Elemental Sulfur-Promoted Oxidative Rearranging Coupling between o-Aminophenols and Ketones: A Synthesis of 2-Alkyl benzoxazoles under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.7b01775

In the presence of N-methylpiperidine, elemental sulfur was found to act as excellent oxidant in promoting oxidative rearranging coupling between o-aminophenols and ketones. A wide range of 2-alkylbenzoxazoles was obtained under mild conditions.

Full text of DOI:10.1021/acs.orglett.7b01775

Letter
pubs.acs.org/OrgLett
Elemental Sulfur-Promoted Oxidative Rearranging Coupling
between o‑Aminophenols and Ketones: A Synthesis of 2‑Alkyl
benzoxazoles under Mild Conditions
Thanh Binh Nguyen* and Pascal Retailleau
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite
Terrasse, 91198 Gif-sur-Yvette, France
́ ́
Paris-Sud, Universite Paris-Saclay, 1, avenue de la
S
* Supporting Information
ABSTRACT: In the presence of N-methylpiperidine, elemental
sulfur was found to act as excellent oxidant in promoting
oxidative rearranging coupling between o-aminophenols and
ketones. A wide range of 2-alkylbenzoxazoles was obtained under
mild conditions.
with a solution of elemental sulfur in aqueous ammonium
sulfide (Scheme 1).
enzoxazoles represent an important class of aza-hetero-
Bcycles and have been widely used as synthetic building
blocks, bioactive molecules, pharmaceuticals,1 and functional
materials.2 There are many methods available for the synthesis
of 2-substituted benzoxazoles. Traditional methods such as
condensation of carboxylic acids or derivatives with o-
aminophenols require high reaction temperatures in the
presence of strong acids.3 This approach thus suffers from
side reactions on both starting materials as well as the resulting
benzoxazoles. An alternative to this strategy is based on
dehydrogenative or oxidative coupling reactions of o-amino-
phenol with aldehydes, alcohols, or amines.4
Scheme 1. Willgerodt Reaction as a New Way of C−H
Functionalization
The most recent method consists of a transition metal-
catalyzed C−H functionalization of 2-unsubsubstituted benzox-
azoles.5 Similar to this approach is the sequence of
deprotonation by strong lithium bases/electrophilic trapping
that requires cooling conditions with strong electrophiles and
is, in general, incompatible with unprotected acidic or
electrophilic functional groups.6 The development of simple
conditions using inexpensive reagents/starting materials
provides new opportunities in the synthesis of such an
important heterocyclic family.7 In the course of our study, we
identify elemental sulfur as an excellent and versatile tool for
organic synthesis.8 Herein, we show that the combination of
this element with an organic base leads to the efficient oxidative
coupling between o-aminophenols and ketones to provide 2-
alkylated benzoxazoles under simple and mild conditions that
tolerate a wide range of functional groups in both coupling
partners.
Although relatively inactive under ambient conditions in the
absence of activator, under thermal activation or in the
presence of Lewis bases such as amines, ammonia, or
phosphines, sulfur has been well-known to act as nucleo-
electrophilic sulfuration reagent via ring opening of cyclo-
octasulfur to afford nucleophilic and electrophilic species. A
well-known example is the Willgerodt rearrangement9 in which
phenylthioacetamide is obtained when acetophenone is heated
Further development of this reaction included using other
nitrogen bases such as morpholine/piperidine than ammonia
and allowed the reaction to occur at lower temperatures and
broader scopes.10 In this kind of reaction, if other nucleophiles
are present in the reaction media, the primary thioamides will
transform further into sulfur-free product via transthioamida-
tion. The latter process requires, however, high activating
energy, which results in high reaction temperatures.11 In the
case where two-fold nucleophilic attack occurs, sulfur-free
product will be obtained, and the global reaction constitutes a
new strategy of C−H functionalization with concomitant
reorganization of oxidation degrees of the carbon chain.
