An expeditious and efficient synthesis of symmetrical tris(indolyl)methanes under catalyst-free conditions in fluorinated alcohols

Article abstract of DOI:10.1016/j.jfluchem.2012.01.002

Hexafluoro-2-propanol (HFIP) is explored as an effective medium for the synthesis of symmetrical tris(indolyl)methanes through the reaction of indole derivatives with orthoesters at room temperature. The solvent (HFIP) can be readily separated from reaction products and recovered in excellent purity for direct reuse.

Full text of DOI:10.1016/j.jfluchem.2012.01.002

Journal of Fluorine Chemistry 136 (2012) 8–11
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
An expeditious and efficient synthesis of symmetrical tris(indolyl)methanes
under catalyst-free conditions in fluorinated alcohols
*
Samad Khaksar , Seyed Mohammad Vahdat, Mahnaz Gholizadeh, Saeed Mohammadzadeh Talesh
Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Hexafluoro-2-propanol (HFIP) is explored as an effective medium for the synthesis of symmetrical
tris(indolyl)methanes through the reaction of indole derivatives with orthoesters at room temperature.
The solvent (HFIP) can be readily separated from reaction products and recovered in excellent purity for
direct reuse.
Received 8 November 2011
Received in revised form 3 January 2012
Accepted 13 January 2012
Available online 24 January 2012
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Fluorinated alcohols
Tris(indolyl)methane
Nucleophilicity
Reusable
1. Introduction
associated with reported protocols as well as increasing importance
of tris(indolyl)methane derivatives in pharmaceuticaland industrial
Recently, indolederivativeshaveattractedmuchattentiondueto
the broad scope of their biological activity [1–6]. Among various
indole analogs, tris(indolyl)methane derivatives (TIMs) display
versatile biological and pharmacological activities [7]. TIMs show
an affinity for hydride ions [8] and dye materials [9,10] and can
potentially be utilized as acceptors for these substances. They are
chemistry, there still remains a high demand for the development of
more general, efficient, and eco-friendly protocol to assemble such
scaffolds. The development of cost-effective and environmentally
benign catalytic systems is one of the main themes of contemporary
organic synthesis. From the viewpoint of green chemistry, the
fluorinated alcohols are attracting growing interest as alternative
reaction media for various organic transformations [24–39].
Fluorinated alcohols are solvents with peculiar properties [40] such
aslow nucleophilicity, highpolarity, stronghydrogenbonddonating
ability and ability to solvate water. Reactions in fluorinated solvents
are generally selective and without effluents, allowing thus a facile
isolation of the product and a recovery of the solvent by distillation.
As part of our ongoing programme to develop highly efficient and
environmentally benign synthetic processes [41–49], we have
developed a mild and expedient synthesis of symmetrical tris(in-
dolyl)methanes (TIMs) under mild reaction conditions in hexa-
fluoro-2-propanol (HFIP) (Scheme 1).
also effective frameworks for the construction of very bulky p-acidic
phosphine ligands [11]. Moreover, the TIMs motifs is present in
many products isolated from bacteria [12] serve as bacterial
metabolic [13] and cytotoxic agents [14]. As a result of their
biological and synthetic importance, a number of synthetic methods
for preparation of tris(indolyl)methane derivatives have been
reported in the literature by reaction of indole derivatives with
various orthoesters in the presence of catalysts [15–20]. TIMs are
also obtained from the reaction of indoles and acetic–formic
anhydride [21] or diethoxycarbenium salts [22] and N,N-dimethyl-
formamide dimethyl acetal [23]. These protocols often suffer from
disadvantages, however, suchas the hightoxicity orcorrosiveness of
the promoters employed, or the requirement to use expensive
reagents. Furthermore, on completion of the reaction, the Lewis acid
is often destroyed in an aqueous work-up, liberating quantities of
waste that must be disposed of. Keeping in view the disadvantages
2. Results and discussion
In preliminary experiments, indole (3 mmol) in 1 mL of
trifluoroethanol (TFE) was allowed to stir at room temperature
with trimethylorthoformate. After 10 h, only 50% of expected
tris(indol-3-yl)methane 3a was obtained. Our efforts were then
focused on HFIP. As a strong H-bond donor (a = 1.96, pKa = 9.3),
with high ionizing power (YOTs = 3.79), and polarity (Ps = 11.08), it
could activate the orthoesters towards the nucleophilic attack [45].
