Catalytic Asymmetric [4 + 2] Cycloaddition of in situ Generated o

determined by chiral high-performance liquid chromatography (chiral HPLC). The chiral columns used for the determination of enantiomeric ratios by chi...
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Article Cite This: J. Org. Chem. 2018, 83, 614−623

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Catalytic Asymmetric [4+2] Cycloaddition of in Situ Generated o‑Quinone Methide Imines with o‑Hydroxystyrenes: Diastereo- and Enantioselective Construction of Tetrahydroquinoline Frameworks Lin-Zhi Li,† Cong-Shuai Wang,† Wei-Feng Guo, Guang-Jian Mei,* and Feng Shi* School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 221116, China S Supporting Information *

ABSTRACT: A catalytic asymmetric [4+2] cycloaddition of ortho-quinone methide imines in situ generated from oaminobenzyl alcohols with o-hydroxystyrenes has been established under the catalysis of chiral phosphoramide, which afforded chiral tetrahydroquinolines in moderate to good yields, good enantioselectivities, and excellent diastereoselectivities (up to 82% yield, 93:7 er, all >95:5 dr). In this catalytic asymmetric [4+2] cycloaddition, the hydrogen-bonding interaction between chiral phosphoramide and two substrates was proposed to play a crucial role in controlling the enantioselectivity. This reaction not only provides a useful approach for constructing chiral tetrahydroquinoline frameworks, but also demonstrates the great practicability of ortho-quinone methide imines in catalytic asymmetric cycloadditions.

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INTRODUCTION Enantioenriched tetrahydroquinolines are structurally common heterocyclic motifs, which are widely found in natural alkaloids and synthetic bioactive compounds (Figure 1).1 For instance,

important synthetic intermediates in organic synthesis, developing new methodologies for the construction of tetrahydroquinoline frameworks, especially in a catalytic asymmetric fashion, has attracted continuous interests from the chemistry community.6 Ortho-quinone methides (o-QMs) have proven to be versatile intermediates in organic chemistry.7 Owing to their high reactivity, o-QMs-involved catalytic asymmetric 1,4conjugate addition reactions with different nucleophiles8 and catalytic asymmetric [4+n] cycloaddition reactions9−11 with various dienophiles have been well-developed (Scheme 1a). In sharp contrast, the catalytic asymmetric reactions of orthoquinone methide imines (o-QMIs), namely, aza-ortho-quinone methides, have received less attention.7e,12 As analogues of oQMs, o-QMIs can also be trapped by nucleophiles and dienophiles via 1,4-conjugate addition or cycloaddition reactions (Scheme 1b). For example, the Rueping group has demonstrated a catalytic asymmetric approach for the 1,4addition of o-QMIs with alcohols, thiophenols and indoles.13 Scheidt and Schneider revealed that the catalytic asymmetric formal [4+2] cycloadditions of o-QMIs could be achieved by reactions with enols or enamides, leading to chiral 1,4dihydroquinolines or dihydroquinolones, respectively.14 In spite of their pioneering work, developing catalytic asymmetric reactions of o-QMIs is still urgently needed.

Figure 1. Selected natural products and synthetic compounds containing the tetrahydroquinoline core.

alkaloid I was reported to be a new antibiotic from Janibacter limosus Hel 1.2 Alkaloids II−III showed inhibitory activity against glutamate toxicity and lipid peroxidation.3 In addition, compounds IV−VI possessed antibacterial and antitumoral properties, respectively.4 Compound VII was identified as an agonist of the large-conductance calcium-activated potassium channel (BKCa).5 Due to the their significance in drug discovery and medicinal chemistry, as well as the utility as © 2017 American Chemical Society

Received: October 5, 2017 Published: December 25, 2017 614

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry Scheme 1. Profile of o-QMs and o-QMIs Involved Catalytic Asymmetric Reactions

Table 1. Screening of Catalysts and Optimization of Reaction Conditionsa

Our group has been interested in the synthesis of chiral heterocycles with potential biological activity via o-QMs.9a,15 In addition, we have recently developed a racemic [4+3] cycloaddition of o-QMIs generated from o-aminobenzyl alcohols 1 with azomethine imines in the presence of Brønsted acid (BH) (Scheme 2, eq 1).16 In this context, we envisioned entry

cat.

solvent

additive

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

(R)-4a (R)-4b (R)-4c (R)-4d (R)-4e (R)-5 (S)-6 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7 (R)-7

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 AcOEt toluene CH3CN CH2Cl2 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

3 3 3 3 3 3 3 3 3 3 3 3

Scheme 2. Design of Catalytic Asymmetric [4+2] Cycloaddition of o-QMIs for the Construction of Chiral Tetrahydroquinoline Frameworks

that chiral tetrahydroquinoline frameworks could be constructed by the catalytic asymmetric [4+2] cycloaddition of oQMIs with o-hydroxystyrenes 2 under the catalysis of chiral phosphoric acids (CPAs).17 As illustrated in eq 2, the o-QMIs would be generated in situ from o-aminobenzyl alcohols 1 via dehydration. Then, CPA would activate both o-QMIs and ohydroxystyrenes 2 simultaneously via hydrogen-bonding interactions to facilitate a diastereo- and enantioselective [4+2] cycloaddition between them, leading to the construction of enantioenriched tetrahydroquinolines 3.

Å Å Å Å Å Å Å Å Å Å Å Å

MS MS MS MS MS MS MS MS MS MS MS MS

4 Å MS 5 Å MS Na2SO4 MgSO4 5 Å MS 5 Å MS 5 Å MS

yield (%)b 88 63 52 40 25 52 22 48 N.R. 20 N.R. 40 45 48 55 49 50 57 59 60

drc

erd

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5

71:29 65:35 0 80:20 52:48 79:21 74:26 85:15

>95:5

67:33

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5

74:26 82:18 87:13 89.5:10.5 88:12 88:12 90:10 90.5:9.5 91:9

a

Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale and catalyzed by 10 mol% 4−7 in a solvent (1 mL) at 25 °C for 48 h, and the molar ratio of 1a:2a was 1:1.2. bIsolated yield. c The dr value was determined by 1H NMR and HPLC. dThe er value was determined by HPLC. ePerformed in 2 mL of solvent. fPerformed in 4 mL of solvent. gPerformed in 8 mL of solvent. N.R. = no reaction.

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delight, the desired product 3aa was obtained with an acceptable enantioselectivity of 85:15 er under the catalysis of chiral phosphoramide (CPN) 7 (entry 8). So, CPN 7 was selected as the optimal catalyst for the subsequent condition optimization. Screening of the solvents indicated that chloroform was the best solvent (entry 8 vs entries 9−12). Furthermore, it was found that additives had some effect on the enantioselectivity (entries 8 and 13−17). Using 5 Å molecular sieves (MS) as additives, a higher enantioselectivity of 89.5:10.5 er was observed (entry 15). In addition, it was found that diluting the reaction concentration could further improve the enantioselectivity (entry 15 vs entries 18−20). Finally, the optimal reaction conditions were set in line with

RESULTS AND DISCUSSION Our investigation on the designed catalytic asymmetric [4+2] cycloaddition of o-QMIs was initiated by reaction condition optimization (Table 1). The reaction between o-aminobenzyl alcohol 1a and o-hydroxystyrene 2a was selected as a model reaction. First, a series of BINOL-derived CPAs 4 were screened (entries 1−5). The results revealed that the designed [4+2] cycloaddition reaction indeed occurred, but the product 3aa was generated with poor enantioselectivities. Moreover, H8−BINOL-derived CPA 5 and SPINOL-derived CPA 6 failed to improve the enantioselectivity (entries 6 and 7). To our 615

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of o-Aminobenzyl Alcohols 1a

entry

3

Ar/R/R1 (1)

yield (%)b

drc

erd

1 2 3 4 5 6 7 8 9 10 11 12 13 14e 15 16 17 18 19 20e 21 22

3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma 3na 3oa 3pa 3qa 3ra 3sa 3ta 3ua 3va

p-MeOC6H4/H/Ph (1a) o-FC6H4/H/Ph (1b) o-ClC6H4/H/Ph (1c) o-BrC6H4/H/Ph (1d) o-MeOC6H4/H/Ph (1e) m-FC6H4/H/Ph (1f) m-BrC6H4/H/Ph (1g) m-CF3C6H4/H/Ph (1h) m-MeOC6H4/H/Ph (1i) m-MeC6H4/H/Ph (1j) p-FC6H4/H/Ph (1k) p-PhC6H4/H/Ph (1l) p-MeOC6H4/4-tBu/Ph (1m) p-MeOC6H4/5-Me/Ph (1n) p-MeOC6H4/5-Br/Ph (1o) p-MeOC6H4/4-Cl/Ph (1p) p-MeOC6H4/H/p-ClC6H4 (1q) p-MeOC6H4/H/p-MeC6H4 (1r) p-MeOC6H4/H/o-MeC6H4 (1s) p-MeOC6H4/H/Me (1t) p-MeOC6H4/H/CHCH2 (1u) p-MeOC6H4/H/H (1v)

60 53 60 68 53 73 82 68 57 65 74 65 45 80 48 57 57 61 75 48 N.R. N.R.

