Tandem indole C-H alkenylation/arylation for tetra-substituted alkene synthesis

Article abstract of DOI:10.1039/c1cc13094c

Alkynyl indoles undergo a novel sequence of Pd-catalysed indole C-H activation/alkyne carbopalladation/arylation, with diaryliodonium salts providing the aryl components. An array of functionalised indole alkenes have been prepared in good to excellent yield, with the reaction being selective for the Z-alkene.

Full text of DOI:10.1039/c1cc13094c

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 7992–7994
www.rsc.org/chemcomm
COMMUNICATION
Tandem indole C–H alkenylation/arylation for tetra-substituted alkene
synthesisw
Laura Lopez Suarez and Michael F. Greaney*
Received 26th May 2011, Accepted 3rd June 2011
DOI: 10.1039/c1cc13094c
Alkynyl indoles undergo a novel sequence of Pd-catalysed
indole C–H activation/alkyne carbopalladation/arylation, with
diaryliodonium salts providing the aryl components. An array of
functionalised indole alkenes have been prepared in good to
excellent yield, with the reaction being selective for the Z-alkene.
the arylating agents, as these compounds are known to oxidise
organo-Pd(II) species to the Pd(IV) complexes.10 We were
pleased to find that treatment of 5a with 1.2 equiv of diphenyl-
iodonium tetrafluoroborate, 6a, in trifluoroethanol at 80 1C
gave the expected 6-exo-dig alkene product 7a in 47% yield as
a 5 : 1 Z/E mixture (Table 1, entry 1).
Transition metal-catalysed hydroarylation of alkynes using
C–H activation is a highly atom economic route for stereo-
controlled alkene synthesis. The reaction was pioneered by
Fujiwara, who established that electron poor propiolates
would react with electron rich arenes, such as mesitylene,
under Pd(II) catalysis.1 The alkene products (2) formally arise
from arene C–H activation2 and carbopalladation affording
alkenyl palladium 1, followed by protonolysis (Scheme 1).
Fujiwara’s initial reaction system has since been shown to have
excellent generality and been extended to a variety of C–H
components, alkynes and catalyst systems.3,4
Our interests in catalytic C–H activation chemistry5 led us
to study this reaction with the aim of capturing the alkenyl-
palladium intermediate 3 for an additional C–C bond-forming
step. Whilst protonolysis of 3 affords useful di- or tri-substituted
alkynes, we reasoned that the addition of a third component
could add significant value to the transformation. Such a tandem
process would represent a versatile, one step route to tetra-
substituted alkenes, 4, important compounds in medicinal and
materials chemistry that are usually prepared over several
steps.6 We planned to explore the proposed transformation
using Pd(II)/Pd(IV) catalysis.7 Such cycles frequently operate
under mild and simple reaction conditions relative to the
analogous Pd(0)/Pd(II) systems,8,9 potentially affording an
alkene synthesis with enhanced substrate scope that could
function close to room temperature.
Table 1 Optimisation data
Ligand
Entry (10 mol%)
Yield of
T/1C 7a (%)a
Base
Solvent
1
2
—
—
—
—
CF3CH2OH
CF3CH2OH
80
rt
47 (5 : 1)
57
62
86
3
SIMes.HCl Cs2CO3 CF3CH2OH
SIMes.HCl Cs2CO3 chloro-benzene 30
rt
4b,c
Conditions: Indole 5a (1 equiv), diaryliodonium salt 6a (1.2 equiv),
catalytic Pd(OAc)2 (5 mol%), plus additives where indicated in solvent
(3 mL). Reactions were carried out on a 0.3 mmol scale for 24 h in a
sealed tube.a Isolated yields. Ratio shown in brackets indicates 7a
isolated as a Z/E mixture, with ratio determined by 1H NMR.
b
c
1.05 equiv of 6a used. Reaction time of 2 h. SIMes.HCl =
1,3-dimesityl-4,5-dihydroimidazol-2-ylidene.
Characterisation of 7a was complicated by the fact that
Z/E interconversion appeared facile, with NMR samples of
Z/E-7a in CDCl3 undergoing equilibration over the course of
a day. Furthermore, the indole C3 proton of the major isomer
was significantly shielded, resonating at d = 5.8 in the 1H NMR
spectrum. Subsequent X-ray analysis of the analogue prepared
With these considerations in mind we designed indole 5a as
our primary substrate. By installing both C–H and alkyne
components in the same molecule, we hoped to facilitate the
first step and focus our efforts on developing the second
intermolecular arylation. We chose diaryliodonium salts as
School of Chemistry, University of Edinburgh, King’s Buildings,
West Mains Rd, Edinburgh, EH9 3JJ, UK.
