Reactions of cyanomethanesulfonamides with aldehydes and synthesis of 2-benzyl-2,3-dihydrobenzopyrano[3,2-e] [1,2,4]thiadiazine 1,1-dioxides

Article abstract of DOI:10.1007/s00706-006-0541-x

Reactions of cyanomethanesulfonamides with aromatic aldehydes in the presence of AcOH and piperidine produced the addition products, the 1-cyano-2-arylethenesulfonamides, whereas reactions with benzonitrile yielded the 2-amino-1-cyano-2-phenylethenesulfon

Full text of DOI:10.1007/s00706-006-0541-x

Monatshefte f€ur Chemie 137, 1441–1451 (2006)
DOI 10.1007/s00706-006-0541-x
Reactions of Cyanomethanesulfonamides
with Aldehydes and Synthesis
of 2-Benzyl-2,3-dihydrobenzopyrano[3,2-e]
[1,2,4]thiadiazine 1,1-Dioxides
Martin Winterwerber1, Rouzita Geiger1, Ursula Predoiu2,
and Hans-Hartwig Otto1;ꢀ
1
Department of Pharmaceutical=Medicinal Chemistry, Institute of Pharmacy,
University of Greifswald, Greifswald, Germany
2
Institute of Pharmacy, University of Freiburg, Freiburg, Germany
Received April 29, 2006; accepted May 2, 2006
Published online October 27, 2006 # Springer-Verlag 2006
Summary. Reactions of cyanomethanesulfonamides with aromatic aldehydes in the presence of
AcOH and piperidine produced the addition products, the 1-cyano-2-arylethenesulfonamides, whereas
reactions with benzonitrile yielded the 2-amino-1-cyano-2-phenylethenesulfonamides only when done
in THF with BuLi. No addition products were isolated from the analogue reactions with 2-hydroxy-
benzaldehyde (salicylaldehyde). Instead, we obtained 2-imino-2H-chromene-3-sulfonamides with
good to excellent yields. These 2H-chromene derivatives allowed a number of transformations, from
which the reactions with orthoformates opened an approach to the hitherto unknown benzopyrano[3,2-e]
[1,2,4]thiadiazine ring system.
Keywords. Cyanomethanesulfonamide; Aldehyde; Condensation; Cyclization; Benzopyrano[3,2-e]
[1,2,4]thiadiazine 1,1-dioxide.
Introduction
In a preceding paper [1] we have reported about reactions of cyanomethanesulfonyl
chloride with amines, and about the transformation of the obtained cyanomethane-
sulfonamides into various heterocyclic sulfonamides. These heterocycles exhibit
interesting biological properties as diuretics, antihypertensives and others. In con-
tinuation, we report here about our results concerning the reactions of cyanomethane-
sulfonamides with aromatic aldehydes and related systems intending to find by
this way an easy route to pharmacological active compounds, especially as some
related compounds have been described [2] but prepared by a more complex way.
ꢀ
Corresponding author. E-mail: ottohh@pharmazie.uni-greifswald.de

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M. Winterwerber et al.
Results and Discussion
The methylene function of the cyanomethanesulfonamides 1 allowed not only
condensation reactions with orthoformates or the parent N-derivatives as described
[1] but also reactions with nitriles or aldehydes. For example, when 1b or 1d were
reacted with benzonitrile and BuLi in THF at 0ꢁC, the expected 2-amino-2-phenyl-
cyanoethenesulfonamides 2a and 2b became available as crystalline compounds
with good yields (Scheme 1).
Experiments to use these conditions for reactions with aromatic aldehydes either
failed completely or resulted in poor yields only. But when we performed the re-
actions between 1a–1e and substituted benzaldehydes in the presence of a few
drops of piperidine and a few drops of AcOH in refluxing toluene until the sep-
Scheme 1
Scheme 2

Reactions of Cyanomethanesulfonamides
1443
aration of H2O was completed, we isolated the substituted benzylidenecyano-
methanesulfonamides 3a–3g as crystalline compounds with yields up to 80%. The
1-cyano-4-phenylbutadiene-1-sulfonamide 4 was prepared from 1b and cinnamic
aldehyde, yield 60%. The formation of 6 from 5, yield 80%, under these drastic
conditions (reflux for 4 h) demonstrated the high stability of the N-acetyl-N-benzyl-
sulfonamide structure of 5 (Scheme 1).
The synthesis of the sulfonylurea derivatives 7a and 7b was possible by the
reaction of 3a and 3b with chlorosulfonyl isocyanate at ꢂ78ꢁC in THF with BuLi
under a nitrogen atmosphere. Using analogue conditions, the derivative 8 was ob-
tained from the reaction with phenyl isocyanate. Finally, the reaction between 3c
and acetyl chloride demonstrated the general possibility of N-acylation of these
N-monosubstituted sulfonamide derivatives (Scheme 2).
The IR spectra of all benzylidene derivatives were characterized by a strong band at ꢀꢀ¼ 2210–
2230 cmꢂ1 indicating the conjugated CꢃN group, two bands around 1350 and 1170 cmꢂ1 from the
sulfonyl group, and the bands of H–N and other substituents. These bands are slightly shifted in the
spectra of the aminobenzylidene derivatives 2a and 2b. The signal of the CꢃN group was found at
2200 cmꢂ1, whereas the sulfonyl bands were detected at 1320 and 1150 (1130) cmꢂ1, indicating the
1
influence of the amino group at C-2. The H NMR spectra of the N-alkylated compounds 3a–3f
showed a sharp singlet at ꢄ8.0 ppm indicating the proton at C-2. This signal is shifted to ꢄ8.3 ppm in
the spectra of the additionally acylated derivatives 7a, 7b, 8, and 9. We see the fact that the spectra
exhibited only one sharp signal for 2-H as an indicator for the existence of only one diastereoisomer,
and we deduce from calculations [3] and from the results of the following reactions with salicylalde-
hyde, that this isomer showed (E)-configuration.
