Sept. 20, 1955
2-VINYLPYRIDINE WITH
[CONTRIBUTION NO. 949 FROM
THE
SECONDARY
4913
AMINES
DEPARTMENT O F CHEMISTRY, UNIVERSITY
OF
PITTSBURGH]
The Pyridylethylation of Active Hydrogen Compounds. 111. The Reaction of 2-Vinylpyridine with Secondary Amines BY HENRYE. REICH' AND ROBERTLEVINE RECEIVED MARCH11, 1955 Several secondary amines have been condensed with 2-vinylpyridine under acidic conditions to give good yields of tertiary R ~ . and 2,5-dimethylpyrrole, which are too weakly basic to be pyridylethyamines of the type ~ - C ~ H & J C H Z C H ~ NPyrrole lated under acidic conditions, condense with 2-vinylpyridine in high yields with sodium metal as the catalyst. The structures of several of the products have been established by comparison with authentic samples prepared by the Mannich reaction and/or the carbamyl chloride route. Mechanisms for the pyridylethylation reactions are proposed.
In earlier work from this Laboratory the pyridylAlthough in our hands H6ou-F6o's method6J for ethylation of a number of ketones was reported.2s3 effecting the Mannich reaction gave only a tarry The present report is concerned with the addition mixture, varying the experimental conditions of a number of secondary amines to 2-vinylpyri- gave a 23% yield of 2- (P-diethylaminoethy1)-pyridine. Before our study was initiated, Doering and dine (A, R = CzH5). The physical properties of Wei14 reported the non-catalytic pyridylethylation both this compound and its dipicrate agree with of piperidine in 8670 yield by refluxing 2-vinylpy- those of the corresponding materials obtained by ridine with excess piperidine for six hours. These the direct pyridylethylation of diethylamine. workers also found that when a solution of diethyl- The structure of the diethylamine-2-vinylpyridine amine and 2-vinylpyridine is heated a t 165" for 15 adduct was established further by the carbamyl hours a l2Y0 yield of pyridylethylated product is chloride route. The Mannich reaction (Table 11) obtained. After our study was in progress, Som- and/or the carbamyl chloride route (Table 111) also mers, et reported that although they were able were used to establish the structures of several of to add piperidine, morpholine and l-methylpipera- our other products.
j. and Route RzNCH2CHsCbH4N-2 I n dicyclohexylamine. the present study, nine LiAlH4 A secondary amines have been RZNCOCI 2-CsH4NCH2Li +R2NCOCH&5H4N-2 pyridylethylated using non-cataWe have found that several amines (diisopropyllytic conditions or an acid (hydrochloric or acetic) as the condensing agent. These results are sum- amine, di-sec-butylamine, dicyclohexylamine, pyrrole, 2,5-dimethylpyrrole and diphenylamine) could marized in Table I . Because the addition of an amine t o the side not be pyridylethylated under acidic conditions. chain of 2-vinylpyridine may, a priori, give rise to It appears that the reaction failed with the first the isomeric compounds A and B, the structures of three amines because of steric reasons and that the several of our products were established by prepar- second three amines failed to react because they are so feebly basic. ing authentic samples. Therefore, i t seemed reasonable that pyrrole, ~-C~HIXCH=CH $-~RzXH + 2,5-dimethylpyrrole and diphenylamine might be ~ - C ~ H ~ N C H ~ C Hf~2-C5Har\'CH( NRZ NRP)CHI pyridylethylated using sodium metal as the conA B densing agent-a method which had been used suc~>~ the pyridylethylation of keIn the non-catalytic reaction between 2-vinylpy- cessfully e a ~ - l i e rfor ridine and diethylamine, Doering and Wei14 indi- tones. Under these conditions (Table I) although cate that the compound obtained is 2- (P-diethyl- pyrrole gave an 89% yield and 2,5-dimethylpyrrole aminoethy1)-pyridine (I) (A, R = C2H5). As evi- a 537c yield of pyridylethylated product, diphenyldence for this structure these workers have used the amine failed to react. That pyrrole is pyridylethylated on its nitrogen facts that the melting points of their derivatives atom is shown by the fact that a Zerewitinoff reacagree with those in the l i t e r a t ~ r e . ~ - ~ tion with the product gave only 5 7 , of methane in (1) American Cyanamid Co. Research Fellow, 1952-1954. accord with the 4% obtained in a similar reaction (2) R. Levine and M. H. Wilt, THISJ O U R N A L , 74, 342 (1952). (3) M. H . Wilt and R. Levine, i b i d . , 75, 1368 (1953). with 2-(@-diethylaminoethyl)-pyridine. The evo(4) W. E. Doering and R . A. N. Weil, i b i d . , 69, 2461 (1947). lution of these small amounts of methane probably ( 5 ) A. H . Sommers, M. Freifelder, H. B. Wright and A. W. Weston, is due to the fact that the Grignard reagent reacted ibid.,7 6 , 57 (1952).
