Regiochemistry of radical cyclisations (6-exo/7-endoand 7-exo/8-endo) ofN-(o-alkenylphenyl)-2,2-dichloroacetamides

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1991 Regiochemistry of Radical Cyclisations (6-exo/7-endoand 7-exo/8-endo)of N-(0-Alkenyl phenyl) -2,2-dichloroacetamides Tatsunori Sato, Satoshi Ishida, Hiroyuki Ishibashi and Masazumi lkeda * Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607,Japan N-o-(Alk-I -enyl)phenyl -2,2-dichloroacetamides, when treated with 2.2 rnol equiv. of Bu3SnH in the presence of a catalytic amount of azoisobutyronitrile, gave quinolin-2(1 H)-one (6-ex0 closure) and/or 2H-1- benzazepin-2-one (7-endo closure) systems. In general, the 6-ex0 cyclisation is favoured over the 7-endo closure, unless a large group such as phenyl is present at the I-position of the alkene. N-o-(1-Methylethenyl) phenyllacetamide congeners underwent a 6-ex0 closure followed by rearrangement to give 1,5-dihydro-4-methyl-2H-I -benzazepin-2-ones. A similar treatment of N-o-(prop-2-enyl)phenylacetamide derivatives gave 2H-1 -benzazepin-2-ones (7-exo) and/or 1-benzazocin-Z(1H)-ones (8-endo).Recently we reported on the radical cyclisation of N-(prop-2- eny1)acetamide derivatives which proceeds in a highly regio- selective manner to give five-membered lactams (5-em-closure).rsquo;.rsquo;The 5-ex0 preference is also observed with the 2-methylprop-2-enyl congener. As an extension of this chemistry, we were then led to examine the regiochemistry of the z-carbamoylmethyl radical cyclisation in the formation of the larger ring. To this end, we chose N-o-(alk-1-enyl)phenyl-acetamide 2 (6-ex0/7-endo) and N-0-(alk-2-eny1)p heny I -acetamide derivatives 17 (7-exo/8-endo)as suitable models. We report here the results of a study of the radical cyclisation of compounds 2 and 17.In this paper a rearrangement that was encountered with N-o-(1-methylethenyl)phenylacetamide f derivatives is also described. The radical precursors 2a-h, 3-6and 17a, b were prepared from the corresponding aniline derivatives la-h and 16 by standard methods (see Experimental section). 1a-h a; Rrsquo; = Me, R2= R3= H b; Rrsquo;= R3= Me, R2= H c; Rrsquo;= R2=H, R3=Me d; Rrsquo; = R2= H, R3 = C02Me Me 3 28-h e; Rrsquo; = R2= Me, R3= H f; Rrsquo;= R3=H, R2=Me g; Rrsquo;=Me, R2=Ph, R3=H h; Rrsquo; = R3 = H, R2= Ph Ye Me 4 X=CI, Y=SMe 5 X=Y=SPh 6 X=CI.Y=H A mixture of tributyltin hydride (Bu,SnH) (1.1 mol equiv.) and a catalytic amount of azoisobutyronitrile (AIBN) in toluene was added to a boiling solution of the dichloroacetamide 2a in toluene (6 x lop3 mol drn-,) during 40 min, and the resulting mixture was refluxed for an additional hour.To eliminate the second chlorine atom from the initially formed cyclised product (this procedure is not necessary for the cyclisation of the monochloroacetamide derivatives), a solution of Bu,SnH (1.1 rnol equiv.) and AIBN in toluene was added, and the mixture was again heated under reflux for 2 h. Evaporation of the solvent followed by chromatography on silica gel afforded 3,4- dihydro- 1,4-dimethylquinolin-2( lH)-one 7a in 49 yield. The same product 7a was also obtained from the bis(pheny1- thio)acetamide 3 in 50 yield upon treatment with Bu,SnH (2.2 mol equiv.) (when 1.1 mol equiv.of Bu3SnH was used, the reaction was very slow). Similarly the dichloroacetamides 2b-d with Bu,SnH (2.2 mol equiv.) gave the corresponding 3,4- dihydroquinolin-2( 1H)-ones 7b (79 yield), 7c (100) and 7d (100). In view of the fact that cyclisation of the N-unsubstituted N-(prop-2-enyl)acetamides is an unfavourable process,rsquo;*4 it is somewhat surprising that the N-unsubstituted acetamides 2c and 2d gave the cyclised products 7c, d in excellent yields.$ The closeness of the radical centre and acceptor may be responsible for this anomaly. In contrast, similar treatment of 2,2-dichloro-N-o-( 1 -methyl-etheny1)phenyllacetamide 2e gave a rearranged product, 13-dihydro-1,4-dimethyl-2H-l-benzazepin-2-one8 (68yield), the 3,4-dihydroquinolin-2( 1 H)-one 9 (24), and an inseparable mixture of 173,4,5-tetrahydro-l,5-dimethyl-10 and 1,3,4,5-tetrahydro-174-dimethyl-2H-1-benzazepin-2-ones 11 (10;2 :1).The structure 8 was deduced from the spectroscopic and chemical evidence. The lsquo;H NMR spectrum of compound 8 revealed a methyl signal at 6 1.97 (d, J 1.5 Hz), a methylene singlet at 6 3.23, and an olefinic proton signal centred at 6 5.60 (1 H, m). Catalytic hydrogenation of compound 8 over 10 Pd-carbon in methanol gave