Aryl-aryl coupling via directed lithiation and oxidation

Article abstract of DOI:10.1039/b501939g

Aryl lithium reagents formed by directed lithiation reactions undergo transmetallation with copper(I) salts to form organocuprates, which may be efficiently oxidized to yield ortho-substituted biaryls. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b501939g

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Aryl–aryl coupling via directed lithiation and oxidation{
a
David S. Surry, David J. Fox, Simon J. F. Macdonald and David R. Spring*
a
b
a
Received (in Cambridge, UK) 9th February 2005, Accepted 1st April 2005
First published as an Advance Article on the web 12th April 2005
DOI: 10.1039/b501939g
Aryl lithium reagents formed by directed lithiation reactions
undergo transmetallation with copper(I) salts to form organo-
cuprates, which may be efficiently oxidized to yield ortho-
substituted biaryls.
Table 1 Intermolecular biaryl bond formation
Entry Substrate (1)
Product (2)
Yield
a
a
75%
The formation of biaryl bonds is one of the most important
processes in organic chemistry due to the appearance of this motif
in numerous natural products, pharmaceuticals, agrochemicals,
dyes and chiral catalysts and as such remains an area of intensive
a
b
c
52%
1
research. The oxidation of aromatic organocuprates is known to
2
give biaryls. Such cuprates have been formed by a halogen–metal
2
c
exchange between an aryl halide and an alkyl lithium or
2
d
magnesium reagent, followed by transmetallation with a
copper(I) salt. The disadvantage of these methods is the
requirement for a halogen atom to be present on the aromatic
nucleus, which increases the number of steps required in a
synthetic sequence. Furthermore, halogen–metal exchange can be
b
79%
3
slow for electron rich substrates. An organolithium species,
4
formed by a directed lithiation reaction with 1, could also be used
c
d
59%
in this context to yield a substituted biaryl (2) without the need for
a halogen atom to be present on the aromatic nucleus (Scheme 1)
and would be applicable to electron rich compounds.
We began by investigating the ortho-lithiation of anisole and
were pleased to find that the organolithium generated by this
method underwent an efficient transmetallation when treated with
copper(I) bromide-dimethyl sulfide complex to give an organo-
cuprate which could be oxidized to the dimer 2a in good yield
d
e
60%
(Table 1).
The choice of oxidant is critical to the success of this sequence. It
has recently been reported that dinitroamide 3 is effective in the
oxidation of organocuprates derived from Grignard reagents,
allowing facile separation of products from oxidant derived by-
e
f
54%
2c
products by an aqueous acid wash during work-up. It was
pleasing to discover that 3 was equally successful when used in
this system. The reaction is not limited to the use of the
methoxy directing group: alkoxy ethers (1c), sulfonamides (1d),
a
Lithiation conditions: n-BuLi (1.2 equiv.), TMEDA (1.2 equiv.),
b
O, RT. t-BuLi (1.1 equiv.), Et
c
Et
2
2
O, 0 uC. n-BuLi (1.1 equiv.),
d
Et
2
O, 270 uC to 0 uC. LiTMP (4 equiv.), THF, 278 uC to 0 uC.
e
n-BuLi (1.1 equiv.), THF 220 uC to RT.
5
carboxylates (1e) and heterocycles (1f) also proved effective.
Scheme 1 General reaction sequence. DG 5 directing group.
The applicability of the reaction to the formation of tetra-ortho-
substituted biaryls (2b and 2e) encouraged us to employ a chiral
directing group in the hope of performing diastereoselective biaryl
{ Electronic supplementary information (ESI) available: analytical and
spectroscopic data for all new compounds. See http://www.rsc.org/
suppdata/cc/b5/b501939g/
*drspring@ch.cam.ac.uk
6
bond formation. An enantiopure, valinol-derived oxazoline
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2589–2590 | 2589

