Synthesis of 7-Azido-3-Formylcoumarin – A Key Precursor in Bioorthogonally Applicable Fluorogenic Dye Synthesis

Article abstract of DOI:10.1002/jhet.3151

Coumarins represent an important group of natural products and a common part of various drugs and fluorescent dyestuffs. Herein, we present the synthesis of a coumarin that can serve as a key starting material in the design and synthesis of bioorthogonally applicable fluorogenic dyes. The synthesis of 7-azido-3-formylcoumarin started from 7-diallylaminocoumarin. This allyl protected aminocoumarin is otherwise hard to obtain by conventional methods but was conveniently accessed in good yields by a sequential, Wittig-reaction–UV isomerization process. This sequential approach was studied in more details and applied for the synthesis of a series of substituted coumarins even in one-pot.

Full text of DOI:10.1002/jhet.3151

Month 2018
Synthesis of 7-Azido-3-Formylcoumarin – A Key Precursor in
Bioorthogonally Applicable Fluorogenic Dye Synthesis
*
*
and András Herner
Zoltán Pünkösti, Péter Kele,
Chemical Biology Research Group. Magyar tudósok krt. 2, Research Centre for Natural Sciences, Institute of Organic
Chemistry, Hungarian Academy of Sciences, Budapest H-1117, Hungary
*
E-mail: kele.peter@ttk.mta.hu; herner.andras@gmail.com
Received November 15, 2017
DOI 10.1002/jhet.3151
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Coumarins represent an important group of natural products and a common part of various drugs and fluo-
rescent dyestuffs. Herein, we present the synthesis of a coumarin that can serve as a key starting material in
the design and synthesis of bioorthogonally applicable fluorogenic dyes. The synthesis of 7-azido-3-
formylcoumarin started from 7-diallylaminocoumarin. This allyl protected aminocoumarin is otherwise hard
to obtain by conventional methods but was conveniently accessed in good yields by a sequential, Wittig-
reaction–UV isomerization process. This sequential approach was studied in more details and applied for
the synthesis of a series of substituted coumarins even in one-pot.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
convenient precursor that can be condensed with species
harboring carbon-nucleophiles to render polymethine
frames (Fig. 1) [7]. Substituents on the coumarin frame
substantially affect the overall spectroscopic features, and
this is especially profound at the seventh position. Our
ongoing project aims at designing and synthesizing azide
quenched, bioorthogonally applicable fluorogenic probes,
and we wanted to study 7-azidocoumarin based
fluorogenic species. As discussed earlier, the azide group
can act as a quencher of fluorescence and a biorthogonal
functional group at the same time. Previously, we have
reported on a series of azide-quenched, bioorthogonally
applicable fluorogenic species [5d,7a], however, until
now, we were not able to access 7-azidocoumarin-based
dye precursors that could have served as starting
materials for such fluorogenic species. Introduction of the
azide group is possible at different stages of synthetic
The coumarin (2H-chromen-2-one, benzopyran)
framework is an important building block of naturally
occurring compounds [1]. Its derivatives find broad range
of applications, and its core structure can be recognized
in many antibiotics, anticoagulants (e.g., warfarin) [2],
antipsoriatic and anti-inflammatory agents, and anti-HIV
drugs, for example, as inhibitors of HIV’s reverse
transcriptase [3]. Moreover, the beneficial photophysical
properties of coumarins raise this framework to one of
the most frequently used building blocks in fluorescent
dyes [4]. Over the years, we and others reported on the
development of fluorogenic scaffolds based on several
fluorescent cores, including coumarin [5]. The
fluorescence of fluorogenic scaffolds can be quenched by
several means, for example, by photoinduced electron
transfer [5a], twisted intramolecular charge transfer [5b],
energy transfer [5c], or by moieties that suppress
fluorescence by opening non-radiative relaxation
pathways by biasing vibrational release of energy [5d].
