HETEROCYCLES

Note | Special issue | Vol. 77, No. 1, 2009, pp. 575-585
Received, 8th May, 2008, Accepted, 23rd June, 2008, Published online, 26th June, 2008.
DOI: 10.3987/COM-08-S(F)21

■ 8-Endo-Selective Aryl Radical Cyclization Leading to 3-Benzazocines

Tsuyoshi Taniguchi, Hisaaki Zaimoku, and Hiroyuki Ishibashi*

Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

Bu3SnH-mediated radical cyclization of N-acyl-3-(2-bromophenyl)-N-ethenypropylamines (14) occurred in an endo-selective manner to give the 3-benzazocine derivatives (15) in good yields.

INTRODUCTION
In a previous paper, we reported that Bu3SnH-mediated radical cyclization of enamide (1) gave an isoquinoline derivative (2) as the major product along with a 3-benzazepine derivative (3) in a ratio of 3:1, and the cyclization of enamide (4) gave exclusively a 3-benzazepine derivative (5) (Scheme 1).1 These results strongly indicated that positional change in the carbonyl group of enamide played an important role in deciding the course of radical cyclization. When the carbonyl group of starting enamide could be

incorporated into the newly formed ring, exo radical cyclization predominated (e.g., 1→2), whereas when the carbonyl group was not incorporated into the newly formed ring, endo cyclization might result (e.g., 4→5). We soon found, however, that exo-selectivity of the radical cyclization was lost even when the carbonyl group is incorporated into the newly formed ring. The radical cyclization of enamide (6) gave a 7-exo cyclization product (7) and an 8-endo cyclization product (8) in almost equal amounts (Scheme 2), although total yields of the cyclization products were low: the major product was a so-called reduction product (9).2

We then turned our attention to enamides (14), whose radical cyclizations were expected to occur in an 8-endo-selective manner, since their carbonyl groups were not incorporated into the newly formed ring. We describe herein a synthesis of 3-benzazocine derivatives (15) by radical cyclization of enamides (14).3

RESULTS AND DISCUSSION
Scheme 3 shows the synthetic route to the requisite enamides (14). Amine (12) was obtained by condensation of carboxylic acid (10) with 2-(phenylthio)ethylamine followed by reduction of the carbonyl group of the resulting amide (11) with BH3. Acylation of amine (12) with acetyl chloride, pivaloyl chloride, carbobenzoxy chloride or (Boc)2O gave amides (13a-d), whose oxidation followed by thermal elimination of the phenylsulfinyl group gave enamides (14a-d) in 68%, 70%, 57% and 62% yields based on amides (13a-d), respectively.
When enamide (14a) was treated with a mixture of Bu3SnH and azobis(cyclohexanecarbonitile) (ACN) (by using the slow addition technique) in boiling toluene, 3-acetyl-3-benzazocine derivative (15a) was obtained in 57% yield along with the reduction product (16a) (30% yield) (Scheme 3). No 7-exo cyclization product was obtained. Similarly, enamides (14b-d) gave 3-benzazocine derivatives (15b), (15c) and (15d) in 67%, 58% and 63% yields, respectively. It should be noted that the radical cyclization of enamides (14a-d) exclusively took place in an endo-manner to give 3-benzazocines (15a-d) in good yields.

We next examined the cyclization of enamides (19a) and (19b) having the methyl or phenyl group at the terminus of the alkenic bond, respectively. Compounds (19a) and (19b) were prepared by condensation of amine (17) and propionaldehyde or phenylacetaldehyde followed by acetylation of the resulting imines (18a) and (18b) with acetyl chloride, respectively (Scheme 4).
Treatment of compound (19a) with Bu3SnH-ACN in boiling toluene gave 1-methyl-3-benzazocine derivative (20a) and 1-ethyl-2-benzazepine derivative (21a) in 45% and 9% yields, respectively, along with reduction product (22a) in 38% yield (Scheme 4). 7-Exo cyclization product (21a) may arise from a stable intermediate of a methyl-substituted radical. As expected, treatment of phenyl-substituted compound (19b) increased the yield of 7-exo cyclization product (21b), due to the more stable phenyl-substituted radical intermediate. The ratio of the 8-endo cyclization product (20b) and the 7-exo cyclization product (21b) was ca. 1:1.

