1.2- Dihydropyridine reaction with dienophiles

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). 

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... 

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... 

Support-bound pyridines and partially saturated pyridines can be valuable synthetic intermediates, enabling various types of chemical transformation. Piperidinones can be prepared on cross-linked polystyrene by the addition of organometallic reagents to tetrahydropyridinones (Entry 10, Table 15.23). 1,2-Dihydropyridines are electron-rich dienes that can undergo Diels-Alder reaction with electron-poor dienophiles. Diels-Alder cycloaddition of support-bound 1,2-dihydropyridines has been used to prepare nitrogen-containing polycyclic systems (Entry 12, Table 15.23). 

Linear tricyclic systems have been obtained from intramolecular photocyclization of l,2-dihydropyridin-2-one to give an olefinic bicyclic product and subsequent Diels-Alder reaction with an acyclic dienophile to give the tricyclic compound. Reactions of this type have been mentioned in Sections 2.04.6.3 and 2.04.7.2. 

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... 

Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile 38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition, the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct 40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield.3... 

Heterocycles with a similar 1,4-dihydropyridine ring, such as TV-substituted 1,4-dihydroquinolines (39), have also been allowed to react with dimethyl acetylenedicarboxylate. Depending on the substituent at the ring, a (2 + 2)-cycloadduct (40)60 or a linear Michael adduct (41)59 was formed. The (2 + 2)-cycloadducts (43) of l,2-dihydropyridines(42) with dimethyl acetylenedicarboxylate are far less stable. Only NMR spectroscopy at —10° to 0° has provided evidence for the formation of 43. At room temperature the (2 + 2)-cycloaddition was followed by isomerization to the corresponding 1,2-dihydroazocine (44).15>6 The reaction took a different course when other dienophiles were employed for instance, with iV-phenylmaleimide or maleic anhydride, Diels-Alder-type adducts were formed. Reaction of a 1,2-dihydropyrazine (45) with dimethyl acetylenedicarboxylate yielded a bicyclic compound, which was shown to be not the expected (2 + 2)-cycloadduct 46, but the isomeric 2,7-diazabicyclo(4.2.0]octa-2,4-diene (47). This compound was claimed to result from initial (2 + 2)-cycloaddition, ring opening, and subsequent m/ramolecular (2 + 2) cycloaddition [Eq. (9)1.62... 

Oxy-Cope rearrangements (95, 98, 99) have been extensively used in natural product synthesis to generate l-oxo-hexa-l,5-diene systems which are then elaborated to introduce the functionality presented in the selected targets. Wender and his coworkers have utilized this methodology in a key step in the synthesis of reserpine (36, 37). They envisioned that the DE-ring precursor 128 could arise from the hydroisoquinoline 129 which could be generated by oxy-Cope rearrangement of isoquinuclidene 130 (Scheme 3.20). This key intermediate, in turn, could be prepared by Diels-Alder reaction of dihydropyridine 131 with an appropriately substituted dienophile 132. 

Diels-Alder reactions of 1,2-dihydropyridines with reactive dienophiles such as azo compounds and maleimides are also known (76JHC481). 

Recently reported has been a comprehensive experimental and theoretical study of the Diels-Alder reaction of 1,2-dihydropyridines such as 56, 94 and 112 with numerous dienophiles to form 2-azabicyclo[222]octenes <2007JOC3458>. It was discovered that in all cases the kinetic preference was for the endo-aAAuct. Theoretical calculations showed that for the dienophile methyl vinyl ketone the total transition state energy favored the... 

Studies on the addition of acyl nitroso compounds to 1,2-dihydropyridine derivatives have been described, and some of the results are shown in equation (38). It was found that the nitroso dienophiles produced from hydroxamic acids (100) reacted with dihydropyridine (99) at di erent rates and afforded the ratios of regioisomeric products indicated. Both the relative reaction rates and orientation are in accord with a HOMO-diene/LUMO-dienophile controlled process. 

A convenient synthesis of functionalized isoquinuclidines, with very good endo (64, 90%)/exo (65, 10%) selectivity, from N-benzyl-3-ethyl-l,6-dihydropyridine that offers the advantage of avoiding the need to isolate and purify the unstable DHP entity (generated in situ and trapped by the dienophile present in the reaction mixture) was recently reported [69]. This approach is outlined below ... 

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