Anhydrous CeCl3 catalyzed C3-selective propargylation of indoles with tertiary alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.06.112

Anhydrous CeCl₃ was successfully used as catalyst for the synthesis of several 3-propargyl indoles in good yields through the reaction of indole with propargyl alcohols in nitromethane.

Full text of DOI:10.1016/j.tetlet.2010.06.112

Tetrahedron Letters 51 (2010) 4560–4562
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Anhydrous CeCl3 catalyzed C3-selective propargylation of indoles
with tertiary alcohols
*
Claudio C. Silveira , Samuel R. Mendes, Lucas Wolf, Guilherme M. Martins
Departamento de Química, Universidade Federal de Santa Maria, UFSM, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Anhydrous CeCl3 was successfully used as catalyst for the synthesis of several 3-propargyl indoles in good
yields through the reaction of indole with propargyl alcohols in nitromethane.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 May 2010
Revised 21 June 2010
Accepted 23 June 2010
Available online 27 June 2010
Keywords:
Indole
3-Propargyl indoles
Cerium(III) chloride
1. Introduction
we decided to study the electrophilic substitution reaction of in-
doles (1) with propargyl alcohols (2) to obtain 3-propargyl indoles
Facile access to indole and their derivatives is of general interest
since they are widely present in bioactive metabolites of numerous
compounds isolated from natural sources.1 Thus, the selective
functionalization of indoles has attracted considerable attention.2
From the synthetic point of view, the direct catalytic substitution
of indoles with propargyl alcohols is a very interesting reaction
due to the fact that water is the only by-product of the process.
Thus, several approaches for the preparation of 3-propargyl in-
doles have been described in recent years. The most useful ap-
proaches are based on transition-metal,3 Lewis4 and Brønsted
acid5 catalyzed methodologies for the direct substitution reaction
of alcohols with indoles. However, major drawbacks are still pres-
ent such as accessibility, substrate compatibility and stability of
these reagents. Hence, a mild general approach for the 3-propargy-
lation of indoles is still necessary.
Cerium(III) chloride has emerged as a very useful Lewis acid
imparting high regio- and chemoselectivity in various chemical
transformations over the past few years. It is an inexpensive,
nontoxic and water-tolerant catalyst and has been used in several
different forms, alone as heptahydrate, anhydrous, and in combi-
nation with NaI.6 The salt has also been used in solid supports,7
which modify its reactivity. Organocerium compounds also find
extensive use in organic synthesis.8
(3, Scheme 1).
2. Results and discussion
Initially, we chose indole and 2,4-diphenylbut-3-yn-2-ol (2a) as
the starting materials to establish the best conditions for the reac-
tion. At first, we found that by using 0.3 equiv of CeCl3 in MeCN, the
3-propargyl indole (3a) was obtained in 10% yield after stirring
under reflux for 5 h (Table 1, entry 1). We employed other solvents,
such as glycerin, DMA, i-PrOH and MeNO2 (Table 1, entries 2–5).
The best yield was obtained with MeNO2 (60% isolated yield; Table
1, entry 5).
The use of larger amounts of CeCl3 had no effect on the yield of the
reaction and the time to completion of the reaction was the same
(Table 1, entry 6). However, when 0.1 equiv of dry CeCl3 was used,
25% of 3a was obtained (Table 1, entry 7). Replacing anhydrous CeCl3
with CeCl3Á7H2O, gave no product (Table 1, entry 8).
In a search for an even higher yield, we decided to employ ZnO
as an additive, due to the fact that metal–oxides were described as
a convenient and practical base that forms a strong metal–nitrogen
R2
R1
In view of our interest in the development of new, cleaner
R3
X1
X2
OH
R2
CeCl3 (30 mol%)
ZnO (1 equiv.)
MeNO2, reflux, Ar
methods for classical reactions promoted by cerium(III) species,9
R3
X1
X2
R1
N
N
X3
1 a-e
2 a-g
3 a-l
X3
* Corresponding author. Tel./fax: +55 55 32208754.
E-mail address: silveira@quimica.ufsm.br (C.C. Silveira).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.112

