Addressing subphthalocyanines and subnaphthalocyanines features relevant to fluorescence imaging

Article abstract of DOI:10.1016/j.tet.2018.01.029

A series of new synthetic subphthalocyanines bear structural features aimed at allowing either fluorescence activation or a bathochromic shift of the absorption band towards the near-infrared window, relevant to optical imaging. X-ray diffraction studies of four subphthalocyanines are reported. Spectrofluorimetric studies on subnaphthalocyanines and activatable subphthalocyanine pro-fluorophores are reported.

Full text of DOI:10.1016/j.tet.2018.01.029

Tetrahedron 74 (2018) 1047e1052
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Addressing subphthalocyanines and subnaphthalocyanines features
relevant to fluorescence imaging
Yann Bernhard, Philippe Richard, Richard A. Decr eꢀ au*
University of Burgundy-Franche Comt ꢀe in Dijon, Institute of Molecular Chemistry ICMUB, Sciences Mirande, 9 Avenue Alain Savary, 21078, Dijon, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 September 2017
Received in revised form
A series of new synthetic subphthalocyanines bear structural features aimed at allowing either fluo-
rescence activation or a bathochromic shift of the absorption band towards the near-infrared window,
relevant to optical imaging. X-ray diffraction studies of four subphthalocyanines are reported. Spectro-
fluorimetric studies on subnaphthalocyanines and activatable subphthalocyanine pro-fluorophores are
reported.
16 January 2018
Accepted 17 January 2018
Available online 31 January 2018
©
2018 Elsevier Ltd. All rights reserved.
Keywords:
Subphthalocyanine
Subnaphthalocyanine
Optical window
Turn-ON fluorescence
Fluorogenic
Pro-fluorophore
1. Introduction
2. Results and discussion
Subphthalocyanines (SubPcs) are tris-isoindolic phthalocyanine
analogs that were reported as synthons for ring enlargement to
2.1. Syntheses of subphthalocyanine (SubPc)
1
afford A3B phthalocyanines. Their fluorescence properties place
2.1.1. Activatable N-Alkylaminophenoxy subphthalocyanine (pro-
fluorophores)
2
them properly in the Lavis and Raines diagram. Their concave
shape and the axial substituent are useful to prevent aggregation,
which made SubPc interesting fluorophores for biological studies.
They were shown to be pH-sensitive and be of interest for
fluorescence turn-ON at biological pH. The newer versions pre-
sented therein may afford pKa fine-tuning by adjusting the nature
of the apical aniline as mentioned on other fluorescent dialkylated
3
We recently reported pH-sensitive SubPc absorbing in the 570 nm
window.3 Herein, we present in the first section of the study the
synthesis of SubPc species with features relevant to fluorescence
imaging studies (Fig. 1): a) range of substituents for future turn-ON
fluorescence at various biological pH (probes 1e4), b) substituents
responsible for a bathochromic shift up to the near-infrared win-
dow, i.e. the “optical window” where biological tissues are most
5
aminoplatforms as follows: a) secondary and tertiary anilines have
higher pKa than primary anilines, hence they will be more suitable
for biology; b) para vs meta orientation may affect the outcome, not
only because of the electronic effect of the O donor atom, but also
because the meta orientation may get the donor Nitrogen atom
closer to the fluorescent platform, hence facilitating the transfer; c)
the lenght of the alkyl chains grafted on the aniline may also
address the pKa. Herein, N-alkylaminophenoxy groups were
introduced in apical position of the subphtalocyanine ring. Alkyl
groups are either methyl or ethyl groups, leading to organosoluble
SubPcs. Future studies in aqueous media will necessitate subse-
quent incorporation in liposomes. Two synthetic routes were
examined to afford N-alkylaminophenoxy-substituted sub-
4
transparent (probes 5e7). A hanging function X is appended to the
probe for subsequent conjugation to a biomolecule or another
contrast agent or therapeutic agent (bi-modality/theranostic).
Subsequent characterization and examination of the optical prop-
erties (spectrofluorimetry studies) are presented in the last two
sections of the study.
phthalocyanines: direct alkylation of SubPc-NH
stitution of SubPc-Cl 9 with alkyl amine bearing phenol groups. The
2
8 or apical sub-
*
Corresponding author.
