An efficient and convenient bromination of BODIPY derivatives with copper(II) bromide

Article abstract of DOI:10.1055/s-0031-1289637

Efficient and convenient methods for the mono- and dibromination of 1,3,5,7-tetramethyl-substituted BODIPYs were developed by using copper(II) bromide as the bromination reagent under mild reactions, in good to excellent yields. The selectivity of mono- o

Full text of DOI:10.1055/s-0031-1289637

104
PAPER
An Efficient and Convenient Bromination of BODIPY Derivatives with
Copper(II) Bromide
B
rominati
i
on of
B
a
O
DIP
Y
D
e
-
rivativesHai Ye,*a Guangpu Wang,a Chengmei Huang,b Zhengjuan Hu,a Whenchao Zhang,a Yan Zhang*b
a
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P. R. of China
Fax +86(25)84315857; E-mail: yejiahai@mail.njust.edu.cn
b
School of Chemistry and Chemical Engineering, Key Laboratory of Analytical Chemistry for Life Science,
Ministry of Education of China, Nanjing University, Nanjing 210093, P. R. of China
Received 19 September 2011; revised 8 November 2011
clic compounds, including thiazoles, pyrroles, and
indoles.13 Herein, we wish to disclose an efficient and
convenient mono- and dibromination of 1,3,5,7-tetra-
methyl-substituted BODIPYs at the 2- or 2,6-positions,
Abstract: Efficient and convenient methods for the mono- and di-
bromination of 1,3,5,7-tetramethyl-substituted BODIPYs were de-
veloped by using copper(II) bromide as the bromination reagent
under mild reactions, in good to excellent yields. The selectivity of
mono- or dibromination depends strongly on the additives of the re- which was carried out with copper(II) bromide as the in-
actions.
expensive bromide source (Scheme 1).
Key words: copper, bromination, selectivity, fluorescent dyes, 4,4-
difluoro-4-bora-3a,4a-diaza-s-indacenes
R
R
CuBr2
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)
dyes have received much interest in research areas, such
as labeling reagents,1 fluorescent switches,2 chemosen-
sors,3 near-IR absorbing/emitting dyes, nonlinear optical
materials, mesogenic materials,4 supramolecular poly-
mers,5 light-harvesting systems,6 photodynamic therapy,7
molecular logic systems,3e,8 and dye-sensitized solar
cells,9 owing to their many intriguing optical and chemi-
cal properties such as photostability, high absorption co-
efficients, long wavelength emission, relative
insensitivity to environment, and high fluorescence quan-
tum yields (typically 0.6–1.0).4,10 In addition, functional-
ization of BODIPY dyes allows manipulation of the
spectroscopic and electronic properties by introduction of
suitable substituents to the BODIPY peripherals. Among
synthetic precursors for functionalized BODIPYs, bromi-
nated BODIPYs are one of the most useful building
blocks on the basis of a transition-metal-catalyzed cross-
coupling strategy for the construction of extended p-elec-
tron conjugation affording red-shifted BODIPY
derivatives11 and can act as photodynamic therapy re-
agents.7a To the best of our knowledge, bromine, N-bro-
mosuccinimide (NBS), and the NBS–AIBN [2,2¢-
azobis(isobutyronitrile)] system have been utilized for the
bromination of BODIPYs;7a,11,12 however, these methods
suffer from some drawbacks and limitations: the use of
expensive, toxic, or corrosive bromination reagents, high
reaction temperature, and difficult handling of the reac-
tion procedure. It is well known that copper(II) bromide
can serve as an effective alternative of NBS and bromine
for a-bromination of carbonyl compounds and bromina-
tion of alkenes, alkynes, aromatic systems, and heterocy-
X
Br
N
N
N
N
B
B
F
F
F
F
1
2
3
X = Br
X = H
Scheme 1
First, we started our studies with the reaction of the
1,3,5,7-tetramethyl-BODIPY 1a in the presence of copper
salts to establish the reaction conditions for dibromination
at the 2,6-positions (Table 1). Initially, the reaction of 1a
with copper(I) bromide (2.5 equiv) was conducted in tol-
uene at 100 °C under air or oxygen atmosphere for more
than 20 hours; unfortunately, the bromination barely oc-
curred (Table 1, entries 1 and 2). Subsequently, the reac-
tion of 1a with copper(I) bromide (0.1 equiv) or copper(II)
bromide (0.1 equiv) as the catalyst in the presence of po-
tassium bromide as the bromide source was carried out
(Table 1, entries 3 and 4). Similarly, no obvious amount
of product 2a was observed.
