Catalytic Desymmetrization of meso-Aziridines with Benzofuran-2(3H

Letter pubs.acs.org/acscatalysis

Catalytic Desymmetrization of meso-Aziridines with Benzofuran2(3H)‑Ones Employing a Simple In Situ-Generated Magnesium Catalyst Dan Li,† Linqing Wang,† Dongxu Yang, Bangzhi Zhang,* and Rui Wang* Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China S Supporting Information *

ABSTRACT: The first example of catalytic desymmetrization of meso-aziridines with benzofuran-2(3H)-ones is realized by employing a magnesium catalyst utilizing BINOL as a simple and commercially available chiral ligand. Both of the enantiomers of the ring-opening product could be easily accessed by employing (R)- or (S)-BINOL as chiral ligand, respectively. A variety of enantioenriched 3,3disubstituted benzofuran-2(3H)-ones containing multiple linear continuous stereocenters were obtained with moderate to good yields, diastereo- and enantioselectivities. KEYWORDS: desymmetrization, meso-aziridines, benzofuran-2(3H)-ones, magnesium catalyst, BINOL

C

many biologically active natural products and pharmaceutically relevant compounds.12 Many of them feature a chiral quaternary stereocenter at the C3-position of the heterocyclic ring. To date, there are still limited works on enantioselective synthesis of such significant structures, and the catalytic asymmetric reaction of benzofuran-2(3H)-ones is relatively undeveloped.13 Notably, there is still no report on the catalytic ring-opening reactions of meso-aziridines with benzofuran2(3H)-ones which could build multiple linear stereocenters in one step (Scheme 1). On the basis of our recent interest in asymmetric ringopening reactions of meso-aziridines10 and the development of in situ generated magnesium catalysts,11 at the outset we tried the reaction between benzofuran-2(3H)-one 1a and mesoazirindine 2a by screening a series of in situ-generated magnesium catalysts. Initially, we tried using oxazoline−OH ligand L110c,11l,m in the in situ-generated magnesium catalysis but only led to a moderate yield and er value (Table 1, entry 1). To our delight, the employment of BINOL (L2) as a simple chiral ligand gave a more promising result (81% yield, 89.5:10.5 er). However, to our frustration, we found serials of 3,3′substituted BINOLs did not give improved enantioselectivities, and it is notable the utilization of sterically hindered BINOL such as 3,3′-phenyl-BINOL (L7) would dramatically decrease the er value (Table 1, entries 2−7). Next we screened other detailed conditions such as solvents and additives of the current asymmetric ring-opening reactions. The results showed that

atalytic asymmetric ring-opening reaction of mesoaziridines is a direct and efficient route to build enantioenriched amino motifs with different cyclic structures. Tremendous works of desymmetrization of meso-aziridines have been well documented with the development of different powerful catalysis strategies. However, to date, the studies of enantioselective ring-opening reactions of meso-aziridines are significantly limited to the utilization of heteroatom type nucleophiles, such as TMSN3,1 amines,2 alcohols,3 thioalcohols,4 acids,5 phosphates,6 and halogens.7 On the other hand, the utilization of carbon-type nucleophiles are relatively less developed. The catalytic desymmetrization of meso-aziridines with TMSCN and enolates were realized by Shibasaki and Ooi group independently using different catalysis strategies.8,9 By analyzing these studies, we note that the utilization of these aforementioned nucleophiles in desymmetrization of mesoaziridines could build two continues stereocenter in a one-step ring-opening process, so we tried to use latent chiral carbontype nucleophiles in the catalytic desymmetrization of mesoaziridines that could build more stereocenters in a one-step reaction. In our recent work, we have finished the catalytic ringopening reactions of meso-aziridines with types of aromatic compounds and α-isothiocyanato compounds by developing a series of in situ generated magnesium catalysis.10,11 Herein, we report the first example of catalytic desymmetrization of mesoaziridines with benzofuran-2(3H)-ones by employing a simple magnesium catalyst utilizing BINOL as a simple and commercially available chiral ligand. The direct asymmetric synthesis of 3,3-disubstituted benzofuran-2(3H)-ones framework is highly desirable because this skeleton is an important structural motif which exists in © XXXX American Chemical Society

Received: September 28, 2015 Revised: November 8, 2015

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DOI: 10.1021/acscatal.5b02177 ACS Catal. 2015, 5, 7432−7436

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ACS Catalysis Table 1. Screening for the Optimized Conditionsa

