Aerobic visible-light photoredox radical C-H functionalization: Catalytic synthesis of 2-substituted benzothiazoles

Article abstract of DOI:10.1021/ol2028866

An aerobic visible-light driven photoredox catalytic formation of 2-substituted benzothiazoles through radical cyclization of thioanilides has been accomplished. The reaction features C-H functionalization and C-S bond formation with no direct metal involvement except the sensitizer. The reaction highlights the following: (1) visible-light is the reaction driving force; (2) molecular oxygen is the terminal oxidant, and (3) water is the only byproduct.

Full text of DOI:10.1021/ol2028866

ORGANIC
LETTERS
2012
Vol. 14, No. 1
98–101
Aerobic Visible-Light Photoredox Radical
CꢀH Functionalization: Catalytic
Synthesis of 2-Substituted Benzothiazoles
Yannan Cheng, Jun Yang, Yue Qu, and Pixu Li*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering, and Materials Science, Soochow University, 199 RenAi Road,
Suzhou, Jiangsu, 215123, China
lipixu@suda.edu.cn
Received October 26, 2011
ABSTRACT
An aerobic visible-light driven photoredox catalytic formation of 2-substituted benzothiazoles through radical cyclization of thioanilides has been
accomplished. The reaction features CꢀH functionalization and CꢀS bond formation with no direct metal involvement except the sensitizer. The
reaction highlights the following: (1) visible-light is the reaction driving force; (2) molecular oxygen is the terminal oxidant, and (3) water is the only
byproduct.
2þ
Visible-light driven organic chemical reactions are con-
sidered to be a sustainable approach, as sunlight is a clean
and unlimited energy source.1 The study of Ru(bpy)32þ as
the sensitizer in photoredox organic reactions began ∼30
years ago.2 In 2008, the reports of seminal work on the
direct asymmetric alkylation of aldehyde by MacMillan
et al.3 and the [2 þ 2] enone cycloaddition reaction by
Yoon et al.4 revealed the power of visible-light catalysis in
radical-involving organicsynthesis5 and drew theattention
of many researchers.6 However, the precursors that form
radical intermediates under visible-light photoredox reac-
tion conditions are still very limited. Currently, most of the
reports are on the reactions of activated CꢀX bonds and
the CꢀH bond next to a N-atom. Although organosulfur
compounds form radicals easily and have been widely used
in radical reactions, the only Ru(bpy)3 photocatalytic
reaction involving a sulfur radical to date is the oxidation
of sulfides to sulfoxides reported by Zen et al.2d Dioxygen
is the ultimate environmentally benign oxidant, as it is
green and readily accessible. Visible-light induced oxida-
tion by molecular oxygen is an attractive but very challeng-
ing goal to chemists.2d,6k,6n,6p,7 Here, we report a novel
(6) For selected recent reports: (a) Du, J.; Espelt, L. R.; Guzei, I. A.;
Yoon, T. P. Chem. Sci. 2011, 2, 2115. (b) Dai, C.; Narayanam, J. M. R.;
Stephenson, C. R. J. Nat. Chem. 2011, 3, 140. (c) Furst, L.; Narayanam,
J. M. R.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2011, 50, 9655.
(d) Hurtley, A. E.; Cismesia, M. A.; Ischay, M. A.; Yoon, T. P. Tetrahedron
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Nagib, D. A.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2011, 50,
6119. (h) Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011,
47, 9615. (i) Rueping, M.; Vila, C.; Koenigs, R. M.; Poscharny, K.;
Fabry, D. C. Chem. Commun. 2011, 47, 2360. (j) Rueping, M.; Zhu, S.;
Koenigs, R. M. Chem. Commun. 2011, 47, 8679. (k) Su, Y. J.; Zhang,
L. R.; Jiao, N. Org. Lett. 2011, 13, 2168. (l) Tucker, J. W.; Narayanam,
J. M. R.; Shah, P. S.; Stephenson, C. R. J. Chem. Commun. 2011, 47,
5040. (m) Xie, Z.; Wang, C.; deKrafft, K. E.; Lin, W. J. Am. Chem. Soc.
2011, 133, 2056. (n) Xuan, J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.;
Xiao, W.-J. Chem. Commun. 2011, 47, 8337. (o) Zhu, M.; Zheng, N.
Synthesis 2011, 2223. (p) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.;
Rong, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171.
(7) (a) Su, F.; Mathew, S. C.; Moehlmann, L.; Antonietti, M.; Wang,
X.; Blechert, S. Angew. Chem., Int. Ed. 2011, 50, 657. (b) Arends, I. W. C. E.;
Perez, D. I.; Grau, M. M.; Hollmann, F. Chem. Commun. 2009, 6848.
(c) Ma, W. H.; Zhang, M. A.; Chen, C. C.; Zhao, J. C. Angew. Chem., Int.
Ed. 2008, 47, 9730.
(1) Ciamician, G. Science 1912, 36, 385.
(2) (a) Cano-Yelo, H.; Deronzier, A. J. Chem. Soc., Perkin Trans. 2
1984, 1093. (b) Cano-Yelo, H.; Deronzier, A. Tetrahedron Lett. 1984, 25,
5517. (c) Cano-Yelo, H.; Deronzier, A. J. Photochem. 1987, 37, 315.
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r
10.1021/ol2028866
Published on Web 12/06/2011
2011 American Chemical Society

