Alkali Metal/Ammonia Reductions of Ketones Should Be Run in the Presence of Ammonium Ion

Abstract

SummaryReduction of ( +)- [3,3-2H,]camphor ([3,3-,H2]1) with lithium, sodium or potassium in ammonia and a co-solvent gave: 1) the enolate of [3,3-2H2]1 and the alcoholates of (-)- [2,3,3-2H3]isoborneol ([2,3,3-2H3]2) and ( +)- [2,3,3-2H3]borneol ([2,3,HJ3); 2) the alcoholates of [3,3-2H,] [3,3-2H,]3) under certain conditions. Different values for these ratios were found in the reductions with each metal, all of which corresponded to low overall diastereoselectivities. Reactions 1 and 3 persisted when the reductions were carried out in ammonia/water/co-solvent mixtures and the enolate formed via reaction 1 was protonated and the resulting [end0-3-~H]1 recycled. Reaction 2 cannot be monitored under these conditions. Reactions 1 and 3, and by inference also reaction 2, were almost completely suppressed when analogous reductions were carried out in the presence of ammonium chloride, [3,3-,H2]2 and [3,3-2H,]3 being obtained almost exclusively, in a 6 :94 ratio, with all three metals. A parallel reduction of 1 afforded 2 and 3 in a 6 : 94 ratio. It is proposed that the mechanism outlined in House [l] was dominant when, and only when, ammonium ion was the proton source; it may have competed when water was the proton source.

The Stereochemical Outcomes – the Isoborneol/Borneol Ratios – in Lithium, Sodium and Potassium/Ammonia Reductions without a Proton Source of the Enantiomers and the Racemate of Camphor Differ Strongly

“…This I discuss below. We recently reported independent evidence for precisely such a bimolecular step, using (1 R)- [3, 3-2H2]-1 as the substrate [4]. The bimolecular reaction is either a major or the main reaction under the conditions used by Rassat et al and Huffman et al Our experiments suggest that the most likely mechanism is ketyl disproportionation, i.e.…”

“…The disproportionations probably take place between ketyls that are tightly bound to metal cations [4]. This suggests that xl/yl, x21y2 and x3/y3 are different for each metal.…”

“…Our experiments with (lR)- [3,3-2H2]-l showed that there is a further, but minor, competing reaction with the medium [4].…”

“…These experiments probably involve mainly single cycles of the overall reactions 1 and 1 to 4 (see below) in which the protonations of the enolates regenerate the substrates which can then be isolated. Tabfe In our parallel experiments with ( 1 R)- [3, 3-2H2]-1 [4], the substrate rapidly lost its labels through base-catalyzed exchanges with the ammonia. This explains why reductions with excess metal under these conditions proceed until the substrates are completely transformed into the corresponding alcoholates.…”

“…165-167", 95% pure, [n]8=Ok0.05° (c= 10.8, EtOH)6). Experimental and analytical procedures correspond to those in [4].…”