Synthesis of S-thioacyl dithiophosphates, efficient and chemoselective thioacylating agents

Article abstract of DOI:10.1039/b201233b

Easily available acyl dithiophosphates are not stable and isomerise reversibly to O-thioacyl monothiophosphates, especially when subjected to heating. Much slower but probably irreversible isomerisation to S-thioacyl monothiophosphates occurs. Since equilibrium states are established and S-thioacyl (mono)thiophosphates form slowly, reaction mixtures contain generally both thioacylating and acylating agents, and consequently cannot be used for efficient thioacylation. On the other hand, treatment of a mixture of isomeric anhydrides with an excess of a dithiophosphoric acid leads to exclusive formation of S-thioacyl dithiophosphates. They appear to be excellent thioacylating agents: relatively stable, inert towards water and oxygen and therefore easy to handle. Reactions with nitrogen or sulfur nucleophiles proceed very rapidly under ambient conditions, yielding respective thioacyl derivatives. Isolation of the products is very simple. Due to the low reactivity of S-thioacyl dithiophosphates towards oxygen nucleophiles they can be used for direct thioacylation of multifunctional nucleophiles with unprotected hydroxy groups. Respective thioacyl derivatives cannot readily be obtained using other methods.

Full text of DOI:10.1039/b201233b

View Online / Journal Homepage / Table of Contents for this issue
Synthesis of S-thioacyl dithiophosphates, efficient and
chemoselective thioacylating agents†
Leszek Doszczak and Janusz Rachon*
1
Department of Organic Chemistry, Chemical Faculty, Technical University of Gdan´sk,
ul. Narutowicza 11/12, 80-952 Gdan´sk, Poland
Received (in Cambridge, UK) 4th February 2002, Accepted 19th March 2002
First published as an Advance Article on the web 10th April 2002
Easily available acyl dithiophosphates are not stable and isomerise reversibly to O-thioacyl monothiophosphates,
especially when subjected to heating. Much slower but probably irreversible isomerisation to S-thioacyl monothio-
phosphates occurs. Since equilibrium states are established and S-thioacyl (mono)thiophosphates form slowly,
reaction mixtures contain generally both thioacylating and acylating agents, and consequently cannot be used
for efficient thioacylation. On the other hand, treatment of a mixture of isomeric anhydrides with an excess of a
dithiophosphoric acid leads to exclusive formation of S-thioacyl dithiophosphates. They appear to be excellent
thioacylating agents: relatively stable, inert towards water and oxygen and therefore easy to handle. Reactions
with nitrogen or sulfur nucleophiles proceed very rapidly under ambient conditions, yielding respective thioacyl
derivatives. Isolation of the products is very simple. Due to the low reactivity of S-thioacyl dithiophosphates towards
oxygen nucleophiles they can be used for direct thioacylation of multifunctional nucleophiles with unprotected
hydroxy groups. Respective thioacyl derivatives cannot readily be obtained using other methods.
Introduction
Thioacyl derivatives can be obtained using two main
approaches. The first one consists of subsequent stages of acti-
vation of carboxylic acid, acylation of a nucleophile, and
treatment of the formed acyl derivative with a so-called thionat-
Scheme 1 Isomerisation of mixed anhydrides of type 1.
ing agent. The most popular thionating agents are phosphorus
phosphinites) 2, 3, which are active derivatives of thiocarb-
oxylic acids.
If it were possible then it would be a comfortable method
pentasulfide and Lawesson’s reagent.1,2 Numerous other
reagents have been described [e.g., R3OBF4–NaHS,3 R2PSX,4
POCl3–(Me3Si)2S,5 (Et2Al)2S,1 B2S3 or SiS2 ]. However, they
have not found as wide an application as the first two. The
other, more chemoselective strategy leading to thioacyl deriv-
atives consists of thioacylation of nucleophiles with an active
derivative of thiocarboxylic acid. Unfortunately, thioacylat-
ing agents described in the chemical literature [e.g., thio-
acyloxybenzotriazoles,6 phenylmercury dithiocarboxylates,7
bis(thioacyl) sulfides,8 thioacyl trifluorosulfonyl sulfides,9
N-methyl-S-thioacyl-2-sulfanylpyridinium iodides,10 thioacyl
halides,1 succinimides,1 phthalides,11 benzimidazolones,12
fluorobenzimidazolones,13 imidazoles, triazoles or tetrazoles,1
etc.] show many disadvantages. Most of these thioacylating
agents are unstable (especially the aliphatic derivatives), and
their synthesis is complicated or expensive. Less reactive
reagents (like thioesters) react with nucleophiles very slowly or,
in case of larger steric hindrance, do not react at all.1 Moreover,
most of the reagents described can only be prepared from
dithiocarboxylic acids, which are scarce as commercial reagents
and are not easy to synthesise in high yield or to handle in pure
form. Furthermore, dithiocarboxylic acids generally have
obnoxious odors.
1
1
of synthesis of thioacylating agents, benefiting from easily
available starting materials (carboxylic acids).
We have recently communicated14 our results in this field and
here we present the details of our research.
Results and discussion
For our studies we chose derivatives of 5,5-dimethyl-2-sulfanyl-
2-thioxo-1,3,2-dioxaphosphinan 4 due to numerous advantages
of this model [an easy-to-prepare (Scheme 2), crystalline, almost
Scheme 2 Synthesis of 5,5-dimethyl-2-sulfanyl-2-thioxo-1,3,2-dioxa-
phosphinan 4.
odorless dithiophosphoric acid; derivatives should have clear
NMR spectra].
Reaction of the dithiophosphoric acid 4 with acyl chlorides
in the presence of triethylamine or pyridine immediately yields
the expected acyl dithiophosphates 5 (Scheme 3). In order to
Therefore, we aimed to establish whether mixed anhydrides
of dithiophosphoric (dithiophosphonic or dithiophosphinic)
and carboxylic acids of type 1 could be isomerised (Scheme 1) to
O-thioacyl or S-thioacyl monothiophosphates (phosphonates,
† Proofs for the reversibility of isomerisation of anhydrides 1 to 2,
melting points of amides and thioamides obtained from anhydrides 5–7
and 1H, 13C NMR and IR data of isolated anhydrides 5–7, 17 are
available as supplementary data. For direct access, see http://
www.rsc.org/suppdata/p1/b2/b201233b/
Scheme
3
Synthesis of acyl (5,5-dimethyl-2-thioxo-1,3,2-dioxa-
phosphinan-2-yl) sulfides 5.
DOI: 10.1039/b201233b
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279
1271
This journal is © The Royal Society of Chemistry 2002

View Online
Table 1 Yields and chemical shifts of acyl (5,5-dimethyl-2-thioxo-
1,3,2-dioxaphosphinan-2-yl) sulfides 5
Table 3 Direct synthesis of acyl dithiophosphates 5 from carboxylic
acids
Entry
R
31P NMR, δ/ppm
Yield (%)
Entry
R
31P NMR, δ (ppm)
Yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
Ph
69.1
70.3
65.9
69.6
69.7
69.1
70.1
70.6
70.8
71.0
67.9
68.9
69.4
69.2
98
85
85
100
93
89
92
98
96
93
90
90
94
100
5a
5d
5f
5g
5i
5n
5o
5p
Ph
69.1
69.6
69.1
70.1
70.8
69.2
65.7
67.7
94a
C6H4OMe-p
C6H4NO2-p
1-Naphthyl
CH᎐CHPh (E)
Me
1-Naphthyl
Me
81a
95b
Pr
98b
But
84a; 99b
99b
᎐
(CH2)4COOMe
CH2NPhth
CH2CH2NPhth
Pr
81a
Pri
93a
But
a Method A: RCOOH ϩ CDI ϩ 3 (RO)2PSSH. b Method B: RCOOH ϩ
CDI ϩ (RO)2PSSH ϩ 2CF3COOH.
