Synthesis of seminaphtho-phospha-fluorescein dyes based on the consecutive arylation of aryldichlorophosphines

Article abstract of DOI:10.1039/c7cc04323f

Seminaphtho-phospha-fluorescein (SNAPF), a phosphine-oxide-containing unsymmetric fluorescein dye, was synthesized based on the consecutive arylation of PhPCl₂, followed by Friedel-Crafts cyclization. The resulting SNAPF exhibited several attractive photophysical properties including an intense fluorescence in the NIR region and a large Stokes shift.

Full text of DOI:10.1039/c7cc04323f

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Synthesis of seminaphtho-phospha-fluorescein dyes based on the
consecutive arylation of aryldichlorophosphines
Aiko Fukazawa,*a Junichi Usuba,a Raúl A. Adler,b and Shigehiro Yamaguchi*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
(a)
Seminaphtho-phospha-fluorescein (SNAPF), a phosphine-oxide-
containing unsymmetric fluorescein dye, was synthesized based
on the consecutive arylation of PhPCl2, followed by a Friedel-
Crafts cyclization. The resulting SNAPF exhibited several attractive
photophysical properties including an intense fluorescence in the
NIR region and a large Stokes shift.
Ar
P
O
P
OH
R2N
NR2
O
Ph
O
R'
Phospha-rhodamine
1a (R' = Me)
1b (R' = OEt or O–)
Phospha-fluorescein
(POF)
(b)
via xanthone-type precursors
Ar
P
O
P
X
Ar
M
Water-soluble fluorescent dyes that exhibit light-absorption
and fluorescence in the far-red to near-infrared (NIR) region
have attracted increasing attention due to their application as
fluorescent probes in bioimaging.1 Among various types of
small-molecule dyes, xanthene dyes, such as fluoresceins and
rhodamines, represent dye skeletons that exhibit several
advantages, including high solubility in aqueous media, large
molar absorption coefficients, and high fluorescence quantum
yields. However, the absorption and fluorescence wavelengths
of the parent fluoresceins and rhodamines remain in the
visible region. One promising strategy to induce
bathochromically shifted absorption and fluorescence is the
replacement of the endocyclic oxygen atom in the xanthene
skeleton with another main-group element such as B (group
13),2 Si and Ge (group 14),3–5 P (group 15),6–8 or S, Se, and Te
(group 16).9 These structural modifications afforded various
intriguing fluorescent probes with characteristic properties.
Y
Y
Y
Y
Y'
Y'
X = CH2 or (P=O)R
Y = OR or NR2
M = Li or MgX
R
O
R
O
Y = O or NR2
via condensation/cyclization/oxidation
1) sec-BuLi
(EtO)PCl2
Br
CHO
H+
2) H2O2
3) chloranil
NR2
Br
NR2
P
NR2
NR2
Br
NR2
RO
O
(c) This work
S
O
S
Ar
Ar
MeO
Li
Cl
Cl ClZn
OMe
Ar
Ar
P
MeO
P
OMe
then oxidation
and deprotection
Ph
O
Ph
2
Ar
Ar
Ar
MgBr
OH
Ar
Ar
Ar
Ar
O
P
OH
MeO
P
3
OMe
O
Ph
O
Ph
POF
Among
these
probes,
phosphine-oxide-containing
xanthene dyes, such as phospha-fluoresceins (POFs)6 and
phospha-rhodamines 1,7,8 are of particular importance (Figure
1a). The introduction of an electron-withdrawing P=O moiety
decreases the energy levels of both the HOMO and LUMO,
Fig. 1 (a) Molecular structures of phospha-xanthene dyes; (b) previously reported
synthetic routes to phospha-xanthene dyes; (c) alternative synthetic route to POF
explored in this study.
which results in a significant bathochromic shift of the which we have recently reported, exhibited an intense far-red
absorption and emission bands to reach the NIR region. POF,
fluorescence (λem = 656 nm) and a high fluorescence quantum
yield (0.33) in water at pH = 9. The P=O group also lowered the
pKa value to 5.7 relative to that of the parent fluorescein (~6.2),
while retaining the characteristic pH-dependent character and
high cell-membrane permeability.
