Pyridazine lithiation

Side-chain lithiation with lithium diisopropylamide and subsequent alkylation or acylation is a practical method for the preparation of various alkyl-, alkenyl- and acyl-methyl-pyridazines 78CPB2428, 78CPB3633, 79CPB916) (Scheme 47). 

Pyrazino[2,3-d]pyridazine-5,8-dione chlorination, 3, 347 lithiation, 3, 347 synthesis, 3, 359 Pyrazino[2,3- d]pyridazin-5-one reactivity, 3, 347 synthesis, 3, 360... 

The protons of pyrimidines, pyrazines and pyridazines are relatively acidic even without halogen activation, and the three simple heterocycles 240-242 have been lithiated (with varying success) with LiTMP (Scheme 120). ... 

The lithiation of methoxypyridazines (which, for 251, works even with BuLi) has been used to develop new routes to heterocyclic biaryls such as 252 (Scheme 124) . In the pyridazine series MeO turns out to be a stronger director than Cl, as expected . It also... 

The direct metalation of 5-methylpyrimidine and 5,5 -bipyrimidinyl in the 4-position has been reported with LDA in low yield [74TL2373 75AG(E)713], but apart from that there are few other reports on the direct metalation of unactivated diazines. However, as with pyridine and quinoline, directed metalation can readily be achieved with all three of the diazine systems when the appropriate substituent groups are present [91AHC(52)187]. Thus, the direct lithiation of pyridazine in the 4-position has now been achieved with both the 3,6-dichloro and the... 

Examples of the 3-lithiation of both 2- and 2,6-disubstituted chloro- and methoxypyrazines, as well as 2-thiomethylpyrazine are known (88S881 90JOC3410 91JHC765, 91JOM(412)301] (Scheme 117). As with pyridazine, LiTMP has so far been the only base employed, and this same base system has also recently been used for the directed metalation of pyrazine... 

The metallation, especially the lithiation, of pyridazines, mentioned briefly in CHEC-II(1996) <1996CHEC-11(6)1 >, has been developed extensively since 1995 by Queguiner and co-workers for the derivatization of pyridazines and benzopyridazines. The bases of choice are usually lithium 2,2,6,6-tetramethylpiperidide (LTMP) and lithium diisopropylamide (EDA). Special efforts have been made to achieve regioselective lithiations. 

As can be seen also with pyridazines and pyrimidines, the protons of pyrazines are relatively acidic <2001T4489>, and the simple pyrazine is lithiated with 4 equiv of LTMP at —75 °C <1995JOC3781>. Since the lithio intermediate, however, is highly unstable, the subsequent substitution with electrophiles should be carried out within a very short reaction period. 

Direct lithiation of pyridazine 132 followed by trapping with chiral sulfinate esters produced chiral sulfoxides 133, analogous to the pyrimidine reaction covered in Section 6.2.2.2 <99JOC4512>. Queguiner and co-workers demonstrated that a second lithiation/trapping sequence can provide fully substimted pyridazines 134 with high diastereoselectivities. 

The usually very powerfully orthodirecting groups such as secondary carboxamide surprisingly do not always lead to ortholithiation on pyrazine and pyridazine rings lithiation of 386 and 387, for example, takes place principally (at least kinetically) at the meta and para positions.339 340... 

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. 

Moderate to good yields of trapped products can be obtained either by using very short lithiation times (pyridazine and pyrazine) or by in situ trapping, where the electrophile is added before the metaUating agent.4-Lithiopyridazine can be prepared by transmetallation of the corresponding tri-n-butylstannane using n-butyllithium. 

The reactivity of pyridazine and pyridazine iV-oxide methyl substituents is reviewed in CHEC-I <84CHEC-l(3B)l>. In particular, susceptibility to oxidation to the aldehydes or acids, condensation with aldehydes, and reactions of lithiated intermediates are discussed for instance, treatment of 3-methylpyridazine-1 -oxide with acetic anhydride gives, after hydrolysis, 3-hydroxymethylpy ridazine. 

Weinreb amides are another type of electrophiles that can be used with lithiated pyridazine to access long-chain a-ketopyridazines, a class of potent inhibitors of fatty acid amide hydrolase (eq 8). An excess of pjnidazine (4—6 equiv) is needed for optimal results (78-86% yields based on the amide). 

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