CH(CH2)5
CH2OPh
CH2Ph
CHPh2
(CH2)4COOMe
Table 2 Yields of amides† obtained by acylation of amines with acyl
(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-2-yl) sulfides 5
Entry
R
Amine
Yield of amide (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
H2NPh
HNEt2
99
94
96
97
90
95
97
99
99
95
95
C6H4OMe-p
C6H4NO2-p
1-Naphthyl
CH᎐CHPh (E)
Me
H2NPh
H2NPri
Scheme 4 Synthesis of acyl dithiophosphates 5 from carboxylic acids
HNEt2
H2NPh
H2NPh
H2NPh
H2NPh
H2NPh
HN(CH2)2O(CH2)2
᎐
with CDI as condensing agent.
Pr
Pri
dioxaphosphinan 4, poorly nucleophilic, and well soluble in the
reaction medium. These conditions are fulfilled by trifluoro-
acetic acid. The method based on addition of carboxylic acid
to CDI, followed by addition of dithiophosphoric acid and 2
eq. of trifluoroacetic acid, allows the obtention of acyl dithio-
phosphates 5 with high yields (the results are shown in Table 3).
Studying the synthesis of acyl dithiophosphates 5 we noticed
that solutions of these anhydrides turn yellow to orange and,
after a longer time, become pink to violet (especially on heat-
ing). Monitoring of reaction mixtures with 31
But
5j
5k
CH(CH2)5
CH2OPh
obtain pure anhydrides 5, the reaction mixture should be
cooled with ice–water and work-up should be as fast as
possible. Evaporation of the solvent should be carried out at
room temperature, especially in the case of acyl chlorides with
electron-donating groups. Then very good yields can be
obtained, as can be seen from the data collected in Table 1.
Acylation of dithiophosphates is efficient even in the case of
sterically hindered pivaloyl chloride (Table 1, entry 5i), as well
as of acyl chlorides with electron-withdrawing groups (Table 1,
5c,k–m) and electron-donating groups (Table 1, 5b,h–j).
Unsaturated derivatives can also be prepared (Table 1, 5e). The
acyl dithiophosphates 5 are colorless crystalline solids. Their
31P chemical shifts lay in a narrow range of δP 69–71 (only
anhydrides with electron-withdrawing groups have slightly
lower shifts). 1H, 13C NMR, IR and MS data also confirm their
structure. Additional chemical proof comes from the treatment
of anhydrides 5 with amines (in the presence of triethylamine)
to yield amides (Table 2).‡
P NMR and TLC
(see Fig. 1 and the results collected in Table 4 indicated that
Although synthesis of acyl dithiophosphates from acyl chlor-
ides is very efficient, we searched for a method of acyl dithio-
phosphate synthesis directly from carboxylic acids. Many of the
condensing agents we tested were unsuccessful; however, we
found that carbonyldiimidazole (CDI) can be used for efficient
synthesis of anhydrides 5. Due to the high nucleophilicity of
imidazole formed in the course of the reaction, three equiv-
alents of dithiophosphoric acid 4 should be used (Scheme 4),
which allows the preparation of acyl dithiophosphates with
high yield (Table 3).
Due to the necessity of an excess of the reagent certain
preparative issues, such as cost, solubility, isolation of prod-
ucts, etc., make it advisable to modify the procedure. Thus,
we decided to replace 2 eq. of dithiophosphoric acid with
an acid which would be inexpensive, stronger than the
Fig. 1 Example of 31P NMR spectrum of the reaction mixture formed
by heating a solution of an acyl dithiophosphate 5 (R = Ph, 80 ЊC, 4 h).
these changes in color were due to two types of compounds
being formed. One type, of lower polarity than the starting
materials, has a 31P NMR chemical shift of δP 48.5–51 whereas
the other, being more polar, has δP 4–7. We managed to isolate
some of these products (see Table 5). Based on analytical data,
1
such as 31P, 13C, H NMR, IR, MS, and reactions with amines
yielding thioamides (see Tables 4 and 5) we assigned the
expected structures of O-thioacyl 6 and S-thioacyl monothio-
phosphates 7, respectively, to these products (Scheme 5). Our
study is the first one where isomerisation of mixed anhydrides
‡ Detailed structural studies were necessary because we found the
literature concerning mixed anhydrides confusing.
1272
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279

View Online
Table 4 Chemical shifts and proportions (based on relative 31P NMR signal intensities) of products, observed after heating acyl dithiophosphates 5
for 2 hours; yields of derived amides and thioamides†
31P NMR, δ (ppm)
Yield (%) of
amide
Entry
R
5
6
7
Proportions of 5 : 6 : 7
thioamide
a
b
c
d
f
g
h
i
Ph
67.7
68.9
65.6
68.7
69.0
69.7
70.1
71.1
70.6
67.6
49.8
50.2
49.6
49.4
49.5
50.0
49.5
50.1
50.8
48.5
4.1
4.8
4.0
3.7
6.0
5.6
4.9
5.1
5.5
33 : 62 : 5
24 : 54 : 22a
22 : 78 : tr
51 : 6 : 43a
49 : 50 : 1
74 : 12 : 14
85 : 10 : 5
75 : 15 : 10
33 : 35 : 32
92 : 8 : 0
27b
15c
25b
45d
45b
65b
78b
74b
30b
85e
60
70
59
42
45
20
7
22
53
5
C6H4OMe-p
C6H4NO2-p
1-Naphthyl
Me
Pr
Pri
But
j
k
CH(CH2)5
CH2OPh
a 1 h of heating; b Reaction with aniline; c Reaction with diethylamine; d Reaction with isopropylamine; e Reaction with morpholine.
Table 5 Yields of isolated thioacyl thiophosphates 6, 7
reaction mixtures formed during heating of benzene solutions
of selected anhydrides 5 for 8 h. The results are shown in Table
7. Results of the experiments described above allow us to state
that in most cases heating of acyl dithiophosphates leads to
O-thioacyl monothiophosphates 6 comparatively rapidly and
equilibrium mixtures† generally contain high amounts of start-
ing material. Longer heating leads to formation of S-thioacyl
monothiophosphates 7 but the process is very sluggish and only
two models used (5b,d; R = 4-MeOC6H4, 1-naphthyl) were
completely converted to these thioacylating agents. This sug-
gests that electron-donating groups, especially those exercising
an M ϩ effect, promote the formation of both types of thioacyl
monothiophosphate. Consequently, heating of acyl dithio-
phosphates 5 cannot be used as a general, efficient synthetic
method for thioacylating agents of this type.
Entry
R
Reaction time (t/h)
Yield (%)
6a
7a
7b
7d
7i
Ph
Ph
2
20
8
34
47
79
100
70
C6H4OMe-p
1-Naphthyl
But
15a
28
a Or 1 week at room temperature.
Table
6
Yields of thioamides obtained from S-thioacyl thio-
phosphates 7
Entry
R
RЈ
RЉ
Yield (%)
Therefore, we searched for a dithiophosphoric acid whose
acyl derivatives could isomerise quickly and completely to
acyl monothiophosphates. To investigate the influence of
phosphorus atom substituents we prepared benzoyl dithio-
phosphinites, -phosphonates and -phosphates (Table 8) and
heated them in benzene for 8 hours, monitoring the reaction
mixtures with 31P NMR and TLC.
