Sulfonamide analogues of creatinine. The synthesis of 3-amino-4,5-dihydro-l,2,4-thiadiazole 1,1-dioxides from base-induced cyclization reactions

Article abstract of DOI:10.1071/C97159

We report the preparation of 3-amino-4,5-dihydro-l,2,4-thiadiazole 1,1-dioxide and of its 4-methyl derivative which are of interest as potential analogues of creatinine. The thiadiazoles are obtained from chloromethylsulfonylation of S-benzylisothiourea, followed by cyclization of the chloromethanesulfonamide under basic conditions in the presence of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile or of methyl iodide.

Full text of DOI:10.1071/C97159

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 50, 1997
© CSIRO Australia 1997
A journal for the publication of original research
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Aust. J. Chem., 1997, 50, 1027–1029
Sulfonamide Analogues of Creatinine. The Synthesis
of 3-Amino-4,5-dihydro-1,2,4-thiadiazole 1,1-Dioxides
from Base-Induced Cyclization Reactions
Fares A. Fares, Damon D. Ridley and Ping Yin
School of Chemistry, University of Sydney, N.S.W. 2006.
We report the preparation of 3-amino-4,5-dihydro-1,2,4-thiadiazole 1,1-dioxide and of its 4-methyl
derivative which are of interest as potential analogues of creatinine. The thiadiazoles are obtained from
chloromethylsulfonylation of S-benzylisothiourea, followed by cyclization of the chloromethanesulfonamide
under basic conditions in the presence of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile or of methyl
iodide.
Creatinine amidohydrolyase catalyses the hydro-
lysis of the amide bond in creatinine (1) to give
creatine.1 In order to investigate potential inhibitors of
this enzyme, we sought 3-amino-4-methyl-4,5-dihydro-
1,2,4-thiadiazole 1,1-dioxide (2) because of its structural
similarity to the possible transition state in the enzymic
hydrolysis of creatinine.
they reported that the hydrolysis of the carbamate
group under various acidic or basic conditions failed.
In order to prepare the sulfonamide (2), we inves-
tigated two routes both starting from the chloro
sulfonamide (7b). We found that the choice of cycliza-
tion conditions was crucial, but under appropriate
conditions both the parent substance and the N -
methyl derivative (2) could be obtained in satisfactory
yields.
Lawson and Tinkler2 ꢀrst reported the synthe-
sis of some 4-substituted 3-phenyl-4,5-dihydro-1,2,4-
thiadiazole 1,1-dioxide derivatives (3a–d) from the
alkali-induced cyclization reaction of the iodomethane-
sulfonamide (4a) in the presence of an acyl chloride. In
a later paper, Lawson and Tinkler3 reported the synthe-
sis of related 4-substituted 3-phenyl-1,2,4-thiadiazole
1,1-dioxide derivatives by base-induced cyclization of
iodomethanesulfonamide derivatives (4b), which were
prepared from reaction of the imino chloride (5) with
the corresponding amine.
Results and Discussion
In a modiꢀcation of the method of El-Hewehi,5
1,3,5-trithian was converted into chloromethanesulfonyl
chloride which on treatment with S-benzylisothiourea
aꢁorded
the
chloromethanesulfonamide
(7b).
Attempted direct cyclizations of (7b) with sodium
hydroxide, or sodium hydrogen carbonate in aqueous
solution, or with sodium hydride in tetrahydrofuran
were unsuccessful since complex mixtures of products
resulted. However, when the cyclization of the chloro
sulfonamide (7b) with 2 mol. equiv. of sodium hydrox-
ide in the presence of 2-(t-butoxycarbonyloxyimino)-2-
phenylacetonitrile was closely monitored by thin-layer
chromatography, and when the reaction was stopped
when most of the starting material had been consumed,
In 1974, Etienne et al.4 reported the synthesis of
3-thio- and 3-oxy-1,2,4-thiadiazole 1,1-dioxides (6) from
the base-induced reaction of the amidines (7a,b) in the
presence of carbamoyl chlorides as acylating agents.
