A Multistep Preparation of 3-Aryl-8-Methoxythiazolo [3’, 2’ : 2, 3] [1, 2, 4] Triazino [5, 6-b] Indoles Under Microwave Ir-radiations

Introduction:

Bridgehead nitrogen heterocycles containing thiazole and related heterocycles (thiadiazole and thiadiazine) exhibit antihistaminic, antithyroid, antitubercular, antifungal & antibacterial activities^1-3 and their synthetic importance has been greatly enhanced by the recent uses of their condensed bridgehead nitrogen heterocycles as anthelminitics, antidepressants, platelet aggregation inhibitors, antineoplastic, vulcanization accelerators and photographic sensitizers.^4-11   The indoles are already been synthesized by different method But they requires longer reaction time and tedious workup.^12-21 Microwave assisted reactions are gaining much more importance in synthetic organic chemistry due to dramatic reduction in time from days to hours and hours to minutes or seconds.^22-23

Scheme 1: Click here to View Scheme

 

The present work reports the synthesis of 3-Aryl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino[5, 6-b]indoles in a multi step preparation in high yield in shorter reaction time(Scheme-I). Our work started by reacting  6-methoxyisatin with thiosemicarbazide in Anhyd. ethanol under microwave irradiation at 560W for 5-minutes to give 6-Methoxyisatin-3-thiosemicarbanzone (I). After separation, the 6-Methoxyisatin-3-thiosemicarbanzone(I) reacts with 5% KOH under microwave irradiation at 560W for 5-minutes to give 7-Methoxy-5H-2,3-dihydro [1, 2, 4] triazino [5, 6-b] indole-3-thione (II). The compound 7-Methoxy-5H-2,3-dihydro [1, 2, 4] triazino [5, 6-b] indole-3-thione (II) further reacts with p-chlorophenacyl bromide under microwave irradiation at 560W for 5-minutes to give 5H-3-(p-chlorophenacylthio-7-methoxy [1, 2, 4] triazino [5, 6-b] indole hydrobromide (IIIa; Ar = p-C1C₆H₄). Similarly, 7-Methoxy-5H-2,3-dihydro [1, 2, 4] triazino [5, 6-b] indole-3-thione(II) was also irradiated with p-cholorophenacyl bromide, phenacyl bromide, under microwave irradiation at 560W for 5-minutes to give 5H-3-(p-bromophenacylthio-7-methoxy [1, 2, 4] triazino [5, 6-b] indole hydrobromide(IIIb, Ar = p-Br C₆H₄) and 5H-3-(phenacylthio-7-methoxy [1, 2, 4] triazino [5, 6-b] indole hydrobromide (IIIa; Ar = C₆H₅) respectively. The results are shown in Table-1.

Table:1  3-p-Chlorophenyl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino [5, 6-b] indole

Sr. NO.	Substrate(R)	Time(in minutes)	Yield(%)	m.p.(oC)
1.	-pClC6H4-(IIIa)	5	94	> 260OC
2.	-pBrC6H4-(IIIb)	5	91	> 260OC
3.	-C6H5(IIIc)	5	98	> 260OC

 

We further explore our work by irradiated 5H-3-(p-chlorophenacylthio-7-methoxy [1, 2, 4] triazino [5, 6-b] indole hydrobromide (IIIa; Ar = p-C1C₆H₄) in a mixture of H₃PO₄/P₂O₅ under microwave irradiation at 560W for 5-minutes to give 3-(p-chlorophenyl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino[5, 6-b]indole(IVa, R = Cl). Similarly, 5H-3-(p-bromophenacylthio-7-methoxy [1, 2, 4] triazino [5, 6-b] indole hydrobromide (IIIb; Ar = p-BrC₆H₄) and 5H-3-(phenacylthio-7-methoxy [1, 2, 4] triazino [5, 6-b] indole hydrobromide (IIIa; Ar = C₆H₅) were also irradiated in a mixture of H₃PO₄/P₂O₅ under microwave irradiation at 560W for 5-minutes to give 3-(p-bromophenyl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino[5, 6-b]indole(IVa, R = Br) and 3-(phenyl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino[5, 6-b]indole(IVa, R = H) respectively. The results are shown in Table-2.