9a
9b
9c
9d
Ph
Ph
Et
H
Et
H
H
81
93
96
94
C6H4OMe-p
1-Naphthyl
But
Pri
Ph
Scheme 5 Isomerisation of acyl dithiophosphates 5.
of type 1 has been confirmed by isolation of respective
isomers.
As expected, the isolated thioacyl monothiophosphates 6, 7
can be effectively applied to thioacylation of amines (Scheme 6,
As shown by our experiments, dithio-phosphinites 10 and
-phosphonates 11 do not isomerise (at least in boiling benzene)
and two alkoxy groups are necessary for the isomerisation. Acyl
O,O-diisopropyl dithiophosphates 12 isomerise much more
slowly than do anhydrides 5 but due to their superior resistance
to hydrolysis they are easier to handle. These properties allowed
us to isolate pure O-thiobenzoyl O,O-diisopropyl monothio-
phosphate 14a. However, during the synthesis of benzoyl
(4,4,5,5-tetramethyl-2-thioxo-1,3,2-dioxaphospholan-2-yl) sul-
fide 13a, immediately after triethylamine was added to a
solution of 4,4,5,5-tetramethyl-2-sulfanyl-2-thioxo-1,3,2-dioxa-
phospholan 15 and benzoyl chloride, a mixture of benzoyl
(4,4,5,5-tetramethyl-2-thioxo-1,3,2-dioxaphospholan-2-yl) sul-
fide 13a (δP 85.87) and O-thiobenzoyl (4,4,5,5-tetramethyl-2-
thioxo-1,3,2-dioxaphospholan-2-yl) ether 16a (δP 68.52) was
formed (Scheme 7, Fig. 2). However, in that case the equilibrium
mixture also contained the acyl derivative. Consequently,
Scheme 6 Thioacylation of amines with S-thioacyl thiophosphates 7.
Table 6). Reaction proceeds at room temperature, immediately
yielding thioamides. Since ammonium monothiophosphates
formed in this reaction are water-soluble, isolation of the prod-
uct is exceptionally simple and yields are very good.
In an attempt to investigate the kinetics of thioacyl mono-
thiophosphate formation, we applied 31P NMR to monitor
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279
1273

View Online
Table 7 Proportions (based on relative 31P NMR signal intensities) of anhydrides 5 : 6 : 7 in mixtures formed while refluxing benzene solutions of
anhydrides 5
Time/Proportions of 5 : 6 : 7
Entry
R
1 h
2 h
4 h
8 h
a
b
c
d
h
i
Ph
36 : 64 : 0
24 : 54 : 22
23 : 77 : 0
51 : 6 : 43
93 : 5 : 2
91 : 9 : 0
97 : 3 : 0
33 : 62 : 5
6 : 15 : 79
22 : 78 : tr
4 : 0 : 96
85 : 10 : 5
75 : 15 : 10
92 : 8 : 0
29 : 55 : 16
4 : 8 : 88
12 : 83 : 5
3 : 0 : 97
73 : 11 : 16
68 : 7 : 25
86 : 14 : 0
25 : 56 : 19
tr : 1 : 99
10 : 85 : 5
1 : 0 : 99
48 : 6 : 46
52 : 5 : 43
85 : 15 : 0
C6H4OMe-p
C6H4NO2-p
1-Naphthyl
Pri
But
k
CH2OPh
Table 8 31P NMR δ and proportions (based on relative 31P NMR signal intensities) of anhydrides 1 : 2 : 3 in mixtures formed while refluxing
benzene solutions of benzoyl dithiophosphinites, dithiophosphonates and dithiophosphates of type 1 (R = Ph)
δP (ppm)/Anhydride type
proportions of 1 : 2 : 3/Time
No.
RЈ, RЉ
1
2
3
2 h
8 h
10a
11a
12a
13a
5a
Ph, Ph
60.8
89.1
76.9
84.9
67.7
100 : 0 : 0
100 : 0 : 0
82 : 18 : 0
9 : 75 : 16
33 : 62 : 5
100 : 0 : 0
100 : 0 : 0
69 : 31 : tr
10 : 64 : 26
25 : 56 : 19
p-MeOC6H4, MeO
PriO, PriO
57.7
68.8
49.8
14.5
17.0
4.1
OC(Me)2C(Me)2O
OCH2C(Me)2CH2O
Scheme 7 Reaction of 4,4,5,5-tetramethyl-2-sulfanyl-2-thioxo-1,3,2-
dioxaphospholan 15 with benzoyl chloride.
Fig. 2 31P NMR spectrum of products formed by benzoylation of
4,4,5,5-tetramethyl-2-sulfanyl-2-thioxo-1,3,2-dioxaphospholan 15.
addition of aniline and triethylamine to this mixture yielded
benzanilide (37%) and thiobenzanilide (59%).
Scheme 8 Thioacylation of nucleophiles with S-thioacyl dithio-
phosphates 17 obtained from carboxylic acids.
Results of the experiments carried out in our laboratory
show that isomerisation of S-acyl dithiophosphates leads to the
formation of active derivatives of thiocarboxylic acids, namely
thioacyl monothiophosphates. Despite that, the reaction can-
not be used for efficient thioacylation as the mixtures formed by
heating acyl dithiophosphates generally contain high amounts
of acylating agents 5 (starting materials). Nonetheless, we have
discovered that addition of the dithiophosphoric acid to the
mixture of isomeric anhydrides 5, 6 and 7 leads to the form-
ation of S-thioacyl dithiophosphates 17. Therefore, we were
able to develop an efficient method of synthesis of new thio-
acylating agents (Scheme 8). S-Thioacyl dithiophosphates
are formed exclusively when a benzene solution of an S-acyl
dithiophosphate 5 (or mixture of isomeric anhydrides 5, 6
and 7) and two equivalents of the dithiophosphoric acid 4 is
refluxed for 1.5–6 h (until the complete disappearance of start-
ing material). As indicated by the data collected in Table 9,
aromatic (17a,b,d) and aliphatic (17f,g,i,n) derivatives can be
obtained. Reagents with electron-donating (Table 9, 17i) and
electron-withdrawing groups (Table 9, 17b) as well as sterically
hindered reagents (Table 9, 17i) and those possessing additional
ester functionality (Table 9, 17n) have been shown to give high
yields.
1274
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279

View Online
Table 9 S-Thioacyl dithiophosphates 17
Entry
R
31P NMR δ (ppm)
Time (t/h)
Yield (%)
17a
17b
17d
17f
17g
17i
Ph
68.6
2
6
1.5
3
3
4
4
94
C6H4NO2-p
1-Naphthyl
Me
86a
90
67.8
68.4
68.5
70.7
67.2
88a
92a
91
Pr
But
17n
(CH2)4COOMe
88a
a Yield based on the isolated derivative.
