Organocatalytic Synthesis of 4-Aryl-1,2,3,4-tetrahydropyridines from

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Organocatalytic Synthesis of 4-Aryl-1,2,3,4-tetrahydropyridines from MoritaBaylis-Hillman Carbonates through a One-Pot Three-Component Cyclization Jian Wei, Yuntong Li, Cheng Tao, Huifei Wang, Bin Cheng, Hongbin Zhai, and Yun Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02818 • Publication Date (Web): 29 Dec 2017 Downloaded from http://pubs.acs.org on December 29, 2017

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The Journal of Organic Chemistry

Organocatalytic Synthesis of 4-Aryl-1,2,3,4-tetrahydropyridines from Morita-Baylis-Hillman Carbonates through a One-Pot ThreeComponent Cyclization Jian Wei,† Yuntong Li,† Cheng Tao,† Huifei Wang,‡ Bin Cheng,† Hongbin Zhai,*,‡ and Yun Li*,†,

⊥

†

The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China

‡

Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China ⊥ State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China Supporting Information Placeholder

ABSTRACT: An efficient DABCO-catalyzed three-component formal [3+2+1] annulation, involving a Morita-Baylis-Hillman carbonate, a 1,3-ketoester, and a primary amine, leading to one-pot synthesis of substituted 4-aryl-1,2,3,4-tetrahydropyridines, has been developed. The densely functionalized products were generally obtained in good to excellent yields under mild conditions. The structures including the relative stereo-configurations of the representative products were confirmed by X-ray diffraction analysis. INTRODUCTION Tetrahydropyridines (THP) are one of the most important heterocyclic skeletons widely found in natural products, biologically interesting compounds, and medicines,1-4 such as ciprofloxacin (1), homoclausenamide (2), and aphylline (3) shown in Figure 1. Unsurprisingly, research work towards the synthesis of these scaffolds has been a topic of significant interest and longstanding effort.1f,5 During the last few decades, many effective approaches have thus been developed for the construction of 1,2,3,4-tetrahydropyridines.5d,5i,6 Among them, hydrogenation of pyridines or dihydropyridines and dehydrogenation of piperidines, represent the most common approaches to such heterocycles.7 Another important strategy involves the cyclization of simple precursors through a step-by-step or onepot cascade fashion, such as Diels-Alder reaction of azadienes,5n,8 double functionalization of aziridines,9 intramolecular amidocarbonylation or Heck cyclization of N-homo-ally amides or allenamides,10 ring-closing metathesis-isomerization of acyclic dienes,11 condensation of aldehydes or acetal with amines,12 and C-H amination with oxaziridines.13 However, most of these methods often employ expensive reagents or catalysts and suffer from lacking of operational simplicity and/or broad functional group tolerance. Consequently, development of highly efficient synthetic methods to construct the structurally diverse THPs under mild conditions remains a considerable challenge. Recently, as pioneered by Chen,14 Batra,15 Kim16 and other researchers,17 organocatalyzed domino reactions of MoritaBaylis-Hillman (MBH) carbonates have emerged as powerful and straightforward methods for the generation of molecular

Figure 1. Representative Bioactive Tetrahydropyridine Derivatives.

complexity. The chemistry is centered around the double nucleophilic substitution (SN2’/SN2’) of MBH carbonates catalyzed by a Lewis base such as tertiary amine or phosphine. Based on our previous research experience,18 we envisioned that acetoacetate 5 might react with MBH carbonate 4 to deliver functionalized acetoacetate C under the catalysis of a proper tertiary amine through a two-step double nucleophilic substitution (SN2’/SN2’) as illustrated in Scheme 1. This intermediate would be further converted into multi-substituted tetrahydropyridine 6 through a two-step condensation in the presence of a primary amine added after the initial transformations. As part of our continuing interest in developing the synthesis of biologically important functionalized pyridines19 and their derivatives, we launched a program concerning rapid preparation of 4-aryl-1,2,3,4-tetrahydropyridines through a DABCO-catalyzed tandem allylation-cyclization involving an MBH carbonate, an acetoacetate and a primary amine as the three components under mild conditions.

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Scheme 1. Strategy for Construction of 4-Aryl-1,2,3,4tetrahydropyridines

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Table 2. Screenings of Substrate Scopea,d,e OR3

OBoc CO2R2

1) DABCO (0.1 equiv) rt, 2 h

O +

2) NH2R4 (20 equiv) rt, 20 h

O 1

R

4

5

O2N

NC

CO2Et

6a: 97% dr = 50:50 R

RESULTS AND DISCUSSION To validate our hypothesis, the reaction of MBH carbonate 4a and commercially available ethyl acetoacetate 5a was initially conducted with DABCO in DME. Upon full consumption of 4a (within ca. 4 h), methylamine was added and the resulting reaction mixture was stirred for another 20 h. Indeed, the reaction proceeded smoothly to provide the desired tetrahydropyridine 6a in 42% (dr = 1:1) isolated yield (Table 1, entry 1). Next, several solvents, such as CH2Cl2, acetonitrile, THF, 1,2dichloroethane, toluene and 1,4-dioxane were examined (entries 2~7). The best yield (97%) was obtained when the reaction was carried out in CH2Cl2 (entry 7) while the other solvents gave inferior results. Notably, it was found that the amount of NH2Me is vital to the success of the second-step cyclization. Attempts to decrease the amount of NH2Me to 1 equiv fail to deliver the cyclized product 6a (entry 8). Further increasing the amount of NH2Me to 30 equiv (entry 10) gave the comparable yield as 20 equiv NH2Me was employed. Other Lewis bases such as PPh3, DMAP, and Et3N were also screened for this reaction, and only the latter two nitrogen-

AcHN

N

MeO2C 6c: 64%b dr = 62:38

CO2Et

CO2Et O2N

N

MeO2C

CO2Et

6b: 90% dr = 50:50

CO2Et

R4

6

N

MeO2C

N

R2O2C

MeO

CO2Et

N

MeO2C

CO2R3

R1

N

MeO2C

6d (R = H): 77%b; dr = 67:33 6e (R = Me): 63%b; dr = 67:33 6f (R = Br): 82%b; dr = 57:43

N

MeO2C

6g: 81%b dr = 63:37

6h: 85% dr = 50:50

CO2Et

CO2Et MeO

Br N

MeO2C

N

MeO2C 6j: 78%b dr = 62:38

6i: 83%b dr = 57:43 OMe

X-Ray structure of 6hb (syn-isomer of 6h)

OMe

O O

MeO

CO2Et MeO

CO2Et

CO2Et

MeO N

MeO2C

N

MeO2C

6m: 62%b dr = 57:43

6l: 76%b dr = 58:42

6k: 90%b dr = 62:38

N

MeO2C

CO2Et CO2Et

Table 1. Screenings of the Catalysts and Solventsa

N

MeO2C

N

MeO2C 6n: 83%b dr = 83:17

6o: 71%b dr = 67:33

X-Ray structure of 6na (anti-isomer of 6n) O2N

O2N

CO2Et

CO2Et

CO2Et

O N

MeO2C

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 a

cat. DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO PPh3 DMAP Et3N

NH2Me (equiv) 20 20 20 20 20 20 20 1 10 30 20 20 20

solvent DME MeCN THF DCE PhMe Dioxane CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

yieldb (%) 42 65 79 82 75 60 97 NR 79 96 NR 41 40

Reaction conditions: MBH carbonate 4a (1.0 equiv, 0.1 M), acetoacetate 5a (1.05 equiv) and DABCO (0.1 equiv) in solvents, methylamine (20 equiv) was added, 20 h, room temperature. bIsolated yield. cDiastereomeric ratio (anti : syn = 50:50) was determined by 1H NMR spectroscopy.

BuO2C

BuO2C c

6p: 74%b dr = 75:25 O2N

N

t

N

n

6r: 70% dr = 50:50

6q: 95% dr = 50:50 O2N

CO2tBu

N

MeO2C

CO2Et

Bn

CO2Et

O2N

CO2Et

MeO2C

N

PMB

c

6u: 68% dr = 70:30

6t: 67% dr = 67:33

6s: 87% dr = 50:50 O2N

N

MeO2C

O2N

CO2Et

CO2Et Ph

MeO2C

N

R

6v (R = Et) : 86% dr = 57:43 6w (R = n-Bu) : 87%c dr = 55:45

MeO2C

N

6x: 70%c dr = 60:40

MeO2C

N 6y: 30%

a

Reaction conditions: MBH carbonate 4 (1.0 equiv, 0.1 M), acetoacetate 5 (1.05 equiv) and DABCO (0.1 equiv) in CH2Cl2, primary amine (20 equiv) was added, 20 h, room temperature. bReactions were performed in 1,2-dichloroethane. cReaction time was extended to 72 h. dIsolated yield. eDiastereomeric ratio (anti : syn) was determined by 1H NMR spectroscopy.

