An efficient method of chemical modification of BODIPY core

Article abstract of DOI:10.1016/j.tet.2013.01.050

A simple approach to the modification of BODIPY nucleus has been developed. The method is based on the reaction of acetaldehyde-substituted dye with primary amines followed by cyclization of enamine intermediates. This procedure allowed preparing a series of new BODIPY derivatives with functional substituents useful for various practical purposes, including bioconjugation and other biomedical applications. The synthesized BODIPYs annealed to a pyridone fragment are stable compounds and intense fluorophores with emission maximum around 615 nm. This λ_em may be red-shifted by the introduction of styryl substituent.

Full text of DOI:10.1016/j.tet.2013.01.050

Tetrahedron 69 (2013) 2233e2238
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient method of chemical modification of BODIPY core
Yuriy V. Zatsikha a, Viktor P. Yakubovskyi a, Mykola P. Shandura a, Igor Ya Dubey b,
,
Yuriy P. Kovtun a
*
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska Str., 02094 Kyiv, Ukraine
b Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., 03680 Kyiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple approach to the modification of BODIPY nucleus has been developed. The method is based on
the reaction of acetaldehyde-substituted dye with primary amines followed by cyclization of enamine
intermediates. This procedure allowed preparing a series of new BODIPY derivatives with functional
substituents useful for various practical purposes, including bioconjugation and other biomedical ap-
plications. The synthesized BODIPYs annealed to a pyridone fragment are stable compounds and intense
fluorophores with emission maximum around 615 nm. This lem may be red-shifted by the introduction
of styryl substituent.
Received 25 October 2012
Received in revised form 27 December 2012
Accepted 15 January 2013
Available online 24 January 2013
K
EYWORDS:
BODIPY compounds
Dyes/pigments
Ó 2013 Elsevier Ltd. All rights reserved.
UV/vis spectroscopy
Fluorophores
1. Introduction
Alkylthio-substituted BODIPYs can enter into LiebeskindeSrogl
cross-coupling,11 and halogen derivatives into Pd-catalyzed Suzuki,
Borondipyrromethene dyes (4,4-difluoro-4-bora-3a,4a-diaza-s-
indacene, BODIPY, BDP) have found numerous applications, espe-
cially in biochemistry and molecular biology, owing to their ex-
cellent thermal, chemical and photochemical stability, high molar
absorptivity, high fluorescence quantum yield, and low sensitivity
to both solvent polarity and pH.1 Since practical applications of the
dye often require specific modification of the basic nucleus for
specific tasks, the selective functionalization of the dye is one of the
main challenges of borondihydromethene chemistry. Thus, ap-
proaches have been developed for the introduction of functional
substituents at each position of BODIPY nucleus. Functional groups
can be introduced either at early steps of syntheses using appro-
priately substituted pyrroles as the precursors or at later stages by
functionalization of intermediate dipyrromethene or directly the
BODIPY core.
Heck or Sonogashira reactions.12 Oxidative13a,b or vicarious nucle-
ophilic substitution13c of hydrogen atom can be performed at free
a-position.
Methyl groups at
a-positions provide various possibilities for
the modification of BODIPY core, for example, via the Knoevenagel
condensation.14 This method was used for the synthesis of nu-
merous derivatives, including combinatorial series.14f,i In addition
to modification of the basic structure, an important consequence of
this reaction is essential red shift for both absorption and emission
bands of the products. Knoevenagel reaction can be performed also
at methyl groups at C-1, C-715 and meso-position16 that allows
obtaining unusual structures with specific spectral properties.
Moreover, a
-CH3 can be oxidized to aldehyde group17 or bromi-
nated with subsequent nucleophilic substitution.18
We have recently found a new possibility of using the
a
-methyl
For instance, electrophilic substitution reactions, such as nitra-
group of BODIPY for chemical transformations. It was discovered
that aldehyde function can be readily introduced at this position.19
Reactions of acetaldehyde 1 (Scheme 1) allowed the preparation of
a large number of derivatives, including some rather nontrivial
structures with intense fluorescence and deep color. In particular,
reaction of this aldehyde with methylamine led to the formation of
BODIPY 4b with annealed pyridone ring, stable, and highly fluo-
rescent dye with labs¼586 nm and lem¼614 nm. Although the re-
action performed with heating in toluene in the presence of acetic
acid was very fast, the yield of 4b was only 40% and large amounts
of side products were formed. Nevertheless, this approach has great
tion,2 sulfonylation,2,3 formylation4 or palladium-catalyzed CeH
functionalization,5 are known to proceed easily at free
b-positions of
BODIPY nuclei. Halogenation primarily occurs at the same posi-
tions,2,6 however polyhalogenation is possible when other unsub-
stituted positions are available.7 Halogen atoms at -(C-3 or C-5),8
a
C-1 and C-79 position can undergo nucleophilic substitution;
S-methyl group at C-8 (meso-) position may be substituted as well.10
* Corresponding author. E-mail address: kovtun@ioch.kiev.ua (Y.P. Kovtun).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.050

2234
Y.V. Zatsikha et al. / Tetrahedron 69 (2013) 2233e2238
Ph
Ph
Ph
Ph
RNH
2
CO Et
2
EtO C
2
CO Et
2
EtO C
2
N
N
N
N
B
B
F
F
F
F
CHO
Ac O
2
NHR
RNH
2
3b-j
1
ref.19
CHCl
3
Ph
Ph
NaOAc i-PrOH
NH OAc EtOH
4
CO Et
2
EtO C
2
N
N
B
Ph
Ph
Ph
Ph
F
F
O
O
N
OAc
EtO C
2
2
EtO C
2
N
N
N
N
B
N
H
B
R
F
F
F
F
4a
4b-j
(d), CH CH OH (e), CH CH OCH (f),
R = CH (b), n-Bu (c), C
3
H
18 37
2
2
2
2
3
CH CH=CH (j)
2
(CH ) CO H (g), CH CH N (h), CH C CH (i),
3
2
2
5
2
2
2
2
Scheme 1. Synthetic route to pyridone BODIPY dyes 4aej.
