Amination of pyridazines

The A-amination of pyridazines with hydroxylamine-O-sulfonic acid and its aryl derivatives was summarized in CHEC-I <84CHEC-I(3B)1>. For 3-substituted pyridazines A-amination occurs at N-2 in the case of methyl and amino, but at N-1 in 3-methoxy derivatives. 

Scheme 24 Amination of pyridazine Af-oxides using NH3/BCMn04 system... 

If pyridazine is substituted at the 4-position, amination occurs at C-5 for example, 30a gives 31a in a 38% yield (variant 1). In the presence of an oxidant, electron-withdrawing groups facilitate oxidative amination of pyridazines and thus push the reaction even in the absence of amide salt. In liquid NH3,4-nitropyridazine gives 5-amino-4-nitropyridazine in an excellent 98% yield, while the nitropyridazine 30b gives the amino adduct 31b in 93% yield (variant 2). 

These pyridazines are subject to direct deactivation of the leaving group. It would appear from the conditions used in its reactions with ammonia (115°) and methylamine (50°) that 4-chloro-2-ethylthiopyrimidine (225) is somewhat deactivated (indirect). In various aminations of pyrimidines, the effect of an alkylthio group seems to be very mildly deactivating, like that of methyl groups. However, these surmises from the conditions used are not as reliable as the direct qualitative comparison described above and the kinetic data. 

The catalytic effect of protons, of bifunctional catalysts, and of base is demonstrated in the amination of chloro derivatives of pyridazine, pyrimidine, and s-triazine (Tables V and VI). Anilino-s-triazines containing NH groups act as catalysts in their own formation. The catalytic action of protons on anhino-dechlorination of 2-chloro-4,6-diamino-s-triazine and of 2-amino-4-chloropyrimidine was reported in the classic paper by Banks. ... 

Whereas silylation-amination of 2-amino-5,8-dihydroxypyrimido[4,5-d]pyridazine 269 with 3-amino-l-propanol, HMDS 2, and TsOH affords, after 24 h at 120-140 °C, the mono-8-hydroxypropylamino derivative 270 in 50% yield [79], reaction of 269 with a shght excess of ethanolamine and HMDS 2 provides, after 30 h at 120-150°C, only 20% of the bis(amino) product 271 [79]. (Scheme 4.31) A larger excess of ethanolamine and longer reaction times wiU certainly increase the yield of 271. 

The silylation-amination of l-benzyl-4,7-dihydroxy-l,2,3-triazolo[4,5-d]pyridazine 272 with N-methylpiperazine, HMDS 2, and (NH4)2S04 gives, after 24 h at... 

In 2006 Maes and co-workers described the intramolecular Pd-catalyzed amination of A-(2-chloropyridin-3-yl)pyr-idazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine which involves intramolecular coordination of Pd(ll) to the N-2 nitrogen of the A-arylpyridazin-3-amine entity (Equation 8). A-(2-Chloropyridin-3-yl)pyridazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine are intermediates in the auto tandem amination of 2-chloro-3-iodo-pyridine and 2,3-dibromopyridine with pyridazin-3-amine, respectively <2004CC2466, 2006JOC260>. In the former case the ring closure proceeds partly via an SNAr process. 

In the reaction of pyridazine 26 with perfIuoro-(2-butyl-3-propyloxaziridine) 38 both pyridazin-1-oxide 39 and T-(perf1uorobutanoyl)pyridazinium-l-aminide 40 were formed (Equation 9) <1996J(P1)2517>. In CHEC(1984) <1984CHEC(2)1> and CHEC-II(1996) <1996CHEC-11(6)1>, the N-amination with hydroxylamine-O-sulfonic acid and derivatives was covered. 

Nucleophilic reactivity at positions 5 and 8 of pyrimido[4,5-i pyridazines was reviewed in CHEC(1984) <1984CHEC(3)329> and in CHEC-II(1996) <1996CHEC-II(7)737>. More recently, the preparation and amination of a 4-chloro species (Scheme 15) has been reported, although details given are limited <1998W098/35967>. 

The pyridazin-3-ones are interesting because they include herbicides having two different modes of action, distinguished only by small changes in substitution pattern. Thus pyrazon (8) (61GEP1105232) is a photosynthesis inhibitor, while other discussed later are carotenoid biosynthesis inhibitors. The pyridazin-3-one ring is constructed by condensation of phenyl-hydrazine with 3,4-dichloro-2,5-dihydro-5-hydroxyfuran-2-one (9), in turn produced by chlorination of furan-2-carbaldehyde. Amination of (10) then occurs exclusively at the 5-position to give pyrazon (Scheme 4). 

This type of cyclization has been already illustrated by the formation of 7-azaindole on Chichibabin amination of 3-ethynylpyridine (Scheme 2). Similarly, 6-alkynyl-l,3-dimethyllumazines 137 (03RCB1403, 05JHC413) and 3-alkynyl-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6//,8//)-diones 140 (05JHC413, 03RCB441)... 

Basicity is not important for compounds that can be aminated under homogeneous conditions. Many weak bases with n-electron deficiency can be easily aminated in liquid ammonia at low temperature (Section 11,A,3 and 4). Highly TT-electron-deficient compounds, such as quinoxaline, pyrazine, pyridazine, and triazine, although readily aminated in liquid ammonia, decompose when aminated under heterogeneous conditions at elevated temperatures (86MI1). An exception is the successful amination of 5-methylpyri-midine under heterogeneous conditions (Section IV,D) (84EUP0098684A2). 

N-Amination of heterocycles disclosed useful synthons, the N-amino-heterocycles. Several pyridazines were transformed by hydroxylamine-0-sulfonic acid into the corresponding 1-aminopyridazinium derivatives. Substituted pyridazines, like 3-methyl-, or 3-methyl-6-methoxypyridazine were aminated only at but 3-methoxypyridazine gives the 1-amino... 

The reaction of pyridazin-3-amine 1-oxide with diethyl (ethoxymethylene)malonatc gives A-[bis(eLhoxycarbonyl)methylene]pyridazin-3-amine 1-oxide (1), the starting compound for a thermal cyclization to give ethyl 5-oxo-5,8-dihydropyrido[2,3-r]pyridazine-6-carboxylate 2-oxide (2).27 By analogy to the second step of the Gould-Jacobs reaction,28 the acylation step is facilitated by the A-oxide function. 

The condensation of pyridazin-3-amine 1-oxide with ethyl acetoacetate, ethyl 2-oxocyclopen-tanecarboxylate or -hexanecarboxylate gives the corresponding pyrido[2,3-c]pyridazin-7(8/7)-one 2-oxides, e.g. 1 (see Section 7.2.1.1.1.1.5.), which can be brominated in the 4-position to give 2.27... 

The amidation of pyrido[2,3-cf]pyridazine with sodium amide occurs in position 2 to give 7. In such Chichibabin reactions, the product-determining loss of hydride ion appears to be mainly influenced by the negative charge on the adjacent N-atom 88 the higher charge density on the pyridine nitrogen of the pyrido[2,3-rf]pyridazine system favors ortho amination of the pyridine part.83... 

The reaction of pyridazin-5-amines containing a carbonyl group in the 4-position with various reaction partners, each containing a C-N bond, may also be used to synthesize pyrimido[4,5-tf]pyridazines. Thus, 2-aminopyrimido[4,5-tf]pyridazin-4-ol (2) is formed from ethyl 5-aminopyridazine-4-carboxylate (1) and guanidine.57... 

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