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Oct 18, 2017 - 1,2-Aryl migration, with its unique manner of reconstructing a molecular skeletal, has become one of the most fundamental strategies in...
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TBHP/TBAI-Mediated Oxidative Cascade Reaction Consisting of Dimerization, Cyclization, and 1,2-Aryl Migration: Metal-Free Synthesis of Pyrrolin-4-ones and Highly Substituted Pyrroles Xiaoyuan Zhao,† Yong Zhang,† Jun Deng,‡ Daisy Zhang-Negrerie,† and Yunfei Du*,† †

Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China ‡ School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing 401331, China S Supporting Information *

ABSTRACT: Treatment of enamino esters with TBHP (tbutylhydroperoxide) and TBAI (t-butylammonium iodide) in HFIP (hexafluoroisopropanol) was found to afford a variety of substituted pyrrolin-4-one compounds. This metal-free oxidative cascade reaction consists of the key steps of coupling of two radical intermediates, an intramolecular ring closure, and an exclusive 1,2-aryl radical migration. Upon treatment with a base, the obtained pyrrolin-4-ones could be converted to the highly substituted pyrrole compounds. ical properties including anti-HIV-1,17 antimalarial,18 and antimicrobial activities.19 For example, compound A (Figure 1, A) is a synthetic analogue of a native peptide that can function as an inhibitor of HIV-1 protease;17a TDR32750 (Figure 1, B) has potent activity against Plasmodium falciparum K1,18a and reutericyclin (Figure 1, C), isolated from Lactobacillus sp., shows activity against a broad spectrum of Gram-positive bacteria.19 However, only a few methods have been developed for the construction of this class of framework.20 In this work, we report a metal-free approach for the construction of the pyrrolin-4-one skeleton via a cascade reaction involving a radical 1,2-aryl migration. As a continuation of our effort in searching for new, efficient methods for constructing heterocyclic compounds under metalfree conditions, we investigated the aziridation reaction of enamines mediated by the oxidative system of TBHP and TBAI.21 However, when 1a was treated with TBHP and TBAI in dichloromethane (DCM), no product was detected after 24 h (Table 1, entry 1). Upon using a different solvent, trifluoroethanol (TFE), a rather unexpected product, pyrrolin-4-one 2a, was obtained in a yield of 20% (Table 1, entry 3). The structure of 2a was undoubtedly confirmed by X-ray crystallography analysis.22 This result pointed us into the direction of establishing a new method for the synthesis of pyrrolin-4-ones. A careful literature survey indicated that, in 2007, Dong and co-workers reported a PIFA-mediated cyclization reaction for the construction of pyrrolin-4-ones by using enaminones as starting materials.20a Then a similar oxidative tandem

1,2-Aryl migration, with its unique manner of reconstructing a molecular skeletal, has become one of the most fundamental strategies in organic synthesis.1 1,2-Aryl migration has found broad applications in the assembly of a variety of complex compounds.1b,2 In recent years, chemists have invested a great deal of research effort in developing novel synthetic routes by utilizing such processes. Generally speaking, 1,2-aryl migration can be categorized into three types: (i) via a carbocation intermediate, either generated in an acidic environment (TfOH,3 H2SO4,4 BF3·Et2O5) or in the presence of a transition-metal catalyst (Rh,6 Sm7) (Scheme 1a); (ii) via a Scheme 1. Three Types of 1,2-Aryl Migration

carbanion intermediate, such as in the classic Zimmerman− Grovenstein rearrangement reaction (Scheme 1b);8 (iii) via a free radical intermediate, generated upon treatment with a metal catalyst (Cu,1c,9 Pd,10 Ag,11 Ni12), a nonmetal oxidant (TBPB,13 DTBP,14 TBHP,15 hypervalent iodine2a), or photoirradiation (Scheme 1c).16 However, only a few examples involving 1,2-aryl migration via a radical intermediate have been reported for synthesis of heterocyclic compounds. Pyrroline-4-one derivatives are an important class of heterocyclic compounds, which possess diverse pharmacolog© 2017 American Chemical Society

Received: October 1, 2017 Published: October 18, 2017 12682

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

The Journal of Organic Chemistry

Figure 1. Biologically active pyrroline-4-one derivatives.

Table 1. Reaction Conditions Studya

Scheme 2. Strategies for the Synthesis of Pyrrolin-4-ones

entry

catalyst

solvent

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e

TBAI TBAI TBAI TBAI CuI KI I2 none TBAI TBAI TBAI TBAI TBAI TBAI TBAI

DCM CH3CN TFE HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP

rt rt rt rt rt rt rt rt 30 40 50 60 40 40 40

trace trace 20 60 54 54 56 43 60 72 70 70 52 71 70

dosage to 5 equiv did not raise the yield (Table 1, entries 10, 13, and 14). Finally, running the reaction under an inert environment (N2) did not improve the yield either (Table 1, entry 15). On the basis of all of the screening results, the optimized conditions were concluded to be 40 °C, 3 equiv of TBHP, and 0.2 equiv of TBAI with 1 mmol of 1a in HFIP (4 mL) (Table 1, entry 10). Under the optimized reaction conditions, we explored the substituent tolerance aspect of this cascade reaction. The results, summarized in Table 2, show that a variety of benzyl enamines substituted with alkyl (1b and 1c), methoxy (1d and 1e), halogen (1f and 1h), and trifluoromethyl (1i) groups at the ortho, meta, or para positions were conveniently converted to the corresponding substituted pyrroline-4-ones 2 in good yields. In general, phenyl enamine substrates possessing electron-donating groups gave higher yields than those bearing an electron-withdrawing one (1b−e vs 1f−i). In addition, enamines bearing other aromatic moieties such as naphthyl (1j) and thienyl (1k) groups not only afforded the respective pyrroline-4-one derivative but also afforded higher yields than their phenyl counterpart. The substrate with the R2 group switched from methyl ester to n-butyl ester also underwent a smooth reaction with the desired product 2l, which was isolated in 89% yield. Substrates bearing a methyl (1m), n-butyl (1n), phenyl (1o), substituted phenyl (1p and 1q), and benzyl (1r) as the R1 group were all transformed to the desired products in satisfactory to good yields. Finally, steric effect has been observed in this reaction: substrate 1c (70%) afforded a lower yield than 1b (80%), and substrates bearing a bulky aryl R1 group such as 1o−q afforded lower yields (50−66%) than the other substrates of 1a, 1m, 1n, and 1r (71−82%). One control experiment we conducted was to add 3 equiv of a radical-trapping reagent, TEMPO, into the reaction mixture.

