Organocatalytic Asymmetric Allylic Alkylation of Morita–Baylis–Hillman

Science, Guangxi Teachers Education University, Nanning, Guangxi 530001, People's Republic of China. J. Org. Chem. , 2017, 82 (23), pp 12202–122...
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Organocatalytic Asymmetric Allylic Alkylation of Morita−Baylis− Hillman Carbonates with Diethyl 2‑Aminomalonate Assisted by In Situ Protection Yu Zheng,† Jing Wang,† Peng-Ju Xia,† Qing-lan Zhao,† Jun-An Xiao,‡ Hao-Yue Xiang,† Xiao-Qing Chen,† and Hua Yang*,† †

College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, People’s Republic of China College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning, Guangxi 530001, People’s Republic of China

‡

S Supporting Information *

ABSTRACT: With the aid of in situ protection by N-(2formylphenyl)-4-methyl-benzenesulfonamide, enantioselective allylic alkylation of Morita−Baylis−Hillman carbonates with diethyl 2-aminomalonate was successfully realized. The corresponding adducts can be obtained in up to 99% yield with up to 98% ee as well as excellent regioselectivity. Besides, the adducts with opposite configurations were readily prepared by utilizing easily available and inexpensive quinine or quinidine as organocatalyst. Facile deprotection of the resulting adduct provides straightforward access to enantiopure αmethylene-γ-lactam.

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INTRODUCTION Construction of a C−C bond in an asymmetric fashion stands as a major challenge in synthetic science that continues to gather intensive attention from the chemical society.1 Effective pathways for the stereoselective construction of C−C bonds have been enthusiastically pursued and have persistently attracted wide interest in the realm of asymmetric synthesis. Notably, asymmetric allylic alkylation as one of the valuable carbon−carbon bond-forming reactions has attracted considerable attention in recent years, which allows for the rapid construction of stereocenter while maintaining the functionality of alkene.2,3 In particular, Morita−Baylis−Hillman adducts as a class of versatile C3 synthons have been involved in numerous asymmetric transition-metal-catalyzed and organocatalyzed transformations, which can facilely afford densely functionalized molecules as valuable starting materials in the synthesis of a wide array of heterocycles and bioactive molecules.4,5 Multifunctionalized Morita−Baylis−Hillman carbonates have been extensively reported as highly reactive allyl-alkylating agents.6 Yet, due to inherent multiple reactive sites for MBH adduct, regioselectivity always draws concern in the nucleophilic addition to MBH adduct.7 In recent years, booming organocatalysis offered an effective solution to this issue by employing phosphine or tertiary amine to regioselectively have the SN2′− SN2′ reaction process proceed with remarkably improved regioselectivity.8 On the other hand, dialkyl 2-aminomalonates as a class of important building blocks are finding wide synthetic utilities in the synthesis of complex molecules or pharmaceuticals.9 Especially, α-imino esters derived from dialkyl 2-amino© 2017 American Chemical Society

malonates act as reactive azomethine yildes in 1,3-diploar cycloaddition, assembling various heterocyclic scaffolds.10 Surprisingly, little attention was paid to the direct functionalization of α-carbon in dialkyl 2-aminomalonate, which might provide innovative modes for asymmetric carbon−carbon formation.11 In fact, binary nucleophilic sites in dialkyl 2aminomalonate usually give rise to problematic regioselectivity in the nucleophilic attack (as shown in Scheme 1). In 2014, Rios and co-workers reported an asymmetric synthesis of αmethylene-γ-lactams via nucleophilic substitution of MBH carbonates by 2-aminomalonates, where Boc-protected 2aminomalonates were necessitated to enable an allylic addition-initiated reaction sequence to give α-methylene-γlactams.12 However, only moderate enantioselectivity and ambiguous regioselectivity were obtained. We postulated that rational design of protecting group for 2-aminomalonate might help us to fully harness its reactivity in a variety of direct functionalization. In 2016, Wang and co-workers documented an organocatalytic asymmetric allylic alkylation between N2,2,2-trifluoroethylisatin ketimines and MBH carbonates in excellent yields and stereoselectivities, in which N-methyl isatin moiety acted as an effective protecting group.13 Our continued interest in imine or enamine catalysis promoted by secondary amino acid sulfonamide prompted us to exploit a multifunctional protecting group by integrating sulfonamide with imine.14 We wondered if the designed protecting group for 2aminomalonate could serve dual roles: muting the nucleophilReceived: August 15, 2017 Published: November 1, 2017 12202

DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208

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The Journal of Organic Chemistry

