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Article Cite This: ACS Omega 2017, 2, 7746-7754

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Tandem Oxidative α‑Hydroxylation/β-Acetalization Reaction of β‑Ketoamides and Its Applications Zhiguo Zhang,*,†,§ Xiaolong Gao,† Haifeng Yu,‡ Jingjing Bi,† and Guisheng Zhang*,† †

Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Henan Normal University, 46# East of Construction Road, Xinxiang, Henan 453007, China ‡ School of Chemistry and Life Science, Anshan Normal University, 33# Ping An Street, Tiedong District, Anshan, Liaoning 114007, China § Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal University, Changchun, Jilin 130024, China S Supporting Information *

ABSTRACT: A tandem oxidative α-hydroxylation/β-acetalization reaction of β-ketoamides was developed in the presence of PIDA and NaOH. This reaction proceeded at 25 °C in the absence of a metal catalyst to provide 2-hydroxy-3,3-dimethoxy-Nsubstituted butanamides in good to excellent yields from readily available starting materials. The application of this chemistry to the construction of α-hydroxy-β-ketoamides and quinolinones was also described. lyzed reactions.27−49 They are also used for the acetalization of carbonyl compounds.26,50 In 2005, in a perspective of Moriarty group’s work in hypervalent iodine chemistry, it was reported that the alcoholysis of iodobenzene diacetate (PIDA: PhI(OAc) 2 ) in MeOH can generate the active reagent (dimethoxyiodo)benzene (PhI(OMe)2).26 The concomitantly formed enolate anion 1′ subsequently adds to the PhI(OMe)2 to yield intermediate A, which results in intermediate B via the addition of a methoxide anion. Then, the oxirane C is formed, accompanying the release of one molecule of PhI from the intramolecular B nucleophilic displacement via the alkoxide anion. The reaction is completed with the attack of a second methoxide ion on oxirane C to yield product 2 (Scheme 1). The procedure has been shown to work well for a large range of structural types.26,51−55 However, a literature review disclosed that no systematic work has focused on this type of reaction starting from β-ketoamides to date.55−57 Herein, we present our recent progress on a hypervalent-organoiodine-promoted controllable tandem oxidative intramolecular α-hydroxylation/ β-acetalization reaction of β-ketoamides as well as the application

1. INTRODUCTION α-Hydroxy-β-keto ester and amide moieties are the main structural units of certain natural products and pharmaceutical compounds, serving as important contributors to various biological activities.1−4 These functional units, also serving as key intermediates, appear in many multistep reaction sequences, such as the Aspidosperma alkaloids 11-demethoxyvindoline and vindoline, Passerini adducts, and 3-substituted oxindoles.5−9 To date, a number of methods with a variety of electrophilic oxidants, including oxaziridines,10−13 oxygen,1,14−17 DDQ,18 dimethyldioxirane,19 nitroso compounds,20 m-CPBA,8 and Mn(OAc)3,21 have been developed to prepare α-hydroxy-βdicarbonyl moieties,22−25 and the hydroxylation of β-dicarbonyl enolates is the most direct approach to this structural unit. However, despite considerable efforts in the area of synthesis methods toward α-hydroxycarbonyl derivatives, the development of practical, diverse synthesis procedures to access αhydroxy-β-ketoamides starting from β-ketoamides in the presence of novel oxygen sources is highly desirable. Organoiodine reagents, possessing reactivity similar to that of transition metals,26 are widely used in various organic reactions as selective oxidants and environmentally friendly reagents, including aminations, oxidations, halogenations, C−C bondforming reactions, rearrangements, and transition-metal-cata© 2017 American Chemical Society

Received: October 14, 2017 Accepted: October 30, 2017 Published: November 9, 2017 7746

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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Table 1. Survey of the Reaction Conditionsa

Scheme 1. Schematic of the α-Hydroxydimethylacetal Formation Reaction of Enolizable Ketone

of this chemistry to the construction of α-hydroxy-β-ketoamides and quinolinone derivatives. We recently developed a facile and direct oxidative reaction for the synthesis of vicinal tricarbonyl amides (VTAs) in moderate to good yields (53−88%) starting from various readily available β-ketoamides (1) in the presence of phenyliodine(III) bis(trifluoroacetate) (PIFA) (Figure 1).58 While optimizing

entry

oxidant (equiv)

base (percent, volume/mL)

T/°C

yield of 2a/%

1 2 3 4 5 6 7 8 9 10 11 12 13 14

PIDA (1.5) PIDA (1.0) PIDA (2.0) PIFA (1.5) PhIO (1.5) IBX (1.5) DMP (1.5) PIDA (1.5) PIDA (1.5) PIDA (1.5) PIDA (1.5) PIDA (1.5) PIDA (1.5) PIDA (1.5)

NaOH (50%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.5) NaOH (30%, 0.2) NaOH (60%, 0.2) NaOH (50%, 0.2) NaOH (50%, 0.2) KOH (50%, 0.2) K2CO3 (50%, 0.2)

