Sulfur-Promoted Synthesis of Benzoxazoles from 2-Aminophenols and Aldehydes

Article abstract of DOI:10.1002/ejoc.202000523

Elemental sulfur (S₈) was found to be an excellent stoichiometric oxidant to promote oxidative condensation of 2-aminophenols with a wide range of aldehydes, including aliphatic aldehyde such as cyclohexanecarboxaldehyde. The reactions were catalyzed by sodium sulfide in the presence of DMSO as an additive. The benzoxazole products were obtained in satisfactory yields. The reaction conditions could be applied to larger syntheses (10–50 mmol).

Full text of DOI:10.1002/ejoc.202000523

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Sulfur-promoted Synthesis of Benzoxazoles from 2-
Aminophenols and Aldehydes
Authors: Le Anh Nguyen, Thai Duy Dang, Quoc Anh Ngo, and Thanh
Binh Nguyen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000523
Link to VoR: https://doi.org/10.1002/ejoc.202000523
01/2020

10.1002/ejoc.202000523
European Journal of Organic Chemistry
COMMUNICATION
Sulfur-promoted Synthesis of Benzoxazoles from 2-
Aminophenols and Aldehydes
Le Anh Nguyen,[b],[c] Thai Duy Dang,[b] Quoc Anh Ngo,*[b],[c] and Thanh Binh Nguyen*[a]
[a]
Dr. T. B. Nguyen
Institut de Chimie des Substances Naturelles, CNRS UPR 2301
Université Paris-Sud, Université Paris-Saclay
1, avenue de la Terrasse, Gif-sur-Yvette, 91198, France.
E-mail: thanh-binh.nguyen@cnrs.fr
https://icsn.cnrs.fr/en/cv/nguyen
[b]
[c]
Mr. L. A. Nguyen, Mr T. D. Dang, Pr. Q. A. Ngo
Institute of Chemistry
Vietnam Academy of Science and Technology
18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
Graduate University of Science and Technology
Vietnam Academy of Science and Technology
18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
Supporting information for this article is given via a link at the end of the document.
Abstract: Elemental sulfur (S8) was found to be an excellent
stoichiometric oxidant to promote oxidative condensation of 2-
aminophenols with a wide range of aldehydes, including aliphatic
aldehyde such as cyclohexanecarboxaldehyde. The reactions were
catalyzed by sodium sulfide in the presence of DMSO as additive. The
benzoxazole products were obtained in satisfactory yields. The
In this context, using other alternative oxidants that could avoid
the above-mentioned drawbacks of oxygen to perform selectively
and cleanly the oxidation transformation would be highly desirable,
especially for large-scale productions.
Recently, our laboratories are interested in using elemental sulfur
as a versatile tool in organic synthesis of a wide range of
reaction conditions could be applied to larger syntheses (10-50 mmol). molecules of interest. [22]-[27] As a waste of oil and gas industry with
annual global production around 70 million metric tons, sulfur is
an inexpensive and user-friendly starting material due to its
Benzoxazole derivatives have attracted considerable attention
physical properties as well as its low reactivity under ambient
due to the presence of this heterocyclic motif in a variety of natural
conditions. Interestingly, under suitable thermal or catalytic
activation, sulfur displays a wide range of reactivities that can be
products and bioactive molecules (Figure 1).[1],[2]
The most commonly used synthetic approach to such molecules
useful in the development of new redox transformation.
involve condensation of 2-aminophenols with carboxylic acids[3],[4]
or derivatives[5],[6] under non oxidant conditions or with
alcohols,[7],[8]
amines,[9],[10]
ketones,[11]
aldehydes,[12]-[15]
O
NH2
HO
methylarenes[16] or related compounds[17] in the presence of an
oxidant or at high temperatures with concomitant
dehydrogenation.[18]-[19] However, most of the traditional synthetic
methods required strongly acidic conditions[6], prolonged heating
at high temperatures and significant amounts of catalysts[14]
H
N
NH
Me
O
HO
N
N
Me
OH
O
O
O
Me
MeHN
O
N
OH
Me
O
Me
Calcimycin, an antibiotic and
divalent cation ionophore
Boxazomycins A, an antibiotic from
Actinomycetes strains No. G495-11
[5],[7],[13],[15]-
(including expensive/toxic transition metal catalysts)
[16],[18]-[21]
as well as toxic/harmful reagents and solvents.
Me
[3],[4],[8],[12],[16]
F
O
O
Although the aerobic oxidation[12],[15],[20]-[21] is in general very green
because of its high atom economy with water as the only
stoichiometric byproduct in most cases, a major drawback of
using oxygen as an oxidant is the risk of explosion of flammable
organic substrates, especially in large-scale syntheses at reaction
temperatures above the flashpoint of the reaction components.
Moreover, due to its gaseous state, exact stoichiometric control of
oxygen amounts used in the reaction is not readily possible. The
reaction requires high volume of gas if performed at 1 atm without
bubbling the gas through the reaction mixture. As a matter of fact,
11.2 L of oxygen under standard conditions for temperature and
pressure has the same the same equivalent as 32 g or 16 mL of
solid S8. Consequently, over oxidation as well as oxidation
reactions of other functional groups present in the molecules are
among the most encountered side reaction of aerobic oxidation,
especially for high-pressure reactions at high temperature.
N
O
O
S
N
O
H
H
OH
HO
N
N
O
N
H
N
O
O
O
H2N
HN
O
PTP1B inhibitor
HO
O
CAP1/PRSS8 inhibitor
Me
N
Me
O
O
N
O
N
N
F
F
N
O
N
S
Anti-TB agent
HIV inhibitor
Figure 1. Natural products and bioactive molecules containing benzoxazole
core
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.

