Pyridazine triflates

Pyridazine triflates are readily prepared in high yield by reaction of triflic anhydride either with 3(2//)-pyridazinones in pyridine at room temperature or with the lithium salts in THE at — 78°C (Equation (26)). These triflates, which are white crystalline solids stable at 0°C, are useful in palladium catalysed coupling reactions <94H(38)1273>. 

Fluorophenyl 3-pyridazinyl ketone has been used as starting material for the synthesis of 3-pyridazinyl substituted 1,4-benzodiazepines, quinolines, 2,1-benzisoxazolines and for the preparation of diazaacridones of type 23 and 24 [94H(38)125]. Pd(0) cross-coupling reactions of pyridazine triflates permits to prepare 3-alkynylpyridazines of type 25 [94H(38)1273]. 

The good availability of pyridazin-3(2/T)-ones make triflate esters preferred substrates to access bond formation via palladium catalysis. It avoids the use of POCI3, PCI5, POBr3, or PIh which are often used as reagent and solvent (see Section 13.1.4). Moreover, triflate esters are more reactive towards oxidative addition than the corresponding bromo and chloro derivatives. Pyridazin-(3(2//)-on)e triflates are air stable compounds that can be stored in the cold without decomposition. 

In 2002, Wonnacott published the synthesis and biological evaluation of a pyridazine analog (62) of nicotinic acetylcholine receptor agonist UB-165 [45]. This aza-UB-165 analog (62) was synthesized via Negishi cross-coupling reaction on triflate 60 with pyridazin-3-ylzinc halide (59). Compound 59 could be obtained from 3-bromopyridazine (58) via lithiation and subsequent transmetalation with zinc chloride. 

Besides halopyridazines, pseudohalopyridazines have been used as substrates for Stille reactions [29]. 6-Methylpyridazin-3-yl trifluoromethanesulfonate (96) reacted with arylstannanes using a procedure based on Stille s original conditions for aryl triflates. Although 3-methyl-6-(2-thienyl)pyridazine was obtained in a good yield (77%) under these conditions, trialkyl(phenyl)stannanes reacted only very slowly in comparison with tributyl(2-thienyl)stannane. Trimethyl(phenyl)stannane and tributyl (phenyl) stannane gave 3-methyl-6-phenylpyridazine in only 22 and 6% yield, respectively. 

A pyridazine-containing bioisostere of (-)-ferruginine was obtained via the coupling of triflate 159 with 4-(tributylstannyl)pyridazine (156) [71]. Several reaction conditions were tried to optimize the yield of this reaction. The best results were obtained using 10 mol% Pd(PhCN)2Cl2, 20 mol% Ph. As. and 20 mol% Cul in combination with three equivalents of LiCI in V-mcthyl pyr roll done. Removal of the carbamate group of 160 finally afforded the bioisostere of (-)-ferruginine (161). 

Because 3-chloropyridazines were not found to be very reactive in palladium coupling reactions and the bromo and iodo analogues are not readily available, the preparation and use of triflate esters of pyridazines have been developed. The readily prepared triflates undergo coupling with terminal acetylenes in the presence of palladium and copper iodide (Equation (27)). Reactions are rapid, normally complete in 0.5 to 6 hours at room temperature, and yields are high. In a comparative experiment 3-chloro-4-methyl-6-phenylpyridazine with 3,3-dimethyl-3-hydroxy-l-propyne gave only a 33% yield of 3-(3,3-dimethyl-3-hydroxy-l-propynyl)-4-methyl-6-phenylpyridazine after 12... 

Synthetic approaches that have been developed or extended in the review period and have the potential for general use include radical alkoxycarbonylation to give 4-alkoxycarbonylpyridazines (Section 6.01.5.6) preparation of 4(5)-aminopyridazines by direct amination with ammonia or amide ions followed by oxidation (Section 6.01.5.4.3) C—C bond formation by palladium catalyzed coupling reactions of pyridazine O-triflates (Section 6.01.7.12.2) and halopyridazines (Section... 

Pyridazine-3-carboxylic acids as methyl esters 267 have been prepared by methyloxy-carbonylation of 3-pyridazinyl triflates in methanol using Pd(OAc)2 and 1,1-bis (diphenylphosphino)ferrocene as the catalyst system together with carbon monoxide at atmospheric pressure in methanol (Scheme 96). 

Scheme 19 Ring-closing metathesis/elimination/triflation approach to pyridazines 68.

In a similar manner to that for pyridines, pyridazines 68 were synthesized from functionalized hydrazines 66 via pyridazones 67 using an RCM/elimination/ triflation approach (09CC3008). The metathesis precursors 66 were synthesized in two steps from commercially available tosyl hydrazide (not shown). Substituents can be incorporated at aU ring positions, which was clearly exemplified by the introduction of a methyl group in different positions of the pyridazine (Scheme 19). 

A modified protocol involving pivahc acid as an additive was developed in order to perform the arylation of pyridine A-oxides with aryl triflates as the electrophile. Similar to other Het-H functionalization reactions, palladium acetate is used as the catalyst in conjunction with di-/eri-hutyl(methyl)phosphonium tetrafluoroborate as the ligand, leading to the efficient arylation of a diverse set of pyridine (eq 4), pyridazine (eq 5), pyrimidine (eq 6), and pyrazine A-oxides (eq 7). This method also minimizes... 

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