Synthesis of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine

Article abstract of DOI:10.1016/j.tetlet.2014.10.025

The synthesis of a series of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine is described. The reaction protocol is simple, inexpensive and leads to the formation of the corresponding coumarin derivatives in good yield and high purity. A key intermediate as well as several iodo byproducts were isolated.

Full text of DOI:10.1016/j.tetlet.2014.10.025

Accepted Manuscript
Synthesis of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reac-
tion catalyzed by molecular iodine
Jami DeGrote, Stephen Tyndall, Koon Fai Wong, Melissa VanAlstine-Parris
PII:
S0040-4039(14)01708-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.025
TETL 45254
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 July 2014
2 October 2014
6 October 2014
Please cite this article as: DeGrote, J., Tyndall, S., Wong, K.F., VanAlstine-Parris, M., Synthesis of 7-alkoxy-4-
trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine, Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.025
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Synthesis of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed
by molecular iodine
Jami DeGrote, Stephen Tyndall, Koon Fai Wong and Melissa VanAlstine-Parris*
Department of Chemistry, Adelphi University, 1 South Avenue, Garden City, NY 11530, USA
*Corresponding author.
Phone: 516 877 4133
Fax: 516 877 4485
E-mail: mvanalstine@adelphi.edu
Abstract:
The synthesis of a series of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction
catalyzed by molecular iodine is described. The reaction protocol is simple, inexpensive and
leads to the formation of the corresponding coumarin derivatives in good yield and high purity.
A key intermediate as well as several iodo byproducts were isolated.
Keywords:
4-trifluoromethylcoumarin, von Pechmann condensation, molecular iodine, fluorescent

Introductions:
Coumarins, a class of bicyclic lactones, have a wide variety of uses. Some coumarin
derivatives are biologically active,1 such as the anticoagulant warfarin. Other coumarins, such as
umbelliferone, fluoresce, which makes them useful as laser dyes.2 When a coumarin contains an
electron-withdrawing group, such as trifluoromethyl, at the 4-position and electron-donating
group, such as alkoxy or hydroxyl, at the 7-position, the fluorescence is strengthened
dramatically. Thus 7-alkoxy-4-trifluoromethylcoumarins (AFC) have good fluorescence
properties and are used as fluorescent dyes.3 These AFCs are currently used by pharmaceutical
companies as synthetic substrates in fluorometric high-throughput screening assays for
cytochrome P450s.4 The synthesis and characterization of some of these compounds have never
been reported in the literature and are the subject of this paper.
Various methods can be used to synthesize 4-substituted coumarin derivatives with the
von Pechmann reaction5 being the most common and versatile. This method involves the
condensation of a phenol with a β-ketoester in the presence of a condensing agent. The original
reaction used harsh conditions with concentrated sulfuric acid as the catalyst and solvent5. A
wide variety of condensing agents have been developed for the Pechmann reaction but only a
few of these catalysts have been used to synthesize 4-trifluoromethyl coumarins. Brønsted-
Lowry acids (ex. CF3CO2H),6 Lewis acids (AgOTf,7 Bi(NO3)3,3,8 I27,9, Mg(NTf2)2,10 ZnCl2 ), and
11
solid acid catalysts (ex. Amberlyst-15),12 have been used successfully to synthesize 7-hydroxy-4-
trifluoromethylcoumarins (HFC). However, most of these catalysts have not been used in the
synthesis of the alkoxy derivatives, AFCs. Molecular iodine has been shown to catalyze the
synthesis of HFC in 99% yield.7 This paper reports the use of molecular iodine as a catalyst for
the synthesis of AFCs.

