DTBB-Catalyzed lithiation of 2 , 6-bis ( chloromethyl ) pyridine

The DTBB-catalyzed lithiation of 2,6-bis(chloromethyl)pyridine 1 in the presence of various different carbonyl compounds [i-BuCHO, t-BuCHO, Me2CO, Et2CO, n-Pr2CO (CH2)4CO, (CH2)5CO, and norbornan-2-one] in THF at –90°C gives, after hydrolysis with water at temperatures ranging between –90°C and room temperature, the corresponding dihydroxypyridines 2. Despite the moderate yields obtained, the reaction can be of synthetic interest owing to the easy isolation and purification of the products 2, whose preparation is difficult by other methodologies.


Introduction
2,6-Disubstituted pyridines of type I containing two coordinating heteroatoms -one in each arm -are interesting structures for the preparation of organometallic complexes II used in catalytic processes. 1Thus, examples of compounds II containing osmium, 2 zirconium, 3 tungsten, 3 molybdenum, 1,4 titanium, 1,5 zinc, 6 cobalt, 6 silicon 7 and ruthenium 8 have been reported.In the case of the oxygenated derivatives (Y = O), the corresponding substituted parent compounds have been prepared by successive double deprotonation of 2,6-dimethylpyridine (2,6-lutidine) using n-butyllithium and then further reaction with a carbonyl compound.This method has the problem that after the introduction of the first electrophilic fragment (to give intermediate III), the second α-deprotonation (to give intermediate IV) competes with the α'one (to give intermediate V), so variable amounts of the corresponding by-product VI are produced after hydrolysis, together with the desired product VII.6b,9 In order to avoid separation problems, we thought that an alternative route for generating the di-anionic intermediate VIII would be a halogen-lithium exchange, starting from the corresponding 2,6bis(halomethyl)pyridine (Chart 1).Namely, starting from commercially available 2,6bis(chloromethyl)pyridine (1), it would be possible to perform the corresponding lithiation and reaction with a carbonyl compound.However, one problem associated with the benzylic chlorine-lithium exchange is the Wurtz-type coupling of the organolithium intermediate, which is generally the main process. 10One way to avoid the problem could be to perform the lithiation at low temperature and in the presence of the electrophile (Barbier-type conditions). 113][14] In this paper we describe the application of this methodology to the lithiation of 2,6-bis(chloromethyl)pyridine in the presence of various carbonyl compounds in order to prepare compounds of type I with Y = O.

Results and Discussion
The reaction of commercially available 2,6-bis(chloromethyl)pyridine ( 1) with an excess of lithium powder (1:7 molar ratio; theoretical ratio 1:4) and a catalytic amount of 4,4'-di-tertbutylbiphenyl (DTBB; 1:0.05 molar ratio; 1.25 mol %) in the presence of a carbonyl compound (1:3 molar ratio) in THF at -90°C led, after hydrolysis with water at temperatures between -90°C and room temperature, to the expected diols 2 in moderate yields (Scheme 1 and Table 1).In all cases, the reaction is very clean, compound 2 being contaminated only with the corresponding product of monolithiation 2' from which chromatographic separation was very simple.The process shown in Scheme 1 had to be performed in the presence of the electrophile because, when the same reaction was carried out step-by-step (lithiation followed by addition of the electrophile: Grignard conditions), even at very low temperature, only compound 3 was isolated (95% isolated yield). 15When fluorenone was used as electrophile, the only compound isolated (apart from the corresponding 'reduced' compound of type 2') was the 'dimer' 4, in poor yield (ca. 15%) (Chart 2).
Concerning a possible mechanism to explain the formation of the products 2-4, we think that the initially monolithiated intermediate IX reacts with the electrophile present in the reaction medium to give the alkoxide X, which then suffers a second lithiation to give the new organolithium intermediate XI that condenses with a second molecule of the same carbonyl compound to afford the dialkoxide XII, the precursor of the final diols 2. In the absence of the electrophile, the very reactive intermediate IX self-condenses to give the corresponding dimer 3. Finally, with a bulky ketone such as fluorenone, intermediate X prefers to react with the species IX (which reacts more slowly with the electrophile) giving the intermediate XIII, which by successive lithiation and condensation with a second molecule of the electrophile gives the corresponding dialkoxide precursor of the compound 4 (Chart 3).

ISSN 1424-6376
Page 13 Finally, we studied the ability of compounds of type 2 to give cyclic compounds.Thus, reaction of the diol 2 with dichlorodiphenylsilane in the presence of triethylamine and using dichloromethane and the solvent, gave compound 5 16 in 67% isolated yield (81% conversion).

Experimental Section
General Procedures.All reactions were carried out under an atmosphere of argon in oven-dried glassware.All reagents were commercially available (Acros, Aldrich) and were used without further purification.Commercially available anhydrous THF (99.9%, water content ≤ 0.006%, Acros) was used as solvent in all the lithiation reactions.Lithium powder was prepared as we have reported previously. 17Melting points were obtained with a Reichert Thermovar apparatus.Thin layer chromatography was carried out on TLC aluminum sheets with aluminum oxide 60 F 254 neutral (Merck).IR spectra were measured (film) with a Nicolet Impact 400 D-FT Spectrometer.NMR spectra were recorded with a Bruker AC-300 or a Bruker ADVANCE DRX-500 using CDCl 3 as the solvent.LRMS and HRMS were measured with Shimadzu GC/HS QP-5000 and Finnigan MAT95 S spectrometers, respectively.

Chart 1 .
Structures I to VIII.