A new selenium-transferring reagent - Triphenylphosphine selenide

Article abstract of DOI:10.1039/b101002f

Triphenylphosphine selenide and its polymer-supported counterpart are found to be efficient selenium-transferring reagents for the conversion of H-phosphonate diesters and phosphite triesters into the corresponding phosphoroselenoate derivatives.

Full text of DOI:10.1039/b101002f

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A new selenium-transferring reagent—triphenylphosphine selenide
Martin Bollmarka and Jacek Stawinski*ab
a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
b Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.
E-mail: js@organ.su.se
Received (in Cambridge, UK) 29th January 2001, Accepted 13th March 2001
First published as an Advance Article on the web 3rd April 2001
Triphenylphosphine selenide and its polymer-supported
counterpart are found to be efficient selenium-transferring
reagents for the conversion of H-phosphonate diesters and
phosphite triesters into the corresponding phosphorosele-
noate derivatives.
In the last two decades organoselenium chemistry became a
rapidly expanding field of organic chemistry as various
selenium-based reagents have enabled chemists to perform
important synthetic transformations simply and in high
yields.1
Thus, triethyl phosphite in chloroform was treated with
selenide 1 (1.1 equiv.) and progress of the reaction was followed
by 31P NMR spectroscopy. It was rewarding to find that transfer
In 1957 Schwarz and Foltz2 found that selenium is an
essential nutrient for mammals (previously known as Factor 3
present in yeast) and prevents dietary necrotic degeneration of
liver, heart and other organs. This unexpected nutritional role of
selenium3 has been a powerful incentive to study the bio-
chemistry of organoselenium compounds.4 Kindled by hopes of
finding novel, useful theraputic properties, selenium has been
incorporated into various biologically important compounds,†
e.g. carbohydrates,5 lipids,6,7 nucleosides8 and oligonucleo-
tides.9–11
1
of selenium from 1 (dP = 36.5, JPSe = 640 Hz) to triethyl
phosphite (dP = 139.0) occurred rapidly (within 5 min) and
quantitatively with the formation of triethyl phosphorosele-
noate§ (dP = 72.0, 1JPSe = 938 Hz) and triphenylphosphine (dP
= 24.2). Encouraged by this result we assessed TPPSe as a
selenizing reagent for dinucleoside phosphite 3¶ (Scheme 2).
The reaction of 3 with 1.1 equiv. of selenide 1 was only slightly
slower than that with triethyl phosphite (completion within 20
min) and produced the expected phosphoroselenoate triester 4
as a ca. 1+1 mixture of diastereomers (dP = 74.6 and 74.2, 1JPSe
= 969 and 970 Hz). Compound 4 was isolated by silica gel
chromatography (ca. 70% yield) and its structure was con-
firmed by NMR spectroscopy and MALDI data.
Organoselenophosphorus compounds are usually prepared12
via PIII intermediates (e.g. phosphite triesters,9,10,13 H-phospho-
nate-6,11 or H-phosphonothioate11 diesters), with a crucial step
involving an oxidative transfer of selenium to phosphorus. As a
source of electrophilic selenium in such transformations
elemental selenium6,14,15 and potassium selenocyanate,10,13,16
are most commonly used. However, the low reactivity of these
reagents and serious problems in their application in solid phase
synthesis, led to the development of two selenizing agents
soluble in organic solvents, 3H-1,2-benzothiaselenol-3-one
(BTSe),11 and bis(di-O,O-isopropyl phosphinothionyl)disele-
nide.17
To expand this short list of available selenizing reagents, we
have embarked on investigations of a selenium exchange
phenomenon between phosphine selenides and various PIII
compounds as a viable route to selenophosphates. The rationale
behind this was the observation that selenium-transfer from
tertiary phosphine selenides to tertiary phosphines,18 in contra-
distinction to phosphine sulfides, occurs readily at ambient
temperature to produce an equilibrium mixture of the corres-
ponding PIII and PV species, as shown in Scheme 1.
Although established in a general sense, this reaction has not
been recognised as a possible way of synthesising selenophos-
phorus compounds.
Somewhat surprisingly, attempted selenization of diethyl H-
phosphonate with selenide 1 (2 equiv.) failed as no selenium-
transfer occurred within 24 h (31P NMR spectroscopy) in
pyridine or in chloroform in the presence of triethylamine
(5 equiv.). However, the conversion of diethyl H-phosphonate
(dP = 7.6) into the corresponding silyl phosphite∑ (dP = 128.5)
furnished rapid ( < 10 min) and clean selenization upon addition
of selenide 1 (1.1 equiv.) with the formation of diethyl
1
phosphoroselenoate diester (dP = 56.2, JPSe = 934 Hz). We
also found that selenization of diethyl H-phosphonate with 1
(2 equiv.) in pyridine could be effected without presilylation,
when diazabicyclo[5.4.0]undec-7-ene (DBU, 5 equiv.) was
used as base (completion within 25 min).
The efficacy of this approach for selenization of nucleoside
H-phosphonate diesters was evaluated by reacting dinucleoside
H-phosphonate 5a with TPPSe (1.1 equiv.) in pyridine in the
To find out if the selenium exchange process also occurs
readily between phosphine selenides and other PIII compounds,
we first investigated the reaction of triphenylphosphine selenide
(TPPSe, 1) with triethyl phosphite. Triphenylphosphine sele-
nide 114,16 seemed most attractive as a possible source of
electrophilic selenium, since it is a stable, crystalline, inex-
pensive, commercial reagent, with good solubility in organic
solvents.‡
Scheme 1