E-mail: Michael.Greaney@ed.ac.uk
w Electronic supplementary information (ESI) available: Data for new
compounds and experimental procedures. CCDC 813229 and 813230.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc13094c
Scheme 1 Fujiwara hydroarylation and proposed three component
coupling reaction.
c
7992 Chem. Commun., 2011, 47, 7992–7994
This journal is The Royal Society of Chemistry 2011

View Online
was isolated as an inseparable E/Z mixture. The electron poor
m-CF3 salt by contrast gave the alkene 7f in 86% yield as a
single Z-isomer. Strongly electron withdrawing groups such as
nitro gave very poor yields in the reaction.
We used the p-tolyl arylating agent to investigate the effects
of varying the iodonium salt structure. Mixed salts containing
a dummy ligand such as mesityl were productive,11,12 affording
7b in the slightly reduced 75% yield. The alternative triflate
salt was equally effective as the tetrafluoroborate, producing
7b in an identical 90% yield (supporting information).
We could display additional functionality on both the indole
and tethering aryl components without compromising the
efficiency of the reaction. 3-Me, 5-OMe, 5-CO2Et and 6-F
indole derivatives were all successful in the reaction (7g–7j),
with the more electron rich substrate the most effective
(7h, 88% yield, crystal structure available). A fluoro group
in the aryl linker gave a moderate 49% yield of 7k, whereas
bismethoxy substitution afforded alkene 7l in a good 78%
yield. We were pleased to find similar substrate tolerance
with the alkyne substituent, which might be expected to be
more sensitive to modification given its proximity to the key
bond-forming steps. Branched alkyl groups at both the a and
b-positions were well tolerated (7m and 7n), as was the
electron poor propiolate 7o. The versatile silane group could
also be introduced, albeit in lower yield (7p, 42%, 71% based
on recovered SM). Bis-aryl substituted (R2 = Ar) and terminal
(R2 = H) alkynes were not good substrates for reaction.
Having established good versatility amongst the three func-
tional components of the reaction, we extended the process
to more fundamental alterations of the indole-alkene-arene
structure. Pleasingly, the reaction was viable for the pyrrole
series, with the annulated heterocycle 7q being formed in a
good 70% yield. We altered the tethering ring size and
observed exclusive 5-exo-dig cyclisation in the formation of
cyclopentane derivative 7r, with no sign of the alternative
6-endo pathway. 7-exo-dig cyclisation was also feasible in the
formation of 7s. The amide derivative 7t was formed in a lower
46% yield as a mixture of E and Z isomers, fitting the pattern
of electron poor indoles being poorer substrates for the
reaction. Simple indole arylation was not observed as a
competing reaction for any substrate, and appears to be a
slow process under the basic reaction conditions (supporting
information).
Scheme 2 Substrate scope.
from di(p-tolyl)iodonium tetrafluoroborate revealed the C3
indole proton pointing towards the face of the tolyl group, in
the shielded zone of the aromatic ring (supporting information).
The reaction proved to be viable at room temperature (entry 2),
and that under these mild conditions we could isolate the
Z-isomer exclusively in 57% yield. A screen of various Pd salts
and phosphine ligands failed to improve on the ligandless
Pd(OAc)2 system (supporting information). The N-heterocyclic
carbene (NHC) ligand generated from SIMes.HCl, however,
offered an improved yield of 62% in the presence of 1 equivalent
of Cs2CO3 (entry 3).11 The yield could be increased further
through solvent optimisation, with chlorobenzene delivering
the product 7a in a very good 86% yield as a single isomer,
after just 2 h at 30 1C (entry 4).
With this optimised process in hand, we first attempted to
establish whether the Z-selectivity was intrinsic to the reaction
or a consequence of equilibration under the reaction conditions.
Exposure of a 2 : 1 Z/E mixture of 7a to the optimised reaction
conditions (which are Z-selective) gave no change in the
isomer ratio over 24 h, indicating that the Z-isomer is a kinetic
product of the reaction. We then examined the reaction scope
for each component in more detail (Scheme 2).
