Iodine-mediated synthesis of indazolo-quinazolinones via a multi-component reaction

Abstract

We report an expeditious synthesis of selected indazolo-quninazolinone derivatives via an iodine-mediated multi-component reaction (MCR). The MCR involved an in situ generation of the 1H-indazol-3-amine derivative in ethanol followed by its reaction with the diketone and aryl aldehyde in acetonitrile. A number of compounds have been synthesized using this methodology in good yields.

---

Introduction

Heterocycles have attracted attention in organic chemistry due to availability in natural products and array of biological properties.¹ Efforts have been made to design syntheses for use in therapeutic applications. A recent literature survey reveals several synthesis and pharmacological properties of ring-junction heterocyclic (bridge-headed heterocyclic) compounds, including bridge-head nitrogen compounds. A quinazolinone nucleus is an important scaffold found in a wide range of biologically active compounds, including natural products and synthetic drugs.^2–4 Camptothecin and mappicine, recently approved by the U.S. Food and Drug Administration, have the bridge-headed nitrogen motif. These two drugs have possible uses in antiparasitic, antimicrobial, anticancer and antibiotic actions.^5–7

At present atom-economical synthesis (transformation) with readily available reactants into complex organic molecules⁸ is highly desirable.^9–11 In a multi-component reaction (MCR), three or more reactants are converted into a higher molecular weight compound in a one-pot method.¹² The MCR has become very popular in the development of pharmaceutically active compounds due to experimental simplicity, atom economy and high product yield.^13–15 Our current work encompasses synthesizing selected quinazolinone-indazole-fused, nitrogen ring-junction heterocycles. Replacement of a carbon atom in a ring junction position by heteroatoms such as nitrogen, sulphur or oxygen in five- or six-membered rings leads to a wide variety of heterocycles. For instance, fascaplysin is a marine alkaloid that was originally isolated from the sponge Fascaplysinopsis Bergquist.¹⁶ This red pigment exhibits a wide range of activities such as antibacterial, antifungal, antiviral, and so on. Mianserin was an important anxiolytic or anti-depressant¹⁷ drug developed with the use of this heterocycle. Alkaloids such as rhazinal¹⁸ and rhazinilam¹⁹ have potent spindle toxins by virtue of their capacity to disrupt the dynamic interconversion of tubulin and microtubules required for the normal mitotic division of cells.^20,21 These and other indolizidine alkaloids, derived from amphibians and ants, have proved popular targets for total synthesis of both structural conformation and examination of potent bioactivities that many possess.²¹

In recent years, organic synthesis using molecular iodine as an inexpensive reagent has received considerable attention. The mild Lewis acidity associated with iodine enhanced its usage to perform several organic transformations using stoichiometric levels to catalytic amounts.²² Here we continue our earlier discussion of organic synthesis,^23,24 in which we report on molecular iodine-mediated indazolo-quinazolinones synthesis.

Results and discussion

Pal and colleagues have synthesized five- and six-membered fused quinazolinones via MCR.²⁵ This methodology has involved the reaction of isatoic anhydride, hydrazine and o-halo benzaldehyde in the presence of palladium as a catalyst. In recent studies, iodine-mediated organic transformations are enriched with MCR.^26–30 Our efforts are focused on designing and synthesizing nitrogen-bridged head indazolo-quinazolinones under the MCR condition. We have identified a retro-synthetic pathway to synthesize the indazolo-quinazolinone, outlined in Scheme 1. In this work, we report the synthesis of a new series of indazolo[3,2-b]quinazolin-8(5H)-one derivatives using molecular iodine. Synthesised compounds 5(a–l) and 6(a–f) were confirmed by melting point, ¹H NMR, ¹³C NMR, and HRMS analysis.

Scheme 1 The retrosynthetic route for 7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one from low cost and easily available reactants.

