New, efficient and chemoselective method of thioacylation, starting from carboxylic acids

Article abstract of DOI:10.1039/b005911k

S-Acylation of dithiophosphoric acids yields mixed anhydrides 3; they readily isomerize to O-thioacyl 4 and S-thioacyl monothiophosphates 5, which treated with the excess of dithiophosphoric acid 2 can be easily converted into thioacyl dithiophosphates 6, excellent thioacylating reagents.

Full text of DOI:10.1039/b005911k

New, efficient and chemoselective method of thioacylation, starting from
carboxylic acids†
Leszek Doszczak and Janusz Rachon*
Department of Organic Chemistry, Chemical Faculty, Technical University of Gdansk, ul. Narutowicza 11/12, 80-952
Gdansk, Poland
Received (in Liverpool, UK) 19th July 2000, Accepted 19th September 2000
First published as an Advance Article on the web 9th October 2000
Table 1 Acylation of dithiophosphoric acid 2
S-Acylation of dithiophosphoric acids yields mixed anhy-
drides 3; they readily isomerize to O-thioacyl 4 and S-
Chemical shift
thioacyl monothiophosphates 5, which treated with the
Entry
R
(ppm) 31P NMR
Yield (%)
excess of dithiophosphoric acid 2 can be easily converted
into thioacyl dithiophosphates 6, excellent thioacylating
reagents.
3a
3b
3c
3d
3e
3f
3g
3h
3i
1-Naphthyl
Ph
4-PhOMea
4-PhNO2
CHNCH2Pha
Me
Pr
iPr
tBu
CH2NPht
CH2CH2NPht
CH2OPh
(CH2)4COOMe
69.6
69.1
70.1
65.9
69.7
69.1
70.1
70.6
70.8
65.8
67.7
67.9
69.2
100
98
85
85
93
89
92
98
96
82
93
90
100
Thioacyl derivatives are mainly obtained by treating acyl
derivatives with a thionating agent such as phosphorus
pentasulfide or Lawesson’s reagent.1,2 Numerous other exam-
ples of sulfurating reagents have been reported (e.g. R3OBF4–
NaHS,3 R2PSX,4 POCl3–(Me3Si)2S,5 (Et2Al)2S,1 B2S3 or
1
1
SiS2 ) but are less well-known. Another strategy is to
3j
3k
3l
thioacylate nucleophiles with active derivatives of thiocar-
boxylic acids. Unfortunately, the known thioacylating agents
(e.g. thioacyl halides,1 thioacyl benzimidazolones,6 thioacyl
imidazoles, triazoles or tetrazoles,1 thioacyloxybenzotriazoles,7
thioacyl trifluorosulfonyl sulfides,8 phenylmercury dithiocar-
boxylates9 or bis(thioacyl) sulfides10 etc.) show many disadvan-
tages. They are generally unstable, expensive or their synthesis
is complicated. In the case of less reactive reagents (like
thioesters) reaction times are very long or the product cannot be
obtained at all.1 Most of the described reagents can only be
prepared from dithiocarboxylic acids, which are scarcely
obtainable commercially and are not easy to synthesise in high
yield or to handle in pure form.
Here we report a new procedure for thioacylation with S-
thioacyldithiophosphates, starting from carboxylic acids and
dithiophosphoric acid. The usefulness of those kinds of reagents
(namely thioacyl diphenylthiophosphinic sulfides) have been
described by Kato et al.11 but only derivatives of aromatic
dithioacids were prepared by his group and the method of
synthesis required cesium (or piperidinium) salts of dithio-
carboxylic acids (general drawback). Moreover thioacyl diph-
