Nitriles 2-keto

Tertiary amines capable of eliminating a secondary amine to form a conjugated system can react with hydrogen cyanide to form y-keto nitriles by amine replacement. Thus (I) yields p-benzoylpropionitrile (IV) ... 

Isoxazoles unsubstituted in the 3-position react with hydroxide or ethoxide ions to give )3-keto nitriles (243) -> (244). This reaction involves nucleophilic attack at the 3-CH group. 1,2-Benzisoxazoles unsubstituted in the 3-position similarly readily give salicylyl nitriles (67AHC(8)277), and 5-phenyl-l,3,4-oxadiazole (245) is rapidly converted in alkaline solution into benzoylcyanamide (246) (61CI(L)292). A similar cleavage is known for 3-unsubstituted pyrazoles and indazoles the latter yield o-cyanoanilines. 

The early stages of the reaction of the quaternary salt can be regarded as proceeding in a manner exactly analogous to that by which the isoxazoles themselves are degraded, the j8-oxoketene imine structure (148) being one mesomeric form of a compound which could alternatively be formulated as a nitrilium betaine. However, by contrast with the products from the isoxazoles (i.e., enolates of /3-keto-nitriles), this is electrically neutral and susceptible to further nucleophilic attack. 

The above keto-nitrile (15 grams) was methylated with a solution of diazomethane in ether. (The diazomethane solution was prepared using 20 grams of N-nitrosomethylurea.) The ether and excess diazomethane were evaporated on the steam bath and the oil dissolved in ethanol (50 ml). To this was added a solution of guanidine in ethanol (100 ml) (prepared from 8.1 grams of the hydrochloride). The solution was refluxed for 5 hours, the alcohol removed and the residue treated with 5N sodium hydroxide. The insoluble material was then filtered. After purification by precipitation from dilute acetic acid with sodium hydroxide and by recrystallization from ethanol the product formed clear colorless needles (8.0 grams), MP 218°-220°C as described in U.S. Patent 2,602,794. 

Treatment of 2-cyclohexenone with HCN/KCN yields a saturated keto nitrile rather than an unsaturated cyanohydrin. Show the structure of the product, and propose a I. mechanism for the reaction. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

White-rot fungus has been used as a biocatalyst for reduction and alkylation. The reaction of aromatic -keto nitriles with the white-rot fungus Curvularia lunata CECT 2130 in the presence of alcohols afforded alkylation-reduction reaction [291]. Alcohols such as ethanol, propanol, butanol, and isobutanol could be used (Figure 8.39d). 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

In the case of unsymmetrical ketones, the attack usually comes from the less highly substituted side, so that CH3 is more reactive than RCH2, and the R2CH group rarely attacks. As in the case of 10-118, this reaction has been used to effect cycliza-tion, especially to prepare five- and six-membered rings. Nitriles are frequently used instead of ketones, the products being 3-keto nitriles. 

In another procedure, acyl radicals derived from phenyl selenoesters ArCOSePh I by treatment of them with Bu3SnH) add to a,P-unsaturated esters and nitriles to give y-keto esters and y-keto nitriles, respectively. ... 

In the Thorpe reaction, the a carbon of one nitrile molecule is added to the CN carbon of another, so this reaction is analogous to the aldol reaction (16-38). The C=NH bond is, of course, hydrolyzable (16-2), so p-keto nitriles can be prepared in this manner. The Thorpe reaction can be done intramolecularly, in which case it is... 

Keto nitriles, by cnnjugate addition of aldehydes, 59,5 6 KETONES, acetylemic, 55, 52... 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

The l,4-dihydropyrimido[l,2- ]pyridazine 101 was obtained by tandem cyclization from [4+2, 6+0] atom fragments by reacting [3-keto nitriles and the 2-cyanopropylhydrazine 100 (Equation 10) <2000MI639>. 

