Cinnolines, formation

Cumulative efforts of Stoermer, Simpson and Schofield have led to a fairly comprehensive understanding of the circumstances in which the Widman-Stoermer reaction might be expected to succeed. Initial efforts of Simpson and Schofield, " demonstrated that cinnoline formation is not expected to succeed for o-vinyl anilines (1) where Ri = H or CO2H and R2 = aryl, CO2H, CO2R, CN, 2-pyridyl, or 2-quinolyl. On the other hand, for compounds (1)... 

Internal electrophilic substitution by a diazonium group can occur in alkenylpyridines of the types (58) and (59). In the case of (58 Ar = j -MeO. G6H4), the pyridyl group cannot remove electrons from the a-carbon atom sufficiently to affect the reaction, and the high yield of cinno-line is independent of pH, but with (58 Ar == Ph) cinnoline formation (in poor yield) occurs only in dilute acid. With (59), dilute acid must also be used, and cinnoline formation proceeds better with the 3- than with the... 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

IV-Oxidation of cinnoline (2) with hydrogen peroxide in acetic acid results in the formation of four products cinnoline 1-oxide (92 26%), cinnoline 2-oxide (93 50%), cinnoline... 

This type of cyclization is important only for the formation of cinnolines. In all cases, the starting compounds have an ortho amino group, which upon diazotization undergoes ring closure with the other functionality, most frequently with a multiple bond. 

In a similar manner to the formation of pyridazines from AT-aminopyrroles, cinnolines or phthalazines are obtainable from the corresponding 1-aminooxindoles or 2-amino-phthalimides. If the relatively inaccessible 1-aminooxindoles are treated with lead tetraacetate, mercuric acetate, r-butyl hypochlorite (69JCS(C)772) or other agents, cinnolones are formed as shown in Scheme 105. The reaction was postulated to proceed via an intermediate... 

Reactions involving quinoline hydrazide derivatives have been noted in the pyridazino-[4,3-c]- (64MI21500), -[4,5-f ]- (31M(58)238) and -[4,5-c]-quinoline (71CB3341) series, whilst the double cyclization of (358) to the pyridazino[4,5-f ]quinoline (359) (80CPB3457) and related cyclizations in the same series (80H(14)267) are of a basically similar type. A lone cyclization of this type from cinnoline intermediates involves the o-acetonylcarboxamide type formation of the pyridine ring to give the pyrido[3,4-c]cinnoline (360) (76JCS(Pl)592). 

The reactivity of the methyl group in 4-methylcinnoline ethiodide indicates that the structure of this compound is 5, and this evidence has also been interpreted to mean that N-1 is the basic group in cinnolines. However, evidence of this type is only indicative since the formation of quaternary salts is subject to kinetic control, whereas protonation yields predominantly the thermodynamically more stable cation. The quinazoline cation has been shown to exist in the hydrated, resonance-stabilized form 6 7 by ultraviolet spectro-... 

In the first reported solid-phase Richter reaction, cinnolines 143 were prepared through a two step sequence of a Heck-type coupling to give intermediates 142 followed by intramolecular ring formation and release of ciimolines 143 <99TL6201>. 

Although no new method for formation of simple pyridazino[3,4-f]pyridazines has appeared since the publication of CHEC-II(1996), a further method for the construction of benzo-fused derivatives has been described <1997CHE750>. Electrophilic attack of the diazonium salts formed from aromatic amines 5, with sodium nitrite in acetic acid, upon the neighboring methoxyarene results in formation of pyridazino[3,4-f]cinnolines 1. 

It was previously mentioned1 that cinnoline and 3-substituted cinnolines (94) could be prepared from the condensation products (95) between an o-nitrobenzaldehyde and a nitroalkane by electrochemical reduction. The reaction has been further studied,138 and it was noticed that when the reduction was carried out stepwise, anthranils (96) were formed, especially at elevated temperatures. The final ring closure was catalyzed by traces of oxygen, whereas too much oxygen produced the cinnoline JV-oxide (97) the ring closure was believed to be a radical chain reaction where the formation of the aromatic cinnoline was part of the driving force [Eq. (76)]. 

Benzo[c]cinnoline derivatives of different oxidation levels are prepared by N-N bond formations from suitable 2,2 -disubstituted biphenyls as outlined in Scheme 5. 

Halocinnolines can be prepared by treatment of polystyrene-bound (2-alkynyl-phenyl)triazenes with hydrogen chloride or hydrogen bromide (Entry 6, Table 15.27). This reaction involves the initial release of 2-alkynylphenyldiazonium salts into solution, which then cyclize to the halocinnolines. The corresponding 4-hydroxycinnolines are obtained as by-products in variable amounts. Hydrogen fluoride or hydrogen iodide do not lead to the formation of cinnolines [324]. 

It has been known for some time that irradiation of azobenzene (324) in either 22 N sulfuric acid350 351 or acetic acid with added ferric chloride 352 yields benzo[c]cinnoline (325). This is accompanied by the formation of an almost equal quantity of benzidine (326), undoubtedly arising by rearrangement of hydrazobenzene (327). The mechanism of this reaction differs, therefore, from that of the stilbene cyclodehydrogenation, and azobenzene itself functions as the hydrogen acceptor. Yields of not more than 50% of benzo[c]cinnoline are generally observed. 

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cydophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cydophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cydopiloselloidin synthesis, 3, 743 Cydopolymerization heterocycle-forming, 1, 292-293 6 ff-Cy clopropa[5 a,6a]pyrazolo[ 1,5- a]pyrimidine pyrazoles from, S, 285 Cy dopropab enzopy ran synthesis, 3, 700 Cydopropachromenes synthesis, 3, 671 Cyclopropa[c]cinnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

This reaction appears to be similar to the imidazo-pyridine formation mentioned above, most likely via a [5+1] insertion reaction of the isocyanide into the corresponding hydrazone. This reaction mechanism seems likely since only electron-rich aromatic hydrazines yielded cinnolines. The Ugi 4-CR reaction with phe-nylhydrazine is known and has been reported to give the expected Ugi-type 4-CR product. 

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