Synthesis of 1-benzoxepin-5-ones (ols) from salicylaldehydes via
ring-closing metathesis
Sie-Rong Li,a,b Hsing-Ming Chen,c Liang-Yeu Chen,b Jui-Chi Tsai,b Po-Yuan Chen,a
Sodio Chih-Neng Hsu,a and Eng-Chi Wanga*
aFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City,
Taiwan 807
bInstitute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung City, Taiwan
807
cSchool of Medical and Health Sciences, Fooyin University, Kaohsiung County, Taiwan 831
E-mail: [email protected]
Abstract
A new synthetic method for 1-benzoxepin-5-ones and 1-benzoxepin-5-ols from salicylaldehydes was described. Based on O-allylation, Grignard reaction, oxidation, and ring-closing metathesis in sequence, salicylaldehydes were converted to the target compounds in good yields, respectively.
Keywords: Ring-closing metathesis, salicylaldehydes, 1-benzoxepin-5-ones, 1-benzoxepin-5-ols
Introduction
The 1-benzoxepine moiety which plays a core structure both in naturally occurring products1 and in certain synthetic biological molecules,2 have abstracted the attention of chemists. In addition, benzoxepinone which has been employed as starting material, can be converted to corresponding quinoline by the Friedlander reaction,3 and can be transformed into benzoxepine by isomerization of double bond, reduction of carbonyl group, and dehydration of giving alcohol in sequence.4 The major synthetic methods for benzoxepinones which were reported in literatures, include the cyclopropanation and sequential reductive cleavage of flavones,5 the reaction of bromoalkyl ketones through the sequential reduction and oxidation,6 the reaction of dihydrobenzoxepinone via silylation and following by desilylation with DDQ and collidine.7 The drawbacks of those reported methods include the lack of conciseness, straightforward, and commercial available starting materials. Furthermore, the synthesis of benzoxepin-5-ols was paid little attention in reported literatures.4,8 Therefore, to develop a concise and practical method for the title compounds is requisite and significant. Since Grubbs’ catalyst was developed in 1995,
the ring-closing metathesis (RCM) has been widely applied to the compounds which were difficulty to be synthesized by the previous reported methods.9 However, the synthesis of 1-benzoxepin-5-ols and 1-benzoxepin-5-ones utilized RCM has not been reported in current publications. Based on the chemistry of RCM, herein we would like to report a concise and practical method for those compounds (Scheme 1).
R1 R2 CHO O R1 R2 O OH a. R1 = R2 = R3 = H b. R1 = R3= H, R2 = OMe c. R1 = OMe, R2 = R3 = H d. R1 = R2 = H, R3 = Br e. R1 = R3 = Cl, R2 = H MgBr R1 R2 O R1 R2 O R1 R2 O Grubbs' cat. Grubbs' cat. MnO2 R1 R2 CHO OH Br K2CO3 THF 1 2 3 4 6 5 95-98% 73-87% 70-80% 64-85% 76-84% O R3 R3 R3 R3 R3 R3 O HO CH3CN Scheme 1
Results and Discussion
By the reaction of salicylaldehydes (1a-e) and allyl bromide in the presence of potassium carbonate in refluxing acetonitrile for 4h, allyloxybenzaldehydes (2a-e) was obtained in 95-98% yields. At the same condition if the reaction was carried out in refluxing acetone instead of acetonitrile, the yield of 2a-e was decreased.10 Subsequently, 2a-e was reacted with vinylmagnesium bromide to give (2-allyloxyaryl)-2-propen-1-ols (3a-e) in 73-87% yields, respectively. The giving 3a-e which are all new compounds except 3c, have satisfactory spectral data. Followed by oxidation of 3a-e with MnO2 in dichloromethane, (2-allyloxyaryl)-2-propen-1-ones (4a-e) were obtained in 70-80% yields, respectively, together with small amount of unidentified by-product. The products 4a-e which are all new compounds except 4c, have satisfactory spectral data. Subsequently, by the treatment of 4a-e with Grubbs catalyst (2nd generation) in dichloromethane at room temperature for 6 hr, 2H-1-benzoxepin-5-ones (5a-e) were produced in 76-84% yields, respectively. Furthermore, by the treatment of (2-allyloxyaryl)-2-propen-1-ol (3a-e) with Grubbs catalyst (2nd generation) in dichloromethane at room temperature for 6 hr, 2H-1-benzoxepin-5-ol (6a-e) were given in 64-85% yields, respectively. Thus, we have established a new route to both ones and 2H-1-benzoxepin-5-ols. The structure of 5a-e and 6a-e were respectively elucidated by spectral data such as 1
H-NMR, 13C-NMR and mass spectra. The typical signals of 1H-NMR of 2H-1-benzoxepin-5-ones
(5a-e) and 2H-1-benzoxepin-5-ols (6a-e), such as H-2, H-3, H-4, and H-5, together with typical
carbonyl carbon of 13C-NMR of 5a-e were summarized in Table 1.