To optimize the reaction condition, we screened for different conditions (Table 1). We performed the reaction to synthesize 7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5a) in the absence of a catalyst, with a negative result (entry 1 in Table 1). We planned to utilize the catalyst to get our target compound (5). We varied the catalyst such as DBU, DABCO, CAN, I₂ and CuI to get 7-phenyl-7,9,10,11-tetrahydroindazolo [3,2-b]quinazolin-8(5H)-one (Table 1). Our attempt for the synthesis of 7-phenyl-7,9,10,11-tetrahydroindazolo [3,2-b]quinazolin-8(5H)-one favours only the presence of I₂ as a medium. We obtained 5% product (isolated) by using 10 mol% of molecular iodine with ethanol as a solvent. To increase the yield up to 85%, we increased the iodine mol percentage from 10 to 20 mol% along with the ethanol and acetonitrile (1 : 2) combination.

Table 1 Effect of reaction conditions on MCR for synthesis of 7-phenyl-7,9,10,11-tetrahydroindazolo [3,2-b]quinazolin-8(5H)-one^a

Entry	Solvent	Catalyst	Yield^b
a Reaction conditions: 2-flurobenzonitrile (1 mmol), hydrazine hydrate (1 mmol), benzaldehyde (1 mmol), 1,3-cyclohexadione (1 mmol) and molecular iodine (20 mol%) in ethanol (5 mL) and acetonitrile (10 mL) at 90 °C for 4 h. Yield.b Isolated yield.
1	EtOH	—	—
2	EtOH	I2 (10 mol%)	5%
3	EtOH	CAN (10 mol%)	—
4	EtOH	DBU	Traces
6	EtOH	DABCO	—
7	EtOH	CuI (10 mol%)	—
8	EtOH/ACH	I2 (10 mol%)	55%
9	EtOH/ACH	I2 (20 mol%)	85%
10	EtOH/ACH	I2 (30 mol%)	45%

---

With the optimized reaction condition, we employed various aromatic aldehydes 4(a–l) to the required nitrogen ring-junction compounds 5(a–l) with good to excellent yields (Scheme 2).

Scheme 2 Synthesis of indazolo[3,2-b]quinazolin-8(5H)-one derivatives.

The products 5(a–l) thus obtained from the above reaction were highly selective. When we introduced a wide range of functional groups like chloro, bromo, nitro, methyl, isopropyl, methoxy, and hydroxyl in the aldehyde, it remained intact in the reaction condition. The electron withdrawing and electron releasing group on the phenyl motif did not provide vast yield variations. But in the case of the isopropyl derivative, we achieved about a 91% yield.

The springiness of this reaction was tested with different diketones and amines; the resultant products 6(a–f) are listed in Scheme 3. From this observation, we found that only cyclic diketones that had undergone such transformation and linear diketones such as acetyl acetone and dibenzoyl methane did not give a positive result.

Scheme 3 Scope for various amines and dicarbonyls.

This implies that cyclic diketones are more likely to form an indazolo-quinazolinone–fused ring system with moderate to good yields. The proposed mechanism for the formation of 7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one is shown in Scheme 4. Initially, the reaction was initiated by iodine, which reacts with aldehyde and diketone to form an adduct of diketo hydroxyl compound. On the other hand, the amine source was generated from 2-fluoro benzonitrile and hydrazine, which react with adduct and upon loss of water molecules followed by cycloaddition to give the target product 5a.

Scheme 4 A plausible reaction mechanism for the iodine mediated MCR.

Conclusion

In conclusion, we have developed an efficient and easy protocol for synthesizing the indazolo-quinazolinone fused ring system through MCR using molecular iodine. Moreover, this method offers many advantages, including less reaction time, and noticeable yields and reactants. Some of the derivatives show fluorescent activity. In future we plan to develop fluorescent and biological activities of synthesised compounds.

Experimental section

All commercially available reagents were used without any further purification and reactions were monitored via thin-layer chromatography (TLC). ¹H and ¹³C nuclear magnetic resonance (NMR) results were obtained using a Bruker Avance 400-Mz spectrometer in DMSO d₆ solvent with TMS as an internal standard. Chemical shift values (δ) were expressed in parts per million (ppm). Abbreviations follow: s, singlet; d, doublet; t, triplet; m, multiplet. Melting points were measured on an Elchem Microprocessor-based DT apparatus using open capillary tubes, and are uncorrected. Mass spectra were obtained via high-resolution mass spectrometer.

