Unexpected thioketene derivative formation during thioacyl dithiophosphate synthesis

Article abstract of DOI:10.1081/SCC-120018942

The scope and limitations of the thioacylation method using thioacyl dithiophosphates were investigated. Thioacyl dithiophosphates are formed in the reaction of acyl dithiophosphates with dithiophosphoric acid. However when the acyl moiety contains two α-substituents then a thioketene derivative is formed thus lowering the yield of expected thioacyl dithiophosphate.

Full text of DOI:10.1081/SCC-120018942

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Unexpected Thioketene Derivative Formation During
Thioacyl Dithiophosphate Synthesis
Leszek Doszczak a , Victor Ch. Kravtsov b , Jan F. Biernat a & Janusz Rachon a
a Faculty of Chemistry , Technical University of Gdańsk , Gdańsk, Poland
b Institute of Applied Physics , Academy of Sciences of Moldova , Kishinev, Republic of
Moldova
Published online: 17 Aug 2006.
To cite this article: Leszek Doszczak , Victor Ch. Kravtsov , Jan F. Biernat & Janusz Rachon (2003) Unexpected Thioketene
Derivative Formation During Thioacyl Dithiophosphate Synthesis, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:10, 1797-1808
To link to this article: http://dx.doi.org/10.1081/SCC-120018942
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 10, pp. 1797–1808, 2003
Unexpected Thioketene Derivative Formation
During Thioacyl Dithiophosphate Synthesis
2
1
Leszek Doszczak,1 Victor Ch.Kravtsov, Jan F.Biernat,
and Janusz Rachon1,
*
1Faculty of Chemistry, Technical University of Gdansk,
Gdansk, Poland
2Institute of Applied Physics, Academy of Sciences of
Moldova, Kishinev, Republic of Moldova
ABSTRACT
The scope and limitations of the thioacylation method using thioacyl
dithiophosphates were investigated. Thioacyl dithiophosphates are
formed in the reaction of acyl dithiophosphates with dithiophospho-
ric acid. However when the acyl moiety contains two a-substituents
then a thioketene derivative is formed thus lowering the yield of
expected thioacyl dithiophosphate.
Key Words: Thioketene derivatives; Thioacylation; Acyl dithio-
phosphates; Thioacyl dithiophosphates.
*Correspondence: Janusz Rachon, Faculty of Chemistry, Technical University
of Gdansk, ul. Narutowicza 11/12, 80-952 Gdansk, Poland.
1797
DOI: 10.1081/SCC-120018942
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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Doszczak et al.
INTRODUCTION
Over the years, thioesters, thioamides (including thiopeptides) and
thiohydroxamic acids have been the subject of interest of many labora-
tories because of their chemical and biological properties as well as tech-
nical applications. Thioacyl derivatives are mainly obtained by treating
acyl derivatives with thionating agent such as P2S5 or Lawesson’s
reagent.[1–3] Another strategy consists in thioacylation of nucleophiles
with active derivatives of thiocarboxylic acids. Unfortunately, the
known thioacylating agents (e.g., thioacyl halides,[1] benzimidazolones,[4]
trifluorosulfonyl sulfides[5]; bis(thioacyl) sulfides[6] or thioacyloxybenzo-
triazoles[7] etc.) show many disadvantages and most of them can only be
prepared from dithiocarboxylic acids, which rarely are commercially
available. They often are synthesized in low yield and are difficult to
handle in pure form.
Recently we have discovered[8] a new strategy for the conversion of
carboxylic acids 1 into thioacyl dithiophosphates 7 (Sch. 1). This class of
compounds appeared to be very useful in the thioacylation of nitrogen or
sulfur nucleophiles.
Acylation of dithiophosphoric acid yields acyl dithiophosphates 4
(Sch. 1) which tend to isomerise to O-thioacyl monothiophosphates 5
and very slowly to S-thioacyl monothiophosphates 6 (potential thio-
acylating reagents). However, at equilibrium substrate 4 generally dom-
inates. In our method mixture of isomers 4, 5 and 6 is treated with
Scheme 1. Thioacylation method starting from carboxylic acids via acyl
dithiophosphates 4.

