8 g
(80%); mp 74ꢁC (MeOH); IR: ꢂꢀ¼ 3480 (NH), 3050, 2840 (CH), 1660 (COSEt), 1310, 1125 (SO2)

1340
M. Winterwerber et al.
cmꢃ1; 1H NMR: ꢃ ¼ 1.1–1.3 (t, J ¼ 7 Hz, Me), 2.8–3.1 (q, J ¼ 8 Hz, CH2), 4.31, 4.88, 5.15 (3s, 3 CH2),
5.3–5.5 (s, NH2), 7.2–7.4 (m, 10 ar H) ppm.
2-Amino-2-(benzoyloxyimino)-N-benzyl-N-(ethoxycarbonyl)ethane-1-sulfonamide
(17a, C19H21N3O6S)
From 13a (1.1g, 3 mmol) and ethyl chloroformate (0.35 g, 3 mmol) as described for 3a. Purification by
CC (CH2Cl2=AcOEt). Yield 0.75 g (60%); mp 157–158ꢁC (CH2Cl2=n-pentane); IR: ꢂꢀ¼ 3400 (NH2),
1
1720 (CO), 1640 (C¼N), 1360, 1170 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 1.1–1.4 (t, J ¼ 7 Hz,
Me), 4.1–4.5 (q, J ¼ 8 Hz, CH2), 4.56, 4.93 (2s, 2 CH2), 6.0–6.2 (m, NH2), 7.0–8.3 (m, 10 ar H) ppm.
2-Amino-2-(benzoyloxyimino)-N-benzyl-N-(phenoxycarbonyl)ethane-1-sulfonamide
(17b, C23H21H3O6S)
From 13a (3.4g, 10mmol) and phenyl chloroformate (1.56g, 10mmol) as described for 13a. Yield 2.8g
(60%); mp 156–157ꢁC (MeOH); IR: ꢂꢀ¼ 3460, 3380 (NH2), 1725 (CO), 1630 (C¼N), 1360, 1170 (SO2)
cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.65, 5.07 (2s, 2 CH2), 6.3–6.6 (s, NH2), 7.0–8.3 (m, 15 ar H) ppm.
2-Amino-2-(benzoyloxyimino)-N-benzyl-N-(4-nitrophenoxycarbonyl)ethane-1-sulfonamide
(17c, C23H20N4O8S)
From 13a (1.7g, 5 mmol) and 4-nitrophenyl chloroformate (1.0g, 5 mmol) as described for 13a. Pur-
ification byCC(CHCl3=AcOEt¼ 10=1). Yield1.3 g (50%);mp 78–81ꢁC (CHCl3=AcOEt);IR: ꢂꢀ¼ 3480,
3380 (NH2), 3080, 3030, 2920 (CH), 1730 (CO), 1640 (C¼N), 1520 (NO2), 1350, 1160 (SO2) cmꢃ1
1H NMR (acetone-d6): ꢃ ¼ 4.45, 5.1 (2s, 2 CH2), 5.2–5.4 (s, NH2), 7.4–8.5 (m, 14 ar H) ppm.
;
N-Benzyl-cyano(hydroxyimino)methanesulfonamide (18a, C9H9N3O3S)
An ice-cold solution of NaNO2 (2.1g, 30 mmol) in 50cm3 H2O was added with vigorous stirring and
cooling to a solution of 2c (2.1g, 10 mmol) in 30cm3 AcOH. After stirring at room temperature for
12h 1.25cm3 HCl (36%) were added, the mixture was extracted with THF, the organic layer was dried
(MgSO4), and evaporated in vacuo. The residue was dissolved in a few cm3 CHCl3, and stored at 0ꢁC.
Yield 1.4 g (58%); mp 108–109ꢁC (CHCl3); IR: ꢂꢀ¼ 3400, 3280 (OH, NH), 3070 (CH), 1330, 1165
1
(SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 4.4 (d, J ¼ 6 Hz, CH2), 7.3 (s, 5 ar H), 7.9–8.1 (t, NH), 15.9
(s, OH) ppm.
Cyano(hydroxyimino)-N-phenylmethanesulfonamide (18b, C8H7N3O3S)
From 2b (2.0g, 10 mmol) as described for 18a. Yield 1.4 g (65%); mp 128ꢁC (MeOH); IR: ꢂꢀ¼ 3260
1
(OH, NH), 1370, 1180 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 7.3 (s, 5 ar H), 9.6–9.8 (s, NH),
13.5–14.0 (s, OH) ppm.
Cyano(hydroxyimino)methanesulfonylmorpholide (18c, C6H9N3O4S)
From 2n (1.9g, 10mmol) as described for 18a. Yield 1.3g (60%); mp 142–146ꢁC (dec, MeOH); IR:
1
ꢂꢀ¼ 3420 (OH), 2920, 2800 (CH), 1360, 1180 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 3.2–3.5 (m, 2
CH2), 3.6–3.8 (m, 2 CH2), 14.0–14.02 (s, OH) ppm.
