Synthesis of furanochromones: A new step in improvement of fluorescence properties

Article abstract of DOI:10.1016/S0040-4039(02)01547-2

New 3-hydroxychromone derivatives with a fused furan heterocycle (2-aryl-3-hydroxyfurano[3,2-g]chromones) have been synthesized. This was achieved by an important improvement in the synthetic procedure. Like their parent analogs, these new compounds exhibit two intensive fluorescence emission bands belonging to normal (N*) and tautomer (T*) excited-state forms. While the spectral position of the N* band remains unchanged, the T* band is shifted to longer wavelengths, providing larger separation between the two bands. The new compounds exhibit increased molecular extinction and, more importantly, have about twice as high fluorescence quantum yields. These properties make them very promising for designing new two-band fluorescence sensors.

Full text of DOI:10.1016/S0040-4039(02)01547-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7079–7082
Synthesis of furanochromones: a new step in improvement of
fluorescence properties
Andrey S. Klymchenko,a,b,* Turan Ozturka and Alexander P. Demchenkoa,c
aTUBITAK RIGEB and TUBITAK MRC, Gebze-Kocaeli 41470, Turkey
bDepartment of Chemistry, Kyiv National Taras Shevchenko University, 01033 Kyiv, Ukraine
cA. V. Palladin Institute of Biochemistry, 9 Leontovicha str., 02030 Kyiv, Ukraine
Received 2 May 2002; revised 27 June 2002; accepted 26 July 2002
Abstract—New 3-hydroxychromone derivatives with a fused furan heterocycle (2-aryl-3-hydroxyfurano[3,2-g]chromones) have
been synthesized. This was achieved by an important improvement in the synthetic procedure. Like their parent analogs, these new
compounds exhibit two intensive fluorescence emission bands belonging to normal (N*) and tautomer (T*) excited-state forms.
While the spectral position of the N* band remains unchanged, the T* band is shifted to longer wavelengths, providing larger
separation between the two bands. The new compounds exhibit increased molecular extinction and, more importantly, have about
twice as high fluorescence quantum yields. These properties make them very promising for designing new two-band fluorescence
sensors. © 2002 Elsevier Science Ltd. All rights reserved.
3-Hydroxyflavones have recently attracted the attention
of researchers due to their interesting photochemical
behavior and as prospective two-band fluorescence sen-
sors. This is a unique organic dye family that undergoes
an excited state intramolecular proton transfer (ESIPT)
reaction resulting in two highly intensive, well separated
and solvent-dependent emission bands originating from
the normal excited form (N*) and the phototautomer
(T*).1,2 The introduction of an electron donor, a dialkyl-
amino group, to the 4%-position of 1 increased the
charge-transfer character of the N* form, which made
the relative intensity of the N* band much higher and
strongly dependent on solvent polarity.3–5 This property
resulted in a variety of applications for substituted
3-hydroxyflavones as ion sensors6 and as probes in the
studies of organized systems such as micelles7,8 and
phospholipid vesicles.9–12 Attempts to provide further
improvements to these valuable properties resulted in
the synthesis of 2-benzo/naphthofuryl-3-hydroxy-
chromone derivatives.13 They showed increased fluores-
cence quantum yields and strong red shifts in
absorption and fluorescence spectra. Finally, the intro-
duction of a dialkylamino group to the 6%-position of
2-(2-benzo[b]furanyl)-3-hydroxychromone (2) resulted
in the longest wavelengths in absorption and fluores-
cence reported for 3-hydroxychromone derivatives to
date.14 However, in order to serve better as fluorescence
sensors for biological systems, some fluorescence prop-
erties of 3-hydroxychromones still have to be improved.
It is favorable to increase the fluorescence quantum
yield, which is normally lower than 30%, and the
extinction coefficient, usually about 35,000.5,14 Further-
more, for dual color measurements and imaging in
microscopy, it is desirable to apply the probes having
high separation between fluorescence maxima, which
appears to be insufficient for 3-hydroxychromone
probes exposed to highly polar and non-homogeneous
* Corresponding author. Tel.: +90-262-641-2300/3625; fax: +90-262-
641-2309; e-mail: andrey@rigeb.gov.tr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01547-2

