Stereoselective α-Tertiary Alkylation of N-(Arylacetyl)oxazolidinones

Abstract

A method has been developed for the α-tertiary alkylation of zirconium enolates of N-(arylacetyl)oxazolidinones. This reaction directly installs an all-carbon quaternary center vicinal to a benzylic tertiary carbon in a highly diastereoselective manner.

Graphical Abstract

Construction of carbon–carbon bonds between two sterically congested centers in a stereospecific manner is a challenging transformation in organic synthesis.¹ In terms of carbon–carbon bond formation, enolate alkylation is a classic approach that is still widely used to this day.² However, the use of tertiary alkyl halides as electrophiles has been largely limited by their inability to undergo direct substitution through an S_N2 mechanism and by their tendency to undergo elimination. This problem was overcome by Reetz and co-workers through activation of tertiary alkyl electrophiles with Lewis acids.³ However, this method requires prior formation of a silyl enol ether before the carbonyl α-tert-alkylation, and it does not proceed with any stereoselectivity.

Chiral oxazolidinones are common auxiliaries used to achieve stereoselectivity in enolate alkylation.⁴ The electrophile scope for N-acyloxazolidinones has been further expanded by taking advantage of the biradical character of their corresponding group IVa metal enolates.⁵ Various stereoselective radical α-functionalizations were demonstrated by the groups of Zakarian⁶ and Urpi.⁷ We surmised that the distinct reactivity of these enolates might permit the incorporation of tertiary alkyl electrophiles. Here, we describe the development of stereoselective alkylation of N-(arylacetyl)oxazolidinones with tertiary alkyl halides via zirconium enolates.

We began our study by exploring the alkylation of 4-benzyl-5,5-dimethyl-3-(phenylacetyl)-1,3-oxazolidin-2-one (1) with t-BuBr. We hypothesized that TiCl₄ might act in both the generation of the enolate and as a Lewis acid for electrophile activation. When 2.2 equivalents of TiCl₄ were added to the reaction mixture, the corresponding tert-butylated product 1a was isolated in 2% yield (Table 1 entry 1). We then began to screen other Lewis acids for electrophile activation. Among the reagents screened, SnCl₄ gave the best results (entries 2–5). Regarding the group IVa metal source, ZrCl₄ proved to yield superior results (entry 6), in agreement with results from a previously reported trifluoromethylation of N-acyloxazolidinones.^6b To enhance the practicality of this reaction, we explored the effects of reduced equivalents of base and tert-butyl bromide (entries 7–9). Whereas the use of fewer equivalents of base resulted in diminished yields, presumably due to lower efficiency of enolate formation, the amount of tert-butyl bromide could be lowered to 1.5 equivalents without a significant effect on the yield. Lastly, the base and solvent were modified. Sterically encumbered bases showed diminished yields (entries 10 and 11), also implying the importance of efficiency during enolate formation. Among the various solvents, chloroform showed improved yields along with a high diastereoselectivity (entries 12–14).

Table 1.

Optimization of the α-tert-Butylation of an N-(Phenylacetyl)oxazolidinone^a

Entry	M	Et3N (equiv)	t-BuBr (equiv)	Additive	Conv.(%)(dr)a
1	Ti	3.0	4.4	TiCl4	2
2	Ti	3.0	4.4	MgCl2	1
3	Ti	3.0	4.4	ZnCl2	2
4	Ti	3.0	4.4	AlCl3	11
5	Ti	3.0	4.4	SnCl4	23
6	Zr	3.0	4.4	SnCl4	77 (33:1)
7	Zr	3.0	1.5	SnCl4	63 (14:1)
8	Zr	2.0	1.5	SnCl4	57 (16:1)
9	Zr	1.5	1.5	SnCl4	50 (25:1)
10	Zr	3.0c	1.5	SnCl4	41 (20:1)
11	Zr	3.0d	1.5	SnCl4	22
12e	Zr	3.0	1.5	SnCl4	26 (16:1)
13f	Zr	3.0	1.5	SnCl4	63 (10:1)
14g	Zr	3.0	1.5	SnCl4	77 (50:1)

^aSee the typical procedure⁸ for the reaction setup.

