Isoquinolines ring opening

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Reaction of 1-chloroisoquinoline with 5-phenyltetrazole gave 3-phenyl[l,2,4]triazolo[3,4-n]isoquinoline (428). It has been suggested that the initial 2-tetrazolylisoquinoline (425) underwent ring opening to (426) which readily lost N2 giving (427). This nitrilimine is a 1,5-dipole, and on cyclization the [l,2,4]triazolo[3,4-n]isoquino-line (428) is formed (70CB1918). 

The second proposed mechanism involves initial ring opening of the phthalimide. Alkoxide attack on one of the imide carbonyls furnishes amide anion 26. Proton transfer affords enolate 27, which undergoes Diekmann type condensation followed by aromatization to afford the requisite isoquinoline 23. 

Hydrolysis and subsequent oxidation of 2-methyl-4,6,7,l Ifi-tetra-hydro[l,3]oxazino[2,3-n]isoquinoline-4-one (42) afforded ring opened product 43 (99TL8269). 

Isoquinoline 2-oxide was converted by bromine in acetic anhydride in the presence of sodium acetate into the 4-bromo 2-oxide, presumably via an addition-elimination process (84MI2). Metallic derivatives have been used occasionally to prepare bromoisoquinolines, as in the formaton of 79, a process accompanied by ring-opening [87JCS(PI)1865]. 

Extension of these studies to benzologues of tetrazolo[l,5- ]pyridine, that is, for tetrazolo[l,5- ]quinoline 21 and tetrazolo[5,l- ]isoquinoline 22, led to interesting results <2003JOC1470> as shown in Scheme 7. Both of these fused tetrazoles resulted in formation of a nitrene 23 and 24, respectively, which could be interconverted via formation of the fused cyclic carbodiimide derivative 25. Isoquinolylnitrene 24, furthermore, was found to undergo subsequent reactions ring opening afforded the vinylnitrene 26, which was transformed to o-cyanophe-nylacetonitrile 27 by a 1,2-H shift and to 4-cyanoindole 28 by an intramolecular cyclization in 40% and 25% yields, respectively. 

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. 

It has been found that the cupric sulfate-mediated aminolysis of 3-bromo[ N]isoquinoline with ethanolic ammonia (130°C, 7 days reaction time) yields a mixture of 13 and 14, ratio 75 25 (74RTC198). It shows that also with the weaker nucleophile ammonia a part of 3-bromoisoquinoline can undergone a ring-opening, ring-closure process. 

The (diphenylmethylene)aminocyclobutenecarboxylates 109 obtained by rearrangement of the DMPA-H adducts of 1-Me, 2-Me, contain a 2-azadiene unit and a cyclobutene moiety. Indeed, the parent compound 109 a reacted with 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD, [80]) at room temperature in a [4-1-2] cycloaddition mode to yield the tricyclic tetraazaundecene 132 in almost quantitative yield (Scheme 44) [8]. As substituted cyclobutenes, compounds 109 should be capable of opening up to the corresponding butadienes [1, 2b, 811. When compounds 109 were subjected to flash vacuum pyrolysis, the dihydro-isoquinolines 135 were obtained, presumably via the expected ring-opened intermediates 133, which subsequently underwent bn electrocyclization followed by a 1,5-shift, as is common for other 3-aza-l,3,5-hexatrienes [82]. 

Whereas with quinoline the benzo ring is the more susceptible to oxidative ring opening, with isoquinoline the matter is more finely balanced. Use of ozone or alkaline permanganate results in attack on both the rings, the products being phthalic acid and pyridine-3,4-dicarboxylic acid (cinchomeronic acid) (38 Scheme 25). 

Whereas 1-methyl-1,2,3,4-tetrahydro-6//-pyrimido[l,2-b]isoquinolin-6-one and its 11-benzyl derivative were resistant to hot acid and alkali, and cw-ll,lla-H-ll-benzyl-l-methyl-l,2,3,4,ll,lla-hexahydro-6//-pyrimido-[l,2-b]isoquinolin-6-one (41) to alkali, the latter gave ring-opened product 42 in hot 2 N hydrochloric acid (88HCA77). 

Treatment of dimethyl l-phenyl-2-oxo-l,llb-dihydro-2//-pyrimido[2,l-a]-isoquinoline-3,4-dicarboxylate (64) with 20% hydrochloric acid, with sodium methylate in methanol, or with aniline yielded ring-opened products (Scheme 3) (67CB1094). 

Treatment of l,3,3-triphenyl-l,3,4,llh-tetrahydro-2//-pyrimido[2,l-a]-isoquinoline-2,4-dione (68) with aniline and cone, hydrochloric acid in diox-ane afforded ring-opened products (67CB1107). 

Irradiation of compound 357 (R = Me) in methanol and ethanol at 300 nm gave ethyl 2-methyl-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-car-boxylate (371) and 3-alkoxy-2-methyl 4//-pyrimido[2,l-a]isoquinoline-4-ones (369, R = Me, R1 = Me, Et) along with two imidazo[2,l-a]isoquino-lines (368, R = Me and 372) and a ring-opened product (92AJC1811). At 254 nm the yields of 4//-pyrimido[2,l-a]isoquinolin-4-ones (369, R = Me and 371) and 368, (R = Me) were lower no formation or trace of them was observed in acetonitrile, acetone, acetic acid, and ethyl acetate. Irradition of compound 357 (R = Me) at 300 nm in acetonitrile containing 36% hydrochloric acid afforded 3-chloro-2-methyl-4//-pyrimido[2,l-a]isoquinolin-4-one (373) in 31-81% yields and other products. 

Treatment of 2,3,4,6,7,11 h-hexahydro[l,3]oxazino[2,3-a]isoquinolines with hydrogen bromide, benzylmagnesium chloride, acyl chloride, or hydrogen cyanide afforded ring-opened 1,2,3,4-tetrahydroisoquinoline derivatives (66AP817). 

Evidently, the stability of 3-hydroxy-3,4-dihydroisoquinolines 137, formed as the result of heterocyclization, is also determined by the anne-lated benzenoid ring. The lower tendency toward aromatization for these compounds, compared to monocyclic analogs, leads to the ability of 137 to react as a cyclic azomethine. The addition of a molecule of nucleophile to the C=N bond causes opening of the isoquinoline ring and formation of a new ring system (for instance, a-naphthols 141 in alkaline aqueous solutions). Such conversions occur even under conditions of the recyclization reaction of 2-benzopyrylium salts, namely, on heating 137 in alcoholic ammonia a mixture of isoquinoline 138 and a-naphthylamine 140 results (88MI1). 

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