A metathesis approach to aromatic heterocycles

Article abstract of DOI:10.1002/ejoc.200500113

The ring closing metathesis (RCM) reaction can be used to prepare substituted furans and pyrroles. By utilising a Pd-catalysed coupling reaction with methoxyallene, allylic alcohols and sulfonamides can be converted into substrates that are ideal precursors to ring closing metathesis. After the RCM reaction is complete, the addition of acid promotes an elimination of methanol to form the fully aromatised system. A range of different substitution patterns and functional groups are compatible with this sequence. Double allene coupling, RCM and elimination reactions are also possible and allow the formation of biaryl systems. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200500113

SHORT COMMUNICATION
A Metathesis Approach to Aromatic Heterocycles
Timothy J. Donohoe,*[a] Allan J. Orr,[a] Katherine Gosby,[a] and Matilda Bingham[b]
Keywords: Metathesis / Aromatic heterocycles / Methoxyallene
The ring closing metathesis (RCM) reaction can be used to
prepare substituted furans and pyrroles. By utilising a Pd-
catalysed coupling reaction with methoxyallene, allylic
alcohols and sulfonamides can be converted into substrates
that are ideal precursors to ring closing metathesis. After the
RCM reaction is complete, the addition of acid promotes an
elimination of methanol to form the fully aromatised system.
A range of different substitution patterns and functional
groups are compatible with this sequence. Double allene
coupling, RCM and elimination reactions are also possible
and allow the formation of biaryl systems.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
This project was designed to alter the application of the
RCM reaction, from one that is capable of forming isolated
alkenes to one, which provides intermediates at the correct
oxidation state to prepare fully aromatised compounds (in
this case heteroaromatic compounds). The use of RCM to
form heteroaromatic compounds has only recently ap-
peared in the literature[3–11] and given the central position
of these compounds to medicinal chemistry another flexible
approach was considered to be beneficial. (In some cases
the formation of aromatic compounds from a RCM reac-
tion was viewed as an undesirable degradation product fol-
The metathesis reaction has recently emerged as one of
the most powerful methodologies for alkene formation and
works particularly well in intramolecular coupling reactions
to form cyclic olefins.[1] Notably, ring closing metathesis
(RCM) is high yielding, easy to perform and tolerant of a
wide variety of functional groups. Recently, Grubbs and
others have introduced new classes of reactive catalysts,[1,2]
which will perform RCM reactions on heavily function-
alised substrates and which are even capable of synthesising
tetra-substituted cyclic alkenes.[2a]
Figure 1. Gerneral strategy for formation of aromatic compounds.
lowing metathesis, see ref.[4,13b]) Therefore, our strategy was
to construct the backbone of the target molecule by the
formation of an X–Y bond (e.g. a carbon–heteroatom bond
forming reaction to form A, Figure 1) followed by metathe-
sis to form the ring-closed intermediate B. Elimination of
the leaving group (LG) at this stage would provide a stable
aromatic compound, hopefully in one pot (AǞC). In this
paper, we report the success of this strategy for the synthesis
[a] Department of Chemistry, University of Oxford, Chemistry Re-
search Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK
Fax: +44-01865-275708
E-mail: timothy.donohoe@chem.ox.ac.uk
[b] Department of Medicinal Chemistry, Organon Laboratories
Ltd.,
Newhouse, Lanarkshire, ML1 5SH, Scotland, UK
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 1969–1971
DOI: 10.1002/ejoc.200500113
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1969

T. J. Donohoe, A. J. Orr, K. Gosby, M. Bingham
SHORT COMMUNICATION
of substituted furans and pyrroles. Our approach to making compounds were obtained. The RCM reactions proceeded
the X–Y bond (i.e. E, Figure 1) relied upon the reaction smoothly, and it was discovered that the aromatisation of
of allylic alcohols and sulfonamides with methoxyallene[12] these heterocycles could be performed in the same reaction
under Pd catalysis.[13] Subsequent RCM and then elimi- pot as the metathesis reaction, simply by adding acid. For
nation of methanol was expected to form the aromatic com- example, 2 Ǟ 4 proceeded in 90% yield in a one-pot pro-
pounds F directly.
cess. However, the main drawback with this approach is
that the nonpolar aromatic products were often contami-
nated with (nonpolar) phosphane residues from the metath-
esis catalyst. Therefore, we adopted a protocol whereby the
metathesis reaction was quenched, the (more polar) dihy-
drofuran product purified by chromatography and then
aromatised separately by reaction with acid. Using this
methodology, a range of differently substituted furans 4, 7,
10 were prepared in good yield, Scheme 1. The tolerance of
aryl, alkyl and carbonyl functional groups to this sequence
is noteworthy.
Results and Discussion
Initial synthetic studies focused on the formation of fu-
rans using the approach detailed in Figure 1. Thus, a range
of differently substituted allylic alcohols (1,[14] 5,[15] 8[16]
)
were prepared by (short) routes described in the literature,
Scheme 1. Each alcohol was subsequently reacted with
methoxyallene under palladium(ii) catalysis conditions to
furnish a variety of unsymmetrical mixed acetals (2, 6, 9,
as a mixture of stereoisomers where appropriate).
The possibility of forming pyrroles by this route
(Scheme 2) was also examined. The strategy followed sim-
ilar lines to that described above and was also successful in
Scheme 1. a) Methoxyallene, 5% Pd(OAc)2, 5% dppp, Et3N,
MeCN, Δ; b) 10% 3, CH2Cl2, Δ; c) TFA.
The key C–C bond forming metathesis reaction was per-
formed on these mixed acetals using Grubbs catalyst 3 and,
in each case, the expected unsaturated five-membered ring Pd(PPh3)4, PhI, C6H5CH3.
Scheme 2. a) Methoxyallene, 5% Pd(OAc)2, 5% dppp, Et3N,
MeCN, Δ; b) 10% 3, CH2Cl2, Δ; c) TFA; d) methoxyallene, 5%
Scheme 3. a) Methoxyallene, 5% Pd(OAc)2, 5% dppp, Et3N, MeCN, Δ; b) 10% 3, CH2Cl2, Δ; c) TFA.
1970
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Eur. J. Org. Chem. 2005, 1969–1971

A Metathesis Approach to Aromatic Heterocycles
SHORT COMMUNICATION
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conditions, followed by double RCM on acetal 23 and treat-
ment of the product with acid. Pleasingly, the bisfuran 24
was produced in good yield for the overall sequence. The
selectivity observed during RCM for formation of five-
membered rings, at the expense of other-sized rings, is pre-
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proach holds many opportunities for the rapid construction
of polyaryl compounds.
To conclude, we have reported a novel and versatile ap-
proach to the synthesis of furans and pyrroles that uses me-
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that this methodology holds for the formation of poly-sub-
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Acknowledgments
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We thank Organon for funding this project. AstraZeneca, Pfizer,
Novartis, and Merck are thanked for generous unrestricted fund-
ing.
[22] Supporting information which describes experimental pro-
cedures and spectroscopic data for key compounds for this arti-
cle is available on the WWW under http://www.eurjoc.org or
from the author:
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39, 3012; b) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54,
4413; c) S. K. Armstrong, J. Chem. Soc., Perkin Trans. 1 1998,
Received: February 10, 2005
Eur. J. Org. Chem. 2005, 1969–1971
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1971