Azide derived fluorogenic frames are of special
importance as they can be applied in biorthogonal
labeling schemes due to the two-in-one feature of this
small, biologically inert, yet highly energetic function
being a biorthogonal handle and a quencher moiety at the
same time [6]. The excitation and emission wavelengths
of coumarin based dyes can be easily shifted towards the
biologically more advantageous red regime by extension
of the conjugated system as part of polymethine chains.
routes mostly by
a diazotization/azide substitution
sequence of corresponding amines. However, the harsh
conditions of diazotization often limit the possible
functional groups. Direct condensation of 7-azido-3-
formylcoumarin as
a key precursor with carbon-
nucleophiles would greatly simplify access to fluorogenic
species, not to mention that it could also offer library
based screen for fluorogenic species by modular
approach. Thus, we aimed to synthesize 7-azido-3-
formylcoumarin. There are several means for the
formation of coumarin scaffolds, such as the Perkin
reaction [8]. Besides Perkin condensation, other named
reactions such as the Knoevenagel condensation [9] or
the von Pechmann reaction [10] are also well known for
For this, 3-formylcoumarin scaffolds serve as
a
© 2018 Wiley Periodicals, Inc.

Z. Pünkösti, P. Kele, and A. Herner
Vol 000
Figure 1. Coumarin-based polymethine frames accessed from a 3-formylcoumarin precursor.
the synthesis of coumarins. Alternative means to build
the coumarin frame are also reported, including, for
example, condensation of salicylaldehydes with
acetic acid derivatives [11], the Baylis-Hillman reaction
[12], or oxidative cyclization of Z-cinnamic acids [13].
Pd-catalyzed reactions were also applied in various ways,
for example, Heck-type coupling [14], ring closing of
aryl alkynoate [15], or acrylate [16] derivatives through
C─H activation. A very recent paper reports on the
synthesis of coumarins by mimicking the natural
biosynthetic pathway where the coumarin scaffold is
obtained from aryl-E-cinnamates under photoirradiation
in the presence of riboflavin as photocatalyst [17]. We
sought for routes involving suitably protected
aminocoumarins as precursors for further transformations
in order to access the target compound. While these
synthetic routines are well credited, each has certain
limitations. For example, routes starting from phenols or
salicylaldehydes require electron-rich substituents.
Furthermore, these methods are not universal in terms of
substituents to be installed at different positions of the
coumarin scaffold, not to mention that the applied – and
isomers are formed, and mechanistic studies showed that
the isomeric ratio depends both on the type of the ylide
and the transition state of the formed intermediate [19].
E-cinnamates are not capable of ring closure via lactone
formation but can be isomerized to their respective
Z-forms either thermally or upon UV irradiation in an
equilibrium process. Spontaneous lactonization shifts
the equilibrium and, as a consequence, irrespective of the
original E/Z ratio, all cinnamates are converted into
coumarins. Similar approaches exist in the literature,
however, they either resulted in low yields or were not
exploited for the synthesis of protected comarins [20].
RESULTS AND DISCUSSION
We wished to study the proposed reaction sequence in
more details before devising a route to access the target
compound. We chose 4-methoxy-2-hydroxy-benzaldehyde
(1d) and two easily accessible ylides, that is,
methyl(triphenylphosphoranylidene)acetate and methyl
2-(triphenylphosphoranylidene)propanoate
as
model
sometimes very harsh
–
conditions have limited
compounds. In both case, the Wittig-reaction resulted in a
mixture of Z/E cinnamates. The reaction mixtures were
analyzed in order to assess the obtained Z/E ratios. NMR
studies indicated the presence of 77% E-cinnamate in case
of 2d together with 23% 7-methoxycoumarin (4d, see
Data S1 for NMR spectra). Formation of the latter product
supported that Z-cinnamates undergo spontaneous ring-
closing lactonization to give the respective coumarin
scaffold. In case of the reaction between 1d and
methyl 2-(triphenylphosphoranylidene)propanoate, similar
analysis indicated nearly the sole presence (i.e., >95%) of
the E-cinnamate (3d, see Data S1 for NMR spectra).
Following purification, the reaction products were
subjected to UV irradiation, and coumarins 4d and 5d
were obtained in 69% and 63% yields, respectively.
functional group tolerance. Although strategies exist for
the introduction of substituents onto the coumarin core,
the substrate scope of these routines usually has narrow
range. Unfortunately, the previously listed reactions either
did not work or gave only very poor yields when
attempted to reach our aims.
