3,5-Bis(acetaldehyde) substituted BODIPY

Article abstract of DOI:10.1039/c2ob27004h

Two versions of a facile and efficient synthetic approach to 3,5-bis(acetaldehyde) substituted BODIPY have been developed and this compound has been used to obtain, in high yields, a variety of 3,5-divinyl BODIPY derivatives (vinylacetates, enamines, vinyl chlorides, and some multiple-functionalized products). As shown, vinyl substituents have an additive effect on the position of the BODIPY absorption maximum. The dyes synthesized are quite stable and exhibit intense absorption and fluorescence with wavelengths longer than 600 nm. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob27004h

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3,5-Bis(acetaldehyde) substituted BODIPY†
Cite this: DOI: 10.1039/c2ob27004h
Mykola P. Shandura, Viktor P. Yakubovskyi and Yuriy P. Kovtun*
Two versions of a facile and efficient synthetic approach to 3,5-bis(acetaldehyde) substituted BODIPY
have been developed and this compound has been used to obtain, in high yields, a variety of 3,5-divinyl
BODIPY derivatives (vinylacetates, enamines, vinyl chlorides, and some multiple-functionalized products).
As shown, vinyl substituents have an additive effect on the position of the BODIPY absorption maximum.
The dyes synthesized are quite stable and exhibit intense absorption and fluorescence with wavelengths
longer than 600 nm.
Received 15th October 2012,
Accepted 13th November 2012
DOI: 10.1039/c2ob27004h
www.rsc.org/obc
(α-positions)9 and at 1 or 710 of the BODIPY nucleus can be
nucleophilically substituted. The methylthio group at meso-
Introduction
Boron-dipyrromethene dyes (4,4-difluoro-4-bora-3a,4a-diaza- position is likewise substitutable.11 Alkylthio-substituted
s-indacene, BODIPY, BDP) have found numerous applications, BODIPYs also enter into the Liebeskind–Srogl cross-coup-
especially in biochemistry and molecular biology, owing to ling,12 whereas their halogen-containing analogues undergo
their excellent thermal, chemical and photochemical stability, palladium-catalyzed reactions like Suzuki, Heck, or Sonoga-
high molar absorptivity, high fluorescence quantum yield, and shira.13 With free α-positions, oxidative14a,b or vicarious
low sensitivity to both solvent polarity and pH.1 For the dyes to nucleophilic substitution of hydrogen14c can occur.
be used as fluorescent indicators for pH, metal ions, anions,
α-Methyl groups on the BODIPY ring appear especially
or biomolecules, they need to be appropriately functionalized promising in the context of chemical modification, first of all
(with the carboxyl, amino, azido groups, etc.).2 Since functiona- because they readily enter into the Knoevenagel conden-
lization presents one of the main challenges in the boron- sation.15 Therefore, this method was employed to obtain a
dipyrromethene chemistry, the methods have been developed great variety of derivatives including combinatorial series.15f
to substitute the nucleus concerned at all possible positions. Very importantly, the Knoevenagel condensation leads not
Substituted BODIPYs can be obtained from correspondingly only to the structural variations of the parent BODIPY system
functionalized pyrrole precursors as well as by functionalizing but also to a significant red shift both in absorption and emis-
intermediate dipyrromethanes or directly the BODIPY nucleus. sion of the reaction products. Methyl groups at the 1-, 7-,16
Electrophilic substitution reactions such as nitration,3 sulfo- and meso-positions17 can be reacted likewise affording nontri-
nation,3,4 formylation,5 or palladium-catalyzed C–H functionali- vial structures with specific spectral properties. Further, the
zation6 are known to proceed at positions 2 and 6 (β-positions) α-methyl can be oxidized to an aldehyde group18 or bromi-
of the BODIPY core (Fig. 1). Halogenation occurs first at the nated followed by nucleophilic substitution.19
same positions,3,7 but can further involve other unsubstituted
We have recently found another use of the α-methyl group
carbon atoms as well.8 Halogen atoms at positions 3 or 5 in BODIPY functionalization: it produces a formylmethyl
group in the reaction with DMF acetal (conversion 1 → 3 in
Scheme 1).20 Thus obtained acetaldehyde 3 shows great syn-
thetic promise since it gives rise to a wide variety of derivatives
(including some rather unusual structures) with intense long-
wavelength absorption and fluorescence. The tempting poten-
tialities of this approach have also motivated us to develop it
further in the present work which addresses the synthesis of
3,5-bis(acetaldehyde) substituted BODIPY 8 and its derivatives.
Fig. 1 Numbering of positions in BODIPY nucleus.
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Results and discussion
5 Murmanska Street, 02094 Kyiv, Ukraine. E-mail: kovtun@ioch.kiev.ua
†Electronic supplementary information (ESI) available: These data include
copies of 1H and 13C NMR spectra for all compounds. See DOI:
10.1039/c2ob27004h
Compound 1 (Scheme 1) contains β-ethoxycarbonyl groups
which activate α-methyl groups in electrophilic substitution
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Scheme 1 Synthesis of dialdehyde 8 via enole acetate 4.
reactions. This activation is sufficient to obtain enamine 2 by
the reaction with DMF dimethyl acetal (but insufficient to run
the Vilsmeier reaction). However, aldehyde 3 became inconve-
nient for some further manipulations due to the additional
activation of methylene group in its molecule, as it is easily
involved in side reactions. Thus, the corresponding enamine
cannot be obtained directly from 3 by the reaction with DMF
dimethyl acetal; instead, a complex mixture of products is
formed.20 To circumvent the problem, enolacetate 4 was used
as a starting compound and it indeed produced desired
product 5 readily and in high yield. Under the conditions of
acid hydrolysis, only an amine molecule is eliminated from
this substance to give aldehyde 6. To obtain free dialdehyde 8,
we had to additionally synthesize dienamine 7, which was
then easily hydrolyzed by acid.
