Metallaphotoredox-Mediated Csp2-H Hydroxylation of Arenes under Aerobic Conditions

Article abstract of DOI:10.1021/acs.orglett.8b01973

The direct hydroxylation of 2-arylpyridines and 2-arylbenzothiazoles via the merger of organic photoredox and metal catalysis is reported where 4CzIPN is used as the visible-light photocatalyst and Pd(OAc)₂ as the metal catalyst. This method has been employed to synthesize organic molecules exhibiting excited-state intramolecular proton transfer properties for generating tunable luminescence responses.

Full text of DOI:10.1021/acs.orglett.8b01973

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metallaphotoredox-Mediated C −H Hydroxylation of Arenes under
sp2
Aerobic Conditions
Sk. Sheriff Shah, Amrita Paul, Manoranjan Bera, Yarra Venkatesh, and N. D. Pradeep Singh*,†
†
†
†
†
†Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal 721302, India
*
S Supporting Information
ABSTRACT: The direct hydroxylation of 2-arylpyridines and 2-
arylbenzothiazoles via the merger of organic photoredox and metal
catalysis is reported where 4CzIPN is used as the visible-light
photocatalyst and Pd(OAc) as the metal catalyst. This method
2
has been employed to synthesize organic molecules exhibiting
excited-state intramolecular proton transfer properties for
generating tunable luminescence responses.
Owing to its mild and renewable nature, light-induced catalysi1s
has gained considerable attention over the past few decades.
Metal and organic photocatalysts have been used independ2-
ently to synthesize medicinal agents and bioactive molecules.
Recently, the merger of transition-metal catalysis and photo-
catalysis, known as metallaphotocatalysis, has emerged as a
Scheme 1. Hydroxylation of Arenes under Various
Conditions
3
powerful method for cross-coupling reactions. MacMillan,
Sanford, Molander, and various research groups have utilized
metallaphotocatalysis for C−N, C−S, C−O, and C−C bond
2
,4−10
formations.
To date, significant effort has been dedicated to synthesizing
phenol and hydroxylated arenes, as they are the building blocks
of many bioactive molecules, pharmaceuticals, polymers, and
1
1−13
light-emitting materials.
The direct C−H oxidation
leading to hydroxylation is an attractive method for generating
important phenol products.
14,15
In 2009, Yu et al. showed
carboxylic group directed ortho-hydroxylation of benzoic acids
16a
using a Pd-catalyst with 1 atm of O or air. The same group
2
has also explored the Cu(II)-catalyzed ortho-C−H hydrox-
1
6b
ylation of aryl C−H bonds.
Further, carbonyl-directed
hydroxylation of arenes has been achieved successfully by the
groups of Ackermann and others.
14a
14b,c
Of late, Jiao et al. have
described C −H hydroxylation of 2-phenylpyridines using
sp2
PdCl and NHPI (N-hydroxyphthalimide) co-catalysts
2
17
(
Scheme 1, entry a). Guin et al. also showed direct C−H
hydroxylation of 2-arylpyridines using n-butyraldehyde as a
hydroxy radical source. Generally, these hydroxylation
methods required the use of stoichiometric oxidants and
high temperature as well as limited substrate scope (Scheme 1,
entry b).
1
8
Pd(OAc) , under visible-light irradiation in the presence of O .
2
2
To check the viability of our proposed metallaphotocatalysis,
an initial study was carried out by using 4CzIPN (2 mol %) as
the organic photocatalyst in a reaction mixture of 2-
phenylpyridine (0.2 mmol), Pd(OAc) (10 mol %), BrCCl
Thus, the development of a mild and clean method for the
2
3
(
0.4 mmol), and toluene (1.5 mL) under visible-light
C −H hydroxylation of arenes would be attractive (Scheme
sp2
irradiation in the presence of O . The reaction provided the
2
1
, entry c).
hydroxylation product 2a in 25% yield (Table 1, entry 1). This
encouraged us to optimize the reaction conditions. Solvent
studies revealed that the maximum hydroxylation product was
Based on the literature survey, we hypothesized that a
metallaphotocatalysis protocol could be used for the
hydroxylation reactions. Here, we report for the first time,
the direct hydroxylation of 2-arylpyridines and 2-arylbenzo-
thiazoles via the merger of photocatalyst, 4CzIPN [1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene] and metal catalyst,
Received: June 24, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of the Reaction Conditions
Scheme 2. Visible-Light-Induced Hydroxylation of 2-
a
Arylpyridines.