Among the condensation reactions between the cyanomethanesulfonamides 1b,
1c, and 10a–10g and aromatic aldehydes the reactions with salicylaldehyde gave
the most interesting results. These reactions were performed in refluxing CHCl3 in
the presence of AcOH and piperidine. After work-up we obtained the 2-imino-2H-
chromene derivatives 11a–11h as colorless to light yellow crystals with yields
between 50 and 80%. Formation of these derivatives is best explained by an attack
of the hydroxyl group to the nitrile after formation of the condensation product,
which we could not isolate. Compound 13 was obtained from a reaction between
the disubstituted sulfonamide 12 and salicylaldehyde (Scheme 3).
The 2-imino-2H-chromene derivatives 11a–11i allowed some interesting trans-
formations. Acylation of the imino group was demonstrated by refluxing of 11a in
Ac2O yielding the crystalline derivative 14 with 90% yield. Refluxing of 11a in
THF under acidic conditions resulted in the isolation of the oxoisoquinoline deri-
vative 16, yield 50%, a reaction best understood as a Dimroth rearrangement. Three
examples, starting from 11a, 11b, and 13 demonstrated the hydrolysis of the imino
group yielding the coumarine sulfonamides 15a, 15b, and 15c, stable, crystalline
compounds with yields of ca. 90% (Scheme 3).
Structures of the 2H-chromene derivatives were established by spectroscopic
data. The IR spectra of 11 were characterized by the absorption bands of the sul-
fonamide group at ꢀꢀ¼ 1320–1360 and 1160–1130 cmꢂ1, and the imino band
between 1630 and 1680 cmꢂ1, whereas the lactone group of 15a–15c caused a
strong band at 1730 cmꢂ1, and the oxo group of 17a was identified by the band
at 1725 cmꢂ1. The spectrum of 14 showed an amide band at 1650 and an H–N band
at 3290 cmꢂ1 caused by the sulfonamide H–N. The 1H NMR spectra contained all

1444
M. Winterwerber et al.
Scheme 3
expected signals of the substituents and a sharp singlet at 7.96–7.98 (11a–11i),
8.34–8.47 (15a–15c), 8.50 (16), and 8.22 ppm (14), which was assigned to the
proton at C-4.
Scheme 4

Reactions of Cyanomethanesulfonamides
1445
Finally, the iminochromene derivatives 11a–11i were refluxed in an orthofor-
mate solution, and we isolated from this reactions the benzopyrano[3,2-e][1,2,4]thia-
diazine 1,1-dioxides 17a–17i and 18a, 18b, and 18d–18h. All derivatives were
obtained as stable, crystalline compounds, the yields varied between 30 and 80%
(Scheme 4). The pharmacological potency of these compounds was tested in differ-
ent systems, and the most interesting aspect was the fact, that all compounds were
able to lower high blood pressure in a way comparable to the so-called sartanes [4].
Experimental
For instrumentation details see Ref. [1]. Compounds 1a–1e, 5, 10a, 10b, and 12 were prepared as
described in Ref. [1].
2-Amino-N-benzyl-2-phenyl-1-cyanoethenesulfonamide (2a, C16H15N3O2S)
At 0ꢁC, BuLi (7.5cm3, 10.5mmol) was added to a solution of 1b (1.0g, 5 mmol) in THF, then,
benzonitrile (1.63 cm3, 16mmol) was added, and the mixture was stirred for 1 h at 0ꢁC and 12 h at
room temperature. Then, the mixture was hydrolyzed with dil. HCl and an aqueous satd. NaCl solution,
the organic layer was separated, dried (MgSO4), and evaporated in vacuo. Yield 1.0 g (64%); colorless
crystals; mp 132ꢁC (CHCl3); IR: ꢀꢀ¼ 3320, 3420 (NH2), 2200 (CN), 1620 (C¼C), 1320, 1150 (SO2)
1
cmꢂ1; H NMR (acetone-d6): ꢁ ¼ 4.4 (s, CH2), 7.2–7.6 (m, 10 ar H, NH2, NH) ppm.
2-Amino-N-(4-chlorobenzyl)-1-cyano-2-phenylethenesulfonamide (2b, C16H14ClN3O2S)
From 1d (1.2g, 10 mmol) as described for 2a. Yield 0.6 g (35%); colorless crystals; mp 156ꢁC
1
(MeOH); IR: ꢀꢀ¼ 3460, 3340 (NH), 2200 (CN), 1620 (C¼C), 1320, 1130 (SO2) cmꢂ1; H NMR
(acetone-d6): ꢁ ¼ 4.4 (d, J ¼ 6.6 Hz, CH2), 7.2–7.6 (m, 9 ar H, NH2), 7.9 (s, NH) ppm.
General Procedure for the Synthesis of 3, 4, and 6
Compound 1 (5), the aldehyde, 4 drops of piperidine, and 2 drops of AcOH were refluxed in 150cm3
toluene (CHCl3 for salicylaldehyde) with a water separator until the reaction was complete (ca. 4 h).
After cooling to room temperature, the mixture was washed with H2O, dried (MgSO4), and evaporated
in vacuo. The residue was crystallized as noted.
