Synthesis of primary: N -arylthioglyoxamides from anilines, elemental sulfur and primary C-H bonds in acetophenones

Article abstract of DOI:10.1039/d0ra08740h

A simple method for coupling of anilines, acetophenones, and elemental sulfur to afford N-arylthioglyoxamides has been developed. Reactions proceeded in the presence of Na2SO3 and DMSO, thus eliminating the need for transition metals and external oxidants. Functionalities such as halogen, ester, methylthio, and heterocycle groups were compatible with the conditions. Electron-poor acetophenones sometimes gave isosteric glyoxamides. This journal is

Full text of DOI:10.1039/d0ra08740h

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Synthesis of primary N-arylthioglyoxamides from
anilines, elemental sulfur and primary C–H bonds in
acetophenones†
Cite this: RSC Adv., 2020, 10, 44743
ab
ab
ab
ab
Khoa M. Tran, Nguyen H. K. Nguyen, Thuy T. Bui, Tuong A. To,
ab
ab
ab
Nam T. S. Phan,
Ha V. Le* and Tung T. Nguyen
*
A
simple method for coupling of anilines, acetophenones, and elemental sulfur to afford N-
Received 14th October 2020
Accepted 7th December 2020
arylthioglyoxamides has been developed. Reactions proceeded in the presence of Na SO and DMSO,
2
3
thus eliminating the need for transition metals and external oxidants. Functionalities such as halogen,
ester, methylthio, and heterocycle groups were compatible with the conditions. Electron-poor
acetophenones sometimes gave isosteric glyoxamides.
DOI: 10.1039/d0ra08740h
rsc.li/rsc-advances
5
2
Primary N-arylthioglyoxamides are prominent precursors to in arylacetic acids or picolines. Sulfuration of acidic sp C–H
1
6
afford useful heterocycles. Yet, only a few methods for the bonds with elemental sulfur is known.
2
synthesis of thioglyoxamides have been reported (Scheme 1).
Wu and co-workers described an I
tophenones, anilines, and sodium hydrosulde in DMSO to useful functionalities have been presented. Herein, we report
Recently, multicomponent reactions that included elemental
2
-mediated coupling of ace- sulfur for synthesis of S-heterocycles and other synthetically
7
2
a
furnish such a-ketothioamides. The work suffered from the
a method for synthesis of N-arylthioglyoxamides from
use of a hygroscopic reagent as well as the formation of a toxic commercial anilines, acetophenones, and elemental sulfur. No
by-product, dimethyl sulde. An aerobic, iron-catalyzed oxidants or transition metals were required. Such thioglyox-
3
sulfuration/amination of sp C–H bonds in acetophenones amides could be obtained from nitroarenes as amine surro-
with elemental sulfur, a somewhat friendlier agent than sodium gates, albeit in low yields.
2b
hydrosulde, was later disclosed. Notably, the scope of amines
The study was started with the oxidative coupling of aniline
was limited to aliphatic compounds. Prefunctionalized, 1a, acetophenone 2a, and elemental sulfur. Some results of
acetophenone-derived molecules such as a-azidoacetophe- optimization are presented in Table 1. It should be noted that
nones or enaminones could be used to couple with elemental the desired product was only observed if reactions were run
2
c,d
2 3
sulfur as well. It should be protable if a method for coupling under argon atmosphere. An early attempt to use Na CO base
of simple, commercial substrates and allowing general scopes afforded the desired product in 13% yield (entry 1). Switching
of substrates is developed, thus N-arylthioglyoxamides could be the base to NaHCO3 increased the yield to 28% (entry 2).
obtained feasibly.
Organic, tertiary amine bases such as DABCO (entry 3) and N,N-
Elemental sulfur mediated functionalization of C–H bonds
has been extensively studied. Many examples focus on the
3
synthesis of heterocycles. Methods for using elemental sulfur
to obtain S-containing functionalities are recently presented.
Nguyen and co-workers reported a couple examples in which
oxidative coupling of benzylic C–H bonds in benzyl amines or
4
those in terminal alkynes with elemental sulfur occurred. Such
the desired thioamides were affordable via redox-neutral
3
processes involving nitroarenes and activated sp C–H bonds
a
Faculty of Chemical Engineering, Ho Chi Minh City University of Technology
(
HCMUT), 268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Vietnam. E-mail:
lvha@hcmut.edu.vn; tungtn@hcmut.edu.vn
b
Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc District,
Ho Chi Minh City, Vietnam
†
Electronic supplementary information (ESI) available: Details of experimental
procedures, characterization of the products. See DOI: 10.1039/d0ra08740h
Scheme 1 Synthesis of N-arylthioglyoxamides.