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containing catalysts could promote the transformation even though low yields were observed in these cases. (entries 1113). The optimal reaction conditions (Table 1, entry 7) was then applied to the synthesis of various 4-aryl-1,2,3,4tetrahydropyridines (6a–y, Table 2). Substituents on the aromatic ring of the MBH carbonates were first screened. Substrates with electron-withdrawing substituent such as nitro, cyano group smoothly afforded 6a and 6b in 97% and 90% yields respectively. However, when the substituent switched to electron-donating ones, the yields decreased dramatically. To our delight, this problem could be solved by switching the solvent from CH2Cl2 to 1,2-dichloroethane (Method B). With method B, para-substituted MBH carbonates successfully delivered the desired products (6c-g) with good yields. Other substrates with meta-substituent or multi-substituent MBH carbonates also afforded desired products (6h–m). Both αand β-naphthyl substrates provided good yields under the standard conditions B (6n, 6o). Interestingly, the former gave better diastereoselectivity (83:17). The relative configuration of the major anti-isomer 6na was confirmed by X-ray crystallographic analysis. Substrate with furan motif was also converted to desired product (6p) by this method in moderate yields as well. MBH carbonates or acetoacetates with a more sterically demanding ester motif also worked efficiently and afforded the desired products in 70–95% yields (6q–s). In addition, a variety of primary amines including benzyl, pmethoxybenzyl, ethyl, butyl, and phenethylamines were also employed in this reaction, the desired products (6t-x) were isolated in good yields. When a non-substituted carbonate was treated as the same reaction condition, the desired product 6y could be isolate in albeit of lower yield. The relative configuration for all the products in Table 2 (both anti- and synisomers of 6a-6x) were confirmed by the analogy to the crystallographic analysis of compound 6na (anti-isomer of 6n) and 6hb (syn-isomer of 6h). Table 3. Synthesis of Multi-functionalized Lactamsa,b,c

Interestingly, when α-naphthyl substituted 4n was treated with more sterically hindered methyl isobutyrylacetate 5c, a pair of 6-membered lactams 7a was generated as the major products instead of tetrahydropyridines (Table 3). The structure and the relative configuration of 7aa (anti-isomer of 7a) were confirmed by X-ray crystallographic analysis. Other carbonate such as pbromophenyl substituted 4f also delivered the corresponding lactam 7b. The distinctly different chemoselectivity observed in the cyclization step of intermediate C (Scheme 1) might be attributed to enhanced steric hindrance around the ketone motif, which favoured the amidation over the condensation with the ketone moiety in the presence of a primary amine. Scheme 2. Stereoselective reduction of 4-Aryl-1,2,3,4tetrahydropyridine

To demonstrate the utility of the tetrahedropyridine products, a stereoselective reduction of enamine moiety was then attempted. After carefully condition screening, we found that compound 6na could be converted to multisubstituted piperidine 8 with excellent diastereoselectivity and yield under the reduction of sodium cyanoborohydride and trifluoroacetic acid combination (Scheme 2). The relative configuration of 8 was determined by nuclear Overhauser effect correlated (NOESY) spectra. This result would no wondering greatly expanded the structural diversity of our products. CONCLUSIONS In conclusion, we have developed a facile DABCO-catalyzed synthesis of 4-aryl-1,2,3,4-tetrahydro-pyridines through a multi-component reaction with steadily available Morita-BaylisHillman carbonates as the starting materials. Considering its operational simplicity, good functionality tolerance, and excellent reaction efficiency, the current formal [3+2+1] cycloaddition provided a rapid access to an array of synthetically valuable tetrahydropyridines and piperidines as well. EXPERIMENTAL SECTION

a

Reaction conditions: MBH carbonate 4 (1.0 equiv, 0.1 M), methyl isobutyrylacetate 5c (1.05 equiv) and DABCO (0.1 equiv) in 1,2-dichloroethane, methylamine (20 equiv) was added, 20 h, room temperature. bIsolated yield. cDiastereomeric ratio (anti : syn) was determined by 1H NMR spectroscopy.

General Information. All melting points are uncorrected. All isolated compounds were characterized on Varian 300, Bruker 400, and Varian 600 MHz spectrometers in CDCl3. Chemical shifts are reported as δ values relative to internal chloroform (δ 7.26 for 1H NMR and 77.00 for 13C NMR), and multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Coupling constants (J) are reported in Hertz (Hz). High-resolution mass spectral analysis (HRMS) data were measured on a Bruker ApexII mass spectrometer by means of the ESI technique with orbitrap elite analyzer type. Column chromatography was performed on silica gel. Anhydrous THF, and PhMe were distilled over sodium benzophenone ketyl under argon, anhydrous DCM were distilled over calcium hydride under argon



gas. All other solvents and reagents were used as obtained from commercial sources without further purification. General Procedure for Synthesis of Tetrahydropyridines 6. To a stirred solution of 4a (101 mg, 0.3 mmol) in dry DCM (3 mL) was added 1,4-diazabicyclo[2.2.2]octane (DABCO) (3.3 mg, 0.03 mmol) at room temperature, and the reaction mixture was stirred for 10 min. Thereafter, ethyl acetoacetate (41 mg, 0.315 mmol) was added, and the reaction was continued at room temperature for 2 h, then followed by the addition of methylamine (33 wt.% in absolute ethanol, 740 µL, 6.0 mmol). The reaction was stirred at room temperature for another 20 h and then directly concentrated under reduced pressure. The residue was purified by chromatography on silica gel with elution of PE:EA = 10:1-5:1, and 6a (105 mg, 97% yield) was obtained as a yellow foam. General Procedure for Synthesis of Multi-functionalized Lactams 7. To a stirred solution of 4n (205 mg, 0.3 mmol) in dry 1,2-dichloroethane (3 mL) was added 1,4-diazabicyclo[2.2.2]octane (DABCO) (3.3 mg, 0.03 mmol) at room temperature, and the reaction mixture was stirred for 10 min. Thereafter, methyl 4methyl-3-oxopentanoate (46 mg, 0.315 mmol) was added, and the reaction was continued at room temperature for 2 h, then followed by the addition of methylamine (33 wt.% in absolute ethanol, 740 µL, 6.0 mmol). The reaction was stirred at room temperature for another 20 h and then directly concentrated under reduced pressure. The residue was purified by chromatography on silica gel with elution of PE:EA = 10:1-5:1, and 7a (66 mg, 60% yield) was obtained as a white oil. Procedure for Synthesis of Multisubstituted Piperidine 8. To a stirred solution of 6na (50 mg, 0.136 mmol) in CH2Cl2 (5 mL) were added sodium cyanoborohydride (17 mg, 0.272 mmol) and trifluoroacetic acid (80 µL, 1.088 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3 (10 mL×3) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography using aluminum oxide with elution of PE:EA = 10:1-5:1, and 8 (47 mg, 93% yield) was obtained as a colorless oil. Characterization Data of Products 5-Ethyl 3-methyl 1,6-dimethyl-4-(4-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6a (105 mg, Y = 97%). Compound 6aa (anti-isomer) was isolated as a yellow solid; mp 100–102 oC. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 4.69 (s, 1H), 4.00–3.80 (m, 2H), 3.73 (s, 3H), 3.40 (dt, J = 12.8, 2.4 Hz, 1H), 3.10 (dd, J = 12.8, 3.6 Hz, 1H), 3.08 (s, 3H), 2.71 (q, J = 3.2 Hz, 1H), 2.55 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 156.4, 154.6, 146.4, 128.5, 123.6, 92.4, 58.8, 52.4, 47.3, 44.3, 41.1, 39.5, 16.8, 14.2; ESI-HRMS m/z calcd for C18H23N2O6 [M+H]+: 363.1551, found 363.1548. Compound 6ab (syn-isomer) was isolated as a yellow solid; mp 133–135 oC. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 4.62 (d, J = 4.8 Hz, 1H), 4.00–3.82 (m, 2H), 3.60 (s, 3H), 3.38 (t, J = 13.2 Hz, 1H), 3.21 (ddd, J = 13.2, 4.4, 1.6 Hz, 1H), 3.16–3.02 (m, 4H), 2.58 (s, 3H), 0.99 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 167.7, 156.0, 151.1, 146.7, 129.3, 123.1, 95.0, 59.0, 51.7, 46.9, 42.0, 41.5, 39.3, 16.7, 14.2;

