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Vol. ‘78
A I O S H E XVRAMOFF AND >-AIR S P R I N Z a K
was then vacuum distilled. The yields and boiling ranges of these esters are listed in Table I. ETHYLp- ( X-HETEROCYCLIC) -p-PHENYLPROPIONATE HYDRO- Reaction of Saturated Heterocyclic Amines with CinnaCHLORIDES mate Esters.-Since the procedure used in preparing the 6-(N-heterocyclic)-P-phenylpropionate esters was basically 0 the same in all cases, detailed directions are given for only II one representative compound. The physical properties of these compounds are listed in Tables I1 and 111. Ethyl p-( 1-Piperidyl)-p-phenylpropionate.-Ethyl cinnamate 0 7 . 6 g.,.0.1 mole) and piperidine (8.5 g., 0.1 mole) .HC1 were dissolved in 30 ml. of heptane and the solution refluxed IIeterocyclic Ygjd, Carbon, % Hydrogen, 5% Molecular for 8 hr. -After the solution had cooled to room temperazo Calcd. Found Calcd. Found group formula ture, i t was washed with three 30-ml. portions of distilled 1-Pyrrolidyl C16Hz~iYOd21 18 6 3 . 6 2 63.28 7 . 8 2 7 . 7 6 water. The organic layer was then extracted with two 301-Piperidyi Ci6Hzah-OzCI 30 64.52 64.36 8 . 1 2 8 . 2 3 ml. portions of 3 iV hydrochloric acid. These acid aqueous 20 80.09 G O , 43 7 . 4 0 7 . 4 9 4-Rlorpholinyl C16HzzSO3Cl extracts were combined and made basic to p H 8 by the addi17 65.47 65.42 8 . 4 2 8 . 4 0 1-(4-Me)-piperidyl CirHacS02CI tion of granular potassium carbonate. The resultant oil was then extracted with two 50-1111. portions of ether. The TABLE 111 ethereal extracts were combined and dried over anhydrous ALKYL p-( PIPERID IDYL) -p-PHESTLPROPIONATE HYDROCHLO-calcium sulfate. The dry ether solution was then treated with dry hydrogen chloride until acid to congo red paper. RIDES T h e precipitated white solid was recrystallized three times from 2-propanol; yield 6.0 g., 20.1%. It was found t h a t the yield of product was increased to 45% of the theoretical when the reaction was run in toluene solution in the presence of 1 ml. of a 10% aqueous solution of tetramethylammonium hydroxide solution. By employing a two-mole excess of piperidine, the yield was increased Carbon, 570 Hydrogen, % Molecular Yield, 75% of the theoretical. formula Alkyl group 570 Calcd. Found Calcd. Found to N-Cinnamy1piperidine.--X mixture of ethyl cinnamate 19 63.47 63.34 7 . 8 2 7 . 9 5 CisHzzNOxCl Methyl (52.8 g., 0.3 mole) and piperidine (25.5 g., 0.3 mole) was 20 64.52 64.36 8.15 8 . 2 2 CieHzrNOzCl Ethyl refluxed for 70 hr. The unchanged reactants and ethanol 22 65.47 65.83 8 . 4 2 8 . 5 5 Ci7H2eNOaCI n-Propyl were removed by distillation at 0.5 mm. When the tempera16 66.33 66.10 8 . 6 7 8 . 6 8 CisHz8NOzCl *-Butyl ture reached 80°, the distillation was discontinued. After 67.13 67.24 8 . 9 1 8.76 ClQHaOPu‘OZC1 12 n-Amyl cooling to room temperature, the material in the pot solidi8 67.86 67.76 9.13 9 . 2 2 CioHjzNOaCl n-Hexyl fied. This solid material, S-cinnamylpiperidine, was re7 66.33 66.16 8 . 6 7 8 . 5 5 CiaHsaNOzCl _‘-Methylprop)-l crystallized twice from absolute ethanol and washed with 6 66.33 66.48 8 . 6 7 8 . 5 7 CiaHzsh-OzCl 1-Methylpropyl petroleum ether, yield 46.5 g., 71%. 4 67.13 67.10 8 . 9 1 8.87 CisHaoN02C1 1-Methylbutyl Anal. Calcd. for CI4H1,NO: C, 78.14; H , 7.97. Found: C, 78.23; H, 8.03. cium sulfate. T h e solvent was removed by distillation on the steam-bath under mater-pump vacuum. The residue GAISESVILLE,FLORIDA
TABLE I1
O-~HCH~COC~H~
[CONTRIBUTION FROM
THE
DANIELSIEFF RESEARCHINSTITUTE, LVEIZMANN INSTITUTE
OF SCIENCE]
Reduction and Benzylation by Means of Benzyl Alcohol. 111. Experiments in the Pyridine Series1 BY ~IOSH XVRAMOFF E
AND YAIR SPRINZAK
RECEIVEDJANUARY 14, 1956 The behavior of pyridine, its benzologs and their derivatives toward benzyl-alcoholic potassium hydroxide has been studied. iMethyl groups in the pyridine ring are readily benzylated. On prolonged heating, dibenzylated products are obtained. It is shown t h a t t h e reaction involves condensation with benzaldehyde and reduction of the resulting styryl derivative, Two instances of benzylation of a “non-active” side-chain have been encountered. Quinoline is transformed into 1,2,3,4-tetrahydroquinoline, 3-benzylquinoline and 3-benzyl-l,2,3,4-tetrahydroquinoline, which can be obtained in good yield. The formation of these products is explained in terms of partial reduction of the pyridine ring, followed by two concurrent reactions : (1) reduction t o 1,2,3,4-tetrahydroquinoline and ( 2 ) condensation of dihydroquinoline with benzaldehyde which isomerizes t o &benzylquinoline. The.latter is then reduced t o 3-benzyl-1,2,3,4to form 3-benzal-3,4-clihydroquinoline, tetrahydroquinoliIie. 3-Methyl- and 3-phetiyl-quiiioliiie are also reduced under the same conditions. Carbostyryl yields 3-benzylcarbostyryl. Isoquinoline is benzylated t o .l-benzylisoquinoliiie. S o reduction products have been observed in t h e pyridine and isoquinoline series.