We needed a synthetic route that uses mild conditions
therefore investigated
followed by photoisomerization
salicylaldehydes in order to access coumarin derivatives
as starting materials for our further aims. o-Hydroxy-Z-
cinnamates are known to undergo spontaneous
lactonization reaction giving rise to coumarins [18].
During the Wittig reaction, however, both Z and E
a
sequential Wittig reaction
starting from
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Next, we wanted to test the scope and limitations of this
synthetic route without the intermediate purification step.
To this end, we have chosen a set of salicylaldehydes
bearing various substituents. Synthesis of coumarins were
carried out in the following manner: salicylaldehydes
(1a–j) were mixed with the ylids overnight in methylene
chloride at room temperature. Full conversions (>95%)
were reached according to thin layer chromatography
(tlc) analysis. Methylene chloride was removed, and
without any purification, the obtained cinnamate–
coumarin mixtures were dissolved in methanol in a
quartz reaction flask and irradiated with low pressure
mercury lamps until full consumption of the cinnamates
as indicated by t.l.c. (Scheme 1). The coumarin products
were then purified by column chromatography (SiO2).
With the exception of 4-iodo-2-hydroxy benzaldehyde,
where iodine elimination occurred (ca. 60% of the
coumarins
were
deiodonated
by
gas
chromatography-mass spectrometry analysis, not listed
earlier), all substrates gave moderate to excellent yields
(Fig. 2). Derivatives bearing substituents only at position
7 (1d, f, g, i, and j) generally gave higher isolated yields.
Sterically demanding julolidine derivative (4h and 5h)
and 6,7-dimethoxy coumarin (4e and 5e) were obtained
in lower yields.
Regarding the necessary irradiation time, compounds
with strongly electron donating groups (4f–g) required
shorter times for full conversion. Although we did not
determine Z/E ratios for each cinnamate, we suspect
that the time required for full conversion is strongly
dependent on the ratio of the primarily obtained
cinnamate isomers, thus, the coumarin formed
spontaneously during the Wittig reaction. Furthermore, it
was observed that in case of R2 = Me, less time was
necessary than for the corresponding R2 = H products.
We also were curious whether the two steps could be
driven in a one-pot manner without intermediate solvent
exchange. To this end, we chose 4-hydroxy
salicylaldehyde (1f) and reacted with both ylides in
MeOH in a quartz flask. Following full conversion, the
mixture was directly exposed to UV light for 4–9 h.
Following work-up, target coumarins were isolated in
Figure 2. Prepared coumarins with the necessary irradiation time to reach
full conversion and isolated yields. aWittig reaction was carried out in
MeOH, followed by irradiation (one pot).
good and excellent yields (74% and 97% for 4f and 5f,
respectively).
Following these pre-studies, we have devised a synthetic
path aiming at synthesizing of 7-azido-3-formylcoumatrin
(11), starting from 4-diallylamino salicylaldehyde
(Scheme 2). Wittig reaction and subsequent UV-mediated
coumarin formation resulted 4j in good yields (attempt
for the synthesis of 4j by Knoevenagel condensation
resulted very poor yields). 7-Diallylaminocoumarin was
then subjected to Vilsmeyer–Haack formylation to result
in 7-diallylamino-3-formylcoumarin, 6, in 80% yield.
Subsequent reduction of the formyl group was effected
by treatment with NaBH4 to obtain 7 in 49% yield.
Formation of silyl protected derivative, 8, was necessary
due to the very low solubility of amine-alcohol
derivative. Pd-mediated removal of the allyl protecting
groups gave 9 in good yield. Diazotization of 9 and
removal of the triisopropylsilyl group provided 10 in
Scheme 1. Synthesis of substituted coumarins via the Wittig–UV irradiation sequence. (i) CH2Cl2, room temperature, 16 h, (ii) MeOH, irradiation,
40–50°C, 4–40 h, 25–97%.
