Facile synthesis and characterization of indene-fused 4-methylcoumarins and an unexpected skeletal rearrangement via Pechmann condensation

Article abstract of DOI:10.1016/j.tetlet.2020.151917

The Pechmann condensation of phenolic fluorenes with ethyl acetoacetate afforded indene-fused 4-methylcoumarins. In addition to the expected indeno[1,2-g]coumarin, a skeletal rearranged compound was obtained as a concomitant product when 9,9-dimethyl-9H-fluorene-2,7-diol was utilized as the substrate. X-ray crystallography was used to identify the structures of the isomers. Photochemical and photophysical studies indicated that compared with the non-rearranged products, the skeletal rearranged isomers have red shifted absorption maxima and much higher fluorescence quantum yields. A mechanism involving two competitive pathways for the simultaneous production of isomers was proposed.

Full text of DOI:10.1016/j.tetlet.2020.151917

Journal Pre-proofs
Facile synthesis and characterization of indene-fused 4-methylcoumarins and
an unexpected skeletal rearrangement via Pechmann condensation
Jie Wu, Wei Liu, Li Liang, Ya Gan, Shuang Xia, Xiaojun Gou, Xiaohua Sun
PII:
S0040-4039(20)30360-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151917
TETL 151917
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 February 2020
31 March 2020
3 April 2020
Please cite this article as: Wu, J., Liu, W., Liang, L., Gan, Y., Xia, S., Gou, X., Sun, X., Facile synthesis and
characterization of indene-fused 4-methylcoumarins and an unexpected skeletal rearrangement via Pechmann
condensation, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151917
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Tetrahedron Letters
Facile synthesis and characterization of indene-fused 4-methylcoumarins and an
unexpected skeletal rearrangement via Pechmann condensation
Jie Wua, Wei Liub, Li Lianga, Ya Ganb, Shuang Xiac, Xiaojun Goua, and Xiaohua Suna,d,
a Sichuan Industrial Institute of Antibiotics, Chengdu University, Sichuan Province, 610052, P. R. China
b College of Pharmacy and Biological Engineering, Chengdu University, Sichuan Province, 610106, P. R. China
c College of Pharmaceutical and Material Engineering, Jinhua Polytechnic, Zhejiang Province, 321017, P. R. China
d Jinhua Branch of Sichuan Industrial Institute of Antibiotics, Chengdu University. Zhejiang Province, 321017, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Pechmann condensation of phenolic fluorenes with ethyl acetoacetate afforded indene-fused
4-methylcoumarins. In addition to the expected indeno[1,2-g]coumarin, a skeletal rearranged
compound was obtained as a concomitant product when 9,9-dimethyl-9H-fluorene-2,7-diol was
utilized as the substrate. X-ray crystallography was used to identify the structures of the isomers.
Photochemical and photophysical studies indicated that compared with the non-rearranged
products, the skeletal rearranged isomers have red shifted absorption maxima and much higher
fluorescence quantum yields. A mechanism involving two competitive pathways for the
simultaneous production of isomers was proposed.
Available online
Keywords:
Fused coumarin
Indeno[1,2-g]coumarin
Indeno[2,1-g]coumarin
Pechmann condensation
Skeletal rearrangement
2009 Elsevier Ltd. All rights reserved.
absorption maxima of coumarin chromophores usually fall in the
UV range; the intrinsic phototoxicity to living cells and poor
penetration depth in organic tissues of UV light has greatly
restricted their application in biological systems. To address this
issue, structural modification of the coumarin core to red shift its
absorption maximum has been applied. The introduction of
electron-donating and electron-withdrawing groups onto the
Introduction
The Pechmann condensation is an efficient strategy to
synthesize coumarins via the reaction of phenols with -keto
esters.1 Coumarins are attractive molecules with versatile
applicability. In addition to their widely studied pharmaceutical
applications, such as anticoagulant,2 antioxidant,3 anticancer4 and
anti-Alzheimer,5 coumarins are popular in photochemical studies
due to their rigid planar skeleton and delocalized charge between
the aromatic ring and the pyrone moiety. For example, they are
used as fluorescent probes,6 fluorescent chemosensors7 and
photoremovable caging groups for bioactive molecules.8
Photoremovable
caging
groups,
also
known
as
photoremovable protecting groups (PPGs), are photolabile
compounds that can be covalently bonded to bioactive molecules
to cage their activities. Once irradiated at a specific wavelength,
the benign precursors can be triggered and instantaneously
release active molecules at target sites. With this strategy, precise
drug delivery is achieved in a spatiotemporal controlled manner.9
Coumarin is one of the most commonly used PPGs. It was first
reported by Givens as a photoactivatable phosphate-caging
group10 which led to the development of a new class of
coumarinyl-4-methyl PPGs11 (Scheme 1).
Although coumarin based PPGs have been widely applied in
many areas, they are not suitable for biological applications. The
Scheme 1. Coumarinyl-4-methyl PPGs for various functional groups.
———
 Corresponding author. e-mail: sunxh@cdu.edu.cn (X. -H. Sun).