Keto nitriles, such as 138, function admirably as substrates in reductive cycliza-tions [56, 57], Two product types are obtained, one the simple ketone 140, the other 139, incorporating the a-hydroxy ketone (ketol) functionality that is present in many natural products (note Eq. 42). Both controlled potential and constant current conditions have been utilized. Of the electrodes examined (Ag, Cd, Pb, Zn, C-fiber, and Sn), tin generally proved most effective. Using tin, the controlled potential reduction of 138 in i-PrOH at —2.8 V vs SCE (divided cell, ceramic diaphragm) afforded a 76% yield of ketol 139 accompanied by 2% of ketone 140. As illustrated in Table 7, the preference for ketol formation drops when the transformation is carried out at constant current or without using a diaphragm. 

Selective reduction of the nitrile group in 87% yield without the reduction of the carbonyl was achieved by stannous chloride [1153]. Oximes of keto nitriles are reduced preferentially at the oximino group by catalytic hydrogenation in acetic anhydride over 5% platinum on carbon (yield 85%)... 

Cyano-substituted 1,2,4-trioxolanes (107) react with dimethyl sulfide at — 78°C to give the expected keto nitriles (106) <90TL3299>. Triphenylphosphine gives an unexpected result, with the involvement of a cyclic intermediate and a 1,3-cyano shift used to explain the product (108) obtained (Scheme 27). 

XLIV) centers about elaboration of hydroxymethylene ketone (574) into the tricyclic diketone (578). Alkylation of keto nitrile 575 proceeds exclusively cis to the angular methyl groups as does the subsequent reductive methylation. These authors were not able to achieve aldol cycUzation of keto aldehyde 576 and consequently proceeded to enol lactone 577 The addition of a methyl group to 578 could be achieved regioselectively. Subsequently dehydration gave 579 and its endocyclic isomer which were separated chromatographically. 

RuCl2(CO)3]j The oxidative dehydrogenation of a-hydroxy esters RCH(OH) COOR and cyanohydrins RCH(OH)(CN) to the corresponding a-keto esters and a-keto nitriles was effected by [RuCl3(CO)3]3/TBHP/CgHg, and the reaction was also catalysed by RuBrj, Ru(acac)3, RuClj(PPh3)3 and Ru3(CO)j2 [695],... 

Aldehydo nitriles are readily available and can be used to prepare 4-amino-6-unsubstituted pyrimidines carrying one or more substituents in any of the other positions. Equivalents of the formyl group are also often used, for example, a 3-ethoxy-, 3-amino-, or 3-haloacrylonitrile. Most syntheses with /3-keto nitriles are carried out with equivalents thereof Such equivalents are /3-substituted /3-alkoxy-, /3-amino-, or /3-haloacrylonitriles. /3 -Ester nitrile reactions are also well established. Malononitriles and substituted malononitriles react readily with thiourea and N-substituted thioureas in refluxing ethanolic sodium ethoxide to form pyrimidine-4,6-diamines. An example is the reaction of N2-malononitrile 680 with N2-thiourea 681 to give N4- 4,6-diamino-2-(l//)-pyrimidinethione 682 which was then used in the synthesis of Ns-labeled adenine derivatives <2001JOC5463>. 

The three-carbon component in this subgroup is either a /3-dicarbonyl compound or a /3-keto nitrile. The N and C-N components in the reactions with /3-dicarbonyl compounds come from formamide, a nitrile, a thiocyanate, or a cyanamide <1994HC(52)1>. 

POLYMER-SUPPORTED CHIRAL SULFONAMIDE CATALYZED REDUCTION OF j -KETO NITRILES A PRACTICAL SYNTHESIS OF (R)-FLUOXETINE... 

Enantioselective reduction of jS-keto nitriles to optically active 1,3-amino alcohols has been carried out in one step using an excess of borane-dimethyl sulfide complex as a reductant and a polymer-supported chiral sulfonamide as a catalyst with moderate to high enantioselectivity (Figure 3.11). The facile and enantioselective method to prepare optically active 1,3-amino alcohols has been used to prepare 3-aryloxy-3-arylpropylamine type antidepressant drugs, for example (l )-fluoxetine. 

Acid derivatives that can be converted to amides include thiol acids RCOSH, thiol esters RCOSR,911 acyloxyboranes RCOB(OR )2,912 silicic esters (RCOO)4Si, 1,1,1-trihalo ketones RCOCX3,913 a-keto nitriles, acyl azides, and nonenolizable ketones (see the Haller-Bauer reaction 2-33). 

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