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. 2024 Oct 16;146(43):29523–29530. doi: 10.1021/jacs.4c09327

Ni-Catalyzed Asymmetric Reductive Arylation of α-Substituted Imides

Li-Ming Chen †, Chungkeun Shin †, Travis J DeLano †, Alba Carretero-Cerdán †,‡, Golsa Gheibi †, Sarah E Reisman †,*
PMCID: PMC11528402  PMID: 39413404

Abstract

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α-Aryl imides are common structural motifs in bioactive molecules and proteolysis-targeting chimeras designed for targeted protein degradation. An asymmetric Ni-catalyzed reductive cross-coupling of imide electrophiles and (hetero)aryl halides has been developed to synthesize enantioenriched α-arylglutarimides from simple starting materials. Judicious selection of electrophile pairs allows for coupling of both electron-rich and electron-deficient (hetero)aryl halides in good yields and enantioselectivities.

Introduction

α-Aryl imides are found in a variety of bioactive compounds (Figure 1a)1,2 and have garnered interest as promising candidates for the treatment of asthma, rheumatoid arthritis, and cardiovascular disease.3,4 In particular, α-arylglutarimides have drawn significant attention in the field of targeted protein degradation, a flourishing therapeutic modality capable of targeting previously undruggable pathology-driving proteins.5 α-Arylglutarimides serve as designed analogs of molecular glues such as thalidomide, lenalidomide, and other α-N-heterocyclic glutarimides (Figure 1a), which bind to the E3 ligase cereblon to induce ubiquitination of target proteins.6−8 These glutarimides can be integrated into the design of heterobifunctional proteolysis-targeting chimeras (PROTACs), where they serve as the ligase-binding moiety (Figure 1a).9−11 Despite their cereblon-binding activity, glutarimides such as thalidomide suffer from hydrolytic instability and are known to racemize under physiological conditions.12,13 α-Arylglutarimides often show increased stability, where the substituents on the arene can influence the acidity at the α-position, potentially giving rise to configurationally stable analogues.14,15 Given that the two enantiomers of these products can have vastly different biological activities,16 the ability to prepare these compounds enantioselectively can be advantageous for drug discovery efforts.

Figure 1.

Figure 1

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Significance of α-arylimides and context for this study.

Prior routes to α-arylglutarimides typically require multistep sequences that incorporate the arene prior to imide formation. A common approach involves the synthesis of α-aryl cyanoesters, which are then hydrolyzed and cyclized under acidic conditions to form the glutarimide moiety (Figure 1b).14,17 A second approach functionalizes a 2,6-dibenzyloxypyridine by cross-coupling, followed by simultaneous debenzylation and hydrogenation to produce the glutarimide (Figure 1c).13 Although these approaches provide access to the α-arylglutarimides, the incorporation of functional groups early in the synthesis can make rapid analog generation more cumbersome. Additionally, preserving acid-sensitive and reduction-prone functionalities during imide formation steps can be challenging. Moreover, neither strategy allows for direct access to enantioenriched products, hampering the investigation of the role of chirality in their biological properties.16

To address these issues, we have developed an asymmetric Ni-catalyzed reductive cross-coupling (RCC) to prepare α-arylglutarimides (Figure 1d). This operationally simple approach is highly modular, proceeds under mild conditions, and provides access to highly enantioenriched products.18,19 We demonstrate that by matching the reactivity of the aryl and imide cross-coupling partners, α-arylglutarimides with both electron-rich and electron-deficient arenes can be prepared. During the development of this work, Baran and co-workers concurrently demonstrated an elegant Ni-catalyzed electroreductive cross-coupling reaction between α-bromoimides and aryl halides to access similar α-arylglutarimides as racemates.20 Taken together, these methods provide complementarity in accessing α-arylglutarimides, showcasing diverse reaction conditions that cater to different substrate preferences and enabling the preparation of both racemic and enantioenriched compounds.

