Visible-light-initiated photo-oxidative cyclization of phenolic amidines using CBr4-A metal free approach to 2-aminobenzoxazoles

Article abstract of DOI:10.1039/c3ra46314a

A mild and efficient one-pot operation for the amination of benzoxazoles has been achieved via ring opening of benzoxazoles followed by visible-light-mediated aerobic photo-oxidative cyclization of the resulting o-phenolic amidines using CBr₄ as a mild oxidant. The protocol is economical and environmentally benign as it utilizes visible light and does not require any photosensitizers, additives, heating or inert conditions.

Full text of DOI:10.1039/c3ra46314a

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Visible-light-initiated photo-oxidative cyclization
of phenolic amidines using CBr – A metal free
4
Cite this: RSC Adv., 2014, 4, 5815
approach to 2-aminobenzoxazoles†
Received 31st October 2013
Accepted 12th December 2013
Twinkle Keshari, Vishnu P. Srivastava and Lal Dhar S. Yadav*
DOI: 10.1039/c3ra46314a
www.rsc.org/advances
A mild and efficient one-pot operation for the amination of benzox- to the traditional C–N bond formation involving nucleophillic
azoles has been achieved via ring opening of benzoxazoles followed displacement of 2-halogenated benzoxazoles or their precursors
6
by visible-light-mediated aerobic photo-oxidative cyclization of the with amines. However, various metal-based established
resulting o-phenolic amidines using CBr as a mild oxidant. The methods have disadvantages of using toxic and/or expensive
4
protocol is economical and environmentally benign as it utilizes visible metal catalysts, even traces of which are to be removed for
light and does not require any photosensitizers, additives, heating or pharmaceutical applications. Hence, several metal-free
inert conditions.
methods employing various reagents or catalysts such as
7
TEMPO, TBAI, I
2
, and NIS have been reported. Furthermore,
elegant synthetic routes to access 2-aminobenzoxazoles utilis-
ing aminophenols as substrates have also been developed.
Introduction
8,9
Besides, Chang and co-workers have recently developed an
elegant method for the synthesis of 2-aminobenzoxazoles
through a unique ring opening of benzoxazoles with secondary
amines followed by an oxidative ring closure of the resulting o-
The potential of developing new synthetic methodologies using
visible light has recently received much attention from a
number of research groups. This is because solar energy
1
(visible light) is clean, easy to handle and an unlimited energy
10
phenolic amidines with iodobenzene diacetate (DIB). Later on,
Bhanage and co-workers have implemented this strategy using
source having great prospects for the development of sustain-
2
able and eco-friendly protocols for organic synthesis. Most
11
2
-iodobenzoic acid (IBX) as the oxidant. These metal-free
visible-light-initiated photochemical organic reactions gener-
ally require expensive and potentially toxic ruthenium and
methods use expensive and potentially explosive oxidants. Very
recently, we have developed a convenient synthesis of 2-ami-
3
iridium complexes as photosensitizers or photocatalysts. Thus,
nobenzoxazoles from o-phenolic amidines using Ru(dpy) Cl as
the search for novel synthetically useful photochemical reac-
tions without the need for visible-light photosensitization
would be a welcome move, especially in terms of economical
and environmental issues. The 2-aminobenzoxazole scaffold is
a key structural motif in promising pharmaceuticals for the
treatment of various disorders, such as Alzheimer's disease,
2
2
12
a visible-light photoredox catalyst.
In view of the above discussion and our continued efforts for
12,13
developing efficient heterocyclization reactions,
we envi-
sioned that a metal- and photosensitizer-free visible-light-initi-
ated cyclization of o-phenolic amidines to the corresponding 2-
aminobenzoxazoles could be feasible and highly interesting
4
schizophrenia, HIV and inammatory diseases. Fascinated by
(Scheme 1). For this purpose, we focused on CBr
4
, which is
the medicinal worth of 2-aminobenzoxazoles, great efforts have
been made for their synthesis.
solid, easy to handle, and absorbs visible light to generate active
14
radical species, hence expected to be suitable for our envis-
aged cyclization reaction.
2-Aminobenzoxazoles have been generally synthesized by
direct amination of benzoxazoles with an amine or its surro-
5
gates through transition-metal-catalyzed C–H bond activation.
These methods are quite benecial and appreciable compared
Results and discussion
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad
In order to realize our goal, we commenced the study with a
model reaction of 2-(piperidin-1-yl-methyleneamino)phenol 1a
using a stoichiometric amount of CBr4 in acetonitrile as a
solvent under visible light irradiation with an 18 W CFL for 1 h
in the presence of air at rt. To our delight, 2-aminobenzoxazole
2
5
11 002, India. E-mail: ldsyadav@hotmail.com; Fax: +91 532-246-0533; Tel: +91
32-250-0652
1
†
Electronic supplementary information (ESI) available: Detailed procedures, H,
13
C
NMR and HRMS spectral data of all the products. See DOI:
1
0.1039/c3ra46314a
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 5815–5818 | 5815

