Synthesis of 8-heteroatom-substituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene dyes (BODIPY)

Article abstract of DOI:10.1016/j.tet.2006.03.036

Thioketones, bis-(5-R-1H-pyrrol-2-yl)-methanethiones (R=H, Me, Et), 4 react with methyl iodide or isopropyl triflate to give the pyrrolium salts, which are treated with tertiary amine and boron trifluoride to produce the 8-(thiomethyl/thioisopropyl) 4,4-d

Full text of DOI:10.1016/j.tet.2006.03.036

Tetrahedron 62 (2006) 5084–5091
Synthesis of 8-heteroatom-substituted 4,4-difluoro-4-bora-3a,
4a-diaza-s-indacene dyes (BODIPY)
y
*
Thirumani Venkateshwar Goud, Ahmet Tutar and Jean-Franc¸ois Biellmann
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
Received 15 December 2005; revised 10 March 2006; accepted 13 March 2006
Available online 17 April 2006
Abstract—Thioketones, bis-(5-R-1H-pyrrol-2-yl)-methanethiones (R¼H, Me, Et), 4 react with methyl iodide or isopropyl triflate to give the
pyrrolium salts, which are treated with tertiary amine and boron trifluoride to produce the 8-(thiomethyl/thioisopropyl) 4,4-difluoro-3,5-di-R-
4-bora-3a,4a-diaza-s-indacenes 6a–6c and 8a–8c. The reaction of the methyl thioether group of 6a and 6b with aniline gives the substitution
products whose structure corresponds to formula 10. The structures of the thioethers 6a–6c and compound 10a were determined by X-ray
diffraction. The thiomethyl groups in 6a–6c are close to be coplanar to the flat ring system, the strain due to the interaction of methyl
with the hydrogen at C1 is released by shifting of the sulfur atom away from carbon C1 and opening of the angle C8–S-methyl. This copla-
narity of the thiomethyl group with ring system agrees with the preference of the syn conformation of methyl vinyl thioether. In the structures
of the aniline compound 10a the length of the nitrogen to C8 is close to that of N]C double bond. Thioethers 6a–6c show high wavelength
absorption at 523–530 nm and fluorescence with a Stokes shift of 12–24 nm and with a quantum yield of 0.15–0.37. In contrast the aniline
substituted compounds 10a and 10b showed absorption at 410 and 430 nm, respectively, with no fluorescence. According to their spectral
properties they are better described by structure 10 than 7.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Earlier we described a thiol reagent sulfone 1. The reaction
of this sulfone 1 with thiol gave thioether 2 whose long
wavelength absorption appears on the reaction.6 But this
vinylic thioether 2 is not fluorescent. So we planned synthe-
sis of thioether with the 4,4-difluoro-4-bora-3a,4a-diaza-s-
indacene (BODIPY) group. BODIPY dyes are prepared
by reaction of pyrroles with acid chlorides (or aldehydes)
to the dipyrrolomethenes (or dipyrrolomethanes oxidized
to former). The dipyrrolomethenes are then condensed to
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene by action of a
tertiary base and boron trifluoride. A limited range of
functional groups are compatible with these reaction con-
ditions. In order to avoid further condensation, the pyrroles
have to be substituted at C-2. In view of the interest of
the spectral properties of this system, there is a need of
preparation methods under milder reaction conditions
compatible with most functional groups. We report herein
such a reaction for the synthesis of sulfur containing
BODIPY.
In recent years, the search for selective and sensitive fluo-
rescent probes for metal ions has tremendously gained an
importance. The development of functional group molecules
capable of performing chemically and/or physically con-
trolled actions and reporting on or transducing these through
luminescence signal has attracted considerable attention.
Examples of functional supramolecular systems communi-
cating through the luminescence include molecular scale
sensors,1 switches,2 motors and machines,3 wires or arrays,4
cascades and cassettes that operate through energy or elec-
tron transfer process. Herein, we report the synthesis of
sulfur containing BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene) compounds under mild reaction conditions in
good to reasonable yield. The high wavelength absorption
at 523–530 nm and the fluorescence with a Stokes shift of
12–24 nm compounds are well described. BODIPY dyes
are used for their physical properties in biotechnological
applications.5
SO2CH3
S
Et
HN Ph
* Corresponding author. Tel.: +886 2 2789 8526; fax: +886 2 2783 1237;
e-mail: jfb@chem.sinica.edu.tw
N
N
N
I-
I-
I-
y
¨
Present address: Sakarya Universitesi, Fen-Edebiyat Fakultesi, Kimya
Me
Me
¨
Me
1
2
3
Bolumu, Esentepe 54140, Sakarya, Turkey.
