Synthesis of 3-aminoBODIPY dyes via copper-catalyzed vicarious nucleophilic substitution of 2-halogeno derivatives

Article abstract of DOI:10.1039/c4ob02626h

2-Halogeno BODIPYs undergo copper catalysed nucleophilic substitution with alkyl amines and anilines and an amide to give the corresponding 3-aminoBODIPY derivatives. The substrates are readily prepared by the regioselective 2-halogenation of the chemically robust, preformed BODIPYs thus providing an alternative to direct nucleophilic substitution of the corresponding 3-halogenoBODIPYs which requires regioselective 3-halogenation of the more sensitive dipyrromethane intermediate. 2-Halogenation expands the scope of vicarious substitution of BODIPYs to include weaker nitrogen nucleophiles.

Full text of DOI:10.1039/c4ob02626h

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Synthesis of 3-aminoBODIPY dyes via copper-
catalyzed vicarious nucleophilic substitution of
2-halogeno derivatives†
Cite this: DOI: 10.1039/c4ob02626h
Julian G. Knight,* Rua B. Alnoman and Paul G. Waddell
2-Halogeno BODIPYs undergo copper catalysed nucleophilic substitution with alkyl amines and anilines
and an amide to give the corresponding 3-aminoBODIPY derivatives. The substrates are readily prepared
by the regioselective 2-halogenation of the chemically robust, preformed BODIPYs thus providing an
alternative to direct nucleophilic substitution of the corresponding 3-halogenoBODIPYs which requires
regioselective 3-halogenation of the more sensitive dipyrromethane intermediate. 2-Halogenation
expands the scope of vicarious substitution of BODIPYs to include weaker nitrogen nucleophiles.
Received 18th December 2014,
Accepted 16th February 2015
DOI: 10.1039/c4ob02626h
www.rsc.org/obc
as biological markers and fluorescence probes for reporting on
the intracellular environment,3 organic light emitting diodes
Introduction
Boron dipyrromethenes (BODIPY, Fig. 1)1 are fluorescent dyes and laser dyes,4 and as the photosensitizer for applications in
which display high molar absorption coefficients, high fluo- photocatalysis,5 photodynamic therapy6 and dye-sensitized
rescence quantum yields, narrow absorption and emission solar cells.7
bandwidths, and excitation and emission wavelengths in the
BODIPYs containing a pendant amine which is able to act
visible/near infra red region.2 The absorption and emission as an electron donor often display significant conjugative
characteristics can be fine-tuned by modification of the substi- effects on the position of the absorption and emission
tuents on the periphery of the BODIPY core. These favourable maxima and/or fluorescence quenching due to intramolecular
photophysical properties are complemented by chemical and charge transfer. These effects can in principle be attenuated by
photochemical robustness, including stability to air, water, co-ordination of the nitrogen lone pair to a Lewis or Brønsted
and irradiation, a low tendency for self-aggregation in solu- acid, leading to restoration of the BODIPY fluorescence (switch
tion, good solubility in many organic solvents, and good syn- on sensors).8 Although the majority of the reported amine-con-
thetic accessibility. As a result, they have found extensive use taining BODIPYs have the nitrogen appended to a substituent,
there are a number of examples in which the amine is directly
substituted onto the BODIPY core and these have recently
been the subject of very detailed structural and photophysical
investigations motivated by the high level of current interest in
elucidating the effects of the nature of the substituents on the
properties of these fluorophores.9
The introduction of amine substituents directly linked to
Fig. 1 Numbering scheme for 4,4-difluoro-4-bora-3a,4a-diaza-s-inda-
the BODIPY core is normally achieved by nucleophilic substi-
cene (BODIPY).
tution (SNAr) of a BODIPY carrying a suitable nucleofuge (e.g.
halogen, methylthio, or methoxy).9,10 In principle, because of
the electronic requirements for SNAr, aminolysis of halogen-
oBODIPYs is expected only to be possible in the 1,3,5,7, and
8 (meso) positions because attack at these positions allows the
School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
E-mail: julian.knight@ncl.ac.uk
†Electronic supplementary information (ESI) available: Modified synthetic pro-
cedures for previously reported compounds 1 and 6, X-ray crystal structure of
resulting intermediate anion to be effectively delocalised onto
one of the nitrogen atoms of the BODIPY core.
An interesting alternative to SNAr displacement of 3-halo-
genoBODIPYs is the vicarious oxidative nucleophilic hydrogen
substitution by amines which occurs in the 3-position of un-
halogenated 8-arylBODIPYs in the presence of a stoichiometric
compound 4a, Schemes showing potential redox and base catalysed halogen
dance mechanisms which were discounted by experiment, copies of NMR
spectra for all compounds, and CIF files giving details of crystal data, structure
solution, and refinement, atomic coordinates, bond distances, bond angles, and
anisotropic displacement parameters for compounds 4a and 5a. CCDC
1040230–1040231. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob02626h
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
oxidant (DDQ, CAN, permanganate, or O2). This reaction is
reported to be successful for primary and secondary alkyl
amines but to fail in the case of anilines.11
We report here a related copper catalysed amination12 of
2-halogenoBODIPYs which allows substitution at the 3-posi-
tion to take place with a wider range of amine nucleophiles
than the oxidative hydrogen substitution, to include more
weakly nucleophilic anilines and even an amide.
Scheme 2 Cu/CuI catalysed amination of BODIPY 2.
Results and discussion
Synthesis of the 2-iodoBODIPY 2
mise the yield of this reaction we screened a series of bidentate
ligands L1–L4 (Fig. 2). Buchwald has reported the use of the
diketone L1 for room temperature amination of aryl halides,
including 3-iodothiophene,15 Ding has reported the use of
β-ketopyridine L2, which is prepared in one step from tetra-
hydroquinoline, for amination of aryl halides,16 and N,N′-
dimethyl ethylenediamine17 L3 and 1,10-phenanthroline18 L4
are commonly used ligands for copper catalysed aminations.
Table 1 shows the results of the amination of the 2-iodo-
BODIPY 2 catalysed by copper(I)iodide in the presence of
ligands L1–L4. The choice of solvent, base, catalyst and ligand
The 2-unsubstituted BODIPY 1 was prepared in good yield
using a standard synthetic sequence2b from pyrrole and anisal-
dehyde via boron trifluoride-etherate catalysed condensation
to the dipyrromethane,13 DDQ oxidation to the corresponding
dipyrromethene and reaction with boron trifluoride-etherate
(Scheme 1). Regioselective iodination10g of 1 with ICl produced
the 2-iodo-substituted BODIPY 2 together with a minor
amount of the 2,6-diiodide 3 which were separable by column
chromatography.
Copper catalysed amination of 2-iodoBODIPY 2
Although there are many reports of copper catalysed amination
of halogenobenzene derivatives, the amination of 3-halogeno-
5-membered heteroaromatic compounds is much less well
studied. We first attempted to couple the iodoBODIPY 2 with
hexylamine using
a mixture of copper : copper(I) iodide
catalyst in dimethylaminoethanol; conditions reported by
Twieg for the copper catalysed amination of halothiophenes
(Scheme 2).14
We were pleased to observe that amination had occurred,
albeit in only 16% yield, but surprised to find that the product
4a appeared to have been aminated in the 3-position. The
structural assignment of 4a was confirmed unambiguously by
X-ray structure determination (Fig. S1, ESI†).
Fig. 2 Ligands screened in the amination of 2-iodoBODIPY 2.
Table 1 Ligand variation in the amination of iodoBODIPY 2
In this amination, dimethylaminoethanol acts both as a
ligand for the copper and also as the solvent. In order to opti-
Entrya
R
Ligand
Product
Yieldb
1
2
3
4
5
6
7
8
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
CH3(CH2)5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
PhCO
L1
L2
L3
L4
L1
L2
L3
L4
L1
L2
L3
L4
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4c
4c
30
20
35
60
6
70
30
84
6
9
10
11
12
PhCO
PhCO
PhCO
11
10
15
a Reagents and conditions: BODIPY 2 (0.235 mmol), amine/amide
(0.470 mmol), CuI (5 mol%), ligand (20 mol%), Cs2CO3 (0.470 mmol),
DMF (0.8 mL), 80 °C, 24 h. b Isolated yield of 3-substituted product 4.
Scheme 1 Reagents: (a) BF3.OEt2, rt, 4 h (87%); DDQ, CH2Cl2, 0 °C,
30 min; BF3.OEt2, i-Pr2NEt, rt, 2 h (77%); (b) ICl, CH2Cl2–MeOH, rt, 2 h (2,
65%; 3, 15%). (Ar = 4-MeOC6H4).
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
loading were taken from Buchwald’s report15 using L1. Selec-
tion of 80 °C was based on an initial screen of reaction temp-
erature using L3 which indicated that no reaction with
hexylamine was observed at 25 or 50 °C. It was confirmed that
no reaction with hexylamine occurred at room temperature for
any of these ligands.
As shown in Table 1, reaction with n-hexylamine, p-tolui-
dine and benzamide proceeded to give the corresponding
3-substituted products 4a, 4b, and 4c respectively. Ligand L4
(1,10-phenanthroline) proved to give the highest yield regard-
less of the nature of the nucleophile (entries 4, 8, 12). Good
yields were obtained in the case of the primary alkyl amine
(entry 4) and the aniline (entry 8) and the reaction was success-
ful even using the much more weakly nucleophilic benzamide
albeit in low yield (entry 12).