visible-light photoredox catalytic synthesis of benzothia-
zoles via a radical CꢀH functionalization/CꢀS bond forma-
tion using dioxygen as the terminal oxidant.
Table 1. Optimization of Reaction Conditions
2-Arylbenzothiazoles are an important class of com-
pounds with broad biological and pharmaceutical pro-
perties.8,9 Typically, benzothiazoles are prepared via oxi-
dative intramolecular cyclization of thiobenzanilides.10ꢀ12
The use of a stoichiometric or excess amount of oxidants
limits the functionality tolerance and is environmentally
unfriendly. Transition-metal (Pd and Cu) catalyzed direct
CꢀH functionalization/cyclizaiton of thiobenzanilides is
very attractive as prefunctionalization is unnecessary.11e,l,m
However, the reported methods involved more than one
type of metal and a high reaction temperature, which limit
their synthetic applications.
catalyst
product
(yield)
entry substrate
(1 mol %)
solvent base
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
Ru(bpy)3Cl2•6H2O DMF
ꢀ
3a
Ru(bpy)3Cl2•6H2O CH3CN ꢀ
3a
3a
3a
3b
3b
3
Ru(bpy)3Cl2•6H2O CH2Cl2
Ru(bpy)3Cl2•6H2O DMSO
ꢀ
ꢀ
4
5
Ru(bpy)3Cl2•6H2O CH3CN ꢀ
Believing that the sulfur in a thioamide could be oxidized
in a Ru(bpy)32þ photoredox cycle to form a radical inter-
mediate, we started our investigation of visible-light driven
synthesis of benzothiazoles using thioamides 1a and 1b.
Ru(bpy)3Cl2•6H2O was used as the catalyst, and the reac-
tion was placed under a household 14 W fluorescent light.
It was found that without base all the reactions afforded
3a and 3b. No desired product 2a or 2b was observed in
various solvents (Table 1, entries 1ꢀ6).11e,13
6
Ru(bpy)3Cl2•6H2O DMF
Ru(bpy)3Cl2•6H2O DMF
ꢀ
7
DBU 2b (86%)a
DBU 2b (87%)a
DMAP N.R.
8
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
DMF
DMF
DMF
9
10
Proton 3b
sponge
11
12
13
14
15
16
17
1b
1b
1b
1b
1b
1b
1b
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
ꢀ
DMF
DMF
DMF
DMF
DMF
DMF
DMF
TMP 2b (21%)b
DBN 2b (81%)a
DBU 2b (85%)b,c
K2CO3 2b (71%)a,c
DBU d 2b (80%)a,c
DBU N.R.c
Bases were added to promote the formation of a
more oxidizable imidothiolate anion. To our delight,
Ru(bpy)3(PF6)2
DBU N.R.c,e
a HPLC yield. b Isolated yield. c Under 5% O2 balloon. d 0.5 equiv of
DBU was used. e Reaction was carried out in the dark.
(8) For review: Westwell, A. D.; Weekes, A. A. Curr. Med. Chem.
2009, 16, 2430.
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Moon, H. R.; Chung, H. Y. Bioorg. Med. Chem. Lett. 2011, 21, 2445.
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A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 6, pp 322ꢀ326.
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L.; Antonietti, M.; Wang, X.; Blechert, S. Angew. Chem., Int. Ed.
2011, 50, 657. (b) Ranjit, S.; Liu, X. Chem.;Eur. J. 2011, 17, 1105. (c)
Tamba, S.; Okubo, Y.; Tanaka, S.; Monguchi, D.; Mori, A. J. Org.
Chem. 2010, 75, 6998. (d) Kumar, A.; Sharma, S.; Maurya, R. A.
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Kawasaki, J.; Hiroya, K.; Doi, T. Adv. Synth. Catal. 2010, 352, 2643.
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2010, 49, 2202. (g) Feng, E. G.; Huang, H.; Zhou, Y.; Ye, D. J.; Jiang,
H. L.; Liu, H. J. Comb. Chem. 2010, 12, 422. (h) Bose, D. S.; Idrees, M.
Synthesis 2010, 1983. (i) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.;
Paul, R.; Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (j) Moghaddam,
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Chem. 2007, 72, 8087.
with 1,8-diazabicycloundec-7-ene (DBU), benzothiazole 2b
formed in 86% HPLC yield (Table 1, entry 7). Switching the
catalyst toRu(bpy)3(PF6)2 afforded a similar result (Table 1,
entry 8). 4-Dimethylaminopyridine (DMAP) did not effec-
tively promote the reaction (Table 1, entry 9). Addition of 1,
8-bis(dimethylamino)naphthalene (proton sponge) gave 3b
as the only product (Table 1, entry 10). With 2,2,6,6-tetra-
methylpiperidine (TMP), 2b was isolated in 21% yield
(Table 1, entry 11). The use of 1,5-diazabicyclo(4.3.0)non-
5-ene (DBN), a base similar to DBU, afforded 2b in 81%
HPLC yield.
We then questioned what was the terminal oxidant in
thisoxidative cyclization reaction, asthe reaction was done
under a N2 atmosphere. The net reaction would generate
two hydrogen atoms without an oxidant. A reaction was
carried out in an apparatus to measure the gas volume
change. To our surprise, it was observed that a stoichio-
metric amount of gas was consumed. Further investigation
revealed that dioxygen from the residual air in the appa-
ratus participated in the reaction. Interestingly, the
reaction is very sensitive to the level of the dioxygen
concentration. The reaction works very well under a low
level of dioxygen. Introduction of less than a stoichio-
metric amount of dioxygen caused a partial reaction with
complete consumption of dioxygen. However, when the
reaction was carried out under an air atmosphere (∼21%
oxygen), 74% of the benzothiazole (2b) was formed along
with some undesired side product 3b. When 100% oxygen
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(a) Bose, D. S.; Idrees, M. Synthesis 2010, 398. (b) Jackson, Y. A.;
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D. S.; Idrees, M. Tetrahedron Lett. 2007, 48, 669. (e) Bose, D. S.; Idrees,
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3087.
Org. Lett., Vol. 14, No. 1, 2012
99