a Reaction conditions: 1a (1 mmol), catalyst (TBAI) (0.2 equiv), oxidant (TBHP, 3 equiv), in a solvent (4 mL). TBHP (70% in water) was first extracted with petroleum ether, which was later evaporated before use. bIsolated yield. cTBHP (1 equiv). dTBHP (5 equiv). e Under N2.

cyclization/1,2-alkyl migration of enamino amides for the synthesis of pyrrolin-4-ones was established by Guan.20b In 2016, Nishiwaki reported a synthesis of polysubstituted pyrrolinones by dimerization of 3-amino-2-butenamides upon treatment with p-TsOH under mild reaction conditions.20c Most recently, Zhang presented a novel construction of pyrrolin-4-ones from β-oxoamides with amine hydrochlorides mediated by an in situ generated TEMPO oxoammonium salt.20d However, all of the above approaches afforded pyrrolin4-one products involving a 1,2-alkyl migration progress, while our method differs from theirs by a 1,2-aryl migration in process and using TBHP/TBAI as an oxidative system (Scheme 2). We started out the reaction condition optimization with solvent screening. Results showed that HFIP (hexafluoroisopropanol) was by far the most favored solvent in comparison to DCM, acetonitrile (CH3CN), and TFE (Table 1, entries 1−4). Various catalysts were then investigated with TBHP as the oxidant and HFIP as the solvent. None of them showed to be more effective than TBAI, although the differences in the yield values did not carry big gaps (Table 1, entries 5−7). Product 2a was formed in 43% yield with no catalyst present (Table 1, entry 8). The most preferable temperature was identified to be 40 °C (Table 1, entries 9−12). Adjusting the oxidant dosage showed that reducing TBHP from 3 to 1 equiv of TBHP decreased the yield from 72% to 52%, while increasing the 12683

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

The Journal of Organic Chemistry Table 2. Substituent Tolerance Study for the TBHP/TBAI-Mediated Cascade Synthesis of Pyrrolin-4-onesa,b

a

Reaction conditions: 1 (1 mmol), TBHP (3 equiv), TBAI (0.2 equiv) in HFIP (4 mL) at 40 °C. bIsolated yield.

provides an additional route for generating the radicals, as TBHP can be expected to decompose into t-BuO• and the hydroxide radical under the reaction temperature without any catalyst.) Next, a hydrogen abstraction in enamine 1a led to the formation of radicals A and B. The coupling reaction between the two radicals led to the generation of intermediate C, which was then hydrolyzed to give intermediate F through an intramolecular cyclization process. A second hydrogen abstraction in F gave intermediate G. 1,2-Aryl migration took place in this step and resulted in the formation of intermediate I. A third hydrogen abstraction took place in I and eventually furnished the final 2a. One practical application of the obtained pyrrolin-4-ones was to be further transformed into various 4-hydroxypyrroles, via a simple decarboxylation and enol tautomerization process. For some of products 2, the conversion was easily carried out in 10% aqueous NaOH at room temperature. Table 3 lists the

The reaction was found to be greatly suppressed with only 20% of the product 2a obtained (Scheme 3). This result indicated that the reaction was at least partially radical in nature. Here, we propose a plausible mechanism (Scheme 4) based on the results from previous studies as well as this one.13−15,20,21c Initially, the interaction between TBHP and the iodide anion through a single-electron transfer process (SET) generated the t-BuOO• and t-BuO• radicals. (This step Scheme 3. Control Reaction with TEMPO

12684

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

The Journal of Organic Chemistry Scheme 4. Plausible Mechanism

Table 3. Base-Mediated Synthesis of 4-Hydroxypyrroles from Pyrrolin-4-onesa,b,c

a

Reaction conditions: 2 (1 mmol) in 10% aqueous NaOH at room temperature unless otherwise stated. bIsolated yield. cThe reaction was performed at 80 °C. follows: s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; m, multiplet, dd, doublet of doublets, brs, broad singlet. The coupling constants (J) are reported in hertz (Hz). High-resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro spectrometer. Melting points were determined with a Micromelting point apparatus without corrections. Organic solutions were concentrated by rotary evaporation below 40 °C in a vacuum. TLC plates were visualized by exposure to ultraviolet light. Reagents were purchased as reagent grade and were used without further purification except TBHP (70% in water, extracted with petroleum ether and was evaporated before use). The solvents were dried by CaH2 before use. All reactions were performed in standard glassware, heated at 70 °C for 3 h before use. Flash column chromatography was performed over silica gel 200−300 m, and the eluent was a mixture of ethyl acetate (EA) and petroleum ether (PE). General Procedure for the Synthesis of Substrates 1. Method 1 (Preparation of 1a−k).23 Substrates 1a−k were prepared adapted from a previously reported procedure with some modification: to a solution of ketone (20 mmol) in THF (80 mL) was added methyl

substrates that were turned into their corresponding 4hydroxypyrroles in the NaOH solution in 50% of yields or higher. In summary, we have described a metal-free synthesis of pyrrolin-4-ones from enamine esters via a one-pot cascade reaction, which consisted of dimerization, cyclization, and 1,2aryl migration processes via a radical mechanism. The obtained pyrrolin-4-ones, in good to excellent yields, could be further transformed into the biologically interesting compounds of 4hydroxypyrroles.

■

EXPERIMENTAL SECTION

General Information. All reactions were carried out at room temperature under air unless otherwise stated. 1H and 13C NMR spectra were recorded on a 400 or 600 MHz spectrometer at 25 °C. Chemical shift (δ) values are given in ppm and referred as the internal standard to TMS, 0.00 ppm. The peak patterns are indicated as 12685