Scheme 2 Synthesis of dialdehyde 8 via acetal 9.
derivatives. For instance, acetylation with acetic anhydride in
the presence of DMF leads to dienol acetate 11 (Scheme 3). On
treating the product with aniline, one acetyl group is substi-
tuted with ease to provide dye 12. However, an attempted sub-
stitution of the other acetyl group does not give the expected
Like its mono analogue 3, dialdehyde 8 undergoes keto–
1
enol tautomerism. The H NMR spectrum recorded in CDCl3
indicates the presence of dialdehyde in the form of 8 solely, di(anilinovinyl) derivative but only a complex mixture of
inseparable products.
whereas all three forms exist in DMSO-d6. As evidenced by the
Short heating of compound 8 with phosphorus oxychloride
intensity ratio 0.2 : 1 : 0.1 for the respective meso-proton signals
at 7.07 (8), 6.7 (8a), and 6.62 ppm (8b), the monoenol form produces di(chlorovinyl) derivative 13 which can be converted
to disulfide 14 by the reaction with sodium p-chlorothiopheno-
late. On heating 8 in acetic acid in the presence of boron
accounts for 77%, the dialdehyde for 15%, and the dienol
for 8% of the total amount of compound 8 in DMSO-d6.
It should be noted that the same tautomerism was observed trifluoride etherate for 15 min, a compound results which has
for α-phenacyl substituted BODIPY.14a
λmax = 579 nm in dichloromethane; the same absorption
maximum is characteristic of the peri-condensed cyclic dye with
Further studies resulted in another, one step shorter and
more facile, synthetic route to compound 8. It has been found the bridgehead boron atom obtained from the corresponding
monoaldehyde under similar conditions.20 This dye, though not
that diethyl acetal 9, if heated for a short time in xylene with
isolated, is supposed with good reason to have structure 15.
Indeed, further heating causes the cyclization of the second
aldehyde moiety, this time at the carboxyl group rather than
the boron atom, so that pyranone system 16 is formed.
Similar to monoaldehyde 3, dialdehyde 8 also reacts with
aliphatic amines to form dye 17 but this conversion proceeds
more smoothly with dienol acetate 11. Since compounds of
DMF dimethyl acetal in the presence of acetic anhydride,
affords compound 10 in high yield (89%) as shown in
Scheme 2. According to 1H NMR data, the condensation
occurs just at the methyl rather than methylene group of the
acetal moiety. Compound 10 is efficiently hydrolyzed (in 83%
yield) in a mixture of dioxane and hydrochloric acid to
produce dialdehyde 8.
The ability of acetaldehyde fragments of product 8 to exist this kind have low solubility, the reaction was performed with
isoamylamine.
in enol forms allows for very easy formation of some its divinyl
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Scheme 3 Chemical transformations of dialdehyde 8.
pyranone cyclization by 34 nm. The combined effect of two
cyclic moieties in compound 16 amounts to 90 nm (much the
same as 94 nm, the sum of individual red shifts). As another
example of quasi-additivity, an acetoxyvinyl and anilinovinyl
moieties induce respective bathochromic shifts of 33 and
107 nm, whereas their combined effect for compound 12 is
found to be 136 nm. A more electron-unsymmetric structure,
e.g., compound 5 containing the aminovinyl and acetoxyvinyl
groups, exhibits more pronounced deviations from additivity:
the sum of individual bathochromic effects of the two substitu-
ents is 135 nm whereas a real red shift is 124 nm. It is thus poss-
ible to predict, with good accuracy, the absorption maximum
position for a divinyl-substituted BODIPY based on the indivi-
dual spectral effects of the corresponding substituents.
Table 1 Phothophysical properties of dyes 5–18 in dichloromethane
Dye
λabs, nm(ε × 10−3, M−1 cm−1
)
fwhm, cm−1
λem, nm (φ)
5
6
7
8
643 (49)
552 (104)
728 (79)
519 (95)
522 (105)
622 (65)
585 (114)
655 (75)
578 (90)
648 (81)
609 (82)
658 (134)
960 (47)
2619
926
1236
820
774
2417
987
2010
1094
1638
1235
767
684 (0.001)
567 (0.91)
—
535 (0.95)
536 (0.98)
658 (0.001)
601 (0.71)
695 (0.16)
596 (0.81)
680 (0.60)
638 (0.45)
683 (0.74)
—
9
10
11
12
13
14
16
17
18
—
Unsymmetrical dyes containing an aminovinyl moiety are
The spectral characteristics of the dyes synthesized are listed characterized by the broadest absorption bands, with fwhm
in Table 1. In the symmetrically substituted compounds, vinyl values of 2400 to 2600 cm−1 (Table 1). A much narrower (with
groups have an additive effect on the position of absorption fwhm of 1236 cm−1) and, accordingly, more intense absorption
maximum, so that the first and second substituents cause the band is observed for symmetrically substituted dienamine 7.
same red shift. For example, the bathochromic effect of one The absorption intensity is enhanced the most if the BODIPY
chlorovinyl group is 28 nm, whereas two such groups increase structure is symmetrically annelated with pyridone rings. The
the absorption wavelength by 59 nm; the red shifts caused by thus diannelated dye 17 has the molar absorptivity of 134 000
one and two p-chlorophenylthiovinyl groups are 65 and 129 nm, M−1 cm−1 (cf. to the corresponding value of its monoannelated
respectively; the corresponding values for one and two dimethyl- counterpart,20 95 000 M−1 cm−1).
aminovinyl groups are 102 and 209 nm (from here on, all data
for monosubstituted dyes are taken from ref. 20 and batho- fluorescence quantum yields (φ = 0.45–0.95) except amino
chromic effects are estimated with reference to parent dye 1).
derivatives in which the enamine moiety so drastically reduces
All the synthesized vinyl-substituted BODIPYs exhibit high
The additivity of substituent spectral effects is retained for emission that it could not even be detected for dienamine 7.
unsymmetrically substituted dyes provided the substituents do The above observation is in good agreement with the pre-
not differ strongly in their electron-donor properties. For viously reported view of boron-dipyrromethene optical proper-
instance, the cyclization of the enol moiety at the boron atom ties, as free conjugated terminal amino groups most often
shifts dye absorption to longer wavelengths by 60 nm and the lead to fluorescence quenching.21 At the same time, φ = 0.16
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residue is one of the least electron-donor groups applied in the
conventional cyanine chemistry.24
Conclusions
Scheme 4 Synthesis of dye 18.
