Enantio- and regioselective nickel/photoredox-catalyzed cross-electrophile coupling of benzylic aziridines with alkynyl bromides

Abstract

Alkynes with a proximal stereogenic center are a key structural element of many bioactive compounds, chemical probes, and functional materials and serve as a valuable synthon in organic synthesis. Here, a nickel/photoredox-catalyzed asymmetric C(sp³)─C(sp) cross-electrophile coupling (XEC) between racemic aryl aziridines and readily available alkynyl bromides was achieved in an enantioconvergent manner, affording β-alkynylethylamines in good to excellent enantioselectivity with complete regiocontrol. The obtained enantioenriched benzylic alkynes are indeed versatile synthetic intermediates and can be readily transformed into various synthetically useful chiral synthons and biologically active molecules, such as valuable β-ethylamine derivatives, heterocyclic amines, and β²–amino acids. Mechanistic studies were indicative of the aziridine being activated through a regioselective nucleophilic halide ring opening and subsequent enantioselective XEC of the generated β-amino benzyl halides with alkynyl bromides.

Cross-electrophile coupling of aryl aziridines and alkynyl bromides yields chiral β-alkynylethylamines.

INTRODUCTION

Chiral alkyne motifs bearing an α-stereocenter are important building blocks in polymer synthesis, viscoelastic damping materials, medicinal chemistry, and biomedical applications (Fig. 1) (1–5). Moreover, their sp-hybridized carbons act as versatile synthons, readily transforming into valuable sp²- or sp³-hybridized carbon frameworks. As a result, efficient strategies for catalytic, enantioselective C(sp³)─C(sp) coupling to introduce the C ≡ C moiety have long been sought (6–8). In recent years, several groups have achieved the synthesis of alkynes containing chiral molecules through inter alia C(sp³)-H alkynylation, catalytic C(sp³)-C(sp) coupling, alkene difunctionalization, or asymmetric addition to C═X (X = N, O) bonds (Fig. 2A) (9–20). For instance, Huang et al. (21) disclosed an elegant nickel-catalyzed asymmetric 1,2-borylalkynylation of unactivated alkenes with the assistance of carbonyl directing groups. Liu and colleagues have demonstrated a copper-catalyzed enantioselective Sonogashira C(sp³)─C(sp) cross-coupling of racemic benzyl halides and terminal alkynes (22, 23). The Zhu group has reported an elegant Ni-catalyzed enantioselective alkynylation of styrenes via a migratory hydroalkynylation process (24). Despite these indisputable advances, asymmetric C─C alkynylations through formal C─N activation has thus far proven elusive.

Fig. 1. Representative bioactive molecules based on β-substituted saturated amines.

TAAR1, trace amine-associated receptor 1; HTR1A, 5-Hydroxytryptamine Receptor 1A.

Fig. 2. Research background of asymmetric alkynylative ring opening of aziridines.

(A) Common strategies to enantioenriched alkynes. (B) Known process to enantioselective functionalization of cycloamines. (C) This work: Photocatalytic asymmetric alkynylation of aziridines. Cat., catalyst; TM, transition metal; PC, Photocatalyst; NHTs, N-tosyl group (a nitrogen bearing a hydrogen and a tosyl group); NTs, N-tosyl group (a nitrogen without the hydrogen).

Aryl aziridines are versatile C(sp³)-type electrophiles, and thus ring opening of such strained compounds constitutes an appealing approach to preparing β-substituted amine scaffolds (25–48), which are prevalent in bioactive molecules and pharmaceuticals, including dopamine receptor agonists (49, 50). Although highly regioselective transformations of aziridines have been achieved, enantioselective transformations are challenging and less explored, probably due to the propensity for stereospecificity in transition metal–catalyzed nucleophilic ring openings (51, 52). Thus far, substantial progress has been achieved in nickel-catalyzed asymmetric C(sp³)─C(sp²) and C(sp³)─C(sp³) cross-electrophile coupling (XEC) reactions. Various transformations, including arylation, alkenylation, and alkylation, have been successfully demonstrated by several groups using racemic aryl aziridines as substrates, using either stoichiometric metallic reductants or photochemical or electrochemical activation (Fig. 2B). Nevertheless, the products obtained from these methods typically lack reactive functional groups, constraining their potential for postsynthetic modification and limiting access to diverse chiral phenethylamine derivatives. To overcome this limitation, we envisioned that introducing highly active alkynyl groups into the skeleton of phenethylamine through asymmetric catalysis to prepare chiral β-alkynylethylamines would greatly improve the applicability of such phenethylamine derivatives.