Fig. 3 Structure of 3-amino-6-iodoBODIPY by-product 5 and mole-
cular structure of 5a. Hydrogen atoms have been omitted for clarity. The
asymmetric unit comprises four independent molecules; one is shown
here as the rest are similar.
The substrate scope of this reaction was investigated by
applying these conditions, using phenanthroline (L4), to the
reaction of the 2-iodoBODIPY 2 with a range of alkyl amines
and anilines (Table 2).
The reaction works well with primary alkyl amines (entries
1 and 4–6) and the yields were also good with the secondary
alkyl amines morpholine (entry 7) and pyrrolidine (entry 8).
Yields were high for electron rich (entries 2, 10) primary ani-
lines but were slightly lower in the cases of the less nucleophi-
lic electron deficient anilines (entries 11, 12, 13), the more
sterically hindered ortho-methylaniline (entry 9) and a second-
Scheme 3 Reagents and conditions: pyrrolidine (2.0 eq.), CuI (5 mol%),
ary aniline (entry 14). In several cases the product 4 was L4 (20 mol%), Cs2CO3 (2.0 eq.), DMF, 80 °C, 24 h.
accompanied by formation of a small amount of the corres-
ponding 3-amino-6-iodoBODIPY 5 (Table 2, yields in paren-
thesis, Fig. 3). The structure of this by-product was confirmed
unambiguously by X-ray structure determination in the case of
the hexylamine derivative 5a (Fig. 3).
Table 2 Scope of the amination of iodoBODIPY 2
The reaction is equally successful from the 2-bromoBODIPY
6 which was prepared by treatment of the unsubstituted
BODIPY 1 with NBS (73%). The 2-bromo derivative 6 reacted
with pyrrolidine to give the 3-amino product 4h in 80% yield,
together with a minor amount (5%) of the corresponding
3-amino-6-bromo byproduct 7 (Scheme 3).
Entrya
R1
R2
Product
Yieldb
Surprisingly, the 2,6-diiodoBODIPY 3 is unchanged under
the reaction conditions and does not produce any singly or
doubly aminated products.19
1
2
3
4
CH3(CH2)5
4-MeC6H4
PhCO
H
H
H
H
4a
4b
4c
4d
60 (5)c
84 (5)c
15
PhCH2
64
5
H
4e
65
Mechanism of reaction
No reaction occurs between the iodide 2 and pyrrolidine in the
absence of copper iodide and, as Table 1 indicates, the nature
of the ligand influences the amination yield. In the absence of
any added ligand the amination product 4h was formed in
50% yield (together with a trace of 5h). If the base (Cs2CO3) is
omitted then the product 4h is formed in low yield (14%)
together with 5h (10%). Thus copper is obligatory for the
amination to occur and the ligand and base improve the con-
version.20 Scheme 4 shows a mechanism which is similar to
that proposed for the oxidative hydrogen displacement of non-
halogenated BODIPYs with alkyl amines.11 The necessity for
copper catalysis suggests that the nucleophile might be an
6
7
8
9
10
11
12
13
14
Cyclohexyl
O(CH2CH2)2
CH2CH2CH2CH2
2-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NCC6H4
2-Pyridyl
Ph
H
4f
78 (4)
85
87 (4)
60
78 (6)
66 (13)c
77 (15)c
60 (14)c
40
4g
4h
4i
4j
4k
4l
H
H
H
H
H
Me
4m
4n
a Reagents and conditions: BODIPY 2 (0.235 mmol), amine/amide
(0.470 mmol), CuI (5 mol%), phenanthroline (L4) (20 mol%), Cs2CO3
(0.470 mmol), DMF (0.8 mL), 80 °C, 24 h. b Isolated yield of
3-substituted product 4. c Yield of 6-iodo-3-amino by-product 5 (see
later).
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 3 Absorption and fluorescence data for compounds 1, 4a–n in
THF
λabs (max)/
nm
ε/104 M−1
λem (max)/
nm
BODIPYa
cm−1
Φf b (λex)
1
494
493
508c
500
522
498
496
496
484
476
500
501
508
533
527
500
4.59
3.51
2.09c
4.34
4.69
3.43
3.09
3.56
3.23
4.15
3.07
1.99
4.53
5.34
0.97
1.95
508
525
524c
0.075 (479)
0.026 (484)
0.058c (484)
4a
4ac
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
d
d
—
—
534
525
528
525
0.050 (492)
0.030 (484)
0.033 (485)
0.015 (484)
d
d
—
—
540
0.005 (490)
d
d
—
—
d
d
—
—
565
557
549
0.007 (475)
0.015 (500)
0.022 (497)
Scheme 4 Suggested mechanistic pathway initiated by nucleophilic
attack.
d
d
—
—
a All spectra were recorded in THF. b Φf determined vs. rhodamine 6G
in ethanol (Φf = 0.95)27 as reference. Excitation wavelength (λex/nm)
shown in brackets. c Value determined in cyclohexane. d Virtually non-
fluorescent.
amido copper species such as 8.21 Initial nucleophilic attack at
C-3 leads to an anion 9 which could be copper-bound, corres-
ponding to an amidocupration, but may be delocalised over
the BODIPY π-system. In order to produce the product, iodide
must be lost and this requires protonation at C-2 to give 10 fol-
lowed by base-mediated elimination of HI. There are reports of
the acid- or Lewis-acid-catalysed reaction of nitrogen nucleo-
philes with 3-haloindoles in which substitution occurs at the
adjacent 2-position22 and although these are proposed to be
initiated by protonation the mechanism otherwise resembles
that in Scheme 4.23,24
Isotopic labelling was employed to support the proposed
mechanistic scheme. The 2,6-diiodoBODIPY 3 was converted
to the 6-deuterio-2-iodoBODIPY 11 by palladium catalysed
reduction with dideuterium (Scheme 5). A minor amount
(17%) of the 2,6-dideuteriated BODIPY (2,6-2H2-1) was also
formed but was easily separated by column chromatography.
Amination of the iodide 11 with pyrrolidine produced a 70 : 30
ratio of the 3-amino-6-deuterioBODIPY 12 together with the
regioisomeric 3-amino-2-deuterioBODIPY 13 (Scheme 5).
Formation of 3-amino-6-deuterioBODIPY 12 as the major
product is consistent with the straightforward nucleophilic
substitution mechanism (as shown in Scheme 4), but the pres-
ence of the regioisomeric 2-deuteriated product 13 indicates a
minor pathway involving nucleophilic attack by the amine at
C-5 in the iodoBODIPY 11 (and 2). The unequal ratio of pro-
ducts 12 : 13 rules out any mechanisms involving prior dehalo-
genation to generate the unsubstituted BODIPY 1 in situ. Two
other potential mechanisms, one based on a redox cycle23 and
one on a Base Catalysed Halogen Dance24 were discounted on
the basis of the results above.
Photophysical properties of the 3-aminoBODIPYs 4
The absorption and fluorescence data for the 3-aminoBODIPY
compounds 4a–n and the parent unsubstituted compound 1
are summarized in Table 3.
Fig. 4 shows the absorption and fluorescence spectra for
the parent 8-(4-methoxyphenyl)BODIPY 1, and for the repre-
sentative amine and aniline derivatives 4a and 4l respectively.
The photophysical properties of amino-substituted
BODIPYs have previously been reported in detail.9,10 As shown
in Table 3, all of the compounds have low quantum yields,
and some are essentially non-fluorescent which can be attribu-
ted in part to the free rotation of the aryl substituent in the
Scheme 5 Reagents: (a) D2, Pd/C, CH2Cl2, rt, 5 h (60%); (b) pyrrolidine
(2.0 eq.), CuI (5 mol%), L4 (20 mol%), Cs2CO3 (2.0 eq.), DMF, 80 °C, 24 h
(95%; 12 : 13 = 70 : 30). (Ar = 4-MeOC6H4).
Fig. 4 Absorption spectrum (heavy lines) in terms of the molar absorp-
tion coefficient (ε) and normalised fluorescence spectrum (feint lines)
for 1 ( ), 4a ( ), and 4l ( ) in THF.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
8-position and partly due to the influence of the amine. determined using dilute solutions with an absorbance below
Although low fluorescence of this type of BODIPY might be 0.1 at the excitation wavelength and using Rhodamine 6G (Φf =
considered detrimental it is in fact a key feature in their use as 0.95)27 in ethanol as standard. TLC was carried out on glass
‘switch-on’ fluorescent probes and this has recently been plates pre-coated with silica gel 60F254 and flash column
demonstrated to good effect.8,9g,10f,i The red-shift in the chromatography was performed on Fluorochem LC3025
absorption maximum, relative solvent insensitivity of the emis- (40–63 μm) silica gel. Compounds 1,30 and 610h were prepared
sion maximum, and slight increase in quantum yield in cyclo- by modifications to the reported procedures (see ESI†).
hexane compared to the more polar THF for the hexylamine
X-ray crystal structure analysis
derivative 4a (Table 3) are all in accord with reports on other
3-aminoBODIPYs.4d,9f,10b,n,o,11
Single crystals were prepared by slow diffusion of hexane into
a solution of the compound in chloroform. Crystal structure
data was collected at 150 K on an Oxford Diffraction (Agilent
Technologies) Gemini A Ultra using MoKα radiation (λ =
0.71073 Å) and equipped with an Oxford Cryosystems Cryo-
Conclusions
2-Halogeno BODIPYs undergo copper catalysed vicarious stream open-flow N2 cooling device. Cell refinement, data col-
nucleophilic substitution with alkyl amines and anilines to lection and data reduction were carried out using Oxford
give the corresponding 3-aminoBODIPY derivatives. The Diffraction CrysalisPro.31 The intensities were corrected for
corresponding reaction with a less nucleophilic amide also absorption semi-empirically based on repeated, symmetry-
proceeded albeit in low yield. The observation that the 2,6-di- equivalent reflections in the case of 4a and analytically using a
iodoBODIPY does not react under these conditions allows multi-faceted crystal model in the case of 5a.32
straightforward separation of this byproduct after the
amination.
