On-water, microwave-assisted, Pd-catalyzed synthesis of indoles from imines and o-difunctionalized arenes

Article abstract of DOI:10.1002/chem.201000753

Regioselectively substituted indoles are prepared by a Pd-catalyzed C-C/C-N bond-forming sequence from imines and o-dihaloarenes or o-haloarene sulfonates. The heterogeneous reaction as a suspension in water and under microwave heating offers important advantages in comparison with the conventional reaction in an organic solvent, among them, operational simplicity, the employment of KOH solutions instead of alkoxides, and a dramatic reduction of reaction times.

Full text of DOI:10.1002/chem.201000753

FULL PAPER
DOI: 10.1002/chem.201000753
“On-Water,” Microwave-Assisted, Pd-Catalyzed Synthesis of Indoles from
Imines and o-Difunctionalized Arenes
Josꢀ Barluenga,* Agustꢁn Jimꢀnez-Aquino, Fernando Aznar, and Carlos Valdꢀs*[a]
À
Abstract: Regioselectively substituted indoles are prepared by a Pd-catalyzed C
À
C/C N bond-forming sequence from imines and o-dihaloarenes or o-haloarene
Keywords: heterogeneous catalysis ·
sulfonates. The heterogeneous reaction as a suspension in water and under micro-
indoles
palladium · water chemistry
· microwave chemistry ·
wave heating offers important advantages in comparison with the conventional re-
action in an organic solvent, among them, operational simplicity, the employment
of KOH solutions instead of alkoxides, and a dramatic reduction of reaction times.
Introduction
The indole ring is one of the most important heterocyclic
substructures in medicinal chemistry.[1] For this reason, al-
though the repertoire of methodologies for the synthesis of
indoles is enormous,[2] the discovery of new, efficient meth-
ods that allow the high-throughput synthesis of structurally
diverse indoles is still a matter of great interest.[3]
In this context, we have recently reported a new Pd-cata-
lyzed methodology for the synthesis of indoles from imines
and o-dihaloarenes or o-haloarene sulfonates. The reaction
consists in a cascade process that involves an imine a-aryla-
À
tion, followed by an intramolecular C N-bond-forming reac-
tion, promoted by the same Pd catalyst. We have shown that
À
À
Scheme 1. Synthesis of indoles through a Pd-catalyzed C C/C N cas-
cade.
this methodology is very general and allows for the synthesis
of a wide variety of indoles, which are regioselectively sub-
stituted on both rings (Scheme 1).[4]
In recent years, the use of water as a solvent for organic
reactions has gained increasing attention, mainly for eco-
nomic, safety, and environmental reasons. In particular, the
combination of water as the solvent and microwave heating
as the energy source is becoming increasingly popular in
sustainable chemistry.[5] Nevertheless, the attractiveness of
water as a reaction medium is not only associated with the
concept of Green Chemistry. In many cases, remarkable
beneficial effects, in terms of reaction rates and selectivity,
have been observed for reactions between reagents that are
insoluble in aqueous media and therefore take place under
suspension in water; the term “on water” was coined by
Sharpless et al. to refer to this type of reaction.[6] As shown
in a recent review,[7] the “on water” effect has been ob-
served in different types of reactions, such as cycloadditions,
pericyclic reactions, nucleophilic substitutions, and also in
transition-metal-catalyzed, and in particular, Pd-catalyzed
reactions.[8]
[a] Prof. J. Barluenga, Dr. A. Jimꢀnez-Aquino, Prof. F. Aznar,
Dr. C. Valdꢀs
Instituto Universitario de Quꢁmica Organometꢂlica “Enrique Moles”
Universidad de Oviedo, c/Juliꢂn Claverꢁa 8. Oviedo 33006 (Spain)
Fax : (+34)985103450
Taking into account the synthetic potential of the modular
synthesis of indoles that we have developed, we wanted to
investigate whether modification of the reaction conditions
by the application of the “on water” concept, and the em-
E-mail: barluenga@uniovi.es
acvg@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000753.
Chem. Eur. J. 2010, 16, 11707 – 11711
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11707

Table 1. Preliminary results for the indolization reaction of o-chlorosul-
fonates reacting as a suspension in water.
ployment of microwave heating, might exert any influence
and lead to an improvement of the process. Our results have
indeed shown remarkable and beneficial differences be-
tween the “on-water”/microwave-assisted reaction and the
conventional process. Herein, we wish to report our conclu-
sions.
