HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 8, 2015, pp. 1660-1667
Received, 27th May, 2015, Accepted, 29th June, 2015, Published online, 8th July, 2015.
DOI: 10.3987/COM-15-13257

■ Synthesis of 2-(Arylmethylene)-1,4-benzoxazin-3-one by One-Pot Sonogashira and 6-exo-Dig Cyclization

Dahye Lee, Sunhwa Park, Yosep Yu, Kye Jung Shin, and Jae Hong Seo*

College of Pharmacy, The Catholic University of Korea, 43 Jinong-ro Wonmi-gu Bucheon, Gyeonggi-do, 420-743, Korea

Abstract

A novel, efficient one-pot approach to synthesize 2-(arylmethylene)-1,4-benzoxazin-3-ones has been developed. This method effectively combined the Sonogashira reaction of electron-deficient propiolamide and successive 6-exo-dig cyclization to selectively provide (Z)-isomers of 2-(arylmethylene)-1,4-benzoxazin-3-ones in good yield.

1,4-Benzoxazin-3-ones have been found in numerous natural products and drugs, and show various biological activities.2 Among them, 1,4-benzoxazin-3-ones with an arylmethylene group at the C2 position have been reported to have unique activities, such as neuroprotection and tyrosine kinase inhibition.3 However, synthetic methods for 2-(arylmethylene)-1,4-benzoxazine have not been well-studied. Generally, 2-(arylmethylene)-1,4-benzoxazines 1 have been prepared by the condensation reaction between arylaldehyde 3 and proper nucleophilic derivatives of 1,4-benzoxazin-3-ones 2, such as Knoevenagel (X = H)3 and Wittig (X = Br)2a reactions (Scheme 1). Recently we reported a one-pot approach to synthesize 3-(arylmethylene)oxindoles combining Sonogashira, Heck and Suzuki-Miyaura reactions from the corresponding propiolamides.4 The electron-deficient alkyne group of propiolamides has low reactivity toward general Sonogashira reactions, which hampers the development of a tandem reaction, including a Sonogashira reaction of propiolamides. As part of our ongoing efforts to develop novel synthetic methods for heterocycles by combining the Sonogashira reaction of electron-deficient alkyne substrate and other reactions, we describe a new, efficient approach for synthesizing 2-(arylmethylene)-1,4-benzoxazin-3-ones 1 from propiolamide 4 and aryl iodide 5, connecting the Sonogashira reaction and successive 6-exo-dig cyclization.

First, model substrate 8 was prepared from known benzoxazolone 65 by modifying the procedure of Overman’s group (Scheme 2).6 The addition of TBS-acetylide to 6 yielded TBS-protected propiolamide 7, in which the TBS group was deprotected by TBAF under AcOH-buffered conditions to provide the desired propiolamide 8 in 97% yield.

Next, we tried to find optimal reaction conditions for a one-pot Sonogashira reaction and cyclization with propiolamide 8 (Table 1). Under Sonogashira reaction conditions of Zhu et al.,7 which we used in our previous work, propiolamide 8 was successfully transformed into Sonogashira adduct 9 in 97% yield (entry 1). To facilitate cyclization, the reaction temperature was increased to 90 ºC after completion of the Sonogashira reaction. As expected, cyclized product 10 was formed at 90 ºC in 38% yield in combination with remaining intermediate 9 (20% yield) (entry 2). The stereochemistry of the olefin of 10 was determined to be Z configuration by comparing the known chemical shift of the vinyl proton (δH = 6.95 ppm for Z isomer, 6.75 ppm for E isomer).8 To determine the effect of a base on the reaction, various bases were tested. Reactions with KOAc, Na2CO3 and K2CO3 were completed before increasing the temperature to 90 ºC. However, various unassignable by-products were also formed with the desired product 10 in low yield (26–27%) (entries 3-5). Using CsF and K3PO4 as a base helped to increase the yield of 10 to 35% and 33%, respectively. These reactions provide another cyclized product 11 in 8% and 28% yield, which was produced by direct cyclization of 8 before the Sonogashira reaction (entries 6 and 7). The best result was obtained with Cs2CO3, which gave 10 in 67% yield with a relatively small amount of 11 (3% yield) (entry 8). The reaction at room temperature with Cs2CO3 increased the amount of by-product 11 (22% yield) with moderate yield of 10 (50% yield) (entry 9). Increasing the reaction temperature to 90 ºC shortened the reaction time (0.5 h) but the yield of 10 was slightly lower than that of 60 ºC (57%, entry 10 vs 67%, entry 8). These results indicated that the reaction was strongly affected by the type of base and reaction temperature. With an optimal combination of base (Cs2CO3) and reaction temperature (60 ºC), the formation of by-product 11 was reduced, and the desired 1,4-benzoxazin-3-one 10 was obtained in good yield.

