Rapid synthesis of 2-cyanobenzothiazole, isothiocyanate and cyanoformanilide derivatives of dapsone

Article abstract of DOI:10.1039/a908742g

The rapid synthesis of 2-cyanobenzothiazole, isothiocyanate and cyanoformanilide derivatives of dapsone was examined. The derivatives of the leprostatic drug dapsone were prepared by way of imino-1,2,3-dithiazoles obtained by condensation of aromatic prim

Full text of DOI:10.1039/a908742g

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Rapid synthesis of 2-cyanobenzothiazole, isothiocyanate and
cyanoformanilide derivatives of dapsone†
Thierry Besson,a Jérôme Guillarda and Charles W. Reesb
1
a Laboratoire de Génie Protéique et Cellulaire, UPRES 2001, Groupe de Chimie Organique,
Pôle Sciences et Technologie, Université de La Rochelle, Avenue Marillac,
F-17042 La Rochelle cedex 1, France. E-mail: tbesson@bio.univ-lr.fr
b Department of Chemistry, Imperial College of Science, Technology and Medicine,
London, UK SW7 2AY. E-mail: c.rees@ic.ac.uk
Received (in Cambridge, UK) 2nd November 1999, Accepted 8th December 1999
New derivatives of the leprostatic drug dapsone are prepared by way of imino-1,2,3-dithiazoles obtained by
condensation of aromatic primary bisamines, including dapsone, with 4,5-dichloro-1,2,3-dithiazolium chloride
(Appel salt). Reactions, including microwave irradiation, initiated by nucleophilic attack at different sites of the
dithiazole ring transform the bisiminodithiazoles into the symmetrical, and some unsymmetrical, title compounds.
Primary aromatic amines are readily converted into stable
N-arylimino-1,2,3-dithiazoles in high yield.1,2 We have recently
shown that these derivatives are versatile synthetic intermedi-
ates undergoing a variety of reactions initiated by nucleophilic
attack at different sites on the dithiazole ring.3 Some of these
reactions transform the dithiazole ring only, e.g. to give isothio-
cyanates, whilst others involve cyclisation onto an adjacent
aromatic ring. As part of a search for compounds with poten-
tial pharmacological value, it seemed that these transform-
ations might provide a simple way to modify the structure of
the leprostatic drug dapsone4 [bis(4-aminophenyl) sulfone],
and a new synthesis of the corresponding bisisothiocyanate 8,
the anthelmintic drug centsulphone.5 Dapsone remains one of
the main drugs for the treatment of leprosy, although its
action is only bacteriostatic, and it has been used for the
treatment of dermatitis herpetiformis. Isothiocyanates like
centsulphone are also of pharmacological use as irreversible
acylating agents to label proteins and enzymes. Furthermore,
these reactions would illustrate the applicability or otherwise
of Appel salt chemistry to aromatic diamines; we also hoped
to extend our use of a focused microwave oven (open oven,
Scheme 1
monomode system) as an alternative to the direct thermolysis
of dithiazoles.6
Results and discussion
Using a standard method for the preparation of N-arylimino-
1,2,3-dithiazoles, the starting bisamines were condensed
with 4,5-dichloro-1,2,3-dithiazolium chloride 11 (2 equiv.) in
Bis(4-aminophenyl) sulfone (dapsone) derivatives (Scheme 2)
dichloromethane at room temperature, followed by addition
of pyridine, to give the desired imines 2, 3 and 4 in good yields
(58–78%) (Scheme 1). To our initial surprise, we did not isolate,
or detect, any of the monoimines, e.g. 5. With less than 2
equivalents of Appel salt 1 we simply obtained correspondingly
lower yields of the bisimines, 2–4. This is understandable for the
sulfones 2 and 3 where the remaining amino group, e.g. in 5,
is probably more nucleophilic than in the starting bisamines
because of strong electron release from the iminodithiazole
(in its aromatic dipolar form 5) neutralising electron withdrawal
from the sulfone group. The sulfone 2 was also prepared by
oxidation of the sulfide 4 with m-chloroperbenzoic acid
(MCPBA), without oxidation of the dithiazole sulfur atoms.
