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16.8.4.1.4.4.2 Variation 2: Introduction of Aryl Groups

DOI: 10.1055/sos-SD-016-00192

Haider, N.; Holzer, W.Science of Synthesis, (200416201.

For the palladium(0)-catalyzed introduction of (het)aryl groups into position 3 or 4 of the pyridazine skeleton, both (het)arylstannanes (Stille coupling) or (het)arylboronic acids (Suzuki coupling) can be used. In general, the latter reagents are preferred due to their broad commercial availability, very low toxicity, and ease of use and workup. The starting pyridazine can be a chloro-,[‌383‌,‌501‌‌504‌] bromo-,[‌387‌,‌494‌,‌505‌] or iodopyridazine,[‌383‌,‌506‌,‌507‌] as well as a pyridazinyl trifluoromethanesulfonate.[‌508‌,‌509‌] Whereas in other palladium(0)-catalyzed cross-coupling reactions aryl chlorides require significantly harsher conditions than the corresponding bromo or iodo compounds, chloropyridazines have been found to react smoothly under Stille or Suzuki conditions, even if they bear an electron-donating amino group.[‌501‌,‌502‌] Nevertheless, pyridazines with two different leaving groups have been shown to undergo selective arylation in two consecutive Suzuki couplings with different arylboronic acids (reactivity: iodo > chloro;[‌383‌] trifluoromethylsulfonyloxy > bromo[‌508‌]). The reaction is usually carried out with tetrakis(triphenylphosphine)palladium(0) as catalyst in toluene or 1,2-dimethoxyethane solution at reflux temperature and in the presence of aqueous alkali carbonate. In the case of halopyridazinones, N-substituted substrates are preferred, whereas N-unsubstituted halopyridazinones may completely fail to react.[‌494‌] The scope of the method is illustrated by the synthesis of 6-arylpyridazin-3-amines 155 (see Scheme 59),[‌502‌] as well as by selected further examples given in Table 7.

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(M=M) (M=Me)
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MeM(MM)8 Me(MMe8)8, Me8MM8, eeeeeee, eeeeee 88 [‌888‌]
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