Straightforward synthesis of benzoxazoles and benzothiazoles via photocatalytic radical cyclization of 2-substituted anilines with aldehydes

Article abstract of DOI:10.1016/j.catcom.2020.106120

Eosin Y-catalyzed one-pot coupling and cyclization of o-substituted anilines with aldehydes to form benzoxazoles and benzothiazoles under mild condition has been developed. The reaction scope was broadly tolerant of various 2-substituted anilines and aldehydes. The desired products were obtained in high yields with the use of eosin Y as a photocatalyst under a substantial refinement of reaction conditions in comparison with previous literature. Based on the experimental results observed, a plausible mechanism involving a radical process has been proposed.

Full text of DOI:10.1016/j.catcom.2020.106120

Journal Pre-proof
Straightforward synthesis of benzoxazoles and benzothiazoles via
photocatalytic radical cyclization of 2-substituted anilines with
aldehydes
Hao Anh Nguyen Le, Long Hoang Nguyen, Quynh Nhu Ba
Nguyen, Hai Truong Nguyen, Khang Quoc Nguyen, Phuong
Hoang Tran
PII:
S1566-7367(20)30196-5
DOI:
https://doi.org/10.1016/j.catcom.2020.106120
CATCOM 106120
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
15 April 2020
28 June 2020
21 July 2020
Please cite this article as: H.A.N. Le, L.H. Nguyen, Q.N.B. Nguyen, et al., Straightforward
synthesis of benzoxazoles and benzothiazoles via photocatalytic radical cyclization of
2
1
-substituted anilines with aldehydes, Catalysis Communications (2019), https://doi.org/
0.1016/j.catcom.2020.106120
This is a PDF file of an article that has undergone enhancements after acceptance, such
as the addition of a cover page and metadata, and formatting for readability, but it is
not yet the definitive version of record. This version will undergo additional copyediting,
typesetting and review before it is published in its final form, but we are providing this
version to give early visibility of the article. Please note that, during the production
process, errors may be discovered which could affect the content, and all legal disclaimers
that apply to the journal pertain.
©
2019 Published by Elsevier.

Journal Pre-proof
Straightforward synthesis of benzoxazoles and benzothiazoles via photocatalyticradical cyclization of 2-
substituted anilines with aldehydes
‡
,a,b
‡b,c
‡,a,b
a,b
HaoAnh Nguyen Le , Long Hoang Nguyen a,b,,* Quynh Nhu Ba Nguyen , HaiTruong Nguyen ,
a
Khang Quoc Nguyen and Phuong Hoang Tran
a
Department of Organic Chemistry, Faculty of Chemistry, University of Science, Ho Chi Minh City, 721337,
Vietnam
b
Vietnam National University – Ho Chi Minh City, 721337, Vietnam
c
School of Biotechnology, International University, Ho Chi Minh City, Vietnam
‡
These author contributed equally to this work.
Corresponding author: thphuong@hcmus.edu.vn
Abstract: Eosin Y-catalyzed one-pot coupling and cyclization of o-substituted anilines with
aldehydes to form benzoxazoles and benzothiazoles under mild condition has been developed.
The reaction scope was broadly tolerant of various 2-substituted anilines and aldehydes. The
desired products were obtained in high yields with the use of eosin Y as a photocatalyst under a
substantial refinement of reaction conditions in comparison with previous literature. Based on the
experimental results observed, a plausible mechanism involving a radical process has been
proposed.
Keywords: Eosin Y; 2-substituted anilines; photocatalyst; benzoxazoles; benzothiazoles.
1
. Introduction
Aromatic heterocycles, especially 2-phenylbenzoxazoles and benzothiazoles are
commonly ubiquitous motifs in natural products, pharmaceuticals, agrochemicals, ligand
scaffolds, and valuable building blocks in drug design [1]. Furthermore, its luminescent
properties play a crucial role in liquid crystal, mesogenic material, and photochromic material
(Scheme 1) [2]. These molecules are most commonly synthesized by acid-catalyzed oxidative-
aromatization, transition-metal-catalyzed cross-coupling. While these methods are sufficiently
applicable in most cases, they still suffered from a disadvantage of the pre-functionalization of
starting substrates or catalyst.
In the past few years, increasing efforts have been made to bypass the challenging
requirement of pre-functionalization of starting materials and catalysts, such as ligand directed
transition metal-promoted cross-coupling reaction of substituted benzoxazole with
(
pseudo)halide arene or intramolecular C-N and C-O bond formation, affording 2-
phenylbenzoxazole derivatives [3]. On the other hand, intramolecular ring-closing methods for
-substituted benzoxazole that tolerate various functional groups remain a challenge for synthetic
2

