A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides

Abstract

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

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Introduction

The introduction of fluoroalkyl substituents in organic molecules has an important effect on their physical and chemical properties, including those relevant to biomedical applications such as biodisponibility and metabolic stability.¹ The importance of these properties in pharmacological and agrochemical applications has inspired the organic chemistry community during the last few decades and a huge effort has been dedicated to the development of synthetic methods for organofluorine compounds,² even in an enantioselective fashion.³ From the synthetic point of view, the synthesis of carbonyl compounds decorated with fluoroalkyl substituents is especially appealing, as they allow for further modification in virtually every functional group. Specifically, the synthesis of difluorinated carbonyl compounds has attracted attention due to the oxygen bioisosteric properties of the –CF₂– group⁴ and the biological activity of some of these compounds (Fig. 1).⁵ α,α-Difluorocarbonyl compounds can also serve as versatile building blocks for the synthesis of other fluorinated moieties.⁶ On the other hand, the difluoromethylene group attached to a stereogenic centre can be found as a structural motif in drugs and bioactive compounds (Fig. 1).⁷ However, the enantioselective synthesis of chiral compounds bearing such a structural motif is not a trivial task as the presence of the fluorine atoms may alter the reactivity of the involved functional groups or the interaction of the substrates with the chiral catalyst, hampering the enantiomeric control.⁸ Thus, while the electronegativity of fluorinated substituents has facilitated their use as electrophilic starting materials,⁹ the enantioselective introduction of fluorine-containing scaffolds as nucleophiles is a more challenging task that requires the use of special reagents.¹⁰

Fig. 1 Some examples of bioactive compounds bearing an α,α-difluorocarbonyl moiety or a CF₂ attached to a stereogenic centre.

In this context, the employment of difluoroenoxysilanes¹¹ as nucleophiles has been demonstrated to be an efficient tool for the synthesis of difluoromethyl-containing compounds. However, the number of examples involving the nucleophilic addition of difluoroenoxysilanes in an enantioselective fashion is scarce and almost limited to nucleophilic addition to imines,^12,13 while the Mukaiyama aldol-type reaction¹⁴ remains almost unexplored and only two organocatalytic examples involving reactive α-keto esters¹⁵ or isatins¹⁶ have been reported by Zhou, to the best of our knowledge (Scheme 1).

Scheme 1 Enantioselective Mukaiyama aldol reaction with difluoroenoxysilanes.

2-Acylpyridine N-oxides are interesting substrates for asymmetric catalysis. Their capacity to form a chelate with a chiral metal complex makes them ideal electrophilic substrates for stereoselective transformations, providing pyridine derivatives with chiral pendants. Taking advantage of these properties, these compounds have been widely used in enantioselective transformations. Jørgensen and co-workers described in 2006 the Cu-BOX catalysed addition of ketene silyl–enol ethers to the N-oxides of formylpyridine.¹⁷ Since then, a variety of transformations have been reported with these substrates by our group¹⁸ and others,¹⁹ giving access to enantioenriched compounds containing a widely spread pyridine moiety. Herein, we report our results on the copper-catalysed Mukaiyama aldol reaction of difluoroenoxysilanes and 2-acylpyridine N-oxides (Scheme 1c).

Results and discussion

Optimisation of the reaction conditions

At the onset of our investigation, we chose 2-acetylpyridine N-oxide (1a) and difluoroenoxysilane 2a as reaction partners for the optimization process. Taking into account the precedent reported by our research group,¹⁸ we envisioned that Cu(II)/BOX could serve as an effective catalytic system. Therefore, we screened a series of BOX chiral ligands with different substitution patterns, using Cu(OTf)₂ as the metal source (Scheme 2 and Table 1). Despite the modest reactivity of the system, promising levels of enantioinduction were obtained with L8 (Table 1, entry 8). Further optimization of the copper(II) source revealed an improvement in enantioselectivity when Cu(BF₄)₂ was used, albeit still with modest reactivity (Table 1, entry 10). An increase in the equivalents of nucleophile 2a led to the expected improvement in yield, although with a moderate decrease in the enantioselectivity (Table 1, entry 11).§ We next studied the effect of the solvent, observing a further improvement in yield when using THF, keeping the good levels of enantioselectivity (Table 1, entry 14). Finally, we performed the reaction at different temperatures. The reaction virtually shuts down at −20 °C, while an increase to 50 °C has a detrimental effect on the enantioinduction (Table 1, entries 16 and 17). Therefore, we established BOX ligand L8 in combination with Cu(BF₄)₂ to be our optimal catalytic system, while performing the reaction in THF as the solvent at room temperature.