In summary, we have developed two versions of the facile and
efficient method to obtain dialdehyde 8 which appears to be a
useful synthon in the preparation of various 3,5-divinyl
BODIPY derivatives. Many of these compounds are character-
ized by intense absorption and fluorescence in the wavelength
region longer than 600 nm, i.e., in the so-called “photothera-
peutic window” (about from 600 to 900 nm) which is of par-
ticular biological significance. Importantly, these dyes are
quite stable substances. As also shown, dialdehyde 8 in its
dienol acetate form 11 is readily condensed with CH acids; for
instance, it reacts with 2-methylbenz[c,d]indolium salt to
produce previously inaccessible NIR dye 18 having peculiar
spectral properties. The above-described reactions illustrate
well that dialdehyde 8 has much synthetic potential in further
functionalization of the BODIPY nucleus.
Fig. 2 Absorption spectra of dye 18 in CH2Cl2.
Experimental section
Absorption spectra were recorded on a Shimadzu UV-3100
spectrophotometer. 1H NMR (300 MHz, 25 °C, TMS as internal
standard) and 13C NMR (75 MHz, CDCl3 as internal standard)
spectra were obtained on a Varian VXR-300 instrument. Fluor-
escence spectra were recorded on a Solar CM 2203 fluor-
escence spectrophotometer. The relative fluorescent quantum
yields (φ) were determined using Rhodamine 6G (φ = 0.95,
EtOH) and indodicarbocyanine iodide (φ = 0.25, EtOH) as the
references. Column chromatography was performed using
Fluka Silica Gel 100 (0.063–0.200 mm).
for aminovinyl derivative 12 and φ = 0.17 for its monosubsti-
tuted analogue20 represent few cases when relatively strong
fluorescence persists in spite of the mentioned quenching
effect.9a,b,22
As already noted, dienol acetate 11 appears to be a better
reagent than free dialdehyde 8 thus offering new synthetic
opportunities as, for instance, condensations with CH acids.
We have recently obtained a number of peculiar polymethine
dyes which contain the BODIPY nucleus as a central moiety of
the conjugated chromophore.23 The most interesting of these
compounds are those containing a terminal groups of low elec-
tron-donor ability. However, the method employed by us for
dye synthesis, viz., the reaction between hemicyanines and
compound 1, was not always successful. In particular, we
could not thus obtain dye 18 containing the benz[c,d]indolium
nucleus. The reaction presented in Scheme 4 also fails to
provide the desired product, if performed with dialdehyde 8
which is prone to self-condensation under basic conditions; in
contrast, compound 11 is smoothly converted to dye 18.
The absorption spectra of this dye (Fig. 2) and its analogues
(previously analyzed in detail23) are qualitatively similar.
Among the compounds of this series, dye 18 is noted for its
most red-shifted first absorption band (λabs = 960 nm in
CH2Cl2) and for the most intense multicomponent short-wave-
length absorption. In addition, it proved to be quite stable on
storage and fairly photostable. At the typical spectroscopic con-
centration, its solution in dichloromethane remained
unchanged on standing in diffuse light for three months. This
behaviour of dye 18 is consistent with the previously esta-
blished fact that the stability of α-borondipyrromethenecyanine
dyes increases with decreasing electron-donor ability of term-
inal heterocyclic nuclei.23 Indeed, the 2-benz[c,d]indolium
3-(2-Acetoxyethen-1-yl)-5-(2-dimethylaminoethen-1-yl)-
1,7-diphenyl-2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene (5)
A solution of compound 4 (4.9 g, 8.4 mmol), of DMF dimethyl
acetal (4.97 g, 41.8 mmol), of acetic anhydride (8.53 g,
83.6 mmol) of in o-xylene (20 mL) was refluxed for 1 min. After
cooling, the mixture was evaporated to dryness under reduced
pressure, the residue was washed with i-PrOH and filtered.
Yield: 4.71 g (88%). M.p. 174–175 °C. 1H NMR (CDCl3): δ =
0.91 (t, J = 6.6 Hz, 3 H, CH3), 0.99 (t, J = 6.6 Hz, 3 H, CH3), 2.22
(s, 3 H, COCH3), 3.10 (s, 3 H, NCH3), 3.33 (s, 3 H, NCH3),
4.01–4.13 (m, 4 H, CH2), 6.21 (d, J = 13.2 Hz, 1 H, CH), 6.42
(s, 1 H, meso-H), 7.14–7.36 (m, 11 H, 10 Ar-H, CH), 8.54 (d, J =
13.2 Hz, 1 H, CH), 8.62 (d, J = 12.9 Hz, 1 H, CH) ppm. Anal.
calcd for C35H34BF2N3O6: C, 65.52; H, 5.30; N, 6.55. Found: C,
65.65; H, 5.19; N, 6.71.