* Corresponding author. Fax: +98 121 2517071.
E-mail addresses: S.khaksar@iauamol.ac.ir, samadkhaksar@yahoo.com
(S. Khaksar).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.01.002

S. Khaksar et al. / Journal of Fluorine Chemistry 136 (2012) 8–11
9
R
R1
N
R1
R2
O
R1
N
O
HFIP
r.t, 15-60 min
O
+
R
N
R1
R2
R
1
2
N
R= H, Me
R
R1= H, Br, OMe
R2= H, Me
3
Scheme 1. Synthesis of tris(indolyl)methanes 3 in HFIP.
The reaction was then investigated in HFIP: where a solution of
indole (3 mmol), trimethylorthoformate (1 mmol) in HFIP (Table 1,
entry 1) was stirred at room temperature. The reaction was
remarkably fast (20 min) and, after distilling off the HFIP, the
tris(indol-3-yl)methane 3a was isolated in 95% yield. Further
experiments revealed that a similar procedure is applicable for the
preparation of a wide range of compounds analogous to adduct 3
(Table 1). As shown in Table 1, for both reactive and unreactive
substituted indoles, the condensation proceeded smoothly in HFIP
to provide the desired products in excellent yields (88–98%) at
room temperature. For all the substrates, the reaction time was
reduced drastically even under ambient conditions in contrast to
reported methods [15–20], and better yields were obtained. As it is
expected, N-methyl indole provided better yields of products in
comparison with indole under the same reaction conditions. When
trimethylorthoacetate was used, the reaction time would get
longer and the yield was lower, which was presumably due to the
fact that trimethylorthoacetate was more sterically hindered than
the trimethylorthoformate. The reactions were clean and the
products were obtained in high yields without the formation of any
side products such as N-alkylated product. To further expand the
scope of the reaction, we next examined the reactions using
different molar ratio of both substrates. Surprisingly, in all cases
the symmetrical tris(indolyl)methanes were the main product. The
possible mechanism is shown in Scheme 2.
In this process, HFIP act as Brønsted acid [50] and play a
significant role in increasing the electrophilic character of the
orthoester. Interestingly, the reaction did not proceed to comple-
tion when either ethanol or water alone was used as solvent, even
at higher temperatures.
Table 1
Synthesis of symmetrical tris(indolyl)methanes in HFIP.
Entry
1
Indole
Ortho-ester
CH(OMe)3
Time (min)
20
Product
Yield %ref
9520
3a
N
H
2
3
4
CH(OEt)3
20
60
25
3b
3c
3d
9220
9020
9220
N
H
CH3CH(OMe)3
CH(OMe)3
N
H
Me
Me
N
H
5
CH(OEt)3
20
3e
9415
N
H
6
7
3 CH(OMe)3
CH(OMe)3
40
30
3f
9415
Me
N
H
3g
9020
Me
Me
N
H
8
CH(OEt)3
30
3g
9015
N
H

10
S. Khaksar et al. / Journal of Fluorine Chemistry 136 (2012) 8–11
Table 1 (Continued )
Entry
9
Indole
Ortho-ester
CH(OEt)3
Time (min)
20
Product
Yield %ref
9620
3h
MeO
N
H
10
11
12
13
CH(OMe)3
CH(OEt)3
30
30
15
30
3i
3j
3k
3l
9020
8820
9816
9516
Br
Br
N
H
N
N
H
CH(OMe)3
CH3CH(OMe)3
N
Me
N
Me
MeO
H
HFIP
H
MeO
O
O
OMe
OMe
OMe
O
indole
HFIP
indole
H
-2 MeOH
N
N
H
H
N
H
HFIP
H
HFIP
HFIP
-MeOH
CH
3
indole
N
N
H
N
H
HFIP
Scheme 2. Proposed mechanism for the synthesis of tris(indolyl)methanes.
