Synthesis of sultams by cycloalkylation of (alkoxycarbonylmethane) sulfonanilides

Article abstract of DOI:10.1007/s10593-008-0066-9

(Methoxycarbonylmethane)sulfonanilides are alkylated by α, ω-dihaloalkanes in K₂CO₃-DMF with the formation of sultams. A high sensitivity has been detected for the reaction rate on the electronic effect of substituents in the aromatic nucleus, although substituents in the ortho position do not obstruct the reaction and in the case of 2,6-disubstituted derivatives the reaction rate and sultam yield were maximal. Tertiary sulfonamides form derivatives of 1-sulfamoylcyclopropanecarboxylic acid under these conditions.

Full text of DOI:10.1007/s10593-008-0066-9

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
SYNTHESIS OF SULTAMS
BY CYCLOALKYLATION
OF (ALKOXYCARBONYL-
METHANE)SULFONANILIDES
V. A. Rassadin, A. A. Tomashevskii, V. V. Sokolov, and A. A. Potekhin*
(Methoxycarbonylmethane)sulfonanilides are alkylated by α,ω-dihaloalkanes in K2CO3–DMF with the
formation of sultams. A high sensitivity has been detected for the reaction rate on the electronic effect of
substituents in the aromatic nucleus, although substituents in the ortho position do not obstruct the
reaction and in the case of 2,6-disubstituted derivatives the reaction rate and sultam yield were
maximal. Tertiary sulfonamides form derivatives of 1-sulfamoylcyclopropanecarboxylic acid under
these conditions.
Keywords: (methoxycarbonylmethane)sulfonanilides, sultams, cyclopropanes, heterocyclization.
Many compounds having a sulfonamide group in their composition are used in medicinal practice, for
example as antibacterial or hypoglycemic preparations [1, 2]. To this day interest in sulfonamides as potential
medicinal preparations is fairly great [3. 4].
Although the generally applied method of obtaining sulfonamides is the interaction of sulfonyl chlorides
with amines, the synthesis of cyclic analogues (sultams) is not so simple. One of the possible solutions is the
intramolecular alkylation of sulfonamides where means of creating an electrophilic center may be varied. In this
connection cycloalkylation with the participation of sulfonamides having an additional C-nucleophilic center
with dihalides or their equivalent may possess obvious merit.
From this point of view the sulfonamides 2 obtained from readily available alkoxycarbonyl-
methanesulfonyl chlorides 1a,b may posses a high potential [5]. Although heterocyclization of these
sulfonamides by intramolecular condensation of carbonyl and active methylene groups [6] or transposition of
C,N-diallyl derivatives [7] is known, their alkylation by aliphatic dihalides has not been described and attracted
our attention.
Py, MeCN
R1R2NH
ClO2SCH2CO2Me +
R1R2NSO2CH2CO2Me
20 oC
2a–i
1a
2 a R1 = Ph, b R1 = Ph, c R1 = 2-MeC6H4, d R1 = 4-MeC6H4,
e R1 = 2,6-Me2C6H3, f R1 = 4-ClC6H4, g R1 = 3,5-Cl2C6H3,
h R1 = 4-MeC6H4, i R1 = 4-EtOCOC6H4; a, c–i R2 = H, b R2 = Me
_______
* Deceased.
_________________________________________________________________________________________
Saint Petersburg University, Saint Petersburg 198504, Russia; e-mail: vsokolo@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 605-617, April. 2008. Original article submitted October 8,
2007.
474
0009-3122/08/4404-0474©2008 Springer Science+Business Media, Inc.

Sulfonamides 2a-i were obtained as starting materials (Tables 1, 2).
The interaction of sulfonyl chloride 1a with anilines took place without complications from the ester
group and led to sulfonamides 2a-i in high yield. However in the aliphatic series even the not very nucleophilic
benzylamine begins to react competitively with the ester. In order to avoid this complication in obtaining
N-benzylamide 2j it was necessary to use ethyl ester 1b and carry out the reaction at reduced temperature.
