Cross-coupling/annulations of quinazolones with alkynes for access to fused polycyclic heteroarenes under mild conditions

Abstract

Ruthenium-catalyzed regioselective oxidative cross-coupling/annulations of quinazolones with alkynes were successfully developed for direct access to fused polycyclic heteroarenes. The transformation proceeded well with a broad substrate scope under mild conditions to achieve moderate to high yields.

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Introduction

In the last few decades, transition metal-catalyzed C–H bond activation for the construction of C–C bonds proved to be the most direct and efficient preparation of complex chemical compounds in an atom- and step-economic manner.¹ Undoubtedly, the rhodium (Rh) catalyst was the most widely used to promote the oxidative coupling/cyclization sequence via C–H bond activation. A variety of directing groups have been successfully introduced for various Rh-complexes mediated dehydrogenative annulation processes.² General functional groups containing oxygen or nitrogen atoms like carboxylic acid,³ ketone carbonyl,⁴ phenolic hydroxyl,⁵ imine,⁶ oxime,⁷ benzamide,⁸ benzhydroxamic acid,⁹ hydroxamic acid,¹⁰ amide,¹¹ acetanilide,¹² acrylamide,¹³ enamine,¹⁴ urea,¹⁵ azide¹⁶ and some small heterocycles¹⁷ including azole, benzimidazole, imidazole, benzoxazole, indole and pyridine etc., all served as potential directing groups. Very recently, a much less expensive ruthenium (Ru) catalyst has been employed by Ackermann et al. to replace the Rh catalyst for many similar processes.¹⁸

At the same time, fused polycyclic heteroaromatic frameworks bearing one or more nitrogen atoms have attracted significant attention for their unique biological and photo-electrochemical properties.¹⁹ However, the traditional synthetic routes were long and were usually costly and complicated to carry out. Recently, transition metal mediated C–H functionalizations have become an alternative and have partially circumvented the existing shortcomings. Moreover, alkynes have recently been used for extensive applications in various catalytic tandem sequential transformations to access multicyclic structures.^2–18,20 Our group is always interested in the synthesis of quinazoline derivatives²¹ and we anticipated that the quinazolinone core structure may participate in catalytic tandem reactions with alkynes, because it contains an amide moiety, which has been proven to be an effective directing group (Scheme 1).^18e,20 Herein, we present a useful ruthenium-catalyzed oxidative cross-coupling/annulation between quinazolones and alkynes for facile access to fused polycyclic heteroarenes in a regioselective fashion under mild conditions.

Scheme 1 Recent examples of amide directing transition metal-catalyzed oxidative coupling/annulations of alkynes.

Results and discussion

As an initial attempt, 2-p-tolyl-4-quinazolinone (1a) was treated with diphenylacetylene (2a) in the presence of a Ru catalyst (5 mol% [RuCl₂(p-cymene)]₂), oxidant (2.2 equiv. of Cu(OAc)₂) and base (2.0 equiv. of Na₂CO₃) in PhCl at 90 °C under a N₂ atmosphere for 16 hours. To our delight, the reaction proceeded to isolate 3a in 82% yield (Table 1, entry 1). The structure of 3a was confirmed by X-ray diffraction analysis (see ESI†). When the reaction was performed in air under identical conditions, the yield did not fluctuate (Table 1, entry 1). This result indicated that the atmosphere did not exert any influence on the transformation. The following optimizations of reaction parameters were all conducted systematically under air for simple experimental operation. Firstly, the solvent effects were investigated (see ESI†). When toluene was used, the yield increased to 92% (Table 1, entry 2), while halogenated solvent DCE provided a moderate yield of 75% (see the ESI† for detailed information). Further examination, including some aprotic polar solvents, such as THF, DMF, NMP and MeCN all delivered inferior outcomes. Protic MeOH was also examined and gave low efficiency (see ESI†). Therefore the aromatic solvent toluene was chosen as the optimal solvent for further optimization. Next, a group of oxidants, such as copper salts and silver salts were screened (see ESI†). The counter anion played a significant role in the process. Only acetate could enhance the catalytic activity, while others turned out to be unsuitable, which is in agreement with the literature description of carboxylate assistance for transition metal-catalyzed C–H functionalization. Then, both inorganic and organic bases were evaluated as additives (see ESI†). Only K₃PO₄ gave a good yield of 79%, while other inorganic bases including K₂CO₃, Cs₂CO₃, NaOH, and t-BuOK all gave a moderate yield. On the other hand, among the organic bases, triethylamine generated the highest yield of 85%, while DBU and DABCO just provided lower yields. Finally, the reaction temperature was also investigated for its well-known significant influence on the reaction rate. Higher or lower temperatures seemed to be inappropriate for the transformation because decreased yields were generated in such cases (Table 1, entries 6 and 7).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Oxidant	Base	T (°C)	Yield^b (%)
a The reaction was carried out on 0.2 mmol of 1a with 1.5 equiv. of 2a in the presence of 5 mol% catalyst [RuCl2(p-cymene)]2, 2.2 equiv. oxidant and 2.0 equiv. base additive in 3 mL solvent at the indicated temperature for 16 hours. b Isolated yield. c The data in parentheses was obtained under N2 atmosphere reaction conditions.
1^c	PhCl	Cu(OAc)2	Na2CO3	90	81(82)^c
2	Toluene	Cu(OAc)2	Na2CO3	90	92
3	Toluene	AgOAc	Na2CO3	90	87
4	Toluene	Cu(OAc)2	Et3N	90	85
5	Toluene	Cu(OAc)2	Na2CO3	120	67
6	Toluene	Cu(OAc)2	Na2CO3	60	87
7	Toluene	Cu(OAc)2·H2O	Na2CO3	90	86

