A Simple One-pot Organometallic Formylation/Trapping Sequence UsingN-Formylcarbazole

Abstract

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,

A Concise Enantioselective Synthesis of the Chlorosulfolipid Malhamensilipin A

“…We began our studies with unsaturated ester 13 , which underwent a slow dihydroxylation (>95% ee) under the modified Sharpless dihydroxylation conditions reported by Bittman for a similar enyne ester substrate (Scheme ). Semireduction of the alkyne using Lindlar’s catalyst was unreliable, but P-2 Ni/ethylenediamine cleanly afforded ( Z )-allylic alcohol 14 .…”