An expedient, regioselective synthesis of 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]indoles

Article abstract of DOI:10.1016/j.tetlet.2005.02.125

1-Benzenesulfonyl-5-aminoindole 5, prepared from 5-nitroindole 3, was condensed with alkyl isothiocyanates and separately with carbon disulfide and alkyl bromides/iodides to furnish efficiently the corresponding N-alkyl-thioureidoindoles 6a-c and the alky

Full text of DOI:10.1016/j.tetlet.2005.02.125

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2865–2868
An expedient, regioselective synthesis of 2-alkylamino- and
2-alkylthiothiazolo[5,4-e]indoles
Manas Chakrabarty,a,* Taraknath Kundu,a Shiho Arimab 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 22 December 2004; revised 17 February 2005; accepted 21 February 2005
Abstract—1-Benzenesulfonyl-5-aminoindole 5, prepared from 5-nitroindole 3, was condensed with alkyl isothiocyanates and sepa-
rately with carbon disulfide and alkyl bromides/iodides to furnish efficiently the corresponding N-alkyl-thioureidoindoles 6a–c and
the alkyl N-(indol-50-yl)dithiocarbamates 9a–e, respectively. Their cyclisation using N-bromosuccinimide (NBS) and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), in the cold, followed by indolic N-deprotection, furnished regioselectively the 2-alkylamino- and the 2-
alkylthiothiazolo[5,4-e]indoles 8a–c and 11a–e, respectively, in good overall yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Thiazoles are important heterocycles and continue to be
synthetic targets because thiazolyl (hetero)arenes and
several classes of annulated thiazoles display a diverse
array of biological activities. The cruciferous phytoalex-
ins, camalexins and spirobrassinins, are examples of
thiazolyl heteroarenes,1 whereas annulated thiazoles
comprise the cytotoxic thiazoloquinazolines, -quino-
lines, -acridines, -acridones, 2-cyano-thiazolobenzodiox-
ins, 2-(4-amino)phenyl- and 2-cyanobenzothiazoles and
thiazolocarbazoles,2 the cytotoxic thiazoloquinazoli-
nones,3 the antitumor and antitubercular thiazoloimi-
dazoles,4 the central dopamine agonists thiazoloindans
and -benzopyrans,5 the thiazolooxindole-based CDK-2
inhibitors6 and the thiazolothiazepine-based HIV-1
integrase inhibitors.7
of serotonin antagonists, the 5-substituted thiazolo-
[5,4-f]indole 2 was synthesised from 1-acetyl-6-amino-
indoline in four steps in ca. 8% overall yield.10 We be-
came interested in developing a new synthetic route to
the [5,4-e]-TI ring contained in 1, in which we would
construct the thiazole nucleus on the benzene ring of
an indole, in contrast to the construction of the pyrrole
nucleus on the benzene ring of a benzothiazole, as was
used in the synthesis of 1. As a result, we have been able
to develop a new synthesis of 2-alkylamino- and 2-alkyl-
thio[5,4-e]-TIs. Our successful findings are presented in
this letter.
Me
2
S
N
Me
Me
S
2
Motivated by the bioactive potential of annulated thiazo-
les, we have recently reported a new synthetic route to
thiazolocarbazoles.8 In continuation, we became inter-
ested in thiazoloindoles (TIs), only two isomeric types
of which appear to have been synthesised up to now.
Thus, for preparing polymethine dyes, 2,7,8-trimeth-
6
5
N
N
N
H
1
N
ylthiazolo[5,4-e]indole
Fischer indole reaction of N-(2-methyl-6-benzo-
1
was synthesised by the
CH2CH2C6H4F(p-)
2
thiazolyl)hydrazine with 2-butanone.9 Later, in search
Our plan was to cyclise N-alkylthioureidoindoles.
Accordingly, commercially available 5-nitroindole 3
was reduced (hydrazine hydrate, palladised charcoal,
refluxing methanol)11a to 5-aminoindole (90%) which
was then condensed with methyl isothiocyanate in
Keywords: Thiazolo[5,4-e]indoles; Regioselective synthesis; Thioureido-
indoles; Indolyldithiocarbamates; NBS–DBU.
