1.2.3.4- tetrahydroisoquinoline derivatives

A common modification of the Bischler-Napieralski reaction involves reduction of the dihydroisoquinoline product 2 to provide a tetrahydroisoquinoline derivative 19. A variety of different reducing agents have been employed, with NaBHi used with the greatest frequency. In many cases the reduction is carried out on the crude product of the Bischler-Napieralski reaction purification of the dihydroisoquinoline prior to reduction is usually not necessary. 

The Pictet-Spengler reaction is an acid-catalyzed intramolecular cyclization of an intermediate imine of 2-arylethylamine, formed by condensation with a carbonyl compound, to give 1,2,3,4-tetrahydroisoquinoline derivatives. This condensation reaction has been studied under acid-catalyzed and superacid-catalyzed conditions, and a linear correlation had been found between the rate of the reaction and the acidity of the reaction medium. Substrates with electron-donating substituents on the aromatic ring cyclize faster than the corresponding unsubstituted compounds, supporting the idea that the cyclization process is involved in the rate-determining step of the reaction. 

Stereoselectivity in the condensation reaction of 2-arylethylamines with carbonyl compounds to give 1,2,3,4-tetrahydroisoquinoline derivatives was somewhat dependent on whether acid catalysis or superacid catalysis was invoked. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed with trifluorosulfonic acid (TFSA) as compared with the weaker acid, trifluoroacetic acid (TFA). Compound 43 was cyclized in the presence of TFA to give modest to good transicis product ratios. The analogous compound 44 was cyclized in the presence of TFSA to give slightly improved transicis product ratios. 

The chiral (V-camphanoyl iminium ion 7, prepared by hydride abstraction from 2-camphanoyl-l,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 6 (see Appendix) with triphenylcarbenium te-trafluoroborate, reacts with silyl enol ethers to give 1-substituted tetrahydroisoquinoline derivatives with reasonable diastereoselectivity, 0°. On addition of titanium(IV) chloride, prior to the addition of the silyl enol ether, the diastereoselectivity gradually rises to an optimum at 2.5 equivalents of the Lewis acid, but the yield drops by 20%. 

Paluchowska et al. (2002) reported the synthesis, pharmacological studies, and conformational analysis utilizing classical molecular modeling approaches of some arylpiperazine or 1,2,3,4-tetrahydroisoquinoline derivatives of the known and flexible 5-HT ia receptor ligands with different intrinsic activities at nanomolar levels [63]. The SAR is shown in Table 4. The synthetic steps involved for some of the compounds mentioned in Table 4 are shown in Scheme 2 [63]. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

The significance of monoamine oxidase inhibition as a contributory factor, to the antihypertensive action of some adrenergic neurone blocking dmgs (see p. 186), has received further support. The tetrahydroisoquinoline derivatives debrisoquine (VII) and guanisoquin (LXVil, R = 7-Br, = H) are... 

Examples of the direct 5-metalation of nonfused compounds containing heterocyclic sp3-nitrogen are quite limited, often because of competing side-reactions such as benzylic deprotonation. However, with the appropriate substitution pattern 8-metalation can occur even in those cases where benzylic deprotonation is a possibility. Examples of successful 8-lithiation include the imidazolidine 172 and 2-methyloxazolidine 173 (91G249), as well as the tetrahydroisoquinoline derivative 174 [69CI(L)621], although in this latter case subsequent steps resulted in only a 10% yield of the desired product 175. 

In the case of electron-rich aromatic rings, for example, 472 it is possible to take advantage of the activating substituents to effect a Pictet-Spengler reaction to prepare the tetrahydroisoquinoline derivative 473 as shown in Scheme 7.153. ... 

