Copper(II)-catalyzed cascade approach for the synthesis of pyrrolo[2,1-f][1,2,4]triazine-fused isoquinolines

Abstract

We report herein a one-pot copper(II)-catalyzed coupling-cyclization leading to small molecules based on a novel structural motif, i.e. the pyrrolo[2,1-f][1,2,4]triazine moiety fused with an isoquinoline ring. The reaction is easy to perform in good to excellent yields with high atom economy and exhibits a broad substrate scope.

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Introduction

The development of synthetic organic chemistry in pharmaceutical science provides new opportunities to synthesize new bioactive chemical entities. The transition-metal-catalyzed cascade cyclization reaction has been used as a major method to construct heterocyclic scaffolds from readily accessible organic compounds.¹ In the past few years, Lewis acids (complexes of Ag, Cu, Fe, Au, Pd etc.) have emerged as powerful catalysts for the purpose. The feasibility of activating C-heteroatom bonds like C–O, C–N, C–S bond by coordination to these catalysts has led to the development of a variety of catalytic reactions involving C-heteroatom bond formation with high atom economy.²

As a privileged fragment, pyrrolo[2,1-f][1,2,4]triazine skeleton is an important moiety that has been found to be present in several pharmaceutical candidates, exhibiting anticancer,³ anti-inflammatory⁴ activities (Fig. 1). For example, EGFR tyrosine kinase inhibitors BMS690514,⁵ BMS599626 ⁶ and IGF1R inhibitor BMS754807 ⁷ all contain a pyrrolo[2,1-f][1,2,4]triazine scaffold. Therefore, the design and synthesis of novel pyrrolo[2,1-f][1,2,4]triazine scaffolds attract the attention of both organic and medicinal chemists.⁸

Fig. 1 Examples of pyrrolo[2,1-f][1,2,4]triazine derivatives and isoquinolines.

Isoquinoline-fused polycyclic compounds are important structural moieties that appear in both natural products and therapeutic agents and have wide applications in pharmaceutical research (Fig. 1).⁹ Considerable efforts have been made to develop efficient methods for the synthesis of this class of compounds. Using cascade addition of nucleophiles and cyclization, many reports in the literature^9b,10 have showed the successful synthesis of fused 1,2-dihydroisoquinolines in the presence or absence of Lewis acid catalysts like AgOTf,¹¹ AuCl,¹² or Yb(OTf)₃ (ref. 13) (Scheme 1 eqn 1).

Scheme 1 A possible route for the construction of diverse 4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one.

As a part of our interest in the construction of heterocyclic scaffolds using substituted N-amino pyrroles as building blocks to expand medicinal chemistry space,^8a,14 in this paper we hypothesized that the condensation reaction of 2-alkynylbenzaldehydes and N-amino pyrrole-2-carboxyamide would provide the corresponding imine intermediate, which would follows cascade addition of nucleophiles and cyclization to afford fused isoquinolines in the presence of appropriate Lewis acids (Scheme 1 eqn (2)).

Results and discussion

In order to explore this proposal, methyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1a) was treated with 1.2 equiv. of 2-((4-chlorophenyl)ethynyl)benzaldehyde (2a) in the presence of a variety of transition metal catalysts and solvents. The results were summarized in Table 1. When the reaction was treated by AuCl (0.1 equiv.) in the presence of 4 Å MS in dichloroethane (DCE) at room temperature, the expected product 3a was not obtained, but imine 4a was isolated in 59% yield (Table 1, entry 1). Elevating the temperature to 80–90 °C gave the product 3a in 30% yield and the imine 4a in 20% yield (Table 1, entry 2). When gold(I) chloride was replaced by more cheaper copper catalyst Cu(OTf)₂, the same yield was obtained (Table 1, entry 3 vs. entry 2). In order to improve the solubility of reactants, dimethyl formamide (DMF) was employed as the solvent and the product 3a was obtained in 65% yield (Table 1, entry 4). Then other catalysts such as CuCl₂·2H₂O and CuBr₂ were screened. 3a was obtained in 72% and 83% yields, respectively (Table 1, entries 5 and 6). Without the catalyst the target product 3a was not afforded, with a result of imine 4a obtained in 73% yield (Table 1, entry 12). However, CuCl, Cu(NO₃)₂·3H₂O, anhydrous FeCl₃ did not make this transformation proceed under the conditions (Table 1, entries 7–9), and only the imine 4a was obtained. We speculate the transformation may proceed through the imine intermediate. So we conducted an experiment using imine 4a and CuBr₂ in DMF at 80–90 °C to prove the proposition. Fortunately the imine can transform to the target compound in 81% yield (shown in Scheme 2). However, addition of base and ligand failed to give the desired product 3a (Table 1, entries 10 and 11). Finally we also investigated the effect of reaction time. The yield was slightly lowered when monitored the progress in 2 hours, and the yield did not change when extending reaction time to 7 hours (Table 1, entries 13 and 14). The compound 3a was characterized by the ¹H NMR, ¹³C NMR and DEPT spectra analysis.

