A novel and efficient regiospecific preparation of arenesulfonamide derivatives of 3,5-diamino-1,2,4-triazole

Article abstract of DOI:10.1055/s-2002-19793

A new simple and efficient procedure was designed for the regiospecific preparation of arenesulfonamide derivatives of 3,5-diamino-1,2,4-triazole 1 which are precursors of N-([1,2,4] triazolo [1,5-a]pyrimidin-2-yl)arenesulfonamides 2, an important family of herbicidal and antibacterial agents. The key feature of this procedure is the preparation of a wide range of compounds 1 on a large scale, in pure form and high yield without the need for any workup or the use of the highly hazardous hydrazine. This was made possible by a novel tandem reaction promoted by sulfuryl chloride to effect the formation of the triazole ring.

Full text of DOI:10.1055/s-2002-19793

PAPER
185
A Novel and Efficient Regiospecific Preparation of Arenesulfonamide
Derivatives of 3,5-Diamino-1,2,4-triazole
A
renesulfonamide
e
D
erivative
l
s of 3,5
l
-Diami
y
no-1,2,4-triazole Chibale,*a Jérôme Dauvergne,a,1 Paul G. Wyattb
a
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax +27(21)6897499; E-mail: chibale@science.uct.ac.za
b
Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY,
U.K.
Received 27 September 2001; revised 30 October 2001
The initial objective of our research programme was to
simplify the experimental procedure and increase the
yields in the first step as well as finding alternative and
safer reaction conditions for the second step. In this paper,
Abstract: A new simple and efficient procedure was designed for
the regiospecific preparation of arenesulfonamide derivatives of
3,5-diamino-1,2,4-triazole 1 which are precursors of N-([1,2,4]tria-
zolo[1,5-a]pyrimidin-2-yl)arenesulfonamides 2, an important fami-
ly of herbicidal and antibacterial agents. The key feature of this we wish to report both improvements in the preparation of
procedure is the preparation of a wide range of compounds 1 on a
the building blocks 1, as well as the use of sulfuryl chlo-
large scale, in pure form and high yield without the need for any
ride in a new tandem reaction leading to the construction
workup or the use of the highly hazardous hydrazine. This was
of the triazole ring.
made possible by a novel tandem reaction promoted by sulfuryl
chloride to effect the formation of the triazole ring.
R2
Key words: triazole ring formation, heterocycles, cyclizations, tan-
R1
R3
dem reactions, herbicidal agents
H
N
N
NH2
N
N
N
O
S
O
S
N
N
N-(5-Amino-1H-[1,2,4]triazol-3-yl)arenesulfonamides 1
are key intermediates in the synthesis of N-([1,2,4]triazo-
lo[1,5-a]pyrimidin-2-yl)arenesulfonamides 2 (Figure 1),
a class of compounds displaying important herbicidal and
antibacterial activities.2 As part of our ongoing medicinal
chemistry project, we intended to prepare chemical librar-
ies of compounds 2 in array format for lead optimization.
Hence we needed a straightforward and simple approach
to prepare large quantities of building blocks 1. The pro-
cedures described previously in the literature3,4 both in-
volve a two-step formation of the triazole ring from
commercially or readily available arenesulfonamides 3.
However, both methods exhibit several disadvantages in-
cluding the use of reflux3 or high temperature4 conditions,
moderate and inconsistent yields3,4 as well as the use of
two highly hazardous chemicals, hydrazine3 or carbon
disulfide.4 We reasoned that the first procedure3 involving
a two-step construction of the heterocyclic ring starting
from 3 and dimethyl cyanodithioiminocarbonate (4) was
amenable to optimisation in order to avoid the aforemen-
tioned drawbacks. In the original publication, two differ-
ent methods were described for the first step yielding the
intermediate methyl N-(arylsulfonyl)-N’-cyanoimidothio-
carbamates 5, but both required reflux conditions and
yields were inconsistent and often quite low. The second
step involved hydrazine as a reagent, and was thus unsat-
isfactory on safety grounds.
NH
NH
R
R
O
O
1
2
Figure 1 Chemical structures of arenesulfonamides 1 and 2
To perform the coupling of 3 and 4, we were looking for
a simplified procedure which avoids reflux conditions and
affords compounds 5 in higher and more consistent yields.
Presumably reflux conditions were desirable in order to
address solubility problems. We decided to use DMF as a
solvent for the coupling in order to circumvent these prob-
lems. This choice consequently allowed us to work with
highly concentrated reaction media. We used potassium
carbonate as a base due to its water solubility which, cou-
pled with the water miscibility of DMF simplified the fi-
nal product isolation procedure. As a matter of fact,
operating with concentrations as high as 3 molar, we were
able to precipitate the pure products 5 in high yields
(Table 1) by simply adding aqueous 2 M hydrochloric
acid to the reaction mixture.
It is noteworthy that the new procedure resulted in a dra-
matic increase in isolated yields of products compared
with the previously published results, as shown below.
