1,2-Dihydropyridines rearrangement

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],... 

The formation of pyridine 210 appears to start with dimerization of aminobutenone 207 due to carbonyl-amino group interaction. Then the intermediate 208 undergoes [3,3]-sigmatropic rearrangement, whereupon dihydropyridine 209 eliminates ammonia. 

Dimethyl 3,4-dimethyl-2-methylene-3-azabicyclo[4.1.0]hept-4-ene-l,5-dicarboxylate (26), formed by the action of sodium tert-butoxide on dimethyl 4-(chloromethyl)-l,2,6-trimethyl-l,4-dihydropyridine-3,5-dicarboxylate, undergoes rapid rearrangement in the presence of acid to give dimethyl l,2,7-trimethyl-l//-azepine-3,6-dicarboxylate (27).126... 

Related to the above rearrangements is the ring expansion of dimethyl 2,6-dimethyl-2-[(tosyloxy)methyl]-l,2-dihydropyridine-3,5-dicarboxylate(3), in hot pyridine, to the 3/f-azepine 4.76 The bisazepine 5, which is also formed, is in thermal equilibrium with the 3/f-azepine, and in refluxing chlorobenzene reverts quickly, and quantitatively, to the monomeric azepine 4. 

The unstable cycloadducts 207, obtained from the dihydropyridines 205 (R = Me or Bn) and the benzoyl nitroso compound 206, undergo a hetero-Cope rearrangement in the presence of silicic acid to yield fused dioxazines 208 (equation 114)106. Adding the racemic hydroxamic acid 209 (R = r-Bu, cyclohexyl or Ph) to a two-phase mixture of... 

Some unusual reactions have been described for 2-(4-chlorophenyl)-2-(3,3-dimethylallyl)-4-phenyl-5(277)-oxazolone 84. This compound undergoes a Lewis acid-catalyzed rearrangement to give a tetrahydrofuropyrrole 85. On the other hand, depending on the reaction conditions, thermolysis of 84 produces the azabicyclohexene 86 or a substituted 2,3-dihydropyridine 87 together with the caged compound 88 formed by dimerization of the 2,3-dihydropyridine and the azabicyclohexene (Scheme 7.21). " ... 

Studies on the photochemical reactions of dihydropyridines have proven to be interesting. There are a number of 1,4-dihydropyridines that are known to disproportionate when irradiated (equation 19) (B-76PH240). Analogous intramolecular reductions have also been observed by other workers (55JA447). In contrast to these results, the 1,4-dihydropyridine (59) rearranged to its 1,2-dihydro isomer (60). Further irradiation resulted in dimerization. Interestingly, the photodimer (61) cyclized to the cage compound (62). 

The simple 1,2-dihydropyridine (63) cyclizes to the 2-azabicyclo[2.2.0]hexene (64) derivative upon irradiation (79JA6677). This reaction is the basis of a general synthetic route to dihydropyridines that are difficult to prepare by other means (Scheme 3). Dihydropyridines with more complicated substitution patterns, i.e. (66), undergo a photochemical rearrangement to valence isomers (68) and (69) (71T2957). The 1-azahexatriene (67) is believed to be an intermediate in this reaction (equation 21). 

In connection with the above work, it should be noted that the 2-azabicyclo[3.1.0]hexene ring system can also be prepared by carbenoid addition to N-methoxycarbonylpyrrole. Thermally it rearranges to the dihydropyridine but the mechanistic pathway depends upon the substituent attached to the cyclopropane ring (equation 22) (72JA6495). 

Dihydropyridines have also been starting points for stereospecific syntheses of hydro-phenanthridines and isoquinolines. Interest exists in these compounds because of the occurrence of this structural feature in alkaloids. For example, isoquinuclidine (263), derived from JV-alkoxycarbonyl-l,2-dihydropyridine, undergoes a Cope rearrangement to give the isoquinoline derivative (264) (80JA6157). Further chemical transformations of (264) provided a formal total synthesis of reserpine (Scheme 50). 

