Concise and Highly Stereoselective Synthesis of β,β-Disubstituted α,β-Unsaturated Esters

Abstract

Building on our previously reported techniques, we developed a concise and highly stereoselective synthesis method for β,β-disubstituted α,β-unsaturated esters. This synthesis comprises 3 reactions: the aldol reaction of acetic ester derivatives with ketones, the acetylation of tert-alcohols, and an elimination reaction utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). During the acetylation process, acetic anhydride and 4-dimethylaminopyridine (DMAP) facilitated the smooth acetylation of bulky tert-alcohols; however, employing DBU as a base reduced the yields. Additionally, the removal of excess DMAP effectively suppressed the formation of unwanted byproducts during the elimination step.

Introduction

Multisubstituted α,β-unsaturated carbonyl compounds are extensively utilized in synthetic organic chemistry,^1–5) and often serve as partial structural units in bioactive compounds.^6–8) The geometry of the carbon–carbon double bond in α,β-unsaturated carbonyl compounds plays a crucial role in determining their chemical properties and biological activities.^8,9) β,β-Disubstituted α,β-unsaturated carbonyl compounds are characterized by 2 distinct substituents at the β-position and are commonly found in various bioactive molecules.^6,8,10–13) Consequently, numerous synthetic methodologies have been developed for these compounds, including Wittig,^14–16) Horner–Wadsworth–Emmons,^17–22) and Peterson reactions^23–25); transformations using alkyne derivatives with various metal catalysts^26–35); Heck reactions^36–41); reactions catalyzed by iron porphyrins or methyltrioxorhenium with diazoacetate and ketones^42,43); and cross-coupling reactions employing stereo-defined enol carbamates, enol tosylates, and enol phosphonates as substrates.^44–46) Despite these extensive efforts, challenges persist in the synthesis of β,β-disubstituted α,β-unsaturated carbonyl compounds, such as issues with stereo- and regioselectivity, limited substrate applicability, cumbersome procedures requiring the pre-preparation of unstable ylide derivatives, the formation of large quantities of by-products (e.g., phosphonates or phosphine oxides), the use of toxic or commercially unavailable reagents, and the necessity for pre-preparing stereo-defined substrates to achieve high stereoselectivity.

Recently, we reported an efficient and highly stereoselective synthesis of trisubstituted α,β-unsaturated esters⁴⁷⁾ (Chart 1a). This synthetic method integrates 3 established reactions: the aldol reaction, acetylation of the β-hydroxy group, and the E1cB reaction employing 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU). Additionally, we developed a more practical synthetic route for these esters, wherein the activation of the β-hydroxyl group in compound 1 and the subsequent E1cB reaction occur in tandem⁴⁸⁾ (Chart 1b). In both of our developed synthetic methods, another key feature is that only commercially available reagents are employed.

Chart 1. Our Previous Work and the Present Work Focused on the Synthesis of Multisubstituted α,β-Unsaturated Esters

Building on this foundation, we aimed to develop a stereoselective synthesis of β,β-disubstituted α,β-unsaturated esters 6 (Chart 1c) to further extend the applicability of our methodologies. This process involves the aldol reaction of acetic acid esters with ketones, and activation of the β-hydroxyl group in aldol products 4, followed by an elimination reaction using a base.^49–51)

Results and Discussion

Initially, we optimized the elimination reaction to produce the desired β,β-disubstituted α,β-unsaturated esters from aldol compound 4 (Table 1). Following our previous methodology (Chart 1b), we attempted synthesis via a tandem reaction. Aldol compound 4a was synthesized through the aldol reaction of tert-butyl acetate with acetophenone under standard conditions, using lithium diisopropylamide as the base, which resulted in a 96% yield. This compound was then subjected to a tandem acetylation–elimination reaction using acetic anhydride (Ac₂O), 4-dimethylaminopyridine (DMAP), and DBU in refluxing toluene. Unfortunately, only a small amount of the desired β,β-disubstituted α,β-unsaturated ester 6a was obtained, with a yield of 5%, while 86% of the starting material 4a remained unreacted (entry 1). Increasing the quantities of Ac₂O and DMAP slightly improved the yield of 6a (entry 2). Catalysts with higher reactivity than DMAP also proved ineffective (entries 3 and 4). In an intriguing development, the acetylation of the β-hydroxy group was achieved efficiently using Ac₂O and DMAP, without the necessity for DBU (entry 5). Given the effectiveness of these acetylation conditions for the bulky tert-alcohol group, we employed a one-pot synthesis strategy. This approach involved acetylation with Ac₂O and DMAP at ambient temperature, followed by an elimination reaction initiated by adding DBU under reflux conditions in a single vessel (entry 6). Consequently, the desired β,β-disubstituted α,β-unsaturated ester 6a was synthesized with a commendable yield of 87% and high stereoselectivity (94:6), accompanied by a minor formation of the isomerized by-product 7a at a 3.0% yield. Following the acetylation of the β-hydroxy group with Ac₂O and DMAP in toluene at room temperature, the reaction mixture was subjected to short column chromatography to eliminate excess DMAP. The mixture in toluene was then refluxed in the presence of DBU (entry 7). This procedure ultimately yielded compound 6a with an 85% yield and maintained high stereoselectivity (94:6), while reducing the isomerized by-product 7a to a 1.5% yield.⁵²⁾