NMM, Et2O
BnNHSO2CH2CO2Et
ClO2SCH2CO2Et
BnNH2
+
0°C
NMM – N-methylmorpholine
2j
1b
Two nucleophilic centers exist in sulfonamides 2a,c-j with no clear previous relative reactivity. In
reality on interacting sulfonamide 2a with an equivalent amount of benzyl chloride in the system K2CO3–DMF a
mixture is formed of the products of N- and C,N-alkylation (2k and 3a respectively) in a 4:3 ratio.
Ph
N
Bn
Ph
N
BnCl, K2CO3, DMF
20°C
S
CO2Me
Ph
+
S
CO2Me
Bn
Bn
O
O
O
O
2k
3a
2a
AllBr, K2CO3, DMF
55°C
N
S
CO2Me
All
O
O
2l
However on using a dilute solution of allyl bromide the reaction was carried out successfully and the
sole product was that of N-alkylation 2l.
O
O
BrCH2CH2Br, K2CO3, DMF
R1
S
CO2R
2a, c–f, h–j
N
4a, c-f, h-j
O
O
1. KOH, MeOH–H2O
2. HCl
R1
S
CO2H
4a
N
60°C
5a
4a, c–f, h, i R = Me, j R = Et
Alkylation of sulfonamides 2a,c-j with 1,2-dibromoethane in the same system led to the desired sultams
4 (Tables 3, 4). With a high degree of conversion of sulfonamide 2a the formation was observed of a product of
further alkylation of unestablished structure. A change to the less polar acetonitrile or a protic solvent, and also
replacement of potassium carbonate by a weaker base might increase the yield of sultam 4a. However the
reaction did not proceed in methanol, and on using acetonitrile in combination with various bases (calcium
carbonate, triethylamine, N,N-dimethylaniline) its rate was heavily reduced.
475

TABLE 1. Alkoxycarbonylmethanesulfonamides 2a-j
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, ºС
C
H
N
2a
2b
C9H11NO4S
79-80 [7]
63-64
74
79
C10H13NO4S
C10H13NO4S
C10H13NO4S
C11H15NO4S
C9H10ClNO4S
C9H9Cl2NO4S
C10H13NO5S
C12H15NO6S
C11H15NO4S
49.36
49.37
49.20
49.37
49.36
49.37
51.42
51.35
41.12
40.99
36.03
36.26
46.23
46.32
47.63
47.83
5.38
5.39
5.50
5.39
5.60
5.39
5.74
5.88
4.09
3.82
3.18
3.04
5.05
5.05
4.98
5.02
5.93
5.76
6.05
5.76
6.02
5.76
5.57
5.44
5.33
5.31
4.73
4.70
5.54
5.40
4.62
4.65
2c
2d
2e
2f
55-56
72
85
82
72
78
71
83
60
77-79
105-106
99-100
132-133
85-86
2g
2h
2i
98-99
2j
51.42
51.35
5.67
5.88
5.30
5.44
56-57
The K2CO3–DMF system therefore proved to be the most suitable for obtaining sultam 4a in dilute
solution.
To clarify the limits of applicability of the reaction, the set of sulfonamides 2a,c-i and several
α,ω-dihaloalkanes were studied. As a result it became clear that in the case of sulfonanilides the given reaction
is extremely sensitive to the electronic effect of substituents. Electron-withdrawing groups strongly slowed the
process, and for its completion extended stirring at a higher temperature is necessary than in the case of
sulfonamide 2a. It is evident that this is linked with the reduced nucleophilicity of the resulting anion. Donor
substituents in the benzene ring, on the other hand, aid the passage of the reaction. Sulfonanilides 2d,h reacted
more rapidly than sulfonanilide 2a.