CONCLUSION
We revealed that Bu3SnH-mediated radical cyclization of N-acyl-3-(2-bromophenyl)-N-ethenylpropyl-amines occurred exclusively in an endo-manner to give 3-benzazocine derivatives in good yields. A similar cyclization of a compound having the methyl or phenyl substituent at the terminus of the alkenic bond, however, occurred partially in an exo manner to give 2-benzazepine derivatives.

EXPERIMENTAL
General Melting points are uncorrected. Infrared (IR) spectra were recorded on a Shimadzu FTIR-8100 spectrophotometer for solutions in CHCl3. 1H NMR and 13C NMR spectra were measured on a JEOL EX 500 (500 MHz) or a JEOL JNM-EX 270 (270 MHz) spectrometer. Chemical shifts (δ) quoted are relative to tetramethylsilane. High resolution mass spectra (HRMS) were obtained with a JEOL JMS-SX-102A mass spectrometer. Column chromatography was carried out on silica gel 60N (Kanto Kagaku Co., Ltd., spherical, neutral, 63–210 μm) under pressure.

3-(2-Bromophenyl)-N-(2-phenylthioethyl)propanamide (11) To a solution of 3-(2-bromophenyl)propionic acid (2.24 g, 9.78 mmol) in CH2Cl2 (50 mL) were added 2-(phenylthio)ethylamine4 (1.50 g, 9.80 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (2.25 g, 11.7 mmol) at rt, and the mixture was stirred for 2 h. The mixture was diluted with water and the organic layer was separated. The organic phase was washed successively with brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (hexane/AcOEt, 1:1) to give 11 (3.00 g, 84%) as colorless crystals, mp 84.5-86.0 ˚C (hexane): IR (CHCl3) υ 1665 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 2.45 (2H, t, J = 7.4 Hz), 3.00 (2H, t, J = 6.3 Hz), 3.06 (2H, t, J = 7.4 Hz), 3.43 (2H, q, J = 6.3 Hz), 5.76 (1H, br), 7.03-7.37 (8H, m), 7.52 (1H, d, J = 8.4 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 31.9, 33.2, 36.1, 38.5, 124.1, 126.3, 127.5, 127.9, 129.0, 129.4, 130.5, 132.7, 134.9, 139.8, 171.8. Anal. Calcd for C17H18BrNOS: C, 56.05; H, 4.98; N, 3.84. Found: C, 55.76; H, 5.04; N, 3.76.

3-(2-Bromophenyl)-N-(2-phenylthioethyl)propylamine (12) To a solution of 11 (2.80 g, 7.69 mmol) in THF (20 mL) was added a 1 M solution of BH3･THF (35 mL, 34.3 mmol) at rt, and the mixture was heated at reflux for 1.5 h. MeOH was added to the reaction mixture, and the mixture was stirred at rt for 30 min. After evaporation of the solvent, 1N HCl was added to the residue, and the mixture was heated at reflux for 1 h. The mixture was basified by adding 1N NaOH, and the mixture was extracted with CHCl3. The organic phase was washed successively with brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (hexane/AcOEt, 1:1) to give 12 (2.41 g, 90%) as a colorless oil: 1H NMR (270 MHz, CDCl3) δ (ppm): 1.52 (1H, s), 1.79 (2H, quint, J = 7.4 Hz), 2.67 (2H, t, J = 7.4 Hz), 2.76 (2H, t, J = 7.4 Hz), 2.86 (2H, t, J = 6.6 Hz), 3.08 (2H, t, J = 6.6 Hz), 7.01-7.38 (8H, m), 7.51 (1H, d, J = 7.7 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 30.1, 33.7, 34.1, 48.2, 48.7, 124.3, 126.0, 127.3, 127.4, 128.8, 129.4, 130.2, 132.7, 135.8, 141.2. Anal. Calcd for C17H20BrNS: C, 58.28; H, 5.75; N, 4.00. Found: C, 58.27; H, 5.87; N, 4.12.