With the optimal reaction conditions, we next investigated the substrate scope of the reaction (Table 2). Aryl iodides with electron-withdrawing groups gave the desired products in good yield (entries 1-3). An electron-donating group (4-MeO) of aryl iodide decreased the yield to 42% (entry 4). This low yield is probably due to low reactivity of electronically-sufficient aryl iodide toward the Sonogashira reaction. However, the reaction with aryl iodide bearing the 3-methoxy group proceeded smoothly to give 12e in 67% yield (entry 5). The chemical shifts of the vinyl proton for all compounds (6.89~6.91 ppm) except 12c (6.99 ppm) were similar to that of 10 (6.91 ppm), which supported the Z configuration of olefins. The olefin stereochemistry of 12c was determined by measuring the coupling constant between the carbonyl carbon and vinyl proton (3JC-H = 3.2 Hz) in non-decoupling 13C NMR, which Honda et al. used to determine the olefin geometry of similar benzoxazin-3-one derivatives (Z isomer: 3JC-H = 3.1 Hz).3a

To support the intermediacy of Sonogashira adduct 9 in the reaction with Cs2CO3, 9 was exposed to the standard reaction conditions, which provide 10 in 68% yield. However, under the same reaction conditions, directly cyclized product 11 could not be transformed into 10 to be recovered quantitatively (Scheme 3). These results suggested that the reaction goes through a Sonogashira reaction followed by 6-exo-dig cyclization.9

In conclusion, a novel, efficient synthetic method for 2-(arylmethylene)-1,4-benzoxazin-3-ones was developed by combining the Sonogashira reaction and 6-exo-dig cyclization, which provides the (Z)-isomer as the sole detectable isomer.

EXPERIMENTAL
All reactions were performed under an argon atmosphere with dry solvents, unless otherwise stated. All commercially available reagents were purchased and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (Merck TLC Silica Gel 60 F254) using UV light or PMA (an ethanolic solution of phosphomolybdic acid) as visualizing agent. Purification of products was conducted by column chromatography through silica gel 60 (0.060–0.200 mm). Melting points of all solid compounds were determined by Buchi M-565. NMR spectra were obtained on Bruker AVANCE III 500 MHz using residual undeuterated solvent as an internal reference. High-resolution mass spectra (HR-MS) were recorded on a JEOL JMS-700 using EI (electron impact).

