Dichlorothiophosphoric acid and dichlorothiophosphate anion as thionating agents in the synthesis of thioamides

Article abstract of DOI:10.1134/S1070363208070098

A method for the thionation of carboxylic acid amides with dichlorothiophosphoric acid and dichlorothiophosphate anion, providing thioamides in high yields, was developed. The facility of the thionation and the yields of the final products were shown to depend on the nature of the starting amide. The optimal reaction conditions are reported.

Full text of DOI:10.1134/S1070363208070098

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 7, pp. 1341–1344. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © L.V. Bezgubenko, S.E. Pipko, A.D. Sinitsa, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 7, pp. 1104–1108.
Dichlorothiophosphoric Acid and Dichlorothiophosphate Anion
as Thionating Agents in the Synthesis of Thioamides
L. V. Bezgubenko, S. E. Pipko, and A. D. Sinitsa
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
Received December 25, 2007
Abstract—A method for the thionation of carboxylic acid amides with dichlorothiophosphoric acid and
dichlorothiophosphate anion, providing thioamides in high yields, was developed. The facility of the thionation
and the yields of the final products were shown to depend on the nature of the starting amide. The optimal
reaction conditions are reported.
DOI: 10.1134/S1070363208070098
The high synthetic potential of thioamides causes
their wide application in organic synthesis, especially
for preparing sulfur-containing heterocycles [1–3].
Representatives of this class of compounds are applied
in medicine as antitubercular remedies, such as
ethionamide and propionamide.
thiochloride in the presence of 2/mol of triethylamine
(procedure a).
2Et3NH+
H2O + 2 Et3N
PSCl3
Cl2POS_Cl_
CHCl3
I
II
RCONR'Me
The synthesis of thioamides is well documented.
Most commonly, thioamides are prepared by the thio-
nation of the corresponding amides with such reagents
as P2S5 [4, 5] and Lawesson reagent [6–8]. Reactions
of this type are still intensively studied. Recently such
new effective thionating reagents as R3OBF4/NaHS
[9], (Et2Al)2S [10] and (PhCH2NEt3)2MoS4 [11] were
offered.
III
RCSNR'Me
IV
R' = Me: R = H (IVа), R = Me (IVb), R = t-Bu (IVc); R' =
Me: R = Ph (IVd), R = п-Me2NC6H4 (IVe), R = п-O2C6H4
(IVf); R' = H: R = Me (IVg), R = Ph (IVh); R' = Me: R =
NMe2 (IVi).
The synthesis of several thioamides by the reaction
of phosphorus thiochloride with amides has been des-
cribed in one of the early works of Lawesson [12]. This
method has not been further developed, since even
upon heating for 5–15 h at 80–150ºC in excess PSCl3
the yields of thioamides were no higher than 20–38%.
The first stage of the process, hydrolysis of PSCl3,
is exothermic. At the second stage, heating of the
components at the solvent boiling point is required.
The yields of products IV are fairly high, 60–90%
(see table). This method was used to synthesize sec-
ondary and tertiary thioamides IVа–IVh and also
tetramethylthiocarbamide IVi. Under the reaction con-
ditions, benzamide undergoes dehydration to form of
benzonitrile (V) as the main product. However,
attempted thionation of acetamide and N,N'-dimethyl-
carbamide failed, and thionated products were not
found.
Earlier in a short communication [13] we described
a new synthetic approach to thioamides, involving the
dichlorothiophosphate anion (II) as a thionating agent.
In the present work we studied in detail some variants
of application of anion II and its conjugate acid VI for
the synthesis of carboxylic acid thioamides of various
nature.
The first variant involves the reaction of a
carboxylic acid amide with the dichlorothiophosphate
anion formed by controlled hydrolysis of phosphorus
We found that increased electron density on the
oxygen atom of the amido group favors thionation.
1341

