Heterocumulenes reactions with organometallic reagents: XV. Quantum-chemical investigatiom of skeleton rearrangements of 2-methyl-6-methoxy-3H-azepine originating from valence tautomerism

Abstract

In the framework of quantum-chemical simulation (DFT) the structure was explored of six potentially probable tautomeric forms of 2-methyl-6-methoxy-3H-azepine and their relative thermodynamic stability was evaluated. In the tautomers obtained the preferred gradient channels are localized of [1,n]-H shifts capable of initiating their tautomerism. The most probable typical concerted reactions were analyzed of the formation of valence isomers, fused three-/six-and four-/five-membered carbo-and heterocycles, azabicyclo[4.1.0]hepta-2,4-dienes (azanorcaradienes) and azabicyclo[3.2.0]hepta-3,6-dienes respectively. Azepines (azacycloheptatrienes) and their hydrogenated derivatives were recently described in many synthetic, theoretical, and medical publications [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21], first of all owing to the biological activity of these substances [2][3][4]. Azepine derivatives find wide and versatile application in pharmacology, mainly as psychotropic, antidepressant and anticonvulsant drugs, and also as antiviral, antibacterial, and anticancer pharmaceuticals [4]. The azepine structures find also interesting applications in the organic synthesis [5]. Besides these heterocycles are convenient models for further investigation of aromaticity and antiaromaticity [6][7][8], for the study of valence tautomerism [8][9][10][11][12][13][14][15][16][17][18], sigmatropic rearrangements [16,17,19], various stereochemical problems (transannular effect of the unshared electron pair of the heteroatom, formation of intramolecular hydrogen bonds) [2,13,16,20], for quantum-chemical calculations [6, 11-13, 20, 21]. The heightened interest to the seven-membered azaheterocycles stimulates the search for and development of new and at the same time simpler, cheaper and more general procedures for their preparation, in particular, those that lead to new derivatives, for the range of available representatives of this class compounds is still narrow.Recently [22,23] we developed a fundamentally new general approach to the simultaneous building up of azepine and dihydroazepine cycles by a mild deprotonation of 2-aza-1,3,5-triene systems that in their turn easily formed from lithiated allenes or alkynes and isothiocyanates [24]. For instance, previously unknown and difficultly available by another route 2-methyl-6-methoxy-3H-azepine (Ia) and 7-methyl-2-(methyl-sulfanyl)-3-methoxy-4,5-dihydro-3H-azepine (II) were synthesized from α-lithiated methoxyallene, isopropyl isothiocyanate, and methyl iodide along Scheme 1 [23]. In the absence of the deprotonating base 1-aza-1,3,4-triene III and the product of its [1,5]-sigmatropic rearrangement, 2-aza-1,3,5-triene IV, undergo thermally induced intramolecular cyclization reactions with the formation of pyrrole V and 2,3-dihydropyridine VI [24].The azepine molecules (according to XRD and NMR data existing mainly in the boat conformation) are known [2] to be fairly labile that shows in slow stereochemical transformations, sigmatropic rearrangements with the ...

Reactions of heterocumulenes with organometallic reagents: XVI. Quantum-chemical study on the mechanisms of formation of homo- and heteroannular azacycloheptadienes in reactions of 2-aza-1,3,5-trienes with potassium tert-butoxide

“…We recently showed that 2-aza-1,3,5-trienes I available in one preparative step from α-lithiated allenes (e.g., methoxyallene or protected allenyl alcohol) and s-alkyl isothiocyanates (e.g., isopropyl isothiocyanate) (Scheme 1) [3] by the action of potassium tert-butoxide in tetrahydrofuran-dimethyl sulfoxide are readily (-30°C, 30 min) transformed into previously unknown 4,5-dihydro-3H-azepines II (Scheme 2); these results were briefly reported in [4,5]. On the basis of our experimental data [4][5][6] and those reported in [7], we presumed that the formation of dihydroazepine ring includes two steps, deprotonation of 2-aza-1,3,5-triene I and [1,7]-electrocyclization of azatrienyl anion A into azacycloheptadienyl anion B (Scheme 2). Removal of the acetal protection [R 1 = EtOCH(Me)] afforded 7-methyl-2-methylsulfanyl-4,5-dihydro-3H-azepin-3-ol (IIIa) whose structure was reliably confirmed by NMR (1H, 13 C, 13 C JMOD, COSY, HSQC, HMBC) [5] and mass spectra [8], as well as by X-ray analysis (unpublished data).…”

“…The most stable is homoannular azacycloheptadienyl anion IVa′, and its heteroannular analog IVb′ is the least stable. Preferential formation of the homoannular structure by [1,7]-electrocyclization of azatriene carbanion Ic″ is also determined by kinetic factor. The rearrangement Ic″ → IVa′ is characterized by the lowest activation barrier (41.14 kcal/mol, TS3) compared to the rearrangements Ic″ → IVb′ and Ic″ → VI (the corresponding barriers are higher by 10.87 and 8.50 kcal/mol; Figs.…”

“…Analysis of gradient channels for the second reaction step, involving [1,7]-electrocyclization of azatriene carbanions Ic″ and Id″ with formation of homo-(IVa′, Va′) or heteroannular (IVb′, Vb′) azacycloheptadienyl anions (Scheme 6), was performed for isolated complexes of potassium cation with anions Ic″ and Id″ (Fig. 2).…”