Table 10 Thioacylations with S-thioacyl dithiophosphates 17
Entry
R
Nucleophile
Product
Yield (%)
9e
9a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NH3 (aq)
PhNH2, NEt3
(CH2)5NH, NEt3
HOCH2CH2NH2, NEt3
MeNHOHؒHCl, NEt3
PriNHOHؒ(COOH)2, NEt3
NaN3 (aq)
PhCSNH2
PhCSNHPh
PhCSN(CH2)5
95
99
98
94
68
9f
9g
PhCSNHCH2CH2OH
PhCSN(OH)Me
18a
18b
19a
9h
PhCSN(OH)Pri
73
b
PhCSN3
89
C6H4NO2-p
1-Naphthyl
Me
PhNH2, NEt3
p-O2NC6H4CSNHPh
1-NaphthylCSNHPri
MeCSNHPh
85a
96
9c
PriNH2, NEt3
9i
PhNH2, NEt3
PhNH2, NEt3
PhNH2, NEt3
CH2᎐᎐HCH2NH2, NEt3
o-HOC6H4NH2, NEt3
MeNHOHؒHCl, NEt3
NaN3 (aq)
HOCH2CH2SH, NEt3
(CH2)5NH, NEt3
88a
92a
97
9j
Pr
PrCSNHPh
9d
But
ButCSNHPh
9k
9l
But
ButCSNHCH2CH᎐CH2
100
99
71
᎐
But
o-ButCSNHC6H4OH
18c
19b
20a
9m
But
ButCSN(OH)Me
But
ButCSN3
92
b
But
ButCSSCH2CH2OH
97
(CH2)4COOMe
MeOCO(CH2)4CSN(CH2)5
88a
a Procedure B; b Thioacyl azides are an unstable species and isomerise in situ to thiatriazoles.
Compounds 17 show relative stability and resistance towards
air and water (they can even be washed with 10% aq. NaOH).
They can be isolated, as well as handled without special pre-
cautions, or used in situ for thioacylation reaction. Thioacyl
dithiophosphates 17 in the presence of triethylamine (pyridine)
react with nitrogen and sulfur nucleophiles at room temper-
ature very rapidly, producing the respective thioacyl derivatives
in very good yields. Reaction proceeds with ammonia (Table 10,
9e), primary (Table 10, 9a,c,d,g–l) and secondary amines (Table
10, 9f,m). Unsaturated amines are efficiently thioacylated as
well (Table 10, 9k). Thioacyl derivative can be easily separated
from water-soluble salts of thiophosphoric acids. As anhydrides
17 do not react with alcohols or water (under our given reaction
conditions), they can chemoselectively thioacylate nitrogen
and sulfur nucleophiles in the presence of oxygen ones. This
property allowed us to obtain hydroxy thioamides (Table 10,
9g,l), thiohydroxamic acids (18a–c), and hydroxy dithioesters
(20a) directly from substrates not protected on the hydroxy
group. It is worth mentioning that these kinds of compounds
are only difficulty available via thionation of non-protected
hydroxy amides, hydroxy-S-thioesters, or hydroxamic acids
with Lawesson’s reagent.15,16 Thioacylation of azide anion is
also an interesting reaction because thioacyl azides thus
formed are unstable and isomerise in the reaction mixture to
5-substituted 1,2,3,4-thiatriazoles17 (Scheme 9, Table 10, 19a,b),
Due to the low reactivity of thioacyl dithiophosphates
towards oxygen nucleophiles, thioacylation reactions can be
performed in two-phase systems with water as a solvent.
Another advantage of our method is that the synthesis of thio-
acyl dithiophosphates and the thioacylation reaction can be
monitored easily, because the thioacyl dithiophosphates are
colorful. During the synthesis of anhydrides 17 the reaction
mixture turns from pink to dark violet and during the reac-
tion with a nucleophile the color changes to yellow or the
reaction mixture becomes colorless.
Conclusions
Acyl dithiophosphates can be obtained in high yield by acyl-
ation of dithiophoshoric acids with acyl chlorides in the
presence of a base or by acylation with acylimidazoles gener-
ated in situ. These compounds are not stable and isomerise to
O-thioacyl monothiophosphates and an equilibrium mixture
is formed. The reaction is accompanied by a much slower
formation of S-thioacyl monothiophosphates. For some sub-
stituents on the acyl moiety the latter process seems to be
irreversible. Acyl dithio-phosphinites and -phosphonates do
not isomerise (at least in boiling benzene) and two alkoxy sub-
stituents on the phosphorus atom appear to be crucial for the
isomerisation. The mixture of isomers contains acylating and
thioacylating agents, and therefore can hardly be used for
efficient thioacylation. Nonetheless, the reaction of this mixture
Scheme
9
Synthesis of 1,2,3,4-thiatriazoles 19 by reaction of
S-thioacyl dithiophosphates 17 with sodium azide.
which are hard to obtain using other methods (to our best
knowledge, sulfuration of acyl azides has not been reported).
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279
1275

View Online
with an excess of a dithiophosphoric acid leads to exclusive
formation of S-thioacyl dithiophosphates. These proved to be
excellent thioacylating agents. They are relatively stable, and
inert towards water and oxygen. Crystalline products can be
stored for months without noticeable change. Even thioacyl
dithiophosphates derived from aliphatic acids can be handled
without special precautions. The reactions with nitrogen and
sulfur nucleophiles proceed very rapidly at ambient conditions,
yielding the respective thioacyl derivatives. Isolation of the
product is very simple. Due to the low reactivity of thioacyl
dithiophosphates towards oxygen nucleophiles, our method can
be employed for direct thioacylation of multifunctional nucleo-
philes containing unprotected hydroxy groups. These types
of thioacyl derivatives can be obtained only with diffculty
using other methods. To recapitulate, we have developed a new
strategy of thioacylation, starting from carboxylic acids. In this
Yields and 31P NMR chemical shifts are collected in Table 1;
HRMS measurements and melting points of anhydrides 5 are
collected in Table 11; 1H, 13C NMR and IR data are available as
supplementary data.†
Benzoyl diphenyldithiophosphinite 10a. Yield 100 %; mp 119–
120 ЊC (lit.,21 120–121 ЊC); δP(CDCl3) 60.82; m/z 354.03117
(C19H15OPS2 requires M, 354.03019).
Mixture of benzoyl (4,4,5,5-tetramethyl-2-thioxo-1,3,2-dioxa-
phospholan-2-yl) sulfide 13a and O-thiobenzoyl (4,4,5,5-tetra-
methyl-2-thioxo-1,3,2-dioxaphospholan-2-yl) ether 16a. Yield
100%; mp 76–79 ЊC; νmax/cmϪ1 1748 (C᎐O), 1162 (C᎐S), 1592,
᎐
᎐
1453 (C᎐C ), 1013, 945 (P–O–C); m/z 316.03497 (C H O PS
᎐
Ar
13 17
3
2
requires M, 316.03567); δP(CDCl3) 85.87 (anhydride 13a); δP
68.52 (anhydride 16a).
one-pot method the exchange of a C᎐O into a C᎐S group and
activation of the thiocarboxylic function occur simultaneously.
᎐
᎐
Reaction of the mixture of benzoyl (4,4,5,5-tetramethyl-2-
thioxo-1,3,2-dioxaphospholan-2-yl) sulfide 13a and O-thio-
benzoyl (4,4,5,5-tetramethyl-2-thioxo-1,3,2-dioxaphospholan-
2-yl) ether 16a with aniline
Experimental
General
A mixture of anhydrides 13a and 16a (0.632, 2 mmol), obtained
as described above, was dissolved in benzene (6 cm3) and a
mixture of aniline (2 mmol) and triethylamine (0.202 g, 2
mmol) was added dropwise while cooling with ice–cold water.
The reaction mixture was washed with water, next dried with
MgSO4, and the solvent was evaporated. The obtained mixture
was subjected to column chromatography on silica gel using
chloroform as eluent. Thiobenzanilide (0.252 g, 59.2%), mp
97–98 ЊC4 and benzanilide (0.146 g, 37.1%), mp 162–164 ЊC22
were obtained.
