A convenient method for phosphorylation using triallyl phosphite

Article abstract of DOI:10.1016/j.tetlet.2015.06.030

Abstract A direct method for the phosphorylation of alcohols, phenols, saccharides and nucleosides using triallyl phosphite is described. From primary or secondary alcohols, the corresponding diallyl-protected phosphorylated compounds are obtained in good

Full text of DOI:10.1016/j.tetlet.2015.06.030

Tetrahedron Letters 56 (2015) 4694–4696
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient method for phosphorylation using triallyl phosphite
⇑
⇑
Si-Zhe Li, Mohammed Ahmar, Yves Queneau , Laurent Soulère
Université de Lyon, INSA Lyon, ICBMS, Chimie Organique et Bioorganique, Bât J. Verne, 20 avenue Albert Einstein, 69621 Villeurbanne Cedex, France
ICBMS, CNRS, UMR 5246, Université Lyon 1, INSA-Lyon, CPE-Lyon, Bât CPE, 43 bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct method for the phosphorylation of alcohols, phenols, saccharides and nucleosides using triallyl
phosphite is described. From primary or secondary alcohols, the corresponding diallyl-protected phos-
phorylated compounds are obtained in good to high yields. The method was found to be selective for pri-
mary alcohols and to be applicable to diverse simple and functionalized alcohols, including amino acids,
carbohydrates and nucleosides.
Received 18 May 2015
Revised 8 June 2015
Accepted 10 June 2015
Available online 17 June 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Phosphorylation
Phosphite
Allyl-protecting groups
The phosphite/iodine phosphorylation method is based on the
sequence shown in Scheme 1, starting with an Arbuzov reaction
of alkyl phosphite with iodine19 leading to the formation of the
corresponding dialkyl phosphoriodidate 4. Once produced, this
reactant reacts with alcohols or phenols directly or via its
reaction with pyridine, as initially described.17,20 DMAP can also
Orthogonal allyl-based protecting groups are essential in pep-
tide1,2 and nucleotide3,4 synthesis and, more generally, in total syn-
thesis.5 In particular, phosphorylation reactions leading to
orthogonally allyl-protected phosphates are useful because their
deprotection can be achieved in mild conditions by allylic transfer
to a scavenger (butyl amine,2–4,6 pyrrolidine7,8 or others9), catal-
ysed by tetrakis(triphenylphosphine)palladium)1 or by using palla-
dium chloride10 in methanol.11,12 Several methods have been
reported for the synthesis of allyl-protected phosphates,10 namely
the use of diallyl chlorophosphate 1,12,13 phosphoramidite
22,7–9,14,15 and, more recently, the catalytic Lewis acid phosphory-
lation with pyrophosphates such as compound 3.16 However, the
combination of phosphite and iodine, a cheap, easy-to-handle
method which does not require prior synthesis of the reagent,
has never been reported for access to allyl phosphates whereas it
is an established method for the introduction of methyl, ethyl or
benzyl protected phosphates.17 Moreover, triallyl phosphite is
commercially available and quite inexpensive, or it can be easily
prepared from phosphorus trichloride.18 In this study, we report
the results of our investigations into this method which offers a
simple, direct and cheap alternative for accessing allyl phosphory-
lated alcohols, phenols, nucleosides and sugars.
I
I2
R
P+
O
O
P
O
O
R
O
I-
O
R
R
R
R
phosphite
I
R
R'O
P
I
P
R'-OH
4
O
O
O
O
O
O
R
R
R
R
Product
N
DMAP
OAll
R'-OH
O
P
O
P
O
P
N+
P
O
5
AllO
AllO
OAll
OAll
OAll
OAll
P
N
OAll
Cl
I-
O
O
O
3
2
1
R
R
⇑
Corresponding authors. Fax: +33 4 72 43 88 96.
E-mail addresses: yves.queneau@insa-lyon.fr (Y. Queneau), laurent.soulere@
Scheme 1. Proposed mechanism of phosphorylation using phosphite: the dialkyl
phosphoriodidate (4) and the 4-(dimethylamino)pyridin-1-ium (5) are the reac-
tants for the phosphorylation process.17,19,20
insa-lyon.fr (L. Soulère).
http://dx.doi.org/10.1016/j.tetlet.2015.06.030
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S.-Z. Li et al. / Tetrahedron Letters 56 (2015) 4694–4696
4695
to 98%. As shown for the reaction with tribenzyl phosphite,20 the
reaction proved to be selective for primary alcohols with good to
