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Article

De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization †

by
Kazuya Ito
1,
Takayuki Doi
1 and
Hirokazu Tsukamoto
1,2,*
1
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
2
Department of Pharmaceutical Sciences, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan
*
Author to whom correspondence should be addressed.
†
This paper is dedicated to late Professor Jiro Tsuji.
Catalysts 2023, 13(2), 319; https://doi.org/10.3390/catal13020319
Submission received: 29 December 2022 / Revised: 20 January 2023 / Accepted: 24 January 2023 / Published: 1 February 2023
(This article belongs to the Special Issue Theme Issue in Memory to Prof. Jiro Tsuji (1927–2022))
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Abstract

:
We report an efficient method to prepare polysubstituted 3-hydroxypyridines from amino acids, propargyl alcohols, and arylboronic acids. The process involves Pd(0)-catalyzed anti-selective arylative cyclizations of N-propargyl-N-tosyl-aminoaldehydes with arylboronic acids (“anti-Wacker”-type cyclization), oxidation of the resulting 5-substituted-3-hydroxy-1,2,3,6-tetrahydropyridines to 3-oxo derivatives, and elimination of p-toluenesulfinic acid. This method provides diverse polysubstituted 3-hydroxypyridines, whose hydroxy group can be further substituted by a cross-coupling reaction via a triflate.

Graphical Abstract

1. Introduction

Pyridines are important motifs found in natural products, pharmaceutical molecules, and agricultural chemicals [1,2,3,4,5,6,7]. Therefore, a wide variety of methods for the synthesis of pyridine and its derivatives have been developed; the proposed strategies rely on the modification of a pre-existing aromatic core [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] or the implementation of de novo synthetic technologies [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. However, it is still difficult to introduce multiple substituents into the pyridine skeleton in a perfectly regioselective manner. For example, 3-hydroxypyridines [27,28,29,30,31] have been identified as not only bioactive compounds [1,2,3,4,5,6,7] but also useful intermediates for transformation into more functionalized pyridines [30]. In contrast to 2- and 4-hydroxypyridines, which readily tautomerize to the corresponding pyridones, 3-hydroxypyridines cannot form keto tautomers and are transformed into 3-subsituted pyridines through a cross-coupling reaction of their triflates under palladium catalysis [44,45,46,47,48,49]. Donohoe [50] and Yanagisawa [51] independently reported de novo syntheses of 3-hydroxypyridines by the ring-closing metathesis of N-allyl-N-(2-oxobut-3-en-1-yl)amino derivative 1 (Scheme 1, top equation). However, the synthesis of each of the 3-hydroxypyridines 3 requires the preparation of the respective precursors from building blocks that are difficult to obtain, including polysubstituted allylic alcohols and alkenylmetal species. Alkylative cyclization to convert a single precursor into multiple cyclized products with a wide variety of substituents could be more desirable for the diversity-oriented synthesis of 3-hydroxypyridines. Herein, we describe a practical and regioselective synthesis of 3-hydroxypyridines by the Pd(0)-catalyzed anti-selective arylative-, alkylative, or alkynylative cyclizations (“anti-Wacker”-type cyclization [52,53,54]) of alkynals 4, which can be easily prepared from available amino acid derivatives and propargyl alcohols (Scheme 1, bottom equation). Polysubstituted 3-hydroxypyridines are obtained with a simple two-step sequence: oxidation of cyclization products 5 and subsequent desulfinative aromatization developed by Boger [50,51,55]. The “anti-Wacker”-type cyclization proceeds through the newly proposed “anti-Wacker”-type oxidative addition of alkynyl electrophiles that do not form oxapalladacycles, transmetalation with organometallic reagents, and reductive elimination [52,53]. Both substituents at the alkyne terminus and phosphine ligands affect the regioselectivity of the cyclization reaction, with a combination of terminal alkynes and triphenylphosphine and that of aryl- and 1-alkynyl substituents and tricyclohexylphosphine favoring the formation of endocyclic products over exocyclic products. However, the effect of substituents at the α-positions of the alkyne and carbonyl on the diastereoselectivity and how many substituents are allowed are poorly understood [54]. N-Tosyl-tethered aldehyde 4 with an α-substituent of the carbonyl group can be readily prepared from amino acids. The tosyl-protecting group promotes not only the N-propargylation step of the substrate preparation but also the cyclization step by the electron-withdrawing inductive effect and the Thorpe–Ingold effect, which is eliminated after oxidation of the resulting allylic alcohols 5 to afford 3-hydroxypyridines 3. Through the synthesis of multisubstituted 3-hydroxypyidines, we explored the scope and limitations of the “anti-Wacker”-type cyclization and established the structures of six-membered endocyclic products.

2. Results and Discussion

The preparation of alkyne-aldehydes 4a–o for the “anti-Wacker”-type cyclization was commenced with the N-alkylation of N-tosyl amino acid methyl esters via the SN2 reaction with propargyl bromides or the Mitsunobu reaction with propargyl alcohols (Scheme 2). The terminal alkyne in methyl esters 6a·b was also able to be substituted with aryl, 1-alkenyl, and 1-alkynyl groups by the Sonogashira or Cadiot–Chodkiewicz coupling reactions [56,57]. The ester intermediates were subsequently reduced with DIBAL to give aldehydes 4a–o.
The terminal alkyne 4a (R1=R2=R4=H) derived from glycine underwent the Pd(PPh3)4-catalyzed “anti-Wacker”-type cyclization with arylboronic acids 7A–C upon heating at 80 °C in methanol to afford 5-substituted-3-hydroxy-1,2,3,6-tetrahydropyridines 5aA–C in good to moderate yields (Scheme 3). In addition to the aryl group, the alkyl and alkynyl groups were also effectively introduced into products 5aD and 5aE using the triethylborane 7D and alkynylcopper species generated in situ from phenylacetylene 7E along with a catalytic amount of copper iodide, respectively [52,53]. The α-substituted aldehydes 4b–e derived from alanine, leucine, phenylalanine, and valine also participated in the arylative cyclization with 7A to furnish 5b–eA with cis-disubstituents as the predominant products in high yields [54]. The stereochemical outcome observed herein provides useful information about the transition states. The observed cis-diastereoselectivity would result from the steric effect of the substituent at the pseudoequatorial position of the twist boat transition state shown in Figure 1, where there is maximum overlap between the π-orbital of the incoming alkyne and the π*-orbital of the carbonyl [58,59]. The bulky isopropyl group in 4e would increase the gauche interaction with the N-Ts group and be partially oriented in the pseudoaxial position, leading to lower cis-diastereoselectivity.
On the other hand, a substituent (R2) at the α-position of the alkyne functionalities in glycine-derived terminal alkyne-aldehydes 4f–h dramatically affected the yield of products 5f–hA, with the sterically demanding phenyl group resulting in much lower yields (Scheme 3). Interestingly, cis-diastereoselectivity was consistently high, regardless of the steric bulkiness of the substituents. The nucleophilic attack of a Pd(0) species would be hindered more significantly by the propargyl substituent at the pseudoequatorial position than by the substituent at the pseudoaxial position (Figure 2). The favored transition state with the substituent at the pseudoaxial position leads to cis-disubstituted products. Surprisingly, the introduction of two cis-oriented substituents at both the α-positions of the aldehyde and alkyne moieties led to the formation of not only the endocyclic product 5iA but also the exocyclic product 8iA. To the best of our knowledge, this is the only example of the formation of both endocyclic and exocyclic products during the arylative cyclization of terminal alkyne-aldehydes under Pd(PPh3)4 catalysis.
The arylative cyclizations of internal alkyne-aldehydes 4j–o with p-methoxyphenylboronic acid 7A under the catalysis of the strongly σ-donating tricyclohexylphosphine-ligated palladium also provided 4,5-disubstituted-3-hydroxy-1,2,3,6-tetrahydropyridines 5j–oA, along with 8j–oA, in good to moderate yields (Scheme 4). For the predominant endocyclic closure that affords the tetrahydropyridines, the alkyl, aryl, 1-alkynyl, or polysubstituted 1-alkenyl groups at the alkyne terminus were necessary [53]. The arylative cyclization of alkyl-substituted alkyne-aldehyde 4j was relatively slow and gave an inseparable mixture of 5jA and 8jA. The former tetrahydropyridine 5jA can be alternatively prepared with a two-step sequence: arylative cyclization of conjugated diyne-aldehyde 4m, followed by chemoselective hydrogenation of the internal alkyne 5mA in the presence of a tetra-substituted alkene [53]. Further substitution at the α-position of the carbonyl group in 4o preserves the high yield of product 5oA with two cis-oriented substituents, which would also result from the similar transition state shown in Figure 1.
The 5-substituted 3-hydroxy-1,2,3,6-tetrahydropyridines were transformed into the corresponding 3-hydroxypyridines through the following two steps (Scheme 5). The Dess–Martin oxidation of the hydroxy group in 5 afforded enone 2, although that of the acid-sensitive 5eA required the addition of sodium bicarbonate to prevent acid-mediated dehydration. Subsequent elimination of the p-toluenesulfinic acid moiety in 2 was achieved using 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) to furnish the desired multiply substituted 3-hydroxypyridines 3 in good yields. For reasons unknown, the eliminated product was not formed in the case of 2mA with the 1-alkynyl group at the C4 position.
Finally, the hydroxyl group at the C3 position of 3cA was substituted with an aryl group via triflate 9cA. After a brief screening of the Suzuki–Miyaura cross-coupling reaction, we found that the use of lithium chloride [60] successfully transformed triflate 9cA into 2-substituted 3,5-diarylpyridine 10 in excellent yield (Scheme 6).

