Cationic Pd(II)-catalyzed tandem reaction of 2-arylethynylanilines and aldehydes: An efficient synthesis of substituted 3-hydroxymethyl indoles

Article abstract of DOI:10.1021/ol1011086

(Equation Presented). An efficient cationic palladium(II)-catalyzed synthesis of substituted 3-hydroxymethylindoles from readily accessible starting materials is developed. This tandem reaction involves an intramolecular aminopalladation of an alkyne and an addition to the carbonyl group to quench the carbon-palladium bond to complete the catalytic cycle without the necessity of a redox system.

Full text of DOI:10.1021/ol1011086

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3336-3339
Cationic Pd(II)-Catalyzed Tandem
Reaction of 2-Arylethynylanilines and
Aldehydes: An Efficient Synthesis of
Substituted 3-Hydroxymethyl Indoles
Xiuling Han and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
xylu@mail.sioc.ac.cn
Received May 13, 2010
ABSTRACT
An efficient cationic palladium(II)-catalyzed synthesis of substituted 3-hydroxymethylindoles from readily accessible starting materials is developed.
This tandem reaction involves an intramolecular aminopalladation of an alkyne and an addition to the carbonyl group to quench the
carbon-palladium bond to complete the catalytic cycle without the necessity of a redox system.
Heterocyclic compounds, particularly indoles, are of interest
because they widely occur in nature as partial structures of
alkaloids and have unique biological activities.1 As synthetic
procedures, palladium(0)- or palladium(II)-catalyzed het-
eroannulations are now emerging as a unique, powerful, and
versatile synthetic approach toward a variety of structural
cores of complex heterocycles.2 Among them, Pd(II)-
catalyzed annulation reactions of 2-alkenyl- or 2-alkynyla-
niline derivatives are often used for the synthesis of
substituted indoles.3 From the literature, it can be seen that
reactions of 2-alkynylaniline derivatives are more useful
because the starting materials can be easily prepared from
2-haloanilines and terminal alkynes by the palladium-
catalyzed Sonogashira cross-coupling reaction. Another
advantage of utilizing these substrates is that no redox
system is required in their annulation reactions (compare
eqs 1 and 2).
In addition, tandem reactions cannot occur for alkylpal-
ladium species (the intermediate in eq 1) due to the rapidly
occurring ꢀ-hydride elimination reaction, but the indolylpal-
ladium species as the intermediate (eq 2) can undergo further
tandem reactions such as insertion of carbon-carbon double
bonds4 or carbon monoxide5 to form multiply functionalized
indoles. In the latter cases, the only drawback is that a redox
(1) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (b)
Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, UK,
1996; Vol. 2, p 207. (c) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19,
148. (d) Rahman, A.; Basha, A. Indole Alkaloids; Harwood Academic
Publishers: Amsterdam, 1998; p 141. (e) Dewick, P. M. Medicinal Natural
Products; J. Wiley & Sons: Chichester, 1997; Chapter 6.
(2) For general reviews on palladium-catalyzed formation of heterocyclic
compounds, see: (a) Tsuji, J., Ed. Palladium in Organic Synthesis; Springer:
New York, 2005. (b) Negishi, E., Ed. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley-Interscience: New York, 2002. (c)
Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry, Pergamon:
Oxford, 2000. (d) Patil, S.; Buolamwini, J.-K. Curr. Org. Synth. 2006, 3,
477.
(4) (a) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1799. (b) Yasuhara, A.; Kaneko, M.; Sakamoto, T. Heterocycles 1998,
48, 1793. (c) Yasuhara, A.; Takeda, Y.; Suzuki, N.; Sakamoto, T. Chem.
Pharm. Bull. 2002, 50, 235. (d) Lu, X.; Shen, Z. Tetrahedron 2006, 62,
10896. (e) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19, 775.
(5) (a) Kondo, Y.; Sakamoto, T.; Yamanaka, H. Heterocycles 1989, 29,
1013. (b) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H.
Tetrahedron 1994, 50, 11803. (c) Tang, S.; Yu, Q.-F.; Peng, P.; Li, J.-H.;
Zhong, P.; Tang, R.-Y. Org. Lett. 2007, 9, 3413.
(3) For the reviews, see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004,
104, 2285. (b) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (c)
Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644. (d) Luo, P.; Tang,
R.-Y.; Zhong, P.; Li, J.-H. Chin. J. Org. Chem. 2009, 29, 1924.
10.1021/ol1011086  2010 American Chemical Society
Published on Web 07/12/2010