All reactions were carried out under argon atmosphere in dry
solvents (benzene and THF dried over benzophenone ketyl,
methylene dichloride and alcohols over CaH2, chloroform
over P2O5, hexane and cyclohexane over potassium). Chrom-
atography was carried out on Silica Gel 60 (0.15–0.3 mm)
Macherey Nagel®. NMR was performed on a Varian Gemini
500 MHz, with J-values in Hz; IR on a Bruker IFS66 (liquids:
film; solids: KBr tablet); MS were acquired on a MASPEC II
system [II32/99D9] in EI mode, and if necessary liquid SIMS
technique was applied.
S-Benzoyl O,O-diisopropyl dithiophosphate 12a
5,5-Dimethyl-2-sulfanyl-2-thioxo-1,3,2-dioxaphosphinan 4
Benzoyl chloride (0.422 g, 3 mmol) was added dropwise to a
suspension of triethylammonium O,O-diisopropyl dithiophos-
phate (0.945, 3 mmol) in benzene (10 cm3). After 15 min the
reaction mixture was filtered through a short pad of silica gel.
After the solvent had been evaporated, pure product was
This was prepared from P2S5 and 2,2-dimethylpropane-1,3-diol
according to the method described by Chauhan et al.,18 in
79.7% yield; mp 81–82 ЊC; δP(CDCl3) 77.68.
obtained (0.9 g, 94.3%), mp 46–47 ЊC; νmax/cmϪ1 1682 (C᎐O),
᎐
4,4,5,5-Tetramethyl-2-sulfanyl-2-thioxo-1,3,2-dioxaphospholan
15
1594, 1580, 1468, 1450 (C᎐C ), 1027, 982 (P–O–C), 687 (P᎐S);
᎐
᎐
Ar
δP(CDCl3) 76.87; δH(CDCl3) 7.93 (2H, d, J 7.3), 7.61 (1H, t,
J 7.8), 7.47 (2H, t, J 7.8), 5.06 (1H, spt, J 6.4), 5.04 (1H, spt,
J 5.9), 1.42 (6H, d, J 6.3), 1.36 (6H, d, J 5.9); δC(CDCl3) 186.54,
136.67, 134.59, 129.12, 128.35, 74.98 (d, JP–C 6.6), 24,12 (d, JP–C
4.4), 23.45 (d, JP–C 5.3); m/z 318.05246 (C13H19O3PS2 requires
M, 318.05132).
This was prepared from P2S5 and 1,1,2,2-tetramethylethane-
1,2-diol according to the method described by Chauhan et al.,18
in 61% yield; mp 68–69 ЊC; δP(CDCl3) 93.18.
Diphenyldithiophosphinic acid
This was prepared from P2S5 and benzene in the presence of
AlCl3 according to the procedure of Higgins et al.,19 in 75%
yield; mp 54–56 ЊC; δP(CDCl3) 56.5.
S-Benzoyl O-methyl 4-methoxyphenyldithiophosphonate 11a
This was prepared according to the method of Shabana,23 in
30% yield; δP(CDCl3) 89.06.
Triethylammonium O,O-diisopropyl dithiophosphate
Reactions of acyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-
2-yl) sulfides 5 with amines
This was prepared from P2S5, propan-2-ol and triethylamine
according to Almasi et al.,20 in 61% yield; mp 100–102 ЊC;
δP(CDCl3) 108.28.
A mixture of amine (aniline, isopropylamine, diethylamine)
(1 mmol) and triethylamine (0.101 g, 1 mmol) was added drop-
wise to a solution of an acyl (5,5-dimethyl-2-thioxo-1,3,2-
dioxaphosphinan-2-yl) sulfide 5 (1 mmol) in benzene (3 cm3)
while cooling with ice-cold water. Triethylammonium (5,5-
dimethyl-2-thioxo-1,3,2-dioxaphosphinan-2-yl)thiolate precipi-
tated immediately. After 15 min the reaction mixture was
filtered through silica gel and the amide was eluted with methyl-
ene dichloride. All products were compared with authentic
samples. Yields and melting points are collected in Table 2.
S-Acyl dithio-phosphates and -phosphinites 5, 10, 13;
general procedure
An acyl chloride (3 mmol) was added to a solution of the
appropriate dithiophosphoric (dithiophosphinic) acid (3 mmol)
in benzene (10 cm3). Subsequently, triethylamine (0.303 g,
3 mmol) or pyridine (0.237g, 3 mmol) was added dropwise to
the ice-cold solution. Immediately, triethylammonium chloride
precipitated. After 15 min the reaction mixture was filtered
through a short pad of silica gel. After the solvent had been
evaporated, pure product was obtained.
Synthesis of acyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-
2-yl) sulfides 5 directly from carboxylic acids; general procedure
In the case of 4-nitrobenzoyl (5,5-dimethyl-2-thioxo-1,3,2-
dioxaphosphinan-2-yl) sulfide 5c, methylene dichloride was
used instead of benzene to avoid problems with solubility.
Method A. A solution of carbonyldiimidazole (0.324 g,
2 mmol) in methylene dichloride or chloroform (3 cm3) was
1276
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279

View Online
Table 11 Melting points and HRMS measurements for anhydrides 5–7, 17
No.
R
Mp (θ/ЊC)
Formula
Calculated
Found
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
6a
7a
7b
7d
7i
Ph
114–115
92–93
159–162
106–108
105–107
71–72
C12H15O3PS2
C13H17O4PS2
C12H14NO5PS2
C16H17O3PS2
(M ϩ Na) C14H17NaO3PS2
C7H13O3PS2
C9H17O3PS2
C9H17O3PS2
C10H19O3PS2
(M ϩ H) C12H22O3PS2
C13H17O4PS2
(M ϩ H) C13H18O3PS2
C19H21O3PS2
(M ϩ H) C12H22O5PS2
C15H16NO5PS2
C16H18NO5PS2
C12H15O3PS2
C12H15O3PS2
C13H17O4PS2
C16H17O3PS2
C10H19O3PS2
302.02002
332.03059
347.00510
352.03567
351.02544
240.00437
268.03568
268.03568
282.05132
309.07480
332.03059
317.04350
392.06697
341.06463
385.02075
399.03640
302.02002
302.02002
332.03059
352.03567
282.05132
317.99718
368.01283
298.02848
302.01975
332.02928
347.00457
352.03241
351.02681a
239.99691
268.03562
268.03526
282.05046
309.07423a
332.03128a
317.04472a
392.06543
341.06308a
385.02138
399.03584
302.01921
302.01934
332.03009
352.03243
282.05073
317.99997
368.01032
298.02853
C6H4OMe-p
C6H4NO2-p
1-Naphthyl
CH᎐CH2Ph
Me
᎐
Pr
98–99
70–71
Pri
But
112–113
96–97
113–114
100–101
130–131
≈ 25
CH(CH2)5
CH2OPh
CH2Ph
CHPh2
(CH2)4COOMe
CH2NPhth
CH2CH2NPhth
Ph
166–168
120–122
102–103
≈ 20
Ph
C6H4OMe-p
1-Naphthyl
But
83–85
144–145
115–117
95–97
139–140
153–154
17a
17d
17i
Ph
C12H15O2PS3
C16H17O2PS3
C10H19O2PS3
1-Naphthyl
But
a LSIMS method.
added dropwise to a solution (or suspension) of the carboxylic
acid (2 mmol) in methylene dichloride or chloroform (1 cm3).
Following complete evolution of CO2 (15–30 min), a solution
are collected in Table 5; HRMS measurements and melting
points are collected in Table 11; 1H, 13C NMR and IR data are
available as supplementary data.†
of 5,5-dimethyl-2-sulfanyl-2-thioxo-1,3,2-dioxaphosphinan
4
(1.188 g, 6 mmol) in methylene dichloride (chloroform) (3 cm3)
was added, while cooling with ice–water. After being stirred for
15 min under ambient conditions, the reaction mixture was
washed with water, and the organic layer was dried over
MgSO4. Solvent evaporation yielded a crude product, which
was purified by means of silica gel chromatography or crystal-
lisation from a benzene–cyclohexane mixture. Results are
collected in Table 3.
