1 -Acyl-1,2-dihydropyridine derivative

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. 

Hilgeroth, A., Baumeister, U. and Heinemann F.W., Solution-dimerization of 4-Aryl- 1,4-dihydropyridines, Eur. J. Org. Chem., 2000, 245-250 Hilgeroth, A., Baumeister, U. and Heinemann F.W., Rotameric properties of novel N acyl and N-acyloxy dimeric 4-phenyl-1,4-dihydropyridines derived from developed solid-state synthesis, Heterocycles, 1999, 51, 2367-2376. 

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. 

Ai-methylpyridinium-2-carbaldoxime (2-PAM = a Figure 36.30b) constitutes the most potent reactivator of acetylcholinesterase poisoned by organophosphorus acylation. However, due to its quaternary nitrogen, 2-PAM penetrates the biological membranes poorly and does not appreciably cross the blood-brain barrier. For this compound Bodor et designed an ingenious dihydropyridine-pyridinium salt type of redox delivery system. The active drug is administered as its 5,6-dihydropyridine derivative (Pro-2-PAM = b), which exists as a stable immonium salt c. The lipoidal b (pA"a = 6.32) easily penetrates the blood-brain barrier where it is oxidized to the active a. 

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 resulting nucleophilic acyl radical adds onto the protonated heterocycle and the resulting heterocyclic radical is reduced by the Fe(II) salt into the corresponding dihydropyridine derivative that is subsequently oxidized into the corresponding products. The use of a TBHP/ri(in) redox system allowed for the isolation and charaeterization of the dihydropyridine intermediate. - ... 

A high density of electrons associated with atoms C(3) and C(5) of 1,4-dihydropyridines and 1,4-dihydropyrimidines is also observed when these heterocycles undergo electrophilic substitutions such as Friedel-Crafts [315, 316, 317, 318, 319, 320] and Vilsmeier [297, 321] reactions (Scheme 3.99). In [315] it was shown that treatment of dihydropyridines 371 with aroyl or acyl chlorides 372 in the presence of SnCl4 leads to acylation of the heterocycle at position 3 (compounds 373). Dihydropyridines 374 and dihydroazolopyrimidines 376 undergo Vilsmeier reaction with the formation of the corresponding derivatives 375 and 377. It is interesting that imine heterocycle 376 after Vilsmeier reaction exists in the enamine tautomeric form. The tautomerism of dihydroazines and factors influencing it will be discussed in detail in Sect. 3.8. 

Chiral I-acyl-2-alkyl-l,2-dihydropyridines.1 The useful 1,2-dihydropyridines can be prepared by reaction of Grignard reagents with the chloroformate 1 derived from reaction of (—)-8-phenylmenthol with 4-methoxy-3-(triisopropylsilyl)pyridinc. The bulky group at C, is essential for high diastcreosclectivity in this reaction, and the C4-mcthoxy group facilitates removal of the chiral auxiliary. Reaction of Grignard reagents with 1... 

Schroif-Gregoire C, Travert N, Zaparucha A, Al-Mourabit A (2006) Direct access to marine pyrrole-2-aminoimidazoles, oroidin, and derivatives, via new acyl-l,2-dihydropyridin intermediates. Org Lett 14 2961-2964... 

Two unselective approaches to the two alkaloids are illustrated in Scheme 50. A straightforward synthesis by King relied on acid-induced intramolecular Mannich reaction of ammoketone 396, prepared from 5-aminopentanal diethyl acetal and pent-3-en-2-one, to give a mixture of ( )-394 (55%) and ( )-395 (20%) (367). The synthesis by Pilli et at. involved a one-pot trimethylsilyl triflate-catalyzed condensation between pent-3-en-2-one and the acyliminium ion derived fium JV-Boc-2-ethoxypiperidine (397) (368,369). Under the reaction conditions, the intermediate 398 underwent spontaneous V-deprotection and cyclization to give a 5.5 1 mixture of ( )-394 and ( )-395 (67%). In the same Scheme is also shown the much shorter stereoselective synthesis of ( )-394 by Beckwith et al, who used a radical-mediated cyclization on the V-acylated 2,3-dihydropyridin-4-one 399 to give the bicyclic product 400 as the sole diastereomer (91%) (370). Compound 400 was readily converted into the target alkaloid by reduction of both carbonyl groups with lithium aluminum hydride followed by reoxidation of the secondary alcohol at C-2. 

The formation of N-acylpyridinium ions from acyl chlorides and pyridines is effectively promoted by (la) and i-Pr3SiOTf. The N-acylpyridinium ions are usable for the synthesis of dihydropyridines and their derivatives by alkylation with Grignard reagents [128]. This reaction sequence has been applied to asymmetric alkylation of pyridines using a chiral acyl chloride [129]. 

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