Tunable BODIPY derivatives amenable to 'click' and peptide chemistry

Article abstract of DOI:10.1016/j.tet.2013.05.037

Novel azido- and amino-functionalised fluorescent probes based on the BODIPY framework have been developed. The probes can be easily and cheaply synthesised, exhibit the highly desirable BODIPY fluorescent properties, and are amenable to 'click' and pepti

Full text of DOI:10.1016/j.tet.2013.05.037

Tetrahedron 69 (2013) 8527e8533
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tunable BODIPY derivatives amenable to ‘click’ and peptide
chemistryq
Anna Mette Hansen a, Alan L. Sewell a, Rasmus H. Pedersen b, De-Liang Long a,
, ,
y
Nikolaj Gadegaard b, Rodolfo Marquez a
*
a School of Chemistry, University of Glasgow, Glasgow G12 8QQ, United Kingdom
b School of Engineering, University of Glasgow, Glasgow G12 8LT, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel azido- and amino-functionalised fluorescent probes based on the BODIPY framework have been
developed. The probes can be easily and cheaply synthesised, exhibit the highly desirable BODIPY
fluorescent properties, and are amenable to ‘click’ and peptide chemistry methodologies. These probes
provide a stable and readily available tool amenable for the visualisation of both solution and solid
supported events.
Received 20 February 2013
Received in revised form 29 April 2013
Accepted 13 May 2013
Available online 18 May 2013
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
BODIPY
Click chemistry
Fluorescence
Nano-printing
1. Introduction
Thus, it is not surprising that a large number of BODIPY analogues
have been generated and a set of them is commercially available.4
Visualisation of intracellular processes is a key and integral part
of biological chemistry and drug discovery. As such, a wide variety
of fluorescent probes has been designed and synthesised in-
corporating a wide variety of fluorophores. 4,4-Difluoro-4-bora-
3a,4a-diaza-s-indacene (BODIPY) has emerged as an excellent
fluorescent dye due to its large molar absorption coefficient, tun-
able fluorescence and high quantum yield, which is responsible for
their brightness (Fig. 1).1e3
2. Results and discussion
As part of our own investigations into intracellular processes, we
became interested in the development of 3-azido-BODIPY units as
visualisation tools amenable for ‘click’ and peptide chemistry li-
gation. Although there have been reports of BODIPY derivatives
bearing an azide substituent, the derivatives reported thus far lack
the wavelength range of the original BODIPY dyes.5 A wide range of
8-azido and 8-amino-BODIPY derivatives on the other hand, have
also been developed, however substitution at the C8 position
causes significant wavelength shifts and can make these units dif-
ficult to visualise and distinguish from background emissions.6
Thus, it was decided to focus on the synthesis of novel 3-azido
and 3-amino substituted BODIPY units able to match the wave-
length range of commercially available BODIPY dyes, and as such
facilitate their practical use in biological and material applications.
A key part of our BODIPY synthesis was focused on the de-
velopment of a simple, reliable and economic approach that could
be reproduced without the need of elaborate set-ups or specialist
training and would also yield significant amounts of compound
quickly and efficiently.
N
F
N
F
B
Fig. 1. BODIPY basic framework.
The BODIPYs also exhibit excellent photostability, and a small
Stokes shift between their absorption and emission spectra. Fur-
thermore, their absorption and emission spectra is located in the
visible spectrum and is not affected by the choice of solvent used.
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.
* Corresponding author. Tel.: þ44 0141 330 5953; fax: þ44 0141 330 488; e-mail
address: rudi.marquez@glasgow.ac.uk (R. Marquez).
Our synthesis began with pyrrole carbaldehyde 2, which was
subjected to a Wittig olefination to afford conjugated ester 3 as
a single double bond isomer.7 Sequential 1,4 and 1,2-reductions
yielded primary alcohol 5 in excellent yield for both steps.8
y
Ian Sword Reader of Organic and Bioorganic Chemistry.
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http://dx.doi.org/10.1016/j.tet.2013.05.037

8528
A.M. Hansen et al. / Tetrahedron 69 (2013) 8527e8533
Activation of the alcohol unit as mesylate 6 followed by azide dis-
placement then gave the desired azide building block 7 in good
yield. Finally, phosphorous oxychloride promoted coupling of
azido-pyrrole 7 with 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde
89 followed by treatment with boron trifluoride diethyl etherate
gave the desired azido-BODIPY analogue 9 in good yield (Scheme
1). The structure of azido-BODIPY 9 was corroborated by X-ray
crystallography (Fig. 2).10
being the reaction with alkyne 12, which resulted in a 1:1 ratio of
regioisomeric products. The lack of selectivity is likely due to the
p
stacking interaction between the phenyl ring of alkyne 12 with the
BODIPY core unit, which counteracts the steric repulsion.
Having demonstrated the ability of azido-BODIPY 9 to undergo
‘click’ cycloadditions without any detrimental effects, we decided
to evaluate its synthetic flexibility and versatility. We were partic-
ularly keen to explore its suitability as a 3-amino-BODIPY precursor,
which would allow for the quick fluorescent labelling of carboxyl-
ate derived units.
In practice, the selective reduction of azido-BODIPY 9 proved
extremely difficult to achieve without loss of fluorescence, pre-
sumably due to reduction of the difluoroboronate motif. Gratify-
ingly however, after a significant amount of experimentation, the
selective reduction of azido-BODIPY 9 was achieved through
the use of Staudinger conditions12 using solid supported
triphenylphosphine to yield the desired 3-amino substituted
BODIPY derivative 20 in very good yield, without the need for
chromatographic purification (Scheme 2).
CO2Me
80%
Ph3P
H2, Pd/C
quant.
N
H
N
H
CHO
CO2Me
OH
2
3
MsCl, TEA
94%
Dibal-H
quant.
N
N
H
CO2Me
H
5
4
NaN3, DMF
88%
OMs
N3
N
H
N
H
6
7
N
H
POCl3, BF3.OEt2
82%
CHO
8
N
F
N
B
F
SS-Ph-PPh2,
THF, H2O
9
N3
N
F
82%
N
F
N
F
N
F
B
B
Scheme 1.
9
20
NH2
N3
Scheme 2.
As expected, coupling of amino-BODIPY 20 with a variety of
different acid chlorides proceeded to yield the desired BODIPY
derived amides in reasonable yields. Fluorescence was retained
throughout the coupling and purification procedures (Table 2).
Fig. 2. Crystal structure of azido-BODIPY 9.
Table 2
Peptide couplings of amino-BODIPY 20
Having ascertained the fluorescence spectrum of the azido-
BODIPY dye 9, its reaction with a set of alkynes was explored
(Table 1).11 We are pleased to report that in all cases, azido-BODIPY
9 underwent smooth Cu(I) catalysed [2,3]-dipolar cycloaddition
with a variety of terminal alkynes without the loss of fluorescence.
