Tetrahydroisoquinoline, from isoquinoline

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

A number of pharmaceuticals are derived from isoquinoline. The long-known isoquinoline alkaloid papaverine 56 (synthesis on p 344) is still important as a spasmolytic. The antidepressant nomifensin 88 and the antibilharzia drug praziquantel 89 are derived from 1,2,3,4-tetrahydroisoquinoline. 

No new TV-benzyltetrahydroisoquinolines have been isolated from natural sources in recent years. However, the structure of corgoine has been confirmed by three syntheses. The first involves reduction of the 7V-benzyl quaternary salt derived from isoquinoline 1, whereas the second approach utilizes the Pictet-Spengler reaction to cyclize the substituted phenethylamine 2 (see Scheme 31.1). The third synthesis of corgoine involves heating 6-methoxy-7-hydroxy-tetrahydroisoquinoline with / -hydroxybenzyl alcohol to afford the alkaloid in 44% yield. The A -benzylation probably occurs through the intermediacy of /7-benzoquinone methide which adds to the basic nitrogen of the isoquinoline. ... 

When the 1-monoximes or dioximes of 4-acetyl-l-tetralones are hydrogenated in the presence of palladium, mixtures of diastereoisomeric 1-aminotetralones are formed. The m-aminoketone isomers readily form dehydrobenzoisoquinuclideines (3,4-disubstituted-1,4-dihydro-1,4-ethano-isoquinolines). Quaternary immonium salts prepared from these bicyclic imines are then converted by bases to bicyclic enamines [2,4-disubstituted-3-alkylidene-1,4-ethano-1,2,3,4-tetrahydroisoquinolines (25)]. 

The thermal condensetion of p-benzyloxyphenylacetic acid and of 3-methoxy-4-hydroxy-phenethylamine occurs and gives, with a yield of 86% to 92%, the N-(3-methoxy4-hydroxy-phenethyl-p-benzyloxyphenylacetamide from this latter, by cyclization according to Bischler-Napieralski with phosphorus oxychloride in acetonitrile, followed by reduction with sodium borohydride, there is obtained with a yield of 75% to 80% the 1-(p-benzyloxybenzyl)-6-meth-oxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline, which is methylated with formaldehyde and formic acid giving 1 (p-benzyloxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline with a yieid of 90%. 

B. 2-Acetyl-6,l-dimethoxy-l-methylene-l,2,3,4-tetrahydroisoquinoline [Isoquinoline, 2-acetyl-l,2, A,4-tetrahydro-6,7-dimethoxy-l-methylene-]. A 1-1., three-necked, round-bottomed flask equipped with a mechanical stirrer, a reflux condenser topped with a calcium chloride drying tube, and a thermometer is charged with 110 ml. of acetic anhydride, 110 ml. of pyridine, and 45.0 g. (0.22 mole) of the dihydroisoquinoline prepared in Part A. The reaction mixture is stirred and heated at 90-95° for 30 minutes, stored at room temperature overnight, and concentrated by distillation at 50° using a rotary evaporator. The residue is diluted with 20 ml. of ethyl acetate, and another evaporation under reduced pressure gives material that can be crystallized from 75 ml. of ethyl acetate to yield 38.5 41.0 g. (72-77%) of product, m.p. 106-107° (Note 11). 

Intramolecular Diels-Alder reaction of substituted fiirans has been investigated as a route to the synthesis of isoquinoline alkaloids. Tetrahydroisoquinoline 81 was prepared from furan 80 in 40% yield <95JCS(P1)2393>. 

A 6,6-dimethyl-6,7-dihydropyrido[l,2-c]quinazolinium salt was obtained from the reaction of 2-(2-aminophenyl)-pyridine and acetone <1997AJC109>. Reaction of 3-methyl-l,2,3,4-tetrahydroisoquinoline-l-acetamides 195 (R = H) with 36% aqueous CH20 gave 1,3,4,6,7,11 b-hcxahydro-2//-pyrirmido[6,1 - ]isoquinolin-2-oncs 153 and their 3-methyl derivatives <1997LA1165>. When the reaction was carried out in the presence of 37% aqueous NaOH, 3-hydroxymethyl derivatives 152 were obtained. Reactions with PhCHO were stereospecific affording only diastereomers 196 (Equation 41). 

