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1-Methyl-2-formyl-5-bromopyrrole 1 was prepared in 48% total yield by initial bromination of the intermediate 1-methyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)pyrrole 5 with N-bromosuccinimide to give the intermediate 1-methyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)-5-bromopyrrole 6, which was finally hydrolyzed to the product 1.

Three series of new 1-methyl-2-substituted-5-pyrrolylcarbonyl fluorinated nitroxides, i.e., 3 (R f =C 2 F 5 ), 4 (R f = n -C 3 F 7 ) and 5 (R f = n -C 7 F 15 ), generated by the H-abstraction/spin-trapping reaction of eleven 1 -methyl-2-substituted-pyrrole-5-carbaldehydes ( 6 ) with the H-abstracting agent [R f N(O • )R f ] 1 and the spin-trapping agent R f NO 2 , were studied by EPR. Correlation analysis of their a N values with polar and spin-delocalization substituent constants shows that a N values are mainly affected by the polar effect of the 2-substituent, but the spin-delocalization effect also exists.

Indolizines and pyrrolo[2,1-a]isoquinolines are synthesized by 1,3-dipolar cycloadditions of pyridinium benzotriazolylmethylides or isoquinolinium benzotriazolylmethylides with ethylenes and acetylenes.

1,5-Disubstituted pyrrolidin-2-ones 18a-g, 19a-h, and 20a-f were synthesized in good to excellent yields via the nucleophilic substitution of 5-(benzotriazol-1-yl)-1-substituted-pyrrolidin-2-ones 9 with allylsilanes, organozinc reagents, and phosphorus compounds. Compounds 9 and 5-(benzotriazol-2-yl)-1-substituted-pyrrolidin-2-one isomers 10 are readily prepared in total 70-84% yields from 2, 5-dimethoxy-2,5-dihydrofuran (7), primary amines 8, and benzotriazole; 9 and 10 react identically with nucleophiles.

1,5,6,10b-Tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-ones 17a,b, 17d,e, and 5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-ones 22a−e were prepared by intramolecular cyclizations of 1-(2-arylethyl)-5-benzotriazolyl-pyrrolidin-2-ones 15a,b, 15d,e, and 3-benzotriazolyl-2-(2-arylethyl)-1-isoindolinones 20a−e, respectively, in the presence of titanium chloride. Products from chiral amines were obtained with stereoselectivities of ≥94%.

1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a−e, 12 and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones 9a−f, 14 are readily available from reactions of benzotriazole (4), 2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran (5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-benzothiazepines 7a−e and 10a−f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines 13 and 15, respectively.

1H-Imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones 6a–i are synthesized in 67–96% yields with high stereoselectivities (de 88–99%, except 6e with a 58% de value) via intermolecular condensation of 2-formylbenzoic acid (5) and α-amino amides 4a–i in the presence of a catalytic amount of toluene-p-sulfonic acid. Intermediates 4 are obtained in two steps from easily available chiral N-Boc-α-amino acids 1.

N- Benzotriazolylmethyl- N -phenethylamines 5a – 5c and 11a – 11c cyclize in the presence of aluminum chloride to produce 1,2,3,4-tetrahydroisoquinolines 6a – 6c and 12a – 12c (70–89%) via electrophilic attack of a transient iminium cation X on the tethered phenyl ring. The Bt group in 2 - benzotriazolylmethyl-1,2,3,4-tetrahydroisoquinolines 6a – 6b was replaced (i) with hydrogen by sodium borohydride to afford N -methyl-1,2,3,4-tetrahydroisoquinolines 7a – 7b or (ii) by nucleophiles, such as Grignard reagents, a silyl enol ether or triethyl phosphite, to furnish novel N -substituted-1,2,3,4-tetrahydroisoquinolines 13a – 13c , 14 or 15 , respectively. Optically active 3-substituted-1,2,3,4-tetrahydroisoquinolines 12a – 12c were similarly prepared in high yields without racemization.

4-Benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benzothiazepines 5a,b, -1,4-benzoxazepine (12) and -1,4-benzodiazepine (20) are obtained via aluminium chloride mediated intramolecular cyclizations of N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(arylthio)ethan-1-amines 4a,b, -2-(phenoxy)ethan-1-amine (11) and -N-[2-(N′-methylanilino)ethyl]amine (19), respectively. Subsequent nucleophilic substitutions of the benzotriazolyl group in 5a,b, 12 and 20 succeeded with Grignard reagents, triethyl phosphite, sodium borohydride, and a silyl enol ether to give novel 2,3,4,5-tetrahydro-1,4-benzothiazepines 6–9, -1,4-benzoxazepines 13 and 14, and -1,4-benzodiazepines 21–23 in good yields.

Chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones 11a–11f, 14b,14c and 17a,b were prepared in 78–93% yields with high stereoselectivities (d.e. >99%) by the intermolecular condensations of 2-formylbenzoic acids 10 or 13 or 2-acetylbenzoic acid 15 with chiral diamines 9a–9f and 9h. Compounds 9a–9f and 9h were readily prepared in three steps from optically active N-Boc-α-amino acids 5a–5d.

1-Benzotriazolylmethyl-3-propylhexahydropyrimidine (1) and 1,3-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-1,2,3,4-tetrahydroquinazoline (3) were readily prepared by reactions of N-propyl-1,3-propanediamine or 2-aminobenzylamine with benzotriazole and formaldehyde, respectively. Intermediate 1 reacted with alkyl and aryl Grignard reagents to produce N,N'-unsymmetrically substituted hexahydropyrimidines 2a,b in 90 and 92% yields, respectively. Nucleophilic substitutions of 3 with Grignard reagents, allylsilane, and triethyl phosphite gave N,N'-disubstituted 1,2,3,4-tetrahydroquinazolines 4a-f, 5, and 6 in good to excellent yields. Successive treatment of 3 with two different Grignard reagents in one-pot reaction led regiospecifically to N,N'-unsymmetrically substituted tetrahydroquinazoline derivatives 8a,b.

Alpha-(N-substituted amino)esters were prepared in a two-step procedure from available unsubstituted alpha-amino esters. alpha-Amino esters are first converted into the corresponding N-benzotriazolylmethyl derivatives; in the second step, the benzotriazole group is substituted by various nucleophiles with or without the presence of a Lewis acid to give substituted alpha-amino esters in high overall yield under mild conditions with no signs of racemization. Boc-protected amino acids were converted into alpha-amino amides; subsequent deprotection allowed the conversion into N-substituted derivatives analogously to the alpha-amino esters, without racemization in high yields under mild conditions.

Reactions of pyrrole (2) or 1-methylpyrrole (4) with readily available N-acylbenzotriazoles 1a−g (RCOBt, where R = 4-tolyl, 4-nitrophenyl, 4-diethylaminophenyl, 2-furyl, 2-pyridyl, 2-indolyl, or 2-pyrrolyl) in the presence of TiCl4 produced 2-acylpyrroles 3a−g and 5a−g in good to excellent yields. 1-Triisopropylsilylpyrrole (6) under the same conditions gave the respective 3-acylpyrroles 7a−g. Similarly, indole (9) and 1-methylindole (11) gave the corresponding 3-acylated derivatives 10a−g and 12a−g. These results demonstrate that N-acylbenzotriazoles such as 1c,f,g are mild, regioselective, and regiospecific C-acylating agents of particular utility when the corresponding acid chlorides are not readily available.

Ethyl (4R)-3-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,3-thiazolane-4-carboxylate (6) and 1-[1,3-benzothiazol-3(2H)-ylmethyl]-1H-1,2,3-benzotriazole (8) were readily prepared by reactions of L-cysteine ethyl ester hydrochloride and 1-aminothiophenol with benzotriazole and formaldehyde, respectively. Chiral thiazolidine esters 7a-c were obtained by reactions of intermediate 6 with organozinc derivatives. Nucleophilic substitutions of 8 with Grignard reagents gave N-substituted dihydrobenzothiazoles 9a-c.

2-Aminopyridines 1a-c and 1-aminoisoquinoline with 1-chloromethylbenzotriazole give 2-amino-1-[alpha-benzotriazol-1-ylmethyl]pyridinium chlorides 2a-c and 1-amino-2-(alpha-benzotriazol-1-ylmethyl)isoquinolinium++ + chloride 12, respectively. Compounds 2a-c and 12 react with aryl aldehydes 3a-h to afford imidazolo[1,2-a]pyridines 7a-k and imidazolo[2, 1-a]isoquinolines 13a,b in good yields.

Readily available N-acylbenzotriazoles 2a−q efficiently acylate aqueous ammonia and primary and secondary amines to give primary, secondary, and tertiary amides in good to excellent yields. The wide applicability of the procedure is illustrated by the preparation of (i) α-hydroxyamides from α-hydroxy acids and of (ii) perfluoroalkylated amides.