Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-05-21
1995-08-01
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546290, C07D21308, C07D21309, C07D21312
Patent
active
054381436
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of a substituted pyridine by reaction of a 1-aza-1,3-butadiene.
A process of this type for the preparation of pyridines is disclosed by Komatsu et al. (J. Org. Chem. 49, pp. 2691-2699 (1984)). They prepare asymmetric 3,5-substituted pyridines by allowing 1 equivalent of enamine and 1 equivalent of imine to react to form a 1-aza-1,3-butadiene. This product then reacts in the course of 20-24 hours at 200.degree. C. with another enamine to form an asymmetrically substituted pyridine. The yield varies, depending on the substituents, between 23% and 73%.
Symmetrical 3,5-substituted pyridines are prepared by allowing 2 equivalents of enamine to react in the presence of acid at 200.degree. C. for 9 hours with 1 equivalent of imine. This gives pyridines in a yield, depending on the substituents, of 67 to 87%. In this case the 1-aza-1,3-butadiene is formed in situ from the enamine and the imine.
This preparation process has various disadvantages, The production of symmetrical pyridines proceeds via a 3-step synthesis, that is to say the synthesis of, respectively, the imine, the enamine and the pyridine. Asymmetrically substituted pyridines are prepared via a 4-step synthesis, that is to say synthesis of, respectively, the imine, the enamine, the 1-aza-1,3-butadiene and the pyridine. The reaction time for the formation of the pyridine is long. The enamine is usually prepared by reaction of a secondary amine with an aldehyde. However, this preparation frequently results in low yields, especially if the process is carried out using reactive aldehydes which are not sterically hindered. Problems in the preparation of enamines are described, inter alia, in Whitesell and Whitesell (Synthesis, July 1983, page 517-536). They give a yield of 26% for the formation of the enamine from acetaldehyde and N-butyl-N-isobutylamine. They explain this as follows: "The low yield in the preparation of the enamine from acetaldehyde described above was very probably the consequence of the occurrence of competitive condensation reactions and is typical of the results to be expected in the use of reactive aldehydes which are not sterically hindered."
In the preparation of the enamine, equivalent amounts of secondary amine and aldehyde are used. For the formation of 1 equivalent of pyridine, 2 equivalents of enamine, so also 2 equivalents of secondary amine, are needed. Since secondary amines are often expensive, it makes the reaction economically unattractive. The fact that the preparation of the enamine frequently proceeds with a low yield, as a result of which an unnecessarily large amount of secondary amine and aldehyde are consumed, does not make the reaction economically attractive either.
The object of the invention is to avoid the abovementioned disadvantages.
This is achieved according to the invention in that a pyridine according to formula 1 ##STR1## where R.sub.1 may be H or R.sub.1 and R.sub.3 can independently be chosen from (cyclo)alkyl, alkenyl, aryl, carboxyalkyl, carboxyaryl, aryloxy, alkoxy, arylthio, arylsulphonyl, NR'R" with 1-20 C-atoms, and halogens, where R' and R" can independently be chosen from H, (cyclo)alkyl and aryl, and R.sub.2 can be chosen from H, aryl, alkenyl, and (cyclo)alkyl with 1-20 C-atoms, and only 1 of the groups R.sub.1 and R.sub.2 may be H, R.sub.4 is chosen from H, (cyclo)alkyl, aryl, carboxyalkyl and carboxyaryl with 1-20 C-atoms or R.sub.3 and R.sub.4 form together with the C-atoms to which they are attached a cycloalkyl-group with 4-8 C-atoms, is formed by allowing the 1-aza-1,3-butadiene according to formula 2 ##STR2## where R.sub.5 is a OH, alkyl, aryl or alkoxy group with 1-20 C-atoms and R.sub.1 and R.sub.2 have the meaning described above, to react, in the presence of a catalytic amount of secondary amine and acid, with an aldehyde or ketone according to formula 3 ##STR3## where R.sub.3 and R.sub.4 have the meaning described above.
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 usually contain 1-20 C atoms and may optionally be substituted. Po
REFERENCES:
K. Takabe, et al, Tetrahedron Letters, No. 49, Dec. 1975, pp. 4375-4376.
M. Komatsu, et al., J. Org. Chem. 1984, vol. 49, pp. 2691-2699.
D. A. Evans, et al., Tetrahedron Letters, No. 26, No. 32, pp. 3787-3790; Aug. 1985.
B. Unterhalt, Chem. Abs., vol. 73, p. 329, 87581u; Oct. 26, 1970.
B. Unterhalt, et al., Chem. Abs, vol. 105, p. 563 208557f; Dec. 08, 1986.
B. Unterhalt, et al., Chem. Abs., vol. 106, p. 568 66838t; Mar. 02, 1987.
C. Hickson, et al, J. Chem. Soc., Perkin Trans. I, 1984, pp. 1569-1572.
Arts Henricus J.
Castelijns Anna M. C. F.
DSM N.V.
Rotman Alan L.
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