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

Gade Srinivas Reddy; Prataprao Anil Kumar; Ramasamy Vijaya Anand; Kaga Mukkanti; Padi Pratap Reddy

doi:10.1055/s-0029-1217178

LETTER

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 Reddy^a,b, Prataprao Anil Kumar^a, Ramasamy Vijaya Anand^a, Kaga Mukkanti^b, 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

Abstract

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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

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Referenzen

References and notes

1

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

2a Eicher T. Hauptmann S. The Chemistry of Heterocycles 2nd ed.: Wiley-VCH; Weinheim: 2003. p.461-479

2b Bellantuono C. Reggi G. Tognoni G. Garattini S. Drugs 1980, 19: 195

3a Sternbach LH. J. Med. Chem. 1979, 22: 1

3b Williams M. J. Med. Chem. 1983, 26: 619

3c Snieckus V. Streith J. Acc. Chem. Res. 1981, 14: 348

3d Itto MYA. Hasnaoui A. Riahi A. Lavergne J.-P. Tetrahedron Lett. 1997, 38: 2087

3e Quan H.-J. Koyanagi J. Hagiwara K. Cui X.-R. Isshiki Y. Kondo S. Komada F. Saito S. Chem. Pharm. Bull. 2006, 54: 73

4 Sui Z, and Walsh SP. inventors; US Patent, 6821993B1.

5 Lenman MM. Lewis A. Gani D. J. Chem. Soc., Perkin Trans. 1 1997, 2297

6a Seebacher W. Michl G. Weis A. Tetrahedron Lett. 2002, 43: 7481

6b Rezessy B. Zubocics Z. Kovacs J. Toth G. Tetrahedron 1999, 55: 5909

6c Adamo MFA. Baldwin JE. Adlington RM. J. Org. Chem. 2005, 70: 3307 ; and references cited therein

7a Saveleva EA. Rozin YA. Kodess MI. Meervelt LV. Dehaen W. Morzherin YY. Bakulev VA. Tetrahedron 2004, 60: 5367

7b Zaleska B. Trzewik B. Grochowski J. Serda P. Synthesis 2003, 2559

7c Katritzky AR. Fan W.-Q. Greenhill JV. J. Org. Chem. 1991, 56: 1299

7d Lenman MM. Lewis A. Gani D. J. Chem. Soc., Perkin Trans. 1 1997, 2297

7e Bouteau B. Imbs J.-L. Lancelot J.-C. Barthelmebs M. Robba M. Chem. Pharm. Bull. 1991, 39: 81

7f Kirchner E. Bretschneider H. Monatsh. Chem. 1971, 102: 162

8 Scott AI. Acc. Chem. Rev. 1970, 3: 151

9a Flynn BL. Hamel E. Junk MK. J. Med. Chem. 2002, 45: 2670

9b Chao W.-R. Yean D. Amin K. Green C. Jong L. J. Med. Chem. 2007, 50: 3412

9c Breslin HJ. Miskowski TA. Kukla MJ. Leister WH. Winter HLD. Gauthier DA. Somers MVF. Peeters DCG. Roevens PWM. J. Med. Chem. 2002, 45: 5303

10 Pletnev AA. Tian Q. Larock RC. J. Org. Chem. 2002, 67: 9276

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.

13a Cho SY. Kang SK. Ahn JH. Ha JD. Choi J.-K. Tetrahedron Lett. 2006, 47: 9029

13b Srivastava RM. de Morais LPF. de Melo Souto SC. Carpenter GB. de Carvalho LT. Tetrahedron Lett. 2006, 47: 3173

13c Tabei K. Kawashima E. Takada T. Kato T. Chem. Pharm. Bull. 1982, 30: 3987

14 Butler RN. McMahon JM. McDonald PD. Pyne CS. Schambony S. McArdle P. Cunningham D. J. Chem. Soc., Perkin Trans. 1 1997, 1047

15 Makula D, Druet M, and Gonthier B. inventors; US Patent, 3696099.

16 Hansen DW, Hallinan EA, Awasthi AK, Metz S, Scholten JA, Snyder JS, Toth MV, and Webber RK. inventors; US Patent, 6774126B2.

17 Takacs K, Simay A, Kiss I, Nagy PL, Hetvey M, Escery M, Szegy J, Viragh S, and Nagy SJ. inventors; US Patent, 4308270.

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.