Abstract
A multicomponent reaction between isatin, tetrahydroisoquinoline, and terminal alkyne in the presence of benzoic acid for the synthesis of N-(substituted-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamides is described. This three-component reaction proceeds via sequential formation of spirooxindole, generation of isocyanate functionality via cleavage of the C2–C3 bond in the isatin subunit of spirooxindole, and addition of the second molecule of tetrahydroisoquinoline to the isocyanate group to offer title compounds. Expansion of the protocol to four-component by including an additional primary amine affords 1-substituted-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea in low to moderate yields. However, the reaction of intermediate spirooxindole with tetrahydroisoquinoline or any primary or secondary amine produced the title compound in excellent yields.
Introduction
Pyrrolo[2,1-a]isoquinoline and 5,6-dihydropyrrolo[2,1-a]isoquinoline represent the core structure of lamellarin-type alkaloids and various bioactive compounds displaying a wide spectrum of biological activities (Figure 1).1 For instance, Lamellarin I has multidrug-resistant reversal activity at nontoxic doses, whereas Lamellarin K is cytotoxic to different cancer cell lines.2 Lamellarin K and L are reported to have immunomodulatory activity in the micromolar range.3 Furthermore, Lamellarin D is cited to be a potent inhibitor of DNA topoisomerase I,4a whereas Lamellarin α-20-sulfate is a selective inhibitor of HIV-1 integrase.4b
Figure 1.
Representative examples of bioactive compounds having pyrrolo[2,1-a]isoquinoline and 5,6-dihydropyrrolo[2,1-a]isoquinoline frameworks.
Given the diverse biological properties, synthetic chemists have formulated several elegant strategies for constructing differently substituted pyrrolo[2,1-a]isoquinoline cores.5 Recently, we have reported the dehydrative transformation of spirooxindoles to pyrido[2,3-b]indoles in the presence of POCl3.6 The reaction could be performed as a one-pot two-step process. However, our attempts to prepare the spirooxindole 4 by reacting isatin (1a) with 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2) and phenyl acetylene (3a) as reported were unsuccessful.7 After a short screening for identifying conditions to access 4, we were successful in synthesizing it under microwave irradiation albeit in only 5% yield (Scheme 1). It was reported the reaction between isatin (1a), 1,2,3,4-tetrahydroisoquinoline (THIQ) (5a), and alkenes in the presence of trifluoroacetic acid (TFA) in toluene or montmorillonite K10 leads to the formation of spirooxindoles.8 Notably, however, the fate of this multicomponent reaction (MCR) using terminal alkynes instead of alkenes remains unknown, though it could be reasoned that such a reaction should also afford a spirooxindole (6). As a consequence, we considered investigating the MCR between isatin, THIQ, and terminal alkyne in the presence of an acid catalyst. Accordingly, the reaction between 1a, 3a, and 5a in the presence of TFA in toluene as the medium at 50 °C was attempted. We found that the reaction was incomplete even after 12 h, but post-workup at this stage, the major isolated product (34%) was established as N-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 7aaa instead of the spirooxindole 6 (Scheme 2). This result suggested consumption of 2.0 equiv of 5a, and therefore we repeated the reaction with 2.0 equiv of THIQ, and it was pleasing to discover that the reaction was completed in 22 h to afford 7aaa in 72% yield. Earlier, Stoltz et al. reported a base-mediated skeletal rearrangement (C2–C3 bond cleavage) of substituted oxindole to offer a urea derivative via intermediacy of isocyanate.9 However, the propensity of the protocol to afford 5,6-dihydropyrrolo[2,1-a]isoquinolines incorporating the urea moiety directly via an acid-catalyzed MCR between isatin, THIQ, and terminal alkyne together with lack of too many reports10 on C2–C3 bond cleavage of oxindoles evoked us to investigate the reaction comprehensively.
Scheme 1. Proposed Route for the Synthesis of Spirooxindole 4.
Scheme 2. Comparison of This Work with the Reported Work.
Herein, we report the details of the results of our study and the scope of this MCR.
Results and Discussion
At the outset of the study, we considered optimizing the reaction condition for the formation of product 7, and the results are summarized in Table 1. As stated above, performing the reaction of 1a and 3a with 2.0 equiv of 5a in TFA as the medium at 50 °C resulted in the formation of 7aaa in 72% yield (entry 1). Increasing the temperature of the reaction to 80 °C produced 7aaa in 81% isolated yield within 18 h (entry 2). Next, to investigate the effect of different acid catalysts, the reaction was carried out in the presence of AcOH, benzoic acid, or p-TSA, and it was found that benzoic acid gave 7aaa in a superior yield (84%) (entries 3–5). We discovered that this reaction was successful even in the absence of acid to furnish 7aaa in 71% yield in 26 h (entry 6). Probe for identifying a suitable solvent for the reaction revealed that it was successful in MeCN, dioxane, 1,2-dichloroethane (DCE), and water but, the best yield of 7aaa was obtained in toluene (entries 7–10). Optimization with respect to reaction temperature identified 90 °C to be the most suited for the formation of 7aaa (86%) (entry 11). Therefore, the optimized conditions for the synthesis of 5,6-dihydro-pyrrolo[2,1-a]isoquinoline 7aaa were identified as heating isatin 1a (1.0 equiv), THIQ 5a (2.0 equiv), and terminal alkyne 3a (1.0 equiv) in the presence of 20 mol % benzoic acid in toluene at 90 °C for 16 h.
Table 1. Results of the Optimization Studya.
| entry | acid catalyst (20 mol %) | solvent | temp (°C) | time (h) | yield (%)b of 7aaa |
|---|---|---|---|---|---|
| 1 | TFA | toluene | 50 | 22 | 72 |
| 2 | TFA | toluene | 80 | 18 | 81 |
| 3 | AcOH | toluene | 80 | 18 | 77 |
| 4 | PhCO2H | toluene | 80 | 18 | 84 |
| 5 | p-TSA | toluene | 80 | 18 | 79 |
| 6 | - | toluene | 80 | 26 | 71 |
| 7 | PhCO2H | MeCN | 80 | 20 | 79 |
| 8 | PhCO2H | dioxane | 80 | 24 | 72 |
| 9 | PhCO2H | DCE | 80 | 22 | 75 |
| 10 | PhCO2H | H2O | 80 | 24 | 66 |
| 11 | PhCO2H | toluene | 90 | 16 | 86 |
| 12 | PhCO2H | toluene | 100 | 16 | 86 |
Reaction conditions: 1a (0.68 mmol), 5a (1.36 mmol), 3a (0.68 mmol), and solvent (5 mL).
Isolated yield after column chromatography.
With optimized reaction conditions in hand, the scope of the protocol was investigated initially with respect to a variety of isatins and alkynes (Scheme 3). In the first set of experiments, treating differently substituted isatins (1b–i) with THIQ (5a) and phenyl acetylene (3a) under standard conditions furnished the corresponding 5,6-dihydropyrrolo[2,1-a]isoquinolines 7baa–7iaa in excellent yields. The electronic character of the substituents on isatin did not influence the formation of products. The X-ray crystallographic analysis of one of the products 7eaa unambiguously secured the structure as 5,6- dihydropyrrolo[2,1-a]isoquinolines. Subsequently, testing the scope of the reaction with several terminal alkynes 3b–3g revealed that all substrates smoothly afforded the respective products 7aab–7aag in 78–85% yields. Altering the phenyl ring with heteroaromatic rings in terminal alkynes was also found to be compatible with the protocol as the alkyne 3h bearing pyridine and 3i containing thiophene furnished 7aah and 7aai in 78 and 80% yields, respectively. Finally, the fate of the MCR using terminal alkynes bearing aliphatic groups was evaluated. The terminal alkyne 3j bearing the cyclohexene ring gave the corresponding product 7aaj in 74% yield, whereas aliphatic alkynes such as cyclopropylacetylene (3k) and trimethylsilylacetylene (3l) furnished 7aak and 7aal in moderate yields only. Next, the scope of the reaction was investigated with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 5b, which furnished 7aba in 82% yield, whereas 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 5c afforded the corresponding product 7aca in 84% yield. Replacing isoquinoline with other secondary amine N-methylbenzylamine 5d however failed to offer the desired product 7ada. The activated alkyne like methyl propiolate (3m) and the internal alkyne dimethyl acetylenedicarboxylate (3n) were however discovered to offer the corresponding Michael adducts 8am and 8an only (Scheme 4). Finally, performing the reaction between 1a, 3a, and 5a at a gram scale afforded 7aaa in 85% isolated yield, thereby indicating that the reaction can be conducted at higher scales without attenuation of the yield.
Scheme 3. Scope of the Reaction,
Reaction conditions: 1 (2.04 mmol), 5 (4.08 mmol), 3 (2.04 mmol), and toluene (15 mL).
For 1b–1f, R1 is at C-5; for 1h, R1 is at C-6; and for 1i, R1 is at C-7 of isatin.
Scheme 4. Reaction with Activated Alkynes.
Reaction conditions: 1a (2.04 mmol), 5a (4.08 mmol), 3 (2.04 mmol), and toluene (15 mL).