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Encouraged by the above preliminary results, we continued to investigate the effect of catalyst and reagent loading on the catalytic process. The results are summarized in Table 2. The yield decreased sharply, accompanied by a reduction in the catalyst loading, oxidant loading or base loading (Table 2, entries 1, 4 and 6). On the other hand, when the dose of the three reagents increased, the yield stopped increasing (Table 2, entries 3, 5 and 7). Additionally, the control experiments showed that in the absence of any one of the reaction parameters or reagents, the reaction could no longer proceed. Furthermore, several other kinds of ruthenium catalysts, such as Ru(PPh₃)Cl₂, [Ru(bipy)₃]Cl₂·6H₂O, Ru(COD)Cl₂ and RuCl₃·H₂O were also examined, but only a trace amount of the expected product was detected.

Table 2 Catalyst and reagent loading screening^a

Entry	Ru catalyst (x mol%)	Cu(OAc)2 (y equiv.)	Na2CO3 (z equiv.)	Yield^b (%)
a The reaction was carried out on 0.2 mmol of 1a with 1.5 equiv of 2a in the presence of x mol% catalyst [RuCl2(p-cymene)]2, y equiv. Cu(OAc)2 and z equiv. Na2CO3 in 3 mL toluene at 90 °C for 16 hours. b Isolated yield.
1	2.5	2.2	2.0	54
2	5.0	2.2	2.0	92
3	7.5	2.2	2.0	93
4	5.0	1.2	2.0	52
5	5.0	3.2	2.0	92
6	5.0	2.2	1.5	69
7	5.0	2.2	2.5	92

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With the optimized reaction conditions in hand, the substrate scope was explored. As illustrated in Table 3, a wide range of quinazolinones and alkynes could be well tolerated in our catalytic system. Different substituents on the 2-position benzene ring were firstly probed (3a–3h). The substrates bearing electron-donor substitutions generally afforded better outcomes than electron-withdrawing ones. It was noteworthy that the halo atoms could be tolerated under identical conditions, albeit with moderate yields. Nevertheless, when the 2-position of the benzene ring was substituted by a methyl group on the 2′-position (3h), the yield sharply decreased to 37%, along with 56% recovery of the starting material 1h, probably due to the large steric hindrance. After finishing the above examination, we moved on to check the mother aromatic ring of the quinazolinone. The opposite influence of the electronic properties on the catalytic transformation was observed this time. Unlike the previous results, the electron-deficient quinazolinones all produced higher yields than electron-rich ones, no matter what the situations of the 2-position substituted benzene rings were (3i–3o). Subsequently, different symmetric internal alkynes were also assessed. Gratifyingly, both the alkyl and aryl alkynes could react smoothly with quinazolinone 1a to provide the expected product in high yields (3p–3t). Notably, diethyl acetylene generated the best result to give an almost quantitative yield of 3p.

