Fluorogenic aldehydes bearing arylethynyl groups: Turn-on aldol reaction sensors for evaluation of organocatalysis in DMSO

Article abstract of DOI:10.1016/j.tetlet.2014.02.007

Fluorogenic aromatic aldehydes bearing arylethynyl groups were developed. They were used for monitoring the reaction progress of organocatalytic aldol reactions in DMSO through an increase in the fluorescence intensity based on the formation of the florescent aldol product. The ratios of the fluorescence intensities of the aldols to the aldehydes were more than 300. These results suggest that the fluorescence assay system using the aldehyde is useful for the rapid identification of superior aldol catalysts and reaction conditions.

Full text of DOI:10.1016/j.tetlet.2014.02.007

Tetrahedron Letters 55 (2014) 1946–1948
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Tetrahedron Letters
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Fluorogenic aldehydes bearing arylethynyl groups: turn-on
aldol reaction sensors for evaluation of organocatalysis in DMSO
a
a
a
a
a
Nobuyuki Mase a, , Taishi Ando , Fumiya Shibagaki , Atsushi Sugita , Tetsuo Narumi , Mitsuo Toda ,
⇑
Naoharu Watanabe a, Fujie Tanaka b,
⇑
a Department of Applied Chemistry and Biochemical Engineering, Graduate School of Engineering, and Green Energy Research Division, Research Institute of Green Science
and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan
b Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorogenic aromatic aldehydes bearing arylethynyl groups were developed. They were used for moni-
toring the reaction progress of organocatalytic aldol reactions in DMSO through an increase in the fluo-
rescence intensity based on the formation of the florescent aldol product. The ratios of the fluorescence
intensities of the aldols to the aldehydes were more than 300. These results suggest that the fluorescence
assay system using the aldehyde is useful for the rapid identification of superior aldol catalysts and reac-
tion conditions.
Received 11 December 2013
Revised 31 January 2014
Accepted 4 February 2014
Available online 13 February 2014
Keywords:
Fluorogenic probe
Ó 2014 Elsevier Ltd. All rights reserved.
Fluorescent molecules
High-throughput screening
CarbonAcarbon bond formation
Organocatalysis
The methods for monitoring the reaction progress of chemical
transformations through an increase in the fluorescence intensity
are useful for screening of catalysts and reaction conditions, as well
as the characterization of catalysis on a small scale.1 Various fluo-
rogenic substrates have been developed for monitoring the reac-
tion progress of catalytic cleavage reactions, functional group
transformations,2–4 and bond-forming including carbon–carbon
bond-forming reactions.5–9 Practical utility of the substrates have
been demonstrated.10 Herein, we report the synthesis and the
use of fluorogenic aldehydes bearing arylethynyl groups that are
suitable for monitoring the organocatalytic aldol reactions in
DMSO that is frequently used as an organic solvent in such
reactions.
peptide-catalyzed aldol reactions in aqueous solutions.7c However,
the reactivity of 9-anthraldehyde was relatively low in both
aqueous and DMSO conditions (vide infra); this may be because
the 9-anthracene moiety acts as a bulky group and hinders the
reactions. To develop fluorescence monitoring systems with
appropriate reactivity that retain desired fluorescence features of
9-anthraldehyde and its aldols, aldehydes smaller than 9-anthra-
ldehyde such as naphthaldehydes and benzaldehyde derivatives
conjugated to aryl groups were designed (Scheme 1). These alde-
hydes and their aldol products were synthesized or purchased
and evaluated in fluorescence and organocatalytic reactivity in
DMSO.
As previously reported, aldol reaction progress can be
monitored through an increase in fluorescence using a fluorogenic
aldehyde.7 To be of practical use, the ratio of fluorescence intensity
of the aldol product to that of the fluorogenic aldehyde should be
high and the aldehyde should show no fluorescence or very weak
fluorescence.7 In addition, the reactivity of the aldehyde group in
fluorogenic aldehyde should be appropriate for the use.11 We
have recently reported the use of 9-anthraldehyde to monitor
O
aldol reaction
DMSO
O
OH
O
+
H
R
R
1
2
Fluorescence "OFF"
Ar
Fluorescence "ON"
R =
Ar
Ar
c
a
b
⇑
Corresponding authors. Tel./fax: +81 53 478 1196 (N.M.); tel.: +81 98 966 1552;
fax: +81 98 966 1064 (F.T.).
Ar = A: 9-anthryl; B: 1-naphthyl; C: 2-naphthyl
E-mail addresses:
(F. Tanaka).
tnmase@ipc.shizuoka.ac.jp (N. Mase),
ftanaka@oist.jp
Scheme 1. Fluorogenic substrates for aldol reactions.
http://dx.doi.org/10.1016/j.tetlet.2014.02.007
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

