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Original article
12 (
8
); 4220-4230
doi:
10.1016/j.arabjc.2016.05.009

Ultrasound assisted synthesis of 6-flavonyl substituted 1,4-dihydro-benzo[d][1,3]oxazin-2-ones via Suzuki–Miyaura coupling under Pd/C catalysis

, , ,
a Department of Chemistry, Krishna University, Krishna Dist., Andhra Pradesh, India
b Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India

⁎Corresponding author. Tel.: +91 40 6657 1500. vbrmandava@yahoo.com (Mandava Venkata Basaveswara Rao), manojitpal@rediffmail.com (Manojit Pal)

Received: , Accepted: ,
© The Author(s) 2016
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Pd/C facilitated Suzuki–Miyaura coupling of 2-aryl-3-bromoflavones with 4,4-disubstituted (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acids under ultrasound irradiation. The methodology involving the use of 10%Pd/C-TBAB-K2CO3 system in DMF/H2O afforded corresponding 6-flavonyl substituted 1,4-dihydro-benzo[d][1,3]oxazin-2-ones in good yield within a short reaction time. The role of ultrasound and catalyst along with the recyclability of Pd/C was examined and a reaction mechanism is proposed.

Keywords

Pd/C
Ultrasound
Suzuki–Miyaura coupling
Flavones
Benzoxazin-2-one
1

1 Introduction

Compounds containing 1,4-dihydrobenzoxazin-2-one framework (A, Fig. 1) attracted attention of organic/medicinal chemist way back in 1971 (Marchi et al., 1971). Indeed, one of the several 1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives (B, Fig 1) synthesized at that time showed anticonvulsant activity against chemically and electrically induced seizures and low acute toxicity in mice. The 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones have been explored as HIV reverse transcriptase inhibitors (Christ et al., 1998) and compound C i.e. efavirenz (Sustiva™) (Fig. 1) (Hamed, 2004) was approved as anti-HIV drugs by the Food and Drug Administration (FDA) (Young et al., 1995). In 2002, a series of 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones (D, Fig 2) were synthesized and tested as progesterone receptor (PR) antagonists and several of them showed selectivity for PR over other steroid receptors (Zhang et al., 2002). Due to a range of pharmacological properties shown by its derivatives, the framework A attracted our particular attention. The 3-substitutes flavones (E, Fig 2) on the other hand had drawn our attention (Pal et al., 2003, 2004) during 2004–2005 when we reported the synthesis and in vitro cytotoxic evaluation of 3-enynyl-substituted flavones (Pal et al., 2005). In continuation of this research we became interested in synthesizing a library of compounds based on F that is derived by integrating the structural features of D and E in a single molecular entity (Fig. 2). The connectivity of these two moieties in F was made in such a way that C-3 substitution pattern on the flavone ring (e.g. D) and C-6 substitution pattern on benzoxazin-2-one ring (e.g. E) is maintained. We anticipated that this design may afford library of small new molecules of potential pharmacological interest.

1,4-Dihydrobenzoxazin-2-one (A) and its known bioactive derivatives.
Figure 1 1,4-Dihydrobenzoxazin-2-one (A) and its known bioactive derivatives.
New bioactive agents F derived by integration structural features of D and E in a single molecular entity.
Figure 2 New bioactive agents F derived by integration structural features of D and E in a single molecular entity.

The 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-one derivatives were prepared via Suzuki–Miyaura coupling (Selepe and Van Heerden, 2013) of either 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one with aryl boronic acids or bromoarenes with (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (Scheme 1) (Zhang et al., 2002). However, these methods require heating of the reaction mixture at 85 °C for 3 h and involved the use of relatively expensive and air sensitive Pd(PPh3)4 as a source of Pd-catalyst. Moreover, the Pd-catalyst used is destroyed during the work-up procedure and therefore cannot be recovered or reused. The possibility of metal contamination (originated from the catalyst used) with the product is also high in these types of reactions performed under homogenous catalysis. The product yield also varied in a wide range i.e. 40–80%.

Reported synthesis of 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones.
Scheme 1 Reported synthesis of 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones.

The use of Pd/C as a heterogenous catalyst for the Suzuki–Miyaura coupling has been reported earlier (Marck et al., 1994; Gala et al., 1997; Ennis et al., 1999; LeBlond et al., 2001; Sakurai et al., 2002; Heidenreich et al., 2002; Colacot et al., 2002; Tagata and Nishida, 2003). As a catalyst Pd/C has advantages over the other homogenous or heterogenous Pd-complexes or salts. For example, Pd/C is less expensive, insensitive to air and moisture, easy to handle and recyclable (LeBlond et al., 2001; Heidenreich et al., 2002; Felpin et al., 2006). The Pd/C catalyst can be separated easily from the product via simple filtration and the product mostly remained uncontaminated with the transition metal. Moreover, it can be stored for a long time without taking any extra precautions. All these advantages made Pd/C a potential catalyst amenable for large-scale preparations. Indeed, the use of Pd/C for hydrogenation reaction in industrial scale is known for over several decades.

Ultrasound assisted reactions on the other hand are also considered as attractive techniques in organic and medicinal chemistry (Cella and Stefani, 2012) because of shorter reaction time, mild conditions and high yields of products. These reactions appeared to be more convenient and advantageous compared to the traditional methods. It is therefore not surprising that ultrasound assisted Suzuki–Miyaura coupling under Pd/C catalysis has been explored as an effective strategy for the synthesis of biaryl derivatives (Polácková et al., 2005; Cravotto et al., 2005). Thus, combination of Pd/C with ultrasound irradiation appeared as an attractive and greener option to us for the Suzuki–Miyaura coupling of 3-haloflavones with arylboronic acids leading to compound F. Herein, we report Pd/C-catalyzed coupling of 2-aryl-3-bromoflavone derivatives (1) with 4,4-disubstituted (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acids (2) under ultrasound irradiation to afford the corresponding coupled products 3 (or F, Scheme 2). While a number of reports are available on Suzuki–Miyaura coupling of 3-haloflavones with arylboronic acids to the best of our knowledge, the use of Pd/C-based strategy under ultrasound irradiation for the synthesis of 3 or similar class of compounds has not been reported earlier.

