Abstract
A novel three-component reaction of 2-oxo-2H-chromene-3-carbaldehydes with isocyanides and anilines was developed for one-pot assembly of biologically intriguing chromeno[4,3-b]pyrrol-4(1H)-ones, which can also be transferred into diverse polycyclic fused scaffolds through further synthetic manipulations. The described method tolerates a broad substrate scope and proceeds in moderate to good yield via a sequential multicomponent reaction and intramolecular Michael cyclization.
Introdution
Multicomponent reactions (MCRs) represent powerful tools for construction of structurally diverse scaffolds. Through MCRs, three or more simple starting materials could react in a programmed and domino fashion to install the structurally complex products in a one-pot process.1 Simple operation, atom economy, and versatility have rendered the MCR methodology extremely appealing, enriching the toolbox of medicinal chemistry.2 In the past two decades, many elegant MCR-based methods have been developed and further utilized in the synthesis of natural products and bioactive compounds.3 Nevertheless, it is still highly desirable to develop novel MCR-based methods for the rapid construction of the privileged scaffolds in medicinal chemistry.
Chromene is a pharmaceutically important structural motif in medicinal chemistry, and its derivatives display a variety of biological activities.4 In particular, the fusions of chromene with other heterocycles lead to the discovery of the molecules with interesting biological profiles. Chromone-fused pyrazole I was found to be a selective (A2A or A1) adenosine receptor antagonist (Figure 1).5 Chromenone-based tetrahydropyridine II was identified as the potent inhibitor of inositol-requiring enzyme 1 (IRE-1),6 whereas chromenone-pyridine skeletons (III) have antibacterial and antimicrobial activities.7 In addition, chromone-fused heterocycle systems are widely present in many natural products of biological significance. Lamellarin D (IV) is a novel marine natural product containing a chromenone-pyrrole core structure, displaying important activities such as human topoisomerase I inhibitors.8 Neotanshinlactone (V), a component isolated from Tanshen (the rhizome of Salvia miltiorrhiza Bunge), featured chromenone-furan as a core structure and showed significant selective in vitro antibreast cancer activity.9 Deguelin (VI), a rotenoid natural product with a chromone-fused dihydrochremene scaffold, displays antitumor activities through multiple mechanisms.10 As such, combination of chromene with other heterocycles would lead to a broad range of interesting biological profiles, and these types of scaffolds have emerged as synthetic targets for medicinal chemists.
Figure 1.
Representative bioactive chromenone-containing compounds.
As part of the goal to develop efficient methods or strategies for building pharmaceutically relevant scaffolds, we are interested in developing an MCR-based method for the synthesis of chromene-fused pyrroles due to their impressive biological activities. In this respect, the MCR-based method can bypass lengthy synthetic steps and efficiently install the product in a single chemical step. Furthermore, the MCR-based method has a potential to explore more chemical space, which is highly pursued in drug discovery.11 In a previous paper, we have developed a diastereoselective synthesis of diverse dihydrochromeno[3,4-c]pyrrolidin-3,4-diones through sequential Ugi-4CR and intramolecular Michael addition.12 As a continuing work, we report here a novel synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones utilizing an MCR and cyclization strategy.
Results and Discussion
We envisioned that chromeno[4,3-b]pyrrol-4(1H)-ones 5 could be formed through the cyclization of intermediate 4 followed by a 1,3-H shift and auto-oxidation reaction driven by the formation of aromatic pyrrole (Scheme 1). The α-amino amidine 4 in turn can be installed through the MCR reaction of 2-oxo-2H-chromene-3-carbaldehyde 1, two molecules of aniline 2, and isocyanide 3.13 Noteworthy, it is difficult for 5-endo-trig cyclization to take place in 4 since the 2H-chromen-2-one motif in 4 is not a good Michael acceptor. We conjectured that the Michael acceptor in 4 could be further activated under basic conditions via the generation of intermediate 4-II, which ought to proceed 5-endo-trig cyclization smoothly.
Scheme 1. MCR–Cyclization Strategy for the Chromeno[4,3-b]pyrrol-4(1H)-one Scaffolds.
To verify our design speculation, we chose α-amino amidine 4a as a model substrate to investigate the key 5-endo-trig cyclization. The multicomponent reaction proceeded smoothly in methanol at room temperature to deliver 4a in 87% yield starting from 3-aldehyde coumarins 1a, 2 equiv. of 4-chloroaniline 2a, and tert-butyl isocyanide 3a. Due to the labile nature of amidine, its purification is usually carried out through filtration and recrystallization rather than silicon column chromatography. In this respect, our synthetic concept could expand the application of this MCR through converting the labile α-amino amidines to high-value heterocycles.14 Considering the possibility of a one-pot process, we first studied the cyclization reactions using methanol as a solvent in the presence of various bases, and the reaction temperature ranged from room temperature to refluxing temperature. Among the bases (Table 1, entries 1–5), pyridine was found to be the only base to promote the cyclization reaction providing the product 5a in 3% yield (entry 3). The structure of 5a was unambiguously confirmed by NMR spectroscopy, HRMS, and single-crystal X-ray diffraction analysis (Figure S107 in the Supporting Information). With pyridine as a base, the solvent effect was then studied and toluene was found to be the most effective, leading to the formation of 5a in 81% yield (entries 6–9). In this solvent, the yield was further improved to 92% when the reaction temperature was dropped to 90 °C, and further lowering the temperature led to a slightly lower yield (entries 10 and 11). Finally, switching the base to pyridine derivatives or other bases lowered the yield of 5a (entries 12–16). Overall, the condition screenings identified pyridine as the optimum base and toluene as the most effective solvent.
Table 1. Syntheses of Chromeno[4,3-b]pyrrol-4(1H)-ones under the Indicated Conditionsa.
| entry | base | solvent | temp. (°C) | yields (%) |
|---|---|---|---|---|
| 1 | K2CO3 | MeOH | 25–65 | n.d.b |
| 2 | Cs2CO3 | MeOH | 65 | n.d. |
| 3 | pyridine | MeOH | 65 | 3 |
| 4 | Et3N | MeOH | 65 | n.d. |
| 5 | DBU | MeOH | 65 | n.d. |
| 6 | pyridine | THF | 65 | 12 |
| 7 | pyridine | CH3CN | 80 | 57 |
| 8 | pyridine | PhMe | 100 | 81 |
| 9 | pyridine | 1,4-dioxane | 100 | 79 |
| 10 | pyridine | PhMe | 90 | 92 |
| 11 | pyridine | PhMe | 80 | 79 |
| 12 | 2,6-lutidine | PhMe | 90 | 67 |
| 13 | DMAP | PhMe | 90 | 64 |
| 14 | K2CO3 | PhMe | 90 | n.d. |
| 15 | Et3N | PhMe | 90 | 13 |
| 16 | DBU | PhMe | 90 | n.d. |
General conditions for the annulation: substrate 4a (0.25 mmol), base (0.75 mmol) in solvent (3 mL) at indicated temperature for 24 h.
No desired product.
In order to further improve the efficiency and practicality of this synthetic strategy, we next started to combine the MCR and cyclization in a one-pot process. After the MCR reaction in methanol at room temperature, the solvent methanol was condensed without further purification followed by the addition of toluene and pyridine to conduct the cyclization reaction at 90 °C, delivering the desired product 5a in a one-pot process in 65% yield (Table 2, entry 1).