¨ ¨
¨
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.036

T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
5085
CH3
The reaction of thiophosgene with pyrrole and substituted
S
S
pyrroles is fast and provides thioketones 4 in rather mild
conditions. Even pyrrole itself gives the thioketone 4a in
a good yield.7 The reaction is specially interesting because
no further condensation products have been detected. This
may be due to the reduced reactivity of the intermediate
and of the thioketone 4. We prepared the thioketones
4a–4c by the reaction of thiophosgene with pyrrole, 2-
methyl- and 2-ethyl-pyrrole in yields close to the published
ones.7
CH3I
CSCl2
NH HN+
I
R
NH HN
CH2Cl2
N
H
R
R
R
R
5 a R= H
b R= Me
c R= Et
4 a R= H
b R= Me
c R= Et
CH3
HN
S
1
7
8a
N
F
7a
N+
F
NEt3
BF3·OEt2
C6H5-NH2
CH2Cl2
8
N+
N
B
B
R
R
F
2. Results and discussion
F R
R
6 a R= H
b R= Me
c R= Et
7 a R= H
b R= Me
The reaction of thioketones with electrophilic reagents
tends to occur at the sulfur. With thiopyridone, for instance,
one obtains the pyridinyl thioether.8 So, we explored the
reaction of the thioketones 4a–4c with methyl iodide and
isopropyl triflate. The reaction of thioketones 4a–4c
with methyl iodide gives the dipyrrolomethene probably as
hydroiodides 5a–5c as brown gummy solids. These com-
pounds are not too stable and were characterized as crude
products. Their purity seems to be high and they showed
a high absorption in the range of 458–480 nm. Their
NMR spectra indicate that they are present as single isomer
or that the interconvertion of the (E) and (Z) isomers is
rapid. The chemical shifts of the ring protons of pyrrolo-
methenes 5a–5c are shifted to lower fields when compared
to the pyrrolomethenes taken as base in CS2.9 So, we favor
the presence of the pyrrolomethenes 5a–5c as hydro-
iodides.
CH3
H3C
CH3
H3C
S
S
S
B
Iso propyl triflate
NEt3
+
N
NH N+
BF3.OEt2
rt, 30 mnts
NHHN
R
4 a R= H
b R= Me
c R= Et
N
Added at 0°C
CH2Cl2
R
R
F
8 a R = H
b R = Me
c R = Et
R
R
R
F
rt, 24-36 hrs.
SPh
H
C
C
O
H
H
C
H
H
1)Yb(NTf2)3 5 mol%
2)DDQ
+
C
C
N
N
CH3
N
H
B
PhS
3)NEt3, BF3·OEt2
CH2Cl2, rt
H3C
CH3
F
F
9
Scheme 1.
Reaction of pyrrolomethenes 5a–5c with boron trifluoride
etherate in presence of triethylamine gave the red colored
8-(thiomethyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes
6a–6c. The thiomethyl group of 6a and 6b is displaced by
aniline to give 8-(anilino) compounds, which initially we
presented as 7a and 7b. But their spectral properties are
in better agreement with structures 10a and 10b. In future
discussion we use the structures 10a and 10b. The sub-
stitution reaction is similar to the one observed with
N-methyl 4-thiomethylvinylic pyridinium salt.10 The reac-
tion of indacene 6c with aniline was very slow and was
not studied.
+
N
H
HN
N+
F
N
F
–
N
F
–
N
F
B
B
R
R
R
R
7 a R= H
b R= Me
10 a R= H
b R= CH3
KOH
Acid
EtO2C
CO2Et
EtO2C
CO2Et
The same reaction sequence of thioketones 4a–4c first with
isopropyl triflate and later with boron trifluoride gave the
isopropyl thioethers 8a–8c. These compounds 8a–8c were
obtained as amorphous material and failed to crystallize in
our hands.
+
–
N
F
N
–
N
F
N
B
F
B
F
12
11
3. Structure
In order to compare the spectral properties of vinylic thio-
ether, we prepared 8-(2-thiophenylethene) 4,4-difluoro-3,5-
Structures of the three indacenes 6a–6c were determined by
X-ray diffraction study. As the indacene 6a (Fig. 1) crystal-
lized with two different molecules in the asymmetric unit,
we have four structures. The general features of these four
structures will be presented here. The indacene atoms except
the fluorine atoms are close to be in one plane. The methyl
group of the thiomethyl group is close to the plane of
the indacene system (torsion angle CH3–S–C8–C7a of
0.00ꢀ; 2.21ꢀ; 2.39ꢀ; 4.48ꢀ, respectively) and in close contact
with the hydrogen at C7 (C of methyl group–H (at C7) 2.50–
dimethyl-4-bora-3a,4a-diaza-s-indacene
9 (Scheme 1).
The condensation of 2-methylpyrrole with 3-(phenylthio)-
propenal in presence of ytterbium (III) trifluoromethane
sulfonamide in catalytic amount gave the nonisolated dipyr-
rolomethane, which was oxidized by DDQ to the pyrrolo-
methene. By reaction of boron trifluoride etherate in presence
of triethylamine, the indacene 9 was obtained in low yield.
But the spectral properties of the vinylic thioether 9 were
not what we had expected so that we did only limited attempts
in preparing compound 9 and the related ones.
˚
2.53 A) whereas the van der Waals distance for hydrogen

5086
T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
thioether structures Ar–S–CH3 collected in the data bank
at the date of writing is about 150, if the ortho-disubstituted
are excluded. On closer examination one finds that 47% have
a torsional angle in the range of 0–5ꢀ, 67% in 0–10ꢀ, 80% in
0–15ꢀ, and 85% in 0–20ꢀ. Such abundance could reflect
a preference for the syn conformation in solution of such
thioethers.
In order to have more information about the systems studied
here, we prepared the isopropyl thioethers 8a–8c with the
idea that the isopropyl group would be out of the indacene
plane. But in our hands these thioethers failed to crystallize.
In view of the unexpected spectral data of the aniline com-
pounds, we determine the structure of the two allotropic
forms of 10a. One contains two molecules in a different
arrangement in the lattice, so we have the data for three
molecules. The ring system is close to be planar except the
two fluorine atoms and the phenyl group. The phenyl group
makes an angle of 83ꢀ, 88ꢀ, and 56ꢀ with the plane of the ring
system (Fig. 1). The noticeable feature is the short nitrogen–
˚
˚
˚
C8 (1.23 A, 1.33 A, and 1.34 A). This bond length is close to
12
˚
the one found for Car-C]N–C (1.28 A).