Thermolysis of the neat sulfone 2 at 200 ЊC gave only the
corresponding bis(cyanoimidoyl chloride) 6. This result accords
with our previous work on the thermolysis of N-arylimino-
1,2,3-dithiazoles; electron-releasing groups on the aryl ring
favoured formation of the benzothiazole ring whilst strongly
electron-withdrawing groups may lead exclusively to the cyano-
imidoyl chloride.7 However the bis(benzothiazolyl) sulfone 7
was rapidly prepared in good yield (70%) by microwave irradi-
ation of the bis(bromoaryliminodithiazole) 38 in pyridine in the
presence of cuprous iodide (CuI) where the aryl ortho positions
are activated towards attack by the dithiazole ring6b (Scheme 2).
Treatment of the bis(imino-1,2,3-dithiazole) 2 with 4 equiv.
of ethylmagnesium bromide in THF afforded the bisisothio-
cyanate 8 (centsulphone5) in 38% yield. We recently reported3a
that various N-aryliminodithiazoles may also be reduced with
† This work is a part of the PhD thesis of J. G. under the supervision of
T. B.
DOI: 10.1039/a908742g
J. Chem. Soc., Perkin Trans. 1, 2000, 563–566
This journal is © The Royal Society of Chemistry 2000
563

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was produced in modest yield (40%) with 2 equiv. of triphenyl-
phosphine.
The results of testing for the biological activity of these com-
pounds will be reported elsewhere.
Experimental
Mps were determined on a Kofler melting point apparatus
and are uncorrected. IR spectra were recorded on a Perkin-
Elmer Paragon 1000PC instrument. 1H (400 MHz) and 13C
NMR (100 MHz) were recorded on a JEOL JNM LA400
spectrometer (Centre Commun d’Analyse, Université de La
Rochelle, France); chemical shifts (δ) are reported in parts per
million (ppm) downfield from tetramethylsilane (TMS), which
was used as internal standard. Mass spectra were recorded on a
Varian MAT311 in the Centre Régional de Mesures Physiques
de L’Ouest (C.R.M.P.O.), Université de Rennes, France. Chrom-
atography was carried out on Merck silica gel 60 (70–230
mesh). TLC was performed on Merck Kieselgel 60 F254 alu-
minium-backed plates. Light petroleum refers to the fraction
with distillation range 40–60 ЊC. Focused microwave irradi-
TM
ations were carried out with a Synthewave S402 Prolabo
microwave reactor (monomode system, 2450 MHz, 300 W)
which has variable-speed rotation, visual control, irradiation
monitored by PC computer, IR measurement and continuous
feedback temperature control (by PC).9 Samples were dried
over MgSO4.
Scheme 2
one equivalent of sodium hydride to give the cyanothioform-
anilides which react further with sodium hydride, with elimin-
ation of cyanide, to give isothiocyanates, and this overall
transformation can be done in one pot. In the present case the
Grignard reagent method gave better results. The sulfone imine
2 was also converted into the corresponding bis(cyano-
thioformanilide) 9 (87%) with four mole equivalents of
triphenylphosphine in dichloromethane at room temperature.
Microwave irradiation of a solution of the bisisothiocyanate 8
in tert-butyl alcohol, in the presence of three mole equivalents
of N,N-dimethylethylenediamine, gave the corresponding
bisthiourea 10 in 98% yield (Scheme 2).
