A clay-mediated, regioselective synthesis of 2-(aryl/alkyl)amino- thiazolo[4,5-c]carbazoles

Article abstract of DOI:10.1016/j.tetlet.2004.04.129

The 3-aminocarbazoles 1a-e were condensed with phenyl and benzyl isothiocyanates on montmorillonite K10 clay or TLC-grade silica gel at room temperature to furnish efficiently the N-phenyl and N- benzylthioureidocarbazoles, 2a-e and 2f, respectively, within minutes. When adsorbed on montmorillonite K10 clay impregnated with para-toluene sulfonic acid (1:1, w/w) and heated at 60-70°C, 2a-e and 2f furnished the 2-anilino and 2-benzylaminothiazolo[4,5-c]carbazoles, 3a-e and 3f, respectively, regioselectively in high yields. The cyclisation was also effective for the N-methylthioureidocarbazoles 2g-i.

Full text of DOI:10.1016/j.tetlet.2004.04.129

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4955–4957
A clay-mediated, regioselective synthesis of 2-(aryl/alkyl)amino-
thiazolo[4,5-c]carbazoles
Manas Chakrabarty,a,* Nandita Ghosha and Yoshihiro Harigayab
aDepartment of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700009, India
bSchool of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108, Japan
Received 30 September 2003; revised 5 April 2004; accepted 16 April 2004
Available online 13 May 2004
Abstract—The 3-aminocarbazoles 1a–e were condensed with phenyl and benzyl isothiocyanates on montmorillonite K10 clay or
TLC-grade silica gel at room temperature to furnish efficiently the N-phenyl and N-benzylthioureidocarbazoles, 2a–e and 2f,
respectively, within minutes. When adsorbed on montmorillonite K10 clay impregnated with para-toluene sulfonic acid (1:1, w/w)
and heated at 60–70 °C, 2a–e and 2f furnished the 2-anilino and 2-benzylaminothiazolo[4,5-c]carbazoles, 3a–e and 3f, respectively,
regioselectively in high yields. The cyclisation was also effective for the N-methylthioureidocarbazoles 2g–i.
Ó 2004 Elsevier Ltd. All rights reserved.
The thiazole ring embodied in many recently synthesised
thiazolyl compounds and condensed thiazoles with
proven and potential bioactivities is an important
pharmacophore. Some notable condensed thiazoles are
the antitumour 2-(4-aminophenyl)benzothiazoles,1
prepared by carrying out the reactions in solution phase,
and more importantly, both angular [4,5-c]-TCs and
linear [5,4-b]-TCs were formed. Moreover, both 9-bromo
angular TCs and 6-bromo linear TCs were additionally
formed in our method. This complete lack of
regioselectivity in the three extant routes to the TCs and
the growing recognition of the environment-friendliness
of clay-mediated reagents in organic synthesis18
prompted us to develop a regioselective, two-step
synthesis of 2-anilino/benzylamino[4,5-c]-TCs from 3-
aminocarbazoles, which is presented in this communi-
cation. In both steps, we used montmorillonite K10
clay19 as a crucial agent.
thiazolo[5,4-a]acridines,2;3
2-cyanobenzothiazoles,4;5
thiazolo[5,4-b]quinolines,6 imidazo[2,1-b]thiazoles,7 2-
cyanothiazolobenzodioxins8 and thiazolo[5,4-f]quina-
zolines.9 In continuation of our recent efforts on the use
of silica gel10 and montmorillonite K10 clay11–13 in the
study of reactions of indoles and carbazoles, we became
interested in developing a new synthesis of thiazolocar-
bazoles (TCs), which have been synthesised to date by
three different routes.14–17
When a mixture of each of the 3-aminocarbazoles
1a–e20;21 and a stoichiometric equivalent of phenyl iso-
thiocyanate was adsorbed on montmorillonite K10 clay
at room temperature, the reaction was complete within
5 min in each case. Leaching of the clay with a suitable
solvent furnished the corresponding 3-(N-phenyl)thio-
ureidocarbazoles 2a–e as the sole products in excellent
yields. When montmorillonite K10 clay was replaced by
TLC-grade silica gel, the same products were obtained
in practically the same yields but required slightly longer
periods, 10–15 min, perhaps because of the lower surface
area and lower acidity of silica gel.19 The diagnostic
appearance of a 13C NMR signal at around d 180
(NHCSNH) and the appearance of peaks corresponding
to the loss of 34 m.u. (H2S), 93 m.u. (PhNH2),
135 m.u. (PhNCS) and 151 m.u. (NHCSNHPh) from the
In the first route, 2-methyl-TCs were prepared by the
Fischer indolisation of the phenylhydrazones of tetra-
hydrobenzo[d]thiazol-5/6-ones.14 In the second route,
cytotoxic 2-cyano-TCs were synthesised by thermolysis
of
5-(N-carbazolylimino)-4-chloro-5H-1,2,3-dithiaz-
oles.15;16 In the third route, developed by us, 2-methyl-
amino-TCs were prepared by cyclisation of 3-(N-
methyl)thioureidocarbazoles by bromine in acetic acid.17
In all three routes, both TCs and their precursors were
Keywords: Thiazolo[4,5-c]carbazoles; Regioselective synthesis; Clay-
mediated.
* Corresponding author. Tel.: +91-33-350-2402; fax: +91-33-2350-67-
90; e-mail: chakmanas@yahoo.co.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.129