Journal Pre-proof
chemists. Prevalently reported methods sustain significant drawbacks involving the requirement
of high temperature and the use of strongly basic or acidic media (Scheme 2-A) [3c, 4, 5a-b, 8,
9
b].
In a search for a new photocatalytic method that would circumvent the aforementioned
challenges in intramolecular ring-closing of 2-substituted benzoxazole, we are enlightened by the
work of Srivastava [8] and Wang [9b], wherein benzoxazoles were prepared by radical
cyclization. However, these methods still required an extra step of isolating reaction
intermediates prior to proceeding to the formation of benzoxazoles. Thus, we herein search for a
viable photocatalyst [10,11], which could be employed to facilitate the preparation of
benzoxazole under visible light without the need of isolating the intermediates (Scheme 2-B).
We suppose the present work could make the reaction more synthetically accessible by (1)
eliminating the requirement for high temperature, strong acid/base and/or use of transition-metal,
(2) precluding the necessity for pre-synthesized starting materials, intermediates and catalysts,
and (3) widening the diversities of the (presently narrow) substrate scope.
2
. Results and discussion
Our present work focuses on the use of in situ formation of 2-hydroxylbenzoimines.
These intermediates can be readily made from 2-aminophenol and various aldehydes. We first
examine our reaction with benzaldehyde and 2-aminophenol, eosin Y as a photocatalyst and
TBHP as co-oxidant in acetonitrile (Table 1, entry 1) afforded only trace amounts of 2-
phenylbenzoxazole. Meanwhile, the addition of K2CO3 gives rise to an outstandingly increasing
yield of compound 3a up to 85% yield (entry 2). Further studies by varying catalysts, bases,
oxidants, and solvents were also conducted to search for possibly better conditions. In a different
series, the use of alternative photocatalysts, i.e. rhodamine B or fluorescein, led to a decreasing
yield of 3a (entries 4 and 5). Of the examined oxidants, TBHP shows the best performance
giving 3a in the highest yield (entry 2), whereas K2S2O8 or H2O2 (entry 6 and 7) failed to afford
the title product. It is indicated that solvents also have a strong impact on the studied reaction. A
reduction in yield was observed upon performing the reaction employing different solvents such
as DMF, DMSO, and DCM (entries 9-11). Finally, the optimal condition was confirmed by the
control experiment; the compound 3a is not detected in the absence of either the base, visible
light irradiation, or the photocatalyst. Further optimization attempts showed that the
photocatalyst loading can be decreased as low as 1 mol%, still affording a yield of 33%. Finally,
a 10 mol% catalyst loading was conducted, and the yield of 3a was obtained in 64%.
After the optimization study, the scope and limitations of each reactant, i.e. aldehyde and
substituted aniline, were then explored. As shown in Scheme 3, a wide range of aldehydes 1,
including cyclic, aliphatic, and aromatic ones containing electron-withdrawing or electron-
donating groups, were first reacted with 2a under the standard condition (3a-3h). The result
observed from the experiment indicated this reaction tolerates various aldehydes, including
cyclic, aliphatic, aromatic, and (hetero) aromatic aldehydes. All compounds were characterized