Bis(4-amino-3-bromophenyl) sulfone8
To a solution of bis(4-aminophenyl) sulfone (dapsone) (1.0 g,
4.03 mmol) in acetic acid (20 ml) was added bromine (0.206 ml,
4.03 mmol). The mixture was stirred at room temperature for
40 min then water (20 ml) was added. The white precipitate
obtained was filtered off, washed with water and dried. The
crude product was purified by column chromatography
(dichloromethane–ethyl acetate, 9:1) to give the title compound
(0.142 g, 35%) as colourless needles, mp 192–193 ЊC (from
EtOH) (Found: Mϩ, 403.8822. C12H1079Br2N2O2S requires M,
403.8829); νmax (KBr)/cmϪ1 3364, 1614, 1573, 1557, 1494, 1403,
1320, 1139 and 731; δH (400 MHz; acetone-d6) 5.8 (4H, br s,
NH2), 6.93 (2H, d, J 8.5 Hz, Harom), 7.59 (2H, dd, J1 2.2, J2 8.5
Hz, Harom), 7.88 (2H, d, J 2.1 Hz, Harom); δC (100 MHz; acetone-
d6) 107.4, 115.5, 128.9, 131.7, 132.6, 150.6; m/z 406 (Mϩ, 100%),
404 (Mϩ, 50), 220 (56), 218 (57), 188 (50), 186 (61), 172 (16), 171
(15), 170 (21), 91 (72), 90 (98).
Bis(4-aminophenyl) sulfide derivatives
The bis(iminophenyl) sulfide 4 was similary converted into
products (Chart 1) analogous to those shown in Scheme 2 for
Bis[4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenyl]
sulfone 2
From bis(4-aminophenyl) sulfone (dapsone). 4,5-Dichloro-
1,2,3-dithiazolium chloride 1 (0.416 g, 2 mmol) was added to a
solution of dapsone (0.248 g, 1 mmol) in dichloromethane (10
ml) and the mixture was stirred at room temperature until the
amine was consumed (TLC). Then pyridine (0.324 ml, 4 mmol)
was added and the mixture was stirred for a further 1 h, filtered
and the crude product obtained by evaporation of the solution
was purified by column chromatography (dichloromethane)
to give the title compound 2 (0.405 g, 78%) as yellow needles,
mp 209 ЊC (from light petroleum) (Found: Mϩ, 517.8615.
C16H835Cl2N4O2S5 requires M, 517.8628); νmax (KBr)/cmϪ1 3054,
1570, 1499, 1483, 1399, 1318, 1288, 1221, 1151, 1103 and 867;
δH (400 MHz; CDCl3) 7.29 (4H, d, J 7.9 Hz, Harom), 8.04 (4H, d,
J 8.4 Hz, Harom); δC (100 MHz; CDCl3) 120.1, 129.9, 138.6,
147.8, 155.5, 160.9; m/z 520 (Mϩ, 5%), 518 (Mϩ, 5), 456
(Mϩ Ϫ [S2], 35), 454 (Mϩ Ϫ [S2], 4), 427 (Mϩ Ϫ [Cl,CN,S], 2),
425 (Mϩ Ϫ [Cl,CN,S], 5), 392 (Mϩ Ϫ [Cl2,CN,S], 38), 390
(Mϩ Ϫ [Cl2,CN,S], 6), 64 ([S2], 100).
Chart 1
the sulfone 2, though some of these reactions also gave the
unsymmetrical products of reaction at only one dithiazole ring.
Microwave irradiation of 4 gave the bisbenzothiazole 11 (66%).
Ethylmagnesium bromide (2 equiv.) in THF gave the bisisothio-
cyanate 12 but in very poor yield (11%), together with the
monoisothiocyanate 13 (17%); the yield of the bisisothio-
cyanate 12 was not improved with 4 or 6 equiv. of the Grignard
reagent. Triphenylphosphine (4 equiv.) gave the biscyanothio-
formanilide 14 (60%), and the monocyanothioformanilide 15
From
bis[4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-
phenyl] sulfide 4. To a cooled (0 ЊC) solution of the bisimino-
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dithiazole 4 (0.2 g, 0.41 mmol) in dichloromethane (10 ml) was
added MCPBA (0.282 g, 0.82 mmol). The mixture was stirred
at 0 ЊC for 1 h. Purification by column chromatography with
dichloromethane as eluent afforded the title compound (0.129
g, 61%), identical with that described above.