Table 2. Substrate Scope for the Syntheses of Chromeno[4,3-b]pyrrol-4(1H)-ones in a One-Pot Processa.
| entry | R1 | R2 | R3 | product | yield (%) |
|---|---|---|---|---|---|
| 1 | H | 4-Cl | t-Bu | 5a | 65 |
| 2 | H | 4-Br | t-Bu | 5b | 75 |
| 3 | H | 4-F | t-Bu | 5c | 44 |
| 4 | H | 4-CF3 | t-Bu | 5d | 59 |
| 5 | H | 4-t-Bu | t-Bu | 5e | 46 |
| 6 | H | H | t-Bu | 5f | 42 |
| 7 | H | 3-CF3 | t-Bu | 5g | 65 |
| 8 | H | 3- C2H5 | t-Bu | 5h | 59 |
| 9 | H | 3-OMe | t-Bu | 5i | 35 |
| 10 | H | 2-Cl | t-Bu | 5j | 63 |
| 11 | H | 2-I | t-Bu | 5k | 50 |
| 12 | H | 2-CO2Me | t-Bu | 5l | 60 |
| 13 | H | 3-Cl-4-F | t-Bu | 5m | 55 |
| 14 | 6-Cl | 4-Cl | t-Bu | 5n | 62 |
| 15 | 6-Cl | 4-Br | t-Bu | 5o | 65 |
| 16 | 6-Cl | 4-CF3 | t-Bu | 5p | 65 |
| 17 | 6-Cl | 4-CN | t-Bu | 5q | 55 |
| 18 | 6-Cl | 4-t-Bu | t-Bu | 5r | 45 |
| 19 | 6-Cl | H | t-Bu | 5s | 52 |
| 20 | 6-Cl | 3-CF3 | t-Bu | 5t | 64 |
| 21 | 6-Cl | 3-Cl | t-Bu | 5u | 72 |
| 22 | 6-Cl | 2-CO2Me | t-Bu | 5v | 69 |
| 23 | 6-Cl | 3-Cl-4-F | t-Bu | 5w | 51 |
| 24 | 6-Br | 4-CF3 | t-Bu | 5x | 50 |
| 25 | 6-Br | 4-Br | t-Bu | 5y | 58 |
| 26 | 6-Br | 4-Cl | t-Bu | 5z | 59 |
| 27 | 6-Br | 4-F | t-Bu | 5aa | 82 |
| 28 | 6-Br | 4-CN | t-Bu | 5ab | 43 |
| 29 | 6-Br | 4-i-Pr | t-Bu | 5ac | 58 |
| 30 | 6-Br | 4-C2H5 | t-Bu | 5ad | 49 |
| 31 | 6-Br | H | t-Bu | 5ae | 40 |
| 32 | 6-Br | 3-CF3 | t-Bu | 5af | 57 |
| 33 | 6-Br | 3-Cl | t-Bu | 5ag | 75 |
| 34 | 7-OCH3 | 4-CF3 | t-Bu | 5ah | 42 |
| 35 | 7-OCH3 | 4-Cl | t-Bu | 5ai | 36 |
| 36 | 7-OCH3 | 4-F | t-Bu | 5aj | 47 |
| 37 | 7-OCH3 | 4-Br | t-Bu | 5ak | 48 |
| 38 | 7-OCH3 | 4-t-Bu | t-Bu | 5al | 36 |
| 39 | 7-OCH3 | H | t-Bu | 5am | 47 |
| 40 | 7-OCH3 | 3-CF3 | t-Bu | 5an | 58 |
| 41 | 7-OCH3 | 3-Cl | t-Bu | 5ao | 42 |
| 42 | 7-OCH3 | 3-C2H5 | t-Bu | 5ap | 39 |
| 43 | 7-OCH3 | 2-Cl | t-Bu | 5aq | 42 |
| 44 | 7-OCH3 | 2-CO2Me | t-Bu | 5ar | 44 |
| 45 | 7-OCH3 | 3-Cl-4-F | t-Bu | 5as | 58 |
| 46 | H | 4-Br | Cy | 5at | 41 |
| 47 | H | 2-CO2Me | Cy | 5au | 44 |
With the optimized protocol in hand, we then evaluated the scope of three components, leading to one-pot synthesis of structurally diverse chromeno[4,3-b]pyrrol-4(1H)-ones, as demonstrated in Table 2. We first explored the scope of the aniline along with aldehyde 1a and tert-butyl isocyanide (Table 2, entries 1–13). A range of substituted anilines with varied electronic and steric properties is well tolerated, affording chromeno[4,3-b]pyrrol-4(1H)-ones 5a–5m in 35–75% yield. We observed that electron-deficient anilines provided better yield compared with electron-rich ones, exemplified by the cases of 4-Cl/4-t-Bu (entries 1 and 5) and 3-CF3/3-OMe substituted substrates (entries 7 and 9). In regard to the steric effect, ortho-substituted anilines such as 2-Cl, 2-I, and 2-CO2Me are also suitable for this protocol (entries 10–12) and gave a satisfying yield of 50–63%. It should be noted that the compatibility of 2-I and 2-CO2Me enables further transformations possible. Likewise, aldehydes bearing electron-withdrawing groups including chloro (entriesy 14–23) and bromo (entries 24–33) also reacted smoothly with various anilines and tert-butyl isocyanide to form chromeno[4,3-b]pyrrol-4(1H)-ones 5n–5ag in 40–82% yield, and aldehydes bearing electron-donating groups such as methoxyl (entries 34–45) gave the corresponding products 5ah–5as in slightly lower yields (36–58%). Finally, we also investigated the variation of the isocyanide component. When tert-butyl isocyanide was changed to cyclohexyl isocyanide, we noted that the corresponding products 5at–5au were obtained in a lower yield.
Afterward, we directed our attention to the application of the developed method to make structurally diverse scaffolds. Considering two amino groups in chromeno[4,3-b]pyrrol-4(1H)-one scaffolds, we envisioned that various acids can condense with the two amino groups to form a new imidazole. Thus, the tetracyclic fused heterocycles 6a–6e could be easily generated in 41–52% yields starting from compound 5a. On the other hand, compound 5k can be transferred into the polycyclic fused heterocycle 7 through the intramolecular Buchwald–Hartwig reaction (Scheme 2).15
Scheme 2. Synthesis of Fused Polycyclic Chromeno[4,3-b]pyrrol-4(1H)-one Scaffolds.
Conclusions
In conclusion, we have developed a highly efficient method for the synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones through a multicomponent reaction and a cyclization strategy in a one-pot fashion. The synthesized chromeno[4,3-b]pyrrol-4(1H)-ones can be further transferred into structurally diverse polycyclic scaffolds, such as imidazole- or quinoxaline-fused chromeno[4,3-b]pyrrol-4(1H)-ones. The described method tolerates a broad substrate scope under mild reaction conditions and can serve as a medchem reaction tool for late-stage modification of natural products or drugs. We anticipate that this interesting method and post-transformations can find many applications in parallel synthesis and high-throughput medicinal chemistry.
Experimental Section
General Information
Unless noted otherwise, all reactions were performed under a nitrogen atmosphere, and materials obtained from commercial suppliers were used without further purification. Purification of products was conducted by flash column chromatography on a silica gel (200–300 mesh). 1H NMR spectra were recorded on a 300, 400, or 500 MHz spectrometer using a residual solvent (δ (CDCl3) = 7.26) as an internal standard. All the coupling constants are reported in Hz. 13C NMR spectra were recorded on the same instruments, and chemical shifts were measured relative to solvent resonances (δ (CDCl3) = 77.0). High-resolution mass spectra were obtained on a quadrupole time-of-flight (QqTOF) mass spectrometer utilizing an electrospray ionization (ESI) method.
