Synthesis of pyrrolidin-2-ones by 5-endo-trigonalradical cyclisation ofN-vinyl-2,2-bis(phenylsulfanyl)acetamides

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 Synthesis of pyrrolidin-2-ones by 5-endo-trigonal radical cyclisation of N=vinyl-2,2-bis(phenylsulfanyl)acetamides Tatsunori Sato, Noriko Chono, Hiroyuki Ishibashi and Masazumi Ikeda* Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan A series of N-methyl-N-( 1 -substituted or 1,2-disubstituted vinyl)-2,2-bis(phenylsulfanyl)acetamides, upon treatment with tributyltin hydride in the presence of a catalytic amount of AIBN in boiling toluene, underwent smooth cyclisation in a 5-endo-trig manner to give the corresponding pyrrolidin-2-ones. In contrast, the N-( 1 -unsubstituted 2-phenylvinyl) congener gave predominantly the reduction product. These results imply that, for the 5-endo cyclisation to proceed effectively, the developing a-acylamino radicals in the transition state of the 5-endo cyclisation must be stabilised by an aryl or an alkyl group.An application of this method to a synthesis of ( &)-continine is also described. During the last decade, the use of radical cyclisations for the synthesis of nitrogen-containing heterocycles has increased dramatically. We are interested in developing new synthetic methods for lactams by using cyclisation of carbamoylmethyl radicals and in applying them to the synthesis of biologically active compounds.2 This radical approach was found to be very effective, particularly for the synthesis of five-membered lactams using a 5-exo-trig cyclisation of the N-allylic carbamoylmethyl radicals 1. We were then led to examine the behaviour of the N-vinylic carbamoylmethyl radicals 2 and found that they undergo a so-called ‘disfavoured’ 5-endo-trig radical cyclisation to give the fused five-membered lactams 3 (Scheme l).4 As an extension of these studies, we have now 1 Me 5-endo-trigI d$k0-tho€!I be 3 2 Scheme 1 examined the radical cyclisation of N-( 1-or 2-arylvinyl)-2-halo- or 2-(phenylsulfany1)-substitutedacetamides 4 in order to see the effect of the substituents on the vinylic double bond in 5-endo-trig cyclisation.In this paper, we describe the synthesis of 4-or 5-arylpyrrolidin-2-ones by tributyltin hydride-mediated radical cyclisation of the acetamides 4.’ An application of this method to a synthesis of ( k )-cotinine,6 a metabolite of nicotine, is also described.We began our study with the N-(l-phenylvinyl)-2-halo-or 2-(phenylsulfany1)-substituted acetamides 4. The radical pre- cursors 4a, b were prepared by N-acylation of acetophenone N-methylimine with chloroacetyl chloride or dichloroacetyl chloride in 47 and 80%yields, respectively. The acetamides 4c, d were synthesised by substitution of 4a and 4b with iodide ion and phenylthiolate ion, respectively, as shown in Scheme 2. ... 111 ___) 4c ivJL 1:;-PhJLNX! ph he O Me 4b 4d PhJLN$Me 4a R’=c~,R~=H 4b R* =R2=ci 4c R’ =I,R~=H a R~=R~=SP~ Scheme 2 Reagents and conditions: i, ClCH,COCI, CH,CI,; ii, CI,CHCOCI, CH,Cl,; iii, NaI, MeCN; iv, PhSNa, EtOH; v, Bu,SnH, AIBN, toluene, reflux In general, 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 these substrates in toluene during 2 h, and the resulting mixture was refluxed for 5 h.In order to complete the reaction (since the reaction was very slow) and also to eliminate the second chlorine atom or phenylsulfanyl group from the initially formed cyclised product in the case of 4b, d the same procedure was repeated two or three times. After evaporation of the solvent, the crude material was treated with 8% aqueous KF to remove the tin derivatives formed, and then chromatographed on silica gel to give the pyrrolidin-2-ones 5. The cyclisation was found to be highly dependent upon the nature of the radical precursors.Thus, treatment of the monochloroacetamide 4a with Bu,SnH gave only a small amount of the cyclised product 5 ( 17%) along with the reduction product 6 (1 8%) and the recovery of a large amount of the starting material (50%). The dichloroacetamide 4b failed to cyclise even after the prolonged refluxing time: a complex mixture