The thioamidation ofgem-dibromoalkenes in an aqueous medium

Article abstract of DOI:10.1039/d0ob02319a

The direct integration of sulphur and amine groups with 1,1-dibromoalkenes for thioamide synthesis has been achieved in an aqueous medium. The presented green protocol emphasizes the suitability of aqueous media for the thioamidation reaction and enables greater selectivity with synthetic utility. A wide range of thioamides in moderate to excellent yields has been achieved using readily available starting materials, with the use of no organic solvents, catalysts, or additives.

Full text of DOI:10.1039/d0ob02319a

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The thioamidation of gem-dibromoalkenes in an
aqueous medium†
Cite this: Org. Biomol. Chem., 2021,
19, 2473
a
Jigarkumar K. Vankar, a Ankush Gupta, a Jaydeepbhai P. Jadav,
a
Shankara H. Nanjegowdab and Guddeangadi N. Gururaja
*
The direct integration of sulphur and amine groups with 1,1-dibromoalkenes for thioamide synthesis has
been achieved in an aqueous medium. The presented green protocol emphasizes the suitability of
aqueous media for the thioamidation reaction and enables greater selectivity with synthetic utility. A wide
range of thioamides in moderate to excellent yields has been achieved using readily available starting
materials, with the use of no organic solvents, catalysts, or additives.
Received 20th November 2020,
Accepted 17th February 2021
DOI: 10.1039/d0ob02319a
rsc.li/obc
Thioamides with different nucleophilic and electrophilic
Introduction
centres have been widely exploited in medicinal5,7 and
The quest for the development of environmentally benign and polymer chemistry applications.5 In addition, being biologi-
sustainable reaction conditions has remained a challenging cally active, many thioamides also serve as a precursor for the
task in reaction design. In particular, the use of green solvents, synthesis of natural products and heterocyclic compounds.6,8
such as water, in organic synthesis,1 which give an enhanced Thioamide, as a substituent in peptides, was found to exhibit
reaction rate and selectivity, is appealing. Organic synthesis an enhanced bioactivity9a and has also been employed in the
without toxic and harmful solvents, reagents or catalysts is determination of the structure, stability and conformation of
highly desirable.1e Although, the advantages of the hydro- peptides and proteins.9
phobic effects2 of water makes organic reactions feasible, the
Thioamides have been synthesized using various methods,
use of it as a solvent in complex organic synthesis remains elu- including thionation of amides using Lawesson’s reagent.10
sive.1a Various green approaches towards water-mediated reac- The Willgerodt–Kindler reaction of elemental sulphur and
tions have drawn our attention to their limitations, such as the amine is reported under varying conditions, such as high
solubility of the reactants, the longer reaction time, reduced temperatures and microwave conditions.11 Although strategies
rate and the lack of expected selectivity.1e These limitations including the use of lithium alkynides,12a alkynes,11d,12b,c and
have been addressed, to a certain extent, by adopting different in situ generated terminal alkynes from 1,1-dibromoalkenes12d
strategies, such as mixing water with miscible solvents,3 the have been developed for the efficient synthesis of thioamides
use of surfactants,1f,3 application of a high temperature,4 (Scheme 1).
microwave synthesis1e and so on. As part of our efforts to
develop novel strategies for synthesis, we considered a three-
component reaction which has been proved to be efficient in
thioamide synthesis.5 Structurally diverse small molecule
thioamides, which are building blocks for synthesis,6 have
attracted our attention. We intended to perform the synthesis
of small molecules using water as a solvent, which poses a
challenge to the commonly used reaction design.
The unique properties of the thioamide moiety have
extended the scope from chemistry to materials science.5
aSchool of Chemical Sciences, Central University of Gujarat, Gandhinagar 382030,
India. E-mail: gururaja.n@cug.ac.in
bInstitution of excellence, University of Mysore, Mysuru 570 006, India
†Electronic supplementary information (ESI) available. CCDC 2056656. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ob02319a
Scheme 1 Different approaches for the synthesis of thioamides.
