Palladium-catalyzed direct oxidative Heck-Cassar-Sonogashira type alkynylation of indoles with alkynes under oxygen

Article abstract of DOI:10.1039/c0cc00014k

A novel Pd^II catalyzed direct oxidative Heck-Cassar-Sonogashira type alkynylation of indoles with terminal alkynes under an atmosphere of O ₂ is developed. Unlike previous methods, the reaction does not require the pregeneration of indolyl halide or alkynyl halide. Furthermore, only a catalytic amount of base is required and oxygen was used as the ultimate green terminal oxidant.

Full text of DOI:10.1039/c0cc00014k

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Palladium-catalyzed direct oxidative Heck–Cassar–Sonogashira type
alkynylation of indoles with alkynes under oxygenw
Luo Yang, Liang Zhao and Chao-Jun Li*
Received 18th February 2010, Accepted 1st April 2010
First published as an Advance Article on the web 4th May 2010
DOI: 10.1039/c0cc00014k
A
novel PdII catalyzed direct oxidative Heck–Cassar–
Table 1 Optimization of the Pd-catalyzed oxidative HCS-type alky-
nylation of indoles with terminal alkynes and O2
a
Sonogashira type alkynylation of indoles with terminal alkynes
under an atmosphere of O2 is developed. Unlike previous
methods, the reaction does not require the pregeneration of
indolyl halide or alkynyl halide. Furthermore, only a catalytic
amount of base is required and oxygen was used as the ultimate
‘‘green’’ terminal oxidant.
The palladium catalyzed Heck–Cassar–Sonogashira (HCS)
coupling of aryl halides with terminal alkynes in the presence
of a stoichiometric amount of base, is among the most useful
organic transformations in modern synthetic chemistry.1 The
coupling has been widely used in the synthesis of various
important alkyne compounds and conducting materials.2
Substituted indoles,3 being a class of privileged structural
motifs, exist in numerous natural products and pharmaceuticals
and exhibit a wide range of privileged biological activities.4
Entry
Catalyst
T/1C
t/h
Yieldb/%
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(TFA)2
PdCl2
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
10
10
10
10
10
10
10
10
10
10
10
24
24
24
24
20
15
65
44
(COD)PdCl2
(PPh3)2PdCl2
K2PdCl4
K2PdCl4
K2PdCl4
K2PdCl4
K2PdCl4
K2PdCl4
K2PdCl4
PdCl2
45
51
5c
3d
9
51e
40f
48g
71 (66)
66
10
11
12
13
14
15
Recently
a palladium-catalyzed intramolecular oxidative
alkylation of indole was reported by Fagnou.3i Typically,
alkynylation of indoles are realized by Pd0 catalyzed classical
HCS coupling of (pseudo)halogenated indoles and alkynes
(Scheme 1, eqn (a)).5 Alternatively, alkynylindoles can be
synthesized from indoles and (pseudo)halogenated alkynes
(Scheme 1, eqn (b)).6 Herein, we report an unprecedented PdII
catalyzed oxidative Heck–Cassar–Sonogashira (HCS) type
alkynylation of indoles directly with terminal alkynes using
O2 as a terminal oxidant (Scheme 1, eqn (c)).7
K2PdCl4
K2PdCl4
46
42
a
Conditions: 1a (0.1 mmol), 2a (0.2 mmol), 10 mol% [Pd], 20 mol%
Cs2CO3 and 200 mol% PivOH in DMSO (0.2 mL+1.0 mL)8 under
1 atm O2; unless otherwise noted. Determined by 1H NMR analysis
of the crude reaction mixture using an internal standard; isolated yield
b
c
is in parentheses. Without PivOH. Without Cs2CO3. Cs2CO3 was
d
e
f
g
replaced by K2CO3. Cs2CO3 was replaced by K3PO4. PivOH was
replaced by AcOH.
We began our study by testing the reaction of 1,3-dimethyl-
indole (1a) with phenylacetylene catalyzed by palladium under
oxidative conditions.z Using a buffer system composed of
20 mol% Cs2CO3 and 200 mol% pivalic acid (PivOH),
1,3-dimethylindole reacted with phenylacetylene (2a), catalyzed
by Pd(OAc)2, to produce the C2 alkynylation product 3a in
20% yield (Table 1, entry 1). To suppress its homocoupling,
the phenylacetylene was dissolved in DMSO and added slowly
using a syringe pump.8
Subsequently, the catalytic activities of different palladium
sources for the reaction were investigated (Table 1, entries 1–6).