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ESI-HRMS m/z calcd for C18H23N2O6 [M+H]+: 363.1551, found 363.1547. 5-Ethyl 3-methyl 4-(4-cyanophenyl)-1,6-dimethyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6b (91 mg, Y = 90%). Compound 6ba (anti-isomer) was isolated as a yellow solid; mp 104–106 oC. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.63 (s, 1H), 3.97–3.78 (m, 2H), 3.71 (s, 3H), 3.38 (dt, J = 12.8, 2.4 Hz, 1H), 3.15–2.98 (m, 4H), 2.68 (q, J = 2.8 Hz, 1H), 2.52 (s, 3H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 156.3, 152.5, 132.1, 128.5, 119.0, 109.9, 92.2, 58.7, 52.3, 47.3, 44.3, 41.2, 39.5, 16.8, 14.1; ESI-HRMS m/z calcd for C19H23N2O4 [M+H]+: 343.1652, found 343.1650. Compound 6bb (syn-isomer) was isolated as a yellow solid; mp 141–143 oC. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.55 (d, J = 4.8 Hz, 1H), 3.89 (q, J = 7.2 Hz, 2H), 3.59 (s, 3H), 3.35 (t, J = 12.8 Hz, 1H), 3.19 (ddd, J = 13.6, 4.4, 2.0 Hz, 1H), 3.14–2.99 (m, 4H), 2.56 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 167.7, 155.9, 149.0, 131.6, 129.3, 119.0, 110.3, 95.0, 58.9, 51.6, 46.9, 42.1, 41.7, 39.2, 16.7, 14.2; ESIHRMS m/z calcd for C19H23N2O4 [M+H]+: 343.1652, found 343.1646. 5-Ethyl 3-methyl 4-(4-methoxyphenyl)-1,6-dimethyl-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6c (66 mg, Y = 64%). Compound 6ca (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.56 (s, 1H), 3.99–3.83 (m, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.34 (dt, J = 12.4, 2.0 Hz, 1H), 3.14 (dd, J = 12.4, 3.6 Hz, 1H), 3.04 (s, 3H), 2.68 (q, J = 2.8 Hz, 1H), 2.51 (s, 3H), 0.96 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 168.8, 157.8, 155.3, 138.8, 128.6, 113.5, 93.6, 58.6, 55.2, 52.1, 47.3, 44.7, 39.9, 39.4, 16.8, 14.2; ESI-HRMS m/z calcd for C19H26NO5 [M+H]+: 348.1805, found 348.1801. Compound 6cb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 4.48 (d, J = 4.4 Hz, 1H), 3.98–3.85 (m, 2H), 3.76 (s, 3H), 3.60 (s, 3H), 3.40 (t, J = 12.8 Hz, 1H), 3.14 (ddd, J = 13.2, 4.4, 2.4 Hz, 1H), 3.07 (s, 3H), 2.98 (dt, J = 12.4, 4.8 Hz, 1H), 2.54 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.1, 168.4, 158.1, 155.0, 135.0, 129.4, 113.1, 96.5, 58.8, 55.1, 51.4, 47.0, 42.5, 40.7, 39.1, 16.7, 14.3; ESI-HRMS m/z calcd for C19H26NO5 [M+H]+: 348.1805, found 348.1800. 5-Ethyl 3-methyl 1,6-dimethyl-4-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6d (73 mg, Y = 77%). Compound 6da (anti-isomer) was isolated as a yellow solid; mp 77–79 oC. 1H NMR (400 MHz, CDCl3) δ 7.31–7.21 (m, 2H), 7.20–7.11 (m, 3H), 4.61 (s, 1H), 3.99–3.81 (m, 2H), 3.72 (s, 3H), 3.34 (dt, J = 12.8, 2.0 Hz, 1H), 3.15 (dd, J = 12.4, 3.6 Hz, 1H), 3.05 (s, 3H), 2.72 (q, J = 2.8 Hz, 1H), 2.53 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 168.7, 155.6, 146.7, 128.2, 127.6, 126.0, 93.3, 58.6, 52.1, 47.3, 44.6, 40.8, 39.4, 16.7, 14.1; ESI-HRMS m/z calcd for C18H24NO4 [M+H]+: 318.1700, found 318.1697. Compound 6db (syn-isomer) was isolated as a yellow solid; mp 131–133 oC. 1H NMR (400 MHz, CDCl3) δ 7.24–7.11 (m, 3H), 7.07–6.96 (m, 2H), 4.52 (d, J = 4.0 Hz, 1H), 3.91 (q, J = 7.2 Hz, 2H), 3.59 (s, 3H), 3.42 (t, J = 12.8 Hz, 1H), 3.14 (ddd, J = 12.8, 4.0, 2.0 Hz, 1H), 3.08 (s, 3H), 3.02


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(dt, J = 12.4, 4.4 Hz, 1H), 2.56 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 172.0, 168.3, 155.2, 142.9, 128.5, 127.7, 126.5, 96.2, 58.8, 51.4, 47.0, 42.4, 41.5, 39.1, 16.7, 14.2; ESI-HRMS m/z calcd for C18H24NO4 [M+H]+: 318.1700, found 318.1697. 5-Ethyl 3-methyl 1,6-dimethyl-4-(p-tolyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6e (62 mg, Y = 63%). Compound 6ea (anti-isomer) was isolated as a white oil. 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 4H), 4.58 (s, 1H), 3.99–3.84 (m, 2H), 3.71 (s, 3H), 3.33 (dt, J = 12.8, 2.4 Hz, 1H), 3.14 (dd, J = 12.8, 4.0 Hz, 1H), 3.04 (s, 3H), 2.70 (q, J = 2.4 Hz, 1H), 2.52 (s, 3H), 2.30 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 168.8, 155.4, 143.6, 135.4, 128.8, 127.5, 93.4, 58.6, 52.1, 47.3, 44.6, 40.3, 39.4, 21.0, 16.8, 14.2; ESI-HRMS m/z calcd for C19H26NO4 [M+H]+: 332.1856, found 332.1851. Compound 6eb (syn-isomer) was isolated as a white solid; mp 97– 99 oC. 1H NMR (300 MHz, CDCl3) δ 7.00 (d, J = 7.5 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 4.49 (d, J = 3.9 Hz, 1H), 4.00–3.83 (m, 2H), 3.60 (s, 3H), 3.40 (t, J = 12.6 Hz, 1H), 3.20–3.04 (m, 4H), 2.99 (dt, J = 12.6, 4.8 Hz, 1H), 2.55 (s, 3H), 2.27 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 172.1, 168.4, 155.1, 139.7, 135.8, 128.5, 128.3, 96.4, 58.8, 51.4, 47.1, 42.4, 41.1, 39.1, 21.0, 16.7, 14.2; ESI-HRMS m/z calcd for C19H26NO4 [M+H]+: 332.1856, found 332.1852. 5-Ethyl 3-methyl 4-(4-bromophenyl)-1,6-dimethyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6f (97 mg, Y = 82%). Compound 6fa (anti-isomer) was isolated as a yellow solid; mp 100–102 oC. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.55 (s, 1H), 4.00–3.79 (m, 2H), 3.71 (s, 3H), 3.35 (dt, J = 12.8, 2.4 Hz, 1H), 3.10 (dd, J = 12.8, 3.6 Hz, 1H), 3.04 (s, 3H), 2.66 (q, J = 2.8 Hz, 1H), 2.51 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 168.5, 155.8, 145.8, 131.2, 129.4, 119.8, 92.9, 58.7, 52.2, 47.2, 44.5, 40.4, 39.4, 16.7, 14.12; ESI-HRMS m/z calcd for C18H23BrNO4 [M+H]+: 396.0805, found 396.0799. Compound 6fb (syn-isomer) was isolated as a yellow solid; mp 155–157 oC. 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.48 (d, J = 4.8 Hz, 1H), 3.98–3.82 (m, 2H), 3.60 (s, 3H), 3.37 (t, J = 12.8 Hz, 1H), 3.16 (ddd, J = 12.8, 4.4, 2.0 Hz, 1H), 3.08 (s, 3H), 3.02 (dt, J = 13.2, 5.2 Hz, 1H), 2.55 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 168.0, 155.4, 142.1, 130.9, 130.2, 120.4, 95.8, 58.9, 51.5, 46.9, 42.2, 41.0, 39.2, 16.7, 14.2; ESI-HRMS m/z calcd for C18H23BrNO4 [M+H]+: 396.0805, found 396.0805. 5-Ethyl 3-methyl 4-(4-acetamidophenyl)-1,6-dimethyl-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6g (90 mg, Y = 81%). Compound 6ga (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.56 (s, 1H), 3.98–3.81 (m, 2H), 3.69 (s, 3H), 3.32 (dt, J = 12.4, 1.6 Hz, 1H), 3.10 (dd, J = 12.8, 3.6 Hz, 1H), 3.02 (s, 3H), 2.67 (q, J = 2.8 Hz, 1H), 2.49 (s, 3H), 2.11 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 168.9, 168.6, 155.6, 142.2, 136.2, 128.0, 119.8, 93.2, 58.7, 52.0, 47.3, 44.5, 40.2, 39.4, 24.3, 16.8, 14.2; ESI-HRMS m/z calcd for C20H27N2O5 [M+H]+: 375.1914, found 375.1912. Compound 6gb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 6.96