Table 1. The typical signals of 1H-NMR of 2H-1-benzoxepin-5-one (5a-e) and 2H-1-benzo-oxepin-5-ol (6a-c) R1 R2 O 5 R3 O R1 R2 O 6 R3 HO a. R1 = R2 = R3 = H b. R1 = R3= H, R2 = OMe c. R1 = OMe, R2 = R3 = H d. R1 = R2 = H, R3 = Br e. R1 = R3 = Cl, R2 = H 1 2 3 4 5 1 2 3 4 5 Compound H-2 H-3 H-4 H-5 C-5a 5a 4.55 (dd) 6.75 (dt) 6.43 (dt) - 189.86 5b 4.68 (dd) 6.69 (dt) 6.41 (dt) - 188.14 5c 4.78 (dd) 6.76 (dt) 6.44 (dt) - 190.37 5d 4.73 (dd) 6.78 (dt) 6.41 (dt) - 188.22 5e 4.81 (dd) 6.80 (dt) 6.41 (dt) - 187.89 6a 4.52, 4.60 (ddd) 5.48 (m) 5.99 (ddt) 5.50 (m) - 6b 4.48, 4.57 (ddd) 5.46 (m) 5.97 (ddt) 5.38 (m) - 6c 4.52, 4.59 (ddd) 5.47 (m) 5.97 (ddt) 5.54 (m) - 6d 4.46, 4.63 (ddd) 5.48 (m) 5.92 (ddt) 5.58 (m) - 6e 4.47, 4.70 (ddd) 5.46 (m) 5.89 (ddt) 5.69 (m) - aThe chemical shifts of carbonyl carbon (C-5) of 5a-e in 13C-NMR spectra.
In conclusion, a new synthetic method for benzoxepinones and benzoxepinols from salicylaldehydes was established. The application of α,β-unsaturated carbonyl functionality of benzoxepinones and allyl alcoholic functionality of benzoxepinols to synthesize some related compounds is in progressive.
Experimental Section
General Procedures. Melting points (Yanaco micro melting-point apparatus) were uncorrected.
1H-NMR and 13C-NMR spectra were obtained on a Varian Gemini-200 or Varian Unity plus 400 Spectrometer. Chemical shifts were measured in parts per million with respect to TMS. Mass spectra were recorded on a Chem/hp/middle spectrometer connected to a Hewlett Packard series II model gas-liquid chromatograph. HRMS spectra were performed on a JEOL JMS SX/SX 102A instrument. Silica gel (230-400 mesh) for column chromatography and precoated silica gel
plates (60 F-254) for TLC was purchased from E. Merck Company. UV light (254 nm) was used to detect spots on TLC plates after development.
General procedure for the preparation of 2-allyloxybenzaldehydes (2a-e)
The 2-hydroxybenzaldehydes (1a-e) (100 mmol) dissolved in anhydrous acetonitrile (150 mL) was added anhydrous K2CO3 (120 mmol). The mixture which was obtained was stirred and added allyl bromide (120 mmol) and heated to reflux for 4 hr. Work-up as in the general procedure gave crude 2a-e which was further purified by silica-gel column (ethyl acetate: n-hexane = 1: 15) to give pure 2a-e.
2-Allyloxybenzaldehyde (2a).10 (15.69 g, 97%) was obtained as colorless liquid, Rf = 0.16 (ethyl acetate: n-hexane = 1: 15), 1H-NMR (CDCl3, 400 MHz) δ 4.65 (dt, J = 5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.34 (ddt, J = 10.4, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.45 (ddt, J = 17.2, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 6.01 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H, OCH2CH=CH2), 6.97 (m, 1H, ArH), 7.02 (m, 1H, ArH), 7.52 (m, 1H, ArH), 7.83 (m, 1H, ArH), 10.53 (s, 1H, CHO); 13 C-NMR (CDCl3, 100 MHz) δ 69.0, 112.8, 117.9, 120.7, 125.0, 128.3, 132.3, 135.8, 160.8, 189.6; EI-MS (70 eV) m/z (rel. intensity, %) 163 ([M+1]+, 100), 162 (M+, 24), 161 (54), 133 (24), 121 (76), 120 (19), 105 (18), 92 (26); HRMS calcd for C10H10O2: 162.0681. Found: 162.0680.
2-Allyloxy-4-methoxybenzaldehyde (2b).11 (18.24 g, 95%) was obtained as colorless crystal, mp 37-38oC, Rf = 0.33 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 200 MHz) δ 3.85 (s, 3H, OCH3), 4.62 (dt, J = 5.2, 1.4 Hz, 2H, OCH2CH=CH2), 5.33 (ddt, J = 10.6, 1.4, 1.4 Hz, 1H, OCH2CH= CHaHb), 5.45 (ddt, J = 17.4, 1.4, 1.4 Hz, 1H, OCH2CH=CHaHb), 6.04 (ddt, J = 17.4, 10.6, 5.2 Hz, 1H, OCH2CH=CH2), 6.43 (d, J = 2.0 Hz, 1H, ArH), 6.54 (dd, J = 8.8, 2.0 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH), 10.35 (s, 1H, CHO); 13C-NMR (CDCl3, 50 MHz) δ 55.6, 69.1, 99.0, 106.0, 118.1, 119.2, 130.4, 132.2, 162.6, 166.0, 188.2; EI-MS (70 eV) m/z (rel. intensity, %) 193 ([M+1]+, 30), 192 (M+, 35), 164 (28), 163 (54), 151 (100), 150 (91), 135 (45), 122 (27), 95 (28); HRMS calcd for C11H12O3: 192.0786. Found: 192.0784.
2-Allyloxy-3-methoxybenzaldehyde (2c).12 (18.82 g, 98%) was obtained as colorless liquid, Rf = 0.26 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 200 MHz) δ 3.86 (s, 3H, OCH3), 4.62 (dt, J = 6.0, 1.2 Hz, 2H, OCH2CH=CH2), 5.33 (ddt, J = 10.2, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.45 (ddt, J = 17.4, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 6.04 (ddt, J = 17.4, 10.2, 6.0 Hz, 1H, OCH2CH=CH2), 7.10 (m, 2H, ArH), 7.37 (m, 1H, ArH), 10.41 (s, 1H, CHO); 13C-NMR (CDCl3, 50 MHz) δ 55.9, 75.0, 113.3, 117.9, 118.9, 124.0, 130.0, 133.0, 151.1, 152.9, 190.2; EI-MS (70 eV) m/z (rel. intensity, %) 193 ([M+1]+, 100), 192 (M+, 54), 175 (17), 166 (20), 164 (29), 163 (55), 151 (83), 136 (17) , 131 (20), 122 (20); HRMS calcd for C11H12O3: 192.0786. Found: 192.0783.