was obtained from which the starting material (39%) and the monochloroacetamide 4a (6%) were isolated, but no cyclised product 5 was detected. In contrast, the more reactive iodide 4c underwent cyclisation to give 5 in 47% yield together with the reduction product 6 (12%). The disulfanyl- acetal4d was found to be the radical precursor of choice and gave 5 as a sole product in 75% yield.The formation of different ratios of the cyclised and reduced products according to the leaving group may be explained as follows. The slow reaction of the tin radical on chlorine atoms is provoking a higher instantaneous concentration of tin hydride since it is not consumed as rapidly as it is added, which leads to an increased amount of reduced compound. With iodine, there is a faster consumption of tin hydride and as a result less reduced compound. With the sulfide, even if there is the formation of reduced compound, the presence of a second reactive function on this compound gives a second chance of cyclisation. On the basis of these results, we next investigated the cyclisation of the N-(2-phenylvinyl)-2,2-bis(phenylsulfanyl)-acetamides 4e-h.The radical precursors 4e-g were prepared by acylation of the corresponding imines, prepared from the corresponding ketones and methylamine, with bis(phenylsu1f- any1)acetyl chloride in the presence of triethylamine and 4-dimethylaminopyridine (DMAP) in 60, 69 and 22% yields, respectively. The bis(phenylsulfany1)acetamide 4h was not obtained by the same sequence starting from phenylacetalde- hyde, but was prepared from ethyl 2-phenyl-2-(methylsulfanyl)-acetate 7 according to the following reaction sequence reported previously by us:' (1) treatment of 7 with methylamine in a sealed tube, (2) reduction of the amide 8 with borane-THF followed by N-acylation of the amine with dichloroacetic acid, (3) oxidation of the sulfide 9 with sodium metaperiodate, (4) heating of the resulting sulfoxide in xylene, and (5) treatment of the dichloroacetamide 10 with 2.2 equiv.of sodium phenylthiolate to give the desired 4h (Scheme 3). The (E)-stereochemistry of 10 and 4h was assigned on the basis of the observed large coupling constants between the two olefinic protons (J 14 and 14.5 Hz, respectively). 7 8 9 1 iv,v t 4h 10 4e R=Ph lln,b R=Ph 13 R=Bn 4f R=Bn 12 R=Bn 15 R=H 4g R=Me 14 R=Me 4h R=H 16 17 Scheme 3 Reagents and conditions: i, MeNH,, toluene, 120°C; ii, BH,, THF; iii, Cl,CHCO,H, Me,N(CH,),N=C=NEt.HCl, Et,N, DMAP, CH,CI,; iv, NaIO,; v, NaHCO,, xylene, reflux; vi, PhSNa, MeOH; vii, Bu,SnH, AIBN, toluene, reflux J.CHEM. SOC. PERKIN TRANS. I 1995 Radical cyclisation of 4e with Bu,SnH in the presence of AIBN gave a mixture of the cis-and trans-lactams lla and llb in 67 and 25% yields, respectively. The stereochemistry of lla and llb is based on an NOE experiment. Thus, when 5-H of the cis isomer lla was irradiated, the signal due to 4-H was enhanced (16%), and irradiation of 4-H in turn resulted in 10% enhancement of the signal due to 5-H. On the other hand, when the same experiments were performed on the trans isomer llb, only a small enhancement of the same signals (4 and 5%, respectively) was observed. Formation of the cis-isomer lla as the major product is consistent with the idea of a kinetically controlled tin hydride attack at the less hindered side of the acylamino radical intermediate.The acetamide 4f afforded the isomeric lactams 12 (46%; the isomeric ratio of 72:28 was determined by GLC) as an inseparable mixture, along with the reduction product 13 (10%). The acetamide 4g also underwent cyclisation to give an inseparable mixture of the isomeric lactams 14 (53%, 81 :19). The stereochemistry of the lactams 12 and 14 is not known at present, but it is highly probable that the major isomers of 12 and 14 have the cis configuration for the same reason as that described for the formation of cis-lla. In contrast, the acetamide 4h lacking a substituent at the 1-position of the vinyl group gave the reduction product 15 (68%) and a mixture (17%) of the lactams whose structures were assigned to be p-lactam 168and y-lactam 