N-Benzyl-N-(benzyloxycarbonyl)cyano(4-methylphenylhydrazono)methane-sulfonamide
(20a, C24H22N4O4S)
At 0ꢁC, a solution of NaNO2 (0.7g) in 3 cm3 H2O was added with stirring to a solution of p-toluidine
(1.1g, 10 mmol) in 3.5 cm3 HCl (36%). This solution was dropwise added with stirring to a suspension
of 3d (3.45 g, 10mmol) and AcONa (4.55 g) in 8 cm3 H2O at max 5ꢁC. After stirring for 12h at room
temperature, the precipitate was separated and dried in vacuo. Yield 3.2 g (70%); mp 118ꢁC (MeOH);
IR: ꢂꢀ¼ 3230 (NH), 3030 (CH), 2200 (CN), 1740 (CO), 1530 (C¼N–NH–), 1380, 1170 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 2.31 (s, Me), 5.00 (s, CH2), 5.2 (s, CH2), 7.0–7.4 (m, 14 ar H), 9.8 (s, NH) ppm.

Synthesis of Heterocyclic Sulfonamides
1341
N-(Benzyloxycarbonyl)cyano-N-(4-methoxybenzyl)-(4-methyl-phenylhydrazono)methanesulfonamide
(20b, C25H24N4O5S)
From 3e (3.75 g, 10 mmol) and p-toluidine (1.1g, 10mmol) as described for 20a. Yield 3.9 g (80%);
mp 134–135ꢁC (MeOH); IR: ꢂꢀ¼ 3220 (NH), 3050, 2930 (CH), 2200 (CN), 1740 (CO), 1530 (C¼N–
NH–), 1380, 1165 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 2.33 (s, Me), 3.73 (s, OMe), 4.97 (s, CH2), 5.26 (s, CH2),
6.8–7.5 (m, 13 ar H), 9.4 (s, NH) ppm.
N-Benzyl-N-(benzyloxycarbonyl)cyano(phenylhydrazono)methanesulfonamide
(20c, C23H20N4O4S)
From 3d (3.45 g, 10 mmol) and aniline (1.0g, 10mmol) as described for 20a. Yield 3.1 g (70%); mp
137ꢁC (MeOH); IR: ꢂꢀ¼ 3240 (NH), 3060 (CH), 2200 (CN), 1760 (CO), 1530 (C¼N–NH–), 1385,
1165 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 5.07 (s, CH2), 5.28 (s, CH2), 7.1–7.5 (m, 15 ar H), 11.5
(s, NH) ppm.
Cyano-N-(methoxycarbonyl)(4-methylphenylhydrazono)-N-phenylmethanesulfonamide
(20d, C17H16N4O4S)
From 3a (2.5 g, 10mmol) and p-toluidine (1.1g, 10mmol) as described for 20a. Yield 2.2g (60%); mp
151ꢁC (MeOH); IR: ꢂꢀ¼ 3180 (NH), 2950 (CH), 2200 (CN), 1720 (CO), 1540 (C¼N–NH–), 1380,
1180 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 2.38 (s, Me), 3.85 (s, OMe), 7.2–7.8 (m, 9 ar H), 12.8 (s, NH) ppm.
N-Benzylcyano-N-(methoxycarbonyl)-4-(methylphenylhydrazono)methanesulfonamide
(20e, C18H18N4O4S)
From 3b (2.6g, 10 mmol) and p-toluidine (1.1g, 10mmol) as described for 20a. Yield 2.8 g (70%); mp
140ꢁC (MeOH); IR: ꢂꢀ¼ 3200 (NH), 3030, 2950 (CH), 2200 (CN), 1730 (CO), 1540 (C¼N–NH–),
1370, 1170 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 2.30 (s, Me), 3.81 (s, OMe), 5.00 (s, CH2), 7.0–7.5 (m, 9 ar H),
9.5–10.0 (s, NH) ppm.
N-Benzylcyano-N-(phenylcarbamoyl)(phenylhydrazono)methanesulfonamide (20f, C22H19N5O3S)
From 4b (3.3g, 10mmol) and aniline (1.0 g, 10mmol) as described for 20a. Yield 3.3 g (78%); mp
132ꢁC (MeOH); IR: ꢂꢀ¼ 3370 (NH), 3070, 2970 (CH), 2200 (CN), 1710 (CO), 1530 (C¼N–NH–),
1370, 1160 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 5.07 (s, CH2), 7.0–7.6 (m, 15 ar H), 9.2 (s, NH),
11.4 (s, NH) ppm.
N-Carbamoylcyano-N-phenyl(phenylhydrazono)methanesulfonamide (20g, C15H13N5O3S)
From 4a (2.4g, 10mmol) and aniline (1.0g, 10 mmol) as described for 20a. Yield 2.9 g (72%); mp
131ꢁC (MeOH); IR: ꢂꢀ¼ 3470, 3360 (NH), 3010, 2970 (CH), 2205 (CN), 1700 (CO), 1530 (C¼N–
1
NH–), 1370, 1180 (SO2) cmꢃ1; H NMR (DMSO-d6): ꢃ ¼ 6.8 (s, NH2), 7.2–7.7 (m, 10 ar H) 11.4
(s, NH) ppm.
