Synthesis 2019; 51(02): 500-507
DOI: 10.1055/s-0037-1610910
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Isoquinoline-Fused Quinazolinones through Ag(I)-Catalyzed Cascade Annulation of 2-Aminobenzamides and 2-Alkynylbenzaldehydes

Amol D. Sonawane
a  Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
,
Yunnus B. Shaikh
a  Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
,
Dinesh R. Garud
b  Department of Chemistry, Sir Parashurambhau College, Tilak road, Pune 411030, India   Email: [email protected]
,
Mamoru Koketsu*
a  Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
› Author Affiliations
This study was supported by JSPS KAKENHI Grant Number 17550099 to M.K.
Further Information

Publication History

Received: 31 July 2018

Accepted after revision: 23 August 2018

Publication Date:
21 September 2018 (online)

 


Abstract

A new route for the expedient synthesis of a specific regioisomer of isoquinoline-fused quinazolinones is reported. Silver(I)-catalyzed cascade cyclization of 2-aminobenzamides and 2-alkynylbenzaldehydes followed by in situ oxidation gives 12-butyl- or 12-aryl-6H-isoquinolino[2,1-a]quinazolin-6-ones in 69–91% yields. The structure of the isoquinoline-fused quinazolinone was confirmed by X-ray crystallography analysis.


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Over the past few decades, transition-metal-catalyzed C–H bond functionalizations for C–C bond formation have proved to be a powerful method for the construction of complex chemical compounds[2] in an atom- and step-economic manner.[3] To date these transformations are widely used in the area of synthesis of both natural products and therapeutic agents. Among the transition-metal-catalyzed organic transformations, Ag-catalyzed C–H/C–C bond functionalization is one of the frontier areas in organic chemistry.[4] Compared with other transition metals such as gold or platinum, Ag(I) salts represent an inexpensive alternative for the electrophilic activation of alkynes under mild conditions.[4e] [5] Thus, the development of new systems catalyzed by Ag(I) for C–H/C–C functionalization represents a central challenge for the construction of various types of fused N-heterocycles. Nitrogen-containing heterocycles are important molecular motifs in natural products, materials, and bioactive molecules.[6] In this regard, quinazolinone derivatives represent a class of privileged N-heterocyclic motifs present in a broad range of alkaloid natural products.[7] Furthermore, they also show a wide range of biological activities.[8] [9] Much effort has focused on synthetic methods for ring-fused quinazolinone derivatives.[10] In particular, synthetic strategies for ring-fused quinazolinones, as the core structural skeletons in a variety of natural products and pharmaceutical molecules, have been intensely explored in recent years. Isoquinolines are ubiquitous structural motif present in a numerous biologically active natural products and pharmaceutically important compounds.[11] Molecular skeletons that integrate isoquinoline and quinazolinone moieties might possess the properties of both and enhance their activity.[12]

Several reports are available for the synthesis of isoquinoline-fused quinazolinones.[13] Pal and co-workers reported the synthesis of 4b,5-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-ones via one-pot Yb(III)-mediated cascade reaction [Scheme [1] (A)].[14] Patil and co-workers reported Au(I)-catalyzed synthesis of optically pure 4b,5-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-ones [Scheme [1] (B)][15] and Yan and co-workers used the Ir-catalyzed intramolecular acceptorless dehydrogenative cross-coupling of tertiary amines and amides for the synthesis of 12,13-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-ones [Scheme [1] (C)].[13f] However, some of these procedures have significant drawbacks, such as low yield, long reaction times, harsh reaction conditions, and the use of expensive reagents. In an effort to synthesize N-fused heterocycles by a transition-metal-catalyzed C–C functionalization, herein we report, the synthesis of isoquinoline-fused quinazolinones via a AgNO3-catalyzed one-pot cascade cyclization of 2-aminobenz­amides and 2-alkynylbenzaldehydes through an oxidation process.

Zoom Image
Scheme 1 Approaches for the synthesis of quinazolinones

In the synthesis of isoquinoline-fused quinazolinones, the fusion of quinazolinone ring may occur in two different ways (linear and angular) for two different types of nitrogen atoms that would lead to the formation of two regioisomers. Both of the isomers should have certain unique pharmacological features. Therefore, a synthetic method that can exclusively provide a single regioisomer instead of a mixture is highly desirable. With this in mind, we initially began with reaction optimization conditions with 2-aminobenzamide (1a) and 2-(phenylethynyl)benzaldehyde (2a) as model substrates (Table [1]). We initially subjected compounds 1a and 2a in an equimolar ratio to oxidative conditions using 30 mol% of AgOTf in DMSO solvent at 100 °C for 5 hours (Table [1], entry 1). To our delight, the reaction was very much regioselective and only a single regioisomer 4a was formed (from TLC) as confirmed by NMR in low yield (29%).