Table 3 Substrate scope exploration^a

a The reaction was carried out on 0.2 mmol of 1a with 1.5 equiv. 2a in the presence of 5 mol% catalyst [RuCl₂(p-cymene)]₂, 2.2 equiv. Cu(OAc)₂ and 2 equiv. Na₂CO₃ in 3 mL toluene at 90 °C for 16 hours. Isolated yield.

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The regioselectivities were evaluated by substitution in the 3′-position of the benzene ring of substrate 4 and unsymmetric alkynes 6 and 8 (Scheme 2). In the case of 4, only a single regioisomer 5a was detected, probably caused by the difference in steric hindrance. However, when unsymmetric alkynes 6 and 8 were utilized, moderate regioselectivities of 3 : 1 and 6 : 1, respectively, were obtained. The structures of 7b and 9b were also confirmed by X-ray diffraction analysis (see ESI†).

Scheme 2 Evaluation of the regioselectivity.

Moreover, some preliminary investigations were further carried out for better understanding the details of the exact reaction mechanism (Scheme 3). When the directing group amide was blocked by the methyl group (10), the reaction could not proceed any further. This means that the directing group was a pivotal element for the transition metal catalytic transformation. Then, when the 2-position aromatic ring was replaced by the alkyl chain, the much more challenged sp³ C–H bond activation did not occur. However, 2-propyl substituted quinazolinone 11 underwent coupling with diphenylacetylene (2a) via the N–H bond cleavage, to provide the product 12 in moderate yield. This phenomenon indicated that the N–H bond could be functionalized solely without the participation of the C–H bond activation.

Scheme 3 Preliminary investigation of the reaction mechanism.

Conclusions

In summary, we have demonstrated an unprecedented ruthenium-catalyzed regioselective oxidative cross-coupling/cyclization of quinazolones with alkynes for the facile construction of fused tetracyclic heteroarenes. The transformation proceeded well with a broad substrate scope under mild conditions to achieve moderate to high yields. Moreover, the preliminary investigations of the reaction mechanism showed that the N–H bond could be functionalized solely without C–H bond cleavage. Further work is currently underway in our laboratory for better understanding of the exact reaction pathway.

Experimental section

All reactions were performed in reaction tubes under air. Flash column chromatography was performed using silica gel (60 Å pore size, 32–63 μm, standard grade). Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light. Organic solutions were concentrated on rotary evaporators at ∼20 Torr (house vacuum) at 25–35 °C. Commercial reagents and solvents were used as received. Nuclear magnetic resonance (NMR) spectra are recorded in parts per million from internal tetramethylsilane on the δ scale.

General experimental procedure for synthesis of 3

A mixture of quinazolinone (1) (0.2 mmol, 1.0 eq.), the alkyne (2) (0.3 mmol, 1.5 eq.), [RuCl₂(p-cymene)]₂ (5%), Na₂CO₃ (0.4 mmol, 2.0 eq.), Cu(OAc)₂ (0.44 mmol, 2.2 eq.), toluene (2 ml) were added to a reaction tube. The mixture was stirred at 90 °C for 16 hours. Afterwards, it was diluted with CH₂Cl₂ and transferred to a round bottomed flask. Silica was added to the flask and volatiles were evaporated under reduced pressure. The purification was performed by flash column chromatography on silica gel.

3-Methyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3a). White solid (yield 92%), mp: 264–265 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.00 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.27–7.23 (m, 3H), 7.10–7.05 (m, 7H), 6.95 (s, 1H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.4, 147.7, 147.0, 142.7, 137.2, 135.6, 135.3, 134.4, 133.9, 131.2, 129.8, 128.5, 128.0, 127.7, 127.2, 127.2, 126.8, 126.7, 126.2, 125.4, 124.9, 120.1, 22.0; HRMS (ESI) calcd for C₂₉H₂₀KN₂O (M + K⁺), 451.1213; Found, 451.1224; IR (cm⁻¹) ν 2922, 1706, 1599, 1541, 1487, 1444, 1292, 1155, 822, 770, 694.

