Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLES15 Nov 2022Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation Tangyu Zhan, Liangkun Yang, Qiyou Chen, Rui Weng, Xiaohua Liu and Xiaoming Feng Tangyu Zhan Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Liangkun Yang Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Qiyou Chen Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Rui Weng Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author , Xiaohua Liu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author and Xiaoming Feng *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202405 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The Norrish type II reaction is an interesting photochemical process through Csp3-H functionalization of N,N-disubstituted oxo-amine or oxo-amide provides access to diverse synthetic building blocks by different pathways. Due to the finite lifetime of the excited state and rapid changes in the intermediates, there are significant challenges in controlling the stereochemical outcomes of this reaction over the strong racemic background reaction. The oxazolidin-4-one skeleton is a useful structural motif found in bioactive molecules, and it is the one that is produced by a not well-studied route among the three routes in Norrish type II cyclization. Herein we report the asymmetric version of this process, and a variety of oxazolidin-4-ones is achieved from aryl α-oxoamides via triplet excimers with three H-transfer steps interspersed by a cyclization step under mild, visible light. In the presence of chiral N,N-dioxide/metal complex catalysts, diastereo- and enantiocontrol in this photochemical reaction happens with enantioselective protonation of enol intermediates as the crucial stereo-determining step, getting the better of the thermodynamical control pathway. Trans-oxazolidine-4-ones can be obtained in high enantioselectivity, which can be transferred into optically active cis-oxazolidine-4-ones after the treatment with a base. Download figure Download PowerPoint Introduction The Norrish type II reaction is one of the most important photochemical processes in ketones,1–9 and has recently been reinvestigated with the focus on photocatalysis and C(sp3)-H functionalization. A well-studied example is the photolysis of N,N-disubstituted oxo-amine or oxo-amide which is initiated through a biradical intermediate, then undergoes three types of transformations, that is, Norrish–Yang type, to afford the alcohol or β-lactam, elimination or fragmentation, followed by addition, and 1,4-hydrogen shift, followed by cyclization to yield the oxazolidinone (Scheme 1a).10–13 Early efforts to achieve enantioselectivity in this photorearrangement included absolute asymmetric synthesis of single crystals or chiral host-achiral substrate guest inclusion complexes in the solid state.14–16 These studies also gave a glimpse of the excited state geometry required in the reaction.17–20 Bach and coworkers21 explored enantioselective Norrish–Yang cyclization of imidazolidinone under the induction of a chiral host through hydrogen bonds to give the alcohols in moderate enantiomeric excess in toluene (Scheme 1b). Chiral auxiliary approaches have also been employed to asymmetric induction in the α-oxoamide to β-lactam.14 Almost 30 years ago, Henin, Muzart and co-workers22 were concerned with the enantioselective protonation of simple enols generated from a Norrish type II photoelimination process using acatalytic amount of (-)-ephedrine. As an interesting variant, the Norrish type II reaction of α-acylated saturated heterocycles via fragmentation to give ring contraction products was recently discovered by Sarpong and co-workers,23 covering seven examples in asymmetric version via chiral phosphoric acid-accelerated intramolecular imine-enol addition (Scheme 1c). Scheme 1 | General information about the Norrish type II reaction. Download figure Download PowerPoint The oxazolidin-4-one skeleton is a useful structural motif found in natural products and bioactive molecules,24–26 which is usually the accompanying product in the Norrish type II transformation of oxo-amines, especially in protic solvent27,28 (Scheme 1d). As a matter of fact, asymmetric catalytic Norrish type II transformation into α-oxazolidinone remains rare and challenging. To develop a chiral catalyst for this type of photochemical reaction is critical not only to control the competitive pathways to form a single product, but also to guide the cyclization and protonation