in a balloon was used, the intramolecular cyclization
reaction was almost completely stopped. 40% of 3b was
formed along with 60% unreacted starting material 1b. At
the end, a balloon with 5% oxygen was used in the
optimized reaction conditions (Table 1, entry 13). The
reaction worked with an inorganic base, K2CO3, at lower
yield (Table 1, enty 14). More importantly, a reaction with
0.5 equiv of DBU afforded 80% of 2b indicating the base
was a catalyst in the reaction as well (Table 1, entry 15). To
make sure Ru(bpy)32þ and light did participate in the reac-
tion, two control reactions, one without Ru(bpy)3(PF6)2
(Table 1, entry 16) and one in the dark (Table 1, entry 17),
were carried out. No reaction occurred under either con-
dition. The results showed that both light and sensitizer
were essential to the reaction.
Table 2. Synthesis of 2-Phenylbenzothiazolesa
With the standard protocol in hand, we started to
investigate the scope and functional group compatibility
of the new visible-light photocatalytic reaction. The reac-
tion is very mild and tolerates many functional groups
(Table 2). The reaction works very well with electron-
donating groups and weak electron-withdrawing groups
(Table 2, entries 1ꢀ13). For halogen substituted com-
pounds, mixtures of the desired product and dehaloge-
nated benzothiozole (2a) were obtained with o-Br and p-I
substitutions (Table 2, entries 14ꢀ15). o-I substitution
afforded 76% of the dehalogenated product (2a) as the
only isolated product, while other halogen substituted
compounds afforded the CꢀH functionalized product
(Table 2, entries 8ꢀ13). The trend seemed to be parallel
to the CꢀX bond dissociation energies. Moderate yields
were obtained with strong electron-withdrawing substitu-
tions on the aromatic ring (Table 2, entries 16ꢀ17). The
nitro group completely inhibited the reaction (Table 2,
entry 18) probably because the electron transfer occurred
on the benzene ring.14
a Reaction conditions: substrate 1 (1 equiv), DBU (1 equiv), Ru-
(bpy)3(PF6)2 (1 mol %), 14 W CFL light, DMF, rt, 5% O2 balloon, 24 h.
b Isolated yield. c Contained 5% C-5 substituted product. d Contained
15% C-5 substituted product. e Along with the isolation of 42%
dehalogenated product 2a. f Isolated as a mixture of 10% 2o and 34%
dehalogenated product 2a by 1H NMR.
The new visible-light photoredox catalytic reaction is
probably the mildest oxidative formation of 2-substituted
benzothiazoles as the oxidation-sensitive thioether
survived the reaction (Table 2, entry 5), which is in
contrast with what was reported previously under very
similar conditions.2d Another important fact is that the
meta substitued thioanilides afforded major products
with the substitution on C-7 (ortho to the newly formed
CꢀS bond) (Table 2, entries 6 and 13), which is differ-
ent from the previously reported C-5 (para to the CꢀS
bond) substituted products via ionic intermediates.11e,l,m
The ortho-selective arylation results strongly suggest
that the reaction goes through a radical-based pathway.15
The scope of the substrate investigation was extended
to the substitutions on the 2-aryl group. The results are
showninTable3. Botheletron-donating and -withdrawing
groups are tolerated. Good to moderate yields were
obtained.
Table 3. Substitutions on the 2-Phenyl Groupa
a Same reaction conditions as those in Table 2. b Isolated yield.
Based on our observations and literature reports, a
2þ
(14) Poupko, R.; Rosenthal, I. J. Phys. Chem. 1973, 77, 1722.
(15) (a) Tiecco, M.; Testaferri, L. In Reactive Intermediates, Vol. 3;
Abramovitch, R. A., Ed.; Plenum Press: New York, 1983; p 61. (b)
Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 11640.
plausible mechanism is proposed in Scheme 1. Ru(bpy)3
readily accepts a photon to generate the excited *Ru-
2þ
(bpy)32þ. It has been reported that *Ru(bpy)3 can be
100
Org. Lett., Vol. 14, No. 1, 2012