3. Materials and Methods

3.1. General Techniques

All commercially available reagents and anhydrous solvents including tetrahydrofuran (THF), dichloromethane (DCM), and 1,2-dimethoxyethane (DME) were purchased and used without further purification. Anhydrous methanol (MeOH), N,N-dimethylformamide (DMF), and toluene were obtained using distillation from magnesium, calcium hydride, and sodium, respectively. All reactions were monitored using thin-layer chromatography (TLC) performed using 0.25 mm silica gel glass plates (60 F254) using UV light and ethanolic p-anisaldehyde-sulfuric acid, ethanolic molybdatophosphoric acid, aqueous cerium sulfate-hexaammonium heptamolybdate-sulfuric acid, or aqueous potassium permanganate-potassium carbonate-sodium hydroxide solutions as visualizing agents. Flash column chromatography was carried out with silica gel (spherical, neutral, 100–210 µm grade). Preparative thin-layer chromatography was performed using 0.75 mm Wakogel® B-5F PLC plates. Yields refer to chromatographically and spectroscopically homogenous materials. Melting points were measured with a melting point apparatus and were uncorrected. Only the strongest and/or structurally important absorptions of infrared (IR) spectra are reported in reciprocal centimeters (cm−1). The 1H-NMR spectra (400 MHz or 600 MHz) and 13C{1H}NMR spectra (100 MHz or 151 MHz) were recorded in the indicated solvent. Chemical shifts (δ) are reported in delta (δ) units, parts per million (ppm). Chemical shifts for the 1H-NMR spectra are given relative to signals for internal tetramethylsilane (0 ppm) or residual nondeuterated solvents, i.e., chloroform (7.26 ppm). Chemical shifts for the 13C-NMR spectra are given relative to the signal for chloroform-d (77.0 ppm). Multiplicities are reported as the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Coupling constants (J) are represented in hertz (Hz). The 1H and 13C-NMR chemical shifts were assigned using a combination of COSY, NOESY, HMQC, and HMBC. Low- and high-resolution mass spectra were measured using TOF-MS with EI, FAB, or ESI probes.

3.2. Materials

Ynals 4a, 4b, 4d, 4j, 4k, 4m, and 4n were prepared according to the literature procedure [61,62,63]. Ynals 4c and 4e were prepared from N-tosyl amino acid methyl ester [64] and propargyl bromide. Ynals 4f, 4g, and 4i were prepared from N-tosyl amino acid methyl ester and propargyl alcohols. Ynal 4h was prepared from N-benzylidene-p-toluenesulfonamide [65], ethynylmagnesium bromide, and methyl bromoacetate. Ynals 4l and 4o were prepared through Sonogashira reaction of terminal alkyne 6a·b with 1-iodo-4-nitrobenzene. The details of procedures for the preparation of ynals are described in Supplementary Materials.

3.3. Methods

3.3.1. General Procedure for the Pd(PPh3)4-Catalyzed Arylative Cyclizations of Terminal Alkyne-Aldehyde 4a–i with Arylboronic Acid 7A–C

To a test tube containing 4a–i (1 equiv), arylboronic acid 7A–C (1.5 equiv), and Pd(PPh3)4 (5 mol%) was added anhydrous MeOH (0.1 M) under argon. The resulting mixture was sealed with a screw cap and agitated at 80 °C for the time described in Scheme 3. The reaction mixture was cooled down to room temperature and then treated with polymer-supported diethanolamine (PL-DEAMTM, 1.72 mmol/g, 3 equiv, X g) and THF (10 × X mL) to remove an excess of 7A–C. The mixture was agitated at room temperature for 2 h. The mixture was filtered, and the resin was thoroughly rinsed with CHCl3. The filtrate was concentrated in vacuo and the residue was purified with preparative TLC or silica gel column chromatography to give endocyclic products 5(a–i)(A–C) in the yield described in Scheme 3.

Procedure for 5-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5aA)

Method: 5aA (16.6 mg, 90%) was obtained from 4a (12.9 mg, 0.0513 mmol), 7A (11.4 mg), and Pd(PPh3)4 (2.9 mg) and isolated with silica gel column chromatography eluting with 15% EtOAc/hexane. Spectra data of 5aA were in agreement with those reported in the literature [52].

Procedure for 1-(4-(5-hydroxy-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)ethan-1-one (5aB)

Method: 5aB (12.3 mg, 70%) was obtained from 4a (11.9 mg, 0.0474 mmol), 7B (12.3 mg), and Pd(PPh3)4 (2.9 mg) and isolated with preparative TLC eluting with 20% EtOAc/toluene. Spectra data of 5aB were in agreement with those reported in the literature [53].

Procedure for 5-(4-nitrophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5aC)

Method: 5aC (28.2 mg, 51%) was obtained from 4a (37.7 mg, 0.150 mmol), 7C (37.6 mg), and Pd(PPh3)4 (8.6 mg) and isolated with preparative TLC eluting with 20% EtOAc/toluene.
Pale-brown oil. IR (neat): 3620–3200, 1681, 1604, 1344, 1271, 1167, 1094, 819, 755, 660 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.19 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 4.45 (ddd, J = 4.8, 4.0, 5.6 Hz, 1H), 4.09 (d, J = 16.0 Hz, 1H), 3.76 (d, J = 16.0 Hz, 1H), 3.37 (dd, J = 12.0, 4.8 Hz, 1H), 3.24 (dd, J = 12.0, 4.0 Hz, 1H), 2.60 (d, J = 5.6 Hz, 1H), 2.44 (s, 3H); 13C-NMR (151 MHz, CDCl3): δ 147.7, 144.3, 143.7, 135.0, 132.9, 130.0, 128.1, 127.7, 126.3, 124.0, 63.7, 49.7, 46.2, 21.6. LRMS (EI) m/z (relative intensity) 374 ([M]+, 2), 356 (3), 184 (100), 155 (61). HRMS (EI, [M]+): m/z calcd for C18H18N2O5S, 374.0936; found, 374.0956.

