Download PDF
Synlett 2008(19): 3011-3015  
DOI: 10.1055/s-0028-1087298
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Sequential Aza-Claisen Rearrangement and Ring-Closing Metathesis as a Route to 1-Benzazepine Derivatives

Debalina Ghosh, Latibuddin Thander, Sanjay K. Ghosh, Shital K. Chattopadhyay*
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax: +91(33)25828282; e-Mail: skchatto@yahoo.com;
Further Information

Publication History

Received 23 June 2008
Publication Date:
23 October 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

A synthetic strategy based on sequential application of aza-Claisen rearrangement and ring-closing metathesis reaction as key steps has been developed for the synthesis of various 1-benzazepine derivatives of pharmaceutical relevance.

Key words

aza-Claisen rearrangement - benzazepine - ring-closing metathesis

19

Representative Procedure for the Sequence of Reactions in Scheme 1: N , N -Diallyl-4-methylaniline (6b)
Allyl bromide (2.7 mL, 31.4 mmol) was added dropwise to a solution of 5b (1.7 g, 15.7 mmol) and Et3N (4.4 mL, 31.4 mmol) in dry MeCN (25 mL), and the mixture was heated to reflux for 18 h. It was then allowed to come to r.t., concentrated under reduced pressure, and the residual mass was extracted with EtOAc (50 mL). The extract was washed successively with H2O (25 mL), brine (25 mL), and then dried (Na2SO4). It was filtered, concentrated under reduced pressure, and the residue was purified by chromatography over SiO2 using PE as eluent to afford 6b as a pale yellow viscous liquid (2.09 g, 71%). IR(neat): 1642, 1619, 1521, 1235, 1182 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.01 (d, 2 H, J = 8.2 Hz), 6.62 (d, 2 H, J = 7.8 Hz), 5.89-5.80 (m,
2 H), 5.20-5.12 (m, 4 H), 3.88 (d, 4 H, J = 4.8 Hz), 2.23 (s, 3 H). Anal. Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.34; H, 9.28; N, 7.39.
N ,2-Diallyl-4-methylaniline (7b)
Boron trifluoride etherate (1.8 mL, 15 mmol) was slowly added to a solution of 6b (1.9 g, 10 mmol) in PhCl (15 mL) under nitrogen, and the mixture was heated to reflux for 5 h. It was then allowed to come to r.t., quenched with sat. aq NaHCO3 solution (20 mL), and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic mixture was washed successively with H2O (25 mL), brine (25 mL), and then dried (Na2SO4). It was filtered, concentrated under reduced pressure, and the residue was purified by chromatography over SiO2 using PE as eluent to give starting 6b (0.17g, 9%) followed by the product 7b (1.31g, 69%) as a pale yellow viscous liquid. IR(neat): 3442, 3387, 1636, 1618, 1515, 1313 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.94 (d, 1 H, J = 8.1 Hz), 6.87 (s, 1 H), 6.55 (d, 1 H, J = 8.1 Hz), 5.98-5.92 (m, 2 H), 5.28-5.06 (m, 5 H), 3.76 (dt, 2 H, J = 5.4, 1.5 Hz), 3.28 (d, 2 H, J = 6.2 Hz), 2.24 (s, 3 H). Anal. Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.40; H, 9.26; N, 7.43.
N -Allyl- N -(2-allyl-4-methylphenyl)-4-methylbenzene-sulfonamide (8b)
p-Toluenesulfonyl chloride (1.71 g, 9 mmol) was added to a solution of 7b (1.1g, 5.9 mmol) and Et3N (1.7 mL, 12 mmol) in dry CH2Cl2 (20 mL), and the reaction mixture was stirred at r.t. for 12 h. It was then diluted with CH2Cl2 (20 mL), and the solution was washed successively with HCl (1 N, 2 × 25 mL), H2O (25 mL), brine (25 mL), and then dried (Na2SO4). It was filtered, concentrated under reduced pressure, and the residue was purified by chromatography over SiO2 using EtOAc-PE (1:19) as eluent to give the product as a colorless viscous liquid (1.7 g, 85%). IR (CHCl3): 1638, 1598, 1497, 1349, 1219, 1164, 1062 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.58 (d, 2 H, J = 8.2 Hz), 7.26 (d, 2 H, J = 8.1 Hz), 7.09 (s, 1 H), 6.85 (d, 1 H, J = 7.9 Hz), 6.46 (d, 1 H, J = 8.0 Hz), 5.97-5.84 (m, 1 H), 5.80-5.68 (m, 1 H), 5.14-5.08 (m, 2 H), 5.01-4.93 (m, 2 H), 4.30 (dd, 1 H, J = 14.0, 5.6 Hz), 3.85 (dd, 1 H, J = 14.0, 7.6 Hz), 3.55 (dd, 1 H, J = 15.5, 6.5 Hz), 3.45 (dd, 1 H, J = 15.4, 6.5 Hz), 2.44 (s, 3 H), 2.30 (s, 3 H). Anal. Calcd for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10. Found: C, 70.48; H, 6.88; N, 4.29.
