Propargylation of aromatic compounds using Ce(OTf)3 as catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.01.046

Ce(OTf)₃ was successfully employed as catalyst for the activation of the hydroxyl group in the Friedel-Crafts reaction of aromatic compounds with propargylic alcohols in nitromethane. The products were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.01.046

Tetrahedron Letters 53 (2012) 1567–1570
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Tetrahedron Letters
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Propargylation of aromatic compounds using Ce(OTf)3 as catalyst
Claudio C. Silveira a, , Samuel R. Mendes b, Guilherme M. Martins a
⇑
a Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
b GAPAM, Departamento de Química, Universidade do Estado de Santa Catarina, 89219-719 Joinville, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Ce(OTf)3 was successfully employed as catalyst for the activation of the hydroxyl group in the Friedel–
Crafts reaction of aromatic compounds with propargylic alcohols in nitromethane. The products were
obtained in good to excellent yields.
Received 21 November 2011
Revised 9 January 2012
Accepted 11 January 2012
Available online 26 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Propargylation
Propargylic alcohol
Aromatic substitution
Cerium(III) triflate
Table 1
Introduction
Optimization of the propargylation reactiona
In view of their suitability for further transformations, propar-
gylic derivatives of aromatic compounds are one of the most useful
motifs found in synthetic intermediates. These compounds can
undergo different modifications affording allenes, alkenes, alkynes,
and enynes.1 In addition, their cyclization is an important strategy
toward various bicyclic systems, such as indenes,2 benzofurans3
and indoles.4
The Friedel–Crafts mediated propargylation of aromatic com-
pounds with propargylic alcohols provides key intermediates for
the synthesis of pharmaceuticals and natural products.5 In recent
years, this transformation has been studied using simple Brønsted6
and Lewis acids,7 as well as complexes involving metals such as
rhenium,8 ruthenium,9 and gold.10
Lanthanide salts are often employed as catalysts in organic
synthesis,11 mainly due to their low toxicity, affordability, stability,
and ease of handling.12 In pursuit of our interest in developing new
methods for reactions catalyzed by cerium(III) salts13 and taking
into account that lanthanide triflates have been reported as pro-
moters of Friedel–Crafts reactions,14 we decided to study the direct
alkylation of aromatic compounds with propargylic alcohols under
Ce(OTf)3 assistance. This salt, which remains scarcely explored as
catalyst,15 is a highly stable and easy to handle solid, readily avail-
able from the reaction of CeCl3 and triflic acid.
Entry Solvent
Ce(OTf)3
(equiv)
Temperature
(°C)
Time
(h)
Yieldb
(%)
1
2
CH3CN
MeNO2
0.3
0.3
40
40
40
40
40
40
40
40
80
rt
3.0
1.75
3.0
3.0
3.0
3.0
3.0
1.75
1.75
3.0
35
75
d
3
Glycerol 0.3
–
d
4
DMA
0.3
0.3
0.1
0.2
0.5
0.3
0.3
–
d
5
6
7
8
9
10
2-PrOH
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
–
40
60
75
75c
75
a
The reactions were performed with phenol (1a, 1.0 mmol) and 2-methyl-4-
phenylbut-3-yn-2-ol (2b, 1.1 mmol).
b
Isolated yield.
Isomeric ratio (o/p) = 1:4.
No reaction.
c
d
Results and discussion
In preliminary experiments, the best reaction conditions
were established by the use of phenol (1a, 1.0 mmol) and 2-
methyl-4-phenylbut-3-yn-2-ol (2b, 1.1 mmol) as starting materi-
als (Table 1). The effect of solvent, amount of catalyst, and reaction
temperature were analyzed. The reaction was tested in CH3CN,
MeNO2, glycerol, DMA, and 2-propanol (entries 1–5), employing
0.1–0.5 equiv of the catalyst (entries 2, 6–8). The results revealed
that both variables affected the reaction, being the use 0.3 equiv
of Ce(OTf)3 in MeNO2 the conditions furnishing the best perfor-
mance (entry 2). A decrease in selectivity was observed when the
transformation was carried out at 80 °C (entry 9, 1:4, o/p ratio),
⇑
Corresponding author. Tel./fax: +55 55 3220 8754.
E-mail address: silveira@quimica.ufsm.br (C.C. Silveira).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.046

1568
C. C. Silveira et al. / Tetrahedron Letters 53 (2012) 1567–1570
Ar
OH
Ce(OTf)3 (30 mol%)
R3
H2O
Ar-H
R3
R1
R1
MeNO2, 40 °C
R2
R2
3a-l
2a-e
1a-e
R1, R2 = H, Me, Ph
R3 = Ph, Bu
Ar = indole, phenol, anisole, o-cresol, furan.