promise for specific modification of borondipyrromethene nuclei,
so we decided to explore its synthetic potential. Here we describe
an efficient method of BODIPY functionalization that employs the
cyclization of N-substituted enamine intermediates.
carbonate, sodium acetate, etc.). This is critically important since in
the presence of large quantities of the base side reactions dominate.
Finally, we have developed an optimized protocol for the
modification of BODIPY core. Enamines 3 are readily obtained by
the reaction of enol acetate 2 with corresponding amines in chlo-
roform at room temperature. These compounds are isolated and
without special purification refluxed in isopropanol with 5% mol
sodium acetate. The cyclization reaction is complete in 1e1.5 h; it is
faster for amines with electron-donor substituents and slower
when they contain electron-withdrawing groups. Compound 4a is
a separate case: it is easily formed in ethanol in the presence of
ammonium acetate, and enamine intermediate cannot be isolated.
Using this general approach, we have prepared in high yields
(84e92%) a series of BODIPY derivatives 4aej containing various
functional substituents. These dyes can be used in diverse appli-
cations, depending on the introduced substituent.
For example, BODIPY dye 4d containing a hydrophobic octa-
decyl group is well soluble in hexane, so presumably it should be
well soluble in lipid systems and thus useful for cell membrane
studies. Compound 4g is functionalized with carboxyalkyl group
suitable for bioconjugation reactions, e.g., for the fluorescent la-
beling of peptides, proteins, and other amine-containing bio-
molecules via the formation of amide bond. Dyes 4h,i are modified
2. Results and discussion
Upon the addition of excess aliphatic primary amine to the so-
lution of aldehyde 1 in a neutral solvent (alcohols, chloroform,
dichloromethane, toluene, DMF) the reaction is complete in few
minutes. TLC analysis demonstrates the disappearance of starting
compound
1 and formation of several productsdblue non-
fluorescent enamine 3 and larger or smaller amount of pyridone
4, along with numerous impurities (Scheme 1).
In this mode of the reaction the isolation of pure enamines 3 is
often difficult, although they are quite stable compounds in their
individual state. The main reason is the presence of excess amine;
the latter promotes both enamine cyclization and side reactions.
Moreover, the addition of another primary amine to enamine 3
results in the formation of the mixture of two different pyridones 4.
Perhaps it can be due to the formation of an intermediate full-
aminal form 5 from the semiaminal enamine form of aldehyde 3
(Scheme 2).
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2 NH2
-RNH
O
N
O
N
2
EtO C
2
EtO C
2
+
EtO C
2
CO Et
2
EtO C
2
CO Et
2
N
N
N
N
N
N
N
N
-EtOH
R2
R1
B
B
B
B
NHR1
NHR2
F
F
F F
F
F
F
F
NHR1
5
4
3
Scheme 2. Formation of the mixture of pyridones 4 from individual enamine 3.
An understanding of these aspects of the reaction mechanism
allowed us to make two important practical conclusions. First, for
the preparation of enamine 3 from aldehyde 1 a large excess of the
amine should be avoided, and the addition of acetic acid is desir-
able. But the best way to obtain enamines is the use of enol acetate
2; in this case the reaction is virtually instantaneous and quanti-
tative. Second, the presence of base is necessary to promote the
cyclization of enamines 3 into pyridones 4. It was found that this
process is clean and efficient when just a catalytic amount (5e10 M
%) of the base is used (triethylamine, Hunig’s base, potassium
with azide and acetylene function, respectively, to be used as re-
agents in ‘click chemistry’. Alkene fragment was introduced into
compound 4j (either for polymerization or further modification of
the dye via the oxidation of ethylene bond).
The transformation of BODIPY into a colorless anionic dipyrro-
methane form like 6 caused by alkalies was first observed by Alfred
Treibs, the founderof dipyrromethene chemistry, more than 50 years
ago.20 In case of pyridones 4 this transformation occurs instantly and
without a significant excess of the base, in contrast to aldehyde 1 or
its precursors. Undoubtedly, this is due to electron-acceptor action of

Y.V. Zatsikha et al. / Tetrahedron 69 (2013) 2233e2238
2235
the pyridone ring. Dipyrromethane form 6 appeared to be quite
stable. For example, even after the compound 4 was kept in aqueous
alcohol alkaline solution for 6e8 h at ambient temperature, its
acidification resulted in almost complete recovery of the parent
pyridone form (Scheme 3).
approach has been employed to further deepen the color of BODIPY
dyesdwe have obtained styryl derivatives 8e10 starting from
n-butyl pyridone 4c (Scheme 4).
