Indium trichloride catalyzed three component one-pot route to 1-hydroxymethyl-3-aminomethyl indoles

Article abstract of DOI:10.1016/j.tetlet.2012.08.034

A one-pot synthesis of 1-hydroxymethyl-3-aminomethyl indoles 3 could be achieved in excellent yield by reacting indoles 1 with formaldehyde and secondary amines 2 in the presence of molecular sieves (3 ?) and catalytic amount of InCl₃ (10 mol %) in 1,4-dioxane at room temperature for 3-5 h. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.034

Tetrahedron Letters 53 (2012) 5548–5551
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium trichloride catalyzed three component one-pot route
to 1-hydroxymethyl-3-aminomethyl indoles
⇑
Chiranjit Acharya, Sumit Dey, Parasuraman Jaisankar
Department of Chemistry, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of 1-hydroxymethyl-3-aminomethyl indoles 3 could be achieved in excellent yield
by reacting indoles 1 with formaldehyde and secondary amines 2 in the presence of molecular sieves
(3 Å) and catalytic amount of InCl3 (10 mol %) in 1,4-dioxane at room temperature for 3–5 h.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 June 2012
Revised 4 August 2012
Accepted 6 August 2012
Available online 14 August 2012
Keywords:
Indium trichloride
1-Hydroxymethyl-3-aminomethyl indoles
Formaldehyde
Diethyl amine
Piperidine
Indole scaffolds are widespread in biologically active com-
pounds and natural products.1 Their main importance is in medic-
inal chemistry and drug discovery which has resulted in continued
interest in their synthesis.2 Indole and its synthetic analogs are
known to possess important biological activities such as antipy-
retic,3 analgesic4 anticonvulsant etc.5 Among various indole deriv-
atives, 3-aminomethyl indoles6,7 were found to possess inhibitory
with formaldehyde and piperidine (2a) in 1,4-dioxane it resulted
in the formation of 1-hydroxymethyl-3-aminomethyl indole 3a
in 15% yield as well as expected products such as 1,3-diaminom-
ethyl indole 4a18a (12%) and 1-aminomethyl indole 5a18 (10%)
(Table 1, entry 1). When activated molecular sieves (MS) (3 Å) were
added to the reaction mixture, the duration of the reaction de-
creased to 14 h but not much improvement in the yield and selec-
tivity in the formation of 3a (Table 1, entry 2). To our delight,
simple addition of 10 mol % of InCl3 as Lewis acid catalyst into
the above reaction afforded the 1-hydroxymethyl-3-aminomethyl
indole 3a as the sole product in 84% yield in 4 h (Table 1, entry 3).
The role of molecular sieves, most likely, is to absorb the water
generated during the reaction. To investigate the role of solvent
in the reaction, we have used various other solvents (Table 1) such
as THF, MeOH, and MeCN, and it seems that 1,4-dioxane is the per-
fect solvent choice for this reaction (Table 1, entry 3). Then we
investigated the effects of different Lewis acid catalysts in the same
reaction and observed that InCl3 was found to be the best among
the various catalysts used to afford the desired 1-hydroxy-
methyl-3-aminomethyl indole 3a (Table 2).
activity toward phosphorylation of kinase pp60c-Src 7,8
which is a
,
non-receptor protein tyrosine kinase (PTK), participating in many
cellular activities including cell adhesion, invasion, motility, differ-
entiation, and growth factor receptor signaling.9 Hemiaminals10 of
indoles are also reported to possess good anti-tumor activity.11
Hemiaminals are generally used as prodrugs to increase the bio-
availability12 of drug molecules containing indole and other N-
heterocyclic moieties, due to their labile nature, hemiaminals
generally fragment into formaldehyde and indole or other N-
heterocyclic compounds.13 It is well known that InCl3 has the
ability to promote Diels-Alder,14a aldol,14b Mannich,14c Friedel–
Crafts,14d and various other important organic transfomations.14e,15
Also indium salts have shown notable tolerance toward mois-
ture and other co-coordinating functional groups present in the
substrates.16 We have been able to use InCl3 as catalyst for the syn-
thesis of various hetereocycles17 of biological importance over the
years. We have now observed that when indole (1a) was treated
This optimized method was then exploited to prepare a number
of substituted 1-hydroxymethyl-3-aminomethyl indoles 3b–o by
varying indoles and secondary amines. The results are summarized
in the following table (Table 3).
It is pertinent to mention that when 3-methyl indole (1f) was
reacted with formaldehyde and piperidine (2a) in the presence of
10 mol % of InCl3 and 3 Å MS in 1,4-dioxane afforded only
1-hydroxymethyl-3-methyl indole (6)10 as product in 83% yield,
⇑
Corresponding author. Tel.: +91 33 24995790; fax: +91 33 24735197.