(d, J = 8.4 Hz, 2H), 4.49 (d, J = 4.4 Hz, 1H), 3.99–3.81 (m, 2H), 3.59 (s, 3H), 3.39 (t, J = 12.8 Hz, 1H), 3.14 (ddd, J = 13.2, 4.4, 2.0 Hz, 1H), 3.07 (s, 3H), 2.99 (dt, J = 12.4, 4.8 Hz, 1H), 2.54 (s, 3H), 2.13 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 168.3, 168.1, 155.2, 138.7, 136.4, 129.0, 119.0, 96.1, 58.8, 51.4, 47.0, 42.4, 40.9, 39.1, 24.6, 16.8, 14.2; ESIHRMS m/z calcd for C20H27N2O5 [M+H]+: 375.1914, found 375.1912. 5-Ethyl 3-methyl 1,6-dimethyl-4-(3-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6h (92 mg, Y = 85%). Compound 6ha (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.12–8.00 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 4.70 (s, 1H), 3.99–3.81 (m, 2H), 3.73 (s, 3H), 3.41 (dt, J = 13.2, 2.4 Hz, 1H), 3.11 (dd, J = 12.8, 3.6 Hz, 1H), 3.08 (s, 3H), 2.73 (q, J = 2.8 Hz, 1H), 2.55 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.1, 156.5, 149.1, 148.3, 134.0, 129.1, 122.5, 121.3, 92.2, 58.7, 52.3, 47.2, 44.4, 40.9, 39.6, 16.8, 14.2; ESI-HRMS m/z calcd for C18H23N2O6 [M+H]+: 363.1551, found 363.1544. Compound 6hb (syn-isomer) was isolated as a yellow solid; mp 145–147 oC. 1H NMR (400 MHz, CDCl3) δ 8.01–7.99 (m, 1H), 7.93 (s, 1H), 7.45– 7.34 (m, 2H), 4.62 (d, J = 4.4 Hz, 1H), 3.99–3.83 (m, 2H), 3.63 (s, 3H), 3.36 (t, J = 13.2 Hz, 1H), 3.21 (ddd, J = 13.6, 4.4, 2.0 Hz, 1H), 3.15–3.04 (m, 4H), 2.59 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 167.7, 156.1, 148.0, 145.5, 134.7, 128.7, 123.2, 121.7, 94.9, 58.9, 51.7, 46.8, 42.0, 41.3, 39.3, 16.7, 14.2; ESI-HRMS m/z calcd for C18H23N2O6 [M+H]+: 363.1551, found 363.1551. 5-Ethyl 3-methyl 4-(3-bromophenyl)-1,6-dimethyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6i (98 mg, Y = 83%). Compound 6ia (anti-isomer) was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35–7.31 (m, 1H), 7.29 (dt, J = 6.8, 2.0 Hz, 1H), 7.17–7.08 (m, 2H), 4.57 (s, 1H), 4.04–3.82 (m, 2H), 3.71 (s, 3H), 3.36 (dt, J = 12.8, 2.4 Hz, 1H), 3.12 (dd, J = 12.8, 4.0 Hz, 1H), 3.05 (s, 3H), 2.69 (q, J = 2.8 Hz, 1H), 2.52 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 168.4, 156.0, 149.2, 130.6, 129.7, 129.1, 126.3, 122.3, 92.5, 58.6, 52.2, 47.2, 44.4, 40.6, 39.5, 16.7, 14.2; ESI-HRMS m/z calcd for C18H23BrNO4 [M+H]+: 396.0805, found 396.0804. Compound 6ib (syn-isomer) was isolated as a white solid; mp 112–114 oC. 1H NMR (400 MHz, CDCl3) δ 7.31–7.27 (m, 1H), 7.17 (t, J = 1.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.48 (d, J = 4.4 Hz, 1H), 3.92 (q, J = 6.8 Hz, 2H), 3.61 (s, 3H), 3.38 (t, J = 13.2 Hz, 1H), 3.16 (ddd, J = 13.2, 4.4, 2.0 Hz, 1H), 3.08 (s, 3H), 3.02 (dt, J = 12.4, 4.4 Hz, 1H), 2.56 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.6, 168.0, 155.6, 145.6, 131.6, 129.6, 129.3, 127.1, 122.0, 95.4, 58.8, 51.5, 46.9, 42.3, 41.3, 39.2, 16.7, 14.2; ESI-HRMS m/z calcd for C18H23BrNO4 [M+H]+: 396.0805, found 396.0807. 5-Ethyl 3-methyl 4-(3-methoxyphenyl)-1,6-dimethyl-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6j (81 mg, Y = 78%). Compound 6ja (anti-isomer) was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.75–6.66 (m, 2H), 4.58 (s, 1H), 4.01–3.83 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.34 (dt, J = 12.4, 2.0 Hz, 1H), 3.17 (dd, J = 12.4, 3.6 Hz, 1H), 3.04 (s, 3H), 2.72 (q, J = 2.4 Hz, 1H), 2.52 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,



CDCl3) δ 172.7, 168.7, 159.5, 155.6, 148.5, 129.1, 120.2, 113.8, 110.9, 93.1, 58.6, 55.2, 52.1, 47.3, 44.4, 40.8, 39.4, 16.7, 14.2; ESI-HRMS m/z calcd for C19H26NO5 [M+H]+: 348.1805, found 348.1807. Compound 6jb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 8.4, 2.4 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.59–6.54 (m, 1H), 4.49 (d, J = 4.4 Hz, 1H), 4.01–3.85 (m, 2H), 3.75 (s, 3H), 3.61 (s, 3H), 3.43 (t, J = 12.8 Hz, 1H), 3.14 (ddd, J = 12.8, 4.0, 1.6 Hz, 1H), 3.07 (s, 3H), 3.00 (dt, J = 12.8, 4.8 Hz, 1H), 2.55 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 159.1, 155.2, 144.6, 128.6, 121.1, 114.8, 111.2, 96.0, 58.8, 55.0, 51.4, 47.1, 42.4, 41.5, 39.1, 16.7, 14.2; ESI-HRMS m/z calcd for C19H26NO5 [M+H]+: 348.1805, found 348.1808. 5-Ethyl 3-methyl 4-(3,5-dimethoxyphenyl)-1,6-dimethyl-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6k (101 mg, Y = 90%). Compound 6ka (anti-isomer) was isolated as a yellow solid; mp 105–107 oC. 1H NMR (400 MHz, CDCl3) δ 6.34 (d, J = 2.0 Hz, 2H), 6.28 (t, J = 2.4 Hz, 1H), 4.54 (s, 1H), 4.03–3.85 (m, 2H), 3.76 (s, 6H), 3.71 (s, 3H), 3.34 (dt, J = 12.8, 2.0 Hz, 1H), 3.19 (dd, J = 12.8, 4.0 Hz, 1H), 3.03 (s, 3H), 2.72 (q, J = 2.4 Hz, 1H), 2.50 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 168.7, 160.6, 155.6, 149.5, 106.0, 97.6, 93.0, 58.6, 55.3, 52.1, 47.4, 44.3, 41.0, 39.4, 16.8, 14.3; ESI-HRMS m/z calcd for C20H28NO6 [M+H]+: 378.1911, found 378.1912. Compound 6kb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.28 (t, J = 2.4 Hz, 1H), 6.19 (d, J = 2.4 Hz, 2H), 4.45 (d, J = 4.0 Hz, 1H), 4.02–3.86 (m, 2H), 3.73 (s, 6H), 3.63 (s, 3H), 3.45 (t, J = 12.8 Hz, 1H), 3.14 (ddd, J = 13.2, 4.4, 2.0 Hz, 1H), 3.06 (s, 3H), 2.98 (dt, J = 12.8, 4.8 Hz, 1H), 2.54 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 160.1, 155.2, 145.5, 107.1, 98.0, 96.0, 58.8, 55.1, 51.4, 47.2, 42.3, 41.8, 39.1, 16.7, 14.3; ESI-HRMS m/z calcd for C20H28NO6 [M+H]+: 378.1911, found 378.1908. 5-Ethyl 3-methyl 1,6-dimethyl-4-(3,4,5-trimethoxyphenyl)1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6l (93 mg, Y = 76%). Compound 6la (anti-isomer) was isolated as a white solid; mp 106–108 oC. 1H NMR (400 MHz, CDCl3) δ 6.38 (s, 2H), 4.53 (s, 1H), 4.05–3.86 (m, 2H), 3.81 (s, 6H), 3.80 (s, 3H), 3.71 (s, 3H), 3.36 (dt, J = 12.8, 2.0 Hz, 1H), 3.17 (dd, J = 12.4, 3.6 Hz, 1H), 3.04 (s, 3H), 2.73 (q, J = 2.8 Hz, 1H), 2.50 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 168.7, 155.4, 152.9, 142.5, 136.2, 104.7, 93.5, 60.8, 58.7, 56.1, 52.1, 47.6, 44.8, 41.1, 39.4, 16.8, 14.3; ESI-HRMS m/z calcd. for C21H30NO7 [M+H]+: 408.2017, found 408.2013. Compound 6lb (syn-isomer) was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.24 (s, 2H), 4.46 (d, J = 4.0 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 6H), 3.62 (s, 3H), 3.41 (t, J = 12.8 Hz, 1H), 3.17 (ddd, J = 12.8, 4.4, 2.0 Hz, 1H), 3.06 (s, 3H), 2.99 (dt, J = 12.8, 4.8 Hz, 1H), 2.55 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.8, 168.3, 155.1, 152.5, 138.5, 136.7, 105.8, 96.4, 60.8, 58.9, 56.0, 51.5, 47.3, 42.6, 41.7, 39.1, 16.7, 14.3; ESI-HRMS m/z calcd for C21H30NO7 [M+H]+: 408.2017, found 408.2012. 5-Ethyl 3-methyl 4-(benzo[d][1,3]dioxol-5-yl)-1,6-dimethyl1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6m (67 mg, Y = 62%). Compound 6ma (anti-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.74–6.66 (m, 2H),

