Tetrahydrocinnoline

Tetrahydro-[l,2,4]triazolo[4,3-h]cinnolines have been prepared from 3-hydrazino-5,6,7,8-tetrahydrocinnolines and the reagents just described for (17) (71BSF3043), and also by condensing 2-hydroxymethylenecyclohexanone with 4-amino-1,2,4-triazole (79JCS(P1)3085). 

Tetrahydroindoxazene-3-carboxylic acids (89) are transformed into 3-amino-2-phenyl-4,5,6,7-tetrahydroindazoles by boiling phenylhydra-zine.98 On reduction with hydrogen and Raney nickel in ethanol, the acid hydrazides of 89 undergo ring opening to the imines 90 followed by cyclization to 4-amino-5,6,7,8-tetrahydrocinnolin-3-ones." The phenylhydrazone of 3-benzoyl-4,5,6,7-tetrahydroindoxazene behaves similarly.100... 

Acetoxy-2-methyl-2,3,4,5,6,7-hexahydrobenzofuran-3-one (170) with hydrazine gave 3-methyl-5,6,7,8-tetrahydro-4(l//)-cinnolinone (171) (EtOH, 20°C, 12 h 85%) or with methylhydrazine gave a separable mixture of 1,3-dimethyl-5,6,7,8-tetrahydro-4(17/)-cinnolinone (172) and 2,3-dimethyl-5,6, 7,8-tetrahydrocinnolin-2-ium-4-olate (173) (EtOH, 0°C 20°C, 12 h 67% and 15%, respectively) the related substrate, 2-methoxy-2-methyl-... 

Hydroxyiniino-2-methyl-2-morpholino-2,3,4,5,6,7-tetrahydro-3a//-mdole 1-oxide (188) gave 5-hydroxyimino-3-methyl-5,6,7,8-tetrahydrocinnoline (189) (H2NNH2 H2O, AcOH, H2O, reflux, 15 min 85%). ... 

In contrast, 5,6,7,8-tetrahydro-3(2//)-cinnolinethione (6) gave a highly unstable octahydrocinnoline (7) that underwent aerial oxidation during treatment with picric acid to afford only 5,6,7,8-tetrahydrocinnoline (8) as picrate (Raney Ni, EtOH, reflux, 2h then picric acid], 15%). 

Cinnoline (18) gave 3-chlorocinnoline (neat POCI3, reflux, 10 days 91%) ° ° the reduced substrate, 5,6,7,8-tetrahydro-3(2//)-cinnolinone (19), likewise gave 3-chloro-5,6,7,8-tetrahydrocinnoline (neat POCI3, 100°C, until substrate dissolved 20%). ... 

Chloro-5,6,7,8-tetrahydrocinnoline (31) gave 3-hydrazino-5,6,7,8-tetrahydro-cinnoline (32) (neat H2NNH2 H2O, reflux, 2h 71%). ... 

Another important class of dienes which react readily with ADC compounds are the vinyl arenes. However, the reaction of styrene with ADC compounds does not give simple tetrahydrocinnolines. Styrene and DEAZD give a 1 2 adduct formed by the initial Diels-Alder adduct reacting rapidly in an ene reaction with more DEAZD (Eq. 18).181 Substituted styrenes react... 

The formation of a double bond during anodic oxidations can result from eliminations of protons, carbon dioxide or acylium cations. The electrooxi dative aromatization of dihydropyridine derivatives and heterocycles containing nitrogen atom (di-hydroquinoxalines, tetrahydrocinnolines) involves an ECE mechanism as previously... 

Dihydropyridines are oxidised to the pyridine at a graphite anode [239, 240]. Similarly, 1,2,3,4-tetrahydrocinnolines can be oxidised at the potential of the first wave to give the 1,4-dihydrocinnoline and at the potential of the second wave to give the cinnoline [241 ]. 

Many examples of the cycloaddition of substituted butadienes with 1,2-disubstituted diazenes such as diethyl azodicaboxylate, yielding substituted 1,2,3,6-tetrahydropyridazines, were mentioned in CHEC(1984) <1984CHEC(2)1> and CHEC-II(1996) <1996CHEC-II(6)1>. The method has also been used to synthesize 1,2,3,4-tetrahydrocinnolines when styrenes were used as substrates. 

