Well-defined chiral dinuclear copper-catalyzed tandem asymmetric propargylic amination–carboxylative cyclization sequence toward chiral 2-oxazolidinone derivatives

Abstract

We report a novel strategy for the synthesis of chiral 2-oxazolidinones via a dinuclear copper-catalyzed asymmetric propargylic amination–carboxylative cyclization sequence of propargylic esters with nucleophilic alkyl amines under ambient pressure of carbon dioxide. A variety of chiral 2-oxazolidinones featuring an exocyclic methylene moiety was obtained in good yields with high enantioselectivities via a one-pot operation.

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Introduction

Five-membered heterocyclic compounds like 2-oxazolidinones have found wide ranging applications in medicinal chemistry, organic synthesis and agrochemistry (Scheme 1a).¹ Moreover, chiral 2-oxazolidinones have been shown to be of great significance in the realm of asymmetric synthesis, serving as a versatile class of chiral auxiliaries or ligands in the stereoselective synthesis of enantioenriched compounds.² Therefore, the efficient synthesis of chiral 2-oxazolidinones and their derivatives is of great interest in organic chemistry and medicinal sciences.³

Scheme 1 Asymmetric propargylic amination–carboxylative cyclization sequence toward chiral 2-oxazolidinone derivatives.

Utilization of carbon dioxide (CO₂) as an inexpensive, nontoxic, and renewable C1 feedstock has attracted attention in the past decades.⁴ A variety of methods has been developed for the synthesis of achiral 2-oxazolidinones through the cyclization of propargylamines and carbon dioxide.⁵ However, the use of CO₂ in catalytic asymmetric tandem reactions for the synthesis of chiral 2-oxazolidinones in one pot is largely underdeveloped.^6,7 In this context, two elegant methods have been developed for the synthesis of chiral N-aryl 2-oxazolidinones based on a tandem process, including the synthesis of chiral propargylamines from an asymmetric aldehyde–alkyne–amine (A³) coupling reaction⁶ or an asymmetric transfer hydrogenation of alkynyl ketimines,⁷ followed by a carboxylative cyclization with CO₂. However, the synthesis of chiral 2-oxazolidinones bearing an exocyclic methylene motif has been less explored. Therefore, the development of a novel catalytic strategy for the asymmetric synthesis of chiral 2-oxazolidinones derivatives is still highly desirable.³

Although various bi/multi-nuclear copper complexes have been reported,⁸ their applications in asymmetric catalysis are still much less developed.⁹ Recently, we disclosed the successful development of a series of binuclear copper catalysts¹⁰ based on chiral benzo[c]cinnoline dioxazoline frameworks,¹¹ and their applications in catalytic asymmetric propargylic substitution reactions. Since van Maarseveen and Nishibayashi's pioneering work in 2008,¹² copper-catalyzed asymmetric propargylic amination of propargylic esters has been an efficient method for the synthesis of chiral propargyl amines.¹³ Herein, we report a novel strategy for the synthesis of chiral 2-oxazolidinones via a dinuclear copper-catalyzed asymmetric propargylic amination–carboxylative cyclization sequence of propargylic esters with alkyl amine hydrochlorides under an ambient pressure of carbon dioxide (Scheme 1b).¹⁴ A variety of chiral 2-oxazolidinones featuring an exocyclic methylene motif and a N-alkyl group was obtained in good yields with excellent enantioselectivities.