2
Tetrahedron Letters
Figure 1. X-ray crystal structures of 3 (CCDC 1946838）and 4 (CCDC
1946839.
condensation. The rigid planar molecular structure of the
introduced fluorene moiety provides an expanded -conjugated
scaffold to the fused coumarins. Meanwhile, the high fluorescent
quantum yield of fluorene derivatives would be beneficial to
improve the performance of PPGs.
Results and Discussion
Scheme 2. Synthesis of indene-fused 4-methylcoumarins. Reagents and
9,9-Dimethylfluorene was heated at reflux with 1.2 equiv. or
3.5 equiv. of acyl chloride in the presence of aluminum chloride
in 1,2-dichloroethane to afford mono-acylated product 5 in 88%
yield or di-acylated product 10 in 91% yield (Scheme 2).
Following subsequent Baeyer-Villiger oxidation, esters 6 and 11
were obtained. Compound 8 was afforded by heating compound
6 with N-bromosuccinimide (NBS) in N,N-dimethylformamide
(DMF) at 60 C for 4 h. Esters 6, 8 and 11 were hydrolyzed to
phenolic fluorenes 7, 9 and 12 using a 10% NaOH solution.
Finally, the Pechmann reaction was applied by stirring the
phenols with ethyl acetoacetate in the presence of 70% H2SO4 at
room temperature to give coumarin 1 from compound 9 and 2
from compound 7, respectively. Interestingly, the Pechmann
condensation of compound 12 with ethyl acetoacetate produced
not only the expected compound 13 but also an isomer 14 in
which the oxygen atom at the C-7 position of the fluorene
skeleton had transferred to the C-6 position. Methylation of 13
and 14 yielded compounds 3 and 4, respectively.
conditions: (i) CH3COCl, AlCl3, 1,2-dichloroethane, reflux, 88-91% yield;
(ii) mCPBA, CF3COOH, CHCl3, r.t, 91-93% yield; (iii) NBS, DMF, 60 oC,
84% yield; (iv) 10% NaOH (aq), r.t, 81-88% yield; (v) ethyl acetoacetate,
70% H2SO4, r.t, 21-49% yield; (vi) CH3I, K2CO3, DMF, rt, 90-92% yield
aromatic ring and extension of the molecular -conjugation
system are frequently adopted methods to make coumarin PPGs
favourable for long wavelength stimuli.12 Expanding the -
system of the coumarin scaffold by fusing it to aromatic or
heterocyclic
moieties
typically
results
in
altered
chemical/physical properties, which offers an alternative to
develop novel coumarinyl caging groups.13 In addition to their
use as PPGs, fused coumarins were also studied as possible anti-
cancer14 or anti-inflammatory agents,15 as well as fluorescent
probes for thiol,16 hydrazine17 and carbon monoxide.18
Due to the diverse applications of fused coumarins in various
areas, efforts have been dedicated to the design and synthesis of
novel -expanded coumarins. In addition to the Pechmann
reaction, strategies including the Knoevenagel condensation,19
metal-catalyzed reactions20 and microwave technology21 have
also been reported. To increase the diversity of fused coumarin
derivatives as well as to expand the library of coumarinyl PPGs
for potential applications, herein we report a facile approach to
prepare indene- fused 4-methylcoumarins via the Pechmann
The molecular structures of 1 and 2 were confirmed with
NMR and HRMS analyses. However, we were unable to
differentiate compounds 3 and 4 due to their structural similarity.
1
The H NMR spectra of their parent molecules 13 and 14 were
similar (ESI, Fig. S1). Two-dimensional NMR spectroscopy gave
detailed structural information about the individual compounds;
Scheme 3. Proposed mechanism for the competitive synthesis of compound 13 and isomer 14.