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A. S. Klymchenko et al. / Tetrahedron Letters 43 (2002) 7079–7082
environments. This problem is particularly important
for 4%-dialkylamino-substituted 3-hydroxyflavones, the
strongly solvatochromic N* band of which shifts to the
red and overlaps with the T* band.10,14 In this letter we
report two 2-aryl-3-hydroxyfurano[3,2-g]chromone
derivatives 1a and 2a, in which the fused furan hetero-
cycle provides a 3-hydroxychromone chromophore with
improved fluorescence properties. Moreover, we suggest
a modified procedure for the synthesis of 3-hydroxy-
chromone derivatives, which is essential for obtaining
the reported compounds.
nature of the 3-hydroxychromones synthesized via the
modified procedure, this could be a breakthrough in the
synthesis of advanced chromones.
Absorption and fluorescence properties of 3-hydroxy-
furano[3,2-g]chromones 1a and 2a were studied with
respect to the parent 3-hydroxychromones 1 and 2 in
six solvents of different polarity: hexane, toluene, ethyl
acetate, chloroform, acetonitrile and ethanol.20 In all
the solvents the furanochromones show absorption
spectra shifted to longer wavelengths by 4–5 nm (210–
300 cm−1), which is, for 1a, accompanied by increased
extinction coefficients, ca. 5,000 l×mol−1×cm−1 (Fig. 1
and Table 1). Thus, the introduction of a furan hetero-
cycle at different sites of the chromone chromophore
results in different spectral effects. The fused furan in
the case of 1a favors significant growth of molecular
extinction, without a strong red shift, while the intro-
duced furan in the case of 2 results in the strong red
shift accompanied by a relatively small increase in
molecular extinction. In fluorescence spectra fura-
nochromones 1a and 2a exhibit two bands, the intensity
ratio (IN*/IT*) of which is highly sensitive to solvent
polarity. This behavior is typical for 3-hydroxy-
chromone derivatives.4,5 The observed effects on the
positions of the fluorescence bands are very interesting.
Introduction of the furan heterocycle to chromones 1
and 2 results in a red shift of the T* emission band,
while the N* band remains at almost the same position
(see Figs. 2 and 3 and Table 1). This is very unusual,
since all the modifications provided previously on mod-
ulation of the donor properties of the 2-aryl substituent
in 3-hydroxychromones affected both of the bands with
stronger shifts of the N* band.5,14 The red shift of the
T* band, which appears to be stronger in less polar
solvents (Table 1), increases band separation for fura-
nochromones 1a and 2a by 12–17 nm (360–520 cm−1)
and 7–13 nm (180–320 cm−1), respectively (Figs. 2 and
3). The other prominent feature of furanochromones is
their high fluorescence quantum yield. It is approxi-
mately twice that of the parent chromones and reaches
record values compared to all the reported 3-hydroxy-
chromones, 70% for 1a in ethanol and 61% for 2a in
chloroform (Table 1).
4%-Diethylamino-3-hydroxy-furano[3,2-g]flavone
(1a)
and 2-(6-diethylaminobenzo[b]furan-2-yl)-3-hydroxy-
furano[3,2-g]chromone (2a) were synthesized in four
steps starting from 2%,4%-dihydroxyacetophenone
(Scheme 1). The latter was transformed to its sodium
salt with sodium hydride, and then reacted with bro-
moacetaldehyde diethylacetal in DMSO at 50°C, using
KI as a catalyst. The product 315 was refluxed in
toluene in the presence of polyphosphoric acid (PPA)
for 2 h. The resulting benzofuran derivative 416 was
isolated after silica gel column chromatography (hex-
ane/ethyl acetate, 8/1, v/v). An attempt to convert 4
into the corresponding 3-hydroxychromones by a gen-
eral two-step procedure17,18 failed. Therefore, the condi-
tions for both of the steps were modified. For
condensation of 4 with aldehydes 5 and 6, we applied
sodium methoxide in DMF instead of the commonly
used sodium hydroxide in aqueous water. The reaction
was completed in 1 h, while with the common method
it took several weeks. The mixture was diluted with
ethanol, then, subsequently, a 20 molar excess of
sodium methoxide and a 15 molar excess of 30% hydro-
gen peroxide were added. It was then refluxed for less
than 1 min, cooled to room temperature and poured
into water. After neutralization, the resultant precipi-
tate was filtered. The target chromones were purified by
crystallization from butanol.19 The yields of 1a and 2a
for the last two steps were found to be 25 and 12%,
respectively. The failure of the general procedure17,18 in
this case could be due to the effect of p-electron dona-
tion by the dialkylamino group and the fused furan
heterocycle. Considering the complicated structural
Figure 1. Normalized absorption spectra of the studied
Scheme 1. Synthesis of chromones 1a and 2a.
chromones in toluene.