Pd/C catalyzed Suzuki–Miyaura coupling of 1 and 2 under ultrasound irradiation leading to 3.
Scheme 2 Pd/C catalyzed Suzuki–Miyaura coupling of 1 and 2 under ultrasound irradiation leading to 3.

2

2 Material and methods

2.1

2.1 General methods

Unless stated otherwise, reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60 F254), visualizing with ultraviolet light or iodine spray. Column chromatography was performed on silica gel (60–120 mesh) using distilled petroleum ether and ethyl acetate. 1H and 13C NMR spectra were determined in CDCl3 solution using a Varian 400 MHz spectrometer. Proton chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.0) as internal standard and expressed in parts per million. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), and m (multiplet) as well as b (broad). Coupling constants (J) are given in Hertz. Infrared spectra were recorded on a JASCO FTIR-4200 spectrometer (Switzerland). Melting points were determined by using a Buchi melting point B-540 apparatus. MS spectra were obtained on a HP-5989A mass spectrometer.

2.2

2.2 Preparation of 1-(2-amino-5-bromophenyl)ethanone (5) (Baker et al., 2001; Zhou et al., 2010)

To a cold solution of 2-amino acetophenone 4 (30 mmol) in CH2Cl2 (900 mL) was added pyridine hydrobromide perbromide (30 mmol) slowly maintaining the temperature at 0–5 °C. The reaction mixture was stirred for 10 min at the same temperature and then at room temperature for 26 h. After completion of the reaction (indicated by TLC), the mixture was diluted with cold water (400 mL) and extracted with CH2Cl2 (3 × 80 mL). The organic layers were collected, combined, washed with cold water (2 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue obtained was purified by column chromatography on silica gel using 5–10% EtOAc-hexane to give the desired product as an off white solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 1H, J = 2.4 Hz, ArH), 7.33 (dd, J = 10.8 and 3.0 Hz, 1H, ArH), 6.55 (d, J = 10.8 Hz, 1H, ArH), 6.28 (brs, 2H, NH2), 2.64 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 199.5 (C⚌O), 149.0, 136.8, 134.0, 119.1, 118.8, 106.4, 27.6 (CH3); MS (EI): m/z 215 (M + 2)+, 213 (M+).

2.3

2.3 Preparation of 2-(2-amino-5-bromophenyl) substituted dialkyl alcohol (6)

To a solution of ketone 5 (10 mmol) in THF (40 mL) was added appropriate alkyl magnesium chloride (2.0 M, 30 mmol) at −78 °C under a nitrogen atmosphere. The reaction mixture was stirred at −78 °C for 4–6 h and allowed to warm to room temperature. After completion of the reaction (indicated by TLC) the mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 30 mL). The organic layers were collected, combined, washed with aq NH4Cl (3 × 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue was purified by column chromatography on silica gel using 25–30% EtOAc-hexane to give the desired product. Spectral data for 2-(2-amino-5-bromophenyl)pent-4-en-2-ol (6c): light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.26–7.22 (m, 2H), 6.61 (d, J = 9.8 Hz, 1H), 5.93–5.83 (m, 1H), 5.30–5.25 (m, 2H), 4.83 (brs, 2H), 2.93–2.88 (m, 1H), 2.73–2.65 (m, 1H), 1.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 133.2, 131.1, 130.4, 129.0, 119.2, 118.8, 109.1, 75.0, 44.3, 27.1; MS (EI): m/z 257 (M + 2)+, 255 (M+).

2.4

2.4 Preparation of 4-alkyl substituted 6-bromo-4-methyl-1H-benzo[d][1,3]oxazine-2(4H)-one (7)

To a stirring solution of compound 6 (15.0 mmol) in THF (150 mL) was added 1,10-carbonyldiimidazole (16.0 mmol) at room temperature and the mixture was heated to reflux for 48–50 h. After completion of the reaction (indicated by TLC) the mixture was cooled to room temperature, diluted with cold water (300 mL) and extracted with EtOAc (3 × 80 mL). The organic layers were collected, combined, washed with aqNH4Cl (3 × 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue was purified by flash column chromatography on silica gel using 20–25% EtOAc-hexane to afford the desired product.

2.4.1

2.4.1 6-Bromo-4-methyl-4-pentyl-1H-benzo[d][1,3]oxazin-2(4H)-one (7a)

Light brown gum; 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H, D2O exchangeable, NH), 7.29 (d, J = 8.3 Hz, 1H, ArH), 7.18–7.12 (m, 1H, ArH), 6.88 (d, J = 8.3 Hz, 1H, ArH), 2.03–1.98 (m, 2H, CH2), 1.75 (s, 3H, CH3), 1.47–1.33 (m, 6H, CH2), 0.94 (t, J = 6.7 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 153.1, 133.9, 131.5, 127.6, 124.8, 117.4, 114.7, 85.5, 41.1, 31.7, 27.0, 23.1, 22.4, 14.6; MS (EI): m/z 313 (M + 2)+, 311 (M+).

2.4.2

2.4.2 6-Bromo-4-methyl-4-vinyl-1H-benzo[d][1,3]oxazin-2(4H)-one (7b)

Light yellow gum; 1H NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H, D2O exchangeable, NH), 7.22 (d, J = 8.1 Hz, 1H, ArH), 7.06–7.0 (m, 1H, ArH), 6.90 (d, J = 7.8 Hz, 1H, ArH), 5.81–5.72 (dd, J = 10.1, 17.5 Hz, 1H), 5.16–4.96 (m, 2H,⚌CH2), 1.72 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 153.2 (C⚌O), 136.3, 131.3, 128.8, 124.1, 123.8, 123.0, 117.1, 114.9, 85.0 (C-4), 26.2 (CH3); MS (EI): m/z 269 (M + 2)+, 267 (M+).