Table 1 Selected optimization studies^a

Entry	Catalyst	Additive	Solvent	Temp./°C	Yield of 3a^b	4a^c
a Reaction condition: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (0.02 mmol), solvent (3 ml), 4 h.b Yield isolated by column chromatograph.c Yield isolated by column chromatograph.d Phen (0.04 mmol), DBU (0.4 mmol) was added.e Reaction time for 2 h.f Reaction time for 7 h. r.t.: room temperature. Phen: 1,10-phenanthroline. DBU:1,8-diazabicyclo[5.4.0]undec-7-ene. n.d. = not detected.
1	AuCl	4 Å MS	DCE	r.t.	0	59
2	AuCl	—	DCE	80–90	30	20
3	Cu(OTf)2	—	DCE	80–90	31	15
4	Cu(OTf)2	—	DMF	80–90	65	0
5	CuCl2·H2O	—	DMF	80–90	72	0
6	CuBr2	—	DMF	80–90	83	0
7	CuCl	—	DMF	80–90	n.d.	30
8	FeCl3	—	DMF	80–90	n.d.	40
9	Cu(NO3)2·3H2O	—	DMF	80–90	n.d.	46
10^d	CuCl2·H2O	Phen	DMF	80–90	n.d.	28
11^d	CuCl2·H2O	Phen + DBU	DMF	80–90	n.d.	24
12	—	—	DMF	80–90	0	73
13	CuBr2	—	DMF	80–90	61^e	Trace
14	CuBr2	—	DMF	80–90	83^f	0

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Scheme 2 Transformation of 4a to the target compound 3a.

With the optimal conditions in hand, we examined the scope of the copper(II)-catalyzed annulation strategy with the results shown in Table 2. We first investigated the electron effects of substituents of 2-(phenylethynyl)benzaldehydes. When R was phenyl, it was found that the electron-withdrawing groups (–Cl, –F, –CO₂CH₃, –NO₂) on the R afforded the target products in good to excellent yields (60–85%, Table 2, entries 1, 4, 5, 8, 12, 13, and 16). And the electron-donating groups (–CH₃, –OCH₃) on the R could also give moderate to excellent yields (56–92%, Table 2, entries 2, 3, 6, 9, 11, 14, and 15). The similar results were also observed when R₂ was electron-withdrawing group fluoride or electron-donating group methoxyl except 2g (Table 2, entries 5, 6, 8, and 9). We proposed that the two electron-donating groups of 2g reduced the electrophilicity at the remote end of the alkyne, which thereby reduced the efficiency of the desired transformation by a 6-endo-dig cyclization approach (Table 2, entry 7). To our delight, the reaction went smoothly when R was alkyl or substituted alkyl. For example, alkyne 2j bearing a cyclopropyl group provided the target product 3j in 77% yield (Table 2, entry 10). Alkyne 2l and 2n, containing the aliphatic chain with hydroxyl group, were also suitable substrates for this reaction with excellent yields (71–94%, Table 2, entries 18, 19, 21, 22). We also investigated the electron effects of substituents on N-amino pyrrole-2-carboxyamide. The results showed that the electron-withdrawing group (–CO₂CH₃) gave much lower yields than that of un-substituted substrates (Table 2, entry 2 vs. 14, 3 vs. 11, 4 vs. 13, 8 vs. 16, 18 vs. 19, and 21 vs. 22) and the electron-donating group (-isopropyl) was also tolerated in this reaction (Table 2, entry 23).

Table 2 Synthesis of substituted 4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one compounds^a

Entry	1	2	3	Yield^b (%)	Entry	1	2	3	Yield^b (%)
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), CuBr2 (0.02 mmol), DMF (3 ml), 80 °C, 4 h.b Isolated yield.c An inseparable mixture of unidentified products was obtained.d An inseparable mixture of 3l and its brominated product in a ratio of 83 : 17 detected by LC-MS.e The pure compound 3l was obtained in the presence of Cu(OTf)2.
1				83	13	1b	2d		81
2	1a			79	14	1b	2b		92
3	1a			56	15	1b	2i		73
4	1a			75	16	1b	2h		85
5	1a			64	17	1b	2j		72
6	1a			78	18	1b			84
7	1a			—^c	19	1a	2l		71
8	1a			60	20	1b			64
9	1a			75	21	1b			94
10	1a			77	22	1a	2n		75
11	1a	2c		81	23		2a		71
12				67^d
				40^e

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On the basis of all the above results, the mechanism hypothesis, by taking the reaction of 1b and 2m as an example, has been proposed and shown in Scheme 3. At first, Condensation between 1b and 2m would generate imine 4b. Imine 4b can be converted to the final product 3t through a cascade process proposed in two approaches. In path I, intermediate B2, formed by the attack of the nitrogen of the tautomer of amide at the imine, would carry on regiospecific hydroamination reaction, leading to the formation of D. In path II, copper-coordinated isoquinolinium cation C1, formed by nucleophilic attack of imine nitrogen atom at the alkynyl group, would be trapped by the tautomer of pyrrolo-2-amide, with the result of formation of D. Finally protonation might then occur to give compound 3t. Furthermore, the structure of compound 3t was determined by the X-ray crystallographic analysis (Fig. 2).

Scheme 3 A possible mechanism for the Cu(II)-catalysed cyclization of 1b with 2m as an example.

Fig. 2 X-ray crystal structure of 3t.

Conclusions

In conclusion, we have developed a Cu(II)-catalyzed coupling–cyclization reaction that allowed facile access to an impressive variety of pyrrolo[2,1-f][1,2,4]triazine-fused isoquinolines in good to excellent yields. The reaction proceeded with high 6-endo-dig regioselectivity, and the product was confirmed by X-ray crystallographic study. This method appeared to be compatible with different substituted starting materials that have different electronic properties, increasing its applicability to various functional groups. Furthermore this reaction is easy to operate and atom-economical, which will make it attractive for the construction of variety of bioactive heterocyclic compounds. Currently biological evaluation of these compounds is under investigation.