(3e) was tested in this reaction. Pleasingly, the corresponding imine was rapidly formed in situ between 2a and 3e. As expected, the desired allylic alkylation product 4a was obtained in 85% yield with excellent regioselectivity. Next, we turned our attention to carrying out the title reaction in an enantioselective manner. Various readily available alkaloids including quinine, quinidine, cinchonine, and cinchonidine were employed as organocatalyst to promote this reaction, and the results are shown in Table 2. To our delight, the employment of quinine gave adduct 4a in good yield (76%) with excellent enantioselectivity (95% ee) (entry 1). With quinidine, 4a with the opposite configuration was obtained in moderate yield (65%) with good enantioselectivity (80% ee) (entry 2). However, cinchonine and cinchonidine only provided inferior yields and enantioselectivities (entries 3 and 4). Next, various solvents such as THF, toluene, CH3OH, and dichloromethane were examined. It turned out that CHCl3 was still the best solvent for this reaction in terms of enantioselectivity, while toluene gave the best yield for 4a (91%) (entry 7). Subsequently, additives were then evaluated to further improve the chemical yield and enantioselectivity. Addition of K2CO3 slightly decreased the yield with a comparable enantioselectivity (entry 10). Interestingly, chemical yield was remarkably improved to 91% with excellent enantioselectivity (98% ee) in the presence of 4 Å molecular sieves (entry 11). We speculate that the addition of 4 Å molecular sieves removes water and promotes the formation of imine. Cutting down the catalyst loading to 10 mol % was deleterious to the chemical yield (entry 12). Satisfyingly, the alkylation product with the opposite configuration can be readily achieved in moderate yield and excellent enantioselectivity (65% yield and 96% ee) by simply changing the catalyst to quinidine and switching the solvent to toluene (entry 14). With the optimal conditions available, we sought to examine the substrate tolerance for this reaction (Table 3). Various MBH carbonates (1a−1q) were subjected to the standard conditions, respectively. Initially, a change of R2 from OBoc to OAc led to a sharp decline in yield, albeit with excellent enantioselectivity (45%, 96% ee, entry 2). The substitution effect of the phenyl moiety in MBH carbonates was evaluated (Table 3, entries 3−12). In general, substituents with various electronic natures on different positions of benzene ring were well tolerated. Specifically, the introduction of the fluoro group at the ortho-position caused an obvious decrease in enantioselectivity (4b, entry 3). Noticeably, an electron-

Scheme 1. Organocatalytic Allylic Alkylation of MBH Adduct

icity of the amino group to improve the regioselectivity and providing extra binding sites for stereocontrol to secure high enantioselectivity. Herein, we disclose our success in the asymmetric allylic addition of 2-aminomalonate with MBH carbonate through an in situ protection by utilizing N-(2formylphenyl)-4-methylbenzenesulfonamide. This developed protocol catalyzed by quinine or quinidine shows excellent stereoselectivity and regioselectivity.

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RESULTS AND DISCUSSION To test our hypothesis, various functionalized aromatic aldehydes were evaluated in the model reaction of MBH carbonate 1a and diethyl 2-aminomalonate (2a) promoted by 1,4-diazabicyclo[2.2.2]octane (DABCO) (as shown in Table 1). Initially, using benzaldehyde (3a) only gave an extremely complex reaction. Next, 2-hydroxybenzaldehyde (3b), 2[(phenylmethyl) amino]-benzaldehyde (3c), and tert-butyl (2formylphenyl)carbamate (3d) with different side arms attached to the phenyl ring were also examined in the reaction. Unfortunately, only the corresponding imines were obtained for 3b and 3c, and the desired alkylation product was not formed. It was even worse that no obvious reaction was observed for 3d due to the demanding steric hindrance. Ultimately, N-(2-formylphenyl)-4-methyl-benzenesulfonamide

Table 1. Screening In Situ Protection for Diethyl 2-Aminomalonate in the Alkylation of MBH Carbonatea

a

Unless otherwise noted, all reactions were carried out using 1a (0.20 mmol), 2a (0.30 mmol), 3 (0.15 mmol), and DABCO (0.17 mmol, 1.1 equiv) in CHCl3 (1.0 mL). 12203

DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208

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The Journal of Organic Chemistry Table 2. Optimization of the Reaction Conditionsa

entry

solvent

time (h)

catalyst (0.2 equiv)

1 2 3 4 5 6 7 8 9 10d 11e 12e,f 13e 14e

CHCl3 CHCl3 CHCl3 CHCl3 THF CH3OH toluene DCM DCE CHCl3 CHCl3 CHCl3 CHCl3 toluene

72 72 72 72 72 72 72 72 72 72 72 72 72 72

quinine quinidine cinchonine cinchonidine quinine quinine quinine quinine quinine quinine quinine quinine quinidine quinidine

additive

K2CO3 4 Å MS 4 Å MS 4 Å MS 4 Å MS

yieldb (%)

eec (%)

76 65 30 55 43

95 −80 41 −13 86

91 68 56 51 91 47 72 65

93 92 73 93 98 95 −90 -96

a

Unless otherwise noted, all reactions were carried out using 1a (0.20 mmol), 2a (0.30 mmol), 3e (0.15 mmol), and catalyst (0.03 mmol, 20 mol %) in solvent (1.0 mL). bIsolated yields. cDetermined by HPLC on a chiral stationary phase. dK2CO3 (1.0 equiv) was added. e4 Å MS (40 mg) was added. fQuinine (10 mol %) was added.

