Cooperative Activating Effect of Tertiary Amine/DMSO on Elemental Sulfur: Direct Access to Thioaurones from 2′-Nitrochalcones under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.7b03547

A new mode for the activation of elemental sulfur is reported. In the presence of both DMSO and a tertiary aliphatic amine (triethylamine or N-methylpiperidine), this element reacts directly with a wide range of 2′-nitrochalcones 1 to provide the corresponding thioaurones 2 in high yields even at room temperature and in the absence of transition metal catalyst.

Full text of DOI:10.1021/acs.orglett.7b03547

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cooperative Activating Effect of Tertiary Amine/DMSO on Elemental
Sulfur: Direct Access to Thioaurones from 2′-Nitrochalcones under
Mild Conditions
Thanh Binh Nguyen* and Pascal Retailleau
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite
91198 Gif-sur-Yvette, France
́ ́
Paris-Sud, Universite Paris-Saclay, 1 avenue de la Terrasse,
S
* Supporting Information
ABSTRACT: A new mode for the activation of elemental sulfur
is reported. In the presence of both DMSO and a tertiary aliphatic
amine (triethylamine or N-methylpiperidine), this element reacts
directly with a wide range of 2′-nitrochalcones 1 to provide the
corresponding thioaurones 2 in high yields even at room
temperature and in the absence of transition metal catalyst.
he ready availability of compounds bearing C(sp2)−NO2
or hemithioindigos 2, which are important scaffolds in dyes,
cosmetics, and photoswitches.2 They can also be used as
synthetic intermediates for other bioactive sulfur-containing
molecules.3 Although many synthetic methods for 2 have been
developed,4 they are all based on organosulfur starting
materials, the syntheses of which require additional steps
involving malodorous sulfides or thiols. Using elemental sulfur
as the sulfur precursor would be an excellent solution for this
drawback, which is also frequently encountered in sulfur
chemistry.
2
Tand C(sp )−H bonds and the synthetic versatility of
elemental sulfur have prompted us to focus our efforts on
exploiting their synthetic utility together.1 For such purposes,
we initiated a project aimed at constructing two C−S bonds
from a direct combination of these three fragments (Scheme 1).
Scheme 1. Construction of Two C−S Bonds from a C(sp2)−
H Bond, a C(sp2)−NO2 Bond, and Sulfur
Accordingly, we set up a screening of conditions for the
reaction between elemental sulfur and 2′-nitrochalcone 1a by
varying different activators (Table 1). At 80 °C, N-
methylpiperidine (NMP) was shown to be an excellent sulfur
activator, leading to the clean and total conversion of 1a into
thioaurone 2a (Table 1, entry 1). Other aliphatic amines such
as N-methylmorpholine (NMM) and DIPEA were also found
to be capable of promoting the transformation, although their
efficiencies were lower than that of N-methylpiperidine (Table
1, entries 2 and 3). Chalcone 1a remained totally unaffected by
sulfur with weakly or non basic additives such as 3-picoline,
DMF, or DMSO (Table 1, entries 3−6). At room temperature,
the activating effect of N-methylpiperidine was not observed
(Table 1, entry 7). Pleasingly, we serendipitously found that
when both N-methylpiperidine and DMSO were present in the
reaction medium, a noticeable color change was observed even
at rt, and thioaurone product 2a was consequently obtained in
excellent yield (Table 1, entry 8).
Very recently, we reported an example of the synthesis of 2-
benzoylbenzothiophenes 4 starting from 2-nitrochalcone
substrates 3 using elemental sulfur activated by diisopropyle-
thylamine (DIPEA) at 80 °C.1a Lowering the reaction
temperature is a challenging task, especially in the absence of
a transition metal catalyst, and will broaden the scope of
substrates.
