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Synthesis in the pyridine series : Part 1. The synthesis of new 3,4,5-trialkylated pyridines ; part 2.… Tabata, Takao 1962

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SYNTHESIS IN THE PYRIDINE SERIES Part I The Synthesis of New 3,4,5-Trialkylated Pyridines Part II The Synthesis of New J,5-Dimethyl-4-Substituted Pyridines. Steric Effects as an Aid to Synthesis TAKAO TABATA B.Sc, The University of B r i t i s h Columbia, I960 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of Chemistry We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September, 1962 In presenting t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . I t i s understood t h a t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be allowed without my w r i t t e n permission. Department of The U n i v e r s i t y of B r i t i s h Columbia, Vancouver 8, Canada. Date sda*f Z 2/ fff'2 ABSTRACT PART I A synthetic sequence leading to new and inacces-sible 3 »4 - , 5-trialkylated pyridines has been developed. 3,4-Dimethyl-5-cyanopyridine was converted to 3,4-dimethyl-5-acetylpyridine on treatment with methylmagnesium iodide and the acetylpyridine was subsequently treated with ethylmagnesium iodide to yield 3»4~dimethyl-5(2-hydroxy-2-butyl)pyridine. Removal of the hydroxyl group was accom-plished by means of red phosphorus and hydriodic acid and the resulting olefinic compounds were catalytieally hydro-genated to 3».4—dimethyl-5-s-butylpyridine. For further studies in this area, 3 »4~dimethyl-5-acetylpyridine was reduced to 3dimethyl - 5-ethylpyridine by the Wolff-Kishner reaction and the latter was condensed with benzaldehyde to afford 3-methyl -4-styryl-5-ethyl-pyridine. This, on ozonolysis, was converted to 3-nieth.yl-5-ethyl isonicotinic acid which was subsequently methylated with diazomethane to methyl 3-methyl -5-ethyl -4-pyridine-carboxylate. The nature of the synthesis allows the preparation of virtually any type of 3»4-,5-trialkylated pyridine by straightforward variations at the appropriate stage. PART II In relation to Part I, the synthesis of 3»5-dimethyl-4—substituted pyridines was undertaken. 3»5-Lutidine was reacted with acetic anhydride and zinc to afford in good yield the unexpected 3,5-dimethyl-4~acetyl-pyridine. This was then conveniently converted to 3»5-dimethyl-5-ethylpyridine on reduction with acetic acid and zinc thereby confirming the structure of the acetylpyridine. The acetylpyridine was also reduced with lithium aluminum hydride to 3»5-dimethyl-4-(l-hydroxyethyl)pyridine which in turn was readily dehydrated with phosphorus pentoxide to 3 J5-dimethyl-4-vinylpyridine. Both the hydroxypyridine and the vinylpyridine on treatment with hydrobromic acid yielded 3,5-dimethyl-4(2-bromoethyl)-pyridine hydrobromide. This was then converted to 3,5-dimethyl-4-(2-cyanoethyl)pyridine. The preparation of these compounds was possible due to the utilization of the steric effects enforced by the two neighbouring methyl groups at the 3 and 5 positions of the pyridine ring. This sequence of reactions provides a valuable method by which 3,5-dimethyl-4~substituted pyridines can be synthesized owing to the availability of the starting material and to the relatively high yielding reactions. ACKNOWLEDGEMENTS The author i s indebted to Dr. James P. Kutney f o r h i s valuable advice, encouragement and guidance during the course of t h i s research. F i n a n c i a l a i d from the National Research Council of Canada and E l i L i l l y and Company i s very g r a t e f u l l y acknowledged. The author wishes to thank the R e i l l y Tar and Chemical Corporation f o r a g i f t of 3 , 5 - L u t i d i n e . Thanks are also due to Dr. D. McGreer f o r running N.M.R. spectra and to Miss K. Tabata and Miss S. Tabata f o r drawing the diagrams. TABLE OF CONTENTS Page PART I Introduction . . . . 1 Discussion 10 Conclusion 18 Experimental 19 Bibliography 30 L i s t of Figures 1. Preparation of 3,4,5-collidine from d i e t h y l -^cyano-<=V#'tf -trimethylglutaconate by Tsuda et a l 3 2. Rogerson and Thorpe's o r i g i n a l preparation of glutaconates and the subsequent c y c l i z a t i o n products 3 3. Preparation of 3,5-dimethyl-4-alkylpyridines by Vaculik and Kuthan 6 4. Synthesis of 3,4-dimethyl-5-isopropylpyridine from 5-cyano-3,4-dimethylpyridine by Kutney and Selby 8 5. Synthesis of new 3,4,5-trialkylated pyridines from 5-cyano-3,4-dimethylpyridine 12 PART I I Introduction 32 Discussion 39 Conclusion 48 Page Experimental . . . 4-9 Bibliography 61 L i s t of Figures 1. Preparation of ^-alkylpyridines by the Wibaut-Arens alkylation method 34-2. Ionic mechanism of the Wibaut-Arens alkylation reaction proposed by Mosher . . . . 35 3. Free radical mechanism of the Wibaut-Arens alkylation reaction proposed by Bachman and Schisla 36 4-. Synthesis of new 3,5-dimethyl-4~substituted pyridines with steric effects as an aid to synthesis 42 PART I THE SYNTHESIS OP NEW 3 , 4 - , 5-TRIALKYLATED PYRIDINES INTRODUCTION In connection with, the structural elucidation of a new alkaloid, skytanthine, ( 1 , 2 ) isolated from a Chilean plant, Skytanthus acutus Meyen, i t became necessary to consider the identity of several 3 , 4 - , 5-trialkylated pyridine derivatives. The particular compounds which were necessary for study were the two possible dimethylisopropylpyridines, namely, 3,4—dimethyl-5-isopropylpyridine and 3,5-dimethyl-4-isopropylpyridine. Investigation of the literature revealed however, that 3 , 4 - , 5-trialkylated pyridines were not readily available and especially pyridines of this type possessing even the simplest branched chains were unknown. Hence investigation toward the synthesis of these trialky-lated pyridines were undertaken. Apart from the fact that 3 , 4 , 5-trialkylated pyridines were not readily synthesized except for the simple alkylated pyridines ( 3 , 4 , 5 , 6 , 7 ) , perusal of the literature also revealed that these compounds were not commonly found in nature. In this connection, Tsuda, Mishima, and Maruyama ( 8 ) and Arnall (9) have reported the isolation of 3,4,5-trimethylpyridine from coal tar bases and this is the only compound of this type shown to exist in nature. 2 In order to facilitate the identification of this collidine from amongst the many polymethylated pyridine constituents in coal tar, Tsuda and his co-workers (8) prepared 3,4-,5-trimethylpyridine from ^-cyano-^,lf-trimethylglutaconate as shown "by the following sequence of reactions (Figure 1). The method, however, was applied with increasing difficulty to the synthesis of such higher straight chain alkylated homologues as 3-ethyl-4 ,5 -dimethylpyridine and 3,5-diethyl-4-methylpyridine (6). This method utilized by Bailey and Brunskill was merely a modification of a previously established synthetic sequence leading to the closely related substance,V-cyano-^V^-trimethylglutaconate. This latter substance was converted to 3,4,5-trimethyl-2,6-dihydroxypyridine as reported by Eogerson and Thorpe (8,10). The original sequence of reactions is represented by figure 2. It was apparent therefore that replacement of the methyl iodide by the appropriate alkyl iodide in one of the above alkylation steps could conceivably lead to the required modification. Hence Bailey and Brunskill (6) prepared <* ,/^,^-trialkylglutaconates (I,R=CH^,R'sCgH^; R = R * zzGgR^) by alkylating the crude potassium derivative of the products formed by condensing ethyl cyanoacetate and ethyl acetoacetate. An attempt to obtain the potassium derivative of the oc-ethyl-^-methyl ester ( I j R s G g H ^ j E ' =H) by condensing ethyl oc- acetobutyrate with ethyl cyanoacetate ia$$ .Iggr I M A * «$ + N a y * H3G C N • H C l + HOC X ^ . u t a c o m a b c s a s c l t h e 4-was unsuccessful (6,10) although a similar preparation of the(^-dimethyl analogue (I,R=CH^ ,R' =H) had "been previously described (6,11,12). Ethyl propionylacetate also failed to condense in the same manner with cyanoacetate so that this preparative approach was applicable only to the syn-thesis of 4-methylated homologues. Furthermore, significant quantities of crotonic esters were isolated in the preparation of the trialky-cyanoglutaconic esters (III,X=CN) but only small quantities of the expected trialkylated esters were obtained (6,10,13). This was particularly true when the alkyl group represented by R was an ethyl group. The cyclization of the crotonates also furnished a very low yield of the key intermediate compound II. It was therefore obvious that this method could not be utilized to prepare any of the 3,4-,5-trial-kylated pyridines which were necessary for our work. Another group of workers, Vaculik and Kuthan (7) have contributed to this field but once again the synthetic method for the preparation of 3,4,5-trialkylated pyridines has been restricted to the preparation of symmetrically substituted pyridines possessing only the straight chain alkyl groups (Figure 3). The symmetrically substituted base (IV) was prepared by condensation of <* -dimethyl acetone 5 dicarboxylic acid ethyl ester with formaldehyde and benzylamine and converted to l-benzyl-3,5-&imethyl-4-piperidone (V) via a keto ester cleavage. This compound, on treatment with the Grignard reagent gave the corres-ponding tertiary alcohol (VI) which on catalytic dehydro-genation yielded the 3,5-dimethyl-4-alkylpyridine (VII). It is noticeable here that this synthetic scheme, due to the nature of i t s starting material, can lead only to sym-metrical and simple alkylation. The synthesis of 3,4-dimethyl-5-isopropylpyridine reported by Kutney and Selby ( 2 ) represents the f i r s t suc-cessful preparation of a branched chain 3,4 - ,5-trialkylated pyridine. Before the successful method which did provide the d i f f i c u l t l y accessible pyridine is discussed i t is of some interest to elaborate on the previous work leading to their success since i t does indicate some of the difficulties encountered in the synthesis of alkylated pyridines of this type. The f i r s t consideration to synthesize the unsym-metrical dimethylisopropylpyridine was an endeavour to pre-pare the appropriate diethyl isopropyl glutaconate (Figure 2). This method was unsuccessful in that the introduction of the third alkyl group resulted in the isolation of undesirable low boiling esters. Similar difficulties in preparing the higher trialkylcyanoglutaconates have been encountered by other workers ( 6 ) . 