Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2017 Oct 17;2(10):6844–6851. doi: 10.1021/acsomega.7b00626

Ammonium Acetate-Promoted One-Pot Tandem Aldol Condensation/Aza-Addition Reactions: Synthesis of 2,3,6,7-Tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones

Zhiguo Zhang †,§,*, Xiaolong Gao †, Yameng Wan †, Yuanyuan Huang †, Guoqing Huang ‡, Guisheng Zhang †,*
PMCID: PMC6645481  PMID: 31457270

Abstract

graphic file with name ao-2017-006263_0001.jpg

An efficient tandem intermolecular one-pot aldol condensation/aza-addition reaction of 2-methyl-3-carbamoylpyrroles and aldehydes was developed for the synthesis of 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones. The reaction proceeded using only 3.0 equiv of ammonium acetate promoter in green solvent poly(ethylene glycol)-400 at 100 °C to afford a series of pyrrolo[3,2-c]pyridinone derivatives in good to excellent yields.

1. Introduction

Pyrrolo[3,2-c]pyridinones are important nitrogen-containing fused heterocyclic compounds that act as essential structures in the skeletons of numerous biologically active molecules, such as TAK-4411 and PH-089 (Figure 1).2 These molecules possess a wide variety of bioactivities, including DP receptor antagonists, CK1γ inhibitors, CB2 agonists, Cdc7 kinase inhibitors, PLK1 inhibitors, ATP competition, MK2 inhibitors, and NAMPT inhibitors.3 Pyrrolo[3,2-c]pyridinones are also valuable intermediates in organic synthesis.4 The two strategies most commonly used to access this type of fused heterocycle are cyclizations of preprepared functionalized pyrroles or pyridine derivatives via multistep procedures.5 Other efficient methods to prepare these compounds from simple materials via multicomponent domino reactions have also been established.6 In 2004, Xi et al.6a reported the development of a multicomponent domino reaction for the preparation of pyrrolo[3,2-c]pyridines, which involved the reaction of Si-tethered diynes with three different organonitriles in the presence of a zirconocene species. Despite these advances, the development of a one-pot approach to the construction of pyrrolo[3,2-c]pyridines in an environmentally benign and economically viable manner and with a broad substrate scope remains largely unrealized. Herein, we report the synthesis of 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones via the one-pot domino aldol condensation/aza-addition reaction of functionalized pyrroles and aldehydes using only 3.0 equiv of ammonium acetate promoter in green solvent poly(ethylene glycol)-400 (PEG-400).

1. 1
1. 2

Figure 1.

Figure 1

Open in a new tab

Structures of TAK-441 and PH-089.

In 2014, we developed an iron-catalyzed vinylogous aldol condensation of Biginelli reaction products with aryl aldehydes for the synthesis of potential bioactive (E)-6-arylvinyl-dihydropyrimidin-2(1H)-ones.7 These materials were shown to be valuable synthetic precursors to druglike pyrido[4,3-d]pyrimidine derivatives via the intramolecular addition reaction of alkenes with the amide group at the 5-position in the dihydropyrimidin-2(1H)-ones. In 2015, we developed a facile and efficient one-pot approach to the synthesis of 1H-pyrrolo[3,2-c]pyridin-4(5H)-one derivatives via the domino ring-opening/cyclization/aza-addition reaction of doubly activated cyclopropanes with amines, which did not require a catalyst or additives (eq 1).6b Our interest in the construction of this type of heterocycle has continued with the new strategy reported herein. Ammonium acetate, a mild weak-acid weak-base salt, is widely used in organic synthesis and has frequently served as an important ammonia source in the synthesis of various heterocyclic scaffolds,8 a base for effective Knoevenagel condensations,9 an acid in a variant of the Pummerer reaction,10 and to facilitate dissolution.11 Combining these applications with our recent work on heterocycle synthesis,12 especially regarding pyrrole derivatization,13 we deduced that readily available 2-methyl-3-carbamoylpyrroles (1)14 and aldehydes (2) would undergo condensation followed by an intramolecular aza-addition reaction to afford fused heterocycles 1H-pyrrolo[3,2-c]pyridin-4(5H)-ones in the presence of ammonium acetate (eq 2).15

2. Results and Discussion

With this reaction in mind, N-(4-chlorophenyl)-2-methyl-1-(p-tolyl)-4,5-dihydro-1H-pyrrole-3-carboxamide (1a) was selected as a model substrate13e and reacted with benzaldehyde (2a) to optimize the reaction conditions. The results of these optimization experiments are summarized in Table 1. Compound 3a was isolated as a white solid in 92% yield when 1a and 2a were treated with 5 equiv of ammonium acetate in PEG-400 (3 mL) under N2 atmosphere at 100 °C for 4 h (Table 1, entry 1).16 Further investigation showed that 3 equiv of ammonium acetate was adequate for this transformation (Table 1, entry 2). However, the yield of 3a dropped dramatically when the reaction was performed in the presence of 1 equiv of ammonium acetate for 5 h (Table 1, entry 3). Decreasing or increasing the reaction temperature was not helpful to improve the yield of 3a (Table 1, entries 4 and 5). Similar results were observed under an O2 atmosphere, open-air conditions, and even with the addition of oxidant DDQ under N2 atmosphere (Table 1, entries 6–8). Five different ammonium-containing salts, namely, NH4F, FeSO4(NH4)2SO4·6H2O, NH4VO3, NH4HCO3, and (NH4)2SO4, were evaluated in the reaction. The experiments indicated that these ammonium salts showed a slightly lower catalytic efficiency than that of ammonium acetate (Table 1, entries 9–13). Significantly lower yields of 3a (40–80%) were obtained when dimethyl sulfoxide (DMSO), ethanol (EtOH), 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4), and 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF6) were used as solvents instead of PEG-400 (Table 1, entries 14–17).

Table 1. Survey of Reaction Conditionsa.

2.

entry ammonium salt (equiv) solvent time/h 3a/%
1 NH4OAc (5.0) PEG-400 4 88
2 NH4OAc (3.0) PEG-400 5 90
3 NH4OAc (1.0) PEG-400 5 85
4 NH4OAc (3.0)/80 °C PEG-400 5 83
5 NH4OAc (3.0)/120 °C PEG-400 4 87
6 NH4OAc (3.0)/Air PEG-400 3 70
7 NH4OAc (3.0)/O2 PEG-400 5 80
8 NH4OAc (3.0)/DDQ (2.2) PEG-400 6 0b
9 NH4F (3.0) PEG-400 5 83
10 FeSO4(NH4)2SO4·6H2O (3.0) PEG-400 5 80
11 NH4VO3 (3.0) PEG-400 5 78
12 NH4HCO3 (3.0) PEG-400 5 86
13 (NH4)2SO4 (3.0) PEG-400 5 85
14 NH4OAc (3.0) DMSO 5 80
15 NH4OAc (3.0) EtOH 5 40
16 NH4OAc (3.0) [BMIM]BF4 5 70
17 NH4OAc (3.0) [BMIM]PF6 5 65
Open in a new tab
a

Unless otherwise indicated, all reactions were carried out in a sealed tube with 1a (0.5 mmol) and 2a (0.55 mmol) in solvent (3 mL) at 100 °C under N2.

b

1,5-Bis(4-chlorophenyl)-6-phenyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (4a) was isolated in 90% yield.