Experimental section

Reagents (chemicals) were purchased from commercial sources, and used without further purification. Analytical thin layer chromatography (TLC) used was HSGF 254 (0.15–0.2 mm thickness, Yantai Jiangyou company, China). Nuclear magnetic resonance spectra were recorded on Varian Mercury-300 and/or Varian Mercury-500 spectrometers with TMS as internal standard. Chemical shift were reported in parts per million (ppm, δ) downfield from TMS. Low- and high-resolution mass spectra (LRMS and HRMS) were recorded on a Finnigan/MAT-95 spectrometer. Melting points (m.p.) were measured by Büchi 510 melting point apparatus and were uncorrected.

General procedure for the synthesis of 2f, 2g and 2l

To a stirred solution of 2-bromobenzaldehyde (2 mmol) and terminal aromatic alkynes (2.4 mmol) in Et₃N (10 ml) was added PdCl₂(PPh₃) (0.04 mmol) and CuI (0.02 mmol). The resulted mixture was heated under a nitrogen atmosphere at 50 °C for 4 h and then cooled to room temperature. After the separation of ammonium salt by filtration and removing of solvent under reduced pressure, the residue was purified by column chromatography on silica gel to afford the corresponding 2-(arylethyl)benzaldehyde 2f, 2g and 2l.

4-Methoxyl-2-(phenylethynyl)benzaldehyde (2f). White solid. Yield 75%. m.p. 65–68 °C. ¹H NMR (300 MHz, CD₃Cl) δ 10.51 (d, J = 0.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.59–7.54 (m, 2H), 7.41–7.36 (m, 3H), 7.09 (d, J = 2.6 Hz, 1H), 6.97 (ddd, J = 8.8, 2.6, 0.8 Hz, 1H), 3.91 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 190.4, 163.8, 131.7, 129.6, 129.5, 129.2, 129.0, 128.6, 122.2, 117.0, 115.6, 96.1, 84.9, 55.7. HRMS (ESI) calcd for C₁₆H₁₂O₂ [M + H]⁺: 237.0916, found: 237.0918.

4,5-Dimethoxy-2-(phenylethynyl)benzaldehyde (2g). White solid. Yield 86%. m.p. 90–94 °C. ¹H NMR (300 MHz, CD₃Cl) δ 10.50 (s, 1H), 7.56 (dd, J = 6.7, 3.1 Hz, 2H), 7.43 (s, 1H), 7.41–7.34 (m, 3H), 7.06 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 190.5, 153.7, 149.7, 131.6, 130.2, 128.9, 128.5, 122.5, 121.6, 114.3, 108.2, 95.0, 84.8, 56.4, 56.2. HRMS (ESI) calcd for C₁₇H₁₅O₃ [M + H]⁺: 267.1021, found: 267.1024.

4-Fluoro-2-(3-hydroxyprop-1-yn-1-yl)benzaldehyde (2l). Yellow solid. Yield 81%. m.p. 72–75 °C. ¹H NMR (300 MHz, CDCl₃) δ 10.41 (d, J = 0.8 Hz, 1H), 7.93 (dd, J = 8.7, 5.8 Hz, 1H), 7.25–7.10 (m, 2H), 4.57 (d, J = 4.4 Hz, 2H), 2.13 (t, J = 6.7 Hz, 1H, OH). ¹³C NMR (151 MHz, CDCl₃) δ 190.0, 165.6 (d, ¹J_C,F = 253 Hz), 132.8 (d, ⁴J_C,F = 2.6 Hz), 130.3 (d, ³J_C,F = 10.2 Hz), 128.5 (d, ³J_C,F = 10.9 Hz), 120.0 (d, ²J_C,F = 23.4 Hz), 116.8 (d, ²J_C,F = 22.1 Hz), 95.5, 80.2 (d, ⁴J_C,F = 2.8 Hz), 51.5. HRMS (ESI) calcd for C₁₀H₈FO₂ [M + H]⁺: 179.0508, found: 179.0509.

General procedure for the AuCl-catalyzed reaction for synthesis of 4a and 4b

To a DCE (3 ml) solution of 1a (0.2 mmol) and 2a (0.24 mmol) in 10 ml two-neck flask was added AuCl (10 mmol%) and some molecular sieves under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5–1 hour. The white precipitate was collected by filtration, washed by water and ether, and then dried in vacuo to obtain white solid 4a.

(E)-Methyl 5-carbamoyl-1-(2-((4-chlorophenyl)ethynyl) benzylidene)amino-1H-pyrrole-3-carboxylate (4a). White solid. m.p. 265–270 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.36–8.34 (m, 1H), 8.08–8.04 (m, 1H), 7.86–7.81 (m, 1H), 7.78–7.73 (m, 1H), 7.70–7.55(m, 5H), 7.56–7.50 (m, 2H), 7.17–7.13 (m, 1H), 3.76 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 164.0, 160.7, 155.7, 134.5, 133.8, 133.7, 133.4, 132.5, 130.0, 129.4, 128.3, 127.6, 123.6, 122.2, 121.2, 115.0, 114.0, 94.7, 87.9, 51.8. IR (KBr): ν 3409.53, 3139.54, 1708.62, 1679.69, 1490.70, 1238.08, 761.74, 516.83 cm⁻¹. LCMS (ESI): m/z 406.2 [M + H]⁺, 428.1 [M + Na]⁺. HRMS (ESI) calcd for C₂₂H₁₇ClN₃O₃ [M + H]⁺ 406.0958, found 406.0965.