17 on the basis of the IR (two carbonyl bands at 1755 and 1695 cm-', respectively) and 'H NMR spectroscopic data (see Experimental).These results revealed that, for the 5-endo-trig cyclisation of the acetamides 4 to proceed effectively, it is necessary that the developing m-acylamino radicals in the transition state of the cyclisation must be stabilised by an aryl or an alkyl group. Finally, we applied this methodology to a synthesis of ( 2)-cotinine 20. The key bis(phenylsulfany1)acetamide 19 was prepared from 3-acetylpyridine in 77% yield according to the same procedure as that described for the preparation of 4d. Treatment of 19 with Bu,SnH and AIBN afforded ( 5)-cotinine 20 in 97% yield as a sole product (Scheme 4).iiiI 20 19 Scheme 4 Reagents and conditions: i, MeNH,, toluene, 100 "C; ii, Cl,CHCOCl, CH,Cl,; iii, PhSNa, EtOH; iv, Bu,SnH, AIBN, toluene, reflux Experimental Mps were measured on a Yanaco MP-J3 micro melting point apparatus and are uncorrected. IR spectra were recorded on a JASCO-IR-A-100 spectrophotometer. 'H NMR (60 and 300 MHz) and I3C NMR (75.4 MHz) spectra were determined with a JEOL JNM-PMX 60 or a Varian XL-300 spectrometer for solutions in CDCI,. &Values quoted are relative to' tetramethylsilane, and J-values are given in Hz. Exact mass determinations were obtained on a Hitachi M-80 instrument at 20 eV. Column chromatography was performed on Silica gel 60 PF254 (Nacalai Tesque) under pressure.J. CHEM. SOC. PERKIN TRANS. 1 1995 ZChloro-N-methyl-N-(l-phenylvinyl)acetamide4a A solution of acetophenone (2.0 g, 16.6 mmol) in toluene (10 cm3) was added to methylamine (3 cm3) at -78 "C and the mixture was heated in a sealed tube at 100 "C for 2 h. The reaction mixture was then concentrated and the residue was dissolved in dichloromethane (30 cm3). Chloroacetyl chloride (2.26 g, 20.0 mmol) was added to the solution at 0 "C and the mixture was stirred at that temperature for 15 min when sat. aqueous NaHCO, (40 cm3) was added to it and the whole was stirred for a further 30 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO,) and concentrated. The residue was chromatographed on silica gel [hexane-ethyl acetate (9:2)] to give the title compound (1.65 g, 47%) as colourless crystals, mp 49.5-50.5 "C (from hexane-ethyl acetate) (Found: C, 63.0; H, 5.8; N, 6.6.C,,H,,ClNO requires C, 63.0; H, 5.8; N, 6.7%); v,,,(CC1,)/cm-' 1675; 6,(60 MHz) 3.13 (3 H, s, NMe), 4.08 (2 H, s, COCH,), 5.33 (1 H, s, one of the olefinic protons), 5.75 (1 H, s, one of the olefinic protons) and 7.42 (5 H, s, ArH). 2,2-Dichloro-N-methyl-N-( 1-phenylviny1)acetamide 4b Following a procedure similar to that describd above for the preparation of 4a, compound 4b (1.62 g, 80%)was obtained by acylation of acetophenone N-methylimine prepared from acetophenone (1 .O g, 8.32 mmol) and methylamine (5 cm3), with dichloroacetyl chloride (1.47 g, 9.99 mmol) as an oil (Found: C, 53.6; H, 4.5; N, 5.7.C1,H,,C12N0 requires C, 54.1; H, 4.5; N, 5.7%); v,,,(CCl,)/cm~' 1695; &(60 MHz) 3.14 (3 H, s, NMe), 5.38 (1 H, s, one of the olefinic protons), 5.80 (1 H, s, one of the olefinic protons), 6.37 (1 H, s, CHCl,) and 7.41 (5 H, s, ArH). 2-Iodo-N-methyl-N-( 1-phenylviny1)acetamide 4c Sodium iodide (228 mg, 1.52 mmol) was added to a solution of compound 4a (300 mg, 1.43 mmol) in acetonitrile (1 5 cm3) and the mixture was stirred at room temperature for 5 h when the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed on silica gel [hexane-ethyl acetate (5: l)] to give the title compound (345 mg, 80%) as an oil; v,,,(CCl,)/cm-' 1660; 6,(60 MHz) 3.10 (3 H, s, NMe), 3.78 (2 H, s, COCH,), 5.42 (1 H, s, one of the olefinic protons), 5.73 (1 H, s, one of the olefinic protons) and 7.40 (5 H, s, ArH). Due to its lability, this compound was used immediately for the cyclisation. N-Methyl-N-( l-phenylvinyl)-2,2-bis(phenylsulfanyl)acetamide 4d Benzenethiol (993 mg, 9.01 mmol) was added to a solution of sodium ethoxide in ethanol [prepared from sodium (207 mg, 9.01 mmol) and ethanol (10 cm3)] at 0 OC, and the mixture was stirred at room temperature for 30 min.A solution of compound 