Despite the potential utility of POFs, the lack of a versatile
synthetic method has so far restrained a systematic fine-tuning
of their structures. The synthetic methods reported to date
can be divided into two sub-classes. One is based on phospha-
xanthone precursors (Figure 1b; top), which allowed Wang and
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co-workers7 and our group6 to independently reported the
synthesis of phospha-rhodamine 1a and POF, respectively.
However, the phospha-xanthone precursors themselves can so
far only be accessed via laborious synthetic procedures, and
the introduction of bulky aryl groups in the xanthones by
nucleophilic addition of arylmetal reagents generally suffers
from low yields despite the importance for highly emissive
character.10 The other method is based on the condensation of
m-bromoanilines with benzaldehydes. Whereas Stains and co-
workers have reported a relatively short synthesis of phospha-
rhodamine 1b using this approach (Figure 1b; bottom), this
method is limited to the synthesis of rhodamine derivatives.8
Moreover, the synthesis of unsymmetrically substituted
phospha-xanthene dyes from either method is nontrivial.
In this context, a diversity-oriented synthesis of POFs that
provides general access to even unsymmetrically substituted
skeletons would be highly desirable for the systematic fine-
tuning of these dyes. Our strategy to achieve this goal is based
on the assembly of three aryl groups in a stepwise manner to
generate arylhydroxymethyl-substituted phosphine oxides 3,
from which a Friedel-Crafts cyclization and a subsequent
oxidation should furnish POFs11 (Figure 1c). Herein, we report
the details of this synthetic protocol. A seminaphtho-phospha-
fluorescein thus synthesized as an example of unsymmetrically
substituted POFs showed intriguing photophysical properties.
The first step of this synthesis involves the assembly of two
aryl groups onto a phenylphosphine moiety starting from
PhPCl2. As an example of the key intermediate, we examined
the synthesis of o-formyl-substituted triarylphosphine oxide 2a
(Scheme 1). Wittig and coworkers have reported that the
reaction of PhPCl2 with arylzinc reagents results in a selective
monoarylation.12 Accordingly, PhPCl2 was initially treated with
1 equiv of m-methoxyphenylzinc chloride, before the second
1)
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DOI: 10.1039/C7CC04323F
Ar
Ar
O
P
OH
MgBr
THF, –78 °C
MeO
OMe
2) H+
MeO
P
OMe
O
Ph
O
Ph
2a
3a-Me (Ar = o-Tol)
3a-Me2 (Ar = Xyl)
Ar
Ar
OMe
H
H
3) TsOH
+
toluene
100 °C
MeO
P
OMe
MeO
P
Ph
Ph
O
O
cis/trans
cis/trans
6aa-Me2
6aa-Me2
6ab-Me
6ab-Me2
NMR ratio of regioisomers
6aa/6ab
Isolated yield of
trans-6aa / %
Ar
o-Tol
Xyl
69/31
43/57
38
23
Scheme
2 Synthesis of cyclic triarylphosphine oxides 6 from unsymmetric
triarylphosphine oxides 2 by the nucleophilic addition and the intramolecular Friedel-
Crafts cyclization of o-(hydroxymethyl)arylphosphine oxides.
Ar
Ar
1) t-BuONa
O2 gas
H
OH
DMSO, rt
2) H+
MeO
P
OMe
MeO
P
OMe
O
Ph
O
Ph
trans-6aa-Me (Ar = o-Tol)
trans-6aa-Me2 (Ar = Xyl)
7aa-Me
7aa-Me2
Ar
P
3) conc. HBr
90 °C
O
OH
O
Ph
POF-Me (Ar = o-Tol) 62%
POF-Me2 (Ar = Xyl) 91%
arylation
was
carried
out
with
2-dithiolanyl-5-
O
P
OH
O
P
OH
O
P
OH
O
Ph
O
Ph
O
Ph
methoxyphenyllithium, followed by oxidation with an aqueous
H2O2 solution to yield unsymmetrically substituted triaryl-
phosphine oxide 5a. The mixture was subsequently treated
with AgNO3 to promote deprotection of the dithiolane moiety.
