Dihydroazines

A multicomponent assembly of pyrido-fused tetrahydroquinolines has been accomplished by Lavilla and coworkers in a one-pot process by the interaction of dihydroazines, aldehydes, and anilines (Scheme 6.242) [425], The reactions were conducted with 20 mol% of scandium(III) triflate as a catalyst in dry acetonitrile in the presence of 4 A molecular sieves, employing equimolar amounts of the building blocks. This protocol provided the cycloadducts shown in Scheme 6.242 in 80% yield as a 2 1 mixture of diastereoisomers following microwave irradiation at 80 °C for 5 min. The same reaction at room temperature required 12 h to reach completion. 

It is possible to suggest at least three mechanisms to explain different directions of the abovementioned MCRs (Scheme 21) [1, 79, 80]. It should be noted that the reaction passing according to pathway I is not an independent method for the formation of the dihydroazine system and corresponds to the normal treatment of a,p-unsaturated carbonyls, because the generation of the latter occurs in situ. On the contrary, reaction pathways II and III follow different mechanisms leading to compounds like 45, which are hard to synthesize by other methods. 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

The properties of substituted dihydropyridines and dihydropyrimidines have been thoroughly described in the literature. There are several reviews devoted to their reactions and modifications [246, 247, 248, 249, 250, 251, 252, 253, 254, 255]. In this section of the book we have systematized the data mentioned in these reviews and supplemented them with results of investigations of dihydroazines fused with azoles. 

The most investigated field of the chemistry of dihydroazines is reactions of their heteroaromatization (Scheme 3.88). Interest in these processes is due, first of all, to the very important role of hydrogenation-dehydrogenation reactions in biochemistry, particularly in cell energy interchange. 

Dihydroazolopyrimidine heterocycles possess enhanced stability towards heteroaromatization by air oxygen in comparison with nonfused dihydroazines [158, 162, 172, 174, 175]. Oxidation of azolopyrimidines 331-333 becomes easier owing to rapid ionization in alkaline-alcoholic solutions (Scheme 3.91). 

Reduction of dihydroazines 343 can lead both to tetrahydro derivatives 344 and to perhydro heterocyles 345 [246, 247] (Scheme 3.92). It was shown [294] that the reaction of catalytic hydrogenation of dihydroazines 343 can be... 

Stereoselective reduction to the appropriate tetrahydro derivatives is observed in the case of the reaction of heteroannelated dihydroazines (R5and R6 are Het, X is N, for example, compounds 346, 348 and 350) with sodium borohydride [174, 295, 296, 297] or with hydrogen in the presence of Pd on A1203 under 3,000 Torr [298] (Scheme 3.93). Reduction of the enamines 346 and... 

When stabilizing substituents are absent or in the case of symmetrically substituted dihydroazines (R2 is the same as R6 and/or R3 is the same as R5), both catalytic hydrogenation and the use of LiAlH4 (NaBH4) lead to a structure like 345 [299, 300, 301, 302, 303, 304, 305, 306]. Sometimes a reduction of the functional groups is also observed [306] (Scheme 3.94). 

Reactions of alkylation and acylation are characteristic for dihydroazines and there are a lot of examples of such processes in the literature. In this book we would like to discuss the general similarities of these reactions with some illustrations without citing dozens of publications. 

N-Unsubstituted 1,4-dihydroazines very easily undergo N-alkylation and N-acylation in basic media—KOH [308], NaOH [309], NaOMe [310], LiN(-SiMe3)2 [311], pyridine [312], DMAP [313], etc. [246, 247]. 

Alkylation or acylation reactions of dihydroazines can proceed as intramolecular processes and follow with heterocyclizations [308, 310] (Scheme 3.98). 

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. 

The high reactivity of dihydroazines enhances their ability to cause chemical modifications and to form new heterocyclic systems. The presence in 1,4-dihydropyridines of an enamine double bond increases their ability to cause cycloaddition reactions. 

Several publications are devoted to the reactions of olefin cycloaddition to dihydroazines in the presence of Lewis acid and to an intramolecular addition in 1,4-dihydropyridines containing <9/+/z<9-alkenylaryl substituents at position 4 [374, 375, 376, 377, 378, 379]. 

Polycyclic lactones based on dihydroazines can be obtained in several ways. For example, trimethylsilyl ester 395 after passing through silica gel is converted to the appropriate lactone 396 [398] (Scheme 3.127). This method is a fast and facile procedure providing lactones 396 in high yields. 

Cyclization reactions can involve two functional groups of dihydroazines. For example, treatment of 2-methyl-3,5-biscarbethoxy derivatives of 1,4-dihy-dropyridine 404 and 405 sequentially with sodium hydride and 1,3,5-triazine yields either l,4,5,6-tetrahydro-l,6-naphthyridine-3-carboxylate 406 [402, 403, 404, 405] or pyrido[2,3-J pyrimidines 407 [406] (Scheme 3.129). 

Another example of heterocyclizations with the participation of substituents in positions 2 and 3 of the dihydroazine cycle is a treatment of compounds 408 with sodium ethoxide, leading to thienopyridine derivatives 409 [407] (Scheme 3.130). 

Thus, at the present time, many effective and facile approaches to the synthesis of diverse heterocycles by modification of dihydroazine derivatives are described. These methods provide strong possibilities using dihydroazines as building-blocks for the construction of new heterocyclic compounds. 

In practice, the equilibrium of tautomers in dihydroazines can be observed by experimental methods only in the case of those with similar energies, but this situation occurs rarely. Analysis of the data in the literature shows that for dihydropyridine derivatives A(B), as a rule, dihydroform A is more stable and only in a few cases [414, 415] tautomers B are described. For instance, compound 423 was obtained by dehydration of tetrahydropyridine 422 under mild conditions [414] (Scheme 3.135). In the presence of acids, dihydro derivative 423 is converted to a more thermodynamically stable 1,4-dihydro form 424. 

Chemistry of Dihydroazines, 38, 1. Wentrup, C., Carbenes and Nitrenes in Heterocyclic Chemistry Intramolecular Reactions, 28, 231. 

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