1-Cyano-N-phenyl-2-phenylethene-1-sulfonamide (3a, C15H12N2O2S)
From 1a (3.85 g, 20mmol) and benzaldehyde (2.1g, 20mmol). Yield 2.1 g (75%); colorless crystals;
mp 132ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3220 (NH), 3040, 3060 (CH), 2220 (CN), 1360, 1170 (SO2) cmꢂ1
;
1H NMR (acetone-d6): ꢁ ¼ 7.0–8.0 (m, 10 ar H), 8.10 (s, 2-H), 9.4 (s, NH) ppm.
N-Benzyl-1-cyano-2-phenylethene-1-sulfonamide (3b, C16H14N2O2S)
From 1b (4.2g, 20mmol) and benzaldehyde (2.1g, 20mmol). Yield 4.8 g (80%); colorless crystals;
mp 101ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3260 (NH), 2215 (CN), 1350, 1170 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 4.3
(s, CH2), 5.4–5.5 (s, NH), 7.2–7.9 (m, 10 ar H), 7.90 (s, 2-H) ppm.
1-Cyano-2-(4-methylphenyl)-N-phenylethene-1-sulfonamide (3c, C16H14N2O2S)
From 1a (1.9g, 10mmol) and 4-methylbenzaldehyde (1.4g, 10 mmol). Yield 2.4 g (80%); colorless
crystals; mp 132ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3260 (NH), 2215 (CN), 1350, 1170 (SO2) cmꢂ1; 1H NMR
(acetone-d6): ꢁ ¼ 2.3 (s, Me), 7.0–7.9 (m, 9 ar H), 8.0 (s, 2-H), 8.0–8.5 (s, NH) ppm.
1-Cyano-2-(4-nitrophenyl)-N-phenylethene-1-sulfonamide (3d, C15H11N3O2S)
From 1a (1.9g, 10 mmol) and 4-nitrobenzaldehyde (1.5g, 10 mmol). Yield 2.65g (80%); light yellow
crystals; mp 138ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3260 (NH), 3200, 3050 (CH), 2220 (CN), 1520 (NO2),

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M. Winterwerber et al.
1
1350, 1170 (SO2) cmꢂ1; H NMR (acetone-d6): ꢁ ¼ 7.1–7.5 (m, 5 ar H), 7.92 (s, 2-H), 8.0–8.5 (m,
4 ar H), 9.3–9.7 (s, NH) ppm.
2-(4-Chlorophenyl)-1-cyano-N-(4-fluorobenzyl)ethene-1-sulfonamide (3e, C16H12ClFN2O2S)
From 1c (2.3g, 10mmol) and 4-chlorobenzaldehyde (2.8g, 20mmol). Yield 1.5 g (43%); colorless
1
crystals; mp 130ꢁC (n-hexane); IR: ꢀꢀ¼ 3327 (NH), 2223 (CN), 1364, 1159 (SO2) cmꢂ1; H NMR
(acetone-d6): ꢁ ¼ 4.4 (s, CH2), 7.0–7.7 (m, 8 ar H), 7.90 (t, J ¼ 1.8 Hz, NH), 8.0 (s, 2-H) ppm.
N-(4-Chlorobenzyl)-2-(4-chlorophenyl)-1-cyanoethene-1-sulfonamide (3f, C16H12Cl2N2O2S)
From 1d (2.4 g, 10 mmol) and 4-chlorobenzaldehyde (2.8 g, 20 mmol). Yield 1.7 g (46%); light
yellow crystals; mp 140ꢁC (toluene); IR: ꢀꢀ¼ 3265 (NH), 2230 (CN), 1353, 1156 (SO2) cmꢂ1
;
1H NMR (acetone-d6): ꢁ ¼ 4.4 (s, CH2), 7.20–7.70 (m, 8 ar H), 7.90 (t, J ¼ 1.9 Hz, NH), 8.0
(s, 2-H) ppm.
N-(4-Bromophenyl)-2-(4-chlorophenyl)-1-cyanoethenesulfonamide (3g, C15H10ClBrN2O2S)
From 1e (2.7g, 10mmol) and 4-chlorobenzaldehyde (2.8g, 20mmol). Yield 1.1 g (28%); light yellow
1
crystals; mp 145ꢁC (toluene); IR: ꢀꢀ¼ 3234 (NH), 2231 (CN), 1356, 1164 (SO2) cmꢂ1; H NMR
(acetone-d6): ꢁ ¼ 7.2–7.7 (m, 8 ar H), 7.95 (t, J ¼ 1.6 Hz, 2-H (E-Isomer)), 8.1 (d, J ¼ 1.6 Hz, 2-H
(Z-Isomer)), 8.2 (s, NH) ppm.
N-Benzyl-1-cyano-4-phenylbutadiene-1-sulfonamide (4, C18H16N2O2S)
From 1b (2.1g, 10mmol) and cinnamic aldehyde (1.3g, 10mmol). Yield 1.9 g (60%); mp 175–177ꢁC
1
(CHCl3=CCl4); IR: ꢀꢀ¼ 3320 (NH), 2210 (CN), 1610 (C¼C), 1350, 1160 (SO2) cmꢂ1; H NMR
(acetone-d6): ꢁ ¼ 4.4 (d, J ¼ 6 Hz, CH2), 7.1–8.1 (m, 10 ar H, 3 ¼ CH-), 7.7–8.7 (s, NH) ppm.