To the best of our knowledge, no enantioselective C(sp³)─C(sp) XEC reactions have been reported to date. We attribute this to the key challenge that highly reactive alkynyl bromides tend to undergo homocoupling, yielding 1,3-diynes rather than the desired cross-coupled products (53, 54). To test this hypothesis, we used N-tosyl styrenyl aziridines and triisopropylsilylethynyl bromides as starting materials, following reported methods (55–58). However, the mismatched reaction rates predominantly yielded the 1,3-diyne and no target product (please see the Supplementary Materials and table S1), underscoring the need to explore previously unknown reaction systems to achieve efficient XEC between alkynyl electrophiles and aziridines. In this context, we report, here, on an unprecedented nickel-catalyzed enantioconvergent C(sp³)─C(sp) XEC between racemic N-sulfonyl styrenyl aziridines and alkynyl bromides, providing efficient access to structurally diverse β-alkynylethylamines with good to excellent levels of enantioselectivity with complete regiocontrol via cooperative nickel/photoredox catalysis under mild reaction conditions (Fig. 2C). This mild protocol demonstrates excellent compatibility with late-stage functionalization of pharmacologically relevant scaffolds. Notably, the resulting β-alkynylethylamines product is a versatile synthetic intermediate that can be efficiently diversified into a broad spectrum of chiral, structurally complex architectures.

RESULTS

Reaction design

Our investigation toward this Ni/photoredox-catalyzed enantioselective aziridine alkynylation reaction commenced by selecting racemic N-tosyl styrenyl aziridines 1a and commercially available triisopropylsilylethynyl bromides 2a as model components to obtain β-alkynylethylamines using a variety of chiral ligands in the presence of magnesium salt and base (Fig. 3). After systematic evaluation of the reaction parameters, we were delighted to find that, in the presence of 3.0 mol % Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, 10 mol % NiBr₂·DME, 12 mol % chiral Biimidazoline (BiIM) ligand L1, 25 mol % MgI₂, and 5.0 equivalents (equiv) of Et₃N in tetrahydrofuran (THF) under the irradiation of 20-W 390-nm blue light-emitting diodes (LEDs), the desired alkynylation product 3aa could be afforded in 72% isolated yield with 95% enantiomeric excess (ee; entry 1). Decreasing the size of aryl substituents on BiIM ligands (L2 and L3) resulted in relatively low enantioselectivities. Several common chiral bidentate ligands (such as pyridineoxazoline, bisoxazoline, and pyridine-bisoxazoline) were ineffective, affording a small amount of product or resulting in no conversion (L4 to L7). Different nickel precatalysts, such as NiBr₂·diglyme, afforded the corresponding product with lower yields but comparable ee (entry 2). The yield was significantly decreased with MgCl₂ instead of MgI₂ as an additive (entry 3), which is thought to be due to the low reactivity of the halide intermediates generated by ring opening of aziridines. A screening of solvents revealed that 1,2-dimethoxyethane (DME), 1,4-dioxane, and N,N-dimethylformamide were all less effective than THF (entries 4 to 6). Other common organic bases such as triethylenediamine (DABCO) and N,N-diisopropylethylamine (DIPEA) were shown to be unsuitable additives (entries 7 and 8). Meanwhile, the XEC decreased markedly, and a certain amount of 1,3-diyne was obtained when Zn or Mn powder was used instead of the photocatalyst and triethylamine (NEt3) as the additive (entry 9). In addition, light wavelength proved crucial; switching to 456- or 425-nm LEDs gave inferior results (entry 10). Control experiments indicated that photocatalyst, Ni salt, ligand, MgI₂, NEt3, and light are required for this transformation (entries 11 and 12).

Fig. 3. Reaction development.