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However, the methods used to synthesise thioamide to date 1–5). These results prompted us to screen other parameters,
lack the direct installation of dimethylamine and necessitate such as the temperature, catalysts/additives and so on. When
the use of surrogates, such as dimethylformamide12c,d or di- the reaction was carried out at different temperatures, such as
methylammonium dimethylcarbamate.11d This may be due to 60 °C and 100 °C without organic solvents, the desired
the gaseous form or because commercially available dimethyl- product was obtained in a good yield, inferring the critical role
amine is a 40 wt% solution in water. In addition, the use of of the temperature on the reaction (Table 1, entries 8 and 9).
elemental sulphur in thioamide synthesis was not successful Then, we turned our attention to determine the role of metallic
with substrates such as 1,1-dibromoalkenes.12d Moreover, the salts and iodine as catalysts. However, significant changes in
thioamidation reaction in water media alone is a rational the yield were not observed (Table 1, entries 10–13). The opti-
design that can be used to address several green chemistry mized reaction conditions revealed that a suitable temperature
principles. We anticipate that the effective combination of alone provided the best conditions (Table 1, entry 9), and we
easily available amine in water with elemental sulphur will began additional experiments to investigate the water-
provide ideal conditions for a reaction to occur with 1,1-dibro- mediated three-component reaction.
moalkene. The development of an efficient green protocol
To explore the reaction further, different 1,1-dibromoalk-
enabling an environmentally benign and economically pleas- enes were screened using the optimized reaction conditions
ing transformation is highly desirable. Therefore, the non-reac- (Scheme 2).
tivity of elemental sulphur12d and the issues associated with
the reaction in aqueous media, such as the homogeneity, rate
and selectivity can be addressed.1e Herein, we report our
efforts on the efficient three-component synthesis of thio-
amides in aqueous media.
Results and discussion
To evaluate the feasibility of the three-component thioamide
synthesis we examined the reaction of 1,1-dibromoalkene 1a
with a solution of dimethylamine 2a in water and elemental
sulphur in different solvents (Table 1).
The initial results with varying solvents were encouraging,
as the positive change can be observed even though the reac-
tions rate was observed to be rather sluggish (Table 1, entries
Table 1 Optimization of reaction condition for the reaction between
1,1-dibromoalkene, elemental sulphur and dimethylaminea
Solvent
(mL)
Catalyst/
additive
Temp
(°C)
Time
(h)
Yield
(%)
Entry
1.
2.
3.
4.
5.
6.
7.
8.
THF
THF
THF
MeOH
CH3CN
DCM
Toluene
—
—
—
—
—
—
—
—
—
—
—
—
—
Rt
60
24
24
24
24
24
24
24
24
24
24
24
24
24
Trace
10
23
08
30
—
—
43
74
100
100
100
100
100
60
100
100
100
100
100
9.
—
10.
11.
12.
13.
SnCl2
CuBr
AgNO3
I2
40
Trace
23
—
Trace
Scheme 2 The substrate scope of the thioamidation reaction a.
a 1 (0.5 mmol), S8 (5 mmol), Me2NH (40 wt% in H2O): 5 mL. b side
product α-ketothioamide 4ka, 4ma were also isolated, c mixture of pro-
ducts could not be separated, d the reaction carried out at 60 °C.
a Reaction conditions: 1a (0.5 mmol), S8 (5 mmol), Me2NH (40 wt% in
H2O): 2 mL with 3 mL of added solvent, or 5 mL in all other cases,
catalyst/additive (10 mol%).
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1,1-Dibromoalkene containing different functional groups
was proved to be tolerated under the optimized conditions
(Table 1, entry 9). The substrate, with varying electronic
effects, afforded the desired product in a reasonably good
yield. 1,1-Dibromoalkene with the electron-withdrawing group
was proven to be a good candidate for a three-component reac-
tion and the corresponding thioamides, 3aa–3ia, were
obtained in a good to excellent yield. Moreover, a substrate
with a nitro functionality offered the desired product in an
optimal period of less than 1 h. It is interesting to note that
the nitro group that is reported to be reduced by elemental
sulphur under basic conditions13 is unaffected under these
conditions. Nevertheless, the substrate containing electron-
donating group also afforded products 3ma–3oa in good to
excellent yields within a reasonable time. Substrates with a
p-methoxy group also afforded the product 3la, which could
not be separated using the purification procedures.
Heteroaromatic substrates also reacted under a similar pro-
cedure to give the product 3pa. All the thioamides synthesized
were characterized using the spectral data and one of the
representative compounds 3oa was analysed using a single-
crystal X-ray measurement (Fig. 1). Interestingly, among the
substrates screened, the α-ketothioamides14 4ka and 4ma were
also isolated in lower yields as a side product, along with 3ka
and 3ma. The α-ketothioamide products are usually observed
in the Willgerodt–Kindler synthesis of thioamide using alkyl
and aryl ketones owing to the failure to reduce the carbonyl
group.11e,15,16,19
Scheme 3 The reaction of 1,1-dibromoalkene, elemental sulphur and
amine a. a 1o (0.5 mmol), S8 (5 mmol), aliphatic/aromatic amine (40 wt%
in H2O): 5 mL, b no reaction.