In addition it was discovered that substituents in the ortho position do not prevent this reaction, and in
the case of sulfonamide 2e the reaction proceeds most rapidly and with maximal yield. A possible explanation is
that in the present case, due to the loss of a portion of the degree of freedom, the loss in entropy of the system as
a result of the reaction is less than in the case of other sulfonamides, which is analogous to the well known gem-
dialkyl effect in cyclization reactions [9]. The high steric strain of the products of cycloalkylation of
sulfonamide 2e with all three α,ω-dihaloalkanes is confirmed, judging by the diastereotopicity of the C-methyl
groups according to NMR spectra.
On reacting N-benzylsulfonamide 2j with dibromoethane a multicomponent mixture is formed, the
resolution of which made it possible to obtain ethyl 2-benzyl-1,2-thiazolidine-5-carboxylate 1,1-dioxide (4j) in
extremely small yield. Such a result is probably linked with the low acidity of sulfonamide 2j, consequently the
use of a stronger base might have aided the reaction process. However in the system NaH–THF
(benzylaminosulfonyl)acetic acid (9j) was obtained in quantitative yield. In passing, this reaction goes through
the intermediate formation of a β-lactam.
O
S
BrCH2CH2Br,
NaH, THF
O
O
Ph
H2O
N
O
CO2H
S
2j
Ph
N
H
O
9j
476

477

TABLE 3. Sultams
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp, ºC
Yield, %
C
N
4a
4c
4d
4e
4f
C11H13NO4S
C12H15NO4S
C12H15NO4S
C13H17NO4S
C11H12ClNO4S
C12H15NO5S
C14H17NO6S
C13H17NO4S
C12H15NO4S
C14H19NO4S
C15H21NO4S
C17H17NO4S
51.69
51.75
53.40
53.52
53.43
53.52
55.19
55.12
45.48
45.60
50.58
50.53
51.48
51.37
5.15
5.13
5.62
5.61
5.54
5.61
6.11
6.05
4.12
4.17
5.26
5.26
5.31
5.23
5.56
5.56
5.07
5.20
5.18
5.20
4.89
4.94
4.89
4.83
4.93
4.91
4.12
4.28
96-97
70
68
76
86
56
74
18
1.5
73
84
27
53
69-70
99-100
107-108
121-122
125-126
143-144
—
4h
4i
4j
6a
6e
7e
10a
53.40
53.52
56.46
56.55
57.86
57.86
61.48
61.61
5.60
5.61
6.44
6.44
6.91
6.80
5.31
5.17
5.20
5.20
4.72
4.71
4.45
4.50
4.27
4.23
59-60
172-174
127-128
137-138
To clarify the possibility of obtaining six- and seven-membered derivatives the alkylation of
sulfonamides 2a,e with 1-bromo-3-chloropropane and 1,4-dibromobutane was investigated.
1. KOH,
MeOH–H2O
2. HCl
O
O
O
O
Br(CH2)3Cl,
K2CO3, DMF
1
R
1
R
S
S
CO2Me
CO2H
N
N
2a,e
60°C
8a
6a,e
O
O
1
R
Br(CH2)4Br,
K2CO3, DMF
O
O
CO2Me
1
R
S
N
S
CO2Me
N
70°C
H
2e
7e
1-Bromo-3-chloropropane reacts somewhat more slowly than dibromoethane. In the present case slower
addition of alkylating agent is required otherwise several products are formed. As expected, sulfonamide 2e,
which was the most reactive in the reaction with dibromoethane, reacted far more rapidly in the present case
than the unsubstituted analog 2a.
More vigorous and extended heating was required to carry out the reaction with 1,4-dibromobutane. In
the case of sulfonamide 2e we successfully isolated methyl 2-(2,6-dimethylphenyl)-1,2-thiazepane-
7-carboxylate 1,1-dioxide (7e) in 27% yield, but in the case of amide 2a a multicomponent mixture was formed,
resolution of which was unsuccessful. This result is fairly logical since the rate of formation of seven-
478

membered rings is far lower than that of five- and six-membered. However on using a sterically more rigid
alkylating agent the probability of intramolecular reaction grows. Thus on alkylating sulfonamide 2a with
1,2-bis(bromomethyl)benzene 4-methoxycarbonyl-2-phenyl-1,2,4,5-tetrahydro[d][1,2]thiazepine 3,3-dioxide
(10a) was successfully isolated in 53% yield.