As expected, the regiochemical outcome of the addition was dic-
tated by the steric nature of the alkyne substituent. The exception
H2N
BODIPY
O
O
20
DIPEA, DMAP
DCM, 0 oC, 1 h
R
N
H
BODIPY
BODIPY
R
Cl
O
O
Cl
1)
2)
3)
N
48%
55%
51%
H
21
25
O
O
O
Table 1
Cl
Cl
N
H
BODIPY
BODIPY
22
26
‘Click’ couplings of azido-BODIPY 9
O
BODIPY
CuI (cat), DIPEA (cat)
9
N3
R
BODIPY
R
N
N
N
H
23
27
N
O
O
4)
Cl
59%
N
H
BODIPY
1)
2)
TBDPSO
MeO2C
85%
N
BODIPY
BODIPY
TBDPSO
N
N
N
24
28
10
15
MeO2C
MeO2C
82%
84%
83%
N
N
N
N
CO2Me
11
16
After having determined the suitability of azido-BODIPY 9 as
a stable labelling reagent and labelling intermediate under both
‘click’ and peptide couplings conditions, respectively, we returned
our attention to the design and development of an analogous azido-
BODIPY unit with different absorption and emission spectral bands.
The synthesis of the new azido-BODIPY dye was readily ach-
ieved starting from styryl-pyrrole 2913, which was subjected to
VilsmeireHaack conditions to generate carbaldehyde 30. Coupling
of carbaldehyde 30 with azido-pyrrole 7 under our previously used
conditions yielded the desired novel azido-BODIPY analogue 31
(Scheme 3). The structure of azido-BODIPY 31 was corroborated by
X-ray crystallographic analysis (Fig. 3).14
Ph
3)
4)
5)
i
BODIPY
17
12
N
O
O
MeO
MeO
N
BODIPY
BODIPY
13
18
N
N
O
O
68%
O
O
N
14
19
S
S
S
N
N
S
i) Obtained as 1:1 mixture of regioisomers

A.M. Hansen et al. / Tetrahedron 69 (2013) 8527e8533
8529
POCl3, DMF
70%
N
H
N
H
OHC
30
29
POCl3,
N
N3
N
H
86%
N
F
BF3OEt2
8
B
F
31
N3
Scheme 3.
Fig. 5. Fluorescence (left) and atomic force (right) microscope images of patterned
BODIPY material on a gold surface, obtained by microcontact printing.
and provide access to different parts of the visible spectrum. These
probes provide a stable and readily available tool amenable for the
visualisation of both solution and solid supported events and as
such will be a useful tool in biological chemistry, drug discovery,
materials science and nano-fabrication.
3. Experimental
3.1. General
The reactions were carried out in glassware dried in an oven
(130 ꢀC) under an argon atmosphere. Tetrahydrofuran, toluene and
dichloromethane were purified through a Pure Solv 400-5MD sol-
vent purification system (Innovative Technology, Inc). All reagents
were used as received, unless otherwise stated. Solvents were
evaporated under reduced pressure at 40 ꢀC.
Column chromatography was performed under pressure using
silica gel (Fluoro Chem Silica LC 60A) as the stationary phase. Re-
actions were monitored by thin layer chromatography on alumin-
ium sheets pre-coated with silica gel (Merck Silica Gel 60 F254). The
plates were visualised by the quenching of UV fluorescence (lmax
254 nm) and/or by staining with a KMnO4 solution or anisaldehyde
dip.
Fig. 3. Crystal structure of azido-BODIPY 31.
As intended, both azido-BODIPY 9 and azido-BODIPY 31 display
absorption and emission bands in close proximity to each other,
and closely match those of commercially available BODIPY-FLÒ and
BODIPY-564/570Ò, respectively (Fig. 4).
Proton magnetic resonance spectra (1H NMR) and carbon
magnetic resonance spectra (13C NMR) were recorded at 400 MHz
and 100 MHz or at 500 MHz and 125 MHz using either a Bruker DPX
Avance400 instrument or a Bruker AvanceIII500 instrument, re-
spectively. IR spectra were obtained employing a Golden GateÔ
attachment that uses a type IIa diamond as a single reflection ele-
ment so that the IR spectrum of the compound (solid or liquid) was
detected directly (thin layer) without any sample preparation
(Shimadzu FTIR-8400). Only significant absorptions are reported.
High resolution mass spectra were recorded by the analytical
group of the School of Chemistry at Glasgow University & the
University of Dundee using a JEOL JMS-700 mass spectrometer by
electrospray and chemical ionisation operating at a resolution of
15,000 full widths at half height. UV/vis data was acquired on
Fig. 4. Absorption and emission spectra of azido-BODIPY 9 (green) and azido-BODIPY
31 (pink). Slit width 3ꢁ3 nm.
The successful ‘click’ cycloaddition of azido-BODIPY 9 with
propargyl lipoic acid derivative 14 provided us with a potentially
useful tool for the quick and easy visualization of solid surface
patterning.15 The principle being based on the use of BODIPY dyes
for micro- and nano-pattern visualisation on gold surfaces through
microcontact printing.16
Thus, a polydimethylsiloxane (PDMS) master with a micron-
scale honeycomb test pattern was inked with a solution of the
BODIPY derived lipoic acid derivative 19 in acetonitrile at a con-
centration of approximately 0.2 mg/mL. The substrate was pre-
pared by e-beam evaporation of 30 nm of Au on a clean glass slide.
Master and substrate were pressed together at gentle pressure in
a home-built imprint stepper. The obtained pattern was imaged
using fluorescent microscopy and AFM. As seen in Fig. 5, a clear
honeycomb pattern was obtained on the gold surface.
In conclusion, we have developed a new set of azido- and
amino-functionalised fluorescent probes based on the BODIPY
framework. The probes can be cheaply, easily and quickly syn-
thesised without the need for specialist training or equipment. The
probes exhibit the highly desirable BODIPY fluorescent properties,
and are amenable to ‘click’ and peptide chemistry methodologies
a
Perkin Elmer Lambda 25.
A Shimadzu RF-3501 spectro-
fluorophotometer was used to obtain the emission data.
