1.2- Dihydropyridines cycloaddition

Chiral dihydropyridines such as 103 were also accessible from Zincke-derived N-alkyl pyridinium salt 102 (Scheme 8.4.34). The dihydropyridine underwent cycloaddition with methylacrylate, providing chiral isoquinuclidine derivative 104 as the major diastereomeric product. ... 

A number of dihydropyridines and tetrahydropyridines undergo cycloaddition reactions. 

Dihydropyridines 28 behave as enamines and undergo [2 - - 2] cycloaddition reactions with dienophiles such as acrylonitrile (29) and dimethyl acetylenedicar-boxylate (32). For instance, A -alkyl-l,4-dihydropyridine 28 reacts with 29 to give... 

The [2 + 2] cycloaddition reaction of A -benzyl-l,4-dihydropyridine 34b with acrylonitrile, followed by catalytic reduction gave two pairs of diastereoisomeric amides 36 and 37 with a low diastereomeric excess, probably due to the large distance between the asymmetric center and the site of acrylonitrile attack. Compounds 36 and 37 were resolved into the four individual diastereoisomers (ca 5% for compound 36 and 15% for 37) [97JCR(M)321], Irradiation of 1,4-dibenzyl-1,4,5,6-tetrahydropyridine 38 in the presence of 29 gave two stereoisomers. 

A -Alkyl-l,2-dihydropyridines that are not stabilized by electron-withdrawing groups on the ring could behave as dienophiles towards alkynes. For example, N-methyl-l,2-dihydropyridine 41a reacts with dimethyl acetylenedicarboxylate (32) to give [2 + 2] cycloaddition product 42, which rearranges to give the azocine derivative 43 [74JCS(P1)2496],... 

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). 

Cycloadditions are in general an effective way of constructing cyclobutane rings. A wide variety of heterocyclic systems dimerize in this way. 1,3-Diacetylindole, for example, affords the head-to-tail dimer 242 on irradiation in ethanol.185 Ethyl 2-ethoxy-l,2-dihydroquinoline-l-carboxy-late is similarly converted in diethyl ether into the trans head-to-head dimer.186 Notable among many analogous photodimerizations are those reported in 1,4-dihydropyridines,187 in furo[3,2-b]pyridin-2(4//)-ones,188 in 8-methyl-s-triazolo[4,3-a]pyridine,189 and in 2H-2-benzazepine-1,3-diones.190 The [ 2 + 2] dimerization of amidopyrine is the first reported example of a photocycloaddition in a 4-pyrazolin-3-one.191... 

Cycloadditions to a cyano group are comparatively rare. The high-temperature reactions of 1,3-dienes, e.g. butadiene, isoprene and 2-chloro-l,3-butadiene, with dicyanogen, propionitrile or benzonitrile result in formation of pyridines (equation 80)70. Sulfonyl cyanides 147, obtained by the action of cyanogen chloride on sodium salts of sulfinic acids, add to dienes to give dihydropyridines 148, which are transformed into pyridines 149 by oxidation (equation 81)71. 

Cycloaddition reaction of the l-acyl-l,2-dihydropyridine derivative 240 with methyl cyanodithioformate afforded adduct 241, which was converted by three steps to solenopsin A (Id) (Scheme 13) (399). This route constitutes a completely stereoselective synthesis of this alkaloid however, details are not available. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Similar strategies have been pursued by other workers. The reaction of indolyl acrylate (231) is of interest because of the formation of (252) in addition to the expected isoquinu-clidine (253) (81CC37). Although (252) was formed in low yield, it is unusual because cycloadditions involving the 3,4-double bond of the dihydropyridine are rare (81CC37). 

The 1,2-dihydropyridines are also known to undergo [2 + 2] cycloadditions of the enamine double bond with alkynes (74JCS(P1)2496). The products of these reactions are azocine derivatives such as (259), which, after removal of the A-protecting group, have been used as intermediates in pyrrolizine synthesis (Scheme 47) (77JOC2903). 