Zoom Image
Figure 1 X-ray crystal structure of 4a (ORTEP diagram); thermal ellipsoids are drawn at 50% probability level

Table 1 Optimization of the Synthesis of 12-Phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4a)a

Entry

Ag catalyst 3 (mol%)

Solvent

Time (h)

Temp (°C)

Yieldb (%)

 1

AgOTf (30)

DMSO

 5

100

29

 2

AgOTf (30)

DMSO

 4

120

54

 3

AgOTf (10)

DMSO

 8

120

43

 4

AgOTf (20)

DMSO

 4

120

73

 5

Ag2O (20)

DMSO

 6

120

 9

 6

AgClO4 (20)

DMSO

 6

120

33

 7

AgPF6 (20)

DMSO

 6

120

 5

 8

AgNO3 (2)

DMSO

10

120

77

 9

AgNO3 (5)

DMSO

 9

120

82

10

AgNO3 (20)

DMSO

 6

120

89

11

AgNO3 (20)

DMSO

 6

120

13c

12

AgNO3 (20)

DMF

 6

120

42

13

AgNO3 (20)

DMAd

 6

120

58

14

AgNO3 (20)

toluene

 6

110

34

a Reaction conditions: 2-aminobenzamide (1a; 0.242 mmol), 2-(phenylethynyl)benzaldehyde (2a; 0.242 mmol); solvent (4 mL), open flask.

b Isolated yield.

c Reaction was carried out under N2 atmosphere. 4a was obtained together with 12-phenyl-4b,5-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-one (72%).

d DMA = dimethylacetamide.

Next, the yield of compound 4a was increased to 54% by increasing the temperature to 120 °C (entry 2). However, the use of 10 mol% AgOTf in the reaction at this temperature resulted in a decrease in the product yield to 43% (entry 3). A significant improvement in the yield was observed when 20 mol% of AgOTf was used in the reaction and the desired product was isolated in 73% yield (entry 4). On the other hand, the use of Ag2O and AgPF6 catalysts in the reaction afforded desired product 4a in 9% and 5% yields, respectively (entries 5 and 7); AgClO4 yielded only 33% of product 4a (entry 6). To improve the yield of the reaction, different solvents were screened with 20 mol% of AgNO3 (entries 10, 12–14) and the best result was obtained when the reaction was carried out in DMSO solvent at 120 °C which provided required product 4a in 89% yield (entry 10). Also, we carried out reaction of 2-aminobenzamide (1a) and 2-(phenylethynyl)benzaldehyde (2a) under a nitrogen atmosphere (entry 11), interestingly we obtained unaromatized 12-phenyl-4b,5-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-one[15] in 72% yield and only 13% of the required product 4a.

Next, to assess the substrate scope and generality of the newly developed AgNO3-catalyzed cascade reaction, a variety of 2-alkynylbenzaldehydes 2 bearing different variously substituted alkynyl groups and/or substitution on the benzaldehyde ring and a range of 2-aminobenzamides 1 were employed under the optimized reaction conditions (Scheme [2]). As shown in Scheme [2], 2-alkynylbenzaldehydes 2 with alkynyl groups bearing a variety of substituents, such as butyl, phenyl, 4-methoxyphenyl, and 4-fluoro-3-methylphenyl, and/or the benzaldehyde ring containing electron-withdrawing halide groups or electron-donating methoxy groups were well tolerated under the present reaction conditions and afforded the desired isoquinoline-fused quinazolinones 4an in good to excellent yields (Scheme [2, 69–91]%). Electron-donating groups on the benzaldehyde aromatic ring were also well tolerated. The presence of an electron-withdrawing halide group in the 2-aminobenzamide ring also did not make a significant difference to the yield. The synthesized compounds 4an were characterized by IR, HRMS, 1H and 13C NMR spectral analysis.

Finally, the regioselectivity achieved through Ag(I)-catalyzed cascade annulation of 2-aminobenzamides and 2-alkynylbenzaldehydes in the synthesis of isoquinoline-fused quinazolinones 4 was confirmed by X-ray crystallography analysis. The crystal structure of the representative compound 12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4a) was confirmed by the X-ray crystallography analysis (Figure [1]).[16]

A plausible mechanism for the formation of isoquinoline-fused quinazolinones 4 is presented in Scheme [3]. The reaction of 2-aminobenzamide 1 and 2-alkynylbenzaldehyde 2 gives an imine in which the C≡C bond coordinates to the Ag catalyst to give intermediate I. Intermediate I on 6-endo-dig cyclization via protodemetalation delivers intermediate II. Finally, in situ oxidation of intermediate II delivers the desired isoquinoline-fused quinazolinone derivative 4 and regenerates the silver catalyst for a new catalytic ­cycle.

Zoom Image
Scheme 2 Synthesis of 12-substituted 6H-isoquinolino[2,1-a]quinazolin-6-one derivatives 4 via AgNO3 catalyst. Reagents and conditions: 2-aminobenz­amide 1 (0.24 mmol), 2-alkynylbenzaldehyde 2 (0.24 mmol), AgNO3 (20 mol%), DMSO, 120 °C; isolated yields are given.
Zoom Image
Scheme 3 Plausible mechanism for the formation of isoquinoline-fused quinazolinones

In summary, we developed a novel AgNO3-catalyzed cascade cyclization of 2-aminobenzamides and 2-alkynylbenzaldehydes which underwent in situ oxidation to deliver isoquinoline-fused quinazolinone derivatives in good to excellent yields. This novel synthetic approach is amenable to the generation of a library of isoquinoline-fused quinazolinone analogues. Further expansion of the current strategies and evaluation of biological activities are in progress.