Scheme 1. Ce(OTf)3-catalyzed propargylation of aromatic compounds.
Table 2
Propargylation of aromatic compounds using Ce(OTf)3 as catalyst at 40 °C
Entry
Aromatic compounds
Alcohol
Product
Time (min)
0.50
Yielda (%)
HO
Ph
Me
Ph
HO
Ph
1a
1
92b
Ph
2a
Ph
HO
3a
HO
Me
Me
Ph
2
1a
1a
0.75
75
Me
2b
Ph
HO
3b
OH
3
4
2.50
0.50
65b
95b
Ph
2a
2b
2c
HO
3c
Ph
MeO
1b
Ph
MeO
3d
Me
Me
5
6
1b
1.50
0.25
75
Ph
MeO
HO
3e
Me
Ph
HO
2a
93b
1c
Ph
Me
Me
3f
Me
7
8
9
1c
2b
2a
1.75
1.50
1.50
87
83c
53c
Ph
HO
Ph
Me
3g
Ph
N
H
1d
N
H
3h
HO
Ph
Me
Ph
Ph
Ph
Me
1d
2d
N
H
3i

C. C. Silveira et al. / Tetrahedron Letters 53 (2012) 1567–1570
1569
Table 2 (continued)
Entry
Aromatic compounds
Alcohol
Product
Time (min)
2.75
Yielda (%)
Me
HO
Ph
Ph
10
1d
45c
Me
2e
N
H
3j
Ph
O
11
12
1e
2a
2b
1.50
1.75
77
60
O
Me
Ph
Ph
3k
3l
Me
1e
O
a
Isolated yields.
b
The 2-substituted product was detected by GC–MS in the crude reaction mixture (3a0: 7%; 3c0: 8%; 3d0: 5%; 3f0: 3%).
The reaction performed at 80 °C.
c
while at room temperature slightly longer reaction times were
required for completion (entry 10); therefore, 40 °C was selected
as the most suitable reaction temperature.
success of reaction. However, the cerium catalyst produces an
additional effect evidenced by the high para regioselectivity
obtained, even if the reaction is performed at high temperatures.
In summary, we have developed a simple and efficient Ce(OTf)3-
promoted propargylation of aromatic compounds. The promoter,
which is stable, easy to prepare, and handle, affords good yields
of products, with high regioselectivity and in short reaction times,
being a useful alternative to triflic acid and other usual catalysts.
In order to explore the scope and limitations of the method, the
transformation of Scheme 1 was extended to other examples, un-
der the optimized conditions.16 The corresponding Friedel–Crafts
products were obtained in good yields from aromatic compounds
such as phenol, anisole, o-cresol, furan, and indole (Table 2).
The transformation was highly selective, as determined by 1H
NMR and GC–MS. Propargylation of furan took place selectively at
position 2, while indole gave the 3-substituted derivative, and the
phenolic substrates yielded mainly the corresponding 4-alkylated
products, accompanied by small amounts of the related ortho-
derivatives (entries 1, 3, 4, and 6). In the case of indole, the reaction
was carried out at 80 °C in order to ensure complete consumption of
starting materials in reasonable reaction times.
Acknowledgments
The authors thank FAPERGS (PRONEX-10/0005-1), CAPES and
MCT/CNPq for financial support.
References and notes
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Comparatively lower yields were observed when hindered
propargylic alcohols were employed. For example, the reaction of
phenol (1a) with 1,3-diphenylprop-2-yn-1-ol (2a) gave 92% of 3a
in 0.5 h at 40 °C, while the same reaction with 2-methyl-4-phenyl-
but-3-yn-2-ol (2b) afforded 75% of 3b after 1.75 h. Analogous
variations can also be observed in other cases, suggesting that
steric factors may have some influence on the transformation.