Table 3. Substrate Scope of MBH Adduct 1 in the Title Reactiona

entry

1/R1, R2, R3

2/R4

4

time (h)

yieldb (%)

eec (%)

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

1a, Ph, OBoc, Me 1b, Ph, OAc, Me 1c, 2-F-Ph, OBoc, Me 1d, 3-F-Ph, OBoc, Me 1e, 4-F-Ph, OBoc, Me 1f, 4-Cl-Ph, OBoc, Me 1g, 2-Br-Ph, OBoc, Me 1h, 3-Br-Ph, OBoc, Me 1i, 4-Br-Ph, OBoc, Me 1j, 4-OMe-Ph, OBoc, Me 1k, 4-Me-Ph, OBoc, Me 1l, 4-CF3-Ph, OBoc, Me 1m, 2-naphthyl, OBoc, Me 1n, 2-thienyl, OBoc, Me 1o, 2-furyl, OBoc, Me 1p, Ph, OBoc, Et 1q, Ph, OBoc, t-Bu 1a, Ph, OBoc, Me

2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2a, Et 2b, Me

4a 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q

72 72 24 48 72 72 72 72 72 96 96 48 48 24 24 72 72 72

91 45 98 72 77 72 74 71 60 61 77 83 85 98 99 78 78 62

98 96 85 90 96 95 93 97 92 90 92 82 95 90 89 94 94 90

a

Unless otherwise noted, all reactions were carried out using MBH adduct 1 (0.20 mmol), 2 (0.40 mmol), 3e (0.15 mmol), and quinine (0.03 mmol, 20 mol %) in CHCl3 (1.0 mL). bIsolated yields. cDetermined by HPLC on a chiral stationary phase. 12204

DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208

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The Journal of Organic Chemistry Table 4. Selected Substrates for the Title Reaction Promoted by Quinidinea

a Unless otherwise noted, all reactions were carried out using MBH adduct 1 (0.20 mmol), 2a (0.40 mmol), 3e (0.15 mmol), and quinidine (0.03 mmol, 20 mol %) in CHCl3 (1.0 mL).

the basis of all of the obtained stereochemical information, a plausible transition state is proposed in Figure 1. Presumably,

donating group significantly slowed the reaction, leading to inferior yields for 4i and 4j even in an elongated reaction duration (entries 10 and 11). Pleasingly, heterocyclic analogues 4m and 4n were also obtained in excellent yields with good enantioselectivity (entries 14 and 15). Finally, switching methyl to ethyl or tert-butyl ester (1p and 1q) also gave excellent enantioselectivity, but with decreased chemical yield (entries 16 and 17). On the other hand, dimethyl 2-aminomalonate (2b) was also applicable to this protocol, giving the corresponding product 4q in 62% yield and 90% ee (entry 18). Noticing the fact that replacement of quinine with quinidine can readily afford the other enantiomer of 4a in high enantioselectivity (Table 2, entry 15), we randomly chose four substrates (1e, 1g, 1i, and 1p) to test the viability of the reaction system using quinidine. To our delight, four products 4d′, 4f′, 4h′, and 4o′ were persistently achieved in good enantioselectivity and moderate to good yield respectively (Table 4). The scalability of this protocol was convincingly demonstrated by performing the model reaction at large scale (1 mmol), in which excellent enantioselectivity (96% ee) was obtained for 4a albeit with a slightly dropped yield (74% yield) (Scheme 2, eq a). Finally, synthetic utility of the corresponding

Figure 1. Plausible transition state.

quinine initially attacked MBH carbonate via an SN2′ process to form an ammonium species. Subsequently, another SN2′-type process took place where the corresponding imine derived from 2 and 3e served as the actual nucleophile to attack the carbon− carbon double bond, which was stereocontrolled by the hydrogen bonding between the hydroxyl group of quinine and the diester moiety in 2a. Noticeably, given the remarkable difference of stereoselectivity between quinine and cinchonine, the interaction between catalyst and nucleophile might be further reinforced through an extra hydrogen bonding between the sulphonamide moiety and the methoxyl group in quinine. As a result, excellent enantioselectivity was achieved through the dual-hydrogen-bonding-directed nucleophilic attack.