7 Consideration of another synthetic path however led to the desirable 3,4-dimethyl-5-isopropylpyridine. This synthetic sequence in fact provided a general approach to new and otherwise d i f f i c u l t l y accessible 3,4,5-trialky-lated pyridines (Figure 4). The i n i t i a l starting point of the synthesis was the preparation of 5-cyano-2,6-dihydroxy-3,4-dimethyl-pyridine (VIII), a compound which had been previously reported by Guareschi (14). The Guareschi-type cyclization had also been employed in several other cases by Ruzicka ( 1 5 ) , Hope ( 1 2 ) and Bobbit (16). A simple modification of the previous sequences permitted the preparation of the desirable dihydroxy compound (VIII). The preparation of 5-cyano-3,4-dimethylpyridine (IX) provided a versatile intermediate which was easily converted to the pyridine carboxylate (X). Reaction of (X) with methylmagnesium iodide allowed the preparation of.the tertiary alcohol (XI) which in turn was transformed to 3,4-dimethyl-5-isopropyl-pyridine (XII). With this achievement, 5-cyano-3,4-dimethyl-pyridine became a valuable intermediate for the synthesis of various types of new and otherwise d i f f i c u l t l y accessible 3,4,5-trialkylated derivatives. Since numerous modifi-cations of the cyano function were apparent, the compound lent it s e l f to a rather general approach to pyridines of the type mentioned above (Figures 1 , 2 , 3 , 4 ) . Some result supporting this view are described in this part of the thesis. DISCUSSION There are numerous possible modifications of the cyano group and i t was already indicated that conversion of t h i s group to an ester f u n c t i o n provides an intermediate f o r the preparation of pyridines of type A (Figure 5)« In order to provide an entry into another s e r i e s of branched chain pyridines (type B), 3 , 4-dimethyl - 5-cyanopyridine XIII was reacted with methylmagnesium iodide to a f f o r d 3 , 4 -dimethyl - 5-acetylpyridine (XIV). The success of t h i s r e a c t i o n was c l e a r l y shown by the i n f r a r e d spectrum of the product, which indicated the disappearance of the cyano function ( 4 . 4 3 u ) and the appearance of a strong carbonyl absorption at 5»94u. This acetylpyridine was then treated with ethylmagnesium iodide to y i e l d the expected alcohol (XV) as a l i g h t viscous l i q u i d . This substance however r e s i s t e d a l l attempts to c r y s t a l l i z e - a rather unusual behaviour since an analogous substance, 3 , 4-dimethyl - 5 -(2-hydroxy-2-propyl)-pyridine, previously prepared by us, was c r y s t a l l i n e . The i n f r a r e d spectrum of t h i s compound showed the usual intense and broad hydroxyl band at 2 .95u-3»30u and the N.M.R. spectrum here was very i n f o r -mative. The presence of a t r i p l e t at high f i e l d (9.22T) indicated a methyl group flanked by a methylene carbon which 11 in turn was split into a quartet at 8.16?'. Another absorption at 8.50fwas assigned to the tertiary methyl group attached to an oxygen "bearing carbon and a singlet at 4-.60r was attributed to the hydroxyl proton. The remaining signals at 7.85?" and 7.58^ were characteristic of methyl groups attached to the pyridine nucleus (2) and a doublet at low applied magnetic f i e l d (2.08?) was assigned to the two <a> protons of the pyridine ring. These signals clearly indicate that an unsymmetrical substitution of the ring at 3,4-, and 5 positions was present, thus con-clusively establishing the structure of the alcohol (XV). The removal of a hydroxyl function of this type has been successfully accomplished by previous workers by means of red phosphorus and hydriodic acid and this reaction has been frequently employed in the pyridine series (2,18, 19). Consequently the utilization of this method was attempted in this series. However, in contrast to the successful conversion of 3»4—dimethyl-5-(2-hydroxy-2-propyl)-pyridine to 3,4—dimethyl-5-isopropylpyridine by conducting the reaction at the reflux temperature for 24- hours, the corresponding conversion of XV to the desired 3,4~dimethyl-5-s-butylpyridine (XVII) did not proceed to completion. Even under more stringent conditions (4-8 hrs. reflux) the product of the reaction s t i l l contained a mixture of the desirable compound, XVII, and the olefinic substances XVI. 13 The greater resistance of the o l e f i n i c bonds to reduction was f u r t h e r exemplified by hydrogenation studies. When hydrogenation of XTI was performed under s i m i l a r conditions used to reduce the corresponding 3,4-dimethyl-5-isopro-penylpyridine, (Adams c a t a l y s t , atmospheric pressure, room temperature) incomplete reduction was s t i l l observed, as ind i c a t e d by the o l e f i n i c s i g n a l s i n the N.M.R. spectrum. Nevertheless, the desired compound, XVII, was obtained under more d r a s t i c r e a c t i o n conditions (Adams c a t a l y s t , 32 p s i ) . The u l t r a v i o l e t spectrum was c h a r a c t e r i s t i c of an alk y l a t e d p y r i d i n e and the N.M.R. spectrum provided strong support f o r the s t r u c t u r e . The successful completion of t h i s sequence now allows the preparation of v i r t u a l l y any type of t r i a l k y l a t e d pyridine possessing branched a l k y l chains at the 3 p o s i t i o n . I t has been r e c e n t l y reported that s t e r i c e f f e c t s of substituents attached to carbon atoms 3 and 5 on the pyrid i n e r i n g appeared to play an important r o l e i n i n f l u -encing the course of re a c t i o n of f u n c t i o n a l groups at the 4-position of the pyridine r i n g . For example, Kutney and Selby (2) have found that 3,5-cLimethyl-4-acetylpyridine possessed a very unreactive carbonyl f u n c t i o n that r e s i s t e d r e a c t i o n under various conditions to organometallie reagents. This f a c t o r , must be a t t r i b u t e d , at l e a s t i n part, to the s t e r i c influence of the two neighbouring 14 methyl groups. In hope of obtaining more information as to the s t e r i c e f f e c t s of the substituents at the 3 and Im-p o s i t i o n s on the r e a c t i v i t y of a l k y l groups at the 4-p o s i t i o n , an aldol-type condensation r e a c t i o n of 3,4— dimethyl-5-ethylpyridine with benzaldehyde was considered. This type of r e a c t i o n has been well u t i l i z e d i n pyrid i n e chemistry on numerous occasions and has proven to be of considerable synthetic value (22, p. 200). For the preparation of 3»4~dimethyl-5-ethylpyri-dine, a d i r e c t reduction of the a c e t y l f u n c t i o n to the et h y l group was then considered. The most convenient method f o r t h i s conversion appeared to be the Wolff-Kishner r e a c t i o n since t h i s procedure has been frequently employed i n the pyridine s e r i e s (20). When 3,4-dimethyl-5-acetyl-pyridine was reduced under the Huang-Minion mo d i f i c a t i o n of the Wolff-Kishner r e a c t i o n (20), the expected 3,4—dimethyl-5-ethylpyridine was obtained. The N.M.R. spectrum was i n complete agreement with the assignment of the structure i n that i t ind i c a t e d a t r i p l e t at high f i e l d (8.84r) and a quartet at (7.4-2?