Synthesis of α-ketothioamides via willgerodt-kindler reaction of arylglyoxals with amines and sulfur under solvent-free conditions

Article abstract of DOI:10.1055/s-0032-1316897

Willgerodt-Kindler reaction of arylglyoxal hydrates with secondary amines and elemental sulfur under solvent-free conditions at 80 °C is developed, in which α-ketothioamides are obtained in 70-90% yield in 0.6-1 hour. The X-ray crystal-structure analysis for one compound was obtained. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1316897

LETTER
▌977
lSetyternthesis of α-Ketothioamides via Willgerodt–Kindler Reaction of Aryl-
glyoxals with Amines and Sulfur under Solvent-Free Conditions
α-Ketothioamides via Willgerodt–Kindler Reaction
Bagher Eftekhari-Sis,*a Saleh Vahdati Khajeh,a Orhan Büyükgüngörb
a
Department of Chemistry, University of Maragheh, Golshar, P. O. Box. 55181-83111, Maragheh, Iran
Fax +98(421)2276066; E-mail: eftekharisis@maragheh.ac.ir; E-mail: eftekhari.sis@gmail.com
b
Ondokuz Mayis University, Department of Physics, 55139, Samsun, Turkey
Received: 22.01.2013; Accepted after revision: 17.03.2013
also isolated in 0–42% yield. A number of limited differ-
ent approaches for the synthesis of α-ketothioamides has
been developed,24 but these have disadvantages such as
limited scope, expensive reagents or catalysts, and need
for harsh reaction conditions. Recently, the copper-cata-
lyzed aerobic oxidation of arylglyoxals in the presence of
amines to produce α-ketoamides 4 was reported.25 Herein
we report a green and efficient route to synthesize the cor-
responding α-ketothioamides 3 in good to high yields in
the absence of catalyst (Scheme 1).
Abstract: Willgerodt–Kindler reaction of arylglyoxal hydrates
with secondary amines and elemental sulfur under solvent-free con-
ditions at 80 °C is developed, in which α-ketothioamides are ob-
tained in 70–90% yield in 0.6–1 hour. The X-ray crystal-structure
analysis for one compound was obtained.
Key words: α-ketothioamides, Willgerodt–Kindler reaction, aryl-
glyoxals, green chemistry, solvent-free
The thioamides moiety is incorporated in the structure of
many natural and unnatural products, such as closthio-
amide,1 with a wide range of biological properties, such as
pesticidal,2 fungicidal,3 insecticidal,4 antioxidant,5 antitu-
bercular,6 and anthelmintic activity.7 Thioamides have
also been widely used as building blocks in organic syn-
thesis,8 especially for the synthesis of heterocycles.9 Fur-
thermore, thioamides have a wide range of applications in
the fields of peptide chemistry,10 polymers,11 and organo-
catalysis.12 Numerous methods are available in the litera-
ture for the preparation of thioamides, including
thionation of amides using P4S10,13 (Me3Si)2S,14
PSCl3/H2O/Et3N,15 S8/Cl3SiH/amine,16 ammonium phos-
phorodithioate,17 and Lawesson’s reagent,18 and Friedel–
Crafts reaction of aromatic compounds with KSCN in
MeSO3H.19 The Willgerodt–Kindler reaction is extensive-
ly used to synthesize various thioamides,20,5a but suffers
from disadvantages, such as long reaction times, low
yields, and need for high reaction temperatures and toxic
organic solvents.