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

The Journal of Organic Chemistry

NMR (600 MHz, CDCl3): δ 7.62−7.42 (m, 2H), 7.18−6.87 (m, 2H), 4.92 (s, 1H), 3.70 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.6, 163.9 (d, J = 207.3 Hz), 159.5, 133.8, 128.1 (d, J = 7.0 Hz), 115.8 (d, J = 18 Hz), 84.5, 50.4. HRMS (ESI) m/z: calcd for C10H11FNO2+ [M + H]+, 196.0768; found, 196.0766. Methyl (Z)-3-Amino-3-(4-chlorophenyl)acrylate (1g). Following the general procedure, 1g was purified by silica gel chromatography (10% EA/PE). Yield: 70% (2.9 g), a white solid, mp 86−88 °C. 1H NMR (600 MHz, CDCl3): δ 7.47 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.93 (s, 1H), 3.71 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.6, 159.3, 136.3, 136.0, 129.1, 127.5, 84.7, 50.5. HRMS (ESI) m/z: calcd for C10H11ClNO2+ [M + H]+, 212.0473; found, 212.0477. (Z)-Methyl 3-Amino-3-(3-bromophenyl)acrylate (1h). Following the general procedure, 1h was purified by silica gel chromatography (10% EA/PE). Yield: 81% (4.1 g), a yellow oil. 1H NMR (600 MHz, CDCl3): δ 7.69 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 4.94 (s, 1H), 3.71 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.5, 158.9, 139.7, 133.2, 130.4, 129.4, 124.9, 122.9, 85.1, 50.57. HRMS (ESI) m/z: calcd for C10H1179BrNO2+ [M + H]+, 255.9968; found, 255.9969. (Z)-Methyl 3-Amino-3-(3-(trifluoromethyl)phenyl)acrylate (1i). Following the general procedure, 1i was purified by silica gel chromatography (10% EA/PE). Yield: 70% (3.4 g), a white solid, mp 37−38 °C. 1H NMR (600 MHz, CDCl3): δ 7.80 (s, 1H), 7.73− 7.70 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 4.98 (s, 1H), 3.72 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.4, 158.9, 138.52, 131.4 (q, J = 32.7 Hz), 129.6, 129.5, 126.9 (q, J = 3.0 Hz), 123.7 (q, J = 225.6 Hz), 123.2 (q, J = 3.1 Hz), 85.5, 50.6. HRMS (ESI) m/z: calcd for C11H11F3NO2+ [M + H]+, 246.0736; found, 246.0733. (Z)-Methyl 3-Amino-3-(naphthalen-2-yl)acrylate (1j). Following the general procedure, 1j was purified by silica gel chromatography (10% EA/PE). Yield: 80% (3.6 g), a white solid, mp 80−82 °C. 1H NMR (600 MHz, CDCl3): δ 8.05 (s, 1H), 7.92−7.84 (m, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.57−7.51 (m, 2H), 5.11 (s, 1H), 3.74 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ 170.8, 160.5, 134.9, 134.2, 133.0, 128.7, 128.5, 127.7, 127.2, 126.8, 125.8, 123.6, 84.8, 50.5. HRMS (ESI) m/z: calcd for C14H14NO2+ [M + H]+, 228.1019; found, 228.1017. (Z)-Methyl 3-Amino-3-(thiophen-2-yl)acrylate (1k). Following the general procedure, 1k was purified by silica gel chromatography (10% EA/PE). Yield: 70% (2.5 g), a white solid, mp 45−46 °C. 1H NMR (600 MHz, CDCl3): δ 7.37−7.35 (m, 2H), 7.07 (dd, J = 4.8, 3.6 Hz, 1H), 5.12 (s, 1H), 3.71 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.5, 153.2, 140.0, 127.9, 127.3, 125.7, 84.0, 50.5. HRMS (ESI) m/z: calcd for C8H10NO2S+ [M + H]+, 184.0427; found, 184.0427. (Z)-Butyl 3-Amino-3-phenyl acrylate (1l). Following the general procedure, 1l was purified by silica gel chromatography (10% EA/PE). Yield: 61% (2.5 g), light yellow oil. 1H NMR (600 MHz, CDCl3): δ 7.52 (d, J = 6.6 Hz, 2H), 7.46−7.32 (m, 3H), 4.95 (s, 1H), 4.10 (t, J = 6.6 Hz, 2H), 1.71−1.57 (m, 2H), 1.49−1.34 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 170.6, 160.5, 137.7, 130.2, 128.8, 126.2, 84.6, 62.9, 31.1, 19.3, 13.8. HRMS (ESI) m/z: calcd for C13H18NO2+ [M + H]+, 220.1332; found, 220.1333. (Z)-Methyl 3-(Methylamino)-3-phenyl acrylate (1m). Following the general procedure, 1m was purified by silica gel chromatography (10% EA/PE). Yield: 71% (2.7 g), a yellow solid, mp 39−40 °C. 1H NMR (600 MHz, CDCl3): δ 8.49 (s, 1H), 7.41−7.40 (m, 3H), 7.35− 7.33 (m, 2H), 4.60 (s, 1H), 3.68 (s, 3H), 2.77 (d, J = 5.4 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 170.9, 165.7, 135.9, 129.2, 128.5, 128.4, 127.9, 84.4, 50.2, 31.5. HRMS (ESI) m/z: calcd for C11H14NO2+ [M + H]+, 192.1019; found, 192.1017. Methyl (Z)-3-(Butylamino)-3-phenyl acrylate (1n). Following the general procedure, 1n was purified by silica gel chromatography (10% EA/PE). Yield: 72% (3.4 g), a yellow oil. 1H NMR (600 MHz, CDCl3): δ 8.55 (s, 1H), 7.39−7.38 (m, 3H), 7.35−7.33 (m, 2H), 4.57 (s, 1H), 3.68 (s, 3H), 3.05 (dd, J = 13.2, 7.2 Hz, 2H), 1.48−1.43 (m, 2H), 1.33−1.29 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 170.8, 165.2, 136.3, 129.1, 128.3, 127.8, 84.3, 50.2, 44.3, 33.1, 19.8, 13.7. HRMS (ESI) m/z: calcd for C14H20NO2+ [M + H]+, 234.1489; found, 234.1488.