25 25 25 25 25 25 25 25 25 25 0 50 25 25

78 65 61 70 74 0 0 63 73 64 76 65 69 55

a

Reaction conditions: 1a (0.2 mmol), oxidant (1.5 equiv), and base in MeOH (1.5 mL) in 1 h at 25 °C temperature.

increasing the reaction temperature (Table 1, entries 11 and 12). Other bases, such as KOH and K2CO3, only afforded the desired product 2a in 69 and 55% yields, respectively (Table 1, entries 13 and 14). With the optimized conditions in hand (Table 1, entry 1), we proceeded to investigate the scope of this tandem oxidative αhydroxylation/β-acetalization reaction. The variation of amide moieties (substituents of the R1 and R2) was investigated first. As shown in Table 2, a phenyl group (1a) and various other aryl groups bearing electron-donating groups (e.g., 1b−j: −OMe and −Me) and electron-withdrawing groups (e.g., 1k−o: −Cl and −NO2) at the ortho, meta, or para position of the phenyl ring converted to the corresponding α-hydroxylated and β-acetalized amides 2a−o in 57−81% yields. Furthermore, N,N′-(1,4phenylene)bis(acetoacetamide) 1p also gave the target compound 2p in 20% yield via the formation of six new C−O bonds simultaneously in one pot. N-Benzyl-substituted starting materials 1q and 1r and other N-alkyl-substituted aliphatic secondary and tertiary amides 1s and 1t also afforded the desired products 2q−t in 54−74% yields. However, the primary amide 1u was poorly tolerated by this tandem reaction, and some of the decomposition products were detected by LC−MS. This observation prompted us to explore a wider range of starting material 1. Compounds 1v and 1w were then selected and tested as starting materials. The results revealed that the reaction failed to afford the desired products 2v and 2w but resulted in an unidentified complex mixture. This limitation suggested that the amide moiety is important to the conversion. The investigation of the R3 group disclosed that it could affect the reaction significantly. Compound 1x (R3 = Ph) afforded product 2x in only 30% yield, along with the recovered 1x (15%) and some unidentified complex mixtures; moreover, the yield of 2x could not be further improved by increasing the amount of PIDA (3.0 equiv) or the reaction temperature. This might be caused by the large steric hindrance of the phenyl group. Hence, Et-substituted starting material 1y was employed in the reaction. As a result, we obtained a slightly higher yield of 2y (50%) than that of 2x (30%). Furthermore, compared with the reactions using Me-, Et-, iPr-, and tBu-substituted starting materials (1a

Figure 1. Our recent work on the synthesis of VTAs.

reaction conditions, a small amount of byproduct was isolated under alkaline conditions in MeOH solvent and characterized as 2-hydroxy-3,3-dimethoxy-N-phenylbutanamide (2a) based on its NMR spectral and analytical data. This delightful preliminary result prompted us to attempt to develop a controllable tandem oxidative α-hydroxylation/β-acetalization reaction of β-ketoamides in the preparation of functionalized amides 2 because this type of product is useful in the synthesis of 2-indolinones and quinolines.5,56,59

2. RESULTS AND DISCUSSION In light of these findings, commercially available β-ketoamide (1a) was selected as a model substrate to explore the optimal conditions for this tandem reaction. Some of the key experiments are summarized in Table 1. We found that the highest yield of the desired compound 2a was 78% when compound 1a (0.2 mmol) was treated with phenyliodonium diacetate (PIDA) (1.2 equiv) and NaOH (50% aq, 0.2 mL) in MeOH at 25 °C after 1 h (Table 1, entry 1). However, increasing or decreasing the amount of PIDA both led to a slightly lower yield of 2a (Table 1, entries 2 and 3). Other trivalent iodine reagents, including PIFA and PhIO, could also promote the reaction but gave a lower yield than PIDA (Table 1, entries 4 and 5). Further investigation using pentavalent iodine reagents, such as IBX and DMP, confirmed that they were entirely inefficient for the conversion (Table 1, entries 6 and 7); similar reports have disclosed a different oxidation capacity with trivalent iodine and pentavalent iodine reagents.28,49 Different percentages of NaOH were also tested for the reaction, and they all gave yields lower than that of entry 1 (Table 1, entries 8−10). The experiments also showed that it is of no use to further increase the yield of 2a by decreasing or 7747

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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Table 2. Extension of the Reaction Scopea,b

Unless otherwise indicated, all reactions were carried out with 1 (0.2 mmol) and PIDA (1.5 equiv) in alcohol (1.5 mL) at 25 °C. bIsolated yield. 95% of 1w was recovered. d15% of 1x was recovered. e21% of 1y was recovered, and the yield of 2y was not increased by prolonging the reaction time. a c

and 1y−a′), it was found that the yields of 2a and 2y−a′ were gradually reduced (from 77 to 50 to 20 to 0%) with increasing steric hindrance. In an attempt to investigate a wider scope of alcohol-substituted starting materials, ethylene glycol and 1pentanol were also tested with the reaction. They performed poorly in the reaction; only ethylene glycol led to the desired

product 2b′ in 20% yield in addition to a complex mixture, and compound 2c′ was not detected by thin-layer chromatography (TLC). To our delight, α-methyl-substituted starting material 1d′ still afforded the desired product 2d′ in 41% yield. The previous studies clearly demonstrated that α-hydroxy amide derivatives are important building blocks for the 7748

