Isoquinolines 1,2,3,4-tetrahydro— from

Aryl-ethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydro-isoquinolines resnlt from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. Routine dehydrogenation easily converts the tetrahydro-isoqninolines into fnlly aromatic species. 

In support of the hypothetical phytochemical formation of tetrahydro-isoquinoline derivatives from phenethylamine derivatives and aldehydes, Schopf and Bayerle (118) examined the condensation of acetaldehyde with... 

MkheNamines. Atropisomeric dimeric naphthyl-(tetrahydro)isoquinoline alkaloids from the tropical lianas Ancistrocladus korupensis and A. abbreviatus. C46H48N2O8, Mr 756.89. 

Pomerantz synthesis, 2, 429 synthesis, 2, 413 from benzynes, 2, 432 Isoquinoline, 1,2,3,4-tetrahydro-mass spectrometry... 

Pellotine and Anhalonidine. The A -acetyl derivative of mezcaline (I NHj— NHAc), on treatment with phosphoric oxide, yields 6 7 8-trimethoxy-l-methyl-3 4-dihydrowoquinoline (picrate, m.p. 181-2°), which, on successive catalytic hydrogenation and treatment with methyl sulphate, yields 6 7 8-trimethoxy-l 2-dimethyl-l 2 3 4-tetrahydro-isoquinoline identical with 0-methylpellotine (picrate, m.p. 167-8°), whence it appears that pellotine must be a dimethyl ether of 6 7 8-trihydroxy-1 2-dimethyl-l 2 3 4-tetrahydrowoquinoline. Pellotine and anhalonidine on complete methylation yield the same product, and as anahalonidine is a secondary base and differs from pellotine by containing —CHj less, it must be a dimethyl ether of 6 7 8-trihydroxy-l-methyl-1 2 3 4-tetrahydrowoquinoline, and pellotine should be A -methyl-anahalonidine. 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Alkoxy-3-(4-biphenyl)perhydropyrido[], 2-c][], 4]oxazines were obtained from 3-hydroxy derivative with PrOH and Br(CH2)30H in a boiling acidified medium (00JMC609, 00MIP13). Spontaneous dehydration of b-hydroxy-1,3,4,6,7,1 lZ -hexahydro[l,4]oxazino[3,4-n]isoquinolin-4-one 258 in CHCI3 gave 3,4,6,7-tetrahydro derivative 259 (97JOC2080). 

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). 

An asymmetric synthesis of 1-aryltetrahydroisoquinolines 79 from chiral amide 78 was reported <96TL(37)4369>. Optically active cis- or rranj-1,3-disubstituted tetrahydro-isoquinolines can he prepared hy a modification of this procedure. 

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. 

Iodophenethylamine derivatives were found to undergo palladium catalysed cyclization to indolines.45 Starting from the appropriate tetrahydro-isoquinoline derivative the reaction was extended by Buchwald to the preparation of tricyclic natural products (3.37.),46... 

Catalytic hydrogenation of 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-diones (93) and 3,3-diethyl-9,10-dimethoxy-3,4,6,7-tetrahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (94) over Pt02 and Pd/C catalysts gave l,3,4,6,7,llb-hexahydro-2/7-pyrimido[2,l-a]isoquinoline-2,4-diones (95) [69YZ649 71JPP71/09466]. From the mother liquid of compounds 93 (R = H, R1 = Et and R = R1 = Et) 3-ethyl-2-hydroxy-6,7-dihydro-and -8,9,10,1 l-tetrahydro-4//-pyrimido[2,l-a]isoquinolin-4-ones, and 3,3-diethyl-l,3,4,llb-tetrahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione, also could be isolated as minor products. Reduction of 3,3-diethyl-l,3,4,6,7,llfo-hexahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (95, R = R1 = Et, R2 = H) with LAH in tetrahydrofuran at 70°C for 9 h afforded 3,3-diethyl-l,3,4,6,7,llb-hexahydro-2//-pyrimido[2,l-a]isoquinoline (96). 

---