1342
BEZGUBENKO et al.
Thionation times and yields of thioamides by procedures a–d
Procedure а
time, h yield, %
4а [13]
Procedure b
Procedure c
time, h yield, %
Procedure d
time, h yield, %
Comp.
no.
time, h
yield, %
91
93
IVа
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
V
16а [13]
40
9
60
30
8
9b
60
69
81
80
7
3
85
75
70
3
70
7
86
10
36
18
10
15
83
9
traces
75
10
8
60
75
89
70c
50c
7
a
b
c
The reaction was carried out at room temperature. In an acid medium, dimethylamide hydrochloride is thionated. The yield of
benzonitrile was determined by 1H NMR spectroscopy.
Thus, the reaction rates of N,N-dimethylbenzamides
IIId–IIIf decrease in the following order:
N,N-dimethylbenzamide (IIId), and 51% of N,N-
dimethyl-p-nitrobenzamide are thionated within 3 h.
The slowest reaction (38% within 3 h) takes place with
compound IIIe' containing a protonated dime-
thylamino group.
O
O
NMe2
NMe2
N,N-Dimethyltrifluoroacetamide and N-methyltri-
fluoroacetamide, which contain strong electron-
acceptor substituents at the carbonyl carbon, fail to
enter the thionation reaction. On the other hand, bulky
substituents at the carbonyl carbon atom do not prevent
reaction, as evidenced by the thionation of N,N-
dimethylpivalamide.
Me2N
IIIe
IIIe
O
O
NMe2
NMe2
Me+2NH
Cl _
O2N
The above findings suggest that the most probable
thionation mechanism includes nucleophilic attack by
the amide oxygen atom on phosphorus with sub-
sequent migration of the imidoyl group in the O–P–S
triad and thioamide elimination (see scheme).
IIIf
IIIe'
Under identical reaction conditions, 69% of N,N-
dimethyl-p-(dimethylamino)benzamide (IIIe), 53% of
O
S
R
R
R
R
NR'Me
+
NR'Me
MeR'N+
MeR'N+
C
S
O_
+
C
O
S
O
_S
PCl2
O_
PCl2
O _
_
_
Cl2P
Cl2P
O
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

DICHLOROTHIOPHOSPHORIC ACID AND DICHLOROTHIOPHOSPHATE ANION
1343
According to this mechanism, an increase in the
electrophilicity of the phosphorus atom, for example,
in going from anion II to its protonated form VI
should increase reaction rate. Actually, as seen from
the table, the use of dichlorothiophosphoric acid VI
(methods b and c) allows the reaction time to be
shortened considerably. Probably, in procedure a, too,
the active species is acid VI formed in the reaction
mixture in a small amount due to the equilibrium
established at an elevated temperature:
chromatographic purification of the target products.
Procedure d can be used for preparative syntheses of
mono- and disubstituted thioamides of carboxylic
acids.
EXPERIMENTAL
1
The 31Р and Н NMR spectra of СНCl3 (31Р) and
CDCl3 (1Н) solutions were recorded on a Varian VXR-
300 instrument (121.42 and 299.95 МHz, respectively)
against external 85% Н3РО4 (31Р) and internal ТМS
(1Н). The reactions were carried out in moisture-proof
conditions under dry air. Dry solvents were prepared
by distillation (CHCl3 over P4O10, dioxane over KOH).
The constants of the same compounds obtained by
different methods were coincident.
Cl2POS_
Et3NH+
+
Et3N.
Cl2POSH
+
VI
II
According to procedure b, dichlorothiophosphoric
acid VI is generated in the reaction of PSCl3 with
equimolar quantities of water and triethylamine.
Procedure c is based on acidification of anion II with
dry HCl.
Carboxylic acid thioamides (general procedures).
a. Water, 0.51 g, was added dropwise to a stirred
solution of 5 g (0.0295 mol) of PSCl3 and 5.97 g of
triethyl-amine in 12 ml of anhydrous chloroform. After
a few minutes self-heating of the reaction mixture to
boiling occurred. The 31Р NMR spectrum of the
reaction mix-ture, taken after cooling, contained a
signal at 43 ppm corresponding to anion II. Carboxylic
acid amide, 0.029 mol, was added to the reaction
mixture containing II. The mixture was heated under
reflux until the thionation reaction was complete. The
reaction progress was monitored by the 31Р NMR spec-
tra in which the signal at 43 ppm, corresponding to
anion II, gradually disappeared, and a signal at –6 ppm
corresponding to the dichlorophosphate anion
appeared. After the thionation reaction was complete,
the mixture was diluted with 50 ml of water. The
product was extracted with 50 ml of chloroform, and
the extract was dried over sodium sulfate. The solvent
was removed under a vacuum, and the residue was
recrystallized from hexane.
HCl
H2O, Et3N
PSCl3
II.
Cl2POSH
_Et3N HCl
VI
method b
method c
Direct hydrolysis with PSCl3 seems to be the most
convenient way to generate acid VI. However, in the
absence of a base, the reaction with water scarcely
proceeds even on prolonged boiling. We found that the
reaction of PSCl3 with water is sharply accelerated in
the presence of amides which apparently act as
nucleophilic catalysts. In this case, hydrolysis proceeds
in a few minutes with self-heating of the reaction
mixture. This observation formed the basis of
procedure d in which the reaction is carried out by
dissolving the starting amide, PSCl3, and water in
dioxane and refluxing the reaction mixture after
completion of heat release.
b. Water, 0.51 g, was added dropwise to a stirred
solution of 5 g of PSCl3 and 2.98 g of triethylamine in
12 ml of anhydrous chloroform. The formation of the
thionating agent was monitored, and the thionation
reaction was carried out as described in procedure a.
dioxane
I + H2O + III
VI + III
IV.
Procedure d allows the reaction time to shortened
3–5 times compared to procedure a and provides not
only N,N-dialkylamides, but also N-monoalkyl-
thioamides in high yields.
c. A solution of anion II in anhydrous chloroform
was prepared by method a. A necessary amount of dry
HCl was bubbled through the solution, and then the
reaction was carried out as described in procedure a.
Our discovered thionation reaction involves ac-
cessible regents and gives readily soluble by-products,
which makes the target compounds much easier to
isolate. The facility of isolation of thioamides is an
experimental advantage of our described methods over
thionation with the Lawesson reagent, which requires
d. Water, 0.51 g, was added dropwise to a stirred
solution of 5 of PSCl3 and 0.0295 mol of carboxylic
acid amide in 12 ml of dioxane. The 31Р NMR spec-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