Thinking about the fact that copper(II) bromide is an effi-
cient bromination reagent for many heterocyclic com-
pounds,13 we attempted to perform the bromination of 1a
with 2.5 equivalents of copper(II) bromide in different
solvents at room temperature (Table 1, entries 5–9 and
12). To our delight, an excellent yield (94%) of dibromi-
nation product 2a was obtained when the reaction mixture
of 1a with copper(II) bromide (2.5 equiv) was stirred in
acetonitrile at room temperature in the presence of oxygen
(1 atm, balloon). The amount of copper(II) bromide and
the reaction atmosphere can also slightly affect the yield
of the dibromination product 2a (Table 1, entries 10 and
11). Based on the above research results, the optimized re-
action conditions were obtained: reaction of 1a with 2.5
equivalents of copper(II) bromide in acetonitrile carried
out at room temperature in the presence of oxygen (bal-
SYNTHESIS 2012, 44, 104–110
x
x
.x
x
.2
0
1
1
Advanced online publication: 05.12.2011
DOI: 10.1055/s-0031-1289637; Art ID: H90011SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Bromination of BODIPY Derivatives
105
Table 1 Optimization of the Reaction Conditions for Dibromination of 1aa
Ph
Ph
Cu, [O]
solvent
Br
Br
N
N
N
N
B
B
F
F
F
F
1a
2a
Entry
Metal salt
Solvent
toluene
toluene
toluene
toluene
DMF
[O]
Temp (°C)
100
100
100
100
r.t.
Yielda,b (%)
1
2
CuBr (2.5 equiv)
CuBr (2.5 equiv)
air
O2
air
O2
O2
O2
O2
O2
O2
air
O2
O2
n.r.
trace
n.r.
trace
n.r.
n.r.
65
3
CuBr (0.1 equiv), KBr (2.0 equiv)
CuBr2 (0.1 equiv), KBr (2.0 equiv)
CuBr2 (2.5 equiv)
4
5
6
CuBr2 (2.5 equiv)
DMSO
THF
r.t.
7
CuBr2 (2.5 equiv)
r.t.
8
CuBr2 (2.5 equiv)
toluene
xylene
MeCN
MeCN
MeCN
r.t.
58
9
CuBr2 (2.5 equiv)
r.t.
60
10
11
12
CuBr2 (2.5 equiv)
r.t.
91c
86
CuBr2 (2.2 equiv)
r.t.
CuBr2 (2.5 equiv)
r.t.
94
a Reaction time = 12 h unless otherwise specified.
b Isolated yield; n.r. = no reaction.
c Reaction time = 24 h.
loon) for 12 hours gave 94% isolated yield of 2a. The bro- the reaction process and promotes the production of the
mination efficiency of BODIPYs depends on parameters dibromination product.14 In an attempt to overcome this
such as the reactants for the source of bromide, and the problem, we considered the possibility of addition of base.
solvent.
We rationalized that the employment of base, including
inorganic and organic bases, could potentially help in neu-
tralizing hydrogen bromide and thus promote the yield of
the target products as well as inhibit the production of the
dibromination products. The effects of various bases
(such as K3PO4, K2CO3, KOAc, Na2CO3, Et3N, and pyri-
dine) were studied for this conversion. Of these bases, po-
tassium carbonate was found to be effective in terms of
the best conversion. The scope of the monobromination
was explored using reaction conditions similar to the di-
brominations as above, in the presence of 3.0 equivalents
of potassium carbonate and 1.5 equivalents of copper(II)
bromide under an oxygen atmosphere. Generally, the re-
action proceeded in good yield for both electron-rich and
electron-deficient aromatic groups at the meso-position of
the BODIPYs. The scope and generality of this process is
illustrated with respect to various meso-aryl-1,3,5,7-tet-
ramethyl-BODIPYs; the results are presented in Table 3.
In all cases, the di- and monobromination products 2 and
With the optimized reaction results in hand, the scope of
dibromination of BODIPYs was examined by using cop-
per(II) bromide as the bromination reagent with a series of
meso-aryl-1,3,5,7-tetramethyl-BODIPYs under the opti-
mized reaction conditions; the full results are summarized
in Table 2. All reactions proceeded smoothly to produce
the products 2 in good to excellent yields. The results
were not dependent on the nature of the substituent on the
meso-aryl of the BODIPYs, but were dependent on the po-
sition of the aromatic substituent when the substituent was
an electron-withdrawing group (see Table 2, entries 3–6,
8, 9, and 11).
Encouraged by the above results, we then investigated the
monobromination of 1,3,5,7-tetramethyl-BODIPYs. Ini-
tially, the reaction of BODIPY 1a with only one equiva-
lent of copper(II) bromide was carried out under oxygen
atmosphere in acetonitrile at room temperature. Surpris-
ingly, the dibromination product 2a was also observed to-
gether with the target monobromination product 3a in
56% total yield (2a/3a = 39:61). This result may be attrib-
uted to hydrogen bromide (HBr) which is evolved from
1
3 were characterized by H NMR, 13C NMR, and mass
spectroscopy.
In summary, copper(II) bromide has proved to be a useful
and highly efficient reagent for the bromination of
© Thieme Stuttgart · New York
Synthesis 2012, 44, 104–110

106
J.-H. Ye et al.