N-Acetyl-N-benzyl-1-cyano-2-phenylethene-1-sulfonamide (6, C18H16N2O3S)
From 5 (0.25 g, 1 mmol) and benzaldehyde (0.1g, 1 mmol). Yield 0.27g (80%); mp 102ꢁC (MeOH);
1
IR: ꢀꢀ¼ 3030, 2980, 2920 (CH), 2215 (CN), 1700 (CO), 1360, 1160 (SO2) cmꢂ1; H NMR: ꢁ ¼ 2.42
(s, Me), 5.05 (s, CH2), 7.1–8.2 (m, 10 ar H, 2-H) ppm.
N-Carbamoyl-1-cyano-N,2-diphenylethene-1-sulfonamide (7a, C16H13N3O3S)
At ꢂ78ꢁC, BuLi (6.5 cm3, 10 mmol) was added to a solution of 3a (2.8 g, 10 mmol) in 50 cm3 THF.
After 10 min, a solution of chlorosulfonyl isocyanate (1.45 g, 10 mmol) in 10 cm3 THF was added,
and after stirring for 0.5 h at ꢂ78ꢁC 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 2.7 g (85%); mp 129–131ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3490, 3380 (NH2), 2210 (CN), 1720 (CO),
1
1370, 1170 (SO2) cmꢂ1; H NMR (acetone-d6): ꢁ ¼ 6.1–6.3 (s, NH2), 7.5–8.2 (m, 10 ar H), 8.32 (s,
2-H) ppm.
N-Benzyl-N-carbamoyl-1-cyano-2-phenylethene-1-sulfonamide (7b, C17H15N3O3S)
From 3b (3.0g, 10 mmol) and chlorosulfonyl isocyanate (1.45 g, 10 mmol) as described for 7a. Yield
2.8 g (85%); mp 140–141ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3490, 3380 (NH2), 3050 (CH), 2220 (CN), 1720
(CO), 1360, 1170 (SO2) cmꢂ1; 1H NMR (acetone-d6): ꢁ ¼ 5.05 (s, CH2), 6.5–7.2 (s, NH2), 7.1–8.1 (m,
10 ar H), 8.24 (s, 2-H) ppm.
N-Benzyl-1-cyano-2-phenyl-N-(phenylcarbamoyl)ethene-1-sulfonamide (8, C23H19N3O3S)
From 3b (3.0 g, 10 mmol) and phenyl isocyanate (1.2 g, 10 mmol) as described for 7a. Yield 2.6 g
(80%); mp 120ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3370 (NH), 3020 (CH), 2215 (CN), 1730 (CO), 1380,
1
1160 (SO2) cmꢂ1; H NMR (acetone-d6): ꢁ ¼ 5.10 (s, CH2), 7.1–8.1 (m, 15 ar H), 8.27 (s, 2-H),
9.1 (s, NH) ppm.

Reactions of Cyanomethanesulfonamides
1447
N-Acetyl-1-cyano-2-(4-methylphenyl)-N-phenylethene-1-sulfonamide (9, C18H16N2O3S)
From 3c (1.5g, 5 mmol) and acetyl chloride (0.4g, 5 mmol) as described for 7a. Yield 0.8 g (50%); mp
1
141ꢁC (MeOH); IR: ꢀꢀ¼ 3040 (CH), 2210 (CN), 1720 (CO), 1370, 1170 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 1.96 (s, Me), 2.44 (s, Me), 7.2–8.0 (m, 9 ar H), 8.30 (s, 2-H) ppm.
General Procedure for the Synthesis of 10
At 0ꢁC, a solution of cyanomethanesulfonyl chloride (1.4g, 10 mmol) in 20–30cm3 Et2O was slowly
added to a solution of the amine (freshly distilled!) in 50–60 cm3 Et2O. The mixture was stirred for
2 h at room temperature, the precipitate was separated, and the filtrate was washed with H2O, dried
(Na2SO4) and evaporated. The residue was crystallized as noted.
N-[4-(Trifluoromethyl)benzyl]cyanomethanesulfonamide (10c, C10H9F3N2O2S)
From 4-(trifluoromethyl)benzylamine (3.5g, 20mmol). Yield 1.1 g (40%); mp 89–92ꢁC; IR: ꢀꢀ¼ 3270
(NH), 3090 (CH), 2988, 2938 (CH2), 2268 (CN), 1338, 1147 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.9 (s, CH2),
4.45 (d, CH2), 5.7 (s, NH), 7.6 (s, 4 ar H) ppm.
N-(3-Chlorobenzyl)cyanomethanesulfonamide (10d, C9H9ClN2O2S)
From 3-chlorobenzylamine (2.85 g, 20 mmol). Yield 1.3 g (53%); mp 90ꢁC; IR: ꢀꢀ¼ 3310 (NH), 3090
(CH), 2991, 2935 (CH2), 2265 (CN), 1341, 1148 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.95 (s, CH2), 4.45 (d, CH2),
5.6 (s, NH), 7.4 (s, 4 ar H) ppm.
N-[2-(Trifluoromethyl)benzyl]cyanomethanesulfonamide (10e, C10H9F3N2O2S)
From 2-(trifluoromethyl)benzylamine (3.5g, 20mmol). Yield 0.9 g (32%); mp 39–40ꢁC; IR: ꢀꢀ¼ 3282
(NH), 3090 (CH), 2985, 2938 (CH2), 2262 (CN), 1342, 1140 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.95 (s, CH2),
4.55 (d, CH2), 5.6 (s, NH), 7.6 (m, 4 ar H) ppm.
N-[3-(Trifluoromethyl)benzyl]cyanomethanesulfonamide (10f, C10H9F3N2O2S)
From 3-(trifluoromethyl)benzylamine (3.5g, 20mmol). Yield 0.9g (32%); mp 59ꢁC; IR: ꢀꢀ¼ 3281
(NH), 3080 (CH), 2990, 2931 (CH2), 2267 (CN), 1327, 1139 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.95 (s, CH2),
4.5 (d, CH2), 5.6 (s, NH), 7.6 (s, 4 ar H) ppm.