Typical Procedure for One-Pot Synthesis of Chromeno[4,3-b]pyrrol-4(1H)-ones
To a solution of aldehyde (0.2 mmol, 1 equiv.), aromatic amine (0.4 mmol, 2 equiv.), and isocyanide (0.2 mmol, 1 equiv.) in 2 ml of methanol was added p-toluenesulfonic acid (0.05 equiv.), and the reaction mixture was stirred at room temperature overnight. Then, the solution was concentrated under reduced pressure, and the residue was redissolved in 3 ml of toluene. To the solution was added dropwise pyridine (0.6 mmol, 3 equiv.), and the resulting mixture was heated at 90 °C overnight. After completion, the solvent was removed under vacuum, and the residue was purified by flash chromatography (ethyl acetate/n-hexane: 1/30) to afford the desired product.
2-(tert-Butylamino)-1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5a)
64 mg, 65% yield, yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8 Hz, 2H), 7.39–7.37 (m, 3H), 7.31–7.29 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.97–6.93 (m, 1H), 6.80–3.71 (m, 3H), 0.81 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 152.1, 142.8, 135.7, 135.3, 131.0, 130.5, 130.0, 129.3, 128.9, 128.2, 124.0, 123.7, 120.8, 119.6, 118.0, 117.1, 113.8, 102.9, 55.1, 30.2. HRMS (m/z, ESI) calcd for C27H24Cl2N3O2 (+) 492.1246, found 492.1243.
1-(4-Bromophenyl)-3-((4-bromophenyl)amino)-2-(tert-butylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5b)
87 mg, 75% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.80 (dt, J = 2.7, 8.4 Hz, 2H), 7.40–7.30 (m, 6H), 6.96 (t, J = 8.4 Hz, 1H), 6.75–3.72 (m, 3H), 0.81 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.5, 153.7, 145.0, 137.4, 134.5, 133.3, 132.8, 132.2, 130.9, 129.7, 125.3, 125.2, 122.3, 121.1, 119.6, 119.1, 115.4, 112.8, 104.6, 56.7, 31.8. HRMS (m/z, ESI) calcd for C27H24Br2N3O2 (+) 580.0235, found 580.0218.
2-(tert-Butylamino)-1-(4-fluorophenyl)-3-((4-fluorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5c)
40 mg, 44% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.37–7.28 (m, 6H), 6.98–6.91 (m, 3H), 6.84–6.79 (m, 2H), 6.70–6.67 (m, 1H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 164.5, 161.2, 159.2, 158.4, 155.3, 152.0, 140.3, 140.2, 132.8, 132.7, 131.5, 131.4, 130.0, 129.2, 128.0, 123.6, 120.7, 120.3, 117.9, 117.3, 117.2, 116.8, 116.5, 115.5, 115.2, 113.9, 102.5, 54.9, 30.1. HRMS (m/z, ESI) calcd for C27H24F2N3O2 (+) 460.1837, found 460.1823.
2-(tert-Butylamino)-1-(4-(trifluoromethyl)phenyl)-3-((4-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5d)
66 mg, 59% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.42–7.39 (m, 1H), 7.35–7.27 (m, 1H), 6.98 (t, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.69–6.65 (m, 2H), 0.79 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.7, 152.0, 147.1, 139.9, 132.0, 131.6, 131.3, 130.2, 129.6, 128.4, 126.7, 126.6, 126.5, 126.4, 126.3, 126.2, 125.3, 123.8, 122.9, 121.7, 121.0, 120.7, 120.6, 118.9, 118.0, 114.8, 113.5, 103.4, 55.2, 30.1. HRMS (m/z, ESI) calcd for C29H24F6N3O2 (+) 560.1773, found 560.1769.
1-(4-(tert-Butyl)phenyl)-3-((4-(tert-butyl)phenyl)amino)-2-(tert-butylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5e)
49 mg, 46% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 8.7 Hz, 2H), 7.37–7.32 (m, 4H), 7.24–7.22 (m, 2H), 6.92–6.82 (m, 3H), 6.72 (d, J = 8.1 Hz, 1H), 1.44 (s, 9H), 1.29 (s, 9H), 0.78 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.3, 153.0, 151.9, 142.0, 141.8, 134.0, 130.7, 129.0, 128.9, 127.5, 126.4, 125.6, 123.3, 120.9, 120.0, 117.7, 115.8, 114.2, 102.4, 54.8, 34.9, 33.9, 31.5, 31.3, 30.0. HRMS (m/z, ESI) calcd for C35H42N3O2 (+) 536.3277, found 536.3272.
2-(tert-Butylamino)-1-phenyl-3-(phenylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5f)
36 mg, 42% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.64–7.61 (m, 3H), 7.46–7.43 (m, 2H), 7.38 (dd, J = 0.9, 8.4 Hz, 1H), 7.28–7.22 (m, 3H), 6.92–6.81 (m, 4H), 6.68 (dd, J = 1.2, 8.1 Hz, 1H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.3, 151.9, 144.3, 140.1, 136.8, 130.7, 129.7, 129.6, 129.0, 128.9, 127.7, 123.4, 120.9, 119.4, 119.2, 117.8, 115.9, 114.0, 102.7, 54.9, 30.1. HRMS (m/z, ESI) calcd for C27H26N3O2 (+) 424.2025, found 424.2021.
2-(tert-Butylamino)-1-(3-(trifluoromethyl)phenyl)-3-((3-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5g)
73 mg, 65% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.1 Hz, 1H), 7.83–7.75 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.42–7.33 (m, 3H), 7.11–6.92 (m, 4H), 6.73 (s, 1H), 6.66 (dd, J = 1.2, 8.1 Hz, 1H), 0.76 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.9, 152.1, 144.3, 137.4, 133.0, 132.5, 132.1, 131.5, 131.1, 130.3, 130.2, 129.5, 129.4, 128.4, 126.8, 126.7, 126.3, 126.2, 126.0, 123.7, 122.4, 120.6, 119.6, 118.8, 118.1, 115.8, 115.7, 113.5, 112.2, 103.0, 55.1, 29.9. HRMS (m/z, ESI) calcd for C29H24F6N3O2 (+) 560.1773, found 560.1764.
2-(tert-Butylamino)-1-(3-ethylphenyl)-3-((3-ethylphenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5h)
57 mg, 59% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.53 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.37 (d, 7.2 Hz, 1H), 7.26–7.21 (m, 3H), 7.15 (t, J = 7.8 Hz, 1H), 6.89 (t, J = 6.9 Hz, 1H), 6.74–6.66 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.3, 151.9, 146.2, 145.0, 144.3, 136.7, 130.7, 129.5, 129.1, 129.0, 128.8, 128.7, 127.6, 126.7, 123.3, 120.9, 119.5, 118.9, 117.7, 115.6, 114.1, 113.2, 102.5, 54.8, 30.1, 28.9, 28.7, 15.6, 15.5. HRMS (m/z, ESI) calcd for C31H34N3O2 (+) 480.2651, found 480.2647.
2-(tert-Butylamino)-1-(3-methoxyphenyl)-3-((3-methoxyphenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5i)
34 mg, 35% yield, yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.52 (t, J = 8 Hz, 1H), 7.37 (d, J = 8 Hz, 1H), 7.16–7.12 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.95–6.89 (m, 2H), 6.73 (d, J = 6.8 Hz, 1H), 6.49 (d, J = 5.1 Hz, 3H), 6.40 (d, J = 5.7 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 0.86 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.6, 160.5, 159.2, 152.0, 146.0, 137.8, 131.3, 130.4, 129.6, 129.0, 127.7, 123.5, 121.8, 121.0, 118.9, 117.8, 115.4, 115.3, 114.0, 108.7, 104.4, 102.9, 102.0, 55.7, 55.2, 54.9, 30.2. HRMS (m/z, ESI) calcd for C29H30N3O4 (+) 484.2236, found 484.2232.