Our recent review article on arylglyoxal chemistry21 re-
vealed that there is no report of the Willgerodt–Kindler re-
action of arylglyoxals and this encouraged us to
investigate the Willgerodt–Kindler reaction of arylglyox-
al hydrates 1 with amines 2 and elemental sulfur to afford
α-ketothioamides 3. However, in previously reported
Willgerodt–Kindler reactions of aryl methyl ketones, the
corresponding α-ketothioamides were isolated as byprod-
ucts in very low yields.22 Recently, Penieres-Carrillo et
al.23 reported the modified Willgerodt–Kindler reaction
under uncatalyzed solvent-free conditions using IR ener-
gy to produce α-ketothioamides in 12–67% yield, in
which the corresponding aryl methyl thioamides were
O
R
N
R2NH (2)
Ar
R
O
[Cu], air
O
4
OH
OH
Ar
O
R
R2NH (2), S8
N
Ar
R
80 °C, 0.6–1 h
1
S
3
Scheme 1 Willgerodt–Kindler reaction of arylglyoxal hydrates 1
with secondary amines 2
For optimization of reaction conditions, we conducted the
Willgerodt–Kindler reaction of phenylglyoxal hydrate,
piperidine 2b, and sulfur under different conditions. To
maximize environmental acceptability, we carried out the
reaction in water at different temperatures. At room tem-
perature, the reaction time was long (over 24 h), and con-
sequently 80 °C was chosen as the optimum temperature,
which afforded the corresponding α-ketothioamide 3h in
61% yield within one hour. Additionally, we found that a
1:2:2 ratio of phenylglyoxal/piperidine/sulfur was optimal
for the generation of 3h. In addition to the desired keto-
thioamide 3h, the corresponding α-ketoamide 4 was ob-
tained in low yield, which presumably results from
hydrolysis of 3h under the reaction conditions. To over-
come this problem, we carried the similar reaction under
solvent-free conditions at 80 °C to afford 3h in 85% yield,
without formation of the corresponding α-ketoamide 4.
The scope of the reaction was investigated using different
arylglyoxal hydrates 1 (prepared by oxidation of aceto-
phenones using SeO2 in refluxing dioxane in the presence
of water according to Riely et al.26) and different second-
ary amines 2 under solvent-free conditions at 80 °C. The
results are summarized in Table 1.
SYNLETT 2013, 24, 0977–0980
Advanced online publication: 05.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316897; Art ID: ST-2013-D0070-L
© Georg Thieme Verlag Stuttgart · New York

978
B. Eftekhari-Sis et al.
LETTER
As shown in Table 1, arylglyoxals with electron-with- bond angles, and torsion angles of 3h see Supporting In-
drawing groups, such as chloro and bromo, and with elec- formation.
tron-donating substituents, such as methoxy, reacted well
but in the case of 4-nitrophenylglyoxal the Willgerodt–
Kindler reaction did not occur (Table 1, entries 15 and 22)
and polymeric material was produced. This can be attrib-
uted to the reduction of the nitro group to an amine in the
presence of elemental sulfur followed by the reaction with
the carbonyl group of another arylglyoxal molecule. Het-
erocyclic amines 2a–c worked well in the Willgerodt–
Kindler reaction with arylglyoxals. However, reaction
with secondary acyclic amines, such as diethylamine 2d,
led to a complex mixture of products. In the early stages
of the reaction with diethylamine the corresponding α-ke-
tothioamides could be identified using TLC, but these
were then consumed under the reaction conditions. This
can be attributed to low nucleophilicity and steric hin-
drance of the alkyl residue in diethylamine.
Figure 1 ORTEP representation of the crystal structure of 3h (35%
ellipsoid probability)
Table 1 Willgerodt–Kindler Reaction of Arylglyoxal Hydrates un-
der Solvent-Free Conditionsa
A plausible mechanism for the Willgerodt–Kindler reac-
tion of phenylglyoxal with piperidine 2b and elemental
sulfur is shown in Scheme 2. Firstly, iminium salt 5 is pro-
duced by condensation of phenylglyoxal hydrate with 2b.
Subsequent nucleophilic addition of 2b to sulfur, followed
by elimination of S7, piperidinium sulfide leads to 6. Inter-
mediate 7 is then produced by nucleophilic addition of 6
to iminium salt 5, which is finally converted into the de-
sired α-ketothioamide 3h by the elimination of a molecule
of piperidine.
Entry R2NH 2
Ar 1
Product 3 Yield (%)b
1
2
3
4
5
6
Ph
3a
3b
3c
3d
3e
3f
90
70
80
80
85
75
90
4-ClC6H4
4-BrC6H4
4-PhC6H4
3-MeOC6H4
4-MeOC6H4
NH
2a
7
3,4-(MeO)2C6H3 3g
8
9
10
11
12
13
14
15
Ph
3h
3i
3j
3k
3l
3m
90
78
80
85
85
85
90
4-ClC6H4
4-BrC6H4
4-PhC6H4
3-MeOC6H4
4-MeOC6H4
O
O
2b
OH
NH
Ph
N
Ph
OH
5
2b
1
3,4-(MeO)2C6H3 3n
4-O2NC6H4
H
S
S8
– S7
c
–
–
N
S–
7
NH
3o
3p
3q
3r
3s
3t
–
90
83
70
85
85
85
90
16
17
18
19
20
21
22
Ph
4-ClC6H4
4-BrC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
4-O2NC6H4
2b
O
O
NH
H
H
N
S
H
Ph
5
N
3h
2c
N
S–
c
–
6
7
NH
d
23
24
Ph
4-ClC6H4
–
–
–
–
d
Scheme 2 Plausible mechanism for Willgerodt–Kindler reaction of
phenylglyoxal with 2b and sulfur
2d
a See also Scheme 1.