The high concentration of the reaction medium and the
simplicity of the purification process certainly accounts
for the substantial improvement in chemical yields ob-
served.
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2001,0,02,0185,0190,ftx,en;E06301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

186
K. Chibale et al.
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Table 1 Compounds 5 Synthesized
O
S
NH2
Compound
R
Yielda (%)
82 (45)
83 (55)
92
N
R
O
S
5a
5b
5c
5d
5e
5f
H
3
O
S
N
i
+
NH
4-Me
4-Cl
77-99%
R
O
H3CS
N
5
N
ii
SCH3
2-Cl
99 (69)
95
4
3-Cl
4-Br
88
H
N
O
NH2
5g
5h
5i
2-naphthylb
2,4,6-Pr-i
2-CO2Me
4-OMe
87
O
N
HN
S
N
N
O
S
N
iii
56-72%
97 (40)
77
NH2
NH
O
S
R
O
NH
R
O
1
5j
88
a Yields reported in the literature3are given in parenthesis.
b 2-Naphthylsulfonamide (3g) was used in place of benzenesulfona-
mide (3a, R = H).
6
Scheme 1 Synthesis of triazoles 1 Reagents and conditions: i)
K2CO3/DMF, r.t., then 2 N aq HCl; ii) t-BuNHNH2/MeCN, 60 °C; iii)
a. SO2Cl2/CH2Cl2, r.t., b. EtOH–H2O,
Following the previously described procedure, the second
step required the use of either anhydrous hydrazine or hy-
drazine monohydrate, which are both highly toxic and
dangerous chemicals. Thus we clearly needed to find a
different approach in order to comply with health and
safety regulations. The most evident choice appeared to
be the utilization of tert-butyl carbazate, a protected hy-
drazine derivative usually used as its equivalent in synthe-
sis, or as a way of introducing the Boc protecting group.
At this juncture we were prompted to think about an alter-
native method for the smooth and selective tandem depro-
tection-cyclization protocol for accessing our target
compounds 1. The previous experiments revealed that un-
der the reaction conditions used, elimination of the arene-
sulfonamide moiety was surprisingly highly competitive
with the elimination of methanethiol during the addition-
elimination process leading to the formation of the triaz-
ole ring. The challenge was for us to find conditions fa-
voring the elimination of the sulfide moiety, possibly by
increasing its tendency to behave as a good leaving group.
At this point our attention turned to sulfuryl chloride.
We initially envisaged carrying out the coupling of com-
pounds 5 with tert-butyl carbazate followed by addition of
trifluoroacetic acid (TFA) to deprotect the expected inter-
mediate adduct 6 in situ (Scheme 1) and effect the cycliza-
tion leading to the formation of the triazole ring.
Unfortunately, our attempts using this strategy were un-
satisfactory. Reactions with both compounds 5a and 5b
using TFA for deprotection and subsequent cyclization
yielded a mixture of compounds 1a and 1b respectively,
together with 3-amino-5-methylthio-1,2,4-triazole (7)
(Figure 2) as a major byproduct (over 50% in both cases).
The coupling typically required heating to 60 °C for good
reaction rates. Different solvents (dichloromethane, ace-
tonitrile, 1,4-dioxane) and conditions (adding TFA in the
first place or after the intermediate 6 has formed, isolating
6 and carrying out the second step at room temperature us-
ing diluted hydrochloric acid instead of TFA) were tried
but none gave satisfactory results.
It is known in the literature that sulfuryl chloride is a pow-
erful chlorinating agent capable of generating chlorine in
situ. Besides this, sulfuryl chloride is also known to cata-
lyze the deprotection of tert-butyl esters. Although sulfu-
ryl chloride is well documented as a carbon chlorinating
agent, its use as a sulfur chlorinating agent is rare.5 We
reasoned that chlorine generated in situ from the sulfuryl
chloride-mediated deprotection of the tert-butoxycarbon-
yl (Boc) group might lead to chlorination of the methyl
sulfide moiety to generate a methylchlorosulfonium cat-
ion and subsequent elimination of methylsulfenyl chlo-
ride. Gratifyingly, we found that treatment of the isolated
crude intermediate 6 in the presence of sulfuryl chloride in
dichloromethane at room temperature mainly gave the ex-
pected arenesulfonamide derivative of triazole 1, which
simply precipitated out of solution. In most cases, the
amount of byproduct 7 was less than 10%. Subsequently
we also found that refluxing a suspension of the crude sol-
id for a few minutes in a 1:1 mixture of ethanol and water
allowed us, after filtration, to obtain compounds 1 in pure
form without dramatically affecting the yield of the two-
step procedure (Table 2).