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Unexpected Thioketene Derivative Formation
1799
dithiophosphoric acid to yield S-thioacyl dithiophosphates 7, excellent
thioacylating agents. These compounds are easy to obtain, they do not
have to be isolated prior to thioacylation although in many cases
isolation is simple and provides stable crystalline compounds. We have
prepared[8] a setof anhydrides 7 in high yield for aromatic (7a–d) and
aliphatic (7e–h) substituents. For both electron-donating (7b,g) and
electron-withdrawing (7c) groups yields were high. The method was
efficientfor bulky residues ( 7g) as well as moieties with additional ester
functionality (7h).
RESULTS AND DISCUSSION
However, when we attempted to obtain thioacyl dithiophos-
phates 7 with two a-substituents in acyl moiety (R¼CH(CH3)2,
CH(CH2CH2)2CH2) products with ca 86 ppm 31P chemical shiftappeared
in the reaction mixtures. After prolonged heating of S-isobutyryl
dithiophosphate 4i (R1¼R2¼Me) with dithiophosphoric acid 3 an
equilibrium mixture was formed with about 1:10 ratio of anhydride 7i
to the new compound. We managed to isolate this product and basing
on analytical data, such as 31P, 1H and 13C NMR (see Fig. 1) we assigned
a structure of thioketene derivative 9i (R1 ¼ R2 ¼ Me) to this product
(Sch. 2).
Compound 9i is comparatively stable and can be crystallized from
hot cyclohexane solution providing prismatic yellow crystals suitable for
X-ray studies. Crystallographic analysis confirmed formerly proposed
structure. Figure 2 shows the general view of the molecule 9i. The
5,5-dimethyl-2-thiono-1,3,2-dioxaphosphorinan (six membered) ring is
in a chair conformation with bond distances and angles not significantly
different from those found in other 1,3,2-dioxaphosphorinanes.[9–12] The
P¼S sulfur atom is in equatorial position while the position of sulfur S(2)
of the side chain is axial. The bond lengths P(1)¼S(1) 1.901(2) A and
P(1)–S(2) 2.082(2) A are consistent with the literature data cited above.
The torsion angles S(1)–P(1)–S(2)–C(6) 58.2(2)ꢀ, P(1)–S(2)–C(6)–S(3)
85.0(3)ꢀ and S(2)–C(6)–S(3)–C(10) 84.7(3)ꢀ around the bonds including
sulfur atoms are gauche, while torsion angle C(6)–S(3)–C(10)–C(11)
174.5(5)ꢀ is anti. The S–C single type bonds show an excellent relation-
ship between the bond length and the corresponding torsion angle. The
S(2)–C(6) and S(3)–C(6) distances coincide with the standard deviations
and are equal to 1.778(6) and 1.761(6) A, respectively, but the S(3)–C(10)
bond is shorter and is equal 1.718(6) A. The conformation of the

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Unexpected Thioketene Derivative Formation
1801
Scheme 2. Formation of thioketene derivatives during synthesis of a,a-disubsti-
tuted thioacyl dithiophosphates.
Figure 2. X-ray structure of compound 9i, ORTP grap.
molecule may be described by the dihedral angles between the plane of
S(1), P(1) and S(2) atoms, the planar 2-methyl-1-propeno-1,1-dithiolo
fragment and the plane of valence bonds of C(10) atom in dithioisobu-
tyrate moiety which are 83.7(1) and 86.4(1)ꢀ, respectively.
Formation of compound 9i, as we believe, is based on the enolization
of thioacyl dithiophosphate and the subsequent thioacylation of thiol
group with the second equivalent of thioacyl dithiophosphate (Sch. 3).
In order to verify whether other a,a-disubstituted thioacyl dithiopho-
sphates demonstrate similar reactivity we ran a reaction starting from
cyclohexanecarboxylic acid derivative 4j (R1,R2¼(CH2)5). In that case
following prolonged heating of compound 4j with dithiophosphoric
acid 3 an equilibrium mixture consisted of anhydride 7j and thioketene
derivative 9j in 1:1 ratio. Isolation of the products was troublesome, thus
we decided to convert compound 7j into thioamide treating the reaction
mixture with aniline. We obtained thioamide 8a (R¼CH(CH2)5,