3-(2-Acetoxyethen-1-yl)-5-(2-formylmethyl)-1,7-diphenyl-
2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (6)
A mixture of compound 5 (0.25 g, 0.4 mmol), water (2 mL) and
trifluoroacetic acid (0.5 mL) was boiled for 1 min. After cooling
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to room temperature, the precipitate was filtered and recrystal- 163.2, 163.6 ppm. Anal. calcd for C34H37BF2N2O6: C, 66.01; H,
lized from the mixture of i-PrOH and hexane. Yield: 0.16 g 5.99; N, 4.52. Found: C, 66.13; H, 6.27; N, 4.65.
(71%). M.p. 150–152 °C. 1H NMR (CDCl3): δ = 1.01–1.08
3-(2,2-Diethoxyethyl)-5-(2-dimethylaminoethen-1-yl)-
1,7-diphenyl-2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene (10)
(m, 6 H, CH3), 2.26 (s, 3 H, COCH3), 4.11–4.13 (m, 4 H, CH2),
4.52 (s, 2 H, CH2CHO), 6.97 (s, 1 H, meso-H), 7.06 (d, J =
12.9 Hz, 1 H, CH), 8.69 (d, J = 12.9 Hz, 1 H, CH), 9.82 (s, 1 H, CHO)
ppm. 13C NMR (CDCl3): δ = 13.6, 13.8, 20.6, 43.5, 60.5, 61.3, A mixture of compound 9 (2.95 g, 5 mmol), of DMF dimethyl
104.9, 127.8, 127.9, 128.3, 129.0, 129.3, 129.6, 130.3, 131.3, acetal (2.98 g, 25 mmol) and of acetic anhydride (5.1 g,
131.6, 133.9, 135.5, 146.4, 147.8, 148.7, 153.1, 153.6, 163.2, 50 mmol) in o-xylene (20 mL) was boiled for 1 min. After
164.0, 166.9, 195.3 ppm. Anal. calcd for C33H29BF2N2O7: C, cooling, solvent was evaporated under reduced pressure and
64.49; H, 4.72; N, 4.56. Found: C, 64.59; H, 5.01; N, 4.71.
the residue was refluxed in 15 mL of i-PrOH. A resulting pre-
cipitate was filtered and washed with i-PrOH. Yield: 2.89 g
(89%). M.p. 165–167 °C. 1H NMR (DMSO-d6): δ = 0.94 (t, J =
8.5 Hz, 3 H, CH3),1.03–1.08 (m, 9 H, CH3), 3.09 (s, 3 H, NCH3),
3.32 (s, 3 H, NCH3), 3.36 (t, J = 7 Hz, 2 H, CH2), 3.47–3.51 (m, 4
H, CH2CH3), 4.01–4.13 (m, 4 H, CH2CH3), 4.77 (t, J = 7.5 Hz, 1
H, CH), 6.03 (d, J = 16.5 Hz, 1 H, CH), 6.35 (s, 1 H, meso-CH),
7.25–7.45 (m, 10 H, Ar-H), 8.18 (d, J = 15 Hz, 1 H, CH) ppm.
13C NMR (DMSO-d6): δ = 13.9, 14.2, 15.6, 32.5, 59.8, 61.4, 62.2,
88.7, 102.6, 115.6, 119.3, 123.3, 127.8, 128.3, 128.7, 129.6,
130.3, 131.5, 133.7, 134.9, 137.5, 146.2, 148.6, 155.6, 157.8,
164.9 ppm. Anal. calcd for C37H42BF2N3O6: C, 65.97; H, 6.24;
N, 6.23. Found: C, 66.02; H, 6.54; N, 6.35.
3,5-Bis(2-dimethylaminoethen-1-yl)-1,7-diphenyl-
2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (7)
To a solution of compound 5 (4 g, 6.2 mmol) in of acetonitrile
(30 mL) of 30% aqueous dimethylamine (1.80 g, 12 mmol) was
added. After 1 h, 10 ml of water was added, the precipitate was
filtered and washed with i-PrOH. Yield: 3.6
g (92%).
1
M.p. 216–218 °C. H NMR (CDCl3): δ = 0.89 (t, J = 7.2 Hz, 6 H,
CH3), 3.05 (s, 12 H, NCH3), 3.97 (q, J = 7.2 Hz, 4 H, CH2), 6.11
(d, J = 13.5 Hz, 2 H, CH), 6.34 (s, 1 H, meso-H), 7.20–7.30
(m, 10 H, Ar-H), 8.12 (d, J = 13.5 Hz, 1 H, CH) ppm. 13C NMR
(DMSO-d6): δ = 14.0, 60.46, 87.8, 114.6, 118.2, 128.4, 129.8,
133.3, 133.5, 142.7, 151.0, 153.1, 165.5 ppm. Anal. calcd for
C35H37BF2N4O4: C, 67.09; H, 5.91; N, 8.94. Found: C, 67.33; H,
6.07; N, 9.05.
3,5-Bis(2-acetoxyethen-1-yl)-1,7-diphenyl-2,6-dicarbethoxy-
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (11)
A solution of compound 8 (0.28 g, 0.5 mmol) in acetic anhy-
dride (2 mL) and DMF (0.25 mL) was boiled for 1 min. After
cooling to room temperature, the mixture was diluted with
10 mL of diethyl ether and the precipitate was filtered. Yield:
0.23 g (70%). M.p. 238–240 °C. 1H NMR (DMSO-d6): δ = 0.96
(t, J = 7.5 Hz, 6 H, CH3), 2.29 (s, 6 H, COCH3), 4.08 (q, J =
7.2 Hz, 4 H, CH2), 6.92–6.96 (m, 3 H, CH), 7.45 (m, 10 H, Ar-H),
8.60 (d, J = 13.2 Hz, 2 H, CH) ppm. 13C NMR (DMSO-d6): δ =
13.9, 60.5, 87.8, 114.6, 118.2, 128.4, 128.5, 129.8, 133.3, 133.5,
142.7, 151.0, 153.1, 165.5 ppm. Anal. calcd for C35H31BF2N2O8:
C, 63.94; H, 4.72; N, 4.26. Found: C, 64.09; H, 4.83; N, 4.39.