To extend the scope and limitations of the water-mediated
thioamidation reactions, different aliphatic and aromatic
amines were considered (Scheme 3). Initially, the aliphatic aniline 2i, N-ethyl aniline 2j and diphenylamine 2k were
primary amines, such as n-propylamine 2b, n-butylamine 2c, found to be unreactive owing to their immiscibility with the
cyclohexylamine 2d, and aliphatic secondary amines, such as aqueous media under these conditions after prolonged
diethylamine 2e, morpholine 2f and pyrrolidine 2g, were heating for 30 h.
reacted with the model substrate 1o. It is worth mentioning
Next, we turned our attention to explore the role of water on
that the aliphatic secondary amines were found to be more the thioamidation reaction. As observed from our earlier
compatible with the aqueous media with thioamide selecti- experiments, the presence of another solvent with water
vity. The desired thioamides, 3oe–g, were isolated in good to affected the rate and yield of the thioamidation reaction
excellent yields under these conditions. To our surprise, (Table 1). To establish the role of water alone on the rate and
although aliphatic primary amines are reactive under estab- yield, other additional experiments were performed (Table 2).
lished conditions, the reaction is not straightforward with The reaction of 1,1-dibromoalkene 1a with elemental sulphur
regards to yield and selectivity as complex side products are and dimethylamine 2a in a solvent, such as THF, was per-
formed along with the desired thioamide 3ob–d. formed instead of water. After prolonged heating for 24 h, no
Furthermore, different aromatic amines were tested with a significant changes were observed. Furthermore, the reaction
model substrate 1o under similar conditions. However, mixture was non-homogeneous under these conditions.
amines such as aniline 2h, N-substituted amines; N-methyl Hence, we imagined that water plays a significant role in the
thioamidation reaction.
Furthermore, aromatic amines such as N-methyl aniline 2i
and diphenylamine 2k which are soluble in tetrahydrofuran
were treated with 1a under similar conditions. After, prolonged
heating for several hours no significant changes were
observed. Additionally, these aromatic amines were dissolved
in tetrahydrofuran and mixed with an appropriate proportion
of water and reacted with 1a under established conditions.
However, no considerable changes were observed as the
Fig. 1 The single-crystal X-ray structure (CCDC 2056656, ESI†) of 3oa.
mixture was non-homogeneous at the various monitored temp-
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Table 2 The implications of the use of a water medium in thioamide
synthesisa
R
2
R′, R″
Solvent
3
Yield (%)
23b
1.
2.
3.
4.
5.
6.
2a
2a
2i
2k
2i
Me, Me
Me, Me
Me, Ph
Ph, Ph
Me, Ph
Ph, Ph
H2O/THF
THF
THF
THF
H2O/THF
H2O/THF
3aa
3aa
3ai
3ak
3ai
c
—
c
—
c
—
c
—
c
2k
3ak
—
a Reaction conditions: 1a (0.5 mmol), S8 (5 mmol), amine (40 wt% in
solvent), H2O/THF (1 : 1). b Table 1, entry 3. c No reaction.
Scheme 5 Plausible mechanism of thioamidation in an aqueous
medium.
eratures. Based on these experiments, we can conclude that
the miscibility and homogeneity of the amine in water are
essential for thioamidation reactions.
To explore further, control experiments were performed to
establish the mechanism of the thioamidation reactions
(Scheme 4).
Me2NH 2a in water with 1,1-dibromoalkene 1a and elemen-
tal sulphur with 1,1-dibromoalkene 1a were reacted separately
at 100 °C. As expected, no changes were observed. However,
when Me2NH 2a in water and sulphur were reacted, the detect-
able colour change observed indicated the reaction of a
nucleophilic amine with sulphur to form polysulphide 5,12b,20
followed by the addition of 1,1-dibromoalkene 1a to polysul-
phide 5 to give the desired thioamide 3aa (see ESI†).
Based on the above described experiment, we proposed an
additional elimination sequence during the reaction; the
sequential addition of polysulphide 5 and dimethylamine to
1,1-dibromoalkene 1 to form the desired intermediate 9. The
presence of water is essential as product 3 is formed by proto-
nation of the intermediate 11. During substrate screening, in a
few cases α-ketothioamide 4 is also formed as a side product
with the desired thioamide 3. We envisioned that water may
act as
a weak nucleophile to give the side product
α-ketothioamide 4. It may be concluded that the rate of proto-
nation may be faster than the nucleophilic attack by water,
hence in most of the cases, thioamide 3 is formed as a major
product compared to α-ketothioamide 4 (Scheme 5).
After studying the scope and limitations of the thioamida-
tion reaction in water, we intended to demonstrate the syn-
thetic utility of the thioamidation reaction. A rection employ-
ing 2.84 mmol of 1,1-dibromoalkene 1o was performed under
similar conditions with a stoichiometric quantity of dimethyl-
amine 2a and the product thioamide 3oa was obtained in an
81% yield (see ESI†).
