Oxidative Intramolecular 1,2-Amino-Oxygenation of Alkynes under AuI/AuIIICatalysis: Discovery of a Pyridinium-Oxazole Dyad as an Ionic Fluorophore

Article abstract of DOI:10.1002/anie.201609335

Oxidative intramolecular 1,2-amino-oxygenation reactions, combining gold(I)/gold(III) catalysis, is reported. The reaction provides efficient access to a structurally unique ionic pyridinium-oxazole dyad with tunable emission wavelengths. The application of these fluorophores as potential biomarkers has been investigated.

Full text of DOI:10.1002/anie.201609335

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International Edition: DOI: 10.1002/anie.201609335
German Edition: DOI: 10.1002/ange.201609335
Fluorescent Probes
Oxidative Intramolecular 1,2-Amino-Oxygenation of Alkynes under
AuI/AuIII-Catalysis: Discovery of Pyridinium-Oxazole Dyad as an Ionic
Fluorophore
Aslam C. Shaikh, Dnyanesh S. Ranade, Pattuparambil R. Rajamohanan, Prasad P. Kulkarni,
and Nitin T. Patil*
Abstract: Oxidative intramolecular 1,2-amino-oxygenation
reactions, combining gold(I)/gold(III) catalysis, is reported.
The reaction provides efficient access to a structurally unique
ionic pyridinium-oxazole dyad with tunable emission wave-
lengths. The application of these fluorophores as potential
biomarkers has been investigated.
carbonyl gold-carbenoids, formed through oxygen-atom
transfer from the sulfoxide. On the basis of this reactivity,
the research groups of Liu,[10] Davies,[11] Ye,[12] Zhang,[13] and
others[14] reported variety of reactions involving oxidative
gold catalysis. Yet another approach in this field features
external-oxidant-powered AuI/AuIII catalysis, where the metal
oxidation state changes during the catalytic cycle.[7,15]
T
he design and synthesis of organic fluorophores is essential
A historical retrospect on the progress in the field of
external-oxidant-powered AuI/AuIII catalysis reveals that the
chemistry is either based on coupling reactions of in situ
generated vinyl-gold species (Scheme 1a)[16] or cross-coupling
reactions between respective substrates (Scheme 1b).[17]
Zhang and Toste, independently reported gold-catalyzed
carboheterofunctionalization reaction of alkenes with aryl-
boronic acids (Scheme 1c).[18] Pioneering work from the
group of Zhang and MuÇiz reported the amino-arylation
and diamination of alkenes by AuI/AuIII catalysis
(Scheme 1d).[19] To our surprise, there exists no report on
the difunctionalization of alkynes utilizing the AuI/AuIII
for progress in many areas of chemistry, biology, and func-
tional-materials research.[1] In particular, ionic fluorophores
are gaining much attention because of their unique properties
such as high thermal stabilities, phase tunabilities, and water
solubilities.[2] These features have inspired their application in
a number of fields including materials science[3] and biology.[4]
Recently, it was shown that ionic fluorophores which contain
positively charged groups, such as triphenylphosphonium or
quaternized pyridine moieties, are often applied in mitochon-
drial tracking because of their ability to cross the inner-
mitochondrial membranes.[4c,5] To facilitate advancement in
this field, design and synthesis of novel ionic fluorophores for
selective detection of mitochondria as cell organelles are
highly warranted.
Over the last decade, homogeneous gold catalysis (p-acid
catalysis) has emerged as a powerful tool for building
molecular complexity.[6] While the search for novel reactions
are likely to be continued in the future, there is an urgent need
to enable entirely new modes of reactivities. In recent years,
oxidative gold-catalyzed reactions have emerged as a new
research field.[7] In 2007, the groups of Toste[8] and Zhang[9]
independently reported gold(I)-catalyzed oxidative rear-
rangements of alkynyl sulfoxides which proceed via a-
[*] A. C. Shaikh, Dr. N. T. Patil
Division of Organic Chemistry, CSIR—National Chemical Laboratory
Dr. Homi Bhabha Road, Pune, 411 008 (India)
and
Academy of Scientific and Innovative Research (AcSIR)
New Delhi, 110 025 (India)
E-mail: n.patil@ncl.res.in
Dr. P. R. Rajamohanan
Central NMR Facility, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune, 411 008 (India)
D. S. Ranade, Dr. P. P. Kulkarni
Bioprospecting Group, Agharkar Research Institute
Pune, 411 004 (India)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201609335.