-) providing strong support f o r an eth y l group. The remaining s i g n a l at 7*86rwas r e a d i l y a t t r i b u t e d to the methyl protons of carbons attached to the pyridine r i n g and the weak s i g n a l at low f i e l d (1.96?) was t y p i c a l of oc -protons on the pyridine nucleus. Now, when the ethylpyridine was reacted with 15 benzaldehyde, under rather d r a s t i c conditions, the corresponding 3-methyl-4-styryl - 5-ethylpyridine XVIII was obtained i n a reasonable y i e l d . The success of t h i s r e a c t i o n was c l e a r l y evident from spectroscopic consider-ations. The i n f r a r e d spectrum indicated that a new o l e f i n i c bond had been formed (6.12u) and the N.M.R. spectrum cer-t a i n l y supported t h i s evidence. The o l e f i n i c proton region exhibited a c h a r a c t e r i s t i c AB s p l i t t i n g pattern with a separation of l ? c p s , suggesting a trans o r i e n t a t i o n of the o l e f i n i c bond. The c h a r a c t e r i s t i c signals f o r the e t h y l group were s t i l l present, and more importantly, the intense s i g n a l due to the methyl groups attached to the 3 - and 4-p o s i t i o n s of the pyridine r i n g i n the s t a r t i n g material was s i g n i f i c a n t l y reduced and consistent with the presence of only one methyl group. The presence of the aromatic signals due to the s t y r y l moiety and the cc protons served to further confirm the 4 - s t y r y l p y r i d i n e structure. The u l t r a v i o l e t spectrum, on the other hand, was considerably d i f f e r e n t from the spectra reported previously f o r com-pounds of t h i s type ( 2 3,24). The main absorption at 278mu represented a r e l a t i v e l y small bathoehromic s h i f t from the usual a l k y l p y r i d i n e absorption (263-268mu) but t h i s absor-p t i o n i s considerably lower than that of 4 - s t y r y l p y r i d i n e (307mu) and the i n t e n s i t y i s s i g n i f i c a n t l y l e s s . This anamolous spectrum can be due to the f a c t that the a l k y l substituents at the 3 and 5 p o s i t i o n s cause the s t y r y l 16 moiety to l i e out of the plane of the pyridine ring thereby reducing the extended conjugation. The fact that the yield was somewhat lower in this ease than that already reported in the other series ( 2 5 ) , gives some support to the view that the 4-methyl group is somewhat hindered although i t is s t i l l capable of entering into condensation reactions with carbonyl compounds. The isolation of 3-methyl-4-styryl-5-ethylpyridine from the condensation reaction proved to be very useful in providing a synthetic intermediate for the synthesis of pyridine derivatives having different functions at the 4-position. Hence several methods to transform the linkage to a carboxyl function were considered. This type of .reaction has been extensively employed in pyridine chemistry for the synthesis of pyridine aldehydes and carboxylic acids (5,p.207). Because methods such as nitric acid oxidation (26) and permanganate oxidation ( 2 7 ) were not too attractive, the reaction of choice involved ozonolysis. When 3-methyl-4-styryl-5-ethylpyridine was subjected to this reaction the expected 3-methyl-5-ethyl isonicotinic acid (XIX) was obtained as a high melting crystalline compound. Recently the ozonolysis of vinyl-pyridines has been shown to give pyridine carboxylic acids under analogous conditions (28). The isolation of this pyridine carboxylic acid in 17 turn furnished a substance with a versatile functional group at the 4 -position of the pyridine ring. Hence attempts were made to esterify the carboxylic acid. After the usual types of acid-catalysed esterification procedure (29,30) failed, an equally attractive method was tried. The pyridine carboxylic acid on treatment with an ethereal solution of diazomethane afforded the expected methyl ester (XX), Apart from the expected ultra violet and the infrared spectrum, the consideration of the N.M.R. spectrum proved to establish beyond any doubt, the structure of this ester. The characteristic ethyl and methyl groups attached to the pyridine nucleus were clearly evident and the appearance of a sharp signal at 6.17Tdue to the methyl group of the ester function was observed. CONCLUSION In conclusion, these studies discussed in this part have provided intermediates which can he utilized to prepare any type of 3,4-, 5-trialkylated pyridines. Firstly, i t is obvious that any Grignard reaction on 3,4~dimethyl-5-cyanopyridine, followed by the appropriate steps, pro-vides numerous variation to the type of groups attached to C^. Secondly, the appropriate ester analagous to XX provides entry into various possibilities at C^, and finally the nature of the alkyl group at C^  can be varied. It i s pertinent to note that in the original Guareschi cyclization, which provides the starting material for this work, the nature of the alkyl group at C^  is determined by the nature of the acetoacetic ester molecule used in the cyclization. Consequently appropriate variations in the synthetic sequence will yield numerous new and otherwise di f f i c u l t l y accessible 3,4-, 5-trialkylated pyridines. EXPERIMENTAL A l l melting points were determined on a Fischer-Johns apparatus and are uncorrected. The u l t r a v i o l e t spectra were recorded i n 95% ethanol on a Cary 14 recording spectrophotometer. Infrared spectra were recorded on a Perkin-Elmer model 21 spectrophotometer. The N.M.R. spectra were taken at 60 Mc on a Varian A60 instrument. In a l l cases i n t e g r a t i o n of areas under the signals was c a r r i e d out and the number of protons corresponding to each s i g n a l i s indicated i n parentheses. Values are given i n the Tiers T scale with tetramethylsilane used as the external standard, set at 10.0f u n i t s . The solvent used was carbon t e t r a c h l o r i d e . The analyses were performed by Dr. A. Bernhardt and h i s associates, Mulheim (Ruhr), Germany, and by Mrs. A. Aldridge, U n i v e r s i t y of B r i t i s h Columbia. 3.4-Dimethyl-5-acetylpyridine (XIV) A s o l u t i o n of 3,4-dimethyl -5-cyanopyridine C*:!i;22.2g) i n anhydrous ether (350 ml) was added slowly to a s t i r r e d s o l u t i o n of methylmagnesium iodide, prepared i n the usual manner (48 .5 g MS» 385 S methyl iodide) i n dry ether (630 ml). A f t e r the addition was complete, the 20 reaction mixture was refluxed for 4- hours and then allowed to stand overnight at room temperature. The excess Grignard and the complex were destroyed by the addition of dilute ammonia until there was no further reaction. The resulting mixture was saturated with sodium chloride and extracted exhaustively with ether. The ether extract was dried over anhydrous magnesium sulphate and the solvent evaporated to yield a liquid product. Distillation of this material at a bath temperature of 120-130° at 2 .5 mm pro-vided a clear liquid product (10.9 g)• This material was suitable for subsequent reactions although i t contained traces of the starting cyano compound, which was very diff i c u l t to remove by distillation. Chromatography of a small portion ( 3 . 8 g) of this liquid on alumina (250 g) provided a good separation. Elution with petroleum ether - ethyl ether (4:1) yielded a mixture of the acetylpyridine and the cyanopyridine in the i n i t i a l fractions, and then the pure 3,4-dimethyl-5-acetylpyridine (1.2 g) was obtained in the later fractions. Elution with pure ether removed the remaining material. An analytical sample of the acetylpyridine distilled at 144° at 22 mm; n D 2 0 1.4166; infrared: 5.94 u; ultraviolet: X m a x 231 mu (log6= 3 . 7 3 ) , A M A X 271 mu (log*=3.40), A M I N 254 mu (logt=3.24). Found: C, 72.43; H, 7 . 3 8 ; 0, 10.74; N, 9.39. Calc. for CQH1,0N: C, 72.45; 21 H, 7.4-3; 0, 10 .72; H, 9 -39 . A picrate, m.p. 162-163°, was prepared in ethanol and recrystallized several times from ethanol. Found: 0,4-7.82; H , 3.81; 0, 33 .52; N, 14.90. Calc. for C^H^OgH^: C, 47.62; H , 3.73; 0, 33.84; N , 14.81. 3.4-Dimethyl-5-(2-hydroxy-2-butyl)-pyridine (XV) A solution of 3,4—dimethyl-5-acetylpyridine (0.81 g) in anhydrous ether (14 ml) was added slowly to a stirred solution of ethylmagnesium iodide (1.8 ml ethyl iodide, 0 .52 g Mg turnings) in ether (20 ml). After the addition was complete, the reaction mixture was refluxed for 12 hours and then allowed to stand overnight at room temperature. The mixture was cautiously treated with dilute ammonia and the resulting basic mixture was saturated with solium chloride. The reaction mixture was then extracted several times with ether and the ethereal layer dried over anhydrous magnesium sulphate. Removal of the solvent yielded a viscous liquid (1 .07 g). This material was taken up in a small amount of chloroform and placed on a column of alumina (100 g). Elution with petroleum ether - ethyl ether (9:1) yielded traces of the starting material. Further elution with ethyl ether and chloroform provided the desired alcohol (XV.:, 0.54- g). A small portion of this material was distilled to yield the analytical sample of the alcohol, as a light yellow viscous liquid (b.p. 144° at .01 mm); infrared: 2.95-3.2 ju, very broad; ultraviolet: A M A X 265 mu (log6= 3.36), A M A X 271 mu (log*- 3 . 3 0 ) , A M I N 236 mu (log 6= 2.83); N.M.R. signals: triplet centered at 9.22 T (methyl of ethyl group, area = 3 H ) , 8 .5 7- (CH^ -C-OH, area = 3 H ) , quartet centered at 8.16 r (methylene of CH^ Ch^ -C-OH), 7 . 8 5 $ 7.58 r (methyls attached to ring, area = 6H), 4.6 T (OH, area & IH), doublet centered at 2.08T (-»<H, area - 2H). Found: 0, 73.37; H, 9.4-0; 0, 9.11; N, 8 . 2 7 . Calc. for C^H-^ON: C, 73.70; H, 9.56; 0, 8.93; N, 7-81. The picrate, prepared in the usual manner, was recrystallized several times from ethanol to yield an analytical sample which melted at 136-137»5°. Found: C, 5 0 . 