On the sulfurization of h-phosphonate diesters and phosphite triesters using elemental sulfur

Article abstract of DOI:10.1080/10426500802715619

Sulfurization of tetracoordinate and tricoordinate P(III) derivatives, namely, H-phosphonate diesters, H-phosphonothioate diesters, and phosphite triesters with elemental sulfur under various experimental conditions, was investigated.

Full text of DOI:10.1080/10426500802715619

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Phosphorus, Sulfur, and Silicon
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On the Sulfurization of H-
Phosphonate Diesters and
Phosphite Triesters Using
Elemental Sulfur
Richard Wallin a , Marcin Kalek a , Agnieszka
Bartoszewicz a , Mats Thelin a & Jacek Stawinski a b
a Department of Organic Chemistry, Arrhenius
Laboratory , Stockholm University , Stockholm,
Sweden
b Institute of Bioorganic Chemistry, Polish Academy
of Sciences , Poznan, Poland
Published online: 26 Mar 2009.
To cite this article: Richard Wallin , Marcin Kalek , Agnieszka Bartoszewicz , Mats
Thelin & Jacek Stawinski (2009) On the Sulfurization of H-Phosphonate Diesters and
Phosphite Triesters Using Elemental Sulfur, Phosphorus, Sulfur, and Silicon and the
Related Elements, 184:4, 908-916, DOI: 10.1080/10426500802715619
To link to this article: http://dx.doi.org/10.1080/10426500802715619
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Phosphorus, Sulfur, and Silicon, 184:908–916, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802715619
On the Sulfurization of H-Phosphonate Diesters and
Phosphite Triesters Using Elemental Sulfur
Richard Wallin,1 Marcin Kalek,1
Agnieszka Bartoszewicz,1 Mats Thelin,1
and Jacek Stawinski1,2
1Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Stockholm, Sweden
2Institute of Bioorganic Chemistry, Polish Academy of Sciences,
Poznan, Poland
Sulfurization of tetracoordinate and tricoordinate P(III) derivatives, namely, H-
phosphonate diesters, H-phosphonothioate diesters, and phosphite triesters with
elemental sulfur under various experimental conditions, was investigated.
Keywords Elemental sulfur; phosphite triesters; H-phosphonate diesters; H-
phosphonothioate diesters; sulfurization
INTRODUCTION
Although a variety of sulfurizing reagents, e.g., 3H-1,2-benzo-
dithiol-3-one 1,1-dioxide,1 3H-1,2-benzodithiol-3-one,2 tetraethylthi-
uram disulfide,3 dibenzoyl tetrasulfide,4 bis(O,O-diisopropoxyphos-
phinothioyl) disulfide,5 1,2,4-dithiazolidine-3,5-dione,6 bis (3-
(triethoxysilyl)propyl)tetrasulfide,7 etc., have been proposed for
the conversion of P(III) derivatives into the corresponding phospho-
rothioates or phosphorodithioates, it is elemental sulfur8 that still
remains the reagent of choice for the majority of applications during
solution syntheses.
Sulfurization of H-phosphonate diesters is mechanistically more
complex than that of tervalent phosphorus compounds since it involves
Received 19 December 2007; accepted 31 January 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
Financial support from the Swedish Research Council is gratefully acknowledged.
Address correspondence to Jacek Stawinski, Institute of Bioorganic Chemistry,
Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland. E-mail:
js@organ.su.se
908

Sulfurization of H-Phosphonate Diesters
909
generation of the corresponding phosphite form as the first step of the
reaction. For this reason, both polarity of the solvent and the base used
for the generation of a phosphite form might influence significantly
the rates of sulfurization. In this article, we address these and related
problems connected with sulfurization of tetra- and tricoordinate P(III)
derivatives.
RESULTS AND DISCUSSION
As model compounds for this study, separate diastereomers of dinucle-
oside H-phosphonate 1a and dinucleoside H-phosphonothioate 1b were
chosen (Scheme 1).
SCHEME 1
The sulfurization was carried out under homogenous reaction con-
ditions as described in the Experimental section. The results for the
conversion of H-phosphonates 1a into the corresponding phosphoroth-
ioates 2a are summarized in Tables I and II. (For solubility of sulfur
in various organic solvents, see the Experimental section and Table V).
The data indicate that the solvent and the base used for the reaction had
a profound effect on the rate of sulfurization of H-phosphonates 1a, as
was expected for reactions involving the generation of anionic species.
The sulfurization was very fast in highly polar solvents (Table I,
entries 1, 2, and 6), and its dependence on the amount of the sulfur

