Redox-neutral iron-sulfur promoted transformation of 2-nitrophenols and 2,6-disubstituted p -cresols into 2-arylbenzoxazoles

Article abstract of DOI:10.1055/s-0033-1338995

A catalyst based on iron and elemental sulfur has been shown to efficiently promote a redox-neutral reaction between 2-nitrophenols and 2,6-disubstituted p-cresols, allowing for the preparation of 2-arylbenzoxazoles in good yields. This synthetic methodology also affords high atom economy without the use of any external oxidizing and/or reducing reagents. This is the first redox-condensation reaction of 2-nitrophenols with 2,6-disubstituted p-cresols. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338995

LETTER
▌1565
lRetteerdox-Neutral Iron–Sulfur Promoted Transformation of 2-Nitrophenols and
2,6-Disubstituted p-Cresols into 2-Arylbenzoxazoles
Synthesis of 2-Arylbenzoxazoles
Masahiko Saibara,*a Kazuhito Ashida,a Kouji Satomi,a Toshiyuki Iwai,b Takeo Nakai,b Masatoshi Mihara,b
Takatoshi Ito,b Takumi Mizuno*b
a
Research Center, Honshu Chemical Industry Co., Ltd., 2-5-115, Kozaika, Wakayama 641-0007, Japan
b
Organic Materials Research Division, Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax +81(6)69638030; E-mail: tmizuno@omtri.or.jp
Received: 03.03.2014; Accepted after revision: 06.04.2014
reactions. In this context, utilization of iron and elemental
Abstract: A catalyst based on iron and elemental sulfur has been
sulfur, which is nontoxic, stable under ambient condi-
shown to efficiently promote a redox-neutral reaction between
tions, easy to handle, and readily available in its pure
form, could be an excellent solution. Indeed, iron and ele-
2-nitrophenols and 2,6-disubstituted p-cresols, allowing for the
preparation of 2-arylbenzoxazoles in good yields. This synthetic
methodology also affords high atom economy without the use of mental sulfur often work together synergistically, thereby
any external oxidizing and/or reducing reagents. This is the first re-
dox–condensation reaction of 2-nitrophenols with 2,6-disubstituted
p-cresols.
acting as redox reagent, catalyst, etc.; this can often result
in interesting reactivity.
Benzoxazoles are important building blocks for the con-
struction of pharmaceuticals, natural products, functional
Key words: heterocycles, iron, sulfur, annulation, domino reaction
materials, and agrochemical compounds. New strategies
for the synthesis of benzoxazolone using elemental sulfur
In order to address the problems of natural resource deple-
have been a recent area of focus in our lab,1 and in this
tion and environmental pollution, a great deal of effort has
context, several conventional synthetic methodologies for
been made towards developing greener and more sustain-
the preparation of benzoxazoles have been explored.
able modern chemical processes, particularly with regards
These methodologies include the condensation–cycliza-
to large-scale production. In the course of our research,
tion of 2-aminophenols with carboxylic acids (carboxylic
we have continuously tried to develop useful chemical
derivatives),2 the oxidation of cyclic hemiaminals formed
processes that are straightforward and applicable to the
from 2-aminophenols by reacting with aldehydes,3 and the
synthesis of biologically active and/or industrially impor-
condensation–cyclization of carboxylic acid derivatives
tant molecules. The aim was to develop synthetic process-
with (2-halo)anilines (which includes an intramolecular
es that meet one or more of the following criteria: 1) use
C–O bond formation in the presence of copper catalyst;
readily available starting materials and catalysts; 2) em-
Scheme 1).4
ploy environmentally benign reaction conditions; 3) have
high atom economy; 4) involve catalytic and/or cascade
H
N
R
NH2
OH
RCOOH
(RCOCl)
condensation
O
OH
H
N
NH2
OH
N
R
N
O
RCHO
oxidation
R
H
R
O
OH
H
N
NH2
X
R
coupling
RCOCl
O
X
X = H, halogen
Scheme 1 Conventional syntheses of 2-arylbenzoxazoles
SYNLETT 2014, 25, 1565–1570
Advanced online publication: 20.05.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338995; Art ID: st-2014-u0187-l
© Georg Thieme Verlag Stuttgart · New York

1566
M. Saibara et al.
LETTER
Although benzoxazole synthesis via the condensation of To resolve the limitations of redox–condensation reac-
2-aminophenols and aldehydes has been extensively used, tions on methyl aromatics, we focused on redox reactions
this approach cannot afford an atom-economic transfor- using cresols which have relatively low redox potentials.
