Picoline IV-oxide

The reaction between heteroaromatic iV-oxides and 2-chloro, 5-dihydroimidazole 955 results in a formal ureida-tion of the heteroaryls. This reaction was extended to 2- and 4-picoline iV-oxides for the synthesis of 956 and 957, respectively (Scheme 232) <2002JHC911>. The 2-bromine of nitronyl nitroxide 958 is easily displaced with sodium azolides to give spin-labeled azoles (imidazole, pyrazole, triazole) 959 which are prone to hydrolysis to hydroxamide acid anion 960 <2004T99>. 

For the synthesis of 13-hydroxysparteine the starting material was a-picoline iV-oxide (CXVIII) which was nitrated and the nitro group then replaced by benzyloxy. The action of acetic anhydride induced the Boekelheide rearrangement to the acetoxymethyl derivative CXIX. The latter, via the alcohol, the chloride, the cyanide, and the ester, was condensed with ethyl hydroxymethylenepyridylacetate to the quinol-izone CXX, hydrogenation and reduction of which with lithium aluminum hydride gave a separable mixture of hydroxysparteines. The... 

Oxidation of Alkyl Halides. Pyridine iV-oxide oxidizes even unactivated alkyl halides to carbonyl compounds (eqs 7-9). This is of some importance as most related methods (e.g. Krohnke and Kornblum oxidations) are limited to activated halides. The reaction can be performed in two ways. In the first, the halide is treated with thelV-oxide in the presence of a base such as NaHCOs. In the second, the intermediate N- alkoxypyridinium salt is isolated before base treatment. " 2-Picoline IV-oxide may be used in a similar oxidation reaction. ... 

The above reactions have been illustrated for 2- and 4-alkylpyridines. They generally fail if no heteroatom is a or 7, as in 3-alkylpyridines and 5-alkylpyrimidines. a- and [3-Alkyl groups in pyridine A-oxides are somewhat more reactive than those on the corresponding pyridines. In addition to the reactions already mentioned, 2-picoline 1-oxide undergoes Claisen condensation with ethyl oxalate to yield the pyruvic ester (630) (for the conversion of alkyl substituents in A-oxides into CH,OAc groups see Section 3.2.3.12.5.iv). 

Reaction of Zn(C104)2 with 2-picolinic acid IV-oxide (HL) yields ZnL in which the ligand is... 

An improved procedure for the preparation of 4-chloropicolinyl chloride from picolinic acid and thionyl chloride has been developed (Equation 42) <20020PD777>. Phosphoryl chloride in the presence of triethylamine converts pyridine iV-oxide into 2-chloropyridine in 90% yield <2001SC2507>. 

Compounds (p-YC6H4)2SbBr2(acac) (Y = N02, Cl, H, CI[3, CHsO) were prepared from p-YC6H4SbO(OH)2 11, 18h) and p-YC6H4SbCl3(acac) (Y = N()2, H, CH3) were obtained from corresponding stibonic acid (18a, b). HMPA = hexamethylphosphoric triamide DMSO = dimethyl sulfoxide PyO = pyridine iV-oxide 4-CHjPyO = y-picoline JV-oxide TPPO = triphenylphosphine oxide. 

Pyridine and quinoline iV-oxides react with phosphorus oxychloride or sulfuryl chloride to form mixtures of the corresponding - and -chloropyridines. The reaction sequence involves first formation of a salt (e.g., 276), then attack of a chloride ion on this, followed by rearomatization (see also Section 3.2.3.12.5) involving the loss of the /V-oxidc oxygen and thence formation of 2-chloropyridine. Treatment of pyridazine 1-oxides with phosphorus oxychloride also results in an -chlorination with respect to the Ar-oxide group and simultaneous deoxygenation. If the -position is blocked substitution occurs at the -position. Thionyl chloride chlorinates the nucleus of certain pyridine carboxylic acids, e.g., picolinic acid 277, probably by a similar mechanism. 

As seen in many of the above examples, acetic anhydride and zinc chloride each make effective condensation catalysts for the free bases, presumably by efficient coordination with the ring nitrogen. The quaternary salts condense readily in the presence of piperidine. Potassium hydroxide, methoxide or piperidinium acetate are suitable for condensations with 2- and 4-methylpyridine iV-oxides. For example, the Claisen condensation is effective with these iV-oxides using ethoxide catalyst (Scheme 45) but the reaction fails with the parent picolines unless activated by nitro substitution (69JHC775). 

Badger and Rao reported that the treatment of the iV -oxide (45) with potassium ethoxide and ethyl oxalate in ethanol at room temperature gave none of the expected pyruvate but a little of the bispicolyl (46). It had been shown in 1954 that 2- and 4-picoline 1-oxides readily condensed with ethyl oxalate to give the pyruvates in good yield. The electron-attracting influence of the iV-oxide is known to make the... 

Figure 5. Free energy surface for picolinic acid iV-oxide in chloroform solution as a function of OH and OO distances calculated on the B3LYP/6-31+G(d, ) level. Solvent reaction field method of Tomasi and Persico was used to calculate the free energy of solvation. The applied dielectric permitivity was 4.9.

Figure 6. Chemical shift of the C3 atom as a function of OH and OO distance in picolinic acid iV-oxide, according to Ref [26]. Reprinted from Ref [26] by permission granted by the American Chemical Society. For each OH and OO value all other geometry parameters were optimized. The inner contour labelled 2 pertains to the energy value of 2kcal mol above the minimum successive contours are drawn at 2 kcal mol intervals, according to Ref. [26].

Early publications on [VO(/3-diketonato)2] have been reviewed. More recently, complexes with benzoyl m-nitroacetanilide, benzoyl acetanilide and l,l -(l,3-phenylene)-bis(butane-1,3-dione have been synthesized. Other [VO(jS-dik)2] adducts have been isolated, for example [VO(acac)2] adducts with a series of pyridine AT-oxides and several pyridine carboxamides, and [VO(bzac)2] adducts with pyridine, methylamine, isoquinoline and 4-picoline. Equilibrium constants of 1 1 and 2 1 adducts of pyrazine with [VO(tfacac)2] have been determined (equation 38). ° In the 2 1 complex, the pyrazine bridge between two equatorial sites of adjacent vanadium atoms promotes a weak exchange interaction. The nitroxide radical 2,2,6,6-tetramethylpiperidinyl iV-oxide also forms an adduct with [VO(hfacac)2] in which there is a strong interaction between the electrons on the metal and nitroxide. ... 

O.5H2O (L H = 2-picolinic acid iV-oxide) and cobalt (ii) complexes of triazine... 

Contrary to a previous report, the reaction of pyridine-l-oxide with acetic anhydride does not give exclusively 2-pyridone 2-aminopyridine and yV-(2-pyridyl)-2-pyridone (IX-23) are also formed. Similarly, 6-amino-3-picoline and 3-methyl-A -(5-methyl-2-pyridyl)-2-pyridone were isolated in the reaction of 3-picoline-l-oxide with acetic anhydride (see also Chapter IV). 

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