(E)-1-((2-(Phenylethynyl)benzylidene)amino)-1H-pyrrole-2-carboxamide (4b). White solid. m.p. 190–194 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.05–8.00 (m, 1H), 7.83–7.80 (m, 1H), 7.79–7.76 (m, 1H), 7.74–7.70 (m, 1H), 7.66–7.61 (m, 2H), 7.60–7.54 (m, 2H), 7.47–7.41 (m, 4H), 6.83 (dd, J = 4.0, 1.8 Hz, 1H), 6.29 (dd, J = 4.0, 3.1 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 161.2, 150.7, 133.9, 133.509, 132.1, 131.9, 129.9, 129.8, 129.3, 127.3, 127.0, 123.6, 122.3, 117.1, 115.7, 109.0, 95.9, 86.7. IR (KBr): ν 3401.82, 3160.76, 1658.48, 1641.13, 1454.06, 1255.43, 755.96 cm⁻¹. HRMS (ESI) calcd for C₂₀H₁₆N₃O [M + H]⁺ 314.1293, found 314.1306.

General procedure for the Cu(II)-catalyzed annulation reaction

In a 10 ml reaction tube, N-amino-1H-pyrrole-2-carboxyamide (0.2 mmol), 2-alkynylbenzaldehyde (0.24 mmol), CuBr₂ (0.02 mmol) were mixed and stirred at room temperature for 5 min. Then the system was vigorously stirred at 80–90 °C for 4 h. After completion of the reaction, the mixture was poured into water, and then extracted with ethyl acetate (10 ml × 3). The combined organic layer was washed by saturated brine, and then concentrated in vacuo to afford the crude product. The pure product was obtained after purification of the residue by silica gel column chromatography (eluted with petroleum ether–ethyl acetate 3 : 1).

Methyl 12-(4-chlorophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3a). White solid. m.p. 283–287 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.48–7.45 (m, 1H), 7.41(d, J = 7.0 Hz, 2H), 7.33–7.26 (m, 4H), 7.07 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 1.2 Hz, 1H), 6.36 (s, 1H), 6.05 (s, 1H), 3.65 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.6, 157.8, 142.7, 134.2, 132.9, 130.9, 130.7, 130.4, 128.6, 128.1, 127.7, 127.7, 126.7, 125.6, 125.5, 112.8, 111.0, 108.79, 69.36, 51.73. IR (KBr): ν 3137.62, 3058.55, 1725.98, 1654.62, 1560.13, 759.82 cm⁻¹. LCMS (ESI): m/z 406.2 [M + H]⁺, 428.1 [M + Na]⁺. HRMS (ESI) calcd for C₂₂H₁₇ClN₃O₃ [M + H]⁺ 406.0958, found 406.0965.

Methyl 12-(4-methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo [2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3b). Green solid. m.p. 245–250 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.43–7.35 (m, 3H), 7.32–7.24 (m, 2H), 6.95–6.89 (m, 3H), 6.82–6.76 (m, 2H), 6.34 (s, 1H), 5.97 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.6, 159.9, 157.9, 143.7, 131.3, 130.3, 130.0, 128.0, 127.7, 127.3, 126.5, 126.2, 125.6, 125.3, 113.9, 112.6, 110.8, 108.1, 69.4, 55.6, 51.6. IR (KBr): ν 3399.89, 3139.54, 1718.26, 1664.27, 1560.13, 1508.06, 759.82 cm⁻¹. LCMS (ESI): m/z 402.2 [M + H]⁺, 424.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₃H₂₀N₃O₄ [M + H]⁺: 402.1454, found 402.1471.

Methyl 12-p-tolyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3c). White solid. m.p. > 300 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.44–7.36 (m, 3H), 7.32–7.25 (m, 2H), 7.05 (d, J = 7.5 Hz, 2H), 6.92–6.87 (m, 3H), 6.34 (s, 1H), 5.97 (s, 1H), 3.63 (s, 3H), 2.23 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.7, 157.9, 143.9, 138.8, 131.2, 130.4, 129.0, 128.5, 128.0, 127.7, 127.4, 126.6, 125.6, 125.4, 112.6, 110.9, 108.2, 69.4, 51.7, 21.2. IR (KBr): ν 3426.89, 3164.61, 2921.63, 1724.05, 1658.48, 759.82 cm⁻¹. LCMS (ESI): m/z 386.2 [M + H]⁺, 408.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₃H₂₀N₃O₃ [M + H]⁺: 386.1505, found 386.1490.

Methyl 12-(4-carboxylmethylphenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3d). Yellow solid. m.p. 240–245 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J = 8.2 Hz, 2H), 7.49–7.41 (m, 1H), 7.35–7.31 (m, 2H), 7.27–7.21 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.96–6.94 (m, 1H), 6.22–6.19 (s, 1H), 5.93 (s, 1H), 5.82 (s, 1H), 3.90 (s, 3H), 3.70 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 166.4, 163.6, 157.8, 142.8, 137.7, 130.9, 130.8, 130.6, 129.5, 128.5, 127.9, 126.9, 126.6, 125.9, 125.7, 124.4, 114.0, 113.1, 108.6, 70.1, 52.3, 51.5. IR (KBr): ν 3145.33, 1714.41, 1656.55, 1562.06, 759.82 cm⁻¹. LCMS (ESI): m/z 430.2 [M + H]⁺, 452.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₄H₂₀N₃O₅ [M + H]⁺: 430.1403, found 430.1399.

