New approach to the synthesis of 4-aryl-3,5-dicyano-6-oxo- 1,4,5,6-tetrahydropyridin-2-olates (salts of guareschi imides)
Derivatives of 2,6-dioxopiperidine-3,5-dicarbonitrile (Guareschi imides) are of practical interest as anticonvulsants, sedatives, and analgesics [1] as well as promising building blocks for the preparation of bispidine (3,7-diazabicyclo[3.3.1]nonane) derivatives [2, 3] and biologically active compounds [4–6]. The most convenient method for the preparation of these compounds is the Guareschi reaction, namely, the reaction of ethyl cyanoacetate with ketones and ammonia [7–11] or, in an alternative variant, the reaction of 2-cyanoacrylates with cyanoacetamide [4, 6, 12, 13]. The classical Guareschi reaction has its disadvantages. The yields and reaction times vary. Also, there are limitations related to the need to use only ketones as the carbonyl components. Guareschi imides are known to undergo facile oxidation by atmospheric oxygen [14]. When aldehydes are used in this reaction instead of ketones, the final products are only the oxidation products, namely, 4-alkylor 4-aryl-6-hydroxy-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles or their salts [15–19]. Only a few examples of the preparation of 4-aryl-2,6-dioxopiperidine-3,5-dicarbonitriles or their salts have been reported [1, 20, 21]. As a rule, either the products are obtained in low yield or the methods require the use of exotic reagents such as Li3N as the source of NH3. We have found that the salt of the Guareschi imide, triethylammonium 4-(2-chlorophenyl)-3,5-dicyano6-oxo-1,4,5,6-tetrahydropyridine-2-olate (1), may be synthesized under mild conditions by the Michael reaction of readily available 1-cyanoacetyl-3,5-dimethylpyrazole 2 [22, 23] with 3-(2-chlorophenyl)-2-cyanoacrylamide 3. Pyridinolate 1 is formed in 76% yield as a mixture of cis and trans diastereomers and, according to the H NMR spectrum, does not contain oxidation product impurities. This method is the first efficient procedure for preparing 4-aryl-ubstituted Guareschi imides and one of the first examples of the use of azolide 2 as an active methylene compound serving as an alternative to ethyl cyanoacetate. Work on the optimization of the method and clarification of its scope is currently underway.