dicarbonate (60 mmol) and NaH (40 mmol, 60%). The reaction mixture was refluxed until TLC indicated the total consumption of the ketone. After cooling, the reaction mixture was poured into ice water (100 mL), acidified with aqueous HCl (3 M) to pH 2−3, and extracted with EA (100 mL × 3). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The desired pure product was obtained by silica gel chromatography using a mixture of EA/PE (v/v = 1/9) as the eluent. The obtained β-keto ester (15 mmol) was dissolved in absolute methanol (60 mL), followed by the addition of ammonium formate (75 mmol). The reaction mixture was stirred under reflux for about 5 h and then was filtered through a short pad of Celite. The filtrate was concentrated in vacuo. To the residue was added water (100 mL); then EA (100 mL × 3) was used to extract the mixture, and the organic layer was combined, dried over Na2SO4, and evaporated to dryness. The desired pure product was obtained by silica gel chromatography using a mixture of PE and EA as the eluent. Enamine 1l was prepared under a similar enamination approach by using dibutyl carbonate as the starting material. Method 2 (Preparation of 1m−q).24 A mixture of β-ketone ester (20 mmol), substituted aniline (30 mmol), and glacial acetic acid (30 mmol) was stirred at 80 °C under a nitrogen atmosphere until TLC indicated the total consumption of the β-ketone ester. Then, the resulting mixture was purified by column chromatography using a mixture of EA/PE (v/v = 1/9) as the eluent to afford N-aryl enamines 1. Enamine 1r was prepared according to the literature procedure.25 Methyl (Z)-3-Amino-3-phenyl acrylate (1a). Following the general procedure, 1a was purified by silica gel chromatography (10% EA/PE). Yield: 75% (2.6 g), a white solid, mp 53−54 °C. 1H NMR (600 MHz, CDCl3): δ 7.54 (d, J = 7.2 Hz, 2H), 7.45−7.40 (m, 3H), 4.97 (s, 1H), 3.71 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.8, 160.6, 137.6, 130.3, 128.9, 126.2, 84.2, 50.5. HRMS (ESI) m/z: calcd for C10H12NO2+ [M + H]+, 178.0863; found, 178.0866. (Z)-Methyl 3-Amino-3-p-tolyl acrylate (1b). Following the general procedure, 1b was purified by silica gel chromatography (10% EA/ PE). Yield: 78% (2.9 g), a light yellow solid, mp 63−64 °C. 1H NMR (600 MHz, CDCl3): δ 7.43 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.96 (s, 1H), 3.70 (s, 3H), 2.38 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.8, 160.7, 140.6, 134.7, 129.5, 126.0, 83.7, 50.4, 21.3. HRMS (ESI) m/z: calcd for C11H13NO2+ [M + H]+, 192.1019; found, 192.1019. (Z)-Methyl 3-Amino-3-o-tolyl acrylate (1c). Following the general procedure, 1c was purified by silica gel chromatography (10% EA/PE). Yield: 75% (2.8 g), a yellow oil. 1H NMR (600 MHz, CDCl3): δ 8.11 (brs, 1H), 7.27−7.24 (m, 2H), 7.20−7.16 (m, 2H), 4.73 (brs, 1H), 4.60 (s, 1H), 3.65 (s, 3H), 2.38 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.6, 161.6, 138.1, 135.1, 130.6, 129.1, 127.9, 125.8, 85.6, 50.3, 19.5. HRMS (ESI) m/z: calcd for C11H13NO2+ [M + H]+, 192.1019; found, 192.1016. Methyl (Z)-3-Amino-3-(4-methoxyphenyl)acrylate (1d). Following the general procedure, 1d was purified by silica gel chromatography (10% EA/PE). Yield: 75% (3.1 g), a yellow solid, mp 77−79 °C. 1H NMR (600 MHz, CDCl3): δ 7.49 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 4.94 (s, 1H), 3.84 (s, 3H), 3.71 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.8, 161.3, 160.4, 129.8, 127.5, 114.2, 83.3, 55.4, 50.4. HRMS (ESI) m/z: calcd for C11H14NO3+ [M + H]+, 208.0968; found, 208.0966. (Z)-Methyl 3-Amino-3-(3,4-dimethoxyphenyl)acrylate (1e). Following the general procedure, 1e was purified by silica gel chromatography (10% EA/PE). Yield: 81% (3.8 g), a yellow solid, mp 124−126 °C. 1H NMR (600 MHz, CDCl3): δ 7.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.94 (s, 1H), 3.90 (s, 6H), 3.71 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.7, 160.6, 150.8, 149.0, 130.2, 118.8, 111.0, 109.3, 83.4, 56.0, 50.4. HRMS (ESI) m/z: calcd for C12H15NO4+ [M + H]+, 238.1074; found, 238.1073. Methyl (Z)-3-Amino-3-(4-fluorophenyl)acrylate (1f). Following the general procedure, 1f was purified by silica gel chromatography (10% EA/PE). Yield: 75% (2.9 g), a white solid, mp 53−55 °C. 1H 12686

