Nitrile from primary amides

Claremon, D. A., Phillips, B. T. An efficient chemoselective synthesis of nitriles from primary amides. Tetrahedron Lett. 1988, 29, 2155-2158. 

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 ... 

Phenyl-l,3,4-oxathiazol-2-one (370), prepared from primary amides and tri-chloromethanesulfenyl chloride, undergoes a ready thermal elimination of carbon dioxide with the formation of the nitrile sulfide ylide (371). This can be trapped by a wide variety of unsaturated dipolarophiles, and with an alkyne provides a ready route to isothiazoles (372) (see Chapter 4.17). Applications to 1,2,4-thiadiazole synthesis are described in Chapter 4.25. Thermolysis of l,3,4-oxadiazolin-5-ones (500 C/10 mmHg) results in the loss of CO2 and generation of the corresponding nitrilimine (78JOC2037). 

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

A carbodiimide-related reagent is 2-chloro-l,3-dimethylimidazolinium chloride (CDC). It can act as a powerful dehydrating agent, equivalent to DCC. Nitriles 1379 can be prepared from primary amides 1377 or aldoximes 1380 on several structures at room temperature within reaction times of 4-72 h and in yields of 64-99% [1137]. As a strong electrophile, CDC reacts with 0-nucleophiles to form 1506,... 

General procedure. Nitriles 1379 from primary amides 1377 [1138] PyBOP (1.145 g, 2.2 mmol) was added to a stirred, ice-cooled solution (or suspension) of the amide 1377 (2.0 mmol) in anhydrous dichloromethane (10 mL) and anhydrous N,N-di-isopropylethylamine (569 mg, 4.4 mmol) under N2. The reaction mixture was... 

Whereas the phosphorodiamidate (19) formed from primary amides and HMPA fragments to give the derived nitrile, such a course is not possible when secondary amides are employed, when amidines are produced (Scheme 54). 

Kumar and Das (2013) observed that solid supported ruthenium can be used as a heterogeneous catalyst for the reduction of aromatic, a,p-unsaturated and aliphatic nitriles to primary amides at 130-140°C for 0.5-2 h in microwave. The catalyst was found to be very stable under moisture and microwave irradiation, easily separable from the reaction mixture and recyclable up to ten times without any loss of catalytic activity. 

The bioconversion of nitriles and primary amides has been used in the production of optically active a-hydroxy or a-amino acids such as L-phenylalanine, L-lactic acid, and L-phenylglycine, which are chiral synthons in many pharmaceutical syntheses. Nitrilase has been isolated from organisms belonging to the genera Brevibacterium, Rhodococcus, and Pseudomonas [187-190]. 

Primary amides can also be generated in situ from nitriles. Thus, one-pot synthesis of A -acyl-a-amino acids by Pd-catalyzed amidocarbonylation of alkyl- and arylnitriles has been developed.For example, acetonitrile was hydrolyzed to acetamide first and subjected to the reaction with cyclohexanecarbaldehyde in the same reaction vessel to give A-acetyl-2-cyclohexylglycine 13 in 92% yield (Equation (2)). This process is... 

Amides are also available from nitriles, which have the same oxidation level. Direct acid or base hydrolysis of a nitrile usually requires fairly severe conditions and often does not stop at the amide stage but goes on the carboxylic acid. Treatment of nitriles with a solution of HC1 in ethanol furnishes an imidate ester which is hydrolyzed in aqueous acid to the amide. Because a nitrile is the starting material, only primary amides can be produced by this process. 

Surprisingly, detailed analysis of several NMR spectra of isolated and purified compounds and a crystal structure analysis revealed the formation of 2-amino-4-cyano-amides. This reaction is the first case in which the oxygen for the newly formed amide bond emerges not from the solvent (H2O) but rather from the amide bond of a reactant. Also noteworthy is the concomitant nitrile formation from the primary amide, which does not normally occur under such mild conditions. Typical examples and their yields are given in Scheme 3.9. 

Ferrini and Marxer65 have recently shown that vinylene carbonate reacts with primary amides, in the presence of polyphosphoric acid, to yield 2-substituted oxazole derivatives. Yields are low (2-34%), and phenoxy- and phenyl-acetamide, p-methylbenzamide, and salicylamide do not give oxazole derivatives. Although the reaction has been interpreted according to Scheme 3, the nucleophilic attack of a nitrile molecule (from the amide dehydration), with a nitrilium salt as intermediate (Scheme 4), cannot be excluded.06... 

Reduction Nitriles and amides can be easily reduced to alkylamines using lithium aluminium hydride (LiAlH4). In the case of a nitrile, a primary amine is the only possible product. Primary, secondary, and tertiary amines can be prepared from primary, secondary and tertiary amides, respectively. 

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. 

Although nitriles lack an acyl group, they are considered acid derivatives because they hydrolyze to carboxylic acids. Nitriles are frequently made from carboxylic acids (with the same number of carbons) by conversion to primary amides followed by dehydration. They are also made from primary alkyl halides and tosylates (adding one carbon) by nucleophilic substitution with cyanide ion. Aryl cyanides can be made by the Sandmeyer reaction of an aryldiazonium salt with cuprous cyanide. a-Hydroxynitriles (cyanohydrins) are made by the reaction of ketones and aldehydes with HCN. 

Imino and iminium inflates derived from secondary and tertiary amides respectively, react with l,l,l-2-hydroxymethyl-2-methyl-propane-l,3-dioJ in the presence of pyridine to give the OBO derivative [Scheme 2.112],234 Primary amides cannot be used as substrates because they dehydrate to the nitrile under the reaction conditions. 

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°). 

Hydrogen and carbon monoxide were lost from the latter to form the Fe" complexes (XCIV x=0). The appearance of an absorption assigned to indicated the formation of an unstable Fe—H intermediate. Carbonyla-tion of (XCIV X = 0) gave the red cis complex (XCIV x = 2) 344). Noncoordinate irnine groups were postulated for the product (XCV R =/)-MeOC6H4) from the reaction of Fe2(CO)9 and p-methoxythio-benzamide, which contrasts with the normal reaction of iron carbonyls with primary amides and thioamides, w hich proceed to nitriles 16). 

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." ... 

Phosgene, as well as the easier to handle diphosgene (chloroformic acid trichloromethyl ester) or triphosgene (carbonic acid bis(trichloromethyl) ester) transform primary, secondary and tertiary amides and thioamides to chloromethyleneiminium chlorides (25 equation 15), whereby the reaction with thioamides is of broader scope and proceeds with fewer side reactions. The amide chlorides derived from primary and secondary amides can lose HCl, giving nitriles or imidoyl halides, respectively. /V-Sub-stituted formamides can be converted to isonitriles via amide halides. ... 

Amides - nitriles.1 Primary acid amides are dehydrated to nitriles by treatment with titanium tetrachloride and a base (triethylamine, N-methylmorpholine) in THF at 0°. Yields range from 65 to 95 %. 

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