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Paper No. 8 iJi:.. ,.'. . . TITLE: MODEL STUDIES ON NICOTINE ANALOGUES. SYNTHESIS AND NITROSATION REACTIONS AUTHORS: J. Masaryk*, K. D. Brunnemann and D. Hoffmann -AFFILIATION: American Health Foundation, Valhalla, NY 10595 ~ Nicotine as well as minor alkaloids deriving from nicotiana are known to for~ m .tobacco-specific N-nitrosamines during tobacco processing an smoking. It was the goal of this study to investigate the properties of some nicotine analogues in regard to their N-nitrosation products. The nicotine analogues were synthesized, . whereas commercially available nicotine was usedl. ,10 , : ., \N CH3 _N cH3 N ~ CH3 "CH3 Ir 1' T , ~ N N' ~ N ~ ~_ 7f _. ~ }.- ~ r. L~ ,. .. . ... . .. ~ . . . _ . . . v~~: ~ _ ~{\ Xi'' anicotine [1] nicotine [2] Y-nicotine [3] phenylnicotine [4] .i n , ..... ) ~'Ththif1 []d [3]li e s ess o y an was accompshed by preparing 2-myosmine and 4- ~'`~~} myosmine which were obtained by condensation of the ethyl esters of 2- and 4- f~ '` pyridinecarboxylic acids with N-trimethylsilyl-l-pyrroline using n-butyl lithium. `` For the synthesi s of [4], 2-pfienyl-1-pyrrol idine was prepared by reacting phenyl bidithbbtitil fll magnesiumrome w Y-romo-uyronreoowed by cyclization in xylene . These resulting myosmine analogues were reduced to nornicotine analogues using NaBH;~,-followed by methylation with formaldehyde and subsequent reduction with 3 Xt'cyanoborohydride to yield' thitil[13d 4]"Thiti e ncone anaogues.,, an :ese ncone _ `r "`~~~ = analogues and nicotine i'tself were subjected to N-nitrosation at pH 4.5 for 3 hours at 90C using a 5-fold excess of NaN02. 'In the case of nicotine, the major nitrosation products are N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK). The following table lists our first data of these m troso analogues obtained from the compounds studied (% yield) { ~,~ :.7 .'7.i.l. .. . .' - ...,... ,. ... . __ . . ... . .. . T .. ~.i~.i.:.. Nitrosation Analogue ~ . . I NNH ~r not detected 0.38 0.23 l 0.48 n fV t t,.44 ~ k NNK ~ . 0.38 0.38 0.33 'T,I t,~ ~r 0.36 ~ ; ~ ;J~~,i~V~c~'u~ . ,ts.T REVIEW: This paper described the syntheses of NNN and N-methyl-2-phenyl-pyrrolidine,'" j~ ,+0~ - which were based on literature procedures.1-5 The majorr portion of the talk involved the investigation of the reaction between compounds 1-4 and sodium j'"* ~''-nitrite in an aqueous media (pH 4.5). The products were analyzed on a 12' x. ~`- -1/4" 2mm ID column packed with 20% apiezon N on Chromosorb W-HP at 210'C (and a '=-f1!ow rate of 40ml Argon/min). The following retention times were found on this column: NNN/20 min; NAT/22 min; NAB/23 min; and NNK/36 min. Under the reaction cond'itions, compounds 2-4 gave comparable products (the corresponding NNN, NAT, NAB, and NNK). Compound 1 gave one product, believed to be X-NNK. The nitro- sation of N-methyl(d3)-nornicotine also gave the same products as nicotine,2 but in different ratios. Also believed to be present in these reactions was the corresponding cotinine. A mechanism was proposedas follows: addition of X-N0'%llllllllll` to the pyrrole nitrogen; abstraction of the hydrogen from the pyrrole methyl to 0 yield tne nitrogen ylide; collapse of the ylide to give anatabine; and nitro 0 - sation of this to give NAT. ,,.,,. .._ .z. References: *1) M. W. Hu, W. E. Bondinell, and 0. Hoffman, J. LaDelled Compounds and Radio ' Pharmaceuticals 10 (1) 79 , (1974). 2) I. eeman, H. V. Secor and G. Forrest, J. Labelled Compounds and Radio Pharmaceuticalis 16 (3), 387.(1979). 3) h r. rc an A. I. Hass id, J. Or . Chem. 37 (10), 1673 1972). 4) D. F. Glenn and W. B. Edwards, , r Chem. 43 (14), 2860 (1978) ~= ~ ~ 5) L C Crai H Bulbrook . an . Chem. Soc:! rg,d R M. Hixon,53, 1831.. 1931) ,.. s.. -. ~„r .•T 'a-Nicotine [1] Nicotine [2] Y-Nicot3ne [3]