Nitriles from organometallic reagents

C. Montagne, M. Shipman, Synlett 2006, 2203-2206. Modified Bucherer-Bergs reaction for the one-pot synthesis of 5,5 -disubstituted hydantoins from nitriles and organometallic reagents. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

Not only alkenes and arenes but also other types of electron-rich compound can be oxidized by oxygen. Most organometallic reagents react with air, whereby either alkanes are formed by dimerization of the metal-bound alkyl groups (cuprates often react this way [80]) or peroxides or alcohols are formed [81, 82]. The alcohols result from disproportionation or reduction of the peroxides. Similarly, enolates, metalated nitriles, phenolates, enamines, and related compounds with nucleophilic carbon can react with oxygen by intermediate formation of carbon-centered radicals to yield dimers (Section 5.4.6 [83, 84]), peroxides, or alcohols. The oxidation of many organic compounds by air will, therefore, often proceed faster in the presence of bases (Scheme 3.21). 

Discussed in this chapter, for the most part, are documented cases where complexes derived from (one or more equivalents of) a Grignard or organolithium reagent, in combination with a copperfl) salt, have been used to add to an aldehyde, ketone, imine, amide or nitrile moiety. In the majority of examples, the key issue is one of stereocontrol. Hence, where available, data within the organocopper manifold versus those for other organometallic reagents are provided for comparison. 

Swamer et a/.246 described the formation of l,2-dihydro-2,4,6-triphenyl-1,3,5-triazine (154b) (yield 14%) from benzonitrile in the presence of sodium hydride and proposed a detailed mechanism (Scheme 8), which is, presumably, valid for all trimerizations of nitriles in the presence of organometallic reagents.243-246... 

Primary amines have been obtained from nitriles in high yield by the successive addition of organometallic reagents according to Scheme 2 ... 

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

Please note that this whole section—indeed all of the chapter so far—relates to the C-C disconnection between the carbonyl group and whatever is joined to it 2. The nucleophilic reagent is an organometallic derivative of Li, Cu or Mg and the electrophile is an acid chloride, a tertiary amide or a nitrile. In the next section we disconnect the C-C bond one further from the carbonyl. 

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