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5

91:9 91:9 90:10 87:13 86:14 90:10 90:10 92:8 93:7 92:8 90:10 90:10 89:11 85:15 87:13 91:9 80:20 79:21 91:9 90:10

Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in chloroform (8 mL) with 5 Å MS (100 mg) at 25 °C for 48 h, and the molar ratio of 1:2a was 1:1.2. bIsolated yield. cThe diastereomeric ratio (dr) was determined by 1H NMR. dThe enantiomeric ratio (er) was determined by HPLC. ePerformed at 50 °C. a

phenyl groups, delivering products 3qa−3sa in uniformly excellent diastereoselectivities and moderate to good enantioselectivities (entries 17−19). More importantly, the R1 substituents could be changed from phenyl groups to alkyl groups such as a methyl group (entry 20), which smoothly took part in the [4+2] cycloaddition in an acceptable yield of 48% with an excellent diastereoselectivity and a high enantioselectivity (>95:5 dr, 90:10 er). However, when R1 substituent was a vinyl group or a hydrogen atom, no reaction occurred (entries 21−22). Nevertheless, the results in Table 2 demonstrated that the substrate scope of o-aminobenzyl alcohols 1 was wide, which could give chiral tetrahydroquinolines 3 bearing different Ar/R/R1 substituents. Next, the substrate scope of o-hydroxystyrenes 2 was examined by the reactions with o-aminobenzyl alcohol 1a. As shown in Table 3, o-hydroxystyrenes 2 bearing either electrondonating or electron-withdrawing groups on different positions of the benzene ring were suitable for the catalytic asymmetric [4+2] cycloaddition, leading to the generation of tetrahydroquinoline products 3 in overall high diastereoselectivities (all >95:5 dr) and good enantioselectivities (90:10 to 93:7 er). In detail, the position of the substituents seemed to have little influence on the reaction, in terms of the similar yields and enantioselectivities of products 3ab and 3ac (entry 2 vs 3). The electronic nature of the substituents might have some effect on the reactivity because o-hydroxystyrenes 2d−2e bearing electron-withdrawing groups were superior to their counterparts 2f−2g substituted with electron-donating groups with regard to the yields (entries 4−5 vs 6−7). Moreover, when

what was illustrated in entry 20, which could provide the tetrahydroquinoline product 3aa in an acceptable yield of 60% and with a good enantioselectivity of 91:9 er. With the optimal conditions in hand, we carried out an investigation on the substrate scope of o-aminobenzyl alcohols 1 by the reactions with o-hydroxystyrene 2a (Table 2). As shown in entries 1−12, this catalytic asymmetric [4+2] cycloaddition reaction was applicable to a wide range of oaminobenzyl alcohols 1 bearing different Ar substituents, affording the etrahydroquinoline products 3 in generally considerable yields (53−82%), good enantioselectivities (86:14 to 93:7 er), and excellent diastereoselectivities (all >95:5 dr). It seems that the electronic nature and the position of the Ar substituents have some delicate effect on the enantioselectivity. For example, para- and meta-methoxylsubstituted substrates 1a and 1i delivered the reaction in higher enantioselectivity than ortho-methoxyl-substituted substrate 1e (entries 1 and 9 vs 5). Among these substrates, metabromo-substituted substrate 1g afforded the product in the highest yield of 82% (entry 7), while meta-methoxyl-substituted substrate 1i offered the product in the best enantioselectivity of 93:7 er (entry 9). In addition, several o-aminobenzyl alcohols 1 bearing different R substituents on the phenyl ring could also be employed to the [4+2] cycloaddition (entries 13−16), which generated the corresponding tetrahydroquinoline products 3 in acceptable yields (45−80%), excellent diastereoselectivities (all >95:5 dr) and considerable enantioselectivities (85:15 to 91:9 er). Moreover, the R1 substituents of substrates 1 could also be altered from a phenyl group to substituted 616

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry Table 3. Substrate Scope of o-Hydroxystyrenes 2a

Table 4. Applicability of Other Styrenes 2a

entry

3

R (2)

yield (%)b

drc

erd

1 2 3 4 5 6 7

3aa 3ab 3ac 3ad 3ae 3af 3ag

H (2a) 3-F (2b) 5-F (2c) 5-Cl (2d) 5-Br (2e) 5-Me (2f) 5-MeO (2g)

60 55 50 67 66 51 57

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5

91:9 91:9 92:8 91:9 90:10 91:9 93:7

entry

3

R (2)

yield (%)b

drc

erd

1 2 3e 4 5e

3ai 3aj 3ak 3al 3am

4-OH (2i) 3-OH (2j) 4-F (2k) 4-MeO (2l) H (2m)

N.R. N.R. 45 53 40

>95:5 >95:5 >95:5

72:28 79:21 78:22

a

Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in chloroform (8 mL) with 5 Å MS (100 mg) at 25 °C for 48 h, and the molar ratio of 1a:2 was 1:1.2. bIsolated yield. cThe diastereomeric ratio (dr) was determined by 1H NMR. dThe enantiomeric ratio (er) was determined by HPLC. ePerformed at 50 °C in the presence of 30 mol % (R)-7.

a

Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in chloroform (8 mL) with 5 Å MS (100 mg) at 25 °C for 48 h, and the molar ratio of 1a:2 was 1:1.2. bIsolated yield. cThe diastereomeric ratio (dr) was determined by 1H NMR. dThe enantiomeric ratio (er) was determined by HPLC.

indicated that the position of the hydroxyl group played a crucial role in controlling the reactivity. In addition, we also utilized styrenes 2k−2m without the ortho-hydroxyl group in the reaction (entries 3−5). Gratifyingly, these commonly used styrenes bearing either electronically poor, rich or neutral substituents could undergo the [4+2] cycloadditions in acceptable yields and excellent diastereoselectivities although the enantioselectivities were in a moderate level. These results suggested that the ortho-hydroxyl group was not a necessity for styrenes to perform the [4+2] cycloaddition. However, the moderate enantioselectivities in these cases demonstrated that the existence of the ortho-hydroxyl group was helpful for controlling the enantioselectivity of the [4+2] cycloaddition. In general, the successful application of styrenes 2k−2m to the reaction greatly enlarged the generality of the [4+2] cycloaddition. Based on the experimental results, we suggested two possible reaction pathways and activation modes (Scheme 4). In the cases of reactions involving o-hydroxystyrenes 2, a dual activation mode of CPN to two reaction partners was suggested. As shown in the Scheme 4a, as exemplified by the formation of product 3aa, the o-QMI intermediate A was generated in situ from o-aminobenzyl alcohol 1a under the catalysis of CPN 7. Then, catalyst 7 simultaneously generated two hydrogen bonds with both the o-QMI intermediate A and o-hydroxystyrene 2a, which facilitated a diastereo- and enantioselective [4+2] cycloaddition to give product 3aa with the observed relative and absolute configurations. While in the cases of styrenes 2k−2m without the ortho-hydroxyl group, a mono activation mode of CPN to one reaction partner was proposed. As exemplified by the formation of product 3am (Scheme 4b), when styrene 2m was engaged in the reaction, catalyst 7 could only generate one hydrogen bond with the oQMI intermediate A, which resulted in the stereoselective [4+2] cycloaddition and the generation of product 3am. However, because the effect of mono activation mode in controlling the enantioselectivity is weaker than dual activation mode, the enantioselectivities in these cases were lower than those involving o-hydroxystyrenes. The observed excellent diastereoselectivities in all cases might be attributed to the concerted reaction pathway. In addition, the C2−C4 cisconfiguration of products 3 might be largely ascribed to the Econfigured o-QMIs, which would undergo the [4+2] cyclo-