Procedure for (2S,3S)-5-(4-methoxyphenyl)-2-methyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5bA)

Method: 5bA (33.1 mg, 87%, dr >95:<5) was obtained from 4b (27.1 mg, 0.102 mmol), 7A (22.8 mg), and Pd(PPh3)4 (5.8 mg) and isolated with preparative TLC eluting with 10% EtOAc/toluene.
Colorless oil. Rf 0.40 (50% EtOAc/hexane). [α]D23 −5.8 (c 0.60, CHCl3). IR (neat): 3497, 1608, 1335, 1515, 1160, 1030, 816, 752, 659 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.0 Hz, 2H) 7.32–7.28 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 5.82 (s, 1H), 4.49 (m, 1H), 4.47 (d, J = 16.0 Hz, 1H), 4.34 (m, 1H), 3.81 (s, 3H), 3.74 (d, J = 16.0 Hz, 1H), 2.42 (s, 3H), 1.88 (br-s, 1H), 0.91 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.9, 143.5, 137.0, 133.5, 129.8, 129.5, 127.0, 126.3, 123.2, 114.0, 67.0, 55.3, 50.8, 41.5, 21.5, 9.4. HRMS (ESI, [M + Na]+) m/z calcd for C20H23NNaO4S 396.1240, found 396.1242.

Procedure for 2-isobutyl-5-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5cA)

Method: 5cA (19.1 mg, 92%, dr 91:9) was obtained from 4c (15.4 mg, 0.0501 mmol), 7A (11.5 mg), and Pd(PPh3)4 (3.0 mg) and isolated with preparative TLC eluting with 10% EtOAc/toluene.
For (2S,3S)-5cA as a major diastereomer: Colorless oil. Rf 0.38 (10% EtOAc/toluene). [α]D22 −131 (c 0.52, CHCl3). IR (neat): 3505, 2955, 1608, 1514, 1331, 1158, 817, 745, 660 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.76 (s, 1H), 4.52 (d, J = 18.0 Hz, 1H), 4.33–4.20 (m, 2H), 3.83 (d, J = 18.0 Hz, 1H), 3.82 (s, 3H), 2.34 (s, 3H), 1.80–1.64 (m, 2H), 1.36 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.6, 143.3, 138.0, 129.7, 129.3, 126.8, 126.5, 126.2, 123.4, 114.0, 65.7, 55.3, 52.7, 41.5, 33.0, 24.3, 23.9, 21.5 (one signal missing due to an overlap). HRMS (ESI, [M + Na]+) m/z calcd for C23H29NNaO4S 438.1710, found 438.1707.
For (2S,3R)-5cA as a minor diastereomer: Colorless oil. Rf 0.42 (10% EtOAc/toluene). IR (neat): 3600–3200, 2926, 2869, 1607, 1515, 1335, 1247, 1158, 1093, 1031, 827, 754, 655 cm−1; 1H-NMR (600 MHz, CDCl3): δ 7.79 (d, J = 8.2 Hz, 2H), 7.33–7.28 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 6.1 Hz, 1H), 4.51 (d, J = 17.5 Hz, 1H), 4.19 (t, J = 7.2 Hz, 1H), 3.99 (dd, J = 10.5, 6.1 Hz, 1H), 3.82 (s, 3H), 3.76 (d, J = 17.5 Hz, 1H), 2.43 (s, 3H), 1.96 (d, J = 10.5, 1H), 1.61–1.51 (m, 1H), 1.20–1.14 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H); 13C-NMR (151 MHz, CDCl3): δ 160.0, 143.6, 137.2, 136.4, 129.74, 129.70, 127.4, 126.5, 120.6, 114.1, 66.7, 56.8, 55.4, 41.7, 37.6, 25.1, 22.7, 22.6, 21.5. HRMS (ESI, [M + Na]+) m/z calcd for C23H29NNaO4S 438.1710, found 438.1707.

Procedure for (2R*, 3R*)-2-benzyl-5-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydro-pyridin-3-ol (5dA)

Method: 5dA (42.5 mg, 95%, dr >95:<5) was obtained from 4d (33.0 mg, 0.100 mmol), 7A (22.8 mg), and Pd(PPh3)4 (5.8 mg) and isolated with preparative TLC eluting with 50% EtOAc/hexane.
Pale-yellow oil. Rf 0.50 (50% EtOAc/hexane). IR (neat): 3492, 1607, 1514, 1248, 1157, 1096, 752, 660 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.34 (d, J = 6.8 Hz, 2H), 7.27–7.13 (m, 7H), 7.08 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.94 (s, 1H), 4.64 (dd, J = 5.4, 6.0 Hz, 1H), 4.57 (ddd, J = 4.8, 5.4, 9.6 Hz, 1H), 4.47 (d, J = 18.0 Hz, 1H), 3.86 (d, J = 18.0 Hz, 1H), 3.11 (dd, J = 4.8, 14.2 Hz, 1H), 2.56 (dd, J = 9.6, 14.2 Hz, 1H), 2.36 (s, 3H), 1.77 (d, J = 6.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 159.6, 143.0, 138.6, 137.1, 133.4, 129.5, 129.4, 129.1, 128.4, 126.9, 126.3, 126.2, 123.6, 114.0, 66.7, 56.4, 55.3, 41.6, 31.2, 21.4. HRMS (ESI, [M + Na]+) m/z calcd for C26H27NNaO4S 472.1553, found 472.1548.

Procedure for 2-isopropyl-5-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5eA)

Method: 5eA (33.8 mg, 86%, dr 70: 30) was obtained from 4e (15.4 mg, 0.525 mmol), 7A (11.5 mg), and Pd(PPh3)4 (3.0 mg) and isolated with preparative TLC eluting with 15% EtOAc/toluene.
For (2S,3S)-5eA as a major diastereomer: Colorless oil. Rf 0.39 (15% EtOAc/toluene). [α]D23 −82 (c 0.58, CHCl3). IR (neat): 3509, 2962, 1608, 1515, 1464, 1333, 1251, 1159, 1090, 1046, 816, 758, 663 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.4 Hz, 2H), 7.31–7.20 (m, 4H), 6.87 (d, J = 6.8 Hz, 2H), 5.88 (s, 1H), 4.44 (d, J = 18.0 Hz, 1H), 4.35 (m, 1H), 3.98–3.90 (m, 2H), 3.80 (s, 3H), 2.39 (s, 3H), 2.00 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.6, 143.2, 138.0, 133.0, 129.7, 129.4, 126.7, 126.2, 124.2, 114.0, 67.3, 60.2, 55.3, 43.5, 27.0, 21.5, 20.9 (one signal missing due to an overlap). HRMS (ESI, [M + Na]+) m/z calcd for C15H19NNaO4S 424.1553, found 424.1551.
For (2S,3R)-5eA as a minor diastereomer: Colorless oil. Rf 0.44 (15% EtOAc/toluene). [α]23D –122 (c 2.25 in CHCl3). IR (neat): 3600–3260, 2964, 1607, 1515, 1457, 1326, 1250, 1156, 1093, 1033, 826, 760, 657 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.4 Hz, 2H), 7.31–7.20 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.11 (d, J = 5.5 Hz, 1H), 4.46 (d, J = 18.3 Hz, 1H), 4.32–4.20 (m, 1H), 3.89–3.73 (m, 5H), 2.40 (s, 3H), 1.84 (d, J = 9.3 Hz, 1H), 1.76–1.61 (m, 1H), 1.01 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.9, 143.4, 137.7, 136.3, 129.6, 129.5, 127.3, 126.3, 120.5, 114.0, 64.7, 64.5, 55.3, 41.9, 27.5, 21.5, 20.8, 20.3. HRMS (ESI, [M + Na]+) m/z calcd for C15H19NNaO4S 424.1553, found 424.1551.