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>. 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

Oxidation of 2-(3-aminopropyl-l,2,3,4-tetrahydroisoquinoline with mercuric acetate in 4% aqueous acetic acid at 50°C for 6 h, and then at room temperature overnight followed by the treatment of the filtered solution with 20% potassium hydroxide solution, yielded 1,3,4,6,7,llb-hexahydro-2//-pyrimido[2,l-a]isoquinoline (16, R = R1 = H) in 27% yield (73JOC437). 1,3,4,6,7,llb-Hexahydro-2//-primido[2,l-a]isoquinolines (16, R = H, MeO, R1 = H) and their 2-oxo derivatives (18, R = H, MeO, R1 = H) were obtained from 2-(3-aminopropyl)- and 2-(2-aminocarbonylethyl)-3,4-dihydroisoquinolinium salts (17 and 19, R = H, MeO, R1 = H) by treatment with a base (62CB2122,62MI1). The adjustment of the pH value of a solution of l-methyl-2-(2-aminocarbonylethyl)-3,4-dihydroisoquinolinium perchlorate (19, R = H, R1 = Me, X = C104) in 10% aqueous acetic acid with sodium carbonate to 9 yielded 1 lb-methyl-1,3,4,6,7,1 lb-hexahydro-2//-primido[2,l-a]isoquinolin-2-one (111) (93KGS499). 

The isoquinoline system is conveniently prepared from treatment of o-iodobenzylamines with the enolate ions derived from symmetrical ketones (or ketones with one a-position blocked), aldehydes, or the dimethyl acetal of pyruvaldehyde, to give aminocarbonyl compounds which condensed in situ to give 2- and/or 3-substituted 1,2-dihydroisoquinolines. Catalytic dehydrogenation or borohydride reduction of these products then led to the corresponding isoquinolines or tetrahydroisoquinolines in moderate to high... 

Heating a well-mixed mixture of l-(2-hydroxyethyl)-2-ethoxycarbo-nyl-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline and solid NaOMe at 130 °C for 45 min followed by extraction of the reaction mixture with EtOAc provided 9,10-dimethoxy-1,6,7,11 b-tetrahydro-2H,4H-[l, 3]oxa-zino[4,3- ]isoquinolin-4-one in 52% yield (09T8021). 1,3,4,6,7,11b-Hexahydro-2H-pyrimido[6,l-fl]isoquinolin-4-one 53 was obtained from pyrimidinone 91 by a Pictet-Spengler reaction in CH2C12 in the action of TFA at ambient temperature (09OL1559). 

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. 

In addition to MPTP, other endogenously produced neurotoxins, namely, the monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-l,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. A-methylated isoquinolines were found to be oxidized by MAO, and hydroxyl radicals were found to be produced by this reaction. In addition, by incubation with the A-methylated isoquinolines, ATP was depleted from a dopaminergic cell model. Pretreatment of the cells with MAO inhibitors such as selegiline could, however, protect against ATP depletion. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1 -methyl-1,2,3,4-tetrahydroisoquinoline and 1 -methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino-... 

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]. 

Cyclic amines6 70 including triazoles71 and aziridines,72,73 Good yields of the desired N-substituted 4,4-dimethyl-4-sila-1,2,3,4-tetrahydroisoquinolines are obtained from primary amines and the benzyl bromide derivative. However, due to further reaction, the formation of the non-substituted parent isoquinoline occurs in very low yield. 

The insertion of the N(2)-G(3) unit in reduced isoquinolines remains a topic of interest, especially stereoselective examples. The iminoglycinate 43 undergoes reaction with the dibromo 44 in the presence of the -symmetric chiral quaternary ammonium bromide phase-transfer catalyst (Equation 130) <2001S1716>. A high-yielding tetrahydro-isoquinoline resulted in excellent enantioselectivity. Reaction of the chiral anion generated from 45 with benzylidene also produces chiral tetrahydroisoquinolines (Equation 131) <1999EJO503>. 

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... 

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