General procedure for synthesis of 7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5a)

A mixture of 2-fluorobenzonitrile (1 mmol) and hydrazine (1 mmol) were mixed in 50 mL in two-neck, round-bottom flask containing 5 mL of absolute ethanol as a solvent. The mixture was refluxed for 30 min and the temperature increased to 100 °C to reduce the ethanol volume up to 90 percentage points. Benzaldehyde (1 mmol), diketone (1 mmol) and iodine (20%) in 10 ml acetonitrile were added to the reaction mixture at room temperature. Then the reaction mixture and progress of the reaction were monitored by TLC, and the formed precipitate was filtered, washed with water and dried; the product was off-white solid.

Characterization data for compounds [5(a–l) and 6(a–f)]

7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5a)

Off-white solid; isolated yield, 88%; mp: 316–318 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.13 (bs, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.26–7.15 (m, 6H), 6.92 (t, J = 8.0 Hz, 1H), 6.49 (s, 1H), 2.83–2.72 (m, 2H), 2.36–2.23 (m, 2H), 2.07–1.91 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 26.0, 31.5, 63.8, 110.8, 112.5, 115.9, 121.6, 124.5, 124.9, 131, 8, 132.1, 132.6, 133.3, 135.2, 147.8, 152.5, 155.8, 198.1; HRMS: m/z calcd for C₂₀H₁₇N₃O 315.1372, found 315.1370.

7-(4-chlorophenyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5b)

Off-white solid; isolated yield, 80%; mp: 352–354 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.20 (bs, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36–7.30 (m, 3H), 7.24–7.21 (m, 3H), 6.94 (t, J = 7.6 Hz, 1H), 6.50 (s, 1H), 2.83–2.72 (m, 2H), 2.37–2.24 (m, 2H), 2.08–1.93 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.7, 26.3, 36.2, 58.1, 105.1, 107.2, 116.4, 119.4, 119.6, 126.7, 128.1, 128.7, 129.9, 132.0, 141.5, 147.5, 150.7, 193.0; HRMS: m/z calcd. for C₂₀H₁₆ClN₃O 349.0982, found 349.0980.

7-(p-tolyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5c)

Off-white solid; isolated yield, 81%; mp: 342–344 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.08 (bs, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.11–7.03 (m, 4H), 6.93 (t, J = 7.6 Hz, 1H), 6.46 (s, 1H), 2.83–2.71 (m, 2H), 2.38–2.24 (m, 2H), 2.21 (s, 3H), 2.08–1.89 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.5, 20.8, 26.3, 36.3, 58.3, 105.7, 107.2, 116.4, 119.1, 119.6, 126.4, 126.7, 128.6, 129.8, 136.6, 139.8, 147.3, 150.4, 192.8; HRMS: m/z calcd for C₂₁H₁₉N₃O329.1528 found 329.1520.

7-(4-bromophenyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5d)

Off-white solid; isolated yield, 79%; mp: 358–360 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.19 (bs, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4, 2H), 7.35 (d, J = 8.8, 1H), 7.21–7.16 (m, 3H), 6.96–6.92 (m, 1H), 6.48 (s, 1H), 2.83–2.72 (m, 2H), 2.38–2.23 (m, 2H), 2.08–1.93 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.8, 26.3, 36.2, 58.2, 105.1, 107.2, 116.4, 119.3, 119.6, 120.5, 126.6, 129.0, 129.9, 131.0, 141.9, 147.5, 150.7, 192.9; HRMS: m/z calcd for C₂₀H₁₆BrN₃O 393.0477, found 393.0470.