10.1002/ejoc.202000523
European Journal of Organic Chemistry
COMMUNICATION
In continuation of our interest in the exploration of new and useful
chemical behavior of elemental sulfur, we report herein the use of
this element as a stoichiometric oxidant to promote oxidative
coupling of 2-aminophenols with aldehydes to provide 2-
substituted benzoxazoles.
Initially, the reaction between equimolar amount of benzaldehyde
1a, 2-aminophenol 2a and elemental sulfur was selected as a
model reaction for optimization as summarized in Table 1.
Inexpensive hydrated sodium sulfide Na2S•5H2O was chosen as
a catalyst to activate elemental sulfur.[28]
both starting materials. 2-Aminophenols bearing alkyl, chloro as
well as methylsulfone groups are competent substrates to provide
benzoxazole 3ab-3af. In a similar manner, methyl, halogen and
methoxy groups as well as hydroxy, cyano or nitro groups in
benzaldehyde substrates were found to be compatible with the
present reaction conditions.
More importantly, the reaction conditions could also be applied to
an aliphatic aldehyde such as cyclohexanecarboxaldehyde to
afford a 70% yield of benzoxazole 3pa.
Na2S•5H2O
(10 mol %)
HO
O
+
+
CHO
S
R'
R'
R
R
70 ºC, 16 h
DMSO (0.1 mL)
N
H2N
Table 1. Screening of the reaction conditions
3
1a-1n
(1 mmol)
2a-2f
(1 mmol)
(1 mmol)
Na2S•5H2O
HO
O
(x mol %)
+
+
CHO
S
T ºC, 16 h
additive
N
Me
N
O
N
O
H2N
N
O
3aa
1a
(1 mmol)
2a
(1 mmol)
Me
Cl
(1 mmol)
3ab (73%)
3ac (90%)
3ad (72%)
Entry[a]
Additive
-
x (mol %)
T (°C)
Yield (%)
1
10
10
10
10
10
0
80
80
70
90
60
70
70
70
70
70
70
ND[b]
69
72
67
ND[b]
62
65
0
Cl
SO2Me
N
O
N
N
O
Me
Br
O
2
DMSO (0.1 mL)
DMSO (0.1 mL)
DMSO (0.1 mL)
DMSO (0.1 mL)
DMSO (0.2 mL)
DMSO (0.05 mL)
DMF (0.1 mL)
3ae (77%)
3af (80%)
3ba (70%)
3
N
O
N
O
N
O
4
F
Cl
5
3ca (75%)
3da (72%)
3ea (78%)
6
MeO
MeO
MeO
N
O
N
N
O
7
0
MeO
O
MeO
8
10
10
10
10
3fa (75%)
3ga (70%)
3ha (70%)
9
DMAc (0.1 mL)
DMSO (0.1 mL)
DMSO (0.1 mL)
0
N
10[c]
11[d]
0
N
O
N
O
HO
NC
O
OH
71
3ia (68%)
3ja (60%)
3ka (67%)
[a]
[b]
[c]
Reaction performed under an argon atmosphere.
Not determined.
N
O
Reaction without elemental sulfur. [d] Reaction performed under air (1 atm).
N
O
N
O
The model experiment conducted at 80 °C in the absence of any
additive did not lead to the expected product 3aa (entry 1).
Gratifyingly, in the presence of DMSO (0.1 mL, 1.5 equiv), the
starting materials were completely consumed, the desired product
3aa was isolated in 69% (entry 2). Further screening of other
temperatures (entries 3-4) revealed that the reaction was best
performed at 70 °C (entry 3). While variation of DMSO quantities
did not lead to any improvement (entries 6-7), the important role
of DMSO was clearly demonstrated as other aprotic additives
such as DMF or N,N-dimethylacetamide (DMAc) (entries 8-9)
failed to promote the oxidative coupling. The role of sulfur as
oxidant was confirmed as its absence in the reaction mixture did
not lead to the benzothiazole product (entry 10).
O2N
OMe
3la (65%)
3ma (70%)
3na (40%)
CH3
N
O
N
N
O
Cl
O
F
3pa (70%)
3oa (55%)
3db (78%)
Scheme 1. Scope of 2-aminophenols 1 and aldehydes 2
Finally, the synthesis of 2-phenylbenzoxazole 3aa from 2-
aminophenol and benzaldehyde was performed in larger scales
(10 mmol and 50 mmol). In both case, the expected 2-
Finally, in view of the high yield, the best reaction conditions were
selected as indicated in entry 3. For comparison purpose, the
optimal reaction repeated under air atmosphere led to similar yield. phenylbenzoxazole product was obtained in comparable yields
With the optimized conditions in hand, we evaluated the synthetic
potential of this reaction with various 2-aminophenols and a range
