Benzylation of β-dicarbonyl compounds and 4-hydroxycoumarin using TMSOTf catalyst: A simple, mild, and efficient method

Article abstract of DOI:10.1016/j.tetlet.2010.08.019

The direct benzylation of 1,3-dicarbonyl compounds and 4-hydroxycoumarin with a wide variety of benzylic alcohols was achieved using trimethylsilyl trifluoromethanesulfonate as an efficient catalyst. The reaction proceeded under very mild conditions at ro

Full text of DOI:10.1016/j.tetlet.2010.08.019

Tetrahedron Letters 51 (2010) 5454–5458
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Tetrahedron Letters
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Benzylation of b-dicarbonyl compounds and 4-hydroxycoumarin using
TMSOTf catalyst: a simple, mild, and efficient method
⇑
Palani Theerthagiri, Appaswami Lalitha
Department of Chemistry, Periyar University, Salem 636 011, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct benzylation of 1,3-dicarbonyl compounds and 4-hydroxycoumarin with a wide variety of ben-
zylic alcohols was achieved using trimethylsilyl trifluoromethanesulfonate as an efficient catalyst. The
reaction proceeded under very mild conditions at room temperature providing the desired products in
good to excellent yields.
Received 25 April 2010
Revised 3 August 2010
Accepted 8 August 2010
Available online 11 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
TMSOTf-catalyzed
Benzylation
Benzylic alcohols
b-Dicarbonyl compounds
4-Hydroxycoumarin
The construction of carbon-carbon bonds is one of the funda-
mental tasks in synthetic organic chemistry.1 Among the several
methods employed to achieve this goal, the alkylation of 1,3-dicar-
bonyl compounds2 is found to be one of the best opted. In view of
the demand for ecologically valuable processes to avoid large
quantities of waste production,3 the catalytic direct alkylation with
unmodified electrophiles such as alcohols, which provides water as
the only by-product, would be a suitable alternative. However, the
main limitation of this strategy is due to the poor leaving ability of
the hydroxyl group. Direct alkylations of 1,3-dicarbonyl com-
pounds with alcohols catalyzed by Pd,4 Co,5 Cu,6 BF3ÁOEt2,7 InCl3,8
InBr,9 FeCl3,10 Bi(OTf),11 Ln(OTf)3 [Ln = La, Yb, Sc, Hf],12 p-toluene-
sulfonic acid,13 dodecyl benzene sulfonic acid,14 molecular io-
to report the use of TMSOTf as a powerful catalyst for the alkyl-
ation of b-dicarbonyl compounds with secondary benzylic alcohols
that proceeded in good to excellent yields (Scheme 1).
Initially, the reaction of 1-phenylethanol (1) with acetyl acetone
(2a) in the presence of TMSOTf was selected as a model reaction to
develop the optimum reaction conditions. The effect of solvents
was investigated and it was observed that the rate of the reaction
and the yield were highly influenced by the solvent used which
may be attributed to the stability of benzylic carbocation and also
the stability of the catalyst in the particular solvent.
The reaction of 1-phenylethanol with acetyl acetone in acetoni-
trile and dichloroethane afforded the product in only moderate
yields. However, the corresponding product was obtained in low
yields even after 6 h when toluene or tetrahydrofuran was used
as the solvent. The best result was achieved in nitromethane,
affording the desired product in 92% yield within 30 min at room
temperature.
dine,15 PMA/SiO2,16 and B(C6F3)3 have been reported. Alkylation
17
reactions using metal-triflates as heterogeneous catalysts have also
been studied.11 Inspired by this, we developed a new, mild alkyl-
ation of 1,3-dicarbonyl compounds with alcohols, where an organ-
ic-triflate could be used as a homogeneous catalyst that leads to
reduction of the reaction time and practical difficulties of using
the heterogeneous catalyst in large-scale experiments. Trimethyl-
silyl trifluoromethane sulfonate (TMSOTf) has recently been shown
to be a versatile reagent in mediating a wide variety of organic
transformations such as aldol and Sakurai allylation,18 bis-silyla-
tion,19 deprotection,20 and Baylis–Hillman reaction.21a As part of
our ongoing research program in the development of new syn-
thetic methods of important organic products,21b herein we wish
We then turned our attention to optimize the amount of cata-
lyst. The conversion was very slow at room temperature when
O
OH
O
O
R1
TMSOTf (15 mol %)
CH3NO2, RT
+
R1
R2
R2
O
1
2
3
R1=R2=Me, 2a
R1=Ph; R2=Me, 2b
R1=Me; R2=OEt, 2c
⇑
Corresponding author. Tel.: +91 427 2345271; fax: +91 427 2345124.
E-mail address: lalitha2531@yahoo.co.in (A. Lalitha).
Scheme 1. Benzylation of b-dicarbonyl compound.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.019