2-Allyloxy-5-bromobenzaldehyde (2d).13 (23.03 g, 96%) was obtained as colorless liquid, Rf = 0.50 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400 MHz) δ 4.60 (dt, J = 5.2, 1.6 Hz, 2H, OCH2CH=CH2), 5.31 (ddt, J = 10.8, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.40 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 6.02 (ddt, J = 17.2, 10.8, 5.2 Hz, 1H, OCH2CH=CH2), 6.84 (d, J = 8.8 Hz, 1H ArH), 7.54 (dd, J = 8.8, 2.8 Hz, 1H, ArH), 7.84 (d, J = 2.8 Hz, 1H, ArH),
10.38 (s, 1H, CHO); 13C-NMR (CDCl3, 100 MHz) δ 69.3, 113.4, 114.8, 118.4, 126.1, 130.7, 131.8, 138.1, 159.6, 188.1; EI-MS (70 eV) m/z (rel. intensity, %) 242 ([M+2]+, 20), 240 (M+, 21), 201 (48), 200 (44), 199 (56), 198 (34), 143 (24), 133 (70) , 132 (100), 64 (27), 63 (54); HRMS calcd for C10H9BrO2: 239.9786. Found: 239.9786.
2-Allyloxy-3,5-dichlorobenzaldehyde (2e).14 (21.85 g, 95%) was obtained as colorless crystal, mp 43-44oC, Rf = 0.61 (ethyl acetate: n-hexane = 1: 15), 1H-NMR (CDCl3, 400 MHz) δ 4.61 (d,
J = 6.4 Hz, 2H, OCH2CH=CH2), 5.32 (d, J = 10.4 Hz, 1H, OCH2CH=CHaHb), 5.39 (dd, J = 16.8,
1.2 Hz, 1H, OCH2CH=CHaHb), 6.07 (ddt, J = 16.8, 10.4, 6.4 Hz, 1H, OCH2CH=CH2), 7.61 (d, J = 2.8 Hz, 1H, ArH), 7.69 (d, J = 2.8 Hz, 1H, ArH), 10.27 (s, 1H, CHO); 13C-NMR (CDCl3, 100 MHz) δ 76.6, 120.3, 126.5, 129.9, 130.4, 131.6, 131.7, 135.6, 156.2, 187.9; EI-MS (70eV) m/z (rel. intensity, %) 232 ([M+2]+, 5), 230 (M+, 8), 203 (44), 201 (69), 191 (59), 190 (72), 189 (100), 188 (95) , 167 (42), 135 (34), 133 (57), 97 (63); HRMS calcd for C10H8Cl2O2: 229.9901. Found: 229.9902.
General procedure for the preparation of (2-allyloxyaryl)-2-propen-1-ol (3a-e)
Under N2, the O-allyloxybenzaldehydes (2a-e) (30 mmol) dissolved in anhydrous THF (100 mL) was stirred and cooled to 0oC and was subsequently added vinylmagnesium bromide (1.6 M) (22.5 mL, 36 mmol). The resulting mixture was stirred at 0oC for 0.5 hr and then at room temperature for 2 hr and then, quenched with saturated aq. NH4Cl. The giving mixture was concentrated in vacuo to remove THF and the resulting residue was extracted with ethyl acetate (20 mL x 5). The organic layer was combined and washed with brine, and then dried over anhydrous MgSO4, and filtered in sequence. The giving filtrate was concentrated in vacuo to remove the solvent. The residue which was obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 15) to give pure 3a-e.
1-(2-Allyloxyphenyl)-2-propen-1-ol (3a). (4.60 g, 81%) was obtained as colorless liquid, Rf = 0.38 (ethyl acetate: n-hexane = 1: 10), 1H-NMR (CDCl3, 400 MHz) δ 2.87 (br d, J = 6.0 Hz, 1H, OH), 4.57 (dt, J = 5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.16 (ddd, J = 10.4, 1.2 Hz, 1.2 Hz, 1H, CH(OH)- CH=CHaHb), 5.29 (ddt, J = 10.4, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.32 (ddd, J = 17.6, 1.2, 1.2 Hz, 1H, CH(OH)CH=CHaHb), 5.41 (ddt, J = 17.6, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.44 (m, 1H, CH(OH)CH=CH2), 6.05 (ddt, J = 17.6, 10.4, 5.2 Hz, 1H, OCH2CH=CH2), 6.13 (ddd, J = 17.6, 10.4, 5.6 Hz, 1H, CH(OH)CH=CHaHb), 6.87 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.23 (m, 1H, ArH), 7.31 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 68.9, 71.6, 111.9, 114.5, 117.6, 121.1, 127.5, 128.6, 131.0, 132.0, 139.4, 155.7; EI-MS (70 eV) m/z (rel. intensity, %) 190 (M+, 6), 150 (10), 149 (100), 147 (18), 133 (12), 132 (19), 131 (97), 121 (81), 107 (25), 103 (26), 93 (14), 91 (19); HRMS calcd for C12H14O2: 190.0988. Found: 190.0986.