All solvents and reagents were purchased from the suppliers and used without further purification. IR spectra were recorded on a JASCO FT/IR-460 Plus spectrophotometer. Reactions were monitored by TLC on silica plates using UV-light or I2 chamber for visualization. Evaporation and condensation were carried out in vacuo. NMR spectra were recorded with JEOL JNM-ECS 400 spectrometers with TMS as an internal standard. The data of all known compounds data are consistent with the literature reports. Scale up reactions also performed as per the given general procedure without any deviation. Melting points were measured by a Yanaco micro melting point apparatus.


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2-(Phenylethynyl)benzaldehyde (2a); Typical Procedure[17]

To a solution of 2-bromobenzaldehyde (500 mg, 2.7 mmol, 1 equiv) in THF (10 mL) were added PdCl2(PPh3)2 (95 mg, 5 mol%) and Et3N (820 mg, 8.1 mmol, 3 equiv); the resulting mixture was stirred and purged with N2 gas for 10 min. Then phenylacetylene (414 mg, 4.054 mmol, 1.5 equiv) and CuI (26 mg, 5 mol%) were added. The mixture was further stirred under N2 gas at r.t. for 24 h. After completion, the reaction was quenched with sat. NH4Cl and extracted with EtOAc. Organic layer was washed with brine, dried (Na2SO4), and evaporated. The crude residue was purified by chromatography (silica gel, EtOAc/n-hexane 3:97) to afford 2a (347 mg, 62%) as a brown oil. Spectroscopic data are consistent with those previously reported.[17]


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12-Butyl- or 12-Aryl-6H-isoquinolino[2,1-a]quinazolin-6-ones 4; General Procedure

To a solution of 2-aminobenzamide 1 (0.24 mmol, 1 equiv) and 2-alkynylbenzaldehyde 2 (0.24 mmol, 1 equiv) in DMSO (4 mL) was added AgNO3 (8 mg, 20 mol%). The resulting mixture was then heated at 120 °C for 4 h. After completion of the reaction, the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography (silica gel, acetone/hexane 20:80) to afford the product.


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12-Phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4a)

White solid; yield: 70 mg (89%); mp 211–213 °C.

IR (neat): 2999, 1655, 1630, 1599, 1586, 1561, 1479, 1467, 1254, 1179, 1136, 1066, 858, 832, 752, 676, 580, 542 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.69 (d, J = 8.1 Hz, 1 H), 8.08 (d, J = 6.7 Hz, 1 H), 7.87 (d, J = 4.0 Hz, 2 H), 7.71 (q, J = 3.9 Hz, 1 H), 7.50 (d, J = 3.6 Hz, 2 H), 7.40–7.46 (m, 5 H), 7.31 (t, J = 7.2 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 166.44, 153.40, 138.49, 138.23, 136.86, 133.54, 130.44, 129.10, 128.91, 128.70, 127.48, 127.02, 126.79, 126.70, 126.49, 125.30, 122.28, 122.19, 117.16.

HRMS (ESI): m/z [M + H]+ calcd for C22H15N2O: 323.1184; found: 323.1155.


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12-(4-Methoxyphenyl)-6H-isoquinolino[2,1-a]quinazolin-6-one (4b)

Yellow solid; yield: 62 mg (83%); mp 235–236 °C.

IR (neat): 3067, 2905, 1651, 1626, 1602, 1523, 1510, 1337, 1258, 1023, 831, 822, 772, 762, 544 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.65 (d, J = 8.1 Hz, 1 H), 8.05 (d, J = 6.3 Hz, 1 H), 7.82 (d, J = 5.4 Hz, 2 H), 7.63–7.67 (m, 1 H), 7.39–7.45 (m, 3 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.27 (s, 1 H), 6.97 (dd, J = 14.8, 8.5 Hz, 3 H), 3.77 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 166.43, 159.57, 153.43, 138.40, 138.36, 133.71, 133.44, 130.35, 129.16, 128.90, 128.31, 126.73, 126.60, 126.43, 125.09, 122.20, 122.13, 116.15, 114.44, 55.28.

HRMS (ESI): m/z [M + Na]+ calcd for C23H16N2O2Na: 375.1109; found: 375.1133.


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12-Butyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4c)

Brown solid; yield: 60 mg (74%); mp 95–96 °C.

IR (neat): 2931, 2872, 1647, 1634, 1603, 1592, 1516, 1456, 1343, 1271, 1189, 1114, 1066, 787, 759, 710, 544 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.58 (d, J = 8.1 Hz, 1 H), 8.14 (dd, J = 7.9, 1.6 Hz, 1 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.74–7.83 (m, 3 H), 7.60–7.66 (m, 2 H), 7.27 (s, 1 H), 3.12 (t, J = 7.6 Hz, 2 H), 1.37–1.44 (m, 2 H), 1.08–1.16 (m, 2 H), 0.72 (t, J = 7.4 Hz, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 166.22, 153.40, 140.10, 137.75, 133.76, 133.34, 131.57, 127.89, 127.42, 126.60, 126.53, 126.03, 124.60, 122.32, 121.39, 114.50, 33.67, 30.98, 21.50, 13.48.

HRMS (ESI): m/z [M + H]+ calcd for C20H19N2O: 303.1497; found: 303.1469.


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12-(4-Fluoro-3-methylphenyl)-6H-isoquinolino[2,1-a]quinazolin-6-one (4d)

Brown solid; yield: 63 mg (85%); mp 86–87 °C.