compound 11. The structures lo6 and 11 were deduced from a comparison of the NMR spectrum of the mixture and the gas-liquid chromato- graphy (GLC) retention time with those of each authentic sample.The same rearrangement was also observed with the dichloroacetamide 2f, the 2-chloro-2-(methylthio)acetamide4, and the bis(pheny1thio)acetamide 5, giving the rearranged 2H- 1-benzazepin-2-ones 12 (4473, 8 (48) and 8 (4579, re-spectively, along with other, minor products (see Experimental section). Treatment of the chloroacetamide 6 with Bu,SnH (1.1 rnol equiv.) gave compound 9 (19?;), and a mixture of benzazepinones 10 and 11 (24 total yield, 1: 1). One possible mechanism for the formation of the rearranged product 8 would involve a neophyl radical intermediate (B) formed by a 6-ex0 closure of the initially formed radical (A). The radical (B) could then attack the phenyl ring activated t N-(o-1sopropenylphenyl)acetamide.1In contrast, the N-(prop-2-ynyl)acetamide counterparts have recently been shown to undergo efficient radical cyclisation to give the five- membered lactams.5 354 J.CHEM. SOC. PERKIN TRANS. I 1991 fR3 -2a-d R' 7a-d .Me Me, *Me Me '0 Me a 9 10 R2=Me, R3=H 11 R2=H, R3=Me -9 L B 1 C D t 10 8 11a; Me H 12 13 Ph Ph 14a R=Me 15 14b R=H Scheme 1 Reagents: i, Bu,SnH (2 mol equiv.), AIBN Table 1 Effect of the substituents at the radical centre on the U-carbamoylmethyl radical cyclisation Products ()' Starting The 7-exo The 8-endo Entry material product product Others 1 17ab I1 (48) d 2 17b' 21 (47) 17f (10) 3 17c' 11 (38) 20 (44)4 17d' 18 (58) 22 (36) 5 17e' 19 (23) 23 (63) 'Isolated yield.* The reaction was carried out using Bu,SnH (2.2 mol equiv.) in refluxing toluene. 'The reaction was carried out using Bu,SnH (1.1 mol equiv.) in refluxing toluene. Some unidentified products were formed. by the o-acylamino group to give the three-membered-ring intermediate (C), which undergoes ring opening followed by dechlorination to give product 8 (Scheme 1). The formation of compound 11 is of special interest, since it may result from trapping of the postulated radical intermediate (D) by hydrogen abstraction from Bu,SnH. A similar process (a neophyl rearrangement) has been postulated in a radical transform- ation of 2-bromo-4-methoxy-3-(2-methylprop-2-enyloxy)-benzaldehyde to 5-formyl-8-methoxy-3-methylbenzopyran.7 Compound 10 is a 7-endo cyclisation product of the radical (A).Our results thus far indicate that the 6-exo-closure is much favoured over the 7-endo-closure in cyclisation of the a-carbamoylmethyl radicals derived from the N-o-(alk- 1-enyl)-phenyllacetamides 2a-f and 3-6. However, cyclisation of the l-phenyl congener 2g proceeded exclusively in a 7-end0 manner to give the 2H-l-benzazepin-2-one 14a in 83 yield. Similarly, compound 2h gave 14b9 in 43yield, along with the reduction product 15 (33). Two explanations for these results are: (i) the presence of the phenyl group at the l-position retards the rate of 6-ex0 cyclisation due to steric reasons and (ii) the transition states leading to the 7-endo products are stabilised by resonance with the l-phenyl group.Probably both the steric and the electronic factors are operating to favour the 7-endo cyclisation. J. CHEM. SOC. PERKIN TRANS. 1 1991 We next investigated the behaviour of the N-o-(prop-2- eny1)phenyllacetamide derivatives 17 (7-exo/8-endo). The dichloroacetamide 17a, upon treatment with Bu,SnH (2.2 mol equiv.), gave only the 2H-1-benzazepin-2-one 11 (a 7-exo product) in 49 yield. Interestingly, when the bis(pheny1- thio)acetamide 17b was treated with Bu,SnH (1.1 mol equiv.), the 1-benzazocin-2( lH)-one 21 (an 8-endo product) was obtained in 47 yield, together with the reduction product 17f (9). The structure 21 was confirmed by desulphurisation with Raney nickel to the known 1-benzazocin-2( 1H)-one 20." These observations suggest that regiochemistry of the cyclisation of compounds 17 is highly affected by the substituent on the radical centre.Me 16 17a-f a; X=Y=CI b; X=Y=SPh C; X=CI, Y =H d; X=CI, Y=Me e; X = CI, Y = Ph f; X=H, Y=SPh .Me -18 Y=Me 20 Y=H 19 Y=Ph 21 Y=SPh 22 Y=Me 23 Y=Ph In order to study further the effect of the substituent on the regiochemistry, several radical precursors 17c-e were synthe- sized and subjected to the cyclisation conditions. The results are summarised in Table 1. Unfortunately, no simple relationship between the structure and regiochemistry was found, but our observations seem to suggest that the exclusive formation of compounds 11 and 21 is rather exceptional. The electronic and steric structures of the initially formed carbamoylmethyl radicals are likely responsible for the observed selectivity.Further experiments, including the evaluation of the possible role of the heteroatom on the radical centre, would appear to be desirable. Experimental IR spectra were recorded with a JASCO-IR-A-100 spectro- photometer. 