Primary Amides into Nitriles

Many methods for the dehydration of primary amides to nitriles involve the use of strong acids and/or other reagents which are incompatible with sensitive functionality. French workers have recently described an unusual, mild, efficient (64-92%) and fairly general procedure for the RCONH2 — RCN transformation which simply involves heating a mixture of the amide, an aldehyde and formic acid under reflux in acetonitrile for 12 hours. The following observations were made  

Give a mechanistic interpretation for this RCONH2 — RCN conversion. 

Heating of a mixture of 2-phenyl-1,4-naphthoquinone (1 eq.) with dimethyl malonate (4 eq.) and manganese(III) acetate (6 eq.) in acetic acid at 80°C for 16 hours gives 1 in 76% yield, and this has been shown to be a general type of reaction for a variety of 2-aryl-l,4-naphthoquinones. 

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A catalytic route for nucleophilic substitution of alcohols using simple CPN 55 as a catalyst was also developed by Lambert in 2011 (Scheme 6.18a) [46]. In this reaction, oxalyl chloride acts as an activating reagent for 55. The catalytic system is also employed for the conversion of oximes and primary amides into nitriles (Scheme 6.18b) [47]. 

Lead(fV) ethanoate, Pb(02CCH3)4, (Pb(ll)ethanoate plus CI2) is a powerful oxidizing agent which will convert vicinal glycols to aldehydes or ketones and 1,2-dicarboxylic acids into alkenes. Primary amides give ketones and amines give nitriles. 

Thioamides have been transformed into the corresponding nitriles. Treatment of primary thioamides by tellurium tetrachloride or selenium tetrachloride in combination with triethylamine affords nitriles.66 Treatment of primary amides and thioamides with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) gives nitriles.67 Reactions of thioamides with metal carboxylates in organic solvents enables the selective preparation of nitriles, imides or amides depending on the substitution pattern of the starting material (Scheme 33).68... 

Dehydration of amides.1 Primary amides are converted by this reagent into nitriles at 25° in 82-92% yield. Actually, this reaction occurs more readily than dehydration of a secondary hydroxyl group. 

Figure 7.2 illustrates the phosphorus pentoxide-mediated dehydration of a primary amide to a nitrile, using the transformation of nicotine amide (A) into nicotine nitrile (B) as an example. The reaction of phosphorus pentoxide at the carboxyl oxygen furnishes the partially ring-opened iminium ion E (simplified as F) via the polycyclic iminium ion C. E is deprotonated to give the mixed anhydride G from imidic acid and phosphoric acid. Imidic acids are characterized by the functional group R-C(=NH)-OH. This anhydride is transformed into the nitrile B by an El elimination via the intermediate nitrilium salt D. Nitrilium salts are iV-pro-tonated or V-alkylated nitriles. 

We ve already seen in Sections 21.7 and 21.8 bow amines can be prepared by reduction of amides and nitriles with l.tAlHf. The two-step sequence of S 2 displacement with CN" followed by reduction i an excellent method for (inverting an alky] halide into a primary alkylamine having one more carbon atom. Amide reduction provides an excellent method for converting... 

In structural studies on oxytetracycline (Terramycin) and chlorotetracycline (Aureomycin) a Pfizer group found that tosyl chloride in cold pyridine converts the antibiotics into nitrile derivatives through dehydration of the primary carbox-amido group. They then found that simpler amides are dehydrated to nitriles in good yield by adding 1 equivalent of tosyl chloride slowly to a mixture of the amide with 2.25 equivalents of pyridine at a rate such as to maintain a temperature of about 70°. The mechanism proposed involves O-tosylation. 

Nitriles from primary amides. Benzamide is converted into benzonitrile when heated in THF with triphenylphosphine-carbon tetrachloride (yields up to 83% depending on conditions). The reaction probably proceeds as follows ... 

Yields are in the range 25-90%. Primary amides are also converted into nitriles (65-80% yield). Tris(triphenylphosphine)chlororhodium is not the true catalyst in these reactions, since no nitrile is formed if the reaction mixture is heated in an atmosphere of argon unless the reagent is treated first with air or oxygen. ... 