7-(4-isopropylphenyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5e)

Off-white solid; isolated yield, 91%; mp: 338–340 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.12 (bs, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8, 1H), 7.19–7.10 (m, 5H), 6.95–6.91 (m, 1H), 6.46 (s, 1H), 2.85–2.71 (m, 3H), 2.34–2.24 (m, 2H), 2.08–1.90 (m, 2H) 1.13 (d, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.8, 23.7, 23.7, 26.3, 33.0, 36.3, 58.3, 105.6, 107.2, 116.4, 119.2, 119.6, 126.0, 126.4, 126.8, 129.8, 140.1, 147.3, 147.4, 150.5, 192.9; HRMS: m/z calcd for C₂₃H₂₃N₃O 357.1841, found 357.1840.

7-(4-methoxyphenyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5f)

Off-white solid; isolated yield, 88%; mp: 320–322 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.08 (bs, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.19–7.13 (m, 3H), 6.93 (t, J = 6.8, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.44 (s, 1H), 3.68 (s, 3H), 2.84–2.70 (m, 2H), 2.36–2.25 (m, 2H), 2.08–1.90 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.8, 26.3, 36.3, 55.0, 58.0, 105.7, 107.2, 113.4, 116.4, 119.1, 119.6, 126.4, 128.0, 129.7, 134.9, 147.3, 150.4, 158.5, 192.9; HRMS: m/z calcd for C₂₁H₁₉N₃O₂ 345.1477, found 345.1470.

7-(4-hydroxyphenyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5g)

Off-white solid; isolated yield, 88%; mp: 358–360 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.18 (bs, 1H), 9.36 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.19 (t, J = 6.8, 1H), 7.04–7.00 (m, 1H), 6.95–6.91 (m, 1H), 6.93 (t, J = 7.6, 1H), 6.64–6.55 (m, 3H), 6.40 (s, 1H), 2.82–2.71 (m, 2H), 2.38–2.26 (m, 2H), 2.06–1.93 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 26.0, 31.5, 41.5, 63.6, 110.9, 112.5, 118.9, 119.6, 121.7, 122.6, 124.5, 124.8, 131.8, 134.3, 135.2, 149.1, 152.6, 155.8, 162.3, 198.2; HRMS: m/z calcd for C₂₀H₁₇N₃O₂ 331.1321, found 331.1320.

7-(4-nitrophenyl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5h)

Yellow solid; isolated yield, 78%; mp: 338–340 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.31 (bs, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 6.8 Hz, 1H), 6.96 (t, J = 7.6, 1H), 6.63 (s, 1H), 2.84–2.74 (m, 2H), 2.39–2.25 (m, 2H), 2.08–1.93 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.7, 26.3, 36.2, 58.3, 104.7, 107.2, 116.5, 119.6, 119.7, 123.4, 126.8, 128.2, 130.0, 146.7, 147.6, 149.4, 151.0, 192.9; HRMS: m/z calcd for C₂₀H₁₆N₄O₃ 360.1222, found 360.1220.

7-(Naphthalen-1-yl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5i)

Yellow solid; isolated yield, 86%; mp: 320–322 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.23 (bs, 1H), 8.75 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.38–7.35 (m, 3H), 7.23 (d, J = 8.8 Hz, 1H), 7.12 (t, J = 6.8 Hz, 1H), 6.90 (t, J = 8.0, 1H), 2.94–2.83 (m, 2H), 2.36–2.20 (m, 2H), 2.19–2.00 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.9, 26.4, 36.3, 106.4, 107.2, 116.3, 119.1, 119.6, 124.2, 125.2, 125.4, 125.6, 126.1, 126.4, 128.0, 128.1, 129.5, 130.8, 133.0, 139.8, 147.1, 150.7, 192.9; HRMS: m/z calcd for C₂₄H₁₉N₃O 365.1528 found 365.1520.