3,5-Bis(2-formylmethyl)-1,7-diphenyl-2,6-dicarbethoxy-
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8)
A mixture of compound 10 (2.58 g, 4 mmol), of dioxane
(25 ml), of water (6 mL) and of concentrated hydrochloric acid
(2.85 g) was stirred at room temperature for 18 h. After that,
the mixture was washed with water, the precipitate was filtered
and recrystallized from the mixture of benzene and hexane.
1
Yield: 1.8 g (83%). M.p. 185–186 °C. H NMR (CDCl3): δ = 1.1
(t, J = 6.5 Hz, 6 H, CH3), 4.14 (q, J = 6.5 Hz, 4 H, CH2CH3), 4.53
(s, 4 H, CH2), 7.08 (s, 1 H, meso-CH), 7.31–7.42 (m, 10 H, Ar-H),
9.81 (s, 2 H, CHO) ppm. 13C NMR (CDCl3): δ = 13.8, 43.5, 60.7, 3-(2-Acetoxyethen-1-yl)-5-(2-phenylaminoethen-1-yl)-
121.3, 127.9, 128.4, 129.3, 130.3, 131.2, 132.0, 134.6, 148.7, 1,7-diphenyl-2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-
155.4, 162.9, 194.7 ppm. Anal. calcd for C31H27BF2N2O6: C, s-indacene (12)
65.03; H, 4.72; N, 4.89. Found: C, 65.13; H, 5.05; N, 5.12.
To a hot solution of compound 11 (0.2 g, 0.3 mmol) in aceto-
nitrile (6 mL) was added of aniline (0.11 g, 1.2 mmol). After
3-(2,2-Diethoxyethyl)-5-methyl-1,7-diphenyl-2,6-dicarbethoxy-
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (9)
cooling to room temperature, the precipitate was filtered.
1
Yield: 0.12 g (57%). M.p. 229–230 °C. H NMR (DMSO-d6): δ =
A suspension of compound 3 (2.25 g, 4.1 mmol) in of anhy- 0.87–0.95 (m, 6 H, CH3), 2.28 (s, 3 H, COCH3), 3.99–4.13
drous EtOH (30 mL) and of trifluoroacetic acid (0.7 g, (m, 4 H, CH2), 6.44 (s, 1 H, meso-CH), 6.68 (d, J = 12.9 Hz, 1 H,
6.14 mmol) was refluxed for 5 h. After cooling, the precipitate CH), 7.01 (d, J = 12.6 Hz, 1 H, CH), 7.11–7.21 (m, 3 H, Ar-H),
was filtered and washed with EtOH. Yield: 1.88 g (78%). 7.30–7.46 (m, 12 H, Ar-H), 8.52 (d, J = 12.9 Hz, 1 H, CH), 8.88
1
M.p. 148–150 °C. H NMR (DMSO-d6): δ = 1.06–1.09 (m, 12 H, (t, J = 12.6 Hz, 1 H, CH), 11.14 (d, J = 12.6 Hz, 1 H, NH) ppm.
CH3), 2.84 (s, 3 H, CH3), 3.41 (t, J = 7 Hz, 2 H, CH2), 3.57–3.64 13C NMR (DMSO-d6): δ = 13.8, 13.9, 21.0, 60.6, 61.5, 94.8,
(m, 4 H, CH2CH3), 4.13 (q, J = 7 Hz, 4 H, CH2CH3), 4.81 (t, J = 105.6, 116.7, 117.4, 118.7, 123.7, 124.5, 128.5, 128.8, 129.7,
7.2 Hz, 1 H, CH), 7.01 (s, 1 H, meso-CH), 7.45 (m, 10 H, Ar-H) 130.2, 130.5, 131.5, 132.1, 133.2, 137.7, 140.6, 142.3, 143.0,
ppm. 13C NMR (DMSO-d6): δ = 14.1, 15.0, 15.5, 33.1, 60.6, 60.7, 147.0, 148.7, 164.9, 165.0, 168.0 ppm. Anal. calcd for
62.5, 102.1, 120.8, 123.4, 128.4, 128.7, 129.6, 130.4, 130.6, C39H34BF2N3O6: C, 67.82; H, 4.92; N, 6.09. Found: C, 68.01; H,
130.8, 131.4, 131.6, 133.1, 133.5, 146.1, 147.7, 157.3, 160.3, 5.18; N, 6.23.
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3,5-Bis(2-chloroethen-1-yl)-1,7-diphenyl-2,6-dicarbethoxy-
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (13)
12 H, CH3), 1.59 (m, 6 H, 4 CH2, 2 CH), 3.90 (t, J = 7.2 Hz,
4 H, NCH2), 6.78 (d, J = 6.8 Hz, 1 H, CH), 7.32 (d, J = 6.8 Hz,
1 H, CH), 7.37 (s, 1 H, meso-H), 7.44 (m, 6 H, Ar-H), 7.58
(m, 4 H, Ar-H) ppm. Anal. calcd for C37H37BF2N4O2: C, 71.84;
H, 5.99; N, 9.06. Found: C, 71.78; H, 6.06; N, 8.97.
A mixture of compound 8 (2.0 g, 3.5 mmol), of N,N-diethylani-
line (2.0 g, 14 mmol) and phosphorus oxychloride (10 mL) was
heated at 100 °C for 15 min. After cooling, the mixture was
poured into ice water, the precipitate was filtered, washed with
water, i-PrOH and recrystallized from mixture of toluene and
hexane. Yield: 0.90 g (42%). M.p. 224–226 °C. 1H NMR
(CDCl3): δ = 1.03 (t, J = 6.5 Hz, 6 H, CH3), 4.13 (q, J = 6.5 Hz,
4 H, CH2), 6.99 (s, 1 H, meso-CH), 7.28–7.28 (d, J = 6 Hz, 4 H,
Ar-H), 7.40–7.43 (m, 6 H, Ar-H), 7.55 (d, J = 13.5 Hz, 2 H, CH),
7.72 (d, J = 13.5 Hz, 2 H, CH) ppm. Anal. calcd for
C31H25BCl2F2N2O4: C, 61.08; H, 4.10; N, 4.59. Found: C, 61.18;
H, 4.41; N, 4.72.