The structures were solved via direct methods and refined
on F2 values for all unique data. Refinements were performed
There are two existing approaches to these products, but using SHELXL33 within the Olex2 program.34 Hydrogen atoms
both have limitations:
were positioned geometrically and defined as riding on their
(i) Direct nucleophilic substitution of the corresponding parent atoms.
3-halogenoBODIPYs, which requires regioselective introduc-
Materials
tion of the halogen into the 3-position which must be per-
formed either on the somewhat sensitive dipyrromethane
2-Iodo-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-3a,4a-diaza-
intermediate28,10h or involves lengthier synthesis of a haloge- s-indacene 2 and 2,6-diiodo-8-(4-methoxyphenyl)-4,4-difluoro-
nated acylpyrrole;29
4-bora-3a,4a-diaza-s-indacene 3. 8-(4-Methoxyphenyl)-4,4-
(ii) Direct oxidative hydrogen substitution of a 3,5-unsubsti- difluoro-4-bora-3a,4a-diaza-s-indacene 1 (0.200 g, 0.67 mmol)
tuted BODIPY is known11 but this method cannot be used was taken in dry CH2Cl2–MeOH (1 : 1, 48 mL). A solution of ICl
with weak nitrogen nucleophiles such as anilines or amides.
(0.11 g, 0.67 mmol) in MeOH (5 mL) was added to the mixture
dropwise. The mixture was stirred at room temperature for 2 h.
The solvent was then removed under reduced pressure and the
crude product was dissolved in CH2Cl2 (50 mL) and washed
with H2O (2 × 100 mL). The organic layer was dried (MgSO4)
and the solvent was removed under reduced pressure. The
Experimental
General
All manipulations involving air-sensitive materials were resulting red crude product was purified by column chromato-
carried out using standard Schlenk line techniques under an graphy (CH2Cl2–petroleum ether 1 : 1) to give:
atmosphere of nitrogen in flame-dried glassware. CHCl3,
First eluted, the 2,6-diiodide 3 as a pink solid (0.055 g,
1
CH2Cl2 and NEt3 were distilled from CaH2; MeOH and EtOH 15%), mp 246–248 °C. Rf = 0.4 (CH2Cl2–petrol, 1 : 1). H NMR
from magnesium; 1,4-dioxane, Et2O and THF from Na/benzo- (400 MHz, CDCl3) δ 7.85 (s, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.13
phenone; toluene from sodium; and MeCN from K2CO3, under (s, 2H), 7.06 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H).13C NMR
an atmosphere of nitrogen. DMF was dried over activated 4 Å (101 MHz, CDCl3) δ 162.86, 147.74, 145.96, 137.50, 135.93,
molecular sieves and stored under nitrogen. All other chemi- 132.64, 125.62, 114.57, 72.07, 55.75. 11B NMR (128 MHz,
cals were purchased from commercial suppliers and used CDCl3) δ −1.27 (t, JBF = 28.0 Hz). 19F NMR (376 MHz, CDCl3)
without further purification. 1H and 13C{1H} NMR spectra were δ −144.63 (q, JFB = 28.0 Hz). IR (neat): νmax/cm−1: 3113, 2930,
recorded on either a JEOL ECS 400 or a Bruker Avance 300 1725, 1596, 1566, 1528, 1466, 1342, 1246, 1074, 984, 896, 707.
instrument. All NMR were referenced relative to CDCl3 (δH
7.26, δC = 77.16). IR spectra were recorded on a Varian 800 572.8920.
FT-IR Scimitar Series infrared spectrometer. Mass spectra were Second eluted, the monoiodide 2 as a red solid (0.185 g,
=
HRMS-ES Calcd for C16H11BN2OF2I2 + Na+: 572.8920. Found:
1
recorded on Waters ACQUITY UPLC LCT premier MS in posi- 65%), mp 206–208 °C. Rf = 0.3 (CH2Cl2–petrol, 1 : 1). H NMR
tive ion mode. UV-vis and fluorescence spectra were recorded (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.81 (s, 1H), 7.52 (d, J =
at 20 °C on a Shimadzu UV-1800 and Hitachi F2500 machines 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 4H), 6.59 (d, J = 4.3 Hz, 1H),
respectively. Relative fluorescence quantum yields (Φf) were 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.51, 146.73,
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
146.11, 145.22, 135.99, 135.78, 135.08, 133.00, 132.57, 125.95, 3H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.74, 158.94,
119.46, 114.36, 70.73, 55.69. 19F NMR (376 MHz, CDCl3) 136.20, 135.72, 135.01, 134.70, 133.13, 132.91, 132.17, 131.83,
δ −144.72 (q, JFB = 28.0 Hz). 11B NMR (128 MHz, CDCl3) 130.38, 126.96, 122.89, 121.24, 113.97, 113.85, 111.16, 55.50,
δ −1.26 (t, JBF = 28.0 Hz). IR (neat): νmax/cm−1: 3109, 2849, 21.08.
IR
(neat):
νmax/cm−1
:
3368,
2914,
2839,
1721, 1603, 1573, 1532, 1470, 1400, 1349, 1250, 1062, 982, 706. 1606,1580,1523,1489, 1397, 1293, 1241, 1175, 1032, 973, 787.
HRMS-ES Calcd for C16H12BN2OF2I + Na+: 446.9953. Found: 19F NMR (376 MHz, CDCl3) δ −148.37 (q, JFB = 33.0 Hz). 11B
446.9961.
NMR (128 MHz, CDCl3) δ 0.06 (t, JBF = 33.0 Hz).HRMS-ES
Calcd for C23H20BN3OF2 + H+: 404.1742. Found: 404.1740.
6-Iodo-3-((4-methylphenyl)amino)-8-(4-methoxyphenyl)-4,4-
General procedure for copper catalysed amination
2-Iodo-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s- difluoro-4-bora-3a,4a-diaza-s-indacene
indacene 2 (0.100 g, 0.235 mmol), the amine (0.470 mmol), CH2Cl2–petroleum ether (1 : 1). Purple solid (0.007 g, 5%), H
CuI (2.2 mg, 0.01 mmol, mol%) Cs2CO3 (0.154 g, NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.42 (d, J = 3.8 Hz, 2H),
5b. Eluted
with
1
5
0.470 mmol), and 1,10-phenanthroline (8.5 mg, 0.047 mmol, 7.40 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H),
20 mol%) were taken in a flame-dried Schlenk tube and 6.99 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 6.37 (d, J =
flushed with N2 several times. Dry DMF (0.8 mL) was then 4.9 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 1H), 2.37 (s, 3H).13C NMR
added and the mixture was stirred at 80 °C for 24 h. The (101 MHz, CDCl3) δ 160.88, 159.64, 136.79, 136.39, 135.70,
mixture was dissolved in ethyl acetate (30 mL) and washed 134.56, 134.26, 133.53, 132.88, 131.73, 130.44, 126.43, 126.06,
with water (2 × 100 mL). The organic layer was dried (MgSO4) 123.28, 114.00, 112.47, 65.60, 55.52, 21.10. IR (neat): νmax
/
and the solvent was removed under reduced pressure. The cm−1
:
3374.918, 2934.681, 1712.014, 1604.078, 1519.013,
crude product was purified by column chromatography. In all 1477.763, 138.029, 1250.856, 1031.766, 733.380. HRMS-ES
cases the 3-amino-6-iodo byproduct 5 eluted from the column Calcd for C23H19BN3OF2I + Na+: 551.0568. Found: 551.0565.
first and the 3-amino compound 4 second.