Procedure for 5-(4-methoxyphenyl)-6-methyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5fA)

Method: 5fA (17.0 mg, 90%, dr 94: 6) was obtained from 4f (13.3 mg, 0.0507 mmol), 7A (11.4 mg), and Pd(PPh3)4 (2.9 mg) and isolated with preparative TLC eluting with 10% EtOAc/toluene (developed six times).
For (3R*,6S*)-5fA as a major diastereomer: Colorless oil. Rf 0.37 (17% EtOAc/toluene). IR (neat): 3492, 1607, 1514, 1248, 1157, 252, 660 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.2 Hz, 2H) 7.27–2.22 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.29 (s, 1H), 4.96 (q, J = 6.8 Hz, 1H), 4.18 (dd, J = 6.4, 10.0 Hz, 1H), 4.07 (dd, J = 6.4, 13.6 Hz, 1H), 3.81 (s, 3H), 2.90 (dd, J = 10.0 Hz, 13.6 Hz, 1H), 2.39 (s, 3H), 2.15 (br-s, 1H), 1.16 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.5, 143.4, 142.0, 137.9, 130.4, 129.7, 127.5, 126.7, 125.2, 114.0, 63.1, 55.3, 50.6, 43.5, 21.4, 18.3. HRMS (ESI, [M + Na]+) m/z calcd for C20H23NNaO4S 396.1240, found 396.1239.
For (3R*,6R*)-5fA as a minor diastereomer: Colorless oil. Rf 0.38 (17% EtOAc/toluene). IR (neat): 3600–3160 (br), 2979, 2934, 2838, 1607, 1513, 1335, 1247, 1155, 1122, 1088, 1013, 815, 741, 654 cm−1; 1H-NMR (600 MHz, CDCl3): δ 7.81 (d, J = 8.6 Hz, 2H) 7.33–7.24 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 5.93 (d, J = 4.1 Hz, 1H), 5.05 (q, J = 6.9 Hz, 1H), 4.18–4.12 (m, 1H), 3.90 (d, J = 14.4 Hz, 1H), 3.82 (s, 3H), 3.33 (d, J = 14.4 Hz, 1H), 2.42 (s, 3H), 1.95 (d, J = 10.3 Hz, 1H), 1.06 (d, J = 6.9 Hz, 3H); 13C-NMR (151 MHz, CDCl3): δ 159.9, 144.1, 143.5, 137.6, 130.5, 129.8, 127.7, 127.3, 122.2, 114.1, 63.6, 55.3, 50.5, 45.1, 21.5, 16.6. HRMS (ESI, [M + Na]+) m/z calcd for C20H23NNaO4S 396.1240, found 396.1238.

Procedure for (3R*,6S*)-5-(4-methoxyphenyl)-6-propyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5gA)

Method: 5gA (21.6 mg, 78%, dr >95:<5) was obtained from 4g (20.2 mg, 0.0689 mmol), 7A (15.7 mg), and Pd(PPh3)4 (4.0 mg) and isolated with preparative TLC eluting with 10% EtOAc/toluene.
Pale-yellow oil. Rf 0.30 (33% EtOAc/hexane). IR (neat): 3494, 2959, 2934, 1606, 1513, 1336, 1248, 825, 761, 661 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.0 Hz, 2H) 7.25 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.55 (s, 1H), 4.82 (t, J = 10.0 Hz, 1H), 4.08 (dd, J = 6.8 Hz, 14.0 Hz, 1H), 3.90 (dd, J = 6.8, 10.0 Hz, 1H), 3.83 (s, 3H), 2.96 (dd, J = 10.0 Hz, 14.0 Hz, 1H), 2.41 (s, 3H), 1.77 (br-s, 1H), 1.61–1,30 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.5, 143.4, 141.7, 138.1, 130.8, 129.6, 127.3, 126.8, 124.8, 114.1, 62.0, 55.3, 43.8, 43.8, 34.6, 21.5, 19.9, 13.6. HRMS (ESI, [M + Na]+) m/z calcd for C22H27NNaO4S 424.1553, found 424.1550.

Procedure for (3R*,6S*)-5-(4-methoxyphenyl)-6-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5hA)

Method: 5hA (2.9 mg, 36%, dr >95:<5) was obtained from 4h (16.4 mg, 0.0501 mmol), 7A (11.4 mg), and Pd(PPh3)4 (2.9 mg) and isolated with preparative TLC eluting with 15% EtOAc/toluene.
Pale-yellow oil. Rf 0.40 (50% EtOAc/hexane). IR (neat): 3491, 1606, 1513, 1335, 1250, 1160, 1034, 815, 744, 704, 661 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.4 Hz, 2H) 7.39 (d, J = 6.8 Hz, 2H), 7.30–7.15 (m, 7H), 6.77 (d, J = 8.8 Hz, 2H), 6.05 (s, 1H), 6.02 (s, 1H), 4.18 (dd, J = 7.6, 10.3 Hz, 1H), 3.88 (dd, J = 7.6 Hz, 14.1 Hz, 1H), 3.74 (s, 3H), 2.84 (dd, J = 10.3, 14.1 Hz, 1H), 2.37 (s, 3H), 1.82 (br-s, 1H); 13C-NMR (100 MHz, CDCl3): δ 159.4, 143.4, 137.8, 137.68, 137.66, 130.0, 129.6, 129.0, 128.5, 128.0, 127.2, 127.0, 126.5, 113.9, 62.8, 57.5, 55.2, 43.6, 21.5. HRMS (ESI, [M + Na]+) m/z calcd for C25H25NNaO4S 458.1397, found 458.1398.

Procedure for (2S,6R)-5-(4-methoxyphenyl)-2,6-dimethyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5iA) and (2S,5R)-4-((E)-4–methoxybenzylidene)-2,5-dimethyl-1-tosylpyrrolidin-3-ol (8iA)

Method: 5iA (98 mg, 45%, dr >95:<5) and 8iA (44 mg, 20%, dr >95:<5) were obtained from 4i (158 mg, 0.566 mmol), 7A (129 mg), and Pd(PPh3)4 (49.0 mg) and isolated with preparative TLC eluting with 40% EtOAc/hexane.
For 5iA: Pale-yellow oil. Rf 0.30 (40% EtOAc/hexane). [α]D21 –163 (c 0.55, CHCl3). IR (neat): 3492, 1607, 1514, 1248, 1157, 752, 660 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.0 Hz, 2H) 7.32–7.20 (m, 4H), 6.88 (d, J = 8.8 Hz, 2H), 5.56 (s, 1H), 4.97 (q, J = 7.2 Hz, 1H), 4.26 (m, 1H), 4.13 (m, 1H), 3.82 (s, 3H), 2.40 (s, 3H), 1.78 (br-s, 1H), 1.31 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.4, 143.3, 142.0, 138.4, 130.9, 129.8, 127.9, 126.8, 123.8, 113.9, 65.8, 55.3, 49.8, 49.7, 22.1, 21.5, 14.8. HRMS (ESI, [M + Na]+) m/z calcd for C21H25NNaO4S 410.1397, found 410.1396.
For 8iA: Pale-yellow oil. Rf 0.33 (40% EtOAc/hexane). IR (neat): 3491, 1606, 1513, 1250, 1160, 744, 661 cm−1; 1H-NMR (600 MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.35 (s, 1H), 4.77 (q, J = 6.9 Hz, 1H), 4.22 (dd, J = 5.5, 6.5 Hz, 1H), 3.84 (s, 3H), 3.66 (dq, J = 5.5, 6.5 Hz, 1H), 2.37 (s, 3H), 1.65 (d, J = 5.5 Hz, 1H), 1.56 (d, J = 6.5 Hz, 3H), 1.38 (d, J = 6.9 Hz, 3H); 13C-NMR (151 MHz, CDCl3): δ 159.1, 143.3, 141.3, 135.3, 129.9, 129.6, 128.0, 127.2, 125.1, 113.9, 76.9, 58.2, 56.9, 55.3, 23.5, 21.5, 16.5. HRMS (ESI, [M + Na]+) m/z calcd for C21H25NNaO4S 410.1397, found 410.1396.