Scheme 1. Strategies for Asymmetric Synthesis of 3,3Disubstituted Benzofuran-2(3H)-one Framework

toluene still gave best results and the introduction of 4 Å MS into the reaction could further enhance the results (Table 1, entries 8−15). Interestingly, the addition of a trace amount of H2O in the reaction would dramatically decrease the chemical yield and er values, which might be because the addition of H2O would lead to generate the polymeric magnesium catalyst that could obviously change the reaction’s results (Table 1, entry 16).14 Finally, we found the overloading of 1a to 2.0 equiv could give better results, and it is speculated the overloaded 1a could coordinate to the magnesium center to give a better chiral environment (Table 1, entry 16, 17). Having established the optimized conditions for the current catalytic asymmetric ring-opening reaction of meso-aziridines and benzofuran-2(3H)-ones by utilization of a simple in situgenerated magnesium catalyst, next the substrate scope was first investigated with respect to a series of meso-aziridines. As shown in Scheme 2, different types of meso-aziridines containing cyclic or acyclic substituents were collaborated in the current ring-opening reactions and resulted in moderate to good chemical yields and good to excellent diastereo- and enantioselectivities. It is notable that part of the meso-aziridines need to be carried out with longer reaction time to give relatively higher chemical yields. The absolute configuration of the ring-opening reaction was determined by X-ray crystallographic analysis of product 3a (Figure 1). Furthermore, the enantiomeric product of the current ring-opening reaction could be obtained by using (S)-BINOL as a chiral ligand, giving the enantiomerer 3a′ in good results (Scheme 2, 75% yield, >20:1 dr, 97.5:2.5 er). Next the substrate adaptability and limitations of benzofuran2(3H)-ones were also investigated under standard reaction conditions. It should be noted that the employment of benzofuran-2(3H)-ones equipped with substituted aryl groups on the C3-position would lead to obvious decreased enantioselectivities (Scheme 3, 3i−3l), especially for the ortho-methyl-substituted substrates only resulted in 78:22 er value. Benzofuran-2(3H)-ones equipped with diverse substituents with different electronic effects at the C5- and C7-position were tolerable under current conditions and generally provided the corresponding alkylation products in acceptable results (Scheme 3, 3m−3p). A 3-(phenylthio)-benzofuran-2(3H)-one 1j was also tested in the present ring-opening reactions with meso-aziridine 2h,

entry

L

solvent

yield (%)b

drc

erd

1 2 3 4 5 6 7 8 9 10 11 12 13e 14e,f 15e,g 16e,h 17e,f,i 18e,f,j

L1 L2 L3 L4 L5 L6 L7 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2

toluene toluene toluene toluene toluene toluene toluene DCM THF ether p-xylene Ph−Cl toluene toluene toluene toluene toluene toluene

49 81 83 66 50 52 59 73 45 51 73 94 82 84 74 36 86 80

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

64:36 89.5:10.5 85:15 69.5:30.5 56.5:43.5 77.5:22.5 53:47 66.5:33.5 56:44 64:36 86.5:13.5 85.5:14.5 90:10 93:7 89:11 63.5:36.5 97:3 97:3

a

Reactions were performed with 0.11 mmol of 1a and 0.10 mmol of 2a in toluene (1 mL) in the presence of L (20 mol %) and Bu2Mg (1.0 M in heptanes) (20 mol %) at rt for 36 h. bIsolated yield. cThe diastereoselectivities were determined by 1H NMR (300 MHz) of the crude reaction mixtures. dEnantiomeric excesses were determined by chiral stationary phase HPLC. eReaction was carried out at 0 °C. f20 mg of 4 Å MS was added. g20 mg of MgSO4 was added. h10 mol % of H2O was introduced. i0.20 mmol of 1a and 0.10 mmol of 2a were used. j0.20 mmol of 1a and 0.10 mmol of 2a were used, and the reaction was carried out under 10 mol % magnesium catalyst (in situ generated from L2 (10 mol %) and Bu2Mg (1.0 M in heptanes) (10 mol %)).

leading to the ring-opening product 3q in relatively lower chemical yield with good diastereo- and enantioselectivities (Scheme 4, 31% yield, > 20:1 dr, 93:7 er). Notably, an N-benzoyl-protected aziridine (2i) was further tried in the ring-opening reaction with benzofuran-2(3H)-one 1a under current catalytic systems, but this did not lead to the ring-opening product. The results indicate the pyridine carbonyl group in aziridines plays a key important role for its bidentate coordination ability (Scheme 5). To investigate the coordination environment of the Mg(II) catalyst in situ generated from 1:1 ratio of BINOL and Bu2Mg, we studied the nonlinear effect of the asymmetric ring-opening reaction between the benzofuran-2(3H)-one 1a and the mesoazirindine 2a. As the results show in Figure 2, a clear negative nonlinear effect was observed in the reaction when using L2 with varying ee values. The negative nonlinear effect results indicate that the homogeneous oligomeric Mg(II) complex 7433

DOI: 10.1021/acscatal.5b02177 ACS Catal. 2015, 5, 7432−7436

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ACS Catalysis Scheme 2. Substrate Scope with respect to Aziridines*

Scheme 3. Substrate Scope with respect to Benzofuran2(3H)-one*

*

Reactions were performed with 0.20 mmol of 1a and 0.10 mmol of 2 in toluene (1 mL) in the presence of L2 (10 mol %) and Bu2Mg (1.0 M in heptanes) (10 mol %) at 0 °C. aThe reaction was performed with 20 mol % magnesium catalysis.

