A Convenient Method for the Preparation of Symmetrical or Unsymmetrical Ethers by the Coupling of Two Alcohols via a New Type of Oxidation-reduction Condensation Using Tetrafluoro-1,4-benzoquinone

Article abstract of DOI:10.1246/cl.2003.984

A new type of oxidation-reduction condensation by using tetrafluoro-1,4-benzoquinone (fluoranil), alcohols and alkoxydiphenylphosphines, in situ formed from ⁿBuLi-treated alcohols and chlorodiphenylphosphine, proceeded smoothly to afford the corresponding symmetrical or unsymmetrical ethers in good to high yields.

Full text of DOI:10.1246/cl.2003.984

984
Chemistry Letters Vol.32, No.11 (2003)
A Convenient Method for the Preparation of Symmetrical or Unsymmetrical Ethers
by The Coupling of Two Alcohols via A New Type of Oxidation–reduction
Condensation Using Tetrafluoro-1,4-benzoquinone
Taichi Shintouy;yy and Teruaki MukaiyamaÃy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received August 4, 2003; CL-030718)
A new type of oxidation–reduction condensation by using tet-
R
rafluoro-1,4-benzoquinone (fluoranil), alcohols and alkoxydiphe-
nylphosphines, in situ formed from nBuLi-treated alcohols and
chlorodiphenylphosphine, proceeded smoothly to afford the cor-
responding symmetrical or unsymmetrical ethers in good to high
yields.
n
BuLi
O
Ph
Ph
F
F
F
F
Ph2POR
OR'
ROH
P
Ph PCl
2
F
F
O
O
H
OR'
OH
O
O
F
F
R
O
O
F
Ph
F
O
F
P
F
Ph
Ph
+
ROR'
Ph
P
Preparation of ethers is one of the most fundamental and fre-
quently used important reactions in synthetic organic chemistry.
For example, several O-alkylation reactions are carried out by us-
ing alkyl halides (Williamson ether synthesis),1 olefins,2 dialkyl
phosphates,3 aldehydes,4 nitro compounds,5 p-toluene sulfonic
acid,6 and imidates.7 Of these etherifications, however, to prepare
ethers in high yields under mild conditions is still a challenging
topic. As reported in our previous communications,8 alkylation
of various carboxylic acids or phenols with alkoxydiphenylphos-
phines, in situ formed from various nBuLi-treated primary, bulky
secondary and tertiary alcohols, chlorodiphenylphosphine and
2,6-dimethyl-1,4-benzoquinone turned out to be a new type of ox-
idation–reduction condensation while O-alkylation reaction using
2,6-dimethyl-1,4-benzoquinone, alcohols, and in situ formed al-
koxydiphenylphosphines was not successfully carried out. On
treating with oxidants such as 2,6-dimethyl-1,4-benzoquinone, al-
koxydiphenylphosphines are considered to form an important in-
termediate phosphonium salt quite effectively as the alkoxy part
was introduced to phosphine in advance. However, thus formed
intermediate phosphonium salt was not in turn converted smooth-
ly to a so-called penta-valent phosphorus compound by abstract-
ing one hydrogen atom from alcohols. In order to extend the scope
of the above reaction, a new type of oxidation–reduction conden-
sation by using more powerful oxidant such as fluoranil, alcohols,
and alkoxydiphenylphosphines which were in situ formed from
nBuLi-treated alcohols and chlorodiphenylphosphine, was tried.
It was found then that the intermediate phosphonium salt was in
turn converted smoothly to a so-called penta-valent phosphorus
compound by catching one hydrogen atom from alcohols and
the corresponding symmetrical or unsymmetrical ethers were suc-
cessfully prepared in good to high yields (Scheme 1).
O
OH
F
F
F
F
Scheme 1.
Table 1. Effect of quinone derivatives on etherification of 2-phenylethanol
Ph(CH ) OH
2 2
n
BuLi
(2.0 equiv.)
Ph
BnOH
Ph2POBn
O
Ph
Quinone
(1.0 equiv.)
Ph PCl
2
(1.0 equiv.)
CH Cl , rt, 3 h
2
2
Entry
Quinone
2,6-dimethyl-
1,4-benzoquinone
DDQ
chloranil
Yield/%
N.R.
1
2
3
4
18
6
72
fluoranil
Entries 2 and 3). Interestingly, the desired product was obtained in
72% yield at room temperature when an oxidant such as fluoranil
was allowed to react under the above conditions for 3 h (Table 1,
Entry 4).
