Photosensitizer-free visible light-mediated gold-catalysed: Cis -difunctionalization of silyl-substituted alkynes

Article abstract of DOI:10.1039/c7sc02294h

A new photosensitizer-free visible light-mediated gold-catalysed cis-difunctionalization reaction is developed. The reaction was chemoselective towards silyl-substituted alkynes with excellent regioselectivity and good functional group compatibility, givi

Full text of DOI:10.1039/c7sc02294h

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. K. Wong, J.
Deng, W. Chan, N. C. Lai, B. Yang, C. Tsang, B. C. Ko and S. L. Chan, Chem. Sci., 2017, DOI:
1
0.1039/C7SC02294H.
Volume
7
Number
1
January 2016 Pages 1–812
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemical
Science
Accepted Manuscripts are published online shortly after
www.rsc.org/chemicalscience
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Francesco Ricci et al.
Electronic control of DNA-based nanoswitches and nanodevices
rsc.li/chemical-science

Page 1 of 9
Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
View Article Online
DOI: 10.1039/C7SC02294H
Journal Name
ARTICLE
Photosensitizer-free visible light-mediated gold-catalysed cis-
difunctionalization of silyl-substituted alkynes
ab
b
ab
ab
b
Jie-Ren Deng, Wing-Cheung Chan, Nathanael Chun-Him Lai, Bin Yang, Chui-Shan Tsang, Ben
Received 00th January 20xx,
Accepted 00th January 20xx
b†
ab†
ab
Chi-Bun Ko, Sharon Lai-Fung Chan, and Man-Kin Wong*
DOI: 10.1039/x0xx00000x
A new photosensitizer-free visible light-mediated gold-catalysed cis-difunctionalization reaction is developed. The reaction
was chemoselective towards silyl-substituted alkynes with excellent regioselectivity and good functional group compatibility,
giving a series of silyl-substituted quinolizinium derivatives as products. The newly synthesized fluorescent quinolizinium
compounds, named JR-Fluor-1, possessed tunable emission properties and large Stokes shifts. With unique photophysical
properties, the fluorophores have been applied in photooxidative amidations as efficient photocatalysts and cellular imaging
with switchable subcellular localization properties.
www.rsc.org/
afforded in the majority of the examples.3c,e,5c,6a However,
Introduction
Over the past years, homogeneous gold catalysis has become a
powerful tool for synthesis of complex organic molecules,
particularly in activation of C–C multiple bonds with gold
catalysts acting as strong soft π-Lewis acids. In recent years,
instead of accessing hydrofunctionalized products, a promising
cross-coupling strategy involving Au(I)/Au(III) catalytic cycles
visible light-mediated cis-difunctionalization of alkynes still
remains largely unexplored. Inspired by a stereo- and
7
regioselective gold-catalysed hydroamination of internal
8
alkynes reported by Stradiotto et al., we set out to combine
visible light mediated Au(I)/Au(III) catalysis with plausible syn
insertion pathway to achieve alkyne cis-difunctionalization
1
7
b-c
products.
2
has been developed to afford difunctionalized products. With
a significantly high redox potential of Au(I)/Au(III) couple, strong
oxidants are required to access the oxidation of Au(I) species,
while the functional group compatibility could be hampered.3a
A complementary approach to overcome this barrier was
3
4
developed by Glorius and Toste through merging gold
catalysis with photoredox catalysis, which promoted oxidation
of Au(I) species employing photosensitizers and aryl radicals
generated in situ under irradiation. This approach inspired the
development of diverse organic transformations including
Scheme 1 Literature works and our strategy for visible light-
mediated gold-catalysed alkyne cis-difunctionalization.
Development of organic fluorescent materials has become
an emerging and important research area due to their wide
applications in chemistry, biology and materials science.9
Compared to the intensive investigations on scaffolds such as
3b-c,4b
5a
3e,5b-c
difunctionalization of alkenes,
allenes and alkynes,
and C–P4c cross-coupling reactions.
Recently, Hashmi and co-workers reported visible light-
3d,4d,5d-f
as well as C–C
6a
mediated gold-catalysed oxyarylation of alkynes and aryl-aryl
1
0
fluorescein, BODIPY and recently Seoul-Fluor, only a few
examples of cationic fluorophores have been reported,
although the unique properties of fluorophores containing
positive charge have been demonstrated in photocatalysis and
6
b
coupling reaction which could be conducted without addition
of photosensitizers.
For alkyne difunctionalization reactions, undergoing an anti
nucleophilic addition, trans-difunctionalized products are
1
1
cellular imaging.
Quinoliziniums, cationic aromatic
heterocycles bearing quaternary bridgehead nitrogen, were
firstly investigated in alkaloids chemistry and recently employed
a.The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen,
12
People’s Republic of China
State Key Laboratory of Chirosciences and Department of Applied Biology and
as efficient DNA intercalators.
However, structure
b.
photophysical property relationship (SPPR) studies and
applications in photocatalysis and cellular imaging of
Chemical Technology, The Hong Kong Polytechnic University, Hung Hum, Hong
Kong
13
†
Dr. Sharon Lai-Fung Chan designed and performed the spectroscopic studies and
quinolizinium compounds still remain elusive.
