Ping Lue

Amidines and guanidines in medicinal chemistry

Publisher Summary This chapter focuses on amidines and guanidines in medicinal chemistry. The drugs are classified under their main physiological activities and within each group are arranged roughly in order of increasing molecular complexity. Many of the compounds have given temporary excitement to their discoverers and then been dropped—the commonest experience in medicinal chemistry. There are important, clinically used, medicines in all the major categories of therapeutic action discussed in the chapter. This simple and very unstable compound is not only a neurotransmitter in the brain, but acts in the dilation of blood vessels and activates leucocytes to attack tumour cells, fungi, and bacteria. In addition, nitric oxide can inhibit blood coagulation by preventing platelet aggregation and appears to be the regulator of the male erection. No doubt other functions will be discovered in the future, but the interesting finding for the present chapter is that the NO is formed by nitric oxide synthetase from arginine—the only essential amino acid which carries a guanidine group. Since most of the active guanidine drugs have at least one unsubstituted =NH or NH 2 group, it is interesting to speculate that they will be shown to act by giving nitric oxide as well.

Benzotriazol-1-ylmethyl isocyanide, a new synthon for CHNC transfer. Syntheses of α-hydroxyaldehydes, 4-ethoxy-2-oxazolines and oxazoles

Abstract Readily prepared benzotriazol-1-ylmethyl isocyanide (BetMIC) reacts under mild conditions with ketones and aldehydes, to afford oxazolines (convertible into α-hydroxyaldehydes) and oxazoles, respectively.

Benzotriazole-assisted synthesis of enamines

Abstract A new, facile preparation of enamines was achieved via a two-step sequence: (i) the ready formation of an N-(α-aminoalkyl)benzotriazole derivative from equimolar amounts of benzotriazole, an aldehyde, and a secondary amine, (ii) the elimination of benzotriazole from the derivative by sodium hydride in tetrahydrofuran (THF). The method provides enamines in good overall yields based on the quantity of amine used.

Isomerizations of N-(α-aminoalkyl)-1,2,4-triazoles and N-(α-aminoalkyl)tetrazoles

The title compounds exist as equilibrium mixtures of the N-1 and N-2 isomers in solution. However, the crystal structure of 3-(1-hydroxycyclohexyl)-1-(α-pyrrolidinomethyl)-1,2,4-triazole discloses only this isomer in the solid state. Evidence for the nature of the isomerization processes in solution is provided. The kinetic and thermodynamic parameters are measured and qualitatively assessed.

Synthesis of 3(5)-substituted 1,2,4-triazoles by lithiation of 1-(1-pyrrolidinomethyl)-1,2,4-triazole

1,2,4-Triazole 1 is readily converted into 3(5)-substituted 1,2,4-triazoles 4 by a three-step sequence: (i) Mannich reaction with formaldehyde and pyrrolidine; (ii) lithiation of 1-(1-pyrrolidinomethyl)-1, 2,4-triazole 2, followed by addition of an electrophile; (iii) deprotection of the N-aminal groups of the N-protected 3-substituted 1,2,4-triazoles 3 using sodium borohydride (NaBH4) in ethanol. 3(5)-Substituted 1,2,4-triazoles 4 result in good overall yields.

Formaldehyde: A Reagent for Simultaneous Protection of Heterocyclic NH and Activation of Alternative Locations to Electrophilic Attack. Part II. A New Synthetic Method for the 5(3)-Substitution of N-Unsubstituted Pyrazoles

Abstract N-Unsubstituted pyrazole 1 is readily converted into 5-substituted [tautomeric with 3-substituted 8] derivatives 2 in moderate to good overall yields in a one-pot sequence, using formaldehyde both for N-protection and to mediate lithiation at the 5-position. The dilithiohemiaminals 5 react with electrophiles at the pyrazole 5-position to give 5-substituted 1-lithioxymethylpyrazoles 6 which undergo smooth dehydroxymethylation under mild conditions (acid hydrolysis or silica gel) to give N-unsubstituted 5(3)-substituted pyrazoles.

The chemistry of N-substituted benzotriazoles: a novel route to dienamines

Abstract Readily prepared 1,3-bisbenzotriazolyl tertiary amines were converted into dienamines via the elimination of benzotriazole moieties with sodium hydride in tetrahydrofuran. Yields compare favourably with other methods.

The chemistry of N-substituted benzotriazoles. Part 14. Novel routes to secondary and tertiary amines and to N, N-disubstituted hydroxylamines

Tertiary amines of types R4R3CHNR1R2(2), (R2CH2)2NR1(10) and (11), or (R2CH2)3N (12), secondary amines of type (R2CH2)2NH (8), and N, N-disubstituted hydroxylamines of type (R2CH2)2NOH (9), are prepared in high yield by the action of Grignard reagents or sodium borohydride on easily available N, N-dialkyl-N-[benzotriazolylalkyl-(or arylalkyl-)]amines (1) or tris(benzotriazolylmethyl)amine (7), on bis(benzotriazolylmethyl)amines (3), (5), and (6), and on N, N-bis(benzotriazolylmethyl)hydroxylamine (4), respectively.