Phosphanes are widely used as reagents in organic synthesis, triphenylphos-phane being the most commonly applied due to its stability towards oxidation. The polymer-supported analog has so far found use in the transformation of alcohols into alkyl halides and acids into acid halides, using either carbon tetrachloride or carbon tetrabromide as the halogen source (Scheme 6.4) [7, 11-14], This system can also successfully transform primary amides and oximes into nitriles, whereas secondary amides are transformed into imidoyl chlorides (Scheme 6.5) [15],... 

Deacetylanisomycin (14) has been synthesized from 62 by transformation into the primary amide 63 by reaction with ammonia in ethanol, followed by dehydration with trifluoroacetic anhydride to give the nitrile 64 (Scheme 7). Treatment of 64 with 4-CH30C6H4CH2MgCl followed by BnNH2 and subsequent reduction with sodium boro-hydride afforded the diastereomeric iV-beuzylamines 65 and 66 in 81 19 ratio and 80%... 

Reduction of amides and imides to amines. Tertiary amides (1) can be reduced to amines (3) by conversion to the Vilsmeier complex (2) followed by reduction with NaBHi. The method is applicable to secondary amides, (4) -> (6), but primary amides are converted into nitriles. ... 

The easy conversions of primary amides and aldoximes into nitriles and of secondary amides and ketoximes into imidoyl chlorides using triphenylphosphine and carbon tetrachloride have been found to produce greater yields of desired products using polymer-supported triphenylphosphine in carbon tetrachloride. The work-up procedure is much simplified as the products do not have to be separated from triphenylphosphine oxide. 

Iron pentacarbonyl in boiling dibutyl ether converts primary thioamides to nitriles [47] in moderately good yields, for example, m-toluonitrile (66%), ben-zonitrile (64%). Reduction of a carboxamide by sodium borohydride requires fairly drastic conditions [48] but if the amide is first converted into the imino-ether by means of Meerwein s reagent and this is then treated with the reducing agent in ethanol at 60°, a good yield of the nitrile is obtained replacing the borohydride by sodium ethoxide raises the yield appreciably [49], for example, benzonitrile (95%), pentanenitrile (90%), 2,2-dimethylpropanenitrile (86%), diphenylacetonitrile (100%). 

Technically important Fatty Acid Derivatives. Nitrogen-containing lipids such as primary, secondary and tertiary amines, quaternary ammonium bases, amides and nitriles, all of which find many varied applications in the plastic and textile industries, can be separated into classes on silica gel G by using ammonia-containing solvents (see Table 68) [19, 121, 162]. The first four solvents in Table 68 have been used in succession in the stepwise development technique (see p. 87) for analysing complex mixtures [121]. 

In 2013, Xiang, Wang and co-workers developed a copper-catalysed an-nulation reaction of 1,2-dihaloarenes with nitriles. In this procedure, the nitriles were hydrated by a base into the corresponding primary amides in situ and then coupled with 1,2-dihaloarenes. In this system, combined bases (CS2CO3 and KOH) and a relative high temperature were needed. Later on, they found that the reaction conditions can be much milder by adding acetaldoxime as an additive. In this new procedure, the role of acetaldoxime... 

In summary, the reactivity of various functional groups toward Li 9-BBNH is classified into four broad categories [18] (1) rapid- or fast-reduction aldehyde, ketone, ester, lactone, acylchloride, acid anhydride, epoxide, disulfide, -alkyli-odide, and tosylate (2) slow-reduction tertiary amide, alkylbromide, and aromatic nitrile (3) sluggish-reduction carboxylic acid, aliphatic nitrile, primary amide, nitro and azoxy compounds, and secondary alkylbromide and tosylate (4) inert olefin, oxime, alkylchloride, sulfoxide, azo-compound, sulfide, sulfone, and sulfonic acid. 

Wang L, Shen C, H-p Wang, W-y Zhou, F-a Sun, He M-Y, Chen Q (2012) Selective conversion of aldehydes into nitriles and primary amides in aqueous media. J Chem Res 36 (8) 460- 2... 

The preparation of amines by the methods described m this section involves the prior synthesis and isolation of some reducible material that has a carbon-nitrogen bond an azide a nitrile a nitro substituted arene or an amide The following section describes a method that combines the two steps of carbon-nitrogen bond formation and reduction into a single operation Like the reduction of amides it offers the possibility of prepar mg primary secondary or tertiary amines by proper choice of starting materials... 

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