Stereoselective synthesis of (E)-α,β-unsaturated esters: triethylamine-catalyzed allylic rearrangement of enol phosphates

Abstract

α,β-Unsaturated esters are key structural motifs widely distributed in various biologically active molecules, and their Z/E-stereoselective synthesis has always been considered highly attractive in organic synthesis. Herein, we present a >99% (E)-stereoselective one-pot synthetic approach towards β-phosphoroxylated α,β-unsaturated esters via a mild trimethylamine-catalyzed 1,3-hydrogen migration of the corresponding unconjugated intermediates derived from the solvent-free Perkow reaction between low-cost 4-chloroacetoacetates and phosphites. Versatile β,β-disubstituted (E)-α,β-unsaturated esters were thus afforded with full (E)-stereoretentivity by cleavage of the phosphoenol linkage via Negishi cross-coupling. Moreover, a stereoretentive (E)-rich mixture of a α,β-unsaturated ester derived from 2-chloroacetoacetate was obtained and both isomers were easily afforded in one operation.

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α,β-Unsaturated carbonyl motifs, such as the relevant esters, amides, and aldehydes, are widely distributed in biologically active molecules as key structural components (Fig. 1).^1–4 Generally, the (Z) and (E)-isomers of those molecules possess very different living activities.⁵ Moreover, ubiquitous α,β-unsaturated esters are also widely employed as useful intermediates for enantioselective hydrogenation,⁶ allylic substitution,⁷ conjugate addition,⁸ and especially for the stereoselective generation of acyclic substituted alkenes in either (Z) or (E)-isomeric forms.⁹

Fig. 1 Selected bioactive α,β-unsaturated carbonyl motifs.

Whilst numerous methods have been developed towards α,β-unsaturated esters,^10–13 configuration-retentive transition-metal catalyzed (TMC) cross-coupling of alkenyl (pseudo)halides is universally recognized as one of the most practical methodologies.¹⁴ Among the known non-classical pseudohalides,¹⁵ diethylphosphoroxyl (DEP) functionality has been proved as a good leaving group in many organic reactions and the corresponding enol phosphates (EPs), possessing high stability and accessibility, were found to participate in various organic transformations.¹⁶ Particularly, EPs have been utilized in many types of TMC coupling reactions including Suzuki–Miyaura, Stille, Negishi, and Heck reactions by cleavage of the enol-linkage affording highly substituted alkenes.¹⁷ However, the EPs-involved (Z) and (E)-stereocomplementary synthetic method towards α,β-unsaturated esters with sufficient substrate generality is still quite limited at present. The latest impressive approach was reported by Tanabe group, which employed N-methylimidazole (NMI)-promoted phosphorylation of β-ketoesters to obtain (Z) and (E)-α,β-unsaturated esters, but which suffers from pre-activation of the unstable diphenyl phosphorochloridate (DPPCl) and usage of strong metallic tert-butoxide bases.¹⁸ Based on our recent progress in regioselective solvent-free synthesis of EPs,¹⁹ we envisioned that phosphoroxylated (Z) and/or (E)-α,β-unsaturated esters may act as the universal synthon of α,β-unsaturated esters and should be facilely obtained from the commercially available and low-cost chloroacetoacetates and phosphites via a simple metal-free Perkow reaction. Herein, we wish to present a stereoselective one-pot synthetic approach towards β-phosphoroxylated (E)-α,β-unsaturated esters, which are subsequently converted into the corresponding disubstituted α,β-unsaturated esters by Negishi cross-coupling (Scheme 1).

Scheme 1 E-Stereoselective synthesis of α,β-unsaturated esters from enol phosphates.

Since both 2-chloroacetoacetates and 4-chloroacetoacetates are capable of undergoing Perkow reaction with phosphites, we then took them together for comparison. Solvent-free Perkow reaction conditions were initially selected in view of high regioselectivity.¹⁹ As shown in Scheme 2, reaction between (EtO)₃P and 2-chloroacetoacetate 2a gave a mixture of (E) and (Z)-isomers of β-phosphoroxylated α,β-unsaturated ester 4a in ratio of 2.6 : 1, whereas reaction between (EtO)₃P and 4-chloroacetoacetate 3a gave the β-phosphoroxylated allylic ester 5a as the only product. In other words, only moderate E/Z-stereoselectivity can be achieved if using 2-chloroacetoacetate, while no conjugated EP product can be obtained if using 4-chloroacetoacetate. However, according to Seeman's report that bases, such as NaH, are supposed to be able to promote 1,3-hydrogen relocation of allyl compounds, we then suspect that the unconjugated EP product 5a may be able to be transformed into the conjugated one in a stereoselective way.²⁰

Scheme 2 Perkow reaction of phosphite with chloroacetoacetate.