IR (neat): 3015, 1651, 1646, 1629, 1519, 1362, 1215, 1157, 1033, 824, 754, 666, 645, 537 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.95 (d, J = 8.1 Hz, 1 H), 8.33 (d, J = 8.1 Hz, 1 H), 7.75 (t, J = 7.0 Hz, 1 H), 7.61 (dd, J = 13.0, 7.6 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.22–7.29 (m, 2 H), 7.10 (s, 1 H), 6.97–7.03 (m, 3 H), 2.27 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 168.03, 162.79, 160.26, 154.24, 138.50, 137.89, 133.57, 132.80, 130.65, 130.32, 130.26, 128.75, 128.20, 127.72, 126.88, 126.54, 126.46, 126.40, 125.99, 122.45, 122.03, 117.53, 116.23, 116.00, 14.76, 14.72.

HRMS (ESI): m/z [M + Na]+ calcd for C23H15N2OFNa: 377.1066; found: 377.1096.


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2,3-Dimethoxy-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4e)

Yellow solid; yield: 56 mg (78%); mp 209–211 °C.

IR (neat): 3061, 1644, 1621, 1602, 1495, 1416, 1368, 1195, 1131, 991, 752, 698, 641, 529, 501 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 12.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 6 H), 7.20 (t, J = 7.9 Hz, 1 H), 7.01 (q, J = 8.7 Hz, 3 H), 4.09 (s, 3 H), 4.05 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 168.13, 154.63, 153.62, 150.59, 138.61, 137.68, 137.25, 130.43, 129.52, 129.43, 128.96, 127.70, 127.21, 126.68, 122.50, 122.31, 120.11, 117.53, 108.19, 106.56, 56.80, 56.41.

HRMS (ESI): m/z [M + Na]+ calcd for C24H18N2O3Na: 405.1215; found: 405.1226.


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12-Butyl-2,3-dimethoxy-6H-isoquinolino[2,1-a]quinazolin-6-one (4f)

Brown sticky liquid; yield: 60 mg (81%).

IR (neat): 2934, 2961, 1719, 1630, 1604, 1592, 1439, 1398, 1340, 1267, 1226, 1166, 1064, 1032, 998, 878, 862, 771, 755, 664, 644 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.42 (d, J = 7.6 Hz, 1 H), 8.28 (s, 1 H), 7.66 (d, J = 3.6 Hz, 2 H), 7.55–7.60 (m, 1 H), 6.94 (d, J = 5.8 Hz, 2 H), 4.06 (s, 3 H), 4.04 (s, 3 H), 3.13 (t, J = 7.6 Hz, 2 H), 1.47–1.54 (m, 2 H), 1.17–1.25 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 168.03, 154.56, 153.76, 150.11, 138.66, 138.30, 131.03, 129.78, 128.10, 127.24, 123.04, 120.72, 119.50, 115.18, 107.99, 105.88, 56.77, 56.37, 34.71, 32.31, 22.23, 13.78.

HRMS (ESI): m/z [M + H]+ calcd for C22H23N2O3: 363.1709; found: 363.1679.


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8-Bromo-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4g)

Yellow solid; yield: 21 mg (91%); mp 218–219 °C.

IR (neat): 3027, 1772, 1630, 1508, 1482, 1491, 1317, 1250, 1183, 1168, 895, 814, 712, 638, 529 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.69 (d, J = 8.1 Hz, 1 H), 8.14 (d, J = 2.2 Hz, 1 H), 7.88 (q, J = 1.8 Hz, 2 H), 7.69–7.74 (m, 1 H), 7.49–7.55 (m, 3 H), 7.42–7.45 (m, 4 H), 6.91 (d, J = 9.4 Hz, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 165.22, 153.56, 138.32, 137.40, 136.57, 133.75, 133.60, 133.02, 129.22, 129.07, 128.82, 128.55, 127.52, 127.07, 126.91, 125.16, 124.64, 123.84, 119.46, 117.40.

HRMS (ESI): m/z [M + H]+ calcd for C22H14N2OBr: 401.0289; found: 401.0300.


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8-Bromo-12-(4-methoxyphenyl)-6H-isoquinolino[2,1-a]quinazo­lin-6-one (4h)

Yellow solid; yield: 23 mg (85%); mp 254–256 °C.

IR (neat): 1648, 1628, 1603, 1506, 1478, 1317, 1277, 1248, 1163, 1122, 1026, 890, 833, 813, 793, 618, 540 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 8.66 (d, J = 8.1 Hz, 1 H), 8.12 (d, J = 2.2 Hz, 1 H), 7.86 (dd, J = 14.6, 8.3 Hz, 2 H), 7.66–7.70 (m, 1 H), 7.53 (dd, J = 9.2, 2.5 Hz, 1 H), 7.46 (d, J = 9.0 Hz, 2 H), 7.33 (d, J = 7.2 Hz, 1 H), 6.94–7.00 (m, 3 H), 3.79 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 165.25, 159.70, 153.62, 138.30, 137.56, 133.79, 133.69, 132.99, 129.03, 128.91, 128.50, 126.87, 124.98, 124.54, 123.89, 119.41, 116.43, 114.58, 55.31.

HRMS (ESI): m/z [M + H]+ calcd for C23H16N2O2Br: 431.0395; found: 431.0394.