3.1.1. (E)-Methyl
3-(1H-pyrrol-2-yl)acrylate,
3. 1H-Pyrrole-2-
carboxaldehyde 2 (2.50 g, 26.3 mmol) and methyl (triphenylphos-
phoranylidene)acetate (17.6 g, 52.6 mmol) were heated in benzene
(200 mL) until completion by TLC analysis (18 h). The reaction was
cooled down and the solvent was removed in vacuo to give the
crude product as yellow oil. Purification by flash column chroma-
tography (silica gel, elution gradient 15e20% EtOAc/petroleum
ether) afforded the desired conjugated ester 3 as a single trans
isomer (3.15 g, 80%) and as a white solid. 1H NMR (CDCl3, 400 MHz)
d
: 8.78 (1H, br s), 7.58 (1H, d, J¼15.9 Hz), 6.95e6.94 (1H, m),
6.58e6.57 (1H, m), 6.30e6.28 (1H, m), 6.03 (1H, d, J¼15.9 Hz), 3.79
(3H, s). 13C NMR (CDCl3,100 MHz)
: 168.2,134.5,128.4,122.5,114.5,
d

8530
A.M. Hansen et al. / Tetrahedron 69 (2013) 8527e8533
111.0, 110.8, 51.4. The NMR data obtained is in accordance with the
literature.7
10 mmol). The resulting mixture was allowed to warm up to rt, and
then heated to 40 ꢀC until completion as indicated by TLC analysis
(18 h). The reaction was then cooled down to rt and diluted with
EtOAc (30 mL). The resulting solution was washed with H2O
(8ꢁ50 mL), brine (3ꢁ50 mL), dried (Na2SO4) and concentrated in
vacuo to afford the crude as a dark brown solid. Column chroma-
tography (silica gel, 50% Et2O/petroleum ether) afforded (1.1 g, 82%)
of the desired pyrrole carbaldehyde 8 as an off white solid. 1H NMR
3.1.2. Methyl 3-(1H-pyrrol-2-yl)propanoate, 4. A solution of (E)-
methyl 3-(1H-pyrrol-2-yl)acrylate 3 (3.15 g, 21.1 mmol) in MeOH
(160 mL) was placed under at atmosphere of argon. Pd/C (246 mg,
10%) was added, followed by replacement of the argon with a hy-
drogen atmosphere. The reaction was then stirred at rt until com-
pletion as indicated by TLC analysis (16 h). The crude mixture was
filtered over a bed of Celite, and the Celite plug was eluted a further
aliquot of MeOH (50 mL). The combined MeOH washes were then
concentrated in vacuo to afford ester 4 (3.13 g, 100%) as a pale
yellow oil, which required no further purification. The NMR data
obtained for ester 4 is in accordance with the literature. 1H NMR
(CDCl3, 400 MHz) d: 10.14 (1H, br s), 9.49 (1H, s), 5.89 (1H, s), 2.32
(3H, s), 2.30 (3H, s). 13C NMR (CDCl3, 100 MHz)
128.8, 112.1, 13.2, 10.5.
d: 176.0, 138.5, 134.8,
3.1.6. 7-(3-Azidopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-
c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 9. A 0 ꢀC solution of 2-(3-
azidopropyl)-1H-pyrrole 7 (400 mg, 2.66 mmol) in CH2Cl2 (20 mL)
was treated with 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde 8
(360 mg, 2.93 mmol) and the resulting solution was treated by the
(CDCl3, 400 MHz) d: 8.53 (1H, br s), 6.69e6.68 (1H, m), 6.13e6.10
(1H, m), 5.94e5.93 (1H, m), 3.71 (3H, s), 2.93 (2H, t, J¼6.6 Hz), 2.66
(2H, t, J¼6.6 Hz). 13C NMR (CDCl3, 100 MHz)
d: 174.5, 130.9, 116.8,
108.0, 105.5, 51.8, 34.4, 22.5.
dropwise addition of POCl3 (431
mixture was stirred for 6 h at rt before being cooled back down to
0
ꢀC. The mixture was then treated with BF3$(OEt)2 (1.31 mL,
mL, 2.93 mmol). The reaction
3.1.3. 3-(1H-Pyrrol-2-yl)propan-1-ol, 5. A 0 ꢀC solution of methyl 3-
(1H-pyrrol-2-yl)propanoate 4 (2.64 g, 17.5 mmol) in Et2O (130 mL)
was treated by the slow addition of LiAlH4 (996 mg, 26.3 mmol). The
resulting suspension was allowed to warm up to rt and stirred until
completion as indicated by TLC analysis (16 h). The reaction mixture
was then quenched with the dropwise addition of 1 M aq NaOH
until pH neutral. The Et2O layer was decanted off, and the remaining
aluminium salts were washed with Et2O (3ꢁ50 mL). The combined
organic phases were dried over Na2SO4, filtered and concentrated in
vacuo to yield alcohol 5 (2.15 g, quant.) as a clear oil, which required
10.6 mmol) and N,N-diisopropylethylamine (1.9 mL,11.2 mmol) and
the reaction was stirred at rt for 12 h. The mixture was then diluted
with H2O (15 mL) and CH2Cl2 (10 mL) before being filtered through
a bed of Celite. The Celite was washed through with CH2Cl2
(2ꢁ15 mL) and the organic phases combined. The solution was then
dried over Na2SO4 and concentrated in vacuo to afford a dark red/
green crude solid residue. Purification of the crude solid by flash
column chromatography (silica gel, elution gradient 2e7% EtOAc/
petroleum ether) afforded 660 mg (82%) of the desired azide 9 as
red oil, which solidified upon cooling. Mp 49e50 ꢀC. 1H NMR
no further purification. 1H NMR (CDCl3, 400 MHz)
d: 8.24 (1H, br s),
6.70e6.68 (1H, m), 6.15e6.13 (1H, m), 5.95e5.94 (1H, m), 3.73 (2H,
t, J¼5.9 Hz), 2.75 (2H, t, J¼7.3 Hz), 2.72 (1H, br), 1.93e1.87 (2H, m).
(CDCl3, 500 MHz)
d
: 7.09 (1H, s), 6.91 (1H, d, J¼3.9 Hz), 6.28 (1H, d,
J¼3.9 Hz), 6.12 (1H, s), 3.40 (2H, t, J¼7.0 Hz), 3.05 (2H, t, J¼7.4 Hz),
13C NMR (CDCl3, 100 MHz)
d: 131.8, 116.4, 108.3, 105.2, 62.3, 32.2,
2.57 (3H, s), 2.27 (3H, s), 2.07e2.01 (2H, m). 13C NMR (CDCl3,
24.2. The NMR data is in accordance with the literature.8
125 MHz) d: 160.3, 157.6, 143.7, 135.0, 133.2, 128.1, 123.6, 120.3,
116.5, 50.8, 28.0, 25.6, 14.8, 11.1. IR nmax (film)/cmꢂ1 2959, 2932,
2870, 2091. HRMS (ESI) calcd for C14H17BF2N5 [MþH]þ 304.1545 m/
z, found 304.1528 m/z.
