Asymmetric Synthesis of Dihydrocoumarins through Chiral Phosphoric

Dec 7, 2017 - Zhi-Pei Zhang, Kai-Xue Xie, Chen Yang, Man Li, and Xin Li. J. Org. Chem. , Just Accepted Manuscript. DOI: 10.1021/acs.joc.7b02750...
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Asymmetric Synthesis of Dihydrocoumarins through Chiral Phosphoric Acid-Catalyzed Cycloannulation of para-Quinone Methides and Azlactones Zhi-Pei Zhang, Kai-Xue Xie, Chen Yang, Man Li, and Xin Li* State key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China S Supporting Information *

ABSTRACT: A chiral phosphoric acid-catalyzed approach constructing dihydrocoumarin motifs by the addition of azlactones to para-quinone methides (p-QMs) was developed. The reaction proceeded smoothly with a wide range of p-QMs and azlactones to generate corresponding products in high yields with excellent diastereoselectivities (>19:1 dr) and enantioselectivities (up to 99% ee). Two possible pathways were proposed to explain the stereoselectivity.

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INTRODUCTION Chiral dihydrocoumarin skeletons are widely found in many natural products, pharmaceuticals, and biologically active compounds.1 This structural motif also served as prominent intermediates in organic chemistry.2 Accordingly, much attention has been paid to the asymmetric construction of chiral dihydrocoumarin compounds, and great progress has been achieved in recent years, including [4+2] cycloaddition of o-QMs, Michael addition, aza-Diels−Alder, kinetic resolution, and so on.3 Among the above-mentioned strategies, azlactone, which has both nucleophilic and electrophilic properties,4,5 was found as a frequently used substrate for the synthesis of aminosubstituted chiral dihydrocoumarins.6 For example, the Xiao, Feng, and Zhou groups reported the [4+2] cycloaddition reactions between o-QMs (or in situ-generated o-QMs) and azlactones by different catalytic processes.6a,f Because of the importance of chiral dihydrocoumarin derivatives, the development of new methods for the synthesis of amino-substituted chiral dihydrocoumarins is still highly desirable (Figure 1). However, para-quinone methides (p-QMs) are a variety of compounds containing the zwitterionic resonance structure of a cyclohexadiene moiety in para-conjugation with a carbonyl group, which enhances the electrophilic character at the δposition. Consequently, they are important reactive intermediates for chemical, medicinal, and biological processes.7 In 2013, Fan reported the first example of the asymmetric catalytic 1,6conjugate addition of p-QMs with malonates by a phase transfer catalyst.8 Soon after, Jørgensen reported the organo© 2017 American Chemical Society

Figure 1. Examples of dihydrocoumarin derivatives.

catalytic 1,6-conjugated addition of enamines to p-QMs.9 Over the past five years, the 1,6-conjugated addition reaction of pQMs has become one of the most prevailing topics in the field of organic synthesis, and different catalytic systems, such as chiral hydrogen-bond catalysts, chiral Brønsted acids, transition metals, N-heterocyclic carbenes, phosphine, and some other catalysts, were successfully established for the 1,6-conjugate addition of p-QMs.10,11 However, the most progress mentioned above focused on the one-step 1,6-conjugate addition of p-QMs (Scheme 1a). Recently, Enders reported an asymmetric organocatalytic domino oxa-Michael/1,6-addition reaction of ortho-hydroxyphenyl-substituted p-QMs and isatin-derived Received: October 30, 2017 Published: December 7, 2017 364

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry Scheme 1. Strategies for the Addition of ortho-Hydroxyphenyl-Substituted p-QMs

of the solvent showed that hexafluorobenzene was the optimal one, in which 3a was obtained in 83% yield with >19:1 dr and 98% ee. (Table 1, entry 20). With the optimal reaction conditions in hand, the substrate scope was investigated. First, 4-methyl-substituted azlactone was used as the substrate to test the substituent effect of the pQMs (Table 2). As shown in Table 2, the electronic properties and positions of the substituent on the aryl ring group of pQMs had a slight influence on the reaction outcomes, in which the desired products 3a−3h were obtained in good yields (up to 94%) and high stereoselectivities (up to >19:1 dr and 98% ee). Naphthyl-substituted p-QM also showed a very good reactivity and stereoselectivity that gave 3i in 75% yield with >19:1 dr and 95% ee. Furthermore, when a tert-butyl group of the p-QM was replaced by a less bulky methyl group, the reaction readily proceeded affording the product 3j with good results (98% yield with >19:1 dr and 89% ee). We then focused our attention on different azlactones (Table 3). Satisfyingly, using 4-OMe-substituted p-QM as the partner, a number of azlactones substituted with either electronwithdrawing or electron-donating groups on different positions of the phenyl ring were smoothly converted into the desired products 3k−3q in good yields and excellent stereoselectivities (62−94% yields with >19:1 dr and 91−99% ee). To our delight, azlactones containing furan and thiophene groups (R3) were also found to be suitable substrates and the corresponding products 3r and 3s were obtained with excellent results under

enoates for the synthesis of important chromans derivatives (Scheme 1b).12 Despite the impressive achievements in this field, the development of a new strategy for the tandem reaction of p-QMs is still a challenging and meaningful work. Herein, we reported a chiral phosphoric acid-catalyzed reaction of azlactones and para-quinone methides (Scheme 1c), in which a number of functionalized dihydrocoumarin derivatives were synthesized in high yields and excellent stereoselectivities.13 It is notable that 1,6-addition/transesterification path A and [4+2] cycloaddition/ring opening path B were both possible.

