CsF-Al2O3 mediated rapid condensation of phenols with aryl halides: Comparative study of conventional heating vs. microwave irradiation

Article abstract of DOI:10.1039/b001824o

Biaryl ethers and thio ethers are formed in high yields by the condensation of phenols and thiophenols with electron-deficient aryl halides using CsF supported on Al₂O₃ under microwave irradiation in solvent-free conditions.

Full text of DOI:10.1039/b001824o

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CsF–Al O mediated rapid condensation of phenols with aryl halides:
2 3
comparative study of conventional heating vs. microwave irradiation¤
Jhillu S. Yadav* and Basi V. Subba Reddy
Organic Chemistry Division-I, Indian Institute of Chemical T echnology, Hyderabad 500 007,
India
L e t t e r
Received (in Montpellier, France) 28th February 2000, Accepted 14th April 2000
Published on the Web 14th June 2000
Biaryl ethers and thio ethers are formed in high yields by the
condensation of phenols and thiophenols with electron-deÐcient
aryl halides using CsF supported on Al O under microwave
Ñuorides bearing nitro or cyano groups. The extent of electron
deÐciency and the nature of the substituent on the aryl halide
moiety show some e†ect on this conversion. The cyano-
substituted aryl halides require comparatively longer irradia-
tion times (5È6 min) to attain yields (75È90%) comparable
with those of their nitro-substituted counterparts (80È90%).
Di†erent inorganic Ñuorides like LiF, NaF, KF and CsF
doped on an Al O matrix were studied for their e†ect.
2
3
irradiation in solvent-free conditions.
Biaryl ethers are synthetically challenging compounds used in
the Ðeld of drugs and agrochemicals.1 The important
UllmannÏs protocol for the synthesis of biaryl ethers involves
the reaction of an aryl halide with an alkali metal aryl oxide
in the presence of copper salts.2 Other methods for their syn-
thesis include Pummerer-type rearrangements,3 inter- and
2
3
CsFÈAl O is found to be more efficient in terms of conver-
2
3
sion and reaction times than KF.
The present study has unequivocally conÐrmed that con-
ventional heating at 110 ¡C and longer reaction times are
required for the condensation of phenols with activated aryl
halides. These conditions are improved using microwave irra-
diation, which is becoming an alternate heating source. When
1 equiv. of phenol, 1 equiv. of activated aryl halide and
CsFÈAl O (3 wt. equiv.) were admixed thoroughly in a Pyrex
intramolecular S Ar reactions,4 arene metal complexes,5
N
thallium-promoted oxidative couplings,6 phenolic addition to
cyclohexene oxides,7 and DielsÈAlder cyclisation.8 The S Ar
N
strategy is employed for the formation of simple biaryl ethers
through the condensation of phenols with electron-deÐcient
aromatic halides in the presence of base. Several bases like
Li CO , K CO , Cs CO , NaHCO , P But, NaHÈpyridine,
2
3
test tube and exposed to microwave irradiation at 450 W for
3È6 min., high yields (82È94%) of biaryl ethers were obtained
after Ðltration through a small silica gel column. These reac-
tions, however, require approximately 6È24 h of heating at
110 ¡C (highest temperature observed during microwave
irradiation) to achieve yields comparable with those obtained
by microwave irradiation. Invariably the products obtained
by microwave irradiation were puriÐed with more ease.
2
3
2
3
2
3
3
4
etc.,9 have been used for biaryl ether formation through