PAPER
Table 2 Dibromination of BODIPYs 1 with Copper(II) Bromide
Table 3 Monobromination of BODIPYs 1 with Copper(II) Bromide
Ar
Ar
Ar
Ar
CuBr2, K2CO3
MeCN, r.t.
CuBr2, O2
MeCN, r.t.
Br
Br
Br
N
N
N
N
N
N
N
N
B
B
B
B
F
F
F
F
F
F
F
F
1
2
1
3
Yielda (%)
Entry Ar
Product 2
Yielda (%)
Entry
Ar
Product 3
1
2
Ph
2a
2b
2c
2d
2e
2f
94
92
86
96
83
84
86
95
94
91
82
89
1
2
Ph
3a
3b
3c
3d
3e
3f
81
75
76
80
86
84
80
78
81
79
74
87
4-Tol
4-Tol
3
4-MeOC6H4
3
4-MeOC6H4
3,4-(MeO)2C6H3
4-ClC6H4
4
3,4-(MeO)2C6H3
4-ClC6H4
4
5
5
6
2-ClC6H4
6
2-ClC6H4
7
4-(HC≡CCH2O)C6H4
4-O2NC6H4
4-F3CC6H4
4-NCC6H4
2g
2h
2i
7
4-(HC≡CCH2O)C6H4
4-O2NC6H4
4-F3CC6H4
4-NCC6H4
3g
3h
3i
8
8
9
9
10
11
12
2j
10
11
12
3j
3-F3CC6H4
1-Naph
2k
2l
3-F3CC6H4
1-Naph
3k
3l
a Isolated yield.
a Isolated yield.
BODIPYs at their 2-/2,6-positions, in combination with
different additives, under mild conditions. In addition to
its simplicity and efficiency, this method selectively pro-
duces mono- or dibrominated BODIPYs in good to excel-
lent yields. This method provides an easy access to a wide
range of potentially valuable meso-aryl-1,3,5,7-tetrameth-
yl-BODIPYs. The use of readily available and inexpen-
sive copper(II) bromide makes this method simple,
convenient, cost-effective, and practical.
sure. The crude product was further purified using column chroma-
tography (EtOAc–petroleum ether) to afford the dibromide 2.
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-phenyl-4-bora-
3a,4a-diaza-s-indacene (2a)12
Yield: 90.6 mg (94%); red solid; mp 229–231 °C.
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 6 H, CH3), 2.63 (s, 6 H,
CH3), 7.26–7.28 (m, 2 H, ArH), 7.54–7.55 (m, 3 H, ArH).
13C NMR (125 MHz, CDCl3): d = 152.9, 141.0, 139.6, 133.3, 129.3,
128.5, 128.4, 126.7, 110.7, 12.6.
EI-MS: m/z = 482 [M]+.
All chemicals were obtained from commercial suppliers and used
without further purification except for CH2Cl2 which was distilled
from P2O5 and MeCN which was distilled from CaH2. Column
chromatography was carried out over silica gel (BDH 200–300
mesh) and TLC was performed using silica gel GF254 (Merck)
Anal. Calcd for C19H17BBr2F2N2: C, 47.35; H, 3.56; N, 5.81. Found:
C, 47.39; H, 3.64; N, 5.76.
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-(4-methylphe-
nyl)-4-bora-3a,4a-diaza-s-indacene (2b)
Yield: 91.3 mg (92%); red solid; mp 191–193 °C.
1H NMR (500 MHz, CDCl3): d = 1.41 (s, 6 H, CH3), 2.48 (s, 3 H,
CH3), 2.62 (s, 6 H, CH3), 7.14 (d, J = 7.95 Hz, 2 H, ArH), 7.34 (d,
J = 7.8 Hz, 2 H, ArH).
1
plates. H and 13C NMR spectra were recorded in CDCl3 using a
Bruker Avance III 500-MHz spectrometer. Mass spectra (EI and
ESI) were measured with Jeol JMS-DX300 and Thermo Fisher
LCQ instruments. Elemental analyses were obtained using a Perkin-
Elmer 240C analyzer. Melting points were measured with a Shang-
hai WRS-1B digital melting-point apparatus and are uncorrected.
The substrates 1 were prepared according to the literature.3a
13C NMR (125 MHz, CDCl3): d = 153.7, 142.6, 140.7, 139.6, 131.3,
130.5, 130.1, 127.6, 111.6, 21.5, 13.8, 13.7.
EI-MS: m/z = 496 [M]+.
Dibromides 2a–l; General Procedure
A mixture of the 1,3,5,7-tetramethyl-BODIPY 1 (0.2 mmol) and
CuBr2 (0.5 mmol) in anhyd MeCN (20 mL) was stirred under O2 at-
mosphere (balloon) at r.t. for 12 h. The residue obtained after the re-
moval of the solvent by rotary evaporation was extracted with
EtOAc (3 × 40 mL), and the extracts were washed with H2O (3 × 30
mL), dried (anhyd Na2SO4), and concentrated under reduced pres-
Anal. Calcd for C20H19BBr2F2N2: C, 48.43; H, 3.86; N, 5.65. Found:
C, 48.39; H, 3.90; N, 5.63.
