Pyridazines pyridines

The total -deficiency (TOT d) of a ring can be defined as the sum of the positive charges on all carbon atoms. The -deficiency of azines is determined by the number of heteroatoms and their mutual disposition. According to HMO calculations (Table 1), the total -deficiency changes in the sequence 1,3,5-triazine > pyrimidine > 1,2,4,5-tetrazine pyrazine > pyridazine > pyridine. 

Local -deficiency (LOC D) is the largest positive charge on any one carbon atom in the ring and this property decreases in a different order 1,3,5-triazine > pyrimidine > 1,2,4,5-tetrazine > pyridazine pyridine > pyrazine. This order is in closer agreement with a -deficiency scale ( A) based on 13C NMR chemical shifts <19820MR192, CHEC-111(9.02.2)97 >. 

Keywords Azepines Benzimidazoles Benzofurans Benzopyranones Benzothlazoles Benzothiophenes Benzoxazoles Benzoxocanes DIoxepanes Dioxocanes DIoxolanes Dithiiranes Dithioles Furans Imidazoles Indazoles Indoles Indollnes Indollzines Isoquinolines Isoxazoles Isoxazolines Oxazines Oxazoles Oxepanes Oxiranes Pyrazines Pyrazoles Pyridazines Pyridines Pyrimidines Pyrroles Pyrrolidines Pyrrolines Pyrrolizines Quinolines Thietanes Thiophenes Triazoles... 

In general, pyridazine can be compared with pyridine. It is completely miscible with water and alcohols, as the lone electron pairs on nitrogen atoms are involved in formation of hydrogen bonds with hydroxylic solvents, benzene and ether. Pyridazine is insoluble in ligroin and cyclohexane. The solubility of pyridazine derivatives containing OH, SH and NH2 groups decreases, while alkyl groups increase the solubility. Table 1 lists some physical properties of pyridazine. 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

Pyridazines with an appropriate side chain attached to the sulfur atom at position 3 can be transformed into bicyclic systems. For example, pyridazinyl /3-ketoalkyl sulfides are cyclodehydrated in sulfuric acid to give thiazolopyridazinium salts, and 3-carboxymethyl-thiopyridazines are transformed by acetic anhydride in pyridine into 3-hydroxythiazolo[3,2-6]pyridazinium anhydro salts (Scheme 52). 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Amongst miscellaneous UV spectra recorded are those of alkylthio adducts of pyrido[3,2-c]pyridazine (78KGS1272), various pyrido[3,4-d]pyridazines (57AC(R)728) and several vinyl-pyridine-azodicarboxylic ester adducts (79T2027, 79KGS639). 

Acetyl (79GEP2808070,71FES1074) and Other groups on the pyridine ring have been oxidized to the corresponding carboxylic acids in the pyrido-[2,3-c]- and -[3,4-d]-pyridazine fields. Acid groups in pyridopyridazines behave normally on esterification (66CPB1010). 

Early experiments with pyridine-2,3-dicarboxylic mono- and bis-phenylhydrazides were unsuccessful (32JIC145), but later these were cyclized in acetic acid (66CPBIOIO) to give only the 7-phenylpyrido[2,3-[Pg.242]

The only example of a simple pyridopyridazine synthesis of this kind from a pyridine intermediate involves a variant of a well known cinnoline synthesis in which the Japp-Klingemann intermediate (363) gives the pyrido[3,4-c]pyridazine (364) with PPA (69JHC977). 

The vast majority of syntheses of pyrido[2,3-t/]- and pyrido[3,4-t/]-pyridazines fall into this category, resulting from the cyclization of various o-substituted pyridine derivatives (2,3- or 3,4-, respectively) with hydrazine or its congeners. 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

Furo[3,4-d]pyridazine-1,4-diones synthesis, 4, 985 Furopyridazines, 4, 984 Furo[2,3-6]pyridine, 3-amino-synthesis, 4, 977 Furo[2,3-6]pyridine, 4-methyl-synthesis, 4, 976 Furo[2,3-6]pyridine, 6-methyl-synthesis, 4, 976 Furo[2,3-6]pyridine, 5-nitro-synthesis, 4, 977 Furo[3,2-c]pyridine, 4-allyl-synthesis, 4, 982 Furopyri dines H NMR, 4, 983 physical data, 4, 983 properties, 4, 982 synthesis, 4, 974-982 UV spectroscopy, 4, 983 Furo[6]pyri dines HMO data, 4, 975 Furo[2,3-6]pyri dines synthesis, 4, 974-977 7, 512 Furo[3,2-6]pyri dines C NMR, 4, 982 synthesis, 4, 648, 981 Furo[c]pyri dines HMO data, 4, 976 Furo[2,3-c]pyri dines synthesis, 4, 977 Furo[3,2-c]pyri dines nitration, 4, 983 synthesis, 4, 978-981 Furo[3,4-c]pyri dines synthesis, 4, 982 Furo[3,2-c]pyridin-3-ols synthesis, 4, 980 Furo[2,3-6]pyridin-6-ones synthesis, 4, 976 Furo[3,4-c]pyridin-4-ones synthesis, 4, 982... 

Paal-Knorr synthesis, 4, 118, 329 Pariser-Parr-Pople approach, 4, 157 PE spectroscopy, 4, 24, 188-189 photoaddition reactions with aliphatic aldehydes and ketones, 4, 232 photochemical reactions, 4, 67, 201-205 with aliphatic carbonyl compounds, 4, 268 with dimethyl acetylenedicarboxylate, 4, 268 Piloty synthesis, 4, 345 Piloty-Robinson synthesis, 4, 110-111 polymers, 273-274, 295, 301, 302 applications, 4, 376 polymethylation, 4, 224 N-protected, 4, 238 palladation, 4, 83 protonation, 4, 46, 47, 206 pyridazine synthesis from, 3, 52 pyridine complexes NMR, 4, 165... 

Thieno[3,2-c]pyridazine-3-carboxylic acid synthesis, 4, 819-820 Thienopyridazines, 4, 1015 Thieno[2,3- hjpyridazines nitration, 4, 1016 synthesis, 4, 791, 1015 Thieno[3,2-c]pyridazines synthesis, 4, 1016 Thieno[3,4-d]pyridazines synthesis, 4, 1016 Thieno[2,3-6]pyridine, 4-amino-synthesis, 4, 1005... 

Pyridines and pyridazines bearing bulky perfluorinated groups behave similarly [149, ISO, ISI], although their photochemical rearrangement is not always clearly documented [752] Azaprismanes, however, have been isolated and fully characterized [75J] (equation 37)... 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

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