3-(N-Benzamido)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-
3-(Hexylamino)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-3a,4a- 3a,4a-diaza-s-indacene 4c. Eluted with CH2Cl2–petroleum
1
diaza-s-indacene 4a. Eluted with CH2Cl2–petroleum ether ether (1 : 1). Orange solid (0.015 g, 15%); H NMR (400 MHz,
(1 : 1). Dark yellow solid (0.056 g, 60%); mp 202–204 °C; 1H CDCl3) δ 9.61 (s, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.67 (s, 1H), 7.63
NMR (400 MHz, CDCl3) δ 7.45–7.37 (m, 3H), 6.97 (dd, J = 6.7, (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.0 Hz, 2H), 7.51 (d, J = 8.4 Hz,
4.7 Hz, 2H), 6.94 (s, 1H), 6.44 (d, J = 3.5 Hz, 1H), 6.33 (dd, J = 2H), 7.39 (d, J = 4.7 Hz, 1H), 7.09 (d, J = 4.7 Hz, 1H), 7.03 (d, J =
3.6, 2.4 Hz, 1H), 6.23 (s, 1H), 6.16 (d, J = 5.0 Hz, 1H), 3.86 (s, 8.4 Hz, 2H), 6.79 (d, J = 3.8 Hz, 1H), 6.53–6.40 (m, 1H), 3.90 (s,
3H), 3.38 (dd, J = 13.5, 6.8 Hz, 2H), 1.75–1.62 (m, 2H), 3H). 13C NMR (101 MHz, CDCl3) δ 164.04, 161.68, 152.47,
1.45–1.35 (m, 2H), 1.34–1.25 (m, 4H), 0.89 (dd, J = 9.0, 4.5 Hz, 142.51, 137.46, 135.05, 133.70, 133.35, 132.55, 132.22, 131.26,
3H). 13C NMR (101 MHz, CDCl3) δ 161.67, 160.49, 136.12, 129.28, 127.61, 127.01, 126.29, 116.29, 114.09, 113.34, 55.60.
133.40, 132.80, 132.75, 131.75, 130.84, 127.15, 119.78, 113.74, 11B NMR (128 MHz, CDCl3) δ −0.15 (t, JBF = 33.1 Hz). 19F NMR
113.39, 110.06, 55.47, 44.82, 31.44, 30.18, 26.32, 22.59, 14.08. (376 MHz, CDCl3) δ −146.81 (q, JFB = 33.1 Hz). IR (neat): νmax
11B NMR (128 MHz, CDCl3) δ −0.01 (t, JBF = 33.5 Hz). 19F NMR cm−1: 3402, 2919, 1692, 1588, 1503, 1444, 1348, 1287, 1250,
(376 MHz, CDCl3) δ −149.24 (q, JFB = 33.5 Hz). IR (neat): νmax 1176, 1057, 1033 977, 699. HRMS-ES Calcd for C23H18BN3O2F2
/
/
cm−1: 3413, 3127, 2923, 1606, 1524, 1471, 1397, 1372, 1243, + Na+: 440.1358. Found: 440.1360.
1178, 1021, 977, 759. HRMS-ES Calcd for C22H26BN3OF2 + Na+:
419.2071. Found: 419.2060.
3-(Benzylamino)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-
3a,4a-diaza-s-indacene 4d. Eluted with CH2Cl2–petroleum
3-(Hexylamino)-6-iodo-8-(4-methoxyphenyl)-4,4-difluoro- ether (1 : 1). Dark orange solid (0.061 g, 61%); mp 132–134 °C;
4-bora-3a,4a-diaza-s-indacene
5a. Eluted
with
CH2Cl2– 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.42 (d, J = 8.7 Hz,
petroleum ether (1 : 1). Dark yellow solid (0.006 g, 5%), 1H 2H), 7.40–7.36 (m, 1H), 7.34 (d, J = 6.6 Hz, 2H), 7.33–7.28 (m,
NMR (400 MHz, CDCl3) δ 7.42–7.34 (m, 3H), 7.01–6.93 (m, 3H), 2H), 6.97 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 4.9 Hz, 1H), 6.64 (s,
6.47 (s, 1H), 6.31 (s, 1H), 6.23 (d, J = 5.0 Hz, 1H), 3.40 (q, J = 1H), 6.48 (d, J = 3.6 Hz, 1H), 6.34 (dd, J = 3.5, 2.5 Hz, 1H), 6.11
6.8 Hz, 2H), 1.68 (p, J = 7.3 Hz, 2H), 1.43–1.28 (m, 6H), (d, J = 4.9 Hz, 1H), 4.60 (d, J = 6.3 Hz, 2H), 3.86 (s, 3H).13
C
0.93–0.86 (m, 3H).13C NMR (101 MHz, CDCl3) δ 162.04, 160.65, NMR (101 MHz, CDCl3) δ 161.71, 160.60, 136.81, 136.14,
136.78, 134.61, 134.21, 133.74, 131.67, 131.05, 126.57, 124.84, 133.85, 133.28, 132.85, 131.78, 131.51, 129.15, 128.16, 127.02,
113.92, 111.30, 65.08, 55.51, 44.97, 31.41, 30.19, 26.30, 22.57, 126.93, 120.55, 113.78, 113.68, 110.04, 55.48, 48.22. 11B NMR
14.07. HRMS-ES Calcd for C22H25BN3OF2 + Na+: 546.1001. (128 MHz, CDCl3) δ 0.02 (t, JBF = 33.5 Hz). 19F NMR (376 MHz,
Found: 546.1005.
CDCl3) δ −148.95 (q, JFB = 33.5 Hz). IR (neat): νmax/cm−1: 3360,
3-((4-Methylphenyl)amino)-8-(4-methoxyphenyl)-4,4-difluoro- 2970, 1705, 1619, 1466, 1379, 1160, 1128, 951, 816. HRMS-ES
4-bora-3a,4a-diaza-s-indacene 4b. Eluted with CH2Cl2– Calcd for C23H20BN3OF2 + Na+: 426.1565. Found: 426.1584.
petroleum ether (1 : 1). Orange solid (0.080 g, 84%); mp
186–188 °C; H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.43 (s, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene 4e. Eluted with
1H), 7.39 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.09 (d, J = CH2Cl2–petroleum ether (1 : 1). Orange solid (0.065 g, 65%);
3-((2-(Thiophen-2-yl)ethyl)amino)-8-(4-methoxyphenyl)-
1
1
8.5 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 6.47 (d, J = mp 119–120 °C; H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 9.0,
3.3 Hz, 1H), 6.35–6.30 (m, 1H), 6.28 (d, J = 4.9 Hz, 1H), 3.81 (s, 2.4 Hz, 3H), 7.18 (dd, J = 5.1, 1.3 Hz, 1H), 6.96 (t, J = 7.1 Hz,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
3H), 6.91 (dd, J = 2.9, 2.2 Hz, 2H), 6.46 (d, J = 3.5 Hz, 1H), 6.36 ether (1 : 1). Dark yellow solid (0.075 g, 87%); mp 171–173 °C;
(s, 1H), 6.33 (dd, J = 3.7, 2.3 Hz, 1H), 6.06 (d, J = 5.0 Hz, 1H), 1H NMR (400 MHz, CDCl3) δ 7.46–7.42 (m, 1H), 7.39 (d, J = 8.7
3.86 (s, 3H), 3.65 (q, J = 6.6 Hz, 2H), 3.18 (t, J = 6.7 Hz, Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 5.1 Hz, 1H), 6.35
2H).13C NMR (101 MHz, CDCl3) δ 161.45, 160.55, 139.31, (d, J = 3.1 Hz, 1H), 6.34–6.32 (m, 1H), 6.15 (d, J = 5.1 Hz, 1H),
136.06, 133.32, 132.79, 131.78, 131.21, 127.53, 127.04, 126.43, 3.94 (br,s, 4H), 3.86 (s, 3H), 2.11–2.00 (m, 4H). 13C NMR
124.69, 120.20, 113.77, 113.58, 109.73, 55.50, 46.23, 30.84. 11B (101 MHz, CDCl3) δ 160.27, 160.17, 135.53, 135.37, 132.02,
NMR (128 MHz, CDCl3) δ −0.04 (t, JBF = 33.2 Hz), 19F NMR 131.83, 130.89, 129.96, 127.76, 117.46, 114.35, 113.60, 113.09,
(376 MHz, CDCl3) δ −148.47–−149.21 (m). IR (neat): νmax
/
55.46, 51.35, 25.68. 11B NMR (128 MHz, CDCl3) δ 0.01 (t, JBF
=
cm−13361, 2923, 178, 1606, 1401, 1293, 1257, 1025, 792. 31.0 Hz). 19F NMR (376 MHz, CDCl3) δ −128.23 (q, JFB = 31.0
HRMS-ES Calcd for C22H20BN3OF2S + H+: 424.1466. Found: Hz).IR (neat): νmax/cm−1: 3360, 2923, 1577, 1510, 1395, 2350,
424.1456
1251, 1094, 1028, 908, 778. HRMS-ES Calcd for C20H20BN3OF2
3-(Cyclohexylamino)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora- + Na+: 490.1565. Found: 490.1546.