Inspired by the above idea, we then turned to examine the possibility of the base-promoted 1,3-hydrogen rearrangement of 5a. As shown in Table 1, among the eight kinds of bases examined, including inorganic t-BuOK, CH₃ONa, NaOH, NaH, K₂CO₃, and organic Et₃N, Pyridine (i-Pr)₂NEt, only Et₃N and (i-Pr)₂NEt exhibited the supposed promoting abilities, affording the desired product E-4a, but encouragely both in >99% (E)-stereoselectivity. Though only 20% yield was obtained by 1.2 equivalent (i-Pr)₂NEt after 24 h reaction in THF at room temperature (Table 1, entry 8), while up to 90% yield was acquired by using Et₃N (Table 1, entry 6). The following screening of solvents demonstrated that acetonitrile seemed to the best choice that the reaction could be accomplished in only 4 h and gave a higher yield of 92% (Table 1, entry 10). Further investigation about the loadage of Et₃N showed that only 0.1 equivalent Et₃N was sufficient to promote the rearrangement effectively, affording the comparative yield though with a few longer time of 12 h (Table 1, entry 14). Less loadage of Et₃N and lower temperature both led to much longer reaction times (Table 1, entry 15&16). Though the reaction time could be shortened to 4 h at a higher temperature of 80 °C (Table 1, entry 17), we finally preferred the more benign room temperature for the following preparations.

Table 1 Optimization of base-promoted 1,3-hydrogen rearrangement of unconjugated β-phosphoroxylated allylic ester 5a ^a

Entry	Base	Load (x eq.)	Solvent	T (^oC)	Time (h)	Yield^b (%)	E/Z (4a)^c
a Reaction conditions: 5a (1.0 equiv.), base (x equiv.), solvent (3 ml).b Isolated yields.c Determined by NMR.
1	t-BuOK	1.2	THF	rt	24	0	—
2	CH3ONa	1.2	THF	rt	24	0	—
3	NaOH	1.2	THF	rt	24	0	—
4	NaH	1.2	THF	rt	24	0	—
5	K2CO3	1.2	THF	rt	24	0	—
6	Et3N	1.2	THF	rt	24	90	>99 : 1
7	Pyridine	1.2	THF	rt	24	0	—
8	(i-Pr)2NEt	1.2	THF	rt	24	20	>99 : 1
9	Et3N	1.2	CH3CN	rt	4	92	>99 : 1
10	Et3N	1.2	DCM	rt	20	90	>99 : 1
11	Et3N	1.2	CH3OH	rt	22	83	>99 : 1
12	Et3N	1.2	DMF	rt	24	75	>99 : 1
13	Et3N	0.5	CH3CN	rt	7	92	>99 : 1
14	Et3N	0.1	CH3CN	rt	12	92	>99 : 1
15	Et3N	0.05	CH3CN	rt	20	93	>99 : 1
16	Et3N	0.1	CH3CN	0	24	95	>99 : 1
17	Et3N	0.1	CH3CN	80	4	90	>99 : 1

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Considering the convenience of experimental operation, we then turned into the possibility of one-pot manipulation. It was found that product E-4a was afforded in 92% yield if using the crude intermediate 5a directly for the subsequent rearrangement reaction. Therefore, a mild E-stereoselective one-pot synthetic approach of β-phosphoroxylated α,β-unsaturated esters was thus established: 3 (1.0 eq.) and P(III)-reagents (1.0 eq.) react 1 h at 40 °C neatly, then added triethylamine (0.1 eq.) and acetonitrile (3 mL), and further react about 12 h at room temperature.