Figure 1. X-ray crystal structures of compounds 6a (left) and 10a (right).
The carbon and hydrogen atoms are in black, the boron atoms in green,
the nitrogen is magenta, and sulfur in yellow. The two molecules of
compound 6a present in the asymmetric unit are presented.
4. Spectral properties
to carbon is 2.9–3.0 A.10 The sulfur is displaced toward car-
˚
bon C1 so that the angles at C8 are in the range of 127.2–
127.8ꢀ for S–C8–C7a and of 111.8–112.2ꢀ for S–C8–C8a.
The distance of the sulfur to the hydrogens at C7 and C1
The absorption maximum of the thioethers 6a, 6b (Fig. 2),
and 6c is shifted to higher wavelength 523–530 nm
(MeOH) (Table 1). Indeed related systems such as 4,4-
difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-prop-
anol show an absorption maximum at 505 nm in ethanol.14
So the introduction of a thioether group at C8 induces a shift
of 18–25 nm to be compared to the shift 22–40 nm on going
from N-methyl pyridinium salt to N-methyl 4-thiomethyl
pyridinium salt.15 The absorption maximum of 1-methyl-
4-ethenylpyridinium iodide is at 265 nm (15,000)16 and
that of 1-methyl-4-[2-ethylsulfanyl-1-ethenyl]pyridinium
salt 2 at 362 nm. So a shift of about 100 nm is observed
by introduction of a thioether group in this system. In the
crystal structure the thiovinylic group forms a torsion angle
of 6.7ꢀ with the pyridinium plane so that conjugation may be
˚
˚
are in the range of 2.77–2.83 A and 3.31–3.33 A so that
˚
the sulfur atom is shifted by 0.25 A. The van der Waals dis-
tance for sulfur to H is 2.91 A.11 The bond angles CH3–S–C8
˚
in 4a–4c are in the range 109.89–110.22ꢀ to be compared
with 104ꢀ found in thioethers. So the strain was in part re-
leased by increasing the angles C7a–C8–S and CH3–S–C8.
˚
The length of the S–CH3 bond is 1.77–1.78 A compared to
˚
1.789 A (s¼0.008) for such bond whereas the length of
˚
the C8–S bond is 1.77 A in the range for such bond
12
˚
1.773 A (s¼0.009). In solution no hindrance of the rota-
tion could be detected by NMR spectroscopy and this is
not unexpected, since the barrier calculated for the methyl
vinyl thioether is low.13 The systems in the crystals are de-
void of symmetry so that the bond distances are different.
The solid state NMR of products 6a and 6b showed that
all the carbon atoms were different in the solid.
UV
1.0
Emission
0.8
0.6
0.4
0.2
0.0
The strain induced by the interaction of the methyl group
with the hydrogen at C7 must reflect a preference of the
methyl group to be coplanar with the indacene system.
Indeed the experimental evidence and calculations show
a preference for the syn conformation of methyl vinyl thio-
ether over the next gauche preferred conformation by about
6.92 kJ mol .
ꢁ1 13 The effect of a donor–acceptor substituent
on the equilibrium gauche–syn of vinylic thioethers as pres-
ent in 6a–6c does not seem to have been evaluated. The
structure of vinylic thioethers seems to have been scarcely
determined. We had prepared the vinylic thioether 2, had
determined its structure by X-ray diffraction, and found
the cis conformation in the crystalline state with the torsion
300 350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
angle Et–S–C–C of 2.23ꢀ and the distance of the sulfur to the
Figure 2. Absorption and fluorescence spectrum (excitation at 530 nm) of
compound 6b in methanol.
6
˚
syn hydrogen of 2.62 A. The number of aromatic methyl

T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
5087
Table 1. Spectroscopic data for compounds 6a–c, 8a–c, 9 and 10a–b
UV of 10a
UV of 10b
1.0
0.8
0.6
0.4
0.2
0.0
Compound Absorption
lmax (nm)
3
Emission Stokes Quantum
lmax (nm) shift
(Mꢁ1 cmꢁ1
)
yield
6a
6b
6c
8a
8b
8c
527
530
523
513
526
528
528
410
430
40,000
45,000
35,000
30,000
40,000
35,000
20,000
40,000
20,000
539
554
544
534
544
542
580
12
24
21
0.15
0.37
0.27
9
10aa
10ba
a
Taken in MeOH except in CH2Cl2.
1.0
UV
Emission
200
300
400
500
600
700
800
0.8
Wavelength (nm)
Figure 4. Absorption spectrum of compounds 10a and 10b in dichloro-
methane.
0.6
0.4
0.2
0.0
base treatment of 1,3,5,7,8-pentamethyl-2,6-carboethoxy
derivative 11. As found for the compounds 10a and 10b,
compound 12 does not show any long wavelength absorption
and fluorescence.19 The related 3-phenyl imonomethyl
indole hydrochloride has been described with an absorption
maximum at 390 nm close to the maximum found for the
compounds 10a and 10b.20
Compounds 6a, 6b, 6c, 8a, 8b, 8c, and 9 show fluorescence
when excited at the wavelength of the absorption maximum.
The emission spectrum of compound 9 shows an inflexion
point at 550 nm.