excellent yields when conducted on 1,2-hexanediol, 1,2-O-iso-
Table 1
Conditions for the phosphorylation of p-cresol and benzyl alcohol (the phosphory-
lating reagent was prepared following the typical experiment)
propylidene-a-D-xylofuranose and octyl b-D-glucopyranoside.
O
P
OAll
P(OAll)3, I2
R-OH
DMAP, CH2Cl2
OAll
R-O
Table 2
Phosphorylation of various alcohols using triallyl phosphitea
O
P
OAll
R2
R
Conditions
Temperature
(°C)
Yield
(%)
OH
R2
P(OAll)3, I2
OAll
O
R1
CH3Ph– P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
RT
52
52
49
47
75
75
75
75
73
82
DMAP, CH2Cl2
R1
(1 equiv)
CH3Ph– P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
0
(1 equiv)
Entry Alcohols
Products
Yield
(%)
CH3Ph– P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
ꢀ10
ꢀ30
0
(1 equiv)
O
P
CH3Ph– P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
1
2
Cyclohexanol
2-Naphtol
39
98
(1 equiv)
OAll
O
CH3Ph– P(OAll)3 (2.2 equiv), I2 (2 equiv), DMAP
(2 equiv)
OAll
O
P
OAll
Bn–
Bn–
Bn–
Bn–
Bn–
P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
(1 equiv)
P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
(1 equiv)
P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
(1 equiv)
P(OAll)3 (1.2 equiv), I2 (1 equiv), DMAP
(1 equiv)
RT
0
OAll
O
O
P
ꢀ10
ꢀ30
0
OAll
3
4
5
a
-Methylbenzyl alcohol
42
94
64
O
OAll
O
P
P(OAll)3 (2.2 equiv), I2 (2 equiv), DMAP
(2 equiv)
Decan-1-ol
BocSerOMe
OAll
O
8
OAll
NHBoc
MeOOC
be used, as shown by Soulère et al.,21 with triethylphosphite lead-
ing to the production of 1-(bis(alkyl)phosphoryl)-4-(dimethy-
lamino)pyridin-1-ium (5) (Scheme 1).20
O
P
OAll
O
OAll
NHBoc
MeOOC
To screen several reaction conditions, benzyl alcohol was used
as a model primary alcohol and p-cresol as a model phenol. We
then examined the influence of temperatures, (0 °C, ꢀ10 °C,
ꢀ30 °C or RT) and of different amounts of iodine (1 or 2 equiv)
and triallyl phosphite (1.2 or 2.2 equiv). The phosphite was always
used in excess to ensure complete consumption of iodine (Table 1).
Though the role of DMAP can be catalytic, it is used in stoichiomet-
ric amount for neutralizing the hydrogen iodide formed in the pro-
cess, in order to prevent undesired acid catalyzed side reactions on
more fragile functions of the substrates and products. The reaction
was efficient, with comparable yields for both alcohols at 0 °C,
ꢀ10 °C, ꢀ30 °C or RT. As expected, the yields increased in both
cases when 2 equiv of the phosphorylating agent were used.
In a typical experiment for the phosphorylation of benzyl alco-
hol, iodine (2 equiv) was added at 0 °C to a solution of triallyl phos-
phite (2.2 equiv) in anhydrous DCM (5 mL). After 10 min at 0 °C,
the solution was warmed up to room temperature and added,
drop-wise for 5 min, to a solution of benzyl alcohol (0.5 mmol)
and DMAP (2 equiv) in anhydrous DCM (5 mL) at RT. After 4 h,
the solution was diluted with DCM and washed with saturated
NaHSO4, saturated NaHCO3 and brine. The organic layer was dried
over Na2SO4 and evaporated under reduced pressure. The diallyl-
benzylphosphate was purified by flash chromatography and char-
acterized by standard analytical procedures.
O
P
OAll
NH2
6
BocTyrOMe
77
62
OAll
O
N
N
20,30-Isopropylidene
adenosine
AllO
O
O
7b
N
P
O
N
O
AllO
O
O
O
O
N
NH
20,30-Isopropylidene
uridine
AllO
AllO
8b
68
O
P
O
O
O
O
AllO
P
9
1,2-Hexanediol
72
67
AllO
O
OH
O
O
O
O
P
1,2-O-Isopropylidene-a-D-
xylofuranose
AllO
AllO
10
O
HO
O
P
The scope of the reaction was investigated using various alco-
hols, including secondary and functionalized alcohols such as
BocSerOMe, BocTyrOMe, 20,30-isopropylideneadenosine and 20,30-
isopropylideneuridine. We also used 1,2-hexanediol, 1,2-O-iso-
propylidene-a-D-xylofuranose and octyl b-D-glucopyranoside as
polyols to examine the selectivity toward primary alcohols
OAll
OAll
O
11
Octyl b-
D-glucopyranoside
67
73
O
HO
O
HO
OH
OAc
C8H17
(Table 2). The phosphorylation reaction was less effective on sec-
O
2,3,4,6-Tetra-O-acetyl-D-
glucopyranose
12c
AcO
AcO
OAll
ondary alcohols, such as cyclohexanol or
a-methylbenzyl alcohol,
O
OAc
P
OAll
with 39% and 42% yields, respectively. For all other alcohols, the
reaction was found to be efficient with yields ranging from 62%
O
(continued on next page)

