Synthesis of α-Keto Thioamides by Metal-Free C-C Bond Cleavage in Enaminones Using Elemental Sulfur

Article abstract of DOI:10.1021/acs.joc.8b02670

An unprecedented method for cleaving the C-C bond in N,N-disubstituted enaminones in the presence of elemental sulfur and N,N-dimethyl-4-aminopyridine is disclosed. Without using any metal catalyst or additive, the cascade functionalization of both C?C an

Full text of DOI:10.1021/acs.joc.8b02670

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Note
Synthesis of #-Keto Thioamides by Metal-Free C=C
Bond Cleavage in Enaminones Using Elemental Sulfur
Lu Gan, Yong Gao, Li Wei, and Jie-Ping Wan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02670 • Publication Date (Web): 18 Dec 2018
Downloaded from http://pubs.acs.org on December 18, 2018
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Synthesis of α-Keto Thioamides by Metal-Free C=C Bond
Cleavage in Enaminones Using Elemental Sulfur
Lu Gan,# Yong Gao,# Li Wei, Jie-Ping Wan*
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aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China
Email: wanjieping@jxnu.edu.cn
#These authors contributed equally to this work
Metal-free
O
O
R1
N
Air as the only oxidant
shelf stable reagents
C=C bond sulfuration
DMAP, S8
DMF, 90 oC
R1
R1
R
N
R1
R
S
22 examples
Abstract An unprecedented way of cleaving the C=C bond in N,N-disubstituted
enaminones in the presence of elemental sulfur and N,N-dimehtyl-4-aminopyridine
(DMAP) is disclosed. Without using any metal catalyst or additive, the cascade
functionalization of both C=C and C-H bonds takes place to enable the formation of
new C=S and C-N bonds, thus providing a facile and practical method for the
synthesis of N,N-disubstituted α-keto thioamides.
The carbon-sulfur bonds are ubiquitous as characteristic moiety in natural products,
polymeric materials, pharmaceuticals and biologically valuable lead compounds.1
According to the chemical valence of the sulfur atom, the carbon-sulfur bonds usually
present in two different forms: the C-S single bond and the C=S double bond.
Because of the features of high stability and enriched pathways of bond formation, the
construction of singe C-S bond is accessible via a large number of different synthetic
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approaches such as cross coupling, substitution and addition reactions etc.2 On the
contrary, as the other form of carbon-sulfur bond, the C=S double bond has received
much less advances in terms of synthetic methodology. However, because the C=S
double bond is known as featured fragment in a large number of organic compounds
possessing valuable biological profiles as well as pharmaceutical activities, devising
synthetic routes enabling the construction of C=S double bond is thus highly critical
work. Traditionally, the Lawessons’ reagent is a reliable option in the C=S double
bond forming reaction by transforming the carbonyl group into thiocaronyl group.3
The high cost and production of phosphorus waste, however, are restrictions
preventing the widespread application of this reagent. Thanks to the efforts been made
by researchers, some more easily available and environmentally friendly sulfurating
reagents, such as alkali sulfide and elemental sulfur have been found as practical
alternatives in several sulfuration reactions. For example, the coupling reactions of
amine, elemental sulfur with an alkyne,4 amine,5 aldehyde,6 and active methyl C-H
bonds7 have been reported as effective methods in the synthesis of thioamides via
C=S bond construction. In addition, the decarboxylation of arylacetic and cinnamic
acids has also been developed for the synthesis of thioamides by reacting with
elemental sulfur and amines.8 On the other hand, the reactions of alkali sulfide,
aldehyde with amines/amides,9 amines/haloalkynes,10 or aryl nitriles11 can provide
divergent thioamides, too. Recently, novel synthetic methods towards thioamides
have been established by employing various other sulfur sources such as methylene
thiols, isothiocyanates, 2-thioxothiazolidinone, P4S10 and tetramethylthiuram disulfide
2
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etc.12
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Generally, all the formation of C=S double bond in these presently known methods
involve the transformation of C=O, C-H or C≡C triple bonds. It is interesting that a
reaction transforming C=C double bond to C=S bond is not yet known. Recently, the
functionalization on the C=C double bond in enaminones has been revealed as robust
tool in the designation of enriched organic syntheses by us and other groups.13 In view
of our previous works on and continuous interests in the synthetic chemistry based on
enaminones,14 we envisage that it is possible to achieve the generation of a C=S bond
by functionalizing the C=C double bond of enaminones, which may provide α-keto
thioamide as products resulting from such transformation.