changing the substituent at the C5 position to an electrondonating group (MeO), the enantioselectivity was increased to a high level (entry 7). Notably, all of the reactions proceeded with excellent diastereoselectivities. The absolute configuration of product 3fa was unambiguously determined to be (R,S) by single-crystal X-ray diffraction analysis (Scheme 3a).18 The absolute configurations of other Scheme 3. Single-Crystal Structure of Product 3fa and Control Experiment

products 3 were assigned by analogy. To further verify the interaction between CPN and two substrates, a control experiment was carried out (Scheme 3b). When the protected o-hydroxystyrene 2h was employed in the reaction with 1a under the standard conditions, the designed [4+2] cycloaddition did not occur at all. The control experiment indicated that the hydroxyl group of o-hydroxystyrenes 2 played an important role in this reaction by forming a hydrogen bond with CPN. In addition, the hydrogen-bonding interaction between CPN 7 and o-hydroxystyrene 2a has been supported to some extent by the 1H NMR experiment, which found the signal of hydroxyl group in 2a was diminished after mixing 2a with CPN 7 (see the Supporting Information for details). To gain some insights into the ortho-hydroxyl group in ohydroxystyrenes 2, we investigated the applicability of other styrenes (Table 4). First, p-hydroxystyrene 2i and mhydroxystyrene 2j were employed as substrates to the reaction (entries 1−2). However, no reaction occurred. This result 617

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry Scheme 4. Suggested Reaction Pathways and Activation Modes

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CONCLUSIONS In summary, we have established a catalytic asymmetric [4+2] cycloaddition of o-QMIs in situ generated from o-aminobenzyl alcohols with o-hydroxystyrenes under the catalysis of chiral phosphoramide, which afforded chiral tetrahydroquinolines in moderate to good yields, high enantioselectivities, and excellent diastereoselectivities (up to 82% yield, 93:7 er, all >95:5 dr). In this catalytic asymmetric [4+2] cycloaddition, the hydrogenbonding interaction between chiral phosphoramide and two substrates was proposed to play a crucial role in controlling the enantioselectivity. This reaction not only provides a useful approach for constructing chiral tetrahydroquinoline frameworks, but also demonstrates the great practicability of o-QMIs in catalytic asymmetric cycloadditions.

addition via an endo transition state to give the C2−C4 cisproducts. In addition, the catalytic asymmetric [4+2] cycloaddition of o-aminobenzyl alcohol 1a with o-hydroxystyrene 2a could be performed on a 1 mmol scale under the standard conditions (Scheme 5a), which afforded product 3aa in a maintained Scheme 5. 1 mmol Scale Synthesis and Preliminary Derivation

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EXPERIMENTAL SECTION

1

H and 13C NMR spectra were measured respectively at 400 and 100 MHz, respectively. The solvent used for NMR spectroscopy was CDCl3, using tetramethylsilane as the internal reference. HRMS (ESI) was determined by a HRMS/MS instrument. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography (chiral HPLC). The chiral columns used for the determination of enantiomeric ratios by chiral HPLC were Chiralpak IA, OD-H, and AD-H columns. Optical rotation values were measured with instruments operating at λ = 589 nm, corresponding to the sodium D line at the temperatures indicated. The X-ray source used for the single crystal X-ray diffraction analysis of compound 3fa was CuKα (λ = 1.54178), and the thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column chromatography were distilled before use. All starting materials commercially available were used directly. Substrates 1 were synthesized according to the literature method.13 General Procedure for the Synthesis of Products 3. To the mixture of o-aminobenzyl alcohols 1 (0.1 mmol), o-hydroxylstyrenes 2

moderate yield of 58%, excellent diastereoselectivity of >95:5 dr and good enantioselectivity of 91:9 er compared with the small scale reaction (Table 2, entry 1). Moreover, the hydroxyl group of product 3aa could be conveniently removed by a sequential reaction to give compound 3am with nearly retained enantioselectivity, demonstrating the preliminary utility of this reaction in organic synthesis (Scheme 5b). 618

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry

(100 MHz, CDCl3) δ 155.1, 144.8, 143.7, 135.8, 133.0, 129.4, 129.2, 128.9, 128.8, 128.7, 128.6, 128.3, 127.8, 127.2, 126.8, 123.7, 120.4, 119.4, 116.8, 115.7, 62.5, 53.0, 44.3, 39.0; IR (KBr): 3445, 1541, 1521, 1508, 1491, 1455 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H25BrNO 470.1114, Found 470.1122; Enantiomeric ratio: 87:13, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 5.54 min (major), tR = 4.36 min (minor). 2-((2R,4S)-1-(2-Methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ea). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 53% (22.2 mg); light-yellow sticky solid; mp 156.5−157.3 °C; [α]D20 = +53.2 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 2H), 7.25−7.07 (m, 7H), 7.02−6.90 (m, 2H), 6.86− 6.76 (m, 4H), 6.72−6.67 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.90 (d, J = 16.4 Hz, 1H), 4.65 (dd, J = 12.0, 3.6 Hz, 1H), 4.42 (d, J = 16.4 Hz, 1H), 4.14 (dd, J = 12.4, 4.0 Hz, 1H), 3.65 (s, 3H), 2.67−2.54 (m, 1H), 2.30−2.25 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.8, 155.9, 145.0, 143.8, 130.3, 129.4, 129.0, 128.8, 128.7, 128.6, 128.5, 128.2, 127.5, 126.8, 126.6, 124.6, 120.1, 119.9, 119.6, 117.5, 116.8, 110.2, 63.0, 55.0, 48.6, 44.3, 39.3; IR (KBr): 3446, 1541, 1521, 1490, 1456 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H28NO2 422.2115, Found 422.2124; Enantiomeric ratio: 86:14, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.59 min (major), tR = 5.02 min (minor). 2-((2R,4S)-1-(3-Fluorobenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3fa). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 73% (30.0 mg); light-yellow solid; mp 133.2−134.1 °C; [α]D20 = +48.2 (c 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.28 (m, 2H), 7.26−7.15 (m, 7H), 6.98−6.91 (m, 2H), 6.90−6.80 (m, 3H), 6.77− 6.71 (m, 2H), 6.65−6.60 (m, 1H), 5.03 (d, J = 16.0 Hz, 1H), 4.59− 4.40 (m, 1H), 4.18 (d, J = 16.0 Hz, 1H), 4.07 (dd, J = 12.4, 4.0 Hz, 1H), 2.66−2.53 (m, 1H), 2.29−2.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.7 (J = 244 Hz), 155.9, 144.2, 143.7, 130.8, 130.0, 129.9, 129.6, 129.0, 128.7, 128.6, 127.7, 126.8, 125.8, 124.2, 120.3, 120.2, 117.3, 117.0, 115.6, 115.3 (J = 21 Hz), 114.4 (J = 20 Hz), 62.2, 52.8, 44.3, 38.8; IR (KBr): 3446, 1593, 1489, 1342, 1248 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H25FNO 410.1915, Found 410.1929; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.38 min (major), tR = 4.66 min (minor). 2-((2R,4S)-1-(3-Bromobenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ga). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 82% (38.3 mg); light-yellow solid; mp 143.1−144.3 °C; [α]D20 = +44.4 (c 0.77, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40−7.36 (m, 1H), 7.34−7.28 (m, 2H), 7.25−7.15 (m, 7H), 7.11 (t, J = 7.8 Hz, 1H), 6.99−6.96 (m, 2H), 6.90−6.83 (m, 2H), 6.79−6.72 (m, 1H), 6.66− 6.60 (m, 1H), 4.98 (d, J = 16.0 Hz, 1H), 4.50 (d, J = 9.6 Hz, 1H), 4.17 (d, J = 16.0 Hz, 1H), 4.07 (dd, J = 12.4, 4.0 Hz, 1H), 2.66−2.53 (m, 1H), 2.28−2.23 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 155.9, 144.2, 143.6, 138.8, 131.7, 130.8, 130.6, 130.0, 129.6, 129.0, 128.7, 128.6, 127.7, 127.0, 126.8, 122.4, 120.3, 120.5, 117.3, 117.0, 62.2, 52.8, 44.2, 38.7; IR (KBr): 3565, 1595, 1557, 1541, 1508, 1490 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H25BrNO 470.1114, Found 470.1123; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.74 min (major), tR = 4.64 min (minor). 2-((2R,4S)-4-Phenyl-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ha). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 68% (31.2 mg); light-yellow solid; mp 119.2−120.3 °C; [α]D20 = +37.2 (c 0.62, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.6 Hz, 1H), 7.40−7.28 (m, 5H), 7.25−7.14 (m, 6H), 6.96 (d, J = 6.8 Hz, 1H), 6.90−6.80 (m, 2H), 6.79−6.71 (m, 1H), 6.67−6.59 (m, 1H), 5.05 (d, J = 16.0 Hz, 1H), 4.45 (d, J = 10.4 Hz, 1H), 4.26 (d, J = 16.0 Hz, 1H), 4.05 (dd, J = 12.4, 4.0 Hz, 1H), 2.66−2.53 (m, 1H), 2.28−

