Intramolecular iodoarylation reaction of alkynes: Easy access to derivatives of benzofused heterocycles

Article abstract of DOI:10.1039/b500303b

The iodoarylation reaction of heteroatom-tethered ω-aryl-alkynes offers an efficient and straightforward entry to heterocycles. As a result, both C-C ring-closing from readily available precursors, and concomitant selective iodination take place. The firs

Full text of DOI:10.1039/b500303b

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Intramolecular iodoarylation reaction of alkynes: easy access to
derivatives of benzofused heterocycles{
Jose´ Barluenga,* Mo´nica Trincado, Mar´ıa Marco-Arias, Alfredo Ballesteros, Eduardo Rubio and
Jose´ M. Gonza´lez
Received (in Cambridge, UK) 13th January 2005, Accepted 4th February 2005
First published as an Advance Article on the web 22nd February 2005
DOI: 10.1039/b500303b
The iodoarylation reaction of heteroatom-tethered v-aryl-
alkynes offers an efficient and straightforward entry to
heterocycles. As a result, both C–C ring-closing from readily
available precursors, and concomitant selective iodination take
place. The first related study conducted in water is presented.
The implementation of flexible, conceptually simple and synthe-
tically promising approaches that bring about a rapid access to
heterocycles is highly desirable, as there is widespread interest in
their preparation. The use of organometallic catalysts and/or
reagents to assist this task holds a prevailing position among the
organic community.1 The Friedel–Crafts reaction is well suited to
promote the arylation reaction of alkenes; however, the related
process using alkynes suffers from major limitations.2 In this
challenging scenario, transition metals have provided excellent
results, overriding many of the otherwise encountered limitations.3
We are engaged on a project aimed at uncovering the potential
offered by iodonium ions in synthesis,4 including several alter-
natives for making C–C bonds.5 Herein, we describe a robust and
versatile process for the construction of derivatives of benzofused
heterocycles, based on a successful iodoarylation reaction of
alkynes for the ring-closing step (Scheme 1), the heteroatom being
just used as an easy tethering component for the assembling of the
v-arylalkyne precursor.
Scheme 2 Cyclization of compounds 1 (X: O, NTs, NMs) using
First, the reactivity of different derivatives of phenyl propargyl
iodoarylation reactions for the ring-closing step.
ether as well as of related N-mesyl propargyl anilines was screened.
Thus, following the above depicted approach, there is no need for
additional substitution in the aromatic ring, the reaction giving rise
ion, as it is a fine partner while searching for selective trans-
formations.6 The formed derivatives 27 can be rationalized
to a smooth C–H functionalization. Our initial results are sum-
marized in Scheme 2. Tetrafluoroborate of bis(pyridine)iodonium
assuming initial formation of a vinyliodonium intermediate and
(IPy2BF4) was the reagent first tested as the source of iodonium
its subsequent trapping by the arene, in a Friedel–Crafts type
process.8 Interestingly, though terminal alkynes failed to react,
their masked halogenated forms were excellent partners, opening
attractive synthetic possibilities for diversity oriented synthesis.9 In
this regard, compounds such as 2c are particularly useful for
further elaboration by merging the resulting halogenated structures
of this approach with the potential of metal-catalyzed cross-
coupling reactions (Scheme 3). Overall, this methodology renders
an alternative and easy entry into a class of valuable tetra-
substituted cycloalkenes,10 featuring structural motifs that are
Scheme 1 Iodonium-mediated preparation of benzofused heterocycles
present in molecules used as ligands as potential selective estrogen
modulators (SERMs).11
by intramolecular arylation of an X-tethered alkyne (X: heteroatom).
Furthermore, as depicted in Scheme 4, the cyclization allows for
{ Electronic supplementary information (ESI) available: experimental
procedures, characterization data for compounds 2, 4, 6, 8 (including H
additional substitution at the propargylic position retaining chiral
information included in 1j,12 as well as for carrying out more than
1
and 13C NMR spectra). See http://www.rsc.org/suppdata/cc/b5/b500303b/
*barluenga@uniovi.es
one ring-closing step, as in the cases of 6 and 8.