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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AVANCE/400 (1H: 400 MHz and 13C{1H}: 100 MHz at 25 °C) using tetramethylsilane as internal standard. Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, and m = multiplet), and coupling constants in hertz (Hz). All high-resolution mass spectra (HRMS) were measured on a mass spectrometer by using electrospray ionization (ESI-oaTOF), and the purity of all samples used for HRMS (>95%) was confirmed by 1H NMR and 13C{1H} NMR spectroscopic analyses. Melting points were measured on a melting point apparatus equipped with a thermometer and were uncorrected. All reactions were monitored by TLC with GF254 silica gelcoated plates. Flash chromatography was carried out on SiO2 (silica gel 200−300 mesh). 4.2. Typical Experimental Procedure for 2 (2a as an Example). To a round-bottom flask (25 mL) were added 3-oxoN-phenylbutanamide 1a (35 mg, 0.2 mmol), (diacetoxyiodo)benzene (96.6 mg, 0.3 mmol), and NaOH (0.2 mL, 50% aq), and the mixture was well-stirred for 1 h in MeOH (1.5 mL) at 25 °C (the whole process was closely monitored by TLC). After the completion of the reaction, the residue was purified by a short flash silica gel column chromatography (eluent: EA/PE = 1/20) to give 2-hydroxy-3,3-dimethoxy-N-phenylbutanamide 2a as a white solid (37 mg, 77%). 4.2.1. 2-Hydroxy-3,3-dimethoxy-N-phenylbutanamide (2a). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (37 mg, 77%); mp: 104−106 °C; 1 H NMR (600 MHz, CDCl3): δ 8.57 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 4.27 (d, 1H), 4.08 (d, J = 3.6 Hz, 1H), 3.39 (d, J = 10.8 Hz, 6H), 1.28 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.3, 137.1, 129.2, 124.7, 119.7, 101.9, 77.2, 77.0, 76.8, 71.0, 48.8, 48.7, 17.0. HRMS (ESI), m/z calcd for C12H17NNaO4 ([M + Na]+), 262.1050; found, 262.1045. 4.2.2. 2-Hydroxy-3,3-dimethoxy-N-(4-methoxyphenyl)butanamide (2b). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a brown solid (35 mg, 65%); mp: 94−96 °C; 1H NMR (600 MHz, CDCl3): δ 8.44 (s, 1H), 7.42 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 4.26 (d, 1H), 4.10 (d, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.38 (d, J = 8.4 Hz, 6H), 1.28 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.2, 156.7, 130.3, 121.5, 114.3, 101.9, 70.9, 55.5, 48.8, 48.7, 17.0. HRMS (ESI), m/z calcd for C13H19NNaO5 ([M + Na]+), 292.1155; found, 292.1155. 4.2.3. 2-Hydroxy-3,3-dimethoxy-N-(3-methoxyphenyl)butanamide (2c). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (38 mg, 71%); 1H NMR (600 MHz, CDCl3): δ 8.57 (s, 1H), 7.28 (t, 1H), 7.24 (t, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.0, 1.0 Hz, 1H), 6.70 (dd, J = 8.1, 1H), 4.26 (d, 1H), 4.07 (d, J = 3.6 Hz, 1H), 3.82 (s, 3H), 3.39 (d, J = 10.8 Hz, 6H), 1.28 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.5, 160.3, 138.4, 129.9, 111.9, 110.4, 105.6, 101.9, 71.1, 55.4, 48.8, 48.7, 17.0. HRMS (ESI), m/z calcd for C13H19NNaO5 ([M + Na]+), 292.1155; found, 292.1162. 4.2.4. 2-Hydroxy-3,3-dimethoxy-N-(2-methoxyphenyl)butanamide (2d). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (43 mg, 80%); mp: 110−112 °C; 1H NMR (600 MHz, CDCl3): δ 9.38 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 3.6 Hz, 1H), 4.16 (d, 1H), 3.91 (s, 3H), 3.40 (d, J = 8.4 Hz, 6H), 1.26 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.4, 148.4, 127.1, 124.2, 121.2, 120.0, 110.1, 101.8, 71.1, 55.8, 48.8, 48.7, 16.8.

construction of 2-indolinones and quinolines.5,56,59 According to these reports, we randomly selected several 2-hydroxy-3,3dimethoxy-N-arylbutanamides (2) for further derivatization using the method detailed herein. It was found that compounds 2a, 2f, 2i, and 2l cyclized smoothly to the quinoline derivatives 3a, 3f, 3i, and 3l in yields of 66, 75, 84, and 74%, respectively (Scheme 2). It is noteworthy that the dimethyl acetal protecting Scheme 2. Application of 2 for the Synthesis of Quinoline Derivatives 3

group at the 3 position was removed simultaneously during the cyclization process.60 This result prompted us to attempt to obtain controlled deprotected products 4 from 2. Still in the presence of sulfuric acid, the reaction could produce the deprotecting products 4j, 4l, 4o, 4s, and 4t in 48−88% yields when we only reduce the reaction temperature from 80 to 25 °C (Scheme 3). All of these applications demonstrated the usefulness of compound 2, although they are very elementary. Scheme 3. Deprotection of 2 to Deprotected Products 4