'H NMR spectra were determined with a JEOL JNM-PMX 60 (60 MHz) or a Varian XL-300 (300 MHz) spectrometer, and ' NMR spectra with a Varian XL-300 (75 MHz), for solutions in CDCl,, and amp;values quoted are relative to tetramethylsilane. Exact mass (MS) determinations were obtained on a Hitachi M-80 instrument operating at 20 eV. GLC was carried out on a Shimadzu GC-14A gas chromatograph (helium carrier gas; capillary column at 220 "C).Chromatographic separation was performed with silica gel 60 PF254 (Merck) under pressure. Light petroleum refers to the fraction boiling in the range 4amp;60 "C except where stated otherwise. Materials.-N-Methyl-o-(prop-1 -enyl)aniline 1 b,' ' o-(prop-1-eny1)aniline lc,' methyl 3-(o-aminophenyl)propenoate ld,13 N-methyl-o-( 1-methyletheny1)aniline le,14 0-(1-methyletheny1)-aniline lf,' 0-(1-phenyletheny1)aniline lh,' N-methyl-o-( 1- phenyletheny1)aniline lg,6 and N-methyl-o-(prop-2-enyl)aniline 16 ' were prepared according to the reported procedure. o-Ethenyl-N-methylaniline la.-To a suspension of K2C03 (16.7 g) and 2-o-(aminopheny1)lethanol '' (3.68 g, 26.8 mmol) in acetone (50 cm3) was added dropwise ethyl chloroformate (8.73 g, 80.5 mmol) and the mixture was refluxed for 2 h.After cooling, the inorganic material was removed by filtration and the filtrate was concentrated to give 2-o-(ethoxycarbonyl- amino)phenylethyl ethyl carbonate (7.35 g, 97:lJ as a crude oil, which was used for the next stage without further purification. A solution of the carbonate (7.35 g, 26.1 mmol) in anhydrous diethyl ether (5 cm3) was added dropwise to a suspension of lithium aluminium hydride (2.04 g, 53.7 mmol) in anhydrous diethyl ether (50 cm3) at 0 "C and the mixture was refluxed for 1 h. Usual work-up gave 2-o-(N-methylamino)phenyl-ethanol l9 (4.06 g, quant.) as an oil. By essentially the same procedure as that of Sabetay et al.," KOH (ca. 5.0 g) was added to the aforementioned aminophenylethanol (3.90 g, 26.0 mmol) and the mixture was heated at 80-90 "C (bath temperature) for 10 min at 5 mmHg.Hydroquinone (50 mg) was added and the mixture was distilled to give the aniline la (1.84 g, 62), b.p. 59-61 "C/3 mmHg (lit.,20 108 "C/14 mmHg). General Procedure for the Preparation of 2,2- Dichloro-N-Lo- (alk-1-enyl)phenylacetamides2a-h.-A solution of dichloro- acetyl chloride (1.58 g, 10.7 mmol) in diethyl ether (5 cm3) was added dropwise to a solution of the aniline 1 (9.76 mmol) and triethylamine (1.09 g, 10.7 mmol) in diethyl ether (20 cm3) at 0 OC, and the mixture was stirred at room temperature for 10 min and diluted with water. The organic layer was separated, washed successively with saturated aq.NaHCO, and brine, dried (MgSO,) and concentrated. The residue was chromato- graphed on silica gel hexane-AcOEt (7:1) to give the acetanilide. The following compounds were thus obtained. 2,2-Dichloro-N-(o-ethenylphenyl)-N-methylacetamide 2a (96), an oil (Found: C, 53.9; H, 4.5; N, 5.75. CllHllC12N0 requires C, 54.1; H, 4.5; N, 5.7); v,,,(CCl,)/cm-' 1700 6 3.36 (3 H, s, NMe), 5.41 (1 H, dd, J 11.5 and 2 Hz, one of CH=CH2), 5.76 (1 H, s, CHC12), 5.82 (1 H, dd, J 17.5 and 2 Hz, one of CH=CH2), 6.69 (1 H, dd, J 17.5 and 11 Hz, CH=CH2) and 7.0-7.85 (4 H, m, ArH). (Z)-and (E)-2,2-Dichloro-N-methyl-N-o-@rop-1-enyl)-phenyllacetamide 2b (5573, an oil (Found: C, 55.6; H, 5.1; N, 5.4. C12H13C12N0requires C, 55.8; H, 5.1; N. 5.4).(Z)-and (E)-2,2-Dichloro-N-o-(prup-1-enyl)phenyl-acetamide 2c (59) (Found: C, 54.0; H, 4.6; N, 5.9. C11HllC12N0 requires C, 54.1; H, 4.5; N, 5.7); m.p. 144.5- 146.0 "C (from hexane-AcOEt). (E)-Methyl 3-o-(2,2-Dichloroacetamido)phenylpropenoate 2d (quant.) (Found: C, 50.0; H, 3.8; N, 4.95. C12H1,C12N03 requires C, 50.0; H, 3.85; N, 4.9); m.p. 137.5-138.5 "C from THF-light petroleum. 2,2-Dichloro-N-methyl-N-o-( 1 -methylethenj,l )phenyl- acetamide 2e (82) (Found: C, 55.8; H, 5.1: N, 5.5. Cl,Hl,C12N0 requires C, 55.8; H, 5.1; N, 5.47;); m.p. 57.5-58.5 "C (from hexane). 2,2-Dichloro-N-o-(l-meth~vlethenyl)phenyllacetantide 2f (98) (Found: C, 54.1; H, 4.8; N, 5.6. C H IC12N0 requires C, 54.1; H, 4.5; N, 5.7); m.p.43.544 "C (from hexane). 