3,5-Bis(3-(1-butyl-1H-benz[c,d]indole-2-ylidene)propen-1-yl)-
1,7-diphenyl-2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene (18)
A mixture of dienole acetate 8 (0.2 g, 0.3 mmol), of 1-butyl-
2-methylbenz[c,d]indolium tetrafluoroborate (0.25 g, 0.8 mmol),
of DIEA (0.2 g, 1.55 mmol) in toluene (4 mL) was heated with
stirring at 90 °C for 30 min. After cooling, a solution was fil-
tered and evaporated to dryness under reduced pressure. The
residue was boiled with acetonitrile, the product was filtered
and recrystallized from the mixture of benzene and hexane.
Yield: 0.12 g (40%). M.p. 218–220 °C. 1H NMR (CDCl3): δ =
3,5-Bis(2-(4-chlorophenylsulfanyl)ethen-1-yl)-1,7-diphenyl-
2,6-dicarbethoxy-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (14)
To a solution of compound 13 (150 mg, 0.25 mmol) in DMF 0.99–1.04 (m, 12 H, CH3), 1.54 (m, 4 H, CH2), 1.86, (m, 4 H,
(2 mL) was added a solution of sodium p-chlorothiophenolate CH2), 3.93 (t, J = 6.8 Hz, 4 H, NCH2), 4.17 (q, J = 7.2, 4 H, CH2),
(from p-chlorothiophenol (92 mg, 0.64 mmol) and sodium 6.52 (d, J = 12 Hz, 2 H, CH), 6.70 (d, J = 6 Hz, 2 H, Ar-H), 6.78
hydroxide (26 mg, 0.65 mmol) in EtOH (1 mL). After 30 min, (s, 1 H, meso-H), 6.90 (d, J = 8 Hz, 2 H, Ar-H), 7.09 (t, J = 7.2 Hz,
the mixture was diluted with 10% aqueous ammonium chlo- 2 H, Ar-H), 7.17 (d, J = 8 Hz, Ar-H), 7.25 (m, 2 H, Ar-H), 7.61
ride, the precipitate was filtered and flesh-chromatographed on (d, J = 6.4 Hz, 2 H, Ar-H), 7.70 (d, J = 15.2 Hz, 2 H, CH), 8.13
silica gel (eluent dichloromethane). Yield: 150 mg (74%). M.p (t, J = 13.2 Hz, 2 H, CH) ppm. Anal. calcd for C63H57BF2N4O4:
1
170–171 °C. H NMR (CDCl3): δ = 0.97 (t, J = 7 Hz, 6 H, CH3), C, 76.91; H, 5.80; N, 5.70. Found: C, 76.63; H, 6.07; N, 5.75.
4.07 (q, J = 7 Hz, 4 H, CH2), 6.83 (s, 1 H, meso-CH), 7.25–7.29
(m, 6 H, 2 CH, 4 Ar-H), 7.37–7.41 (m, 10 H, Ar-H), 7.48 (d, J =
8.5 Hz, 4 H, Ar-H), 8.14 (d, J = 16 Hz, 2 H, CH) ppm. Anal.
calcd for C43H33BCl2F2N2O4S2: C, 62.54; H, 4.00; N, 3.39.
Acknowledgements
Found: C, 62.65; H, 4.31; N, 3.53.
This work was partially financially supported by the NATO
“Science for Peace” program, project NUKR.SFPP 984189.
Compound 16
A solution of compound 7 (0.23 g, 0.4 mmol) and boron tri-
fluoride etherate (1.14 g, 4 mmol) in acetic acid (15 mL) was
heated at 75 °C for 2 h. After cooling, the reaction mixture was
Notes and references
diluted with water and product was extracted with dichloro-
methane. The organic layer was dried over sodium sulfate,
evaporated to dryness and the residue was chromatographed
1 (a) R. Ziessel, G. Ulrich and A. Harriman, New J. Chem.,
2007, 31, 496; (b) A. Loudet and K. Burgess, Chem. Rev.,
2007, 107, 4891; (c) G. Ulrich, R. Ziessel and A. Harriman,
Angew. Chem., Int. Ed., 2008, 47, 1184; (d) M. Benstead,
on silica gel (eluent hexane–ethylacetate, 3 : 1). Yield: 0.08 g
(40%). M.p. 125–127 °C. 1H NMR (CDCl3): δ = 1.25 (t, J =
G. H. Mehl and R. W. Boyle, Tetrahedron, 2011, 67, 3573.
7.5 Hz, 3 H, CH3), 4.26 (q, J = 7.5 Hz, 2 H, CH2), 6.74 (d, J =
2 (a) R. P. Haugland, The Handbook. A Guide to Fluorescence
5.5 Hz, 1 H, CH), 7.10 (d, J = 6 Hz, 1 H, CH), 7.16 (s, 1 H, meso-H),
Probes and Labeling Technologies, Invitrogen Corp., Eugene,
7.44–7.49 (m, 8 H, Ar-H), 7.54–7.56 (m, 3 H, 1 CH, 2 Ar-H),
OR, 10th edn, 2005; (b) N. Boens, V. Leen and W. Dehaen,
7.62 (d, J = 6 Hz, 1 H, CH) ppm. 13C NMR (DMSO-d6): δ = 14.2,
Chem. Soc. Rev., 2012, 41, 1130.