CO2Me
O
K2CO3, DMF
S
O
Br
Br
2a
+
N
65°C
10a
1
In the H NMR (but not the 13C) spectrum of this compound a strong broadening was observed of the
proton signals of the seven-membered ring, which indicates the presence of a conformational coalescence
transition close to room temperature.
All the obtained sultams 4-7 contain an ester grouping which may be hydrolyzed under mild conditions
with the formation of the corresponding acids 5a, 8a without decarboxylation, which opens the possibility of
further functionalization at the carboxyl group.
For the tertiary sulfonamide 2b it was shown possible to obtain the cyclopropane derivative 11b in high
yield.
O
O
1. KOH, EtOH–H2O
2. HCl
BrCH2CH2Br,
K2CO3, DMF
O
O
O
O
S
CO2H
N
S
CO2Me
S
CO2Me
N
N
60°C
Me
12b
55°C
Me
Me
2b
11b
The obtained ester 11b was readily hydrolyzed to the corresponding acid 12b, and on boiling the latter
for 15 h in N,N-dimethylacetamide no decarboxylation occurred.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Bruker DPX 300 instrument (300 and 75 MHz
respectively) in CDCl3. Chemical shifts were determined relative to the solvent signal in 1H NMR spectra: 7.26
(for CHCl3) and 2.49 ppm (for DMSO-d5); in 13C NMR spectra: 77.1 (for CDCl3), 39.5 (for DMSO-d6) and
204.1 ppm (acetone-d6). Coupling constants in proton spectra were measured to a first order approximation. The
standard impulse sequence DEPT-135 was used to determine the multiplicity of signals in the 13C NMR spectra.
Mass spectra were obtained on a Finnigan MAT Incos 50 instrument, ionization by electron impact (EI) with
energy of ionizing electrons 70 eV. Elemental analyses were carried out on a Hewlett Packard HP-185B
automatic CHN analyzer. The degree of progress of a reaction, the Rf values, and purity of products was checked
by TLC on ALUGRAM® SIL G/UV254, eluent ethyl acetate–hexane, 1:2, if not shown otherwise.
479

480

481

Methoxycarbonylmethanesulfonyl chloride (1a). Yield 77%; bp 115-116oC (15 mm Hg) [10].
Ethoxycarbonylmethanesulfonyl chloride (1b). Yield 72%; bp 124-126oC (15 mm Hg) [11].
Synthesis of Methoxycarbonylmethanesulfonyl Amides 2a-i (General Method). Ester 1a (17.25 g,
100 mmol) dissolved in acetonitrile (30 ml) was added slowly to a stirred solution of arylamine (110 mmol) and
pyridine (8.96 g, 110 mmol) in acetonitrile (70 ml) at 15-20°C. The reaction mixture was heated to 35°C and
maintained at the same temperature for 15 min. The mixture was diluted with water (600 ml) with stirring, and
acidified with conc. HCl to pH ≤2. The precipitated solid was filtered off and recrystallized from a mixture of
diethyl ether and hexane.
4'-Methoxy(methoxycarbonyl)methanesulfonanilide (2h) was synthesized previously [3], but not
characterized.
N-Benzyl(ethoxycarbonyl)methanesulfonamide (2j). A mixture of benzylamine (5.35 g, 50 mmol)
and N-methylmorpholine (5.05 g, 50 mmol) in ether (50 ml) was added dropwise with stirring and cooling to a
solution of sulfonyl chloride 1b (9.3 g, 50 mmol) in diethyl ether (100 ml) at such a rate that the temperature did
not exceed 2oC. The reaction mixture was then diluted with water (150 ml) and acidified with conc. HCl to pH
≤2. The ether layer was separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The organic
phases were combined, dried over sodium sulfate, and evaporated to dryness. The product was recrystallized
from diethyl ether. Yield was 60%; mp 56-57°C.