Table 2: 3-p-Chlorophenyl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino [5, 6-b] indole

Sr. NO.	Substrate(R)	Time(in minutes)	Yield(%)	m.p.(oC)
1.	-Cl(IVa)	5	91	> 250OC
2.	-Br(IVb)	5	90	> 250OC
3.	-H(IVc)	5	96	> 250OC

 

Experimental

All the melting points reported are uncorrected. Infrared spectra (n_max in cm^-1) were recorded in nujol mull or KBr on a Perkin-Elmer 842/Beckman IR-20 / Hitachi 215 spectrometers. The proton magnetic resonance spectra were recorded on a VXR-200 MHz or R-32 Perkin-Elmer 90 MHz spectrometer in CDC1₃ or DMSO-d₆ using tetramethylsilane (TMS) as internal reference stadnard. The chemical shifts are expressed in d (ppm) units downfield from TMS. Mass spectra were scanned on a Jeol JMX-DX-300 spectrometer operating at 70 eV. Carbon, hydrogen and nitrogen analyses were carried out on a Yanaco MT-3 (JAPAN) instrument. Thin layer chromatography (TLC) were performed on silica-gel plates using acetone-benzene (1 : 3 or 1 : 2) as solvent system and iodine chamber as visualizing agent.

Typical procedure for the synthesis of 6-Methoxyisatin-3-thiosemicarbanzone(I)

A mixture of 6-methoxyisatin(0.18g, 0.001 mol) in Anhyd. ethanol (2ml) and thiosemicarbazide (0.1g, 0.0011 mol) in a mixture of water (2 ml) and glacial acetic acid (0.5 ml) was irradiated under microwave irradiation at 560W for 5-minutes. A yellow coloured solid formed during irradiation. The solid was filtered, washed well with water and crystallized from ethanol-DMF furnishing yellow crystals. yield 0.247g (95%), m.p. 265^OC.[Found : N, 22.68, S, 12.62. C₁₀H₁₀N₄O₂S requires N, 22.40; S, 12.80%]; IR : 825, 860 (1, 2, 4-trisubstituted benzene ring), 1115 (C=S), 1125 & 1370 (C-O-C stretching), 1620 (C=N), 1700 (C=O), 3200, 3280, 3400 (NH, NH₂).

Typical procedure for the synthesis of 7-Methoxy-5H-2,3-dihydro [1, 2, 4] triazino [5, 6-b] indole-3-thione(II)

6-Methoxyisatin-3-thiosemicarbazone (I, 0.125g, 0.0005 mole) in 5% KOH (3.5 ml) was irradiated under microwave irradiation at 560W for 5-minutes. The reaction mixture was cooled and the insoluble material removed by filtration. The filtrate on neutralisation with dil. HCl gave a yellow solid which was filtered, washed well with water and crystallised from aq. DMF furnishing yellow crystals, yield 0.108 g (92%), m.p. > 260^OC [Found : C, 51.91; H, 3.57; N, 23.84; S, 13.58. C₁₀H₈N₄SO requires C, 51.72; H, 3.45; N, 24.13; S, 13.79%]; IR : 810, 860 (1, 2, 4-Trisubstituted benezene ring), 1150 (C=S), 1170, 1370 (C-O-C stretching), 1590, 1610 (C=N), 3200 (N-H stretching).