N-[3-(2-Bromophenyl)propyl]-N-(2-phenylthioethyl)acetamide (13a) General procedure To a solution of 12 (1.3 g, 3.71 mmol) in CH2Cl2 (40 mL) was added acetyl chloride (437 mg, 5.57 mmol) and Et3N (676 mg, 6.68 mmol) at 0 ˚C, and the mixture was stirred at the same temperature for 30 min. The mixture was diluted with water and extracted with CH2Cl2. The organic phase was washed successively with a saturated aqueous solution of NaHCO3 and brine. After drying (MgSO4), the mixture was concentrated. The residue was chromatographed on silica gel (hexane/AcOEt, 2:1) to give 13a (1.38 g, 95%) as a colorless oil, whose 1H NMR showed it to be a mixture of two rotamers: IR (CHCl3) υ 1630 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.75-1.90 (2H, m), 1.98 and 2.00 (total 3H, both s), 2.66-2.73 (2H, m), 2.99-3.16 (2H, m), 3.28-3.55 (4H, m), 7.04-7.56 (9H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 13.4, 13.9, 19.2, 21,6, 22.8, 24.7, 28.3, 35.5, 40.2, 126.9, 127.1, 127. 2, 127.6, 128.4, 138.5, 172.0. Anal. Calcd for C19H22BrNOS: C, 58.16; H, 5.65; N, 3.57. Found: C, 58.05; H, 5.83; N, 3.78.

N-[3-(2-Bromophenyl)propyl]-N-(2-phenylthioethyl)trimethylacetamide (13b) Yield = quant.; colorless oil: IR (CHCl3) υ 1615 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.17 (9H, s), 1.78-1.89 (2H, m), 2.69 (2H, t, J = 7.6 Hz), 3.08 (2H, t-like, J = 7.9 Hz), 3.42 (2H, t-like, J = 7.6 Hz), 3.50 (2H, t-like, J = 7.9 Hz), 7.04-7.41 (8H, m), 7.53 (1H, dd, J = 6.6, 1.3 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 26.5, 28.3, 28.8 (br), 33.4, 38.9, 47.8, 48.1 (br), 124.3, 127.5, 127.9, 129.0, 130.3, 132.9, 177.4; HRMS calcd for C22H2879BrNOS: 433.1075, found: 433.1081.
N-Benzyloxycarbonyl-N-[3-(2-bromophenyl)propyl]-2-phenylthioethylamine (13c) Yield = quant.; colorless oil: IR (CHCl3) υ 1695 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.83 (2H, br), 2.62-2.73 (2H, m), 3.00-3.16 (2H, m), 3.30-3.51 (2H, m), 5.13 (2H, s), 7.01-7.34 (13H, m), 7.51 (1H, d, J = 7.9 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 28.9, 31.1, 33.4, 46.9, 47.8, 67.2, 124.3, 126.1, 127.4, 127.7, 127.8, 128.0, 128.5, 129.0, 130.1, 130.2, 132.8, 136.5, 140.6, 140.8; HRMS calcd for C25H2679BrNO2S: 483.0868, found: 483.0866.

N-[3-(2-Bromophenyl)propyl]-N-tert-butoxycarbonyl-2-phenylthioethylamine (13d) Yield = 96%; colorless oil: IR (CHCl3) υ 1685 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.43 (9H, s), 1.74-1.86 (2H, m), 2.68 (2H, t, J = 7.9 Hz), 3.06 (2H, br), 3.27 (2H, br), 3.39 (2H, br), 7.05-7.37 (8H, m), 7.51 (1H, d, J = 7.9 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 28.4, 31.5, 31.7, 33.5, 47.3, 79.7, 124.3, 126.0, 126.2, 127.4, 127.6, 129.0, 129.2, 130.2, 132.8, 140.9, 170.9; HRMS calcd for C22H2879BrNO2S: 449.1024, found: 449.1012.