Methyl 3-fluoro-12-phenyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3e). Yellow solid. m.p. 270–274 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H), 7.38–7.20 (m, 7H), 7.02 (d, J = 7.2 Hz, 2H), 6.88 (d, J = 1.6 Hz, 1H), 6.36 (s, 1H), 6.04 (s, 1H), 3.61 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 163.6, 161.5 (d, ¹J_C,F = 245 Hz), 157.8, 143.2, 132.9, 129.6 (d, ²J_C,F = 17.9 Hz), 129.3, 129.1 (d, ³J_C,F = 7.4 Hz), 128.8, 128.4, 128.3, 127.6 (d, ³J_C,F = 7.4 Hz), 127.5, 127.4, 127.2, 124.3, 117.7 (d, ²J_C,F = 22.2 Hz), 113.9 (d, ²J_C,F = 20.0 Hz), 113.0, 69.7 (d, ⁴J_C,F = 1.4 Hz), 51.5. IR (KBr): ν 3409.53, 3149.19, 1712.48, 1654.62, 1562.06, 757.89 cm⁻¹. LCMS (ESI): m/z 390.2 [M + H]⁺: 412.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₂H₁₇N₃O₃F [M + H]⁺: 390.1254, found 390.1236.

Methyl 2-methoxy-12-phenyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3f). White solid. m.p. 302–305 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.36–7.17 (m, 5H), 7.04–6.96 (m, 2H), 6.89–6.84 (m, 3H), 6.29 (s, 1H), 5.96 (s, 1H), 3.77 (s, 3H), 3.62 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 164.49, 161.70, 158.76, 145.14, 134.88, 133.30, 130.27, 130.19, 129.56, 129.37, 128.52, 126.36, 120.12, 113.95, 113.46, 111.65, 111.38, 109.15, 70.00, 56.64, 52.56. IR (KBr): ν 3399.89, 3139.54, 1718.26, 1664.27, 1560.13, 1508.06, 759.82 cm⁻¹. LCMS (ESI): m/z 402.2 [M + H]⁺, 424.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₃H₂₀N₃O₄ [M + H]⁺: 402.1454, found 402.1471.

Methyl 2-fluoro-12-(4-nitrophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3h). Yellow solid. m.p. > 300 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 1.7 Hz, 1H), 7.52–7.46 (m, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.23–7.16 (m, 2H), 6.91 (d, J = 1.7 Hz, 1H), 6.44 (s, 1H), 6.16 (s, 1H), 3.62 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.5, 163.4 (d, ¹J_C,F = 244.8 Hz), 157.7, 148.1, 143.1, 140.2, 132.9 (d, ³J_C,F = 9.4 Hz), 130.5 (d, ³J_C,F = 9.2 Hz), 130.4, 127.7, 125.4, 123.6, 123.1 (d, ⁴J_C,F = 3.2 Hz), 114.7 (d, ²J_C,F = 22.4 Hz), 113.1, 112.3 (d, ²J_C,F = 23.0 Hz), 111.4, 108.8, 68.8, 51.7. IR (KBr): ν 3392.17, 3201.25, 1662.34, 1635.34, 1521.56, 1348.00, 750.17 cm⁻¹. LCMS (ESI): m/z 435.2 [M + H]⁺, 457.1 [M + Na]⁺. HRMS (ESI) calcd for C₂₂H₁₅FN₄O₅Na [M + Na]⁺: 457.0924, found 457.0930.

Methyl 3-fluoro-12-(4-methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3i). White solid. m.p. 261–265 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.39 (s, 1H), 7.35–7.25 (m, 3H), 6.94–6.89 (m, 3H), 6.81–6.76 (m, 2H), 6.34 (s, 1H), 5.98 (s, 1H), 3.69 (s, 3H), 3.64 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.6, 160.6 (d, ¹J_C,F = 245 Hz), 159.9, 157.8, 143.1, 130.1 × 2, 128.4 (d, ³J_C,F = 8.3 Hz), 128.0 (d, ⁴J_C,F = 3.2 Hz), 127.8, 127.4 (d, ³J_C,F = 7.9 Hz), 126.1, 125.5, 117.2 (d, ²J_C,F = 20.9 Hz), 115.1 (d, ²J_C,F = 23.3 Hz), 113.9, 112.7, 111.0, 107.2, 68.9, 55.6, 51.7. IR (KBr): ν 3401.82, 3139.54, 1712.48, 1652.70, 1562.06, 1509.99, 833.10, 759.82 cm⁻¹. LCMS (ESI): m/z 420.2 [M + H]⁺, 442.1 [M + Na]⁺. HRMS (ESI) calcd for C₂₃H₁₉FN₃O₃ [M + H]⁺: 420.1360, found 420.1345.

