Alkynylboration Reaction Leading to Boron-Containing π-Extended cis-Stilbenes as a Highly Tunable Fluorophore

Article abstract of DOI:10.1021/acs.orglett.9b01132

An unprecedented boron-containing fluorophore, π-extended cis-stilbene, obtained via alkynylboration reaction of alkynamide is reported. Boron-containing π-extended cis-stilbenes emit fluorescence with high quantum yields in the solid state and exhibit aggregation-induced emission enhancement. The broad substrate scope of the alkynylboration reaction offers facile access to electronically diverse structures, enabling fine-tuning of light absorption/emission characteristics. The boron-containing π-extended cis-stilbene with a diphenylamino group displays solvatofluorochromism via an intramolecular charge-transfer transition.

Full text of DOI:10.1021/acs.orglett.9b01132

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Alkynylboration Reaction Leading to Boron-Containing π‑Extended
cis-Stilbenes as a Highly Tunable Fluorophore
Marina Nogami,† Keiichi Hirano,*,† Kensuke Morimoto,† Masaru Tanioka,† Kazunori Miyamoto,†
Atsuya Muranaka,‡ and Masanobu Uchiyama*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Cluster for Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama
351-0198, Japan
S
* Supporting Information
ABSTRACT: An unprecedented boron-containing fluoro-
phore, π-extended cis-stilbene, obtained via alkynylboration
reaction of alkynamide is reported. Boron-containing π-
extended cis-stilbenes emit fluorescence with high quantum
yields in the solid state and exhibit aggregation-induced
emission enhancement. The broad substrate scope of the
alkynylboration reaction offers facile access to electronically
diverse structures, enabling fine-tuning of light absorption/
emission characteristics. The boron-containing π-extended cis-
stilbene with a diphenylamino group displays solvatofluor-
ochromism via an intramolecular charge-transfer transition.
considered to be due to the rigid structure8 made by the
luorescent organic molecules are widely used as imaging
1
Fprobes for medical diagnostics, elements of organic light-
boron-containing five-membered ring. Substituted stilbenes
emitting diodes (OLEDs),2 functional dyes,3 etc. Thus, there is
great interest in novel and highly tunable fluorophores. Small
organic compounds are especially useful due to their generally
good solubility in organic/aqueous solvents and the ease of
chemical elaboration of their molecular structures.4
We have extensively studied boration chemistry based on
inter-/intramolecular Lewis basic activation of boron reagents,5
and we recently developed a trans-alkynylboration reaction of
propargylic alcohols I without the aid of transition-metal
catalysts (Figure 1a).5b,6 Notably, the “boron-containing π-
extended cis-stilbene” products II emit very strong blue-violet
fluorescence upon excitation with ultraviolet (UV) light, even in
the solid state.7 The high fluorescence quantum yield is
such as tri- and tetraarylethylenes enjoy a position as major
players in the research field of aggregation-induced emission
enhancement (AIEE),9 which is a powerful tool for imaging of
proteins causing physical disorders, such as Alzheimer’s and
Parkinson’s diseases, as a result of aggregation.10 Our boron-
containing dye II is potentially of interest in this field, but a
major drawback is the limitation of available substituents at the
acetylenic terminus.5b Electron-rich aromatics can hardly be
installed, so the electronic status of the π-system cannot be
drastically modified. Here, in place of tertiary alkoxide used in
our previous studies,5b we focused on surrogates of carbox-
ylate11 as an activator of alkynylboronates in order to boost the
electrophilicity of the alkyne on the acceptor side and thus
enable a much broader choice of the terminal substituent
(Figure 1b).
Our preliminary investigation with phenylpropiolic acid was
not fruitful, as we had previously experienced in diboration
reaction.5d After exhaustive screening, we found that our
alkynylboration reaction was applicable to N-ethylpropiolamide
(1a) to afford the desired boron-containing π-extended cis-
stilbene 3a, which showed a blue fluorescence emission with a
good fluorescence quantum yield (λem = 420 nm, ΦFL = 37.4%)
upon irradiation with a UV lamp, as envisioned (Scheme 1).
After a brief investigation of the reaction conditions,12 3a was
obtained in 92% yield. It is important to note that this
Figure 1. Synthesis of boron-containing π-extended cis-stilbenes:
alkynylboration of alkyne via pseudo-intramolecular activation.
Received: March 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Proof of Concept
transformation can easily be scaled up without loss of yield (1.16
g, 91%).