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6.63 (dd, J = 8.0, 1.6 Hz, 1H), 5.94–5.88 (m, 2H), 4.52 (s, 1H), 4.03–3.85 (m, 2H), 3.70 (s, 3H), 3.34 (dt, J = 12.8, 2.4 Hz, 1H), 3.16 (dd, J = 12.4, 3.9 Hz, 1H), 3.04 (s, 3H), 2.67 (q, J = 2.4 Hz, 1H), 2.50 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 168.7, 155.4, 147.4, 145.7, 140.8, 120.6, 108.2, 107.9, 100.8, 93.4, 58.7, 52.1, 47.3, 44.7, 40.5, 39.4, 16.8, 14.3; ESI-HRMS m/z calcd for C19H24NO6 [M+H]+: 362.1598, found 362.1596. Compound 6mb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 8.0 Hz, 1H), 6.57–6.44 (m, 2H), 5.90 (s, 2H), 4.45 (d, J = 4.4 Hz, 1H), 3.94 (q, J = 6.8 Hz, 2H), 3.62 (s, 3H), 3.42 (t, J = 12.8 Hz, 1H), 3.14 (ddd, J = 13.2, 4.4, 2.0 Hz, 1H), 3.07 (s, 3H), 2.97 (dt, J = 12.8, 4.8 Hz, 1H), 2.53 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 155.1, 147.2, 146.0, 136.9, 121.6, 108.9, 107.6, 100.7, 96.4, 58.8, 51.4, 47.0, 42.4, 41.2, 39.1, 16.8, 14.3; ESI-HRMS m/z calcd for C19H24NO6 [M+H]+: 362.1598, found 362.1595. 5-Ethyl 3-methyl 1,6-dimethyl-4-(naphthalen-1-yl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6n (90 mg, Y = 83%). Compound 6na (anti-isomer) was isolated as a white solid; mp 148–150 oC. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 5.48 (s, 1H), 3.99–3.62 (m, 5H), 3.32 (d, J = 12.4 Hz, 1H), 3.15 (dd, J = 12.8, 3.6 Hz, 1H), 3.08 (s, 3H), 2.85 (s, 1H), 2.59 (s, 3H), 0.72 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 168.8, 155.9, 142.1, 134.0, 130.7, 129.0, 126.8, 126.2, 125.5, 125.4, 125.2, 122.9, 93.1, 58.5, 52.3, 47.4, 42.5, 39.4, 36.9, 16.8, 14.0; ESI-HRMS m/z calcd. for C22H26NO4 [M+H]+: 368.1856, found 368.1852. Compound 6nb (syn-isomer) was isolated as a white solid; mp 148–150 oC. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.53–7.31 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 5.50 (d, J = 4.8 Hz, 1H), 3.91–3.77 (m, 1H), 3.76–3.66 (m, 1H), 3.62 (t, J = 13.6 Hz, 1H), 3.14 (s, 3H), 3.10 (s, 3H), 3.25–2.97 (m, 2H), 2.62 (s, 3H), 0.73 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 171.9, 168.3, 155.2, 139.8, 133.6, 131.9, 128.5, 127.1, 126.2, 125.1, 125.0, 124.9, 123.6, 97.6, 58.8, 51.2 , 47.4, 41.8, 39.2, 35.3, 16.7, 14.0; ESI-HRMS m/z calcd

for C22H26NO4 [M+H]+:368.1856, found 368.1848. 5-Ethyl 3-methyl 1,6-dimethyl-4-(naphthalen-2-yl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6o (78 mg, Y = 71%). Compound 6oa (anti-isomer) was isolated as a white oil. 1 H NMR (400 MHz, CDCl3) δ 7.90–7.72 (m, 3H), 7.55 (s, 1H), 7.49–7.34 (m, 3H), 4.79 (s, 1H), 3.88 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.35 (dt, J = 12.4, 2.0 Hz, 1H), 3.17 (dd, J = 12.8, 3.6 Hz, 1H), 3.08 (s, 3H), 2.82 (q, J = 2.4 Hz, 1H), 2.60 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 168.8, 155.8, 144.2, 133.4, 132.1, 127.9, 127.7, 127.4, 126.4, 126.1, 125.8, 125.2, 93.0, 58.6, 52.1, 47.2, 44.4, 40.9, 39.4, 16.8, 14.2; ESIHRMS m/z calcd for C22H26NO4 [M+H]+: 368.1856, found 368.1856. Compound 6ob (syn-isomer) was isolated as a white solid; mp 122–124 oC. 1H NMR (400 MHz, CDCl3) δ 7.81–7.72 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.44–7.37 (m, 2H), 7.20 (dd, J = 8.4, 1.6 Hz, 1H), 4.70 (d, J = 4.4 Hz, 1H), 3.96–3.78 (m, 2H), 3.58 (s, 3H), 3.48 (t, J = 12.8 Hz, 1H), 3.17 (ddd, J = 12.8, 4.0, 2.0 Hz, 1H), 3.14–2.98 (m, 4H), 2.62 (s, 3H), 0.96 (t, J


Page 7 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 168.3, 155.4, 140.6, 133.2, 132.4, 127.8, 127.5, 127.2, 127.2, 127.2, 125.6, 125.2, 96.1, 58.8, 51.4, 47.1, 42.6, 41.6, 39.2, 16.8, 14.2; ESIHRMS m/z calcd for C22H26NO4 [M+H]+: 368.1856, found 368.1857. 5-Ethyl 3-methyl 4-(furan-2-yl)-1,6-dimethyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6p (68 mg, Y = 74%). Compound 6pa (anti-isomer) was isolated as a brown oil. 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 6.36–6.13 (m, 1H), 5.90 (d, J = 3.2 Hz, 1H), 4.65 (s, 1H), 4.10–3.90 (m, 2H), 3.70 (s, 3H), 3.47–3.33 (m, 1H), 3.19 (dd, J = 12.4, 3.6 Hz, 1H), 3.10– 2.93 (m, 4H), 2.45 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 168.6, 158.5, 155.6, 140.9, 110.0, 106.4, 91.4, 58.7, 52.1, 47.9, 40.9, 39.3, 34.8, 16.8, 14.3; ESIHRMS m/z calcd. for C16H22NO5 [M+H]+: 308.1492, found 308.1490. Compound 6pb (syn-isomer) was isolated as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 6.30–6.16 (m, 1H), 5.90 (d, J = 2.8 Hz, 1H), 4.61 (d, J = 3.2 Hz, 1H), 4.09–3.93 (m, 2H), 3.70 (s, 3H), 3.38 (t, J = 12.4 Hz, 1H), 3.18 (ddd, J = 12.8, 4.4, 2.4 Hz, 1H), 3.03 (s, 3H), 2.89 (dt, J = 12.4, 4.4 Hz, 1H), 2.50 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 168.2, 156.2, 155.7, 141.3, 109.9, 107.5, 93.6, 58.8, 51.8, 47.9, 41.2, 39.1, 35.8, 16.8, 14.4; ESI-HRMS m/z calcd for C16H22NO5 [M+H]+: 308.1492, found 308.1492. 3-Butyl 5-ethyl 1,6-dimethyl-4-(4-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. Compound 6q (114 mg, Y = 95%). Compound 6qa (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.70 (s, 1H), 4.21–4.02 (m, 2H), 3.87 (q, J = 7.2 Hz, 2H), 3.47–3.32 (m, 1H), 3.14–2.98 (m, 4H), 2.75–2.65 (m, 1H), 2.53 (s, 3H), 1.64–1.52 (m, 2H), 1.41–1.28 (m, 2H), 0.92 (q, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.4, 168.0, 156.3, 154.5, 146.4, 128.5, 123.5, 92.1, 64.9, 58.7, 47.3, 44.3, 41.0, 39.4, 30.6, 19.0, 16.6, 14.2, 13.6; ESI-HRMS m/z calcd for C21H29N2O6 [M+H]+: 405.2020, found 405.2019. Compound 6qb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 4.60 (d, J = 4.8 Hz, 1H), 4.05–3.94 (m, 1H), 3.93–3.85 (m, 3H), 3.38 (t, J = 13.2 Hz, 1H), 3.20 (ddd, J = 13.2, 4.4, 2.0 Hz, 1H), 3.12–3.03 (m, 4H), 2.57 (s, 3H), 1.58–1.44 (m, 2H), 1.31–1.19 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 167.7, 155.9, 151.2, 146.6, 129.4, 123.0, 95.0, 64.6, 58.9, 46.9, 42.2, 41.6, 39.2, 30.4, 19.0, 16.7, 14.2, 13.6; ESI-HRMS m/z calcd for C21H29N2O6 [M+H]+: 405.2020, found 405.2023. 3-(Tert-butyl) 5-ethyl 1,6-dimethyl-4-(4-nitrophenyl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6r (85 mg, Y = 70%). Compound 6ra (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 4.67 (s, 1H), 4.00–3.79 (m, 2H), 3.36 (dt, J = 12.8, 2.4 Hz, 1H), 3.06 (s, 3H), 3.02 (dd, J = 13.2, 4.0 Hz, 1H), 2.64 (q, J = 2.8 Hz, 1H), 2.54 (s, 3H), 1.43 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 170.6, 168.2, 156.3, 154.5, 146.3, 128.5, 123.4, 92.2, 81.3, 58.6, 47.7, 45.0, 41.2, 39.4, 27.9, 16.6, 14.2; ESI-HRMS m/z calcd for C21H29N2O6 [M+H]+: 405.2020, found 405.2018. Compound 6rb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz,

