An efficient method for alkylation of alcohols with alkyl P,P-diphenyl-N-(methanesulfonyl)phosphinimidates

Article abstract of DOI:10.1246/cl.2005.1016

Alkyl P,P-diphenyl-N-(methanesulfonyl)phosphinimidates, easily prepared from alkyl diphenylphosphinites and methanesulfonyl azide, are used as a useful reagent for O-alkylation of alcohols in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (Me₃SiOTf). Copyright

Full text of DOI:10.1246/cl.2005.1016

1016
Chemistry Letters Vol.34, No.7 (2005)
An Efficient Method for Alkylation of Alcohols
with Alkyl P,P-diphenyl-N-(methanesulfonyl)phosphinimidates
Hidenori Aokiy;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641
(Received April 5, 2005; CL-050450)
Table 1. Effect of solvent on benzylation of 2-phenylethyl
alcohol
Alkyl P,P-diphenyl-N-(methanesulfonyl)phosphinimidates,
easily prepared from alkyl diphenylphosphinites and methane-
sulfonyl azide, are used as a useful reagent for O-alkylation of
alcohols in the presence of a catalytic amount of trimethylsilyl
trifluoromethanesulfonate (Me3SiOTf).
Ph(CH2)2OH (1.0 equiv.)
OBn
Ph2P
(1.0 equiv.)
O
Me3SiOTf (10 mol%)
Ph(CH2)2OBn
N
P(OPh)2
Solvent, 80 °C, 1 h
Entry Solvent Yield/% Entry
Solvent
Yield/%
1a
2
3
4
EDCb
EDC
Toluene
THF
N.R.
16
27
33
5
6
7
1,4-Dioxane
DMEc
Acetonitrile
54
55
7
Alkylation of alcohols is one of the most fundamental and
frequently used important reactions in synthetic organic chemis-
try. A number of approaches to the preparation of ethers have
been reported since the method of using alkyl halide and metal
alkoxide was reported by Williamson in 1850.1 Recently, vari-
ous new methods for the ether synthesis using phosphorus com-
pounds such as alkyl diphenylphosphinites2 or alkyl diphenyl-
phosphinates3 were reported from our laboratory. Further, it is
important to develop a useful method of alkylation of alcohols
under even milder conditions for the preparation of ethers.
In the Staudinger reaction, phosphines (R3P) were shown to
react with azide compounds to form iminophosphoranes (R3P=
NX) along with a loss of nitrogen.4 Likewise, alkyl diphenyl-
phosphinites (ROPPh2),5 prepared from alcohols and chlorodi-
phenylphosphine, reacted with azide compounds to give phos-
phinimidates (Scheme 1).6 Although there is an expectation for
the phosphinimidates to work as good alkylating agents like
alkyl diphenylphosphinates,3 few reports have been introduced
concerning alkylation of alcohols with phosphinimidates except
for the glycosylation reaction in carbohydrate chemistry.7 Here,
we would like to show the high-yielding preparation of ethers by
using alcohols and stable alkyl P,P-diphenyl-N-(methanesul-
fonyl)phosphinimidates, prepared from alkyl diphenylphosphin-
ites and methanesulfonyl azide, in the presence of Me3SiOTf.
In the first place, the benzylation reaction of 1.0 equiv. of
2-phenylethyl alcohol was tried by using 1.0 equiv. of benzyl
P,P-diphenyl-N-(diphenylphosphoryl)phosphinimidate, prepared
from benzyl diphenylphosphinite and commercially available di-
phenylphosphoryl azide, in 1,2-dichloroethane. However, the ex-
pected product was not obtained and both the phosphinimidate
and the alcohol were thus recovered quantitatively (Table 1,
Entry 1). When 10 mol % of Me3SiOTf was used as an activator,
on the other hand, the corresponding ether was obtained in 16%
yield (Entry 2). After screening several solvents, 1,2-dimethoxy-
ethane was found to have the most suitable effect (Entries 3–7).
Next, the effect of the substituent of phosphinimidate was
examined. When two phenyl groups on the phosphorus atom
aThe reaction was carried out without Me3SiOTf. b1,2-Di-
chloroethane. 1,2-Dimethoxyethane.
c
Table 2. Effect of substituents of phosphinimidate on benzyl-
ation of 2-phenylethyl alcohol
Ph(CH2)2OH (1.0 equiv.)