Along with our ongoing interest in gold-catalysed organic
computational experiments of this research. Dr. Ben Chi-Bun Ko designed the
cellular imaging experiments.
Electronic Supplementary Information (ESI) available: [details of any supplementary
14
transformations, herein, we report a new photosensitizer-free
information available should be included here]. See DOI: 10.1039/x0xx00000x
visible light-mediated gold-catalysed alkyne cis-difunctionaliza-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Page 2 of 9
ARTICLE
Journal Name
tion reaction affording a series of silyl-substituted fluorescent chemoselective towards silyl-substituted alkynesV.ieTwoArtsiculepOpnolinret
quinolizinium compounds. Spectroscopy experiments and DFT our hypothesis, alkyne 2z bearing DdOipI:h1e0.n10y3le9t/hCy7SnCy0l22a9n4Hd
calculations were conducted to study the SPPR of the trimethylsilylethynyl
groups
was
used,
and
only
quinolizinium derivatives. Applications of the fluorescent trimethylsilylethynyl cis-difunctionalization product 4w was
quinolizinium compounds as efficient photocatalysts for obtained in 46% yield, which convinced us of the
photooxidative amidation and as fluorescent dyes for live cell chemoselecitivty of this gold-catalysed transformation. Further
imaging have also been conducted.
expansion of the scope employing diazoniums 1b
different structure skeletons and heterocycles gave desired
products 5a and 6a in up to 60% yield. These results indicated
that the reaction was well compatible with various diazoniums
and highly selective towards silyl-substituted alkynes.
-d bearing
-
c
Results and discussion
We initiated the reaction screening by treatment of
quinoline-substituted aryl diazonium 1a (0.12 mmol, 1.2 equiv.),
Table 1 Optimization of Reaction Conditions and Control
a
Experiments
(4-fluorophenylethynyl)trimethylsilane 2a (0.10 mmol, 1 equiv.)
with Ph PAuCl 3a (10 mol%) to afford silyl-substituted
3
quinolizinium 4a in 71% yield (Table 1, entry 1). To our surprise,
no cross-coupling product 4aa (reported by Toste et al. using
phenyl diazoniums as substrates) was obtained in our
4
d
experiments.
Besides, the reaction was exceptionally
regioselective giving no regioisomer 4a’. The gold(I) catalyst 3b
bearing comparatively electron-rich phosphine led to a lower
yield of product formation, while catalysts 3c
electron-poor phosphine gave higher yields of 4a (entries 3-4).
No desired product was obtained when Ph PAuBF 3e was
employed as catalyst (entry 5). Using gold(I) catalyst 3f
possessing diphosphine ligand led to product formation in 21%
yield (entry 6). Only a trace amount of product was observed
when simple AuCl 3g was used (entry 7). In addition, employing
-d bearing
3
4
Au
cat.
N2/
Air
Yield
[%]
71
Entry
Photo cat.
Light
Solvent
b
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
-
-
-
-
-
-
-
-
-
-
-
bluec
bluec
bluec
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
N
2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
58
75
gold(III) catalysts 3h
-
j
resulted in no product formation (entries
bluec
83
n.d.d
8
-10). Without addition of gold catalyst, no desired product was
bluec
bluec
bluec
bluec
bluec
bluec
observed (entry 11), indicating that the gold(I) phosphine
chloride catalyst played a crucial role in this transformation.
21
3g
3h
3i
trace
n.d.d
n.d.d
Addition of transition metal-based photocatalysts Ru(bpy)
3 2
Cl ,
Ru(bpy) (BF , Ir(ppy) or organic photocatalyst Rose Bengal
3
4
)
2
3
led to lower yields of the desired product (entries 12-15).
Control experiment in dark gave no product formation (entry
n.d.d
1
1
1
1
1
0
1
2
3
4
3j
1
6). These results suggested that this reaction was conducted
bluec
n.d.d
-
under photosensitizer-free reaction conditions. Additionally,
only a trace amount of product was detected when the reaction
was conducted in toluene, dichloromethane or methanol as
solvent (entries 17-19), and a lower yield (35%) of product was
afforded when the reaction was carried in open air (entry 20).
With the optimized reaction conditions, we expanded the
scope of this reaction by using various diazoniums (0.60 mmol,
3a
3a
3a
3a
3a
3a
3a
3a
3a
Ru(bpy)
Ru(bpy) (BF
Ir(ppy)
3
Cl
2
bluec
bluec
bluec
bluec
9
3
4
)
2
trace
trace
65
n.d.d
trace
trace
trace
35
3
15
16
Rose Bengal
-
-
-
-
-
dark
bluec
bluec
bluec
bluec
1
1
1
2
7
8
9
0
Toluene
CH Cl
OH
CN
1
.2 equiv.) and alkynes (0.50 mmol, 1.0 equiv.) as substrates.