There are isolated reports where these dihydropyridines are involved in cycloaddition reactions. For example, the thermal rearrangement of 1,2-dihydropyridines gives 2,3-dihydropyridines. It has been postulated that the formation of (287) from the 1,2-dihy-dropyridine (284) occurs by rearrangement to (286) via the 2,3-dihydropyridine (285). An intramolecular cycloaddition reaction of (286) gives the observed product (Scheme 57) (78JA6696). 

Dihydropyridines (510) are susceptible to electrophilic attack. The 5-position is the kinetic site of protonation giving a 2,5-dihydropyridinium cation (511) which slowly rearranges to the thermodynamically more stable 2,3-dihydropyridinium ion (512). Alkylation of a 1,2-dihydropyridine at the 5-position can be carried out under phase-transfer conditions (513 — 514). 

Carbanions, such as that from malonodinitrile, generate dienes (66) which ring-close to iV-acyl-l,2-dihydropyridines (67). Subsequently these products may rearrange to 2-amidopyridines (Scheme 21) (75BCJ73). However, if substituted malonodinitriles are employed in this reaction the intermediate 6H-1,3-oxazines can be isolated for now deprotonation and ring opening are inhibited. 

The reaction of ketocarbenoids with pyrroles leads to either substitution or cyclopropanation products, depending on the functionality on nitrogen. With N-acylated pyrrole (209) reaction of ethyl diazoacetate in the presence of copper(I) bromide generated the 2-azabicyclo[3.1.0]hex-3-ene system (210) and some of the diadduct (211 Scheme 44).162163 On attempted distillation of (210) in the presence of copper(I) bromide rearrangement to the 2-pyrrolylacetate (212) occurred, which was considered to proceed through the dipolar intermediate (213). In contrast, on flash vacuum pyrolysis (210) was transformed to the dihydropyridine (214). A plausible mechanism for the formation of (214) involved rearrangement of (210) to the acyclic imine (215), which then underwent a 6ir-electrocyclization. 

Tetrahydroquinolones can be transformed also by (diacetoxyiodo)benzene 3 to the aromatic arylquinolines, a structure found in various alkaloids [101]. Depending on the reagent, it is possible to oxidize flavanones 50 either into flavones 51 or into rearranged isoflavones 52 [102, 103]. (Diacetoxyiodo)-benzene 3 or the polymer-supported reagent 18 were also efficient reagents for the oxidation of 1,4-dihydropyridines 53 to the corresponding pyridine derivatives 54, Scheme 23 [104]. 

Various 2-substituted iV-phenyl-6-phenylimino-3,6-dihydro-2//-thiopyran-4-amines, which are available from 6-substitutcd-5,6-dihydro-2//-thiopyran-2-thioncs, thermally rearrange to 5,6-dihydropyridine-2(l//)-thiones. A resonance stabilized thioamide anion is proposed as the intermediate (Scheme 107) <2001T8305>. 

The versatility of d,v-aminoindanol as chiral auxiliary has been considered in various Claisen9293 rearrangements and was found to be particularly efficient in the 6-azaelectrocyclization reaction.93 Indeed, the reaction of ( >3-carbonyl-2,4,6-trienal 98 with enantiopure m-aminoindanol 1 proceeded under remarkably mild conditions to produce pentacyclic piperidine 99 as a single isomer. The reaction was thought to proceed via isomerization of dihydropyridine intermediate 100 toward the thermodynamically more stable aminoacetal 99 (Scheme 24.22). 

Treatment of 3-phenyl-l-oxo-l//-pyrido[2,l-c][l,4]oxazinium bromide with NH4OAc in AcOH, then with AC2O yielded l-hydroxy-3-phenylpyrido[ 1,2-a]pyrazinium bromide (64CB3566). 6,10-Dioxo-6,10-dihydropyrido[2,l-c][l,4]benzoxazine-7,8-dicarboxylate was rearranged into l-(2-hydroxyphenyl)-2-oxo-l,2-dihydropyridine-4,5-dicarboxylate by heating in DMF [85H(23)2401 89JHC847]. 

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