2-(tert-Butylamino)-1-(2-chlorophenyl)-3-((2-chlorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5j)
62 mg, 63% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 7.5 Hz, 1H), 7.62–7.58 (m, 2H), 7.40–7.29 (m, 3H), 7.14 (t, J = 7.2 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.79–6.72 (m, 2H), 6.61–6.58 (m, 2H), 0.84 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.5, 152.0, 140.7, 134.9, 134.3, 131.7, 131.6, 131.2, 130.8, 129.6, 129.4, 128.1, 127.7, 127.1, 123.7, 121.1, 120.1, 119.2, 118.6, 117.9, 114.7, 113.9, 103.8, 54.6, 30.2. HRMS (m/z, ESI) calcd for C27H24Cl2N3O2 (+) 492.1246, found 492.1240.
2-(tert-Butylamino)-1-(2-iodophenyl)-3-((2-iodophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5k)
67 mg, 50% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.66–7.56 (m, 1H), 7.54–7.53 (m, 1H), 7.40–7.31 (m, 2H), 7.30–7.17 (m, 1H), 6.91–6.88 (m, 2H), 6.56–6.55 (m, 2H), 6.46 (dd, J = 1.2, 8.1 Hz, 1H), 0.84 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.6, 152.0, 143.8, 140.2, 139.9, 131.4, 131.3, 130.4, 129.2, 128.8, 128.6, 128.0, 123.7, 120.7, 120.2, 119.7, 117.9, 115.2, 113.9, 103.4, 100.5, 87.7, 54.5, 30.4. HRMS (m/z, ESI) calcd for C27H24I2N3O2 (+) 675.9958, found 675.9949.
Methyl 2-((2-(tert-Butylamino)-1-(2-(methoxycarbonyl)phenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)amino)benzoate (5l)
65 mg, 60% yield, yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8 Hz, 1H), 7.98 (d, J = 8 Hz, 1H), 7.78–7.68 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.37–7.23 (m, 3H), 6.88 (t, J = 8 Hz, 1H), 6.76–6.60 (m, 3H), 3.93 (s, 3H), 3.72 (s, 3H), 0.78 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.3, 166.8, 159.1, 153.9, 150.6, 138.3, 136.6, 135.5, 134.3, 133.4, 133.2, 133.1, 132.1, 131.6, 131.3, 129.4, 124.8, 122.3, 119.4, 118.7, 117.7, 115.5, 115.4, 113.2, 106.5, 55.7, 54.0, 53.1, 31.9. HRMS (m/z, ESI) calcd for C31H30N3O6 (+) 540.2135, found 540.2129.
2-(tert-Butylamino)-1-(3-chloro-4-fluorophenyl)-3-((3-chloro-4-fluorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5m)
58 mg, 55% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.55 (dd, J = 2.4, 6.3 Hz, 1H), 7.46–7.29 (m, 4H), 7.06–6.96 (m, 2H), 6.91 (dd, J = 2.7, 6.0 Hz, 1H), 6.73–6.69 (m, 2H), 0.84 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.2, 159.0, 156.9, 153.6, 152.0, 150.4, 140.9, 140.8, 133.2, 133.1, 131.9, 130.3, 129.7, 129.6, 129.5, 128.4, 123.8, 122.5, 122.3, 121.0, 120.7, 120.6, 119.7, 118.1, 117.7, 117.4, 116.7, 116.4, 115.3, 115.2, 113.5, 102.8, 55.1, 30.2. HRMS (m/z, ESI) calcd for C27H22N3O2F2Cl2 (+) 528.1057, found 528.1051.
2-(tert-Butylamino)-8-chloro-1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5n)
65 mg, 62% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.66 (dt, J = 2.7, 8.7 Hz, 2H), 7.38 (dt, J = 3.0, 8.4 Hz, 2H), 7.32–7.24 (m, 2H), 7.21–7.17 (m, 2H), 6.79 (dt, J = 3.0, 9.0 Hz, 2H), 6.65 (d, J = 2.1 Hz, 1H), 0.81 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.5, 150.2, 142.6, 136.1, 134.6, 131.0, 130.7, 130.0, 129.0, 127.9, 127.7, 124.1, 120.3, 119.7, 119.2, 117.1, 114.8, 103.3, 22.5, 30.1. HRMS (m/z, ESI) calcd for C27H23N3O2Cl3 (+) 526.0856, found 526.0851.
1-(4-Bromophenyl)-3-((4-bromophenyl)amino)-2-(tert-butylamino)-8-chlorochromeno[4,3-b]pyrrol-4(1H)-one (5o)
80 mg, 65% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.7 Hz, 2H), 7.34–7.21 (m, 6H), 6.74 (d, J = 6.9 Hz, 2H), 6.65 (d, J = 2.4 Hz, 1H), 0.81 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 150.2, 143.1, 135.1, 133.0, 131.7, 131.1, 131.0, 128.9, 127.9, 127.7, 124.1, 120.3, 119.5, 119.1, 117.5, 114.7, 111.3, 103.3, 55.2, 30.1. HRMS (m/z, ESI) calcd for C27H22Br2ClN3NaO2 (+) 635.9665, found 635.9652.
2-(tert-Butylamino)-8-chloro-1-(4-(trifluoromethyl)phenyl)-3-(((4-trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5p)
77 mg, 65% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.34–7.31 (m, 1H), 7.27–7.23 (m, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 2.4 Hz, 1H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.1, 150.3, 146.9, 139.3, 132.4, 132.0, 131.9, 130.1, 129.0, 128.2, 128.1, 126.9, 126.8, 126.5, 126.4, 126.3, 126.2, 125.2, 122.9, 121.6, 121.2, 120.8, 120.3, 119.2, 118.9, 114.8, 114.5, 55.3, 30.1. HRMS (m/z, ESI) calcd for C29H23N3O2F6Cl (+) 594.1383, found 594.1380.
4-((2-(tert-Butylamino)-8-chloro-1-(4-cyanophenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)amino)benzonitrile (5q)
56 mg, 55% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.35–7.26 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.59 (s, 1H), 6.58 (s, 1H), 0.78 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.9, 150.3, 147.7, 139.9, 133.6, 133.5, 132.2, 130.5, 129.2, 128.6, 128.3, 120.3, 119.9, 119.4, 118.4, 117.4, 115.1, 114.2, 114.1, 104.1, 101.4, 55.4, 30.9. HRMS (m/z, ESI) calcd for C29H22N5O2NaCl (+) 530.1360, found 530.1357.
1-(4-(tert-Butyl)phenyl)-3-((4-(tert-butyl)phenyl)amino)-2-(tert-butylamino)-8-chlorochromeno[4,3-b]pyrrol-4(1H)-one (5r)
51 mg, 45% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 2H), 7.33–7.25 (m, 5H), 7.18–7.14 (m, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 2.4 Hz, 1H), 1.45 (s, 9H), 1.29 (s, 9H), 0.82 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.8, 153.7, 150.2, 142.2, 141.7, 133.5, 131.3, 128.9, 128.6, 127.6, 127.1, 126.6, 125.7, 120.6, 120.0, 118.8, 115.9, 115.2, 102.8, 55.0, 35.0, 33.9, 31.5, 31.3, 30.1. HRMS (m/z, ESI) calcd for C35H41N3O2Cl (+) 570.2887, found 570.2880.
2-(tert-Butylamino)-8-chloro-1-phenyl-3-(phenylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5s)
48 mg, 52% yield, yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 3H), 7.43 (s, 3H), 7.30–7.17 (m, 3H), 6.88–6.82 (m, 3H), 6.56 (s, 1H), 6.47 (s, 1H), 0.80 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 150.3, 144.2, 136.3, 131.5, 130.0, 129.8, 129.5, 129.0, 128.8, 127.6, 127.4, 120.5, 119.7, 119.4, 119.0, 116.0, 115.2, 103.2, 55.0, 30.1. HRMS (m/z, ESI) calcd for C27H25N3O2Cl (+) 458.1635, found 458.1631.