250–252 ЊC (from PriOH) (Found: Mϩ, 381.9664. C16H6N4O2S3
requires M, 381.9653); νmax (KBr)/cmϪ1 3065, 2236 (CN), 1789,
1587, 1471, 1400, 1321, 1275, 1162, 1134, 1108, 886, 824, 774
and 618; δH (400 MHz; CDCl3) 8.18 (2H, dd, J1 1.8, J2 8.7 Hz,
Harom), 8.36 (2H, d, J 8.8 Hz, Harom), 8.74 (2H, d, J 1.7 Hz,
Harom); δC (100 MHz; CDCl3) 112.6, 122.9, 126.7, 126.7, 135.9,
140.9, 141.2, 154.8; m/z 382 (Mϩ, 40%), 207 (100), 176 (8), 159
(27), 107 (20).
Bis[3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-
phenyl] sulfone 3
A solution of the bis(3-bromo-4-aminophenyl) sulfone (0.519
g, 1 mmol) and pyridine (0.324 ml, 4 mmol) in dichloromethane
(20 ml) was stirred at 0 ЊC for 15 min. 4,5-Dichloro-1,2,3-
dithiazolium chloride 1 (0.416 g, 4 mmol) was added and the
mixture was stirred for a further 4 h. The crude product was
purified by column chromatography (light petroleum–dichloro-
methane, 3:7) to give the title compound (0.413 g, 61%) as
yellow needles, mp 196–198 ЊC (from PriOH) (Found: Mϩ,
674.6901. C16H679Br235Cl2N4O2S5 requires M, 674.6916); νmax
(KBr)/cmϪ1 3075, 1610, 1574, 1463, 1379, 1318, 1232, 1161, 866
and 739; δH (400 MHz; CDCl3) 7.22 (2H, d, J 8.4 Hz, Harom),
7.96 (2H, dd, J1 2.1, J2 8.3 Hz, Harom), 8.26 (2H, d, J 2 Hz,
Harom); δC (100 MHz; CDCl3) 116.1, 119.3, 128.8, 133.4, 139.0,
147.4, 154.6, 162.40; m/z 678 ([M ϩ H]ϩ, 90%), 676 ([M ϩ H]ϩ,
100), 613 (20), 410 (72), 289 (26), 136 (64).
Bis(4-isothiocyanatophenyl) sulfone 8 (centsulfone)
Under an argon atmosphere, commercial ethylmagnesium
bromide (4 mmol; 1 M in THF) was added dropwise to a solu-
tion of the bisimine 2 (0.519 g, 1 mmol) in THF. The brown
mixture obtained was heated at reflux until the starting material
was consumed (3 h; TLC). After addition of dichloromethane
(20 ml), the solution was washed with water and the organic
layer dried over sodium sulfate. The crude product obtained
was purified by column chromatography (light petroleum–
dichloromethane, 6:4) to give product 8 (0.126 g, 38%) as
colourless needles, mp 181 ЊC (from hexane) (lit.,5 180 ЊC)
(Found: Mϩ, 331.9743. C18H8N2O2S3 requires M, 331.9748);
νmax (KBr)/cmϪ1 3094, 3035, 2121 (NCS), 1585, 1488, 1406,
1319, 1287, 1152, 1069, 933 and 836; δH (400 MHz; CDCl3) 7.32
(4H, d, J 8.3 Hz, Harom), 7.91 (4H, d, J 8.8 Hz, Harom); δC (100
MHz; CDCl3) 126.6, 129.3, 136.8, 139.3, 139.7; m/z 332 (Mϩ,
100%), 182 (86), 150 (41), 134 (40).
Bis[4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenyl]
sulfide 4
4,5-Dichloro-1,2,3-dithiazolium chloride 1 (0.416 g, 2 mmol)
was added to a solution of bis(4-aminophenyl) sulfide (0.216 g,
1 mmol) in dichloromethane (10 ml) and the mixture was
stirred at room temperature until the amine was consumed
(TLC). Then pyridine (0.324 ml, 4 mmol) was added and the
mixture was stirred for a further 1 h, filtered and the crude
product obtained by evaporation of the solution was purified
by column chromatography (light petroleum–dichloromethane,
1:1) to give the title compound (0.283 g, 58%) as orange needles,
mp 138–140 ЊC (from hexane) (Found: Mϩ, 485.8748.