4b (1 .O g, 4.1 mmol) in ethanol (5an3)was added to the above solution and the mixture was stirred at room temperature for 16 h when the solvent was removed and the residue dissolved in dichloromethane.The solution was dried (MgSO,) and concentrated and the residue was chromato- graphed on silica gel [hexane-ethyl acetate (7 :l)] to give the title compound (1.49 g, 93%) as an oil (Found: C, 70.5; H, 5.4; N, 3.8. C,,H,,NOS, requires C, 70.55; H, 5.4; N, 3.6%); v,,,(CCl,)/cm-' 1665; S,(60 MHz) 3.06 (3 H, s, NMe), 4.90 (1 H, s, one of the olefinic protons), 5.10 [1 H, s, CH(SPh),], 5.39 (1 H, s, one of the olefinic protons) and 7.20 (15 H, br s, ArH). Radical cyclisation of the chloroacetamide 4a General procedure A. A solution of Bu,SnH (725 mg, 2.66 mmol) and AIBN (40 mg, 0.24 mmol) in toluene (40 cm3) was added to a boiling solution of compound 4a (500 mg, 2.38 mmol) in toluene (30 cm3) using a syringe pump over a period of 2 h and the mixture was heated under reflux for 6 h.Then, a solution of Bu3SnH (775 mg, 2.66 mmol) and AIBN (40 mg, 0.24 mmol) in toluene (25 cm3) was added to it during 1 h and the mixture was refluxed for a further 8 h. The solvent was removed, diethyl ether (30 cm3) and 8% aqueous KF (30 cm3) were added to the residue, and the mixture was stirred vigorously at room temperature for 30 min when the organic layer was separated, dried (MgSO,), and concentrated. The residue was chromatographed on silica gel [hexane-ethyl acetate (2: l)]. The first fraction gave unchanged 4a (248 mg, 50%). The second fraction gave N-methyl-N-( 1-phenylvinyl)-acetamide 69 (73 mg, 18%) as an oil; v,,,(CCl,)/~m-~ 1660; S,(60 MHz) 2.02 (3 H, s, COMe), 3.09 (3 H, s, NMe), 5.20 (1 H, s, one of the olefinic protons), 5.66 (1 H, s, one of the olefinic protons) and 7.36 (5 H, s, ArH).The third fraction gave 1-methyl-5-phenylpyrrolidin-2-one5 lo (72 mg, 17%) as an oil; v,,,(CCl,)/cm-' 1695; 6,(60 MHz) 1.48-2.94 (4 H, m), 2.67 (3 H, s, NMe), 4.51 (1 H, td, J6.5 and 2.0) and 7.05-7.55 (5 H, m, ArH). Radical cyclisation of the dichloroacetamide 4b Following the general procedure A, compound 4b (554 mg, 2.27 mmol) was treated two times with Bu,SnH (771 mg, 2.65 mmol) and AIBN (40 mg, 0.24 mmol). Since TLC analysis showed that the starting material still remained, a solution of Bu,SnH (771 mg, 2.65 mmol) and AIBN (40 mg, 0.24 mmol) in toluene (10 cm3) was added to it, and the whole was refluxed for 15 h.After work-up as described in general procedure A, the crude material was chromatographed on silica gel [hexane-ethyl acetate (7:1)] to give unchanged 4b (216 mg, 39%) and the monochloroacetamide 4a (29 mg, 6%). Radical cyclisation of the iodoacetamide 4c Following the general procedure A, compound 4c (342 mg, 1.13 mmol) was treated with Bu,SnH (493 mg, 1.70 mmol) and AIBN (18 mg, 0.1 1 mmol) followed by Bu3SnH (329 mg, 1.13 mmol) and AIBN (1 8 mg, 0.1 1 mmol), and the crude material was chromatographed on silica gel [hexane-ethyl acetate (2: l)]. The first fraction gave the amide 6 (24 mg, 12%) and the second fraction gave the lactam 5 (93 mg, 47%). Radical cyclisation ofthe bis(phenylsu1fanyl)acetamide 4d General procedure B.A solution of Bu3SnH (491 mg, 1.69 mmol) and AIBN (25 mg, 0.15 mmol) in toluene (50 cm3) was added to a boiling solution of compound 4d (600 mg, 1.53 mmol) in toluene (40 cm3) over 2 h, and the whole was refluxed for 5 h. A solution of Bu,SnH (491 mg, 1.69 mmol) and AIBN (25 mg, 0.15 mmol) in toluene (30 cm3) was added to the reaction mixture over 1.5 h and the mixture was refluxed for a further 3 h. Again a solution of Bu,SnH (491 mg, 1.69 mmol) and AIBN (25 mg, 0.15 mmol) in toluene (20cm3) was added to the reaction mixture over 1 h and the mixture was refluxed for 2 h when the solvent was evaporated off, diethyl ether (30 cm3) and 8% aqueous KF (30 cm3) were added to the residue, and the mixture was vigorously stirred at room temperature for 30 min.The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were dried (MgSO,) and concentrated and the residue was chromatographed on silica gel [hexane-ethyl acetate (2 :l)] to