Benzonitrile arylation

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of halides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsiiyl cyanide in EtiN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

Isoxazole-3-carbaldehyde has been obtained as a minor product from the reaction of acetylene with a mixture of nitric oxide and nitrogen dioxide (61JOC2976). Although 3-aryl-4-formylisoxazoles have been synthesized in good yields from the reaction of benzonitrile Af-oxides with 3-(dimethylamino)-2-propen-l-one (71S433), the parent member of the series, isoxazole-4-carbaldehyde, has never been reported. It may possibly be obtained by the addition of fulminic acid to 3-(dimethylamino)-2-propen-l-one. 

Photochemical [2 + 2] cycloaddition of benzonitrile and of 1- and 2-naphthonitriles to electron-rich alkenes such as 2,3-dimethyIbut-2-ene gives the corresponding 2-aryl-l-azetines in poor yield 72JA5929,76CC729, 77JOC4238). This does not appear to be a versatile route to 1-azetines. 

HECK REACTIONS OF ARYL CHLORIDES CATALYZED BY PALLADIUM/TRI-tert-BUTYLPHOSPHINE (E)-2-METHYL-3-PHENYLACRYLIC ACID BUTYL ESTER AND (E)-4-(2-PHENYLETHENYL)BENZONITRILE... 

It is noted that the reaction of aryl diazonium salts with CuCN to give benzonitrile derivatives is also called the Sandmeyer reaction. It is usually conducted in neutral solution to avoid liberation of HCN. 

A closely related reaction that is currently receiving much attention is the palladium-catalysed Suzuki coupling of arylboronic acids with aryl halides (Fu and Littke, 1998). For example, this technology has recently been applied by Clariant workers for the production of o-tolyl-benzonitrile (Eqn. (13)), an intermediate to a series of so-called angiotensin-II antagonists, a new class of antihypertensive drugs (Bernhagen, 1998). 

The reaction of 2-isothiocyanato benzonitrile with aryl acetonitrile anions was used to prepare quinazoline thione derivatives 53 <06S3067>. 

Interesting oxadiazole-substituted benzonitriles prepared from the respective aryl iodides were transformed into the corresponding (dioxadiazolephenyl)tetrazoles. Despite the high temperature and other drastic conditions, the oxadiazole ring stayed intact during both reactions (Scheme 20) <1999JOC6425>. 

Aryl halodiazarines 119 when reduced with potassium ethyl xanthate are reported to give 3-aryl-5-ethoxy-1,2,4-thiadiazoles 120 (13%) along with the expected product benzonitrile (87%) (Equation 31). A mechanism involving fragmentation of the diazirine 119 is proposed <1999TL29>. 

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

For more than a century, stoichiometric methods were presumed in the preparation of benzonitriles in laboratory and industry. These particularly include the Rosenmund-von Braun reaction of aryl halides, the diazotization of anilines and subsequent Sandmeyer reaction, and the ammoxidation. Because of (over)stoichiometric amounts of metal waste, lack of functional group tolerance, and harsh reaction conditions, these methods do not meet the criteria of modern sustainable synthesis. 

Recently, addition of organorhodium species to nitriles has been reported.420 4203 4201 Intermolecular reaction of benzonitrile with phenylborate (accompanied with r//w-aryiation) (Equation (65)), arylative cyclization of acetylenic nitriles (Equation (66)), and cyclization of 2-cyanophenylboronic acid with alkynes or strained alkenes (Equation (67)) are proposed to proceed via this process. 

Scheme 65) <60G1290>. Oxadiazolines (156) are produced by cycloaddition of cyanamides and nitrile oxides aryl (Scheme 66) <66JPR22l>. Thus, for un- and monosubstituted cyanamides, cycloaddition occurs to the C=N double bond of a tautomeric carbodiimide form rather than to a nitrile triple bond. On the other hand, dicyandiamide (157) and benzonitrile oxide furnish (158) (Scheme 67). 

Reaction of the 5-substituted aminothiadiazole (88 R = Bu ) with aryl nitriles produced amidines (89) in yields dependent on the reactivity of the nitriles (Scheme 14). Decreasing the electron density of the cyano group by such electron-withdrawing groups as p-nitrophenyl-, and 2- and 4-cyanopyridyl, led to higher yields as compared to unsubstituted benzonitrile. A bis thiadiazole (92 R = Bu ) was prepared by reacting the sodium salt of (88) with 2-methanesulfonyl-5-(-butyl-1,3,4-thiadiazole (91) <84JHC1377>. 

Beim Erhitzen von 5-Aryl-2-(2-benzyliden-l-phenyl-hydrazino)-l,3,4-oxadiazolen erhalt man unter Eliminierung von Benzonitril 2-Anilino-5-aryl-1,3,4-oxadiazole547. Fur diese Re-aktion wird analog anderen pyrolytischen /J-Eliminierungen692 ein cyelischer 6-Zentren-ProzeB vorgeschlagen. 

Aryl-4,5-dihydro-l,2-oxazole aligemeine Arbeitsvorschrift2 0,02 mol (/ )-l-Nitro-l-alken in 20 m/ trockenem Ether werden tropfenweise unter starkem Riihren zu einer Losung von 0,01 mol Benzonitril-oxid in 80 ml trockenem Ether bei 0° gegeben. Nach 12 h Riihren bei 25° wird die Mischung 2 h zum RiickfluB erhitzt, i.Vak. eingeengt und dcr Riickstand i.Vak. destilliert oder umkristallisiert. 

Benzoyl chloride condenses with benzonitrile or aryl cyanates in the presence of aluminum trichloride to give 1,3,5-oxadiazinium salts (Scheme 58) (67CB3736). 

Phenylsodium is formed initially in the reaction between benzonitrile and sodium (Scheme 79) (59JOC208). Trimerizations of aryl or heterocyclic nitriles catalyzed by amines or alkoxides resemble the reactions of the perfluoronitriles described above (Schemes 77 and 78 respectively). Kurabayashi et al. (71BCJ3413) studied the trimerization of benzonitrile under pressure in methanol, and have shown that the rate determining step is the reaction of the benzimino ether with benzonitrile. Steric factors exert an important influence in the trimerizations of aryl cyanides. The cyclizations of ort/zo-substituted aryl cyanides need more severe conditions than either the corresponding meta or para derivatives (Table 14). 

In this context it is interesting to note that benzonitrile, Ph—C=N, trimerizes to a triazine on a Raney nickel surface. It was assumed that Jt-bonded nitriles were involved in the reaction mechanism.10 This reaction resembles the well-known template synthesis of phthalocyanine complexes from phthalodinitrile. Formation of linear polymers [—C(R)—N—] occurs on heating aryl or alkyl cyanides with metal halides.11... 

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