N-[3-(2-Bromophenyl)propyl]-N-ethenylacetamide (14a) General procedure To a solution of 13a (1.38 g, 3.52 mmol) in CH2Cl2 (90 mL) was added dropwise a solution of m-chloroperbenzoic acid (mCPBA, 65% purity) (934 mg, 3.52 mmol) in CH2Cl2 (90 mL) at 0° C over 1.5 h. To the mixture was added 10% aqueous solution of Na2S2O3, and the mixture was stirred at the same temperature for 10 min. The organic layer was separated, and washed successively with a saturated aqueous solution of NaHCO3 and brine, dried (MgSO4), and concentrated. A mixture of the residue containing N-[3-(2-bromophenyl)propyl]-N-(2-phenylsulfinylethyl)acetamide in xylene (170 mL) was heated at reflux for 16 h in the presence of NaHCO3 (1.09 g, 13.0 mmol). The reaction mixture was filtered, and the filtrate was concentrated. The reside was chromatographed on silica gel (hexane/AcOEt, 5:1) to give 14 a (671 mg, 68%) as a colorless oil: IR (CHCl3) υ 1625, 1665 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.82-1.89 (2H, m), 2.21 (3H, s), 2.76 (2H, t-like, J = 7.9 Hz), 3.70 (2H, t-like, J = 7.7 Hz) 4.32 (1H, d, J = 9.2 Hz), 4.39 (1H, d, J = 15.5 Hz), 6.74 (1H, dd, J = 15.5, 9.2 Hz), 7.02-7.35 (3H, m), 7.52 (1H, d, J = 7.7 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 22.0, 26.5, 33.5, 41.1, 93.6, 124.4, 127.4, 127.7, 130.2, 132.8, 133.1, 140.7, 169.2: HRMS calcd for C13H1679BrNO: 281.0415, found: 281.0408.

N-[3-(2-Bromophenyl)propyl]-N-ethenyltrimethylacetamide (14b) Yield = 70%; colorless oil: IR (CHCl3) υ 1615, 1655 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.32 (9H, s), 1.83-1.93 (2H, m), 2.75 (2H, t-like, J = 8.1 Hz), 3.70 (2H, t-like, J = 7.7 Hz) 4.26 (1H, d, J = 9.4 Hz), 4.35 (1H, d, J = 15.5 Hz), 7.01-7.08 (1H, m), 7.11 (1H, dd, J = 15.5, 9.4 Hz), 7.22-7.24 (2H, m), 7.52 (1H, d, J = 7.7 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 26.7, 28.5, 33.6, 39.5, 43.2, 92.2, 124.3, 127.4, 127.6, 130.2, 132.7, 134.0, 140.9, 176.5; HRMS calcd for C16H2279BrNO: 323.0885, found: 323.0886.
N-Benzyloxycarbonyl-N-[3-(2-bromophenyl)propyl]ethenylamine (14c) Yield = 57%; colorless oil: IR (CHCl3) υ 1630, 1705 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.90 (2H, br), 2.74 (2H, br), 3.62 (2H, br), 4.20-4.35 (2H, m), 5.20 (2H, s), 7.03-7.06 (2H, m), 7.15-7.21 (2H, m), 7.30-7.36 (4H, m), 7.51 (1H, d, J = 7.9 Hz); 13C NMR (125 MHz, CDCl3) δ (ppm): 26.7, 27.2, 33.4, 42.9, 67.8, 91.8, 124.4, 127.4, 127.7, 128.0, 128.2, 128.5, 130.1, 132.2, 132.8, 136.0; HRMS calcd for C19H2079BrNO2: 373.0677, found: 373.0665.

N-tert-Butoxycarbonyl-N-[3-(2-bromophenyl)propyl]ethenylamine (14d) Yield = 62%; colorless oil: IR (CHCl3) υ 1630, 1700 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.48 (9H, s), 1.81 (2H, quint, J = 7.1 Hz), 2.75 (2H, t-like, J = 8.1 Hz), 3.60 (2H, br), 4.15-4.25 (2H, m), 7.02-7.09 (1H, m), 7.20-7.26 (2H, m), 7.52 (1H, d, J = 8.1 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 27.1 (br), 28.2, 33.5, 42.7 (br), 81.0, 90.5, 124.4, 127.4, 127.7, 130.1, 132.8, 140.9; HRMS calcd for C16H2279BrNO2: 340.0912, found: 340.0910.