Conclusions
We have successfully demonstrated the design of a water-
based reaction for the synthesis of structurally diverse thio-
amides. This methodology provides access to different thio-
amides, which could be synthesized without any hazardous
organic solvents, metal catalysts, or additives. The compatibil-
ity with an aqueous medium has been proven to be the driving
force for different aliphatic amines in the thioamidation reac-
tion. The dissolved amine in the water plays a crucial role in
bringing together the reactants in the medium to form the
desired product. Hence, the scope and limitations of water-
based thioamidation reactions were also addressed in relation
to the rate and selectivity. Although two products could be
expected using this mechanism, the water-based reaction
shows greater selectivity towards the thioamide. These thio-
amides will find potential applications in the synthesis of
heterocyclic compounds that are of medicinal importance.
Scheme 4 Control experiments to assign tentative mechanism for
thioamidation reaction.
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1596 (s), 1508 (s), 1371 (w), 1284 (w), 1106 (s), 816 (s), 497 (m);
1H NMR (500 MHz, CDCl3) δ 3.15 (s, 3H), 3.43 (s, 3H), 4.20 (s,
2H), 6.95 (t, J = 7.9 Hz, 2H), 7.23 (t, J = 6.0 Hz, 2H); 13C NMR
Experimental section
General information
The melting points recorded are uncorrected. The IR spectra (125 MHz, CDCl3) δ 41.2, 43.8, 48.8, 114.6 (d, JC–F = 21.2 Hz),
were recorded using a PerkinElmer Spectrum Version 10.4.2. 128.6 (d, JC–F = 8.7 Hz), 130.3 (d, JC–F = 3.8 Hz), 160.8 (d, JC–F
=
The NMR spectra were recorded with TMS as the internal stan- 243.7 Hz), 199.4; 19F NMR (476 MHz, CDCl3) δ −115.6;
dard using a Bruker NMR AV500 MHz instrument. The coup- HRMS-ESI (+) m/z: calculated for C10H12FNS [M + H]+,
ling constants, J values, are given in Hz. The high-resolution 198.0747; found 198.0747.
mass spectra were recorded using a Waters Synept G2 high
2-(2-Fluorophenyl)-N,N-dimethylethanethioamide
(3ea).17
detection mass spectrometry under electrospray ionization Red liquid: yield 54 mg, 56%; IR, (cm−1) 2926 (s), 2853 (w),
quadrupole time-of-flight (ESI Q-TOF) conditions. Single 1645 (s), 1488 (s), 1394 (m), 1230 (m), 1157 (m), 1049 (w),
1
crystal X-ray diffractometry (X-RD) data were collected on a 755 (s); H NMR (500 MHz, CDCl3) δ 3.16 (s, 3H), 3.43 (s, 3H),
Rigaku XtaLAB mini-CCD diffractometer and software for 4.17 (s, 2H), 6.96 (t, J = 9.0 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H),
refinement is SHELXS and SHELXL. 1,1-Dibromoalkene was 7.16 (dd, J = 13.0, 7.0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H); 13C NMR
prepared using the literature procedure.21 All other reagents (125 MHz, CDCl3) δ 41.1 (d, JC–F = 2.5 Hz), 41.6 (d, JC–F
=
and sulphur were purchased from commercial suppliers and 2.5 Hz), 43.8, 114.2 (d, JC–F = 21.3 Hz), 122.0 (d, JC–F = 15.0 Hz),
were used without any further purifications.
123.4 (d, JC–F = 3.8 Hz), 127.7 (d, JC–F = 8.7 Hz), 128.7 (d, JC–F =
3.0 Hz), 158.9 (d, JC–F = 243.7 Hz), 198.6; 19F NMR (476 MHz,
CDCl3) δ −118.0; HRMS-ESI (+) m/z: calculated for C10H12FNS
General procedure for the synthesis of thioamides
To a stirred solution of 1 (0.5 mmol, 1.0 equiv.), in 5 mL of [M + H]+, 198.0747; found 198.0749.
amine 2 (40 wt% in H2O), elemental sulphur (5 mmol, 10
N,N-Dimethyl-2-(4-nitrophenyl) ethanethioamide (3fa).12d
equiv.) was added. The reaction mixture was refluxed at 100 °C Yellow solid: yield 75 mg, 67%; mp 118–120 °C; IR, (cm−1
)
until completion of the reaction. After completion of the reac- 2919 (m), 1595 (m), 1509 (s), 1345 (s), 1262 (w), 1103 (s), 972
tion as determined by thin layer chromatography (TLC), (w), 826 (s), 727 (s), 662 (w), 502 (w); 1H NMR (500 MHz,
the reaction mixture was cooled to room temperature. CDCl3) δ 3.28 (s, 3H), 3.53 (s, 3H), 4.38 (s, 2H), 7.52 (d, J = 7.9
Subsequently, it was quenched with saturated NaHCO3, Hz, 2H), 8.17 (d, J = 7.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
diluted with water, and extracted using chloroform. The com- 42.3, 44.8, 49.8, 123.8, 129.4, 143.6, 146.8, 198.6; HRMS-ESI (+)
bined organic phase was evaporated under reduced pressure. m/z: calculated for C10H12N2O2S [M + H]+ 225.0692, found
The resulting crude product was subjected to silica gel column 225.0699.