Condensation reactions at a-methyl group have been performed
by heating the compound 4c with corresponding aldehydes in
-
Ph
OH Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
SO
4
NaOH
H +
O
Me2
O
N
NaOH
O
O
Na+
Na+
EtO C
2
EtO C
2
EtO C
2
EtO C
2
-
N
N
F
N
N
N
N
N
N
H +
B
NR
B
NR
B
B
N
for R = H
F
F
F
F
F
F
F
λ
= 597 nm
Colorless
max
4b
7
4
6
Scheme 3. Action of bases on pyridones 4.
BODIPY 4a in alkaline medium behaves differently compared to
other derivatives. In this case the action of the base leads to the
bathochromic shift caused by the formation of deprotonated
structure 7. We had hoped to use that for N-alkylation of pyridone
ring that would provide additional synthetic possibilities. However,
the success of this approach was limited (Scheme 3). Indeed, upon
heating of compound 4a with dimethyl sulfate in the presence of
K2CO3 in acetonitrile or DMF the formation of small amount of
pyridone 4b in the reaction mixture was detected by TLC. But only
decomposition of starting compound was observed when less ac-
tive alkylating agents (methyl tosylate, methyl iodide, propane
sultone etc.) were used. Control experiments confirmed that
dipyrromethene 4a rather quickly decomposes upon heating in the
presence of bases.
Intermediate enamines 3bej absorb at around 620 nm, but
these compounds are virtually devoid of fluorescent properties. It is
in good agreement with the view of borondipyrromethene optical
properties, since free conjugated terminal amino groups as a rule
lead to the fluorescence quenching.21 Some of these intermediates
were obtained as analytically pure samples (their NMR spectra are
presented in Supplementary data), other enamines were used at
the next step without additional purification.
benzene in the presence of piperidine and acetic acid, i.e., under
conditions most often found in the literature.14
As expected, the introduction of styryl substituent led to a sig-
nificant bathochromic shift (50e70 nm) in both the absorption and
emission spectra, but, unfortunately, fluorescence quantum yields
decreased. The best brightness was achieved for p-methoxy
substituted styryl dye 9 (Table 1, Fig. 1), which is consistent with
literature data.14
3. Conclusions
In summary, we have developed a very simple synthetic pro-
cedure that allows an efficient introduction of functional substituents
into BODIPY core using aliphatic amines. Functionalized dyes con-
taining alkyl, carboxyalkyl, azide, acetylene, and other groups have
been obtained. The prepared stable dyes are intense fluorophores
with emission maximum in the region of 610e615 nm, which may be
further red-shifted by the transition to styryl derivatives. These dyes
can be used, e.g., in biomedical research for the fluorescent labelingof
biomolecules via the amide bond formation or click reactions,
membrane studies, etc. It should be especially noted that the above
described general method allows the preparation of unsymmetrical
Spectral characteristics of pyridones 4aej are presented in
Table 1. All these compounds have close spectral parameters and
are bright fluorophores. It should be noted that in addition to high
fluorescence quantum yields they demonstrate good chemical and
photostability: their solutions of spectral concentration have been
stored for two months under diffuse daylight with no changes.
At the same time, biological applications sometimes require
longer wavelength dyes emitting at the region of so-called ‘pho-
totherapeutic window’ (in the range 600e900 nm). So a known
BODIPY derivativeswithdifferentsubstituents attwoa-positions. We
believe that this approach lays the foundation for a new combina-
torial strategy in the family of BODIPY dyes, which is now considered
to be of great importance in fluorescent probe development.22
4. Experimental section
4.1. General
Absorption spectra were recorded on a Shimadzu UV-3100
spectrophotometer. 1H NMR (500 MHz, CDCl3, TMS as internal
standard) and 13C NMR (125 MHz, DMSO-d6) spectra were obtained
at 25 ꢀC on a Bruker Avance 500 instrument. Chemical shifts are
given in parts per million. Chromato-mass spectrometry mea-
surements were performed with LC/MS system consisting of Agi-
lent 1100 Series HPLC instrument equipped with a diode matrix
detector, and Agilent LC/MSD SL mass detector. APCI (Atmospheric
Pressure Chemical Ionization) technique with detection of positive
ions was used. Column chromatography was performed using Silica
gel 100 (Fluka, 0.063e0.200 mm). Fluorescence spectra were
recorded on a Solar CM 2203 fluorescence spectrophotometer. The
relative fluorescence quantum yields (4) were determined using
Nile Blue (4¼0.27, EtOH) as the reference.
Table 1
Photophysical properties of the dyes in dichloromethane
Dye
labs, nm
fwhm,a cmꢁ1
lem, nm (4)
(ε$10ꢁ3, Mꢁ1 cmꢁ1
)
4a
578 (105)
586 (95)
588 (100)
588 (85)
584 (83)b
584 (89)
586 (118)
588 (80)
582 (88)
579 (91)
584 (98)
642 (90)
656 (113)
660 (86)
1083
1146
1179
1184
1422
1303
1194
1185
1152
1147
1150
1040
1104
1469
603 (0.97)
614 (0.73)
618 (0.86)
618 (0.81)
609 (0.81)b
614 (0.84)
617 (0.95)
617 (0.88)
612 (0.91)
607 (0.82)
612 (0.80)
665 (0.41)
686 (0.36)
683 (0.28)
4b19
4c
4d
4e
4f
4g
4h
4i
4j
8
9
10
4.1.1. 2-Carbethoxy-3-methyl-1,9-diphenyl-4,4-difluoro-3a,4a,7-
triaza-4-bora-cyclopenta[b]fluoren-8-on (4a). A mixture of alde-
hyde 1 (544 mg, 1.0 mmol) and ammonium acetate (308 mg,
a
fwhm¼full width at half-maximum height.
b
In hexane.