C16H835Cl2N4S5 requires M, 485.8729); νmax (KBr)/cmϪ1 3047,
1892, 1697, 1588, 1566, 1543, 1480, 1396, 1226, 1135, 858 and
775; δH (400 MHz; CDCl3) 7.22 (4H, d, J 8.8 Hz, Harom), 7.44
(4H, d, J 8.8 Hz, Harom); δC (100 MHz; CDCl3) 120.7, 132.3,
133.7, 148.2, 149.7, 158.3; m/z 488 (Mϩ, 3%), 486 (Mϩ, 3), 360
(Mϩ Ϫ [2 × S2], 11), 358 (Mϩ Ϫ [2 × S2], 15), 258 (10), 256 (35),
160 (37), 128 (36), 96 (25), 64 (S2, 100).
Bis[4-(cyanothioformamido)phenyl] sulfone 9
Stirring of the bisimine 2 (0.519 g, 1 mmol) with triphenyl-
phosphine (1.072 g, 4 mmol) in dichloromethane (10 ml) at
room temperature for 3 h, followed by column chromatography
(dichloromethane–ethyl acetate, 1:1), gave the title compound
9 (0.336 g, 87%) as orange needles, mp 106 ЊC (from EtOH);
νmax (KBr)/cmϪ1 3262, 3064, 2235, 1592, 1493, 1376, 1299, 1154,
1106, 839 and 725; δH (400 MHz; DMSO-d6) 8.06 (4H, d, J 8.9
Hz, Harom), 8.11 (4H, d, J 8.4 Hz, Harom), 13.72 (2H, br s,
NH-CSCN); δC (100 MHz; CDCl3) 113.7, 123.3, 128.7, 138.7,
142.1, 162.6; m/z 386 (Mϩ, not detected), 332 (Mϩ Ϫ 2[HCN],
52%), 277 (100), 199 (37), 182 (34).
Bis(4-{N3-[2-(dimethylamino)ethyl]thioureido}phenyl) sulfone
10
A stirred mixture of bis(4-isothiocyanatophenyl) sulfone 8
(0.332 g, 1 mmol) and N,N-dimethylethylenediamine (0.264 g,
3 mmol) in tert-butyl alcohol (2 ml) was placed in a microwave
reactor in an open flask. The solution was irradiated (with
a delay of 10–15 s to obtain the reflux) for 5 min. The hot
solution obtained was filtered, the solvent evaporated off, and
the crude product purified by column chromatography (ethyl
acetate–dichloromethane, 1:1) to give the title compound 10
(0.452 g, 89%) as colourless needles, mp 198–200 ЊC (from
PriOH) (Found: MHϩ, 509.1820. C22H32N6O2S3 requires MH,
509.1827); νmax (KBr)/cmϪ1 2950, 2774, 1625, 1593, 1537, 1494,
1317, 1156, 1105, 1045, 944, 842 and 742; δH (400 MHz;
DMSO-d6) 1.02 (3H, s, CH3), 1.03 (3H, s, CH3), 2.41 [2H, t, J 6
Hz, NH2CH2CH2N(CH3)2], 3.53 [2H, m, NH2CH2CH2-
N(CH3)2], 7.76–7.83 (4H, m, Harom), 7.97 (1H, br s, NHCS),
10.1 (1H, br s, NHCS); δC (100 MHz; DMSO-d6) 41.7, 44.95
(2 × Me), 56.9, 121.1, 127.9, 135.0, 144.4, 179.8; m/z 509
([M ϩ H]ϩ, 100%), 421 ([M ϩ H]ϩ Ϫ [NH2CH2CH2N(CH3)2],
36), 376 (47), 289 (15).
