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

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

References and Notes

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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].