(0.12 mmol), 5 Å MS (100 mg) and catalyst (R)-7 (0.01 mmol) was added chloroform (8 mL), which was stirred at 25 °C for 48 h. After the completion of the reaction which was indicated by TLC, the reaction mixture was filtered to remove the molecular sieves. The resultant solution was concentrated under the reduced pressure to give the residue, which was purified through preparative thin layer chromatography to afford pure products 3. 2-((2R,4S)-1-(4-Methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3aa). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 60% (25.4 mg); light-yellow solid; mp 162.7−163.8 °C; [α]D20 = +32.3 (c 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32−7.27 (m, 3H), 7.24−7.14 (m, 6H), 6.99−6.92 (m, 2H), 6.91−6.81 (m, 3H), 6.80−6.69 (m, 3H), 6.62−6.58 (m, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.46 (dd, J = 12.4, 3.2 Hz, 1H), 4.10 (d, J = 15.6 Hz, 1H), 4.00 (dd, J = 12.4, 4.0 Hz, 1H), 3.78 (s, 3H), 2.62−2.50 (m, 1H), 2.21−2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 156.3, 144.4, 143.8, 131.3, 130.1, 129.5, 128.8, 128.7, 128.6, 128.2, 127.6, 126.8, 125.9, 120.1, 118.2, 117.0, 113.8, 61.8, 55.2, 52.8, 44.3, 38.8; IR (KBr): 3444, 1557, 1510, 1489, 1453 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H28NO2 422.2115, Found 422.2113; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 8.65 min (major), tR = 7.19 min (minor). 2-((2R,4S)-1-(2-Fluorobenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ba). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 53% (21.8 mg); light-yellow solid; mp 146.7−147.8 °C; [α]D20 = +67.0 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34−7.28 (m, 2H), 7.25−7.17 (m, 4H), 7.15−7.06 (m, 4H), 7.02−6.96 (m, 3H), 6.87− 6.80 (m, 2H), 6.75−6.68 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.92 (d, J = 16.4 Hz, 1H), 4.63 (dd, J = 12.0, 2.8 Hz, 1H), 4.44 (d, J = 16.4 Hz, 1H), 4.10 (dd, J = 12.4, 3.6 Hz, 1H), 2.67−2.56 (m, 1H), 2.30−2.26 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 161.1 (J = 245 Hz), 155.7, 144.3, 143.6, 130.7, 130.3, 130.2, 129.2, 129.0 (J = 8 Hz), 128.8, 128.7, 128.6, 127.5, 126.8, 126.0, 123.8, 123.5, 120.1, 120.0, 117.4, 116.8, 115.5 (J = 22 Hz), 99.9, 61.7, 47.2 (d, J = 3 Hz), 44.2, 39.0; IR (KBr): 3446, 1558, 1541, 1521, 1474, 1455 cm−1; HRMS (ESI-TOF) m/z: [M+H] + Calcd for C 28 H25 FNO 410.1915, Found 410.1924; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.77 min (major), tR = 6.28 min (minor). 2-((2R,4S)-1-(2-Chlorobenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ca). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; raction time = 48 h; yield: 60% (25.4 mg); light-yellow solid; mp 160.7−161.9 °C; [α]D20 = −49.8 (c 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 3H), 7.30−7.27 (m, 2H), 7.25 (s, 1H), 7.18−7.07 (m, 5H), 6.95 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 4.97 (d, J = 17.2 Hz, 1H), 4.75 (dd, J = 11.6, 2.8 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.24 (dd, J = 12.4, 4.0 Hz, 1H), 2.71−2.62 (m, 1H), 2.38−2.33 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.3, 144.7, 143.6, 134.3, 133.7, 129.7, 129.6, 129.2, 128.9, 128.8, 128.7, 128.6, 128.1, 127.8, 126.8, 126.5, 120.3, 119.5, 116.8, 116.0, 61.4, 50.5, 44.2, 39.0; IR (KBr): 3489, 1683, 1650, 1541, 1455 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H25ClNO 426.1619, Found 426.1629; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.22 min (major), tR = 8.16 min (minor). 2-((2R,4S)-1-(2-Bromobenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3da). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 68% (31.7 mg); light-yellow solid; mp 132.7−134.0 °C; [α]D20 = −41.8 (c 0.63, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.0 Hz, 1H), 7.37−7.27 (m, 4H), 7.25−7.12 (m, 4H), 7.10−7.04 (m, 2H), 6.96 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.73−6.65 (m, 2H), 4.94 (d, J = 17.2 Hz, 1H), 4.77 (d, J = 9.2 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.26 (dd, J = 12.4, 4.0 Hz, 1H), 2.72−2.60 (m, 1H), 2.39−2.34 (m, 1H); 13C NMR 619

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry 2.23 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.8, 144.2, 143.6, 131.7, 130.8, 130.5, 129.6, 129.0, 128.9, 128.7, 128.6, 127.7, 126.8, 125.5 (J = 3.7 Hz), 124.3 (J = 3.5 Hz),, 122.6, 120.4, 120.3, 117.3, 117.0, 62.2, 53.2, 44.3, 38.7; IR(KBr): 3446, 1650, 1541, 1489, 1454 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H25F3NO 460.1883, Found 460.1881; Enantiomeric ratio: 92:8, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 4.93 min (major), tR = 4.02 min (minor). 2-((2R,4S)-1-(3-Methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ia). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 57% (23.9 mg); light-yellow solid; mp 118.2−119.7 °C; [α]D20 = −32.0 (c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35−7.27 (m, 3H), 7.24−7.14 (m, 6H), 6.99−6.96 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.82−6.70 (m, 2H), 6.62 (t, J = 8.1 Hz, 2H), 6.58−6.55 (m, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.52 (dd, J = 12.0, 3.2 Hz, 1H), 4.15 (d, J = 15.6 Hz, 1H), 4.05 (dd, J = 12.6, 4.0 Hz, 1H), 3.67 (s, 3H), 2.67−2.52 (m, 1H), 2.25−2.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.5, 156.1, 144.5, 143.8, 137.9, 131.0, 129.5, 129.4, 128.8, 128.7, 128.6, 127.6, 126.8, 125.9, 121.0, 120.2, 117.9, 117.0, 114.0, 113.2, 62.2, 55.1, 53.4, 44.3, 38.8; IR (KBr): 3446, 1541, 1521, 1508, 1489, 1455 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H28NO2 422.2115, Found 422.2102; Enantiomeric ratio: 93:7, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.63 min (major), tR = 7.95 min (minor). 2-((2R,4S)-1-(3-Methylbenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ja). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 65% (26.3 mg); light-yellow solid; mp 116.5−117.7 °C; [α]D20 = +54.9 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.27 (m, 2H), 7.26−7.15 (m, 6H), 7.14−7.09 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99−6.94 (m, 1H), 6.92−6.80 (m, 4H), 6.77−6.69 (m, 1H), 6.64− 6.57 (m, 1H), 5.03 (d, J = 15.6 Hz, 1H), 4.52 (dd, J = 12.0, 3.2 Hz, 1H), 4.15 (d, J = 15.6 Hz, 1H), 4.05 (dd, J = 12.4, 4.0 Hz, 1H), 2.67− 2.52 (m, 1H), 2.27 (s, 3H), 2.25−2.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.2, 144.6, 143.8, 138.0, 136.3, 130.9, 129.6, 129.4, 128.8, 128.7, 128.6, 128.3, 128.2, 127.6, 126.8, 126.1, 125.6, 120.1, 120.0, 117.8, 117.0, 62.1, 53.3, 44.3, 38.9, 21.5; IR (KBr): 3449, 1600, 1452, 1327 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H28NO 406.2166, Found 406.2156; Enantiomeric ratio: 92:8, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 5.82 min (major), tR = 4.21 min (minor). 2-((2R,4S)-1-(4-Fluorobenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ka). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 74% (30.2 mg); light-yellow solid; mp 152.0−153.7 °C; [α]D20 = −16.2 (c 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.27 (m, 2H), 7.25−7.15 (m, 6H), 7.03−6.97 (m, 2H), 6.97−6.82 (m, 5H), 6.79− 6.71 (m, 1H), 6.64−6.58 (m, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.45 (dd, J = 12.0, 2.8 Hz, 1H), 4.15 (d, J = 15.6 Hz, 1H), 4.02 (dd, J = 12.4, 4.0 Hz, 1H), 2.69−2.51 (m, 1H), 2.30−2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.2 (J = 244 Hz), 156.1, 144.2, 143.7, 132.0, 131.1, 130.3 (J = 8 Hz), 129.6, 128.9, 128.7, 128.6, 127.7, 126.8, 125.8, 120.2, 117.8, 117.0, 115.3 (J = 21 Hz), 61.9, 52.7, 44.3, 38.7; IR(KBr): 3445, 1600, 1508, 1489, 1453 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H25FNO 410.1915, Found 410.1926; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak IA, hexane/ isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.55 min (major), tR = 8.10 min (minor). 2-((2R,4S)-1-([1,1′-Biphenyl]-4-ylmethyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3la). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 65% (30.5 mg); light-yellow solid; mp 114.3−145.8 °C; [α]D20 = +70.8 (c 0.61, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.62−7.54 (m, 2H), 7.52−7.39 (m, 4H), 7.38−7.28 (m, 4H), 7.25− 7.16 (m, 5H), 7.11 (d, J = 8.4 Hz, 2H), 7.02−6.97 (m, 1H), 6.95−6.80 (m, 2H), 6.77 (t, J = 7.1 Hz, 1H), 6.68−6.60 (m, 1H), 5.12 (d, J = 15.6