These 3-thio and 3-oxy derivatives were easily converted
into 3-amino or 3-chloro derivatives, and the 3-chloro
derivative could be further functionalized. However,
O
O
O
N
O
O
N
O
O
N
O
O
N
O
O
N
O
O
N
S
S
S
I
S
S
S
I
Cl
N
RHN
N
N
N
Cl
R'O
N
H2N
Me
R
Me
Ph
NH2
Ph
NH2
Ph
R
R
O
(1)
(2)
(4a) R = H
(4b) R = alkyl, aryl
(5)
(6)
(3a) R = R'OCO
(3b) R = PhCO
(3c) R = PhSO2
(3d) R = MeSO2
(7a) R = MeS, MeO,
EtO, PhO
R = MeS, PhCH2S, PhO,
EtO or MeO
(7b) R = PhCH2S
R' = Me, Et, PhCH2 or Ph
Manuscript received 8 September 1997
᭧ CSIRO Australia 1997
0004-9425/97/101027$05.00
10.1071/CH97159

1028
Short Communications
was complete, the mixture was stirred for 5 h at room temper-
ature during which time a yellow oil separated. The reaction
mixture was poured into iced water, and was extracted with
ether. The ether layer was washed with a 5% solution of sodium
hydrogen carbonate, then with water, and ꢀnally was dried
over magnesium sulfate. Removal of the solvent under reduced
pressure gave a yellow oil which upon distillation aꢁorded
chloromethanesulfonyl chloride (18ꢀ5 g, 62%) as a colourless
oil, b.p. 70ꢀ/15 mm (lit.5 70ꢀ/15 mm). 1H n.m.r. (CDCl3) ꢀ
5ꢀ00, s, CH2.
the butoxycarbonyl derivative (8a) was obtained in
61% yield. Attempts to improve the yield of (8a) by
using longer reaction times, or using sodium hydrogen
carbonate, or using more than 2 mol. equiv. of sodium
hydroxide were unsuccessful since substantial amounts
of decomposition products resulted. Further, attempted
cyclization of the chloro sulfonamide (7b) with sodium
hydride in tetrahydrofuran in the presence of 2-(t-
butoxycarbonyloxyimino)-2-phenylacetonitrile was sim-
ilarly unsuccessful.
S-Benzyl-N-chloromethylsulfonylisothiourea (7b)
O
O
O
O
O
O
A
mixture of chloromethanesulfonyl chloride (7ꢀ9 g,
S
S
53 mmol), S-benzylisothiouronium hydrochloride (10ꢀ7 g, 53
mmol) and anhydrous sodium carbonate (28ꢀ0 g) in anhydrous
ethyl acetate (200 ml) was stirred under nitrogen for 2 days
at room temperature. The reaction mixture was ꢀltered and
the solvent was removed under reduced pressure. The yellow
oil was puriꢀed by ꢂash chromatography (eluent: hexane/ethyl
acetate (1 : 2)) and gave the chloromethanesulfonamide (7b)
(10ꢀ2 g, 69%) as a colourless oil which slowly crystallized, m.p.
47–48ꢀ (lit.4 48ꢀ). 1H n.m.r. (200 MHz, (CD3)2SO) ꢀ 4ꢀ23,
s, 2H, CH2Cl; 4ꢀ73, s, 2H, CH2S; 7ꢀ30–7ꢀ35, m, 5H, ArH;
8ꢀ3–8ꢀ7, br s, 2H, NH2.