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

The Journal of Organic Chemistry

Dimethyl 3-Oxo-2,5-di-o-tolyl-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (2c). Following the general procedure, 2c was purified by silica gel chromatography (40% EA/PE). Yield: 70% (265 mg), a white solid, mp 214−215 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.61 (s, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.36−7.22 (m, 6H), 7.15 (d, J = 7.8 Hz, 1H), 3.76 (s, 3H), 3.45 (s, 3H), 2.25 (s, 6H). 13C NMR (150 MHz, DMSO-d6): δ 188.9, 180.6, 166.8, 162.5, 137.5, 135.2, 134.0, 131.8, 131.3, 129.9, 129.8, 128.6, 127.8, 127.2, 126.2, 125.6, 99.9, 77.0, 53.4, 50.1, 19.8, 18.8. HRMS (ESI) m/z: calcd for C22H21NO5Na+ [M + Na]+, 402.1312; found, 402.1310. Dimethyl 2,5-Bis(4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (2d). Following the general procedure, 2d was purified by silica gel chromatography (40% EA/PE). Yield: 76% (312 mg), a white solid, mp 180−181 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.50 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.70 (s, 3H), 3.51 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.9, 178.5, 166.6, 163.2, 162.3, 159.3, 131.0, 127.8, 126.5, 121.8, 113.5, 113.5, 96.8, 74.3, 55.5, 55.2, 53.3, 50.2. HRMS (ESI) m/z: calcd for C22H21NO7Na+ [M + Na]+, 434.1210; found, 434.1207. Dimethyl 2,5-Bis(3,4-dimethoxyphenyl)-3-oxo-2,3-dihydro-1Hpyrrole-2,4-dicarboxylate (2e). Following the general procedure, 2e was purified by silica gel chromatography (EA). Yield: 81% (381 mg), a white solid, mp 200−202 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.43 (brs, 1H), 7.33 (dd, J = 8.4, 1.8 Hz, 1H), 7.29 (d, J = 1.8 Hz, 2H), 7.19−7.10 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.52 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.7, 178.1, 166.5, 163.2, 152.0, 149.0, 148.2, 147.8, 126.8, 122.6, 121.7, 118.7, 112.5, 111.2, 110.9, 110.7, 97.1, 74.2, 55.7, 55.6, 55.5, 53.4, 50.2. HRMS (ESI) m/z: calcd for C24H25NO9Na+ [M + Na]+, 494.1422; found, 494.1420. Dimethyl 2,5-Bis(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2f). Following the general procedure, 2f was purified by silica gel chromatography (40% EA/PE). Yield: 62% (240 mg), a white solid, mp 179−180 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.78 (s, 1H), 7.81−7.78 (m, 2H), 7.74−7.67 (m, 2H), 7.42 (t, J = 8.4 Hz, 2H), 7.27 (t, J = 9.0 Hz, 2H), 3.73 (s, 3H), 3.50 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.5, 178.8, 166.0, 163.9 (d, J = 269.5 Hz), 162.8, 162.3 (d, J = 233.4 Hz), 131.6 (d, J = 7.6 Hz), 130.4, 128.7 (d, J = 7.0 Hz), 126.4, 115.2 (d, J = 18.5 Hz), 115.1 (d, J = 18.1 Hz), 97.5, 74.4, 53.7, 50.2. HRMS (ESI) m/z: calcd for C20H16F2NO5+ [M + H]+, 388.0991; found, 388.0990. Dimethyl 2,5-Bis(4-chlorophenyl)-3-oxo-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2g). Following the general procedure, 2g was purified by silica gel chromatography (40% EA/PE). Yield: 69% (289 mg), a white solid, mp 212−216 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.85 (s, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.66−7.65 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 3.73 (s, 3H), 3.50 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.1, 178.9, 165.7, 162.6, 136.7, 133.4, 132.9, 130.7, 128.7, 128.4, 128.3, 128.2, 97.7, 74.4, 53.7, 50.3. HRMS (ESI) m/z: calcd for C20H1635Cl2NO5+ [M + H]+, 420.0400; found, 420.0438. Dmethyl 2,5-Bis(3-bromophenyl)-3-oxo-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2h). Following the general procedure, 2h was purified by silica gel chromatography (40% EA/PE). Yield: 61% (309 mg), a yellow solid, mp 220−223 °C. 1H NMR (600 MHz, DMSOd6): δ 10.91 (s, 1H), 7.91 (s, 1H), 7.87−7.85 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 7.8, 1.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 3.75 (s, 3H), 3.51 (s, 3H). 13 C NMR (150 MHz, DMSO-d6): δ 187.8, 178.6, 165.5, 162.5, 136.2, 134.5, 132.1, 131.5, 131.0, 130.5, 130.3, 129.3, 128.0, 125.5, 121.5, 121.1, 98.0, 74.3, 53.8, 50.4. HRMS (ESI) m/z: calcd for C20H1579Br81BrNO5Na+ [M + Na]+, 531.9189; found, 531.9187. Dimethyl 3-Oxo-2,5-bis(3-(trifluoromethyl)phenyl)-2,3-dihydro1H-pyrrole-2,4-dicarboxylate (2i). Following the general procedure, 2i was purified by silica gel chromatography (40% EA/PE). Yield: 53% (258 mg), a white solid, mp 202−205 °C. 1H NMR (600 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.07 (d, J = 3.6 Hz, 2H), 8.04 (t, J = 7.0 Hz, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 3.77 (s, 3H), 3.50 (s, 3H). 13C

Methyl (Z)-3-Phenyl-3-(phenylamino)acrylate (1o). Following the general procedure, 1o was purified by silica gel chromatography (10% EA/PE). Yield: 65% (3.3 g), a yellow solid, mp 80−83 °C. 1H NMR (600 MHz, CDCl3): δ 10.28 (s, 1H), 7.35−7.33 (m, 3H), 7.31−7.26 (m, 2H), 7.07 (t, J = 7.8 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 7.8 Hz, 2H), 5.00 (s, 1H), 3.74 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.5, 159.3, 140.3, 136.0, 129.5, 128.6, 128.5, 128.3, 123.1, 122.3, 90.7, 50.72. HRMS (ESI) m/z: calcd for C16H16NO2+ [M + H]+, 254.1176; found, 254.1177. Methyl (Z)-3-((4-Methoxyphenyl)amino)-3-phenyl acrylate (1p). Following the general procedure, 1p was purified by silica gel chromatography (10% EA/PE). Yield: 62% (3.5 g), a yellow solid, mp 86−87 °C. 1H NMR (600 MHz, CDCl3): δ 10.20 (s, 1H), 7.34−7.29 (m, 3H), 7.27−7.24 (m, 2H), 6.68−6.56 (m, 4H), 4.94 (s, 1H), 3.73 (s, 3H), 3.69 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.6, 160.1, 155.9, 136.0, 133.4, 129.3, 128.4, 128.3, 124.4, 113.9, 89.1, 55.3, 50.6. HRMS (ESI) m/z: calcd for C17H18NO3+ [M + H]+, 284.1281; found, 284.1286. Methyl (Z)-3-((4-Chlorophenyl)amino)-3-phenyl acrylate (1q). Following the general procedure, 1q was purified by silica gel chromatography (10% EA/PE). Yield: 65% (3.7 g), a colorless solid, mp 94−96 °C. 1H NMR (600 MHz, CDCl3): δ 10.24 (s, 1H), 7.36− 7.34 (m, 1H), 7.33−7.27 (m, 4H), 7.03 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 5.03 (s, 1H), 3.74 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.4, 158.8, 139.0, 135.5, 129.7, 128.7, 128.6, 128.3, 128.2, 123.3, 91.4, 50.81. HRMS (ESI) m/z: calcd for C16H15ClNO2+ [M + H]+, 288.0786; found, 288.0788. Methyl (Z)-3-(Benzylamino)-3-phenyl acrylate (1r). Following the general procedure, 1r was purified by silica gel chromatography (10% EA/PE). Yield: 50% (2.7 g), a yellow solid, mp 45−47 °C. 1H NMR (600 MHz, CDCl3): δ 8.92 (s, 1H), 7.39−7.30 (m, 5H), 7.27 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 4.69 (s, 1H), 4.25 (d, J = 6.0 Hz, 2H), 3.66 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.7, 164.9, 139.3, 135.9, 129.4, 128.7, 128.5, 128.2, 127.9, 127.3, 126.9, 85.9, 50.3, 48.4. HRMS (ESI) m/z: calcd for C17H18NO2+ [M + H]+, 268.1332; found, 268.1333. General Procedure for the Synthesis of Products 2 and 3. To a suspension of enamine 1 (1 mmol) and TBAI (0.2 mmol) in HFIP (4 mL) was added TBHP (3 mmol) dropwise at 40 °C. The resulting mixture was kept at the same temperature until TLC indicated that the total consumption of enamine 1. The solvent was removed, and the residue was purified by flash column chromatography on silica gel (EA/PE = 4/6) to afford the desired compound 2. Compound 2 (0.1 mmol) was added to a 10% aqueous NaOH (1 mL) solution and stirred at room temperature or 80 °C until TLC indicated that the total consumption of pyrroline-4-ones 2. The residue was extracted with EA (10 mL × 3). The organic phase was washed with brine (20 mL × 1) and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by flash column chromatography on silica gel (EA/PE = 1/9) to afford the desired compounds 3. Dimethyl 3-Oxo-2,5-diphenyl-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (2a). Following the general procedure, 2a was purified by silica gel chromatography (40% EA/PE). Yield: 72% (252 mg), a white solid, mp 212−214 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.76 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.66−7.63 (m, 3H), 7.57 (t, J = 7.8 Hz, 2H), 7.46−7.36 (m, 3H), 3.73 (s, 3H), 3.48 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.5, 179.7, 166.1, 162.8, 134.3, 131.8, 130.1, 128.7, 128.4, 128.2, 128.1, 126.5, 97.5, 75.0, 53.5, 50.2. HRMS (ESI) m/z: calcd for C20H17NO5Na+ [M + Na]+, 374.0999; found, 374.0999. Dimethyl 3-Oxo-2,5-di-p-tolyl-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (2b). Following the general procedure, 2b was purified by silica gel chromatography (40% EA/PE). Yield: 80% (303 mg), a light yellow solid, mp 220−223 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.63 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 3.72 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.7, 179.3, 166.3, 163.0, 142.1, 137.8, 131.6, 128.8, 128.7, 128.6, 127.1, 126.4, 97.2, 74.8, 53.4, 50.2, 21.1, 20.6. HRMS (ESI) m/z: calcd for C22H21NO5Na+ [M + Na]+, 402.1312; found, 402.1312. 12687

