Iridium-Catalyzed Highly Regioselective and Diastereoselective Allylic

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Iridium-Catalyzed Highly Regioselective and Diastereoselective Allylic Etherification To Access cis-2,6-Disubstituted Dihydropyridinones Wangze Song,*,† Ming Li,† Nan Zheng,†,‡ Karim Ullah,† Junhao Li,† Kun Dong,† and Yubin Zheng‡ †

State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024, P. R. China ‡ School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, P. R. China

J. Org. Chem. 2018.83:12822-12830. Downloaded from pubs.acs.org by REGIS UNIV on 10/19/18. For personal use only.

S Supporting Information *

ABSTRACT: A highly regio- and diastereoselective method to access cis-2,6-disubstituted dihydropyridinones under mild conditions by an iridium-catalyzed allylic etherification is reported. cis-2,6Disubstituted dihydropyridinones are important precursors for the de novo synthesis of the corresponding piperidine alkaloids and iminosugars. This strategy features a broad substrate scope, high yields, and excellent regio- and diastereoselectivities. A π-allyl-Ir intermediate is involved in the mechanism. The strong A1,3-strain from the tosyl group may also favor the formation of cis-products in this transformation.

P

nones and piperidinones remains challenging.1a Two major approaches have been adopted to increase the regio- and stereoselectivities of these reactions and the diversity of accessible products (Scheme 1b). Acyclic precursors could be transformed to piperidine analogues by regio- and stereoselective cyclization reactions such as the amination of alkenes,4 enzyme-catalyzed Mannich reactions,1e,5 and Pictet− Spengler reactions.6 The other approach is the regio- and stereocontrolled substitution of existing rings. Substituted pyridinium ions7 or cyclic imines8 are usually employed as the intermediates for the synthesis of piperidine. Padwa, O’Doherty, and other groups have finished the synthesis of related (±)-all-cis-piperidinol alkaloids or iminosugars through the formation of iminium ions under strongly acidic conditions.9 The Liu group disclosed an enantioselective C− H oxidation process to generate iminium ions.10 However, a general method for accessing pyridinones or piperidinones under mild conditions for strong acid- or oxidant-sensitive substrates is still undeveloped. In this context, other intermediates should be explored instead of the iminium ions, which usually require harsh conditions to form. Recently, Tang’s group developed an Ir-catalyzed dynamic kinetic stereoselective etherification reaction involving novel π-allyl intermediates.11 However, the diastereomeric ratios of the cisproducts are generally low (11:1−1:1) even when using smaller nucleophiles to attack a bulkier group at the C2 position of the lactol. Inspired by Tang’s pioneering work, herein, we combine the above two piperidine synthesis approaches into a regio- and diastereoselective preparation of

iperidine rings, the most prevalent nitrogen-containing heterocycles, are ubiquitous in drugs and natural products.1 For example, (±)-azimic acid, (±)-deoxocassine, (±)-cassine, and (±)-spicigerine share the same all-cispiperidinol structure.2 β-Nojirimycin, β-mannonojirimycin, and β-galactonojirimycin, as the polyhydroxylated piperidines or iminosugars, own the same cis-2,6-disubstituted patterns3 (Scheme 1a). However, the regio- and stereoselective functionalization of piperidine derivatives including pyridiScheme 1. Synthesis of Piperidines from cis-2,6Disubstituted Pyridinones

Received: June 26, 2018 Published: September 20, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

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

entry

catalyst

ligand/additive

solvent

yieldb

drc

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

[Ir(cod)Cl]2 [Ir(cod)Cl]2 [Ir(cod)Cl]2 [Ir(cod)Cl]2 [Ir(cod)Cl]2 − PdCl2(PPh3)2 [Rh(CO)2Cl]2 B(C6F5)3 [Ir(cod)Cl]2 [Ir(cod)Cl]2 [Ir(cod)Cl]2 [Ir(cod)Cl]2

P(PhO)3/(PhO)2P(O)OH −/(PhO)2P(O)OH P(PhO)3/− P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH P(PhO)3/(PhO)2P(O)OH

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 DCM DCE MeCN hexane

86% 74% trace 57% 84% trace 26% trace trace 80% 62% NR NR

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

a

Reaction conditions: 1a (1.3 equiv), 2a (1.0 equiv), solvent (0.1 M), catalyst (2.5 mol %), ligand (10 mol %), additive (0.5 equiv), at rt under an air atmosphere for 12 h. bYields were determined by 1H NMR of the crude mixture with an internal standard. cThe diastereomeric ratios of cis/ trans were determined by 1H NMR of the crude mixture. d0.2 equiv additive was used. e1 equiv additive was used. COD = 1,5-cyclooctadiene, DCE = 1,2-dichloroethane.

cis-2,6-disubstituted products by an aza-Achmatowicz rearrangement/Ir-catalyzed allylic etherification sequence under mild conditions. The aza-Achmatowicz rearrangement reaction could sustainably convert biomass-derived acyclic precursors to the corresponding dihydropyridinones,12 which could further undergo Ir-catalyzed allylic etherification under mild conditions in high regio- and diastereoselectivities to afford cis-2,6disubstituted dihydropyridinones (Scheme 1c). In addition, it is very unique that the π-allyl intermediates derive from cyclic allylic alcohols in this transformation. Compared to the previous reports, this method shows a broader substrate scope and excellent regio- and diastereoselectivities and avoids strongly acidic or oxidative environments. Although the cisproducts could be further transformed to the flat iminium ions for the postmodification in some literatures, this π-allyl-Ir method still provides a significantly complementary and alternative approach to the existing methods, especially for the pH- or oxidant-sensitive substrates in the de novo synthesis of iminosugars. Substrate 2a was prepared by an aza-Achmatowicz rearrangement. The exclusive cis-geometry was controlled by the A1,3-strain from the tosyl group forcing the 2,6-substituents to adopt a pseudoaxial orientation.13 A sulfonamide protecting group provided the necessary stability.14 We first optimized the allylic etherification between benzyl alcohol (1a) and 2a using chloroform (amylene as the stabilizer) as the solvent at room temperature without inert gas protection (Table 1). [Ir(cod)Cl]2 was demonstrated to be the best catalyst with triphenyl phosphite as the ligand and diphenyl phosphate as an additive, giving the desired cis-2,6-disubstituted dihydropyridinone 3a in excellent regio- and diastereoselectivity (Table 1, entry 1). The reaction could also proceed without triphenyl phosphite in spite of the lower yield (Table 1, entry 2). The reaction did not proceed if the diphenyl phosphate or [Ir(cod)Cl]2 was removed (Table 1, entries 3 and 6). The amounts of the additive were also examined (Table 1, entries 4 and 5). Using Pd(II) as the catalyst provided a very low yield but good diastereoselectivity (Table 1, entry 7). None of the desired

