A ridge walk between reaction modes: An unprecedented Pd-catalyzed domino sequence of diynyl-substituted bromoarenes

Article abstract of DOI:10.1021/ol2030923

Diynyl-substituted bromoarenes underwent a novel Pd-catalyzed domino reaction to provide benzofurans, pyridinofurans, isochromenes, and indole derivatives. Slight changes of the substrate push the reaction in another direction resulting in benzene annulation.

Full text of DOI:10.1021/ol2030923

ORGANIC
LETTERS
2012
Vol. 14, No. 1
346–349
A Ridge Walk between Reaction Modes:
An Unprecedented Pd-Catalyzed Domino
Sequence of Diynyl-Substituted
Bromoarenes
Markus Leibeling,† Martin Pawliczek,† Daniel Kratzert,‡ Dietmar Stalke,‡ and
Daniel B. Werz*,†
€
Institut fu€r Organische und Biomolekulare Chemie der Georg-August-Universitat
€
€
€
Gottingen, Tammannstr. 2, D-37077 Gottingen, Germany, and Institut fur Anorganische
€
€
€
Chemie der Georg-August-Universitat Gottingen, Tammannstr. 4, D-37077 Gottingen,
Germany
dwerz@gwdg.de
Received November 18, 2011
ABSTRACT
Diynyl-substituted bromoarenes underwent a novel Pd-catalyzed domino reaction to provide benzofurans, pyridinofurans, isochromenes, and
indole derivatives. Slight changes of the substrate push the reaction in another direction resulting in benzene annulation.
Palladium-catalyzed transformations have emerged as
some of the most powerful CÀC coupling reactions dur-
ing the past decades.1 Commonly, catalytic cycles involve
Pd(0)/Pd(II) species being easily converted into each other.
The ability of Pd complexes to react with π systems
leading to an insertion of either an alkene or an alkyne unit
in the PdÀC bond (carbopalladation) sets the stage for a fast
and efficient synthesis of a variety of complex target
molecules.2 Often the complexity gained in such a reaction
can be further increased by offering several alkene or alkyne
moieties resulting in multiple carbopalladation steps.2 De-
pending on the substrate the species obtained during these
processes might be prone to a variety of other reaction
modes such as cross-coupling steps, pericyclic reactions,
CÀH activations, or CO insertions.3 Commonly, the final
step of such a Pd-catalyzed domino reaction3À5 consists of a
(3) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(4) Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
(5) Some representative examples of recent domino reactions:
† Institut f€ur Organische und Biomolekulare Chemie.
‡ Institut f€ur Anorganische Chemie.
(1) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
€
€
(a) Tietze, L. F.; Dufert, A.; Lotz, F.; Solter, L.; Oum, K.; Lenzer, T.;
Beck, T.; Herbst-Irmer, R. J. Am. Chem. Soc. 2009, 131, 17879–17884.
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€
(b) Cvengros, J.; Schutte, J.; Schlorer, N.; Neudorfl, J.-M.; Schmalz,
H. G. Angew. Chem. 2009, 121, 6264–6267. Angew. Chem., Int. Ed. 2009,
48, 6148–6151. (c) Saget, T.; Cramer, N. Angew. Chem. 2010, 122
9146–9149. Angew. Chem., Int. Ed. 2010, 49, 8962–8965. (d) Wegner,
H. A.; Ahles, S.; Neuburger, M. Chem.;Eur. J. 2008, 14, 11310–11313.
Reactions; Wiley-VCH: Weinheim, 2004.
(2) (a) Abelman, M. M.; Overman, L. E. J. Am. Chem. Soc. 1988, 110,
2328–2329. (b) Zhang, Y.; Wu, G.; Agnel, G; Negishi, E. J. Am. Chem.
Soc. 1990, 112, 8590–8592. (c) Petrignet, J.; Boudhar, A.; Blond, G.;
Suffert, J. Angew. Chem. 2011, 123, 3343–3347. Angew. Chem., Int. Ed.
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r
10.1021/ol2030923
Published on Web 12/13/2011
2011 American Chemical Society

