DIPEA-Promoted Reaction of 2-Nitrochalcones with Elemental Sulfur: An Unusual Approach to 2-Benzoylbenzothiophenes

Article abstract of DOI:10.1021/acs.orglett.7b02321

DIPEA was found to be an excellent sulfur activator to promote the reaction of 2-nitrochalcones with elemental sulfur. A wide range of 2-benzoylbenzothiophenes was obtained as a result of a cascade of alkene C=C bond thiolation, aromatic sulfur-denitratio

Full text of DOI:10.1021/acs.orglett.7b02321

Letter
pubs.acs.org/OrgLett
DIPEA-Promoted Reaction of 2‑Nitrochalcones with Elemental Sulfur:
An Unusual Approach to 2‑Benzoylbenzothiophenes
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: DIPEA was found to be an excellent sulfur
activator to promote the reaction of 2-nitrochalcones with
elemental sulfur. A wide range of 2-benzoylbenzothiophenes
was obtained as a result of a cascade of alkene CC bond
thiolation, aromatic sulfur-denitration.
pathway, giving rise to 2-benzoylbenzothiophene 2 at 100 °C
(Table 1, entry 1).
romatic nitro compounds are one of the most common
Aand versatile starting materials in organic synthesis due to
their easy preparation and ready availability. In most of
theorganic reactions involving aromatic nitro groups, this
function plays the building-block role and is transformed into
other nitrogen-containing functional groups or a part of newly
created aza-heterocycles. The transformations in which
aromatic nitro groups act as leaving groups are, however,
much less encountered and developed. In these kinds of
reactions,1 the presence of either transition metal catalysts such
as Cu,2 Rh,3 Pd,4 or strongly activating groups5 is required.
During the course of our study in the development of new
reactions involving aromatic nitro compounds using elemental
sulfur as a polyvalent synthetic tool, the building-block
behaviors of the nitro groups are the most frequently observed.6
For example, on heating with elemental sulfur in N-
methylmorpholine or 3-picoline, we found recently that 2-
nitrochalcones 1 transformed smoothly into sultames 3
(Scheme 1).7
a
Table 1. Optimization of the Reaction Conditions
b
entry
base (equiv) (pKa)8
DIPEA (10.61)
n
temp (°C)
yield (%)
70
1
5
5
5
5
5
5
5
5
5
2
5
100
100
100
100
80
e
2
NEt3 (10.65)
65
3
N(n-Pr)3 (10.65)
62
15
d
4
TMEDA (10.40)
f
5
DIPEA (10.61)
74 (76 )
c
6
DIPEA (10.61)
70
45
c
7
N-methylmorpholine (7.41)
pyridine (5.23)
80
0
c
8
80
0
9
N-methylpiperidine (10.08)
DIPEA (10.61)
80
20
35
70
When diisopropylethylamine (DIPEA) was used as base, we
noticed that the reaction proceeded in a totally different
10
11
80
NEt3 (10.65)
80
a
Reaction conditions: 1a (0.2 mmol), S (2 or 5 equiv, 0.4 or 1 mmol,
13 mg or 32 mg), base (1 mmol, 5 equiv) under an argon atmosphere.
Scheme 1. Reactions of 2-Nitrochalcone 1a with S8 in the
Presence of Different Bases
b
c
Isolated yield. Determined by 1H NMR of the crude reaction
d
e
mixture. N,N,N′,N′-tetramethylethylenediamine. Reaction per-
formed in a sealed tube under an argon atmostphere. Yield for the
f
reaction performed on 1 mmol scale.
This unexpected result prompted us to carry out a
comparative study on the behaviors of some related tertiary
amines (Table 1). Under similar conditions, triethylamine and
tri-n-propylamine behaved in the same manner and gave rise to
a similar product, benzothiophene 2a, despite in lower yields
(entries 2 and 3). When TMEDA was used as a dibasic
activator, 2a was also formed along with extensive degradation
Received: July 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of the base (entry 4). The reaction with DIPEA could be
efficiently performed at a temperature as low as 80 °C but the
conversion was incomplete at 70 °C (entries 5 and 6 vs entry
1). At the optimal temperature for DIPEA (80 °C), N-
methylmorpholine and pyridine did not display any activating
effect, 2-nitrochalcone 1a remained unchanged (entries 7−8).
On the other hand, N-methylpiperidine exhibited stronger
activating effect, leading to a complex mixture from which we
could isolate both benzothiophene 2a and sultam 3a in low
yields (20 and 23%, respectively) (entry 9). Under optimal
conditions, lower sulfur loading resulted in lower yield (entry
10). Finally, we noticed that the reaction could be performed
also with less expensive triethylamine at 80 °C (entry 11).
We next studied the substrate scope. A variety of 2-
nitrochalcones bearing different substituents at different
positions of the phenyl ring was evaluated under our optimized
conditions (Scheme 2).
chalcones 1k−n were found to react in the same manner, giving
rise to benzothiophenes 2k−n in good to excellent yields.
The reactions were subsequently investigated with substrates
bearing different substituents on the nitrobenzene ring
(Scheme 3). Chalcone 1o bearing two methoxy groups
Scheme 3. Formation of 2-Benzoylbenzothiophene 2b−n
Scheme 2. Formation of 2-Benzoylbenzothiophene 2b−n
remained intact and failed to give the expected benzothiophene
2o at 80 °C, possibly due to its low solubility. Gratifyingly,
clean conversion was observed when the reaction was