2H), 7.27 (d, J = 8.8 Hz, 2H), 4.56 (d, J = 4.8 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 3.35 (t, J = 13.2 Hz, 1H), 3.18 (ddd, J = 13.2, 4.4, 1.6 Hz, 1H), 3.10 (s, 3H), 2.97 (dt, J = 12.8, 4.8 Hz, 1H), 2.55 (s, 3H), 1.32 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.0, 167.8, 155.7, 151.3, 146.6, 129.9, 122.8, 95.3, 81.6, 58.9, 47.2, 42.7, 41.5, 39.2, 28.0, 16.7, 14.2; ESI-HRMS m/z calcd for C21H29N2O6 [M+H]+: 405.2020, found 405.2026. 5-(Tert-butyl) 3-methyl 1,6-dimethyl-4-(4-nitrophenyl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. Compound 6s (102 mg, Y = 87%). Compound 6sa (anti-isomer) was isolated as a yellow solid; mp 114–116 oC. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 4.58 (s, 1H), 3.73 (s, 3H), 3.37 (ddd, J = 12.8, 3.6, 2.0 Hz, 1H), 3.10 (dd, J = 12.8, 3.6 Hz, 1H), 3.05 (s, 3H), 2.68 (q, J = 3.6 Hz, 1H), 2.50 (s, 3H), 1.15 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 167.8, 155.6, 155.2, 146.4, 128.6, 123.5, 94.7, 78.3, 52.3, 47.6, 44.9, 41.8, 39.4, 28.2, 16.7; ESI-HRMS m/z calcd for C20H27N2O6 [M+H]+: 391.1864, found 391.1866. Compound 6sb (syn-isomer) was isolated as a yellow solid; mp 145–147 oC. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 4.52 (d, J = 5.2 Hz, 1H), 3.59 (s, 3H), 3.35 (t, J = 12.8 Hz, 1H), 3.18 (ddd, J = 13.2, 4.0, 1.6 Hz, 1H), 3.13–3.00 (m, 4H), 2.54 (s, 3H), 1.19 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 171.4, 167.3, 155.4, 151.6, 146.6, 129.4, 123.0, 96.6, 78.5, 51.6, 46.8, 42.3, 42.1, 39.2, 28.2, 16.7; ESI-HRMS m/z calcd for C20H27N2O6 [M+H]+: 391.1864, found 391.1862. 5-Ethyl 3-methyl 1-benzyl-6-methyl-4-(4-nitrophenyl)-1,2,3,4tetra hydropyridine-3,5-dicarboxylate. Compound 6t (90 mg, Y = 67%). Compound 6ta (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H), 7.41–7.34 (m, 4H), 7.33–7.27 (m, 1H), 7.19 (d, J = 7.2 Hz, 2H), 4.71 (s, 1H), 4.69 (d, J = 16.6 Hz, 1H), 4.48 (d, J = 16.6 Hz, 1H), 3.99–3.84 (m, 2H), 3.68 (s, 3H), 3.41 (ddd, J = 13.2, 3.2, 2.0 Hz, 1H), 3.08 (dd, J = 12.8, 4.0 Hz, 1H), 2.71 (q, J = 3.2 Hz, 1H), 2.63 (s, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 155.6, 154.5, 146.5, 137.2, 128.9, 128.5, 127.6, 126.6, 123.6, 93.9, 59.0, 55.0, 52.2, 45.9, 44.6, 41.1, 16.9, 14.1; ESI-HRMS m/z calcd for C24H26N2O6 [M+H]+: 439.1864, found 439.1861. Compound 6tb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 2H), 7.45–7.37 (m, 2H), 7.36–7.30 (m, 1H), 7.25 (s, 1H), 7.24–7.21 (m, 2H), 7.20 (s, 1H), 4.70 (d, J = 16.6 Hz, 1H), 4.67 (d, J = 4.0 Hz, 1H), 4.55 (d, J = 16.6 Hz, 1H), 4.01–3.84 (m, 2H), 3.56 (s, 3H), 3.36 (t, J = 12.8 Hz, 1H), 3.22 (ddd, J = 13.6, 4.4, 2.0 Hz, 1H), 3.12 (dt, J = 12.4, 4.4 Hz, 1H), 2.66 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 167.7, 155.2, 150.9, 146.8, 136.9, 129.4, 129.1, 127.8, 126.4, 123.1, 95.8, 59.1, 54.6, 51.6, 44.9, 42.3, 41.7, 16.7, 14.2. ESI-HRMS m/z calcd for C24H26N2O6 [M+H]+: 439.1864, found 439.1859. 5-ethyl 3-methyl 1-(4-methoxybenzyl)-6-methyl-4-(4-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. 6u (96 mg, Y = 68%). Compound 6ua (anti-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.70 (s, 1H), 4.63 (d, J = 16.3 Hz, 1H), 4.40 (d, J = 16.2 Hz, 1H), 3.98–3.84 (m, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.43–3.36 (m, 1H), 3.04 (dd, J = 12.9, 3.9 Hz, 1H), 2.70 (q, J = 3.4 Hz, 1H),


The Journal of Organic Chemistry 13

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2.64 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 172.0, 168.2, 159.1, 155.6, 154.5, 146.5, 129.0,

128.4, 127.9, 123.6, 114.2, 93.7, 59.0, 55.3, 54.4, 52.3, 45.6, 44.6, 41.1, 16.9, 14.2; ESI-HRMS m/z calcd for C25H29N2O7 [M+H]+: 469.1969, found 469.1970. Compound 6ub (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 4.66 (d, J = 5.1 Hz, 1H), 4.62 (d, J = 16.4 Hz, 1H), 4.49 (d, J = 16.3 Hz, 1H), 3.92 (qd, J = 7.1, 1.4 Hz, 2H), 3.83 (s, 3H), 3.56 (s, 3H), 3.32 (t, J = 13.0 Hz, 1H), 3.20 (ddd, J = 13.5, 4.3, 1.8 Hz, 1H), 3.08 (dt, J = 12.6, 4.6 Hz, 1H), 2.67 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 167.8, 159.3, 155.3, 151.0, 146.7, 129.4, 128.7, 127.8, 123.0, 114.4, 95.6, 59.1, 55.4, 54.0, 51.6, 44.6, 42.3, 41.7, 16.8, 14.2; ESI-HRMS m/z calcd for C25H29N2O7 [M+H]+: 469.1969, found 469.1966. 5-ethyl 3-methyl-1-ethyl-6-methyl-4-(4-nitrophenyl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. 6v (97 mg, Y = 86%). Compound 6va (anti-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 4.68 (s, 1H), 3.99–3.81 (m, 2H), 3.72 (s, 3H), 3.49– 3.31 (m, 3H), 3.09 (dd, J = 12.9, 3.8 Hz, 1H), 2.71 (q, J = 3.2 Hz, 1H), 2.55 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.9, 168.2, 155.6, 154.8, 146.3, 128.5, 123.6, 92.2, 58.8, 52.3, 46.0, 44.7, 44.4, 41.0, 16.1, 14.2, 13.5; ESI-HRMS m/z calcd for C19H25N2O6 [M+H]+: 377.1707, found 377.1704. Compound 6vb (syn-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 4.8 Hz, 1H), 3.97–3.85 (m, 2H), 3.61 (s, 3H), 3.56–3.45 (m, 1H), 3.44–3.31 (m, 2H), 3.26–3.16 (m, 1H), 3.05 (dt, J = 12.6, 4.7 Hz, 1H), 2.59 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 167.8, 155.2, 151.3, 146.6, 129.3, 123.1, 94.8, 58.9, 51.7, 46.1, 44.0, 42.1, 41.6, 16.0, 14.2, 13.4; ESIHRMS m/z calcd for C19H25N2O6 [M+H]+: 377.1707, found 377.1707. 5-ethyl 3-methyl 1-butyl-6-methyl-4-(4-nitrophenyl)-1,2,3,4tetrahydropyridine-3,5-dicarboxylate. 6w (105 mg, Y = 87%). Compound 6wa (anti-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.67 (s, 1H), 4.02–3.77 (m, 2H), 3.72 (s, 3H), 3.43 (dt, J = 12.9, 2.5 Hz, 1H), 3.19–3.37 (m, 2H), 3.08 (dd, J = 12.9, 3.8 Hz, 1H), 2.70 (q, J = 3.2 Hz, 1H), 2.54 (s, 3H), 1.64–1.44 (m, 2H), 1.39–1.22 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 168.2, 155.8, 154.9, 146.3, 128.4, 123.6, 92.1, 58.8, 52.3, 51.4, 45.2, 44.4, 41.0, 30.5, 20.0, 16.4, 14.2, 13.9; ESI-HRMS m/z calcd for C21H29N2O6 [M+H]+: 405.2020, found 405.2017. Compound 6wb (antiisomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 4.9 Hz, 1H), 3.95–3.81 (m, 2H), 3.60 (s, 3H), 3.49–3.24 (m, 3H), 3.21 (ddd, J = 13.4, 4.1, 1.8 Hz, 1H), 3.04 (dt, J = 12.6, 4.4 Hz, 1H), 2.58 (s, 3H), 1.69–1.49 (m, 2H), 1.42–1.28 (m, 2H), 0.97 (td, J = 7.2, 2.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.5, 167.8, 155.4, 151.3, 146.6, 129.3, 123.1, 94.6, 58.9, 51.7, 51.5, 44.6, 42.1, 41.6, 30.5, 20.0, 16.2, 14.2, 13.9; ESI-HRMS m/z calcd for C21H29N2O6 [M+H]+: 405.2020, found 405.2014.