E-mail address: jaisankar@iicb.res.in (P. Jaisankar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.034

C. Acharya et al. / Tetrahedron Letters 53 (2012) 5548–5551
5549
Table 1
Solvent optimization studies for the reaction of indole (1a), formaldehyde and piperidine (2a)
N
Lewis acid catalyst
N
+
+
HCHO
+
+
3 Å MS, solvent,
rt, 4-24 h
N
H
N
N
H
N
N
N
OH
3a
N
1a
2a
4a
5a
Entrya
Solvent
Lewis acid catalyst
Time (h)
Yieldb (%)
3a
4a
5a
1
2
3
4
5
6
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THF
Methanol
MeCN
No catalystc
No catalyst
InCl3
InCl3
InCl3
24
14
4
13
14
12
15
21
84
20
33
62
12
15
—
23
25
18
10
14
—
14
12
9
InCl3
a
b
c
Reaction conditions: 1a (1 mmol), formaldehyde (4 mmol), 2a (1.5 mmol), InCl3 (10 mol %), and MS (3 Å) (200 mg) in the solvent specified (10 mL) at room temperature.
Isolated yield.
Reaction was performed without MS (3 Å).
In order to investigate the mechanism of the reaction, we have
Table 2
performed proton NMR analysis of the crude reaction mixture (see
Supplementary data) of indole (1a), piperidine (2a), and formalde-
hyde in the presence of InCl3 and molecular sieves. It revealed that
A (not isolable) was formed after 30 min of stirring, which on fur-
ther stirring for 3.5 h was converted into product 3a (Scheme 2).
Therefore, the formation of 1-hydroxymethyl-3-aminomethyl in-
dole 3a may be explained as, the iminium ion generated from
the reaction between formaldehyde and piperidine (2a) under
the influence of InCl3 undergoes spontaneous electrophilic substi-
tution at C-3 of indole (1a) to afford 3-aminomethyl indole A,
which further reacts with the activated formaldehyde to give 3a
(Scheme 2).
The effect of Lewis acid catalysts in the reaction of indole (1a), formaldehyde and
piperidine (2a)
Entrya
Solvent
Lewis acid catalyst
Time (h)
Yieldb (%)
4a
3a
5a
1
2
3
4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
InCl3
FeCl3
ZnCl2
BF3.OEt2
4
5
7
5
84
61
48
45
—
17
19
18
—
8
8
9
a
Reaction conditions: 1a (1 mmol), formaldehyde (4 mmol), 2a (1.5 mmol),
Lewis acid catalyst (10 mol %) and MS (3 Å) (200 mg) in 1,4-dioxane (10 mL) at
room temperature.
b
Isolated yield.
The structures of all the synthesized compounds have been de-
duced mainly by NMR, high resolution mass, and IR. Moreover the
structure of (3-(piperidin-1-ylmethyl)-1H-indol-1-yl) methanol
(3a) has been confirmed by single crystal X-ray analysis20 (Fig. 1).
whereas 1,2-dimethyl indole (1g) furnished the anticipated
product 3-aminomethyl-1,2-dimethyl indole 719 in 79% yield
(Scheme 1).
CH3
CH3
InCl3 (10 mol %)
+
HCHO
+
3 Å MS, 1,4-dioxane
rt, 5 h
N
H
N
H
N
OH
, 83%
6
2a
1f
InCl3 (10 mol %)
N
HCHO
+
+
CH3
N
CH3
3 Å MS, 1,4-dioxane
rt, 3 h
N
N
CH3
CH3
H
1g
2a
7
, 79%
Scheme 1. Regioselectivity of the reaction.
H
N
H
H
H
N
H
O
InCl3
H
H
N
N
N
N
+
-InCl3
O
InCl3
N
H
N
H
A
N
2a
OH
3a
(not isolable)
Scheme 2. Plausible mechanism for the InCl3 catalyzed formation of 1-hydroxymethyl-3-aminomethyl indole 3a.

5550
C. Acharya et al. / Tetrahedron Letters 53 (2012) 5548–5551
Table 3
InCl3 catalyzed synthesis of 1-hydroxymethyl-3-aminomethyl indoles 3b–o
R''
R''
InCl3 (10 mol %)
NR2
+
+
R2NH
HCHO
3 Å MS, 1,4-dioxane
rt, 3-5 h
N
H
R'
N
R'
OH
2a-c
1a-e
N
N
1a : R' = R" = H
2a :
R2N =
3b-o
1b
: R' = Me, R'' = H
1c : R' = Ph, R'' = H
2b : R2N =
2c : R2N =
N
1d
: R' = H, R'' = OMe
1e : R' = H, R'' = Br
Et2N
Entry
Indoles 1
Amines 2
Time (h)
Yield of products
3b–oa (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
4.5
3.5
4
4
4.5
3
3.5
4
3
3.5
5
4
85 (3b)
83 (3c)
84 (3d)
86 (3e)
84 (3f)
94 (3g)
89 (3h)
91 (3i)
85 (3j)
84 (3k)
83 (3l)
88 (3m)
87 (3n)
86 (3o)
3.5
4.5
a
Isolated yields.