N. Mase et al. / Tetrahedron Letters 55 (2014) 1946–1948
1947
Table 1
O
O
4
ArB(OH)2
10%Pd/C
Fluorescent properties of aryl aldehyde derivatives 1 and the corresponding aldols 2
H
H
Entry
Wavelength (nm)
Fluorescence intensity
Fold
H2O/EtOH
rt, 24 h
Br
Ar
kex
kem
Aldehyde 1
Aldol 2
3
1bA (21%)
1
2
3
4
5
6
7
8
9
265
220
235
265
300
270
270
330
330
419
—
—
401
342
363
432
351
347
1aA
1aB
1aC
1bA
1bB
1bC
1cA
1cB
1cC
1.66 Â 101
2aA
2aB
2aC
2bA
2bB
2bC
2cA
2cB
2cC
5.34 Â 103
—
—
322
—
—
60
4.6
16
133
368
303
1bB
(94%)
—
1bC (93%)
—
1) TMSA, PdCl2, Cu(OAc)2,
PPh3, Et3N, reflux, 6 h
2) K2CO3, MeOH, rt, 24 h
4.17 Â 101
5.66 Â 101
8.51 Â 101
6.16 Â 101
2.08 Â 101
2.12 Â 101
2.49 Â 103
2.63 Â 102
1.33 Â 103
8.21 Â 103
7.65 Â 103
6.42 Â 103
O
O
ArBr 6
Pd(PPh3)4
H
H
toluene
i-Pr2NH
All measurements were carried out in 1.0
lM DMSO solution.
Ar
80 °C, 20 h
5
1cA
(37%)
1cB (40%)
1cC (58%)
(2 steps, 76%)
L-proline
O
O
OH
Ar
O
+
Ar = A: 9-anthryl; B: 1-naphthyl; C: 2-naphthyl
Scheme 2. Preparation of benzaldehyde derivatives 1.
H
1aA
Ar
1cB
DMSO
rt, 1 h
7
2aA
2cB
or
or
Ar =
The syntheses of 4-arylbenzaldehyde derivatives 1b and
4-arylethynylbenzaldehyde derivatives 1c are shown in Scheme 2.
The Pd/C-catalyzed phosphine-free Suzuki–Miyaura reactions12 of
4-bromobenzaldehyde (3) and boronic acids 4 at room tempera-
ture afforded the 4-arylbenzaldehyde derivatives 1bA–1bC in
moderate to excellent (21–94%) yields (Scheme 2). 4-Ethynylbenz-
aldehyde (5) was synthesized from 3 and trimethylsilylacetylene
(TMSA) in 76% yield over two steps.13 The Sonogashira coupling
reactions14 of aldehyde 5 and aryl bromides 6 at 80 °C afforded
the corresponding aldehydes 1cA–1cC in moderate to good
(37–58%) yields.
aA:
cB:
4
1aA → 2aA
1cB → 2cB
3
2
1
0
Aldols
2 were prepared by the organocatalytic L-proline-
catalyzed aldol reactions15 between acetone and benzaldehyde
derivatives 1 (Scheme 3). Nine derivatives 2aA–2cC were prepared
in moderate to good (41–81%) yields at room temperature without
any special operation.
First, aldehydes 1aA–1aC were evaluated. 9-Anthraldehyde
(1aA) emits very weak fluorescence in many solvents upon UV
irradiation at the appropriate wavelengths;16 whereas, it is known
that anthracen-9-ylmethanol emits strong blue fluorescence.17
Similarly, aldol 2aA was highly fluorescent in DMSO.7c The ratio
of the fluorescence intensities of 2aA to 1aA was 322 in DMSO
(Table 1, entry 1). To test the utility of 1aA for monitoring the
reaction progress of a typical organocatalytic aldol reaction, the
reaction between acetone and aldehyde 1aA was performed using
0.0
0.2
0.4
0.6
0.8
1.0
Time (h)
Figure 1. Fluorescence monitoring of aldol reactions; reaction conditions: aldehyde
(10 M), -proline (1 mM) in 20% acetone/75% DMSO/5% H2O; reaction volume
l
L
3 mL; the reaction was performed in a quartz cuvette. For the reaction of 1aA with
acetone, the fluorescence intensity of 2aA was monitored at kex = 265 nm and
kem = 420 nm; the slope over 1 h was 0.09. For the reaction of 1cB with acetone, the
fluorescence intensity of 2cB was monitored at kex = 330 nm and kem = 351 nm; the
slope over 1 h was 3.68.
L-proline as the catalyst, and the fluorescence intensity was
recorded (Fig. 1, see also the Supplementary Material for the
details of the fluorescence spectra). Although aldol 2aA was highly
fluorescent, the increase in the fluorescence intensity observed
during the reaction was low; the slope over 1 h was 0.09. The
to afford 2aA was too slow to obtain any reasonable data. The bulk-
iness of the 9-anthryl group probably caused the slow reaction.
When less bulky naphthalene derivatives 1aB/2aB and 1aC/2aC
were evaluated, no fluorescence was observed at 1 lM concentra-
L-proline-catalyzed aldol reaction of aldehyde 1aA with acetone
tion in DMSO under the UV irradiation at 220 and 235 nm, respec-
tively (Table 1, entries 2 and 3). Although naphthalene derivatives
are known to be fluorescent,18 the results of the fluorescence mea-
surements of 1aB/2aB and 1aC/2aC in DMSO indicate that naph-
thaldehydes are not good fluorogenic substrates for the analysis
of the formation of the aldols at the initial stages of the reactions.
Next, arylbenzene derivatives 1b and arylethynylbenzene
derivatives 1c were evaluated. Aldehydes 1bA–1bC and 1cA–1cC
emitted very weak fluorescence, whereas aldols 2bA–2bC and
2cA–2cC emitted strong fluorescence in DMSO under the irradia-
tion at appropriate wavelengths (Table 1, entries 4–9). The ratios
of the fluorescence intensities of 2b/1b varied from 4.6 to 60
(Table 1, entries 4–6), whereas those of 2c/1c were more than
100 (Table 1, entries 7–9). The best pair of aldol/aldehyde among
O
O
OH
L-proline
H
R
R
acetone
rt, 96 h
1aA-1cC
2aA (42%) 2bA (56%) 2cA (81%)
2aB 2bB 2cB
(51%)
2aC (48%) 2bC (41%) 2cC (54%)
(49%)
(76%)
R =
Ar
Ar
Ar
c
a
b
Ar = A: 9-anthryl; B: 1-naphthyl; C: 2-naphthyl
Scheme 3. Organocatalytic aldol reactions of benzaldehyde derivatives 1.