reductive elimination of the Pd(II) species to regenerate the
catalyst.1,2
Table 1. Optimization Studies for the Domino Reaction
Recently, we studied the formation of chromans and
isochromans in a Pd-catalyzed domino reaction starting
from carbohydrate derivatives.6,7 To achieve this goal we
utilized a twofold carbopalladation process followed by a
ring closure and elimination of the Pd species. A similar
annulation of a benzene ring was previously published by
Grigg.8 However, a very special pattern of heteroatoms
proved to be the prerequisite for a successful outcome
(see Scheme 1). Recently, also intermolecular twofold
carbopalladations of diynes with aromatic cores were
explored.9
Catalyst/
Ligand
(mol %)
Base
Yield
(%)
Entry
(equiv)
Solvent
We started our investigations with the diyne 3a as a
model compound to yield naphthalene derivatives similar
to compounds obtained by Grigg. In contrast, our sub-
strates consist of a butano tether between the two alkyne
moieties. Furthermore, 3a contains an O-linked diyne
chain without any donor functionality at the terminus to
force a ring closure by CÀH activation.10 While carrying
out the reaction with 3a, surprisingly, we detected as the
only isolable product a molecule embodying a furan
moiety and two alkene units. A benzene annulation, as
originally anticipated, did not take place.
1
2
3
4
5
6
7
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(OAc)2 (10)
PPh3 (20)
HNiPr (5)
HNiPr (5)
HNiPr (5)
LiOAc (5)
Cs2CO3 (5)
CsF (5)
MeCN
35
56a
54
20
75
75
52
dioxane
toluene
toluene
toluene
toluene
toluene
Cs2CO3 (5)
8
Pd(OAc)2 (10)
dppe (20)
Cs2CO3 (5)
Cs2CO3 (5)
CsF (10)
toluene
toluene
toluene
64
62
80
9
Pd(OAc)2 (10)
Josiphos (20)
Pd(PPh3)4 (10)
10
a Inseparable impurities occurred.
Scheme 1. Domino Reaction by Grigg et al.
was optionally accomplished by a hydroxy functionality
or an acetylated amine, but also hydroxymethyl groups
were successfully employed. At the terminus of the diyne
chain an aryl group, either electron-rich (with OMe groups)
or electron-poor (with F substituents or even pyridine
units), was installed. With the exception of one example
(3e) the tether between the two triple bonds consisted of
four methylene units. Our investigations revealed that the
desired transformations proceeded smoothly and yielded
the products in up to 80% yield. By utilizing this domino
reaction we were able to access benzofurans 4aÀ4d, iso-
chromenes 4eÀ4f, pyridinofurans 4gÀ4h, and indoles
4iÀ4k respectively (Scheme 2).11 Limitations were ob-
served in terms of terminal (H-substituted) diynes; in
these cases no product formation was observed. With
propano tethers between the alkyne moieties mostly in-
separable mixtures of compounds were obtained (with the
exception of 4e).
Encouraged by this unexpected result we performed an
intensive screening of various Pd sources, ligands, bases,
and solvents. Some results of the optimization are com-
piled in Table 1. The most efficient catalytic system for the
transformation of 3a into 4a turned out to be Pd(PPh3)4,
CsF in toluene at 110 °C (entry 10).
With the optimal reaction conditions for 3a in hand, the
scope of this Pd-catalyzed domino process was explored
with a variety of diynyl-substituted bromoarenes of type 3
(see Supporting Information for their syntheses). The
arene was either a benzene or a pyridine derivative. The
attachment of the diyne chain to the six-membered ring
To our delight, two structures of these domino pro-
ducts could also be proven unambiguously by X-ray
(6) (a) Leibeling, M.; Koester, D. C.; Pawliczek, M.; Schild, S. C.;
Werz, D. B. Nat. Chem. Biol. 2010, 6, 199–201. (b)Leibeling, M.;Koester,
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menes, and indoles: (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 3676–3677. (b) Liang, Y.; Zhang, S.; Xi, Z. J. Am. Chem. Soc.
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Org. Lett., Vol. 14, No. 1, 2012
347

