6- -3,4-dihydropyridine adducts

Treatment of iV-methyl nicotinamide with MeLi, n-BuLi, and PhLi has been shown to give 1,4-dihydropyridine adducts (83TL4735). 

Formation of a dihydropyridine -adduct at the chain-end was shown by NMR and UV" spectral analysis. Anderson and collaborators proposed that the actual initiator would be adduct 34, formed by reaction of s-BnLi with pyridine (equation 40), which implies that the a-end-group of PMMA is a dihydropyridine group. This hypothesis was not experimentally confirmed. However, in the specific case of the e-caprolactone (3, n = 4) polymerization initiated by the BnLi/pyridine addnct, no characteristic NMR signal of dihydropyridine could be detected. The polymerization mechanism was therefore revised, based on the alkyllithium as the actual initiator and the establishment of an equilibrium between an active uncomplexed enolate (35) and a dormant cr-complex (36) as the basis for polymerization control (equation 41)" . 

Pyrazol-3-one 392 reacts with arylidene malononitriles 393a-c in basic ethanolic medium to yield the 6-(3-oxopyrazol-4-yl)-2-oxo-l,2,3,4-tetrahydropyridine/ 2-hydroxy-6-(3-oxopyrazol-4-yl)-3,4-dihydropyridine adducts 397 398a-c in a 1 1 ratio (87AP140) (Scheme 109). The mechanism is assumed to proceed via intermediate 396 formed from Michael adduct 394 or possible isomer 395. The pyran derivative 396 rearranges to the pyrid-2(l//)-one/2-hydroxypyridine tautomeric mixture 397/398. 

In a similar way, pyridine phosphonium salts and phosphonates can be prepared by reaction of trivalent phosphorus compounds with the more accessible iV-trifluoromethanesulfonyl-pyridinium salts, when tri-fluoromethanesulfone is the leaving group from nitrogen (as sulfinate anion) attack is normally at C-4, as illustrated below. The A -trifluoromethanesulfonyl-pyridinium salts also react with ketones or with electron-rich aromatic compounds to give 1,4-dihydropyridine adducts. Subsequent treatment with potassium t-butoxide brings about elimination of trifluoromethanesulfinic acid, and thus aromatisation. It is also possible to utilise phosphonates in reaction with aldehydes, leading finally to 4-substimted pyridines. ... 

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. ... 

Rudler H, Martin-Vaca B, Nicolas M, Audouin M, Vaissermann J. Formation and selective trapping of 2,5-dihydropyridine and its isopropylidene derivative by tungsten(O) alkylidene complexes. X-ray structure of the 5-isopropylidene-2,5-dihydropyridine adduct. Organometallics. 1998 17 361-366. 

The shortest synthesis of (5Z,9Z)-indolizidine 223AB (1566) was reported in 2007 by Ma and coworkers (Scheme 223, first two lines) In this approach the copper(I) complex of the chiral bis(oxazoline) ligand 1772 catalyzed the enantioselective addition of hept-l-yn-3-one to the N-acylpyridinium salt 1773, producing the (2S)-dihydropyridine adduct (+)-1774 in 70% yield and an ee of 91%. Selective hydrogenation over... 

Methyl propiolate and pyridine give a rather unstable 2 1 molar adduct which is the 1,2-dihydropyridine (112). The reaction sequence proposed to account for its formation is identical in principle to a similar scheme proposed earlier in the acridine series (Section II,A,2) and is also supported by the observation that the 1-benzoyl-pyridinium cation with the phenylacetylide anion yields (113). ... 

Dihydropyridines 8 react with dienophiles such as A -phenyl maleimide (2) and l,2,4-triazoline-3,5-dione 9 to give the Diels-Alder adducts 10 and 11, respectively (76JHC481). Fowler observed that when a mixture of 1,2- and 1,4-dihydropyridines was treated with maleic anhydride (12), only 1,2-dihydro-pyridines yielded the Diels-Alder adducts 13, whereas the 1,4-dihydropyridines showed no reactivity with 12 (72JOC1321) (Scheme 1). 

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. 

Evidently, the reaction proceeds via the formation of bis-adduct 289 which undergoes cyclization to dihydropyridine 290. A similar reaction with methoxybutenone, but in the presence of ammonia, which is likely to involve replacement of methoxy group, has been described (80MI2). 