Journal Pre-proof
1
13
by H and C NMR spectroscopy and MS (see SI for detail). Halogen, methyl, t-butyl, and
methoxy functional groups permitted the reaction affording corresponding products with
moderate to high yield. Furthermore, aromatic heterocycle 4-pyridinecarboxaldehyde reacted
with 2a provided the desired product 3i in good yield. After examined the reaction scope with
benzaldehydes, aliphatic aldehyde and heteroaromatic aldehyde 3g-3l, radical-sensitive aldehyde
containing unsaturated double bond 3l were also conducted, and the desired products were
attained in good yields. Interestingly, trans-cinnamaldehyde reacted with 2a to form the
1
5a
corresponding product with 84% with no side products.
With the above results in hand, we investigated the substitution of substrate 2a with 2-
amino-4-methylphenol, 2-mercaptophenol, 4-chloro-2-aminophenol for the formation of
benzoxazole and benzothiazole derivatives. As shown in Scheme 4, a series of substrates 2 were
surveyed in the optimal condition. Delightfully, all of the substrates 2 reacted smoothly to
produce products 4a-4p from moderate to high yields. Benzothiazole derivatives were
synthesized from 2-mercaptophenol with various aromatic aldehydes gave good yields (4c-4k).
Aliphatic aldehyde, such as 1-heptanal, was also reactive, affording the compound 4p in 90%
yield under the current method. Aryl aldehydes participate in the reaction with 2-amino-4-
methylphenol, and 4-chloro-2-aminophenol gave 2-arylbenzoxazoles with yields ranging from
7
5% to 90%. Therefore, the present reaction significantly exhibits high selectivity and broad
substrate to afford benzoxazole, benzothiazole building blocks from 2-aminophenol and 2-
mercaptophenol derivatives.
The desired products 4 can be achieved using several other reported methods, yet those
with high yield and selectivity under the mild condition for diverse substrates still remain rare.
To further understand how the product is formed, preliminary mechanistic studies were
conducted. The first experiment on the imine adduct derived from 1a and 2a under the optimized
condition gave 3a in a comparable yield (82%) with that of the same compound obtained in the
studied approach, verifying the in situ generation of imine intermediate during the reaction
course (Scheme 5, eq 1). The second experiment comprising of reactions proceeding in the
presence of radical scavenger TEMPO showed a steady decrease of product yield with an
increasing amount of TEMPO indicated the reaction proceeds through a radical mechanism by
decreasing the yields of products when the amount of TEMPO was increased (Scheme 5, eq 2).
In addition, the reaction of 2,4-dihydroxybenzaldehyde 1b with 2a failed to afford the
corresponding product. This phenomenon is well known for imine derivatives of salicylaldehyde
series, whose stabilization can be accomplished via intramolecular hydrogen bonding. Thus,
when hydroxyl moiety on the aldehyde was replaced with methoxy (-OMe), the reaction
proceeded smoothly, forming corresponding product with good yield.
Preliminary mechanistic studies and control experiments reveal that visible light
irradiation plays a vital role in the reaction mechanism. The cyclization reaction ceased when the
light was switched off and only recommences when the light was switched on (see SI). These
control experiments are entirely consistent with the proposed mechanism (see Scheme 6).