To expand the substrate scope of the present protocol, we examined a four-component reaction (4CR) by treating isatin 1a (1.0 equiv) with THIQ 5a (1.0 equiv), phenyl acetylene 3a (1.0 equiv), and aniline 9a (1.0 equiv) under standard conditions (Scheme 5). This reaction resulted in the formation of 1-phenyl-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea 10aaaa (27%) together with 7aaa (45%). The success of this 4CR to give new products invoked us to investigate a variety of amines in the protocol. The reaction with substituted anilines like 4-methylaniline (9b), 4-chloroaniline (9c), and 3-bromoaniline (9d) produced the desired 4CR products 10aaab–aaad in 25–37% yields together with 7aaa. However, reactions with 3-nitroaniline (9e), 4-aminobenzoic acid (9f), or N-Boc-1,4-phenylenediamine (9g) failed to afford the desired products, though the 3CR product 7aaa (27–65%) was isolated from each reaction. The heterocyclic amine such as 8-aminoquinoline (9h) resulted in the formation of 10aaah in 35% yield only along with 7aaa in 57% yield. The reactions of 5-aminoindole (9i), 2-aminopyridine (9j), and 2-amino-5-chlorobenzothiazole (9k) also did not afford the respective 4CR products, but 7aaa was isolated in 56–61% yields. Further, the scope of the reaction was investigated with aliphatic amines such as benzylamine 9l, N-methylcyclohexylamine 9m, and N-methylbenzylamine 5d, and it was discovered that these reactions resulted in a complex mixture from which the required product could not be isolated. Pleasingly, however, aliphatic amines having a bulky group like 1-adamantylamine (9n) or tert-butylamine (9o) furnished the desired urea 10aaan or 10aaao in 21–43% yields together with 7aaa.
Scheme 5. Scope of the Four-Component Reaction.
Reaction conditions: 1 (2.04 mmol), 5a (2.04 mmol), 3 (2.04 mmol), 9 (2.04 mmol), and toluene (15 mL). Yields are calculated based on the amount of 5a.
Based on the literature, we anticipated the formation of an isocyanate intermediate, but to delineate the stepwise mechanism of our reaction, we performed a few control experiments. To ascertain the essentiality of N-unprotected isatin for this reaction, we carried out the reaction with N-protected isatin 1j under standard conditions, which resulted in a complex mixture of products (Scheme 6). In our attempt to isolate the isocyanate intermediate, the reaction between 1a, 3a, and 5a was monitored carefully. The thin layer chromatography (TLC) analysis of the reaction mixture after 4 h showed the presence of two new spots beside the starting material. Arresting the reaction followed by workup resulted in isolation of 7aaa in 28% yield together with another solid product (49%) that was spectroscopically established to be the spirooxindole 6a. Additionally, arresting the reaction between 1f, 3a, and 5a after 4 h gave spirooxindole 6b in 35% yield together with 7faa in 24% yield. However, all efforts to obtain spirooxindole 6 exclusively from the reactions between isatin 1, 3a, and 5a were unsuccessful. Isolation of 6 suggested that the reaction proceeds via the intermediacy of spirooxindole, which then undergoes C2–C3 bond cleavage followed by the attack of the second THIQ unit. To ascertain it unambiguously, we heated the spirooxindole 6a with 5a in toluene, which produced 7aaa in 94% yield (Scheme 7). Further treating spirooxindole 6a with 9a furnished 10aaaa in 81% yield. Although we could not isolate the isocyanate, it was discovered that the reaction of spirooxindole 6a with Cs2CO3 in dimethylformamide (DMF) gave the aniline 11 in 93% yield as reported earlier9 (Scheme 7).
Scheme 6. Results of Control Experiments.
Scheme 7. Reactions of Spirooxindole 6 with THIQ, Cs2CO3, and Different Amines.
These control reactions inferred that the reaction of spirooxindole 6a with any primary or secondary amine should offer the corresponding urea derivative 10. Accordingly, 6a was treated with different amines 9a, 9l, 9p, or 9q, and gratifyingly in each case, the corresponding urea 10aaaa, 10aaal, 10aaap, or 10aaaq was isolated in excellent yields (Scheme 7). Based on these studies, the plausible mechanism for the formation of urea derivatives is delineated in Scheme 8. The initial imine formation between the isatin 1 and THIQ 5 leads to azomethine ylide A, which, via [3+2] cycloaddition of the alkyne 3, produces spirooxindole 6. However, under basic conditions, 6 undergoes C2–C3 bond cleavage to offer the isocyanate B, which suffers the nucleophilic attack by the amine to afford the title compound 7. The extended conjugation of the pyrrole and the benzene ring as observed in 7 is anticipated to be one of the influencing factors for the skeletal rearrangement in spirooxindole 6. To gain support for this reasoning, we performed the reactions of Cs2CO3 with spirooxindoles 4 and 12,6 which were unsuccessful (Scheme 9).
Scheme 8. Plausible Mechanism for the Formation of 7.
Scheme 9. Reaction of 4 and 12 with Cs2CO3.
Finally, to explore the synthetic transformations of 7aaa, we performed a few robust synthetic transformations. Oxidative thiocyanation of 7aaa with ammonium thiocyanate (NH4SCN) in the presence of ceric ammonium nitrate (CAN) in methanol furnished 13 in 89% yield (Scheme 10).11 The halogenation reaction of 7aaa using N-bromosuccinimide (NBS)5i resulted in the formation of 14 in 87% yield. Basic hydrolysis of the urea moiety of 7aaa afforded aniline 11 in 58% yield. Next, we treated 7aaa with Lawesson’s reagent in toluene as the medium under microwave heating for 2 h, which gave aniline 11 in 94% yield, instead of the expected thiourea derivative 15. Nonetheless, treating 11 with 3-chlorophenyl isothiocyanate in methanol afforded the thiourea derivative 15a in 55% yield. To investigate whether the spirooxindole 6 would undergo the POCl3-mediated dehydrative transformation as reported by us earlier,6 we heated 6a and 6b with POCl3 at 90 °C for 24 and 48 h, respectively, to obtain fused-pyrido[2,3-b]indoles 16a and 16b in 74–84% yield.
Scheme 10. Synthetic Transformations of Dihydropyrrolo[2,1-a]isoquinoline 7aaa and Spirooxindole 6.
Yield calculated based on % conversion of the starting material.
Conclusions
In conclusion, we have developed a multicomponent route for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines incorporating the urea moiety using isatins, THIQ, and terminal alkynes as the starting substrates. A variety of isatins and terminal alkynes are compatible in the reaction to offer the corresponding N-(substituted-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamides in moderate to excellent yields. The four-component reactions between isatin, THIQ, primary amines, and terminal alkynes were found to be successful to afford 1-substituted-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)ureas (from primary amines) in moderate yields together with carboxamides (from THIQ). However, we demonstrate that this limitation of the 4CR can be circumvented by performing the reaction of the spirooxindole intermediate with primary or secondary amines to prepare the 1-substituted-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)ureas in excellent yields. This protocol allows generation of molecular complexity from the readily available starting materials in a single step under transition metal-free conditions. We have also demonstrated the utility of the obtained products for further diversification for medicinal chemistry programs. Studies concerning newer applications of the present protocol and biological assessment of the synthesized 5,6-dihydropyrrolo[2,1-a]isoquinolines are underway in the laboratory.
Experimental Section
General Information
All reactions were monitored by thin layer chromatography (TLC) on precoated silica gel plates. After elution, the TLC plate was visualized under UV illumination at 254 nm. The melting points were recorded on a hot stage apparatus and are uncorrected. IR spectra were recorded on a FTIR spectrophotometer. The NMR spectra were recorded on Bruker 300, 400, and 500 MHz spectrometers. Chemical shifts are reported in ppm, and peak multiplicities of NMR signals are designated as s (singlet), d (doublet), dd (doublet of doublet), dt (doublet of triplet), t (triplet), q (quartet), and m (multiplet). The ESI-MS were recorded on an Ion Trap Mass spectrometer. The HRMS spectra were recorded as ESI-HRMS on a Q-TOF LC–MS/MS mass spectrometer. Commercial grade reagents and solvents were used as received without further purification. The microwave reactions were carried out in a Monowave reactor equipped with magnetron to deliver continuous microwave power.
Experimental Procedure for the Synthesis of 2′-Phenyl-10′,10a′-dihydro-5′H-spiro[indoline-3,3′-pyrrolo[1,2-b]isoquinolin]-2-one (4)
A 30 mL microwave vial was charged with isatin 1a (4.078 mmol, 0.6 g), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2a (4.078 mmol, 0.72 g), and phenyl acetylene 3a (4.078 mmol, 0.446 g) and molecular sieves (4 Å) (0.55 g) in 5 mL of acetonitrile. The vial was irradiated at 150 °C for 1 h, after which the reaction mixture was passed through a bed of Celite using EtOAc. The filtrate was collected and concentrated to obtain a crude residue, which was purified by column chromatography over silica gel using hexanes/EtOAc (75:25, v/v) as the eluent to obtain 0.08 g (5%) of 4 as an off-white solid. mp 219–224 °C; Rf = 0.68 (hexanes/EtOAc, 6:4 v/v); IR (KBr) νmax: 1736 (C=O), 3451 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.92–3.04 (m, 1H), 3.06–3.16 (m, 1H), 3.54 (d, J = 13.9 Hz, 1H), 4.03 (d, J = 13.8 Hz, 1H), 4.38–4.48 (m, 1H), 6.66 (s, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.91–6.99 (m, 2H), 7.08–7.22 (m, 10H), 7.92 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 35.9, 46.7, 62.6, 78.3, 109.9, 123.5, 125.9, 126.1, 126.4, 127.0, 127.9, 128.5, 128.5, 129.7, 129.8, 132.6, 133.7, 134.7, 135.3, 141.6, 142.9, 177.8. MS (ESI+): m/z = 365.3. ESI-HR-MS calculated for C26H21NO [MH]+: 365.1648, found: 365.1649.
General Experimental Procedure for the Synthesis of N-Substituted-2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamides 7 As Exemplified for 7aaa
To a stirred solution of isatin 1a (2.04 mmol, 0.3 g) in toluene (15 mL) were added THIQ 5a (4.08 mmol, 0.543 g), phenyl acetylene 3a (2.04 mmol, 224 μL), and benzoic acid (20 mol %, 0.049 g), and the mixture was heated at 90 °C for 16 h. After completion, the solvent was evaporated to obtain a crude product, which was purified by column chromatography over silica gel using hexanes/EtOAc (70:30, v/v) as eluent to furnish 0.869 g (86%) of 7aaa as a white solid.
