Phosphazene P4-But base for the Ullmann biaryl ether synthesis

Article abstract of DOI:10.1039/a805783d

In the presence of phosphazene P₄-Bu^t base and CuBr, aryl halides couple with phenols to give biaryl ethers at ca. 100 °C.

Full text of DOI:10.1039/a805783d

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t
Phosphazene P -Bu base for the Ullmann biaryl ether synthesis
4
Claudio Palomo,*† Mikel Oiarbide, Rosa López and Enrique Gómez-Bengoa
Departamento de Química Orgánica, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastián, Spain
t
In the presence of phosphazene P
4
-Bu base and CuBr, aryl
also proceeded well to afford the corresponding biaryl ether in
69% yield. In these two latter cases, once again, no coupling
reaction was observed when either DBU or TBD§ were used.
Under the established reaction conditions, both electron-rich
(entry 6) and electron-poor (entries 7–9) aryl halides also were
effective in their coupling with phenols.
On the other hand, from the examples in Table 1 it also seems
that the reaction conditions used are compatible with various
functional groups. Nevertheless, neither the amino or the amido
functionalities were inert under these reaction conditions. In
fact, treatment of 3,5-dimethyliodobenzene with both aniline
and p-toluidine afforded, under the above reaction conditions,
the corresponding biaryl amines in 78 and 71% yield,
halides couple with phenols to give biaryl ethers at ca.
00 °C
1
The reaction of aryl halides with sodium or potassium
aryloxides promoted by copper additives results in the forma-
tion of aryl ethers, the classical Ullmann biaryl ether synthesis.1
The major problems of this reaction are the competitive
2
reduction of the aryl halide to the dehalogenated arene and the
requirement for extremely harsh conditions, i.e. 200–300 °C,
long reaction times and strong polar and often toxic solvents.3
These reaction conditions probably account for an additional
problem, namely the formation of isomeric biaryl compounds
via substitution through an elimination-addition mechanism. On
the other hand, the reductive homocoupling of the aryl halide
component is also another inherent problem of this reaction.4
Despite considerable success to date, these efforts have
identified the same solution to these problems, namely, the
preactivation of the aryl halide component via, for instance, the
t
Table 1 The Ullmann reaction promoted by P -Bu
4
base in combination
Yield (%)b
with CuBra
Entry Halide
Phenol
Me
Product
Me
5
l
use of transition metals or by placing an electron-withdrawing
substituent ortho or para to the leaving group. Although these
HO
O
81c (73)
1
6
Me
Me
Me
variants have a prevalent position in the synthesis of complex
macrocyclic peptides,6 there exists no general solution for the
,7
Me
Me
Me
Me
l
l
8
O
direct coupling of aryl halides with phenols.
Recently Buchwald et al. described the first case of biaryl
ether synthesis with unactivated aryl halides. The reaction
Me
HO
72d (54)
2
3
9
Me
Me
Me
Me
HO
occurs at ca. 110 °C using Cs
2
CO
3
as the key reaction
But
But
element.
O
56
We describe here an efficient method for the direct coupling
Me
of aryl halides with phenols that is based on the so-called ‘naked
anion’ phenomenon.10 Our procedure‡ combines this concept
Me
Me
Me
Me
l
HO
O
11
4
5
69 (69)
with the use of Schwesinger’s phosphazene bases. The
synthesis and properties of these bases have been described
recently. We have found that P -Bu base in combination with
4
Cu salts in either dioxane or toluene effects the Ullmann
reaction of electron-rich, electron-neutral and electron-poor aryl
halides with a variety of phenols (Scheme 1). For example,
iodobenzene reacted with 2,4-dimethylphenol to produce the
corresponding biaryl ether in 81% isolated yield under condi-
tions where the use of other conceptually different bases
produced only traces of the expected product, if at all.§ Other
12
t
I
l
HO
Me
O
81c (72)e
OMe
OMe
Me
Me
l
HO
O
70e (25)
80f
6
7
MeO
Cl
Me MeO
Me
Me
Me
2
copper salts such as CuCl, CuI and (CuOTf) –benzene were
l
HO
O
II
also effective, but Cu salts did not give the coupling product.
As shown in Table 1, the best results were attained using
stoichiometric quantities of CuBr, although in some cases the
reaction also proceeded well under CuBr catalysis (entries 1, 4,
Cl
Br
Br
HO
HO
O
O
8
9
76 (80)
61
5
and 8). The method is particularly suitable for electron-neutral
NC
NC
aryl halides and ortho-substituted phenols. For example 2,6-di-
methylphenol (entry 2) provided the corresponding biaryl ether
in good yield and even the o-tert-butyl phenol (entry 3) coupled
with p-iodotoluene to give the desired biaryl ether in 56% yield.
The coupling reaction of o-iodotoluene and o-cresol (entry 4)
O
O
a
Reactions conducted on a 1 mmol scale; aryl halide:phenol:CuBr = 1:2:2
in toluene as solvent unless otherwise stated. b Yields in parentheses refer to
the reaction under catalytic conditions for Cu (20 mol% of CuBr).
Dioxane as solvent. Reaction carried out in the presence of DMF (10%
I
HO
O
I
i
c
d
+
e
5
6–81%
v/v). Reaction carried out in the presence of galvinoxyl radical (10 mol%);
in the absence of this radical inhibitor undesired byproducts were dominant.
R′
R
R
R′
f
Under catalytic conditions a mixture of isomeric biaryl ethers was
t
Scheme 1 Reagents and conditions: i, P
4
-Bu , CuBr, toluene, reflux
formed.
Chem. Commun., 1998
2091