N-Benzylcyano-(phenylhydrazono)methanesulfonamide (20h, C15H14N4O2S)
A solution of 0.45 g Na in 50cm3 MeOH was slowly added to a solution of 20f (4.3g, 10mmol) in
50cm3 MeOH. The mixture was refluxed for 6 h, hydrolyzed with HCl (36%), and evaporated in
vacuo. The residue was dissolved in Et2O, washed with H2O, dried (Na2SO4), and the solvent was
evaporated in vacuo. Yield 2.5 g (79%); mp 108ꢁC (CHCl3=CCl4); IR: ꢂꢀ¼ 3250 (NH), 3070 (CH),
1
2200 (CN), 1330, 1170 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 4.4 (s, CH2), 7.1–7.5 (m, 10 ar H),
7.3–7.7 (s, NH), 10.4–11.1 (s, NH) ppm.
2-Amino-N-benzyl-1,2-bis(hydroxyimino)ethane-1-sulfonamide (21, C9H12N4O4S)
From 18a (2.4g, 10 mmol) and H2NOHꢅHCl (1.4g, 20mmol) as described for 2i. The viscous residue
was purified by CC (AcOEt). Yield 1.3g (50%); mp 120ꢁC (AcOEt); IR: ꢂꢀ¼ 3480, 3390 (NH2, OH),

1342
M. Winterwerber et al.
1
3270 (NH), 3010, 2930 (CH), 1350, 1170 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 4.33 (d, J ¼ 7 Hz,
CH2), 5.7–5.9 (br s, NH2), 6.9–7.1 (t, NH), 7.2–7.5 (m, 5 ar H), 9.0–16.0 (br s, 2 OH) ppm.
4-Amino-N-benzyl-1,2,5-oxadiazol-3-sulfonamide (22, C9H10N4O3S)
Method a. A solution of 0.2g Na in 10cm3 EtOH was slowly added to a suspension of 21 (1.35 g,
5 mmol) in 20cm3 EtOH, the mixture was refluxed for 4 h, cooled to room temperature, neutralized
with HCl (36%), and evaporated in vacuo. The residue was dissolved in CHCl3, washed with H2O,
dried (Na2SO4), and evaporated in vacuo. The residue was purified by CC (CHCl3=AcOEt¼ 5=1).
Method b. Compound 21 (0.27 g, 1 mmol) in 20 cm3 POCl3 was stirred at room temperature for
2 h, the solvent was evaporated in vacuo, the residue was dissolved in THF, washed with a satd NaCl
solution, dried (Na2SO4), and the solvent was evaporated in vacuo.
Yield a. 0.6g (50%), b. 0.1 g (40%); mp 76ꢁC (CHCl3=AcOEt); IR: ꢂꢀ¼ 3480, 3340, 3300 (NH2,
NH), 3060, 2920 (CH), 1630 (C¼N), 1350, 1150 (SO2) cmꢃ1
;
1H NMR (acetone-d6): ꢃ ¼ 4.5
(d, J ¼ 6 Hz, CH2), 5.3–5.9 (br s, NH2), 7.4 (s, 5 ar H), 7.9–8.1 (br s, NH) ppm; MS (70 eV): m=z
(%) ¼ 255 (9.56, Mþ+1), 91 (100, C7H7þ).
N-Benzyl-4-formylamino-1,2,5-oxadiazol-3-sulfonamide (23, C10H10N4O4S)
The crude 24 was dissolved in CHCl3, the solution was washed with H2O, dried (Na2SO4), and the
solvent was evaporated in vacuo. Yield 1.15g (80%); mp 84–85ꢁC (CHCl3); IR: ꢂꢀ¼ 3340 (NH), 3090,
2890, 2870 (CH), 1700 (CO), 1360, 1150 (SO2) cmꢃ1; 1H NMR (acetone-d6): ꢃ ¼ 4.3 (s, CH2), 7.2 (s, 5
ar H), 7.5–8.0 (br s, NH), 8.6–8.8 (br s, NH, CHO) ppm; MS (70 eV): m=z (%) ¼ 283 (13.91, Mþ), 91
(100, C7H7þ).
N-Benzyl-4-(ethoxymethylimino)-1,2,5-oxadiazol-3-sulfonamide (24, C12H14N4O4S)
Compound 21 (1.35 g, 5 mmol) in 20 cm3 HC(OEt)3 was refluxed for 4 h, formed EtOH was distilled
off, then the mixture was cooled to room temperature, and the solvent was evaporated in vacuo. The
1
crude product, H NMR: ꢃ ¼ 1.2–1.5 (t, J ¼ 7 Hz, Me), 4.0–4.5 (m, 2 CH2), 5.9–6.1 (br s, NH),
7.2–7.4 (s, 5 ar H), 8.12 (s, N¼CH) ppm, was immediately used for the synthesis of 23.
4-Acetylamino-N-benzyl-1,2,5-oxadiazol-3-sulfonamide (25, C11H12N4O4S)
Compound 21 (1.35 g, 5 mmol) in 30 cm3 Ac2O was refluxed for 4 h, cooled to room temperature,
concentrated in vacuo, dissolved in CHCl3, washed with H2O, dried (Na2SO4), and the solvent was
evaporated in vacuo. Yield 1.35g (80%); mp 90ꢁC (CHCl3); IR: ꢂꢀ¼ 3340 (NH), 3040, 2980, 2930
1
(CH), 1720 (CO), 1360, 1150 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 2.28 (s, Me), 4.5 (s, CH2), 7.3
(s, 5 ar H), 7.6–7.9 (br s, NH). 9.3–9.6 (br s, NH) ppm.