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As a class of typical thioamide derivatives, the α-keto thioamides are reported with
important functions in organic synthesis and biological studies.15 Previously, the
synthesis of α-keto thioamides can be accessed via the reactions of methyl ketones
with various thiol amide reagents such as (N,N-dimethylthiocarbamoyl)lithium,16
amine/sodium hydrosulfide,17 elemental sulfur/amine,18 or elemental sulfur/amide.19
In other cases, arylglyoxal hydrates have been used as more active equivalents of
methyl ketones for the synthesis of similar products.20 The overall availability for
α-keto thioamides, however, is yet inadequate for diversity oriented α-keto thioamide
synthesis. In this background, devising reactions initiated by unprecedented
transformation models is highly demanding. Herein, we report a new approach for the
metal-free synthesis of α-keto thioamides via the reactions of elemental sulfur21 and
enaminones under aerobic condition, which is also hitherto the first example of
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carbon-carbon bond cleavage-based synthesis of α-keto thioamides.
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Initially, the model reaction of enaminone 1a with elemental sulfur 2 was first run in
DMF by heating at 90 oC, but no reaction took place (entry 1, Table 1). Interestingly,
the employment of DMAP as additive led to the formation of product 3a with good
yield (entry 2, Table 1). In parallel entries, other organic bases such as
N-methylmorpholine (NMM) and DABCO could not promote this reaction (entries
3-4, Table 1). Subsequently, reducing the amount of elemental sulfur was found to be
negative, and considerably lower yield of 3a was afforded (entries 5-6, Table 1). Later
on, toluene, dioxane and DMSO were employed as alternative reaction medium,
respectively (entries 7-9, Table 1), but none was practical. In the experiments
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o
conducted at different temperature, 90 C was proved to be most favorable (entries
10-11, Table 1). In addition, decreasing the loading of DMAP undermined the yield of
3a (entry 12, Table 1). Subsequently, a control entry performed under nitrogen
atmosphere gave 3a in only trace amount, indicating that the oxygen in air was
indispensable for this reaction (entry 13, Table 1). As further comparison, the reaction
using 2,6-ludine as base additive didn’t lead to the synthesis of 3a, indicating the
specific function of DMAP for this reaction (entry 14, Table 1). Conducting the same
reaction with catalytic amount of DMAP in the present of 1 equiv NaOH was not
practical, either (entry, 15, Table 1). Finally, the parallel reaction using K2S as the
alternative sulfur source with 1a gave only trace amount of 3a with the optimal
parameters in entry 2.
Table 1 Optimization on the reaction conditions for α-keto thioamide synthesisa
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O
O
5
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N
amine, air
N
S8
+
solvent, T
S
1a
3a
2
9
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entry
1
2
3
4
5c
6d
7
8
9
10
11
12e
13f
14
15g
additive
-
DMAP
NMM
solvent
DMF
DMF
DMF
DMF
DMF
DMF
toluene
dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
T (oC)
90
90
90
90
90
90
90
90
90
80
100
90
90
yield (%)b
0
78
0
DABCO
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
2,6-lutidine
DMAP
0
trace
10
0
0
trace
trace
64
47
trace
0
90
90
5
aThe general conditions: 1a (0.2 mmol), 2 (0.8 mmol) and additive (0.2 mmol) in 2
o
b
mL of solvent, stirred at 90 C for 24 h under air atmosphere. Yield of isolated
product based on 1a. cThe loading of sulfur was 0.2 mmol. dThe loading of sulfur was
e
f
g
0.4 mmol. The loading of DMAP was 0.1 mmol. Reaction under N2. 20 mol%
DMAP and 1 equiv NaOH were used.