of aromatic aldehydes (Scheme 1). In general, most of reactions
proceeded smoothly to give the expected 2-substituted
benzoxazoles in good to excellent yields regardless of the
electronic character of substituents on the aromatic moieties of
(70 and 68%, respectively) after a simple aqueous workup,
extraction with dichloromethane and filtration through a short pad
of silica gel.
On the basis of these results and our previous works, a
reasonable mechanism is proposed as depicted in Scheme 2.
With the assistance of sulfide anion from sodium sulfide as a
.
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10.1002/ejoc.202000523
European Journal of Organic Chemistry
COMMUNICATION
[3]
[4]
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6499.
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nucleophilic polysulfide anions A were formed and engage in the
addition to imine B generated from condensation of aldehyde 1
with 2-aminophenol 2a. The resulting polysulfide-amide C could
undergo a proton shift to provide phenolate D, which could cyclize
to benzoxazoline E. The aromatization E to the final product 3
serves as a driving force to trigger the elimination of a hydrogen
sulfide assisted by the resultant polysulfide A’. It is possible the
role of DMSO is to stabilize key anionic intermediates B-C.
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2a
+
RCH=O
-H2O
HO
N
1
S
S
S
S
S
S
S
S
[9]
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H
R
HO
R
H
-S
S-
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B
S2-
Sn
S
N
A
Sn
-S
C
S-
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Sn
R
O
O
-HS-
O
N
HS
R
S
H
R
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Sn-1
HN
-S
N
H
A'
3
E
D
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Scheme 2. Proposed reaction mechanism
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reaction, this toxic gas is trapped in the reaction medium. Indeed,
we did not observe any overpressure throughout the reaction.
While the exact mechanism of this process is not fully understood,
we suggest that H2S reacts with DMSO to regenerate sulfur and
release dimethyl sulfide.[29] This volatile liquid (bp 37.3 °C) is in
turn kept in the reaction medium by complexing with DMSO. In
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In conclusion, we have developed an efficient method for the
synthesis of 2-substituted benzoxazoles from 2-aminophenols
and aldehydes by using in expensive elemental sulfur in
stoichiometric amount as an oxidant and Na2S•5H2O as sulfur
activating catalyst in minimum amount of DMSO. Compared to
similar reactions using oxygen as oxidant, our method is
characterized by its simplicity with low reaction volume while
avoiding high pressure apparatus even for larger scales (10-50
mmol).
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Acknowledgements
We thank Vietnam Academy of Science and Technology for
valuable financial support (KHCBHH.01/18-20).
Keywords: elemental sulfur • oxidative coupling • aldehyde • 2-
aminophenol • benzoxazole
[1]
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2019, 149-478.
.
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10.1002/ejoc.202000523
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here. ((Please ensure your graphic is in one of following formats))
Na2S•5H2O
HO
O
N
(10 mol %)
+
CHO
S
R'
R'
R
R
+
70 ºC, 16 h
DMSO (0.1 mL)
H2N
22 examples
1 equiv
Oxidation with sulfur: Elemental sulfur (S8) was found to be an excellent stoichiometric oxidant to promote oxidative condensation of
2-aminophenols with a wide range of aldehydes to provide benzoxazoles.
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