Methyl 12-cyclopropyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3j). White solid. m.p. 255–260 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J = 1.7 Hz, 1H), 7.42–7.33 (m, 2H), 7.25–7.21 (m, 2H), 7.13 (d, J = 7.5 Hz, 1H), 6.11 (d, J = 1.3 Hz, 1H), 5.72 (d, J = 1.2 Hz, 1H), 5.63 (s, 1H), 3.85 (s, 3H), 1.02–0.92 (m, 1H), 0.79–0.59 (m, 2H), 0.55–0.38 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 164.1, 157.6, 145.4, 131.0, 130.6, 127.7, 127.0, 126.4, 125.5, 125.2, 124.5, 114.1, 112.7, 103.8, 70.1, 51.6, 11.4, 6.7, 5.1. IR (KBr): ν 3421.10, 3176.18, 3131.83, 1708.62, 1656.55, 1562.06, 763.67 cm⁻¹. LCMS (ESI): m/z 336.2 [M + H]⁺, 358.2 [M + Na]⁺. HRMS (ESI) calcd for C₁₉H₁₈N₃O₃ [M + H]⁺ 336.1348, found 336.1364.

12-p-Tolyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3k). White solid. m.p. 222–226 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (ddd, J = 8.6, 7.6, 4.0 Hz, 1H), 7.29 (dd, J = 4.0, 0.9 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 7.7 Hz, 2H), 6.90 (dd, J = 4.3, 1.6 Hz, 1H), 6.87–6.81 (m, 2H), 6.35 (dd, J = 2.8, 1.6 Hz, 1H), 6.23 (d, J = 1.7 Hz, 1H), 5.86–5.81 (m, 2H), 5.70 (s, 1H), 2.30 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 158.7, 144.6, 138.8, 131.4, 131.0, 130.4, 128.7, 128.3, 127.1, 126.5, 125.9, 125.4, 123.8, 123.5, 112.1, 107.2, 106.4, 70.2, 21.3. IR (KBr): ν 3419.17, 3172.33, 1731.76, 1654.62, 763.67, 738.60 cm⁻¹. LCMS (ESI): m/z 328.2, [M + H]⁺, 350.2, [M + Na]⁺. HRMS (ESI) calcd for C₂₁H₁₈N₃O [M + H]⁺, 328.1450, found 328.1430.

12-(4-Nitrophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3l). Yellow solid. m.p. 302–306 °C. ¹H NMR (300 MHz, CDCl₃) δ 8.10–7.99 (m, 2H), 7.46 (ddd, J = 7.6, 6.8, 2.1 Hz, 1H), 7.40–7.22 (m, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.91 (dd, J = 4.3, 1.6 Hz, 1H), 6.35 (dd, J = 2.8, 1.6 Hz, 1H), 6.24 (d, J = 1.5 Hz, 1H), 5.93 (s, 1H), 5.86 (dd, J = 4.3, 2.8 Hz, 1H), 5.67 (s, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 158.5, 147.9, 142.6, 141.1, 130.7, 130.3, 130.2, 128.1, 127.9, 127.1, 125.7, 124.3, 123.9, 123.4, 111.2, 109.1, 106.6, 69.6. IR (KBr): ν 3397.96, 3178.11, 1666.20, 1348.00, 727.03 cm⁻¹. LCMS (ESI): m/z 359.2 [M + H]⁺, 381.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₀H₁₄N₄NaO₃ [M + Na]⁺,381.0964, found 381.0981.

12-(4-Carboxylmethylphenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3m). White solid. m.p. >300 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J = 8.1 Hz, 2H), 7.48–7.40 (m, 1H), 7.37–7.19 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.89 (dd, J = 4.2, 1.7 Hz, 1H), 6.32 (dd, J = 2.8, 1.6 Hz, 1H), 6.23 (s, 1H), 5.90 (s, 1H), 5.82 (dd, J = 4.3, 2.7 Hz, 1H), 5.62 (s, 1H), 3.89 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 166.2, 158.5, 143.6, 139.2, 130.9, 130.3, 130.1, 129.1, 128.1, 127.6, 127.0, 125.5, 124.3, 123.9, 110.9, 108.3, 106.4, 69.5, 52.7. IR (KBr): ν 3423.03, 3174.26, 1720.19, 1652.70, 771.39, 738.60 cm⁻¹. LCMS (ESI): m/z 372.2 [M + H]⁺, 394.2[M + Na]⁺. HRMS (ESI) calcd for C₂₂H₁₇N₃O₃Na [M + Na]⁺, 394.1168, found 394.1171.

12-(4-Methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3n). Yellow solid. m.p. 240–246 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.46–7.38 (m, 1H), 7.32–7.27 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 6.93–6.84 (m, 3H), 6.73–6.64 (m, 2H), 6.36–6.33 (m, 1H), 6.22 (t, J = 2.0 Hz, 1H), 5.88–5.83 (m, 2H), 5.55 (s, 1H), 3.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.9, 158.6, 144.2, 131.4, 130.4, 129.7, 127.0, 126.5, 126.2, 125.8, 125.4, 123.8, 123.4, 113.3, 112.1, 107.2, 106.4, 70.1, 55.2. IR (KBr): ν 3137.62, 3064.33, 1658.48, 1550.49, 1509.99, 736.67 cm⁻¹. LCMS (ESI): m/z 344.2, [M + H]⁺, 366.2, [M + Na]⁺. HRMS (ESI) calcd for C₂₁H₁₈N₃O₂ [M + H]⁺, 344.1399, found 344.1411.