4-Amino-N-benzyl-N-(methoxycarbonyl)-1,2,5-oxadiazol-3-sulfonamide (26, C11H12N4O5S)
Under N2 and withstirring, methyl chloroformate(0.2g, 2 mmol) in5 cm3 THF was added toa solution of
21 (0.54 g, 2 mmol) in 50 cm3 THF, stirring was continued for 30 min, then Et3N (0.4g, 4 mmol) and
additional methyl chloroformate (0.2 g, 2 mmol) in 5 cm3 THF were added. The mixture was refluxed for
1 h, cooled to room temperature, washed with a satd NaCl solution, dried (MgSO4), and evaporated in
vacuo. The residue was purified by CC (CHCl3). Yield 0.3 g (50%); mp 110–111ꢁC (CHCl3); IR:
ꢂꢀ¼ 3490, 3360 (NH2), 1720 (CO), 1330, 1140 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 3.76 (s, OMe), 4.6–5.1 (br
s, NH2, CH2), 7.4 (m, 5 ar H) ppm; MS (70 eV): m=z (%) ¼ 313 (5.16, Mþ+1), 164 (100, C9H10NO2).
2-Amino-N-benzyl-N-(benzyloxycarbonyl)-2-hydroxyimino-1-(4-methylphenylhydrazono)ethane-
1-sulfonamide (27a, C24H25N5O5S)
From 20a (4.6g, 10mmol) and 1.4 g H2NOHꢅHCl as described for 11a. Yield 4.4 g (90%); mp 109ꢁC
(MeOH); IR: ꢂꢀ¼ 3460–3260 (NH2, NH, OH), 3030 (CH), 1700 (CO), 1360, 1160 (SO2) cmꢃ1
;
1H NMR (acetone-d6): ꢃ ¼ 2.28 (s, Me), 5.03 (s, CH2), 5.13 (s, CH2), 5.8–6.0 (br s, NH2), 7.0–7.6
(m, 14 ar H, OH), 12.9–13.1 (br s, NH) ppm.

Synthesis of Heterocyclic Sulfonamides
1343
2-Amino-N-(benzyloxycarbonyl)-2-hydroxyimino-N-(4-methoxybenzyl)-1-
(4-methylphenylhydrazono)ethane-1-sulfonamide (27b, C25H27N5O6S)
From 20b (4.9g, 10mmol) and 1.4 g H2NOHꢅHCl as described for 11a, 2 h at 50ꢁC, 12 h of room
temperature. Yield 4.4g (85%); mp 114–116ꢁC (MeOH=H2O ¼ 9=1); IR: ꢂꢀ¼ 3520, 3420, 3300 (NH),
3050, 2950, 2850 (CH), 1720 (CO), 1620 (C¼N), 1520 (C¼N–NH–) 1340, 1170 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 2.4 (s, Me), 3.8 (s, OMe), 5.0 (s, CH2), 5.2 (s, CH2), 5.6–5.8 (br s, NH2), 6.8–7.4
(m, 13 ar H, OH), 11.9–12.1 (br s, NH) ppm.
2-Amino-N-benzyl-2-hydroxyimino-N-(methoxycarbonyl)-1-(4-methylphenylhydrazono)ethane-
1-sulfonamide (27c, C18H21N5O5S)
From 20e (3.8g, 10mmol) and 1.4g H2NOHꢅHCl as described for 11a. Yield 3.8 g (90%); mp 155ꢁC
(MeOH); IR: ꢂꢀ¼ 3500, 3250 (NH), 3030, 2960, 2920, 2860 (CH), 1730 (CO), 1350, 1170 (SO2) cmꢃ1
;
1H NMR (acetone-d6): ꢃ ¼ 2.4 (s, Me), 3.71 (s, OMe), 5.06 (s, CH2), 5.8–6.1 (br s, NH2), 7.0–7.6 (m, 9
ar H, OH). 13.9–14.1 (br s, NH) ppm.
2-Amino-N-benzyl-N-(benzyloxycarbonyl)-2-hydroxyimino-1-phenylhydrazonoethane-
1-sulfonamide (27d, C23H23N5O5S)
From 20c (4.5 g, 10mmol) and 1.4g H2NOHꢅHCl as described for 11a. Purification by CC (CHCl3=
AcOEt 20=1). Yield 0.48g (10%); mp 133–136ꢁC (CHCl3=AcOEt); IR: ꢂꢀ¼ 3480–3260 (NH2, NH, OH),
3060, 3020, 2970 (CH), 1730 (CO), 1330, 1150 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 5.15 (s, CH2), 5.22 (s, CH2),
5.6–5.8 (br s, NH2), 6.0–7.0 (br s, OH), 7.0–7.5 (m, 15 ar H), 12.5–12.7 (br s, NH) ppm.