3a,4a-diaza-s-indacene 4f. Eluted with CH2Cl2–petroleum
6-Iodo-3-(pyrrolidin-1-yl)-8-(4-methoxyphenyl)-4,4-difluoro-4-
ether (1 : 1). Orange solid (0.073 g, 78%); mp 130–131 °C; 1H bora-3a,4a-diaza-s-indacene 5h. Eluted with CH2Cl2–pet-
1
NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2H), 6.96 (d, J = roleum ether (1 : 1). Dark orange solid (0.005 g, 4%), H NMR
8.6 Hz, 2H), 6.93 (d, J = 5.0 Hz, 1H), 6.43 (d, J = 3.3 Hz, 1H), (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H), 6.96
6.32 (dd, J = 3.6, 2.4 Hz, 1H), 6.19 (s, 1H), 6.16 (d, J = 5.0 Hz, (d, J = 8.7 Hz, 2H), 6.92 (d, J = 5.2 Hz, 1H), 6.39 (s, 1H), 6.21 (d,
1H), 3.86 (s, 2H), 3.43 (d, J = 8.8 Hz, 1H), 2.02 (d, J = 10.2 Hz, J = 5.1 Hz, 1H), 4.04 (s, 4H), 3.86 (s, 3H), 2.07 (t, J = 6.7 Hz,
2H), 1.81 (d, J = 13.3 Hz, 2H), 1.63 (d, J = 16.3 Hz, 1H), 4H). 13C NMR (101 MHz, CDCl3) δ 160.49, 160.33, 135.85,
1.53–1.14 (m, 4H).13C NMR (101 MHz, CDCl3) δ 160.76, 160.45, 133.82, 133.52, 132.53, 131.75, 129.11, 127.17, 122.68, 115.55,
136.09, 133.34, 132.78, 132.47, 131.73, 130.67, 127.19, 119.56, 113.77, 64.87, 55.50, 52.13, 25.75. IR (neat): νmax/cm−1
:
113.74, 113.29, 110.49, 55.47, 53.79, 33.62, 25.21, 24.53. 11B 2988.020, 2359.166, 1794.501, 1694.386, 1599.758, 1513.181,
NMR (128 MHz, CDCl3) δ −0.01 (t, JBF = 30.0 Hz). 19F NMR 1392.300, 1248.277, 1027.897, 779.549. HRMS-ES Calcd for
(376 MHz, CDCl3) δ −149.24 (q, JFB = 30.0 Hz) IR (neat): νmax
/
C20H19BN3OF2I + Na+: 516.0532. Found: 516.0531.
3-((2-Methylphenyl)amino)-8-(4-methoxyphenyl)-4,4-difluoro-
cm−1: 2931, 2858, 1718, 1604, 1511, 1293, 1253, 1175, 1062,
1027, 839, 795. HRMS-ES Calcd for C22H24BN3OF2 + Na+: 4-bora-3a,4a-diaza-s-indacene 4i. Eluted with CH2Cl2–pet-
418.1878. Found: 418.1879.
3-(Cyclohexylamino)-6-iodo-8-(4-methoxyphenyl)-4,4-difluoro- 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.45 (t, J = 7.7 Hz,
4-bora-3a,4a-diaza-s-indacene 5f. Eluted with CH2Cl2– 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.30 (d, J =
roleum ether (1 : 1). Orange solid (0.057, 60%); mp 227–229 °C;
petroleum ether (1 : 1). Dark yellow solid (0.005 g, 4%), 1H 7.3 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 5.1 Hz, 1H),
NMR (400 MHz, CDCl3) δ7.35 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 3.4 Hz, 1H), 6.39–6.34 (m, 1H), 5.62 (d, J = 5.1 Hz,
6.96 (d, J = 7.8 Hz, 2H), 6.97 (s, 1H), 6.46 (s, 1H), 6.23 (s, 2H), 1H), 3.96 (s, 2H), 3.85 (s, 2H). 13C NMR (101 MHz, CDCl3)
3.86 (s, 3H), 3.52–3.38 (m, 1H), 2.08–1.98 (m, 2H), 1.86–1.75 δ 163.14, 160.34, 146.93, 135.59, 134.17, 132.93, 132.04,
(m, 2H), 1.65 (d, J = 12.8 Hz, 1H), 1.50–1.21 (m, 5H). 13C NMR 131.82, 131.17, 130.20, 128.10, 127.57, 126.72, 118.74, 116.18,
(101 MHz, CDCl3) δ 161.11, 160.61, 136.72, 134.45, 134.21, 113.65, 113.57, 55.45, 43.11. 11B NMR (128 MHz, CDCl3) δ 0.04
133.70, 131.66, 130.77, 126.62, 124.63, 113.91, 111.71, 65.00, (t, JBF = 33.0 Hz). 19F NMR (376 MHz, CDCl3) δ −148.10 (q,
55.51, 54.04, 33.64, 25.14, 24.53. IR (neat): νmax/cm−1
:
JFB = 33.0 Hz). IR (neat): νmax/cm−1: 3378, 2925, 1620, 1578,
3372.915, 2916.489, 1608.145, 1573.648, 1518.964, 1480.453, 1489, 1398, 1258, 1085, 1021, 786. HRMS-ES Calcd for
1392.344, 1251.759, 1101.075. HRMS-ES Calcd for C23H20BN3OF2 + Na+: 426.1565. Found: 426.1577.
C22H23BN3OF2I + Na+: 544.0845. Found: 544.0850.
3-((4-Methoxyphenyl)amino)-8-(4-methoxyphenyl)-4,4-difluoro-
3-(Morpholino)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora- 4-bora-3a,4a-diaza-s-indacene 4j. Eluted with CH2Cl2–
3a,4a-diaza-s-indacene 4g. Eluted with CH2Cl2–petroleum petroleum ether (9 : 1). Orange solid (0.077 g, 78%); mp
ether (9 : 1). Orange solid (0.076 g, 85%); mp 214–215 °C; 1H 245–247 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H),
NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.49–7.46 (m, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.9 Hz,
6.97 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 5.1 Hz, 1H), 6.42 (d, J = 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.95–6.90 (m, 3H), 6.52 (d, J =
3.3 Hz, 1H), 6.37–6.33 (m, 1H), 6.20 (d, J = 5.1 Hz, 1H), 3.93 (d, 3.6 Hz, 1H), 6.36 (dd, J = 3.7, 2.3 Hz, 1H), 6.23 (d, J = 4.9 Hz,
J = 5.1 Hz, 4H), 3.88 (d, J = 5.1 Hz, 4H), 3.87 (s, 3H).13C NMR 1H), 3.87 (s, 3H), 3.85–3.80 (m, 3H). The compound was
(101 MHz, CDCl3) δ 162.07, 160.50, 135.83, 135.11, 133.61, insufficiently soluble to determine 13C NMR. 19F NMR
132.07, 131.87, 131.75, 127.37, 119.51, 113.91, 113.72, 112.44, (376 MHz, CDCl3) δ −148.45 (q, JFB = 32.5 Hz). 11B NMR
66.87, 55.49, 50.56. 11B NMR (128 MHz, CDCl3) δ 0.14 (t, JBF
=
(128 MHz, CDCl3) δ 0.07 (t, JBF = 32.5 Hz). IR (neat): νmax/cm−1
:
33.5 Hz), 19F NMR (376 MHz, CDCl3) δ −135.24 (q, JFB = 33.5 3368, 2914, 1580, 1293, 1241. HRMS-ES Calcd for
Hz).IR (neat): νmax/cm−1: 3361, 2923, 2852, 2360, 1590, 1536, C23H20BN3O2F2 + Na+: 442.1514. Found: 442.1499.
1512, 1408, 1287, 1244, 1178, 1019, 902, 760. HRMS-ES Calcd
for C20H20BN3O2F2 + Na+: 405.1551. Found: 405.1551.
6-Iodo-3-((4-methoxyphenyl)amino)-8-(4-methoxyphenyl)-
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene 5j. Eluted with
3-(Pyrrolidin-1-yl)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora- CH2Cl2–petroleum ether (9 : 1). Orange solid (0.008 g, 6%),
3a,4a-diaza-s-indacene 4h. Eluted with CH2Cl2–petroleum 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.42 (s, 1H), 7.41 (d,
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
J = 8.9 Hz, 2H), 7.21 (d, J = 6.9 Hz, 2H), 6.98 (d, J = 6.5 Hz, 2H), 6.48 (d, J = 4.9 Hz, 1H), 3.83 (s, 3H). IR (neat): νmax/cm−1
:
6.96 (s, 1H), 6.93 (d, J = 6.9 Hz, 2H), 6.55 (s, 1H), 6.27 (d, J = 3366.735, 2995.752, 2227.815, 1597.598, 1566.083, 1474.928,
4.9 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H). The compound was 1394.394, 1253.863, 1101.720. HRMS-ES Calcd for
insufficiently soluble to determine 13C NMR. IR (neat): νmax
/
C23H16BN4OF2I + Na+: 563.0328. Found: 563.0323.