Preparation of Propiolamide 8
3-(tert-Butyldimethylsilyl)-N-(2-hydroxyphenyl)-N-methylpropiolamide (7)
To a solution of (tert-butyldimethylsilyl)acetylene (0.22 mL, 1.2 mmol, 1.2 equiv) in THF (5 mL) was added n-BuLi (2.0 M in THF, 0.55 mL, 1.1 mmol, 1.1 equiv) at –78 °C. After 30 min a solution of N-methyl-2-benzoxazolinone (150 mg, 1.0 mmol, 1.0 equiv) in THF (5 mL) was added to the mixture, and the resulting solution was gradually warmed to 0 °C. After 5 h stirring at 0 °C, the mixture was diluted with sat. aq. NH4Cl (1.0 mL), EtOAc (20 mL), and H2O (10 mL) in order. Organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2) to yield TBS-propiolamide 7 (235 mg, 0.81 mmol, 81% yield) as a white solid. 7: mp 152.2 °C; Rf = 0.50 (silica gel, CH2Cl2 : EtOAc 9 : 1); 1H NMR (500 MHz, CDCl3, 1.6:1 atropisomeric mixture): δ 7.25–7.21 (m, 1H, major), 7.16 (dd, J = 8.0, 1.7 Hz, 1H, major), 7.15 (dd, J = 8.3, 1.5 Hz, 1H, minor), 7.07 (dd, J = 8.3, 1.3 Hz, 1H, minor), 7.01–6.98 (m, 1H, major and minor), 6.96–6.93 (m, 1H, minor), 6.89 (td, J = 15.3, 1.3 Hz, 1H, major), 6.68 (s, 1H, minor), 5.97 (s, 1H, major), 3.67 (s, 3H, minor), 3.26 (s, 3H, major), 1.01 (s, 9H, minor), 0.69 (s, 9H, major), 0.24 (s, 6H, minor), –0.06 (d, J = 2.0 Hz, 6H, major) ppm; 13C NMR (125 MHz, CDCl3, major and minor): δ 155.0, 154.2, 152.6, 151.1, 130.9, 130.3, 129.8, 129.2, 128.9, 124.2, 121.6, 121.1, 120.9, 117.3, 100.0, 97.3, 96.8, 96.6, 40.7, 35.7, 26.2, 25.9, 16.8, 16.3, –5.0, –5.3 ppm; HRMS (EI): calcd for C16H23NO2Si [M+]: 289.1498, found 289.1498.
N-(2-Hydroxyphenyl)-N-methyl-3-phenylpropiolamide (8)
To a solution of TBS-propiolamide 7 (400 mg, 1.38 mmol, 1.0 equiv) in THF (15 mL) were added AcOH (0.079 mL, 1.4 mmol, 1.0 equiv) and TBAF (1.0 M in THF, 1.5 mL, 1.5 mmol, 1.1 equiv) at 0 °C, and the resulting solution was stirred at 0 °C for 12 h. Then, the mixture was diluted with sat. aq. NH4Cl (5 mL) and EtOAc (20 mL). Organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes : EtOAc 2 : 1) to yield propiolamide 8 (234 mg, 1.34 mmol, 97% yield) as a white solid. 8: mp 149.5 °C; Rf = 0.15 (silica gel, hexanes : EtOAc 2 : 1); 1H NMR (500 MHz, CDCl3, 1.6:1 atropisomeric mixture): δ 7.28–7.23 (m, 1H, major and minor), 7.19–7.15 (m, 1H, major and minor), 7.08 (dd, J = 8.3, 1.3 Hz, 1H, minor), 7.02–7.00 (m, 1H, major and minor), 6.94 (td, J = 15.3, 1.3 Hz, 1H, major), 6.44 (s, 1H, minor), 5.91 (s, 1H, major), 3.68 (s, 3H, minor), 3.37 (s, 1H, minor), 3.28 (s, 3H, major), 2.79 (s, 1H, major) ppm; 13C NMR (125 MHz, CDCl3, major and minor): δ 154.6, 153.8, 152.7, 151.0, 130.54, 130.45, 129.3, 129.2, 124.6, 121.7, 121.0, 120.7, 117.6, 81.8, 79.6, 75.9, 75.8, 40.6, 35.9 ppm; HRMS (EI): calcd for C10H9NO2 [M+]: 175.0633, found 175.0634.