effect (KH/KD = 5) was observed suggesting that the
CꢀH bond breaking step was the rate-determining step.
Scheme 1. Proposed Mechanism
Scheme 2. Intramolecular Kinetic Study
Finally, all the above studies were carried out in a
standardlaboratoryfumehood using householdCFL light
to mimic visible-light irradiation. To demonstrate the
photoredox reaction works under sunlight, a reaction
was carried out under sunshine. 2-Phenylbenzothiazole
(2a) was afforded in 65% yield after 24 h of direct sun
light irradiation over 2 days.
In summary, we have developed an aerobic visible-light
photoredox synthesis of 2-substituted benzothiazoles via
CꢀH functionalization/CꢀS bond formation. The meth-
odology expands the scope of substrates for visible-light
photoredox chemistry. It does not need any sacrificing of
electron donor or acceptor. Moreover, the reaction uses
affordable, readily available molecular oxygen as the
terminal oxidant. This method is complementary to the
existing benzothiozole synthesis with the advantages of
high efficiency, unique selectivity, and an environmental-
friendly nature. The reaction conditions are very mild and
can tolerate many functional groups. Further applications
of this method in the construction of other heterocyclic
compounds are under investigation.
oxidized to Ru(bpy)33þ by molecular oxygen, in which O2
•ꢀ
turned into the O2 radical anion after receiving an
electron.16 In some of our experiments, the reaction mix-
ture color turned green at the beginning of the reaction.
3þ
This is a strong indication of the formation of Ru(bpy)3
,
which is known to be green.16a Therefore, we believe that
Ru(bpy)3 goes through an oxidative catalytic cycle
in our system. It is different from the recently reported
areobic Ru(bpy)3 photoredox reactions.6k,n,p On the
2þ
2þ
other hand, thioanilide is deprotonated to form anion 4.
It is then reduced to radical 5 through single eletron
2þ
transfer (SET) by Ru(bpy)33þ, regenerating Ru(bpy)3
to complete the photoredox cycle. The sulfur radical in 5
attacks the benzene ring to form intermediate 6. Upon
giving away a hydrogen to the O2•ꢀ radical anion, radical 6
rearomatizes to provide benzothiazole 2a and completes
the reaction. However, a reductive quenching mechanism,
in which *Ru(bpy)32þ is reduced to Ru(bpy)3þ by anion 4
to form the same radical intermediate 5, and then molec-
ular oxygen turns Ru(bpy)3þ back to Ru(bpy)32þ and gen-
erates the O2•ꢀ radical anion, could not be ruled out.
To investigate the reaction kinetics, monodeuterated
thioanilide 7 was prepared and subjected to the photo-
redox reaction (Scheme 2). An intramolecular isotope
Acknowledgment. Financial support is provided by the
Specialized Research Fund for the Doctoral Program of
Higher Education (20103201120006), NSFC (21102097),
the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD), and Soochow
University. Y.C. acknowledges the sponsorship from the
Jiangsu Province Higher Education Graduate Student
Research and Innovation Project (CXLX11_0067).
(16) (a) Das, A.; Joshi, V.; Kotkar, D.; Pathak, V. S.; Swayambu-
nathan, V.; Kamat, P. V.; Ghosh, P. K. J. Phys. Chem. A 2001, 105, 6945.
(b) Zhang, X.; Rodgers, M. A. J. J. Phys. Chem. 1995, 99, 12797. (c)
Kotkar, D.; Joshi, V.; Ghosh, P. K. Chem. Commun. 1987, 4. (d) Ghosh,
P. K.; Brunschwig, B. S.; Chou, M.; Creutz, C.; Sutin, N. J. Am. Chem.
Soc. 1984, 106, 4772.
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra, and IR spectra for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
101