3 2 ; H, 4.40; 0, 31.22; N, 1 3 . 7 3 . Calc. for C17 H20°8 N4 : °» 5 0*°°; H» 4*8^5 °» 31.34-; N, 1 3 . 7 2 . Subsequent preparations of this alcohol were carried out very conveniently from the acetylpyridine without careful purification of the intermediates. That i s , the crude product from the reaction of 3,4— dimethyl-5-:cyanopyridine and methylmagnesium iodide was treated directly with ethylmagnesium iodide and this product chromatographed as above. An overall yield of 27% of the pure alcohol was obtained. 5,4--Dimethyl-5-s-butylpyridine (XVII) A mixture of 5-(2-hydroxy-2-butyl)-3,4— 23 dimethylpyridine (0.85 g), concentrated hydriodic acid ( 9 . 3 nil, 4 7 % ) , and red phosphorus ( 1 . 1 g) was refluxed for 24 hours. After the mixture had been cooled,-the phos-phorus was removed by filtration and the filtrate con-centrated by distillation in vacuo. The dark residual o i l was taken up in water (6 ml) and decolorized by the addition of sodium bisulphite. The mixture was made alkaline by the addition of potassium hydroxide pellets and the alkaline mixture was then extracted thoroughly with ether. After the ethereal extract had been dried over anhydrous sodium sulphate, the solvent was removed and the residual liquid was dis t i l l e d using a bath temperature of 60-100° at 0 . 0 7 mm. The yield of the colorless liquid product was 478 mg. This product was a mixture of the desired material and some olefin resulting from incomplete reduction ( N . M . R . signal at 4.5 T), This olefinic material was present in small quantities even if. the reflux period was increased to 48 hours. Consequently, i t was found most convenient to carry out the reduction under catalytic hydrogenation conditions. A portion of the distilled liquid product ( 1 0 2 mg) was dissolved in glacial acetic acid (14 ml) and catalytically hydrogenated over Adam's catalyst ( 1 0 0 mg) at room temper-ature with a hydrogen pressure of 3 2 p.s.i. After 5 hours, the catalyst was filtered and the solvent removed on a steam bath in vacuo. The residue was treated with water (3 ml), and made alkaline by the addition of sodium bicarbonate and the resulting mixture was extracted exhaustively with ether. After the ethereal extract had been dried over anhydrous magnesium sulphate, the solvent was removed and the residual liquid distilled at 6 0 - 7 0 ° (bath temp.) at 0 . 0 5 mm to provide 73 mg of a pure liquid. A small portion was redistilled for an analytical sample (b.p. 1 3 5 ° at 22 mm); n D 2 0 1 . 5 0 7 8 ; ultraviolet:A m a x 2 6 4 mu (loge= 3 . 4 1 ) , A m a x 2 7 2 mu (loge- 3 . 3 3 ) , \ i n 231 mu (log*-2 . 3 9 ) ; N.M.R. signals: triplet centered at 9.1Q-T (methyl of ethyl group, area = 3 H ), doublet centered at 8 . 8 0 y (CHj-C-H, area = 3E)» multiplet centered at 8 . 3 8 ? " (methylene of ethyl group, area = 2 H ) , 7 . 8 3 ^ . * (intense, methyls attached to ring, area = 6 H ) t multiplet centered at . 7 . 2 r (H-0-OHj, area = IH), doublet centered at 1 . 9 8 ? " (*H, area = 2 H ) . Found: C, 8 0 . 9 5 * , H, 1 0 . 5 2 ; N, 8 . 4 0 . Calc. for Ci:LH17N: C, 8 0 . 9 2 ; H, 1 0 . 5 0 ; N, 8 . 5 8 . A picrate was readily prepared in the usual manner, and this upon several recrystallizations from alcohol pro-vided a pure sample, m.p. 1 3 1 - 1 3 2 ° . Found: C, 5 2 * 0 7 ; H, 5 . 0 3 ; N, 1 4 . 4 3 ; Calc. for ^ T ^ O W C, 5 2 . 0 4 ; N, 5 . 1 4 ; N, 1 4 . 2 8 . 3,4-Dimethyl-5-ethylpyridine The reaction product ( 1 1 . 1 g) resulting from the reaction of 3,4-dimethyl-5-cyanopyridine ( 2 0 g) with a fourfold excess of methylmagnesium iodide was treated with hydrazine ( 6 . 5 ml), potassium hydroxide pellets ( 9 0 g), 25 and diethylene glycol (13 ml) and heated in an o i l hath at 1 5 0 - 1 7 0 0 for 2 hours. The bath temperature was then raised to 200° and the reaction mixture was kept at this temperature for a further 2 hours. The cooled reaction mixture was treated cautiously with a small portion of water and the resulting mixture was dis t i l l e d . The fraction which came over at 109-116° was treated with more water ( 2 5 0 ml) and this aqueous mixture was thoroughly extracted with ether. After the ether extract had been dried over anhydrous magnesium sulphate, the solvent was removed and the residual liquid was distilled from potassium hydroxide pellets. A fraction ( 7 * 6 g) d i s t i l l i n g over at 5 0 - 7 0 ° (bath temp.) at 0.14- mm was completely free from any carbonyl or cyanide impurities and proved to be the desired material. A small portion of this liquid was redistilled (b.p. 115-116° at 22 mm) and provided an analytical sample. n D 2 0 1 . 5 1 5 1 ; ultraviolet:. A m a x 263 mu (loge= 3 . 3 9 ) , \ a x 266 mu (log 6» 3 . 3 8 ) , X m a x 271 mu (loge= 3-31), 238 mn (log£= 2.91); N.M.R. signals: triplet centered at 8.84 T (methyl of ethyl group, area = 3H), 7 . 8 6 T (intense, area = 6 H , methyls attached to ring), quartet centered at 7.4-2 T (methylene of ethyl group, area = 2 H ) , 1 . 9 8 T (o(H, area = 2 H ) . Literature values ( 6 ) : D 1 . 5 1 3 6 ; b.p. 2 1 7 ° at 744 mm. Found: C, 79-82; H, 9 . 6 9 ; N, 1 0 . 2 5 . Calc. for C^H^N: C, 7 9 - 9 5 ; H, 9 . 6 9 ; N, 1 0 . 3 6 . A picrate of the substance was prepared in ethyl 26 alcohol and after several recrystallizations from this solvent an analytical sample, m.p. 130-131°, was obtained. Literature (6): m.p. 133°'. Found: C, 49.54; H , 4.34; 0, 30.88; N , 15.23. Calc. for C ^ H ^ N ^ O r , : C, 49.45; H , 4.43; Q, 30.74; N , 15-38. 3-Methyl-4-styryl-5-ethylpyridine (XVIII) A mixture of 3,4-dimethyl-5-ethylpyridine (2.82 g), benzaldehyde (6.3 ml), potassium acetate (1.95 g), acetic anhydride (5.9 ml), and a small crystal of iodine was refluxed for 40 hours. The resultant dark brown reaction mixture was cooled and treated with aqueous hydrochloric acid until acidic, and the excess benzaldehyde was removed by steam distillation. The residue .from the steam d i s t i l -lation was extracted with ether to remove acidic or neutral materials and the resulting aqueous layer was then made basic by the addition of sodium hydroxide pellets. This basic layer was extracted several times with ether, the ether extract dried over anhydrous magnesium sulphate, and the solvent removed. The residual liquid product was fractionally distilled and a fraction d i s t i l l i n g up to 140° (bath temp.) at 0.4 mm, which contained a considerable amount of starting material, was separated. The subsequent fraction (2.59 g) came over as a yellow slightly viscous liquid at a bath temperature up to 240° at 0.45 mm. A small portion was distilled again to provide an analytical sample (b.p. 153° at 0.02 mm). Infrared: 6.12 u.; 27 n-g 1.6144; ultraviolet: ^ m a x 276 mu (broad, loge= 4.20), 'min 2 5 9 ^ l o s 6= 3 . 7 3 ) ; N.M.R. signals: triplet centered at 8.84-r (methyl of ethyl group, area - 3H), 7.1%T (methyl attached to ring at C^, area = 3H), quartet centered at 7 . 3 7 ? (methylene of ethyl group, area = 2H), four signals centered at 3»2^ (olefinic H, area = 2H), multiplet centered at 2 . 7 2 / " (aromatic H, area s 5H), 1.82 T (<AH, area = 2H). Found: C, 85.42; H, 7 * 5 2 ; N, 6.44. Gale, for C 1 6H 1 7N: C, 86 . 0 5 ; H, 7«67; N, 6.2?. A picrate of this substance was prepared in ethyl alcohol and after several recrystallizations from this solvent, an analytical sample, m.p. 182-183% was obtained. Found: C, 58 . 2 3 ; H, 4 . 5 0 ; 0, 24.50; N, 12.52. Calc. for C22 H20 N4 ° 7 : °» 5 8* 4°5 H» 4 - 4 6 ' °> 24.76; N, 12.39. 3-Methyl-5-ethyl isonicotinic Acid (XIX) A solution of 3-methyl-4-styryl-5-ethylpyridine (2 . 3 2 g, 0.01 mole) in glacial acetic acid (70 ml) was treated with ozone (0 . 0 1 5 mole) at room temperature. The reaction mixture was treated with 3% aqueous hydrogen peroxide (10 ml) and the mixture was refluxed for 10 minutes. The solvent was removed in vacuo and the residue washed with ether to remove the benzoic acid. To the ether-insoluble residue water (4 ml) was added, and the mixture was warmed in a steam bath until a l l the material had dissolved. As the solution gradually cooled, small, needle-like crystals separated (304 mg). Recrystallization 28 of this substance from absolute ethanol provided the pure acid, m.p. 268-269°, infrared: 5.88^u. An additional 1.51 g of material was recovered from the mother liquors. Although this latter crop was not as crystalline as the i n i t i a l crop, i t was shown to be the desired acid since on esterification with diazomethane, in a subsequent experiment, i t provided the identical methyl ester. Found: C, 65.29; H, 7.00; 0, 19.69. Calc. for GgH^OgN: C, 65.44; H, 6 . 