R
Base
(equiv)/[N]
Conditions[a]
t
T
Conversion
[%][b,c]
N
[h] [8C]
[0.7] TBAB (0.5 equiv) 14 100
[0.7] TBAB (0.5 equiv) 20 100
[0.7] TBAB (0.5 equiv) 20 100
[0.7] TBAB (0.5 equiv) 20 100
[1.5] TBAB (0.5 equiv) 20 100
C4F9 KOH (6)/[1.5]
Results and Discussion
1
2
3
4
5
6
CF3 NaOH (2.8)/
C4F9 NaOH (2.8)/
A
50
80
75
90 (65)
99 (75)
E
To test for conditions for the reaction as a suspension in
water, we chose the synthesis, from o-dibromobenzene (1a)
and imine 2a, of indole 3a. We employed the optimized cat-
alytic system for the indolization in organic solvents, which
C4F9 LiOH (2.8)/
C4F9 KOH (2.8)/
C4F9 KOH (6)/
G
E
AHCTUNGTRENNUNG
E
TBAB (1 equiv), 20 reflux 66
toluene/H2O, 1:2
consists of [Pd2ACHTUNGTRENNUNG(dba)3] (dba=dibenzylideneacetone) as the
metal source and 2-dicyclohexylphosphino-2’,4’,6’-triisopro-
pylbiphenyl (Xphos) as the ligand. Notably, both coupling
partners, as well as the ligand, are completely insoluble in
aqueous media. Nevertheless, after some experimentation,
we observed that the indolization reaction proceeds with
good yield in an aqueous NaOH solution (0.7n), in the pres-
ence of tetrabutylammonium bromide (TBAB) as a phase-
transfer catalyst (Scheme 2). Remarkably, the reaction as a
[a] Reaction conditions: [Pd2ACTHNGUTER(NNUG dba)3] (2 mol%), Xphos (8 mol%), imine
2a (0.5 mmol), ArOSO2R 4a or 5a (0.75 mmol). [b] Conversion based
upon the disappearance of imine 2a (GC/MS). [c] Isolated yield is indi-
cated in brackets.
ploying a solution of KOH (1.5m) in the presence of TBAB,
as a phase-transfer catalyst.
Some remarkable differences must be noted between the
reaction “on water” and in organic solvent: 1) the reaction
in an organic solvent is extremely demanding in terms of
the base, we obtained the indole only if LiOtBu or NaOtBu
was used as the base, whereas the “on water” reaction pro-
ceeds in either NaOH or KOH solutions; and 2) for the re-
action in an organic solvent the sulfonate must be added
slowly, over a period of 10 h, in order to achieve good con-
version and to avoid decomposition to the alkoxide, whereas
in the “on-water” process, the sulfonate is added in one por-
tion at the beginning of the reaction and, in the heterogene-
ous mixture, is not hydrolyzed by the base.
Notably, if the reaction was carried out in a toluene/water
biphasic mixture under otherwise identical reaction condi-
tions (Table 1, entry 6), lower conversion was obtained than
in the reaction in the absence of the organic solvent. These
observations point to the important role of the “on-water”
effect, which compares favorably, both with the homogenous
reaction and with the reaction in a biphasic mixture. Howev-
er, the reactions that occur as a suspension in water still re-
quire very long reaction times. For this reason, we decided
to study the same transformations under microwave heating.
To find suitable reaction conditions, we employed the reac-
tion of 1a with 2a to form 3a (depicted in Scheme 2) as a
model reaction. In Table 2, representative data from the op-
timization process are presented.
Scheme 2. Indolization reaction “on water”: preliminary results.
suspension in water takes place with NaOH employed as
the base, whereas, in our previous studies in organic sol-
vents, these reactions were very demanding in terms of the
nature of the base and proceeded, successfully, only in the
presence of NaOtBu.
These preliminary results prompted us to investigate this
transformation in more detail and also to direct our atten-
tion to the reactions with o-chlorosulfonates. We have
shown that these reactions are more versatile, from a syn-
thetic point of view, since they represent a valuable strategy
for the regioselective synthesis of indoles with substituents
on the benzene ring. However, the reactions with sulfonates
require very finely tuned experimental conditions, as a
result of the lability of sulfonates in the presence of bases.
As prototype reactions, we again chose the synthesis of 3a,
but employing o-chlorotriflate 4a and o-chlorononaflate 5a.
In a series of experiments, we searched for a successful com-
bination of reaction conditions for these transformations.