2.4.3

2.4.3 4-Allyl-6-bromo-4-methyl-1H-benzo[d][1,3]oxazine-2(4H)-one (7c) (Zhou et al., 2010)

Pale yellow oil; 4-allyl-6-bromo-4-methyl-1H-benzo[d][1,3]oxazine-2(4H)-one (7c): pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H, D2O exchangeable, NH), 7.21 (td, J = 7.4 Hz, 1.4 Hz, 1H, ArH), 7.07–7.01 (m, 1H, ArH), 6.92 (d, J = 7.9 Hz, 1H, ArH), 5.77–5.68 (m, 1H,⚌C—H), 5.11–5.06 (m, 2H,⚌C—H), 2.75–2.65 (m, 2H, CH2), 1.71 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 153.2, 134.0, 131.3, 128.7, 124.1, 123.7, 123.1, 119.7, 114.6, 84.6, 45.3, 26.1; MS (EI): m/z 283 (M + 2)+, 281 (M+).

2.5

2.5 Preparation of boronic acids (2)

To a solution of compound 7 (10 mmol) in anhydrous THF (70 mL) was added a solution of n-BuLi in hexane (10 M, 30 mmol) at −78 °C under a nitrogen atmosphere. The solution was stirred at −78 °C for 30 min. and then treated with triisopropyl borate (32 mmol). The reaction mixture was warmed slowly to room temperature and quenched with cold 1 N aqHCl (80 mL). The mixture was extracted with EtOAc (3 × 70 mL) and the separated organic layers were collected. The combined organic layer was washed with brine (70 mL) and dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue was purified by a flash chromatography on silica gel using 2:1 EtOAc:hexane to afford the desired product.

2.5.1

2.5.1 (4-Methyl-2-oxo-4-pentyl-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)boronic acid (2a)

Light orange solid; 1H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H, D2O exchangeable), 7.40 (d, J = 8.3 Hz, 1H, ArH), 7.17 (s, 1H, ArH), 6.85 (d, J = 8.3 Hz, 1H, ArH), 2.02–1.97 (m, 2H, CH2), 1.74 (s, 3H, CH3), 1.48–1.34 (m, 6H, CH2), 0.93 (t, J = 6.9 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 153.0 (C⚌O), 133.5, 131.7, 127.0, 126.8, 116.4, 115.7, 85.4, 41.0, 31.8, 27.1, 23.2, 22.5 (CH3), 14.7 (CH3); IR (KBr): 3413, 3190, 2972, 1720 (C⚌O), 1649, cm−1; MS (EI): m/z 278 (M + 1, 100).

2.5.2

2.5.2 (4-Methyl-2-oxo-4-vinyl-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)boronic acid (2b)

Off white solid; 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H, D2O exchangeable, NH), 7.96 (s, 2H, D2O exchangeable, OH), 7.67 (d, J = 10 Hz, 2H, ArH), 6.82 (d, J = 7.8 Hz, 1H, ArH), 6.01 (dd, J = 10.3, 17.8 Hz, 1H,⚌C—H), 5.15 (d, J = 10.3 Hz, 1H,⚌C—H), 4.97 (d, J = 16.9 Hz, 1H,⚌C—H), 1.72 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 153.3 (C⚌O), 140.5, 137.3, 136.4, 131.3, 128.8, 123.8, 116.1, 115.0, 85.1, 26.2 (CH3); IR (KBr): 3407, 3277, 2975, 2930, 1717 (C⚌O), 1643 cm−1; MS (EI): m/z 234 (M + 1, 100).

2.5.3

2.5.3 (4-Allyl-4-methyl-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)boronic acid (2c)

Ash colored solid; 1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H, D2O exchangeable, NH), 7.90 (s, 2H, D2O, exchangeable, OH), 7.60 (dd, J = 3.6, 3.6 Hz, 2H, ArH), 6.77 (d, J = 8.4 Hz, 1H, ArH), 5.61–5.55 (m, 1H,⚌C—H), 5.06–5.01 (m, 2H,⚌C—H), 2.65–2.61 (m, 1H, CH), 2.54–2.50 (m, 1H, CH), 1.54 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 153.1 (C⚌O), 137.2, 136.0, 132.7, 131.1, 128.6, 124.5, 121.1, 114.8, 85.8, 45.0, 27.6 (CH3); IR (KBr): 3431, 3156, 2977, 2933, 1719 (C⚌O), 1656, cm−1; MS (EI): m/z 248 (M + 1, 100).

2.5.4

2.5.4 (1,4-Dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (2d) (Zhang et. al., 2002)

Pale yellow solid; 1H NMR (DMSO-d6) δ 10.31 (s, 1H, D2O exchangeable), 7.74 (s, 1H), 7.61 (m, 3H), 7.44 (dd, J = 7.8, 7.8 Hz, 1H), 7.38 (dd, J = 7.0, 1.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 1.66 (s, 6H); MS (EI): m/z 222 (M + 1, 100).

2.6

2.6 General procedure for the preparation of compound 3

A mixture of arylboronic acid 2 (1 mmol), 10% Pd/C (1.5 mol% total Pd vs. arylhalide), K2CO3 (3 mmol) and TBAB (1 mmol) in 5: 1 DMF/H2O (5 mL) was stirred at room temperature under a nitrogen atmosphere. To this was added bromo compound 1 (1 mmol) and the mixture was stirred at 55–60 °C under ultrasound irradiation using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz. The temperature of the bath was maintained by adding cold water time to time in case an increase in temperature was observed due to the prolonged irradiation. The reaction continued according to the time mentioned in Table 2. After cooling the mixture to room temperature, the catalyst was filtered off and the filtrate was diluted with cold water (25 mL). The mixture was then extracted with EtOAc (3 × 20 mL). The organic layers were separated, and collected. The combined organic layer was washed with cold water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue was purified by column chromatography on silica gel using EtOAc-hexane to give the desired product.