Journal Pre-proof
Therefore, the mechanistic experiment indicated any radical chain progress in the reaction is very
short-live and only under visible light irradiation that the reaction will proceed normally.
The mechanism has not been clearly established, but one reasonable process has been
proposed to explain the formation of 3a product. The proposed mechanism begins with the in
situ formation of imine (5) from aldehyde and 2-aminophenol, and the excitation of eosin Y
under blue LEDs irradiation (Scheme 5). Based on Chen’s previous reports of benzoxazole
synthesis using 4-OMe TEMPO as a radical-based catalyst, we believe that eosin Y* reacts with
•
-
•
TBHP generates t-Bu and OH anion [14,15b,16]. Then t-Bu undergoes hydrogen atom
•
abstraction with imine (5) in the hydroxyl (-OH) moiety to produce Ar-O phenoxy radical (6)
and t-BuOH. Phenoxy (6) additionally stabilized by the imine then undergoes intramolecular 5-
endo cycloaddition to the imine, followed by the formation of aminyl radical (7). The generation
of tertiary carbanion (8) was promoted by K2CO3. Finally, single-electron transfer of (8) with
eosin Y radical anion regenerates ground state eosin Y affording the corresponding product.
3
3
. Experimental
.1.Materials and methods
2
-Aminophenol (assay 99%), tert-butyl hydroperoxide (TBHP) (70% in water),
acetonitrile (99.8%), eosin Y (99 %), rhodamine B (≥ 95%, HPLC), dimethyl sulfoxide (≥
9.9%), triphenylphosphine (≥ 99%), triethylamine (≥ 99%), NEM (99%), 4-fluorobenzaldehyde
98%), 4-chlorobenzaldehyde (97%), cyclohexane carbaldehyde (97%), 2,5-
9
(
dimethoxybenzaldehyde (99%), 4-pyridinecarboxaldehyde (97%), trans-cinnamaldehyde (99%),
phthaldialdehyde (≥ 99%, HPLC), furan-2-carbaldehyde (99%), 2-aminolthiophenol (99%), 2-
amino-4-chlorophenol (97%), 4-bromobenzaldehyde (99%), 2-amino-4-methylphenol (97%),
and DMF (99.8%) were purchased from Sigma-Aldrich. Benzaldehyde (> 99%, for synthesis),
4
-methylbenzaldehyde (97%), 4-methoxybenzaldehyde (98%), and 4-(tert-butyl)benzaldehyde
(97%) were purchased from Merck. Analytical thin-layer chromatography (TLC) was acquired
on F-254 silica gel coated aluminum plates from Merck. Column chromatography was
performed with silica gel (60, 230-400 mesh) from Merck. Ethyl acetate (purity ≥ 99.5%), n-
hexane, and chloroform (purity ≥ 99%) were obtained from Xilong Chemical Co., Ltd (China).
Chloroform-d, 99.8 Atom %D, stab. with Ag was obtained from Armar (Switzerland). All
1
13
starting materials and solvents were used without further purification. The H and C NMR
spectra were obtained on a Bruker Advance 500 instrument using CDCl3 as a solvent. HRMS
(ESI) data were collected using Bruker micrOTOF-QII MS. FT-IR spectroscopy was performed
on a Bruker Vertex 70. GC-MS analyses were recorded on an Agilent GC system 7890 equipped
with a mass selective detector Agilent 5973N and a capillary DB-5MS column (30 m x 250 µm x
0
.25 µm).
3
.2. General procedure for the synthesis of benzoxazole/benzothiazole:

Journal Pre-proof
All reactions were carried out in an 8 mL vial equipped with a stirring bar. Aldehyde (1
mmol), 2-aminophenol or 2-aminothiophenol (1 mmol), acetonitrile (3 mL), and a base, i.e.,
K2CO3 or Et3N (2 mmol) were mixed in the vial and stirred at room temperature for 30 minutes.
The vial was then charged with eosin Y (5 mol%) and oxidant (2 mmol), capped, and purged
with argon. The stirred reaction mixture was irradiated by 3 W blue LEDs (5 cm away, with a
fan to maintain the reaction at room temperature) for 24-36 h. The resulting mixture was
transferred to a separatory funnel, partitioned between water (15 mL) and EtOAc (3 x 15 mL).
The organic extract was washed with NaHSO3 10% (30 mL), dried with anhydrous Na2SO4,
filtered, concentrated using a rotavap, and analyzed by GCMS using naphthalene as an internal
standard. The product was purified by flash column chromatography with hexane/EtOAc mixture
as the eluent for NMR characterization.
4
. Conclusions
In summary, we have developed a one-pot reaction between available feedstock chemical
aldehydes and 2-aminophenol, 2-mercaptophenol derivatives, enriching methods for
benzoxazole, benzothiazole preparation. A wide range of aldehydes, including aliphatic
aldehydes and aromatic aldehydes, can tolerate and undergo this present method smoothly to
afford corresponding products in good to excellent yields. This current method bypasses several
aforementioned limitations as it circumvents the requirement of transition-metal, high
temperature, and pre-synthesized catalyst/ligand scaffold. Future insights in seeking reaction
mechanisms, as well as applying this method on complex molecules, are in progress.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This research is funded by Vietnam National University, Ho Chi Minh City (VNU-HCM) under
the grant number 562-2020-18-01.
References
1
. (a) O. Daugulis, H. Q. Do, D. Shabashov, Palladium- And Copper-Catalyzed Arylation of
Carbon-Hydrogen Bonds, Acc. Chem. Res. 42 (2009) 1074-1086; (b) S. Kakkar, S.Tahlan, S. M.
Lim, K. Ramasamy, V. Mani, S. A. A. Shah, B. Narasimhan, Benzoxazole Derivatives: Design,
Synthesis and Biological Evaluation, Chem. Cent. J. 12 (2018) 92-107; (c) K. Seth, S. K Garg,
R. Kumar, P. Purohit, V. S. Meena, R. Goyal, U. C. Banerjee, A. K. Chakraborti, 2-(2-
Arylphenyl)benzoxazole as a novel anti-inflammatory scaffold: Synthesis and biological
evaluation, ACS Med. Chem. Lett. 5 (2014) 512-516; (d) M. A. Abdelgawad, R. B. Bakr, W.
Ahmad, M. M. Al-Sanea, H. A. H. Elshemy, New pyrimidine-benzoxazole/benzimidazole
hybrids: Synthesis, antioxidant, cytotoxic activity, in vitro cyclooxygenase and phospholipase