3-Acetyl-1,2,3,4,5,6-hexahydro-3-benzazocine (15a) and N-ethenyl-N-(3-phenylpropyl)acetamide (16a) General procedure for radical reaction of N-acyl-3-(2-bromophenyl)propyl-N-ethenylamines (14) To a boiling solution of 14a (200 mg, 0.709 mmol) in toluene (70 mL) was added dropwise a solution of Bu3SnH (309 mg, 1.06 mmol) and ACN (34.6 mg, 0.142 mmol) in toluene (30 mL) over 4 h, and the mixture was further heated at reflux for 1 h. After evaporation of the solvent, the residue was chromatographed on silica gel containing KF (10%) (hexane/AcOEt, 3:1). The first eluate gave 16a (43.0 mg, 30%) as a colorless oil, whose 1H NMR spectrum showed it to be a mixture of rotamers: IR (CHCl3) υ 1620, 1665 cm-1; 1H NMR (270 MHz, CDCl3, for one rotamer) δ (ppm): 1.81-1.95 (2H, m), 2.18 (3H, s), 2.64 (2H, t, J = 7.6 Hz), 3.64 (2H, t, J = 7.6 Hz), 4.27 (1 H, d, J = 8.2 Hz), 4.35 (1H, d, J = 15.3 Hz), 6.70 (1 H, dd, J = 15.3, 8.2 Hz), 7.14-7.34 (5H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 22.0, 27.8, 33.2, 41.1, 65.3, 93.5, 124.0, 125.9, 126.9, 127.7, 128.28, 128.83, 128.5, 129.2, 133.1, 141.4, 169.2; HRMS calcd for C13H17NO: 203.1310, found: 203.1315. The second eluate gave 15a (81.9 mg, 57%) as colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of isomers: IR (CHCl3) υ 1630 cm-1; 1H NMR (270 MHz, CDCl3, for one isomer) δ (ppm): 1.85-2.05 (2H, m), 1.94 and 2.10 (total 3H, s and s), 2.66-2.75 (2H, m), 2.85-2.93 (2H, m), 3.12-3.23 (2H, m), 3.49-3.51 and 3.68 (total 2H, m and br), 7.13-7.27 (4H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 21.0, 21.9, 28.6, 29.1, 30.7, 31.3, 34.6, 34.7, 46.8, 47.5, 49.8, 52.7, 126.4, 126.8, 127.0, 127.2, 129.1, 129.2, 129.6, 129.7, 137.9, 139.3, 139.8, 140.9, 170.0, 170.8; HRMS calcd for C13H17NO: 203.1310, found: 203.1312.

1,2,3,4,5,6-Hexahydro-3-trimethylacetyl-3-benzazocine (15b) and N-ethenyl-N-(3-phenylpropyl)-trimethylacetamide (16b) 15b: yield = 67%; colorless oil: IR (CHCl3) υ 1615 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.24 (9H, s), 1.92 (2H, br), 2.69 (2H, t, J = 6.3 Hz), 2.94 (2H, br), 3.13 (2H, br), 3.71 (2H, br), 7.10-7.20 (4H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 28.6, 29.5, 30.5, 35.7, 39.0, 48.4, 52.0, 126.3, 127.2, 129.3, 129.5, 138.3, 141.0, 177.1; HRMS calcd for C16H23NO: 245.1780, found: 245.1781. 16b: yield = 32%; colorless oil: IR (CHCl3) υ 1615 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.31 (9H, s), 1.82-1.93 (2H, m), 2.63 (2H, t-like, J = 7.8 Hz), 3.64 (2H, t-like, J = 7.8 Hz) 4.23 (1H, d, J = 9.3 Hz), 4.27 (1H, d, J = 15.4 Hz), 7.09 (1H, dd, J = 15.4, 9.3 Hz), 7.18-7.31 (5H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 28.0, 28.5, 33.3, 39.5, 43.3, 92.1, 125.9, 128.29, 128.31, 134.0, 141.5, 176.4; HRMS calcd for C16H23NO: 245.1780, found: 245.1770.

3-Benzyloxycarbonyl-1,2,3,4,5,6-hexahydro-3-benzazocine (15c) and N-benzyloxycarbonyl-N-ethenyl-3-phenylpropylamine (16c) 15c: yield = 58%; colorless oil; 1H and 13C NMR spectrum showed compound 15c to be a mixture of isomers: IR (CHCl3) υ 1680 cm-1; 1H NMR (270 MHz, CDCl3, for one isomer) δ (ppm): 1.82-2.02 (2H, m), 2,69 (2H, dd, J = 13.5, 5.9 Hz), 2.82-2.86 (2H, m), 3.02-3.12 (2H, m), 3.58 (2H, br), 5.08 and 5.14 (total 2H, s and s), 7.06-7.34 (9H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 29.2, 29.5, 30.1, 30.6, 35.07, 35.09, 46.2, 47.4, 50.9, 51.3, 66.7, 66.9, 126.4, 126.6, 126.95, 127.0, 127.6, 127.7, 127.78, 127.83, 128.40, 128.43, 129.2, 129.4, 129.5, 129.7, 136.9, 137.0, 139.0, 139.5, 140.1, 140.5, 155.3, 156.2; HRMS calcd for C16H23NO: 245.1780, found: 245.1781. 16c: yield = 32%; colorless oil: IR (CHCl3) υ 1630, 1705 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.80-1.95 (2H, m), 2.62 (2H, br), 3.57 (2H, br), 4.22 (2H, br d), 5.19 (2H, s), 7.15-7.35 (11H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 23.0, 24.7, 28.0, 30.9, 33.1, 42.8, 67.8, 91.7, 125.9, 127.9, 128.0, 128.19, 128.24, 128.3, 128.5, 132.7, 136.0; HRMS calcd for C16H23NO: 245.1780, found: 245.1770.