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RESULTS AND DISCUSSION We selected p-QM 1a and azlactone 2a as model substrates to start our research. The model reaction was initially performed in toluene at room temperature, and the desired cyclization product 3a was obtained in 21% yield with >19:1 dr and 46% ee by a bifunctional thiourea A (Table 1, entry 1). When bifunctional squaramide catalyst B was used, 3a was achieved almost racemic (Table 1, entry 2). Then, several chiral phosphoric acids based on BINOL and SPINOL backbones were evaluated. As exhibited in Table 1, the catalysts’ backbone displayed remarkable effects on the outcome of the reaction (Table 1, entries 3−14). To our delight, the phosphoric acid catalyst E3 with a 3,3′-substituted 3,5-diCF3Ph scaffold delivered 3a in 93% ee (Table 1, entry 13). A further screening 365

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

time (h)

solvent

yield (%)b

drc

ee (%)d

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

A B (S)-C1 (S)-C2 (S)-C3 (S)-C4 (S)-C5 (S)-C6 (S)-D1 (S)-D2 (S)-E1 (S)-E2 (S)-E3 (S)-F (S)-E3 (S)-E3 (S)-E3 (S)-E3 (S)-E3 (S)-E3

72 72 18 18 18 18 42 18 42 18 42 42 18 18 12 16 16 12 16 24

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene CHCl3 CCl4 benzene PhCF3 1,4-diCF3C6H4 C6F6

21 57 86 79 79 83 57 57 76 83 64 29 79 99 59 57 66 86 75 83

>19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1

46 3 35 31 51 71 21 52 26 31 69 2 93 41 95 92 91 94 97 98

a

The reactions were carried out with 1a (0.05 mmol), 2a (0.06 mmol), and 10 mol % bifunctional catalyst or 5 mol % chiral phosphoric acid in 0.5 mL of solvent at rt. bIsolated yield. cDetermined by 1H NMR analysis. dDetermined by HPLC analysis.

optimal reaction conditions with a lower loading of the catalyst. As a result, the desired product 3c was obtained in 87% yield with >19:1 dr and 95% ee (Scheme 2). To further investigate the synthetic potential of this work, the transformation of 3c was conducted (Scheme 2). After treating 3c with 10 equiv of AlCl3 in refluxing toluene for 5 h under an Ar atmosphere, the di-tert-butylation product 4r was obtained in 75% yield without a loss of stereoselectivity. The reduction of 3c by lithium aluminum hydride in anhydrous THF afforded 5c in 80% yield with >19:1 dr and 95% ee. By a further treatment with diethyl azodicarboxylate and PPh3, product 6c with a chroman

the optimal conditions. Furthermore, when benzyl group (R4) was replaced by a chlorine-substituted benzyl group or alkyl groups, the reactions worked well and gave products 3t−3v with good diastereoselectivities and enantioselectivities (>19:1 dr and 96−98% ee). Moreover, the phenyl-substituted azlactone can also tolerate this reaction, in which 3w was obtained in 79% yield with >19:1 dr and 90% ee. The absolute configuration of 3e was determined by X-ray crystallographic analysis.14 To probe the potential applicability of this methodology, a gram-scale reaction of 1c and 2f was investigated under the 366

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry Table 2. Evaluation of the Substrate Scope of the p-QMsa,b,c,d

a The reactions were carried out with 1 (0.05 mmol), 2 (0.06 mmol), and 5 mol % (S)-E3 in 0.5 mL of C6F6 at rt for 12−72 h. bIsolated yield. cThe dr values were determined by 1H NMR analysis. dThe ee values were determined by HPLC analysis.

pathways were proposed to explain the observed stereoselectivity.

skeleton, which was widely found in natural products and pharmaceuticals,15 was obtained and stereoselectivity was maintained. In order to investigate the reaction pathway, the control experiment was carried out (Scheme 3). No reaction occurred when treating OH protected p-QM 1gg or OH group free pQM 1ga with azlactone 2g. This result indicates that the OH group is necessary in this system, and this reaction may conduct through [4+2] cycloaddition. Theoretical calculations manifest that the isomerization energy of 1a and 1a′ is 6.7 kcal mol−1, indicating that the transformation of p-QM to o-QM was not difficult.16 However, considering Enders’s plausible transition state,12 we could not exclude the possibility that this reaction may conduct via the 1,6-addition/transesterification process. Therefore, two plausible reaction pathways are proposed to explain the reaction process as shown in Scheme 4. In path A, under the action of chiral phosphoric acid E3, o-QM in situgenerated by p-QM 1c reacted with the enol tautomer of the azlactone 2f via [4+2] cycloaddition in an endo manner affording intermediate 3cf, followed by ring opening to furnish the target product 3c. In path B, the OH group of chiral phosphoric acid E3 activates p-QM 1c and carbonyl activates OH group of enol tautomer of the azlactone 2f. The si face of 1c is attacked by the activated p-QM 1c in 1,6-addition, affording intermediate 3cf′, followed by transesterification/ring opening to furnish the target product 3c.

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EXPERIMENTAL SECTION

General Information. Commercial reagents were used as received, unless otherwise stated. 1H and 13C NMR were recorded on a 400 MHz spectrometer. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard. The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted were designated as a multiplet (m). Mass spectra were obtained using an electrospray ionization (ESI) mass spectrometer. The enantiomeric excesses were determined by HPLC analysis, which employed a chiral stationary phase column specified in the individual experiment, by comparing the samples with the appropriate racemic mixtures. The ortho-hydroxyphenyl-substituted para-quinone methides (p-QMs) 1a−1j were prepared according to the reported literature procedures.12,17 The azlactones 2a−2n were prepared according to the reported literature procedures.18 2,6-Di-tert-butyl-4-(5-fluoro-2-hydroxybenzylidene)cyclohexa2,5-dien-1-one (1b): yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.51 (s, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.18 (ddd, J = 23.2, 13.3, 2.8 Hz, 3H), 6.94 (dd, J = 8.9, 4.8 Hz, 1H), 1.25 (d, J = 12.7 Hz, 18H); 13C NMR (101 MHz, DMSO-d6) δ 186.2, 155.6 (d, 1JC−F = 234.7 Hz), 153.6, 148.3, 146.9, 140.0, 136.0, 131.0, 128.4, 123.6, 123.6, 118.2, 118.0, 117.3, 117.3, 117.1, 35.5, 35.2, 29.8, 29.6; HRMS (ESITOF) m/z [M + H]+ calcd for C21H26FO2 329.1911, found 329.1913. 2-(tert-Butyl)-4-(2-hydroxy-3-methoxybenzylidene)-6-methylcyclohexa-2,5-dien-1-one (1j): yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 9.44 (d, J = 12.7 Hz, 1H), 7.66−7.45 (m, 2H), 7.30 (dd, J = 13.2, 2.3 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.03−6.94 (m, 1H), 6.90 (td, J = 7.9, 4.9 Hz, 1H), 3.85 (d, J = 1.1 Hz, 3H), 1.93 (d, J = 1.2 Hz, 3H), 1.26 (d, J = 15.9 Hz, 9H); 13C NMR (101 MHz, DMSO-d6) δ 185.6, 147.9, 147.8, 146.2, 146.1, 144.5, 141.0, 140.5, 137.8, 137.3, 135.5, 130.7, 130.0, 129.7, 123.0, 122.8, 122.7, 119.2, 119.1, 113.3,