*

Reactions were performed with 0.20 mmol of 1a and 0.10 mmol of 2 in toluene (1 mL) in the presence of L2 (10 mol %) and Bu2Mg (1.0 M in heptanes) (10 mol %) at 0 °C. aCombined yield of both diastereoselectivities owing to the hard separation. bThe diastereoselectivities were determined by 1H NMR (300 MHz) of the crude reaction mixtures. cEnantiomeric excesses were determined by chiral stationary phase HPLC. dThe reaction was carried out with (S)-L2 as chiral ligand. eThe reaction was performed with 20 mol % magnesium catalysis at rt.

Scheme 4. 3-(Phenylthio)-Benzofuran-2(3H)-one in the Asymmetric Ring-Opening Reaction

in asymmetric cyanation reactions, the monomeric BINOLMg(II) species was identified by ESI-MS analysis.15 So we speculated the homogeneous oligomeric Mg(II) complex in situ generated from a 1:1 ratio of BINOL and Bu2Mg could be dissociated into highly active monomeric species under higher temperature or other conditions. Finally, on the basis of the nonlinear effect results and our previous studies on the ESI-MS analysis of Mg(II) catalyst

Figure 1. X-ray crystallographic analysis of the ring-opening product 3a.

should be easily formed and act as less active catalytic species. Moreover, in our previous work on the BINOL-Mg(II) catalyst 7434

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ACS Catalysis Scheme 5. N-Benzoyl Aziridines in the Current RingOpening Reaction

Figure 3. Proposed mechanism of the catalytic desymmetrization of meso-aziridines with benzofuran-2(3H)-ones. (A) Formation of monoBINOL-Mg(II)-species. (B) Generation of homogeneous oligomeric Mg(II) complex. (C−E) Speculated coordination and asymmetric ring-opening process. (F) Proposed favored transition state. (G) Proposed unfavorable transition state.

Figure 2. Nonlinear effects studies of the ring-opening reaction.

generated from a 1:1 ratio of BINOL and Bu2Mg, a possible mechanism for this catalytic asymmetric ring-opening reaction between meso-aziridines and benzofuran-2(3H)-ones is proposed (Figure 3). First, the mono-Mg(II)-species could be smoothly formed from (R)-BINOL and Bu2Mg after the neutralization process (Figure 3A), and on the basis of the nonlinear results, it is speculated the homogeneous oligomeric Mg(II) complex should be generated which often act as less active species (Figure 3B). Then the aziridines and benzofuran2(3H)-ones should coordinate to the magnesium center and finish the asymmetric ring-opening process (Figure 3C−E), and we speculated the steric effect between the C3-aryl group of benzofuran-2(3H)-ones and the axial chirality of the BINOL skeleton determined the favored chiral environment during the asymmetric ring-opening alkylation process (Figure 2F, G). In summary, we have developed the catalytic asymmetric ring-opening reaction between meso-aziridines and benzofuran2(3H)-ones by an in situ generated magnesium catalyst. (R)BINOL is employed as a simple and cheap chiral ligand in the in situ generated magnesium catalysis. A series of enantioenriched 3,3-disubstituted benzofuran-2(3H)-ones bearing multiple linear continuous stereocenters were obtained with moderate to good yields, diastereo- and enantioselectivities. The enantiomeric product could be also easily accessed by employing (S)-BINOL as a simple chiral ligand. Further investigation of the simple in situ-generated magnesium catalyst in other asymmetric reactions is currently under study.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.5b02177. Experimental details, analytic data (NMR, HPLC, ESI− HRMS) (PDF) Crystallographic data of 3a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions †

D.L. and L.W. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC (21432003, 91413107, 81473095, 81202400), the National S&T Major Project of China (2012ZX09504001-003), the Program for Chang-jiang Scholars and Innovative Research Team in University (PCSIRT: IRT_15R27), and the Innovation Group of Gansu Province (1210RJIA002, 1304FKCA084). 7435

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ACS Catalysis

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DOI: 10.1021/acscatal.5b02177 ACS Catal. 2015, 5, 7432−7436