Synthesis of Nitriles from Aldoximes

Synthesis of nitriles from aldoxime with aldoxime dehydratase ... 

The dehydration reaction of aldoxime to form nitriles using the resting cells of Rhodococcus sp. YH3-3 was optimized. We found that the enzyme was induced by aldoxime and catalyzed the stoichiometric synthesis of nitriles from aldoximes at pH 7.0 and 30°C. Phenylacetonitrile once synthesized from phenylacetaldoxime was hydrolyzed to phenylacetic acid, since the strain has nitrile degradation enzymes such as nitrile hydratase and amidase. We have been successful in synthesizing phenylacetonitrile and other nitriles stoichiometrically by a selective inactivation of nitrile hydratase by heating the cells at 40°C for 1 h. Various nitriles were synthesized under optimized conditions from aldoximes in good yields. 

Singh MK, Lakshman MK (2009) A simple synthesis of nitriles from aldoximes. J Org Chem 74(8) 3079-3084... 

Shu Z, Ye Y, Deng Y, Zhang Y, Wang J (2013) Palladium(II)-catalyzed direct conversion of methyl arenes into aromatic nitriles. Angew Chem Int Ed 52(40) 10573-10576 Kim HS, Kim SH, Kim JN (2009) Highly efficient Pd-catalyzed synthesis of nitriles from aldoximes. Tetrahedron Lett 50(15) 1717-1719... 

SCHEME 1.179 Synthesis of nitriles from aldoximes in the KOH/DMSO system. 

Olah, G.A. and YD. Vankar. 1978. Synthetic methods and reactions. 52. Preparation of nitriles from aldoximes via dehydration with trimethylamine/sulfur dioxide complex. Synthesis 9 702-703. 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

Aldoximes are prepared from aldehydes and hydroxylamine by condensation reaction, and the dehydration reaction of aldoxime is one of the most important methods of nitrile synthesis in organic chemistry." We speculated that it would become one of the most important examples in Green Chemistry if the dehydration reaction could be realized by an enzymatic method, and started studies on a new enzyme, aldoxime dehydratase, and its use in enzymatic nitrile synthesis. Furthermore, we clarified the relationship between aldoxime dehydratase and nitrile-degrading enzymes in the genome of the microorganisms and the physiological role of the enzyme. 

Poly(ethylene glycol) supported liquid-phase syntheses by both the reaction of (polyethylene glycol (PEG))-supported imines with nitrile oxides, generated in situ from aldoximes, (300) and 1,3-dipolar cycloadditions of nitrile oxide, generated in situ on soluble polymers with a variety of imines (301, 302) have been described. The solid-phase synthesis of 1,2,4-oxadiazolines via cycloaddition of nitrile oxide generated in situ on solid support with imines has also been elaborated (303). These syntheses of 1,2,4-oxadiazolines provide a library of 1,2,4-oxadiazolines in good yields and purity. 

The [2 + 3] cycloaddition reaction of nitrile oxides, easily accessible from corresponding aldoximes, with different alkenes is known as an excellent route to isoxazohne derivatives . The reactions of asymmetric addition ° or addition of unsaturated ger-manes and stannanes to nitrile oxides were reviewed in recent years. In this subsection only the main directions of the synthesis of isoxazole derivatives are briefly reported. 

The Brown allylboration was used in the enantioselective total synthesis of (-)-calicheamicinone 3318 (Scheme 3.1o). Thus the lactol 34, readily prepared from tetronic acid, was treated with the allylborane d35 to give 36 in a highly stereoselective manner (95% ee, > 98% de). Compound 36 was converted to the aldoxime 37 by standard chemistry. Generation of the nitrile oxide with aqueous sodium hypochlorite was accompanied by spontaneous [3 + 2]-dipolar cycloaddition to afford 38 in 65% yield. 

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. 

Table I presents data from McFarlane al, (8) showing that the multi-step oxidation of L-tyroslne to p-hydroxymandelonltrlle requires only 02 and a source of reducing power, most effectively supplied by an NADFH generating system. The table also shows that some of the L-tyroslne Is converted to p-hydroxyphenylacetaldoxime (aldoxime) as well as a trace of p-hydroxyphenylacetonltrlle (nitrile). The production of the aldoxime and nitrile In this experiment was the first Indication that the microsomal preparation from sorghum might constitute an organized enzyme entity Involved In the synthesis of dhurrln. If this were true, it should be possible to demonstrate each individual step of the reaction sequence between tyrosine and p-hydroxymandelontrlle.

