Microwave irradiation for accelerating each step for the synthesis of 1,2,4-triazino[5,6-b]indole-3-thiolsand their derivatives from isatin and 5-chloroisatin

Article abstract of DOI:10.1055/s-2004-815437

Microwave irradiation has been used to accelerate the conversion of isatin (1), 5-chloroisatin (2), and N-benzylisatin (3) to their thiosemicarbazones and their subsequent cyclization into 1,2,4-triazino[5,6-e]indole-3-thiols 7 and 8; and the W-benzyl derivative 9. Selective and complete alkylation of 1, 7, 8, and 9 has also been achieved under microwave irradiation.

Full text of DOI:10.1055/s-2004-815437

LETTER
723
Microwave Irradiation for Accelerating each Step for the Synthesis of
1,2,4-Triazino[5,6-b]indole-3-thiolsand their Derivatives from Isatin and
5-Chloroisatin
A
cclerated Synt
l
hesis of 1,2,4
S
-Triazino[5,6
a
-
b
]indole-3
y
-
thiolsandby
e
Mircrowav
d
e
Irradiation H. El Ashry,* El Sayed Ramadan, Hamida M. Abdel Hamid, Mohamed Hagar
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Fax +20(3)4271360; E-mail: eelashry60@link.net; E-mail: eelashry60@hotmail.com
Received 18 December 2003
carbazide in ethanol under microwave irradiation for 2.5
minutes.36–39 The reaction times and solvent volumes are
thus reduced compared to the conventional method.
Abstract : Microwave irradiation has been used to accelerate the
conversion of isatin (1), 5-chloroisatin (2), and N-benzylisatin (3) to
their thiosemicarbazones and their subsequent cyclization into
1,2,4-triazino[5,6-b]indole-3-thiols 7 and 8; and the N-benzyl deriv-
ative 9. Selective and complete alkylation of 1, 7, 8, and 9 has also
been achieved under microwave irradiation.
The cyclization of isatin 3-thiosemicarbazones to 1,2,4-
triazino[5,6-b]indole-3-thiols has been reported to take
place in aqueous K2CO3,7,40 and steric factors appear to
have marked affects upon the rate of cyclization. Thus, in
the case of isatin 3-thiosemicarbazone 4, the reaction re-
quired heating under reflux for 7–10 hours, and the 1-me-
thyl analogue of 4 required 7 hours; whereas the 1-
benzylisatin 3-thiosemicarbazone 6 requires 6 days for its
cyclization. This extended duration of heating under re-
flux to achieve the cyclization has been markedly reduced
by using microwave irradiation whereby the cyclization
of 4, 5, and 6 to the corresponding 1,2,4-triazino[5,6-b]in-
dole-3-thiols 7 and 8 as well as the benzyl derivative 9
takes place in a much shorter period of time; 15–30 min-
utes being required for the completion of the reaction. Al-
ternatively, a one pot synthesis of compound 9 was
achieved by irradiating a mixture of 3 and thiosemicarba-
zide in aqueous K2CO3 for 30 minutes.41–43 Benzylation of
7 and 8 could also be achieved under microwave irradia-
tion with benzyl chloride in aqueous K2CO3 to give the re-
spective S-benzylated derivatives 10 and 11 rather than
the 5-N-benzyl analogue 9. Further benzylation of the N-
5 of 10 and 11 under similar conditions did not lead to
complete conversion of 10 or 11 to 13 or 14, respectively.
However, further benzylation could be effected by the ir-
radiation of their sodio derivatives, prepared in situ from
10 and 11 and sodium hydride in DMF, with benzyl chlo-
ride and NaI to give the corresponding 3-benzylthio-5-
benzyl-1,2,4-triazino[5,6-b]indoles (13) and its 8-chloro
derivative 14. Alternatively, 13 was also prepared by the
irradiation of 9 and benzyl chloride in aqueous K2CO3.44
Under similar conditions, the presence of NaI did not
cause a useful increase in the yield of products in the ben-
zylation of 7, 8, and 9. This could be due to the high nu-
cleophilicity of the sulfide anion presumably generated
from 7, 8, and 9. However, the presence of NaI accelerates
the rate of benzylation of N-5 of 10, in this instance irra-
diation for 6 minutes (instead of 20 min in the absence of
NaI) led to the yield being improved to 85% from 69%.