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Scheme 4 Chromenes upon iodoarylation of alkynes: retention of
stereochemistry and multiple ring-closing reactions.
Table 1 Intramolecular iodoarylation reaction of alkynes in water
Scheme 3 Reagents and conditions: (a) i: 2c (1 equiv.),
p-MeC6H4(CHLCH2) (1.5 equiv.), Pd(OAc)2 (2.3 mol%), P(o-MeC6H4)3
(3 mol%), NEt3, 120 uC (sealed tube), 10 h. ii: 3a (1 equiv.),
p-MeOC6H4B(OH)2 (1.1 equiv.), Pd(Ph3)4 (2 mol%), Na2CO3 (3 equiv.),
C6H6–EtOH, 80 uC, 48 h (b) i: 2c (1 equiv.), C6H5B(OH)2 (1.1 equiv.),
Pd(dba)2 (0.5 mol%), PPh3 (1 mol%), KOH (1.1 equiv.), C6H6–EtOH,
80 uC, 15 h. ii: 3b (1 equiv.), p-MeOC6H4B(OH)2 (1.1 equiv.), Pd(PPh3)4
(2 mol%), Na2CO3 (3 equiv.), C6H6–EtOH, 80 uC, 48 h. (c) i: 2c (1 equiv.),
3-[B(OH)2]thiophene (1.1 equiv.), Pd(dba)2 (0.5 mol%), PPh3 (1 mol%),
KOH (1.1 equiv.), C6H6–EtOH, 80 uC, 15 h. ii: 3c (1 equiv.),
p-MeC6H4(CMCH) (1.5 equiv.), Pd(OAc)2 (2 mol%), P(o-MeC6H4)3
(3 mol%), CuI (15 mol%), NEt3, 120 uC (sealed tube), 15 h.
Entry
R1
R2
X
‘‘I+’’a
Product
Yield (%)b
1
2
3
4
5
6
7
8
a
Ph
Ph
Ph
Ph
Me
n-Bu
Ph
H
H
H
H
H
H
OMe
OMe
O
A
A
B
B
B
2a
2k
2k
2a
2l
2m
2n
2n
50
CH2
CH2
O
CH2
CH2
O
52c
90
75d
e
—
B
35f
55g
90i
B
Ph
O
Bh
In connection with our interest in organic processes in water,13
we were attracted by the stimulating problem of developing C–C
bond forming reactions in that media.14 Initial and promising
results were gathered using conditions based on our previous work
on iodohydroxylation of alkenes, Table 1 (entries 1–2).13a
Thus, NaI can be activated to give both carbo- and hetero-
cyclization reactions involving a scantly reported iodoarylation of
alkynes now, for the first time, taking place in water.15 Alongside
this study we also used iodine as the source for the electrophile.
Running the reaction in water,16 cyclization was observed in
variable yield, as a function of the alkyne substituent. For simple
alkyl groups, the cyclization outcome was dramatically dependent
on the length of the chain (entries 517 and 6), whereas satisfactory
results were accomplished if the alkyne bore an aryl group
(entries 3 and 4).
Method A: NaI (1 equiv.), H2O2 (6 equiv. of H2O2, 30% aqueous
solution), H2SO4 (8 equiv.), H2O (15 mL/1 mmol 1), 40 uC, 5 h.
Method B: I2 (2 equiv.), H2O (15 mL/1 mmol 1), rt, 2 h. Isolated
b
c
d
yield referred to 1. Reaction for 20 h. 3 equiv. of I2 used.
e
f
1-[(E)-3,4-diiodopent-3-enyl]benzene 9 was formed (95%). 1-[(E)-
3,4-diiodooct-3-enyl]benzene 10 was the major product isolated
from the reaction mixture. 4-phenyl chromane 11 was also formed
g
and isolated (30%). Amberlyst1-15wet (1g of resin/1 mmol of 1)
was incorporated as additive to the reaction. 11 was formed as by-
product (9%).
h
i
additives. Best results were obtained using a solid acid-resin (see
entries 7 and 8); in the same way, addition of sulfuric acid gave a
similar result.