1-(2-Allyloxy-4-methoxyphenyl)prop-2-en-1-ol (3b). (5.74 g, 87%) was obtained as colorless
liquid, Rf = 0.31 (ethyl acetate: n-hexane = 1: 9),1H-NMR (CDCl3, 200 MHz) δ 2.82 (br d, J = 5.2 Hz, 1H, OH), 3.77 (s, 3H, OCH3), 4.53 (dt, J = 5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.14 (ddd, J = 10.4, 1.2, 1.2 Hz, 1H, CH(OH)CH=CHaHb), 5.28 (ddt, J = 10.4, 1.4 Hz, 1.4 Hz, 1H,
OCH2CH=CHaHb), 5.30 (ddd, J = 17.2, 1.2, 1.2 Hz, 1H, CH(OH)CH=CHaHb), 5.40 (m, 1H, CH(OH)CH=CH2), 5.41 (ddt, J = 17.2, 1.4 Hz, 1.4 Hz, 1H, OCH2CH=CHaHb), 6.04 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H, OCH2CH=CH2), 6.11 (ddd, J = 17.2, 10.4, 5.4 Hz, 1H, CH(OH)CH=CH2), 6.44 (d, J = 2.4 Hz, 1H, ArH), 6.47 (dd, J = 8.0, 2.4 Hz, 1H, ArH), 7.20 (d, J = 8.0 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 55.2, 68.8, 70.8, 99.8, 104.5, 114.1, 117.6, 123.7, 128.0, 132.8, 139.7, 156.6, 160.1; EI-MS (70 eV) m/z (rel. intensity, %) 221 ([M+1]+, 4), 220 (M+, 21), 203 (100), 202 (50), 201 (13), 164 (15), 161 (13), 151 (11); HRMS calcd for C13H16O3: 220.1099. Found: 220.1099.
1-(2-Allyloxy-3-methoxyphenyl)prop-2-en-1-ol (3c).15 (5.62 g, 85%) was obtained as colorless liquid, Rf = 0.33 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400 MHz) δ 2.93 (br d, J = 4.4 Hz, 1H, OH), 3.83 (s, 3H, OCH3), 4.52 (ddt, J = 12.0, 5.6, 1.6 Hz, 1H, OCHaHbCH=CH2), 4.56 (ddt, J = 12.0, 5.6, 1.6 Hz, 1H, OCHaHbCH=CH2), 5.15 (ddd, J = 10.4, 1.6, 1.6 Hz, 1H, CH(OH)CH=CHaHb), 5.23 (ddt, J = 10.4, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.31 (ddd, J = 17.2, 1.6, 1.6 Hz, 1H, CH(OH)CH=CHaHb), 5.36 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, OCH2CH= CHaHb), 5.47 (m, 1H, CH(OH)CH=CH2), 6.07 (ddd, J = 17.2, 10.4, 5.2 Hz, 1H, CH(OH)CH= CH2), 6.07 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H, OCH2CH=CH2), 6.84 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 6.93 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 7.04 (t, J = 8.0 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 55.6, 70.6, 73.7, 111.6, 114.3, 117.5, 119.1, 124.1, 134.0, 136.4, 139.9, 146.0, 152.4; EI-MS (70 eV) m/z (rel. intensity, %) 220 (M+, 19), 204 (17), 203 (100), 202 (59), 201 (11), 164 (23), 163 (11), 162 (20), 161 (32); HRMS calcd for C13H16O3: 220.1099. Found: 220.1100.
1-(2-Allyloxy-5-bromophenyl)prop-2-en-1-ol (3d). (5.85 g, 73%) was obtained as colorless liquid, Rf = 0.32 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 2.73 (br s, 1H, OH), 4.54 (dt, J = 5.2, 1.6 Hz, 2H, OCH2CH=CH2), 5.18 (ddd, J = 10.4, 1.6, 1.6 Hz, 1H, CH(OH)CH=CHaHb), 5.30 (ddt, J = 10.4, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.33 (ddd, J = 17.2, 1.6, 1.6 Hz, 1H, CH(OH)CH=CHaHb), 5.39 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, OCH2CH= CHaHb), 5.42 (m, 1H, CH(OH)CH=CH2), 6.02 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H, OCH2CH=CH2), 6.06 (ddd, J = 17.2, 10.4, 5.4 Hz, 1H, CH(OH)CH=CH2), 6.73 (d, J = 8.8 Hz, 1H, ArH), 7.32 (dd, J = 8.8, 2.6 Hz, 1H, ArH), 7.46 (d, J = 2.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 69.1, 70.5, 113.4, 113.6, 115.1, 117.9, 130.1, 131.1, 132.58, 133.3, 138.7, 154.6; EI-MS (70 eV) m/z (rel. intensity, %) 270 ([M+2]+, 17), 268 (M+, 17), 211 (71), 209 (72), 148 (57), 132 (41),
131 (100), 120 (72), 103 (62), 91 (56); HRMS calcd for C12H13BrO2: 268.0099. Found: 268.1100.
1-(2-Allyloxy-3,5-dichlorophenyl)prop-2-en-1-ol (3e). (5.81 g, 75%) was obtained as colorless
liquid, Rf = 0.35 (ethyl acetate: n-hexane = 1: 9),1H-NMR (CDCl3, 200 MHz) δ 2.39 (d, J = 4.6 Hz, 1H, OH), 4.52 (dt, J = 5.6, 1.6 Hz, 2H, OCH2CH=CH2), 5.24 (ddd, J = 10.2, 1.4, 1.4 Hz, 1H, CH(OH)CH=CHaHb), 5.30 (ddt, J = 10.2, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.37 (ddd, J = 17.2, 1.4, 1.4 Hz, 1H, CH(OH)CH=CHaHb), 5.42 (ddt, J = 17.0, 1.6, 1.6 Hz, 1H, OCH2CH= CHaHb), 5.50 (m, 1H, CH(OH)CH=CH2), 6.02 (ddd, J = 17.2, 10.2, 5.4 Hz, 1H, CH(OH)CH= CH2), 6.10 (ddt, J = 17.0, 10.2, 5.4 Hz, 1H, OCH2CH=CH2), 7.30 (d, J = 2.6 Hz, 1H, ArH), 7.32 (d, J = 2.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 69.7, 74.6, 115.8, 118.6, 126.3, 128.6,
129.4, 129.9, 132.8, 138.8, 139.1, 150.9; EI-MS (70 eV) m/z (rel. intensity, %) 260 ([M+2]+, 53%), 258 (M+, 1), 203 (16), 202 (42), 201 (71), 200 (66), 199 (100), 189 (17) , 167 (19), 165 (39), 137 (18);HRMS calcd for C12H12Cl2O2: 258.0214. Found: 258.0214.
