Functionalized Organolithium Compounds Through an Arene-Catalyzed Lithiation

Naphthaleneor DTBB-catalyzed lithiation of chloroimines 1, deprotonated chlorobenzyl alcohols, mercaptanes or amines 4, and 3-phenylthiopropylamine 7 in THF at -78deg.C leads to the formation of the corresponding intermediates 2, 5 and 8, which by reaction with carbonyl compounds as electrophiles afford the expected bifunctionalized compounds 3, 6 and 9, respectively.


Introduction
Functionalized organolithium compounds [1] are versatile intermediates in synthetic organic chemistry due to their ability to transfer their own functionality to electrophilic reagents, so making possible to prepare polyfunctionalized molecules in only one reaction step.In this communication we report our last findings in this field.
The successive reaction of chlorinated benzylic derivatives 4 with n-butyllithium and lithium in the presence of a catalytic amount of 4,4'-di-tert-butylbiphenyl (DTBB, 4 mol %) in THF at -78deg.C led to a solution of the corresponding dianion 5, which by treatment with different electrophiles [Bu t CHO, PhCHO, (CH 2 ) 5 CO yielded, after hydrolysis with water at the same temperature, the expected products 6 (Scheme 2).Deprotonation of amine 7 with n-butyllithium in THF at -78[integral]C followed by lithiation in the presence of a catalytic amount (2.5 mmol%) of DTBB led to the dianionic intermediate 8, which reacted with carbonyl compounds [Bu t CHO, PhCHO, Me 2 CO, (CH 2 ) 5 CO at the same temperature giving, after hydrolysis with water, the expected aminoalcohols 9 (Scheme 3).

Conclusion
The here described methodology (arene-catalyzed lithiation) allows the preparation under very mild reaction conditions of different functionalized organolithium intermediates, which are versatile reagents for the condensation with carbonyl compounds as electrophiles, yielding polyfunctionalized organic structures.

Experimental Part
For general information, see reference [4].
To a green suspension of lithium powder (0.1g, 14mmol) and naphthalene (0.01g, 0.08mmol) in THF (5ml) was slowly added (ca. 10 min) a solution of chloroimine 1 (1mmol) in THF (2ml) at -78deg.C.Stirring was continued for 2 hr and then, the excess of lithium was filtered off at -78deg.C.Isobutyraldehyde (0.11ml, 1.2mmol) was added to the filtered solution and the mixture was stirred during 12 hr allowing the temperature to rise to 20deg.C.The reaction mixture was hydrolyzed with water (5ml) and extracted with ethyl acetate (3x10ml).The organic layer was dried over anhydrous sodium sulfate and evaporated (15Torr).The residue was purified by column chromatography (silica gel, hexane/EtOAc) to afford the corresponding title product (0.075g, 36%).To a solution of 2-chlorobenzyl alcohol (0.29g, 2mmol) in THF (3ml) was added a solution of n-butyllithium in hexane (1.25ml, 2mmol) at -78deg.C for 10 min.The resulting mixture was transferred via cannula to a suspension of lithium powder (0.15g, 20mmol) and DTBB (0.03g, 0.1mmol) in THF (5ml) at -78deg.C, being it then stirred for ca.45 min at the same temperature.Then, pivaldehyde (0.22ml, 2mmol) was added and the mixture was stirred at -78deg.C for 30 min, when the green colour was recovered.The resulting mixture was then hydrolyzed with water (5ml) at -78 to 20deg.C, extracted with ethyl acetate (3x10ml), the organic layer was dried over anhydrous sodium sulfate and evaporated (15Torr) to give a residue, which was purified by column chromatography (silica gel, hexane/EtOAc) affording the pure title compound (0.123g, 43% Preparation of 4-(Isopropylamino)-1-phenyl-1-butanol (9b).Typical Procedure.
To a solution of amine 7 (0.21g, 2mmol) in THF (2ml) was added a solution of n-butyllithium in hexane (1.25ml, 2mmol) at -78deg.C for 10 min.The resulting mixture was transferred via cannula to a suspension of lithium powder (0.1g, 14mmol) and DTBB (0.03g, 0.1mmol) in THF (5ml) at -78deg.C, being it then stirred for 1 hr at the same temperature.Then, benzaldehyde (0.2ml, 2mmol) was added and the mixture was stirred overnigth, allowing the temperature to rise to 20deg.C.The resulting mixture was then hydrolyzed with water (5ml), followed by addition of HCl 3M (50ml) and extracted with ethyl acetate (3x10ml).To the acid aqueous layer was added Na 2 CO 3 until basic pH and then, the mixture was extracted with ethyl acetate (3x10ml), this organic layer was dried over anhydrous sodium sulfate and evaporated (15Torr) to give the pure title compound (0.29g, 70%).