C. C. Silveira et al. / Tetrahedron Letters 51 (2010) 4560–4562
4561
Table 1
ZnO (1 equiv) and CeCl3 (30 mol %) in MeNO2, which increased
the product yield to 87% after 2 h (Table 1, entry 9).
Optimization of conversion of 1a–3aa
Then, the effect of the amounts of the zinc oxide and cerium
chloride was evaluated. When the reaction was performed with
1 equiv of ZnO in the absence of CeCl3, no product was obtained
(Table 1, entry 12); however, employing 30 mol % of CeCl3 gave
the best conversions. Lowering the reaction temperature to 65 °C
(oil bath temperature) furnished very similar product yields, but
a longer reaction time was required (6 h, Table 1, entry 14).
Thus, the best conditions for the C3-selective propargylation of
indoles with tertiary alcohols were the use of CeCl3 (0.3 mmol),
ZnO (1.0 mmol), indole (1.0 mmol), propargyl alcohol (1.1 mmol),
in refluxing MeNO2 (2 mL), under argon (Scheme 1).11
With these optimized conditions in hand, we next extended the
transformation to some other examples in order to find out the
scope and limitations of the present method. (Table 2, Scheme
1).11 For almost all the studied examples, the 3-propargyl indoles
3 were obtained in good yields after stirring at reflux temperature
for 2–3 h (Table 2).
Entry Solvent
CeCl3
(equiv)
ZnO
(equiv)
Temp
(°C)
Time
(h)
Yield
(%)
1
2
3
MeCN
Glycerin
DMA
0.3
0.3
0.3
0.3
0.3
0.5
0.1
0.3c
0.3
0.2
0.5
—
—
—
—
—
—
—
—
—
1.0
1.0
1.0
1.0
0.5
1.0
Reflux
90
100
5
5
5
3
3
3
3
5
2
5
2
5
3
6
10
b
—
—
b
4
5
6
7
8
9
10
11
12
13
14
i-PrOH
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
65
49
60
60
25
b
—
87
68
86
b
—
0.3
0.3
69
84
a
Reaction conditions: indole (1a, 1.0 mmol); 2,4-diphenylbut-3-yn-2-ol (2a,
1.1 mmol), and solvent (2 mL).
b
No reaction.
Reaction performed with CeCl3Á7H2O.
c
The exceptions were observed when secondary and dimethyl
alcohols were used, which furnished the products 3d and 3e in
lower yields (Table 2, entries 4 and 5). Also, the use of an hexyne
derivative gave lower yield of product 3g which was observed, as
a consequence of the lower stabilization of the charged intermedi-
bond and may increase the nucleophilicity of the annular carbon
centers of the heteroarene.10 The reaction was carried out with
Table 2
Synthesis of 3-propargyl indoles 3
Entry
Product 3
Time (h)
Yielda (%)
Entry
7
Product 3
Time (h)
Yielda (%)
1
2
87
3
55
3a
3g
N
H
N
H
Cl
Br
2
3
2
2
78
85
8
9
2
2
88
80
3h
3b
N
N
H
H
O
Cl
Br
3c
3i
N
H
N
H
O
Br
4
5
12
12
41
28
10
11
2
2
82
79
3d
3j
N
N
H
H
3e
N
H
3k
N
O
H
6
2
72
12
3
71
3l
3f
N
N
H
CH3
Yields of pure products isolated by column chromatography (hexanes/AcOEt, 98:2) and identified by GC–MS, 1H and 13C NMR.
a

