Acid chloride, alcohols from reduction

Optically pure 1,2-diols.1 The acyllactones 1, obtained by reaction of a Grig-nard reagent with the acid chloride derived from (R)-( -)- or S-( + )-glutamic acid, are reduced by lithium tri-sec-butylborohydride almost exclusively to syn-alcohols (2), regardless of the nature of the R group. In contrast, reduction of 1 with sodium... 

The at complex from DIB AH and butyllithium is a selective reducing agent.16 It is used tor the 1,2-reduction of acyclic and cyclic enones. Esters and lactones are reduced at room temperature to alcohols, and at -78 C to alcohols and aldehydes. Acid chlorides are rapidly reduced with excess reagent at -78 C to alcohols, but a mixture of alcohols, aldehydes, and acid chlorides results from use of an equimolar amount of reagent at -78 C. Acid anhydrides are reduced at -78 C to alcohols and carboxylic acids. Carboxylic acids and both primary and secondary amides are inert at room temperature, whereas tertiary amides (as in the present case) are reduced between 0 C and room temperature to aldehydes. The at complex rapidly reduces primary alkyl, benzylic, and allylic bromides, while tertiary alkyl and aryl halides are inert. Epoxides are reduced exclusively to the more highly substituted alcohols. Disulfides lead to thiols, but both sulfoxides and sulfones are inert. Moreover, this at complex from DIBAH and butyllithium is able to reduce ketones selectively in the presence of esters. 

Reduction of aldehydes and ketones allylic alcohols from a, 3-unsaturated aldehydes and ketones alcohols from carboxylic acid chlorides amines from aliphatic azides.21 ... 

The procedure is to pass purified hydrogen through a hot solution of the pure acid chloride in toluene or xylene in the presence of the catalyst the exit gases are bubbled through water to absorb the hydrogen chloride, and the solution is titrated with standard alkali from time to time so that the reduction may be stopped when the theoretical quantity of hydrogen chloride has been evolved. Further reduction would lead to the corresponding alcohol and hydrocarbon ... 

The mechanism of this Grignard reaction is similar to that of L1AIH4 reduction. The first equivalent of Grignard reagent adds to the acid chloride, loss of (T from the tetrahedral intermediate yields a ketone, and a second equivalent of Grignard reagent immediately adds to the ketone to produce an alcohol. 

The facile homogeneous catalysed reduction of acid chlorides to alcohols has many advantages over reduction with sodium borohydride in hydroxylic solvents where rapid reaction of the acid chloride with the solvent can occur [10]. The procedure has been incorporated into a simple one-pot conversion of aroyl chlorides into the corresponding benzyl chlorides (Scheme 11.1) under liquidrliquid or solid-liquid two-phase conditions [11], The reduction of a limited number of aryl compounds was reported with ca. 70% overall yields, although poorer yields result from the reduction of 4-nitro-, 2-cyano- and 2,4-dichlorobenzoyl chlorides, and the reduction failed completely with terphthaloyl chloride and with its 2,3,5,6-tetrafluoro derivative [11]. 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

Methylamine occurs in herring brine 2 in crude methyl alcohol from wood distillation,3 and in the products obtained by the dry distillation of beet molasses residues.4 It has been prepared synthetically by the action of alkali on methyl cyanate or iso-cyanurate 5 by the action of ammonia on methyl iodide,6 methyl chloride,7 methyl nitrate,8 or dimethyl sulfate 9 by the action of methyl alcohol on ammonium chloride,10 on the addition compound between zinc chloride and ammonia,11 or on phos-pham 12 by the action of bromine and alkali on acetamide 13 by the action of sodamide on methyl iodide 14 by the reduction of chloropicrin,15 of hydrocyanic or of ferrocyanic acid,16 of hexamethylenetetramine,17 of nitromethane,18 or of methyl nitrite 19 by the action of formaldehyde on ammonium chloride.20... 

Numerous methods for the synthesis of salicyl alcohol exist. These involve the reduction of salicylaldehyde or of salicylic acid and its derivatives. The alcohol can be prepared in almost theoretical yield by the reduction of salicylaldehyde with sodium amalgam, sodium borohydride, or lithium aluminum hydride by catalytic hydrogenation over platinum black or Raney nickel or by hydrogenation over platinum and ferrous chloride in alcohol. The electrolytic reduction of salicylaldehyde in sodium bicarbonate solution at a mercury cathode with carbon dioxide passed into the mixture also yields saligenin. It is formed by the electrolytic reduction at lead electrodes of salicylic acids in aqueous alcoholic solution or sodium salicylate in the presence of boric acid and sodium sulfate. Salicylamide in aqueous alcohol solution acidified with acetic acid is reduced to salicyl alcohol by sodium amalgam in 63% yield. Salicyl alcohol forms along with -hydroxybenzyl alcohol by the action of formaldehyde on phenol in the presence of sodium hydroxide or calcium oxide. High yields of salicyl alcohol from phenol and formaldehyde in the presence of a molar equivalent of ether additives have been reported (60). Phenyl metaborate prepared from phenol and boric acid yields salicyl alcohol after treatment with formaldehyde and hydrolysis (61). 

A more recent example, which involves an enantiomerically pure compound, reverts to the original lead by incorporating a hydroxyl group on the benzylic carbon. Preparation of this close relative of ibutilide (5-3) uses the same starting material. Acylation of w-dibutylamine with the acid chloride from the treatment of (6-1) with tert-butylcarbonyloxy chloride leads to the amide (6-2). Reduction of the carbonyl group in this compound with chloro-(+)-diisopropylcamphemyl borane (DIPCl) proceeds to afford the R alcohol (6-3) in high enantiomeric exess. 

Naphthaldehyde has been made from a-naphthonitrile by reduction with stannous chloride, and from naphthalene by the action of aluminum chloride, hydrogen cyanide, and hydrochloric acid. The best preparation is the Sommelet reaction from a-chloro- or a-bromomethylnaphthalene and hexamethylenetetramine in aqueous alcohol is.is. .is.w or glacial acetic acid. This method has been improved in the present procedure by the use of 50% acetic acid as solvent. 

Carboxylic acids are considerably less reactive than acid chlorides, aldehydes and ketones towards reduction. They cannot be reduced by catalytic hydrogenation or sodium borohydride (NaBH4) reduction. They require the use of a powerful reducing agent, e.g. LiAlH4. The reaction needs two hydrides (H ) from LiAlITj, since the reaction proceeds through an aldehyde, but it cannot be stopped at that stage. Aldehydes are more easily reduced than the carboxylic acids, and LiAltLj reduces all the way back to 1° alcohols. 

Notes A reducing agent. Alcohols are generated from aldehydes, ketones, esters and acid chlorides. Nitriles can be converted to aldehydes. Tosylates will be replaced by -H halides are inert. Amides are reduced to amines. Reduction of lactones can provide a useful synthetic strategy ... 

Reduction of halides.1 The reagent prepared from NaBH3CN and SnCl2 in a 2 1 ratio does not reduce primary or secondary alkyl halides or aryl halides in ether at 25°, but does reduce tertiary, allyl, and benzyl halides. It is thus comparable to NaBH3CN-ZnCl2 (12, 446). Aldehydes, ketones, and acid chlorides are reduced to alcohols, but esters and amides are inert. 

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