Silica-supported ceric ammonium nitrate catalyzed chemoselective formylation of indoles

Article abstract of DOI:10.1016/j.tetlet.2014.04.124

Selective formylation of free (N-H) indoles at C3 can be achieved by using formylating species generated from hexamethylenetetramine (HMTA) and silica-supported ceric ammonium nitrate (CAN-SiO₂). The use of a catalytic amount of this solid-supported reagent was found to be compatible with a range of substituents on the indoles and generated the corresponding products with good yields. A plausible mechanism for the formylation involving an electron transfer process is discussed.

Full text of DOI:10.1016/j.tetlet.2014.04.124

Accepted Manuscript
Silica-supported ceric ammonium nitrate catalyzed chemoselective formylation
of indoles
Sukanya Tongkhan, Widchaya Radchatawedchakoon, Senee Kruanetr, Uthai
Sakee
PII:
S0040-4039(14)00761-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.124
TETL 44586
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
17 February 2014
11 April 2014
30 April 2014
Please cite this article as: Tongkhan, S., Radchatawedchakoon, W., Kruanetr, S., Sakee, U., Silica-supported ceric
ammonium nitrate catalyzed chemoselective formylation of indoles, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.04.124
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Silica-supported ceric ammonium nitrate catalyzed chemoselective formylation of indoles
Sukanya Tongkhan, Widchaya Radchatawedchakoon, Senee Kruanetr, Uthai Sakee

1
Tetrahedron Letters
jour nal homepage: w ww.elsevier. com
Silica-supported ceric ammonium nitrate catalyzed chemoselective formylation of
indoles
Sukanya Tongkhan, Widchaya Radchatawedchakoon, Senee Kruanetr, Uthai Sakee∗
Center of Excellence for Innovation in Chemistry (PERCH-CIC), Department of Chemistry, Faculty of Science, Mahasarakham University, Mahasarakham
44150, Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Selective formylation of free (N-H) indoles at C3 can be achieved by using formylating species
generated from hexamethylenetetramine (HMTA) and silica-supported ceric ammonium nitrate
(CAN-SiO2). The use of a catalytic amount of this solid-supported reagent was found to be
compatible with a range of substituents on the indoles and generated the corresponding products
with good yields. A plausible mechanism for the formylation involving an electron transfer
process is discussed.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
indole
formylation
3-formyl indole
indole-3-carboxaldehyde
ceric ammonium nitrate
The C-formylation of indoles is a very useful key step in the
preparation of biologically active natural products, including
cryptosanguinolentine,1 homofascaplysin C,2 FR-9004823 and
indole alkaloids.4 A number of synthetic methods have been
reported in the literature for the formylation of indoles and
various reagents are available for use in this reaction.
Traditionally, the Vilsmeier–Haack reagent (e.g. POCl3 + DMF)
was efficient for such transformation, but it is not
environmentally benign.5 The Duff,5a Reimer–Tiemann,6 and
Gattermann–Koch reactions7 are also powerful methods leading
to formylated products, which generally require heating at
elevated temperatures with an excess of strong base or acid in the
work-up processes. Nevertheless, these indole formylation
methods are not compatible with functional groups that are labile
under acidic or basic conditions. Catalytic formylations have
received considerable attention due to their mild, safe and
environmentally friendly characteristics. Hence, the development
of novel access to formylindoles using environmentally benign
reagents under mild conditions is still of much significance. A
reaction utilizing N-methylaniline as the carbonyl source has
been reported for the Ru8 or nBu4NI9 catalyzed formylation of
Ceric(IV) reagents can function as a one-electron transfer catalyst
in various organic reactions.12 Recently, CAN supported on silica
gel has been reported for bromination,13 removal of protecting
groups14 and oxidation reactions.15
Table 1
Formylation of indole with various catalysts and solvents
Entrya
Catalyst
CAN-SiO 2
CAN
Solvent Time (h)
Yieldb (%)
81
c
1
2
3
CH3CN
CH3CN
CH3CN
22
7
29
SiO2
24
trace
4
5
6
7
8
AlCl3
FeCl3
Amberlyst-15
CAN-SiO 2
CAN-SiO 2
CH3CN
CH3CN
CH3CN
MeOH
EtOH
24
24
24
7
4
24
24
19
36
10
10
20
indoles.
More recently, Fei and coworkers reported the
c
formylation of indoles using DMSO as the carbonyl source.10
c
The development of non-toxic, low cost, eco-friendly,
recyclable catalyst systems has received significant attention in
organic synthesis.11 Cerium(IV) ammonium nitrate (CAN) has
proved to be very useful with advantages such as low toxicity,
ease of handling and solubility in a number of organic solvents.12
c
9
10
CAN-SiO 2
CAN-SiO 2
DMF
THF
58
trace
c
a
Reaction conditions: indole (1 mmol), HMTA (2 mmol), catalyst (10
mol%), solvent (5 mL); b Isolated yield; c 10% (by weight) of CAN
———
∗ Corresponding author. Tel.: +6-643-754-246; fax: +6-643-754-246; e-mail: uthai.s@msu.ac.th