3.1.4. 2-(3-Azidopropyl)-1H-pyrrole, 7. A 0 ꢀC solution of 3-(1H-
pyrrol-2-yl)propan-1-ol 5 (1.00 g, 8.13 mmol) in CH2Cl2 (60 mL)
was treated sequentially with Et3N (2.26 mL, 16.26 mmol) and
methanesulfonyl chloride (755
mL, 9.76 mmol). The resulting re-
3.1.7. Methyl-6-heptynoate, 13.17 A solution of 6-heptynoic acid
action mixture was stirred at 0 ꢀC for 1 h before being allowed to
warm up to rt at which point, TLC analysis indicated reaction
completion. The reaction was then transferred to a separating
funnel and was washed with 1 M HCl (20 mL), followed by aq satd
NaHCO3 (20 mL) and brine (20 mL). The solution was dried over
Na2SO4, filtered and concentrated in vacuo to afford mesylate 6
(1.52 g, 94%). The crude mesylate was then dissolved in DMF
(60 mL), treated with sodium azide (1.48 g, 22.7 mmol) and the
resulting homogeneous solution was heated to 70 ꢀC until com-
pletion as indicated by TLC analysis (16 h). The reaction was cooled
down to rt and diluted with EtOAc (60 mL) and H2O (60 mL). The
layers were separated and the aqueous phase was extracted with
EtOAc (2ꢁ60 mL). The combined organics were washed with brine
(5ꢁ100 mL), dried over Na2SO4, filtered and concentrated in vacuo
to afford azide 7 (947 mg, 88%) as a yellow oil, which required no
(500 mL, 3.95 mmol) in acetone was treated with K2CO3 (273 mg,
1.98 mmol). The mixture was then stirred for 30 min and MeI
(2.5 mL, 39 mmol) was then added. The reaction mixture was
stirred for 18 h and then quenched with aq satd. NaHCO3 (5 mL).
The solution was washed with 10% aq Na2S2O3 (20 mL), brine
(20 mL), and dried over Na2SO4. The solvent was then removed
under vacuum to give 406 mg (75%) of the desired methyl ester 13
as a colourless oil. 1H NMR (CDCl3, 500 MHz)
d: 3.69 (3H, s), 2.36
(2H, t, J¼7.3 Hz), 2.23 (2H, td, J¼7.0, 2.6 Hz), 1.95 (1H, t, J¼2.7 Hz),
1.81e1.75 (2H, m), 1.62e1.56 (2H, m). 13C NMR (CDCl3, 125 MHz)
d:
174.1, 83.8, 68.6, 51.4, 33.4, 27.9, 23.9, 18.0.
3.1.8. 2-Propynyl 5-(1,2-dithiolan-3-yl)pentanoate, 14. A solution of
propargyl alcohol (130 L, 2.2 mmol) in CH2Cl2 (30 mL) was
m
treated with thioctic acid (500 mg, 2.42 mmol) and the resulting
mixture was stirred for 30 min at 0 ꢀC. The solution was then
treated with EDC (404 mg, 2.42 mmol) followed by DMAP
(188 mg, 1.54 mmol). The reaction mixture was allowed to warm
up to rt and was then stirred for 18 h. The reaction was then
washed with water (30 mL), brine (30 mL), and the organic phase
was dried over Na2SO4. The solution was then concentrated under
reduced pressure to yield a crude oil, which was then purified by
flash column chromatography (silica gel, 20% EtOAc/petroleum
ether) to afford 505 mg (94%) of the desired ester as a yellow oil.
further purification. 1H NMR (CDCl3, 400 MHz)
d: 7.98 (1H, br s),
6.70e6.69 (1H, m), 6.16e6.15 (1H, m), 5.96e5.95 (1H, m), 3.34 (2H,
t, J¼6.6 Hz), 2.73 (2H, t, J¼7.4 Hz), 1.95e1.89 (2H, m). 13C NMR
(CDCl3, 100 MHz) d: 130.7, 116.5, 108.5, 105.5, 50.7, 28.9, 24.7. IR nmax
(film)/cmꢂ1 3379, 2940, 2870, 2091. HRMS (EI) calcd for C7H11N4
[MþH]þ 151.0984 m/z, found 151.0987 m/z.
3.1.5. 2-Formyl-3,5-dimethyl-1H-pyrrole, 8. POCl3 (1.00 mL, 11
mmol) was added dropwise at 0 ꢀC to DMF (20 mL) and the
resulting mixture was stirred for 5 min. The solution was then
stirred at rt for 30 min before being cooled back down to 0 ꢀC. The
solution was then treated with 3,5-dimethyl-1H-pyrrole (1.0 mL,
The NMR data obtained is in accordance with the literature.14 1
NMR (CDCl3, 500 MHz)
: 4.61 (2H, d, J¼2.4 Hz), 3.50 (1H, ddt,
J¼14.8, 8.3, 6.4 Hz), 3.14e3.09 (1H, m), 3.07e3.02 (1H, m),
H
d

A.M. Hansen et al. / Tetrahedron 69 (2013) 8527e8533
8531
2.43e2.36 (1H, m), 2.41 (1H, t, J¼2.4 Hz), 2.31 (2H, t, J¼7.5 Hz),
1.88e1.80 (1H, m), 1.69e1.57 (4H, m), 1.49e1.34 (2H, m). 13C NMR
27.5, 25.7, 14.8, 11.1. IR nmax (film)/cmꢂ1 2960, 2924, 2848, 1599,
1527, 1481. Mp 85e88 ꢀC.
(CDCl3, 125 MHz)
d
: 172.8, 77.7, 74.9, 56.3, 51.8, 40.2, 38.5, 34.6,
Compound 17b: 1H NMR (CDCl3, 500 MHz)
d: 7.20e7.16 (3H, m),
33.8, 28.7, 24.6. IR nmax (film)/cmꢂ1 3284, 2918, 1735, 1159. HRMS
7.12e7.08 (3H, m), 7.00 (1H, s), 6.82 (1H, d, J¼4.3 Hz), 6.24 (1H, d,
J¼4.3 Hz), 6.03 (1H, s), 4.32 (2H, t, J¼7.4 Hz), 2.99e2.92 (4H, m),
2.90e2.86 (2H, m), 2.49 (3H, s), (2H, quintet, J¼7.4 Hz), 2.18 (3H, s).
(CI/Isobutane) exact mass calculated for
C
11H17O2S2 [M]þ
244.0592 m/z, found 244.0595 m/z.
13C NMR (CDCl3, 125 MHz)
d: 160.5, 157.1, 150.9, 143.9, 141.1, 135.3,
3.1.9. 7-(3-(4-((tert-Butyldimethylsilyloxy)methyl)-1H-1,2,3-triazol-
1-yl)propyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:10,20-f]
[1,3,2]diazaborinin-4-ium-5-uide, 15. A solution of tert-butyldime-
thyl(prop-2-ynyloxy)silane 10 (37 mg, 0.21 mmol) in THF (2 mL)
was treated with azido-BODIPY 9 (50 mg, 0.16 mmol), CuI (5 mg,
133.3, 128.5, 128.3, 128.0, 126.0, 125.5, 123.7, 120.4, 116.7, 50.1, 35.2,
30.3, 28.2, 25.5,14.9,11.2. IR nmax (film)/cmꢂ13122,þ3028, 2541, 2848,
1599, 1529, 1485, 775. Mp 120e124 ꢀC. HRMS (EI ) exact mass cal-
culated for C24H26BF2N5 [MþH]þ 433.2249 m/z, found 433.2246 m/z.