5-Amino-N-benzyl-N-(benzyloxycarbonyl)-2-(4-methylphenyl)-2H-1,2,3-triazol-4-sulfonamide
(28a, C24H23N5O4S)
At 0ꢁC, 27a (1.0g, 2 mmol) and 30cm3 POCl3 were stirred for 1 h, the mixture was concentrated
invacuo, the residuewas dissolvedinCHCl3, washedwithanaqueousNaHCO3 solution, dried (Na2SO4),
and the solvent was evaporated in vacuo. Yield 0.95 g (90%); mp 168–169ꢁC (MeOH); IR: ꢂꢀ¼ 3380,
3280 (NH2), 3030, 2990 (CH), 1730 (CO), 1630 (C¼N), 1380, 1170 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 2.35
(s, Me), 5.02 (s, CH2), 5.16 (s, CH2), 5.3–5.5 (br s, NH2), 7.0–7.5 (m, 14 ar H) ppm.
5-Amino-N-(benzyloxycarbonyl)-N-(4-methoxybenzyl)-2-(4-methylphenyl)-
2H-1,2,3-triazol-4-sulfonamide (28b, C25H25N5O5S)
From 27b (2.2g, 4 mmol) as described for 28a. Yield 1.7 g (80%); mp 157–158ꢁC (MeOH); IR: ꢂꢀ¼ 3460
(NH2), 3040, 2980 (CH), 1730 (CO), 1635 (C¼N), 1385, 1165 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 2.42 (s, Me),
3.75 (s, OMe), 5.00 (s, CH2), 5.15 (s, CH2), 5.2–5.4 (br s, NH2), 6.7–7.5 (m, 13 ar H) ppm.
5-Amino-N-benzyl-N-(methoxycarbonyl)-2-(4-methylphenyl)-2H-1,2,3-triazol-4-sulfonamide
(28c, C18H19N5O4S)
From 27c (4.2g, 10mmol) as described for 28a. Yield 3.6 g (90%); mp 142ꢁC (MeOH); IR: ꢂꢀ¼ 3400
1
(NH2), 3020, 2920 (CH), 1730 (CO), 1630 (C¼N), 1380, 1170 (SO2) cmꢃ1; H NMR (acetone-d6):
ꢃ ¼ 2.36 (s, Me), 3.66 (s, OMe), 5.03 (s, CH2), 6.2–6.4 (br s, NH2), 7.2–7.6 (m, 9 ar H) ppm.
5-Amino-N-benzyl-N-(benzyloxycarbonyl)-2-phenyl-2H-1,2,3-triazol-4-sulfonamide
(28d, C23H21N5O4S)
From 27d (1.0g, 2 mmol) as described for 28a. Yield 0.9 g (90%); mp 120ꢁC (MeOH); IR: ꢂꢀ¼ 3450
(NH2), 3060, 3030, 2950 (CH), 1730 (CO), 1630 (C¼N), 1380, 1160 (SO2) cmꢃ1; 1H NMR: ꢃ ¼ 5.01
(s, CH2), 5.12 (s, CH2), 5.7–5.9 (br s, NH2), 7.1–7.5 (m, 15 ar H) ppm.
5-Amino-N-benzyl-2-(4-methylphenyl)-2H-1,2,3-triazol-4-sulfonamide (29a, C16H17N5O2S)
A solution of 0.2 g Na in 10cm3 EtOH was added to a solution of 28a (0.5g, 1 mmol) in 20cm3 EtOH.
The mixture was stirred at room temperature for 1 h, neutralized with HCl (36%), evaporated in vacuo,

1344
M. Winterwerber et al.
and the residue was purified by CC (CHCl3=AcOEt). Yield 0.17g (50%); mp 103–105ꢁC (MeOH); IR:
1
ꢂꢀ¼ 3450, 3280 (NH), 3020, 2830 (CH), 1630 (C¼N), 1340, 1160 (SO2) cmꢃ1; H NMR: ꢃ ¼ 2.35
(s, Me), 4.3 (d, J ¼ 7 Hz, CH2), 5.4–5.6 (br s, NH2), 6.0–6.1 (t, J ¼ 7 Hz, NH), 7.2–7.4 (m, 9 ar H)
ppm; MS (70 eV): m=z (%) ¼ 344 (1.57, Mþ), 106 (100, C7H8N).
5-Amino-N-(4-methoxybenzyl)-2-(4-methylphenyl)-2H-1,2,3-triazol-4-sulfonamide
(29b, C17H19N5O3S)
From 28a (0.5g, 1 mmol) as described for 29a. Yield 0.21g (60%); mp 183–184ꢁC (CHCl3=
cyclohexane); IR: ꢂꢀ¼ 3490, 3260 (NH), 3030, 2830 (CH), 1635 (C¼N), 1350, 1165 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 2.42 (s, Me), 3.72 (s, OMe), 4.4 (d, J ¼ 7 Hz, CH2), 5.9–6.0 (br s, NH2), 6.6–7.3 (m, 8 ar
H, NH) ppm; MS (70 eV): m=z (%) ¼ 372 (3.8, Mþ ꢃ 1); 136 (100, C8H10NO).