With optimized reaction conditions in hand (Table 1, entry 2), this tandem aldol/aza-addition reaction was extended to an array of functionalized pyrroles 1 and aldehydes 2 to explore the scope and limitations of the reaction. The results are summarized in Table 2. The impact of the R1 substituent on the amide moiety of pyrroles 1 on the outcome of this tandem reaction was evaluated. The results indicated that starting materials 1a–e, which bear electron-withdrawing groups (EWG) or electron-donating groups (EDG) on the aryl moiety, reacted efficiently with 2a to afford corresponding products 3a–f in 72–93% yields, except for 3e, which was isolated in a slightly lower yield (65%). R1 groups with aliphatic substituents were not tested due to the limited availability of preparation methods for these types of starting materials. However, a variety of R2 substituents were tested, with substrates bearing chloro- or methoxyl- groups at the para-, meta-, or ortho-positions of the benzene ring found to be well tolerated (3g–l). In addition to phenyl derivatives at R2, we also examined aliphatic substrates. The transformation proceeded well using benzyl- and cyclohexyl-substituted substrates 1m and 1n, affording desired compounds 3m and 3n, respectively, in excellent yields.

Table 2. Extension of the Reaction Scopea.

2.

Open in a new tab
a

Unless otherwise indicated, all reactions were carried out with 1 (0.5 mmol), 2 (0.55 mmol), and NH4OAc (3.0 equiv) in PEG-400 (3 mL) at 100 °C under an N2 atmosphere in a sealed tube.

The scope of the methodology with respect to the aldehyde was also evaluated in reactions with pyrrole derivative 1a. The results showed that the electronic nature and position (ortho-, meta-, or para-) of the substituents (−OMe, −Cl, and −CO2Et) on the phenyl ring had little impact on the yield of the corresponding fused cyclic compounds 3o–x (79–88%). Similarly, cyclohexanecarbaldehyde, cyclopropanecarbaldehyde, and heterocyclic formaldehydes, such as 2-thenaldehyde and 2-pyridinecarboxaldehyde, were well tolerated in the reaction, affording the desired products 3y–b′ in 67–75% yields.

During this research, we failed to isolate any intermediates from the reaction mixture. However, liquid chromatography–mass spectrometry analysis of the reaction mixtures showed molecular ion peaks with almost the same m/z value (415.3036) as that of the product 3a (415.2387).17 It suggested that species A might be a reaction intermediate. Accordingly, a plausible reaction mechanism was proposed, as shown in Scheme 1. First, compounds 1 and 2 undergo aldol condensation to afford intermediate A, assisted by ammonium acetate.9a,18 Subsequently, intermediate A undergoes an intramolecular nucleophilic aza-addition reaction to afford the final product 3.6b,19 However, another plausible mechanism involving an ammonium acetate-assisted 6π-azaelectrocyclization could not be excluded.20

Scheme 1. Proposed Mechanism.

Scheme 1

Open in a new tab

3. Conclusions

In summary, a facile and efficient one-pot domino reaction has been developed for the synthesis of 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones from 2-methyl-3-carbamoylpyrroles and aldehydes in the presence of ammonium acetate (3.0 equiv) in green solvent PEG-400 at 100 °C. This high atom economy protocol uses readily available starting materials, affords good to excellent yields, and has a broad substrate scope.

4. Experimental Section

4.1. General Remarks

All reactions were carried out at 100 °C, unless otherwise indicated. All other reagents were purchased from commercial sources and used without further treatment, unless otherwise indicated. Starting material 1 was prepared by following previous methods.14 Petroleum ether (PE) used here refers to the 60–90 °C boiling point fraction of petroleum. Ethyl acetate is abbreviated as EA. 1H NMR and 13C NMR spectra were recorded on Bruker Avance/600 (1H: 600 MHz, 13C: 150 MHz at 25 °C) or Bruker Avance/400 (1H: 400 MHz, 13C: 100 MHz at 25 °C) and tetramethylsilane as the 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 orthogonal acceleration time-of-flight (ESI-oa-TOF), and the purity of all samples used for HRMS (>95%) was confirmed by 1H NMR and 13C NMR spectroscopic analysis. Melting points were measured on a melting point apparatus equipped with a thermometer and were uncorrected. All reactions were monitored by thin-layer chromatography (TLC) with GF254 silica gel-coated plates, and in general, it was designated as the end of the reaction when the starting material 1 was consumed 1 h later. Flash chromatography was carried out on SiO2 (silica gel 200–300 mesh).

4.2. Typical Experimental Procedure for the Synthesis of 3 (3a as an Example)

To a sealed tube with a branch pipe (25 mL) were added N-(4-chlorophenyl)-2-methyl-1-(p-tolyl)-4,5-dihydro-1H-pyrrole-3-carboxamide 1a (163 mg, 0.5 mmol), benzaldehyde 2a (58.3 mg, 0.55 mmol), and NH4OAc (115.6 mg, 1.5 mmol) and filled with nitrogen through the branch pipe by standard Schlenk techniques; then, the mixture was well stirred for 5 h in PEG-400 (3 mL) at 100 °C (the whole process was closely monitored by TLC). After the completion of the reaction, the reaction was quenched by water (10 mL) and the mixture was extracted with dichloromethane (3 × 5 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude product was purified by flash column chromatography with EA/PE to afford 3a (191 mg, 90%).

4.2.1. 5-(4-Chlorophenyl)-6-phenyl-1-(p-tolyl)-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3a)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (191 mg, 90%): mp 181–182 °C; 1H NMR (400 MHz, CDCl3) δ 7.27–7.16 (m, 5H), 7.13 (d, J = 8.8 Hz, 2H), 7.06 (m, 4H), 6.73 (d, J = 8.0 Hz, 2H), 5.11–5.04 (m, 1H), 3.96–3.88 (m, 2H), 3.3–3.30 (dd, J = 16.8, 5.6 Hz, 1H), 3.08–3.00 (m, 1H), 2.95–2.86 (m, 1H), 2.81 (d, J = 14.4 Hz, 1H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.9, 140.9, 140.5, 138.4, 134.2, 130.6, 130.1, 128.9, 128.7, 127.9, 126.9, 126.7, 121.2, 62.5, 54.3, 32.4, 25.6, 20.9. HRMS (ESI), m/z calcd for C26H23ClN2ONa ([M + Na]+) 437.1391, found: 437.1391.

