Hydrides synthesis from acids

Acid chlorides are reduced by organotin monohydrides as easily as aliphatic bromides. Benzaldehyde is reduced by triphenyltin hydride (4S) and tri-n-butyltin hydride (J2). Inasmuch as aldehydes are reduced quite slowly by the monohydrides this reaction would appear to constitute a convenient method for their synthesis from acid chlorides. However, the reaction product mixture invariably contains ester as well as aldehyde. In the case of benzoyl chloride, for example, reduction with tri- -butyltin hydride in ether provided benzaldehyde (54%) as the major reduction product in the absence of solvent benzyl benzoate (58%) predominated. The reaction sequence (57-60) has been postulated to account for the products formed (32). 

Although the synthesis of acid 3 developed by our Medicinal Chemistry colleagues proceeded in a single step from commercial starting materials the yield was modest, and there were significant safety concerns about the use of sodium hydride in DMF on a larger scale. After some experimentation it was found that use of the ester in conjunction with just 1 equiv of KHMDS as base gave a clean... 

The methoxy substituents on each azulenyl ring stabilized the carbocation effectively (12). The reaction of 6-methoxyazuiene (13) with 6-methoxyazulene-1-carbaldehyde (12) in acetic acid did not afford the condensation product 14, because of low reactivity of these compounds and lack of stability of product 14 under the reaction conditions. However, a high-pressure reaction (10 kbar) afforded the desired hydro derivative 14 in 6% yield. Synthesis of the cation 15+ was accomplished by hydride abstraction from the hydro derivative 14 (Figure 9). 

Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler-Clarke reductive alkylation of amines. 

LVI) was proved 54) by Esohweiler-Clarke methylation to methyl-holaphylline and was further confirmed by a synthesis from pregnenolone (LIX) via 3 8-tosyloxy-20-oximinopregn-5-ene (LX) which on treatment with sodium azide in methanol yielded a mixture of 3 3-azido-20-oximino-pregn-5-ene (LXI) and the 3a,6a-cyclo-6 -azido isomer. Selective reduction with lithium aluminum hydride followed by acid hydrolysis yielded holaphyllamine along w ith its 3,5-cyclo isomer which could be separated by chromatography (55). 

D. Basavaiah and co-workers achieved the simple and convenient stereoselective synthesis of ( )-a-methylcinnamic acids via the nucleophilic addition of hydride ion from sodium borohydride to acetates of Bayiis-Hillman adducts (methyl 3-acetoxy-3-aryl-2-methylenepropanoates), followed by hydrolysis and crystaliization. The potential of this methodology was demonstrated in the synthesis of ( )-p-(myristyloxy)-a-methylcinnamic acid, which is an active hypolipidemic agent. 

Geissoschizoline [= pereirine (106)] is an indoline derivative with a Strychnos carbon keleton. The complete structure was elucidated by partial synthesis from (—)-akuammicine (117) the latter on reduction with zinc and acid forms 2/ ,16jS-dihydroakuammicine which on lithium aluminium hydride reduction followed by catalytic hydrogenation gives geissoschizoline (106). The base can also be obtained by degradation of the strychnine derivative (1IS). " ... 

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of BFg-EtaO or of HC104, jS-phenylpropio-phenone (76) was obtained as by-product its formation is due to hydride transfer to the conjugate acid of chalcone (75), which is the acceptor (experimental data and theoretical calculations show that chalcones are protonated at the oxygen atom). Balaban obtained a 72% yield in the conversion 70 -> 37 using as acceptor chalcone and as catalysts perchloric or sulfuric acids (i.e., 75). The formation of j8-phenylpropiophenone (76) in the Chichibabin synthesis of pyridines from chalcones and ketones in the presence of ammonium acetate, and in the pyrimidine synthesis from chalcones and amidines is undoubtedly due to a similar hydride transfer. 

Sparteine [(— )-34] is an alkaloid frequently occurring in Fabiaceae. It is commercially available, mostly as the sulfate, and comparatively inexpensive, so there is no need for synthesis. The other enantiomer, named (- j-pachycarpine [(+ )-34], can be obtained by partial synthesis from racemic lupanine, involving resolution with camphorsulfonic acid and lithium aluminum hydride reduction28. 

Among the ethers of prolinol, (5)-2-methoxymethylpyrrolidinc [SMP, (S)-10] has found most applications. It is readily prepared from prolinol by the normal sodium hydride/iodo-methane technique9,13 (sec also Section 2.3. for O-alkylations of other amino alcohols) and is also commercially available. An improved synthesis from proline avoids the isolation of intermediates and gives the product (which is highly soluble in water) by continuous extraction14. SMP has been used as the lithium salt in deprotonation and elimination reactions (Section C.) and as an auxiliary for the formation of chiral amides with carboxylic acids, which in turn can undergo carbanionic reactions (Sections D.l.3.1.4., D.l. 1.1.2.. D.l. 1.1.3.1., in the latter experimental procedures for the formation of amides can be found). Other important derivatives are the enamines of SMP which are frequently used for further alkylation reactions via enolates (Sections D.l.1.2.2.. where experimental procedures for the formation of enamines are... 

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