E-mail address: Richard.Decreau@u-bourgogne.fr (R.A. Decr eꢀ au).
https://doi.org/10.1016/j.tet.2018.01.029
040-4020/© 2018 Elsevier Ltd. All rights reserved.
0

1048
Y. Bernhard et al. / Tetrahedron 74 (2018) 1047e1052
Scheme 2. Syntheses of subphtalocyanines bearing an apical chlorine atom, and
various atoms/groups at the periphery: 12 Hydrogen atoms (9), twelve fluorine atomes
5), three nitro groups and nine Hydrogen atoms (6).
(
Fig. 1. Three structural modifications to adapt Subphthalocyanines to fluorescence
imaging studies in biology by addressing: a) SubPc pKa and turn-ON fluorescence at
various biological pHs, b) bathochromic shift to address the (near-infrared) “optical
window”, c) introduction of apical function X to future conjugation of other contrast
agent or biomolecule.
when tetrafluorophtalonitrile and 4-nitrophtalonitrile were used,
subphtalocyanines 5 and 6 were obtained in satisfactory yields.
1,6
However, with non-substituted phthalonitrile, isolated yields in 9
6
was not greater than 9%, unlike the 82% reported yields. We hy-
pothesize that solubility issues may possibly explain such low
yields: either the poor solubility of the starting phtalonitrile may
not favor the reaction, or the poor solubility of subphtalocyanine 9
in common organic solvents (such as dichloromethane) may
explain why its purification on column is so tricky and leads to
severe loss of compound. Such a phenomenon is less an issue in the
case of substituted subphtalocyanines 5 and 6, that are much more
soluble. Isolation of the subphthalocyanine by precipitation as re-
first strategy allowed to get alkylated species 1 et 2 using two equiv.
methyl iodide or ethylbromide in the presence of potassium car-
bonate in DMF (Scheme 1A). Low yields were obtained because the
reactions also led to mono-alkylated products and more polar tri-
alkylated/quaternized cationic, that were eliminated upon purifi-
cation of silica column chromatography. In the second synthetic
route no alkylation was achieved, commercially available meta-
substituted phenols were used instead (Scheme 1B). The apical
chlorine atom in compound 9 could be substituted with phenols
using classical operating conditions. Such a reaction with meta-
substituted phenols appeared to be quite long (48 h), and led to
the SubPcs 3 and 4 in 58 and 51% yield, respectively.
6
ported in the literature, was not satisfactory in our hands.
Although the amount of isolated product is significantly higher,
1
H NMR analysis indicates mild purity even after numerous
1
19
washings. A careful analysis of H NMR and F NMR spectra was
achieved to characterize compounds 5 and 6, showing that they are
free of starting phthalonitrile.
Apical substitution of the chlorine atom could be achieved on
compounds 9 and 5, upon condensation of p-substituted phenol in
excess (3.3 equiv., 4-bromophenol with 9, 4-nitrophenol with 5)
under refluxing conditions in toluene until complete consumption
of the starting phthalonitrile (CCM monitoring) (Scheme 3AB).
Reaction times vary and appeared to be a function of both the
electron density of the SubPc aromatic platform and the nature of
the phenol. The yield of apical substitution was found to be 75% (10)
and 71% (11).
2
.1.2. Bathochromically shifted subphthalocyanines
We recently studied subphthalocyanines bearing twelve H
atoms (H12) at the peripheral isoindolic moieties, which absorb in
3
the 570 nm window. Although they fit well in the Lavis and Raynes
diagram,2 they still lie below the so-called “optical window”.
4
Herein, a few examples report the appending of a series of
electron-withdrawing nitro groups or fluorine atoms, or the
extension of the conjugation on the SubPc ring to one more phenyl
(
Subnaphthalocyanine), which results in a bathochromic shift that
One pot cyclotrimerization þ apical substitution Another and
more straightforward method consists in the cyclo-trimerization of
the subphthalocyanine ring immediately followed by evaporation
becomes an asset for optical imaging in deeper tissues.