^aReaction conditions: epoxides 1a (0.1 mmol), alkynyl bromides 2a (3.0 equiv), photocatalyst (2.0 mol %), NiBr₂·DME (10 mol %), L1 (0.012 mmol, 12 mol %), MgCl₂ (25 mol %), Et₃N (5.0 equiv), and THF (1.0 ml); 425 nm, room temperature (rt.), 48 hours, N₂. ^bIsolated yields. ^cDetermined by high-performance liquid chromatography on a chiral stationary phase. DBU, 1,8-diazabicyclo[5.4.0]-7-undecene. n.d., no detected; w/o, without; TIPS, Triisopropylsilyl group; n.r., no reaction

Scope of the methodology

With the optimized conditions established, we sought to investigate the reaction scope of this photoredox/nickel-catalyzed enantioselective alkynylation of aziridines (Fig. 4). A diverse array of aryl aziridines bearing electron-donating groups (−Me, −tBu, −Ph, −O^tBu, and −OAc), electron-withdrawing groups (−CF₃ and −COOMe), and halogen groups (F, Cl, and Br) at different positions of the phenyl ring readily underwent efficient XEC with alkynyl bromides, affording the enantioenriched β-alkynylethylamines (3ba to 3ua) in moderate to good yields with excellent regio- and enantioselectivity. Modest to good enantiocontrol could be achieved in the case of the ortho-substituted (Me, F, and Br) aziridines, demonstrating that increased steric hindrance has some effect on this transformation efficiency and enantioselectivity. Substrates featuring a coordinating cyano group on the arene ring afforded the desired products (3wa) in good yield but with low enantioselectivity, likely due to competitive coordination between the nitrile functionality and the chiral ligand for the nickel catalyst. In addition, benzylic aziridines bearing -NO₂, or -NHPiv groups failed to react with alkynyl bromide under the standard conditions. This lack of reactivity also extended to aziridines with acetyl protecting groups, β-substituted substrates, and alkyl aziridines (please see the Supplementary Materials). This inability to achieve alkynylation is likely due to insufficient electrophilic activation of the aziridine or incompatibility of the functional groups with the reaction conditions. Furthermore, the reaction of 2-naphthyl–substituted aziridines resulted in the formation of alkynylation products with good yields and enantioselectivities. Fortunately, 5-indolyl–substituted aziridines proved suitable substrates, affording products (3xa) in 76% yield with 92% ee.

Fig. 4. Substrate scope.

Reaction conditions: aziridine 1 (0.1 mmol), alkynyl bromide 2 (0.3 mmol, 3.0 equiv), Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (3.0 mol %), Ni(dme)Br₂ (10 mol %), L1 (12 mol %), MgI₂ (25 mol %), Et₃N (5.0 equiv), and THF (1.0 ml); 390 nm, rt., 48 hours, N₂. Isolated yield. ^bMgI₂ (100 mol %); 48 hours. ^cMgI₂ (50 mol %); 60 hours. TES, Triethylsilyl; TMS, Trimethylsilyl; OTBS, O-tert-butyldimethylsilyl; d.r., diastereomeric ratio.

Then, we turned our attention to exploring the versatility of ethynyl bromides. First, we examined alkynyl bromides with other silyl groups such as trimethylsilyl, triethylsilyl, and dimethyl-tert-butylsilyl, efficiently delivering the desired alkynylated products (3ab to 3ad). Furthermore, a broad range of silyl-substituted ethynyl bromides with different sterically hindered groups were prepared from biologically active carbonyl compounds, including straight-chain and cyclic ketones, and were shown to be viable substrates (3ae to 3ah). To our delight, alkyl and aryl alkynyl bromides were tolerated as well, and the corresponding alkynylation products were formed with moderate yields and enantioselectivities (3ai to 3ak). Furthermore, this method is applicable in the late-stage functionalization of biologically active drugs. Reactions using ethynyl bromides derived from (−)-menthone (3al), and aryl aziridines derived from dl-menthol (4aa), estrone (4ba), and (+)-α-tocopherol (4ca), were achieved with good to excellent ee under the standard conditions. Furthermore, x-ray diffraction analysis unambiguously determined the absolute configuration of 3ab [Cambridge Crystallographic Data Center (CCDC): 2467473], with all other alkynylation products assigned by analogy.

