3-Halo-4-aminopyridines

The reaction of 3-halo-4-aminopyridines with acyl chlorides in the presence of triethy-lamine gives pyridin-4-yl a-substituted acetamides in which an Al-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution resulting in a formal two-carbon insertion (Scheme 205). " ... 

The regioselective halogenation of pyridinium-A -(2 -pyridyl)aniinide 7 with N-halosuccinimides, combined with a reduction of the N-N bond, provides a convenient preparation of 5-halo- and 3,5-dihalo-2-aminopyridines 8 <95T(51)8649>. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

Table 14 Synthesis of imidazo[1,2-a]pyridines through cyclocondensation of 2-aminopyridine and a-halo carbonyls 2-Aminopyridine a-Halo carbonyl Conditions Product Yield (%) Reference...

When the blocking group is other than a halogen atom or a keto group, only tars are formed. 8-Hydroxy- 1,7-naphthyridine61 is obtained from 3-amino-2-hydroxypyridine, and 1,5-naphthyridine is obtained from the 2-halo-3-aminopyridines when they are subjected to the Skraup reaction. 3-Aminopyridine 1-oxide aifords the parent 1,5-naphthyridine,62 and both 3-amino-6-hydroxypyridine and 3-amino-6-chloropyridine give 2-hydroxy-l,5-naphthyridine.63 Hart64 has applied the Skraup synthesis to 3-amino-4-hydroxypyridine and has obtained the expected 4-hydroxy-l,5-naphthyridine. 

By reacting 2-aminopyridine and epichlorohydrin, Knunjanz187 obtained the hydrochloride of 3-hydroxy-3,4-dihydro-2H-pyrido[l,2-a]pyrimidine (131 R = OH). Analogous products from 4-methyl-, 5-methyl-, 5-halo- and 3,5-dibromo-substituted 2-aminopyridines have been prepared by Soviet workers.188,189 The same products arose from the reaction of 2-aminopyridines and l,3-dichloro-2-propanol.188 189 Klusis and Kuthevicius190 reacted 2-aminopyridine with 3-chloro-1,2-propanediol (127) or 2,3-... 

Aminopyridines may be synthesized by conventional nucleophilic displacement of halide substituents. In general, 4-halo substituents are more easily displaced than those at the 2-position. It has been discovered that this order of reactivity is reversed in the presence of a bulky trialkylsilyl group at the 3- or 5-position <20050L127>. For instance, 2,4,6-trifluoro(3-triethylsilyl)pyridine undergoes reaction with hydrazine monohydrate exclusively at the 6-position (Equation 103). 

Halogenation of the 3-hydroxypyridines follows the pattern set by the 3-aminopyridines in that substitution takes place at the 2-position. Chlorination with hydrochloric acid and hydrogen peroxide,102 bromination with one equivalent of bromine in pyridine,192 and iodination with iodine and sodium carbonate102 all give the 2-halo-3-hydroxypyridine. Chelation and formation of a cyclic transition state does not appear a likely possibility in these reactions. Under more vigorous conditions or with an excess of the halogen, 2,6-disubstitu-tion162,183 and 2,4,6-trisubstitution can occur.162... 

The most common approach to the [5-6] imidazo-fused systems involves the cyclocondensation of 2-aminopyridine with an -halo carbonyl compound as exemplified in Scheme 25 <2004BML2245, CHEC-III(11.10.6.7.1)463>. 

A carboxylic acid derivative which also contains an activated neighbouring halo atom may be cyclized by warming with an amidine (or guanidine) or 2-aminopyridine (a cyclic amidine). In some reactions of this type, it is advantageous to add a base such as TEA. The chlorine atom of the thienopyridine (6[Pg.422]

The ring synthesis of imidazo[l,2-a]pyridines is based on the Chichibabin route to indolizines (Section 25.1.2), but using 2-aminopyridines instead of 2-alkylpyridines. The initial reaction with the halo-ketone is regioselective for the ring nitrogen, so isomerically pure products are obtained. 2-Oxoimidazo[l,2-a]pyridines are the products when an o-bromo-ester is used instead of a ketone. 

Shreeve et al. have synthesized a range of new ionic liquids based on oxazoli-dine, morpholine and 1,2,4-triazole. These have been found to be good solvents for the Cu(I)-mediated nucleophilic trifluoromethylation of benzyl bromide [155]. Nucleophilic substitution has also been carried out on alkenes in the form of 2-tosyltropone, where the tosyl group was substituted for a chloride in [BMIM][BF4] [156]. Aminopyridines [157] and aminopyrimidines [158] react with a-halo ketones to form imidazopyridines and imidazopyrimidines. These reactions have been investigated in [Bp4] and [PFs]" ionic liquids and found to give fester reaction rates than in organic solvents [159]. 

Chloro- and bromoaminopyridines are oxidized by persulfuric acid at 0° to their nitro derivatives thus, 3-chloro-, and 3-bromo-4-aminopyridine are converted to the respective 3-halo-4-nitropyridines. However, 4-araino-3-iodo-pyridine is not oxidized under these conditions. 4-Amino-2,3,5,6-tetrafluoro-pyridine is difficult to oxidize and requires refluxing peroxytrifiuoroacetic acid for 22 hours in order to yield the 4-nitro derivative. Potassium bromate has been used to oxidize S-amino-3-methyl-2-pyridone, but the product was not a nitro compound instead 3-hydroxy-6-methyl-2-aza-l,4-benzoquinone-4-(2,6-di-hydroxy-5-methyl-3-pyridyl)imine (IX-S7) was obtained. ... 

On this basis, other halides might be expected to effect nucleophilic halo-genation in fact, benzoyl chloride converts 4-aminopyridine 1-oxide into 4-benzamido-2-chloropyridine . j -Toluenesulphonyl chloride behaves differently (p. 235). 

Labeled heterocyclic systems of the imidazopyridine type are accessible from halo [ " ]-acetates. For example, the reaction between 2-aminopyridine and chloro[2- C]acetic acid produced (2-imino-l,2-dihydropyridin-l-yl)[2- C]acetic acid (1411 in 76% yield (Figure 6.46). Treatment of 141 with POCI3 induced cyclization and chloro-dehydration to furnish 2-chloro[3- C]imidazo[l,2-a]pyridine (1421 in 99% yield. The latter was a key intermediate in the synthesis of the carbon-14-labeled herbicide MON 37500 (1431. ... 

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