2.1.2.1. SubPc with peripheral EW groups. Cyclotrimerization re-
3
of both solvents (p-xylene) and liquid reagents (BCl ) in the reac-
actions were achieved following a general procedure consisting of
the stochiometric condensation of Boron trichloride (1 M in p-
xylene) and dry phthalonitrile, according to a procedure reported
tion mixture without isolation of the chlorinated sub-
phthalocyanine 9. Both dry toluene and phenol reagent were
subsequently added to the residue, and the resulting suspension
was heated under reflux (Scheme 3B). The subphthalocyanine was
subsequently purified by a) filtration on alumina plug (short col-
umn) that allowed the elimination of excess phenol, b) followed by
chromatography column on silica, c) and recrystallization if
necessary. The overall yield in compound 10 vary depending on the
protocol: from 7% (two-steps procedure) to 26% (one-pot proced-
ure). However, the overall yield droped significantly as the amount
of starting phthalonitrile was raised, which hampered the larger-
scale synthesis of subphthalocyanine synthons.
6
by Claessens et al. (Scheme 2). The reaction mixture was heated
under refluxing conditions for 30 min under inert atmosphere.
Solvent and excess BCl were subsequently removed by evapora-
3
tion, and the resulting residue was subjected to chromatography on
silica. Three phthalonitriles were selected to examine this reaction:
2.1.2.2. Extended conjugation: subnaphthalocyanine (SubNc).
The « one-pot » general procedure described for synthons 10e11
was adapted to the synthesis of apical nitrophenoxy group bearing
naphthalocyanine by replacing phthalonitrile for naphthalonitrile
(Scheme 4). TLC analysis of the reaction mixture shows four blue
spots, which were isolated by column chromatography on silica.
Mass spectrometry analysis (MALDI-TOF) showed that one of these
fractions corresponds to subnaphthalocyanine 7 that was obtained
in a low 1.7% isolated yield (Note that the other two isolated
2
Scheme 1. A: Methylation and ethylation of SubPc-NH 8 to afford targets 1 and 2. B:
Syntheses of targets 3 and 4 upon substitution of the apical chlorine atom in com-
pound 9.

Y. Bernhard et al. / Tetrahedron 74 (2018) 1047e1052
1049
Scheme 3. Two-steps vs « one-pot » syntheses of subphthalocyanines 10 and 11
bearing Br, NO e substituted apical groups for future reactions, in the H12 vs F12 series.
2
Fig. 2. Top: X-ray diffraction studies of compounds 3 (left, CCDC 1555141) and 4 (right,
CCDC 1555142). Compound 4 co-crystallized with one molecule of dichloromethane.
Bottom: ORTEP views of p-substituted-phenoxy-bearing subphthalocyanines in the
H12 series (10, left, CCDC 1555143) and F12 series (11, right, CCDC 1555144).
2
Scheme 4. Synthesis of naphthalocyanine SubNc-NO 7.
on the UV/Vis spectra of all Subphthalocyanines and Sub-
naphthalocyanines (Fig. 3). Such an effect leads to a bathochromic
shift of the Q bands. In the case of the trinitro-derivative 6, the
broadening of the bands and spectrum and the decrease of the
epsilon may be the result of likely internal charge transfer (ICT)
between the three nitro groups and the aromatic SubPc. UV/Vis
absorption spectrum in SubNc 7 shows Soret band at 327 nm and Q
band at 656 nm, which corresponds to a 93 nm bathochromic shift
fractions may be assigned to the chlorinated version (SubNc-Cl)
prior substitution with phenoxy group, and another resulting from
hydrolysis at the apical position leading to SubNc-OH), and the last
one could not be identified).
2
.2. Characterization of subphthalocyanine (SubPc)
2
compared to the Q bands in SubPc-NO 10a. Hence, the SubNc
1
The structure of the alkylated species was assessed by H NMR,
derivative is far better than the SubPc analog in term of absorption
in the « optical window » with respect to biological requirements.
However, its cyclotrimerization requires optimization prior to
transposing the apical substitution steps and future reactions.
Subsequent fluorescence emission of the molecules occurs at
570e574 nm (SubPc 10a) and 670 nm (SubNc 7), respectively.