Journal of Heterocyclic Chemistry
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Z. Pünkösti, P. Kele, and A. Herner
Vol 000
Scheme 2. Synthesis of 7-azido-3-formylcoumarin. (a) POCl3,
dimethylformamide, 0°C, 10 min, 80%; (b) NaBH4, tetrahydrofuran/
MeOH, 0°C, 5 min, 49%; (c) triisopropylsilyl (TIPS)-Cl, imidazole
CH2Cl2, 0°C → room temperature (r.t), 16 h, 93%; (d) Pd(PPh3)4, 1,3-
dimethylbarbituric acid, CH2Cl2, 35°C, 16 h, 82%; (e) NaNO2, HCl/EtOH,
NaN3, 0°C → r.t, 1 h then tetrahydrofuran, TBAF.3H2O, r.t, 15 min, 85%;
(f) Dess–Martin periodane, CH2Cl2, r.t. 2 h, 96%.
purification. Analytical thin-layer chromatography (TLC)
was performed on silica gel 60 F254 precoated
aluminium TLC plates from Merck. ZEOprep 60 silica
gel (0.060–0.200 mm) was used for column
chromatography from Zeochem. Flash column
chromatography was performed on a Teledyne Isco
CombiFlash® Rf + automated flash chromatography
apparatus using silica gel (0.025–0.040 mm) from
Zeochem. Visualization of TLC samples was performed
with a 254/365 nm UV. NMR spectra were recorded on a
Bruker Avance 250 MHz or a Varian Inova 500 MHz
spectrometer. Chemical shifts (δ) are given in parts per
million (ppm) using solvent signals as the reference.
Coupling constants (J) are reported in Hertz (Hz).
Splitting patterns are designated as
s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of a doublet), and brs (broad singlet). High
resolution mass spectrometric measurements were
performed using a Q-TOF Premier mass spectrometer
(Waters Corporation, Milford, MA, USA) in positive
electrospray ionization mode. The UV reactor was
equipped with 9 × 10 W low pressure mercury lamps
surrounding the quartz flask in a cylinder with a diameter
of 23 cm. The quartz flask was at around 6–7 cm from
the UV lamps. The solution was stirred with magnetic
stirrer, and the temperature was around 40–50°C due to
the irradiation.
85% yield. Finally, oxidation of 10 with Dess–Martin
periodane gave target compound 11 in 96% yield
(Scheme 2).
Synthetic procedures. Typical two-step Wittig–UV
CONCLUSION
sequential procedure.
The solution of 0.75–1.50 mmol
(1.0 eq.) salicylaldehyde and 1.05 eq. ylide in 20 cm3
CH2Cl2 were stirred overnight at room temperature (r.t.).
Solvent was removed under reduced pressure, and the
residue was dissolved in 15–20 cm3 MeOH and then
irradiated by UV light until full conversion of the
cinnamates (monitored by TLC). The solvent was
removed under reduced pressure, and the coumarin
products were purified by column chromatography.
In conclusion, we have applied a mild synthetic route
suitable for the synthesis of problematic coumarin
derivatives that are hard to access by conventional
methods. The functional group tolerance of the method
allows access to variously substituted coumarins,
including protected amines that can be useful starting
materials for bioconjugatable fluorogenic coumarin dyes
and halogenated scaffolds offering further derivatization
steps, for example, through cross-coupling reactions.
With the key precursor in hand, we plan to extend the
conjugated system using a set of C-nucleophilic modules
in order to screen for new, bioorthogonally applicable
fluorogenic compounds with biologically relevant spectral
properties and high fluorogenicity. This work is underway
in our laboratory, and results will be presented in due
course.
One-pot synthesis of coumarins.
A solution of the
salicylaldehyde (0.50 mmol, 1.00 eq.) and the appropriate
ylide (0.55 mmol, 1.1 eq.) in 10 mL MeOH in a quartz
flask was stirred at r.t. for until full consumption of the
starting material. The reaction mixture was then
subsequently irradiated with UV light until full
conversion (monitored by TLC). Following evaporation
of the solvent, the product was purified by column
chromatography.
Synthesis of 3-formyl-7-azidocoumarin. 3-Formyl-7-
diallylaminocoumarin (6).