Scheme 2. Scale-Up Reaction and Deprotection of the Product

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CONCLUSIONS

In summary, with the assistance of in situ protection by N-(2formylphenyl)-4-methyl-benzenesulfonamide, asymmetric allylic alkylation of MBH adducts with dialkyl 2-aminomalonate catalyzed by quinine was successfully realized in good yield with good to excellent enantioselectivity and excellent regioselectivity. The corresponding adducts with opposite configuration were easily prepared in high enantioselectivity by utilizing quinidine. Moreover, deprotection of the obtained adduct facilely gave enantiopure α-methylene-γ-lactam. This developed strategy employing in situ protection might find broader application in amino-group-involved asymmetric chemical transformations.

product 4 was exemplified by removing the in situ formed protecting group under acidic conditions, and enantiopure αmethylene-γ-lactam 5 (97% ee) was facilely assembled in 91% yield without eroding enantiopurity in the process (Scheme 2, eq b).12 Finally, the chemical structure and absolute configuration of adduct 4h were unambiguously established by single-crystal Xray analysis (for details, see the Supporting Information).15 On 12205

DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208

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= 244 Hz), 142.5, 138.5 (d, 3JC−F = 7 Hz), 138.3, 137.9, 136.0, 133.3, 131.5, 128.6, 128.4 (d, 3JC−F = 8 Hz), 127.8, 126.4, 125.3 (d, 4JC−F = 3 Hz), 121.3, 119.1, 116.8 (d, 2JC−F = 22 Hz), 116.3, 113.4 (d, 2JC−F = 21 Hz), 78.9, 61.7, 61.5, 51.3, 49.0, 20.5, 13.0, 12.9. HRMS (TOF-ESI) m/z [M + H]+ calcd for C32H34FN2O8S+ 625.2014, found 625.1997; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 11.1 min (major), 12.4 min (minor). Adduct 4d. White solid (72 mg, yield 77%), 96% ee, [α]20D = −37.5 (c = 0.7 in CH2Cl2) (catalyzed by quinine); (71 mg, yield 76%), −95% ee, [α]20D = +28.7 (c = 0.7 in CH2Cl2) (catalyzed by quinidine); mp 128−129 °C; IR (KBr) ν 3416, 2984, 1741, 1502, 1159, 1012, 874 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.61 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.30−7.34 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 6.96−7.03 (m, 2H), 6.86−6.90 (m, 2H), 6.48 (s, 1H), 6.18 (s, 1H), 5.48 (s, 1H), 4.28−4.37 (m, 2H), 4.15−4.22 (m, 2H), 3.71 (s, 3H), 2.36 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.2, 167.9, 167.5, 167.0, 162.1 (d, 1JC−F = 245 Hz), 143.6, 139.3, 139.2, 137.0, 134.4, 132.6 (d, 3JC−F = 8 Hz), 132.52, 132.50 (d, 4JC−F = 3 Hz), 129.6, 128.2, 127.4, 122.3, 120.1, 117.2, 114.8 (d, 2JC−F = 21 Hz), 80.1, 62.7, 62.5, 52.32, 52.28, 49.72, 49.68, 21.6, 21.5, 14.0, 13.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C32H33FN2NaO8S+ 647.1834, found 647.1807; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/ hexane, 1.0 mL/min, UV 254 nm) tR = 11.8 min (major), 14.4 min (minor). Adduct 4e. White solid (69 mg, yield 72%), 96% ee, [α]20D = −47.8 (c = 0.7 in CH2Cl2) (catalyzed by quinine); (64 mg, yield 67%), −90% ee, [α]20D = +42.2 (c = 0.6 in CH2Cl2) (catalyzed by quinidine); mp 95−96 °C; IR (KBr) ν 3416, 2978, 1744, 1636, 1342, 1092, 821 cm−1; 1 H NMR (CDCl3, 400 MHz) δ 12.56 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.70, (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.29−7.35 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.97−7.05 (m, 2H), 6.48 (s, 1H), 6.17 (s, 1H), 5.45 (s, 1H), 4.27−4.37 (m, 2H), 4.15−4.22 (m, 2H), 3.71 (s, 3H), 2.36 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.4, 166.8, 166.4, 166.0, 142.6, 138.3, 138.0, 136.0, 134.5, 133.4, 132.4, 131.5, 131.2, 128.6, 127.4, 127.1, 126.3, 121.3, 119.0, 116.2, 78.9, 61.7, 61.5, 51.3, 48.8, 20.5, 13.0, 13.9; HRMS (TOF-ESI) m/z [M + H]+ calcd for C32H34ClN2O8S+ 641.1719, found 641.1713; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 10.9 min (major), 13.0 min (minor). Adduct 4f. White solid (76 mg, yield 74%), 93% ee, [α]20D = −43.4 (c = 0.8 in CH2Cl2); mp 155−156 °C; IR (KBr) ν 3414, 2996, 1952, 1740, 1254, 1160, 881 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.23 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.23−7.27 (m, 1H), 7.16−7.19 (m, 4H), 7.00 (td, J = 7.6, 1.2 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.44 (s, 1H), 5.83 (s, 1H), 5.75 (s, 1H), 4.17−4.28 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.68 (s, 3H), 2.29 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.4, 166.9, 166.6, 166.1, 142.6, 138.2, 137.64, 137.59, 136.0, 133.9, 132.1, 131.5, 129.7, 128.6, 127.6, 126.4, 126.3, 124.9, 121.3, 119.3, 116.0, 77.7, 61.7, 61.5, 51.1, 47.9, 20.5, 12.9, 12.5; HRMS (TOF-ESI) m/z [M + H]+ calcd for C32H34BrN2O8S+ 687.1199, found 687.1193; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 5.8 min (major), 10.1 min (minor). Adduct 4g. White solid (73 mg, yield 71%), 97% ee, [α]20D = −57.5 (c = 0.7 in CH2Cl2); mp 138−139 °C; IR (KBr) ν 3417, 2980, 1760, 1439, 1208, 1161, 871 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.55 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.43 (t, J = 1.6 Hz, 1H), 7.30−7.35 (m, 3H), 7.22 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 8.0 Hz, 1H), 6.96−7.03 (m, 2H), 6.51 (s, 1H), 6.21 (s, 1H), 5.46 (s, 1H), 4.28−4.38 (m, 2H), 4.15−4.26 (m, 2H), 3.72 (s, 3H), 2.35 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, 100 MHz) δ 167.4, 166.7, 166.3, 165.8, 142.5, 138.3, 138.1, 137.7, 136.0, 133.4, 133.0, 131.5, 129.5, 128.6, 128.4, 127.7, 126.3, 121.3, 120.8, 119.1, 116.3, 78.9, 61.8, 61.6, 51.3, 49.1, 20.5, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + H]+ calcd for C32H34BrN2O8S 687.1199, found 687.1220; HPLC analysis (CHIR-