give the lactam 5 (200 mg, 75%). N-Met hyl-N-( 1,2-diphenylvinyl)-2,2-bis(phenylsulfany1)-acetamide 4e A solution of benzyl phenyl ketone (2.0 g, 10.2mmol) in toluene (10 cm3) was added to methylamine (3 cm3) at -78 "C and the mixture was heated in a sealed tube at 100°C for 4 h. The reaction mixture was then concentrated and the residue was dissolved in dichloromethane (30 cm3) containing triethyl- amine (1.34 g, 13.3 mmol) and DMAP (0.13 g, 1.O mmol). To the solution was added dropwise at 0°C a solution of bis(phenylsulfany1)acetyl chloride (3.91 g, 13.3 mmol) in dichloromethane (10 cm3) and the whole was stirred at room temperature for 30 min and then diluted with water.The organic layer was separated, washed with saturated aqueous NaHCO, and brine, dried (MgSO,) and concentrated. The residue was chromatographed on silica gel Pexane-ethyl acetate (1 0 :l)] to give the title compound (2.9 g, 60%), mp 110.5-111 "C (from hexane-ethyl acetate) (Found: C, 74.7; H, 5.4; N, 3.0. C29H25NOS2requires C, 74.5; H, 5.4; N, 3.0%); v,,,(CCl,)/cm-' 1660; 6,(60 MHz) 2.98 (3 H, s, NMe), 5.54 [l H, s, CH(SPh),], 6.36 (1 H, s, PhCH=) and 6.67.9 (20 H, m, ArH). N-Methyl-( 1 -benzyl-2-phenylvinyl)-2,2-bis(phenylsulfanyl)-acetamide 4f Following a procedure similar to that described above for the preparation of 4e,compound 4f(3.17 g, 69%) was obtained by acylation of the N-methylimine, derived from dibenzyl ketone (2.0 g, 9.5 mmol) and methylamine, with bis(phenylsulfany1)- acetyl chloride (3.6 g, 12.4 mmol) as an oil (Found: C, 74.6; H, 5.6; N, 3.0.C30H27NOS2 requires C, 74.8; H, 5.65; N, 2.9%); v,,(CCl,)/cm-' 1660; 6,(60 MHz) 2.75 (3 H, s, NMe), 3.52 (2 H, br s, PhCH,), 5.23 [1 H, s, CH(SPh),], 6.3 1 (1 H, s, PhCH=) and 6.75-7.7 (20 H, m, ArH). N-Methyl-(1-methyl-2-phenylvinyl)-2,2-bis(phenylsulfanyl)-acetamide 4g Following a procedure similar to that described for the preparation of 4e,compound 4g (0.33 g, 22%) was obtained by acylation of the N-methylimine, derived from benzyl methyl ketone (0.50 g, 3.7 mmol) and methylamine, with bis(phenylsu1- fany1)acetyl chloride (1.4 g, 4.8 mmol) as an oil (Found: C, 71 -2; H, 5.7; N, 3.4.C,,H,,NOS, requires C, 71.1; H, 5.7; N, 3.45%); ~,,~(CCl,)/cm-~ 1660; 6,(60 MHz) 1.69 (3 H, s, CMe), 3.08 (3 H, s, NMe), 5.34 [l H, s, CH(SPh),], 6.22 (1 H, br s, PhCH=) and 6.75-7.7 (15 H, m, ArH). Radical cyclisation of the bis(phenylsulfany1)acetamide 4e Following the general procedure B, compound 4e(600 mg, 1.28 mmol) was treated three times with Bu,SnH (410 mg, 1.41 mmol) and AIBN (20 mg, 0.13 mmol) and the crude product was purified by chromatography on silica gel [hexane-ethyl acetate (3 : l)]. The first fraction gave trans-1-methyl-4,5- diphenylpyrrolidin-2-one 11b (80 mg, 25%), mp 127.5- 128 "C (from hexane-ethyl acetate) (Found: C, 81.2; H, 6.9; N, 5.5.C17H17N0 requires C, 81.2; H, 6.8; N, 5.6%); v,,,(CCl,)/cm~' 1700; 6,(300 MHz) 2.70 (1 H, ddd, J 17.0,8.1 and 0.7, one of 3- H2), 2.73 (3 H, s, NMe), 2.99 (1 H, ddd, J 17.0,9.3 and 0.7, one of3-H2),3.32(1H,ddd,J9.3,8.1and6.3,4-H),4.45(1H,d,J 6.3, 5-H), 7.09-7.15 (4 H, m, ArH) and 7.22-7.40 (6 H, m, ArH); ~5~28.45 (NMe), 38.3 (3-C), 48.1 (4-C), 72.7 (5-C), 126.6, 127.1, 127.2, 128.3, 128.85, 129.0, 139.5, 141.5 and 174.3. The second fraction gave cis- 1-methyl-4,5-diphenylpyrrolidin-2-one lla (216 mg, 67%), mp 173.5-173°C (from hexane-ethyl acetate) (Found: C, 81.3; H, 6.8; N, 5.5%); ttmaX(CCl,)/cm-' 1695; 6,(300 MHz) 2.68 (1 H, ddd, J 16.7,8.2 and 0.7, one of 3- H2),2.85(3H,s,NMe),2.89(1H,dd,J16.7and11.2,oneof3-H2), 3.99 (1 H, dt, J 11.2 and 8.2,4-H), 4.80 (1 H, d, J 8.2, 5-H), 6.70-6.82 (4 H, m, ArH) and 7.01-7.17 (6 H, m, ArH); 6, 28.8 (NMe), 34.8 (3-C), 44.5 (C-4), 69.2 (C-5), 126.8, 127.0, 127.7, 127.9, 128.2, 135.9, 137.3 and 174.8.Radical cyclisation ofthe bis(phenylsulfany1)acetamide 4f Following the general procedure B, compound 4f(500 mg, 1.04 mmol) was treated three times with Bu,SnH (333 mg, 1.14 J. CHEM. SOC. PERKIN TRANS. 