N-Benzyl(methoxycarbonyl)methanesulfonanilide (2k). Benzyl chloride (0.5 g, 4 mmol) was added
to a mixture of sulfonamide 2a (0.92 g, 4 mmol) and potassium carbonate (0.83 g, 6 mmol) in DMF (40 ml). The
reaction mixture was stirred for 1 h at 20°C, after which it was heated to 40°C and stirred for 1 h further, then
diluted with water (100 ml), acidified to pH ≤2, and extracted with dichloromethane (3×50 ml). The organic
layer was washed with 2% HCl (5×80 ml), dried over sodium sulphate, and evaporated to dryness. The product
was isolated by chromatography on silica gel (eluent ethyl acetate–hexane, 1:2, Rf 0.4). Yield was 24%, light-
1
yellow oil. H NMR spectrum, δ, ppm: 3.88 (3H, s, OCH3); 4.05 (2H, s, SO2CH2); 4.94 (2H, s, NCH2); 7.22-
7.41 (10H, m, ArH). 13C NMR spectrum, δ, ppm: 53.2 (OCH3); 54.5 (CH2); 57.0 (CH2); 127.9 (CArH), 128.5
(CArH); 128.5 (CArH); 128.6 (CArH); 129.5 (CArH); 129.5 (CArH); 136.3 (CAr); 138.3 (CAr); 164.2 (CO). Mass
spectrum, m/z (Irel, %): 319 (8) [M]+, 181 (18), 104 (12), 91 (100), 84 (30), 77 (25), 51 (11). An analytically pure
sample was not successfully obtained.
N-Allyl(methoxycarbonyl)methanesulfonanilide (2l). Allyl bromide (0.48 g, 4 mmol) was added with
stirring at 55oC during 1.5 h to a mixture of sulfonamide 2a (0.92 g, 4 mmol) and potassium carbonate (0.83 g, 6
mmol) in DMF (60 ml). The product was isolated analogously to sulfonamide 2k. Yield was 68%, brown oil. 1H
NMR spectrum, δ, ppm (J, Hz): 3.83 (3H, s, OCH3); 3.99 (2H, s, SO2CH2); 4.36 (2H, d, J = 6.5, NCH2); 5.09-
13
5.16 (2H, m, CH=CH2); 5.80 (1H, ddt, J = 6.5, J = 10.2, and J = 16.7, CH=CH2); 7.34-7.47 (5H, m, ArH). C
NMR spectrum, δ, ppm: 53.2 (OCH3); 54.6 (CH2); 55.6 (CH2); 119.0 (CH=CH2); 128.5 (p-CAr); 129.3 (o/m-
CAr); 129.5 (m/o-CAr); 133.1 (CH=CH2); 138.4 (ipso-CAr); 164.0 (CO). Mass spectrum, m/z (Irel, %): 269 [M]+
(24), 238 (10), 132 (100), 117 (51), 104 (79), 91 (35), 77 (94), 65 (16), 57 (18), 51 (32). An analytically pure
sample was not successfully obtained.