*
Corresponding author. Tel.: +91 33 23506619; fax: +91 33
23506790; e-mail: chakmanas@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.125

2866
M. Chakrabarty et al. / Tetrahedron Letters 46 (2005) 2865–2868
refluxing dry methanol to furnish 5-(N-methyl)thi-
oureidoindole efficiently (92%). However, when we at-
tempted cyclisation using bromine in acetic acid in the
cold12 or on montmorillonite K10clay- para-toluenesulf-
onic acid (TsOH) at 60 ꢁC,8b it underwent complete
decomposition in both the cases. In order to overcome
this difficulty, 5-nitroindole was first protected as its
N-benzenesulfonyl derivative 4 (96%) and then reduced
to the 5-amino derivative 5 by transfer hydrogenation
using 10% palladised charcoal and either ammonium
formate11b (75%) or hydrazine hydrate11a (94%). The
amine 5 was then condensed separately with methyl,
ethyl and benzyl isothiocyanates in refluxing dry metha-
nol to give the respective 1-benzene-sulfonyl-5-(N-alkyl-
thioureido)indoles 6a–c13 in ca. 90% yields. The
conspicuous appearance of, (i) a 13C NMR signal at d
181–182 for the thiocarbonyl carbon, (ii) the peaks aris-
ing from the loss of H2S (34 m.u.), RNH2 (31/45/
107 m.u.) and RNCS (73/87/149 m.u.) from the respec-
tive molecular ion-peaks in their mass spectra and (iii)
supportive NMR and analytical data consolidated the
structures of 6a–c.
O2N
H2N
(ii) 75% or
(iii) 94%
(iv)
89-92%
N
N
H
SO2Ph
5
3 : R = H
(i)
96%
RHN
4 : R = SO2Ph
2
S
H
N
N
RHN
8
(v)
70-78%
S
4
N
N
5
R'
SO2Ph
6a-c
7a-c : R' = SO2Ph
(vi)
85-95%
8a-c : R' = H
For 6-8 : R = Me (a), Et (b), CH2Ph (c)
Scheme 1. Reagents and conditions: (i) NaOH, n-Bu4N+HSO4
ꢀ
,
CH2Cl2, rt, 1 h, PhSO2Cl, 3 h; (ii) HCO2NH4, 10% Pd–C, MeOH,
reflux, 6–7 h; or (iii) NH2NH2ÆH2O, 10% Pd–C, MeOH, reflux, 3 h; (iv)
RNCS (1.2 equiv), dry MeOH, reflux, 3–7 h; (v) NBS (1 equiv),
CH2Cl2, ꢀ10 ꢁC, 5–10min, DBU (2 equiv), stir, 30min; (vi) K 2CO3 (4
equiv), MeOH–H2O (3:1), reflux, 6–8 h.
N-(10-benezensulfonylindol-30-yl)dithiocarbamates 9a–e.18
The molecular weights of 9a–e were determined from
FAB-MS, which recorded peaks corresponding to
(M+H), (M+HꢀH2S) and (M+HꢀRSH), thereby
additionally consolidating the presence of the alkyl
dithiocarbamate side-chain in each of them. The appear-
ance of the thiocarbonyl carbon at d 197 for 9a and d
201 for 9b–e in their 13C NMR spectra lent addi-
tional support to the derived structures.
Since, in the case of thiazolocarbazoles, bromine in ace-
tic acid had earlier been shown by us to lead to both
angular and linear cyclisations and additionally to cause
nuclear bromination,8a whereas clay-TsOH at 60 ꢁC re-
sulted in regioselective cyclisations,8b 6c, as a representa-
tive substrate, was adsorbed on clay-TsOH and heated
at 60 ꢁC for a few hours, but unfortunately it remained
completely unchanged.
Since, inter alia, NBS–DBU14a and NBS–Et3N14b had
been used previously for the cyclisation of the phyto-
alexin brassinin, an (indol-30-yl)methyldithiocarbamate,
to the corresponding indolothiazine, cylobrassinin, we
decided to try NBS for the cyclisation of thioureido-
(hetero)arenes to thiazolo(hetero)-arenes. Accordingly,
each of 6a–c was separately treated with NBS in dichlo-
romethane at ꢀ10 ꢁC and then with DBU, and the
substrates cyclised rapidly and regioselectively to 6-
benzenesulfonyl-2-alkylamino-thiazolo[5,4-e]indoles 7a–c
in good yields.15 Subsequent indolic N-deprotection16
using methanolic potassium carbonate furnished the
2-alkylaminothiazolo[5,4-e]indoles 8a–c17 in 48–62%
overall yields starting from 3 (Scheme 1).