13
10
C NMR, B-NMR, mass spectrometry, and X-Rays diffraction
studies for compounds 3, 4,10 and 11 (Fig. 2). The presence of apical
substituents in bromophenoxy-substituted compound 10 was
demonstrated by H NMR spectrometry. Doublets that correspond
to the protons of the phenoxy groups are quite shielded (5.27 and
1
6
.84 ppm) compared with that of the phenol precursor (6.84 and
7
.43 ppm) because these protons lie in the anisotropy cone of the
2.3.2. Activation and spectrofluorimetry
10
aromatic subphtalocyanine. The B-NMR spectrum shows a singlet
at ꢀ15.68 ppm in the case of chlorinated species 9, which shifts
to ꢀ15.07 ppm in compound 10. Crystals of subphthalocyanines 10
and 11 were obtained upon slow evaporation from a solution of the
subphthalocyanines in dichloromethane. The conical aspect of the
subphthalocyanine aromatic structure and the presence of apical
para-bromophenoxy are clearly observed by X-ray diffraction
studies (Fig. 2).
Fluorescence quantum yields of the subphthalocyanines were
measured in DMF, or in DMF in the presence of H
2 4
SO (Table 1),
following procedure previously reported with other sub-
a
3a
phthalocyanines. Spectrofluorimetric studies carried out on 1
showed fluorescence turn-on upon gradual addition of acid in the
medium (Fig. 4). Fluorescence quantum yields are negligible prior
to protonation, and were raised to up to 4e10% upon fluorescence
activation by adding sulfuric acid. The Increase Factor (F) corre-
sponds to the ratio between the two fluorescence quantum yields
(before activation (in DMF) and after activation with acid (in
2.3. Optical properties and fluorescence activation
DMF þ H
2 4
SO ), Table 1): it corresponds to the efficacy of the fluo-
rophore as an activatable probe. This process is reversible: upon
addition of a base to the mixture of protonated aniline-containing
2
.3.1. UVevis spectroscopy
The electron-withdrawing effect of the substituents is observed

1050
Y. Bernhard et al. / Tetrahedron 74 (2018) 1047e1052
from a synthesis and properties standpoint. First, from a synthetic
standpoint: a) Overall the cyclotrimerization reaction leading to
subphthalocyanine proceeded in ca 9% yield under the general
protocol developed, although it dropped to about 1e2% in the case of
the subnaphthalocyanine. When no isolation of the chlorinated
species was attempted subsequent substitution of the apical chlorine
atom with phenol groups was achieved allowing to raise the overall
yield up to 36% in the H12 series. When the reaction was conducted
on platforms bearing electron-withdrawing fluorine atoms/groups,
yields were significantly raised up to 75%. b) Bromo and nitro SubPcs/
SubNc 6,7,10,11 are an entry point to future conjugations to groups
relevant to biomedical studies, such as chelates for the complexation
3
b,8
of medically relevant metals, peptides, as we previously reported
:
bromo-SubPc 7 may for instance be engaged in Sonogashira for
alkyne groups and future Click conjugations. Nitro synthons 6,10,11
may be reduced into amine and subsequently acylated and engaged
in peptide bond formations. The presence of nitro group and
bromine atom at the para position of the apical phenoxy-group is an
entry point for future reactions, which may afford conjugation to
other contrast/therapeutic agents (i.e. bimodality/theranostics).
Second, from a properties standpoint: c) Twelve fluorine atoms or
three nitro groups at the isoindolic position of the SubPc ring led to
modest (5e10 nm) bathochromic shifts, whereas extending the
conjugation to an extra phenyl ring led to about 100 nm shift, which
now brings the subsequent SubNc on the edge of the therapeutical
Fig. 3. Absorption spectra of: A) Subphthalocyanines 8, 5 et 6 measured in chloroform
molar extinction coefficient as a fonction of wavelength); B) of apical nitrophenoxy-
bearing subphthalocyanines 10a vs nitrophenoxy-bearing naphthalocyanines 7 with
fluorescence emission of the subnaphthalocyanine.
(
2,4
window. (Interestingly, it should be noted that such trinitro- and
perhalogenated subphthalocyanines and and sub-
5
6
Table 1
naphthalocyanine 7 are the tri-isoindolic/isobenzoindolic versions of
Absorption, emission and activation properties of SubPcs 1e4 (298 K; Reference
tetraisoindolic phthalocyanines/naphthalocyanines, i.e. tetranitro-
rhodamine 6G in MeOH,
F
F
¼ 0.96,
lex ¼ 488 nm; measure error: ±10%).