0.03 mmol), DIPEA (100
m
L, 0.59 mmol) in a sealed tube. The re-
3.1.12. 5,5-Difluoro-7-(3-(4-(7-methoxy-7-oxoheptyl)-1H-1,2,3-
triazol-1-yl)propyl)-1,3-dimethyl-5H-dipyrrolo[1,2-c:10,20-f][1,3,2]di-
azaborinin-4-ium-5-uide, 18. A solution of methyl-6-heptynoate 13
(30 mg, 0.21 mmol) in THF (2 mL) was treated with azido-BODIPY 9
action mixture was then heated up to 70 ꢀC for 18 h. Solvent
evaporation followed by purification of the crude residue by flash
column chromatography (silica gel, elution gradient 25e50%
EtOAc/petroleum ether) afforded 66 mg (85%) of the desired tri-
azole 15 as an orange solid. Mp 93e95 ꢀC. 1H NMR (CDCl3,
(50 mg, 0.16 mmol), CuI (5 mg, 0.03 mmol), DIPEA (100
mL,
0.59 mmol) in a sealed tube. The reaction mixture was then heated
up to 70 ꢀC for 18 h. Solvent evaporation followed by purification of
thecrude residue byflashcolumnchromatography(silicagel, elution
gradient 50e100% Et2O/petroleum ether) afforded 61 mg (83%) of
400 MHz)
d
: 7.50 (1H, s), 7.09 (1H, s), 6.89 (1H, d, J¼4.2 Hz), 6.26
(1H, d, J¼4.2 Hz), 6.12 (1H, s), 4.84e4.83 (2H, m), 4.41 (2H, t,
J¼7.3 Hz), 3.03 (2H, t, J¼7.6 Hz), 2.57 (3H, s), (2H, quint, J¼7.4 Hz),
2.26 (3H, s), 0.91 (9H, s), 0.09 (6H, s). 13C NMR (CDCl3, 125 MHz)
d:
the desired triazole 18 as an orange oil. 1H NMR (CDCl3, 400 MHz)
d:
160.4, 157.0, 148.6, 143.8, 135.2, 133.3, 128.0, 123.8, 121.6, 120.5,
116.8, 57.9, 49.7, 29.5, 25.8, 25.7, 23.7, 18.3, 14.8, 11.1, ꢂ5.3. IR nmax
(film)/cmꢂ1 2951, 2928, 2858, 1600, 1259. HRMS (CI/Isobutane)
exact mass calculated for C23H35BF2N5OSi [MþH]þ 474.2672 m/z,
found 474.2677 m/z.
7.36 (1H, s), 7.13 (1H, s), 6.92 (1H, d, J¼3.9 Hz), 6.29 (1H, d, J¼3.9 Hz),
6.16 (1H, s), 4.43 (2H, t, J¼6.9 Hz), 3.70 (3H, s), 3.05 (2H, t, J¼7.5 Hz),
2.77e2.73 (2H, m), 2.60 (3H, s), 2.43e2.35 (4H, m), 2.29 (3H, s),
1.76e1.71 (4H, m). 13C NMR (CDCl3, 125 MHz)
d: 174.1, 160.5, 157.1,
147.8, 144.1, 135.2, 133.4, 128.2, 123.8, 120.7, 120.4, 116.8, 51.2, 49.5,
33.7, 30.4, 29.4, 28.8, 25.7, 25.3, 14.8, 11.2. IR nmax (film)/cmꢂ1 2947,
2926, 2858, 1732, 1599, 1435, 729. HRMS (CI/Isobutane) exact mass
3.1.10. 5,5-Difluoro-7-(3-(4-(3-methoxy-2-(methoxycarbonyl)-3-
oxopropyl)-1H-1,2,3-triazol-1-yl)propyl)-1,3-dimethyl-5H-dipyrrolo
[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 16. A solution of di-
calculated for
444.2387 m/z.
C
22H28BF2N5O2 [MþH]þ 444.2382 m/z, found
methyl 2-(prop-2-ynyl)malonate11 (32
mL, 0.21 mmol) inTHF (2 mL)
was treated with azido-BODIPY 9 (50 mg, 0.16 mmol), CuI (5 mg,
3.1.13. 7-(3-(4-((5-(1,2-Dithiolan-3-yl)pentanoyloxy)methyl)-1H-
1,2,3-triazol-1-yl)propyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo
[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 19. A solution of 2-
propynyl 5-(1,2-dithiolan-3-yl)pentanoate 14 (40 mg, 0.16 mmol)
in THF (2 mL) was treated with azido-BODIPY 9 (41 mg, 0.14 mmol),
0.03 mmol), DIPEA (100 mL, 0.59 mmol) in a sealed tube. The reaction
mixture was then heated up to 70 ꢀC for 18 h. Solvent evaporation
followed by purification of the crude residue by flash column
chromatography (silica gel, elution gradient 50e80% Et2O/petro-
leum ether) afforded 64 mg (82%) of the desired triazole 16 as an
CuI (5 mg, 0.03 mmol), DIPEA (100 mL, 0.59 mmol) in a sealed tube.
orange solid. Mp 117e119 ꢀC. 1H NMR (CDCl3, 500 MHz)
d: 7.29 (1H,
The reaction mixture was then heated up to 70 ꢀC for 18 h. Solvent
evaporation followed by purification of the crude residue by flash
column chromatography (silica gel, elution gradient 50e100% Et2O/
petroleum ether) afforded 50 mg (68%) of the desired triazole 19 as
s), 7.00 (1H, s), 6.80 (1H, d, J¼4.0 Hz), 6.16 (1H, d, J¼4.0 Hz), 6.04 (1H,
s), 4.30 (2H, t, J¼7.6 Hz), 3.81 (1H, t, J¼7.4 Hz), 3.64 (6H, s), 3.33 (2H, d,
J¼7.4 Hz), 3.03 (2H, t, J¼7.3 Hz), 2.59 (3H, s), 2.37 (2H, quintet,
J¼7.4 Hz), 2.28 (3H, s). 13C NMR (CDCl3, 125 MHz)
d
: 169.1, 160.7,
an orange oil. 1H NMR (CDCl3, 500 MHz)
d: 7.61 (1H, s), 7.09 (1H, s),
156.8, 143.9 (2C), 135.2, 133.2, 128.2, 123.9, 122.0, 120.5, 116.7, 51.5,
49.7, 30.3, 29.4, 25.6, 25.0, 14.8, 11.2. IR nmax (film)/cmꢂ1 3053, 2958,
2847, 1747, 1730, 1138. HRMS (CI/Isobutane) exact mass calculated
for C22H27BF2N5O4 [MþH]þ 474.2124 m/z, found 474.2128 m/z.
