Dihydropyridine derivatives Diels-Alder reaction

When methyl 2-(indol-2-yl)acrylate derivative (22a) reacted with A-methoxy-carbonyl-l,2-dihydropyridine (8a) in refluxing toluene, in addition to the dimer of 22a (25%), a mixture of the expected isoquinculidine 23a and the product 24a (two isomers) was obtained in 7% and 45% yields, respectively (81CC37). The formation of 24a indicates the involvement of the 3,4-double bond of dihydropyridine. Similarly, Diels-Alder reaction of methyl l-methyl-2-(indol-2-yl)acrylate (22b) with 8a gave, in addition to dimer of 22b, a mixture of adducts 23b and 24b. However, in this case, product 23b was obtained as a major product in a 3 2 mixture of two isomers (with a- and (3-COOMe). The major isomer shows an a-conhguration. The yields of the dimer, 23b, and 24b were 25%, 30%, and 6%, respectively. Thus, a substituent on the nitrogen atom or at the 3-position of indole favors the formation of the isoquinuclidine adduct 23. 

In Diels-Alder reactions a nitroolefin may function as an electron-deficient ene com-onent or a 1,2-dihydropyridine derivative may be used as a diene component. Both types of iactants often yield cyclic amine precursors in highly stereoselective manner (R.K. Hill, 1962 i. BOchi, 1965, 1966A). 

The 4 + 2-cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosoben-zene produces [2.2.2]bicycloadducts, which are readily reduced by alane to trans-2-substituted 3-amino-l,2,3,6-tetrahydropyridines stereospeciflcally.123 The intramolec- (g) ular nitroso-Diels-Alder reaction of a-acetoxynitroso derivatives in aqueous medium produces 3,6-dihydro-l,2-oxazines in high yield.124 The nitroso-Diels-Alder reaction of acyclic OTIPS-dienes (115) and 6-methyl-2-nitrosopyridine (114) in the presence of (g) [Cu(MeCN)4(difluorosegphos)]PF6 yielded the dihydro 1,2-oxazine cycloadduct (116) with high yield and enantioselectivity (Scheme 33). 125 (Fe)... 

Stereoselective Diels-Alder reactions have been reported in several cases. Enantioselective Diels-Alder reactions of l-phenoxycarbonyl-l,2-dihydropyridine with 1-alkylated acryloyl-pyrazolidin-3-ones using a chiral cationic palla-dium-phophinooxazolidine catalyst afforded chiral isoquinuclidines with excellent enantioselectivity <2005TL5677>. Bismuth(lll) chloride-mediated diasteroselective intramolecular [4-f2] cycloaddition reactions of A-allyl derivatives of pyrazole aldehydes led to fused sulfur-containing pyrazole heterocycles <2003SC3063>. A highly diastereoselective intramolecular hetero-Diels-Alder approach toward tetracyclic pyrazoles from 5-(3-methyl-2-butenylthio)-3-methyl-l-phenyl-4-pyrazolecarboxaldehyde has been reported <1997SL1155>. 

AT-Alkoxy- or iV-aryloxycarbonyl-pyridiniums can be reductively trapped as dihydro derivatives by borohydride no further reduction occurs because the immediate product is an enamide and not an enamine and therefore does notprotonate under the conditions of the reduction. The 1,2-dihydro-isomers, which can be produced essentially exclusively by reduction at -70 °C in methanol, can serve as dienes in Diels-Alder reactions. Irradiation causes conversion into 2-azabicyclo[2.2.0]hexenes removal of the carbamate and iV-alkylation gives derivatives that are synthons for unstable iV-alkyl-dihydropyridines, and convertible into the latter thermally. °... 

Two atypical reactions of tetrazines involve a dienatnine and a dihydropyridine. Acyclic diena-mines react with two molecules of 3,6-diaryl-l,2,4,5-tetrazines to give a mixture of 3,6-diaryl-pyridazines and the corresponding 4-dialkylamino derivatives (Scheme 112) reaction proceeds by cycloaddition to the terminal double bond and then to the enamine double bond by a second tetrazine to give the postulated intermediate (149), followed by loss of nitrogen and, finally, aromatization is achieved by an unusual carbon-carbon cleavage to give the two products <87H(26)337>. The expected inverse electron demand Diels-Alder reaction between the Ar-methyl-l,4-dihyropyridine (150) and... 

There are two other classes of dienyl lactams that have been used synthetically, A -alkyl-2-pyridones (160) and Al-acyl-l,2-dihydropyridines (161). Pyridones tend to be relatively unreactive, requiring high temperatures and often giving low yields of the cycloadduct.Al-Acyl pyrrole derivatives also function as diene partners in the Diels-Alder reaction. 

The initial product 2 loses N2 in a retro-DiELS-Alder reaction forming the 3,4-dihydropyridine 3, which aromatizes giving the pyridine derivative 4 by elimination of amine or alcohol. The geometry of the transition state of this [4+2] cycloaddition with inverse electron demand follows from the reaction of 3- or 6-phenyl-1,2,4-triazine 5 or 8 with enamines of cyclopentanone. It is apparently influenced by the secondary orbital interaction between the amino and phenyl groups. 3-Phenyl-1,2,4-triazine 5 favours the transition state 11. It leads first to the 3,4-dihydropyridine 6 which, on oxidation followed by a Cope elimination, affords the 2-phenyldihydrocyclopenta[c]pyridine 7. However, 6-phenyl-1,2,4-triazine 8 favours the transition state 12 leading to 3,4-dihydropyridine 9. Elimination of amine yields 5 -phenyldihydrocyclopenta[c]pyridine 10 ... 

Interestingly, the electrocyclic ring opening of dihydropyridines 119 is apparently slower than the intramolecular flZfl-Diels-Alder reaction depicted in Scheme 35. So, when triazine 118 is reacted with the enamine derived from cyclobutanone and diallylamine in situ, the tetracycle 114f is the sole product, isolated in quantitative yield (04TL8607) (Scheme 41). 

The Au(I)- or Ag(I)-catalysed intermolecular hetero-Diels—Alder cycloaddition of push-pull l,3-dien-5-ynes (76) with aldimines or silylaldimines (77) produced 5,6-dihydropyridin-2-ones (78) with high diastereo- and regio-selectivities (Scheme 24). A copper-catalysed intramolecular aza-Diels—Alder reaction has been used to produce dihydrochromeno[4,3-Mpyrrolo[3,2-/ quinolmes in good yields. The cinchonidine-derived quaternary ammonium catalyst, A-2, 3, 4 -trifluorobenzyl-0-benzylcinchonidinum bromide (79), catalysed the aza-Diels—Alder reactions between... 

An alternative asymmetric Diels-Alder reaction was reported by the Fukuyama group in which a dihydropyridine derivative and acrolein were used to build the cyclohexene ring (Scheme 16.2). Dihydropyridine 10 was synthesized from pyridine 9 by NaBH4 reduction in the presence of Cbz-Cl. An asymmetric Diels-Alder reaction between the dihydropyridine 10 and the acrolein in the presence of MacMillan catalyst 11 at room temperature... 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

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