Organic Process Research & Development
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water and EtOAc were added to the mixture. The organic layer
was extracted, washed by water, and concentrated at 50 °C to
give the title compound 15 (10.25 g, quant.) as a pale-yellow
(dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.74 (t, J =
7.5 Hz, 1H), 5.18 (brs, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.69 (s,
3H), 3.53 (s, 2H), 2.68 (dt, J = 7.5, 6.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): δ 172.4, 154.6, 145.3, 141.4, 133.6, 132.1,
130.0, 129.1, 127.5, 126.2, 125.7, 124.0, 119.7, 70.5, 62.6, 52.1,
40.1, 33.3; MS ESI (+) m/z 325 [M + H]+.
1
oil: H NMR (CDCl3, 300 MHz) δ 7.58 (dd, J = 7.7, 1.1 Hz,
1H), 7.53 (dd, J = 7.7, 1.3 Hz, 1H), 7.32 (td, J = 7.7, 1.3 Hz,
1H), 7.21 (d, J = 8.8 Hz, 2H), 7.17 (td, J = 7.7, 1.1 Hz, 1H),
6.93 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H), 3.68 (s, 3H), 3.57 (s,
2H); 13C NMR (CDCl3, 75 MHz): δ 172.3, 157.6, 136.3, 132.6,
130.3, 129.2, 128.9, 127.6, 126.7, 122.2, 115.0, 69.5, 52.0, 40.3;
MS ESI (+) m/z 337, 335 [M + H]+.
(Z)-11-[(3-Dimethylamino)propylidene]-6,11-
dihydrobenz[b,e]oxepin-2-acetic Acid Hydrochloride
(1). To methyl (Z)-11-[(3-hydroxy)-propyridene]-6,11-
dihydrobenz[b,e]oxepin-2-acetate (6) (21.0 g, 64.7 mmol) in
pyridine (160 mL) was added methanesulfonyl chloride (28.0
g, 3.8 equiv) gradually at 5 °C. The reaction mixture was heated
to room temperature and stirred for 2 h. The mixture was
quenched with water and then extracted with ethyl acetate. The
organic layer was washed with saturated aqueous NaCl and
concentrated. To a solution of obtained oil in MeOH (400 mL)
was add 50% aqueous dimethylamine (120 mL,18.0 equiv). and
the mixture was stirred under reflux for 3 h. NaOH solution (2
mol/L, 100 mL) was added to the reaction mixture, then the
mixture was stirred under reflux for 2 h. Water and butyl acetate
were added to the reaction mixture, and the aqueous layer was
adjusted to pH 2 with 2 mol/L HCl. The organic layer was
concentrated to afford the title compound 1 (21.4 g, 88.4%).
Methyl 4-(2-Bromobenzyloxy)-3-iodophenylacetate
(14). Iodine (7.28 g, 1.0 equiv) and AgSO4 (8.71 g, 1.0
equiv) were added to methanol (15 mL), and the mixture was
stirred until iodine was dissolved. To the mixture was added a
solution of methyl 4-hydroxyphenylacetate (15) (9.44 g, 28.1
mmol) in methanol (15 mL) at room temperature. The mixture
was stirred at 18 °C for 2 h, then the mixture was filtrated and
washed with EtOAc. The filtrate was concentrated at 50 °C to
form a yellow solid. The solid was slurried in methanol and
corrected by filtration to give the title compound 14 (11.00 g,
86%) as a white colorless crystal; 1H NMR (CDCl3, 300 MHz)
δ 7.78 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.59 (dd, J
= 7.9, 1.1 Hz, 1H), 7.37 (td, J = 7.9, 1.0 Hz, 1H), 7.25−7.21
(m, 2H), 6.83 (d, J = 8.3 Hz, 1H), 5.18 (s, 2H), 3.70 (s, 3H,),
3.55 (s, 2H); 13C NMR (CDCl3, 75 MHz): δ 171.7, 156.1,
140.2, 135.8, 132.6, 132.4, 130.4, 129.1, 128.7, 127.7, 121.5,
112.4, 86.5, 70.3, 52.1, 39.6; MS ESI (−) m/z 461, 459 [M −
H]−.