system is required for the regeneration of the catalytic
palladium species.
we explored a new annulation route for the preparation of
substituted 3-hydroxymethyl indoles in one step employing
substituted 2-arylethynylanilines and aldehydes as starting
materials. In the literature, such compounds are usually syn-
thesized from indoles and aldehydes by a Friedel-Crafts
reaction.8
The reaction of N-tosyl-2-phenylethynylaniline (1a) with
p-nitrobenzaldehyde (2a) was first conducted to screen the
optimal reaction conditions, and the results are sum-
marized in Table 1. Initially, the catalysts and temperature
Table 1. Optimization of the Reaction Conditionsa
In our previous work, we reported an efficient method for
the synthesis of 2,3-disubstituted indoles with high selectivity
from 2-alkynylaniline derivatives and R,ꢀ-unsaturated car-
bonyl compounds under the catalysis of Pd(OAc)2 in the
presence of bromide ion (Scheme 1).4d,e This is a tandem
yieldb (%)
entry
catalyst (mol %)
3aa
4aa
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)/bpy (5.5)
16
trace
70
10
Pd(COOCF3)2 (5)/bpy (5.5)
Pd(MeCN)4(BF4)2 (5)/bpy (5.5)
Pd(OTf)2·2H2O (5)/bpy (5.5)
Pd(dppp)(H2O)2(OTf)2 (2)
Pd(dppp)(H2O)2(BF4)2 (2)
Pd(bpy)(H2O)2(OTf)2 (2)
Pd(bpy)(H2O)2(BF4)2 (2)
[(bpy)Pd(µ-OH)]2(OTf)2 (2)
Pd(bpy)(H2O)2(OTf)2 (2)
Pd(bpy)(H2O)2(OTf)2 (2)
Pd(bpy)(H2O)2(OTf)2 (2)
NR
Scheme 1. Palladium(II)-Catalyzed Tandem Reaction for the
Synthesis of Substituted Indoles from 2-Alkynylanilines and
trace
trace
16
60
50
42
21
46
75
trace
88
62
30
29
28
25
30
17
R,ꢀ-Unsaturated Carbonyl Compounds
9
10c
11d
12e
a 1a (0.1 mmol), 2a (0.12 mmol, 1.2 equiv), and the catalyst were stirred
in dioxane at 60 °C overnight. b Isolated yields. c The reaction was carried
out at 25 °C for 40 h. d The reaction was carried out at 100 °C for 6 h.
e The amount of 2a was 2.0 equiv with respect to 1a.
reaction involving trans-aminopalladation of an alkyne
(similar to eq 2), insertion of an enone, and protonolysis of
the carbon-palladium bond. The divalent palladium species
was regenerated in the protonolysis step to complete the
catalytic cycle without the necessity of a redox system.
Recently, our group also established some cationic palladium-
catalyzed procedures for the addition of carbon-palladium
species to carbon-heteroatom multiple bonds.6 As compared
with the neutral palladium species, such as Pd(OAc)2 or
PdCl2(CH3CN)2, the cationic palladium(II) species facilitate
the addition to carbon-heteroatom multiple bonds due to
its vacant coordination sites and harder metal property.7 Also,
a divalent palladium species was regenerated for the catalytic
cycle. As part of our continuing studies on the scope of cationic
palladium-catalyzed addition reactions of arylpalladium or
vinylpalladium species to carbon-heteroatom multiple bonds,
effects on the reaction were examined. It was found that
Pd(OAc)2/bpy or some in situ prepared cationic palladium
salts/bpy were ineffective to catalyze the reaction, giving
product 3aa in very low yields together with the byproduct
4aa, which came from protonolysis of the intermediate (Table
1, entries 1-4). Then, some isolated cationic palladium
complexes bearing bipyridine or dppp as ligands were used.
It was exciting that the catalyst Pd(bpy)(H2O)2(OTf)2 was
the best one to catalyze this tandem aminopalladation-addition
reaction in dioxane (60% yield, Table 1, entry 7). However,
when the reaction temperature was lowered to 25 °C or raised
to 100 °C, the yield of 3aa was decreased to 21% and 46%,
respectively (Table 1, entries 9 and 10). Some other solvents
such as toluene, CH3NO2, THF, ClCH2CH2Cl, and DMSO
were also tried, but most of them were ineffective or
(6) Cationic Pd(II)-catalyzed addition reactions of arylboronic acids to
carbon-heteroatom bonds, see: (a) Liu, G.; Lu, X. J. Am. Chem. Soc. 2006,
128, 16504. (b) Zhao, B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765. (c)
Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (d) Dai, H.; Lu, X. Org. Lett.
2007, 9, 3077. (e) Liu, G.; Lu, X. AdV. Synth. Catal. 2007, 349, 2247. (f)
Lin, S.; Lu, X. J. Org. Chem. 2007, 72, 9757. (g) Dai, H.; Lu, X. AdV.
Synth. Catal. 2008, 350, 249. (h) Yang, M.; Zhang, X.; Lu, X. Org. Lett.
2007, 9, 5131. (i) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9,
2947. (j) Yu, X.; Lu, X. Org. Lett. 2009, 11, 4366. (k) Han, X.; Lu, X.
Org. Lett. 2010, 12, 108.
(8) For reviews of Friedel-Crafts reactions, see: (a) Olah, G. A.
Friedel-Crafts Chemistry; Wiley-Interscience: New York, 1973. (b)
Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation Chemistry. A
Century of DiscoVery; Marcel Dekker: New York, 1984. (c) Heaney, H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 2, p 733. (d) Smith, M. B. Organic
Synthesis; McGraw-Hill: New York, 1994; p 1313.
(7) Mikami, K.; Hatano, M.; Akiyama, K. Top. Organomet. Chem. 2005,
14, 279, and references cited therein.
Org. Lett., Vol. 12, No. 15, 2010
3337