N-(3,4-Dimethoxybenzyl)cyanomethanesulfonamide (10g, C11H14N2O4S)
From 3,4-dimethoxybenzylamine (3.4g, 20mmol). Yield 0.5 g (18%); mp 125ꢁC; IR: ꢀꢀ¼ 3277 (NH),
3060 (CH), 2968, 2921 (CH2), 2260 (CN), 1341, 1148 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.73 (s, CH2), 3.85
(s, 2 CH3), 4.4 (d, CH2), 5.6 (s, NH), 6.95 (s, 3 ar H) ppm.
N-Benzyl-2-imino-2H-chromene-3-sulfonamide (11a, C16H14N2O3S)
From 1b (2.1g, 10 mmol) and salicylaldehyde (1.2g, 10mmol) as described for 3. Yield 2.5 g (80%);
mp 123ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3310, 3200 (NH), 3060, 2950 (CH), 1660 (C¼NH), 1600 (C¼C),
1
1330, 1155 (SO2) cmꢂ1; H NMR: ꢁ ¼ 4.20 (s, CH2), 5.7–6.5 (br, s, NH), 7.0–7.6 (m, 9 ar H, NH),
7.96 (s, ¼CH–) ppm.
2-Imino-N-(4-methoxybenzyl)-2H-chromene-3-sulfonamide (11b, C17H16N2O4S)
From 10a (2.4g, 10 mmol) and salicylaldehyde (1.2g, 10mmol) as described for 3. Yield 2.75g
(80%); mp 128ꢁC (CHCl3=cyclohexane); IR: ꢀꢀ¼ 3300, 3290 (NH), 3060, 2980, 2950, 2850 (CH),
1680 (C¼NH), 1600 (C¼C), 1320, 1160 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.55 (s, Me), 4.2 (s, CH2), 6.1–6.3
(br, s, NH), 6.6–7.5 (m, 8 ar H, NH), 7.88 (s, 4-H) ppm.
N-(2-Chlorobenzyl)-2-imino-2H-chromene-3-sulfonamide (11c, C16H13ClN2O3S)
From 10b (2.4g, 10mmol) and salicylaldehyde (1.2g, 10mmol) as described for 3. Yield 2.1 g (57%);
colorless to light yellow crystals; mp 114ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3310 (NH), 3060, 2950 (CH),

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M. Winterwerber et al.
1
1630 (C¼NH), 1600 (C¼C), 1330, 1155 (SO2) cmꢂ1; H NMR: ꢁ ¼ 4.20 (s, CH2), 6.0-6.5 (s, NH),
7.0–7.6 (m, 8 ar H, NH), 7.96 (s, 4-H) ppm.
2-Imino-N-[4-(trifluoromethyl)benzyl]-2H-chromene-3-sulfonamide (11d, C17H13F3N2O3S)
From 10c (2.8g, 10 mmol) and salicylaldehyde (1.2g, 10 mmol) as described for 3. Yield 2.7 g (70%);
colorless to light yellow crystals; mp 135ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3321 (NH), 3060, 2950 (CH),
1
1630 (C¼NH), 1611 (C¼C), 1372, 1125 (SO2) cmꢂ1; H NMR: ꢁ ¼ 4.20 (s, CH2), 6.4–6.5 (s, NH),
7.0–7.6 (m, 8 ar H, NH), 7.98 (s, 4-H) ppm.
N-(3-Chlorobenzyl)-2-imino-2H-chromene-3-sulfonamide (11e, C16H13ClN2O3S)
From 10d (2.4g, 10mmol) and salicylaldehyde (1.2g, 10mmol) as described for 3. Yield 2.0 g (57%);
colorless to light yellow crystals; mp 85ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3335 (NH), 3060, 2950 (CH), 1650
(C¼NH), 1601 (C¼C), 1339, 1160 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 4.20 (s, CH2), 6.4–6.5 (s, NH), 7.0–7.6
(m, 8 ar H, NH), 7.96 (s, 4-H) ppm.
2-Imino-N-[2-(trifluoromethyl)benzyl]-2H-chromene-3-sulfonamide (11f, C17H13F3N2O3S)
From 10e (2.8g, 10 mmol) and salicylaldehyde (1.2g, 10 mmol) as described for 3. Yield 2.0 g (52%);
colorless to light yellow crystals; mp 50–53ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3294 (NH), 3060, 2950 (CH),
1658 (C¼NH), 1601 (C¼C), 1341, 1162 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 4.30 (s, CH2), 6.4 (s, NH), 7.0–7.6
(m, 8 ar H, NH), 7.98 (s, 4-H) ppm.
2-Imino-N-[3-(trifluoromethyl)benzyl]-2H-chromene-3-sulfonamide (11g, C17H13F3N2O3S)
From 10f (2.8g, 10 mmol) and salicylaldehyde (1.2g, 10mmol) as described for 3. Yield 2.5g (65%);
colorless to light yellow crystals; mp 103ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3342 (NH), 3060, 2950 (CH),
1657 (C¼NH), 1603 (C¼C), 1330, 1162 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 4.20 (s, CH2), 6.45 (s, NH), 7.0–7.7
(m, 8 ar H, NH), 7.96 (s, 4-H) ppm.