300 350 400 450 500 550 600 650 700 750 800
Wavelength (nm)
Figure 3. Absorption and fluorescence spectrum (excitation at 528 nm) of
compound 9 in methanol.
5. Conclusion
achieved.1 However, the introduction of the double bond as
in 9 (Fig. 3) induces no shift, the absorption maximum is
located at 528 nm in 9 compared to 523–530 nm for 6a–6c.
This can be attributed to the fact that the thiovinylic group
of 9 is not coplanar with indacene plane due to the presence
of the hydrogens at carbon C1 and C7. The torsion angle of
the phenyl group at C8 in related indacene system (with
hydrogens at C1 and C7) with the dipyrrolomethane is in the
range of 51.5–87.8ꢀ.17 So, for 8-phenyl substituted indacenes
and product 9, the conjugation between the aryl group and
the thiovinylic group with the indacene system is low.18
The reaction of the electrophilic reagents occurs at the sulfur
atom under mild conditions. This should allow the introduc-
tion of more functionalized groups. The vinylic thiother 9
does not show the spectral properties for a reporting group,
so the preparation of the corresponding activated vinylic
group was not undertaken. Also the thioethers directly
attached to the ring as in 6 show some interesting properties,
but we did not succeed in preparing any activated derivative,
which would give rise to the thioethers 6 by substitution
reaction.
In contrast the anilino substituted compounds 10a and 10b
(Fig. 4) do not show any long wavelength absorption and
any fluorescence. The analogous compound 3 shows absorp-
tion at 424 nm (3 40,000).10 This difference is unexpected. In
the crystalline state of compound 10a, the C8–N bond length
6. Experimental
6.1. General procedure
˚
(1.23–1.34 A) is definitely shorter than a nitrogen bond to
˚
carbon of an aromatic ring (1.42 A) and close to nitrogen–
All the reactions were carried out under an atmosphere of
nitrogen. Melting points (mp) were taken on capillary tube
apparatus and are uncorrected. UVand the fluorescent spec-
tra were recorded in MeOH solution unless otherwise stated.
The quantum yield was determined as in Ref. 21. FTIR
carbon double bond, so we propose that the structure of
aniline substituted compounds is better described by struc-
ture 10 instead of structure 7. In the NMR spectrum of these
compounds one notices the upfield shift of about 1 ppm of
the signals of indacene ring protons in agreement with the
aromatic character of the structure 10. The properties
expected for structure 10 are close to the ones described
by Treibs and Kreuzer about the compound 12 obtained by
1
spectra were recorded in CH2Cl2 solution. H NMR and
13C NMR spectra were recorded in CDCl3 solution, chemi-
cal shifts were reported using TMS (0 ppm) and CDCl3
(77.0 ppm) as internal standards. Purification by column
chromatography was carried out with neutral silica gel 60

5088
T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
(70–230). MS spectra were determined on VG 70-250S
spectrometer. HRMS spectra were collected on Autospec
orthogonal acceleration-time of flight mass spectrometer
with a resolution of 6000 (5%).
6.1.4. 5-Methyl-2-[(5-methyl-1H-pyrrol-2-yl)-methylsul-
fanyl-methylene]-2H-pyrrolium iodide (5b). To a solution
of compound bis-(5-methyl-1H-pyrrol-2-yl)-methanethione
4b (0.30 g) in anhydrous dichloromethane (5 ml) was added
methyl iodide (0.41 ml) at rt. The reaction mixture was
stirred for 24 h for completion (TLC monitoring). Solvent
was removed under reduced pressure to obtain brown col-
ored gummy solid. The obtained compound 5b is directly
Caution: handling thiophosgene requires a fume hood and
container has to be kept tightly closed for storage. Thiophos-
gene is highly toxic.
1
used for the next reaction. H NMR (CDCl3): d 2.60 (s,
6.1.1. Bis-(5-methyl-1H-pyrrol-2-yl)-methanethione (4b).
A solution of 2-methylpyrrole (0.81 g)22 in dry ether (15 ml)
was added dropwise to a vigorously stirred solution of thio-
phosgene (0.55 g) in dry toluene (13 ml) at 0 ꢀC. After
10 min, aqueous methanol (10%) (12 ml) was added and
the mixture stirred for further 30 min at room temperature
(rt). The solvents were removed in vacuo and the residue,
dissolved in toluene/chloroform (9:1), was chromato-
graphed on neutral alumina. The pure compound fraction
was collected, which, after removal of the solvents in vacuo,
yielded the thioketone 4b as a crystalline orange red solid
(0.64 g; 65%), mp 106–108 ꢀC. lmax: 419 nm (3 50,000),
6H), 2.76 (s, 3H), 6.35 (2H, d, J¼8.0 Hz), 7.02 (2H, d,
J¼8.0 Hz), 11.6 (br s). 13C NMR (CDCl3): d 14.8 (CH3),
21.9 (CH3), 118.1 (CH), 129.4 (CH), 129.8 (C), 152.6 (C),
156.3 (C). Mass spectrum (EI): m/z 218 (M+); HRMS calcd
for C12H15N2S 219.0951, found 219.0956.
6.1.5.