6.88 (1H, d, J¼3.9 Hz), 6.25 (1H, d, J¼3.9 Hz), 6.13 (1H, s), 5.20 (2H, s),
4.43 (2H, t, J¼7.4 Hz), 3.57e3.50 (1H, m), 3.19e3.06 (2H, m), 3.02 (2H,
t, J¼7.6 Hz), 2.57 (3H, s), 2.47e2.31 (5H, m), 2.26 (3H, s), 1.92e1.84
(1H, m), 1.70e1.60 (4H, m), 1.43e1.30 (2H, m). 13C NMR (CDCl3,
125 MHz) d: 173.2,160.7,156.6,144.1,142.9,135.4,133.3,128.1,123.9,
3.1.11. 5,5-Difluoro-1,3-dimethyl-7-(3-(4-phenethyl-1H-1,2,3-triazol-
1-yl)propyl)-5H-dipyrrolo[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-
uide, 17a and 5,5-difluoro-1,3-dimethyl-7-(3-(5-phenethyl-1H-1,2,3-
triazol-1-yl)propyl)-5H-dipyrrolo[1,2-c:10,20-f][1,3,2]diazaborinin-4-
123.8, 120.6, 116.6, 57.6, 56.3, 49.8, 40.2, 38.4, 34.5, 33.9, 29.4, 28.6,
25.6, 24.5,14.9,11.2. IR nmax (film)/cmꢂ13005, 2924, 2858,1732,1593,
1479, 1431, 1244, 709. HRMS (ESI) exact mass calculated for
C
25H33BF2N5O2S2 [MþH]þ 548.2137 m/z, 548.2137 found m/z.
ium-5-uide, 17b. A solution of 3-butynylbenzene 12 (30
0.21 mmol) in THF (2 mL) was treated with azido-BODIPY 9 (50 mg,
0.16 mmol), CuI (5 mg, 0.03 mmol), DIPEA (100 L, 0.59 mmol) in
mL,
3.1.14. 7-(3-Aminopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo
[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 20. To a solution of
m
a sealed tube. The reaction mixture was then heated up to 70 ꢀC for
18 h. Solvent evaporation followed by purification of the crude
residue by flash column chromatography (silica gel, elution gradi-
ent 50e80% Et2O/petroleum ether) afforded 60 mg (84%) of the
triazole 17 as a 1:1 mixture of regioisomers.
azido-BODIPY 9 (25 mg, 83
m
mol) in THF (1 mL) was added polymer
bound triphenylphosphine (103 mg, 1.6 mmol gꢂ1) and H2O (50
mL).
The resultant suspension was heated at 50 ꢀC for 4 h, following re-
action progress by TLC. Upon completion, the suspension was
allowed to cool down to rt before filtering through a bed of Celite.
Solvent removal under reduced pressure afforded the desired
amino-BODIPY 20 as red oil (70%). The material was used without
any further purification.
Compound 17a: 1H NMR (CDCl3, 500 MHz)
d: 7.21e7.16 (2H, m),
7.11e7.08 (3H, m), 7.06 (1H, s), 6.99 (1H, s), 6.79 (1H, d, J¼4.0 Hz),
6.15 (1H, d, J¼4.0 Hz), 6.03 (1H, s), 4.28 (2H, t, J¼7.1 Hz), 2.96e2.89
(6H, m), 2.48 (3H, s), (2H, quintet, J¼7.3 Hz), 2.17 (3H, s). 13C NMR
(CDCl3, 125 MHz)
d
: 160.4, 157.0, 147.2, 143.9, 141.3, 135.2, 133.3,
3.1.15. General procedure for the coupling of amino-BODIPY 20 to
acid chlorides. To a 0 ꢀC solution of 3-amino-BODIPY 20 (1 equiv) in
128.4, 128.3, 128.1, 126.0, 123.7, 120.9, 120.4, 116.7, 49.5, 35.6, 29.5,

8532
A.M. Hansen et al. / Tetrahedron 69 (2013) 8527e8533
CH2Cl2 was sequentially added the desired acid chloride (1.5 equiv),
DIPEA (1.5 equiv) and a catalytic amount of DMAP. The reaction was
then stirred at 0 ꢀC until completion as indicated by TLC analysis
(1 h). The crude mixture was then concentrated in vacuo and the
crude residue was purified by flash column chromatography (silica
gel, eluting with CH2Cl2) to afford the desired products as red oils.
(1H, d, J¼4.0 Hz), 6.01 (1H, s), 6.00 (1H, br), 3.31e3.28 (2H, m), 3.00
(2H, t, J¼7.2 Hz), 2.57 (3H, s), 2.26 (3H, s), 2.08e2.04 (1H, m),
1.98e1.91 (2H, m), 1.89e1.84 (2H, m), 1.78e1.74 (2H, m), 1.67e1.64
(2H, m), 1.45e1.35 (2H, m), 1.29e1.20 (2H, m). 13C NMR (CDCl3,
100 MHz) d: 176.26, 159.5, 159.3, 143.5, 134.8, 133.2, 128.7, 123.6,
120.2, 117.1, 45.6, 38.4, 29.6, 28.8, 25.9 (2C), 25.7, 14.9, 11.3. IR nmax
(film)/cmꢂ1 3423, 3291, 2926, 2853, 1599. HRMS (ESI) calcd for
3.1.16. 7-(3-Benzamidopropyl)-5,5-difluoro-1,3-dimethyl-5H-di-
pyrrolo[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 25. 3-Amino-
C
21H28BF2N3NaO [MþNa]þ 410.2186 m/z, found 410.2184 m/z.
BODIPY 20 (18 mg, 65
cooled down to 0 ꢀC before the sequential addition of benzoyl
chloride (12 L, 97 mol), DIPEA (17 L, 97 mol) and DMAP (cat).
m
mol) was dissolved in CH2Cl2 (0.5 mL) and
3.1.20. (E)-5-Styryl-1H-pyrrole-2-carboxaldehyde, 30. POCl3 (163 mL,
1.11 mmol) was added dropwise to DMF (5 mL) at 0 ꢀC and the
resulting mixture was stirred for 5 min. The solution was then
warmeduptortandstirredforanadditional30min. Thereactionwas
then cooled back down to 0 ꢀC, and treated with (E)-2-styryl-1H-
pyrrole 2912 (171 mg, 1.0 mmol). The resulting reaction mixture was
left to warm up to rt and subsequently heated to 40 ꢀC for 18 h. The
reaction was then cooled back down to rt and diluted with EtOAc
(30 mL). The solution was washed with H2O (8ꢁ20 mL), brine
(3ꢁ20 mL), dried (Na2SO4) and concentrated invacuo to yield a crude
dark brown solid. Purification of the crude residue by flash column
chromatography(50%Et2O/petroleumether) afforded48 mg(24%) of
m
m
m
m
TLC analysis showed reaction completion after 1 h. Column chro-
matography (neat CH2Cl2) afforded the desired amide 25 as red oil
(12 mg, 48%). 1H NMR (CDCl3, 400 MHz)
d: 7.81e7.79 (2H, m),
7.48e7.44 (1H, m), 7.39e7.35 (2H, m), 7.05 (1H, s), 6.90 (1H, d,
J¼4.0 Hz), 6.88 (1H, br), 6.34 (1H, d, J¼4.0 Hz), 6.14 (1H, s),
3.52e3.49 (2H, m), 3.10 (2H, t, J¼7.2 Hz), 2.60 (3H, s), 2.27 (3H, s),
2.13e2.06 (2H, m). 13C NMR (CDCl3,100 MHz)
d: 167.36,159.5,159.4,
143.5,134.8,134.7, 133.2,131.1,128.9,128.3,127.0,123.6,120.2,117.2,
39.0, 28.9, 25.8, 14.9, 11.3. IR nmax (film)/cmꢂ1 3416, 3306, 2957,
2920, 2851, 1597. HRMS (ESI) calcd for C21H22BF2N3NaO [MþNa]þ
404.1716 m/z, found 404.1715 m/z.