Here we report our preliminary example of exploring of this
strategy. A two-fold nucleophilic attack is best realized with bis-
nucleophile to lower the required energy of the desulfuration
step. The oxidative rearranging coupling of acetophenone 2a
with o-aminophenol 1a as bis-nucleophile was chosen as a
Received: June 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01775
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Letter
model reaction at 80 °C (Table 1). In the absence of an
activator (Table 1, entry 1) or when toluene (Table 1, entry 2),
Scheme 2. Reaction Scope of Different Methyl Ketones
Table 1. Optimization of Reaction Conditions
a
entry
additive
t (°C)
yield (%)
b
1
2
3
4
5
6
7
8
80
80
80
80
80
80
80
60
0
b
toluene
pyridine
5
b
15
b
N,N-dimethylformamide
dimethyl sulfoxide
20
b
25
c
N-methylmorpholine
N-methylpiperidine
N-methylpiperidine
68
c
85
c
72
a
Reaction conditions (unless otherwise noted): 1a (1 mmol), S (1.5
mmol, 32 mg.mmol−1, 96 mg), 2a (2 mmol), additive (1 mmol), t °C,
16 h. Conversion determined by H NMR. Isolated yield.
b
c
1
a weakly interacting compound, was used as additive, traces of
the desired benzothiazole were observed. Stronger interacting
additives such as pyridine, DMF, and DMSO resulted in
improved conversions (Table 1, entries 3−5). In case of
DMSO, parasite oxidation promoted by this additive was also
observed, which led to a rather complex reaction mixture.
Gratifyingly, when sulfur was activated by cyclic tertiary amines
such as N-methylmorpholine12 and N-methylpiperidine13
(Table 1, entries 6 and 7), benzoxazole 3aa was formed in
good to excellent yields. The reaction was best performed at 80
°C (Table 1, entry 7 vs 8) in N-methylpiperidine as sulfur
activator. It should be noted that, in contrast to classical
Willgerodt-type reactions that required high temperatures,4f,14
a
temperature of 80 °C only was enough for full conversion.
The optimized reaction conditions were next applied to the
coupling of o-aminophenol with other acetophenone (Scheme
2). The reaction conditions were found to tolerate a range of
common substituents such as alkyl (3ab), halogens (3ac−3ae,
3ai−3aj), and alkoxy (3af−3ah). The structure of brominated
benzoxazole 3ae was confirmed by X-ray diffraction. o-
Substituted acetophenones 2i−k by an methyl or a halogen
groups proved to be good substrates for this reaction.
Gratifyingly, the ketones containing important pharmacophores
such as pyridines and thiophene as well as chromophore
naphthalenes were also suitable substrates, which gave rise to
the corresponding benzothiazoles products.
As pyridine as sulfur activator was found to be capable of
promoting this reaction (Table 1, entry 3), we wondered if
acetylpyridine 2m−o could reaction in the same manner with o-
aminophenol in the absence of N-methylpiperidine. While the
reactions of 2- or 4-acetylpyridine 2l, 2n proceeded with
extensive decomposition of these ketones, 3-acetylpyridine 2m
provided the desired product 3am in high yield. One of the
possible explanation for this difference was the basicity of 3-
acetylpyridine 2m being higher than that of its two
regioisomers due to lack of conjugation between the nitrogen
double bond and the carbonyl group in the first case.
conditions, a mono/di 2:1 mixture of benzoxazolated products
was obtained if two organic starting substrates were used in
equimolar amount. The dibenzoxazolated product 3at′ could
be formed exclusively in good yield if the stoichiometry of both
organic starting materials for its formation was respected upon
heating at 100 °C for 24 h.
The oxidative rearranging coupling reactions between
different o-aminophenols with acetophenone 2a were possible
under the optimized reaction conditions (Scheme 3). The
variety of aryl substituents tolerated in these reactions, such as
chloro, sulfamide, and sulfone, provides possibilities for further
molecular elaboration.