3. CONCLUSIONS A systemically oxidative intramolecular α-hydroxylation/βacetalization tandem reaction of β-ketoamides was described for the synthesis of 2-hydroxy-3,3-dimethoxy-N-substituted butanamides in the presence of PIDA and NaOH. Notably, this metal-free reaction is advantageous owing to its readily available starting materials, simple operation, moderate to good yields, and dense and flexible substitution patterns. Further applications of this chemistry to the construction of α-hydroxy-βketoamides and quinolinone derivatives have been developed simultaneously so that the method, at present, can be considered as an alternative procedure for producing these types of functionalized small molecules. 4. EXPERIMENTAL SECTION 4.1. General Remarks. All reactions were carried out under air atmosphere, unless otherwise indicated. Other all reagents were purchased from commercial sources and used without further treatment, unless otherwise indicated. Petroleum ether (PE) used refers to the 60−90 °C boiling point fraction of petroleum. Ethyl acetate is abbreviated as EA. 1H NMR and 13 C{1H} NMR spectra were recorded on a Bruker AVANCE/ 600 (1H: 600 MHz and 13C{1H}: 150 MHz at 25 °C) or a Bruker 7749

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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HRMS (ESI), m/z calcd for C13H19NNaO5 ([M + Na]+), 292.1155; found, 292.1155. 4.2.5. N-(2,5-Dimethoxyphenyl)-2-hydroxy-3,3-dimethoxybutanamide (2e). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a light yellow solid (36 mg, 60%); mp: 77−79 °C; 1H NMR (600 MHz, CDCl3): δ 9.41 (s, 1H), 8.03 (d, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.61 (dd, J = 9.0, 1H), 4.30 (d, 1H), 4.13 (d, J = 3.6 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.39 (d, J = 7.8 Hz, 6H), 1.27 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.4, 154.0, 142.6, 127.8, 111.0, 109.0, 106.2, 101.8, 71.1, 56.4, 55.8, 48.8, 48.7, 16.9. HRMS (ESI), m/z calcd for C14H21NNaO6 ([M + Na]+), 322.1261; found, 322.1261. 4.2.6. 2-Hydroxy-3,3-dimethoxy-N-(p-tolyl)butanamide (2f). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (41 mg, 81%); mp: 89−91 °C; 1 H NMR (600 MHz, CDCl3): δ 8.50 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.26 (d, J = 3.6 Hz, 1H), 4.10 (d, J = 3.6 Hz, 1H), 3.38 (d, J = 8.4 Hz, 6H), 2.33 (s, 3H), 1.27 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 169.3, 134.6, 134.4, 129.6, 119.8, 101.9, 71.0, 48.8, 48.6, 20.9, 17.0. HRMS (ESI), m/z calcd for C13H19NNaO4 ([M + Na]+), 276.1206; found, 276.1206. 4.2.7. 2-Hydroxy-3,3-dimethoxy-N-(m-tolyl)butanamide (2g). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow solid (29 mg, 57%); mp: 78−80 °C; 1 H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 7.36 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.26 (d, J = 2.8 Hz, 1H), 4.09 (d, J = 3.2 Hz, 1H), 3.39 (d, J = 7.6 Hz, 6H), 2.36 (s, 3H), 1.28 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.4, 139.2, 137.1, 129.0, 125.5, 120.4, 116.9, 101.9, 71.1, 48.8, 48.7, 21.5, 17.0. HRMS (ESI), m/z calcd for C13H19NNaO4 ([M + Na]+), 276.1206; found, 276.1203. 4.2.8. 2-Hydroxy-3,3-dimethoxy-N-(o-tolyl)butanamide (2h). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (35 mg, 70%); 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 13.8, 7.8 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 4.32 (d, J = 3.2 Hz, 1H), 4.16 (d, J = 3.6 Hz, 1H), 3.40 (d, J = 4.4 Hz, 6H), 2.27 (s, 3H), 1.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.4, 135.5, 130.5, 127.4, 127.0, 124.9, 121.5, 101.9, 71.1, 48.9, 48.8, 17.7, 16.9. HRMS (ESI), m/z calcd for C13H19NNaO4 ([M + Na]+), 276.1206; found, 276.1201. 4.2.9. N-(2,4-Dimethylphenyl)-2-hydroxy-3,3-dimethoxybutanamide (2i). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (36 mg, 67%); mp: 79−81 °C; 1H NMR (600 MHz, CDCl3): δ 8.54 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.03 (t, 2H), 4.31 (d, J = 3.6 Hz, 1H), 4.17 (d, J = 3.6 Hz, 1H), 3.40 (d, J = 4.2 Hz, 6H), 2.30 (s, 3H), 2.23 (s, 3H), 1.30 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.3, 134.7, 132.9, 131.2, 127.6, 127.5, 121.7, 101.9, 70.9, 48.8, 48.8, 20.8, 17.6, 16.9. HRMS (ESI), m/z calcd for C14H21NNaO4 ([M + Na]+), 290.1363; found, 290.1365. 4.2.10. 2-Hydroxy-N-mesityl-3,3-dimethoxybutanamide (2j). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (37 mg, 65%); mp: 103−105 °C; 1 H NMR (600 MHz, CDCl3): δ 7.99 (s, 1H), 6.90 (s, 2H), 4.36 (s, 1H), 4.15 (s, 1H), 3.40 (s, 6H), 2.27 (s, 3H), 2.18 (s, 6H), 1.38 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.7, 137.1, 134.6, 130.7, 129.1, 101.9, 70.7, 48.8, 48.7, 20.9, 18.6, 17.0. HRMS (ESI), m/z calcd for C15H23NNaO4 ([M + Na]+), 304.1519; found, 304.1520.