enantioselectively over the strong racemic background reaction. Lewis acid has a pronounced effect on the acceleration of reactions via changing the frontier orbital energies, bond polarity, ground-excited state energies, and the spin states and lifetime of excimers as well in photocatalysis.29–42 In recent progress, Huang and Maggers,43 Yoon,44 and Bach et al.35,45 witnessed its function in chiral Lewis acid-promoted visible-light photocatalytic asymmetric synthesis. We envisage that the employment of a chiral Lewis acid catalyst to induce stereocontrol in both the cyclization and protonation steps in Norrish type II cyclization is possible, in view of the fact that the NMR study on N-substituted α-oxoamides using lanthanide shift reagents revealed that metal salt preferably bonds with the amide carbonyl oxygen.46–48 However, to accomplish this, the interaction of the catalyst cannot weaken the irradiation of aryl α-oxoamides, and chiral ligand should guarantee fitting pocket for the configuration requirement of active intermediate variation and rotation, as well as provide hydrogen-bond net for facial-selective protonation, which are nearly barrierless but stereoselective subsequent steps (Scheme 1d).49–58 As part of the continuing study of chiral N,N'-dioxide-based Lewis acid catalysis,59–73 herein we report an asymmetric Norrish type II reaction of aryl α-oxoamides to form optically active α-oxazolidinones, which is irradiated by a blue light. Specifically, the chiral Lewis catalyst enabled by zinc(II) generated a number of α-oxazolidinones in good to excellent yield (up to 98%) and satisfied enantioselectivity for the trans-isomer (up to 98% ee), which was transferred into the more stable cis-isomer while maintaining enantiomeric excess upon late-stage treatment. Experimental Methods General procedure for asymmetric reaction with 1a A mixture of L3-PrMe2Ad (10 mol %, 0.02 mmol, 15.6 mg), and Zn(BF4)2.6H2O (10 mol %, 0.02 mmol, 7.0 mg) was added to a dry glass quartz test tube under a nitrogen atmosphere. Then the mixture was stirred in anhydrous dichloromethane (DCM) (1.0 mL) at 35 °C for 30 min, and DCM was removed under reduced pressure. Then, 1a (0.2 mmol) was added to the dry glass quartz test tube containing the prepared catalyst with anhydrous CH3CN (0.2 M). The resulting mixture was degassed by bubbling it with N2 for 20 min. Then it was stirred under 400–440 nm 30 W irradiation at −20 °C with photoreactor B. The reaction progress was monitored by thin-layer chromatography (TLC). After 12 h, the solvent was removed in vacuo, and the desired products were purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/3 to 2/3). Results and Discussion We undertook photochemical investigation of phenyl α-oxoamide 1a as the model substrate under irradiation of a blue light in CH3CN at −20 °C. As shown in Table 1, we found that there was a strong background reaction upon irradiation with blue light (400–440 nm), and the α-oxazolidinone 2a was isolated in 78% yield and 30:70 trans:cis ratio. We next sought to identify optimal chiral catalyst to control the stereoselectivity. The optimization of chiral ligands in the presence of Zn(BF4)2·6H2O showed that the chiral N,N'-dioxide ligands (Figure 1) appeared to be effective in favoring the stereoselective synthesis of α-oxazolidinone 2a (see Supporting Information for more details). Using L-proline as the starting chiral material, and several bisamine-oxides bearing different amide subunits were examined (entries 2–7). This revealed that the steric hindrance of the amides had an obvious effect on both the yield and stereoselectivity. Less sterically hindered benzyl and phenyl groups resulted in poor enantioselectivity (entries 2 and 3), but the enantioselectivity of the trans- 2a increased to 94% ee when 2,6-dimethylaniline-based L3-PrMe2 was employed. In order to improve the diastereoselectivity, subtle modification of substitutions at the aniline unit was carried out (entries 5–8), and it was observed that introduction of sterically hindered 1-adamantyl group into the para-position, ( L3-PrMe2Ad) led to a slightly higher diastereoselectivity, and the trans- 2a became the major diastereomer with up to 98% ee (entry 8). However, if the steric hindrance of 2,6-disubstituents increased, such as 2,6-diethyl or 2,6-diisopropyl groups, both the reactivity and the stereoselectivity dropped noticeably (entries 9 and 10). We also tested the performance of N,N'-dioxide ligands coordinated with other metal salts, and found that not