3-tert-Butoxycarbonyl-1,2,3,4,5,6-tetrahydro-3-benzazocine (15d) and N-tert-Butoxycarbonyl-N-ethenyl-3-phenylpropylamine (16d) 15d: yield = 63%; colorless oil; 1H NMR spectrum showed compound 15d to be a mixture of isomer: IR (CHCl3) υ 1680 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.35 and 1.44 (total 9H, both s), 1.8-1.98 (2H, m), 2.67-2.71 (2H, m), 2.80-2.87 (2H, m), 2.95 and 3.06 (total 2H, br and t, J = 5.8 Hz), 3.46-3.52 (2H, m), 7.10-7.18 (4H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 28.3, 28.5, 29.3, 29.6, 30.5, 30.7, 34.8, 35.2, 46.4, 47.1, 50.5, 50.9, 79.0, 79.2, 126.3, 126.5, 126.80, 126.83, 129.1, 129.39, 129.47, 129.7, 139.0, 139.7, 140.2, 141.0, 154.7, 155.5. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.52; H, 9.09; N, 5.50. 16d: yield = 28%; colorless oil: IR (CHCl3) υ 1625, 1700 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.47 (9H, s), 1.83-1.94 (2H, m), 2.63 (2H, t like, J = 7.9 Hz), 3.50 (2H, br), 4.16 (2H, br d), 7.05 (1H, br), 7.17-7.30 (5H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 28.2, 28.3, 33.2, 42.5 (br), 81.0, 90.4, 125.9, 128.26, 128.34, 132.7, 132.8, 141.4; HRMS calcd for C16H23NO: 261.1729, found: 261.1727.

N-3-(2-Bromophenyl)propyl-N-(1-propenyl)acetamide (19a) A mixture of 3-(2-bromophenyl)-propylamime (300 mg, 1.40 mmol) and propionaldehyde (81.3 mg, 1.40 mmol) in THF (12 mL) was stirred at 0 °C for 3 h in the presence of MS 4Å (powder, 300 mg). Acetyl chloride (132 mg, 1.68 mmol) and Et3N (313 mg, 2.10 mmol) were added to the reaction mixture containing imine (18a) at 0 °C, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water and the organic layer was separated. The organic phase was washed successively with a saturated aqueous solution of NaHCO3 and brine, After drying (MgSO4), the mixture was concentrated. The residue was chromatographed on silica gel (hexane/AcOEt, 5:1) to give 19a (173.1 mg, 42%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of two rotamers: IR (CHCl3) υ 1645 cm-1; 1H NMR (270 MHz, CDCl3, for one isomer) δ (ppm): 1.72 (3H, d, J = 6.6 Hz), 1.80-2.00 (2H, m), 2.17 (3H, s), 2.74 (2H, t, J = 8.1 Hz), 3.67 (2H, t, J = 7.7 Hz), 5.00 (1H, dq, J = 13.8, 6.8 Hz), 6.43 (1H, d, J = 13.8 Hz), 7.02-7.27 (4H, m), 7.52 (1H, d, J = 7.7 Hz); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 15.6, 22.2, 26.8, 33.5. 42.3, 107.8, 124.4, 127.4, 127.6, 128.2, 130.2, 132.7, 140.9, 168.8; HRMS calcd for C14H1879BrNO: 295.0572, found: 295.0565.

