A Stereoselective Route to Polysubstituted Tetrahydroquinolines by Benzotriazole-Promoted Condensation of Aliphatic Aldehydes and Aromatic Amines

Abstract

By the promotion of benzotriazole (20 mol %), two molecules of anilines (or other arylamines) and two molecules of phenylacetaldehyde (or o-bromophenylacetaldehyde) condensed to give a series of 1,2,3,4-tetrahydroquinolines in a stereoselective manner. By the catalysis of SmI(2) or SmI(3), the N-(alpha-aminoalkyl)benzotriazoles derived from anilines and (R)-glyceraldehyde acetonide dissociated to the corresponding iminium and enamine species, which underwent asymmetric [4 + 2] cycloadditions to give optically active tetrahydroquinolines.

Experimental Evidence for Intramolecular ipso Substitution of Alkyl Groups

“…General Procedure: The corresponding aldimine (0.30 mol) (see Discussion Ϫ Schemes 2 and 11) was slowly added dropwise to a stirred solution of allylmagnesium bromide, prepared from allyl bromide (39 mL, 0.45 mol) and magnesium turnings (22.0 g, 0.90 mol), in absolute ether (300 mL) at reflux (for amines 2aϪn), or to a solution of (methallyl)magnesium chloride, prepared from methallyl chloride (41 mL, 0.45 mol) and magnesium turnings (22.0 g, 0.90 mol) in a mixture of THF/ether (1:1; 300 mL) at reflux (for amines 9a,b). After the addition of the Schiff base, the reaction mixture was stirred at room temperature for 1 h. The cooled reaction mixture was taken up in saturated aqueous NH 4 Cl solution (300 mL) under ice cooling, and the mixture was extracted with diethyl ether (3 ϫ 120 mL). The organic layer was dried with MgSO 4 and concentrated.…”

“…Moreover, many new methods for the synthesis of tetrahydroquinoline derivatives have been developed. [4] However, there are very few publications that describe the construc-…”

Vicinal Functionalization of N‐Alkoxyenamines: Tandem Umpolung Phenylation–Nucleophilic Addition Reaction Sequence

“…Therefore, nucleophilic addition to the imine intermediate is efficient when it occurs in an intramolecular manner, and cyclic compounds such as 2,3,4-trisubstituted tetrahydroquinolines, [10] 1,3-diaminotetralines, [11] and other cycloadducts [12] are obtained by vicinal functionalization of enamines [Scheme 1, Equation (2)]. In contrast, intermolecular nucleophilic addition to the imine intermediate is virtually unknown.…”

Asymmetric synthesis of novel tetrahydroquinoline derivatives with a sugar building block and their bioactivities

“…[3][4][5][6] Among these approaches, the inverse electron demand heteroDiels-Alder reaction is regarded as one of the most powerful approaches to asymmetric six-membered heterocyclic compounds due to its high regioselectivity and diastereoselectivity. 7,8 Much previous work was accordingly focused on [4+2] cycloaddition reactions of electron-deficient Schiff bases with electron-rich dienophiles.…”

“…When anilines bearing electron-donating substituents (entries 1-5) were used, the reaction afforded the expected corresponding THQ derivatives (2)(3)(4)(5)(6). But with p-aminophenol (entry 4) the reaction gave product 5 in poor yield due to the poor solubility of p-aminophenol in CH 2 Cl 2 .…”