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9-Chloro-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4i)

Yellow solid; yield: 76 mg (88%); mp 268–270 °C.

IR (neat): 3170, 3040, 1707, 1646, 1629, 1586, 1509, 1474, 1302, 1067, 869, 843, 832, 756, 705, 681, 547 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.99 (d, J = 7.6 Hz, 1 H), 8.29 (d, J = 8.5 Hz, 1 H), 7.77–7.81 (m, 1 H), 7.66 (t, J = 7.2 Hz, 2 H), 7.46 (t, J = 3.4 Hz, 3 H), 7.36–7.39 (m, 3 H), 7.12 (s, 1 H), 6.96 (d, J = 1.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 167.24, 154.53, 139.20, 138.44, 137.04, 136.31, 133.79, 133.53, 129.61, 129.51, 129.19, 128.96, 128.35, 127.37, 127.21, 126.47, 125.87, 122.12, 120.72, 117.88.

HRMS (ESI): m/z [M + H]+ calcd for C22H14N2OCl: 357.0795; found: 357.0770.


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9-Chloro-12-(4-methoxyphenyl)-6H-isoquinolino[2,1-a]quinazo­lin-6-one (4j)

Yellow solid; yield: 71 mg (87%); mp 177–178 °C.

IR (neat): 3066, 3000, 1655, 1630, 1599, 1586, 1479, 1467, 1316, 1254, 1136, 1098, 833, 788, 754, 663, 453 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.93 (d, J = 7.6 Hz, 1 H), 8.25 (d, J = 8.5 Hz, 1 H), 7.75 (t, J = 7.4 Hz, 1 H), 7.60 (t, J = 8.8 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.00 (d, J = 9.0 Hz, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 3.86 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 167.25, 160.48, 154.63, 139.36, 138.34, 136.93, 133.72, 129.13, 128.61, 128.28, 127.29, 126.29, 125.69, 122.09, 120.76, 116.99, 114.96, 55.53.

HRMS (ESI): m/z [M + Na]+ calcd for C23H15N2O2ClNa: 409.0720; found: 409.0749.


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12-Butyl-9-chloro-6H-isoquinolino[2,1-a]quinazolin-6-one (4k)

Brownish sticky liquid; yield: 63 mg (69%).

IR (neat): 2960, 2873, 1719, 1561, 1479, 1466, 1450, 1423, 1340, 1316, 1266, 1155, 913, 876, 780, 564, 515 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.86 (d, J = 8.1 Hz, 1 H), 8.34 (d, J = 8.5 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.67 (s, 1 H), 7.54–7.60 (m, 3 H), 7.00 (s, 1 H), 3.10 (t, J = 7.9 Hz, 2 H), 1.50–1.58 (m, 2 H), 1.27 (d, J = 7.2 Hz, 2 H), 0.83–0.90 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 167.10, 154.62, 139.18, 138.87, 137.60, 133.68, 133.57, 129.63, 128.28, 128.01, 127.78, 125.67, 125.36, 121.21, 120.34, 115.85, 34.34, 32.02, 22.07, 13.64.

HRMS (ESI): m/z [M + H]+ calcd for C20H18N2OCl: 337.1108; found: 337.1097.


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9-Chloro-12-(4-fluoro-3-methylphenyl)-6H-isoquinolino[2,1-a]quinazolin-6-one (4l)

Brown solid; yield: 66 mg (81%); mp 252–254 °C.

IR (neat): 3139, 3033, 1637, 1597, 1583, 1511, 1501, 1481, 1444, 1318, 1128, 1120, 833, 809, 772, 754, 611 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.97 (d, J = 7.6 Hz, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 7.77–7.81 (m, 1 H), 7.65 (t, J = 7.2 Hz, 2 H), 7.39 (dd, J = 8.3, 1.6 Hz, 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 7.14 (q, J = 2.4 Hz, 1 H), 7.05–7.10 (m, 2 H), 6.99 (d, J = 1.7 Hz, 1 H), 2.30 (d, J = 1.8 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 167.23, 162.94, 160.40, 154.50, 139.14, 137.56, 137.05, 133.83, 133.46, 132.17, 132.13, 130.26, 130.21, 129.24, 128.96, 128.31, 127.44, 126.82, 126.63, 126.49, 126.42, 125.80, 121.96, 120.71, 117.73, 116.41, 116.19, 14.73, 14.70.

HRMS (ESI): m/z [M + H]+ calcd for C23H15N2OClF: 389.0857; found: 389.0827.


#

9-Chloro-2,3-dimethoxy-12-phenyl-6H-isoquinolino[2,1-a]quin­azolin-6-one (4m)

Yellow solid; yield: 67 mg (86%); mp 256–258 °C.

IR (neat): 3061, 3004, 1619, 1584, 1495, 1454, 1393, 1270, 1220, 1195, 1072, 998, 880, 771, 701, 646, 532 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 7.43–7.45 (m, 3 H), 7.34–7.37 (m, 3 H), 7.05 (d, J = 14.8 Hz, 2 H), 6.97 (d, J = 1.3 Hz, 1 H), 4.09 (s, 3 H), 4.05 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 167.38, 154.92, 153.91, 150.77, 139.32, 137.47, 136.91, 136.62, 129.69, 129.56, 129.38, 129.24, 127.30, 127.25, 122.37, 120.83, 119.95, 117.73, 108.29, 106.66, 56.84, 56.46.