7
and perhalogenated phthalocyanine, naphthalocyanine). E) This
3
Compounds
Solvent
l
abs
/
l
em
ε (.10
f
F
F
study also reported the syntheses of a series of dimethyl vs diethyl
para-amino vs meta-amino phenoxy subphthalocyanines, which
should have different pKa values suggesting turn-ON fluorescence
may occur at various biological pHs. At this stage of the study, it has
been demonstrated that the fluorescence of such sub-
phthalocyanines bearing distal aniline moieties may be switched-on
upon addition of small volumes of acid in the mixture, which augurs
well for the activation in relevant biological systems at low pH
(nm)
mol-1.L cmꢀ1
)
1
2
3
4
DMF
563/572
564/573
565/572
564/573
564/570
565/573
564/570
564/573
79.6
76.9
72.4
73.1
72.1
83.6
72.1
83.6
0.009
0.067
0.008
0.054
0.002
0.101
0.003
0.083
7.4
DMF þ H
2
SO
2
SO
2
SO
2
SO
4
4
4
4
DMF
6.8
DMF þ H
DMF
50.5
27.7
DMF þ H
DMF
DMF þ H
(
hypoxic tumors, lysosomes). Future studies will focus on the mea-
surement of pKa values of dialkylaminophenoxysubphthalocyanines
e4, subphthalocyanine, encapsulation in liposome carriers and
SubPc, fluorescence intensity goes down. Fluorescence is OFF in
compounds 1e4 and is turned-on upon addition of acid by pro-
tonation of the Nitrogen in the distal aniline, that results in the
suppression of the photo-induced electron transfer (PeT) and/or
internal charge transfer (ICT). This is unlike compounds 7, 11 the
fluorescence of which (see spectrum in the SI) is always ON,
because they do not have such quenching amine moieties.
1
subsequent delivery and staining of living cells, as we previously
8
reported for other subphthalocyanines/phthalocyanines and the
scale-up of subnaphthalocyanines.
4. Experimental
4.1. Materials and methods
3
. Conclusion
Chemicals were used as supplied. Subphthalocyanine UV/Vis
At this stage of the study two sets of conclusions may be raised,
spectra were recorded on a Shimadzu UVe 2550 spectrophotom-
eter. Spectra were recorded in DMF in glass cuvettes 1 ꢁ 1x3 cm
(1 cm path).
Fluorescence measurements were performed on a Jasco FP-8500
spectrofluorometer equipped with a Xe source. Fluorescence
quantum yields were calculated using Rhodamine 6G methanol as a
reference (
F
F ¼ 0.94). Excitation was performed at 488 nm for the
reference and 560 nm for the sample. Emission spectra were
recorded for an absorbance at 560 nm comprised between 0.03 and
0.07 (i.e. 1
F
mM). Fluorescence quantum yields (F ) were determined
by the comparison method, using the following equation:
!
Fig. 4. A: example of spectrofluorimetry studies on Subphthalocyanine 1 in solution in
DMF (emission spectra were recorded for an absorbance at 560 nm comprised between
ꢀ
ꢁ
2
ꢀ
ꢁ
Abs
h
1 ꢀ 10
AðStdÞ
f ¼ f ðStdÞ ꢁ
ꢁ
ꢁ
F
F
ꢀ
AbsðStdÞ
0.03 and 0.07 (i.e. 1
mM concentration in 1). B: SubPc 1 fluorescence intensity increases
h
ðStdÞ
1 ꢀ 10
A
upon gradual addition of acid (H
2
SO ) until it reaches a plateau.
4

Y. Bernhard et al. / Tetrahedron 74 (2018) 1047e1052
1051
Std corresponds to the standard fluorophore (Rhodamine 6G);
and (Std): fluorescence quantum yields; and (Std):
refractive index of the solvent (MeOH for standard; DCM, DMF or
water for samples); Abs and Abs(Std): absorbances at excitation
wavelength (560 nm) A and A(Std): areas under the fluorescence
curves.
chromatography (eluent: DCM/MeOH 99:1), to afford the desired
F
F
F
F
h
h
subphthalocyanine 20 (33 mg, 51%).
1
3
H NMR (300 MHz, CDCl
3
, 300 K):
d
(ppm) ¼ 0.91 (t, J ¼ 6.8 Hz,
3
6H); 3.30 (q, J ¼ 6.8 Hz, 4H); 4.68 (m, 2H); 5.94 (m, 1H); 6.57 (m,
1H); 7.88 (m, 6H); 8.84 (m, 6H). MS MALDI-TOF: m/z ¼ 559.88
þ
þ
[MþH] (calcd for C34
H27BN
7
O : 560.24).