5-Ethyl-2-[(5-ethyl-1H-pyrrol-2-yl)-methylsul-
fanyl-methylene]-2H-pyrrolium iodide (5c). To a solution
of compound 4c (0.30 g) in anhydrous dichloromethane
(5 ml) was added methyl iodide (0.36 ml) at rt. The reaction
mixture was stirred for 24 h for completion (TLC monitor-
ing). Solvent was removed under reduced pressure to obtain
brown colored gummy solid. The obtained compound 5c is
directly used for the next reaction. 1H NMR (CDCl3):
d 1.21(6H, t, J¼7.0 Hz), 2.72 (4H, q, J¼7.0 Hz), 2.93
(s, 3H), 6.34–6.35 (m), 6.93–6.94 (m, 2H). 13C NMR
(CDCl3): d 12.8 (CH3), 21.6 (CH3), 116.0 (CH), 129.2
(CH), 129.7 (C), 156.7 (C), 158.1 (C). Mass spectrum
(EI): m/z 247 (M+); HRMS calcd for C14H19N2S 247.1268,
found 247.1262.
1
293 (3 3200). IR (CH2Cl2): 3405, 3360, 1280. H NMR
(CDCl3): d 2.78 (s, 6H), 6.10 (2H, d, J¼6.0 Hz), 6.90 (2H,
d, J¼6.0 Hz), 9.58 (1H, br s). 13C NMR (CDCl3): d 14.0
(CH3), 111.7 (CH), 115.8 (CH), 137.4 (C), 139.5 (C),
187.2 (C). Mass spectrum (EI): m/z 204 (M+); Anal. Calcd
for C11H12N2S: C, 64.67; H, 5.92; N, 13.71. Found: C,
64.62; H, 5.88; N, 13.67.
6.1.2. Bis-(5-ethyl-1H-pyrrol-2-yl)-methanethione (4c). A
solution of 2-ethylpyrrole (0.81 g)22 in dry ether (15 ml) was
added dropwise to a vigorously stirred solution of thiophos-
gene (0.486 g) in dry toluene (10 ml) at 0 ꢀC. After 10 min,
aqueous methanol (10%) (12 ml) was added and the mixture
stirred for further 30 min at rt. The solvents were removed
in vacuo and the residue, dissolved in toluene/chloroform
(9:1), was chromatographed on neutral alumina. The pure
compound fraction was collected, which, after removal of
the solvents in vacuo, yielded the thioketone 4c as a crystal-
6.1.6. 8-(Thiomethyl)4,4-difluoro-4-bora-3a,4a-diaza-s-
indacene (6a). To a solution of compound 5a (0.30 g) in
anhydrous dichloromethane (7 ml) under nitrogen atmo-
sphere at rt was added triethylamine (0.22 ml). After stirring
for 30 min BF3$OEt2 (0.18 ml) was added. The mixture was
stirred for 30 min at rt. After the evaporation of solvents
under vacuum, the crude product was chromatographed on
silica gel (70–230 mesh, using 15% EtOAc in hexane),
yielded compound 6a as a dark red solid (0.21 g; 60%),
mp 88–90 ꢀC. lmax: 527 nm (3 40,000). IR (CH2Cl2):
line orange red solid (0.62 g; 63%), mp 110–111 ꢀC. lmax
:
416 nm (3 50,000), 295 (3 3100). IR (CH2Cl2): 3400,
1
1489, 1264 cmꢁ1. H NMR (CDCl3): d 2.88 (s, 3H), 6.50–
1
3362, 1280. H NMR (CDCl3): d 1.29 (6H, t, J¼7.2 Hz),
6.51 (m, 2H), 7.39–7.40 (m, 2H), 7.77–7.78 (m, 2H). 13C
NMR (CDCl3): d 20.0 (CH3), 117.6 (CH), 127.3 (CH),
133.4 (C), 140.8 (C), 154.0 (C). 19F (CCl3F in CDCl3):
d ꢁ145.6, ꢁ145.7, ꢁ145.8, ꢁ145.9. Mass spectrum (EI):
m/z 238 (M+); Anal. Calcd for C10H9BF2N2S: C, 50.45; H,
3.81; N, 11.77. Found: C, 50.38; H, 3.78; N, 11.67.
2.66 (4H, q, J¼7.2 Hz), 6.12–6.14 (m, 2H), 6.91–6.93 (m,
2H), 9.59 (1H, br s). 13C NMR (CDCl3): d 12.8 (CH3),
21.1 (CH2), 110.1 (CH), 115.7 (CH), 137.0 (C), 145.4 (C),
188.4 (C). Mass spectrum (EI): m/z 232 (M+); Anal. Calcd
for C13H16N2S: C, 67.20; H, 6.94; N, 12.06. Found: C,
67.15; H, 6.90; N, 12.02.
6.1.7. 8-(Thiomethyl) 4,4-difluoro-3,5-dimethyl-4-bora-
3a,4a-diaza-s-indacene (6b). To a solution of compound
5b (0.30 g) in anhydrous dichloromethane (7 ml) under
nitrogen atmosphere at rt was added triethylamine (0.19 ml).
After stirring for 30 min BF3$OEt2 (0.16 ml) was added.
The mixture was stirred for 30 min at rt. After the evapo-
ration of solvents under vacuum, the crude product was
chromatographed on silica gel (70–230 mesh, using 15%
EtOAc in hexane), yielded compound 6b as a dark red solid
(0.23 g; 63%), mp 96–97 ꢀC. lmax: 515 (inflexion), 530 nm
6.1.3. 2-[Methyl sulfanyl-(1H-pyrrol-2-yl)-methylene]-
2H-pyrrolium iodide (5a). To a solution of compound
bis-(1H-pyrrol-2-yl)-methanethione 4a (0.30 g) (1b) in
anhydrous dichloromethane (5 ml) was added methyl iodide
(0.48 ml) at rt. The reaction mixture was stirred for 24 h for
completion (TLC monitoring). Solvent was removed under
reduced pressure to obtain brown colored gummy solid.