N
S
NH
N
NH2
7
Figure 2 Chemical structure of the byproduct 1,2,4-triazole 7
Synthesis 2002, No. 2, 185–190 ISSN 0039-7881 © Thieme Stuttgart · New York

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Arenesulfonamide Derivatives of 3,5-Diamino-1,2,4-triazole
187
Table 2 Preparation of 1
Compound
R
Yielda (%)
72 (70)
56 (89)
67
O
S
O
Cl-
Cl
Cl
O
1a
1b
1c
1d
1e
1f
H
O
S
H
O
O
HN
S
N
N
6
O
Cl
NH2
4-Me
4-Cl
N+
N
O
O
S
H
NH
R
-SO2
O
2-Cl
60 (77)
63
-isobutene
3-Cl
H2N
NH
N
N
O
NH2
O
4-Br
62
-CO2
H
N N
2-naphthylb
2,4,6-i-Pr
68
S
1g
1h
H
Cl Cl
64 (84)
a Yield over two steps. Yields reported in the literature3 are given in
parenthesis.
b Methyl N’-cyano-N-(2-naphthylsulfonyl)imidothiocarbamate (5g)
was used in place of methyl N’-cyano-N-(phenylsulfonyl)imidothio-
carbamate (5a, R = H).
H
Cl-
N
H
NH2
N
H
HN
NH
N
N
N
N-
NH2
S+
Cl
S+
Cl
The only limitation observed with this method was in the
case of compounds 5i and 5j. TLC monitoring of the reac-
tion in these cases revealed the formation of a number of
byproducts, which probably resulted from sensitivity of
the ester6 and ether7 moieties to sulfuryl chloride.
-CH3SCl
H
N
N
NH2
H+
NH2
N
HN
In order to account for the modified reactivity of com-
pounds 6 under the conditions described above, we pro-
pose the mechanism depicted in Scheme 2. In this
mechanism, the reaction is initiated by the sulfuryl chlor-
ide-mediated deprotection of the Boc group in which
chlorine is generated. Subsequent chlorination of the me-
thyl sulfide moiety to give the corresponding chlorosulfo-
nium cation is accompanied by concomitant cyclization.
Since sulfuryl chloride is known to generate Cl2 in situ, it
is reasonable to envisage an alternative mechanism in-
volving initial chlorination followed by Boc deprotection.
O
S
O
N
N
NH
S
NH
R
R
O
O
1
Scheme 2 Proposed mechanism for the sulfuryl chloride initiated
tandem reaction
Table 3 Comparison of the Overall Yields for the Transformation 3
1
Preparation
3a 1a
3b 1b
3c 1c
R
Yielda (%)
59 (32,3 354)
46 (49,3 414)
62 (354)
A summary of the overall yields obtained for transforma-
H
tion 3
1 in comparison with those from previously de-
scribed procedures is presented in Table 3. Whereas all
results are at least as good as those previously reported, a
dramatic increase in the yields was observed in some cas-
es. This clearly demonstrates that avoiding the use of hy-
drazine or carbon disulfide does not adversely affect the
efficiency of the preparation of the title compounds.
4-Me
4-Cl
2-Cl
2,4,6-Pr-i
3d 1d
3h 1h
59 (533)
62 (343)
a Overall yield. Literature yields are given in parenthesis.
In conclusion, we have described an efficient and high
yielding route to the preparation of N-(5-amino-1H-
[1,2,4]triazol-3-yl)arenesulfonamides 1 of high purity interesting utilization of sulfuryl chloride, a powerful and
from commercially available arenesulfonamides 3. This versatile inorganic reagent for organic synthesis, in a nov-
new procedure avoids using highly hazardous hydrazine el tandem reaction for which a plausible mechanism has
and also excludes any purification techniques other than been proposed.
filtration. In this respect, it is perfectly suited for large
scale synthesis as demonstrated here on 5 g batches. The
All materials were purchased from commercial suppliers and used
series of compounds 2 prepared as described in this paper
will be used as scaffolds for the generation of chemical li-
braries of N-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)arene-
sulfonamides 2. In addition, we have presented an
without further purification. Dimethyl cyanodithioiminocarbonate
was purchased from Lancaster (99% purity). TLC was performed
on aluminum backed silica gel 60 F254 plates and visualized by UV
light. Melting points were measured using a Reichert–Jung Ther-
movar hot-stage microscope and are uncorrected. Microanalyses
Synthesis 2002, No. 2, 185–190 ISSN 0039-7881 © Thieme Stuttgart · New York

188
K. Chibale et al.
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were determined using a Fisons EA 1108 CHNS-O instrument.
Mass spectra (EI) were recorded on a VG Micromass 16F spectrom-
eter. All 1H NMR spectra were recorded on a Varian Gemini (300
MHz) or a Varian Unity Spectrometer (400 MHz), using the resid-
ual proton signal of the deuterated solvent as an internal reference:
for CDCl3 ( = 7.26), acetone-d6 ( = 2.05), and DMSO-d6
( = 2.50). All 13C NMR spectra were recorded on the same instru-
ments at 75 MHz or 100 MHz, using the 13C signal of the deuterated
solvent as an internal reference: for CDCl3 ( = 77.0, central signal),
acetone-d6 ( = 29.8, central signal, and = 205.7), and DMSO-d6
MS (EI): m/z (%) = 289 (M+, 1), 242 (M+ – SCH3, 9), 175
(C6H4ClSO2 , 68), 111 (C6H4Cl+, 100).