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Doszczak et al.
Scheme 3. Probable mechanism of formation of compound 9i.
Nu¼NHPh). Compound 9j does not react with amine and was isolated
with 34% yield. For NMR data see Fig. 3.
In summary, acyl dithiophosphates possessing two substituents next
to carbonyl group react with dithiophosphoric acid yielding enolizable
thioacyl dithiophosphates. Subsequent reaction leads to the formation
of a thioketene derivative. The product is stable in the presence of moist-
ure and oxygen and does not thioacylate amines (at least at the same
conditions as thioacyl dithiophosphates do). However other aliphatic
acyl dithiophosphates with one (or non) ‘a-substituent’, prepared by us,
treated with dithiophosphoric acid do not give substantial amount of the
title derivatives consequently thioacyl dithiophosphates are formed with
high yield and can be used for the efficient thioacylation.
EXPERIMENTAL
Acyl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphorinanyl)
sulfides 4, General Procedure
Acyl chloride (3 mmol) was added to the solution of 5,5-dimethyl-
2-thiolo-2-thiono-1,3,2-dioxaphosphorinane (3) (3 mmol) in benzene
(10 mL). Subsequently, to the ice cooled solution triethylamine (0.303 g,
3 mmol) was added dropwise. Immediately triethylammonium chloride
precipitated. After 15 min reaction mixture was filtered through a short
pad of silica gel. After the solvent evaporation a pure product was
obtained.
Isobutyryl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphorinanyl) sulfide
(4i): Yield 97.5%. HRMS: Mþ ¼ 268.03526 (M calcd. for C9H17O3PS2 ¼
268.03568). IR: 1730 (C¼O); 1046, 991 (P-O-C); 672 (P¼S).