POCl3 (2.5 cm3) was
EXPERIMENTAL
added dropwise to N,N-dimethylformamide (3.4 cm3) at
0°C under N2 atmosphere. After 10-min stirring, the
mixture was allowed to warm to r.t., and 2 cm3 CHCl3
was added followed by 7-diallylaminocoumarin, 4j
(1.07 g, 4.43 mmol) in dimethylformamide (3 cm3). The
reaction mixture was stirred for 4 h at 60°C then cooled
Unless otherwise indicated, starting materials were
obtained from commercial suppliers (Sigma-Aldrich,
Fluka, Merck, Alfa Aesar, Reanal, Molar Chemicals,
Romil, TCI Chemicals) and used without further
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Month 2018
Bioorthogonal Fluorogenic Dyes
to r.t. The mixture was poured onto ~100 g of crushed ice,
and the pH was set to ~6 using cc.NaOH solution. The
mixture was extracted with CH2Cl2 (3 × 100 cm3). The
combined organic layers were washed with 150 cm3
brine and dried over MgSO4. The solution was filtered,
and the solvent was removed in vacuo. The crude
product was purified by flash column chromatography
(SiO2, hexanes/EtOAc, EtOAc%: 0 → 30 v/v) to give 6
as bright orange crystals (0.96 g, 80%). m.p.: 114–117°C,
Rf = 0.30 (hexanes/EtOAc 3:1 v/v). IR (neat) ν = 3082,
flash column chromatography (SiO2, hexanes/EtOAc,
EtOAc: 0 → 10 v/v) to provide 8 as a colorless oil
(367 mg, 93%). Rf = 0.47 (hexanes/EtOAc 5:1 v/v). IR
(neat) ν = 3056, 2935, 1678, 1601, 1562, 1515, 1261,
1126 cmÀ1. δH(500 MHz; CDCl3) 7.71 (1H, s), 7.26 (1H,
3
4
4
d, 3 J 8.8), 6.58 (1H, dd, J 8.7, J 2.3), 6.55 (1H, d, J
2.0), 5.89–5.74 (2H, m), 5.22–5.10 (4H, m), 4.67 (2 H,
3
s), 3.95 (4H, d, J 4.5), 1.22–1.14 (3H, m), 1.09 and 1.08
(18H, 2 × s). δC(126 MHz; CDCl3) 161.5, 155.2, 151.1,
137.5, 132.7, 128.4, 122.4, 116.7, 109.7, 109.5, 98.5,
60.4, 53.1, 18.1, 12.1. HRMS (ESI) [M + Na]+ calcd. for
[C25H37NO3SiNa]+: 450.2435, found: 450.2442.
2922, 2860, 1713, 1611, 1568, 1506, 1231, 1179 cmÀ1
δH(500 MHz; CDCl3) 10.05 (1H, s), 8.18 (1H, s), 7.36
.
3
3
4
(1H, d, J 9.0), 6.62 (1H, dd, J 8.9, J 2.3), 6.48 (H, d,
4J 2.0), 5.85–5.75 (2H, m), 5.22 (2H, d, J 10.4), 5.15
3
3-((Triisopropylsilyl)oxy)methyl)-7-aminocoumarin
(2H, d, 3J 17.1), 4.03–3.98 (4H, m). δC(126 MHz;
CDCl3) 187.8, 161.6, 158.6, 154.6, 145.5, 132.3, 131.4,
117.4, 115.1, 110.8, 108.8, 98.2, 53.2. HRMS (ESI)
[M + H]+ calcd. for [C16H16NO3]+: 270.1125, found:
270.1124.
(9).
3-((Triisopropylsilyl)oxy)methyl)-7-
diallylaminocoumarin, 8 (200 mg, 0.47 mmol, 1.0 eq.),
1,3-dimethylbarbituric acid (438 mg, 2.81 mmol, 6.0 eq.),
and Pd(PPh3)4 (14 mg, 0.012 mmol, 0.025 eq.) were
mixed in CH2Cl2 (1.5 cm3) and stirred at 35°C for 16 h.
Next, CH2Cl2 (20 cm3) was added to the reaction
mixture, and the organic phase was washed with sat.