The MW technique could also be applied successfully to
the alkylation of 7 with ethyl chloroacetate to give 12
which, upon further alkylation, gave 15.44,45 The structure
of products was confirmed from their spectral data,44 the
Key words: isatin, N-benzylisatin, microwave, thiosemicarba-
zones, triazinoindoles
The importance of the indole nucleus has been well estab-
lished in pharmaceutical chemistry, as many of its deriva-
tives are used as antipyretic, anticonvulsant, analgesic,
and antidepressant agents.1–3 A series of isatin-3-thio-
semicarbazones has shown broad antiviral activity4–7 and
these have proved to be excellent precursors for triazino
[5,6-b]indoles. Some of the triazinoindoles are active in
vitro against a range of viruses.8–11
In the previous work from our laboratory,12–20 we reported
the synthesis of a number of triazinoindoles and triazolo-
triazinoindoles by conventional methods. Recently, we
were interested in the use of microwave irradiation in or-
ganic synthesis,21,22 since its use can provide improve-
ments in environmental and economical aspects.23–31 In
the present work, microwave irradiation has been used for
practical conversion of commercially available isatin and
5-chloroisatin to the respective 1,2,4-triazino[5,6-b]in-
dole-3-thiols and their alkylated derivatives.
The synthesis of N-benzylisatin (3) was achieved in 72%
yield by microwave irradiation of isatin (1) in aqueous
K2CO3 followed by addition of benzyl chloride and NaI
and reirradiation for 7 minutes.32,33 However, the reaction
did not proceed in the absence of NaI even on increasing
the irradiation time to 12 minutes. This method is more
practical than the conventional method, which requires
the use of sodium ethoxide to give 12% yield of product34
or sodium hydride to give 68% yield35 (Scheme 1).
The conversions of 1, 2, and 3 to the respective isatin 3-
thiosemicarbazones 4, 5-chloroisatin 3-thiosemicarba-
zone 5, and 1-benzylisatin 3-thiosemicarbazone 6 have
been carried out simply by their reaction with thiosemi-
SYNLETT 2004, No. 4, pp 0723–0725
0
9.
0
3.
2
0
0
4
Advanced online publication: 29.01.2004
DOI: 10.1055/s-2004-815437; Art ID: D14603ST
© Georg Thieme Verlag Stuttgart · New York

724
E. S. H. El Ashry et al.
LETTER
Scheme 1
resonances at d 4.51 and 5.43 ppm in the 1H NMR spec- References
trum of e.g 13 were assigned to the protons of S–CH2 and
(1) Bell, M. R.; Zalay, A. W.; Osterlin, R.; Clemans, S. D.;
Dumas, D. J.; Bradford, J. C.; Rozitis, J. J. Med. Chem.
N–CH2 groups, respectively. The interpretation of these
signals was based on the comparison with those signals
assigned for 10 (d 4.55) and 9 (d 5.44). The assignment of
the resonances of the heterocyclic ring in the 1H and 13C
NMR spectra of 13 was based on the reported chemical
shifts for the triazinoindole derivatives.14–20
1977, 20, 537.
(2) Popp, F. D. J. Heterocycl. Chem. 1984, 21, 1641.
(3) Jan, K. C.; Pathak, V. N.; Jain, S. K. Pharmazie 1980, 35,
677.
(4) Bauer, D. J.; Sadler, P. W. Br. J. Pharmacol. 1960, 15, 101.
(5) Bauer, D. J.; Apostolov, K.; Selway, J. W. T. Ann. N. Y.
Acad. Sci. 1970, 173, 314.
(6) Bauer, D. J.; Apostolov, K. Science 1966, 154, 796.
(7) Gladych, J. M. Z.; Hornby, R.; Hunt, J. H.; Jack, D.; Boyle,
J. J.; Ferlauto, R. J.; Haff, R. F.; Kormendy, C. G.; Stanfield,
F. J.; Stewart, R. C. J. Med. Chem. 1972, 15, 277.
(8) Gladych, J. M. Z.; Hunt, J. H.; Jack, D.; Haff, R. F.; Boyle,
J. J.; Stewart, R. C.; Ferlauto, R. J. Nature (London, U.K.)
1969, 221, 286.