To probe the reaction mechanism, propargylation experiments
of 1a and 1b were carried out with 2-methyl-4-phenylbut-3-yn-
2-ol (2b), under different conditions. It was observed that addition
of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) completely inhib-
ited the reaction, and no product was observed even after 8 h at
40 °C. On the contrary, when triflic acid was employed instead of
Ce(OTf)3, a fast transformation took place at room temperature,
furnishing mixtures of isomers, as detected by GC/MS. In the case
of phenol, the reaction with 5 mol % TfOH gave 60% of a 38:62 (o/
p) mixture, while use of 10 mol % of triflic acid provided a 72% yield
of products, with the same isomeric ratio. The reaction of 1b and
2b in the presence of 10 mol % of triflic acid exhibited a similar
behavior, affording a mixture of all 3 isomers [15:3:82 (o/m/p) by
GC/MS] in an 80% yield. Olah and co-workers proposed that when
Lewis acids are exposed to protic solvents or substrates, Brønsted
acids may be the actual catalysts.17 From the above experiments,
it can be concluded that a mechanism involving a Brønsted acid
is likely to be operating, the reaction being catalyzed by triflic acid,
released to the medium from the cerium salt. Inhibition of the
reaction by DTBMP, an organic base which is known not to interact
with the metal catalyst,18 shows that triflic acid is critical for the
10. (a) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 14180;
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C. C. Silveira et al. / Tetrahedron Letters 53 (2012) 1567–1570
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compounds. Compound 3a:19 1H NMR (200 MHz, CDCl3) d = 7.40–7.46 (m, 4H),
7.19–7.31 (m, 8H), 6.74–6.76 (m, 2H), 5.13 (s, 1H), 4.12 (br s, 1H, OH). 13C NMR
(50 MHz, CDCl3) d = 154.5, 142.0, 134.0, 131.6, 129.1, 128.6, 128.2, 127.9,
127.8, 126.8, 123.5, 115.4, 90.5, 84.7, 42.9. MS (EI): m/z (%) = 284 (100) [M+],
207 (76), 191 (22), 73 (9). Compound 3b:20 1H NMR (200 MHz, CDCl3) d = 7.48–
7.37 (m, 4H), 7.28–7.25 (m, 3H), 6.81 (d, J = 8.5 Hz, 2H), 5.94 (s, 1H), 1.63 (s,
6H). 13C NMR (50 MHz, CDCl3) d = 154.0, 139.3, 131.5, 128.1, 127.6, 126.8,
123.8, 114.9, 96.7, 81.8, 35.7, 31.8. MS (EI): m/z (%) = 236 (19) [M+], 221 (100),
178 (6), 127 (18), 101 (5), 77 (7). Compound 3f:21 1H NMR (200 MHz, CDCl3)
d = 7.40–7.48 (m, 4H), 7.18–7.33 (m, 6H), 7.07–7.18 (m, 2H), 6.64–6.68 (d,
J = 8.1 Hz, 1H), 5.10 (s, 1H), 4.57 (br s, 1H, OH), 2.17 (s, 3H). 13C NMR (50 MHz,
CDCl3) d = 152.7, 142.1, 133.8, 131.6, 130.4, 128.5, 128.2, 127.9, 127.7, 126.7,
126.4, 124.1, 123.5, 114.9, 90.6, 84.6, 42.9, 15.9. MS (EI): m/z (%) = 298 (100)
[M+], 283 (55), 207 (36), 191 (25), 126 (8), 73 (8). Compound 3i:6a 1H NMR
(200 MHz, CDCl3) d = 7.77 (s, 1H), 7.60–6.92 (m, 15H), 2.07 (s, 3H). 13C NMR
(50 MHz, CDCl3): d = 146.1, 137.0, 131.6, 128.1, 127.7, 126.5 (2C), 126.4, 125.9,
125.6, 123.7, 121.9, 121.5, 121.0, 119.2, 111.1, 95.0, 83.0, 39.8, 31.0. MS (EI): m/
z (%) = 321 (69) [M+], 306 (100), 244 (18), 152 (19). Compound 3k:22 1H NMR
(200 MHz, CDCl3) d = 7.49–7.45 (m, 4H), 7.39–7.27 (m, 7H), 6.32–6.26 (m, 2H),
5.25 (s, 1H). 13C NMR (50 MHz, CDCl3) d = 153.7, 142.2, 138.8, 131.7, 128.6,
128.2, 128.1, 127.8, 127.3, 123.1, 110.3, 106.6, 87.4, 83.9, 37.8. MS (EI): m/z
(%) = 258 (100) [M+], 229 (97), 215 (38), 152 (33), 101 (12), 77 (11).
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16. Typical procedure. A mixture of the aromatic substrate (1.0 mmol) and Ce(OTf)3
(0.176 g, 0.3 mmol) in MeNO2 (2 mL) was treated with the appropriate
propargylic alcohol (1.1 mmol). The reaction mixture was stirred at the
temperature indicated in Table 2, and the reaction progress was monitored by
GC–MS. After complete consumption of the aromatic substrate, the reaction
mixture was cooled to rt, H2O (15 mL) was added and the resulting mixture
was extracted with EtOAc (3 ꢀ 10 mL). The combined organic phases were
successively washed with water and brine, and dried over anhydrous MgSO4.
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chromatographed (ethyl acetate–hexanes, 5:95). Spectral data of selected
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