4.2.2. 5-(3-Chlorophenyl)-6-phenyl-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3b)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (178.0 mg, 86%): mp 73–76 °C; 1H NMR (400 MHz, CDCl3) δ 7.33–7.26 (m, 6H), 7.13 (t, J = 8 Hz, 3H), 7.06 (t, J = 9.2 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.18–5.17 (m, 1H), 4.03–3.89 (m, 2H), 3.40 (dd, J = 16.8, 6.4 Hz, 1H), 3.03 (t, J = 10.6 Hz, 1H), 2.99–2.92 (m, 1H), 2.88 (d, J = 15.6 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.6, 143.7, 140.5, 138.5, 133.7, 133.5, 129.8, 129.2, 128.6, 127.6, 126.4, 125.5, 124.8, 123.1, 120.8, 62.1, 53.7, 32.2, 25.4, 20.7. HRMS (ESI), m/z calcd for C26H23ClN2ONa ([M + Na]+) 437.1391, found: 437.1398.

4.2.3. 5-(2-Chlorophenyl)-6-phenyl-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3c)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (176.0 mg, 85%): mp 72–75 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.36–7.26 (m, 5H), 7.19 (dd, J = 7.6, 2.0 Hz, 1H), 7.16–7.12 (m, 4H), 6.85 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 6.4, 4 Hz, 1H), 4.10–3.95 (m, 2H), 3.54 (dd, J = 16.8, 6.8 Hz, 1H), 3.10–2.98 (m, 2H), 2.94–2.89 (m, 1H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.5, 153.7, 140.5, 139.3, 139.0, 133.0, 132.7, 131.9, 130.0, 129.7, 128.4, 128.1, 127.6, 127.1, 127.0, 120.6, 105.0, 61.6, 53.4, 31.9, 25.5, 20.7. HRMS (ESI), m/z calcd for C26H23ClN2ONa ([M + Na]+) 437.1391, found: 437.1402.

4.2.4. Ethyl 4-(4-Oxo-6-phenyl-1-(p-tolyl)-1,2,3,4,6,7-hexahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)benzoate (3d)

The product was isolated by flash chromatography (eluent: EA/PE = 2/10) as a white solid (210.2 mg, 93%): mp 143–145 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.24–7.20 (m, 6H), 7.18 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.18 (dd, J = 6.4, 2.4 Hz, 1H), 4.28–4.23 (m, 2H), 3.94–3.84 (m, 2H), 3.35 (dd, J = 16.8, 6.0 Hz, 1H), 3.03–2.94 (m, 1H), 2.89–2.80 (m, 2H), 2.25 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.3, 165.5, 146.7, 140.5, 138.4, 133.6, 129.8, 128.7, 127.6, 126.4, 125.8, 123.7, 120.8, 61.7, 60.7, 53.7, 32.2, 25.4, 20.7, 14.3. HRMS (ESI), m/z calcd for C29H28N2O3 ([M + Na]+) 475.1992, found: 475.2002.

4.2.5. 5-(4-Methoxyphenyl)-6-phenyl-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3e)

The product was isolated by flash chromatography (eluent: EA/PE = 1/5) as a white solid (133.3 mg, 65%): mp 146–147 °C; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 7.08–7.02 (m, 3H), 6.84–6.81 (m, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.11 (s, 1H), 4.11–4.07 (m, 2H), 3.73 (s, 3H), 3.50–3.43 (m, 2H), 3.15 (s, 1H), 3.91–2.86 (m, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.7, 153.5, 141.1, 140.7, 138.7, 133.3, 129.9, 129.8, 128.6, 128.4, 127.5, 126.52, 126.49, 120.7, 105.5, 62.1, 53.6, 32.3, 25.4, 20.7. HRMS (ESI), m/z calcd for C27H27N2O2 ([M + H]+) 411.2067, found: 411.2074.

4.2.6. 6-Phenyl-5-(pyridin-3-yl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3f)

The product was isolated by flash chromatography (eluent: EA/PE =2/10) as a yellow solid (137 mg, 72%): mp 60–62 °C; 1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 8.27 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.28–7.24 (m, 6H), 7.15 (t, J = 5.7 Hz 1H), 7.10 (d, J = 7.2 Hz, 2H), 6.77 (d, J = 7.2 Hz, 2H), 5.17 (s, 1H), 3.98–3.92 (m, 2H), 3.37 (dd, J1 = 16.5 Hz, J2 = 5.1 Hz, 1H), 3.04–2.98 (m, 1H), 2.95–2.86 (m, 2H), 2.30 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 165.8, 154.0, 146.4, 145.5, 140.4, 139.1, 138.6, 133.6, 132.6, 129.9, 128.8, 127.8, 126.6, 123.0, 121.0, 105.2, 77.3, 77.1, 76.9, 62.0, 53.7, 32.4, 25.5, 20.8. HRMS (ESI), m/z calcd for C25H24N3O ([M + H]+) 382.1914, found: 382.1932.

4.2.7. 1,5-Bis(4-chlorophenyl)-6-phenyl-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3g)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (188.8 mg, 87%): mp 203–205 °C; 1H NMR (400 MHz, CDCl3) δ 7.35–7.27 (m, 2H), 7.27–7.22 (m, 5H), 7.19–7.17 (m, 2H), 7.13–7.10 (m, 2H), 6.76 (d, J = 8.8 Hz, 2H), 5.15 (dd, J = 6.4, 3.2 Hz, 1H), 3.99–3.85 (m, 2H), 3.41 (dd, J = 16.4, 6.4 Hz, 1H), 3.05–2.90 (m, 2H), 2.86 (d, J = 19.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 165.5, 152.2, 140.8, 140.5, 139.8, 130.2, 129.3, 128.7, 128.5, 128.2, 127.7, 126.5, 126.5, 121.1, 107.2, 62.1, 53.2, 32.4, 25.5. HRMS (ESI), m/z calcd for C25H20Cl2N2ONa ([M + Na]+) 457.0845, found: 457.0864.

4.2.8. 1-(3-Chlorophenyl)-5-(4-chlorophenyl)-6-phenyl-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3h)

The product was isolated by flash chromatography (eluent: EA/PE = 1/20) as a white solid (184.9 mg, 85%): mp 192–193 °C; 1H NMR (400 MHz, CDCl3) δ 7.30–7.26 (m, 2H), 7.25 (d, J = 7.2 Hz, 3H), 7.20–7.16 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 7.2 Hz, 1H), 6.79 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.14 (d, J = 3.2 Hz, 1H), 3.97–3.87 (m, 2H), 3.45–3.41 (m, 1H), 3.01–2.94 (m, 1H), 2.89 (d, J = 15.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 165.4, 151.9, 142.4, 140.8, 140.4, 135.0, 130.4, 130.2, 128.8, 128.5, 127.7, 126.6, 126.5, 122.8, 119.7, 117.8, 107.8, 62.2, 53.1, 32.5, 25.5. HRMS (ESI), m/z calcd for C25H20Cl2N2ONa ([M + Na]+) 457.0845, found: 457.0869.