Hz, 1H), 4.57 (dd, J = 12.0, 2.8 Hz, 1H), 4.24 (d, J = 16.0 Hz, 1H), 4.09 (dd, J = 12.4, 4.0 Hz, 1H), 2.67−2.56 (m, 1H), 2.30−2.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.1, 144.5, 143.8, 140.61, 140.3, 135.4, 131.0, 129.5, 129.1, 128.8, 128.8, 128.7, 128.6, 127.6, 127.3, 127.1, 126.9, 126.8, 125.9, 120.2, 120.1, 117.8, 117.0, 62.1, 53.0, 44.2, 38.8; IR (KBr): 3447, 1650, 1598, 1488, 1453 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C34H30NO 468.2322, Found 468.2325; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 15.09 min (major), tR = 6.02 min (minor). 2-((2R,4S)-7-(tert-Butyl)-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4tetrahydroquinolin-2-yl)phenol (3ma). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield:45% (21.5 mg); light-yellow solid, mp 160−162 °C; [α]D20 = +34.7 (c 0.43, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.30 (d, J = 8.4 Hz, 3H), 7.22−7.15 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.98−6.91 (m, 3H), 6.91−6.86 (m, 1H), 6.86−6.80 (m, 1H), 6.80− 6.75 (m, 2H), 6.74 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.45 (dd, J = 12.4, 3.2 Hz, 1H), 4.10 (d, J = 15.6 Hz, 1H), 3.97 (dd, J = 12.4, 4.0 Hz, 1H), 3.78 (s, 3H), 2.59−2.49 (m, 1H), 2.23−2.12 (m, 1H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.9, 156.2, 149.5, 144.3, 140.6, 131.4, 130.0, 129.5, 128.7, 128.2, 127.4, 125.9, 125.4, 120.1, 120.0, 118.1, 116.9, 113.7, 61.9, 55.2, 52.7, 43.7, 38.9, 34.4, 31.3; IR (KBr): 3146, 1772, 1617, 1540, 1399 cm−1; HRMS (ESI-TOF) m/z: [M-H]− Calcd for C33H34NO2 476.2595, found m/z 476.2599; Enantiomeric ratio: 89:11, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 5.04 min (major), tR = 4.00 min (minor). 2-((2R,4S)-1-(4-Methoxybenzyl)-6-methyl-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3na). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 80% (34.8 mg); light-yellow solid, mp 130−132 °C; [α]D20 = +14.0 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 7.30 (t, J = 7.2 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.22−7.18 (m, 2H), 7.17−7.13 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 6.97−6.91 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 6.86−6.81 (m, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.39 (s, 1H), 4.97 (d, J = 15.6 Hz, 1H), 4.40 (dd, J = 12.4, 3.2 Hz, 1H), 4.07 (d, J = 15.6 Hz, 1H), 3.95 (dd, J = 12.4, 4.0 Hz, 1H), 3.78 (s, 3H), 2.59−2.48 (m, 1H), 2.20−2.13 (m, 1H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 156.4, 143.9, 141.8, 131.1, 130.1, 129.8, 129.5, 128.7, 128.5, 128.2, 126.6, 125.9, 119.9, 118.4, 116.9, 113.7, 61.8, 55.1, 52.9, 44.2, 38.9, 20.5; IR (KBr): 1733, 1635, 1489 cm−1; HRMS (ESITOF) m/z: [M-H]− Calcd for C30H28NO2 434.2125, found 434.2120; Enantiomeric ratio: 85:15, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 8.40 min (major), tR = 6.64 min (minor). 2-((2R,4S)-6-Bromo-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3oa). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 48% (24.0 mg); light-yellow solid, mp 140−142 °C; [α]D20 = −11.6 (c 0.27, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.35−7.28 (m, 3H), 7.25−7.17 (m, 2H), 7.17−7.11 (m, 3H), 6.99− 6.92 (m, 3H), 6.89 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.80 (t, J = 5.6 Hz, 2H), 6.69 (d, J = 1.2 Hz, 1H), 4.94 (d, J = 15.6 Hz, 1H), 4.47 (dd, J = 12.0, 2.8 Hz, 1H), 4.10 (d, J = 15.6 Hz, 1H), 3.96 (dd, J = 12.4, 4.0 Hz, 1H), 3.79 (s, 3H), 2.59−2.48 (m, 1H), 2.24−2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 155.9, 143.6, 142.8, 133.2, 131.9, 130.4, 129.9, 128.9, 128.8, 128.7, 128.5, 127.8, 127.1, 125.5, 120.3, 119.6, 117.0, 113.8, 112.4, 61.5, 55.2, 52.5, 44.1, 38.5; IR (KBr): 3029, 1610, 1455 cm−1; HRMS (ESI-TOF) m/z: [M-H]− Calcd for C29H25BrNO2 498.1074, found 498.1073; Enantiomeric ratio: 87:13, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.68 min (major), tR = 5.28 min (minor). 2-((2R,4S)-7-Chloro-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3pa). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 57% (26.0 mg); light-yellow solid, mp 177−179 °C; [α]D20 = −25 (c 0.52, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 620