only the metal center and the ligand structure, but also trace amounts of water in the system dramatically influenced the enantioselectivity, indicating that the enantio-determining step might be the protonation step (entries 11–13). If using Zn(OTf)2 instead of Zn(BF4)2·6H2O, both the reactivity and the stereoselectivity dropped a little (entry 14 vs. entry 8). When the reaction took place at room temperature, the outcome decreased due to the stronger background reaction. Thus, the optimal reaction condition for this photocatalysis was rationalized as the combination of Zn(BF4)2·6H2O and L3-PrMe2Ad at −20 °C in CH3CN under the irradiation of 400–440 nm light (entry 8). Table 1 | Optimization of the Reaction Conditionsa Entry Variation from Std. Yield (%) trans∶cisb ee (%)b 1 Without zinc salt and L* 78 30∶70 0/0 2 L3-PrBn 89 31∶69 25/8 3 L3-PrPh 72 33∶67 12/12 4 L3-PrMe2 93 48∶52 94/22 5 L3-PrMe3 88 49∶51 95/24 6 L3-PrMe2Br 98 60∶40 95/3 7 L3-PrMe2 t Bu 90 61∶39 95/20 8 None 92 67∶33 98/3 9 L3-PrEt2Ad 83 49∶51 87/43 10 L3-Pr i Pr2Ad 79 37∶63 80/31 11 Dy(OTf)3 65 42∶58 56/46 12c Dy(OTf)3/H2O 72 42∶58 90/77 13 Yb(OTf)3 61 44∶56 71/61 14 Zn(OTf)2 68 57∶43 90/38 15 Room temp. 75 52∶48 83/28 aUnless otherwise noted, the reactions were carried out with α-oxoamide 1a (0.2 mmol), Zn(BF4)2·6H2O /L3-PrMe2Ad (1∶1, 10 mol %) in CH3CN (0.2 M) at −20 °C for 12 h. bThe trans/cis ratio and ee value were determined by 1H NMR spectroscopy or HPLC analysis. cAdding 15 μL of H2O. Figure 1 | Chiral N,N′-dioxide ligands used in the study. Download figure Download PowerPoint Under optimal conditions, the substrate scope of Norrish type II reaction of aryl α-oxoamides was evaluated as listed in Table 2. A series of α-oxazolidinones could be obtained in moderate to excellent yields (50–98%) and enantioselectivity (63–98% ee) for the trans-diastereomers. The substrates containing either electron-donating or electron-withdrawing substitution at the para-position of the aryl group were tolerable, and the yield and enantioselectivity were not affected obviously ( 2b– 2n). Notably, functional groups, such as trifluoromethyl ( 2k), cyano ( 2l), ester ( 2m), and pyrazole ( 2n), were compatible in the transformation. 3,4-Disubstituted substrates underwent the reaction well with good enantioselectivity ( 2o– 2r). Generally, electron-donating groups, such as 4-OMe and 3,4-OMe substitutions, were negative for the transformation which led to lower yield of the related products 2e and 2o, due to readily formed of δ-lactam byproduct via direct biradical coupling. Ortho-bromo-substituted product 2s was isolated in 97% yield with 98% ee for the trans-isomer. 2-Methyl or 2-fluror-containing product 2t and 2u were afforded in decreased diastereo- and enantioselectivity. In addition, the phenyl ring could be replaced by 2-naphthyl ( 2v), 2-benzofuran ( 2w), 2-thiophene ( 2c), but the yield of the latter two also dropped a lot as a result of formation of the related Norrish–Yang cyclization adducts. Unfortunately, neither the diastereoselectivity nor the enantioselection of the minor isomer was satisfactory. The absolute configuration of the trans-isomer of the product 2n was determined to be (2S, 8aS) by X-ray crystallography analysis (Table 2; see Supporting Information for more details). Table 2 | Substrate Scope of Benzoyl α-Oxoamidesa aReaction conditions: oxo-ketoamide 1 (0.2 mmol), Zn(BF4)2·6H2O /L3-PrMe2Ad (1∶1, 10 mol %) and CH3CN (0.2 M) under nitrogen with 400–440 nm 30 W irradiation at −20 °C. The trans/cis ratio was determined by 1H NMR spectroscopy of the crude products. The ee values were determined by UltraPerformance Convergence Chromatography (UPCC) analysis. The yields are the combined isolated yields of the two diasteroisomers. Table 3 | Substrate Scope of Piperidine Ringsa aReaction conditions: phenyl α-oxoamides 3 (0.2 mmol), Zn(BF4)2·6H2O /L3-PrMe2Ad (1∶1, 10 mol %) in CH3CN (0.2 M) under nitrogen with irradiation with 400–440 nm light (30 W) at −20 °C; and the trans/cis ratio was determined by 1H NMR spectroscopy of crude products. The ee value was determined by UPC2 analysis. Isolated yield. bAdding 15 μL of H2O, with 20 mol % Gd(OTf)3/ L3-PrMe2Br as the catalyst. Subsequently, we turned our attention to the variation of the amide subunits of phenyl α-oxoamides ( 3a– 3s) to illustrate the desymmetric reaction (Table 3). First, we examined the effect of the C4-substituent at the piperidine ring on the reaction ( 4a– 4l). We found that there were only two diastereomers where the two