2,6-Dibromo-4,4-difluoro-8-(4-methoxyphenyl)-1,3,5,7-tetra-
methyl-4-bora-3a,4a-diaza-s-indacene (2c)
Yield: 88.1 mg (86%); red solid; mp 236–238 °C.
Synthesis 2012, 44, 104–110
© Thieme Stuttgart · New York

PAPER
Bromination of BODIPY Derivatives
107
1H NMR (500 MHz, CDCl3): d = 1.47 (s, 6 H, CH3), 2.62 (s, 6 H,
CH3), 3.91 (s, 3 H, OCH3), 7.06 (d, J = 8.65 Hz, 2 H, ArH), 7.16 (d,
J = 8.65 Hz, 2 H, ArH).
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-(4-nitrophe-
nyl)-4-bora-3a,4a-diaza-s-indacene (2h)
Yield: 100.1 mg (95%); red solid; mp >300 °C.
13C NMR (125 MHz, CDCl3): d = 160.6, 153.7, 142.3, 140.6, 130.9,
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 6 H, CH3), 2.64 (s, 6 H,
CH3), 7.55 (d, J = 8.6 Hz, 2 H, ArH), 8.44 (d, J = 8.65 Hz, 2 H,
ArH).
13C NMR (125 MHz, CDCl3): d = 155.3, 148.7, 141.2, 140.0, 138.6,
129.6, 124.6, 112.5, 14.0, 13.8.
130.8, 129.1, 128.8, 126.3, 114.8, 111.7, 55.4, 13.9, 13.7.
EI-MS: m/z = 512 [M]+.
Anal. Calcd for C20H19BBr2F2N2O: C, 46.96; H, 3.74; N, 5.47.
Found: C, 47.02; H, 3.72; N, 5.50.
ESI-MS: m/z = 527 [M]+.
2,6-Dibromo-8-(3,4-dimethoxyphenyl)-4,4-difluoro-1,3,5,7-tet-
ramethyl-4-bora-3a,4a-diaza-s-indacene (2d)
Yield: 104.1 mg (96%); red solid; mp 230–232 °C.
Anal. Calcd for C19H16BBr2F2N3O2: C, 43.31; H, 3.06; N, 7.97.
Found: C, 43.27; H, 3.12; N, 7.95.
1H NMR (500 MHz, CDCl3): d = 1.49 (s, 6 H, CH3), 2.62 (s, 6 H,
CH3), 3.88 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 6.76 (d, J = 1.85
Hz, 1 H, ArH), 6.82 (dd, J = 1.9, 8.15 Hz, 1 H, ArH), 7.01 (d,
J = 8.15 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 153.7, 150.1, 142.0, 140.6, 130.7,
126.4, 120.3, 111.7, 110.8, 56.1, 56.0, 13.8, 13.7.
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-[4-(trifluoro-
methyl)phenyl]-4-bora-3a,4a-diaza-s-indacene (2i)
Yield: 103.4 mg (94%); red solid; mp 227–229 °C.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 6 H, CH3), 2.64 (s, 6 H,
CH3), 7.47 (d, J = 8.0 Hz, 2 H, ArH), 7.84 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 154.8, 140.2, 139.8, 138.2, 132.0
ESI-MS: m/z = 541 [M – H]+.
(q, JC-F = 32.9 Hz), 131.9, 130.0, 128.7, 126.4, 123.7 (q, JC-F =
2
1
270.0 Hz, CF3), 112.2, 13.8, 13.7.
ESI-MS: m/z = 551 [M + H]+.
Anal. Calcd for C21H21BBr2F2N2O2: C, 46.53; H, 3.91; N, 5.17.
Found: C, 46.49; H, 3.89; N, 5.23.
Anal. Calcd for C20H16BBr2F5N2: C, 43.68; H, 2.93; N, 5.09. Found:
C, 43.70; H, 3.01; N, 5.05.
2,6-Dibromo-8-(4-chlorophenyl)-4,4-difluoro-1,3,5,7-tetra-
methyl-4-bora-3a,4a-diaza-s-indacene (2e)
Yield: 85.7 mg (83%); red solid; mp 212–214 °C.
2,6-Dibromo-8-(4-cyanophenyl)-4,4-difluoro-1,3,5,7-tetrameth-
yl-4-bora-3a,4a-diaza-s-indacene (2j)
Yield: 92.3 mg (91%); red solid; mp >300 °C.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 6 H, CH3), 2.63 (s, 6 H,
CH3), 7.47 (d, J = 8.3 Hz, 2 H, ArH), 7.87 (d, J = 8.3 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 155.1, 140.0, 139.3, 138.9, 133.1,
129.7, 129.2, 117.8, 113.9, 112.4, 13.9, 13.7.
1H NMR (500 MHz, CDCl3): d = 1.43 (s, 6 H, CH3), 2.63 (s, 6 H,
CH3), 7.24 (d, J = 8.35 Hz, 2 H, ArH), 7.55 (d, J = 8.35 Hz, 2 H,
ArH).