View Article Online
RSC Advances
Communication
necessary for the initiation of the cyclization reaction. Thus,
various bromine sources were tested and it was found that CBr4
was the best in terms of the yield and reaction time (Table 1,
entry 1). However, in the case of tetrabutyl ammonium bromide
(TBNBr) no cyclization of o-phenolic amidine 1a was observed
which might be due to inability of TBNBr to give bromine
radical under the given reaction conditions (Table 1, entry 9).
Keeping in view the potential of CBr as an efficient reagent
4
for visible-light-initiated photo-oxidative cyclization of
o-phenolic amidines in CH CN (Table 1, entry 1), we switched to
3
investigate the substrate scope of the reaction. As depicted in
Table 2, phenolic amidines bearing electron-neutral, electron-
donating or electron-withdrawing substituents generally affor-
ded 2-aminobenzoxazoles in excellent yields (80–92%). This
shows little electronic effect of the substituents on the oxidative
cyclization reaction. Interestingly, amidines with various func-
Scheme 1 Amination of benzoxazoles.
3 3 2 3
tionalites such as CH , OCH , NO , Cl, Ph and CF were easily
tolerated to give aminobenzoxazoles in excellent yields and high
purity. However, on the part of secondary amines, structurally
diverse cyclic and acyclic amines were evaluated and found to
undergo the photo-oxidative cyclization very smoothly.
2
a was obtained in 92% yield aer 1 h. To ensure the necessity
of the reaction parameters such as CBr , air and visible light for
4
the present photo-oxidative cyclization, a series of control
experiments were performed which revealed that in the absence
of any one of the parameters, a little or no product formation
was observed (Table 1, entries 10–12). On performing the
cyclization under inert argon atmosphere, a decrease in
the yield was observed (Table 1, entry 11). Next, optimization of
Table 2 Photo-oxidative cyclization of o-phenolic amidines to yield
a
2-aminobenzoxazoles
the solvent was carried out which revealed CH
solvent for the reaction (Table 1, entry 1). However, several other
solvents such as THF, dioxane, DCM, CH NO , and toluene
were also explored which did not give satisfactory results
Table 1, entries 2–6). Notably, a radical generating bromine
3
CN to be the best
3
2
(
source was also found to be one of the major parameters
a
Table 1 Optimization of reaction conditions
e
Entry
Reagent
Solvent
CH CN
THF
Dioxane
DCM
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CBr
CBr
CBr
CBr
CBr
CBr
4
4
4
4
4
4
3
1
6
6
6
6
6
1
3
6
6
6
6
92
25
30
35
20
15
71
67
0
3 2
CH NO
Toluene
Br
2
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
NBS
TBNBr
9
b
1
1
1
0
1
2
CBr
CBr
—
4
0
12
0
c
4
d
a
Reaction conditions: o-phenolic amidine (1 mmol), reagent (1 mmol),
a
b
solvent (3 mL), under 18 W CFL (Compact uorescent lamp; Philips,
See ESI for detailed procedure. All compounds are known and were
1 13
6
500 k, 1010 1 m, 85 mA) irradiation under an air atmosphere at rt. characterized by comparison of their H, C NMR and HRMS data with
b
c
d
10,15,16
c
In dark. Under inert Ar atmosphere. Absence of bromine source. those reported in the literature.
Yields of isolated pure
e
Isolated yield of 2a aer ash chromatography.
compounds.
5816 | RSC Adv., 2014, 4, 5815–5818
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
(2,2,6,6-tetramethyl-1-piperidinyloxy), which is a traditional
radical scavenger (Scheme 3, eqn (I)).
The key steps include: (i) on photo-irradiation, CBr is acti-
4
vated to give cBr and cCBr radicals which initiate the reaction
3
3
(Scheme 3, eqn (II)). (ii) cCBr or cBr radical abstracts phenolic H
to give 3 which undergoes intramolecular cyclization to
generate an aminyl radical 4. (iii) The aminyl radical 4 is prone
to undergo 1,2 H shi to form a more stable carbon radical 5,
and (iv) the radical 5 is efficiently oxidized by giving an electron
Scheme 2 One-pot sequential amination of benzoxazoles.
to cBr or O to generate a highly stabilised carbocation 6, which
2