All these procedures were conducted in one pot without
isolation of any intermediates to yield 2a in 47% over four
steps from PhPCl2.
Subsequently, the third aryl group was introduced. The
nucleophilic addition of Grignard reagents, such as o-tolyl-
magnesium bromide and 2,6-dimethylphenylmagnesium
POF-Me
POF-Me2
SNAPF-Me2
Scheme 3 Synthesis of POFs.
bromide, to 2a cleanly afforded diastereoisomer mixtures of
3a-Me and 3a-Me2, respectively. Without isolation of the
products,
a
subsequent intramolecular Friedel-Crafts
cyclization was conducted (Scheme 2). A screening of Lewis
and Brønsted acids including AlCl3, Sc(OTf)3, TsOH, and
camphorsulfonic acid showed that TsOH most effectively
promoted the intramolecular Friedel-Crafts reaction. The
cyclization produced two regioisomers (6aa and 6ab), both of
which were obtained as a mixture of cis/trans isomers with
respect to the orientation of the C–Ar and P–Ph bonds.§
Purification by column chromatography afforded trans-6aa-Me
and trans-6aa-Me2 in 38% and 23% yield, respectively.
Finally, the oxidation of trans-6aa-Me and trans-6aa-Me2
with t-BuONa under an atmosphere of oxygen afforded the
corresponding benzylic alcohols 7aa-Me and 7aa-Me2 (Scheme
3). Further treatment with HBr furnished POF-Me and POF-
Me2 in good to excellent yields.
2)
S
1)
S
MeO
Li
Cl
Cl
ClZn
THF
OMe
P
Cl
P
OMe
THF, –98 °C
3) H2O2 aq., 0 °C
Ph
–78 °C to rt
Ph
4a
O
P
S
S
4) AgNO3
EtOH/H2O
rt
MeO
P
OMe
MeO
OMe
O
Ph
O
Ph
5a
2a 47%
(4 steps)
In principle, this synthetic method should be applicable to
various unsymmetric POF analogues using appropriate
Scheme 1 Synthesis of unsymmetric triarylphosphine oxides via the consecutive
arylation of PhPCl2.
2 | J. Name., 2012, 00, 1-3
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6
(a)
(b)
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DOI: 10.1039/C7CC04323F
5
O3
H14
4
C7
C6
O1
C4
C13
C16
C3
C14
C8
C9
C5
P1
P1
C
A
B
3
O1
C2
O2
C12
O3
C17
C11
C10
C15
C1
H14
P1
O1
H14
O3
2
ε
1
(c)
0
400
500
600
700
800
900
1000
1100
Wavelength / nm
O
P
I
OH
HO
P
O
O
Ph
O
Ph
II
Fig. 3 UV-vis-NIR absorption (dashed lines) and fluorescence spectra (solid lines) for
POF-Me2 (blue) and SNAPF-Me2 (red) in pH-buffer solutions (pH
Na2CO3/NaHCO3) containing 1% DMSO.
= 9; 0.1 M
Fig. 2 X-ray crystal structures of (a) SNAPF-Me2 and (b) the corresponding dimer
through hydrogen bonds (thermal ellipsoids set to 50% probability; only selected atoms
are labeled) and (c) tautomerization of SNAPF-Me2.
diminished upon increasing the pH value of the solution from 3
to 11, and a new broad band emerged at λabs = 628 nm with an
isosbestic point at 537 nm (Fig. S9). This bathochromically
arylmetal reagents. As
a
proof-of-concept study,
a
seminaphtho-phospha-fluorescein (hereafter abbreviated to shifted absorption band under basic conditions was ascribed to
SNAPF-Me2) was synthesized using 7-methoxy-2-naphthylzinc an anionic form of POF-Me2. The photophysical properties of
chloride as a nucleophile in the first step (Schemes 1 and S2–4), POF-Me2 are almost identical to those of the previously
which afforded deep red crystals of SNAPF-Me2.
reported POF-Me,6 indicating that the increased steric demand
A single-crystal X-ray diffraction analysis revealed the at the 9-position does not affect the photophysical properties
characteristic features of unsymmetrically π-extended SNAPF- of POFs.