71 ; 0, 19 .57. Methyl 3-Methyl-5-ethyl-4-pyridinecarboxylate (XX) To a stirred solution of 3-niethyl-5-ethyl isoni-nicotinic acid (1 .5 g) in absolute ethyl alcohol ( 3 0 0 ml) an ethereal solution of diazomethane (containing 2 g G H2 W2^ w a s ad-<3-e<1, T l i e reaction mixture was cooled in ice and stirred at ice-bath temperature for 3 hours. The reaction mixture was then treated with 2N hydrochloric acid ( 3 5 ml) and extracted with ether to remove any neutral contaminants. The aqueous layer was made basic by the addition of sodium bicarbonate and then extracted con-tinuously with ether for 20 hours. The ether extract was dried over anhydrous magnesium sulphate and the solvent removed to yield a liquid product. Distillation of this material at 70-100° (bath temp.) at 0.2 mm yielded 0 .50 g of a clear liquid. A small portion of this substance was 29 d i s t i l l e d again to provide an analytical sample ("b.p. 135° at 22 mm); n D 2 G 1.5025; infrared: 5.78 u; ultra-violet: A m a x 274 mu (log** 3.48), \ ± n 238 mu (log<s^ 2.85); N . M . R . signals: triplet centered at 8 . 9 r (methyl of ethyl group, area = 3H), 7.85 T (methyl attached to ring, area « 3H)» quartet centered at 7 . 5 ^ (methylene of ethyl group, area = 2H), 6.21T (-COOCB^ , area - 3H), 1.83r (*H, area = 2H). Found: C, 67.16; H, 7.26; N , 7.90. Calc. for O ^ R ^ G ^ N : C, 67.12; H, 7-31; N , 7.82. The ester formed a picrate readily and this derivative, after recrystallizing from alcohol, melted at 151-153°. Found: C, 47.21; H, 4 . 0 9 ; 0, 35.15; N , 13.43. Calc. for 0 1 6 H 1 6 0 9 N 4 : C, 47.16; H, 3-95; 0, 35-27; N, 13 .72. It should he pointed out that we found i t very convenient to convert the entire reaction product into the picrate, purify the picrate by several crystallizations from alcohol, and finally regenerate the ester by decom-position of the picrate with lithium hydroxide ( 3 1 ) . The recovery in this reaction i s good and this provided an excellent method for purifying small quantities. BIBLIOGRAPHY References to Part I 1 . a) C. D j e r a s s i , J . P. Kutney, M. Shamma, J . N. Shoolery, L. F. Johnson. Chem. and Ind. 210 ( 1 9 6 1 ) . b) C. D j e r a s s i , J . P. Kutney and N. Shamma. Tetrahedron. 18, 183 (1962). 2 . J . P. Kutney and R. C. Selby. J . Org. Chem. 26, 2733 ( 1 9 6 1 ) . 3 . E. Durkof and H. Gottsch. Ber. 2 1 , 6 8 5 ( 1 8 9 0 ) . 4 . E. Klingsberg. "Heterocyclic Compounds, Pyridine and I t s Derivatives." Part 1 , Interscience Publishers Inc., New York, 1 9 6 1 , p. 4 7 4 , 4 7 6 . 5 . A. E. Tschitschibabin and M. P. Oparina. J . parkt. Chem. 1926, 102, 154. 6. A. S. Ba i l e y and J. S. A. B r u n s k i l l . J . Chem. Soc. 1 9 5 9 , 2 5 5 4 . 7 . P. Vaculik and J. Kuthan. C o l l e c t i o n Czechoslov. Chem. Communs. 24, 174 ( 1 9 5 9 ) . 8 . K. Tsuda, H. Mishima and M. Maruyama. Pharm. B u l l . (Japan) 1 9 5 3 , 1 , 283. 9 . P. A r n a l l . J . Chem. Soc. 1 9 5 8 , 1 7 0 2 . 1 0 . H. Rogerson and T. F. Thorpe. J . Chem. Soc. 82, 1685 ( 1 9 0 5 ) . 1 1 . G. A. R. Kon and K. R. Nanji. J . Chem. Soc. 1 9 3 1 , 5 6 0 . 1 2 . E. Hope, J . Chem. Soc. 1 9 2 2 , 1 2 1 , 2216. 1 3 . E. Hope and W. Sheldon. J . Chem. Soc. 1 9 2 2 , 2 2 3 3 . 14. I. Guareschi. a) E s t r . Mem. Reale Accad. S c i . Torino, i i 46. b) J . Chem. Soc. 1 8 9 7 , 22, Pt. 1 , 3 1 1 5 . L. Ruzicka and V. Fornasir. Helv. Chem. Acta 2, 3 3 8 ( 1 9 1 9 ) . 16. J . M. Bohbitt and D. A. Seola. J . Org. Chem. 25_, 560 (I960). 1 7 . W. G. Schneider, H. J . Bernstein, and J . A. Pople. Can. J . Chem. *>5_, 1487 ( 1 9 5 7 ) . 18. 1. Nakashima, J . Pharm. Soc. (Japan). £5_> 1010 ( 1 9 5 5 ) Chem. Abstr. 5.0, 4944e (1956). 19. R. Lukes and M. Pergal. Chem. L i s t y . $2, 68 (1958). 20. C. T. Kyte, G. H. J e f f e r y , and A. I . Vogel. J . Chem. Soc. I960, 4454. 21. Huang-Minion. J . Am. Chem. S 0c. 68, 2487 (1946). 22. E. Klingsberg. "Heterocyclic Compounds, Pyridine and I t s Derivatives. 1 1 Part 2. Interscience Publishers Inc., New York, 1961. 2 3 . E. R. Blout and V. W. Eager. J . Am. Chem. Soc. 62, 1315 (1945). 24. J . L. R. Williams, S. K. Webster, and J . A. Van A l l a n . J . Org. Chem. 2£, 4893 (1961). 2 5 . A. P. P h i l l i p s . J . Am. Chem. Soc. 26, 3986 (1954-)• 26. F. Melescher. Ber. 88, 1208 ( 1 9 5 5 ) . S. M. McElvain ed. Organic Syntheses Col. V o l . I , Wiley, 2nd Ed., 1958, p. 385. 27. F. Kogel, G. M. Van Der Want, and C. A. Salmenk. Rec. t r a v . Chim. 6JZ, 29 (194-8). 28. R. H. Callighan and M. H. W i l t . J . Org. Chem. 26, 4912 (1961). 2 9 . H. 0. Burrus and G. Powell. J . Am. Chem. Soc. 62, 1468 ( 1 9 4 - 5 ) . 3 0 . M. A. Newman. J . Am. Chem. Soc. 63_, 2431 (194-1). 3 1 . A. Burger. J . Am. Chem. Soc. 62, 1615 (194-5). P A R T I I T H E S Y N T H E S I S OP NEW 3,5-DIMETHYL-4--S U B S T I T U T E D P Y R I D I N E S S T E R I G E F F E C T S A S A N A I D TO S Y N T H E S I S INTRODUCTION As indicated in Part I, Kutney et al (1,2) investigated the synthesis of 3,4,5-trialkylated pyridines "because these compounds were virtually unknown and were not readily available from natural sources or synthetic routes. On accomplishing the synthesis of 3,4-dimethyl-5-isopropylpyridine (1) and 3,4-dimethyl-5-s-butylpyridine (2), a general synthetic approach to virtually any type of trialkylated pyridine of this type was soon realized. In relation to these studies, Kutney and Selby (1) also became involved in the synthesis of the sym-metrical 3,5-dimethyl-4-isopropylpyridine. To approach this problem they considered the preparation of 3,5-dimethyl-4-ethylpyridine by a possible extension of the Wibaut-Arens alkylation method (3-11)• This alkylation reaction has been utilized extensively in the preparation of various ^ -alkylated pyridines. The method was f i r s t described by Dohrn and Horster (6) and developed by Wibaut and Arens (3,7) and by Emmert and Wolpert (8). The reaction consists of the treatment of a pyridine with the corresponding acid anhydride followed by a rearrangement to a 1,4-diacyl-l, 33 4-dihydropyridine (II-Figure 1) and reduction of this compound to a 4-alkylpyridine (III). A possible mechanism which has been proposed by Mosher (10) involves a resonance-stabilized ionic inter-mediate IV (Figure 2 ) . On the other hand, Bachman and Schisla (11) -have postulated that the reaction involves a free radical mechanism after the formation of the ionic intermediate IV suggested by Mosher (10) (Figure 3 ) . The mechanism of the dissociation of I has been studied by Frank et al (4 , 9 ) and they support the view that the key intermediate taking part in the reaction is N,N'-dia-cyltetrahydro-4-4 1-dipyridyl, I. Although this reaction works well with unsub-stituted pyridines, i t was found in our laboratory that treatment of 3 ,5-lutidine with acetic anhydride and zinc according to the specified conditions (3-11) did not however, lead to the expected product, 3,^-dimethyl^-ethyl-pyridine (l) but to 3,5-dimethyl-4-acetylpyridine. This acetylpyridine was converted to the 4-ethylpyridine only under much more drastic reaction conditions. Apparently the steric hindrance by the two neighbouring methyl groups had been sufficient to allow isolation of the 3,5-dimethyl-4-acetylpyridine. In order to provide a route to pyridine 1 figo*?© 2 . Ionic Eschaniea Q£ the Wltaut^rftnts 37 derivatives possessing branched alkyl chains at the ^-position, Kutney et al (1) attempted to react the acetyl-pyridine with various organometallic reagents, although i t was anticipated that the steric factor might prevent a successful reaction. Reaction of this pyridine with methylmagnesium iodide and bromide under various reaction conditions met with failure. It should be pointed out that in an attempt to obtain a reaction, these experiments were performed under drastic conditions using high boiling solvents such as diglyme and dibutylcarbitol. In the latter case a trace of an alcoholic component was obtained but the extremely poor yield discouraged any further characterization. Similar unsuccessful attempts were also made with methyllithium. It thus became evident that the steric hindrance of the carbonyl function was so effective as to make this group completely unreactive toward organo-metallic reagents. Furthermore, the Wittig reagent derived from methyltriphenylphosphonium bromide (12,13) also failed to react with 3,5-dimethyl-4-acetylpyridine. A simple modification of Vaculik's method (14) (see Part I, Figure 3), in which an attempt to react l-benzyl-3,5-dimethyl-4-piperidone with isopropylmagnesium bromide under a variety of reaction conditions, was also unsuccessful. This supports the view that the methyl 38 groups at the 3 and 5 positions of the pyridine ring have a considerable blocking effect. It therefore became apparent to us that the steric influence of the methyl groups at the/^-positions could be utilized to advantage in synthesizing new 3*4-, 5-trialkylated pyridines since the 4—acetylpyridine deri-vative is a very versatile synthetic intermediate. Hence studies in this direction were undertaken and the results are presented in this part of the thesis. DISCUSSION As has been already mentioned, the Wibaut-Arens alkylation method has been used quite extensively for the introduction of alkyl substituents into the ^-position of the pyridine ring but i t was found in our laboratory that the application of this method to 3,5-lutidine yielded the unexpected compound, 3,5-dimethyl-4—acetylpyridine, VII, rather than the corresponding 3,5-dimethyl-4-ethylpyridine. This preparation of the acetylpyridine has now been repeated according to the Wibaut-Arens procedure and