3.3.2. Procedure for 5-ethyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5aD)

To a test tube containing 4a (50.3 mg, 0.200 mmol) and Pd(PPh3)4 (11.6 mg, 5 mol%) were added anhydrous MeOH (2.0 mL) and 1.0 M Et3B solution in THF (0.30 mL, 1.5 equiv) under argon. The resulting mixture was sealed with a screw cap and agitated at 80 °C for 1 h. The reaction mixture was cooled down to room temperature and then concentrated in vacuo. The residue was purified with preparative TLC eluting with 20% EtOAc/toluene to give 5aD (42.8 mg, 76%) as a colorless oil. Spectra data of 5aD were in agreement with those reported in the literature [52].

3.3.3. Procedure for 5-(phenylethynyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5aE)

To a test tube containing 4a (25.1 mg, 0.100 mmol), CuI (1.2 mg, 6 mol%), PhCCH (22 μL, 2.0 equiv), and Pd(PPh3)4 (5.8 mg, 5 mol%) was added anhydrous MeOH (1.0 mL) under argon. The resulting mixture was sealed with a screw cap and agitated at 80 °C for 1.5 h. The reaction mixture was cooled down to room temperature and then concentrated in vacuo. The residue was purified with preparative TLC eluting with 20% EtOAc/toluene to give 5aE (27.3 mg, 77%) as a pale-yellow oil. Spectra data of 5aE were in agreement with those reported in the literature [53].

3.3.4. General Procedure for the Pd/PCy3-Catalyzed Arylative Cyclizations of Internal Alkyne-Aldehyde 4j–o with 7A

To a test tube containing 4j–o (1 equiv), p-methoxyphenylboronic acid (7A, 1.5 equiv), (η3-allyl)CpPd (10 mol%), and PCy3 (30 mol%) was added anhydrous MeOH (0.10 M) under argon. The resulting mixture was sealed with a screw cap and agitated at 80 °C for the time described in Scheme 4. The reaction mixture was cooled down to room temperature and then treated with PL-DEAMTM (1.72 mmol/g, 2 equiv, X g) and THF (10 × X mL) to remove an excess of 7A. The mixture was agitated at room temperature for 2 h. The mixture was filtered, and the resin was thoroughly rinsed with CHCl3. The filtrate was concentrated in vacuo and the residue was purified with preparative TLC to give 5(j–o)A along with a small amount of 8(j–o)A in the yield described in Scheme 4.

Procedure for 4-hexyl-5-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5jA) and (E)-4-(1-(4-methoxyphenyl)heptyli–dene)-1-tosylpyrrolidin-3-ol (8jA)

Method: 5jA (28.4 mg, 65%) and 8jA (3.6 mg, 8%) were obtained from 4j (33.5 mg, 0.0999 mmol), 7A (23.0 mg), (η3-allyl)CpPd (1.1 mg), and PCy3 (4.2 mg) and isolated with preparative TLC eluting with 15% EtOAc/toluene (developed four times). Spectra data of 5jA and 8jA were in agreement with those reported in the literature [53].

Procedure for 5-(4-methoxyphenyl)-4-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5kA)

Method: 5kA (32.5 mg, 98%) was obtained from 4k (24.6 mg, 0.0751 mmol), 7A (17.1 mg), (η3-allyl)CpPd (1.5 mg), and PCy3 (5.7 mg) and isolated with preparative TLC eluting with 20% EtOAc/toluene. Spectra data of 5kA were in agreement with those reported in the literature [53].

Procedure for 5-(4-methoxyphenyl)-4-(4-nitrophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5lA)

Method: 5lA (15.8 mg, 80%) was obtained from 4l (15.3 mg, 0.0411 mmol), 7A (11.4 mg), (η3-allyl)CpPd (1.0 mg), and PCy3 (3.8 mg) and isolated with preparative TLC eluting with 20% EtOAc/toluene.
Pale-yellow oil. Rf 0.40 (50% EtOAc/hexane). IR (neat): 3600–3160 (br), 2925, 1598, 1514, 1449, 1344, 1250, 1166, 1092, 1032, 760, 661 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.8 Hz, 2H) 7.73 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.59–4.51 (m, 1H), 4.39 (d, J = 17.1 Hz, 1H), 3.97 (dd, J = 12.1, 2.4 Hz, 1H), 3.74 (s, 3H), 3.37 (d, J = 17.1 Hz, 1H), 2.92 (dd, J = 12.1, 2.7 Hz, 1H), 2.45 (s, 3H), 2.46–2.36 (m, 1H); 13C-NMR (100 MHz, CDCl3): δ 159.4, 146.48, 146.45, 144.3, 136.8, 133.7, 132.4, 130.2, 130.1, 130.0, 129.1, 127.9, 123.3, 114.0, 67.1, 55.2, 50.8, 49.6, 21.5. HRMS (ESI, [M + Na]+) m/z calcd for C25H24N2NaO6S 503.1247, found 503.1246.

Procedure for 4-(hex-1-ynyl)-5-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydropyridin-3-ol (5mA)

Method: 5mA (12.0 mg, 70%) was obtained from 4m (14.0 mg, 0.0422 mmol), 7A (9.6 mg), (η3-allyl)CpPd (0.8 mg), and PCy3 (3.2 mg) and isolated with preparative TLC eluting with 25% EtOAc/toluene. Spectra data of 5mA were in agreement with those reported in the literature [53].

Procedure for 4-(cyclohex-1-en-1-yl)-5-(4-methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5nA) and (E)-4-(cyclohex-1–en-1-yl(4-methoxyphenyl)methylene)-1-tosylpyrrolidin-3-ol (8nA)

Method: 5nA (13.0 mg, 53%) and 8nA (1.6 mg, 7%) were obtained from 4n (18.5 mg, 0.0558 mmol), 7A (12.7 mg), (η3-allyl)CpPd (1.2 mg), and PCy3 (4.7 mg) and isolated with preparative TLC eluting with 40% EtOAc/hexane. Spectra data of 5nA and 8nA were in agreement with those reported in the literature [53].

Procedure for (2S,3S)-5-(4-methoxyphenyl)-2-methyl-4-(4-nitrophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-3-ol (5oA)

Method: 5oA (21.0 mg, 90%, dr >95:<5) was obtained from 4o (18.2 mg, 0.0471 mmol), 7A (11.4 mg), (η3-allyl)CpPd (1.0 mg), and PCy3 (3.8 mg) and isolated with preparative TLC eluting with 20% EtOAc/toluene.
Pale-yellow oil. Rf 0.40 (50% EtOAc/hexane). [α]D22 −29 (c 0.22, CHCl3). IR (neat): 2932, 1607, 1596, 1512, 1344, 1248, 1160, 1031, 757, 662 cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.8 Hz, 2H) 7.74 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 7.6 Hz, 2H), 4.79 (m, 1H), 4.46 (m, 1H), 4.28 (d, J = 18.0 Hz, 1H), 3.89 (d, J = 18.0 Hz, 1H), 3.72 (s, 3H), 2.45 (3H, s), 1.09 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 158.9, 146.3, 144.9, 143.6, 143.6, 136.8, 134.5, 133.7, 130.9, 129.9, 129.5, 127.1, 122.9, 113.8, 68.1, 55.1, 51.0, 45.2, 21.5, 9.8. HRMS (ESI, [M + Na]+) m/z calcd for C26H26N2NaO6S 517.1404, found 517.1401.

