Efficient methods for the preparation of alkyl-aryl and symmetrical or unsymmetrical dialkyl ethers between alcohols and phenols or two alcohols by oxidation-reduction condensation

Article abstract of DOI:10.1021/ja0487877

Oxidation-reduction condensation via alkoxydiphenylphosphines (diphenylphosphinite esters) (1), generated in situ from chlorodiphenylphosphine (2) and alcohols, 2,6-dimethyl-1,4-benzoquinone (3), and phenols proceeds smoothly to afford alkyl-aryl ethers in good to high yields under neutral conditions. In a similar fashion, a new and efficient method for the preparation of symmetrical or unsymmetrical dialkyl ethers in good to high yields is established via tetrafluoro-1,4-benzoquinone (fluoranil) (4), alcohols, and 1 formed in situ from ⁿBuLi-treated alcohols and 2. This method is applicable also to the etherification of chiral secondary or tertiary alcohols with retention or inversion of configurations. The inverted ethers are afforded by treating chiral alkoxydiphenylphosphines and achiral alcohols, while the reaction of achiral alkoxydiphenylphosphines and chiral alcohols forms retained ethers.

Full text of DOI:10.1021/ja0487877

Published on Web 05/19/2004
Efficient Methods for the Preparation of Alkyl-Aryl and
Symmetrical or Unsymmetrical Dialkyl Ethers between
Alcohols and Phenols or Two Alcohols by
Oxidation-Reduction Condensation
Taichi Shintou† and Teruaki Mukaiyama*,†,‡
Contribution from the Center for Basic Research, The Kitasato Institute, 6-15-5 Toshima,
Kita-ku, Tokyo 114-0003, Japan, and Kitasato Institute for Life Sciences, Kitasato UniVersity,
5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Received March 3, 2004; E-mail: mukaiyam@abeam.ocn.ne.jp
Abstract: Oxidation-reduction condensation via alkoxydiphenylphosphines (diphenylphosphinite esters)
(1), generated in situ from chlorodiphenylphosphine (2) and alcohols, 2,6-dimethyl-1,4-benzoquinone (3),
and phenols proceeds smoothly to afford alkyl-aryl ethers in good to high yields under neutral conditions.
In a similar fashion, a new and efficient method for the preparation of symmetrical or unsymmetrical dialkyl
ethers in good to high yields is established via tetrafluoro-1,4-benzoquinone (fluoranil) (4), alcohols, and 1
formed in situ from nBuLi-treated alcohols and 2. This method is applicable also to the etherification of
chiral secondary or tertiary alcohols with retention or inversion of configurations. The inverted ethers are
afforded by treating chiral alkoxydiphenylphosphines and achiral alcohols, while the reaction of achiral
alkoxydiphenylphosphines and chiral alcohols forms retained ethers.
1985) was reported from our laboratory.9 Olah and co-workers
also demonstrated trimethylsilyl iodide catalyzed reductive
Introduction
The preparation of ethers is one of the most fundamental and
frequently used important reactions in synthetic organic chem-
istry. In 1850, the first examples of the formation of carbon-
oxygen single bonds were reported via alkoxides and alkyl
halides (Williamson ether synthesis).1 The attack of alkoxides
on alkyl halides, however, was synthetically effective only when
the primary alkyl halide was used. When the secondary or
tertiary alkyl halides were used, the desired ethers were obtained
in low yields together with the corresponding olefins simulta-
neously formed by elimination reactions. Several O-alkylation
reactions took place when olefins (in 1963),2 dialkyl phosphates
(in 1972),3 aldehydes (in 1987),4 nitro compounds (in 1987),5
p-toluenesulfonic acid (in 1990),6 or imidates (in 1998)7 were
allowed to react with alcohols. The trimethylsilyl triflate-
catalyzed reaction of acetals and trialkylsilanes was also reported
by Noyori et al. in 1979.8 Another method of ether synthesis
by treating carbonyl compounds such as aldehydes and trieth-
ylsilane in the presence of trityl perchlorate as a catalyst (in
coupling of carbonyl compounds with trialkylsilanes (in 1987).10
Recently, Nishiyama et al. reported ether synthesis via magne-
sium alkoxides and trifluoromethanesulfonic anhydride (in
1999).11 Even after the above publications, the preparation of
various ethers in high yields under mild conditions still remains
a challenging topic in synthetic chemistry.
There are a number of examples for SN2 displacement
reactions of chiral secondary or tertiary centers with nucleophiles
that form the inverted chiral substituted products.12 Of these
SN2 displacement reactions via compounds which have a
secondary carbon, a coupling reaction of chiral secondary
alcohols with phenols in the presence of diethyl azodicarboxylate
(DEAD) and triphenylphosphine is most widely employed for
the synthesis of alkyl-aryl ethers.13 Ingold14 first reported that
the corresponding methyl ether, tert-aliphatic compound, was
obtained with 34% inversion by SN2 replacement when (R)-3-
chloro-3,7-dimethyloctane was treated with methanol (1950).
Doering15 then reported the solvolysis of (+)-hydrogen 2,4-
dimethyl-4-hexyl phthalate in refluxing MeOH which afforded
the corresponding ether with 54% inversion and 46% racem-
† The Kitasato Institute.
‡ Kitasato University.
(1) March, J. March’s AdVanced Organic Chemistry, Reaction, Mechanism,
and Structure, 5th ed.; John Wiley & Sons: New York, 2001; pp 477-
478.
(9) Kato, J.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1985, 743.
(10) Olah, G. A.; Yamato, T.; Iyer, P. S.; Prakash, G. K. J. Org. Chem. 1986,
51, 2826.
(11) Nishiyama, T.; Kameyama, H.; Maekawa, H.; Watanuki, K. Can. J. Chem.
1999, 77, 258.
(2) Callahan, F. M.; Anderson, G. W.; Paul, R.; Zimmerman, J. E. J. Am. Chem.
Soc. 1963, 85, 201.
(3) Kashman, Y. J. Org. Chem. 1972, 37, 912.
(4) Torii, S.; Takagishi, S.; Inokuchi, T.; Okumoto, H. Bull. Chem. Soc. Jpn.
1987, 60, 775.
(12) Dirlam, N. L.; Moore, B. S.; Urban, F. J. J. Org. Chem. 1987, 52, 3587.
(13) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughs, D. L. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons: New York, 1992; Vol. 42, p
335. (c) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127.
(14) Hughes, E. D.; Ingold, C. K.; Martin, R. J. L.; Meigh, D. F. Nature 1950,
166, 679.
(5) Sammers, P. G.; Thetford, D.; Voyle, M. J. Chem. Soc., Chem. Commun.
1987, 1373.
(6) Toda, F.; Takumi, H.; Akehi, M. J. Chem. Soc., Chem. Commun. 1990,
1270.
(7) Nakajima, N.; Saito, M.; Ubukata, M. Tetrahedron Lett. 1998, 39, 5565.
(8) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1979, 20, 4679.
(15) Derling, W. von E.; Zeiss, H. H. J. Am. Chem. Soc. 1953, 75, 4733.
9
10.1021/ja0487877 CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 7359-7367
7359