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Unexpected Thioketene Derivative Formation
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1806
Doszczak et al.
Cyclohexanecarbonyl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphori-
nanyl) sulfide (4j). Yield 93.4%. HRMS (LSIMS): M þ Hþ ¼ 309.07423
(M calcd. for C12H22O3PS2¼309.07480). IR: 1732 (C¼O); 1045, 990
(P-O-C); 678 (P¼S).
Reaction of Acyl 2-(5,5-Dimethyl-2-thiono-1,3,2-
dioxaphosphorinanyl) Sulfides 4, with 5,5-Dimethyl-2-thiolo-
2-thiono-1,3,2-dioxaphosphorinane (3), General Procedure
The solution of acyl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphori-
nanyl) sulphide (4) (3 mmol) and 5,5-dimethyl-2-thiolo-2-thiono-1,3,2-
dioxaphosphorinane (3) (6 mmol) in 30 mL of benzene was heated
under reflux for 17–21 h (until no essential changes were noticed in
31P NMR spectrum). Subsequently the reaction mixture was washed
with the aqueous solution of Na2CO3 and then water. Next organic
layer was dried with MgSO4 and benzene was evaporated.
Isobutyryl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxa-phosphorinanyl) sulfide
(4i): as starting material: after 17 h of heating and workup as above
0.651 g of orange oil was obtained. Chromatography on silica gel
(CH2Cl2:(CH2)6, 3:10) yielded 0.394 g (71%) of S-2-(5,5-dimethyl-2-
thiono-1,3,2-dioxaphosphorinanyl) S-thioisobutyryl 2-methyl-1-propeno-
1,1-dithiol (9i). Crystallization from hot cyclohexane solution yielded
yellow crystals. HRMS: Mþ ¼ 370.03178 (M calcd. for C13H23O2S4P¼
370.03186). IR: 1585 (C¼C); 1211 (C¼S); 1047, 994 (P-O-C); 687 (P¼S);
m.p.108–109ꢀC. Crystallography: The prismatic yellow crystals of com-
pound 9i are monoclinic, space group P21/c, a ¼ 15.796(4), b ¼ 10.578(3),
c ¼ 11.556(4) A, ꢀ ¼ 101.46(2)ꢀ; V ¼ 1892.4(10) A3. The experimental data
were collected from a monocrystal (0.3 ꢁ 0.15 ꢁ 0.1 mm) on a KUMA
Diffraction KM4 diffractometer using graphite monochromatized
Mo-Ka radiation (reflections collected 3612, unique 3422 [R(int)¼
0.0658]); T ¼ 293(2)K. Lattice parameters were determined from least-
squares refinements of the 32 reflection with 9.1ꢀ ꢂ 2ꢁ ꢂ 18.4ꢀ. The struc-
ture was solved by direct method and refined by full-matrix least-squares in
anisotropic approximation using SHELX-97 programs.[13] Final R indices
R1 ¼ 0.0446, wR2 ¼ 0.0906 for 1009 reflection with [I > 2ꢂ(I)]. Positions
of hydrogen atoms were calculated from geometrical consideration
and refined as constrained to bonding atoms in a ‘ride’ mode.
(Crystallographic data (excluding structure factors) for the structure in
this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC 174564.
Copies of the data can be obtained, free of charge, on application to

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Unexpected Thioketene Derivative Formation
1807
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: þ44 (0) 1223-
336033 or E-mail: deposit@ccdc.cam.ac.uk]).
Cyclohexanecarbonyl 2-(5,5-dimethyl-2-thiono-1,3,2-dioxaphosphori-
nanyl) sulfide (4j): as starting material: after 21 h of heating and
workup as above 0.784g of orange oil was obtained, dissolved in 1 mL
of benzene and treated with 0.25 g of aniline. After a few minutes anili-
nium dithiophosphate precipitated. Subsequently, after solvent evapora-
tion, the residue was chromtographed on silica gel (THF:(CH2)6, 1:40)
yielding 0.188 g (28.6%) of N-cyclohexanethiocarbonyl aniline
(1H NMR: 7.65 (d, J ¼ 7.3 Hz, 2H); 7.81 (t, J ¼ 7.8, 2H); 7.25 (t, 7.3 Hz,
1H); 2.64 (tt, J ¼ 11.7, 3.4 Hz, 1H); 1.98 (dd, J ¼ 13.2, 1.5 Hz, 2H); 1.86
(td, J ¼ 13.2, 2.9 Hz, 2H); 1.73 (m, 1H); 1.69 (tdd, J ¼ 12.7, 12.2, 3.4 Hz,
2H); 1.36 (tdt, J ¼ 13.2, 12.7, 3.4 Hz, 2H); 1.26 (qt, J ¼ 12.7, 3.4, 1H),
13C NMR: 210.26; 138.83; 129.11; 127.08; 124.34; 56.65; 33.31; 26.21;
25.83) and 0.229 g (33.9%) of S-2-(5,5-dimethyl-2-thiono-1,3,2-dioxapho-
sphorinanyl) S-cyclohexanethiocarbonyl cyclohexylidenemethanodithiol
(9j). HRMS: Mþ ¼ 450.09664 (M calcd. for C19H31O2S4P¼450.09446).
IR: 1568 (C¼C); 1192 (C¼S); 1045, 991 (P-O-C); 685 (P¼S).
ACKNOWLEDGMENTS
We gratefully acknowledge the Polish State Committee for Scientific
Research for financial support(GrantNo. 3 T09A 061 16).
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