N-(3,4-Dimethoxybenzyl)-2-imino-2H-chromene-3-sulfonamide (11h, C18H18N2O5S)
From 10g (2.7g, 10mmol) and salicylaldehyde (1.2g, 10mmol) as described for 3. Yield 1.5g (40%);
colorless to light yellow crystals; mp 132ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3285 (NH), 3060, 2934 (CH),
1
1659 (C¼NH), 1603 (C¼C), 1328, 1121 (SO2) cmꢂ1; H NMR: ꢁ ¼ 3.75, 3.85 (2s, 2 CH3), 4.20
(s, CH2), 6.3 (s, NH), 6.5–7.6 (m, 7 ar H, NH), 7.96 (s, 4-H) ppm.
N-(4-Fluorobenzyl)-2-imino-2H-chromene-3-sulfonamide (11i, C16H13FN2O3S)
From 1c (2.4g, 10mmol) and salicylaldehyde (1.2 g, 10 mmol) as described for 3. Yield 1.4 g (42%);
colorless to light yellow crystals; mp 69ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3310 (NH), 3060, 2950 (CH), 1630
(C¼NH), 1600 (C¼C), 1330, 1155 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 4.20 (s, CH2), 6.0–6.5 (s, NH), 7.0–7.6
(m, 8 ar H, NH), 7.96 (s, 4-H) ppm.
N-Benzyl-N-(benzyloxycarbonyl)-2-imino-2H-chromene-3-sulfonamide (13, C24H20N2O5S)
From 12 (1.6g, 5 mmol) and salicylaldehyde (0.6g, 5 mmol) as described for 3. Yield 1.65g (75%);
mp 143ꢁC (MeOH); IR: ꢀꢀ¼ 3500–3300 (NH), 1730 (CO), 3060, 3020 (CH), 1600 (C¼C), 1360, 1170
1
(SO2) cmꢂ1; H NMR: ꢁ ¼ 5.10, 5.11 (2s, 2 CH2), 7.0–8.2 (m, NH, 4-H, 14 ar H) ppm.
2-Acetylimino-N-benzyl-2H-chromene-3-sulfonamide (14, C18H16N2O4S)
Compound 11a (1.6g, 5 mmol) was refluxed in 20cm3 Ac2O for 1 h, and then stirred at room
temperature for 2 h. The mixture was evaporated in vacuo, the residue was dissolved in CHCl3, washed
with H2O, dried (Na2SO4), and the solvent evaporated in vacuo. Yield 1.6 g (90%); mp 165–166ꢁC
1
(MeOH); IR: ꢀꢀ¼ 3290 (NH), 3060 (CH), 1650 (amide), 1340, 1180 (SO2) cmꢂ1; H NMR: ꢁ ¼ 2.27
(s, Me), 4.4 (d, J ¼ 7 Hz, CH2), 5.9–6.1 (t, J ¼ 7 Hz, NH), 7.2–7.8 (9 ar H), 8.22 (s, 4-H) ppm.

Reactions of Cyanomethanesulfonamides
1449
N-Benzyl-2-oxo-2H-chromene-3-sulfonamide (15a, C16H13NO4S)
Compound 11a (0.63 g, 2 mmol) was refluxed in 30cm3 dil. HCl, cooled to room temperature, and
extracted with CHCl3. The organic layer was dried (Na2SO4), and evaporated in vacuo. Yield 0.6 g
(95%); mp 115ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3300 (NH), 3070, 2950 (CH), 1730 (CO), 1330, 1170 (SO2)
cmꢂ1; 1H NMR: ꢁ ¼ 4.2–4.3 (d, J ¼ 7 Hz, CH2), 5.6–5.8 (t, J ¼ 7 Hz, NH), 6.9–7.8 (m, 9 ar H), 8.38
(s, 4-H) ppm.
N-(4-Methoxybenzyl)-2-oxo-2H-chromene-3-sulfonamide (15b, C17H15NO5S)
From 11b (0.65 g, 2 mmol) as described for 15a. Yield 0.6 g (90%); mp 172ꢁC (MeOH); IR: ꢀꢀ¼ 3300
(NH), 1730 (CO), 1330, 1160 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.5 (s, OMe), 4.3 (d, J ¼ 6 Hz, CH2), 6.2–6.4
(t, NH), 6.6–7.8 (m, 8 ar H), 8.34 (s, 4-H) ppm.
N-Benzyl-N-(benzyloxycarbonyl)-2-oxo-2H-chromene-3-sulfonamide (15c, C24H19NO6S)
From 13 (0.45 g, 1 mmol) as described for 15a. Yield 0.35 g (80%); mp 174ꢁC (MeOH); IR: ꢀꢀ¼ 3060,
3020 (CH), 1740, 1720 (CO), 1600 (C¼C), 1370, 1170 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 5.05 (s, CH2), 5.17
(s, CH2), 7.0–7.6 (m, 14 ar H), 8.47 (s, 4-H) ppm.
N-Benzyl-1,2-dihydro-2-oxoquinoline-3-sulfonamide (16, C16H14N2O3S)
Methyl chloroformate (1.2g, 11mmol) in 10 cm3 THF was dropwise added to a solution of 11a (3.1g,
10mmol) in 20 cm3 THF. Then, the mixture was refluxed for 2 h, cooled to room temperature, washed
with a satd. NaCl solution, dried (MgSO4), and evaporated in vacuo. Yield 1.55 g (50%); mp 120–
121ꢁC (CHCl3=CCl4); IR: ꢀꢀ¼ 3300 (NH), 3080, 2960 (CH), 1725 (CO), 1330, 1170 (SO2) cmꢂ1
;
1H NMR: ꢁ ¼ 4.4 (d, J ¼ 6 Hz, CH2), 5.9–6.1 (t, NH), 7.0–8.0 (m, 9 ar H, NH), 8.5 (s, 4-H) ppm.
