Aldehyde synthesis, from Grignard reagent

Aldehyde synthesis from Grignard reagents and trialkyl orthoformate see also Bouveault (see 1st edition). 

Acetic formic anhydride has been prepared by the reaction of formic acid with acetic anhydride2 3 and ketene,4,5 and of acetyl chloride with sodium formate.6 The present procedure is essentially that of Muramatsu.6 It is simpler than others previously described and gives better yields. It is easily adapted to the preparation of large quantities, usually with an increase in yield. Acetic formic anhydride is a useful intermediate for the formyl-ation of amines,3,7 amino acids,8,9 and alcohols,2,10 for the synthesis of aldehydes from Grignard reagents,11 and for the preparation of formyl fluoride.12... 

Preparation of the aldehyde required for the synthesis of cyclothiazide (182) starts by carbonation of the Grignard reagent obtained from the Diels-Alder adduct (186) from allyl bromide and cyclopentadiene.The resulting acid (187) is then converted to the aldehyde (189) by reduction of the corresponding diethyl amide (188) with a metal hydride. 

There is a short cut in the synthesis. The cyano-amlne (13), available from aldehyde (12), reacts with a Grignard reagent with loss of cyanide to give (9) directly. 

Trialkylsilyl groups have a modest stabilizing effect on adjacent carbanions (see Part A, Section 3.4.2). Reaction of the carbanions with carbonyl compounds gives (3-hydroxyalkylsilanes. (3-Hydroxyalkylsilanes are converted to alkenes by either acid or base.270 These eliminations provide the basis for a synthesis of alkenes. The reaction is sometimes called the Peterson reaction.211 For example, the Grignard reagent derived from chloromethyltrimethylsilane adds to an aldehyde or ketone and the intermediate can be converted to a terminal alkene by acid or base.272... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

As mentioned in Section 10.6.2, synthesis of 1-hydroxyethylene peptides can be initiated by adding a ferf-butoxycarbonyl N-protected a-amino aldehyde to an optically active Grignard reagent (Scheme 7)J11-13 This reaction affords a diastereomeric mixture of the C4 epimers of the hydroxy ether in good yields. In most cases the mixture is enriched in the 45-epimer and the epimers are readily separable. The yields and the ratios of the resulting 45- and 4R-epimers obtained from several examples of this reaction are summarized in Table 1. When this reaction was attempted with the aldehyde prepared from Aa,Ae-bis-tert-butoxycarbonyl-protected Lys, the desired product was not obtained. The anion of the Lys Ne-tert-butoxy-carbonylamino group probably reacts with the aldehyde to form a cyclic aminol that does not... 

Bicyciic methy/enecyclopentanes. Trostand Chan2 have extended their synthesis of mcthylenecyclopentanes by cycloaddition of trimethylenemethanepalladium complexes to alkenes (9,454-455J3 to an intramolecular [3 + 2] cycloaddition to give bicyciic mcthylenecyclopentanes. The substrates (2) can be prepared by reaction of Ihc Grignard reagent prepared from 2-bromo-3-(trimethylsilyl)propene (1) with a suitable bifunctional aldehyde (equation I). 

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