Asymmetric synthesis of CF₂-functionalized aziridines by combined strong Brønsted acid catalysis

Abstract

A diastereo- and enantioselective approach to access chiral CF₂-functionalized aziridines from difluorodiazoethyl phenyl sulfone (PhSO₂CF₂CHN₂) and in situ-formed aldimines is described. This multicomponent reaction is enabled by a combined strong Brønsted acid catalytic platform consisting of a chiral disulfonimide and 2-carboxyphenylboronic acid. The optical purity of the obtained CF₂-substituted aziridines could be further improved by a practical dissolution–filtration procedure.

Introduction

Chiral aziridines are prevalently found in natural products and artificially made bioactive molecules, thus receiving significant attention in the past decades [1–6]. Among them, the introduction of fluorine or fluoroalkyl groups into three-membered N-heterocycles has emerged as an attractive direction due to the unique fluorine effect in pharmaceuticals and biology [7–11]. In this context, it is not surprising that the syntheses of trifluoromethylaziridines have been pursued from versatile precursors [12–25]. However, catalytic asymmetric approaches to chiral CF₃-functionalized aziridines have only been reported by Cahard in 2012, who utilized trifluorodiazoethane (CF₃CHN₂) as the nucleophile to react with aldimines catalyzed by chiral phosphoric acid (Scheme 1a) [26]. In comparison, there is a significant dearth of available synthetic approaches to CF₂-functionalized aziridines, particularly in a stereocontrolled manner. Indeed, a handful of reported methods document the employment of difluoromethylimines, difluoromethyl phenyl sulfone, and difluoromethyl vinyl sulfonium salts as the fluorinating partner en route to various CF₂-substituted aziridines [27–31], and a general protocol to chiral CF₂-aziridines remains an unsolved challenge. Thus, herein we report a diastereo- and enantioselective aza-Darzens reaction between in situ-generated aldimines and our recently developed difluorodiazo reagent PhSO₂CF₂CHN₂ acting as the difluorinated nucleophile [32–35], providing access to a variety of chiral CF₂-fuctionalized aziridines under mild conditions (Scheme 1b). The key to this multicomponent transformation hinges upon the discovery of a combined strong Brønsted acid system comprised of a chiral disulfonimide and 2-carboxyphenylboronic acid.

Scheme 1.

Preparation of chiral aziridines from fluorinated diazo reagents.

Results and Discussion

We commenced the desired one-pot transformation by conducting the model reaction between phenylglyoxal monohydrate (1a), 4-methoxyaniline (2a), and PhSO₂CF₂CHN₂ (3, Ps-DFA). Initial screenings were focused on the evaluation of various chiral phosphoric acids that have proven effective in similar aza-Darzens reactions of diazo esters and trifluorodiazoethane [36–39]. Unfortunately, these endeavors resulted in either no conversion or no enantioselectivity at all. As arylboronic acids have been harnessed to enhance the Brønsted acidity in asymmetric organocatalysis in combination with chiral diols or chiral aminoalcohols [40–44], we envisioned that the simultaneous use of arylboronic acids and chiral Brønsted acids may bring about a complementary catalytic platform. Encouragingly, the targeted CF₂-functionalized aziridine 4a was obtained in up to 51% ee and high diastereoselectivity, albeit in a low yield (Table 1, entries 1 and 2). The difficulty in further improving the conversions might be ascribed to the limited Brønsted acidity of chiral phosphoric acids. Bearing this in mind, we then turned our attention to chiral disulfonimides developed by List, which have been established as a unique type of stronger Brønsted acids [45]. Putting it into practice, a range of BINOL-derived disulfonimides was used as the chiral additive in combination with 2-carboxyphenylboronic acid (COOH-BA) in the model reaction (Table 1, entries 3–8). We were pleased to find that CDSI-4 gave the most promising result in terms of both yield and enantioselectivity (64% isolated yield with 73% ee, Table 1, entry 6). An examination on various arylboronic acids, solvent, temperature, and catalyst loadings resulted in no obvious improvement (Table 1, entries 9–15). Among them, the highest yield of 4a was observed (81%, Table 1, entry 12), albeit with slightly reduced ee value. This enhancement in catalytic activity could be attributed to the increased Brønsted acidity when the strong electron-withdrawing trifluoromethyl group was placed on the benzene ring of the arylboronic acid. Removing the boronic acid from the reaction system leads to a dramatic decrease in both yield and enantiocontrol (Table 1, entry 16).