enyldithiophosphinates are less reactive than dithiophosphates.
We would like to describe a new and efficient method of
synthesis of corresponding species and expand the scope of
their applications (Scheme 1).‡
Acylation of dithiophosphoric acids (at the moment our best
choice is 5,5-dimethyl-2-thiolo-2-thiono-1,3,2-dioxaphosphor-
inane12 (2)) yields mixed anhydrides of type 3 almost
quantitatively (see Table 1). These compounds in solution
isomerize to O-thioacylmonothiophosphates 4 and S-thio-
acylmonothiophosphates 5 (as we have proved, potential
thioacylating reagents) but in an equilibrium mixture com-
pounds 3 generally predominate.§ However, we have found that
treatment of that mixture with excess of dithiophosphoric acid
leads to the formation of mixed anhydrides of type 6 in high
yields (see Table 2). Compounds of type 6 are relatively inert
towards water and oxygen and are very good thioacylating
agents. They react immediately with nitrogen and sulfur
nucleophiles at rt. Thioacyl derivative 7 can be easily separated
from water-soluble salts of thiophosphoric acids. Anhydrides 6
chemoselectively thioacylate nitrogen or sulfur nucleophiles in
the presence of hydroxy groups. This property allows us to
3m
a Due to fast isomerization obtained in mixtures with anhydride 4 (chemical
shift 31P NMR of 4c: 50.1 ppm; 4e: 50.3 ppm).
obtain e.g. hydroxythioamides (Table 3, 7g, 7l) or hydrox-
ydithioesters (7m) or thiohydroxamic acids (7e, 7f, 7k) as well,
from substrates with an unprotected oxygen atom. It is worth
mentioning that these kinds of compound are not available via
thionation of unprotected hydroxyamides, hydroxythiolesters or
hydroxamic acids with Lawesson’s reagent.13
In summary we have developed a new strategy of thioacyla-
tion, starting from carboxylic acids. In one pot the exchange of
CNO into CNS occurs and at the same time activation of the
thiocarboxyl function is performed. The method is simple and
efficient and cheap reagents are used. The thioacylating agents
formed are stable and can be stored for months without
noticeable changes. Even thioanhydrides derived from aliphatic
acids can be handled without special precautions. The reaction
with N- or S-nucleophiles is very fast under ambient conditions
and isolation of the product is very simple.
Our efforts to apply the isomerization of anhydrides of type
3 for the synthesis of thioacylating reagents are focused on a
search for dithiophosphoric acids better suited for the described
procedure. Our results will be published in a full paper soon.
We gratefully acknowledge the Polish State Committee for
Scientific Research for financial support (Grant No. 3 T09A 061
16).
Table 2 Thioacyl dithiophosphates 6
Chemical shift
Entry
R
(ppm) 31P NMR Time/h
Yield (%)
6a
6b
6f
6g
6i
1-Naphthyl
Ph
Me
Pr
67.8
68.6
68.4
68.5
70.7
67.2
1.5
2
3
3
4
90
94
88
92
91
88
tBu
6m
(CH2)4COOMe
4
† Presented in part at 13th ICOS, Warsaw 2000, Poland, pp. 139.
DOI: 10.1039/b005911k
Chem. Commun., 2000, 2093–2094
This journal is © The Royal Society of Chemistry 2000
2093

