Strategy for the Synthesis of Polymeric Supports with Hydrazone Linkers for Solid-Phase Alkylation of Ketones and Aldehydes

Abstract

A new approach to polymeric supports useful for the immobilization of aldehydes and ketones via hydrazone linkers is reported. The new strategy gives supports with better properties and is effective for the synthesis of all supports previously used for the alkylation of ketones anchored as hydrazones. In contrast to other approaches, the new strategy also provided a polymer with an economical C2 spacer linker. The supports were used for immobilization of ketones 3-pentanone, acetone, N-benzylpiperidone, and aldehydes hexanal and 3-phenylpropanal in the form of their hydrazones. The polymer-supported hydrazones were subjected to alpha-alkylation (LDA/RX) followed by acidic, reductive, or oxidative cleavage/workup procedures to provide alpha-alkylated aldehydes or ketones as well as corresponding primary amines, alcohols, nitriles or acids.

N,N-Dialkylhydrazones in Organic Synthesis. From Simple N,N-Dimethylhydrazones to Supported Chiral Auxiliaries

“…296 The polymers with N,N-dialkylhydrazine functional groups that could be used for binding carbonyl compounds as hydrazones are not available commercially, and therefore, synthesis of polymer-supported hydrazines is a precondition. The supported N,N-dialkylhydrazines have been prepared on Merrifield-type polymers by typical reduction of previously produced N-nitrosoamines, [299][300][301][302][303][304] anchoring protected N,Ndialkylhydrazines, 62,[305][306][307] or the direct functionalization of the polymer with N-alkylhydrazine. 46 The last method is the simplest but may be limited by poor regioselectivity of monalkyl hydrazine alkylation.…”

“…313 Ketone (cyclohexanone, tert-butylcyclohexanone) hydrazones 488 served as protection for the hydrazine group during O-alkylation of hydroxy hydrazines 451 with benzyl chloride and its polymeric analogue, the Merrifield resin (Scheme 90). 62 A highly enantiomerically enriched [6,7]-cis-fused system, 493, was obtained by addition of vinyllithium to the RAMPhydrazone of (η 6 -arene)tricarbonylchromium(0) complex 490 (Scheme 91) followed by acetylation (MeI, CO), methylation with methyl iodide, and allylation. 314 The N,N-dialkylhydrazone group served simultaneously as a heteroaryl activating group and a masked formyl and nitrile group.…”

tert-Butyl Nitrite

“…2 (C) Secondary amines were nitrosated with TBN to give quantitative formation of N-nitrosamine, which were used to prepare hydrazines by reduction with lithium aluminium hydride. 3 (D) Introduction of the oximino group in a-position to the carbonyl group could be achieved by nitrosation with TBN in both acidic and alkaline condition. 4 (E) Cycloalkanes were treated with TBN in the presence of Nhydroxyphthalimide (NHPI) followed by triethylamine to form the oxime, which could be transformed into the lactam with cyanuric chloride via Beckmann rearrangement.…”

1,4‐Conjugate Additions of Methoxyamine and 1,1‐Dimethylhydrazine to Hex‐3‐yne‐2‐one: A Facile Synthesis of Functionalized Isoxazole and Pyrazole Precursors

“…Central to the success of this chemistry was the observation that only the 1,4-conjugate addition reaction was observed when hex-3-yne-2,5-dione (2) was reacted with either methoxyamine or 1,1-dimethylhydrazine. The synthesis of a new hydrazine anchor has recently been reported [7] and our described approach may also have utility in the solid-phase synthesis of these compounds because the reactivity of alkynyl-1,4-diones may help to compensate for the reduced reactivity of polymer-bound reagents. [6] This reactivity may help to reduce the necessity for large excesses of reagents, which are typically used in solid-phase synthesis, and to make these routes also amenable to scaling.…”

“…calcd. for C 7 H 11 NO 3 Preparation of the 3-(N,N-dimethylhydrazone) of 2,3,5-hexanetrione (7). To a solution of 2.21 g (0.02 mol) of hex-3-yne-2,5-dione (2) [6] in 50 mL of carbon tetrachloride, which had been cooled to 210 8C, 1.53 mL (0.02 mol) of 1,1-dimethyl hydrazine in 10 mL of carbon tetrachloride was added over a 15-min period.…”