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry 3H), 7.25−7.17 (m, 2H), 7.17−7.11 (m, 2H), 6.99−6.93 (m, 3H), 6.92−6.83 (m, 2H), 6.83−6.77 (m, 2H), 6.69 (dd, J = 8.4, 2.0 Hz, 1H), 6.51 (dd, J = 8.4, 1.2 Hz, 1H), 4.94 (d, J = 15.6 Hz, 1H), 4.48 (d, J = 9.6 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H), 3.94 (dd, J = 12.4, 4.0 Hz, 1H), 3.79 (s, 3H), 2.58−2.48 (m, 1H), 2.29−2.12 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 155.8, 145.7, 143.2, 133.1, 130.6, 129.9, 129.4, 128.9, 128.8, 128.7, 128.6, 127.8, 126.9, 120.3, 119.8, 117.6, 117.0, 113.9, 61.4, 55.2, 52.4, 43.8, 38.5; IR (KBr): 2954, 1609, 1400 cm−1; HRMS (ESI-TOF) m/z: [M-H]− Calcd for C29H25ClNO2 454.1579, found 454.1578; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 11.33 min (major), tR = 9.26 min (minor). 2-((2R,4S)-4-(4-Chlorophenyl)-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3qa). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 57% (26.0 mg); light-yellow solid, mp 170−172 °C; [α]D20 = +42.5 (c 0.52, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.33−7.27 (m, 2H), 7.26−7.25 (m, 1H), 7.23−7.17 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.96 (dd, J = 7.6, 1.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.88−6.83 (m, 1H), 6.78−6.72 (m, 3H), 6.55 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.44 (dd, J = 12.0, 3.2 Hz, 1H), 4.09 (d, J = 15.6 Hz, 1H), 3.98 (dd, J = 12.4, 4.0 Hz, 1H), 3.78 (s, 3H), 2.57−2.46 (m, 1H), 2.21−2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 156.2, 144.4, 142.3, 132.4, 130.6, 130.0, 129.3, 128.9, 128.8, 128.7, 128.0, 127.7, 125.7, 120.1, 118.3, 117.0, 113.7, 61.6, 55.2, 52.7, 43.6, 38.6; IR (KBr): 3128, 1609, 1400 cm−1; HRMS (ESI-TOF) m/z: [M-H]− Calcd for C29H25ClNO2 454.1579, found 454.1576; Enantiomeric ratio: 80:20, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 10.72 min (major), tR = 8.79 min (minor). 2-((2R,4S)-1-(4-Methoxybenzyl)-4-(p-tolyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ra). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 61% (26.5 mg); light-yellow solid, mp 165−167 °C; [α]D20 = +37.2 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.22−7.16 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.99−6.91 (m, 3H), 6.91−6.88 (m, 1H), 6.87−6.82 (m, 1H), 6.79−6.75 (m, 2H), 6.73 (d, J = 7.2 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.45 (dd, J = 12.4, 3.2 Hz, 1H), 4.10 (d, J = 15.6 Hz, 1H), 4.01−3.88 (m, 1H), 3.78 (s, 3H), 2.61−2.50 (m, 1H), 2.33 (s, 3H), 2.25−2.06 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.9, 156.3, 144.3, 140.7, 136.2, 131.5, 130.0, 129.4, 129.2, 128.7, 128.5, 128.2, 127.4, 125.9, 120.2, 120.0, 118.2, 116.9, 113.7, 61.9, 55.2, 52.8, 43.8, 38.8, 21.0; IR (KBr): 3162, 1653, 1489 cm−1; HRMS (ESI-TOF) m/z: [M-H]− Calcd for C30H28NO2 434.2125, found 434.2123; Enantiomeric ratio: 79:21, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 9.22 min (major), tR = 7.35 min (minor). 2-((2R,4S)-1-(4-Methoxybenzyl)-4-(o-tolyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3sa). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 75% (32.6 mg); light-yellow solid, mp 135−137 °C; [α]D20 = +50.6 (c 0.65, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.24−7.16 (m, 3H), 7.15−7.11 (m, 2H), 7.05 (s, 1H), 7.01−6.94 (m, 3H), 6.93−6.89 (m, 1H), 6.89−6.84 (m, 1H), 6.81−6.77 (m, 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.53 (s, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.49 (d, J = 10.0 Hz, 1H), 4.23 (dd, J = 12.4, 3.2 Hz, 1H), 4.12 (d, J = 15.6 Hz, 1H), 3.79 (s, 3H), 2.66−2.54 (m, 1H), 2.34 (s, 3H), 2.22−2.09 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.9, 156.2, 144.6, 141.8, 136.3, 131.1, 130.0, 128.9, 128.8, 128.7, 128.3, 127.4, 126.5, 125.9, 120.3, 120.1, 118.3, 116.9, 113.7, 62.1, 55.2, 52.9, 38.9, 37.7, 19.6; IR (KBr): 3146, 1610, 1488, 1400 cm−1; HRMS (ESITOF) m/z: [M-H]− Calcd for C30H28NO2 434.2125, found 434.2126; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 95/5, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 10.04 min (major), tR = 8.79 min (minor). 2-((2R,4R)-1-(4-Methoxybenzyl)-4-methyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ta). Flash column chromatography eluent,

petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 48% (17.2 mg); light-yellow solid, mp 128−129 °C; [α]D20 = +32.5 (c 0.19, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 7.26−7.17 (m, 4H), 6.99−6.95 (m, 1H), 6.93−6.85 (m, 5H), 6.73 (d, J = 8.8 Hz, 2H), 4.95 (d, J = 15.6 Hz, 1H), 4.34 (dd, J = 11.2, 4.8 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H), 3.76 (s, 3H), 2.88−2.79 (m, 1H), 2.09−1.99 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 156.3, 144.1, 132.4, 129.9, 128.7, 128.6, 128.3, 127.2, 126.4, 126.3, 120.3, 120.0, 118.2, 116.9, 113.6, 61.7, 55.1, 52.9, 39.0, 30.8, 19.3; IR (KBr): 3161, 1558, 1489, 1399 cm−1; HRMS (ESITOF) m/z: [M-H]− Calcd for C24H24NO2 358.1812, found 358.1814; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 95/5, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 8.67 min (major), tR = 10.54 min (minor). 3-Fluoro-2-((2R,4S)-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ab). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 55% (24.1 mg); light-yellow solid; mp 139.4−140.8 °C; [α]D20 = +21.6 (c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32−7.27 (m, 3H), 7.25−7.12 (m, 5H), 7.01−6.90 (m, 3H), 6.81− 6.72 (m, 5H), 6.64−6.56 (m, 1H), 4.97 (d, J = 15.6 Hz, 1H), 4.56 (d, J = 11.2 Hz, 1H), 4.07 (d, J = 15.6 Hz, 1H), 3.98 (dd, J = 12.4, 3.6 Hz, 1H), 3.78 (s, 3H), 2.60−2.45 (m, 1H), 2.24 (dd, J = 9.6, 3.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 159.0, 151.5 (J = 241 Hz), 143.6, 129.9, 129.3, 128.6 (J = 8 Hz), 127.6, 126.7, 123.5, 119.7 (J = 8 Hz), 115.1(J = 18 Hz), 113.8, 55.2, 53.4, 53.3, 44.1, 38.9; IR (KBr): 3448, 1541, 1508, 1489, 1457 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H27FNO2 440.2021, Found 440.2019; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 9.21 min (major), tR = 7.70 min (minor). 5-Fluoro-2-((2R,4S)-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ac). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 50% (21.8 mg); light-yellow solid; mp 164.4−166.0 °C; [α]D20 = +31.2 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34−7.28 (m, 3H), 7.26−7.12 (m, 4H), 6.95−6.91 (m, 2H), 6.88 (dd, J = 8.0, 3.2 Hz, 1H), 6.90−6,76 (m, 3H), 6.75 (d, J = 7.2 Hz, 1H), 6.70 (dd, J = 8.8, 2.8 Hz, 1H), 6.63−6.54 (m, 1H), 5.02 (d, J = 15.6 Hz, 1H), 4.40 (dd, J = 12.0, 3.2 Hz, 1H), 4.13−3.92 (m, 2H), 3.79 (s, 3H), 2.60−2.47 (m, 1H), 2.25−2.12 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 156.6 (J = 236 Hz), 144.3, 143.6, 131.2, 130.0, 129.5, 128.7, 128.6, 127.9, 127.6, 126.8, 120.3, 118.2, 117.8 (J = 7.7 Hz), 115.2, 115.0, 114.8 (J = 23 Hz), 113.9, 61.5, 55.2, 53.2, 44.1, 38.5; IR (KBr): 3452, 1649, 1611, 1491, 1454 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H27FNO2 440.2021, Found 440.2024; Enantiomeric ratio: 92:8, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.18 min (major), tR = 4.60 min (minor). 5-Chloro-2-((2R,4S)-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ad). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 67% (30.4 mg); light-yellow solid; mp 162.1−164.0 °C; [α]D20 = +56.3 (c 0.61, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35−7.27 (m, 3H), 7.26−7.18 (m, 2H), 7.15 (d, J = 7.6 Hz, 3H), 6.97−6.91 (m, 3H), 6.84−6.73 (m, 4H), 6.60 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.41 (d, J = 9.6 Hz, 1H), 4.07 (d, J = 15.6 Hz, 1H), 3.97 (dd, J = 12.4, 3.2 Hz, 1H), 3.79 (s, 3H), 2.60−2.45 (m, 1H), 2.20 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 155.0, 144.1, 143.5, 131.3, 130.0, 129.5, 128.7, 128.6, 128.3, 127.8, 127.7, 126.9, 124.6, 120.5, 118.4, 118.3, 113.9, 61.5, 55.2, 53.4, 44.1, 38.7; IR (KBr): 3504, 1650, 1540, 1486, 1456 cm−1; HRMS (ESITOF) m/z: [M+H]+ Calcd for C29H27ClNO2 456.1725, Found 456.1720; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 5.14 min (major), tR = 4.42 min (minor). 5-Bromo-2-((2R,4S)-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ae). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 66% (32.9 mg); light-yellow solid; mp 150.1−151.0 °C; 621

