generally controlled by the introduction of differentially
reactive halogen atoms on the central aromatic ring (e.g., Cl
and Br/I)8 or by the use, as starting materials, of dibromo or
-iodo substrates with each halogen being discriminated by
its electronic and/or steric environment.9 The case of
symmetrical dihalo compounds is even more delicate, and
the question of selective introduction of two different
aromatic substituents via controlled sequential monoaryla-
tions has been only rarely addressed.10 It is therefore in this
context that we wish to describe the direct synthesis of
tri(hetero)aryl products of type Ar1-Ar2-Ar3 by application
of simultaneous double Suzuki-Miyaura couplings to sym-
metrical dibromoaryl substrates.
We initially envisaged the synthesis of diarylpyrroles
starting from symmetrical dibromopyrroles via palladium-
catalyzed coupling reactions. This has received considerable
attention recently1a,11 for the preparation of both natural
products12 and biologically active compounds1a,13 and was
accomplished by application of the aforementioned sequential
couplings10a or by prior monobromine-lithium exchange.14
We have thus recently shown that the 2,5-dibromopyrrole 1
reacts with 1 equiv of N-Boc-indole-2-boronic acid (2) under
palladium catalysis to give the product of monocoupling 3,
a second coupling with phenylboronic acid 4 then affording
the 2,5-unsymmetrically substituted pyrrole 5 (Scheme 2).15
little dicoupled product being obtained when boronic acid 4
was used in the first coupling reaction. This difference in
reactivity prompted us to attempt an unprecedented simul-
taneous one-pot Pd-catalyzed preparation of 5 from 2,5-
dibromopyrrole 1 and the two boronic acids 2 and 4. We
reasoned that, provided the indoleboronic acid 2 coupled
more rapidly than the phenyl counterpart, the monocoupled
2-indole-5-pyrrole derivative 3 would first be formed pref-
erentially and could then react with the arylboronic acid
present in the reaction mixture to give the desired 2,5-
substituted pyrrole 5.
Despite the statistical bias against appreciable formation
of the desired 2-indole-5-arylpyrrole 5,16 an initial three-
component palladium-catalyzed coupling was performed
using the following procedure. Thus, N-Boc-2,5-dibromopyr-
role and 1.5 equiv of each boronic acid in a 4:1 mixture of
toluene/ethanol were treated with 10 mol % Pd(PPh3)4 and
Na2CO3 for 3 h at 100 °C. While unsurprisingly many side
products were obtained, 18% of the expected disubstituted
pyrrole derivative 5 could indeed be isolated from the
reaction mixture by chromatography (Table 1, entry 1).
Table 1. Optimization of the One-Pot Strategy
Scheme 2. From a Stepwise to a One-Pot Procedure
entry
2 (equiv)
4 (equiv)
salt (equiv)
yield (%)a
1
2
3
4
5
6
7
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
none
none
18
37
50
67
59
69
55
LiCl (1.0)
LiCl (3.0)
LiBr (3.0)
KCl (3.0)
KCl (5.0)
a Isolated yields after flash chromatography.
An important observation made during the course of this
study was that the coupling order could not be reversed, very
Encouraged by this result, we set out to optimize the reaction
conditions. Interestingly, decreasing the proportion of both
boronic acids to only 1 equiv led to a doubling of the yield
(6) For examples, see: (a) Noguchi, H.; Shioda, T.; Chou, C.-M.;
Suginome, M. Org. Lett. 2008, 10, 377–380. (b) Sinclair, D. J.; Sherburn,
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White, D. J.; Grodberg, J.; Lam, K. S.; Potts, B. C. M. J. Nat. Prod. 2008,
71, 1732–1737. (b) Smith, J. A.; Ng, S.; White, J. Org. Biomol. Chem.
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G. V.; Lukashev, N. V. Russ. Chem. Bull. 2005, 54, 215–219. (b) Antelo
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(16) In addition to compound 5, up to eight other products could be
expected from such a reaction: the monocoupled compound 3, monocoupled
2-arylpyrrole of type 6 (and their dehalogenated 2-indolyl- and 2-arylpyrrole
analogs), 2,5-diindolylpyrrole 7, 2,5-diarylpyrrole 8, and the two homo-
coupling products 9 and 10 (see Figure 1).
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Org. Lett., Vol. 11, No. 8, 2009