Bis-tetrahydroisoquinolines

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 . 

Synthesis of antitumor bis-tetrahydroisoquinoline alkaloids, saframycins and ecteinascidins 05CJO42. 

ScIiOr has published on the vitro fibrinolytic activity of bisobrin (EN-1661), a bis tetrahydroisoquinoline 2. This cosqpound has been found by Moser to be active in the lysis of vivo clots in the dog and Ambrus has reported on the promising clinical use of bisobrin. 

Scheme 2.7 Conjugate addition of malonates to nitroalkenes with a preformed l,l -bi(tetrahydroisoquinoline)-type diamine nickel catalyst, and an in situ generated nickel catalyst from a biisoindoline ligand.

Phosphinous amides, based on proline and tetrahydroisoquinoline carboxylic acid, bearing a second donor center (50, Ar=Ph R =H, CH3,Tr, Ph R =H, CH3,Tr, Ph and 51, R =H,Tr R =H,Tr) (Scheme 40) have been developed for use in allylic alkylation and amination of substituted propenyl acetates, yielding the corresponding products in 87-98% (5-94% ee) and 29-97% (14-93% ee) respectively [55, 167]. With bidentate ligands of type 38 where R=(S)-PhMeCH, and with the bis(aminophosphanes) 52 (R=Ph) similar allylic alkylations have been also tested [168,169]. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

Stereostructures of a co-crystal of (li )-l- 4-[(9aA)-perhydropyrido[l,2- ]pyrazin-2-yl]phenyl -2-phenyl-7-hydroxy-l, 2,3,4-tetrahydroisoquinoline with ERa-LBD301-553/C — S triple mutant <2005JME364> and iV-[2-(4-hydroxyphenyl)ethyl]-a-propyl-3-[(4-hydroxyphenyl)methyl]-l,4-dioxo-l,2,3,4,ll,l la-hexahydro-67/-pyrazino[l,2- ]isoquinoline-3-acetamide with fructose-1,6-biphosphatase <2003JBC51176> were determined by X-ray crystallography. The structure of a complex formed from 3-[( -methylphenyl)amino]-4-[(4-methylphenyl)imino]-4//-pyrido[l,2-tf]pyrazine with sodium bis(trimethylsilyl)amide and (norbornadiene)Mo(CO)4 in THF was characterized by single crystal X-ray diffraction <1995JPR38>. 

Two molecules with comparable geometry in an asymmetric unit were found for 3,4-bis(4-fluorophenyl)-l,2,5-oxadiazole 2-oxide. The bond length of the dipolar N-O bond is 1.107 (7) A <2006AXEo4827>. In the molecule of 5-(6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-2-yl)-4-phenyl-l,2,5-oxadiazole Ar-oxide, the six-membered heterocyclic ring has a flattened boat form. Intermolecular C-H- O hydrogen bonds link the molecules into dimers, which may be effective in the stabilization of the crystal structure <2006AXEo3130>. 

The initial attack in the anodic oxidation of papaverine73 probably involves a similar attack further oxidation and dimerization leads to the isolated product, 12,12 -bis-(2,3,9,10-tetramethoxyindolo[2,l-a])isoquin61yl. The electrooxidation of a tetramethoxy substituted 2-methyl-l-phenethyl-1,2,3,4-tetrahydroisoquinoline to a dibenzoquinolizinium derivative is analogous.76... 

Seebach, D. Lohmann, J.-J. Syfrig, M. A. Yoshifuji, M. Alkylation of the isoquinoline skeleton in the 1-position. Lifhiated 2-pivaloyl and 2-bis(dimefhylamino)phosphinoyl-l,2,3,4-tetrahydroisoquinolines. Tetrahedron 1983, 39, 1963-1974. 

S)-l-Alkyl-l,2, 4-tetrahydroisoquinolines. The bis(trimethylsilyl) ether (2) of 1 has been used as a chiral auxiliary to effect alkylation of tetrahydroisoquinoline (equation 1) with high enantioselectivity. The chiral propanediol is much more effective than (R)-(— )-a-phenethylamine, and moreover leads consistently to (S)-l-alkyl derivatives. 

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 initial attack in the anodic oxidation of papaverine [75] probably involves a similar attack further oxidation and dimerization leads to the isolated product, 12,12 -bis-(2,3,9,10-tetramethoxyindolo[2,l-fl]isoquinolyl). An analogous reaction is the electrooxidation of a tetramethoxy-substituted 2-methyl-l-phenethyl-l,2,3,4-tetrahydroisoquinoline to a dibenzoquinolizinium derivative [76] and the oxidation of A,A -triphenyl-( -phenyle-nediamine to 9,10-diphenylphenazine [77]. Intramolecular Michel addition of nitrogen in a tetrahydroquinoline derivative to an o-quinone moity have resulted in the formation of a 5,6-dihydrodibenz[6,d]indolizine derivative [78]. A similar ring closure occurs during the oxidation of various catecholamines [79] and similar compounds [79] to indoles. Cyclic a-carbonylazo compounds, generated by anodic oxidation of the hydrazines, may be trapped by reaction with dienes to the expected heterocycles [80]. 

Perhydropyrido[l,2-c][l,3]oxazin-l-ones were prepared in the reaction of the appropriate 2-(2-piperidyl)ethanols and ethyl chloroformate (63AP38) in the presence of sodium ethylate in boiling benzene, or when 2-(2-piperidyl)ethanol was reacted with dimethyl carbonate in the presence of sodium methylate (91X1311). l-Hydroxymethyl-9,10-dimethoxy-l,2,4,6,7,llb-hexahydro-[l,3]oxazino[4,3-fl]isoquinoline-4-oneand 4-thione were prepared from l-[bis(hydroxymethyl)methyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline with ethyl chloroformate in the presence of sodium methylate, and thiophosgene in the presence of NEts, respectively... 

---