Tetrahydroisoquinolines formation

In 1911, Ame Pictet and Theodor Spengler reported that P-arylethyl amines condensed with aldehydes in the presence of acid to give tetrahydroisoquinolines. Phenethylamine 6 was combined with dimethoxymethane 7 and HCl at elevated temperatures to give tetrahydroisoquinoline 8. Soon after, the Pictet-Spengler reaction became the standard method for the formation of tetrahydroisoquinolines. 

Friedel-Crafts reaction remains unexplored, possibly due to the difficulty of the cycloalkyne formation. A mild, versatile, and efficient method for the one-step synthesis of substituted dihydro- and tetrahydroisoquinolines has been developed by the FeCl3-6H20-catalyzed intramolecular allenylation/cyclization reaction of benzylamino-substituted propargylic alcohols, representing the first example of the intramolecular Friedel-Crafts reaction of propargylic alcohols (Scheme 8) [24, 25]. FeCls, InCls, and Yb(OTf)3 also exhibit good catalytic activity for the reaction. 

Marsden BJ, Nguyen TM-D, Schiller PW. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Peptide Protein Res 1993 41 313-316. 

The antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

The subject of metabolism of tetrahydroisoquinolines and related alkaloids in mammalian metabolic systems has recently been reviewed (205, 206). The formation of biogenic amine-derived alkaloids in mammals and their transformation by O-methylation reactions have been described. 

In 2004, Taylor and Jacobsen suggested a procedure for the enantioselective acetyl-Pictet-Spengler reaction, that is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ion enabling access to substituted tetrahydro-P-carbolines and tetrahydroisoquinolines that are core structure elements in natural and synthetic organic compounds [202, 203]. Screening various thiourea catalyst candidates such as 47 in the formation of model product Np-acetyl-... 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

Desai, and S. S. Hecht. Evidence for endogenous formation of tobacco—specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite. Carcinogenesis 1997 18(3) 587—592. NT257 Mendez-Alvarez, E., R. Soto-Otero, I. Sanchez-Sellero, and M. Lopez-Ri-vadulla Lamas. Inhibition of brain monoamine oxidase by adducts of 1, 2,3,4-tetrahydroisoquinoline with components of cigarette smoke. Life Sci 1997 60(19) 1719-1727. 

Polystyrene-bound o-quinodimethanes, which are formed upon thermolysis of ben-zocyclobutanes, can be converted into 1,2,3,4-tetrahydroisoquinoline derivatives by reaction with /V-sulfonylimines. Reaction of o-quinodimethanes with electron-poor nitriles leads to the formation of 1,4-dihydroisoquinolines, which undergo elimination with simultaneous release of isoquinolines into solution (Entry 7, Table 15.25). 

In relation to their biosynthesis, it was proposed that A-B units of Et s are most likely formed by condensation of two Dopa-derived building blocks and that the tetrahydroisoquinoline ring in unit B is closed by condensation (Pictet-Spengler) with a serine(or glycine)-derived aldehyde, as in the case of the related saframycins. S-Adenosylmethinonine is the likely source of the methyl groups. A plausible route for the formation of unit C was proposed later [75]. This was partially demonstrated by incorporation of radiolabeled tyrosine and cysteine by Kerr and Miranda [80] and by incorporation of labeled methionine, glycine and tryptophan by Morales and Rinehart [81]. 

There are several reports of tetrahydroisoquinolines with a fused furan ring that could be argued (for the sake of the classification used in this collection) as an oxidative attack by the a-hydrogen of the 1-benzyl onto the 8-HO substituent, in a manner similar to the formation of a seven-membered ether ring seen in the cularines. It can also be seen as a similar oxidative attack from an a-hydroxy group (a commonly encountered benzyl substituent) on the 8-hydrogen position. The first of these two mechanisms (illustrated above) is used in this collection. 

The prefix "seco" is an unusual term occasionally encountered in the literature of natural products. Just as the term "ortho-attack" indicates the generation of a new ring, the term "seco" indicates the destruction of a ring. A secoisoquinoline is formed from a 1-substituted tetrahydroisoquinoline by the loss of the 1,2-bond. Transferring a hydrogen atom from the a-carbon to the nitrogen, and reshuffling the electrons, results in the formation of a new double bond. 

Treatment of l-(3, 4 -methylenedioxybenzyl)-2-methyl-6,7-dimethoxyisoquinolinium iodide with lithium aluminium hydride in ether followed by immediate treatment with 2N hydrochloric acid resulted in formation of an intense red-violet colour which very quickly faded to yellow. Basification of the reaction mixture and extraction with chloroform gave an oil which was reduced by treatment with sodium borohydride in ethanol. This gave a product which was isomeric with, but different from, l-(3 ,4 -methylenedioxybenzyl)-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the expected product from this sequence of reactions. 

The treatment of a mixture of tetrahydroisoquinoline-3-aldehyde 252 and tricyclic pyrazino[l,2-fc]isoquinolin-4-one 253 with MeS03H lead to an efficient domino process with the formation of a mixture of pentacyclic compounds 254 and 255 (Scheme 5) (07AGE3962). 

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