Pyridines 1,4-dihydro-, ring synthesis

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Extensive stmcture activity relationship (SAR) studies in this series revealed that unsymmetrical substitution on the heterocyclic ring and hence the introduction of chirality on the central carbon atom led to increased potency. Such asymmetrical dihydro-pyridines can be prepared by stepwise variation of the Hantzsch synthesis, based on the hypothetical alternate route to nifedipine. Thus, aldol condensation of methyl acetoacetate with 2,3-dichlorobenzaldehyde (13-1) gives the cinnamyl ketone (13-2). Reaction of that with the enamine (13-3) from ethyl acetoacetate gives the calcium channel blocker felodipine (13-4) [14]. 

While the synthesis of benzofuran derivatives from suitable furan derivatives has been comparatively little investigated, the synthesis of fused two-ring and three-ring compounds containing a pyridine nucleus from furan derivatives has been more successful furo[3,2-c]pyridines (345),752>753 2,3-dihydrofuro[2,3-a ]quinolines (from 4,5-dihydro-3-furoic acid),754 acrophyllin (346), and 7-hydroxydictamnine (347) (from ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate),755 are examples of compounds in this class which have been prepared. 

Synthesis of thiazolo[3,2-a]pyridin-3(2//)-one can also be accomplished by an alternate route in which a thiazole ring is built onto a pyridine ring. Thus, copper-catalyzed reaction of piperidine-2-thione (95) with methyl diazoacetate affords 5,6-dihydro-7//-thiazolo[3,2-a]pyridin-3(2//)-one 97) (80LAI68) (Scheme 22). During the reaction uncyclized intermediate (96) could not be isolated, it evidently cyclized immediately to the bicyclic product (97), whereas with the pyrrolidine-2-thione the corresponding uncyclized product was isolated (80LAI68) (Scheme 22). 

Synthetic ways to dihydropyridines can be classified into ring-forming processes and ring transformations, liie first general approach is best represented by the versatile Hantzsch synthesis. This method conveniently affords 1,4-dihydro- or 3,4-dihydro-, but not 1,2-dihydro-pyridines. The second approach may be illustrated by partial reduction of pyridines or pyridinium salts and nucleophilic addition of organometallic reagents to pyridines and pyridinium salts leading to 1,2- or l,4-dihydropyridines . 

The 3,4-dihydro derivative (182) was hydrogenated in the pyridine ring to afford the corresponding 3,4,6,7,8,9-hexahydro derivative (205) (Equation (44)) <73BSF985>. Another synthesis of the latter has also been described <79JOC3847>. 

Prior to this synthesis, Pictet and Finkelstein (22) had attempted a synthesis of the alkaloid by way of its 3,4-dihydro derivative but were unable to remove the two extra hydrogen atoms from its pyridine ring. Spath and Burger (19) completed this synthesis by dehydrogenating 3,4-dihydro-papaverine with palladized asbestos at 200°. Homoveratrylamine and homoveratroyl chloride were condensed, and the amide (XXXIII) converted to 3,4-dihydropapaverine (XXXIV) by a Bischler-Napieralski iso-... 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

Startg. m. treated with 0.1 M pyridine hydrochloride in pyridine at 25° for 12 h product. Y 71%. The method allows the overall transformation of a cw-glycol to a conjugated enal via 0,0 -stannylene derivs. and subsequent Horner (or heterodiene) synthesis. F.e. and with aq. AcOH, also 2-alkylidene-l,5-dialdehydes from 2-alkoxy-3,4-dihydro-2//-pyran ring, s. C. Burnouf et al.. Tetrahedron Letters 29, 5533-4 (1988). 

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