Alternative iodonium salts were viable with the electron rich
p- and o-tolyl, anisyl and bromo derivatives participating in
high yield (7b–7e). The most electron rich alkene 7d (anisyl)
Scheme 3 Mechanistic pathways.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7992–7994 7993

View Online
We also altered the carbon skeleton of the substrates such
that the alkyne was linked via the indole 3-position, rather
than the N-atom. 6-exo-dig cyclisation proceeded as before to
give the structural isomer 7u in 64% yield as a single geometric
isomer (assigned as Z by analogy).
not occur): J. A. Tunge and L. N. Foresee, Organometallics, 2005,
24, 6440.
3 Reviews: (a) T. Kitamura, Eur. J. Org. Chem., 2009, 1111;
(b) C. Nevado and A. M. Echavarren, Synthesis, 2005, 167;
(c) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001,
34, 633.
4 Recent examples: (a) J. Mo and P. H. Lee, Org. Lett., 2010,
12, 2570; (b) D. J. Schipper, M. Hutchinson and K. Fagnou,
J. Am. Chem. Soc., 2010, 132, 6910; (c) K. Komeyama, R. Igawa
and K. Takaki, Chem. Commun., 2010, 46, 1748; (d) T.-S. Jiang,
R.-Y. Tang, X.-G. Zhang, X.-H. Li and J.-H. Li, J. Org. Chem.,
2009, 74, 8834; (e) S. Suarez-Pantiga, D. Palomas, E. Rubio and
J. M. Gonzalez, Angew. Chem., Int. Ed., 2009, 48, 7857;
(f) N. Chernyak and V. Gevorgyan, Adv. Synth. Catal., 2009,
351, 1101; (g) H.-H. Lu, H. Liu, W. Wu, X.-F. Wang, L.-Q. Lu and
W.-J. Xiao, Chem.–Eur. J., 2009, 15, 2742; (h) N. Chernyak and
V. Gevorgyan, J. Am. Chem. Soc., 2008, 130, 5636.
5 (a) D. G. Pintori and M. F. Greaney, J. Am. Chem. Soc., 2011,
133, 1209; (b) F. Zhang and M. F. Greaney, Org. Lett., 2010,
12, 4745; (c) F. Zhang and M. F. Greaney, Angew. Chem. Int. Ed.,
2010, 49, 2768.
6 A. B. Flynn and W. W. Ogilvie, Chem. Rev., 2007, 107, 4698.
7 P. Sehnal, R. J. K. Taylor and I. J. S. Fairlamb, Chem. Rev., 2010,
110, 824.
8 Seminal work: (a) R. Grigg, P. Kennewell, A. Teasdale and
V. Sridharan, Tetrahedron Lett., 1993, 34, 153; (b) S. Brown,
S. Clarkson, R. Grigg and V. Sridharan, Tetrahedron Lett., 1993,
34, 157; (c) R. Grigg, V. Loganathan and V. Sridharan,
Tetrahedron Lett., 1996, 37, 3399; (d) R. C. Larock, M. J. Doty,
Q. Tian and J. M. Zenner, J. Org. Chem., 1997, 62, 7536. See also:
G. Dyker, J. Org. Chem., 1993, 58, 234.
9 Recent examples: (a) N. Chernyak, D. Tilly, Z. Li and
V. Gevorgyan, Chem. Commun., 2010, 46, 150; (b) D. Chernyak
and V. Gevorgyan, Org. Lett., 2010, 12, 5558; (c) S. Jaegli,
J. Dufour, H.-l. Wei, T. Piou, X.-H. Duan, J.-P. Vors,
L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498;
(d) N. Chernyak and V. Gevorgyan, Adv. Synth. Catal., 2009,
351, 1101; (e) D.-J. Tang, B.-X. Tang and J.-H. Li, J. Org. Chem.,
2009, 74, 6749; (f) S. Tang, P. Peng, P. Zhong and J.-H. Li, J. Org.
Chem., 2008, 73, 5476; (g) A. Pinto, L. Neuville and J. Zhu, Angew.