We observed that the indolization of chlorosulfonates can,
indeed, be performed as a suspension in water. The prelimi-
nary results showed that, akin to the conventional reactions,
nonaflate 5a gave better results than triflate 4a (Table 1, en-
tries 1 and 2).[9] Therefore, the optimization reactions were
carried out with 5a. The best results were obtained by em-
Poor results were obtained under microwave irradiation
for the reactions in dioxane. However, as a suspension in
water, the microwave-promoted reactions proceeded with
high conversions and in much shorter reaction times than
the thermally heated equivalents, taking advantage of the
high temperatures that can be achieved in the microwave
heated experiments. Under the optimized reaction condi-
tions (Table 2, entry 10), the reaction can be carried out in
45 min, providing the indole in excellent yield. Moreover,
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Synthesis of Indoles
FULL PAPER
Table 2. Optimization of the microwave-promoted, “on-water” reaction.
with triflates (Table 3, entries 12 vs. 16, and 15 vs. 19). Im-
portantly, under these conditions, the regioselectivity is also
retained if o-bromochloro or o-chloroiodobenzene deriva-
À
tives are employed (Table 3, entries 6–8); the C C-bond for-
mation occurs at the position of the more reactive halogen.
The reactions with o-chlorosulfonates also proceed with
Base
(equiv)/[N]
Conditions[a]
t
ACHTUNGTRENNUNG
T
Conversion
À
total regioselectivity (Table 3, entries 11–20), with the C C-
G
[min] [8C] [%][b,c]
bond formation taking place at the position of the sulfonate.
This is an important feature as it allows the regioselective
synthesis of indoles with substituents on the six-membered
ring by employing o-chlorophenols as starting materials.
1
2
3
4
5
6
7
8
9
NaOtBu (2.8)
NaOtBu (2.8)
NaOtBu (2.8)
dioxane
dioxane
dioxane
20
20
20
60
20
20
110 14
150 30
160 52
140 77
140 80
150 80
140 72
150 99 (75)
140 60
KOH (3)/
KOH (3)/[1.5]
KOH (3)/[1.5]
KOH (3)/
A
E
H2O, TBAB (1 equiv)
H2O, TBAB (1 equiv)
R
A
Conclusion
KOH (7.5)/[3N] H2O, TBAB (1 equiv)
KOH (7.5)/[3N] H2O
30
45
10 KOH (7.5)/[3N] H2O, TBAB (0.12 equiv) 45
140 99 (89)
We have reported the beneficial effect of the “on-water”–
microwave combination on the Pd-catalyzed cascade synthe-
sis of indoles. The reactions take place under heterogeneous
conditions: the coupling partners (imines and arenes), as
well as the ligand for Pd, are insoluble in water. The main
[a] Reaction conditions: [Pd2ACTHNGUTRE(NNUG dba)3] (2 mol%); Xphos (4 mol%); imine
2a (0.5 mmol), 1,2-dibromobenzene (1a, 0.5 mmol). [b] Conversion based
upon the disappearance of imine 1a (GC/MS). [c] Isolated yield is indi-
cated in brackets.
the quantity of the phase-trans-
Table 3. Generality of the microwave, “on-water” synthesis of indoles 3.
fer catalyst can be reduced to
only 12 mol%. In the absence
of TBAB, the indolization also
takes place, but in lower con-
version (Table 2, entry 9).
These conditions were ap-
plied to the synthesis of indoles
from a set of imines and o-diha-
lobenzene derivatives, as well
as o-chlorosulfonates. Repre-
sentative examples are present-
ed in Table 3.
The results obtained show
that the “on-water”/microwave-
promoted reaction provides
comparable results, in terms of
generality and yield, to the
thermal process in an organic
solvent that has previously been
described, but shows significant
advantages, such as a dramatic
reduction in reaction times and
the replacement of the tert-but-
oxide bases by a simple KOH
Arene
Imine
Conditions[a,b] Indole 3
Yield
[%][c]
45 min
1408C
1
2
3
1a
1b
1a
2a
2a
2b
3a
3a
3b
89
72
67
45 min
1408C
45 min
1608C
60 min
1608C
4
5
6
7
8
9
1a
1a
1c
1d
1e
1 f
2c
2d
2a
2a
2a
2e
3c
3d
3e
3 f
3g
3h
60
77
62
61
68
60
40 min
1408C
45 min
1608C
30 min
1508C
45 min
1608C
solution. Moreover, from
a
practical point of view, in the
reactions that occur as a sus-
pension in water, the slow addi-
tion of the sensitive sulfonate is
not required. Nevertheless, an
excess of the sulfonate is still
necessary to achieve complete
conversion. As expected, the
reactions with nonaflates pro-
vided better results than those
30 min
1508C
45 min
1608C
10
11
1a
4a
2 f
2a
3i
64
75
45 min
1608C
3a
Chem. Eur. J. 2010, 16, 11707 – 11711
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11709

J. Barluenga, C. Valdꢀs et al.
imines and noncommercial 1,2-diha-
loarenes, o-chlorotriflates and o-chlor-
ononaflates, were prepared as previ-
ously reported in reference [4b].