The compound 5a was used without further purification
1
for the next reaction. H NMR (CDCl3): d 2.89 (s, 3H),
6.63–6.64 (m, 2H), 7.23–7.24 (m, 2H), 7.87–7.88 (m, 2H),
12.0 (br s). 13C NMR (CDCl3): d 21.5 (CH3), 116.7 (CH),
128.6 (CH), 129.3 (CH), 138.4 (C), 162.2 (C). Mass spec-
trum (EI): m/z 190 (M+); HRMS calcd for C10H11N2S
191.0637, found 191.0640.
(3 45,000). IR (CH2Cl2): 1558, 1264 cmꢁ1 1H NMR
.
(CDCl3):d2.57(s, 6H), 2.68(s, 3H), 6.24(2H, d, J¼5.2 Hz),
7.26 (2H, d, J¼5.2 Hz). 13C NMR (CDCl3): d 14.8 (CH3),
21.5 (CH3), 119.1 (CH), 128.2 (CH), 135.3 (C), 144.2 (C),
156.8(C). Massspectrum(EI):m/z266(M+);Anal. Calcdfor

T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
5089
C12H13BF2N2S: C, 54.16; H, 4.92; N, 10.53. Found:C, 54.10;
H, 4.87; N, 10.50.
6.1.11. 8-(Thioisopropyl) 4,4-difluoro-3,5-diethyl-4-bora-
3a,4a-diaza-s-indacene (8c). To a dried 50 ml round-
bottom flask was added compound 4c (0.20 g) in anhydrous
dichloromethane (10 ml) under nitrogen atmosphere at 0 ꢀC
and then isopropyl triflate (0.33 ml) was added and the reac-
tion mixture was stirred for 12–16 h at rt. To the reaction
mixture triethylamine (0.102 ml) was added, after stirring
for 30 min BF3$OEt2 (0.086 ml) was added and the reaction
mixture was stirred for another 30 min at rt. Solvents were
evaporated in vacuo, the above crude product was chromato-
graphed on silica gel (70–230 mesh, using 15% EtOAc in
hexane), yielded compound 8c (0.085 g: 36%) as a dark
red gummy liquid. lmax 528 nm (3 35,000). IR (CH2Cl2):
6.1.8. 8-(Thiomethyl) 4,4-difluoro-3,5-diethyl-4-bora-
3a,4a-diaza-s-indacene (6c). To a solution of compound
5c (0.30 g) in anhydrous dichloromethane (7 ml) under
nitrogen atmosphere at rt was added triethylamine (0.17 ml).
After stirring for 30 min BF3$OEt2 (0.14 ml) was added.
The mixturewas stirred for 30 min at rt. After the evaporation
of solvents under vacuum, the crude product was chromato-
graphed on silica gel (70–230 mesh, using 15% EtOAc in
hexane), yielded compound 6c as a dark red solid (0.21 g;
58%), mp 96–98 ꢀC. lmax (CH2Cl2): 523 nm (3 35,000),
1
1
378 (3 17,000). IR (CH2Cl2): 1546, 1262 cmꢁ1. H NMR
2937, 1548, 1266 cmꢁ1. H NMR (CDCl3): d 1.28 (6H,
(CDCl3): d 1.31 (6H, t, J¼6.2 Hz), 2.66 (s, 3H), 3.02 (4H,
q, J¼6.2 Hz), 6.32 (2H, d, J¼3.2 Hz), 7.30 (2H, d,
J¼3.2 Hz). 13C NMR (CDCl3): d 12.6 (CH3), 21.5 (CH3),
21.9 (CH2), 117.0 (CH), 128.2 (CH), 135.0 (C), 144.5 (C),
162.7 (C). Mass spectrum (EI): m/z 294.16 (M+); Anal. Calcd
for C14H17BF2N2S: C, 57.16; H, 5.82; N, 9.52. Found: C,
57.10; H, 5.78; N, 9.47.
d, J¼6.8 Hz), 1.30 (6H, t, J¼6.0 Hz), 3.01 (4H, q, J¼
6.0 Hz), 3.53–3.55 (sept, 1H), 6.32 (2H, d, J¼4.4 Hz),
7.33 (2H, d, J¼4.4 Hz). 13C NMR (CDCl3): d 12.6 (CH3),
22.0 (CH2), 23.7 (CH3), 44.2 (CH), 117.2 (CH), 129.6
(CH), 137.6 (C), 140.1 (C), 164.0 (C). Mass spectrum
(EI): m/z 322 (M+); HRMS calcd for C16H21BF2N2S
322.1487, found 322.1489.
6.1.9. 8-(Thioisopropyl) 4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene (8a). To a dried 50 ml round-bottom flask was
added compound 4a (0.250 g) in anhydrous dichloro-
methane (10 ml) under nitrogen atmosphere at 0 ꢀC and then
isopropyl triflate (0.545 ml)23 was added and the reaction
mixture was stirred for 12–16 h at rt. To the reaction mixture
triethylamine (0.161 ml, 1.14 mmol) was added. After stir-
ring for 30 min BF3$OEt2 (0.13 ml) was added and the reac-
tion mixture was stirred for another 30 min at rt. Solvents
were evaporated in vacuo, the above crude product was chro-
matographed on silica gel (70–230 mesh, using 15% EtOAc
in hexane), yielded compound 8a (0.10 g: 34%) as a dark red
gum. lmax: 513 nm (3 30,000), 388 (3 3000). IR (CH2Cl2):
6.1.12.