HRMS (ESI): m/z [M + H]+ calcd for C24H18N2O3Cl: 417.1006; found: 417.0987.


#

12-Butyl-9-chloro-2,3-dimethoxy-6H-isoquinolino[2,1-a]quin­azolin-6-one (4n)

Yellow solid; yield: 62 mg (77%); mp 96–97 °C.

IR (neat): 2959, 2931, 1634, 1603, 1592, 1516, 1481, 1343, 1271, 1155, 962, 935, 760, 710, 622, 473 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 8.1 Hz, 1 H), 8.25 (s, 1 H), 7.67 (d, J = 1.8 Hz, 1 H), 7.54 (dd, J = 8.5, 1.8 Hz, 1 H), 6.94 (d, J = 6.7 Hz, 2 H), 4.06 (s, 3 H), 4.04 (s, 3 H), 3.10 (t, J = 7.9 Hz, 2 H), 1.51–1.58 (m, 2 H), 1.26 (td, J = 14.7, 7.5 Hz, 2 H), 0.85 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 167.26, 154.80, 154.05, 150.26, 139.04, 138.22, 137.44, 129.77, 129.73, 127.72, 121.36, 120.57, 119.34, 115.66, 108.05, 105.99, 56.78, 56.41, 34.49, 32.29, 22.19, 13.77.

HRMS (ESI): m/z [M + Na]+ calcd for C22H21N2O3ClNa: 419.1138; found: 419.1145.


#
#

Supporting Information

  • References

  • 1 Affiliated to Savitribai Phule Pune University, Pune 411007 India (formerly University of Pune).

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    • 2m Deiters A. Martin SF. Chem. Rev. 2004; 104: 2199
    • 2n Zeni G. Larock RC. Chem. Rev. 2004; 104: 2285
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      For perspectives on atom-, step-, and redox-economy, respectively, see
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    • 7g List B. Synlett 2001; 1675
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      For selected examples, see:
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    • 8f Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem. 1990; 33: 161
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    • 8h Horton DA. Bourne GT. Smythe ML. Chem. Rev. 2003; 103: 893
    • 8i Steinmuller SR. Puschett JB. Kidney Int. 1972; 1: 169
    • 8j Abbas SE. Awadallah FM. Ibrahin NA. Said EG. Kamel GM. Eur. J. Med. Chem. 2012; 53: 141
    • 8k Rudolph J. Esler WP. Connor SO. Coish PD. Wickens PL. Brands M. Bierer DE. Bloomquist BT. Bondar G. Chen L. J. Med. Chem. 2007; 50: 5202
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    • 8m Aly MM. Mohamed YA. El-Bayouki KA. Basyouni WM. Abbas SY. Eur. J. Med. Chem. 2010; 45: 3365
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      Reviews on quinazolinone alkaloids:
    • 9a Abdou IM. Al-Neyadi SS. Heterocycl. Commun. 2015; 21: 115
    • 9b Khan I. Ibrar A. Abbas N. Saeed A. Eur. J. Med. Chem. 2015; 90: 124
    • 9c He L. Li H. Chen J. Wu X.-F. RSC Adv. 2014; 4: 12065

      For selected examples, see:
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    • 10b Witt A. Bergman J. Curr. Org. Chem. 2003; 7: 659
    • 10c Ma Z. Hano Y. Nomura T. Heterocycles 2005; 65: 2203
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    • 10e Demeunynck M. Baussanne I. Curr. Med. Chem. 2013; 20: 794
    • 10f Khan I. Ibrar A. Abbas N. Saeed A. Eur. J. Med. Chem. 2014; 76: 193
    • 10g Duan F. Liu M. Chen J. Ding J. Hu Y. Wu H. RSC Adv. 2013; 3: 24001
    • 11a Bentley KW. Nat. Prod. Rep. 2006; 23: 444
    • 11b Bentley KW. Nat. Prod. Rep. 2005; 22: 249
    • 11c Chrzanowska M. Rozwadowska MD. Chem. Rev. 2004; 104: 3341
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  • 16 CCDC 1819564 for 4a contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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  • References

  • 1 Affiliated to Savitribai Phule Pune University, Pune 411007 India (formerly University of Pune).

    • For reviews, see:
    • 2a Gladysz JA. Chem. Rev. 2011; 111: 1167
    • 2b Transition Metals for Organic Synthesis . Beller M. Bolm C. Wiley-VCH; New York: 2004
    • 2c Metal-Catalyzed Cross-Coupling Reactions . de Meijere A. Diederich F. Wiley-VCH; New York: 2004
    • 2d Organometallics in Process Chemistry . Larsen RD. Springer; Berlin: 2004
    • 2e Chen X. Engle KM. Wang D.-H. Yu J.-Q. Angew. Chem. Int. Ed. 2009; 48: 5094
    • 2f Gutekunst WR. Baran PS. Chem. Soc. Rev. 2011; 40: 1976
    • 2g Stokes BJ. Driver TG. Eur. J. Org. Chem. 2011; 4071
    • 2h Mei T.-S. Kou L. Ma S. Engle KM. Yu JQ. Synthesis 2012; 44: 1778
    • 2i Yamaguchi J. Yamaguchi AD. Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
    • 2j Wencel-Delord J. Glorius F. Nat. Chem. 2013; 5: 369
    • 2k Yoshikai N. Wei Y. Asian J. Org. Chem. 2013; 2: 466
    • 2l Ardkhean RD. Caputo FJ. Morrow SM. Shi H. Xiong Y. Anderson EA. Chem. Soc. Rev. 2016; 45: 1557
    • 2m Deiters A. Martin SF. Chem. Rev. 2004; 104: 2199
    • 2n Zeni G. Larock RC. Chem. Rev. 2004; 104: 2285
    • 2o Nakamura I. Yamamoto Y. Chem. Rev. 2004; 104: 2127

