Nitrile from carboxamide

General procedure. Nitriles from carboxamides (or thiocarboxamides) [1130] Phenyl chlorothionoformate (1.1 mmol) was added dropwise to a stirred, ice-cooled solution (or suspension) of the amide (1.0 mmol) in dry dichloromethane (5 mL) and anhydrous pyridine (2.0 mmol) at such a rate that the temperature was kept below 5 °C. The reaction mixture was then allowed to warm to room temperature for the requisite time and was then quenched with water (2 mL). The resulting mixture was extracted with dichloromethane (2 x 15 mL). The combined organic phases were washed with saturated brine, dried (Na2S04), and the solvent was removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel. Pure nitriles were obtained in yields of 80-95%. 

A new method has recently been described for the preparation of nitriles from carboxamides or carbaldoximes using a combination of aluminum chloride and sodium iodide (AlCls/Nal) [1139]. The conversion of 1 equiv. of amide or oxime requires 2 equiv. of AICI3 and 6 equiv. of Nal. Reactions are performed in refluxing acetonitrile, the reaction time is 2.5 h, and yields are quoted as 80-95%. 

General procedure. Nitriles from carboxamides [1144] A solution of the carboxamide (5 mmol) in dry benzene (50 mL), containing silver oxide (1.8 g, 7.7 mmol) and powdered 4 A molecular sieves (5.0 g) was stirred in the dark at 25 °C for 12 h. lo-doethane (0.86 g, 0.44 mL, 5.5 mmol) was then added, and the mixture was heated to reflux under argon for 17 h. The cooled solution was then Altered (Celite) and the filtrate was concentrated under reduced pressure. Purification was accomplished by chromatography on silica gel, eluting with hexane and ethyl acetate in varying proportions. 

Hydration of nitriles providing carboxamides is usually carried out m strongly basic or acidic aqueous media - these reactions require rather bars conditions and suffer from incomplete selectivity to the desired amide product. A few papers in the literature deal with the possibihty of transition metal catalysis of this reaction [28-30]. According to a recent report [30], acetonitrile can be hydrated into acetamide with water-soluble rhodium(I) complexes (such as the one obtained from [ RhCl(COD) 2] and TPPTS) under reasonably mild conditions with unprecedently high rate... 

Applications in organic synthesis of the iminoacylation reaction of oximes have recently been found at kinetically labile Zn11- or Con-oxime systems. The former catalyzes the hydrolysis of nitriles to carboxamides (23)37 and the Co11 system catalyzes the conversion of nitriles into amidines (24) (also involving C N bond formation upon reaction with ammonia, formed from competitive hydrolysis of the nitrile).110... 

Methods derived from this fundamental process involve the condensation of one-, two- and three-carbon units such as amidines, amino-nitriles and carboxamides, which represent intermediate stages of the ammonia/hydrogen cyanide reaction. Pyrimidines or imidazoles are usually intermediates. ... 

Nitriles, which are important intermediates in the manufacture of a wide variety of organic compounds such as amines, aldehydes, amidines, and heterocycles, are manufactured either from alkali cyanides or from carboxamides. The cyanides route is obviously highly toxic, whereas the carboxamide consumes the reagent in stoichiometric quantities. Solid superacids offer a clear alternative to the traditional catalysts. Thus the use of sulfated zirconia enables the dehydration to be accomplished under much milder conditions in the liquid state (Joshi and Rajadhyaksha, 1986 Rajadhyaksha and Joshi, 1991). 

General procedure. Nitriles 1379 from carboxamides 1377 [1061]. Method A To a... 

General procedure. Nitriles 1319 from carboxamides 1377 [1125] Triflic anhydride... 

Synthesis of Nitriles from Amides. Aryl carboxamides and other electron-rich amides could be converted to the corresponding nitriles in good yields by treatment with Ag20 and EtI in benzene at reflux (eq 23). This technique is typically compatible with acid-labile moieties or protecting groups (TBDPS, isopropy-lidene). Although this technique was found to be very efficient for the transformation of electron-rich carboxamides, simple aliphatic amides are rarely suitable for this purpose. 

Pyridazinecarboxamides are prepared from the corresponding esters or acid chlorides with ammonia or amines or by partial hydrolysis of cyanopyridazines. Pyridazinecarboxamides with a variety of substituents are easily dehydrated to nitriles with phosphorus oxychloride and are converted into the corresponding acids by acid or alkaline hydrolysis. They undergo Hofmann degradation to give the corresponding amines, while in the case of two ortho carboxamide groups pyrimidopyridazines are formed. 

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). 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

A potential versatile route into a-amino acids and their derivatives is via a combination of (i) nitrile hydratase/amidase-mediated conversion of substituted malo-nonitriles to the corresponding amide/acid followed by (ii) stereospecific Hofmann rearrangement of the amide group to the corresponding amine. Using a series of a,a-disubstituted malononitriles 14, cyanocarboxamides 15 and bis-carboxamides 16, the substrate specificity of the nitrile hydratase and amidase from Rhodococcus rhodochrous IF015564 was initially examined (Scheme 2.7). The amidase hydrolyzed the diamide 16 to produce (R)-17 with 95% conversion and 98%e.e. Amide 17 was then chemically converted to a precursor of (S)-a-methyldopa. It was found... 

A 2-Dehydroquinuclidinyl-2- and 3-carboxamides were formed from the corresponding esters by the action of alcoholic ammonia.47,49 Quinuclidinecarboxylic esters were also used in the preparation of hydrazides and their hydrazones,95,132 and the amides in the synthesis of nitriles.47,49,90... 

In recent years there has been considerable interest in the reactions of nitriles in the coordination sphere of metal ions. Breslow et al.312 first reported that the hydrolysis of 2-cyano-l,10-phenanthro-line to the corresponding carboxamide is strongly promoted by metal ions such as copper(II), nickel(II) and zinc(II). Base hydrolysis of the 1 1 nickel complex is 107 times faster than that of the uncomplexed substrate. The entire rate acceleration arises from a more positive value of AS. Somewhat similar effects have been observed for base hydrolysis of 2-cyanopyridine to the corresponding carboxamide. In this case rate accelerations of 109 occurred with the nickel(II) complex.313... 

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