6-Methyl-2-aminopyridine, reaction

Another pharmaceutically important fused-imidazole ring system is the popular sleeping aid medication zolpidem. Bromination of 4-methylacetophenone and condensation with methylated 2-amino pyridine provides the fused-imidazole in good overall yield. Note that the ring nitrogen on the aminopyridine reaction reacts with the bromide carbon. Mannich-type alkylation at the unsubstituted 5-position provides the dimethylaminomethyl substituent in good yield. Further elaboration yields zolpidem. ... 

The second group of chemical methods is based on a comparison of the structure (s) of the reaction product(s) with that of the starting material. These methods can be illustrated by the observation that l-methylpyrid-2-onimine (38) is formed when 2-aminopyridine (37) is allowed to react with methyl iodide followed by treatment with alkali. From these data it was incorrectly concluded that 2-aminopyridine reacted, or existed, in the imino form. Actually, the... 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

Reaction of 2-aminopyridine with dimethyl 2-methylmalonate in the presence of some drops of cone. HCl at 150°C for 1 h (96EUP733633), and with diethyl 2-(l-decyl)malonate at 120°C for 5 min (94JCR(S)206) gave 2-hydroxy-3-methyl- and 2-hydroxy-3-(l-decyl)-4//-pyrido[l, 2-n]pyrimidin-4-ones in 2.2% and 7.5% yields, respectively. Reaction of 3-benzyl-2-aminopyridine and diethylmalonate at 190-200 °C for 4 h yielded 9-benzyl-2-hydroxy-4//-pyrido[l, 2-n]pyrimidin-4-one (01MIP9). Cyclocondensation... 

Reaction of 2-aminopyridine and its 4-methyl derivative and diethyl alkylidenemalonates 356 at 175°C for 1.5-2.5h yielded 3-vinyl derivatives 358, after the isomerization of the exocyclic double bond in 357 (99ACS901). Reaction of 2-amino-4-methylpyridine and bis(2,4,6-trichlor-ophenyl) benzylidenemalonate in the presence of NEt3 afforded only non-cyclised product 359. 2-Aminopyridine and its 4-methyl derivative with diethyl benzylidene- and hexylidenemalonates at 190 °C did not give cyclized products (99ACS901, 99MI29). 

Reaction of 2-aminopyridine and its 3-, 4-, 5-, and 6-methyl derivatives with 3-chloro-3-trifluoromethyl-3-ethoxycarbonyl- and -2-cyanoacrylnitrils in CHCI3, sometimes in the presence of NEt3, afforded 4-oxo- and... 

Reaction of 2-aminopyridine with ethyl 2-cyano-3-ethoxy-3-methyl-, -3-ethyl-, -3-phenylacrylates and ethyl 2-ethoxycarbonyl-3-ethoxy-3-methyl-, -3-phenylacrylates in boiling xylene yielded 2-substituted 4/f-pyrido[l,2-u]pyrimidine-3-carbonitriles and -3-carboxylates (99MI7). Similar reactions of 2-aminopyridine with 2-cyano-3-ethoxyacrylonitrile and its 3-methyl, 3-ethyl, -3-phenyl derivatives in boiling MeCN afforded 4-imino-4//-pyrido[l,2-u]-pyrimidine-3-carbonitrile and its 2-substituted derivatives. 

Katritzky et al.508 have measured rates of deuteration of aminopyridine by deuterated sulphuric acid (Table 146), and for the 4-amino and 2-amino-5-methyl compounds, the general increase in rate with increasing acidity, dlogkjd (—H0) 0.6, shows reaction to be occurring on the conjugate acids. For the latter compound this is only true at acidities > —H0 = 4.0, below which rates are relatively independent of acidity indicating reaction on the free base. For the 2,6-dichloro... 

The reaction is not limited to Z—CH2—Z compounds. Other acidic CH hydrogens, which include, for example, the methyl hydrogens of a-aminopyridines, the methyl hydrogens of ynamines of the form CH3CSCNR2 (the product in this... 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

Reactions of stable N-substituted iminopropadienones with 2-methylaminopyridine in CH2C12 yielded 1 -methyl-2-(iV-substituted imino)-l,2-dihydropyrido[l,2- ]pyridinium-5-ium-4-olates <2002JOC2619>. Reactions of N-substituted iminopropadienones with 2-aminopyridines provided 2-(substituted aruino)-l//-pyrido[ 1, Z-a pyrimi-din-4-ones, which were accompanied by a small amount of isomeric 4-(substituted arnino)-2/7-pyrido[ 1,2- ]pynrnidin-2-ones. In refluxing toluene, a larger amount of the 2-oxo isomers formed. In the case of 2-amino-3-methylpyridine and... 

Nitration of the aminopyridines and their methyl derivatives reveals some interesting facets. The amino group strongly activates the positions ortho and para to itself towards nitration, but reaction proceeds via the N-nitroamines. 4-Aminopyridine undergoes nitration via the iV-nitroamine (65) to yield 4-amino-3-nitropyridine (equation 40). Nitration... 

---