3-(Pyridin-2-ylamino)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-
cm−1
:
3342.169, 3119.175, 2929.044, 1725.014, 1613.144,
1511.895, 1480.277, 1390.170, 1249.831, 1101.578. HRMS-ES 3a,4a-diaza-s-indacene 4m. Eluted with CH2Cl2–petroleum
Calcd for C23H19BN3OF2I + Na+: 568.0481. Found: 568.0489. ether (7 : 3). Pink solid (0.055 g, 60%); mp 213–215 °C; 1H
3-((4-Chlorophenyl)amino)-8-(4-methoxyphenyl)-4,4-difluoro- NMR (400 MHz, CDCl3) δ 8.40–8.34 (m, 2H), 7.71–7.63 (m, 1H),
4-bora-3a,4a-diaza-s-indacene 4k. Eluted with CH2Cl2– 7.54 (s, 1H), 7.52 (d, J = 4.9 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H),
petroleum ether (1 : 1). Dark yellow solid (0.066 g, 66%); mp 7.04 (d, J = 4.9 Hz, 1H), 7.02 (d, J = 3.5 Hz, 1H), 7.00 (s, 2H),
1
178–180 °C; H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.51 (s, 6.95 (d, J = 8.9 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 6.39 (dd, J =
1H), 7.45 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 3.5, 2.3 Hz, 1H), 3.89 (s, 3H).13C NMR (101 MHz, CDCl3)
8.7 Hz, 2H), 7.02–6.96 (m, 3H), 6.58 (d, J = 3.7 Hz, 1H), 6.39 δ 189.77, 160.98, 155.85, 151.33, 148.49, 138.37, 137.20,
(dd, J = 3.7, 2.4 Hz, 1H), 6.34 (d, J = 4.9 Hz, 1H), 3.88 (s, 135.35, 133.61, 133.11, 132.11, 131.98, 126.85, 122.93, 118.88,
3H).13C NMR (101 MHz, CDCl3) δ 160.90, 157.99, 136.36, 114.51, 113.89, 113.03, 55.52. 11B NMR (128 MHz, CDCl3)
136.13, 135.74, 133.16, 132.97, 132.82, 131.86, 131.34, 129.95, δ 0.01 (t, JBF = 33.2 Hz).19F NMR (376 MHz, CDCl3) δ −147.12–
126.76, 123.72, 122.37, 114.42, 113.89, 110.26, 55.52. 11B NMR −147.70 (m). IR (neat): νmax/cm−1: 3385, 3029, 2356, 1629,
(128 MHz, CDCl3) δ −0.01 (t, JBF = 33.0 Hz). 19F NMR 1603,1562, 1496, 1393, 1340, 1297, 1247, 1097, 1028, 972, 769.
(376 MHz, CDCl3) δ −148.10 (q, JFB = 33.0 Hz).IR (neat): νmax
/
HRMS-ES Calcd for C21H17BN4OF2 + H+: 391.1542. Found:
cm−1: 3348, 2926, 2860, 1726, 1578, 1519, 1476, 1385, 1292, 391.1549.
1251, 1180, 1096 971, 784. HRMS-ES Calcd for
C22H17BN3OF2Cl + Na+: 446.1019. Found: 446.1019.
6-Iodo-3-(pyridin-2-ylamino)-8-(4-methoxyphenyl)-4,4-difluoro-
4-bora-3a,4a-diaza-s-indacene 5m. Eluted with CH2Cl2–pet-
6-(Iodo)-3-((4-chlorophenyl)amino)-8-(4-methoxyphenyl)-4,4- roleum ether (7 : 3). Pink solid (0.017 g, 14%); 1H NMR
difluoro-4-bora-3a,4a-diaza-s-indacene
5k. Eluted
with (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.39–8.34 (m, 1H), 7.69 (td, J =
CH2Cl2–petroleum ether (1 : 1). Pink solid (0.013 g, 13%); 1H 7.8, 1.9 Hz, 1H), 7.59 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 1.1 Hz,
NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.44 (d, J = 14.0 Hz, 2H), 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 5.1 Hz, 1H), 7.05–7.02
7.39 (d, J = 9.0 Hz, 3H), 7.21 (d, J = 8.6 Hz, 2H), 7.01 (d, J = (m, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.2 Hz, 1H),
5.2 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 6.61 (s, 1H), 6.38 (d, J = 6.66–6.60 (m, 1H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3)
5.0 Hz, 1H), 3.88 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 161.35, δ 161.14, 156.70, 150.97, 148.57, 138.51, 136.88, 136.16,
156.52, 141.60, 138.11, 136.69, 136.47, 134.33, 133.96, 132.60, 135.34, 134.38, 132.49, 131.91, 127.54, 126.31, 119.36, 115.96,
131.81, 128.85, 125.88, 121.11, 118.24, 114.10, 110.82, 108.49, 114.06, 113.29, 66.24, 55.57. IR (neat): νmax/cm−1: 3384.942,
66.93, 55.51. IR (neat): νmax/cm−1
: 33762.294, 2970.918, 2997.326, 1629.610, 1604.071, 1563.166, 1496.334, 1393.697,
1581.968, 1524.811, 1397.159, 1250.096, 1113.533, 1028.771, 1248.697, 1029.204, 972.232, 769.562. HRMS-ES Calcd for
785.061. HRMS-ES Calcd for C22H16BN3OF2ICl
571.9985. Found: 571.9990.
+
Na+: C21H16BN4OF2I + Na+: 539.0328. Found: 539.0326.
3-(Methyl(phenyl)amino)-8-(4-methoxyphenyl)-4,4-difluoro-
3-((4-Cyanophenyl)amino)-8-(4-methoxyphenyl)-4,4-difluoro- 4-bora-3a,4a-diaza-s-indacene 4n. Eluted with CH2Cl2–
4-bora-3a,4a-diaza-s-indacene 4l. Eluted with CH2Cl2–pet- petroleum ether (1 : 1). Orange solid (0.038, 40%); mp
1
roleum ether (9 : 1). Pink solid (0.075 g, 77%); mp 204–207 °C; 220–221 °C; H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.45 (t,
1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.68 (d, J = 8.8 Hz, J = 7.7 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H),
2H), 7.61–7.55 (m, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 7.30 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 5.1
Hz, 2H), 7.02 (dd, J = 10.7, 6.8 Hz, 3H), 6.67 (d, J = 4.6 Hz, 1H), Hz, 1H), 6.52–6.16 (m, 1H), 5.62 (d, J = 5.1 Hz, 1H), 3.96 (s,
6.50 (d, J = 4.8 Hz, 1H), 6.43 (dd, J = 3.9, 2.3 Hz, 1H), 3.89 (s, 1H), 3.85 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 163.15, 160.34,
3H).13C NMR (101 MHz, CDCl3) δ 161.26, 155.54, 142.19, 146.92, 135.59, 134.17, 132.92, 132.04, 131.82, 131.16, 130.20,
138.61, 135.53, 135.12, 133.99, 133.21, 132.27, 131.97, 126.45, 128.10, 127.56, 126.72, 118.73, 116.18, 113.65, 113.55, 55.45,
124.45, 120.55, 118.55, 115.33, 114.01, 109.54, 107.74, 55.56. 43.11. 11B NMR (128 MHz, CDCl3) δ 0.17 (t, JBF = 32.5 Hz). 19F
11B NMR (128 MHz, CDCl3) δ −0.09 (t, JBF = 32.0 Hz). 19F NMR NMR (376 MHz, CDCl3) δ −129.68 (q, JFB = 32.5 Hz). IR (neat):
(282 MHz, CDCl3) δ −147.61 (q, JFB = 32.0 Hz).IR (neat): νmax
/
νmax/cm−1: 2962, 2919, 1681, 1603, 1513, 1298, 1258, 1020,
cm−1: 3383, 3072, 2224, 1599, 1560, 1524, 1476, 1396, 1251, 932, 794. HRMS-ES Calcd for C23H20BN3OF2 + Na+: 425.1602.
1175, 1113, 1024, 936, 780. HRMS-ES Calcd for C23H17BN4OF2 Found: 425.1598.
+ Na+: 437.1361. Found: 437.1367.
6-Deuterio-2-iodo-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-
3-((4-Cyanophenyl)amino)-6-iodo-8-(4-methoxyphenyl)-4,4- 3a,4a-diaza-s-indacene 11. 2,6-Diiodo-8-(4-methoxyphenyl)-4,4-
difluoro-4-bora-3a,4a-diaza-s-indacene 5l. Eluted with difluoro-4-bora-3a,4a-diaza-s-indacene 3 (0.38 g, 0.69 mmol)
CH2Cl2–petroleum ether (9 : 1). Pink solid (0.019 g, 15%); 1H was dissolved in CH2Cl2 (31 mL). Et3N (0.09 mL, 0.69 mmol),
NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), K2CO3 (0.31 g, 2.25 mmol) and 10% Pd/C (0.38 g) were added.
7.46 (s, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), The mixture was stirred under nitrogen for 15 min and the
7.02 (d, J = 4.9 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.64 (s, 1H), nitrogen line was replaced with a deuterium-filled balloon.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
The mixture was stirred at room temperature for 4 h and then
filtered through Celite, washing with CH2Cl2. The solvent was
removed under reduced pressure and the orange crude
product was purified by column chromatography eluting with
CH2Cl2–petroleum ether (1 : 1) to give, first eluted: the 6-deu-
terio-2-iodoBODIPY 11 as an orange solid (0.177 g, 60%) mp
Notes and references
1 A. Treibs and F. H. Kreuzer, Liebigs Ann. Chem., 1968, 718,
208.
2 (a) G. Ulrich, R. Ziessel and A. Harriman, Angew. Chem.,
Int. Ed., 2008, 47, 1184; (b) A. Loudet and K. Burgess, Chem.
Rev., 2007, 107, 4891.