b Yields refer to isolated products.
c Polymeric material was produced.
d Nonidentified mixture was obtained.
The Willgerodt–Kindler reaction of a primary amine, ben-
zylamine, with phenylglyoxal hydrate and sulfur under
the same conditions was also investigated but a complex
mixture was produced. Finally, the reaction of an aromatic
amine, aniline, with phenylglyoxal and sulfur, was carried
out for an extended period, and the corresponding α-keto-
imine was identified without incorporation of sulfur. This
can be attributed to the low nucleophilicity of aniline too.
As Okamoto et al.28 have reported, we added Na2S to the
reaction mixture and this resulted in the disappearance of
A single crystal of 1-phenyl-2-(piperidin-1-yl)-2-thioxo-
ethanone (3h) suitable for X-ray analysis27 was obtained
via slow evaporation and its ORTEP representation with
atom numbering is shown in Figure 1. For crystal data,
structure refinement details, selected bond distances,
Synlett 2013, 24, 977–980
© Georg Thieme Verlag Stuttgart · New York

LETTER
α-Ketothioamides via Willgerodt–Kindler Reaction
979
the α-ketoimine, but a nonidentifiable mixture was ob-
tained.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
copies of the 1H NMR and 13C NMR spectra of all compounds.SnugIifo
maoirtnSupgIpifom
r
p
t
trornat
Another characteristic feature of the present protocol is
the high chemoselectivity of the Willgerodt–Kindler reac-
tion toward phenylglyoxal, in preference to benzaldehyde
and acetophenone as shown in Scheme 3. Thus, when the
reaction of phenylglyoxal with piperidine in the presence
of one equivalent of either benzaldehyde or acetophenone
was carried out under the same conditions, only 3h was
isolated and benzaldehyde or acetophenone was recov-
ered.
References and Notes
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O
O
O
2b, S8
OH
OH
3h
+
Ph
R
Ph
+
Ph
R
80 °C
1
R = H, Me
recovered
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Scheme 3 Chemoselectivity of the Willgerodt–Kindler reaction
In conclusion, we have reported an efficient and green
methodology for the synthesis of α-ketothioamides via the
Willgerodt–Kindler reaction of arylglyoxal hydrates with
secondary amines and elemental sulfur under solvent-free
conditions. Arylglyoxals with electron-donating and elec-
tron-withdrawing groups (except the nitro group) are
good substrates. Heterocyclic secondary amines afford
the corresponding α-ketothioamides in good to high
yields, while reactions with secondary acyclic amines pro-
duce a nonisolable mixture. Reaction with primary amines
does not occur. Finally, the reaction shows excellent che-
moselectivity toward phenylglyoxal in preference to
benzaldehyde and acetophenone.
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General Procedure for the Preparation of Arylglyoxal Hydrates
Aryl methyl ketone (50 mmol) was added to a solution of SeO2 (50
mmol) in dioxane (30 mL) containing H2O (1 mL) and heated under
reflux conditions for 4–6 h. Then the hot solution was decanted to
remove the precipitated selenium. The dioxane was removed by dis-
tillation, and the obtained yellow liquid was recrystallized from hot
H2O to obtain the corresponding arylglyoxal.26
General Procedure for the Willgerodt–Kindler Reaction
A mixture of arylglyoxal hydrate 1 (1 mmol), amine 2 (2 mmol),
and elemental sulfur (2 mmol) was heated at 80 °C for 0.6–1 h. Af-
ter completion of the reaction, (as monitored by TLC, n-hexane–
EtOAc, 7:3), the unreacted sulfur was removed by adding EtOH (2
mL), heating, and then filtering while hot. On cooling the filtrate,
the corresponding α-ketothioamides crystallized and were isolated
by filtration. Further purification for elemental analysis was carried
out by recrystallization from n-hexane or EtOH. In the case of oily
products, column chromatography was used for purification. All
compounds were characterized spectrosopically. Compounds 3a–
g,j–n,r,t are novel and were also characterized by elemental analy-
sis.29
Acknowledgment
This work was supported by the Research Council of the University
of Maragheh. B.E.S. gratefully acknowledges Mr. Biglari (IASBS)
for recording NMR spectra.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 977–980

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B. Eftekhari-Sis et al.