Table 1. Optimization Study of Elimination Reaction of Compound 4a

Entry	Ac2O (equiv.)	Activating reagent (equiv.)	DBU (equiv.)	Temperature/time	6		5a	7a
					Yield (%)	6A/6Ba)	Yield (%)	Yield (%)
1	1.1	DMAP (0.1)	5	130 °C/6 h	5	99/1	—	—
2	5	DMAP (5)	10	130 °C/8 h	29	99/1	—	—
3	5	(5)	10	130 °C/8 h	28	99/1	—	—
4	5	(5)	10	130 °C/6 h	45	99/1	—	—
5	5	DMAP (5)	—	r.t./19 h	—	—	90	—
6	4	DMAP (4)	5	r.t./24 h → 130 °C/6 h	87	94/6	—	3.0
7b)	4	DMAP (4)	5	r.t./17 h → 130 °C/6 h	85	94/6	—	1.5

a) Selectivities were determined by ¹H-NMR measurement. b) After the acetylation using Ac₂O and DMAP at room temperature was completed, the mixture was passed through short column chromatography, and then the mixture was refluxed in the presence of DBU.

Upon establishing optimal reaction conditions, we investigated the substrate scope⁵³⁾ (Table 2). Aldol compounds 4b–n were synthesized in moderate to excellent yields via the aldol reaction of acetic ester derivatives with ketones. Initially, we assessed the impact of the electrophilic properties of substituents on the aromatic ring at the β-position (entries 2–6). In all instances, the targeted compounds 6b–f were obtained in good to excellent yields with high stereoselectivities, regardless of the substituent's electrophilicity on the aromatic ring. Notably, the use of a substrate containing a methyl group at the ortho position of the aromatic ring resulted in an inversion of the stereoselectivity of product 6g (entry 7). Subsequently, we examined the effect of heteroaromatic rings at the β-position. The furan and thiophene rings were well-tolerated, resulting in the formation of compounds 6h and 6i with good to excellent yields and high stereoselectivity (entries 8 and 9). However, the reaction involving the N-methylpyrrole ring reversed the stereoselectivity of product 6j, similar to the observed behavior with compound 6g (entry 10). The outcomes for compounds 6g and 6j indicate that the steric hindrance of the substituent on the aromatic ring significantly impacts the stereoselectivity of the products in the elimination reaction.⁵⁴⁾ The reaction with substrate 6k, containing an ethyl ester group instead of a tert-butyl ester group, achieved a good yield with high stereoselectivity (entry 11). Additionally, we explored reactions using substrates with bulkier substituents than the methyl group at the β-position to evaluate the influence of the alkyl group at this position (entries 12–14). Substrate 4l, featuring a trifluoromethyl group, which is a slightly bulkier substituent than the methyl group, yielded the desired product 6l in good yield; however, an inversion of stereoselectivity was noted, as observed with compounds 6g and 6j (entry 12). Unfortunately, the reaction of 4m, which bears an n-propyl group, resulted in a poor yield of 6m, along with a significant amount of an isomerized by-product (45% yield) and recovery of the starting material (12% yield) (entry 13). The starting material 4n was recovered from the reaction of a substrate with a c-hexyl group (entry 14).⁵⁵⁾

Table 2. Examination of Scope and Limitations

Entry		R1	R2	R3	4	6
					Yield (%)	Yield (%)	6A/6Ba)
1	a	tBu	Ph	Me	96	85	94/6
2	b	tBu	4-Cl-Ph	Me	87	93	93/7
3	c	tBu	4-F-Ph	Me	73	67	96/4
4	d	tBu	4-Br-Ph	Me	78	73	92/8
5	e	tBu	4-Me-Ph	Me	83	78	95/5
6	f	tBu	4-MeO-Ph	Me	79	80	94/6
7	g	tBu	2-Me-Ph	Me	63	70	36/64
8	h	tBu		Me	61	90	99/1
9	i	tBu		Me	64	91	99/1
10	j	tBu		Me	83	60	9/91
11	k	Et	Ph	Me	71	87	96/4
12	l	tBu	Ph	CF3	72	63	7/93
13	m	tBu	Ph	nPr	98	37	87/13
14b)	n	tBu	Ph	cHex	89	—	—

a) Selectivities were determined by ¹H-NMR measurement. b) Starting material 4n was quantitatively recovered.

In summary, we have developed a concise and highly stereoselective method for synthesizing β,β-disubstituted α,β-unsaturated esters 6. In our study, we observed that the acetylation of bulky tert-alcohol derivatives proceeded efficiently using Ac₂O and DMAP without DBU as a base. Moreover, the formation of undesired isomerized byproducts during the elimination reaction was suppressed by removing excess DMAP prior to the reaction. These findings facilitate the synthesis of various β,β-disubstituted α,β-unsaturated esters. Further research into the synthesis of tetrasubstituted alkenes and asymmetric syntheses using β,β-disubstituted α,β-unsaturated esters is ongoing.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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