Copper-Catalyzed Four-Component A³-Based Cascade Reaction: Facile Synthesis of 3-Oxetanone-Derived Spirocycles

Abstract

3-Oxetanone-derived spirooxazolidines represent a class of building blocks for accessing diverse saturated heterocycles, but their synthetic methods remain unexplored. Herein, we demonstrate a highly atom-economic approach for the synthesis of diverse 3-oxetanone-derived N-propargyl spirooxazolidines via a CuBr₂/TFA co-catalyzed four-component A³-based cascade reaction of a 1,2-amino alcohol, a 3-oxetanone, a formaldehyde, and an alkyne. This strategy is characterized by a wide substrate range and excellent chemoselectivity. In addition, the synthesized spirocycles could also be easily converted into other valuable compounds, facilitating potentially useful synthetic applications.

1. Introduction

In recent years, spirocycles have received increasing attention in drug discovery due to their potential to confer favorable physicochemical and metabolic properties to drug candidates [1,2,3,4,5,6]. As a result, a wide variety of spirocycle scaffolds have been designed and synthesized [7,8,9], and a large number of synthetic methods have been developed to construct these compounds [10,11,12]. Among these, oxetane-containing spirocycles such as 3-oxetanone-derived spirocycles, oxetanyl N,O-acetal spirocycles, and so on exhibit important and valuable properties, including attenuation of the biological activities of the molecules [13,14,15], and have served as building blocks for the development of challenging and creative transformations [16,17,18]. For example, Carreira and co-workers reported a series of ring expansion reactions of oxetanyl N,O-acetal spirocycles to access various saturated heterocycles [19,20]. These results indicate that the incorporation of oxazolidines into 3-oxetanone-derived spirocycles has become an important synthetic intermediate for the synthesis of nitrogen heterocycles. Current synthetic methods for constructing N-substituted oxetanyl N,O-acetal spirocycles, A, mainly involve multi-step reactions of amino alcohols and 3-oxetanone (Scheme 1a) [16,19,20,21,22]. However, a selective one-step synthesis of N-functionalized 3-oxetanone-derived spirooxazolidines, in which the incorporation of an N-functional group can enrich the chemical transformation, has been less thoroughly explored.

Inspired by the success of the construction of oxazolidines from 1,2-amino alcohols [23,24,25], our group has recently focused on the development of selective ring-opening functionalizations of N-propargyl oxazolidines using palladium catalysts or under base-promoted conditions [26,27]. In addition to these reports, we also disclosed the copper-catalyzed domino annulation and A³ reaction of amino alcohols, two kinds of aldehydes, and alkynes to afford the N-propargyl oxazolidines B (Scheme 1b) [28]. Using amino alcohols, 3-oxetanone, aldehydes, and terminal alkynes as the model substrates, we envisaged that further investigation of this domino annulation/A³ reaction might lead to the preparation of spiroheterocycles. However, our previous studies showed that the domino A³-based reaction of a 1,2-amino alcohol, a 3-oxetanone, a formaldehyde, and a phenylacetylene gave only a low yield of the desired spirocyclic compound (

Table 1. Optimization of reaction conditions ¹.

Entry	Catalyst (mol%)	Solvent	Temperature (oC)	Time (h)	Yield (%) 2
1	CuCl2 (20)	DCE	80	10	34
2	CuBr2 (20)	DCE	80	10	41
3	CuBr (20)	DCE	80	10	28
4	CuBr2 (30)	DCE	80	10	40
5	CuBr2 (10)	DCE	80	10	54
6	CuBr2 (10)	CHCl3	60	10	48
7	CuBr2 (10)	1,4-dioxane	80	10	51
8	CuBr2 (10)	toluene	80	10	30
9	CuBr2 (10)	CH3CN	80	10	trace
10	CuBr2 (10)	THF	80	10	31
11	CuBr2 (10)	petroleum ether	80	10	57
12	CuBr2 (10)	n-heptane	80	10	55
13	CuBr2 (10)	n-hexane	80	10	59
14	CuBr2 (10)/TFA (20)	n-hexane	80	10	76
15	CuBr2 (10)/AcOH (20)	n-hexane	80	10	70
16	CuBr2 (10)/conc.HCl (20)	n-hexane	80	10	63
17	CuBr2 (10)/TFA (10)	n-hexane	80	10	73
18	CuBr2 (10)/TFA (30)	n-hexane	80	10	69
19	CuBr2 (10)/TFA (20)	n-hexane	70	10	70
20	CuBr2 (10)/TFA (20)	n-hexane	90	10	71
21	CuBr2 (10)/TFA (20)	n-hexane	80	8	66
22	CuBr2 (10)/TFA (20)	n-hexane	80	12	72

¹ Reaction conditions: starting materials 1a (0.55 mmol), 2 (0.50 mmol), 3a (0.55 mmol), 4a (0.40 mmol), catalyst (10–30 mol%), and solvent (2 mL) were heated in a closed vial tube at 70–90 °C for 8–12 h. ² Isolated yield based on 4a.