aldehyde 30 as a dark brown solid.1H NMR (CDCl3, 400 MHz)
d: 10.15
(1H, br s), 9.51 (1H, s), 7.54e7.50 (2H, m), 7.42e7.37 (2H, m),
7.34e7.29 (1H, m), 7.16 (1H, d, J¼16.6 Hz), 7.03 (1H, d, J¼16.5 Hz), 7.01
(1H, dd, J¼4.0, 2.3 Hz), 6.52 (1H, dd, J¼4.0, 2.3 Hz). 13C NMR (CDCl3,
3.1.17. 5,5-Difluoro-1,3-dimethyl-7-(3-(3-methylbut-2-enamido)pro-
pyl)-5H-dipyrrolo[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide,
100 MHz) d: 178.5,139.0,136.3,132.9,130.9,128.8,128.3,126.6,122.9,
26. 3-Amino-BODIPY 20 (14 mg, 51
(0.5 mL) and cooled down to 0 ꢀC before being treated with 3,3-
dimethyl acryloyl chloride (11 L, 76 mol), DIPEA (13 L, 76 mol)
mmol) was dissolved in CH2Cl2
117.3, 110.7. IR nmax (film)/cmꢂ1 3209, 2958, 2922, 2852, 1631. HRMS
(EIþ) calcd for C13H11NO [M]þ 197.0841 m/z, found 197.0843 m/z.
m
m
m
m
and DMAP (cat). TLC analysis showed reaction completion after 1 h.
Column chromatographyof the crude residue (neat CH2Cl2) afforded
the desired amide 26 as a red oil (10 mg, 55%). 1H NMR (CDCl3,
3.1.21. 3(E)-7-(3-Azidopropyl)-5,5-difluoro-3-styryl-5H-dipyrrolo
[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 31. A 0 ꢀC solution of
2-(3-azidopropyl)-1H-pyrrole 8 (48 mg, 0.24 mmol) and 5-styryl-
1H-pyrrole-2-carboxaldehyde 30 (33 mg, 0.22 mmol) in CH2Cl2
400 MHz)
d
: 7.09 (1H, s), 6.92 (1H, d, J¼4.0 Hz), 6.32 (1H, d, J¼4.0 Hz),
6.12 (1H, s), 5.86 (1H, br), 5.53e5.52 (1H, m), 3.38e3.28 (2H, m), 3.02
(2H, t, J¼7.2 Hz), 2.58 (3H, s), 2.26 (3H, s), 2.15 (2H, d, J¼1.2 Hz),
(5 mL) was treated by the dropwise addition of POCl3 (22 mL,
0.24 mmol). The mixture was then allowed to warm up to rt and
was then stirred for 6 h before being cooled back down again to
0 ꢀC. Once at 0 ꢀC, the reaction mixture was treated with BF3$(OEt)2
2.01e1.95 (2H, m),1.82 (2H, d, J¼1.2 Hz).13C NMR (CDCl3,100 MHz)
d:
167.1, 159.5, 159.3, 150.1, 143.4, 134.8, 133.2, 128.7, 123.6, 120.1, 118.8,
117.1, 38.2, 28.8, 27.1, 25.8, 19.7, 14.9, 11.3. IR nmax (film)/cmꢂ1 3418,
3298, 2955, 2924, 2857, 1597. HRMS (ESI) calcd for C19H24BF2N3NaO
[MþNa]þ 382.1853 m/z, found 382.1857 m/z.
(109
mL, 0.89 mmol) and N,N-diisopropylethylamine (162 mL,
0.93 mmol). The reaction was then allowed to warm up to rt and
was stirred for a further 12 h. The reaction was then diluted with
H2O (10 mL) and CH2Cl2 (5 mL) before being filtered through a bed
of Celite. The Celite was washed with CH2Cl2 (2ꢁ10 mL), and the
organic phases were combined, dried over Na2SO4 and concen-
trated under reduced pressure to yield a dark pink/purple solid.
Purification of the crude residue by flash column chromatography
(silica gel, elution gradient 15e20% Et2O/petroleum ether) afforded
79 mg (86%) of the desired azide (79 mg, 86%) as a purple oil, which
solidified upon standing. Mp 137e138 ꢀC. 1H NMR (CDCl3,
3.1.18. 7-(3-Butyramidopropyl)-5,5-difluoro-1,3-dimethyl-5H-di-
pyrrolo[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide, 27. 3-Amino-
BODIPY 20 (11 mg, 39
cooled down to 0 ꢀC before being treated with butyryl chloride (6
59 mol), DIPEA (10 L, 59 mol) and DMAP (cat). TLC analysis
mmol) was dissolved in CH2Cl2 (0.5 mL) and
mL,
m
m
m
showedreactioncompletionafter1h.Columnchromatographyofthe
crude residue (neat CH2Cl2) afforded the desired amide 27 as a red oil
(7 mg, 51%). 1H NMR (CDCl3, 400 MHz)
d: 7.09 (1H, s), 6.93 (1H, d,
500 MHz)
d
: 7.63 (1H, d, J¼16.4 Hz), 7.64e7.62 (2H, m), 7.43e7.33
J¼4.0), 6.32(1H, d, J¼4.0 Hz), 6.12(1H, s), 6.00(1H, br), 3.32e3.28(2H,
m), 3.02(2H, t, J¼7.2Hz), 2.57(3H, s), 2.26(3H, s), 2.12(2H, t,J¼7.5 Hz),
2.00e1.93 (2H, m), 1.69e1.60 (2H, m), 0.94 (3H, t, J¼7.4 Hz). 13C NMR
(4H, m), 7.08 (1H, s), 7.04 (1H, d, J¼4.3 Hz), 6.98 (1H, d, J¼4.3 Hz),
6.92 (1H, d, J¼4.4 Hz), 6.37 (1H, d, J¼4.0 Hz), 3.44 (2H, t, J¼6.7 Hz),
3.14 (2H, t, J¼7.9 Hz), 2.11e2.05 (2H, m). 13C NMR (CDCl3, 125 MHz)
(CDCl3,100 MHz)
d: 173.1,159.6,159.2,143.5,134.9,133.2,128.7,123.6,
d: 160.0, 156.2, 137.7, 136.3, 136.2, 134.9, 130.2, 129.3 (2C), 128.8,
120.2, 117.1, 38.8, 38.4, 28.7, 25.7, 19.1, 14.9, 13.8, 11.3. IR nmax (film)/
127.6, 125.6, 119.0, 117.9, 116.7, 50.9, 28.0, 26.0. IR nmax (film)/cmꢂ1
2956, 2924, 2858, 2096. HRMS (ESI) calcd for C20H19BF2N5 [MþH]þ
378.1702 m/z, found 378.1690 m/z.
cmꢂ1 3420, 3295, 2961, 2928, 2872, 1597. HRMS (ESI) calcd for
C
18H24BF2N3NaO [MþNa]þ 370.1873 m/z, found 370.1881 m/z.