General procedure for the preparation of (2-allyloxyphenyl)-2-propen-1-one (4a-e)
The (2-allyloxyphenyl)-2-propen-1-ol (3a-e) (20 mmol) which was dissolved in anhydrous CH2Cl2 (85 mL) was added MnO2 (200 mmol). The mixture was stirred at room temperature for 5 hr. After concentration in vacuo, the residue which was obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 20) to give pure 4a-e.
1-(2-Allyloxyphenyl)-2-propen-1-one (4a). (3.01 g, 80%) was obtained as colorless liquid, Rf = 0.53 (ethyl acetate: n-hexane = 1: 10), 1H-NMR (CDCl3, 400 MHz) δ 4.61 (dt, J = 5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.28 (ddt, J = 10.4, 1.2, 1.2 Hz, 1H, OCH2CH=CH2), 5.42 (ddt, J = 17.2, 1.2, 1.2 Hz, 1H, OCH2CH=CH2), 5.79 (dd, J = 10.4, 1.6 Hz, 1H, COCH=CHaHb), 6.03 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H, OCH2CH=CH2), 6.28 (dd, J = 17.2 Hz, 1.6 Hz, 1H, COCH=CHaHb), 6.95 (m, 1H, ArH), 7.00 (m, 1H, ArH), 7.04 (dd, J = 17.2, 10.4 Hz, 1H, COCH=CH2), 7.43 (m, 1H, ArH), 7.58 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 69.3, 112.9, 117.6, 120.9, 128.2, 128.9, 130.5, 132.5, 132.9, 136.7, 157.2, 193.3; EI-MS (70 eV) m/z (rel. intensity, %) 189 ([M+1]+, 6), 188 (M+, 2), 170 (16), 169 (26), 147 (38), 131 (24), 121 (100), 91 (22); HRMS calcd for C12H12O2: 188.0837. Found: 188.0839.
1-(2-allyloxy-4-methoxyphenyl)-2-propen-1-one (4b).(3.08 g, 70%) was obtained as colorless liquid, Rf = 0.38 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 3.83 (s, 3H, OCH3), 4.59 (dt, J = 5.2, 1.6 Hz, 2H, OCH2CH=CH2), 5.30 (ddt, J = 10.6, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.44 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.70 (dd, J = 10.4, 1.8 Hz, 1H, COCH=CHaHb), 6.04 (ddt, J = 17.2, 10.6, 5.2 Hz, 1H, OCH2CH=CH2), 6.32 (dd, J = 17.2, 1.8 Hz, 1H, COCH=CHaHb), 6.45 (d, J = 2.2 Hz, 1H, ArH), 6.54 (dd, J = 8.8, 2.2 Hz, 1H, ArH), 7.18 (dd, J = 17.2, 10.4 Hz, 1H, COCH=CH2), 7.71 (d, J = 8.8 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 55.4, 69.3, 99.6, 105.7, 117.7, 121.7, 126.7, 132.3, 132.8, 136.8, 159.4, 164.1, 190.7; EI-MS (70eV) m/z (rel. intensity, %) 219 ([M+1]+, 68), 218 (M+, 48), 217 (29), 188 (32), 163 (40), 151 (100), 121 (42), 91 (42), 77 (38), 63 (38); HRMS calcd for C13H14O3: 218.0943. Found: 218.0945.
1-(2-Allyloxy-3-methoxyphenyl)-2-propen-1-one (4c).15 (3.24 g, 74%) was obtained as colorless liquid, Rf = 0.38 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 3.87 (s, 3H, OCH3), 4.50 (dt, J = 5.8, 1.2 Hz, 2H, OCH2CH=CH2), 5.17 (ddt, J = 10.2, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.28 (ddt, J = 17.2, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.86 (dd, J = 10.4, 1.4 Hz, 1H, COCH=CHaHb), 6.00 (ddt, J = 17.2, 10.2, 5.8 Hz, 1H, OCH2CH=CH2), 6.22 (dd, J = 17.6, 1.4 Hz, 1H, COCH=CHaHb), 6.94 (dd, J = 17.2, 10.4 Hz, 1H, COCH=CH2) 7.07 (m, 3 H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 55.8, 74.8, 115.0, 117.7, 120.7, 123.9, 129.2, 133.4, 133.9, 136.5, 146.3, 152.7, 193.6; EI-MS (70eV) m/z (rel. intensity, %) 219 ([M+1]+, 100), 218 (M+, 34), 177 (22), 164 (13), 162 (15), 151 (52), 150 (20), 122 (21) , 121 (35), 91 (22); HRMS calcd for C13H14O3: 218.0943. Found: 218.0943.