1
214–215 °C; H NMR (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.75 (s,
1H), 7.46 (d, J = 8.7 Hz, 2H), 7.05–6.93 (m, 4H), 3.85 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 162.45, 146.66, 146.03, 145.07,
135.90, 135.72, 135.01, 132.81, 132.49, 125.88, 119.19 (t, J =
27.07 Hz), 114.29, 70.65, 55.61. 19F NMR (282 MHz, CDCl3)
δ −144.96 (q, JFB = 28.5 Hz). 11B NMR (96 MHz, CDCl3) δ 0.45
(t, JBF = 28.5 Hz). HRMS-ES Calcd for C16H112HBN2F2IO + Na+:
448.0115. Found: 448.0112.
Second eluted: 2,6-dideuterio-8-(4-methoxyphenyl)-4,4-
difluoro-4-bora-3a,4a-diaza-s-indacene 2,6-2H2-1 as an orange
solid (0.035 g, 17%) mp 133–135 °C.1H NMR (300 MHz, CDCl3)
δ 7.84 (s, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H),
6.89 (s, 2H), 3.83 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.11,
147.44, 143.31, 134.82, 132.44, 131.27, 126.30, 118.45, 118.12,
3 (a) K. Umezawa, D. Citterio and K. Suzuki, Anal. Sci., 2014,
30, 327; (b) Y. Ni and J. Wu, Org. Biomol. Chem., 2014, 12,
3774; (c) L. D. Lavis and R. T. Raines, ACS Chem. Biol.,
2008, 3, 142.
4 (a) I. Esnal, I. Valois-Escamilla, C. F. A. Gõmez-Durán,
A. Urías-Benavides, M. L. Betancourt-Mendiola, I. Lõpez-
Arbeloa, J. Bañuelos, I. García-Moreno, A. Costela and
E. Peña-Cabrera, ChemPhysChem, 2013, 14, 4134;
(b) Y. Yang, L. Zhang, B. Li, L. Zhang and X. Liu, RSC Adv.,
2013, 3, 14993; (c) G. Duran-Sampedro, A. R. Agarrabeitia,
I. Garcia-Moreno, A. Costela, J. Bañuelos, T. Arbeloa,
I. López Arbeloa, J. L. Chiara and M. J. Ortiz, Eur. J. Org.
Chem., 2012, 6335; (d) M. Liras, J. B. Prieto, M. Pintado-
Sierra, F. L. Arbeloa, I. García-Moreno, Á. Costela,
L. Infantes, R. Sastre and F. Amat-Guerri, Org. Lett., 2007, 9,
4183.
117.77, 114.08, 55.55. 11B NMR (96 MHz, CDCl3) δ 0.31 (t, JBF
=
29.0 Hz). 19F NMR (282 MHz, CDCl3) δ −145.02 (q, JFB = 29.0
Hz). HRMS-ES Calcd for C16H112H2BN2F2O + Na+: 323.1112.
Found: 323.1110.
5 (a) J. Zhao, W. Wu, J. Sun and S. Guo, Chem. Soc. Rev.,
2013, 42, 5323; (b) S. Guo, L. Ma, J. Zhao, B. Küçüköz,
A. Karatay, M. Hayvali, H. G. Yaglioglu and A. Elmali,
Chem. Sci., 2014, 5, 489.
6-Deuterio-3-(pyrrolidin-1-yl)-8-(4-methoxyphenyl)-4,4-difluoro-
4-bora-3a,4a-diaza-s-indacene 12 and 2-deuterio-3-(pyrrolidin-
1-yl)-8-(4-methoxyphenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-inda-
cene 13. Following the General Procedure for copper catalysed
amination, 6-deuterio-2-iodo-8-(4-methoxyphenyl)-4,4-difluoro-
4-bora-3a,4a-diaza-s-indacene 11 (0.105 g, 0.247 mmol) was
reacted with pyrrolidine (0.035 g, 0.494 mmol). Purification by
column chromatography eluting with CH2Cl2–petroleum ether
(1 : 1) gave a 70 : 30 mixture of the 6-deuterio and 2-deuterio-
BODIPYs 12 and 13 respectively as an orange solid (0.08 g,
88%). For the mixture: 1H NMR (500 MHz, CDCl3) δ 7.48 (br, s,
1H), 7.41 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.93–6.88
(m, 1H), 6.48–6.25 (m, 1H), 6.16 (d, J = 5.1 Hz, 1H), 3.94 (br, s,
4H), 3.89 (s, 3H), 2.08–2.05 (m, 4H). 11B NMR (96 MHz, CDCl3)
δ 1.00 (t, JBF = 32.5 Hz). 19F NMR (282 MHz, CDCl3) δ −128.25
(q, JFB = 32.5 Hz). HRMS-ES Calcd for C20H192HBN3F2O + Na+:
391.1628. Found: 391.1623. For the major product 12: 13C
NMR (126 MHz, CDCl3) δ 160.22 (C3), 160.13 (C4′), 135.46
(C8a), 135.24 (C1), 131.94 (C7a), 131.75 (C2′,C6′), 130.74 (C8),
129.74 (C5), 127.68 (C1′), 117.23 (C7), 114.35 (C2), 113.55 (C3′,
C5′), 112.97 (C6), 55.37 (OMe), 51.26, 25.58. For the minor
product 13: 13C NMR (126 MHz, CDCl3) δ 160.17 (C3), 160.13
(C4′), 135.46 (C8a), 135.12 (C1), 131.94 (C7a), 131.75 (C2′,C6′),
130.74 (C8), 129.82 (C5), 127.68 (C1′), 117.23 (C7), 114.35 (C2),
113.55 (C3′,C5′), 112.97 (C6), 55.37(OMe), 51.26, 25.58.
6 (a) A. Kamkaew, S. H. Lim, H. B. Lee, L. V. Kiew,
L. Y. Chung and K. Burgess, Chem. Soc. Rev., 2013, 42, 77;
(b) S. G. Awuah and Y. You, RSC Adv., 2012, 2, 11169.
7 (a) J. F. Lefebvre, X. Z. Sun, J. A. Calladine, M. W. George
and E. A. Gibson, Chem. Commun., 2014, 50, 5258;
(b) A. M. Poe, A. M. Della Pelle, A. V. Subrahmanyam,
W. White, G. Wantz and S. Thayumanavan, Chem.
Commun., 2014, 50, 2913; (c) A. Bessette and G. S. Hanan,
Chem. Soc. Rev., 2014, 43, 3342; (d) S. Erten-Ela,
M. D. Yilmaz, B. Icli, Y. Dede, S. Icli and E. U. Akkaya, Org.
Lett., 2008, 10, 3299; (e) S. Hattori, K. Ohkubo, Y. Urano,
H. Sunahara, T. Nagano, Y. Wada, N. V. Tkachenko,
H. Lemmetyinen and S. Fukuzumi, J. Phys. Chem. B, 2005,
109, 15368.
8 For examples see: (a) R. Gotor, P. Gaviña, L. E. Ochando,
K. Chulvi, A. Lorente, R. Martínez-Máñez and
A. M. Costero, RSC Adv., 2014, 4, 15975; (b) X. Li, X. Gao,
W. Shi and H. Ma, Chem. Rev., 2014, 114, 590; (c) H. Zhu,
J. Fan, S. Zhang, J. Cao, K. Song, D. Ge, H. Dong, J. Wang
and X. Peng, Biomater. Sci., 2014, 2, 89; (d) A. Nano,
P. Retailleau, J. P. Hagon, A. Harriman and R. Ziessel, Phys.
Chem. Chem. Phys., 2014, 16, 10187; (e) A. Barba-Bon,
L. Calabuig, A. M. Costero, S. Gil, R. Martínez-Máñez and
F. Sancenón, RSC Adv., 2014, 4, 8962; (f) W. Qin,
M. Baruah, M. Van Der Auweraer, F. C. De Schryver and
N. Boens, J. Phys. Chem. A, 2005, 109, 7371.
Acknowledgements
We gratefully acknowledge the Department of Chemistry,
Faculty of Science, Taibah University, Saudi Arabia for a scho-
larship (R.B.A.).
9 (a) N. Boens, L. Wang, V. Leen, P. Yuan, B. Verbelen,
W. Dehaen, M. Van Der Auweraer, W. D. De Borggraeve,
L. Van Meervelt, J. Jacobs, D. Beljonne, C. Tonnelé,
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
R. Lazzaroni, M. J. Ruedas-Rama, A. Orte, L. Crovetto,
M. Baruah, W. Qin, N. Boens and W. Dehaen, Chem.
Commun., 2006, 266; (p) V. Goud, A. Tutar and
J. F. Biellmann, Tetrahedron, 2006, 62, 5084; (q) M. Baruah,
W. Qin, R. A. L. Vallée, D. Beljonne, T. Rohand, W. Dehaen
and N. Boens, Org. Lett., 2005, 7, 4377.
E. M. Talavera and J. M. Alvarez-Pez, J. Phys. Chem. A, 2014,
118, 1576; (b) I. Esnal, J. Bañuelos, I. López Arbeloa,
A. Costela, I. Garcia-Moreno, M. Garzón, A. R. Agarrabeitia
and M. José Ortiz, RSC Adv., 2013, 3, 1547; (c) I. Esnal,
I. Valois-Escamilla, C. F. A. Gõmez-Durán, A. Urías-Bena- 11 V. Leen, V. Z. Gonzalvo, W. M. Deborggraeve, N. Boens and
vides, M. L. Betancourt-Mendiola, I. Lõpez-Arbeloa, W. Dehaen, Chem. Commun., 2010, 46, 4908.