Table 1 Effect of reaction conditions on Pd/C-catalyzed Suzuki–Miyaura coupling of 1a with 2a.a
Entry Base Solvent Additive Time (min) % yieldb
1. K2CO3 DMF/H2O (5:1) – 37
2. K2CO3 DMF/H2O (5:1) TBAB 20 85c
3. K2CO3 DMF/H2O (5:1) TBAB 20 57d
4. K2CO3 DMF/H2O (5:1) TBAC 20 79
5. KOH DMF/H2O (5:1) TBAB 20 51
6. Na2CO3 DMF/H2O (5:1) TBAB 20 78
7. K2CO3 DME/H2O (5:1) TBAB 20 75
8. K2CO3 1,4-Dioxane/H2O (5:1) TBAB 20 74
9. K2CO3 DMF/H2O (5:1) TBAB 120 42e
a Reactions were performed using 1a (1 mmol), 2a (1.1 mmol), 10%Pd/C (1.5 mol%), base (3 mmol) in a solvent (5 mL) at 55–60 °C under ultrasound irradiation.
b Isolated yield.
c 1.0 equiv of TBAB was used.
d 0.5 equiv of TBAB was used.
e Reaction was performed in the absence of ultrasound.
Table 2 Ultrasound assisted synthesis of 6-flavonyl substituted 1,4-dihydro-benzo[d][1,3]oxazin-2-ones (3) via Suzuki–Miyaura coupling of 1 and 2 under Pd/C catalysis (3).a
Entry 1; Ar⚌ 2; R⚌ Products (3) Yieldb (%)
1. 1a; 3,4,5-(MeO)3C6H2 2a; n-C5H11 3a 85
2. 1a 2b; —CH⚌CH2 3b 86
3. 1a 2c; —CH2CH⚌CH2 3c 82
4. 1b; 3,4-(MeO)2C6H3 2a 3d 86
5. 1b 2b 3e 89
6. 1b 2c 3f 88
7. 1c; 4-MeOC6H4 2a 3g 89
8. 1c 2b 3h 90
9. 1c 2c 3i 91
10. 1c 2d; Me 3j 87
a Reactions were performed using 1 (1 mmol), 2 (1.1 mmol), 10%Pd/C (1.5 mol%), K2CO3 (3 mmol), TBAB (1 mmol) in DMF/H2O (5:1) (5 mL) at 55–60 °C for 20 min.
b Isolated yield.

2.6.1

2.6.1 4-Methyl-6-{4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl}-4-pentyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3a)

Off white solid, mp 153–155 °C [lit mp 155–158 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 1H, D2O exchangeable, NH), 8.27 (d, J = 7.8 Hz, 1H, ArH), 7.71 (dd, J = 7.8, 7.8 Hz, 1H, ArH), 7.51–7.43 (m, 2H, ArH), 7.30 (d, J = 8.3 Hz, 1H, ArH), 7.15 (s, 1H, ArH), 7.08 (s, 2H, ArH), 6.78 (d, J = 7.8 Hz, 1H, ArH), 3.92 (s, 9H, OCH3), 1.91–1.88 (m, 2H, CH2), 1.64 (s, 3H, CH3), 1.30–1.22 (m, 6H, CH2), 0.82 (t, J = 6.9 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.2 (C⚌O), 161.8 (C⚌O), 155.5, 153.0, 152.8, 140.5, 134.4 (2C), 133.5, 131.7, 127.8, 127.0, 126.8, 126.6, 126.0, 121.7, 118.0, 116.4, 115.7, 109.0, 107.1 (2C), 85.4, 61.0 (OCH3), 56.4 (2C, OCH3), 41.0 (CH2), 31.7 (CH2), 27.1 (CH3), 23.1 (CH2), 22.4 (CH2), 14.0 (CH3); IR (KBr): 3255, 2954, 1707 (C⚌O), 1681 (C⚌O), 1654, 1613 cm−1; MS (EI): m/z 545 (M + 1, 50); HPLC: 98.6%, column: X-Bridge C-18 150 ∗ 4.6 mm 5 μm, mobile phase A: 0.1% HCOOH in water mobile phase B: CH3CN (gradient) T/%B: 0/20, 3/20, 12/95, 25/95, 27/20, 30/20; flow rate: 1.0 mL/min; UV 280 nm.

2.6.2

2.6.2 4-Methyl-6-{4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl}-4-vinyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3b)

Ash colored solid; mp 144–146 °C [lit mp 140–145 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 8.94 (s, 1H, D2O exchangeable, NH), 8.27 (d, J = 7.8 Hz, 1H, ArH), 7.71–7.67 (m, 2H, ArH), 7.50 (s, 1H, ArH), 7.35 (dd, J = 8.3, 1.8 Hz, 1H, ArH), 7.11 (d, J = 7.4 Hz, 1H, ArH), 7.05 (dd, J = 7.4, 7.4 Hz, 1H, ArH), 7.0 (d, J = 8.3 Hz, 1H, ArH), 6.85 (d, J = 7.9 Hz, 1H, ArH), 6.03–5.97 (m, 1H,⚌C—H), 5.24–5.04 (m, 2H,⚌CH2), 3.95 (s, 3H, OCH3), 3.94 (s, 6H, OCH3), 1.80 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.2 (C⚌O), 161.8 (C⚌O), 155.5, 153.0, 139.3 (2C), 134.3 (2C), 132.2, 129.3 (2C), 127.8, 127.4 (2C), 126.6, 125.8, 124.4, 123.4, 118.0, 115.6, 114.6, 107.0 (3C), 82.3, 61.1 (OCH3), 56.4 (2C, OCH3), 25.6 (CH3); IR (KBr): 3268, 2957, 1712 (C⚌O), 1690 (C⚌O), 1653, 1620 cm−1; MS (EI): m/z 501 (M + 1, 70); HPLC: 99.9%, column: Symmetry C-18 75 ∗ 4.6 mm 3.5 μm, mobile phase A: 0.1% TFA in water mobile phase B: CH3CN (gradient) T/%B: 0/20, 0.5/20, 2/95, 8/95, 10/20, 12/20; flow rate: 1.0 mL/min; UV 275 nm; Elemental Analysis: found C, 69.52; H, 5.08; N, 3.12; C29H25NO7 requires C, 69.73; H, 5.04; N, 2.80.