2236
Y.V. Zatsikha et al. / Tetrahedron 69 (2013) 2233e2238
H
Ph
Ph
Ph
Ph
Ph
Ph
H
O
R
O
N
O
N
O
N
O
EtO C
2
EtO C
2
EtO C
2
N
N
N
N
N
N
AcOH
B
B
AcOH
Bu
Bu
B
Bu
N
F
F
F
F
N
F
F
R
4c
8 (R = H), 9 (R = OMe)
10
Scheme 4. Synthesis of styryls 8e10.
hexane. Yield (490 mg, 88%), green solid, mp 250e251 ꢀC; [found:
C, 69.84; H, 5.33; N, 7.40. C32H30BF2N3O3 requires C, 69.45; H, 5.46;
N, 7.59%]; Rf (25% EtOAc/hexane) 0.55; nmax (KBr) 2970, 1720, 1680,
1590, 1530, 1440, 1390, 1270, 1230, 1140, 1090, 1000, 920, 805, 755,
9
4c
1,0
690, 585 cmꢁ1
; dH (500 MHz, CDCl3) 7.51 (2H, m, Ph), 7.41e7.38 (6H,
4c
9
m, Ph), 7.31e7.27 (3H, m, PhþCH), 7.14 (1H, s, meso-CH), 6.75 (1H, d,
J 7.6 Hz, CH), 4.15 (2H, q, J 7.2 Hz, OCH2Me), 3.88 (2H, t, J 7.2 Hz,
CH2(CH2)2Me), 2.95 (3H, s, CMe), 1.69e1.66 (2H, m, CH2CH2CH2Me),
1.37e1.32 (2H, m, (CH2)2CH2Me), 1.08 (3H, t, J 7.2 Hz, OCH2Me), 0.91
(3H, t, J 7.2 Hz (CH2)3Me); dC (125 MHz, DMSO-d6) 163.0, 161.6,
158.7, 152.6, 148.1,142.5, 135.7,135.5, 131.5,131.4,130.9,130.6, 130.2,
129.8, 129.6, 128.4, 128.2, 121.4, 95.9, 60.6, 47.9, 31.4, 19.8, 15.1, 14.0;
LCeMS: m/z MHþ, found 554. C32H30BF2N3O3 requires 553.42.
0,5
0,0
400
600
λ nm
800
4.2.3. 2-Carbethoxy-3-methyl-7-octadecyl-1,9-diphenyl-4,4-
difluoro-3a,4a,7-triaza-4-bora-cyclopenta-[b]fluoren-8-on
(4d). Yield (660 mg, 88%), dark brown solid, mp 131e132 ꢀC;
[found: C, 73.97; H, 7.68; N, 5.40. C46H58BF2N3O3 requires C, 73.69;
H, 7.80; N, 5.60%]; Rf (25% EtOAc/hexane) 0.74; nmax (KBr) 2940,
2870, 2210, 1720, 1680, 1625, 1600, 1530, 1450, 1390, 1270, 1240,
Fig. 1. Absorption (C¼1ꢂ10ꢁ5 M, solid line) and normalized fluorescence (dashed line)
spectra of compounds 4c and 9 in CH2Cl2.
4 mmol) in ethanol (15 mL) was refluxed for 5 min. After cooling to
room temperature, the precipitate was filtered. Yield (420 mg, 84%),
green solid, mp >250 ꢀC; [found: C, 67.85; H, 4.35; N, 8.25.
C28H22BF2N3O3 requires C, 67.63; H, 4.46; N, 8.45%]; Rf (10% MeOH/
CHCl3) 0.82; nmax (KBr) 3170, 1720, 1680, 1590, 1430, 1390, 1260,
1195, 1140, 1100, 1005, 910, 805, 755, 690, 590 cmꢁ1
; dH (500 MHz,
CDCl3) 7.53e7.52 (2H, m, Ph), 7.40 (6H, m, Ph), 7.31e7.21 (3H, m,
PhþCH), 7.14 (1H, s, meso-CH), 6.75 (1H, d, J 7.6 Hz, CH), 4.13 (2H, q, J
7.2 Hz, OCH2Me), 3.86 (2H, t, J 7.2 Hz, CH2(CH2)16Me), 2.95 (3H, s,
CMe), 1.68 (2H, t, J 6.8 Hz, CH2CH2(CH2)15Me), 1.27e1.22 (30 H, m,
(CH2)2(CH2)15Me), 1.08 (3H, t, J 7.2 Hz, OCH2Me), 0.85 (3H, t, J 7.2 Hz,
(CH2)17Me); LCeMS: m/z MHþ, found 751. C46H58BF2N3O3 requires
749.80.
1150, 1000, 920, 750, 690, 640, 585, 560 cmꢁ1
; dH (500 MHz, CDCl3)
9.43 (1H, s, NH), 7.55e7.54 (2H, m, Ph), 7.41e7.39 (6H, m, Ph),
7.32e7.31 (2H, m, Ph), 7.18e7.14 (2H, m, meso-CHþCH), 6.77 (1H, d, J
8.0 Hz, CH), 4.12 (2H, q, J 7.2 Hz, OCH2Me), 2.96 (3H, s, CMe), 1.09
(3H, t, J 7.2 Hz, CH2Me), dC (125 MHz, DMSO-d6) 163.1, 160.7, 159.7,
153.7, 147.8, 145.2, 138.9, 135.4,135.3, 131.6, 131.4, 130.8, 130.6, 130.1,
129.9, 129.6, 128.4, 128.3, 121.2, 118.3, 107.3, 95.8, 60.6, 15.1, 14.1.
