3-Methyl-2-aminopyridine

Catalytic hydroacylation. Aldimines of 3-methyl-2-aminopyridine and aromatic aldehydes react with chlorotris(triphenylphosphine)rhodium(I) (1) in THF at 55 to afford products of imine C—H insertion (3). Aminals of 2-aminopyridine and aldehydes with a-hydrogens (4) similarly react with 1 to give 5 presumably, the aminals are in equilibrium with the corresponding imines under these conditions. These complexes undergo hydroacylation reactions with ethylene as illustrated for 2. The overall reaction can be performed with catalytic quantities of 1, as indicated for the reaction of 4. 

Ketone synthesis." A meiho 3-methyl-2-aminopyridine and exp) to stabilize cyclic rhodia-ketimine i In situ hydrolysis of the demetalaie ... 

Ketone synthesis." A method for ketone synthesis is based on A-allylation of 3-methyl-2-aminopyridine and exploiting the coordination ability of the pyridine moiety to stabilize cyclic rhodia-ketimine intermediates that are active in insertion to 1-alkenes. In situ hydrolysis of the demetalated ketimine products affords ketones. 

The product of Step 2 has also been prepared by the condensation of 2-bromooctanoic acid and (2)-3-hydroxyltetradeconate in 4-methyl-aminopyridine in the presence of 1,3-dicyclohexylcarbodiimide and is discussed (2). 

Aminopytidine reacts with 2-benzo-l, S-dioxepanylformyl chloride to form iV-3-pyridyl-2-benzo-l,5-dioxepanylformamide, which, on reduction with lithium aluminum hydride, yields 3-[3,4-dihydro-2ff-l,5-benzodioxepin-2-yl)-methyl] aminopyridine. ... 

A one-pot synthesis of unsymmetrical tertiary alcohols from the N-methyl-aminopyridine amides (2) by successive addition of two metallo-nucleophiles (Grignard reagents or organolithiums) has been developed (Scheme 3). Substitution of LiAlH4 for the second organometallic reagent leads to secondary alcohols. 

Amine oxides, prepared to protect tertiary amines during methylation and to prevent their protonation in diazotized aminopyridines, can be cleaved by reduction (e.g., SO2/H2O, 1 h, 22°, 63% yield H2/Pd-C, AcOH, AC2O, 7 h, 91% yield Zn/HCl, 30% yield). Photolytic reduction of an aromatic amine oxide has been reported [i.e., 4-nitropyridine A-oxide, 300 nm, (MeO)3PO/CH2Cl2, 15 min, 85-95% yieldl. ... 

Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

Syntheses of Nicotine. Pictet and Cr pieux found that 3-aminopyridine mueate on dry distillation yielded l-(3-pyridyl)pyrrole (I), and this, in accordance with the usual behaviour of such pyrrole derivatives, transfers its pyridyl substituent from the 1- to the 2-position at a red heat giving 2-(3-pyridyl)pyrrole (II), which is nomieotyrine. The potassium derivative of this reacts with methyl iodide to form l-methjd-2-(3-pyridyl)-pyrrole methiodide, which is identical with nieotyrine methiodide (III), and on distillation with lime yields nieotyrine (IV Cl — CH). For a re-investigation of this synthesis see Spath and Kainrath. ... 

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). 

PPA and AcOH at 100°C for 4 h gave 9-hydroxy-2,3-dimethyl-4/f-pyrido-[1,2-n]pyrimidin-4-one in 24% yield (96EUP733633). Reaetion of 2-aminopyridine and ethyl 2-aeetoxyaeetoaeetate in boiling EtOH gave 2-methyl-3-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one in 47% yield (94KFZ(10)23). 

Methyl-4//-pyrido[l,2-n]pyrimidin-4-ones were also prepared in the reaetion of 2-aminopyridines and ethyl 3-methoxy-2-butenoate in PPA at 80-85 °C for 3h (93MI2). 

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... 

Cyclocondensation of 2-aminopyridines with methyl 3-(A,A-dimethyla-mino)-2-(benzyloxycarbonylamino)acrylate in boiling AcOH for several hours gave 3-(benzyloxycarbonylamino)-4//-pyrido[l, 2-n]pyrimidin-4-ones 370 (99CCC177, 00MI33). 2-Amino-6-methylpyridine afforded only condensation product 371. 

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. 

Cyclocondensation of 2-aminopyridine and its 3-, 4-, and 5-methyl derivatives with ethyl 2-(bismethylthiomethylene)cyanoacetate in boiling BuOH for 5 h afforded 2-methylthio-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carbonitriles in 55-87% yields (96FES781). 

Ciclopirox may be produced as follows 2 g of 4-methyl-6-cyclohexyl-2-pyrone were heated with 1 g of hydroxylamine hydrochloride and 5 g of 2-aminopyridine to B0°C for B hours. 

Chloroethyl)-3-[ (2-methyl-4-aminopyridin-5-yl)methyl] urea Sodium nitrite Hydrogen chloride... 

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... 

FIGURE 6.16 Rp values of aromatic amines obtained on silica gel plate 1, 3 — isocratic development with 5 and 50% solutions of methyl ethyl ketone in cyclohexane, respectively, 2 — two-stepwise gradient development with both solvents open squares, N, N-dimethyla-niline, open triangles, iV-ethylaniline, open circles, aniline, diamonds, 2-phenylenediamine, filled squares, 3-phenylenediamine, filled triangles, 4-phenylenediamine, filled circles, 3-aminopyridine. (From Soczewinski, E. and Czapinska, K., J. Chromatogr. 168, 230-233, 1979. With permission.)... 

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... 

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