Table 3. (Continued)
Arene
Imine
Conditions[a,b] Indole 3
Yield
[%][c]
General procedure for the synthesis of
indoles 3 under suspension in water
45 min
1608C
12
13
14
4b
4c
4d
2a
2a
2a
3j
3k
3l
76
49
47
and microwave heating:
A reaction
tube was charged with Xphos
(24.9 mg, 0.04 mmol, 8 mol%), tetra-
45 min
1608C
butylammonium
0.062 mmol, 0.125 equiv), [Pd CHTUNGTRENNUNG
bromide
(20 mg,
2A(dba)3]
(9.62 mg, 0.01 mmol, 2 mol%), imine
2 (0.5 mmol), the corresponding 1,2-di-
haloarene 1 (0.5 mmol) or o-halosulfo-
nate 4 or 5 (0.75 mmol), and aqueous
KOH (1.25 mL, 3n, 7.5 equiv). The
tube was sealed and irradiated at the
appropriate temperature (140–1608C)
45 min
1608C
45 min
1608C
15
16
4e
5b
2a
2a
3m 48
for
a
period of 30–45 min (see
45 min
1608C
3j
92
63
Table 3). The reaction mixture was al-
lowed to cool to RT and treated with
CH2Cl2 (10 mL). The layers were sepa-
rated and the aqueous layer extracted
with additional CH2Cl2 (3ꢄ5 mL). The
combined organic layers were dried
over Na2SO4 and concentrated under
reduced pressure. The crude product
mixture was purified by column chro-
matography.
45 min
1608C
17
5c
2a
3k
45 min
1608C
18
19
20
5d
5e
5b
2a
2a
2c
3n
93
45 min
1608C
3m 70
Most of the indoles 3 synthesized have
previously been reported by us in ref-
erence [4b]. Characterization data for
new compounds is included in the
Supporting Information.
45 min
1608C
3o
85
[a] Reactions with o-dihaloarenes: [Pd2ACTHNUTRGNEUNG(dba)3] (2 mol%), Xphos (4 mol%), imine 1 (0.5 mmol), 1,2-dihaloar-
ene 2 (0.5 mmol). [b] Reactions with o-haloarene sulfonates 4 or 5: [Pd2ACTHNUTRGEN(UNG dba)3] (2 mol%), Xphos (8 mol%),
imine (0.5 mmol), sulfonate (0.75 mmol). [c] Isolated yield.
Acknowledgements
Financial support of this work by the
Ministerio de Ciencia of Spain (CTQ2007-61048/BQU) and the Conseje-
rꢁa de Educaciꢅn y Ciencia of Principado de Asturias (IB08-088). A FPI
predoctoral fellowship from the Ministerio Ciencia e Innovaciꢅn of Spain
to A.J.-A. is gratefully acknowledged.
advantages to performing the reaction under heterogeneous
conditions and microwave heating, over the homogenous re-
action in organic solvent under conventional heating, are as
follows: 1) the reaction times are dramatically reduced;
2) the use of an organic solvent is avoided; 3) an aqueous
solution of KOH is employed, in place of alkaline tert-but-
oxide; 4) the slow addition of the sensitive o-haloarene sul-
fonates is no longer necessary; and 5) the catalyst loading
can be reduced. As a consequence, the advantages and sim-
plicity of this experimental protocol cause it to be, in many
cases, the method of choice for the high-speed synthesis of
substituted indoles.
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General information: The reactions under thermal conditions were car-
ried out in a RR98030 12 place Carousel Reaction StationTM from Rad-
leys Discovery Technologies, equipped with gas-tight threaded caps with
a valve, cooling reflux head system, and digital temperature controller.
The reactions under microwave irradiation were carried out in a Biotage
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Synthesis of Indoles
FULL PAPER
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Received: March 25, 2010
Published online: August 26, 2010
Chem. Eur. J. 2010, 16, 11707 – 11711
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11711