Results and discussions
Previous work by Wu et al7 showed that molecular iodine could be used as a catalyst in
the Pechmann condensation of resorcinol and β-keto esters (Scheme 1). Their conditions were
optimized using ethyl acetoacetate (R = H) yet they reported that if ethyl 4,4,4-
trifluoromethylacetoacetate (R = F) was used the catalyst load had to be increased to 50 mol%.
They did not report any further optimization. Since we wanted to synthesize a series of 7-alkoxy-
4-trifluoromethylcoumarins, optimizing the reaction conditions for resorcinol and ethyl 4,4,4-
trifluoromethylacetoacetate was necessary (Table 1).
Scheme 1. Synthesis of coumarins using molecular iodine
Table 1. Optimization of reaction conditions for synthesis of 7-hydroxy-4-
trifluoromethylcoumarin (HFC)a
Catalyst
volume amount Yieldb
Temperature
(°C)
Entry
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
nitrobenzene
THF
(mL)
1
(mol%)
50
(%)
50
59
71
89
86
44
41
50
11
52
1
2
80
90
1
50
3
100
90
1
50
4
1
25
5
90
1
15
6
90
1
5
7
100
90
5
50
8
1
25
9
reflux
1
25
10
90
none
25
a All reactions were performed with resorcinol (5 mmol), and
ethyl 4,4,4-trifluoroacetoacetate (6 mmol).
b Isolated yield.

Wu et al reported that 7-hydroxy-4-alkylcoumarins can be synthesized from resorcinol
and β-ketoesters with molecular iodine in toluene at 80 °C in 3-12 h.7 In our lab, the reaction did
not go to completion in 3-12 hours based on the presence of resorcinol by TLC. If the reaction
was allowed to run overnight, resorcinol was no longer visible by TLC but there were many new
spots. The isolated yield of HFC was low (50 %) at 80 °C (entry 1). The other components of the
reaction were isolated and it was determined that an intermediate was present (1, Figure 1). If the
temperature was increased to 90 °C the yield increased (entry 2) and the amount of intermediate
decreased. When the temperature was increased to 100 °C the reaction went to completion (entry
3).
Figure 1. Intermediate isolated from reactions performed at lower temperature.
Previous researchers have tried to monitor the synthesis of coumarins by the Pechmann
condensation but were unable to detect the presence of intermediates.13 This is the first report of
an isolated intermediate in the Pechmann reaction. The Pechmann condensation reaction
involves three steps: transesterification, electrophilic aromatic substitution and dehydration. The
isolated intermediate is formed from only undergoing the transesterification and electrophilic
aromatic substitution (EAS). All previous mechanistic studies have been done on the synthesis
of 7-hydroxy-4-methylcoumarin,14 where this work focused on the trifluoromethyl derivative.
This strong electron withdrawing group appears to play an important role in the ability to isolate
an intermediate and will be studied further.

In the process of isolating and identifying byproducts we also determined that both the
starting phenol and product becomes iodinated (Figure 2). The most common iodo byproducts
were 4-hydroxy-2-iodophenol (2), 3-hydroxy-2,6-diiodophenol (3), and 7-hydroxy-6-iodo-4-
trifluoromethyl coumarin (4). These byproducts are formed due to the mild Lewis acidity of the
catalyst iodine and its ability to function as an electrophile in EAS. The position of the iodine
implies that the hydroxyl group is preferentially directing the iodine ortho.
CF3
I
I
I
HO
OH
HO
OH
HO
O
O
I
2
4
3
Figure 2. Most common iodinated byproducts.
Due to the presence of iodinated byproducts, the amount of catalyst required for the
reaction was studied. When the catalyst load was reduced to 25 and 15 mol% the amount of
iodinated byproducts was reduced and the yield improved to 89 and 86% (entry 4 and 5,
respectively). If the catalyst load was further reduced to 5 mol% the yield dropped off to 44%
(entry 6).
The role of the solvent was the studied. The original report did not state the volume of
solvent used, therefore we assessed the solvent amount. It was found that increasing the amount
of solvent from 1 to 5 mL dramatically reduced the yield from 71 to 41 % (entry 3 and 7,
respectively). Different observations have been reported in the literature with respect to solvent
polarity. Most commonly non-polar solvents favor the Pechmann reaction while polar solvents
cause cleavage.15 When more polar solvents were used, nitrobenzene and THF, the yield
decreased to 50 and 11%, respectively (entry 8 and 9, respectively). We believe the yield in THF
was so small because the boiling point of THF is low. Many Pechmann reactions give high