At this stage, we wondered whether this double activation
could be extended to other amines. Unsurprisingly, Et3N (pKa
= 10.65) and DIPEA (pKa = 10.61), which are as basic as NMP
(pKa = 10.08), exhibited the same activating effect (Table 1,
entries 9 and 10). Weaker bases such as NMM (pKa = 7.41)
and 3-picoline (pKa = 5.68) were much less efficient (Table 1,
As a part of our ongoing project, we considered whether the
same strategy could be extended to 2′-nitrochalcones 1. Such a
transformation would allow the direct synthesis of thioaurones
Received: November 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03547
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Letter
Table 1. Optimization of the Reaction Conditions
Scheme 2. Formation of Thioaurones 2b−u from 2′-
Nitrochalcones 1b−u
a
Reaction conditions: 1a (0.2 mmol), S (1 mmol, 32 mg), base (1
b
mmol, 5 equiv). Determined by 1H NMR analysis of the crude
mixtures. Isolated yield. 86% on a 1 mmol scale.
c
d
entry 11) or totally inefficient (Table 1, entry 12). Finally, we
found that as a second additive, DMSO is better than DMF. In
fact, the reaction activated by Et3N/DMF was incomplete and
less clean than those with Et3N/DMSO and NMP/DMSO.
The optimized conditions with the Et3N/DMSO activator
pair were chosen for the investigation of the scope of 2′-
nitrochalcones substrates 1 (Scheme 2). Reaction of
halogenated chalcones 1b−f, including a fluorine, chlorine, or
bromine atom at different positions of the aromatic ring B,
proceeded well, delivering products 2b−f in good yields.
Substrates bearing an electron-donating group such as methoxy,
dimethylamino, or acetamido (1g−j) were less reactive. Their
reactions at rt were incomplete, and the conversion was proven
to depend on the electron-donating capacities of these
substituents. While the conversion at rt was low for the
substrate bearing a strongly donating p-N,N-dimethylamino
group (2i), the reactivity was improved significantly with p-
acetamido substituent (2j). The conversions at rt with
methoxy-substituted substrates 1g and 1h remained moderate
and depended on the substituent position. Gratifyingly, all of
these electron-enriched substrates 1g−j were fully transformed
into the expected thioaurones 2g−j upon heating at 50−60
°C.5
In contrast, the rt conditions were successfully applied to
other chalcones bearing an electron-withdrawing substituent
such as nitro or trifluoromethyl (1k−m). It should be noted
that between the two nitro groups of chalcones 1k and 1l, only
the 2′-nitro group was reactive. The structure of 2m was
confirmed by X-ray crystallography. The reaction worked well
also with both naphthyl (1n, 1o) and thienyl (1p, 1q)
substrates, although gentle heating at 50 °C was required to
achieve high yields for the latter cases.
The scope of 2′-nitrochalcones with different functional
groups on ring A was next examined. When ring A was
substituted with oxygen-containing substituents as in substrates
1r and 1s, the reactivity was low at rt. This phenomenon is
consistent with an SNAr mechanism. Via an addition−
a
Yield determined by 1H NMR analysis of the crude reaction mixture.
NMP was used instead of Et3N.
b
elimination pathway of the nitro group by a sulfur moiety,
the negatively charged intermediate adduct D is generated and
destabilized by electron-donating groups (see Scheme 4).
Interestingly, high yields of the corresponding thioaurones 2r
and 2s could be achieved at 60 °C.
B
DOI: 10.1021/acs.orglett.7b03547
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The efficiency of the present conditions was further
evaluated on a twofold reaction with substrates 1t and 1u. In
these cases, because of the low solubilities of the products
(including mono- and bisthioaurones), gentle heating at 60 °C
was applied to facilitate the stirring. Accordingly, bisthioaurones
2t and 2u were isolated in high yields as orange (2t) and bright-
yellow (2u) precipitates by simple filtration followed by
washing with common laboratory solvents (toluene, CH2Cl2,
MeOH), even on a small scale. Their solubilities were found to
be extremely low even in DMSO, especially when they were
pure.6
Scheme 4. Proposed Mechanism for the Formation of
Thioaurones 2 from 2′-Nitrochalcones 1
We further interrogated the mechanism of the reaction.
