Modulating NHC catalysis with fluorine

Abstract

SummaryFluorination often confers a range of advantages in modulating the conformation and reactivity of small molecule organocatalysts. By strategically introducing fluorine substituents, as part of a β-fluoroamine motif, in a triazolium pre-catalyst, it was possible to modulate the behaviour of the corresponding N-heterocyclic carbene (NHC) with minimal steric alterations to the catalyst core. In this study, the effect of hydrogen to fluorine substitution was evaluated as part of a molecular editing study. X-ray crystallographic analyses of a number of derivatives are presented and the conformations are discussed. Upon deprotonation, the fluorinated triazolium salts generate catalytically active N-heterocyclic carbenes, which can then participate in the enantioselective Steglich rearrangement of oxazolyl carbonates to C-carboxyazlactones (e.r. up to 87.0:13.0).

Advances in the Synthesis of Methylated Products through Indirect Approaches

“…In 2013, Gilmour and Rey reported the synthesis of the methylated intermediates (106, 108,S cheme 14) throught he reductiono ft he primary bromides (105, 107)w ith H 2 (Pd/C). [41] Using alkyl and aryl bromides as the substrates, Grubbsa nd co-workers developed ac atalytic method using i-PrOHa st he hydrogen source.T able 8d emon-strates some representativee xamples from alkyl bromides. [42] Ther esults for 110 indicate that the chemistry proceeded well with both the chloride substrate and the bromides ubstrate,w hile at osylate analogue was stable under the conditions.T he chemistry of 111 showcases ap otential applicationo ft his methodology:a nA ppel reaction of ac hiral amino alcohol, followed by the reductionw hich produces the relevant chiral amine.…”

“…In 2013, Gilmour and Rey reported the synthesis of the methylated intermediates ( 106 , 108 , Scheme ) through the reduction of the primary bromides ( 105 , 107 ) with H 2 (Pd/C) …”

Synthesis of Fluoropyrrolidines and (Fluoroalkyl)pyrrolidines

“…Of note, the intermediate 2-(trifluoromethyl)pyrrolidinone 49 was involved in the synthesis of NHC pre-catalyst 51 of interest in the Steglich rearrangement of oxazolyl carbonate derivatives. 27 Asymmetric synthesis of functionalized 2-(trifluoromethyl)prolines 56 and 57 has been explored for the preparation of analogues of amino acids in order to study the influence of the CF 3 group on the conformation of resulting peptides. The most popular synthesis uses 3-allyl-3-(trifluoromethyl)morpholin-2-one 54, obtained from ethyl 3,3,3trifluoropyruvate (52) and phenylglycinol 53, as the pyrrolidine precursor (Scheme 15).…”

Enhancement of stereoselectivities in asymmetric synthesis using fluorinated solvents, auxiliaries, and catalysts

“…Another example of NHC catalyst 51 was developed for asymmetric Steglich rearrangement of oxazolecarbonates (Scheme 39). 57 A couple of uorines located on each position of Cinchona alkaloids are versatile catalysts for asymmetric synthesis because of the remarkable performance in transformations, the natural abundance, and commercial availability. Gilmour and co-workers designed C9-substituted alkaloid catalysts 52 expecting uorine stereoelectronic and electrostatic effects for conformational control (Scheme 40).…”