1 -Methyl-1,2-dihydropyridine, reaction with

The ability of 1,2 (or l,6)-dihydropyridines to undergo a Diels-Alder reaction with dienophiles such as methyl vinyl ketone, methyl acrylate, and acrylonitrile has been utilized in the synthesis of polyfunctional isoquinuclidine as a key intermediate in the synthesis of aspidosperma- and iboga-type alkaloids (66JA3099). 

For example, the Diels-Alder reaction of A-benzyl-3-carboxamido-1,6-dihydro-pyridine (14a) andlV-benzyl-3-cyano-l,6-dihydropyridine (14b) with methyl vinyl ketone yielded isoquinuclidines 15a and 15b, respectively, which can be converted into ibogamine alkaloid (16). 

Another example in which A-methyl-l,2-dihydropyridine (41a) behaves as an enamine rather than a diene is its reaction with methyl vinyl ketone (44) (64JCS2165). The product is a pyran 45, which is obtained in 100% yield, rather than an isoquinuclidine derivative (80JOC1657). 

Similarly, the regiospecific 1,3-dipolar cycloaddition reaction of 1-methyl-1,2-dihydropyridines 41 with cyanogen azide (50a) and selected organic azides 50c and 50g afforded 2-methyl-2,7-diazabicyclo[4.1.0]hept-4-enes 57, which can be elaborated to 1-methyl-l,2,5,6-tetrahydropyridylidene-2-cyanamide (58) and 1-methyl-2-piperidylidenes 59a-d (85CJC2362). 

Alkyl-1,4-dihydropyridines on reaction with peracids undergo either extensive decomposition or biomimetic oxidation to A-alkylpyridinum salts (98JOC10001). However, A-methoxycarbonyl derivatives of 1,4- and 1,2-dihydro-pyridines (74) and (8a) react with m-CPBA to give the methyl tmns-2- 2>-chlorobenzoyloxy)-3-hydroxy-1,2,3,4-tetrahydropyridine-l-carboxylate (75) and methyl rran.s-2-(3-chlorobenzoyloxy)-3-hydroxy-l,2,3,6-tetrahydropyridine-l-carboxylate (76) in 65% and 66% yield, respectively (nonbiomimetic oxidation). The reaction is related to the interaction of peracids with enol ethers and involves the initial formation of an aminoepoxide, which is opened in situ by m-chlorobenzoic acid regio- and stereoselectively (57JA3234, 93JA7593). 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

The product (15-2) from aldol condensation of meto-nitrobenzaldehyde with the dimethyl acetal from ethyl 4-formylacetoacetate (15-1) provides the starting material for a dihydropyridine in which one of the methyl groups is replaced by a nitrile. Reaction of (15-2) with the eneamine from isopropyl acetoacetate gives the corresponding dihydropyridine hydrolysis of the acetal function with aqueous acid affords the aldehyde (15-3). That function is then converted to its oxime (15-4) by reaction with hydroxylamine. Treatment of that intermediate with hot acetic acid leads the oxime to dehydrate to a nitrile. There is this obtained nilvadipine (15-5) [16]. 

Methyl groups attached to the pyridine ring are not usually involved in reactions with MP, but a minor product from 4-methylpyridine is the dihydropyridine 102.291 It could be formed via a zwitterion corresponding to 95, proton transfer giving 101, addition to another molecule of MP, and a further proton shift. 

Another application of additions to chiral vinylic sulfoxides constitutes the Hantzsch-type reaction of methyl 3-aminocrotonate with compound (109), yielding the dihydropyridine derivative (110) as a single... 

Bis-silyloxy-3,4-dihydropyridines are stable dienes easily synthesized from glutarimide. The Diels-Alder reaction of azadiene 47 with iV-methylmaleimide in benzene at 60 °C gives predominantly the endo-adduct 48, whereas the selectivity is reversed in reaction with lithium trifluoromethanesulfonimide in ether giving predominantly the < vo-adduct 49 (Scheme 12) <1995SL565>. When methyl acrylate is used as the dienophile, the reaction... 

There has been extensive research into electrophilic additions to 3-substituted-l,4-dihydropyridines, such as N-methyl-3-cyano-l,4-dihydropyridine 138, which readily undergoes addition across the more reactive enamine-like 5,6-alkene to give 2,3,5-trisubstituted-l,2,3,4-tetrahydropyridines (Scheme 38) <1998JOC2728, 2000CEJ1763, 2003TL8449>. In an unusual example, the reaction with sulfinyl chlorides and triethylamine results in the formation of the 1,4-dihydropyridine sulfoxide 139, where in the absence of an additional nucleophile, the iminium intermediate is deprotonated to yield the monosubstituted 1,4-dihydropyridine product 139. 

Derivatives of pyridine-3,5-dicarboxylic acid have been shown to undergo reaction with lithium aluminum hydride by attack on the pyridine ring to form 1,4-dihydropyridines.57,58 Presumably the decrease in electron-density at the ring carbon atoms due to these substituents causes the ring to be extremely susceptible to hydride attack. Similar results were obtained with 3,5-dicyanopyridine derivatives. Methyl nicotinate, however, underwent reaction with LAH with exclusive reduction of the ester function.57 Recently the 3,5-dicyanopyridines have been reported to give mixtures of 1,2- and 1,4-dihydropyridines on reduction with LAH or sodium boro-hydride.20 ... 

Azine approach. Pyridine TV-oxides undergo 1,3-dipolar cycloaddition reactions with aryl isocyanates. The first formed 1,2-dihydropyridines are unstable and rearrange at once to the 2,3-dihydropyridines (287). From 3-picoline 1-oxide both the 6-methyl and 7a-methyl isomers are formed. The adduct (288) from 3,5-dibromopyridine 1-oxide reacts further to eliminate HBr, thereby giving the fully aromatic system (79CPB2261). 

Dihydropyridines are reactive 1,3-dienes, but their reactions with dienophiles are strongly dependent on the nature of the latter and the reaction conditions. Thus, l-methyl-l,2-dihydropyridine 539 reacts with methyl acrylate at IOC to give a product of overall [2 + 2] cycloaddition 540 by reaction as an enamine. On the other hand, at +80 C compound 539... 

Treatment of lV-methanesulfonyl-l,4-dihydFopyridine with n-butyllithium, followed by benzyl bromide, leads to the corresponding lV-l-(2-phenylethyl)sulfonyl-l,4-dihydropyridine in low yield. The sulfonamide shown in Scheme 131 (entry c) has proved a valuable c -isoprenoid synthon which allows the two-step C -homologation of allyl halides. This synthon was used for the remarkable two-step stereoselective synthesis of nerol from 3-methyl-2-butenyl chloride (Scheme 131, entry c). Finally, the a-chloro dicarbanion of 4-(a-chlon>methanesulfonyl)morpholine is readily availabl on reaction with 2 equiv. of n-butyllithium in THF, and it leads to the corresponding dimethyl derivative with no detectable monoalkylated product or starting sulfonamide on methylation. Intramolecular versions of these reactions allow the low yield synthesis of neopentyl cyclopropanesulfonate (scheme 131, entry d) and the efficient preparation of cyclopropanesulfomorpholine (scheme 131, entry e). ... 

DHPs and their equivalents are very beneficial in the synthesis of nitrogen-containing compounds as well as natural products [52]. The simplest 1,2-dihydropyridine unencumbered by perturbing substituents is V-methyl-1,2-DHP (53) which, on reaction with methyl acrylate, yields a mixture of endo and exo adducts (54a and 54b) (Scheme 1) [53,54]. 

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