3.3.5. General Procedure for the Transformations of Tetrahydropyridine 5 into 3-Hydroxypyridine 3

To a solution of tetrahydropyridine 5 (1 equiv) in anhydrous DCM (0.2 M) was added Dess–Martin periodinane (1.5 equiv) at room temperature. In the oxidation of 5eA, sodium bicarbonate (2 equiv) was added prior to Dess–Martin periodinane to prevent acid-mediated dehydration. After being stirred at the same temperature for 1 h, the reaction mixture was diluted with Et2O and treated with saturated aqueous sodium thiosulfate and saturated aqueous NaHCO3. The resulting mixture was stirred for 1 h and then extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give enone, which was used for the next step without further purification.
To a solution of the crude enone (1 equiv) in anhydrous toluene (0.33 M) was added DBU (2.0 equiv) at room temperature under argon. After being stirred at the same temperature for 4 h, the reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC eluting with 10% MeOH/CHCl3 to give 3-hydroxypyridine 3.

Procedure for 5-(4-methoxyphenyl)pyridin-3-ol (3aA)

Method: 3aA (2.3 mg, 80%) was obtained from 5aA (5.0 mg, 0.0139 mmol), DMPI (8.3 mg), and DBU (4.2 µL).
Pale-yellow oil. Rf 0.61 (10% MeOH/CHCl3). IR (neat): 2929, 2853, 1609, 1583, 1518, 1440, 1290, 1251, 1221, 1180, 1149, 1031, 828, 755 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.24 (s, 1H), 8.06 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 159.6, 153.9, 138.0, 135.1, 129.6, 128.0, 120.9, 114.3, 109.2, 55.1. HRMS (ESI, [M + H]+) m/z calcd for C12H12NO2 202.0863, found 202.0862.

Procedure for 1-(4-(5-hydroxypyridin-3-yl)phenyl)ethan-1-one (3aB)

Method: 3aB (10.2 mg, 73%) was obtained from 5aB (25.0 mg, 0.0673 mmol), DMPI (40.0 mg), and DBU (20.0 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2925, 1684, 1604, 1267, 1162, 755, 668 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.33 (s, 1H), 8.17 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 2.66 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 198.4, 154.0, 142.1, 138.5, 136.9, 136.5, 136.3, 128.9, 127.2, 121.5, 26.4. HRMS (ESI, [M + H]+) m/z calcd for C13H12NO2 214.0863, found 214.0858.

Procedure for 5-(4-nitrophenyl)pyridin-3-ol (3aC)

Method: 3aC (6.5 mg, 65%) was obtained from 5aC (17.3 mg, 0.0462 mmol), DMPI (27.5 mg), and DBU (14.0 µL).
Pale-yellow oil. Rf 0.53 (10% MeOH/CHCl3). IR (neat): 2923, 1598, 1521, 1345, 1159, 795 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.34 (s, 1H), 8.33 (d, J = 8.0 Hz, 2H), 8.21 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 154.1, 147.5, 143.9, 138.4, 137.6, 135.4, 127.8, 124.1, 121.5. HRMS (ESI, [M + H]+) m/z calcd for C11H9N2O3 217.0608, found 217.0607.

Procedure for 5-ethylpyridin-3-ol (3aD)

Method: 3aD (15.2 mg, 86%) was obtained from 5aD (40.5 mg, 0.144 mmol), DMPI (91.6 mg), and DBU (43.0 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2968, 1585, 1438, 1225, 756, 707 cm−1; 1H-NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.94 (s, 1H), 7.16 (s, 1H), 2.63 (q, J = 7.8 Hz, 2H), 1.24 (t, J = 7.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 155.2, 141.6, 138.8, 133.6, 124.6, 25.9, 15.0. LRMS (EI) m/z (relative intensity) 123 ([M]+, 100), 108 (70), 95 (12). HRMS (EI, [M]+): m/z calcd for C7H9NO, 123.0684; found, 123.0684.

Procedure for 5-(phenylethynyl)pyridin-3-ol (3aE)

Method: 3aE (4.2 mg, 50%) was obtained from 5aE (14.5 mg, 0.0410 mmol), DMPI (24.2 mg), and DBU (12.8 µL).
Pale-yellow oil. Rf 0.57 (10% MeOH/CHCl3). IR (neat): 2924, 2644, 2568, 2216, 1579, 1425, 1325, 1248, 1150, 1124, 1022, 868, 754, 688 cm−1; 1H-NMR (600 MHz, CDCl3:CD3OD = 3:1): δ 8.19 (s, 1H), 8.08 (s, 1H), 7.57–7.48 (m, 2H), 7.44–7.35 (m, 3H), 7.33 (s, 1H); 13C-NMR (151 MHz, CDCl3:CD3OD = 3:1): δ 153.2, 142.1, 136.5, 131.2, 128.4, 128.0, 124.8, 122.0, 120.8, 91.9, 85.5. LRMS (EI) m/z (relative intensity) 195 ([M]+, 100), 139 (25), 69 (11). HRMS (EI, [M]+): m/z calcd for C13H9NO, 195.0684; found, 195.0700.

Procedure for 5-(4-methoxyphenyl)-2-methylpyridin-3-ol (3bA)

Method: 3bA (8.7 mg, 67%) was obtained from 5bA (22.6 mg, 0.0605 mmol), DMPI (35.9 mg), and DBU (18.1 µL).
Pale-yellow oil. Rf 0.50 (10% MeOH/CHCl3). IR (neat): 2922, 1604, 1515, 1444, 1287, 1220, 1163, 773 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.03 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.24 (s, 1H), 6.93 (d, J = 7.2 Hz, 2H), 3.80 (s, 3H), 2.40 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 159.3, 144.5, 136.7, 135.3, 129.9, 127.7, 126.7, 119.7, 114.2, 55.1, 17.1. HRMS (ESI, [M + H]+) m/z calcd for C13H14NO2 216.1019, found 216.1015.

Procedure for 2-isobutyl-5-(4-methoxyphenyl)pyridin-3-ol (3cA)

Method: 3cA (7.8 mg, 59%) was obtained from 5cA (21.5 mg, 0.0517 mmol), DMPI (30.7 mg), and DBU (15.5 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2955, 1608, 1608, 1521, 1393, 1252, 1165, 1033, 830, 772 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.14 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.30 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 2.71 (d, J = 7.8 Hz, 2H), 2.15 (t–sept, J = 7.8, 6.8 Hz, 1H), 0.96 (d, J = 6.8 Hz, 6H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 159.3, 151.7, 147.7, 136.6, 135.0, 129.9, 127.7, 119.9, 114.1, 55.0, 40.4, 27.9, 22.1. HRMS (ESI, [M + H]+) m/z calcd for C16H20NO2 258.1489, found 258.1487.

Procedure for 2-benzyl-5-(4-methoxyphenyl)pyridin-3-ol (3dA)

Method: 3dA (82.2 mg, 95%) was obtained from 5dA (133 mg, 0.296 mmol), DMPI (176 mg), and DBU (88.4 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 1600, 1522, 1433, 1392, 1257, 1176, 1027, 827 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.16 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 7.2, 7.2 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 4.19 (s, 2H), 3.85 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 159.3, 151.5, 146.7, 139.3, 137.1, 135.7, 129.8, 128.6, 128.0, 127.8, 125.7, 120.4, 114.2, 55.0, 37.7. LRMS (EI) m/z (relative intensity) 291 ([M]+, 100), 274 (12). HRMS (EI, [M]+): m/z calcd for C19H17NO2, 291.1259; found, 291.1248.