2-(tert-Butylamino)-8-chloro-1-(3-(trifluoromethyl)phenyl)-3-((3-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5t)
76 mg, 64% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.74–7.73 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.39–7.32 (m, 2H), 7.26–7.23 (m, 1H), 7.11–7.10 (m, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.68 (s, 1H), 6.56 (d, J = 2.4 Hz, 1H), 0.76 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 150.3, 144.1, 136.8, 132.9, 132.7, 132.3, 131.1, 130.8, 130.5, 129.5, 129.1, 128.2, 128.0, 126.6, 124.9, 120.3, 119.8, 119.3, 118.9, 116.0, 115.9, 114.6, 112.3, 112.2, 103.4, 55.2, 29.9. HRMS (m/z, ESI) calcd for C29H23N3O2F6Cl (+) 594.1383, found 594.1378.
2-(tert-Butylamino)-8-chloro-1-(3-chlorophenyl)-3-((3-chlorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5u)
76 mg, 72% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.69–7.58 (m, 2H), 7.47–7.46 (m, 1H), 7.37–7.13 (m, 4H), 6.87–6.80 (m, 2H), 6.75–6.71 (m, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.52 (s, 1H), 0.83 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 150.3, 145.2, 137.2, 135.5, 134.7, 131.4, 130.7, 130.3, 129.9, 129.7, 128.9, 127.9, 127.8, 120.4, 120.3, 119.4, 119.2, 119.1, 119.0, 115.7, 114.7, 113.9, 103.4, 55.2, 30.1. HRMS (m/z, ESI) calcd for C27H23N3O2Cl3 (+) 526.0856, found 526.0850.
Methyl 2-((2-(tert-Butylamino)-8-chloro-1-(2-(methoxycarbonyl)phenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)amino)benzoate (5v)
79 mg, 69% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.24 (dd, J = 1.8, 7.5 Hz, 1H), 7.99 (dd, J = 1.8, 8.1 Hz, 1H), 7.83–7.71 (m, 2H), 7.54 (dd, J = 1.5, 7.8 Hz, 1H), 7.34–7.27 (m, 2H), 7.21 (dd, J = 2.4, 8.7 Hz, 1H), 6.74–6.67 (m, 2H), 6.51 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.75 (s, 3H), 0.79 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.7, 165.1, 157.0, 150.5, 148.9, 136.1, 135.6, 134.0, 132.8, 131.8, 131.6, 131.5, 130.3, 130.1, 128.5, 128.4, 127.6, 120.3, 119.0, 117.2, 116.3, 114.9, 113.7, 111.5, 105.4, 54.3, 52.6, 51.6, 30.2. HRMS (m/z, ESI) calcd for C31H29N3O6Cl (+) 574.1745, found 574.1736.
2-(tert-Butylamino)-8-chloro-1-(3-chloro-4-fluorophenyl)-3-((3-chloro-4-fluorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5w)
57 mg, 51% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.54 (dd, J = 2.7, 6.3 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.37–7.24 (m, 2H), 7.06 (t, J = 8.7 Hz, 1H), 6.91 (dd, J = 2.7, 6.3 Hz, 1H), 6.73–6.68 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.47 (s, 1H), 0.84 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.4, 158.4, 157.0, 153.7, 150.6, 150.3, 140.7, 140.6, 132.6, 132.5, 131.8, 130.9, 129.5, 129.4, 129.1, 128.1, 127.9, 122.8, 122.5, 121.1, 120.8, 120.2, 119.9, 119.3, 117.8, 117.5, 116.7, 116.4, 115.4, 115.3, 114.5, 103.2, 55.2, 30.2. HRMS (m/z, ESI) calcd for C27H21N3O2F2Cl3 (+) 562.0667, found 562.0665.
8-Bromo-2-(tert-butylamino)-1-(4-(trifluoromethyl)phenyl)-3-((4-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5x)
64 mg, 50% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 3 Hz, 2H), 7.41–7.24 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.685 (d, J = 2.4 Hz, 1H), 6.60 (s, 1H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.1, 150.8, 146.9, 139.3, 132.1, 131.9, 131.0, 130.1, 128.8, 127.9, 126.9, 126.8, 126.5, 126.4, 123.4, 121.3, 120.8, 119.6, 118.9, 118.5, 116.5, 115.0, 114.8, 112.8, 103.9, 55.3, 30.8. HRMS (m/z, ESI) calcd for C29H23N3O2F6Br (+) 638.0878, found 638.0874.
8-Bromo-1-(4-bromophenyl)-3-((4-bromophenyl)amino)-2-(tert-butylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5y)
77 mg, 58% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.82 (dt, J = 2.7, 8.7 Hz, 2H), 7.39–7.22 (m, 6H), 6.79 (d, J = 2.1 Hz, 1H), 6.74 (dt, J = 3.3, 8.7 Hz, 2H), 6.46 (s, 1H), 0.81 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 150.7, 143.1, 135.1, 133.0, 131.7, 131.2, 130.9, 130.7, 127.6, 124.0, 123.4, 119.5, 119.4, 117.5, 116.4, 115.2, 111.3, 103.3, 55.2, 30.9. HRMS (m/z, ESI) calcd for C27H23Br3N3O2 (+) 657.9340, found 657.9333.
8-Bromo-2-(tert-butylamino)-1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5z)
67 mg, 59% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.66 (dt, J = 3.0, 8.7 Hz, 2H), 7.38 (dt, J = 2.7, 8.7 Hz, 3H), 7.25–7.17 (m, 3H), 6.80 (dt, J = 3.3, 8.7 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 150.7, 142.6, 136.1, 134.6, 131.1, 130.7, 130.6, 130.0, 128.8, 127.6, 124.1, 123.4, 119.6, 119.4, 117.0, 116.4, 115.3, 103.3, 55.2, 30.9. HRMS (m/z, ESI) calcd for C27H23N3O2Cl2Br (+) 570.0351, found 570.0347.
8-Bromo-2-(tert-butylamino)-1-(4-fluorophenyl)-3-((4-fluorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5aa)
88 mg, 82% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.50–7.34 (m, 5H), 7.25–7.22 (m, 1H), 6.99–6.92 (m, 2H), 6.83–6.79 (m, 2H), 6.75 (d, J = 2.4 Hz, 1H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 164.7, 161.4, 158.6, 155.4, 150.7, 140.0, 132.2, 132.1, 131.3, 131.2, 130.6, 130.5, 127.5, 123.3, 120.5, 119.4, 117.4, 117.3, 117.0, 116.7, 116.4, 115.6, 115.4, 115.2, 102.9, 55.0, 30.1. HRMS (m/z, ESI) calcd for C27H23N3O2F2Br (+) 538.0942, found 538.0936.
4-((8-Bromo-2-(tert-butylamino)-1-(4-cyanophenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)amino)benzonitrile (5ab)
48 mg, 43% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.44–7.39 (m, 1H), 7.29–7.25 (m, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.73–6.70 (m, 2H), 0.78 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.9, 150.8, 147.6, 139.9, 133.6, 133.5, 132.1, 131.4, 130.5, 128.1, 123.3, 119.8, 119.7, 118.4, 117.3, 116.7, 115.1, 114.7, 114.2, 104.2, 101.5, 55.5, 30.1. HRMS (m/z, ESI) calcd for C29H22N5O2NaBr (+) 574.0855, found 574.0863.