Results and discussion

Reaction development and scope

The studies were initiated by taking the reaction of propargyl carbonate (1a) with benzylamine hydrochloride (2a) under an atm of CO₂ as the model reaction and the feasibility of the proposed asymmetric propargylic amination–carboxylative cyclization sequence using the binuclear Cu complexes C₁–C₈ as catalysts was investigated. A careful survey of the reaction parameters using catalyst C₁ revealed that the reaction proceeded well in CF₃CH₂OH at room temperature for 36 h in the presence of ^tBuONa (2.0 equiv.) and Ag₂CO₃ (30 mol%) as additives, affording the desired product 3aa in 51% yield with 73% ee (Table 1, entry 1). Under otherwise identical conditions, other bicopper catalysts, C₂–C₈, with different substituents on the oxazoline units or the cinnoline backbone of the ligands were subsequently evaluated in the reaction (Table 1, entries 2–8). The reaction catalyzed by C₂, with a benzyl group on the oxazoline unit, gave product 3aa in 54% yield with 70% ee (entry 2). To our delight, upon using catalyst C₃ with the ligand derived from 2-aminoindanol, the desired product 3aa was obtained with an improved ee value of 79% (entry 3). The reaction using catalyst C₄, with increased steric hinderance of the oxazoline units, led to a significant improvement in the ee to 85% (entry 4). Using catalyst C₅ featuring further enhanced steric hindrance of the oxazolyl moiety, the ee value of 3aa was increased to 87% (entry 5). Proceeding further by using C₆ bearing cyclohexyl groups on the indanyl scaffold as the catalyst, the reaction afforded 3aa in good isolated yield (64%) with excellent enantioselectivity (91% ee, entry 6). However, the introduction of an electron-withdrawing (–Br) group on the indanyl scaffold of catalyst C₇ significantly decreased the enantioselectivity of the reaction (entry 7). In addition, catalyst C₈, with large steric hinderance on the indenyl scaffold, was also tested, resulting in poor catalytic performance (47% yield, 70% ee) (entry 8). Furthermore, various silver salts had similar impact on the reaction and Ag₂CO₃ was found to be optimal for the reaction (see the ESI† for reaction details). In addition, free benzylamine was also tested under the optimized conditions (as shown in entry 6), and the desired product was obtained in 74% yield with slightly lower ee (88%). In comparison to free amines, amine hydrochloride salts present a more appealing option due to their widespread commercial availability, cost-effectiveness, and relative stability under atmospheric conditions.¹⁵

Table 1 Investigation of the dinuclear copper-catalyzed asymmetric propargylic amination–carboxylative cyclization sequence^a

Entry	Cat.	Yield^b (%)	ee^c (%)
a Unless otherwise noted, reaction conditions are as follows: 1a (0.1 mmol), 2a (0.15 mmol), ^tBuONa (2.0 equiv.), Ag2CO3 (30 mol%), Cx (2 mol%), CF3CH2OH (1 mL), rt, 36 h. b ^1H NMR yield using mesitylene as the internal standard. c The ee value of 3aa was determined by HPLC on a chiral column IA. d Isolated yield.
1	C1	51	73 (S)
2	C2	54	70 (S)
3	C3	49	79 (R)
4	C4	64	85 (R)
5	C5	59	87 (R)
6	C6	70 (64)^d	91 (R)
7	C7	54	65 (R)
8	C8	47	70 (R)

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Reaction scope

Under the optimized reaction conditions, the scope of propargyl carbonates 1 was first explored in the reaction with benzylamine hydrochloride 2a, and the results are shown in Scheme 2a. The propargyl carbonates bearing either electron-donating (–^tBu) or electron-withdrawing (–F, Cl, Br, CF₃, –OCF₃ and pyridine-containing carbonate) substituents at the para-position of the aryl group reacted smoothly with 2a, affording the corresponding 2-oxazolidinones 3ba–3ha in 42–66% yields with 90–92% ee. Substrates bearing meta-methyl, meta-chloro, and 3,4,5-trimethoxy substituted arenes were also amenable to the procedure, and the reactions provided 3ia–3ka in good yields (40–72%) with 80–91% ee. However, the reactions using the cycloalkyl substituted propargylic carbonate 1l only provided a trace amount of the corresponding product 3la.

Scheme 2 Substrate scope. Reaction conditions: unless otherwise noted, all reactions were carried out using 1 (0.1 mmol), 2 (0.15 mmol), ^tBuONa (2.0 equiv.), Ag₂CO₃ (30 mol%), C₆ (2.0 mol%), CF₃CH₂OH (1.0 mL), rt, 36 h. ^a Leaving group of the propargyl substrate = OBoc.

Subsequently, the scope of alkyl amines hydrochloride 2 was further evaluated in the reactions with propargyl carbonate 1a (Scheme 2b). To our delight, this catalytic system exhibited good tolerance toward various hydrochloride salts of alkyl amines. For instance, the reactions of benzylamines bearing either electronic donating (–Me, and –^tBu) or withdrawing (–F, –Br, –I and –CN) groups on the phenyl ring afforded the corresponding products 3ab–3ag in 44–67% yields with good enantioselectivities (87–96% ee). Changing the substituents of the benzylamines from the para- to meta- or ortho-position had no negative effect on the catalysis, smoothly leading to products 3ah–3al in 45–69% yields with 86–92% ee. The absolute configuration of 3ah was established as (R) by X-ray crystallography (CCDC 2356244†), while those of other chiral 2-oxazolidinone products were assigned by analogy. The catalytic system also turned out to be effective for the reactions of poly-substituted benzylamines 2m–2o, giving the corresponding products 3am–3ao in 44–55% yields with 80–95% ee. Furthermore, amine substrates containing an α- or a β-naphthyl group (2p and 2q) were compatible with the protocol, and the reactions gave the corresponding products 3ap and 3aq in 83–88% yields with 93–96% ee. In addition, a primary amine hydrochloride bearing a long alkyl chain, such as 2r, was also a suitable substrate, leading to the formation of the desired 2-oxazolidinone 3ar in 40% yield with 80% ee. Notably, a variety of important functional groups, including –OMe, –F, –Br, –Cl, –I, –CF₃, –OCF₃, –CO₂Me, –CN, and –NO₂, was tolerated in the reaction, and the corresponding products showed good compatibility for downstream transformations.