+
Anal. Calcd for C9H8ClN3O2S2: C, 37.31; H, 2.78; N, 14.50; S,
22.13. Found: C, 37.18; H, 2.42; N, 14.61; S, 22.31.
Methyl N-[(2-Chlorophenyl)sulfonyl]-N’-cyanoimidothio-car-
bamate (5d)
Scale: 26.1 mmol; white solid; mp 132–133 °C (Lit.3 mp 126.5 °C,
dec.); Rf 0.14 (CHCl3–EtOH, 8:2).
1H NMR (300 MHz, acetone-d6): = 2.78 (s, 3 H, SCH3), 7.61–7.80
(m, 3 Harom, 2 Hmeta and 1 Hpara), 8.19 (dd, 1 Harom, J = 8.0 Hz, J =
1.4 Hz, Hortho).
13C NMR (75 MHz, acetone): = 16.3 (CH3), 112.0 (C), 129.2
(CH), 133.2 (C), 133.5 (CH), 134.0 (CH), 137.1 (CH), 137.9 (C),
171.7 (C).
1
( = 39.6, central signal). For the H NMR spectral data, coupling
constants (J) are reported in Hz. Carbon multiplicities were as-
signed by DEPT experiments. Some quaternary carbon atoms have
very slow relaxation times, in which case they do not appear in the
assignment.
Methyl N-(Arylsulfonyl)-N’-cyanoimidothiocarbamates 5a–j;
General Procedure
LRMS (EI): m/z (%) = 289 (M+, 3), 242 (M+ – SCH3, 12), 207 (M+
+
– SCH3 – Cl, 10), 175 (C6H4ClSO2 , 66), 111 (C6H4Cl+, 100).
A mixture of arenesulfonamide 3a–j (6.4 mmol), an equimolar
amount of both dimethyl N-cyanodithioiminocarbonate and finely
ground anhyd K2CO3 in DMF (10 mL) were stirred at r.t. for 15 h.
Then an aq solution of 2 N HCl (150 mL) was added to the reaction
mixture and stirred for an additional 8 h. The white precipitate
formed was collected by filtration and washed successively with an
aq solution of 2 N HCl and a small amount of ether. Further drying
under vacuum afforded the imidothiocarbamate 5a–j. The yields are
listed in Table 1.
Anal. Calcd for C9H8ClN3O2S2: C, 37.31; H, 2.78; N, 14.50; S,
22.13. Found C, 37.21; H, 2.40; N, 14.55; S, 22.51.
Methyl N-[(3-Chlorophenyl)sulfonyl]-N’-cyanoimidothio-car-
bamate (5e)
Scale: 26.1 mmol; white solid; mp 129–130 °C; Rf 0.11 (CHCl3–
EtOH, 8:2).
1H NMR (300 MHz, acetone-d6): = 2.77 (s, 3 H, CH3), 7.71 (m, 1
H
arom, Hmeta), 7.80 (m, 1 Harom, Hpara), 7.98 (m, 1 Harom, Hortho), 8.00
Methyl N’-Cyano-N-(phenylsulfonyl)imidothiocarbamate (5a)
Scale: 31.8 mmol; white solid; mp 132–134 °C (Lit.3 mp 122 °C,
dec.); Rf 0.18 (CHCl3–EtOH, 8:2).
1H NMR (400 MHz, acetone-d6): = 2.76 (s, 3 H, SCH3), 7.68 (m,
2 Harom, Hmeta), 7.77 (m, 1 Harom, Hpara), 8.03 (m, 2 Harom, Hortho).
13C NMR (100 MHz, acetone-d6): = 14.9 (CH3), 128.6 (2 CH),
(d, 1 Harom, J = 1.5, Hortho).
13C NMR (75 MHz, acetone-d6): = 15.2 (CH3), 111.6 (C), 127.5
(CH), 128.5 (CH), 131.6 (CH), 134.8 (CH), 135.0 (C), 141.5 (C),
171.5 (C).
Anal. Calcd for C9H8ClN3O2S2: C, 37.31; H, 2.78; N, 14.50; S,
22.13. Found C, 37.62; H, 2.36; N, 14.74; S, 22.50.
129.4 (2 CH), 134.6 (CH), 170.9 (C).
+
MS (EI): m/z (%) = 255 (M+, 1), 208 (M+ – SCH3, 10), 141 (PhSO2 ,
Methyl N-[(4-Bromophenyl)sulfonyl]-N’-cyanoimidothio-car-
42), 77 (Ph+, 100).
bamate (5f)
Scale: 21.2 mmol; white solid; mp 132–133 °C; Rf 0.11 (CHCl3–
EtOH, 8:2).
1H NMR (400 MHz, acetone-d6): = 2.77 (s, 3 H, CH3), 7.88 (d, 2
Anal. Calcd for C9H9N3O2S2: C, 42.34; H, 3.55; N, 16.46; S, 25.11.
Found: C, 42.24; H, 3.30; N, 16.39; S, 25.02.