Methyl 2-(N-benzyl-N-phenylaminosulfonyl)-3-phenylpropionate (3a) was obtained analogously to
1
sulfonamide 2k, Rf 0.3. Yield was 16%; mp 115-116°C. H NMR spectrum, δ, ppm (J, Hz): 3.38 (1H, dd,
J = 12.8 and J = 13.7, CHCHH'), 3.50 (1H, dd, J = 4.7 and J = 13.7, CHCHH'); 3.75 (3H, s, OCH3); 4.29 (1H,
dd, J = 4.7 and J = 12.8, CHCH2), 4.72 (1H, d, J = 14.5, NCHH'); 4.96 (1H, d, J = 14.5, NCHH'); 7.16-7.27
(15H, m, ArH). 13C NMR spectrum, δ, ppm: 33.8 (CHCH2); 53.1 (OCH3); 57.1 (NCH2); 68.5 (CHCH2); 127.4
(CArH); 128.0 (CArH); 128.4 (CArH); 128.5 (CArH); 128.8 (CArH); 128.9 (CArH); 129.0 (CArH); 129.4 (CArH);
129.6 (CArH); 136.1 (CAr); 136.1 (CAr); 138.4 (CAr); 166.4 (CO). Mass spectrum, m/z (Irel, %): 409 [M]+ (1), 182
(31), 131 (11), 121 (22), 104 (18), 91 (100), 77 (40), 65 (11), 51 (11). Found, %: C 67.44; H 5.72; N 3.25.
C23H23NO6S. Calculated, %: C 67.46; H 5.66; N 3.42.
482

Synthesis of Sultams 4a,c-f,h-j (General Method). A solution of 1,2-dibromoethane (0.9 g, 4.8 mmol)
in DMF (40 ml) was added during 1.5 h at 55-75°C to a mixture of the appropriate sulfonamide 2a,c-f,h-j (4
mmol) and potassium carbonate (1.66 g, 12 mmol) in DMF (60 ml) and the mixture was stirred until the end of
reaction (check by TLC). The reaction mixture was then diluted with water (150 ml), acidified with conc. HCl to
pH ≤2, and extracted with dichloromethane (3×50 ml). The organic phase was washed with 2% HCl (5×80 ml),
dried over sodium sulfate, and evaporated to dryness. The product was crystallized from a mixture of diethyl
ether and hexane.
Methyl 2-(4-Ethoxycarbonylphenyl)-1,2-thiazolidine-5-carboxylate 1,1-Dioxide (4i) was isolated by
chromatography on silica gel, Rf 0.25.
Ethyl 2-Benzyl-1,2-thiazolidine-5-carboxylate 1,1-Dioxide (4j) was isolated by chromatography on
silica gel, oil, Rf 0.35. An analytically pure sample was not successfully obtained.
2-Phenyl-1,2-thiazolidine-5-carboxylic Acid 1,1-Dioxide (5a). A 10% KOH solution (2.7 g,
4.8 mmol) was added to a solution of sultam 4a (1.02 g, 4 mmol) in 50% aqueous methanol (50 ml) and the
mixture stirred for 0.5 h. Water (100 ml) was added and the methanol distilled off in vacuum at 30°C on a rotary
evaporator. After this, ethyl acetate (70 ml) was added to the aqueous solution and the mixture accurately
acidified with 3% HCl to pH ≤2. The organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (2×30 ml). The organic phases were combined, dried over sodium sulfate, and evaporated to
dryness. The product was recrtystallized from a mixture of diethyl ether and hexane. Yield was 92%; mp
1
137-138°C. H NMR spectrum, δ, ppm (J, Hz): 2.54-2.73 (2H, m, H-4); 3.72-3.82 (2H, m, H-3); 4.47 (1H, t,
J = 8.4, H-5); 7.14-7.36 (5H, m, ArH). 13C NMR spectrum, δ, ppm: 21.6 (C-4); 44.4 (C-3); 62.4 (C-5); 119.4
(o-CAr); 124.0 (p-CAr); 128.9 (m-CAr); 137.8 (ipso-CAr); 164.9 (CO). Mass spectrum, m/z (Irel, %): 241 [M]+ (31),
132 (58), 105 (100), 77 (65), 51 (20). Found, %: C 49.64; H 4.61; N 6.08. C10H11NO4S. Calculated, %: C 49.78;
H 4.60; N 5.81.
