O-Arylation of Iodophenols
Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1 119
(0.050 mmol) of TEBAC in a closed vial was irradiated in a
CEM Discover microwave reactor at 120-140 °C for 2 hours.
The reaction mixture was taken up in 25 mL of ethyl acetate
and the suspension was filtered. Evaporation of the volatile
components provided the crude product that was passed
through a thin (ca. 2–3 cm) layer of silica gel using ethyl
acetate as the eluant to give an oil that was analysed by GC–
MS or GC.
REFERENCES
[1]
Dimmock, J.R.; Puthucode, R.N. Preparation of phenoxybenzalde-
hyde semicarbazones as nervous system agents. WO1996040628,
US5741818, Chem. Abstr., 1997, 126, 117797.
[2]
Puthucode, R.N.; Pugazhenthi, U.; Quail, J.W.; Stables, J.P.;
Dimmock, J.R. Anticonvulsant activity of various aryl, arylidene
and aryloxyaryl semicarbazones. Eur. J. Med. Chem., 1998, 33,
595-607.
[3]
Ilyin, V.I.; Hodges, D.D.; Whittemore, E.R.; Carter, R.B.; Cai,
S.X.; Woodward, R.M. V102862 (Co102862): A potent, broad-
spectrum state-dependent blocker of mammalian voltage-gated
sodium channels. British J. Pharmacol., 2005, 144, 801-812.
Victory, S.F.; Kyle, D.J.;Goehring, R.R. Preparation of
arylpyrimidines as sodium channel blockers. WO2003076414,
Chem. Abstr., 2003, 139, 261310.
Goehring, R.R.; Marra, J.M.; Stasaitis, L.R.; Perez, J. A synthesis
of 2-arylpyrimidine-4-carboxylic acid amide derivatives, useful as
modulators of Na+ channel activity. WO2004111011, Chem.
Abstr., 2004, 142, 74594.
Similar reactions were carried out in 3 mL of acetonitrile
or N,N-dimethylformamide as the solvent. The work-up was
similar to that described for the solvent-free alkylations
above, but in this case, ethyl acetate did not have to be
added.
[4]
[5]
The major components of the above reactions, such as
compounds 2, 3 and 8 were obtained in a pure form by
repeated chromatography as above, but using longer
columns.
[6]
[7]
Goehring, R.R.; Victory, S.F.; Shao, B.; Sun, Q. Preparation of
aryl-substituted pyridinecarboxamides as sodium channel blockers
for treatment of neuronal damage and neurodegenerative
conditions. WO2003022276, Chem. Abstr., 2003, 138, 238021.
Goehring, R.R.; Shao, B. Preparation of substituted 2-(4-
phenoxyphenyl)pyridine derivatives and related compounds as
sodium channel blockers for the treatment of neuronal damage and
neurodegenerative conditions. WO2003022285, Chem. Abstr.,
2003, 138, 238022.
In a few cases, control experiments were performed in a
similar way under conventional heating.
The following compounds were thus prepared:
4-iodophenyl 2-formylphenyl ether (2) [34] Yield:
85%; 13C NMR (CDCl3): ꢂ 87.3 (C4’), 118.7 (C3), 121.3
(C2’), 123.9 (C5), 127.1 (C1), 128.7 (C6), 135.8 (C4), 139.1
(C3’), 156.6 (C1’), 159.2 (C2), 189.0 (C=O); 1H NMR
(CDCl3): ꢂ 6.83 (d, J = 8.6 Hz, 2H, C2’H), 6.91 (d, J = 8.3
Hz, 1H, C3H), 7.23 (t, J = 7.6 Hz, 1H, C5H), 7.54 (t, J = 7.9
Hz, 1H, C4H), 7.68 (d, J = 8.6 Hz, 2H, C3’H), 7.95 (d, J = 7.7
[8]
Sun, Q.; Zhou, X.; Kyle, D.J. Preparation of aryl-substituted
benzimidazoles and their use as sodium channel blockers.
WO2004011439, Chem. Abstr., 2004, 140, 146139.
[9]
Sun, Q.; Kyle, D.J. Aryl substituted hydantoin compounds, their
preparation, and their use as sodium channel blockers.
WO2004010950, Chem. Abstr., 2004, 140, 157472.
[10]
[11]
Sun, Q.; Kyle, D.J. Preparation of aminoalkyl-substituted aryl
compounds and their use as sodium channel blockers.
WO2004013114, Chem. Abstr., 2004, 140, 163577.
Ayer, M.B.; Meinke, P.T.; Parsons, W.H.; Kuo, H.C.H.;
Chakravarty, P.K.; Tyagarajan, S.; Preparation of aryloxyaryl,
arylheteroaryl, and biaryl methylenethiazolidinediones as sodium
channel blockers for the treatment of pain. WO2004024061, Chem.
Abstr., 2004, 140, 287373.
Hz, 1H, C6H), 10.46 (s, 1H, C(O)H); [M+Na]+
346.9547, C13H9O2NaI requires 346.9545.
