Carboxylates reaction with nitriles

If 4-(ethoxymethylene)-2-phenyl-5(47/)-oxazolone 403 is used as the dipolar-ophile, reaction with nitrile oxides yields cycloadducts 682 with reversed regio-chemistry. Further reaction of 682 can then yield 4-aminoisoxazoline-4-carboxylic acids 683 or 4-amino-3-arylisoxazoles 684 depending on the reaction conditions... 

The reactions of Grignard reagents with aldehydes and ketones give alcohols, reaction with acid chlorides and esters give tertiary alcohols, reaction with carbon dioxide to give carboxylic acids, reaction with nitriles give ketones, and reaction with epoxides give alcohols. 

Anions of type (4), for example (7), react with carbon dioxide at —70° to give 1,3-dithianes of a-keto carboxylic acids (11) in 70-75% yield. The reaction of carboxylic acid derivatives is more complex, but the reaction with nitriles to give 1,3-dithianes of 1,2-diketones such as (12) usually proceeds without complication.4... 

When the reactivity of reactant (R-CH2-X) is relatively high, the condensation reactions take place more easily than the degradation reactions. As a result, the selectivity to the condensation products becomes high. This is the case of the reaction with aldehydes or ketones. The reaction with carboxylic acids and esters is more difficult and the reaction with nitriles is the most difficult especially in view of the selectivity based on HCHO. 

C.iii. Reaction with Nitriles. Nitriles are carboxylic acid derivatives and react with Grignard reagents (also sec, 8.2.C).l Initial attack generates an intermediate iminium salt that can be hydrolyzed (with loss of ammonia) to the corresponding ketone. HO The best yields are obtained with aryl nitriles, and this is illustrated... 

More recently, Zibinsky and Fokin obtained synthetically useful Rh (11) carbenes from7V-(l,2,4-triazolyl)-substituted 1,2,3-triazoles and Rh(II) carboxylates [45], The resulting carbenes provided ready asymmetric access to secondary homoaminocy-clopropanes 68 (80-95% ee, dr >20 1) via reactions with olefins and also engaged in efficient transannulation reactions with nitriles (Scheme 5.47). 

Some of the physical properties of fatty acid nitriles are Hsted in Table 14 (see also Carboxylic acids). Eatty acid nitriles are produced as intermediates for a large variety of amines and amides. Estimated U.S. production capacity (1980) was >140, 000 t/yr. Eatty acid nitriles are produced from the corresponding acids by a catalytic reaction with ammonia in the Hquid phase. They have Httie use other than as intermediates but could have some utility as surfactants (qv), mst inhibitors, and plastici2ers (qv). 

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

The nitrile may best be saponified with methyl alcoholic potash while heating to 190° to 200°C with application of pressure. After the methyl alcohol has evaporated the salt is introduced into water and by the addition of dilute mineral acid until the alkaline reaction to phenolphthalein has just disappeared, the amphoteric 1-methyl-4-phenyl-piperidine-4-carbOxylic acid is precipitated while hot in the form of a colorless, coarsely crystalline powder. When dried On the water bath the acid still contains 1 mol of crystal water which is lost only at a raised temperature. The acid melts at 299°C. Reaction with ethanol yields the ester melting at 30°C and subsequent reaction with HCI gives the hydrochloride melting at 187° to 188°C. 

Carboxylic acids can be prepared from nitriles by reaction with hot aqueous acid or base by a mechanism that we ll see in Section 20.9. Since nitriles themselves are usually made by Sts 2 reaction of a primary or secondary7 alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitiile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr —> RC=N RC02H). 

Nitriles are analogous to carboxylic acids in that both have a carbon atom with three bonds to an electronegative atom, and both contain a tt bond. Thus, some reactions of nitriles and carboxylic acids are similar. Both kinds of... 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

The hydrolysis of nitriles to carboxylic acids is one of the best methods for the preparation of these compounds. Nearly all nitriles give the reaction, with either acidic or basic catalysts. Hydrolysis of cyanohydrins, RCH(OH)CN, is usually carried out under acidic conditions, because basic solutions cause competing reversion of the cyanohydrin to the aldehyde and CN . However, cyanohydrins have been hydrolyzed under basic conditions with borax or alkaline borates. ... 

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). 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

Optically active 3-arylisoxazoline-5-carboxylic acid derivatives 403 or 404 have been, prepared by the reaction of (S)- or (/ )-3-acryloyl-4-benzyl-5,5-dimethyloxazolidin-2-one (405 or 406) with nitrile oxides, obtained from benzo-hydroximoyl chloride and its substituted derivatives in the presence of a catalytic amount of metal salt, for example, Yb(OTf)3 (445). This procedure improves the diastereoselectivity of compounds 403 or 404, which are industrially useful as intermediates for various drugs and agrochemicals. It also enables the amount... 

Dehydration (cf., 6, 648). A reagent (1), prepared in situ from (C6H5),PO and Tf20 in the molar ratio 2 1, effects dehydration, usually at 25°, of amides or oximes to nitriles in >90% yield. It also effects condensation of acids and amines to form amides. The reaction of an aryl carboxylic acid with an o-phenylenediamine promoted by 1 provides 2-arylbenzimidazoles in >80% yield (equation I). If the... 

The nitrile produced in the above reaction can be converted into the corresponding carboxylic acid by acid hydrolysis, l.e. reaction with water catalysed by hydrogen ions from the acid. 

The basic hydrolysis (reaction with water) of a nitrile (R-CN) followed by acidification yields a carboxylic acid. In general, an reaction (nucleophilic substitution) of an alkyl halide is used to generate the nitrile before hydrolysis. Figure 12-12 illustrates the formation of a carboxylic acid beginning with an alkyl halide. 

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