4562
C. C. Silveira et al. / Tetrahedron Letters 51 (2010) 4560–4562
Tetrahedron Lett. 2007, 48, 7160; (c) Yadav, J. S.; Subba Reddy, B. V.;
Raghavendra Rao, K. V.; Narayana Kunar, G. G. K. S. Synthesis 2007, 3205; (d)
Srihari, P.; Bhunia, D. C.; Sreedhar, P.; Mandal, S. S.; Shyam Sunder Reddy, J.;
Yadav, J. S. Tetrahedron Lett. 2007, 48, 8120.
ate compared to a phenyl group on the propargylic alcohol. When
5-bromo-1H-indole was used, the respective brominated products
were obtained with yields compared to indole (Table 2, entries 8–
10).
5. (a) Sanz, R.; Gohain, M.; Miguel, D.; Martínez, A.; Rodríguez, F. Synlett 2009,
1985; (b) Sanz, R.; Miguel, D.; Álvarez-Gutiérrez, J. M.; Rodríguez, F. Synlett
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6006; (e) Le Bras, J.; Muzart, J. Tetrahedron 2007, 63, 7942.
6. (a) Sabitha, G.; Yadav, J. S In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley-VCH: Weinheim, 2006; (b) Bartoli, G.; Di Antonio, G.;
Giovannini, R.; Giuli, S.; Lanari, S.; Paoletti, M.; Marcantoni, E. J. Org. Chem.
2008, 73, 1919; (c) Yadav, J. S.; Subba Reddy, B. V.; Suresh Reddy, Ch.; Krishna,
A. D. Tetrahedron Lett. 2007, 48, 2029; (d) Meng, Q.; Sun, Y.; Ratovelomanana-
Vidal, V.; Genêt, J. P.; Zhang, Z. J. Org. Chem. 2008, 73, 3842.
7. (a) Ahmed, N.; Van Lier, J. E. Tetrahedron Lett. 2007, 48, 13; (b) Bartoli, G.; Bosco,
M.; Giuli, S.; Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri, L.; Torregiani, E. J.
Org. Chem. 2005, 70, 1941; (c) Bartoli, G.; Bartolacci, M.; Giuliani, A.;
Marcantoni, E.; Massaccesi, M.; Torregiani, E. J. Org. Chem. 2005, 70, 169; (d)
Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2003, 68, 4594.
It is worth mentioning that the indole nitrogen does not require
protection. Nevertheless, we also performed the transformation
with a nitrogen protected indole derivative. When the reaction
was carried out with 1-methyl-1H-indole and 2,4-diphenylbut-3-
yn-2-ol and in the presence of ZnO, the corresponding product 3l
was obtained in 71% yield after 3 h. Since in this case no N–H bond
is present, the same reaction was also performed in the absence of
ZnO. However, reduced yields were observed (64%, mean of three
reactions), indicating that the beneficial effect of ZnO is still pres-
ent. However, when 1-tosyl-1H-indole was used, no reaction was
observed even after several hours of reaction, presumably as a con-
sequence of the deactivation effect of the tosyl group.
8. (a) Bartoli, G.; Belluci, M. C.; Bosco, M.; Dalpozzo, R.; De Nino, A.; Sambri, L.;
Tagarelli, A. Eur. J. Org. Chem. 2000, 99; (b) Liu, H. J.; Shia, K. S.; Shang, X.; Zhu, B.
Y. Tetrahedron 1999, 55, 3803.
9. (a) Silveira, C. C.; Mendes, S. R.; Wolf, L.; Martins, G. M. Tetrahedron Lett. 2010,
51, 2014; (b) Silveira, C. C.; Mendes, S. R.; Libero, F. M. Synlett 2010, 790; (c)
Silveira, C. C.; Mendes, S. R.; Ziembowicz, F. I.; Lenardão, E. J.; Perin, G. J. Braz.
Chem. Soc. 2010, 21, 371; (d) Silveira, C. C.; Mendes, S. R.; Libero, F. M.;
Lenardão, E. J.; Perin, G. Tetrahedron Lett. 2009, 50, 6060; (e) Silveira, C. C.;
Mendes, S. R.; Rosa, D. D.; Zeni, G. Synthesis 2009, 4015; (f) Silveira, C. C.;
Mendes, S. R. Tetrahedron Lett. 2007, 48, 7469.
In conclusion, we have described a convenient method for the
preparation of 3-propargyl indoles from the propargyl alcohols in
a reaction mediated by cerium(III) chloride. The method is simple,
general and the products are obtained in good yields.
Acknowledgments
This project was funded by MCT/CNPq, and CAPES. G.M.M.
thanks FAPERGS for an undergraduate fellowship.
10. (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; (b)
Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580; (c) Sezen, B.; Sames, D. J.
Am. Chem. Soc. 2003, 125, 5274.
11. General procedure for the synthesis of 3-propargyl indoles: To a mixture of
MeNO2 (2 mL), indole (1, 1.0 mmol) and propargyl alcohol (2, 1.1 mmol), under
Ar, was added anhydrous CeCl3 (0.072 g, 0.3 mmol) and ZnO (0.081 g,
1.0 mmol). The reaction mixture was then heated under reflux for the time
indicated in Table 2. The reaction mixture was followed by TLC. Next, the
reaction mixture was cooled to rt and water (20 mL) was added. The mixture
was extracted with ethyl acetate (3 Â 10 mL), the organic phase was washed
with brine and dried over anhydrous MgSO4. The solvent was removed under
reduced pressure and the residue purified by chromatography on silica gel
(ethyl acetate–hexanes, 02:98) to afford pure products (3a–l). Spectral data of
selected compounds: 3a:5b mp 32–35 °C. 1H NMR (200 MHz, CDCl3): d = 7.77
(br s, 1H), 7.60–6.92 (m, 15 H), 2.07 (s, 3H). 13C NMR (50 MHz, CDCl3):
d = 146.1, 137.0, 131.6, 128.1, 127.7, 126.5, 126.4, 125.9, 125.6, 123.7, 121.9,
121.5, 121.0, 119.2, 111.1, 95.0, 83.0, 68.9, 39.8, 31.0. MS: m/z (%) 321 (M+, 69),
306 (100), 244 (18), 152 (19); 3l:5b 1H NMR (200 MHz, CDCl3): d = 7.62–6.92
(m, 15H), 3.71 (s, 3H), 2.09 (s, 3H). 13C NMR (50 MHz, CDCl3): d = 146.2, 137.8,
131.6, 129.0 (2C), 127.6, 126.6, 126.4, 126.2, 126.1, 123.9, 121.5, 121.2, 120.2,
118.8, 109.1, 95.2, 83.0, 39.8, 32.7, 31.0. MS: m/z (%) = (M+, 60), 320 (100), 258
(17), 159 (18), 127 (7), 77 (4).
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