After the reaction, HFIP can be easily separated (by distillation)
andreused without decrease initsactivity. Forexample, the reaction
of indole and trimethylorthoformate afforded the corresponding
tris(indol-3-yl)methane derivative in 95%, 95%, 93%, 92% and 92%
isolatedyieldoverfivecycles. The notableadvantagesofthismethod
are the operational simplicity, direct use of indoles and inexpensive,
reusable and non-toxic HFIP medium which render this method an
important alternative to previously reported methods.
evaporation of the HFIP (for liquid products) to yield the highly
pure tris-indolyl methane derivatives. The physical data (mp, IR,
and NMR) of known compounds were found to be identical with
those reported in the literature. Spectroscopic data for selected
examples are shown below.
4.1.1. Tri(1H-indol-3-yl)methane (3a)
mp = 238–240 8C, IR (KBr): 3395, 3048, 1484, 1455, 1418, 1336,
1216, 1009, 801 cmÀ1. 1H NMR (CDCl3, 400 MHz):
d = 6.19 (s, 1H),
3. Conclusions
6.88 (t, J = 7.8 Hz, 3H), 6.92 (s, 3H), 7.03 (t, J = 7.8 Hz, 3H), 7.37 (d,
J = 7.8 Hz, 3H), 7.47 (d, J = 7.8 Hz, 3H), 7.92 (br s, 3H, NH); 13C NMR
In conclusion, we have developed an efficient methodology for
the symmetrical tris(indolyl)methanes through the reaction of
indole derivatives with orthoesters at room temperature. The
reaction is performed in HFIP as solvent and requires no use of any
acid or metal promoter.
(CDCl3, 100 MHz):
127.5, 137.4.
d = 31.5, 111.4, 118.4, 119.2, 119.7, 121.1, 123.5,
4.1.2. Tris(2-methyl-1H-indol-3-yl)methane (3f)
mp = 333–335 8C, IR (neat): 3393, 3051, 2908, 1618, 1461,
1427, 1340, 1297, 1218, 1010, 816, 747 cmÀ1 1H NMR (CDCl3,
.
4. Experimental
400 MHz):
(d, J = 8.1 Hz, 3H), 6.85 (t, J = 8.1 Hz, 3H), 7.18 (d, J = 8.1 Hz, 3H),
7.93 (br s, 3H, NH); 13C NMR (CDCl3, 100 MHz):
= 10.5, 28.6,
d = 1.91 (s, 9H), 6.08 (s, 1H), 6.61 (t, J = 8.1 Hz, 3H), 6.78
4.1. Typical experimental procedure
d
101.1, 111.2, 113.0, 117.8, 124.2, 127.8, 132.4, 152.4.
To a solution containing trimethylorthoformate (1 mmol), in
HFIP (0.5 mL) was added the indole (3 mmol) and the mixture
was vigorously stirred at r.t. for appropriate reaction time. After
completion of the reaction as indicated by TLC, the products
were isolated by filtration (for solid products) or after selective
4.1.3. Tris(5-methoxy-1H-indol-3-yl)methane (3h)
mp = 221–223 8C, IR (KBr): 3413, 2932, 1620, 1579, 1483, 1450,
1290, 1212, 1172, 1039, 842 cmÀ1 1H NMR (CDCl3, 400 MHz):
= 3.61 (s, 9H), 6.04 (s, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 3H), 6.94 (d,
;
d

S. Khaksar et al. / Journal of Fluorine Chemistry 136 (2012) 8–11
11
[16] G. Da-Gong, J. Shun-Jun, Chinese J. Chem. 26 (2008) 578–582.
[17] E. Akgun, U. Pindur, M. Muller, J. Heterocycl. Chem. 20 (1983) 1303–1305.
[18] E. Akgun, M. Tunali, U. Pindur, Arch. Pharm. 320 (1987) 397–401.
J = 1.2 Hz, 3H), 6.97 (d, J = 2.4 Hz, 3H), 7.27 (d, J = 8.7 Hz, 3H), 7.92
(br s, 3H, NH); 13C NMR (CDCl3, 100 MHz):
= 31.7, 55.1, 102.1,
d
111.0, 112.0, 118.8, 124.2, 127.9, 132.5, 153.4.