3-Methoxy-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3b). White solid (yield 95%), mp: 246–247 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.04 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.84–7.76 (m, 2H), 7.73–7.70 (m, 1H), 7.54–7.51 (m, 1H), 7.35 (t, J = 6.8 Hz, 1H), 7.28–7.22 (m, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.13–7.11 (m, 3H), 7.08–7.05 (m, 4H), 6.57 (d, J = 6.4 Hz, 1H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 161.4, 147.5, 147.2, 137.1, 135.9, 135.5, 134.4, 131.1, 129.3, 128.5, 128.1, 127.6, 127.3, 127.2, 127.2, 126.9, 126.5, 125.1, 120.7, 119.8, 116.3, 109.0, 55.4; HRMS (ESI) calcd for C₂₉H₂₀N₂NaO₂ (M + Na⁺), 451.1422; Found, 451.1440; IR (cm⁻¹) ν 2918, 1700, 1608, 1541, 1492, 1461, 1285, 1236, 857, 761, 702.

3-(Dimethylamino)-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3c). Yellow solid (yield 96%), mp: 278–279 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.79–7.71 (m, 3H), 7.52–7.51 (m, 1H), 7.31–7.22 (m, 3H), 7.10–6.97 (m, 6H), 6.98 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 2.88 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6, 152.6, 148.2, 147.7, 137.6, 136.1, 135.6, 134.2, 132.3, 131.1, 130.9, 128.9, 128.7, 128.5, 127.9, 127.2, 127.1, 126.6, 126.2, 124.2, 119.5, 116.0, 113.5, 106.6, 39.1; HRMS (ESI) calcd for C₃₀H₂₄N₃O (M + H⁺), 442.1919; Found, 442.1920; IR (cm⁻¹) ν 2960, 1728, 1608, 1537, 1492, 1467, 1290, 1124, 842, 778, 698.

5,6-Diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3d). White solid (yield 77%), mp: 261–262 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.11 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 6.8 Hz, 1H), 7.62 (t, J = 6.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 6.8 Hz, 1H), 7.25 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.12–7.07 (m, 7H); ¹³C NMR (100 MHz, CDCl₃) δ 161.3, 147.5, 146.9, 137.0, 135.5, 135.2, 134.5, 133.9, 132.0, 131.2, 128.5, 128.3, 128.0, 127.8, 127.3, 127.2, 127.1, 126.9, 126.8, 126.2, 125.6, 120.3; HRMS (ESI) calcd for C₂₈H₁₉N₂O (M + H⁺), 399.1497; Found, 399.1506; IR (cm⁻¹) ν 2930, 1697, 1607, 1546, 1487, 1468, 1298, 1137, 768, 696.

3-Fluoro-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3e). White solid (yield 67%), mp: 247–248 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.13 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.87–7.82 (m, 2H), 7.41 (t, J = 6.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.35–7.36 (m, 3H), 7.14–7.06 (m, 7H), 6.84 (d, J = 9.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 165.1 (d, ¹J_CF = 252 Hz), 161.2, 146.9, 146.8, 136.7, 136.6, 136.3 (d, ³J_CF = 10 Hz), 135.0, 134.6, 131.0, 130.3, 130.2, 128.4, 128.3, 127.6, 127.2, 127.1, 127.0, 126.7, 125.7, 123.7, 120.1, 116.6 (d, ²J_CF = 23 Hz), 111.9 (d, ²J_CF = 23 Hz); HRMS (ESI) calcd for C₂₈H₁₈FN₂O (M + H⁺), 417.1403; Found: 417.1423; IR (cm⁻¹) ν 2919, 1704, 1613, 1549, 1489, 1469, 1292, 1202, 863, 766, 695.

3-Chloro-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3f). White solid (yield 66%), mp: 236–237 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.84–7.77 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 6.8 Hz, 1H), 7.26 (m, 3H), 7.12–7.06 (m, 8H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1, 146.8, 146.7, 138.6, 136.7, 136.6, 135.3, 134.8, 134.6, 131.1, 128.9, 128.7, 128.4, 128.3, 127.6, 127.2, 127.1, 126.8, 126.6, 125.9, 125.7, 125.6, 120.2; HRMS (ESI) calcd for C₂₈H₁₈ClN₂O (M + H⁺), 433.1108; Found: 433.1115; IR (cm⁻¹) ν 2959, 1701, 1613, 1549, 1488, 1469, 1292, 1117, 863, 775, 695.