N-(2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aaa)
mp 80–84 °C; Rf = 0.68 (hexanes/EtOAc, 6:4 v/v); IR (KBr) νmax: 1670 (C=O), 3405 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.65 (t, J = 5.7 Hz, 2H), 2.87–3.03 (m, 2H), 3.23–3.34 (m, 2H), 3.67–3.73 (m, 1H), 3.85–3.92 (m, 1H), 4.11–4.22 (m, 2H), 6.73 (s, 1H), 6.92–6.95 (m, 2H), 7.02–7.24 (m, 9H), 7.27–7.38 (m, 4H), 7.40–7.45 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.8, 29.4, 41.2, 41.8, 45.4, 103.0, 120.6, 121.3, 122.6, 122.6, 123.8, 125.2, 126.2, 126.3, 126.4, 126.7, 127.4, 128.2, 128.3, 128.8, 129.0, 129.8, 131.1, 131.5, 131.7, 133.1, 134.9, 135.1, 138.3, 154.5. MS (ESI+): m/z = 496.1. ESI-HR-MS calculated for C34H29N3O [MH]+: 496.2383, found: 496.2378.
N-(4-Methyl-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7baa)
Yield: 89% (0.844 g from 0.3 g of 1b); a white solid, mp 135–138 °C; Rf = 0.46 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1723 (C=O), 3434 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.37 (s, 3H), 2.64 (t, J = 5.9 Hz, 2H), 2.86–3.03 (m, 2H), 3.25–3.29 (m, 2H), 3.67–3.74 (m, 1H), 3.85–3.92 (m, 1H), 4.10–4.20 (m, 2H), 6.62 (s, 1H), 6.92–6.94 (m, 2H), 7.03–7.35 (m, 13H), 7.63 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 20.8, 28.7, 29.3, 41.1, 41.7, 45.2, 102.8, 120.7, 121.3, 122.5, 123.5, 125.3, 126.0, 126.2, 126.6, 127.2, 128.0, 128.2, 128.7, 129.0, 130.3, 131.0, 131.4, 131.5, 131.9, 133.1, 134.9, 135.1, 135.6, 154.5. MS (ESI+): m/z = 510.2. ESI-HR-MS calculated for C35H31N3O [MH]+: 510.2540, found: 510.2543.
N-(4-Methoxy-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7caa)
Yield: 92% (0.818 g from 0.3 g of 1c); a white solid, mp 196–199 °C; Rf = 0.51 (hexanes/EtOAc, 6:4 v/v); IR (KBr) νmax: 1660 (C=O), 3414 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.58 (t, J = 5.8 Hz, 2H), 2.79–2.95 (m, 2H), 3.16–3.26 (m, 2H), 3.64–3.70 (m, 1H), 3.76 (s, 3H), 3.81–3.87 (m, 1H), 4.03–4.12 (m, 2H), 6.39 (s, 1H), 6.83–6.88 (m, 3H), 6.91–6.96 (m, 2H), 7.02–7.10 (m, 5H), 7.14–7.23 (m, 4H), 7.27–7.28 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.7, 29.2, 41.0, 41.7, 45.2, 55.6, 102.8, 114.7, 116.6, 122.5, 122.8, 123.1, 123.6, 125.1, 126.1, 126.2, 126.2, 126.3, 126.6, 127.2, 128.1, 128.2, 128.7, 128.9, 131.0, 131.4, 131.5, 133.1, 134.9, 135.0, 154.7, 155.0. MS (ESI+): m/z = 526.1. ESI-HR-MS calculated for C35H31N3O2 [MH]+: 526.2489, found: 526.2485.
N-(4-Fluoro-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7daa)
Yield: 87% (0.81 g from 0.3 g of 1d); a brown solid, mp 215–218 °C; Rf = 0.60 (hexanes/EtOAc, 6:4 v/v); IR (KBr) νmax: 1674 (C=O), 3352 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.66 (t, J = 5.8 Hz, 2H), 2.88–3.05 (m, 2H), 3.22–3.33 (m, 2H), 3.69–3.75 (m, 1H), 3.87–3.94 (m, 1H), 4.11–4.20 (m, 2H), 6.59 (s, 1H), 6.92–6.95 (m, 2H), 7.02–7.33 (m, 13H), 7.64 (d, J = 7.7 Hz, 1H), 8.08 (dd, J1 = 9.1 Hz, J2 = 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.6, 29.1, 41.1, 41.7, 45.2, 103.0, 116.2 (d, J = 22 Hz), 117.6 (d, J = 22 Hz), 122.6, 122.7, 123.0, 123.1, 123.8, 124.0, 126.1, 126.3, 126.5, 126.6, 127.2, 128.0, 128.2, 128.7, 128.7, 130.0, 130.8, 131.8, 132.9, 134.3, 134.7, 134.7, 154.4, 157.9 (d, J = 243 Hz). MS (ESI+): m/z = 514.1. ESI-HR-MS calculated for C34H28FN3O [MH]+: 514.2289, found: 514.2297.
N-(4-Chloro-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7eaa)
Yield: 90% (0.787 g from 0.3 g of 1e); a white solid, mp 141–142 °C; Rf = 0.56 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1664 (C=O), 3412 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.65 (t, J = 5.5 Hz, 2H), 2.89–3.06 (m, 2H), 3.24–3.28 (m, 2H), 3.67–3.73 (m, 1H), 3.88–3.94 (m, 1H), 4.09–4.20 (m, 2H), 6.70 (s, 1H), 6.93–6.95 (m, 2H), 7.03–7.40 (m, 13H), 7.64 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.6, 29.2, 41.1, 41.8, 45.2, 103.0, 121.8, 122.6, 122.8, 123.4, 124.2, 126.2, 126.3, 126.3, 126.4, 126.5, 126.7, 127.2, 127.3, 128.1, 128.2, 128.7, 128.8, 129.6, 130.8, 130.9, 132.0, 132.9, 134.6, 134.8, 136.9, 154.1. MS (ESI+): m/z = 530.1. ESI-HR-MS calculated for C34H28ClN3O [MH]+: 530.1994, found: 530.1993.
N-(4-Bromo-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7faa)
Yield: 89% (0.677 g from 0.3 g of 1f); a white solid, mp 201–202 °C; Rf = 0.7 (hexanes/EtOAc, 8:2 v/v); IR (CHCl3) νmax: 1661 (C=O), 3405 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.65 (t, J = 5.5 Hz, 2H), 2.90–2.98 (m, 1H), 3.01–3.08 (m, 1H), 3.21–3.30 (m, 2H), 3.68–3.74 (m, 1H), 3.89–3.95 (m, 1H), 4.09–4.20 (m, 2H), 6.71 (s, 1H), 6.93–6.95 (m, 2H), 7.03–7.05 (m, 1H), 7.10–7.24 (m, 7H), 7.30–7.34 (m, 3H), 7.49–7.54 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.8, 29.4, 41.3, 41.9, 45.3, 103.2, 114.8, 122.2, 122.8, 123.3, 123.5, 124.3, 126.3, 126.4, 126.5, 126.6, 126.7. MS (ESI+): m/z = 574.2. ESI-HR-MS calculated for C34H28BrN3O [MH]+: 574.1489, found: 574.1486.
N-(4-Nitro-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7gaa)
Yield: 82% (0.692 g from 0.3 g of 1 g); a yellow solid, mp 218–220 °C; Rf = 0.50 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1676 (C=O), 3393 (N–H) cm–1.1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.57–2.60 (m, 2H), 2.93–3.00 (m, 1H), 3.05–3.12 (m, 1H), 3.21–3.26 (m, 2H), 3.71–3.77 (m, 1H), 3.91–3.97 (m, 1H), 4.09–4.25 (m, 2H), 6.96–6.98 (m, 1H), 7.07–7.19 (m, 10H), 7.25–7.32 (m, 2H), 7.72 (d, J = 7.5 Hz, 1H), 7.80 (s, 1H), 8.08 (d, J = 9.1 Hz, 1H), 8.26–8.30 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 28.3, 28.7, 41.5, 41.9, 45.6, 103.9, 120.7, 122.9, 123.1, 123.6, 123.7, 125.3, 126.3, 126.4, 126.5, 126.7, 126.9, 127.5, 127.8, 128.5, 128.7, 128.9, 129.0, 131.6, 131.8, 133.4, 135.0, 135.4, 142.1, 146.0, 153.6. MS (ESI+): m/z = 541.0. ESI-HR-MS calculated for C34H28N4O3 [MH]+: 541.2234, found: 541.2230.
N-(5-Chloro-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7haa)
Yield: 85% (0.743 g from 0.3 g of 1h); a brown solid, mp 83–85 °C; Rf = 0.52 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1673 (C=O), 3398 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.65 (t, J = 5.6 Hz, 2H), 2.88–3.04 (m, 2H), 3.21–3.30 (m, 2H), 3.65–3.72 (m, 1H), 3.83–3.90 (m, 1H), 4.09–4.21 (m, 2H), 6.76 (s, 1H), 6.92–6.94 (m, 2H), 7.03–7.34 (m, 13H), 7.64 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.8, 29.3, 41.3, 41.8, 45.3, 103.1, 119.4, 120.5, 122.6, 122.7, 123.8, 124.2, 126.3, 126.5, 126.6, 126.8, 127.4, 128.2, 128.3, 128.9, 131.0, 132.1, 132.3, 132.9, 134.8, 134.8, 135.6, 139.4, 154.1. MS (ESI+): m/z = 530.01. ESI-HR-MS calculated for C34H28ClN3O [MH]+: 530.1994, found: 530.2001.