(9) Boyle, J. J.; Raupp, W. G.; Stanfield, F. J.; Haff, R. F.; Dick,
E. C.; D’Alessio, D.; Dick, C. R. Ann. N. Y. Acad. Sci. 1970,
173, 477.
In conclusion, a straightforward multi-step sequence of
reactions has been achieved for a successful conversion of
isatin and its N-benzyl derivative to the corresponding 3-
thiosemicarbazones and subsequent cyclization to the
respective 1,2,4-triazino [5,6-b] indole-3-thiols using mi-
crowave irradiation. Selective and complete alkylation
with various alkylating agents has been also carried out on
such tricyclic systems. These reactions have been also
successfully extended to thiols derived from 5-chloro-
isatin.
Synlett 2004, No. 4, 723–725 © Thieme Stuttgart · New York

LETTER
Acclerated Synthesis of 1,2,4-Triazino[5,6-b]indole-3-thiolsand by Microwave Irradiation
725
(10) Gwaltney, J. M. Proc. Soc. Exp. Biol. Med. 1970, 133, 1148.
(11) Haff, R. F.; Flagg, W. B.; Gallo, J. J.; Hoover, J. R. E.;
Miller, J. A.; Pinto, C. A.; Pagano, J. F. Proc. Soc. Exp. Biol.
Med. 1972, 141, 475.
(12) El Ashry, E. S. H.; Rashed, N.; Taha, M.; Ramadan, E. Adv.
Heterocycl. Chem. 1994, 59, 39.
(13) El Ashry, E. S. H.; Rashed, N.; Mousaad, A.; Ramadan, E.
Adv. Heterocycl. Chem. 1994, 61, 207.
(14) Mousaad, A.; Abdel Hamid, H.; El Nemr, A.; El Ashry, E. S.
H. Bull. Chem. Soc. Jpn. 1992, 65, 546.
(15) Mousaad, A.; Rashed, N.; Ramadan, E.; El Ashry, E. S. H.
Spectrosc. Lett. 1994, 27, 677.
(16) Rashed, N.; El Nemr, A.; El Ashry, E. S. H. Spectrosc. Lett.
1993, 26, 1817.
(17) El Ashry, E. S. H.; Rashed, N.; Abdel Hamid, H.; Ramadan,
E. Z. Naturforsch., B: Chem. Sci. 1997, 52, 873.
(18) Rashed, N.; Abdel Hamid, H.; Ramadan, E.; El Ashry, E. S.
H. Nucleosides Nucleotides 1998, 17, 373.
(19) Abdel Hamid, H.; Mousaad, A.; Ramdan, E.; El Ashry, E. S.
H. Heterocyl. Commun. 1999, 5, 473.
(20) El Ashry, E. S. H.; Abdel Hamid, H.; Mousaad, A.;
Ramadan, E. J. Chem. Res., Miniprint 2002, 752.
(21) Abdel-Rahman, A. A. H.; El Ashry, E. S. H. Synlett 2002,
2043.
(22) Abdel Hamid, H.; Ramadan, E.; Hagar, M.; El Ashry, E. S.
H. Synth. Commun. 2004, 34, 365.
(23) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(24) Gedye, R. N.; Smith, F. E.; Westaway, K. C. Can. J. Chem.
1988, 66, 17.
(38) Antrich, O. Justus Liebigs Ann. Chem. 1885, 227, 364.
(39) Jancevska, M. Glas. Hem. Tehnol. Makedonkja. 1974, 1, 57;
Chem. Abstr. 1977, 87, 184415.
(40) Allen and Hanburys Ltd Neth. Pat. 6410823, 1965; Chem.
Abstr. 1965, 63, 13295.