þ
þ
HR-MS ESI: m/z ¼ 560.23497 [MþH] (calcd for C34
H
27BN
7
O :
3
ꢀ1
ꢀ1
4
.2. B-(4-(N,N-dimethyl)aminophenoxy)[subphthalocyaninato]
boron(III) (1)
560.23706). UVeVis (DMF):
lmax (nm) (ε ꢁ 10 L mol cm ) ¼ 309
(36.2), 564 (73.6). CCDC 1555142.
To a solution of compound 8 (50 mg, 0.1 mmol) in DMF (5 mL)
4.6. B-chloro[1,2,3,4,7,8,9,10,15,16,17,18-
was added potassium carbonate (59 mg, 0.4 mmol), then methyl
dodecafluorosubphthalocyaninato]boron(III) (5)
ꢂ
iodide (12.3
m
L, 0.2 mmol). The reaction mixture was stirred at 50 C
®
for 12 h, then filtered off on clarcel and finally evaporated under
reduced pressure. The residue was subjected to silica gel column
chromatography (eluent: DCM/MeOH 99:1) and dried under
3
BCl (4 mL, 1 M solution in p-xylene) was added to dry tetra-
fluorophthalonitrile (800 mg, 4 mmol under an argon atmosphere.
The vessel was placed in a preheated oil bath (150 C) and the
ꢂ
reduced pressure (12 mg, 37%).
mixture was stirred and left to reflux for 30 min. The solvent was
removed under reduced pressure and the resulting solid was sub-
jected to silica gel column chromatography (eluent: DCM) (455 mg,
1
H NMR (300 MHz, CDCl
3
, 300 K):
d
(ppm) ¼ 2.67 (s, 6H); 5.32 (d,
3
3
J ¼ 8.9, Hz, 2H); 6.17 (d, J ¼ 8.9 Hz, 2H); 7.90 (m, 6H); 8.84 (m, 6H).
þ
þ
MS MALDI-TOF: m/z ¼ 531.77 [MþH] (calcd for C32
H23BN
7
O :
53%).
3
ꢀ1
ꢀ1
19
5
(
32.21). UVeVis (DMF):
l
max (nm) (ε ꢁ 10 L mol cm ) ¼ 307
F NMR (282 MHz, CDCl
3
, 300 K):
NMR (96 MHz, CDCl
(ppm) ¼ ꢀ14.20 (s, 1B). UVeVis (CHCl ): max (nm)
d
(ppm) ¼ ꢀ146.95 (m,
11
33.3), 563 (79.7).
6F); ꢀ136.65 (m, 6F).
B
3
,
300 K):
d
3
l
3
ꢀ1
ꢀ1
4.3. B-(4-(N,N-diethyl)aminophenoxy)[subphthalocyaninato]
(ε ꢁ 10 L mol cm ) ¼ 307 (43.0), 573 (100.2).
boron(III) (2)
4.7. B-chloro[2,9(10),16(17)-trinitrosubphthalocyaninato]
To a solution of B-(4-aminophenoxy)[subphthalocyaninato]
boron(III) 8 (50 mg, 0.1 mmol) in DMF (5 mL) was added potassium
boron(III) (6)
carbonate (59 mg, 0.4 mmol), then bromoethane (12.3
m
L,
BCl (4 mL, 1 M solution in p-xylene) was added to dry 4-
3
ꢂ
0
.2 mmol). The reaction mixture was stirred at 50 C for 12 h, then
nitrophthalonitrile (690 mg, 4 mmol), under an argon atmo-
®
ꢂ
filtered off on clarcel and evaporated under reduced pressure. The
residue was subjected to silica gel column chromatography (eluent:
DCM/MeOH 99:1) and the isolated product was dried under
sphere. The vessel was placed in a preheated oil bath (150 C) and
the mixture was stirred and left to reflux for 30 min. The solvent
was removed under reduced pressure and the resulting solid was
subjected to silica gel column chromatography (eluent: DCM)
(287 mg, 38%).
reduced pressure (19 mg, 31%).
1
H NMR (300 MHz, CDCl
3
, 300 K):
d
(ppm) ¼ 0.95 (s, 6H); 3.42 (q,
3
3
1H NMR (300 MHz, CDCl
(m, 3H); 9.73 (m, 3H).