Scheme 1. Literature reports and present work.
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catalysis toolbox. Herein, we report the intramolecular 1,2-
amino-oxygenation of alkynes, to access an ionic pyridinium-
oxazole dyad, and their application in cell imaging.
combination with (C6F5)3PAuCl. However, none of them gave
superior results (entries 11 and 12). To our pleasure, when 2-
tert-butoxy-6-[2(phenylethynyl)-phenyl] pyridine (1a’) was
employed as a substrate, the yield increased to 62%
(entry 13). Gratifyingly, an improved yield of 3a was realized
with the use of anhydrous CH3CN (entry 14). The product 3a
was isolated in 82% yield when 1.5 equivalents of Selectfluor
was used (entry 15). The highest yield (92%) was obtained
when 2.0 equivalents of Selectfluor was employed (entry 16).
Lowering the catalyst loading had a detrimental effect on the
reaction yield (entry 17). It should be noted that the presence
of Selectfluor is crucial for the reaction. In the absence of
Selectfluor, the undesired products 3a’ and 3a’’ were obtained
(entry 18).[21]
Having established optimal reaction conditions (Table 1,
entry 16), we set out to explore the scope of the intra-
molecular 1,2-amino-oxygenation reactions. As can be judged
from Table 2, the pyridinoalkynes bearing aromatic rings
(R = Ar) such as Ph, 1-Np, 2-Np, 9-Phen, and 1-Pyrenyl,
efficiently afforded the corresponding pyridinium-oxazole
dyads 3a–e in 63–92% yields. However, pyridinoalkyne
substrates bearing R as aliphatic group failed to yield the
desired products. Further, we investigated the scope of the
reaction with respect to aryl group attached to the alkyne. The
reaction was found to be well tolerated with both electron-
We chose 2-methoxy-6-[2(phenylethynyl)-phenyl] pyri-
dine (1a) as a model substrate (Table 1) to investigate the
feasibility of the proposed reaction. Accordingly, 1a was
treated with 5 mol% of Ph3PAuCl and 1.2 equivalents of
Selectfluor in CH3CN/H2O (99:1 v/v) at 808C.[20] Gratifyingly,
the desired product 3a was obtained, albeit, in 28% yield
(entry 1). A significant amount of pyrido-isoquinolinone (3a’)
and pyrido-isoindolone (3a’’) were isolated. Next, we inves-
tigated various gold(I) complexes [LAuX] (X = halide). The
use of electron-rich gold complexes such as [JohnPhosAuCl]
(entry 2), [CyJohnPhosAuCl] (entry 3), and IPrAuCl
(entry 4) gave either 3a’ and/or 3a’’, and in none of the
cases was 3a detected. Interestingly, an increase in yield of 3a
was noted when electron-deficient gold complexes such as (4-
FC6H4)3PAuCl, (4-CF3C6H4)3PAuCl, and (C6F5)3PAuCl were
used as catalysts (entries 5–7). Various solvents such as DCE,
CHCl3, and toluene were also screened (entries 8–10) and
finally concluded that CH3CN was the best. Other oxidants
such as PhI(OAc)2 and PhI(O2CCF3)2 were also tried in
Table 1: Optimization of reaction conditions.[a,b]
Table 2: Scope of 1, 2 amino-oxygenation reaction.[a,b]
Entry
[Au]
R
Solvent
Yield [%]
3a/3a’/3a’’
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph3PAuCl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
tBu
tBu
tBu
tBu
tBu
tBu
CH3CN[c]
CH3CN[c]
CH3CN[c]
CH3CN[c]
CH3CN[c]
CH3CN[c]
CH3CN[c]
DCE[c]
28:28:30
–:–:82
–:–:65
JohnPhosAuCl
CyJohnPhosAuCl
IPrAuCl
–:15:60
41:34:15
52:30:10
57:28:–
18:58:12
12:28:16
–:–:–
(4-FC6H4)3PAuCl
(4-CF3C6H4)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
(C6F5)3PAuCl
[c]
CHCl3
toluene[c]
CH3CN[c]
CH3CN[c]
CH3CN[c]
CH3CN[d]
CH3CN[d]
CH3CN[d]
CH3CN[d]
CH3CN[d]
–:30:11[e]
11:36:10[f]
62:–:–
72:–:–
80:–:–[g]
92:–:–[h]
80:–:–[i]
–:72:22[j]
[a] Reaction conditions: 0.25 mmol 1a/1a’, 1.2 equiv 2, 5 mol% AuLn,
solvent (2 mL), 808C, 6 h. [b] Yields of isolated products. [c] Used
CH3CN/H2O (99:1) as solvent (entries 1–13). [d] Used anhydrous
CH3CN as solvent (entries 14–18). [e] PhI(OAc)2 was used as an oxidant.