4.2.9. 1-(2-Chlorophenyl)-5-(4-chlorophenyl)-6-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3i)

The product was isolated by flash chromatography (eluent: EA/PE = 1/20) as a white solid (176.2 mg, 81%): mp 187–190 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 1H), 7.30–7.26 (m, 6H), 7.19–7.13 (m, 6H), 5.09 (m, 1H), 4.03 (s, 1H), 3.70 (s, 1H), 3.09–3.03 (m, 2H), 3.02–2.09 (m, 1H), 2.49 (d, J = 12.0 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 165.7, 155.5, 141.3, 140.9, 132.7, 130.7, 130.1, 128.7, 128.6, 128.4, 128.2, 127.8, 127.6, 126.8, 126.6, 62.2, 54.9, 31.5, 26.2. HRMS (ESI), m/z calcd for C25H20Cl2N2ONa ([M + Na]+) 457.0845, found: 457.0876.

4.2.10. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-6-phenyl-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3j)

The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (184.9 mg, 86%): mp 134–137 °C; 1H NMR (400 MHz, CDCl3) δ 7.30–7.27 (m, 3H), 7.24–7.22 (m, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.84–6.73 (m, 4H), 5.11 (dd, J = 6.0, 3.2 Hz, 1H), 3.92 (t, J = 9.6 Hz, 2H), 3.78 (s, 3H), 3.29 (dd, J = 16.8, 6.4 Hz, 1H), 3.09–3.01 (m, 1H), 2.97–2.89 (m, 1H), 2.76 (d, J = 14.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 165.8, 156.7, 141.0, 140.6, 134.2, 130.2, 128.7, 128.5, 127.7, 126.64, 126.57, 123.4, 114.6, 62.2, 55.6, 54.8, 32.1, 25.6. HRMS (ESI), m/z calcd for C26H24ClN2O2 ([M + H]+) 431.1521, found: 431.1531.

4.2.11. 5-(4-Chlorophenyl)-1-(3-methoxyphenyl)-6-phenyl-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3k)

The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (187.1 mg, 87%): mp 138–140 °C; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 5.6 Hz, 2H), 7.30–7.28 (m, 3H), 7.23 (d, J = 8.4 Hz, 3H), 7.17 (d, J = 8.8 Hz, 2H), 6.64 (dd, J = 8.4, 2.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 5.19–5.17 (m, 1H), 4.07–3.94 (m, 2H), 3.81 (s, 3H), 3.55–3.46 (m, 1H), 3.11–3.05 (m, 1H), 3.00–2.97 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 165.6, 160.3, 152.9, 142.4, 140.9, 140.6, 130.2, 130.0, 128.7, 128.5, 127.6, 126.6, 112.7, 108.1, 106.6, 62.3, 55.3, 53.3, 32.5, 25.5. HRMS (ESI), m/z calcd for C26H24ClN2O2 ([M + H]+) 431.1521, found: 431.1543.

4.2.12. 5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-6-phenyl-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3l)

The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (182.8 mg, 85%): mp 147–149 °C; 1H NMR (400 MHz, CDCl3) δ 7.29–7.26 (m, 1H), 7.22 (t, J = 3.8 Hz, 4H), 7.16–7.11 (m, 3H), 7.08–7.06 (m, 2H), 6.82 (t, J = 8.0 Hz, 3H), 5.00 (dd, J = 6.4, 2.8 Hz, 1H), 3.92–3.86 (m, 1H), 3.74–3.69 (m, 1H), 3.50 (s, 3H), 3.04–2.86 (m, 3H), 2.46 (d, J = 16.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 165.5, 160.2, 153.2, 142.2, 140.8, 140.4, 130.1, 129.9, 128.6, 128.4, 127.6, 126.53, 126.46, 112.6, 108.1, 106.5, 62.2, 55.2, 53.3, 32.4, 25.4. HRMS (ESI), m/z calcd for C26H24ClN2O2 ([M + H]+) 431.1521, found: 431.1552.

4.2.13. 1-Benzyl-5-(4-chlorophenyl)-6-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3m)

The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (165.6 mg, 80%): mp 89–91 °C; 1H NMR (400 MHz, CDCl3) δ 7.37–7.29 (m, 5H), 7.22–7.17 (m, 3H), 7.17–7.13 (m, 4H), 6.87–6.83 (m, 2H), 5.16–5.14 (m, 1H), 4.27 (d, J = 16.0 Hz, 1H), 4.10 (d, J = 16.0 Hz, 1H), 3.47–3.39 (m, 1H), 3.35–3.18 (m, 2H), 2.93–2.77 (m, 2H), 2.73 (d, J = 16.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 165.5, 156.9, 141.5, 141.1, 136.3, 129.4, 128.6, 128.2, 127.43, 127.36, 126.8, 126.4, 126.2, 101.3, 61.7, 51.3, 50.2, 31.0, 25.3. HRMS (ESI), m/z calcd for C26H24ClN2O ([M + H]+) 415.1572, found: 415.1576.

4.2.14. 5-(4-Chlorophenyl)-1-cyclohexyl-6-phenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3n)

The product was isolated by flash chromatography (eluent: EA/PE = 1/10) as a white solid (164.4 mg, 81%): mp 137–140 °C; 1H NMR (400 MHz, CDCl3) δ 7.26–7.18 (m, 5H), 7.11–7.05 (m, 4H), 5.06 (dd, J = 6.8, 3.6 Hz, 1H), 3.51–3.32 (m, 2H), 3.11–3.01 (m, 2H), 2.83–2.69 (m, 2H), 1.77 (d, J = 12.8 Hz, 1H), 1.66 (dd, J = 15.2, 2.0 Hz, 1H), 1.58 (d, J = 12.8 Hz, 1H), 1.41–1.35 (m, 1H), 1.30–1.20 (m, 4H), 1.17–1.11 (m, 1H), 1.05–0.92 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 165.4, 157.0, 141.5, 141.2, 129.1, 128.4, 128.0, 127.2, 126.3, 126.2, 100.5, 61.5, 54.7, 46.5, 31.0, 30.5, 25.3, 25.1, 24.8. HRMS (ESI), m/z calcd for C25H27ClN2ONa ([M + Na]+) 429.1704, found: 429.1700.

