Isoquinolines 4-benzylation

Isoquinoline, 3 -benzoyltetrahydro-synthesis, 2, 413 Isoquinoline, 1-benzyl-nitration, 2, 335 Isoquinoline, 4-benzyl-nitration, 2, 335 synthesis... 

The formation of quaternary salts from benzyl halides and related compounds occurs readily and has been known for many years. More recently, Krohnke and co-workers, who have studied the reactions of many heterocyclic quaternary salts, reported the formation of 5 from pyridine and benzylidene dibromide on heating the reactants together for 1 hr at 100°. The salt is sufficiently stable to be recrystallized from methanol containing a trace of hydrogen bromide. Isoquinoline gives a similar salt. 

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). 

Thermolysis of the vinyl azide 11 in toluene furnishes a mixture of ethyl 2-phenyl-l//-3-benz-azepine-4-carboxylate(12), ethyl 4-(2-phenylvinyl)indole-2-carboxylate(13) and ethyl 1-benzyl-isoquinoline-3-carboxylate (14).82... 

Isoquinoline, 2-acetyl-l, 2,3,4-tettahydro-6,7-dimethoxy-l-inethylene-, 4 Isoquinoline, 2-benzoyl-l -benzy 1-1-cyano-1,2-dihydro- [1-Isoquinolinecarbo-mtrile, 2-benzoyl-l, 2-dihydro-l -(phenjlmethyl)-), 23 Isoquinoline, 2-benzoyl-l -cyano-1,2-di-hydro l-Isoquinohnecarbomtrile, 2-ben2oyl-l, 2-dihydro-], 20 ISOQUINOLINE, 1-BENZYL- [ISOQUINOLINE, HPHENYLMFTHYL)-], 19 Isoquinoline, 3,4-dihydro-6,7-dimethoxy-l-methyl-, 4... 

C-9, and C-10, always with a phenolic hydroxy group at the 8a position. Moreover, they differ from one another by the oxidation state of the benzylic C-13 as well as by substitution and degree of saturation of the isoquinoline fragment. These alkaloids, classified as benzylisoquinoline alkaloids (2,70-74), have recently been called by Shamma et al. (75-77) pseudobenzyliso-quinolines originating from protoberberine alkaloids. In Table V a list of 8,8a-secoberbine alkaloids, sources, and spectral data are presented. 

Structures of 3-[(4-methylphenyl)amino]-47/-pyrido[l,2-tf]pyrazine-4-thione, iV-tosyl-3-[(4-methylphenyl)a-mino]-4//-pyrido[l,2-tf]pyrazine 4-imine, and 246 were confirmed by X-ray investigations <1999JPR332>. The stereostructures of (4A,llaA)-lla-ethoxycarbonylT,3,4,6,lla-hexahydro-l,3,4,6,ll,lla-hexahydro-4-methox-ycarbonyl-l-oxo-[l,4]oxazino[4,3-A isoquinoline <1995ZK787>, 2//-pyrazino[l,2- ]isoquinolinc-l,4-dione 247 <2001TL543>, 4-benzyl-2-methyl-1,3,4,6,7,11 b-hcxahydro-2//-pyrazino[2,l -zz] isoqu incline-3,6-dione... 

An appropriately functionalized isoquinoline (38) bearing a benzyl group is prepared from an aromatic aldehyde (37). The benzyl position is metalated with LDA and the resulting carbanion is reacted with a highly substituted methyl benzoate to produce a ketone (39). The isoquinoline nitrogen is alkylated with ethyl a-bromoacetate and the resulting quaternary salt is cyclized... 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

In another example increased yields of products are obtained under ultrasonic irradiation in the PTC alkylation of the isoquinoline derivatives using 50% aqueous NaOH as base [125]. Efficient mixing is not easy to achieve for this system under normal reaction conditions due to the viscosity of the aqueous base. In the specific case of alkylation with benzyl chloride ultrasound plus [Et3NCH2Ph] Cl achieved 60% yield in 20 min compared with only 50% in 2 h with stirring (Eq. 3.25). 

Kinetic studies of various systems have been carried out as follows the reaction of 2,2 -dichlorodiethyl sulfide and of 2-chloroethyl ethyl sulfide with diethylenetriamine and triethylamine in 2-methoxyethanol ° the catalysed reactions of substituted phenols with epichlorohydrin the reactions of para-substituted benzyl bromides with isoquinoline under high pressure the reactions of O-alkylisoureas with OH-acidic compounds [the actual system was N, N -dicyclohexyl-0-(l-methylheptyl)isourea with acetic acid] and tlie ring opening of isatin in aqueous binary mixtures of methanol and acetonitrile cosol vents. 

Fig. 8. Benzyl[c]isoquinoline alkaloids from Sanguinaria canadensis and H. canadensis rhizomes with anti-HP activity.

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

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. 

Unexpected oxazoline formation was observed during a study to prepare nonsedating anxiolytic 1-styrylisoquinolines 27a-h from 2-(trifluoromethyl)aryl-ethylamines 25a-h under Pictet-Gams conditions (POCI3 in refluxing toluene). This deviation from the normal reaction pathway was hypothesized to result from the electron-withdrawing effect of trifluoromethyl group that inhibited the formation of a benzylic cation required for isoquinoline formation (Scheme 8.12). 

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