Pyridines N-oxidation

Treatment of pyridine N-oxide (13) with acetic anhydride leads chiedy to 2-pyridone (16) formation (eq. 2) (11). 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

There are several reports that alkylated pyridine N-oxides react with Grignard reagents to give 2-alkylated pyridines (50,51). 

While pyridine N-oxide does not react with enaniines in the absence of an acylating agent, other nitrone systems have formed adducts (615,616). 

The Boekelheide reaction and related reactions involves treating pyridine N Oxides 1 with acylating agents to afford rearranged products 2. Traditionally, the rearrangement occurs at the a-position but variations andyor side-products of this reaction afford y-position modification. 

Extensive data are available on the N—O stretching frequency at about 1265 cm in substituted pyridine N-oxides. Unfortunately the data from different laboratories are not readily comparable since they were obtained under different conditions, particularly in different solvents in addition, in the realm of the small differences generally encountered in infrared spectra, differences between instruments and... 

Another rather extensive series of similar data, obtained using CS2 solutions and nujol mulls, has been published by Shindo (Fig. 4). His series include considerable data for jS-substituted compounds, for which the question of a choice of substituent constants does not arise. His data also show considerable scatter but seem to suggest strongly that <7+-values are indicated for + M substituents and normal <7-values for —M substituents. The conclusion is confirmed by the short series of similar data reported by Costa and Blasina and by Shupack and Orchin. The data of the latter authors for the NO frequencies in mws-ethylene pyridine N-oxide dichloroplatinum(II) complexes are also moderately well correlated with <7+-values. 

Kubota and Miyazaki studied the polarographic reduction of pyridine N-oxides and found a satisfactory correlation with the <7-values. The values increase with increasing pH. 

The pyridine-N-oxide 245 was converted into the cyanopyridine 246 and its isomer (Scheme 80). Grignard reaction, Fischer s indole synthesis, and N-protection gave a pyridinyl indole 247. Selenium dioxide selectively oxidized the methyl group to give the isonicotinic acid. The synthesis of Flavocarpine (244) was finally accomplished by a set of standard reactions as outlined in Scheme 80 (87TL5259). 

Kobayashi and co-workers reported similar enantioselectivity switch in the bi-nol-yterrbium(III) triflate complex-catalyzed cycloaddition reactions [69] between N-benzylidenebenzylamine N-oxide and 3-crotonoyl-2-oxazolidinone [70]. The reaction in the presence of MS 4 A showed an exclusively high enantioselectivity of 96% ee, while that in the absence of MS 4 A (-50% ee) or in the presence of pyridine N-oxide (-83% ee) had the opposite enantioselectivity (Scheme 7.24). This chirality switch happens generally for the combination of a wide variety of nitrones and dipolarophiles. 

Both amine oxides related to pyridines and aliphatic amine oxides (/25) are easily reduced, the former the more so. Pyridine N-oxide has been reduced over palladium, platinum, rhodium, and ruthenium. The most active was rhodium, but it was nonselective, reducing the ring as well. Palladium is usually the preferred catalyst for this type of reduction and is used by most workers 16,23,84 158) platinum is also effective 100,166,169). Katritzky and Monrol - ) examined carefully the selectivity of reduction over palladium of a... 

Nucleophilic halogenations tend to favor the pyridine moiety. The Meisenheimer reaction of thieno[3,2-6]pyridine N-oxide (125) gave only a 24% yield of a 1.4 1 mixture of the 5- and 7-chloro derivatives. Nucleophilic displacement of a 7-nitro group provided a more satisfactory route to the 7-chloro (73%) and 7-bromo (39%) derivatives (85JHC1249). 

The use of molybdenum catalysts in combination with hydrogen peroxide is not so common. Nevertheless, there are a number of systems in which molybdates have been employed for the activation of hydrogen peroxide. A catalytic amount of sodium molybdate in combination with monodentate ligands (e.g., hexaalkyl phosphorus triamides or pyridine-N-oxides), and sulfuric acid allowed the epoxidation of simple linear or cyclic olefins [46]. The selectivity obtained by this method was quite low, and significant amounts of diol were formed, even though highly concentrated hydrogen peroxide (>70%) was employed. 

High enantiomeric excesses for the addition of chloride to meso-epoxides were also obtained with use of a planar-chiral pyridine N-oxide 17 developed by Fu... 

A kinetic study of the electrophilic substitution of pyridine-N-oxides has also been carried out50b,c. Rate-acidity dependencies were unfortunately given in graphical form only and the rate parameters (determined mostly over a 30 °C range) are given in Table 4b. There is considerable confusion in Tables 3 and 5 of the original paper, where the rate coefficients are labelled as referring to the free base. In fact the rate coefficients for the first three substituted compounds in... 

RATE PARAMETERS FOR REACTION OF PYRIDINE-N-OXIDES WITH HN03-H2S04... 

The partial rate factor for nitration of pyridine-N-oxide in the 4 position was estimated as 4x 10"6 which is, therefore, close to that found for the 3 position of pyridine, and 2-phenylpyridine-N-oxide was evaluated as 2xl0-4 times less reactive than benzene from rate measurements in 74.7-78.6 wt. % acid at 25 °C. 

---