Isoquinoline 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). 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

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]. 

Mono- and dilithio derivatives of p-tosylmethyl isocyanide 297a were shown to display interesting reactions. Reaction of the monoanion with unsaturated esters was shown to give pyrrole derivatives . Dianion 297b was found to add to the carbon-nitrogen double bonds of isoquinoline, quinoline and quinoxaline affording compounds 298, 299 and 300, respectively. In the reactions with pyridine iV-oxide and pyridazine iV-oxide, unstable open-chain products 301 and 302 were obtained . 

In recent years a number of new isoquinoline alkaloids of untypical structures, i.e., structures with open heterocyclic rings, have been isolated from natural sources. These bases were named secoisoquinoline alkaloids because they were believed to be produced in vivo from classic isoquinoline alkaloids as a result of various degradation processes causing oxidative cleavage of some bonds. 

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. 

A series of transformations via nitrene formation similar to the previously discussed case was also found under flash vacuum thermolytic (FVT) conditions by the same team as shown in Scheme 8 <2003JOC1470>. 9-Phenyltetrazolo[l,5- ]quinoline 29 underwent nitrene 30 and cyclic carbodiimide 31 formation, and this intermediate - similar to the previous case - could open up to the isoquinoline nitrene 32 in which, however, proximity of the nitrene to the phenyl substituents allowed the ring closure to the stable tetracyclic ring system 33 which was obtained in 73% yield. 

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. 

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