Dehydration of primary amide to nitrile

Scheme 44 Plausible pathway of Fe-catalyzed dehydration of primary amides to 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 ... 

Phosphorus nitrile chloride forms adduct (10) with DMF in the ratio 1 4, which is useful for the preparation of formamidines and azavinylogous formamidinium salts. It is supposed that the dehydration of primary amides to nitriles with (PNChls as well as the formation of 2-alkylbenzothiazoles from 2-(methylthio)anilides and (PNChls in the presence of triethylamine proceed via similar adducts." ... 

TfzO and a base can effect dehydration of primary amides to nitriles. This procedure is particularly mild, with no epimer-ization observed at the stereogenic a-carbon of several substrates (eq 63). ... 

Itagaki S, KamataK, Yamaguchi K, Mizuno N (2013) Amonovacantlacunary silicotungstate as an efficient heterogeneous catalyst for dehydration of primary amides to nitriles. ChemCatChem 5 1725-1728... 

Other dehydration reactions include the conversion of primary amides to nitriles, aldehydes to nitriles (via the hydroxylamine) (eq 13), and carboxylic acids to ketenes (eq 14). ... 

New polymer-supported reagents for sulfide transfer have been developed to avoid exposure to malodorous and toxic sulfur reagents. Ley et al.15 prepared a stable aminothiophosphate polystyrene resin for the conversion of secondary and tertiary amides to thioamides in high conversion and purity (Table III, entry 11). This procedure is extremely clean and affords the desired product with short reaction times in comparison to Law-esson s reagent. In addition, the aminothiophosphate resin dehydrates primary amides to nitriles. 

Nitriles can be prepared by the SN2 reaction of a cyanide ion with a primary alkyl halide. However, this limits the nitriles that can be synthesised to those having the following general formula RCH2CN. A more general synthesis of nitriles involves the dehydration of primary-amides with reagents such as thionyl chloride or phosphorus pentoxide ... 

Figure 7.4 illustrates the dehydration of primary amides A to nitriles B using trifluo-romethanesulfonic acid anhydride. All intermediates correspond to the ones discussed above. When the mixed anhydrides F finally release trifhioromethanesulfonic acid in two steps hy the already familiar El mechanism, the formation of the nitrile B is completed. 

Nitriles can be prepared by dehydration of primary amides (reaction 8) or of aldoximes (reaction 9), catalyzed by the Re trioxo compounds [ReOsX] (X = OSiMes, OReOs, OH) in azeotropic (e.g. toluene/water or mesitylene/water) reflux. Aqueous perrhenic acid (X = OH) is the most convenient catalyst in view of the moisture sensitivity of the others. The oxophilicity of the Re(VII) oxo-complexes is believed to play a determining role in the reactions, which are proposed to involve six-membered cyclic transition states formed upon preferential (9-coordination, relative to A-coordination, of the amide or oxime. ... 

Nitriles from aldoxlmes. The system trifluoroacetic anhydride and pyridine, which converts primary amides to nitriles, also converts aldoximes to nitriles. The geometrical configuration of the substrate determines the ease of dehydration (E)-Aldoximes are less reactive than (Z)-aldoximes. However, high yields can also be obtained from the former substrates if the amount of pyridine is increased or if the reaction is conducted at higher temperatures (60-65°). 

Dibutyltin oxide catalyses the dehydration of primary amides or thionoamides to nitriles under neutral conditions. The reaction can be represented as a cyclic elimination involving the 0-stannyl (or S-stannyl) isomer.56... 

Isocyanides can be made from treatment of formamides with tosyl chloride in pyridine, as illustrated in eq 42. Similarly, nitriles can be synthesized in moderate to good yields by dehydration of primary amides using tosyl chloride in p)Tidine or... 

A versatile method for the conversion of aromatic and aliphatic primary amides to nitriles, using dibutyltin oxide as a catalytic neutral dehydrating agent, has been applied in various cases. The reaction temperature is about 110 °C, the reaction time is 12-18 h, and product yields are 70-95% [1145]. A reaction mechanism has been proposed. 

Hydrolysis of primary amides cataly2ed by acids or bases is very slow. Even more difficult is the hydrolysis of substituted amides. The dehydration of amides which produces nitriles is of great commercial value (8). Amides can also be reduced to primary and secondary amines using copper chromite catalyst (9) or metallic hydrides (10). The generally unreactive nature of amides makes them attractive for many appHcations where harsh conditions exist, such as high temperature, pressure, and physical shear. 

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. 

In the dehydration of primary aliphatic or aromatic amides to nitriles with CDI, the CDI is activated by an excess of a reactive halide, such as allyl bromide or benzyl bromide (2 equiv. of CDI, 8 equiv. of reactive halide, refluxing CH3CN, 2-5h) [12]... 

Chiral nitriles.2 This reagent is recommended for the dehydration in 60% yield of primary amides with an asymmetric center at the a-position to chiral nitriles with negligible racemization. The most satisfactory reagents for dehydration of optically active oximes to chiral nitriles is l,l -carbonyldiimidazole or N,N -tlicyclohexylcarbodiimide. 

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. 

Fig. 7.4. Triftuoromethane-sulfonic acid an hydride/pyridine-mediated dehydration of primary carboxylic acid amides (A) to give the corresponding nitriles (B) with the reagents converting into pyridinium trifluormethanesulfonate pyrH F3C-S03 .

The adduct of DMF and dichlorophenylphosphine has been used to convert primary aromatic amides to nitriles by dehydration," as well as to synthesize 2,5-diaryl-1,3,4-oxadiazoles from A iV -diacylhydra-zides. ... 

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