Results and Discussion

We initiated studies on the cross-coupling between 3-chloropiperidine-2,6-dione (1) and 4-iodotoluene (2a) (Table 1). By screening several ligand scaffolds commonly used for asymmetric Ni-catalysis, such as bi(oxazoline) (BiOX), bis(oxazoline) (BOX), and pyridine-oxazoline (PyOX),21 we determined that 4-heptylBiOX (L1) provided the highest enantioselectivity (Figure S1, Supporting Information). With NiBr2·diglyme as the Ni precatalyst, Zn0 as the terminal reductant, trimethylsilyl chloride (TMSCl) as an additive, and 30% N,N-dimethylacetamide (DMA)/tetrahydrofuran (THF) as the solvent, the desired cross-coupled product can be obtained in 85% yield and 94% ee (Table 1, entry 1). This cosolvent system provided an optimal balance between reactivity and enantioselectivity, outperforming either DMA (entry 2) or THF (entry 3) as the sole solvent.22 With biimidazoline (BiIM) ligand L2, which was recently reported as a more effective ligand than BiOX ligands in related reactions,23,245a was formed in diminished 61% yield and 61% ee (entry 4). We note that use of achiral ligand 2,2′-bipyridine (bpy) provides racemic 5a in 87% yield (entry 5). The Ni loading can be reduced to 7.5 mol % with only a modest decrease in ee (entry 6); however, further reducing the loading to 5 mol % resulted in lower yield of 5a (entry 7). Substitution of Mn0 for Zn0 powder gave 5a in comparable yield (entry 8). Use of the soluble organic reductant, tetrakis(dimethylamino)ethylene (TDAE), failed to provide any of the desired product (entry 9).25

Table 1. Optimization of Reaction Conditions for the RCC between α-Chloroimides and Aryl Iodides.

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entry deviation from standard conditions yield 5a (%)a ee 5a (%)b yield 6 (%)a
1 none 85 (84) 94 (92) 9
2 DMA as solvent 75 90 16
3 THF as solvent 19 90 39
4 L2 instead of L1 61 –61 16
5 bpy instead of L1 87   10
6 Ni/L1 7.5/8.25 mol % 85 93 9
7 Ni/L1 5/5.5 mol % 76 93 11
8 Mn0 instead of Zn0 83 92 11
9 TDAE instead of Zn0 0   0
10 no Ni/L1 0   51
11 7 instead of 1 0   51
12 4-BrPhMe (4a) instead of 2a <10   33
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a

Determined by 1H NMR versus 1,3,5-trimethoxybenzene as external standard. Isolated yield is provided in parentheses.

b

Determined by HPLC-SFC relay analysis using a chiral stationary phase. Enantiomeric excess after purification is provided in parentheses.

A control experiment performed in the absence of Ni/L1 afforded no cross-coupled product, suggesting that the C(sp2)–C(sp3) bond formation is mediated by nickel. Under these conditions, the protodehalogenation product 6 was formed in 51% yield (entry 10). This suggests that 1 can be directly reduced by Zn0, although it does not reveal if this process interfaces with productive C–C bond formation.26−28 Unfortunately, use of commercially available α-bromoimide 7 instead of 1 failed to give the desired product under standard conditions; again, substantial amounts of protodehalogenation product 6 were observed (entry 11). However, α-bromoimide 7 can be converted to α-chloroimide 1 by treatment with KCl and 18-crown-6, which can then be used in the Ni-catalyzed RCC (see Supporting Information for details). Only minimal yield of 5a was observed when 4-bromotoluene (4a) was employed instead of 2a (entry 12).

To evaluate the scope of the reaction, a variety of aryl iodides were coupled with 1 under standard conditions (Figure 2, method A). The yields of 5 were found to be sensitive to the electronics of the arene coupling partners, with more electron-rich aryl iodides giving the products in better yields (5a–5d). Free aniline (2l) and phenol (2m) derivatives could be cross-coupled in 54% and 51% yield, respectively; however, access to 5m required in situ silylation of the iodide 2m by pretreatment with Zn0 and TMSCl. These easily oxidized functional groups are useful handles for further elaboration but can be incompatible with related electrochemical approaches. Additional functional groups such as esters (2g), nitriles (2i), pinacol boronate esters (2j), and triflates (2k) were also compatible with the reaction conditions. Aryl iodides with ortho-substituents (2n and 2t) were tolerated in the RCC, although the yield and ee dropped with increasing steric bulk (2o). The absolute stereochemistry of 5u was determined by single crystal X-ray diffraction; the configuration of the rest of the products was assigned by analogy.