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

The Journal of Organic Chemistry NMR (150 MHz, DMSO-d6): δ 187.8, 179.0, 165.4, 162.5, 135.0, 133.0, 130.9, 130.5, 129.5, 129.4, 129.0 (d, J = 26.4 Hz), 128.8 (d, J = 26.8 Hz), 128.4, 125.5 (d, J = 3.4 Hz), 125.4 (d, J = 3.0 Hz), 124.0 (q, J = 225.6 Hz), 123.8 (q, J = 225.8 Hz), 123.3 (d, J = 3.3 Hz), 98.2, 74.5, 53.9, 50.3. HRMS (ESI) m/z: calcd for C22H16F6NO5+ [M + H]+, 488.0927; found, 488.0924. Dimethyl 2,5-Di(naphthalen-2-yl)-3-oxo-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2j). Following the general procedure, 2j was purified by silica gel chromatography (40% EA/PE). Yield: 83% (374 mg), a white solid, mp 240−241 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.40 (s, 1H), 8.16−8.15 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.05−7.99 (m, 2H), 7.96−7.95 (m, 1H), 7.83 (dd, J = 9.0, 1.8 Hz, 1H), 7.76 (dd, J = 8.4, 1.8 Hz, 1H), 7.72−7.64 (m, 2H), 7.58−7.56 (m, 2H), 3.78 (s, 3H), 3.51 (s, 3H). 13 C NMR (150 MHz, DMSO-d6): δ 188.7, 179.9, 166.3, 162.9, 134.3, 132.6, 132.4, 132.0, 131.8, 128.9, 128.9, 128.7, 128.1, 127.9, 127.7, 127.4, 127.0, 126.7, 126.5, 125.6, 125.4, 124.7, 98.0, 75.4, 53.6, 50.3. HRMS (ESI) m/z: calcd for C28H21NO5Na+ [M + Na]+, 474.1312; found, 474.1311. Dimethyl 3-Oxo-2,5-di(thiophen-2-yl)-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2k). Following the general procedure, 2k was purified by silica gel chromatography (40% EA/PE). Yield: 95% (345 mg), a light yellow solid, mp 188−189 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.18−8.17 (m, 2H), 7.56 (d, J = 4.8 Hz, 1H), 7.36 (t, J = 4.2 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 7.06 (t, J = 3.6 Hz, 1H), 3.73 (s, 3H), 3.62 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.0, 170.4, 165.6, 163.3, 136.3, 135.4, 134.4, 129.4, 127.8, 126.8, 126.5, 125.8, 95.8, 72.8, 53.6, 50.6. HRMS (ESI) m/z: calcd for C16H13NO5S2Na+ [M + Na]+, 386.0127; found, 386.0124. Dibutyl 3-Oxo-2,5-diphenyl-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (2l). Following the general procedure, 2l was purified by silica gel chromatography (40% EA/PE). Yield: 72% (313 mg), a white solid, mp 124−125 °C. 1H NMR (600 MHz, DMSO-d6): δ 10.65 (s, 1H), 7.67−7.62 (m, 5H), 7.57 (t, J = 7.8 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 4.21−4.10 (m, 2H), 3.88 (t, J = 6.6 Hz, 2H), 1.57−1.50 (m, 2H), 1.38−1.25 (m, 4H), 1.14−1.05 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, DMSOd6): δ 188.7, 179.6, 165.5, 162.3, 134.2, 131.5, 130.6, 128.4, 128.3, 128.1, 128.1, 126.5, 97.8, 75.1, 65.8, 62.4, 30.1, 29.9, 18.5, 18.4, 13.5, 13.4. HRMS (ESI) m/z: calcd for C26H29NO5Na+ [M + Na]+, 458.1938; found, 458.1938. Dimethyl 1-Methyl-3-oxo-2,5-diphenyl-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2m). Following the general procedure, 2m was purified by silica gel chromatography (40% EA/PE). Yield: 71% (259 mg), a white solid, mp 160−161 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.59−7.58 (m, 3H), 7.52−7.42 (m, 7H), 3.85 (s, 3H), 3.40 (s, 3H), 2.81 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 187.9, 181.3, 164.9, 162.2, 132.6, 130.5, 129.4, 128.8, 128.8, 128.5, 127.6, 127.5, 99.5, 81.0, 53.8, 50.1, 32.4. HRMS (ESI) m/z: calcd for C21H19NO5Na+ [M + Na]+, 388.1155; found, 388.1154. Dimethyl 1-Butyl-3-oxo-2,5-diphenyl-2,3-dihydro-1H-pyrrole-2,4dicarboxylate (2n). Following the general procedure, 2n was purified by silica gel chromatography (40% EA/PE). Yield: 77% (313 mg), a white solid, mp 125−127 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.61−7.56 (m, 3H), 7.53−7.38 (m, 7H), 3.84 (s, 3H), 3.40 (s, 3H), 3.36−3.31 (m, 1H), 3.24−3.16 (m, 1H), 0.94−0.91 (m, 1H), 0.73 (dt, J = 14.4, 7.2 Hz, 2H), 0.66−0.63 (m, 1H), 0.41 (t, J = 7.8 Hz, 3H). 13C NMR (100 MHz, DMSO): δ 188.8, 181.7, 166.2, 162.7, 133.9, 130.7, 130.4, 129.5, 129.2, 128.9, 128.7, 127.7, 100.7, 81.5, 54.1, 50.6, 45.7, 31.1, 19.5, 13.3. HRMS (ESI) m/z: calcd for C24H25NO5Na+ [M + Na]+, 430.1625; found, 430.1627. Dimethyl 3-Oxo-1,2,5-triphenyl-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (2o). Following the general procedure, 2o was purified by silica gel chromatography (40% EA/PE). Yield: 66% (282 mg), a yellow solid, mp 179−181 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.44 (d, J = 7.2 Hz, 2H), 7.41−7.35 (m, 6H), 7.33 (t, J = 7.8 Hz, 2H), 7.12−7.05 (m, 3H), 6.81−6.80 (m, 2H), 3.75 (s, 3H), 3.50 (s, 3H). 13 C NMR (150 MHz, DMSO-d6): δ 189.3, 180.5, 165.4, 162.3, 136.9, 133.4, 130.6, 129.5, 129.0, 128.9, 128.7, 128.6, 128.4, 128.2, 128.0,