the structure of the 3,5-dimethyl-4~acetylpyridine has been confirmed. The acetylpyridine possessed a strong carbonyl absorption in the infrared spectrum (5.84 y) and the ultraviolet spectrum was characteristic of a trialkylated pyridine of this type (2). Furthermore, the N.M.R. spectrum showed a sharp signal at 7.167 which established the presence of an acetyl group. In addition, a strong signal at high fiel d (7.83T), typical of methyl groups attached at the^-positions of the pyridine ring, and a weak signal at low fiel d (1.827), attributable to the x protons on the nucleus (1,2), served to confirm the structure• 40 The reduction of this acetylpyridine to the known compound, 3,5-dimethyl-4-ethylpyridine (15,16) on treatment with acetic acid and zinc, provided complete chemical evidence for the assigned structure. Because i t had "been reported that the carbonyl function of this acetylpyridine resisted any reaction with organometallic reagents, an attempt to reduce the acetyl group to the corresponding alcohol was then made. It was felt that the latter compound could lend i t s e l f to a variety of interesting reactions. When 3»5-dimethyl-4-acetylpyridine was treated with lithium aluminum hydride the expected alcohol, VIII, was obtained as a crystalline substance. The success of the reaction was clearly evident from spectroscopic considerations. Apart from the typical strong hydroxyl band in the infrared spectrum at 3»09u, and the characteristic ultraviolet spectrum of a pyridine (1,2), the N.M.R. spectrum was very instructive. The presence of the hydroxyethyl group was shown by a doublet at high fiel d centered at 8.627, as would be expected for a methyl group, and a quartet centered at 4.88y due to the tertiary proton attached to the oxygen-bearing carbon. The remaining signals at 7*75? and 2.28?" were assigned to the -methyl groups and the oc protons on the pyridine ring respectively. Having obtained the desired alcohol, VIII, 4-1 conversion to other analogues in this series was then pro-posed. The f i r s t reaction attempted was the preparation of the bromoethylpyridine, XII, by treatment with hydro-bromie acid in the normal manner (17,18). Because these methods were unsuccessful, a more drastic procedure was then applied and a crystalline substance was obtained. After consideration of both the spectroscopic and the analytical data, the product of the reaction appeared not to be the expected compound, XII, but an isomeric substance. The infrared spectrum had indicated that the hydroxyl function had been removed and the analytical figures further supported this inference. On these grounds alone i t could be argued that a simple displacement of the hydroxyl function had taken place and that the structure was the expected compound, XII. However, this argument was quickly dismissed after close inspection of the N.M.R. spectrum. A feature which was obviously absent was a doublet at high applied magnetic fi e l d which would be expected for the methyl group i f the correct structure was XII. Moreover, the tertiary proton of the bromoethyl group should exhibit a quartet. The highest signal observed in the spectrum in this case was a singlet at 7*327 and i t s position as well as its intensity indicated beyond doubt, that this signal was due to the^ -methyl groups attached to the pyridine nucleus (1,2). The remaining signals were at lower fields and therefore, i t was clear that the Hem ^* 43 substance obtained i n t h i s r e a c t i o n was not XII. Taking i n t o consideration the nature of the e n t i r e N.M.R. spectrum and the integrated areas, i t was deduced that the a l t e r -native structure, IX, was the correct one. A more d e t a i l e d d e s c r i p t i o n of the N.M.R. r e s u l t s i s given i n the experi-mental s e c t i o n . In order to confirm that the assignment of the structure, IX, was correct and eliminate any doubt as to the actual chemical s h i f t s that a methyl group of the type shown i n XII should e x h i b i t , an unambiguous synthesis of a compound having analogous s t r u c t u r a l features to XII was then devised. The most d i r e c t approach to t h i s problem was r e a c t i o n of 4-ethylpyridine with N-bromosuccinimide (NBS), a reagent which has been r e c e n t l y u t i l i z e d to i n t r o -duce a bromine atom i n t o a 2-methylpyridine d e r i v a t i v e ( 1 9 ) • When 4-ethylpyridine was treated with NBS, the expected 4-(l-bromoethyl)-pyridine, XIII, was obtained as a c r y s t a l -l i n e m a t e r i a l . The a n a l y t i c a l and the spectroscopic data were i n complete agreement with the expected s t r u c t u r e . The N.M.R. spectrum of XIII was of p a r t i c u l a r importance here since i t served to confirm the assignment of the signals i n the N.M.R. spectrum of IX. The presence of the 1-bromoethyl group i n XIII was established by a doublet at 7 . 8 9 T as would be expected f o r the methyl group attached to the halogen-bearing carbon atom, and a quartet at 4.66T for the tertiary hydrogen atom. It should he mentioned here that 4(l,l-dibromoethyl)-pyridine, XIV, was also obtained by reacting the corresponding ethylpyridine with NBS under more drastic reaction conditions. Details of this reaction are given in the experimental portion. The isolation of IX is of some theoretical interest since i t is apparent that a simple substitution of the hydroxyl group by the halogen atom has hot taken place. The reaction path appears to be similar to that previously encountered in the hydriodic acid—red phos-phorus reaction in which the reductive removal of the hydroxyl function gave the intermediate olefinic sub-stances (1,2). Undoubtedly, in these instances, the ole-finic compounds arose from an acid catalyzed elimination reaction. The subsequent addition of the hydrobromic acid to the olefinic bonds, in our case, provides the product actually isolated. The mode of electrophilic addition to the double bond of alkenylpyridines has not been studied in great detail and, in particular, l i t t l e is known about the addition of hydrogen halide to these types of compounds (20, p. 364). Although products resulting from the addition of hydrogen halide to vinyl pyridines have been reported (21,22), there is no conclusive evidence as to the correct structure of these substances. It has been suggested (20, p. 364) that the halogen atom would enter 4 5 at the carbon atom adjacent to the pyridine nucleus. Our present studies do not bear out this statement although i t must be recognized that steric factors may play a dominant role in directing the addition in our compound. Further studies are obviously necessary before any definite con-clusions can be reached. In this connection, the intro-duction of bromine at the methylenic carbon of 3,5-dimethyl-4-ethylpyridine with NBS, under conditions identical to those used in the unsubstituted 4-ethylpyridine, has met with failure. This result lends some support to the importance of the steric factor. We believe that the formation of the hydrobromide, IX, from the alcohol, VIII, involves the formation of the intermediate olefinic substance, 3 ,5-dimethyl-4—vinyl-pyridine. In order to provide some support for this pro-posal, we undertook to prepare the vinylpyridine by an unambiguous synthetic route and then react this compound under the identical reaction conditions to those used for the treatment of the hydroxyethylpyridine, VIII, with hydrobromic acid. Indeed, when the reaction was run in this manner, we obtained, in excellent yield, the same crystalline hydrobromide, IX. Therefore this sequence of reaction shows that the vinylpyridine could be an inter-mediate in the conversion, VIII IX. The structure of the vinylpyridine obtained by 46 dehydration of VIII was r e a d i l y established from spectro-scopic data. The i n f r a r e d spectrum i n d i c a t e d the formation of a new double bond (6.11u) and the u l t r a v i o l e t spectrum of the product showed a s i g n i f i c a n t bathochromic s h i f t due to an extended conjugation. Furthermore, appearance of mult i p l e t s i n the N.M.R. spectrum at 4 . 