, entry 1) [29]. Herein we describe a four-component A³-based cascade reaction for the facile synthesis of 3-oxetanone-derived N-propargyl spirooxazolidines C by using CuBr₂/TFA catalysis (Scheme 1c). This multicomponent domino reaction addresses the challenge of avoiding the generation of byproduct B (R³ = H) and the ring-opening transformation of B to produce dipropargylation of amino alcohol compound 8 [25] (see Table S1 in the Supporting Information), where the introduction of lower activity of 3-oxetanone would make the reaction perform well in forming byproducts B and 8.

2. Materials and Methods

General Information: ¹H NMR, ¹³C, and ¹⁹F spectra were recorded in CDCl₃ operating at 400 MHz, 101 MHz, and 376 MHz, respectively. Proton chemical shifts are reported relative to the residual proton signals of the deuterated solvent CDCl₃ (7.26 ppm). The chemical shifts scale is based on internal TMS. Chemical shifts are reported in δ (parts per million) values. Coupling constants J are reported in Hz. Proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), and multiple (m). High-resolution mass spectra were recorded on a liquid chromatograph mass spectrometer (LCMS-IT-TOF). Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. All solvents were purified and dried according to standard methods prior to use. Products were purified by flash column chromatography on 200–300 mesh silica gel, SiO₂.

General Procedure for the Synthesis of Compound 5: A vial tube was equipped with a magnetic stir bar and charged with substituted amino alcohol 1 (0.55 mmol), 37% formaldehyde solution 2 (0.50 mmol), 3-oxetanone 3a (0.55 mmol), terminal alkyne 4 (0.40 mmol), CuBr₂/TFA (10 mol%/20 mol%), and hexane (2 mL). Then, the tube was sealed and stirred at 80 °C for 10 h. After the reaction was quenched by the addition of a saturated NaHCO₃ solution, the mixture was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate. The concentration in vacuo followed by silica gel column purification with petroleum ether/ethyl acetate eluent gave the desired product.

3. Results and Discussion

We started our studies by investigating the coupling of phenylglycinol 1a, formaldehyde solution 2, 3-oxetanone 3a, and phenylacetylene 4a. To our delight, the target spirooxazolidine 5a was obtained in 34% yield using 20 mol% CuCl₂ as a catalyst and 1,2-dichloroethane (DCE) as a solvent at 80 °C for 10 h (Table 1, entry 1). Further optimization of the reaction conditions, such as the amount and type of catalyst, the type of solvent, the reaction time, and the temperature, was carried out (Table 1). In evaluating the copper catalysts, we found that when the reaction was treated with CuBr₂, the yield of 5a was improved to 41% (Table 1, entry 2). However, CuBr gave a negative result, giving only 28% yield of 5a (Table 1, entry 3). Next, we changed the amount of CuBr₂; with the decrease in the amount of catalyst, there was an upward trend in the yield (up to 54%) (Table 1, entries 4 and 5). From the examination of different solvents, we found that chloroform (CHCl₃), 1,4-dioxane, toluene, acetonitrile (CH₃CN), and tetrahydrofuran (THF) had negative effects on the yield, while some non-polar solvents such as petroleum ether and n-heptane led to positive effects (Table 1, entries 6–12). The highest yield of the product 5a was observed with 59% when n-hexane was introduced (Table 1, entry 13). To our delight, the addition of 20 mol% TFA improved the yield of 5a to 76% (Table 1, entry 14), owing to the addition of acid effectively enhancing the condensation of oxazolidine intermediate with 3-oxetanone (see proposed mechanism). Although other acids such as acetic acid and concentrated hydrochloric acid could also improve the yield of 5a, it was worse than TFA (Table 1, entries 15 and 16). In addition, no better results were observed by changing the amount of TFA (Table 1, entries 17 and 18). Finally, the reaction temperature and time were screened. The results indicated that the reaction was not particularly sensitive to the reaction temperature, and the yield of 5a was slightly reduced by both increasing and decreasing the reaction temperature (Table 1, entries 19 and 20). Prolonging the reaction time to 12 h or reducing the reaction time to 8 h was not sufficient to increase the yield of 5a (Table 1, entries 21 and 22).