7-Methyl-1-tosyl-2,5-dihydro-1 H -benzo[ b ]azepine (10b)
Catalyst 9 (14 mg, 5 mol%) was added to a solution of 8b (0.11g, 0.32 mmol) in dry, degassed CH2Cl2 (30 mL) under nitrogen, and the reaction mixture was stirred at r.t. for 2 h. It was then concentrated under reduced pressure and the residue was chromatographed over SiO2 using EtOAc-PE (1:13) as eluent to give the product 10b (83 mg, 83%) as a colorless solid; mp 114 ˚C. IR (CHCl3): 1598, 1496, 1343, 1157 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.64 (d, 2 H, J = 8.2 Hz), 7.24 (d, 2 H, J = 8.5 Hz), 7.16 (d, 1 H, J = 8.0 Hz), 7.00 (d, 1 H, J = 7.9 Hz), 6.87 (s, 1 H), 5.66-5.60 (m,
1 H), 5.45-5.41 (m, 1 H), 4.35 (br s, 2 H), 2.92 (br s, 2 H), 2.42 (s, 3 H), 2.29 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 143.1, 140.8, 138.7, 138.3, 136.0, 129.9, 129.7, 129.4, 128.0, 127.0, 125.8, 125.3, 49.1, 32.2, 21.5, 21.0. Anal. Calcd for C18H19NO2S: C, 68.98; H, 6.11; N, 4.47. Found: C, 69.13; H, 6.18; N, 4.58. MS (TOFMS ES+): m/z = 336 [M+ + Na].
Selected Data Compound 10c: Mp 128 ˚C. IR (KBr): 1602, 1500, 1341, 1159 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.63 (d, 2 H, J = 8.2 Hz), 7.24 (d, 2 H, J = 8.1 Hz), 7.19 (d, 1 H, J = 8.8 Hz), 6.71 (dd, 1 H, J = 8.6, 2.9 Hz), 6.58 (d, 1 H, J = 2.7 Hz), 5.65-5.59 (m, 1 H), 5.45-5.41 (m, 1 H), 4.35 (br s, 2 H), 3.78 (s, 3 H), 2.88 (br s, 2 H), 2.42 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 159.2, 143.1, 142.5, 138.6, 131.2, 131.1, 129.4, 127.0, 125.9, 124.9, 114.6, 112.1, 55.3, 49.2, 32.4, 21.5. Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.80; H, 5.98; N, 4.43. MS (TOFMS ES+):
m/z = 352 [M+ + Na].
Compound 12b: Mp 135 ˚C. IR (KBr): 1715, 1596, 1491, 1352, 1168 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.91 (d, 2 H, J = 8.3 Hz), 7.41 (d, 1 H, J = 8.0 Hz), 7.32 (d, 2 H, J = 8.1 Hz), 7.18 (d, 1 H, J = 8.1 Hz), 7.03 (s, 1 H), 2.48-2.44 (m, 2 H), 2.38 (s, 3 H), 2.23 (s, 3 H), 2.10-2.04 (m,
3 H), 1.79-1.77 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 172.7, 144.8, 139.4, 136.6, 135.8, 133.4, 129.7, 129.3, 129.1, 128.8, 127.9, 34.4, 29.1, 27.3, 21.7, 21.1. Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.78; H, 6.04; N, 4.48. MS (TOFMS ES+): m/z = 352 [M+ + Na].
Compound 16: IR (CHCl3): 1735, 1597, 1342, 1160, 1109 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.91 (d, 1 H, J = 10.0 Hz), 7.68 (d, 2 H, J = 8.2 Hz), 7.35 (d, 1 H, J = 8.8 Hz), 7.30 (d, 2 H, J = 8.1 Hz), 7.17 (d, 1 H, J = 8.7 Hz), 6.43 (d, 1 H, J = 9.9 Hz), 5.79-5.71 (m, 1 H), 5.54-5.50 (m, 1 H), 4.37 (br s, 2 H), 3.34 (d, 2 H, J = 4.0 Hz), 2.45 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 159.7, 153.7, 143.6, 140.3, 139.6, 138.0, 135.2, 132.6, 129.7, 126.9, 126.7, 123.5, 116.5, 116.3, 115.5, 48.7, 24.6, 21.4. Anal. Calcd for C20H17NO4S: C, 65.38; H, 4.66; N, 3.81. Found: C, 65.66; H, 4.83; N, 3.96. MS (TOFMS ES+): m/z (%) = 390(100) [M + Na], 368(41) [M + H].
Compound 20: mp 224 ˚C IR (KBr): 1654, 1578, 1455, 1333, 1158, 1123 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.90 (d, 1 H, J = 10.0 Hz), 7.68 (d, 2 H, J = 8.2 Hz), 7.47 (d, 1 H, J = 9.0 Hz), 7.30-7.22 (m, 3 H), 6.72 (d, 1 H, J = 10.0 Hz), 5.80-5.73 (m, 1 H), 5.52-5.48 (m, 1 H), 4.13 (br s, 2 H), 3.71 (s, 3 H), 3.35 (d, 2 H, J = 4.3 Hz), 2.44 (s,
3 H). ¹³C NMR (75 MHz, CDCl3): δ = 161.6, 143.5, 140.2, 140.1, 138.4, 134.5, 133.4, 131.6, 129.7, 126.9, 124.1, 121.7, 118.1, 113.2, 49.0, 29.8, 24.6, 21.5. Anal. Calcd for C21H20N2O3S: C, 66.29; H, 5.30; N, 7.36. Found: C, 66.36; H, 5.41; N, 7.24. MS (TOFMS ES+): m/z = 403 [M + Na].