386G
J. C . CRAIG,N . Y. MARY,N. L. GOLDMAN, AND LYNNWOLF
pound If was identified by characterization of the 2,4-dinitrophenylhydrazone; Id was identified by infrared and n.m.r. spectra taken on the crude compound and characterization of the pure 2,4-dinitrophenylhydrazone. PreparaJion of Dialkyl Aroylphosphonate 2,4-Dinitrophenylhydrazones.-The data in Table I1 were accumulated in experiments performed it1 essentially the following manner. A stock solution of 2,4-dinitrophenylhydrazinewas prepared by placing 6 g. of the reagent (m.p. 198-199") in 30 ml. of concentrated sulfuric acid and adding this mixture t o 40 ml. of water and 140 ml. of 957" ethanol. T o 25 ml. of this solution was added 0.5 g . of the dialkyl aroylphosphonate t o give a precipitate of the corresponding highly colored 2,4-dinitrophenylhydrazone. Methanol was used to recrystallize all of the derivatives.
Vol. 86
Acid Hydrolysis of Dimethyl p-Anisoylphosphonate (Ib).-A flask was charged with 2.44 g. (0.01 mole) of I b and 10 ml. of 0.1 N hydrochloric acid. The reaction mixture was stirred for 4 hr. a t room temperature without any noticeable change in composition. After stirring for 24 hr. the mixture deposited 1.50 g. (98.7%) of p-anisic acid. Basic Hydrolysis of Dimethyl p-Anisoylphosphonate (Ib).-In a system identical with that used for acid hydrolysis was added 2.44 g. (0.01 mole) of I b and 10 ml. of 0.1 N sodium hydroxide. Within 15 min. a heavy white precipitate was observed in the reaction mixture. The solid material was filtered off and the free p-anisic acid was regenerated from its sodium salt by treatment with 0.1 Nhydrochloric acid. The acid (1.43 g., 94.1%) had m.p. 184" after recrystallization from ether.
[CONTRIBUTION FROM T H E DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, UNIVERSITY OF CALIFORNIA, SANFRANCISCO 22, CALIF]
Tertiary Amine Oxide Rearrangements. 111. The Mechanism of the Demethylation of Nicotine' B Y J. CYMERMAN CRAIG,NOURIY. MARY,^ NORMAN L. GOLDMAN, AND LYNNWOLF RECEIVED OCTOBER 19, 1963 The metal complex catalyzed rearrangement of nicotine N-oxide has been shown, by the combined use of thin layer and gas chromatography, to yield formaldehyde and nicotine, N-methylmyosmine, nornicotine, myosmine, nicotyrine, and cotinine. A simple unified mechanism is capable of rationalizing the formation of these nicotine alkaloids as well as of all other known metabolites of nicotine
Nicotine (I) is metabolized in animals and plants t o In the preceding paperI6 the rearrangement of Ngive a variety of products of 'which only nornicotine (11) benzyldimethylamine oxides was shown to proceed conmay he accounted for by a simple demethylation. currently along two pathways giving formaldehyde and Other metabolic products of nicotine include : nicotine the appropriate benzaldehyde, in a ratio determined (in 1 '-oxide (111) ("oxynicotine") , 3 3-methylaminopropyl the absence of steric factors) by the available a-protons 3'-pyridyl ketone (IV) ("pseudooxyni~otine"),~3( i e . , adjacent to nitrogen) and by their relative acidinicotinoylpropionic acid (V) ,4,5 N-methylmyosmine ties. In the case of nicotine 1' oxide (111), this rear(VI)6 (which in aqueous solution is present, by a reversirangement may occur in the following three possible ble dehydration-hydration, in equilibrium with IV in the ways, since three different types of a-proton exist in form of its cyclic aminoketal IVa), nicotyrine (VII),3d.6c,7 111: A. Loss of the proton from the N-methyl group, y-3-pyridyl-y-methylaminobutyric acid (VIII)8-'o leading to the methylolamine (XIV) known to give (which cyclizes spontaneously