Procedure for 2-isopropyl-5-(4-methoxyphenyl)pyridin-3-ol (3eA)

Method: 3eA (6.8 mg, 64%) was obtained from 5eA (16.3 mg, 0.0406 mmol), DMPI (26.3 mg), NaHCO3 (6.9 mg), and DBU (12.4 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2969, 2932, 1610, 1518, 1290, 1251, 1229, 1176, 1033, 830, 756 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.33 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.26 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.47 (sept, J = 7.2 Hz, 1H), 1.35 (d, J = 7.2 Hz, 6H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 159.6, 152.6, 149.8, 138.5, 135.1, 130.0, 128.0, 120.5, 114.4, 53.3, 29.1, 21.1. HRMS (ESI, [M + H]+) m/z calcd for C15H18NO2 244.1332, found 244.1330.

Procedure for 5-(4-methoxyphenyl)-6-methylpyridin-3-ol (3fA)

Method: 3fA (9.3 mg, 67%) was obtained from 5fA (24.2 mg, 0.0648 mmol), DMPI (38.5 mg), and DBU (19.4 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2931, 1610, 1515, 1453, 1290, 1248, 1176, 1031, 834, 771, 707 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 7.97 (s, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 6.98 (d, J = 8.0 Hz, 2H), 3.87 (s, 3H), 2.38 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 158.8, 151.7, 145.9, 137.5, 134.4, 131.7, 129.8, 124.7, 113.6, 55.0, 21.2. HRMS (ESI, [M + H]+) m/z calcd for C13H14NO2 216.1019, found 216.1015.

Procedure for 5-(4-methoxyphenyl)-6-propylpyridin-3-ol (3gA)

Method: 3gA (7.2 mg, 74%) was obtained from 5gA (16.0 mg, 0.0398 mmol), DMPI (23.7 mg), and DBU (12.0 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2960, 2931, 1610, 1516, 1452, 1288, 1248, 1175, 1032, 835, 755, 705 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.27 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 3.68 (s, 3H), 2.71 (t, J = 7.8 Hz, 2H), 1.57 (tq, J = 7.8, 7.2 Hz, 2H), 0.81 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 159.0, 152.6, 150.6, 138.4, 134.5, 131.8, 130.1, 126.9, 113.8, 55.3, 35.6, 23.7, 14.0. HRMS (ESI, [M + Na]+) m/z calcd for C15H17NNaO2 266.1152, found 266.1151.

Procedure for 5-(4-methoxyphenyl)-6-phenylpyridin-3-ol (3hA)

Method: 3hA (6.6 mg, 80%) was obtained from 5hA (12.8 mg, 0.0294 mmol), DMPI (17.5 mg), and DBU (8.8 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2917, 1610, 1514, 1447, 1290, 1249, 1177, 1030, 833, 752, 702 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 8.14 (s, 1H), 7.44 (s, 1H), 7.25–7.18 (m, 5H), 7.06 (d, J = 6.8 Hz, 2H), 6.79 (d, J = 6.8 Hz, 2H), 3.78 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 158.8, 151.5, 141.3, 137.2, 135.7, 135.4, 133.6, 130.9, 130.3, 129.4, 128.5, 127.9, 113.4, 54.8. HRMS (ESI, [M + H]+) m/z calcd for C18H16NO2 278.1176, found 278.1170.

Procedure for 5-(4-methoxyphenyl)-2,6-dimethylpyridin-3-ol (3iA)

Method: 3iA (23.8 mg, 73%) was obtained from 5iA (55.2 mg, 0.142 mmol), DMPI (90.7 mg), and DBU (44.5 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2924, 1516, 1289, 1249, 1161, 1033, 840, 812, 719, 668 cm−1; 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1): δ 7.36 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 2.46 (s, 3H), 2.38 (s, 3H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1): δ 158.7, 149.2, 144.8, 144.0, 135.0, 132.0, 129.9, 123.7, 113.6, 55.1, 21.1, 17.6. HRMS (ESI, [M + H]+) m/z calcd for C14H16NO2 230.1176, found 230.1171.

Procedure for 4-hexyl-5-(4-methoxyphenyl)pyridin-3-ol (3jA)

Method: 3jA (9.3 mg, 48%) was obtained from 5jA (30.8 mg, 0.0694 mmol), DMPI (41.2 mg), and DBU (20.7 µL).
Pale-yellow oil. Rf 0.50 (10% MeOH/CHCl3). IR (neat): 2955, 1611, 1517, 1501, 1425, 1289, 1244, 1176, 1036, 831 cm−1; 1H-NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.96 (s, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 3.87 (s, 3H), 2.64 (t, J = 2.8 Hz, 2H), 1.60–1.48 (m, 2H), 1.30–1.10 (m, 6H), 0.81 (t, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.1, 153.8, 140.1, 139.0, 138.9, 134.1, 130.4, 130.1, 113.7, 55.3, 31.4, 29.4, 28.8, 26.8, 22.5, 14.0. HRMS (ESI, [M + H]+) m/z calcd for C18H24NO2 286.1802, found 286.1801.

Procedure for 5-(4-methoxyphenyl)-4-phenylpyridin-3-ol (3kA)

Method: 3kA (22.3 mg, 80%) was obtained from 5kA (43.6 mg, 0.100 mmol), DMPI (59.4 mg), and DBU (29.9 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2933, 1609, 1425, 1290, 1249, 1178, 1033, 831, 750, 699 cm−1; 1H-NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 8.16 (s, 1H), 7.35–7.25 (m, 3H), 7.20 (d, J = 6.8 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 2H), 3.75 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 158.8, 151.5, 141.3, 137.2, 135.7, 135.4, 133.6, 130.9, 130.3, 129.4, 128.5, 127.9, 113.5, 55.1. HRMS (ESI, [M + H]+) m/z calcd for C18H16NO2 278.1176, found 278.1173.

Procedure for 5-(4-methoxyphenyl)-4-(4-nitrophenyl)pyridin-3-ol (3lA)

Method: 3lA (25.9 mg, 77%) was obtained from 5lA (50.2 mg, 0.104 mmol), DMPI (62.1 mg), and DBU (33.1 µL).
Pale-yellow oil. Rf 0.51 (10% MeOH/CHCl3). IR (neat): 2933, 1515, 1247, 1176, 1110, 1033, 830, 753 cm−1; 1H-NMR (600 MHz, CDCl3:CD3OD = 1:1): δ 8.21 (s, 1H), 8.16–8.09 (m, 3H), 7.39 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H); 13C-NMR (151 MHz, CDCl3:CD3OD = 1:1): δ 158.7, 146.5, 141.4, 140.7, 135.5, 132.6, 131.3, 130.4, 128.4, 122.4, 113.3, 54.5. (two signals missing due to an overlap). HRMS (ESI, [M + H]+) m/z calcd for C18H15N2O4 323.1026, found 323.1025.

Procedure for 4-(cyclohex-1-en-1-yl)-5-(4-methoxyphenyl)pyridin-3-ol (3nA)

Method: 3nA (26.4 mg, 58%) was obtained from 5nA (71.2 mg, 0.162 mmol), DMPI (96.2 mg), and DBU (49.0 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2931, 1610, 1511, 1452, 1246, 1170, 1032, 832, 758, 664 cm−1; 1H-NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 8.12 (s, 1H), 7.34 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 5.98–5.94 (m, 1H), 3.85 (s, 3H), 2.24–2.19 (m, 2H), 2.73–2.69 (m, 2H), 2.61–2.54 (m, 2H), 2.52–2.44 (m, 2H)’ 13C-NMR (151 MHz, CDCl3): δ 159.3, 148.7, 142.1, 136.2, 135.4, 135.0, 132.6, 131.5, 130.0, 129.9, 113.7, 55.3, 28.1, 25.4, 22.5, 21.6. HRMS (ESI, [M + H]+) m/z calcd for C18H20NO2 282.1489, found 282.1486.