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a
Table 1 Studies of reaction conditions
DMSO to obtain a reasonable yield of 3aa. No other common
solvents such as DMF, 1,4-dioxane, or acetonitrile were able to
afford the product. Furthermore, increasing the amount of
acetophenone was crucial (entries 12 and 13). If 3 equivalents of
2a was used, the thioglyoxamide 3aa was obtained in 74% yield
(
(
entry 13). The reaction progress was carefully monitored by GC
entries 14 and 15). Notably, it could be stopped at 14 h, since no
signicant improvement of yield was observed aer that.
Scope of the reaction with respect to anilines was next
studied. The results are shown in Scheme 2. The unsubstituted
N-phenylthioglyoxamide 3aa was isolated in good yield.
Methoxy-substituted anilines successfully coupled with aceto-
phenone 1a; however, yields of the products were varied.
Notably, 3-methoxyaniline was much less active than the other
two isomers. Bromo-substituted aniline was a competent
substrate, giving the product 3ea that was useful for further
modication. Ester functionality was somewhat prone to
condition, although isolation of the thioglyoxamide 3fa was still
affordable. Aliphatic amines such as cyclohexylamine could be
used, affording the desired sulfurative coupling product 3ga in
DMSO amount,
(mL)
Yield of 3aa
(%)
Entry
Base
Na CO
NaHCO
DABCO
DiMePi
1a : 2a ratio
1
2
3
4
5
6
7
2
3
1
1
1
1
1
1
1
1
1.5
2
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 2
13
28
44
34
60
39
Trace
47
61
68
40
72
74
78
82
3
Na
NaOAc
Cs CO
2
SO
3
2
3
b
8
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
SO
3
SO
3
SO
3
SO
3
SO
3
SO
3
SO
3
SO
3
9
1
1
1
1
1
1
0
1
2
3
4
5
3
2
2
2
1 : 3
1 : 3
1 : 3
47% yield. Ortho- chloro and methylthio anilines were
c
compatible with reaction conditions, albeit giving the thio-
glyoxamides in low yields (3ha, 3ia).
d
2
a
ꢀ1
1
a (0.5 mmol), 2a (0.75 mmol), elemental sulfur (1 mmol, 32 g mol ),
base (1 mmol), DMSO, under argon at 120 C for 16 h. Yields of 3aa are
Uses of acetophenones were also investigated (Scheme 3).
Meta-substituted substrates coupled with aniline 1a to afford
the products in moderate yields (3ab, 3ac, 3ae). Sterically
hindered acetophenones such as 2f were still compatible with
reaction conditions. 4-Methoxy and 4-triuoromethyl aceto-
phenones successfully furnished the thioglyoxamides, albeit in
moderate yields (3ad, 3ag). Heterocycle-derived acetophenones
were competent substrates, affording the reasonable yields of
the desired products (3ah, 3ai). The conditions were limited to
very electron-poor ketones. In those cases, such as that con-
ꢁ
GC yields using diphenyl ether internal standard. Abbreviations:
b
ꢁ
c
d
DiMePi ¼ N,N-dimethylpiperazine. 100 C. 14 h. 8 h.
taining SO Me (2j) and CN (2k) groups at the para positions to
2
ketones, glyoxamides were the major products (3aj, 3ak).
Our group has shown that nitroarenes could be used as the
aniline surrogates in sulfur-mediated functionalization of C–H
5
bonds. Thus, attempts to couple nitro compounds with ace-
tophenones were investigated. However, low yields of products
and limited scope of substrates were obtained. Use a nitro-
derived imidazole 4a afforded the thioglyoxamide 5aa in 19%
yield. Notably, the 3-aminopyrazole failed to couple with ace-
tophenone. If a hindered 1-nitronaphthalene 4b was reacted
with acetophenone, a 2-benzoylbenzothiazole derivative 5ab
was isolated. Attempts to develop more efficient conditions for
sulfurative coupling of nitroarenes are ongoing.
Scheme 2 Scope of anilines. Conditions: 1a–1i (0.5 mmol), 2a (1.5
ꢀ1
mmol), elemental sulfur (1 mmol, 32 g mol ), Na
SO
2 3
(1 mmol), DMSO
ꢁ
(
2 mL), under argon at 120 C for 14 h. Yields are isolated yields.