3-Bromo-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3g). White solid (yield 56%), mp: 223–224 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.85–7.78 (m, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.40 (t, J = 6.8 Hz, 1H), 7.29–7.27 (m, 4H), 7.13–7.05 (m, 7H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1, 147.0, 146.7, 136.7, 136.6, 135.5, 134.7, 134.6, 131.6, 131.0, 128.9, 128.7, 128.4, 128.3, 127.6, 127.2, 127.1, 126.8, 126.5, 126.1, 125.9, 120.3; HRMS (ESI) calcd for C₂₈H₁₈BrN₂O (M + H⁺), 477.0603; Found: 477.0597; IR (cm⁻¹) ν 2930, 1712, 1604, 1544, 1479, 1330, 1288, 1175, 868, 744, 702.

1-Methyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3h). White solid (yield 37%), mp: 226–227 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.44–7.37 (m, 3H), 7.26–7.24 (m, 3H), 7.09–7.06 (m, 8H), 3.25 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6, 148.3, 146.2, 141.1, 137.0, 136.3, 135.6, 134.9, 134.2, 132.7, 131.3, 130.8, 128.5, 128.0, 127.2, 127.0, 126.9, 125.8, 125.7, 124.8, 120.1, 27.2; HRMS (ESI) calcd for C₂₉H₂₀N₂NaO (M + Na⁺), 435.1473; Found, 435.1486; IR (cm⁻¹) ν 2926, 1689, 1606, 1552, 1490, 1443, 1282, 1139, 802, 764, 701.

11-Methyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3i). White solid (yield 70%), mp: 251–252 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.09 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.72–7.67 (m, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.56–7.52 (m, 2H), 7.25–7.18 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 7.11–7.07 (m, 6H), 2.54 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1, 147.6, 146.9, 145.4, 137.1, 135.6, 133.9, 132.3, 131.8, 131.1, 130.9, 128.8, 128.4, 128.2, 128.0, 127.4, 127.3, 127.2, 127.1, 127.0, 126.8, 126.4, 126.1, 117.9, 22.0; HRMS (ESI) calcd for C₂₉H₂₀N₂NaO (M + Na⁺), 435.1473; Found, 435.1464; IR (cm⁻¹) ν 2960, 1690, 1610, 1544, 1483, 1442, 1282, 1074, 790, 700.

10-Bromo-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3j). White solid (yield 86%), mp: 230–231 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.06 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61–7.54 (m, 2H), 7.26–7.25 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.13–7.06 (m, 7H); ¹³C NMR (100 MHz, CDCl₃) δ 160.1, 147.8, 145.7, 137.6, 136.7, 135.3, 135.1, 133.9, 132.3, 131.1, 131.0, 129.6, 128.7, 128.5, 128.2, 128.1, 127.4, 127.3, 127.2, 127.1, 126.3, 121.4, 118.8; HRMS (ESI) calcd for C₂₈H₁₈BrN₂O (M + H⁺), 477.0603; Found, 477.0582; IR (cm⁻¹) ν 2930, 1711, 1600, 1542, 1482, 1466, 1288, 1134, 821, 758, 697.

9-Fluoro-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3k). White solid (yield 82%), mp: 223–224 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.07 (d, J = 8.0 Hz, 1H), 7.74–7.69 (m, 2H), 7.67–7.59 (m, 3H), 7.54–7.52 (m, 1H), 7.30–7.26 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.11–7.06 (m, 6H), 7.03–7.01 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 161.0 (d, ¹J_CF = 265 Hz), 158.3, 148.9, 148.4, 136.4, 135.3, 135.0, 134.5 (d, ³J_CF = 10 Hz), 134.2, 132.4, 132.3, 131.1, 131.0, 128.9, 128.5 (d, ⁴J_CF = 5 Hz), 128.1, 127.8, 127.4, 127.1 (d, ⁴J_CF = 4 Hz), 126.8, 126.3, 122.6 (d, ⁴J_CF = 4 Hz), 111.7 (d, ²J_CF = 21 Hz), 110.0 (d, ⁴J_CF = 7 Hz); HRMS (ESI) calcd for C₂₈H₁₈FN₂O (M + H⁺) 417.1403; Found: 417.1413; IR (cm⁻¹) ν 2933, 1710, 1611, 1544, 1488, 1444, 1284, 1141, 815, 777, 700.