127.9, 102.8, 83.2, 53.5, 50.6. HRMS (ESI) m/z: calcd for C26H21NO5Na+ [M + Na]+, 450.1312; found, 450.1311. Dimethyl 1-(4-Methoxyphenyl)-3-oxo-2,5-diphenyl-2,3-dihydro1H-pyrrole-2,4-dicarboxylate (2p). Following the general procedure, 2p was purified by silica gel chromatography (40% EA/PE). Yield: 50% (228 mg), a brown solid, mp 163−164 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.52−7.26 (m, 10H), 6.73 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H), 3.59 (s, 3H), 3.49 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 189.3, 180.8, 165.4, 162.3, 158.3, 133.5, 130.3, 129.8, 129.7, 129.2, 128.9, 128.8, 128.6, 128.4, 127.8, 113.8, 102.2, 83.3, 55.1, 53.5, 50.5. HRMS (ESI) m/z: calcd for C27H23NO6Na+ [M + Na]+, 480.1418; found, 480.1420. Dimethyl 1-(4-Chlorophenyl)-3-oxo-2,5-diphenyl-2,3-dihydro1H-pyrrole-2,4-dicarboxylate (2q). Following the general procedure, 2q was purified by silica gel chromatography (40% EA/PE). Yield: 58% (267 mg), a gray solid, mp 151−152 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.45 (d, J = 8.4 Hz, 2H), 7.41−7.34 (m, 8H), 7.18 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.77 (s, 3H), 3.51 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 189.1, 180.3, 165.3, 162.2, 135.9, 133.2, 132.4, 130.7, 130.1, 129.3, 129.0, 129.0, 128.8, 128.6, 128.6, 128.0, 103.2, 83.2, 53.7, 50.6. HRMS (ESI) m/z: calcd for C26H2135ClNO5+ [M + H]+, 462.1103; found, 462.1100. Dimethyl 1-Benzyl-3-oxo-2,5-diphenyl-2,3-dihydro-1H-pyrrole2,4-dicarboxylate (2r). Following the general procedure, 2r was purified by silica gel chromatography (40% EA/PE). Yield: 82% (361 mg), a light yellow solid, mp 137−138 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.58−7.31 (m, 10H), 7.08−7.05 (m, 3H), 6.64 (d, J = 7.8 Hz, 2H), 4.80 (d, J = 16.8 Hz, 1H), 4.47 (d, J = 16.8 Hz, 1H), 3.48 (s, 3H), 3.41 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 188.6, 181.7, 165.6, 162.1, 135.0, 132.9, 130.1, 129.6, 128.9, 128.8, 128.2, 128.1, 128.0, 127.4, 127.2, 126.7, 101.0, 80.7, 53.2, 50.2, 48.5. HRMS (ESI) m/z: calcd for C27H23NO5Na+ [M + Na]+, 464.1468; found, 464.1469. Methyl 4-Hydroxy-2,5-diphenyl-1H-pyrrole-3-carboxylate (3a). Following the general procedure, 3a was purified by silica gel chromatography (10% EA/PE). Yield: 90% (26 mg), a white solid, mp 180−183 °C. 1H NMR (600 MHz, CDCl3): δ 8.68 (s, 1H), 8.08 (brs, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.45−7.39 (m, 5H), 7.18 (t, J = 7.8 Hz, 1H), 3.78 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 167.9, 145.3, 133.0, 132.0, 130.9, 128.9, 128.8, 128.6, 128.3, 125.5, 123.3, 113.2, 101.0, 51.18. HRMS (ESI) m/z: calcd for C18H16NO3+ [M + H]+, 294.1125; found, 294.1124. Methyl 2,5-Bis(4-chlorophenyl)-4-hydroxy-1H-pyrrole-3-carboxylate (3b). Following the general procedure, 3b was purified by silica gel chromatography (10% EA/PE). Yield: 73% (26 mg), a white solid, mp 199−201 °C. 1H NMR (600 MHz, CDCl3): δ 8.66 (s, 1H), 8.03 (brs, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 167.5, 145.5, 134.8, 132.0, 131.0, 130.2, 130.1, 129.2, 129.0, 128.6, 124.5, 112.7, 101.3, 51.32. HRMS (ESI) m/z: calcd for C18H1435Cl2NO3+ [M + H]+, 362.0345; found, 362.0347. Methyl 2,5-Bis(4-fluorophenyl)-4-hydroxy-1H-pyrrole-3-carboxylate (3c). Following the general procedure, 3c was purified by silica gel chromatography (10% EA/PE). Yield: 96% (32 mg), a white solid, mp 180−181 °C. 1H NMR (600 MHz, CDCl3): δ 8.55 (s, 1H), 8.02 (s, 1H), 7.60 (dd, J = 8.4, 5.4 Hz, 2H), 7.51 (dd, J = 8.4, 5.4 Hz, 2H), 7.13−7.07 (m, 4H), 3.77 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 167.6, 162.7 (d, J = 267.4 Hz), 161.0 (d, J = 264.4 Hz), 144.6, 132.0, 130.7 (d, J = 6.8 Hz), 128.0, 127.1, 125.0 (d, J = 6.4 Hz), 115.9 (d, J = 18.0 Hz), 115.4 (d, J = 18.0 Hz), 112.5, 101.1, 51.2. HRMS (ESI) m/z: calcd for C18H14F2NO3+ [M + H]+, 330.0936; found, 330.0935. Methyl 4-Hydroxy-2,5-di-o-tolyl-1H-pyrrole-3-carboxylate (3d). Following the general procedure, 3d was purified by silica gel chromatography (10% EA/PE). Yield: 52% (17 mg), a white solid, mp 158−161 °C. 1H NMR (600 MHz, CDCl3): δ 8.15 (s, 1H), 7.76 (brs, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.35−7.12 (m, 7H), 3.66 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 167.8, 143.1, 137.7, 136.4, 132.2, 132.1, 130.9, 130.4, 130.3, 130.1, 129.0, 128.8, 127.4, 125.9, 125.4, 112.6, 101.6, 51.1, 20.7, 20.0. HRMS (ESI) m/z: calcd for C20H20NO3+ [M + H]+, 322.1438; found, 322.1436. 12688