Me3SiOTf (10 mol%)
R2P(=NX)OBn
(1.0 equiv.)
Ph(CH2)2OBn
DME, 80 °C, 1 h
Entry
R
X
Yield/%
1
2
3
4
5
Ph
i-Pr
Ph
Ph
Ph
(PhO)2P(O)
(PhO)2P(O)
55
38
77
89
93
Bz
Ts
Ms
were replaced by two isopropyl groups, the yield decreased,
whereas the yield increase up to 77% was observed when a di-
phenylphosphoryl group on the nitrogen atom was replaced by
a benzoyl group (Table 2, Entris 1–3). In the case of the phosphi-
nimidate having more an electron-withdrawing p-toluenesulfon-
yl or methanesulfonyl group8 than a benzoyl group was used,
the desired product was obtained in 89% and 93% yields, respec-
tively (Entries 4 and 5).
Alkylation of several alcohols with alkyl P,P-diphenyl-N-
(methanesulfonyl)phosphinimidates was tried next (Table 3).
As a result, etherification of the alcohols having alkali- or
acid-sensitive groups was found to proceed smoothly to afford
the corresponding ethers in high yields in the presence of a cata-
lytic amount of Me3SiOTf, while the desired ether was not af-
forded when less reactive L-menthyl P,P-diphenyl-N-(methane-
sulfonyl)phosphinimidate was used (Entry 11). In the case with
ethyl (S)-(ꢁ)-lactate, the corresponding benzyl ether was exclu-
sively obtained without accompanying any epimerization (Entry
3). Contrary to the above result, a racemic product was obtained
when (S)-1-phenylethyl P,P-diphenyl-N-(methanesulfonyl)-
phosphinimidate was reacted with 2-phenylethy alcohol or 2-
methyl-4-phenyl-2-butanol, respectively (Entries 9 and 10).
OR
OR
Ph P
Ph P OR
- N
2
2
Ph POR
Ph P NX
2
2
+
NX
2
NX
N
N
XN
3
N
N
phosphinimidate
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
1017
Table 3. Alkylation of alcohols with alkyl P,P-diphenyl-N-
(methanesulfonyl)phosphinimidates and Me3SiOTf
Ph P
HNMs
5
O
2
1
+
ROR
Ph P OR
2
XOTf
NMs
1
Me3SiOTf
R1OH
ROR1
X = TMS, H
+
Ph2P(=NMs)OR
(1.0 equiv.)
DME, rt, Time
(1.0 equiv.)
1
Me3SiOTf Time Yield
/mol %
R OH + 4
Entry Ph2P(=NMs)OR R1OH
OTf
Ph POR
2
/h
/%
XNMs
R
OTf
3
1a
2
3
4
5
6
7
8
9
A
A
A
A
A
B
C
D
E
E
F
1
2
3
4
5
4
1
1
1
6
1
10
10
10
10
10
10
20
20
1
1
3
3
3
3
24
24
24
95
94
88
77
2
Ph P
O
2
XNMs
4
73
72b
55
Scheme 2.
57
Thus, it is noted that a moisture- and air-resistant alkyl P,P-
diphenyl-N-(methanesulfonyl)phosphinimidates are easy to han-
dle and are used as a useful O-alkylation reagent of alcohols.
Further study on this type of reaction is now in progress.
0.5
0.5
24
85c
83c
N.D.
10
11
1
30
aThe desired ether was obtained in 91% yield when TfOH was
used instead of Me3SiOTf. 1.2 equivalent of the phosphinimi-
b
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
date was used. cRacemic product was obtained.
Ph2POBn
Ph2POAllyl
Ph2PO
NMs
Ph
References and Notes
1
NMs
NMs
a) J. March, in ‘‘March’s Advanced Organic Chemistry,
Reaction, Mechanism, and Structure,’’ 5th ed., John Wiley &
Sons, New York (2001), pp 477–478. b) F. M. Callahan,
G. W. Anderson, R. Paul, and J. E. Zimmerman, J. Am. Chem.
Soc., 85, 201 (1963). c) Y. Kashman, J. Org. Chem., 37, 912
(1972). d) S. Torii, S. Takagishi, T. Inokuchi, and H. Okumoto,
Bull. Chem. Soc. Jpn., 60, 775 (1987). e) P. G. Sammers, D.