2
Table 2
Evaluation of the catalytic activity of ceric ammonium nitrate on silica gel (CAN-SiO2) in the formylation of indole
Entrya
%wt.
CANc (mol%)
HMTA (eq.)
Time (h)
26
Yieldb (%)
1
2
3
4
5
6
7
8
9
10% CAN-SiO2
10% CAN-SiO2
10% CAN-SiO2
5% CAN-SiO2
15% CAN-SiO2
5% CAN-SiO2
15% CAN-SiO2
10% CAN-SiO2
10% CAN-SiO2
10% CAN-SiO2
5
2
2
63
81
81
57
78
81
73
79
87
88
10
15
5
22
2
2
22
22
15
10
10
10
10
10
2
20
2
2
22
20
1.5
2.5
3
22
20
20
10
a
Reaction conditions: indole (1 mmol), HMTA, catalyst , CH3CN (5 mL), reflux ; b Isolated yield; c amount of CAN in the reaction
In the search of an eco-friendly procedure using an
inexpensive and reusable catalytic system, we report for the first
time the use of silica-supported CAN as a mild and highly
efficient, recyclable catalyst for the C-fomylation of indoles.
With the optimized reaction conditions in hand, we next
explored the substrate scope using CAN-SiO2 as the catalyst. The
CAN-SiO2 catalyzed C3-selective formylation of free N-H
indoles was compatible with a range of substituents on the
benzene and pyrrole ring of indole, and generated the
corresponding products with reasonable to good yields (entries 1-
10, Table 3). In addition, we also studied the reusability of the
catalyst after filtration, washing with EtOAc18 and drying. The
results of the recycling show that the catalyst can be recycled
once (87 and 81% yield, respectively, Table 4).
The study was initiated by carrying out the formylation of
indole with hexamethylenetetramine (HMTA) by screening a
variety of catalysts (SiO2, CAN and CAN-SiO217) in CH3CN
under refluxing conditions.18 The results from the optimization
studies are summarized in Table 1. We found that catalysts
including SiO2 and CAN were either ineffective or less effective
than CAN-SiO2 (entries 1-6). The effect of the solvent on the
reaction efficiency was also studied (entries 7-10). Among the
tested solvents, CH3CN gave the best result (entry 1).
The adsorption of HMTA on to the silica gel impregnated
with CAN could bring the substrates and the catalyst into close
proximity.16 This facilitates the electron transfer process between
CAN and the substrates. The use of silica gel as a support could
also increase the effective surface area and constrain both the
substrate and the reactant in pores thus decreasing the entropy of
activation for electron transfer.14 We propose a mechanism in
Scheme 1 for the formylation of indole using CAN-SiO2. HMTA
was adsorbed on CAN-SiO2 to afford I. The proximity of HMTA
to CAN in I results in a favorable entropy of activation and,
consequently, a rate enhancement of the reaction. Oxidation of
HMTA in I gives the corresponding radical cation in II, while
reduction of Ce(IV) to Ce(III) takes place. The radical cation then
undergoes fragmentation to give an iminium cation and an amine
radical as shown in III. The reduction of the amine radical III to
amine anion IV allows regeneration of Ce(IV) from Ce(III).
Meanwhile, protonation of the amine anion IV give an iminium
ion V and allows regeneration of CAN-SiO2. The nucleophilic
aromatic substitution of indole with iminium V generates VI.
Further, to check the effectiveness of the catalyst, the reaction
was carried out in the presence of various amounts of the CAN-
SiO2 in CH3CN (Table 2). The results showed no improvement in
the product yield using different amounts of CAN-SiO2. The
number of equivalents of HMTA was also studied (Table 2,
entries 8-10). The yield of 3-formylindole increased when using
2.5 and 3.0 equiv. of HMTA (87% and 88%, respectively).
Table 3
Synthesis of 3-formylindole derivatives
Entrya R1
R2
Time (h)
Yieldb (%)
Table 4
1
2
3
H
H
20
9
15
6
87
65
60
70
77
88
78
70
81
89
The recycling of CAN-SiO2 in the formylation with indole
4-MeO
5-MeO
6-MeO
7-MeO
H
H
H
Entrya
No. of cycles
Time (h)
Yieldb (%)
4
H
5
6
H
Ph
12
12
12
12
12
12
1
2
3
1
2
3
20
22
24
87
81
68
7
H
4-MeOC6H4
4-MeC6H4
3-MeOC6H4
Ph
8
H
9
H
4
4
24
65
10
5-MeO
a Reaction conditions: indole (1 mmol), HMTA (2.5 equiv.), 10% CAN-SiO2
a Reaction conditions: indole (1 mmol), HMTA (2.5 equiv.), 10% CAN-SiO2
(10 mol% of CAN in reaction), CH3CN (5 mL), reflux;b Isolated yield and
products were identified by comparison of their 1H NMR and 13C NMR
spectral data with those reported in the literature.
(10 mol% of CAN in the reaction), CH3CN (5 mL), reflux ;b Isolated yield.