2
2
Silyl-substituted alkynes 2a bearing ether, alkyl, halogen,
-
q
CH
3
aldehyde, carboxylic acid, cyanide, trifluoromethyl, nitro and
hetero-aromatics as substituents were well tolerated with the
Air
CH
3
a
reactions giving quinolizinium products 4a
-
q
in 31-69% yield.
Reaction conditions: treatment of 1a (0.12 mmol), 2a (0.10 mmol),
gold catalyst 3a (10 mol%) with or without photocatalyst (5 mol%)
in 5 mL of solvent under N
at room temperature for 16 h. b Yield of
Increasing the steric bulkiness using ortho-disubstituted
phenylethynylsilane 2r gave a trace amount of product. Using
triethylsilyl group gave quinolizinium 4u in slightly lower yield
-j
2
4a was determined by 19F-NMR using fluorobenzene as internal
c
(
45%). Further increasing the bulkiness employing tert-
butyldiphenylsilyl-substituted alkyne 2t gave no product 4v
Interestingly, employing terminal alkyne phenylacetylene 2u
standard. Blue LEDs (λmax = 469 nm) was employed as light source.
d
.
,
n.d.: product formation could not be detected.
To provide insight on this visible light-mediated gold-
cyclohexylacetylene 2v or internal alkyne 1,2-diphenylethyne catalysed cis-difunctionalization reaction, stoichiometric
, 1-phenyl-1-propyne 2x, 1-phenyl-1-butyne 2y gave no reactions were set up by treatment of aryl diazonium 1a (0.10
2
w
desired product 7a-e, suggesting that the reaction was mmol) with Ph
3
PAuCl 3a (0.10 mmol) under irradiation for 0 to
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 9
Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Journal Name
ARTICLE
1
2
40 min. H-NMR monitoring revealed that aryl diazonium 1a
View Article Online
DOI: 10.1039/C7SC02294H
consumed and new signals appeared gradually from 0 to 60 min,
suggesting the formation of plausible intermediates (Fig. 1a).
Irradiation for longer time gave slight decomposition of the
plausible intermediates. These results were consistent to those
observed by P-NMR analysis, which indicated gradual
appearance of new signals at 31.0, 44.2 and 45.3 ppm (Fig. 1b).
The reaction mixtures were further treated with silyl-
substituted alkyne 2a (1.5 equiv.) for 60 min in dark, resulting in
disappearance of the newly observed signals after irradiation
and concomitant formation of the signals of the quinolizinium
product 4a (Fig. S3a-b in the ESI†). The yield of the product
(
a)
31
19
formed was monitored by F-NMR analysis through addition of
fluorobenzene as internal standard (Fig. S3c in the ESI†). In
addition, regeneration of the Ph PAuCl 3a could be recovered
3
as precipitates from the reaction mixtures.
Table 2 Expansion of the substrate scopeab
(
b)
1
Fig. 1 (a) H-NMR studies on reaction mixtures
X
0-240min in CD
3
CN;
3
1
(
b) P-NMR studies on reaction mixtures
X0-240min in CD CN.
3
Due to difficulties in isolation of the reaction intermediates,
we sought to investigate the plausible Au(III) species through
ESI-MS analysis by treatment of aryl diazonium 1a (0.12 mmol)
with Ph
Experimental results indicated that rather than the formation of
(m/z = 204.0792) by displacement of N of 1a in ESI-MS
analysis, plausible Au(III) intermediates (m/z = 698.1014) and
B’ (m/z = 960.1910) were found (Fig. 2a). Further treatment of
the afforded reaction mixture with silyl-substituted alkyne 2a
1.5 equiv.) in dark for 1 h afforded reaction mixture Y’. ESI-MS
analysis of reaction mixture Y’ revealed that no signal of or B’
was observed, and the signal of quinolizinium product 4a
appeared, suggesting that both and B’ were consumed and
reacted with 2a to form quinolizinium product 4a (Fig. 2b). For
detailed understanding of the plausible Au(III) intermediates
3
PAuCl 3a (0.10 mmol) under irradiation for 1 h.
A
2
B
Y
(
B
B
B
a
and B’, ESI-MS/MS analysis of species B (precursor ion m/z = 698)
and B’ (precursor ion m/z = 910) was conducted. Product ions
phosphonium B-I (m/z = 459.0483) and Au(I) species B-II (m/z =
Reaction conditions: treatment of 1a
mmol) and 3a (10 mol%) in 5 mL of CH
LEDs) and N
-
d
(0.60 mmol), 2a
-z (0.50
3
CN under irradiation (blue
at room temperature for 16 h. b Isolated yield.