H
arom, J = 8.8 Hz, Hmeta), 7.96 (d, 2 Harom, J = 8.8 Hz, Hortho).
Methyl N’-Cyano-N-[(4-methylphenyl)sulfonyl]imidothio-car-
bamate (5b)
13C NMR (100 MHz, acetone-d6): = 15.9 (CH3), 112.3 (C), 130.1
(C), 131.6 (CH), 133.7 (CH), 139.2 (C), 171.9 (C).
Scale: 29.2 mmol; white solid; mp 133–134 °C (Lit.3 mp 137.5–139
°C); Rf 0.19 (CHCl3–EtOH, 8:2).
1H NMR (400 MHz, acetone-d6): = 2.46 (s, 3 H, CH3), 2.75 (s, 3
H, SCH3), 7.49 (d, 2 Harom, J = 8.4 Hz, Hmeta), 7.91 (d, 2 Harom, J =
8.4 Hz, Hortho).
13C NMR (100 MHz, acetone-d6): = 14.8 (CH3), 20.9 (CH3), 111.7
(C), 128.8 (2 CH), 129.9 (2 CH), 135.8 (C), 145.9 (C), 170.9
(C).
Methyl N’-Cyano-N-(2-naphthylsulfonyl)imidothiocarbamate
(5g)
Scale: 24.1 mmol; white solid; mp 138–140 °C; Rf 0.14 (CHCl3–
EtOH, 8:2).
1H NMR (400 MHz, acetone-d6): = 2.77 (s, 3 H, CH3), 7.75 (td, 1
H, J = 8.1, 1.6 Hz), 7.78 (td, 1 H, J = 8.1, 1.6 Hz), 8.02 (dd, 1 H, J
= 8.8, 2.0 Hz), 8.08 (d, 1 H, J = 8.1 Hz), 8.18 (d, 1 H, J = 8.8 Hz),
8.20 (d, 1 H, J = 8.1 Hz), 8.69 (d, 1 H, J = 2.0 Hz).
13C NMR (100 MHz, acetone-d6): = 16.0 (CH3), 112.5 (C), 124.1
(CH), 129.2 (CH), 129.3 (CH), 130.7 (CH), 130.9 (CH), 131.0
(CH), 131.8 (CH), 133.2 (C), 136.8 (C), 136.9(C), 171.9 (C).
MS (EI): m/z (%) = 269 (M+, 1), 222 (M+ – SCH3, 6), 155
+
+
(C6H4CH3SO2 , 59), 91 (C6H4CH3 , 100).
Anal. Calcd for C10H11N3O2S2: C, 44.59; H, 4.12; N, 15.60; S,
23.81. Found: C, 44.96; H, 3.89; N, 15.93; S, 24.20.
Methyl N-[(4-Chlorophenyl)sulfonyl]-N’-cyanoimidothio-car-
bamate (5c)
Scale: 20.9 mmol; white solid; mp 133–134 °C; Rf 0.15 (CHCl3–
EtOH, 8:2).
1H NMR (400 MHz, acetone-d6): = 2.77 (s, 3 H, SCH3), 7.72 (d,
2 Harom, J = 8.8 Hz, Hmeta), 8.03 (d, 2 Harom, J = 8.8 Hz, Hortho).
Methyl N’-Cyano-N-[(2,4,6-triisopropylphenyl)sulfonyl]imido-
thiocarbamate (5h)
Scale: 17.6 mmol; white solid; mp 237–238 °C (dec.) (Lit.3 mp
165–165.5 °C); Rf 0.18 (CHCl3–EtOH, 8:2).
1H NMR (400 MHz, acetone-d6): = 1.19 (d, 12 H, J = 6.6 Hz,
CHCH3), 1.23 (d, 6 H, J = 6.6 Hz, CHCH3), 2.33 (s, 3 H, SCH3),
2.90 (septet, 1 H, J = 6.6, CHCH3), 3.40 (br s, 1 H, NH), 4.61 (sep-
tet, 2 H, J = 6.6 Hz, CHCH3), 7.14 (s, 2 Harom).
13C NMR (75 MHz, acetone-d6): = 15.7 (CH3), 112.2 (C), 130.5
(2 CH), 131.4 (2 CH), 138.5 (C), 141.3 (C), 171.9 (C).
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Arenesulfonamide Derivatives of 3,5-Diamino-1,2,4-triazole
189
13C NMR (100 MHz, acetone-d6): = 15.1 (CH3), 23.4 (2 CH3),
24.4 (4 CH3), 29.1 (2 CH), 34.1 (CH), 122.8 (2 CH), 138.0
(C), 149.7 (C), 150.6 (C).
1H NMR (400 MHz, DMSO-d6): = 5.82 (br s, 2 H, NH2), 7.46–
7.53 (m, 3 Harom, 2 Hmeta and 1 Hpara), 7.78 (dd, 2 Harom, J = 8.0, 1.6
Hz, Hortho), 11.40–11.90 (br s, 2 H, 2 NH).
