Yu. B. Koptelov

Regioselectivity in the Addition of 1,3-Dipolarophiles to 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes

Thermolysis of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of 1,3-dipolarophiles having an unsymmetrically substituted double C=C bond (such as N-arylimides derived from 2-aryl-substituted maleic, citraconic, and itaconic acids, ethyl propynoate, aryl isocyanates, and aryl isothiocyanates) leads to formation of the corresponding 1,3-dipolar cycloaddition products. The reaction is regioselective, and in most cases only one regioisomer is obtained. The addition direction depends on the 1,3-dipolarophile structure, i.e., electronic and steric factors determining the most effective orbital interaction upon approach of the reagent to substrate.

Stable azomethine imines derived from pyrazolidin-3-one and their cycloaddition to N-arylmaleimides

Reactions of (Z)-1-arylmethylidene-3-oxopyrazolidin-1-ium-2-ides (stable analogs of azomethine imines generated by thermal opening of the diaziridine fragment in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes) with N-arylmaleimides having no ortho substituents in the aryl group are stereoselective: the products are mixtures of the corresponding cis and trans adducts, the latter prevailing (∼1.4–2.6: 1). trans Adducts are formed as the only products in the reactions with di-ortho-substituted N-arylmaleimides. (Z)-1-[(2,6-Dichlorophenyl) methylidene]-3-oxopyrazolidin-1-ium-2-ide reacts with both para- and ortho-substituted N-arylmaleimides to give exclusively trans adducts. Labile azomethine imines generated by thermolysis of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes are likely to have Z configuration as well.

( Z )-1-alkylidene- and 1-arylmethylidene-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ides and their cycloaddition to N -arylmaleimides

The reaction of (Z)-1-arylmethylidene-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ides with para-substituted N-arylmaleimides at 110°C is cis-stereoselective [cis/trans-adduct ratio ≥(9–10): 1]. Under analogous conditions, the conversion of (Z)-1-(2,6-dichlorophenylmethylidene)-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ide in the reaction with N-(4-methoxyphenyl)maleimide in 6-7 h did not exceed 1–2%. The cycloaddition of (Z)-1-ethylidene- and (Z)-1-(2-methylpropylidene)-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ides to N-arylmaleimides, regardless of the substituent in the phenyl group of the latter, gave preferentially the corresponding trans-adducts, which cannot be rationalized only by steric effect of substituents in terms of the concerted mechanism.

Stable azomethine imines having a 3,4-dihydroisoquinoline fragment and their cycloaddition to N-arylmaleimides

Aroylation of 5,6,8,8a,13,14,16,16a-octahydro[1,2,4,5]tetrazino[6,1-a:3,4-a′]diisoquinoline or 1,3,4,8b-tetrahydro[1,2]diazireno[3,1-a]isoquinoline, as well as reactions of 2-(2-bromoethyl)benzaldehyde with aroylhydrazines followed by treatment with triethylamine, led to the formation of stable azomethine imines, aroyl(3,4-dihydroisoquinolinium-2-yl)azanides. 1,3-Dipolar cycloaddition of the latter to N-mesitylmaleimide was stereoselective: the ratio of the trans- and cis-adducts was ∼(3–7): 1, the former prevailing. The reactions with N-arylmaleimides having no ortho-substituents in the aryl group gave the corresponding cis-adducts as the major products [trans/cis ratio ∼1: (2.5–10)].

Catalytic opening of the diaziridine fragment in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes

Treatment of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with Lewis acids [BF3·Et2O or In(OTf)3] promotes opening of the diaziridine ring, followed by formation of 1,3-dipolar cycloaddition products with N-arylmaleimides. The conversion of the initial diaziridine depends on the nature of the 6-aryl group. Diazabicyclohexanes with donor substituents react quantitatively to give (in the absence of dipolarophiles) the corresponding azomethine imine dimers, 1,2,4,5-tetrazine derivatives. The conversion of diazabicyclohexanes having acceptor substituents is poor; simultaneously, the fraction of the hydrolysis products increases. The stereoselectivity in the 1,3-dipolar cycloaddition, i.e. the ratio of the cis-and trans-adducts, depends on the catalyst and solvent. Azomethine imine dimers react with N-arylmaleimides in the presence of indium(III) trifluoromethanesulfonate to give the same 1,3-dipolar cycloaddition products as those obtained from parent 1,5-diazabicyclohexanes.