hydrogens at the stereogenic centers of the piperidine ring adopt trans-configuration. The diastereoselectivity of the reaction was similar to the unsubstituted products 2, occurring at the oxazolidinone ring. Methyl ( 4a), benzyl ( 4b), or phenyl ( 4c) substituted products were given in moderate yield (60–76%) and high enantioselectivity for the trans-isomers (93–95% ee). When the C4 position was substituted by an ester group ( 4d– 4f), with the steric hindrance of the ester group increased, the enantioselectivity dropped, but the yield improved. When C4-position was decorated with cyano ( 4g) or trifluoromethyl ( 4h), the trans:cis ratio raised slightly with good enantioselectivity. But introducing a pyrazole substitution at the aryl group simultaneously led to the product 4i with reversal of cis-preference and a drop in ee value. Although ethyl acetate group ( 4l) or 1,3-dioxolan-2-yl ( 4j) group at the C4-positon were applicable, morpholine substitution ( 4k) resulted in lower yield and enantioselectivity. The 3,5-dimethyl substituted piperidine-based amide afforded the product 4m in 90% yield but without enantioselectivity. If the piperidine ring at the amide unit was altered into morpholine, the corresponding ketoamide gave rise to the product 4n in good yield and moderate enantioselectivity. In comparison, azepane-based amide underwent the reaction well to provide the product 4o in 64% yield and 93% ee for the trans-isomer. For these N-heterocycle-based amide substrates, the enantioselectivity of the minor diastereomers was not satisfactory. The reason for the low yield in some cases is the competition of the formation of Norrish cyclization lactam products (up to 30% yield). The acyclic N,N′-dialkyl containing phenyl α-oxoamides, such as isopropyl, ethyl, n-propyl, and n-butyl substitution, performed the reaction with moderate to excellent enantioselectivity (75–94% ee) for the trans-isomer ( 4q– 4s). The corresponding cis-isomer was also isolated in moderate ee value (70–80% ee) in the presence of Gd(OTf)3/ L3-PrMe2Br catalyst. The isopropyl group bearing one shiftable hydrogen afforded dimethyl-bearing α-oxazolidinone 4p in 78% yield and 75% ee. With the straight chain extended, the reactivity decreased a lot. To illustrate the potential synthetic utility of the current catalytic system, a scale-up synthesis of 2h was performed. As shown in Scheme 2a, under the optimized reaction conditions, 1h (4.07 mmol) smoothly delivered the desired product in 98% yield with 68∶32 dr and 98% ee for the trans- 2h. In view of the epimerization property of the product via the enolization process, we treated optically enriched trans-product 2h (98% ee), whose diastereomers were separated, with 1,8-Diazabicyclo[5,4,0]undec-7-ene (DBU) in CH2Cl2, and found that the cis- 2h was isolated in 60% yield, maintaining enantioselectivity (98% ee). The absolute configuration of this cis- 2h was confirmed to be (2R, 8aS) by X-ray crystallography analysis (see Supporting Information for more details). As a result, the configuration of the initial trans- 2h was assigned as (2S, 8aS). In addition, using the enantiomer of the chiral ligand L3-PrMe2Ad instead, the other two isomers were also obtained in high enantioselectivity (Scheme 2b). This process enabled the access to the four isomers in high enantioselectivity, which partially compensates for the unsatisfactory ee value of the cis-products via direct asymmetric catalytic reaction. It is noteworthy that the cis-isomer seems to be the thermodynamically stable one, which implies the difficulty of yielding the trans-isomer in a highly selective manner. Scheme 2 | Gram-scale synthesis and further transformations. Download figure Download PowerPoint To gain insight into the reaction process, we carried out deuterium-labelling experiments to trace the proton transfer steps. As shown in Scheme 3, when 5 equiv of D2O was added into the reaction of 1a in the presence of Zn(OTf)2 /L3-PrMe2Ad, [D]1-product 2a was obtained with 68% D-ratio. Inserting product 2a into the chiral catalytic system and adding 5 equiv of D2O, no [D]1-2a was detected. This indicates that D2O or H2O in the reaction system may participate in proton transfer in the final step. The transformation of deuterium-labelled benzoyl ketoamide D-1a (97%) was examined, and the products of [D]2-2a was detected as a 25% D-ratio at the α-position. This data indicate that trace amounts of water in the catalytic system might be more readily involved in the 1,4-hydrogen transfer or enol