Bis{4-N-[chloro(cyano)methyleneamino]phenyl} sulfone 6
The bisiminodithiazole 2 (0.10 g, 1.9 mmol) was heated under
nitrogen at 200 ЊC for 6 min (graphite-bath). Purification by
column chromatography with dichloromethane as eluent
afforded the title compound 6 (0.0185 g, 25%) as colourless
needles, mp 122–124 ЊC (from PriOH) (Found: Mϩ, 389.9756.
C16H835Cl2N4O2S requires M, 389.9745); νmax (KBr)/cmϪ1 3095,
2241, 1652, 1646, 1587, 1485, 1404, 1321, 1288, 1154, 1103,
1048 and 843; δH (400 MHz; CDCl3) 7.17 (4H, d, J 8.6 Hz,
Harom), 8.05 (4H, d, J 8.7 Hz, Harom); δC (100 MHz; CDCl3)
111.6, 118.4, 121.3, 129.3, 140.2, 147.7; m/z 392 (Mϩ, 25%), 390
(Mϩ, 35), 357 (Mϩ Ϫ [Cl2], 5), 355 (Mϩ Ϫ [Cl2], 12), 213 (39),
211 (100), 181 (13), 179 (53).
Bis(2-cyanobenzothiazol-6-yl) sulfone 7
A stirred mixture of bis-1,2,3-dithiazole 3 (0.677 g, 1 mmol)
and cuprous iodide (0.209 g, 1.1 mmol) in pyridine was placed
in a microwave reactor (Synthewave 402) in an open flask. The
solution was irradiated (with a delay of 10–15 s to obtain the
temperature desired) at 90 ЊC for 20 min. After cooling of the
mixture dichloromethane (10 ml) was added and the organic
layer was washed twice with aq. sodium thiosulfate (20%). The
crude product was purified by column chromatography to give
the title compound 7 (0.271 g, 70%) as colourless needles, mp
Bis(2-cyanobenzothiazol-6-yl) sulfide 11
A solution of the bisimine 4 (0.1 g, 0.2 mmol) in toluene (1 ml)
was placed in a microwave oven in a glass 10 ml vial with a
screw-cap lid. The irradiation was programmed for 7 min with a
delay of 5 s to obtain 100% power output (300 W). The tem-
perature (IR measurement) was constant over a period of 30 s
J. Chem. Soc., Perkin Trans. 1, 2000, 563–566
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to 2 min followed by a sharp increase in temperature, over a
period of 1 min, which appeared to reach a plateau (80 ЊC) for
1 min. Thereafter the temperature increased over a period of
3 min to 140 ЊC. After cooling, the brown reaction mixture (oil)
was purified by column chromatography (light petroleum–ethyl
acetate, 9:1) to give the title compound 11 (0.25 g, 66%) as
yellow needles, mp 250–252 ЊC (from light petroleum) (Found:
Mϩ, 349.9760. C16H6N4S3 requires M, 349.9755); νmax (KBr)/
cmϪ1 2228 (CN), 1582, 1538, 1463, 1397, 1144, 1087 and 810;
δH (400 MHz; CDCl3) 7.62 (2H, dd, J1 1.9, J2 9 Hz, Harom), 7.94
(2H, d, J 2 Hz, Harom), 8.18 (2H, d, J 8.8 Hz, Harom); δC (100
MHz; CDCl3) 112.7, 123.6, 126.0, 130.9, 136.6, 136.7, 137.1,
151.6; m/z 350 (Mϩ, 100%), 266 (5), 253 (5), 191 (3), 175 (3), 139
(7), 127 (5), 107 (6).
354 (Mϩ, not detected), 327 (Mϩ Ϫ [HCN], 8%), 300 (Mϩ Ϫ
2[HCN], 63), 184 (Mϩ Ϫ 2[NHCSCN], 14), 27 (100).