Journal Pre-proof
A2-V inhibition, Bioorg. Chem. 92 (2019) 103218-103223; (e) L. Gou, Q. Wu, S. Lin, X. Li, J.
Liang, X. Zhou, D. An, Z. Deng, Z. Wang, Mutasynthesis of pyrrole spiroketal compound using
calcimycin 3-hydroxy anthranilic acid biosynthetic mutant, Appl. Microbiol. Biotechnol. 97
(2013) 8183-8191; (f) M. Prudhomme, G. Dauphin, G. Jeminet, J Antibiot. 39 (1986) 922-933;
(g) X. Yuan, Q. Yang, T. Liu, K. Li, Y. Liu, C. Zhu, Z. Zhang, L. Li, C. Zhang, M. Xie, J. Lin, J.
Zhang, Y. Jin, Design, Synthesis and in vitro evaluation of 6-amide-2-aryl
benzoxazole/benzimidazole derivatives against tumor cells by inhibiting VEGFR-2 kinase, Eur.
J Med. Chem. 179 (2019) 147-165; (h) B. Wang, P. Li, T. Miao, L. Zou, L. Wang, Visible-light
induced decarboxylative C2-alkylation of benzothiazoles with carboxylic acids under metal-free
conditions, Org. Biomol. Chem. 17 (2018) 115-121; (i) M. B. Reddy, R. Anandhan, Visible light
initiated amino group ortho-directed copper(I)-catalysed aerobic oxidative C(sp)–S coupling reaction:
synthesis of substituted 2-phenylbenzothiazoles via thia-Wolff rearrangement Chem. Commun. 56
(2020) 3781-3784; (j) L. A. Nguyen, P. Retailleau, T. B. Nguyen, Adv. Synth. Catal. 361 (2019)
2
864-2869; (k) T. B. Nguyen, P. Retailleau, Elemental sulfur-promoted oxidative rearranging
coupling between o-aminophenols and ketones: A synthesis of 2-alkyl benzoxazoles under mild
conditions, Org. Lett. 19 (2017) 3887-3890; (l) T. B. Nguyen, L. Ermolenko, A. Al- Mourabit,
Nitro-methyl redox coupling: Efficient approach to 2-hetarylbenzothiazoles from 2-
halonitroarene, methylhetarene, and elemental sulfur, Org. Lett. 15 (2013) 4218-4221; (m) T. B.
Nguyen, L. Ermolenko, W. A. Dean, A. Al-Mourabit, Benzazoles from aliphatic amines and o-
amino/mercaptan/hydroxyanilines: elemental sulfur as a highly efficient and traceless oxidizing
agent, Organic Lett. 14 (2012) 5948-5951.
2
. (a) C. Carayon, S. Fery-Forgues, 2-Phenylbenzoxazole derivatives: A family of robust emitters of
solid-state fluorescence, Photochem. Photobiol. Sci. 16 (2017) 1020-1035; (b) Y. Chen, D. X.
Zeng, Study on photochromic diarylethene with phenolic schiff base:ꢀ Preparation and
photochromism of diarylethene with benzoxazole, J. Org. Chem 69 (2004) 5037-5040; (c) T. B.
Nguyen, L. P. A. Nguyen, T. T. T. Nguyen, Sulfur‐catalyzed oxidative coupling of dibenzyl
disulfides with amines: Access to thioamides and aza heterocycles, Adv. Synth. Catal. 361
(2019) 1787-1791; (d) L. A. Nguyen, Q. A. Ngo, P. Retailleau, T. B. Nguyen, Elemental sulfur as
a polyvalent reagent in redox condensation with o-chloronitrobenzenes and benzaldehydes: three-
component access to 2-arylbenzothiazoles, Green Chem. 19 (2017) 4289-4293; (e) T. B. Nguyen,
K. Pasturaud, L. Ermolenko, A. Al-Mourabit, Concise access to 2-aroylbenzothiazoles by redox
condensation reaction between o-halonitrobenzenes, acetophenones, and elemental sulfur, Org.
Lett. 17 (2015) 2562-2565; (f) T. B. Nguyen, L. Ermolenko, P. Retailleau, A. Al-Mourabit,
Elemental sulfur disproportionation in the redox condensation reaction between o‐
halonitrobenzenes and benzylamines, Angew. Chem. Int. Ed. 53 (2014) 13808-13812; (g) T. B.
Nguyen, L. Ermolenko, A. Al-Mourabit, Selective autoxidation of benzylamines: application to the
synthesis of some nitrogen heterocycles, Green Chem. 15 (2013) 2713-2717; (h) S. Kumar, D.
Parshuram Satpute, G. Nikhil Vaidya, M. Nagpure, S. Kumar Lokhande, D. Meena, D. Kumar,
Micellar
catalysis
enabled
synthesis
of
indolylbenzothiazoles
and
their