S
N
N
N
N
N
N
ButOCO
Me
H
R
SCH2Ph
R
(10)
(9a) R = SCH2Ph
(9b) R = NH2
(8a) R = SCH2Ph
(8b) R = NH2
Removal of the t-butoxycarbonyl group occurred
readily when the derivative (8a) was treated with tri-
ꢂuoroacetic acid, and gave the deprotected thiadiazole
(9a). However, this product was very insoluble in
nearly all organic solvents and because of this further
transformations of (9a) proved impossible. On the
other hand, the t-butoxycarbonyl derivative (8a) was
easily converted into the 3-amino derivative (8b) by
reaction with ammonia in chloroform, and this product,
on treatment with triꢂuoroacetic acid gave one of the
required creatinine analogues (9b).
When methyl iodide was used instead of 2-(t-
butoxycarbonyloxyimino)-2-phenylacetonitrile in the
carefully controlled cyclization of the chloromethane-
sulfonamide (7b), the N -methyl derivative (10) was
obtained in satisfactory yield, and subsequent reaction
of the product with liquid ammonia gave the desired
N -methyl analogue (2).
Attempts to cyclize the chloro sulfonamide (7b) with-
out added 2-(t-butoxycarbonyloxyimino)-2-phenylaceto-
nitrile or methyl iodide in the presence of 2 mol. equiv.
of sodium hydroxide were unsuccessful. Complex mix-
tures only were obtained. It is possible that the initial
cyclization occurred, but, in separate experiments, we
noted that derivatives of the type (9a) which did not
have substituents at the 4-position were very rapidly
decomposed under basic conditions, so the failure to
eꢁect cyclization without added acylating or alkylat-
ing reagents may simply be due to instability of the
initial product. It is possible that under the reaction
conditions the 4-unsubstituted derivatives are ionized
and that their instability is due to decomposition of
the anion.
3-Benzylthio-4-t-butoxycarbonyl-4,5-dihydro-1,2,4-
thiadiazole 1,1-Dioxide (8a)
To a stirred solution of the chloro sulfonamide (7b) (7ꢀ3 g,
26 mmol) and 2-(t-butoxycarbonyloxyimino)-2-phenylaceto-
nitrile (7ꢀ03 g, 28 mmol) in acetone (250 ml) under nitrogen
at room temperature was added dropwise a solution of 10 M
sodium hydroxide (5ꢀ2 ml, 52 mmol) over a period of 1 h, and
the mixture was stirred for another 1 h. After removal of
the sodium chloride precipitate by ꢀltration, the solvent was
evaporated and the solid residue was dissolved in ethyl acetate.
The solution was washed with 1 M sodium hydroxide, then
with brine, and ꢀnally was dried over anhydrous magnesium
sulfate. The solvent was removed under reduced pressure,
and the solid residue was recrystallized from methanol to give
the title 1,1-dioxide (8a) (5ꢀ5 g, 61%) as colourless crystalline
needles, m.p. 127–128ꢀ (Found: C, 48ꢀ9; H, 5ꢀ4; N, 8ꢀ3.
C
14H18N2O4S2 requires C, 49ꢀ1; H, 5ꢀ3; N, 8ꢀ2%). 1H n.m.r.
(400 MHz, CDCl3) ꢀ 1ꢀ53, s, 9H, But; 4ꢀ32, s, 2H, CH2S;
4ꢀ66, s, 2H, CH2SO2; 7ꢀ29–7ꢀ39, m, 5H, ArH. 13C n.m.r.
(400 MHz, CDCl3) ꢀ 28ꢀ5, Me; 39ꢀ1, CH2S; 62ꢀ6, CH2SO2;
87ꢀ7, (CH3)3C; 128ꢀ6, 129ꢀ4, 130ꢀ1, 134ꢀ9, Ar; 148ꢀ5, C=O;
168ꢀ8, C=N. Mass spectrum m/z 342 (M, 13%), 286 (24), 57
(100), 91 (81).
3-Benzylthio-4,5-dihydro-1,2,4-thiadiazole 1,1-Dioxide (9a)
A solution of the t-butoxycarbonyl derivative (8a) (150 mg,
0ꢀ438 mmol) in triꢂuoroacetic acid (10 ml) was stirred at room
temperature for 30 min. The triꢂuoroacetic acid was removed
under reduced pressure and the white solid was dissolved
in ethyl acetate. The ethyl acetate solution was washed
with saturated sodium hydrogen carbonate solution, then with
brine and ꢀnally was dried over anhydrous magnesium sulfate.