=
found
2-iodophenyl 2-formylphenyl ether (3) Yield: 75%; 13
C
NMR (CDCl3): ꢂ 89.2 (C2’), 117.3 (C6’), 120.5 (C3), 123.5
(C5), 126.3 (C1), 126.5 (C4’), 128.6 (C5’), 129.9 (C6), 135.7
1
(C4), 140.3 (C3’), 155.4 (C1’), 159.4 (C2), 189.3 (C=O); H
[12]
Olofsson, K.; Hallberg, A.; Larhed, M. In: Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002; pp. 379-
403.
NMR (CDCl3): ꢂ 6.75 (d, J = 8.3 Hz, 1H, C6’H), 6.96 (d, J =
7.5 Hz, 1H, C3H), 6.99 (t, J = 7.9 Hz, 1H, C4’H), 7.20 (t, J =
7.4 Hz, 1H, C5H), 7.37 (t, J = 8.1 Hz, 1H, C5’H), 7.50 (t, J =
8.2 Hz, 1H, C4H), 7.91 (d, J = 7.8 Hz, 1H, C3’H), 7.97 (d, J =
[13]
[14]
[15]
Osborne, R. Microwave assisted chemistry. RSC Drug Discov. Ser.,
2012, 11, 63-89.
Patel, D.; Patel, B. Microwave assisted organic synthesis: an
overview. J. Pharm. Res., 2011, 4, 2090-2092.
Starks, C. M.; Liotta, C. L.; Halpern, M. Phase Transfer Catalysis:
Fundamentals, Applications andIndustrial Perspectives, 1st ed.;
Chapman & Hall: New York, 1994
7.7 Hz, 1H, C6H), 10.59 (s, 1H, C(O)H); [M+Na]+
346.9551, C13H9O2NaI requires 346.9545.
=
found
3-iodophenyl 2-formylphenyl ether (10) Yield: 81%;
13C NMR (CDCl3): ꢂ 94.4 (C3’), 118.4 (C6’), 118.9 (C3),
124.0 (C5), 127.0 (C1), 128.1 (C2’), 128.7 (C5’), 131.3 (C6),
133.3 (C4’), 135.8 (C4), 157.0 (C1’), 159.0 (C2), 188.9 (C=O);
1H NMR (CDCl3): ꢂ 6.92 (d, J = 8.3 Hz, 1H, C6’H), 7.00–
7.14 (m, 2H, C3H, C5’H), 7.23 (t, J = 8.3 Hz, 1H, C5H), 7.41
(s, 1H, C2’H), 7.52 (t, J = 8.7 Hz, 1H, C4H), 7.56 (d, J = 7.4
Hz, 1H, C4’H), 7.94 (d, J = 7.7 Hz, 1H, C6H), 10.45 (s, 1H,
C(O)H); ꢂ[35] (CDCl3) 6.90-7.96 (m, 8H), 10.48 (s, 1H);
[M+Na]+found = 346.9551, C13H9O2NaI requires 346.9545.
[16]
[17]
[18]
[19]
[20]
Campbell, L.J.; Borges, L.F.; Heldrich F.J. Microwave accelerated
preparation of aryl 2-(N,N-diethylamino)ethyl ethers. Bioorg. Med.
Chem. Lett., 1994, 4, 2627-2630.
Sarju, J.; Danks, T.N.; Wagner, G. Rapid Microwave-assisted
Synthesis of Phenyl Ethers under Mildly Basic and Non-aqueous
Conditions. Tetrahedron Lett., 2004, 45, 7675-7677.
Mitra, A.K.; De, A.; Karchaudhuri, N. Microwave enhanced
synthesis of aromatic methyl ether. Indian J. Chem., 2000, 39B,
387-389.
Peng, Y.; Song, G. ombined microwave and ultrasound assisted
Williamson ether synthesis in the absence of phase-transfer
catalysts. Green Chem., 2002, 4, 349-351.
Keglevich, G.; Novák, T.; Vida, L.; Greiner, I. Microwave
irradiation as an alternative to phase transfer catalysis in the liquid-
solid phase, solvent-free C-alkylation of active methylene
containing substrates. Green Chem., 2006, 8, 1073-1075.
Keglevich, G.; Majrik, K.; Vida, L.; Greiner, I. Microwave
irradiation as a green alternative to phase transfer catalysis: Solid-
liquid phase alkylation of active methylene containing substrates
under solvent-free conditions. Lett. Org. Chem., 2008, 5, 224-228.
Greiner, I.; Grün, A.; Ludányi, K.; Keglevich, G. Solid–liquid two-
phase alkylation of tetraethyl methylenebisphosphonate under
microwave irradiation. Heteroatom Chem., 2011, 22, 11-14.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflicts of interest.
[21]
[22]
ACKNOWLEDGEMENTS
The above project was supported by the Hungarian
Scientific and Research Fund (OTKA No K83118).