Thiobenzoyl (5,5-dimethyl-2-thioxo-1,3,2,-dioxaphosphinan-2-
yl) ether 6a. 2 h of heating; eluent CHCl3–hexane 2 : 5.
Thiobenzoyl (5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinan-2-yl)
sulfide 7a. 20 h of heating; eluent CH2Cl2.
4-Methoxythiobenzoyl
(5,5-dimethyl-2-oxo-1,3,2-dioxa-
phosphinan-2-yl) sulfide 7b. 8 h of heating; after cooling, the
product precipitated. Filtration yielded pure product.
Method B. 2 mmol of an acylimidazole was generated as
above and a solution of 5,5-dimethyl-2-sulfanyl-2-thioxo-1,3,2-
dioxaphosphinan 4 (0.396 g, 2 mmol) in methylene dichloride
(chloroform) (1 cm3) was added, with cooling of the reaction
mixture with ice–water. Then trifluoroacetic acid (0.456 g, 4
mmol) was added dropwise. After 15 min of stirring at ambient
conditions, imidazolium trifluoroacetate precipitated. Then, the
reaction mixture was filtered through a short pad of silica gel.
Solvent evaporation yielded pure product. Yields and 31P NMR
chemical shifts are collected in Table 3; HRMS measurements
and melting points are collected in Table 11; 1H, 13C NMR and
IR data are available as supplementary data.†
1-Thionaphthoyl (5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinan-
2-yl) sulfide 7d. 15 h of heating; after solvent evaporation pure
enough product was obtained.
Thiopivaloyl
(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinanyl)
sulfide 7i. 28 h of heating; eluent CH2Cl2.
Thioacylation of amines with thioacyl (5,5-dimethyl-2-thioxo-
1,3,2-dioxaphosphinan-2-yl) ethers 6 and thioacyl (5,5-dimethyl-
2-oxo-1,3,2-dioxaphosphinan-2-yl) sulfides 7; general procedure.
A mixture of triethylamine (0.101 g, 1 mmol) and an amine
(isopropylamine, aniline or diethylamine) (1 mmol) was added
to a solution of an anhydride 6 or 7 (1 mmol) in benzene
(5 cm3). The color of the reaction mixture changed and triethyl-
Isomerisation of acyl (5,5-dimethyl-2-thioxo-1,3,2-dioxa-
phosphinan-2-yl) sulfides 5; general procedure
A solution of anhydride 5 (3 mmol) in benzene (20 cm3) was
refluxed for 1–28 h. For analytical purposes, ≈0.5 cm3 of the
reaction mixture was taken to perform 31P NMR measurement
(≈0.2 cm3 of C6D6 was added to set up the lock). When the
experiment was finished, a mixture of an amine (aniline,
isopropylamine, diethylamine, or piperidine) (3 mmol) and
triethylamine (0.303 g, 3 mmol) was added dropwise while
cooling. Such a reaction mixture was subjected to column
chromatography. Thioamide was eluted with benzene and then
the amide was eluted with methylene dichloride. Results are
collected in Tables 4 and 6.
ammonium
(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinan-2-
thiolate 8a precipitated. After 15 min the reaction mixture was
filtered through a short pad of silica gel, and after evaporation
of the solvent the corresponding pure thioamide 9 was
obtained.
Reaction of thiobenzoyl (5,5-dimethyl-2-thioxo-1,3,2-dioxa-
phosphinan-2-yl) ether 6a with aniline. Thiobenzanilide 9a was
isolated; yield 93%; mp 98–99 ЊC.4
To isolate anhydrides 6 and 7, after heating anhydrides 5, the
solvent was evaporated off and the residue was subjected to
column chromatography. Yields and 31P NMR chemical shifts
Reaction of thiobenzoyl (5,5-dimethyl-2-oxo-1,3,2-dioxa-
phosphinan-2-yl) sulfide 7a with aniline. Thiobenzanilide 9a was
isolated; yield 81.4%; mp 97–98 ЊC.4
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279
1277

View Online
Reaction of 4-methoxythiobenzoyl (5,5-dimethyl-2-oxo-1,3,2-
dioxaphosphinan-2-yl) sulfide 7b with diethylamine. N,N-diethyl-
4-methoxythiobenzamide 9b was isolated; yield 93.2%; mp
43–45 ЊC,24 δH(CDCl3) 7.19 (2H, d, J 8.8), 6.84 (2H, d, J 8.5),
4.11 (2H, q, J 7), 3.79 (3H, s), 3.47 (2H, q, J 7), 1.14 (3H, t, J 7),
1.37 (3H, t, J 7), δC(CDCl3) 200.68, 159.69, 136.78, 126.99,
113.86, 48.09, 46.54, 14.15, 11.53.
Thiopivaloyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-2-
yl) sulfide 17i. Reaction time 4 h. Before being washed with aq.
NaHCO3, the reaction mixture was diluted with chloroform
because the product started to precipitate. Crystallisation was
from benzene.
Thiobenzamide 9e. A solution of thiobenzoyl (5,5-dimethyl-
2-thioxo-1,3,2-dioxaphosphinan-2-yl) sulfide 17a (0.636 g, 2
mmol) in benzene (10 cm3) with 1 cm3 of 30% aqueous ammo-
nia was stirred vigorously overnight. The, organic layer was
diluted with chloroform, separated, washed with water, and
dried over MgSO4. After the mixture had been evaporated,
thiobenzamide 9e was obtained (0.259 g, 94.5%); mp 115–118
ЊC.27
Reaction of 1-thionaphthoyl (5,5-dimethyl-2-oxo-1,3,2-dioxa-
phosphinan-2-yl) sulfide 7d with isopropylamine. N-(1-Thio-
naphthoyl)-isopropylamine 9c was isolated; yield 96.1%; mp
99–100 ЊC.25
Reaction of thiopivaloyl (5,5-dimethyl-2-oxo-1,3,2-dioxa-
phosphinanyl) sulfide 7i with aniline. Two hours were necessary
to complete the reaction; the product was eluted with chloro-
form; N-thiopivaloylaniline 9d was isolated; yield 94.3%; mp
88–89 ЊC.26
Thioacylation with thioacyl dithiophosphates 17;
general procedure
Method A. A solution of an amine or thiol (5 mmol) and
pyridine or triethylamine (5,5 mmol) in benzene (5 cm3) was
added dropwise to a solution of a thioacyl (5,5-dimethyl-2-
thioxo-1,3,2-dioxaphosphinan-2-yl) sulfide 17 (5 mmol) in
benzene (15 cm3). Pyridinium or triethylammonium dithio-
phosphate precipitated out and was removed by filtration or by
successive washings with water and aqueous sodium carbonate.
Evaporation of the solvent generally yielded pure-enough
product. If necessary, the thioacyl derivative was purified by
means of chromatography or crystallisation.