At this moment, two possible pathways were hypothesized as
those shown in Scheme 5. Firstly, reaction could occur via
a conventional Willgerodt–Kindler coupling of 1a and 2a to
dimethylpiperazine (entry 4) could be used for the sulfurative
coupling, albeit furnishing 3aa in moderate yields. In this
8
afford the thioamide 7. This step was in agreement with the
result of substrate scope with respect to acetophenones, since
electron-poor carbonyl compounds were known to slowly join in
reaction, Na
amide in 60% yield (entry 5). Attempts to vary the use of base
including NaOAc and Cs CO were unsuccessful (entries 6 and
). Lowering the reaction temperature negatively affected the
2 3
SO was a superior base, affording the thioglyox-
8b
the rst step. Oxidation of 7 in the presence of sulfur and/or
2
3
co-oxidant DMSO would render the desired thioglyoxamide
7
3
aa. Notably, such the similar pathway was proposed by Nguyen
reaction (entry 8). A prominent effect of DMSO amount was
observed (entries 9–11). The reaction should be run with 2 mL of
2b,9
and co-workers.
oxidation of sp C–H bond in 2a afforded phenylglyoxal 8 or its
An alternative route could begin with the
3
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condensation of 1a and 8 (as a hydrate) was set up. Since desired
product 3aa was obtained in 80% (GC) yield, the oxidation step
(2a / 8) could occur during the reaction course. Furthermore,
reaction of norbonene 11 with possible trisulde radical inter-
5b
mediate (10 / 11) was unsuccessful. This result implied that
the formation of such a strong nucleophilic sulde could be
excluded.
Conclusions
In conclusion, we have developed a general method to couple
anilines, acetophenones, and elemental sulfur to afford N-
arylthioglyoxamides. The transformation did not need uses of
any external oxidants, prefunctionalized substrates, or transi-
tion metals. Nitroarenes were also attempted to couple with
acetophenones. Control experiments implied the oxidation of
a C–H bonds followed by imine condensation or Willgerodt–
Scheme 3 Scope of acetophenones. Conditions: 1a (0.5 mmol), 2b– Kindler-typed sulfuration.
ꢀ
1
2
k (1.5 mmol), elemental sulfur (1 mmol, 32 g mol ), Na
SO
2 3
(1 mmol),
ꢁ
DMSO (2 mL), under argon at 120 C for 14 h. Yields are isolated yields.
Experimental section
General procedure A (for Schemes 2 and 3)
In a typical experiment, an aniline (0.5 mmol), an acetophenone
(
1
1.5 mmol), Na
2 3
SO (126 mg, 1 mmol), elemental sulfur (32 mg,
ꢀ1
mmol, 32 g mol ), and DMSO (2 mL) were added to an 8 mL
vial equipped with a magnetic stir bar. The vial was ushed with
argon for 5 min, capped then placed into a preheated bath (120
ꢁ
C) and stirred for 14 h. The crude mixture was diluted with
ethyl acetate (5 mL) and brine (5 mL). The aqueous phase was
extracted with ethyl acetate (3 ꢂ 5 mL). Combined organic
Scheme 4 Coupling of nitroarenes and acetophenone. Conditions:
2 4
layers were dried over Na SO , ltered, and concentrated under
4
a or 4b (0.5 mmol), 2a (0.9 mmol), elemental sulfur (1.2 mmol, 32 g vacuum. The resulting residue was adsorbed onto silica gel (the
ꢀ1
ꢁ
3
(0.9 mmol), DMSO (1.2 mL), under argon at 120 C for
mol ), NaHCO
4 h. Yields are isolated yields.
weight was 10 or 15 times larger than that of the residue) then
diluted with hexanes/ethyl acetate to afford the product.
1
General procedure B (for Scheme 4)
In a typical experiment, a nitroarene (0.5 mmol), acetophenone
2
3
a (108 mg, 0.9 mmol), NaHCO (75 mg, 0.9 mmol), elemental
ꢀ
1
sulfur (38 mg, 1.2 mmol, 32 g mol ), and DMSO (1.2 mL) were
added to an 8 mL vial equipped with a magnetic stir bar. The
vial was ushed with argon for 5 min, capped then placed into
ꢁ
a preheated bath (120 C) and stirred for 14 h. The crude
mixture was diluted with ethyl acetate (5 mL) and brine (5 mL).
The aqueous phase was extracted with ethyl acetate (3 ꢂ 5 mL).
2 4
Combined organic layers were dried over Na SO , ltered, and
concentrated under vacuum. The resulting residue was adsor-
bed onto silica gel (the weight was 10 or 15 times larger than
that of the residue) then diluted with hexanes/ethyl acetate to
afford the product.
Scheme 5 Mechanistic consideration.
thio-derived isostere 9. Imine condensation of this intermediate
and 1a would furnish 10 followed by a sulfur attack and
oxidation to afford 3aa. To clarify this pathway, a control
Conflicts of interest
10
There are no conicts to declare.
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5
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Acknowledgements
The Viet Nam National Foundation for Science and Technology
Development (NAFOSTED) is acknowledged for supporting this
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