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5-ethyl 3-methyl-6-methyl-4-(4-nitrophenyl)-1-phenethyl1,2,3,4-tetrahydropyridine-3,5-dicarboxylate. 6x (95 mg, Y = 70%). Compound 6xa (anti-isomer) was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.7 Hz, 2H), 7.37–7.29 (m, 4H), 7.28–7.22 (m, 1H), 7.21–7.15 (m, 2H), 4.67 (s, 1H), 4.03–3.79 (m, 2H), 3.73 (s, 3H), 3.71–3.59 (m, 1H), 3.56–3.42 (m, 2H), 3.06 (dd, J = 12.8, 3.7 Hz, 1H), 2.98–2.77 (m, 2H), 2.70 (q, J = 3.2 Hz, 1H), 2.51 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 168.1, 155.4, 154.7, 146.4, 138.1, 128.7, 128.6, 128.5, 126.8, 123.5, 92.6, 58.8, 53.4, 52.4, 45.6, 44.3, 41.0, 35.1, 16.3, 14.1; ESI-HRMS m/z calcd for C25H29N2O6 [M+H]+: 453.2020, found 453.2016. Compound 6xb (anti-isomer) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.7 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.20 (dd, J = 11.9, 7.9 Hz, 4H), 4.60 (d, J = 5.0 Hz, 1H), 3.96–3.80 (m, 2H), 3.74–3.64 (m, 1H), 3.61 (s, 3H), 3.59–3.51 (m, 1H), 3.37 (t, J = 13.0 Hz, 1H), 3.19 (dd, J = 13.3, 2.4 Hz, 1H), 3.02 (dt, J = 12.6, 4.6 Hz, 1H), 2.98–2.81 (m, 2H), 2.56 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 167.7, 155.1, 151.1, 146.6, 137.8, 129.3, 128.8, 128.7, 126.9, 123.1, 95.2, 59.0, 53.2, 51.7, 44.9, 42.0, 41.6, 35.0, 16.2, 14.2; ESI-HRMS m/z calcd for C25H29N2O6 [M+H]+: 453.2020, found 453.2019. 5-ethyl 3-methyl 1,6-dimethyl-1,2,3,4-tetrahydropyridine-3,5dicarboxylate. 6y (21 mg, Y = 30%). Compound 6y was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.09 (q, J = 7.0 Hz, 2H), 3.70 (s, 3H), 3.39–3.24 (m, 2H), 2.96 (s, 3H), 2.83–2.66 (m, 2H), 2.55–2.30 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.0, 168.8, 155.0, 92.5, 58.8, 52.0, 51.9, 39.1, 37.8, 26.6, 16.6, 14.6. ESI-HRMS m/z calcd for C12H19NO4 [M+Na]+: 264.1206, found 264.1208. Methyl (Z)-5-(1-hydroxy-2-methylpropylidene)-1-methyl-4(naphthalen-1-yl)-6-oxopiperidine-3-carboxylate. Compound 7a (66 mg, Y = 60%). Compound 7aa (anti-isomer) was isolated as a white solid; mp 97–99 oC. 1H NMR (400 MHz, CDCl3) δ 15.90 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67–7.58 (m, 1H), 7.58–7.49 (m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 5.34 (s, 1H), 3.85 (s, 3H), 3.47 (dt, J = 12.8, 1.6 Hz, 1H), 3.17 (dd, J = 12.8, 3.6 Hz, 1H), 3.06 (s, 3H), 3.04–3.01 (m, 1H), 2.53–2.37 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 180.4, 171.8, 170.6, 138.7, 134.1, 130.3, 129.4, 127.9, 126.8, 125.9, 125.8, 125.4, 122.2, 93.2, 52.6, 45.6, 43.3, 37.1, 34.6, 29.8, 19.8, 18.7; ESI-HRMS m/z calcd for C22H26NO4 [M+H]+: 368.1856, found 368.1855. Compound 7ab (syn-isomer) was isolated as a white foam. 1H NMR (400 MHz, CDCl3) δ 15.72 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.89–7.81 (m, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.58–7.37 (m, 3H), 7.17 (dd, J = 7.2, 0.4 Hz, 1H), 5.29 (d, J = 4.8 Hz, 1H), 3.72 (t, J = 12.8 Hz, 1H), 3.31 (dt, J = 12.0, 4.4 Hz, 1H), 3.26–3.18 (m, 4H), 3.14 (s, 3H), 2.62–2.44 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 0.44 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 179.7, 170.9, 170.8, 137.0, 133.7, 131.1, 129.2, 127.9, 126.7, 126.0, 125.4, 125.2, 122.1, 97.6, 51.5, 46.0, 43.2, 35.8, 34.8, 29.9, 19.3, 18.8; ESI-HRMS m/z calcd for C22H26NO4 [M+H]+: 368.1856, found 368.1856.


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Methyl (Z)-4-(4-bromophenyl)-5-(1-hydroxy-2-methylpropylidene)-1-methyl-6-oxopiperidine-3-carboxylate. Compound 7b (60 mg, Y = 65%). 1H NMR (400 MHz, CDCl3) δ 15.69 (s, 0.33H), 15.62 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 0.67H), 7.38 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 0.67H), 6.91 (d, J = 8.4 Hz, 2H), 4.51 (s, 0.33H), 4.37 (d, J = 4.4 Hz, 1H), 3.74 (s, 1H), 3.64 (s, 3H), 3.50–3.39 (m, 1.33H), 3.27 (ddd, J = 12.8, 4.8, 1.2 Hz, 1H), 3.21–3.11 (m, 1.33H), 3.07 (s, 3H), 3.00 (s, 1H), 2.80 (dt, J = 4.1, 2.4 Hz, 0.3H), 2.67–2.45 (m, 1.33H), 1.11 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 1H), 0.83 (d, J = 6.8 Hz, 1H), 0.65 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 180.3, 179.6, 171.4, 170.6, 170.5, 170.1, 142.4, 139.7, 131.8, 131.5, 129.8, 129.2, 121.2, 120.8, 95.7, 92.4, 52.5, 51.8, 45.3, 45.2, 43.4, 41.0, 40.0, 34.7, 34.6, 29.6, 19.6, 19.3, 19.1, 18.8. Compound 7bb (synisomer) was isolated as a white solid; mp 139–141 oC. 1H NMR (400 MHz, CDCl3) δ 15.62 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.37 (d, J = 4.4 Hz, 1H), 3.64 (s, 3H), 3.45 (t, J = 12.8 Hz, 1H), 3.27 (ddd, J = 12.8, 4.8, 1.2 Hz, 1H), 3.16 (dt, J = 12.4, 4.4 Hz, 1H), 3.07 (s, 3H), 2.65–2.51 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 179.6, 170.6, 170.5, 139.8, 131.6, 129.8, 121.2, 95.7, 51.8, 45.4, 43.5, 41.0, 34.7, 29.7, 19.3, 19.1. ESI-HRMS m/z calcd for C18H22BrNO4 [M+H]+: 396.0805, found 396.0803. (2R,3R,4R,5R)-3-ethyl 5-methyl 1,2-dimethyl-4-(naphthalen-1yl)piperidine-3,5-dicarboxylate. 8 (47 mg, Y = 93%). Compound 8 was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.41– 7.31 (m, 2H), 4.38 (td, J = 11.5, 3.6 Hz, 1H), 4.04 (dd, J = 11.9, 4.7 Hz, 1H), 3.86–3.63 (m, 2H), 3.46 (s, 3H), 3.37 (dd, J = 11.1, 3.7 Hz, 1H), 3.03 (t, J = 4.1 Hz, 1H), 2.56–2.47 (m, 1H), 2.41 (t, J = 11.1 Hz, 1H), 2.34 (s, 3H), 1.17 (d, J = 6.4 Hz, 3H), 0.77 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.9, 171.0, 135.6, 133.8, 131.3, 129.0, 127.4, 126.2, 125.3, 125.2, 123.9, 122.3, 60.7, 60.2, 59.5, 51.7, 51.7, 43.3, 42.2, 41.2, 18.4, 13.9; ESI-HRMS m/z calcd for C22H28NO4 [M+H]+: 370.2013, found 370.2006.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H, 13C NMR spectra for substrates and all new compounds (PDF) X-ray crystallographic information for compound 6hb, 6na, 7aa and 7bb (CIF)

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS We thank NSFC (21572089, 21732001, 21672017, 21472072), Shenzhen Science and Technology Innovation Committee

(JCYJ20150529153646078, JSGG20160229150510483), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT_15R28), FRFCU (lzujbky-2016-52, lzujbky-2016-ct02), and “111” Program of MOE for financial support.