(RS)-2-Benzyl-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine 1,1-dioxide
(17a, C18H16N2O4S)
Compound 11a (3.1g, 10mmol) was refluxed in 20cm3 HC(OMe)3 for 2 h, and the formed MeOH was
distilled off. After cooling to room temperature, the mixture was evaporated in vacuo. Yield 2.1 g
(60%); mp 153ꢁC (MeOH); IR: ꢀꢀ¼ 1650 (C¼N), 1350, 1180 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.4 (s, OMe),
4.3 (s, CH2), 6.0 (s, 3-H) 7.0–7.7 (9 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-(4-Methoxybenzyl)-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17b, C19H18N2O4S)
From 11b (3.5g, 10mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 1.4 g (36%); light yellow
1
crystals; mp 147ꢁC (MeOH); IR: ꢀꢀ¼ 1650 (C¼N), 1350, 1180 (SO2) cmꢂ1; H NMR: ꢁ ¼ 3.4, 3.8
(2s, 2 OMe), 4.2 (dd, J ¼ 2.2, 17.6Hz, 1H, CH2), 4.6 (dd, J ¼ 1.1, 17.6Hz, 1H, CH2), 6.0 (s, 3-H),
7.0–7.7 (m, 8 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-(2-Chlorobenzyl)-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17c, C18H15ClN2O4S)
From 11c (3.5g, 10 mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 1.33 g (34%); light
yellow crystals; mp 166ꢁC (MeOH); IR: ꢀꢀ¼ 1650 (C¼N), 1350, 1180 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 3.4
(s, OMe), 4.2 (dd, J ¼ 2.2, 17.6Hz, 1H, CH2), 4.6 (dd, J ¼ 1.1, 17.6Hz, 1H, CH2), 6.0 (s, 3-H), 7.0–7.7
(m, 8 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-[4-(Trifluoromethyl)benzyl]-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17d, C19H15F3N2O4S)
From 11d (3.8g, 10mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 1.9 g (45%); light
yellow crystals; mp 175ꢁC (MeOH); IR: ꢀꢀ¼ 1657 (C¼N), 1601 (C¼C), 1327, 1164 (SO2) cmꢂ1
;
1H NMR: ꢁ ¼ 3.4 (s, OMe), 4.3 (m, CH2), 6.0 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0 (s, 10-H) ppm.

1450
M. Winterwerber et al.
(RS)-2-(3-Chlorobenzyl)-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17e, C18H15ClN2O4S)
From 11e (3.5g, 10mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 2.6g (67%); light yellow
1
crystals; mp 99ꢁC (MeOH); IR: ꢀꢀ¼ 1654 (C¼N), 1599 (C¼C), 1350, 1175 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 3.4 (s, OMe), 4.2 (m, CH2), 6.0 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-[2-(Trifluoromethyl)benzyl]-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17f, C19H15F3N2O4S)
From 11f (3.8g, 10 mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 1.8 g (42%); light yellow
1
crystals; mp 140ꢁC (MeOH); IR: ꢀꢀ¼ 1649 (C¼N), 1611 (C¼C), 1354, 1172 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 3.4 (s, OMe), 4.5 (dd, J ¼ 2.2, 17.6Hz, CH2), 6.0 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-[3-(Trifluoromethyl)benzyl]-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17g, C19H15F3N2O4S)
From 11g (3.8g, 10mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 3.1 g (73%); light yellow
1
crystals; mp 180ꢁC (MeOH); IR: ꢀꢀ¼ 1658 (C¼N), 1613 (C¼C), 1365, 1197 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 3.4 (s, OMe), 4.4 (dd, J ¼ 2.2, 17.6Hz, CH2), 6.0 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-(3,4-Dimethoxybenzyl)-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (17h, C20H20N2O6S)
From 11h (3.7g, 10mmol) and 20 cm3 HC(OMe)3 as described for 17a. Yield 3.3 g (80%); light
yellow crystals; mp 147ꢁC (MeOH); IR: ꢀꢀ¼ 1647 (C¼N), 1597 (C¼C), 1368, 1171 (SO2) cmꢂ1
;
1H NMR: ꢁ ¼ 3.4 (s, OMe), 3.7, 3.8 (2s, 2 OMe), 4.3 (s, CH2), 6.0 (s, 3-H), 6.7–7.7 (m, 7 ar H), 7.9
(s, 10-H) ppm.
(RS)-2-(4-Fluorobenzyl)-2,3-dihydro-3-methoxybenzopyrano[3,2-e][1,2,4]thiadiazine 1,1-dioxide
(17i, C18H15FN2O4S)
From 11i (3.3g, 10 mmol) and 20cm3 HC(OMe)3 as described for 17a. Yield 1.6 g (43%); light yellow
1
crystals; mp 104ꢁC (MeOH); IR: ꢀꢀ¼ 1650 (C¼N), 1350, 1180 (SO2) cmꢂ1; H NMR: ꢁ ¼ 3.4 (s,
OMe), 4.2 (dd, J ¼ 2.2, 17.6Hz, 1H, CH2), 4.6 (dd, J ¼ 1.1, 17.6Hz, 1H, CH2), 6.0 (s, 3-H), 7.0–7.7
(m, 8 ar H), 8.0 (s, 10-H) ppm.