1 1995 mmol) and AIBN (17 mg, 0.10 mmol), and the crude product was purified by chromatography on silica gel [hexane-ethyl acetate (10: l)]. The first fraction gave an oily mixture of cis- and trans-5-benzyl- 1-methyl-4-phenylpyrrolidin-2-one12 (total 128 mg, total 46%; cis:trans, 72:28, determined by GLC) (Found: C, 81.5; H, 7.4; N, 5.1.C,,H,,NO requires C, 81.5; H, 7.2; N, 5.3:;); vma,(CCl,)/cm~' 1695; for the major isomer: 6, (300 MHz) 2.36 (1 H, ddd, J 17.1,4.3 and 0.5, one of 3-H,), 2.61 (1 H,ddd,J17.1,9.4andO.5,oneof3-H2),2.85(1H,dd, J14.1 and 7.0, one of CH,Ph), 2.91 (3 H, s, NMe), 3.01 (1 H, dd, J 14.1 and 4.9, one of CH2Ph), 3.16 (1 H, dt, J9.4 and 4.3,4-H), 3.75(1 H,ddd, J7.0,4.9and4.3,5-H),6.95-7.00(2H,m,ArH) and 7.11-7.33 (8 H, m, ArH); for the minor isomer: 6,(300 MHz) 2.48 (1 H, dd, J 14.1 and 5.7, one of CH,Ph), 2.54-2.65 (1 H, m, one of 3-H,), 2.56 (1 H, dd, J 14.1 and 7.7, one of CH,Ph), 2.63 (3 H, s, NMe), 2.71 (1 H, dd, J 15.5 and 9.5, one of3-H2),3.71-3.80(lH,m,4-H),4.11(lH,td,J7.7and5.7,5-H), 6.84-6.90 (2 H, m, ArH) and 7.12-7.36 (8 H, m, ArH); for the major isomer: ~3~28.5 (NMe), 38.0,38.7,41.5 (C-4), 69.1 (C- 5), 126.5, 126.81, 126.84, 128.6, 128.8, 129.3, 136.55, 143.9and 174.0; for the minor isomer: 6, 29.5 (NMe), 34.9, 36.15, 42.6 (C-4), 65.4(C-5), 126.4, 127,2, 128.1, 128.3, 128.5, 129.0, 137.8, 138.4 and 174.3.The second fraction gave N-( 1-benzyl-2-phenyluiny1)-N-methylacetamide13 (30 mg, 10%) as an oil (Found: M+, 265.1472. C,,H,,NO requires M, 265.1465); v,,,(CCl,)/cm-' 1660; 6,(60 MHz) 1.57 (3 H, s, COCH,), 3.01 (3 H, s, NMe), 3.60 (2 H, s, PhCH,), 6.26 (1 H, br s, PhCH=) and 6.7-7.6 (10 H, m, ArH). Radical cyclisation of the bis(phenylsulfany1)acetamide 4g Following the general procedure B, compound 4g(400 mg, 0.98 mmol) was treated three times with Bu,SnH (314 mg, 1.08 mmol) and AIBN (1 6 mg, 0.10 mmol), and the crude product was purified by chromatography on silica gel [hexane-ethyl acetate (10: l)] to give an oily mixture of cis- and trans-1,5- dimethyl-4-phenylpyrrolidin-2-one14 (total 100 mg, total 53%; cis:trans, 81 : 19 determined by GLC) (Found: M', 189.1 136. C ,H ,,NO requires M, 189.1153); v,,,(CCl,)/cm-' 1695; for the major isomer: 6,(300 MHz) 0.80 (3 H, d, J 6.2, 5-Me), 2.66 (1 H,ddd,J16.6,8.5and0.7,oneof3-H2),2.77(1H,dd,J16.6 and 9.0, one of 3-H,), 2.86 (3 H, s, NMe), 3.70 (1 H, ddd, J9.0, 8.5 and 7.5, 4-H), 3.87 (1 H, dq, J7.5 and 6.6, 5-H), 7.14-7.19 (2 H, m, ArH) and 7.21-7.37 (3 H, m, ArH).The spectrum also exhibited a small doublet at 6 1.26 (J6.2) due to a methyl group at the 5-position of the minor isomer. N-Methyl-2-methylsulfanyl-2-phenylacetamide8 A solution of ethyl 2-methylsulfanyl-2-phenylacetate (1.647 g, 7.80 mmol) and methylamine (ca. 10 cm3) in toluene (5 cm3) was heated in a sealed tube at 120 "C for 2 h when the reaction mixture was concentrated to give the title compound (1.49 g, 98%), mp 83-84OC (from hexane-ethyl acetate) (Found: C, 61.7; H, 6.7; N, 7.1. C,,H,,NOS requires C, 61.5; H, 6.7; N, 7.2%); 6,(60 MHz) 2.08 (3 H, s, SMe), 2.82 (3 H, d, J 5.5, NMe), 4.47 (1 H, s, CH), 6.5-7.0 (1 H, br, NH) and 7.1-7.55 (5 H, m, ArH). N-Meth yl-N-( 2-methylsulfanylphenethyl)-2,2dichloro-acetamide 9 To borane-THF (1 mol drn-,; 5 1.2 mmol) was added dropwise a solution of compound 8 (2.0 g, 10.2 mmol) in THF (40 cm3) and the mixture was refluxed for 1 h when the excess of borane was decomposed with 6 mol dm-, HCl and THF was evaporated off.The aqueous layer was made alkaline with 10% aqueous NaOH, and extracted with diethyl ether. The extract was dried (K,CO,) and concentrated and the residue was purified by chromatography on silica gel [hexane-ethyl acetate (1 : l)] to give N-methyl-2-methylsulfanylphenethylamine(1.46 J. CHEM. SOC. PERKIN TRANS. 