Alkylation of pyridone

Liquid liquid two-phase alkylation of pyridones and related systems... 

O-Alkylation of pyridones can be effected with diazomethane 2-pyridone forms 2-methoxypyr-idine. Frequently O- and iV-alkylation occur together 4-pyridone with CH2N2 yields 4-methoxypyridine and l-methyl-4-pyridone. Et30+ and similar active alkylating agents also alkylate the carbonyl oxygen of pyridones and pyrones. 

Scheme 19.100 Inter- and intramolecular nickel-catalyzed alkylation of pyridones.

Deuterium-labeling and mass spectrometry prove that the mechanism of the thermal O to N rearrangement of 4-alkoxypyridines to N-alkyl-4-pyridones is intermolecular (88CS347). 

The Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course of synthesis of analogs of the antitumor agent camptothecin. 

Treatment of pyridones 638a (X = CH) <1997CHE596> and pyrazinones 638b (X = N) <1998JHC655> with - V-alkyl and W-aryl triazolidinediones provides tricyclic derivatives 639 containing the title bicyclic moiety in good yields (Equation 94). 

The most efficient routes to the cationic oxazolo[3,2- ]pyridine ring system 351 rely on the method of Bradsher and Zinn <1967JHC66> involving the cyclocondensation of iV-phenacyl-2-pyridones 349 obtained by alkylation of readily available 2-pyridones 347 (Scheme 95). This method has been used by Babaev et al. to prepare a series of 6-nitro-oxazolo[3,2- ]pyridines 355 from 5-nitro-2-pyridone 352 in excellent yields <2003MOL460>. Similarly, tricyclic oxazolo[3,2- ]pyridines 359 have been prepared from the corresponding quinolin-2(177)-ones 356 <2003H(60)131>. 

Alkylation of potentially tautomeric heteroaromatic systems under basic phase-transfer catalytic conditions normally occurs on the softer heteroatom [cf 57]. Thus, although 2- and 4-pyridones are alkylated on the annular nitrogen atom and the exocyclic oxygen atom, -alkylation of the 2-pyridones predominates to the extent of ca. 5 1 (or greater under soliddiquid reaction conditions [58]), whereas the relative predominance of A -alkylation of the 4-isomer is only ca. 3 1 [59] (Table 5.37 and 5.38). These ratios are comparable with those obtained for the base-catalysed alkylation of the pyridones by traditional methods and, not unexpectedly, S-alkyla-tion of the corresponding pyridthiones occurs to the total exclusion of A-alkylation [60]. Catalysed soliddiquid acylation has also been reported [58]. 

The presence of substituents on the pyridine ring, which reduce the basicity of the annular nitrogen atom, not only shifts the pyridone-hydroxypyridine equilibrium towards the hydroxy form [62], but they also inhibit A-alkylation. Thus, for example, 3,5,6-trichloro-2-hydroxypyridine is alkylated preferentially on the oxygen atom. Predictably, alkylation of 3-hydroxypyridine and of 2-amino-3-hydroxypyridine leads to the 3-alkoxypyridines in high yield under basic conditions [63] (see Chapter 3). 

It has been reported that alkylation of 2-pyridone and 2-quinolone and other related potentially tautomeric azinones under solid-liquid phase-transfer catalytic conditions generally produces the A-alkylated derivatives exclusively in 65-90% yield [58], although it has been suggested that the yield of the O-alkylated derivative can be increased by the use of long-chain quaternary ammonium salts and when bulky alkylating agents are used [69]. 

Finally, reaction of 2,4-diphenyl-5(4//)-oxazolone 322 with 4-phenyl-A -tosyl-1-azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-A-tosyl-1-azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6-triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324—327. The marked differences in reactivity of 4-phenyl-A-tosyl-l-azabuta-l,3-diene relative to A-alkyl- or A-aryl-1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107). ... 

Alkylation of Hydroxypyridines, Pyridones and their Benzo Analogues... 

Alkylation of the silver salt of pyrid-2-ones usually gives exclusive O-alkylation, whereas alkylation of the sodium or potassium salt gives predominantly TV-alkylation, e.g. Scheme 98. However, the course of such reactions is strongly dependent on conditions. Not only is the nature of the metal salt important but also the structure of the halide, the substituents on the pyridone ring and the solvent used (770PP5,70JOC2517,67JOC4040). 

Alkylation of hydroxyazines where reaction does not lead to quaternization is not considered. Molecules such as 4-pyridone usually exist largely as the carbonyl, but not as the 4-hydroxypyridine, tautomer in polar solvents8 [Eq. (1)]. Monoalkylation of the neutral species of such molecules can take place preferentially at either the annular nitrogen atom of the OH form or the oxygen atom of the N—H form in each case subsequent proton loss yields a neutral product. Dialkylation then gives rise to a cationic product, the second alkyl group being introduced at the other site. 

Alkylation of hydroxypyridines137 has been studied under PT conditions. The results depend on the position of the hydroxy group and on the nature of the experimental conditions. 2- And 4-pyridone are alkylated at both nitrogen and oxygen with a little preference for nitrogen.138 3-Hydroxy-pyridine and 2-amino-3-hydroxypyridine139 (see next section) give only O-alkylation. 

Reaction of pyridones with diazoalkanes involves deprotonation as the first step, forming an alkyldiazonium cation which then rapidly alkylates the pyridone anion 2-pyridone gives mainly 0-methyl derivatives, but 4-pyridone gives mixed 0- and A-methyl derivatives. 

Sliwa (70BSF646) was the first to prepare the parent compound (6) using an intramolecular O-alkylation of a pyridone (Scheme 4). Furo[2,3-6]pyridine was obtained as a colorless oil with b.p. 95 °C (22mmHg). Essentially the same procedure has been used for the preparation of 4-methylfuro[2,3-ft]pyridine (17 Scheme 5) (73MI31700) and 6-methyl-furo[2,3]pyridine (26) (72CHE1395). 

As shown in the previous section, N-alkyl nitroanilines 23 are obtained in the reaction of pyridone 1 with ketones 22 in the presence of amines. In this case, amines are introduced as the dialkylamino substituents. On the contrary, different reactivity is observed when ammonia is used instead of amines. The TCRT reaction proceeds to afford 2,3-dialkyl-5-nitropyridines 24 upon treatment of pyridone 1 with ketones 22 in the presence of ammonia (Table 2) [42,43]. The C4 - C5 - C6 unit is derived from pyridone 1, the C2 - C3 unit is derived from ketone, and the ring nitrogen (Nl) is from ammonia, namely the new ring consists of three components. As electrophilic nitration of pyridines is quite difficult, the present TCRT will be an alternative method for preparation of nitropyridine derivatives. 

The alkylation of 2-pyridone was effected under mild conditions by use of cesium fluoride. Benzyl and allyl chlorides furnished the A-alkylated product selectively, while secondary alkyl iodides gave O-alkylation selectively <95SL845>. 

Attempted alkylation of 2-pyridones often leads to mixtures of N- and O-alkylated products with the selectivity dependent on the reaction conditions. Alkylation of the sodium salt of 2-pyridone often leads to iV-alkylation while alkylation of the silver salt results in O-alkylation. For example, /3-D-galactopyranose pentaacetate reacts with silver 2-pyridoxide in toluene under reflux to give the pyridylgalactopyranoside 100 in good yield (Equation 67) <2001T3267>. 

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