General Procedure for Sonogashira and 6-exo-dig Cyclization
To a stirred solution of propiolamide 8 (0.25 mmol, 1.0 equiv) in DMF (2.5 mL) were added the corresponding aryl iodide (0.28 mmol, 1.1 equiv), CuI (0.0013 mmol, 5 mol%), Cs2CO3 (0.75 mmol, 3.0 equiv) and Pd(PPh3)4 (0.025 mmol, 10 mol%) at 25 °C. The reaction mixture was stirred at 60 °C for 1 h. Then, the mixture was cooled to 25 °C and diluted with EtOAc (100 mL). Organic layer was washed with H2O (15 mL X 3) and brine (15 mL), then dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, CH2Cl2) to yield 1,4-benzoxazin-3-ones (10, 11, 12a-e) and/or phenylpropiolamide 9.
N-(2-Hydroxyphenyl)-N-methyl-3-phenylpropiolamide (9)
Yellow solid; mp 124.1 °C; Rf = 0.49 (silica gel, hexanes : EtOAc 1 : 1); 1H NMR (500 MHz, CDCl3, 5.3:1 atropisomeric mixture): δ 8.38 (s, 1H, major), 7.56–7.54 (m, 2H, minor), 7.41 (t, J = 7.5 Hz, 1H, minor), 7.33 (t, J = 7.5 Hz, 2H, minor), 7.28 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H, major), 7.24 (t, J = 1.2 Hz, 1H, minor), 7.21 (dd, J = 8.0, 1.5 Hz, 2H, major), 7.19–7.17 (m, 2H, minor), 7.13 (dd, J = 8.3, 1.3 Hz, 1H, major), 7.09 (t, J = 7.8 Hz, 2H, major, 1H, mionr), 6.98 (dd, J = 8.3, 1.3 Hz, 2H, major), 6.95–6.93 (m, 1H, minor), 6.89 (td, J = 15.3, 1.5 Hz, 1H, major), 3.69 (s, 3H, minor), 3.35 (s, 3H, major) ppm; 13C NMR (125 MHz, CDCl3, major and minor): δ 156.0, 155.2, 153.2, 151.2, 132.8, 130.9, 130.8, 130.3, 130.1, 129.9, 129.4, 129.0, 128.8, 128.3, 124.6, 121.6, 120.74, 120.68, 120.3, 120.0, 117.6, 93.6, 91.6, 82.1, 81.7, 40.7, 35.8 ppm; HRMS (EI): calcd for C16H13NO2 [M+]: 251.0946, found 251.0946.
(Z)-2-Benzylidene-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (10)
White solid; mp 155.1 °C [Lit.,10 155-156 °C]; Rf = 0.60 (silica gel, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.20–7.18 (m, 1H), 7.10–7.07 (m, 2H), 7.02–7.00 (m, 1H), 6.96 (s, 1H), 3.48 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 157.4, 142.0, 141.2, 133.9, 130.1, 128.7, 128.3, 127.6, 123.9, 123.4, 116.1, 114.5, 113.0, 28.8 ppm; HRMS (EI): calcd for C16H13NO2 [M+]: 251.0946, found 251.0947.
4-Methyl-2-methylene-2H-benzo[b][1,4]oxazin-3(4H)-one (11)
White solid; mp 98.3 °C; Rf = 0.57 (silica gel, hexanes : EtOAc 3 : 1); 1H NMR (500 MHz, CDCl3): δ 7.07–7.00 (m, 3H), 6.98–6.95 (m, 1H), 5.61 (d, J = 1.6 Hz, 1H), 5.06 (d, J = 1.6 Hz, 1H), 3.43 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 156.5, 147.9, 142.1, 127.3, 123.9, 122.9, 115.7, 114.3, 98.8, 28.4 ppm; HRMS (EI): calcd for C10H9NO2 [M+]: 175.0633, found 175.0627.
(Z)-2-(4-Chlorobenzylidene)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12a)