Among the catalysts tested, PdCl2 and K2PdCl4 gave the best
results. The use of a buffer system mentioned above was found
to be crucial, possibly for the deprotonation of the terminal
alkyne and reoxidation of Pd0 to PdII. The yields dropped
sharply in the absence of either the base or the acid (Table 1,
entries 7 and 8). Other bases such as K2CO3 and K3PO4 can
also be used (Table 1, entries 9 and 10), and pivalic acid was
found to be more effective than acetic acid for the reaction
(Table 1, entry 11). When the reaction time was extended to
24 h, the alkynylation yield catalyzed by K2PdCl4 was slightly
higher than the one catalyzed by PdCl2 and the NMR yield
increased to 71% with a 66% isolated yield (Table 1, entries 12
and 13). The influence of temperature was also examined and
lower yields were obtained when the reaction temperature was
either increased or decreased (Table 1, entries 14 and 15).
Scheme 1 Approaches for alkynylation of indoles.
Department of Chemistry, McGill University, Montreal, QC Canada
H3A 2K6. E-mail: cj.li@mcgill.ca; Fax: +01-514-398-3797;
Tel: +01-514-398-8457
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/c0cc00014k
ꢀc
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4184 | Chem. Commun., 2010, 46, 4184–4186

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Table 2 Substrate scope for the Pd-catalyzed oxidative HCS-type
alkynylation of indoles with terminal alkynesa
Entry
Product
Yieldb/%
1
66
Scheme 2 Pd-catalyzed oxidative HCS-type alkynylation of indoles
with terminal alkynes.
Under the optimized conditions, the substrate scope of this
novel oxidative Heck–Cassar–Sonogashira-type alkynylation
of indoles was explored (Scheme 2). As shown by the results in
Table 2, various terminal alkynes reacted with 1,3-dimethyl-
indoles smoothly. Aromatic alkynes with an electron-rich
alkyl or alkoxyl substituent at the para-position coupled with
1a effectively to furnish the alkynylation products (Table 2,
entries 2–5, 3b, 3c, 3d and 3e). 4-Ethynylbiphenyl also gave the
coupling product in good yield (Table 2, entry 6, 3f). Electron-
deficient aromatic alkynes were also feasible and gave the HCS
coupling products in slightly lower yields (Table 2, entries 7
and 8, 3g and 3h). Besides aromatic terminal alkynes,
(triisopropylsilyl)acetylene could be used in the coupling
reaction, which would make further modifications and
derivatizations of the alkynylation product 3i readily possible
(Table 2, entry 9). It is worth noting that 1-decyne could also
take part in this reaction (3j) albeit in a lower yield (with most
1,3-dimethylindole being recovered), possibly due to the
decreased electrophilic nature of the corresponding alkynyl-
palladium intermediate being generated during the reaction
(Table 2, entry 10).
2
62
72
73
68
72
47
51
72
15
54
58
73
3
4
5
6
7
8
Other 1,3-dialkylindoles with different substituents were
also applicable to this oxidative HCS-type alkynylation
(Table 2). 1-Benzyl-3-methyl indoles reacted with 2a effectively
to produce 3k and 3l, in 54% and 58% yields, respectively
(Table 2, entries 11 and 12). The presence of either electron-
donating (methyl and methoxyl) or electron-withdrawing
(chloro) substituents at the C5 or C8 position of indoles had
no obvious influence on the coupling reaction (Table 2, entries
13–16, 3m, 3n, 3o and 3p). However, under the same reaction
conditions, 1-methylindole and 1,2-dimethylindole were not
reactive and 495% of the starting materials were recovered;
the cause of which is under further investigation.
