Oxyacylation of Iodoalkynes: Gold(I)-Catalyzed Expeditious Access to Benzofurans

Article abstract of DOI:10.1021/acs.orglett.9b02551

(Acetonitrile)[1,3-bis(2,6-diisopropylphenyl)-imidazole-2-ylidene] gold(I) catalyzes the cycloisomerization of 2-(iodoethynyl)aryl esters to give 3-iodo-2-acyl benzofurans. This catalytic transformation is the result of an unprecedented selective syntheti

Full text of DOI:10.1021/acs.orglett.9b02551

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxyacylation of Iodoalkynes: Gold(I)-Catalyzed Expeditious Access
to Benzofurans
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Paula Fernandez-Canelas, Eduardo Rubio, and Jose M. Gonzalez*
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Departamento de Química Organica e Inorganica and Instituto Universitario de Química Organometalica “Enrique Moles”,
́
Universidad de Oviedo, C/Julian Clavería 8, 33006 Oviedo, Spain
S
* Supporting Information
ABSTRACT: (Acetonitrile)[1,3-bis(2,6-diisopropylphenyl)-imidazole-
2-ylidene] gold(I) catalyzes the cycloisomerization of 2-(iodoethynyl)-
aryl esters to give 3-iodo-2-acyl benzofurans. This catalytic trans-
formation is the result of an unprecedented selective synthetic event,
which comprises a [1,2]-iodine shift, a C−O ring-closure step, and a C−
C bond-formation that installs the ketone functionality into the new ring.
Experimental evidence supports the involvement of a β-iodo-substituted
gold vinylidene as the intermediate species. The reaction tolerates
different substitution patterns at the phenol moiety and a wide diversity
of groups at the carboxylic fragment, including not only alkyl but also
alkenyl, aryl, and heteroaryl groups.
known, but the related transformation involving a selective
migration to C-2 is missing (Scheme 1B).
rganic synthesis contributes to the welfare of modern
Osociety, providing access to crucial chemicals. Thus,
identifying new reactions is of prime interest. For this purpose,
alternative catalytic protocols for the generation of intermediate
species such as metal vinylidenes play a main role in
contemporary synthetic methodology.1 Gold vinylidenes are
relatively new players in the field, but increasingly gaining
significance.2,3 Now, we are reporting an unprecedented
catalytic transformation furnishing 2-acyl-3-iodobenzo[b]furan
cores and evolving through a gold vinylidene intermediate. At
the same time, it reveals a distinctive cyclization pattern for
coinage-metal-catalyzed isomerization reactions of related
precursors, adding interest to this process (Scheme 1A).4,5
Thus, catalytic reactions giving C-3-substituted benzo[b]-
furans as the result of a selective transfer of the oxygen
substituent to the C-3 position of the assembled heterocycle are
Readily available esters derived from phenols containing the
o-iodoethynyl fragment were chosen as substrates. According
with early observations on accessing gold vinylidene complexes
from iodoalkynes [1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene] [bis(trifluoromethanesulfonyl)imide]gold(I)
(IPrAuNTf2) was chosen as catalyst.6 Heating o-(iodoethynyl)
2-phenylacetate 1a (0.1 M solution in 1,2-dichloroethane) with
2.5 mol % of the gold catalyst at 80 °C furnishes 1-(3-
iodobenzofuran-2-yl)-2-phenyl ethanone 2a, in 80% yield
(Scheme 2). The influence of the counteranion over the
Scheme 2. Gold(I)-Catalyzed Deep Rearrangement
Scheme 1. Catalytic Isomerizations to 2,3-Benzo[b]furans
reaction was tested. A faster reaction was observed for
(acetonitrile)[1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene]gold(I)hexafluoroantimoniate [IPrAu(CH3CN)]-
[SbF6], giving 2a in virtually the same isolated yield.7
Overall, three bonds were formed along the catalytic event,
namely the C(sp2)−I and new C(sp2)−O and C(sp2)−C(sp2)
bonds. The C−I bond suggests interest for building-block
diversification. Interestingly, the ester moiety catalytically turns
Received: July 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02551
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of the Catalytic Isomerization
a
b
Reactions were conducted on 0.2 mmol scale. Yields refer to the isolated product after purification. Five mol % added catalyst.
into a ketone selectively attached at the elusive C2-position.
Metal-catalyzed 1,1-oxyacylation reactions are scarce8 and
unprecedented using gold catalysis.
The presence of a substituent at the ortho-position is also
compatible with this catalytic cyclization, as noticed in the
cyclization yielding 2k, as confirmed by X-ray diffraction
analysis. The possibility of using this reaction to obtain
bis(heteroaryl) ketones was tested for esters obtained from
heteroaromatic carboxylic acids. Precursors 1l and 1m, obtained
from 2-furan and 2-thiophene carboxylic acids, gave 2l and 2m,
respectively. This catalytic cyclization also yields α,β-unsatu-
rated ketones. Remarkably, the reaction is also efficient on a
gram-scale basis. Thus, 1.45 g of 2o was prepared on comparable
78% yield to that reported for the smaller scale.
The fact that the process relies on a simple ester preparation
brings interest to this catalytic cycloisomerization for a late stage
modification of bioactive molecules. Naproxen, a known
nonsteroidal anti-inflammatory (NAISD) drug with the
structure of (S)-2-(6-methoxynaphthalen-2-yl)propanoic
acid,12 was chosen for this purpose. A commercial sample of
this bioactive molecule (purity (HPLC) ≥ 97.5%) was
converted to ester 1p (Scheme 4). Partial erosion of the
enantiomeric purity occurred at this stage (er: 89:11). Next,
enantioenriched 1p was exposed to gold(I) catalysis and led to
the new hybrid structure 2p. Interestingly, the integrity of the
stereocenter (er: 87:13) was virtually preserved along the
catalytic transformation.
With these preliminary results in hand, and taking into