[19] M. Chakrabarty, S. Sarkar, A. Linden, B.K. Stein, Synth. Commun. 34 (2004)
1801–1810.
[20] Z.H. Zhang, J. Lin, Synth. Commun. 37 (2007) 209–215.
[21] J. Bergman, J. Heterocycl. Chem. 8 (1971) 329–330.
[22] U. Pindur, C. Flo, Arch. Pharm. 323 (1990) 79–81.
[23] L. Selic, B. Stanovnik, Tetrahedron 57 (2001) 3159–3164.
[24] I.A. Shuklov, N.V. Dubrovina, A. Børner, Synthesis (2007) 2925–2943.
[25] J.-P. Be´gue´, D. Bonnet-Delpon, B. Crousse, Synlett 1 (2004) 18–29.
[26] M. Westermaier, H. Mayr, Org. Lett. 8 (2006) 4791–4794.
[27] M.O. Ratnikov, V.V. Tumanov, W.A. Smit, Angew. Chem. Int. Ed. 47 (2008)
9739–9742.
4.1.4. Tris(5-bromo-1H-indol-3-yl)methane (3i)
mp = 260–262 8C, IR (KBr): 3428, 2924, 1562, 1457, 1417, 1213,
1090, 868 cmÀ1. 1H NMR (CDCl3, 400 MHz):
= 6.06 (s, 1H), 6.98 (s,
d
3H), 7.13 (d, J = 8.4 Hz, 3H), 7.32 (d, J = 8.4 Hz, 3H), 7.50 (s, 3H), 7.90
(br s, 3H, NH); 13C NMR (CDCl3, 100 MHz):
118.1, 122.0, 123.9, 125.6, 129.0, 135.9.
d = 30.9, 111.4, 114.2,
[28] M. Westermaier, H. Mayr, Chem. Eur. J. 14 (2008) 1638–1647.
[29] K. De, J. Legros, B. Crousse, D. Bonnet-Delpon, J. Org. Chem. 74 (2009) 6260–6265.
[30] N. Nishiwaki, R. Kamimura, K. Shono, T. Kawakami, K. Nakayama, K. Nishino, T.
Nakayama, K. Takahashi, A. Nakamura, T. Hosokawa, Tetrahedron Lett. 51 (2010)
3590–3592.
[31] J. Choy, S. Jaime-Figueroa, T. Lara-Jaime, Tetrahedron Lett. 51 (2010) 2244–2246.
[32] Y. Kuroiwa, S. Matsumura, K. Toshima, Synlett (2008) 2523–2525.
[33] H. Tanabe, J. Ichikawa, Chem. Lett. 39 (2010) 248–249.
[34] M. Yokota, D. Fujita, J. Ichikawa, Org. Lett. 9 (2007) 4639–4642.
[35] R. Ben-Daniel, S.P. de Visser, S. Shaik, R. Neumann, J. Am. Chem. Soc. 125 (2003)
12116–12117.
4.1.5. Tri(1-methyl-1H-indole-3-yl)methane (3l)
mp = 264–266 8C, IR (KBr): 3048, 1484, 1455, 1418, 1336, 1216,
1009, 801 cmÀ1. 1H NMR (CDCl3, 400 MHz):
= 2.51 (s, 3H), 3.71 (s,
9H), 6.88 (s, 3H), 6.93 (t, J = 7.8 Hz, 3H), 7.17 (t, J = 7.8 Hz, 3H), 7.37
(d, J = 7.8 Hz, 3H), 7.47 (d, J = 7.8 Hz, 3H), 7.92 (br s, 3H, NH); 13C
d
NMR (CDCl3, 100 MHz):
d = 26.7, 34.1, 42.2, 112.4, 117.4, 119.2,
119.8, 122.1, 123.5, 128.5, 137.2.
References
[36] S. Kobayashi, H. Tanaka, H. Amii, K. Uneyama, Tetrahedron 59 (2003) 1547–1552.
[37] K. Neimann, R. Neumann, Org. Lett. 2 (2000) 2861–2863.
[38] K.S. Ravikumar, Y.M. Zhang, J.P. Be´gue´, D. Bonnet-Delpon, Eur. J. Org. Chem. (1998)
2937–2940.