mation. Both of the starting materials are typically ob- By employing cresols as a hydrogen source in place of
tained via opposite reactions that include the reduction of methyl heteroaryl compounds, we herein report the suc-
2-nitrophenol to the corresponding 2-aminophenol and cessful redox-neutral and high atom-economic transfor-
the oxidation of toluene to the corresponding aldehyde, mation of 2-nitrophenols 1 and 2,6-disubstituted p-cresols
respectively (Scheme 2). An effective direct hydrogen 2 to afford 2-arylbenzoxazoles 3, promoted by a catalyst
transfer from toluene to 2-nitrophenol would be highly de- based on iron and elemental sulfur.
sirable, and greatly improve the atom economy of the
overall process. Ideally, the three reactions involved in the
overall process (oxidation, reduction, and condensation)
could be carried out in a single step.
Initial experiments were conducted using 2-nitrophenol
(1a) with 2.0 equivalents of o-cresol or p-cresol as starting
materials in the presence of 10 mol% of iron and 10 mol%
of elemental sulfur at 180 °C for 24 hours in o-dichloro-
Recently, synthetic methodologies that employ this hy- benzene (ODCB) under an atmosphere of argon. Trace
drogen-transfer type reaction have been extensively in- amounts of the corresponding 2-arylbenzoxazoles were
vestigated because they do not require additional reagents detected by GC–MS analysis.
to promote oxidation or reduction.5 For example, the prep-
aration of 2-arylbenzoxazoles from 2-nitrophenols and
benzyl alcohols, and the formation of 2,3-diarylquinazoli-
nones from 2-nitrobenzamides and benzyl alcohols using
Inspired by these promising results, the reaction between
2-nitrophenol (1a) and 2,6-di-tert-butyl-4-methylphenol
(2a, BHT), which has low redox potential, was chosen as
a model to screen and optimize the redox–condensation
conditions (Table 1). In the absence of a catalyst, the reac-
tion proceeded sluggishly, affording a low yield of 2-(3,5-
di-tert-butyl-4-hydroxyphenyl)benzoxazole (3aa) with
large amount of unreacted raw material (1a, Table 1, entry
1,1′-bis(diphenylphosphino)ferrocene (dppf) as a catalyst
have been reported.6 However, there are some disadvan-
tages associated with these syntheses. For example, it re-
quires the use of an excess amount of the benzyl alcohols
theoretically and the loading of large amount of the ex-
1).
pensive dppf catalyst; the former leads to the formation of
The addition of elemental sulfur somewhat improved the
unwanted byproducts. Another hydrogen-transfer type re-
yields of 3aa (Table 1, entries 2 and 3) and iron was also
action for the synthesis of 2-heteroaryl benzimidazoles
effective (Table 1, entry 4), while a mixture of both iron
and benzoxazoles employs 2-amino-/hydroxynitroben-
and elemental sulfur dramatically accelerated the redox–
zenes and methyl heteroaryl compounds as starting mate-
condensation reaction.
rials.7,8 This redox–condensation reaction theoretically
proceeds by using the same amount of 2-amino-/hy-
droxynitrobenzenes and methyl heteroaryl compounds
(redox neutral) in the presence of an iron sulfide catalyst.
Despite these advances, redox–condensation reactions of
methyl aromatics such as xylenes and mesitylene remain
an outstanding challenge to date.