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry [α]D20 = +83.6 (c 0.66, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 4H), 7.25−7.19 (m, 2H), 7.17−7.12 (m, 2H), 7.12− 7.06 (m, 1H), 6.94−6.88 (m, 2H), 6.83−6.73 (m, 4H), 6.63−6.53 (m, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.41 (dd, J = 12.4, 3.2 Hz, 1H), 4.06 (d, J = 15.6 Hz, 1H), 3.96 (dd, J = 12.4, 4.0 Hz, 1H), 3.79 (s, 3H), 2.55−2.45 (m, 1H), 2.26−2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 155.5, 144.2, 143.5, 131.5, 131.3, 131.1, 130.0, 129.5, 128.7, 128.1, 127.8, 127.7, 126.9, 120.5, 118.9, 118.4, 113.9, 111.8, 61.5, 55.2, 53.4, 44.1, 38.7; IR (KBr): 3491, 1609, 1511, 1484, 1420 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H27BrNO2 500.1220, Found 500.1224; Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 95/5, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 12.80 min (major), tR = 10.39 min (minor). 2-((2R,4S)-1-(4-Methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)-5-methylphenol (3af). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 51% (22.1 mg); light-yellow solid; mp 141.5−142.7 °C; [α]D20 = +33.7 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33−7.26 (m, 3H), 7.25−7.14 (m, 4H), 7.03−6.94 (m, 3H), 6.81− 6.75 (m, 4H), 6.73 (t, J = 7.2 Hz, 1H), 6.61−6.57 (m, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.49−4.42 (m, 1H), 4.13 (d, J = 15.6 Hz, 1H), 4.00 (dd, J = 12.4, 4.0 Hz, 1H), 3.81−3.73 (m, 4H), 2.52−2.50 (m, 1H), 2.26 (s, 3H), 2.25−2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.9, 153.9, 144.5, 143.8, 131.2, 130.0, 129.4, 129.2, 129.1, 128.7, 128.6, 128.4, 127.5, 126.7, 125.6, 120.0, 118.1, 116.7, 113.8, 61.9, 55.2, 52.7, 44.3, 38.9, 20.6; IR (KBr): 3445, 1610, 1510, 1489 cm−1; HRMS (ESITOF) m/z: [M+H]+ Calcd for C30H30NO2 436.2271, Found 436.2268; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.64 min (major), tR = 6.24 min (minor). 5-Methoxy-2-((2R,4S)-1-(4-methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenol (3ag). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 57% (25.6 mg); light-yellow solid; mp 142.5−143.7 °C; [α]D20 = +49.4 (c 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36−7.27 (m, 3H), 7.25−7.14 (m, 4H), 6.96(d, J = 8.4, 2H), 6.83 (d, J = 8.8, 1H), 6.81−6.70 (m, 4H), 6.62−6.51 (m, 2H), 5.01 (d, J = 15.6 Hz, 1H), 4.42 (dd, J = 12.0, 2.8 Hz, 1H), 4.16−4.06(m, 1H), 4.00 (dd, J = 12.4, 4.0 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.64−2.50 (m, 1H), 2.28−2.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 153.2, 149.9, 144.5, 143.8, 131.1, 130.0, 129.4, 128.7, 128.6, 127.6, 126.8, 120.0, 118.0, 117.5, 114.3, 113.8, 61.8, 55.8, 55.2, 52.8, 44.2, 38.6; IR (KBr): 3486, 1509, 1489, 1453, 1406 cm−1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H30NO3 452.2220, Found 452.2229; Enantiomeric ratio: 93:7, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.62 min (major), tR = 6.23 min (minor). (2R,4S)-2-(4-Fluorophenyl)-1-(4-methoxybenzyl)-4-phenyl1,2,3,4-tetrahydroquinoline (3ak). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 45% (19.4 mg); light-yellow solid, mp 140−142 °C; [α]D20 = −10.6 (c 0.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz, 2H), 7.26−7.23 (m, 2H), 7.23−7.16 (m, 3H), 7.11−7.01 (m, 3H), 6.94 (t, J = 8.8 Hz, 2H), 6.85−6.77 (m, 3H), 6.65−6.49 (m, 2H) 4.66 (d, J = 16.4 Hz, 1H), 4.58 (dd, J = 9.6, 6.2 Hz, 1H), 4.14 (dd, J = 10.4, 5.6 Hz, 1H), 3.95 (d, J = 16.4 Hz, 1H), 3.79 (s, 3H), 2.40−2.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.9 (d, J = 244 Hz), 158.4, 146.5, 143.7, 139.2, 130.5, 128.8, 128.7, 128.6, 128.5, 128.1, 127.4, 126.6, 116.9, 115.3 (d, J = 21 Hz), 113.7, 113.6, 61.8, 55.2, 51.9, 44.0, 42.6; IR (KBr): 3161, 1653, 1510, 1400 cm−1; HRMS (ESI-TOF) m/ z: [M-H]− Calcd for C29H25FNO 422.1925, found 422.1923; Enantiomeric ratio: 72:28, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 4.40 min (major), tR = 5.74 min (minor). (2R,4S)-1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-4-phenyl1,2,3,4-tetrahydroquinoline (3al). Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; reaction time = 48 h; yield: 53% (23 mg); light-yellow solid, mp 137−139 °C; [α]D20 = −15.4 (c 0.46, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37−7.31 (m,