Scheme 2 Enantioselective reaction between 1a and 2a and BOX ligands used in this study.

Table 1 Copper-catalysed enantioselective reaction of 1a and 2a. Optimization of the reaction conditions^a

Entry	Cu salt	L	Solvent	Yield^b (%)	ee^c (%)
a 1a (0.1 mmol), 2a (0.12 or 0.5 mmol), Cu salt (0.01 mmol), L (0.01 mmol), room temperature, 4d. b Isolated yields. c Determined by chiral HPLC analysis. d 2a (0.12 mmol. e 2a (0. 5 mmol). f Reaction performed at −20 °C. g Reaction performed at 50 °C.
1^d	Cu(OTf)2	L1	CH2Cl2	37	−15
2^d	Cu(OTf)2	L2	CH2Cl2	43	48
3^d	Cu(OTf)2	L3	CH2Cl2	40	10
4^d	Cu(OTf)2	L4	CH2Cl2	27	55
5^d	Cu(OTf)2	L5	CH2Cl2	24	41
6^d	Cu(OTf)2	L6	CH2Cl2	42	67
7^d	Cu(OTf)2	L7	CH2Cl2	20	0
8^d	Cu(OTf)2	L8	CH2Cl2	32	83
9^d	CuBr2	L8	CH2Cl2	30	81
10^d	Cu(BF4)2	L8	CH2Cl2	24	91
11^e	Cu(BF4)2	L8	CH2Cl2	70	85
12^e	Cu(BF4)2	L8	DCE	38	80
13^e	Cu(BF4)2	L8	CHCl3	48	84
14^e	Cu(BF4)2	L8	THF	90	87
15^e	Cu(BF4)2	L8	Toluene	42	66
16^e^,^f	Cu(BF4)2	L8	THF	9	—
17^e^,^g	Cu(BF4)2	L8	THF	87	73

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Study of the reaction scope

With the optimized reaction conditions in hand (Table 1, entry 14), we explored the scope of our methodology by reacting enol ether 2a with different 2-acylpyridine N-oxides 1 (Scheme 3). Alkyl substituents are well tolerated at different positions of the pyridine ring of 1. Substrate 1b, bearing a methyl group at position 4 (R¹ = 4-Me), delivered the desired product 3ba in fair yield and enantioselectivity (57%, 77% ee). Better results were obtained when using substrate 3c substituted at position 5 (R¹ = 5-Me) that provided 3ca in 72% yield and 89% ee. Interestingly, N-oxides 1d (R¹ = 6-Me) and 1e (R¹ = 6-Br), which have potentially problematic substituents at position 6 of the pyridine ring near the N-oxide coordination site, reacted satisfactorily to provide 3da and 3ea in high yields and still remarkable enantioselectivities (79% and 60% ee, respectively). At this point, we explored other ketones 1f–h bearing a larger ethyl group attached to the carbonyl group. These reacted with 2a to give compounds 3fa, 3ga and 3ha in good yields and with high enantioselectivities (84%, 93% and 83% ee, respectively).

Scheme 3 Enantioselective Mukaiyama-aldol reaction of acylpyridine N-oxides 1 and difluoroenoxysilanes 2. Reaction conditions: 1 (0.2 mmol), 2 (1 mmol), Cu(BF₄)₂ (0.02 mmol), L8 (0.02 mmol), THF (2 mL), room temperature, 4 days. Isolated yields. Ee determined by chiral HPLC analysis.

Next, the substitution in the difluorosilyl enol ether moiety was evaluated, albeit with diverse success. Unexpectedly, switching from phenyl to the 4-methylphenyl substituent in 2b had a detrimental effect on enantioinduction (3ab, 68% yield, 57% ee). Interestingly, the excellent selectivity was re-established when 2b was reacted with 1c, which afforded compound 3cb in moderate yield but with excellent enantioselectivity (61%, 89% ee). Moreover, phenyl rings substituted at different positions with electron-donating groups 2c (R³ = 4-MeOC₆H₄), 2d (R³ = 3-MeOC₆H₄), or halogens 2e (R³ = 4-ClC₆H₄) and 2f (R³ = 4-FC₆H₄) were tolerated, giving the expected products 3ac–3af with fair to good enantiomeric excesses. Finally, enol ether 2g bearing a heterocyclic ring (R³ = 2-thienyl) could be employed, yielding aldol 3ag in moderate yield and good enantiomeric excess (83%). Unfortunately, difluoroenoxysilanes 2 bearing an alkyl R³ group (Bn) did not react under the optimised conditions.

