Pyrido -isoquinoline derivative

The only other synthesis of a benzo fused derivative involves the pyridazino[4,3-cjisoquinoline series, the isoquinoline derivative (377) reacting with hydrazine to give (378) (74YZ607), although an s-triazolo-fused pyrido[2,3-tf Ipyridazine was obtained in the reaction of l-amino-3-iminoisoindolenine with hydrazine and formic acid (56GEP951993). 

Benzo derivatives of the pyrido[l,2-f][l,3,2]oxazaphosphorine ring system, [l,3,2]oxazaphosphorino[4,3- ]isoquino-lines 195, 196, were synthesized by the reaction of hydroxyethyl isoquinoline derivatives 183, 184 with phenylphos-phonic dichloride, bis(2-chloroethyl)phosphonic dichloride or phosphoryl chloride. In almost all cases, the products were formed in about a 1 1 diastereomeric ratio. The only exception observed was when phosphoryl chloride was used as the reagent (X = C1) in this reaction one single diastereomer 196 (R2 = R3 = H) was obtained (Scheme 28) <2000JST(554) 119, 2000JOC316>. 

In investigations by the author (1), Chen (2), and Cochran (3), imidazo-, (I), pyrido[2,3-d]pyrimidin-7-ones, (II), and isoquinoline derivatives, (HI), respectively, were prepared, which were effective in treating p38 kinase-mediated disorders by modulating IL-1, IL-6, and IL-8 and TNF-a. These agents were used in treating pathophysiological disorders such as rheumatoid arthritis, fever, and reduction of bone resorption. 

Treatment of N-2,4-dinitrophenylpyridinium chloride (778) with phenyl-hydrazine in acetic acid causes reductive cyclization to yield the pyrido[l,2-ajimidazole (779). 3-Aminocrotononitrile, MeC(NH2)=CHCN, condenses with quinoline 1-oxide and isoquinoline 2-oxide to form the tricyclic compounds (780) and (781), respectively." The imidazo[5,l-a]isoquinoline derivative (783) is obtained by the action of phenyl isothiocyanate on the sodium salt of the Reissert compound (782)." ° Triethyl phosphite reduces the o-nitrophenyldipyr-rolylmethane (784 R=N02) to the nitrene (784 R = N), which forms the pyrrolo[3,2-6]quinoline derivative (785) by an intramolecular insertion reac-tion." 3-Amino-177-isoindole (786) reacts with acetylacetone in the presence of perchloric acid to yield the pyrimidoisoindolium salt (787). ... 

Herradon and coworkers [98] showed that the stereochemistry of the newly formed exo-cyclic double bond is dependent on substrate and reaction conditions in selected cases. Cyclization of 127 in the presence of a silver salt gave pyrido[l,2- ]-isoquinoline derivative 128 quantitatively as a single (Z)-isomer at the exo-cyclic double bond no conversion was seen at all under Jeffery conditions (Scheme 6.35). Conversely, the deoxo substrate 129 was... 

Sdnchez-Sancho, F., Mann, E. and Herradon, B. (2001) Efficient synthesis of chiral isoquinoline and pyrido[l,2-6]-isoquinoline derivatives via intramolecular Heck reactions. Adv. Synth. Catal., 343, 360-8. 

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)... 

Cyclization occurred at the N-3 atom when 4-(3-bromopropylaruino)-l, 6,7,1 1 b-tctrahydro-2//-pyrimido[6,l -zz -isoquinoline was treated with NaH to give a tetracyclic derivative <2003M1271>. 9,10-Dimethoxy-2-(arylimino)-2,3,6,7-tetrahydro-4//-pyrimido[6,l- ]isoquinolin-4-ones were N-3-alkylated with iV-(ra-bromoalkyl)phthalimides in the presence of K2C03 and a catalytic amount of I2 in boiling 2-butanone in 13-67% yields <2000W020/058308>. Treatment of the 2-[(4-methoxyphenyl)methyl] derivative of 2,3,6,7-tctrahydro-l //,5//-pyrido[3,2,l-/ylqninazolinc-... 

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