Typical procedure for the synthesis of 5H-3-(p-chlorophenacylthio-7-methoxy[1, 2, 4]triazino [5, 6-b] indole hydrobromide (IIIa; Ar = p-C1C₆H₄)

A mixture of II(0.232 g, 0.001 mol) and p-cholorophenacyl bromide (0.234 g, 0.001 mol) in DMF (6 ml) was irradiated under microwave irradiation at 560W for 5-minutes, and poured into ice-water. The solid thus separated, was filtered, washed with water and crystallized from aq. DMF to give IIIa as yellow crystals, yield 0.415 g (94%), m.p. > 260 [Found: N, 12.20; S, 6.92. C₁₈H₁₄N₄O₂ SBrCl requires N, 12.03; S, 6.87%]; IR : 810, 860 (1, 2, 4-trisubstituted benzene ring), 1170, 1370 (C-O-C stretching), 1570 (C-N stretching), 1590, 1610 (C=NO, 1690 (C=O), 3180 (N-H stretching). Following members of the series were also prepared in a similar way : IIIb (Ar = p-BrC₆H₄-), yield (91%), m.p. > 260^OC [Found : N, 11.23; S, 6.38, C₁₈H₁₄N₄O₂SBr₂ requires, N, 10.98; S, 6.27%]; IR: 1570 (C-N stretching), 1610 (C=N), 1690 (C=O), 3190 (N-H). IIIc (Ar = C₆H₅), yield (98%) m.p. > 260^OC [Found : N, 14.62; S, 8.18.C₁₈H₁₅N₄O₂SC1 requires N, 14.49; S, 8.27%]; IR : 1575 (C-N stretching), 1600 (C=N), 3240 (N-H stretching).

Typical procedure for the synthesis of 3-p-Chlorophenyl-8-methoxythiazolo[3’, 2’ : 2, 3][1, 2, 4] triazino [5, 6-b] indole(IVa, R = C1)

Ketone IIIa(0.1g) in a mixture of H₃PO₄ (0.3ml) and P₂O₅ (0.4g) was irradiated under microwave irradiation at 560W for 5-minutes. The reaction mixture was poured into water and neutralised with aq. K₂CO₃ solution. The solid, thus separated, was filtered, washed well with water and  crystallised from aq. DMF to furnish IVa as dark red crystals, yield 0.071 g (91%), m.p. > 250⁰ [Found : C, 59.17; H, 3.11; N, 15.16; S, 8.91.C₁₈H₁₁N₄SOCI requires C, 58.93; H, 3.01; N,15.27; S, 8.73%]; IR; 1515 (C-N stretching) 1600 (C=N). PMR (DMSO-d₆) : 3.95 (3H, s, C₈-OCH₃), 7.40 [2H, d (J=7.5Hz), H-3’ and H-5’], 7.70 [2H,d (J = 7.5.Hz), H-2’ and H-6’], 7.90 (1H,s,C₂-H), 6.9-8.1 (3H, m, aromatic protons of indole moiety). Following members of the series were also prepared in a similar way: IVb (R = Br): yield (90%), m.p. > 250^OC [Found : C, 52.38; H, 2.76; N, 13.42; S, 7.51.C₁₈H₁₁N₄SOBr requires C, 52.55; H, 2.67; N, 13.62; S, 7.78%]; IR : 1520 (C-N stretching), 1610 (C = N). IVc (R = H) : yield (96%), m.p. > 250^OC[Found : C, 64.92; H, 3.68; N, 16.64; S, 9.87.C₁₈H₁₁N₄SO requires C, 65.06; H, 3.61; N, 16.86; S, 9.63%]; IR : 1520 (C-N stretching), 1610 (C = N).

Acknowledgment

We thank Professor D. Villemin (France), Dr. R. Sharma (Dayton, USA) and Professor A.J. Bellamy (Swindon, UK) for inspiration.