4.2.11. N-(5-Chloro-2-methoxyphenyl)-2-hydroxy-3,3-dimethoxybutanamide (2k). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (36 mg, 65%); mp: 60−62 °C; 1H NMR (600 MHz, CDCl3): δ 9.40 (s, 1H), 8.37 (d, 1H), 7.03 (dd, J = 8.4, 1H), 6.80 (d, J = 9.0 Hz, 1H), 4.29 (d, 1H), 4.06 (d, 1H), 3.89 (s, 3H), 3.39 (d, J = 9.0 Hz, 6H), 1.26 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.6, 146.9, 127.9, 126.2, 123.6, 119.9, 110.9, 101.8, 71.2, 56.1, 48.8, 48.7, 16.9. HRMS (ESI), m/z calcd for C12H18ClNaNO5 ([M + Na]+), 326.0766; found, 326.0770. 4.2.12. N-(4-Chlorophenyl)-2-hydroxy-3,3-dimethoxybutanamide (2l). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a light yellow solid (44 mg, 80%); mp: 106−108 °C; 1H NMR (600 MHz, CDCl3): δ 8.60 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.26 (d, 1H), 4.03 (d, J = 3.6 Hz, 1H), 3.37 (d, J = 15.6 Hz, 6H), 1.26 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ 169.5, 135.7, 129.7, 129.2, 121.0, 120.9, 101.8, 71.1, 48.9, 48.8, 17.0. HRMS (ESI), m/z calcd for C12H16ClNNaO4 ([M + Na]+), 296.0660; found, 296.0663. 4.2.13. N-(3-Chlorophenyl)-2-hydroxy-3,3-dimethoxybutanamide (2m). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (36 mg, 65%); mp: 110−112 °C; 1H NMR (600 MHz, CDCl3): δ 8.62 (s, 1H), 7.62 (t, 1H), 7.38 (dd, J = 7.8, 1H), 7.29−7.26 (m, 1H), 7.12 (dd, J = 7.8, 1H), 4.27 (d, J = 3.6 Hz, 1H), 3.99 (d, J = 3.6 Hz, 1H), 3.39 (d, J = 16.8 Hz, 6H), 1.28 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.6, 138.3, 134.9, 130.2, 124.8, 119.9, 117.7, 101.8, 71.3, 48.9, 48.8, 17.0. HRMS (ESI), m/z calcd for C12H16ClNNaO4 ([M + Na]+), 296.0660; found, 296.0660. 4.2.14. N-(2-Chlorophenyl)-2-hydroxy-3,3-dimethoxybutanamide (2n). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (28 mg, 51%); 1H NMR (600 MHz, CDCl3): δ 9.44 (s, 1H), 8.37 (dd, J = 8.4, 1H), 7.39 (dd, J = 8.4, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 4.34 (d, 1H), 4.06 (d, J = 3.6 Hz, 1H), 3.41 (d, J = 13.8 Hz, 6H), 1.29 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.0, 134.4, 129.2, 127.9, 125.0, 123.0, 121.5, 101.8, 71.3, 49.0, 48.8, 17.0. HRMS (ESI), m/z calcd for C12H16ClNNaO4 ([M + Na]+), 296.0660; found, 296.0654. 4.2.15. 2-Hydroxy-3,3-dimethoxy-N-(4-nitrophenyl)butanamide (2o). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow solid (40 mg, 70%); mp: 94−96 °C; 1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 8.37 (t, J = 2.0 Hz, 1H), 8.01−7.93 (m, 2H), 7.52 (t, J = 8.2 Hz, 1H), 4.32 (d, J = 3.2 Hz, 1H), 3.91 (d, J = 3.2 Hz, 1H), 3.40 (d, J = 16.4 Hz, 6H), 1.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.0, 148.7, 138.2, 130.1, 125.4, 114.5, 101.8, 71.6, 49.0, 17.1. HRMS (ESI), m/z calcd for C12H16N2NaO4 ([M + Na]+), 307.0901; found, 307.0902. 4.2.16. N,N′-(1,4-Phenylene)bis(2-hydroxy-3,3-dimethoxybutanamide) (2p). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a light yellow solid (16 mg, 20%); mp: 165−167 °C; 1H NMR (600 MHz, CDCl3): δ 8.57 (s, 2H), 7.51 (s, 4H), 4.27 (d, 2H), 4.03 (d, 2H), 3.39 (d, J = 13.2 Hz, 12H), 1.28 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 169.4, 133.8, 120.5, 101.8, 71.1, 48.9, 48.7, 17.0. HRMS (ESI), m/z calcd for C18H28N2NaO8 ([M + Na]+), 423.1738; found, 423.1753. 4.2.17. N-Benzyl-2-hydroxy-3,3-dimethoxybutanamide (2q). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (37 mg, 74%); 1H NMR (400 MHz, CDCl3): δ 7.35 (t, J = 7.0, 2H), 7.32−7.26 (m, 3H), 7.01 7750