account the biological prevalence9 and the interest in the
preparation of this heterocyclic motif,10 the scope of the reaction
was investigated, using [IPrAu(CH3CN)][SbF6] as the catalyst
(Scheme 3). Besides, IPrAuNTf2 was tested over some
additional substrate, giving rise always to the corresponding
product 2 in lower yield, even after extended reaction time.
Using as precursors esters derived from carboxylic acids
having other alkyl chains, the conversion was completed in <1 h
for 2.5 mol % catalyst loading, affording compounds 2b−d in
synthetically useful isolated yields. The assigned structures for
compounds 2 are based on their characterization data, including
extensive NMR studies. Single-crystal X-ray diffraction analysis
of 2c nicely endorses the proposed structure.11
Esters based on o-(iodoethynyl)phenol and different aryl
carboxylic acids were subjected to the conditions described
above. Ester 1f, derived from an electron-rich arene carboxylic
acid, was rapidly consumed; however, side reactions partly
limited the formation of 2f, which was isolated only in moderate
yield. On the contrary, esters 1e and 1g derived, respectively,
from benzoic acid and the related p-bromophenyl motif reacted
slower but more efficiently in terms of giving the target
benzofuranyl ketones 2e and 2g. The reaction tolerates
substituents at the phenol moiety in 1. The process transformed
1h and 1j, bearing modestly deactivated or activated
substituents (4-Cl or 4-Me) at the para-position, into the
compounds 2h and 2j. It also performs nicely if a more electron-
withdrawing group is present at the para-position, which gives 2i
in fair isolated yield, though after an extended reaction time.
In order to postulate a reaction mechanism, additional
experimental work was conducted. The outcome of a potential
crossover experiment was tested (Scheme 5). A 1:1 mixture of
1h and 1m was subjected to the standard reaction conditions
and the crude reaction mixture monitored by 1H NMR (CH2Br2
added as internal standard). Only formation of 2h and 2m was
noticed. The absence of crossover products is compatible with
an intramolecular process. However, it does not support in full
B
DOI: 10.1021/acs.orglett.9b02551
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Late Stage Functionalization of (S)-Naproxen
Scheme 7. Mechanistic Proposal
Scheme 5. Crossover Experiment
bioactive compounds. The process encodes a new cyclization
mode in the context of coinage metal-catalyzed reactions of
derivatives of o-alkynylphenols. Now, the original substituent
onto oxygen gets selectively attached at the C-2 position of the
assembled benzo[b]furan. Mechanistic insights are provided
supporting the involvement of an intermediate gold vinylidene.
A number of products were obtained via a new reaction
comprising the selective migration of both iodine and the acyl
moiety at the time of elaborating the heterocyclic scaffold.
an alternative initial O-cyclization path followed by the release
into the solution of the acyl cation.13
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02551.
■
S
Interestingly, when 1e was exposed to the gold(I) catalyst in
the presence of an excess of triethylsilane, the cyclization leading
to 2e was inhibited. Conversely, the analysis of the crude
reaction mixture by NMR revealed the formation of the product
3e, which reasonably arises from an alternative trapping of the
intermediate gold vinylidene species by insertion into the silane,
leading to the hydrosilylation product. Along the purification
step (column chromatography over silica gel, eluting with
mixtures of hexanes and ethyl acetate), an easy proto-
desilylation took place, and a clean generation of 4e was noticed
(Scheme 6).
Experimental procedures, compound characterization,
and NMR spectra (PDF)
Accession Codes
CCDC 1917876−1917877 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Trapping Intermediate Gold Vinylidene Species
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jmgd@uniovi.es.
Notes
The authors declare no competing financial interest.
On this basis, a mechanistic proposal is depicted in Scheme 7.
Coordination of gold(I) to 1 would release the nitrile and
activate the alkyne. Then, a 1,2-iodine migration facilitated by
the donor ability of the ligand at gold would furnish the key gold
vinylidene intermediate, which is supported by the above given
trapping experiment with silane affording 3.14 Insertion of the O-
acyl bond into this reactive species would account for the
assembly of 2,15 without forming scrambled products in the
attempted crossover experiment, while at the time preserving the
stereochemical integrity.
In short, a new gold(I)-catalyzed cycloisomerization reaction
of practical utility is presented. The ketone that is formed at the
time of elaborating the benzo[b]furan core is of significance.
The accessibility of an ester as the tether bringing together the
two main fragments conveniently enables a catalytic increasing
of molecular complexity in a simple and straightforward manner,
which can be implemented for a late stage diversification of
ACKNOWLEDGMENTS
P.F.C. is grateful to the Spanish Ministerio de Economia,
Industria y Competitividad for a FPI predoctoral fellowship.
■
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Agencia Estatal de Investigacion (AEI), Fondo Europeo de
Desarrollo Regional (FEDER) is acknowledged for financial
support, grant CTQ2016-76840-R (AEI/FEDER, UE). Useful
́
comments from our colleague Dr. Ruben Vicente and help from
́
Dr. Angel Luis Suarez-Sobrino to solve the X-ray structures are
acknowledged. This manuscript is dedicated to Professor Dr.
Pablo Espinet on the occasion of his 70th birthday.
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D
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Org. Lett. XXXX, XXX, XXX−XXX