Table 3 Thioacylations with dithiophosphates 6
Entry
R
Nucleophile
Product
Yield (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Pr
tBu
tBu
tBu
Aq. NH3
PhNH2–NEt3
PhCSNH2
PhCSNHPh
95
99
98
0
(CH2)5NH–NEt3
MeOH–NEt3
MeNHOH·HCl–NEt3
iPrNHOH·HCl–NEt3
HOCH2CH2NH2–NEt3
PhNH2–NEt3
PhNH2–NEt3
PhNH2–NEt3
MeNHOH·HCl–NEt3
2-HOPhNH2–NEt3
HOCH2CH2SH–NEt3
(CH2)5N–NEt3
PhCSN(CH2)5
PhCSOMe
PhCSN(OH)Me
PhCSN(OH)iPr
PhCSNHCH2CH2OH
MeCSNHPh
PrCSNHPh
tBuCSNHPh
tBuCSN(OH)Me
2-tBuCSNHPhOH
tBuCSSCH2CH2OH
MeOCO(CH2)4CSN(CH2)5
68
73
94
88a
96a
92
71
99
97
88a
tBu
(CH2)4COOMe
a Procedure B.
Scheme 1 Conversion of carboxylic acids into thioacylating reagents and their reaction with nucleophiles.
5a,b,i) and to fully characterize them. Reactivity and the mechanism of
formation of the species are under investigation. We would like to
emphasize that apart from not well proven reports14 of isomerization of
anhydrides of type 3 to 4, formation of compounds type 5 from 3 (or a
mixture of 3 and 4) have not been previously reported in the literature
(excluding the speculations of Cherkasov,15 which however do not agree
with our results).
Notes and references
‡ Acyl dithiophosphates 3, typical procedure: acyl chloride (5 mmol) is
added to a solution of 5,5-dimethyl-2-thiolo-2-thiono-1,3,2-dioxaphosphor-
inane (2) (5 mmol) in 15 ml of benzene. The solution is cooled with iced
water and subsequently pyridine or triethylamine (5 mmol) is added
dropwise. Immediately, ammonium chloride precipitates. After 15 minutes
the reaction mixture is filtered through a short layer of silica gel. Following
solvent evaporation a pure enough product is obtained.
Thioacyl dithiophosphates 6, typical procedure: A solution of 5 mmol of
acyl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphorinanyl) sulfide (3) and
5,5-dimethyl-2-thiolo-2-thiono-1,3,2-dioxaphosphorinane (2) (10 mmol) in
35 ml of benzene is heated under reflux for 2–6 h. Subsequently phosphoric
thioacids 2 and 8 are removed by washing with an aq. solution of sodium
carbonate and then water. The organic layer is then dried with magnesium
sulfate and the benzene is evaporated. The crude product is used for
thioacylation without further purification, or if necessary is purified by
means of silica gel chromatography or crystallization.
1 S. Scheithauer and R. Mayer, in Thio- and Dithiocarboxylic Acids and
their Derivatives, A. Senning, ed., Thieme, Stuttgart, 1979, vol. 4.
2 R. Cherkasov, G. Kutyriev and A. Pudovik, Tetrahedron, 1985, 41,
2567; M. Cava and M. Levinson, Tetrahedron, 1985, 41, 5061.
3 J. Bodine and M. Kaloustian, Synth. Commun., 1982, 12, 787.
4 B. Pedersen and S. Lawesson, Bull. Soc. Chem. Belg., 1977, 86, 693.
5 D. Smith, S. Lee and P. Fuchs, J. Org. Chem., 1994, 59, 348.
6 B. Zacharie, G. Sauve and C. Penney, Tetrahedron, 1993, 49, 10 489.
7 T. Hoeg-Jensen, C. Olsen and A. Holm, J. Org. Chem., 1994, 59,
1257.
Thioacylation with thioacyl dithiophosphates 6, typical procedure A: A
solution of amine or thiol (5 mmol) and pyridine or triethylamine (5.5
mmol) in benzene is added dropwise to a solution of thioacyl 2-(5,5-dime-
thyl-2-thiono-1,3,2-dioxaphosphorinanyl) sulfide (6). Triethylammonium
(or pyridinium) dithiophosphate precipitates and can be removed by means
of filtration or washing with water and aq. sodium carbonate. Drying and
evaporation of the solvent generally yields pure enough product. If
necessary, the thioacyl derivative can be purified by means of chromatog-
raphy or crystallisation.
Typical procedure B: A solution of acyl 2-(5,5-dimethyl-2-thiono-
1,3,2-dioxaphosphorinanyl) sulfide (3) (5 mmol) and 5,5-dimethyl-
2-thiolo-2-thiono-1,3,2-dioxaphosphorinane (2) (10 mmol) in 35 ml of
benzene is heated under reflux for 2–6 h. A solution of amine or thiol (5
mmol) and pyridine or triethyl amine (16.5 mmol) in benzene is then added.
The resulting mixture is worked up as above.
§ On the basis of our 31P NMR experiments we were able to estimate the
composition of the equilibrium mixtures and additionally we managed to
isolate a few examples of S- and O-thioacylmonothiophosphates (e.g. 4b,
8 A. Katritzky, J. Moutou and Z. Yang, Synthesis, 1995, 1497.
9 S. Kato, E. Hattori, H. Sato, M. Mizuta and M. Ishida, Z. Naturforsch.,
1981, 86b, 783.
10 S. Kato, H. Shibahashi, T. Katada, T. Tagaki, I. Noda, M. Mizuta and M.
Goto, Lieb. Ann. Chem., 1982, 1229.
11 S. Kato, M. Goto, R. Hattori, K. Nishivaki, M. Mizuta and M. Ishida,
Chem. Ber., 1985, 118, 1668.
12 Acid 2 can be obtained from P2S5 and 2,2-dimethylpropane-1,3-diol
according to R. Edmundson, Tetrahedron, 1965, 21, 2379.
13 W. Przychodzen´ and A. Chimiak, Phosphorus, Sulfur Silicon Relat.
Elem., 1998, 143, 77.
14 N. Yousif, U. Pedersen, B. Yde and S. Lawesson, Tetrahedron, 1984, 40
(14), 2663; A. V. Alfonsof, D. Pudovik, E. Batyeva and A. Pudovik, Zh.
Obshch. Khim., 1985, 55, 2303; N. Yuosif and M. Salama, Phosphorus,
Sulfur Silicon Relat. Elem., 1987, 32, 51; N. Yuosif, Phosphorus, Sulfur
Silicon Relat. Elem., 1989, 46, 79.
15 N. Zabirov, F. Schamsevaliev and R. Cherkasov, Zh. Obshch. Khim.,
1991, 61(3.1), 558.
2094
Chem. Commun., 2000, 2093–2094