61.2, 98.6, 99.3, 110.8, 119.0, 125.6, 127.0, 128.6, 128.7, 129.5,
129.7, 130.3, 130.5, 130.7, 130.8, 131.0, 135.5, 136.1, 139.5,
141.6, 147.9, 150.1, 150.8, 153.0, 154.2, 158.1, 161.3,
162.2 ppm. Anal. calcd for C29H20BFN2O5: C, 68.77; H, 3.95; N,
3 M. Shah, K. Thangaraj, M.-L. Soong, L. T. Wolford,
J. H. Boyer, I. R. Politzer and T. G. Pavlopoulos, Heteroat.
Chem., 1990, 1, 389.
4 (a) L. Li, B. Nguyen and K. Burgess, J. Org. Chem., 2008, 73,
5.52. Found: C, 68.81; H, 4.16; N, 5.71.
1963; (b) H. J. Wories, J. H. Koek, G. Lodder, J. Lugtenburg,
R. Fokkens, O. Drissen and G. R. Mohn, Recl. Trav. Chim.
Pays-Bas, 1985, 104, 288.
Compound 17
A mixture of compound 11 (196 mg, 0.3 mmol) and isoamyl-
amine (117 mg, 1.3 mmol) in EtOH (3 mL) was refluxed for
45 min. After cooling, the product was filtered. Yield: 100 mg
(54%). M.p. 182–183 °C. 1H NMR (CDCl3): δ = 0.92 (d, J = 5.6 Hz,
5 (a) L. Jiao, C. Yu, J. Li, Z. Wang, M. Wu and E. Hao, J. Org.
Chem., 2009, 74, 7525; (b) C. Yu, L. Jiao, H. Yin, J. Zhou,
W. Pang, Y. Wu, Z. Wang, G. Yang and E. Hao,
Eur. J. Org. Chem., 2011, 5460; (c) S. H. Lim, C. Thivierge,
Org. Biomol. Chem.
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Paper
P. Nowak-Sliwinska, J. Han, H. Bergh, G. Wagniere,
K. Burgess and H. B. Lee, J. Med. Chem., 2010, 53, 2865.
M. Van der Auweraer, N. Boens and W. Dehaen, Org. Lett.,
2011, 13, 1470.
6 C. Thivierge, R. Bandichhor and K. Burgess, Org. Lett., 15 For selected examples, see: (a) T. Bura, D. Hablot and
2007, 9, 2135.
R. Ziessel, Tetrahedron Lett., 2011, 52, 2350; (b) A. Coskun,
E. Deniz and E. U. Akkaya, Org. Lett., 2005, 7, 5187;
(c) W. Qin, T. Rohand, W. Dehaen, J. N. Clifford,
K. Driesen, D. Beljonne, B. Van der Averbeke, M. Van der
Auweraer and N. Boens, J. Phys. Chem. A, 2007, 111, 8588;
(d) Z. Ekmekci, M. D. Yilmaz and E. U. Akkaya, Org. Lett.,
2008, 10, 461; (e) Q. Zheng, G. Xu and P. N. Prasad, Chem.–
Eur. J., 2008, 14, 5812; (f) S. Lee, N. Kang, Y. K. Kim,
A. Samanta, S. Feng, H. K. Kim, M. Vendrell, J. H. Park and
Y. T. Chang, J. Am. Chem. Soc., 2009, 131, 10077;
(g) S. Ozlem and E. U. Akkaya, J. Am. Chem. Soc., 2009, 131,
48; (h) S. Atilgan, I. Kutuk and T. Ozdemir, Tetrahedron
Lett., 2010, 51, 892.
7 (a) T. Yogo, Y. Urano, Y. Ishitsuka, F. Maniva and
T. Nagano, J. Am. Chem. Soc., 2005, 127, 12162;
(b) S. Atilgan, Z. Ekmeci, A. L. Dogan, D. Guc and
E. U. Akkaya, Chem. Commun., 2006, 4398; (c) E. Deniz,
G. I. Isbasar, A. Bozdemir, L. T. Yildirim, A. Siemiarczuk
and E. U. Akkaya, Org. Lett., 2008, 10, 3401.
8 (a) L. Jiao, W. Pang, J. Zhou, Y. Wei, X. Mu, G. Bai and
E. Hao, J. Org. Chem., 2011, 76, 9988; (b) M. J. Ortiz,
A. R. Agarrabeitia, G. Duran-Sampedro, J. B. Prieto,
T. A. Lopez, W. A. Massad, H. A. Montejano, N. A. Garcia
and I. L. Arbeloa, Tetrahedron, 2012, 68, 1153.
9 (a) T. Rohand, M. Baruah, W. Qin, N. Boens and
W. Dehaen, Chem. Commun., 2006, 266; (b) M. Baruah, 16 (a) O. Buyukcakir, O. A. Bozdemir, S. Kolemen, S. Erbas
W. Qin, R. A. L. Vallee, D. Beljonne, T. Rohand, W. Dehaen
and N. Boens, Org. Lett., 2005, 7, 4377; (c) L. Li, B. Nguyen
and E. U. Akkaya, Org. Lett., 2009, 11, 4644; (b) N. Bura,
D. Hablot and R. Ziessel, Tetrahedron Lett., 2011, 52, 2370.
and K. Burgess, Bioorg. Med. Chem. Lett., 2008, 18, 3112; 17 (a) V. P. Yakubovskyi, M. P. Shandura and Yu. P. Kovtun,
(d) O. Dilek and S. L. Bane, Bioorg. Med. Chem. Lett., 2009,
19, 6911; (e) T. K. Khan, M. R. Rao and M. Ravikanth,
Eur. J. Org. Chem., 2010, 2314; (f) V. Leen, T. Leemans,
N. Boens and W. Dehaen, Eur. J. Org. Chem., 2011, 4386;
Eur. J. Org. Chem., 2009, 3237; (b) V. P. Yakubovskyi,
M. P. Shandura and Yu. P. Kovtun, Dyes Pigm., 2010, 87, 17;
(c) N. Shivran, S. Mula, T. K. Ghanty and S. Chattopadhyay,
Org. Lett., 2011, 13, 5870.
