Catalytic Enantioselective Alkyne Addition to Nitrones Enabled by Tunable Axially Chiral Imidazole-Based P,N-Ligands

Abstract

Although catalytic enantioselective alkyne addition is an established method for the synthesis of chiral propargylic alcohols and amines, addition to nitrones presents unique challenges and no general chiral catalyst system has been developed. In this manuscript, we report the first Cu-catalyzed enantioselective alkyne addition to nitrones utilizing tunable axially chiral imidazole-based P,N-ligands. Our approach effectively overcomes difficulties in both reactivity and selectivity, resulting in a simple Cu-catalyzed protocol. The reaction accommodates a wide range of nitrones and alkynes, enabling the streamlined synthesis of chiral propargyl N-hydroxylamines via enantioselective C−C bond formation. A diverse array of optically active nitrogen-containing compounds, including chiral hydroxylamines, can be accessed directly through facile transformations of the reaction products.

Graphical Abstract

Advances in enantioselective catalysis, fueled by the design of new chiral ligands and catalysts, have revolutionized the synthesis of enantioenriched molecules.¹ In metal-catalyzed enantioselective alkyne addition to C=O and C=N electrophiles, the use of specific metal-based catalysts such as copper or zinc obviate the need for strong bases or stoichiometric amounts of preformed metal acetylides.² This strategy enables the direct addition of abundant, commercially available terminal alkynes. A variety of chiral ligands or chiral cocatalysts have been applied in these enantioselective C−C bond forming reactions, providing chiral propargylic alcohols³ and amines⁴ efficiently.

In contrast, nitrones are versatile intermediates used in the synthesis of biologically important nitrogen-containing compounds,⁵ but the corresponding reaction is quite difficult vide infra. Nitrones can be easily prepared through condensation of aldehydes with hydroxylamines or catalytic oxidation of secondary amines.⁵ Unlike the corresponding imines, nitrones are typically stable crystalline solids that are easy to handle and purify. The configurational stability of nitrones is also beneficial for stereoselective transformations.⁶ There is a growing interest in preparing chiral hydroxylamines due to their unique N–O bond properties in pharmaceuticals and agrochemicals.⁷ Through stereoselective alkyne addition to nitrones, chiral propargyl N-hydroxylamine can be prepared by selective C–C bond formation from simple starting materials. While diastereoselective alkyne addition to nitrones is constrained by the availability of chiral nitrones,⁸ a more general approach to synthesizing chiral propargyl N-hydroxylamine is highly desirable.

Despite the advantages of a catalytic enantioselective addition,⁹ and what might be a perceived similarity to other imine/iminium addition reactions, few enantioselective methods have been reported (Figure 1A). With the seminal work on Zn(OTf)₂-catalyzed alkyne addition to nitrone,^9a Carreira later utilized a mannose-derived chiral auxiliary on nitrones with substoichiometric Zn(OTf)₂¹⁰ or stoichiometric ZnCl₂¹¹ for selective alkyne addition. Complicating matters, direct cyclization to isoxazoline has been observed as a side reaction.¹⁰ An alternative approach involves use of a tartaric acid ester as a chiral reagent with stoichiometric Me₂Zn to prepare the alkynylzinc, but this limits the scope of both the nitrone and alkyne.¹² Attempts with chiral ligands for Zn-^9a and In-catalysts^9c in enantioselective alkyne addition to nitrones have not been successful. These results reveal a distinct, and perhaps unexpected dichotomy between nitrones and aldehydes/imines in metal-catalyzed alkyne addition.^3e,3f,13 Unlike aldehydes or imines, the heteroatom with the lone pair in nitrones is positioned further away from the prochiral reaction site; and, to achieve enantiocontrol, a chiral catalyst with distinctly different recognition features may be required to circumvent the inherent challenges posed by Zn- or In-catalysts.

Figure 1.