[39] J. Legros, B. Crousse, D. Bonnet-Delpon, J.P. Be´gue´, Eur. J. Org. Chem. (2002)
3290–3293.
[1] R.J. Sundberg, The Chemistry of Indoles, Academic Press, New York, 1970.
[2] B. Holmstedt, J.E. Lindgren, T. Plowman, L. Rivier, R.E. Schultes, O. Tovar, Indole
Alkaloids in Amazonian Myristicaceae: Field and Laboratory Research, Harvard
Botanical Museum Leaflets, 1980.
[3] J.E. Saxton, Chemistry Heterocyclic Compounds, Indoles, vol. 25, Wiley, New York,
1983.
[40] L. Eberson, M.P. Hartshorn, O. Persson, F. Radner, Chem. Commun. (1996)
2105–2112.
[41] A. Heydari, S. Khaksar, M. Tajbakhsh, Synthesis 19 (2008) 3126–3130.
[42] A. Heydari, S. Khaksar, M. Tajbakhsh, Tetrahedron Lett. 50 (2009) 77–80.
[43] A. Heydari, S. Khaksar, M. Tajbakhsh, H.R. Bijanzadeh, J. Fluorine Chem. 130
(2009) 609–614.
[44] A. Heydari, S. Khaksar, M. Tajbakhsh, H.R. Bijanzadeh, J. Fluorine Chem. 131
(2010) 106–110.
[45] S. Khaksar, A. Heydari, M. Tajbakhsh, S.M. Vahdat, J. Fluorine Chem. 131 (2010)
1377–1381.
[46] M. Tajbakhsh, R. Hosseinzadeh, H. Alinezhad, S. Ghahari, A. Heydari, S. Khaksar,
Synthesis (2011) 490–496.
[47] N. Montazeri, S. Khaksar, A. Nazari, S.S. Alavi, S.M. Vahdat, M. Tajbakhsh,
J. Fluorine Chem. 132 (2011) 450.
[48] S. Khaksar, S.M. Ostad, J. Fluorine Chem. 132 (2011) 937.
[49] S. Khaksar, E. Fattahi, E. Fattahi, Tetrahedron Lett. 52 (2011) 5943–5946.
[50] D. Vuluga, J. Legros, B. Crousse, A.M.Z. Slawin, C. Laurence, P. Nicolet, D. Bonnet-
Delpon, J. Org. Chem. 76 (2011) 1126–1133.
[4] R.J. Sundberg, Indoles, Academic Press, San Diego, CA, 1996.
[5] G.W. Gribble, J. Chem. Soc. Perkin Trans. 1 (2000) 1045–1075.
[6] G.R. Humphrey, J.T. Kuethe, Chem. Rev. 106 (2006) 2875–2911.
[7] A. review:, M. Shiri, M.A. Zolfigol, H.G. Kruger, Z. Tanbakouchian, Chem. Rev. 110
(2010) 2250–2293.
[8] M.N. Preobrazhenskaya, A.M. Korolev, I.I. Rozhkov, L.N. Yudina, E.I. Lazhko, E.
Aiello, A.M. Almerico, F. Mingoia, Farmaco 54 (1999) 265–274.
[9] J. Harly-Mason, J.D. Bulock, Biochem. J. 51 (1952) 430–432.
[10] R. Muthyala, A.R. Katritzky, X. Lan, Dyes Pigments 25 (1994) 303–324.
[11] M.R. Mason, T.S. Barnard, M.F. Segla, B. Xie, K. Kirschbaum, J. Chem. Crystallogr. 33
(2003) 531–540.
[12] R. Veluri, I. Oka, I. Wagner-Dobler, H. Laatsch, J. Nat. Prod. 66 (2003) 1520–1523.
[13] T.R. Garbe, M. Kobayashi, M. Shimizu, N. Takesue, M. Ozawa, H. Yukawa, J. Nat.
Prod. 63 (2000) 596–598.
[14] J. Li, L. Wang, B. Li, G. Zhang, Heterocycles 60 (2003) 1307–1315.
[15] Z. Xiao-Fei, J. Shun-Jun, S. Xiao-Ming, Chinese J. Chem. 26 (2008) 413–416.