The alkylation of 3- or 4-hydroxycinnolines has been shown to occur at the 2-position. Reduction of these cinnolinium salts with lithium aluminum hydride gave 2-alkyl-l,2,3,4-tetrahydrocinnolines which darkened rapidly on exposure to air but could be converted to stable derivatives.1370,6... 

By disproportionation. Dihydro compounds often disproportionate (Scheme 73), i.e., form a mole equivalent of aromatic and a mole equivalent of tetrahydro derivative for example, the dihydrocinnoline 498 on treatment with hydrochloric acid gives 4-phenylcinnoline and 4-phenyl-l,2,3,4-tetrahydrocinnoline 2H- (e.g., 499) and 4/7-thiins on treatment with acid form thiinium salts and the corresponding tetrahydrothiin. 

Dihydrocinnoline derivative 230 can be synthesized from the [2-(2,2-dimethoxyethyl)phenyl]hydrazine 229 via acid-catalyzed cyclization in dioxane. When methanol is used as solvent a 3-methoxy-l,2,3,4-tetrahydrocinnoline 231 is formed (Scheme 131) <1995LA1303>. 

Reduction of pyridazin-4-ones seems not to have been reported, f. Derivatives of Cinnoline. 3-Hydroxycinnoline (222)44 is reduced in a two-electron wave from pH 0 to 11. In strongly acid solution the main product is 1-aminooxindole (223), which is also obtained on reduction with zinc and sulfuric acid.232 Reduction in an emulsion of an aqueous phosphate buffer (pH 6.5) and n-butanol produced a nearly quantitative yield of 3-keto-l,2,3,4-tetrahydrocinnoline (224) this compound was easily reoxidized to 3-hydroxycinnoline. 

Oxidation of a 1,1-disubstituted hydrazine in MeCN containing HCIO4 [132-134] or anhydrous HBF4 [135] forms a diazenium cation that may react with alkenes in a cycloaddition reaction to a tetrahydrocinnoline. If both substituents on nitrogen are aryl, an oxidative coupling between them may compete with the dipolar reaction [135]. 

Hydroxycinnoline (LXXVI) [101] in acid solution is reducible in two, two-electron steps. The product from the first two-electron reduction is 4-keto-l,2,3,4-tetrahydrocinno-line (LXXVII). This compound is a derivative of phenylhydrazine and can thus be oxidized anodically in alkaline solution to an azo compound (LXXVIIT), which then tautomerizes to LXXVI. The carbonyl group of LXXVII is activated by the phenyl ring and—in contrast to 3-keto-l,2,3,4-tetrahydrocinnoline—is thus further reducible the reduction yields 4-hydroxy-1,2,3,4-tetrahydrocinnoline (LXXIX). On standing, this compound loses water with the formation of 1,4-dihydrocinnoline. If, however, the compound is oxidized in alkaline solution, the product (LXXX) loses water and forms cinnoline. 

On reduction with LAH, cinnolines generally yield di- and tetrahydro derivatives. The LAH reduction of 5,6,7,8-tetrahydro-3-cinnolinones (304) in THF leads to mixtures of the dihydrocinnolines 305, the decahydro cinnolines 306 and the deoxygenated tetrahydrocinnolines 307. The ratio of products is dependent on the substituents and the amount of LAH used. ... 

Morpholinocyclohex-l-ene (150) and ethyl (2,2,2-trichloro-l-phenylethylide-ne)hydrazinecarboxylate (151) gave a separable mixture of ethyl 4-chloro-3-phenyl-l,5,6,7-tetrahydro-l-cinnolinecarboxylate (152, R = C02Et) and 4-chloro-3-phenyl-l,5,6,7-tetrahydrocinnoline (152, R = H) (or tautomer) (EtP4N, CH2CI2, N2, reflux, 5 h 44% and 9%, respectively). - - - ... 

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