nally aromatizes through deprotonation to give the product 2.
Furthermore, owing to an easy, rapid and high yielding
10
conversion of benzoxazoles into o-phenolic amidines, we pro-
ceeded for one-pot synthesis of 2-aminobenzoxazoles starting
Conclusion
from benzoxazoles and secondary amines (Scheme 2). Thus, we In summary, we have developed a highly efficient, mild and
stirred benzoxazole (1 mmol) and piperidine (2 mmol) under unique strategy for a one-pot synthesis of 2-aminobenzoxazoles.
neat condition at rt for 10 min. Aer conrming the complete The protocol involves ring opening of benzoxazoles with
conversion of benzoxazole to corresponding amidine by TLC, secondary amines followed by photo-oxidative intramolecular
CH CN (3 mL) and CBr (1 mmol) were added and the reaction cyclization of the resulting o-phenolic amidines using visible-
3
4
mixture was irradiated with an 18 W CFL for 1.5 h. To our delight, light as a mild source of energy and CBr as an oxidant. The use
4
the one-pot procedure was also effective and the desired product, of visible-light irradiation without the need for any metal or
2-aminobenzoxazole 2a was obtained in a decent yield (89%).
non-metal photosensitizers or photocatalysts makes our
On the basis of the above observations and the literature method sustainable, ecofriendly and superior to the other
12,14,17,18
precedents,
a plausible mechanism for the present existing methods for the amination of benzoxazoles.
visible-light-initiated photo-oxidative cyclization of o-phenolic
amidines 1 to afford 2-aminobenzoxazoles 2 is depicted in
Scheme 3. The cyclization of amidines might follow a radical
Acknowledgements
pathway, as the reaction was quenched on addition of TEMPO We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. T. K. is grateful to the
CSIR, New Delhi, for the award of a junior Research Fellowship
(File no. 09/001(0370)/2012-EMR-1). V. P. S. is grateful to the
Department of Science and Technology (DST) Govt. of India, for
the award of a DST-Inspire Faculty position (Ref. IFA-11CH-08)
and nancial support.
References
1
For selected reviews, see: (a) K. Zeitler, Angew. Chem., Int. Ed.,
2009, 48, 9785; (b) P. Melchiorre, Angew. Chem., Int. Ed., 2009,
48, 1360; (c) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem.,
2010, 2, 527; (d) J. M. R. Narayanam and C. R. J. Stephenson,
Chem. Soc. Rev., 2011, 40, 102; (e) F. Teply, Collect. Czech.
Chem. Commun., 2011, 76, 859; (f) J. W. Tucker and
C. R. J. Stephenson, J. Org. Chem., 2012, 77, 1617.
2
3
(a) G. Ciamician, Science, 1912, 36, 385; (b) X. Sala, I. Romero,
M. Rodriguze, E. Lluis and A. Llobet, Angew. Chem., Int. Ed.,
2
009, 48, 2842.
For reviews, see: (a) K. Kalyanasundaram, Coord. Chem. Rev.,
982, 46, 159; (b) A. Juris, V. Balzani, F. Barigelletti,
1
S. Campagna, P. Belser and A. von Zelewsky, Coord. Chem.
Rev., 1988, 84, 85; (c) L. Flamigni, A. Barbieri, C. Sabatini,
B. Ventura and F. Barigelletti, Top. Curr. Chem., 2007, 281, 143.
(a) Y. Sato, M. Yamada, S. Yoshida, T. Soneda, M. Ishikawa,
T. Nizato, K. Suzuki and F. Konno, J. Med. Chem., 1998, 41,
4
3015; (b) M. Cheung, P. Harris, M. Hasegawa, S. Ida,
K. Kano and N. Nishigaki, PCT WO 02/44156A2, 2002,
Scheme 3 Plausible pathway for the photo-oxidative amination of
benzoxazoles.
Chem. Abstr., 2002, 137, 1679; (c) S. Yoshida, T. Watanabe
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 5815–5818 | 5817

