R. N. Ram, V. Singh / Tetrahedron Letters 47 (2006) 7625–7628
7627
Table 2. Biaryl homo-coupling of aryl halides with PdCl2/EDTA/ascorbic acid in water–ethanola
Entry
Aryl halide
Time (h)
Biaryl product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Bromobenzene
4-Bromotoluene
8
8
7
7.5
6
4
9
5
10
9
9
Biphenyl
64
58
84
80
74
63
15 (60)d
35e
33
66
70
62
54
4,40-Dimethylbiphenyl
4,40-Bisacetylbiphenyl
4,40-Bisbenzoylbiphenyl
3,30-Dinitrobiphenyl
4-Bromoacetophenoneb
4-Bromobenzophenoneb
3-Bromonitrobenzeneb
4-Bromonitrobenzeneb
4-Bromonitrobenzeneb,c
4-Bromonitrobenzeneb
4-Chloronitrobenzene
4-Bromochlorobenzene
4-Bromobenzoic acid
2-Iodobenzoic acid
4-Bromoanisole
4-Amino-40-nitrobiphenyl
4-Amino-40-nitrobiphenyl
4-Amino-40-nitrobiphenyl
4-Amino-40-nitrobiphenyl
4,40-Dichlorobiphenyl
4,40-Diphenic acid
8
2,20-Diphenic acid
10
10
10
11
10
4,40-Dimethoxybiphenyl
3,30-Dimethoxybiphenyl
4,40-Dihydroxybiphenyl
4,40-Bis(N,N-dimethylamino)biphenyl
2,20-Bipyridyl
3-Bromoanisole
4-Bromophenol
4-Bromo-N,N-dimethylaniline
2-Bromopyridine
63
25
64f
27
a Reaction conditions: aryl halide (1 mmol), PdCl2 (3 mol %), EDTA (3 mol %), ascorbic acid (1 mmol), K2CO3 (3 mmol) in refluxing water–ethanol
(13 ml, 5:1 v/v) under an air atmosphere.
b A mixture of water–ethanol (2:1 v/v) was used as the solvent.
c Reaction with 0.5 mol equiv of ascorbic acid.
d Recovered starting material.
e Reaction with glucose (1 mol equiv) as the reductant in place of ascorbic acid.
f Isolated as the hydrochloride salt.
pling of electron-deficient arenes where other methods
fail or give products in lower yields due to reduction
or reductive dehalogenation. To the best of our knowl-
edge, this is the first example of the application of ascor-
bic acid in the biaryl homo-coupling of aryl halides.
References and notes
1. Pu, L. Chem. Rev. 1998, 98, 2405–2494.
2. Chelma, D. S.; Zyss, J. Non Linear Optical Properties of
Organic Molecules and Crystals; Academic Press: Orlando,
1987.
3. Elsenbauer, R. L.; Schacklett, L. W. In Handbook of
Conducting Polymers; Skotheim, T. A., Ed.; Marcel
Dekker: New York, 1986; Vol. 1, Chapter 7.
4. Supramolecular Chemistry, 1st ed.; Lehn, J. M., Ed., VCH
Verlasgesellschaft: Weinheim, Germany, 1995.
5. Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.;
Tasler, S. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E.,
Eds.; Springer: New York, 2001; Vol. 82, pp 1–293.
6. Review: Bringmann, G.; Walter, R.; Weirich, R. Angew.
Chem., Int. Ed. Engl. 1990, 29, 977–991.
7. Review: Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004,
2419–2440.
8. Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J.
Org. Chem. 2002, 67, 1199–1207.
9. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359–1469.
10. Metal-catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
11. Review: Handy, C. J.; Manoso, A. S.; McElroy, W. T.;
Seganish, W. M.; DeShong, P. Tetrahedron 2005, 61,
12201–12225.
12. Review: Campeau, L.-C.; Fagnou, K. Chem. Commun.
2006, 1253–1264.
13. Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini,
H. J. Am. Chem. Soc. 2006, 128, 6829–6836.
14. Review: Fanta, P. E. Synthesis 1974, 9–21.
15. Massicot, F.; Schneider, R.; Fort, Y.; Illy-Cherrey, S.;
Tillement, O. Tetrahedron 2001, 57, 531–536.
16. Lin, G.-q.; Hong, R. J. Org. Chem. 2001, 66, 2877–2880.
17. Lourak, M.; Vanderesse, R.; Fort, Y.; Caubere, P. J. Org.
Chem. 1989, 54, 4840–4844.
3. General experimental procedure
To a 0.004 M solution of PdCl2 in water (7.5 ml,
0.03 mmol, 3 mol %), a 0.008 M aqueous solution of
EDTA (3.75 ml, 0.03 mmol, 3 mol %), ascorbic acid
(176 mg, 1 mmol), K2CO3 (417 mg, 3 mmol) and a solu-
tion of the aryl halide (1 mmol) in ethanol (2 ml, 5 ml in
the case of sparingly soluble aryl halides, that is just en-
ough to ensure that the solution became homogeneous
on warming) were added. The aqueous-ethanolic solu-
tion (5:1 v/v, 2:1 v/v in the case of sparingly soluble
halide) was stirred under reflux for the specified time
(Table 2) until TLC monitoring showed the absence of
the aryl halide. The reaction mixture was cooled and
evaporated under reduced pressure to remove most of
the ethanol. The concentrate was extracted with ether
or dichloromethane (4 · 10 ml). The combined organic
extract was washed successively with water (2 · 5 ml)
and brine (1 · 5 ml), dried over Na2SO4, filtered and
evaporated under reduced pressure. The crude biaryl
product thus obtained was found to be sufficiently pure
in most cases as indicated by their spectra and compar-
ison of melting points with the reported values. Where
necessary, the crude product was purified by column
chromatography on neutral alumina.
Acknowledgement
18. Seganish, W. M.; Mowery, M. E.; Riggleman, S.; De-
Shong, P. Tetrahedron 2005, 61, 2117–2121.
One of us (V.S.) is thankful to AICTE, New Delhi, for
financial assistance under QIP.