8-Bromo-2-(tert-butylamino)-1-(4-isopropylphenyl)-3-((4-isopropylphenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5ac)
68 mg, 58% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz, 2H), 7.33–7.27 (m, 2H), 7.21 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 1.8 Hz, 1H), 6.41 (s, 1H), 3.15–3.06 (m, 1H), 2.89–2.80 (m, 1H), 1.39 (d, J = 6.9 Hz, 6H), 1.23 (d, J = 6.6 Hz, 6H), 0.83 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.7, 151.4, 150.6, 142.1, 139.9, 133.7, 131.1, 130.9, 129.9, 129.3, 127.7, 127.4, 126.8, 123.6, 119.9, 119.1, 116.2, 115.6, 102.8, 55.0, 34.1, 33.2, 30.1, 24.2, 24.0. HRMS (m/z, ESI) calcd for C33H37N3O2Br (+) 586.2069, found 586.2067.
8-Bromo-2-(tert-butylamino)-1-(4-ethylphenyl)-3-((4-ethylphenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5ad)
55 mg, 49% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.33–7.27 (m, 3H), 7.21 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 2.1 Hz, 1H), 6.40 (s, 1H), 2.85 (q, J = 7.8 Hz, 2H), 2.59 (q, J = 7.8 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H), 1.21 (t, J = 7.8 Hz, 3H), 0.83 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.7, 150.6, 146.7, 142.0, 135.2, 133.7, 131.3, 129.9, 129.2, 129.1, 128.2, 127.4, 123.6, 119.9, 119.2, 116.2, 116.1, 115.7, 102.9, 54.9, 30.1, 28.7, 28.0, 15.9, 15.8. HRMS (m/z, ESI) calcd for C31H33N3O2Br (+) 558.1756, found 558.1749.
8-Bromo-2-(tert-butylamino)-1-phenyl-3-(phenylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5ae)
40 mg, 40% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.67–7.65 (m, 3H), 7.44–7.41 (m, 2H), 7.34–7.21 (m, 4H), 6.88–6.82 (m, 3H), 6.71 (d, J = 2.1 Hz, 1H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.6, 150.7, 144.1, 136.2, 131.3, 130.2, 129.9, 129.8, 129.4, 128.9, 127.4, 123.5, 119.6, 119.4, 119.3, 116.2, 115.9, 115.6, 103.1, 55.0, 30.9. HRMS (m/z, ESI) calcd for C27H25N3O2Br (+) 502.1130, found 502.1125.
8-Bromo-2-(tert-butylamino)-1-(3-(trifluoromethyl)phenyl)-3-((3-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5af)
73 mg, 57% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.38–7.32 (m, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.10–7.08 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.69 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.3, 150.7, 144.2, 136.8, 132.9, 132.7, 132.2, 131.5, 131.1, 130.9, 127.9, 126.7, 126.6, 126.5, 126.4, 126.0, 124.9, 123.3, 122.4, 121.4, 119.7, 119.6, 118.9, 116.5, 116.0, 115.9, 115.0, 112.3, 112.2, 103.4, 55.2, 29.9. HRMS (m/z, ESI) calcd for C29H23N3O2F6Br (+) 638.0878, found 638.0874.
8-Bromo-2-(tert-butylamino)-1-(3-chlorophenyl)-3-((3-chlorophenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5ag)
86 mg, 75% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.69–7.58 (m, 2H), 7.48–7.45 (m, 1H), 7.39–7.33 (m, 2H), 7.26–7.13 (m, 2H), 6.87–6.70 (m, 4H), 6.51 (s, 1H), 0.83 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.3, 150.7, 145.2, 137.2, 135.5, 134.7, 131.4, 130.7, 130.6, 130.3, 129.9, 129.7, 127.8, 127.7, 123.5, 119.5, 119.4, 119.2, 116.4, 115.7, 115.2, 113.9, 103.4, 55.2, 30.1. HRMS (m/z, ESI) calcd for C27H23N3O2Cl2Br (+) 570.0351, found 570.0347.
2-(tert-Butylamino)-7-methoxy-1-(4-(trifluoromethyl)phenyl)-3-((4-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5ah)
50 mg, 42% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 2H), 6.61–6.53 (m, 3H), 3.82 (s, 3H), 0.77 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.9, 158.8, 153.7, 147.1, 140.0, 131.9, 131.4, 130.5, 130.3, 126.7, 126.6, 126.5, 126.4, 126.3, 125.3, 122.9, 121.7, 120.9, 120.5, 118.7, 114.7, 111.5, 106.8, 102.3, 101.5, 55.5, 30.1. HRMS (m/z, ESI) calcd for C30H26N3O3F6 (+) 590.1878, found 590.1881.
2-(tert-Butylamino)-1-(4-chlorophenyl)-3-((4-chlorophenyl)amino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5ai)
38 mg, 36% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.59 (dt, J = 2.7, 8.7 Hz, 2H), 7.38 (dt, J = 2.7, 8.4 Hz, 2H), 7.19 (dt, J = 2.1, 8.7 Hz, 2H), 6.90 (d, J = 2.4 Hz, 1H), 6.79 (dt, J = 3.0, 8.7 Hz, 2H), 6.65–6.62 (m, 1H), 6.57–6.53 (m, 1H), 3.81 (s, 3H), 0.79 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.7, 159.2, 153.6, 142.8, 135.5, 135.3, 130.9, 130.3, 129.8, 129.4, 128.8, 123.7, 121.7, 119.4, 116.9, 111.5, 107.1, 102.1, 100.9, 55.5, 55.0, 30.1. HRMS (m/z, ESI) calcd for C28H25N3O3NaCl2 (+) 544.1171, found 544.1164.
2-(tert-Butylamino)-1-(4-fluorophenyl)-3-((4-fluorophenyl)amino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5aj)
46 mg, 47% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.43–7.38 (m, 2H), 7.34–7.27 (m, 2H), 6.97–6.89 (m, 3H), 6.83–6.78 (m, 2H), 6.61–6.51 (m, 2H), 6.43 (s, 1H), 3.80 (s, 3H), 0.79 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.6, 159.3, 153.6, 140.3, 132.8, 132.7, 132.0, 131.5, 131.4, 130.2, 128.9, 121.6, 120.1, 117.2, 117.1, 116.7, 116.4, 115.5, 115.2, 111.4, 107.2, 102.1, 100.8, 100.7, 55.5, 54.8, 30.1. HRMS (m/z, ESI) calcd for C28H25N3O3F2Na (+) 512.1762, found 512.1747.
1-(4-Bromophenyl)-3-((4-bromophenyl)amino)-2-(tert-butylamino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5ak)
59 mg, 48% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.7 Hz, 2H), 7.33–7.27 (m, 4H), 6.90 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 6.66–6.58 (m, 1H), 6.57–6.54 (m, 1H), 3.81 (s, 3H), 0.80 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.7, 159.1, 153.6, 143.4, 135.8, 132.8, 131.7, 131.3, 130.3, 129.5, 123.5, 121.7, 119.2, 117.3, 111.5, 110.9, 107.0, 102.1, 101.1, 55.5, 55.1, 30.1. HRMS (m/z, ESI) calcd for C28H26N3O3Br2 (+) 610.0341, found 610.0322.
1-(4-(tert-Butyl)phenyl)-3-((4-(tert-butyl)phenyl)amino)-2-(tert-butylamino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5al)
41 mg, 36% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.27–7.24 (m, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.64–6.61 (m, 1H), 6.51–6.47 (m, 1H), 3.80 (s, 3H), 1.44 (s, 9H), 1.29 (s, 9H), 0.77 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.4, 159.3, 153.5, 152.9, 141.9, 141.8, 134.1, 129.9, 129.7, 129.1, 126.3, 125.6, 121.8, 119.7, 115.8, 111.1, 107.6, 102.0, 100.6, 55.4, 54.7, 34.9, 33.9, 31.5, 31.3, 30.0. HRMS (m/z, ESI) calcd for C36H44N3O3 (+) 566.3383, found 566.3377.