N-(2-Fluoro-6-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7iaa)
Yield: 81% (0.755 g from 0.3 g of 1i); a white solid, mp 149–151 °C; Rf = 0.64 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1664 (C=O), 3406 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.67 (t, J = 6.1 Hz, 2H), 2.91–2.99 (m, 2H), 3.31–3.35 (m, 2H), 3.83–3.95 (m, 2H), 4.14–4.29 (m, 2H), 5.75 (s, 1H), 6.78 (s, 1H), 6.97–7.03 (m, 2H), 7.10–7.25 (m, 13H), 7.57 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.7, 29.2, 41.3, 41.9, 45.6, 103.1, 116.5 (d, J = 21 Hz), 122.5, 123.9, 125.1, 125.9, 126.0, 126.1, 126.2, 126.2, 126.6, 126.7, 127.1, 127.2, 128.0, 128.4, 128.8, 129.0, 129.4, 131.1, 131.4, 133.0, 134.8, 135.5, 154.3, 157.8 (d, J = 250 Hz). MS (ESI+): m/z = 514.5. ESI-HR-MS calculated for C34H28FN3O [MH]+: 514.2289, found: 514.2283.
N-(2-(2-(p-Tolyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aab)
Yield: 81% (0.84 g from 0.3 g of 1a); a brown solid, mp 110–113 °C; Rf = 0.43 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1668 (C=O), 3388 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.28 (s, 3H), 2.66 (t, J = 5.6 Hz, 2H), 2.90–3.03 (m, 2H), 3.23–3.35 (m, 2H), 3.66–3.72 (m, 1H), 3.84–3.91 (m, 1H), 4.11–4.21 (m, 2H), 6.75 (s, 1H), 6.92–6.94 (m, 2H), 7.02–7.35 (m, 12H), 7.40–7.44 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 21.0, 28.7, 29.3, 41.1, 41.6, 45.3, 102.8, 120.5, 121.4, 122.4, 122.5, 123.7, 124.7, 126.1, 126.2, 126.2, 126.6, 127.2, 128.0, 128.2, 129.0, 129.4, 129.6, 130.9, 131.3, 131.5, 132.0, 133.1, 134.8, 135.7, 138.1, 154.4. MS (ESI+): m/z = 510.1. ESI-HR-MS calculated for C35H31N3O [MH]+: 510.2540, found: 510.2542.
N-(2-(2-(4-(tert-Butyl)phenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aac)
Yield: 79% (0.89 g from 0.3 g of 1a); a white solid, mp 95–98 °C; Rf = 0.51 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1711 (C=O), 3409 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 1.26 (s, 9H), 2.58–2.67 (m, 2H), 2.84–3.02 (m, 2H), 3.20–3.29 (m, 2H), 3.65–3.71 (m, 1H), 3.83–3.90 (m, 1H), 4.10–4.24 (m, 2H), 6.77 (s, 1H), 6.92–6.92 (m, 2H), 7.02–7.18 (m, 8H), 7.27–7.30 (m, 3H), 7.34 (dd, J1 = 7.6 Hz, J2 = 1.3 Hz, 1H), 7.41–7.45 (m, 1H), 7.64 (d, J = 7.7 Hz, 1H). 8.18 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 28.2, 28.8, 31.5, 34.4, 41.4, 41.7, 45.5, 103.5, 122.2, 122.7, 122.8, 123.4, 123.8, 125.5, 125.7, 126.0, 126.4, 126.8, 127.4, 128.5, 128.7, 129.1, 129.4, 130.8, 131.4, 132.1, 132.7, 133.7, 135.0, 138.9, 148.2, 154.5. MS (ESI+): m/z = 552.2. ESI-HR-MS calculated for C38H37N3O [MH]+: 552.3009, found: 552.3003.
N-(2-(2-(4-Bromophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aad)
Yield: 85% (0.99 g from 0.3 g of 1a); a yellow solid, mp 174–177 °C; Rf = 0.50 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1658 (C=O), 3382 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.67 (t, J = 5.8 Hz, 2H), 2.86–3.03 (m, 2H), 3.25–3.36 (m, 2H), 3.66–3.72 (m, 1H), 3.83–3.90 (m, 1H), 4.14–4.23 (m, 2H), 6.65 (s, 1H), 6.90–6.93 (m, 2H), 7.03–7.18 (m, 8H), 7.27–7.32 (m, 4H), 7.41–7.45 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.7, 29.3, 41.3, 41.8, 45.5, 102.7, 119.9, 120.7, 121.0, 122.6, 122.7, 125.3, 126.3, 126.5, 126.6, 126.8, 127.4, 127.8, 128.2, 128.4, 128.8, 130.0, 131.1, 131.4, 131.9, 131.9, 133.1, 134.1, 134.9, 138.4, 154.4. MS (ESI+): m/z = 574.1. ESI-HR-MS calculated for C34H28BrN3O [MH]+: 574.1489, found: 574.1485.
N-(2-(2-(4-Fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aae)
Yield: 78% (0.82 g from 0.3 g of 1a); a brown solid, mp 92–95 °C; Rf = 0.45 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1662 (C=O), 3385 (N–H) cm–1.1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.63 (t, J = 5.6 Hz, 2H), 2.92–3.06 (m, 2H), 3.28–3.33 (m, 2H), 3.74–3.87 (m, 2H), 4.26 (s, 2H), 6.98–7.03 (m, 4H), 7.10–7.11 (m, 2H), 7.15–7.24 (m, 6H), 7.32 (t, J = 7.4 Hz, 1H), 7.38–7.40 (m, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 28.3, 28.8, 41.4, 41.8, 45.7, 103.6, 115.0 (d, J = 21.2 Hz), 121.8, 122.7, 123.5, 123.8, 124.7, 126.3, 126.3, 126.4, 126.6, 126.7, 127.4, 128.2 (d, J = 7.7 Hz), 128.4, 128.7, 129.3, 129.4, 130.6, 131.5, 132.2, 132.5, 133.9, 135.1, 139.3, 154.8, 160.7 (d, J = 241.5 Hz). MS (ESI+): m/z = 514.1. ESI-HR-MS calculated for C34H28FN3O [MH]+: 514.2289, found: 514.2286.
N-(2-(2-(2-Chlorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aaf)
Yield: 84% (0.906 g from 0.3 g of 1a); a white solid, mp 117–120 °C; Rf = 0.42 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1670 (C=O), 3451 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.76 (t, J = 5.8 Hz, 2H), 2.82–2.89 (m, 1H), 2.94–3.01 (m, 1H), 3.47 (t, J = 5.5 Hz, 2H), 3.69–3.76 (m, 1H), 3.79–3.86 (m, 1H), 4.31–4.45 (m, 2H), 6.59 (s, 1H), 6.96–6.99 (m, 1H), 7.03–7.10 (m, 7H), 7.12–7.15 (m, 3H), 7.25–7.30 (m, 2H), 7.33–7.37 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.8, 29.4, 41.6, 42.0, 45.7, 106.2, 121.2, 121.3, 122.0, 122.6, 122.8, 126.4, 126.8, 126.9, 127.4, 128.0, 128.2, 128.4, 129.1, 129.7, 130.0, 130.7, 131.0, 131.9, 132.9, 133.3, 134.1, 134.9, 138.5, 154.7. MS (ESI+): m/z = 530.5. ESI-HR-MS calculated for C34H28ClN3O [MH]+: 530.1994, found: 530.1990.
N-(2-(2-(3,4-Dichlorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aag)
Yield: 83% (0.95 g from 0.3 g of 1a); a brown solid, mp 96–99 °C; Rf = 0.44 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1642 (C=O), 3452 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.69 (t, J = 5.8 Hz, 2H), 2.87–2.93 (m, 1H), 2.97–3.03 (m, 1H), 3.31–3.36 (m, 2H), 3.68–3.73 (m, 1H), 3.84–3.89 (m, 1H), 4.19–4.26 (m, 2H), 6.61 (s, 1H), 6.90–6.94 (m, 2H), 6.99–7.02 (m, 1H), 7.04–7.06 (m, 1H), 7.11–7.22 (m, 6H), 7.29–7.32 (m, 2H), 7.44–7.48 (m, 2H), 7.65 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.7, 29.3, 41.5, 41.9, 45.6, 102.7, 120.6, 120.8, 121.5, 122.8, 122.9, 125.4, 125.7, 126.3, 126.6, 126.8, 126.9, 127.5, 128.0, 128.3, 128.4, 128.7, 129.7, 130.3, 130.7, 131.1, 131.3, 132.1, 132.7, 132.9, 134.8, 135.5, 138.4, 154.4. MS (ESI+): m/z = 564.2. ESI-HR-MS calculated for C34H27Cl2N3O [MH]+: 564.1604, found: 564.1609.
N-(2-(2-(Pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aah)
Yield: 78% (0.79 g from 0.3 g of 1a); a yellow solid, mp 75–78 °C; Rf = 0.67 (hexanes/EtOAc, 3:7 v/v); IR (KBr) νmax: 1655 (C=O), 3412 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.68 (t, J = 5.7 Hz, 2H), 2.91–3.02 (m, 2H), 3.30–3.33 (m, 2H), 3.68–3.75 (m, 1H), 3.83–3.89 (m, 1H), 4.16–4.25 (m, 2H), 6.64 (s, 1H), 6.93–6.94 (m, 1H), 6.97 (s, 1H), 7.02–7.04 (m, 1H), 7.06–7.10 (m, 3H), 7.13–7.18 (m, 3H), 7.29–7.33 (m, 2H), 7.44–7.47 (m, 2H), 7.66 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.36 (dd, J1 = 4.8 Hz, J2 = 1.1 Hz, 1H), 8.72 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.7, 29.2, 41.4, 41.8, 45.5, 102.6, 120.3, 120.6, 120.6, 122.8, 122.9, 123.7, 125.9, 126.3, 126.5, 126.8, 126.9, 127.5, 128.3, 128.4, 130.3, 131.1, 131.2, 131.4, 132.2, 133.0, 133.1, 134.8, 138.5, 147.1, 147.7, 154.4. MS (ESI+): m/z = 497.4. ESI-HR-MS calculated for C33H28N4O [MH]+: 497.2336, found: 497.2341.