Using 10 mol% of iron and 10 mol% of elemental sulfur
gave 3aa in 52% yield (Table 1, entry 5). The best result
(76% yield) was obtained in the presence of 10 mol% of
iron and 100 mol% of elemental sulfur (Table 1, entry 6).9
Using one equivalent of 2a, 3aa was obtained in good
yield (59%). These results suggested that iron with ele-
mental sulfur effectively promotes the reaction. However,
NO2
OH
NO
OH
NHOH
OH
NH2
OH
+ 2e–
+ 2e–
+ 2e–
reduction
reduction
reduction
H
N
condensation
– H2O
O
H
– 2e–
– 2e–
oxidation
CH2OH
CHO
– 2e–
Me
oxidation
oxidation
N
O
Scheme 2 Redox-neutral reaction
Synlett 2014, 25, 1565–1570
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Arylbenzoxazoles
1567
commercially available iron sulfide did not show any cat- functionalities (methyl and methoxy) afforded consider-
alytic activity (Table 1, entry 7). Additionally, the use of ably good yields of the corresponding 2-arylbenzoxazoles
various iron salts [FeCl3, dppf, Fe(acac)3, and FeSO4] and (3ba–ea, Table 2, entries 2–5), while the presence of an
iron salts with elemental sulfur afforded 3aa in low yields electron-withdrawing functionality (trifluoromethyl) low-
(Table 1, entries 8–15). Interestingly, although, commer- ered the yield (Table 2, entry 6). Surprisingly, the reaction
cially available iron sulfide was not effective in promoting of 2-nitroaniline (1g) with 2a afforded the corresponding
this reaction, the iron sulfide formed in situ from FeSO4 product 3ga in poor yield (Table 2, entry 7) although the
and Na2S exhibited high catalytic activity (Table 1, entry reaction of 1g with methyl heteroaryl compounds gave the
16). The use of a polar solvent such as NMP and aerobic corresponding 2-heteroarylbenzimidazoles in better
reaction conditions lowered the resulting yields of 3aa yields.7
(Table 1, entries 17 and 18).
Replacing the tert-butyl groups with methoxy groups at
With optimized conditions in hand, the scope and limita- the 2,6-positions resulted in a decrease in the yield (Table
tions of the reaction were investigated; first, the effects of 2, entry 8), like in the case of cresols with vacant para or
employing substituted 2-nitrophenols were investigated ortho positions (2c and 2d, Table 2, entries 9 and 10). In
(Table 2). The reaction of 1a with 2a provided 3aa in a the latter examples, small amounts of sulfides (4a and 4b,
good isolated yield (Table 2, entry 1). Electron-donating respectively) could be isolated and identified as the prima-
Table 1 Optimization of Reaction Conditionsa
t-Bu
OH
t-Bu
t-Bu
OH
t-Bu
2a (2 equiv)
N
O
NO2
OH
catalyst
Me
+
3aa
1a
Entry
Catalyst (mol%)
Yield (%)b
1
2
–
16
S (10)
23
3
S (100)
32
4
Fe (10)
35
5
Fe (10), S (10)
Fe (10), S (100)
FeS (10)
52
6
76 (59)c
13
7
8
FeCl3 (10)
FeCl3 (10), S (10)
dppf (10)
51
9
48
10
11
12
13
14
15
16
17
18
39
dppf (10), S (10)
40
Fe(acac)3 (10), S (10)
FeSO4 (10)
24
26
FeSO4 (10), S (10)
FeSO4 (10), S (100)
FeSO4 (10), Na2S (10)
Fe (10), S (10)
32
61
60
24d
15e
Fe (10), S (10)
a Reaction conditions: 1a (3.0 mol), 2a (6.0 mmol), ODCB (8.0 mL), 180 °C, 24 h, Ar.
b LC yields.
c An equivalent of 2a was used.
d NMP was used as a solvent.
e Under oxygen atmosphere.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1565–1570

1568
M. Saibara et al.
LETTER
ry byproducts (Figure 1). This is perhaps reasonable, as a Encouraged by these results, we applied a newly devel-
patent reported the generation of sulfides by the reaction oped methodology to the synthesis of bifunctional 2-aryl-
of elemental sulfur and substituted cresols.10 These results benzoxazoles (Scheme 3). Bifunctional 2-arylbenz-
suggest that to obtain the resulting products in good yields oxazoles can be used as building blocks for conjugated
it is necessary to employ ortho- and para-substituted cre- polymers and oligomers, which have applications in thin-
sols.
film transistors (TFT), organic light-emitting diodes
(OLED), and photovoltaic cells (PVC).11 This synthetic
methodology was successfully applied, and 3ha was pre-
pared in 50% yield after 48 hours.
OH
OH
t-Bu
HO
t-Bu
OH
t-Bu
S
t-Bu
S
Finally, a series of experiments were performed to gain
mechanistic insight. Firstly, in order to probe the possibil-
ity of a radical-based mechanism, 4.0 equivalents of
TEMPO were added to the reaction of 1a and 2a under
similar conditions that were employed in Table 1, entry 6,
with 3aa obtained in 11% yield (compared to 76% under
the original conditions). This experiment clearly implied
the participation of a radical species in the mechanism.