product was obtained in this transformation when Rh(I) or B(C6F5)3 was used as the catalyst (Table 1, entries 8 and 9). The reaction could also proceed smoothly with good regioand diastereoselectivities in other solvents such as dichloromethane and 1,2-dichloroethane (Table 1, entries 10 and 11). However, the reaction failed to occur in a more polar solvent (MeCN) or nonpolar solvents (hexane) due to the difficult combination of the substrates with Ir(I) (Table 1, entries 12 and 13). Remarkably, this reaction could be carried out under mild conditions without the exclusion of air. With the optimized conditions in hand, we explored the scope of the Ir-catalyzed regio- and diastereoselective allylic etherification. Various nucleophiles 1 were used as substrates at room temperature without inert gas protection and exclusively afforded cis-2,6-disubstituted pyridinones in good yields (up to 86%) and excellent diastereoselectivities (more than 20:1) (Scheme 2). When primary alcohols were used as nucleophiles, the electronic effects were not obvious for the para- and metasubstituted benzyl alcohols although the yield (3d) for the para-nitrobenzyl alcohol was much lower (61%) than others (3a−3c, 3e, 3f). The yields (3g, 3h) for ortho-substituted benzyl alcohols were slightly lower than those for the para- and meta-substituted derivatives. Good yields (3i, 3j) could be achieved using disubstituted benzyl alcohols as substrates. The yield of 3k dropped to 64% when furfuryl alcohol was used as the substrate. The diastereoselectivity decreased to 3:1 (3l) when 2-phenylethanol was used as the substrate. Methanol, ethanol, and n-butyl alcohol worked well and afforded 3m, 3n, and 3o in similar yields with excellent diastereoselectivities. The absolute cis-geometries of the products were confirmed by analysis of 3m and 3n (see the Supporting Information). When secondary alcohols were used as nucleophiles, the yields could be further increased to 82% (3p, 3q) and 77% (3r). However, with tertiary alcohol as the nucleophile, the reaction required a higher temperature and produced a lower yield (52%, 3s) with excellent diastereoselectivity. Encouragingly, allyl alcohol could participate in this reaction smoothly without other side reactions occurring (82%, 3t). In addition to oxygen 12823

DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

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The Journal of Organic Chemistry Scheme 2. Substrate Scope of the Nucleophilesa

Scheme 3. Substrate Scope of the Hemiaminalsa

a Conditions: 1 (1.3 equiv), 2 (1.0 equiv), [Ir(cod)Cl]2 (2.5 mol %), P(PhO)3 (10 mol %), (PhO)2P(O)OH (0.5 equiv), CHCl3 (0.1 M) rt under an air atmosphere for 12−24 h. The diastereomeric ratios of cis/trans were >20:1 unless otherwise noted (determined by 1H NMR of the crude reaction mixture).

Subsequently, other nucleophiles were screened (Scheme 4a). No reaction was observed when using nitrogen or Scheme 4. Application of the Ir-Catalyzed Regio- and Diastereoselective Allylic Etherification

a Conditions: 1 (1.3 equiv), 2 (1.0 equiv), [Ir(cod)Cl]2 (2.5 mol %), P(PhO)3 (10 mol %), (PhO)2P(O)OH (0.5 equiv), CHCl3 (0.1 M) rt under an air atmosphere for 12−24 h. The diastereomeric ratios of cis/trans were >20:1 unless otherwise noted (determined by 1H NMR of the crude reaction mixture). Yield of isolated product. bThe diastereomeric ratios of cis/trans were 3:1. cThe reaction was conducted at 60 °C.

nucleophiles, thiols were also evaluated in this transformation. Benzyl mercaptan and para-chloro and para-methoxy benzyl mercaptan could give the desired cis-products in moderate yields and excellent diastereoselectivities (3u−3w). Encouragingly, dodecyl mercaptan (DDM) could also achieve this transformation in moderate yield (3x). The scope of hemiaminals was next briefly investigated (Scheme 3). The use of alkyl or aryl substituted hemiaminals could also provide the desired cis-2,6-disubstituted products in good yields and excellent diastereoselectivities. The yield with the ethyl-substituted hemiaminal (83%, 3y) was similar to that of the methyl-substituted one (86%, 3b). Cyclopropyl and nbutyl substituted hemiaminals still displayed good yields and excellent diastereoselectivities for the present Ir-catalyzed reaction (75% for 3z, 74% for 3aa). However, when phenylor p-tolyl-substituted hemiaminals were used as substrates, the yields dramatically decreased (62% for 3ab, 66% for 3ac). The broad substrate scope offers potential opportunities for the postmodification of the cis-2,6-disubstituted dihydropyridinones.

phosphorus nucleophiles, possibly due to the weaker nucleophilicities of these species. Surprisingly, dimer product 3ad was isolated in similar yields with excellent diastereoselectivities in these two examples. Cyclic allylic alcohol 2a could serve as both the nucleophile and electrophile to form dimer product 3ad. When 1,3-propanediol was used as the nucleophile in a 0.5 equiv amount compared to 2a (1 equiv), only one hydroxyl group could undergo the reaction 12824

DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

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The Journal of Organic Chemistry

In summary, we have developed a highly regio- and diastereoselective iridium-catalyzed allylic etherification method to access cis-2,6-disubstituted dihydropyridinones under mild conditions. cis-2,6-Disubstituted dihydropyridinones are important precursors for the de novo synthesis of the corresponding piperidine alkaloids and iminosugars. This strategy features a broad substrate scope, high yields, and excellent regio- and diastereoselectivities. The ionization step, as the rate- and stereodetermining step in the Ir-catalyzed allylic etherification, may be the cause of the high diastereoselectivities. The strong A1,3-strain from the tosyl group may also play a key role in this transformation. Comprehensive mechanistic studies and advanced theoretical calculations for the catalysts and intermediates are underway in our laboratory.

(3ae). It was difficult to obtain the symmetric diethers. Unfortunately, carbon nucleophiles, such as 1-methylindole and diethyl malonate, provided messy results. The applicability of this reaction was also examined. cis-2,6-Disubstituted dihydropyridinone 3a could be diastereoselectively reduced to allylic alcohol 4a. Treatment with another nucleophile, such as the sodium azide or a Grignard reagent, afforded functionalized piperidiones in good regio- and diastereoselectivities (Scheme 4b). Notably, this is the first diastereoselective method for accessing 3-trans-azide piperidione,15 which could be further reduced to the corresponding amine or undergo “click chemistry”. The steric hindrance between the pseudoaxially oriented substituents at C2 and C6, and the equatorial approach of the nucleophile, may be the cause of the excellent diastereoselectivities of the 1,4-addition.14 cis-2,6-Disubstituted dihydropyridinones could be prepared by the Ir-catalyzed allylic etherification in excellent regio- and diastereoselectivities under mild conditions. To further understand the Ir-catalyzed process, the mechanism is proposed in Scheme 5. The Ir catalyst coordinates with the olefin of