3-Fluoro-12-(4-methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3o). White solid. m.p. 240–245 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.25–7.16 (m, 1H), 7.12 (td, J = 8.5, 2.6 Hz, 1H), 7.04 (dd, J = 8.1, 2.6 Hz, 1H), 6.89 (dd, J = 4.3, 1.6 Hz, 1H), 6.85 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.34 (dd, J = 2.8, 1.6 Hz, 1H), 6.19 (s, 1H), 5.85 (dd, J = 4.3, 2.8 Hz, 1H), 5.83 (s, 1H), 5.62 (s, 1H), 3.76 (s, 3H). ¹³C NMR (125 MHz, DMSO-d₆) δ 160.5 (d, ¹J_C,F = 243.2 Hz), 159.4, 158.1, 143.3, 129.4, 128.3 (d, ³J_C,F = 7.2 Hz), 127.8 (d, ⁴J_C,F = 2.5 Hz), 127.7 (d, ³J_C,F = 6.4 Hz), 126.2, 123.8, 123.6, 116.5 (d, ²J_C,F = 21.8 Hz), 114.7 (d, ²J_C,F = 23.5 Hz), 113.3, 110.3, 106.1, 105.8, 68.69, 55.06. IR (KBr): ν 3423.03, 3176.18, 1735.62, 1658.48, 1511.92, 734.75 cm⁻¹. LCMS (ESI): m/z 362.2 [M + H]⁺, 384.2 [M + Na]⁺. HRMS (ESI) calcd for C₂₁H₁₇FN₃O₂ [M + H]⁺ 362.1305, found 362.1311.

2-Fluoro-12-(4-nitrophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3p). Yellow solid. m.p. 296–300 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.52–7.45 (m, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.20–7.16 (m, 2H), 6.79 (s, 1H), 6.66–6.62 (m, 1H), 6.38 (s, 1H), 6.10 (s, 1H), 5.87–5.81 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.4 (d, ¹J_C,F = 244.6 Hz), 158.4, 148.0, 143.8, 140.7, 133.3 (d, ³J_C,F = 9.3 Hz), 130.5(d, ³J_C,F = 8.8 Hz), 130.1, 124.2, 124.0, 123.5, 123.3(d, ⁴J_C,F = 3.2 Hz), 114.4 (d, ²J_C,F = 22.4 Hz), 112.1(d, ²J_C,F = 22.7 Hz), 111.3, 108.2, 106.7, 68.9. IR (KBr): ν 3396.03, 3201.25, 1664.27, 1635.34, 1521.56, 1348.00, 750.17 cm⁻¹. LCMS (ESI) m/z 377.2 [M + H]⁺, 399.2 [M + Na]⁺. HRMS: calcd for C₂₀H₁₄N₄O₃F [M + H]⁺: 377.1050, found 377.1045.

12-Cyclopropyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3q). White solid. m.p. 196–201 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.42–7.33 (m, 1H), 7.22 (d, J = 4.0 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.06 (dd, J = 2.8, 1.6 Hz, 1H), 6.97 (dd, J = 4.2, 1.6 Hz, 1H), 6.20 (dd, J = 4.2, 2.8 Hz, 1H), 6.13 (d, J = 1.5 Hz, 1H), 5.68 (d, J = 1.3 Hz, 1H), 5.40 (s, 1H), 0.98–0.86 (m, 1H), 0.77–0.57 (m, 2H), 0.49 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 158.4, 146.5, 131.3, 130.3, 126.6, 126.3, 125.8, 125.0, 124.3, 123.4, 111.9, 106.6, 102.8, 70.2, 11.3, 7.1, 5.0. IR (KBr): ν 3133.76, 2923.56, 1650.77, 757.89, 730.89 cm⁻¹. LCMS (ESI): m/z 278.2 [M + H]⁺, 300.2 [M + Na]⁺. HRMS (ESI) calcd for C₁₇H₁₅N₃ONa [M + Na]⁺, 300.1113, found 300.1131.

2-Fluoro-12-hydroxymethyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3r). White solid. m.p. 256–260 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.18 (dd, J = 8.3, 5.3 Hz, 1H), 7.00 (dd, J = 2.8, 1.5 Hz, 1H), 6.92–6.80 (m, 3H), 6.15 (dd, J = 4.3, 2.8 Hz, 1H), 5.99 (d, J = 6.2 Hz, 2H), 3.80 (d, J = 14.8 Hz, 1H), 3.60 (d, J = 14.9 Hz, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.4 (d, ¹J_C,F = 243.9 Hz), 158.1, 146.5, 133.6(d, ³J_C,F = 9.3 Hz), 130.1 (d, ³J_C,F = 9.1 Hz), 124.1, 123.9, 123.1 (d, ⁴J_C,F = 3.2 Hz), 113.1 (d, ²J_C,F = 22.1 Hz), 111.3 (d, ²J_C,F = 22.7 Hz), 110.8, 106.6, 102.3, 68.9, 58.1. IR (KBr): ν 3351.68, 3183.90, 2919.70, 1643.05, 1619.91, 740.53 cm⁻¹. LCMS (ESI): m/z 286.2 [M + H]⁺, 308.1 [M + Na]⁺. HRMS (ESI) calcd for C₁₅H₁₃N₃O₂F [M + H]⁺ 286.0992, found 286.1015.