yields in solvent-free conditions,10,13,15,16 however this was not the case with iodine as the
catalyst. In solvent-free conditions, with 1.2 eq. of the β-ketoester the yield was only 52% (entry
10). Often in solvent-free conditions the β-ketoester is increased to 2 eq. We found that
increasing the amount of β-ketoester slightly improved the yield to 61% but it also caused a
dimer to form. Therefore it appears that non-polar toluene is the best solvent.
Using the optimized conditions with molecular iodine in toluene at 90 °C, we report the
synthesis of 7-methoxy-4-trifluoromethylcoumarin (2b), 7-ethoxy-4-trifluoromethylcoumarin
(2c), and 7-benzyloxy-4-trifluoromethylcoumarin (2d) in 42-82% yield (Table 2). These
coumarins are made from inexpensive, commercially available starting materials. Reactions were
monitored by TLC and products were purified by column chromatography.
Table 2
Reaction of phenols 5 with ethyl 4,4,4-trifluoroacetoacetate catalyzed by molecular iodine.a
Entry
R
Phenol
Coumarin Yieldb
(%)
89
5
6
a
b
c
d
H
resorcinol
3-methoxyphenol
3-ethoxyphenol
HFC
MFC
EFC
CH3
82
CH2CH3
65
CH2C6H5 3-benzyloxyphenol BFC
42
a All reactions were performed with 1 (5 mmol), ethyl 4,4,4-
trifluoroacetoacetate (6 mmol) and 25 mol % molecular iodine
(1.25 mmol) in toluene (1 mL) at 90 °C for 18 h.
b Isolated yield.

All the products were characterized by 1H, 13C and 2D NMR analysis. All coumarin
derivatives were identified by comparison of their physical and spectral data with the
literature3,7,10,17,18 or commercial samples. The HMBC spectra for HFC shows that the carbon
peak at 159 ppm correlates to the 1H peak at 6.76 ppm (3CH) while the carbon peak at 162 ppm
correlates to the 1H peak at 7.56 (5CH), 10.96 (OH) and 6.84 ppm (8CH). Therefore the 13C peak
at 159 ppm should be assigned to C2 and the peak at 162 should be assigned to C7. These
assignments were switched in comparison to Wang’s assignments.10
Conclusions
In summary, molecular iodine was shown to be a suitable catalyst for the synthesis of
several 7-alkoxy-4-trifluoromethyl coumarins from a phenol and ethyl 4,4,4-trifluoro-
acetoacetate. This study demonstrated that if the reaction is not heated to 90 °C the hydrated
intermediate is still present. This study also showed that the iodine catalyst substitutes ortho to
the phenol causing unwanted byproducts.
Acknowledgements
This research was supported by a Horace G. McDonell Fellowship to JD and an Adelphi
University Faculty Development Grant to MVP.
Supplemental data
Supplemental data associated with this article can be found in the online version. The
data includes spectroscopic data for the most important compounds described.
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Catalyst
volume amount Yield
Temperature
(°C)
Entry
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
nitrobenzene
THF
(mL)
1
(mol%)
50
(%)
50
59
71
41
89
86
44
50
11
61
1
2
80
90
1
50
3
100
100
90
1
50
4
5
50
5
1
25
6
90
1
15
7
90
1
5
8
90
1
25
9
reflux
90
1
25
10
none
25
aAll reactions were performed with resorcinol (5 mmol) and ethyl
4,4,4-trifluoroacetoacetate (6 mmol).
b Isolated yield.

Entry
R
Phenol
5
Coumarin Yieldb
(%)
89
6
a
b
c
H
resorcinol
HFC
CH3
3-methoxyphenol MFC
82
CH2CH3 3-ethoxyphenol
3-
EFC
65
d
CH2C6H5 benzyloxyphenol BFC
42
a All reactions were performed with 1 (5 mmol), ethyl 4,4,4-trifluoroacetoacetate (6 mmol) and 25 mol %
molecular iodine (1.25 mmol) in toluene (1 mL) at 90 °C for 18 h.
b Isolated yield.