5-Amino-N-benzyl-2-phenyl-2H-1,2,3-triazol-4-sulfonamide (29c, C15H15N5O2S)
From 28d (0.46 g, 1 mmol) as described for 29a. Yield 0.16g (50%); mp 120–121ꢁC (CHCl3=cyclo-
cyclohexane); IR: ꢂꢀ¼ 3450–3350 (NH), 3020 (CH), 1620 (C¼N), 1340, 1160 (SO2) cmꢃ1; 1H NMR
(acetone-d6): ꢃ ¼ 4.4 (d, J ¼ 6 Hz, CH2), 6.0–6.3 (br s, NH2), 7.0–7.6 (m, 10 ar H, NH) ppm.
2-Acetoximino-2-amino-N-benzyl-N-(benzyloxycarbonyl)-1-phenylhydrazonoethane-
1-sulfonamide (30, C25H25N5O6S)
Compound 27d (0.5g, 1 mmol) in 20cm3 Ac2O was refluxed for 1 h. The mixture was evaporated in
vacuo, the residue was dissolved in CHCl3, washed with a NaHCO3 solution, dried (Na2SO4), and
evaporated in vacuo. Yield 0.25g (50%); mp 84ꢁC (MeOH); IR: ꢂꢀ¼ 3480, 3380, 3260 (NH2, NH),
3060, 3030 (CH), 1760, 1730 (CO), 1620 (C¼N), 1530 (C¼N–NH), 1340, 1160 (SO2) cmꢃ1
;
1H NMR: ꢃ ¼ 2.17 (s, Me), 5.04 (s, CH2), 5.11 (s, CH2), 5.8–6.0 (br s, NH2), 7.0–7.5 (m, 15 ar H),
13.4–13.6 (s, NH) ppm.
5-Acetylamino-N-benzyl-N-(benzyloxycarbonyl)-2-(4-methylphenyl)-2H-
1,2,3-triazol-4-sulfonamide (31, C26H25N5O5S)
Compound 28a (0.47 g, 1 mmol), 20cm3 AcOH, and 20cm3 Ac2O were refluxed for 2 h, cooled to
room temperature, and evaporated in vacuo. The residue was dissolved in CHCl3, washed with an
aqueous NaHCO3 solution, dried (Na2SO4), and evaporated in vacuo. Yield 0.4g (80%); mp 157ꢁC
(MeOH); IR: ꢂꢀ¼ 3380, 3280 (NH), 3060, 3030 (CH), 1730 (CO), 1370, 1165 (SO2) cmꢃ1; 1H NMR:
ꢃ ¼ 2.13 (s, Me), 2.41 (s, Me), 5.0–5.2 (2s, 2 CH2), 5.4–5.6 (br s, NH), 7.0–7.5 (m, 14 ar H) ppm.
5-(S-Ethylthiocarbonylamino)-N-(4-methoxybenzyl)-2-(4-methylphenyl)-2H-1,2,3-triazol-4-
sulfonamide (32, C20H23N5O4S2)
Under N2 at ꢃ78ꢁC, 0.65cm3 BuLi were added to 29b (0.35 g, 1 mmol) in 50cm3 THF, then, after
10min S-ethyl chlorothioformate (0.12 g, 1 mmol) in 10cm3 THF was added, and after stirring for 1 h
0.2 cm3 BuLi were added. The mixture was warmed to room temperature, washed with a satd NaCl
solution, dried (MgSO4), and evaporated in vacuo. Yield 0.35g (80%); mp 165–167ꢁC (MeOH); IR:
1
ꢂꢀ¼ 3420 (NH2), 1680 (COSEt), 2960, 2920 (CH), 1630 (C¼N), 1370, 1155 (SO2) cmꢃ1; H NMR:
ꢃ ¼ 1.0–1.3 (t, J ¼ 7 Hz, Me), 2.39 (s, Me), 2.7–3.0 (q, J ¼ 7 Hz, CH2), 3.75 (s, OMe), 5.05 (s, CH2),
5.6 (br s, 2 NH), 6.8–7.5 (m, 8 ar H) ppm.
4-Amino-N-benzylpyrimidine-5-sulfonamide (33a, C11H12N4O2S)
Compound 2c (2.1g, 10mmol) and formamidinium acetate (6.3g, 60mmol) in 50cm3 BuOH were
refluxed for 6 h, the mixture was cooled to room temperature, the precipitate was separated, and the
filtrate was concentrated yielding more precipitate. The combined precipitates were crystallized. Yield
2.1 g (80%); mp 210ꢁC (THF); IR: ꢂꢀ¼ 3420, 3300 (NH), 3120, 3020, 2920 (CH), 1650 (C¼N), 1320,
1130 (SO2) cmꢃ1; 1H NMR (DMSO-d6): ꢃ ¼ 4.2 (s, CH2), 7.2–7.5 (m, 5 ar H, NH2), 8.3–8.5 (m, 2 ar
H, NH) ppm.