Journal Pre-proof
functionalization via Mn(II)-catalyzed C2–H amination using pyridines, Tetrahedron Lett. 61
(
2020) 152017; (i) S. M. Sondhi, S. Arya, R. Rani, Microwave-assisted conversion of aromatic
heterocyclic nitriles to various heterocyclic molecules, Green Chem. Lett. Rev. 5 (2012) 409-
14; (j) K. Seth, P. Purohit, A. K. Chakraborti, Microwave Assisted Synthesis of Biorelevant
Benzazoles, Curr. Med. Chem. 24 (2017) 4638-4676.
4
3
. (a) D. S. Bose, M. Idrees, Dess-martin periodinane mediated intramolecular cyclization of
phenolic azomethines: A solution-phase strategy toward benzoxazoles and benzothiazoles,
Synthesis (2010) 398-402; (b) K. T. Neumann, A. T. Lindhardt, B. Bang-Andersen, T.
Skrydstrup, Access to 2-(het)aryl and 2-styryl benzoxazoles via palladium-catalyzed
aminocarbonylation of aryl and vinyl bromides, Org. Lett. 17 (2015) 2094-2097; (c) Q. T.
Nguyen, A.-Thi Hang, H. T.-L. Ho Nguyen, D.-K. Nguyen Chau, P. H. Tran, Phosphonium acidic
ionic liquid: an efficient and recyclable homogeneous catalyst for the synthesis of 2-arylbenzoxazoles, 2-
arylbenzimidazoles, and 2-arylbenzothiazoles, RSC Adv. 8 (2018) 11834-11842; (d) P. H Tran,. A.-
H. Thi Hang, Deep eutectic solvent-catalyzed arylation of benzoxazoles with aromatic aldehydes, RSC
Adv. 8 (2018) 11127-11133; (e) T. B. Nguyen, J. C. Lung, Iron‐catalyzed sulfur‐promoted
decyanative redox condensation of o ‐nitrophenols and arylacetonitriles: an unprecedented route
to 2‐arylbenzoxazoles, Eur. J. Org. Chem. (2018) 5815-5818; (f) T. B. Nguyen, L. Ermolenko,
A. Al-Mourabit, Iron sulfide catalyzed redox/condensation cascade reaction between 2-
amino/hydroxy nitrobenzenes and activated methyl groups: A straightforward atom economical
approach to 2-hetaryl-benzimidazoles and -benzoxazoles, J. Am. Chem. Soc. 135 (2013) 118.
4
. J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D. Larsen, M. M. Faul, A highly
efficient palladium/copper cocatalytic system for direct arylation of heteroarenes: An unexpected
effect of Cu(Xantphos)I , J. Am. Chem. Soc. 132 (2010) 3674-3675.
5
. (a) M. M. Guru, M. A. Ali, T. Punniyamurthy, Copper(II)-catalyzed conversion of
bisaryloxime ethers to 2-arylbenzoxazoles via C−H functionalization/C−N/C−O bonds
formation, Org. Lett. 13 (2011) 1194-1197; (b) G. Evindar, R. A. Batey, Parallel synthesis of a
library of benzoxazoles and benzothiazoles using ligand-accelerated copper-catalyzed
cyclizations of ortho-halobenzanilides, J. Org. Chem 71 (2006) 1802-1808.
6
. (a) R. D. Viirre, G. Evindar, R. A. Batey, Copper-catalyzed domino annulation approaches to
the synthesis of benzoxazoles under microwave-accelerated and conventional thermal conditions,
J. Org. Chem. 73 (2008) 3452-3459; (b) H.-Q. Do, O. Daugulis, Copper-Catalyzed Arylation of
Heterocycle C−H Bonds, J. Am. Chem. Soc. 129 (2007) 12404-12405; (c) K. Oshimoto, H.
Tsuji, M. Kawatsura, Synthesis of benzoxazoles via the copper-catalyzed hydroamination of
alkynones with 2-aminophenols, Org. Biomol. Chem. 17 (2019) 4225-4229.
7
. (a) X.-B. Shen, Y. Zhang, W.-X. Chen, Z.-K. Xiao, T.-T. Hu, L.-X. Shao, Direct C–H bond
arylation of (benzo)oxazoles with aryl chlorides catalyzed by N-heterocyclic carbene–
palladium(II)–1-methylimidazole complex, Org. Lett. 16 (2014) 1984-1987; (b) P. Ren, I. Salihu,