1 1995 g, 78%). To a solution of the thus obtained amine (500 mg, 2.76 mmol), triethylamine (0.31 g, 3.04 mmol) and DMAP (34 mg, 0.28 mmol) in dichloromethane (50 cm3) were added dichloroacetic acid (0.39 g, 3.04 mmol) and 1-ethyl-3-(3-dimethylaminopropy1)carbodiimidehydrochloride (0.79 g, 4.14 mmol) at 0 "C, and the whole was stirred at room temperature for 1.5 h.The mixture was washed successively with 1 mol dmP3 HCl, saturated aqueous NaHCO,, and brine, then dried (MgSO,) and concentrated. The residue was purified by chromatography on silica gel [hexane+thyl acetate (5 : 1)J to give the title compound (0.74 g, 91%) as an oil (Found: C, 49.0; H, 5.05; N, 4.5. CI2H,,Cl2NOS requires C, 49.3; H, 5.2; N, 4.8%); v,,,(CCl,)/cm-' 1685 and 1660; 6,(60 MHz) 1.99 (3 H, s, SMe),2.89(3H,s,NMe),3.24.4(3H,m),6.14(1H,s,CHCl,) and 7.30 (5 H, s, ArH). (E)-N-Methyl-N-(2-phenylvinyl)-2,2dichloroacetamide10 A solution of NaIO, (1.46 g, 6.84 mmol) in water (7 cm3) was added to a solution of compound 9 (1.0 g, 3.42 mmol) in acetone (8 cm3) and the mixture was stirred at room temperature for 1.5 h.The precipitated solid was filtered off, acetone was evaporated off, the aqueous solution was extracted with dichloromethane and the extract was dried (MgSO,) and concentrated to give the crude sulfoxide. A mixture of this crude sulfoxide (0.97 g, 3.1 mmol) and NaHCO, (0.66 g) in xylene (10 cm3) was refluxed for 2.5 h and the insoluble salt was filtered off. The filtrate was concentrated and the residue was purified by chromatography on silica gel [hexane-ethyl acetate (20 : l)] to give the title compound (0.47 g, 61%), mp 73-73.5 "C (from hexane-ethyl acetate) (Found: C, 54.15; H, 4.55; N, 5.9.Cl1H,,Cl2NO requires C, 54.1; H, 4.5; N, 5.7%); v,,,(CCl,)/cm~' 1700, 1675 and 1640; 6,(60 MHz) 3.30 (3 H, s, NMe), 6.15 (1 H, d, J 14, PhCH=), 6.41 (1 H, s, CHCl,), 7.30 (5 H, s, ArH) and 7.51 (1 H, d, J 14, NCH=). (E)-N-Methyl-N-(2-phenylvinyl)-2,2bis(phenylsulfanyl)-acetamide 4h Following a procedure similar to that described for the preparation of 4d, compound 4h (0.75 g, 84%) was prepared from 10 (0.47 g, 1.93 mmol) and benzenethiol (0.47 g, 4.24 mmol) as an oil (Found: C, 70.5; H, 5.45; N, 3.9. C,,H,,NOS, requires C, 70.55; H, 5.4; N, 3.6%); ~,,,(CCl,)/cm~~ 1670 and 1635;6,(60 MHz) 3.19 (3 H, s, NMe), 5.30 [l H, s, (PhS),CHJ, 5.99 (1 H, d, J 14.5, PhCH=) and 6.6-8.3 (16 H, m, NCH= and ArH). Radical cyclisation of the bis(phenylsulfany1)acetamide 4h Following the general procedure B, compound 4h (800 mg, 2.04 mmol) was treated three times with Bu,SnH (654 mg, 2.25 mmol) and AIBN (34 mg, 0.20 mmol) and the crude product was purified by chromatograhy on silica gel [hexane-ethyl acetate (5 : l)]. The first fraction gave N-methyl-N-(2-phenyluin-yl)acetarnide 15 (245 mg, 68%), mp 81-81.5 "C (from hexane) (Found: C, 75.6; H, 7.5; N, 8.1.C,,H,,NO requires C, 75.4; H, 7.5; N, 8.0%); v,,,(CCl,)/cm-' 1680 and 1635; 6,(60 MHz) 2.28 (3 H, s, COCH,), 3.19 (3 H, s, NMe), 5.91 (1 H, d, J 14.0, PhCH=) and 7.0-7.5 (6 H, m, NCH= and ArH). The second fraction gave an oily mixturt (ca. 1: 1) of 4-benzyl-N-methyl-2- azetidinone 16 and N-methyl-4-phenylpyrrolidin-2-one17 (total 62 mg, total 17%), whose structures were assigned on the basis of their IR [v,,,(CCl,)/cm-' 1755 (for 16) and 1695 (for 17)] and 'H NMR spectroscopic data; for 16:6,(300 MHz) 2.65 (1 H, ddd, J 14.5, 2.3 and 0.9, one of 3-H,), 2.74 (3 H, s, NMe), 2.80 (1 H, dd, J 13.9 and 7.8, one of PhCH,), 2.98 (1 H, dd, J 14.5 and 4.9, one of 3-H,), 3.06 (1 H, dd, J 13.9 and 5.9, one of PhCH,), 3.72-3.78 (1 H, m, 4-H) and 7.15-7.8 (5 H, m); for 17: 6,(300 MHz) 2.56 (1 H, ddd, J 16.8 and 8.3, one of 3-H,), 2.83 (1 H,dd,J16.8and9.2,oneof3-Hz),2.92(3H,s,NMe),3.42(1 H, dd, J9.5 and 7.0, one of 5-H,), 3.53-3.64 (1 H, m, 4-H), 3.76 (1 H, dd, J 9.5 and 8.3, one of 5-HJ and 7.15-7.8 (5 H, m).N-Methyl-2,2dichloro-N-[1-(3-pyridyl)vinyl] acetamide 18 Following a procedure similar to that described for the preparation of 4b, compound 18 (2.07 g, quant.) was obtained from 3-acetylpyridine (1 .O g, 8.25 mmol), methylamine (5 cm3) and dichloroacetyl chloride (1.46 g, 9.91 mmol), mp 121- 123 "C (from hexane4thyl acetate) (Found: C, 48.9; H, 4.1 ;N, 11.4. CloHloC12N20 requires C, 49.0; H, 4.1; N, 11.4%); v,,,(CC1,)/cm-' 1680; 6,(60 MHz) 3.16 (3 H, s, NMe), 5.51 (1 H, d, J 1.5, one of the olefinic protons), 5.89 (1 H, d, J 1.5, one of the olefinic protons), 6.40 (1 H, s, CHCl,), 7.35 (1 H, dd, J 8 and 5, ArH), 7.72 (1 H, dt, J 8 and 2, ArH) and 8.6-8.8(2 H, m, ArH).N-Methyl-2,2-bis(phenylsulfanyl)-N-[l-(3-pyridyl)vinyl]-acetamide 19 Following a procedure similar to that described for the prep- aration of 4d, compound 19 (1.86 g, 77%) was obtained from the dichloroacetamide 18 (1.5 g, 6.1 mmol) and benzene- thiol(l.48 g, 13.5 mmol) as a yellow oil (Found: C, 67.1;H, 5.0; N, 7.3.C,,H,,N,OS, requires C, 67.3; H, 5.1; N, 7.1%); v,,,(CCl,)/cm~' 1670; 6,(60 MHz) 3.04 (3 H, s, NMe), 5.01 (1 H, d, J 1.5, me of the olefinic protons). 