3,11-Dimethyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3l). White solid (yield 80%), mp: 252–253 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.72–7.66 (m, 2H), 7.53 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.28–7.24 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.12–7.02 (m, 6H), 6.95 (s, 1H), 2.55 (s, 3H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.1, 147.8, 147.1, 145.4, 142.6, 137.3, 135.7, 135.3, 133.9, 132.3, 131.2, 131.0, 129.8, 128.9, 128.5, 128.0, 127.5, 127.2, 127.1, 126.8, 126.3, 126.1, 125.0, 117.8, 22.1, 22.0; HRMS (ESI) calcd for C₃₀H₂₂N₂NaO (M + Na⁺), 449.1630; Found, 449.1652; IR (cm⁻¹) ν 2918, 1729, 1610, 1543, 1487, 14639, 1287, 1124, 787, 695.

10-Bromo-3-methyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3m). White solid (yield 95%), mp: 254–255 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 8.0 Hz, 1H), 8.23 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.28–7.21 (m, 3H), 7.12–7.05 (m, 7H), 6.93 (s, 1H), 2.35 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 160.1, 147.9, 145.9, 143.0, 137.4, 136.9, 135.5, 135.3, 134.0, 131.1, 129.9, 129.5, 128.6, 128.5, 128.1, 128.0, 127.3, 127.2, 127.1, 126.9, 126.2, 124.8, 121.3, 118.4, 21.9; HRMS (ESI) calcd for C₂₉H₂₀BrN₂O (M + H⁺), 491.0759; Found: 491.0740; IR (cm⁻¹) ν 2923, 1689, 1597, 1541, 1489, 1463, 1292, 1153, 840, 728, 695.

3-Chloro-11-methyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazo-lin-8-one (3n). White solid (yield 57%), mp: 286–287 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.20–7.15 (m, 4H), 7.05–6.96 (m, 8H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.0, 147.0, 146.8, 145.7, 138.5, 136.8, 136.7, 135.3, 134.8, 131.1, 128.8, 128.7, 128.4, 128.2, 127.6, 127.5, 127.2, 127.1, 127.0, 126.4, 125.8, 125.6, 117.9, 22.1; HRMS (ESI) calcd for C₂₉H₂₀ClN₂O (M + H⁺), 447.1264; Found: 447.1294; IR (cm⁻¹) ν 2919, 1689, 1608, 1544, 1482, 1442, 1287, 1197, 875, 787, 708.

10-Bromo-3-chloro-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3o). White solid (yield 84%), mp: 232–233 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.30–7.24 (m, 3H), 7.17–7.04 (m, 8H); ¹³C NMR (100 MHz, CDCl₃) δ 159.9, 147.1, 145.5, 138.9, 137.7, 136.5, 136.4, 135.3, 134.6, 131.0, 129.6, 128.9, 128.6, 128.4, 128.3, 127.7, 127.3, 127.3, 127.1, 125.7, 125.5, 121.4, 119.0; HRMS (ESI) calcd for C₂₈H₁₇BrClN₂O (M + H⁺), 511.0213; Found: 511.0233; IR (cm⁻¹) ν 2927, 1705, 1617, 1541, 1479, 1444, 1287, 1217, 885, 828, 696.

5,6-Diethyl-3-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3p). White solid (yield 98%), mp: 103–104 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 7.76–7.73 (m, 2H), 7.48 (s, 1H), 7.40 (t, J = 6.4 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 3.23 (q, J = 7.2 Hz, 2H), 2.91 (q, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.4, 147.7, 146.8, 142.4, 137.5, 134.0, 132.7, 128.7, 127.5, 126.7, 126.4, 125.1, 125.0, 124.6, 123.0, 120.0, 23.5, 22.1, 20.5, 14.5, 14.2; HRMS (ESI) calcd for C₂₁H₂₀N₂NaO (M + Na⁺) 339.1473; Found: 339.1493; IR (cm⁻¹) ν 2964, 2873, 1684, 1603, 1541, 1468, 1296, 1180, 820, 764, 698.

3-Methyl-5,6-dip-tolyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3q). White solid (yield 93%), mp: 298–299 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.96–6.93 (m, 7H), 2.36 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.5, 147.8, 147.1, 142.6, 136.7, 136.2, 135.3, 134.3, 134.2, 132.6, 131.0, 129.6, 128.9, 128.7, 128.3, 128.0, 127.7, 127.2, 127.1, 126.6, 126.2, 125.2, 124.9, 120.2, 22.0, 21.4, 21.3; HRMS (ESI) calcd for C₃₁H₂₄N₂NaO (M + Na⁺), 463.1786; Found, 463.1791; IR (cm⁻¹) ν 2921, 1706, 1602, 1542, 1491, 1467, 1291, 1123, 831, 769, 694.