Projects (NWP 0033 and IAP 0001). The author C. A. acknowledges
the UGC, New Delhi, India for the financial support in the form of
Research Fellowship. Thanks are also due to Mr. S. Samaddar for
IR analyses.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.034. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
1. For abundance of Indole in natural products, see: (a) Eicher, T.; Hauptmann, S.
The Chemistry of Heterocycles; Wiley-VCH: Weinheim, 2003; (b) Joule, J. A.;
Mills, K. Heterocyclic Chemistry; Blackwell Science Ltd.: Oxford, 2000; (c) Cordel,
G. A Introduction to the Alkaloids; Wiley - Interscience Publication, 1981. pp.
574.
2. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
3. For antipyretic activity of indole derivatives, see: Foye, Williams O. Principles of
Medicinal Chemistry, Fourth edition, 1995, pp. 553.
4. For analgesic activity of indole derivatives, see: Pahari, N.; Saha, D.; Jain, V. K.;
Jain, B.; Mridha, D. Int. J. Pharma. Sci. Res. 2010, 1, 399.
Figure 1. X-ray crystal structure of 3a with a water molecule. The crystallographic
data were collected at 298 K; hence hydrogen atoms of the water molecule could
not be assigned due to thermal disorder.
In summary, an efficient Indium trichloride catalyzed one-pot
synthesis of 1-hydroxymethyl-3-aminomethyl indoles21 was
achieved from the reaction of indoles, formaldehyde, and second-
ary amines in excellent yield. Biological activities of the synthe-
sized 1-hydroxymethyl-3-aminomethyl indoles are underway
and the results will be reported in due course.
5. For anticonvulsant activity of indole derivatives, see: Rajak, H.; Veerasamy, R.;
Gupta, A. K.; Kharya, M. D.; Misra, P. Int. J. Pharma. Sci. Nanotech. 2009, 2, 661.
6. Shchekotikhin, A. E.; Shtill, A. A.; Luzikov, Y. N.; Bobrysheva, T. V.; Buyanov, V.
N.; Preobrazhenskaya, M. N. Bioorg. Med. Chem. Lett. 2005, 13, 2285.
_
7. For activity of aminomethyl indoles towards PTK, see: Ißsgör, Y. G.; Kılıç, Z.;
Ölgen, S. Chem. Biol. Drug Des. 2008, 72, 599.
8. For tyrosine kinase, see: Ölgen, S.; Isgör, Y. G.; Çoban, T. Arch. Pharm. 2008, 341,
113.
9. Warmuth, M.; Damoiseaux, R.; Liu, Y.; Fabbro, D.; Gray, N. Curr. Pharm. Des.
2003, 9, 2043.
10. For hemiaminals, see: Hsu, H.-C.; Hou, D.-R. Tetrahedron Lett. 2009, 50, 7169.
11. For anti-tumor activity of hemiaminals, see: (a) Kemnitzer, W.; Drewe, J.; Jiang,
S.; Zhang, H.; Crogan-Grundy, C.; Labreque, D.; Bubenick, M.; Attardo, D.;
Denis, R.; Lamothe, S.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med.
Acknowledgments
This project was funded by the Council of Scientific and Indus-
trial Research (CSIR), New Delhi, India in the form of Network

C. Acharya et al. / Tetrahedron Letters 53 (2012) 5548–5551
5551
Chem. 2008, 51, 417; (b) Liou, J.-P.; Wu, C.-Y.; Hsieh, H.-P.; Chang, C.-Y.; Chen,
C.-M.; Kuo, C.-C.; Chang, J.-Y. J. Med. Chem. 2007, 50, 4548.
18. (a) Sambasiva, S.; Krishnaiyer, N. Chem. Ber. 1966, 99, 889; (b) Love, B. E.;
Nguyen, B. T. Synlett 1998, 1123.
12. For bioavailability of hemiaminals, see: (a) Zhu, Z.; Chen, H.-G.; Goel, O. P.;
Chan, O. H.; Stilgenbauer, L. A.; Stewart, B. H. Bioorg. Med. Chem. Lett. 2000, 10,
1121; (b) Bundgaard, H. In Design of Prodrugs; Bundgaard, H., Ed.; Springer:
Amsterdam, 1985. pp. 1.