P. Theerthagiri, A. Lalitha / Tetrahedron Letters 51 (2010) 5454–5458
5455
Table 1
TMSOTf-catalyzed alkylation of 1,3-dicarbonyl compounds under the optimum conditions
Entrya
Alcohol
OH
Nu-H
Product
Timeb (h)
0.5
Yieldc (%)
O
O
1
2a
85
78
OH
O
O
2
2a
0.5
Cl
Cl
OH
O
O
3
4
5
6
2a
2a
2a
2a
0.5
1.0
91
67
73
94
OH
OH
O
O
Br
Br
O
O
O
O
0.75
0.5
OH
O
O
OH
O
O
7
8
2a
2a
0.5
0.5
96
90
MeO
OMe
MeO
OMe
OH
O
O
F
F
F
F
OH
OH
O
O
Cl
Cl
9
2a
2a
0.75
0.5
86
88
Cl
Cl
O
O
10
OH
O
O
11
2a
2b
1.0
0.5
65
F3C
F3C
OH
O
O
Ph
12d
82
(continued on next page)

5456
P. Theerthagiri, A. Lalitha / Tetrahedron Letters 51 (2010) 5454–5458
Table 1 (continued)
Entrya
Alcohol
Nu-H
Product
Timeb (h)
0.5
Yieldc (%)
OH
OH
OH
O
O
Br
Ph
13
14
2b
78
Br
O
O
O
Ph
2b
2b
0.5
1.0
71
60
O
O
O
Ph
15
F3C
F3C
O
OH
O
Ph
16
17
2b
2b
0.5
0.5
96
94
Ph
OH
O
Ph
O
MeO
OMe
MeO
OMe
OH
O
Ph
O
18
2b
0.75
92
F
F
F
F
OH
OH
O
Ph
Cl
Cl
O
O
19
2b
2b
2b
0.5
0.5
1.0
90
87
80
Cl
Cl
O
Ph
O
20d
OH
O
Ph
21
F3C
F3C
O
OH
OH
OEt
O
22d
2c
2c
1.0
0.5
54
65
O
OEt
O
23
OH
O
OEt
O
24
2c
0.75
68
MeO
OMe
MeO
OMe

P. Theerthagiri, A. Lalitha / Tetrahedron Letters 51 (2010) 5454–5458
5457
Table 1 (continued)
Entrya
Alcohol
Nu-H
Product
Timeb (h)
Yieldc (%)
OH
O
OEt
O
25
2c
1.0
70
F
F
F
F
OH
OEt
O
Cl
Cl
O
26d
2c
2c
0.5
0.5
65
62
Cl
Cl
OH
O
OEt
O
27
a
Alcohol (1 mmol), 1,3-dicarbonyl compound (2 equiv), TMSOTf (15 mol %) at rt.
Reaction monitored by TLC.
Isolated yield.
b
c
d
Mixture of diastereomers (8:2).
5 mol % of TMSOTf was used as catalyst, then it was found that
15 mol % of TMSOTf was the optimum amount for this transforma-
tion. Encouraged by these results, we next investigated the scope
of the reaction to various alcohols and 1,3-dicarbonyl compounds
under these optimized conditions and the results are summarized
in Table 1.
by-product when alcohol is used as alkylating agent. Thus, we re-
port herein a new and simple method for the synthesis of alkyl-
substituted 4-hydroxycoumarin from substituted 1-phenyletha-
nols and diphenylmethanols, using only a catalytic amount of
TMSOTf (Scheme 2).
Initially, the reaction of 4-hydroxycoumarin (4) and diphenyl-
methanol was chosen as the prototype reaction to develop the
optimum reaction conditions (Scheme 2). It was found that treat-
ing of alcohols (1 equiv) with 4-hydroxycoumarin in the presence
of 15 mol % TMSOTf using nitromethane/dioxane (1:1) as the sol-
vent at room temperature gave the corresponding 3-alkylated 4-
hydroxycoumarin (5a–j) in 91% yield (Table 2).
After optimizing the reaction conditions, we applied the proce-
dure to a series of substituted benzylic alcohols and 4-hydroxy-
coumarin. These results are summarized in Table 2. As shown in
Table 2, various diphenylmethanol derivatives were efficiently re-
acted with 4-hydroxycoumarin and most of them provided the cor-
responding products in good to excellent yields under the
optimized reaction conditions. Whereas, when 1-phenylethanol
was used as the alkylating agent, the desired products were iso-
lated in slightly poor yields irrespective of the electron-withdraw-
ing (Table 2, entry 8) or electron-donating (Table 2, entry 10)
groups on the phenyl ring.
Acetyl acetone with 1-arylethanols in the presence of TMSOTf in
nitromethane gave the corresponding benzylated products, in good
yields (Table 1). However, the reaction of 2a with simple benzyl
alcohol did not proceed under the optimized conditions, whereas
heating at 100 °C yielded only 5–10% of the corresponding benzy-
lated product. However, the reaction of benzoyl acetone (2b) and
ethylacetoacetate (2c) with differently substituted 1-arylethanols
proceeded smoothly to give the corresponding products in good
yields. The presence of electron-donating substituent in para-posi-
tion of the benzene ring in 1-phenylethanol can increase the reac-
tivity, while the electron-withdrawing substituent in para-position
of benzene ring in 1-phenylethanol seems to have a negative effect
on the benzylation reaction (Table 1, entries 2 and 15), whereas,
such effects of electron-donating/electron-withdrawing substitu-
ent are not observed in diphenylmethanol and the reaction pro-
ceeded very smoothly to give the corresponding benzylated
products in good yields (Table 1, entries 7–10).
The alkylation of 4-hydroxycoumarin is undoubtedly one of the
most important and challenging reactions in organic chemistry as
the resulting structures exhibit a wide range of biological activities
such as anti-HIV, antibacterial, and cytotoxic.22 Among the differ-
ent substituted coumarins, 3-(benzyl)-substituted 4-hydroxy-
coumarin stands as a significant class of compound due to the
frequent existence of such structures in pharmaceutically impor-
tant compounds.23 The earlier methods reported for the alkylation
of 4-hydroxycoumarin involve organic halides or boronic acids in
the presence of Pd catalyst or a base.24 A few methods that have
been reported for the C3-alkylation of 4-hydroxycoumarin so far
with alcohols including Yb(OTf)3,13 strong acids, Amberlite IR-
120,25 and recently molecular iodine26 require a longer reaction
time and high temperatures. Therefore, the development of a
new efficient, catalytic method for the direct C3-alkylation of 4-
hydroxycoumarin using alcohols is of greater importance and
highly desirable. Moreover, the TMSOTf has received much atten-
tion as an inexpensive and readily available catalyst due to its
moderate Lewis acidity and also it produces only water as a
The plausible mechanism of this reaction can be speculated
(Scheme 3) based on the experimental observations. One of the
probable routes could be a direct alkylation of C with a stabilized
carbocation derived from the alcohol. Another probable pathway,
we21b and others12a have previously observed that with a catalytic
amount of triflates or other Lewis acids, benzylic alcohols were
rapidly converted to dimeric ethers (A) by elimination of water.
The ether is polarized by triflate to generate the incipient benzylic
carbocation, which may act as the alkylating species. The nucleo-
philic attack of the b-dicarbonyl compound onto the resulting ben-
zyl carbocation produces the final alkylated product after the
OH
O
OH
OH
R3
R3
O
TMSOTf (15 mol%)
CH3NO2, RT
+
O
O
5
R3= alkyl/aryl
4
Scheme 2. Benzylation of 4-hydroxycoumarin.