J. Bañuelos, I. García-Moreno, A. Costela and E. Peña- 12 For selected reviews of copper catalysed amination see:
Cabrera, ChemPhysChem, 2013, 14, 4134; (d) R. I. Roacho,
A. Metta-Magaña, M. M. Portillo, E. Peña-Cabrera and
K. H. Pannell, J. Org. Chem., 2013, 78, 4245;
(a) C. Sambiagio, S. P. Marsden, A. J. Blacker and
P. C. McGowan, Chem. Soc. Rev., 2014, 43, 3525;
(b) I. P. Beletskaya and A. V. Cheprakov, Organometallics,
2012, 31, 7753; (c) D. S. Surry and S. L. Buchwald, Chem.
Sci., 2010, 1, 13; (d) E. Sperotto, G. P. M. Van Klink, G. Van
Koten and J. G. De Vries, Dalton Trans., 2010, 39, 10338.
(e)
C.
A.
Osorio-Martínez,
A.
Urías-Benavides,
C. F. A. Gómez-Durán, J. Bañuelos, I. Esnal, I. López
Arbeloa and E. Peña-Cabrera, J. Org. Chem., 2012, 77, 5434;
(f) W. Qin, V. Leen, T. Rohand, W. Dehaen, P. Dedecker, 13 E. Kuhn, V. Bulach and M. W. Hosseini, Chem. Commun.,
M. Van Der Auweraer, K. Robeyns, L. Van Meervelt, 2008, 5104.
D. Beljonne, B. Van Averbeke, J. N. Clifford, K. Driesen, 14 Z. Lu and R. J. Twieg, Tetrahedron, 2005, 61, 903.
K. Binnemans and N. Boens, J. Phys. Chem. A, 2009, 113, 15 A. Shafir and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128,
439; (g) X. Shao, R. Kang, Y. Zhang, Z. Huang, F. Peng,
8742.
J. Zhang, Y. Wang, F. Pan, W. Zhang and W. Zhao, Anal. 16 D. Wang and K. Ding, Chem. Commun., 2009, 1891.
Chem., 2015, 87, 399; (h) M. Gupta, S. Mula, M. Tyagi, 17 For example, in amination of 3-bromothiophene, see:
T. K. Ghanty, S. Murudkar, A. K. Ray and S. Chattopadhyay,
Y. B. Huang, C. T. Yang, J. Yi, X. J. Deng, Y. Fu and L. Liu,
Chem. – Eur. J., 2013, 19, 17766; (i) H. Yokoi, N. Wachi,
J. Org. Chem., 2011, 76, 800.
S. Hiroto and H. Shinokubo, Chem. Commun., 2014, 50, 18 S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003,
2715; ( j) H. Yokoi, S. Hiroto and H. Shinokubo, Org. Lett.,
2014, 16, 3004.
42, 5400; A. Rolfe and P. R. Hanson, Tetrahedron Lett.,
2009, 50, 6935.
10 (a) X. He, J. Zhang, X. Liu, L. Dong, D. Li, H. Qiu and 19 A consequence of this is that amination can be performed
S. Yin, Sens. Actuators, B, 2014, 192, 29; (b) E. Ganapathi,
S. Madhu, T. Chatterjee, R. Gonnade and M. Ravikanth,
Dyes Pigm., 2014, 102, 218; (c) M. De Lourdes Betancourt-
on a mixture of the mono- and di-iodoBODIPYs 2 and 3 to
give the 3-aminoBODIPY 4 and unreacted diiodide 3,
which can be easily separated by column chromatography.
Mendiola, E. Peña-Cabrera, S. Gil, K. Chulvi, L. E. Ochando 20 Since iodoBODIPY compounds are known to act as
and A. M. Costero, Tetrahedron, 2014, 70, 3735;
(d) Y. A. Volkova, B. Brizet, P. D. Harvey, A. D. Averin,
C. Goze and F. Denat, Eur. J. Org. Chem., 2013, 4270;
(e) L. Y. Niu, H. Li, L. Feng, Y. S. Guan, Y. Z. Chen,
C. F. Duan, L. Z. Wu, Y. F. Guan, C. H. Tung and
Q. Z. Yang, Anal. Chim. Acta, 2013, 775, 93; (f) X. Jia, X. Yu,
X. Yang, J. Cui, X. Tang, W. Liu and W. Qin, Dyes Pigm.,
initiators for photooxidation,5 the reaction between the
iodide 2 and 4-cyanoaniline was repeated with careful
exclusion of light and also with a 5-cycle freeze–pump–
thaw sequence to degas the solution prior to reaction. This
did not significantly change the yields of the products (4l
and 5l) and so the reaction does not appear to be photo-
initiated or require the presence of dioxygen.
2013, 98, 195; (g) M. J. Ortiz, A. R. Agarrabeitia, G. Duran- 21 Hartwig has suggested the intermediacy of highly reactive
Sampedro, J. Bañuelos Prieto, T. A. Lopez, W. A. Massad,
H. A. Montejano, N. A. García and I. Lopez Arbeloa, Tetra-
hedron, 2012, 68, 1153; (h) L. Jiao, W. Pang, J. Zhou, Y. Wei,
bisamido cuprate species in aminations catalysed by CuI/
phenanthroline: R. Giri and J. F. Hartwig, J. Am. Chem. Soc.,
2010, 132, 15860.
X. Mu, G. Bai and E. Hao, J. Org. Chem., 2011, 76, 9988; 22 (a) V. Bocchi and G. Palla, J. Chem. Soc., Chem. Commun.,
(i) S. C. Dodani, S. C. Leary, P. A. Cobine, D. R. Winge and
C. J. Chang, J. Am. Chem. Soc., 2011, 133, 8606;
( j) J. Bañuelos, V. Martín, C. F. A. Gómez-Durán,
I. J. A. Córdoba, E. Peña-Cabrera, I. García-Moreno,
1983, 1074; (b) M. Poirier, S. Goudreau, J. Poulin, J. Savoie
and P. L. Beaulieu, Org. Lett., 2010, 12, 2334; (c) For a
review of ‘vicarious’ hydrogen substitution see:
M. Makosza, Pure Appl. Chem., 1997, 69, 559.
A. Costela, M. E. Pérez-Ojeda, T. Arbeloa and I. L. Arbeloa, 23 Reductive loss of iodine from C-2 might have been
Chem. – Eur. J., 2011, 17, 7261; (k) C. F. A. Gómez-Durán,
I. García-Moreno, A. Costela, V. Martin, R. Sastre,
J. Bañuelos, F. López Arbeloa, I. López Arbeloa and
E. Peña-Cabrera, Chem. Commun., 2010, 46, 5103;
(l) D. W. Domaille, L. Zeng and C. J. Chang, J. Am. Chem.
Soc., 2010, 132, 1194; (m) L. Li, B. Nguyen and K. Burgess,
Bioorg. Med. Chem. Lett., 2008, 18, 3112; (n) O. Dilek and
S. L. Bane, Tetrahedron Lett., 2008, 49, 1413; (o) T. Rohand,
linked to oxidation of the copper(I) catalyst25 [e.g. via a
copper(I)/copper(III) cycle or single electron transfers
involving copper(II)] (Scheme S2, ESI†). Such a mechan-
ism would provide the oxidant required for direct
nucleophilic hydrogen displacement by the amine11 and
could explain formation of the iodinated byproduct 5.
The unreactivity of the 2,6-diiodide 3, the formation of a
1 : 1 ratio of 12 : 13 in the amination of the
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
deuterioBODIPY 11 (Scheme 5) and the success of the 26 For a review see: M. Schnürch, M. Spina, A. F. Khan,
amination with aniline nucleophiles all indicate that
such a mechanism does not operate.
M. D. Mihovilovic and P. Stanetty, Chem. Soc. Rev., 2007,
36, 1046.
24 A base-catalysed halogen dance26 (BCHD) might also be 27 M. Fischer and J. Georges, Chem. Phys. Lett., 1996, 260, 115.
envisaged involving reversible sequential deprotonations to 28 M. Baruah, W. Qin, N. Basarić, W. M. De Borggraeve and
give anionic intermediates which abstract the halogen
from another molecule to set up an equilibrium of iodi- 29 V. Leen, T. Leemans, N. Boens and W. Dehaen, Eur. J. Org.
nated BODIPY species. The ultimate outcome of the reac- Chem., 2011, 4386.
tion would be determined by nucleophilic interception of 30 C. Yu, L. Jiao, H. Yin, J. Zhou, W. Pang, Y. Wu, Z. Wang,
the 3-iodo species to give the product 4 (Scheme S3, ESI†). G. Yang and E. Hao, Eur. J. Org. Chem., 2011, 5460.
N. Boens, J. Org. Chem., 2005, 70, 4152.
The insensitivity of the reaction to the nature of the 31 CrysAlisPro version 1.171.35, Agilent Technologies, 2010.
halogen (Scheme 3) and the failure of an attempted copper 32 R. C. Clark and J. S. Reid, Acta Crystallogr., Sect. A: Fundam.
catalysed amination of a 1 : 1 mixture of the unhalogenated
BODIPY 1 and the 2,6-diiodide 3 with pyrrolidine strongly 33 G. M. Sheldrick, Acta Crystallogr., Sect. A: Fundam. Crystal-
suggest that a BCHD is not involved. logr., 2008, 64, 112.
25 For a related proposal see: A. John and K. M. Nicholas, 34 O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard
Crystallogr., 1995, 51, 887.
Organometallics, 2012, 31, 7914.
and H. Puschmann, J. Appl. Crystallogr., 2009, 42, 229.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.