■

EXPERIMENTAL SECTION

General Information. Unless otherwise noted, all commercially available reagents and solvents were used without further additional purification. Thin layer chromatography was performed using precoated silica gel plates and visualized with UV light at 254 nm. Flash column chromatography was performed with silica gel (40−60 μm). 1H and 13C nuclear magnetic resonance spectra (NMR) were obtained on a Bruker Avance II 400 MHz or Bruker Avance III 500 MHz recorded in ppm (δ) downfield of TMS (δ = 0) in CDCl3 unless noted otherwise. Signal splitting patterns were described as singlet (s), doublet (d), triplet(t), quartet (q), quintet (quint), multiplet (m), and broad (br) with coupling constants (J) in hertz (Hz). High resolution mass spectra (HRMS) were performed by an Agilent apparatus (TOF mass analyzer type) on an Electron Spray Injection (ESI) mass spectrometer. Melting points were determined by an XP-4 melting point apparatus. General Procedure for the Preparation of the Hemiaminals. To a stirred solution of 2-furfural (1 equiv, 30 mmol) in toluene (30 mL) were added p-toluenesulfonamide (1 equiv, 30 mmol) and ptoluenesulfonic acid (0.05 equiv, 1.5 mmol). The mixture was placed in a round-bottom flask with a Dean−Stark trap and heated at reflux for 20 h. After the mixture cooled to room temperature, the solvent was removed under reduced pressure to give N-1-furan-2-ylmethylene-4-methylbenezenesulfonamide as a brown solid. It could be used directly in the next step without further purification. To a stirred solution of N-1-furan-2-ylmethylene-4-methylbenezenesulfonamide (1 equiv, 8 mmol) in THF (32 mL) was added RMgBr (2 equiv, 16 mmol) at 0 °C. The mixture was stirred at room temperature. When the reaction was completed as determined by TLC, the mixture was quenched with a saturated aqueous NaHCO3 solution (30 mL) and then extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by column chromatography gave the corresponding benzenesulfonamide. To a stirred solution of benezenesulfonamide (1 equiv, 1 mmol) in DCM (4 mL) was added m-CPBA (2 equiv, 2 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The mixture was quenched with a saturated aqueous NaHCO3 solution (10 mL) and then extracted with ethyl acetate (3 × 20 mL). The organic phase was washed by brine, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by column chromatography gave the corresponding cis-hemiaminals. All substrates 2a−2ac were known compounds and prepared by a similar procedure.18 General Procedure of Iridium-Catalyzed Etherification. Standard conditions: To a vial containing [Ir(cod)Cl]2 (3.4 mg, 0.025 equiv, 0.005 mmol) and triphenyl phosphite (6.2 mg, 0.1 equiv, 0.02 mmol) in CHCl3 (2 mL) under air were added cis-6-hydroxy-2methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (56 mg, 1 equiv, 0.2 mmol), diphenyl phosphate (25 mg, 0.5 equiv, 0.1 mmol), and benzyl alcohol (28 mg, 1.3 equiv, 0.26 mmol). It was necessary to add benzyl alcohol in the last step. The vial was closed, and the mixture was stirred at rt for 12 h. The mixture was purified with flash column

Scheme 5. Proposed Mechanism for the Ir-Catalyzed Diastereoselective Allylic Etherification

substrates 2 from the bottom face opposite the R-group to avoid steric interactions to generate intermediate A. Then, πallyl-Ir intermediate B is formed by oxidative addition. Diphenyl phosphate, as the Brønsted acid, could activate the allylic alcohol and promote the formation of intermediate B.16 The nucleophiles prefer to attack intermediate B from the top face leading to the excellent cis-diastereoselectivities. Intermediate C is generated by nucleophilic substitution at the C6 position rather than the C4 position followed by reductive elimination.16 It may be due to the unfavorable electronic factors in the C4 position. cis-2,6-Disubstituted dihydropyridinones 3 are derived from intermediate C. Undesirable intermediate B′ could be formed by the dissociation/ association of Ir, which would result in trans-products 3′ and decrease the diastereoselectivities. The Brønsted acid mediated epimerization between 2 and trans-2 may be the alternative mechanism to generate the undesirable intermediate B′. It is known that the rate- and stereodetermining step in transitionmetal-catalyzed allylations is either the ionization or nucleophilic addition step.17 From the experimental observations, the ionization step is likely the rate- and stereodetermining step in the present Ir-catalyzed allylic etherification. In addition, the strong A1,3-strain of the tosyl group may force the nucleophiles and R-group to adopt a pseudoaxial orientation, which also exclusively provides the cis-products. 12825

DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

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The Journal of Organic Chemistry

126.7, 78.8, 69.3, 57.3, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H20ClNO4SNa 428.0694, found 428.0697. cis-2-Methyl-6-((4-nitrobenzyl)oxy)-1-tosyl-1,6-dihydropyridin3(2H)-one (3d). 51 mg, cis/trans > 20:1, 61% yield, yellow solid, mp = 167−169 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 8.22 (d, J = 8.0 Hz, 2H), 7.56−7.52 (m, 4H), 7.23 (d, J = 8.0 Hz, 2H), 6.81 (dd, J = 8.0, 4.0 Hz, 1H), 5.85 (d, J = 12.0 Hz, 1H), 5.74 (d, J = 4.0 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 4.85 (d, J = 12.0 Hz, 1H), 4.33 (q, J = 8.0 Hz, 1H), 2.37 (s, 3H), 1.59 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.0, 147.6, 144.6, 144.5, 141.9, 135.8, 130.2, 128.3, 126.9, 126.8, 123.8, 79.1, 68.6, 57.2, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H20N2O6SNa 439.0934, found 439.0937. cis-6-((3-Methoxybenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3e). 69 mg, cis/trans > 20:1, 86% yield, white solid, mp = 94−96 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.58 (d, J = 8.0 Hz, 2H), 7.31−7.28 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.03−6.99 (m, 2H), 6.90−6.88 (m, 1H), 6.81 (dd, J = 8.0, 4.0 Hz, 1H), 5.84 (d, J = 8.0 Hz, 1H), 5.78 (d, J = 4.0 Hz, 1H), 4.95 (d, J = 12.0 Hz, 1H), 4.75 (d, J = 8.0 Hz, 1H), 4.38 (q, J = 8.0 Hz, 1H), 3.84 (s, 3H), 2.40 (s, 3H), 1.65 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.5, 159.8, 144.2, 142.7, 138.6, 136.1, 130.1, 129.6, 126.9, 126.6, 120.5, 113.7, 113.7, 78.9, 70.1, 57.3, 56.2, 21.5, 21.1. HRMS (ESITOF) m/z: [M + Na]+ calcd for C21H23NO5SNa 424.1189, found 424.1199. cis-6-((3-Chlorobenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3f). 67 mg, cis/trans > 20:1, 83% yield, white solid, mp = 109−111 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.58 (d, J = 8.0 Hz, 2H), 7.41 (s, 1H), 7.32−7.28 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H), 6.82 (dd, J = 8.0, 4.0 Hz, 1H), 5.86 (d, J = 12.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 4.95 (d, J = 12.0 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.37 (q, J = 8.0 Hz, 1H), 2.40 (s, 3H), 1.63 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.3, 144.3, 142.4, 139.2, 136.0, 134.4, 130.1, 129.8, 128.2, 128.1, 126.8, 126.7, 126.2, 79.0, 69.3, 57.2, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H20ClNO4SNa 428.0694, found 428.0696. cis-2-Methyl-6-((2-methylbenzyl)oxy)-1-tosyl-1,6-dihydropyridin-3(2H)-one (3g). 58 mg, cis/trans > 20:1, 75% yield, white solid, mp = 72−76 °C. 1H NMR (500 MHz, CDCl3, TMS): δ 7.57 (d, J = 5.0 Hz, 2H), 7.40−7.38 (m, 1H), 7.25−7.19 (m, 5H), 6.77 (dd, J = 8.0, 4.0 Hz, 1H), 5.82−5.79 (m, 2H), 4.95 (d, J = 10.0 Hz, 1H), 4.76 (d, J = 15.0 Hz, 1H), 4.36 (q, J = 10.0 Hz, 1H), 2.38 (s, 6H), 1.61 (d, J = 10.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.4, 144.2, 142.7, 137.0, 136.2, 135.1, 130.4, 130.0, 128.9, 128.3, 126.7, 126.5, 126.0, 79.2, 68.8, 57.3, 21.5, 21.1, 19.0. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H23NO4SNa 408.1240, found 408.1245. cis-6-((2-Bromobenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3h). 65 mg, cis/trans > 20:1, 72% yield, white solid, mp = 124−126 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.59−7.56 (m, 3H), 7.45−7.43 (m, 1H), 7.32−7.29 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.19−7.16 (m, 1H), 6.85 (dd, J = 12.0, 4.0 Hz, 1H), 5.85−5.82 (m, 2H), 4.97 (d, J = 12.0 Hz, 1H), 4.83 (d, J = 12.0 Hz, 1H), 4.36 (q, J = 8.0 Hz, 1H), 2.38 (s, 3H), 1.59 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.4, 144.2, 142.4, 136.5, 136.1, 132.9, 130.1, 130.0, 129.6, 127.5, 126.9, 126.7, 123.7, 79.6, 70.3, 57.3, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H20BrNO4SNa 472.0194, found 472.0195. cis-6-((3,5-Dimethoxybenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3i). 65 mg, cis/trans > 20:1, 75% yield, white solid, mp = 96−98 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.54 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.77 (dd, J = 8.0, 4.0 Hz, 1H), 6.55 (d, J = 4.0 Hz, 2H), 6.41 (t, J = 4.0 Hz, 1H), 5.80 (d, J = 12.0 Hz, 1H), 5.73 (d, J = 4.0 Hz, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 12.0 Hz, 1H), 4.34 (q, J = 8.0 Hz, 1H), 3.78 (s, 6H), 2.37 (s, 3H), 1.61 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.4, 160.9, 144.2, 142.7, 139.4, 136.1, 130.1, 126.9, 126.6, 106.0, 100.1, 78.8, 70.1, 57.3, 55.4, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H25NO6SNa 454.1295, found 454.1296. cis-6-((2,6-Dichlorobenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3j). 61 mg, cis/trans > 20:1, 70% yield, yellow solid,