N-(2-(2-(Thiophen-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aai)
Yield: 80% (0.82 g from 0.3 g of 1a); a brown solid, mp 101–102 °C; Rf = 0.44 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1710 (C=O), 3413 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.67 (t, J = 5.4 Hz, 2H), 2.85–3.04 (m, 2H), 3.26–3.37 (m, 2H) 3.66–3.74 (m, 1H), 3.82–3.91 (m, 1H), 4.13–4.24 (m, 2H), 6.80 (s, 1H), 6.88–6.95 (m, 2H), 6.96–7.00 (m, 1H), 7.05–7.23 (m, 8H), 7.27–7.34 (m, 2H), 7.42–7.48 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.8, 29.4, 41.2, 41.8, 45.4, 102.7, 118.3, 119.5, 120.4, 121.1, 122.5, 122.6, 124.8, 125.7, 126.3, 126.4, 126.5, 126.7, 127.4, 128.2, 128.4, 129.0, 130.0, 131.1, 131.3, 131.5, 133.1, 134.9, 135.8, 138.6, 154.5. MS (ESI+): m/z = 502.4. ESI-HR-MS calculated for C32H27N3OS [MH]+: 502.1948, found: 502.1947.
N-(2-(2-(Cyclohex-1-en-1-yl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aaj)
Yield: 74% (0.75 g from 0.3 g of 1a); a brown solid, mp 79–82 °C; Rf = 0.56 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1706 (C=O), 3394 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 1.57–1.63 (m, 4H), 1.91–2.11 (m, 4H), 2.77–2.81 (m, 2H), 2.82–2.98 (m, 2H), 3.52 (t, J = 5.9 Hz, 2H), 3.56–3.66 (m, 1H), 3.72–3.86 (m, 1H), 4.31–4.54 (m, 2H), 5.81 (s, 1H), 6.69 (s, 1H), 6.91 (s, 1H), 6.97–7.01 (m, 1H), 7.05–7.16 (m, 7H), 7.22–7.25 (m, 1H), 7.36–7.42 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.05 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 22.3, 23.2, 25.8, 28.2, 28.9, 29.4, 41.4, 41.6, 45.6, 102.2, 120.1, 122.2, 122.5, 123.0, 123.9, 126.1, 126.3, 126.5, 126.8, 127.3, 128.1, 128.4, 129.2, 129.5, 130.7, 131.0, 131.1, 131.5, 133.2, 134.9, 138.7, 154.7. MS (ESI+): m/z = 500.4. ESI-HR-MS calculated for C34H33N3O [MH]+: 500.2696, found: 500.2690.
N-(2-(2-Cyclopropyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aak)
Yield: 59% (0.55 g from 0.3 g of 1a); a brown solid, mp 86–88 °C; Rf = 0.66 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1663 (C=O), 3395 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 0.72–0.74 (m, 2H), 1.16–1.19 (m, 2H), 2.70–2.74 (m, 2H), 2.77–2.81 (m, 1H), 2.84–2.90 (m, 1H), 3.44–3.51 (m, 2H), 3.53–3.60 (m, 1H), 3.69–3.75 (m, 1H), 4.04 (q, J = 7.12 Hz, 1H) 4.29–4.33 (m, 1H), 4.43–4.47 (m, 1H), 6.14 (s, 1H), 6.88–6.93 (m, 2H), 6.98–7.04 (m, 6H), 7.14–7.16 (m, 1H), 7.19–7.21 (m, 1H), 7.30–7.35 (m, 1H), 7.44 (d, J = 7.7 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 7.6, 8.9, 8.9, 28.9, 29.5, 41.5, 41.7, 45.7, 99.2, 119.9, 120.8, 122.2, 122.4, 125.6, 126.1, 126.4, 126.5, 126.6, 126.9, 127.3, 128.2, 128.5, 129.3, 129.6, 130.9, 131.2, 131.5, 133.2, 135.0, 139.0, 154.8. MS (ESI+): m/z = 460.3. ESI-HR-MS calculated for C31H29N3O [MH]+: 460.2383, found: 460.2390.
N-(2-(2-(Trimethylsilyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aal)
Yield: 56% (0.561 g from 0.3 g of 1a); a yellow oil; Rf = 0.47 (hexanes/EtOAc, 7:3 v/v); IR (CHCl3) νmax: 1678 (C=O), 3421 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 0.09 (s, 9H), 2.70–2.83 (m, 3H), 2.90–2.98 (m, 1H), 3.40–3.54 (m, 2H), 3.59–3.74 (m, 2H), 4.18–4.47 (m, 2H), 6.54 (s, 1H), 6.82 (s, 1H), 6.88 (d, J = 7.4 Hz, 1H), 7.04 (t, J = 7.6 Hz, 2H), 7.08–7.18 (m, 4H), 7.29–7.35 (m, 2H), 7.43–7.52 (m, 1H), 7.68 (d, J = 7.7 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 0.03, 28.5, 29.4, 41.5, 41.5, 45.7, 109.6, 118.5, 119.4, 122.1, 122.6, 122.9, 126.1, 126.2, 126.4, 126.8, 127.3, 128.4, 129.3, 130.1, 130.6, 131.4, 131.8, 132.9, 133.9, 134.6, 139.4, 154.3. MS (ESI+): m/z = 492.1. ESI-HR-MS calculated for C31H33N3OSi [MH]+: 492.2466, found: 492.2465.
N-(2-(8,9-Dimethoxy-2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxamide (7aba)
Yield: 82% (1.02 g from 0.3 g of 1a); a brown solid, mp 115–118 °C; Rf = 0.56 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1674 (C=O), 3394 (N–H) cm–1.1H NMR (400 MHz, DMSO-d6): δ (ppm) = 2.57 (s, 2H), 2.83–2.95 (m, 2H), 3.21–3.36 (m, 2H), 3.66–3.72 (m, 1H), 3.80 (s, 7H), 3.89 (s, 3H), 3.97 (s, 3H), 4.04–4.17 (m, 2H), 6.41 (s, 1H), 6.51 (s, 1H), 6.71 (d, J = 19.7 Hz, 2H), 6.84 (s, 1H), 7.14 (s, 3H), 7.20–7.25 (m, 2H), 7.30–7.38 (m, 3H), 7.40–7.46 (m, 1H), 8.12 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 28.3, 29.0, 41.4, 41.9, 45.2, 56.1, 56.3, 101.8, 106.1, 109.3, 111.3, 111.4, 120.7, 121.5, 121.8, 122.6, 123.6, 123.8, 124.8, 124.9, 126.1, 126.3, 126.8, 128.8, 129.8, 131.5, 131.8, 135.2, 138.3, 147.7, 147.9, 148.1, 148.6, 154.6. MS (ESI+): m/z = 616.1. ESI-HR-MS calculated for C38H37N3O5 [MH]+: 616.2806, found: 616.2796.
N-(2-(8-Phenyl-4,5-dihydrothieno[2,3-g]indolizin-7-yl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (7aca)
Yield: 84% (0.87 g from 0.3 g of 1a); a yellow solid, mp 94–97 °C; Rf = 0.60 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1669 (C=O), 3403 (N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.61–2.70 (m, 2H), 2.93–3.00 (m, 1H), 3.06–3.13 (m, 1H), 3.34–3.41 (m, 1H), 3.47–3.53 (m, 1H), 3.74–3.80 (m, 1H), 3.92–4.10 (m, 3H), 6.61 (d, J = 5.1 Hz, 1H), 6.67 (s, 1H), 6.74 (s, 1H), 7.04 (d, J = 5.1 Hz, 1H), 7.11–7.25 (m, 6H), 7.30–7.36 (m, 3H), 7.42 (t, J = 7.3 Hz, 1H), 8.08 (d, J = 8.3 Hz,1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 24.7, 24.9, 41.5, 42.6, 44.2, 102.0, 120.8, 121.6, 122.7, 123.2, 123.2, 124.0, 124.7, 126.2, 126.3, 128.8, 129.7, 129.9, 130.2, 130.3, 131.4, 131.5, 133.6, 135.0, 138.1, 154.6. MS (ESI+): m/z = 508.2. ESI-HR-MS calculated for C30H25N3OS2 [MH]+: 508.1512, found: 508.1510.
(E)-Methyl 3-(3,4-Dihydroisoquinolin-2(1H)-yl)acrylate (8am)
Yield: 83% (0.83 g from 0.29 g of 3m); a yellow oil; Rf = 0.68 (hexanes/EtOAc, 6:4 v/v); IR (CHCl3) νmax: 1674 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.91 (t, J = 5.89 Hz, 2H), 3.50 (t, J = 5.84 Hz, 2H), 3.68 (s, 3H), 4.34 (s, 2H), 4.71 (d, J = 13 Hz, 1H), 7.10–7.22 (m, 4H), 7.61 (d, J = 13 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 50.7, 84.6, 126.3, 126.8, 127.0, 128.4, 127.7, 130.0, 134.4, 151.7, 170.2. MS (ESI+): m/z = 218.3. ESI-HR-MS calculated for C13H15NO2 [MH]+: 218.1176, found: 218.1171.
Dimethyl 2-(3,4-Dihydroisoquinolin-2(1H)-yl)fumarate (8an)
Yield: 96% (0.572 g from 0.18 g of 3n); a yellow oil; Rf = 0.64 (hexanes/EtOAc, 6:4 v/v); IR (CHCl3) νmax: 1685 (C=O), 3449 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.91 (t, J = 5.8 Hz, 2H), 3.42 (t, J = 5.8 Hz, 2H), 3.65 (s, 3H), 3.97 (s, 3H), 4.31 (s, 2H), 4.78 (s, 1H), 7.08–7.15 (m, 2H), 7.19–7.22 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.0, 45.6, 48.7, 51.0, 53.1, 85.2, 126.3, 126.8, 127.2, 128.4, 131.9, 134.2, 154.2, 166.2, 168.2. MS (ESI+): m/z = 276.2. ESI-HR-MS calculated for C15H17NO4 [MH]+: 276.1230, found: 276.1229.