The cyclisation of 9a–e by similar treatment with NBS–
DBU, as in the cases of 6a–c, furnished only the angu-
larly cyclised products, viz 2-alkylthio-6-benzenesulfo-
nylthiazolo[5,4-e]indoles 10a–e in very good yields. In
10a–e, the disappearance of the thiocarbonyl carbon sig-
nals and the appearance of signals at d 164–165 were
suggestive of cyclisations occuring. Also, the appearance
of two one-proton, doublets at d 7.8 and 8.0with
J = 9 Hz in 10a–e demonstrated angular cyclisations.
Subsequent indolic N-deprotection using methanolic
potassium carbonate resulted in the smooth formation
of the 2-alkylthiothiazolo[5,4-e]indoles 11a–e19 in 64–
71% overall yields starting from 3 (Scheme 2). Cleavage
The appearance of two one-proton doublets at d 7.25/
7.39/7.27 and d 7.20/7.32/7.20 (refer to H-4 and H-5,
respectively, of the TI skeleton) with J = 8.5 Hz consoli-
dated their angular structures, since the corresponding
protons, H-4 and H-8, of the alternative linear [4,5-f]-
TI structures would have appeared as one-proton sing-
lets. Also, the shift of the 13C NMR signals of C-8 from
d 108 in 7a–c to ca. d 100 in 8a–c was a pointer to the
cleavage of the N-benzenesulfonyl group.
RS
S
N
H
N
RS
(ii)
(i)
5
82-86%
S
90-98%
N
N
R'
SO2Ph
9a-e
10a-e : R' = SO2Ph
(iii)
92-98%
11a-e : R' = H
For 9-11: R = Me (a), Et (b), n-Pr (c), n-Bu (d), i-Bu (e)
This success prompted us to extend this methodology
for a similar synthesis 2-alkylthiothiazoloindoles. There-
fore, 5 was separately treated with carbon disulfide and
each of methyl, ethyl, n-propyl, n-butyl and i-butyl bro-
mides/iodides in the presence of pyridine and triethyl-
amine to furnish efficiently, the respective alkyl
Scheme 2. Reagents and conditions: (i) CS2 (1.2 equiv), Py–Et3N,
0 ꢁC, 30–45 min, RX (1.2 equiv; R = Br for 6d and I for the
remainder), 2–3 h; (ii) NBS (1 equiv), CH2Cl2, ꢀ10 ꢁC, 5–10min,
DBU (2 equiv), stir, 30min; (iii) K 2CO3 (4 equiv), MeOH–H2O (3:1),
reflux, 6–8 h.

M. Chakrabarty et al. / Tetrahedron Letters 46 (2005) 2865–2868
2867
Table 1. Regioselective synthesisa,b of 2-alkylamino-TIs 8a–c and 2-alkylthio-TIs 11a–e starting from 5
Thioureidoindoles
Time (h); yields (%)
N-SO2 Ph-TIs
Yields (%)
2-Alkylamino-TIs
Yields (%)
6a
6b
6c
3.0; 90
4.5; 92
7.0; 89
7a
7b
7c
70
78
75
8a
8b
8c
85
95
90
Indolyldithiocarbamates
Yields (%)
9a
9b
9c
9d
9e
95
98
93
90
90
1
10a
10b
10c
10d
10e
85
82
85
86
84
11a
11b
11c
11d
11e
98
95
94
92
96
a All products were identified by IR, H and 13C NMR, DEPT 135, MS, elemental analysis/HRMS, and in some cases additionally by HMQC and
HMBC spectra.
b Refer to isolated pure products.
8. (a) Chakrabarty, M.; Ghosh, N.; Harigaya, Y. Hetero-
cycles 2004, 62, 779–786; (b) Chakrabarty, M.; Ghosh, N.;
Harigaya, Y. Tetrahedron Lett. 2004, 45, 4955–4957.
9. Dzyabenko, V. G.; Abramenko, P. I. Zh. Org. Khim. 1988,
24, 831–835, Chem. Abstr. 1988, 109, 56555w.
10. Kitazawa, N.; Ueno, K.; Takahashi, K.; Kimura, T.;
Sasaki, A.; Kawano, K.; Okabe, T.; Komatsu, M.;
Matsunaga, M.; Kubota, A. EP 0976732; Chem. Abstr.
1998, 129, 302552.
11. (a) Kyziol, J. B.; Daszkiewicz, Z. Pol. J. Chem. 1983, 57,
839–847; (b) Ram, S.; Ehrenkaufer, R. E. Tetrahedron
Lett. 1984, 25, 3415–3418.