A R T I C L E S
Shintou and Mukaiyama
Scheme 1. Etherification of Phenols or Alcohol with 3 or 4
Scheme 2. Etherification with Retention or Invertion
ization (1953). In 2000, Mu¨ller16 reinvestigated the methanolysis
of (R)-3-chloro-3,7-dimethyloctane to study the solvent effects
on steric course of solvolysis via thionyl chloride and pyridine.
Tertiary-acyclic derivatives such as (R)-3-chloro-3,7-dimethyl-
octane in methanol or ethanol, etc., afforded the inverted ethers
in 18-40% yields with 76-87% inversion. Recently, the
stereospecific synthesis of chiral tertiary alkyl-aryl ethers by
Mitsunobu reaction was introduced by Shi17 et al. in which the
complete inversion of configuration was attained with about 50%
chemical yields (2003).
As shown in our previous reports, oxidation-reduction
condensation using in situ-generated 1, carboxylic acids, and
318 or 1,4-benzoquinone19 (5) provided a new and efficient
method for the preparation of primary, inverted secondary, and
tertiary alkyl carboxylates from the corresponding alcohols under
mild and neutral conditions without any assistance from acids
or bases. A reaction of alkoxydiphenylphosphine with a weak
oxidant such as quinone was therefore considered to form a
key intermediate, phosphonium salt, more smoothly than that
of triphenylphosphine because of the increased reducing ability.
In addition, alkoxydiphenylphosphine which was formed by the
introduction of an alkoxy part to a trivalent phosphorus com-
pound in advance worked more effectively in the formation of
alkoxyphosphonium salt, an important key intermediate. To
extend the scope of these reactions, condensation reactions of
in situ-formed alkoxydiphenylphosphine from 2 and alcohols
with phenols or alcohols were investigated.
This Article describes an efficient method for the preparation
of alkyl-aryl ethers and symmetrical or unsymmetrical dialkyl
ethers in good to high yields by oxidation-reduction condensa-
tion using 3 or 4,20 phenol or alcohols, and 1 in situ-formed
from 2 and alcohols under mild conditions (Scheme 1). The
present etherification of chiral secondary or tertiary alcohols
proceeded with retention or inversion of configuration; that is,
treatment of chiral alkoxydiphenylphosphines with phenols or
achiral alcohols expectedly afforded the inverted ethers, and
the reaction of achiral alkoxydiphenylphosphines with chiral
alcohols afforded the retained ethers (Scheme 2).
(16) Mu¨ller, P.; Rossier, J.-C. J. Chem. Soc., Perkin Trans. 2 2000, 2232.
(17) Shi, Y.-J.; Hughes, D. L.; McNamara, J. M. Tetrahedron Lett. 2003, 44,
3609.
Results and Discussion
(18) (a) Shintou, T.; Kikuchi, W.; Mukaiyama, T. Chem. Lett. 2003, 32, 22. (b)
Mukaiyama, T.; Kikuchi, W.; Shintou, T. Chem. Lett. 2003, 32, 300. (c)
Shintou, T.; Kikuchi, W.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2003, 76,
1645. (d) Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc.
2003, 125, 10538.
Preparation of Alkyl-Aryl Ethers by Oxidation-Reduc-
tion Condensation Using Phenols. There are a number of
(19) Shintou, T.; Mukaiyama, T. Chem. Lett. 2003, 32, 1100.
(20) Shintou, T.; Mukaiyama, T. Chem. Lett. 2003, 32, 984.
9
7360 J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004