Removal of the solvent under reduced pressure aꢁorded a white
powder that was puriꢀed by recrystallization from methanol
to give the 4-unsubstituted 1,1-dioxide (9a) (88 mg, 83%) as
colourless needles, m.p. 112–113ꢀ (Found: C, 44ꢀ6; H, 4ꢀ6; N,
11ꢀ4. C9H10N2O2S2 requires C, 44ꢀ6; H, 4ꢀ2; N, 11ꢀ6%). 1H
n.m.r. (400 MHz, (CD3)2SO) ꢀ 4ꢀ36, s, 2H, CH2S: 4ꢀ52, s,
2H, CH2SO2; 7ꢀ28–7ꢀ43, m, 5H, ArH; 10ꢀ05, br s, 1H, NH.
13C n.m.r. (400 MHz, (CD3)2SO) 34ꢀ9, CH2S; 60ꢀ6, CH2SO2,
127ꢀ6, 128ꢀ6, 129ꢀ0, 136ꢀ5, Ar; 169ꢀ2, C=N.
Experimental
Chloromethanesulfonyl Chloride
To a stirred suspension of 1,3,5-trithian (13ꢀ8 g, 0ꢀ1 mol)
in 10 M hydrochloric acid (500 ml) at 10–15ꢀ was added, in
portions, potassium chlorate (40ꢀ9 g, 0ꢀ3 mol). After addition

Short Communications
1029
3-Amino-4-t-butoxycarbonyl-4,5-dihydro-1,2,4-thiadiazole
1,1-Dioxide (8b)
recrystallized from methanol to give the title 1,1-dioxide (10)
(224 mg, 67%) as colourless crystals, m.p. 128–129ꢀ (Found:
C, 47ꢀ1; H, 5ꢀ0; N, 11ꢀ1. C10H12N2O2S2 requires C, 46ꢀ9; H,
4ꢀ7; N, 10ꢀ9%). 1H n.m.r. (400 MHz, CDCl3) ꢀ 3ꢀ11, s, 3H,
CH3; 4ꢀ36, s, 2H, CH2S; 4ꢀ41, s, 2H, CH2SO2; 7ꢀ35–7ꢀ37, m,
5H, ArH. 13C n.m.r. (400 MHz, CDCl3) ꢀ 33ꢀ8, CH2S; 37ꢀ8,
Me; 66ꢀ0, CH2SO2, 128ꢀ2, 128ꢀ8, 129ꢀ2, 134ꢀ7, Ar; 170ꢀ6,
C=N. Mass spectrum m/z 256 (M, 47ꢀ5%), 192 (9), 122 (12),
91 (100).
Ammonia gas was bubbled into a vigorously stirred solu-
tion of the benzylthio derivative (8a) (300 mg, 0ꢀ87 mmol) in
chloroform (15 ml) for 2 h at room temperature. The solvent
was evaporated and the white solid residue was recrystallized
from methanol to yield the title 1,1-dioxide (8b) (120 mg, 58%)
as a colourless crystalline solid, m.p. 120ꢀ (dec.) (Found: C,
35ꢀ4; H, 5ꢀ8; N, 18ꢀ2. C7H13N3O4S requires C, 35ꢀ7; H, 5ꢀ6;
N, 17ꢀ9%). 1H n.m.r. (400 MHz, CDCl3) ꢀ 1ꢀ55, s, 9H, But;
4ꢀ65, s, 2H, CH2; 6ꢀ59, br s, 1H, NH; 8ꢀ07, br s, 1H, NH. 13C
n.m.r. (400 MHz, CDCl3) ꢀ 28ꢀ5, Me; 62ꢀ1, CH2SO2; 87ꢀ6,
(CH3)3C; 150ꢀ7, C=O; 155ꢀ8, C=N. Mass spectrum m/z 235
(M, 42%), 220 (17), 57 (100).