4-(4-Chloro-5H-1,2,3-dithiazol-5-ylideneamino)phenyl
4-(cyanothioformamido)phenyl sulfide 15
The bisimine 4 (0.350 g, 0.72 mmol) and triphenylphosphine
(0.377 g, 1.44 mmol) were stirred in dichloromethane (10 ml)
at room temperature for 10 h. Purification by column chrom-
atography (dichloromethane) gave the title compound 15 (0.053
g, 40%) as orange needles, mp 138–140 ЊC (from CH2Cl2); νmax
(KBr)/cmϪ1 3266, 2230 (CN), 1589, 1488, 1372, 1222, 1083,
1010, 862 and 826; δH (400 MHz; DMSO-d6 ϩ D2O) 7.26 (2H,
d, J 8.4 Hz, Harom), 7.39 (2H, d, J 8.4 Hz, Harom), 7.48 (2H, d,
J 8.4 Hz, Harom), 7.92 (2H, d, J 8.4 Hz, Harom); δC (100 MHz;
DMSO-d6) 113.7 (CN), 120.9, 123.4, 130.3, 130.8, 133.2, 134.8,
136.7, 146.9, 150.5, 159.9, 160.9; m/z 420 (Mϩ, not detected),
300 (Mϩ Ϫ [HCN, ClCNS], 44%), 192 (21), 184 (11), 167 (27),
76 (100).
Bis(4-isothiocyanatophenyl) sulfide 12 and 4-(4-chloro-5H-
1,2,3-dithiazol-5-ylideneamino)phenyl] 4-isothiocyanatophenyl
sulfide 13
Under an argon atmosphere, a solution of ethylmagnesium
bromide (0.82 mmol; 1 M in THF) was added dropwise to a
solution of the bisimine 4 (0.2 g, 0.41 mmol) in THF (20 ml).
The brown mixture obtained was heated at 50 ЊC for about 2 h.
After addition of dichloromethane (20 ml), the solution was
washed with water, the organic layer dried over sodium sulfate
and the solvent evaporated off. The crude product was purified
by column chromatography (light petroleum–dichloromethane,
7:3) to give the title compound 12 (0.007 g, 11%) as colourless
needles, mp 120–122 ЊC (from light petroleum) (Found: Mϩ,
299.9842. C14H8N2S3 requires M, 299.9849); νmax (KBr)/cmϪ1
2100 (NCS), 1584, 1486, 1380, 1221, 1016 and 870; δH (400
MHz; CDCl3) 7.16 (4H, d, J 8.6 Hz, Harom), 7.28 (4H, d, J 8.3
Hz, Harom); δC (100 MHz; CDCl3) 126.6, 130.6, 132.1, 134.5,
136.7; m/z 300 (Mϩ, 100%), 268 (18), 242 (Mϩ Ϫ [NCS], 5), 209
(8), 184 (38), 166 (15), 108 (28).
Acknowledgements
We thank the Communauté de Villes de l’Agglomération de La
Rochelle (J. G. PhD grant) and the Prolabo company for
financial support, and the Wolfson Foundation for establishing
the Wolfson Centre for Organic Chemistry in Medical Science
at Imperial College. We also thank Axelle Grélard-Michon,
Centre Commun d’Analyse (NMR), Université de La Rochelle,
for helpful technical assistance.
References and notes
1 R. Appel, H. Janssen, M. Siray and F. Knoch, Chem. Ber., 1985, 118,
1632. The salt 1 is a greenish solid, insoluble in organic solvents. It is
completely stable in a dry inert atmosphere but reacts slowly with
moisture to form 4-chloro-1,2,3-dithiazol-5-one.
Further elution (light petroleum–dichloromethane, 1:1)
gave the title compound 13 (0.014 g, 17%) as red needles, mp
150–152 ЊC (from light petroleum) (Found: Mϩ, 392.9288.