4956
M. Chakrabarty et al. / Tetrahedron Letters 45 (2004) 4955–4957
molecular-ion peaks in the mass spectra of 2a–e in
addition to the 1H NMR signals expected of a 3-
substituted carbazolyl group fully supported the struc-
tures of the thioureidocarbazoles 2a–e.
the angular TC 3e was clearly the only possibility.
Noticeably, the chemical shift of C-2 (d 159–160)
appeared to be typical of the 2-anilino angular TCs 3a–e.
This two-step clay-mediated protocol also proved to be
equally effective for a similar regioselective synthesis of
the 2-benzylamino[4,5-c]-TC 3f from 1a via the corres-
ponding thioureidocarbazole 2f, prepared from 1a by
condensation with benzyl isothiocyanate.
When each of 2a–e and 1.2 equivalent of para-toluene
sulfonic acid (TsOH) were adsorbed on montmorillonite
K10 clay and the resulting reactants-on-clay heated at
60–70 °C in an oven, compounds 2a–e were consumed
within 5–7 h. A simple work-up (vide experimental)
furnished the 2-anilinothiazolo[4,5-c]carbazoles 3a–e,
that is, only the angular TCs as the sole products in very
good yields (Scheme 1, Table 1).
This success prompted us to try this methodology for a
similar regioselective synthesis of angular 2-methyl-
amino-TCs 3g–i via 2g–i. However, the condensation of
1a–c with an equivalent amount of methyl isothiocya-
nate failed to furnish any isolable products both on
silica gel and on montmorillonite K10 clay. However,
when 2g–i, prepared by our earlier solution-phase
method,14 were separately adsorbed on montmorillonite
K10 clay-TsOH (1:1.2) and heated at 60–70 °C as be-
fore, 2-methylaminothiazolo[4,5-c]carbazoles 3g–i17
were formed as the only products in moderate yields in
comparable time periods (Scheme 1, Table 1).
Compared to 2a–e, each of the TCs 3a–e lacked two 1H
NMR signals (one NH and H-4) and two 13C NMR
signals (ꢀ d 180: NHCSNH and ꢀ d 117: CH-4) but
exhibited, instead, two 13C NMR signals (ꢀ d 160: C-2
and ꢀ d 122: C-10c), which constituted evidence in
support of cyclisation. The appearance of two one-
proton doublets (H-4,5) with ortho-couplings (J 8/
1
8.5 Hz) at d 7.62–7.66 in the H NMR spectra of 3a–d
consolidated their angular structures, since each of the
corresponding protons (H-4,10) in the alternative linear
[5,4-b]-TCs would have appeared as a one-proton singlet.
From the 2-methyl derivative 2e, the formation of
In order to check the recyclability of montmorillonite
K10 clay, the clay used in the conversion of 1c to 2c and
left after leaching out of the products, was thoroughly
washed with tetrahydrofuran, dried at 110–120 °C for
8 h and, after impregnation with TsOH used for the
cyclisation of 2b in the usual manner. The expected
angular TC 3b was obtained in 65% yield in the same
time period (5 h) required when fresh clay was used.
Montmorillonite K10 clay thus appeared to be reusable
with the same degree of success at least for a second
cycle.
H
5
4
1
5
4
N
S
NH
R'
2
(i)
NHR"
R'
86-93%
N
R
N
R
8
8
1
2a-f
1a-e (1.2 mM)
(ii)
67-73%
10
NHR"
S
H
N
5
4
1
S
N
To the best of our knowledge, the present method is the
first regioselective synthesis of 2-(aryl/alkyl)amino-
thiazolo[4,5-c]carbazoles. We are now working on the
synthesis of another class of condensed thiazoles using
the present methodology.
(ii)
NHCH
3
38-45%
N
R
R'
N
R
4 R'
5
8
7
2g-i
3a-i
For 1-3, R=H (a, e-g), Me (b, h), Et (c, i), n-Pr (d)
R'=H (a-d, f-i), Me (e)
R"=Ph (a-e), PhCH (f), Me (g-i)
2
Acknowledgements
Scheme 1. Reagents and conditions: (i) PhNCS/PhCH2NCS (1 mM),
montmorillonite K10 clay (2 g), rt, <5 min or silica gel (2 g), rt, 10–
15 min; (ii) TsOH (1.2 equiv), montmorillonite K10 clay (2 g), 60–
70 °C, 5–7 h.
The authors sincerely thank the Director, Bose Institute
for laboratory facilities, the CSIR, Govt. of India for
Table 1. Regioselective synthesis of 2-substituted [4,5-c]-TCs 3a–i
Entry 3-NH2-carbazoles (1 mM)
R00NCS (1.2 mM) Thioureidocarbazolesa Yieldsb (%) 2-Substd. TCsc
Time (h)
Yieldsb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1a
––
––
––
PhNCS
PhNCS
PhNCS
PhNCS
PhNCS
BnNCS
––
2a
2b
90
93
90
86
91
92
––
––
––
3a
3b
3c23
3d
3e
3f
7
5
6
5
6
6
6
5
5
73
67
69
70
73
67
41
38
45
2c22
2d
2e
2fd
2g17
2h17
2i17
3g
3h
3i
––
––
a 1a–e and R00NCS adsorbed on montmorillonite K10 clay (2 g) and kept at room temperature for <5 min.
b Refer to yields of isolated pure products.
c From 2a–i (1 mM) with TsOH (1.2 mM) on montmorillonite K10 clay (2 g) at 60–70 °C.
d Using PhCH2NCS (1.2 mM).