chromatography (20% EtOAc in petroleum ether) to give the pure product (60 mg, 81%) as a white solid. General Procedure for the Diastereodivergent Synthesis of Piperidines or Piperidinones. To a stirred solution of cis-6(benzyloxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one 3a (41 mg, 1 equiv, 0.11 mmol) in MeOH (1 mL) was added cerium trichloride (27.2 mg, 1 equiv, 0.11 mmol). The solution was chilled to −40 °C, and NaBH4 (4.7 mg, 1.2 equiv, 0.13 mmol) was added. The solution was stirred for 2 h at −40 °C and then quenched with saturated NaHCO3 (4 mL). The mixture was extracted with ethyl acetate (4 × 5 mL). The combined organic layers were washed with brine (1 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified with flash column chromatography (20% EtOAc in petroleum ether) to give the pure product 4a (22.6 mg, 60%) as a colorless oil. To a stirred solution of cis-6-(benzyloxy)-2-methyl-1-tosyl-1,6dihydropyridin-3(2H)-one 3a (80 mg, 1 equiv, 0.225 mmol) in AcOH (0.6 mL) and water (0.4 mL) was added NaN3 (38.8 mg, 2.7 equiv, 0.6 mmol). The solution was stirred overnight at room temperature and then quenched with saturated NaHCO3 (4 mL). The mixture was extracted with ethyl acetate (4 × 5 mL). The combined organic layers were washed with brine (1 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified with flash column chromatography (20% EtOAc in petroleum ether) to give the pure product 4b (52.2 mg, 56%) as a colorless oil. To a stirred solution of CuI (11.5 mg, 1 equiv, 0.05 mmol) in THF (1.5 mL) was added dropwise EtMgBr (2.4 equiv, 0.12 mmol) at −78 °C. The solution was stirred at −20 °C over 30 min, and then the solution was cooled to −78 °C again. cis-6-(Benzyloxy)-2-methyl-1tosyl-1,6-dihydropyridin-3(2H)-one 3a (18.5 mg, 1 equiv, 0.05 mmol) in THF (1.5 mL) was added, and the mixture was stirred at −78 °C for 1 h. The reaction was quenched with a saturated NH4Cl (4 mL). The mixture was extracted with ethyl acetate (4 × 5 mL). The combined organic layers were washed with brine (1 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified with flash column chromatography (20% EtOAc in petroleum ether) to give the pure product 4c (16.7 mg, 83%) as a colorless oil. cis-6-(Benzyloxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3a). 60 mg, cis/trans > 20:1, 81% yield, white solid, mp = 132−134 °C. 1H NMR (500 MHz, CDCl3, TMS): δ 7.56 (d, J = 10.0 Hz, 2H), 7.42−7.37 (m, 4H), 7.34−7.30 (m, 1H), 7.24 (d, J = 10.0 Hz, 2H), 6.78 (dd, J = 10.0, 5.0 Hz, 1H), 5.82 (d, J = 10.0 Hz, 1H), 5.77 (d, J = 5.0 Hz, 1H), 4.96 (d, J = 15.0 Hz, 1H), 4.74 (d, J = 15.0 Hz, 1H), 4.36 (q, J = 5.0 Hz, 1H), 2.38 (s, 3H), 1.63 (d, J = 10.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.4, 144.2, 142.7, 137.1, 136.2, 130.0, 128.6, 128.3, 128.1, 126.9, 126.5, 78.9, 70.2, 57.3, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H21NO4SNa 394.1084, found 394.1093. cis-6-((4-Methoxybenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3b). 69 mg, cis/trans > 20:1, 86% yield, white solid, mp = 170−171 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.58 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.77 (dd, J = 8.0, 4.0 Hz, 1H), 5.82 (d, J = 12.0 Hz, 1H), 5.76 (d, J = 4.0 Hz, 1H), 4.91 (d, J = 8.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.38 (q, J = 8.0 Hz, 1H), 3.84 (s, 3H), 2.40 (s, 3H), 1.65 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.4, 159.6, 144.2, 142.9, 136.1, 130.1, 130.0, 129.1, 126.9, 126.5, 114.0, 78.6, 69.9, 57.3, 55.3, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H23NO5SNa 424.1189, found 424.1199. cis-6-((4-Chlorobenzyl)oxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3c). 63 mg, cis/trans > 20:1, 78% yield, white solid, mp = 160−162 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.53 (d, J = 8.0 Hz, 2H), 7.32 (s, 4H), 7.22 (d, J = 8.0 Hz, 2H), 6.75 (dd, J = 8.0, 4.0 Hz, 1H), 5.80 (d, J = 12.0 Hz, 1H), 5.70 (d, J = 4.0 Hz, 1H), 4.89 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.33 (q, J = 8.0 Hz, 1H), 2.36 (s, 3H), 1.59 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.3, 144.3, 142.5, 136.0, 135.6, 133.9, 130.1, 129.6, 128.7, 126.8, 12826

DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

Note

The Journal of Organic Chemistry mp = 160−162 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.64 (d, J = 12.0 Hz, 2H), 7.36−7.34 (m, 2H), 7.28 (d, J = 12.0 Hz, 2H), 7.25− 7.21 (m, 1H), 6.87 (dd, J = 8.0, 4.0 Hz, 1H), 5.96 (d, J = 8.0 Hz, 1H), 5.84 (d, J = 8.0 Hz, 1H), 5.35 (d, J = 12.0 Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.40 (q, J = 8.0 Hz, 1H), 2.41 (s, 3H), 1.68 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.4, 144.2, 142.3, 136.9, 136.2, 132.6, 130.3, 130.1, 128.5, 126.9, 126.6, 80.6, 66.4, 57.3, 21.6, 21.4. HRMS (ESI-TOF) m/z: (M + Na) + calcd for C20H19Cl2NO4SNa 462.0304, found 462.0306. cis-6-(Furan-2-ylmethoxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3k). 46 mg, cis/trans > 20:1, 64% yield, yellow solid, mp = 91−93 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.59 (d, J = 8.0 Hz, 2H), 7.48−7.47 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.77 (dd, J = 8.0, 4.0 Hz, 1H), 6.53 (d, J = 4.0 Hz, 1H), 6.41−6.40 (m, 1H), 5.82 (d, J = 8.0 Hz, 1H), 5.78 (d, J = 4.0 Hz, 1H), 4.86 (d, J = 16.0 Hz, 1H), 4.78 (d, J = 16.0 Hz, 1H), 4.37 (q, J = 8.0 Hz, 1H), 2.41 (s, 3H), 1.63 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.4, 150.4, 144.2, 143.4, 142.5, 136.0, 130.1, 126.8, 126.7, 110.7, 110.5, 78.3, 61.7, 57.3, 21.6, 21.0. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H19NO5SNa 384.0876, found 384.0882. cis-2-Methyl-6-phenethoxy-1-tosyl-1,6-dihydropyridin-3(2H)one (3l). 55 mg, cis/trans = 3:1, 72% yield, white solid, mp = 147−149 °C. 1H NMR (400 MHz, CDCl3, TMS): major isomer δ 7.51 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.26−7.20 (m, 5H), 6.74 (dd, J = 12.0, 4.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 5.63 (d, J = 4.0 Hz, 1H), 4.28−4.22 (m, 1H), 4.17−4.11 (m, 1H), 3.92−3.86 (m, 1H), 2.92 (q, J = 8.0 Hz, 2H), 2.36 (s, 3H), 1.38 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.5, 144.1, 142.9, 142.6, 136.2, 130.0, 129.1, 128.4, 126.8, 126.8, 126.5, 126.4, 126.4, 79.3, 69.2, 64.0, 57.2, 57.2, 36.0, 21.5, 20.8, 20.6, 14.9. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H23NO4SNa 408.1240, found 408.1246. cis-6-Methoxy-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3m). 43 mg, cis/trans > 20:1, 72% yield, white solid. 1H NMR (400 MHz, CDCl3, TMS): δ 7.55 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.82 (dd, J = 8.0, 4.0 Hz, 1H), 5.80 (d, J = 8.0 Hz, 1H), 5.56 (d, J = 4.0 Hz, 1H), 4.29 (q, J = 8.0 Hz, 1H), 3.55 (s, 3H), 2.36 (s, 3H), 1.54 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.5, 144.1, 142.5, 136.2, 130.0, 126.8, 126.6, 80.7, 57.3, 56.0, 21.5, 20.8. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H17NO4SNa 318.0771, found 318.0771. Compound 3m is a known compound, and the proton and carbon spectrum are fully consistent with literature reported.9 The regio- and diastereoselectivity are absolutely determined in this case. cis-6-Ethoxy-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3n). 44 mg, cis/trans > 20:1, 71% yield, white solid. 1H NMR (400 MHz, CDCl3, TMS): δ 7.56 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.84 (dd, J = 8.0, 4.0 Hz, 1H), 5.82 (d, J = 12.0 Hz, 1H), 5.69 (d, J = 4.0 Hz, 1H), 4.31 (q, J = 4.0 Hz, 1H), 4.05−4.02 (m, 1H), 3.76−3.70 (m, 1H), 2.40 (s, 3H), 1.59 (d, J = 8.0 Hz, 3H), 1.28 (t, J = 4.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.6, 144.1, 142.9, 136.3, 130.0, 126.8, 126.5, 79.2, 64.0, 57.2, 21.5, 20.8, 14.9. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H19NO4SNa 332.0927, found 332.0934. Compound 3n is a known compound, and the proton and carbon spectrum are fully consistent with literature reported.9 The regio- and diastereoselectivity are absolutely determined in this case. cis-6-Butoxy-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3o). 47 mg, cis/trans > 20:1, 70% yield, white solid, mp = 96−98 °C. 1 H NMR (400 MHz, CDCl3, TMS): δ 7.57 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.82 (dd, J = 8.0, 4.0 Hz, 1H), 5.82 (d, J = 12.0 Hz, 1H), 5.67 (d, J = 8.0 Hz, 1H), 4.31 (q, J = 8.0 Hz, 1H), 3.98− 3.94 (m, 1H), 3.67−3.62 (m, 1H), 2.39 (s, 3H), 1.63−1.59 (m, 2H), 1.57 (d, J = 8.0 Hz, 3H), 1.43−1.37 (m, 2H), 0.95 (t, J = 8.0 Hz, 3H). 13 C NMR (125 MHz, CDCl3): δ 195.6, 144.1, 142.9, 136.3, 130.0, 126.9, 126.4, 79.5, 66.6, 57.2, 31.5, 21.5, 20.9, 19.4, 13.9. HRMS (ESITOF) m/z: [M + Na]+ calcd for C17H23NO4SNa 360.1240, found 360.1245. cis-6-Isopropoxy-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3p). 53 mg, cis/trans > 20:1, 82% yield, white solid, mp = 147−149 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.57 (d, J = 12.0 Hz, 2H),

