Pyridones alkylation

Pyridones, alkylation, 745 O- and N-alkylation with dialkyl sulfates, 752 alkylation with diazomethane, 754... 

Since sulfonate groups have been used in other ground-water tracers, the goal of this work was to synthesize several N-substi-tuted pyridone alkyl sulfonates which might be less susceptible to adsorption as well as more soluble. Alkyl sulfonates of varying chain lengths would be unique in a water system and separately identifiable by HPLC analysis. Two series of compounds were synthesized (Vla-c and Vlla-c). These compounds could be prepared by treating compounds III and IV with the appropriate lu-bromoalkyl sulfonate. 

A complimentary approach to the commonly found 0-alkylated major products in pyridone alkylations was found by Semple and coworkers in their preparation of Kappa Opioid receptor agonists. In their hands, TBP and TMAD gave moderate to good yields of A-alkylated pyridone derivatives (260) as shown below. A solid supported variant of this reaction, in which the alcohol moiety was tethered to the solid support, was developed as well. 

Benzopyridodiazines, 3, 199-262 Benzo-2-pyridone tautomerism, 2, 346 Benzo-4-pyridone tautomerism, 2, 346 Benzopyridones acylation, 2, 352 alkylation, 2, 349 Benzopyrido[3,2-ii]pyrimidine reactions... 

The most demanding test of cesium carbonate as base was with 2,3-dihydroxypyridine (3-hydroxypyridone). The cesium salt was found to be fairly unstable, apparently oxidizing quite rapidly. Model reactions suggested that alkylation would occur 1,3 (N, 0) to give the substituted pyridone. Nevertheless, on the basis of UV and H-nmr analysis, the product of reaction between 2,3-dihydroxypyridine and tetraethylene glycol dibromide was assigned as the pyridocrown (23% yield, mp 77—78.5°) as shown in Eq. (3.60). 

The importance of ring size holds also for tautomerism of -pyrrol-5-ones and. d -dihydro-6-pyridones. While the former compounds behave as cyclic 1-methyl-2-alkyl-2-hydroxy-5-pyrrolidones 179) (76) [or, on distillation, as the dehydrated l-methyl-2-alkyl-J -pyrrolones (77)], the latter compounds exist as acyclic N-methylamides of 8-oxo-acids (78) [as shown by infrared spectroscopy (/80)j. The dehydration of 78 during distillation to form l-methyl-2-alkyl-. -dihydro-6-pyridones (79) is achieved only with difficulty. 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

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). 

Products of cyclization of 5-aminoethylene benzotriazole derivatives with eliminated prototropy of the azole ring can be alkylated on the nitrogen atom of the pyridone and then hydrolyzed to the corresponding acids (76JAP(K)1, 89FA619). The prepared compounds 167-169 and their salts were tested against bacteria (no data) (76JAP(K)1). 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

The salt is an ambient nucleophile and can undergo either N or 0 alkylation. Chung and Tieckelmann (17) have shown that unsubstituted pyridone sodium salts in acetonitrile or dimethylformamide solvent form primarily the N-alkylated product. Using 3-substituted... 

A series of bromoalkyl sulfonates was therefore needed to form the N-alkyl sulfonated 2-pyridones. Formation of bromoalkyl sulfonates has not been described extensively in the literature (19). 

Analytical samples of l-alkyl-3-substituted 2(lH)pyridone sulfonates were obtained by using a Whatman Partisll M-9 10/50 ODS-2 C18 column. The 3-carbamoyl series compounds were obtained using a mobile phase of 90% water and 10% acetonitrile with a flow rate of 3.3 mL per minute. The 3-phenyl series compounds were obtained using a mobile phase of 85% water and 15% acetonitrile with a flow rate of 3.3 mL per minute. Any 3-substituted 2(lH)pyridone was retained at the head of the column. 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

The procedure described here for the preparation of succinimide silver salt is a modification of one reported for the formation of the silver derivative of maleimide. The alkylation step is modeled after the procedure of Comstock and Wheeler/ who prepared 2-ethoxypyrrolin-5-one in unspecified 3deld, and is an improvement over a later procedure developed in the laboratories of the submitters/ The general scheme has been successfully applied to the preparation of a variety of 2-ethoxypyrrolin-5-ones (Table 1) as well as 6-ethoxy- and 6-propoxy-4,5-dihydro-2(3H)-pyridone from the corresponding five- and six-membered cyclic imides/... 

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). 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

Pyridones were studied for N- and C-alkylation reactions by de la Hoz et al. [100] as already mentioned for 1,2,4 triazoles, the selectivity of the alkylation is highly dependent on the activation technique (microwave or conventional heating). 

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>. 

Nitriles attached to [l,2,4]triazolo[l,5- ]pyridones were also converted to hydrazide adducts or 1,3,4-triazoles <2004CPA260>. Sulfur in zwitterionic structure 106 was readily alkylated with ethyl iodide (Equation 14), affording the salt 107 <2003JCM755>. 

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