produced a lower yield of 3aa. Finally, the best yield was
obtained by increasing the amount of substrate 2a to 2.0
equiv with respect to 1a (75% yield, Table 1, entry 12).
Under the optimized reaction conditions as shown in Table
1, entry 12, a series of substituted 2-alkynylanilines and
aromatic aldehydes were chosen to test this annulation
reaction as shown in Table 2. Aldehydes with strong electron-
with 1a successfully to afford the expected product R-hy-
droxyindolyl acetate (6) in the same conditions as shown in
Table 2. Then, a series of substituted N-tosyl-2-phenylethy-
nylanilines were also tested. With the exception of 1k, all
of them, including 1j, which has no reactivity with p-
nitrobenzaldehyde, can react smoothly to provide the cor-
responding R-hydroxyindolyl acetates 6 in good yields (Table
3). In the literature, such compounds usually can be obtained
from the reaction of indoles and ethyl glyoxylate.9
Table 2. Tandem Annulation Reaction of 2-Arylethynylanilines
with Substituted Benzaldehydesa
Table 3. Annulation Reaction of 2-Arylethynylanilines with
Ethyl Glyoxylatea
1
2
entry R1
R2
R3
yieldb (%)
75 (3aa)
63 (3ab)
entry
R1
R2
R3
yieldb (%)
1
2
3
H
H
H
H
H
H
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
p-NO2 (2a)
m-NO2 (2b)
5-Cl-4-NO2 (2c) 93 (3ac)
p-COCH3 (2d)
p-CN (2e)
H (2f)
p-NO2 (2a)
p-NO2 (2a)
p-NO2 (2a)
p-NO2 (2a)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
Ts (1a)
Ts (1b)
Ts (1c)
Ts (1d)
Ts (1e)
Ts (1f)
Ts (1g)
Ms (1j)
COCF3 (1k)
89 (6a)
80 (6b)
81 (6c)
73 (6d)
67 (6e)
83 (6f)
81 (6g)
51 (6j)
NR
4-Me
4-F
4-Cl
5-Cl
H
H
H
H
4c
5d
6
trace
trace
H
complex mixture
65 (3ba)
64 (3ca)
62 (3da)
49 (3ea)
78 (3fa)
62 (3ga)
trace
Me
Br
H
7
8
4-Me Ph (1b)
4-F Ph (1c)
9
4-Cl Ph (1d)
5-Cl Ph (1e)
H
H
H
H
H
10
11
12
13
14
p-MeC6H4 (1f) p-NO2 (2a)
p-BrC6H4 (1g) p-NO2 (2a)
n-Hexyl (1h)
a A mixture of 1 (0.1 mmol), 5 (0.2 mmol, 2.0 equiv), and the catalyst
Pd(bpy)(H2O)2(OTf)2 (2 mol %) was stirred in dioxane at 60 °C overnight.
b Isolated yields.
p-NO2 (2a)
CH3OCH2 (1i) p-NO2 (2a)
trace
a A mixture of 1 (0.1 mmol), 2 (0.2 mmol, 2.0 equiv), and the catalyst
Pd(bpy)(H2O)2(OTf)2 (2 mol %) was stirred in dioxane at 60 °C overnight.
b Isolated yields. c A 35% yield of 4aa can be achieved in a complex reaction
mixture. d Almost no reaction occurred.
Then some other activated ketones such as ethyl 3,3,3-
trifluoropyruvate or ethyl benzoylformate were used to react
with substrate 1a, and it was disappointing that no reaction
occurred for these ketones.
Some control experiments were also run to gain further
insight into the mechanistic details of this sequential process.
Because indoles such as 4aa can be easily produced in many
metal-catalyzed cyclization reactions of 2-alkynylaniline
derivatives,2,3 and they were also the main byproducts in
our reactions, a question arose as to whether products such
as 4aa were formed first in our reactions and they subse-
quently transferred to products 3 by palladium(II)-catalyzed
Friedel-Crafts type reaction.9a To test this hypothesis, 4aa
was employed to react with p-nitrobenzaldehyde in the same
conditions as Table 2, but no reaction occurred at all (Scheme
2), indicating that our reaction is a new tandem reaction,
withdrawing groups such as a nitro group on the benzene
ring and anilines with tosyl group on the nitrogen atom
provided good results (Table 2, entries 1-3). If the sub-
stituent on the aryl aldehyde was an acetyl or nitrile group,
only a trace of the products could be obtained (Table 2,
entries 4 and 5). When benzaldehyde was utilized, the
reaction became complicated (Table 2, entry 6). This might
be due to the change of the electrophilicity of the aldehyde.
For anilines 1, alkynes bearing aryl groups with halo- or
methyl substituents all reacted smoothly with p-nitrobenzal-
dehyde to provide the desired products in moderate yields
(Table 2, entries 7-12). If the substituent R2 was changed
from phenyl to n-hexyl or methoxymethyl, the reaction
became sluggish and only a trace of the products can be
obtained (Table 2, entries 13 and 14). No reaction occurred
for anilines with other N-substituted groups (such as mesyl
or trifluoroacetyl). This may be due to the requirement of a
strong electron withdrawing group on the nitrogen atom to
facilitate the aminopalladation step.
Scheme 2
.
Reaction of 2-Phenyl-N-tosylindole with
p-Nitrobenzaldehyde
Next, we turned our attention to extend this new pal-
ladium-catalyzed annulation reaction by using other active
aldehydes such as ethyl glyoxylate. Similarly, it can react
3338
Org. Lett., Vol. 12, No. 15, 2010