A. S. Klymchenko et al. / Tetrahedron Letters 43 (2002) 7079–7082
Table 1. Spectral properties of the studied chromonesa
7081
Solvent
Hexane
umax abs (nm)
umax fl N* (nm)
umax fl T* (nm)
I
N*/IT*
m (l×mol−1×cm−1
)
€
1
1a
2
403
407
439
445
425
426
457
460
553
571
583
599
0.010
0.0077
0.078
0.088
37000
42000
44800
47000
0.14
0.26
0.20
0.23
2a
Toluene
1
1a
2
408
413
446
451
456
458
508
508
566
581
613
623
0.044
0.0313
0.55
35000
40000
37600
39000
0.14
0.29
0.26
0.36
2a
0.601
EtOAc
CHCl3
CH3CN
EtOH
1
1a
2
401
406
436
440
475
476
537
538
570
584
618
626
0.253
0.133
1.93
35000
41000
37000
38000
0.05
0.13
0.26
0.40
2a
2.24
1
1a
2
413
418
453
458
481
482
545
546
560
0.669
0.422
4.21b
4.07b
35000
41000
37000
38000
0.19
0.34
0.46
0.61
573
621b
629b
2a
1
1a
2
404
408
437
441
509
510
582
582
571
586
–
1.30
1.01
–
35000
38000
36000
37000
0.09
0.18
0.25
0.37
2a
–
–
1
1a
2
412
418
444
449
523
523
600
600
–
–
–
–
–
–
–
–
35000
38000
36000
37000
0.52
0.70
0.09
0.18
2a
a umax abs: positions of absorption maxima; umax fl N* and umax fl T*: positions of fluorescence maxima of N* and T* forms (dashes signify that
the corresponding maxima are not resolved). € is the fluorescence quantum yield determined with 1 as the reference (€=0.52 in ethanol, see Ref.
3), and m-molar extinction coefficient. All the data for compounds 1 and 2, reported in Ref. 14, were reproduced and corrected.
b The values were evaluated from results on deconvolution of the spectra to two bands approximated by log-normal function using the Siano
program kindly provided by the author (A. O. Doroshenko from the Karazin University, Kharkov, Ukraine).
It is essential that the introduction of the furan hetero-
cycle does not change the basic fluorescence property of
3-hydroxychromones—their dual emission. Further-
more, the strong sensitivity of the intensity ratio
between emission bands (IN*/IT*) to solvent polarity is
also preserved. Thus, an increase in solvent polarity
from hexane to acetonitrile results in a strong growth of
IN*/IT* for both furanochromones (Table 1), which is
similar to that for the parent chromones. This is a very
important fact, because it allows further modifications
of the chromone system to be suggested to design new
dual emission dyes.
In conclusion, a new modification of the procedure for
the preparation of 3-hydroxychromones allowed the
synthesis of new 2-aryl-3-hydroxyfurano[3,2-g]chro-
mones in a short time and with relatively high yields.The
highly polarizable p-electron abundant furan heterocycle
provides a 3-hydroxychromone chromophore with sub-
stantially improved fluorescence properties, the most
significant of which are a dramatic increase in the
fluorescence quantum yield and larger separation between
two emission maxima. Finally, it should be noted that
the target furanochromones, due to the high reactivity
of the furan heterocycle, can be very promising for fur-
ther derivatization with the purpose of designing new
molecular sensors.
Figure 2. Normalized fluorescence spectra of 1 and 1a in
chloroform (A) and acetonitrile (B).

7082
A. S. Klymchenko et al. / Tetrahedron Letters 43 (2002) 7079–7082
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15. 1-[4-(2,2-Diethoxyethoxy)-2-hydroxyphenyl]ethan-1-one
isolated by silica gel column chromatography (hexane/
ethyl acetate, 3:1, v/v), yield 32%, mp 50°C, was used in
the next step without characterization.
16. 1-(6-Hydroxybenzo[b]furan-5-yl)ethan-1-one, yield 25%,
mp 101°C, 1H NMR (200 MHz, CDCl3) 2.70 (3H, s),
6.73 (1H, d, J 2.2 Hz), 7.04 (1H, s), 7.56 (1H, d, J 2.2
Hz), 8.00 (1H, s), 12.43 (1H, s), EI m/z 176.0 (M+), 161.0,
149.1, 133.0, 121.0, 105.0, 85.1, 77.0, 71.1, 57.0.
17. Algar, J.; Flynn, J. Proc. Royal Irish. Acad. 1934, B42,
1–8.
Figure 3. Normalized fluorescence spectra of fura-
nochromones 2 and 2a in toluene (A) and ethyl acetate (B).
Acknowledgements
18. Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Hetero-
cycl. Chem. 1968, 5, 425–426.
We thank TUBITAK Marmara Research Center
(Turkey) for providing financial support.
19. 4%-Diethylamino-3-hydroxy-furano[3,2-g]flavone (1a): yield
1
25%, mp 155°C, H NMR (200 MHz, CDCl3) 1.24 (6H,
t, J 7.1 Hz), 3.46 (4H, q, J 7.1 Hz), 6.79 (2H, d, J 9.2 Hz),
6.87 (1H, s), 6.91 (1H, d, J 2.1 Hz) 7.66 (1H, s), 7.72 (1H,
d, J 2.1), 8.19 (2H, d, J 9.2 Hz), 8.46 (1H, s), EI m/z
349.1 (M+), 334.1, 305.0. 2-(6-Diethylaminobenzo[b]furan-
2-yl)-3-hydroxyfurano [3,2-g]chromone (2a): yield 12%,
mp 228°C, 1H NMR (200 MHz, CDCl3) 1.25 (6H, t, J 7.1
Hz), 3.46 (4H, q, J 7.1 Hz), 6.76 (1H, dd, J 8.8, 2.1 Hz),
6.88 (1H, d, J 2.1 Hz), 6.93 (1H, d, J 2.1 Hz), 7.49 (1H,
d, J 8.8 Hz), 7.64 (1H, s), 7.75 (1H, d, J 2.1 Hz), 7.78
(1H, s), 8.49 (1H, s), EI m/z 389.1 (M+), 374.1, 345.1,
209.0, 161.0.
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