2 7 r and 3.62T provided strong support f o r the presence of a v i n y l group. F i n a l l y , we considered the p o s s i b i l i t y of con-v e r t i n g the bromide, IX, i n t o a pyridine d e r i v a t i v e which was somewhat more stable and where one could a c t u a l l y obtain the N.M.R. spectrum of the parent base. I t should be noted at t h i s point that halopyridines are known to be unstable as t h e i r free bases and can only be i s o l a t e d as s a l t s . An a t t r a c t i v e analogue appeared to be the corres-ponding n i t r i l e since i n a d d i t i o n to being comparatively stable, i t would provide a v e r s a t i l e synthetic intermediate f o r a v a r i e t y of 4-substituted p y r i d i n e s . When the hydro-bromide IX was reacted i n an aqueous a l c o h o l i c s o l u t i o n of potassium cyanide ( 2 3 ) , an excellent y i e l d of 3 » 5-dimethyl-4-(2-cyanoethyl)-pyridine was obtained. The i s o l a t i o n of t h i s compound and consideration of the N.M.R. spectrum enabled us to confirm the previous assignment of the structure, IX. The cyanoethylpyridine possessed s i m i l a r s t r u c t u r a l features to the corresponding hydrobromide, IX. 47 The N.M.R. spectrum indicated an intense signal at 7.61T due to the methyl groups attached to the pyridine nucleus. Moreover, the four protons of the cyanoethyl group were clearly evident as two sets of multiplets centered at 6.941- and 7.34T, and f i n a l l y a signal at low f i e l d (1.67r) accounted for the two oc protons on the ring. The relative areas under the signals served to establish the structure, X. Since numerous modification of the cyano function are possible, this material may be u t i l i z e d to prepare new types of 4-substituted pyridine analogues. CONCLUSION It is therefore apparent that the steric hindrance created by substituents attached to the 0-positions of the pyridine nucleus can be used to con-siderable advantage in the synthesis of new and otherwise inaccessible 3,4-, 5-trisubstituted pyridines. EXPERIMENTAL A l l melting points were determined on a Fischer-Johns apparatus and are uncorrected. The ultraviolet spectra were recorded in 95% ethyl alcohol on a Cary 14-recording spectrophotometer. Infrared spectra were recorded on a Perkin-Elmer model 21 spectrophotometer. The N.M.R. spectra were done at 60 Mc on a Varian A60 instrument. The values are given in the Tiers 7 scale with the signal of tetramethylsilane, which was used as the internal standard, set at 10.0^ units. Integration of areas under the signals was carried out in a l l cases and the number of protons is indicated in parentheses. The solvents used were carbon tetrachloride or deuterio-chloroform. The analyses were performed by Dr. A. Bernhardt and his associates, Mulheim (Ruhr), Germany, and by Mrs, A. Aldridge, University of British Columbia. 5.5-Dimethyl-4—acetylpyridine (VII) The zinc which was used in this experiment was activated as follows. Zinc dust (208 g) was stirred in 10% aqueous hydrochloric acid (75 ml) for 2-3 minutes. It was then filtered, washed with distilled water (150 ml), acetone (100 ml), anhydrous ether (50 ml) and dried 50 i n vacuo. I t was then ready f o r use. A 1 - l i t e r 3-necked f l a s k was f i t t e d with a mechanical s t i r r e r and acetic anhydride ( 2 5 0 ml) and 3 , 5 - l u t i d i n e (136 g, dried over calcium oxide and f r e s h l y d i s t i l l e d i n vacuo) were then added to the f l a s k . This s t i r r e d mixture was then treated with small portions of zinc u n t i l a t o t a l of 1G0 g had been added. The addition required about one-half hour during which time the temper-ature of the reaction rose to 70° and the mixture developed a l i g h t green c o l o r . G l a c i a l a c e t i c a c i d ( 1 0 0 ml) and activated zinc (40 g) were added and the re a c t i o n mixture was refluxed f o r 15 minutes. A f t e r allowing to stand overnight at room temperature, the mixture was cooled i n ice and treated cautiously with 40% aqueous sodium hydroxide ( 7 0 0 ml). The r e s u l t i n g brown o i l which formed as a layer at the top was extracted with ether. The ethereal extract was dr i e d over anhydrous magnesium s u l f a t e , and the s o l -vent evaporated to leave a brown viscous l i q u i d ( 172 g). This l i q u i d was f r a c t i o n a l l y d i s t i l l e d to y i e l d an i n i t i a l f r a c t i o n (57«2 g, d i s t i l l i n g up to 1 8 9 ° ) of unreacted 3 , 5 - l u t i d i n e . The second f r a c t i o n (24 . 9 g) d i s t i l l i n g i n the range of 1 9 0 - 2 2 0 ° contained some 3 , 5 - l u t i d i n e and some of the desired acetylpyridine whereas the l a s t f r a c t i o n ( 6 1 . 8 g) c o l l e c t e d at 2 2 0 - 2 9 5 ° was the desired 3 , 5 -dimethyl-4-acetylpyridine. A second d i s t i l l a t i o n of the 51 last fraction at 167-169°/100 mm provided the pure product (55*8 g). An analytical sample could also be conveniently obtained on purification by vapour phase chromatography on the Megachrome, operating at 240° with a column of Apiezon J and using helium as the carrier gas. The retention time was 10.2 minutes. The product after this purification s t i l l d i s t i l l e d at 167-169°/100 mm or 252-254°; n D 2 5 1 .5152; infrared: 5.90 u; ult r a v i o l e t : ^ m a x 270 mu (log£= 3.42), \ i n 2 5 4 ^ ( l GS£= 2.54); N.M.R. signals (CCl^): intense signal at 7*83T (methyls attached to ring, area = 6H), signal at 7.62 r (CEL^-C-, area = 3 H ), 1.82r (*H, area = 2H). Found: C, 72.10; H, 7.48; 0, 10.71; N, 9.32. Calc. for Cyi^NO: C, 72.45; H, 7.43; 0, 10 .72; N, 9.37. A picrate was prepared and after several recry-sta l l i z a t i o n s from alcohol melted at 181-183°. Found: C, 47.81; H, 3-76; 0, 3 3 . 3 7 ; N, 14 .71 . Calc. for C 1 5H 1 40 8N 4: C, 47.62; H, 3 - 7 3 ; 0, 33-84; N, 14.81. It i s pertinent to note that i t was found imperative to carry out the i n i t i a l fractional d i s t i l l a t i o n of the crude reaction product at atmospheric pressure. In this way, the high temperature ensures that the inter-mediates are decomposed to the desired product. If the d i s t i l l a t i o n i s carried out at lower temperatures under 52 reduced pressure, the intermediates are actually d i s t i l l e d over and i t becomes necessary to heat these to a higher temperature to convert them to VII. 3,5-Dimethyl-4-(l-hydroxyethyl) pyridine (VIII) A 50 ml three necked flask was f i t t e d with a dropping funnel, a reflux condenser and a magnetic s t i r r e r , and charged with a solution of lithium aluminum hydride (0.819 g) i n anhydrous ethyl ether (12 ml). . To this was added cautiously from the dropping funnel, a solution of 3,5-dimethyl-4-acetylpyridine (3.22 g) i n anhydrous ether (11 ml), over a period of 20 minutes. After the addition was complete, the reaction mixture was stir r e d at room temperature for one half hour and then water (20 ml) was added slowly to destroy the excess hydride. The reaction mixture was f i l t e r e d , the sol i d which remained on the f i l t e r paper was washed thoroughly with methanol, and the methanol washings were combined with the ethereal f i l t r a t e . The f i l t r a t e was then concentrated and the soluble organic materials were extracted with chloroform. After drying the chloroform extract over anhydrous magnesium sulfate and removing the solvent, the residual product was d i s t i l l e d . The i n i t i a l fraction (220 mg) d i s t i l l i n g up to a temperature of 1 3 0 ° (bath temperature) at 0.5 mm proved to be unreacted I acetyl pyridine. The second fraction (2 .3 g) which came over at 145-210° (bath temp.) at 0.1 mm was the desired 53 alcohol, VIII. An analytical sample was prepared by several recrystallizations from a chloroform-petroleum ether mix-ture, and melted at 85-86°; infrared: 3 . 0 9 n; ultraviolet: ^ 267 mu (log6- 3.4-0), shoulder at 274 mu (loge= 3 . 3 5 ) , \ i n 2 5 1 ^ ( l o S 6 a 2 - 6 9 ) ; N.M.R. signals (CCl^): doublet centered at 8.62 7 (CB^ -COOH, area = 3H), intense signal at 7 . 7 5 7 (methyls attached to ring, area = 6H), quartet centered at 4-.887 (tertiary proton of CH^ -C-OH, area = IH), signal at 2.287 area = 2H). Found: C, 71 .57; H, 8.70; 0, 10.76; N, 9 . 0 7 . Calc. for CgH^ON: C, 71.4-9; H, 8.67; 0, 10.58; N, 9.26. A picrate, m.p. 14-8-148.5°, was prepared in ethanol and recrystallized from the same solvent. Found:: C, 47.88; H, 4.29; N, 14.48. Calc. for G 1 5 H 1 6 0 8 N 4 : C, 47.37; H, 4.24; N, 14.73. 3.5-Dimethyl-4-(2-bromoethyl) pyridine hydrobromide (IX) A mixture of 3,5-dimethyl-4-(l-hydroxyethyl)-pyridine (196 mg) and concentrated hydrobromic acid (171 ml, 48%) was heated at 160° in a sealed tube for 24 hours. After cooling, the contents of the tube was evaporated to dryness in vacuo. The residual material was taken up in ethyl alcohol and recrystallized from a mixture of alcohol-chloroform to yield a f i r s t crop of crystals ( 2 3 5 mg). An additional 66 mg (total 3 0 1 mg) was obtained when the mother liquor was diluted with petroleum. Several 5 4 recrystallizations of this product from ethanol-petroleum ether provided an analytical sample, m.p. 208-209°; infrared: absence of hydroxyl absorption; ultraviolet:: 'max 2 6 6 m u ( l 0 S ^ 3 . 7 6 ) , A m ± n 245 mu (log*- 3.62); N.M.R. signals (CDCl^): intense signal at 7.32?- (methyls attached to ring, area = 6H), multiplet centered at 6.40T (CH2CH2Br, area = 4H), 1.32 T (<KH, area - 2H). Found: C, 36.43; H, 4 .31; N, 4.62; Br, 54.22. Calc. for C 9H 1 3NBr 2: C, 36.64; H, 4.41; N, 4.74; Br, 54.44. 3,5-Dimethyl-4-(2-cyanoethyl) pyridine (X) The pyridine hydrobromide, IX (206 mg) was added to a solution of potassium cyanide (610 mg) i n water (4.6 ml) and methanol (11 ml) and the mixture was refluxed for 2 hours. On cooling, water (10 ml) was added and the reaction mixture was then made alkaline by the addition of sodium bicarbonate. This reaction mixture was extracted exhaustively with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and the solvent was removed to y i e l d a viscous l i q u i d . This l i q u i d was d i s t i l l e d at 100-150° (bath temperature) at 0.1 mm to yiel d lo6 mg of a viscous l i q u i d which s o l i d i f i e d p a r t i a l l y on short standing. Crystallization from a mixture of benzene-petroleum ether-acetone provided a crystalline material m.p. 74-75°. Infrared: 4.46 u.; ul t r a v i o l e t : \uax 2 , 6 6 dog ^ = 3 .31) , \ i n 230 (log *= 2.78); 55 N.M.R. signals (CDCl^): intense signal at 7.61T (methyls attached to ring, area = 6 H ) , two sets of multiplets centered at 7.34- T and 6.94- r (-CH2CH"2-CN, area » 4 H ) , 1 . 