Following the optimization experiments, the application scope of this C=C bond
cleavge-based sulfuration was then examined. The reactions employing different
enaminones to react with elemental sulfur were executed, and the results in
synthesizing different α-keto thioamides 3 via the reactions of N,N-dimethyl tertiary
enaminones were shown in Table 2. According to the acquired results, the present
method was generally applicable for the synthesis of α-aroyl thioamides via the
reactions of corresponding aryl functionalized enaminones. In the reactions of
N,N-dimethyl amino-based enaminones, the substrates with phenyl ring containing
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alkyl, halogen, nitro, alkoxyl, and trifluoromethyl substitution displayed fine
compatibility to the titled reaction regardless the site and property of the substituents,
and no fixed impact of these substituents to the product yield was reflected in the
present data (3a-3l, Table 2). Additionally, the naphthyl (3m and 3n, Table 1) and
heteroaryl (3o-3r, Table 2) functionalized α-keto thiomamides were also smoothly
synthesized with moderate to good yields via the same
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Table 2 Scope on the synthesis of N,N-dimethyl α-keto thioamidesa,b
O
O
DMAP (1 equiv)
air, DMF, 90 oC
N
N
S8
+
Ar
Ar
N
S
3
1
2
O
O
O
O
N
N
N
S
S
S
S
Cl
MeO
3d
3h
, 77%
O
3b
, 82%
O
3c
, 56%
3a
, 78%
O
O
N
N
N
N
N
S
S
S
S
O2N
Br
F3C
3g
, 74%
3e
3f
, 61%
, 74%
, 68%
O
O
NO2
O
O
Cl
Cl
N
S
N
O
O
MeO
N
S
, 78%
O
S
S
3j
, 78%
3i
3k
, 61%
, 75%
O
3l
O
O
N
N
N
N
N
S
S
S
S
, 72%
O
S
S
3o
3p
, 63%
O
, 75%
O
3n
3m
, 70%
O
N
N
N
N
S
S
O
S
, 63%
S
3q
3r
, 72%
not formed
not formed
aThe general conditions: 1 (0.2 mmol), 2 (0.8 mmol) and DMAP (0.2 mmol) in 2 mL
o
b
of DMF, stirred at 90 C for 24 h under air atmosphere. Yield of isolated product
based on 1.
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transformation, demonstrating that this method was generally applicable for the aryl
functionalized enaminones. The reaction employing an enaminone functionalized
with methyl instead of the aryl in 1 did not provide the target product. Similarly, the
reation employing a N,N-dimethyl vinyl enaminone under the present conditions did
not give rise to the expected product, either.
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Next, for further expanding the scope on the synthetic protocols, the tertiary
enaminones functionalized with varied N,N-substitution22 were employed to the
standard reactions conditions with elemental sulfur. As outlined in Table 3, the
enaminones functionalized with pyrrolidine, piperidine as well as morpholine were
found to be identically practical in the individual synthesis of α-keto thioamides
5a-5d. The successful synthesis of these products confirmed the satisfactory
application scope of the present method in the synthesis of N,N-disubstituted α-keto
thioamide. However, the attempts in synthesizing NH-α-keto thioamide 5e and
N-methyl, N-phenyl α-keto thioamide 5f were not successful by this method.
Analyzing the reaction synthesizing 5a led to the simultaneous isolation of 3a as side
product in 28% yield, indicating that DMF was also an active amino source in the
formation of products 3. The result also explained the relatively lower product yields
of 5.
Table 3 Scope on the synthesis of α-keto thioamides with varied N,N-disubstitutiona,b
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O
R
N
O
DMAP (1 equiv)
air, DMF, 90 oC
R
R'
N
S8
+
Ar
Ar
O
S
5
R'
4
2
O
O
O
10
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N
N
S
N
S
S
5c
, 66%
5a
5b
, 68%
, 58%
O
Ph
O
O
O
Ph
N
N
NH
S
, not formed
S
S
Cl
5f
5d
5e
, not formed
, 63%
aThe general conditions: 4 (0.2 mmol), 2 (0.8 mmol) and DMAP (0.2 mmol) in 2 mL
o
b
of DMF, stirred at 90 C for 24 h under air atmosphere. Yield of isolated product
based on 4.
While different intermediates such as 1,2-dioxetane23 or 1,2-oxathietane resulting
from the oxidation of molecular oxygen to the C=C double bond were possible for
this reaction, we analyzed the crude mixture of the model reaction by GC. The results
showed clearly that formaldehyde was formed during the reaction (see SI),
On the basis of the result from control experiments (entry 13, Table 1) and previous
reports on the enaminone C=C bond cleavage, the possible mechanism of the present
sulfuration reaction is proposed (Scheme 1). Originally, the elemental sulfur
incorporates the nucleophilic DMAP24 to form the active pyridine N-S species I
which mediates the transfer of the sulfur atom to enaminones and provides
intermediate 6 via the enaminone’s isomeric version 1’. Subsequently, the
intramolecular cyclization of 6 leads to the formation of thiirane intermediate 7. The
oxidative insertion of molecular oxygen25 to 7 produces 1,2-oxathietane intermediate
8. The ring opening of 8 via the migration of the amino group to the sulfur atom
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7
8
9
enables the formation of 9 which undergoes quick elimination of the secondary amine
to generate intermediate 10. Successively, the nucleophilic attack of the amine to the
thiocarbonyl site provides N,S-acetal intermediate 11. The decomposition of 11 then
yields products 3 and releases formaldehyde. Further oxidation on the formaldehyde
giving formic acid may take place to consume part of DMAP, which is also positive
to the formation of the target product.