Acylnitroso compounds 197 (R = Me, Ph or Bn) react in situ with 1-methoxycarbonyl-1,2-dihydropyridine to yield solely the bridged adducts 198 quantitatively. On the other hand, 1 1 mixtures of the regioisomers 199 and 200 were formed from the nitroso-formates 187 (R = Me or Bn) (equation 110)103. The chiral acylnitroso compounds 201 and 202, which are of opposite helicity, add to cyclohexadiene to give optically active dihydrooxazines in greater than 98% diastereomeric excess (equations 111 and 112)104. Similarly, periodate oxidation of the optically active hydroxamic acid 203 in the presence of cyclopentadiene, cyclohexa-1,3-diene and cyclohepta-1,3-diene affords chiral products 204 (n = 1, 2 and 3, respectively) in 70-88% yields and 87-98% de (equation 113)105. 

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. 

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

Recently, treatment of the esters or amides of l-methylpyridinium-3,5-dicarboxylic acid salts with an alkanethiol and TEA in methylene chloride was found to give a mixture of dihydropyridines (Scheme 77) (80CC1147). These yellow adducts are particularly useful as thiolate transfer agents. Excellent yields of thioesters, for example (133), are formed by the reaction of the adducts with activated acid derivatives. 

Further extension of this approach involved297 the 1,4-singlet-oxy-gen adduct (510) of the 3-cyano-l,2-dihydropyridine derivative 484, which was transformed into methyl 5-aniino-5-N-henzoyl-5-deoxy-DL-... 

The interaction between pyridine and organolithium compounds in benzene was first reported by Ziegler and Zeiser129 and was attributed to the formation of 1 1 adducts. Indirect evidence for intermediates of this kind was based on the formation of dihydropyridines by treatment of the reaction mixture with water. More definite evidence was obtained with quinoline, isoquinoline, and acridine.130 Phenyllithium reacts quantitatively with quinoline in ether to yield an adduct as a yellow powder that can be recrystallized. In order to define the site of attachment, the adducts were hydrolyzed to dihydro derivatives and the latter dehydrogenated. Because this treatment leads mainly to 2-phenyIquinoIine and l-phenylisoquinoline from quinoline and isoquinoline, respectively, the related adducts can be assumed to have structures 80 and 81. Isolation and characterization of the dihydro derivatives have been carried out, as well as in the case of the reaction of acridine with phenyllithium. 

H-NMR Data for Organolithium-Pyridine Adducts and Some of Their 1-Deutero-1,2-Dihydropyridine Derivatives"... 

The acidic hydrogen atoms in the side chain of alkylpyridines may interfere with the formation of o-adducts. Thus 4-isopropylpyridine reacts with phenyllithium in THF to yield a mixture of the 2-adduct 90 and l-lithio-4-(2-propyliden)-l,4-dihydropyridine (91). However, alkyllithiums, such as BuLi, (-BuLi, and MeLi, mainly yield the related 2-adducts 92.136... 

It is worth noting that in some cases adducts may be prepared by routes other than those leading directly to adduct formation. Thus Fraenkel and his co-workers139,140 obtained 4,4-dialkyl-substituted adducts from l-ethoxycarbonyI-4,4-dialkyl-l, 4-dihydropyridines by reaction with organo-metallic compounds, R M (M = Li, Na, K, MgX), according to Scheme 7. The NMR spectra of these adducts consisted of an AB system (J = 6.5-8.0 Hz). The chemical shift values were similar (Table XV) to those reported... 

H-NMR Data for 4-Adducts Obtained by Decomposition of 1-Ethoxycarbonyl-4,4-dlalkyl-1,4-dihydropyridines ... 

The negative charge distribution in the adducts was evaluated on the basis of the chemical shift values and found to be nearly 75% concentrated on the nitrogen atom. In the reactions of l-ethoxycarbonyl-l,4-dihydropyridines with organosodium and organopotassium compounds, the resulting metal-associated (j-adducts were not soluble in aliphatic hydrocarbons alone but were made so by addition of 18-crown-6. This behavior would support ionic structures for the potassium and sodium adducts. 

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