Thetford, and M. Voyle, J. Chem. Soc., Chem. Commun.,
1987, 1373. f) F. Toda, H. Takumi, and M. Akehi, J. Chem.
Soc., Chem. Commun., 1990, 1270. g) N. Nakajima, M. Saito,
and M. Ubukata, Tetrahedron Lett., 39, 5565 (1998), and
references cited therein.
T. Shintou and T. Mukaiyama, J. Am. Chem. Soc., 126, 7359
(2004).
Y. Kobashi, T. Minowa, and T. Mukaiyama, Chem. Lett., 33,
1362 (2004).
For a review, see: Y. G. Gololobov, I. N. Zhmurova, and L. F.
Kasukhin, Tetrahedron, 37, 437 (1981).
Preparation of alkyl diphenylphosphinites, see: K. Ikegai,
W. Pluempanupat, and T. Mukaiyama, Chem. Lett., 34, 638
(2005).
A
B
C
Ph
Ph2PO
MsN
OBn
Ph2PO
NMs
Ph2PO
NMs
Ph
O
D
1
E
F
CO2Et
OH
Ph
HO
Ph
OH
2
3
O
Me OH
CO2Me
Ph
O
O
2
3
4
5
Ph
HO
HO
Ph
BzO
OMe
4
5
6
A proposed reaction mechanism is shown in Scheme 2: in
the first step, alkyl P,P-diphenyl-N-(methanesulfonyl)phosphin-
imidate 1 is silylated or protonated to yield the alkyl cation 3
which is a very reactive electrophile and reacts rapidly with al-
cohols to form ethers along with N-methanesulfonyl diphenyl-
phosphinic amide 5, which is separated easily by washing with
sat. NaHCO3 solution. The proton liberated in this step is subse-
quently involved in the catalytic cycle (Scheme 2).
The typical experimental procedure is as follows: to a stirred
solution of benzyl P,P-diphenyl-N-(methanesulfonyl)phosphin-
imidate (0.3 mmol) and 2-phenylethyl alcohol (0.3 mmol) in
1,2-dimethoxyethane (0.48 mL) under argon atmosphere was
added a solution of Me3SiOTf (10 mol %) in 1,2-dimethoxy-
ethane (0.02 mL) at 0 ꢂC. The reaction mixture was stirred for
1.0 h at room temperature. After completion of the reaction
(detected by TLC), the mixture was quenched with saturated
NaHCO3 and was extracted with ethyl ether. Organic layers
were dried over anhydrous sodium sulfate, then filtered and con-
centrated. The crude product thus obtained was purified by prep-
arative TLC to give the corresponding benzyl 2-phenylethyl
ether (0.0604 g, 95%) as colorless oil.
6
7
8
A. A. El-Kateb and F. M. Soliman, Egypt. J. Chem., 24, 465
(1981).
S. Hashimoto, H. Sakamoto, T. Honda, and S. Ikegami,
Tetrahedron Lett., 38, 5181 (1997).
Synthetic procedure for benzyl P,P-diphenyl-N-(methanesul-
fonyl)phosphinimidate is as follows: methanesulfonyl chloride
(10 mmol) was dissolved in DMF (10 mL) at 0 ꢂC and was
stirred for 1 h at 0 ꢂC. Then, sodium azide (11 mmol) was add-
ed to the mixture at 0 ꢂC to stir for 2 h at 0 ꢂC. After warming
up the reaction mixture to room temperature, a solution of
benzyl diphenylphosphinite (10 mmol) in dichloromethane
(10 mL) was added dropwise and the solution was kept stirring
for 1 h at room temperature and chloroform was added. Then,
the mixture was washed with water and brine and the organic
layer was dried over anhydrous sodium sulfate. After filtration
and evaporation, the resulted crude solid was washed by
diethyl ether to afford the desired product (3.37 g, 87%) as a
white solid.
Published on the web (Advance View) June 18, 2005; DOI 10.1246/cl.2005.1016