Isoquinolines isoquinolinium salts

The disproportionation reaction of isoquinolinium salts to 1,2-dihydro-isoquinolines and isocarbostyril derivatives (Scheme 16) was used by Brown and Dyke for the synthesis of berberine and 8-oxoberberine derivatives (277-279). 

The same reaction with the isoquinolinium salt 338 (under the same conditions) furnishes l-acetyl-3-ethoxycarbonylpyrrolo[2,l-a]isoquinoline (339) in 72% yield. 

Substituted 4-aryl-1 -oxo-1,2-dihydropyrazino[l, 2-i]isoquinolinium salts 402 were obtained when 3-substituted isoquinolines 401 were cleaved from a polymer by treatment 25% TFA (00MIP5). c/i-3,lla-H-3-Phenyl-1,2,3,4,11,11 fl-hexahydropyrazino[l, 2-i]isoquinoline-1,4-dione (404) formed when isoquinoline derivative 403 was cleaved from a resin with 25% TFA during an automated solid-phase synthesis (98BMCL2369). 

Homophthalaldehyde (188) gives isoquinoline, isoquinoline 2-oxide, 3,4-benzopyrylium salts, and 2-alkyl- and 2-aryl-isoquinolinium salts (189) by reaction with NH3, NH2OH, H+ or RNH2, respectively. 

Cyclization of 1-isoquinolyl derivatives (201) in a cold solution of perchloric acid or in cone, sulfuric acid at room temperature afforded 4-hydroxy-3,4-dihydro-2//-[l,3]thiazino[2,3-a]isoquinolinium perchlorates (202) and 2H-[l,3]thiazino[2,3-a]isoquinolinium salts (203), respectively (74IJC1242). Heating l-[(3-phenyl-3-hydroxypropyl)thio]isoquinoline in PPA yielded the l-phenyl-3,4-dihydro-2//-[l,3]thiazino[2,3-a]isoquin-olinium salt (74IJC1242). 6,7-Dihydro derivatives of 2//-[l,3]thiazino-[2,3-a]isoquinolinium perchlorate (203, R = Me) and 4-methyl-2,3,4,6,7, llh-hexahydro-[l,3]thiazino[2,3-a]isoquinoline were obtained by cyclization of the 3,4-dihydro derivative of 201 (R = Me) and 4-[(l,2,3,4-tetrahydroisoquinolin-l-yl)thio]-2-butanol, respectively, in cone, sulfuric acid or in PPA [81IJC(B)372],... 

Isoquinolinium salts are reduced to 2-alkyl-1,2-dihydroisoquinoline derivatives by sodium dithionite,6 lithium aluminum hydride7,8 (LAH), or dialkyl aluminum hydrides.9 LAH is preferred7 to dithionite since it leads to purer products, and will reduce those salts that are inert to dithionite (e.g., papaverine methiodide). Isoquinoline itself10,11 and 3-methyl-6,7-methylenedioxyisoquinolinelz (5) can be reduced to the 1,2-dihydroisoquinoline with LAH, as can isoquinoline... 

A diastereoselective three-component process to prepare 2//-pyrimido[2,1 -a]-isoquinolines 84 from isoquinoline was reported <01OL3575>. Pyrrolo[2,l-a]isoquinolines were also prepared by an annelation reaction with l,l-diiodo-2,2-dinitroethylene and isoquinolinium salts containing active methylene groups <02SL1547>. 

The use of 2,4-dinitn>i enyl aromatic quatemaiy salts prepared directly from the parent isoquinoline compound and 2,4-dinitrophenyl bromide or chloride enhances the electron-deficient nature of the iso-quinolinium salts, accelerates the rate of their [4 2] cycloaddition reacticms with electron-rich alkenes, and has permitted the use of isoquinolinium salts previously regarded as unmanageable. The application of these observations in the total syntheses of methylamottianamide and 14-epicoiynoline is summarized in Scheme 26. - ... 

Qulnolinium salts (68 Scheme 15) can undergo attack at either the 2- or 4-position. The former normally predominates and the latter leads to 1,2,3,4-tetrahydroquinolines (69). 3-Substituents generally produce mixtures of the 1,2- and 1,4-dihydro adducts. Isoquinolinium salts (70 Scheme 15) produce both 1,2-dihydrolsoqulnolines (71) and 1,2,3,4-tetrahydroisoquinolines (72). Reduction in protlc solvents normally produces the tetrahydro adducts, in anhydrous pyridine or dimethylformamide the reduction generally stops at the 1,2-dihydroisoquinoline. Reaction of the enamine system of 1,2-dihydroisoqui-nollnes with electrophiles has been used as a method for generation of 4-substituted isoquinolines. 

The transformation of isoquinolinium salts into naphthalene derivatives described in connection with berberine (c/. Section 11) may have general applicability since similar reaction of isoquinoline methiodide gave -naphthyl acetate, albeit in small yield (see ref. 362). 

A novel cyclo-condensation was reported between l,l-bis(trimethylsilyloxy)ketene acetals 164 and isoquinolinium salts 165 <05TL8997>. This reaction resulted in the carboxylic acid 166 in moderate to good yields. Ultimately, this isoquinoline derivative 166 was used to make a series of 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones 167 shown in Scheme 47. 

Phenylimino)-l-hydroxymethyl-9,10-dimethoxy-l,2,4,6,7,ll -hexahy-dro[l,3]oxazino[4,3-a]isoquinoline was prepared from 4-methylimino and 4-thione derivatives in the presence of HgO and 4-methylthio-l,6,7,llh-tetrahydro-2//-[l,3]oxazino[4,3- ]isoquinolinium salt with aniline (85GEP3510526). 4-Methylthio-l-hydroxymethyl-9,10-dimethoxy-l,6,7,116-tetrahydro-2//-[l,3]oxazino[4,3-a]isoquinolinium iodide was obtained from the l,2,4,6,7,116-hexahydro-4-thione derivative with methyl iodide (85GEP3510526). 1-Hydroxymethyl-9,10-dime thoxy-1,2,4,6,7,116-hexahy-dro-[l,3]oxazino[4,3-fl]isoquinolin-4-thione was obtained from its 4-one derivative by treatment with P4S10 in pyridine (85GEP3510526). 

The Zincke salt (A -(2,4-dmitrophenyl) salt) of isoquinoline is easily transformed into chiral isoquinolinium salts on reaction with chiral amines - an ANRORC sequence in which the ninogen of the chiral amine ends up as the nitrogen of the isoquinolinium product - nucleophilic addition of Grignard reagents to these salts shows good stereoselectivity. ... 

Similar reduction-ring expansion was carried out with variously substituted isoquinolines, the acetic acid being replaced by propionic acid.176 Goeber et al.m expanded the ring of the isoquinolinium salt 183 (R = H, OMe A = OH) on treatment with phenyldiazomethane in methanol to prepare 35 (R1 = R2 = H R3 = Me R4 = Ph R6 = OMe R6 = H, Me R7, R8 = O-CHr-O). Similarly, 183 (R = H, A = C104) treated with diazomethane gave a mixture of 184 and 184a. The crude mixture of these... 

The Zincke salt of isoquinoline is easily transformed into chiral isoquinolinium salts on reaction with chiral amines.Nucleophilic addition of Grignard reagents to these salts shows good stereoselectivity. " ... 

It is important to realise that 1-benzopyrylium salts cannot be converted into quinolines or quinolinium salts by reaction with ammonia or primary amines, whereas 2-benzopyrylium salts are converted, efficiently, into isoquinolines or isoquinolinium salts respectively. ... 

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