(g) O. Dilek and S. L. Bane, Tetrahedron Lett., 2008, 49, 18 (a) G. Santhyamoorthi, L. T. Wolford, A. M. Haag and
1413.
J. H. Boyer, Heteroat. Chem., 1994, 5, 245; (b) A. Haefele,
10 V. Leen, D. Miscoria, S. Yin, A. Filarowski, J. M. Ngongo,
M. Van der Auweraer, N. Boens and W. Dehaen, J. Org.
Chem., 2011, 76, 8168.
C. Zedde, P. Retailleau and R. Ziessel, Org. Lett., 2010, 12,
1672.
19 G. Ulrich, R. Ziessel and A. Haefele, J. Org. Chem., 2012, 77,
11 (a) T. V. Goud, A. Tutar and J.-F. Biellmann, Tetrahedron,
4298.
2006, 62, 5084; (b) J. Bañuelos, V. Martín, C. F. A. Gómez- 20 V. P. Yakubovskyi, M. P. Shandura and Yu. P. Kovtun,
Durán, I. J. A. Córdoba, E. Peña-Cabrera, I. García-Moreno, J. Heterocycl. Chem., 2009, 46, 1386.
Á. Costela, M. E. Pérez-Ojeda, T. Arbeloa and Í. L. Arbeloa, 21 (a) Sh. O. McDonnell, M. J. Hall, L. T. Allen, A. Byrne,
Chem.–Eur. J., 2011, 17, 7261; (c) C. F. A. Gómez-Durán,
I. García-Moreno, A. Costela, V. Martín, R. Sastre,
J. Bañuelos, F. L. Arbeloa, Í. L. Arbeloa and
E. Peña-Cabrera, Chem. Commun., 2010, 5103.
D. F. O’Shea and W. M. Gallagher, J. Am. Chem. Soc., 2005,
127, 16360; (b) M. J. Hall, L. T. Allen and D. F. O’Shea, Org.
Biomol. Chem., 2006, 4, 776; (c) Y.-W. Wang, A. B. Descalzo,
Z. Shen, X.-Z. You and K. Rurack, Chem.–Eur. J., 2010, 16,
2887; (d) V. Yakubovskyi, M. Shandura and Yu. Kovtun,
Synth. Commun., 2010, 40, 944.
12 (a) I. J. Arroyo, R. Hu, B. Z. Tang, F. I. Lopez and
E. Pena-Cabrera, Tetrahedron, 2011, 67, 7244; (b) J. Han,
O. Gonzalez, A. Aguilar-Aguilar, E. Pena-Cabrera and 22 (a) L. Li, B. Nguyen and K. Burgess, Bioorg. Med. Chem.
K. Burgess, Org. Biomol. Chem., 2009, 7, 34.
13 For selected examples, see: (a) T. Rohand, W. Qin, N. Boens
Lett., 2008, 18, 3112; (b) T. Kowada, S. Yamaguchi,
H. Fujinaga and K. Ohe, Tetrahedron, 2011, 67, 3105.
and W. Dehaen, Eur. J. Org. Chem., 2006, 4658; (b) V. Leen, 23 M. P. Shandura, V. P. Yakubovskyi, A. O. Gerasov,
E. Braeken, K. Luckermans, C. Jackers, M. Van der Auwer-
O. D. Kachkovsky, Ye. M. Poronik and Yu. P. Kovtun,
aer, N. Boens and W. Dehaen, Chem. Commun., 2009, 4515;
Eur. J. Org. Chem., 2012, 1825.
(c) D. Zhang, Y. Wen, Y. Xiao, G. Yu, Y. Liu and X. Qian, 24 (a) N. Tyutyulkov, J. Fabian, A. Mehlhorn, F. Dietz and
Chem. Commun., 2008, 4777; (d) L. Jiao, C. Yu, T. Uppal,
M. Liu, Y. Li, Y. Zhou, E. Hao, X. Hu and M. G. H. Vicente,
Org. Biomol. Chem., 2010, 8, 2517; (e) M. R. Rao,
S. M. Mobin and M. Ravikanth, Tetrahedron, 2010, 66,
1728; (f) S. L. Niu, G. Ulrich, R. Ziessel, A. Kiss,
P.-Y. Renard and A. Romleu, Org. Lett., 2009, 11, 2049.
A. Tadjer, A Polymethine Dyes: Structure and Properties,
St. Kliment Ohridski University Press, Sofia, 1991;
(b) G. Bach and S. Daehne, in Cyanine Dyes and Related
Compounds in Rodd’s Chemistry of Carbon Compounds, ed.
M. Sainsbury, Elsevier, Amsterdam, 1997, vol. IVB, ch. 15,
p. 383; (c) A. Mishra, R. K. Behera, P. K. Behera,
B. K. Mishra and B. K. Behera, Chem. Rev., 2000, 100, 1973;
(d) A. Kulinich and A. Ishchenko, Russ. Chem. Rev., 2009,
78, 141; (e) M. Panigrahi, S. Dash, S. Patel and
B. K. Mishra, Tetrahedron, 2012, 68, 781.
14 (a) V. Leen, G. V. Z. Gonzalvo, W. M. Deborggraeve,
N. Boens and W. Dehaen, Chem. Commun., 2010, 4908;
(b) M. Zhang, E. Hao, J. Zhou, C. Yu, G. Bai, F. Wang and
L. Jiao, Org. Biomol. Chem., 2012, 10, 2139; (c) V. Leen,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.