LCeMS: m/z MHþ, found 498. C28H22BF2N3O3 requires 497.31.
4.2.4. 2-Carbethoxy-3-methyl-7-(2-hydroxyethyl)-1,9-diphenyl-4,4-
difluoro-3a,4a,7-triaza-4-bora-cyclopenta[b]fluoren-8-on (4e). The
protocol is similar to 4c. Yield (498 mg, 92%), brown solid, mp
>250 ꢀC; [found: C, 66.86; H, 4.80; N, 7.54. C30H26BF2N3O4 requires
C, 66.56; H, 4.84; N, 7.76%]; Rf (10% MeOH/CHCl3) 0.50; nmax (KBr)
3510, 2990, 1720, 1670, 1610, 1430, 1390, 1270, 1245, 1190, 1140,
4.2. General procedure for the synthesis of dyes 4bej
1.1 mmol of appropriate primary amine was added to the so-
lution of 586 mg (1 mmol) of enol acetate 219 in 50 mL of CHCl3 at
room temperature. In 1 h the solution was washed with water, 5%
aqueous acetic acid and aqueous sodium bicarbonate, dried
(Na2SO4), and then evaporated to dryness. The residue and 10 mg
(0.05 mmol) of sodium acetate were refluxed for 1 h in 50 mL of
i-PrOH. After cooling to room temperature a mixture was diluted
with water, extracted with CH2Cl2, dried (Na2SO4), and evaporated
to dryness. The crude product was purified by silica gel column
chromatography (25% EtOAc/hexane).
1090, 1020, 1000, 970, 915, 800, 750, 695, 580 cmꢁ1
; dH (500 MHz,
CDCl3) 7.52e7.51 (2H, m, Ph), 7.41e7.40 (6H, m, Ph), 7.35e7.31 (3H,
m, PhþCH), 7.16 (1H, s, meso-CH), 6.78 (1H, d, J 8.0 Hz, CH), 4.15 (2H,
q, J 7.2 Hz, OCH2Me), 4.08e4.06 (2H, m, CH2CH2OH), 3.90e3.89 (2H,
m, CH2CH2OH), 2.95 (3H, s, CMe), 2.31 (1H, m, (CH2)2OH),1.08 (3H, t,
J 7.2 Hz, OCH2Me); dC (125 MHz, DMSO-d6) 163.0,160.9,158.8, 152.9,
147.9, 145.3, 143.7, 135.6,135.4,131.6,131.4, 130.8, 130.6, 130.1, 129.8,
129.6, 128.4, 128.3, 121.3, 117.9, 95.4, 60.6, 59.4, 51.0, 15.1, 14.1;
LCeMS: m/z MHþ, found 542. C30H26BF2N3O4 requires 541.37.
4.2.5. 2-Carbethoxy-3-methyl-7-(2-methoxyethyl)-1,9-diphenyl-4,4-
difluoro-3a,4a,7-triaza-4-bora-cyclopenta[b]fluoren-8-on (4f). As in
the previous case, time of boiling in i-PrOH was 3 h. Yield (498 mg,
87%), dark green solid, mp 226e227 ꢀC; [found: C, 67.35; H, 4.95; N,
7.37. C31H28BF2N3O4 requires C, 67.04; H, 5.08; N, 7.57%]; Rf (50%
EtOAc/hexane) 0.54; nmax (KBr) 2910, 1710, 1680, 1590, 1430, 1390,
1350, 1270, 1230, 1200, 1140, 1100, 1005, 980, 915, 800, 750, 690,
4.2.1. 2-Carbethoxy-3,7-dimethyl-1,9-diphenyl-4,4-difluoro-3a,4a,7-
triaza-4-bora-cyclopenta[b]-fluoren-8-on (4b). Methanolic solution
of methylamine was used. After cooling to room temperature the
precipitate was filtered and washed with hexane, yield 92%. All
characteristics were identical to sample from Ref. 19.
4.2.2. 2-Carbethoxy-3-methyl-7-butul-1,9-diphenyl-4,4-difluoro-
3a,4a,7-triaza-4-bora-cyclopenta[b]-fluoren-8-on (4c). After cooling
to room temperature the precipitate was filtered and washed with
650, 580 cmꢁ1
; dH (500 MHz, CDCl3) 7.53e7.52 (2H, m, Ph),
7.39e7.37 (7H, m, PhþCH), 7.31e7.30 (2H, m, Ph), 7.14 (1H, s, meso-
CH), 6.74 (1H, d, J 7.6 Hz, CH), 4.15 (2H, q, J 7.2 Hz, OCH2Me),

Y.V. Zatsikha et al. / Tetrahedron 69 (2013) 2233e2238
2237
4.08e4.06 (2H, m, CH2CH2OMe), 3.61e3.59 (2H, m, CH2CH2OMe),
3.29 (3H, s, OMe), 2.95 (3H, s, CMe), 1.08 (3H, t, J 7.2 Hz, OCH2Me); dC
(125 MHz, DMSO-d6) 163.0, 161.2, 158.7, 152.6, 148.1, 145.2, 143.2,
135.7, 135.4, 131.5, 130.8, 130.6, 130.2, 129.9, 129.7, 128.4, 128.3,
121.5, 117.7, 95.6, 70.2, 60.7, 58.6, 47.8, 15.2, 14.1; LCeMS: m/z MHþ,
found 556. C31H28BF2N3O4 requires 555.39.
