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Copper promoted diaryl ether synthesis; Dimethyl 5-(4-((tert-butoxycarbonylamino)methyl)phenoxy)isophthalate

SyntheticPage 540
DOI: 10.1039/SP540
Submitted Mar 13, 2012, published Mar 29, 2012
Joshua Howgego (joshua.howgego@gmail.com)
A contribution from Tony Davis' research group
Reaction Scheme: Copper promoted diaryl ether synthesis

Chemicals Used

(4-(((tert-butoxycarbonyl)amino)methyl)phenyl) boronic acid
dimethyl 5-hydroxyisophthalate
Copper(II) acetate
Triethylamine
4A molecular seives
Dicloromethane

Procedure

To a 100 mL 2 neck flask under an atmosphere of nitrogen were added the boronic acid (530 mg, 2.11 mmol), dimethyl 5-hydroxyisophthalate (443 mg, 2.11 mmol), Cu(OAc)2 (383 mg, 2.11 mmol) and powdered 4Å molecular sieves (100 mg, ca. 20 wt%). Anhydrous CH2Cl2 (40 mL) was added and the mixture was stirred for 2 min before distilled triethylamine (1.47 mL) was added. After stirring for a further 18 h the reaction mixture was filtered through a plug of celite and concentrated to a crude oil. Purification via flash column chromatography (4:6, EtOAc-hexanes) and concentration yielded an oil. Precipitation of the product via addition of hexanes (50 mL) and subsequent filtration then furnished the desired product as a white solid (832 mg, 95%);

Author's Comments

These types of reaction often call for 2 - 3 equivalents of the boronic acid component because these compounds can undergo side reactions such as triaryl boroxime formation. In the present case I found that a 1:1 ratio of phenol to boronic acid worked well and gave the product in excellent yeild.

Data

Rf = 0.22 (EtOAc-hexanes, 3:7);
FTIR (ATR): νmax = 3413, 2984, 1731, 1705, 1589, 1526, 1506, 1456, 1413, 1391 and 1365 cm -1;

1H NMR (400 MHz, CDCl3) δ = 1.46 (s, 9H, -C(CH3)3), 3.93 (s, 6H, -CO2CH3), 4.32 (d, 2H, J = 5.6 Hz, -CH2NHBoc), 4.87 (bs, 1H, -NHBoc), 6.98 (d, 2H, J = 8.8 Hz, aryl CH), 7.29 (d, 2H, J = 8.6 Hz, aryl CH), 7.82 (d, 2H, J = 1.5 Hz, aryl CH), 8.41 (t, 1H, J = 2 x 1.5 Hz, aryl CH);

13C NMR (125 MHz, CDCl3) δ = 28.4 (-C(CH3)3), 44.1 (-CH2NHBoc), 52.5 (-CO2CH3), 79.6 (-C(CH3)3), 119.5 (aryl CH), 123.5 (aryl CH), 125.2 (aryl CH), 129.25 (aryl Cq), 132.2 (aryl CH), 135.0 (aryl Cq), 155.3 (aryl Cq), 155.9 (-CO2C(CH3)3), 157.8 (aryl Cq), 165.7 (-CO2CH3);

HRMS (ESI): m/z calculated for C22H25NO7Na+ [M+Na]+: 438.1529. Found: 438.1543.

Lead Reference

D. A. Evans, J. L. Katz and T. R. West, Tetrahedron Letters, 1998, 39, 2937-2940.

Other References

 P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon and P. K. Jadhav, Tetrahedron Letters, 2001, 42, 3415-3418.

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Keywords: ethers, substitution, transition metal catalysed