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CONCLUSION In summary, we have developed a highly enantioselective reaction of azlactones and p-QMs by using a chiral phosphoric acid catalyst. A wide range of functionalized dihydrocoumarin derivatives were synthesized in high yields (up to 98%) and excellent diastereoselectivities (up to >19:1) and enantioselectivities (up to 98%) under mild conditions. Two possible 367

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry Table 3. Evaluation of the Substrate Scope of the Azlactonesa,b,c,d

a

The reactions were carried out with 1 (0.05 mmol), 2 (0.06 mmol), and 5 mol % (S)-E3 in 0.5 mL of C6F6 at rt for 12−72 h. bIsolated yield. cThe dr values were determined by 1H NMR analysis. dThe ee values were determined by HPLC analysis. e−20 °C, PhCF3 as a solvent. 113.3, 55.9, 34.7, 34.4, 29.1, 29.0, 16.8, 16.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H23O3 299.1642, found 299.1646. 4-Benzyl-2-(m-tolyl)oxazol-5(4H)-one (2g): white solid; 1H NMR (400 MHz, CDCl3) δ 7.85−7.67 (m, 2H), 7.44−7.16 (m, 7H), 4.68 (dd, J = 6.7, 4.9 Hz, 1H), 3.37 (dd, J = 14.0, 4.9 Hz, 1H), 3.18 (dd, J = 14.0, 6.7 Hz, 1H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 177.8, 162.0, 138.8, 135.4, 133.7, 129.7, 128.8, 128.6, 128.5, 127.3, 125.8, 125.2, 66.6, 37.4, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H16NO2 266.1176, found 266.1174. 4-Benzyl-2-(o-tolyl)oxazol-5(4H)-one (2h): colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.74−7.62 (m, 1H), 7.34 (td, J = 7.5, 1.4 Hz, 1H), 7.30−7.13 (m, 7H), 4.67 (dd, J = 6.3, 5.0 Hz, 1H), 3.35 (dd, J = 13.9, 5.0 Hz, 1H), 3.19 (dd, J = 13.9, 6.3 Hz, 1H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 177.7, 161.9, 139.5, 135.3, 131.7, 131.6, 129.8, 129.7, 128.4, 127.2, 125.9, 124.8, 66.8, 37.2, 21.9; HRMS (ESITOF) m/z [M + H]+ calcd for C17H16NO2 266.1176, found 266.1179. General Procedure for the Asymmetric Synthesis of 3. To a stirred solution of p-QMs 1 (0.05 mmol) and azlactones 2 (0.06 mmol) in dry C6F6 (0.5 mL) at room temperature was added catalyst (S)-E (0.0025 mmol). The reactions were monitored by TLC. After 1 were consumed completely, the reaction solutions were concentrated in vacuo and the crude products were purified by flash chromatography eluting with CH2Cl2/CH3OH (500:1) to afford the products 3. N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxochroman-3-yl)benzamide (3a): yellow solid, 23.3 mg, 83% yield; mp 155− 157 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 21.3, 7.5 Hz, 3H), 7.37−7.25 (m, 6H), 7.22−7.15 (m, 2H), 7.14−7.03 (m, 5H), 5.94 (s, 1H), 5.45 (s, 1H), 5.28 (s, 1H), 3.48 (d, J = 14.3 Hz, 1H), 2.93 (d, J = 14.3 Hz, 1H), 1.37 (s, 18H); 13C NMR (101 MHz, CDCl3) δ

167.3, 166.1, 153.7, 151.0, 135.9, 134.2, 134.1, 131.9, 130.5, 129.0, 128.8, 128.8, 128.6, 127.8, 127.4, 127.1, 125.6, 124.8, 124.4, 116.7, 62.1, 48.1, 36.4, 34.5, 30.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C37H40NO4 562.2952, found 562.2950. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/ hexane 1:9), 1.0 mL/min. Major isomer: t1 = 11.23 min, t2 = 16.67 min; [α]25 D 97.4 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-fluoro-2-oxochroman-3-yl)benzamide (3b): white solid, 27.3 mg, 92% yield; mp 207−209 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.2 Hz, 2H), 7.32−7.26 (m, 3H), 7.17−6.88 (m, 9H), 5.90 (s, 1H), 5.45 (s, 1H), 5.30 (s, 1H), 3.42 (d, J = 14.2 Hz, 1H), 2.92 (d, J = 14.3 Hz, 1H), 2.35 (s, 3H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.4, 165.8, 159.1 (d, 1JC−F = 243.8 Hz), 153.9, 147.0, 142.5, 136.1, 133.9, 131.3, 130.5, 129.3, 128.9, 127.9, 127.4, 127.1, 126.8 (d, 3JC−F = 8.9 Hz), 125.0, 118.0 (d, 3JC−F = 7.8 Hz), 115.7 (d, 2JC−F = 25.2 Hz), 115.4 (d, 2 JC−F = 23.2 Hz), 61.7, 48.2, 36.4, 34.6, 30.4, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41FNO4 594.3014, found 594.3017. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 11.27 min, t2 = 18.94 min; [α]25 D 95.8 (c 0.5, CHCl3). N-(3-Benzyl-6-chloro-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxochroman-3-yl)-4-methylbenzamide (3c): yellow solid, 19.8 mg, 65% yield; mp 176−178 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.2 Hz, 2H), 7.31−7.24 (m, 4H), 7.20−7.02 (m, 8H), 5.88 (s, 1H), 5.34 (s, 1H), 5.31 (s, 1H), 3.44 (d, J = 14.3 Hz, 1H), 2.91 (d, J = 14.3 Hz, 1H), 2.35 (s, 3H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.4, 165.7, 153.9, 149.6, 142.6, 136.1, 133.9, 131.2, 130.6, 129.5, 129.3, 129.0, 128.9, 128.8, 127.9, 127.3, 127.1, 126.7, 125.0, 118.1, 368