Chem., Int. Ed., 2007, 46, 3291; (h) A. Pinto, L. Neuville,
P. Retailleau and J. Zhu, Org. Lett., 2006, 8, 4927.
A number of different mechanisms may be envisaged for
the reaction. The Z-geometry of the alkene group for almost
all substrates, however, is a key feature and implicates alkyne
syn-carbopalladation at the heart of the C–C bond forming
events. Two possible pathways are set out in Scheme 3. Path A
involves direct indole palladation at C213,14 with Pd(OAc)2 to
afford 8, which can then undergo intramolecular 6-exo-dig
carbopalladation. Trapping of the alkenyl Pd(II) intermediate
9 with the iodonium salt then gives the Z-product 7, via Pd(IV)
intermediate 10. This mechanism varies from that of classic
Fujiwara hydroarylation, where initial SEAr addition of the
C–H component to the alkyne would afford an E-alkenyl Pd
intermediate, something not observed in our system. However,
the basic reaction conditions we employ are quite different to
the acidic, ionising character of a typical Fujiwara reaction.15
Path B reverses the order of C–C bond formation, and begins
with intermolecular alkyne carbopalladation using ArPd(OAc)2X
to provide the Z-alkene intermediate 11. Intramolecular C–H
activation at the indole 2-position then gives 12, which reductively
eliminates Pd(II) to access the tetra-substituted alkene products.
This sequence requires the alkyne carbopalladation to be
either regioselective for 11 (Pd on the ‘internal’ position next
to the aryl ring), or for this process to be reversible. Little is
known about alkyne carbopalladation for Pd(IV) species, in
contrast to the analogous reaction with ArPd(II)X complexes,16
and further work is necessary to clarify the differences in the
proposed mechanistic pathways.17
We have developed a novel tetra-substituted alkene synthesis
that comprises a diaryliodonium salt plus alkyne and indole
C–H components. The reaction proceeds under very mild
conditions using Pd(II)/Pd(IV) catalysis, is highly selective for
the Z-alkene isomer and shows excellent substrate scope
around each of the reacting functional groups. Further studies
to apply this reaction to biologically active targets are underway
in our laboratory.
10 N. R. Deprez and M. S. Sanford, Inorg. Chem., 2007, 46, 1924.
11 N. R. Deprez, D. Kalyani, A. Krause and M. S. Sanford, J. Am.
Chem. Soc., 2006, 128, 4972.
12 R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem. Soc.,
2008, 130, 8172.
13 (a) N. P. Grimster, C. D. Godfrey and M. J. Gaunt, Angew. Chem.,
Int. Ed., 2005, 44, 3125; (b) B. S. Lane, M. A. Brown and D. Sames,
J. Am. Chem. Soc., 2005, 127, 8050; (c) F. Bellina, C. Calandri,
S. Cauteruccio and R. Rossi, Tetrahedron, 2007, 63, 1970;
(d) N. Lebrasseur and I. Larrosa, J. Am. Chem. Soc., 2008,
130, 2926; (e) S. Potavathri, K. C. Pereira, S. I. Gorelsky,
A. Pike, A. P. LeBris and B. DeBoef, J. Am. Chem. Soc., 2010,
132, 14676.
14 A kinetic isotope effect of 1.2 was measured for reaction for 5a
deuterated at the indole 2-position (supporting information).
15 C–H Activation and subsequent carbopalladation has been
implicated in Gevorgyan’s intramolecular hydroarylation of
o-alkynyl biaryls under neutral conditions, see ref. 4h.
16 S. Cacchi and G. Fabrizi, in Handbook of Organopalladium Chemistry
for Organic Synthesis, ed. E. Negishi and A. de Meijere, Wiley, NY,
2002, vol. 1, p. 1335.
We thank the EU and the EPSRC funding (Studentship to
LL, Leadership Fellowship to MFG) and the EPSRC mass
spectrometry service at the University of Swansea. Dr Fraser
White is thanked for X-ray crystallography. Dr Gemma
Veitch is thanked for preliminary work in the area.
Notes and references
1 C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura and Y. Fujiwara,
Science, 2000, 287, 1992.
2 Subsequent mechanistic studies, prompted by the exclusive cis
selectivity of the reaction with terminal alkynes, suggest an initial
SEAr step as the most likely pathway (i.e. arene palladation does
17 Trapping experiments to capture 8 and/or 9 in path A with an
external Heck acceptor were unsuccessful, cf. ref. 5a.
c
7994 Chem. Commun., 2011, 47, 7992–7994
This journal is The Royal Society of Chemistry 2011