(RS)-2-Benzyl-2,3-dihydro-3-ethoxybenzopyrano[3,2-e][1,2,4]thiadiazine 1,1-dioxide
(18a, C19H18N2O4S)
From 11a (3.1 g, 10 mmol) and 20 cm3 HC(OEt)3 as described for 17a. Yield 2.8 g (75%);
1
mp 128ꢁC (CCl4); IR: ꢀꢀ¼ 3040, 2980 (CH), 1650 (C¼N), 1350, 1180 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 1.0–1.2 (t, J ¼ 8 Hz, Me), 3.5–3.7 (q, J ¼ 3 Hz, CH2), 4.30 (s, CH2), 6.08 (s, 3-H), 7.2–7.8
(m, 9 ar H), 8.00 (s, 10-H) ppm.
(RS)-2,3-Dihydro-3-ethoxy-2-(4-methoxybenzyl)benzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (18b, C20H20N2O5S)
From 11b (0.7g, 2 mmol) and 20 cm3 HC(OEt)3 as described for 17a. Yield 0.6 (75%); mp 134ꢁC
(MeOH); IR: ꢀꢀ¼ 3040, 2980, 2910 (CH), 1650 (C¼N), 1350, 1170 (SO2) cmꢂ1; 1H NMR: ꢁ ¼ 1.1–1.3
(t, J ¼ 7 Hz, Me), 3.5–3.9 (m, OMe, CH2), 4.27 (s, CH2), 6.18 (s, 3-H), 6.7–8.5 (8 ar H), 7.89
(s, 10-H) ppm.
(RS)-2-[4-(Trifluoromethyl)benzyl]-2,3-dihydro-3-ethoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (18d, C20H17F3N2O4S)
From 11d (3.8g, 10 mmol) and 20 cm3 HC(OEt)3 as described for 17a. Yield 1.7 g (38%); light yellow
1
crystals; mp 144ꢁC (EtOH); IR: ꢀꢀ¼ 1654 (C¼N), 1615 (C¼C), 1355, 1174 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 1.1 (t, Me), 3.7 (m, CH2), 4.4 (m, CH2), 6.15 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0 (s, 10-H) ppm.

Reactions of Cyanomethanesulfonamides
1451
(RS)-2-(3-Chlorobenzyl)-2,3-dihydro-3-ethoxybenzopyrano[3,2-e][1,2,4]thiadiazine 1,1-dioxide
(18e, C19H17ClN2O4S)
From 11e (3.5g, 10mmol) and 20cm3 HC(OEt)3 as described for 17a. Yield 1.7 g (43%); light yellow
1
crystals; mp 150ꢁC (EtOH); IR: ꢀꢀ¼ 1656 (C¼N), 1599 (C¼C), 1347, 1175 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 1.05 (t, Me), 3.5 (dd, J ¼ 2.2, 17.6Hz, CH2), 4.2 (m, CH2), 6.0 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0
(s, 10-H) ppm.
(RS)-2-[2-(Trifluoromethyl)benzyl]-2,3-dihydro-3-ethoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (18f, C20H17F3N2O4S)
From 11f (3.8g, 10 mmol) and 20cm3 HC(OEt)3 as described for 17a. Yield 1.5 g (34%); light yellow
1
crystals; mp 133ꢁC (EtOH); IR: ꢀꢀ¼ 1649 (C¼N), 1599 (C¼C), 1359, 1178 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 1.0 (t, Me), 3.7 (m, CH2), 4.5 (dd, J ¼ 1.1, 17.6Hz, CH2), 6.2 (s, 3-H), 7.0–7.7 (m, 8 ar H), 8.0
(s, 10-H) ppm.
(RS)-2-[3-(Trifluoromethyl)benzyl]-2,3-dihydro-3-ethoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (18g, C20H17F3N2O4S)
From 11g (3.8g, 10mmol) and 20 cm3 HC(OEt)3 as described for 17a. Yield 2.3g (53%); light yellow
1
crystals; mp 173ꢁC (EtOH); IR: ꢀꢀ¼ 1658 (C¼N), 1613 (C¼C), 1330, 1175 (SO2) cmꢂ1; H NMR:
ꢁ ¼ 1.02 (t, Me), 3.6 (q, CH2), 4.3 (d, CH2), 6.05 (s, 3-H), 7.0–7.7 (m, 8 ar H), 7.9 (s, 10-H) ppm.
(RS)-2-(3,4-Dimethoxybenzyl)-2,3-dihydro-3-ethoxybenzopyrano[3,2-e][1,2,4]thiadiazine
1,1-dioxide (18h, C21H22N2O6S)
From 11h (3.7 g, 10 mmol) and 20 cm3 HC(OEt)3 as described for 17a. Yield 2.8 g (64%); light
yellow crystals; mp 167ꢁC (EtOH); IR: ꢀꢀ¼ 1646 (C¼N), 1614 (C¼C), 1371, 1172 (SO2) cmꢂ1
;
1H NMR: ꢁ ¼ 1.25 (t, Me), 3.7, 3.8 (2s, 2 OMe), 4.3 (s, CH2), 6.1 (s, 3-H), 6.7–7.7 (m, 7 ar H), 8.0
(s, 10-H) ppm.
Acknowledgements
We thank Dr. P. Raddatz, E. Merck KGaG, Darmstadt, for extended generous support with chemicals,
with chromatography materials, and for biological testing, and we thank the ‘‘Fonds der Chemischen
Industrie’’, Frankfurt am Main, for continuous financial support.
References
[1] Winterwerber M, Geiger G, Otto H-H (2006) Monatsh Chem accepted
[2] Cragoe EJ Jr (1973) US Pat 3729500
[3] PCModel 3.1, Serena Software
[4] Detailed results will be published elsewhere