macrocyclisation during the synthesis of many important
natural products. Although KFÈAl O 10 has been used for
2
3
the synthesis of biaryl ethers, the method involves long reac-
tion times ranging between many hours to several days and
often uses large quantities of solvents like DMSO or acetoni-
trile, which require tedious aqueous work-up. UllmannÏs pro-
cedure for the synthesis of biaryl ethers su†ers from the
competitive reduction of the aryl halide to the dehalogenated
arene, drastic reaction conditions, long reaction times at ele-
vated temperatures and often the use of toxic solvents. Recent-
ly, an improved protocol for the formation of biaryl ethers
through UllmannÏs procedure has been reported.11 Further-
more, several non-Ullmann methods developed for this
purpose involve expensive and/or hazardous reagents, unsatis-
factory yields and cumbersome experimental and/or work-up
procedures. Organic reactions on solid supported reagents
coupled with microwaves12 are currently of increasing interest
due to their greater selectivity, enhanced reaction rates,
cleaner reaction products and operational simplicity. In con-
tinuation of our work on solid supported reagents13 coupled
with microwaves, herein we report a novel, efficient and high
yielding protocol for the synthesis of biaryl ethers using
CsFÈAl O as catalyst.
In conclusion, this letter describes a rapid and efficient pro-
cedure for the condensation of phenols with aryl halides medi-
ated by CsFÈAl O , either in solution or in solvent-free
2
3
conditions, for the Ðrst time. The method o†ers several advan-
tages like inexpensive catalyst, very short reaction times,
cleaner reactions and high yields of products, which makes
our method a useful addition to the existing methods.
Experimental
Melting points were recorded on a Buchi-535 apparatus. 1H
NMR spectra were recorded on Varian Gemini 200 spectro-
meters. The spectra were recorded in CDCl using tetra-
3
methylsilane as the internal standard. Mass measurements
2
3
Several substituted phenols were reacted with electron-
deÐcient aryl halides under microwave irradiation in the pres-
ence of 37% CsF on Al O (Scheme 1) to a†ord high yields of
2
3
biaryl ethers in solvent-free conditions. Similarly, biaryl thio
ethers are formed in high yields by the reaction of thiophenols
with activated aryl halides. The results summarised in Table 1
clearly show the scope of the method with respect to various
substituted phenols and also aryl chlorides, bromides and
¤ IICT communication No. 4393.
Scheme 1
DOI: 10.1039/b001824o
New J. Chem., 2000, 24, 489È491
489
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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Table 1 CsFÈAl O mediated condensation of phenols with activated aryl halides
2
3
Reaction time (yield/%)
Microwave
irradiationa
Conventional
heatingb
Entry
a
Phenol
Halide
5 min (88)
4 min (94)
6 min (87)
4 min (92)
5 min (88)
5 min (90)
15 h (75)
16 h (80)
20 h (70)
12 h (75)
18 h (68)
12 h (75)
b
c
d
e
f
g
3 min (90)
4 min (88)
10 h (75)
16 h (70)
h
i
5 min (86)
8 h (80)
j
6 min (82)
5 min (87)
5 min (90)
4 min (92)
15 h (62)
10 h (77)
8 h (75)
6 h (78)
k
l
m
n
6 min (75)
24 h (70)
o
p
q
4 min (88)
4 min (90)
6 min (84)
15 h (73)
12 h (70)
20 h (62)
a Microwave was carried out at 450 W using BPL, BMO, 700 T microwave oven by pulsed irradiation technique (1 min with 20 s interval).
b Conventional heating at 110 ¡C.
490
New J. Chem., 2000, 24, 489È491