b
entry
conditions
as shown
as shown
as shown
as shown
solvent
DCE
yield (%)
1
2
3
4
5
6
7
8
9
25
CH CN
5
0
0
3
DMF
DMSO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
c
d
as shown
67, 49, 21
air instead of O2
EY as photocatalyst
RB as photocatalyst
RhB as photocatalyst
41
45
23
33
60
37
12
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
CBr instead of BrCCl
4
3
TBHP instead of BrCCl3
no BrCCl3
BTF instead of toluene
no toluene
no photocatalyst
no Pd(OAc)2
no light
a
Palladium-catalyzed hydroxylation of 2-phenylpyridine with 4CzIPN
in the presence of O under visible-light irradiation. Standard reaction
2
N in place of O
2
0
41
2
conditions: 1 (0.3 mmol), Pd(OAc) (0.1 equiv), 4CzIPN (2 mol %),
e
2
as shown
BrCCl (2 equiv), toluene (3 mL), O (1 atm), 24 h. Yields of isolated
products given.
3
2
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc) (0.1 equiv), 4CzIPN
2
(
2 mol %), BrCCl (2 equiv), O , toluene (1.5 mL), solvent (1.5 mL),
3 2
b
under exposure from a 23 W CFL lamp for 24 h. Isolated products.
c
d
To check the generality of this reaction, we were curious to
explore the effect of other directing groups on the
hydroxylation of arenes. For this purpose, we chose
benzothiazole-directed arenes. The above-mentioned metal-
laphotocatalysis methods were unable to give any satisfactory
results and provide some acylation products.
5
mol % of Pd(OAc) . In the absence of solvent. EY = eosin Y, RB
2
=
rose bengal, RhB = rhodamine b, TBHP = tert-butyl hydroperoxide,
e
BTF = benzotrifluoride. Large-scale reaction: 1a (1.5 mmol).
obtained in MeOH (Table 1, entry 5), while DMF or DMSO
failed to execute the reaction (Table 1, entries 3 and 4).
This prompted us to search for an alternative hydroxyl
radical generator. Surprisingly, the use of cyclohexane in place
of toluene provided the expected hydroxylation product 4a
(Table S1, Supporting Information (SI)). The solvent studies
showed that the maximum yield was obtained in DCE (Table
S1, entry 2). No product was formed in the absence of catalyst,
oxidant, air, cyclohexane, and light (Table S1, entries 3−7).
With the optimization conditions in hand, the substrate scope
was explored (Scheme 3). In this case, the electron-donating
and electron-withdrawing groups provided good yield. The
present method performed equally well with the substrates
containing a halogen group (4b−d). Satisfactory results have
been obtained for substrates containing methyl and methoxy
groups (4g,h).
Reducing the mol % of Pd(OAc) produced lower yield (Table
2
1
, entry 5). Next, the use of atmospheric air instead of O2
reduced the yield (Table 1, entry 6). Interestingly, the use of
other organic photocatalysts (EY, RB, and RhB) instead of
4
CzIPN provided a moderate yield (Table 1, entries 7−9).
Further, the use of CBr or TBHP as a hydrogen abstractor
4
instead of BrCCl furnished a lower yield (Table 1, entries 10
3
and 11). However, in the absence of BrCCl , 2a was produced
3
in 12% yield (Table 1, entry 12). This phenomenon is due to
•−
19
the hydrogen-abstracting ability of O2
.
It is worth noting
that, in the absence of toluene, or the use of BTF instead of
toluene, the reaction was completely inhibited (Table 1, entries
1
3 and 14). The reported method yielded moderately at large
To shed light on the reaction mechanism, control experi-
ments were carried out. The reactions were monitored in the
presence of radical scavenger 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO). The present method was unable to produce
2a or 4a in the presence of 2 equiv of TEMPO (Scheme S1,
SI). The above experiment implied the involvement of a radical
species in the hydroxylation process.
scale (Table 1, entry 19). The screening of the reaction
conditions disclosed that photocatalyst, Pd(OAc) , BrCCl ,
toluene, O , and visible light were all crucial for the
accomplishment of the hydroxylation of 2-arylpyridine.
With the optimized conditions in hand, the hydroxylation
scope of the substituted 2-phenylpyridines was investigated
2
3
2
II
(
Scheme 2). Electron-donating and electron-withdrawing
Further mechanistic studies were carried out using Pd
groups attached to the benzene ring provided good yields.