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respectively.13 Although the precise role played by the
3 For reviews on this subject, see: (a) A. A. Moroz and M. S. Shvartsberg,
Russ. Chem. Rev., 1974, 43, 679; (b) J. Lindley, Tetrahedron, 1984, 40,
t
4
phosphazene P -Bu base in the outcome of the reaction is not
1
433.
clear at present, two observations may give some clue: (i) the
well-known ability of such a base to form highly nucleophilic
4
5
T. Cohen and I. Cristea, J. Am. Chem. Soc., 1976, 98, 748.
For a review, see: L. Balas, D. Jhurry, L. Latxague, S. Grelier, Y. Morel,
M. Hamdani, N. Ardoin and D. Astruc, Bull. Soc. Chim. Fr., 1990, 127,
‘
naked’ anions and, (ii) the complete solubility that the
t
4
otherwise insoluble CuBr exhibits in the presence of P -Bu .
4
01.
Both factors may facilitate the formation of the reactive
intermediate aryloxycopper species,14 which can then react with
the aryl halide under essentially homogeneous conditions. In
any case, the use of this phosphazene base appears to be critical
for performing the coupling reaction under reaction conditions
that are unsuitable for conventional bases.
This work was financially supported by the Basque Govern-
ment (Project EX-1997-108). A grant from the Basque
Government to R. L. is gratefully acknowledged.
6
For reviews, see: A. V. R. Rao, M. K. Gurjar, K. L. Reddy and A. S. Rao,
Chem. Rev., 1995, 95, 2135; J. Zhu, Synlett, 1997, 133.
7 K. Burguess, D. Lim and C. I. Martinez, Angew. Chem., Int. Ed. Engl.,
1996, 35, 1077; K. C. Nicolaou, C. N. C. Boddy, S. Natarajan, T.-Y.
Yuee, H. Li, S. Bräse and J. M. Ramanjulu, J. Am. Chem. Soc., 1997,
1
19, 3421.
8
For some recent methods, see: G. W. Yeager and D. N. Schissel,
Synthesis, 1991, 63; K. Smith and D. Jones, J. Chem. Soc., Perkin Trans.
1
5
, 1992, 407; E. A. Schmittling and J. S. Sawyer, J. Org. Chem., 1993,
8, 3229; M. E. Jung and L. S. Starkey, Tetrahedron, 1997, 53, 8815;
D. M. T. Chan, K. L. Monaco, R.-P. Wang and M. P. Winters
Tetrahedron Lett., 1998, 39, 2933; D. A. Evans, J. L. Katz and T. R.
West, Tetrahedron Lett., 1998, 39, 2937.
Notes and References
†
‡
E-mail: goppanic@sc.ehu.es
General procedure: A mixture of the aryl halide (1 mmol), the
9 J.-F. Marcoux, S. Doye and S. L. Buchwald, J. Am. Chem. Soc., 1997,
119, 10 539.
10 For a definition of this concept, see for example: L. F. Lindoy, The
Chemistry of Macrocyclic Ligand Complexes, Cambridge University
Press, Cambridge, 1989, p. 107.
11 R. Schwesinger, Chimia, 1985, 39, 269; R. Schwesinger, Nachr. Chem.
Tech. Lab., 1990, 38, 1214; R. Schwesinger, in Encyclopedia of
Reagents for Organic Synthesis, ed. L. Paquette, Wiley, New York,
1995, vol. 6, p. 4110.
t
4
corresponding phenol (2 mmol), P -Bu (2 mmol) and CuBr (2 mmol or 0.2
mmol for the catalytic version) in dry, deoxygenated toluene or dioxane (3
ml) was refluxed under a nitrogen atmosphere until the aryl halide was
consumed as determined by GC analysis (typically 16–20 h). The reaction
mixture was then allowed to cool to room temperature, diluted with EtOAc
and washed sequentially with saturated aq. NH
ml) and water (25 ml). The organic layer was dried over Na
4
Cl (25 ml), 0.1
M
NaOH (25
SO and
2
4
concentrated in vacuo. Purification by flash chromatography on silica gel
using hexane afforded the analytically pure product.
12 R. Schwesinger, H. Schlemper, C. Hasenfratz, J. Willaredt, T.
Dambacher, T. Breuer, C. Ottaway, M. Fletschinger, J. Boele, H. Fritz,
D. Putzas, H. W. Rotter, F. G. Bordwell, A. V. Satish, G.-Z. Ji, E.-M.
Peters, K. Peters, H. Georg von Schnering and L. Walz, Liebigs Ann.,
1996, 1055.
§
2
1
2 3 2 3
Among the bases tested, Na CO , K CO and 3,3,6,9,9-pentamethyl-
,10-diazabicyclo[4.4.0]dec-1-ene (PMDBD) were completely uneffective;
,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]-
dec-5-ene (TBD) afforded the coupling product in less than 20% yield along
with the starting material and unidentified side products.
13 For recent methods for the synthesis of biaryl amines, see: J. F. Hartwig,
Synthesis, 1997, 329.
1
4 For mechanistic considerations, see: H. L. Aalten, G. van Koten, D. M.
Grove, T. Kuilman, O. G. Piekstra, L. A. Hulshof and R. A. Sheldon,
Tetrahedron, 1989, 45, 5565; Also, see refs. 2 and 3(b).
1
2
F. Ullmann, Chem. Ber., 1904, 37, 853.
T. Cohen, J. Wood and A. G. Dietz, Jr., Tetrahedron Lett., 1974,
3555.
Received in Liverpool, UK, 23rd July 1998; 8/05783D
2092
Chem. Commun., 1998