7-(2-chlorophenyl)-7,9,10,11-tetrahydroindazolo[3,2 b]quinazolin-8(5H)-one (5j)

Off-white solid; isolated yield–83%; mp: 312–314 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.22 (bs, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36–7.23 (m, 3H), 7.22–7.19 (m, 3H), 6.94–6.90 (m, 1H), 6.86 (s, 1H), 2.86–2.72 (m, 2H), 2.38–2.09 (m, 2H), 2.08–1.91 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.9, 26.4, 36.3, 56.6, 105.0, 106.9, 116.4, 119.2, 119.6, 126.6, 127.1, 129.0, 129.2, 129.9, 130.1, 132.2, 139.9, 147.4, 150.9, 192.8; HRMS: m/z calcd for C₂₀H₁₆ClN₃O 349.0982, found 349.0980.

7-(Pyridin-2-yl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5k)

Off-white solid; isolated yield, 82%; mp: 324–326 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.11 (bs, 1H), 8.31 (d, J = 4.4 Hz, 1H), 7.79–7.72 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.20–7.15 (m, 2H), 6.92 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 2.77–2.76 (m, 2H), 2.37–2.20 (m, 2H), 2.08–1.85 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.8, 26.3, 36.1, 60.2, 105.1, 107.3, 116.3, 119.1, 119.6, 122.5, 122.7, 126.5, 130.5, 136.1, 147.3, 149.1, 150.7, 159.8, 192.9; HRMS: m/z calcd for C₁₉H₁₆N₄O 316.1324, found 316.1320.

7-(Thiophen-2-yl)-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (5l)

Off-white solid; isolated yield, 85%; mp: 318–320 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.24 (bs, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.34–7.33 (d, J = 4.8 Hz, 1H), 7.20 (t, J = 6.8 Hz, 1H), 6.95–6.86 (m, 3H), 6.77 (s, 1H), 2.84–2.76 (m, 2H), 2.38–2.35 (m, 2H), 2.10–1.98 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.8, 26.3, 36.2, 53.3, 105.1, 107.3, 116.5, 119.4, 119.6, 125.4, 125.5, 126.5, 126.6, 129.5, 145.4, 147.4, 150.9, 192.9; HRMS: m/z calcd for C₁₈H₁₅N₃OS 321.0936, found 321.0930.

10-(4-bromophenyl)-7,8,10,12-tetrahydropyrido[2′,3′:3,4]pyrazolo[5,1-b]quinazolin-9(6H)-one (6a)

Off-white solid; isolated yield, 71%; mp: 332–334 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.33 (bs, 1H), 8.52–8.22 (m, 1H), 8.21 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 8.4, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.99–6.96 (m, 1H), 6.49 (s, 1H), 2.81–2.70 (m, 2H), 2.38–2.25 (m, 2H), 2.08–1.94 (m, 2H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.7, 26.2, 36.2, 58.1, 99.8, 105.3, 115.6, 120.7, 129.2, 129.5, 129.7, 131.1, 141.5, 150.6, 152.1, 156.6, 193.1; HRMS: m/z calcd for C₁₉H₁₅BrN₄O 394.0429, found 394.0420.

10,10-Dimethyl-7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (6b)

Off-white solid; isolated yield, 75%; mp: 314–316 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.11 (bs, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27–7.16 (m, 6H), 6.94 (t, J = 8.0 Hz, 1H), 6.47 (s, 1H), 2.71–2.60 (m, 2H), 2.98–2.08 (m, 2H), 1.09 (s, 3H), 1.00 (s, 3H); ¹³C NMR (100 MHz, DMSO d₆) δ 26.7, 28.6, 32.2, 49.8, 58.9, 104.6, 107.3, 116.4, 119.3, 126.5, 126.8, 127.4, 128.1, 130.0, 142.7, 147.4, 148.6, 192.5; HRMS: m/z calcd for C₂₂H₂₁N₃O 343.1685, found 344.1760.