Journal Pre-proof
R. Scopelliti, X. Hu, Copper-catalyzed alkylation of benzoxazoles with secondary alkyl halides,
Org. Lett. 14 (2012) 1748-1751.
8
. V. P. Srivastava, L. D. S. Yadav, Visible-light-triggered oxidative C-H aryloxylation of
phenolic amidines; photocatalytic preparation of 2-aminobenzoxazoles, Synlett 24 (2013) 2758-
2
9
762.
. (a) Y.-X. Chen, L.-F. Qian, W. Zhang, B. Han, Efficient aerobic oxidative synthesis of 2-
substituted benzoxazoles, benzothiazoles, and benzimidazoles catalyzed by 4-methoxy-TEMPO,
Angew. Chem. Int. 47 (2008) 9330-9333. (b) Wang. L. M. Zhi-Gang, L. Qiang, Synthesis of 2-
substituted pyrimidines and benzoxazoles via a visible-light-driven organocatalytic aerobic
oxidation: enhancement of the reaction rate and selectivity by a base, Green Chem. 16 (2014)
3
752-3757
1
0. (a) C. Stephenson, T. Yoon, D.W.C. MacMillan, S. Morris, T. Nguyen, and N. Zheng, Visible
Light Photocatalysis in Organic Chemistry, Wiley-VCH, Weinheim, 2018; (b) J. J. Pesek, J.
Frost, H., Synthesis of imines from aromatic aldehydes and aliphatic amines in aqueous solution,
Synth. Comm. 4 (1974) 367-372; (c) J. Hu, J. Wang, T. H. Nguyen, N Zheng,. The chemistry of
amine radical cations produced by visible light photoredox catalysis, Beilstein J. Org. Chem 9
(2013) 1977-2001.
11. L. Capaldo, D. Ravelli, Hydrogen atom transfer (HAT): A versatile strategy for substrate
activation in photocatalyzed organic synthesis, Eur. J. Org. Chem. (2017) 2056-2071.
1
2. M. Salamone, G. A. DiLabio, M. Bietti, Kinetic solvent effects on hydrogen abstraction
reactions from carbon by the cumyloxyl radical. The importance of solvent hydrogen-bond
interactions with the substrate and the abstracting radical, J. Org. Chem. 76 (2011) 6264-6270.
1
3. (a) C. Ollivier, L. Fensterbank, A triple catalysis for alkyl-alkyl coupling: An advance toward
the ideal synthesis, Chem 3 (2017) 207-208; (b) J. Ye, I. Kalvet, F. Schoenebeck, T. Rovis, Direct
α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics, Nat. Chem. 10
(2018) 1037–1041.
1
4. (a) J. Tan, T. Zheng, Y. Yu, K. Xu, TBHP-promoted direct oxidation reaction of benzylic
3
Csp –H bonds to ketones, RSC Adv. 7 (2017) 15176-15180; (b) H. He, B.-J. Pei, A. W. M. Lee,
Metal free oxidation of alkyl substituted aromatics with aqueous tert-butyl hydroperoxide under
microwave irradiation, Green Chem. 11 (2009) 1857-1861.
1
5. (a) H. Wang, C. Chen, W. Liu, Z. Zhu, Difunctionalization of alkenes with iodine and tert-
butyl hydroperoxide (TBHP) at room temperature for the synthesis of 1-(tert-butylperoxy)-2-
iodoethanes, Beilstein J. Org. Chem. 13 (2017) 2023-2027; (b) J. Li, D. Z. Wang, Visible-light-
promoted photoredox syntheses of α,β-epoxy ketones from styrenes and benzaldehydes under
alkaline conditions, Org. Lett. 17 (2015) 5260-5263.