[f] PhI(O2CCF3)2 was used as an oxidant. [g] Used 1.5 equiv of Selectfluor.
[h] Used 2.0 equiv of Selectfluor. [i] 2 mol% of (C6F5)3PAuCl was used.
[j] Reaction was conducted without Selectfluor.
[a] Reaction conditions: 0.25 mmol 1, 0.50 mmol 2, 5 mol%
(C6F5)3PAuCl, CH3CN (2 mL), 808C, 6 h. [b] Yield of isolated product.
[c] Product was not obtained. [d] Methoxy derivative was used as the
starting material instead of ortho-tert-butoxy because of the difficulties in
accessing the latter one. [e] A mixture of 3z and 3z’ was obtained.
Thermal ellipsoids shown at 50% probability.
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donating and electron-withdrawing groups, thus affording the
would then occur to form another vinylgold(III) intermediate
corresponding pyridinium-oxazole dyads 3h–s in moderate to
good yields (53–86%). Next, we directed our attention to
examining the tolerance of the substituents at C-6 phenyl ring
of pyridyl ring. Pleasingly, introduction of Me, F, and Cl
substituents to the aforementioned phenyl ring resulted in
good yields of the products 3t–x (52–85%). The structures of
3r and 3u were unambiguously confirmed by X-ray crystal
analysis.[21] Switching the pyridyl ring with an isoquinyl ring
did not hamper the reaction and 3y was isolated in 62% yield.
The dimethoxy substitution at C-6 aryl group of pyridine was
also tolerated. However, the reaction led to an inseparable
mixture (1:1) of 3z and its fluorinated derivative 3z’. The
structure of the products were unambiguously determined by
carefully conducted two-dimensional NMR analysis.[21]
While the precise reaction mechanism requires further
studies, a plausible reaction pathway, based on reports from
the groups of Zhang and Toste,[18,19] is depicted in Scheme 2.
Initial oxidation of the LnAuIX by Selectfluor is thought to
provide a cationic gold(III) species capable of activating the
alkyne in 1a’ towards nucleophilic attack of pyridyl nitrogen
atom to generate the intermediate A through anti-amino-
auration (Scheme 2, path a).[18b,19b,21] The loss of isobutylene
(B).[22] Subsequent intramolecular SN2-type nucleophilic dis-
placement in B would then occur to yield 3a with the
regeneration of LnAuIX.[17f,18b] The rate of the SN2-type
nucleophilic displacement is expected to be high with
electron-withdrawing ligands on the gold center.[19a] This
effect could be the reason for the catalytic efficiency of
(C6F5)3PAuCl being higher compared to that of other
catalysts.
An alternative mechanism involving the intermediacy of
C through syn-aminoauration cannot be ruled out (Scheme 2,
path b).[23] The intermediate C would subsequently undergo
loss of isobutylene (cf. D) followed by nucleophilic attack of
amide oxygen atom onto the AuIII center to generate the
cyclic AuIII complex E. The intermediate E is supposed to
undergo facile reductive elimination to yield 3a with the
regeneration of LnAuIX. Whether syn- or anti-aminoauration
is favored cannot be claimed conclusively from the mecha-
nistic evidence gathered so far. However, the results in
Scheme 3 clearly indicate that the reaction follows a concerted
mechanism rather than stepwise pathway.