References

1. Jag Mohan, G.S.R. Anjaneyulu & Kiran, Indian J. Chem. 27B, 128(1988).
2. H.R. Snyder, Jr. and L.E. Benjamin, J. Med. Chem., 9, 402 (1966).
3. Norwich Pharmacal Co. Neth. Appl. 6,400,380 (1964); Chem. Abstr., 62,2780(1965).
4. D.L. Trepanier and P.E. Krieger, U.S. Pat., 3,641,019 (1972); Chem. Abstr., 76, 127024k (1972).
5. C.J. Sharpe, R.S. Shadbolt, A. Ashford and J.W. Ross, J. Med. Chem., 14, 977 (1971).
6. M.M. KOchhar and B.B. Williams, J. Med. Chem., 15, 322 (1972).
7. S. Kano and T. Noguchi, Japan Pat., 71 37,836 (1971); Chem. Abstr., 76, 25295g(1972).
8. E.E. Renfrew and H.W. Pons, U.S. Pat., 3,950,130 (1976); Chem. Abstr., 85, 22753e (1976).
9. P.W. Jenkins and L.G.S. Brooker, U.S. Pat., 3,681,081 (1972); Chem. Abstr., 78, 85949z (1973).
10. M. Hinata, K. SHiba, H. Takei, A. Sato and T. Sakai, Ger. Offen., 2,418,278 (1974); Chem. Abstr., 82,49815K (1975).
11. L.G.S. Brooker, U.S. Pat., 2,089,729 (1937); Chem. Abstr. 31, 6989 (1937).
12. (a) Romagnoli, R; Baraldi, P.G; Cruz-Lopez, C Preti, D Bermejo, J Estavez, F. Chem. Med. Chem. 2009, 4, 1668. (b) Bursavich, M. G Gilbert, A.M Lombardi, S Georgiadis, K. E_; Reifenberg, E₄ Flannery, C. R; Morris, E.A. bioorg. Med. Chem. Lett. 2007,17, 5630. (c) Konkel, M.J Packiarajan, M Chem. H Topiwala, U.P₄ Jimenez, H Talisman, I.J Coate, H Walker, M.W. Bioorg. Med. Chem. Lett, 2006, 16, 3950. (d) Lam, P.Y.S Vinoent, G Clark, C.G Dcudon, S Jadhav, P.K. Tetrahedron Lett, 2001, 42, 3415.
13. Shindikar, A.V Khan, F Viswanathan, C.L. Eur.J.Med. Chem. 2006,41, 786. (b) Moser, P₄ Sallmann, A Wieserberg, I.J. Med. Chem. 1990, 33, 2358. (c) Sarges, R Howard, H. R_­ Koe. H.K Weissman, A.J.Med. Chem. 1989, 32, 437.
14. Peet, N.J. Heterocycl, Chem. 1990, 17, 1514.
15.  For reviews, see: (a) Chem, Y Larock, R.C. In Modern Arylation Methods, Ackerman, J. ED Wiley/ VCH New York, 2009, PP401. (b) Sanz, R.Org. Prep. Proced. Int. 2008, 40, 215.
16. Lin, Z; Larock, R. C. J. Org. Chem. 2006, 71, 3198. (b) Lin, Z; Larock, R. C. Org. Lett. 2003, 5, 4673. (c) Lin, Z; Larock, R. C. Org. Lett. 2004,6, 99.Lin, Z; Larock, R. C. J. AR.Chem. Sec. 2005, 127, 13112.
17. Lin, Z; Larock, R. C. J. AR.Chem. Sec. 2005, 127, 13112.
18. Pintori, D. G Greaney, M.F.Org. Lett. 2010, 12, 168.
19. Yoshida, H Shirakawa, E₄ Honda, Y Hiyama, T. Angew. Chem, Inted. 2002, 41, 3246.
20.  Zhao, J Larock, R.C.J.Org. Chem. 2007, 72, 583.
21.  Rogness D. C Larock, R.C. Tetrahedron Lett 2009, 50, 4003.
22. Lin, Z; Larock, R.C.J. Org. Chem. 2006, 71, 3198.
23. Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.

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