In summary, a versatile entry to heterocycles has been
established on the basis of an efficient iodoarylation of alkynes.
The convenience of this simple but powerful approach is amplified
by further considering the use of the resulting adducts in cross-
coupling reactions, that results in a superb combination for the
rapid preparation of derivatives. Preliminary evidence on the
An interesting effect was noticed in the cyclization of the
propargyl ether derivative of p-methoxyphenol. Improved selec-
tivity towards the formation of the desired chromene18 2n, as well
as a better yield was accomplished upon screening several
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M. Trincado, E. Rubio and J. M. Gonza´lez, J. Am. Chem. Soc.,
2004, 126, 3416.
6 For an example of unusual selectivity for the ortho-iodination in
the aromatic substitution reaction, see: G. Espun˜a, G. Arsequell,
G. Valencia, J. Barluenga, J. Alvarez-Gutie´rez, A. Ballesteros and
J. M. Gonza´lez, Angew. Chem. Int. Ed., 2004, 43, 325.
7 The structures of compounds 2 were established on the basis of their
NMR (1H and 13C) spectroscopic and MS data. All new compounds 2
gave satisfactory elemental analysis and/or HRMS data, according to
the proposed structures.
8 For an intermolecular arylation reaction of alkynes, see: (a) J. Barluenga,
M. A. Rodr´ıguez, J. M. Gonza´lez and P. J. Campos, Tetrahedron Lett.,
1990, 31, 4207; (b) In a recent report using ICl, it was assumed that the
iodoarylation processes should be applicable only to cyclize electron-rich
and conjugated biaryl alkyne fragments, see: T. Yao, M. A. Campo and
R. C. Larock, Org. Lett., 2004, 6, 2677. Clearly, this is not mandatory in
our system, nor was it in our related previous work.
9 (a) D. S. Tan, M. A. Foley, M. D. Shair and S. L. Schreiber, J. Am.
Chem. Soc., 1998, 120, 8565; (b) K. C. Nicolau, J. A. Pfefferkorn,
H. J. Mitchell, A. J. Roecker, S. Barluenga, G.-Q. Cao, R. L. Affleck
and J. E. Lillig, J. Am. Chem. Soc., 2000, 122, 9954; (c) M.-S. Schiedel,
C. A. Briehn and P. Ba¨uerle, Angew. Chem. Int. Ed., 2001, 40, 4677.
10 For the preparation of related tetrasubstituted cycloalkenes and their
use as precursors for the synthesis of cis-3,4-disubstituted chromanes
upon hydrogenation, see: P. S. Bury, L. S. Christiansen, P. Jacobsen,
A. S. Jørgensen, A. Kanstrup, L. Nærum, S. Bain, C. Fledelius,
B. Gissel, B. S. Hansen, N. Korsgaard, S. M. Thorpe and
K. Wassermann, Bioorg. Med. Chem., 2002, 10, 125.
feasibility of conducting related chemistry in water, under an air
atmosphere, are also timely presented and should open interesting
opportunities for future developments of reactions taking place at
this important interface. Further work, dealing with several points
brought about by this communication, is in progress.
This research was partly supported by The Principality of
Asturias (PR-01-GE-9) and by The Spanish DGI (MCT-01-BQU-
3853). M. T. wants to thank Spanish M.E.C. for a fellowship.
Generous support from Merck Sharp & Dohme (UK) is also
gratefully acknowledged.
Jose´ Barluenga,* Mo´nica Trincado, Mar´ıa Marco-Arias,
Alfredo Ballesteros, Eduardo Rubio and Jose´ M. Gonza´lez
Instituto Universitario de Qu´ımica Organometa´lica ‘‘Enrique
Moles’’-Unidad Asociada al C.S.I.C., Universidad de Oviedo, C/Julia´n
Claver´ıa, 8, 33006-Oviedo, Spain. E-mail: barluenga@uniovi.es;
Fax: +34 985103450; Tel: +34 985103450
Notes and references
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