Having identified the optimal reaction conditions, we next set out to examine the scope of this new mild one-pot enol phosphorylation procedure (Table 2). As for the different O-alkyl 4-chloroacetoacetate substrates, all the common P(III)-reagents possessing P–O, P–C, and/or P–N bonds gave the corresponding EPs in high yields. During the preparation of compounds 4e and 4f, the rearrangement reactions were found much accelerated probably due to the higher reactivities of phosphonite and phosphinite compared to phosphites. To demonstrate the practical utility, the reaction towards product 4a was performed at the 50 mmol scale and 92% yield was obtained. The stereoscopic (E)-configuration of solid product 4f was further confirmed by single crystal X-ray analysis.

Table 2 Scope of β-phosphoroxylated (E)-α,β-unsaturated esters^a,b

a Reaction conditions: 1 (1.0 mmol), 3 (1.0 mmol), Et₃N (0.1 mmol), CH₃CN (3.0 mL).b Isolated yields.

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With the E-stereospecific β-phosphoroxylated α,β-unsaturated esters in hand, we then investigated their stereoretentive Negishi cross-coupling to prepare the corresponding E-stereodefined disubstituted α,β-unsaturated esters. Among the typical catalysts screened including Pd(PPh₃)₄, Ni(acac)₂ and Pd(dppb)Cl₂, the latter demonstrated the best performance in this Negishi reaction with only 0.02 equivalent loading by refluxing in acetonitrile. Various aromatic ArZnCl nucleophiles containing electron-donating and/or electron-withdrawing substituents at ortho, meta, and/or para positions were all tolerated well, affording the desired products in good to excellent yields (80–96%) without generating any stereochemical integrity (Table 3, 6a–6m). Disubstituted, condensed and hetero aromatic organometallic substrates also gave 85–92% yields of the products (Table 3, 6n–6r). However, it's regrettable that alkyl organozinc reagents was found unreactive under such conditions.

Table 3 Scope of (E)-α,β-unsaturated esters via a stereoretentive Negishi cross-coupling reaction of 4a ^a,b

a Reaction conditions: 4a (1.0 mmol), ArMgBr (1.5 mmol), ZnCl₂ (1.5 mmol), Pd(dppb)Cl₂ (0.02 mmol), CH₃CN (5.0 mL), reflux about 3 h.b Isolated yields.

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Furthermore, under the above optimal Negishi cross-coupling reaction conditions, both (Z) and (E) isomers of α,β-unsaturated esters 6a could be easily achieved, just by one operation, directly from the (Z) and (E) mixture of 4a in 22% and 70% yields respectively (Scheme 3).

Scheme 3 Preparation of (Z) and (E) isomers of 6a in one operation.

According to the Cram's mechanistic interpretation for the allylic rearrangements, an intra-molecular pathway of the Et₃N-promoted stereoselective 1,3-hydrogen rearrangement of the EPs 5a was proposed because that the degree of the observed intramolecularity depended strongly on the base and solvent used.²¹ As shown in Scheme 4, triethylamine firstly removes the proton from the α-carbon position of ester 5a, resulting in a coplanar anionic allylic system by three carbon atoms. The hydrogen atom of the H–Et₃N ammonium then bonds to both terminal carbon atoms to form the intermediate Int, collapse of which would then give the thermodynamically favourable conjugated α,β-unsaturated ester product E-4a.

Scheme 4 Proposed (E)-stereospecific allylic rearrangement mechanism.

In summary, a mild and environmental trimethylamine-catalyzed E-stereoselective 1,3-hydrogen allylic rearrangement of enol phosphates was firstly developed to afford versatile β-phosphoroxylated (E)-α,β-unsaturated esters which can be then efficiently converted into the corresponding β,β-disubstituted (E)-α,β-unsaturated esters in high yields by a 100% stereoretentive Negishi cross-coupling reaction. Moreover, both (Z) and (E)-α,β-unsaturated esters were able to be achieved in one manipulation when just employing 2-chloroacetoacetate instead of 4-chloroacetoacetate for the solvent and metal-free Perkow reaction.

It is interesting to note that more structure-diverse α,β-unsaturated esters should be easily obtained by derivation reactions at the allylic position of α,β-unsaturated esters and/or by utilizing 2-substituted 4-chloroacetoacetates as the starting materials.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Full experimental details and analytical data. CCDC 2250165. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ra02430j

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