Table 1.

Representative screening results of the asymmetric aziridination reaction of PhSO₂CF₂CHN₂.^a

entry	arylboronic acid (mol %)	chiral Brønsted acid (mol %)	yield of 4a (%)b	ee (%) of 4a and dr of crude mixturec
1	COOH-BA (8)	CPA-1 (5)	24	51, 13:1
2	COOH-BA (8)	CPA-2 (5)	28	25, 11:1
3	COOH-BA (8)	CDSI-1 (5)	21	41, 19:1
4	COOH-BA (8)	CDSI-2 (5)	50	41, 9:1
5d	COOH-BA (8)	CDSI-3 (5)	16	60, 5:1
6d	COOH-BA (8)	CDSI-4 (5)	64	73, 13:1
7	COOH-BA (8)	CDSI-5 (5)	34	33, 10:1
8	COOH-BA (8)	CDSI-6 (5)	47	52, 9:1
9	OH-BA (8)	CDSI-4 (5)	63	68, 28:1
10d	SO3H-BA (8)	CDSI-4 (5)	62	66, 16:1
11d	NO2-BA (8)	CDSI-4 (5)	45	62, 16:1
12	CF3-COOH-BA (8)	CDSI-4 (5)	81	67, 8:1
13e	COOH-BA (8)	CDSI-4 (5)	60	47, 5:1
14f	COOH-BA (8)	CDSI-4 (5)	trace	n.d.
15d	COOH-BA (8)	CDSI-4 (10)	65	70, 12:1
16d	–	CDSI-4 (5)	10	60, >20:1

^aGeneral reaction conditions: 1a (8 mg, 0.05 mmol, 1.0 equiv), 2a (7 mg, 0.055 mmol), arylboronic acid (0.004 mmol), and Na₂SO₄ (40 mg) was stirred in toluene (1 mL) at rt for 30 min, then the chiral Brønsted acid (0.0025 mmol) and 3 (18 mg, 0.075 mmol) were added and the mixture was reacted at rt for 12 hours unless otherwise noted; ^byield of isolated product 4a was given for entries labelled with d; hexafluorobenzene was used as an internal standard to determine the yield in other cases; ^cee of 4a was determined by chiral HPLC analysis, and the dr of the crude reaction mixture was probed by ¹⁹F NMR analysis; ^d0.3 mmol scale of reaction was conducted: 1a (46 mg, 0.3 mmol, 1.0 equiv), 2a (41 mg, 0.33 mmol), arylboronic acid (0.024 mmol), and Na₂SO₄ (200 mg) was stirred in toluene (2 mL) at rt for 30 min, then the chiral Brønsted acid (0.015 mmol) and 3 (105 mg, 0.45 mmol) were added and the mixture was reacted at rt for 12–24 hours; ^eCH₂Cl₂ was used as the solvent; ^freaction was operated at 0 °C.

The challenge to further improve the enantioselectivity promoted us to search for other practical solutions. Considering the poor solubility of 4a in organic solvents, a dissolution–filtration process with isopropanol was found to be workable for increasing the final ee value. This simple procedure could afford 4a with excellent enantiopurity as a single diastereoisomer (>99% ee, >50:1 dr, Scheme 2). By the aid of the developed one-pot aza-Darzens reaction and dissolution–filtration operation, a series of optically-pure CF₂-aziridines 4b–h were furnished in moderate overall yields with uniformly excellent ee and dr values, including alkyl or halogen-substituted phenyl and 2-naphthyl ketones (Scheme 2). Unfortunately, phenylglyoxal monohydrates bearing strong electron-withdrawing groups were not compatible with the current conditions. X-ray analysis of aziridine 4a confirmed the absolute configuration of the chiral centers, pointing at a cis-aziridination process [46].

Scheme 2.