General Experimental Procedure for the Four-Component Reaction for the Synthesis of 1-Substituted-3-(2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)ureas 10 As Exemplified for 10aaaa
To a stirred solution of isatin 1a (2.04 mmol, 0.3 g) in toluene (15 mL) were added THIQ 5a (4.08 mmol, 0.272 g), phenyl acetylene 3a (2.04 mmol, 224 μL), aniline 9a (2.04 mmol, 186 μL), and benzoic acid (20 mol %, 0.049 g), and the reaction mixture was heated at 90 °C under stirring for 20 h. On completion as evident from TLC analysis, the solvent was evaporated to obtain a residue that, upon column chromatography over silica gel using hexanes/EtOAc (80:20 v/v to 70:30 v/v) as eluent, gave 0.255 g (27%) of 10aaaa as a white solid together with 0.463 g (45%) of 7aaa.
1-Phenyl-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaaa)
mp 187–190 °C; Rf = 0.44 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1646 (C=O), 3441 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.80–2.99 (m, 2H), 3.62–3.81 (m, 2H), 6.25 (s, 1H), 6.78 (s, 1H), 6.85 (s, 1H), 6.93–6.99 (m, 3H), 7.09–7.18 (m, 10H), 7.25–7.31 (m, 2H), 7.38–7.43 (m, 1H), 7.59 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.4, 41.7, 103.5, 120.5, 121.7, 121.8, 122.6, 123.2, 124.4, 124.5, 125.0, 126.1, 126.4, 126.8, 127.4, 128.2, 128.6, 129.1, 129.4, 129.9, 131.0, 131.3, 132.0, 135.4, 137.6, 138.2, 153.0. MS (ESI+): m/z = 456.2. ESI-HR-MS calculated for C31H25N3O [MH]+: 456.2070, found: 456.2064.
1-(4-Chloro-2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3-phenylurea (10eaaa)
Yield: 38% (0.38 g from 0.272 g of 5a); a white solid, mp 117–120 °C; Rf = 0.68 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1650 (C=O), 3457 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.81–2.89 (m, 1H), 2.95–3.02 (m, 1H), 3.60–3.66 (m, 1H), 3.75–3.82 (m, 1H), 6.25 (s, 1H), 6.75 (s, 1H), 6.85 (s, 1H), 6.94–6.96 (m, 3H), 7.09–7.22 (m, 9H), 7.27–7.35 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.2, 41.7, 103.6, 121.3, 121.9, 122.6, 123.0, 123.2, 124.7, 124.7, 126.3, 126.5, 126.6, 127.4, 127.8, 128.1, 128.7, 128.7, 129.4, 129.7, 130.8, 131.3, 131.6, 134.9, 136.8, 137.1, 152.7. MS (ESI+): m/z = 490.3. ESI-HR-MS calculated for C31H24ClN3O [MH]+: 490.1681, found: 490.1680.
1-Phenyl-3-(2-(2-(p-tolyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaba)
Yield: 33% (0.32 g from 0.272 g of 5a); a white solid, mp 241–243 °C; Rf = 0.64 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1680 (C=O), 3305 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.23 (s, 3H), 2.81–2.88 (m, 1H), 2.93–3.00 (m, 1H), 3.63–3.69 (m, 1H), 3.76–3.82 (m, 1H), 6.16 (s, 1H), 6.78 (s, 1H), 6.80 (s, 1H), 6.93–7.08 (m, 8H), 7.10–7.18 (m, 5H), 7.28–7.29 (m, 1H), 7.39–7.44 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 21.1, 29.4, 41.7, 103.5, 120.4, 121.6, 121.7, 122.6, 123.2, 124.4, 124.7, 126.4, 126.7, 127.4, 128.2, 129.1, 129.4, 129.4, 129.9, 131.0, 131.3, 131.9, 132.4, 135.8, 137.6, 138.1, 152.9. MS (ESI+): m/z = 470.3. ESI-HR-MS calculated for C32H27N3O [MH]+: 470.2227, found: 470.2231.
1-(2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3-(p-tolyl)urea (10aaab)
Yield: 25% (0.24 g from 0.272 g of 5a); a white solid, mp 179–182 °C; Rf = 0.54 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1649 (C=O), 3339 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.07 (s, 3H), 2.69–2.89 (m, 2H), 3.57–3.67 (m, 2H), 6.17 (s, 1H), 6.75–6.90 (m, 6H), 7.07–7.28 (m, 10H), 7.39 (t, J = 7.0 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 20.7, 29.3, 41.6, 103.5, 120.1, 121.5, 122.6, 123.0, 123.1, 124.4, 125.0, 126.0, 126.3, 126.8, 127.3, 128.1, 128.5, 129.1, 130.0, 130.1, 131.2, 132.0, 134.4, 135.1, 135.4, 138.2, 153.5. MS (ESI+): m/z = 470.2. ESI-HR-MS calculated for C32H27N3O [MH]+: 470.2227, found: 470.2219.
1-(4-Chlorophenyl)-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaac)
Yield: 36% (0.359 g from 0.272 g of 5a); a white solid, mp 195–198 °C; Rf = 0.62 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1649 (C=O), 3339 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.83–3.01 (m, 2H), 3.63–3.82 (m, 2H), 6.31 (s, 1H), 6.78 (s, 2H), 6.89 (d, J = 8.5 Hz, 2H), 7.05–7.16 (m, 10H), 7.25–7.28 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.4, 41.8, 103.3, 120.9, 122.1, 122.7, 122.8, 123.6, 124.3, 125.0, 126.1, 126.5, 127.5, 128.2, 128.9, 129.6, 130.0, 131.1, 131.4, 132.0, 135.2, 136.2, 137.8, 152.9. MS (ESI+): m/z = 490.2. ESI-HR-MS calculated for C31H24ClN3O [MH]+: 490.1681, found: 490.1679.
1-(3-Bromophenyl)-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaad)
Yield: 37% (0.403 g from 0.272 g of 5a); a white solid, mp 176–178 °C; Rf = 0.62 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1683 (C=O), 3432 (broad, N–H) cm–1.1H NMR (400 MHz, CDCl3): δ (ppm) = 2.85–3.02 (m, 2H), 3.65–3.71 (m, 1H), 3.78–3.85 (m, 1H), 6.33 (s, 1H), 6.79 (s, 2H), 6.90–6.98 (m, 2H), 7.07–7.23 (m, 10H), 7.27–7.29 (m, 2H), 7.35–7.40 (m, 1H), 7.57 (d, J = 7.64 Hz, 1H), 8.11 (d, J = 8.16 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.3, 41.7, 110.3, 119.3, 120.9, 121.9, 122.6, 122.7, 123.5, 123.8, 124.9, 126.1, 126.4, 126.6, 126.9, 127.3, 128.1, 128.6, 128.9, 129.7, 130.3, 130.9, 131.4, 131.9, 135.2, 137.6, 139.1, 135.2, 137.6, 139.1, 152.4. MS (ESI+): m/z = 534.1. ESI-HR-MS calculated for C31H24BrN3O [MH]+: 534.1176, found: 534.1167.
1-(Isoquinolin-5-yl)-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaah)
Yield: 35% (0.362 g from 0.272 g of 5a); a white solid, mp 142–145 °C; Rf = 0.52 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1671 (C=O), 3435 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 3.00 (t, J = 6.3 Hz, 2H), 3.82–3.96 (m, 2H), 6.91 (s, 2H), 7.03 (t, J = 7.3 Hz, 1H), 7.12–7.19 (m, 5H), 7.27–7.34 (m, 4H), 7.37–7.41 (m, 2H), 7.46 (t, J = 8.1 Hz, 2H), 7.64 (d, J = 7.7 Hz, 1H), 8.10 (dd, J1 = 8.3 Hz, J2 = 1.4 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.37 (dd, J1 = 7.6 Hz, J2 = 0.9 Hz, 1H), 8.71 (dd, J1 = 4.2 Hz, J2 = 1.5 Hz, 1H), 8.81 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.4, 42.0, 103.8, 115.3, 120.2, 121.2, 121.6, 121.9, 122.7, 123.3, 124.9, 125.3, 126.2, 126.4, 127.1, 127.4, 127.6, 128.2, 128.8, 129.2, 129.7, 131.2, 131.6, 132.0, 135.4, 135.6, 136.4, 137.9, 138.4, 147.9, 152.2. MS (ESI+): m/z = 507.4. ESI-HR-MS calculated for C34H26N4O [MH]+: 507.2179, found: 507.2175.
1-((3s,5s,7s)-Adamantan-1-yl)-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaan)
Yield: 43% (0.451 g from 0.272 g of 5a); a white solid, mp 142–144 °C; Rf = 0.64 (hexanes/EtOAc, 8:2 v/v); IR (KBr) νmax: 1671 (C=O), 3452 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.59 (s, 6H), 1.75–1.81 (m, 6H), 1.98 (s, 3H), 2.98–3.03 (m, 2H), 3.72–3.78 (m, 1H), 3.81–3.88 (m, 1H), 3.94 (s, 1H), 6.25 (s, 1H), 6.90 (s, 1H), 7.06 (dt, J1 = 7.5 Hz, J2 = 1 Hz, 1H), 7.14–7.24 (m, 6H), 7.26–7.31 (m, 3H), 7.36–7.40 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.6, 36.4, 41.8, 42.2, 51.2, 103.4, 119.9, 120.6, 122.3, 124.1, 125.4, 126.2, 126.4, 126.6, 127.4, 128.2, 128.7, 129.1, 129.8, 131.1, 131.4, 131.8, 135.5, 138.8, 153.8. MS (ESI+): m/z = 514.4. ESI-HR-MS calculated for C35H35N3O [MH]+: 514.2853, found: 514.2847.