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

The Journal of Organic Chemistry

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Methyl 2,5-Bis(3,4-dimethoxyphenyl)-4-hydroxy-1H-pyrrole-3carboxylate (3e). Following the general procedure, 3e was purified by silica gel chromatography (40% EA/PE). Yield: 85% (35 mg), a yellow solid, mp 199−200 °C. 1H NMR (600 MHz, DMSO-d6): δ 11.24 (s, 1H), 8.57 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.4, 1.8 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.4, 1.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 3.81 (s, 6H), 3.79 (s, 3H), 3.75 (s, 3H), 3.69 (s, 3H). 13C NMR (150 MHz, DMSO): δ 166.8, 148.8, 148.7, 147.8, 146.3, 142.9, 132.7, 124.7, 124.3, 122.0, 116.4, 113.6, 113.0, 112.2, 111.1, 108.0, 99.9, 55.6, 55.6, 55.5, 50.7. HRMS (ESI) m/z: calcd for C22H24NO7+ [M + H]+, 414.1547; found, 414.1546. Methyl 4-Hydroxy-2,5-di(thiophen-2-yl)-1H-pyrrole-3-carboxylate (3f). Following the general procedure, 3f was purified by silica gel chromatography (10% EA/PE). Yield: 76% (23 mg), a brown solid, mp 96−97 °C. 1H NMR (600 MHz, CDCl3): δ 8.51 (s, 1H), 8.13 (s, 1H), 7.36−7.35 (m, 2H), 7.17 (d, J = 5.4 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 7.06 (t, J = 4.2 Hz, 1H), 7.03 (m, J = 4.2 Hz, 1H), 3.84 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ 167.2, 144.1, 132.8, 132.3, 127.5, 127.5, 127.4, 126.5, 125.7, 122.4, 120.6, 110.2, 100.9, 51.3. HRMS (ESI) m/z: calcd for C14H12NO3S2+ [M + H]+, 306.0253; found, 306.0256. Methyl 1-Butyl-4-hydroxy-2,5-diphenyl-1H-pyrrole-3-carboxylate (3g). Following the general procedure, 3g was purified by silica gel chromatography (10% EA/PE). Yield: 80% (28 mg), a white solid, mp 104−105 °C. 1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.49−7.41 (m, 9H), 7.30 (t, J = 7.8 Hz, 1H), 3.81 (t, J = 7.2 Hz, 2H), 3.61 (s, 3H), 1.23−1.04 (m, 2H), 0.83−0.51 (m, 2H), 0.52 (t, J = 7.2 Hz, 3H). 13 C NMR (150 MHz, CDCl3): δ 167.6, 144.0, 135.0, 131.9, 130.8, 130.8, 129.5, 128.6, 128.4, 127.9, 126.9, 115.8, 100.8, 50.8, 44.8, 32.3, 19.3, 13.3. HRMS (ESI) m/z: calcd for C22H24NO3+ [M + H]+, 350.1751; found, 350.1751. Methyl 4-Hydroxy-1,2,5-triphenyl-1H-pyrrole-3-carboxylate (3h). Following the general procedure, 3h was purified by silica gel chromatography (10% EA/PE). Yield: 50% (18 mg), a white solid, mp 163−165 °C. 1H NMR (600 MHz, CDCl3): δ 8.39 (s, 1H), 7.23−7.04 (m, 13H), 6.90 (d, J = 7.8 Hz, 2H), 3.67 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 167.9, 144.5, 137.6, 134.7, 131.3, 131.3, 130.2, 128.9, 128.8, 128.6, 127.9, 127.9, 127.5, 127.2, 125.9, 116.4, 101.7, 51.1. HRMS (ESI) m/z: calcd for C24H20NO3+ [M + H]+, 370.1438; found, 370.1439.

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ASSOCIATED CONTENT

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02491. Spectral data for all new compounds (PDF) Crystal data for 2a (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jun Deng: 0000-0002-6547-0244 Yunfei Du: 0000-0002-0213-2854 Notes

The authors declare no competing financial interest.

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S Supporting Information *

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Article

ACKNOWLEDGMENTS

We acknowledge the National Science Foundation of China (no. 21472136) and the Tianjin Research Program of Application Foundation and Advanced Technology (no. 15JCZDJC32900) for financial support. 12689

DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690

Article

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NOTE ADDED AFTER ASAP PUBLICATION Table 2 and 3 compounds were added October 30, 2017.

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DOI: 10.1021/acs.joc.7b02491 J. Org. Chem. 2017, 82, 12682−12690