chromatography with an ethyl acetate/hexane gradient elution
N,N-Dimethyl-2-(2-nitrophenyl) ethanethioamide (3ga).
Yellow solid: yield 98 mg, 89%; mp 88–90 °C; IR, (cm−1) 2923
to isolate the product 3.
2-(4-Chlorophenyl)-N,N-dimethylethanethioamide (3aa).12d,17 (s), 2852 (w), 1510 (s), 1337 (s), 1262 (s), 1200 (w), 1104 (w), 792
Yellow solid: yield 78 mg, 74%; mp 85–88 °C; IR, (cm−1) 2926 (w), 701 (w); H NMR (500 MHz, CDCl3) δ 3.33 (s, 3H), 3.48 (s,
1
(w), 1662 (s), 1391 (s), 1283 (w), 1090 (s), 739 (w); 1H NMR 3H), 4.38 (s, 2H), 7.33 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz,
(500 MHz, CDCl3) δ 3.13 (s, 3H), 3.42 (s, 3H), 4.19 (s, 2H), 1H) 7.54 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H); 13C NMR
7.19–7.24 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 42.3, 44.8, (125 MHz, CDCl3) δ 41.0, 43.8, 45.4, 124.1, 127.1, 131.6, 131.9,
50.0, 128.9, 129.5, 132.8, 134.1, 200.0; HRMS-ESI (+) m/z: calcu- 132.5, 147.3, 198.1; HRMS-ESI (+) m/z: calculated for
lated for C10H12ClNS [M + H]+ 214.0452, found 214.0451.
C10H12N2O2S [M + H]+ 2251.0692, found 225.0693.
2-(3-Chlorophenyl)-N,N-dimethylethanethioamide (3ba).
N,N-Dimethyl-2-(3-nitrophenyl) ethanethioamide (3ha).
Colourless solid: yield 63 mg, 56%; mp 68–70 °C; IR, (cm−1
)
Yellow solid: yield 93 mg, 83%; mp 98–100 °C; IR, (cm−1) 2925
1
2920 (s), 1520 (s), 1392 (s),1281 (w), 1107 (m), 778 (m), 682 (w); (w), 1514 (s), 1335 (s), 1270 (m), 1099 (m), 804 (w), 695 (m); H
1H NMR (500 MHz, CDCl3) δ 3.14 (s, 3H), 3.44 (s, 3H), 4.21 (s, NMR (500 MHz, CDCl3) δ 3.22 (s, 3H), 3.46 (s, 3H), 4.28 (s,
2H), 7.13–7.19 (m, 2H), 7.19–7.22 (m, 1H), 7.26 (s, 1H); 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 8.05 (d, J =
13C NMR (125 MHz, CDCl3) δ 41.3, 43.8, 49.1, 125.3, 126.1, 7.9 Hz, 1H), 8.09 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 41.3,
127.1, 129.0, 133.4, 136.6, 198.4; HRMS-ESI (+) m/z: calculated 43.8, 48.5, 121.1, 122.4, 128.6, 133.7, 137.0, 147.3, 197.9;
for C10H12ClNS [M + H]+ 214.0452, found 214.0450.
HRMS-ESI (+) m/z: calculated for C10H12N2O2S [M + H]+
2-(4-Bromophenyl)-N,N-dimethylethanethioamide (3ca).12d,17 225.0692, found 225.0697.
Red solid: yield 102.5 mg, 80%; mp 55 °C; IR, (cm−1) 2922 (s),
2-([1,1′-Biphenyl]-4-yl)-N,N-dimethylethanethioamide (3ia).12d
2360 (m), 1744 (m), 1461 (m), 1261 (m), 1023 (m), 802 (m); Colourless solid: yield 87.9 mg, 70%; mp 98–100 °C; IR, (cm−1
)
1H NMR (500 MHz, CDCl3) δ 3.13 (s, 3H), 3.42 (s, 3H), 4.17 (s, 2921 (s), 2852 (s), 1463 (w), 1260 (w), 1084 (s), 1008 (w), 846
2H), 7.15 (d, J = 10.0 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H); 13C NMR (w), 742 (s), 691 (s), 504 (m); H NMR (500 MHz, CDCl3) δ 3.17
1
(125 MHz, CDCl3) δ 41.2, 43.8, 49.0, 119.8, 128.9, 130.8, 133.6, (s, 3H), 3.45 (s, 3H), 4.28 (s, 2H), 7.26 (t, J = 7.3 Hz, 1H),
198.8; HRMS-ESI (+) m/z: calculated for C10H12BrNS [M + H]+ 7.31–7.39 (m, 4H), 7.46–7.52 (m, 4H); 13C NMR (125 MHz,
257.9947; found 257.9946.
