A-active methylene nitrile

Base-promoted aminothiophene formation from ketone, a-active methylene nitrile and elemental sulfur. 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

Active methylene nitriles condense with o-substituted aryl and heteroaryl azides in a two-step process to give tricyclic triazolopyrimidines without isolation of the triazole intermediates <85BSB441, 87BSB587). 5-Azido-4-formyltriazoles (758) condense with dimethyl 3-oxopentanedioate and tri-ethylamine in ethanol to give 5-(triazol-l-yl)-4-formyltriazoles (759), which undergo cyclization to... 

Amino-1,2,3-triazoles with a substituent at the 4-position have been prepared (i) from azides and active methylene nitriles (ii) from azides and ynamines (iii) from diazomethane and carbo-diimides (iv) from azides and 1,1-diaminoethenes and (v) from the rearrangement of 3-hydrazono-1,2,4-oxadiazoles. Among these, the first method, a regiospecific process, is the most versatile and convenient although it is suitable only for 5-NH2-substituted triazoles. Other methods are used to prepare 5-NHR , 5-NR R - and 5-NHCOR-substituted triazoles. Intramolecular cyclization of suitable precursors also gives 5-aminotriazoles. For example, a-imino-a-piperidyl phenylhydrazones (838), in the presence of copper acetate, give 5-piperidyl-triazoles (839) (Equation (85)) <94H(38)739>. 

A -(Cycloalken-l-yl)pyrazoles 438 were synthesized via elimination of benzotriazole from the corresponding 1-[1-(pyrazolo)cycloalkyl]benzotriazoles 437, prepared from l-(benzotriazolylmethyl)pyrazole 436 (Scheme 49) <2002JOC8230>. The reaction of l-(3,5-dimethylpyrazol-l-yl)acetone 439 with phenyldiazonium chloride afforded the corresponding phenylhydrazone 440, which was converted into pyridazines 441 and 442 by condensation with active methylene nitriles and DMEDMA, respectively (Scheme 50) <2001JHC685>. 

Kappe and co-workers also utilized microwave irradiation to facilitate a three component one-pot synthesis of a library of 3,5,6-substituted 2-pyridones 18 <04T8633>. This method utilizes a CH-acidic substrate 19, dimethylformamide dimethylacetal (DMF-DMA) and diverse active methylene nitriles 20 as building blocks. 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

This variation provides a regiospecific synthesis of isoxazoles with a great variety of substituents. The nitrile A-oxide does not react with the doubly activated methylene group in neutral or acidic medium, but under alkaline conditions the reaction proceeds exother-... 

The bispyrazolodihydropyran 435 was obtained directly as a rapidly formed insoluble by-product in the reaction of 3-methyl-l-phenylpyrazol-5-one 433 with activated nitriles 434 in the presence of catalytic piperidine (Equation 117) <2000MOL746, 2000JCCS937>. It is proposed that the reaction proceeds by loss of the active methylene moiety from the initial Michael adduct, allowing attack by a second molecule of pyrazol-5-one. 

The 1,3-dipolar cycloaddition of azido-l,2,5-oxadiazoles (azidofurazans) to dicarbonyl compounds has been studied and a new procedure for the synthesis of (l,2,3-triazol-l-yl)-l,2,5-oxadiazoles was proposed <2002MC159>. The cycloaddition of 4-amino-3-azido-l,2,5-oxadiazole 168 to nitriles with activated methylene groups has been studied, and 3-amino-4-(5-amino-l/7-l,2,3-triazol-l-yl)-l,2,5-oxadiazoles 169 and the products of their Dimroth rearrangement 170 have been synthesized <2004MC76>. 

Typical liquickliquid alkylation of methylene groups activated by a carbonyl or nitrile group... 

Conversely, activated methylene compounds undergo an addition reaction across the C=N bond of imines. For example, benzylic ketones react with benzylidene anilines to from P-aminoketones [35], whereas the analogous reaction of diphenyl-methylene-protected a-amino esters, and nitriles, produces a disastereomeric mixture of the A-protected a,p-diamino esters, and nitriles [36, 37]. 

Decarboxylation of 1,3-dimethylorotic acid in the presence of benzyl bromide yields 6-benzyl-1,3-dimethyluracil and presumably involves a C(6) centered nucleophilic intermediate which could nonetheless have either a carbene or ylide structure. Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry has been used to explore the gas-phase reactions of methyl nitrate with anions from active methylene compounds anions of aliphatic ketones and nitriles react by the 5n2 mechanism and Fco reactions yielding N02 ions are also observed nitronate ions are formed on reaction with the carbanions derived from toluenes and methylpyridines. 

Triazoles have also been obtained when the carbon atom adjacent to the activated methylene group carries a nitrogen function (i.e., amides, nitriles, amidines, and imines - ). In many of these cases it is impossible to decide, without N-labeling experiments, whether the third nitrogen of the triazole ring is derived from the toluene-p-sulfonyl azide or from the activated methylene compound. With amides, amidines, and nitriles, the first possibility seems more reasonable, but with imines, the third nitrogen is that of the imino group (Scheme... 

Another important reaction in synthetic chemistry leading to C-C bond formation is the Michael addition. The reaction typically involves a conjugate or nucleophilic 1,4-addition of carbanions to a,/l-unsaturated aldehydes, ketones, esters, nitriles, or sulfones 157) (Scheme 21). A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor), which attacks the alkene (acceptor). Strong bases are usually used in this reaction, leading to the formation of byproducts arising from side reactions such as condensations, dimerizations, or rearrangements. 

The nitrosation of aliphatic carbon atoms, particularly of carbon atoms activated by adjacent carbonyl, carboxyl, nitrile, or nitro groups, has been reviewed in great detail [2]. Judging from this review, with few exceptions, nitrosation of active methylene compounds leads to the formation of oximes (unfortunately termed isonitroso compounds in the older literature). The few exceptional cases cited in which true nitroso compounds (or their dimers) were formed involved tertiary carbon atoms in which no hydrogen atoms were available to permit tautomerism to the oxime or involved a reaction which was carried out under neither acidic nor basic conditions. 

Base-catalyzed condensation of 2-azidobenzoic acid or its nitrile with active methylene compounds furnished the 4-substituted 1,2,3-triazolo [l,5-a]quinazolines (290) in good yield [66JCS(C)2290 69JCS(D)423 74JCS(P1)534]. 

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