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a
David S. Surry, David J. Fox, Simon J. F. Macdonald and
a
b
a
David R. Spring*
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: drspring@ch.cam.ac.uk;
a
Fax: +44 (0) 1223 336362; Tel: +44 (0) 1223 336498
GlaxoSmithKline, Centre for Excellence in Drug Discovery, Stevenage,
UK SG1 2NY
b
Notes and references
{
Representative procedure: n-BuLi (1.2 mmol, 0.49 mL of 2.4 M solution
in hexanes) was added to a stirred solution of anisole (1 mmol, 0.11 mL)
and TMEDA (1.2 mmol, 0.18 mL) in Et O (4 mL) under argon at ambient
temperature. After 2 h a solution of CuBr?SMe (0.5 mmol, 0.103 g) and
2
Scheme 2 Diastereoselective biaryl bond formation.
2
LiBr (1 mmol, 0.173 g) in THF (1 mL) was added via cannula followed by
a solution of oxidant 3 (2.5 mmol, 0.735 g) in THF (4 mL). The reaction
mixture was then filtered through a pad of silica, the solvent removed under
reduced pressure and the residue purified by flash column chromatography.
1
2
J. Hassan, M. S e´ vignon, C. Gozzi, E. Sculz and M. Lemaire, Chem.
Rev., 2002, 102, 1359.
(a) For a review, see: T. Kauffmann, Angew. Chem., Int. Ed. Engl., 1974,
1
3, 291; (b) for the first detailed studies, see: G. M. Whitesides,
J. SanFilippo, Jr., C. P. Casey and E. P. Panek, J. Am. Chem. Soc.,
967, 89, 5302; (c) B. H. Lipshutz, K. Siegmann, E. Garcia and
1
Scheme 3 Intramolecular biaryl bond formation to give the 10-
membered medium ring product 7.
F. Kayser, J. Am. Chem. Soc., 1993, 115, 9276; (d) D. S. Surry, X. Su,
D. J. Fox, V. Franckevicius, S. J. F. Macdonald and D. R. Spring,
Angew. Chem. Int. Ed., 2005, 44, 1870.
3
The formation of electron rich aryl Grignard reagents by a halogen–
metal exchange has only recently been reported: A. Krasovskiy and
P. Knochel, Angew. Chem. Int. Ed., 2004, 43, 3333.
7
proved to be the most effective in this role, leading to the
formation of a single diastereomer (d.r. . 50:1) of the desired
4
5
6
(a) V. Snieckus, Chem. Rev., 1990, 90, 879; (b) H. W. Gschwend and
H. R. Rodriguez, Org. React., 1979, 26, 1.
J. Lazaar, A.-S. Rebstock, F. Mongin, A. Godard, F. Tr e´ court,
F. Marsais and G. Qu e´ guiner, Tetrahedron, 2002, 58, 6723.
T. D. Nelson and A. I. Meyers, Tetrahedron Lett., 1993, 34, 3061.
8
biaryl (M)-5 in 38% yield (Scheme 2).
9
Interestingly it has been found that an Ullmann coupling on the
1
0
2
-bromo derivative of 4 gives (P)-5. It has been shown that (P)-5
is the thermodynamically favoured diastereoisomer under the
7 The use of enantiopure secondary amides gave poor diastereocontrol.
8 Although several attempts were made at improving the yield of this
reaction (20–38%) the only other compound that could be isolated was
starting material (30%). (P)-5 was not observed in the crude reaction
mixture.
10b
Ullmann reaction conditions. (M)-5 appears to be the kinetically
favoured product under the low temperature conditions of our
organocuprate oxidation reaction. Our complementary procedure
allows both enantiomers of diphenic acid 2e to be prepared using
the same enantiomer of the oxazoline auxiliary derived from
9
11
natural valine.
Intramolecular reactions are also possible, for example,
performing a double lithiation on 6, followed by intramolecular
cuprate formation and oxidation gives 7 which contains a biaryl
bond within a 10-membered ring (Scheme 3).
9
The configuration about the biaryl axis was determined by ring opening
of the oxazoline (TFA, H O), acetylation (Ac O, pyridine) and
reduction (LiAlH ) to give the corresponding diol (M)-8 (adapted from:
T. D. Nelson and A. I. Meyers, J. Org. Chem., 1994, 59, 2577)
In conclusion, organocuprates formed by an ortho-lithiation–
transmetallation sequence may be oxidized efficiently to yield
biaryls. The reaction is effective when used in both an inter- and an
intramolecular sense and high diastereoselectivity can be achieved
using a valinol-derived oxazoline to direct the lithiation. The
process allows for an efficient synthesis of biaryls which should
prove useful in the synthesis of pharmaceuticals and natural
products.{
Financial support from the EPSRC and GlaxoSmithKline is
gratefully acknowledged. We would also like to acknowledge the
EPSRC National Mass Spectrometry Service Centre, Swansea, for
providing mass spectrometric data.
2
2
4
25
22
D
3 3
[a] 5 267.5 (c 5 0.2, CHCl ) (lit., [a]D 5 243.2 (c 5 1.98, CHCl ),
A. M. Warshawsky and A. I. Meyers, J. Am. Chem. Soc., 1990,
112, 8090).
0 (a) T. D. Nelson and A. I. Meyers, Tetrahedron Lett., 1994, 35, 3259; (b)
1
A. I. Meyers, T. D. Nelson, H. Moorlag, D. J. Rawson and A. Meier,
Tetrahedron, 2004, 60, 4459.
1
1 This diphenic acid is a common building block in ellagitannin synthesis:
(a) S. Quideau and K. S. Feldman, Chem. Rev., 1996, 96, 475; (b)
K. Khanbabaee and T. van Ree, Synthesis, 2001, 1585; hexahydroxy-
biphenyl derivatives also have interesting biological activities:
Y. Kashiwada, L. Huang, L. M. Ballas, J. B. Jiang, W. P. Janzen
and K.-H. Lee, J. Med. Chem., 1994, 37, 195.
2
590 | Chem. Commun., 2005, 2589–2590
This journal is ß The Royal Society of Chemistry 2005