2.6.3

2.6.3 4-Allyl-4-methyl-6-{4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl}-1H-benzo[d][1,3]oxazin-2(4H)-one (3c)

Off white solid, mp 115–117 °C [lit mp 118–120 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 10.05 (s, 1H, D2O exchangeable, NH), 8.17 (dd, J = 7.8, 7.8 Hz, 1H, ArH), 7.74 (s, 1H, ArH), 7.68–7.63 (m, 1H, ArH), 7.54–7.46 (m, 1H, ArH), 7.42–7.34 (m, 1H, ArH), 7.11–7.10 (m, 2H, ArH), 7.03 (s, 1H, ArH), 6.79–6.77 (m, 1H, ArH), 5.67–5.60 (m, 1H,⚌C—H), 5.07–5.03 (m, 2H,⚌CH2), 3.90 (s, 6H, OCH3), 3.79 (s, 3H, OCH3), 2.63–2.53 (m, 2H, CH2), 1.61 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.3 (C⚌O), 162.0 (C⚌O), 153.1, 152.3, 140.5, 135.0, 134.3, 133.6, 132.0, 131.1 (2C), 127.8, 127.1, 126.6, 126.5, 126.0, 121.7, 121.3, 120.4, 118.0, 116.3, 115.6, 107.1 (2C), 84.3, 61.1 (OCH3), 56.5 (2C, OCH3), 45.4 (CH2), 26.2 (CH3); IR (KBr): 3233, 2932, 1715 (C⚌O), 1684 (C⚌O), 1644 cm−1; MS (EI): m/z 515 (M + 1, 50); 98.8%, column: Symmetry C-18 75 ∗ 4.6 mm 3.5 μm, mobile phase A: 0.1% TFA in water mobile phase B: CH3CN (gradient) T/%B: 0/20, 0.5/20, 2/95, 10/95, 10.5/20, 12/20; flow rate: 1.0 mL/min; UV 270 nm.

2.6.4

2.6.4 6-{2-(3,4-Dimethoxyphenyl)-4-oxo-4H-chromen-3-yl}-4-methyl-4-pentyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3d)

Pale yellow solid, mp 106–108 °C [lit mp 109–110 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 9.60 (s, 1H, D2O exchangeable, NH), 7.81–7.70 (m, 1H, ArH), 7.51 (dd, J = 7.6, 7.6 Hz, 1H, ArH), 7.45–7.40 (m, 2H, ArH), 7.30 (d, J = 8.3 Hz, 2H, ArH), 7.14 (s, 2H, ArH), 6.77 (d, J = 8 Hz, 2H, ArH), 3.96 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 1.91–1.87 (m, 2H, CH2), 1.64 (s, 3H, CH3), 1.36–1.27 (m, 8H, CH2), 0.83 (t, J = 7.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.3 (C⚌O), 161.8 (C⚌O), 152.6, 152.7, 151.5, 148.5, 134.1, 133.5, 131.7, 127.0, 126.8, 126.6, 125.7, 125.1, 123.2, 121.7, 117.8, 116.4, 115.7, 112.5, 110.6, 108.6, 85.4, 56.2 (OCH3), 56.1 (OCH3), 41.0 (CH2), 31.8 (CH2), 27.1 (CH3), 23.2 (CH2), 22.4 (CH2), 14.0 (CH3). MS (EI): m/z 515 (M + 1, 70); HPLC: 98.9%, column: Symmetry C-18 75 ∗ 4.6 mm 3.5 μm, mobile phase A: 0.1% TFA in water mobile phase B: CH3CN (gradient) T/B%: 0/20, 0.5/20, 2/95, 10/95, 10.5/20, 12/20; flow rate: 1.0 mL/min; UV 270 nm.

2.6.5

2.6.5 6-{2-(3,4-Dimethoxyphenyl)-4-oxo-4H-chromen-3-yl}-4-methyl-4-vinyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3e)

Light orange solid; mp 138–140 °C [lit mp 139–143 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 8.91 (s, 1H, D2O exchangeable, NH), 8.27 (d, J = 7.9 Hz, 1H, ArH), 7.70 (dd, J = 7.9, 7.9 Hz, 1H, ArH), 7.50 (dd, J = 7.9, 7.9 Hz, 2H, ArH), 7.45 (d, J = 7.4 Hz, 1H, ArH), 7.34 (dd, J = 7.9, 1.4 Hz, 1H, ArH), 7.12 (d, J = 7.5 Hz, 1H, ArH), 7.05 (dd, J = 7.5, 7.5 Hz, 1H, ArH), 7.00 (d, J = 8.3 Hz, 1H, ArH), 6.86 (d, J = 7.5 Hz, 1H, ArH), 6.04–5.95 (m, 1H,⚌C-H), 5.24–5.04 (m, 2H,⚌CH2), 3.94 (s, 6H, OCH3), 1.80 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.3 (C⚌O), 161.8 (C⚌O), 155.6, 151.5, 148.5, 139.3, 134.5, 134.1, 132.2, 129.3, 127.4, 126.6, 125.7, 125.1, 124.4, 123.7, 123.4, 123.2, 121.7, 117.8, 114.7, 112.5, 110.6, 108.6, 83.7, 56.1 (2C, OCH3), 25.6 (CH3); IR (KBr): 3265, 2974, 1712 (C⚌O), 1680 (C⚌O), 1651, 1610, cm−1; MS (EI): m/z 471 (M + 1, 40); HPLC: 99.8%, column: X-Bridge C-18 150 ∗ 4.6 mm 5 μm, mobile phase A: 0.1% HCOOH in water mobile phase B: CH3CN (gradient) T/%B: 0/20, 3/20, 10/95, 23/95, 25/20, 30/20; flow rate: 1.0 mL/min; UV 240 nm.