EXPERIMENTAL SECTION

General Information. Unless otherwise noted, all of the reagents were purchased from commercial suppliers and used without further purification. 1H NMR spectra were recorded at 400 MHz. The chemical shifts were recorded in parts per million relative to tetramethylsilane and with the solvent resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constants (hertz), integration. 13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical shifts are reported in parts per million from the tetramethylsilane with the solvent resonance as an internal standard. Infrared spectra (IR) were recorded by FT-IR apparatus. High-resolution mass spectroscopy (HRMS) was performed on TOF MS ESI mass spectrometer, and methanol was used to dissolve the sample. Column chromatography was conducted on silica gel (200−300 mesh). MBHCs 2a−2q16 and N-(2formylphenyl)-4-methylbenzenesulfonamide 417 were prepared according to the reported protocols. General Procedure for the Synthesis of Compounds 4a−4p. To a solution of diethyl 2-aminomalonate 2 (53 mg, 0.3 mmol) in CHCl3 or toluene (1.0 mL) were added N-(2-formylphenyl)-4-methyl-benzenesulfonamide 3e (41 mg,0.15 mmol), MBH carbonates (0.2 mmol), 4 Å MS (40 mg), and quinine (10 mg, 0.03 mmol) or quinidine (10 mg, 0.03 mmol), respectively, at room temperature. After completion of the reaction (monitored by TLC), the organic solvent was removed in vacuo. The residue then was purified via flash chromatography (9:1 to 4:1 petroleum ether/ethyl acetate) to yield the corresponding product. Adduct 4a. White solid (79 mg, yield 88%), 98% ee (catalyzed by quinine), [α]20D = −36.5 (c = 0.8 in CH2Cl2); (59 mg, yield 65%), −96% ee (catalyzed by quinidine), [α]20D = +27.4 (c = 0.6 in CH2Cl2); mp 163−164 °C; IR (KBr) ν 2171, 1759, 1635, 1428, 1257, 1232, 1092 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.75 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.30−7.35 (m, 3H), 7.19−7.29 (m, 6H), 6.94−6.99 (m, 2H), 6.49 (s, 1H), 6.17 (s, 1H), 5.53 (s, 1H), 4.29−4.39 (m, 2H), 4.16−4.22 (m, 2H), 3.71 (s, 3H), 2.35 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, 100 MHz) δ 168.2, 168.0, 167.5, 167.1, 143.5, 139.32, 139.28, 137.1, 136.8, 134.3, 132.3, 130.8, 129.6, 128.3, 128.0, 127.5, 127.4, 122.2, 120.3, 117.3, 80.1, 62.6, 62.4, 52.23, 52.20, 50.54, 50.51, 21.52, 21.49, 14.0, 13.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C32H34N2NaO8S+ 629.1928, found 629.1914; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 11.3 min (major), 14.4 min (minor). Adduct 4b. White solid (92 mg, yield 98%), 85% ee, [α]20D = −35.9 (c = 0.9 in CH2Cl2); mp 120−121 °C; IR (KBr) ν 3450, 2979, 2171, 1746, 1346, 1199, 934 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.44 (s, 1H), 7.98 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.29−7.33 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.14−7.21 (m, 2H), 6.97−7.03 (m, 3H), 6.51 (s, 1H), 6.12 (s, 1H), 5.72 (s, 1H), 4.27−4.37 (m, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 2.36 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, 100 MHz) δ 168.5, 166.9, 166.4, 165.9, 159.9 (d, 1 JC−F = 246 Hz), 142.6, 138.3, 138.0, 136.0, 133.7, 131.5, 130.48, 130.45, 128.6, 128.0 (d, 3JC−F = 9 Hz), 127.9, 126.3, 124.0 (d, 3JC−F = 14 Hz), 122.72, 122.69, 121.2, 119.2, 116.0, 114.1 (d, 2JC−F = 23 Hz), 77.9, 61.7, 61.5, 51.2, 41.37, 41.35, 20.5, 12.9, 12.7; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C32H33FN2NaO8S+ 647.1834, found 647.1827; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/ hexane, 1.0 mL/min, UV 254 nm) tR = 9.6 min (major), 15.5 min (minor). Adduct 4c. White solid (67 mg, yield 72%), 90% ee, [α]20D = −49.3 (c = 0.7 in CH2Cl2); mp 125−126 °C; IR (KBr) ν 3421, 2171, 1745, 1636, 1250, 1157, 818 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.55 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.29−7.33 (m,1H), 7.23 (d, J = 8.0 Hz, 2H), 7.08−7.17 (m, 3H), 6.96−7.03 (m, 2H), 6.87−6.92 (m, 1H), 6.51 (s, 1H), 6.17 (s, 1H), 5.49 (s, 1H), 4.27−4.37 (m, 2H), 4.17−4.24 (m, 2H), 3.72 (s, 3H), 2.36 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.5, 166.7, 166.4, 166.0, 161.3 (d, 1JC−F 12206

DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208

Article

The Journal of Organic Chemistry

1.23 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.3, 167.0, 166.5, 166.1, 142.5, 138.3, 136.1, 133.3, 131.9, 131.5, 131.3, 129.1, 128.5, 127.7, 127.4, 127.1, 126.43, 126.38, 125.0, 124.9, 121.2, 119.2, 116.3, 79.0, 61.7, 61.4, 51.2, 49.7, 20.5, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C36H36N2NaO8S+ 679.2085, found 679.2068; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 13.9 min (major), 16.5 min (minor). Adduct 4m. White solid (90 mg, yield 98%), 90% ee, [α]20D = −38.9 (c = 0.9 in CH2Cl2); mp 110−111 °C; IR (KBr) ν 3416, 2980, 1743, 1498, 1265, 1159, 818 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.56 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 4.8 Hz, 1H), 6.95−7.02 (m, 3H), 6.86 (t, J = 4.0 Hz, 1H), 6.50 (s, 1H), 6.17 (s, 1H), 5.83 (s, 1H), 4.24−4.36 (m, 4H), 3.75 (s, 3H), 2.35 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H), 1.24 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.0, 166.49, 166.46, 165.9, 142.4, 138.7, 138.3, 137.9, 136.1, 133.3, 131.3, 128.5, 127.9, 127.8, 126.4, 125.5, 124.8, 121.2, 119.5, 116.4, 79.1, 61.7, 61.6, 51.3, 44.6, 20.5, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C30H32N2NaO8S2+ 635.1492, found 635.1492; HPLC analysis (CHIRALCEL AD-H, 10% 2propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 26.2 min (major), 35.3 min (minor). Adduct 4n. White solid (89 mg, yield 99%), 89% ee, [α]20D = −33.2 (c = 0.9 in CH2Cl2); mp 139−140 °C; IR (KBr) ν 3415, 2981, 1744, 1499, 1268, 1056, 876 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.54 (s, 1H), 7.83 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.35 (q, J = 0.8 Hz, 1H), 7.27−7.32 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.14 (dd, J = 7.6, 1.6 Hz, 1H), 6.97−7.01 (m, 1H), 6.46 (s, 1H), 6.26− 6.29 (m, 2H), 6.05 (s, 1H), 5.58 (s, 1H), 4.24−4.34 (m, 4H), 3.78 (s, 3H), 2.35 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13 C NMR (CDCl3, 100 MHz) δ 167.2, 166.4, 166.3, 166.2, 150.0, 142.4, 141.6, 138.4, 136.1, 135.5, 133.5, 131.3, 128.9, 128.5, 126.3, 121.1, 119.3, 116.3, 109.3, 109.1, 78.2, 61.62, 61.60, 51.3, 43.1, 20.5, 12.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C30H32N2NaO9S+ 619.1721, found 619.1717; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 12.0 min (major), 29.2 min (minor). Adduct 4o. White solid (73 mg, yield 78%), 94% ee, [α]20D = −45.1 (c = 0.7 in CH2Cl2) (catalyzed by quinine); (76 mg, yield 81%), −96% ee, [α]20D = +50.2 (c = 0.8 in CH2Cl2) (catalyzed by quinidine); mp 150−151 °C; IR (KBr) ν 3415, 2171, 1744, 1499, 1248, 1091, 935 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.64 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.21−7.26 (m, 3H), 7.10−7.16 (m, 5H), 6.87−6.89 (m, 2H), 6.42 (s, 1H), 6.09 (s, 1H), 5.45 (s, 1H), 4.21−4.31 (m, 2H), 4.02−4.14 (m, 4H), 2.28 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.2, 167.0, 166.5, 165.6, 142.5, 138.5, 138.3, 136.1, 135.8, 133.2, 131.3, 129.9, 128.5, 127.0, 126.9, 126.38, 126.36, 121.2, 119.3, 116.3, 79.0, 61.6, 61.3, 60.0, 49.5, 20.5, 13.1, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + H]+ calcd for C33H37N2O8S+ 621.2265, found 621.2270; HPLC analysis (CHIRALCEL IA, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 7.3 min (minor), 7.9 min (major). Adduct 4p. White solid, 61 mg, yield 63%, [α]20D = −35.2 (c = 0.6 in CH2Cl2); 93% ee (quinine); mp 144−145 °C; IR (KBr) ν 3415, 2171, 1731, 1500, 1255, 1092, 870 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.67 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.20−7.25 (m, 3H), 7.10−7.15 (m, 5H), 6.84−6.90 (m, 2H), 6.34 (s, 1H), 6.01 (s, 1H), 5.40 (s, 1H), 4.21−4.33 (m, 2H), 4.07−4.15 (m, 2H), 2.28 (s, 3H), 1.31 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.2, 167.0, 166.6, 164.7, 142.4, 139.7, 138.3, 136.1, 136.0, 133.2, 131.2, 129.9, 128.5, 126.8, 126.4, 126.3, 126.1, 121.2, 119.3, 116.3, 79.9, 79.0, 61.5, 61.3, 49.7, 26.9, 20.5, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C35H40N2NaO8S+ 671.2398, found 671.2395; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 8.4 min (major), 10.7 min (minor). Adduct 4q. White solid (54 mg, yield 65%), 90% ee, [α]20D = −37.4 (c = 0.6 in CH2Cl2); mp 154−155 °C; IR (KBr) ν 3416, 2954, 1761,