The structure of 3a was confirmed unequivocally by single-
crystal X-ray analysis (Figure 2a). The boron center is
Figure 3. AIEE character of compound 3a in mixtures of water and
THF: (a) emission intensity; (b) transition of fluorescence.
a
Scheme 2. Generality of N-Substituents
Figure 2. (a) Single-crystal X-ray diffraction analysis of 3a with a
molecule of water of crystallization (thermal ellipsoids at 50%
probability). (b) Crystal packing (P−1 (No. 2) prepared from
CH2Cl2/nhexane) without hydrogens and water for clarity. Numbers
indicate bond length or distance between atoms (Å).
significantly pyramidalized, and the bond lengths of B−Csp2
(1.627(2) Å) and B−Oamide (1.601(2) Å) indicate a strong
interaction between boron and oxygen, judging from the sum of
the covalent radii (B−Csp2 1.57 Å; B−O 1.50 Å).13 The 11B
NMR signal measured in CDCl3 was observed at 15.2 ppm, and
this value supports the sp3-hybridized structure of the boron
center.11d,12 These observations indicate that the coordination
of the oxygen atom of the amide moiety to boron efficiently
rigidifies the molecular structure both in the solid state and in
solution. The π-conjugated systems of two molecules in a grid
are far apart (3.91 Å) owing to the repulsive interaction between
them, which arises from the vertically positioned Bpin group.
Electronic communication such as π−π stacking between
molecules, which would result in fluorescence quenching, is
thus avoided, and this should be one of the reasons why 3a is
highly fluorescent even in the solid state.
Compound 3a also shows AIEE character (Figure 3). The
emission spectra of 3a dissolved in mixtures of THF and water in
various ratios were measured. The emission intensity gradually
increased as the water content was increased and increased
sharply at around 80% water content. The emission wavelength
(420 nm) is slightly shorter than that of the representative AIEE
compound, tetraphenylethylene (430 nm).14 Thus, the boron-
containing π-extended cis-stilbene is expected to be an attractive
platform for expanding the scope of AIEE compounds.
a
b
c
d
Isolated yields. 3.2 mmol scale, 1.16 g. Not detected. 1.0 equiv of
e
nBuLi. er of 1l: 98.8:1.2.
products containing thiophene-based electron-rich heterocycles
were also obtained (5n−p), whereas an attempt to prepare the
2-pyridyl product 5q failed, probably due to instability of the
starting material 4q under the reaction conditions. Enyne
substrates can be used in this reaction (5r, 5s). Efficient
conversion of methyl-, hydrogen-, and silyl-substituted alkynes
(4t−v) requires further improvement of the reaction system.
Simple enyne products without an aryl substituent at the vinylic
position such as 5t do not emit strong fluorescence in the
solution or in the solid state.12 This fact clearly indicates the
importance of the “π-extended cis-stilbene” structure as a
fluorophore. Alkynylboronates with an alkyl substituent are also
applicable (6a, 6b), whereas the silyl substrate was not
productive (6c).
The absorption−emission properties of representative
compounds are shown in Table 1. The products exhibit large
Stokes shifts (ca. 5000−10000 cm−1) and emit visible
fluorescence with good to excellent fluorescence quantum yields
(ΦFL). Moreover, the emission wavelength can be fine-tuned by
the appropriate choice of substituent at the acetylenic terminus.
Quantum yields in the solid state are generally much higher than
those in the solution state due to suppression of the twisting
Available boron-containing π-extended cis-stilbene structures
are summarized in Schemes 2 and 3. Various N-substituents of
the amide moiety are tolerated (Scheme 2). The products with
N-alkyl (3a−g, 3i−l) and -aryl groups (3n−q) are generally
obtained in high yields. The siloxyethyl (3i), allyl (3j), and
propargyl (3k) substitutents are especially attractive with
respect to further chemical transformations. Enantiopure (R)-
phenethyl amide 1l was converted to 3l without loss of optical
purity.15
A variety of aromatic groups can be installed on the π-
extended cis-stilbene products 5a−m as well (Scheme 3). The
B
DOI: 10.1021/acs.orglett.9b01132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
the solid state caused by a rigid and planar π-system of the
carbazole unit.