2.6.6

2.6.6 4-Allyl-6-{2-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-3-yl}-4-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3f)

Pale yellow solid, mp 116–118 °C (lit mp 117–119 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H, D2O exchangeable, NH), 8.27 (d, J = 7.8 Hz, 1H, ArH), 7.90 (s, 1H, ArH), 7.26 (dd, J = 7.8, 7.8 Hz, 1H, ArH), 7.52–7.44 (m, 2H, ArH), 7.31 (d, J = 7.8 Hz, 1H, ArH), 7.17 (s, 1H, ArH), 7.10 (d, J = 8.2 Hz, 2H, ArH), 6.78 (d, J = 8.3 Hz, 1H, ArH), 5.72–5.64 (m, 1H,⚌C—H), 5.13–5.08 (m, 2H,⚌CH2), 3.92 (d, 6H, OCH3), 2.66–2.62 (m, 2H, CH2), 1.67 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): δ 173.4 (C⚌O), 162.0 (C⚌O), 155.6, 152.5, 151.5, 148.6, 135.1, 134.2, 133.6, 132.0, 131.1, 127.0, 126.5, 125.8, 125.0, 123.3, 121.7, 120.4, 118.0, 116.3, 115.6, 112.4, 110.6, 108.6, 84.5, 56.2 (OCH3), 56.1 (OCH3), 45.4 (CH2), 26.2 (CH3); IR (KBr): 3264, 2974, 1712 (C⚌O), 1684 (C⚌O), 1650, 1641 cm−1; MS (EI): m/z 485 (M + 1, 70); HPLC: 99.8%, column: X-Bridge C-18 150 ∗ 4.6 mm 5 μm, mobile phase A: 0.1% HCOOH in water mobile phase B: CH3CN (gradient) T/%B: 0/10, 3/10, 10/90, 20/90, 22/10, 25/10; flow rate: 1.0 mL/min; UV 275 nm.

2.6.7

2.6.7 6-{2-(4-Methoxyphenyl)-4-oxo-4H-chromen-3-yl}-4-methyl-4-pentyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3g)

Light orange solid, mp 112–114 °C [lit mp 113–114 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H, D2O exchangeable, NH), 8.13 (dd, J = 7.9, 7.9 Hz, 1H, ArH), 7.77 (d, J = 8.3 Hz, 1H, ArH), 7.67 (dd, J = 7.9, 7.9 Hz, 1H, ArH), 7.41 (m, 2H, ArH), 7.27 (d, J = 8.3 Hz, 1H, ArH), 7.14 (s, 2H, ArH), 6.98 (d, J = 8.3 Hz, 2H, ArH), 6.78 (d, J = 8.3 Hz, 1H, ArH), 3.85 (s, 3H, OCH3), 1.90–1.86 (m, 2H, CH2), 1.63 (s, 3H, CH3), 1.36–1.23 (m, 6H, CH2), 0.81 (t, J = 7.9 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 174.0 (C⚌O), 164.5 (C⚌O), 161.3, 155.9, 153.0, 134.2, 133.6, 131.7 (2C), 131.5, 127.8, 127.0, 126.8, 126.7, 125.8, 119.8, 117.6, 116.5, 115.7, 113.6, 113.5 (2C), 85.3, 55.5 (OCH3), 41.0 (CH2), 31.8 (CH2), 27.1 (CH3), 23.2 (CH2), 22.5 (CH2), 14.1 (CH3); IR (KBr): 3226, 2933, 2868, 1704 (C⚌O), 1685 (C⚌O), 1613 cm−1; MS (EI): m/z 485 (M + 1, 50); HPLC: 97.3%, column: X-Bridge C-18 150 ∗ 4.6 mm 5 μm, mobile phase A: 0.1% TFA in water mobile phase B: CH3CN (gradient) T/B%: 0/20, 3/20, 10/95, 20/95, 22/20, 25/20; flow rate: 1.0 mL/min; UV 270 nm; Elemental Analysis: found C, 74.37; H, 6.09; N, 3.19; C30H29NO5 requires C, 74.52; H, 6.04; N, 2.90.

2.6.8

2.6.8 6-{2-(4-Methoxyphenyl)-4-oxo-4H-chromen-3-yl}-4-methyl-4-vinyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3h)

Pale yellow solid; mp 163–165 °C [lit mp 160–168 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H, D2O exchangeable, NH), 8.26 (d, J = 7.9 Hz, 1H, ArH), 7.80 (d, J = 8.8 Hz, 1H, ArH), 7.7 (dd, J = 8.3, 8.3 Hz, 1H, ArH), 7.46 (d, J = 7.9 Hz, 1H, ArH), 7.43 (dd, J = 7.4, 7.4 Hz, 1H, ArH), 7.36 (dd, J = 8.3, 1.5 Hz, 1H, ArH), 7.12 (d, J = 7.9 Hz, 1H, ArH), 7.07–7.01 (m, 3H, ArH), 6.86 (d, J = 7.9 Hz, 1H), 6.05–5.96 (m, 1H,⚌C—H), 5.25–5.05 (m, 2H,⚌CH2), 3.89 (s, 3H, OCH3), 1.81 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 174.7 (C⚌O), 164.4 (C⚌O), 161.7, 155.8, 153.0, 139.3, 134.1, 132.2, 131.4 (2C), 129.3, 127.4, 127.2, 126.7, 125.8, 124.4, 123.5, 120.0, 117.6, 115.6, 114.7, 113.7 (2C), 113.6, 87.6, 55.5 (OCH3), 25.6 (CH3); IR (KBr): 3255, 2954, 1707 (C⚌O), 1681 (C⚌O), 1654, 1613 cm−1; MS (EI): m/z 441 (M + 1, 80); HPLC: 99.3%, column: Symmetry C-18 75 ∗ 4.6 mm 3.5 μm, mobile phase A: 0.1% TFA in water mobile phase B: CH3CN (gradient) T/B%: 0/20, 0.5/20, 2/95, 10/95, 10.5/20, 12/20; flow rate: 1.0 mL/min; UV 270 nm; Elemental Analysis: found C, 73.98; H, 4.87; N, 3.05; C27H21NO5 requires C, 73.79; H, 4.82; N, 3.19.

