Reduction, acid chlorides amides

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

Reactions of the carboxyl group include salt and acid chloride formation, esterification, pyrolysis, reduction, and amide, nitrile, and amine formation. Salt formation occurs when the carboxyUc acid reacts with an alkaline substance (22)... 

The in-out bicyclic amines prepared by Simmons and Park bear a remarkable semblance to the cryptands but lack the binding sites in the bridges. As a result, these molecules interact with electrophiles in a fashion similar to other tertiary amines and generally do not exhibit strong interactions with alkali or alkaline earth metal ions. The in-out bicyclic amines are prepared by reaction of the appropriate acid chlorides and amines in two stages to yield the macrobicyclic amine after reduction of the amidic linkages. A typical amine is shown above as compound 18. 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

A substituted benzoic acid serves as precursor for the nontricyclic antidepressant bipena-mol (175). Selective. saponification of ester 171 afford.s the half-acid 172. Reaction of the acid chloride derived from this intermediate (173) with ammonia gives the amide 174. Reduction of the last by means of lithium aluminum hydride gives bipenamol (175) [44]. 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Anhydrides are reduced with relative ease. McAlees and McCrindle 20) established the following increasing order of difficulty for various carbonyls acid chlorides > aldehydes, ketones > anhydrides > esters > carboxylic acids > amides. Reduction may proceed by 1,2-addilion of hydrogen or by cleavage of an oxygen-carbonyl bond. If 1,2-addition to the carbonyl occurs, as in the presence of strong protic acids over palladium, 1,1-diesters are formed by acylation 26). 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Rearrangement reaction, 138 Reducing sugar, 992 Reduction, 229. 348 acid chlorides, 804 aldehydes, 609-610. 709 aldoses, 992 alkene, 229-232 alkyne, 268-270 amides, 815-816 arenediazonium salt, 943 aromatic compounds and, 579-580... 

An alternative method for the preparation of AL(l-alkoxylalkyl)amides is the sodium borohy-dride reduction of A -acylimidates. Acyclic A-acylimidates are conveniently obtained by reaction of an acid chloride with an imidate47 in the presence of triethylamine. For acid-labile carboxylic acids a mild one-pot procedure has been developed48. 

Compared with aldehydes and ketones, carboxylic acids and their derivatives are less reactive toward reduction. Nevertheless, it is still possible to reduce various acid derivatives in aqueous conditions. Aromatic carboxylic acids, esters, amides, nitriles, and chlorides (and ketones and nitro compounds) were rapidly reduced by the Sml2-H20 system to the corresponding products at room temperature in good yields... 

A carboxylic acid group may be introduced into the 2-position of dibenzofuran by Friedel-Crafts reaction with 2,2-dichloro-l,3-benzodioxole (catechol dichloromethylene ether) and hydrolysis of the resultant ester. Similarly, reaction with methylphenylcarbamoyl chloride produces the 2-(N-methyl-yV-phenylcarboxamide) or the 2,8-disubstituted derivative under more stringent conditions. Controlled reduction of these amides with lithium aluminum hydride supplies the corresponding aldehydes. ... 

Alternatively, the imide-acid chloride is reacted with methanol to give the imide ester which, after borohydride reduction and triethylsilane/trifluoroacetic acid treatment, furnishes the bicyclic lactam 6 as a racemate. The latter is acylated with either propanoyl chloride or 3-phcnylpropanoyl chloride and the resulting amides 7 deprotonated and alkylated with (bro-momethyljbenzene or iodomethane, respectively, to give the major alkylation products 8 with d.r. >98 2 and in 65% yield3. 

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. 

The hrst step in the preparation of the antidepressant maprotiline (33-5) takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of (30-1) with ethyl acrylate and a relatively mild base leads to the Michael adduct saponihcation of the ester group gives the corresponding acid (33-1). The ketone group is then reduced by means of zinc and ammonium hydroxide. Dehydration of the hrst-formed alcohol under acidic conditions leads to the formation of fully aromatic anthracene (33-2). Diels-Alder addition of ethylene under high pressure leads to the addition across the 9,10 positions and the formation of the central 2,2,2-bicyclooctyl moiety (33-3). The hnal steps involve the construction of the typical antidepressant side chain. The acid in (33-3) is thus converted to an acid chloride and that function reacted with methylamine to form the amide (33-4). Reduction to a secondary amine completes the synthesis of (33-5) [33]. 

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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