Pictet-Spengler synthesis of tetrahydroisoquinolines

Whaley, W. M., Govindachari, T. R. The Pictet-Spengler synthesis of tetrahydroisoquinolines and related compounds. Org. React. 1951, 6, 151-190. 

The Pictet-Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds Wilson M. Whaley and Tutucorin R. Govindachari... 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

The mechanistically similar Pictet-Spengler synthesis is also much used for the preparation of 1,2,3,4-tetrahydroisoquinolines, starting from a... 

Pictet-Spengler synthesis is another method of preparing isoquinolines. (3-phenylethylamine reacts with an aldehyde to produce an imine, which undergoes acid-catalysed cyclization, resulting in the synthesis of the tetrahydroisoquinoline system. Again, tetrahydroisoquinoline can he aromatized hy palladium dehydrogenation to produce an isoquinoline system. 

Chirality can be induced at the C-l position by the cyclization of o-vinylphenethylamine in the presence of a chiral selenium reagent (Equation 68) <1998S162>. Removal of the selenide gives the 2-methyltetrahydroisoquinoline. The use of the Pictet-Spengler reaction in the asymmetric synthesis of tetrahydroisoquinolines remains active. Therefore the intramolecular reaction of /3-iminosulfoxide 33 yields the chiral product 34 (Equation 69) <1998EJ0435>. 

The Pictet-Spengler reaction, the cyclization of an electron-rich aryl or heteroaryl group onto an imine electrophile, is the established method for the synthesis of tetrahydroisoquinoline and tetrahydro-/ -carboline ring systems. Catalytic asymmetric approaches to these synthetically important structures are mostly restricted to asymmetric hydrogenations of cyclic imines [77, 78]. In a noteworthy... 

A titanium precatalyst is described which the authors use in a one-pot synthesis of tetrahydroisoquinolines from phenethylamines and alkynes <03OL4733>. The reaction is a modification of the Pictet-Spengler reaction. 

Pictet-Spengler tetrahydro-isoquinoline synthesis Synthesis of tetrahydroisoquinolines and isoquinolines from B-arylethylamines. 348... 

N-Acyliminium ion-mediated Pictet-Spengler reaction has also been applied to the synthesis of tetrahydroisoquinolines [404]. Thus, supported 4-formylbenzoic acid (569) was reacted with 2-(3,4-dimethoxyphenyl)ethylamine (570), affording the corresponding resin-bound imine (571). The latter underwent N-acyliminium ion-mediated Pictet-Spengler condensation in the presence of a number of acid chlorides, sulfonyl chlorides, and a chloroformate under basic conditions to give (572) better yields and purities were obtained using acid chlorides and the chloroformate (Scheme 119). 

New modifications of the traditional approach to isoquinoline synthesis via carbocation intermediates continue to be reported. Abnormal products of the Bischler-Napieralski reaction were observed <97JCS(P1)2217>. A stereoselective introduction of a quaternary carbon center in the A-acyliminium cyclization (Scheme 14) of the chiral enamide 46 affords an asymmetric synthesis of tetrahydroisoquinolines <97T2449,3045>. An asymmetric Pictet-Spengler reaction has been developed mediated by the chiral urethane 47 <97T16327>. A Pummerer reaction of A-acyl-A-(aryl)methyl-2-(phenylsulfinyl)ethylamine allows cyclization to the 4-phenylthio-... 

The asymmetric synthesis of l-subsliluted-l,23,4-tetrahydroisoquinolines received much attention as well. The Pictet-Spengler reaction of iV-sulfinyl amines such as 77 afforded 1-substituted-l,23,4-tetrahydroisoquinolines (78) with diastereomeric ratios as high as 96 4. The chiral auxiliary can be removed with HCl in ElOH <01TL8885>. A similar method was used... 

SCHEME 36 Synthesis of tetrahydroisoquinolines via Pictet-Spengler cyclization. 

Pictet-Spengler Cyclization Hegediis et al. carried out the one-step synthesis of tetrahydroisoquinolines 50 via Pictet-Spengler cyclization between p-phenylethylamine and ketones/aldehydes in the presence of E4a zeolite in ethanol (Scheme 36) [140]. Ersorb-4 (E4) zeolite is a weakly acidic zeolite-type adsorbent with a small pore size (4A) that seems to show good activity in different condensation reactions. E4a xmder study was obtained by ionic exchange of E4. When the reaction was carried out over montmorillonite KPIO catalyst, which is more acidic than E4a, no product was observed as KPIO is unable to bind the water formed during the reaction. 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

Mannich and Mannich-like reactions are widely used for the chemical synthesis of heterocycles, and in alkaloid biosynthesis in plants. One such reaction important in nature is a biological equivalent of the Pictet-Spengler tetrahydroisoquinoline synthesis (see Section 11.10.4), and offers a slight twist, in that the enol nucleophile is actually a phenol. 

The 1.2.3.4-tetrahydroisoquinoline skeleton represents the framework found in many isoquinoline alkaloid derivatives and not only from plants. Some derivatives attracted much interest because of their anti-cancer activity [124], which has prompted many groups to invest in their chemical synthesis. The Pictet-Spengler reaction has become an important method in the preparation of this alkaloid type, and has often been described with phenylalanine derivatives and pyruvates as starting materials. Synthesis of appropriate tetrahydroisoquinoline-3 and the corresponding tetrahydroisoquinoline-1-carboxylic acid has been the key target [125]. 

Variations and improvements of the Pictet-Spengler reaction continued to be a popular area of research for the synthesis of isoquinolines. Ruchirawat et al. reported a new version of the Pictet-Spengler reaction where V-acylcarbamatcs 122 were partially reduced with DIBAL-H followed by the sequential addition of BF3-OEt2 to provide 1,2-disubstituted tetrahydroisoquinoline derivatives 123 <07TL8182>. 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

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