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry Scheme 2. Gram-Scale Synthesis and Transformation of Compound 3c

2.2 Hz, 1H), 5.85 (s, 1H), 5.28 (s, 1H), 5.24 (s, 1H), 3.51 (d, J = 14.3 Hz, 1H), 2.89 (d, J = 14.3 Hz, 1H), 2.35 (s, 3H), 2.26 (s, 3H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.3, 166.4, 153.7, 148.9, 142.4, 135.8, 134.4, 133.9, 131.4, 130.6, 129.5, 129.3, 129.2, 128.7, 127.7, 127.3, 127.1, 126.0, 124.4, 116.5, 61.9, 48.5, 36.1, 34.6, 30.4, 21.6, 21.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO4 590.3265, found 590.3277. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 10.02 min, t2 = 19.81 min; [α]25 D 96.7 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-4-methylbenzamide (3f): yellow solid, 28.5 mg, 94% yield; mp 131−133 °C; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 6.9 Hz, 3H), 7.17−7.02 (m, 7H), 6.81 (dd, J = 8.9, 3.0 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 5.87 (s, 1H), 5.37 (s, 1H), 5.27 (s, 1H), 3.71 (s, 3H), 3.47 (d, J = 14.2 Hz, 1H), 2.91 (d, J = 14.3 Hz, 1H), 2.35 (s, 3H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.3, 166.3, 156.2, 153.7, 144.9, 142.4, 135.9, 134.3, 131.5, 130.6, 129.3, 128.8, 127.8, 127.4, 127.1, 125.8, 125.6, 117.5, 114.1, 114.0, 61.9, 55.8, 48.4, 36.3, 34.6, 30.5, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO5 606.3214, found 606.3209. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 15.61 min, t2 = 30.74 min; [α]25 D 105.1 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-7-methoxy-2oxochroman-3-yl)-4-methylbenzamide (3g): yellow solid, 13.6 mg, 45% yield; mp 166−168 °C; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 5.1, 1.9 Hz, 3H), 7.15 (d, J = 7.9 Hz, 2H), 7.10−7.02 (m, 5H), 6.73 (d, J = 2.5 Hz, 1H), 6.63 (dd, J = 8.6, 2.6 Hz, 1H), 5.86 (s, 1H), 5.27 (s, 1H), 5.25 (s, 1H), 3.82 (s, 3H), 3.49 (d, J = 14.3 Hz, 1H), 2.88 (d, J = 14.3 Hz, 1H), 2.36 (s, 3H), 1.37 (s, 18H); 13 C NMR (101 MHz, CDCl3) δ 167.3, 166.3, 160.0, 153.6, 151.7, 142.4, 135.8, 134.4, 131.5, 130.6, 129.6, 129.3, 128.8, 127.8, 127.4, 127.1, 126.1, 116.6, 110.4, 102.3, 62.0, 55.7, 47.7, 36.3, 34.5, 30.4, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO5 606.3214,

Scheme 3. Control Experiment

61.6, 48.3, 36.3, 34.6, 30.4, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41ClNO4 610.2719, found 610.2717. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 12.55 min, t2 = 22.74 min; [α]25 D 107.2 (c 0.5, CHCl3). N-(3-Benzyl-6-bromo-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxochroman-3-yl)-4-methylbenzamide (3d): yellow solid, 24.9 mg, 76% yield; mp 173−175 °C; 1H NMR (400 MHz, CDCl3) δ 7.45− 7.37 (m, 3H), 7.35−7.27 (m, 4H), 7.15 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 12.3 Hz, 5H), 5.86 (s, 1H), 5.36 (s, 1H), 5.31 (s, 1H), 3.42 (d, J = 14.3 Hz, 1H), 2.90 (d, J = 14.3 Hz, 1H), 2.36 (s, 3H), 1.38 (s, 18H); 13 C NMR (101 MHz, CDCl3) δ 167.4, 165.6, 154.0, 150.1, 142.6, 136.1, 133.9, 131.9, 131.7, 131.2, 130.5, 129.4, 128.9, 128.0, 127.4, 127.1, 127.1, 125.0, 118.5, 117.0, 61.6, 48.2, 36.4, 34.6, 30.4, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41BrNO4 654.2213, found 654.2210. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/ min. Major isomer: t1 = 11.40 min, t2 = 16.26 min; [α]25 D 68.8 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-2-oxochroman-3-yl)-4-methylbenzamide (3e): yellow solid, 24.8 mg, 84% yield; mp 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 5.2 Hz, 3H), 7.17−7.02 (m, 8H), 6.98 (d, J = 369

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry Scheme 4. Plausible Reaction Pathways