Me2 (Figs. 2a,b). Similar to POF, the π-conjugated skeleton in
In comparison with POF-Me2, SNAPF-Me2 exhibits a more
SNAPF-Me2 adopts a slightly bent structure due to an pronounced bathochromic shift of the absorption band at λabs
envelope-like geometry of the phosphorus-containing six- = 499 nm (pH = 3) to λabs = 654 nm (pH = 9), with an isosbestic
membered ring. The π-skeleton shows pronounced bond point at 550 nm (Fig. 3, Table 1, and Fig. S11). This difference
alternation, i.e., the C9–O3 bond [1.351(2) Å] is substantially was attributed to the expansion of the π-conjugation in
longer than the C2–O2 bond [1.239(2) Å]. The six-membered SNAPF-Me2 relative to POF-Me2. Notably, the π-expansion in
ring C1–C2–C3–C4–C13–C12 exhibits a higher degree of bond SNAPF-Me2 also affects the pKa value. Based on a plot of the
alternation than the six-membered rings in the naphthalene absorbance change at λabs = 654 nm, the pKa value of SNAPF-
moiety (C6–C16-C17–C11–C15–C14 and C7–C8–C9–C10–C17– Me2 was determined to be 7.7, which was much higher than
C16). Moreover, SNAPF-Me2 forms dimers in the crystal lattice, that of POF-Me2 (5.7) (Fig. S13). Considering the results of the
evident from the short interatomic distance between the O1 X-ray crystallographic and the NMR analyses, SNAPF-Me2
and O3 atoms (2.653 Å) in adjacent molecules, which indicates exhibits a certain naphthol character, which should be
the presence of intermolecular hydrogen bonds between a responsible for the increased pKa value.
phenolic proton on the naphthalene moiety and a phosphine
Under basic conditions, deprotonated SNAPF-Me2
oxide moiety.13 These structural features demonstrate the exhibited a sharp fluorescence band at λem = 744 nm (Fig. 3),
predominant contribution of the benzoquinone/naphthol which is by 88 nm bathochromically shifted relative to that of
tautomer I relative to the phenol/naphthoquinone tautomer II POF-Me2 (λem = 656 nm).§§ The Stokes shift of SNAPF-Me2
(Fig. 2c).
(1850 cm–1) is substantially larger than that of POF-Me2 (~ 700
DFT calculations at the B3LYP/6-31+G* level of theory cm–1), indicative of a more pronounced charge-transfer
revealed that tautomer I is by 6.23 kcal mol–1 more stable than character of the lowest-energy excited singlet state (S1) in
II. This difference results most likely from the larger aromatic SNAPF-Me2, where the unsymmetric structure plays a crucial
stabilization gained in I compared to II, which is due to the fact role. Geometry optimizations based on (TD-)DFT calculations
that only one benzene ring retains aromaticity in tautomer II, for the model compounds SNAPF-Me and POF-Me in S0 and S1
while two benzene rings in the naphthalene moiety of I can demonstrated that SNAPF-Me undergoes a large structural
retain aromaticity. An NMR analysis of SNAPF-Me2 suggested relaxation from the Frank-Condon state in S1 to form a more
that tautomer I is also the dominant species in dilute solution unsymmetric structure compared to the ground-state
at ambient temperature (Figs. S42–S48).
structure, with increased and decreased bond alternation in
The photophysical properties of POF-Me2 and SNAPF-Me2 the benzene and naphthalene moieties, respectively (Fig. S7).
were investigated in aqueous buffer solutions containing 1% This behavior stands in stark contrast to that of POF-Me, which
DMSO as a co-solvent (Fig. 3, Table 1, and Figs. S9–12). Both undergoes a symmetric structural change in S1 with a slightly
POF-Me2 and SNAPF-Me2 exhibited pH-dependent absorption increased bond alternation in both benzene rings (Fig. S6).
spectra similar to other fluoresceins. In the absorption
spectrum of POF-Me2, the absorption band at λabs = 488 nm
A comparison with known oxygen-containing seminaphtho-
fluoresceins (hereafter abbreviated as SNAFs; Fig. 4)14,15
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Table 1 Comparison of the photophysical properties and pKa values of SNAPF and
relevant fluorescein derivatives
and Technology Foundation and the Naito Foundation are
gratefully acknowledged. ITbM is supported by the World
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DOI: 10.1039/C7CC04323F
Premier International Research Center Initiative (WPI, Japan).