1948
N. Mase et al. / Tetrahedron Letters 55 (2014) 1946–1948
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Figure 2. Photographs of the solutions of 1-naphthylethynylbenzene derivatives in
DMSO (0.1 mM): (a) aldehyde 1cB and aldol 2cB under visible light; (b) aldehyde
1cB and (c) aldol 2cB under UV light at kex = 254 nm (UV lamp), kem = 300–400 nm
(UV camera with filters BLF-390B and UTVAF-50S-33U, Sigma Koki Co., Ltd, Japan).
those tested was 2cB/1cB with a fluorescence intensity ratio of 368
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with aldehyde 1cB showed a significant increase in the fluores-
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of 1aA with acetone to afford aldol 2aA. These results indicate that
aldehyde 1cB is an excellent fluorogenic aldehyde for monitoring
the reaction progress of aldol reactions in DMSO.
In summary, we developed fluorogenic aldehydes that can be
used to monitor the reaction progress of L-proline-catalyzed aldol
reactions in DMSO through an increase in the fluorescence inten-
sity. This type of fluorescence assay system may be useful for the
rapid identification of superior aldol catalysts. The studies on the
full scope of the fluorescence monitoring systems for chemical
transformations using fluorogenic substrates containing arylethy-
nylbenzene moieties are currently under investigation and will
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This study was supported in part by a Grant-in-Aid for Young
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
007.
References and notes
19. The ratios of the fluorescence intensities of 2cB/1cB in various solvents: 232-fold in
CHCl3 (at kex = 320 nm and kem = 347 nm), 323-fold in AcOEt (at kex = 318 nm
and kem = 343 nm), 22-fold in 2-PrOH (at kex = 318 nm and kem = 343 nm), 764-
fold in CH3CN (at kex = 318 nm and kem = 343 nm), 31-fold in DMF (at
kex = 324 nm and kem = 347 nm), and 15-fold in Na phosphate buffer (pH 7, at
kex = 238 nm and kem = 360 nm). The fluorescence intensity of aldol 2cB in
different solvents analyzed in the above-indicated kex and kem wavelengths
relative to that in DMSO (2cB in DMSO at kex = 330 nm and kem = 351 nm: 100)
was as follows: CHCl3: 97; AcOEt: 117; 2-PrOH: 121; CH3CN: 119; DMF: 108;
Na phosphate buffer (pH 7): 14.
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