8-(2-Thiophenylethene)
4,4-difluoro-3,5-di-
methyl-4-bora-3a,4a-diaza-s-indacene (9). To a solution
of 2-methylpyrrole (162 mg) and 3-(phenylthio) propenal
(164 mg)24 in N2-flushed dichloromethane (20 ml) was
added ytterbium (III) trifluoromethane sulfonimide (50 mg)
at once at rt. After 20 min TLC (silica–hexane/ethylacetate
9:1) showed that the propenal had been consumed. Then
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (0.25 g)
was added at once and the reaction mixture was stirred at rt
under nitrogen atmosphere. After stirring for 10 min, tri-
ethylamine (1 ml) and BF3$OEt2 (1.6 ml) were added and
the mixture was stirred at rt for further 30 min. After evapo-
ration of the solvent, the crude product was chromatographed
on silica gel (70–230 mesh, 10% EtOAc in hexane) to give
compound 9 (7 mg) as red gummy solid. lmax: 528 nm
1
2932, 1552, 1264 cmꢁ1. H NMR (CDCl3): d 1.37 (6H, d,
J¼6.8 Hz), 3.80–3.82 (sept, 1H), 6.49–6.50 (m, 2H), 7.44–
7.45 (m, 2H), 7.81 (2H, d, J¼2.0 Hz). 13C NMR (CDCl3):
d 23.7 (CH3), 44.1 (CH), 118.2 (CH), 129.5 (CH), 137.0 (C),
143.3 (CH), 148.4 (C). Mass spectrum (EI): m/z 266 (M+);
HRMS calcd for C12H13BF2N2S 266.0861, found 266.0864.
1
(3 20,000). H NMR (CDCl3): d 2.58 (s, 6H), 6.22 (2H, d,
J¼4 Hz), 6.64 (1H, d, J¼15 Hz), 6.98 (2H, d, J¼4 Hz),
7.35–7.49 (m, 6H). 13C NMR (CDCl3): d 14.9 (CH3), 118.7
(CH), 120.0 (CH), 127.0 (CH), 128.9 (CH), 129.8 (CH),
131.0 (C), 132.0 (CH), 132.9 (C), 137.6 (C), 142.1 (CH),
156.3 (C); 19F (CCl3F in CDCl3): d ꢁ147.9, ꢁ148.0,
ꢁ148.1, ꢁ148.2. FABMS (m-NBA) m/z 354.0 (M)+;
HRMS calcd for C19H17BF2N2S 354.1174, found 354.1179.
6.1.10. 8-(Thioisopropyl) 4,4-difluoro-3,5-dimethyl-
4-bora-3a,4a-diaza-s-indacene (8b). To a dried 50 ml
round-bottom flask was added compound 4b (0.20 g) in
anhydrous dichloromethane (10 ml) under nitrogen
atmosphere at 0 ꢀC and then isopropyl triflate (0.38 ml) was
added and the reaction mixture was stirred for 12–16 h at rt.
To the reaction mixture triethylamine (0.114 ml) was
added. After stirring for 30 min BF3$OEt2 (0.95 ml) was
added and the reaction mixture was stirred for another
30 min at rt. Solvents were evaporated in vacuo, the above
crude product was chromatographed on silica gel (70–
230 mesh, using 15% EtOAc in hexane), yielded compound
8b (0.09 g: 38%) as a dark red gummy liquid. lmax: 526 nm
(3 40,000). IR (CH2Cl2): 2937, 1550, 1270 cmꢁ1. 1H NMR
(CDCl3): d 1.29 (6H, d, J¼6.8 Hz), 2.58 (s, 6H), 3.53–
3.55 (sept, 1H), 6.24 (2H, d, J¼4.0 Hz), 7.30 (2H, d,
J¼4.0 Hz). 13C NMR (CDCl3): d 14.9 (CH3), 23.7 (CH3),
44.1 (CH), 119.4 (CH), 129.5 (CH), 137.9 (C), 151.0 (C),
158.0 (C). Mass spectrum (EI): m/z 294 (M+); Anal. Calcd
for C14H17BF2N2S: C, 57.16; H, 5.82; N, 9.52. Found: C,
57.10; H, 5.78; N, 9.47.
6.1.13. Compound 10a. To a dried 50 ml round-bottom
flask was added compound 6a (0.20 g) in anhydrous
dichloromethane (5 ml) under nitrogen atmosphere at rt
and then aniline (0.078 ml) was added. The reaction mixture
was stirred for 12 h at rt. Solvent was evaporated in vacuo,
the crude product was chromatographed on silica gel (70–
230 mesh, using 20% EtOAc in hexane), yielded compound
10a as a light red crystals from hexane/chloroform (0.130 g;
55%). Two allotropic forms were obtained: the first from
hexane/chloroform and the second from chloroform:
mp 191–193 ꢀC; 199–201 ꢀC. lmax (CH2Cl2): 410 nm
(3 40,000), 332 (3 21,000). IR (CH2Cl2): 3300, 1699,
1272 cmꢁ1
.