      For perspectives on atom-, step-, and redox-economy, respectively, see
    • 3a Trost BM. Science (Washington, D. C.) 1991; 254: 1471
    • 3b Trost BM. Angew. Chem. Int. Ed. 1995; 34: 259
    • 3c Newhouse T. Baran PS. Hoffmann RW. Chem. Soc. Rev. 2009; 38: 3010
    • 3d Burns NZ. Baran PS. Hoffmann RW. Angew. Chem. Int. Ed. 2009; 48: 2854
    • 4a Weibel J.-M. Blanc A. Pale P. Chem. Rev. 2008; 108: 3149
    • 4b Álvarez-Corral M. Muñoz-Dorado M. Rodríguez García I. Chem. Rev. 2008; 108: 3174
    • 4c Naodovic M. Yamamoto H. Chem. Rev. 2008; 108: 3132
    • 4d Yamamoto Y. Chem. Rev. 2008; 108: 3199
    • 4e Fang G. Bi X. Chem. Soc. Rev. 2015; 44: 8124
    • 4f Silver in Organic Chemistry . Harmata M. Wiley; Hoboken: 2010
    • 4g Rasika Dias HV. Lovely CJ. Chem. Rev. 2008; 108: 3223
    • 4h Munoz MP. Chem. Soc. Rev. 2014; 43: 3164
    • 4i Lo VK.-Y. Chan AO.-Y. Che C.-M. Org. Biomol. Chem. 2015; 13: 6667
    • 4j Sekine K. Yamada T. Chem. Soc. Rev. 2016; 45: 4524
    • 5a Gorin DJ. Toste FD. Nature (London) 2007; 446: 395
    • 5b Fürstner A. Davies PW. Angew. Chem. Int. Ed. 2007; 46: 3410
    • 5c Fürstner A. Chem. Soc. Rev. 2009; 38: 3208
    • 5d Fang G. Cong X. Zanoni G. Liu Q. Bi X. Adv. Synth. Catal. 2017; 359: 1422
    • 5e Liu J. Fang Z. Zhang Q. Liu Q. Bi X. Angew. Chem. Int. Ed. 2013; 52: 6953
    • 5f Liu J. Liu Z. Liao P. Bi X. Org. Lett. 2014; 16: 6204
    • 5g Meng X. Liao P. Liu J. Bi X. Chem. Commun. 2014; 50: 11837
    • 5h Liu J. Liu Z. Wu N. Liao P. Bi X. Chem. Eur. J. 2014; 20: 2154
    • 5i Liu Z. Liu J. Zhang L. Liao P. Song J. Bi X. Angew. Chem. Int. Ed. 2014; 53: 5305
    • 5j Liu Z. Liao P. Bi X. Org. Lett. 2014; 16: 3668
    • 5k Ning Y. Wu N. Yu H. Liao P. Li X. Bi X. Org. Lett. 2015; 17: 2198
    • 5l Huters AD. Quasdorf KW. Styduhar ED. Garg NK. J. Am. Chem. Soc. 2011; 133: 15797
    • 5m Quasdorf KW. Huters AD. Lodewyk MW. Tantillo DJ. Garg NK. J. Am. Chem. Soc. 2012; 134: 1396
    • 6a Majumdar KC. Chattopadhyay SK. Heterocycles in Natural Product Synthesis . Wiley-VCH; Weinheim: 2011
    • 6b Comprehensive Heterocyclic Chemistry III . Katritzky AR. Ramsden CA. Scriven EV. F. Taylor RJ. K. Elsevier; Amsterdam: 2008
    • 6c Lynch MA. Duval O. Sukhanova A. Devy J. MacKay SP. Waigh RD. Nabiev I. Bioorg. Med. Chem. Lett. 2001; 11: 2643
    • 6d Jones G. Abarca B. Adv. Heterocycl. Chem. 2010; 100: 195
    • 6e Chittchang M. Batsomboon P. Ruchirawat S. Ploypradith P. ChemMedChem 2009; 4: 457
    • 6f Padmavathi V. Radha Lakshmi T. Mahesh K. Padmaja A. Chem. Pharm. Bull. 2009; 57: 1200
    • 6g Eamvijarn A. Gomes NM. Dethoup T. Buaruang J. Manoch L. Silva A. Pedro M. Marini I. Roussis V. Kijjoa A. Tetrahedron 2013; 69: 8583
    • 7a Kshirsagar UA. Org. Biomol. Chem. 2015; 13: 9336
    • 7b Ma Z.-Z. Hano Y. Nomura T. Chen Y.-J. Heterocycles 1997; 46: 541
    • 7c Yoshida S. Aoyagi T. Harada S. Matsuda N. Ikeda T. Naganawa H. Hamada M. Takeuchi T. J. Antibiot. 1991; 44: 111
    • 7d Deng Y. Xu R. Ye Y. J. Chin. Pharm. Sci. 2000; 9: 116
    • 7e Wattanapiromsakul C. Forster PI. Waterman PG. Phytochemistry 2003; 64: 609
    • 7f Michael JP. Nat. Prod. Rep. 2004; 21: 650
    • 7g List B. Synlett 2001; 1675
    • 7h Harb HY. Procter DJ. Synlett 2012; 23: 6
    • 7i Müller TJ. J. Synthesis 2012; 44: 159
    • 7j Kocienski P. Synfacts 2012; 8: 5