After examination of reaction condition, it was revealed that
the ether was obtained in 92% yield when 1.0 equiv. of Ph2POBn
and 1.2 equiv. of tetrafuluoro-1,4-benzoquinone were treated with
1.2 equiv. of 2-phenylethanol at room temperature for 3 h
(Table 2, Entry 8).
Next, O-alkylation reaction by using fluoranil, various alco-
hols and alkoxydiphenylphosohines in situ formed from several
nBuLi-treated alcohols and chlorodiphenylphosphine was tried
(Table 3). When benzyl alcohols having electron-donating or
electron-withdrawing groups and primary, secondary, and tertiary
alcohols were used, the corresponding symmetrical or unsymmet-
rical ethers were obtained in good to high yields (Table 3, Entries
1–13). On the other hand, the desired product was obtained in
63% yield by the coupling reaction between primary alcohol such
as nBuOH and p-methoxybenzyl alcohol (Table 3, Entry 20).
Ether-formation reaction between t-butoxydiphenylphosphine
and p-methoxybenzyl alcohol did not take place at all (Table 3,
Entry 22), while, the desired ether was obtained in 89% yield
when p-methoxybenzyloxydiphenylphosphine was treated with
In the first place, O-alkylation reaction of 2 equiv. of 2-phe-
nylethanol in CH2Cl2 with 1 equiv. of 2,6-dimethyl-1,4-benzo-
quinone and 1 equiv. of benzyloxydiphenylphosphine, in situ
n
formed from BuLi-treated benzyl alcohol and chlorodiphenyl-
phosphine, was tried, however, the desired ether was not obtained
(Table 1, Entry 1). When more powerful oxidizing agent such as
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or tetra-
chloro-1,4-benzoquinone (chloranil) was used, the corresponding
ether was obtained in 18% and 6% yields, respectively (Table 1,
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.11 (2003)
985
tBuOH (Table 3, Entry 4). Alcohols having a hydroxy group at ꢀ-
position of carboxylic esters such as ethyl glycolate or methyl (R)-
(À)-mandelate also afforded the desired products in 86% yield or
83% yield (no racemization), respectively (Table 3, Entries 9 and
10). The etherification of several bulky secondary or tertiary alco-
hols with 2-phenylethanol or 2-methyl-1-phenyl-2-propanol
smoothly proceeded to afford the corresponding unsymmetrical
ethers in high yields when the reactions were carried out at room
temperature for 3 h (Table 3, Entries 14–19). It is noted that the
desired ether was obtained with 69% inversion when (R)-(+)-1-
phenylethanol and 2-phenylethanol were used (Table 3, Entry
14). Also, when methyl (R)-(À)-mandelate and p-methoxybenzyl
alcohol were allowed to react under the present condition, the cor-
responding ether was obtained in 89% yield (95% inversion)
(Table 3, Entry 17). Thus, efficient methods for the etherification
of chiral alcohols with retention or inversion, namely, treatment
of chiral alkoxydiphenylphosphine and achiral alcohol afforded
the inverted ether while that of achiral alkoxydiphenylphosphine
and chiral alcohol afforded the ether with retention (Table 3, En-
tries 10 and 17). Also, in the etherification using secondary
alkoxydiphenylphosphine such as L-menthol derivative and p-
methoxybenzyl alcohol afforded the desired ether in 30% yield
with perfect inversion (Table 3, Entry 21).
Table 2. Etherification of 2-Phenylethanol with Ph2POBn and Fluoranil
n
Ph(CH ) OH
2 2
1
BuLi
Ph
BnOH
Ph2POBn
O
Ph
fluoranil
Ph PCl
2
CH Cl , rt, 3 h
2
2
Entry
R2POBn/equiv.
1/equiv.
2.0
1.0
2.0
1.5
1.2
1.0
1.2
1.2
fluoranil/equiv.
Yield/%
72
70
87
88
92
87
92
92
1
2
3
4
5
6
7
8
9
10
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.3
1.2
1.1
1.0
1.2
1.2
85
72
Table 3. Etherification using fluoranil, various alcohols and alkoxydiphe-
nylphosphines in situ formed from alcohols, Ph2Cl and nBuLi
n
R'OH (1.2 equiv.)
BuLi
R
O
R'
ROH
Ph2POR
fluoranil (1.2 equiv.)
CH Cl , rt, 3 h
Ph PCl
2
(1.0 equiv.)