Synthesis of Sultams 6a,e (General Method). A solution of 1-bromo-3-chloropropane (0.75 g,
4.8 mmol) in DMF (60 ml) was added during 1.5 h to a mixture of sulfonamide (2a or 2e) (4 mmol) and
potassium carbonate (1.66 g, 12 mmol) in DMF (60 ml) at 60°C. After this the reaction mixture was stirred until
the end of the reaction (check by TLC). The reaction mixture was processed as for sultams 4a-f.
Methyl 2-(2,6-Dimethylphenyl)-1,2-thiazepane-7-carboxylate 1,1-Dioxide (7e). A solution of
1,4-dibromobutane (0.91 g, 4.2 mmol) in DMF (60 ml) was added during 1.5 h to a mixture of sulfonamide 2e
(1.03 g, 4 mmol) and potassium carbonate (1.66 g, 12 mmol) in DMF (60 ml) at 70oC, and the reaction mixture
was stirred for 100 h. The mixture was diluted with water (150 ml), acidified with conc. HCl to pH ≤2, and
extracted with dichloromethane (3×50 ml). The organic phase was washed with 2% HCl (5×80 ml), dried over
sodium sulfate, and evaporated to dryness. The product was recrystallized from a mixture of ethyl acetate–
hexane.
2-Phenyl-1,2-thiazinan-6-carboxylic Acid 1,1-Dioxide (8a) was obtained analogously to compound
1
5a. Yield was 94%; mp 141-142°C. H NMR spectrum, δ, ppm (J, Hz): 1.96 (2H, m, H-4); 2.40 (2H, m, H-5);
3.45 (1H, m, H-3); 3.91 (1H, m, H-3'); 4.15 (1H, t, J = 7.3, H-6); 7.24-7.40 (5H, m, ArH). 13C NMR spectrum, δ,
ppm : 22.5 (CH2); 27.6 (CH2); 52.8 (C-3); 63.6 (C-6); 126.5 (p-CAr); 126.6 (o/m-CAr); 128.6 (m/o-CAr); 140.8
(ipso-CAr); 165.7 (CO). Mass spectrum, m/z (Irel, %): 255 [M]+ (13), 146 (50), 119 (50), 104 (58), 91 (25), 77
(100), 65 (17), 50 (40), 39 (40). Found, %: C 51.75; H 4.95; N 5.87. C10H11NO4S. Calculated, %: C 51.75; H
5.13; N 5.49.
(N-Benzylaminosulfonyl)acetic Acid (9j). Sodium hydride (100 mg, 2.5 mmol, 60% dispersion in oil)
was added during 0.5 h to a solution of sulfonamide 2j (0.26 g, 1 mmol) and dibromoethane (0.21 g, 0.96 mmol)
in THF (20 ml). After this the reaction mixture was evaporated to dryness in vacuum on a rotary evaporator at
30°C. Diethyl ether (30 ml) and 5% hydrochloric acid (50 ml) were added to the residue. The organic layer was
separated, and the aqueous extracted with ethyl acetate (2×25 ml). The organic phases were combined, dried
over sodium sulfate, and evaporated. The product was recrystallized from a mixture of ethyl
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1
acetate and hexane. Yield was 92%; mp 155-156°C. H NMR spectrum, δ, ppm (J, Hz): 4.05 (2H, s, SO2CH2);
4.19 (2H, d, J = 6.5, NCH2); 7.24-7.35 (5H, m, ArH); 7.93 (1H, t, J = 6.5, NH). 13C NMR spectrum, δ, ppm:
46.4 (NHCH2); 56.9 (SO2CH2); 126.9 (p-CAr); 127.6 (o/m-CAr); 128.0 (m/o-CAr); 137.9 (ipso-CAr); 164.6 (CO).
Mass spectrum, m/z (Irel, %): 229 [M]+ (5), 210 (10), 106 (100), 91 (50), 77 (18). Found, %: C 47.32; H 5.02;
N 6.16. C9H11NO4S. Calculated, %: C 47.15; H 4.84; N 6.11.