13C NMR (100 MHz, DMSO-d6): = 113.9 (C), 117.7 (C), 125.7
(2 CH), 128.7 (2 CH), 131.5 (CH), 148.7 (C).
Methyl 2-({[(Cyanoimino)(methylsulfanyl)methyl]amino}sul-
fonyl)benzoate (5i)
Scale: 23.2 mmol; white solid; mp 133 °C; Rf 0.29 (CHCl3–EtOH,
8:2).
1H NMR (400 MHz,acetone-d6): = 2.75 (s, 3 H, SCH3), 3.98 (s, 3
HRMS (EI): m/z calcd for C8H9N5O2S (M+) 239.0480, found
230.0477; 175 (M+ – SO2, 7), 141 (M+ – C2H4N5, 7), 98 (C2H4N5 ,
+
100), 77 (Ph+, 69).
H, CO2CH3), 7.84–7.92 (m, 3 Harom, 2 Hmeta and 1 Hpara), 8.23 (d, 1
N-(5-Amino-1H-[1,2,4]triazol-3-yl)-4-methylbenzenesulfon-
amide (1b)
Harom, J = 7.2 Hz, Hortho).
13C NMR (100 MHz, acetone-d6): = 14.6 (CH3), 53.2 (CH3), 111.1
(C), 130.7 (CH), 131.7 (2 CH), 132.3 (C), 134.8 (CH), 136.6 (C),
167.2 (C), 170.6 (C).
White solid; mp 312 °C (Lit.3 mp 314–315 °C (Lit.4 mp 306 °C).
1H NMR (300 MHz, DMSO-d6): = 2.34 (s, 3 H, CH3), 5.83 (br s,
2 H, NH2), 7.30 (d, 2 Harom, J = 7.9 Hz, Hmeta), 7.69 (d, 2 Harom, J =
7.9 Hz, Hortho), 11.40 (br s, 1 H, NH), 11.68 (br s, 1 H, NH).
+
LRMS (EI): m/z (%) = 314 (M+, 0.1), 199 [C6H4(CO2CH3)SO2 ,
+
+
100], 135 (C6H4CO2CH3 , 41), 120 (C6H4CO2 , 7), 77 (Ph+, 43).
13C NMR (75 MHz, DMSO-d6): = 20.8 (CH3), 125.7 (2 CH),
Anal. Calcd for C11H11N3O4S2: C, 42.16; H, 3.54; N, 13.41; S,
20.46. Found: C, 42.10; H, 3.29; N, 13.43; S, 20.44.
129.1 (2 CH), 141.3 (C).
LRMS (EI): m/z (%) = 253 (M+, 36), 189 (M+ – SO2, 12), 155 (M+
– C2H4N5, 11), 98 (C2H4N5 , 83), 91 (C6H4CH3 , 100).
+
+
Methyl N’-Cyano-N-[(4-methoxyphenyl)sulfonyl]imidothio-
carbamate (5j)
Scale: 26.7 mmol; white solid; mp 135–136 °C; Rf 0.18 (CHCl3–
EtOH, 8:2).
1H NMR (300 MHz, acetone-d6): = 2.75 (s, 3 H, SCH3), 3.94 (s, 3
Anal. Calcd for C9H11N3O2S: C, 42.7; H, 4.4; N, 27.65; S, 12.7.
Found: C, 42.3; H, 4.1; N, 27.5; S, 12.0.
N-(5-Amino-1H-[1,2,4]triazol-3-yl)-4-chlorobenzenesulfon-
amide (1c)
H, OCH3), 7.16 (dt, 2 Harom, J = 9.0, 2.5 Hz, Hmeta), 7.96 (dt, 2 Harom
J = 9.0, 2.5 Hz, Hortho).
,
White solid; mp 311–312 °C (dec.) (Lit.4 mp 299 °C).
1H NMR (300 MHz, DMSO-d6): = 5.87 (br s, 2 H, NH2), 7.57 (d,
2 Harom, J = 8.8, Hmeta), 7.80 (d, 2 Harom, J = 8.8, Hortho), 11.57 (br s,
1 H, NH), 11.78 (br s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): = 127.5 (C), 128.8 (4 CH),
136.0 (C).
13C NMR (75 MHz, acetone-d6): = 16.1 (CH3), 24.9 (C), 57.0
(CH3), 113.5 (C), 115.8 (2 CH), 131.2 (C), 132.6 (2 CH), 166.0
(C).
LRMS (EI): m/z (%) = 285 (M+, 7), 238 (M+ – SCH3, 2), 171
+
+
[C6H4(OCH3)SO2 , 100], 107 (C6H4OCH3 , 67), 77 (Ph+, 52).
LRMS (EI): m/z (%) = 273 (M+, 12), 111 (C6H4Cl+, 36), 98
Anal. Calcd for C10H11N3O3S2: C, 42.09; H, 3.89; N, 14.73; S,
22.47. Found: C, 41.98; H, 3.74; N, 14.82; S, 22.59.
+
(C2H4N5 , 84).
