Formylations isoquinoline

Several compounds capable of metal chelation inhibit the non-heme iron ribonucleotide reductases with many of these chelators the mechanism of inhibition appears to be more complex than simple competition for the iron atom required by the enzyme. The most potent members of one such group of inhibitors are the thiosemicarbazones of 1-formyl-isoquinoline (I) and 2-formylpyridine (II). 

A newly discovered alkaloid, cherylline, has been shown to have a novel structure (5) derived from 4-phenylisoquinoline. It has been synthesised from the appropriate benzophenone by way of the alcohol, chloride, nitrile, and primary amine, followed by formylation, isoquinoline ring closure, reduction, and methylation. ... 

Reduction of a 7-(2-oxoethyl) derivative with NaBH4 in EtOH at room temperature gave 7-(2-hydroxyethyl)-2-(2-pyrimidinyl)perhydropyrido[l, 2-u]pyrazine (99MIP6). Reduction of 7-formyl-8-[(4-cyanophenyl)methoxy]-1,3,4,6,11,1 lu-hexahydro-2//-pyrazino[l,2-A]isoquinoline-l,4-dione with NaBH4 yielded a 7-hydroxymethyl derivative (98MIP7). 

Vilsmeier formylation of praziquantel (9) with DMF-POCI3 at 60 °C for 5 h gave 2-cyclohexylcarbonyl-3-dimethyliminiummethylene-4-chloro-1,6,7,116-tetrahydro-2//-pyrazino[2,l-u]isoquinoline salt (01PHA146). 

Treatment of 8-[(4-cyanophenyl)methoxy]-7-formyl-2-cyclopentyl-2,3,4,6,11,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione with (Et0)2P(0)CH2C00Et and NaH in THF at 40 °C overnight, or with (2-pyridylmethyl)-, 4-[(ethoxycarbonyl)benzyl]-, (4-nitrobenzyl)-, and (meth-oxymethyl)triphenylphosphonium halogenide in the presence of KH in THF at room temperature gave 7-ethylene derivatives 386 (98MIP7). 

A Vilsmeier reaction of pyridine-2-carbonitriles 126 was found to produce mixtures of l-formyl-2-dimethyl-amino[l,5-4]pyridines with a chlorine atom 127 or a hydrogen 128 at the C-7 position < 1998J(P 1 )3851 >. When extended to isoquinoline-1 -carbonitriles such as 129, this reaction gave in modest yield compounds 130 (Scheme 40). Later on, it was demonstrated that this reaction leads to imidazo[l,5- ]pyridinium chlorides when A,A-dimethylbenzamides were used instead of dimethylformamide (DMF) <1999H(50)887>. 

The addition of the N(2)-C(3) unit to isoquinolines is reported using o-di formyl benzene and phosphoglycine (Equation 123) <1999TL7935>. 

Benzyl-6-oxoperhydropyrido[2,l-c][l,4]oxazine-4-carboxylic acid was prepared from the 7-unsubstituted derivative by alkylation with PhCH2Br in the presence of lithium bis(trimethylsilyl)amide in THF at -78°C (96MIP8). The reaction of 1,3, 4,6,7,116-hexahydro[l,4]thiazino[3,4-a]-isoquinolin-4-one (45) with a Vielsmeier-Haack reagent afforded 3-formyl-4-chloro-l,6,7,llh-tetrahydro[l,4]thiazino[3,4-a]isoquinoIine (111) (81CP 1101857). 

Isoquinolin 3-Brom-l-formyl- E7a, 691 (5-Br — <(l,2,3-triazolo[5,l-a]isoquinolin) -f- Se02)... 

The importance of azaellipticines is illustrated by the fact that 204 (BD-40) is undergoing clinical trials 10,98). Using their new 1-chloroellipticine synthesis (Scheme 20), Bisagni et al. 74) have described an extremely concise route to 10-chloro-5,6-dimethyl-5ff-pyrido[3, 4 4,5]pyrrolo[2,3-g]isoquinoline (208) and the side-chain amine derivatives 209-211 (Scheme 35). Formylation of 1-methyl -5-azaindole (205), followed by reaction with the lithiochloropyridine 124, gave... 

Hydrogenation with homogeneous catalysis has received increasing attention over the last few decades. Hexarhodium hexadecacarbonyl (181 Scheme 35) under water gas shift conditions forms 1,2,3,4-tetrahydroquinoline (128) or N-formyl-1,2,3,4-tetrahydroisoquinoline (182) with the parent hete-roaromatic. When hydrogen is substituted for carbon monoxide, 4-methylquinoline is reduced to 4-methyl-5,6,7,8-tetrahydroquinoline (183) exclusively.Isoquinoline behaves similarly generating A/-formyl-l,2,3,4-tetrahydroisoquinoline (184). Similar reductions under water gas shift or synthesis gas conditions using transition metal carbonyls derived from Mn, Co and Fe, have been recorded.Promotion by phase transfer agents is observed in some cases. 

Isoquinolines are formed by formylation of arylacetonitriles though often in low yields and with other products. The most successful examples involve... 

Homophthalic acid surprisingly yields an isoquinoline upon Vilsmeier formylation, apparently by rearrangement and cyclization of the side-chain formylated intermediate (Scheme 25). This intermediate may be isolated at low temperatures.64 In a related manner the isoquinolone (87) has been synthesized from the toluic acid (86).64a... 

Compound 1 was the major alkaloid present and compounds 2 and 3 were previously unknown as natural products. The related naphthylisoquinoline alkaloids ancistrocladine (5) and its atropisomer hamatine (6) were previously known from other Asian Ancistrocladus species [25] while the 7,3 -linked naphthyl-isoquinoline, ancistrotectorine (8), has been previously isolated from Ancistrocladus lectorius from Thailand [26]. The structure of I was deduced from spectral data (UV, MS, NMR) as well as by its ready conversion to the known 2 through successive mesylation and LiAIH4 reduction. Likewise the structure and relative stereochemistry of 4 were established by spectral analysis (HMBC, NOESY) and by conversion to the known (-)-N-formyl-O-methylancistrocladine derivative 7 via successive formylation followed by methylation (Mel, NaH-DMF). 

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