7.26 (d, J = 8.0 Hz, 2H), 6.77 (dd, J = 12.0, 4.0 Hz, 1H), 5.80 (d, J = 12.0 Hz, 1H), 5.76 (d, J = 4.0 Hz, 1H), 4.36−4.29 (m, 2H), 2.40 (s, 3H), 1.60 (d, J = 12.0 Hz, 3H), 1.30 (d, J = 8.0 Hz, 3H), 1.24 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.6, 144.0, 143.4, 136.2, 130.0, 126.8, 126.3, 68.9, 57.2, 23.0, 21.5, 21.2, 20.6. HRMS (ESI-TOF) m/z: (M + Na)+ calcd for C16H21NO4SNa 346.1084, found 346.1090. cis-6-(Cyclopentyloxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3q). 57 mg, cis/trans > 20:1, 82% yield, white solid, mp = 55−57 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.51 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.70 (dd, J = 8.0, 4.0 Hz, 1H), 5.73 (d, J = 12.0 Hz, 1H), 5.63 (d, J = 4.0 Hz, 1H), 4.55−4.52 (m, 1H), 4.28− 4.22 (m, 1H), 2.33 (s, 3H), 1.86−1.80 (m, 2H), 1.66−1.53 (m, 6H), 1.52 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.8, 144.0, 143.5, 136.2, 130.0, 126.8, 126.3, 78.8, 77.7, 57.3, 32.9, 31.8, 23.8, 23.6, 21.5, 20.9. HRMS (ESI-TOF) m/z: (M + Na)+ calcd for C18H23NO4SNa 372.1240, found 372.1244. cis-6-(Cyclohexyloxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3r). 56 mg, cis/trans > 20:1, 77% yield, colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 7.58 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.77 (dd, J = 8.0, 4.0 Hz, 1H), 5.83−5.80 (m, 2H), 4.35 (q, J = 8.0 Hz, 1H), 4.02−3.97 (m, 1H), 2.40 (s, 3H), 2.13−2.10 (m, 1H), 1.89−1.88 (m, 1H), 1.78−1.75 (m, 2H), 1.60 (d, J = 8.0 Hz, 3H), 1.39−1.25 (m, 6H). 13C NMR (125 MHz, CDCl3): δ 195.7, 144.0, 143.6, 136.3, 130.0, 126.8, 126.2, 76.4, 74.5, 57.3, 33.1, 30.9, 25.7, 24.2, 23.8, 21.5, 21.2. HRMS (ESI-TOF) m/z: (M + Na)+ calcd for C19H25NO4SNa 386.1397, found 386.1381. cis-6-(tert-Butoxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)one (3s). The reaction was set at 60 °C. 35 mg, cis/trans > 20:1, 52% yield, white solid, mp = 88−90 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.57 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.67 (dd, J = 8.0, 4.0 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H), 5.67 (d, J = 8.0 Hz, 1H), 4.30 (q, J = 8.0 Hz, 1H), 2.39 (s, 3H), 1.63 (d, J = 8.0 Hz, 3H), 1.42 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 196.0, 144.7, 144.0, 135.9, 129.9, 127.2, 125.4, 77.4, 74.7, 57.8, 28.5, 21.5, 21.4. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H23NO4SNa 360.1240, found 360.1243. cis-6-(Allyloxy)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3t). 53 mg, cis/trans > 20:1, 82% yield, white solid, mp = 102−104 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.57 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.83 (dd, J = 8.0, 4.0 Hz, 1H), 5.99−5.91 (m, 1H), 5.82 (d, J = 12.0 Hz, 1H), 5.72 (d, J = 4.0 Hz, 1H), 5.40 (d, J = 16.0 Hz, 1H), 5.27 (d, J = 8.0 Hz, 1H), 4.46−4.42 (m, 1H), 4.36− 4.22 (m, 2H), 2.40 (s, 3H), 1.59 (d, J = 8.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.5, 144.1, 142.7, 136.2, 133.4, 130.0, 126.8, 126.6, 118.2, 78.7, 68.9, 57.2, 21.5, 20.9. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H19NO4SNa 344.0927, found 344.0930. cis-6-(Benzylthio)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)one (3u). 43 mg, cis/trans > 20:1, 55% yield, yellow solid, mp = 145− 147 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.53 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.34−7.30 (m, 2H), 7.26−7.21 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.61 (dd, J = 8.0, 4.0 Hz, 1H), 5.73 (d, J = 4.0 Hz, 1H), 5.65 (d, J = 12.0 Hz, 1H), 4.40 (q, J = 8.0 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 12.0 Hz, 1H), 2.34 (s, 3H), 1.63 (d, J = 4.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.1, 144.3, 144.1, 137.5, 136.9, 130.1, 129.3, 128.7, 127.5, 127.0, 125.0, 58.1, 57.8, 36.9, 21.6, 20.6. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H21NO3S2Na 410.0855, found 410.0866. cis-6-((4-Chlorobenzyl)thio)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3v). 46 mg, cis/trans > 20:1, 55% yield, white solid, mp = 153−155 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.58 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.36−7.34 (m, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.70 (dd, J = 8.0, 4.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 5.74 (d, J = 8.0 Hz, 1H), 4.46 (q, J = 8.0 Hz, 1H), 4.24 (d, J = 12.0 Hz, 1H), 4.03 (d, J = 12.0 Hz, 1H), 2.41 (s, 3H), 1.71 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 194.9, 144.4, 143.7, 136.1, 135.8, 133.3, 130.7, 130.1, 128.9, 126.9, 125.3, 58.1, 57.7, 36.1, 21.5, 20.6. HRMS (ESI-TOF) m/z: [M + Na] + calcd for C20H20ClNO3S2Na 444.0466, found 444.0473. 12827

DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

Note

The Journal of Organic Chemistry

(ESI-TOF) m/z: [M + Na]+ calcd for C26H25NO5SNa 486.1346, found 486.1347. cis-6-((4-Methoxybenzyl)oxy)-2-(p-tolyl)-1-tosyl-1,6-dihydropyridin-3(2H)-one (3ac). 63 mg, cis/trans > 20:1, 66% yield, white solid, mp = 148−150 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.63 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.28−7.26 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.80−6.76 (m, 3H), 6.01 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 4.0 Hz, 1H), 5.54 (s, 1H), 4.46 (d, J = 4.0 Hz, 2H), 3.81 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 193.1, 159.4, 144.3, 143.3, 137.8, 136.2, 134.3, 130.1, 130.1, 129.2, 128.9, 128.1, 128.0, 126.9, 113.6, 78.8, 69.8, 62.9, 56.3, 21.6, 21.1. HRMS (ESI-TOF) m/z: (M + Na)+ calcd for C27H27NO5SNa 500.1502, found 500.1509. cis-2-Methyl-6-((cis-6-methyl-5-oxo-1-tosyl-1,2,5,6-tetrahydropyridin-2-yl)oxy)-1-tosyl-1,6-dihydropyridin-3(2H)-one (3ad). The reaction was set at 60 °C. 33 mg, cis/trans > 20:1, 60% yield for nitrogen as nucleophile, 61% yield for phosphorus as nucleophile, white solid, mp = 158−160 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.67 (d, J = 8.0 Hz, 4H), 7.29 (d, J = 8.0 Hz, 4H), 6.91 (dd, J = 8.0, 4.0 Hz, 2H), 6.33 (d, J = 4.0 Hz, 2H), 5.89 (d, J = 12.0 Hz, 2H), 4.35 (q, J = 8.0 Hz, 2H), 2.40 (s, 6H), 1.57 (d, J = 4.0 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 195.1, 144.5, 143.0, 136.0, 130.2, 126.8, 125.7, 80.0, 57.3, 22.2, 21.6. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C26H28N2O7S2Na 567.1230, found 567.1239. cis-6-(3-Hydroxypropoxy)-2-methyl-1-tosyl-1,6-dihydropyridin3(2H)-one (3ae). The reaction was set at 60 °C. 20 mg, cis/trans > 20:1, 60% yield, white solid, mp = 90−92 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.49 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.75 (dd, J = 12.0, 4.0 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 5.61 (d, J = 4.0 Hz, 1H), 4.26−4.20 (m, 1H), 4.09−4.04 (m, 1H), 3.77−3.69 (m, 3H), 2.32 (s, 3H), 1.86−1.82 (m, 2H), 1.66 (br s, 1H), 1.50 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.3, 144.2, 142.4, 136.1, 130.1, 126.8, 126.6, 79.5, 66.7, 60.8, 57.1, 32.1, 21.5, 20.9. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H21NO5SNa 362.1033, found 362.1031. cis-6-(Benzyloxy)-2-methyl-1-tosyl-1,2,3,6-tetrahydropyridin-3ol (4a). 22.6 mg, dr > 20:1, 60% yield, colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 7.69 (d, J = 8.0 Hz, 2H), 7.36−7.29 (m, 5H), 7.25 (d, J = 8.0 Hz, 2H), 5.80−5.76 (m, 1H), 5.61−5.57 (m, 2H), 4.86 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.08−4.06 (m, 1H), 3.89−3.86 (m, 1H), 2.40 (s, 3H), 1.75 (d, J = 8.0 Hz, 1H), 1.27 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 143.8, 138.0, 137.9, 130.5, 129.8, 128.4, 127.9, 127.7, 127.1, 125.6, 79.3, 70.4, 66.3, 49.7, 21.6, 13.3. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H23NO4SNa 396.1240, found 396.1246. 5-Azido-6-(benzyloxy)-2-methyl-1-tosylpiperidin-3-one (4b). 52.2 mg, dr > 20:1, 56% yield, colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 7.78 (d, J = 8.0 Hz, 2H), 7.42−7.33 (m, 5H), 7.32 (d, J = 8.0 Hz, 2H), 5.45 (d, J = 4.0, 1H), 4.96 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.18−4.13 (m, 2H), 3.05 (dd, J = 16.0, 4.0 Hz, 1H), 2.44 (s, 3H), 2.31 (dd, J = 16.0, 4.0 Hz, 1H), 1.62 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 203.6, 144.2, 136.8, 136.3, 129.8, 128.6, 128.1, 127.5, 83.4, 69.8, 60.2, 59.4, 37.3, 21.6, 20.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H22N4O4SNa 437.1254, found 437.1257. 6-(Benzyloxy)-5-ethyl-2-methyl-1-tosylpiperidin-3-one (4c). 16.7 mg, dr > 20:1, 83% yield, colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 7.68 (d, J = 8.0 Hz, 2H), 7.36−7.30 (m, 4H), 7.30−7.25 (m, 3H), 5.25 (d, J = 4.0, 1H), 4.87 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.18 (q, J = 8.0 Hz, 1H), 2.46 (dd, J = 16.0, 4.0 Hz, 1H), 2.41 (s, 3H), 2.09−2.06 (m, 1H), 1.59 (dd, J = 16.0, 4.0 Hz, 1H), 1.51 (d, J = 8.0 Hz, 3H), 1.36−1.29 (m, 1H), 1.14−1.09 (m, 1H), 0.82 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 208.6, 144.2, 137.7, 137.0, 130.0, 128.4, 127.9, 127.7, 127.1, 87.0, 69.7, 59.3, 41.6, 38.6, 25.9, 21.6, 19.7, 11.2. HRMS (ESI-TOF) m/z: (M + Na)+ calcd for C22H27NO4SNa 424.1553, found 424.1556.