Among miscellaneous recent papers concerned with the reactivity of thiono- and dithio-acids and -esters [including those reporting the synthesis of 1,3-thiazine derivatives from 2-iminocyclopentanedithiocarboxylic acid, the use of chlorothionoformates for the conversion of aldoximes into nitriles, and the rapid, exothermic reaction of ethyl dithiopropionate with t-butoxy-bis(dimethylamino)methane, yielding 3-dimethylamino-2,7VA -trimethyl-thioacrylamide (181 = R = R = Me) ] is a... 

In contrast, Cu(I) catalysis makes possible the efficient synthesis of 3,5-disubsti-tuted isoxazoles 57 from aromatic or aliphatic aldehydes and alkynes. Stable nitrile oxides can be isolated and subsequently submitted to the reaction [21] in isolated form and submitted to the reaction in one-pot, three-step process [131]. Here, nitrile oxide intermediates 56 are generated in situ via the corresponding aldoxime and halogenation/deprotonation by Chloramine-T [132]. Capture of the intermediate nitrile oxide by copper(I) acetylides occurs presumably before dimerization. In this case, the Cu catalyst was obtained from copper metal and copper(II) sulfate, and the products were isolated by simple filtration or aqueous work-up. Trace amounts of toluenesulfonamide and unreacted acetylene are easily removed by recrystallization or by passing the product through a short plug of silica gel. 

The cyanides 1408-1412 have all been synthesized by dehydrating their carbox-aldoximes with acetic anhydride [1070-1074]. A pteridine synthesis yielded 75% of 6-cyano-l,3-dimethyUumazine 1408 [1070]. N-Acetyl (3-phenyl-l,2,4-triazolo-5-yl)-thiolacetonitrile 1409 was obtained as the condensation product from a triazole derivative and chloro acetaldehyde, followed by oximation and dehydration, in 79% yield [1071]. endo-l-Cyano-3-acetoxy-8-oxabicyclo[3.2.1]oct-6-ene 1410 (89%) is an intermediate in the synthesis of ll-oxatricyclo[5.3.1.0 Jundecane [1072]. A synthesis of loi,25-dihydroxY-18-norvitamin Dj and la,25-dihydroxy-18,19-dinorvitamin Dj requires the 8j8-acetoxy-des-A,B-cholestane-18-nitrile 1411 (86%) [1073]. A new route to spirooxindoles, a tricyclic system found in a number of interesting natural products, requires the cyanide 1412 (72%) as a key intermediate [1074]. 

Wang N, Zou X, Li F et al (2014) The direct synthesis of A -alkylated amides via a tandem hydration/A/-alkylation reaction from nitriles, aldoximes and alcohols. Chem Commun 50(61) 8303 305... 

Due to their synthetic utility and pharmaceutical applications, a number of synthetic routes to a,P-unsatuiated nitriles have been developed. Classical methods include dehydration of amides [15] or aldoximes [16], Wittig- [17] and Peterson-type [18, 19] olefination processes, ammoxidation of alkenes [20], and carbocyanation of alkynes [21], These approaches suffer variously from high waste generation, low yields and poor stereoselectivity. As such the transition metal-catalysed cyanation of vinyl halides is an attractive route for the synthesis of alkaiyl nitriles. Whilst several instances of such transformations have been reported in the literature, the area remains underdeveloped, particularly in comparison to analagous cyanations of aryl halides. 

In attempts (76IZV690 80KGS1299 81MI4) to extend the pyrrole synthesis from ketoximes and acetylenes to aldoximes, the oximes of both aliphatic and aromatic aldehydes have been found to readily convert to the corresponding nitriles upon moderate heating (60-140°C) in KOH/DMSO. 

The use of carbodiimides in organic synthesis includes the Moffat oxidation of primary alcohols to aldehydes using a dicyclohexylcarbodiimide/DMSO adduct as reagent. Also, conversion of alcohols or phenols into hydrocarbons via hydrogenation of acylisoureas derived from the corresponding carbodiimide adducts is a useful reaction. Furthermore, aldoximes, on treatment with carbodiimides, are converted into nitriles, and numerous uses of carbodiimides as condensation agents or catalysts are known (see Chapter 13). 

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