A Facile and Convenient Synthesis of Trisubstituted (E)-α,β-Unsaturated Esters by Tandem Acetylation-E1cB Reaction

Abstract

A facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in β-hydroxy esters, furnishing α,β-unsaturated esters in shorter steps than the previous method: an acetylation of β-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,β-unsaturated esters.

Introduction

Trisubstituted (E)-α,β-unsaturated esters are one of the most important substrates in organic reactions, such as the Michael addition or the Diels–Alder reaction.^1–5) Natural products having such structures as partial units have attracted organic chemists as well as biologists because of their potent biological and pharmacological activities.^6–11) It is well known that the geometry of α,β-unsaturated esters is reflected in the stereochemistry of the product in various stereoselective reactions. In addition, the biological activities of bioactive compounds including a natural product could be dramatically affected by the geometry of the carbon–carbon double bond.^6,9,12) The Wittig reaction and the Horner–Wadsworth–Emmons reaction have been classically employed as reliable methods for the synthesis of α,β-unsaturated carbonyl compounds; however, these reactions include tedious procedure such as the preliminary preparation of humidity-sensitive ylide derivatives and removal of large amounts of byproducts, e.g., phosphonates or phosphine oxides.^13–16) Thus, many studies on the stereoselective synthesis of trisubstituted (E)-α,β-unsaturated carbonyl compounds have been carried out. For example, E-selective synthesis of trisubstituted (E)-α,β-unsaturated esters based on chemistry of ynolate intermediates were reported by Kowalski and Shindo, independently.^17,18) Verkade and colleagues reported the synthesis of trisubstituted (E)-α,β-unsaturated esters by utilizing expensive pro-azaphosphatrane as the strong base; however the method was not applicable to the synthesis of α,β-unsaturated esters bearing an aliphatic chain at the β-position.¹⁹⁾ Ma and colleagues reported synthesis by an Ni complex-catalyzed carbonylation of alkyne, in which a decrease in regioselectivity was observed in several cases.²⁰⁾ The Baylis–Hillman reaction has been utilized as the key reaction for the synthesis of trisubstituted (E)-α,β-unsaturated esters to date.^21–26) However, the Baylis–Hillman reaction commonly requires a long reaction time, which is a disadvantage for easy access to the desired compound. Synthesis involving the stereoselective elimination of α-substituted β-hydroxy carbonyl derivatives has also been reported by several groups.^5,27–31) Among them, the direct conversion of β-hydroxy carbonyl compounds into α,β-unsaturated carbonyl compounds is a promising method for the practical synthesis: Concellón et al. reported the elimination reaction of SmI₂ and α-halo-β-hydroxy esters,²⁷⁾ in which the preliminary preparation of α-halo-β-hydroxy esters as the substrate of the elimination reaction was required. The synthesis involving the stereospecific dehydration of simple β-hydroxy ester derivatives by ethyldimethylaminopropylcarbodiimide (EDC)/CuCl₂ was reported by Ohmizu and colleagues.^28,29) In that reaction, the use of a single diastereomer of β-hydroxy esters was essential to achieve high E/Z stereoselectivity. Marcantoni and colleagues reported the stereoselective elimination reaction of β-hydroxy carbonyl compounds that used CeCl₃-7H₂O/NaI³⁰⁾; however, that reaction had a limitation that a tert-butyl ester derivative could not be used as the substrate.

Meanwhile, we have reported a practical and highly E stereoselective synthesis of trisubstituted (E)-α,β-unsaturated esters³²⁾ (Chart 1a). Our method consists of three well-known reactions, i.e., the aldol reaction, the acetylation of the β-hydroxy group, and the E1cB reaction using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Herein, we emphasize that the method does not require separation of the diastereomeric mixture of β-hydroxy esters prior to the E1cB reaction. Thus, we endeavored to develop a more facile synthesis of trisubstituted (E)-α,β-unsaturated esters by improving our previous method (Chart 1b): the new method furnished trisubstituted α,β-unsaturated esters in shorter steps than the previous method by conducting an activation of the β-hydroxy group in β-hydroxy ester derivatives by acetylation and the successive E1cB reaction in tandem.

Chart 1. Synthesis of Trisubstituted (E)-α,β-Unsaturated Esters by Our Previous Work and This Work

Results and Discussion

First, to optimize the reaction conditions, we examined the synthesis of trisubstituted (E)-α,β-unsaturated ester 3a by the stereoselective E1cB reaction of α-substituted-β-hydroxy ester 1a (Table 1), which was conventionally prepared from the aldol reaction of tert-butyl propionate with benzaldehyde in 83% yield with dr 1.5 : 1 diastereomeric mixture. When diastereomeric mixture 1a was subjected to the reaction using acetic anhydride (Ac₂O) and a catalytic amount of 4-dimethylaminopyridine (DMAP) in pyridine under reflux conditions, acetylated compound 2a was obtained in 86% yield without any other products (entry 1). This result indicated that the basicity of pyridine was insufficient for the E1cB reaction. Next, we conducted the reaction in the presence of DBU as the base, i.e., 1a was subjected to the reaction using 5 eq of DBU in the presence of Ac₂O (2.5 eq) and DMAP (0.1 eq) in toluene reflux (130°C), and desired compound 3a was obtained in 95% yield with E/Z = 98/2 (entry 2). Moreover, we succeeded in reducing the amount of Ac₂O to 1.1 eq from 2.5 eq under similar reaction conditions to entry 2 (entry 3). It should be noted that the present method was capable of the one-step conversion of 1 into 2 without the separation of a compound having an activated leaving group prior to the E1cB reaction: tandem acetylation-E1cB reaction.