1-(2-Allyloxy-5-bromophenyl)-2-propen-1-one (4d). (3.79 g, 71%) was obtained as colorless liquid, Rf = 0.50 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 4.59 (dt, J = 5.2, 1.4 Hz, 2H, OCH2CH=CH2), 5.29 (ddt, J = 10.6, 1.4, 1.4 Hz, 1H, OCH2CH=CHaHb), 5.40 (ddt, J = 17.2, 1.4, 1.4 Hz, 1H, OCH2CH=CHaHb), 5.84 (dd, J = 10.2, 1.6 Hz, 1H, COCH=CHaHb), 6.00 (ddt, J = 17.2, 10.6, 5.2 Hz, 1H, OCH2CH=CH2), 6.29 (dd, J = 17.2, 1.6 Hz, 1H, COCH=CHaHb), 6.84 (d, J = 8.8 Hz, 1H, ArH), 6.99 (dd, J = 17.2, 10.2 Hz, 1H, COCH=CH2), 7.51 (dd, J = 8.8, 2.6 Hz, 1H, ArH), 7.67 (d, J = 2.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 69.6, 113.3, 114.8, 118.0, 129.0, 130.4, 132.1, 132.9, 135.3, 136.2, 156.2, 191.6; EI-MS (70 eV) m/z (rel. intensity, %) 268 ([M+2]+, 5), 267 ([M+1]+, 10), 266 (M+, 5), 265 ([M-1]+, 9), 227 (33), 225 (36), 201 (96), 199 (100), 198 (67), 170 (24) , 169 (31), 131 (24), 119 (25), 90 (35), 89 (31), 63 (62);HRMS calcd for C12H11BrO2: 265.9942. Found: 265.9944.
1-(2-Allyloxy-3,5-dichlorophenyl)-2-propen-1-one (4e). (3.75 g, 73%) was obtained as
colorless liquid, Rf = 0.61 (ethyl acetate: n-hexane = 1: 15),1H-NMR (CDCl3, 400 MHz) δ 4.43 (dt, J = 6.0, 1.2 Hz, 2H, OCH2CH=CH2), 5.25 (ddt, J = 10.4, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.32 (ddt, J = 17.2, 1.2, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.98 (dd, J = 10.4, 1.2 Hz, 1H, COCH=CHaHb), 5.99 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H, OCH2CH=CH2), 6.29 (dd, J = 17.6, 1.2 Hz, 1H, COCH=CHaHb), 6.91 (dd, J = 17.6, 10.4 Hz, 1H, COCH=CH2), 7.38 (d, J = 2.8 Hz, 1H, ArH), 7.52 (d, J = 2.8 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 76.3, 119.4, 128.1, 129.8, 129.9, 131.4, 132.3, 132.8, 135.5, 135.7, 152.0, 191.5; EI-MS (70 eV) m/z (rel. intensity, %) 258 ([M+2]+, 1), 257 ([M+1]+, 6), 256 (M+, 2), 255 ([M-1]+, 7), 217 (25), 215 (42), 202 (24), 191 (64), 190 (64), 189 (100) , 188 (81), 161 (23), 159 (28), 133 (21), 97 (33); HRMS calcd for C12H10Cl2O2: 256.0058. Found: 256.0060.
General procedure for the preparation of 2H-1-benzoxepin-5-one (5a-e)
The (2-allyloxyphenyl)-2-propen-1-one (4a-e) (10 mmol) dissolved in anhydrous CH2Cl2 (100 mL) was added Grubbs' Catalyst (5 mol %) and the mixture was stirred at room temperature for 6 hr. Then, the mixture was concentrated in vacuo to remove the solvent. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 20) to give pure
5a-e.
2H-1-Benzoxepin-5-one (5a).4 (1.3 g, 81%) was obtained as colorless liquid, Rf = 0.35 (ethyl acetate: n-hexane = 1: 10),1H-NMR (CDCl3, 400 MHz) δ 4.55 (dd, J = 4.8, 1.2 Hz, 2H, OCH2- CH=CHCO), 6.43 (dt, J = 11.6, 1.2 Hz, 1H, OCH2CH=CHCO), 6.75 (dt, J = 11.6, 4.8 Hz, 1H, OCH2CH=CHCO), 7.09 (m, 1H, ArH), 7.17 (m, 1H, ArH), 7.47 (m, 1H, ArH), 7.95 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 68.8, 121.4, 123.9, 129.9, 131.2, 134.4, 134.8, 141.6, 159.0, 189.9; EI-MS (70 eV) m/z (rel. intensity, %) 161 ([M+1]+, 11), 160 (M+, 100), 132 (37), 131 (98), 104 (15), 103 (21), 77 (12); HRMS calcd for C10H8O2: 160.0519. Found: 160.0521.
8-Methoxy-2H-1-benzoxepin-5-one (5b). (1.45 g, 76%) was obtained as colorless liquid, Rf = 0.26 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 3.83 (s, 3H, OCH3), 4.68 (dd, J = 5.2, 1.2 Hz, 2H, OCH2CH=CHCO), 6.41 (dt, J = 11.6, 1.2 Hz, 1H, OCH2CH=CHCO), 6.52 (d, J = 2.4 Hz, 1H, ArH), 6.69 (dt, J = 11.6, 5.2 Hz, 1H, OCH2CH=CHCO), 6.70 (dd, J =
9.0, 2.4 Hz, 1H, ArH), 7.97 (d, J = 9.0 Hz, 1H, ArH);13C-NMR (CDCl3, 50 MHz) δ 55.6, 68.3, 104.7, 111.0, 122.2, 133.2, 135.6, 139.4, 161.4, 164.98, 188.1;EI-MS (70 eV) m/z (rel. intensity, %) 191 ([M+1]+, 34), 190 (M+, 91), 62 (75), 161 (100), 147 (25), 106 (20), 91 (24), 63 (62), 62 (21), 51 (27); HRMS calcd for C11H10O3: 190.0630. Found: 190.0630.
