1.2- Dihydropyridine 2 + 2 cycloaddition with alkynes

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

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). 

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... 

Related [4+2] cycloadditions involving substrates that incorporate heteroatoms into the formed six-membered ring are also known. In representative examples from Matsubara and Ogoshi, the cycloaddition of alkylidene malonates with alkynes provide dihydropyran products, whereas cycloadditions of 1,3-dienes with nitriles provide pyridine products (Scheme 3-22). The formation of pyridines arises from oxidation of initially formed dihydropyridines. 

The nickel-catalysed 2 + 2 + 2-cycloaddition of a 3-methyl-2-pyridyl aldimines with alkynes produced 1,2-dihydropyridine adducts in good yields. A key step in this transformation is the formation of aza-nickelacycle intermediates. The iron-catalysed 2 + 2 + 2-cycloadditions of alkyne nitriles with alkynes, in the presence of pyridyl bisimine ligands (95), formed substituted pyridines in good yields. The nickel-catalysed 2 + 2 + 2-cycloadditions of diynes and cyanamides have been investigated. The reactions have been shown to be regioselective, and cycloadducts are produced in good to excellent yields. ... 

The mesoionic 3-oxido-N-alkylpyridinium betaine 15-whose electronic description formally corresponds to that of 1,3-dipoles a/b - undergoes cycloadditions with activated alkynes and aUcenes. Thus, phenylacetylene (and analogously acrylate) adds via C-2/C-6 to give 8-azabicyclo[3.2.1]octane derivatives 16. In contrast, dimethyl acetylenedicarboxylate adds via O/C-2 to give as primary product the furo-l,2-dihydropyridine 17, which subsequently is converted to the furan derivative 18 by 67t-electrocyclic N/C-2 opening of the dihydropyridine ring [146] ... 

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],... 

Triazines react also with electron-rich dienophiles such as ethyl vinyl ether (401 R = Et) or vinyl acetate (401 R = Ac) in boiling dioxane to yield the pyridine derivatives (376). After the usual [4 + 2] cycloaddition and nitrogen elimination from the bicyclic compound (402), the dihydropyridines (403) eliminate ethanol or acetic acid to give the aromatic pyridines (376). The dienophiles (401) can therefore be used as alkyne equivalents (69TL5171). 

Pentacarbonyl(carbene)chromium complexes with a primary amino group at the alkenyl terminus 32, readily obtained by addition of ammonia to alkynyl-substituted complexes, initially rearranged upon heating to pentacarbonylchromium-coordinated 1-azabuta-l,3-dienes 33, which subsequently underwent [4 + 2] cycloaddition of an alkyne to give coordinated 4-ethoxy-1,4-dihydropyridines the corresponding pyridines, e.g. 34, were formed by 1,4-elimination of ethanol. ... 

Methyl-1,2-dihydropyridine behaves as an enamine rather than as a diene at — 10°C in its primary cycloaddition reactions with alkenes and alkynes. At higher temperatures, the [2 -I- 2] cyclo-adducts, e.g. (79), are unstable, and the more thermodynamically stable Diels-Alder endo- and exo-adducts, e.g. (80) and (81), are formed. ... 

Aiming to develop an efficient route to 1,2-dihydropyridines, Ogoshi et al. performed extensive mechanistic studies with a stoichiometric amount of nickel complex [16]. These studies revealed a plausible mechanistic pathway for this particular cycloaddition reaction. Further experimentation revealed that the use of electron-donating, sterically hindered phosphines actually renders the reaction catalytic. Three catalytic examples were reported. These include the cycloaddition of alkyl-aryl alkynes (72 and 73) and trimethylsilyl acetylene (74) (Scheme 2.19). The moderate yields of cycloadducts and small substrate scope still need to be addressed. 

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