Substrate scope of chiral CF₂-substituted aziridines from PhSO₂CF₂CHN₂. General reaction conditions: Aryl glyoxal monohydrate (1, 0.3 mmol), 2a (41 mg, 0.33 mmol), COOH-BA (4 mg, 0.024 mmol), and Na₂SO₄ (200 mg) were stirred in toluene (2 mL) at rt for 30 min, then CDSI-4 (12 mg, 0.015 mmol) and Ps-DFA 3 (105 mg, 0.45 mmol) were added and the mixture was reacted at rt for 24 hours unless otherwise annotated. The yields are those of isolated products, and the dr was determined by ¹⁹F NMR analysis of the crude mixture. The results in parentheses are those of isolated products after the dissolution–filtration process: The corresponding CF₂-functionalized aziridine 4 was dissolved in isopropanol (0.05–0.2 mL/mg) with the help of ultrasound, followed by filtration, and the obtained solution was concentrated to give 4 with increased ee and dr values. ^a0.006 mmol of COOH-BA was employed. ^bThe reaction was operated at 45 °C for 24 h.

Scaled-up experiments with model substrate 1a also proved to be feasible, delivering the chiral CF₂-aziridine 4a with comparable results (Scheme 3a). The 4-methoxyphenyl group of 4a was cleaved smoothly with ceric ammonium nitrate, giving the free aziridine 5a in 81% yield while maintaining the ee value. The reduction of the carbonyl moiety with either NaBH₄ or LiAlH₄ produced hydroxy-substituted CF₂-functionalized aziridine 5b in excellent yield with exclusive diastereoselectivity [47]. Furthermore, the ring-opening of 4a under acidic conditions underwent well and gave rise to CF₂-functionalized α-chloro-β-amino ketone 5c in 89% yield with >99% ee and >50:1 dr (confirmed by X-ray spectroscopy) [46].

Scheme 3.

Scale-up experiment to 4a and further synthetic transformations.

Conclusion

In summary, an array of chiral CF₂-functionalized aziridines was constructed from in situ-formed aldimines and difluorodiazoetyl phenyl sulfone under mild conditions by a combined strong Brønsted acid system consisting of chiral disulfonimide and 2-carboxyphenylboronic acid. The optical purity of the obtained CF₂-substituted aziridines could be further improved by a practical dissolution–filtration procedure. Substrate expansion and mechanistic investigation are underway and will be reported in due course.

Experimental

General procedure for the preparation of chiral CF₂-functionalized aziridines 4: To a 25 mL Schlenk tube equipped with a stirring bar were added 2,2-dihydroxy-1-arylethan-1-one (1, 0.3 mmol, 1 equiv), 4-methoxyaniline (2a, 40.6 mg, 0.33 mmol), 2-boronobenzoic acid (COOH-BA, 3.98 mg, 0.024 mmol), anhydrous Na₂SO₄ (200 mg) and toluene (1 mL) at room temperature under an argon atmosphere. After reacting for 30 minutes at room temperature, ((2-diazo-1,1-difluoroethyl)sulfonyl)benzene (Ps-DFA 3, 104.5 mg, 77.4 uL, 0.45 mmol) was added with a micro syringe and CDSI-4 (12.3 mg, 0.015 mmol) in toluene (1 mL) was added dropwise. The reaction was allowed to stir for 24 hours at room temperature under an argon atmosphere until the consumption of substrates was completed (as monitored by TLC). The reaction mixture was quenched with saturated aq NaHCO₃ and extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, and then dried over anhydrous Na₂SO₄, filtered and evaporated under vacuum. The residue was purified by neutral alumina column chromatography (eluting with dichloromethane/petroleum ether) to give CF₂-substituted aziridine 4. The enantiomeric excess was determined by chiral HPLC analysis. See Supporting Information File 1 for the dissolution–filtration procedure for each compound.

Supporting Information

File 1

Experimental procedures, compound characterization, NMR spectra of all new compounds, and HPLC traces.

File 2

X-ray data for compound 4a.

File 3

X-ray data for compound 5c.

This article is part of the thematic issue "Organo-fluorine chemistry V".

Funding Statement

This work was supported by the National Key Research and Development Program of China (2019YFA0905100), National Natural Science Foundation of China (Nos. 21772142, 21901181, and 21961142015), and Tianjin Municipal Science & Technology Commission (19JCQNJC04700).