1-(tert-Butyl)-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaao)
Yield: 21% (0.186 g from 0.272 g of 5a); a white solid, mp 147–149 °C; Rf = 0.63 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1662 (C=O), 3426 (broad, N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.19 (s, 9H), 2.98–3.05 (m, 2H), 3.73–3.79 (m, 1H), 3.83–3.89 (m, 1H), 3.97 (s, 1H), 6.19 (s, 1H), 6.89 (s, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.13–7.31 (m, 9H), 7.36–7.40 (m, 1H), 7.64 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.2, 29.5, 103.4, 119.9, 120.7, 122.3, 122.7, 124.1, 125.4, 126.2, 126.5, 126.6, 127.5, 128.2, 128.8, 129.1, 129.8, 131.1, 131.2, 131.8, 135.6, 138.8, 154.0. MS (ESI+): m/z = 436.4. ESI-HR-MS calculated for C29H29N3O [MH]+: 436.2386, found: 436.2385.
6
The spirooxindoles were isolated by arresting the reaction as described for the preparation of 7, in 4 h.
2′-Phenyl-6′,10b′-dihydro-5′H-spiro[indoline-3,3′-pyrrolo[2,1-a]isoquinolin]-2-one (6a)
Yield: 49% (0.364 g from 0.3 g of 1a); a white solid, mp 145–146 °C; Rf = 0.68 (hexanes/EtOAc, 6:4 v/v); IR (KBr) νmax: 1736 (C=O), 3453 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.66–2.72 (m, 3H), 3.19–3.28 (m, 1H), 5.55 (s, 1H), 6.58 (d, J = 7.34 Hz, 1H), 6.78 (dt, J1 = 7.53 Hz, J2 = 0.75 Hz, 1H), 6.86 (d, J = 7.76 Hz, 1H), 6.9 (d, J = 2.32 Hz, 1H), 7.02–7.05 (m, 2H), 7.09–7.25 (m, 7H), 7.28–7.31 (m, 1H), 8.57 (s, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.3, 41.5, 64.8, 79.2, 110.5, 122.8, 124.4, 126.2, 126.3, 126.5, 127.1, 127.9, 128.4, 128.7, 129.0, 129.5, 130.0, 133.4, 135.5, 139.0, 141.1, 142.7, 179.5. MS (ESI+): m/z = 365.2. ESI-HR-MS calculated for C25H20N2O [MH]+: 365.1648, found: 365.1649.
5-Bromo-2′-phenyl-6′,10b′-dihydro-5′H-spiro[indoline-3,3′-pyrrolo[2,1-a]isoquinolin]-2-one (6b)
Yield: 35% (0.205 g from 0.3 g of 1f); a brown solid, mp 168–170 °C; Rf = 0.56 (hexanes/EtOAc, 8:2 v/v); IR (CHCl3) νmax: 1726 (C=O), 3402 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.62–2.72 (m, 3H), 3.21–3.26 (m, 1H), 5.50 (s, 1H), 6.65 (d, J = 1.77 Hz, 1H), 6.74 (d, J = 8.25 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 7.03–7.06 (m, 2H), 7.13–7.16 (m, 5H), 7.27–7.29 (m, 3H), 8.60 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.4, 41.5, 64.89, 79.16, 111.9, 115.8, 124.3, 126.3, 126.4, 126.5, 126.9, 128.3, 128.7, 128.8, 129.5, 130.6, 131.4, 132.5, 133.2, 135.3, 138.9, 140.1, 142.6, 178.9. MS (ESI+): m/z = 443.2. ESI-HR-MS calculated for C25H19BrN2O [MH]+: 443.0754, found: 443.0754.
Experimental Procedure for the Synthesis of 1-Substituted-3-(2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)ureas 10 from 6a As Exemplified for 10aaal
To a stirred solution of spirooxindole 6a (0.275 mmol, 0.1 g) in toluene (5 mL) was added amine 9l (0.275 mmol, 20 μL), and the reaction mixture was heated at 90 °C for 14 h. On completion, the solvent was evaporated to obtain a residue that was directly purified by column chromatography over silica gel using hexanes/EtOAc (80:20, v/v) as eluent to obtain 0.11 g (86%) of 10aaal as a white solid.
1-Benzyl-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaal)
mp 177–179 °C; Rf = 0.6 (hexanes/EtOAc, 8:2 v/v); IR (CHCl3) νmax: 1724 (C=O), 3373 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.85–3.00 (m, 2H), 3.63–3.69 (m, 1H), 3.78–3.85 (m, 1H), 4.15 (d, J = 5.36 Hz, 2H), 4.53 (s, 1H), 6.4 (s, 1H), 6.84 (s, 1H), 7.09–7.12 (m, 4H), 7.16–7.22 (m, 9H), 7.26–7.30 (m, 2H), 7.37–7.41 (m, 1H), 7.60 (d, J = 7.73 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.4, 41.8, 44.5, 103.4, 120.5, 121.3, 122.7, 122.9, 124.2, 125.1, 126.1, 126.4, 126.6, 127.4, 127.4, 127.5, 128.2, 128.7, 128.8, 129.1, 129.8, 131.1, 131.5, 131.9, 135.5, 138.4, 154.9. MS (ESI+): m/z = 470.3. ESI-HR-MS calculated for C32H27N3O [MH]+: 470.2227, found: 470.2228.
1-Cyclopropyl-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)urea (10aaap)
Yield: 87% (0.1 g from 0.1 g of 6a); a yellow oil; Rf = 0.54 (hexanes/EtOAc, 7:3 v/v); IR (CHCl3) νmax: 1642 (C=O), 3374 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.85–3.00 (m, 2H), 3.63–3.69 (m, 1H), 3.78–3.85 (m, 1H), 4.15 (d, J = 5.36 Hz, 2H), 4.53 (s, 1H), 6.4 (s, 1H), 6.84 (s, 1H), 7.09–7.12 (m, 4H), 7.16–7.25 (m, 10H), 7.26–7.30 (m, 2H), 7.37–7.41 (m, 1H), 7.60 (d, J = 7.73 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.4, 41.8, 44.5, 103.4, 120.5, 121.3, 122.7, 122.9, 124.2, 125.1, 126.1, 126.4, 126.6, 127.4, 127.4, 127.5, 128.2, 128.7, 128.8, 129.1, 129.8, 131.1, 131.5, 131.9, 135.5, 138.4, 154.9. MS (ESI+): m/z = 420.4. ESI-HR-MS calculated for C28H25N3O [MH]+: 420.2070, found: 420.2068.
N-(2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)pyrrolidine-1-carboxamide (10aaaq)
Yield: 79% (0.094 g from 0.1 g of 6a); a yellow solid, mp 101–102 °C; Rf = 0.52 (hexanes/EtOAc, 6:4 v/v); IR (CHCl3) νmax: 1646 (C=O), 3392 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.74–1.76 (m, 4H), 2.96–3.05 (m, 6H), 3.69–3.75 (m, 1H), 3.82–3.89 (m, 1H), 6.47 (s, 1H), 6.92 (s, 1H), 7.09–7.22 (m, 7H), 7.28–7.31 (m, 4H), 7.39–7.44 (m, 1H), 7.64 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) = 25.5, 29.5, 29.8, 41.8, 45.4, 103.1, 120.0, 120.9, 122.3, 122.7, 123.9, 125.3, 126.1, 126.4, 127.4, 128.2, 128.7, 129.2, 129.9, 131.1, 131.5, 135.2, 138.8, 153.6. MS (ESI+): m/z = 434.4. ESI-HR-MS calculated for C29H27N3O [MH]+: 434.2227, found: 434.2225.
Experimental Procedure for Transformation of 6a to Aniline 11
To a stirred solution of compound 6a (0.82 mmol) in DMF was added Cs2CO3 (0.268 g, 0.82 mmol) in one portion at room temperature, and the reaction was continued for 24 h. After completion, the reaction mixture was extracted with EtOAc (50 mL × 2) and water (30 mL). The organic layers were pooled, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography over silica gel using hexanes/EtOAc (80:20 v/v to 70:30 v/v) as eluent to obtain 11 (0.257 g, 93%) as a pale yellow oil.
2-(2-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)aniline (11)
Yellow oil; Rf = 0.53 (hexanes/EtOAc, 8:2 v/v); IR (CHCl3) νmax: 3405 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.98 (t, J = 6.3 Hz, 2H), 3.64 (s, 2H), 3.75–3.85 (m, 2H), 6.71–6.79 (m, 2H), 6.87 (s, 1H), 7.07–7.27 (m, 9H), 7.30–7.32 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 29.5, 41.6, 103.3, 115.5, 117.8, 118.6, 122.5, 123.4, 125.5, 126.0, 126.7, 126.7, 127.3, 128.1, 128.4, 129.4, 129.8, 130.7, 131.0, 132.4, 136.1, 146.1. MS (ESI+): m/z = 337.3. ESI-HR-MS calculated for C24H20N2 [MH]+: 337.1699, found: 337.1701.
Experimental Procedure for the Oxidative Thiocyanation of 7aaa
To a stirred solution of 7aaa (0.4 mmol, 0.2 g) in methanol (10 mL) were added ammonium thiocyanate (0.485 mmol, 0.037 g) and ceric ammonium nitrate (1.0 mmol, 0.553 g) at room temperature, and the reaction was continued for 6 h. After completion of the reaction (as monitored by TLC), the solvent was evaporated, and the reaction was quenched with water (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography over silica gel using hexanes/EtOAc (60:40, v/v) as eluent to obtain 0.198 g (89%) of product 13 as a yellow solid.