5,6-Bis(4-methoxyphenyl)-3-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3r). White solid (yield 90%), mp: 276–278 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.42–7.35 (m, 2H), 6.99–6.95 (m, 5H), 6.82 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6, 158.5, 158.0, 147.8, 147.1, 142.6, 135.4, 134.4, 134.3, 132.2, 129.7, 129.6, 129.6, 127.9, 127.5, 127.1, 127.1, 126.6, 126.1, 125.2, 124.9, 120.2, 113.5, 112.7, 55.2, 55.0, 22.0; HRMS (ESI) calcd for C₃₁H₂₅N₂O₃ (M + H⁺), 473.1865; Found, 473.1894; IR (cm⁻¹) ν 2923, 1701, 1601, 1545, 1510, 1468, 1289, 1247, 1176, 830, 768, 694.

5,6-Bis(4-fluorophenyl)-3-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3s). White solid (yield 90%), mp 249–250 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.81–7.77 (m, 2H), 7.43–7.36 (m, 2H), 7.05–6.95 (m, 6H), 6.85–6.81 (m, 3H), 2.34 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.9 (d, ¹J_CF = 246 Hz), 161.4 (d, ¹J_CF = 245 Hz), 161.2, 147.4, 146.9, 142.9, 134.7, 134.5, 133.6, 133.1 (d, ⁴J_CF = 4 Hz), 132.8 (d, ³J_CF = 8.0 Hz), 131.4 (d, ⁴J_CF = 3 Hz), 130.2 (d, ³J_CF = 8.0 Hz), 130.1, 127.2, 127.1, 127.1, 126.8, 125.9, 125.5, 124.9, 120.0, 115.3 (d, ²J_CF = 21 Hz), 114.5 (d, ²J_CF = 22 Hz), 22.0; HRMS (ESI) calcd for C₂₉H₁₉F₂N₂O (M + H⁺), 449.1465; Found, 449.1488; IR (cm⁻¹) ν 2921, 1681, 1600, 1548, 1508, 1467, 1293, 1223, 858, 778, 696.

5,6-Bis(4-chlorophenyl)-3-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3t). Light yellow solid (yield 88%), mp: 256–257 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.84–7.76 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 6.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 9.6 Hz, 4H), 6.84 (s, 1H), 2.35 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.2, 147.3, 146.9, 143.0, 135.5, 134.6, 133.8, 133.6, 133.3, 132.8, 132.4, 131.0, 130.2, 129.7, 128.9, 128.6, 127.7, 127.3, 127.1, 126.8, 125.9, 125.6, 125.0, 119.9, 22.0; HRMS (ESI), calcd for C₂₉H₁₉Cl₂N₂O (M + H⁺), 481.0874; Found: 481.0883; IR (cm⁻¹) ν 2927, 1708, 1602, 1542, 1489, 1467, 1291, 1095, 831, 768, 697.

2-Methyl-5,6-diphenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (5a). White solid (yield 49%), mp: 214–215 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 7.73–7.71 (m, 1H), 7.54–7.52 (m, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.27–7.25 (m, 2H), 7.13–7.10 (m, 3H), 7.08–7.06 (m, 4H), 2.58 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.4, 147.6, 146.9, 138.7, 137.1, 135.7, 134.4, 133.4, 132.3, 131.7, 131.1, 131.0, 128.9, 128.5, 128.0, 127.8, 127.2, 127.2, 126.9, 126.8, 126.7, 126.3, 125.6, 120.2, 21.7; HRMS (ESI) calcd for C₂₉H₂₁N₂O (M + H⁺), 413.1654; Found, 413.1653; IR (cm⁻¹) ν 2920, 1694, 1604, 1548, 1471, 1445, 1286, 1127, 770, 697.

5-(4-Methoxyphenyl)-3-methyl-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (7a). White solid, mp: 226–227 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.97 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.86–7.79 (m, 2H), 7.41 (t, J = 8.4 Hz, 2H), 7.31–7.24 (m, 3H), 7.10–7.04 (m, 2H), 6.97–6.95 (m, 3H), 6.65 (d, J = 8.0 Hz, 2H), 3.72 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6, 158.1, 147.8, 147.0, 142.7, 135.8, 135.1, 134.4, 134.0, 131.2, 129.7, 129.5, 128.1, 127.8, 127.1, 127.1, 126.7, 126.1, 125.3, 124.9, 120.2, 112.7, 55.0, 22.0; HRMS (ESI) calcd for C₃₀H₂₃N₂O₂ (M + H⁺), 443.1760; Found, 443.1736; IR (cm⁻¹) ν 2930, 1699, 1605, 1545, 1492, 1467, 1293, 1246, 832, 779, 696.