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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3H), 0.98 (d, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 170.3, 137.2, 129.2, 124.6, 119.8, 103.9, 71.0, 49.1, 49.1, 33.0, 17.7, 17.6. HRMS (ESI), m/z calcd for C14H21NNaO4 ([M + Na]+), 290.1363; found, 290.1354. 4.2.24. 2-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-N-phenylacetamide (2b′). The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (9 mg, 20%); mp: 67−69 °C; 1H NMR (600 MHz, CDCl3): δ 8.46 (s, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 4.12 (s, 1H), 4.09 (m, 4H), 3.89 (s, 1H), 1.43 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 168.1, 137.1, 129.1, 124.7, 119.9, 119.8, 109.4, 100.0, 73.8, 65.6, 65.0, 29.7, 19.7. HRMS (ESI), m/z calcd for C12H15NNaO4 ([M + Na]+), 260.0893; found, 260.0893. 4.2.25. 2-Hydroxy-3,3-dimethoxy-2-methyl-N-phenylbutanamide (2d′). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (21 mg, 41%); 1H NMR (600 MHz, CDCl3): δ 8.82 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 6.9 Hz, 1H), 4.28 (s, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 1.54 (s, 3H), 1.47 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.5, 137.6, 129.0, 124.3, 119.8, 103.5, 79.3, 51.4, 51.2, 23.4, 15.7. HRMS (ESI), m/z calcd for C13H19NNaO4 ([M + Na]+), 276.1206; found, 276.1204. 4.3. Typical Experimental Procedure for 3 (3a as an Example). To a round-bottom flask (25 mL) was added 2hydroxy-3,3-dimethoxy-N-phenyl-butanamide 2a (47.8 mg, 0.2 mmol), and the mixture was well-stirred for 1 h in H2SO4 (1.0 mL) at 25 °C (the whole process was closely monitored by TLC). After the completion of the reaction, the residue was purified by a short flash silica gel column chromatography (eluent: EA/PE = 1/15) to give 3-hydroxy-4-methylquinolin2(1H)-one 3a as a white solid (23 mg, 66%). 4.3.1. 3-Hydroxy-4-methylquinolin-2(1H)-one (3a). The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (23 mg, 66%); mp: 222−224 °C; 1H NMR (600 MHz, DMSO): δ 11.98 (s, 1H), 9.08 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 24.9, 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 2.28 (s, 3H). 13C NMR (150 MHz, DMSO): δ 158.3, 143.3, 133.4, 126.8, 123.7, 122.6, 121.8, 119.8, 115.6, 11.0. HRMS (ESI), m/z calcd for C10H10NO2 ([M + H]+), 176.0706; found, 176.0711. 4.3.2. 3-Hydroxy-4,6-dimethylquinolin-2(1H)-one (3f). The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (28 mg, 75%); mp: 231−233 °C; 1H NMR (400 MHz, DMSO): δ 11.89 (s, 1H), 9.00 (s, 1H), 7.38 (s, 1H), 7.16 (q, J = 8.4 Hz, 2H), 2.36 (s, 3H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO): δ 157.6, 142.8, 130.9, 130.9, 127.4, 122.9, 121.2, 119.1, 115.0, 20.8, 10.5. HRMS (ESI), m/z calcd for C11H12NO2 ([M + H]+), 190.0863; found, 190.0867. 4.3.3. 3-Hydroxy-4,6,8-trimethylquinolin-2(1H)-one (3i). The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (34 mg, 84%); mp: 237−239 °C; 1 H NMR (600 MHz, DMSO): δ 11.06 (s, 1H), 9.04 (s, 1H), 7.25 (s, 1H), 7.01 (s, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H). 13C NMR (150 MHz, DMSO): δ 158.5, 143.0, 131.1, 129.8, 129.7, 123.6, 121.8, 121.5, 120.0, 21.1, 17.9, 11.2. HRMS (ESI), m/z calcd for C12H14NO2 ([M + H]+), 204.1019; found, 204.1026. 4.3.4. 6-Chloro-3-hydroxy-4-methylquinolin-2(1H)-one (3l). The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (21 mg, 55%); mp: 188−190 °C; 1 H NMR (600 MHz, DMSO): δ 12.10 (s, 1H), 9.36 (s, 1H), 7.59 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 2.25 (s, 3H). 13C NMR (150 MHz, DMSO): δ 158.1, 144.2, 132.2, 126.8,