      For selected examples, see:
    • 8a Cao SL. Feng YP. Jiang YY. S. Liu Y. Ding GY. Li RT. Bioorg. Med. Chem. Lett. 2005; 15: 1915
    • 8b Kung PP. Casper MD. Cook KL. Wilson-Lingardo L. Risen LM. Vickers TA. Ranken R. Blyn LB. Wyatt JR. Cook PD. J. Med. Chem. 1999; 42: 4705
    • 8c De Laszlo SE. Quagliato CS. Greenlee WJ. Patchett AA. Chang RS. L. Lotti VJ. Chen TB. Scheck SA. Faust KA. J. Med. Chem. 1993; 36: 3207
    • 8d Cherm JW. Tao PL. Wang KC. Guicait A. Liu SW. Yen MH. Chien SL. Rong JK. J. Med. Chem. 1998; 41: 3128
    • 8e Malamas MS. Millen J. J. Med. Chem. 1991; 34: 1492
    • 8f Wolfe JF. Rathman TL. Sleevi MC. Campbell JA. Greenwood TD. J. Med. Chem. 1990; 33: 161
    • 8g Mhaske SB. Argade NP. Tetrahedron 2006; 62: 9787
    • 8h Horton DA. Bourne GT. Smythe ML. Chem. Rev. 2003; 103: 893
    • 8i Steinmuller SR. Puschett JB. Kidney Int. 1972; 1: 169
    • 8j Abbas SE. Awadallah FM. Ibrahin NA. Said EG. Kamel GM. Eur. J. Med. Chem. 2012; 53: 141
    • 8k Rudolph J. Esler WP. Connor SO. Coish PD. Wickens PL. Brands M. Bierer DE. Bloomquist BT. Bondar G. Chen L. J. Med. Chem. 2007; 50: 5202
    • 8l Leivers AL. Tallant M. Shotwell JB. Dickerson S. Leivers MR. McDonald OB. Gobel J. Creech KL. Strum SL. Mathis A. J. Med. Chem. 2014; 57: 2091
    • 8m Aly MM. Mohamed YA. El-Bayouki KA. Basyouni WM. Abbas SY. Eur. J. Med. Chem. 2010; 45: 3365
    • 8n Sharma M. Chauhan K. Shivahare R. Vishwakarma P. Suthar MK. Sharma A. Gupta S. Saxena JK. Lal J. Chandra P. J. Med. Chem. 2013; 56: 4374
    • 8o Kamal A. Bharathi EV. Ramaiah MJ. Dastagiri D. Reddy JS. Viswanath A. Sultana F. Pushpavalli S. Pal-Bhadra M. Srivastava HK. Bioorg. Med. Chem. 2010; 18: 526

      Reviews on quinazolinone alkaloids:
    • 9a Abdou IM. Al-Neyadi SS. Heterocycl. Commun. 2015; 21: 115
    • 9b Khan I. Ibrar A. Abbas N. Saeed A. Eur. J. Med. Chem. 2015; 90: 124
    • 9c He L. Li H. Chen J. Wu X.-F. RSC Adv. 2014; 4: 12065

      For selected examples, see:
    • 10a Padala SR. Padi PR. Thipireddy V. Heterocycles 2003; 60: 183
    • 10b Witt A. Bergman J. Curr. Org. Chem. 2003; 7: 659
    • 10c Ma Z. Hano Y. Nomura T. Heterocycles 2005; 65: 2203
    • 10d Connolly DJ. Cusack D. OSullivan TP. Guiry PJ. Tetrahedron 2005; 61: 10153
    • 10e Demeunynck M. Baussanne I. Curr. Med. Chem. 2013; 20: 794
    • 10f Khan I. Ibrar A. Abbas N. Saeed A. Eur. J. Med. Chem. 2014; 76: 193
    • 10g Duan F. Liu M. Chen J. Ding J. Hu Y. Wu H. RSC Adv. 2013; 3: 24001
    • 11a Bentley KW. Nat. Prod. Rep. 2006; 23: 444
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Scheme 1 Approaches for the synthesis of quinazolinones
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Figure 1 X-ray crystal structure of 4a (ORTEP diagram); thermal ellipsoids are drawn at 50% probability level
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Scheme 2 Synthesis of 12-substituted 6H-isoquinolino[2,1-a]quinazolin-6-one derivatives 4 via AgNO3 catalyst. Reagents and conditions: 2-aminobenz­amide 1 (0.24 mmol), 2-alkynylbenzaldehyde 2 (0.24 mmol), AgNO3 (20 mol%), DMSO, 120 °C; isolated yields are given.
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Scheme 3 Plausible mechanism for the formation of isoquinoline-fused quinazolinones