CH2CH]CH2), 4.53 (2H, d, J 5.6 Hz, CH2CH]CH2), 4.17 (2H, q, J 7.2 Hz,
OCH2Me), 2.95 (3H, s, CMe), 1.08 (3H, t, J 7.2 Hz, OCH2Me); dC
(125 MHz, DMSO-d6) 163.0, 161.4, 158.5, 152.5, 148.2, 145.1, 142.1,
135.7, 135.4, 134.0, 131.4, 130.8, 130.6, 130.3, 129.8, 129.7, 128.4, 128.3,
121.5, 117.8, 96.3, 60.7, 49.8, 15.2, 14.1; LCeMS: m/z MHþ, found 538.
C31H26BF2N3O3 requires 537.38.
4.2.6. 2-Carbethoxy-3-methyl-7-(6-carboxyhexyl)-1,9-diphenyl-4,4-
difluoro-3a,4a,7-triaza-4-bora-cyclopenta[b]fluoren-8-on (4g). Time
of boiling in i-PrOH was 2 h. Residue was recrystallized from MeCN.
Yield (550 mg, 90%), brown solid, mp 234e235 ꢀC; [found: C, 66.98;
H, 5.07; N, 6.59. C34H32BF2N3O5 requires C, 66.79; H, 5.28; N,
6.87%]; Rf (10% MeOH/CHCl3) 0.43; nmax (KBr) 3230, 2990, 1725,
1660, 1590, 1430, 1390, 1270, 1240, 1200, 1130, 1100, 1020, 1000,
4.2.10. 2-Carbethoxy-3-styryl-7-(1-butyl)-1,9-diphenyl-4,4-difluoro-
3a,4a,7-triaza-4-bora-cyclopenta-[b]fluoren-8-on (8). The mixture
of pyridone 4c (200 mg, 0.361 mmol), benzaldehyde (53 mg,
0.5 mmol), piperidine (215 mg, 2.53 mmol), and acetic acid
(300 mg, 5.0 mmol) in benzene (10 mL) was refluxed for 2 h. After
cooling to room temperature, the mixture was washed with water,
dried (Na2SO4), and evaporated to dryness. The residue was
recrystallized from i-PrOH. Yield (168 mg, 72%), green solid, mp
168e169 ꢀC; [found: C, 73.34; H, 5.27; N, 6.31. C39H34BF2N3O3 re-
quires C, 73.02; H, 5.34; N, 6.55%]; Rf (25% EtOAc/hexane) 0.45; nmax
(KBr) 2980, 1720, 1680, 1600, 1450, 1295, 1225, 1190, 1135, 1040,
920, 800, 750, 690, 590 cmꢁ1
; dH (500 MHz, CDCl3) 7.52e7.50
(2H, m, Ph), 7.41e7.38 (6H, m, Ph), 7.31e7.26 (3H, m, PhþCH), 7.14
(1H, s, meso-CH), 6.76 (1H, d, J 7.6 Hz, CH), 4.17 (2H, q, J 7.2 Hz,
OCH2Me), 3.88 (2H, t, J 7.2 Hz, CH2(CH2)4COOH), 2.95 (3H, s, CMe),
2.32 (2H, t,
J
7.2 Hz, (CH2)4CH2COOH), 1.76e1.70 (2H, m,
1010, 995, 915, 850, 745, 685, 585 cmꢁ1
; dH (500 MHz, CDCl3)
CH2CH2(CH2)3COOH), 1.68e1.60 (2H, m, (CH2)3CH2CH2COOH),
1.41e1.34 (2H, m, (CH2)2CH2 (CH2)2COOH), 1.08 (3H, t, J 7.2 Hz,
OCH2Me); dC (125 MHz, DMSO-d6) 174.8, 161.8, 161.1, 160.7, 161.1,
158.8,148.1,142.6, 134.7,131.5,131.2,130.6, 130.1,128.8,128.4,128.2,
95.9, 60.7, 48.0, 34.0, 29.6, 29.1, 26.0, 24.6, 15.2, 14.4, 14.1; LCeMS:
m/z MHþ, found 612. C34H32BF2N3O5 requires 611.46.
7.84e7.83 (2H, m, CH]CH), 7.67 (2H, d, J 6.8 Hz, Ph), 7.56 (2H, d, J
6.8 Hz, Ph), 7.40e7.34 (11H, m, Ph), 7.28 (1H, d, J 6.8 Hz, CH), 7.14
(1H, s, meso-CH), 6.81 (1H, d, J 6.8 Hz, CH), 4.20 (2H, q, J 7.2 Hz,
OCH2Me), 3.89 (2H, t, J 7.2 Hz, CH2(CH2)2Me), 1.70e1.67 (2H, m,
CH2CH2CH2Me), 1.38e1.33 (2H, m, (CH2)2CH2Me), 1.05 (3H, t, J
7.2 Hz, OCH2Me), 0.91 (3H, t, J 7.2 Hz, (CH2)3Me); dC (125 MHz,
DMSO-d6) 164.5, 158.7, 146.7, 144.9, 142.7, 141.6, 137.1, 136.1, 136.0,
131.5, 131.1, 130.9, 130.8, 130.1, 129.9, 129.8, 129.0, 128.8, 128.3,
128.0, 126.5, 117.1, 114.6, 95.8, 61.7, 48.0, 44.2, 31.5, 22.7, 19.8, 14.1;
LCeMS: m/z MHþ, found 642. C39H34BF2N3O3 requires 641.53.