Major isomer: t1 = 10.07 min, t2 = 18.62 min; [α]25 D 241.2 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-8-methoxy-2oxochroman-3-yl)-4-methylbenzamide (3j): yellow solid, 17.6 mg, 98% yield; mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 7.9 Hz, 2H), 7.30−7.21 (m, 3H), 7.16−7.04 (m, 5H), 7.04−6.85 (m, 3H), 6.72 (d, J = 7.7 Hz, 1H), 5.87 (s, 1H), 5.29 (s, 1H), 5.02 (s, 1H), 3.90 (s, 3H), 3.54 (d, J = 14.3 Hz, 1H), 2.96 (d, J = 14.3 Hz, 1H), 2.34 (s, 3H), 2.21 (s, 3H), 1.33 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 167.4, 165.6, 152.7, 147.5, 142.3, 140.2, 135.6, 134.3, 131.5, 130.7, 129.8, 129.3, 128.7, 128.3, 127.7, 127.0, 126.5, 125.7, 124.3, 123.4, 120.4, 111.7, 61.6, 56.4, 48.4, 36.2, 34.7, 29.8, 21.6, 16.3; HRMS (ESITOF) m/z [M + H]+ calcd for C36H38NO5 564.2744, found 564.2752. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 23.74 min, t2 = 61.14 min; [α]25 D 148.1 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)benzamide (3k): yellow solid, 24.3 mg, 82% yield; mp 129−131 °C; 1H NMR (400 MHz, CDCl3) δ 7.56−7.39 (m, 3H), 7.39−7.23 (m, 5H), 7.18−7.01 (m, 5H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.70 (dd, J = 2.9, 1.1 Hz, 1H), 5.93 (s, 1H), 5.44 (s, 1H), 5.28 (s, 1H), 3.72 (s, 3H), 3.46 (d, J = 14.2 Hz, 1H), 2.92 (d, J = 14.3 Hz, 1H), 1.37 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.4, 166.2, 156.2, 153.8, 144.8, 135.9, 134.3, 134.1, 131.9, 130.5, 128.9, 128.7, 127.9, 127.5, 127.1, 125.8, 125.4, 124.5, 117.6, 114.0, 62.1, 55.8, 48.2, 36.3, 34.5, 30.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H42NO5 592.3057, found 592.3055. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 13.76 min, t2 = 19.60 min; [α]25 D 71.0 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-4-fluorobenzamide (3l): yellow solid, 24.1 mg,

found 606.3218. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/ min. Major isomer: t1 = 15.31 min, t2 = 25.26 min; [α]25 D 55.6 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-8-methoxy-2oxochroman-3-yl)-4-methylbenzamide (3h): yellow solid, 25.7 mg, 85% yield; mp 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 2H), 7.31−7.23 (m, 3H), 7.15−6.97 (m, 7H), 6.90 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.86 (s, 1H), 5.42 (s, 1H), 5.26 (s, 1H), 3.92 (s, 3H), 3.51 (d, J = 14.2 Hz, 1H), 2.93 (d, J = 14.3 Hz, 1H), 2.34 (s, 3H), 1.37 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.3, 165.6, 153.6, 147.6, 142.3, 140.3, 135.8, 134.2, 131.6, 130.6, 129.2, 128.8, 127.7, 127.5, 127.1, 125.8, 124.2, 120.5, 111.8, 61.7, 56.4, 48.4, 36.3, 34.5, 30.4, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO5 606.3214, found 606.3216. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/ hexane 1:9), 1.0 mL/min. Major isomer: t1 = 12.08 min, t2 = 25.96 min; [α]25 D 89.2 (c 0.5, CHCl3). N-(2-Benzyl-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-oxo-2,3-dihydro-1H-benzo[f ]chromen-2-yl)-4-methylbenzamide (3i): yellow solid, 23.5 mg, 75% yield; mp 110−112 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 1H), 7.80−7.70 (m, 2H), 7.49−7.18 (m, 10H), 7.14 (d, J = 6.3 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 5.72 (s, 1H), 5.23 (s, 1H), 4.64 (s, 1H), 4.00 (d, J = 14.4 Hz, 1H), 2.95 (d, J = 14.5 Hz, 1H), 2.27 (s, 3H), 1.42 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.0, 166.7, 153.8, 149.2, 142.4, 136.3, 136.0, 131.6, 131.3, 131.1, 130.8, 129.9, 129.3, 129.1, 128.3, 127.3, 127.1, 127.0, 126.6, 126.3, 125.0, 122.8, 117.7, 117.2, 61.0, 49.0, 35.1, 34.6, 30.4, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C42H44NO4 626.3265, found 626.3271. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. 370

