The enantioselective synthesis of acyclic pyrrole, indole and other N-carbazole carbinols via ligand-mediated addition of lithium carbazolates to aldehydes, together with studies into their catalytic enantioselective synthesis using substoichiometric base and ligand, are reported. The subsequent exploitation of the resulting stereocentre as a controlling element in 1,3-syn- and anti-selective reduction of beta-ketones and elaboration to homoallylic alcohols is also described.
Treatment of a range of sp 3 -, sp 2 -and sp-nucleophiles with N-formyl carbazole leads to the formation of the metastable anionic carbazole carbinols. In the presence of a second nucleophilic reagent such as phosphonoacetate or an organolithium, these collapse on warming to the aldehyde which is trapped in situ to afford the a,b-unsaturated esters or secondary carbinols respectively.Methods for the formylation of organometallic reagents 1,2 have received much attention over the years due to the obvious synthetic utility of the one carbon homologation procedure and the wealth of reactions possible with the aldehyde product. 3,4 For sp 3 -, sp 2 -or sp-carbanions, the formylating agent is invariably based around an Nformylated amine, which is not only reactive towards the organometallic, but the resulting anionic carbinol is stable until dilute acidic work-up and only then is the aldehyde released. Reports by our group 5 and others 6 have revealed that while N-carbinols of pyrrole are stable in their neutral state, they may be collapsed back to the parent carbonyl compound under basic conditions. This metastability lends itself to the possibility of a one-pot multicomponent formyl transfer/aldehyde trapping procedure 7,8 using Nformyl heterocycles as the reagent (Scheme 1) and herein we wish to report our findings. Scheme 1Initially, N-formylpyrrole and N-formyl-3-methylindole were considered as potential candidates. However in the former case, synthesis was a major set-back and in the latter, the unpleasant odour associated with the skatole starting material focused our attention on other formylation sources. N-Formylcarbazole 2 was subsequently identified as the reagent of choice. The parent heterocycle is cheap and the synthesis can be efficiently carried out on a large scale by simply boiling carbazole 1 in formic acid for 8 hours and the product is isolated by crystallization (Scheme 2). 9 Scheme 2With multigram quantities of N-formylcarbazole 2 in hand, the sequential formylation/aldehyde trapping sequence was investigated. The addition of a range of nucleophiles to 2 was carried out at -78 °C, followed by the addition of Wadsworth-Horner-Emmons reagent. The resulting a,b-unsaturated esters were obtained in reasonable to good yields over the two steps (Scheme 3,
Reactions of organo-metal compounds Reactions of organo-metal compounds O 0350A Simple One-Pot Organometallic Formylation/Trapping Sequence Using N-Formylcarbazole. -The reaction of N-formyl carbazole (I) with organometallic reagents generates metastable anionic carbazole carbinol salts. These salts release aldehydes which are trapped in situ by a second nucleophile forming α,β-unsaturated esters (IV) and (VII) or the alcohols (X). -(DIXON*, D. J.; LUCAS, A. C.; Synlett 2004, 6, 1092-1094; Univ. Chem. Lab., Cambridge Univ., Cambridge CB2 1EW, UK; Eng.) -Mais 38-063
Pyrrole derivatives R 0120Ligand-Mediated Enantioselective Addition of Lithium Carbazolates to Aldehydes. -The addition of lithium pyrrolates and indolates (I) towards aldehydes (II) proceeds with moderate to good enantioselectivity in the presence of chiral diphenyldimethoxyethane (PDME) ligand. The so-formed α-pyrrolylmethanol functionality is successfully applied as stereodirecting group in the hydrogenation of ketone (IIId). First examples of a catalytic and an asymmetric catalytic version of the pyrrolate addition reaction are presented for derivative (IX). -(SCOTT, M. S.; LUCAS, A. C.; LUCKHURST, C. A.; PRODGER, J. C.; DIXON*, D. J.; Org. Biomol. Chem. 4 (2006) 7, 1313-1327; Sch. Chem., Univ. Manchester, Manchester M13 9PL, UK; Eng.) -Mischke 34-108
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