N-3-(2-Bromophenyl)propyl-N-(2-phenylethenyl)acetamide (19b) According to the procedure similar to that described for the preparation of 19a, 3-(2-bromophenyl)propylamime (300 mg, 1.40 mol) and phenylacetaldehyde (168 mg, 1.40 mol) was condensed and the resulting imine (18b) was treated with acetyl chloride (132 mg, 1.68 mmol) and Et3N (313 mg, 2.10 mmol) to give 19b (133.5 mg, 27%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of rotamers: IR (CHCl3) υ 1635 cm-1; 1H NMR (270 MHz, CDCl3, for one rotamer) δ (ppm): 1.85-2.10 (2H, m), 2.31 (3H, s), 2.78-2.86 (2H, m), 3.66-3.84 (2H, m), 5.85 (1H, d, J = 14.5 Hz), 7.04-7.56 (10H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 22.2, 26.7, 32.3, 32.7, 33.5, 41.9, 62.1, 110.6, 111.2, 124.4, 125.3, 125.6, 126.4, 126.5, 127.4, 126.6, 127.8, 128.2, 128.6, 128.7, 128.8, 130.36, 130.38, 132.77, 132.84, 136.5, 140.6, 141.1, 144.8, 169.2; HRMS calcd for C19H2079BrNO: 357.0728, found: 357.0727.

3-Acetyl-1,2,3,4,5,6-hexahydro-1-methyl-3-benzazocine (20a), 2-acetyl-1-ethyl-1,3,4,5-tetrahydro-2(2H)-benzazepine (21a) and N-(3-phenylpropyl)-N-(1-propenyl)acetamide (22a) According to the general procedure described above for the radical reaction of 14a, compound (19a) (150 mg, 0.506 mmol) was treated with Bu3SnH (221 mg, 0.76 mmol) and ACN (24.7 mg, 0.101 mmol), After usual work-up, the residue was chromatographed on silica gel (hexane/AcOEt, 3:1). The first eluate gave 22a (42.6 mg, 38%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of two rotamers: IR (CHCl3) υ 1645 cm-1; 1H NMR (270 MHz, CDCl3, for one rotamer) δ (ppm): 1.69 (3H, d, J = 6.7 Hz), 1.82-1.89 (2H, m), 2.16 (3H, s), 2.61-2.67 (2H, m), 3.62 (2H, t, J = 7.9 Hz), 4,86-4.96 (1H, m), 6.41 (1H, d, J = 13.4 Hz), 7.1-7.4 (5H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 15.5, 22.2, 28.2, 33.2, 42.5, 107.7, 125.8, 128.2, 128.3, 128.5, 141.6, 168.8; HRMS calcd for C14H19NO: 217.1467, found: 217.1465. The second eluate gave 21a (10.0 mg, 9%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of two isomers: IR (CHCl3) υ 1625 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 0.90 (3H × 1/2, t, J = 7.3 Hz), 0.95 (3H × 1/2, t, J = 7.3 Hz), 1.71-1.78 (2H × 1/2, m), 1.87-1.98 (2H × 1/2, m), 2.10 (3H × 1/2, s), 2.13 (3H × 1/2, s), 2.81-2.85 (2H × 1/2, m), 3.03 (1/2 H, br t), 3.10-3.16 (2H × 1/2, m), 3.55 (1/2H, br-t), 3.83 (1/2H, br d), 4.55 (1/2H, dd, J = 9.2, 6.7 Hz), 4.73 (1/2H, br d), 5.52 (1/2H, br), 7.06-7.30 (4H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 11.1, 11.3, 22.4, 25.0, 27.6, 29.2, 35.1, 35.4, 66.2, 126.2, 126.3, 126.9, 127.3, 129.0, 130.5, 131.5, 139.5, 140.3, 140.7, 141.1, 170.1, 170.8; HRMS calcd for C14H19NO: 217.1467, found: 217.1469. The third eluate gave 20a (49.0 mg, 45%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of two isomers: IR (CHCl3) υ 1630 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.41 (3H, d, J = 6.8 Hz), 1.66 (3H × 3/4, s), 1.89-2.17 (2H, m), 2.00 (3H × 1/4, s), 2.65-2.99 (2H, m), 3.01-3.13 (2H, m), 3.23-3.46 (2H, m), 3.66 (3/4H, dt, J = 9.2. 4.5 Hz), 3.88 (1/4H, dd, J = 12.8, 3.0 Hz), 7.10-7.30 (4H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 16.8, 17.7, 21.0, 21.8, 28.5, 30.0, 31.6, 32.1, 34.4, 47.6, 47.9, 55.5, 59.3, 123.9, 124.8, 126.4, 126.5, 126.8, 128.9, 129.7, 139.7, 141.1, 141.6, 142.8, 169.9, 170.5; HRMS calcd for C14H19NO: 217.1467, found: 217.1467.