9-Methoxy-2H-1-benzoxepin-5-one (5c). (1.58 g, 83%) was obtained as colorless crystal, mp 81-82oC, Rf = 0.18 (ethyl acetate: n-hexane = 1: 10), 1H-NMR (CDCl3, 200 MHz) δ 3.90 (s, 3H, OCH3), 4.78 (dd, J = 4.4, 1.4 Hz, 2H, OCH2CH=CHCO), 6.44 (dt, J = 11.6, 1.4 Hz, 1H, OCH2CH=CHCO), 6.76 (dt, J = 11.6, 4.4 Hz, 1H, OCH2CH=CHCO), 7.11 (m, 2 H, ArH), 7.47 (dd, J = 6.6, 3.2 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 56.3, 69.3, 116.4, 121.9, 123.8, 131.8, 133.7, 141.9, 148.3, 151.4, 190.4;EI-MS (70 eV) m/z (rel. intensity, %) 191 ([M+1]+, 44), 190 (M+, 100), 161 (32), 147 (12), 119 (13), 91 (27), 76 (12), 65 (13), 63 (15), 51 (18); HRMS calcd for C11H10O3: 190.0630. Found: 190.0631.
7-Bromo-2H-1-benzoxepin-5-one (5d). (1.95 g, 82 %) was obtained as colorless crystal, mp
72-73oC, Rf = 0.30 (ethyl acetate: n-hexane = 1: 9),1H-NMR (CDCl3, 400 MHz) δ 4.73 (dd, J = 4.8, 1.2 Hz, 2H, OCH2CH=CHCO), 6.41 (dt, J = 11.6, 1.2 Hz, 1H, OCH2CH=CHCO), 6.78 (dt, J = 11.6, 4.8 Hz, 1H, OCH2CH=CHCO), 6.98 (d, J = 8.4 Hz, 1H,ArH), 7.54 (dd, J = 8.4, 2.4 Hz, 1H, ArH), 8.05 (d, J = 2.4 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 68.8, 116.7, 123.4, 131.0, 133.6, 133.9, 137.3, 141.8, 157.9, 188.2; EI-MS (70 eV) m/z (rel. intensity, %) 240 ([M+2]+, 57), 238 (M+, 57), 211 (80), 209 (82), 131 (100), 103 (61), 102 (35), 77 (39) , 63 (42); HRMS calcd for C10H7BrO2: 237.9629. Found: 237.9630.
7,9-Dichloro-2H-1-benzoxepin-5-one (5e). (1.91 g, 84%) was obtained as colorless crystal, mp
111-112oC, Rf = 0.39 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 4.81 (dd, J = 4.6, 1.4 Hz, 2H, OCH2CH=CHCO), 6.41 (dt, J = 11.8, 1.4 Hz, 1H, OCH2CH=CHCO), 6.80 (dt, J = 11.8, 4.6 Hz, 1H, OCH2CH=CHCO), 7.56 (d, J = 2.6 Hz, 1H,ArH), 7.76 (d, J = 2.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 69.4, 128.0, 129.1, 129.5, 132.7, 133.0, 134.2, 142.3, 152.9, 187.9; EI-MS (70 eV) m/z (rel. intensity, %) 230 ([M+2]+, 42), 228 (M+, 64), 201 (68), 199 (100), 165 (33), 136 (21), 102 (31); HRMS calcd for C10H6Cl2O2: 227.9745. Found: 227.9745.
General procedure for the preparation of 2,5-dihydro-1-benzoxepin-5-ol (6a-e)
The (2-allyloxyphenyl)-2-propen-1-ol (3a-e) (10 mmol) dissolved in anhydrous CH2Cl2 (100 mL) was stirred with added Grubbs' catalyst (5 mol %). The mixture was continually stirred at room temperature for 6 hr. Then, it was concentrated in vacuo to remove the solvent. The residue which was obtained was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 15) to give pure 6a-e.
2,5-Dihydro-1-benzoxepin-5-ol (6a).4 (1.30 g, 80%) was obtained as colorless liquid, Rf = 0.18 (ethyl acetate: n-hexane = 1: 10), 1H-NMR (CDCl3, 400 MHz) δ 2.75 (d, J = 8.0 Hz, 1H, OH), 4.52 (ddd, J = 17.2, 4.8, 2.4 Hz, 1H, OCHaHbCH=CH), 4.60 (ddd, J = 17.2, 4.8, 2.4 Hz, 1H, OCHaHbCH=CH), 5.48 (m, 1H, OCH2CH=CHCH(OH)), 5.50 (m, 1H, OCH2CH=CHCH(OH)), 5.99 (ddt, J = 11.6, 4.0, 2.4 Hz, 1H, OCH2CH=CHCH(OH)), 7.08 (m, 1H, ArH), 7.12 (m, 1H,
ArH), 7.25 (m, 1H, ArH), 7.32 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 68.9, 71.0, 121.6, 124.6, 125.4, 127.8, 128.9, 131.6, 139.2, 156.2; EI-MS (70 eV) m/z (rel. intensity, %) 162 (M+, 11), 145 (13), 144 (25), 133 (18), 132 (16), 131 (100), 115 (27), 105 (23), 77 (13); HRMS calcd for C10H10O2: 162.0681. Found: 162.0679.
