2-Substituted-1,2,3,4-tetrahydroisoquinolines and chiral 3-carboxyl analogues from N-benzotriazolylmethyl-N-phenethylamines

Diversity-oriented synthesis of medicinally important 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and higher analogs

“…Meutermans and Alewood 68 have demonstrated a solid phase synthesis of the cis-and trans-Tic derivatives 185 using Merrifield resin as a support. In this connection, the N-protected dimethoxyphenylalanine derivative linked to chloromethylated polystyrene resin 182 was subjected to deprotection with trifluoroacetic acid and then N-acylation Katritzky and co-workers 69 have reported a simple route for the synthesis of chiral Tic derivative 134 involving the treatment of L-phenylalanine methyl ester 186 with benzotriazole and formaldehyde to furnish banzotriazolylmethyl derivatives 187 (92%). In the presence of aluminium trichloride, 187 undergoes an elimination of benzotriazole (Bt) anion to produce an iminium cation, which participates in the intramolecular electrophilic substitution on the phenyl ring to generate optically active Tic derivative 134 in 72% yield (Scheme 32).…”

First Synthesis of (R)‐ and (S)‐1,2,3,4‐Tetrahydroisoquinoline‐3‐phosphonic Acid (TicP) Using a Pictet–Spengler Reaction

“…On the other hand, it has also been reported that Tic 1 can be obtained using a benzotriazole‐assisted methodology. With this background, and applying a procedure described by Katritzky and co‐workers,20 diethyl phosphophenylalaninate (±)‐ 5a , benzotriazole (BtH) and formaldehyde were allowed to react at room temperature, rendering N ‐[(benzotriazolyl)methyl] intermediate 6 . Compound 6 , without additional purification, was treated with aluminum chloride in dichloromethane under refluxing conditions in efforts to generate the desired product (±)‐ 7a .…”

1,2,3-Triazoles

“…The simplest case is represented by derivatives 562 with an electron-rich aromatic ring in a proper distance on one of the amino group substituents. Three examples of [5+1] cyclocondensation of this type (the five-atom unit comes from phenethylamines and the one atom piece comes from formaldehyde) are shown in Scheme 96 <2001TA2427> . Thus, upon treatment with AlCl 3 , an iminium cation generated from N,N -bis[(benzotriazol-1-yl)methyl]phenethylamine 614 , by cleavage of one of the bonds with benzotriazole, attacks the phenyl ring in its ortho position to produce N -[(benzotriazol-1-yl)methyl]-tetrahydroisoquinoline 615 .…”

“…The second benzotriazolyl group can be removed by regular substitution with nucleophiles as discussed above to give tetrahydroisoquinoline 616 . Two additional examples in Scheme 96 show that the cyclization is not affected by even relatively complex substituents on the carbon α of the phenethylamine system, and the stereochemistry can be carried from the starting amines ( 617, 620 ) through the benzotriazolyl intermediates ( 618, 621 ) to the final products ( 619, 622 ) 2001TA2427 , 2002JOC8224 . Some of the nucleophiles used for substitution of benzotriazole in derivatives of type 615 are listed in Scheme 96 , but many others can be successfully employed as well <2002S601> .…”