4.2.15. 5,6-Bis(4-Chlorophenyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3o)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (195.3 mg, 87%): mp 151–152 °C; 1H NMR (400 MHz, CDCl3) δ 7.26–7.24 (m, 2H), 7.18 (t, J = 7.6 Hz, 4H), 7.11 (dd, J = 7.6, 3.6 Hz, 4H), 6.78 (d, J = 8.4 Hz, 2H), 5.11–5.10 (m, 1H), 4.04–3.88 (m, 2H), 3.38 (dd, J = 16.8, 6.4 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.96–2.92 (m, 1H), 2.79 (d, J = 16.4 Hz, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.5, 140.7, 139.0, 138.2, 133.4, 130.3, 129.9, 128.9, 128.5, 127.9, 126.5, 120.9, 61.6, 53.8, 32.1, 25.4, 20.7. HRMS (ESI), m/z calcd C26H22Cl2N2O2Na for ([M + Na]+) 471.1001, found: 471.1002.

4.2.16. 6-(3-Chlorophenyl)-5-(4-chlorophenyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3p)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (190.8 mg, 85%): mp 174–177 °C; 1H NMR (400 MHz, CDCl3) δ 7.45–7.43 (m, 1H), 7.34–7.32 (m, 1H), 7.23–7.21 (m, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.11–7.07 (m, 4H), 6.75 (d, J = 8.4 Hz, 2H), 5.52 (dd, J = 6.8, 2.4 Hz, 1H), 4.04–3.88 (m, 2H), 3.38 (dd, J = 17.2, 7.2 Hz, 1H), 3.10–2.97 (m, 2H), 2.92 (dd, J = 10.0, 2.4 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.9, 140.9, 138.6, 137.6, 133.2, 131.7, 130.1, 129.9, 129.1, 128.6, 128.5, 127.1, 126.3, 120.5, 105.1, 59.3, 53.5, 29.8, 25.4, 20.7. HRMS (ESI), m/z calcd for C26H22Cl2N2ONa ([M + Na]+) 471.1001, found: 471.1024.

4.2.17. 6-(2-Chlorophenyl)-5-(4-chlorophenyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3q)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (181.8 mg, 81%): mp 140–141 °C; 1H NMR (400 MHz, CDCl3) δ 7.45–7.43 (m, 1H), 7.33 (dd, J = 4.8, 2.0 Hz, 1H), 7.24–7.21 (m, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.10–7.08 (m, 4H), 6.75 (d, J = 8.0 Hz, 2H), 5.52 (d, J = 4.8 Hz, 1H), 4.03–3.90 (m, 2H), 3.38 (dd, J = 16.4, 6.0 Hz, 1H), 3.08–2.89 (m, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.9, 140.9, 138.6, 137.6, 133.3, 131.72, 130.2, 130.1, 129.8, 129.1, 128.7, 128.5, 127.1, 126.3, 120.5, 59.3, 53.6, 29.8, 25.4, 20.7. HRMS (ESI), m/z calcd for C26H22Cl2N2ONa ([M + Na]+) 471.1001, found: 471.1020.

4.2.18. Methyl 4-(5-(4-Chlorophenyl)-4-oxo-1-(p-tolyl)-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,2-c]pyridin-6-yl)benzoate (3r)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (203.0 mg, 86%): mp 175–177 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.0 Hz, 4H), 6.76 (d, J = 8.0 Hz, 2H), 5.18 (s, 1H), 3.99–3.91 (m, 2H), 3.89 (s, 3H), 3.40 (dd, J = 16.0, 5.2 Hz, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.97–2.93 (m, 1H), 2.83 (d, J = 15.6 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.5, 165.5, 145.6, 140.6, 138.1, 134.1, 130.5, 130.0, 129.9, 129.7, 128.6 126.6, 126.5, 121.1, 62.04, 54.0, 52.1, 32.0, 25.4, 20.7. HRMS (ESI), m/z calcd for C28H25ClN2O3Na ([M + Na]+) 495.1446, found: 495.1443.

4.2.19. 5-(4-Chlorophenyl)-1,6-di-p-tolyl-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3s)

The product was isolated by flash chromatography (eluent: EA/PE = 3/10) as a white solid (188.3 mg, 88%): mp 147–149 °C; 1H NMR (400 MHz, CDCl3) δ 7.45–7.43 (m, 1H), 7.33 (dd, J = 6.4, 4.8 Hz, 1H), 7.23–7.17 (m, 4H), 7.10–7.08 (m, 4H), 6.74 (d, J = 8.4 Hz, 2H), 5.52 (dd, J = 6.8, 2.4 Hz, 1H), 4.02–3.87 (m, 2H), 3.40–3.34 (m, 1H), 3.30–2.89 (m, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.7, 140.7, 138.2, 137.4, 137.1, 133.9, 130.3, 129.9, 129.4, 128.5, 126.7, 126.4, 120.9, 62.0, 54.0, 32.4, 25.4, 21.0, 20.7. HRMS (ESI), m/z calcd for C27H25ClN2ONa ([M + Na]+) 451.1548, found: 451.1550.

4.2.20. 5-(4-Chlorophenyl)-6-(m-tolyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3t)

The product was isolated by flash chromatography (eluent: EA/PE =3/10) as a white solid (186.2 mg, 87%): mp 160–161 °C; 1H NMR (400 MHz, CDCl3) δ 7.18–7.15 (m, 3H), 7.14–7.09 (m, 4H), 7.06–7.01 (m, 3H), 6.78 (d, J = 8.0 Hz, 2H), 5.10 (dd, J = 6.0, 2.8 Hz, 1H), 4.03–3.88 (m, 2H), 3.39 (dd, J = 16.4, 6.0 Hz, 1H), 3.04 (t, J = 10.6 Hz, 1H), 3.98–2.89 (m, 1H), 2.87 (d, J = 15.2 Hz, 1H), 2.30 (d, J = 2.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 165.5, 154.0, 140.7, 139.1, 138.3, 133.7, 133.4, 130.3, 129.9, 128.8, 128.5, 127.9, 126.5, 120.9, 61.6, 53.7, 53.4, 32.1, 25.4, 20.7. HRMS (ESI), m/z calcd for C27H25ClN2ONa ([M + Na]+) 451.1548, found: 451.1558.

4.2.21. 5-(4-Chlorophenyl)-6-(o-tolyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3u)

The product was isolated by flash chromatography (eluent: EA/PE =3/10) as a white solid (177.6 mg, 83%): mp 164–165 °C; 1H NMR (400 MHz, CDCl3) δ 7.18–7.15 (m, 3H), 7.14–7.09 (m, 4H), 7.06–7.01 (m, 3H), 6.78 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 6.0, 3.2 Hz, 1H), 4.05–3.88 (m, 2H), 3.38 (dd, J = 16.8, 6.4 Hz, 1H), 3.06–2.93 (m, 2H), 2.86 (d, J = 17.2 Hz, 1H), 2.30 (d, J = 2.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 165.7, 140.9, 140.5, 138.5 138.3, 133.4, 130.0, 129.8, 128.5, 128.4, 127.1, 126.5, 123.6, 62.1, 53.7, 32.3, 25.4, 21.5, 20.7. HRMS (ESI), m/z calcd for C27H25ClN2ONa ([M + Na]+) 451.1548, found: 451.1558.