Methyl 4-(2-Bromobenzyloxy)-3-(4-hydroxybutynyl)-
phenylacetate (5). Under N2 atmosphere, a solution of
methyl 4-(2-bromobenzyloxy)-3-iodophenylacetate (14) (5.0 g,
10.8 mmol), PdCl2(PPh3)2 (381 mg, 0.05 equiv), CuI (103 mg,
0.1 equiv), 3-butyn-1-ol (1.84 mL, 2.0 equiv). and Et3N (6.06
mL, 4.0 equiv) in DMF (50 mL) was stirred at 25 °C for 5 h.
The mixture was quenched with water and then extracted with
ethyl acetate. The organic layer was washed with saturated
aqueous NaCl and filtered to remove Pd residue. Then the
organic layer was concentrated and purified by silica gel column
chromatography (EtOAc/hexane = 1:1) to afford the title
compound 5 (4.34 g, 100%) as an amber oil; 1H NMR (CDCl3,
300 MHz) δ 7.64 (ddJ = 7.7, 1.7 Hz, 1H,), 7.57 (dd, J = 7.7, 1.1
Hz, 1H), 7.34 (td, J = 7.7, 1.1 Hz, 1H), 7.33 (d, J = 2.2 Hz,
1H), 7.18 (td, J = 7.7, 1.7 Hz, 1H), 7.14 (dd, J = 8.6, 2.2 Hz,
1H), 6.85 (d, J = 8.6 Hz, 1H), 5.18 (s, 2H), 3.80 (t, J = 6.1 Hz,
2H), 3.69 (s, 3H), 3.53 (s, 2H), 2.73 (t, J = 6.1 Hz, 2H); 13C
NMR (CDCl3, 75 MHz): δ 171.9, 158.1, 136.1, 134.1, 132.5,
130.1, 129.2, 128.6, 127.6, 126.6, 121.8, 113.4, 112.7, 91.0, 78.7,
70.0, 61.1, 52.1, 40.0, 24.2; MS ESI (+) m/z 405, 403 [M +
H]+.
AUTHOR INFORMATION
Corresponding Author
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ACKNOWLEDGMENTS
■
We thank Dr. Toru Sugaya for giving us this attractive research
subject, and Dr. Hitoshi Arai for giving us helpful advice on this
manuscript.
REFERENCES
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Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-
dihydrobenz[b,e]oxepin-2-acetate (6). Under N2 atmos-
phere, a solution of methyl 4-(2-bromobenzyloxy)-3-(4-
hydroxybutynyl)-phenylacetate (5) (200 mg, 0.496 mmol),
Pd(OAc)2 (11.1 mg, 0.1 equiv), tri-o-tolylphosphine (37.7 mg,
0.25 equiv), piperidine (344 μL, 7.0 equiv), and formic acid
(20.5 μL, 1.1 equiv) in DMF (2.0 mL) was stirred at 92 °C for
3 h. The mixture was quenched with water and then extracted
with ethyl acetate. The organic layer was washed with saturated
aqueous NaCl. The organic layer was concentrated, and the
obtained oil was purified by silica gel column chromatography
(ethyl acetate/hexane = 1:2) to afford the title compound 6
(10) Nishimura, K.; Kinugawa, M. PCT Int. Appl. WO/2006/129781
A1, 2006.
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(114 mg, 71%) as a white colorless crystal; H NMR (CDCl3,
300 MHz) δ 7.34−7.23 (m, 4H), 7.17 (d, J = 2.2 Hz, 1H), 7.04
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dx.doi.org/10.1021/op200312m | Org. ProcessRes. Dev. 2012, 16, 225−231