Comparison of thermal stability of acyl dithiophosphinites 10,
dithiophosphonates 11 and dithiophosphates 12, 13
A the solution of an acyl dithophosphate (dithiophosphon-
ate, dithiophosphinite) (3 mmol) in benzene (20 cm3) was
refluxed for 8 h and the reaction mixture was monitored by
31P NMR. The solvent was then evaporated off. In case
of benzoyl diphenyldithiophosphinite 10a and S-benzoyl
O-methyl 4-methoxyphenyldithiophosphonate 11a the start-
ing material was recovered. In the case of S-benzoyl
O,O-diisopropyl dithiophosphate 12a the obtained orange solid
was subjected to column chromatography (eluent benzene–
cyclohexane 1 : 2) and O-thiobenzoyl O,O-diisopropyl thio-
phosphate 14a was isolated (0.357 g, 37.4%) as an orange oil
(solidifying in the fridge); δP(CDCl3) 57.66; δH(CDCl3) 8.15
(2H, dd, J1 8.3, J2 1.5), 7.58 (1H, t, J 7.3), 7.4 (2H, t, J 7.8), 5.04
(1H, sept, J 6.4), 5.03 (1H, sept, J 6.4), 1.43 (6H, d, J 6.4), 1.42
(6H, d, J 6.4); δC(CDCl3) 202.71 (d, JP–C 6.7), 138.59 (d, JP–C
9.2), 133.86, 129.28, 128.59, 75.27 (d, JP–C 6.6), 23.86 (d, JP–C
4.4), 23.6 (d, JP–C 5.3); m/z 318.04909 (C13H19O3PS2 requires M,
318.05132); νmax/cmϪ1 1593, 1465, 1450 (C᎐C ), 1268 (C᎐S),
Method B. A solution of acyl (5,5-dimethyl-2-thioxo-1,3,2-
dioxaphosphinan-2-yl) sulfide 5 (5 mmol) and 5,5-dimethyl-2-
sulfanyl-2-thioxo-1,3,2-dioxaphosphinan 4 (1.98 g, 10 mmol) in
35 cm3 of benzene was heated under reflux for 2–6 hours. A
solution of an amine or thiol (5 mmol) and pyridine or triethyl-
amine (16.5 mmol) in benzene was added dropwise. The result-
ing mixture was worked up as above.
Thiobenzanilide 9a. Method A; yield 98.6%; mp 97–99 ЊC.4
᎐
᎐
Ar
1041, 994 (P–O–C), 686 (P᎐S).
N-(1-Thionaphthoyl)isopropylamine 9c. Method A; filtration
through a short pad of silica gel gave pure product; yield 95.6%;
mp 99–100 ЊC.25
᎐
The reaction mixture obtained from benzoyl (4,4,5,5-
tetramethyl-2-thioxo-1,3,2-dioxaphospholan-2-yl) sulfide 13a
and thiobenzoyl (4,4,5,5-tetramethyl-2-thioxo-1,3,2-dioxa-
phospholan-2-yl) ether 16a contained ≈ 25% of thiobenzoyl
(4,4,5,5-tetramethyl-2-oxo-1,3,2-dioxaphospholan-2-yl) sulfide
(δP 16.99). However, the mixture was inseparable.
N-Thiopivaloylaniline 9d. Method A; the reaction was per-
formed in 100 cm3 of benzene; reaction time 36 h; column
chromatography; eluent benzene–hexane 1 : 1; yield 96.6%; mp
88–89 ЊC.26
Thioacyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-2-yl)
sulfides 17; general procedure
N-Thiobenzoylpiperidine 9f. Method A; column chromato-
graphy, eluent CHCl3; yield 97.7%; mp 62–64 ЊC.28
A solution of an acyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphos-
phinan-2-yl) sulfide 5 (5 mmol) and 5,5-dimethyl-2-sulfanyl-2-
thioxo-1,3,2-dioxaphosphinan 4 (1.98 g, 10 mmol) in 35 cm3 of
benzene was heated under reflux for 1.5–6 hours (until complete
disappearance of the starting material). Then phosphoric thio-
acids were removed by washing successively with aqueous
sodium carbonate and water. Subsequently, the organic
layer was dried with magnesium sulfate and the solvent was
evaporated off. The crude product was used for thioacyl-
ation without further purification or, where necessary, it was
purified by means of silica gel chromatography or crystallis-
ation. Yields and 31P NMR chemical shifts are collected in
Table 9; HRMS measurements and melting points are collected
in Table 11; 1H, 13C NMR and IR data are available as
supplementary data.†
N-Thiobenzoylethanolamine 9g. Method A; the reaction was
performed in chloroform; column chromatography, eluent
ButOMe–CH2Cl2 1 : 6; yield 94.1%; mp 91–92 ЊC.29
4-Nitrothiobenzanilide 9h. Method B; 4 h of heating; column
chromatography, eluent benzene; yield 85.3%; mp 154–155 ЊC.30
Thioacetanilide 9i. Method B; 3 h of heating; column
chromatography; eluent CHCl3; yield 87.8%; mp 74–76 ЊC.31
Thiobutyranilide 9j. Method B; 3 h of heating; column
chromatography; eluent CHCl3; yield 91.8%; mp 31–32 ЊC.32
N-Thiopivaloylallylamine 9k. Method A; reaction mixture
was filtered through a short pad of silica gel. Solvent evapor-
ation yielded pure product; yield 100%; δH(CDCl3) 7.39 (1H,
bs), 5.93 (1H, m), 5.28 (1H, m), 5.21 (1H, m), 4.31 (2H, m), 1.36
(9H, s), δC(CDCl3) 213.98, 132.55, 118.79, 49.15, 45.05, 30.65.33
Thiobenzoyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-2-
yl) sulfide 17a. Reaction time 2 h; eluent benzene.
1-Thionaphthoyl
(5,5-dimethyl-2-thioxo-1,3,2-dioxaphos-
phinan-2-yl) sulfide 17d. Reaction time 1.5 h; eluent benzene.
1278
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279

View Online
2-(Thiopivaloylamino)phenol 9l. Method A; the reaction was
performed in THF; reaction time was 3 h; before washing
with water the reaction mixture was diluted with chloroform;
column chromatography; eluent chloroform–methanol 30 : 1;
yield 99%; mp 123–124 ЊC; δH(CDCl3) 8.72 (1H, s), 7.24 (2H, d,
J 8.3), 6.79 (2H, d, J 8.8), 5.9 (1H, bs), 1.47 (9H, s), δC(CDCl3)
214.42, 155.17, 131.73, 127.06, 116.26, 45.45, 30.53; m/z
209.08827 (C11H15NOS requires M, 209.08744).
1,3,2-dioxaphosphinan-2-yl) sulfide 17i (0.298 g, 1 mmol) in
chloroform (3 cm3), and then triethylamine (0.111 g, 1.1 mmol)
was added dropwise. The reaction mixture immediately
changed color from red to dark yellow. After 15 min the reac-
tion mixture was washed with water and dried over MgSO4.
After the solvent had been evaporated off, the reaction mixture
was subjected to column chromatography (chloroform as elu-
ent) to yield pure 2-(thiopivaloylsulfanyl)ethanol 20a (0.173 g,
97.2%); δH(CDCl3) 3.84 (2H, t, J 5.9), 3.44 (2H, t, J 5.9), 2.4
(1H, s), 1.45 (9H, s), δC(CDCl3) 251.04, 60.29, 52.52, 39.12,
31.96; m/z 178.04944 (C7H14OS2 requires M, 178.04861).
N-[5-(Methoxycarbonyl)thiopentanoyl]piperidine 9m. Method
B; 4 h of heating; column chromatography; eluent methylene
dichloride; yield 87.9%; δH(CDCl3) 4.26 (2H, t, J 5.7), 3.68 (2H,
t, J 5.5), 3.67 (3H, s), 2.88 (2H, t, J 7.7), 2.36 (2H, t, J 7), 1.71
(10H, m); δC(CDCl3) 201.32, 173.63, 51.69, 51.66, 51.02, 43.67,
33.88, 28.69, 27.7, 25.58, 24.81, 24.36; m/z 243.12879
(C12H21NO2S requires M, 243.12930).