^bDetermined by the 500 MHz NMR analysis of the crude mixture of products.

^cEt₃N was replaced with DIPEA.

^dEt₃N was replaced with 1,2,2,6,6-pentamethylpiperidine.

^eToluene was used instead of CH₂Cl₂.

^fDCE was used instead of CH₂Cl₂.

^gCHCl₃ was used instead of CH₂Cl₂.

With the optimized conditions in hand, we explored the substrate scope by varying the arylacetic acid portion of the N-acyloxazolidinone. Both electron-withdrawing and electron-donating functional groups were well tolerated at the para-position, resulting in high diastereoselectivity (Table 2; 2a–4a). It is worth mentioning that the reaction is quite clean: the remaining mass balance is mostly unreacted starting material, which can be recovered in a nearly quantitative yield in most cases. When an N-[(3-methoxyphenyl)acetyl]oxazolidinone was subjected to the optimized reaction conditions, byproducts formed by Friedel–Crafts tert-butylation at the 4- and 6-positions of the aryl ring were obtained in addition to the desired product 5a. These results suggest a cationic tertiary-alkyl intermediate. For ortho-substituted aryl substrates, the desired α-tert-butyl products 8a and 9a were isolated in diminished yields, possibly due to the high steric hindrance around the reaction center. Interestingly, when a conjugated N-(4-phenylbut-3-enoyl)oxazolidinone was used, γ-tert-butylation was favored over α-alkylation (10a and 10b). Limitations of this method include the inability to use N-acyloxazolidinones derived from alkanoic acids or heterocyclic arylacetic acids, such as 2-thienyl-, N-tosylindol-3-yl-, or and benzo[d]oxazol-2-ylacetic acids, which suffered from poor conversions and/or decomposition.

Table 2.

Scope of the N-(Arylacetyl)oxazolidinones in the α-tert-Butylation Reaction^a

^aThe diastereomeric ratios were determined by the 500 MHz NMR analysis of the crude mixture of products.

Next, the use of various tertiary-alkyl bromides as electrophiles was examined. 1-Adamantyl bromide underwent the reaction to afford 1b in modest yield and with high diastereoselectivity (Table 3). However, both linear and cyclic tertiary-alkyl bromides gave reduced yields under the optimized conditions. The yields could be slightly improved by employing an extra equivalent of SnCl₄ (1c–1e). Notably, the primary chloride was preserved in product 1d; this can serve as a synthetic handle for further functionalization.

Table 3.

Scope of Tertiary Alkyl Bromides in the α-tert-Alkylation Reaction^a

^aThe diastereomer ratio was determined by the 500 MHz NMR analysis of the crude mixture of products.

^b2.1 equivalents of SnCl₄ were used.

To further demonstrate the synthetic utility of this reaction, we conducted the reaction on a 2 mmol scale (Scheme 1). An additional 1.5 equiv of t-BuBr, along with a prolonged reaction time, afforded 1a in 82% yield with excellent diastereoselectivity.

Scheme 1.

Scalability of the tert-butylation of an N-(phenylacetyl)oxazolidinone. The diastereomer ratio was determined by 500 MHz NMR analysis of the crude mixture of products.

The reaction products can be converted into enantioenriched building blocks. Hydrolytic cleavage of 1a with LiOH–H₂O₂ gave the corresponding acid 1aa in high yield with no erosion of stereochemistry; moreover, the chiral auxiliary was recovered in nearly quantitative yield (Scheme 2).

Scheme 2.

Preparation of an enantioenriched tert-butylated building block through hydrolytic removal of the chiral auxiliary

In summary, we have developed a highly stereoselective α-tertiary alkylation of N-(arylacetyl)oxazolidinones based on the unique reactivity of group IV metal enolates and the capability of Lewis acids to activate tertiary alkyl halides. Studies are ongoing in our laboratory to modify the reaction system to apply it to a wider array of oxazolidinones and electrophiles.