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry 79% yield; mp 184−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.6, 5.3 Hz, 2H), 7.29 (dd, J = 5.1, 1.9 Hz, 3H), 7.15−6.98 (m, 7H), 6.83 (dd, J = 8.9, 3.0 Hz, 1H), 6.70 (d, J = 2.9 Hz, 1H), 5.86 (s, 1H), 5.49 (s, 1H), 5.28 (s, 1H), 3.72 (s, 3H), 3.43 (d, J = 14.3 Hz, 1H), 2.92 (d, J = 14.3 Hz, 1H), 1.37 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 166.3, 166.2, 157.6 (d, 1JC−F = 248.8 Hz), 144.8, 135.9, 134.0, 130.6, 130.4, 129.5, 129.4, 129.0, 128.0, 127.6, 125.7, 125.3, 117.6, 115.9, 115.6, 114.1, 114.0, 62.2, 55.8, 48.0, 36.3, 34.6, 30.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41FNO5 610.2963, found 610.2964. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 11.40 min, t2 = 15.84 min; [α]25 D 49.7 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-4-chlorobenzamide (3m): yellow solid, 21.6 mg, 69% yield; mp 148−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.6 Hz, 2H), 7.35−7.27 (m, 5H), 7.12 (d, J = 8.6 Hz, 3H), 7.08− 7.03 (m, 2H), 6.87−6.81 (m, 1H), 6.70 (d, J = 4.1 Hz, 1H), 5.87 (s, 1H), 5.48 (s, 1H), 5.29 (s, 1H), 3.72 (s, 3H), 3.43 (d, J = 14.3 Hz, 1H), 2.92 (d, J = 14.3 Hz, 1H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 166.4, 166.2, 156.2, 153.8, 144.8, 138.2, 135.9, 134.0, 132.7, 130.4, 129.0, 129.0, 128.5, 128.0, 127.5, 125.7, 125.2, 117.6, 114.1, 114.0, 62.2, 55.8, 48.0, 36.3, 34.5, 30.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41ClNO5 626.2668, found 626.2665. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 12.08 min, t2 = 19.02 min; [α]25 D 61.7 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-4-bromobenzamide (3n): yellow solid, 20.8 °C, 62% yield; mp 144−146 °C; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 5.1, 1.9 Hz, 3H), 7.12 (d, J = 8.7 Hz, 3H), 7.05 (dd, J = 6.7, 2.8 Hz, 2H), 6.83 (dd, J = 8.8, 3.0 Hz, 1H), 6.69 (dd, J = 3.0, 1.1 Hz, 1H), 5.86 (s, 1H), 5.47 (s, 1H), 5.28 (s, 1H), 3.72 (s, 3H), 3.43 (d, J = 14.3 Hz, 1H), 2.92 (d, J = 14.3 Hz, 1H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 166.5, 166.1, 156.3, 153.8, 153.5, 144.8, 135.9, 134.0, 133.2, 131.9, 130.4, 129.0, 128.7, 128.0, 127.5, 126.7, 125.7, 125.3, 117.6, 114.1, 62.2, 55.8, 48.1, 36.3, 34.6, 30.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41BrNO5 670.2163, found 670.2156. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/ hexane 1:9), 1.0 mL/min. Major isomer: t1 = 12.91 min, t2 = 21.36 min; [α]25 D 89.1 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-4-methoxybenzamide (3o): yellow solid, 23.3 mg, 75% yield; mp 156−158 °C; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 5.4 Hz, 3H), 7.13−7.03 (m, 5H), 6.83 (d, J = 6.9 Hz, 3H), 6.70 (d, J = 3.6 Hz, 1H), 5.83 (s, 1H), 5.39 (s, 1H), 5.28 (s, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.46 (d, J = 14.2 Hz, 1H), 2.90 (d, J = 14.3 Hz, 1H), 1.37 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 166.8, 166.4, 162.5, 156.1, 153.7, 144.8, 135.8, 134.2, 130.5, 129.0, 128.8, 127.8, 127.5, 126.6, 125.8, 125.6, 117.5, 114.0, 114.0, 113.8, 61.8, 55.8, 55.5, 48.3, 36.3, 34.5, 30.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO6 622.3163, found 622.3159. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 22.61 min, t2 = 41.85 min; [α]25 D 93.2 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-3-methylbenzamide (3p): yellow solid, 24.8 mg, 82% yield; mp 180−182 °C; 1H NMR (400 MHz, CDCl3) δ 7.35− 7.27 (m, 4H), 7.26−7.19 (m, 3H), 7.15−7.03 (m, 5H), 6.82 (dd, J = 8.8, 2.9 Hz, 1H), 6.70 (dd, J = 3.0, 1.1 Hz, 1H), 5.89 (s, 1H), 5.41 (s, 1H), 5.28 (s, 1H), 3.72 (s, 3H), 3.46 (d, J = 14.3 Hz, 1H), 2.92 (d, J = 14.3 Hz, 1H), 2.32 (s, 3H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.7, 166.2, 156.2, 153.7, 144.8, 138.5, 135.9, 134.4, 134.2, 132.6, 130.6, 128.8, 128.5, 128.0, 127.8, 127.5, 125.8, 125.5, 123.9, 117.6, 114.0, 114.0, 62.0, 55.8, 48.3, 36.3, 34.5, 30.5, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO5 606.3214, found 606.3211. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:19), 1.0 mL/min. Major isomer: t1 = 23.38 min, t2 = 32.70 min; [α]25 D 81.6 (c 0.5, CHCl3).

N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)-2-methylbenzamide (3q): yellow solid, 21.8 mg, 72% yield; mp 124−126 °C; 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 2H), 7.26 (s, 2H), 7.17−7.03 (m, 7H), 6.97 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.62 (d, J = 2.9 Hz, 1H), 5.57 (s, 1H), 5.30 (s, 1H), 5.22 (s, 1H), 3.71 (s, 3H), 3.53 (d, J = 14.3 Hz, 1H), 2.96 (d, J = 14.3 Hz, 1H), 2.25 (s, 3H), 1.43 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 169.8, 166.3, 156.2, 153.8, 144.9, 137.0, 136.1, 134.5, 131.3, 130.7, 130.4, 128.7, 127.7, 127.2, 127.0, 126.2, 126.0, 125.6, 117.5, 114.2, 113.9, 100.1, 62.3, 55.8, 49.2, 36.4, 34.6, 30.5, 19.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H44NO5 606.3214, found 606.3219. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 19.22 min, t2 = 21.95 min; [α]25 D 47.7 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)furan-2-carboxamide (3r): yellow solid, 24.4 mg, 84% yield; mp 112−114 °C; 1H NMR (400 MHz, CDCl3) δ 7.38− 7.26 (m, 4H), 7.15−7.04 (m, 6H), 6.83 (dd, J = 8.9, 2.9 Hz, 1H), 6.72 (d, J = 1.1 Hz, 1H), 6.46 (d, J = 1.7 Hz, 1H), 6.23 (s, 1H), 5.43 (s, 1H), 5.28 (s, 1H), 3.72 (s, 3H), 3.39 (d, J = 14.3 Hz, 1H), 2.83 (d, J = 14.4 Hz, 1H), 1.36 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 166.0, 157.9, 156.2, 153.7, 147.6, 144.7, 144.1, 135.8, 133.9, 130.4, 128.8, 127.8, 127.6, 125.6, 125.1, 117.6, 115.2, 114.1, 113.9, 112.4, 62.0, 55.8, 48.0, 36.5, 34.5, 30.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C36H40NO6 582.2850, found 582.2857. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/ hexane 1:9), 1.0 mL/min. Major isomer: t1 = 13.16 min, t2 = 16.70 min; [α]25 D 53.4 (c 0.5, CHCl3). N-(3-Benzyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2oxochroman-3-yl)thiophene-2-carboxamide (3s): yellow solid, 22.6 mg, 78% yield; mp 107−109 °C; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 3.9 Hz, 1H), 7.34−7.27 (m, 3H), 7.23 (d, J = 2.6 Hz, 1H), 7.11 (d, J = 8.0 Hz, 3H), 7.05 (d, J = 7.0 Hz, 2H), 6.99 (dd, J = 5.0, 3.7 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 2.9 Hz, 1H), 5.78 (s, 1H), 5.48 (s, 1H), 5.28 (s, 1H), 3.72 (s, 3H), 3.40 (d, J = 14.3 Hz, 1H), 2.88 (d, J = 14.3 Hz, 1H), 1.37 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 166.2, 161.7, 156.2, 153.8, 144.8, 138.4, 135.9, 133.9, 130.5, 130.4, 129.0, 128.8, 128.0, 127.7, 127.6, 125.6, 125.2, 117.6, 114.1, 114.0, 62.1, 55.8, 48.0, 36.4, 34.5, 30.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C36H40NO5S 598.2622, found 598.2627. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 16.32 min, t2 = 19.88 min; [α]25 D 63.2 (c 0.5, CHCl3). N-(3-(4-Chlorobenzyl)-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-6methoxy-2-oxochroman-3-yl)benzamide (3t): yellow solid, 24.4 mg, 78% yield; mp 123−125 °C; 1H NMR (400 MHz, CDCl3) δ 7.51− 7.43 (m, 3H), 7.35 (t, J = 7.6 Hz, 2H), 7.27−7.20 (m, 2H), 7.09 (d, J = 8.9 Hz, 3H), 7.01 (d, J = 8.4 Hz, 2H), 6.81 (dd, J = 8.8, 2.9 Hz, 1H), 6.69 (d, J = 3.0 Hz, 1H), 5.85 (s, 1H), 5.29 (s, 1H), 5.20 (s, 1H), 3.71 (s, 3H), 3.49 (d, J = 14.4 Hz, 1H), 2.90 (d, J = 14.4 Hz, 1H), 1.38 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.3, 166.1, 156.2, 153.8, 144.7, 136.1, 134.1, 133.8, 132.9, 132.1, 131.9, 128.9, 128.8, 127.2, 127.0, 126.7, 125.6, 117.6, 114.1, 114.1, 62.0, 55.8, 48.8, 35.6, 34.6, 30.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41ClNO5 626.2668, found 626.2671. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 9.44 min, t2 = 10.87 min; [α]25 D 80.3 (c 0.5, CHCl3). N-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6-methoxy-3-(2(methylthio)ethyl)-2-oxochroman-3-yl)benzamide (3u): yellow solid, 22.2 mg, 77% yield; mp 123−125 °C; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 9.7 Hz, 2H), 7.55−7.46 (m, 1H), 7.44−7.36 (m, 2H), 7.05 (d, J = 8.9 Hz, 1H), 6.99 (s, 2H), 6.85−6.79 (m, 2H), 6.67 (d, J = 3.0 Hz, 1H), 5.58 (s, 1H), 5.25 (s, 1H), 3.70 (s, 3H), 2.69−2.53 (m, 2H), 2.30−2.19 (m, 1H), 2.01 (s, 3H), 2.00−1.92 (m, 1H), 1.32 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 167.1, 166.6, 156.3, 153.7, 144.7, 135.8, 133.8, 132.1, 128.7, 127.7, 127.3, 125.5, 124.7, 117.6, 114.0, 113.8, 62.2, 55.8, 47.2, 34.4, 30.4, 29.2, 28.1, 15.8; HRMS (ESITOF) m/z [M + H]+ calcd for C34H42NO5S 576.2778, found 371