4.2.7. 2-Carbethoxy-3-methyl-7-(2-azidoethyl)-1,9-diphenyl-4,4-
difluoro-3a,4a,7-triaza-4-bora-cyclopenta-[b]fluoren-8-on
(4h). Yield (250 mg, 90%), brown solid, mp 231e232 ꢀC; [found: C,
63.92; H, 4.33; N, 14.64. C30H25BF2N6O3 requires C, 63.62; H, 4.45;
N, 14.84%]; Rf (25% EtOAc/hexane) 0.26; nmax (KBr) 2120, 1725, 1675,
1600, 1550, 1450, 1390, 1270, 1240, 1190, 1130, 1200, 915, 850, 800,
4.2.11. 2-Carbethoxy-3-(2-(4-methoxyphenyl)vinyl)-7-(1-butyl)-1,9-
diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta[b]fluoren-8-
on (9). The product was prepared using anisaldehyde analogously
to 8. Yield (240 mg, 70%), brown solid, mp 206e207 ꢀC; [found: C,
71.88; H, 5.32; N, 6.11. C40H36BF2N3O4 requires C, 71.54; H, 5.40; N,
6.26%]; Rf (25% EtOAc/hexane) 0.30; nmax (KBr) 2975, 2270, 1720,
1680, 1600, 1530, 1480, 1450, 1390, 1320, 1270, 1220, 1190, 1140,
750, 690, 650, 585 cmꢁ1
; dH (500 MHz, CDCl3) 7.52e7.51 (2H, m,
Ph), 7.42e7.39 (6H, m, Ph), 7.31e7.29 (3H, m, PhþCH), 7.16 (1H, s,
meso-CH), 6.80 (1H, d, J 7.6 Hz, CH), 4.17 (2H, q, J 7.2 Hz, OCH2Me),
4.01 (2H, t, J 5.6 Hz, CH2CH2N3), 3.65 (2H, t, J 5.6 Hz, CH2CH2N3),
2.96 (3H, s, CMe), 1.08 (3H, t, J 7.2 Hz, OCH2Me); dC (125 MHz,
DMSO-d6) 163.0, 158.8, 142.5, 131.4, 131.2, 130.6, 130.1, 129.9, 129.7,
128.7, 128.4, 128.3, 117.6, 96.1, 95.9, 60.7, 49.7, 47.6, 15.2, 14.4, 14.1.
1040, 920, 850, 800, 745, 685, 590 cmꢁ1
; dH (500 MHz, CDCl3) 7.84
(1H, d, J 16.0 Hz, CH]CH), 7.75 (1H, d, J 16.0 Hz, CH]CH), 7.63 (2H,
d, J 8.8 Hz, ArH), 7.56 (2H, d, J 6.8 Hz, Ph), 7.40e7.34 (8H, m, Ph), 7.27
(1H, d, J 7.6 Hz, CH), 7.10 (1H, s, meso-CH), 6.94 (2H, d, J 8.8 Hz, ArH),
6.81 (1H, d, J 7.6 Hz, CH), 4.19 (2H, q, J 7.2 Hz, OCH2Me), 3.90e3.85
(5H, m, CH2(CH2)2MeþOMe), 1.68e1.67 (2H, m, CH2CH2CH2Me),
1.38e1.32 (2H, m, (CH2)2CH2Me), 1.04 (3H, t, J 7.2 Hz, OCH2Me), 0.91
(3H, t, J 7.2 Hz, (CH2)3Me); dC (125 MHz, DMSO-d6) 164.6, 161.8,
158.7, 153.9, 152.1, 146.9, 143.6, 142.0, 136.8, 135.6, 131.5, 131.1, 130.0,
129.9, 129.6, 129.0, 128.8, 128.2, 127.4, 123.2, 117.7, 115.4, 114.7, 96.1,
95.7, 61.7, 55.9, 47.9, 31.5, 25.9, 19.8, 14.0; LCeMS: m/z MHþ, found
672. C40H36BF2N3O4 requires 671.56.
4.2.8. 2-Carbethoxy-3-methyl-7-(1-prop-2-ynyl)-1,9-diphenyl-4,4-
difluoro-3a,4a,7-triaza-4-bora-cyclopenta[b]fluoren-8-on
(4i). Propargylamine was used as hydrochloride, Hunig’s base
(1 mmol) was added to chloroformic solution. Yield (483 mg, 90%),
brown solid, mp 240e241 ꢀC; [found: C, 69.88; H, 4.46; N, 7.63.