5.09 [l H, s, CH(SPh),], 5.48 (1 H, d, J 1.5, one of the olefinic protons), 6.95-7.5 (12 H, m, ArH) and 8.4-8.55 (2 H, m, ArH). ( k )-Cotinine 20 Following the general procedure B, the bis(phenylsulfany1)acet-amide 19 (700 mg, 1.78 mmol) was treated three times with Bu,SnH (571 mg, 1.96 mmol) and AIBN (29 mg, 0.18 mmol). Workup gave ( k )-1-methyl-5-(3-pyridyl)pyrrolidin-2-one (cotinine) 20 (304 mg, 97%) as an oil; v,,,(CHCl,)/cm-' 1680; 6,(300 MHz) 1.73-2.96 (4 H, m), 2.71 (3 H, s, NMe), 4.63 (1 H, td, J6.5and2.0,5-H),7.22-7.78(2H,m,ArH)and8.48-8.70(2 H, m, ArH); 6,(75 Hz) 28.15, 29.9, 62.1, 124.0, 133.7, 136.6, 148.3,149.6 and 175.35. The IR (CHCl,) and 'H NMR (CDCl,) spectra were identical with those of an authentic sample.Acknowledgements This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan. The authors also thank Dr Hajime Matsushita, Life Science Research Laboratory of Japan Tobacco Inc., for providing spectra of cotinine. References 1 For reviews, see (a) B. Giese, Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press, New York, 1986; (b) D. P.Curran, Synthesis, 1988, 417 and 489; (c) C. P. Jasperse, D. P. Curran and T. L. Fevig, Chem. Rev., 1991, 91, 1237. 2 (a) T. Sato, Y. Wada, M. Nishimoto, H. Ishibashi and M. Ikeda, J. Chem. SOC.,Perkin Trans. I, 1989, 879; (b) T. Sato, S. Ishida, H. Ishibashi and M. Ikeda, J. Chem. SOC., Perkin Trans. I, 1991,353; (c) H. Ishibashi, T. S. So, K. Okochi, T. Sato, N. Nakamura, H. Nakatani and M. Ikeda, J. Org. Chem., 1991,56,95; (d)T. Sato, K. Tsujimoto, K. Matsubayashi, H. Ishibashi and M. Ikeda, Chem. Pharm. Bull., 1992, 40,2308; (e) H. Ishibashi, N. Uemura, H. Nakatani, M. Okazaki, T. Sato, N. Nakamura and M. Ikeda, J. Org. Chem., 1993, 58, 2360; (f) H. Ishibashi, C. Kameoka, A. Yoshikawa, R.Ueda, K. Kodama, T. Sat0 and M. Ikeda, Synletr, 1993, 649; (8) H. Ishibashi, C. Kameoka, T. Sat0 and M. Ikeda, Synlett, 1994,445. 3 J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman and R. C. Thomas, J. Chem. SOC.,Chem. Commun., 1976,736. 4 (a)H. Ishibashi, N. Nakamura, T. Sato, M. Takeuchi and M. Ikeda, Telrahedron Lett., 1991, 32, 1725; (b) T. Sato, N. Nakamura, J. CHEM. soc. PERKIN TRANS. 1 1995 K. Ikeda, M. Okada, H. Ishibashi and M. Ikeda, J. Chem. SOC., Perkin Trans. I, 1992,2399. 5 A part of this work has appeared as a preliminary communication: T. Sato, N. Machigashira, H. Ishibashi and M. Ikeda, Heterocycles, 1992,33, 139. 6 For other synthesis of cotinine, see: (a)Y. Tsujino, H. Matsushita, A. Sato, K. Kato, T. Kisaki and M. Noguchi, Agric. Biol. Chem., 1979,43, 871; (b) R. Rastogi, G. Dixit and K. Zutshi, Electrochim. Acta, 1983, 28, 129; (c) R. M. Acheson, M. J. Ferris and N. M. Sinclair, J. Chem. SOC., Perkin Trans. 1, 1980, 579; (d) E. Wenkert and E. C. Angell, Synth. Comrnun., 1988, 18, 1331; (e) R. M. Moriarty, R. K. Vaid, M. P. Duncan, M. Ochiai, M. Inenaga and Y. Nagao, Tetrahedron Lett., 1988,29,6913. 7 H. Ishibashi, I. Takamuro, M. Okano, T. Kenri and M. Ikeda, Chem. Pharm. Bull., 1989,37,2214. 8 For other examples of the 4-exo-trig cyclisations leading to p-lactams, see refs. 2(f), 2(g), 4(a)and 4(h). See also S. L. Fremont, J. L. Belletire and D. M. Ho, Tetrahedron Lett., 1991, 32, 2335. 9 K. Takaki, K. Negoro and T. Agawa, J. Chem. SOC.,Perkin Trans. I, 1979, 1490. 10 M. Malmberg and K. Nyberg, Acta Chern. Scand., Ser. B, 1981,35, 41 1. 11 Y. Ohshiro, N. Ando, M. Komatsu and T. Agawa, Synthesis, 1985, 276. 12 Y. Tamura, H. Shindo, J. Uenishi and H. Ishibashi, Tetrahedron Lett., 1980, 21, 2547. 13 I. N. Kiseleva, M. M. Zobacheva and V. V. Perekalin, Zh. Org. Chem., 1974,10,2224. Paper 4/07 196D Receiued 25th November 1994 Accepted 18th January 1995