2
4
66.1634) were found in MS/MS analysis of species B (Fig. S4a
in the ESI†). Formation of B-I was assumed to be ascribed to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Page 4 of 9
ARTICLE
Journal Name
B, which was found at λabs > 395 nm (Fig. 3a), suggesting that aryl diazoniums
reductive elimination of the Au(III) species
previously reported as a feasible deactivation pathway of could be firstly excited to initiate the DreOaI:c1t0io.1n0.39 To further
phosphine-supported aryl Au(III) complexes.15 In MS/MS support our hypothesis, we measured the difference of the
View Article Online
17
/C7SC02294H
analysis of species B’, product ions of
m/z = 466.1672) and B-II (m/z = 459.0518) were found (Fig. S3b equiv.) with 1a. Spectroscopic analysis indicated that the
in the ESI†). Results suggested that species B’ was composed of fluorescence of 1a could be quenched (I /I = 0.68) after
Au(III) species and triphenylphosphine and presumably addition of Ph PAuCl 3a, providing strong evidence for electron
formed by possible transmetallation. Control experiment transfer from Ph PAuCl 3a to aryl diazonium 1a under
under the same reaction conditions without irradiation led to irradiation (Fig. 3b). In addition, the estimated excited state
no formation of the Au(III) species B’ or product 4a
reduction potential (E*red) of aryl diazonium 1a was 3.28 V,
suggesting that light source was necessary for promotion of the which was much more higher than the redox potential of
3
B (m/z = 698.0994), B-I fluorescence intensity before and after mixing Ph PAuCl 3a (1
(
q
0
B
3
16
3
B
,
,
18
Au(I)/Au(III) transformation in this reaction.
Au(I)/Au(III) couple (E
0
= 1.41 V), indicating that the Ph
3
PAuCl
3
a
could be oxidized by the aryl diazonium 1a in the first step of
(a)
the reaction.
(
a)
2
1
0
.5
2
.5
1
.5
0
250
300
350
400
450
500
550
600
650
700
Wavelength (nm)
(
b)
1
a1a
a1+aP+h3PPhA3uACulCl 3a
(
b)
1
370
420
470
520
570
620
670
Wavelength (nm)
Fig. 3 (a) UV/Vis absorption spectrum of aryl diazonium 1a; (b)
fluorescence quenching of aryl diazonium 1a with Ph PAuCl 3a
3
.
Based on the aforementioned experimental results, a
reaction mechanism is proposed as below (Scheme 2). Under
irradiation, the aryl diazonium compound is firstly excited and
subsequently reduced by single electron transfer from Au(I)
catalyst 3a to form an aryl radical with the generation of a Au(II)
species. The Au(II) species further recombines with the aryl
radical to give Au(III) intermediate
on Au(I) catalyst 3a to form Au(III) intermediate
possible to be a concerted reaction pathway rather than a two-
B
. The oxidation and addition
B
is also
6a
Fig. 2 (a) ESI-MS analysis of the reaction mixture
analysis of the reaction mixture Y’
Y
; (b) ESI-MS step process. The reaction quantum yield was found to be 0.91
(less than 1), suggesting that the radical chain process was not
.
To study the photosensitizer-free reaction conditions, we prominent in this transformation. Then, silyl-substituted alkyne
measured the UV/Vis absorption properties of aryl diazonium is activated by Au(III) intermediate through π-activation to
and Ph
PAuCl 3a. Spectroscopic analysis revealed that no give species . After that, the Au–N bond is regioselectively
absorption peak of Ph
PAuCl 3a was observed at λabs > 395 nm inserted by the π-activated alkyne to form cis vinyl gold species
Fig. S6 in the ESI†), indicating that Ph PAuCl 3a might not be
Then, reductive elimination provides quinolizinium
directly excited by the light source in this reaction which was compound as the cis-difunctionalized product and regenerates
consistent to literature works indicating that photosensitizer the Au(I) catalyst 3a
B
1
a
3
C
3
(
3
D.
.
3
-5
19
was necessary to initiate the reaction. On the contrary, a tail
Pioneered by Cheng and co-workers, rhodium-catalysed
of the lowest energy absorption peak of aryl diazonium 1a was C–H bond activation followed by annulation has been used as a
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 9
Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Journal Name
ARTICLE
powerful tool for synthesis of disubstituted quinolizinium quantum yield up to 0.59. Incorporation of electVrioewn-AdrtoiclneaOtnilninge
compounds. We sought to compare the newly developed groups at the para-position of phenyl moDieOtIy: 1o0r.1i0n3t9r/oCd7uSCc0ti2o2n94oHf
approach of gold-catalysed cis-difunctionalization with the π-excessive heteroaromatics resulted in bathochromic shifts of
rhodium catalysis. Optimized reaction employing 2- the emission properties. Further bathochromic shifts were
phenylquinoline (0.1 mmol, 1 equiv.) with internal alkyne 1,2- observed by introduction of electron-withdrawing ester group
diphenylethyne 2w (0.1 mmol, 1 equiv.), [Cp*RhCl
2 2
] (5 mol%) on the quinolizinium moiety. Substituents bearing heavy atoms
and AgBF (0.1 mmol, 1 equiv.) in 1,2-dichloroethane under (Cl, Br, I) led to lower quantum yields. A positive
4
open air at room temperature for 16 h afforded diphenyl- solvatochromism was found in compound 4b, which indicated
substituted quinolizinium 7c in 68% yield. However, when 1- an increase of dipole moment of the excited state compared to
phenyl-2-trimethylsilylacetylene 2d was employed as substrate, its ground state (Fig. S8 in the ESI†). An unexpectedly low
no desired product 4d was formed. To our knowledge, the quantum yield of 5a (0.02) bearing a dimethylamine substituent
present photosensitizer-free visible light-mediated gold- was observed, in which the fluorescence was proposed to be
catalysed alkyne cis-difunctionalization is the first example for quenched by the amine group via intramolecular photo-induced
highly regioselective synthesis of silyl-substituted quinolizinium electron transfer (PeT). Cyclic voltammetry (CV) experiments
compounds.