3-Acetyl-1,2,3,4,5,6-hexahydro-1-phenyl-3-benzazocine (20b), 2-acetyl-1-benzyl-1,3,4,5-tetrahydro-2(2H)-benzazepine (21b) and N-(2-phenylethenyl)-N-(3-phenylpropyl)acetamide (22b) According to the general procedure described above for the radical reaction of 14a, compound (19b) (110 mg, 0.307 mmol) was treated with Bu3SnH (134 mg, 0.461 mmol) and ACN (15.0 mg, 0.0612 mmol), After usual work-up, the residue was chromatographed on silica gel (hexane/AcOEt, 4:1). The first eluate gave 22b (34.6 mg, 40%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of two rotamers: IR (CHCl3) υ 1635, 1670 cm-1; 1H NMR (270 MHz, CDCl3, for one rotamer) δ (ppm): 1.85-2.0 (2H, m), 2.28 (3H, s), 2.65-2.75 (2H, m), 3.76 (2H, t, J = 7.3 Hz), 5.74 (1H, d, J = 14.0 Hz), 7.13-7.36 (11H, m); 13C NMR (67.8 MHz, CDCl3) δ (ppm): 22.1, 22.2, 27.9, 28.7, 32.0, 32.9, 33.1, 62.1, 110.6, 111.0, 125.3, 125.6, 125.8, 126.0, 126.3, 126.4, 126.5, 126.9, 127.6, 128.38, 128.45, 128.54, 128.6, 128.7, 136.5, 136.8, 140.5, 141.3, 169.0, 169.2; HRMS calcd for C19H21NO: 279.1623, found: 279.1622. The second eluate gave 21b (22.9 mg, 27%) as a colorless oil: IR (CHCl3) υ 1630 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.66-2.00 (3H, m), 1.91 and 1.97 (total 3H, s), 2.82-2.86 (1H, m), 3.14-3.19 (2H, m), 3.33 (1/2H, dd, J = 14.0, 8.5 Hz), 3.47-3.64 (1H, m), 4.61 (1/2H, br d), 4.94 (1/2H, t, J = 7.3 Hz), 5.97 (1/2H, br), 6.84-7.21 (9H, m); 13C NMR (125 MHz, CDCl3) δ (ppm): 22.2, 22.3, 27.6, 29.1, 35.2, 35.4, 37.1, 38.5, 41.0, 65.8, 126.1, 126.3, 126.7, 127.1, 127.5, 128.3, 128.57, 128.66, 128.71, 129.1, 130.5, 131.5, 137.7, 139.6, 139.8, 140.3, 170.0, 170.5; HRMS calcd for C19H21NO: 279.1623, found: 279.1629. The third eluate gave 20b (20.6 mg, 24%) as a colorless oil, whose 1H and 13C NMR spectrum showed it to be a mixture of two rotamers: IR (CHCl3) υ 1630 cm-1; 1H NMR (270 MHz, CDCl3) δ (ppm): 1.72 (3H × 2/3, s), 2.01 (3H × 1/3, s), 2.04-2.20 (2H, m), 2.80-2.85 (1H, m), 3.03 (1H, t, J = 14 Hz), 3.17 (2/3H, br), 3.30 (1/3H, br), 3.43 (1/3H, br), 3.71 (2/3H, br), 3.79-3.87 [(1 + 2/3)H, m], 4.08 (1/3H, m), 4.51-4.54 (1/3H, m), 4.66 (2/3H, dd, J = 10.3, 4.8 Hz), 6.79-7.49 (9H, m); 13C NMR (125 MHz, CDCl3) δ (ppm): 21.1, 21.9, 28.5, 30.9, 31.7, 32.4, 45.4, 47.7, 48.3, 52.2, 55.8, 126.4, 126.5, 126.7, 126.8, 126.93, 126.97, 127.03, 128.2, 128.4, 128.5, 128.6, 128.9, 129.6, 139.7, 141.0, 141.2, 141.4, 142.1, 142.2, 170.2, 170.7; HRMS calcd for C19H21NO: 279.1623, found: 279.1627.

ACKNOWLEDGEMENT
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences and Technology of Japan.

† This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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