2
2
Entry
1
ROH
R'OH
Yield /%
95
Ph(CH2)2OH
p-MeO-C6H4CH2OH
Typical experimental procedure is as follows: to a mixture of
alkoxydiphenylphosphine9 (0.60 mmol) and fluoranil (0.72 mmol)
under argon atmosphere was added a dichloromethane (0.50 mL)
solution of alcohol (0.72 mmol) at room temperature. After the re-
action, that was monitored by TLC, was completed, the reaction
mixture was quenched by adding water and the aqueous layer
was extracted with dichloromethane. The organic layers were
dried over anhydrous sodium sulfate. After filtration and evapora-
tion, the resulted residue was purified by preparative TLC to af-
ford the corresponding ether. The above reactions were also car-
ried out by one-pot procedure and the same results were obtained
even in the presence of lithium chloride.
2
3
90
90
Ph
OH
Cyclohexanol
4
5
tBuOH
89
91
(L)-Menthol
6
Neomenthol
90
94
94
86
Ph
7
OH
8
p-MeO-C6H4CH2OH
9a
HO
COOEt
OH
10a,b
83
Ph
COOMe
Thus, a new and efficient method for the preparation of sym-
metrical or unsymmetrical ethers in good to high yields between
various alcohols was established by way of a new type of oxida-
tion–reduction condensation using in situ formed alkoxydiphenyl-
phosphines, fluoranil, and alcohols. Further study on this type of
condensation reaction is now in progress.
Ph(CH2)2OH
BnOH
11
12
BnOH
92
94
Ph(CH2)2OH
Ph(CH2)2OH
13
p-Cl-C6H4CH2OH
75
90
14c
Ph
OH
OH
Ph(CH2)2OH
15
16
91
90
Ph
This study was supported in part by the Grant of the 21st Cen-
tury COE Program, Ministry of Education, Culture, Sports, Sci-
ence, and Technology (MEXT).
Ph
Ph
OH
OH
17d
18
p-MeO-C6H4CH2OH
89
92
Ph
COOMe
OH
References and Notes
1
J. March, in ‘‘March’s Advanced Organic Chemistry, Reaction, Mechanism, and
Structure,’’ 5th ed., John Wiley & Sons, New York (2001), pp 477-478.
F. M. Callahan, G. W. Anderson, R. Paul, and J. E. Zimmerman, J. Am. Chem.
Soc., 85, 201 (1963).
Ph(CH2)2OH
Ph
2
Et
Ph(CH2)2OH
19
20
88
63
3
4
Y. Kashman, J. Org. Chem., 37, 912 (1972).
S. Torii, S. Takagishi, T. Inokuchi, and H. Okumoto, Bull. Chem. Soc. Jpn., 60,
775 (1987).
Ph
OH
nBuOH
p-MeO-C6H4CH2OH
5
P. G. Sammers, D. Thetford, and M. Voyle, J. Chem. Soc., Chem. Commun.,
1987, 1373.
F. Toda, H. Takumi, and M. Akehi, J. Chem. Soc., Chem. Commun., 1990, 1270.
N. Nakajima, M. Saito, and M. Ubukata, Tetrahedron Lett., 39, 5565 (1998), and
references cited therein.
21e
L-Menthol
tBuOH
p-MeO-C6H4CH2OH
p-MeO-C6H4CH2OH
30
6
7
22
N.R.
a1.0 equiv. of fluoranil was used. bNo racemiczation was observed by HPLC us-
26
D
ing DAICEL CHIRALCEL OD. c½ꢀŠ ¼ À125:7 (c 0.80, CHCl3). The corre-
8
a) T. Mukaiyama, T. Shintou, and W. Kikuchi, Chem. Lett., 2002, 1126. b) T.
Shintou, W. Kikuchi, and T. Mukaiyama, Chem. Lett., 32, 22 (2003). c) T.
Mukaiyama, W. Kikuchi, and T. Shintou, Chem. Lett., 32, 300 (2003). d) T.
Shintou, W. Kikuchi, and T. Mukaiyama, Bull. Chem. Soc. Jpn., 76, 1645 (2003).
Preparation of various alkoxydiphenylphosphines. See Ref. 8.
sponding ether was obtained with 69% inversion. dThe corresponding ether was
obtained with 95% inversion. eThe corresponding ether was obtained with per-
fect inversion. Diastereoselectivities determined by 1H NMR spectroscopy.
9
Published on the web (Advance View) September 27, 2003; DOI 10.1246/cl.2003.984