12. Ambati, N. B.; Anand, V.; Hanumanthu, P. Synth.
Commun. 1997, 27, 1487–1493.
of the benzenesulfonyl groups was apparent from
appropriate MS and NMR data, as well as from the
lowering of the chemical shift of C-8 from d 107–108
in 10a–e to d 101 in 11a–e. A typical cyclisation proce-
dure15 and the yields of both types of condensation
products as well as the TIs (Table 1) are presented.
In conclusion, we have developed an expedient and effi-
cient five-step, regioselective synthesis of both 2-alk-
ylamino- and 2-alkylthiothiazolo[5,4-e]indoles, which
involves the construction of the thiazole nucleus on
the benzene ring of precursor indoles. However, the bio-
active potential of the synthesised TIs remains to be
explored.
13. Data of a representative member, 6a: mp 172–174 ꢁC; IR
1
(nujol): 3370, 1533, 1275, 1109, 1056, 777, 731 cmꢀ1; H
NMR (CDCl3): d 3.08 (3H, d, J = 4.5 Hz), 5.98 (1H, br s),
6.66 (1H, d, J = 3.5 Hz), 7.15 (1H, d, J = 8.5 Hz), 7.40
(1H, s), 7.48 (2H, t, J = 7.5 Hz), 7.58 (1H, t, J = 7.5 Hz),
7.62 (1H, d, J = 3.5 Hz), 7.88 (2H, d, J = 7.5 Hz), 8.0(1H,
d, J = 8.5 Hz), 8.16 (1H, br s); 13C NMR: d 32.4 (CH3),
109.2, 115.3, 119.4, 123.2, 127.2 (·2), 128.3, 129.9 (·2),
134.5 (all Ar–CH), 131.9, 132.2, 133.9, 138.3 (all Ar–C),
182.3 (C@S); EI-MS: m/z 345 (M+), 315, 314, 311, 272,
173, 170 (100%), 141, 131, 77. Anal. Calcd for
C16H15N3O2S2: C, 55.65; H, 4.35; N, 12.17%. Found: C,
55.60; H, 4.34; N, 12.19%.
Acknowledgements
The authors sincerely thank the Director, Bose Institute
for laboratory facilities, the C.S.I.R., Government of In-
dia for providing a fellowship (T.K.), Mr. B. Majumder,
NMR Facilities and Mr. P. Dey, Microanalytical Labo-
ratory, both of B.I., for recording the spectra.
References and notes
14. (a) Monde, K.; Tamura, K.; Takasugi, M.; Kobayashi, K.;
Somei, M. Heterocycles 1994, 38, 263–267; (b) Mehta, R.
G.; Liu, J.; Constantinou, A.; Thomas, C. F.; Hawthorne,
M.; You, M.; Gerha¨user, C.; Pezzuto, J. M.; Moon, R. C.;
Moriarty, R. M. Carcinogenesis 1995, 16, 399–404.
15. General procedure for the cyclisation of 6a–c to 7a–c and
9a–e to 10a–e: To a solution of 6a–c/9a–e (1 mM) in
CH2Cl2 (10mL) at ꢀ10 ꢁC were added NBS (1 mM), and,
after 5–10min, DBU (2 mM). The solution was stirred for
another 30min, then poured into saturated aqueous
Na2S2O3 (15 mL) and extracted with CH2Cl2
(3 · 25 mL). The pooled extracts were washed with water,
dried (Na2SO4), the solvent removed in vacuo and the
residue was purified either by crystallisation (for 10a, 10b)
from CH2Cl2–petroleum ether, bp 60–80 ꢁC or by column
chromatogaphy over neutral alumina (for 7a–c) (elution
with 25–35% EtOAc in pet. ether) or over silica gel (for
10c–e) (elution with 5–10% EtOAc in pet. ether).
1. Pedras, M. S. C.; Okanga, F. I.; Zaharia, I. L.; Khan, A.
Q. Phytochemistry 2000, 53, 161–176.
2. See Refs. 1–9 and 14–16 in Ref. 8b below.
3. Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.;
Besson, T. Tetrahedron Lett. 2003, 44, 4455–4458, and
references cited therein.
4. Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.;
Morigi, R.; Rambaldi, M. Eur. J. Med. Chem. 2001, 36,
743–746.
5. van Vliet, L. A.; Rodenhuis, N.; Wikstro¨m, H. J. Med.