cis-6-((4-Methoxybenzyl)thio)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3w). 45 mg, cis/trans > 20:1, 54% yield, white solid, mp = 122−124 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.60 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.68 (dd, J = 12.0, 4.0 Hz, 1H), 5.79 (d, J = 4.0 Hz, 1H), 5.72 (d, J = 8.0 Hz, 1H), 4.47 (q, J = 8.0 Hz, 1H), 4.21 (d, J = 12.0 Hz, 1H), 4.05 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H), 2.41 (s, 3H), 1.70 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.1, 159.0, 144.3, 136.0, 130.4, 130.4, 130.0, 129.3, 127.0, 124.9, 114.1, 58.1, 57.7, 55.3, 36.4, 21.5, 20.6. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H23NO4S2Na 440.0961, found 440.0967. cis-6-(Dodecylthio)-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)one (3x). 43 mg, cis/trans > 20:1, 46% yield, orange solid, mp = 67− 70 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.54 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.81 (dd, J = 8.0, 4.0 Hz, 1H), 5.79 (d, J = 8.0 Hz, 1H), 5.69 (d, J = 8.0 Hz, 1H), 4.36 (q, J = 8.0 Hz, 1H), 2.99−2.93 (m, 1H), 2.83−2.76 (m, 1H), 2.34 (s, 3H), 1.70−1.66 (m, 2H), 1.64 (d, J = 8.0 Hz, 3H), 1.38−1.36 (m, 2H), 1,22−1.20 (m, 16H), 0.83 (t, J = 4.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 195.2, 144.2, 144.2, 136.0, 130.0, 127.0, 125.3, 58.1, 57.8, 32.7, 31.9, 29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.2, 28.9, 22.7, 21.6, 20.6, 14.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C25H39NO3S2Na 488.2264, found 488.2262. cis-2-Ethyl-6-((4-methoxybenzyl)oxy)-1-tosyl-1,6-dihydropyridin-3(2H)-one (3y). 69 mg, cis/trans > 20:1, 83% yield, white solid, mp = 138−140 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.52 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.60 (dd, J = 12.0, 4.0 Hz, 1H), 5.70 (d, J = 8.0 Hz, 1H), 5.65 (d, J = 4.0 Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.18 (q, J = 4.0 Hz, 1H), 3.81 (s, 3H), 2.36 (s, 3H), 2.05−1.99 (m, 1H), 1.87−1.81 (m, 1H), 1.12 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.2, 159.5, 144.1, 142.3, 136.2, 130.1, 130.0, 129.1, 126.8, 126.5, 114.0, 78.7, 70.1, 63.3, 55.3, 28.0, 21.6, 11.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H25NO5SNa 438.1346, found 438.1357. cis-2-Cyclopropyl-6-((4-methoxybenzyl)oxy)-1-tosyl-1,6-dihydropyridin-3(2H)-one (3z). 64 mg, cis/trans > 20:1, 75% yield, white solid, mp = 143−145 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.49 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.70 (dd, J = 12.0, 4.0 Hz, 1H), 5.77 (d, J = 12.0 Hz, 1H), 5.71 (d, J = 4.0 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 3.80 (s, 3H), 3.41 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H), 1.52−1.48 (m, 1H), 0.74−0.71 (m, 1H), 0.63−0.57 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 193.7, 159.5, 144.1, 142.4, 136.3, 130.1, 130.0, 129.3, 127.0, 126.7, 113.9, 78.8, 69.8, 66.3, 55.3, 21.5, 16.3, 5.6, 4.4. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H25NO5SNa 450.1346, found 450.1356. cis-2-Butyl-6-((4-methoxybenzyl)oxy)-1-tosyl-1,6-dihydropyridin-3(2H)-one (3aa). 66 mg, cis/trans > 20:1, 74% yield, colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 7.53 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.61 (dd, J = 12.0, 4.0 Hz, 1H), 5.71 (d, J = 8.0 Hz, 1H), 5.65 (d, J = 4.0 Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.72 (d, J = 8.0 Hz, 1H), 4.30−4.26 (m, 1H), 3.82 (s, 3H), 2.37 (s, 3H), 2.04−2.00 (m, 1H), 1.76−1.73 (m, 1H), 1.64−1.59 (m, 1H), 1.48−1.47 (m, 1H), 1.39−1.32 (m, 2H), 0.91 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.3, 159.6, 144.1, 142.2, 136.2, 130.0, 129.2, 126.8, 126.5, 114.0, 78.8, 70.0, 61.9, 55.3, 34.4, 28.2, 22.1, 21.5, 13.9. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H29NO5SNa 466.1659, found 466.1665. cis-6-((4-Methoxybenzyl)oxy)-2-phenyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (3ab). 57 mg, cis/trans > 20:1, 62% yield, white solid, mp = 111−113 °C. 1H NMR (400 MHz, CDCl3, TMS): δ 7.60 (d, J = 8.0 Hz, 2H), 7.43−7.40 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.26−7.24 (m, 3H), 6.89 (d, J = 8.0 Hz, 2H), 6.77−6.73 (m, 3H), 5.98 (d, J = 12.0 Hz, 1H), 5.73 (d, J = 4.0 Hz, 1H), 5.54 (s, 1H), 4.42 (s, 2H), 3.77 (s, 3H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 192.9, 159.4, 144.3, 143.4, 137.2, 136.2, 130.1, 130.1, 128.8, 128.5, 128.1, 128.1, 128.0, 126.9, 113.7, 78.8, 69.9, 63.1, 55.3, 21.6. HRMS 12828

DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

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The Journal of Organic Chemistry

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Chemical and Biological Perspectives; Pelletier, S. W., Ed.; WileyInterscience: New York, 1985; Vol. 3, pp 1−90. (3) (a) Pearson, M. S. M.; Mathé-Allainmat, M.; Fargeas, V.; Lebreton, J. Recent Advances in the Total Synthesis of Piperidine Azasugars. Eur. J. Org. Chem. 2005, 2005, 2159−2191. (b) Dragutan, H.; Dragutan, V.; Demonceau, A. Targeted Drugs by Olefin Metathesis: Piperidine-based Iminosugars. RSC Adv. 2012, 2, 719− 736. (4) (a) Luo, J.; Liu, Y.; Zhao, X. Chiral Selenide-Catalyzed Enantioselective Construction of Saturated Trifluoromethylthiolated Azaheterocycles. Org. Lett. 2017, 19, 3434−3437. (b) Yin, G.; Mu, X.; Liu, G. Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes: Bond Forming at a High-Valent Palladium Center. Acc. Chem. Res. 2016, 49, 2413−2423. (c) Zhu, H.; Chen, P.; Liu, G. Palladium-Catalyzed Intramolecular Aminoacetoxylation of Unactivated Alkenes with Hydrogen Peroxide as Oxidant. Org. Lett. 2015, 17, 1485−1488. (5) (a) Poupon, E.; Nay, B. Biomimetic Organic Synthesis; WileyVCH: New York, USA, 2011; Chapter 1. (b) Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach; Wiley: Chichester, U.K., 2009. (6) (a) Taylor, M. S.; Jacobsen, E. N. Highly Enantioselective Catalytic Acyl-Pictet−Spengler Reactions. J. Am. Chem. Soc. 2004, 126, 10558−10559. (b) Seayad, J.; Seayad, A. M.; List, B. Catalytic Asymmetric Pictet−Spengler Reaction. J. Am. Chem. Soc. 2006, 128, 1086−1087. (c) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Catalytic Asymmetric Pictet− Spengler Reactions via Sulfenyliminium Ions. Angew. Chem., Int. Ed. 2007, 46, 7485−7487. (7) (a) Hussain, M.; Banchelin, T. S. L.; Andersson, H.; Olsson, R.; Almqvist, F. Enantioselective Synthesis of Substituted Piperidines by Addition of Aryl Grignard Reagents to Pyridine N-Oxides. Org. Lett. 2013, 15, 54−57. (b) Chau, S. T.; Lutz, J. P.; Wu, K.; Doyle, A. G. Nickel-Catalyzed Enantioselective Arylation of Pyridinium Ions: Harnessing an Iminium Ion Activation Mode. Angew. Chem., Int. Ed. 2013, 52, 9153−9156. (c) Monaco, M. R.; Renzi, P.; Schietroma, D. M. S.; Bella, M. Biomimetic Organocatalytic Asymmetric Synthesis of 2-Substituted Piperidine-Type Alkaloids and Their Analogues. Org. Lett. 2011, 13, 4546−4549. (d) Christian, N.; Aly, S.; Belyk, K. Rhodium-Catalyzed Enantioselective Addition of Boronic Acids to NBenzylnicotinate Salts. J. Am. Chem. Soc. 2011, 133, 2878−2880. (e) Fernández-Ibáñez, M. Á ; Maciá, B.; Pizzuti, M. G.; Minaard, A. J.; Feringa, B. L. Catalytic Enantioselective Addition of Dialkylzinc Reagents to N-Acylpyridinium Salts. Angew. Chem., Int. Ed. 2009, 48, 9339−9341. (f) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. Enantioselective Addition of Activated Terminal Alkynes to 1-Acylpyridinium Salts Catalyzed by Cu-Bis(oxazoline) Complexes. J. Am. Chem. Soc. 2007, 129, 9300−9301. (g) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. New Entries in Lewis Acid−Lewis Base Bifunctional Asymmetric Catalyst: Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives. J. Am. Chem. Soc. 2004, 126, 11808−11809. (8) (a) Lalonde, M. P.; McGowan, M. A.; Rajapaksa, N. S.; Jacobsen, E. N. Enantioselective Formal Aza-Diels−Alder Reactions of Enones with Cyclic Imines Catalyzed by Primary Aminothioureas. J. Am. Chem. Soc. 2013, 135, 1891−1894. (b) Li, C.; Xiao, J. Asymmetric Hydrogenation of Cyclic Imines with an Ionic Cp*Rh(III) Catalyst. J. Am. Chem. Soc. 2008, 130, 13208−13209. (c) Uematsu, N.; Fuji, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Asymmetric Transfer Hydrogenation of Imines. J. Am. Chem. Soc. 1996, 118, 4916−4917. (9) (a) Cassidy, M. P.; Padwa, A. An Aza-Achmatowicz Approach toward the Hydroxylated Piperidine Alkaloids (±)-Azimic Acid and (±)-Deoxocassine. Org. Lett. 2004, 6, 4029−4031. (b) Leverett, C. A.; Cassidy, M. P.; Padwa, A. Application of the Aza-Achmatowicz Oxidative Rearrangement for the Stereoselective Synthesis of the Cassia and Prosopis Alkaloid Family. J. Org. Chem. 2006, 71, 8591− 8601. (c) Haukaas, M. H.; O’Doherty, G. A. Synthesis of d- and lDeoxymannojirimycin via an Asymmetric Aminohydroxylation of

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01598. 1 H NMR, 13C NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Wangze Song: 0000-0003-1012-4456 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the Doctoral Program Foundation of Liaoning Province (20170520378, 20170520274), the Fundamental Research Funds for the Central Universities (DUT16RC(3)114, DUT18LK25), and National Natural Science Foundation of China (21702025, 51703018). We thank Professor Baomin Wang (Dalian University of Technology) for his enthusiastic assistance.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830

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(17) Trost, B. M.; Crawley, M. L. Asymmetric Transition-MetalCatalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921−2943. (18) (a) Claessens, S.; Jacobs, J.; De Kimpe, N. Synthesis of 2-Aza-1cyano-4-hydroxyanthraquinones. Synlett 2007, 2007, 741−744. (b) Hodgson, R.; Kennedy, A.; Nelson, A.; Perry, A. Synthesis of 3Sulfonyloxypyridines: Oxidative Ring Expansion of a-Furylsulfonamides and N→O Sulfonyl Transfer. Synlett 2007, 2007, 1043−1046. (c) Hopman, J. C. P.; van den Berg, E.; Ollero, L. O.; Hiemstra, H.; Speckamp, W. N. Stereoselective Carbon-carbon Bond Formation via Allylic N-sulfonyliminium Ions. Tetrahedron Lett. 1995, 36, 4315− 4318. And also refs 9 and 12.

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DOI: 10.1021/acs.joc.8b01598 J. Org. Chem. 2018, 83, 12822−12830