Na2CO3 (2 × 10 cm3) and brine (1 × 10 cm3). The
organic phase was dried over MgSO4, filtered, and
evaporated. Product was purified with flash column
3-Hydroxymethyl-7-diallylaminocoumarin (7). Compound
6 (910 mg, 3.38 mmol, 1.0 eq.) was dissolved in the mixture
of 20 cm3 tetrahydrofuran and 10 cm3 MeOH, and then
NaBH4 (317 mg, 8.38 mmol, 2.5 eq.) was added in small
portions at 0°C. After 5-min stirring at 0°C, the reaction
was quenched with 2 cm3 cc.NH4Cl and allowed to warm
up to r.t. The organic phases were removed under reduced
pressure. To the remainder was added 30 cm3 of water, and
the mixture was extracted with EtOAc (3 × 70 cm3). The
organic phases were combined, washed with brine
(1 × 100 cm3), dried over MgSO4, and filtered. Solvent was
removed in vacuo, and the crude product was purified
using flash column chromatography (SiO2, hexanes/EtOAc,
EtOAc: 0 → 30 v/v) to result 7 as a yellowish oil (449 mg,
49%). Rf = 0.20 (hexanes/EtOAc 2:1 v/v). IR (neat)
ν = 3404 br, 2866, 1697, 1605, 1521, 1404, 1236,
1165 cmÀ1. δH(500 MHz; CDCl3) 7.55 (1H, s), 7.23 (1H,
chromatography
(SiO2,
hexanes/EtOAc,
EtOAc:
0 → 30 v/v) to result 9 as a yellowish-white powder
(133 mg, 82%). m.p.: 146–151°C. Rf = 0.60 (hexanes/
EtOAc 1:1 v/v). IR (neat) ν = 3478, 3370, 3244, 2943,
2866, 1682, 1599, 1402, 1251, 1132 cmÀ1. δH(500 MHz;
CDCl3) 7.72 (1H, s), 7.24 (1H, d, 3 J 8.4), 6.64 (1H, s),
6.55 (1H, d, 3 J 8.2), 4.66 (2H, s), 4.23 (2H, brs), 1.22–
1.12 (3H, m), 1.09 and 1.07 (18H, 2 × s). δC(126 MHz;
CDCl3) 161.4, 155.0, 150.0, 137.7, 128.9, 123.1, 112.1,
111.1, 100.8, 18.1, 12.1. HRMS (ESI) [M + Na]+ calcd.
for [C19H29NO3SiNa]+: 370.1809, found: 370.1814.
3-Hydroxymethyl-7-azidocoumarin
(10).
3-
3
4
4
((Triisopropylsilyl)oxy)methyl)-7-aminocoumarin
(9)
d, 3 J 8.7), 6.58 (1H, dd, J 8.7, J 2.3), 6.52 (1H, d, J
3
(229 mg, 0.66 mmol, 1.0 eq.) was suspended in the
mixture of 5 cm3 EtOH and 5 cm3 20% HCl-solution.
The solution of NaNO2 (59 mg, 0.86 mmol, 1.3 eq.) in
0.75 cm3 H2O was added dropwise at 0°C and stirred for
10 min at 0°C. NaN3 (64 mg, 0.98 mmol, 1.5 eq.) in
0.75 cm3 H2O was then added dropwise while keeping
the temperature at 0°C. Following the addition, the
mixture was allowed to warm up to r.t. and stirred for 1 h
at ambient temperature. Next, H2O (5 cm3) was added
and the reaction mixture was extracted with CH2Cl2
(3 × 15 cm3) and dried over MgSO4. The solution was
filtered and concentrated in vacuo. The crude product
(mixture of silylated and desilylated compounds) was
dissolved in 4 cm3 tetrahydrofuran, and TBAF.3H2O
(104 mg, 0.33 mmol, 0.5 eq.) was added, and the mixture
was stirred for 15 min at r.t. (monitored by TLC). After
2.1), 5.87–5.76 (2H, m), 5.19 (2H, d, J 11.0), 5.15 (2H, d,
3J 17.8), 4.52 (2H, s), 3.97–3.94 (4H, m), 2.97 (1H, br s).
δC(126 MHz; CDCl3) 162.6, 155.7, 151.5, 139.7, 132.5,
128.7, 121.3, 116.8, 109.7, 109.2, 98.4, 61.4, 53.0. HRMS
(ESI) [M + Na]+ calcd. for [C16H17NO3Na]+: 294.1101,
found: 294.1105.
3-((Triisopropylsilyl)oxy)methyl)-7-diallylaminocoumarin
(8).
3-Hydroxymethyl-7-diallylaminocoumarin
(7)
(249 mg, 0.92 mmol, 1.0 eq.) and imidazole (186 mg,
2.73 mmol, 3.0 eq.) were dissolved in 10 cm3 CH2Cl2.