M. Chakrabarty et al. / Tetrahedron Letters 45 (2004) 4955–4957
4957
22. Preparation of 2a–f. General procedure: A solution of
1a–e (1 mM) in CH2Cl2 (2 mL) was mixed with a solution
of PhNCS/PhCH2NCS (1.2 mM) in MeOH (0.2 mL), the
resulting clear solution adsorbed on montmorillonite K10
clay (2 g) and the solvent allowed to evaporate off inside a
fume-hood at room temperature. The reactants were
consumed (TLC) within 5 min. The clay was then leached
with CH2Cl2 (3 ꢁ5 mL) and the solvent removed from the
extract to furnish a residue, which was crystallised from
petroleum ether (bp 60–80 °C)–CH2Cl2. All new com-
pounds were identified by IR, 1H (500 MHz) and 13C
(125 MHz) NMR, DEPT 135, EI-MS and elemental
analysis or HR EI-MS. Data of a representative member
2c: mp 114–116 °C; IR (Nujol): 3339, 3174, 1597, 1554,
738 cmꢂ1; MS: m=z 345 (Mþ), 311, 252, 210 (100%), 194;
1H NMR (CDCl3): d 1.43 (3H, t, J ¼ 7:0 Hz), 4.35 (2H, q,
J ¼ 7:0 Hz), 7.22 (1H, t, J ¼ 9:0 Hz), 7.24 (1H, t,
J ¼ 7:5 Hz), 7.36 (1H, d, J ¼ 7:5 Hz), 7.37 (1H, d,
J ¼ 8:0 Hz), 7.39–7.46 (5H, m), 7.49 (1H, t, J ¼ 7:5 Hz),
7.81 (1H, br s), 8.03 (1H, s), 8.05 (1H, d, J ¼ 8:0 Hz), 8.16
(1H, br s); 13C NMR: d 14.2 (CH3), 38.1 (CH2), 109.2,
109.8, 119.1, 119.8, 121.1 (2ꢁ), 124.8, 125.5 (2ꢁ), 125.6,
126.9, 127.0 (all Ar–CH), 122.7, 124.0, 129.6, 129.9, 139.3,
140.9, 181.1 (all Ar–C). Anal. Calcd for C21 H19N3S: C,
73.04; H, 5.51; N, 12.17. Found: C, 73.26; H, 5.54; N,
12.13.
providing a fellowship (N.G.), Mr. B. Majumder, NMR
Lab., Mr. J. Chatterjee, R.S.I.C. and Mr. P. Dey,
Microanalytical Lab., all of B.I., for recording the
spectra.
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23. Cyclisation of 2a–i. General Procedure: A solution of 2a–i
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J ¼ 7:25 Hz), 7.36 (2H, t, J ¼ 7:5 Hz), 7.49 (1H, t,
J ¼ 7:5 Hz), 7.62 (1H, d, J ¼ 8:5 Hz), 7.66 (1H, d,
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