Anal. Calcd for C8H8ClN5O2S: C, 35.1; H, 3.0; N, 25.6; S, 11.7.
Found: C, 35.2; H, 2.8; N, 25.8; S, 11.3.
N-(5-Amino-1H-[1,2,4]triazol-3-yl)arenesulfonamides 1a–h;
General Procedure
N-(5-Amino-1H-[1,2,4]triazol-3-yl)-2-chlorobenzenesulfon-
amide (1d)
A mixture of 5a–j (15.0 mmol), and tert-butyl carbazate (1.98 g,
15.0 mmol) in MeCN (50 mL) was stirred and heated to 60 °C for
16 h. Then the mixture was evaporated to dryness to yield the crude
intermediate 6a–j as a white or pale yellow foam. SO2Cl2 (1.45 mL,
18.0 mmol) was added to a stirred solution of this crude intermedi-
ate in CH2Cl2 (250 mL). The pale yellow precipitate formed after
overnight stirring at r.t. was collected by filtration and washed with
CH2Cl2. The solid residue was suspended in 50% aq EtOH (100
mL) and the mixture was refluxed for 15 min, then allowed to cool
to r.t. The solid was collected by filtration and washed successively
with H2O and a small amount of Et2O. Further drying under vacuum
afforded 1a–h. The yields over 2 steps are listed in Table 2.
White solid, mp 315–316 °C (Lit.3 mp 307–309 °C).
1H NMR (400 MHz, DMSO-d6): = 5.85 (br s, 2 H, NH2), 7.44 (td,
1 Harom, J = 7.6, 1.6 Hz, Hpara), 7.51 (td, 1 Harom, J = 7.6, 1.6 Hz, Hme-
ta), 7.55 (dd, 1 Harom, J = 7.6, 1.6 Hz, Hmeta), 8.02 (dd, 1 Harom, J =
7.6, 1.6 Hz, Hortho), 11.49 (br s, 1 H, NH), 11.92 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): = 127.8 (CH), 129.9 (CH),
131.3 (C), 132.1 (CH), 133.3 (CH), 142.1 (C), 149.3 (C), 150.9 (C).
LRMS (EI): m/z (%) = 273 (M+, 29), 238 (M+ – Cl, 4), 209 (M+ –
SO2, 3), 174 (M+ – C2H4N5, 8), 111 (C6H4Cl+, 32), 98 (C2H4N5 ,
+
100).
Intermediate 6a
White foam; Rf 0.75 (CHCl3–EtOH, 8:2).
1H NMR (400 MHz, CDCl3): = 1.44 (s, 9 H, t-C4H9), 2.31 (s, 3 H,
SCH3), 7.23 (br s, 1 H, NH), 7.44 (m, 2 Harom, Hmeta), 7.50 (m, 1
Harom, Hpara), 7.75 (br s, 1 H, NH), 7.92 (m, 2 Harom, Hortho).
Anal. Calcd for C8H8ClN5O2S: C, 35.1; H, 3.0; N, 25.6; S, 11.7.
Found: C, 35.5; H, 2.7; N, 25.2; S, 11.4.
N-(5-Amino-1H-[1,2,4]triazol-3-yl)-3-chlorobenzenesulfon-
amide (1e)
White solid; mp 306–308 °C.
13C NMR (100 MHz, CDCl3): = 16.1 (CH3), 28.1 (3 CH3), 82.8
(C), 127.1 (2 CH), 128.5 (2 CH), 131.9 (CH), 141.9 (C), 155.2
(C), 158.5 (C), 175.4 (C).
1H NMR (300 MHz, DMSO-d6): = 5.89 (br s, 2 H, NH2), 7.51–
7.62 (m, 2 Harom, Hmeta and Hpara), 7.74 (dt, 1 Harom, J = 7.8, 1.8 Hz,
Hortho), 7.81 (t, 1 H, J = 1.8, Hortho), 11.67 (br s, 2 H, 2 NH).
LRMS (FAB+): m/z = 410 (MNa+), 388 (MH+), 332 (M+ – t-Bu).
13C NMR (75 MHz, DMSO-d6): = 124.3 (CH), 125.3 (CH), 130.9
(2 CH), 131.2 (C), 133.3 (C).
N-(5-Amino-1H-[1,2,4]triazol-3-yl)benzenesulfonamide (1a)
White solid; mp 293–294 °C (dec.) (Lit.4 mp 289 °C); Rf 0.18
(CHCl3–EtOH, 8:2).
LRMS (EI): m/z = 273 (M+, 26), 209 (M+ – SO2, 5), 174 (M+ –
C2H4N5, 3), 111 (C6H4Cl+, 34), 98 (C2H4N5 , 100).
+
Synthesis 2002, No. 2, 185–190 ISSN 0039-7881 © Thieme Stuttgart · New York

190
K. Chibale et al.
PAPER
Anal. Calcd for C8H8ClN5O2S: C, 35.1; H, 3.0; N, 25.6; S, 11.7.