Overview of enantioselective catalyst design for alkyne addition to nitrones

Cu-catalyzed A³ coupling reactions with secondary amines demonstrate the potential for enantioselective alkyne addition to iminium intermediates.¹⁴ Unlike imines,^4d–f iminium intermediates lack the heteroatom lone pair for direct interaction with chiral copper catalysts (Figure 1B).¹⁵ To address this challenge, a series of chiral ligands have been designed and applied for alkyne addition to iminium intermediates. While significant advancements have been made using BOX and PyBOX ligands in Cu-catalyzed alkyne addition to cyclic iminium intermediates,¹⁶ axially chiral P,N-ligands¹⁷ have emerged as remarkably successful for both cyclic¹⁸ and acyclic iminium intermediates.¹⁹ By introducing five-membered N-heterocycles in axially chiral P,N-ligands, our group has designed the imidazole-based ligand StackPhos²⁰ and imidazoline-based ligand StackPhim,²¹ that enable challenging secondary amine A³ coupling reactions with high enantioselectivity.²² We sought to explore the potential of our Cu-StackPhos catalyst for enantioselective alkyne addition to nitrones, a reaction not previously achieved with catalysts supported by common privileged chiral ligands.

At the outset, we were cognizant of the potential difficulties in applying a chiral copper catalyst for enantioselective alkyne addition to nitrones (Figure 1C). Firstly, the Kinugasa reaction is a more common pathway with copper catalysts leading to β-lactam,²³ including with some P,N-ligands²⁴ such as N-PINAP.²⁵ Cu-acetylide is also known for its low reactivity for addition to nitrone.^9a Additionally, in most highly enantioselective A³ coupling reactions, the amine features symmetrical or very bulky alkyl groups to avoid isomerism or to minimize size differences;¹⁴ however, this strategy is not applicable to nitrones. Consequently, we envisioned that an activating reagent for nitrone such as TMSOTf²⁶ would silylate the oxygen atom on nitrone, facilitating Cu-acetylide addition²⁷ and also blocking the potential coordination with Cu-catalyst to prevent formation of the Kinugasa product and other 1,3-dipolar cycloaddition side reactions.²⁸ To test this hypothesis, nitrone 1a and alkyne 2a were selected as the model substrates with Cu-StackPhos catalyst. We were excited to find that alkyne addition occurred with a 95% yield in the presence of TMSOTf, albeit in 55% ee (Table 1, entry 1). The choice of activating reagent has a significant effect on both reactivity and selectivity. No product was detected in the absence of any activating reagent (entry 2). The ee increased to 80% when TMSCl was used (entry 3), though the conversion was low. In contrast, with TMSBr the product was again obtained in 80% ee but with excellent yield (entries 4 and 5).

Table 1.

Reaction Optimization

Conditions: CuBr (7.5 mol%), ligand (8 mol%), alkyne (1.2 equiv), iPr₂NEt (1.5 equiv), 0 °C, 18 h;

^aiPr₂NEt (1.2 equiv);

^bReaction temp =−40 °C, 48 h;

^ctoluene:DCM 1:1; See SI for complete details.

Further improvement to the enantioselectivity would be necessary, and to this end, different chiral ligands were screened and perhaps StackPhos could be surpassed by more traditional ligands. Nitrogen donor ligands BOX (Table 1, entry 6) and PyBOX (entry 7), bisphosphine BINAP (entry 8), and P,N-ligand QUINAP (entry 9) were employed, but notably, significant asymmetric induction was only observed using QUINAP (66% ee), demonstrating that axially chiral P,N-ligands appear to be the most selective ligands for this transformation.

Having achieved the highest ee with L1, various derivatives of StackPhos were prepared and screened.²⁹ Tuning the imidazole backbone of StackPhos did not improve enantioselectivity (see SI for details), necessitating a different approach and the influence of different phosphine substituents was investigated. Changing these groups is not common with axially chiral P,N-ligands, but it can be quite important.³⁰ Using our recently reported enantioselective phase transfer benzylation method, different phosphino groups are easily incorporated into Stack-ligands.³¹ Employing bulky and electron-rich phosphino groups L2 and L3 did not result in a significant change in enantioselectivity (Table1, entries 10 and 11). While the enantioselectivity dropped to 75% ee with L4 (entry 12), the F-substituted aryl phosphine L5 led to a significant increase, 88% ee (entry 13). With L6 bearing 2-furyl groups, the selectivity increased to 89% ee (entry 14). It should be noted that 2-furyl groups are also considered electron-withdrawing group for phosphine ligands.³² By lowering the reaction temperature to −40 °C, the enantioselectivity increased to 93% ee at the expense of yield, (30%, entry 15), probably due to the low solubility of the nitrone. The use of a mixed solvent with DCM and toluene led to the full conversion of the nitrone with excellent enantioselectivity (92% yield/93% ee, entry 16). At −40 °C with L1, L4, and L5 the ee also increased (entry 17, 18, 19), but not to the same level observed with L6, and thus the 2-furyl-ligand L6 was deemed optimal.