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2
(a) V. E. Deshpande and N. J. Gokhale, T etrahedron L ett., 1992,
33, 4213; (b) D. L. Boger, S. M. Sakya and D. Yohannes, J. Org.
Chem., 1991, 56, 4204; (c) D. A. Evans and J. A. Ellman, J. Am.
Chem. Soc., 1989, 111, 1963.
were carried out on a CEC-21-110B double focussing mass
spectrometer operating at 70 eV.
Typical procedures
3
4
M. E. Jung, D. Jachiet, S. I. Khan and C. Kim, T etrahedron L ett.,
1995, 36, 364.
(a) D. A. Evans, C. J. Dinsmore, D. A. Evrard and K. M. De
Vries, J. Am. Chem. Soc., 1993, 115, 6426; (b) D. A. Evans and P.
S. Watson, T etrahedron L ett., 1996, 37, 3251; (c) D. L. Boger and
D. Yohannes, J. Org. Chem., 1991, 56, 1763.
(a) A. J. Pearson, P. Zhang and G. Bignan, J. Org. Chem., 1997,
62, 4536; (b) A. J. Pearson, G. Bignan, P. Zhang and M. Chelliah,
J. Org. Chem., 1996, 61, 3940.
(a) H. Konishi, T. Okuno, S. Nishiyama, S. Yamamura, K.
Koyasu and Y. Terada, T etrahedron L ett., 1996, 37, 8791; (b) Y.
Suzuki, S. Nishiyama and S. Yamamura, T etrahedron L ett., 1989,
30, 6043.
M. E. Jung and L. S. Starkey, T etrahedron, 1997, 53, 8815.
(a) R. K. Olsen, X. Feng, M. Campbell, R. Shao and S. K. Math,
J. Org. Chem., 1995, 60, 6025; (b) X. Feng and R. K. Olsen, J.
Org. Chem., 1992, 57, 5811.
Method A (microwave irradiation). Sesamol (1.38 g, 10
mmol) and 1-bromo-4-nitrobenzene (2 g, 10 mmol) were
admixed in a Pyrex test tube with 37% CsF on Al O (3 wt.
2
3
equiv. of phenol) and subjected to microwave irradiation at
450 W using BPL, BMO, 700 T focused microwave oven for 5
min. Then the reaction mass was cooled to room temperature
and charged directly onto a small silica gel column (Aldrich,
100È200 mesh) and eluted with a gradient mixture of ethyl
acetateÈhexane (1 : 9) to a†ord pure product 3a (2.28 g, 88%
yield) as a brown colourless solid. Mp 81È82 ¡C. 1H NMR
5
6
7
8
(CDCl ): d 6.0 (s, 2H), 6.5È6.8 (m, 3H), 7.05 (d, 2H, J \ 8.8
3
Hz), 8.2 (d, 2H, J \ 8.8 Hz). EI-MS: m/z 259 (M`), 213, 137,
122, 91, 57, 40.
9
(a) J. F. Marcoux, S. Doye and S. L. Buchwald, J. Am. Chem.
Soc., 1997, 119, 10539; (b) C. Palomo, M. Oiarbide, R. Lopez and
E. GomezÈBengoa, Chem. Commun., 1998, 2091.
Method B (conventional heating). A mixture of sesamol (1.38
g, 10 mmol), 1-bromo-4-nitrobenzene (2 g, 10 mmol) and
CsFÈAl O was heated at 110 ¡C for the speciÐed time as
10 (a) E. A. Schmittling and J. S. Sawyer, J. Org. Chem., 1993, 58,
3229; (b) J. S. Sawyer, E. A. Schmittling, J. A. Palkowitz and W.
J. Smith, J. Org. Chem., 1998, 63, 6338.
11 (a) D. E. Evans, J. L. Katz and T. R. West, T etrahedron L ett.,
1998, 39, 2937; (b) D. M. T. Chan, K. L. Monaco, R. P. Wang
and M. P. Winters, T etrahedron L ett., 1998, 39, 2933; (c) F. Theil,
Angew. Chem., Int. Ed. Engl., 1999, 38, 2345.
2
3
required to complete the reaction. On completion the reaction
mass was charged directly onto a small silica gel column and
eluted with a gradient mixture of ethyl acetateÈhexane (1 : 9)
to a†ord pure product 3a (1.94 g, 75% yield).
12 (a) R. A. Abramovitch, Org. Prep. Proced. Int., 1991, 23, 685; (b)
S. Caddick, T etrahedron, 1995, 51, 10403; (c) A. Loupy, A. Petit,
J. Hamelin, F. TexierÈBoullet, P. Jacquault and D. Mathe, Syn-
thesis, 1998, 1213; (d) R. S. Varma, Green Chem., 1999, 43.
13 (a) H. M. Samath Kumar, B. V. Subba Reddy and J. S. Yadav,
Chem. L ett., 1998, 639; (b) H. M. Sampath Kumar, B. V. Subba
Reddy, E. Jagan Reddy and J. S. Yadav, Green Chem., 1999, 141;
(c) H. M. Sampath Kumar, B. V. Subba Reddy, E. Jagan Reddy
and J. S. Yadav, T etrahedron L ett., 1999, 40, 2401; (d) H. M.
Sampath Kumar, B. V. Subba Reddy, S. Anjaneyulu, E. Jagan
Reddy and J. S. Yadav, New J. Chem., 1999, 23, 955.
Acknowledgement
BVSR thanks CSIR, New Delhi for the award of a fellowship.
Notes and references
1
(a) J. Zhu, Synlett., 1997, 2, 133 and references cited therein; (b) A.
V. R. Rao, M. K. Gurjar, K. L. Reddy and A. S. Rao, Chem. Rev.,
1995, 95, 2135.
New J. Chem., 2000, 24, 489È491
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