2,2-Dichloro-N-methyl-N-0-( 1-phenylethenj~l)phenyll-acetamide 2g (47) (Found: C, 63.9; H, 4.8; N, 4.3. Cl,H15ClzN0 requires C, 63.8; H, 4.7; N, 4.4"/,); m.p. 114.5- 115.5 "C (from hexane). 2,2-Dichloro-N-o-( 1-phenylethenyl)phenylacet~imide 2h (91) (Found: C, 62.5; H, 4.2; N, 4.7. C,,HI3CI,NO requires C, 62.8; H, 4.3; N, 4.6); m.p. 84-85 "C from light petroleum. N-(0-Ethenylphenyl)-N-methyl-2,2-bis(phenylthio)acetamide 3.-Benzenethiol (596 mg, 5.41 mmol) was added to a solution of sodium ethoxide in ethanol prepared from sodium (124 mg, 5.41 mmol) and ethanol (15 cm3), and the mixture was stirred at room temperature for 10 min. A solution of the dichloride 2a (600 mg, 2.45 mmol) in dichloromethane (5 cm3) was added to the above solution and the mixture was stirred at room temperature for 16 h.After removal of the solvent, the residue was dissolved in water, and extracted with dichloromethane. The extract was dried (MgSO,) and concentrated. The residue was chromatographed on silica gel hexane-AcOEt (7: l) to give the acetamide 3 (518 mg, 54) (Found: C, 70.4; H, 5.4; N, 3.4. C23H,,NOS2 requires C, 70.55; H, 5.4; N, 3.6); m.p. 91.5- 92.5 "C (from hexane-AcOEt); v,,,(CHCl,)/cm-' 1665; 6 3.16 (3 H, s, NMe), 4.67 l H, s, CH(SPh),, 5.22 (1 H, dd, J 11 and 2 Hz, one of CHXH,), 5.64, (1 H, dd, J 18 and 2 Hz, one of CH=CH2) and 6.3-7.7 (1 5 H, m, CH=CH, and ArH). 2- Chloro-N-methyl-N-Lo-( 1 -methylethenyl)phenyl -2- (methy1thio)acetamide 4.-Using a procedure similar to that described for the preparation of compounds 2a-h, the aniline le (1.50 g, 10.2 mmol) was treated with (methy1thio)acetyl chloride (1.40 g, 11.2 mmol) and work-up gave N-methyl-N-o-(1- methylethenyl)phenyl-2-(methylthio)acetamide(1.22 g, 5 1) (Found: C, 66.0; H, 7.5; N, 5.5.Cl3HI7NOS requires C, 66.35; H, 7.3; N, 5.95); m.p. 54.5-56 "C from hexane-light pet r 01 eum . N-Chlorosuccinimide (187 mg, 1.40 mmol) was added by portions to a solution of the sulphide obtained above (300 mg, 1.27 mmol) in tetrachloromethane (10 cm3) at 0deg;C and the mixture was stirred at room temperature for 4 h. The precipitated succinimide was filtered off and the filtrate was concentrated to give the title acetamide 4 in quantitative yield, which was used immediately in the next stage.N- Methyl-N-o-( 1-methylethenyl)phenyl -2,2-bis(phenyl- thio)acetamide 5.-Using a procedure similar to that described for the preparation for compound 3, the acetamide 5 (462 mg, 37) was obtained from the dichloride 2e (800 mg, 3.1 mmol) and sodium benzenethiolate (6.8 mmol) (Found: C, 71.1; H, 5.85; N, 3.6. C2,H2,NOS2 requires C, 71.1; H, 5.7; N, 3.45); m.p. 75.5-77 "C (from hexane); v,,,(CCl,)/cm-' 1665; 6 1.99 (3 H, br s, CMe), 3.20 (3 H, s, NMe), 4.8-5.2 (2 H, m, C=CH2), 4.88 l H, s, CH(SPh), and 6.75-7.4 (14 H, m, ArH). 2- Chloro-N-methyl-N- o-(1-methy lethenyl)phenyl -acetamide 6.-Using a procedure similar to that described for the preparation of compound 2e, the acetamide 6 (1.27 g, 80) was obtained from the aniline le (1.0 g, 6.80 mmol) and chloroacetyl chloride (845 mg, 7.48 mmol) as an oil (Found: C, 64.3; H, 6.5; N, 6.2.CI2H,,CINO requires C, 64.4; H, 6.3; N, 6.3); v,,,(CCl,)/cm-' 1680; 6 2.03 (3 H, br s, CMe), 3.22 (3 H, s, NMe), 3.84 (2 H, s, COCH,CI), 4.95-5.1 (1 H, m, one of C=CH,), 5.15-5.3 (1 H, m, one of CXH,) and 7.1-7.6 (4 H, m, ArH). Radical Cyclisation of the Dichloroacetamide 2a. General Procedure A.-A solution of Bu,SnH (525 mg, 1.80 mmol) and ATBN (27 mg, 0.16 mmol) in dry toluene (40 cm3) was added dropwise to a boiling solution of the acetamide 2a (400 mg, 1.63 mmol) in dry toluene (20 cm3) via a syringe during 40 min and the mixture was refluxed for a further 1 h.Then a further solution of Bu,SnH (525 mg, 1.80 mmol) and AIBN (27 mg, 0.16 mmol) in toluene (5 cm3) was added to this mixture, and the whole was refluxed for 2 h. After the solvent had been J. CHEM. SOC. PERKIN TRANS. I 1991 evaporated off, the residue was dissolved in diethyl ether (20 cm3), 8 aq. KF (20 cm3) was added, and the mixture was stirred at room temperature for 1 h. The organic layer was separated and the aq. layer was extracted with diethyl ether. The combined organic phases were dried (MgSO,) and concentrated. The residue was chromatographed on silica gel hexane-AcOEt (9 :2) to give 3,4-dihydro- 1,4-dimethyl- quinolin-2(1H)-one 7a (139 mg, 49) as an oil (Found: M', 175.0993. Calc.for C, ,HI,NO: M, 175.0996); v,,,(CCl,)/cm-' 1680; 6 1.25 (3 H, d, J 7 Hz, 4-Me), 2.1-3.4 (3 H, m, 3-H, and 4-H), 3.33 (3 H, s, NMe) and 6.8-7.4 (4 H, m, ArH). Radical Cyclisation of' the Bis(pheny1thio)acetarnide 3.