Oxidation−Reduction Condensation
A R T I C L E S
Table 2. Benzylation of Various Phenols with 1a and 3
Table 1. Benzylation of Phenol with 1a and Quinones
a To a mixture of phenol and 3 was added 1a in CH2Cl2 at 0 °C, and
then it was reacted for 0.5 h at room temperature.
reactions that employ alkoxydiphenylphosphines 1, for example,
in peptide syntheses or Arbuzov reactions. Phosphines which
have a primary, secondary, or tertiary alkoxy group are prepared
easily from 2 and the corresponding alcohols in the presence
of a base such as pyridine or triethylamine and are generally
isolated by distillation. Alkoxydiphenylphosphines 1 are also
prepared in situ by treating primary or secondary alcohols with
aminodiphenylphosphine such as (N,N-dimethylamino)diphen-
ylphosphine, while no corresponding alkoxydiphenylphosphine
was detected in the case where tertiary alcohols were used.
Alternatively, alkoxydiphenylphosphines 1 are in situ-generated
from nBuLi-treated primary, secondary, or tertiary alcohols and
2.
Table 3. Alkylation of Phenol or p-Nitrophenol with 1 and 3
As shown in our previous reports, oxidation-reduction
condensation using 1, carboxylic acids, and 3 provided a new
and efficient method for the preparation of primary, secondary,
and tertiary alkyl carboxylates from the corresponding alcohols
under almost-neutral conditions without any assistance from
acids or bases. To extend the scope of these reactions, the
formation of alkyl-aryl ethers via condensation between
alcohols and phenols was examined via the above-mentioned
1. In the first place, benzylation of phenol was examined using
benzyloxydiphenylphosphine (1a), which was isolated by distil-
lation. Benzyl phenyl ether was obtained in 49% yield within
0.5 h by treating phenol and 1.1 equiv of 1a with 1.0 equiv of
5 in dichloromethane at room temperature (Table 1, entry 1).
When quinone 3 was used under the same conditions, the desired
product was obtained in 85% yield (Table 1, entry 2). However,
the yield lowered to 72% when 1.1 equiv each of 3 and 1a
were allowed to react with phenol in dichloromethane at 0 °C
and after stirring was continued for an additional 0.5 h at room
temperature (Table 1, entry 3). Benzylation of phenol proceeded
smoothly to afford the desired ether in 92% yield when 1.5 equiv
of 1a was used (Table 1, entry 5).
Next, benzylation of various phenols was examined via 1.5
equiv of 1a and 1.0 equiv of 3 in dichloromethane (Table 2).
Benzylation of phenols which have electron-donating or electron-
withdrawing groups proceeded smoothly under mild conditions
to afford the corresponding benzyl ethers in good yields (Table
2, entries 1-5). When an ortho-substituted phenol such as 2,6-
dimethylphenol was used under the above conditions for 0.5 h
at room temperature, the corresponding ether was obtained in
70% yield (Table 2, entry 6). Similarly, the desired products
were obtained in 81% and 84% yields, respectively, when
1-naphthol or 2-naphthol was used (Table 2, entries 7 and 8).
Results of alkylations of phenols with 3 and 1 are shown in
Table 3. When alkoxydiphenylphosphines 1 which have primary
or secondary alkoxy groups were used, the corresponding alkyl
1
entry
R
Ph2POR
product
yield (%)
1
2
3
4
5
H
H
H
H
Ph2POMe
Ph2POEt
Ph2POnBu
Ph2POiPr
Ph2POtBu
14
15
16
17
18
88
84
87
81
62a
NO2
a The reaction mixture was refluxed for 10 h.
phenyl ethers were obtained in good yields (Table 3, entries
1-4). In the case of tert-butoxydiphenylphosphine which has
a bulky substituent such as a tert-butyl group, however, the yield
lowered to 62% even after the dichloromethane solution was
refluxed for 10 h (Table 3, entry 5).
One-pot etherification of phenol by the present oxidation-
reduction condensation that used 3 and in situ-formed alkoxy-
diphenylphosphine from (N,N-dimethylamino)diphenylphos-
phine and 1-phenylethyl alcohol at room temperature for 2.0 h
also afforded the desired ether in 82% yield (Scheme 3).21
A new and efficient method for the preparation of primary,
inverted secondary, and tertiary alkyl carboxylates from the
corresponding alcohols under mild and neutral conditions was
also established by the condensation using in situ-generated 1
n
from 2 and BuLi-treated alcohols, various carboxylic acids,
and 3 or 1.7 equiv of simple 5 as shown in previous com-
munications. Reactions of alcohols with phenols forming alkyl-
aryl ethers according to the present one-pot procedure were then
further examined. First, benzylation of phenol with 3 or 5 was
(21) Effective one-pot esterifications of various carboxylic acids have been
established by applying this type of oxidation-reduction condensation using
a combination of 3 and 1 in situ-formed from (N,N-dimethylamino)-
diphenylphosphine and primary or secondary alcohols.
9
J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004 7361