(41) A mixture of 4, 5, or 6 (0.68 mmol) and K2CO3 (0.12 g, 0.86
mmol) in water (30 mL) was irradiated for 15–30 min. The
reaction mixture was acidified with acetic acid and the
product was recrystallized from EtOH–DMF to give 1,2,4-
triazino [5,6-b]indole-3-thiol (7) (0.12 g, 87%), mp >
300 °C, lit.40 mp > 300 °C; 8-chloro-1,2,4-triazino[5,6-
b]indole-3-thiol (8) (0.13 g, 83%), mp > 300 °C; 5-benzyl-
1,2,4-triazino[5,6-b]indole-3-thiol (9) (0.12 g 64%), mp
263–265 °C, lit.7 mp 269-271 °C. Compound 9 was also
obtained by microwave irradiation of 3 (0.2 g, 0.84 mmol),
thiosemicarbazide (0.10 g, 1.10 mmol), and K2CO3 (0.35 g,
2.5 mmol) in water (30 mL) for 30 min (0.2 g, 81%).
(42) Holla, B. S.; Udupa, K. V. J. Indian Chem. Soc. 1988, 65,
524.
(43) Holla, B. S.; Udupa, K. V. Heterocycles. 1991, 32, 1081.
(44) A mixture of 7, 8, or 9 (0.34 mmol) and K2CO3 (0.072 g,
0.52 mmol) in water (10 mL) was irradiated by microwave
till dissolution, then benzyl chloride or ethyl chloroacetate
(1.75 mmol) was added and reirradiated for 2.5 min and the
product was recrystallized from EtOH–DMF to give 3-
benzylthio-1,2,4-triazino[5,6-b]indole (10) (0.08 g, 83%),
mp 272–274 °C; 3-benzylthio-8-chloro-1,2,4-triazino[5,6-
b]indole (11) (0.09 g, 82%) mp 296 °C; 3-carbethoxy-
methylthio-1,2,4-triazino[5,6-b]indole (12) (0.087 g, 89%),
mp 234 °C, lit.45 mp 235–237 °C; 3-benzylthio-5-benzyl-
1,2,4-triazino[5,6-b]indole (13) (0.11 g, 84%), mp 149–
150 °C. Microwave irradiation of a mixture of 10, 11, or 12
(0.9 mmol) in DMF (20 mL), NaH (0.05 g, 2 mmol), benzyl
chloride or ethyl chloroacetate (4.3 mmol) and NaI (0.32 g,
2.15 mmol) for 6 min gave 13 (0.29 g, 85%); 3-benzylthio-
5-benzyl-8-chloro-1,2,4-triazino[5,6-b]indole (14) (0.3 g,
78%), mp 182 °C; 3-carbethoxymethylthio-5-
(25) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20,
1.
(26) Abramovitch, R. A. Org. Prep. Proced. Int. 1991, 23, 683.
(27) Caddick, S. Tetrahedron 1995, 51, 10403.
(28) Laurent, R.; Laporterie, A.; Dubac, J.; Berlan, J.; Lefeuvre,
S.; Audhuy, M. J. Org. Chem. 1992, 57, 7099.
(29) Bogdal, D.; Pielichowski, J.; Jaskot, K. Org. Prep. Proced.
Int. 1998, 30, 427.
carbethoxymethyl-1,2,4-triazino[5,6-b]indole (15) (0.24 g,
70%), mp 162 °C, lit.45 mp160–162 °C. 1H NMR (CDCl3,
300 MHz): 10: d = 4.55 (s, 2 H, S-CH2), 7.42 (ddd, 1 H, H-
8, J8,7 = 7.1 Hz, J8,9 = 7.8 Hz, J8,6 = 0.8 Hz), 7.58 (d, 1 H, H-
6, J6,7 = 8.2 Hz), 7.69 (ddd, 1 H, H-7, J7,6 = 8.2 Hz, J7,8 = 7.1
Hz, J7,9 = 1.2 Hz), 8.31 (d, 1 H, H-9, J9,8 = 7.8 Hz), 7.22–
7.28 (m, 1 H, Ph-H), 7.30–7.35 (m, 2 H, Ph-H), 7.50–7.53
(m, 2 H, Ph-H); 11: d = 4.52 (s, 2 H, S-CH2), 7.56 (d, 1 H, H-
6, J6,7 = 9.1 Hz), 7.66 (dd, 1 H, H-7, J7,6 = 9.1 Hz, J7.9 = 2.2
Hz), 8.29 (d, 1 H, H-9, J9,7 = 2.2 Hz), 7.22 [d, 1 H, Ph-H (p),
(30) Dandia, A.; Sachdeva, H.; Devi, R. J. Chem. Res., Synop.
