Regioselective lithiations of 2-(3,5-dichlorophenyl)-2-(4-fluorophenyl)-1,3-dioxolane

2-(3,5-Dichlorophenyl)-2-(4-fluorophenyl)-1,3-dioxolane on treatment with butyllithium undergoes deprotonation at the 4-position flanked by the two chloro substituents. The corresponding 4-trimethylsilyl derivative was regioselectively lithiated with butyllithium at the 2-position of the dichlorophenyl ring. Deprotonation with butyllithium complexed with N , N , N’ , N”,N”-pentamethyldiethylenetriamine occurred at the site adjacent to the fluorine of the fluorophenyl ring.


Introduction
Since the discovery of diazepam (1) (Figure 1) and the related anxiolytic 1,4-benzodiazepines, 1 substituted diphenylmethane fragments have been considered as important substructures in medicinal chemistry.The key intermediates in the synthesis of benz-anellated heterocycles exhibiting diphenylmethane moieties are the corresponding ortho-functionalized benzophenones.

Results and Discussion
Compound 4 was synthesized by Friedel-Crafts reaction of 3,5-dichlorobenzoyl chloride with fluorobenzene, followed by ketalization of the benzophenone 3 with ethylene glycol under microwave heating 9 (Figure 3).Lithiation of compound 4 with butyllithium at -78 °C in THF occurred regioselectively at the common ortho-site of the two chlorine atoms, as indicated by the formation of the carboxylic acid 5 as the single product after treatment with carbon dioxide.This result shows that -under these conditions -the p-fluorophenyl ring cannot compete with the 3,5-dichlorophenyl ring for the lithium, and that the combined ortho-directing aptitude of the two chloro groups is more powerful than that of the chloro and the 1,3-dioxolan-2-yl substituents.

Figure 3
Lithiation of the ketal 4 with butyllithium complexed with N,N,N',N",N"-pentamethyldiethylenetriamine (PMDTA), 10,11 followed by carboxylation, gave a mixture of carboxylic acids 5 and 6 in a molar ratio of 1:1, as determined by 1 H-NMR analysis of the product mixture.This result suggested that a regioselectivity suitable for our purpose, i.e., lithiation ortho to the 1,3dioxolan-2-yl group, could be achieved only if the common ortho position to the two chloro substituents is blocked, e.g., by introducing the easily removable trimethylsilyl group. 12,13Thus, the lithio derivative obtained by reaction of 4 with butyllithium at -78 °C in THF was treated with chloro(trimethyl)silane, affording compound 7 in high yield.
As expected from our earlier studies (Figure 2), lithiation of the silylated derivative 7 with butyllithium in THF at -78 ° occurred exclusively in the chloro-substituted ring, as demonstrated by the formation of derivatives 8 and 9, respectively, after reaction with the corresponding electrophiles.According to our expectations, 7,14,15,16 lithiation of the ketal 7 with butyllithium complexed with PMDTA, and subsequent carboxylation, resulted in product 10, demonstrating that lithiation took place at the site adjacent to fluorine.
The compounds synthesized are useful intermediates for the synthesis of heterocyclic derivatives.The trimethylsilyl 13,17 and ethylene ketal 2,18,19 protecting groups can be removed at a convenient stage of the subsequent synthetic route under conventional conditions.Just as examples, compound 6 was prepared by desilylation of the derivative 10, and the ketal 9 was hydrolyzed to the benzophenone 11.

Experimental Section
General Procedures.Melting points are uncorrected.Infrared spectra were recorded as KBr pellets. 1 H NMR spectra were recorded at 200 MHz.All unspecified reagents were from commercial sources.Yields are not optimized.