A R T I C L E S
Shintou and Mukaiyama
Scheme 3. Etherification of PhOH with 1-Phenylethyl Alcohol via Ph2PNMe2
Table 4. Benzylation of Phenol with Quinones
Figure 2. Benzylation of phenols via 5 at room temperature (9, phenol;
O, 4-nitrophenol; 2, 4-methoxyphenol).
Figure 1. Benzylation of phenol (b, 1.0 equiv of 3; 9, 1.5 equiv of 5).
examined in CH2Cl2 at room temperature to find suitable
conditions concerning the molar ratio of 1a, in situ-formed from
benzyl alcohol and 2, and 5 (Table 4). The yield of the ether
was not influenced by the amount of 1a (1.5-5.0 equiv) when
1.0 equiv each of phenol and 5 were used (Table 4, entries 3-5).
The reaction conditions that used 3 or 5 were further screened
so as to improve the chemical yield, which showed the desired
product in 49% (Figure 1).
The above benzyl ether was obtained in 93% yield when 1.5
equiv of in situ-formed 1a and 1.0 equiv of 3 were treated with
1.0 equiv of phenol at room temperature for 1 h. In the case of
using 5 under the same conditions, however, ether was obtained
in 49% yield when a combination of 1.1 equiv each of in situ-
formed 1a and 5 were treated with 1.0 equiv of phenol. Next,
etherifications of phenols which have electron-donating or
electron-withdrawing groups such as 4-methoxyphenol or 4-ni-
trophenol with in situ-formed 1a and 5 were examined under
the above conditions; however, the corresponding ethers were
obtained in low yields as shown in Figure 2.
Figure 3. Benzylation of phenols via 5 at 110 °C (9, phenol; O,
4-nitrophenol; 2, 4-methoxyphenol).
the temperature of the oil bath at 110 °C. The outcome of the
corresponding ethers is shown in Figure 3. These results indicate
that reaction using 5, in situ-formed 1a, and phenols afforded
the corresponding benzyl phenols in moderate yields and
byproduct diphenylphosphonic acid 4-benzyloxyphenyl ester
(19) was formed by competitive reaction between the two
benzyloxydiphenylphosphonium salts (Scheme 4). The above
results indicated that the concentration of the reaction mixture
Etherification of the above-mentioned phenols was further
tried under the reaction conditions such that the stirring of the
reaction mixture in toluene was continued for 1.0 h by keeping
9
7362 J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004