To demonstrate the potential synthetic utility of this method in the preparation of β-alkynylethylamine, we carried out gram-scale reactions and product derivatizations (Fig. 5A) (24, 56, 59, 60). Notably, the dual catalytic strategy can be easily scaled up to a 2.0-mmol scale, affording β-alkynylethylamine 3aa in good yield and excellent enantioselectivity. Treatment of 3aa with MeI in the presence of K₂CO₃ resulted in the formation of tertiary amine 5aa in good yield with good ee value. Furthermore, 3aa underwent smooth cyclization with paraformaldehyde to afford 5ab in 72% yield and 90% ee. The alkynylation products underwent semihydrogenation to deliver (Z)-alkenylethylamine 5ac in 86% yield and 96% ee. Subjecting the ring-opening product to cyclization with Ag catalyst or click reaction with (azidomethyl)benzene delivered 2,3-dihydropyrrole 5ad in 66% yield and 87% ee, and 1,2,3-triazole 5ae in 62% yield with 90% ee, respectively. In addition, the bromination of desilylated products yielded the enantioenriched ethynyl bromide 5af (68% yield and 92% ee). Notably, RuCl₃-catalyzed oxidation of the triple bond in alkynylation products efficiently yields chiral p-toluenesulfonyl group (Ts)-protected β-ethylamines 5ag. Subsequent Ts deprotection affords β²–amino acids in high enantiopurity (Fig. 5B). These synthetic chiral nonnatural amino acids serve as versatile synthetic blocks (61, 62), enabling a potential previously unknown route to Akt inhibitors, a promising therapeutic agent for human tumors (63).

Fig. 5. Synthetic applications.

(A) The synthetic applications of desired product 3aa. DCM, dichloromethane. (B) The synthesis of nonnatural amino acids. NBS, N-Bromosuccinimide; DIBAL-H, Diisobutylaluminium hydride; aq., aqueous.

DISCUSSION

A series of control experiments and cyclic voltammetry (CV) studies was designed further to corroborate the mechanism of this asymmetric XEC (Fig. 5). The enantioenriched product 3aa with equal selectivity was obtained with racemic or enantioenriched aryl aziridines as a substrate, demonstrating the stereoconvergent nature of this dual-catalytic system (Fig. 6A). Then, the ee values of both alkynylation product 3aa and remaining starting material (RSM) 1a at different conversions were observed (Fig. 6B). The results show that the enantioselectivities of product 3aa remained constant during the progress of this transformation. In contrast, recovered substrate 1a was always racemic, which confirms an enantioconvergent reaction pathway without kinetic resolution of the racemic aziridine precursors. The ring-opening reaction was carefully analyzed by high-resolution mass spectrometry (HR-MS) to shed light on the formation of halo-generated intermediates (Fig. 6C). β-Iodo-sulfonamide 6aa can be observed in the presence of MgI₂ (1.0 equiv). In sharp contrast, no iodide was detected when NiBr₂·DME was removed from the reaction system (Fig. 6C, top). Furthermore, β-bromo-sulfonamide 7aa was detected by HR-MS in the absence of MgI₂ under the standard conditions. Previous work and the above experimental results demonstrate that magnesium iodide acts as a source of I(−), while the nickel catalyst functions as both a Lewis acid and a bromide source for the ring opening of aziridine. Then, the standard reaction was carried out using the β-iodo-sulfonamide 6aa and β-bromo-sulfonamide 7aa as substrates instead of N-tosyl styrenyl aziridine 1a. Product 3aa was formed successfully in 58 and 21% yield, respectively, with both reactions exhibiting 94% ee value (Fig. 6C, bottom). Furthermore, when triisopropylsilyl iodide (2a′) was used in place of 2a as the reactant in the absence of MgI₂, no desired product was obtained (Fig. 6D). Notably, gas chromatography–mass spectrometry revealed trace amounts of the alkynyl iodide in the template reaction. These results suggest that, while alkynyl iodide can be generated via halogen exchange in the presence of MgI₂, it is unlikely to be the key intermediate in the catalytic cycle. Ni(cod)₂ was used as a catalyst in this asymmetric coupling reaction under standard conditions; the target product was isolated in 78% yield with 94% ee (Fig. 6E). This result suggests that a low-valent nickel species may serve as the key active catalyst in this asymmetric transformation. Upon the addition of the radical quenchers [2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)], the TEMPO-benzyl adduct 8aa was detected through HR-MS. The above adduct 8aa could still be observed when the reaction was conducted without MgI₂ or NiBr₂·DME. However, when neither MgI₂ nor NiBr₂·DME was added, we did not observe the target adducts in this transformation (Fig. 6F, top). These results suggest that a direct single-electron reductive activation of aziridines is unlikely without a nickel catalyst and MgI₂. In addition, the TEMPO-benzyl adduct could be formed when benzyl iodides 1a′ reacted with alkynyl bromides 2a, thus indicating that β-iodo-sulfonamides could be the precursor for the generation of benzyl radicals (Fig. 6F, bottom). CV studies revealed that Ni(dme)Br₂/L1 exhibits irreversible reduction waves at E_onset(Ni^I/Ni⁰) = −1.40 V versus Ag/AgCl in THF and E_onset(Ni^II/Ni^I) = −0.81 versus Ag/AgCl in THF, suggesting that Ni(I) species can be formed in situ from the Ni(II) precatalyst via reduction by Ir photocatalyst (Fig. 6G). The reductive potential of the Ni^I/Ni⁰ is more negative than that of the β-iodo-sulfonamides 6aa (E_onset = −1.05 V versus Ag/AgCl in THF), indicating that the putative β-iodo-sulfonamide intermediates can be reduced by the Ni⁰ species. Furthermore, no reduction peak for aziridine 1a was observed. This demonstrates that the β-iodosulfonamide intermediate is more easily reduced than the starting N-tosyl styrenyl aziridine 1a. Consequently, once formed, the intermediate is expected to be preferentially reduced over the starting material. We next performed a study of the nonlinear effect. A perfect linear relationship was obtained, indicating that a monomeric nickel complex bearing a single bidentate ligand is involved in the enantioselectivity-controlling step (Fig. 6H).