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry

pressure. The crude residue was purified with silica gel by column chromatography (hexane/ethyl acetate 5:1), affording 5c as a white solid (245.7 mg, 80% yield, >19:1 dr, 95% ee). N-(2-Benzyl-1-(5-chloro-2-hydroxyphenyl)-1-(3,5-di-tert-butyl-4hydroxyphenyl)-3-hydroxypropan-2-yl)-4-methylbenzamide (5c): yellow solid, 245.7 mg, 80% yield; mp 112−114 °C; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.39 (s, 2H), 7.22 (d, J = 6.0 Hz, 3H), 7.15−6.89 (m, 8H), 6.16 (s, 1H), 5.31 (s, 1H), 5.18 (s, 1H), 3.88 (d, J = 12.6 Hz, 1H), 3.70−3.59 (m, 1H), 3.54 (d, J = 14.0 Hz, 1H), 3.22 (d, J = 14.0 Hz, 1H), 2.31 (s, 3H), 1.35 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 169.6, 155.0, 153.3, 142.7, 136.5, 134.7, 131.2, 131.0, 130.8, 130.2, 129.3, 128.9, 128.4, 127.6, 127.5, 127.1, 126.6, 124.8, 120.4, 66.8, 65.4, 46.1, 41.2, 34.5, 30.3, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H45ClNO4 614.3032, found 614.3030. The enantiomeric excess was determined by HPLC with an IC column at 210 nm (2-propanol/hexane 1:19), 1.0 mL/min. Major isomer: t1 = 16.49 min, t2 = 20.69 min; [α]25 D 185.8 (c 0.5, CHCl3). 19c Synthesis of 6c. To a solution of 5c (67.6 mg, 0.11 mmol) in anhydrous THF (3 mL) were added PPh3 (43 mg, 0.17 mmol, 1.5 equiv) and DIAD (26 μL, 0.17 mmol, 1.5 equiv). The resulting mixture was stirred for 1 h. The solvent was concentrated under reduced pressure. Then the crude residue was purified with silica gel by column chromatography (hexane/ethyl acetate 5:1), affording 6c as a white solid (55.7 mg, 85% yield, >19:1 dr, 95% ee). N-(3-Benzyl-6-chloro-4-(3,5-di-tert-butyl-4-hydroxyphenyl)chroman-3-yl)-4-methylbenzamide (6c): white solid, 55.7 mg, 85% yield; mp 95−97 °C; 1H NMR (400 MHz, CDCl3) δ 13.40 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.24−6.88 (m, 12H), 4.99 (s, 1H), 4.34 (d, J = 7.9 Hz, 2H), 3.84 (s, 1H), 3.25 (d, J = 14.1 Hz, 1H), 2.85 (d, J = 14.0 Hz, 1H), 2.37 (s, 3H), 1.22 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 164.8, 154.2, 153.0, 143.1, 136.3, 135.7, 133.0, 130.8, 129.3, 128.9, 128.8, 128.5, 128.4, 128.3, 126.8, 126.2, 123.5, 123.1, 120.7, 75.2, 73.6, 62.8, 44.9, 34.2, 30.3, 21.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H43ClNO3 596.2926, found 596.2933. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:99), 1.0 mL/min. Major isomer: t1 = 8.82 min, t2 = 13.11 min; [α]25 D 41.1 (c 0.5, CHCl3). Control Experiment. To a stirred solution of p-QM 1gg or 1ga (0.05 mmol) and azlactones 2g (0.06 mmol) in dry C6F6 (0.5 mL) at room temperature was added catalyst (S)-E (0.0025 mmol). The reactions were monitored by TLC, which indicated that almost no reaction occurred.