-Following general procedure A, the bis(pheny1thio)acetamide 3 (400 mg, 1.02 mmol) was treated with Bu3SnH (327 mg, 1.12 mmol) and AIBN (1 7 mg, 0.1 mmol) in refluxing toluene for 5 h. Since TLC analysis of the reaction mixture showed that considerable amounts of the starting material still remained, a further solution of Bu,SnH (327 mg) and AIBN (17 mg) in toluene (10 cm3) was added dropwise during 15 min and the mixture was refluxed for 2 h. Work-up gave the quinolinone 7a (91 mg, 50) as an oil. Radical Cyclisation of the Dichloroacetamide 2b.-Following general procedure A, the acetamide 2b (260 mg, 1.OO mmol) was treated with Bu,SnH (322 mg, 1.1 mmol) and AIBN (16 mg, 0.1 mmol) twice and work-up gave 4-ethjd-3,4-dihq3dro- 1-rneth?d-quinolin-2(1H)-one 7b (195 mg, quant.) as an oil (Found: M+, 189.1 160.C12H15N0 requires M, 189.1 153); v,,,(CCl,)/cm-' 1680; 6 0.91 (3 H, br t, J 7 Hz, CH2Me), 1.2-3.0 (5 H, br m, 3-H,, 4-H and CH,Me), 3.32 (3 H, s, NMe)and 6.75-7.4 (4 H, m, ArH). Radical Cyclisation of the Dichloroacetamide 2c.-Following general procedure A, the acetamide 2c (180 mg, 0.73 mmol) was treated with Bu,SnH (236 mg, 0.81 mmol) and ATBN (12 mg, 0.07 mmol) twice and work-up gave 4-c.tl?l~l-3,4-dihj,droquinolin-2(1H)-one 7c (102 mg, 79) (Found: C, 75.3; H, 7.5; N, 8.0.C, 1H13N0 requires C, 75.4; H, 7.5; N, 8.0); m.p. 130.5-132.5 "C (from hexane-AcOEt); v,,,(CCl,)/cm-' 1680; 6(300 MHz) 0.94 (3 H, t, J7.4 Hz, CH2Me), 1.5-1.75 (2 H, m, CH,Me), 2.57 (1 H, dd, J 15.5 and 4 Hz, 3-H), 2.77 (1 H, dd, J 15.5 and 6.5 Hz, 3-H), 2.85 (1 H, ddd, J 13.5, 6.5 and 4 Hz, 4-H), 6.82 (1 H,dd, J8 and 1.5 Hz, ArH), 7.01 (1 H, td, J7.5 and 1.5 Hz, ArH), 7.16 (1 H, br d, J8 Hz, ArH), 7.18 (1 H, td, J7.5 and 1.5 Hz, ArH) and 8.63 (1 H, br, NH). Radical Cjdisation of'the Dichloroacetamide 2d.-Following general procedure A, the acetamide 2d (250 mg, 0.86 mmol) was treated with Bu3SnH (278 mg, 0.95 mmol) and AIBN (14 mg, 0.09 mmol) twice and work-up gave methyl ( 1,2,3,4-tetrahq~dro-2-o.uoquinolin-4-~~l)acetate7d (190 mg, quant.) (Found: C, 65.8; H, 6.0; N, 6.4.C12H13N03 requires C, 65.7; H, 6.0; N, 6.4); m.p. 114-1 15 "C (from hexane-AcOEt); v,,,(CHCl,)/cm-' 3400,1730 and 1680; 6 2.3-3.1 (4 H, m, 3-H, and CH,CO,Me), 3.25-3.85 (1 H, m,4-H), 3.62 (3 H, s, OMe), 6.7-7.3 (4 H, m, ArH) and 9.45-9.9 (1 H, br, NH). Radical Cyclisation of the Dichloroacetamide 2e.-Following general procedure A, the acetamide 2e (350 mg, 1.35 mmol) was treated with Bu,SnH (434 mg, 1.49 mmol) and AIBN (22 mg, 0.14 mmol) twice to give a mixture of four products, which was chromatographed on silica gel hexane-AcOEt (7 : l). The first fraction gave 3,4-dihydro- 1,4,4-trimethylquinolin-2(1H)-one 9 (61 mg, 24) as an v,,,(CCl,)jcm-' 1680; 6 1.29 (6 H, s, 4-Me2), 2.47 (2 H, s, 3-H,), 3.37 (3 H, s, NMe) and 6.9- 7.45 (4 H, m, ArH).The second fraction gave a mixture of 1,3,4,5-tetrahydro-l,4- J. CHEM. SOC. PERKIN TRANS. 1 1991 dimethyl-11 and 1,3,4,5-tetrahydro-l,5-dimethyl-2H-l-benz-azepin-2-one 10 (25 mg, 10; 1:2) and the third fraction afforded 1,5-dihydro-l,4-dimethy-2H-l-benzazepin-2-one8 (171 mg, 68) (Found: C, 76.8; H, 7.05; N, 7.8. C,,H,,NO requires C, 77.0; H, 7.0; N, 7.5); m.p. 9697 "C (from hexane); v,,,(CCl,)/cm-' 1665 and 1630; 6 1.97 (3 H, d, J 1.5 Hz, 4-Me), 3.23 (2 H, br s, 5-H,), 3.49 (3 H, s, NMe), 5.6-5.7 (1 H, m, 3-H) and 7.1-7.3 (4 H, m, ArH); S(75 MHz) 167.5, 152.9, 141.8, 135.5, 127.4, 127.2, 125.2, 121.7, 120.0,38.0, 36.7 and 24.4. Compounds lo6 and 11 were identified by comparison of the 'H NMR spectrum of the mixture and the GLC retention time with those of each authentic sample (for the preparation of authentic compound 11, see below).Catalytic Reduction of the Benzazepin-2-one 8.-A solution of compound 8 (50 mg, 0.26 mmol) in methanol (10 cm3) was hydrogenated in the presence of 10 Pd-C (50 mg) under pressure (4 kg/cm2) for 40 h. After the catalyst had been removed by filtration, the filtrate was concentrated. The residue was chromatographed on silica gel hexane-AcOEt (7 :l) to give the unchanged starting material 8 (6 mg recovery) and 1,3,4,5-tetrahydro- 1,4-dimethyl-2H- 1-benzazepin-2-one 11 (35 mg, 69) as an oil (Found: Mf, 189.1158. CI2Hl5NO requires M, 189.1153); v,,,(CCl,)/cm-' 1665; 6 1.04 (3 H, d, J 6 Hz, 4-Me), 1.7-3.1 (5 H, m, 3-H,, 4-H and 5-H2), 3.34 (3 H, s, NMe) and 7.C7.5 (4 H, m, ArH).Radical Cyclisation of the Dichloroacetamide 2f.