The Synthesis of 5'-Alkylnicotines (1986)

The reaction o f cotininec?)wlth alkyl lithium followed by the reduction with NaBH3CN in acidic methanol gave & and trsns-5'-alkylnicotines(3_ and $).The stereochemistry o f t h e products uas di-cussed.To understand t h e biological activities of nicotine(?),t h e synthesis of its analogues for t h e development of structure-activity relationship is important. Although several alkylnicotines have been prepared from thi* point of view, 1 as t o 5'-alkylnicotines only 5 ' -d i m e t h ~l n i c o t ~n e has s o far been ~b t e i n e d . ~In this paper, we uish t o report the synthesls of 5'-monoalkylnicotines.The stereochemistry will also be mentioned.The reaction o f sotinine(?)with alkyl lithium followed by t h e reduction with sodium c ~a n o b o r o h y d r ~d e in acidic methanol gave 5'-monoslkylnisotine.The yield and the stereoselectivity w e r e listed in Table 1.T h e alkylation o f 2 3 : 4_ ( % ) 5'-proton in $? were observed a t laver field than those in 3. Slnse 5 methyl 68 78 : 22 5'-a (pseudo equatorial )-proton in 1 b_ ethyl 47 82 : 18 is a-signed t o t h e lower field 5 n-butyl 70 82 : 18 resonance than 5.-B (pseudo axial )-9 phenyl 66 90 : 10 proton.3 3 end $? were assumed t o $ isopropyl 54 90 : 10 have pseudo axle1 and paeudo equato-f_ m -b u t y l 9 100 : 0 rial protons.respectively.This explanation was further supported by NMR analysis.A s shown in Table 3, t h e chemical shifts of 2 'and 5'-carbons in 3 uere observed a t lower field than those in 5 .This difference was explained t o be caused by t h e steris effect from 5'-substituent.An axial substltuent causes higher field shift o f a and T carbons than an equatorial one in cyclohexane ring.4Therefore, t h e 5'substituents in 3 and $? were considered t o be pseudo equatorial and pseudo axial, respectively.T u o possible conformations of &-5'-slkyl isomer were anticipated, but t h e conformation of ~y r i d i n e ring and alkyl group being both pseudo equatorial w a s more stable than that being both D-eudo axial.Then t h e compounds possessing 5'-pseudo axial Droton and pseudo equatorial 9ubstituent.that is z, were &-isomers.As shown in Table 1, c b -~s o m e r s were predominantly obtained, a n d t h e stereoselectivity increased with an increa9e in t h e bulkiness of 5'-olkyl Scheme 6 148.4 148.7 148.6 148.5 148.6 148.7 148.6 148.6 148.7 148.5 148.3 148.4 * s e e reference 3 hvdride attacks C=N double bond from s i d e B predominantly t o give 3. because side A is hindered by 2'-prridine ring.EXPERIMENTAL Z'S.S'S-5'-MethvInicot1ne(3_a_) and 2'S.S'R-5'-MethvInicotine(r?a_) ---T o a solution of cotinine(?)(5mmol, 0.99) in 20ml of ether w a s added dropwise 6mmol o f methyl lithium in l O m l of ether a t O'C.The reaction mixture w a s stirred a t room temperature.After 1 h, dil.HCI was added t o t h e mixture, made basis with NaHC03, and extracted with ether.The extract was dried over Na2S04.and concentrated in vacuo.The resulting 0 1 1 uas dissolved in 20ml o f methanol, and a trace of bromocresol green ( p H 3.8-5.4)was added followed by HETEROCYCLES, Vol. 24, No. 2, 1986 the addition of a 2N solution of HCl in methanol until the color turned yellow.Then 0.33g(5mmol) of Na8H3CN was added uith stirring.and the methanolis HCl was added dropwise to maintain the yellow color.After stirring at room temperature for lh, the solution was poured into 2Oml of O.1N NaOH.saturated uith NaCl and extracted with ether, The extract was dried over Ne2S04, an concentrated in vacuo to give a mixture of 2'5.5'5-and 2'S,S'R-5'-rnethylnicotine(3~ end 5 ) .These diastereomers were separated by a reversed phase column chromatography (ODs; 22mmQ x 50cm; CH30H : H20 = 4 : I), and 0.47g(53%) of 39 and 0.13g(15%) of $5 were obtained.