Chlorotriisopropylsilane (353 mg, 1.83 mmol, 2.0 eq.)
was added slowly at 0°C, and then the reaction mixture
was allowed to warm up to r.t. and stirred for 16 h. The
mixture was filtered through a pad of Celite, and then the
solvent was removed in vacuo. Product was purified by
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Z. Pünkösti, P. Kele, and A. Herner
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then, CH2Cl2 (25 cm3) was added and the organic phase
was washed with water (1 × 5 cm3), dried over MgSO4,
filtered, and concentrated in vacuo. Product was purified
by flash column chromatography (SiO2, hexanes/EtOAc,
EtOAc%: 0 → 33 v/v) to provide 9 as an off-white
powder (122 mg, 85%). Rf = 0.50 (hexanes/EtOAc
1:1 v/v). IR (neat) ν = 3431 br, 3082, 2937, 2102, 1682,
1614, 1381, 1309, 1273, 1184 cmÀ1. δH(500 MHz;
[2] Link, K. P. Circulation 1959, 19, 97.
[3] (a) Musa, M. A.; Cooperwood, J. S.; Khan, M. O. F. Curr Med
Chem 2008, 15, 2664; (b) Kontogiorgis, C.; Detsi, A.; Hadjipavlou-
Litina, D. Expert Opin Ther Patents 2012, 22, 437; (c) Venugopala, K.
N.; Rashmi, V.; Odhav, B. Biomed. Res. Int. 2013, Article ID 963248.
[4] (a) Sinkeldam, R. W.; Greco, N. J.; Tor, Y. Chem Rev 2010,
110, 2579; (b) Lavis, L. D.; Raines, R. T. ACS Chem Biol 2014, 9, 855.
[5] (a) Shieh, P.; Hangauer, M. J.; Bertozzi, C. R. J Am Chem Soc
2012, 134, 17428; (b) Hörner, A.; Volz, D.; Hagendorn, T.; Fürniss, D.;
Greb, L.; Rönicke, F.; Nieger, M.; Scheepers, U.; Bräse, S. RSC Adv
2014, 4, 11528; (c) Kozma, E.; Estrada Girona, G.; Paci, G.; Lemke, E.
A.; Kele, P. Chem Commun 2017, 53, 6696: (d) Herner, A.; Nikić, I.;
Kállay, M.; Lemke, E. A.; Kele, P. Org BiomolChem 2013, 11, 3297.
[6] (a) Demeter, O.; Fodor, E. A.; Kállay, M.; Mező, G.; Németh,
K.; Szabó, P. T.; Kele, P. Chem A Eur J 2016, 22, 6382; (b) Demeter, O.;
Kormos, A.; Koehler, C.; Mező, G.; Németh, K.; Kozma, E.; Takacs, L.;
Lemke, E. A.; Kele, P. Bioconjug Chem 2017, 28, 1552.
[7] (a) Herner, A.; Girona, G. E.; Nikić, I.; Kállay, M.; Lemke, E.
A.; Kele, P. Bioconjug Chem 2014, 25, 1370; (b) Eördögh, Á.;
Steinmeyer, J.; Peewasan, K.; Schepers, U.; Wagenknecht, H.-A.; Kele,
P. Bioconjug Chem 2016, 27, 457.
3
CDCl3) 7.71 (1H, s), 7.47 (1H, d, J 8.2), 7.00–6.92 (2H,
m), 4.60 (2H, s), 2.50 (1H, brs). δC(126 MHz; CDCl3)
160.9, 154.4, 143.8, 138.2, 129.3, 127.0, 116.3, 116.0,
107.0, 61.1. HRMS (ESI) [M + Na]+ calcd. for
[C10H7N3O3Na]+: 240.0380, found: 240.0385.