Acknowledgements
We gratefully acknowledge the Polish State Committee for
Scientific Research for financial support (Grant No. 3 T09A
061 16).
Synthesis of thiohydroxamic acids 18; general procedure
Triethylamine (respectively, 1 mmol, 2 mmol or 3 mmol) was
added to a solution of hydroxylamine, a suspension of hydroxy-
lamine hydrochloride, or a suspension of hydroxylamine
oxalate (1 mmol) in chloroform (2 cm3). Then a solution of a
thioacyl (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphinan-2-yl)
sulfide 17 (1 mmol) in chloroform (4 cm3) was added dropwise.
After 15 min the reaction mixture was filtered through a short
pad of silica gel and the solvent was evaporated off. The crude
product was purified by means of column chromatography.
References
1 S. Scheithauer and R. Mayer, Thio- and Dithiocarboxylic Acids and
Their Derivatives, ed. A. Senning, Georg Thieme, Stuttgart, 1979,
vol. 4.
2 R. Cherkasov, G. Kutyriev and A. Pudovik, Tetrahedron, 1985, 41,
2567.
3 J. Bodine and M. Kaloustian, Synth. Commun., 1982, 12, 787.
4 B. Pedersen and S.-O. Lawesson, Bull. Soc. Chem. Belg., 1977, 86,
693.
5 D. C. Smith, S. W. Lee and P. L. Fuchs, J. Org. Chem., 1994, 59,
348.
6 A. R. Katritzky, J. Moutou and Z. Yang, Synthesis, 1995, 1497.
7 S. Kato, E. Hattori, H. Sato, M. Mizuta and M. Ishida,
Z. Naturforsch., Teil B, 1981, 36, 783.
8 S. Kato, H. Shibahashi, T. Katada, T. Tagaki, I. Noda, M. Mizuta
and M. Goto, Liebigs Ann. Chem., 1982, 1229.
9 T. Hoeg-Jensen, C. Olsen and A. Holm, J. Org. Chem., 1994, 59,
1257.
10 S. Kato, H. Masumoto, S. Ikeda, M. Itoh, T. Murai and H. Ishihara,
Z. Chem., 1990, 30, 67.
11 C. T. Brain, A. Hallett and S. Y. Ko, J. Org. Chem., 1997, 62,
3808.
N-Hydroxy-N-methylthiobenzamide 18a. N-Methylhydroxyl-
amine hydrochloride was used; eluent ButOMe–hexane 10 : 3;
yield 68.3%; δH(CDCl3) 11 (1H, bs), 7 (5H, m), 3.4 (3H, s);
positive Fe3ϩ test.34
N-Hydroxy-N-isopropylthiobenzamide 18b. N-Isopropyl-
hydroxylamine oxalate was used; eluent benzene; yield 73.3%;
δH(CDCl3) 9.75 (1H, s), 6.9 (5H, s), 4.15 (1H, m), 1.2 (6H, d,
J 6); positive Fe3ϩ test.15
12 B. Zacharie, G. Sauve and C. Penney, Tetrahedron, 1993, 49,
N-Hydroxy-N-methylthiopivalamide 18c. N-Methylhydroxyl-
amine hydrochloride was used; the reaction was performed
10489.
13 B. Zacharie, M. Lagraoui and M. Dimarco, J. Med. Chem., 1999, 42,
2046.
14 L. Doszczak and J. Rachon, Chem. Commun., 2000, 2093.
15 W. Przychodzen and A. Chimiak, Phosphorus Sulfur, 1998, 143,
77.
16 A. Chimiak, W. Przychodzen and J. Rachon, Heteroatom Chem.,
2002, 13, 169.
in methylene dichloride; eluent chloroform; yield 71.1%; νmax
/
cmϪ1 3298 (O–H), 2963, 2874 (C–H), 1221 (C᎐S); δ (CDCl )
᎐
H
3
11.39 (1H, s), 3.72 (3H, s), 1.38 (9H, s), δC(CDCl3) 192.72,
41.74, 40.22, 30.45; m/z 147.07199 (C6H13NOS requires M,
147.07179); positive Fe3ϩ test.
17 S. Ikeda, T. Murai, H. Ishihara and S. Kato, Synthesis, 1990, 415.
18 H. P. S. Chauhan, C. P. Bhasin, G. Srivastava and R. C. Mehrotra,
Phosphorus, Sulfur, Relat. Elem., 1983, 15, 99.
19 W. Higgins, P. Vogel and W. Craig, J. Am. Chem. Soc., 1955, 77,
1864.
20 L. Almasi, A. Hantz, E. Weissmann and E. Hamburg, Rev. Roum.
Chim., 1967, 12, 1269.
21 U.S. Pat. 3 454 937, 1968, Stauffer Chem. Co., (Chem. Abstr., 1969,
71, 61453).
22 J. Gloede and H. Gross, Chem. Ber., 1967, 100, 1770.
23 R. Shabana, Phosphorus Sulfur, 1987, 29, 293.
24 P. K. Bhattacharya, S. Bandyopadhyay and S. Pakrashi, Indian J.
Chem., Sect. B, 1989, 28, 673.
1,2,3,4-Thiatriazoles 19; general procedure
A solution of sodium azide (0.098 g, 1.5 mmol) in 0.5 cm3 of
water was added to a solution of a thioacyl (5,5-dimethyl-2-
thioxo-1,3,2-dioxaphosphinan-2-yl) sulfide 17 (1 mmol) in
metylene dichloride (5 cm3). The reaction mixture was stirred
vigorously overnight, and the organic layer was separated,
washed with water, and dried over MgSO4. After the solution
had been evaporated, the crude product was subjected to col-
umn chromatography.
5-Phenyl-1,2,3,4-thiatriazole 19a. Eluent cyclohexane–THF
80 : 1; yield 88.9%; mp 94–95 ЊC.17
25 W. Walter and C. O. Meese, Chem. Ber., 1977, 110, 2463.
26 D. H. Reid and W. G. Salmond, J. Chem. Soc. C, 1966, 686.
27 J. R. Cashman and R. P. Hanzlik, J. Org. Chem., 1982, 47, 4645.
28 A. B. Tomchin, Zh. Org. Khim., 1981, 17, 589.
29 A. Lawson and C. E. Searle, J. Chem. Soc., 1957, 1556.
30 H. Rivier and J. Zeltner, Helv. Chim. Acta, 1937, 20, 691.
31 R. Mukherjee and R. M. Moriarty, Tetrahedron, 1976, 32, 661.
32 F. Sachs and H. Loevy, Ber. Dtsch. Chem. Ges., 1903, 36, 585.
33 G. Entenmann, Chem.-Ztg., 1977, 101, 508.
34 K. S. Murray, P. J. Newman, B. M. Gatehouse and D. Taylor, Aust. J.
Chem., 1978, 31, 983.
5-tert-Butyl-1,2,3,4-thiatriazole 19b. Eluent cyclohexane–
THF 80 : 1; yield 92%; δH(CDCl3) 1.57 (s); δC(CDCl3) 192.3,
36.02, 31.87.35
2-(Thiopivaloylsulfanyl)ethanol 20a
2-Sulfanylethanol(mercaptoethanol) (0.078 g, 1 mmol) was
added to a solution of thiopivaloyl (5,5-dimethyl-2-thioxo-
35 K. A. Jensen and C. Pedersen, Acta Chem. Scand., 1964, 18, 566.
J. Chem. Soc., Perkin Trans. 1, 2002, 1271–1279
1279