6-(4-Methoxyphenyl)-3-methyl-5-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (7b). White solid, mp: 272–273 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.15–7.13 (m, 3H), 7.07–7.04 (m, 2H), 6.98 (d, J = 8.8 Hz, 3H), 6.81 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.4, 158.5, 147.7, 147.0, 142.7, 137.3, 135.5, 134.4, 134.3, 132.2, 131.0, 129.8, 128.9, 128.5, 127.6, 127.2, 127.1, 126.8, 126.7, 126.2, 125.3, 124.9, 120.1, 113.5, 55.2, 22.0; HRMS (ESI) calcd for C₃₀H₂₃N₂O₂ (M + H⁺), 443.1760; Found, 443.1736; IR (cm⁻¹) ν 2926, 1704, 1602, 1545, 1511, 1468, 1292, 1248, 828, 768, 694.

3,6-Dimethyl-5-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (9a). White solid, mp: 185–186 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.88 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.84–7.81 (m, 2H), 7.53 (t, J = 7.2 Hz, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 6.8 Hz, 2H), 6.80 (s, 1H), 2.50 (s, 3H), 2.35 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.7, 147.8, 147.1, 142.4, 137.2, 134.3, 134.2, 133.5, 130.7, 129.0, 128.9, 128.8, 128.0, 127.1, 126.9, 126.7, 125.5, 125.3, 124.6, 120.2, 21.9, 14.1; HRMS (ESI) calcd for C₂₄H₁₉N₂O (M + H⁺), 351.1497; Found: 351.1492; IR (cm⁻¹) ν 2917, 1701, 1606, 1537, 1491, 1466, 1296, 828, 774, 697.

3,5-Dimethyl-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (9b). White solid, mp: 205–206 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.49–7.39 (m, 4H), 7.35 (t, J = 7.6 Hz, 1H), 7.31 (d, 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.0, 147.4, 147.0, 142.6, 138.0, 134.3, 134.1, 133.8, 129.5, 128.6, 127.8, 127.4, 127.3, 127.1, 126.6, 125.1, 125.0, 123.9, 120.2, 119.9, 22.1, 15.1; HRMS (ESI) calcd for C₂₄H₁₉N₂O (M + H⁺), 351.1497; Found, 351.1492; IR (cm⁻¹) ν 2946, 1701, 1625, 1537, 1467, 1446, 1314, 828, 774, 642.

(E)-3-(1,2-Diphenylvinyl)-2-propylquinazolin-4(3H)-one (12). White solid, mp: 151–152 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 6.8 Hz, 3H), 7.37 (d, J = 8.0 Hz, 3H), 7.26 (t, J = 6.8 Hz, 3H), 7.23–7.18 (m, 3H), 6.84 (d, J = 7.2 Hz, 1H), 2.94 (t, J = 8.0 Hz, 2H), 1.94 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.8, 166.1, 152.2, 150.4, 135.6, 134.0, 133.3, 132.6, 130.5, 129.4, 129.3, 129.2, 128.3, 127.9, 122.8, 119.5, 117.5, 111.6, 42.1, 22.4, 14.1; HRMS (ESI) calcd for C₂₅H₁₉N₂O (M + H⁺), 351.1497; Found, 351.1492; IR (cm⁻¹) ν 2927, 1642, 1580, 1466, 1349, 1214, 1137, 832, 774, 604.

Acknowledgements

Financial support from National Natural Science Foundation of China (no. 21162012, 81261120413, and 21362014), Jiangxi Provincial Department of Science and Technology (for Jiangxi's Key Laboratory of Green Chemistry, and no. 20122BAB203007), Jiangxi Educational Committee (GJJ10386), and Foundation for Young People (Yang Qin) of Jiangxi Normal University is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Characterization data, ¹H and ¹³C NMR spectra of all compounds, X-ray data for compounds 3a, 7b, and 9b (CIF). CCDC 962573–962575. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41955j

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