Table 1. Relative amounts of 13 and 14 under different
reaction conditions.
Solvent
Solvent
(70% H2SO4)
Temp.
(℃)
Entry
(70% H2SO4 + EtOH)b
13 (%)
83
14 (%)
17
13 (%)
14 (%)
1
25
10
0
70
74
68
34
30
26
32
66
2a
3a
4a
85
15
81
19
-10
60
40
a Data were determined by HPLC. Detection wavelength was set at 350
nm. b 70% H2SO4/EtOH = 4/1 (v:v)
however, it was still difficult to distinguish the isomers (ESI, Fig.
S2-S7). Therefore, X-ray crystallography was used (Fig. 1).22 As
shown in Figure 1, compound 3 was verified as an indeno[1,2-
g]coumarin derivative while compound 4 was proved to be an
indeno[2,1-g]coumarin derivative.
We were puzzled by the formation of isomer 14 because, to
the best of our knowledge, there are no reports of structural
rearrangement during the Pechmann condensation. The C-O
covalent bond of the phenolic hydroxyl group at the 7-position of
the fluorene moiety is quite stable due to p- conjugation
between the aromatic ring and the oxygen atom. Theoretically,
only compound 13 should be obtained. HPLC analysis showed
that the molar ratio of intermediates 13 to 14 was 7:3 when the
reaction was carried out at 25 C. It could be slightly increased to
8:2 when 20% of ethanol (v/v) was added to the reaction mixture.
We then conducted a series of reactions by varying the reaction
conditions to investigate the relative amounts of the isomers;
these results are summarized in Table 1.
As shown in Table 1, the reactions conducted in the presence
of ethanol have larger 13 to 14 molar ratios compared with those
without ethanol. Meanwhile, the percentage of compound 14
gradually increased with the decrease of the reaction temperature;
it even became the major product when the reaction was
performed at -10 C under ethanol-free conditions. The various
molar ratios of the isomers in response to the reaction conditions
indicated that compound 13 and 14 were produced
simultaneously in a competitive manner. Isomer 14 was
preferentially formed at low temperatures, which indicated a
kinetically controlled reaction behaviour. Non-rearranged
product 13 was preferentially obtained in a protic solvent
(ethanol) or at higher temperatures, which suggested that 13 was
a thermodynamically controlled product. It is interesting that
only compound 12 underwent the rearrangement reaction. There
were no isomers found in the cases of compound 7 and 9.
The classical Pechmann reaction involves transesterification
of phenols with -keto esters, intramolecular electrophilic
aromatic substitution (EAS) and dehydration. To determine at
which stage of the Pechmann reaction the rearrangement reaction
occurs, we first studied the stability of compound 12 in 70%
H2SO4 solution to see if isomers could be formed before
esterification. We found that compound 12 remained intact after
being stirred for several hours either at room temperature or at
low temperature before the addition of ethyl acetoacetate (ESI,
Fig. S8). We next studied the stability of compound 13 by
stirring with ethyl acetoacetate in 70% H2SO4 to check if 14
could be obtained from 13 via isomerization; this showed that
compound 13 was stable towards the acidic environment (ESI,
Figure 2. UV-vis absorption (a) and emission (b) spectra of indene-fused 4-
methylcoumarins measured in dichloromethane (inset: the normalized
fluorescence spectra).
Fig. S9). Therefore, the fluorene scaffold rearrangement should
occur between the transesterification and the EAS stages of the
Pechmann reaction. Based on the results obtained, a possible
mechanism involving two competitive reactions was proposed in
Scheme 3. As illustrated, 9,9-dimethylfluorene-2,7-diol 12 was
mono-esterified to fluoren-2-ol by transesterification with ethyl
acetoacetate. Following a ring opening reaction in the acidic
medium, a multi-substituted biphenyl derivative was produced.
Subsequent intramolecular Friedel-Crafts alkylation results in
the formation of an unstable spiro-dienone intermediate, which
immediately underwent a 1,2-alkyl shift to revert to the mono-
esterified fluoren-2-ol (Path A), which was converted to
coumarin 13 via the Pechmann reaction. Alternatively, the spiro-
dienone might also undergo a competitive 1,2-phenyl shift to
afford a skeletally rearranged fluoren-2-ol (Path B), which was
finally converted to the rearranged isomer 14.
The photophysical and photochemical properties of the
Table 2. Photophysical and photochemical properties of 1-4 and 13-14 measured in dichloromethane. Fluorescence
quantum yields were determined using an integrating sphere method.
Compounds

abs (nm)

em (nm)
Stokes Shift (nm)
143, 64
144, 65
156, 68
67
(104 M-1 cm-1)
F (%)
2.0a
3.3a
10.4a
59.3a
13.3b
81.9b
1
2
268, 347
268, 347
271, 359
354
411
0.8
1.3
0.9
3.3
0.9
2.9
412
3
427
4
421
13
269, 357
352
437
168, 80
63
14
415
a Data were measured on an Edinburgh Instrument FLS900. b Data were measured on a Hamamatsu Photonics C9920-02.