C31H24BF2N3O3 requires C, 69.55; H, 4.52; N, 7.85%]; Rf (25% EtOAc/
hexane) 0.34; nmax (KBr) 3290, 2110, 1720, 1670, 1600, 1440, 1385,
1270, 1235, 1200, 1140, 1085, 1005, 975, 925, 690, 585 cmꢁ1
; dH
(500 MHz, CDCl3) 7.57 (1H, d, J 7.6 Hz, CH), 7.53e7.51 (2H, m, Ph),
7.40e7.39 (6H, m, Ph), 7.31e7.29 (2H, m, Ph), 7.16 (1H, s, meso-CH),
6.85 (1H, d, J 7.6 Hz, CH), 4.71 (2H, d, J 2.4 Hz, CH2C^CH), 4.15 (2H, q, J
7.2 Hz, OCH2Me), 2.96 (3H, s, CMe), 2.40 (1H, t, J 2.4 Hz, CH2C^CH),
1.08 (3H, t, J 7.2 Hz, CH2Me); dC (125 MHz, DMSO-d6) 162.9, 161.9,
158.1,152.2,148.6,144.8,141.0,135.9,135.2,131.4,130.7,129.9,129.8,
128.4, 128.3, 121.7, 117.4, 96.8, 95.9, 79.5, 76.0, 60.7, 37.0, 15.3, 14.1;
LCeMS: m/z MHþ, found 536. C31H24BF2N3O3 requires 535.36.
4.2.12. 2-Carbethoxy-3-(4-phenylbuta-1,3-dienyl)-7-(1-butyl)-1,9-
diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta[b]fluoren-8-
on (10). The mixture of pyridone 4c (200 mg, 0.361 mmol), 3-
phenyl-2-propenal (85 mg, 0.65 mmol), piperidine (215 mg,
2.53 mmol), and acetic acid (300 mg, 5.0 mmol) in benzene (10 mL)
was refluxed for 2.5 h. After cooling to room temperature, the so-
lution was washed with water, dried (Na2SO4), and evaporated to
dryness. The crude product was purified by silica gel column
chromatography (25% EtOAc/hexane) to give (70 mg, 30%) of 10.
Dark green solid, mp 195e196 ꢀC; [found: C, 73.98; H, 5.34; N, 6.13.
C41H36BF2N3O3 requires C, 73.77; H, 5.44; N, 6.29%]; Rf (30% EtOAc/
hexane) 0.45; nmax (KBr) 2985, 1725, 1680, 1595, 1535, 1485, 1440,
1390, 1275, 1220, 1180, 1130, 1010, 920, 850, 750, 690, 650,
4.2.9. 2-Carbethoxy-3-methyl-7-(1-allyl)-1,9-diphenyl-4,4-difluoro-
3a,4a,7-triaza-4-bora-cyclopenta-[b]fluoren-8-on (4j). Yield (496 mg,
92%), dark brown solid, mp 238e239 ꢀC; [found: C, 69.55; H, 4.79; N,
7.67. C31H26BF2N3O3 requires C, 69.29; H, 4.88; N, 7.82%]; Rf (25%
EtOAc/hexane) 0.37; nmax (KBr) 3000, 1720, 1675, 1595, 1480, 1440,
1390,1270,1230,1200,1140,1090,1000, 970, 915, 800, 750, 690, 650,
590 cmꢁ1
;
dH (500 MHz, CDCl3) 7.53e7.51 (2H, m, Ph), 7.39 (6H, m,
590 cmꢁ1
; dH (500 MHz, CDCl3) 7.83e7.65 (1H, m, CH]CH),
Ph), 7.31e7.25 (3H, m, PhþCH), 7.15 (1H, s, meso-CH), 6.79 (1H, d, J
7.55e7.49 (3H, m, PhþCH]CH), 7.40e7.27 (14H, m, PhþCH),
8.0 Hz, CH), 5.94e5.87 (1H, m, CH2CH]CH2), 5.24e5.17 (2H, m,
7.16e7.14 (1H, m, CH]CH), 7.09 (1H, s, meso-CH), 6.95 (1H, d, J

2238
Y.V. Zatsikha et al. / Tetrahedron 69 (2013) 2233e2238
9. Leen, V.; Miscoria, D.; Yin, S.; Filarowski, A.; Ngongo, J. M.; Van der Auweraer,
16.0 Hz, CH]CH), 6.80 (1H, d, J 8.0 Hz, CH), 4.19 (2H, q, J 7.2 Hz,
OCH2Me), 3.89 (2H, t, J 7.2 Hz, CH2(CH2)2Me), 1.70e1.67 (2H, m,
CH2CH2CH2Me), 1.38e1.33 (2H, m, (CH2)2CH2Me), 1.03 (3H, t, J
7.2 Hz, OCH2Me), 0.91 (3H, t, J 7.2 Hz, (CH2)3Me); LCeMS: m/z MHþ,
found 668. C41H36BF2N3O3 requires 667.57.
M.; Boens, N.; Dehaen, W. J. Org. Chem. 2011, 76, 8168.
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~
ꢀ
ꢀ
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~
J.; Martín, V.; Gomez-Duran, C. F. A.; Cordoba, I. J. A.; Pena-Cabrera, E.;
ꢀ
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García-Moreno, I.; Costel, A.; Perez-Ojeda, M. E.; Arbeloa, T.; Arbeloa, I. L.
Chem.dEur. J. 2011,17, 7261; (c) Gomez-Duran, C. F. A.; García-Moreno, I.; Costela,
ꢀ
ꢀ
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~
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A.; Martín, V.; Sastre, R.; Banuelos, J.; Arbeloa, F. L.; Arbeloa, I. L.; Pena-Cabrera, E.
Chem. Commun. 2010, 46, 5103.
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Acknowledgements
This work was partially supported by the NATO ‘Science for
Peace’ program, project NUKR.SFPP 984189.
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Supplementary data
These data include copies of 1H and 13C NMR spectra. Supple-
mentary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.050.
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