+
(6) T. H6ou-F6o, Cornpi. rend., 1 9 2 , 1242 (1931). (7) T. Hkou-FCo, BuU. soc. chim. (France), [ 5 ] 2 , 105 (1935). ( 8 ) K. LoWer, Be?., 87, 161 (1904). (9) Although H6ou-FioS~:claims t o have made I b y a Mannich reaction involving 2-picoline, pertinent analytical d a t a do not appear in his papers. Also, LoWer claims t o have prepared I by treating 2-(2pyridyll-ethanol with fuming hydrobromic acid a n d phosphorus in a sealed tube and treating t h e resulting bromide I1 with diethylamine, Based on his analytical d a t a , there is little doubt t h a t LofEer obtained either compound A or R (11 = C!Hs). However, it appeared t o 11s
t h a t I1 might not have been @-(Z-pyridyl)-ethyl bromide b u t its rearranged isomer, a-(Z-pyridyl)-ethyl bromide. It also is possible t h a t under LofEer's conditions t h e intermediate bromide(s) might have been dehydrohalogenated by diethylamine t o give a mixture of 2-vinylpyridine and diethylamine hydrobromide or 2-vinylpyridine hydrobromide and diethylamine. Then, each of these pairs of compounds theoretically could react to give t h e observed product. Using this reasoning, we treated 2-vinylpyridine with diethylamine hydrochloride and 2-vinylpyridine hydrochloride with diethylamine and obtained 20 and 22%. respectively, of t h e same product.
HENRYE. REICHAND ROBERT LEVINE
49 14
VOl. 77
2-VP = 2-vinylpyridine. * The amine was used as its Cdhydrochloride. c CsHloKis the 1-piperidino radical. HBON = the 1-morpholino radical. e C4HsN = the l-pyrrolidinoradical. f C4H4S= the 1-pyrryl radical. 0 C$H& = the 2,5-dimethyl-l-pyrryl radical. N. F. Hall and M. R . Sprinkle, THISJOURNAL, 54,3469 (1932). H. Scudder, “The Electrical Conductivity and Ionization Constants of Organic Compounds,” D . Van Nostrand Co., Inc., Kew York, S. Y., 1914, p. 261. j A.R. Ingramand W. F.Luder,THrs JOURNAL, 64,3043 (1942). k L. C. Craig and R. M. Hixon, ibid.. 53.4370(1931). 1 R e*~~ 0 r t e d ~ m .159-160”. n~. . Anal. Calcd.-C;-41.45;- H, 3.29. Found: C, 41.56; H, 3.48. “ A n a l . Calcd. C,42.46; H,3.39. Found: C,42.66; H,3.39. ~~
~
~
~~
~~
~~
TABLE I1 TERTIARY AMIXESFROM THE MANNICH REACTIOSBETWEES 2-PICOLINE, FORMALDEHYDE AXD SECONDARY AMISES 1- Amines,
~-C~HINCH~CHI~-R? yield,4 5%
Secondary amine
tiu
C I C I
fie
.Y .Y
& &
-
.^ r
2 t-
co-
3
% *
i
i
7 % c N
c.
d
37
Dimethylamine 6 23“ Diethylamine Di-n-propylamine 16 13 Di-n-butylamine 19 Diisobutylamine 4c Morpholine 11 Piperidine a Constants of these amines and their picrates agree with those listed in Table I. * Analysis appears in Experimental section. There also was obtained 70% yield of N,N-dimorpholinomethane, b.p. 116-122’ a t 10 mm. ( M . Zief and J. P . Mason, J . Org. Chent., 8, 1 (1943)). TABLE111 TERTIARY AMINESFROM THE LITHICMALUMISUMHYDRIDE OF AMIDESPREPARED BY THE ACYLATION OF REDUCTION 2-PICOLYLLITHILTM WITH CARBAVYL CHLORIDES
?
c.lm d
h h h h h h , - . h
occoc.IocDI
ul
o
m, m
Carbamyl chloride
( CH3)rXCOCI ( C2Hj)rNCOCl
-= o
Amides,
Amines,
2-CaHdNC+CONRia
2-CsH4NCHzCHzNR?
8.0b 46.0’ 68.3‘
43 . 0 56.0 45.0
yield,
5%
yield,“ %
(n-CaHs)rSCOCl CsHsX(CH,)COCI 43. o d 40.0 2-CbH4.X = 2-pyridyl radical. Behaved erratically on analysis. Anal. Calcd. for CljH?rN,O: N, 11.29. Found: S, 11.43. “Anal. Calcd. for ClrHirNzO: K, 12.39. Found: S, 11.88. e Constants of these amines and their picrates agree with those listed in Table I. h
2
-,-. oc
to a small extent with the slightly acidic hydrogen atoms of the methylene group which is attached to the pyridine ring of these tertiary amines. Three mechanisms may be visualized for the pyridylethylation of amines depending on whether the reaction is (I) uncatalyzed, (2) base-catalyzed or (3) acid-catalyzed. The uncatalyzed and acidcatalyzed reactions appear to be initiated by the attack of the amine to be pyridylethylated or its ammonium ion,I0 respectively, on the electron-deficient terminal carbon atom of the vinyl group. The sodium-catalyzed (basic) reactions probably involve the addition of the anion of the secondary amine (formed from the amine and sodium metal) (10) Since t h e dialkylamines which can be pyridylethylated under acidic conditions are stronger bases (Table I) t h a n 2-vinylpyridine I K L = 8.3 X 10-10, this valiie was kindly determined by hlr. T. R Harkins < ) f t l i i q department) and since lhere is never enough i i C I d present i n tlir niediiini 10 cunvert bot11 the dialkylaniint. and the 2 vinylppridine t