Synthesis of Heterocyclic Sulfonamides
1345
4-Amino-N-(4-methoxybenzyl)pyrimidine-5-sulfonamide (33b, C12H14N4O3S)
From 2d (2.4g, 10mmol) as described for 33a. Yield 2.35 g (80%); mp 197–199ꢁC (THF); IR:
1
ꢂꢀ¼ 3430, 3300 (NH), 3120, 2990 (CH), 1660 (C¼N), 1330, 1170 (SO2) cmꢃ1; H NMR (DMSO-
d6): ꢃ ¼ 3.9 (s, OMe), 4.2 (s, CH2), 3.9–5.0 (br s, NH2), 6.8–7.5 (m, 4 ar H), 7.0–8.0 (br s, NH), 8.50,
8.51 (2s, 2 ar H) ppm.
4-Amino-N-phenylpyrimidine-5-sulfonamide (33c, C10H10N4O2S)
From 2b (2.0g, 10mmol) as described for 33a. Yield 2.0 g (80%); mp >250ꢁC (dec, THF); IR:
ꢂꢀ¼ 3430, 3310 (NH2, NH), 3160, 3060, 3020, 2950, 2880 (CH), 1650 (C¼N), 1330, 1140 (SO2)
cmꢃ1; 1H NMR (DMSO-d6): ꢃ ¼ 7.0–7.4 (s, 5 ar H), 6.5–8.5 (br s, NH2), 8.5 (s, 2 ar H), 10.3–10.5 (br
s, NH) ppm.
4-Amino-N-(4-methoxyphenyl)pyrimidine-5-sulfonamide (33d, C11H12N4O2S)
From 2f (2.1 g, 10 mmol) as described for 33a. Yield 2.3 g (80%); mp 291ꢁC (THF); IR: ꢂꢀ¼ 3490,
3290 (NH2), 3120, 2995, 2900 (CH), 1640 (C¼N), 1320, 1160 (SO2) cmꢃ1; 1H NMR (DMSO-d6):
ꢃ ¼ 3.65 (s, OMe), 6.8–7.2 (m, 4 ar H), 8.30, 8.45 (2s, 2 ar H), 9.0–6.5 (br s, NH2), 10.0 (br s,
NH) ppm.
4-Amino-N-propylpyrimidine-5-sulfonamide (33e, C7H12N4O2S)
From 2g (1.6g, 10 mmol) as described for 33a. Purification by CC (AcOEt) yielded 0.1g (5%) 35 as a
by-product. Yield 1.5 g (70%); mp 164ꢁC (AcOEt); IR: ꢂꢀ¼ 3430, 3300 (NH2), 3120, 3020, 2960 (CH),
1
1650 (C¼N), 1325, 1160 (SO2) cmꢃ1; H NMR (acetone-d6): ꢃ ¼ 1.0 (m, Me), 1.4–1.8 (m, CH2),
2.9–3.2 (m, CH2), 6.3–7.5 (br s, NH2, NH), 8.4–8.5 (2s, 2 ar H) ppm.
4-Amino-N-(2-chlorobenzyl)pyrimidine-5-sulfonamide (33f, C11H11ClN4O2S)
From 2h (2.4g, 10 mmol) as described for 33a. Yield 2.2 g (80%); mp 222ꢁC (MeOH); IR: ꢂꢀ¼ 3411,
3319 (NH), 1657 (C¼N), 1331, 1135 (SO2) cmꢃ1; 1H NMR (DMSO-d6, 400MHz): ꢃ ¼ 4.15 (s, CH2),
7.2–7.5 (m, 4 ar H), 8.40, 8.45 (2s, 2 ar H) ppm; MS (70 eV): m=z (%) ¼ 299 (80, Mþ).
4-Amino-N-(4-chlorobenzyl)pyrimidine-5-sulfonamide (33g, C11H11ClN4O2S)
From 2i (2.4g, 10 mmol) as described for 33a. Yield 2.3 g (80%); mp 244ꢁC (MeOH); IR: ꢂꢀ¼ 3411,
1
3319 (NH), 1657 (C¼N), 1331, 1135 (SO2) cmꢃ1; H NMR (DMSO-d6, 90MHz): ꢃ ¼ 4.1 (s, CH2),
7.1–7.5 (m, 4 ar H), 8.4, 8.5 (2s, 2 ar H) ppm.
4-Amino-N-(4-fluorobenzyl)pyrimidine-5-sulfonamide (33h, C11H11FN4O2S)
From 2k (2.3g, 10 mmol) as described for 33a. Yield 2.2 g (80%); mp 197ꢁC (MeOH); IR: ꢂꢀ¼ 3400,
1
3300 (NH), 1650 (C¼N), 1330, 1135 (SO2) cmꢃ1; H NMR (DMSO-d6, 90MHz): ꢃ ¼ 4.1 (s, CH2),
6.97–7.4 (m, 4 ar H), 8.4, 8.5 (2s, 2 ar H) ppm.
4-Amino-N-(4-bromophenyl)pyrimidine-5-sulfonamide (33i, C10H9BrN4O2S)
From 2l (2.7g, 10 mmol) as described for 33a. Yield 2.0 g (60%); mp 300ꢁC (MeOH); IR: ꢂꢀ¼ 3436,
3305 (NH), 1650 (C¼N), 1329, 1135 (SO2) cmꢃ1; 1H NMR (DMSO-d6, 90 MHz): ꢃ ¼ 7.0–7.6 (m, 4 ar
H), 8.5 (s, 2 ar H) ppm.