9
10
11
12
13
A tentative mechanism to rationalize this novel palladium-
catalyzed oxidative HCS-type coupling is illustrated in
Scheme 3. First, neutralization of pivalic acid with Cs2CO3
produces CsOPiv, which reacts with PdII and the terminal
alkyne 2a to form alkynylpalladium species A.9 Second, the
electrophilic attack of intermediate A at the C2 position of
indole 1a generates intermediate B, which will be deprotonated
by CsOPiv to yield intermediate C. Then, reductive elimination
of intermediate C produces the alkynylated product 3a and
Pd0, which will be reoxidized to PdII in the presence of O2 and
PivOH.3h Alternatively, the reaction may start with palladation
of the indole derivatives.3a Subsequent generation of a similar
intermediate C and its reductive elimination results in the
oxidative Heck–Cassar–Sonogashira type product 3a.10
In summary, we have developed a novel PdII catalyzed direct
oxidative Heck–Cassar–Sonogashira type alkynylation of indoles
with terminal alkynes under an atmosphere of O2. Unlike the
classical palladium-catalyzed HCS-type alkynylation between
14
15
66
68
16
66
a
Conditions: 1a (0.1 mmol), 2a (0.2 mmol, slowly added by syringe
pump), 10 mol% K2PdCl4, 20 mol% Cs2CO3 and 200 mol% PivOH in
DMSO (0.2 mL + 1.0 mL)8 under 1 atm O2 at 80 1C for 24 h; unless
b
otherwise noted. Isolated yield.
ꢀc
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2202; 1H NMR (500 MHz, CDCl3, TMS) d (ppm) 7.56–7.59 (m, 3H),
7.36–7.41 (m, 3H), 7.26–7.28 (m, 2H), 7.11–7.14 (m, 1H), 3.84 (s, 3H),
2.47 (s, 3H); 13C NMR (125 MHz, CDCl3, TMS) d (ppm) 137.4, 131.6,
128.7, 128.6, 127.7, 123.6, 123.3, 120.5, 119.49, 119.5, 117.2, 109.4,
97.9, 80.9, 30.9, 10.1; HRMS (ESI) m/z: [M + 1]+ calcd. for C18H16N,
246.1277; found: 246.1275.
1 For representative references, see: (a) K. Sonogashira, in
Handbook of Organopalladium Chemistry for Organic Synthesis,
ed. E.-I. Negishi, John Wiley, 2002, p. 493; (b) K. Sonogashira, in
Metal-catalyzed Cross-coupling Reactions, ed. F. Diederich and
P. J. Stang, Wiley-VCH, 1998, p. 203; (c) D. Alberico, M. Scott
and M. Lautens, Chem. Rev., 2007, 107, 174. For a monograph on
various palladium-catalyzed cross-coupling reactions, see: J. Tsuji,
Palladium Reagents and Catalysts, Wiley, Chichester, UK, 2nd edn,
2004.
2 For representative examples, see: (a) H. Doucet and J.-C. Hierso,
Angew. Chem., Int. Ed., 2007, 46, 834; (b) R. Chinchilla and
C. Najera, Chem. Rev., 2007, 107, 874.
Scheme 3 Proposed mechanism for the Pd-catalyzed oxidative HCS-
type alkynylation of indole 1a with terminal alkyne 2a and oxygen.
3 For recent reports on palladium catalyzed direct functionalization
of indoles, see: (a) N. Grimster, C. Gauntlett, C. R. A. 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) D. R. Stuart and K. Fagnou, Science, 2007,
316, 1172; (d) N. R. Deprez, D. Kalyani, A. Krause and
M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972;
(e) D. R. Stuart, E. Villemure and K. Fagnou, J. Am. Chem.
Soc., 2007, 129, 12072; (f) T. A. Dwight, N. R. Rue, D. Charyk,
R. Josselyn and B. DeBoef, Org. Lett., 2007, 9, 3137; (g) X. Wang,
D. Gribkov and D. Sames, J. Org. Chem., 2007, 72, 1476;
(h) S.-D. Yang, C.-L. Sun, Z. Fang, Y.-Z. Li and Z.-J. Shi, Angew.
Chem., Int. Ed., 2008, 47, 1473; (i) B. Liegault and K. Fagnou,
Organometallics, 2008, 27, 4841.
aryl halides and alkyne together with stoichimetric base, the
current palladium-catalyzed oxidative HCS-type reaction (1)
does not require the pregeneration of indolyl halide or alkynyl
halide; (2) furthermore, only a catalytic amount of base is
required; (3) in addition, oxygen was used as the ultimate ‘‘green’’
terminal oxidant, and (4) ‘‘water’’ was generated as a benign
side-product. The results provide a basis for similar oxidative
HCS-type coupling between terminal alkyne and other arenes
with oxygen as terminal oxidant. The scope, mechanism and
application of this catalytic reaction are ongoing.