ALCEL AD-H, 5% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 44.0 min (major), 48.9 min (minor). Adduct 4h. White solid (62 mg, yield 60%), 92% ee, [α]20D = −51.3 (c = 0.6 in CH2Cl2) (catalyzed by quinine); (72 mg, yield 70%), −97% ee, [α]20D = +41.7 (c = 0.7 in CH2Cl2) (catalyzed by quinidine); mp 135−136 °C; IR (KBr) ν 3415, 2980, 1634, 1497, 1341, 1158, 820 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.47 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.23−7.28 (m, 3H), 7.15−7.19 (m, 4H), 6.98 (dd, J = 7.6, 2.0 Hz, 1H), 6.92 (td, J = 7.2, 0.8 Hz, 1H), 6.41 (s, 1H), 6.10 (s, 1H), 5.36 (s, 1H), 4.20−4.29 (m, 2H), 4.08−4.15 (m, 2H), 3.64 (s, 3H), 2.29 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.4, 166.8, 166.4, 165.9, 142.6, 138.3, 138.0, 136.0, 135.0, 133.4, 131.5, 130.1, 128.6, 127.4, 126.3, 121.3, 120.6, 119.0, 116.2, 78.9, 61.7, 61.5, 51.3, 48.8, 20.5, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + H]+ calcd for C32H34BrN2O8S 687.1199, found 687.1195; HPLC analysis (CHIRALCEL AD-H, 10% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 29.5 min (major), 35.1 min (minor). Adduct 4i. White solid (58 mg, yield 61%), 90% ee, [α]20D = −25.9 (c = 0.6 in CH2Cl2); mp 128−129 °C; IR (KBr) ν 3416, 2980, 1745, 1512, 1251, 1157, 875 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.66 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.21−7.26 (m, 1H), 7.14−7.17 (m, 4H), 6.89−6.91 (m, 2H), 6.63− 6.67 (m, 2H), 6.38 (s, 1H), 6.09 (s, 1H), 5.40 (s, 1H), 4.21−4.31 (m, 2H), 4.09−4.15 (m, 2H), 3.65 (s, 3H), 3.63 (s, 3H), 2.28 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.11, 167.05, 166.6, 166.1, 157.9, 142.5, 138.5, 138.3, 136.1, 133.2, 131.3, 131.0, 128.5, 127.4, 126.7, 126.4, 121.2, 119.3, 116.3, 112.3, 79.1, 61.6, 61.3, 54.2, 51.2, 48.9, 20.5, 13.0, 12.9; HRMS (TOFESI) m/z [M + H]+ calcd for C33H37N2O9S+ 637.2214, found 637.2225; HPLC analysis (CHIRALCEL IA, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 9.8 min (minor), 11.3 min (major). Adduct 4j. White solid (72 mg, yield 77%), 92% ee, [α]20D = −55.0 (c = 0.7 in CH2Cl2); mp 147−148 °C; IR (KBr) ν 3418, 2866, 1637, 1501, 1259, 1095, 802 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.65 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.21−7.26 (m, 1H), 7.12−7.16 (m, 4H), 6.89−6.94 (m, 4H), 6.38 (s, 1H), 6.07 (s, 1H), 5.41 (s, 1H), 4.20−4.30 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.63 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.2, 167.0, 166.5, 166.1, 142.4, 138.4, 138.3, 136.1, 133.2, 132.6, 131.2, 129.6, 128.5, 127.7, 127.0, 126.4, 121.2, 119.3, 116.3, 79.0, 61.6, 61.3, 51.2, 49.2, 20.5, 20.0, 13.0, 12.9; HRMS (TOF-ESI) m/z [M + H]+ calcd for C33H37N2O8S+ 621.2265, found 621.2253; HPLC analysis (CHIRALCEL AD-H, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 9.1 min (major), 12.7 min (minor). Adduct 4k. Yellow solid (84 mg, yield 83%), 82% ee, [α]20D = −13.6 (c = 0.8 in CH2Cl2); mp 130−131 °C; IR (KBr) ν 3415, 2978, 1742, 1325, 1254, 1015, 863 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.49 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.31−7.35 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.97−7.05 (m, 2H), 6.52 (s, 1H), 6.18 (s, 1H), 5.52 (s, 1H), 4.27−4.37 (m, 2H), 4.14−4.22 (m, 2H), 3.72 (s, 3H), 2.36 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.7, 167.7, 167.4, 167.0, 143.7, 141.3, 139.3, 138.8, 137.0, 134.5, 132.7, 131.1, 129.6, 129.5 (d, 2 JC−F = 35 Hz), 128.9, 127.3, 124.9 (q, 3JC−F = 3 Hz), 124.0 (d, 1JC−F = 265 Hz), 122.4, 120.0, 117.1, 79.9, 62.8, 62.6, 52.39, 52.36, 50.0, 21.6, 21.5, 14.0, 13.9; HRMS (TOF-ESI) m/z [M + Na]+ calcd for C33H33F3N2NaO8S+ 697.1802, found 697.1803; HPLC analysis (CHIRALCEL IA, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 8.0 min (minor), 8.9 min (major). Adduct 4l. White solid (84 mg, yield 85%), 95% ee, [α]20D = −64.3 (c = 0.8 in CH2Cl2); mp 155−156 °C; IR (KBr) ν 3416, 2171, 1742, 1501, 1242, 1091, 874 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.69 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.65 (t, J = 8.8 Hz, 2H), 7.59 (t, J = 8.0 Hz, 2H), 7.38−7.41 (m, 2H), 7.27−7.35 (m, 2H), 7.20−7.24 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 6.8 Hz, 1H), 6.45 (s, 1H), 6.17 (s, 1H), 5.61 (s, 1H), 4.23−4.33 (m, 2H), 4.06−4.14 (m, 2H), 3.62 (s, 3H), 2.27 (s, 3H), 12207

DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208

Article

The Journal of Organic Chemistry 1496, 1160, 867 cm−1; 1H NMR (CDCl3, 400 MHz) δ 12.62 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.20− 7.26 (m, 3H), 7.12−7.15 (m, 5H), 6.85−6.91 (m, 2H), 6.41 (s, 1H), 6.07 (s, 1H), 5.47 (s, 1H), 3.79 (s, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.6, 167.3, 166.9, 166.0, 142.5, 138.3, 138.2, 136.1, 135.4, 133.2, 131.4, 129.7, 128.6, 127.1, 126.6, 126.3, 121.3, 119.3, 116.4, 78.8, 52.6, 52.2, 51.2, 49.9, 20.5; HRMS (TOF-ESI) m/z [M + H]+ calcd for C30H31N2O8S+ 579.1796, found 579.1799; HPLC analysis (CHIRALCEL IG, 20% 2propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 26.1 min (major), 31.8 min (minor). Lactam 5.12 To a solution of 4a (61 mg, 0.1 mmol) in CH3OH (1 mL) was added 0.5 mL of 4 N HCl. Stirring was then continued at room temperature until the starting material had been consumed. The solvent was removed in vacuo, and the resulting residue was purified via flash chromatography to yield the corresponding product. White solid (29 mg, 91% yield), 97% ee, [α]20D = −65.2 (c = 0.3 in CH2Cl2); 1 H NMR (CDCl3, 400 MHz) δ 7.32−7.28 (m, 5H), 6.68 (s, 1H), 6.28 (d, J = 2.8 Hz, 1H), 5.35 (d, J = 2.4 Hz, 1H), 5.00 (t, J = 2.8 Hz, 1H), 4.25−4.34 (m, 2H), 3.73−3.81 (m, 1H), 3.50−3.58 (m,1H), 1.29 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H); HPLC analysis (CHIRALCEL IA, 20% 2-propanol/hexane, 1.0 mL/min, UV 254 nm) tR = 7.8 min (minor), 9.3 min (major).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02064. Copies of NMR spectra and HPLC analysis spectra of all compounds (PDF) X-ray structural data for compound 4h (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hao-Yue Xiang: 0000-0002-7404-4247 Hua Yang: 0000-0002-5518-5255 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21576296 and 21676302) and Central South University.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02064 J. Org. Chem. 2017, 82, 12202−12208