4696
S.-Z. Li et al. / Tetrahedron Letters 56 (2015) 4694–4696
solvents, with yields of approximately 80%, thus widening the
Table 2 (continued)
choice when substrates are not soluble enough in DCM (Table 3).
In summary, a convenient direct phosphorylation method for
providing fair to excellent yields of allyl-protected phosphorylated
compounds from cheap and readily available triallylphosphite is
reported. The method was applied to simple primary and
secondary alcohols, as well as to more complex substrates, such
as nucleosides or carbohydrate derivatives. Diols or polyols
possessing both primary and secondary alcohol functions can be
selectively phosphorylated at their primary position.
Entry Alcohols
Products
Yield
(%)
OAc
OAc
AcO
O
2,3,4,6-Tetra-O-acetyl-
galactopyranose
D-
13c
55
OAll
O
OAc
P
OAll
O
a
All reactions were conducted using the standard procedure except for nucleo-
sides and the synthesis of b-glycosyl-1-phosphates: triallyl phosphite (2.2 equiv), I2
(2 equiv) and DMAP (2 equiv) and DCM as solvent.
b
Nucleosides were dissolved with DMAP (4 equiv) in THF and the phosphory-
Acknowledgments
lating agent prepared in DCM was added at ꢀ30 °C. The reaction was stirred
overnight at RT.
Financial support from MESR (France), CNRS (France) and ANR
‘SENSOR’ is gratefully acknowledged. S.Z.L. would like to thank
the Chinese Scholarship Council for a Grant.
c
For the synthesis of b-glycosyl-1-phosphates, triallyl phosphite (7.8 equiv), I2
(7.5 equiv) and DMAP (10 equiv) were used according to the standard procedure.
The reaction was stirred overnight at RT.
Supplementary data
Table 3
Phosphorylation of benzyl alcohol in various solventsa
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
030.
Entry
Solvents
Yield (%)
1
2
3
4
5
6
DCM
THF
82
56
84
85
41
24
Pyridineb
Acetonitrile
DMF
References and notes
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a
All reactions were conducted with triallyl phosphite (2.2 equiv), I2 (2 equiv) and
DMAP (2 equiv) at RT. The solution of the phosphorylation reagent was prepared in
DCM.
b
Without DMAP.
Most reactions were performed using the conditions optimized for
benzyl alcohol (2.2 equiv of phosphite, 2 equiv of iodine, 2 equiv of
DMAP, DCM). However, some substrates required alternative con-
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