interconversion process. Scheme 3 | Deterium-labeling study. Download figure Download PowerPoint The absorption and emission spectra of phenyl α-oxoamide 1a in the absence and presence of zinc complex are shown in Figure 2. There is no obvious absorption spectral change resulting from complexation of 1a with chiral zinc(II) complex of L3-PrMe2Ad, but the absorptance drops a little from the mixture of 1a and Zn(BF4)2. This indicates that the chiral catalyst at least does not diminish the excitation of the substrate, albeit the bathochromic shift or enhanced absorption in visible-light region is not obvious. The change in the luminescence spectra of 1a upon addition of Zn(BF4)2 or chiral zinc complex catalyst is obvious in terms of phosphorescence intensity and lifetime (1.61 vs. 2.14 ms). The slight blueshift and increased intensity of the complex in emission spectra indicates the generation of triplet-excited complex, which is beneficial for the formation of α-oxazolidinone over the Norrish–Yang type cyclization and the noncatalyzed racemic process. Figure 2 | Absorption (solid lines) and phosphorescence (dashed lines) spectra of phenyl α-oxoamide 1a in the presence or absence of the catalyst. Download figure Download PowerPoint Based on the control experiments and previous work, a possible reaction pathway has been proposed (Scheme 4). Initially, the octahedral zinc(II) complex catalyst74,75 bonds with the amide oxygen of the α-oxoamide substrate to form the Int-1. This is irradiated under blue light, and the CO–CO bond rotates to some extent upon excitation, which undergoes 1,5-HAT via the six-membered ring (TS-1) to give the triplet biradical, rotamer Int-2. If the ring closure of the singlet excimer via a four-membered ring occurs, the β-lactam product is generated. Otherwise, the rotation leads to O–C–C–O dihedral angles closer to perform 1,4-H shift via a five-membered ring (TS-2)10,11,76 or in an intermolecular proton-transfer manner, and zwitterionic Int-3 is generated after single electron transfer. Due to the rotation of the single bond of Int-3, it is not easy to control the intramolecular attack of oxygen anion to imine, generating the chiral enol Int-4 and the isomer Int-4′. Finally, facial-selective 1,3-protonation happens to yield the α-oxazolidinone. During this process, due to the thermodynamic stability of the diastereomers of the products, there are two competitive pathways. The substrate-controlled 1,3-protonation results in the formation of (2R,8aS)-product and the other cis-enantiomer. However, as shown in TS-3, water in the catalytic system bonds with the zinc(II) centra to form hydrogen-net, which acts as the proton shutter to accomplish Re-facial selective 1,3-protonation, generating (2S,8aS)-α-oxazolidinone as the major product. Scheme 4 | Proposed catalytic cycle. Download figure Download PowerPoint Conclusion We have described the first example of a highly enantioselective catalytic Norrish type II reaction of α-oxoamides to form oxazolidin-4-one compounds in the presence of chiral N,N′-dioxide/Zn(BF4)2·6H2O catalyst. Various substituted aryl or heteroaryl α-oxoamides can be applied to this desymmetrization process to obtain the target products with good to excellent results (up to 98% yield, 98% ee). The catalyst benefits the generation of triplet excimer and provides suitable space not only for the rotation of the intermediates to meet the configuration requirement in hydrogen transfer processes, but also for a compact hydrogen net for facial-selective protonation, overwhelming the strong racemic background reaction. Further applications of photocatalysis with chiral Lewis acids are ongoing in our laboratory. Supporting Information Supporting Information is available and includes general information, substrates synthesis, experimental procedures, optimization details, control experiments, synthesis transformations, X-ray crystallographic data, product characterization data, and copies of supercritical fluid chromatography (SFC), high-performance liquid chromatography (HPLC), and NMR spectra. Conflict of Interest There is no conflict of interest to report. Funding Information We appreciate the financial support of the National Natural Science Foundation (grant no. 22188101), the Science and Technology Department of Sichuan Province (grant no. 2021YJ0561), and Sichuan University (grant no. 2020SCUNL204) for financial support. Acknowledgments The authors wish to acknowledge Dr. Yuqiao Zhou at Sichuan University for X-ray crystal analysis.