2.6.9

2.6.9 4-Allyl-6-{2-(4-methoxyphenyl)-4-oxo-4H-chromen-3-yl}-4-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3i)

Off white solid; mp 122–124 °C [lit mp 124–125 °C (Kumar and Ahmed, 2015)]; 1H NMR (400 MHz, CDCl3): δ 9.73 (s, 1H, D2O exchangeable, NH), 8.26 (d, J = 7.9 Hz, ArH, 1H), 7.71 (s, ArH, 1H), 7.52–7.49 (m, ArH, 1H), 7.45–7.41 (m, ArH, 1H), 7.30 (d, J = 8.4 Hz, ArH, 2H), 7.16 (s, ArH, 1H), 7.01 (s, ArH, 2H), 7.00 (d, J = 8.4 Hz, ArH, 1H), 6.77 (d, J = 8.4 Hz, ArH, 1H), 5.74–5.65 (m,⚌C⚌H, 1H), 5.12–5.01 (m,⚌CH2, 2H), 3.8 (s, 3H, OCH3), 2.68–2.59 (m, 2H, CH2), 1.66 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.4 (C⚌O), 162.0 (C⚌O), 155.6, 152.4, 151.5, 148.5, 135.1, 134.2, 133.6, 132.0, 131.1 (2C), 127.0, 125.8 (2C), 123.2, 121.7, 120.4, 117.8, 116.3, 115.6, 112.4, 110.5, 108.5, 84.2, 56.2 (OCH3), 45.4 (CH2), 26.2 (CH3); IR (KBr): 3266, 2973, 1712 (C⚌O), 1691 (C⚌O), 1650, 1611 cm−1; MS (EI): m/z 455 (M + 1, 80); HPLC: 97.7%, column: X-Bridge C-18 150 ∗ 4.6 mm 5 μm, mobile phase A: 0.1% HCOOH in water mobile phase B: CH3CN (gradient) T/%B: 0/20, 3/20, 10/95, 23/95, 25/20, 30/20; flow rate: 1.0 mL/min; UV 240 nm; Elemental Analysis: found C, 73.89; H, 5.10; N, 3.01; C28H23NO5 requires C, 74.16; H, 5.11; N, 3.09.

2.6.10

2.6.10 6-{2-(4-methoxyphenyl)-4-oxo-4H-chromen-3-yl}-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one (3j)

Off white solid: mp 115–117 °C; 1H NMR (DMSO-d6) 9.75 (s, 1H, D2O exchangeable), 8.24 (d, J = 7.8 Hz, 1H, ArH), 7.72 (s, 1H, ArH), 7.53–7.50 (m, 1H), 7.45–7.41 (m, 1H, ArH), 7.32 (d, J = 7.8 Hz, 2H), 7.15 (s, 1H), 6.98 (s, 2H), 6.97 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H, ArH), 3.80 (s, 3H, OCH3), 1.7 (s, 6H, CH3); 13C NMR (100 MHz, CDCl3): δ 173.7 (C⚌O), 162.3 (C⚌O), 155.7, 152.4, 150.4, 147.1, 134.3, 133.7, 132.0, 131.5 (2C), 127.0, 125.7 (2C), 123.1, 121.4, 120.2, 117.6, 116.2, 112.3, 110.4, 108.3, 84.1, 56.4 (OCH3), 26.3 (2C, CH3); MS (EI): m/z 429 (M + 1, 100); HPLC: 99.6%, column: Symmetry C-18 150 ∗ 4.6 mm 5 μm, mobile phase A: 0.1% Formic Acid in water mobile phase B: CH3CN (gradient) T/B%: 0/20, 3/20, 12/95, 25/95, 27/20, 30/20; flow rate: 1.0 mL/min; UV 275 nm; Elemental Analysis: found C, 73.21; H, 4.94; N, 3.05; C26H21NO5 requires C, 73.06; H, 4.95; N, 3.28.

3

3 Results and discussion

To test the feasibility of our approach toward the synthesis of 3 we focused on the Pd/C catalyzed Suzuki–Miyaura coupling of 3-bromo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (Cárdenas et al., 2006) (1a) with 4-methyl-2-oxo-4-pentyl-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-ylboronic acid (Zhang et al., 2002) (2a) under various conditions (Table 1). Initially, the reaction was performed in 5:1 DMF/H2O using K2CO3 as a base at 55–60 °C in the absence of any ligand or additive under ultrasound irradiation using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz. The reaction proceeded under the condition employed affording the desired product 3a in low yield after 60 min (entry 1, Table 1). However, significant increase in yield was observed when the reaction was carried out in the presence of equivalent quantity of tetrabutylammonium bromide (TBAB) (Badone et al., 1997) (entry 2, Table 1). The use of lower quantity of TBAB or other additive e.g. tetrabutylammonium chloride (TBAC) was less effective (entry 3 and 4, Table 1). The use of other base such as KOH or Na2CO3 was also less effective (entry 5 and 6, Table 1). Indeed a significant amount of homocoupled product was obtained from 1a in the first case. While all these reactions were performed in 5:1 DMF/H2O an increase in water volume decreased the product yield perhaps due to the inferior solubility of reactants in larger quantity of water (entry 7, Table 1). The reaction proceeded well in other aqueous medium e.g. DME/H2O or 1,4-dioxane/H2O (entry 8 and 9, Table 1) affording good yield of product though not better than that of DMF/H2O. The role of ultrasound was also examined by performing the reaction under silent condition when 3a was isolated only in 42% yield after 2 h (entry 10, Table 1). The role of Pd-catalyst was assessed by performing the reaction in the presence of mercury (Hg). The reaction did not proceed perhaps due to the accumulation of Hg on the charcoal surface [thereby alloying with Pd through dπ-dπ bonding (the catalyst poisoning) (Dunleavy, 2006)] and/or formation of Hg/Pd amalgam with underligated Pd(0) present in solution indicating the role of Pd/C in the present coupling reaction. To test the recyclability of the catalyst the catalytic activity of the recovered Pd/C (obtained via filtration of the reaction mixture of entry 2) was monitored. While a gradual decrease in catalytic activity of the recovered catalyst was observed the product 3a was isolated in 83%, 80% and 79% yield after second, third and fourth run. Overall, the condition of entry 2 was found to be best among all the conditions tested and was used for further study.

