Syntheses of heteroaryl-benzotriazoles by Mannich condensations

Efficient one step syntheses of N -substituted-2-(benzotriazol-1-yl) [isoindoles and pyrroles] are effected by reactions of primary amines with o -phthalaldehyde and 2,5-dimethoxy-2,5-dihydrofuran, respectively, in the presence of benzotriazole. Reaction of 2,5-dimethoxy-2,5-dihydrofuran with benzotriazole gave 2-(benzotriazol-1-yl)furan.


Preparation and reactivity of N-substituted-2-(benzotriazol-1-yl)isoindoles
Isoindoles have attracted considerable theoretical and synthetic interest. 11Previous work showed that double Mannich condensation of o-phthalaldehyde with primary aromatic amines in the presence of excess (3 or 4 equivalents) of benzotriazole in acetonitrile 12 or at 120 o C without solvent 13 gave exclusively or mainly benzotriazole-substituted isoindoline derivatives (1).The para substituent in the arylamine affects the product outcome.Thus p-methylaniline gave 3% 2H-isoindole (2a), while no formation of 2H-isoindole (2b) was detected with pmethoxycarbonylaniline.More 2H-isoindole (2a) was formed by extending the reaction time to 336 h (Scheme 1). 12e now find, somewhat surprisingly, that using benzylamine (instead of an aniline) in methylene chloride at room temperature gives N-benzyl-2-(benzotriazol-1-yl)isoindole 3a in 60% yield; none of the corresponding bis(benzotriazol-1-yl)isoindoline was isolated.Other Nsubstituted-2-(benzotriazol-1-yl)isoindoles (3b-g) were obtained in moderate to good yields (47-80%) by extending this reaction to a range of aliphatic primary amines.In the absence of benzotriazole, primary amines are known to react with o-phthalaldehyde to produce the addition products (4), which can undergo dehydration to the corresponding isoindolinone (5) in low yield. 14When benzotriazole and b -mercaptoethanol were used as dual synthetic auxiliaries 15 or there was an intramolecular auxiliary, e.g.amino acid or amino alcohol, 16 isoindolinone products (5) were obtained in good yield.Under our reaction conditions the amino alcohol, (2S)-2-phenyl-2-aminoethanol, and amino acid esters also gave the corresponding isoindole products in good yields.However, the 1 H and 13 C NMR for compound 3i were not well defined due to lone pair interactions.The structure of 3h was further confirmed by X-ray crystallography (Scheme 2).Not shown in the diagram is the fact that the hydroxyl group is disordered over two positions, each of which involves hydrogen bonding to a nitrogen of a benzotriazole ring in an adjacent molecule.The 2-(benzotriazol-1-yl)isoindoles (3) are quite stable (at room temperature for several months without any change).Heating 3g in biphenyl ether to 250 o C led via benzotriazole thermolysis to phenylimine (6), which was further hydrolyzed to isoindolinone (5a).Interestingly, the thermolysis of 3h in biphenyl ether under similar conditions gave the unusual benzotriazole migration products 9 (benzotriazol-1-yl) and 10 (benzotriazol-2-yl) in the ratio of 1:2, which is postulated to proceed through intermediate 7, along with minor tricyclic lactam product 8 (Scheme 3).The structure of 10 was unambiguously determined by X-ray crystallography.The crystals of 10 contain two independent molecules in the asymmetric unit, one of which is shown in Scheme 3. ISSN
ISSN 1551-7004 Page 475  ARKAT USA, Inc The X-ray structure of 3h

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus without correction.Column chromatography was carried out on silica gel (230-400 mesh).The 1 H and 13 C NMR spectra were measured in CDCl3 solution (300 MHz and 75 MHz respectively), with TMS or CDCl3 as internal references.

ISSN 1551-7004
Page 477 General procedure for preparation of compounds 3a-j A mixture of o-phthalic dicarboxaldehyde (1.34 g, 10 mmol), primary amine (10 mmol) and benzotriazole (2.38 g, 20 mmol) in CH2Cl2 (50 mL) was stirred with molecular sieves (4 Å) at room temperature overnight.The molecular sieves were removed by filtration, and the filtrate washed with 2 N NaOH (3 x 30 mL) and brine (3 x 30 mL).The organic phase was dried and concentrated to give a residue, which was purified by column chromatography (eluent: hexane/EtOAc) to afford compounds 3a-j.

General procedure for the preparation of compounds 12a-e
Primary amine (10 mmol), 2,5-dimethoxy-2,5-dhydrofuran (1.3 mL, 10 mmol), and benzotriazole (2.6 g, 22 mmol) were added to 25 mL of acetic acid and refluxed for 24 h.The mixture was cooled, CH2Cl2 (50 mL) was added and the solution was washed with 2 N NaOH (3 x 30 mL).The organic layer was dried over Na2SO4, and the solvent was removed by evaporation.The crude product was purified by column with hexane/EtOAc as eluent.

X-Ray crystallography
Data were collected with a Siemens SMART CCD area detector, using graphite monochromatized Mo Kα radiation (λ = 0.7107 Å).The structures were solved by direct methods and refined on F 2 using all data by full-matrix least-squares procedures.Hydrogen atoms were included in calculated positions except for the OH hydrogens, which were located from a difference map.