Figure 2.

Figure 2

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Substrate scope of (hetero)aryl halides. Isolated yields are provided for the higher-yielding method of each substrate. qNMR yields are provided in parentheses, and were determined versus 1,3,5-trimethoxybenzene as external standard. Enantiomeric excess was determined by SFC using a chiral stationary phase. aIn situ silylation of 2m with Zn0 (0.9 equiv) and TMSCl (1.65 equiv), cross-coupling, and subsequent deprotection with H2SiF6 (2.0 equiv) (see Supporting Information for details). b3.0 equiv of Zn0 was used.

Through these scope studies, we observed that the yields of 5 decreased with more electron deficient arenes (2g–2i, 2r–2s). 4-Iodopyridine derivatives, such as 2aa and 2ab, also underwent coupling in relatively low yields. In these cases, increased levels of biaryl homocoupling or protodehalogenation side products were generally observed, which we attribute to the faster rates of oxidative addition that were mismatched relative to the rate of activation of α-chloroimide 1. We recognized that electron-deficient aryl bromides should undergo slower oxidative addition than the corresponding aryl iodides,29 and thus might perform better in the reaction. Given the increased commercial availability and generally lower prices of aryl bromides,30,31 we decided to investigate these substrates.

We began by evaluating the RCC of 1 with 4-bromobenzotrifluoride (4h) under the optimal conditions for method A. Unfortunately, α-arylglutarimide 5h was formed in only 23% yield (Table S2, Supporting Information); however, in this case α-chloroimide 1 was fully consumed and significant amounts of unreacted 4h were recovered. These findings suggested that 1 was activated too quickly relative to oxidative addition of aryl bromide 4h, leading to deleterious protodehalogenation. Drawing from prior literature, we hypothesized that imides with α-sulfonates could be converted in situ to the α-haloimide;32−35 this would serve to keep the concentration of the α-haloimide low, thus effectively decreasing the overall rate of activation.

To test this hypothesis, we evaluated α-mesylate 3 and aryl bromide 4h as coupling partners. Under the optimal conditions for method A (see Table 1), no product was formed (Table 2, entry 1), suggesting that α-mesylate 3 either cannot be directly activated by the Ni catalyst or Zn0 reductant, or was activated too slowly by these species. Addition of NaI (1.0 equiv) induced RCC reactivity, forming 5h in 13% yield and 76% ee (entry 2). Increasing the NaI loading to 6 equiv and reducing the amount of DMA from 30% to 5% in THF improved the reactivity (entry 3).36 Extended reaction times (4 h) provided 5h in higher yield but lower ee due to slow racemization under the reaction conditions (entry 4). Further evaluation of solvents revealed that 1,2-dimethoxyethane (DME) suppressed racemization, resulting in 74% yield of 5h with 90% ee after 4 h (entry 5). Under these conditions, only a slight decrease in ee was observed even at extended reaction times (24 h, entry 6). In the absence of Ni/L1, no cross-coupled product was observed, while protodehalogenation product 6 was formed in 60% yield (entry 7), similar to what was observed in the α-chloroimide system. When 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbpy) was used instead of L1, racemic 5h was formed in 64% yield (entry 8).

Table 2. Optimization of Reaction Conditions for the RCC between Imide α-Mesylates and Aryl Bromides.

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entry deviation from standard conditions yield 5h (%)a ee 5h (%)b recovered 3 (%)a yield 6 (%)a
1 30% DMA/THF, no NaI, 21 h 0   57 9
2 30% DMA/THF, 1 equiv NaI, 21 h 13 76 45 6
3 5% DMA/THF, 2 h 60 90 18 9
4 5% DMA/THF 74 79 4 7
5 none 74 (69) 90 (88) 8 5
6 24 h 72 86 0 9
7 no Ni/L1 0   5 60
8 dtbbpy instead of L1c 64   0 24
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a

Determined by 1H NMR versus 1,3,5-trimethoxybenzene as external standard. Isolated yield is provided in parentheses.

b

Determined by HPLC-SFC relay analysis using a chiral stationary phase. Enantiomeric excess after purification is provided in parentheses.

c

Reaction time was 21 h (unoptimized).