Chem. 2000, 43, 3549–3557.
6. Davis, S. T.; Benson, B. G.; Bramson, H. N.; Chapman,
D. E.; Dickerson, S. H.; Dold, K. M.; Eberwein, D. J.;
Edelstein, M.; Frye, S. V.; Gampe, R. T., Jr.; Griffin, R. J.;
Harris, P. A.; Hassell, A. M.; Holmes, W. D.; Hunter, R.
N.; Knick, V. B.; Lackey, K.; Lovejoy, B.; Luzzio, M. J.;
Murray, O.; Parker, P.; Rocque, W. J.; Shewchuk, L.;
Veal, J. M.; Walker, D. H.; Kuyper, L. F. Science 2001,
291, 134–137.
16. Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 6243–
6260.
17. Data of a representative member, 8a: mp 158–160 ꢁC; IR
1
(KBr): 3396, 3224, 3101, 1614, 1564, 1409, 761 cmꢀ1; H
7. Aiello, F.; Brizzi, A.; Garofalo, A.; Grande, F.; Ragno,
G.; Dayam, R.; Neamati, N. Bioorg. Med. Chem. 2004, 12,
4459–4466.
NMR (DMSO-d6): d 2.90(3H, d, J = 3 Hz),), 6.30(1H, s),
7.20and 7.25 (1H, d each, J = 8.5 Hz), 7.31 (1H, s), 7.51

2868
M. Chakrabarty et al. / Tetrahedron Letters 46 (2005) 2865–2868
(1H, br s), 11.13 (1H, s); 13C NMR: d 31.5 (CH3), 99.8,
113.9, 118.3, 122.3, 126.7 (·2), 127.5, 129.3 (·2), 134.0(all
Ar–CH), 131.0, 133.4, 133.7, 138.0 (all Ar–C), 201.0
(C@S); FAB-MS: m/z 391 (M+H)+. Anal. Calcd for
C18H18N2O2S3: C, 55.38; H, 4.61; N, 7.18%. Found: C,
55.31; H, 4.62; N, 7.20%.
110.2, 113.9, 126.4 (all Ar–CH), 120.0, 121.7, 132.6, 146.8,
165.2 (all Ar–C); EI-MS: m/z 203 (M+; 100%), 202, 188,
175, 174, 162, 161, 147. Anal. Calcd for C10H9N3S: C,
59.11; H, 4.43; N, 20.69%. Found: C, 59.02; H, 4.42; N,
20.72%.
19. Data of a representative member, 11c: mp 90–92 ꢁC; IR
18. Data of a representative member, 9c: mp 132–134 ꢁC; IR
(nujol): 1520, 1406, 1372, 1170, 1129, 731 cmꢀ1; 1H NMR
(CDCl3): d 0.97 (3H, t, J = 7 Hz), 1.69 (2H, sextet,
J = 7 Hz), 3.24 (2H, t, J = 7 Hz), 6.65 (1H, dd,
J1 = 4 Hz, J2 = 1 Hz), 7.28 (1H, br d, J = 9 Hz), 7. 45
(2H, t, J = 7.5 Hz), 7.55 (1H, tt, J1 = 7.5 Hz, J2 = 1.5 Hz),
7.60(1H, d, J = 4 Hz), 7.62 (1H, br s), 7.89 (2H, dt,
J1 = 7.5 Hz, J2 = 1.5 Hz), 7.99 (1H, d, J = 9 Hz), 9.10(1H,
br); 13C NMR: d 13.4 (CH3), 22.0, 38.2 (both CH2), 109.1,
(KBr): 3436, 1620, 1411, 1353, 1191, 883, 788 cmꢀ1 1H
;
NMR (CDCl3): d 1.08 (3H, t, J = 7.5 Hz), 1.86 (2H, sextet,
J = 7 Hz), 3.30(2H, t, J = 7 Hz), 6.61 (1H, s), 7.28 (1H, t,
J = 2.5 Hz), 7.43 and 7.73 (1H, d each, J = 9 Hz), 8.68
(1H, s); 13C NMR: d 12.9 (CH3), 22.3, 35.8 (both CH2),
101.2, 109.8, 115.6, 124.2 (all Ar–CH), 120.1, 126.5, 132.1,
147.9, 161.5 (all Ar–C) EI-MS: m/z 248 (M+), 233, 220,
215, 206 (100%), 174, 148; HR EI-MS: m/z 248.0434 (M+).
Calcd for C12H12N2S2: 248.0442.