Homo-condensation of acetophenones toward imidazothiones

Article abstract of DOI:10.1039/d0ra03047c

Direct synthesis of imidazothiones from simple, commercial substrates is not known. We report a method for the condensation of acetophenones, elemental sulfur, and ammonium acetate as a nitrogen source to obtain the hitherto challenging five-membered heterocycles. Functionalities such as halogen, trifluoromethyl, cyano, methylthio, and heteroaryl groups were well tolerated.

Full text of DOI:10.1039/d0ra03047c

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Homo-condensation of acetophenones toward
imidazothiones†
ab
Cite this: RSC Adv., 2020, 10, 40225
ab
Phuc Hoang Pham,
‡
Phuc Thai Thien Nguyen,
‡
Thuy Thu Bui,ab
ab
ab
ab
*
*
Hien Nhat Tra,
Tung Thanh Nguyen
and Nam Thanh Son Phan
Received 4th April 2020
Accepted 30th October 2020
Direct synthesis of imidazothiones from simple, commercial substrates is not known. We report a method
for the condensation of acetophenones, elemental sulfur, and ammonium acetate as a nitrogen source to
obtain the hitherto challenging five-membered heterocycles. Functionalities such as halogen,
trifluoromethyl, cyano, methylthio, and heteroaryl groups were well tolerated.
DOI: 10.1039/d0ra03047c
rsc.li/rsc-advances
Amino-2H-imidazoles such as commercial lanabecestat or benzothienothiazoles via functionalization of C–H bonds in
a pyrimidine derivative, A (Scheme 1) are potent inhibitors acetophenone oximes have been reported.5b,c Nevertheless, the
against BACE-1 (b-site APP cleaving enzyme), and are thus available methods have required a two-step prefunctionaliza-
useful in studies for treating Alzheimer's disease.1 Until now, tion of aryl ketones. Arguably it would be more advantageous if
available methods for the synthesis of amino-2H-imidazoles C–H bonds in acetophenones could be directly functionalized,
oen proceed through substitution of imidazothiones with thus avoiding the unnecessary preparation of oxime substrates.
ammonia.1d It should be noted that this approach suffers from Only a couple of reports, to our best knowledge, have described
the use of toxic, ammable hydrogen sulde gas.2 Development attempts to convert methyl C–H bonds of acetophenones
of continuous-ow conditions has recently increased the without the need of N-oxime esters. Nguyen reported a synthesis
synthetic practicality.2b,c In 2012, Gravenfors and co-workers of 2,4-diarylthiophenes via homo-annulation of acetophenones
reported a rare study of substrate scope with respect to and elemental sulfur.5e The substrate scope was limited to
synthesis of 2,5-diaryl imidazothiones from acetophenones, a- simple functional groups such as alkyls, alkoxys, and halogens.
oxoacetates, and ammonia, followed by sulfur exchange of the Our group has recently presented an annulation of acetophe-
amide intermediates.1d Arguably, methods for directly assem- nones, elemental sulfur, and urea as a nitrogen source.5f The
bling simple, commercial substrates to obtain such ve- reactions afforded benzothienothiazoles that were compatible
membered heterocycles are still decient.
with many functionalities such as methylthio, protected
Studies of using elemental sulfur in organic synthesis has alcohol, and heterocycle groups. As a continuation of our
been extensively investigated over the last few years, probably interests in functionalization of C–H bonds in absence of
because it is cheap, abundant, and easy to handle. The element transition metals, herein a method for synthesis of imidazo-
has replaced the need of heavy phosphorus–sulfur complexes thiones from simple acetophenones, elemental sulfur, and
such as Lawesson's reagent and P2S5 in synthesis of thio-
amides.3 Many methods for incorporation of small molecules
into polycyclic S-heterocycles have been reported.4 In such
transformations, C–H bonds in acetophenones or pseudo oxime
esters have been considered as the major targets.
Oxime-assisted annulation of elemental sulfur and activated
C–H bonds a to carbonyl group oen afford synthetically chal-
lenging polyheterocycles.5
A few examples of furnishing
aFaculty of Chemical Engineering, Ho Chi Minh City University of Technology
(HCMUT), 268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Vietnam. E-mail:
tungtn@hcmut.edu.vn; ptsnam@hcmut.edu.vn
bVietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc District,
Ho Chi Minh City, Vietnam
† Electronic supplementary information (ESI) available: Details of optimization,
experimental procedures, and characterization of unknown compounds. See
DOI: 10.1039/d0ra03047c
‡ These authors equally contributed to this work.
Scheme 1 Importance of imidazothiones.
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solvents rather than DMSO were effective in this transformation
(entries 6 and 7). Lastly, the reaction could reach to the equi-
librium only aer 6 h (entry 8).
Substrate scope with respect to acetophenones was next
studied (Scheme 3). Structures of some imidazothiones were
conrmed by the results of HMQC and HMBC spectra.6 The
simple diphenyl imidazothione 3a was isolated in good yield,
even in a 2 mmol scale. Halo-substituted acetophenones affor-
ded the products regardless of positions of the substituents (3b–
3i). Since synthesis of bromo- (3e, 3f) and iodo- (3i) containing
