Break-and-Build Strategy for the Synthesis of 2-Benzoylbenzoxazoles from o-Aminophenols and Acetophenones

Article abstract of DOI:10.1002/adsc.202100150

Although compounds with a 2-benzoylbenzoxazole motif are biologically relevant, there are only a few methods for synthesizing them, most of which relied on multistep process or required substrates bearing activating groups. Herein, we report an efficient method for the synthesis of such compounds by direct reactions of o-aminophenols with acetophenones promoted by sulfur in DMSO. The reaction was found to proceed via a Willgerodt rearrangement-type benzoxazolation of acetophenones followed by a benzylic oxidation to reinstall the carbonyl function. This method has a broad substrate scope and good tolerance for sensitive functional groups. (Figure presented.).

Full text of DOI:10.1002/adsc.202100150

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DOI: 10.1002/adsc.202100150
Break-and-Build Strategy for the Synthesis of
2-Benzoylbenzoxazoles from o-Aminophenols and Acetophenones
Le Anh Nguyen,b, c Quoc Anh Ngo,b, c,* Pascal Retailleau,a and
Thanh Binh Nguyena,*
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 avenue de la
Terrasse, 91198 Gif-sur-Yvette, France
E-mail: thanh-binh.nguyen@cnrs.fr
Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
b
E-mail: ngoqanh@ich.vast.vn
c
Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay,
Hanoi, Vietnam
Manuscript received: February 1, 2021; Revised manuscript received: March 1, 2021;
Version of record online: March 4, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100150
The intuitive approach based on the construction of
the benzoxazole ring by condensation of o-amino-
Abstract: Although compounds with a 2-benzoyl-
benzoxazole motif are biologically relevant, there
are only a few methods for synthesizing them, most
of which relied on multistep process or required
substrates bearing activating groups. Herein, we
report an efficient method for the synthesis of such
compounds by direct reactions of o-aminophenols
with acetophenones promoted by sulfur in DMSO.
The reaction was found to proceed via a Willgerodt
rearrangement-type benzoxazolation of acetophe-
nones followed by a benzylic oxidation to reinstall
the carbonyl function. This method has a broad
phenols 1 were described with phenylglyoxalic deriva-
tives such as dithioester III[7] or imidoyl cyanide IV[8]
via non redox condensation. Alternatively, when
oxidation conditions were applied, condensation of 1
with derivatives of lower oxidation states such as α,α-
dihaloacetophenones V[9] or 2-bromophenylacetylenes
VI[10] were known. In this context, a direct use of
acetophenones 2, which are inexpensive and readily
available in a wide range of structure, in a selective
oxidative condensation with o-aminophenols 1 would
provide a convenient and cost-effective approach to a
substrate scope and good tolerance for sensitive
library of 2-benzoylbenzoxazoles for drug discovery
functional groups.
study.
We have recently reported a Willgerodt rearrange-
ment-type benzoazolation of acetophenones 2 with o-
Keywords: sulfur; 2-benzoylbenzoxazole; DMSO
aminophenols 1 promoted by sulfur[11] and N-meth-
ylpiperidine (Scheme 2).[12] In this reaction leading to
4aa, while the methyl group of acetophenone 2a was
Benzoxazole derivatives are prevalent in biologically oxidized and benzoxazolized with 2-aminophenol 1a,
and pharmacologically important molecules as well as the carbonyl group was reduced to a methylene group.
in functional materials.[1] A subgroup of this family is Since this methylene group is surrounded by the
2-benzoylbenzoxazoles, which are well-known for phenyl group and the newly installed benzoxazole
their significant biological activities such as antiproli- moiety, this new situation could open up opportunities
ferative activity (compound I),[2] inhibition of fatty for oxidation of 4aa into a carbonyl in 3aa. Such
acid amide hydrolase FAAH[3] (compound II) operation was previously performed on separated 2-
(Scheme 1). Consequently, several methods have been benzylbenzoxazole derivatives using relatively com-
developed
for
the
synthesis
of
2- plex reaction conditions involving strong oxidizing
benzoylbenzoxazoles,[4] most of them were based on agents in the presence of transition metal catalysts.[5m]
functionalization of simpler benzoxazole cores IX[5] or We reason that a direct transformation from 1a and 2a
using complex starting materials which required multi- to 3a could be performed in one-pot in the presence of
step syntheses.[6]
a suitable oxidant in the reaction medium. As DMSO
is well known as an excellent solvent and a mild and
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Table 1. Screening of the Reaction Conditions.