(3%): mass(rn/z); 176(M+; 7), 98(22), 118(7), 130(35), 147(6), 161(100).162(10).175(5): 25-Found: m/z.176.1322.Calcd for C11H16N2: M. 176,1314: -96.4' ( ~~0 .6 , MeOH); ($91: mass(m/z); l76tM+; 10).98(18), 118(7).130(41).147(12).161(100).162(11), 175(8): Found: m/z.176.1325.Calcd for CilH16N2: M, ZT 176.1314:C elsa6 -65.2' (s=0.23.MeOH). 2'S.5'S-S'-Ethylnicotine(3_b)and Z'S.5'R-5'-Ethvlnisotine(l?b_)---The reaction of ?uith ethyl l~thium was carried out in a similar , manner as described above.After separation, 0.37.(39%) of 2'5,5'5-5'-ethyInicotine(2~) and 0.08g(8%) of 2'S,S'R-5'-ethylnicot1ne($b) were obtained.(3P): mass(m/z); 190(M+: 2), 118(7), 130(23), 161(100), 162(11): Found: m / z , 190.1433.Calcd for C12H18N2: M. 190.1471: -40.7' (c=1.15.MeOH); (P_b_): mass(m/z); 190(M+: 4).118(7), 130(42), 161(100), 162(15): Found: m / z , 190.1450.Calcd for C12Hi8N2: M, 190.1471: C a]? -65.5' (c=0.33.MeOH).2'5.5'5-5'-n-ButvInicotine(2~) end 2'S.S'R-5'-n-ButvInicotine(~) ---The reaction of 2 with 0-butyl lithium was carried out in a similar manner as described above.After separation.0.570(53%) of 2'S,5'S-5'-a-butylnicotine (3%) and 0.19~(18%) of Z'S,5'R-5'-~-butvlnicotine(5~) were obtained.(25): mass(m/z): 218(M+: 1).92(4).118(5).130(6), 161(100).171(10).217(1): Found: m / z , 218.1761.Cslcd for C14H22N2: M. 218.1783: C a32D5 -37.6' (c=1.9.MeOH): (5%): mass(m/z); 218(M+; 2).118(3).130(29), 161(100).162(11).217(1): Found: m/z, 218.1759.Calcd for Cl4HZ2N2: M. 218.1783: C a lZ5 -85.1' n (c=0.1,MeOH).Z'S.S'R-5'-PhenvInicotine(?d_) and 2'S15'S-5'-Phenvlnicotine(O_d_) ---The reactlo" of ?uith phenyl lithium was carried out in a similar manner as described above.After separation, 0.71g1594) of 2'S,S'R-5'-~henylnicotine(3_d_) and 0.08.(7%) of 2'S.5'S-5'-phenylnicotin~(4$) uere obtained.(Sd): mass(m/z): 238(M+: 21).91(8), 118(13).130(15), 160(96).161(100).195(4), 209(15).237(33): Found: m/z.238.1493.Calcd for C16H18N2: M. 238.1470: C a 1 2 ~ -8.3' ( ~6 . 1 , MeOH); ('Id): mass(m/z); 238(M+: 30).91(12), 118(16), 130(17).160(100).161(79).195(9), 209(33).237(30): Found: m/z, 238.1441.Cnlcd for 2.r C16H18N2: M. 238.1470: C a3546 -88.9' ( ~1 . 2 6 , MeOH).2'S.5'R-5'-Iso~rc~~lnicotine(~) and 2'S.5'S-5'-Iso~ro~~Inicotine(P_e_) ---The reaction of ? with isopropyl lithium was carried out in a similar manner as described aboue.After .e~aration,0.48g(48%) of 2'S,5'R-5'-ieopropylnicotine (3.) end 0.06gt6X) of 2 ' S , 5 ' S -5 ' -i s o p r o ~y l n i c o t i n e ( ~~) were obtained.(2%): mass(m/z); 204(M+: 11, 118(5), 130(50).161(100), 162(17), 189(1), 203(1): Found: m/z, 204.1611.Calcd for C13H20N2: M. 204.1626: C al22 -29.Y (c=0.6.MeOH); (4%): rnass(m/z); 204(M+; 1).118(7).130(45).161(100).162(11).189(3): Found: m/z, 204.1650.Calcd for Cl3HZ0N2: M, 204.1626:C a 1 $ , 5 -15.0" (c=0.08.MeOH).2'5.5'R-5'-tert-ButvInicotine(2f) ---The reactldn of 2_ with w -b u t y l lithium was carried out in a similar manner as described above.After separation O.IOg(94) of 2'S.5'R-5'-tert-butylni~otine(~f-) was obtained.mass(rn/z); 218(M+: 0.02).130(25), 161(100).162(9), 203(5): Found: m/z,