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Scheme 1 The proposed reaction mechanism
S8
S
N
N
DMAP
I
Ar
Ar
N
N
Ar
N
O
O
O
1
1'
S
S
S
O
O2 (air)
Ar
N
Ar
7
O
O
N
6
8
N
O
S
H
S
S
O
N
O
Ar
O
Ar
Ar
H
O
10
O
9
11
NH
O
[O]
N
HCHO
HCOOH
Ar
3
S
In conclusion, we have identified a novel protocol for the synthesis of α-keto
thioamides via the sulfuration based on enaminone C=C double bond cleavage. The
reactions of easily available tertiary enaminones and elemental sulfur take place
efficiently in air atmosphere without using any metal catalyst or additional oxidant.
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Owing to the special mode of bond transformation, simple operation as well as the
broad substrate tolerance, the present method will be a useful complementary option
in the synthesis of α-keto thioamides.
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Experimental section
General information
All experiments were carried out under air atmosphere. Enaminones 126 and 422 were
prepared following literature processes. Other chemicals and solvents used in the
experiments were acquired from commercial sources and used directly without further
treatment. 1H and 13C NMR were recorded in 400 MHz spectrometer by using CDCl3
as solvent and TMS as internal standard. The chemical shifts were reported in ppm,
and the frequencies for H and 13C NMR test were 400 MHz and 100MHz,
1
respectively. High resolution mass spectrometry (HRMS) data for all new products
were obtained under ESI model in an apparatus equipped with TOF analyzer. The
melting points of solid samples were tested in an X-4A apparatus without correcting
the temperature.
General procedure for the synthesis of α-keto thioamides 3 and 5
To a 25 mL round-bottom flask were added enaminone 1 or 4 (0.2 mmol), sulfur
powder (0.8 mmol), DMAP (0.2 mmol) and DMF (2 mL). Then the resulting mixture
was heated up to 90 oC with oil bath, and stirred at the same temperature for 24 hours
(TLC). After cooling down to room temperature, 5 mL of water was added, and the
suspension was extracted with ethyl acetate (3 × 10 mL). The organic phases were
collected and washed with small amount of water for three times. After drying with
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anhydrous Na2SO4, the solid was filtered and the acquired solution was employed to
reduced pressure to remove the solvent. The residue obtained therein was then
subjected to flash silica gel column chromatography to provide pure products with the
elution of mixed petroleum ether/ethyl acetate (v/v = 10:1).
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N,N-Dimethyl-2-oxo-2-phenylethanethioamide (3a).19 Yield 78%, 30 mg; pale
yellow solid; mp 80-81oC; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 2 H),
7.60 (t, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 2 H), 3.55 (s, 3 H), 3.23 (s, 3 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 196.8, 188.4, 134.2, 133.2, 129.9, 128.8, 42.4, 40.4.
N,N-Dimethyl-2-oxo-2-(p-tolyl)ethanethioamide (3b).19 Yield 82%, 34 mg; yellow
o
solid; mp 118-120 C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.9 Hz, 2 H), 7.28
1
13
(d, J = 7.6 Hz, 2 H), 3.54 (s, 3 H), 3.21 (s, 3 H), 2.42 (s, 3 H); C{ H} NMR (100
MHz, CDCl3) δ 197.0, 188.4, 145.5, 130.6, 130.0, 129.6, 42.5, 40.5, 21.9.
2-(4-Methoxyphenyl)-N,N-dimethyl-2-oxoethanethioamide (3c).19 Yiled 56%, 25
mg; yellow solid; mp 88-89 oC; 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 9.2Hz, 2
1
13
H), 6.95 (d, J = 8.8Hz, 2H), 3.88(s, 3 H), 3.54(s, 3 H), 3.22(s, 3 H); C{ H} NMR
(100 MHz, CDCl3) 197.3, 187.8, 164.5, 132.3, 126.0, 114.2, 55.6, 42.4, 40.5.
