Dehydration nitriles from amides

The use of the triphenylphosphine-carbon tetrachloride adduct for dehydration reactions appears to be a very simple way of synthesizing nitriles from amides, carbodi-imides from ureas, and isocyanides from monosubstituted formamides. All of these reactions involve the simultaneous addition of triphenylphosphine, carbon tetrachloride, and tri-ethylamine to the compound to be dehydrated. The elimination of the elements of water is stepwise. An adduct, e.g. (46), is first formed, chloroform being eliminated, which decomposes to produce hydrogen chloride and the dehydrated product. 

In general, dehydration means loss of water molecules from chemical substances, irrespective of their structure. Even if all cases where water is bonded in hydrate form are excluded, a number of reactions remain which also include formation of nitriles from amides, lactones from hydroxy acids etc. However, the present treatment will concentrate on the heterogeneous catalytic decomposition of alcohols in the vapour phase, which can be either olefin-forming or ether-forming reactions, and on the related dehydration of ethers to olefins. 

General procedure. Nitriles from amides [1128] The procedure used for the dehydration of amides is the same as that described above, except that the reaction mixture is refluxed for 1 h after stirring for 8 h at room temperature. It is then cooled and worked-up as described above. 

Nitriles from Amides. Primary amides are dehydrated to afford nitriles upon heating with PCls. Due to the severity of the reaction conditions, substrates of limited functional complexity are tolerated. The reactions are generally conducted either neat or with POCI3 as a solvent. This method is useful for products... 

Nitdles may be prepared by several methods (1). The first nitrile to be prepared was propionitdle, which was obtained in 1834 by distilling barium ethyl sulfate with potassium cyanide. This is a general preparation of nitriles from sulfonate salts and is referred to as the Pelou2e reaction (2). Although not commonly practiced today, dehydration of amides has been widely used to produce nitriles and was the first commercial synthesis of a nitrile. The reaction of alkyl hahdes with sodium cyanide to produce nitriles (eq. 1) also is a general reaction with wide appHcabiUty ... 

Nitrile Process. Fatty nitriles are readily prepared via batch, Hquid-phase, or continuous gas-phase processes from fatty acids and ammonia. Nitrile formation is carried out at an elevated temperature (usually >250° C) with catalyst. An ammonia soap which initially forms, readily dehydrates at temperatures above 150°C to form an amide. In the presence of catalyst, zinc (ZnO) for batch and bauxite for continuous processes, and temperatures >250° C, dehydration of the amide occurs to produce nitrile. Removal of water drives the reaction to completion. 

Both methods of nitrile synthesis—SN2 displacement by CN- on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

Pictet-Spengler cyclization of L-tryptophan with formaldehyde afforded the monochiral carboxylic acids 20a,b, whereas cyclization with acetaldehyde yielded the diastereomeric carboxylic acids 21a,b (23). Acids 20a,b with a hydrogen at C-1 are enantiomers, but acids 21a,b are diaste-reomers the cis isomer 21a was the major reaction product when the cyclization of L-tryptophan with acetaldehyde was carried out in the presence of sulfuric acid. Direct removal of the carboxy group in these acids is difficult, but it can be accomplished in several steps dehydration of the amides prepared from the acids with phosphorus oxychloride affords nitriles, and the nitrile group can be removed by reduction with sodium borohydride in pyridine-ethanol (31). 

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°). 

The preparation of nitriles by the removal of water from amides can be accomplished in high yields by numerous dehydrating agents including phosphorus pentoxide, phosphorus oxychloride, and thionyl chloride. A Commonly used procedure for the preparation of simple aliphatic nitriles, e.g., isobutyronitrile (86%), consists in heating an Intimate mixture of the dry, powdered amide and phosphorus pentoxide at 100-220° and distilling the product as it is formed, sometimes under diminished pressure. ... 

Aromatic nitriles are also prepared by heating amides with phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, and ammonium sulfamate. In addition, the action of a double salt of aluminum and sodium chlorides, NaCl- AlClj, gives excellent yields of nitriles from both aliphatic and aromatic amides. Heating an amide with phthalic anhydride causes dehydration. A novel synthesis consists in treating a mixture of an aromatic acid and p-toluene-sulfonamide with phosphorus pentachloride the yields of nitriles range from 63% to 79%. ... 

Nitriles may be prepared from amides by dehydration with phosphorus pentoxide, phosphorus oxychloride or thionyl chloride (Scheme 3.87). 