indicated a quasireversible oxidation couple at +1.08 V (vs SCE)
of 5a which was originated from the presence of amine group
and no similar peak was found in 5c (ESI†). Protonation of the
amine group by measuring the emission in HCl/NaOH buffer (pH
changing from 7 to 1) gave a ≥ 100 fold enhancement of the
emission intensity at shorter wavelength (λem = 436 nm) which
supported our hypothesis (Fig. S9 in the ESI†).
Table 3 Photophysical properties of quinolizinium compounds 4a-q,
a
s-u, w and 5a-c
Absorption maximum
Emission
maximum
λ
Stokes
shift
(cm )
Quantum
4
Cpd.
λ
abs (nm) (ε (10
b
yield Ф
F
3
-1
-1
-1
dm mol cm ))
423 (1.39)
430 (1.14)
428 (1.10)
423 (1.45)
424 (1.62)
422 (0.95)
424 (1.00)
423 (1.06)
417 (0.75)
420 (1.30)
420 (1.17)
419 (1.23)
423 (1.45)
424 (1.68)
428 (1.43)
421 (1.50)
423 (1.80)
446 (0.79)
446 (1.05)
424 (1.42)
427 (1.05)
397 (1.74)
405 (1.23)
401 (1.09)
em (nm)
495
569
507
491
494
493
493
480
484
479
479
476
506
508
547
511
511
640
557
494
555
495
504
450
4
a
b
3439
5681
3640
3275
3342
3413
3301
2807
3320
2933
2933
2858
3878
3900
5363
4183
4071
6797
4468
3342
5401
4987
4850
2840
0.49
0.17
0.44
0.44
0.37
0.16
0.03
0.28
0.44
0.28
0.34
0.24
0.18
0.16
0.02
0.11
0.16
0.01
0.08
0.41
0.07
0.02
0.30
0.59
4
4
c
Scheme 2 Proposed reaction mechanism.
4
d
e
4
4
f
4
g
Scheme 3 Rhodium-catalysed synthesis of quinolizinium
compounds.
4
h
4
i
X-ray crystal structure analysis revealed
a twisted
4
j
conformation of quinolizinium 4b, with a torsion angle of
4
k
o
1
07.84 (C1-C2-C18-C19), suggesting that the molecule could be
4
l
divided into two parts: a slightly distorted planar quinolizinium
moiety and a phenyl moiety. This twisted structure suggested
that the two moieties should be weakly coupled conjugatively.
4
m
4n
4
4
4
o
p
q
4
s
t
4
4
u
Fig. 4 X-ray crystal structure of 4b (front view, left view and
vertical view).
4
w
5
a
b
After synthesis of the new silyl-substituted quinolizinium
compounds, we moved on to study their absorption and
emission properties (Table 3). Interestingly, these compounds
possessed lowest energy absorption maximum at λabs > 395 nm,
full color tunable emission properties (λem = 450 to 640 nm) in
5
5
c
a
Absorption and emission properties were measured in CH
2
2
Cl at the
concentration of 1 × 10-5 M. Quantum yields were measured using
b
fluorescein (Ф = 0.95 in 0.1 N NaOH buffer) as standard.
F
-1
visible light region and large Stokes shifts (up to 6797 cm ) with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Page 6 of 9
ARTICLE
For detailed investigation of the SPPR of the quinolizinium com-
Journal Name
View Article Online
pounds, compound 4d was subjected to TDDFT calculation. Results
reveal that the lowest energy absorption band at 435 nm is
originated from HOMO→LUMO. HOMO is composed of π orbital of
quinolizinium and phenyl ring whereas LUMO is composed of π* of
quinolizinium ring. The low energy absorption band can be assigned
as admixture of π→π* transition within the quinolizinium ring and
π→π* transition from phenyl to quinolizinium ring. Hence,
bathochromic shifts were observed by introduction of ester group at
C9 (LUMO was dominant) and introduction of electron-donating
groups at C21 (HOMO was partially dominant).
In line with our interest in amide synthesis,20 we envisioned that
the newly developed quinolizinium fluorophores could be utilized as
photocatalysts for photooxidative amidation of aldehydes and
secondary amines. We first investigated the catalytic activities by
treatment of 4-nitrobenzaldehyde 8a (0.1 mmol, 1 equiv.), piperidine
DOI: 10.1039/C7SC02294H
Fig. 5 HOMO and LUMO diagrams of 4d.