4.2.22. 5-(4-Chlorophenyl)-6-(4-methoxyphenyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3v)

The product was isolated by flash chromatography (eluent: EA/PE =3/10) as a white solid (184.3 mg, 83%): mp 154–156 °C; 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 64 Hz, 3H), 7.13–0.08 (m, 5H), 6.81–6.75 (m, 4H), 5.07 (dd, J = 6.0, 3.2 Hz, 1H), 4.01–3.87 (m, 2H), 3.77 (s, 3H), 3.33 (dd, J = 16.8, 6.4 Hz, 1H), 3.04–2.87 (m, 2H), 2.82 (dd, J = 16.8, 2.4 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.7, 158.9, 153.7, 141.1, 138.7, 133.3, 132.6, 130.0, 129.8, 128.4, 127.7, 126.6, 120.7, 113.9, 100.0, 61.7, 55.2, 53.6, 32.5, 25.5, 20.7. HRMS (ESI), m/z calcd for C27H25ClN2O2Na ([M + Na]+) 467.1497, found: 467.1516.

4.2.23. 5-(4-Chlorophenyl)-6-(3-methoxyphenyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3w)

The product was isolated by flash chromatography (eluent: EA/PE =3/10) as a white solid (179.8 mg, 81%): mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.8 Hz, 2H), 7.14 (s, 2H), 7.11–7.07 (m, 6H), 6.77 (d, J = 8.0 Hz, 2H), 5.10 (dd, J = 6.0, 3.2 Hz, 1H), 4.02–3.88 (m, 2H), 3.36 (dd, J = 16.8, 6.4 Hz, 1H), 3.05–2.92 (m, 2H), 2.85 (d, J = 16.4 Hz, 1H), 2.31 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 165.7, 159.7, 142.2, 140.8, 138.4, 133.6, 130.2, 129.8, 129.7, 128.4, 126.7, 120.8, 118.6, 112.6, 112.5, 62.2, 55.2, 53.8, 32.2, 25.4, 20.7. HRMS (ESI), m/z calcd for C27H25ClN2O2Na ([M + Na]+) 467.1497, found: 467.1490.

4.2.24. 5-(4-Chlorophenyl)-6-(2-methoxyphenyl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3x)

The product was isolated by flash chromatography (eluent: EA/PE =3/10) as a white solid (175.4 mg, 79%): mp 183–186 °C; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.6 Hz, 1H), 7.24–7.22 (m, 1H), 7.20–7.11 (m, 4H), 7.09 (d, J = 8.4 Hz, 2H), 6.91 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 5.47 (dd, J = 6.8, 2.0 Hz, 1H), 4.02–3.85 (m, 2H), 3.77 (s, 3H), 3.31 (dd, J = 16.8, 6.8 Hz, 1H), 3.08–2.89 (m, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.1, 155.7, 141.0, 138.7, 133.0, 129.9, 129.7, 128.7, 128.3, 127.8, 127.7, 126.3, 120.5, 120.4, 110.5, 57.0, 55.2, 53.6, 29.9, 25.3, 20.7. HRMS (ESI), m/z calcd for C27H26ClN2O2 ([M + H]+) 445.1677, found: 445.1677.

4.2.25. 5-(4-Chlorophenyl)-6-cyclohexyl-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3y)

The product was isolated by flash chromatography (eluent: EA/PE =2/10) as a white solid (140.7 mg, 67%): mp 153–156 °C; 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.24–7.20 (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.26 (s, 1H), 6.18 (s, 1H), 5.13 (s, 1H), 4.15–3.94 (m, 2H), 3.23 (d, J = 14.8 Hz, 1H), 3.08–2.86 (m, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.2, 141.2, 138.5, 131.0, 130.0, 129.4, 129.1, 128.72, 128.67, 121.0, 64.0, 54.1, 41.1, 30.3, 29.2, 26.1, 26.0, 25.5, 20.8. HRMS (ESI), m/z calcd for C26H29ClN2ONa ([M + Na]+) 443.1861, found: 443.1883.

4.2.26. 5-(4-Chlorophenyl)-6-cyclopropyl-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3z)

The product was isolated by flash chromatography (eluent: EA/PE =2/10) as a yellow oil (142 mg, 75%); 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J1 = 7.8 Hz, J2 = 1.4 Hz, 1H), 7.55 (dd, J1 = 7.8 Hz, J2 = 1.4 Hz, 1H), 7.43–7.35 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.29–4.01 (m, 3H), 3.26 (dd, J1 = 16.4 Hz, J2 = 6.0 Hz, 1H), 3.14–3.03 (m, 3H), 2.88 (dd, J1 = 16.4 Hz, J2 = 4.8 Hz, 1H), 2.47 (s, 3H), 0.50–0.37 (m, 2H), 0.05–0.00 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 165.5, 155.1, 139.4, 139.2, 133.2, 132.8, 129.8, 128.1, 126.8, 120.4, 104.5, 63.1, 53.3, 30.1, 25.6, 20.7, 14.8, 5.3, 1.8. HRMS (ESI), m/z calcd for C23H24ClN2O ([M + H]+) 379.1572, found: 379.1588.

4.2.27. 5-(4-Chlorophenyl)-6-(thiophen-2-yl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3a′)

The product was isolated by flash chromatography (eluent: EA/PE =3/10) as a white solid (153.3 mg, 73%): mp 143–146 °C; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.8 Hz, 2H), 7.17 (s, 1H), 7.15–7.13 (m, 3H), 7.12 (s, 1H), 6.87 (s, 1H), 6.85–6.83 (m, 2H), 6.79 (d, J = 3.2 Hz, 1H), 5.30 (dd, J = 6.0, 2.0 Hz, 1H), 4.18–4.07 (m, 1H), 3.98–3.91 (m, 1H), 3.51–3.38 (m 1H), 3.07–2.92 (m, 2H), 2.88 (d, J = 16.4 Hz, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.8, 143.6, 140.6, 138.4, 133.6, 130.8, 129.8, 128.6, 127.5, 126.2, 125.8, 124.9, 120.8, 59.2, 53.7, 32.2, 25.4, 20.7. HRMS (ESI), m/z calcd for C24H21ClN2OSNa ([M + Na]+) 443.0955, found: 443.0941.