Fig. 6. Mechanistic studies.

(A) Reactions with chiral aziridines. (B) Monitoring the progress of the reaction. (C) Intermediate confirmation experiment. (D) Reaction with alkynyl iodide. (E) Ni(cod)₂ as a catalyst. (F) Control experiments using TEMPO. (G) Cyclic voltammetry studies. (H) Study of nonlinear effect. R², coefficient of determination.

With the above mechanistic studies and previous report (55–58, 64, 65), a plausible catalytic cycle for the photochemical chiral β-alkynylethylamine synthesis was rationalized as depicted in Fig. 7. Initially, oxidative addition of alkynyl bromide 2 to nickel (0) A generates nickel (II) species B. At the same time, the regioselective ring opening of aziridine 1 occurs in situ to form the racemic benzyl halide intermediate C, which can undergo either halogen atom abstraction (HAA) or single-electron transfer (SET) to form the corresponding secondary radical D. Then, this radical can be trapped by intermediate B to generate nickel (III) species E, followed by reductive elimination to deliver the product β-alkynylethylamine 3 and nickel (I) species F. The nickel (0) catalyst A can then be reformed by reduction of species F by Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, which was generated via reductive quenching with Et₃N.

Fig. 7. Proposed mechanism.

In summary, we report the first nickel/photoredox-catalyzed asymmetric alkynylation of aryl aziridines using alkynyl bromides as electrophilic alkynyl sources, providing efficient access to chiral β-alkynylethylamines with excellent enantioselectivity and complete regioselectivity. This methodology exhibits broad substrate scope on both N-sulfonylstyrenyl aziridines and alkynyl bromides, which can successfully be applied to pharmacologically relevant substrates, subsequent derivatization of the products, and the synthesis of β²–amino acids and drug molecules. A series of preliminary mechanistic investigations provided strong evidence for a Ni(0/II/III/I) manifold within the alkynylations.

MATERIALS AND METHODS

General procedures for the synthesis of chiral β-alkynylethylamines

In a glove box, an oven-dried crimp-cap microwave vial equipped with a magnetic stirring bar was charged with Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (3.4 mg, 0.003 mmol, 3.0 mol %), MgI₂ (7.0 mg, 0.025 mmol, 25 mol %), NEt3 (50.5 mg, 0.5 mmol, 5.0 equiv), aziridine 1 (0.1 mmol), and alkynyl bromide 2 (3.0 equiv). In a separate vial, NiBr₂•DME (3.1 mg, 0.01 mmol, 10 mol %) and L1 (7.2 mg, 0.012 mmol, 12 mol %) were prestirred in 1.0 ml of THF for 10 min to produce an orange solution. The catalyst mixture was added to the reaction vial, and the reaction vial was capped with a septa cap, wrapped with electrical tape, and removed from the glove box. The tube was positioned ~5 cm away from a 20-W blue LED lamp (λ_max = 390 nm). After being stirred at 25°C for 48 hours, the crude reaction mixture was concentrated under reduced pressure and purified by column chromatography.

Supplementary Materials

This PDF file includes:

Supplementary Text

Tables S1 and S2

Figs. S1 to S12

References