Table 5 Photooxidative amidation of aldehydes with secondary
a
amines
9a (0.2 mmol, 2 equiv.), Na
2
CO
3
(0.2 mmol, 2 equiv.) and selected
photocatalysts (5 mol%) in CH
3
CN under irradiation (blue LEDs) and
air for 16 h. Interestingly, the catalytic activities of quinoliziniums
were comparable or even better than the currently used
photocatalysts. The reaction was optimized using 4e as photocatalyst
to afford amide 10a in 86% yield after 48 h. Expansion of the scope
employing different aldehydes and secondary amines gave amides
10b-g in up to 84% yield (Table 5). Further investigations revealed
that the quinolizinium compounds possessed tunable and high
excited state reduction potential (E*red = 1.97 to 2.23 V), which were
comparable to the well-known photocatalyst 9-mesityl-10-
a
Reaction conditions: treatment of 8a-d (0.1 mmol, 1 equiv.), 9b-d
(
0.2 mmol, 2 equiv.), Na
2
CO
3
(0.2 mmol, 2 equiv.) and photocatalyst
CN under blue LEDs and air at room
+
21
4
methylacridinium [Acr -Mes](BF ) developed by Fukuzumi. To our
4
e
(5 mol%) in 5 mL of CH
3
knowledge, this is the first example employing quinoliziniums as
photocatalysts for visible light-mediated photoredox catalysis.
Table 4 Photooxidative amidation using quinolizinium compounds as
temperature for 48 h. b Isolated yield.
The feasibility in cellular imaging was demonstrated by
incubation of HeLa cells with 2 μM of the fluorescent quinolizinium
compounds 4a-b, d, f, h, l-o, s-t, w and 5c, respectively (experimental
details in the ESI†). Confocal fluorescence microscopic images
revealed that the quinoliziniums were selectively localized in
cytoplasm with no transportation into the nucleus, which was
a
photocatalysts
22
different from the known examples of quinoliziniums. Compound
c and 4l were chosen for colocalization studies to track the
Entry
Photo cat.
E*red (V)
1.99
Time (h)
16
Yield [%]b
53
5
1
2
3
4
5
6
7
8
9
4a
subcellular localization. Compound 5c was specifically localized in
mitochondria (Fig. 6a-c), which could be attributed to the presence
of the positively charged quinolizinium skeleton, directing it towards
the mitochondria membrane with -180 mV potential. Interestingly,
apart from localization in mitochondria, compound 4l bearing a nitro
substituent localized mainly in lysosome and partially in late
endosome (Fig. 6d-i). The subcellular localization of the
quinoliziniums could be switched by simply modifying the
substituents, and these compounds would be amenable for the
design of specific molecular probes for individual organelle imaging.
4b
1.97
16
50
4e
4f
2.21
16
61
2.22
16
59
4j
2.24
16
52
4p
2.07
16
53
Eosin Y
Fluorescein
Rose Bengal
1.23c
1.25c
1.18c
2.08c
2.21
16
48
16
47
16
32
+
1
1
0
1
[Acr -Mes](BF
4
)
16
44
4e
4e
48
86
71e
Conclusions
1
2d
2.21
48
In summary, we have developed the first photosensitizer-free
visible light-mediated gold-catalysed cis-difunctionalization
reaction with high chemoselectivity and excellent
regioselectivity for modular synthesis of a series of silyl-
substituted quinolizinium compounds. Control experiments as
well as a combination of NMR, ESI-MS and spectroscopic
analysis indicate a plausible visible light-mediated Au(I)/Au(III)
a
Reaction conditions: treatment of 8a (0.1 mmol, 1 equiv.), 9a (0.2 mmol,
2
equiv.), Na
2
CO
3
(0.2 mmol, 2 equiv.) and photocatalyst (5 mol%) in 5 mL
b
of CH
3
CN under blue LEDs and air at room temperature. Yield was
1
determined by H-NMR using 1,3,5-trimethoxybenzene as internal
standard. E red refers to ref. 9a and literatures cited there. d Reaction was
c
*
performed by treatment of 8a (1 mmol, 1 equiv.), 9a (2 mmol, 2 equiv.),
Na
2
CO
3
(2 mmol, 2 equiv.) and photocatalyst (5 mol%) in 5 mL of CH CN
3
e
under blue LEDs and air at room temperature. Isolated yield.
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Journal Name
ARTICLE
Zheng, Z. Wang, Y. Wang and L. Zhang, Chem. SoVcie.wRAervtic.,le2O0n1lin6e,
catalytic transformation involving a regioselective syn insertion
of silyl-substituted alkynes. Additionally, we have studied
applications of the newly synthesized silyl-substituted
quinolizinium compounds in photooxidative amidation and
cellular imaging. The efficient modular synthesis and unique
photophysical properties of the quinolizinium compounds
would open up a new direction in gold catalysis, photoredox
catalysis and molecular imaging.
4
2
4
5, 4448; j) A. M. Asiri and A. S. K. Hashmi, Chem. Soc. Rev.,
DOI: 10.1039/C7SC02294H
016, 45, 4471; k) W. Zi and F. D. Toste, Chem. Soc. Rev., 2016,
, 4567.
5
2
3
a) M. N. Hopkinson, A. D. Gee and V. Gouverneur Chem. - Eur.