4
8
C
H); 5.29 (d, J ¼ 8.9, Hz, 2H); 6.15 (d, J ¼ 8.9 Hz, 2H); 7.90 (m, 6H);
3
, 300 K):
B
d
(ppm) ¼ 8.83 (m, 3H); 9.06
NMR (96 MHz, CDCl 300 K):
): max (nm)
þ
11
.85 (m, 6H). MS MALDI-TOF: m/z ¼ 559.80 [MþH] (calcd for
3
,
þ
34
H
27BN
7
O :
560.24).
UVeVis
(DMF):
l
max
(nm)
d
(ppm) ¼ ꢀ14.00 (s, 1B). UVeVis (CHCl
3
l
3
ꢀ1
ꢀ1
3
ꢀ1
ꢀ1
(
ε ꢁ 10 L mol cm ) ¼ 308 (39.1), 565 (72.1).
(ε ꢁ 10 L mol cm ) ¼ 311 (52.0), 586 (74.9).
4.4. B-(3-(N,N-dimethyl)aminophenoxy)[subphthalocyaninato]
4.8. B-(4-nitrophenoxy)[subnaphthalocyaninato]boron(III) (7)
boron(III) (3)
3
BCl (5,61 mL, 1 M solution in p-xylene, 5.61 mmol) was added
B-Chloro[subphthalocyaninato]boron(III) 9 (50 mg, 0.12 mmol)
and 3-(N,N-dimethyl)aminophenol (247 mg, 1.8 mmol) dissolved in
toluene (5 mL) were heated to reflux for 36 h. After evaporation of
the solvent, the residue was subjected to alumina gel column
chromatography (eluent: DCM/MeOH, gradient from 100:0 to 99:1)
and then to silica gel column chromatography (eluent: DCM/MeOH
to dry naphthalonitrile (1 g, 5.61 mmol), under an argon atmo-
sphere. The vessel was pourred in a preheated oil bath (150 C),
ꢂ
stirring and left to reflux for 30 min. The solvent and the excess of
boron trichloride were removed under reduced pressure and the
resulting solid was resuspended in toluene (30 mL). An excess of 4-
nitrophenol (2.34 g, 16.83 mmol) was added and the mixture was
heated under reflux for 15 h. After evaporation to dryness, the
residue was subjected to alumina gel column chromatography
(eluent: DCM) and then to silica gel column chromatography
(eluent: DCM/Heptane, gradient from 70:30 to 100:0) (16 mg, 1.3%).
9
9:1) to give the desired subphthalocyanine 19 (36 mg, 58%).
1
H NMR (300 MHz, CDCl
3
, 300 K):
d
(ppm) ¼ 2.64 (s, 6H); 4.81
(
m, 2H); 6.10 (m, 1H); 6.63 (m, 1H); 7.87 (m, 6H); 8.84 (m, 6H). MS
þ
þ
MALDI-TOF: m/z ¼ 531.78 [MþH] (calcd for C32
H
23BN
7
O : 532.21).
þ
þ
1
3
HR-MS ESI: m/z ¼ 532.20509 [MþH] (calcd for C32
H
23BN
7
O :
H NMR (300 MHz, CDCl
3
, 300 K):
d
(ppm) ¼ 5.63 (d, J ¼ 9.2 Hz,
3
ꢀ1
ꢀ1
3
5
32.20573). UVeVis (DMF):
l
max (nm) (ε ꢁ 10 L mol cm ) ¼ 309
2H); 7.72 (d, J ¼ 9.2 Hz, 2H); 7.74 (m, 6H); 8.34 (m, 6H); 9.39 (m,
þ
(
31.3), 565 (72.4). CCDC 1555141.
6H). MS MALDI-TOF: m/z
¼
682.77 [MþH]
(calcd for
max
l (nm)
þ
C
42
H
22BN
7
O
3
:
683.19).