N-(2-(2-Phenyl-1-thiocyanato-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (13)
Mp 86–89 °C; Rf = 0.42 (hexanes/EtOAc, 7:3 v/v); IR (KBr) νmax: 1670 (C=O), 3443 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.75–2.78 (m, 2H), 2.85–3.04 (m, 2H), 3.39 (t, J = 5.9 Hz, 2H), 3.68–3.75 (m, 1H), 3.87–3.93 (m, 1H), 4.28–4.39 (m, 2H), 6.32 (s, 1H), 7.05–7.15 (m, 6H), 7.23–7.35 (m, 7H), 7.37–7.46 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 8.49 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.7, 29.7, 41.7, 42.5, 45.4, 102.7, 118.4, 119.5, 120.4, 121.2, 122.6, 124.8, 125.8, 126.3, 126.4, 126.5, 126.7, 127.4, 128.2, 128.4, 129.0, 130.0, 131.1, 131.4, 131.5, 133.2, 134.9, 135.8, 138.6, 154.5. MS (ESI+): m/z = 553.2. ESI-HR-MS calculated for C35H28N4OS [MH]+: 553.2056, found: 553.2059.
Experimental Procedure for the Oxidative Bromination of 7aaa
To a stirred solution of 7aaa (0.5 mmol, 0.25 g) in DMF (15 mL) was added NBS (0.6 mmol, 0.107 g) in portions at 0 °C, and the reaction was continued at room temperature for 12 h. After completion of the reaction (as monitored by TLC), the reaction mixture was extracted with EtOAc (50 mL × 2) and water (30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel using hexanes/EtOAc (60:40, v/v) as eluent to obtain 0.253 g (87%) of product 14 as a white solid.
N-(2-(1-Bromo-2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (14)
Yield: 87% (0.253 g from 0.25 g of 7aaa); a white solid, mp 132–135 °C; Rf = 0.67 (hexanes/EtOAc, 6:4 v/v); IR (KBr) νmax: 1655 (C=O), 3402 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.76 (t, J = 5.8 Hz, 2H), 2.81–2.88 (m, 1H), 2.94–3.00 (m, 1H), 3.37–3.46 (m, 2H), 3.67–3.73 (m, 1H), 3.83–3.89 (m, 1H), 4.25–4.34 (m, 2H), 6.41 (s, 1H), 7.03–7.14 (m, 6H), 7.19–7.21 (m, 3H), 7.29–7.39 (m, 6H), 7.96 (d, J = 8.2 Hz, 1H), 8.51 (d, J = 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 28.8, 30.1, 41.5, 42.5, 45.8, 94.1, 120.8, 121.6, 122.8, 124.2, 126.4, 126.6, 126.9, 127.1, 127.2, 128.2, 128.3, 128.5, 129.7, 130.0, 131.8, 132.6, 133.0, 133.1, 134.9, 138.2, 154.6. MS (ESI+): m/z = 574.7. ESI-HR-MS calculated for C34H28BrN3O [MH]+: 574.1489, found: 574.1490.
Experimental Procedure for the Basic Hydrolysis of 7aaa
To a solution of 7aaa (0.579 mmol, 0.287 g) in 1,4-dioxane (15 mL) was added aq KOH solution (0.162 g, 2.895 mmol dissolved in 10 mL of water), and the mixture was heated at 90 °C for 24 h. The reaction mixture was allowed to cool to room temperature and extracted with EtOAc (50 mL × 2) and water (20 mL). Organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to furnish the crude product, which was purified by column chromatography over silica gel using hexanes/EtOAc (80:20 v/v to 70:30 v/v) as eluent to furnish 0.113 g (58%) of aniline 11 together with 0.1 g of unreacted starting material 7aaa.
Experimental Procedure for the Reaction of 7aaa with Lawesson’s Reagent
In a 30 mL microwave vial containing 7aaa (0.108 mmol, 0.05 g) in 5 mL of THF, Lawesson’s reagent (0.13 mmol, 0.052 g) was added and irradiated at 120 °C for 2 h. After completion of the reaction (as monitored by TLC), the reaction mixture was extracted with EtOAc (50 mL × 2) and water (30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography over silica gel using hexanes/EtOAc (80:20 v/v to 70:30 v/v) as eluent to obtain 0.032 g (94%) of aniline 11.
Experimental Procedure for the Synthesis of Thiourea 15a from Aniline 11
To a stirred solution of aniline 11 (0.89 mmol, 0.3 g) in MeOH (15 mL) was added 3-chlorophenyl isothiocyanate (0.89 mmol, 0.117 mL) at room temperature, and the reaction was continued for 24 h. After completion, the reaction mixture was extracted with EtOAc (50 mL × 2) and water (30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a residue, which was purified by column chromatography over silica gel using hexanes/EtOAc (80:20, v/v) as eluent to yield 0.248 g (55%) of thiourea 15a as a brown solid.
1-(3-Chlorophenyl)-3-(2-(2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-3-yl)phenyl)thiourea (15a)
Mp 159–161 °C; Rf = 0.6 (hexanes/EtOAc, 8:2 v/v);); IR (KBr) νmax: 1521 (C=S), 3396 (N–H) cm–1. 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.95–2.98 (m, 2H), 3.79 (t, J = 6.7 Hz, 2H), 6.75–6.76 (m, 2H), 6.96 (t, J = 1.7 Hz, 1H), 7.02–7.18 (m, 9H), 7.27–7.37 (m, 2H), 7.40–7.43 (m, 2H), 7.47–7.53 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) =29.5, 42.0, 103.6, 122.7, 123.1, 124.5, 124.6, 125.2, 126.0, 126.1, 126.4, 126.6, 126.7, 127.4, 127.4, 127.4, 128.2, 128.6, 129.1, 129.4, 130.9, 131.1, 131.3, 132.4, 135.2, 135.5, 137.2, 137.8, 179.3. MS (ESI+): m/z = 506.3. ESI-HR-MS calculated for C31H24N3S [MH]+: 506.1452, found: 506.1447.
General Experimental Procedure for the Synthesis of 16 as Exemplified for 16a
In a sealed tube containing spirooxindole 6a (0.18 g, 0.49 mmol) was added POCl3 (462 μL, 4.93 mmol), and the mixture was heated at 90 °C for 24 h under stirring. On completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature and neutralized by adding saturated aqueous NaHCO3 solution and extracted with EtOAc (50 mL × 2). The organic layers were pooled, dried over anhydrous Na2SO4, and evaporated under vacuum to obtain a residue, which was purified by column chromatography over silica gel using CHCl3/MeOH (95:05, v/v) as eluent to afford 0.126 g (74%) of 16a as an orange solid.
8-Phenyl-1,2-dihydroindolo[3′,2′:5,6]pyrido[2,1-a]isoquinoline (16a)
mp 202–205 °C; Rf = 0.6 (CHCl3/MeOH, 9:1 v/v); 1H NMR (400 MHz, CDCl3): δ (ppm) = 3.27 (t, J = 6.6 Hz, 2H), 5.09 (t, J = 6.5 Hz, 2H), 6.99–7.03 (m, 1H), 7.30 (s, 1H), 7.38–7.48 (m, 4H), 7.58–7.67 (m, 4H), 7.76–7.78 (m, 2H), 7.80–7.82 (d, J = 8.1 Hz, 1H), 7.92–7.94 (m, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 27.9, 43.7, 106.9, 117.9, 119.0, 121.7, 122.2, 123.2, 126.0, 127.9, 128.1, 128.5, 128.7, 129.0, 129.3, 129.4, 130.5, 134.9, 138.4, 138.6, 145.9, 153.8, 153.9. MS (ESI+): m/z = 347.3. ESI-HR-MS calculated for C25H18N2 [MH]+: 347.1543, found: 347.1539.
10-Bromo-8-phenyl-1,2-dihydroindolo[3′,2′:5,6]pyrido[2,1-a]isoquinoline (16b)
Yield: 84% (0.178 g from 0.222 g of 6b); a brown solid, mp 256–260 °C; Rf = 0.5 (CHCl3/MeOH, 9:1 v/v). 1H NMR (400 MHz, CDCl3): δ (ppm) = 3.28 (t, J = 6.4 Hz, 2H), 5.07 (t, J = 6.3 Hz, 2H), 7.35 (s, 1H), 7.38–7.40 (m, 1H), 7.43–7.47 (m, 2H), 7.53 (dd, J1 = 8.6 Hz, J2 = 1.7 Hz, 1H), 7.62–7.69 (m, 4H), 7.74–7.75 (m, 3H), 7.94 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 27.9, 44.1, 107.7, 111.9, 119.2, 120.4, 124.6, 124.7, 126.2, 128.2, 128.6, 128.6, 129.0, 129.2, 129.8, 130.6, 131.0, 135.0, 137.9, 139.5, 147.3, 151.5, 153.4. MS (ESI+): m/z = 425.4. ESI-HR-MS calculated for C25H17BrN2 [MH]+: 425.0648, found: 425.0648.
Acknowledgments
Authors A.G. and D.S.B. gratefully acknowledge the financial support from CSIR, New Delhi, whereas S.K. acknowledges the financial support from UGC, New Delhi in the form of fellowships. The authors acknowledge the SAIF, CDRI for providing the spectroscopic data. We thank Dr. Tejender S. Thakur of the Molecular and Structural Biology Division, CSIR-Central Drug Research Institute for supervising the X-ray data collection and structure determination of the compound reported in this paper. The work was supported by the funds under the grant EMR/2016/002162 from SERB, New Delhi. This is CDRI Communication no. 9998.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03546.
Author Contributions
∥ A.G. and S.K. contributed equally to this work.
The authors declare no competing financial interest.
Supplementary Material
References
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