J. 2011, 17, 8248; b) H. A. Wegner and M. Auzias, Angew.
Chem. Int. Ed., 2011, 50, 8236.
a) M. N. Hopkinson, A. Tlahuext-Aca and F. Glorius, Acc. Chem.
Res., 2016, 49, 2261; b) B. Sahoo, M. N. Hopkinson and F.
Glorius, J. Am. Chem. Soc., 2013, 135, 5505; c) M. N.
Hopkinson, B. Sahoo and F. Glorius, Adv. Synth. Catal., 2014,
3
56, 2794; d) A. Tlahuext-Aca, M. N. Hopkinson, B. Sahoo and
F. Glorius, Chem. Sci., 2016, , 89; e) A. Tlahuext-Aca, M. N.
Hopkinson, R. A. Garza-Sanchez and F. Glorius, Chem. - Eur. J.,
016, 22, 5909.
a) M. D. Levin, S. Kim and F. D. Toste, ACS Cent. Sci., 2016,
93; b) X.-Z. Shu, M. Zhang, Y. He, H. Frei and F. D. Toste, J.
Am. Chem. Soc., 2014, 136, 5844; c) Y. He, H. Wu and F. D.
Toste, Chem. Sci., 2015, , 1194; d) S. Kim, J. Rojas-Martinab
and F. D. Toste, Chem. Sci., 2016, , 85.
a) D. V. Patil, H. Yun and S. Shin, Adv. Synth. Catal., 2015, 357
622; b) J. Um, H. Yun and S. Shin, Org. Lett., 2016, 18, 484; c)
(a)
(b)
(e)
(h)
(c)
(f)
(i)
7
2
4
5
2,
2
6
(d)
7
,
2
Z. Xia, O. Khaled, V. Mouriès-Mansuy, C. Ollivier and L.
Fensterbank, J. Org. Chem., 2016, 81, 7182; d) T. Cornilleau, P.
Hermange and E. Fouquet, Chem. Commun., 2016, 52, 10040;
e) V. Gauchot and A.-L. Lee, Chem. Commun., 2016, 52, 10163;
f) V. Gauchot, D. R. Sutherland and A.-L. Lee, Chem. Sci., 2017,
(g)
8
, 2885.
6
7
a) L. Huang, M. Rudolph, F. Rominger and A. S. K. Hashmi,
Angew. Chem. Int. Ed., 2016, 55, 4808; b) S. Witzel, J. Xie, M.
Rudolph and A. S. K. Hashmi, Adv. Synth. Catal., 2017, 359
,
1
522.
a) M. Joost, A. Amgoune and D. Bourissou, Angew. Chem. Int.
Ed., 2015, 54, 15022; b) F. Rekhroukh, R. Brousses, A.
Fig. 6 Confocal fluorescence microscopic images of HeLa cells. (a)
sub-cellular localization of 5c; (b) subcellular localization of
Amgoune and D. Bourissou, Angew. Chem. Int. Ed., 2015, 54
1266; c) F. Rekhroukh, C. Blons, L. Estévez, S. Mallet-Ladeira,
K. Miqueu, A. Amgoune and D. Bourissou, Chem. Sci., 2017,
,
®
8,
MitoTracker Red; (c) merged images of (a) and (b); (d) subcellular
4
2
2
539; d) C. Gryparis, M. Kidonakis and M. Stratakis, Org. Lett.,
®
localization of 4l; (e) subcellular localization of LysoTracker Deep
Red; (f) merged images of (d) and (e); (g) subcellular localization of
013, 15, 6038; e) C. Gryparis and M. Stratakis, Org. Lett.,
014, 16, 1430.
4
l; (h) subcellular localization of mRFP-Rab7; (i) merged images of (g)
8
9
K. D. Hesp and M. Stradiotto, J. Am. Chem. Soc., 2010, 132
18026.
,
and (h).
a) N. A. Romero and D. A. Nicewicz, Chem. Rev., 2016, 116
,
1
1
0075; b) X. Li, X. Gao, W. Shi and H. Ma, Chem. Rev., 2014,
14, 590; c) H. Uoyama, K. Goushi, K. Shizu, H. Nomura and C.
Acknowledgements
Adachi Nature, 2012, 492, 234; d) G. J. Hedley, A. Ruseckas
and I. D. W. Samuel, Chem. Rev., 2017, 117, 796.
0 a) H. Kobayashi, M. Ogawa, R. Alford, P. L. Choyke and Y.
Urano, Chem. Rev., 2010, 110, 2620; b) A. Loudet and K.
Burgess, Chem. Rev., 2007, 107, 4891; c) E. Kim, Y. Lee, S. Lee
and S. B. Park, Acc. Chem. Res., 2015, 48, 538.
We are grateful for the financial support of National Natural
Science Foundation of China (21272198), Hong Kong Research
Grants Council (PolyU 153031/14P, 153001/17P, X-ray
diffractometer-PolyU11/CRF/13E), State Key Laboratory of
1
Chirosciences and Department of Applied Biology and Chemical 11 a) Z. Xu and L. Xu, Chem. Commun., 2016, 52, 1094; b) W. Xu,
Z. Zeng, J. H. Jiang, Y. T. Chang and L. Yuan, Angew. Chem. Int.
Ed., 2016, 55, 13658.
