Pyridine N-oxide ring

Sodium hydride/dimethyl sulfoxide Benzene from pyridine N-oxide ring... 

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). 

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... 

The product (IV) is precipitated on addition of L (L = THT, py, pyridine N-oxide or PPh2Me). The yellow-orange compounds (IV) contain four-membered rings bonded by Au—Au bonds of length 288.9 pm the Au—Ag bonds are 272 pm long. 

The data do not support a reaction as simple as this, however, the rate law implicates a second PyO at this stage. Similar experiments were extended with the use of a series of ring-substituted pyridine N-oxides, RC5H4NO, as the substrates. Correlation of the values of kcat against ctr gave a particularly large and negative Hammett reaction constant, = —3.84. This is so because PyO enters in three steps of the scheme, each of which is improved by electron donation. 

Fig. 24.8) [122]. Whilst this protocol can be used to prepare 3-pyridyl-alanine derivatives [22], the corresponding 2-pyridyl-alanine cannot be made [122]. However, Adamczyk has prepared several 2-pyridyl-alanine analogues through hydrogenation of the pyridine-N-oxide substrates in 80-83% ee (see Fig. 24.8) [123]. In general, only when the 2- and 6-positions of the pyridine ring are occupied can 2-, 3- or 4-pyridyl-alanine derivatives be prepared, without nitrogen modification, via hydrogenation with [phospholane-Rh]+ catalysts [122-124].

The preferred position for electrophilic substitution in the pyridine ring is the 3 position. Because of the sluggishness of the reactions of pyridine, these are often carried out at elevated temperatures, where a free radical mechanism may be operative. If these reactions are eliminated from consideration, substitution at the 3 position is found to be general for electrophilic reactions of coordinated pyridine, except for the nitration of pyridine-N-oxide (30, 51). The mercuration of pyridine with mercuric acetate proceeds via the coordination complex and gives the anticipated product with substitution in the 3 position (72). The bromina-tion of pyridine-N-oxide in fuming sulfuric acid goes via a complex with sulfur trioxide and gives 3-bromopyridine-N-oxide as the chief product (80). In this case the coordination presumably deactivates the pyridine nucleus in the 2 and... 

Lithiation of thiazolo[5,4-b]pyridine-N-oxides (503) by n-butyllithium at -65°C is selectively directed by the pyridine N-oxide moiety, whereas lithiation of the parent heterocycle by LDA at -78°C exclusively occurs at the C-4 position (89TL183). Interestingly, no metalation of the furan ring occurred (Scheme 152). 

Increments of selected substituents in positions 2, 3 and 4 of the pyridine ring are listed in Table 4.83 (b). The 13C shifts of C-2,6 (149.7 ppm), C-3,5 (124.2 ppm) and C-4 (136.2 ppm) have been used as references. As can be seen in Table 4.67, N-oxidation causes a significant shielding (— 10 ppm) of the carbons a and y to nitrogen, while those in the / position are slightly shielded. This analogy to the behavior of pyridine-N-oxide towards electrophilic substitution can be rationalized by remembering the known canno-nical formulae of this molecule in contrast to pyridine itself. 

A great deal of chemistry can be done on pyridine N-oxides because the functionality acts as a modifier of ring reactivity. In some cases, the A-oxide functionality needs to be removed after the transformations of interest have been done a selective, mild reduction process would be of value. 

Hyperfine shifts (ppm) pyridine-N-oxide of ring nuclei in octahedral complexes of Ni2+ with aniline and... 

Heteroaromatic amines can oxidize to the corresponding N-oxide, which are typically stable enough to be isolated and detected as degradation products. The N-oxide functionality typically increases the reactivity of the aromatic ring. For example, the N-oxide functionality in pyridine N-oxide facilitates both electrophilic and nucleophilic substitution at the alpha and gamma positions (57). 

In metal-free catalysis enantioselective ring-opening of epoxides according to Scheme 13.27 path B has been achieved both with chiral pyridine N-oxides and with chiral phosphoric amides. These compounds act as nucleophilic activators for tetrachlorosilane. In the work by Fu et al. the meso epoxides 71 were converted into the silylated chlorohydrins 72 in the presence of 5 mol% of the planar chiral pyridine N-oxides 73 (Scheme 13.36) [74]. As shown in Scheme 13.36, good yields... 

Figure 7.40 Structure of the spherical lanthanide p-sulfonatocalix[4]arene assembly (a) partial space filling view along the pseudo-fivefold axis. Pyridine N oxide and one calixarene are shown in stick mode. S03 groups line the surface of the sphere, aryl rings define the hydrophobic shell and the polar core comprises 30 water molecules and two Na+ ions, (b) cut away view showing an [Na(H20)6] 2 cluster within the core. (Reprinted with permission from AAAS from [52]).

Solvent effects on nuclear magnetic resonance (NMR) spectra have been studied extensively, and they are described mainly in terms of the observed chemical shifts, 8, corrected for the solvent bulk magnetic susceptibility (Table 3.5). The shifts depend on the nucleus studied and the compound of which it is a constituent, and some nuclei/compounds show particularly large shifts. These can then be employed as probes for certain properties of the solvents. Examples are the chemical shifts of 31P in triethylphosphine oxide, the 13C shifts in the 2-or 3-positions, relative to the 4-position in pyridine N-oxide, and the 13C shifts in N-dimethyl or N-diethyl-benzamide, for the carbonyl carbon relative to those in positions 2 (or 6), 3 (or 5) and 4 in the aromatic ring (Chapter 4) (Marcus 1993). These shifts are particularly sensitive to the hydrogen bond donation abilities a (Lewis acidity) of the solvents. In all cases there is, again, a trade off between non-specific dipole-dipole and dipole-induced dipole effects and those ascribable to specific electron pair donation of the solvent to the solute or vice versa to form solvates. 

Oxidation of 2,4,4-trimethyl - A1 -py rroline V-oxide with selenium dioxide, followed by treatment with hydrogen chloride, causes ringopening and reclosure to 2,3,4,5-tetrahydro-3,3-dimethyl-5-oxo-pyridine N-oxide (111). Clemmensen reduction of 111 forms 2,4,4-trimethyl-d 1-pyrroline (112) by ring-contraction.334... 

Buchardt, O., Pedersen, C.L. and Harrit, N. (1972) Photochemical studies. XVIII. Light-induced ring expansion of pyridine N-oxides. Journal of Organic Chemistry, 37 (23), 3592-3595. 

Because the nitrogen atom is nucleophilic, pyridine can be oxidized to pyridine N-oxide with reagents such as m-CPBA or just H2C>2 in acetic acid. These N-oxides are stable dipolar species with the electrons on oxygen delocalized round the pyridine ring, raising the HOMO of the molecule. Reaction with electrophiles occurs at the 2- ( ortho ) and 4- ( para ) positions, chiefly at the 4-position to keep away from positively charged nitrogen. 

Pyridine N -oxides are useful for both electrophilic and nucleophilic substitutions on the same carbon atoms (2-, 4-, and 6-) in the ring. 

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