C15H835ClN3S4 requires M, 392.9289); νmax (KBr)/cmϪ1 2088
(NCS), 1583, 1483, 1398, 1222, 1082, 1010, 928, 863 and 822;
δH (400 MHz; CDCl3) 7.16 (2H, d, J 8.8 Hz, Harom), 7.22 (2H, d,
J 8.8 Hz, Harom), 7.27 (2H, d, J 8.4 Hz, Harom), 7.45 (2H, d, J 8.8
Hz, Harom); δC (100 MHz; CDCl3) 120.8, 126.5, 130.0, 131.2,
132.4, 133.3, 135.8, 137.2, 148.1, 150.3, 159.1; m/z 395 (Mϩ,
26%), 355 (53), 300 (87), 294 (13), 284 (17), 269 (30), 243 (22),
184 (100), 166 (48).
2 C. W. Rees, J. Heterocycl. Chem., 1992, 29, 639.
3 (a) T. Besson, J. Guillard, C. W. Rees and V. Thiéry, J. Chem. Soc.,
Perkin Trans. 1, 1998, 889; (b) T. Besson, G. Guillaumet, C. Lamazzi
and C. W. Rees, Synlett, 1997, 704; (c) O. A. Rakitin, C. W. Rees and
O. G. Vlasova, Tetrahedron Lett., 1996, 37, 4589.
4 T. Ogino, K. Tsuji, T. Tojo, N. Igari, N. Seki, Y. Sudo, T. Manda,
F. Nishigaki and M. Matsuo, Bioorg. Med. Chem. Lett., 1998, 8, 75;
Merck Index, 1996, 12, 478; Dictionary of Drugs, eds. J. Elks and
C. R. Ganellin, Chapman and Hall, London, 1990, p. 370.
5 Dictionary of Drugs, eds. J. Elks and C. R. Ganellin, Chapman and
Hall, London, 1990, p. 1131.
6 (a) T. Besson, M.-J. Dozias, J. Guillard, P. Jacquault, M. D. Legoy
and C. W. Rees, Tetrahedron, 1998, 54, 6475; (b) T. Besson, M.-J.
Dozias, J. Guillard and C. W. Rees, J. Chem. Soc., Perkin Trans. 1,
1998, 3925; (c) V. Bénéteau, T. Besson and C. W. Rees, Synth.
Commun., 1997, 27, 2275.
Bis[4-(cyanothioformamido)phenyl] sulfide 14
The bisimine 4 (0.488 g, 1 mmol) and triphenylphosphine
(1.072 g, 4 mmol) were stirred in dichloromethane (10 ml) at
room temperature for 6 h. Purification by column chromato-
graphy (light petroleum–dichloromethane, 7:3) gave the title
compound 14 (0.213 g, 60%) as red needles, mp 208–210 ЊC
(from MeOH) (Found: (M Ϫ HCN)ϩ, 326.9964. C15H9N3S3
requires M, 326.9958); νmax (KBr)/cmϪ1 3260, 3103, 2232,
1706, 1654, 1590, 1534, 1490, 1388, 1085, 1009 and 825; δH (400
MHz; DMSO-d6) 7.4–7.51 (4H, m, Harom), 7.94 (4H, dd, J1 2.5,
J2 8.8 Hz, Harom), 13.5 (2H, br s, NH-CS); δC (100 MHz;
DMSO-d6) 113.8, 123.5, 131.2, 133.6, 137.1, 161.1; m/z
7 R. F. English, O. A. Rakitin, C. W. Rees and O. G. Vlasova, J. Chem.
Soc., Perkin Trans. 1, 1997, 201; (b) T. Besson and C. W. Rees,
J. Chem. Soc., Perkin Trans. 1, 1995, 1659.
8 Bromination of the starting amine (dapsone) always afforded a
mixture of polybrominated compounds from which the bis-ortho-
bromo derivative was isolated in about 35% yield.
9 R. Commarmot, R. Didenot and J. F. Gardais, Brevet Fr. Pat., 2 560
529, 1985 (to Rhône-Poulenc/Prolabo) (Chem. Abstr., 1986, 105,
17442); P. Jacquault (Prolabo company) Eur. Pat., 545 995 AI (21–12–
92), 1992.
Paper a908742g
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J. Chem. Soc., Perkin Trans. 1, 2000, 563–566