Unsaturated nitriles, synthesis

Unsaturated nitriles are formed by the reaction of ethylene or propylene with Pd(CN)2[252]. The synthesis of unsaturated nitriles by a gas-phase reaction of alkenes. HCN, and oxygen was carried out by use of a Pd catalyst supported on active carbon. Acrylonitrile is formed from ethylene. Methacrylonitrile and crotononitrile are obtained from propylene[253]. Vinyl chloride is obtained in a high yield from ethylene and PdCl2 using highly polar solvents such as DMF. The reaction can be made catalytic by the use of chloranil[254]. 

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

The direct synthesis of o.g-unsaturated nitriles can be accomplished by treating the appropriate carbonyl compound with potassium hydroxide in... 

The cyclization with a,p-unsaturated nitriles has proven effective for the synthesis of 3-aminothiophene 14, a key intermediate for the synthesis of p38 kinase inhibitors."... 

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. 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

In 1969, Szantay and co-workers published a linear synthesis of (+)-yohimbine and (—)-P-yohimbine (75) in full detail (220). Tetracyclic key intermediate 400, obtained from 3,4-dihydro-p-carboline and a properly substituted a,p-unsatu-rated ketone (173), was treated with a proper phosphonoacetic acid derivative to give unsaturated nitrile 401 or unsaturated ester 402. Catalytic reduction of the latter resulted almost exclusively in 404 with normal stereo arrangement, while reduction of 401 supplied a mixture of normal and epialloindolo[2,3-a] quinolizines 403 and 405, respectively. Dieckmann ring closure of diester 404 gave 18a-methoxycarbonylyohimbone (407) as the thermodynamically favored... 

This chapter mainly focuses on the latest achievements and recent developments in asymmetric hydroformylation. Since several reviews have been made in the last decade [9,14-16], the chapter discusses the contributions reported between 2000-2005 in particular, although the main diphoshites and phosphine-phosphite rhodium catalytic systems discovered since 1995 are also considered because of their significance in the subject. Particular attention is paid to mechanistic aspects and characterization of intermediates in the case of the hydroformylation of vinyl arenes because this is one of the most important breakthroughs in the area. The application of this catalytic reaction to different type of substrates, in particular dihydrofurans and unsaturated nitriles is the other main subject of this chapter because of their interest in organic synthesis and their industrial relevance. 

The hydroformylation of unsaturated nitriles such as crotonitrile and allyl cyanide is a potential route towards chiral amino alcohols, which are building blocks in the synthesis of pharmaceuticals. The hydroformylation of acrylonitrile was studied in the early years [5], but lately the hydroformylation of allyl cyanide and crotonitrile have also been investigated [25,81]. 

Keto ester 67 was converted to the unsaturated nitrile 70 in a routine manner. The latter proved to be an exceptionally useful intermediate. Concern that the significant steric demands which are associated with the formation of a sigma bond to the fully substituted beta carbon of the unsaturated nitrile would prevent reaction from occurring, were allayed by the discovery that the controlled potential reduction of 70 at —2.4 V in the presence of dimethyl malonate as the proton donor, alforded a 90% isolated yield of the requisite [3.2.1] adduct 71. This material was subsequently converted to enone 72 [42], a convergent point with an existing synthesis of quadrone (59). 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

For the synthesis of nonannulated 2-amino-4H-pyrans, acyclic carbonyl compounds 24 are used in Methods 1,2, and 3. Generally, readily accessible ketones 24, as well as unsaturated nitriles 25 contain electron-withdrawing substituents (R, X). Consequently, densely functionalized pyrans 22 are formed. UNs, widely used for aminopyran preparation, include 30-34... 

Nan ya et al. (97) also reported the synthesis of isoindolediones by the reaction of miinchnones with 1,4-benzoquinones. Reactions with an unsymmetrical mtinchnone were not regioselective. Several groups have examined the reactions of miinchnones with unsaturated nitriles, including 2-chloroacrylonitrile (98), cinna-monitrile (78,99) and fumaronitrile (78) to give unexpected products in several cases. Eguchi and co-workers (100) smdied the cycloaddition of several mtinch-nones with electron-deficient trifluoromethylated olehns. Thus, miinchnones 176... 

Preparative routes to 5/7-dibenz[6,e]azepine-6,11 -diones (morphanthridinediones) are based mainly on the cyclization of 2-aminobenzophenone-2 -carboxylic acids and their derivatives (55LA(594)89). Studies on a-aminodiphenyImethane-2 -carboxylic acid reveal that cyclization to 5,11 -dibenz[6,e ]azepinone (188) is much slower at room temperature than the cyclizations of the analogous 2-aminobiphenyl-2 -carboxylic acid and the 2 -aminobiphenylacetic acid (189), which at room temperature cyclize spontaneously to phenanthridone and dibenz[f>,d]azepin-6-one (190) respectively (61JOC1329). The hydrogen bromide-induced cyclization of dinitriles (Scheme 16) is adaptable to the synthesis of 2-amino-7-bromo-3//-azepines and 5H-dibenz[c,e]azepin-7-ones (67JOC3325). Apparently, for unsymmetrical dinitriles cyclization is such as always to give the azepine with the bromo substituent attached to the carbon of the a,j8-unsaturated nitrile as exemplified in Scheme 16. 

A more challenging example of an unsaturated nitrile reduction that lacks the carboxylate functional group is the asymmetric reduction of the nitrile shown in Figure 1.15. The product was required in the synthesis of chiral... 

The method was used for oxidation of an unsaturated nitrile (1) to an aromatic acyloin (2) in a projected synthesis of a model for olivin (4), an aglycone of olivomycin antibiotics.2... 

Cyclization reactions effected by intramolecular attack of a heteroatom on a nitrile group provide a useful source of 2-amino heterocycles, e.g. (120) —> (121), and numerous syntheses employ this strategy (vide infra). Thus, the reaction of a,(3-unsaturated nitriles (122) with elemental sulfur in basic media, the Gewald synthesis, provides a most convenient route to 2-aminothiophenes (123), many of which are a useful as intermediates in the preparation of dyestuffs and pharmaceuticals. 

Ring closure of unsaturated nitriles with sulfur (Gewald synthesis) 888... 

Cyanomethyl)zinc bromide, BrZnCH2CN (1). The reagent converts alkyl, ally lie, or propargylic iodides in the presence of HMPT to nitriles. The reaction is particularly useful for synthesis of y,5-unsaturated nitriles.5 Example ... 

See also page 403, Section 6, for the synthesis of a,/3-unsaturated nitriles, carboxylic acids and derivatives, and page 1711, Section 4, for the homologation of carbonyl compounds. 

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