To elucidate the unusual outcome of this reaction
mechanistically a deuterium-labeled diyne 5 was pre-
pared. We were interested in whether the transfer of the
deuterium from the deuterated methylene group next to
the heteroatom takes place in an inter- or an intra-
molecular fashion. In total, 1 equiv of DBr or HBr is
eliminated during the course of the reaction. In the case of
an intermolecular reaction pathway a product mixture
with D as well as H at the trisubstituted alkene would be
the consequence. However, while carrying out the trans-
formation with the deuterium-labeled analog 5 an entire
transfer of deuterium from the methylene group to the
alkene moiety in 6 was observed by NMR spectroscopy.
Scheme 2. Domino Reaction to Benzofurans 4aÀ4d, Isochro-
menes 4eÀ4f, Pyridinofurans 4gÀ4h, and Indoles 4iÀ4k
Scheme 3. Proposed Reaction Pathways for the Benzofuran
Formation with Deuterated Substrate 5: Alternatives A and B
Figure 1. Crystal stucture of benzofuran 4a (left) and indole
derivative 4i (right), depicted with anisotropic displacement
parameters at the 50% probability level.
Mechanistically, we suppose that the domino process
is initiated by two consecutive carbopalladation steps
following the oxidative addition of the Pd(0) species into
the CÀBr bond (Scheme 3). To explain the mechanistic
outcome two different scenarios are conceivable: In the
first one (Alternative A) a rotation of the tetrasubstituted
double bond in intermediate 7 takes place. This assump-
tion might be valid due to the strained geometry of the
crystallographic analysis. Thermal ellipsoid plots of 4a
and 4i are depicted in Figure 1.12,13
(13) The crystal data and experimental details for the X-ray measure-
ments are listed in the Supporting Information. CCDC-849628 (4a),
-849626 (4i), and -849625 (14a) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(14) Agranat, I.; Tapuhi, Y. J. Am. Chem. Soc. 1978, 100, 5604–5609.
Org. Lett., Vol. 14, No. 1, 2012
348

alkene and the temperature of 110 °C.14 In the next step
a [1,5]-sigmatropic rearrangement occurs affording 9.
A 1,3-allyl shift of the Pd and subsequent β-hydride elimi-
nation terminate the sequence. The distinct configuration
of the exocyclic double bond in 6 might be attributed to
the 1,3-allyl strain.
conditions. However, benzofuran derivatives could not be
detected in significant amounts since the reaction pursues
another path. With the use of a sterically highly encum-
bered phosphite ligand and Pd(OAc)2 as a Pd source in
dioxane at 140 °C the originally anticipated benzene
annulation was observed in moderate to very good yields
(Scheme 4). Electron-rich as well as electron-poor bro-
moarenes are suitable, and the same holds true for the aryl
substituent attached to the terminal alkyne unit. Note-
worthy, a bromonaphtalene derivative was successfully
converted into the highly substituted phenanthrene 14j
demonstrating that also sterically hindered bromoarenes
are appropriate starting materials for this domino reac-
tion. The benzene annulation was also not hampered by
the formation of a six-membered ring in the first carbo-
palladation as naphtalene derivative 14k illustrates.
In summary, we found a novel domino reaction starting
with diynyl-substituted bromoarenes. Benzofuran, pyridi-
nofuran, indole, and isochromene systems were success-
fully obtained by this method in yields of 50À80%. The
mechanistic scenario pursuing the two consecutive carbo-
palladation steps is not clear so far; either double bond
isomerization followed by a sigmatropic rearrangement or
the involvement of Pd(IV) species is assumed. A slight
change of the substrates opened another reaction pathway
resulting in the annulation of benzene moieties. Further
investigations with respect to the underlying mechanism
are underway.
A second alternative would involve a Pd(IV) π allyl
complex 11 being created by an oxidative addition into
the CÀD bond of 7.15À17 Reductive elimination would
lead to a Pd(II) π allyl complex 12. A migration of the Pd
affords 10 consisting of benzofuran and a σ-bound Pd
species. Finally, a β-hydride elimination would yield 6.
Both scenarios are compatible with our observation
that butano tethers yield the product whereas propano
tethers are mostly associated only with traces of product.
Because of the larger angle between the two exocyclic
alkene units at a five-membered ring, the double bond,
which has to change its configuration, is slightly less
sterically hindered, thus less twisted and less prone to
rotate. The same argument holds true for a Pd(IV) com-
plex of type 11 which is more difficult to create in the case
of a backbone consisting of a five-membered ring.
Scheme 4. Twofold Carbopalladation, CÀH Activation Se-
quence To Yield Naphthalene Derivatives 14aÀ14ka,b
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie (Emmy Noether Fellowship and
Dozentenstipendium to D.B.W.). M.L. thanks the State
of Lower Saxony for a CaSuS Ph.D. Fellowship. D.S.
thanks the DNSF for funding the CMC. The authors are
grateful to Professor Dr. Lutz F. Tietze and Professor Dr.
€
Armin de Meijere (both University of Gottingen) for
helpful discussions.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and NMR spectra for all new
compounds. Cif files of 4a, 4i, and 14a.13 This material
is available free of charge via the Internet at http://
pubs.acs.org.
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