13C NMR (125 MHz, CDCl3): d = 154.4, 140.4, 140.3, 135.9, 132.8,
130.3, 129.9, 124.4, 120.1, 120.0, 13.9, 13.7.
ESI-MS: m/z = 517 [M + H]+.
Anal. Calcd for C19H16BBr2ClF2N2: C, 44.19; H, 3.12; N, 5.42.
Found: C, 44.22; H, 3.09; N, 5.41.
ESI-MS: m/z = 508 [M + H]+.
Anal. Calcd for C20H16BBr2F2N3: C, 47.38; H, 3.18; N, 8.29. Found:
C, 47.41; H, 3.15; N, 8.26.
2,6-Dibromo-8-(2-chlorophenyl)-4,4-difluoro-1,3,5,7-tetra-
methyl-4-bora-3a,4a-diaza-s-indacene (2f)
Yield: 86.7 mg (84%); red solid; mp >300 °C.
1H NMR (500 MHz, CDCl3): d = 1.44 (s, 6 H, CH3), 2.64 (s, 6 H,
CH3), 7.29 (d, J = 5.0 Hz, 1 H, ArH), 7.46 (t, J = 7.4 Hz, 1 H, ArH),
7.50 (t, J = 7.4 Hz, 1 H, ArH), 7.57 (d, J = 7.9 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 154.5, 140.0, 138.2, 133.4, 132.9,
131.1, 130.8, 130.0, 129.9, 129.7, 128.8, 127.9, 111.8, 13.8, 12.9.
ESI-MS: m/z = 515 [M – H]+.
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-[3-(trifluoro-
methyl)phenyl]-4-bora-3a,4a-diaza-s-indacene (2k)
Yield: 90.2 mg (82%); red solid; mp 227–229 °C.
1H NMR (500 MHz, CDCl3): d = 1.36 (s, 6 H, CH3), 2.64 (s, 6 H,
CH3), 7.53 (d, J = 7.7 Hz, 1 H, ArH), 7.62 (s, 1 H, ArH), 7.72 (t,
J = 7.7 Hz, 1 H, ArH), 7.85 (d, J = 7.85 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 154.8, 140.2, 139.5, 135.3, 132.2
(q, 2JC-F = 32.7 Hz), 131.2, 130.1, 126.3 (q, 3JC-F = 3.65 Hz), 125.2
3
1
(q, JC-F = 3.70 Hz), 123.5 (q, JC-F = 271.0 Hz, CF3), 112.3, 13.8,
Anal. Calcd for C19H16BBr2ClF2N2: C, 44.19; H, 3.12; N, 5.42.
Found: C, 44.20; H, 3.16; N, 5.37.
13.7.
ESI-MS: m/z = 551 [M + H]+.
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-[4-(prop-2-
ynyloxy)phenyl]-4-bora-3a,4a-diaza-s-indacene (2g)
Yield: 92.2 mg (86%); red solid; mp 221–223 °C.
Anal. Calcd for C20H16BBr2F5N2: C, 43.68; H, 2.93; N, 5.09. Found:
C, 43.72; H, 2.92; N, 5.13.
1H NMR (500 MHz, CDCl3): d = 1.44 (s, 6 H, CH3), 2.59 (t, J = 2.4
Hz, 1 H, CH), 2.62 (s, 6 H, CH3), 4.79 (d, J = 2.35 Hz, 2 H, CH2),
7.13 (d, J = 8.65 Hz, 2 H, ArH), 7.18 (d, J = 8.65 Hz, 2 H, ArH).
2,6-Dibromo-4,4-difluoro-1,3,5,7-tetramethyl-8-(1-naphthyl)-
4-bora-3a,4a-diaza-s-indacene (2l)
Yield: 94.7 mg (89%); red solid; mp 248–250 °C.
13C NMR (125 MHz, CDCl3): d = 158.5, 153.9, 141.9, 140.6, 130.7,
1H NMR (500 MHz, CDCl3): d = 1.08 (s, 6 H, CH3), 2.67 (s, 6 H,
CH3), 7.38–7.42 (m, 1 H, ArH), 7.45–7.50 (m, 1 H, ArH), 7.54–7.58
(m, 1 H, ArH), 7.59–7.64 (m, 1 H, ArH), 7.74 (d, J = 8.25 Hz, 1 H,
ArH), 7.94 (d, J = 8.2 Hz, 1 H, ArH), 8.03 (d, J = 8.25 Hz, 1 H,
ArH).
13C NMR (125 MHz, CDCl3): d = 154.1, 140.7, 140.5, 133.6, 131.7,
131.4, 130.9, 129.8, 128.4, 127.6, 126.9, 125.9, 125.8, 124.6, 111.8,
13.7, 13.1.
129.1, 127.3, 116.0, 111.7, 77.8, 76.1, 56.1, 13.9, 13.7.
ESI-MS: m/z = 537 [M + H]+.