-Following general procedure A, the acetamide 2f(400 mg, 1.63 mmol) was treated with Bu,SnH (525 mg, 1.80 mmol) and AIBN (27 mg, 0.16 mmol) twice to give 1,5-dihydro-4-methyl-2H-l-benzazepin-2-one 12 (124 mg, 44) (Found: C, 76.3; H, 6.4; N, 8.1. CllHllNO requires C, 76.3; H, 6.4; N, 8.1); m.p. 158.5-160.5 "C (from hexane-AcOEt); v,,,(CCl,)/cm-' 1675; 6 2.01 (3 H, d, J 1 Hz, 4-Me), 3.28 (2 H, s, 5-H,), 5.65.8 (1 H, m, 3-H), 6.85-7.35 (4 H, m, ArH) and 8.9-9.3 (1 H, m, NH). Other minor products were not characterised. Radical Cyclisation of the 2-Chloro-2-(methyIthio)acetamide 4.General Procedure B.-A solution of Bu3SnH (407 mg, 1.40 mmol) and AIBN (21 mg, 0.13 mmol) in dry toluene (40 cm3) was added dropwise to a boiling solution of the acetamide 4 (345 mg, 1.27 mmol) in toluene (20 cm3) during 1 h and the mixture was then refluxed for 9 h. After work-up as described in procedure A, the crude material was chromatographed on silica gel hexane-AcOEt (15:l)l. The first fraction gave 3,4- dihydro-1,4,4-trirnethyl-3-methylthioquinolin-2(lH)-one 13 (81 mg, 27) (Found: C, 66.1; H, 7.3; N, 6.1. C13H17NOS requires C, 66.35; H, 7.3; N, 5.95); m.p. 77.5-79 "C (from hexane); v,,,(CCl,)/cm-' 1670; 6 1.25 and 1.53 (3 H each, both s, 4-Me2), 2.13 (3 H, s, SMe), 3.19 (1 H, s, 3-H), 3.38 (3 H, s, NMe) and 6.8-7.4 (4 H, m, ArH).The second fraction gave the 1-benzazepinone 8 (113 mg, 48). Radical Cyclisation of the Bis(pheny1thio)acetamide 5.-Following procedure B, the acetamide 5 (400 mg, 0.99 mmol) was treated with Bu,SnH (316 mg, 1.08 mmol) and AIBN (16 mg, 0.1 mmol) to give the 1-benzazepin-2-one 8 (83 mg, 45). Other minor products were not characterised. Radical Cyclisation of the Chloroacetamide 6.-Following procedure B, the acetamide 6 (400 mg, 1.71 mmol) was treated with Bu3SnH (797 mg, 2.74 mmol) and AIBN (42 mg, 0.26 mmol) and work-up gave the quinolinone 9 (60 mg, 19) and a mixture of the benzazepinones 10 and 11 (1: 1; 78 mg, 24). Radical Cyclisation of the Dichloroacetamide 2g.-Following 357 procedure A, the acetamide 2g (400 mg, 1.25 mmol) was treated with Bu,SnH (400 mg, 1.38 mmol) and AIBN (21 mg, 0.1 mmol) twice and work-up gave 1,3,4,5-tetrahydro-l-methyl-5-phenyl-2H-1-benzazepin-2-one 14a (275 mg, SS), m.p.102-103.5 "C (from hexane) (lit.,8 102-104 "C); v,,,(CCl,)/cm-' 1665; 6 2.3-2.6 (4 H, m, 3- and 4-H,), 3.28 (3 H, s, NMe), 4.W.45 (1 H, m, 5-H) and 6.55-7.7 (9 H, m, ArH). Radical Cyclisation of the Dichloroacetamide 2h.-Following procedure A, the acetamide 2h (350 mg, 1.14 mmol) was treated with Bu,SnH (366 mg, 1.25 mmol) and AIBN (18 mg, 0.11 mmol) twice. After work-up, the crude material was chromatographed on silica gel hexane-AcOEt (7: l). The first fraction gave 0-(1-phenyletheny1)acetanilide 15 (88 mg, 3373, m.p. 123-125 "C from acetonitrile-light petroleum (b.p.range 8C110 "C) (1it.,l6 122 "C); v,,,(CHCl,)/cm-' 3410 (NH) and 1690;6 1.75 (3 H, s, COMe), 5.30 (1 H, d, J2 Hz, one of C=CH,), 5.79 (1 H, d, J2 Hz, one of C==CH2), 6.75-7.7 (9 H, m, ArH) and 7.9-8.2 (1 H, m, NH). The second fraction gave 1,3,4,5-tetrahydr0-5-phenyl-2H-1-benzazepin-2-one 14b (115 mg, 4373, m.p. 183-184 "C (from acetonitrile-hexane) (lit.,9 18C182 "C); v,,,(CHCl,)/cm-' 3390 (NH) and 1670; 6 2.1-2.8 (4 H, m, 3- and 4-H,), 3.954.6 (1 H, m, 5-H), 6.67.6 (9 H, m, ArH) and 8.1-8.35 (1 H, br, NH). 2,2-Dichloro-N-methyl-N-o-(prop-2-enyl)pheny~acetamide 17a.-To a solution of the aniline 16 (2.0 g, 13.6 mmol) in dichloromethane (20 cm3) was added dichloroacetic acid (1.93 g, 14.9 mmol) and then a solution of dicyclohexylcarbodiimide (DCC) (3.07 g, 14.9 mmol) in dichloromethane (20cm3) at room temperature, and the mixture was stirred at the same temperature for 16 h.The precipitated dicyclohexylurea was filtered off and the filtrate was washed with saturated aq. NaHCO,, dried (Na,SO,) and concentrated. The residue was chromatographed on silica gel hexane-AcOEt (20: l) to give the amide 17a (1.43 g, 41) as an oil (Found: C, 55.5; H, 5.1; N, 5.55. Cl2Hl3C1,NO requires C, 55.8; H, 5.1; N, 5.4); v,,,(CCl,)/cm-' 1695;6 3.2-3.55 (2 H, m, CH,CH=CH,), 3.25 (3 H, s, NMe), 4.85-5.35 (2 H, m. CH=CH,), 5.55-6.3 (1 H, m, CH=CH,), 5.72 (1 H, s, CHC1,) and 7.1-7.5 (4 H, m, ArH). N-Methyl-2,2-bis(phen~vlthio)-N-o-(prop-2-enyl)phenyl-acetamide 17b.