imidazothiones was viable, late stage functionalization of such
molecules could be possible.1d Methyl (3j, 3k), methoxy (3l–3n),
and methylthio (3o) functionalities were all compatible with
reaction conditions. Uses of acetophenones containing
electron-withdrawing groups were also attempted. Tri-
uoromethyl- (3p) and cyano- (3q) substituted imidazothiones
Scheme 2 An early observation of imidazothione.
ammonium acetate has been developed. It should be noted that
such an one-pot formation of quaternary carbon from simple
reagents is relatively rare in the literature.
While optimizing the reaction of acetophenone 1a with
elemental sulfur and a nitrogen source such as NH4OAc to
obtain benzothienothiazole 2a (eqn (1), Scheme 2),5f we early
observed the formation of imidazothione 3a, especially at the
lower temperature (eqn (2), Scheme 2). Our study then
commenced on obtaining the simplest diphenyl imidazothione
3a from homocoupling of acetophenone 1a. The reaction was
optimized with respect to temperature, nitrogen source, and
solvent. The results are presented in Table 1. A trace amount of
the desired product was detected when running the reaction at
room temperature (entry 1). Increasing the temperature up to
60 ꢀC dramatically increased the yield of 3a (entry 2). However,
above 60 ꢀC some by-products could be detected, thus leading to
drops in yield (entry 3). Unlike our previous report,5f urea could
not be used to incorporate nitrogen atoms into the product
(entry 4). Since NH3 did not give the product, the presence of
acetate anion was pivotal to the formation of 3a (entry 5). No
Table 1 Studies of reaction conditionsa
Temperature
(ꢀC)
Nitrogen
source
Yield of 3a
(%)
Entry
Solvent
1
2
3
r.t.
60
70
60
60
60
60
60
NH4OAc
NH4OAc
NH4OAc
Urea
DMSO
DMSO
DMSO
DMSO
DMSO
Dioxane
DMF
Trace
84
71
n.d.
n.d.
n.d.
n.d.
84
4
5b
6
NH3
NH4OAc
NH4OAc
NH4OAc
7
8c
DMSO
a
Scheme 3 Reaction scope with respect to acetophenones. Reagents
and conditions: acetophenones (0.2 mmol), sulfur (0.3 mmol, 32 g
molꢁ1), NH4OAc (0.5 mmol), DMSO (1 mL, [acetophenones] ¼ 0.2 M),
60 ꢀC, 6 h. Yields are isolated yields. Please see the ESI† for more
details. a2 mmol scale.
Acetophenone (0.2 mmol), elemental sulfur (0.3 mmol, 32 g molꢁ1),
nitrogen source (0.5 mmol, based on nitrogen), solvent (1 mL, [1a] ¼
0.2 M), for 24 h. Yields of 3a are GC yields using diphenyl ether
b
c
internal standard.
Abbreviations: r.t. ¼ room temperature, n.d. ¼ not determined.
NH3 as
a
28% aqueous solution.
6 h.
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Scheme 5 Plausible mechanism.
a dithiazolethione 5 or reacting with 6 following a [3 + 2]
cycloaddition to afford 8. Aer isomerization (8 / 9) and
oxidation of C–S bond, the imidazothione 3a was obtained.
Conclusions
Scheme 4 Mechanistic considerations.
In conclusion, we have developed a simple method for synthesis
of imidazothiones from annulation of methyl C–H bonds in
acetophenones with elemental sulfur and NH4OAc. DMSO was
used as a solvent as well as oxidant in these reactions. A wide
range of functionalities including halogen, methylthio, cyano
groups were compatible with reaction condition. Heteroaryl
methyl ketones were also competent substrates. The method
would offer a rapid route to assemble complex polycyclic
structures from simple, commercial substrates.
could be obtained in good yields. However, running the reaction
of 4-nitroacetophenone did not give the desired product.
Furthermore, our conditions were applied for synthesis of pol-
yheterocyclic imidazothiones (3r, 3s). It should be noted that 2-
acetylheteroarenes sometimes were not competent substrates.
Although most of possible intermediates were unstable and
difficult to independently prepare, some mechanistic studies
still have been investigated (Scheme 4). Similar to previous
studies,5f,g compounds afforded by oxidative sulfuration of
a C–H bonds were detected by GC-MS if the coupling of 1a and
2a was stopped aer 1 h (eqn (1)). The annulation was some-
what affected by the presence of radical quenchers such as
TEMPO or 1,1-diphenylethylene, especially if excess amount of
these compounds was used (eqn (2)). Since DMSO was much
effective more than other solvents, we envisaged that it could
play roles in oxidation steps. Indeed, 53% and 28% of product
3a were obtained if 3 equivalents of DMSO were used in solvents
1,4-dioxane and CH3CN, respectively (eqn (3)). Analysis of the
crude mixture obtained from the reaction of 40-chlor-
oacetophenone and 40-methoxyacetophenone disclosed a 0.8/
0.3/1 ratio of three coupling products, as the major was the
heterocoupling imidazothione (eqn (4)). Given that only one
cross-coupled product was obtained, it was likely that electronic
properties of substituents have played a somewhat important
role during reaction course. Ongoing experiments will include
the isolation of synthetically challenging cross-coupled
imidazothiones.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The Vietnam National Foundation for Science and Technology
Development (NAFOSTED) is acknowleged for supporting this
research under project code 104.01-2019.340.
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40228 | RSC Adv., 2020, 10, 40225–40228
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