3
Removal of the amine groups from VI with CAN-SiO2 could
proceed through a similar mechanism. The first step involves the
oxidation of the secondary amine in VI after coordination to
CAN-SiO2. The resultant radical cation in VIII could then
undergo a ring-opening reaction to give IX. Regeneration of
Ce(IV)-SiO2 from Ce(III)-SiO2 during reduction of the amine
radical in IX affords the amine anion X. Protonation of X then
gives the primary amine XI. Intermediate XI undergoes a 1,5-
hydrogen shift to give iminium ion XII, followed by hydrolysis
to give the 3-formylindole. Another plausible mechanism is
given in the supporting information.
In summary, we have demonstrated the formylation of a
variety of indoles under mild conditions. The formylating species
generated from HMTA and CAN-SiO2 is highly reactive, and the
formylation of indoles proceeded smoothly to provide the
corresponding aldehydes with good yields. The reaction might be
useful for the synthesis of highly functionalized indoles.
Scheme 1. Proposed mechanism

4
Acknowledgments
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3805–3849.
This work was supported by Mahasarakham University,
Human Resource Development in Science Project (Science
Achievement Scholarship of Thailand; SAST), the Center of
Excellence for Innovation in Chemistry (PERCH-CIC) and the
Division of Research Facilitation and Dissemination,
Mahasarakham University.
13. Wang, L.; Jing, H.; Bu, X.; Chang, T.; Jin, L.; Liang, Y.
Catal. Commun. 2007, 8, 80–82.
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Balakumar, A.; Hakimelahi, G. H. J. Org. Chem. 2000, 65,
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2002, ix, 28–36.
Supporting information
15. Ali, M. H.; Niedbalski, M.; Bohnert, G.; Bryant, D. Synth
Commun. 2006, 36, 1751–1759.
Supplementary data associated with this article can be found,
in the online version, at…
16. Clark, J. H.; Rhodes, C. N. Clean Synthesis using Porous
Inorganic Solid Acid Catalysts and Supported Reagents;
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17. Preparation of 10% CAN-SiO2: a solution of CAN (1.01 g)
in H2O (2.0 mL) was added dropwise to silica gel 60 (9.01
g, Merck Kieselgel 60, particle size 0.063–0.200 mm, 70–
230 mesh) under stirring followed by evaporation under
reduced pressure at 60 ºC for 4 h. A dry yellowish powder
was collected and stored in a well-sealed bottle. (Other
loading ratios of CAN-SiO2 were prepared by the same
method (9.51 g silica gel and 0.51 g CAN for 5% CAN-
SiO2, 8.51 g silica gel and 1.51 g CAN for 15% CAN-
SiO2).
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(2.5 mmol) and 10% CAN-SiO2 was refluxed in CH3CN
(5.0 mL). After the reaction was complete, the mixture was
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185.7; IR (KBr): 3129, 2982, 1624, 1468, 1368, 1259, 1213
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11927.
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5
Silica-supported ceric ammonium nitrate
catalyzed chemoselective formylation of indoles
Sukanya Tongkhan, Widchaya Radchatawedchakoon,
Senee Kruanetr, Uthai Sakee