not a one pot, two step process. This may be due to the fact
that our reaction can only proceed for the substrates with a
tosyl group on the nitrogen atom (Tables 2 and 3) which
will decrease the nucleophilicity of C3 in indoles to make
the Friedel-Crafts type reaction impossible.
A possible mechanism that accounts for the formation of
3-hydroxymethylindoles 3 or R-hydroxyindolyl acetates 6
is illustrated in Scheme 3. First, the active palladium species
the intermediate C. Then the carbon-palladium bond in C
adds to the carbonyl group of aldehydes to produce palladium
alkoxide intermediate E, and finally, the product 3 or 6 is
formed by protonolysis of E with regeneration of the
palladium species to make the catalytic cycle possible.
In summary, we have disclosed a novel synthesis of multiply
substituted 3-hydroxymethyl indoles under the catalysis of
cationic palladium(II) complex Pd(bpy)(H2O)2(OTf)2, which is
the first example of a tandem reaction initiated by an amino-
palladation of an alkyne and an addition to the carbonyl group
as the quenching step of the carbon-palladium bond. This will
regenerate the Pd(II) species without the necessity of a redox
system. This tandem reaction provided an efficient way for the
construction of functionalized indoles in one step and only Pd(II)
was used in the catalytic cycle. This strategy may find further
applications in the future for rapidly constructing other useful
heterocycles.
Scheme 3. Proposed Mechanism for the Formation of 3 or 6
Acknowledgment. The National Basic Research Program
of China 2006CB806105 is acknowledged. We also thank
the National Natural Science Foundation of China (20872158)
and Chinese Academy of Sciences for financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra
of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1011086
(9) (a) Hao, J.; Taktak, S.; Aikawa, K.; Yusa, Y.; Hatano, M.; Mikami,
K. Synlett 2001, 1443. (b) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen, C.-
B.; Xiao, W.-J. AdV. Synth. Catal. 2007, 349, 1579. (c) Li, H.; Wang, Y.-
Q.; Deng, L. Org. Lett. 2006, 8, 4063. (d) Willot, M.; Chen, J.; Zhu, J.
Synlett 2009, 577.
A is formed by dissociation of Pd(bpy)(H2O)2(OTf)2, fol-
lowed by an intramolecular aminopalladation on the palla-
dium(II)-coordinated alkyne via intermediate B to generate
Org. Lett., Vol. 12, No. 15, 2010
3339