Entry[a]
x
additive
y
yield (%)[b]
1[c]
2
3
4
5
6
7
8
9
10
11
12
13e
14f
3
3
1
1
0.5
1
1
1
1
1
1
0
1
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
pyridine
N-methylmorpholine
DIPEA
tri-n-propylamine
DABCO
1
1
1
30
65
68
72
54
70
77
71
70
73
52
0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0
–
N-methylmorpholine
N-methylmorpholine
N-methylmorpholine
0.5
0.5
0.5
36
1
0[d]
[a] Reaction conditions: o-aminophenol 1a (1 mmol), acetophe-
none 2a, sulfur (x mmol, 32 mg.mmolÀ 1), additive (y mmol),
Scheme 1. 2-Benzoylbenzoxazoles: Bioactivity and Syntheses.
°
DMSO (0.5 mL), 110 C, 16 h unless otherwise noted.
[b] isolated yield unless otherwise noted.
[c]
°
Reaction temperature 80 C.
[d] Determined by H NMR of the crude mixture.
1
[e] DMSO (0.3 mL) was used.
[f] DMF (0.5 mL) was used in place of DMSO.
Moreover, we noticed that the amount of NMP,
which acted as a basic sulfur activator, could be further
reduced to 0.5 equiv. without lowering the reactivity
(entries 4–5). Interestingly, other nitrogen bases such
as pyridine, N-methylmorpholine (NMM), diisopropy-
lethylamine (DIPEA), tri-n-propylamine or 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) (entries 6–10) could be
Scheme 2. Break-and Build Strategy for the Synthesis of 3.
selective oxidizing agent, especially in the presence of used in place of NMP. It is noteworthy that the
sulfur,[13] we focused our attention to develop this expected product 3aa could be formed even in the
strategy.
absence of a base, despite in lower yield (entry 11).
For this purpose, we first performed the benzox- The reaction in the absence of sulfur resulted in
azolation of acetophenone 2a with 2-aminophenol 1a recovery of unchanged starting materials, which con-
°
under the standard conditions (80 C, 16 h) using sulfur firmed clearly the crucial role of this element in
(3 equiv.), N-methylpiperidine (NMP) (1 equiv.) in the promoting the cascade transformation (entry 12). Fi-
presence of DMSO (3 equiv.) (Table 1, entry 1).
nally, lowering the DMSO amount (entry 13) of
To our delight, this initial test resulted in a 80% replacing DMSO by another polar aprotic solvent such
conversion of 2-aminophenol 1a into a nearly 1:1 as DMF (entry 14) prevented partially or totally the
mixture of 4aa:3aa. Oxidation of the methylene formation of 3aa, which confirmed the importance of
moiety was significantly accelerated by heating at DMSO in this oxidative condensation.
°
higher temperature (110 C, entry 2). At this stage, we
With this set of optimized reaction conditions, we
realized that DMSO could act as oxidant to regenerate next studied the scope and limitations of our strategy.
sulfur from H2S byproduct of the first step of Will- In general, starting from 2-aminophenol 1a and
gerodt-type benzoxazolation, the amount of sulfur acetophenones 2 bearing a wide range of substituents
could be lowered to stoichiometric amount, i.e. of different electronic nature or positions, the reactions
1 equiv. (entry 3).
