Of tetrahydroisoquinoline

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. 

The vinylogous Pummerer reaction of an amido-substituted sulfoxide has been used for the preparation of tetrahydroisoquinoline 83 <95JOC(60)7082>. 

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. 

Scheme 29. Oxidative decarboxylation of tetrahydroisoquinoline-1-carboxylic acids by fungal laccase and horseradish peroxidase.

An elegant one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems has been disclosed by Pawda et al. <1998TL4757, 2000JOC2684>. This method generates a transient thioisomilnchnone 423 that undergoes an intramolecular dipolar cycloaddition. The thus obtained cycloadduct 424 is next reduced with Raney-Ni, followed by LAH to furnish ( )-alloyohimbane 425 in 31% overall yield from 421 (Scheme 109). 

Scheme 3.24 Grieco three-component reaction for the synthesis of tetrahydroisoquinolines (177) [282],...

Takasu examined a series of five imidazolidinone catalysts in the intramolecular conjugate addition of amides to a,p-unsaturated aldehydes to prepare a series of tetrahydroisoquinolines [114]. Although yields were high for these organo-catalytic transformations (70-90%), enantiomeric excesses were low (18-53%) showing further optimisation with regards to the co-acid and solvent are necessary to bring this potentially useful transformation in line with other reactions of this class. 

In the presence of excess nitrile, a second ring closure takes place at the cobalt and leads to derivatives of tetrahydroisoquinoline ( 1) in —60% yield. Compound (22) is obtained analogously from 1,6-heptadiyne. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

From dopamine, the pathway of tetrahydroisoquinoline alkaloids, such as emetine and cephaeline (Figure 37), also begins. Dopamine and secologanin undergo a Mannich-like to produce A-deacetylisoipecoside and ipecoside, and after hydrolysis and transformation, this is converted to emetine and cephaeline. 

Brossi, A. 1991. Mammalian alkaloids Conversion of tetrahydroisoquinoline-1-carboxylic acids derived from Dopamine. Planta Medica, 57 S93-S100 and, Xe, X. S., Tadic, D Brzostowska, M Brossi, A., Bell, M. and Creveling, C. 1991. Mammalian alkaloids - Synthesis and O-methylation of (S)-3 -hydroxycoclaurine and R-3 -hydroxycoclaurine and their N-methylated analogs with S-adenosyl-L-[methyl-C-14]methionine in presence of mammalian catechol O-methyltransferase. Helvetica Chimica Acta, 74 1399-1411. 

Consistently high levels of asymmetric induction have been achieved in the alkylation of tetrahydroisoquinolines using this methodology, as is demonstrated in the synthesis of chiral isoquinolinium alkaloids, e.g., (-)-salsolidine (61% yield, 95% ee)13, ( + )-homolaudanosine (48% yield, 96% op)14, ( —)-norcoralydine (37% yield, 98.5% op)15, some ben-zo[ ]quinolizidines (>99%ee), precursors of natural emetine16, corynantheine alkaloids17 and some azasteroids (93% ee)18. 

Padwa etal. utilized the ammonium ylide [1,2]-shift in the synthesis of tetrahydroisoquinoline and benzazepine fused with a five-membered ring, a structure found in a cephalotaxine family. When diazo ester 172 is treated with a catalytic amount of Cu(acac)2 in refluxing toluene, 5,7-fused compound 174 is isolated in 73% (Equation (25)). Again, use of Rh2(OAc)4 results in slow reaction and eventually gives a complex mixture of the products after a prolonged reaction time. 

Figure 15.13. Pictet-Spengler and Bischler-Napieralski syntheses of tetrahydroisoquinolines and quinolines from 2-arylethylamines.

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 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). 

Cyclization of tetrahydroisoquinoline 284 in the presence of ZnCl2 and MeaSiCN in CF3CH2OH at 23 °C for 1 h afforded three diastereomeric 2,3,4,6,11,1 la-hexahydro-1 /d-pyrazino[l,2-bJ isoquinolines 242 (44%), 243 (12%), and 244 (15%) besides tetracyclic derivative 246 (18%) (05JA16796). A fourth diastereomer 245 (19%) could also be isolated from the reaction mixture after a longer reaction period, 12 h. 

Dess-Martin oxidation of tetrahydroisoquinoline-3-methanols 344 in CH2C12 at room temperature resulted the formation of aldehydes, which immediately cyclized into hexahydro-1 /4-pyrazino[l,2-bJisoquinolines 238 and 345 (08SL2443, 09T5709). 

Reaction of tetrahydroisoquinoline-3-carboxylic acid 434 with primary amines and isonitriles provided 1,2,3,4, 1,11 -hexahydro-6H-pyrazino [l,2-b]isoquinolin-l-ones 435 (06HEC107). 

Derdau, V. Snieckus, V. Condensation of laterally lithiated o-methyl and o-ethyl benzamides with imines mediated by (-)-sparteine. Enantioselective synthesis of tetrahydroisoquinolin- 236 1-ones./. Org. Chem. 2001, 66, 1992-1998. 

---