The scope of aryl bromides was then evaluated using this new set of conditions, enabling the direct comparison with method A (Figure 2, method B). Substrates bearing electron-withdrawing groups such as ester and cyano groups at either the para (4g–4i) or meta position (4r, 4s, and 4w) underwent coupling with higher yields than in method A, albeit with slightly reduced ee. Mildly electron-donating groups such as para-methyl (4a) resulted in comparable yields, but further increase in the electron-donating strength of the substituents led to decrease in yield (4b and 4c). Several heteroaryl bromides (4aa–4af) were evaluated, furnishing the desired products in serviceable yields. We note that the enantioselectivity of these heterocycle-containing products was generally lower, likely due to the increased propensity for these more electron-deficient products to racemize under the reaction conditions. We also note that achiral ligands such as bpy or dtbbpy can be employed under otherwise identical conditions to access these products as racemates (Figure S5, Supporting Information).

To expand the imide scope beyond simple α-substituted glutarimides, we found that a selection of α-substituted imides could also serve as competent coupling partners (Figure 3a). The 7-membered cyclic α-chloroimide 8a underwent cross-coupling to form 9a in good yield and enantioselectivity, while the corresponding 5-membered cyclic substrate provided 9b in low yield and modest ee. β-Substituted imide 8c and N-p-methoxybenzyl imide 8d underwent cross-coupling smoothly in good yield with comparable enantioselectivity to 1 and 3, respectively. With an enantioenriched α-chloroimide bearing an additional stereocenter at the α′-position, both trans- and cis-coupled products (9e) were accessed in good diastereoselectivity using (R)-L1 and (S)-L1, respectively (Figure 3b). Under such catalyst control, the ee of the major diastereomers were further amplified to 97% and >99%, respectively.

Figure 3.

Figure 3

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Substrate scope of α-substituted imides. Isolated yields are provided. Enantiomeric excess is determined by SFC using a chiral stationary phase.

For the RCC between 3 and 4h, a time course analysis was conducted to monitor the conversion of starting materials and the formation of side products (Figure 4a). At early time points, aryl iodide 2h accumulated (presumably the result of Ni-catalyzed halide exchange),37 but then decayed at later time points (Figure 4a, tan line). In contrast, the α-haloimides derived from 3 were not observed over the course of the reaction, indicating that these species, if formed, were rapidly consumed. We note that treatment of 3 with NaI (1.0 equiv) in 5% DMA/DME (in the absence of Ni/L1 and Zn0) results in conversion to the α-iodoimide (11) in 43% yield over 4 h (Figure 4b). We propose that mesylate 3 is converted to the α-haloimide in situ, which undergoes halogen-atom transfer (XAT) by the L1·Ni complex or reduction by Zn0 to generate the radical.

Figure 4.

Figure 4

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(a) Time course study and (b) independent treatment of α-imide mesylate and iodide source. Yield and recovery were determined by 1H NMR versus 1,3,5-trimethoxybenzene as external standard. Enantiomeric excess was determined by SFC using a chiral stationary phase.

Based on previous reports of BiOX·Ni-catalyzed RCC reactions,28,38,39 we propose the following mechanism. Upon reduction of the L1·NiBr2 precatalyst, the L1·NiIX can undergo oxidative addition of the aryl halide followed by reduction (by either by Zn0 or L1·NiIX) to give an L1·NiIIArX species.28,40,41 Simultaneously, the α-haloimide can be activated either via XAT by the L1·NiIX complex,26,42 or reduced by Zn0,27 resulting in the generation of a cage-escaped α-imidoyl radical. This radical can be captured by the L1·NiIIArX species, followed by reductive elimination to yield the final product. Although we propose a radical-type mechanism, we recognize that Zn0 might further reduce the initially formed radical to a zinc enolate, which could engage in the Ni-catalyzed cross-coupling.43 However, we note that this reaction tolerates the acidic N–H of the imide, which would likely rapidly quench a zinc enolate. Since reduction to the zinc enolate may give rise to reduced imide 6 under suboptimal conditions, it seems less likely that it is on the catalytic pathway.