In previous parts? of this series we have discussed the carbon-benzylation of fluorene and its derivatives and the nitrogen-benzylation of primary aromatic amines by means of benzyl-alcoholic potassium hydroxide. It was shown that in both cases the reaction involved the formation of intermedi(1) Presented in part a t t h e X I V t h International Congress of Pure and Applied Chemistry, Zurich, July, 1955. Taken in p a r t from the Ph.D. Thesis submitted t o the Hebrew University of Jerusalem by Moshe Avramoff. ( 2 ) Y.Sprinzak, ( a ) THISJ O U R N A L , 78. 466 (1956); f b ) ibid. 78, 3207 ( 1 0 3 0 ) , r f . British Patent 720.545 ( J a n . 1, 1953).
ate benzylidene derivatives, readily reducible by the reagent. I t was further pointed out that this easy reduction was due to the polar character of thc. newly formed double bond. In the present work the behavior of iiitrogeiicontaining aromatic heterocyclic compounds toward the reagent has been studied. It was expected that the polarity induced by the presence of the tertiary nitrogen atom would give rise to: (a) reduction of the heterocyclic ring and (b) benzylation of “active” side-chains by n process in-
dug. 20, 1956
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BEXZYLATION OF PYRIDIKES
volving condensation with benzaldehyde and reduction of the unsaturated condensation product
theless submitted ?-picoline to the action of the reagent and isolated a small quantity of a benzylated picoline. Our conclusion t h a t benzylation of the /' C ~ H ~ C H P O H methyl group occurred is strengthened by the surC,H,CHO -+ prising finding, reported recently by Brown and - -+ KOH Murphey, that 0-picoline could be methylated in the presence of sodium amide.6,6a In the quinoline group, quinaldine (V) and lepidine (17111) were readily monobenzylated t o the corresponding phenethylyuinolines VI and IX. Similarly, 2,4-dimethylquinoline (XI) yielded 2,4diphenethylquinoline (XII). Its structure has Reactions of type a appeared t o us all the more been proven by comparison with a sample obtained likely in view of an experiment where acridane was by catalytic hydrogenation of 2,4-distyrylquinoline readily formed from acridine by treatment with (XIII). -4s in the phenethylpyridines, the sidechain can be further benzylated t o the diphenylisothe above reagent. propyl group. Thus, IX and XI1 are converted t o X and XIY, respectively. VI, however, is not further benzylated. X possible explanation for this exception will be given below.
+ CsHjCHO Reaction b could be anticipated because of the analogous benzylation of the active methylene group in fluorene.?a Accordingly pyridine, quinoline, isoyuinoline and their derivatives have been submitted t o the action of boiling benzyl-alcoholic potassium hydroxide. Since preliminary experiments have shown that reaction was more effective under anhydrous conditions, water was usually removed froin the hydroxide solution by distillation, prior to the addition of the heterocyclic compound. The potassiuni benzylate solution3so prepared will subsequently be referred to as "the reagent." The discussion of the reactions observed will be divided, in accordance with the products obtained, into side-chain reactions and reactions of the heterocyclic ring. Side-chain Reactions.-% and 4-picoline are benzylated by the reagent t o form the corresponding phenethylpyridines (I and 111) in good yields. There is a marked difference in the reactivity of the picolines, a longer reaction time being required in the case of the 2-isomer. On longer treatmerit, tlic phenethyl group is further benzylated to the diphenylisopropyl group, to give 11 and IY. Here again the reaction is faster with 4-phenethylpyridine. This difference is in contrast with the greater reactivity of 2-picoline as compared with that of 4picoline in the alkylation with heiizyl cliloridc i i i the presence oI potassiiliii :tiiiitlc. ' IC1
I"
I , K1 = H,Kz = CHpCHzChH; 11, K I = 1-1, Ri = CH(CHnC611s1r 111, Ki = CIIzCHaCiiH I\., T i l = CH(CH2CeH
I
x+-- R y
The methyl group in $-picoline has :iIwztys hccn considered as entirely uiireactive toward reagents which attack a- and y-methyl groups." l y e never( 3 ) According t o
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