Me
Me
Me
Me
4a
4b
Figure 1 Sulfides as byproducts (4a and 4b)
Table 2 Synthesis of Various 2-Arylbenzoxazoles 3a
R1
R1
R8
R7
R8
R7
R2
R3
R2
R3
NO2
R4H
N
catalyst
R6
Me
R6
+
R4
R5
R5
1a–g
2a–d
3
Entry
R1
R2
R3
R4
R5
R6
R7
R8
Yield (%)b
1
2
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
1a
1b
1c
1d
1e
1f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
MeO
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
MeO
t-Bu
t-Bu
H
H
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3aa
3ba
3ca
3da
3ea
3fa
58 (76)c
84
H
3
Me
H
H
72
4
Me
H
H
62
5
MeO
CF3
H
H
76
6
H
H
43
7
H
NH
O
1g
1a
1a
1a
H
3ga
3ab
3ac
3ad
5
8
H
H
H
21
9
H
H
O
H
5d
10
H
H
O
H
OH
tracee,f
a Reaction conditions: 1 (3.0 mmol), 2 (6.0 mmol), Fe (0.30 mmol), S (3.0 mmol), ODCB (8.0 mL), 180 °C, 24 h, Ar.
b Isolated yields.
c LC yield.
d Compound 4a was formed as a byproduct.
e Identified by GC–MS analysis.
f Compound 4b was obtained as a byproduct.
t-Bu
OH
t-Bu
t-Bu
HO
t-Bu
t-Bu
OH
HO
OH
O
N
O
Me
+
O2N
NO2
N
t-Bu
50%
1h
2a (4 equiv)
3ha
Scheme 3 Synthesis of bifunctional product 3ha
Synlett 2014, 25, 1565–1570
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Arylbenzoxazoles
1569
OH
OH
Me
t-Bu
t-Bu
t-Bu
t-Bu
H
O
HSx
[O]
•Sx
Fe
2a
5a
NO2
NH2
OH
OH
1a
– H2O
– H2O
[O]
t-Bu
OH
t-Bu
t-Bu
OH
t-Bu
t-Bu
OH
t-Bu
H
N
N
N
O
O
OH
H
H
3aa
5b
5b'
Scheme 4 A possible reaction path
We next attempted to detect any intermediate compound
formed in the reaction of 1a with 2a. Careful monitoring
of this reaction led to the detection of small amounts of 5a
and 5b (or 5b′), thus showing the formation of the corre-
sponding aldehyde 5a obtained from 2a, and 2-aminophe-
nol from 1a in the reaction pathway.12 Based on these
observations, we have proposed a reaction mechanism
(Scheme 4). At the initiation stage, 2a is oxidized to alde-
hyde 5a via a radical species, while 1a is reduced to 2-
aminophenol by hydrogen transfer from 2a in the pres-
ence of an iron and elemental sulfur catalyst. The conden-
sation of 5a with 2-aminophenol affords 5b (or 5b′),
which forms 3aa upon additional oxidation. The similar-
type cyclization is promoted by only elemental sulfur.8 It
is suggested that oxidation and condensation are mainly
promoted by sulfur, and reduction of nitro group is pro-
moted by iron.
References and Notes
(1) (a) Mizuno, T.; Nakai, T.; Mihara, M.; Ito, T. Heteroat.
Chem. 2012, 23, 111. (b) Mizuno, T.; Takahashi, J.; Ogawa,
A. Tetrahedron 2002, 58, 7805. (c) Mizuno, T.; Toba, H.;
Miyata, T.; Nishiguchi, I. Heteroat. Chem. 1994, 5, 437.
(2) (a) Kambe, T.; Maruyama, T.; Nakai, Y.; Oida, H.;
Maruyama, T.; Abe, N.; Nishiura, A.; Nakai, H.; Toda, M.
Bioorg. Med. Chem. 2012, 20, 3502. (b) Xu, Q.; Li, Z.;
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Chawla, V.; Chawla, P.; Saraf, S. K. Pharma Chem. 2010, 2,
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J. Org. Chem. 2009, 74, 3286. (e) Büttner, A.; Seifert, K.;
Cottin, T.; Sarli, V.; Tzagkaroulaki, L.; Scholz, S.; Giannis,
A. Bioorg. Med. Chem. 2009, 17, 4943. (f) Kumar, D.;
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881. (g) Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W.
Tetrahedron Lett. 2006, 47, 4823.
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Pharma Chem. 2012, 4, 761. (b) Bachhav, H. M.; Bhagat, S.
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Y.; Thomé, I.; Kim, S. H.; Chen, D.; Beyer, A.; Bonnamour,
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2006, 71, 1802. (d) Altenhoff, G.; Glorius, F. Adv. Synth.