2-(4-Chlorophenyl)-N,N-dimethyl-2-oxoethanethioamide (3d).4 Yield 77%, 35 mg;
1
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7.46 (d, J = 8.5 Hz, 2 H), 3.55 (s, 3 H), 3.23 (s, 3 H); C{ H} NMR (100 MHz,
CDCl3) δ 196.0, 186.9, 140.8, 131.7, 131.3, 129.2, 42.5, 40.5.
2-(4-Bromophenyl)-N,N-dimethyl-2-oxoethanethioamide (3e). Yield 74%, 40 mg;
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yellow solid; mp 96-97 C; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2 H),
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7.63 (d, J = 8.4 Hz, 2 H), 3.55 (s, 3 H), 3.23 (s, 3 H); C{ H} NMR (100 MHz,
CDCl3) δ 196.0, 187.1, 132.2, 131.3, 129.8, 129.6, 42.5, 40.5; HRMS (ESI) m/z calcd
for C10H11BrNOS (M + H)+ 271.9739, found 271.9737.
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N,N-Dimethyl-2-oxo-2-(4-(trifluoromethyl)phenyl)ethanethioamide (3f).15a Yield
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61%, 32 mg; yellow solid; mp 70-71 C; H NMR (400 MHz, CDCl3) δ 8.10 (d, J =
8.1 Hz, 2 H), 7.75 (d, J = 8.2 Hz, 2 H), 3.57 (s, 3 H), 3.26 (s, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 195.5, 186.3, 136.3, 135.0, 130.2, 125.8, 124.8 (q, Jc-F = 271
Hz), 42.5, 40.5.
2-(4-Nitrophenyl)-N,N-dimethyl-2-oxoethanethioamide (3g).19 Yield 74%, 35 mg;
yellow solid; mp 148-150 oC;1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 9.2Hz, 2H),
8.16 (d, J = 9.2 Hz, 2 H), 3.59(s, 3 H), 3.28(s, 3 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 194.8, 184.9, 150.7, 138.4, 130.9, 123.9, 42.5, 40.5.
N,N-Dimethyl-2-oxo-2-(o-tolyl)ethanethioamide (3h).19 Yield 68%, 28 mg; pale
yellow solid; mp137-138 oC; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.7 Hz, 1 H),
7.44 (t, J = 7.4 Hz, 1 H), 7.31-7.24 (m, 2 H), 3.56 (s, 3 H), 3.29 (s, 3 H), 2.69 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3)δ 198.2, 189.7, 141.8, 133.2, 132.6, 132.1, 131.9,
125.9, 42.5, 40.7, 21.9.
2-(2-Nitrophenyl)-N,N-dimethyl-2-oxoethanethioamide (3i). Yield 61%, 29 mg;
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yellow solid; mp 114-115 C; H NMR (400 MHz, CDCl3) δ 8.03(d, J = 8.0Hz, 1H),
7.87(d, J = 7.6Hz, 1H), 7.74 (t, J = 7.6Hz, 1H), 7.63 (t, J = 7.8Hz, 1H), 3.62(s, 3 H),
3.47(s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.9, 183.3, 134.8, 133.8,
132.4,131.6, 123.7,77.3, 43.1, 42.6; HRMS (ESI) m/z calcd for C10H11N2O3S (M +
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H)+ 239.0485, found 239.0483.
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2-(3-Methoxyphenyl)-N,N-dimethyl-2-oxoethanethioamide (3j).19 Yield 78%, 35
mg; brown liquid; 1H NMR (400 MHz, CDCl3) δ 7.55-7.54 (m, 1 H), 7.50 (d, J = 7.7
Hz, 1 H), 7.37 (t, J = 7.9 Hz 1 H), 7.16-7.13 (m, 1 H), 3.86 (s, 3 H), 3.55 (s, 3 H),
3.22 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.8, 188.2, 160.0, 134.6, 129.9,
122.8, 120.9, 113.6, 77.4, 77.0, 76.7, 55.5, 42.4, 40.4.