2-(tert-Butylamino)-7-methoxy-1-phenyl-3-(phenylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5am)
43 mg, 47% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.63–7.62 (m, 3H), 7.61–7.41 (m, 2H), 7.27–7.21 (m, 2H), 6.90–6.80 (m, 4H), 6.59 (d, J = 9.0 Hz, 1H), 6.48–6.47 (m, 1H), 3.80 (s, 3H), 0.78 (m, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.1, 159.4, 159.3, 153.6, 144.3, 136.9, 130.0, 129.7, 129.5, 129.4, 128.9, 121.8, 119.3, 113.1, 115.8, 111.2, 107.4, 102.0, 100.8, 55.5, 54.8, 30.1. HRMS (m/z, ESI) calcd for C28H28N3O3 (+) 454.2131, found 454.2122.
2-(tert-Butylamino)-7-methoxy-1-(3-(trifluoromethyl)phenyl)-3-((3-(trifluoromethyl)phenyl)amino)chromeno[4,3-b]pyrrol-4(1H)-one (5an)
68 mg, 58% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 1H), 7.80–7.73 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.10–7.07 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.68 (s, 1H), 6.55–6.54 (m, 1H), 3.82 (s, 3H), 0.74 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.9, 159.1, 153.7, 144.4, 137.4, 133.1, 132.8, 132.4, 131.9, 131.5, 131.1, 130.5, 130.2, 129.4, 129.3, 126.9, 126.8, 126.2, 126.1, 126.0, 121.6, 119.4, 118.7, 115.7, 112.1, 112.0, 111.6, 106.8, 102.2, 101.1, 55.5, 54.9, 29.9. HRMS (m/z, ESI) calcd for C30H26N3O3F6 (+) 590.1878, found 590.1875.
2-(tert-Butylamino)-1-(3-chlorophenyl)-3-((3-chlorophenyl)amino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5ao)
44 mg, 42% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.63–7.54 (m, 2H), 7.46–7.44 (m, 1H), 7.36–7.33 (m, 1H), 7.18–7.13 (m, 1H), 6.91–6.85 (m, 2H), 6.83–6.71 (m, 2H), 6.63–6.51 (m, 3H), 3.81 (s, 3H), 0.81 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.8, 159.1, 153.7, 145.5, 137.9, 135.2, 134.7, 130.5, 130.3, 129.9, 129.8, 129.7, 128.0, 121.7, 119.1, 118.9, 115.6, 113.9, 111.5, 107.0, 102.1, 101.1, 95.6, 55.5, 54.9, 30.1. HRMS (m/z, ESI) calcd for C28H26N3O3Cl2 (+) 522.1351, found 522.1338.
2-(tert-Butylamino)-1-(3-ethylphenyl)-3-((3-ethylphenyl)amino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5ap)
46 mg, 39% yield, deep yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.51 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.25–7.22 (m, 2H), 7.15 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.73–6.60 (m, 4H), 6.51–6.45 (m, 2H), 3.80 (s, 3H), 2.81–2.73 (q, J = 7.8 Hz, 2H), 2.65–2.58 (q, J = 7.8 Hz, 2H), 1.32–1.28 (t, J = 7.8 Hz, 3H), 1.27–1.22 (t, J = 7.8 Hz, 3H), 0.78 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.3, 153.5, 146.1, 145.0, 144.4, 136.7, 129.8, 129.7, 129.4, 129.1, 128.9, 128.7, 126.7, 121.9, 119.3, 118.7, 115.5, 113.1, 111.1, 107.5, 101.9, 100.7, 55.4, 54.6, 30.8, 28.9, 28.6, 15.6, 15.5. HRMS (m/z, ESI) calcd for C32H36N3O3 (+) 510.2757, found 510.2748.
2-(tert-Butylamino)-1-(2-chlorophenyl)-3-((2-chlorophenyl)amino)-7-methoxychromeno[4,3-b]pyrrol-4(1H)-one (5aq)
44 mg, 42% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.67–7.66 (m, 1H), 7.62–7.53 (m, 3H), 7.35 (dd, J = 1.2, 7.8 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.79–6.70 (m, 2H), 6.55–6.47 (m, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.8, 153.7, 140.8, 135.0, 134.4, 131.7, 131.0, 130.7, 130.6, 130.3, 129.3, 128.9, 127.7, 127.6, 127.1, 121.1, 119.2, 119.1, 118.5, 114.6, 111.6, 107.3, 102.0, 55.5, 54.5, 30.2. HRMS (m/z, ESI) calcd for C28H25N3O3NaCl2 (+) 544.1171, found 544.1162.
Methyl 2-((2-(tert-Butylamino)-7-methoxy-1-(2-(methoxycarbonyl)phenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)amino)benzoate (5ar)
40 mg, 44% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.20 (dd, J = 1.8, 7.5 Hz, 1H), 7.98 (dd, J = 1.5, 8.1 Hz, 1H), 7.78–7.66 (m, 2H), 7.53–7.50 (m, 1H), 7.34–7.27 (m, 1H), 6.91–6.90 (m, 1H), 6.76–6.68 (m, 2H), 6.65–6.45 (m, 2H), 0.77 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.7, 165.3, 159.5, 157.7, 153.9, 149.1, 136.7, 134.0, 133.9, 132.6, 131.8, 131.6, 131.5, 130.5, 129.6, 121.7, 116.9, 116.0, 114.2, 113.7, 111.4, 111.2, 107.2, 102.9, 101.9, 55.5, 54.1, 52.5, 51.6, 30.2. HRMS (m/z, ESI) calcd for C32H32N3O7 (+) 570.2240, found 570.2235.
2-(tert-Butylamino)-1-(3-chloro-4-fluorophenyl)-3-((3-chloro-4-fluorophenyl)amino)-7-methoxy-chromeno[4,3-b]pyrrol-4(1H)-one (5as)
65 mg, 58% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.54 (dd, J = 2.4, 6.6 Hz, 1H), 7.44–7.31 (m, 2H), 7.05 (t, J = 8.7 Hz, 1H), 6.92–6.88 (m, 3H), 6.73–6.67 (m, 1H), 6.60–6.59 (m, 2H), 3.82 (s, 3H), 0.83 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.9, 159.1, 156.8, 153.7, 141.0, 140.9, 133.3, 131.9, 130.5, 129.7, 129.6, 129.3, 121.6, 119.6, 117.6, 116.7, 116.4, 115.3, 115.2, 111.7, 106.8, 102.2, 55.5, 55.0, 30.1. HRMS (m/z, ESI) calcd for C28H24N3O3F2Cl2 (+) 558.1163, found 558.1147.
1-(4-Bromophenyl)-3-((4-bromophenyl)amino)-2-(cyclohexylamino)chromeno[4,3-b]pyrrol-4(1H)-one (5at)
50 mg, 41% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.7 Hz, 2H), 7.39–7.30 (m, 4H), 7.24–7.20 (m, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.7 Hz, 2H), 6.57 (dd, J = 0.9, 8.1 Hz, 1H), 6.09 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.7, 151.5, 145.2, 135.3, 134.7, 133.7, 131.7, 130.7, 127.7, 127.3, 124.4, 123.6, 119.8, 117.8, 116.5, 113.7, 110.7, 109.9, 104.5, 53.7, 33.9, 25.4, 24.6. HRMS (m/z, ESI) calcd for C29H26N3O2Br2 (+) 606.0392, found 606.0367.