REFERENCES (1) (a) Mateeva, N. N.; Winfield, L. L.; Redda, K. K. Curr. Med. Chem. 2005, 12, 551-571. (b) Yoon, K.; Soliman, K.; Redda, K. Drugs Exp. Clin. Res. 2002, 28, 83-90. (c) Aeluri, R.; Ganji, R. J.; Marapaka, A. K.; Pillalamarri, V.; Alla, M.; Addlagatta, A. Eur. J. Med. Chem. 2015, 106, 26-33. (d) Krishna, P. R.; Reddy, P. S. J. Comb. Chem. 2008, 10, 426-435. (e) Dai, L.; Jacob, M. R.; Khan, S. I.; Khan, I. A.; Clark, A. M.; Li, X.-C. J. Nat. Prod. 2011, 74, 2023-2026. (f) Wilson, T. L.; Redda, K. K. Med. Chem. Res. 2003, 12, 69-86. (g) Quirion, J. -C. Sci. Synth. 2007, 33, 629-658. (2) Davis, R.; Markham, A.; Balfour, J. A. Drugs 1996, 51, 10191074. (3) Yang, L.; Wang, D. X.; Zheng, Q. Y.; Pan, J.; Huang, Z. T.; Wang, M. X. Org. Biomol. Chem. 2009, 7, 2628-2634. (4) Cook, D.; Lee, S. T.; Gardner, D. R.; Pfister, J. A.; Welch, K. D.; Green, B. T.; Davis, T. Z.; Panter, K. E. J. Agric. Food Chem. 2009, 57, 1646-1653. (5) (a) Asadi, B.; Landarani-Isfahani, A.; MohammadpoorBaltork, I.; Tangestaninejad, S.; Moghadam, M.; Mirkhani, V.; Amiri Rudbari, H. ACS Comb. Sci. 2017, 19, 356-364. (b) Cuthbertson, J. D.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2013, 52, 1490-1493. (c) Hu, P.; Hu, J.; Jiao, J.; Tong, X. Angew. Chem., Int. Ed. 2013, 52, 5319-5322. (d) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. Chem. - Eur. J. 2013, 19, 16981-16987. (e) Blumel, M.; Chauhan, P.; Hahn, R.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 6012-6015. (f) Fernández de la Pradilla, R.; Simal, C.; Bates, R. H.; Viso, A.; Infantes, L. Org. Lett. 2013, 15, 49364939. (g) Man, Z.; Dai, H.; Shi, Y.; Yang, D.; Li, C.-Y. Org. Lett. 2016, 18, 4962-4965. (h) Wang, Z.; Xu, H.; Su, Q.; Hu, P.; Shao, P.-L.; He, Y.; Lu, Y. Org. Lett. 2017, 19, 3111-3114. (i) Sun, S.; Cheng, C.; Yang, J.; Taheri, A.; Jiang, D.; Zhang, B.; Gu, Y. Org. Lett. 2014, 16, 4520-4523; (j) Khan, M. M.; Khan, S.; Saigal; Iqbal, S. RSC Adv. 2016, 6, 42045-42061. (6) (a) Dudognon, Y.; Du, H.; Rodriguez, J.; Bugaut, X.; Constantieux, T. Chem. Commun. 2015, 51, 1980-1982. (b) Aurrecoechea, J. M.; Suero, R.; de Torres, E. J. Org. Chem. 2006, 71, 8767-8778. (c) Yoshida, M.; Kinoshita, K.; Namba, K. Org. Biomol. Chem. 2014, 12, 2394-2403; (d) Maestre, L.; Fructos, M. R.; Dı́az-Requejo, M. M.; Pérez, P. J. Organometallics 2012, 31, 7839-7843. (e) Stevens, C.; De Kimpe, N. Synlett 1991, 351-352. (f) Jiang, H.-F.; Li, J.-H.; Chen, Z.-W. Tetrahedron 2010, 66, 9721-9728. (g) Ogawa, T.; Matsumoto, K.; Yoshimura, M.; Hatayama, K.; Kitamura, K.; Kita, Y. Tetrahedron Lett. 1993, 34, 1967-1970. (7) (a) Kita, Y.; Maekawa, H.; Yamasaki, Y.; Nishiguchi, I. Tetrahedron 2001, 57, 2095-2102. (b) Tang, Z.; Mayrargue, J.; Alami, M. Synth. Commun. 2007, 37, 3367-3379. (c) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562-4565. (8) (a) Adelbrecht, J.-C.; Craig, D.; Fleming, A. J.; Martin, F. M. Synlett. 2005, 2643-2647. (b) Beceño, C.; Krappitz, T.; Raabe, G; Enders, D. Synthesis 2015, 47, 3813-3821. (c) Timén, Å. S.;



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Fischer, A.; Somfai, P. Chem. Commun. 2003, 12, 1150-1151; (d) Yadagiri, D.; Anbarasan, P. Chem. Sci. 2015, 6, 5847-5852. (9) Harrity, J. P.; Provoost, O. Org. Biomol. Chem. 2005, 3, 1349. (10) Yan, F.; Liang, H.; Song, J.; Cui, J.; Liu, Q.; Liu, S.; Wang, P.; Dong, Y.; Liu, H. Org. Lett. 2017, 19, 86-89. (11) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390-13391. (11) (12) (a) Suryavanshi, P. A.; Sridharan, V.; Maiti, S.; Menéndez, J. C. Chem. -Eur. J. 2014, 20, 8791-8799. (b) Suryavanshi, P. A.; Sridharan, V.; Menéndez, J. C. Chem. -Eur. J. 2013, 19, 13207-13215. (c) Gawande, M. B.; Bonifácio, V. D. B.; Varma, R. S., Nogueira, I. D.; Bundaleski, N.; Ghumman, C. A. A.; Teodoro, O. M. N. D.; Branco, P. S. Green Chemistry 2013, 15, 1226. (13) Allen, C. P.; Benkovics, T.; Turek, A. K.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 12560-12561. (14) (a) Cui, H.-L.; Peng, J.; Feng, X.; Du, W.; Jiang, K.; Chen, Y.-C. Chem. - Eur. J. 2009, 15, 1574-1577. (b) Jiang, L.; Lei, Q.; Huang, X.; Cui, H.-L.; Zhou, X.; Chen, Y.-C. Chem. - Eur. J. 2011, 17, 9489-9493. (c) Wang, K.-K.; Jin, T.; Huang, X.; Ouyang, Q.; Du, W.; Chen, Y.-C. Org. Lett. 2016, 18, 872-875. (d) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (15) (a) Dighe, S. U.; Mukhopadhyay, S.; Kolle, S.; Kanojiya, S.; Batra, S. Angew. Chem., Int. Ed. 2015, 54, 10926-10930. (b) Batchu, H.; Bhattacharyya, S.; Batra, S. Org. Lett. 2012, 14, 6330-6333. (c) Pathak, R.; Madapa, S.; Batra, S. Tetrahedron 2007, 63, 451-460. (d) Singh, V.; Batra, S. Eur. J. Org. Chem. 2007, 2970-2976. (16) (a) GowriSankar, S.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2004, 45, 6949-6953. (b) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1696-1698. (c) Kim, K. H.; Kim, S. Y.; Ryu, J. Y.; Lee, J.; Kim, J. N. Tetrahedron Lett. 2016, 57, 479-482. (d) Lee, H. S.; Kim, E. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 2274-2277. (e) Lee, H. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2012, 53, 497-501. (17) (a) Yang, Y.; Ma, C.; Thumar, N. J.; Hu, W. J. Org. Chem. 2016, 81, 8537-8543. (b) Zhang, L.; Liu, H.; Qiao, G.; Hou, Z.; Liu, Y.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2015, 137, 43164319. (c) Wang, X.; Guo, P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. J. Am. Chem. Soc. 2014, 136, 405-411. (d) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 46144628. (e) Xie, P.; Y. Huang, Org. Biomol. Chem. 2015, 13, 85788595. (f) Ceban, V.; Putaj, P.; Meazza, M.; Pitak, M. B.; Coles, S. J.; Vesely, J.; Rios, R. Chem. Commun. 2014, 50, 7447-7450. (g) Companyó, X.; Geant, P. Y.; Mazzanti, A.; Moyano, A.; Rios, R. Tetrahedron 2014, 70, 75. (18) Li, Y.; Liang, F.; Li, Q.; Xu, Y. C.; Wang, Q. R.; Jiang, L. Org. Lett. 2011, 13, 6082-6085. (19) Wei, H.; Li, Y.; Xiao, K.; Cheng, B.; Wang, H.; Hu, L.; Zhai, H. Org. Lett. 2015, 17, 5974-5977.


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