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Synlett 2009(9): 1463-1465  
DOI: 10.1055/s-0029-1217178
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Expedient Entry to Fused [1,2,5]-Triazepine Derivatives: Extension to Fused [1,2,5]-Oxadiazine Derivatives, a New Class of Seven-Membered Heterocycles [¹]

Gade Srinivas Reddya,b, Prataprao Anil Kumara, Ramasamy Vijaya Ananda, Kaga Mukkantib, Padi Pratap Reddy*a
a Research & Development, Integrated Product Development, Dr. Reddy’s Laboratories Limited, Bachupally, Ranga Reddy District 500072, Andhra Pradesh, India
e-Mail: prataprp@drreddys.com;
b Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India
Further Information

Publication History

Received 6 January 2009
Publication Date:
13 May 2009 (online)

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Abstract

This document describes an efficient synthesis of fused indole containing tricyclic [1,2,5]-triazepine derivatives from 2-­cyanomethyl indole in two simple and convenient steps. This new methodology allows us to synthesize a variety of substituted [1,2,5]-triazepine derivatives in excellent yields. Further exploration of this methodology using 2-cyanomethyl indole and hydroxylamine directed us to access a new class of seven-membered fused [1,2,5]-oxadiazine derivatives in good to excellent yields.

Key words

heterocycles - indoles - fused-ring systems - [1,2,5]-triazepines - [1,2,5]-oxadiazines

1

IPD communication number: DRL-IPDO-IPM-00176.

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1

IPD communication number: DRL-IPDO-IPM-00176.

11

1-[2-(4-Methoxyphenyl)-2-oxoethyl]-1 H -indole-2-carbonitrile (7a); Typical Procedure
To a solution of 1H-indole-2-carbonitrile (5; 10.0 g, 0.07 mol) in acetone (100 mL) were added p-methoxyphenacyl bromide (6; 17.6 g, 0.077 mol) and anhyd K2CO3 (38.6 g, 0.28 mol) followed by TBAI (0.37 g, 0.001 mol) and the resulting mixture was stirred at reflux temperature for 2 h. Acetone was removed under vacuum and the residue was quenched with H2O and filtered. The crude product 7a was then recrystallized from MeOH to give the pure product as a solid. Yield: 16.0 g (78%); mp 126 ˚C. FT IR (KBr): 2223, 1682, 1602 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.89 (s, 3 H, OMe), 6.05 (s, 2 H, NCH2), 7.15 (d, J = 8.4 Hz, 2 H, Ar), 7.21 (t, J = 7.6 Hz, 1 H, Ar), 7.37 (t, J = 8.4 Hz, 1 H, Ar), 7.52 (s, 1 H, indole CH), 7.62 (d, J = 8.8 Hz, 1 H, Ar), 7.73 (d, J = 8.4 Hz, 1 H, Ar), 8.13 (d, J = 8.4 Hz, 2 H, Ar). ¹³C NMR (50 MHz, DMSO-d 6): δ = 50.5, 55.6, 109.9, 110.5, 113.4, 113.7, 114.2, 121.6, 122.5, 126.1, 126.2, 127.1, 130.4, 138.1, 164.4, 189.6. HRMS (ES): m/z calcd for C18H15N2O2 [M + 1]: 291.1134; found: 291.1121.

12

[1,2,5]-Triazepine Derivative 8a; Typical Procedure A solution of 7a (10.2 g, 0.035 mol) in hydrazine hydrate (50 mL) was refluxed for 2 h. It was cooled to r.t. and filtered to give compound 8a as a solid. Yield: 9.2 g (86%); mp 258-260 ˚C. FT IR (KBr): 3164, 3293, 3053, 1638 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.81 (s, 3 H, OMe), 7.04 (d, J = 8.8 Hz, 2 H, Ar), 7.27 (s, 1 H, indole CH), 7.30 (t, J = 8.0 Hz, 1 H, Ar), 7.40 (t, J = 8.0 Hz, 1 H, Ar), 7.73 (d, J = 8.8 Hz, 2 H, Ar), 7.82 (d, J = 8.0 Hz, 1 H, Ar), 8.14 (s, 1 H, NCH=C), 8.20 (d, J = 8.8 Hz, 1 H, Ar), 10.99 (br s, 1 H, NH). ¹³C NMR (50 MHz): δ = 55.3, 101.1, 102.7, 112.1, 114.0, 122.0, 122.3, 123.5, 124.4, 124.5, 126.8, 126.9, 127.3, 132.2, 157.3, 159.4. HRMS (ES): m/z calcd for C18H17N4O [M + 1]: 305.1402; found: 305.1403.

18

[1,2,5]-Oxadiazine Derivative 9a; Typical Procedure
A mixture of 7a (18.0 g, 0.062 mol), HONH2˙HCl (13.0 g, 0.187 mol) and Na2CO3 (19.8 g, 0.187 mol) in MeOH (100 mL) was refluxed for 30 min. The reaction mixture was quenched with ice-water and filtered. The crude product thus obtained was recrystallized from MeOH-acetone mixture to provide pure 9a. Yield: 16.6 g (88%); mp 220-222 ˚C. FT IR: 3403, 1629 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.81 (s, 3 H, OMe), 6.87 (s, 1 H, indole CH), 7.05 (d, J = 8.8 Hz, 2 H, Ar), 7.18 (t, J = 7.2 Hz, 1 H, Ar), 7.27 (t, J = 7.2 Hz, 1 H, Ar), 7.63 (s, 1 H, NCH=C), 7.63-7,68 (m, 1 H, Ar), 7.67 (d, J = 8.4 Hz, 2 H, Ar), 7.99 (d, J = 8.4 Hz, 1 H, Ar), 8.29 (s, 1 H, NH), 10.37 (s, 1 H, =NH). ¹³C NMR (50 MHz, DMSO-d 6): δ = 55.3, 96.0, 99.3, 110.7, 114.2, 120.8, 121.5, 122.1, 123.6, 124.4, 125.3, 126.4, 127.7, 132.4, 140.4, 159.4. HRMS (ES): m/z calcd for C18H16N3O2 [M + 1]: 306.1243; found: 305.1234.