3-Formyl-7-azidocoumarin (11).
hydroxymethyl-7-azidocoumarin
To a solution of 3-
(10) (153 mg,
0.70 mmol, 1.0 eq.) in 6 cm3 CH2Cl2 Dess–Martin
periodane (385 mg, 0.91 mmol, 1.3 eq.) in 5 cm3,
CH2Cl2 was added, and the reaction mixture was stirred
for 2 h at r.t. Following that, 30 cm3 CH2Cl2 was added,
and the organic phase was washed with H2O (1 × 5 cm3),
dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the product with flash column
chromatography (SiO2, hexanes/EtOAc, EtOAc%:
0 → 33 v/v) afforded 11 as a yellow powder (145 mg,
96%). Rf = 0.76 (hexanes/EtOAc 1:1 v/v). IR (neat)
ν = 3051, 2928, 2124, 1730, 1682, 1595, 1553, 1427,
1356, 1304, 1267, 1171 cmÀ1. δH(500 MHz; CDCl3)
[8] Perkin, W. H. J Chem Soc 1868, 21, 181.
[9] Knoevenagel, E. Ber Dtsch Chem Ges 1898, 31, 2596.
[10] v. Pechmann, H. Ber Dtsch Chem Ges 1884, 17, 929.
[11] (a) Mali, R. S.; Deshpande, J. V. Org Prep Proced Int 1995, 27,
663. b) Shen, W.; Mao, J.; Sun, J.; Sun, M.; Zhang, C. Med Chem Res
2013, 22, 1630; (b) Patil, P. O.; Bari, S. B.; Firke, S. D.; Deshmukh, P.
K.; Donda, S. T.; Patil, D. A. Bioorg Med Chem 2013, 21, 2434.
[12] Kaye, P. T.; Musa, M. A.; Nocanda, X. W. Synthesis 2003, 4,
531.
[13] Li, J.; Chen, H.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. RSC
Adv 2013, 3, 4311.
[14] (a) Gigu re, D.; Cloutier, P.; Roy, R. J Org Chem 2009, 74,
8480; (b) Fernandes, T. A.; Vaz, B. G.; Eberlin, M. N.; da Silva, A. J.
M.; Costa, P. R. R. J Org Chem 2010, 75, 7085.
[15] (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992; (b) Trost, B. M.; Toste, F. D.;
Greenman, K. J Am Chem Soc 2003, 125, 4518.
3
10.22 (1H, s), 8.36 (1H, s), 7.66 (1H, d, J 7.6), 7.02
(2H, s). δC(126 MHz; CDCl3) 187.6, 159.9, 157.0,
147.8, 145.0, 132.4, 120.5, 116.8, 115.4, 107.3. HRMS
(ESI) [M + Na]+ calcd. for [C10H5N3O3Na]+: 238.0223,
found: 238.0224.
[16] Sharma, U.; Naveen, T.; Maji, A.; Manna, S.; Maiti, D. Angew
Chem Int Ed 2013, 52, 12669.
[17] Metternich, J. B.; Gilmour, R. J Am Chem Soc 2016, 138,
1040.
[18] Vedejs, E.; Meier, G. P.; Snoble, K. A. J. J Am Chem Soc
1981, 103, 2823.
[19] Harayama, T.; Nakatsuka, K.; Nishioka, H.; Murakami, K.;
Hayashida, N.; Ishii, H. Chem Pharm Bull 1991, 39, 3100.
[20] (a) Nicolaides, D. N.; Fylaktakidou, K. C.; Litinas, K. E.;
Adamopoulos, S. G. J Heterocyclic Chem 1998, 35, 91; (b) Sakai, H.;
Hirano, T.; Mori, S.; Fujii, S.; Masuno, H.; Kinoshita, M.; Kagechika,
H.; Tanatani, A. J Med Chem 2011, 54, 7055; (c) Gagey, N.; Neveu, P.;
Benbrahim, C.; Goetz, B.; Aujard, I.; Baudin, J.-B.; Jullien, L. J Am
Chem Soc 2007, 129, 9986.
Acknowledgments. Present work was supported by the
Hungarian Scientific Research Fund (OTKA, NN-116265) and
the “Lendület” Program of the Hungarian Academy of Sciences
(LP2013-55/2013). Z. P. is grateful for the support of Hungarian
Academy of Sciences for a Young Researcher Fellowship
(FIKU).
REFERENCES AND NOTES
SUPPORTING INFORMATION
[1] (a) Murray, R. D. H. Nat Prod Rep 1995, 12, 477; (b) Estévez-
Braun, A.; Gonzalez, A. G. Nat Prod Rep 1997, 14, 465; (c) Ramendra,
P.; Vishnu, J. R. Chem Rev 2014, 114, 10476.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet