Regioselective Synthesis of 3- and 5-Functional Derivatives of Pyrazolidine. 1. Synthesis of Ketones of the Pyrazolidine Series

Abstract

When 5-hydroxypyrazolidines reacted with ketones on the surface of basic adsorbents the 3-regioisomers were obtained in addition to the expected 5-oxoalkylpyrazolidines. The conditions for the regiodirection of the process have been found.Keywords: ketones, 3-and 5-oxoalkylpyrazolidines, diastereoselectivity, isomerization, mass spectroscopic analysis of isomers, reactions on the surface of adsorbents.We have shown earlier [1] that 5-hydroxypyrazolidines 1a,b react with CH-acids on the surface of alumina without solvent at 60°C to give the corresponding 5-functional derivatives of the pyrazolidine series; in particular, compound 1a reacted with a number of ketones. The hydroxypyrazolidine 1b, which has a transmethyl group in position 3, does not react with ketones for steric reasons -replacement of the hydroxy group in compound 1b requires more vigorous conditions than for compound 1a [1]. We recently reported [2] that hydroxypyrazolidines 1a,b reacted with acetophenone on a potassium fluoride surface deposited on aluminum oxide (at 80°C) or barium hydroxide (at room temperature) to form mixtures of the regioisomers 3a,b and 5a,b (Table 1).It may be assumed that the reason for the formation of the regioisomers 3 is participation in the reaction of the linear tautomer of hydroxypyrazolidine 1 which readily undergoes "retro-Michael" decomposition to the hydrazide and crotonic aldehyde with subsequent "reverse" addition of the hydrazide to the double bond under conditions of basic catalysis.The regioisomeric hydrazino aldehyde 1b' evidently exists in the linear form only (likes its analog prepared from hydrazobenzene [3]) and reacts directly with acetophenone. In a model experiment on a KF/Al 2 O 3 surface 1-acetyl-2-phenylhydrazine, crotonic aldehyde, and acetophenone were deposited on the surface and subjected to the conditions used for the reacion with hydroxypyrazolidine [2]. As a result the regioisomers 3 and 5 were obtained in close to the same ratio as in the normal reaction which serves as additional support in favor of the proposed scheme for the process. __________________________________________________________________________________________ 1 M.

A new approach to the synthesis of aliphatic triamines and diamino alcohols that are analogs of the anti-TB drug ethambutol

“…The general strategy con sists in initial introduction of nitrogen or oxygen con taining substituents into an accessible N 2 containing ma trix (pyrazolidine ring). 13 Then the introduced functional groups are transformed into substituents containing the desired hydroxy or amino groups. 14a, b The key step of the synthesis is final cleavage of the endocyclic N-N bond, which leads to the target linear triamines or di amino alcohols*.…”

“…The product was enantiomerically pure (1´S,2S,4R,6S) 4 phenylamino 6 ethylamino 2 (1 phenylethylamino) heptane (13). Since the 1 H NMR spectra show no dou bled signals, one can believe that none of the four stereo genic centers undergoes racemization; therefore, we ob tained enantiomerically pure triamine 13 with the specific rotation [α] D + 10.2 (c 2.24•10 -3 , CHCl 3 ).…”

Diastereoselective reductive amination of pyrazolidinyl alkyl ketones

“…The diastereomer of 4d predominating in the mixture was isolated by crystallization as the hydrochloride. In the 1 H NMR spectra of the obtained amines, compared to the initial ketones [10], there was a doublet or doublet of doublets for the proton of the emerging methine group, the signals of the α-protons were displaced from 2.5-4.0 to the 1.5-2.0 ppm region, in compounds 2a,b and 4a,b the signals of the methyl group of the functional substituent (singlet at ~2 ppm) were displaced by ~1 ppm towards high field and split into a doublet. The signals of the remaining protons did not undergo significant changes.…”

“…On the basis of the structure of the initial heterocycle as a racemate of trans structure [10], on condition that (S)-phenylethylamine interacts with enantiomers 3a nonselectively, but the resulting imine is reduced stereoselectively [13], then the structure 1-acetyl-3R-[2R-(1S-phenylethylamino)propyl]-5R-methyl-2-phenylpyrazolidine must be assigned to the other (minor) diastereomer of 4d.…”