UVeVis
(DCM):
3
ꢀ1
ꢀ1
4.5. B-(3-(N,N-diethyl)aminophenoxy)[subphthalocyaninato]
(ε ꢁ 10 L mol cm ) ¼ 327 (43.2), 656 (63.1).
boron(III) (4)
4.9. B-(4-nitrophenoxy)[1,2,3,4,7,8,9,10,15,16,17,18-
A mixture of chloro[subphthalocyaninato]boron(III) 9 (50 mg,
dodecafluorosubphthalocyaninato]boron(III) (11)
0
.12 mmol) and 3-(N,N-diethyl)aminophenol (297 mg, 1.8 mmol) in
toluene (5 mL) was heated under reflux for 36 h. After evaporation
of the solvent, the residue was subjected to alumina gel column
chromatography (eluent: DCM) and then to silica gel column
A mixture of B-chloro[dodecafluorosubphthalocyaninato] bor-
on(III) (100 mg, 0.15 mmol) and 4-nitrophenol (209 mg, 1.5 mmol)
in toluene (5 mL) was heated under reflux for 15 h. After

1052
Y. Bernhard et al. / Tetrahedron 74 (2018) 1047e1052
evaporation of the solvent, the residue was subjected to alumina gel
column chromatography (eluent: DCM) and dried under reduced
pressure (80 mg, 71%).
Acknowledgments
The Burgundy Regional Council, 3MIM and PARI-2, and CNRS
Chaire d’Excellence are acknowledged for funding.
1
3
H NMR (300 MHz, CDCl
3
, 300 K):
d
(ppm) ¼ 5.17 (d, J ¼ 9.1 Hz,
19
2
d
H); 7.47 (d, 3J ¼ 9.1 Hz, 2H). F NMR (282 MHz, CDCl
3
, 300 K):
(ppm) ¼ ꢀ147.14 (m, 6F); ꢀ136.88 (m, 6F). CCDC 1555144.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.01.029.
4
.9.1. B-(4-bromophenoxy)[subphthalocyaninato]boron(III) (7)
Method A:A mixture of B-chloro[subphthalocyaninato]boron(III)
(50 mg, 0.12 mmol) and 4-bromophenol (208 mg, 1.2 mmol) in
3
toluene (5 mL) was brought to reflux for 12 h. After evaporation of
the solvent, the residue was subjected to alumina gel column
chromatography (eluent: DCM) and then recrystallized in a 50:50
DCM/heptane mixture by slow evaporation of DCM, to afford B-(4-
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7 as a bronze
cristalinae solid (51 mg, 75%). Method B: BCl (4 mL, 1 M solution in
3
p-xylene) was added to dry phthalonitrile (500 mg, 4 mmol), under
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2. Lavis LD, Raines RT. ACS Chem Biol. 2008;3:142e155.
3. a) Bernhard Y, Winckler P, Chassagnon R, et al. Chem Commun. 2014;50(90):
ꢂ
(
150 C) and the mixture was stirred and left to reflux for 30 min.
13975e13978;
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4
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(
2.08 g, 12 mmol) was added and the mixture was heated to reflux
during 15 h. After evaporation to dryness, the residue was subjected
to alumina gel column chromatography (eluent: dichloromethane)
to remove the excess of phenol and then to silica gel column
3
6. However, it is important to have a clean BCl solution; heating must proceed
step-wise, heating time must not be too long and temperatures should not
chromatography (eluent: DCM), to afford the desired sub-
ꢂ
exceed 150 C.
1
phthalocyanine 7 (200 mg, 26%). H NMR (300 MHz, DMSO‑d
6
,
7. a) Decreau R, Richard MJ, Julliard M. J Porphyr Phthalocyanines. 2001;5(04):
3
3
3
7
00 K):
.91 (m, 6H); 8.85 (m, 6H). B NMR (96 MHz, CDCl
(ppm) ¼ ꢀ15.07 (s, 1B). UVeVis (DCM): max (nm)
ε ꢁ 10 L mol cm ) ¼ 305 (42.3), 564 (61.7). CCDC 1555143.
d
(ppm) ¼ 5.27 (d, J ¼ 8.8 Hz, 2H); 6.84 (d, J ¼ 8.8 Hz, 2H);
390e396;
11
b) Decr eꢀ au R, Chanon M, Julliard M. Inorg Chim Acta. 1999;293(1):80e87;
3
, 300 K):
c) Alzeer J, Roth PJC, Luedtke NW. Chem Commun. 2009:1970.
d
l
8. Bernhard Y, Gigot E, Goncalves V, et al. Org Biomol Chem. 2016;14(19):
3
ꢀ1
ꢀ1
(
4511e4518.