Tetrahydroisoquinolines series

The alkali-catalysed disproportionation of pseudo-bases in the simple tetrahydroisoquinoline series is assumed to be a heteroanalogous Cannizzaro reaction, intermediate between the acid-catalysed disproportionation of benz-hydrols and the alkali-catalysed Cannizzaro reaction. The benzenoid derivatives (11) and (12) react with ammonium hydroxide under pressure to give norcotamine (13). 6,7-Dihydroxylated tetrahydroisoquinolines can be readily prepared by aqueous hydrobromic acid hydrolysis of the corresponding 6,7-dimethoxy-compounds. ... 

A series of diamine amides based on the phenoxypropyl amine scaffold was reported. Amide 26 displayed an hH3 Ki of 1 nM and was selective versus other histamine receptors [73]. The chirality was removed via cyclic diamines to produce tetrahydroisoquinolines, tetrahydroquinolines, benzazepines and indolines [74]. The benzazepine 27 displayed picomolar hH3 binding affinity. Pharmacokinetic issues were also identified with this diamine series, with i.v. half-lives of 10-12 h in the rat. A strategy to remove the diamine skeleton and prepare new H3... 

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. 

An exhaustive series of reports by Grigg et al. (28) outlined two basic methods for the generation of azomethine ylides proceeding via either a 1,2-prototropic shift, or by a decarboxylative approach (29). The decarboxylative route to azomethine ylides can be exemplified by the condensation of benzaldehyde with the cyclic amino acid tetrahydroisoquinoline (108) (30), in DMF at 120 °C, to generate the intermediate awfi-dipole 109, which underwent subsequent cycloaddition with N-methyl maleimide to furnish a 1 1 endo/exo mixture of adducts 110 (R = Ph), in 82% yield (Scheme 3.30). 

A series of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives 16 (Scheme 10) as inducers of p-turns has also been described. 70 ... 

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... 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

In search for potent and systemically available inhibitors of the matrix metalloproteinase MMP-8 (Matter et al. 1999 Matter et al. 2002) following oral administration, a local ADME model was derived to support lead optimization. For an internal series of inhibitors on the tetrahydroisoquinoline scaffold, hydroxamic acids for zinc ion binding in 3-position are essential for MMP affinity in first generation inhibitors. However, those compounds are characterized by insufficient pharmacokinetic properties and low systemic exposure following oral administration. Driven by X-ray and 3D-QSAR studies (CoMFA), alternative Zn2+ binding groups like carboxylates were... 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

Using an efficient IBX-mediated Ugi-type reaction, Zhu and co-workers reported the synthesis of a series of 1,2-disubstituted tetrahydroisoquinolines 143 in moderate to high yields <07AG(I)5775>. To the best of the author s knowledge, this is the first example of dual acylation at the Cl position and at the N-H group of tetrahydroisoquinoline. 

Chen et al. reported a more environmentally friendly version of the Pictet-Spengler reaction <06H1651>. In this report, a series of 2-phenylsulfonyl-l,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ethyl ester derivatives 114 were synthesized in good yields through the cyclization of A-phenylsulfonyl-P-phenethylamines 115 with a-acyl sulfide 116 using phenyliodine(III) bis(trifluoroacetate) (PIFA) in ionic liquid ([bminjPFJ. The use of the ionic liquid allows for a simple purification and [bmin]PF can conveniently be recycled. 

The Noyori asymmetric transfer hydrogenation was utilized in the synthesis of the chiral 1,2,3,4-tetrahydroisoquinolines by R.A. Sheldon et al. These compounds are important intermediates in the Rice and Beyerman routes to morphine. The "Rice imine" was exposed to a series of chiral Ru " complexes, which was prepared from r -arene-Ru " chloride dimeric complexes and A/-sulfonated 1,2-diphenylethylenediamines along with the azeotropic mixture of HCOOH/NEts. With the best catalyst the desired tetrahydroisoquinoline was isolated in 73% yield and the enantiomeric excess was 99%. 

Protoberberines The protoberberine alkaloids are the most widely distributed benzylisoquinoline alkaloids. Hundreds of alkaloids of this series are discovered that they were yielded from the tetrahydroisoquinoline catalyzed by BBE [16], the berberine bridge... 

The Mexican cactus Pachycereus pecten-aboriginum has been shown to contain salsoline (6 R = H, = Me) and the new bases isosalsoline (6 R = Me, R = H), the isomeric arizonine (7) (which has the same orientation of oxygen substituents as is found in tepenine), and heliamine, which is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Salsoline (6 R = H,R = Me) and salsolidine (6 R = R = Me), on treatment with ethylene oxide, afford the/3>hydroxyethyi compounds (8 R = H, R = OH) and (8 R = Me, R = OH), and these have been converted into a series of esters by reaction with acid chlorides. The jS-chloroethyl compound (8 R = H, R = Cl) has been shown to decrease... 

PheneUiyHetrahydroisoquinoliiie alkaloids. While the benzy l(tetrahydro)isoquinoline alkaloids are built up form a Cj-C2 unit and dopamine, the phenethyl-tetrahydroisoquinolines are formed from dopamine and a (- 3 unit. Similar to the benzylisoquinolines, the compounds can undergo a series of secondary reactions to furnish the corresponding homo compounds. They can be classified into 7 different groups ... 

An important series of in vivo experiments by Kapadia and his colleagues using [ C]-labeled precursors has led to a substantial advance in our understanding of the biogenesis of tetrahydroisoquinoline alkaloids. iV-Acetyl-3-demethylmescaline can act as a precursor for a variety of peyote alkaloids since administration of this amide, labeled as indicated, to peyote, Lophophora williamsii (Lemaire) Coult., generated radioactive anhalamine and anhalonidine. 

The recent isolation of a series of simple tetrahydroisoquinoline alkaloids monooxygenated in ring A, such as longimammatine and longimammidine, raises interesting and still unanswered questions concerning their biogenesis. ... 

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