-Using a procedure similar to that described for the preparation of compound 17a, the aniline 16 (723 mg, 4.91 mmol) was treated with bis(pheny1thio)acetic acid (1.36 g, 4.91 mmol) and DCC (1.12 g, 5.40 mmol) in dichloromethane (5 cm3) at room temperature overnight, and work-up gave the amide 17b (572 mg, 29) as an oil (Found: C, 70.8; H, 5.9; N, 3.4.C,,H2,NOS, requires C, 7 1.1; H, 5.7; N, 3.45); v,,,(CCl,)/cm-' 1665; 6 3.C3.3 (2 H, m, CH,CH=CH,), 3.17 (3 H, s, NMe), 4.7- 5.2 (2 H, m, CH=CH2), 4.71 l H, s, CH(SPh),, 5.55-6.2 (1 H, m, CH=CH2) and 6.67.6 (14 H, m, ArH). 2-Chloro-N-methyl-N-o-(prop-2-enyl)phen~lacetamide 17c.-Using a procedure similar to that described for the preparation of compound 17a, the aniline 16 (1 33 g, 12.4 mmol) was treated with chloroacetic acid (1.29 g, 13.7 mmol) and DCC (2.82 g, 13.7 mmol) in dichloromethane (40 cm3), and work-up gave the amide 17c (1.32 g, 48) as an oil (Found: C, 64.6; H, 6.8; N, 6.6.C12Hl,C1N0 requires C, 64.4; H, 6.3; N, 6.3); v,,,(CCl,)/cm-' 1675; 6 3.2-3.5 (2 H, m, CH,CH=CH,), 3.22 (3 H,s,NMe),3.71(2 H,s,COCH,),4.8-5.3 (2 H,m,CH=CH,), 5.66.3 (1 H, m, CH=CH,) and 7.C7.5 (4 H, m, ArH). 2-Chloro-N-methyl-N-o-(prop-2-enyl)phen~~lpropionamide 17d.-To a solution of the aniline 16 (500 mg, 3.40 mmol) pyridine (857 mg, 10.8 mmol), and 4-(dimethy1amino)pyridine (DMAP) (42 mg, 0.34 mmol) in toluene (20 cm3) at 0 "C was added a solution of 2-chloropropionyl chloride (474 mg, 3.74 mmol) in toluene (5 cm3) and the mixture was stirred at 0 "C for 30 min.The organic layer was washed with saturated aq. NaHCO, (20 cm3), dried (Na,SO,) and concentrated. The residue was chromatographed on silica gel hexane-AcOEt (9:2) to give the amide 17d (324 mg, 40) as an oil (Found: M + ,237.0947. C,,Hl,CINO requires M, 237.0920); vmax(CC14)/ cm-' 1675; 6 1.56 (3 H, d, J 7.0 Hz, CMe), 3.1-3.5 (2 H, m, CH,CH=CH,), 3.23 (3 H, s, NMe), 4.02 and 4.24 (total 1 H, both q, J 7.0 Hz, COCH), 4.8-5.3 (2 H, m, CH=CH2), 5.5-6.4 (1 H, m, CHSH,) and 6.9-7.5 (4 H, m, ArH). 2-Chloro-N-methyl-2-phenyl-N-o-(prop-2-enyl )phenyl- acetamide l7e.-Using a procedure similar to that described for the preparation of compound 17d, the aniline 16 (600 mg, 4.08 mmol) was treated with 2-chloro-2-phenylacetyl chloride (847 mg, 4.48 mmol), pyridine (1.03 g, 13.0 mmol) and DMAP (50 mg, 0.41 mmol) in toluene (30 cm3), and work-up gave the amide 17e (492 mg, 40) (Found: C, 72.2; H, 6.4; N, 5.0.C1 ,Hl amp;IN0 requires C, 72.1; H, 6.05; N, 4.7); m.p. 46.5-48.5 OC (from hexane-AcOEt); v,,,(CC1,)/cm-' 1680;6 2.55-2.85 and 3.3-3.55 (total 2 H, both m, CH,CH=CH,), 3.19 (3 H, s, NMe), 4.6-6.3 (3 H, m, CH=CH2), 5.09 and 5.21 (total 1 H, both s, COCH) and 6.5-7.5 (9 H, m, ArH). Radical Cyclisation of the Dichloroacetamide 17a.-Follow- ing procedure A, the acetamide 17a (410 mg, 1.59 mmol) was treated with Bu,SnH (508 mg, 1.75 mmol) and AIBN (26 mg, 0.18 mmol) twice and work-up gave the 2H- l-benzazepin-2-one 11 (131 mg, 48) as an oil, along with two unidentified, oily products (67 mg and 10 mg).Radical Cyclisation of the Bis(pheny1thio)acetamide 17b.-Following procedure B, the acetamide 17b (3 16 mg, 0.78 mmol) was treated with Bu,SnH (249 mg, 0.857 mmol) and AIBN (13 mg, 0.08 mmol). After work-up, the crude material was chromatographed on silica gel hexane-AcOEt (10: l). The first fraction gave the unchanged starting material 17b (80 mg, 25 recovery). The second fraction gave N-methyl-2-phenylthio- N-o-(prop-2-enyl)phenylacetamide17f (22 mg, 9) (Found: C, 72.4; H, 6.6; N, 4.6. C,,Hl,NOS requires C, 72.7; H, 6.4; N, 4.7); m.p. 43-45 "C (from hexane-AcOEt); ~,,,(CCl,)/cm-~ 1665;6 3.19 (3 H, s, NMe), 3.2-3.6 (2 H, m, CH,CH=CH2), 3.39 (2 H, s, CH,SPh), 4.8-5.3 (2 H, m, CH=CH2), 5.5-6.3 (1 H, m, CH=CH2) and 6.8-7.8 (9 H, m, ArH).The third fraction gave 3,4,5,6-tetrahydro-1 -methyl-3-phenyl- thio- 1 -benzazocin-2( 1 H)-one 21 (102 mg, 47) (Found: C, 72.7; H, 6.6; N, 4.8. Cl8HI9NOS requires C, 72.7; H, 6.4; N, 4.7); m.p. 127.5-129.5 "C (from hexane-AcOEt); vm,,(CCl,)/ cm-' 1665; 6 1.9-3.0 (6 H, m, 4-, 5-and 6-H2), 3.27 (3 H, s, NMe), 3.79 (1 H, dd, J 9 and 4 Hz, 3-H) and 7.0-7.4 (9 H, m, ArH). Desulphurisation of Compound 21 .-A suspension of the sulphide 21 (49 mg, 0.16 mmol) and Raney nickel (ca. 1 g) in ethanol (5 cm3) was refluxed for 2 h. After the catalyst had been removed by filtration, the filtrate was concentrated and the residue was chromatographed on silica gel hexane- AcOEt (5 :l) to give 3,4,5,6-tetrahydro-l-methyl-l-benzazocin-2( 1 H)-one 20 (27 mg, 89), m.p.58.5-59.5 "C (from light petroleum) (lit.," 60-61.5 "C); v,,,(CHC13)/cm-' 1630;6 1.1-3.0 (8 H, br m), 3.30 (3 H, s, NMe) and 7.C7.4 (4 H, m, ArH). Radical Cyclisation of the Chloroacetamide 17c.