The scope was next explored and the results are shown in the Table 2. A diverse range of alkynes, both aromatic and aliphatic, are effectively accommodated in this reaction (Table 2A). A variety of substitutions at different aromatic ring positions were well tolerated with excellent enantioselectivity. Electron-rich arylalkynes, such as 3e and 3f, gave slightly lower, but still very good enantioselectivity (90% ee and 87% ee, respectively). Aliphatic alkynes are commonly more challenging substrates for Cu-catalyzed enantioselective alkynylation with BOX or PyBOX type ligands.^16c,16d With our CuBr-L6 chiral catalyst, aliphatic alkynes, including those with alkyl halides (4b and 4d) and TMS-acetylene (4h), still showed excellent enantioselectivity and high yield. Alkyl alkynes with free alcohols (4i and 4j) can be directly used in this transformation with good enantioselectivity.

Table 2.

Reaction Scope

^atoluene as solvent;

^b2.4 equiv TMSBr, 3 equiv iPr₂NEt;

^c0 °C;

^d0 °C, without TsOH/MeOH desilylation. See SI for full details

A broad range of nitrones were also be employed as substrates (Table 2B). Aromatic nitrones, with different substitution patterns and electronic properties were alkynylated with good yield and excellent enantioselectivity (5a–5f). Despite the diversity observed as this point, and much to our surprise, under the standard conditions, aliphatic nitrones did not provide satisfactory results. For example, with ligand L6, the enantioselectivity was only around 71% ee for 6a. Fortunately, excellent results (86%, 97% ee) were observed using the parent StackPhos L1(see SI for details). Under these conditions, aliphatic nitrones with both acyclic alkyl groups (6a, 6b) and cyclic alkyl groups (6c–6e) underwent the reaction smoothly, displaying excellent enantioselectivity and good yield. Nitrones derived from diverse hydroxylamines (5g, 6f) were also successfully alkynylated, achieving excellent enantioselectivity when a suitable StackPhos type ligand was used. Cyclic nitrones yielded the desired products with high enantioselectivity (6g and 6h). These results highlight the exquisite enantiocontrol exhibited by our Cu-StackPhos catalyst system over both the Z and E configurations of nitrones.

The unique hydroxylamine functional group combined with the alkyne as a synthetic handle makes propargyl N-hydroxylamines highly useful synthons. Pioneering reports on their synthetic utility have mainly focused on the transformation of racemic compounds due to the limited access to chiral propargyl N-hydroxylamines.³³ Our catalytic enantioselective alkyne addition to nitrones method facilitates the efficient synthesis of non-racemic propargyl N-hydroxylamines. This provides new opportunities for the synthesis of diverse chiral nitrogen-containing compounds, as demonstrated by the transformations of 3a in Scheme 1. The hydroxylamine and alkyne functional groups of 3a can be used together for cyclization, forming chiral 4-isoxazoline 7a^33a,33b or 2-acylaziridine 7b.^33c,33d Alternatively, either the alkyne or the hydroxylamine group can be selectively reduced to yield optically active 7c or 7d, while leaving the other functional group available for further transformations. The preparation of 7c shows a general strategy for chiral hydroxylamine synthesis. The transformation to 7d demonstrates that the propargyl N-hydroxylamines can be synthetic surrogates for propargylic amines.

Scheme 1. Applications of Chiral Propargyl N-Hydroxylamines.

[a] 5 mol% Ph₃PAuCl, 5 mol% AgOTf, CH₂Cl₂. [b] 20 mol% AgBF₄, 20 mol% CuCl, CH₂Cl₂. [c] 7.5 wt% Pd(OH)₂/C, H₂, EtOH. [d] 5 mol% Cu(OAc)₂•H₂O, 10 equiv Zn powder, HOAc/H₂O.

In conclusion, we have developed a Cu-catalyzed enantioselective alkyne addition to nitrones, that addresses the challenges faced in Zn- or In-catalyzed processes. By tuning the substituents on the phosphorus of the axially chiral imidazole-based P,N-ligands, a highly enantioselective reaction across a broad scope of alkynes and nitrones was achieved. This method enables the streamlined synthesis of chiral propargyl N-hydroxylamines by enantioselective C−C bond formation and offers a new way to produce optically active nitrogen-containing compounds. Further applications of these ligands will be reported in due course.