10-Methyl-7-phenyl-7,9,10,11-tetrahydroindazolo[3,2-b]quinazolin-8(5H)-one (6c)

Off-white solid; isolated yield, 69%; mp: 335–337 °C; ¹H NMR (400 MHz, DMSO d₆) δ 11.11 (bs, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.35–7.34 (m, 1H), 7.26–7.17 (m, 6H), 6.93 (t, J = 8.0 Hz, 1H), 6.47 (s, 1H), 2.81–2.76 (m, 1H), 2.66–2.60 (m, 1H), 2.40–2.26 (m, 2H), 2.15–2.04 (m, 1H), 1.05 (d, J = 4.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO d₆) δ 20.3, 28.4, 33.8, 44.2, 58.9, 105.1, 107.3, 116.4, 119.2, 119.6, 126.5, 126.8, 127.3, 128.0, 129.9, 142.6, 147.4, 149.4, 192.6; HRMS: m/z calcd for C₂₁H₁₉N₃O 329.1528, found 329.1520.

7-phenyl-5H-indeno[1′,2′:4,5]pyrimido[1,2-b]indazol-8(7H)-one (6f)

Red solid; isolated yield, 78%; mp: 342–344 °C; ¹H NMR (400 MHz, DMSO d₆) δ 12.31 (bs, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.45–7.41 (m, 2H), 7.40–7.36 (m, 1H), 7.34–7.23 (m, 6H), 7.06 (t, J = 8.0 Hz, 1H), 6.62 (s, 1H); ¹³C NMR (100 MHz, DMSO d₆) δ 59.8, 102.3, 108.4, 116.9, 119.5, 119.7, 120.3, 120.7, 126.8, 127.2, 127.8, 128.3, 130.6, 131.8, 134.2, 135.4, 141.3, 147.8, 151.9, 188.1; HRMS: m/z calcd for C₂₃H₁₅N₃O 349.1215, found 349.1210.

Acknowledgements

SMR thanks DST-SERB (SB/FT/CS-126/2012), Government of India, New Delhi for providing the research grant. JP is grateful to DST for providing a research assistant position. We also thank VIT management for providing research facilities, and VIT-SIF, DST-FIST for NMR facilities.