Scheme 3. Control experiments.
Figure 1 shows the photophysical properties of represen-
tative pyridinium-oxazole dyads in CH2Cl2 at room temper-
ature (see Table S1 in the Supporting Information).[21] The PL
range covers the visible region, thus offering a palette of
colors in CH2Cl2 ranging from violet to orange (lem: 400–
588 nm, Figure 1; Table S1[21]). These fluorophores have good
Figure 1. a) Emission spectra in CH2Cl2 at RT (10À5 m). b) Observed
fluorescence under UV excitation (l=365 nm).
Scheme 2. A plausible reaction mechanism.
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photoluminescence capabilities with Ff values ranging from
0.10 to 0.76.
single-crystal X-ray diffraction data. A.C.S. thanks CSIR for
the award of an SPM fellowship.
Next, the feasibility of ionic fluorophores for cell imaging
was studied using MCF-7 cancer cell lines (Figure 2).
Conflict of interest
The authors declare no conflict of interest.
Keywords: cell imaging · cyclization · fluorescent probes · gold ·
synthetic methods
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Figure 2. Confocal fluorescence microscopic images of MCF-7 cells
with 3d (1 mm) for 30 min (a) and 3o (1 mm) for 30 min (c).
b,d) Merged images of (a) and (c) with 1 mm DAPIfor 30 min respec-
tively with 3o (1 mm) for 15 min (e) and MitoTracker Green (FM) (MT,
1 mm) for 15 min (f). (g) DAPI (1 mm) for 15 min. h) Image of panels
(e), (f), and (g) merged. Excitation wavelength: l=410 nm (for 3d),
l=540 nm (for 3o), l=350 nm (for DAPI), and l=440 nm (for MT);
emission filter: l=510–540 nm (for 3d), 610–640 nm (for 3o), 460–
490 nm (for DAPI), and l=490–520 nm (for MT); irradiation time:
8.15 s per scan.
Fluorescence images showed that 3d is non-selective and
localized in the cytoplasm as well as in the nucleus (Fig-
ure 2a,b). On the contrary, 3o was found to be highly
selective for mitochondrial imaging (Figure 2c,d). The co-
staining experiment with MitoTracker green FM (MT),
a commercially available mitochondria imaging agent, clearly
suggested that the observed fluorescence is localized in the
mitochondria of the living MCF-7 cells (Figure 2e–h). More-
over, during the experiment the signal loss of 3o and 3d is less
than 20% and indicates that these compounds have excellent
photostability.
In conclusion, for the first time, we developed an oxidative
intramolecular 1,2-amino-oxygenation reaction for accessing
ionic pyridinium-oxazole dyads with tunable emission wave-
lengths. The application of these fluorophores for cell imaging
has been described. These results should provide a basis for
the future development of fluorescent probes for the selective
detection of chemical species inside mitochondria. Further
investigations to delineate the precise reaction mechanism
through computational studies and understanding the struc-
ture–imaging relationship are currently ongoing.
Acknowledgments
Generous financial support by the Department of Science and
Technology (DST), New Delhi (grant number SB/S1/OC-17/
2013), EMR/2014/001235, and the Council of Scientific and
Industrial Research (CSIR), New Delhi (grant number
CSC0108 and CSC0130) is gratefully acknowledged. We
thank Saibal Bera and Dr. Rahul Banerjee for providing
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Manuscript received: September 23, 2016
Revised: November 22, 2016
Final Article published: && &&, &&&&
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Fluorescent Probes
A. C. Shaikh, D. S. Ranade,
P. R. Rajamohanan, P. P. Kulkarni,
N. T. Patil*
&&&& — &&&&
Oxidative Intramolecular 1,2-Amino-
Oxygenation of Alkynes under AuI/AuIII-
Catalysis: Discovery of Pyridinium-
Oxazole Dyad as an Ionic Fluorophore
Tuned in: Oxidative intramolecular 1,2-
amino-oxygenation reactions, by com-
bining gold(I)/gold(III) catalysis, is
reported. The reaction provides efficient
access to structurally unique ionic pyr-
idinium-oxazole dyads with tunable
emission wavelengths. The application of
these fluorophores as potential biomark-
ers has been investigated.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!