Similar reaction conditions can be used for the oxidative
rearranging coupling of other homologues of acetophenones
(Scheme 4) (n = 1−3, R′ = Ph). Various α-phenyl-ω-
benzoxazol-2-ylalkanes 3au, 3bv−3bx could be obtained in
moderate to good yields, although the yields were lower for
longer alkyl chains. The similar rearrangements were observed
when alkyl phenyl ketones were heated with an aqueous
solution of sulfur, ammonia, and ammonium sulfide from 160−
190 °C.15 Internal dialkyl ketones such as 3-pentanone or 4-
The reactions with methyl alkyl ketones proceeded in the
same manner and gave good yields of benzothiazoles 2-
substituted by long alkyl chains. When diacetyl substrate such
as p-diacetylbenzene 2t was subjected to the reaction
B
DOI: 10.1021/acs.orglett.7b01775
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Subsequently, to confirm the activating effect of basic
nitrogen on sulfur, we performed a reaction in which a primary
aliphatic amine such as cyclohexylamine 4 was used in place of
N-methylpiperidine (Scheme 5, eq 2). The crude reaction
mixture showed a total transformation of 4 into its phenyl-
thioacetamide 5 as in a typical Willgerodt−Kindler reaction
along with 15% of benzoxazole 3aa. Further 24 h heating of the
reaction mixture did not result in any conversion into 3aa. This
indicates that as long as cyclohexylamine is present in the
reaction mixture, sulfur activation is maintained and acetophe-
none can be oxidatively condensed with 1a to yield 3aa.
The mechanism of this oxidative rearranging coupling
reaction was proposed based on the Willgerodt reaction
(Scheme 6). The first step is a ring-opening activation of S8
Scheme 3. Reaction Scope of Different o-Aminophenol
Scheme 6. Proposed Reaction Mechanism
Scheme 4. Reaction Scope of Long Chain Alkyl Ketones
heptanone gave also benzoxazole 3ar−3as under the present
reaction conditions.
We next turned our attention to gain insight into the
mechanism of this oxidative rearranging coupling (Scheme 5).
leading to highly nucleophilic polysulfide zwitterion A.16
Addition of A to acetophenone followed by dehydration leads
to styryl polysulfide B. Subsequence β-sulfuration of B followed
by series of steps of double bond migration via C and D leads
to α-thio thioacetaldehyde E. Migration of β-polysulfide chain
with subsequent nucleophilic attack of 1a provides acetamide
dithioacetal G, which finally cyclizes to 3aa. Other reactions
pathways in which o-aminophenol involves in the earlier stages
thanks to the nucleophilicity of its amino group are also
possible. Although hydrogen sulfide is obviously the byproduct
of this reactions, no pressure buildup was noticed even when
the reactions were performed in closed tubes on heating. This
can be explained by the formation of N-methylpiperidinium
hydrogen sulfide, which is beneficial to avoid the emission of
hydrogen sulfide gas. Moreover, the presence of hydrogen
sulfide ion dissolved in the reaction mixtures may have a
positive catalytic effect on ring opening of the cyclooctasulfur,
an important initial step for catalytic cycle, via nucleophilic
attack to form polysulfide anion similar to A.
Scheme 5. Control Experiments
In conclusion, we have developed a general, inexpensive, and
versatile method for the synthesis of alkylated benzoxazoles,
which are important heterocyclic molecules and materials. The
chemistry is based on the Willgerodt-type rearrangement using
o-aminophenols as weak bis-nucleophiles. The N-methylpiper-
idine/sulfur combination enables the oxidative rearranging
coupling of both aliphatic and aromatic ketones under mild
conditions. Consequently, this strategy is capable of providing a
wide range of 2-alkylated benzoxazoles, which is difficult to
At first, in support of our working hypothesis that an attack at
the carbonyl of acetophenone would initiate, we chose mesityl
methyl ketone 2u in which the carbonyl function was shielded
by both o-methyl groups (Scheme 5, eq 1). The reaction of 2u
with 1a did not lead to the desired benzoxazole 3au, and
starting material as well as N-methylpiperidine remained
unchanged. This excludes the enolate species as intermediates,
which are less sterically demanding.
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01775.
Experimental procedures, copies of NMR spectra (PDF)
Crystallographic data of benzoxazole 3ae (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nguyen@icsn.cnrs-gif.fr.
ORCID
(6) (a) Ji, Y.; Zhang, Y.; Hu, Y.; Shao, L. Tetrahedron 2015, 71, 6818.
(b) Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104, 2667.
(c) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 2958.
Thanh Binh Nguyen: 0000-0001-8779-9641
Notes
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The authors declare no competing financial interest.
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