-Following procedure B, the acetamide 17c (300 mg, 1.34 mmol) was treated with Bu,SnH (429 mg, 1.47 mmol) and AIBN (22 mg, 0.13 mmol) and the crude material was chromatographed on silica J. CHEM. SOC. PERKIN TRANS. 1 1991 gel hexane-AcOEt (9:2). The first fraction gave an unidentified, oily product (15 mg), the second fraction gave the 2H-l-benzazepinone 11 (96 mg, 38) and the third fraction afforded the 1-benzazocin-2( 1 H)-one 20 (1 12 mg, 44).Radical Cyclisation of the Chloropropionamide 17d.-Follow- ing procedure B, the acetamide 17d (250 mg, 1.05 mmol) was treated with Bu3SnH (337 mg, 1.16 mmol) and AIBN (17 mg, 0.11 mmol). After work-up, the crude material was chromato- graphed on silica gel hexane-AcOEt (1 5 :l). The first fraction gave 1,3,4,5-?etrahydro- 1,3,4- trimethyl-2H- 1 -benzazepin-2-one 18 (123 mg, 58 as a stereoisomeric mixture in the ratio 68: 32, determined by 300 MHz 'H NMR spectroscopy) as an oil (Found: M+, 203.1298. C,,HI7NO requires M, 203.1308); v,,,(CCl,)/cm-' 1665; 6 0.9-1.2 (6 H, m), 1.7-3.2 (4 H, m), 3.33 (3 H, s, NMe) and 6.9-7.4 (4 H, m, ArH). The second fraction gave 3,4,5,6-tetrahydro- 1,3-dimethyl- 1- benzazocin-2(1H)-one 22 (78 mg, 36) as an oil (Found: M', 203.1288.C13H1 ,NOrequires M, 203.1308); v,,,(CCl,)/cm-' 1665; 6 1.04 (3 H, d, J6 Hz, 3-Me), 1.4-2.9 (7 H, m), 3.27 (3 H, s, NMe) and 7.0-7.4 (4 H, m, ArH). Radical Cyclisation of the Chloro(pheny1 )ucetamide 17e.- Following procedure B, the acetamide 17e (350 mg, 1.16 mmol) was treated with Bu,SnH (374 mg, 1.28 mmol) and AIBN (19 mg, 0.12 mmol). After work-up, the crude material was chromatographed on silica gel hexane-AcOEt (10: l). The first fraction gave one of the diastereoisomeric isomers of 1,3,4,5- tetrahydro-1,4-dimethy1-3-phenyl-2H-1 -benzazepin-2-one 19 (48 mg, 16) (Found: C, 81.5; H, 7.55; N, 5.5. C1,H,,NO requires C, 81.5; H, 7.2; N, 5.3); m.p. 121-122.5 "C (from hexane); v,,,(CCl,)/cm-' 1670; 6 1.05 (3 H, d, J 6 Hz, 4-Me), 2.1-3.1 (3 H, m), 3.38 (3 H, s, NMe), 3.75-3.9 (1 H, m) and 6.9-7.6 (9 H, m, ArH).The second fraction gave another isomer of compound 19 (21 mg, 7) as an oil (Found: M+, 265.1440. C,,H,,NO requires M, 265.1465); v,,,(CCl,)/cm-' 1670; 6 0.76 (3 H, d, J 6 Hz, 4-Me), 2.3-3.5 (4 H, m), 3.36 (3 H, s, NMe) and 6.9-7.5 (9 H, m, ArH). The third fraction gave 3,4,5,6-tetrahydro- l-methyl-3- phenyl-l-benzazocin-2( 1H)-one 23 (196 mg, 63) (Found: C, 81.3; H, 7.6; N, 5.6. C1,H19N0 requires C, 81.5; H, 7.2; N, 5.3); m.p. 119-120 "C (from hexane); v,,,(CCl,)/cm-' 1665; 6 1.1-3.7 (7 H, m), 3.27 (3 H, s, NMe) and 6.8-7.5 (9 H, m, ArH). References 1 T. Sato, Y. Wada, M. Nishimoto, H. Ishibashi and M. Ikeda, J.Chem. Soc., Perkin Trans. I, 1989,879. 2 H. Ishibashi, T. S. So, T. Sato, K. Kuroda and M. Ikeda, J. Chem. Soc., Chem. Commun., 1989, 762. 3 K. Jones, M. Thompson and C. Wright, J. Chem. Soc., Chem. Commun., 1986, 1 15. 4 G. Stork and R. Mah, Heterocycles, 1989,28, 723. 5 J. M. Clough, G. Pattenden and P. G. Wright, Tetrahedron Lett., 1989,30,7469. 6 T. Sato, T. Ito, H. Ishibashi and M. Ikeda, submitted for publication in Chem. Pharm. Bull. 7 K. A. Parker, D. M. Spero and K. C. Inman, Tetrahedron Lett., 1986, 27, 2833. For other examples of a neophyl rearrangement, see J. A. Franz, R. D. Barrows and D. M. Camaioni, J. Am. Chem. Soc., 1984, 106,3964. 8 L. I. Barsky and W. L. Bencze, J. Med. Chem., 1971, 14,40. 9 L. H. Werner, S. Ricca, A. Rossi and G. destevens, J. Med. Chem., 1967, 10, 575. 10 R. M. Coates and E. F. Johnson, J. Am. Chrm. Soc., 1971,93,4016. 11 R. Wehrli, H. Heimgartner, H. Schmid and H.-J. Hansen, Hell. Chim. Acta., 1977, 60, 2034. 12 A. Padwa and S. Nahm, J. Org. Chem., 1981,46, 1402. 13 L. G. Qiang and N. H. Baine, J. Org. Chem., 1988,53,4218. J. CHEM. SOC. PERKIN TRANS. 1 1991 14 S. Rossi and G. Pagani, Ann. Chim. (Rome), 1966,56,728. 19 Y. Masuoka, T. Asako, G. Goto and S. Noguchi, Chem. Pharm. Bull., 15 C. M. Atkinson and J. C. E. Simpson, J. Chem. SOC.,1947,808. 1986,34,140. 16 R. Stoermer and H. Fincke, Ber. Dtsch, Chem. Ges., 1909, 42, 20 M. Lancaster and D. J. H. Smith, J. Chem. SOC.,Chem. Commun., 3115. 1980,471. 17 M. Schmid, H.-J. Hansen and H. Schmid, Hefu. Chim. Acta, 1973,56, 105. Paper 0/03068F 18 S. Sabetay, J. Bleger and M. Y. Lestrange, Bull. SOC.Chim. Fr., 1931, Received 9th July 1990 49, 3. Accepted 3rd September 1990