2H), 7.28−7.24 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 7.10−7.03 (m, 3H), 6.84−6.78 (m, 5H), 6.57 (d, J = 4.4 Hz, 2H), 4.66 (d, J = 16.4 Hz, 1H), 4.61−4.53 (m, 1H), 4.22−4.09 (m, 1H), 3.99 (d, J = 16.4 Hz, 1H), 3.79 (s, 6H), 2.44−2.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.7, 158.3, 146.7, 144.0, 135.6, 130.8, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 127.4, 126.5, 116.6, 113.8, 113.7, 113.5, 62.1, 55.8, 55.2, 51.6, 44.2, 42.6; IR (KBr): 1635, 1540, 1397 cm−1; HRMS (ESITOF) m/z: [M-H]− Calcd for C30H28NO2 434.2125, found 434.2119; Enantiomeric ratio: 79:21, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 5.78 min (major), tR = 6.87 min (minor). (2R,4S)-1-(4-Methoxybenzyl)-2,4-diphenyl-1,2,3,4-tetrahydroquinoline (3am). Flash column chromatography eluent, petroleum ether/ dichloromethane = 4/1; reaction time = 48 h; yield: 40% (16.2 mg); light-yellow solid, mp 135−137 °C; [α]D20 = +15.5 (c 0.25, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.37−7.27 (m, 4H), 7.26−7.19 (m, 6H), 7.06 (d, J = 8.4 Hz, 3H), 6.86−6.76 (m, 3H), 6.59−6.52 (m, 2H), 4.68 (d, J = 16.4 Hz, 1H), 4.60 (dd, J = 9.6, 6.4 Hz, 1H), 4.14 (dd, J = 10.4, 5.6 Hz, 1H), 3.98 (d, J = 16.4 Hz, 1H), 3.78 (s, 3H), 2.42−2.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.3, 146.6, 143.8, 143.7, 130.6, 129.0, 128.7, 128.6, 128.5 127.9, 127.4, 127.2, 127.1, 126.5, 116.7, 113.7, 113.5, 62.7, 55.2, 51.7, 44.1, 42.6; IR (KBr): 3165, 1647, 1540, 1473 cm−1; HRMS (ESI-TOF) m/z: [M-H]− Calcd for C29H26NO 404.2020, found 404.2021; Enantiomeric ratio: 78:22, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 4.26 min (major), tR = 5.89 min (minor). Procedure for the Derivation of Compound 3aa. To the solution of compound 3aa (421 mg, 1 mmol) in dichloromethane (10 mL) was added pyridine (237 mg, 3 mmol). Then, the solution of Tf2O (423 mg, 1.5 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture at 0 °C, which was stirred overnight at room temperature. After the completion of the reaction indicated by TLC, water (5 mL) was added to the reaction mixture, which was further extracted by dichloromethane and dried by anhydrous Na2SO4. The resultant organic layer was concentrated under the reduced pressure to give the residue, which was purified through flash column chromatography eluent, petroleum ether/dichloromethane = 8/1 to afford pure product 8 (503 mg, 91% yield). 2-((2R,4S)-1-(4-Methoxybenzyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-2-yl)phenyl Trifluoromethanesulfonate (8). Flash column chromatography eluent, petroleum ether/dichloromethane = 8/1; reaction time = 12 h; yield: 91% (503 mg); light-yellow oil; [α]D20 = +30.7 (c 0.56, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50−7.45 (m, 1H), 7.34−7.29 (m, 2H), 7.28−7.26 (m, 1H), 7.25−7.15 (m, 5H), 7.13−7.04 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 6.83−6.79 (m, 2H), 6.67−6.59 (m, 2H), 5.02 (dd, J = 10.0, 5.0 Hz, 1H), 4.60 (d, J = 16.0 Hz, 1H), 4.15 (dd, J = 11.6, 4.0 Hz, 1H), 3.97 (d, J = 16.0 Hz, 1H), 3.79 (s, 3H), 2.85−2.50 (m, 1H), 2.33 (dd, J = 23.6, 11.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.6, 147.0, 146.4, 143.2, 136.4, 129.9, 129.4, 129.0, 128.8, 128.7, 128.6, 128.5, 128.4, 128.1, 127.5, 126.6, 121.2, 118.4 (q, J = 318 Hz), 117.4, 113.9, 113.8, 55.8, 55.2, 53.1, 43.4, 40.6; IR (KBr): 2923, 2854, 1510, 1455 cm−1; HRMS (ESI-TOF) m/ z: [M+H]+ Calcd for C30H27F3NO4S 554.1605, Found 554.1590; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 98/2, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 6.18 min (major), tR = 5.26 min (minor). Methanol (2 mL) was added to the mixture of compound 8 (53.3 mg, 0.1 mmol), Mg (24 mg, 1 mmol), 10% Pd/C (64 mg), and ammonium acetate (240 mg, 3.1 mmol). After the mixture had been stirred at room temperature overnight and the completion of the reaction indicated by TLC, the reaction mixture was filtered, and the filtrate was concentrated under the reduced pressure to give the residue, which was then added to water (5 mL), extracted by ethyl acetate, and dried by anhydrous Na2SO4. The resultant organic layer was again concentrated under reduced pressure to give pure product 3am (29.2 mg, 72% yield). [α]D20 = +22.3 (c 0.35, CHCl3); Enantiomeric ratio: 89:11, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 98/2, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 7.49 min (major), tR = 6.36 min (minor). 622

DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623

Article

The Journal of Organic Chemistry

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2014, 4, 55924. (e) Wang, Z.; Sun, J. Synthesis 2015, 47, 3629. (f) Jaworski, A. A.; Scheidt, K. A. J. Org. Chem. 2016, 81, 10145. (8) (a) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508. (b) Luan, Y.; Schaus, S. E. J. Am. Chem. Soc. 2012, 134, 19965. (c) Guo, W.; Wu, B.; Zhou, X.; Chen, P.; Wang, X.; Zhou, Y.-G.; Liu, Y.; Li, C. Angew. Chem., Int. Ed. 2015, 54, 4522. (d) Lewis, R. S.; Garza, C. J.; Dang, A. T.; Pedro, T. K. A.; Chain, W. J. Org. Lett. 2015, 17, 2278. (9) For examples on catalystic asymmetric [4+1] cycloaddition, see: (a) Jiang, X.-L.; Liu, S.-J.; Gu, Y.-Q.; Mei, G.-J.; Shi, F. Adv. Synth. Catal. 2017, 359, 3341. (b) Lian, X. L.; Adili, A.; Liu, B.; Tao, Z.-L.; Han, Z.-Y. Org. Biomol. Chem. 2017, 15, 3670. (c) Yang, Q.-Q.; Xiao, W.-J. Eur. J. Org. Chem. 2017, 2017, 233. (10) For selected examples on catalystic asymmetric [4+2] cycloaddition, see: (a) El-Sepelgy, O.; Haseloff, S.; Alamsetti, S. K.; Schneider, C. Angew. Chem., Int. Ed. 2014, 53, 7923. (b) Hsiao, C.-C.; Liao, H.-H.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 13258. (c) Hsiao, C.-C.; Raja, S.; Liao, H.-H.; Atodiresei, I.; Rueping, M. Angew. Chem., Int. Ed. 2015, 54, 5762. (d) Tsui, G. C.; Liu, L.; List, B. Angew. Chem., Int. Ed. 2015, 54, 7703. (e) Alamsetti, S. K.; Spanka, M.; Schneider, C. Angew. Chem., Int. Ed. 2016, 55, 2392. (f) Chen, P.; Wang, K.; Guo, W.; Liu, X.; Liu, Y.; Li, C. Angew. Chem., Int. Ed. 2017, 56, 3689. (g) Wang, Z.-B.; Sun, J.-W. Org. Lett. 2017, 19, 2334. (11) For examples on catalystic asymmetric [4+3] cycloaddition, see: (a) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am. Chem. Soc. 2013, 135, 10634. (b) Lv, H.; Jia, W.-Q.; Sun, L.-H.; Ye, S. Angew. Chem., Int. Ed. 2013, 52, 8607. (12) For a review on racemic reactions, see: Wojciechowski, K. Eur. J. Org. Chem. 2001, 2001, 3587. (13) (a) Liao, H. H.; Chatupheeraphat, A.; Hsiao, C. C.; Atodiresei, I.; Rueping, M. Angew. Chem., Int. Ed. 2015, 54, 15540. (b) Chatupheeraphat, A.; Liao, H. H.; Mader, S.; Sako, M.; Sasai, H.; Atodiresei, I.; Rueping, M. Angew. Chem., Int. Ed. 2016, 55, 4803. (14) (a) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 10589. (b) Kretzschmar, M.; Hodik, T.; Schneider, C. Angew. Chem., Int. Ed. 2016, 55, 9788. (c) Hodík, T.; Schneider, C. Org. Biomol. Chem. 2017, 15, 3706. (15) (a) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Angew. Chem., Int. Ed. 2015, 54, 5460. (b) Zhao, J.-J.; Zhang, Y.-C.; Xu, M.M.; Tang, M.; Shi, F. J. Org. Chem. 2015, 80, 10016. (c) Zhang, Y.-C.; Zhu, Q.-N.; Yang, X.; Zhou, L.-J.; Shi, F. J. Org. Chem. 2016, 81, 1681. (16) Mei, G.-J.; Zhu, Z.-Q.; Zhao, J.-J.; Bian, C.-Y.; Chen, J.; Chen, R.-W.; Shi, F. Chem. Commun. 2017, 53, 2768. (17) For related reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008, 4097. (c) Terada, M. Synthesis 2010, 2010, 1929. (d) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156. (e) Wu, H.; He, Y.-P.; Shi, F. Synthesis 2015, 47, 1990. (18) CCDC 1571558 for 3fa, see the Supporting Information for details.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02533. Characterization data (including 1H and 13C NMR spectra) of products 3 and 8, HPLC spectra of products 3 and 8, and 1H NMR study on the interaction between catalyst 7 and substrate 2a (PDF) X-ray crystallographic data of product 3fa (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Feng Shi: 0000-0003-3922-0708 Author Contributions †

L.-Z.L. and C.-S.W. contributed equally to the work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from National Natural Science Foundation of China (21772069 and 21702077), Natural Science Foundation of Jiangsu Province (BK20160003 and BK20170227), and Six Kinds of Talents Project of Jiangsu Province (SWYY-025).

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DOI: 10.1021/acs.joc.7b02533 J. Org. Chem. 2018, 83, 614−623