In summary, the cycloaddition reactions of 1,2-dihydropyridines have proven to be very useful in the total synthesis of natural products. The primary reasons for their utility are that they have electron-rich reactive 7r-systems, they contain a heterocyclic nitrogen atom for alkaloid synthesis, and the stereochemistry is controlled in their cycloaddition reactions. 

The cycloaddition reactions of 1,4-dihydropyridines have not been as extensively studied as those of their 1,2-dihydro isomers. Possibly this is on account of an early report on the attempted reactions of N-trimethylsilyl-l,4-dihydropyridine (69JOC3672). Also, until recently, simple 1,4-dihydropyridines were not as synthetically accessible (75CC480, 80TL2105). 

The other dihydropyridines containing electron-deficient 7r-systems should also be capable of undergoing cycloaddition reactions. However, the instability of these compounds and lack of general methods for their preparation have precluded their study. In principle both the 2,3- and 3,4-dihydropyridines could behave as heterodienes in the Diels-Alder reaction. Although these reactions are known for the 2-azadienes, lack of information in the literature on 1-azadienes suggests that they will be reluctant to participate in cycloadditions double bonds present in the 2,5-dihydropyridine are isolated and would only be expected to behave as two-electron partners in cycloaddition reactions. 

There are isolated reports where these dihydropyridines are involved in cycloaddition reactions. For example, the thermal rearrangement of 1,2-dihydropyridines gives 2,3-dihydropyridines. It has been postulated that the formation of (287) from the 1,2-dihy-dropyridine (284) occurs by rearrangement to (286) via the 2,3-dihydropyridine (285). An intramolecular cycloaddition reaction of (286) gives the observed product (Scheme 57) (78JA6696). 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

Studies focused on the ability of ALvinyl carbodiimides to undergo cycloaddition reactions have been carried out in recent years (Scheme 56). Thus, 2-azadiene derivatives 245 reacted with tetracyanoethylene to yield dihydropyridines 246 (86CL135), whereas treatment of 245 with... 

A fairly general route to 1,2-dihydroazocines (64) is provided by the [2+2] cycloaddition of DMAD to 1,2-dihydropyridines (62) (74JCS(Pi)2496,77JOC2903). The reaction gives good yields of the dihydroazocine-6,7-dicarboxylates with N- alkyl, -aryl or functionally substituted removable protective groups. Other substituents can be present at C-3 or -4 in the pyridine, but carboxyl substituents at N-l or C-5 of the pyridine reduce the enamine character, and Diels-Alder addition of the acetylene occurs at the diene system. The [4.2.0] bicyclic intermediates (63) can be detected at -10 to 0°C by NMR warming to 20 °C causes complete conversion to (64). 

Cycloaddition of 1-alkyl-1,4-dihydropyridines and DMAD gives cyclobutapyridines which are stable and do not undergo ring opening. However the cycloadducts (65) formed from thiocarbamoylmethylenepyridines lead to azocines (66) in 40-70% yields (75CPB2749). Similarly, l-methyl-l,4-dihydroquinoline gives l,6-dihydrobenzazocine-3,4-dicarboxylate (67). 

The 1,2-dihydropyridine ring can also undergo [2 + 2] cycloaddition with alkynes (Scheme 58). 

Cycloaddition of DMAD to 1,2-dihydropyridines (77JOC2903) is a fairly general route to 1,2-dihydroazocines which proceeds via a bicyclic intermediate as described in Section 3.2.2.3.8. 

A one-step synthesis of furo[3,2-c]- and furo[3,2-6]-pyridines has been realized using a cycloaddition reaction of an alkynic compound with 3,5-dichloropyridine 1-oxide (Scheme 15) (75JA3227). Formation of (75) probably proceeds through a 1,2-dihydropyridine (73) with a subsequent 1,5-sigmatropic shift to (74) elimination of hydrogen chloride yields... 

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