View Article Online
RSC Advances
Communication
and Y. Sato, Bioorg. Med. Chem., 2007, 15, 3515; (d) K. G. Liu,
9 T. Guntreddi, B. K. Allam and K. N. Singh, RSC Adv., 2013, 3,
J. R. Lo, T. A. Comery, G. M. Zhang, J. Y. Zhang, D. M. Kowal,
9875.
D. L. Smith, L. Di, E. H. Kerns, L. E. Schechter and 10 J. Joseph, J. Y. Kim and S. Chang, Chem.–Eur. J., 2011, 17,
A. J. Robichaud, Bioorg. Med. Chem. Lett., 2009, 19, 1115; 8294.
e) A. Armstrong and J. C. Collins, Angew. Chem., Int. Ed., 11 Y. S. Wagh, N. J. Tiwari and B. M. Bhanage, Tetrahedron Lett.,
(
2010, 49, 2282.
2013, 54, 1290.
5
6
(a) D. Monguchi, T. Fujiwara, H. Furukawa and A. Mori, Org. 12 V. P. Srivastava and L. D. S. Yadov, Synlett, 2013, 24, 2758.
Lett., 2009, 11, 1607; (b) Q. Wang and S. L. Schreiber, Org. 13 (a) R. Patel, V. P. Srivastava and L. D. S. Yadav, Synlett, 2010,
Lett., 2009, 11, 5178; (c) T. Kawano, K. Hirano, T. Satoh and
M. Miura, J. Am. Chem. Soc., 2010, 132, 6900; (d)
N. Matsuda, K. Hirano, T. Satoh and M. Miura, Org. Lett.,
1797; (b) A. Rai and L. D. S. Yadav, Tetrahedron Lett., 2011, 52,
3933; (c) A. Rai, V. K. Rai, A. K. Singh and L. D. S. Yadav, Eur.
J. Org. Chem., 2011, 4302; (d) A. K. Singh, R. Chawla, A. Rai
and L. D. S. Yadav, Chem. Commun., 2012, 48, 3766; (e)
A. Rai and L. D. S. Yadav, Tetrahedron, 2012, 68, 2459; (f)
V. P. Srivastava, A. K. Yadav and L. D. S. Yadav, Synlett,
2013, 24, 0465.
2011, 13, 2860.
(a) F. Haviv, J. D. Ratajczyk, R. W. DeNet, F. A. Kerdesky,
R. L. Walters, S. P. Schmidt, J. H. Holms, P. R. Young and
G. W. Carter, J. Med. Chem., 1988, 31, 1719; (b) R. Lok,
R. E. Leone and A. J. Williams, J. Org. Chem., 1996, 61, 14 Y. Nishina, B. Ohtani and K. Kikushima, Beilstein J. Org.
289; (c) M. W. Hooper, M. Utsunomiya and J. F. Hartwig, Chem., 2013, 9, 1663.
3
J. Org. Chem., 2003, 68, 2861; (d) M. S. R. Murty, K. R. Ram, 15 M. Lamani and K. R. Prabhu, J. Org. Chem., 2011, 76, 7938.
R. V. Rao, J. S. Yadav, U. S. N. Murty and K. P. Kumar, Med. 16 T. Kawano, K. Hirano, T. Satoh and M. Miura, J. Am. Chem.
Chem. Res., 2011, 20, 626.
Soc., 2010, 132, 6900.
7
8
(a) T. Froehr, C. P. Sindlinger, U. Kloeckner, P. Finkbeiner 17 S. Maity and N. Zheng, Angew. Chem., Int. Ed., 2012, 51, 9562.
and B. Nachtsheim, Org. Lett., 2011, 13, 3754; (b) S. Wertz, 18 (a) Y. Su, L. Zhang and N. Ziao, Org. Lett., 2011, 13, 2168; (b)
S. Kodama and A. Studer, Angew. Chem., Int. Ed., 2011, 50,
1511; (c) Y. S. Wagh, D. N. Sawant and B. M. Bhanage,
Y. Q. Zou, L. Q. Lu, L. Fu, N. J. Chang, J. Rong, J. R. Chen and
W. J. Xiao, Angew. Chem., Int. Ed., 2011, 50, 7171; (c) S. Cai,
X. Zhao, X. Wang, Q. Liu, Z. Li and Z. D. Wang, Angew.
Chem., Int. Ed., 2012, 51, 8050; (d) H. Sun, C. Yang, F. Gao,
Z. Lia and W. Xia, Org. Lett., 2013, 14, 624.
1
Tetrahedron Lett., 2012, 53, 3482.
C. L. Cioffi, J. J. Lansing and H. Yuksel, J. Org. Chem., 2010,
75, 7942.
5818 | RSC Adv., 2014, 4, 5815–5818
This journal is © The Royal Society of Chemistry 2014