3-Amino-4-methyl-4,5-dihydro-1,2,4-thiadiazole
1,1-Dioxide (2)
The benzylthio derivative (10) (65 mg, 0ꢀ25 mmol) was
stirred in liquid ammonia for 8 h. The ammonia was evapo-
rated, and chloroform (10 ml) was added to the solid residue.
The 3-amino 1,1-dioxide (2) (20 mg, 53%) was collected by
ꢀltration, m.p. 182–184ꢀ (Found: C, 24ꢀ0; H, 5ꢀ0; N, 27ꢀ6.
C3H7N3O2S requires C, 24ꢀ2; H 4ꢀ7; N, 28ꢀ2%). 1H n.m.r.
(200 MHz, (CD3)2SO) ꢀ 2ꢀ93, s, 3H, Me; 4ꢀ29, s, 2H, CH2;
7ꢀ27, br s, 2H, NH2. 13C n.m.r. (200 MHz, (CD3)2SO) ꢀ 31ꢀ9,
Me; 66ꢀ0, CH2; 159ꢀ6, C=N. Mass spectrum m/z 149 (M,
19%), 85 (19), 43 (100), 42 (90).
3-Amino-4,5-dihydro-1,2,4-thiadiazole 1,1-Dioxide (9b)
The t-butoxycarbonyl derivative (8b) (100 mg, 0ꢀ425 mmol)
was dissolved in triꢂuoroacetic acid (5 ml), and the solution
was stirred at room temperature for 30 min. The solvent was
removed under reduced pressure and the white solid was recrys-
tallized from methanol to give the 4-unsubstituted 1,1-dioxide
(9b) (35 mg, 61%) as colourless crystals, m.p. 114–117ꢀ (Found:
C, 17ꢀ4; H, 4ꢀ1; N, 31ꢀ0. C2H5N3O2S requires C, 17ꢀ8; H,
3ꢀ7; N, 31ꢀ1%). 1H n.m.r. (400 MHz, (CD3)2SO) ꢀ 4ꢀ17, s,
2H, CH2; 7ꢀ02, br s, 2H, NH2; 7ꢀ70, br s, 1H, NH. 13C n.m.r.
(400 MHz, (CD3)2SO) ꢀ 60ꢀ8, CH2; 160ꢀ0, C=N.
Acknowledgment
We thank the Cooperative Research Centre for
Molecular Engineering and Technology for ꢀnancial
support.
3-Benzylthio-4-methyl-4,5-dihydro-1,2,4-thiadiazole
1,1-Dioxide (10)
Methyl iodide (279 mg, 1ꢀ97 mmol) was added dropwise to a
stirred solution of the chloromethanesulfonamide (7b) (363 mg,
1ꢀ31 mmol) in acetone (15 ml). The mixture was stirred for
15 min; then a solution of 10 M sodium hydroxide (0ꢀ28 ml)
was added dropwise over a period of 30 min under nitrogen at
room temperature and the solution was stirred for another 2 h.
The solvent was removed and the solid residue was dissolved
in ethyl acetate. The solution was washed with brine, and
then was dried over anhydrous magnesium sulfate. The solvent
was removed under reduced pressure and the solid residue was
References
1
Jung, K., Eur. J. Clin. Chem. Biochem., 1991, 29, 725.
Lawson, A., and Tinkler, R. B., J. Chem. Soc. C, 1969,
652.
Lawson, A., and Tinkler, R. B., J. Chem. Soc. C, 1970.
1429.
Etienne, A., Le Berre, A., Lonchambon, G., Lochey, G.,
2
3
4
and Cucumel, B., Bull. Soc. Chim. Fr., 1974, 1580.
El-Hewehi, Z., J. Prakt. Chem., 1964, 23(4), 38.
5