Found: C, 35.3; H, 2.7; N, 25.9; S, 11.5.
H, J = 7.0, CH(CH3)2], 4.38 [br m, 2 H, 2 CH(CH3)2], 5.79 (br s,
2 H, NH2), 7.11 (s, 2 Harom), 11.22 (br s, 1 H, NH), 11.65 (br s, 1 H,
NH).
N-(5-Amino-1H-[1,2,4]triazol-3-yl)-4-bromobenzenesulfon-
amide (1f)
White solid; mp 320–321 °C.
1H NMR (400 MHz, DMSO-d6): = 5.85 (br s, 2 H, NH2), 7.70 (s,
4 Harom), 11.55 (br s, 1 H, NH), 11.82 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): = 24.2 (2 CH3), 25.4
(4 CH3), 29.1 (2 CH), 34.0 (CH), 123.5 (2 CH), 148.7 (C),
151.0 (C).
LRMS (EI): m/z (%) = 365 (M+, 21), 322 (M+ – i-Pr, 5), 301 (M+ –
SO2, 1), 267 (M+ – C2H4N5, 43), 203 (M+ – C2H4N5 – SO2, 14), 98
13C NMR (100 MHz, DMSO-d6): = 125.6 (C), 128.4 (C), 132.5
(C2H4N5 , 12).
+
(4 CH).
LRMS (EI): m/z (%) = 318 (M+, 14), 254 (M+ – SO2, 5), 156
Acknowledgments
(C6H4Br+, 30), 98 (C2H4N5 , 100).
+
We thank GlaxoSmithKline for financial support and access to fa-
cilities at the Medicines Research Centre (Stevenage, UK). Additio-
nal support through the Technology and Human Resources for
Industry Programme (THRIP) of the Department of Trade and In-
dustry (South Africa) is gratefully acknowledged.
Anal. Calcd for C8H8BrN5O2S: C, 30.2; H, 2.5; N, 22.0; S, 10.1.
Found: C, 30.45; H, 2.2; N, 22.3; S, 10.3.
N-(5-Amino-1H-[1,2,4]triazol-3-yl)naphthalene-2-sulfonamide
(1g)
Pale yellow solid; mp 308–309 °C.
1H NMR (300 MHz, DMSO-d6): = 5.86 (br s, 2 H, NH2), 7.58–
7.67 (m, 3 Harom), 7.83 (dd, 1 Harom, J = 8.4, 1.6 Hz), 7.96–8.08 (m,
3 Harom), 8.45 (s, 1 H, H-1), 11.64 (br s, 2 H, 2 NH).
13C NMR (75 MHz, DMSO-d6): = 122.4 (CH), 125.6 (CH), 127.2
(CH), 127.7 (CH), 128.0 (C), 128.7 (CH), 128.9 (CH), 131.7 (C),
133.7 (C).
References
(1) Current address: Charterhouse Therapeutics Ltd.,
Department of Chemistry, Robert Robinson Laboratories,
University of Liverpool, Liverpool L69 7ZD, UK.
(2) (a) Kleschick, W. A.; Costales, M. J.; Vinogradoff, A. P.
Pest. Sci. 1990, 29, 341. (b) Grandoni, J. A.; Marta, P. T.;
Schloss, J. V. J. Antimicrob. Chemother. 1998, 42, 475.
(3) Kleschick, W. A.; Dunbar, J. E.; Snider, S. W.; Vinogradoff,
A. P. J. Org. Chem. 1988, 53, 3120.
LRMS (EI): m/z (%) = 289 (M+, 26), 225 (M+ – SO2, 18), 191 (M+
+
+
– C2H4N5, 6), 127 (C10H7 , 100), 98 (C2H4N5 , 40).
Anal. Calcd for C12H11N5O2S: C, 49.8; H, 3.8; N, 24.2; S, 11.1.
Found: C, 49.5; H, 3.7; N, 24.3; S, 10.5.130
(4) Maybhate, S. P.; Rajamohanan, P. P.; Rajappa, S. Synthesis
1991, 220.
(5) Thaler, W. A.; Medivitt, J. R. J. Org. Chem. 1971, 36, 14.
(6) Lopez, M.; Rodriguez, Z.; Gonzalez, M.; Valdes, B.; Velez,
H.; Fini, A. Farmaco 2000, 55, 40.
(7) Benneche, T.; Undheim, K. Acta Chem. Scand., Ser. B 1983,
B37, 93.
N-(5-Amino-1H-[1,2,4]triazol-3-yl)-2,4,6-triisopropylbenzene-
sulfonamide (1h)
White solid; mp 312–314 °C (dec.) [Lit.3 mp 314 °C (dec.)].
1H NMR (400 MHz, DMSO-d6): = 1.14 [d, 12 H, J = 6.8 Hz,
2
CH(CH3)2], 1.17 [d, 6 H, J = 7.0 Hz, CH(CH3)2], 2.85 [septet, 1
Synthesis 2002, No. 2, 185–190 ISSN 0039-7881 © Thieme Stuttgart · New York