led to the expected 2-benzoylbenzoxazole products 3
in reasonable yields (Scheme 3). Acetophenones bear-
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unprotected hydroxy groups in good to excellent
yields. It should be noted that 3al could serve as a
direct precursor to provide a wide range of bioactive
derivative via acylation of its hydroxy group (com-
pound II in Scheme 1). Acetophenones bearing halo-
gen groups in different positions such as p-Cl, m-Cl, o-
F and m-Br (2m–2p) displayed good reactivities and
gave the products 3am–3ap in good yields. Gratify-
ingly, acetophenones substrates having an electron
withdrawing group such as CF3, CN, CO2Me or NO2,
showed also to be competent substrates. The structure
of nitro 3aw was unambiguously confirmed by X-ray
diffraction analysis.
Although CN and NO2 groups were known to react
with H2S,[14] which is a possible intermediate/by-
product of this transformation, via nucleophilic addi-
tion and reduction, respectively, the expected benzox-
azole products 3as, 3at, 3av and 3ax were obtained
in reasonable yields. In case of p-nitroacetophenone
2v, the superiority of NMM compared to other basic
additive such as NMP and pyridine or without base in
assisting the benzoxazolation process was clearly
demonstrated as NMM was the only base that could
afford the expected benzoxazole 3av, despite in low
yield.
2-Acetonapthone as well as heterocyclic substrates
derived from pyridine, thiophene and benzofuran gave
moderate to good yields of the corresponding benzox-
azole products 3ax–3aaa. The twofold reaction could
be performed when p-diacetylbenzene (0.6 equiv.) was
used.
The reaction conditions could also be applied
successfully
to
substituted
2-aminophenols
(Scheme 4). Benzoxazoles bearing a methyl group 3ba
Scheme 3. Scope of Methyl Aryl Ketones 2.
ing electron donating groups such as methyl, methoxy,
acetamido displayed good reactivity, provide the
expected benzoxazoles 3ab–3aj in moderate to good
yields. We emphasized that the product 3ai (compound
I in Scheme 1) was previous demonstrated to be
biologically active.[2] Interestingly, the reaction con-
ditions could be applied to acetophenones bearing
Scheme 4. Scope of o-Aminophenols 1.
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and 3ca were obtained in yields of 63% and 73%, prepared separately and allowed to react with DMSO
respectively. Chloro substituents were also compatible (0.5 equiv.) (Scheme 5, eq. 3). The product 3aa was
with the reaction conditions: the oxidative coupling formed in high yield under the standard conditions. On
products 3da and 3ea were formed in moderate yields the other hand, performing the similar reaction in the
(63% and 57%, respectively). The presence of an absence of sulfur resulted in recovery of 4aa. This
electron withdrawing groups such as sulfone, sulfona- confirmed unambiguously that the oxygen atom of 2-
mide or nitro on the phenyl ring of 2-aminophenol benzoylbenzoxazole 3aa product comes from DMSO.
could reduce the nucleophilicity of the hydroxy group,
Additionally, we found that diphenylmethane could
they had little effect on the yields. In the case of 4- not be oxidized into benzophenone and remained
nitro-2-aminophenol 1g, thanks to low solubility in unchanged under these oxidizing conditions (eq. 4).
methanol of product 3ga, it was easily isolated from These results suggested the important role of both aryl
the reaction mixture by a simple trituration/filtration and 2-benzoxazolyl substituents as well as the partic-
operation with methanol. The structure of sulfone 3fa ipation of sulfur to the oxidation of methylene moiety.
obtained in 61% yield was confirmed by X-ray
On the basis of these results and our previous
diffraction analysis. o-Aminophenol substrate bearing works,[13] a plausible mechanism is proposed in
an electron donating group MeO 1g showed also good Scheme 6. The reaction commenced with a Willgerodt-
reactivity under our conditions, leading to benzoxazole type reaction as described previously to provide
3ga in good yield.
benzoxazole 4aa.