4.2.28. 5-(4-Chlorophenyl)-6-(pyridin-2-yl)-1-(p-tolyl)-1,2,3,5,6,7-hexahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3b′)

The product was isolated by flash chromatography (eluent: EA/PE =2/10) as a white solid (145.3 mg, 70%): mp 164–165 °C; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 7.19 (d, J = 9.6 Hz, 4H), 7.11 (d, J = 5.6 Hz, 2H), 6.80 (d, J = 6.8 Hz, 2H), 5.36 (s, 1H), 3.91 (s, 2H), 3.40 (s, 2H), 2.98 (s, 1H), 2.84 (s, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.2, 159.5, 154.1, 140.8, 138.4, 133.5, 129.9, 129.4, 128.6, 128.4, 125.6, 122.9, 122.0, 120.8, 120.6, 105.4, 62.6, 53.5, 30.3, 25.4, 20.7. HRMS (ESI), m/z calcd for C25H22ClN3O ([M + Na]+) 438.1344, found: 438.1335.

Acknowledgments

We are thankful to the NSFC (21272057, 21372065, 21772032, 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).

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00626.

  • 1H and 13C NMR spectra for all compounds (PDF)

  • Crystallographic data (CIF)

The authors declare no competing financial interest.

Supplementary Material

ao7b00626_si_001.pdf (1.7MB, pdf)
ao7b00626_si_002.cif (22.1KB, cif)