Synthetic applications and control experiments

5-Methylene 2-oxazolidinones are useful chiral building blocks, as demonstrated by a two-step transformation of 3aa to the synthetically useful chiral γ-amino alcohol 4aa without any erosion of ee value (Scheme 3a). In addition, catalytic hydrogenation of the exocyclic C=C double bond of 3aa using Rh(PPh₃)₃Cl as the catalyst provided (4R,5R)-4ab in high yield (78%) with excellent diastereoselectivity (>95 : 5 dr). To gain an insight into the reaction mechanism, control experiments were carried out (Scheme 3b). Under otherwise standard conditions, the reaction of 1a and 2a in the absence of Ag₂CO₃ delivered the target product 3aa in a low yield of only 21% with 91% ee, along with the generation of a substantial amount of 3aa′ with similar ee value (66%, 90% ee), suggesting that Ag₂CO₃ might promote the carboxylative cyclization of 3aa′ in the title reaction. This was confirmed by the reaction of the intermediate 3aa′ with CO₂ and without Ag₂CO₃ or the Cu catalyst; in this case, the cyclization product 3aa was formed in only 19% yield. In contrast, the reaction of intermediate 3aa′ with CO₂ in the presence of Ag₂CO₃ or the binuclear Cu catalyst gave 3aa in significantly improved yields of 74% and 70%, respectively. These results indicated that the title reaction is a tandem binuclear Cu-catalyzed asymmetric propargylic amination and Ag₂CO₃ promoted the carboxylative cyclization process. The copper catalyst in the first step may also have positive effect on the cyclization process. In addition, the enantioselectivity of 3aa was determined in the propargylic amination step.

Scheme 3 Synthetic applications and control experiments.

Proposed transition state model

Based on the X-ray crystallographic structure of product 3ah and previous computational studies by our group,¹⁰ we proposed a stereochemical model to rationalize the observed chiral induction of the system using catalyst C₁ (Scheme 4). Due to the large steric bulkiness of the –^tBu and the –OCOC₆F₅ moieties located on the upper part of the ligand plane, the nucleophilic alkyl amines would preferentially attack the terminal carbon of the allene moiety from the bottom side. Subsequent carboxylative cyclization of the resulting chiral propargylamine with CO₂ would form the cycloadduct (S)-3aa with retention of the stereochemistry, which is consistent with the results obtained using C₁ as the catalyst.

Scheme 4 Proposed chiral induction model based on the catalyst C₁.

Conclusions

In summary, we have developed an efficient dinuclear copper-catalyzed asymmetric propargylic amination–carboxylative cyclization sequence of propargylic esters with alkyl amine hydrochlorides and CO₂, affording a variety of chiral 2-oxazolidinones bearing an exocyclic methylene moiety in good yields with high enantioselectivities.

Author contributions

Y. L., Q. C., and X. W. directed the project; Y. L., P. L., Z. F., L. S. and Q. C. performed all the experiments and analyzed all the data; Y. L., Q. C, and X. W. wrote the manuscript with contributions from all authors.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors acknowledge financial support from the National Key R&D Program of China (No. 2022YFA1503200), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB0610000), the National Natural Science Foundation of China (92256303, 22171278, and 21821002), the Shanghai Science and Technology Committee (23ZR1482400), the Natural Science Foundation of Ningbo (2023J034) and Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University.

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14. During the submission of this manuscript, a similar Cu-catalyzed reaction via CO₂ shuttling or CO₂ fixation was independently reported: H. Li, J. S. Ma, H. Y. Lu, G. Q. Lin and Z. T. He, Asymmetric Multicomponent Propargylations via Carbon Dioxide Shuttling and Fixation, ACS Catal., 2024, 14, 11646–11656.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 2356244. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01368a

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