Anal. Calcd for C22H19BBr2F2N2O: C, 49.30; H, 3.57; N, 5.23.
Found: C, 49.32; H, 3.54; N, 5.28.
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108
J.-H. Ye et al.
PAPER
ESI-MS: m/z = 531 [M – H]+.
3.97 (s, 3 H, OCH3), 6.05 (s, 1 H, pyrrole-H), 6.77 (d, J = 1.5 Hz, 1
H, ArH), 6.81–6.83 (m, 1 H, ArH), 6.99 (d, J = 8.5 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 157.9, 151.4, 149.9, 149.7, 145.1,
141.7, 138.7, 132.3, 130.1, 126.7, 122.1, 120.4, 111.6, 110.9, 110.5,
56.1, 55.9, 14.7, 14.6, 13.5, 13.4.
Anal. Calcd for C23H19BBr2F2N2: C, 51.92; H, 3.60; N, 5.27. Found:
C, 51.96; H, 3.58; N, 5.22.
Monobromides 3a–l; General Procedure
To a soln of the 1,3,5,7-tetramethyl-BODIPY 1 (0.2 mmol) and
K2CO3 (0.6 mmol) in anhyd MeCN (20 mL) was slowly added a
soln of CuBr2 (0.3 mmol) in MeCN (25 mL). The mixture was
stirred under an O2 atmosphere (balloon) at r.t. for 24 h. The residue
obtained after the removal of the solvent by rotary evaporation was
extracted with EtOAc (3 × 40 mL), and the extracts were washed
with H2O (3 × 30 mL), dried (anhyd Na2SO4), and concentrated un-
der reduced pressure. The crude product was further purified using
column chromatography (EtOAc–petroleum ether) to afford the
monobromide 3.
ESI-MS: m/z = 464 [M + H]+.
Anal. Calcd for C21H22BBrF2N2O2: C, 54.46; H, 4.79; N, 6.05.
Found: C, 54.49; H, 4.82; N, 6.01.
2-Bromo-8-(4-chlorophenyl)-4,4-difluoro-1,3,5,7-tetramethyl-
4-bora-3a,4a-diaza-s-indacene (3e)
Yield: 75.3 mg (86%); red solid; mp 197–199 °C.
1H NMR (500 MHz, CDCl3): d = 1.42 (s, 3 H, CH3), 1.44 (s, 3 H,
CH3), 2.58 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 6.06 (s, 1 H, pyrrole-
H), 7.23 (d, J = 8.5 Hz, 2 H, ArH), 7.52 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 158.4, 151.9, 144.8, 140.2, 138.5,
135.5, 133.1, 131.9, 129.7, 129.5, 128.8, 122.4, 110.8, 14.8, 13.7,
13.5.
2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-phenyl-4-bora-
3a,4a-diaza-s-indacene (3a)
Yield: 65.3 mg (81%); red solid; mp 183–185 °C.
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 1.40 (s, 3 H,
CH3), 2.59 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 6.05 (s, 1 H, pyrrole-
H), 7.25–7.30 (m, 2 H, ArH), 7.49–7.55 (m, 3 H, ArH).
13C NMR (125 MHz, CDCl3): d = 157.9, 151.4, 145.1, 141.8, 138.8,
134.7, 132.0, 129.8, 129.3, 127.9, 122.2, 14.8, 14.5, 13.4.
EI-MS: m/z = 402 [M – H]+.
ESI-MS: m/z = 437 [M]+.
Anal. Calcd for C19H17BBrClF2N2: C, 52.16; H, 3.92; N, 6.40.
Found: C, 52.15; H, 3.88; N, 6.45.
2-Bromo-8-(2-chlorophenyl)-4,4-difluoro-1,3,5,7-tetramethyl-
4-bora-3a,4a-diaza-s-indacene (3f)
Yield: 73.5 mg (84%); red solid; mp 218–220 °C.
Anal. Calcd for C19H18BBrF2N2: C, 56.62; H, 4.50; N, 6.95. Found:
C, 56.60; H, 4.55; N, 6.91.
1H NMR (500 MHz, CDCl3): d = 1.44 (s, 3 H, CH3), 1.45 (s, 3 H,
CH3), 2.60 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 6.07 (s, 1 H, pyrrole-
H), 7.28–7.31 (m, 1 H, ArH), 7.42–7.50 (m, 2 H, ArH), 7.53–7.56
(m, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 158.7, 151.9, 144.6, 138.2, 138.0,
133.7, 132.9, 131.7, 130.9, 130.3, 129.8, 129.3, 127.8, 122.3, 110.7,
14.9, 13.8, 13.6, 12.6.
2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-(4-methylphenyl)-
4-bora-3a,4a-diaza-s-indacene (3b)
Yield: 62.6 mg (75%); red solid; mp 193–195 °C.
1H NMR (500 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.42 (s, 3 H,
CH3), 2.46 (s, 3 H, CH3), 2.58 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 6.04
(s, 1 H, pyrrole-H), 7.14 (d, J = 8.0 Hz, 2 H, ArH), 7.32 (d, J = 7.5
Hz, 2 H, ArH).
