Halides via nitriles

Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

Carboxylic acids from halides via nitriles Labeled compounds... 

The synthesis of (hetero)aryl cyanides from (hetero)aryl halides via transition-metal catalysis is a very valuable reaction since a nitrile can be easily transformed into several other functional groups. Not until 2000 were the first examples on microwave-assisted cyanation reported in the literature. Alter-man and Hallberg found that 3-bromopyridine and 3-bromothiophene were... 

A technique has been recommended for converting furylcarbinols via halides into nitriles that dispenses with the need to isolate the intermediate... 

Another type of reductive amination is shown in Figure 13-18. This reaction illustrates the formation of an amine from a ketone through the formation of an intermediate oxime. Figure 13-19 shows the conversion of a nitrile to an amine. (The nitrile can be formed by the action of cyanide ion, CN", on a halide via an Sf 2 mechanism.)... 

Acid derivatives including esters, amides, halides and nitriles are readily accessible. Dicyanofuroxan (72) shows in its reactions some similarities to phthalonitrile (75LA1029) it also provides a source of fused pyridazino- and oxazino-furoxans (73) and (74) via addition with hydrazine and hydroxylamine, respectively (82H(19)1063). The tetronic acid compound (75) yields a hydroxyamide (76) on aminolysis (79S977). 

Very recently, arylboronic esters have been directly obtained from aiyl halides via the cross-coupling reaction of (tetraalkoxy)diboron (Scheme 2-7) [28]. The reaction tolerates various functional groups such as ester, nitrile, nitro, and acyl groups. 

Vega developed an efficient synthesis of pyrazolo[3,4- /]pyrimidines based on the electrophilic properties of nitrilium salts formed by reaction of 5-aroylaminopyrazoles, nitriles and Lewis acids. Treating iminolyl halides with nitriles with SnCU gave rise of the nonisolated nitrilium salts, which underwent cyclization to generate the desired pyrazolo[3,4-i/]pyrimidines in moderate to good yields. A similar approach was extended to the preparation of 4-amino-2-phenylquinazolines via cyclization of V-arylbenzamides with cyanamide catalyzed by TiCU. ... 

Another FGI that gives carboxylic acid products is the hydrolysis of carboxylic acid derivatives, such as esters and nitriles. Such hydrolysis reactions can either be acid catalyzed (H3O+) or base promoted (1. NaOH, H2O 2. H3O ) and involve an acyl substitution mechanism (addition-elimination) that replaces any acyl leaving group with a hydroxyl group. The synthesis of carboxylic acids via nitriles is especially noteworthy since the introduction of the cyano group via Sn2 with CN involves the formation of a new C-C bond (adds one new carbon to the alkyl halide carbon chain). 

Figure 2.19 A cross-section of results for the copper-catalyzed amination of aryl halides with nitriles to give amides and benzoxazoles via in situ hydrolysis, by Xiang et al. [89].

Palladium complexes have also been reported to catalyze the cyanation of aryl halides via C-CN activation of nitriles, such as phenylacetonitrile [69] and ethyl cyanoacetate [70] (Scheme 21). An excess amount of acetonitrile can also be activated to serve as a cyanating agent in the presence of palladiiun catalyst [71]. The mechanism of C-CN activation in these palladium-catalyzed cyanation reactions is also yet to be understood. 

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

The reaction of titanocene-alkylidenes generated from thioacetals with nitriles followed by hydrolysis affords ketones. Like the reaction of titanocene-methylidene, this reaction may proceed via the azatitanacydobutene 87 and/or the vinylimido complex 88, which reacts with an organic halide to form an a-substituted ketone [80] (Scheme 14.37). 

In addition, arylthiophene 70 was obtained by a one-pot Suzuki coupling of p-methoxyiodobenzene and 3-bromothiophene via an in situ boronate formation using one equivalent of the thermally stable diborane 69 [55], This method avoids the isolation of boronic acids and is advantageous when base-sensitive groups such as aldehyde, nitriles and esters are present. However, the cross-coupling yields are low when both aryl halides are electron-poor because of competitive homocoupling during the reaction. 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

The reaction of the 5-substituted-2-methyl-3(2-77)pyridazinone 383 with nitrile imine 384 generated in situ from the corresponding hydrazonoyl halide has been shown to afford 387 rather than 388. The formation of 387 is believed to proceed via the intermediacy of 385 (Scheme 33) <2000JST13>. 

A compound that includes an aminopyrimidine ring as well as the quaternary salt present in thiamine shows preferential inhibition of absorption of that co-factor by coccidia parasites over uptake by vertebrates. The compound is thus used in poultry where coccidiosis is an economically important disease. Condensation of ethoxymethylenemalononitrile (42-1) with the amidine (42-2) leads to the aminopyrimidine (42-4), probably via the intermediate addition-elimination intermediate (42-3). The nitrile group is then reduced to the methylamino derivative (42-5) by means of hthium aluminum hydride. Exhaustive methylation, for example by reaction with formaldehyde and formic acid, followed by methyl iodide leads to the quaternary methiodide (42-6). The quaternary salt is then displaced by bromine, and the resulting benzyhc-like cylic halide (42-7) is displaced by 2-picoline (42-8). There is thus obtained amprolium (42-9) [43]. 

Alkyl halides undergo Sn2 reactions with a variety of nucleophiles, e.g. metal hydroxides (NaOH or KOH), metal alkoxides (NaOR or KOR) or metal cyanides (NaCN or KCN), to produce alcohols, ethers or nitriles, respectively. They react with metal amides (NaNH2) or NH3, 1° amines and 2° amines to give 1°, 2° or 3° amines, respectively. Alkyl halides react with metal acetylides (R C=CNa), metal azides (NaN3) and metal carboxylate (R C02Na) to produce internal alkynes, azides and esters, respectively. Most of these transformations are limited to primary alkyl halides (see Section 5.5.2). Higher alkyl halides tend to react via elimination. 

Nitriles are most commonly prepared via the conversion of carboxylic acids to primary amides, followed by dehydration with boiling acetic anhydride, or other commonly employed dehydration reagents, e.g. SOCI2 or POCI3. This is a useful synthesis for amide, because it is not limited by steric hindrance. Alkyl nitriles can be prepared by the action of metal cyanides on alkyl halides (see Section 5.5.2). 

Preparation of primary amines Alkyl halide reacts with sodium amide (NaNH2) to give 1° amine via Sn2 reaction. The reaction mechanism for the formation of 1° amine is similar to the formation of nitrile. 

Examples for the oxidation of nitrogen-containing compounds via halide ions as redox catalysts are listed in Table 4, No. 51-56. In this way, primary amines are transformed to nitriles using the system NaBr/MeOH (Table 4, No. 52) Thus, 1,2-diaminocyclohexane is cleaved to yield adiponitrile (Eq. (64))... 

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