2000, 272.
(31) Mojtahedi, M. M.; Saidi, M. R.; Heravi, M. M.;
Bolourtchain, M. Monatsh. Chem. 1999, 130, 1175.
(32) A mixture of 1 (1.0 g, 6.8 mmol) and K2CO3 (2.0 g, 14.5
mmol) in H2O (10 mL) was irradiated (microwave oven EM-
230M; 800 watt output power) until dry (ca. 2 min). Benzyl
chloride (1.5 mL, 12.9 mmol) and NaI (2.0 g, 13.3 mmol)
were added and the mixture was irradiated for 7 min. The
product was triturated with EtOH (15 mL) and the N-
benzylisatin (3) was recrystallized from EtOH as orange
crystals (1.15 g, 72%), mp 130–132 °C; lit.33 mp 131–
132 °C.
Jp,m = 7.6 Hz], 7.30 [t, 2 H, Ph-H (m), Jm,p = 7.6 Hz,
Jm,o = 7.2 Hz], 7.49 [d, 2 H, Ph-H (o), Jo,m = 7.2 Hz]; 13:
d = 4.51 (s, 2 H, S-CH2), 5.43 (s, 2 H, N-CH2), 7.25 (d, 1 H,
H-6, J6,7 = 8.2 Hz), 7.33 (t, 1 H, H-8, J8,7 = 7.6 Hz, J8,9 = 7.6
Hz), 7.49 (ddd, 1 H, H-7, J7,6 = 8.2 Hz, J7,8 = 7.6 Hz,
(33) Hellmann, H.; Hallmann, G.; Lingens, F. Chem. Ber. 1953,
86, 1346.
J7,9 = 1.0 Hz), 8.33 (d, 1 H, H-9, J9,8 = 7.6 Hz), 7.13–7.18
(34) Soliman, F. S. G.; Salama, H. M. Pharmazie 1983, 38, 585.
(35) Autrey, R. L.; Tahk, F. C. Tetrahedron 1967, 33, 901.
(36) A mixture of 1, 2, or 3 (0.21 mmol) and thiosemicarbazide
(0.023 g, 0.25 mmol) in EtOH (5 mL) and one drop of HOAc
was irradiated for 2.5 min. The product was recrystallized
from EtOH–DMF to afford isatin 3-thiosemicarbazone (4)
(0.043 g, 93%), mp 246–248 °C, lit37 mp 247–248 °C; 5-
chloroisatin 3-thiosemicarbazone (5) (0.048 g, 90%), mp
272 °C; 1-benzylisatin 3-thiosemicarbazone (6) (0.06 g,
92%), mp 262–264 °C, lit.38 mp 268 °C.
(m, 4 H, Ph-H), 7.20–7.22 (m, 4 H, Ph-H), 7.41–7.43 (m, 2
H, Ph-H), 13C NMR (CDCl3, 75.47 MHz): d = 35.7 (S-CH2),
45.4 (N-CH2), 187.7 (C-3), 168.4 (C-4a), 141.5 (C-5a),
111.2 (C-6), 135.5 (C-7), 123.5 (C-8), 122.8 (C-9), 99.6 (C-
9a), 147.1 (C-9b), 141.2, 128.9, 129.6, 131.1, 137.8, 127.7,
129.4, 128.6 (2 × C6H5). 14: d = 4.58 (s, 2 H, S-CH2), 5.49
(s, 2 H, N-CH2), 7.19 (d, 1 H, H-6, J6,7 = 6.9 Hz), 7.51 (dd, 1
H, H-7, J7,6 = 6.9 Hz), 8.34 (d, 1 H, H-9, J9,7 = 1.5Hz), 7.24–
7.27 (m, 4 H, Ph-H), 7.29–7.30 (m, 4 H, Ph-H), 7.48–7.49
(m, 2 H, Ph-H).
(37) Bernstein, J.; Yale, H. L.; Losee, K.; Holsing, M.; Martius,
J.; Lott, W. A. J. Am. Chem. Soc. 1951, 73, 906.
(45) Abdel Hamid, H. J. Chem. Res., Synop. 2004, in press.
Synlett 2004, No. 4, 723–725 © Thieme Stuttgart · New York