Axially chiral compounds are common scaffolds in many
natural products that exhibit promising biological activities.5
The marinopyrroles represent the first naturally occurring axially
halogenated chiral 1,3′-bipyrroles. Fenical reported that marinopy-
rrole A exists as a single M-atropoisomer, is stable at room
temperature, and can be racemized in toluene at 120 °C to give
the non-natural (P)-(+)-marinopyrrole A. The fact that the
marinopyrroles were isolated as single atropo-enantiomers
suggests that their biosynthesis probably involves an enzyme-
mediated critical pyrrole coupling.3 Inspired by this idea, we
envisaged to construct the 1,3′-bipyrrole core via an Ullmann-
type coupling reaction for the C(pyrrolyl)-N bond formation
(Scheme 1). During the course of our studies, Fenical’s group tried
to synthesize marinopyrrole A in a similar synthetic approach but
without success.6 Thus, they synthesized bipyrrole derivatives by
the Paal-Knorr reaction which involved the condensation of a
diketo compound onto 3-aminopyrrole. Li and co-workers followed
the same method to prepare a small library of marinopyrrole
analogues to study further the anticancer and antibiotic activities
of this novel class of bioactive compounds.7
Ullmann and Goldberg first reported the coupling of C-C
and C-N bonds by copper complexes more than a century
ago.8 Thereafter, improvements and novel applications of
C-N bond-forming reactions continually appeared in the
literature.9 Among them, the N-arylation of nitrogen-contain-
ing heterocycles has recently received particular attention.
A variety of procedures are available for the N-arylation of
pyrroles including the coupling of pyrroles with aryl halides
in the presence of Pd,10 Cu,11 and Fe12 or coupling of
pyrroles with arylboronic acids.13 Herein, we describe an
easy access to the 1,3′-bipyrrole template by a copper-
mediated N-arylation protocol. An example of the application
of this methodology was demonstrated in the total synthesis
of the natural product (()-marinopyrrole A.
We first examined various intermolecular amination
procedures for the coupling of 3-bromo-N-tosyl-pyrrole 6a14
with pyrrole as the model substrate for optimization of the
reaction conditions (Table 1). Our initial attempts focused
Table 1. Cu-Mediated N-Arylation of Pyrrole 7
yield
entry
1
conditions
(%)a
6a (1.5 equiv), 7 (1 equiv), Cs2CO3
(2 equiv), DMF, 200 °C, (MW), 2 h
-
6a or 6b or 6c (1.5 equiv), 7
(1 equiv), CuI (2 equiv), Cs2CO3
(3 equiv), DMF, 200 °C, (MW), 2 h
2
3
4
5
85-90
6a (1.5 equiv), 7 (1 equiv), CuI
(0.1 equiv), Cs2CO3 (1.5 equiv),
DMF, 200 °C, (MW), 2 h
22
2
6a (1.5 equiv), 7 (1 equiv),
Cu(PPh3)3Br (1 equiv), Cs2CO3
(2 equiv), DMF, 200 °C, (MW), 2 h
6d (1 equiv), 7 (1 equiv),
Cu(OAc)2, Et3N, CH2Cl2, 5 mol %,
MS 4 Å, rt, 24 h
-
a Isolated yield of purified product.
on the Fukuyama modification15 of the Ullmann-Goldberg
reaction, which has been applied to the synthesis of highly
functionalized nitrogen heterocycles.16 Fukuyama and co-
workers used a combination of CuI (2.0 equiv) and CsOAc
providing a mild intramolecular aryl amination of aryl
halides. Building on these studies, You et al. presented an
efficient CuI-catalyzed N-arylation protocol for N-containing
heterocycles including pyrrole with aryl and heteroaryl
bromides or chlorides.17 We, therefore, chose to focus our
initial studies on the cross-couplings of pyrrole through the
use of CuI and Cs2CO3 without the assistance of an additional
chelating ligand in DMF. Under these conditions, the
coupling reaction did not proceed in refluxing DMF, while
deprotection of the tosyl group from compound 6a was
observed. The same results were obtained when the coupling
was tested in the presence of diamine ligands according to
Buchwald18 or the Hartwig procedure with Pd(OAc)2 and
DPPF and the Chan-Evans-Lam-Modified Ullmann con-
densation between boronic acid 6d19 and pyrrole.
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K.; Wohlfarth, M.; Lobin, W. J. Am. Chem. Soc. 2001, 123, 2703–2711.
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For this reason, we decided to attempt the N-arylation using
microwave heating. The use of microwave irradiation proved
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