910
R. Wallin et al.
TABLE I Sulfurization of Dinucleoside H-Phosphonate 1a with
Elemental Sulfur in Different Solvents in the Presence of 2 Equiv. of
Triethylamine
Entry
Solvent
Amount of sulfur
Time for completion
1
2
3
4
5
6
7
DMF
CH3OH
Dioxane
CH2Cl2
Toluene
Pyridine
Carbon disulfide
2 equiv.
2 equiv.
2 equiv. 5 equiv. 10 equiv.
2 equiv. 5 equiv. 10 equiv.
2 equiv. 5 equiv. 10 equiv.
2 equiv.
<1 min
<1 min
40 min 30 min 15 min
60 min 10 min 7 min
40 min 15 min 6 min
10 min
2 equiv.
90 min
used is consistent with a bimolecular rate determining step (Table I,
entries 3, 4, anf 5).
The data in Table II indicate also that the efficiency of sulfurization of
H-phosphonate diesters strongly depends on the basicity of the amine
used for the reaction. Weakly basic heteroaromatic amines (entries
2 and 9) or N-methylimidazole did not promote sulfurization of H-
phosphonates 1a within 2 h (Table II, entries 2, 7, and 9), in contrast
to stronger amines (e.g., TEA or DBU) that furnished fast formation of
phosphorothioate diesters 2a.
For sulfurization in the presence of DBU (Table II), remarkable color
changes were observed during the course of the reaction in all solvents
TABLE II Sulfurization of Dinucleoside H-Phosphonate 1a with 2
Equiv. of Elemental Sulfur and 2 Equiv. of a Base in Different
Solvents
Entry
Base
Dioxane
CH2Cl2
Toluene
1
2
TEA
Pyridine
40 min
nd
60 min
nd
40 min
nd
3
4
5
6
7
8
9
10
11
n-Butylamine
Diisopropylamine
Diisopropylethylamine
DBU
N-Methylimidazole
DABCO
2,4,6-Collidine
Gramine
DMAP
20 min
20 min
50 min
< 1 min
nd
30 min
nd
50 min
60 min
20 h
2 h
50 min
< 1 min
nd
5 h
nd
3 h
2 h
10 min
20 min
50 min
< 1 min
nd
50 min
nd
50 min
20 min
Abbreviations: TEA = Triethylamine; DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene;
DABCO = 1,4-diazabicyclo[2.2.2]octane; Gramine = 3-(dimethylaminomethyl)indole;
DMAP = 4-dimethylaminopyridine.
nd = no sulfurization (or less than 5%) after 2 h.

Sulfurization of H-Phosphonate Diesters
911
investigated. The solutions became blue after the addition of DBU to the
reaction mixture, then turned green, yellow, and became colorless when
the sulfurization was over. Although this may point to a free radical9
rather than an ionic mechanism for the sulfurization under these reac-
tion conditions, further studies are needed to clarify this issue.
The stereochemical course of the sulfurization10 under all conditions
investigated was checked by 31P NMR spectroscopy using separate di-
astereomers of 1a.11,12 In all cases, the sulfurization was completely
stereospecific as evidenced by the transformation of RP 1a (“fast”, δP =
6.8 ppm) into SP 2a (δP = 57.3 ppm) and SP 1a (“slow”, δP = 9.7 ppm)
into RP 2a (δP = 55.8 ppm) (chemical shifts for the reaction in toluene
in the presence of DBU).
Some experiments were also performed on H-phosphonothioates 1b
to find out if there were any differences in the rate of sulfurization
compared to H-phosphonates 1a. In toluene, using 2 equiv. of sulfur
and 2 equiv. of TEA or n-butylamine, the reactions were 4 and 3 times
faster than those for H-phosphonates 1a, respectively. In neat pyridine,
the sulfurization of 1b was 4 times faster than that of 1a. These data
pointed to higher acidity of the P H bond in H-phosphonothioate versus
H-phosphonate diesters.
Since it was reported that the rate-limiting step in sulfurization
of phosphines was the cleavage of the cyclic structure of S8,13–15 we
checked if a “preactivation” of sulfur could speed up sulfurization of
H-phosphonate derivatives. Sulfur in toluene was left standing for 15
min with 2 equiv. of TEA or diisopropylamine, and then 1a was added.
No difference in the rate of sulfurization was noticed compared to the
standard sulfurization procedure (however, vide infra). Also no effect on
the rate of sulfurization was found when the reactions were carried out
in the presence of TEA and hydrogen sulfide, or TEA and thiophenol
(2 equiv.), as potential nucleophile catalysts for cleavage of the ring
structure of sulfur.13,14
Finally, the reactivity of S6 in the sulfurization reaction was eval-
uated. This form of sulfur was prepared according to the literature
procedure,13,14 but it did not show noticeable differences when it was
used instead of commercially available S8 for the sulfurization of H-
phosphonates 1a.
Sulfurization H-Phosphonate Diester Derivatives
with Presilylation
Since transformation of tetracoordinate H-phosphonates into ter-
valent silyl derivatives is known to facilitate oxidation of these

912
R. Wallin et al.
compounds,16–18 we investigated the effect of silylation on sulfuriza-
tion of typical H-phosphonate diesters (Table III).
The conversion of diethyl H-phosphonate diester into its trimethylsi-
lyl ether indeed shortened significantly the time of sulfurization (16 h
vs. 2 min); however, for diphenyl and dinucleoside H-phosphonates, the
silylation had an opposite effect, namely, it slowed down the sulfuriza-
tion reaction. The most dramatic effect was observed for diphenyl H-
phosphonate, which, without presilylation, was sulfurized in less than 2
min, while upon conversion into the corresponding trimethylsilyl ether,
it took 21 h to bring the sulfurization to completion (Table III).
These somewhat unexpected results can be rationalized in light of
reactivity of the generated tervalent species and their concentrations
under the reaction conditions.19 It is reasonable to assume that anionic
species generated by abstraction of the proton from H-phosphonate di-
esters should be more reactive toward elemental sulfur than electrically
neutral, less basic, tervalent silyl ethers, and their concentration under
the reaction condition should be inversely proportional to their basicity.
Thus, for diethyl H-phosphonate, effective nucleophilicity (product of
TABLE III Comparison of the Sulfurization Times of Various
H-Phosphonate Derivatives and Their Trimethylsilyl Ethers
Compound
Time
16 h
Compound
Time
< 2 min
< 2 min*
21 h
10 min
40 min
< 2 min
with TMS-Cl
< 2 min
Reaction conditions: 4 mM substrate, 2 equiv. sulfur, 2 equiv. Et3N in pyridine. The
silylation was performed in situ using 1.5 equiv. of TMS-Cl, and 1 more equiv. of Et3N
was added. The progress of the reactions was followed by 31P NMR spectroscopy.
*Due to the high susceptibility of (PhO)2P(O)H to hydrolysis by adventitious water,
the reaction mixture was 10 times more concentrated.

Sulfurization of H-Phosphonate Diesters
913
reactivity and concentration) of the corresponding phosphonate anion
was expected to be low (high reactivity but exceedingly low concentra-
tion), and thus the conversion into tervalent species (lower reactivity
but high concentration) should speed up sulfurization of this compound.
For diphenyl H-phosphonate, however, due to its higher acidity com-
pared to the diethyl derivatives, effective nucleophilicity of the diphenyl
phosphonate anion was expected to be high (high reactivity and high
concentration20), and thus the conversion into the less reactive silyl
ether should slow down sulfurization of this compound. This was in-
deed observed. From the fact that dinucleoside H-phosphonates 1a,
in contrast to diethyl H-phosphonate, underwent sulfurization faster
without presilylation (Table III), one can infer that the P H bond in
this compound is more acidic than that in the diethyl derivative.
As expected, the presence of TMS-Cl in the reaction mixture did
not affect the rate of sulfurization of H-phosphonothioate 1b, since
this compound cannot be converted into the corresponding silyl ethers
under the reaction conditions.21,22
Sulfurization of Triethyl and Triphenyl Phosphites
As a final step of these studies, we wanted to clarify the issue of a pos-
sible activation of sulfur13,14 by bases. Since during sulfurization of H-
phosphonate diesters a base is an indispensable component of the reac-
tion mixture, we investigated the sulfurization of triethyl and triphenyl
phosphites, which mechanistically do not require presence of a base.23
We found that sulfurization of triethyl phosphite with elemental
sulfur in toluene was very sluggish (Table IV), but it was significantly
accelerated by the addition of triethylamine. The use of trimethylsilyl
chloride in combination with triethylamine had a minor decelerating
effect on the rate of sulfurization, probably due to partial hydrolysis of
the silylating agent and consumption of the base for neutralization of
the acidic products formed.
Triphenyl phosphite turned out to be very resistant to sulfurization
in toluene, and did not produce any detectable amounts of triphenyl
phosphorothioate neither with nor without triethylamine (Table IV).
This is probably due to inductive effect of the phenoxy groups, but also
in part, it reflects lower nucleophilicity of tervalent species compared
to phosphonate anions.
In pyridine, triethyl phosphite underwent sulfurization rapidly,
without a noticeable effect of the triethylamine added. In contrast
to these, sulfurization of triphenyl phosphite in pyridine required the
presence of triethylamine (Table IV), and even so it was rather slow.23

914
R. Wallin et al.
TABLE IV Sulfurization of Triethyl and Triphenyl Phosphite
Under Different Experimental Conditions
Reactants
Toluene Pyridine Toluene Pyridine
2 equiv. S
nd
3 h
5 h
<2 min
<2 min
<2 min
nd
nd
nd
nd
3 h
5 h
2 equiv. S + 10 equiv. Et3N
2 equiv. S + 10 equiv. Et3N + 1.5 equiv. TMS-Cl
Reaction conditions: 4 mM solution of triethyl or triphenyl phosphite in an
appropriate solvent and the reactants as specified in the table. Due to the possible
presence of acidic contaminations in the reaction mixtures, an excess of triethylamine
(10 equiv.) was used to ensure that enough base was available for a putative
activation of sulfur. Progress of the reactions was followed by 31P NMR spectroscopy.
nd = no sulfurization (or less than 5 %) after 3 h.
These preliminary results suggest that triethylamine and pyri-
dine (and most likely other amines and nucleophiles) apparently ac-
tivate sulfur by breaking its eight-member rings as it was postulated
previously.13,14 By comparing the reactivity of triethyl and triphenyl
phosphites towards sulfur in pyridine in the presence and in the ab-
sence of triethylamine, it seems that tertiary aliphatic amines are
more potent activators of sulfur (formation of more reactive polysul-
fide species) than pyridine. As expected, such activation appeared to
be more important for sulfurization of the less reactive triphenyl phos-
phite than that of triethyl phosphite.
In conclusion, sulfurization of tetravalent and tervalent P(III)
derivatives with elemental sulfur strongly depends on the polarity of
the solvent and on the base used. In the case of H-phosphonates, polar
solvents (Table V) stabilize the generated phosphonate anions and po-
lar species formed from the opening of the eight-membered ring struc-
ture of sulfur. Bases that are used for sulfurization of H-phosphonate
diesters seem to play a double role: generation of phosphonate anions
and activation of the elemental sulfur. As to the presilylation step, it
may increase or decrease rates of sulfurization, depending on acidity
of the P-H bond of H-phosphonate diesters. For tervalent P(III) com-
pounds, sulfurization occurs faster in polar solvents (stabilization of
polar transition states) and in the presence of amines, which appar-
ently activate sulfur. The importance of the latter phenomenon in the
sulfurization of H-phosphonate diesters remains to be established.

Sulfurization of H-Phosphonate Diesters
915
TABLE V Approximate Solubility of Elemental Sulfur
(S8) in Different Solvents
Entry
Solvent
Solubility (mg/mL)
1
2
3
4
5
6
7
8
Carbon disulfide
Toluene
Pyridine
THF
Dioxane
DMF
300
18
15
11
4
1.5
0.2
0.1
Methanol
Acetonitrile
EXPERIMENTAL
Dinucleoside H-phosphonates 1a24 and H-phosphonothioates 1b12 were
prepared as described previously. The sulfurization experiments were
carried out in the following way: Stock solutions of sulfur and the
base were prepared in the same solvent as that for the intended re-
action. The solutions were combined in an appropriate ratio, a P(III)
substrate was added, and the volume adjusted to 3 mL (the concen-
tration of the P(III) compound, 4.0 mM). The reactions were followed
either chromatographically by TLC (for 1a and 1b, silica gel plates,
CHCl3 : CH3OH, 9:1, v/v) or by 31P NMR, to ca. 95% completion.
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