Journal Pre-proof
1
6. D. Yang, B. Huang, W. Wei, J. Li, G. Lin, Y. Liu, J. Ding, P. Sun, H. Wang, Visible-light
initiated direct oxysulfonylation of alkenes with sulfinic acids leading to β-ketosulfones, Green
Chem. 18 (2016) 5630-5634.

Journal Pre-proof
Scheme 1. Example of benzoxazole derivatives

Journal Pre-proof
Scheme 2. (A) Known pathways and (B) our report for 2-phenylbenzoxazole

Journal Pre-proof
a
Table 1. Optimization of the reaction condition
b
Entry
Catalyst
mol%)
Solvent
MeCN
[O] (equiv)
Base
Yield
(
1
2
3
4
5
6
7
8
9
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Rhodamine B (5)
Fluorescein (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (1)
Eosin Y (10)
Eosin Y (0.1)
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
none
trace
85%
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
DCM
MeCN
MeCN
MeCN
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
c
14%
trace
75%
trace
no reaction
no reaction
trace
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K CO
1
1
1
1
1
0
1
2
3
4
trace
trace
33%
64%
8%
2
3
a
Unless otherwise noted, all reactions were carried out with 1a (1 mmol), 2a (1.5 mmol),
photocatalyst, oxidant (2 equiv), base (1 equiv), and solvent (3 mL) in a sealed tube under argon;
b
the reaction mixture was irradiated with 3W blue LEDs for 24 h-36 h. Yield of product 3a was
c
determined by GC with an internal standard. The reaction was conducted in the absence of light.

Journal Pre-proof
Scheme 3. Reaction scope with respect to the aldehyde 1. Reaction conditions: A mixture of 1
(1 mmol), 2a (1.5 mmol), eosin Y (5 mol%), TBHP (2 equiv), K2CO3 (2 equiv), and MeCN (3
mL) in a sealed tube under argon was irradiated with 3 W blue LEDs for 24 h.

Journal Pre-proof
Scheme 4. Reaction scope to the 2-aminophenol and 2-mercaptophenol substrate. Reaction
conditions: A mixture of 1 (1 mmol), 2 (1.5 mmol), eosin Y (5 mol%), TBHP (2 equiv), K2CO3
(2 equiv), and MeCN (3 mL) in a sealed tube under nitrogen was irradiated with 3 W blue LEDs
for 24 h.

Journal Pre-proof
Scheme 5. Preliminary mechanistic studies and control experiments

Journal Pre-proof
Scheme 6. Proposed mechanism