LETTER
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Copies of the data can be obtained, free of charge, on
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1-(3,4-Dimethoxyphenyl)-2-(pyrrolidin-1-yl)-2-thioxo-
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Dark yellow solid; mp 113–115 °C. FTIR (KBr): 2967 (CH),
1648 (C=O), 1589 (C=C), 1508 (C=S), 1451 (CH2 bending),
1270 (CO), 1229 (CN), 1019 (C=S) cm–1. 1H NMR (400
MHz, CDCl3): δ = 7.59–7.63 (dd, J = 2.0, 8.4 Hz, 1 H,
CHAr), 7.57 (d, J = 2.0 Hz, 1 H, CHAr), 6.90 (d, J = 8.4 Hz, 1
H, CHAr), 3.96–3.99 (m, 2 H, CH2N), 3.98 (s, 3 H, OCH3),
3.96 (s, 3 H, OCH3), 3.56–3.59 (m, 2 H, CH2N), 2.06–2.17
(m, 4 H, CH2). 13C NMR (100 MHz, CDCl3): δ = 193.1
(C=S), 188.3 (C=O), 154.3, 149.4, 126.0, 125.8, 111.1,
110.2, 56.2, 51.3, 26.1, 23.9. Calcd for C14H17NO3S: C,
60.19; H, 6.13; N, 5.28. Found: C, 60.20; H, 6.13; N, 4.99.
1-(3-Methoxyphenyl)-2-morpholino-2-thioxoethanone
(3r)
Dark yellow oil. FTIR (KBr): 2920 (CH), 1642 (C=O), 1600
(C=C), 1489 (C=S), 1435 (CH2 bending), 1268 (CO), 1246
(CN), 1110 (C=S) cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.51–7.56 (m, 2 H, CHAr), 7.40 (t, J = 8.0 Hz, 1 H,
CHAr), 7.16–7.19 (m, 1 H, CHAr), 4.32–4.35 (m, 2 H, CH2O),
3.90–3.93 (m, 2 H, CH2O), 3.87 (s, 3 H, OCH3), 3.70–3.72
(m, 2 H, CH2N), 3.60–3.62 (m, 2 H, CH2N). 13C NMR (400
MHz, CDCl3): δ = 195.6 (C=S), 187.7 (C=O), 160.1, 134.5,
130.2, 122.8, 121.8, 113.4, 66.7, 55.6, 51.9, 47.1. Anal.
Calcd for C13H15NO3S: C, 58.85; H, 5.70; N, 5.28. Found: C,
58.44; H, 5.39; N, 5.00.
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1-(4-Methoxyphenyl)-2-morpholino-2-thioxoethanone
(3s)
Yellow solid; mp 117–118.5 °C. FTIR (KBr): 3110, 2969
(CH), 1654 (C=O), 1595 (C=C), 1500 (C=S), 1437 (CH2
bending), 1263 (CO), 1234 (CN), 1110 (C=S) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.97–8.01 (m, 2 H, CHAr),
6.97–7.01 (m, 2 H, CHAr), 4.34–4.37 (m, 2 H, CH2O), 3.92–
3.94 (m, 2 H, CH2O), 3.91 (s, 3 H, OCH3), 3.70–3.73 (m, 2
H, CH2N), 3.62–3.63 (m, 2 H, CH2N). 13C NMR (400 MHz,
CDCl3): δ = 196.2 (C=S), 187.3 (C=O), 164.6, 132.3, 126.1,
114.3, 66.5, 55.7, 51.9, 47.1. Anal. Calcd for C14H17NO4S:
C, 56.93; H, 5.80; N, 4.74. Found: C, 56.61; H, 5.80; N, 4.42.
Synlett 2013, 24, 977–980
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