(s, 1H), 4.55 (dd, J = 14.8, 6.0 Hz, 1H), 4.45 (dd, J = 14.8, 5.6 Hz, 1H), 4.16 (d, J = 3.2 Hz, 1H), 4.07 (d, J = 3.6 Hz, 1H), 3.31 (s, 3H), 3.26 (s, 3H), 1.19 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 171.3, 137.9, 128.8, 127.7, 127.6, 101.6, 70.6, 48.7, 48.5, 43.9, 16.8. HRMS (ESI), m/z calcd for C13H19NNaO4 ([M + Na]+), 276.1206; found, 276.1207. 4.2.18. 2-Hydroxy-3,3-dimethoxy-N-(4-methylbenzyl)butanamide (2r). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (36 mg, 67%); 1H NMR (600 MHz, CDCl3): δ 7.15 (s, 4H), 6.97 (s, 1H), 4.50 (dd, J = 14.7, 5.7 Hz, 1H), 4.40 (dd, J = 14.4, 4.8 Hz, 1H), 4.11 (d, J = 33.0 Hz, 2H), 3.30 (s, 3H), 3.25 (s, 3H), 2.34 (s, 3H), 1.18 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 171.2, 137.4, 134.8, 129.4, 127.6, 101.6, 70.6, 48.6, 48.5, 43.7, 21.1, 16.8. HRMS (ESI), m/z calcd for C14H21NNaO4 ([M + Na]+), 290.1363; found, 290.1362. 4.2.19. N-Cyclohexyl-2-hydroxy-3,3-dimethoxy-3-phenylpropanamide (2s). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (44 mg, 72%); mp: 137−139 °C; 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, J = 6.8, 2H), 7.33−7.30 (m, 3H), 6.44 (d, J = 7.6 Hz, 1H), 4.37 (d, J = 4.4 Hz, 1H), 3.74−3.69 (m, 1H), 3.67 (d, J = 4.4 Hz, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 1.89−1.57 (m, 6H), 1.39− 1.10 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 168.8, 135.8, 128.5, 127.8, 127.7, 103.0, 71.6, 49.8, 49.2, 48.5, 33.0, 32.9, 25.5, 24.7. HRMS (ESI), m/z calcd for C17H25NNaO4 ([M + Na]+), 330.1676; found, 330.1676. 4.2.20. 2-Hydroxy-3,3-dimethoxy-N,N-dimethylbutanamide (2t). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white oil (21 mg, 54%); 1H NMR (400 MHz, CDCl3): δ 4.59 (d, J = 8.0 Hz, 1H), 3.91 (d, J = 8.4 Hz, 1H), 3.33 (s, 3H), 3.21 (s, 3H), 3.08 (s, 3H), 3.01 (s, 3H), 1.20 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.1, 102.9, 67.6, 48.5, 48.3, 37.8, 36.5, 17.2. HRMS (ESI), m/z calcd for C8H17NNaO4 ([M + Na]+), 214.1050; found, 214.1049. 4.2.21. 2-Hydroxy-3,3-dimethoxy-N,3-diphenylpropanamide (2x). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (18 mg, 30%); mp: 112−114 °C; 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.44−7.41 (m, 4H), 7.34 (t, J = 7.8 Hz, 2H), 7.31−7.27 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 4.58 (d, J = 4.4 Hz, 1H), 3.62 (d, J = 4.8 Hz, 1H), 3.54 (s, 3H), 3.35 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.4, 137.1, 135.6, 129.1, 128.7, 128.0, 127.5, 124.7, 120.0, 103.3, 72.2, 50.0, 49.3. HRMS (ESI), m/z calcd for C17H19NNaO4 ([M + Na]+), 324.1206; found, 324.1214. 4.2.22. 2-Hydroxy-3,3-dimethoxy-N-phenylpentanamide (2y). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a yellow oil (25 mg, 50%); 1H NMR (600 MHz, CDCl3): δ 8.68 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 4.27 (d, J = 3.6 Hz, 1H), 4.07 (d, J = 3.6 Hz, 1H), 3.38 (d, J = 16.2 Hz, 6H), 1.91 (dd, J = 15.0, 7.8 Hz, 1H), 1.77 (dd, J = 15.0, 7.2 Hz, 1H), 0.89 (t, J = 7.8 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 169.8, 137.2, 129.2, 124.7, 119.8, 103.3, 70.6, 49.2, 48.9, 24.6, 8.1. HRMS (ESI), m/z calcd for C13H19NNaO4 ([M + Na]+), 276.1206; found, 276.1206. 4.2.23. 2-Hydroxy-3,3-dimethoxy-4-methyl-N-phenylpentanamide (2z). The product was isolated by flash chromatography (eluent: EA/PE = 1/15) as a white solid (11 mg, 20%); mp: 51−53 °C; 1H NMR (600 MHz, CDCl3): δ 8.67 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 8.1 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 4.30 (d, J = 3.6 Hz, 1H), 3.98 (d, J = 3.6 Hz, 1H), 3.42 (s, 3H), 3.35 (s, 3H), 2.23−2.21 (m, 1H), 1.07 (d, J = 7.2 Hz, 7751