Scheme 3. Wide Spectrum of Products
The boron-containing π-extended cis-stilbene 5f with the
highest fluorescence quantum yield was further investigated in
solution. The fluorescence wavelength is largely dependent on
the solvent, and a vivid color change from blue to yellow was
observed as the solvent polarity was increased (Figure 4a). DFT
Figure 4. (a) Solvatofluorochromism of 5f (λex = 300 nm), Y-axis was
normalized at the maximum fluorescence intensity. (b) Frontier
molecular orbitals of 5f computed at the level of B3LYP/6-31G*.
calculations revealed that the HOMO is mainly localized over
the triarylamine moiety and the LUMO covers the ene−yne−
amide unit (Figure 4b). Detailed analysis by means of time-
dependent DFT calculations characterized the absorption band
at 425 nm (see Scheme 3, 5f) as being the intramolecular charge-
transfer (ICT) transition from the HOMO to the LUMO, and
this result is in good accordance with the solvatofluorochromism
displayed by 5f. Environmental stimulus-dependent fluorescent
materials can be used as molecular sensors16 and for bioimaging,
and we anticipate that our modular boron-containing π-
extended cis-stilbenes will find versatile applications in these
fields.
a
b
c
n
Isolated yields. 1.0 equiv of BuLi. Not detected.
Table 1. Absorption−Emission Properties of Compound 5
Finally, we examined chemical transformations of the π-
extended cis-stilbene 3 (Scheme 4). In view of the potential
Scheme 4. Transformations
future applications of 3 for molecular sensors and bioimaging,
their suitability for ligation reactions is an important
consideration. We found that the Huisgen cycloaddition
reaction of 3k successfully afforded the triazole product 7 in
90% yield with the boron-containing π-extended cis-stilbene
moiety remaining intact.17 In addition, a BODIPY-like product
8 was obtained by adopting the protocol for preparation of
Molander’s trifluoroborates.18 Strong coordination of the amide
a
Wavelengths in the solid state. Those in CH2Cl2 are in square
b
brackets. Value of the samples in the solid state. Those in CH2Cl2 are
in square brackets. Photographs were taken under UV irradiation at
365 nm.
c
motion of the aryl rings. Compound 5g exceptionally shows the
opposite character, which may be attributed to π−π stacking in
C
DOI: 10.1021/acs.orglett.9b01132
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Jeong, J. H.; Song, J.; Lee, J. Y.; Kwon, J. H. ACS Appl. Mater. Interfaces
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function to boron presumably inhibits the third C−F bond
formation.
In summary, we designed an alkynylboration reaction leading
to an unprecedended boron-containing π-extended cis-stilbene
possessing enormous potential as a luminophore. A wide variety
of these compounds can be easily accessed by the alkynylbora-
tion of alkynamides via pseudo-intramolecular activation. The
fluorescence emission wavelength in the solid state depends on
the substituent at the acetylenic terminus, and aryl substituents
endow the enyne compound with high fluorescence quantum
yield and AIEE character. Detailed studies on the properties of
the boron-containing π-extended cis-stilbenes, focusing on
applications as molecular sensors and bioimaging, are ongoing
in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01132.
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Accession Codes
CCDC 1886119 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: k1hirano@mol.f.u-tokyo.ac.jp.
*E-mail: uchiyama@mol.f.u-tokyo.ac.jp.
ORCID
(11) For transition-metal-free boration of propiolic acid derivatives,
see: (a) Fritzemeier, R.; Gates, A.; Guo, X.; Lin, Z.; Santos, W. L. J. Org.
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(12) See the Supporting Information.
Keiichi Hirano: 0000-0002-2702-9183
Masaru Tanioka: 0000-0003-4714-061X
Kazunori Miyamoto: 0000-0003-1423-6287
Atsuya Muranaka: 0000-0002-3246-6003
Masanobu Uchiyama: 0000-0001-6385-5944
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
́
(13) Cordero, B.; Gomez, V.; Platero-Prats, A. E.; Reves, M.;
This work was partly supported by JSPS KAKENHI (S) (No.
24229011), The Asahi Glass Foundation, Foundation NAGASE
Science Technology Development, and Sumitomo Foundation
(to M.U.), JSPS Grant-in-Aid for Young Scientists (A) (No.
16H06214) (to K.H.) and Challenging Research (Exploratory)
(No. 18K19390) (to K.H.). The calculations were performed on
the RIKEN HOKUSAI GreatWave and BigWaterfall. We thank
the Advanced Center for Computing and Communication
(RIKEN) for providing computational resources.
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2008, 2832.
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DOI: 10.1021/acs.orglett.9b01132
Org. Lett. XXXX, XXX, XXX−XXX