Molecular Sciences C-versus O-arylation of an Enol-lactone Using Potassium Tert- Butoxide

The use of potassium tert-butoxide as the base in arylation reactions of an enol-lactone with a series of benzyl halides was explored. Our work demonstrates that the ratio of C-arylation to O-arylation varies with the substitution pattern of the aryl halide.


Introduction
The alkylation of enolates, derived from 1,3-diketones with alkyl halides, is a well-established method for C-C bond formation [1][2][3].However, the competing O-alkylation often occurred [4].In particular, the alkylation of highly enolic cyclic β-diketones leads to the formation of a significant amount of the O-alkylation products.
As part of our ongoing research effort on potential inhibitors of HIV-1 protease [5], various 3mono-alkylated enol-lactone compounds were designed and synthesized.A variety of basic reagents were screened for selective C-alkylation and potassium tert-butoxide was found to be an appropriate choice [6,7].

Results and Discussion
First, an enolate was generated from enol-lactone 1 using, as previously described [8], potassium tert-butoxide (1.1 equivalent) in DMSO (Scheme 1).Subsequent alkylation of this enolate with a variety of substituted benzyl bromides was performed at room temperature.After completion of the reaction, the C-arylated compounds 2 and O-arylated compounds 3, shown in the scheme below, were isolated.Our results are summarized in the Table 1.

Scheme 1.
Table   The known principle of hard and soft nucleophiles and electrophiles [9] suggests an explanation for these obtained results.This principle stipulates that hard nucleophiles react faster with hard electrophiles and soft nucleophiles react with soft electrophiles.
Also, enolate ions are known to be the most important ambident nucleophiles.The total charge is localized on the oxygen atom.With charged electrophiles, the site of attack will be oxygen while electrophiles having little charge react at the carbon site.In other words, hard electrophiles react at oxygen and soft electrophiles at carbon [10].Our reagent is a substituted benzene halide.The benzene ring is also an ambident nucleophile in function of a substitution.There are three common types of substituents, each of which modifies the reactivity of conjugated systems in different ways.These are (A) simple conjugated systems; (B) conjugated systems like formyl, acetyl, cyano, nitro and carboxy and (C) heteroatoms which carry a lone pair of electrons capable of overlap with the benzene ring.The literature includes simple alkyl groups in this category [11].
The results presented in the table below show that for benzyl halides with type (C) substituants on the benzene ring, the major product arises from C-alkylation (entries 1, 2, 3, 4 and 5).However, with type (B) substituants, the O-alkylation product is the major one (entries 6 and 7).In some cases, di-O,C-alkylation product 4 was also formed as a minor product.

Conclusion
The hard center (oxygen of the enolate) is the site of attack by the hard electrophile (benzene substituted with (C) group type) and the soft center (carbon C-2) is the site of attack by a soft electrophile (benzene substituted with (B) group type).The preparation of other O-arylated and Carylated compounds using this method is presently being carried out in our group and the results of this study will be published in due course.
After extracting twice with ethyl acetate, the organic layer was dried in MgS0 4 .After filtration, the filtrate was evaporated under vacuum.The crude is purified by silica gel chromatography to yield the compound (2-1) as a white solid (76mg, 62%) and the byproduct (3-1) as white solid (18mg, 15%).
* Yields correspond to the isolated material; the balance is the O,C-arylated product.