Table 1. Optimization Study of Direct E1cB Reaction

Entry	Ac2O (eq)	DMAP (eq)	Base (eq)	Solvent	Temp./time	3a		2a yield (%)
						Yield (%)	E/Z a)
1	5.0	0.1	—	Pyridine	r.t./1 h→120°C/2 h	—	—	86
2	2.5	0.1	DBU (5.0)	Toluene	r.t./0.5 h→130°C/2 h	95	98/2	—
3	1.1	0.1	DBU (5.0)	Toluene	130°C/4 h	98	99/1	—

a) Selectivities were determined by ¹H-NMR measurement.

Having established the optimized reaction conditions, we set out to explore the substrate scope (Table 2). First, we examined the synthesis of trisubstituted (E)-α,β-unsaturated esters 3 having an aromatic ring at the β-position. Excellent yields and high stereoselectivities were observed regardless of the electrophilic property of the substituent on the aromatic ring in all cases (entries 1–5). The reactions using 1g–i possessing a heteroaromatic ring at the β-position also provided 3g–i in good to excellent yields with high stereoselectivities (entries 6–8). Next, to examine the influence of an α-substituent, reactions using a substrate having a bulkier substituent than a methyl group were conducted (entries 9–12). β-Hydroxy esters 1j–l having ethyl, benzyl, and isopropyl groups as the α-substituent afforded desired compounds 3j–l in good to excellent yields with relatively high stereoselectivities (entries 9–11). On the other hand, the reaction of substrate 1m having a phenyl group as the α-substituent resulted in an unsatisfactory yield because of the decomposition of 1m by the retro-aldol reaction. Thus, we examined a one-pot reaction that consisted of the acetylation of the β-hydroxy group under mild reaction conditions followed by the E1cB reaction of the acetylated intermediate in a vessel: After 1m was acetylated by Ac₂O and DMAP without DBU in toluene at room temperature, the subsequent E1cB reaction was carried out by the addition of DBU under reflux conditions. As a result, the desired compound 3m was provided in excellent yield with good geoselectivity in one-pot (entry 12). Finally, we explored the applicability of the synthesis to compounds bearing an aliphatic substituent, the reports of which have been few to date²⁴⁾ (entries 13–15). In the cases of substrates 1n and 1o bearing n-hexyl or c-hexyl groups, both reactions afforded desired compounds 3n and 3o in good yields with high stereoselectivities (entries 13 and 14). Unfortunately, the reaction using 1p possessing a t-butyl group resulted in an unsatisfactory yield because the acetylation of the β-hydroxy group did not procced successfully due to the bulkiness of tert-butyl group at β-position. Moreover, the partial decomposition of 1p was observed under the reflux condition used excess reagents (Ac₂O, DBU) to improve the reactivity. Thus, we examined the synthesis by a similar one-pot reaction to the case of compound 3m: 1p was subjected to the acetylation using Ac₂O and DMAP without DBU in toluene at room temperature followed by the E1cB reaction in the presence of DBU under reflux conditions, affording desired 3p in higher yield than that of the previous method (entry 15).

Table 2. Scope and Limitations

^aSelectivities were determined by ¹H-NMR measurement. ^bAfter the acetylation at room temperature was completed, the reaction was refluxed in the presence of DBU. ^cYield and E/Z ratio of 3 by “previous method” meant two-step yield and E/Z ratio from 2 to 3 in our previous report.³²⁾

Regarding the stereoselectivity on the elimination reaction of diastereomeric mixture 1, we consider that the stereoselectivity of the product would be determined on the elimination step not isomerization of the product under thermal reaction condition.³³⁾ As we reported previosly,³²⁾ the E1cB reaction predominantly proceed over an E2 reaction in the present elimination reaction; actually, there are reports that use either a p-toluenesulfonyl group or a methanesulfonyl group as stronger leaving group than the acetyl leaving group, which used in our reaction, decreased the selectivity.^5,31) Thus, high stereoselectivity could be achieved in spite of the fact that the substrate of diastereomeric mixture was employed in the elimination reaction.

In conclusion, we succeeded in the development of a facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters based on our previous method. The new method is capable of the synthesis of trisubstituted (E)-α,β-unsaturated esters more easily than the previous method by tandem acetylation-E1cB reaction: The activation of the β-hydroxyl group in 1 by the acetylation followed by E1cB reaction proceeded in tandem, enabling to circumvent the separation of intermediates having an activated leaving group before the E1cB. Also, the new method can employ diastereomeric mixture 1 as the substrate for the E1cB reaction as well as our previous method and has a wide substrate scope for the synthesis of various trisubstituted (E)-α,β-unsaturated esters. Further studies of the application to the synthesis of multisubstituted alkenes and the asymmetric synthesis using these α,β-unsaturated esters are in progress.

Acknowledgments

This research was financially supported in part by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities, JSPS KAKENHI Grant Number JP22590024, and a Strategic Research Foundation Grant-Aided Project for Private Universities from MEXT, Grant Number S1511024L.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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