6 7 ( ° ^ H , area = 2 H ) . A picrate of this material was readily prepared and upon several recrystallizations from alcohol an analytical sample was obtained, m.p. 1 7 7 - 1 7 8 . 5 ° • Found: C, 4 9 . 0 1 ; H, 4.08; N, 1 7 . 7 8 . Calc. for' G^H^N^: C, 4 9 . 3 6 ; H, 3.88; N, 17 - 9 9 . 3 * 5-Dimethyl-4-vinylpyridine (XI) A solution of 3,5-dimethyl-4-(l-hydroxyethyl)-pyridine ( 9 9 1 mg) in anhydrous xylene ( 3 0 ml) was treated with phosphorus pentoxide (7«73 g) and the mixture was refluxed for 3 hours. After cooling, the reaction mixture was treated cautiously with water ( 2 0 ml) to destroy the excess phosphorus pentoxide and the resulting solution was separated into the respective organic and aqueous portions. The acidic aqueous layer was neutralized, then made alkaline by the addition of potassium hydroxide pellets and this mixture was extracted with ether. The ethereal extract was dried over anhydrous magnesium sulfate and the solvent evaporated to yield a mobile liquid. D i s t i l -lation of this liquid provided the desired vinylpyridine ( 4 7 5 mg, b.p. 146-147° at 9 0 mm.); n D 2 7 1 . 5 3 3 3 ; infrared: 6 . 1 1 u; ultraviolet: A ^ 2 7 3 mu (log€= 3 - 3 9 ) , ^ m i n 261 mu 5 6 (log6= 3 . 3 2 ) , A m a x 234 mu (log*-- 3 . 7 7 ) , A m i n 223 mu (loge= 3 . 7 1 ) ; N.M.R. signals (CCl^): intense signal at 8.02 (methyls attached to ring, area 6H), multiplet centered at 4.72 r (-C=CH2, area = 2H), quartet centered at 3.62 r (-C=C, area = 1H), 2.10 r ( H, area = 2H). Found: C, 80.86; H, 8.34; N, 10.31. Calc. for CgE^N: C, 81.16; H, 8.33; N, 10.52. A picrate of this material was prepared in the usual manner and recrystallized from ethanol several times to yield, an analytical sample which melted at 155-156°. Found: C, 49.75; H, 3.90; 0, 30.45; N, 15.41. Calc. for C15 H14 N4°7 : °» ^ 9 . 7 3 ; H, 3.84; 0, 30.52; N, 1 5 . 2 0 . 3 «5-Dimethyl~4-(2-hromoethyl )-rpyridine hydrobromide (IX) .. from 3«4-Dimethyl-4-vinylpyridine A mixture of 3»5-dimethyl-4-vinylpyridine (188 mg) and concentrated hydrobromic acid (16 ml, 48%) was heated for 24 hours in a sealed tube at 160°. On working up the reaction mixture in exactly the same manner as given above for the alcohol, a crystalline hydrobromide (348 mg) was obtained. This was shown to be (IX) by mixed melting point, infrared, ultraviolet and NMR comparison. 3,5-Pimethyl-4-ethylpyridine A stirred solution of 3,5-dimethyl-4-acetyl-pyridine (19 g) in glacial acid (200 ml) was cautiously 57 treated with activated zinc ( 1 0 g) and the whole mixture was then refluxed for one hour. An additional 18 g of activated zinc was added and refluxing was continued for a further 15 hours, "by which time the reaction mixture had become intensely yellow in color. After cooling, the mixture was made alkaline by the addition of 4-0% aqueous sodium hydroxide (4-00 ml) and the resulting mixture was steam distilled until the distillate was clear. The distillate was then extracted exhaustively with ether and the ethereal extract dried over anhydrous magnesium sulfate. Evaporation of the solvent left a brown residual liquid ( 1 7 .7 g) which upon distillation (b.p. 218 -219°) yielded 1 2 . 7 g of 3,5-dimethyl-4-ethyl-pyridine. Infrared: complete disappearance of carbonyl band; ultraviolet: A m a x 263 mu (log 6 = 3 . 4 - 5 ) , A m a x 2 7 3 mu (log£ = 3 - 3 8 ) , 2 3 1 mu (log 6 = 7 . 8 7 ) ; N.M.R. signals (CCl^): triplet centered at 8.94-T (methyl of ethyl group, area = 3H), intense signal 7 *80 7" (methyls attached to ring, area « 6 H ) , quartet centered at 7.4-27" (methylene of ethyl group, area = 2 H ) , 1.96 7 (*H, area = 2 H ) . A picrate of this compound was readily prepared and the analytical sample melted at 1 5 6 . 5 - 1 5 7 ° . Found: C, 4 -9 .4 -9; H, 4 - . 1 7 ; N, 1 5 . 3 6 . Calc. for ^ ^ ^ m P f - C, 4-9.4-5; H, 4 . 4 3 ; N, 1 5 . 3 8 . The literature values ( 15 , 16) are b.p. 216-217°, 58 2 1 9 - 2 2 0 ° for the base and m.p. 1 5 5 - 1 5 6 ° for the picrate. 4-(1-Bromoethyl)-pyridine hydrobromide (XIII) A solution of 4-ethylpyridine (6.41 g) in anhydrous carbon tetrachloride (200 ml) was treated with N-bromosuccinimide (10.7 g) and benzoyl peroxide (0 .91 g) and the whole mixture was refluxed for three hours. The slightly brown reaction mixture was filtered to remove the solid suspension and the filtrate was washed successively with 4% aqueous sodium hydroxide (100 ml), water (100 ml), 2% aqueous hydrobromic acid (100 ml) and finally dried over anhydrous magnesium sulfate. This dried carbon tetrachloride extract was then saturated with hydrogen bromide and finally the solvent was removed to furnish a residual gum (7.4 g). The latter was taken up in ethanol and then crystallized from a solvent mixture of ethanol-ethyl ether to afford 3*25 g of a crystalline hydrobromide, m.p. 1 5 1 - 1 5 1 . 5 ° ; ultraviolet: v 260 mu (log6= 3 . 50 ) , ^min 2 5 5 T ( l oS^ = 3 . 3 0 ) ; N.M.R. signals (CDCl^):. doublet centered at 7 . 8 9 T (GH^-C-Br, area = 3H), quartet centered at 4 .66T (tertiary hydrogen of CH^ -C-H, area = IH), doublet centered at 1 . 8 5 r (^ H, area = 2H), doublet centered at 0.83 r (°\.H, area - 2H); Found: C, 31.56; H, 3-39; N, 5 .40; Br, 59.87. Calc. for C^NB^: C, 31.47; H, 3 .40; N, 5 . 2 5 ; Br, 59.88. 59 4(l,l-dibromoethyl) pyridine hydrobromide (XIV) A mixture of 4-ethylpyridine (6 .5 g), N-bromo-succinimide (15.0 g) and benzoyl peroxide (1.0 g) in carbon tetrachloride (200 ml) was refluxed for 6 hours. After cooling, the reaction mixture was filtered and the filtrate was washed successively with 4% sodium hydroxide (100 ml), water (100 ml), 2% hydrobromic acid (100 ml), and finally dried over anhydrous magnesium selfate. The carbon tetra-chloride solution was then saturated with hydrogen bromide gas whereupon a light brown gum precipitated but. Upon evaporation of the solvent, the resulting residual gum was taken up in 95% ethanol and left under refrigeration. The fi r s t crop (9*32 g) of crystalline substance was obtained and melted at 129-135°• Repeated crystallization (4 times) from ethanol-petroleum ether afforded an analytically pure sample (308 mg) which decomposed at 158-160°. Ultraviolet: Amax 2 6 4 ( l o s 6 = 5 * ^ 3 ) , A m i n 249 mu (log 6 = 3.37); N.M.R. signals (CDCl^): Intense singlet at 6.95 T (Cfi^-C- , area = 3H), doublet centered at 1.56^ ((3H, area = 2H), doublet centered at 0.75 7" (oc H, area = 2H). Found: C, 24.36; H, 2.54; N, 4.04; Br, 69.40. Calc. for C^ RgNBr^ :; C, 24.29; H, 2 . 3 3 ; N, 4.05; Br, 69 .33 . It was subsequently shown that the product obtained 6 0 under these conditions gave a mixture of mono and dibromo-ethyl pyridines which were separable by fractional crystal-lization. BIBLIOGRAPHY References to Part II 1. J. P. Kutney and R. C. Selby. J. Org. Chem. 26, 2733 ( 1 9 6 1 ) . 2 . J. P. Kutney and T. Tabata. Can. J. Chem. 4-0, 1140 ( 1 9 6 2 ) . 3 . J. P. Arens and J. P. Wibaut. Rec. trav. chim. 61, 59 (194-2). 4-. R. L. Prank and P. V. Smith. Org. Synthesis. 27, 38 (194-7). 5 . S. Wawzonek, M. F. Nelson and P. J. Thelen. J. Am. Chem. Soc. 2ft, 2894- ( 1 9 5 2 ) . 6 . M. Dohrn and H. Horster. German Patent 3 9 0 , 3 3 3 , 1924-. 7 . J. P. Wibaut and J. F. Arens. Rec. trav. chim. 60, 119 (194-1). 8 . B. Emmert and A. Wolpert. Ber., 21, 1015 (194-1). 9 . R. L. Frank, F. Pell i t i e r , and F. W. Starks. J. Am. Chem. Soc. £ 0 , 1767 (1946). 1 0 . H. S. Mosher. "The Chemistry of the Pyridines" in Elderfield, ed. Heterocyclic Compounds. Wiley, New York, 1 9 5 0 , Vol. I, p. 4-82. 1 1 . G. B. Bachman and R. M. Schisla. J. Org. Chem. 2 2 , 1302 ( 1 9 5 7 ) . 1 2 . G. Wittig and V. Schollkopf. Ber., 82, 1318 (1954-) . 1 3 . F. Sondheimer and R. Mechoulam. J. Am. Chem. Soc. 80, 3 0 8 7 ( 1 9 5 8 ) . 14-. P. Vaculik and J. Kuthan. Collection Czecholslov Chem. Communs. 24, 174- ( 1 9 5 9 ) . 62 1 5 . I. Heilbron and H. M. Bunbury. "Dictionary of Organic Compounds," Vol. I, London, Eyre & Spottiswoode, 1946, p. 913. 16. Beilstein. Handbuch. der Organischen Chemie,. 20, 254 (1955): i b i d II. 166 (1953). 17. S. A. Harris and K. Folkers. J. Am. Chem. Soc. 61, 1245 (1939). 18. F. Sorm and L. Sedivy. Collection Czechoslov Chem. Communication. 13_, 289 (1948) C.A. 41, 2996 (1949). 1 9 . J. Hurst and N. G. Vibberley. J. Chem. Soc. 1962 ( 1 1 9 ) . 20. E. Klingsberg. "Heterocyclic compounds, Pyridines and i t s Derivatives," Part 2, Interscience Publishers Inc., New York, 1961. 21. G. H. Lenart. Ann. 410, 95 ( 1 9 1 5 ) . 22. H. Bach. Ber. 2ft, 2223 ( 1 9 0 1 ) . 2 3 . H. S. Mosher and J. E. Tessieri. J. Am. Chem. Soc. 21, 4925 (195D. 

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