Investigations into the effectiveness of deuterium as a “protecting group” for C–H bonds in radical reactions involving hydrogen atom transfer

Abstract

Competition experiments have been carried out to determine the extent to which deuterium can be used as a protecting group for carbon-hydrogen bonds in radical-based intramolecular hydrogen atom transfer processes.Translocation of carbon-centred radicals via intramolecular hydrogen atom transfer, in particular from highly reactive aryl and vinyl radicals, represents a popular and powerful method for the remote functionalisation of positions in molecules which would traditionally be regarded as unreactive. 1 High regioselectivity in the hydrogen atom removal/radical generation is of prime importance for such a process to be of synthetic value, and the stereoelectronic desirability for a linear transition state often results in an overwhelming preference for 1,5-hydrogen atom transfer over other possible modes of radical translocation (Scheme 1).Scheme 1 1,5-Hydrogen atom transfer.In certain instances when using radical-based methodology however, hydrogen atom transfer may occur as an unwanted sidereaction. For example, in the total synthesis of the antitumour agent fredericamycin A, 2 Clive et al. found that 1,7-hydrogen atom transfer from an aryl methoxy group (used as a protecting group) to an intermediate vinyl radical occurred after a radical spirocyclisation onto an alkyne. This led to the formation of a substantial quantity of an undesired by-product with the intramolecular hydrogen atom transfer process being found to be competitive with the required quenching of the vinyl radical with triphenyltin hydride. 3 A solution to this problem was found in deuteration of the methyl group, with the primary kinetic isotope effect for deuterium vs. hydrogen atom transfer efficiently retarding the competing side-reaction. 3,4During our initial studies into the radical-based functionalisation of b-amino alcohols, via 1,5-hydrogen atom transfer, 5 we encountered a similar problem. 6 The extent to which deuterium can be used to block intramolecular hydrogen atom transfer is not straightforward to predict, as extremely high kinetic isotope effects have been observed in cases where the predominant mechanism involves quantum mechanical tunneling. 7 Whilst there are many examples of the exploitation of the primary kinetic isotope effect in mechanistic studies, there are relatively few in synthetic applications 8 and hence, we initiated the systematic studies described herein into the effectiveness of deuterium as a "protecting group" for hydrogen atoms bonded to a carbon atom a-to nitrogen. a-Aminoalkyl radicals are valuable reactive intermediates in the preparation of a wide range of amine and amino acid derivatives 9 and their regioselective generation is the key to their effective synthetic use.Competition experiments using two heterocyclic systems were chosen for these studies, in which protecting-radical translocating (PRT) groups 10 were positioned such that 1,5-transfer of hydrogen or deuterium could occur after initial radical generation using standard tin hydride-based methodology. Initial studies were carried out w...

Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles

“…As 1,5-deuterium transfer is known to be slower than 1,5-HAT 53 , the deuterium atom in D -6d blocks the final stages of the folding cascade and redirects the process. It is known that deuterium can be used as a ‘protecting group’ to prevent HAT processes and thus the outcome of the reaction of D -6d lends further support to the importance of such a process in the folding cascades 54 .…”

Synthetic use of the primary kinetic isotope effect in hydrogen atom transfer: generation of α-aminoalkyl radicals

“…The separated organic phase was then dried (magnesium sulfate), filtered and evaporated in vacuo to give 15 (3.47 2,5-Dioxopyrrolidin-1-yl isonicotinate 15 (1.00 g, 4.6 mmol) was added to a stirred solution of sodium borodeuteride (98 atom% D, 760 mg, 18.2 mmol) in ethanol at room temperature and stirring was continued at this temperature for 18 h. The solvent was removed in vacuo and the crude product was partitioned between water (40 cm 3 ) and ethyl acetate (30 cm 3 ), the separated aqueous phase being extracted with ethyl acetate (2 ¥ 30 cm 3 ). The combined organic extracts were dried (magnesium sulfate), filtered and evaporated in vacuo to give 16 ( (14) and 80 (7).…”

“…Reaction at -50 • C. Tributyltin hydride (390 ml, 1.45 mmol) and 2,2¢-azobisisobutyronitrile (70 mg, 0.43 mmol) were added to a stirred, degassed solution of N-(2-iodobenzyl)-2,2dideuteropyrrolidine 19 (210 mg, 0.73 mmol) and acrylonitrile (280 ml, 4.25 mmol) in fluorobenzene (13 cm 3 ), at -50 • C. The reaction mixture was irradiated with a medium pressure mercury vapour lamp for 6 h, with three further aliquots of 2,2¢azobisisobutyronitrile (70 mg, 0.43 mmol) being added after 1, 3.5 and 5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel containing potassium fluoride (10% w/w) (gradient from 100% petroleum ether to 80% petroleum ether-20% ethyl acetate) to give a mixture of 29 and 30 in a 5.7 : 1 ratio (89 mg, 56%) as a colourless oil ( (M-H) + , 5), 162 (100), 92 (24), 91 (83), 65 (10) and 40 (39); m/z (CI) 217 (MH + , 100%), 162 (10), 127 (8), 106 (6), 52 (18) and 77 (7). 23 Methanesulfonyl chloride (1.05 cm 3 , 13.6 mmol) was added dropwise to a stirred solution of 3-bromobut-3-en-1-ol 34 (1.70 g, 11.3 mmol) and triethylamine (1.82 cm 3 , 13.6 mmol) in dichloromethane (38 cm 3 ) at 0 • C. After stirring for a further 1 h at this temperature, water (38 cm 3 ) was added and the separated aqueous phase was extracted with dichloromethane (3 ¥ 22 cm 3 ).…”

“…The combined organic extracts were dried (magnesium sulfate), filtered and evaporated in vacuo to give 33 (2.33 g, 90%) as a pale yellow oil (Found MH + ( 79 Br, CI) 228. (13), 135 (98), 133 (100), 115 (21), 97 (12), 85 (10), 79 (10), 71 (4), 53 (7) and 51 (7). (Note: Although the preparation of 33 has been reported, 23 no isolation method or characterisation was presented.…”

“…18 We therefore felt it appropriate and important to assess the efficiency of deuterium as a "blocking group" in synthetically useful scenarios in a systematic manner. 7 Our interest in the generation of a-aminoalkyl radicals via 1,5-hydrogen atom transfer highlighted studies carried out by Undheim et al which investigated the radical-based aalkylation of a number of nitrogen-containing heterocycles. Of particular relevance was the remote functionalisation of N-(2iodobenzyl)pyrrolidine 18 shown in Scheme 10.…”