Methyl 2-fluoro-12-hydroxylmethyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3s). Yellow solid. m.p. 300–304 °C. ¹H NMR (300 MHz, CD₃Cl) δ 7.69 (d, J = 1.7 Hz, 1H), 7.35–7.32 (m, 2H), 7.31–7.27 (m, 1H), 7.02–6.91 (m, 2H), 6.09 (m, 2H), 3.85 (m, 4H), 3.83–3.76 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 163.8, 163.4 (d, ¹J_C,F = 244.3), 157.5, 145.1, 133.4 (d, ³J_C,F = 9.4 Hz), 130.2 (d, ³J_C,F = 9.2 Hz), 127.7, 125.3, 122.8 (d, ⁴J_C,F = 3.2 Hz), 113.5 (d, ²J_C,F = 22.4 Hz), 113.2, 111.5 (d, ²J_C,F = 22.8 Hz), 110.9, 103.5, 68.6, 58.5, 51.8. IR (KBr): ν 3482.81, 3183.90, 2919.70, 1700.91, 1666.20, 1560.13, 763.67 cm⁻¹. LCMS (ESI): m/z 344.2 [M + H]⁺, 366.2 [M + Na]⁺. HRMS (ESI) calcd for C₁₇H₁₅N₃O₄F [M + H]⁺ 344.1047, found 344.1029.

12-Phenyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3t). White solid. m.p. 240–245 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.47–7.38 (m, 1H), 7.32–7.27 (m, 3H), 7.24–7.14 (m, 3H), 7.01–6.96 (d, J = 7.3 Hz, 2H), 6.89 (dd, J = 4.3, 1.6 Hz, 1H), 6.35–6.30 (m, 1H), 6.23 (d, J = 1.2 Hz, 1H), 5.88 (s, 1H), 5.81 (dd, J = 4.3, 2.8 Hz, 1H), 5.60–5.52 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 158.7, 144.5, 133.8, 131.2, 130.5, 128.8, 128.5, 128.0, 127.2, 126.5, 125.9, 125.5, 123.7, 123.5, 112.2, 107.3, 106.4, 70.1. IR (KBr): ν 3430.74, 3166.54, 1650.77, 736.67 cm⁻¹. HRMS (ESI) calcd for C₂₀H₁₆N₃O [M + H]⁺ 314.1293, found 314.1306.

3-Chloro-12-hydroxylethyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3u). Yellow solid. m.p. 220–224 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (s, 1H), 7.45–7.32 (m, 3H), 7.18 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 4.0 Hz, 1H), 6.20–6.16 (m, 2H), 5.86 (s, 1H), 4.65–4.60 (m, 1H), 3.42–3.34 (m, 1H), 3.28–3.20 (m, 1H), 2.16–2.09 (m, 1H), 1.95–1.82 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 159.0, 144.1, 131.1, 130.9, 130.7, 128.9, 128.5, 127.0, 125.1, 124.8, 111.7, 107.6, 104.6, 69.6, 59.8, 34.2. IR (KBr): ν 3143.40, 2921.63, 1654.62, 1554.34, 1328.71, 728.96 cm⁻¹. LCMS (ESI): m/z 316.1 [M + H]⁺, 338.1 [M + Na]⁺. HRMS (ESI) calcd for C₁₆H₁₄N₃O₂NaCl, [M + Na]⁺ 338.0672, found 338.0670.

Methyl 3-chloro-12-hydroxylethyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one-8-carboxylate (3v). White solid. m.p. 282–286 °C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.07–8.05 (m, 1H), 7.45–7.37 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 1.7 Hz, 1H), 6.24 (s, 1H), 5.91 (s, 1H), 4.66 (t, J = 5.1 Hz, 1H), 3.76 (s, 3H), 3.42–3.22 (m, 2H), 2.28–2.14 (m, 1H), 1.94–1.80 (m, 1H). ¹³C NMR (125 MHz, DMSO-d₆) δ 164.6, 158.2, 158.2, 143.2, 131.1, 130.9, 128.8, 128.6, 128.5, 127.2, 126.2, 114.1, 111.8, 105.0, 69.3, 59.6, 52.6, 34.0. IR (KBr): ν 3382.53, 3259.11, 1695.12, 1666.20, 1301.72, 767.53 cm⁻¹. LCMS (ESI): m/z 374.2 [M + H]⁺, 396.1, [M + Na]⁺. HRMS (ESI) calcd for C₁₈H₁₆N₃O₄NaCl [M + Na]⁺ 396.0727, found 396.0740.

9-Isopropyl-12-(4-chlorophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one (3w). White solid. m.p. 278–282 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.49–7.38 (m, 1H), 7.37–7.20 (m, 3H), 7.15 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 4.4 Hz, 1H), 6.79 (d, J = 8.3 Hz, 2H), 6.15 (s, 1H), 5.91 (s, 1H), 5.73 (d, J = 4.4 Hz, 1H), 5.55 (s, 1H), 2.48–2.36 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 0.57 (d, J = 7.0 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 158.92, 143.55, 143.28, 135.04, 132.66, 131.29, 130.45, 129.87, 128.40, 127.38, 126.50, 126.23, 125.56, 122.43, 112.66, 108.23, 102.89, 70.31, 25.07, 23.64, 19.87. IR (KBr) ν 3237.62, 3058.55, 1725.98, 1654.62, 1560.13, 1382.15, 1368.40, 920.78, 758.82 cm⁻¹. LCMS (ESI): m/z 390.2 [M + H]⁺, 412.1 [M + Na]⁺. HRMS (ESI) calcd for C₂₃H₂₁ClN₃O [M + H]⁺ 390.1373, found 390.1384.

Acknowledgements

This work was financially supported by the Chinese Academy of Sciences (‘Interdisciplinary Cooperation Team’ Program for Science and Technology Innovation), the National Natural Science Foundation of China (21072205, 81202398), and SKLDR/SIMM (SIMM1105KF-02).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 909484. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra47324d

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