References

  1. a El-Gamal M. I.; Abdel-Maksoud M. S.; El-Din M. M. G.; Yoo K. H.; Baek D.; Oh C.-H. Arch. Pharm. Chem. Life Sci. 2014, 347, 635. 10.1002/ardp.201400051. [DOI] [PubMed] [Google Scholar]; b Huang H.; Acquaviva L.; Berry V.; Bregman H.; Chakka N.; O’Connor A.; DiMauro E. F.; Dovey J.; Epstein O.; Grubinska B.; Goldstein J.; Gunaydin H.; Hua Z.; Huang X.; Huang L.; Human J.; Long A.; Newcomb J.; Patel V. F.; Saffran D.; Serafino R.; Schneider S.; Strathdee C.; Tang J.; Turci S.; White R.; Yu V.; Zhao H.; Wilson C.; Martin M. W. ACS Med. Chem. Lett. 2012, 3, 1059. 10.1021/ml300278f. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Caruso M.; Valsasina B.; Ballinari D.; Bertrand J.; Brasca M. G.; Caldarelli M.; Cappella P.; Fiorentini F.; Gianellini L. M.; Scolaro A.; Beria I. Bioorg. Med. Chem. Lett. 2012, 22, 96. 10.1016/j.bmcl.2011.11.065. [DOI] [PubMed] [Google Scholar]; d Barf T.; Kaptein A.; de Wilde S.; van der Heijden R.; van Someren R.; Demont D.; Schultz-Fademrecht C.; Versteegh J.; van Zeeland M.; Seegers N.; Kazemier B.; van de Kar B.; van Hoek M.; de Roos J.; Klop H.; Smeets R.; Hofstra C.; Hornberg J.; Oubrie A. Bioorg. Med. Chem. Lett. 2011, 21, 3818. 10.1016/j.bmcl.2011.04.018. [DOI] [PubMed] [Google Scholar]; e Kaptein A.; Oubrie A.; de Zwart E.; Hoogenboom N.; de Wit J.; van de Kar B.; van Hoek M.; Vogel G.; de Kimpe V.; Schultz-Fademrecht C.; Borsboom J.; van Zeeland M.; Versteegh J.; Kazemier B.; de Roos J.; Wijnands F.; Dulos J.; Jaeger M.; Leandro-Garcia P.; Barf T. Bioorg. Med. Chem. Lett. 2011, 21, 3823. 10.1016/j.bmcl.2011.04.016. [DOI] [PubMed] [Google Scholar]
  2. a Ishii T.; Shimizu Y.; Nakashima K.; Kondo S.; Ogawa K.; Sasaki S.; Matsui H. Eur. J. Pharmacol. 2014, 723, 305. 10.1016/j.ejphar.2013.11.014. [DOI] [PubMed] [Google Scholar]; b Ohashi T.; Oguro Y.; Tanaka T.; Shiokawa Z.; Tanaka Y.; Shibata S.; Sato Y.; Yamakawa H.; Hattori H.; Yamamoto Y.; Kondo S.; Miyamoto M.; Nishihara M.; Ishimura Y.; Tojo H.; Baba A.; Sasaki S. Bioorg. Med. Chem. 2012, 20, 5507. 10.1016/j.bmc.2012.07.034. [DOI] [PubMed] [Google Scholar]
  3. Anderson D. R.; Meyers M. J.; Vernier W. F.; Mahoney M. W.; Kurumbail R. G.; Caspers N.; Poda G. I.; Schindler J. F.; Reitz D. B.; Mourey R. J. J. Med. Chem. 2007, 50, 2647. 10.1021/jm0611004. [DOI] [PubMed] [Google Scholar]
  4. Giblin G. M. P.; Billinton A.; Briggs M.; Brown A. J.; Chessell I. P.; Clayton N. M.; Eatherton A. J.; Goldsmith P.; Haslam C.; Johnson M. R.; Mitchell W. L.; Naylor A.; Perboni A.; Slingsby B. P.; Wilson A. W. J. Med. Chem. 2009, 52, 5785. 10.1021/jm9009857. [DOI] [PubMed] [Google Scholar]
  5. a Livecchi M.; Calvet G.; Schmidt F. J. Org. Chem. 2012, 77, 5006. 10.1021/jo300481s. [DOI] [PubMed] [Google Scholar]; b Calvet G.; Livecchi M.; Schmidt F. J. Org. Chem. 2011, 76, 4734. 10.1021/jo200480h. [DOI] [PubMed] [Google Scholar]; c Tudge M.; Savarin C. G.; DiFelice K.; Maligres P.; Humphrey G.; Reamer B.; Tellers D. M.; Hughes D. Org. Process Res. Dev. 2010, 14, 787. 10.1021/op100008m. [DOI] [Google Scholar]; d Beccalli E. M.; Broggini G.; Martinelli M.; Paladino G. Tetrahedron 2005, 61, 1077. 10.1016/j.tet.2004.11.066. [DOI] [Google Scholar]; e Herz W.; Tocker S. J. Am. Chem. Soc. 1955, 77, 6353. 10.1021/ja01628a080. [DOI] [Google Scholar]
  6. a Sun X.; Wang C.; Li Z.; Zhang S.; Xi Z. J. Am. Chem. Soc. 2004, 126, 7172. 10.1021/ja0497173. [DOI] [PubMed] [Google Scholar]; b Zhang Z.; Zhang F.; Wang H.; Wu H.; Duan X.; Liu Q.; Liu T.; Zhang G. Adv. Synth. Catal. 2015, 357, 2681. 10.1002/adsc.201500251. [DOI] [Google Scholar]
  7. a Zhang L.; Zhang Z.; Liu Q.; Liu T.; Zhang G. J. Org. Chem. 2014, 79, 2281. 10.1021/jo402773r. [DOI] [PubMed] [Google Scholar]; b Zhang Z.; Zhang L.; Duan X.; Yan X.; Yan Y.; Liu Q.; Liu T.; Zhang G. Tetrahedron 2015, 71, 7745. 10.1016/j.tet.2015.07.039. [DOI] [Google Scholar]
  8. a Huang P.; Zhang R.; Liang Y.; Dong D. Org. Lett. 2012, 14, 5196. 10.1021/ol302314c. [DOI] [PubMed] [Google Scholar]; b Mou X.-Q.; Xu Z.-L.; Wang S.-H.; Zhu D.-Y.; Wang J.; Bao W.; Zhou S.-J.; Yang C.; Zhang D. Chem. Commun. 2015, 51, 12064. 10.1039/C5CC03979G. [DOI] [PubMed] [Google Scholar]; c Shukla G.; Srivastava A.; Singh M. S. Org. Lett. 2016, 18, 2451. 10.1021/acs.orglett.6b00997. [DOI] [PubMed] [Google Scholar]; d Wu L.; Guo S.; Wang X.; Guo Z.; Yao G.; Lin Q.; Wu M. Tetrahedron Lett. 2015, 56, 2145. 10.1016/j.tetlet.2015.03.019. [DOI] [Google Scholar]; e Shankaraiah K.; Chandrasekhar G.; Reddy K. S. N.; Sabitha G. Tetrahedron Lett. 2015, 56, 842. 10.1016/j.tetlet.2014.12.122. [DOI] [Google Scholar]
  9. a SawpathKumar H. M.; Subbareddy B. V.; Anjaneyulu S.; Yadav J. S. Synth. Commun. 1998, 28, 3811. 10.1080/00397919808004934. [DOI] [Google Scholar]; b Sajiki H.; Mori A.; Mizusaki T.; Ikawa T.; Maegawa T.; Hirota K. Org. Lett. 2006, 8, 987. 10.1021/ol060045q. [DOI] [PubMed] [Google Scholar]; c Kour D.; Khajuria R.; Kapoor K. K. Tetrahedron Lett. 2016, 57, 4464. 10.1016/j.tetlet.2016.08.058. [DOI] [Google Scholar]
  10. Fei H.; Yu J.; Jiang Y.; Guo H.; Cheng J. Org. Biomol. Chem. 2013, 11, 7092. 10.1039/c3ob41510d. [DOI] [PubMed] [Google Scholar]
  11. Yin Z.; Zhang Z.; Kadow J. F.; Meanwell N. A.; Wang T. J. Org. Chem. 2004, 69, 1364. 10.1021/jo030234b. [DOI] [PubMed] [Google Scholar]
  12. Zhang Z.; Zheng D.; Ma N.; Bi J. Brønsted Acid-Promoted the Synthesis of Furo[2,3-b]quinolines. Chin. J. Org. Chem. 2017, 37, 1824. 10.6023/cjoc201612032. [DOI] [Google Scholar]
  13. a Zhang Z.; Qian J.; Zhang G.; Ma N.; Liu Q.; Liu T.; Sun K.; Shi L. Org. Chem. Front. 2016, 3, 344. 10.1039/C5QO00417A. [DOI] [Google Scholar]; b Zhang Z.; Li J.; Zhang G.; Ma N.; Liu Q.; Liu T. J. Org. Chem. 2015, 80, 6875. 10.1021/acs.joc.5b00915. [DOI] [PubMed] [Google Scholar]; c Zhang Z.; Zhang W.; Li J.; Liu Q.; Liu T.; Zhang G. J. Org. Chem. 2014, 79, 11226. 10.1021/jo5018487. [DOI] [PubMed] [Google Scholar]; d Zhang Z.; Tian Q.; Qian J.; Liu Q.; Liu T.; Shi L.; Zhang G. J. Org. Chem. 2014, 79, 8182. 10.1021/jo501385w. [DOI] [PubMed] [Google Scholar]; e Qian J. J.; Zhang Z. G.; Liu Q. F.; Liu T. X.; Zhang G. S. Adv. Synth. Catal. 2014, 356, 3119. 10.1002/adsc.201400332. [DOI] [Google Scholar]; f Zhang Z.; Wang D.; Wang B.; Liu Q.; Liu T.; Zhang W.; Yuan B.; Zhao Z.; Han D.; Zhang G. Tetrahedron 2013, 69, 9063. 10.1016/j.tet.2013.08.027. [DOI] [Google Scholar]
  14. a Celerier J. P.; Haddad M.; Jacoby D.; Lhommet G. Tetrahedron Lett. 1987, 28, 6597. 10.1016/S0040-4039(00)96923-5. [DOI] [Google Scholar]; b Jacoby D.; Celerier J. P.; Haviari G.; Petit H.; Lhommet G. Synthesis 1992, 1992, 884. 10.1055/s-1992-26252. [DOI] [Google Scholar]
  15. Zhang Z. G.; Ma N. N.; Zhang G. S.; Liu Q. F.; Huang Y. Y.. A Kind Method of the Synthesis of 1H-Pyrrolo[3,2-c]pyridin-4(5H)-ones. China Patent CN 104829614, 2015.
  16. Zhang R.; Liang Y.; Zhou G.; Wang K.; Dong D. J. Org. Chem. 2008, 73, 8089. 10.1021/jo801289p. [DOI] [PubMed] [Google Scholar]
  17. For more information, please see the SI.
  18. a Yan R.; Zhou X.; Li M.; Li X.; Kang X.; Liu X.; Huo X.; Huang G. RSC Adv. 2014, 4, 50369. 10.1039/C4RA10880A. [DOI] [Google Scholar]; b Chan C.-K.; Chan Y.-L.; Chang M.-Y. Tetrahedron 2016, 72, 547. 10.1016/j.tet.2015.12.021. [DOI] [Google Scholar]
  19. Ichikawa J.; Wada Y.; Kuroki H.; Mihara J.; Nadano R. Org. Biomol. Chem. 2007, 5, 3956. 10.1039/b712965c. [DOI] [PubMed] [Google Scholar]
  20. Liu X.; Zhang N.; Yang J.; Liang Y.; Zhang R.; Dong D. J. Org. Chem. 2013, 78, 3323. 10.1021/jo4001959. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao7b00626_si_001.pdf (1.7MB, pdf)
ao7b00626_si_002.cif (22.1KB, cif)

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES