New efficient synthesis of phosphonofluorodithioates ROP(S)(S2)F and their
structural analogues
Izabela Tworowska and Wojciech Da`bkowski*
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90–363 Oo´dz´, Sienkiewicza 112,
Poland. E-mail: wdabkow@bilbo.cbmm.lodz.pl
Received (in Liverpool, UK) 7th September 1998, Accepted 26th October 1998
The title compounds 3 are formed in very high yield from a
one-pot sequential reaction of 1,3,2-dithiaphospholane PIII
derivatives 1, which are transformed into the corresponding
PIV compounds 2 by addition of elemental sulfur and finally
into fluoridodithioates 3 by TBAF.
To illustrate the power and versality of this strategy several
examples are presented which include the fluoro dithioacids 3
containing alkyl and alkoxyl (nucleosidyloxy) moieties at-
tached to the phosphorus center. The first example comes from
nucleotide chemistry (Scheme 1).† The compounds 1a and 2a
have been prepared according to the modified procedure of
Okruszek and Olesiak.5b The condesation of 1 (R = NPri2) with
5A-dimethoxytritylthymidine was performed in the presence of
TMSCl yielding 1a in very high yield.6†
According to this method O-cholesteryl phosphonofluor-
idodithioate 3b was obtained in quantitative yield (Scheme 1).‡
2-Cholesteryloxy-2-thioxo-1,3,2-dithiaphospholane 2b was the
first prepared by Stec and coworkers.7
An analogous synthetic pathway led to 3c§ starting from 1c
(Scheme 1). Synthesis of the 2-citronellyloxy-1,3,2-dithiaphos-
pholane 1c was achieved by the coupling of 1 (R = NPri2) with
citronellol in the presence of TMSCl as activator.6
The phosphonofluoridodithioate 3d¶ can be conveniently
prepared from 1d, which is readily available from 1 (R = NPri2)
via condensation with 2-cyanoethanol in the presence of
TMSCl. Compound 1d was transformed into 2d¶. Ring opening
with TBAF gave the dithioacid 1d (Scheme 1) which, after
removal in the presence of Et3N of the 2-cyanoethyl group, gave
the phosphonofluoridodithioic acid 4 [dP(CDCl3) 67.50(d);
dF(CDCl3) 20.42 (d, JP–F = 1108.96)].
Phosphorus dithioacids play an important role as reagents,
ligands and stereochemical probes in 31P NMR spectroscopy.1
Dithioacids containing a fluorine ligand attached directly to the
phosphorus atom are rare.2 The method of choice for the
preparation of simple phosphonofluoridodithioates is not appli-
cable for the preparation of phosphonofluoridodithioate mono-
esters derived from natural products. Unlike for nucleoside
phosphonofluoridate3a–c or phosphonofluoridothioate3d mono-
esters, there is only one synthetic method available for the
preparation of nucleoside phosphonofluoridodithioate mono-
esters.3e Stawinski and Bollmark have devised a synthesis of
nucleoside phosphonofluoridodithioate monoesters via oxida-
tion of nucleoside phosphonodithioate with I2 in pyridine in the
presence of TMSCl, followed by addition of triethylamine
trishydrofluoride (TAF) to give the nucleoside phosphono-
fluoridodithioate.3e
The importance of phosphoro-fluorine compounds in pure
and applied chemistry stimulated our interest in the synthesis of
phosphorus dithioacids with P–F bonds. Our studies on the
synthesis of phosphonodithioates from 3A-thiothymidine by
anhydro-ring opening of 2,3A-anhydrothymidine4 required an
efficient synthesis of O,O-disubstituted phosphonodithioic
acids. We now disclose a novel synthesis of the title compounds
3 containing a wide variety of substituents attached to the
phosphorus center (Scheme 1). Our method is based on
1,3,2-dithiaphospholane derivatives 1 which are readily avail-
able from ethane-1,2-dithiol and an appropriate PIII com-
pound.
+
R
S
O– HNEt3
P
+
S– HNEt3
4
The methylphosphonofluoridodithioate 3e∑ was prepared
from compound 1e8 (Scheme 1). The preparation of the latter
involves the condensation of ethane-1,2-dithiol with
methyl(dichloro)phosphine.
The same strategy allowed us to prepare a novel inorganic
structure, the cyanophosphonofluoridodithioate 3f** (Scheme
1). The cyano derivative 1f was prepared by the reaction 1 (R =
Cl) with trimethylsilyl cyanide.
The protocol we have developed involves two consecutive
reactions carried out in one pot: sulfurization of compound 1 to
form compound 2 and finally the reaction with TBAF to open
the dithiaphospholane ring with spontaneous elimination of
ethylene sulfide and formation of the desired acid 3 (Scheme 1).
The roots of this approach are derived from methodology
described by Stec.5
In summary we have developed a novel, efficient and general
method for the synthesis of phosphonofluorodithioates 3.
Yields of the final products are very good, exceeding 95%. They
show high stability at ambient temperature and can be
conveniently converted into free acids by the action of toluene-
p-sulfonic acid. Acids 3 are strong nucleophiles and thus serve
as useful precursors to a wide variety of hitherto unknown
functionalized heteroatom systems and ligands. The new route
leading to phosphonofluorodithioic acids 3 described here is
noteworthy in its flexibility. It can also be extended to
analogues of 2 containing a PNSe group.
S
S
R
R
F
i
ii
S
P
R
P
P
+
S– +NBu4
S
S
S
S
1
2
3
CH3
CH3
H
DMTrO
Th
O
a R =
b R =
H3C
H
CH3
H
O
CH3
O
This work was supported by the German–Polish project
(POI-211-96).
c R =
d R = OCH2CH2CN e R = Me f R = CN
Notes and references
CH2O
† The solvents were reagent grade and were distilled and dried by
conventional methods before use. NMR spectra were recorded on a Bruker
AC200 spectrometer (31P 81.014 MHz, H3PO4 external standard; 19F
Scheme 1 Reagents and conditions: i, S8, benzene; ii, TBAF, THF.
Chem. Commun., 1998, 2611–2612
2611
Tworowska, Izabela