CDCl3) δ 41.3, 43.8, 49.4, 125.9, 126.2, 126.4, 127.5, 127.7,
2-(4-Fluorophenyl)-N,N-dimethylethanethioamide (3da).12d 133.6, 138.8, 139.5, 199.4; HRMS-ESI (+) m/z: calculated for
Red solid: yield 73 mg, 74%; mp 75–78 °C; IR, (cm−1) 2923 (w), C16H17NS [M + H]+, 256.1154; found 256.1156.
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2-(6-Bromobenzo[d] [1,3] dioxol-5-yl)-N,N-dimethyl ethane- 1589 (s), 1418 (m), 1328 (m), 1236 (s), 1001 (m), 738 (w); 1H
thiolamide (3ja). Colourless solid: yield 103.8 mg, 70%; mp NMR (500 MHz, CDCl3) δ 0.81 (t, J = 7.2 Hz, 3H), 1.53 (q, J =
106 °C; IR, (cm−1) 2922 (s), 2853 (w), 1477 (s), 1391 (w), 1237 7.2 Hz, 2H), 3.52 (dd, J = 12.4, 6.3 Hz, 2H), 3.78 (s, 9H), 4.00 (s,
(s), 1105 (s), 1034 (s), 928 (m), 853 (w); 1H NMR (500 MHz, 2H), 6.39 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 10.3, 20.1, 46.7,
CDCl3) δ 3.13 (s, 3H), 3.45 (s, 3H), 4.15 (s, 2H), 5.91(s, 2H), 52.4, 55.1, 59.9, 105.3, 129.2, 136.9, 152.3, 200.5; HRMS-ESI (+)
6.86 (s, 1H), 6.94 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 42.2, m/z: calculated for C14H21NO3S [M + H]+ 284.1315, found
44.8, 50.2, 101.8, 109.2, 112.6, 114.5, 128.5, 147.4, 147.7, 200.0; 284.1320.
HRMS-ESI (+) m/z: calculated for C10H13BrNO2S [M + H]+
n-Butyl-2-(3,4,5-trimethoxyphenyl) ethanethioamide (3oc).
301.9845, found 301.9804.
Red liquid: yield 110 mg, 39%; IR, (cm−1) 2929 (w), 1590 (s),
N,N-Dimethyl-2-phenylethanethioamide (3ka).18 Colourless 1419 (m), 1329 (m), 1236 (s), 1118 (s), 1003 (s), 735 (w), 688
solid: yield 58 mg, 45%; mp 72–75 °C; IR, (cm−1) 2926 (w), (w); H NMR (500 MHz, CDCl3) δ 0.82 (t, J = 7.2 Hz, 3H), 1.22
1
1521 (w) 1392 (s) 1098(s) 852(s) 711(s); 1H NMR (500 MHz, (m, 2H), 1.47 (m, 2H), 3.55 (dd, J = 12.4, 6.3 Hz, 2H), 3.77 (s,
CDCl3) δ 3.13 (s, 3H), 3.43 (s, 3H), 4.25 (s, 2H), 7.16–7.19 (m, 9H), 3.99 (s, 2H), 6.39 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
1H), 7.23–7.27 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 41.2, 13.6, 20.0, 29.7, 45.8, 53.3, 56.1, 60.8, 106.4, 130.1, 137.4,
43.8, 49.9, 125.9, 127.0, 127.7, 134.5, 199.5; HRMS-ESI (+) m/z: 153.7, 201.3; HRMS-ESI (+) m/z: calculated for C15H23NO3S [M
calculated for C10H13NS [M + H]+ 180.0841, found 180.0843.
+ H]+ 298.1471, found 298.1477.