576.2774. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 9.77 min, t2 = 18.45 min; [α]25 D −15.6 (c 0.5, CHCl3). N-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-isopropyl-6-methoxy2-oxochroman-3-yl)benzamide (3v): yellow solid, 8.2 mg, 30% yield; mp 94−96 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.6 Hz, 2H), 7.54−7.48 (m, 1H), 7.44−7.37 (m, 2H), 7.01 (d, J = 8.8 Hz, 3H), 6.78−6.73 (m, 1H), 6.60 (d, J = 2.9 Hz, 1H), 5.92 (s, 1H), 5.39 (s, 1H), 5.24 (s, 1H), 3.69 (s, 3H), 2.17−2.10 (m, 1H), 1.57 (s, 3H), 1.32 (s, 18H), 1.06 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.6, 165.8, 156.2, 153.7, 145.3, 135.9, 134.1, 132.1, 128.8, 127.6, 127.2, 127.0, 125.2, 117.3, 113.3, 112.7, 63.8, 55.8, 48.0, 34.5, 32.1, 30.4, 18.9, 18.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C34H42NO5 544.3057, found 544.3058. The enantiomeric excess was determined by HPLC with an OD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 11.57 min, t2 = 17.13 min; [α]25 D 106.1 (c 0.5, CHCl3). N-(4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2-oxo-3phenylchroman-3-yl)benzamide (3w): yellow solid, 22.8 mg, 79% yield; mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.0 Hz, 2H), 7.58−7.50 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.28 (s, 1H), 7.22−7.14 (m, 3H), 6.80 (ddd, J = 20.4, 8.1, 2.2 Hz, 3H), 6.57 (s, 1H), 6.51 (d, J = 2.7 Hz, 3H), 5.93 (s, 1H), 5.21 (s, 1H), 3.62 (s, 3H), 1.21 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 168.1, 168.1, 156.3, 153.7, 145.0, 135.0, 134.8, 134.3, 132.3, 128.9, 128.8, 128.8, 128.5, 127.3, 127.0, 125.5, 123.9, 117.8, 114.1, 113.8, 66.6, 55.6, 48.4, 34.2, 30.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C37H40NO5 578.2901, found 578.2908. The enantiomeric excess was determined by HPLC with an OD-H column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 19.71 min, t2 = 24.82 min; [α]25 D −20.2 (c 0.5, CHCl3). Gram Scale Reaction of Asymmetric Synthesis of 3c. To a stirred solution of p-QM 1c (690 mg, 4.0 mmol, 1.0 equiv) and azlactone 2f (637 mg, 4.8 mmol, 1.2 equiv) in dry C6F6 (20 mL) at room temperature was added catalyst (S)-E (0.2 mmol). The reaction was monitored by TLC. After 1c was consumed completely, the reaction solution was concentrated in vacuo and the crude products were purified by flash chromatography eluting with CH2Cl2/CH3OH (500:1) to afford the products 3r as a white solid (1.06 g, 87% yield, >19:1 dr, 95% ee). Synthesis of 4c.19a Under an Ar atmosphere, 3c (61.0 mg, 0.1 mmol) was dissolved in 5.0 mL of anhydrous toluene and then AlCl3 (133.3 mg, 1.0 mmol, 10.0 equiv) was added dropwise. The resulting mixture was refluxed for 5 h until completion of the reaction. Then 10 mL of H2O was added to quenched the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified with silica gel by column chromatography (hexane/ethyl acetate 2:1), affording 4c as a white solid (37.3 mg, 75% yield, >19:1 dr, 94% ee). N-(3-Benzyl-6-chloro-4-(4-hydroxyphenyl)-2-oxochroman-3-yl)4-methylbenzamide (4c): white solid, 37.3 mg, 75% yield; mp 259− 261 °C; 1H NMR (400 MHz, acetone-d6) δ 8.62 (s, 1H), 7.59 (s, 1H), 7.46 (d, J = 6.4 Hz, 2H), 7.32−7.27 (m, 1H), 7.24−7.09 (m, 10H), 6.89 (d, J = 6.6 Hz, 2H), 4.98 (s, 1H), 3.61 (d, J = 14.2 Hz, 1H), 3.02 (d, J = 14.2 Hz, 1H), 2.99 (s, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ 167.7, 166.5, 158.2, 151.0, 142.8, 136.4, 132.1, 131.8, 130.0, 129.6, 129.2, 129.1, 128.8, 128.2, 128.0, 127.7, 118.4, 116.6, 62.2, 50.1, 37.0, 21.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H25ClNO4 498.1467, found 498.1467. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2propanol/hexane 1:4), 1.0 mL/min. Major isomer: t1 = 20.02 min, t2 = 33.82 min; [α]25 D 14.8 (c 0.5, CHCl3). Synthesis of 5c.19b To a solution of 3c (305.0 mg, 0.5 mmol) in anhydrous THF (10 mL) was added LiAlH4 (200 mg, 5 mmol, 10.0 equiv). The resulting mixture was stirred for 4 h until completion of the reaction at room temperature. Then 20 mL of H2O was added to quenched the reaction, and the reaction was extracted with Et2O. The organic phase was dried over Na2SO4 and concentrated under reduced

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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/acs.joc.7b02750. Theoretical calculations, 1H NMR, 13C NMR, and HPLC spectra for new products, crystal data and structure refinement for 3e (PDF) Crystal data of 3e (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xin Li: 0000-0001-6020-9170 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the NNSFC (Grant nos. 21390400 and 21421062) for financial support. 372

DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373

Article

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.7b02750 J. Org. Chem. 2018, 83, 364−373