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2-(3,4-Dichlorophenyl)-N,N-dimethyl-2-oxoethanethioamide (3k). Yield 75%, 39
mg; yellow solid; mp 106-108 oC;1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1 H), 7.81 (d,
J = 8.3 Hz, 1 H), 7.57 (d, J = 8.3 Hz, 1 H), 3.55 (s, 3 H), 3.24 (s, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 195.1, 185.4, 138.8, 133.6, 133.1, 131.5, 131.0, 128.8, 42.5,
40.5; HRMS (ESI) m/z calcd for C10H10Cl2NOS (M+H)+ 261.9855, found 261.9854.
2-(Benzo[d][1,3]dioxol-5-yl)-N,N-dimethyl-2-oxoethanethioamide (3l). Yield 78 %,
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37 mg; brown solid; mp 128-129 C; H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.2
Hz, 1 H), 7.45 (s, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.07 (s, 2 H), 3.54 (s, 3 H), 3.22 (s, 3
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H); C{ H} NMR (100 MHz, CDCl3) δ 196.9, 187.3, 152.9, 148.4, 127.8, 127.1,
109.0, 108.4, 102.2, 42.5, 40.5; HRMS (ESI) m/z calcd for C11H12NO3S (M+H)+
238.0532, found 238.0534.
N,N-Dimethyl-2-(naphthalen-2-yl)-2-oxoethanethioamide (3m). Yield 70%, 34 mg;
yellow solid; mp 103-104 oC; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1 H), 8.04 (d, J =
8.6 Hz, 1 H), 7.96-7.87 (m, 3 H), 7.65-7.54 (m, 2 H), 3.61 (s, 3 H), 3.26 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 196.9, 188.6, 136.1, 132.5, 132.4, 130.6, 129.8,
129.2, 128.9, 127.9, 127.1, 124.4, 42.5, 40.6; HRMS (ESI) m/z calcd for C14H14NOS
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(M + H)+ 244.0791, found 244.0789.
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N,N-Dimethyl-2-(naphthalen-1-yl)-2-oxoethanethioamide (3n). Yield 72%, 35 mg;
yellow solid; mp 109-110 oC; 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J = 8.7 Hz, 1 H),
8.07 (d, J = 8.1 Hz, 1 H), 7.98 (d, J = 7.2 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H), 7.69 (t, J
= 7.7 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.49 (t, J = 7.7 Hz, 1 H), 3.59 (s, 3 H), 3.32
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(s, 3 H); C{ H} NMR (100 MHz, CDCl3) δ 197.9, 189.9, 135.3, 134.2, 132.9,
131.5, 129.2, 129.1, 128.7, 126.9, 126.1, 124.3, 42.7, 40.8; HRMS (ESI) m/z calcd for
C14H14NOS (M + H)+ 244.0791, found 244.0786.
N,N-Dimethyl-2-oxo-2-(thiophen-3-yl)ethanethioamide (3o). Yield 63%, 25 mg;
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yellow solid; mp 71-72 C; H NMR (400 MHz, CDCl3) δ 8.19 (s, 1 H), 7.57 (d, J =
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5.1 Hz, 1 H), 7.37-7.28 (m, 1 H), 3.53 (s, 3 H), 3.24 (s, 3 H); C{ H} NMR (100
MHz, CDCl3) δ 196.5, 182.7, 138.2, 135.7, 127.6, 127.0, 42.5, 40.6; HRMS (ESI) m/z
calcd for C8H10NOS2 (M + H)+ 200.0198, found 200.0194.
N,N-Dimethyl-2-oxo-2-(thiophen-2-yl)ethanethioamide (3p).19 Yield 75%, 30 mg;
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yellow solid; mp 92-93 C; 1H NMR (CDCl3, 400 MHz) δ 7.77 (d, J = 8.0 Hz, 1 H),
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7.74 (d, J = 7.6 Hz, 1 H), 7.18-7.12 (m, 1 H), 3.52 (s, 3 H), 3.27 (s, 3 H); C{ H}
NMR (CDCl3, 100 MHz) δ 195.3, 181.6, 140.2, 135.9, 135.6, 128.5, 42.6, 40.7.
N,N-Dimethyl-2-oxo-2-(furan-2-yl)ethanethioamide (3q). Yield 63%, 23 mg;
brown liquid; 1H NMR (CDCl3, 400 MHz,) δ 7.61 (s, 1 H), 7.24 (s, 1 H), 6.52 (s, 1 H),
3.44 (s, 3 H), 3.20 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.7, 176.5, 149.8,
148.2, 121.5, 112.8, 42.4, 40.8; HRMS (ESI) m/z calcd for C8H10NO2S (M + H)+
184.0427, found 184.0424.