An easily tautomerization 4aa 4aa’ facilitated by
*
)
Our reaction conditions were however not applica-
ble to aliphatic methyl ketones such as pinacolone, 3- the presence of both benzoxazole and phenyl moieties
methyl-2-butanone of 2-heptanone (Scheme 5, eq. 1). would favor the formation of polysulfide salt 5. Sulfur
In these cases, the reactions mixtures were found to be extrusion from 5 followed by a sulfur-promoted
complex, possibly because both step of benzoxazola- oxidation of thiol 6 to thione 8 would proceed via
tion of methyl ketones and methylene oxidation polysulfide 7 and its tautomer 7’. Hydrolysis of thione
occurred more difficultly in the absence of an aryl 8 would lead to 3aa.[15] Since the oxygen atom of a
group on the methyl ketone substrates. Indeed, the carbonyl function of a ketone was known to be
presence of the products issued from the first step exchanged rapidly with water, it is not conclusive to
could be detected in the crude mixtures, the subsequent use labelled water to confirm if the ketone oxygen
oxidation of their methylene moiety failed. The atom 3aa was issued from water or not via the
reaction conditions applied to homologous of aceto- hydrolysis step 8!3aa.[16] Water involving in this step
phenones such as propiophenone, butyrophenone or is generated from the recycling of sulfur by oxidation
valerophenone led to complex mixtures since the of hydrogen (poly)sulfide with DMSO.[17] At the
intermediates of Willgerodt rearrangement of the present stage, we cannot exclude the pathway involv-
longer chains underwent uncontrollable oxidation by ing direct functionalization of the methyl group of
DMSO (Scheme 5, eq. 2).
acetophenone 1a without the intermediacy of a Will-
In order to support the proposed reaction mecha- gerodt-type reaction.
nism, the primary Willgerodt-type product 4aa was
Scheme 5. Control Experiments.
Scheme 6. Proposed Reaction Mechanism.
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Kaesnaenen, M. J. Myllymaeki, A. Minkkilae, A. O.
In conclusion, we have reported an efficient method
for a direct access to 2-benzoylbenzoxazoles from 2-
aminophenols and acetophenones via a cascade of
sulfur-promoted Willgerodt type benzoxazolation and
methylene oxidation in DMSO. The reactions con-
ditions are compatible with many functional groups
and heterocycles. The method is highlighted by the
fact that both starting materials o-aminophenols and
acetophenones are inexpensive and readily available in
a wide range of structures. Moreover, since sulfur and
DMSO were used as oxidant in the presence of
substoichiometric amount of N-methylmorpholine as
an additive, our method is inarguably the cheapest and
most convenient method to provide a library of 2-
benzoylbenzoxazoles.
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Experimental Section
A
mixture of 2-aminophenol 1 (1 mmol), acetophenone
(1.2 mmol), elemental sulfur (32 mg, 1 mmol), N-meth-
ylmorpholine (56 mg, 0.5 mmol), and DMSO (0.5 mL) was
°
heated under an argon atmosphere in a 7-mL test tube at 110 C
for 16 h. The product was purified by column chromatography
on silica gel (heptane:EtOAc 1:0 to 5:1 or dichloromethane:
heptane 2:1 to 1:0). For experimental details, full character-
ization, and copies of NMR spectra of all compounds, see
Supporting Information.
CCDC 2045870 and 2042799 contain the supplementary
crystallographic data for 3aw and 3fa, respectively in this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Acknowledgements
[6] For an example of redox condensation between o-nitro-
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C. C. Malakar, J. Conrad, U. Beifuss, J. Org. Chem.
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densely functionalized N-substituted o-aminophenols,
see: b) S. S. K. Boominathan, W.-P. Hu, G. C. Senadi,
J. K. Vandavasi, J.-J. Wang, Chem. Commun. 2014, 50,
6726.
We thank Vietnam Academy of Science and Technology for
valuable financial support (KHCBHH.01/18-20). We thank Dr.
A. Baron, C. Moriou, S. Beaupierre and S. Thoret for their
valuable assistance.
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