ESI-MS: m/z = 437 [M]+.
Anal. Calcd for C19H17BBrClF2N2: C, 52.16; H, 3.92; N, 6.40.
Found: C, 52.13; H, 3.96; N, 6.39.
13C NMR (125 MHz, CDCl3): d = 157.7, 151.2, 145.1, 142.3, 139.2,
138.8, 132.2, 131.6, 129.9, 127.7, 122.0, 110.5, 21.4, 14.7, 14.6,
13.5.
2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-[4-(prop-2-ynyl-
oxy)phenyl]-4-bora-3a,4a-diaza-s-indacene (3g)
Yield: 73.1 mg (80%); red solid; mp 203–204 °C.
1H NMR (500 MHz, CDCl3): d = 1.43 (s, 3 H, CH3), 1.45 (s, 3 H,
CH3), 2.58 (s, 3 H + 1 H, CH3 + CH), 2.61 (s, 3 H, CH3), 4.78 (d,
J = 2.5 Hz, 2 H, CH2), 6.05 (s, 1 H, pyrrole-H), 7.12 (d, J = 8.5 Hz,
2 H, ArH), 7.20 (d, J = 9.0 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 158.3, 157.8, 151.4, 145.1, 141.6,
138.7, 132.4, 130.2, 129.2, 128.8, 127.6, 122.1, 115.8, 110.6, 77.9,
75.9, 56.0, 14.7, 13.6.
ESI-MS: m/z = 416 [M – H]+.
Anal. Calcd for C20H20BBrF2N2: C, 57.59; H, 4.83; N, 6.72. Found:
C, 57.64; H, 4.90; N, 6.68.
2-Bromo-4,4-difluoro-8-(4-methoxyphenyl)-1,3,5,7-tetrameth-
yl-4-bora-3a,4a-diaza-s-indacene (3c)
Yield: 65.8 mg (76%); red solid; mp 163–165 °C.
1H NMR (500 MHz, CDCl3): d = 1.43 (s, 3 H, CH3), 1.45 (s, 3 H,
CH3), 2.58 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 3.89 (s, 3 H, OCH3),
6.05 (s, 1 H, pyrrole-H), 7.04 (d, J = 9.0 Hz, 2 H, ArH), 7.17 (d,
J = 8.5 Hz, 2 H, ArH).
ESI-MS: m/z = 457 [M]+.
Anal. Calcd for C22H20BBrF2N2O: C, 57.80; H, 4.41; N, 6.13.
Found: C, 57.85; H, 4.43; N, 6.08.
13C NMR (125 MHz, CDCl3): d = 160.4, 157.7, 151.2, 145.1, 142.0,
138.8, 130.2, 129.1, 128.8, 126.6, 122.0, 114.7, 110.5, 55.3, 14.7,
13.6, 13.4.
2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-(4-nitrophenyl)-4-
bora-3a,4a-diaza-s-indacene (3h)
EI-MS: m/z = 432 [M – H]+.
Yield: 69.9 mg (78%); red solid; mp >300 °C.
Anal. Calcd for C20H20BBrF2N2O: C, 55.46; H, 4.65; N, 6.47.
Found: C, 55.47; H, 4.70; N, 6.49.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 3 H, CH3), 1.39 (s, 3 H,
CH3), 2.60 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 6.09 (s, 1 H, pyrrole-
H), 7.56 (d, J = 9.0 Hz, 2 H, ArH), 8.42 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 159.2, 152.8, 148.5, 144.4, 141.5,
138.4, 138.2, 131.3, 129.6, 129.0, 124.5, 122.8, 111.3, 14.9, 13.8,
13.6.
2-Bromo-8-(3,4-dimethoxyphenyl)-4,4-difluoro-1,3,5,7-tetra-
methyl-4-bora-3a,4a-diaza-s-indacene (3d)
Yield: 74.1 mg (80%); red solid; mp 162–164 °C.
1H NMR (500 MHz, CDCl3): d = 1.47 (s, 3 H, CH3), 1.50 (s, 3 H,
CH3), 2.57 (s, 3 H, CH3), 2.60 (s, 3 H, CH3), 3.86 (s, 3 H, OCH3),
ESI-MS: m/z = 447 [M – H]+.
Synthesis 2012, 44, 104–110
© Thieme Stuttgart · New York

PAPER
Bromination of BODIPY Derivatives
109
Anal. Calcd for C19H17BBrF2N3O2: C, 50.93; H, 3.82; N, 9.38.
Found: C, 50.98; H, 3.86; N, 9.32.
Anal. Calcd for C23H20BBrF2N2: C, 60.96; H, 4.45; N, 6.18. Found:
C, 60.93; H, 4.46; N, 6.15.