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N,N-Dimethyl-2-oxo-2-(pyridin-2-yl)ethanethioamide (3r). Yield 72%, 28 mg;
black solid; mp 113-114 oC; 1H NMR (CDCl3, 400 MHz) δ 8.69 (dd, J = 3.6, 1.2 Hz,
1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.91-7.89 (m, 1 H), 7.50-7.48 (m, 1 H), 3.58 (s, 3 H),
3.28 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ :197.5, 186.8, 152.1, 149.6, 137.2,
127.5, 124.0, 42.6, 40.2; HRMS (ESI) m/z calcd for C9H11N2OS (M + H)+ 195.0587,
found 195.0583.
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1-Phenyl-2-(pyrrolidin-1-yl)-2-thioxoethan-1-one (5a).18 Yield 68%, 30 mg; yellow
solid; mp 45-46 oC; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 7.5 Hz, 2 H), 7.61 (t,
J = 7.4 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 2 H), 3.96 (t, J = 6.7 Hz, 2 H), 3.55 (t, J = 6.4 Hz,
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2 H), 2.11-2.04 (m, 4 H); C{ H} NMR (100 MHz, CDCl3): 192.8, 188.8, 134.2,
132.9, 130.1, 128.8, 51.3, 51.1, 26.1, 23.9.
1-Phenyl-2-(piperidin-1-yl)-2-thioxoethan-1-one (5b).17 Yield 58%, 27 mg; brown
liquid; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.2 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1
H), 7.48 (t, J = 7.7 Hz, 2 H), 4.25 (t, J = 5.6 Hz, 2 H), 3.54 (t, J = 5.6 Hz, 2 H),
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1.86-1.74 (m, 4 H), 1.62 (s, 2 H); C{ H} NMR (100 MHz, CDCl3): 194.5, 187.9,
134.1, 133.5, 129.8, 128.8, 53.0, 48.1, 26.4, 25.3, 24.1.
2-Morpholino-1-phenyl-2-thioxoethan-1-one (5c).17 Yield 66%, 31 mg; yellow
solid; mp 109-110 oC; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 7.2 Hz, 2 H), 7.62
(t, J = 7.4 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 2 H), 4.34 (t, J = 5.0 Hz, 2 H), 3.91 (t, J = 5.0
Hz, 2 H), 3.70 (t, J = 4.8 Hz, 2 H), 3.60 (t, J = 4.8 Hz, 2 H); 13C{1H} NMR (100
MHz, CDCl3): 195.8, 187.9, 134.4, 133.3, 129.8, 128.9, 66.5, 66.4, 51.9, 47.1.
1-(4-Chlorophenyl)-2-morpholino-2-thioxoethan-1-one (5d).17 Yield 63%, 34 mg;
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yellow solid; mp 137–138 C; H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 2
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H), 7.47 (d, J = 8.4 Hz, 2 H), 4.32 (t, J = 4.8 Hz, 2 H), 3.91 (t, J = 4.8 Hz, 2 H), 3.70
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(t, J = 4.6 Hz, 2 H), 3.59 (t, J = 4.6 Hz, 2 H); C{ H} NMR (100 MHz, CDCl3):
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195.0, 186.4, 141.0, 131.8, 131.2, 129.3, 66.5, 66.4, 52.0, 47.2.
Scale-up synthesis of α-keto thioamides 3a
To a 50 mL round-bottom flask were charged with enaminone 1a (1 mmol), sulfur
powder (4 mmol), DMAP (1 mmol) and DMF (5 mL). The resulting mixture was
o
stirred at 90 C with oil bath heating for 24 hours. After cooling down to room
temperature, 15 mL of water was added, and the suspension was extracted with ethyl
acetate (3 × 15 mL). The organic phases were collected and washed with small
amount of water for three times. After drying with anhydrous Na2SO4, the solid was
filtered, and the acquired solution was employed to reduced pressure to remove the
solvent. The residue obtained therein was then subjected to flash silica gel column
chromatography to provide pure product 3a (50%, 95.8 mg) with the elution of mixed
petroleum ether/ethyl acetate (v/v = 10:1).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI:
1H and 13C NMR spectra for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
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*E-mail: wanjieping@jxnu.edu.cn.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work is financially supported by the National Natural Science Foundation of
China (21562025).
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