Thermolysis of 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes in the Presence of N-Arylmaleimides

Heating of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of N-arylmaleimides gives rise to 2,9-diarylperhydropyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3-diones. It is presumed that thermal cleavage of the C-N bond in the diaziridine fragment of the 6-aryl-1,5-diazabicyclo[3.1.0]hexanes results in formation of labile azomethinimines that react with N-arylmaleimides to afford the products of 1,3-dipolar cycloaddition. The rate of accumulation thereof depends only on the character of substituents in the aromatic ring of the 1,5-diazabicyclo[3.1.0]hexanes and is independent of maleimide. The thermal isomerization of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes without 1,3-dipolarophiles yields the corresponding 2-pyrazolines.

Regio- and diastereoselective cycloaddition of stable cyclic azomethine imines to N-arylitaconimides

Abstract1,3-Dipolar cycloaddition of stable N,N′- and C,N-cyclic azomethine imines based respectively on pyrazolidin-3-one and 3,4-dihydroisoquinoline to N-arylitaconimides proceeds strictly regioselectively resulting in spiro-joint heterocycles in good yields. The regioselectivity of the addition of N,N′-cyclic azomethine imines is reversed with respect to that of C,N-cyclic azomethine imines. The diastereoselectivity of the cycloaddition depends apparently on the substituents at the central nitrogen atom in the azomethine imine fragment.

Generation of azomethine imines via opening of the diaziridine ring in unsymmetrically substituted 6-aryl-1,5-diazabicyclo-[3.1.0]hexanes and their transformations

Thermally induced opening of the diaziridine ring at the carbon-nitrogen bond in unsymmetrically substituted 6-aryl-1,5-diazabicyclo[3.1.0]hexanes is characterized by low regioselectivity which is likely to be determined by the inductive effect of substituents in the trimethylene bridge. 1,3-Dipolar cycloaddition of the resulting azomethine imines to phenyl isocyanate is regioselective: it occurs at the double carbon-nitrogen bond with predominant formation of the corresponding cis adducts due to dipolarophile approach to Z-azomethine imine at the sterically less hindered side. Analogous approach of dipolarophile is also observed in the reaction with N-arylmaleimides.

Thermally induced opening of the diaziridine ring in 6-aryl-2-methyl-1,5-diazabicyclo[3.1.0]hexanes

Thermally induced opening of the diaziridine ring in 6-aryl-2-methyl-1,5-diazabicyclo[3.1.0]-hexanes at the carbon-nitrogen bond is characterized by low regioselectivity; isomerization of unstable intermediate azomethine imines leads to mixtures of the corresponding 1-arylmethyl-5-methyl-4,5-dihydro-1H-pyrazoles and 1-arylmethyl-3-methyl-4,5-dihydro-1H-pyrazoles at a ratio of ∼6:5. Analogous regioselectivity in opening of the three-membered ring is observed in the presence of phenyl isocyanate. In this case, adducts with cis arrangement of the aryl and methyl groups are formed as the major products (cis/trans ratio ∼3:1).

Thermally Induced Tandem Cycloaddition of 2-Alkyl-3-phenylcyclopropenones to 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes

Thermolysis of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of 2-alkyl-3-phenylcyclopropenones gives fused polycyclic systems of the 4a,7b-diazacyclopenta[cd]inden-7-one series as a result of addition of two cyclopropenone molecules and extrusion of CO molecule. The first step of the process is characterized by 100% regioselectivity, leading to the adduct with vicinal arrangement of the aryl groups, while the regioselectivity of the second step is likely to be determined by spatial interactions between substituents in the cyclopropenone molecule and trimethylene bridge of the diazabicyclohexane. Steric hindrances in the second step could eliminate formation of stable products.