1H NMR (CDCl3): d 6.25 (2H, t, J¼2.0,
1.6 Hz), 6.31 (2H, d, J¼1.6 Hz), 7.27 (2H, d, J¼2.0 Hz),
7.46–7.47 (m, 5H), 8.33 (br s). 13C NMR (CDCl3): d 114.3
(CH), 120.5 (C), 123.9 (C), 126.4 (CH), 129.0 (CH), 130.0
(CH), 134.2 (CH), 137.4 (C), 147.7 (C). 19F (CCl3F in

5090
T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
CDCl3): d ꢁ144.8, ꢁ144.9, ꢁ145.0, ꢁ145.1. Mass spectrum
(EI): m/z 283 (M+); Anal. Calcd for C15H12BF2N3: C, 63.64;
H, 4.27; N, 14.84. Found: C, 63.60; H, 4.20; N, 14.80.
7.1.4. Compound 10a (CCDC 289288–289289).
C15H12BF2N3, M¼283.09
- Triclinic space group P-1, a¼9.7381(2), b¼11.7125(2),
ꢀ
ꢀ
˚
6.1.14. Compound 10b. To a dried 50 ml round-bottom
flask was added compound 6b (0.20 g) in anhydrous
dichloromethane (5 ml) under nitrogen atmosphere at rt and
then aniline (0.07 ml) was added. The reaction mixture was
stirred for further 12 h at rt. Solvent was evaporated in vacuo,
the crude product was chromatographed on silica gel (70–
230 mesh, using 20% EtOAc in hexane), yielded compound
10b as a light yellow solid (0.04 g: 20%), mp 198–200 ꢀC.
lmax(CH2Cl2): 430 nm (3 20,000), 343 (3 13,000). IR
c¼12.1698(3) A, a¼97.0980(10) , b¼105.3670(10) ,
ꢀ
˚
3
g¼96.0900(10) , V¼1314.12 A , T¼100(1) K, Z¼4,
m (Mo Ka)¼0.106 mmꢁ1, 4634 reflections measured
(R(int)¼0.0176), which were used in all calculations.
The final wR(F2) was 1.051.
- Triclinic space group P-1, a¼7.3696(3), b¼9.6925(3ꢀ),
ꢀ
˚
c¼9.9641(4) A, a¼109.2870(10) , b¼101.8620(10) ,
3
ꢀ
˚
g¼100.4640 , V¼633.00(4) A , T¼100(1) K, Z¼2,
m (Mo Ka)¼0.110 mmꢁ1, 2222 reflections measured
(R(int)¼0.0194), which were used in all calculations.
The final wR(F2) was 1.040.
(CH2Cl2): 3310, 1692, 1270 cmꢁ1 1H NMR (CDCl3):
.
d 2.54 (s, 6H), 6.03 (2H, d, J¼4.0 Hz), 6.40 (2H, d, J¼
4.0 Hz), 7.24 (s, 1H), 7.36 (2H, d, J¼6.0 Hz), 7.45 (2H, d, J¼
6.0 Hz). 13C NMR (CDCl3): d 14.2 (CH3), 115.4 (CH), 120.3
(CH), 123.8 (C), 126.8 (CH), 128.7 (CH), 130.2 (CH), 138.5
(C), 149.0 (C). Mass spectrum (EI): m/z 311 (M+); HRMS
calcd for C17H16BF2N3 311.1400, found 311.1388.
Acknowledgments
We are grateful to Professor Sunney I. Chan for his constant
encouragement. Mr. Yuh-Sheng Wen solved the X-ray struc-
tures. This work was supported by Academia Sinica.
7. Crystal structure determination
References and notes
Diffraction measurements were made on an Enraf-Nonius
CAD-4 diffractometer by use of graphite-monochromatized
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Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
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7.1.1. 8-(Thiomethyl) 4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene 6a (CCDC 289286). C10H9BF2N2S, M¼238.06
triclinic space group P-1, a¼8.0683(14),ꢀb¼9.0846(14), c¼
ꢀ
ꢀ
˚
14.517(5) A, a¼98.89(2) , b¼92.70(2) , g¼95.868(13) ,
3
˚
V¼1043.6(4) A , T¼298(2) K, Z¼4, m (Mo Ka)¼0.307
mmꢁ1, 3676 reflections measured (R(int)¼0.0214), which
were used in all calculations. The final wR(F2) was 1.010.
7.1.2. 8-(Thiomethyl) 4,4-difluoro-3,5-dimethyl-4-
bora-3a,4a-diaza-s-indacene 6b (CCDC 289285).
C12H13BF2N2S, M¼266.11 orthorhombic space group
10. Holler, M.; unpublished results.
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A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987,
S1–S19.
˚
Pnma, a¼15.994(3), b¼7.053(4), c¼10.856(3) A, V¼
3
ꢁ1
˚
1224.6(9) A , T¼298(2) K, Z¼4, m (Mo Ka)¼0.270 mm
,
1168 reflections measured (R(int)¼0.0000), which were
used in all calculations. The final wR(F2) was 1.041.
7.1.3. 8-(Thiomethyl) 4,4-difluoro-3,5-diethyl-4-bora-
3a, 4a-diaza-s-indacene 6c (CCDC 289287).
C14H17BF2N2S, M¼294.17 monoclinic space group P2(1ꢀ)/
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˚
c, a¼7.4558(3), b¼18.5780(5), c¼10.6193(3) A, a¼90 ,
3
ꢀ
ꢀ
˚
b¼108.188(2) , g¼90 , V¼1397.43(8) A , T¼293(2) K,
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T. V. Goud et al. / Tetrahedron 62 (2006) 5084–5091
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