performed at 100 °C. Halogen substituted chalcones 1p,q
were showed to be competent substrates, leading to the
corresponding product in reasonable yields, although these
halogen atom are activated by the 2-nitro group.
While the detailed mechanism is not clear at this moment,
the choice of base additives is obviously vital to the reaction
outcomes. From the screening results of bases presented in
Table 1 and the previously reported observation,7 we noticed
that the first determining factor is the basicity of the base
additive. Weaker bases such as N-methylmorpholine (pKa 7.41)
or pyridine (pKa 5.23) did not activated sufficiently at lower
temperature (80 °C) although they were found to be efficiently
promoted the formation of sultam 3a at higher temperatures.
Second, for stronger bases such as DIPEA (pKa 10.61), NEt3
(pKa 10.65), N(n-Pr)3 (pKa 10.65), N-methylpiperidine (pKa
10.08) and TMEDA (pKa 10.40), other structural factors could
play additional roles in modifying the reactivity of the present
transformation. DIPEA, distinguished by its highest steric
hindrance around the basic nitrogen atom compared to other
bases discussed here, could attack only the most reachable
electrophile sites. Among sulfur and nitrochalcone 1a, only
cyclooctasulfur is available for this attack thanks to longer S−S
distance and bivalent nature of sulfur atoms. Consequently,
although it is still early to present detailed mechanistic
evidence, we suggest that the transformation is probably
initiated by ring opening of cyclooctasulfur promoted by
DIPEA, providing zwitterion polysulfide A (Scheme 4). As the
alkene double bond of nitrochalcone 2a is activated by both
nitro and benzoyl group, both α and β positions are activated.
Nucleophilic attack of A on the α position of nitrochalcone 2a
would proceed with temporary dearomatization of the
nitrobenzene ring of B. Cyclization of B to C would proceed
with elimination of a polysulfide chain. Finally, an aromatizing
denitration of C would lead to benzothiophene 2a.
The methyl substituted chalcones 1b,c reacted in the same
manner as 1a, even with o-substituted one 1c. The structure of
benzothiophene 2b was unambiguously determined by an X-ray
diffraction study (see the Supporting Information). Halogen-
ated substrates 1e−h were well tolerated, leading to the
corresponding halogenated benzothiophenes 2e−h in good to
excellent yields, regardless the nature and the positions of the
halogen atoms. Gratifyingly, when dinitrochalcones 1i,j were
subjected to the optimized conditions, the expected benzo-
thiophenes 2i,j were formed without any parasite reaction on
the remaining nitro groups. Polyaromatic and heteroaromatic
The unique role of the nitro group as both activating and
leaving group in the present reaction without any transition
metal catalyst is further demonstrated by a comparative
reaction with 2-chloro- and 2-bromochalcones 1x,y (Scheme
5). Their alkene double bond was hydrogenated cleanly to
B
DOI: 10.1021/acs.orglett.7b02321
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Organic Letters
Letter
Scheme 4. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nguyen@icsn.cnrs-gif.fr.
ORCID
Thanh Binh Nguyen: 0000-0001-8779-9641
Notes
The authors declare no competing financial interest.
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propanone 4x,y without any departure of the halogen
substituents. Although detailed mechanism of this trans-
formation is unknown, similar results were documented for
thermal reaction of chalcone with sulfur.9 In this case, hydrogen
sulfide generated in situ from the sulfuration of DIPEA with
elemental sulfur is responsible for the hydrogenation (eq 1,
Scheme 5).10
In conclusion, we have demonstrated a simple synthesis of 2-
benzoylbenzothiophene by simply heating 2-nitrochalcone with
elemental sulfur in DIPEA. This reaction once again high-
lighted complex, multifaceted, but highly attractive chemical
behaviors of both elemental sulfur and nitro group. By selecting
appropriate reaction conditions (in the present case, is the use
of DIPEA as activating base), unconventional reactivities and
selectivities could be observed. Compared to a recent work on
copper-catalyzed synthesis of 2-benzoylbenzothiophenes start-
ing from 2-bromo- or 2-iodo-chalcones using xanthate as sulfur
source,11 our strategy is markedly simpler with higher atom
efficiency and does not require any transition metal catalyst.
Further study on activated sulfur as a polyvalent synthetic tool
is underway in our laboratory.
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ASSOCIATED CONTENT
■
(11) Sangeetha, S.; Sekar, G. Org. Lett. 2017, 19, 1670. Literature on
other synthetic methods of 2-benzoylbenzothiazoles could be found in
this reference.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications Web site. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.7b02321.
Experimental procedures, characterizations of new
compounds, copies of their NMR spectra (PDF)
Crystal data for compound 2b (CIF)
C
DOI: 10.1021/acs.orglett.7b02321
Org. Lett. XXXX, XXX, XXX−XXX