Procedure for 5-(4-methoxyphenyl)-2-methyl-4-(4-nitrophenyl)pyridin-3-ol (3oA)

Method: 3oA (9.3 mg, 72%) was obtained from 5oA (20.5 mg, 0.0415 mmol), DMPI (24.6 mg), and DBU (12.4 µL).
Pale-yellow oil. Rf 0.55 (10% MeOH/CHCl3). IR (neat): 2923, 1513, 1343, 1241, 1219, 1176, 1128, 1106, 1033, 829, 755 cm−1; 1H-NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.8 Hz, 2H), 8.03 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.56 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 158.7, 146.8, 145.8, 141.9, 134.9, 131.47, 131.45, 130.59, 130.56, 128.8, 123.02, 122.99, 113.6, 54.9, 18.5. HRMS (ESI, [M + H]+) m/z calcd for C19H17N2O4 337.1183, found 337.1179.

3.3.6. Procedure for 2-benzyl-3-(3-methoxyphenyl)-5-(4-methoxyphenyl)pyridine (10)

To a solution of 3cA (40.0 mg, 0.137 mmol) and Et3N (38.2 μL, 0.274 mmol) in anhydrous DCM (1.0 mL) was added Tf2O (38.2 μL, 0.164 mmol) at 0 °C under argon. After being stirred at the same temperature for 4 h, the reaction mixture was treated with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with preparative TLC eluting with 10% EtOAc/toluene to give triflate (46.6 mg, 80%).
To a test tube containing the above triflate (8.7 mg, 0.021 mmol), m–methoxyphenylboronic acid (6.2 mg, 2 equiv), Pd(PPh3)4 (1.2 mg, 5 mol%), and LiCl (2.6 mg, 3 equiv) in DME (0.3 mL) was added 2.0 M aqueous Na2CO3 (31 µL) under argon. The resulting mixture was sealed with a screw cap and stirred at 80 °C for 8 h. The reaction mixture was cooled down to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with preparative TLC eluting with 20% EtOAc/toluene to give 10 (7.2 mg, 93%) as a brown solid.
Rf 0.70 (20% EtOAc/toluene). IR (neat): 1609, 1516, 1455, 1440, 1288, 1248, 1179, 1148, 1035, 830, 701 cm−1; 1H-NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.32 (t, J = 8.4 Hz, 1H), 7.24–7.10 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 4.18 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 159.7, 159.4, 155.8, 146.3, 140.9, 140.1, 137.3, 135.6, 133.9, 130.0, 129.8, 129.4, 128.8, 128.2, 128.1, 125.9, 121.5, 114.5, 113.6, 55.3, 55.2, 41.3. HRMS (ESI, [M + H]+) m/z calcd for C26H24NO2 382.1802, found 382.1796.

4. Conclusions

In summary, we have developed a new synthetic method for polysubstituted 3-hydroxypyridines. The starting alkynals, which were readily prepared from N-tosyl amino acid esters and propargyl alcohols, were effectively converted to a wide range of 3-hydroxy-1,2,3,6-tetrahydropyridines with various organometallic reagents in the “anti-Wacker”-type cyclization. The 5-Monosubstituted 3-hydroxypyridnes, 2,5-, 4,5-, and 5,6-disubstituted 3-hydroxypyridnes, and 2,4,5- and 2,5,6-trisubstituted 3-hydroxypyridnes were obtained by the oxidation and elimination of toluenesufinic acid. This approach enables the introduction of substituents into 3-hydroxypyridines one by one in a highly regioselective manner. The hydroxy group at the C3 position can be further substituted with cross-coupling reactions via the corresponding triflate.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal13020319/s1, preparation of substrates, analytical data, 1H and 13C NMR spectra, and more detailed materials and methods. References [52,53,61,62,63,64,65] are cited in Supplementary Materials.

Author Contributions

Conceptualization, H.T.; investigation, K.I. and H.T.; writing—original draft preparation, K.I.; writing—review and editing, H.T. and T.D.; supervision, T.D.; funding acquisition, H.T. and T.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partly funded by the Banyu Pharmaceutical Co. Ltd. Award in Synthetic Organic Chemistry, The Research Foundation for Pharmaceutical Sciences, SUNTRY FOUNDATION for LIFE SCIENCES, Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP19am0101095 and JP19am0101100, and JSPS KAKENHI Grant Numbers JP2459004 and JP15K07849.

Data Availability Statement

All experimental data is contained in the article and Supplementary Material.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 13 00319 sch001 550
Scheme 1. Synthetic methods for 3-hydroxypyridines. (a) Yanagisawa’s method [51], (b) this work.
Scheme 1. Synthetic methods for 3-hydroxypyridines. (a) Yanagisawa’s method [51], (b) this work.
Catalysts 13 00319 sch001
Catalysts 13 00319 sch002 550
Scheme 2. Preparation of alkyne-aldehydes 4a–o.
Scheme 2. Preparation of alkyne-aldehydes 4a–o.
Catalysts 13 00319 sch002
Catalysts 13 00319 sch003 550
Scheme 3. Tetrahydropyridines prepared by Pd/PPh3-catalyzed cyclizations of terminal alkyne-aldehydes.
Scheme 3. Tetrahydropyridines prepared by Pd/PPh3-catalyzed cyclizations of terminal alkyne-aldehydes.
Catalysts 13 00319 sch003
Catalysts 13 00319 g001 550
Figure 1. Diastereoselective cyclizations of 4b–e with a substituent at the α-position to the carbonyl group.
Figure 1. Diastereoselective cyclizations of 4b–e with a substituent at the α-position to the carbonyl group.
Catalysts 13 00319 g001
Catalysts 13 00319 g002 550
Figure 2. Diastereoselective cyclizations of 4f–h with a substituent at the propargyl position.
Figure 2. Diastereoselective cyclizations of 4f–h with a substituent at the propargyl position.
Catalysts 13 00319 g002
Catalysts 13 00319 sch004 550
Scheme 4. Tetrahydropyridines prepared by Pd/PCy3-catalyzed arylative cyclizations of internal alkyne-aldehydes.
Scheme 4. Tetrahydropyridines prepared by Pd/PCy3-catalyzed arylative cyclizations of internal alkyne-aldehydes.
Catalysts 13 00319 sch004
Catalysts 13 00319 sch005 550
Scheme 5. Conversion of 3-hydroxytetrahydropyridines 5 to 3-hydroxypyridines 3.
Scheme 5. Conversion of 3-hydroxytetrahydropyridines 5 to 3-hydroxypyridines 3.
Catalysts 13 00319 sch005
Catalysts 13 00319 sch006 550
Scheme 6. Suzuki–Miyaura cross-coupling of triflate 9cA derived from 3cA.
Scheme 6. Suzuki–Miyaura cross-coupling of triflate 9cA derived from 3cA.
Catalysts 13 00319 sch006
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Ito, K.; Doi, T.; Tsukamoto, H. De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization. Catalysts 2023, 13, 319. https://doi.org/10.3390/catal13020319

AMA Style

Ito K, Doi T, Tsukamoto H. De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization. Catalysts. 2023; 13(2):319. https://doi.org/10.3390/catal13020319

Chicago/Turabian Style

Ito, Kazuya, Takayuki Doi, and Hirokazu Tsukamoto. 2023. "De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization" Catalysts 13, no. 2: 319. https://doi.org/10.3390/catal13020319

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