Notes and references

1. M. Jha, S. Guy and Y. C. Ting, Tetrahedron Lett., 2011, 52, 4337–4371.
2. A. Salgado, C. Varela, A. M. G. Collazo and P. Pevarello, Magn. Reson. Chem., 2010, 48, 614–622.
3. G. Fischer, Adv. Heterocycl. Chem., 2008, 95, 143–219.
4. M. R. Shaaban, T. S. Saleh and A. M. Farag, Heterocycles, 2007, 71, 1765–1777.
5. S. B. Charki, C. Marín, C. R. Maldonado, M. J. Rosales, J. Urbano, R. Guitierrez-Sánchez, M. Quirós, J. M. Salas and M. Sánchez-Moreno, Drug Metab. Lett., 2009, 3, 35–44.
6. G. Ruisi, L. Canfora, G. Bruno, A. Rotondo, T. F. Mastropietro, E. A. Debbia, M. A. Girasolo and B. Megna, J. Organomet. Chem., 2010, 695, 546–551.
7. M. M. A. El-Gendy, M. Shaaban, K. A. Shaaban, A. M. El-Bondkly and H. Laatsch, J. Antibiot., 2008, 61, 149–157.
8. (a) B. M. Trost, Science., 1991, 254, 1471; (b) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259; (c) B. M. Trost, TranstitionMetalsfor Organic Synthesis, ed. M. Beller and C. Bolm, Wiley-VCH, Weinheim, 1998, p. 1.
9. (a) L. F. Tietze, Chem. Rev., 1996, 96, 115–136; (b) L. F. Tietze and F. Haunert, Stimulation Conceptsm, in Chemistry, ed. M. Shibasaki, J. F. Stoddart and F. Vögtle, Wiley-VCH, Weinheim, 2000, p. 39; (c) L. F. Tietze and A. Modi, Med. Res. Rev., 2000, 20, 304–322.
10. A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168–3210.
11. C. Simon, T. Constantieux and J. Rodriguez, Eur. J. Org. Chem., 2004, 24, 4957–4980.
12. M. B. Deshmukh, S. M. Salunkhe, D. R. Patil and P. V. Anbhule, Eur. J. Med. Chem., 2009, 44, 2651–2654.
13. R. Ranjbar-Karimi, K. Beiki-Shoraki and A. Amiri, Monatsh. Chem., 2010, 141, 1101–1106.
14. A. Salgado, C. Varela, A. M. G. Collazo, F. García, P. Pevarello, I. Alkorta and J. Elguero, J. Mol. Struct., 2011, 987, 13–24.
15. C. Qiong, X. L. Zhu, L. L. Jiang, Z. M. Liu and G. F. Yang, Eur. J. Med. Chem., 2008, 43, 595–603.
16. V. B. Olga, E. Z. Maxim and V. D. Sergey, Tetrahedron Lett., 2011, 52, 2397–2398.
17. J. I. Andres, J. Alcazar, J. M. Alonso, A. Diaz, J. Fernandez, P. Gil, L. Iturrino, E. Matesanz, F. Theo, B. Meert, A. Megensc and V. K. Sipidod, Bioorg. Med. Chem. Lett., 2002, 12, 243–248.
18. T. S. Kam, Y. M. Tee and G. Subramaniam, Nat. Prod. Lett., 1998, 12, 307–310.
19. H. H. A. Linde, Helv. Chim. Acta, 1965, 48, 1822–1842.
20. B. David, T. Sévenet, O. Thoison, K. Awang, M. Païs, M. Wright and D. Guénard, Bioorg. Med. Chem. Lett., 1997, 7, 2155–2158.
21. (a) O. Baudoin, F. Claveau, S. Thoret, A. Herrbach, D. Guénard and F. Guéritte, Bioorg. Med. Chem., 2002, 10, 3395–3398; (b) M. G. Banwell, D. A. S. Beck and A. C. Willis, ARKIVOC, 2006,(iii), 163–174.
22. R. G. Puligoundla, S. Karnakanti, R. Bantu, N. Kommu, S. B. Kondra and L. Nagarapu, Tetrahedron, 2013, 54, 2480–2483.
23. (a) S. M. Roopan and F. R. N. Khan, Res. Chem. Intermed., 2011, 37, 919–927; (b) A. Bhrathi, S. M. Roopan, C. S. Vasavi, G. A. Gayathri and M. Gayathri, BioMed Res. Int., 2014, 971519, 1–10; (c) A. Bharathi, S. M. Roopan, A. A. Rahuman and G. Rajakumar, J. Photochem. Photobiol., B, 2014, 140, 359–364.
24. (a) H. R. Reddy, C. V. S. Reddy, R. Subashini and S. M. Roopan, RSC Adv., 2014, 4, 29999–30003; (b) A. Bharathi, S. M. Roopan, A. Kajbafvala, M. S. Darsana and G. N. Kumari, Chin. Chem. Lett., 2014, 25, 324–326; (c) K. Hemalatha, G. Madhumitha, A. Kajbafvala, N. Anupama, R. Sompalle and S. M. Roopan, J. Nanomater., 2013, 341015, 1–23.
25. K. S. Kumar, P. M. Kumar, V. S. Rao, A. A. Jafar, C. L. T. Meda, R. Kapavarapu, K. V. L. Parsa and M. Pal, Org. Biomol. Chem., 2012, 10, 3098–3103.
26. G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy and M. Pal, RSC Adv., 2012, 2, 3387–3395.
27. J. S. Yadav, B. V. S. Reddy and S. R. Hashim, J. Chem. Soc., Perkin Trans. 1, 2000, 3025–3027.
28. J. S. Yadav, B. V. S. Reddy, K. Premalatha and T. Swamy, Tetrahedron Lett., 2005, 46, 2687–2690.
29. J. S. Yadav, B. V. S. Reddy, C. V. Rao, P. K. Chand and A. R. Prasad, Synlett, 2001, 1638–1640.
30. D. Bandyopadhyay, S. Mukherjee and B. K. Banik, Molecules, 2010, 15, 2520–2525.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13779e

---