5458
P. Theerthagiri, A. Lalitha / Tetrahedron Letters 51 (2010) 5454–5458
Table 2
and 4-hydroxycoumarin with various benzylic alcohols as benzy-
lating agents, using TMSOTf as catalyst.27,28 Operational simplicity
and good-to-excellent yields are the key features of this protocol.
TMSOTf-catalyzed alkylation of 4-hydroxycoumarin under the optimum conditions
Entrya
Alcohol
OH
Product
Timeb (h)
Yieldc (%)
Acknowledgments
1
5a
0.5
91
The authors are grateful to Dr. Goutham Das, Bangalore, for giv-
ing permission to carry out the research work.
OH
2
3
4
5b
5c
5d
0.5
0.5
0.5
83
71
81
Supplementary data
MeO
F
OMe
OH
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.019.
F
OH
References and notes
Cl
Cl
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OH
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27. General experimental procedure for the TMSOTf-catalyzed alkylation of 1,3-
dicarbonyl compounds: To a mixture of alcohol (1 mmol) and 1,3-dicarbonyl-
compound (2 mmol) in nitro methane (10 vol), TMSOTf (15 mol %) was added
drop wise. The reaction mixture was stirred at room temperature for 30 min.
After completion of the reaction (monitored by TLC), water was added and
extracted with EtOAc, the organic layer was separated and washed with water,
brine and dried over sodium sulfate and concentrated to furnish the desired
compound. When necessary, the obtained crude sample was purified by column
chromatography.
OH
TMSOTf
H2O
O
O
Ar
Ar
-H+
B
1
R2
Ar
R1
O
O
OH
O
3
R2
R1
R1
R2
2
C
Scheme 3. Plausible mechanism for the TMSOTf-catalyzed benzylation.
28. General experimental procedure for the C3-alkylation of 4-hydroxycoumarins: To a
mixture of 4-hydroxycoumarin (1.0 mmol) and secondary benzyl alcohol
(1.2 mmol) in a MeNO2 (10 ml), TMSOTf (0.15 mmol) was added and the
reaction mixture was stirred for the given time (see Table 2) at room
temperature. After completion of the reaction (monitored by TLC), to the
reaction mixture was added water and extracted with ethyl acetate, the
combined organic phase was dried over anhydrous sodium sulfate and
evaporated under vacuum. The residue was purified by silica gel column
with hexane/ethyl acetate as eluent to afford the corresponding C3-alkylated
4-hydroxycoumarin.
release of proton. Support for this second mechanism was obtained
from the isolation of the symmetric ether at the initial stages (with
in 10 min) whose structure was confirmed by NMR and which after
appropriate time (mentioned in Table 1) was fully converted to the
corresponding alkylated products.
In summary, we have described a simple, convenient, and novel
methodology for the direct benzylation of b-dicarbonyl compounds