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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126.6, 123.4, 122.9, 119.1, 117.3, 10.9. HRMS (ESI), m/z calcd for C10H9ClNO2 ([M + H]+), 210.0316; found, 210.0316. 4.4. Typical Experimental Procedure for 4 (4l as an Example). To a round-bottom flask (25 mL) was added N-(4chlorophenyl)-2-hydroxy-3,3-dimethoxybutanamide 2l (35, 0.2 mmol), and the mixture was well-stirred for 1 h in H2SO4 (1.0 mL) at 25 °C (the whole process was closely monitored by TLC). After the completion of the reaction, the residue was purified by a short flash silica gel column chromatography (eluent: EA/PE = 1/20) to give N-(4-chlorophenyl)-2-hydroxy3-oxobutanamide 4l as a white solid (28 mg, 62%). 4.4.1. 2-Hydroxy-N-mesityl-3-oxobutanamide (4j). The product was isolated by flash chromatography (eluent: EA/PE = 1/18) as a white solid (23 mg, 48%); mp: 70−72 °C; 1H NMR (600 MHz, CDCl3): δ 8.02 (s, 1H), 6.89 (s, 2H), 4.85 (s, 1H), 4.57 (s, 1H), 2.54 (s, 3H), 2.26 (s, 3H), 2.13 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 204.9, 165.2, 137.4, 134.8, 129.8, 129.1, 79.2, 26.1, 20.9, 18.1. HRMS (ESI), m/z calcd for C13H17NNaO3 ([M + Na]+), 258.1101; found, 258.1101. 4.4.2. N-(4-Chlorophenyl)-2-hydroxy-3-oxobutanamide (4l). The product was isolated by flash chromatography (eluent: EA/PE = 1/18) as a yellow solid (28 mg, 62%); mp: 74−76 °C; 1 H NMR (600 MHz, CDCl3): δ 8.58 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 4.77 (s, 1H), 4.59 (s, 1H), 2.56 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 203.9, 164.5, 135.2, 130.1, 129.2, 121.1, 78.9, 26.2. HRMS (ESI), m/z calcd for C10H11ClNO3 ([M + H]+), 228.0422; found, 228.0423. 4.4.3. 2-Hydroxy-N-(4-nitrophenyl)-3-oxobutanamide (4o). The product was isolated by flash chromatography (eluent: EA/ PE = 1/18) as a yellow oil (24 mg, 50%); 1H NMR (600 MHz, CDCl3): δ 8.83 (s, 1H), 8.51 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 4.82 (s, 1H), 4.63 (s, 1H), 2.58 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 203.4, 165.0, 148.7, 137.8, 130.0, 125.3, 119.6, 114.7, 78.9, 26.2. HRMS (ESI), m/z calcd for C10H10N2NaO5 ([M + Na]+), 261.0482; found, 261.0483. 4.4.4. N-Cyclohexyl-2-hydroxy-3-oxo-3-phenylpropanamide (4s). The product was isolated by flash chromatography (eluent: EA/PE = 1/18) as a white solid (46 mg, 88%); mp: 90− 92 °C; 1H NMR (600 MHz, CDCl3): δ 8.22 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 6.78 (s, 1H), 5.50 (s, 1H), 3.65 (d, J = 9.6 Hz, 1H), 1.93 (d, J = 11.4 Hz, 1H), 1.75− 1.57 (m, 5H), 1.33−1.10 (m, 6H). 13C NMR (150 MHz, CDCl3): δ 196.3, 165.9, 134.7, 133.2, 130.9, 128.3, 75.5, 48.4, 32.8, 32.8, 25.4, 24.8. HRMS (ESI), m/z calcd for C15H20NO3 ([M + H]+), 262.1438; found, 262.1438. 4.4.5. 2-Hydroxy-N,N-dimethyl-3-oxobutanamide (4t). The product was isolated by flash chromatography (eluent: EA/PE = 1/18) as a white oil (17 mg, 60%); 1H NMR (600 MHz, CDCl3): δ 4.79 (d, J = 7.2 Hz, 1H), 4.59 (d, J = 6.6 Hz, 1H), 3.09 (s, 3H), 3.03 (s, 3H), 2.21 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 206.5, 167.7, 76.1, 37.1, 36.5, 25.4. HRMS (ESI), m/z calcd for C6H12NO3 ([M + H]+), 146.0812; found, 146.0813.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Fax: (+86)-373-332-5250 (Z.Z.). *E-mail: [email protected]. Fax: (+86)-373-332-5250 (G.Z.). ORCID

Zhiguo Zhang: 0000-0001-6920-0471 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSFC (21272057, 21372065, 21772032, 21702051, and U1604285), Young Backbone Teachers Fund of Henan (2014GGJS-049), Key Project of Henan Educational Committee (15A150015 and 18A150009), Science & Technology Innovation Talents in Universities of Henan Province (17HASTIT002), Outstanding Young Talent Cultivation Project Funding of Henan Normal University (14YR002), and Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (130028742).

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b01526. X-ray single-crystal diffraction data of 2l and 1H and 13C NMR spectra of all compounds (PDF) Crystallographic data of 2l (CIF) 7752

DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754

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DOI: 10.1021/acsomega.7b01526 ACS Omega 2017, 2, 7746−7754