To expand the scope and generality of this methodology leading to the compound 3a a number of reactions were performed using several 3-bromoflavones (1a–c) and boronic acids (2a–d) (Table 2). The 10%Pd/C-TBAB-K2CO3-DMF/H2O system worked well in all these cases as the reaction proceeded to completion affording good yields of desired products (3) (Kumar and Ahmed, 2015). All the bromoflavones (1a–c) were prepared via bromination of the corresponding flavones under mild conditions following the reported methods (Rho et al., 2002; Rocha et al., 2012). The boronic acids were prepared following reported (Zhang et al., 2002; Baker et al., 2001; Zhou et al., 2010) methods as shown in Scheme 3. Thus bromination of 2-amino acetophenone (4) followed by Grignard reaction of the product 5 afforded the secondary alcohol 6 which on CDI mediated intramolecular cyclization gave the benzooxazinone 7. The bromo compound 7 was then converted to the boronic acid derivatives via treatment with triisopropyl borate in the presence of BuLi.

Preparation of boronic acids (3).
Scheme 3 Preparation of boronic acids (3).

All the 6-flavonyl substituted 1,4-dihydro-benzo[d][1,3]oxazin-2-ones (3) synthesized were characterized by spectral data. The 13C signals near 160 and 170 ppm were due to the C⚌O group of benzo[d][1,3]oxazin-2(4H)-one and flavone ring respectively. Similarly, the C⚌O group of these rings caused IR absorptions near 1720 and 1680 cm−1. The CH3 substituent of benzo[d][1,3]oxazin-2(4H)-one moiety appeared near δ 1.7 in the 1H NMR and 27 ppm in 13C NMR spectra. Additionally, the NH moiety appeared near δ 10 in the 1H NMR and 3255 cm−1 in the IR spectra whereas the OCH3 group appeared near δ 3.8 and 56 ppm in the 1H and 13C NMR spectra of 3. The alkyl chain at the C-4 position of the benzo[d][1,3]oxazin-2(4H)-one ring was also characterized by their respective signals appeared in both 1H and 13C NMR spectra.

Based on the study of Chen et al. (2007) a probable reaction mechanism for the present Pd/C-mediated synthesis of 3 under ultrasound showing the key steps involved is depicted in Scheme 4. These steps are as follows: (i) oxidative addition of Pd(0) generated from Pd/C to the bromoflavone (1) affording the organo-Pd(II) species E-1 (ii) reaction of E-1 with base to form E-2 via the exchange of anions (iii) transmetalation of E-2 with the borate complex E-3 (generated via the reaction of boronic acid 2 with the base thereby increasing the polarization of aryl group attached with the boron atom) to form the organo palladium species E-4, (iv) reductive elimination of Pd(0) to give the desired product 3 and complete the catalytic cycle. It is worthy to mention that the role of base in Suzuki–Miyaura coupling has been investigated earlier (Amatore et al., 2011) which showed its role in the generation of Pd(II)-complex (cf E-2) and borate complex (cf E-3), and acceleration of the reductive elimination step. The base in the present case appeared to be Bu4N+OH− that is generated via the reaction of TBAB with aqueous hydroxide ion produced by K2CO3 (Chen et al., 2007) in the presence of water and ultrasound. Notably, the direct use of KOH as a base did not afford better result than K2CO3 (entry 5, Table 1) due to the homocoupling of bromo compound 1 as a side reaction. Nevertheless, it appeared that the overall catalytic cycle operated in solution rather than on the surface and Pd was re-precipitated on the charcoal surface at the end of the reaction. To gain evidence on Pd-leaching in the present case the reaction of 1a with 2a was carried out under the condition of entry 2 of Table 1 for 10 min when ∼50% conversion to 3a was observed. The Pd/C catalyst was then removed by filtration and the reaction was continued for another 15 min without adding any additional catalyst when conversion to 3a was found to reach ∼80%. It is therefore evident that the initial step involves generation of an active Pd(0) species via a Pd leaching process (Chen et al., 2007) from the minor portion of the bound palladium (Pd/C) into the solution. Notably, both aryl halides (e.g. iodides or bromides) and aryl borates but not bases or solvents are known to facilitate the Pd leaching process (Chen et al., 2007). The results of Table 1 clearly suggest that one or more steps of this catalytic cycle were accelerated by ultrasound. Indeed, the shorter reaction time can be explained by faster Pd leaching process assisted by ultrasound thereby facilitating the subsequent steps. The rapid transmetalation and reductive elimination of Pd(0) (to give the product 3) are the other steps that are perhaps facilitated greatly by the ultrasound energy. Nevertheless, both catalyst and ultrasound played key roles in completing the reaction within 20 min.

The proposed reaction mechanism.
Scheme 4 The proposed reaction mechanism.

4

4 Conclusion

In conclusion, Pd/C has been identified as an efficient catalyst for facilitating Suzuki–Miyaura coupling of 2-aryl-3-bromoflavones with 4,4-disubstituted (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acids under ultrasound irradiation. The methodology involved use of 10%Pd/C-TBAB-K2CO3 as a system to facilitate the coupling in aqueous DMF and does not require the use of expensive phosphine ligand. This operationally simple Pd/C-based method afforded desired and corresponding 6-flavonyl substituted 1,4-dihydro-benzo[d][1,3]oxazin-2-ones in good yield within a short reaction time. Studies have shown that both catalyst and ultrasound played a key role in the faster coupling reaction. The recyclability of Pd/C was examined and found to be recyclable indicating better usage of catalyst compared to the traditional Pd complexes or salts. A reaction mechanism describing the generation of actual catalytic species followed by the catalytic cycle is presented. Overall, the methodology may find wide applications in constructing diversity based library of small molecules containing the 6-flavonyl substituted 1,4-dihydro-benzo[d][1,3]oxazin-2-one framework of potential pharmacological interest.

Acknowledgments

The authors thank the management of Dr. Reddy’s Institute of Life Sciences, Hyderabad, India, for continuous support and encouragement.

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