4-Methoxycarbonyl-2-phenyl-1,2,4,5-tetrahydrobenzo[d][1,2]thiazepine 3,3-Dioxide (10a).
A
solution of 1,2-bis(bromomethyl)benzene (1.58 g, 6 mmol) in DMF (40 ml) was added during 2 h to a mixture
of sulfonamide 2a (0.91 g, 4 mmol) and potassium carbonate (1.66 g, 12 mmol) in DMF (60 ml) at 65°C. The
mixture was stirred until the end of the reaction (check by TLC). The mixture was diluted with water (150 ml),
acidified with conc. HCl to pH ≤2, and extracted with dichloromethane (3×50 ml). The organic phases were
combined, washed with 2% HCl (5×80 ml), and evaporated to dryness. The product was recrystallized from
ethyl acetate.
Methyl 1-(N-Methyl-N-phenylaminosulfonyl)cyclopropanecarboxylate (11b).
A
solution of
1,2-dibromoethane (1.65 g, 7.7 mmol) in DMF (40 ml) was added during 2 h to a mixture of sulfonamide 2b
(1.94 g, 8 mmol) and potassium carbonate (3.31 g, 24 mmol) in DMF (60 ml) at 65°C, and the mixture was
stirred for a further 24 h. The reaction mixture was then diluted with water (150 ml), acidified with conc. HCl to
pH ≤2, and extracted with dichloromethane (3×50 ml). The organic phases were combined, washed with 2%
HCl (5×80 ml), dried over sodium sulfate, and evaporated to dryness. Yield was 72%, light-yellow oil. 1H NMR
spectrum, δ, ppm: 1.45 (4H, m, CH2CH2); 3.51 (3H, s, NCH3); 3.79 (3H, s, OCH3); 7.30-7.40 (5H, m, ArH).
13C NMR spectrum, δ, ppm: 17.11 (CH2CH2); 40.70 (NCH3); 40.96 (SO2C); 53.00 (OCH3), 126.67 (o/m-CAr);
127.79 (p-CAr); 129.35 (m/o-CAr); 141.48 (ipso-CAr); 168.27 (CO). Mass spectrum, m/z (Irel, %): 269 [M]+ (12),
106 (100), 77 (53), 51 (12), 39 (25). Found, %: C 53.70; H 5.62; N 5.26. C12H15NO4S. Calculated, %: C 53.52;
H 5.61; N 5.20.
1-(N-Methyl-N-phenylaminosulfonyl)cyclopropanecarboxylic Acid (12b). A 10% solution of KOH
(2.8 g, 5 mmol) was added to a boiling solution of ester 8b (1.07 g, 4 mmol) in 50% aqueous ethanol (20 ml).
The solution was heated for a further 10 min, cooled to room temperature, diluted with water (100 ml), and
acidified with HCl to pH ≤2. The obtained suspension was extracted with ethyl acetate (3×50 ml), the organic
phases were combined, dried over sodium sulfate, and evaporated to dryness. The product was recrystallized
1
from a hexane–ethyl acetate mixture. Yield was 86%; mp 150-151°C. H NMR spectrum (DMSO-d6), δ, ppm:
13
1.24 (4H, m, CH2CH2); 3.43 (3H, s, NCH3); 7.27-7.37 (5H, m, ArH). C NMR spectrum (acetone-d6), δ, ppm:
14.4 (CH2CH2); 38.6 (NCH3); 39.0 (SO2C); 125.9 (p-CAr), 126.1 (o/m-CAr); 127.6 (m/o-CAr); 140.4 (ipso-CAr);
167.0 (CO). Mass spectrum, m/z (Irel, %): 255 (32) [M]+, 106 (100), 79 (21), 77 (62), 51 (12), 39 (44). Found, %:
C 51.70; H 5.22; N 5.56. C11H13NO4S. Calculated, %: C 51.75; H 5.13; N 5.49.
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