at pH 7 into its lactam formaldehyde and nornicotine (11). Since there are cotinine ( I X )1 1 , ' * ) , desmethylcotinine "y-3-pyridthree such protons available, this reaction will have a yl-y-oxo-N-methylbutyramide (XI),l 3 y-3-pyridyl-y-h~- high statistical probability and is the expected route for droxybutyric acid (XII),I4 and myosmine (XIII), a N-demethylation. Nicotine-methyl-l4C has been found naturally occurring nicotine alkaloid16 also formed by to give radioactive respiratory carbon dioxide in autoxidation of n i ~ o t i n e . ~ d in agreement with the expected conversion of formaldehyde to carbon dioxide zcia formic acid. ( I ) This work was supported b y a grant (MH-4582) from the National Institutes of Health, U. S . Public Health Service. B. Another pathway, on the basis of the rearrange( 2 ) O n leave from the University of Baghdad, Iraq, a s Visiting Research ment of the N-benzyldimethylamine oxides,16is by loss Scientist, National Academy of Sciences of the United States of America. of a proton from the a-position adjacent to the pyridine (B) (ai W . C. Frankenburg and A . M Gottscho, J . A m . Chem. Soc., 7 7 , 5728 ( l W 5 ) , (1,) C . H. Kayburn, W. K . Harlan, and H . R . Hanmer, i b i d . , ring, giving a tertiary hydroxynicotine (IVa), the cyclic 6 3 , 115 ( 1 9 4 1 ) ; (c) I_ Weil and J. Maher. Arch. Biochem., 99, 241 (1951); ketal of 3-methylatninopropyl 3 '-pyridyl ketone (IV). ( d ) 1: W a d a , T Kisaki and K Saito. A r c h . Biochem. Biophys., 79, 124 f1950). The expected facile dehydration of the tertiary hydroxyl ( 4 ) I? Wada and K Yamasaki, J A m . Chem. S O L . 78, , 155 (1954). would give the conjugated N-niethylmyosmine (VI). (51 S. I.. Schwartz and H McKennis, Federation P r o c . , 11, 183 (1962). C. Proton remcval from the other a-position of the (6) ( a ) T . Kisaki, hf. Ihida, and E Tamaki, Bull. Apr. Chem. Soc. J a p a n , 1 4 , 71G ( I R l L l i . i b ) A U'rnusch. Z 1.ebensm. U n l e r s u c h . Forsch., 84, 498 pyrrolidine ring gives a new secondary hydroxynicotine ,19421. f c ) I!. We,-le and K . Koekhe, A n n . , SS9, 60 (1949). (XV), the cyclic acetal of a-3-pyridyl-7-methylamino( 7 1 h T s u ~ i m o t o .F o l i o Pharmacni J a p o i i , 13, 553 (1957). butyraldehyde (XVa). Ready dehydrogenation of 181 la) H McKennis, 1.. H '1 urnhull, and E R . Bowman, J . A m . C h r m . S u r , 7 9 , fi.N%f 1 9 5 7 ) , f h ) H. hlrKennis, 1.. B . Turnhull, and E . R . Bowman, this aldehyde to the acid yields the known y-3-pyridylI b i L 80, K i D i (1958) y-methylaminnbutyrie acid ( V I I I ) , easily ring closing '!4' ii 13 Bowman, I, H Turnbull, and H . McKennis, J . P h n r m . E r p l l . i ' h e r n p . . 127, (12 11955). to form its lactam, cotinine (IX), which may also arise 1 0 1 I' S I.arson, H. B. Haag, a n d J K . Finnegan, ibid.. 86, 239 f1916). directly from an osiciation or dehydrogenation of the ( 1 I ) H XicKennis, 1.. €3 Turnhull, E. R Bowman, and E. Wada, J . A m cyclic acetal XV. p\r icotine :rietabolisin in rahbitIs Chi,m h'nc., 81, 34.51 !:959) 112) 1'. 1< Guthrie. K I. P ~ n g e r and , T G . Bowery, I Econ. EnfomoI., forms a hydroxynicotine with the properties of a cyclized 6 0 , 8 2 2 !19.57: f1:L H. I l c K e n n i s , I. €3 '1 tirnhull, B R Bowman, and S .I. Schwartz. .I A n i ChPm .Sot. 8 4 , - I A R S 110G21 ( I t 1 i.. B . Turnhull. R I < . Bowman, and If. M c K e n n i s , F p d r r a l i o n Pro,: , 17, ,325 (195% " R . LVitkop, J . A w C h r w S a c . , 7 6 , 5597 (1954)
IO) J . C . Craig, '\. I ..Mary, and L. Wolf, .I O r g . Chem., in p r e s 17) H. McKenn,s, h Wada, E K . H. !I$! H . 13. €Iuc