Scheme 2
DOI: 10.1039/b101002f
Chem. Commun., 2001, 771–772
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presence of trimethylsilyl chloride (TMS-Cl, 6 equiv.) as a
silylating agent (Scheme 3). The reaction was clean and went to
completion within 15 min producing the silylated phosphor-
oselenoate 6a (dP = 56.9 and 56.6) as the sole nucleotidic
product. Similarly to diethyl H-phosphonate, selenization of H-
phosphonate 5a with 1 (1.1 equiv.) also occurred rapidly ( < 5
min) and cleanly in pyridine in the presence of DBU (5 equiv.)
as a base. The produced dinucleoside phosphoroselenoate 6a
was isolated from the reaction mixture by silica gel chromatog-
raphy in ca. 90% yield and it was identical to 6a prepared in
another way.11
Notes and references
† Selenium compounds are generally toxic to animals. However, toxicity
per se does not rule out a compound for drug use although it frequently
prevents the administration of an effective dose that is also safe.
‡ Triphenylphosphine selenide 1 can also be easily prepared via seleniza-
tion of triphenylphosphine in 1,4-dioxane with elemental selenium or
according to the Nicpon and Meek procedure,16 using KSeCN. Approx-
imate solubility of 1 in organic solvents (solvent, mg mL21): acetonitrile, 6;
THF, 80; pyridine 100; dichloromethane 130; chloroform, 230.
§ Identity of this and other phosphoroselenoates obtained in these studies
(e.g. 4, 6a, 6b) was confirmed by independent synthesis of these compounds
via selenization of the corresponding PIII precursors with elemental
selenium.
¶ Dinucleoside phosphite 4 was generated in situ from 5A-O-dimethoxy-
tritylthymidin-3A-yl methyl N,N-bis(diisopropyl)phosphoramidite and 3A-O-
dimethoxytritylthymidine in chloroform in the presence of tetrazole.
Besides 4, the reaction mixture contained ca. 10% hydrolysis products and
ca. 5% of the unreacted phosphoramidite.
∑ Reaction in chloroform, using bis(trimethylsilyl)acetamide (BSA) and
triethylamine.
** In a typical experiment, H-phosphonate 5a or H-phosphonothioate 5b
(0.1 mmol) was dissolved in pyridine (4 mL) containing triphenylphosphine
selenide 1 (2.0 equiv.), and DBU (5 equiv.) was added. After 5 min the
reaction mixture was diluted with dichloromethane (20 mL), extracted with
0.5 M TEAB buffer (pH = 6.5, 4 3 50 mL) and the organic phase was
subjected to silica gel chromatography using a stepwise gradient of
methanol (0–2%) in chloroform containing 0.2% triethylamine. Yields: 6a
90%, 6b 80%.
†† Polymer-supported phosphine selenide 2 was synthesized by shaking in
THF polystyryl diphenylphosphine resin with KSeCN (3 equiv.) for 4 h.
After that time the 31P NMR spectrum of the suspended polymer beads
showed a complete disappearance of the broad signal at 25.4 ppm due to the
phosphine and a new broad signal at 35.5 ppm due to phosphine selenide.
‡‡ Ca. 10% of the corresponding nucleoside 3A- and 5A-H-phosphonate
monoesters were present in the reaction mixture, probably as a result of
hydrolysis of 6a.
Scheme 3
The above conditions were also found to be most efficient for
the preparation of phosphorothioselenoate 6b11 (dP = 104.2 and
1
103.8, JPSe 759.0 and 756.0 Hz) from the corresponding H-
phosphonothioate 5a (80% isolated yield).** Preliminary data
from selenization of 5a and 5b containing different ratios of
both diastereomers showed that selenide 1 furnished transfer of
selenium to H-phosphonate and H-phosphonothioate diesters in
a stereospecific manner (most likely with retention of config-
uration).
As the final part of these studies we also investigated the
possibility of using a polymer-supported phosphine selenide 2
(PS-TPPSe) as a selenium-transferring reagent. Thus, a com-
mercially available polystyryl diphenylphosphine resin was
converted into selenide 2†† and reacted with selected PIII
derivatives. Preliminary 31P NMR experiments showed that 2
can indeed act as an efficient selenium-transferring reagent.
When triethyl phosphite was treated in dichloromethane with
polymer-supported selenide 2 (4 equiv.), complete conversion
to the corresponding phosphoroselenoate occurred within a few
minutes. Also selenization of dinucleoside H-phosphonate 5a
with selenide 2 (3 equiv.) in the presence of DBU (5 equiv.)
proceeded rapidly ( > 5 min) producing the expected dinucleo-
side phosphoroselenoate 6a.‡‡
In conclusion, we have developed a new and efficient method
for the selenization of PIII compounds based on selenium
exchange. Triphenylphosphine selenide 1, which is proposed as
a new source of electrophilic selenium in this method, is a
stable, easy to handle, inexpensive and commercially available
reagent, with good solubility in organic solvents. Efficiency of
1 as a selenium-transferring reagent was demonstrated by using
it for the conversion of phosphite triesters and H-phosphonate
diesters into the corresponding phosphoroselenoates, as well as
in the transformation of H-phosphonothioate diesters into the
phosphorothioselenoate derivatives. The reactions were fast and
occurred under mild, homogeneous conditions. A polymer-
supported counterpart of reagent 1, triphenylphosphine selenide
2, also showed favourable selenium-transferring properties.
This reagent can be considered as an alternative to 1, especially
if separation problems arise.
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We are indebted to Professor P. J Garegg for his interest in
this work. Financial support from the Swedish Natural Science
Research Council is gratefully acknowledged.
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Chem. Commun., 2001, 771–772