Because the reactivities were lower with substrates bearing
electron-donating substituents on ring B, a possible initiating
step could be a Michael addition of the amine to the alkene
moiety of the 2′-nitrochalcone substrate. Moreover, if this were
the case, any steric factors that could impede this initiating step
would further hamper the reactivity. To confirm this
hypothesis, we first investigated the reaction of 2′-nitrochalcone
substrates 1v and 1w bearing sterically demanding but
electronically neutral groups at both ortho positions of ring B
(Scheme 3). Both of them were transformed slowly at rt,
although full conversions could be achieved cleanly upon
heating at 60 °C.
quaternary ammonium moiety. Finally, elimination of tertiary
amine would lead to thioaurone 2. Although the activating role
of DMSO remains unclear at the moment, it is possible that it
stabilizes some polar intermediates and accelerates the
transformation.
Finally, to demonstrate the cooperative effect of DMSO and
tertiary amine, we employed this activating system to the
reaction of 2-nitrochalcone 3. This reaction was reported
previously by our group to provide 2-benzoylbenzothiophene 4
using DIPEA at 80 °C.1a In the presence of DMSO as a second
additive, the expected product 4 was obtained in good yield
even at rt (Scheme 5).
Scheme 3. Reactions with Sterically Demanding 2′-
Chalcones 1v−x
Scheme 5. 2-Benzoylbenzothiazole 4 from 2-Nitrochalcone 3
at Room Temperature
In conclusion, we have developed a direct method for the
incorporation of one sulfur atom into 2′-nitrochalcones 1
through direct C−H bond functionalization and aromatic
nucleophilic substitution of the nitro group. The corresponding
thioaurones 2 are smoothly formed under mild and metal-free
conditions. The synergy of a tertiary amine (triethylamine or N-
methylpiperidine) and DMSO was shown to be extremely
powerful to activate elemental sulfur, leading to clean and total
conversions even at rt for substrates bearing electronically
neutral or poor substituents. Further development and
applications of this cascade of direct construction of two C−
S bonds from a C(sp2)−H bond, a C(sp2)−NO2 bond, and
elemental sulfur are ongoing in our laboratory. We hope that
new reactivities of elemental sulfur will find their applications in
organic chemistry, especially in green and sustainable syntheses
of high-added-value molecules.
a
Yield determined by 1H NMR analysis of the crude reaction mixture.
NMP was used instead of Et3N.
b
As an extreme case, we evaluated the reactivity of
trimethoxychalcone 1x, which is at the same time electronically
enriched and sterically hindered. As expected, 1x remained
intact at rt to 50 °C and nearly unchanged even at 80 °C.
However, at 100 °C 1x was fully transformed into the
corresponding thioaurone 2x.
On the basis of the above observations, a possible
mechanistic pathway is outlined in Scheme 4. Michael addition
of the tertiary amine to 2′-nitrochalcone 1 would provide 1,3-
ammoniumketone A, which could exist as its enol tautomer B,
stabilized by the proximal positive charge of the quaternary
ammonium group. Enol B (or its deprotonated zwitterion
ammonium enolate) could attack elemental sulfur to provide
polysulfide C. Subsequent fragmentation of S7 with simulta-
neous cyclization via nucleophilic aromatic attack would deliver
zwitterion D. The negative charge on ring A of intermediate D
is stabilized by the adjacent electron-withdrawing carbonyl
group, which is in turn activated further by the nearby
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.7b03547.
Experimental procedures, characterizations of new
compounds, and copies of their NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b03547
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
CCDC 1584932 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*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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D
DOI: 10.1021/acs.orglett.7b03547
Org. Lett. XXXX, XXX, XXX−XXX