Regioselectivity Differentiation in Metalations of 3 , 5-Dichloro-Tertiary versus Secondary Benzamides

Metalation regioslectivity of 3,5-dichlorobenzamides is a function of the type of amide (secondary versus tertiary) used in the sequence. Metalation at the 2-position (adjacent to the carboxamide functional group) occurs when the secondary benzamide is metalated with sec-butyllithium/ TMEDA mediated through complex-induced proximity effects (CIPE) process, whereas metalation with sec-butyllithium/TMEDA occurs exclusively at the 4-position when the tertiary benzamide is used under identical reaction conditions.


Introduction
Among the most powerful techniques for the introduction of electrophilic functional groups onto an aromatic or heteroaromatic ring system is that of Directed ortho-Metalation (DoM) [1].Many review articles have been written on the technique over the past three decades describing both synthetic and mechanistic studies [2]- [7].The importance of this effect has been amply illustrated by adoption of Directed ortho-Metalation as a key synthetic methodology over the past 30 years.
We have previously reported an unexpected regioselectivity observation for the metalation of 3,5-dichloro-N,N-diethylbenzamide 1 [8].Addition of sec-butyllithium to a diethyl ether solution of the benzamide at −78˚C using benzaldehydes as electrophiles afforded the 4-substituted 3,5-dichlorobenzamides 3 in moderate to good yields with no detectable product arising from metalation ortho to the tertiary amide (Scheme 1).Possible explanations proposed for this observation involve steric control, electronic control, or a combination of the two.In an effort to shed light on the physicochemical and/or mechanistic basis for this observation, we turned our attention to the metalation of the corresponding 3,5-dichloro-N-ethylbenzamide (4).This paper summarizes the difference between the metalation proclivities of 3,5-dichloro tertiary benzamides versus the corresponding secondary benzamides due to differences in the degree of complex-induced proximity effects (CIPE).

Results and Discussion
For the case of tertiary benzamide systems (Scheme 1), 1.0 -1.2 molar equivalents of sec-butyllithium is typically employed for metalation, whereas the secondary benzamide requires a minimum of 2.0 molar equivalents of metalating agent, the first equivalent consumed in the generation of the anion 5 resulting from the acid-base reaction with the carboxamide functional group (Scheme 2).Through complex-induced proximity effects [4] [9] the metalated carboxamide functional group (5) directs the ortho-metalation through intermolecular complexation with the second equivalent of metalating agent.Since complexation has been shown to be an acidifying event [5], we felt that this chelation control effect may substantially alter any directing effects exerted by the chlorine atoms in the 3-and 5-positions, thereby resulting in metalation at the 2-position relative to the secondary carboxamide functional group for 3,5-dichloro-N-ethylbenzamide 4.
As before, sec-butyllithium was employed as the metalating agent with aromatic aldehydes used as electrophiles.However, in this case we isolated isobenzofuranones of the type 6 resulting from sequential ortho-metalation to form the bis-metalated intermediate 5 followed by nucleophilic addition to the aldehyde and subsequent intramolecular cyclization [10]- [14].None of the product arising from metalation in the 4-position was detected (Scheme 2).

Conclusion
This study reveals that there are substantial differences in the degree of complexation (CIPE) of the metalating agent to the secondary versus tertiary carboxamide functional group in poly-substituted aromatic systems bearing other directing groups.These differences can and do play a major role in the regiospecificity of metalation reactions [16].Studies detailing the behavior of the comparable 3,5-difluoro derivatives will be reported in due course.

Experimental
General.Tetrahydrofuran was purchased as anhydrous (Fluka) and was stored under a nitrogen blanket and over molecular sieves.Sec-Butyllithium (1.3 M in cyclohexane/hexane) was purchased from Acros Organics or Sigma-Aldrich. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) data were obtained from a Varian Gemini 300 nuclear magnetic resonance spectrometer referencing tetramethylsilane and utilized CDCl 3 lock.IR data were obtained from a Perkin-Elmer Model Spectrum 2000 FT-IR spectrometer.GC/MS data were obtained from an Agilent Technologies 6850 GC/5973 MSD.Microanalyses were performed by Intertek, Whitehouse, NJ.All melting points were obtained from a Mel-Temp heating block apparatus and are uncorrected.1.00 mmol) of 3,5-dichloro-N,N-diethylbenzamide and 5 mL of anhydrous diethyl ether was added a solution of TMEDA (1.2 equiv) in 2 mL of anhydrous diethyl ether.The resulting solution was cooled with magnetic stirring to −78˚C.To the resulting white suspension was added 1.2 equiv of sec-BuLi in cyclohexane dropwise.The resulting yellow suspension was stirred at −78˚C for 30 min, at which point the aryl aldehyde (1.5 equiv) in 2 mL of anhydrous ether was added drop wise to the reaction mixture.The resulting mixture was allowed to slowly warm to ambient temperature and was stirred an additional 2 h.The mixture was quenched by addition to water.The ether layer was separated, sequentially washed with water and 2 N HCl, dried (MgSO 4 ), filtered, and concentrated.The residue was triturated with petroleum ether to afford the final product.