8-Methoxy-2,5-dihydro-1-benzoxepin-5-ol (6b). (1.59 g, 83%) was obtained as colorless liquids,Rf = 0.13 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 3.19 (br s, 1H, OH), 3.76 (s, 3H, OCH3), 4.48 (ddd, J = 17.2, 4.4, 2.2 Hz, 1H, OCHaHbCH=CH), 4.57 (ddd, J = 17.2, 4.4, 2.2 Hz, 1H, OCHaHbCH=CH), 5.38 (m, 1H, OCH2CH=CHCH(OH)), 5.46 (m, 1H, OCH2- CH=CHCH(OH)), 5.97 (ddt, J = 11.6, 4.2, 2.2 Hz, 1H, OCH2CH=CHCH(OH)), 6.64 (d,
J = 2.6 Hz, 1H, ArH), 6.63 (dd, J = 8.8, 2.6 Hz, 1H, ArH), 7.18 (d, J = 8.8 Hz, 1H, ArH); 13
C-NMR (CDCl3, 50 MHz) δ 55.3, 68.5, 70.7, 107.5, 109.3, 126.4, 127.3, 131.0, 131.8, 157.0, 159.9; EI-MS (70 eV) m/z (rel. intensity, %) 193 ([M+1]+, 13), 192 (M+, 100), 177 (29), 175 (37), 161 (45), 150 (80), 121 (29), 91 (47), 77 (42), 63 (39), 51 (35); HRMS calcd for C11H12O3: 192.0786. Found: 192.0786.
9-Methoxy-2,5-dihydro-1-benzoxepin-5-ol (6c). (1.22 g, 64%) was obtained as colorless crystal, mp 99-100oC, Rf = 0.13 (ethyl acetate: n-hexane = 1: 10), 1H-NMR (CDCl3, 400 MHz) δ 2.81 (br d, J = 8.0 Hz, 1H, OH), 3.86 (s, 3H, OCH3), 4.52 (ddd, J = 17.6, 4.8, 2.4 Hz, 1H, OCHaHbCH=CH), 4.59 (ddd, J = 17.6, 4.8, 2.4 Hz, 1H, OCHaHbCH=CH), 5.47 (m, 1H, OCH2CH=CHCH(OH)), 5.54 (m, 1H, OCH2CH=CHCH(OH)), 5.97 (ddt, J = 11.6, 4.4, 2.4 Hz, 1H, OCH2CH=CHCH(OH), 6.88 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 6.93 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 7.07 (t, J = 8.0 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) δ 55.9, 68.6, 70.0, 111.6, 116.8, 124.8, 127.6, 131.6, 141.1, 144.0, 151.9; EI-MS (70 eV) m/z (rel. intensity, %) 193 ([M+1]+, 34), 192 (M+, 86), 175 (27), 177 (19), 163 (34), 131 (36), 103 (100), 91 (49), 77 (38), 51 (24); HRMS calcd for C11H12O3: 192.0786. Found: 192.0788.
7-Bromo-2,5-dihydro-1-benzoxepin-5-ol (6d). (1.86 g, 78%) was obtained as colorless crystal,
mp 111-113oC, Rf = 0.20 (ethyl acetate: n-hexane = 1: 9),1H-NMR (CDCl3, 400 MHz) δ 2.58 (d,
J = 7.6 Hz, 1H, OH), 4.46 (ddd, J = 17.2, 4.8, 2.4 Hz, 1H, OCHaHbCH=CH), 4.63 (ddd, J = 17.2,
4.8, 2.4 Hz, 1H, OCHaHbCH=CH), 5.48 (m, 1H, OCH2CH=CHCH(OH)), 5.58 (m, 1H, OCH2CH=CHCH(OH)), 5.92 (ddt, J = 12.0, 3.6, 2.4 Hz, 1H, OCH2CH=CHCH(OH)), 6.95 (d, J = 8.4 Hz, 1H, ArH), 7.35 (dd, J = 8.4, 2.4 Hz, 1H, ArH), 7.49 (d, J = 2.4 Hz, 1H, ArH); 13 C-NMR (CDCl3, 100 MHz) δ 68.1, 71.0, 117.5, 123.4, 127.4, 128.2, 131.4, 131.5, 141.4, 155.0; EI-MS (70 eV) m/z (rel. intensity, %) 242 ([M+2]+, 17), 240 (M+, 17), 211 (46), 209 (44), 161 (24), 133 (45), 132 (100), 131 (33), 115 (59), 105 (23), 63 (22); HRMS calcd for C10H9BrO2: 239.9786. Found: 239.9788.
7,9-Dichloro-2,5-dihydro-1-benzoxepin-5-ol (6e). (1.95 g, 85%) was obtained as colorless
crystal, mp 139-140oC, Rf = 0.26 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200 MHz) δ 2.53 (d, J = 7.4 Hz, 1H, OH), 4.47 (ddd, J = 17.6, 5.0, 2.4 Hz, 1H, OCHaHbCH=CH), 4.70 (ddd,
J = 17.6, 5.0, 2.4 Hz, 1H, OCHaHbCH=CH), 5.46 (m, 1H, OCH2CH=CHCH(OH)), 5.69 (m, 1H,
OCH2CH=CHCH(OH)), 5.89 (ddt, J = 11.6, 3.6, 2.4 Hz, 1H, OCH2CH=CHCH(OH)), 7.27 (d, J = 2.4 Hz, 1H, ArH), 7.31 (d, J = 2.4 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) δ 67.9, 69.9,
123.5, 126.8, 127.8, 128.5, 123.00, 131.6, 142.7, 149.8; EI-MS (70eV) m/z (rel. intensity, %) 232 ([M+2]+, 26), 230 (M+, 41), 203 (49), 201 (100), 199 (60), 189 (43), 167 (62), 166 (89), 149 (49), 133 (41), 132 (58), 131 (75); HRMS calcd for C10H8Cl2O2: 229.9901. Found: 229.9903.
Acknowledgements
Financial support (Grant no., NSC-96-2113-M-037-006) from NSC, Taiwan is grateful.
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