White solid; mp 214.9 °C; Rf = 0.47 (silica gel, hexanes : EtOAc 3 : 1); 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.20–7.18 (m, 1H), 7.13–7.08 (m, 2H), 7.03–7.01 (m, 1H), 6.91 (s, 1H), 3.49 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 157.1, 141.8, 141.5, 133.9, 132.3, 131.3, 128.9, 127.5, 124.0, 123.6, 116.0, 114.5, 111.6, 28.9 ppm; HRMS (EI): calcd for C16H12ClNO2 [M+]: 285.0557, found 285.0560.
(Z)-4-Methyl-2-(4-(trifluoromethyl)benzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one (12b)
Yellow solid; mp 171.1 °C; Rf = 0.45 (silica gel, hexanes : EtOAc 3 : 1); 1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.16–7.14 (m, 1H), 7.11–7.05 (m, 2H), 6.99–6.97 (m, 1H), 6.91 (s, 1H), 3.44 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 156.6, 142.5, 141.4, 137.2, 130.0, 129.5 (q, 2JCF = 32 Hz), 127.2, 125.5, 125.5 (q, 3JCF = 3.8 Hz), 124.2 (q, 1JCF = 270 Hz), 124.0, 123.7, 116.0, 114.5, 110.9, 28.8 ppm; HRMS (EI): calcd for C17H12F3NO2 [M+]: 319.0820, found 319.0821.
(Z)-4-Methyl-2-(4-nitrobenzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one (12c)
Yellow solid; mp 235.7 °C; Rf = 0.39 (silica gel, hexanes : EtOAc 3 : 1); 1H NMR (500 MHz, CDCl3): δ 8.25 (d, J = 8.9 Hz, 2H), 7.97 (d, J = 8.9 Hz, 2H), 7.23 (dd, J = 7.5, 1.9 Hz, 1H), 7.18–7.12 (m, 2H), 7.06 (dd, J = 7.5, 1.9 Hz, 1H), 6.99 (s, 1H), 3.52 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 156.3, 146.7, 143.6, 141.3, 140.4, 130.3, 127.2, 124.3, 124.1, 123.9, 116.2, 114.7, 110.0, 29.0 ppm; HRMS (EI): calcd for C16H12N2O4 [M+]: 296.0797, found 296.0794.
(Z)-2-(4-Methoxybenzylidene)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12d)
Yellow solid; mp 165.2 °C; Rf = 0.39 (silica gel, hexanes : EtOAc 3 : 1); 1H NMR (500 MHz, CDCl3): δ 7.81 (d, J = 8.8 Hz, 2H), 7.17–7.14 (m, 1H), 7.10–7.03 (m, 2H), 6.99–6.97 (m, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.91 (s, 1H), 3.85 (s, 3H), 3.46 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.6, 157.7, 142.1, 139.7, 131.7, 127.7, 126.6, 123.8, 123.2, 115.9, 114.4, 114.1, 112.9, 55.4, 28.7 ppm; HRMS (EI): calcd for C17H15NO3 [M+]: 281.1052, found 281.1055.
(Z)-2-(3-Methoxybenzylidene)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12e)
Yellow solid; mp 116.0 °C; Rf = 0.34 (silica gel, hexanes : EtOAc 3 : 1); 1H NMR (500 MHz, CDCl3): δ 7.44 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.13–7.12 (m, 1H), 7.08–7.02 (m, 2H), 6.96–6.95 (m, 1H), 6.89 (s, 1H), 6.86 (dd, J = 8.2, 1.9 Hz, 1H), 3.85 (s, 3H), 3.43 (s, 3H); ) ppm; 13C NMR (125 MHz, CDCl3): δ 159.6, 157.1, 141.8, 141.2, 135.0, 129.4, 127.4, 123.8, 123.3, 122.8, 115.9, 115.0, 114.4, 114.2, 112.7, 55.3, 28.7 ppm; HRMS (EI): calcd for C17H15NO3 [M+]: 281.1052, found 281.1052.

ACKNOWLEDGEMENTS
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014R1A1A1038332) and Research Fund 2011 of The Catholic University of Korea.

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