At this point, we performed a control experiment to establish the importance of the N-oxide moiety in our method. Upon subjecting 2-acetylpyridine (4) to the optimized reaction conditions with 2a, the corresponding aldol was obtained in less than 10% yield (Scheme 4). This result showcases the importance of the N-oxide scaffold, especially in order to achieve the required coordination of the electrophilic reaction partner with the metal catalyst. Reduction of the N-oxide functional group was achieved by Pd-catalysed hydrogenolysis with concomitant ketone reduction, affording 6aa without a noticeable erosion of enantiomeric excess. On the other hand, treatment of compound 3ac with m-CPBA yielded the corresponding Baeyer–Villiger product 7ac regioselectively. Noticeably, the Baeyer–Villiger reaction did not proceed with compound 3aa and required an electron-richer substituent attached to the carbonyl group. Finally, addition of MeMgBr to the ketone in 3ha allowed us to obtain the corresponding tertiary alcohol 8ha in good yield and with modest diastereoselectivity.

Scheme 4 Control experiments and synthetic transformations of compounds 3.

Computational studies

Compound 3ag could be crystallized and subjected to X-ray analysis that allowed us to determine the configuration of the stereogenic centre to be S (Fig. 2).¶

Fig. 2 ORTEP plot for the X-ray structure of compound 3ag with thermal ellipsoids drawn at the 50% probability level. Flack parameter 0.01(3).

The stereochemistry of all compounds 3 was assigned by analogy, assuming a common stereochemical pathway. The observed stereochemistry indicates a preferential attack of the silyl enol ether to the Re face of the carbonyl group. To explain this stereochemical outcome, DFT calculations were performed with the UB3LYP-D3 functional,²⁰ as implemented in Gaussian 09,²¹ with 1a and 2a as model substrates (Fig. 3). Geometries were optimized using the 6-31G(d,p) basis set for H, C, N, O, F, and Si, while the LANL2DZ pseudopotential was employed for Cu.²² Based on these geometries, single-point calculations were performed using functional ωB97XD at the 6-311+G(d,p) level of theory for H, C, N, O, F, and Si and LANL2TZ for Cu.²³ As expected, our studies showed that distorted square-planar complexes, with 1a chelating the copper centre with both oxygens, are energetically favoured. Subsequent nucleophilic attack of the silyl enol ether 2a is sterically controlled by the position of the phenyl rings in the ligand, which blocks more efficiently the attack from the Si-face by interaction with the fluorine atoms in 2a. The Re-face approach (TS-Re) presents a barrier of 16.6 kcal mol⁻¹, while the one leading to the attack from the Si face goes up to 18.6 kcal mol⁻¹. This ΔΔG^‡ = 2 kcal mol⁻¹ is in good agreement with our experimental results. Finally, the corresponding INT-B will lead to the observed product by TMS-group transfer.

Fig. 3 DFT calculations for the enantioinduction step. Free energy values are at the ωB97XD/LANL2TZ(Cu)/6-311+G(d,p)//UB3LYP-D3(SMD-tetrahydrofurane)/LANL2DZ (Cu)/6-31G(d,p) level of theory. Hydrogens omitted for clarity.

Conclusions

In conclusion, in this communication we present the first enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides, using a Cu(II)/BOX catalytic system. Moderate to excellent yields and high enantioselectivities are usually obtained for a variety of substitution patterns. This methodology provides an innovative access to novel difluorinated chiral tertiary alcohols, which are of great interest in fields such as medicinal chemistry. Finally, we proved the importance of the N-oxide moiety in the success of the method, and we also demonstrated its removal by Pd-catalysed hydrogenolysis.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Grant PID2020-116944GB-100 funded by MCIN/AEI/ 10.13039/501100011033 and by the “European Union Next Generation EU/PRTR”. Grant CIAICO/2021/147 funded by Conselleria d'Innovació, Universitats, Ciència i Societat Digital. Grant RyC-2016-20187 funded by MCIN/AEI/ 10.13039/501100011033 and by “ESF Investing in your future” to C. V. Access to NMR, MS and X-ray facilities was provided by the Servei Central de Suport a la Investigació Experimental (SCSIE)–UV.

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Footnotes

† Dedicated to Professor Joan Bosch, Universitat de Barcelona, on the occasion of his 75th birthday.

‡ Electronic supplementary information (ESI) available. CCDC 2190657. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2ob01763f

§ The use of 2 equivalents of 2a led to just a modest increase of yield (35%). On the other hand, the triethylsilyl protected difluoroenoxysilane (TES instead of TMS) was not reactive.

¶ CCDC 2190657 contains the supplementary crystallographic data for compound 3ag.

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