Methyl 2-((2-(Cyclohexylamino)-1-(2-(methoxycarbonyl)phenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)amino)benzoate (5au)
50 mg, 44%, yellow solid; 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.83–7.74 (m, 2H), 7.58 (d, J = 6.9 Hz, 1H), 7.35–7.17 (m, 2H), 6.87–6.65 (m, 3H), 6.44 (d, J = 7.8 Hz, 1H), 3.94 (s, 3H), 3.68 (s, 3H), 2.80–2.60 (m, 1H), 1.69–1.40 (m, 4H), 1.05–0.75 (m, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.9, 164.9, 157.6, 151.7, 150.5, 137.8, 136.2, 134.1, 133.7, 132.4, 131.3, 130.9, 130.4, 130.3, 128.9, 127.1, 123.3, 119.6, 113.9, 113.7, 111.2, 107.9, 105.9, 54.5, 52.7, 51.6, 34.0, 25.4, 24.7. HRMS (m/z, ESI) calcd for C33H32N3O6 (+) 566.2291, found 566.2289.
Typical Procedure for the Synthesis of Imidazole-Fused Chromeno[4,3-b]pyrrol-4(1H)-ones
5a (0.1 mmol, 1.0 equiv.), substituted benzoic acid (0.15 mmol, 1.5 equiv.), and PPA (2 mL) were placed in a reaction tube. The mixture was heated and stirred at 180 °C for 4 h. After the reaction was completed, the mixture was allowed to cool to room temperature and poured into cold water (50 mL). The mixture was neutralized with NaHCO3. The resulting precipitate was filtered out, washed several times with water, and purified by flash chromatography (n-hexane/ethyl acetate, 20/1).
7,10-Bis(4-chlorophenyl)-8-phenyl-7,10-dihydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,3-d]imidazol-6-one (6a)
21 mg, 41% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 6.6 Hz, 2H), 7.50–7.32 (m, 9H), 7.17 (dd, J = 1.8, 6.3 Hz, 1H), 6.97 (t, J = 5.7 Hz, 1H), 6.72 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 6.3 Hz, 1H), 6.29 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 161.1, 158.0, 152.1, 143.9, 140.4, 135.6, 135.4, 135.2, 131.8, 131.4, 130.9, 130.3, 129.8, 128.9, 128.6, 128.3, 128.1, 127.7, 123.5, 121.2, 117.6, 113.0, 111.5, 105.6. HRMS (m/z, ESI) calcd for C30H18Cl2N3O2 (+) 522.0776, found 522.0773.
7,10-Bis(4-chlorophenyl)-8-(p-tolyl)-7,10-dihydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,3-d]imidazol-6-one (6b)
28 mg, 52% yield, yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 2.4 Hz, 1H), 7.64–7.60 (m, 2H), 7.45–7.31 (m, 6H), 7.19–7.15 (m, 3H), 6.97 (td, J = 1.2, 8.4 Hz, 1H), 6.74–6.71 (m, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 161.4, 158.1, 152.0, 144.3, 142.5, 140.5, 135.5, 135.4, 134.3, 132.2, 131.3, 130.8, 130.3, 129.7, 129.5, 128.5, 128.2, 127.7, 123.5, 121.1, 117.6, 113.0, 111.1, 105.6, 29.7. HRMS (m/z, ESI) calcd for C31H20Cl2N3O2 (+) 536.0933, found 536.0926.
7,8,10-Tris(4-chlorophenyl)-7,10-dihydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,3-d]imidazol-6-one (6c)
27 mg, 49% yield, yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.76–7.74 (m, 3H), 7.65–7.62 (m, 2H),7.55–7.41 (m, 5H), 7.27 (dd, J = 2.1, 8.4 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 161.9, 157.4, 151.8, 144.9, 142.1, 137.1, 135.6, 134.8, 134.4, 133.9, 131.5, 131.2, 130.7, 130.1, 129.4, 129.1, 128.9, 124.3, 123.5, 121.2, 117.6, 113.0, 110.6, 105.1. HRMS (m/z, ESI) calcd for C30H17Cl3N3O2 (+) 556.0386, found 556.0398.
8-(3-Chlorophenyl)-7,10-bis(4-chlorophenyl)-7,10-dihydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,3-d]imidazole-6-one (6d)
23 mg, 42% yield, yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.78–7.75 (m, 3H), 7.66–7.63 (m, 2H), 7.58–7.52 (m, 2H),7.47–7.41 (m, 4H), 7.25 (dd, J = 2.4, 8.4 Hz, 1H), 7.09 (t, J = 6.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 161.5, 157.4, 151.8, 144.9, 142.0, 137.1, 135.7, 134.9, 134.4, 133.5, 131.9, 131.3, 130.7, 130.1, 129.5, 129.4, 129.0, 128.5, 127.4, 124.3, 123.7, 121.2, 117.6, 113.0, 110.5, 105.1. HRMS (m/z, ESI) calcd for C30H17Cl3N3O2 (+) 556.0386, found 556.0383.
8-(4-(tert-Butyl)phenyl)-7,10-bis(4-chlorophenyl)-7,10-dihydro-6H-chromeno[3′,4′:4,5]pyrrolo[2,3-d]imidazol-6-one (6e)
27 mg, 46% yield, yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J = 2.4 Hz, 1H), 65–7.61 (m, 2H), 7.45–7.31 (m, 8H), 7.17 (dd, J = 2.4, 8.4 Hz, 1H), 6.99–6.92 (m, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 161.2, 158.0, 155.6, 152.1, 144.2, 140.4, 135.5, 132.2, 131.3, 130.8, 130.3, 129.8, 128.5, 128.2, 127.6, 125.9, 124.9, 123.5, 121.2, 121.1, 117.6, 113.0, 111.2, 105.6, 31.0, 29.6. HRMS (m/z, ESI) calcd for C30H17Cl3N3O2 (+) 578.1402, found 578.1401.
12-(tert-Butyl)-13-(2-iodophenyl)-12,13-dihydrochromeno[3′,4′:4,5]pyrrolo[2,3-b]quinoxalin-6(7H)-one (7)
To a solution of 5k (0.1 mmol, 67.5 mg) in 2 mL of 1,4-dioxane were added cesium carbonate (0.3 mmol, 97.7 mg), Pd(dba)2 (0.01 mmol, 5.7 mg), and Me-phos (2-dicyclohexylphosphino-2′-methylbiphenyl) (0.01 mmol, 6.2 mg), and the resulting suspension was heated under reflux at an inert atmosphere for 24 h. The solvent was then removed under vacuum, and the residue was purified by flash chromatography (n-hexane/ethyl acetate, 20/1) to afford the desired product 7 (25 mg, 45%). yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.60–7.50 (m, 2H), 7.42–7.25 (m, 4H), 6.93 (t, J = 8.1 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.9, 156.4, 153.9, 153.8, 147.3, 145.4, 140.0, 139.9, 138.2, 134.3, 131.1, 130.8, 129.4, 128.0, 127.7, 125.0, 124.9, 123.7, 119.1, 118.1, 117.8, 110.9, 100.6, 56.6, 29.2. HRMS (m/z, ESI) calcd for C27H23IN3O2 (+) 548.0835, found 548.0831.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (21977008), Natural Science Foundation of Guangdong Province (2018A0303130052), and Shenzhen Basic Research Project (JCYJ20180503182116931). The authors thank Ali Y. Chahine (School of Chemistry, Monash University) and Hao Xie (PKUSZ) for analysis of single-crystal X-ray diffraction data.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c03589.
The authors declare no competing financial interest.
Supplementary Material
References
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