Only one example has been reported in which an acyclic amine was alkylated with this method32. Using the oxazoline derivative of Af-methylbenzeneamine, deprotonation, subsequent alkylation with iodomethane at — 78 °C and removal of the oxazoline moiety afforded the 7 -confi-gurated a-methylbenzenamine in high yield (95%) with a selectivity of 64% ee. This value is nearly the same as that obtained on reaction of the tetrahydroisoquinoline derivatives at that temperature. Thus, as in the case of methanimidamides, no conclusions concerning the effectiv-ity of this approach in acyclic stereoselection can be drawn at present. 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

Treatment of 2,3,4,6,7,11 h-hexahydro[l,3]oxazino[2,3-a]isoquinolines with hydrogen bromide, benzylmagnesium chloride, acyl chloride, or hydrogen cyanide afforded ring-opened 1,2,3,4-tetrahydroisoquinoline derivatives (66AP817). 

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 a projected synthesis of the protoberberine alkaloid thalictrifoline 1 the tetrahydroisoquinoline derivative 2 was treated with formaldehyde and acid under a variety of conditions. Unexpectedly, the product was the isoquinobenzoxazepine derivative 3, which was obtained in yields of 70-85% depending on the conditions used. 

Closely-related alkaloids cooccurring with mescaline are anhalamine, anhalonine, and anhalonidine (Figure 6.40), which are representatives of simple tetrahydroisoquinoline derivatives. 

In order to evaluate the consequences of the replacement induced by substituting a SiMe2 group for a methylene group on their biological activity, two series of tetrahydrosilaisoquinolines and tetrahydroisoquinolines derivatives have been synthesized and compared.508-511... 

Etoricoxib 102, a 2,3-bipyridine derivative, has been used as a nonopioid analgesic <2003EP0912518>. A bis-tetrahydroisoquinoline derivative, tetrandrine 103, has been used an analgesic and is present in the Chinese drug han-fang-chi . 

Stereocontrolled synthesis of W-methyl-l,2,3,4-tetrahydroisoquinoline derivatives using chromium tricarbonyl 90JOM(400)223. 

The A-tosyl-/3-phenethylamines 95 react with ethyl (methylthio)acetate in the presence of BTIB to give the A-tosyl tetrahydroisoquinoline derivatives 97, probably through the normal Pummerer product 96 (Scheme 29) (02H1). Pictet-Spengler cyclization of 96, with the loss of methanethiol, would lead to 97. 

The asymmetric syntheses of tetrahydroisoquinoline derivatives were also reported. Optically pure 3,4-disubstituted tetrahydroisoquinolines such as 78 were prepared by Friedel-Crafts cyclization of amino alcohols 77 <02TL1885>. Enantioselective syntheses of dihydropyrrolo[2,l-a]isoquinolines via a highly diastereoselective, chiral auxiliary assisted N-acyliminium cyclization was disclosed <02SL593>. The enantioselective synthesis (-)-tejedine, a seco-bisbenzyltetrahydroisoquinoline was also reported. One key step in this synthesis involved a chiral auxiliary-assisted diastereoselective Bischler-Napieralski cyclization <02OL2675>. Additionally, an asymmetric Bischler-Napieralski was reported for the preparation of 1,3,4-trisubstituted 1,2,3,4-tetrahydroisoquinolines <02JCS(P1)116>. 

An example of the retro Mannich type reaction is the formation of the 14-membered ring compound VIII/126a from the tetrahydroisoquinoline derivative VIII/125a in 11% yield, Scheme VIII/24 [77]. 

Conversion of 47 into a-methyldopa was accomplished in the following three-step sequence, since the treatment of 47 with 6 M HC1 gave the corresponding tetrahydroisoquinoline derivative (1) TMSBr/Me2S, (2) 1 M NaOH, (3) 47% aq. HBr. 

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>. 

In two reports Hanzawa and co-workers described a mild and facile Pictet-Spengler reaction catalyzed by perfluorooctane sulfonic acid (PFOSA) in water <07T4039 07TL835>. Many of their examples outline the reaction of 3,4-dimethoxyphenethylamines 124 with a variety of aldehydes catalyzed by PFOSA in water using l,l,l,3,3,3-hexafluoro-2-propanol (HFIP) as an additive resulted in the formation of 1,2-disubstituted tetrahydroisoquinoline derivatives 125 in high yield. 

---