Remarkably, the present method has executed the hydrox-
ylation of the substrates containing a halogen group smoothly
complex (A) as the catalyst instead of Pd(OAc) . The product
2
2a was obtained in 59% yield (eq 1). However, the reaction of
A in the absence of 1a (or any other substrates) failed to
produce 2a under the standard reaction conditions (eq 2).
Furthermore, when the reaction of A was carried out in the
presence of 1f, products 2a and 2f were obtained in 20 and
27% yields, respectively (eq 3). The above results indicate that
(
2e−h). The productivity of this transformation was not
impeded by the substituents at the ortho, meta, or para
positions (2f−h). Moreover, hydroxylation of 2-methylbenzo-
[
h]quinoline gave 2j only in 33% yield.
B
DOI: 10.1021/acs.orglett.8b01973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Visible-Light-Induced Hydroxylation of 2-
Arylbenzothiazoles
Scheme 4. Plausible Mechanism for the Photocatalytic
Hydroxylation of Arenes
a
a
Reaction conditions: 3 (0.3 mmol), Pd(OAc) (0.1 equiv), 4CzIPN
2
(
2 mol %), BrCCl (2 equiv), O , cyclohexane (1.5 mL), DCE (1.5
3 2
b
in toluene-d ). The byproduct benzaldehyde (or cyclo-
mL), under exposure from a 23 W CFL lamp for 24 h. Isolated
8
products.
hexanone) was detected using GC−MS. (v) Reaction of
•
HO with palladacycle 1 (formed by C−H activation of the
III
substrate) furnishes the Pd intermediate 2. (vi) Single-
+
electron oxidation of 2 by PC regenerates the PC and forms
IV
the Pd intermediate 3. Finally, (vii) C−O bond formation by
reductive elimination produces the hydroxylation product and
II
regenerates the Pd catalyst.
To show the application of our direct hydroxylation method,
we synthesized fluorophores (4a, 4f, and 2j) and studied their
fluorescence behavior. The newly generated fluorophores
exhibited emission colors ranging from blue to orange (Figure
1
). This large Stoke’s shift fluorescence of our fluorophores is
22
due to the existence of the ESIPT phenemenon.
In conclusion, we have disclosed a metallaphotoredox
method for the hydroxylation of 2-arylpyridines and 2-
II
the formation of a monomeric Pd intermediate by breaking
II
20c
the dimeric Pd complex A is essential for the hydroxylation.
On the basis of the reaction conditions and a literature
survey, we proposed the hydroxylation mechanism (Scheme
6
,17,20
4
).
The catalytic cycle includes the following steps: (i)
PC (4CzIPN) excites under visible light exposure to its excited
state PC*. (ii) Single-electron transfer from PC* to BrCCl
3
•
+
•
generates CCl radical and PC . (iii) CCl radical abstracts a
3
3
hydrogen from toluene (or cyclohexane) leading to the
formation of benzyl radical (or cyclohexyl radical). (iv) Benzyl
radical (or cyclohexyl radical) is then trapped by O to
2
produce the intermediate peroxo radical, which in turn forms
•
the hydroxyl radical (HO ) and benzaldehyde (or cyclo-
2
1
•
hexanone). The HO was detected by EPR experiments
using DMPO as the trapping agent (SI). Further, the H source
•
in HO was verified by carrying out the hydroxylation reaction
Figure 1. Fluorescence behavior of 4a, 4f, and 2j.
C
DOI: 10.1021/acs.orglett.8b01973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
arylbenzothiazoles. We demonstrated that by integrating
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ASSOCIATED CONTENT
Supporting Information
■
*
S
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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AUTHOR INFORMATION
Corresponding Author
■
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(b) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc. 2013, 135,
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H.-X.; Yu, J.-Q. Chem. Sci. 2017, 8, 1469−1473.
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*E-mail: ndpradeep@chem.iitkgp.ernet.in.
ORCID
Yarra Venkatesh: 0000-0002-4478-1553
N. D. Pradeep Singh: 0000-0001-6806-9774
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DST (SERB) (Grant No. EMR/2016/005885)
for financial support. Sk.S.S. is thankful to UGC for the
fellowship and IIT Kharagpur for instrument facilities. We are
grateful to Prof. Debamalya Banerjee (Physics Department, IIT
Kharagpur) for helping us perform the EPR experiments.
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DOI: 10.1021/acs.orglett.8b01973
Org. Lett. XXXX, XXX, XXX−XXX