4
Tetrahedron Letters
Conclusion
In summary, we have synthesized a series of indene-fused 4-
methylcoumarin derivatives including four indeno[1,2-
g]coumarins 1-3 and 13 together with two indeno[2,1-
g]coumarins 4 and 14 via the Pechmann condensation. An
unexpected rearrangement reaction that gave rise to the formation
of a pair of isomers was observed. The competition between the
thermodynamically and kinetically controlled reactions under
different reaction conditions resulted in various molar ratios of
the isomers. Structures of the fused coumarins were confirmed
with NMR and HRMS. X-ray crystallography was used to
identify the isomers. Photophysical and photochemical studies
found that the structurally rearranged coumarins have red shifted
absorption maxima and higher quantum yields in comparison to
their counterparts. Further investigations regarding the
application of these novel indene-fused 4-methylcoumarins as
photoremovable protecting groups are underway in our group.
Acknowledgments
Figure 3. Photophysical and photochemical properties of 3 and 4 in different
solvents: (a) Absorption spectra of 3; (b) Emission spectra of 3; (c)
Absorption spectra of 4; (d) Emission spectra of 4. Insets: normalized
emission spectra. CyH = cyclohexane, Et2O = diethyl ether, DCM =
dichloromethane, EA = ethyl acetate, ACN = acetonitrile, DMSO = dimethyl
sulfoxide.
We would like to thank the Science and Technology Bureau
of Chengdu Municipal Government (Grant 2016-XT00-00023-
GX) and the Research Foundation of SIIA Jinhua Branch (Grant
SIIAJH-201902) for financial support.
obtained coumarins were characterized (Fig. 2). Coumarins 1-3
and 13 showed similar absorption behaviours in dichloromethane.
They have a strong absorption maximum at about 270 nm and a
broad shoulder with a maximum around 350 nm. In terms of
isomers 4 and 14, the plotted spectra exhibited relatively broad
absorption bands that cover from 300 nm to 400 nm with a
maximum at about 354 nm, i.e. the absorption shoulders of non-
rearranged coumarins are the absorption maxima of the isomers.
Although the absorption properties of the isomers are quite
different to the non-rearranged coumarins, their emission
properties are similar. As shown in Figure 2b, the emission
maxima of these fused coumarins are located between 400 nm
and 440 nm. The solvent effects on the absorption and emission
spectra of isomers 3 and 4 were studied (Fig. 3). Coumarin 3 has
a maximum absorption at 268 nm and a small shoulder peak at
276 nm in cyclohexane (CyH). However, the maximum
absorption red-shifted to 279 nm with a small shoulder peak at
273 nm when 3 was characterized in dimethyl sulfoxide (DMSO).
It seems that the positions of the absorption peak and the
shoulder peak have switched with each other. The absorption
spectrum of isomer 4 measured in CyH exhibited two major
peaks at 351 nm and 369 nm, respectively, as well as a minor
peak at 360 nm. With the increase in solvent polarity, the minor
peak diminished quickly; the shoulder peak at a longer
wavelength also decreased and finally weakened into a small
shoulder peak in DMSO (Fig. 3c). A bathochromic shift of the
fluorescence emission spectra with increasing solvent polarity
was observed in both compounds 3 (Fig. 3b) and 4 (Fig. 3d).
Fluorescence quantum yields (QYs) of the fused coumarins
were measured, and the data are summarized in Table 2.
Compound 1 and 2 have QYs of 2.0 and 3.3, respectively. The
heavy atom effect of bromine might be responsible for the slight
decrease of the QY of compound 1 in comparison to compound 2.
Compound 3 has a higher QY of 10.4 due to the presence of an
electron-donating methoxy group. Isomer 13 has a similar QY to
3 because of their structural similarity. However, isomers 4 and
14 have much higher QYs. As shown in Table 2, the QY of
compound 4 is 59.3, nearly five times larger than that of
compound 3. As for compound 14, the highest QY of 81.9 was
recorded. Since coumarins 3 and 4 (or 13 and 14) are quite
similar in their molecular structures, it is difficult to give a
rational explanation for the vast differences in the QYs. Further
studies are needed to explore the structure-property relationships
of such compounds.
Appendix A. Supplementary data
Supplementary data (general procedures, copies of NMR,
HRMS spectra, HPLC traces) to this article can be found online
at:
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6
Tetrahedron Letters
Research highlights
► The facile synthesis of indene-fused 4-
methylcoumarins
► The observation of a fluorene skeletal
rearrangement during the Pechmann reaction.
► The differences between the photophysical
properties of the indeno[1,2-g]coumarins and
indeno[2,1-g]coumarins.

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Facile synthesis and characterization of indene-fused Leave this area blank for abstract info.
4-methylcoumarins and an unexpected skeletal
rearrangement via Pechmann condensation
Jie Wua, Wei Liub, Li Liang a, Ya Ganb, Shuang Xiac, Xiaojun Goua, and Xiaohua Suna,d,
Sichuan Industrial Institute of Antibiotics, Chengdu University, Sichuan Province, 610052, P. R. China
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