2-(3,4-Dimethoxyphenyl)-N,N-dimethylethanethioamide (3ma).
n-Cyclohexyl-2-(3,4,5-trimethoxyphenyl)ethanethioamide
Orange solid: yield 54 mg, 46%; mp 98–100 °C; IR, (cm−1); (3od). Yellow solid: yield 84 mg, 30%; mp 105–108 °C; IR,
2919 (s), 2364 (s), 2337 (s), 1743 (w), 1589 (w), 1442 (w), (cm−1) 2923 (s), 2360 (s), 1584 (m), 1418 (m), 1257 (s), 1022 (s),
1
1261 (s), 1010 (s), 798 (s); H NMR (500 MHz, CDCl3) δ 3.16 (s, 801 (s), 690 (w); 1H NMR (500 MHz, CDCl3) δ 1.00–1.10 (m,
3H), 3.43 (s, 3H), 3.80 (s, 6H), 4.18 (s, 2H), 6.74 (s, 2H), 6.93 (s, 3H), 1.28–1.34 (m, 2H), 1.52–1.60 (m, 3H), 1.85–1.93 (m, 2H),
1H); 13C NMR (125 MHz, CDCl3) δ 41.1, 43.8, 49.4, 54.8, 54.8, 3.77 (s, 9H), 3.97 (s, 2H), 4.28–4.36 (m, 1H), 6.38 (s, 2H); 13C
110.0, 110.1, 119.1, 126.9, 146.8, 148.0, 199.8; HRMS-ESI (+) NMR (125 MHz, CDCl3) δ 23.4, 24.3, 28.7, 30.0, 52.4, 53.0, 55.1,
m/z: calculated for C12H17NO2S [M + H]+ 240.1053, found 59.8, 105.1, 129.4, 136.9, 152.6, 198.7; HRMS-ESI (+) m/z: calcu-
240.1059.
lated for C17H25NO3S [M + H]+ 324.1628, found 324.1634.
2-(2,5-Dimethoxyphenyl)-N,N-dimethylethanethioamide
N,N-Diethyl-2-(3,4,5-trimethoxyphenyl)ethanethioamide
(3na).12d Orange solid: yield 111 mg, 93%; mp 96–99 °C; IR, (3oe). Yellow solid: yield 91 mg, 60%; mp 62–65 °C; IR, (cm−1
)
(cm−1); 2923 (s), 2854 (s), 2360 (s), 1743 (m), 1461 (w) 1261 2924 (s), 2360 (m), 1743 (w), 1588 (w), 1462 (w), 1264 (s), 1020
1
1
(m), 1022 (m), 798 (m); H NMR (500 MHz, CDCl3) δ 3.18 (s, (m), 803 (s); H NMR (500 MHz, CDCl3) δ 1.10 (t, J = 6.7 Hz,
3H), 3.50 (s, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 4.23 (s, 2H), 6.73– 3H), 1.22 (t, J = 6.7 Hz, 3H), 3.41 (q, J = 6.7 Hz, 2H), 3.77 (s,
6.82 (m, 2H), 7.00 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 42.1, 9H), 3.94 (q, J = 6.7 Hz, 2H), 4.16 (s, 2H), 6.49 (s, 2H); 13C NMR
44.0, 44.7, 55.7, 56.0, 111.2, 112.4, 114.8, 125.3, 150.4, 153.7, (125 MHz, CDCl3) δ 10.7, 13.3, 46.5, 47.6, 50.5, 56.1, 60.9,
201.2; HRMS-ESI (+) m/z: calculated for C12H17NO2S [M + H]+ 104.5, 131.8, 136.6, 153.4, 198.5; HRMS-ESI (+) m/z: calculated
240.1053 found 240.1058.
for C17H25NO3S [M + H]+ 324.1628, found 324.1634.
N,N-Dimethyl-2-(3,4,5-trimethoxyphenyl)ethanethioamide
1-Morpholino-2-(3,4,5-trimethoxyphenyl)ethanethione (3of).
(3oa). Colourless solid: yield 130 mg, 95%; mp 78–80 °C; IR, Colourless solid: yield 138 mg, 90%; mp 80–82 °C; IR, (cm−1
)
(cm−1) 2940 (w), 1585 (s), 1504 (s), 1323 (m), 1232 (s), 1120 (s), 2929 (w), 1589 (s), 1506 (s), 1431 (m), 1318 (w), 1224 (s), 1126
1008 (m), 824 (w); 1H NMR (500 MHz, CDCl3) δ 3.17 (s, 3H), (s), 1003(s), 802 (s), 658 (w), 570 (w); 1H NMR (500 MHz,
3.43 (s, 3H), 3.76 (s, 3H), 3.77 (s, 6H), 4.17 (s, 2H), 6.52 (s, 2H); CDCl3) δ 3.38–3.41 (m, 2H), 3.57–3.61 (m, 2H), 3.67–3.70 (m,
13C NMR (125 MHz, CDCl3) δ 41.3, 43.8, 50.0, 55.1, 59.8, 103.9, 2H), 3.76 (s, 3H), 3.78 (s, 6H), 4.22 (s, 2H), 4.28–4.31 (m, 2H),
130.1, 135.7, 152.3, 199.2; HRMS-ESI (+) m/z: calculated for 6.48 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 49.2, 49.6, 49.7,
C13H19NO3S [M + H]+ 270.1158, found 270.1156. Selected X-ray 55.1, 59.9, 65.1, 65.3, 103.5, 130.2, 136.0, 152.4, 198.5;
data (CCDC 2056656†) C13H19NO3S, space group P21/c, a = HRMS-ESI (+) m/z: calculated for C15H21NO4S [M + H]+
14.183(18), b = 7.331(9), c = 14.82(2), α = 90, β = 111.951 (11), 312.1264, found 312.1266.