2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-[4-(trifluorometh-
yl)phenyl]-4-bora-3a,4a-diaza-s-indacene (3i)
Yield: 76.3 mg (81%); red solid; mp 203–205 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1H NMR (500 MHz, CDCl3): d = 1.36 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3), 2.59 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 6.08 (s, 1 H, pyrrole-
H), 7.47 (d, J = 8.0 Hz, 2 H, ArH), 7.82 (d, J = 8.0 Hz, 2 H, ArH).
Acknowledgment
We thank the Analysis and Testing Center of the School of Chemi-
cal Engineering, Nanjing University of Science and Technology,
and Mrs. R. Yi for assistance with the NMR experiments.
13C NMR (125 MHz, CDCl3): d = 158.7, 152.3, 144.7, 139.6, 138.6,
2
131.9, 131.7 (q, JC-F = 32.5 Hz), 129.4, 128.7, 126.3, 123.8 (q,
1JC-F = 280.0 Hz, CF3), 122.6, 111.1, 14.8, 14.7, 13.6.
ESI-MS: m/z = 471 [M]+.
References
Anal. Calcd for C20H17BBrF5N2: C, 50.09; H, 3.64; N, 5.95. Found:
C, 50.06; H, 3.63; N, 5.91.
(1) Haugland, R. P. The Handbook: A Guide to Fluorescent
Probes and Labeling Technologies, 10th ed.; Invitrogen
Corp.: Eugene (OR, USA), 2005.
2-Bromo-8-(4-cyanophenyl)-4,4-difluoro-1,3,5,7-tetramethyl-4-
bora-3a,4a-diaza-s-indacene (3j)
Yield: 67.6 mg (79%); red solid; mp 229–231 °C.
1H NMR (500 MHz, CDCl3): d = 1.36 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3), 2.59 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 6.09 (s, 1 H, pyrrole-
H), 7.48 (d, J = 8.5 Hz, 2 H, ArH), 7.85 (d, J = 8.0 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 159.0, 152.7, 144.4, 139.7, 138.7,
138.2, 133.0, 131.4, 129.3, 129.1, 122.7, 117.9, 113.6, 111.2, 14.8,
14.7, 13.7, 13.6.
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ESI-MS: m/z = 427 [M – H]+.
Anal. Calcd for C20H17BBrF2N3: C, 56.11; H, 4.00; N, 9.82. Found:
C, 56.16; H, 4.02; N, 9.79.
2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-[3-(trifluorometh-
yl)phenyl]-4-bora-3a,4a-diaza-s-indacene (3k)
Yield: 69.7 mg (74%); red solid; mp 186–188 °C.
1H NMR (500 MHz, CDCl3): d = 1.35 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 2.59 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 6.08 (s, 1 H, pyrrole-
H), 7.53 (d, J = 7.7 Hz, 1 H, ArH), 7.62 (s, 1 H, ArH), 7.69 (t,
J = 7.75 Hz, 1 H, ArH), 7.81 (d, J = 7.85 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 158.7, 152.3, 144.6, 139.3, 138.4,
135.6, 132.1, 131.9 (q, 2JC-F = 32.9 Hz), 131.6, 129.9, 129.5, 126.0
3
3
1
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(q, JC-F = 3.75 Hz), 125.3 (q, JC-F = 3.35 Hz), 123.6 (q, JC-F
=
271.0 Hz, CF3), 122.6, 111.1, 14.8, 14.7, 13.6, 13.5.
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ESI-MS: m/z = 471 [M]+.
Anal. Calcd for C20H17BBrF5N2: C, 50.09; H, 3.64; N, 5.95. Found:
C, 50.14; H, 3.61; N, 5.99.
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2-Bromo-4,4-difluoro-1,3,5,7-tetramethyl-8-(1-naphthyl)-4-
bora-3a,4a-diaza-s-indacene (3l)
Yield: 78.8 mg (87%); red solid; mp 209–211 °C.
1H NMR (500 MHz, CDCl3): d = 1.07 (s, 3 H, CH3), 1.09 (s, 3 H,
CH3), 2.63 (s, 3 H, CH3), 2.66 (s, 3 H, CH3), 6.02 (s, 1 H, pyrrole-
H), 7.40 (d, J = 7.0 Hz, 1 H, ArH), 7.44–7.49 (m, 1 H, ArH), 7.52–
7.57 (m, 1 H, ArH), 7.57–7.62 (m, 1 H, ArH), 7.78 (d, J = 8.4 Hz, 1
H, ArH), 7.93 (d, J = 8.2 Hz, 1 H, ArH), 8.00 (d, J = 8.3 Hz, 1 H,
ArH).
13C NMR (125 MHz, CDCl3): d = 158.1, 151.6, 144.9, 140.4, 138.6,
133.5, 132.6, 132.1, 131.6, 130.3, 129.6, 128.3, 127.4, 126.8, 125.9,
125.8, 124.7, 122.1, 110.6, 14.8, 14.0, 13.5, 12.9.
ESI-MS: m/z = 453 [M]+.
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110
J.-H. Ye et al.
PAPER
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Synthesis 2012, 44, 104–110
© Thieme Stuttgart · New York