Acid amide-triphenylphosphine dihalide adducts (4) have found wide application in organic synthesis. - Synthetic equivalents are adducts (5) from acid amides and triphenylphosphine/CCU, which are prepared in situ from the educts. - With these reagents the following transformations have been performed dehydration of amides or aldoximes to nitriles, preparation of isonitriles from secondary form-amides, preparation of imidoyl halides from amides or acylhydrazines and preparation of ketene imines from amides. Using polymer-supported triphenylphosphine the work-up procedure is much easier to achieve. Triphenylphosphine can be replaced by tris(dialkylamino)phosphines. - Instead of CCI4 hexa-chloroethane, hexabromoethane or l,l,2,2-tetrabromo-l,2-dichloroethane can be used " the adducts thus formed are assumed to be more effective than those from the triphenylphosphine/CCU system. 

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." ... 

Some of these transformations were accompanied by additional reactions, e.g. formylation of the aromatic or heteroaromatic - nucleus or CH-acidic methyl groups further dehydration of amides to nitriles was observed. Adducts from amides and PCI3, sulfonyl halides or SO2CI2/SCXZI2 from which amidines can be obtained by reaction with amine derivatives (compare Section 2.7.2.5 and refs. 5 and 14) have not found wide application for this purpose. An interesting reaction is the preparation of the amidine (294 equation 158) from 7V-pentafluorophenylformamide. By thermal decomposition of the adducts from secondary amides and 7V,iV-dialkylcarbamoyl chlorides amidinium salts were synthesized from which the amidines (295 equation 159) were set free by treatment with bases. " ... 

A small level of monomer in the pyrolysate (about 1 %) indicates that some cleavage of the polymer backbone takes place without dehydration of the amide group. Therefore, some water may be formed by elimination from the small molecules containing amido groups, further leading to the same compounds as those generated by the cleavage of the nitrile type polymer. 

Amides undergo dehydration. Useful dehydrating agents include SOCl2, P4O10 (P20 ), (AcO)20, and POCl3/A. The product is a nitrile, and in fact, dehydration of an amide is one method to produce aryl nitriles. Figure 12-38 shows the synthesis of 2-ethylhexanenitrile from 2-ethylhexanamide with a 94-percent yield. 

Dehydration reactions using the tertiary phosphine-carbon tetrachloride adduct have appeared quite regularly in the literature again this year. Among those reported have been the dehydrations of oximes to nitriles, carboxylic acids to anhydrides, and the amides (37) to the cumulenes (38). Further reaction of the dehydration product from treatment of the... 

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... 

Several phosphorus compounds have been used for the first time as dehydrating scents on amides. Diethyl phosphorochloridate in the presence of triethyl-amine converts aliphatic and benzenoid amides to nitriles at 65° the yields vary from 30% for acetonitrile to 72% for propanenitrile [27]. Even milder conditions suffice when pyrophosphoryl chloride is used [28] this reaction enables a... 

Dehydration with thionyl chloride-dimethylformamide Nitriles from carboxylic acid amides... 

Another widely used dehydration agent for the synthesis of cyanides from amides is phosphoryl chloride. For example, the amide 1430 is dehydrated with this reagent to give amino nitrile 1431, which is an auxiliary with a disymmetric tertiary amino group employed in an asymmetric nucleophilic acylation reaction with an aldehyde according to the following reaction sequence to afford chiral acetophenone 1433 [1089]. 

Chlorosulfonyl isocyanate, Cl-S02-N=00, is an effective dehydrating agent for the preparation of various aryl- and alkyl-nitriles from the corresponding amides and aldoximes in yields of 74-87% and 75-86%, respectively [1128],... 

Triphenylphosphine dibromide is a versatile dehydrating agent for amides. Depending on the starting material, nitriles, carbodiimides, isonitriles, or keteneimines may be obtained. Silicon tetrachloride is a useful coupling agent for amide formation, since it is converted to silica, easily separable from other reaction products. ... 

As the long-chain alkylamines meant here in general derive from fatty acids, they are also termed fatty amines, or more correctly fatty C8-C22 alkylamines. A processing technic is the catalytic dehydration of fatty alcohols at 210-260°C with ammonia or shortchain alkylamines or dialkylamines. Another manufacturing process starts from fats or oils which are transferred to fatty acid amides with ammonia dehydration of the amides leads to nitriles the catalytic hydrogenation of which produces fatty amines ... 

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