3.1.19. 7-(3-(Cyclohexanecarboxamido)propyl)-5,5-difluoro-1,3-
dimethyl-5H-dipyrrolo[1,2-c:10,20-f][1,3,2]diazaborinin-4-ium-5-uide,
Acknowledgements
28. 3-Amino-BODIPY 20 (11 mg, 39
(0.5 mL) and cooled down to 0 ꢀC before being treated with
cyclohexanecarbonyl chloride (8 L, 59 mol), DIPEA (10 L,
59 mol) and DMAP (cat). TLC analysis showed reaction completion
mmol) was dissolved in CH2Cl2
We would like to thank Dr. Ian Sword, the EPSRC and the Uni-
versity of Glasgow for funding.
m
m
m
m
References and notes
after 1 h. Column chromatography of the crude residue (neat
CH2Cl2) afforded the desired amide 28 as red oil (9 mg, 59%). 1H
1. Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891e4932.
NMR (CDCl3, 400 MHz)
d: 7.09 (1H, s), 6.93 (1H, d, J¼4.0 Hz), 6.31
2. Treibs, A.; Kreuzer, F. eH. Justus Liebigs Ann. Chem. 1968, 718, 208e223.

A.M. Hansen et al. / Tetrahedron 69 (2013) 8527e8533
8533
3. Ziessel, R.; Ulrich, G.; Harriman, A. Angew. Chem., Int. Ed. 2008, 47, 1184e1201.
4. BODIPY, Molecular Probes, Invitrogen.
therefore, any request should be accompanied by the full literature citation of
this paper.
5. Verdoes, M.; Florea, B. I.; Hillaert, U.; Willems, L. I.; van der Linden, W. A.; Sae-
Heng, M.; Filippov, D. V.; Kisselev, A. F.; van der Marel, G. A.; Overkleeft, H. S.
ChemBioChem 2008, 9, 1735e1738.
11. a) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057e3064;
b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596e2599; c) Kele, P.; Li, X.; Link, M.; Nagy, K.; Herner, A.; Lor-
incz, K.; Beni, S.; Wolfbeis, O. S. Org. Biomol. Chem. 2009, 7, 3486e3490.
12. Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939e1941.
13. Spaggiari, A.; Vaccari, D.; Davoli, P.; Prati, F. Synthesis 2006, 6, 995e998.
14. Crystal data for 31: C26H39BF2N4O6, Mr¼552.42, orthorhombic system, space
~
ꢀ
ꢀ
ꢀ
~
6. Banuelos, J.; Martín, V.; Gomez-Duran, C. F. A.; Cordoba, I. J. A.; Pena-Cabrera,
ꢀ
E.; García-Moreno, I.; Costela, A.; Perez-Ojeda, M. E.; Arbeloa, T.; Arbeloa, I. L.
Chem.dEur. J. 2011, 17, 7261e7270.
€
7. Gießler, K.; Griesser, H.; Gohringer, D.; Sabirov, T.; Richert, C. Eur. J. Org. Chem.
3
ꢁ
ꢁ
2010, 3611e3620.
group P212121, a¼6.6680(3), b¼11.6004(5), c¼37.70993(15) A, V¼2869.7(3) A .
ꢁ
8. Kray, L. R.; Reinecke, M. G. J. Org. Chem. 1967, 32, 225e227.
9. Liu, X.; Nan, H.; Sun, W.; Zhang, Q.; Zhan, M.; Zou, L.; Xie, Z.; Li, X.; Lu, C.; Cheng,
Y. Dalton Trans. 2012, 41, 10199e10210.
Z¼4, rcalcd¼1.279
g
cmꢂ3
;
MoK radiation,
l
¼0.71073 A,
m
¼0.098 mmꢂ1
,
a
T¼150 K. 21167 data (5515 unique, Rint¼0.0496,
q
<25.8ꢀ). Data were collected
on a Bruker APEXII CCD diffractometer and were corrected for absorption
(transmission 0.971e0.997). The structure was solved by direct methods and
refined by full-matrix least-squares on F2 to give wR2¼0.1405, R1¼0.0576, S¼1.
058 for 371 parameters. Residual electron density extrema were 0.51 and ꢂ0.
10. Crystal data for 9: C14H16BF2N5, Mr¼303.13, monoclinic system, space group
P21/c, a¼24.5866(9), b¼15.2241(5), c¼11.7801(4) A,
b
¼97.089(2)ꢀ, V¼4375.7(3)
ꢁ
3
A . Z¼12, rcalcd¼1.380 g cmꢂ3; MoK radiation,
l
¼0.71073 A,
m
¼0.104 mmꢂ1
,
ꢁ
ꢁ
a
3
ꢁ
T¼150 K. 34251 data (8612 unique, Rint¼0.0448,
q
<26ꢀ). Data were collected on
47 e A . The atomic coordinates for 31 (CCDC deposition number CCDC908573)
are available upon request from the Cambridge Crystallographic Centre, Uni-
versity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1 EW, United
Kingdom. The crystallographic numbering system differs from that used in the
text; therefore, any request should be accompanied by the full literature cita-
tion of this paper.
a Bruker APEXII CCD diffractometer and were corrected for absorption (trans-
mission 0.970e0.997). The structure was solved by direct methods and refined
by full-matrix least-squares on F2 to give wR2¼0.1144, R1¼0.0449, S¼1.014 for
3
ꢁ
601 parameters. Residual electron density extrema were 0.27 and ꢂ0.31 e A .
The atomic coordinates for 9 (CCDC deposition number CCDC908572) are
available upon request from the Cambridge Crystallographic Centre, University
Chemical Laboratory, Lensfield Road, Cambridge, CB2 1 EW, United Kingdom.
The crystallographic numbering system differs from that used in the text;
15. Zhang, G.-F.; Zhan, J.-Y.; Li, H.-B. Org. Lett. 2011, 13, 3392e3395.
16. Xia, Y.; Whitesides, G. Angew. Chem., Int. Ed. 1998, 37, 550e575.
17. Rodini, D. J.; Snider, B. B. Tetrahedron Lett. 1980, 21, 3857e3860.