Having established an effective protocol, we commenced our investigation of the substrate scope of the reaction (Scheme 2). We first examined the range of amino alcohols 1b–1k. In general, different substituents on the amino alcohols seemed to be well tolerated and gave the corresponding spirooxazolidines 5b–5k with moderate to good yields. For example, changing the steric hindrance of R¹ substituents such as methyl, isopropyl, secbutyl, tertbutyl, isobutyl and benzyl all proceeded smoothly and yielded the desired products, 5b–5g, in 41–87% yields. Other amino alcohols including R¹,R²-disubstituted and substituent-free 1,2-amino alcohols were also evaluated, resulting in the generation of products 5h–5j in moderate to good yields. In addition, the use of 1,3-amino alcohol led to the synthesis of the six-membered spirocycle 5k in 60% yield. Subsequently, the feasibility of alkynes in reaction with phenylglycinol 1a was investigated. A number of phenylacetylenes with different functional groups, including electron-donating (phenyl, methyl, and methoxyl) and electron-withdrawing (fluoro and trifluoromethyl) groups, were readily converted to the spirooxazolidines 5l–5r in good yields. Furthermore, heterocyclic and alkyl acetylenes were suitable coupling partners for this domino reaction, providing the target products 5s and 5t in 64% and 59% yields, respectively. Finally, we tried to change the cyclic ketones (see Table S1 in the Supporting Information for details). However, neither simple cyclobutanone, cyclopentanone, and cyclohexanone, nor 3-oxotetrahydrofura and 3-oxocyclobutanecarbonitrile were able to give the target products because of the less activity of these cyclic ketones making the formation of the iminium intermediate from oxazolidine int-2 and cyclic ketones more difficult, which would result in the generation of byproduct 8 by Cu-catalyzed domino three-component coupling of an oxazolidine, a formaldehyde solution, and a phenylacetylene, followed by ring-opening alkynylation.

To demonstrate the synthetic utility of this method, the gram-scale reactions were performed and the applications of the product were exploited (Scheme 3). We performed a gram-scale coupling reaction to synthesize 5i and obtained 83% yield of the target product (Scheme 3A). With the new 3-oxetanone-derived spirocycles in hand, we first examined the reactivity of 5a via a Pd-catalyzed alkyne-enabled C–N activation (Scheme 3B) [29]. To our delight, a good yield of the corresponding compound 6 was produced by performing the reactions in PhCl at 140 °C. Subsequently, we carried out a ring expansion of 5i to construct the saturated nitrogen heterocycles (Scheme 3C) [19]. By using one molecule of 5i with one molecule of trimethylsilyl cyanide (TMSCN), we were able to achieve the desired product 7 in 63% yield though the ring opening of oxazolidine with TMSCN and an intramolecular 6-exo-tet cyclization sequence to access morpholine 7.

To better understand the reaction process, the intermediate int-2 was obtained by the reaction of amino alcohol with formaldehyde solution, and the reaction of int-2, 3-oxetanone, and phenylacetylene proceeded smoothly to give the desired product, 5a, in 50% under standard conditions (Scheme 4a). Based on our experimental data and literature reports [21,22,25,30,31,32], the plausible reaction pathway is described in Scheme 4b. First, the alkyne 4a was activated by the copper catalyst to form the Cu-alkyne species int-1. This Cu-alkyne species would then react with the iminium int-3 to give the iminium-copper-alkyne species int-4. In this process, the iminium int-3 was formed in situ by annulation of amino alcohol 1a and formaldehyde solution 2 to form the oxazolidine int-2 and via Brönsted acid-enhanced condensation of oxazolidine int-2 and 3-oxetanone 3a. Finally, the species int-4 was converted into the ring-opening species int-5 with the release of the Cu catalyst, followed by the intramolecular cyclization of int-5 to afford the titled product 5a.

4. Conclusions

In summary, we have developed a highly efficient copper/TFA catalytic system for the four-component A³-coupling/annulation domino reaction of readily available amino alcohols, formaldehyde, 3-oxetanone, and alkynes to form 3-oxetanone-derived spirocycles in reasonable yields. A wide range of amino alcohols and alkynes with high functional group tolerance could be successfully used in this reaction. The synthetic applications were also demonstrated by the gram-scale preparation of compound 5m; furthermore, the preliminary evaluation of the chemical reactivity of the products reveals that they can serve as novel substrates for the efficient synthesis of valuable molecules.