Catal. 2004, 346, 1661.
In summary, the high atom-economic catalytic synthesis
of 2-arylbenzoxazoles 3 from 2-nitrophenols 1 and 2,6-di-
substituted p-cresols 2 has been achieved by using iron
and elemental sulfur catalysts. The reaction is an overall
redox-neutral process involving hydrogen transfer from 2
to 1. This cascade reaction will provide an environmental
friendly method for the formation of 2-arylbenzoxazoles
3.
(5) (a) Chen, W.; Wilde, R. G.; Seidel, D. Org. Lett. 2014, 16,
730. (b) Li, G.; Wang, J.; Yuan, B.; Zhang, D.; Lin, Z.; Li,
P.; Huang, H. Tetrahedron Lett. 2013, 54, 6934. (c) Nguyen,
T. B.; Bescont, J. L.; Ermolenko, L.; Al-Mourabit, A. Org.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1565–1570

1570
M. Saibara et al.
LETTER
(6) (a) Wang, H.; Cao, X.; Xiao, F.; Liu, S.; Deng, G.-J. Org.
Lett. 2013, 15, 4900. (b) Wu, M.; Hu, X.; Liu, J.; Liao, Y.;
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Chem. Soc. 2013, 135, 118.
1 H), 7.33–7.29 (m, 2 H), 5.64 (s, 1 H), 1.53 (s, 18 H). 13
NMR (75 MHz, CDCl3): δ = 164.1, 157.1, 150.7, 142.4,
136.6, 125.0, 124.3, 124.2, 119.5, 118.4, 110.3, 34.5, 30.2.
MS (EI): m/z = 324 [M + H]+. IR (KBr): ν = 3625 cm–1.
(10) Satomi, K.; Ekawa, K. Jpn. Kokai Tokkyo Koho, 2005343863,
15 Dec 2005.
(11) (a) Tlach, B. C.; Tomlinson, A. L.; Ryno, A. G.; Knoble, D.
D.; Drochner, D. L.; Krager, K. J.; Jeffries-EL, M. J. Org.
Chem. 2013, 78, 6570. (b) Tlach, B. C.; Tomlinson, A. L.;
Bhuwalka, A.; Jeffries-EL, M. J. Org. Chem. 2011, 76,
8670. (c) Mike, J. F.; Makowski, A. J.; Jeffries-EL, M. Org.
Lett. 2008, 10, 4915.
(12) For the mechanism of iron sulfide catalyst, the reaction on
the surface of the iron sulfide cluster was proposed.7
However, in this reaction the formation of aldehyde 5a was
observed. This reaction may proceed in a different pathway.
(13) (a) Hisano, T.; Ichikawa, M.; Tsumoto, K.; Tasaki, M.
Chem. Pharm. Bull. 1982, 30, 2996. (b) Hisano, T.; Koga, H.
Yakugaku Zasshi 1971, 91, 180.
C
(8) The syntheses of benzoxazoles, benzothiazoles, and
benzimidazoles from 2-aminophenol, 2-mercaptoaniline,
and 1,2-diaminobenzene with methyl heteroaryl compounds
in the presence of elemental sulfur were reported.13
(9) 2-Nitrophenol (1a, 417 mg, 3.0 mmol), 2,6-di-tert-butyl-4-
methylphenol (2a, 1.322 g, 6.0 mmol), iron (16.8 mg, 0.3
mmol), sulfur (96.2 mg, 3.0 mmol), and o-dichlorobenzene
(8.0 mL) were placed in a test tube charged with a magnetic
stirring bar and under an atmosphere of argon. The reaction
mixture was heated to 180 °C and vigorously stirred for 24
h. The solution was cooled down to r.t., and the solvent was
removed under vacuum. The resulting crude reaction
mixture was purified by short-column chromatography to
give the corresponding 3aa (559.5 mg, 58%).
2-(3,5-Di-tert-butyl-4-hydroxyphenyl)benzoxazole (3aa)
Mp 169–170 °C (169–170 °C).14 1H NMR (300 MHz,
CDCl3): δ = 8.09 (s, 2 H), 7.75–7.72 (m, 1 H), 7.57–7.54 (m,
(14) Isomura, Y.; Ito, N.; Homma, H.; Abe, T.; Kubo, K. Chem.
Pharm. Bull. 1983, 31, 3168.
Synlett 2014, 25, 1565–1570
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