2 a) G. Anton and I. Heiko, Synlett, 2016, 27, 1775; b) D. Sucunza,
A. M. Cuadro, J. Alvarez-Builla and J. J. Vaquero, J. Org. Chem.,
Technology. We thank Prof. K.-Y. Wong for facilitating the
project by providing access to Bioanalytical Systems (BAS) for
cyclic voltammetry ex-periments and Prof. Z. Zhou and Dr. W.
T.-K. Chan for X-ray crystallographic analysis.
1
2
016, 81, 10126; c) A. Granzhan, H. Ihmels and G. Viola, J. Am.
Chem. Soc., 2007, 129, 1254.
1
1
3 A. Barbafina, A M. melia, L. Latterini, G. G. Aloisi and F. Elisei,
J. Phys. Chem. A, 2009, 113, 14514.
Notes and references
4 a) V. K.-Y. Lo, Y. Liu, M.-K. Wong and C.-M. Che, Org. Lett.,
1
a) A. S. K. Hashmi and G. J. Hutchings, Angew. Chem. Int. Ed.,
2
006, 8, 1529; b) H.-M. Ko, K. K.-Y. Kung, J.-F. Cui and M.-K.
2
3
3
006, 45, 7896; b) A. S. K. Hashmi, Chem. Rev., 2007, 107
180; c) Z. Li, C. Brouwer and C. He, Chem. Rev., 2008, 108
239; d) A. Arcadi, Chem. Rev., 2008, 108, 3266; e) E. Jiménez-
,
,
Wong, Chem. Commun., 2013, 49, 8869; c) J.-F. Cui, H.-M. Ko,
K.-P. Shing, J.-R. Deng, N. C.-H. Lai and M.-K. Wong, Angew.
Chem. Int. Ed., 2017, 56, 3074.
Núñez and A. M. Echavarren, Chem. Rev., 2008, 108, 3326; f)
D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev., 2008, 108
1
5 H. Kawai, W. J. Wolf, A. G. DiPasquale, M. S. Winston and F. D.
Toste, J. Am. Chem. Soc., 2016, 138, 587.
3
351; g) N. Krause and C. Winter, Chem. Rev., 2011, 111, 1994;
h) H.-S. Yeom and S. Shin, Acc. Chem. Res., 2014, 47, 966; i) Z.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Pleas Ce hd eo mni oc ta al dS j cu ise tn mc ea rgins
Page 8 of 9
ARTICLE
Journal Name
1
1
6 W. J. Wolf, M. S. Winston and F. D. Toste, Nat. Chem., 2014,
59.
7 M. S. Winston, W. J. Wolf and F. D. Toste, J. Am. Chem. Soc.,
6,
View Article Online
DOI: 10.1039/C7SC02294H
1
2
014, 136, 7777.
1
1
8 S. G. Bratsch, J. Phys. Chem. Ref. Data, 1989, 18, 1.
9 a) C.-Z. Luo, P. Gandeepan and C.-H. Cheng, Chem. Commun.,
2
013, 49, 8528; b) C.-Z. Luo, P. Gandeepan, J. Jayakumar, K.
Parthasarathy, Y.-W. Chang and C.-H. Cheng, Chem. - Eur. J.,
013, 19, 14181; c) C.-Z. Luo, P. Gandeepan, Y.-C. Wu, C.-H.
Tsai and C.-H. Cheng, ACS Catal., 2015, , 4837.
2
5
2
0 a) W.-K. Chan, C.-M. Ho, M.-K. Wong and C.-M. Che, J. Am.
Chem. Soc., 2006, 128, 14796; b) A. O.-Y. Chan, C.-M. Ho, H.-
C. Chong, Y.-C. Leung, J.-S. Huang, M.-K. Wong and C.-M. Che,
J. Am. Chem. Soc., 2012, 134, 2589; c) G.-L.; Li, K. K.-Y.; Kung
and M.-K. Wong, Chem. Commun., 2012, 48, 4112; d) F. K.-C.
Leung, J.-F. Cui, T.-W. Hui, K. K.-Y. Kung and M.-K. Wong, Asian
J. Org. Chem., 2015, 4, 533.
2
2
1 S. Fukuzumi, H. Kotani, K. Ohkubo, S. Ogo, N. V. Tkachenko
and H. Lemmetyinen, J. Am. Chem. Soc., 2004, 126, 1600.
2 a) R. Bortolozzi, H. Ihmels, L. Thomas, M. Tian and G. Viola,
Chem. - Eur. J., 2013, 19, 8736; b) A. C. Shaikh, D. S. Ranade, P.
R. Rajamohanan, P. P. Kulkarni and N. T. Patil, Angew. Chem.
Int. Ed., 2017, 56, 757.
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
Chemical Science
View Article Online
DOI: 10.1039/C7SC02294H
1
64x82mm (96 x 96 DPI)