1.4- Dihydropyridine, bromination

The immediate outcome of the Hantzsch synthesis is the dihydropyridine which requires a subsequent oxidation step to generate the pyridine core. Classically, this has been accomplished with nitric acid. Alternative reagents include oxygen, sodium nitrite, ferric nitrate/cupric nitrate, bromine/sodium acetate, chromium trioxide, sulfur, potassium permanganate, chloranil, DDQ, Pd/C and DBU. More recently, ceric ammonium nitrate (CAN) has been found to be an efficient reagent to carry out this transformation. When 100 was treated with 2 equivalents of CAN in aqueous acetone, the reaction to 101 was complete in 10 minutes at room temperature and in excellent yield. 

Side-chain bromination of diethyl 2,7-dimethyl-41/-azepine-3,6-dicarboxylate (3) with bromine in carbon tetrachloride is accompanied by ring contraction to the 1,4-dihydropyridine 42, brought about by the liberated hydrogen bromide.29... 

For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in cone, sulfuric acid) at 130 °C (Scheme 2.4). Direct electrophilic substitution is not involved, however, aszwitterionic (dipolar) pyridinium-A-sulfonate is the substrate for an addition of bromide ion. Subsequently, the dihydropyridine that is formed reacts, possibly as a dienamine, with bromine to generate a dibromide, which then eliminates bromide ion from C-2. It is notable that no bromination occurs under similar conditions when oleum is replaced by cone, sulfuric acid alone instead, pyridinium hydrogensul-fate is produced. 

A few syntheses of specific substituted 3,3 -bipyridines have been reported. 6,6 -Dialkyl-3,3 -bipyridines have been shown to be one of the products of the reaction of l-lithio-2-alkyl-l,2-dihydropyridines with perhalometh-anes, cyanogen bromide, or bromine. In an interesting double... 

The reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

Selective bromine-mediated addition of BOC-protected-guanidine 81 to dihydropyridine 56 occurs across the electron-rich 5,6-alkene to give, after acid deprotection, r-2-amino-l,3a,5,7a-dihydroimidazo[4,5-b]pyridine 82 (Scheme 23). Aminal bond cleavage under basic conditions affords substituted 2-aminoimidazole 83 <2004OL3933>. Replacement of guanidine 81 with urea or thiourea leads, similarly, to 2-aminooxazoles or 2-ami-nothiazoles, respectively however, the yields are considerably lower than that of 82 due to the sensitivity of the ureas to bromine oxidation <2005JOC8208>. 

Examples of electrophilic attack on N-protected 1,2-dihydropyridines include bromine-mediated addition of Boc-protected-guanidine 534 to dihydropyridine 533 giving, after acid deprotection, f-2-amino-l,3a,S,7a-dihydroimidazo [4,5- ]pyridine 535 <2004OL3933> formation of 5-trichloroacetyl-l,4-dihydropyridines 536 <2003TL4711> and -formylation with the Vilsmeier reagent <20060L179>. -Aminonitriles which are formed by trapping 2,3-dihydropyr-idinium salts with cyanide ion are stable, but easily converted back into 2,3-dihydropyridinium salts with Lewis acids. 

Fig. 25. The mechanism for the reaction of a pyridinyl radical with bromochloromethane. The initial, rate-limiting, solvent-insaisitive step involves transfer of the bromine atom to tl pyridinyl radical, forming one or more bromodihydropyhdines and a chloromethyl radical. The latter reacts rapidly with another pyridinyl radical to yield two isomeric dihydropyridines, while the former dissociates to a pyridinium bromide...

Reaction of BOC-guanidine with dihydropyridine 1351 in the presence of bromine provides the bicyclic regioisomers 1352. After removal of the Boc-protecting group, the aminal bond in compound 1353 was regioselectively cleaved in boiling aqueous NaOH solution to yield the 2-aminoimidazole 1354 (Scheme 347) <2004OL3933>. 

Substituted pyridines.1 When LDPA is heated with an alkyl halide, benzyl chloride, bromine, or other electrophilic reagent, 3-substituted pyridines are obtained in 40-90% yield. The reaction probably involves alkylation of the 1,2-dihydropyridyl moiety of LDPA to give a 2,5-dihydropyridine, which is then oxidized to the final... 

A further [l,A,4,5]-elimination was observed in the dehydrochlorination of the dihydropyridine 146 with sodium methoxide 84). The 4-Ff-azepine 147 (67 %) reverts to 146 upon the addition of dilute hydrochloric acid 84). The reductive elimination (Ie Zn) of bromine from 1,3-dibromides such as 148 has been realized with several examples85 . The interesting synthesis of methylenecyclobutane (149) (16%)85) is again classified as [l,2,3]-elimination. 

Unsymmetrica l ly substituted acetylenes bearing at least one electron-withdrawing group reacted with 1-p-styry 1-1,2-dihydropyridine in a regiose lective manner to give 3,4-disubstituted 1,8-dihydroazocines. On reaction with bromine, (2) underwent... 

The influence of the methyl group in cyclohexene and the methylene bridge in nor-bornene rings on bromination and its stereochemistry have been studied. The effect of base concentration, base type, reaction temperature, and solvent on bromination at the C(3) and C(5) positions of a 1,4-dihydropyridine was also investigated. ... 

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