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

Key words

isoquinoline - quinazolinone - regioisomer - silver catalyst - cascade annulation

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.

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%).

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 4a–n 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 4a–n 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.

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.

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.

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]

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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