13. (a) Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165; (b)
Smith, M. B.; March, J. In March’s Advanced Organic Chemistry; Wiley-
Interscience: New York, 2007. pp. 1281; (c) Chudek, J. A.; Foster, R.; Young,
D. J. Chem. Soc., Perkin Trans. 2 1985, 1285.
19. Shunji, N.; Kazuo, K.; Yasushi, U.; Shinji, M.; Keiichi, M.; Jun, H. WO 19960704,
1996.
20. CCDC number of 3a is 885058. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. For details see Supplementary data.
21. Representative procedure for the synthesis of 1-hydroxymethyl-3-aminomethyl
indole 3a: To a stirred mixture of 37% formaldehyde solution (w/v) (324
lL,
4 mmol) and piperidine (2a, 149 L, 1.5 mmol) in 1,4-dioxane (10 mL), dry
l
14. For InCl3 catalyzed. Diels–Alder reaction, see: (a) Babu, G.; Perumal, P. T.
Tetrahedron Lett. 1997, 38, 5025. and references cited therein; aldol reaction,
see: (b) Loh, T.-P.; Pei, J.; Lin, M. Chem. Commun. 1996, 2315; Mannich
reactions, see: (c) Loh, T.-P.; Pei, J.; Cao, G.-Q. Chem. Commun. 1819, 1996;
Fridel–Crafts reactions, see: (d) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39,
323; Various other organic transformations, see: (e) Miyai, T.; Onishi, Y.; Baba,
A. Tetrahedron 1999, 1017, 55; (f) Krishna, P. R.; Prapurna, Y. L.; Alivelu, M.
Tetrahedron Lett. 2011, 52, 3460. and references cited therein.
15. For recent review on InCl3 catalyzed organic transformations, see: (a) Singh, M.
S.; Raghuvanshi, K. Tetrahedron (in press) http://www.dx.doi.org/10.1016/
j.tet.06.099; (b) Augé, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739; (c)
Ranu, B. C. Eur. J. Org. Chem. 2000, 2347. and references cited therein.
16. Reddy, L. R.; Reddy, M. A.; Bhanumathi, N.; Rao, K. R. New J. Chem. 2001, 25,
221.
17. For our recent contributions in synthesis of various hetereocyles using InCl3
catalyst, see: (a) Dey, S.; Pal, C.; Nandi, D.; Giri, V. S.; Zaidlewicz, M.;
Krzeminski, M.; Smentek, L.; Hess, B. A.; Gawronski, J.; Kwit, M.; Babu, N. J.;
Nangia, A.; Jaisankar, P. Org. Lett. 2008, 10, 1373; (b) Dey, S.; Nandi, D.;
Pradhan, P. K.; Giri, V. S.; Jaisankar, P. Tetrahedron Lett. 2007, 48, 2573; (c)
Pradhan, P. K.; Dey, S.; Giri, V. S.; Jaisankar, P. Synthesis 2005, 1779; (d) Pal, B.;
Giri, V. S.; Jaisankar, P. Catal. Commun. 2005, 6, 711.
powdered 3 Å MS (200 mg) was added followed by anhydrous indium
trichloride (22 mg, 10 mol %). To the above mixture, indole (1a, 117 mg,
1 mmol) was added and the stirring was continued for 4 h [monitored by TLC
using 8% MeOH in CHCl3]. Then molecular sieves were filtered off over a thin
pad of celite and the filtrate was evaporated in a rotary evaporator. The residue
was then diluted with water (15 mL) and extracted with CHCl3 (3 Â 25 mL).
The organic layer was separated, washed with brine, and then dried over
anhydrous Na2SO4. Removal of solvent resulted in a sticky solid which was
chromatographed over silica gel [60–120 mesh] using chloroform with an
increasing proportion of methanol as eluent. Elution with 5% methanol in
chloroform gave compound 3a (205 mg, 84%) as white solid. mp: 114–116 °C;
FT-IR (KBr): m ;
max 3052, 2934, 2775, 1462, 1349, 1325, 1052, 743 cmÀ1 1H NMR
(CDCl3, 300 MHz): d 7.64 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.22 (t,
J = 7.5 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 6.67 (s, 1H), 5.27 (s, 2H), 3.54 (s, 2H), 2.39
(br s, 4H), 1.43–1.42 (m, 6H); 13C NMR (CDCl3, 75 MHz): d 135.76, 129.31,
127.04, 121.97, 119.87, 118.97, 111.24, 110.14, 69.62, 54.37 (2C), 53.35, 25.32
(2C), 24.19; HRMS (ESI) Calcd. for C15H20N2NaO [M+Na]+: 267.1473, Found:
267.1489. The X-ray suitable crystals of 3a were obtained from CHCl3.