4 For examples, see: (a) M. Bandini and A. Eichholzer, Angew.
Chem., Int. Ed., 2009, 48, 9608; (b) S. Sato, M. Shibuya, N. Kanoh
and Y. Iwabuchi, Chem. Commun., 2009, 6264; (c) P. Buchgraber,
M. M. Domostoj, B. Scheiper, C. Wirtz, R. Mynott, J. Rust and
A. Furstner, Tetrahedron, 2009, 65, 6519.
We are grateful to the Canada Research Chair (Tier I)
Foundation (to CJL), CFI, and NSERC for partial support
of our research.
5 For examples, see: (a) D. Facoetti, G. Abbiati, L. d’Avolio,
L. Ackermann and E. Rossi, Synlett, 2009, 2273; (b) D.-W. Yue
and R. C. Larock, Org. Lett., 2004, 6, 1037; (c) H. Zhang and
R. C. Larock, J. Org. Chem., 2002, 67, 7048.
6 (a) Y.-H. Gu and X.-M. Wang, Tetrahedron Lett., 2009, 50, 763;
(b) F. Besselievre and S. Piguel, Angew. Chem., Int. Ed., 2009, 48,
9553; (c) J. P. Brand, J. Charpentier and J. Waser, Angew. Chem.,
Int. Ed., 2009, 48, 9346.
7 During the preparation of this manuscript, a gold-catalyzed
ethynylation of arenes using hypervalent iodine as oxidant was
reported, see: T. de Haro and C. Nevado, J. Am. Chem. Soc., 2010,
132, 1512.
8 Phenylacetylene (2a) dissolved in 1.0 mL DMSO and was pumped
into the reaction tube using a syringe pump, see ESIw for details.
9 I. V. Seregin, V. Ryabova and V. Gevorgyan, J. Am. Chem. Soc.,
2007, 129, 7742.
Notes and references
z A general experimental procedure for the oxidative HCS-type
coupling is described as following: An oven-dried reaction vessel was
charged with 1,3-dimethylindole 1a (14.5 mg, 0.1 mmol), K2PdCl4
(3.27 mg, 0.01 mmol, 10 mol%), Cs2CO3 (6.5 mg, 0.02 mmol,
20 mol%), pivalic acid (20.4 mg, 0.2 mmol, 200 mol%) and DMSO
(0.2 mL). After being stirred for 15 min at room temperature, the
vessel was vacuumed and refilled with O2. Then, the vessel was linked
to an O2 cylinder and a flow of 1 mL minꢁ1 maintained. Phenyl-
acetylene 2a (22 mL, 0.2 mmol, 2 equiv.) dissolved in DMSO (1.0 mL)
was added slowly in 24 h using a programmable syringe pump at 80 1C
(the needle should be inserted into the reaction mixture). The resulting
mixture was cooled to room temperature, poured into aqueous
NaHCO3 solution (10%, 10 mL), extracted with ethyl acetate
(3 ꢂ 10 mL), and washed with brine (2 ꢂ 10 mL). The organic layer
was dried with anhydrous MgSO4, filtered and concentrated under
vacuum. The residue was chromatographed by TLC (20 cm ꢂ 20 cm)
and developed with a mixture of cyclohexane and benzene (10 : 1) to
give pure alkynylation product 3a. Characterization of the product
10 For other examples of C–C bond formation through the oxidative
reaction of C–H and C–H bonds, see: (a) C.-J. Li, Acc. Chem. Res.,
2009, 42, 335; (b) C. J. Scheuermann, Chem.–Asian J., 2010, 5, 436;
(c) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34,
633.
1,3-dimethyl-2-(phenylethynyl)-1H-indole (3a): Mp 82.0 1C; IR (cmꢁ1
)
ꢀc
This journal is The Royal Society of Chemistry 2010
4186 | Chem. Commun., 2010, 46, 4184–4186