We also performed preliminary studies of the electrochemically driven cross-coupling using paired electrolysis. Under constant current electrolysis with N,N-diisopropylethylamine (Ep/2 = 0.73 V vs SCE)44 as the sacrificial reductant,45 graphite and nickel foam as the anode and cathode, respectively, the RCC proceeded in 32% yield in an undivided cell, suggesting that the nickel catalyst does activate the α-chloroimide 1 (Scheme 1). However, the reaction suffered from low conversion and Faraday efficiency. It is hypothesized that redox of the iodide side products (TBAI, Ep/2 = 0.26 V vs SCE)46 could outcompete the desired transformations. Ongoing efforts are focused on electroanalytical studies to further develop this electrochemically driven RCC.

Scheme 1. Best Electroreductive Arylation Condition to Date.

Scheme 1

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With rapid access to enantioenriched α-arylglutarimides, we became interested in the configurational stability of these molecules. It is known that the model glutarimide-based drug, thalidomide, rapidly racemizes in vivo.47 Therefore, we selected an electronically diverse set of the products and tracked the ee of their solutions in a pH 7 aqueous buffer/acetonitrile mixture at temperatures between 27 and 29 °C (Figure 5). The configurational stability was found to be strongly influenced with the electronic nature of the arene. α-Arylglutarimides with electron-withdrawing substituents at the para position (5h and 5i) racemize rapidly over the course of 24 h. Conversely, products bearing electron-donating groups at the para position were stabilized, with minimal racemization observed after 24 h. Products 5n and 5t, bearing ortho-substitution, demonstrated superior configurational stability over their para-substituted counterparts (5a and 5e, respectively), likely owing to the increased steric hindrance at the site of deprotonation. Building off prior studies by Leach and co-workers, we calculated the deprotonation energy at the α-position of the α-arylglutarimides, which can be related to the rate of racemization (see Supporting Information, Section 6).48 These results suggest that the configurational lability associated with glutarimide-based drugs could be tempered by rational design of the α-aryl substituents. Given that the two enantiomers of thalidomide and related glutarimides have different biological activity,47 enantioselective access to those compounds with higher configurational stability is advantageous.

Figure 5.

Figure 5

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Time course study of product ee with treatment of pH 7 aqueous buffer solution. Enantiomeric excess was determined by SFC using a chiral stationary phase.

Conclusion

In conclusion, we have developed Ni-catalyzed asymmetric RCCs between α-substituted imides and aryl halides. The reaction was found to be sensitive to activation rates of both C(sp2) and C(sp3) coupling partners, where use of electrophile pairs with well-matched rates was crucial for high cross-selectivity. For arenes bearing electron-donating substituents, RCC of the aryl iodide with the α-chloroimide showed superior performance. For arenes with electron-withdrawing substituents, RCC between the aryl bromide and α-imide mesylate proved more effective. Taken together, a broad scope of (hetero)aryl halides can be effectively coupled. This transformation enables the facile assembly of highly enantioenriched α-arylglutarimide motifs, which can serve as a powerful tool for elaboration toward PROTACs and other bioactive molecules. We anticipate that this method will find application in future medicinal chemistry studies.

Acknowledgments

We are grateful to Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the Beckman Institute X-ray Crystallography Facility at Caltech, as well as the Caltech CCE NMR facility and Multiuser Mass Spectrometry Laboratory. We thank Dr. Michael K. Takase and Preston J. Mott for assistance with X-ray crystallography. We thank Dr. Mona Shahgholi for assistance with mass spectrometry measurements. The authors thank Prof. Matthew Sigman and Alex Ring (University of Utah) for helpful discussions. L.-M.C. acknowledges fellowship support by a J. Yang Fellowship from Caltech. A. C.-C. acknowledges the Swedish Research Council for a postdoc fellowship (Vetenskapsrådet, VR-2022-06175). This work was supported by the NSF Center for Synthetic Organic Electrochemistry, CHE-2002158.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c09327.

  • Experimental procedures, characterization data (1H, 13C, and 19F NMR, HRMS, FTIR) for all new compounds, computational details, and X-ray data for compound 5u (CCDC deposition number 2366079) (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja4c09327_si_001.pdf (21.1MB, pdf)

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