γ = 90, Dx = 1.252 g cm−3, Z = 4, F (000) = 576.0, λ = 0.71075,
1-(Pyrrolidin-1-yl)-2-(3,4,5-trimethoxyphenyl)ethanethione
theta(max)
wR2(reflections) = 0.1974(3270).
=
27.569, R(reflections)
=
0.0679(2215) (3og). Colourless solid: yield 81.4 mg, 55%; mp 75–78 °C; IR,
(cm−1) 2924 (s), 2360 (m), 1455 (s), 1115 (s), 793 (w), 605 (w);
2-(Furan-3-yl)-N,N-dimethylethanethioamide (3pa).12d Red 1H NMR (500 MHz, CDCl3) δ 1.85–1.98 (m, 4H), 3.45–3.51 (m,
liquid: yield 43 mg, 52%; IR, (cm−1) 2925 (m), 2360 (w), 1513 (s), 2H), 3.76 (s, 3H), 3.78 (s, 6H), 3.79–3.82 (m, 2H), 4.06(s, 2H),
1390 (s), 1271 (m), 1095 (s), 1009 (s), 731 (s); 1H NMR (500 MHz, 6.55 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 23.3, 25.5, 49.9,
CDCl3) δ 3.29 (s, 3H), 3.43 (s, 3H), 4.22 (s, 2H), 6.16 (s, 1H), 6.27 50.4, 53.2, 55.1, 59.8, 104.3, 129.9, 135.7, 152.2, 195.6;
(s, 1H), 7.28 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 42.4, 43.8, HRMS-ESI (+) m/z: calculated for C15H21NO3S [M + H]+
44.9, 107.4, 110.6, 141.8, 149.8, 197.9; HRMS-ESI (+) m/z: calcu- 296.1315, found 296.1314.
lated for C8H11NOS [M + H]+ 170.0634, found 170.0636.
n-Propyl-2-(3,4,5-trimethoxyphenyl) ethanethioamide (3ob). Colourless solid: yield 19.2 mg, 20%; mp 75–78 °C; IR, (cm−1
Red liquid: yield 71 mg, 35%; IR, (cm−1) 2928(w), 2360 (w), 2921 (s), 2852 (m), 1663 (s), 1537 (m), 1404 (m), 1236 (m), 1115
N,N-Dimethyl-2-oxo-2-phenylethanethioamide (4ka).19
)
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(s), 1098 (m), 947 (s), 845 (s), 793 (s), 700 (m), 544 (w); 1H NMR
(500 MHz, CDCl3) δ 3.23 (s, 3H), 3.56 (s, 3H), 7.48 (t, J = 7.3 Hz,
2H), 7.60 (t, J = 7.3 Hz, 1H), 7.98 (d, J = 7.7 Hz 2H); 13C NMR
(125 MHz, CDCl3) δ 40.4, 42.4, 128.8, 129.8, 133.1, 134.2,
188.4, 196.7; HRMS-ESI (+) m/z: calculated for C10H11NOS [M +
H]+ 194.0634, found 194.0634.
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2-(3,4-Dimethoxyphenyl)-N,N-dimethyl-2-xoethanethio-amide
(4ma). Red yellow solid: yield 20.1 mg, 16%; mp 160 °C; IR,
1
(cm−1) 2921 (s), 1460 (w), 1260 (s), 1014 (s), 796 (s); H NMR
(500 MHz, CDCl3) δ 3.17 (s, 3H), 3.49 (s, 3H), 3.88 (s, 3H), 3.89
(s, 3H), 6.82 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.53 (s,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors thank the Science and Engineering Research
Board (SERB), Government of India for the core-research grant
(SERB-EMR/2017/001531) and CSIR New Delhi, India, for
CSIR grant CSIR-EMR-II No. 02(0315)/17/EMR-II. JKV thanks
DST-SERB for the project fellowship, AG thanks CSIR for SRF
and JPJ thanks CUG Gandhinagar for the fellowship. The
authors thank CIF, CUG for analytical support.
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