Absorption
λabs
nm
Fluorescence
Stokes
shift /
cm–1
Compound
/
ε / 104
λem
/
ΦFL
pKa
M–1 cm–1
2.87
nm
744
656
656
733
732
a
Notes and references
SNAPF-Me2
654
628
627
536
536
0.03b
0.32b
0.33b
n.d.
1850
680
710
5010
5000
7.7
5.7
5.7
8.2
–
a
POF-Me2
5.41
5.13
1.40
2.90
§
Their isomer ratios were determined based on the
POF-Mea,c
SNAF-Hd
integration ratio in the 31P NMR spectrum; for details, see ESI.
§§ At lower pH values, the emission spectrum of SNAPF-Me2 is
dominated by the deprotonated form, even though a second
emission band at λem = 655 nm can be assigned to the emission
from the neutral form (Fig. S12); for details, see: ESI.
SNAF-COOHe
0.0024
apH = 9 in an aqueous pH-buffer solution containing 0.1 M Na2CO3/NaHCO3.
bAbsolute fluorescence quantum yields were determined using an integrating
sphere system. cRef. 6. dRef. 14. eRef. 15.
1
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O
O
O
O
OH
HO
O
OH
SNAF-H
SNAF-COOH
2
3
4
5
Fig. 4 Chemical structures of seminaphtho-fluorescein SNAF-H13 and SNAF-COOH14
.
highlights the characteristic features of SNAPF as a scaffold for
NIR-emitting fluorescent probes. A significant difference
between SNAFs and SNAPFs is evident in their absorption
spectra, where SNAPF exhibits a bathochromically shifted
maximum wavelength by 118 nm compared to SNAF-H (λabs
=
536 nm) in their deprotonated forms. SNAPF moreover
exhibits a bathochromically shifted emission wavelength by 11
nm than SNAF-H (λem = 733 nm), while the fluorescence
quantum yield of e.g. SNAPF-Me2 (ΦFL = 0.03) remains by one
order of magnitude higher than that of e.g. SNAF-COOH (ΦFL
=
6
0.0024). Furthermore, the pKa value of SNAPF-Me2 (7.7) is
lower than that of SNAF-H (8.2), which is most likely due to the
electron-withdrawing character of the phosphine oxide moiety.
In light of the fact that the pH value of cytosol in living animal
cells ranges from 6.8–7.4, SNAPFs should thus represent
potentially suitable materials for pH-responsive fluorophores
for bioimaging.
In summary, we have established a robust synthetic route
to phospha-fluorescein dyes based on the consecutive
arylation of PhPCl2. This protocol provides not only facile
access to POFs with various bulky aryl groups at the 9-position,
but also to unsymmetric POF analogues, which are difficult to
synthesize using conventional methods. As an example of the
latter compound class, SNAPF was synthesized. Compared to
the symmetrically substituted POFs, SNAPF exhibited several
attractive properties, including a high pKa value, red-shifted
absorption, and NIR fluorescence, as well as a large Stokes
shift. This SNAPF may have potential utility as an NIR
fluorescence dye. Further structural modifications of POFs
directed towards applications in bioimaging are currently in
progress in our laboratory.
7
8
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X. Zhou, R. Lai, J. Beck, H. Li and C. Stains, Chem. Commun.,
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The authors would like to thank Prof. T. Sasamori (Nagoya
City Univ.), and Drs. M. Hirai and H. Oshima (Nagoya Univ.) for
their help for the single-crystal X-ray diffraction analysis. This 15 E. Azuma, N. Nakamura, K. Kuramochi, T. Sasamori, N.
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work was partly supported by the JSPS KAKENHI grant
16K13949. Further financial supports from the Nagase Science
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ChemComm
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DOI: 10.1039/C7CC04323F
Journal Name
COMMUNICATION
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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