4-Acetylamino-N-benzylpyrimidine-5-sulfonamide (34a, C13H14N4O3S)
Compound 33a (1.3g, 5 mmol), 20 cm3 AcOH, and 20 cm3 Ac2O were refluxed for 3 h, cooled to room
temperature, and evaporated in vacuo. The residue was dissolved in CHCl3, washed with an aqueous
AcONa solution, dried (Na2SO4), and the solvent was evaporated in vacuo. Yield 1.0 g (65%); mp
218ꢁC (CHCl3=CCl4); IR: ꢂꢀ¼ 3360 (NH), 3120, 2950 (CH), 1650 (C¼N), 1320, 1140 (SO2) cmꢃ1; 1H
NMR: ꢃ ¼ 2.4 (s, Me), 3.2–3.6 (br s, NH), 4.2 (s, CH2), 7.2 (s, 5 ar H), 8.8–9.3 (m, 2 ar H, NH) ppm.

1346
M. Winterwerber et al.
4-Acetylamino-N-acetyl-N-(4-chlorobenzyl)pyrimidine-5-sulfonamide (34b, C15H15ClN4O4S)
From 33g (1.5g, 5 mmol) as described for 34a. Yield 0.8 g (42%); mp 180ꢁC (acetone); IR: ꢂꢀ¼ 3341
1
(NH), 1703 (CO), 1571 (C¼N), 1374, 1147 (SO2) cmꢃ1; H NMR (90 MHz): ꢃ ¼ 2.2 (s, Me), 2.5
(s, Me), 5.1 (s, CH2), 7.1–7.5 (m, 4 ar H), 8.7, 9.0 (2s, 2 ar H), 9.6 (s, NH) ppm.
4-Acetylamino-N-acetyl-N-phenylpyrimidine-5-sulfonamide (34c, C14H14N4O4S)
From 33c (1.3g, 5 mmol) as described for 34a. Yield 0.5g (30%); mp 160ꢁC (acetone); IR: ꢂꢀ¼ 3345
1
(NH), 1710 (CO), 1570 (C¼N), 1375, 1150 (SO2) cmꢃ1; H NMR: ꢃ ¼ 1.9 (s, Me), 2.5 (s, Me),
7.2–7.7 (m, 5 ar H), 8.9, 9.1 (2s, 2 ar H), 9.7 (s, NH) ppm.
2-Amino-N-propyl-1-cyanoethene-1-sulfonamide (35, C6H11N3O2S)
Compound 35 was isolated as by-product from the synthesis of 33e. Yield 0.1 g (5%); IR: ꢂꢀ¼ 3440,
3280 (NH), 2200 (CN), 1650 (C¼C), 1310, 1160 (SO2) cmꢃ1
.
(RS)-2-(4-Chlorobenzyl)-3-ethoxy-3,4-dihydro-2H-pyrimido[4,5-e][1,2,4]thiadiazine
1,1-dioxide (36a, C14H15ClN4O3S)
Compound 33g (0.3g, 1 mmol), 2 cm3 HC(OEt)3, and 3 drops AcOH were refluxed for 6 h, cooled to
room temperature, and the precipitate was isolated. Yield 0.2 g (56%); mp 179ꢁC (MeOH); IR:
1
ꢂꢀ¼ 3180, 2983 (CH), 1593 (C¼N), 1346, 1176 (SO2), 1121 (C–O) cmꢃ1; H NMR (DMSO-d6,
90MHz): ꢃ ¼ 1.1 (t, J ¼ 5.8 Hz, Me), 3.6 (q, J ¼ 11.6 Hz, CH2), 4.3 (d, J ¼ 5.8 Hz, CH2), 5.96 (s, 3-H),
7.4 (s, 4 ar H), 8.7, 8.8 (2s, 2 ar H), 9.6 (br s, NH) ppm.
(RS)-2-(4-Fluorobenzyl)-3-ethoxy-3,4-dihydro-2H-pyrimido[4,5-e][1,2,4]thiadiazine
1,1-dioxide (36b, C14H15FN4O3S)
From 33h (0.3g, 1 mmol) as described for 36a. Yield 0.22g (65%); mp 170ꢁC (MeOH); IR: ꢂꢀ¼ 3179,
1
2984 (CH), 1593 (C¼N), 1345, 1182 (SO2), 1125 (C–O) cmꢃ1; H NMR (DMSO-d6, 300MHz):
ꢃ ¼ 1.03 (t, J ¼ 6.6 Hz, Me), 3.56 (q, J ¼ 9.9 Hz, CH2), 4.2 (d, CH2), 5.8 (s, 3-H), 7.1–7.3 (m, 4 ar H),
8.70, 8.74 (2s, 2 ar H), 9.6 (br s, NH) ppm.
Acknowledgements
We thank Dr. Peter Raddatz, E. Merck KGaG, Darmstadt, for extended generous support with che-
micals, with chromatography materials, and for biological testing, and we thank the ‘‘Fonds der
Chemischen Industrie’’, Frankfurt am Main, for continuous financial support.
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Synthesis of Heterocyclic Sulfonamides
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