Pyridines 4- lithio

All the isomerically pure lithio-pyridines can be prepared by halogen exchange, though 3-bromopyridine requires a lower temperature, or a change to a less-dissociating solvent, to discourage nucleophilic addition bromopicolines can be similarly converted, without deprotonation at the methyl groups. 

An unusual final example of a synthesis from pyridines involves the 4-lithiotetra-chloropyridine (128), which with two moles of benzonitrile gave the trichlorodiphenyl-pyrido[3,4- f]pyrimidine (130) via the intermediate (129) (72JCS(P1)2190). The 2-lithio analogue gave the corresponding [3,2-c] derivative. 

Pyridine, 2-n-butyl-l-lithio-l,2-dihydro-as reducing agent, 2, 267 Pyridine, 4-carboxamido-1-oxide... 

Pyridine, l-lithio-2-phenyl-l,2-dihydro-, 2, 266 Pyridine, 2-methoxy-IR spectroscopy, 2, 129 photoelectron spectroscopy, 2, 140 pulsed ion gas-phase cyclotron resonance spectroscopy, 2, 157 Pyridine, 3-methoxy-nitration, 2, 191 Pyridine, 4-methoxy-pKa,, 2. 150... 

In recent years, a variety of aryl boronic acids are commercially available, albeit in some cases they may be expensive for large scale purposes. During our work in the mid-1990 s boronic acid (II) was not commercially available and so two different protocols were used to prepare this acid. The first approach involved the transmetallation with n-butyl lithium of aryl bromide (I) and trapping the lithio species generated with trialkyl borate followed by an acid quench. Aryl bromide (I) is easily prepared by reaction of o-bromobenzenesulfonyl chloride with 2-propanol in the presence of pyridine as a base. The second approach was a directed metallation of isopropyl ester of benzene sulfonic acid (VII), to generate the same lithio species and reaction with trialkyl borate. The sulfonyl ester is prepared by reaction of 2-propanol with benzenesulfonyl chloride. From a long-term strategy the latter approach is... 

Tetrahydro[l,5-tf]pyridine 52 was also subjected to lithiation by reaction with butyllithium and gave the 1-lithio derivative 56. This compound when treated with methyl iodide afforded the 4-methyl derivative 57. Further interesting transformations of 56 have also been carried out reaction with 1,3-dibromopropane gave first the... 

The synthesis of the four monocarboxylic acids of dibenzothiophene has been recorded in the previous review. However, several modified preparations have since been described. Ethyl 1-dibenzothiophene-carboxylate has been synthesized from 2-allylbenzo[6]thiophene (Section IV,B, 1) hydrolysis afforded the 1-acid (57% overall). In a similar manner, 3-methyl-1-dibenzothiophenecarboxylic acid was obtained from the appropriately substituted allyl compound. This method is now the preferred way of introducing a carbon-containing substituent into the 1-position of dibenzothiophene. 2-Dibenzothiophenecarboxylic acid has been prepared by oxidation of the corresponding aldehyde or by sodium hypoiodite oxidation of the corresponding acetyl compound. Reaction of 2-acetyldibenzothiophene with anhydrous pyridine and iodine yields the acetyl pyridinium salt (132) (92%), hydrolysis of which yields the 2-acid (85%). The same sequence has been carried out on 2-acetyldibenzothiophene 5,5-dioxide. The most efficient method of preparing the 2-acid is via carbonation of 2-lithio-... 

Ethyl pyridine-2-acetate and ethyl 6-methylpyridine-2-acetate have previously been prepared by carboxylation of the lithio derivatives of a-picoline and lutidine, respectively. Use of ethyl carbonate to acylate the organometallic derivative avoids the intermediacy of the (unstable) carboxylic acid, and the yields are better. In the present procedure potassium amide is used as the metalating agent the submitters report that the same esters may be formed by metalation with sodium amide (43% yield) or with w-butyllithium (39% yield). The latter conditions also yield an appreciable amount of the acid (which decarboxylates). 

According to recent MO calculations on the stability of the lithium salts of pyridine, 2-lithiopyridine is energetically more stable than the 3-and 4-derivatives, because it forms the lithio-bridged structure 22... 

Metalation can also occur adjacent to the bridgehead 5p -nitrogen in six-membered rings, and examples include the lithio derivatives of 3-ethylthioimidazo[l,5-fl]pyridine 67 (80TL2I95, 80TL4193), 1,2,3-triaz-... 

The formation of pyridine 3-carbanions is thermodynamically a more favorable process than that for the 2-analogs, and this is exemplified by the exchange reaction between 2-lithio- and 3-bromopyridines (Scheme 107), which occurs readily at -100°C (77JOC257). 

Direct metalation of 2,6-disubstituted pyridines has also been reported to occur at the 4-position under certain conditions. Thus the 2,6-bistrimeth-ylsilyl chromium tricarbonyl compound 96 gave the 4-lithio derivative 102 [91JCS(P1)501], and 2,6-dichloropyridine gave mainly the 4-lithio derivative 103 under kinetic deprotonation conditions, in contrast to the thermodynamic situation where 3-lithiation was preferred (91JOC4793). 

There are several bicyclic compounds with five-membered heterocycles fused to pyridine rings, where metalation occurs in the smaller ring due to activation by the heteroatom. The ring-A lithiation of imidazopyridines and pyrimidines was discussed in Section II,E,6, but in addition, the a-lithio derivatives of thieno[2,3-6]pyridine 119 (74JHC355), thieno[3,2-... 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

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