Mesomeric betaines cycloadditions

Dipolar cycloadditions of dihydropyrimidine-fused mesomeric betaines 389, 391 and 394 with different dipolarophiles afforded 6-oxo-6H-pyrido[l,2-n]pyrimidine-3-carboxylates 390, 392, 393 and 396 (97JOC3109). 

The Diels-Alder cycloaddition potential of fused 4-aryldihydropyrimidine mesomeric betaines has been studied. The cross-conjugated thiazinium betaine 317 underwent 1,4-dipolar cycloaddition with electron-rich dipolaro-philes, and thus 1-diethylaminoprop-l-ine gave the pyrido[l,2-tf]pyrimidine 318 by loss of carbonyl sulfide (Equation 34). Reaction of 317b with 1,1-diethoxyethene resulted in the 8-ethoxy analogue of 318 (R = H) <1997JOC3109>. 

Conjugated heteropentalene mesomeric betaines are electron rich with high-energy HOMO and can be regarded as masked 1,3-dipolarophiles. Their main reactions are electrophilic substitution and cycloaddition reactions with electron-deficient 1,3-dipolarophiles, both were duly discussed in CHEC-II(1996) <1996CHEC-II(8)747>. 

In general, conjugated heterocyclic mesomeric betaines are associated with 1,3-dipoles and cross-conjugated heterocyclic mesomeric betaines are associated with 1,4-dipoles. The dipolar cycloaddition reactions of both types of heterocyclic mesomeric betaines have been widely investigated and its use for the preparation of a diverse variety of heterocyclic compounds was duly covered in CHEC-II(1996) <1996CHEC-II(8)747>. 

The structural requirements of the mesomeric betaines described in Section III endow these molecules with reactive -electron systems whose orbital symmetries are suitable for participation in a variety of pericyclic reactions. In particular, many betaines undergo 1,3-dipolar cycloaddition reactions giving stable adducts. Since these reactions are moderately exothermic, the transition state can be expected to occur early in the reaction and the magnitude of the frontier orbital interactions, as 1,3-dipole and 1,3-dipolarophile approach, can be expected to influence the energy of the transition state—and therefore the reaction rate and the structure of the product. This is the essence of frontier molecular orbital (EMO) theory, several accounts of which have been published. 16.317 application of the FMO method to the pericyclic reactions of mesomeric betaines has met with considerable success. The following section describes how the reactivity, electroselectivity, and regioselectivity of these molecules have been rationalized. 

Fig. 7. Exemplifying two distinct modes of symmetry allowed cycloaddition of mesomeric-betaines (a) conventional 1,3-dipolar cycloaddition (b) addition across peri positions.

The structure of the reaction product of 2-aminopyridine and diethyl malonate, described by Chichibabin as 2,4-dioxo-3,4-dihydro-2//-pyrido-[l,2-<7]pyrimidine,96 was first questioned by Snyder and Robison253 on the basis of the high melting point and poor solubility of the compound. They suggested the tautomeric 2-hydroxy-4-oxo-4H-pyrido[l,2-a]pyrimidine structure. The problem was solved by Katritzky and Waring273 who compared the UV spectrum of the product with that of fixed tautomers and found that the product may best be described as anhydro- 2-hydroxy-4-oxo-4/f-pyrido[l,2- ]pyrimidinium)hydroxide (63). Because of the chemical behavior of these compounds, however, the contribution of other mesomeric forms to the structure has also been considered.122 Thus, PPP-SCF quantum chemical calculations suggest that 1,4-dipolar cycloadditions to the C-3 and C-9a atoms are to be expected.352 This type of reaction does in fact occur (see Section III,C,10). Katritzky and Waring273 estimated the ratio of the mesomeric betaine (63 R = H) and the 2-hydroxy-4-oxo tautomers to be about 20 1. 

Heterocyclic iminium salts, oxidative transformation, 41, 275 Heterocyclic mesomeric betaines and analogs in natural product chemistry, 85, 67 Heterocyclic oligomers, 15, 1 Heterocyclic products, natural, synthesis of by hetero Diels-Alder cycloaddition reactions, 42, 245... 

Figure 3 Frontier orbital interactions in the thermal 1,3-dipolar cycloadditions of type A mesomeric betaines...

In aqueous solution 3-hydroxypyridine 176 equilibrates with the mesomeric betaine 177a for which no uncharged structure can be written. Since these pyridinium-3-olates 177a undergo 1,3-dipolar cycloadditions, it is reasonable to assume that there is also a contribution of the one form 177b to the overall structure. 

The structural requirements of the mesomeric betaines described in Section III endow these molecules with reactive -electron systems whose orbital symmetries are suitable for participation in a variety of pericyclic reactions. In particular, many betaines undergo 1,3-dipolar cycloaddition reactions giving stable adducts. Since these reactions are moderately exothermic, the transition state can be expected to occur early in the reaction and the magnitude of the frontier orbital interactions, as 1,3-dipole and... 

The mesomeric betaine 419 underwent 1,4-dipolar cycloaddition with photochemically generated singlet oxygen in benzene at 5°C to give the stable peroxide 476 in 94% yield (83TL4669). 

Selective synthesis and cycloaddition reactions of new azomethine imines 109 containing a 1,2,4-triazine ring have been reported. 4,5-Dihydro[l,2,4]triazolo[3,4-c]benzo[l,2,4]triazines 108 with aromatic aldehydes gave stable iminium salts which were deprotonated to give new mesomeric betaines 109. These underwent 1,3-dipolar cyclization reactions affording tetra- and pentacyclic heterocycles 110 <05EJO3553 05H1889>. 

Mesomeric betaines (e.g., (158)) undergo 1,4-dipolar cycloadditions with various electron-rich dienophiles thus, with l-A, A -diethylaminopropyne, for example, the adduct (159) is obtained. When heated this expels carbonyl sulfide to generate a-pyridone (160) (Scheme 28) <93TL5408>. 

Peri-, regio-, and stereoselectivity of cycloaddition reactions of substituted mesomeric betaines (106) have been studied with different alkynic and alkenic dipolarophiles. High periselectivity has been observed in cycloaddition with both series of dipolarophiles, with the dipolarophile adding exclusively across the 1,3-azomethine ylide dipole (106a). The formation of 2,2 -bipyrroles (108) could be explained by a rearrangement of initial bicyclic cycloadduct (107) <90JOC910>. All these reactions are shown in Scheme 18. 

The mesomeric betaine (100) underwent 1,3-dipolar cycloaddition, with DMAD in toluene at 100°C, to give a mixture of two products (101) and (102). Compound (101) was formed by initial 1,3-dipolar cycloaddition of DMAD to the azomethine ylid fragment of (100) to yield a tricyclic intermediate which fragmented to (101). Compound (102) was formed via ring opening of (100) to a ketene intermediate which underwent a hetero Diels-Alder reaction with DMAD to give (102) <92JCS(P1)2789>. 

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