1344
BEZGUBENKO et al.
trum of the reaction mixture, after completion of an exo-
thermic reaction and cooling, contained a signal 43 at
ppm, corresponding to dichlorothiphosphoric acid VI.
The reaction mixture was heated on an oil bath at 100–
110°С until the signal at 43 ppm in its 31P NMR
spectrum disappeared completely and then treated as
described in procedure a.
Tetramethylthiocarbamide (IVi) was obtained by
procedure a. mp 78°С (78–79°С [20]). Н NMR spec-
trum (DMSO-d6), δ, ppm: 3.00 s [12Н, (СН3)2N].
Found, %: C 45.45; H 9.17; N 21.20; S 24.20.
Calculated, %: C 45.42; H 9.15; N 21.19; S 24.25.
1
REFERENCES
N,N-Dimethylthiopivalamide (IVc) was obtained
by procedures a, b, and d. Purification was accom-
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ethyl acetate (9:1). mp 43°С (40°С [14]). Н NMR
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(СН3)2N]. Found, %: C 57.80; H 10.24; N 9.61; S 21.42.
Calculated, %: С 57.88; H 10.41; N 9.64; S 22.07.
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by procedures a–d. mp 70°С (69–70 °С [15]). 1Н NMR
spectrum, δ, ppm: 3.17 s [3Н, (СН3)2N], 3.61 s [3Н,
(СН3)2N], 7.33 m (5Н aromatic). Found, %: C 68.28;
H 6.74; N 8.66; S 18.90. Calculated, %: С 65.41;H
6.71; N 8.48; S 19.40.
N,N-Dimethyl-p-(dimethylamino)thiobenzamide
(IVe) was obtained by procedures a and b. mp 101°С
1
(103°С [16]). Н NMR spectrum, δ, ppm : 2.93 s [6Н,
(СН3)2N], 3.18 s [3Н, (СН3)2N], 3.51 s [3Н, (СН3)2N],
3
6.70 d. (2Н aromatic, JHH 9), 7.25 d (2Н aromatic,
3JHH 9). Found, %: С 64.00; H 7.78; N 3.06; S 14.33.
Calculated, %: С 63.42; H 7.74; N 13.45; S 15.39.
N,N-Dimethyl-p-nitrothiobenzamide (IVf) was
obtained by procedures a and b. mp 147°С (145.5–
1
146.5°С [17]). Н NMR spectrum, δ, ppm: 3.10 s [3Н,
(СН3)2N], 3.55 s [3Н, (СН3)2N], 7.39 d (2Н arom.,
3
3JHH 9), 8.16 d (2Н arom., JHH 9). Found, %: С 52.82;
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4.79; N 13.32; S 15.25.
N-Меthylthioacetamide (IVg) was obtained by
procedure d. Purification was accomplished by chro-
matography on silica gel, eluent hexane–ethyl acetate
1
(9:1). Mp 58°С (59°С [18]). Н NMR spectrum, δ,
2
ppm: 2.53 s (3Н, СН3), 3.12 d (3Н, СН3NН, JHH 5),
7.81 s.br (1Н, NH). Found, %: С 40.60; H 7.78; N
15.50; S 34.86. Calculated, %: С 40.41; H 7.91; N
15.71; S 35.96.
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1
procedures a and d. mp 80°С (80–81° С [19]). Н
2
NMR spectrum, δ, ppm: 3.25 d (3Н, СН3NН, JHH 5),
3
3
7.28 t (2Н arom., JHH 7), 7.37 t (1Н arom., JHH 7.5),
7.66 d (2Н arom., 3JHH 7.5), 7.85 sbr (1H, NH). Found,
%: C 63.25; H 5.85; N 9.46; S 21.15. Calculated, %:
C 63.54; H 6.00; N 9.26; S 21.20.
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