Oxidation−Reduction Condensation
A R T I C L E S
Scheme 4. Mechanism of Formation or Inhibition of Byproduct with 3 or 5
Table 5. Etherification of Various Phenols Using Several nBuLi-Treated Primary Alcohols
influenced the formation of byproduct. Thus, it is noted that a
key intermediate, the phosphonium salt, was smoothly provided
by an interaction of alkoxydiphenylphosphine with 3, and benzyl
phenyl, an alkyl aryl ether, was afforded in high yield by further
reaction with phenols.
Next, etherifications of 1.5 equiv of in-situ generated 1 from
2 and several primary alcohols with 1.0 equiv each of various
phenols and 3 were examined (Table 5). When phenols which
have an electron-donating or electron-withdrawing group and
primary alcohol were used, the corresponding alkyl-aryl ethers
were obtained in high yields at room temperature (Table 5,
entries 1-6).
Next, etherifications of various in situ-formed chiral and
achiral secondary or tertiary alkoxydiphenylphosphine 1 with
phenol or 4-nitrophenol were examined (Table 6). The desired
ethers were obtained in 72-86% yields at room temperature in
the case when several achiral secondary or tertiary alcohols and
phenols were used (Table 6, entries 1-3). Etherifications of
chiral secondary alcohols such as (R)-(+)-1-phenylethanol or
methyl (R)-(-)-mandelate with phenol or 4-nitrophenol pro-
ceeded smoothly in dichloromethane at room temperature to
afford the corresponding ethers in good yields with almost
complete inversion of configuration (Table 6, entries 4-7).
Similarly, the desired ethers were obtained in 84% yield with
99% inversion or 88% yield with 99% inversion, respectively,
when a chiral tertiary alcohol such as (S)-2-phenyl-2-butanol
was treated with phenol or 4-nitrophenol (Table 6, entries 8
and 9).
Thus, an effective one-pot etherification of various phenols
was established via the oxidation-reduction process via a
combination of 3 and in situ-formed 1 from 2 and nBuLi-treated
primary, secondary, or tertiary alcohols.
Preparation of Symmetrical or Unsymmetrical Ethers by
Oxidation-Reduction Condensation Using Two Alcohols.
The O-alkylation reaction of 2.0 equiv of 2-phenylethanol in
dichloromethane with 1.0 equiv of 3 and 1.0 equiv of 1a, in
n
situ-formed from BuLi-treated benzyl alcohol and 2, did not
afford the desired ether (Table 7, entry 1). An important
9
J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004 7363

A R T I C L E S
Shintou and Mukaiyama
Table 6. Etherification of Phenol or 4-Nitrophenol Using Various nBuLi-Treated Secondary or Tertiary Alcohols
a DAICEL CHIRALCEL OD column was used for HPLC analysis. b DAICEL CHIRALCEL OJ column was used for HPLC analysis. c DAICEL
CHIRALCEL OB column was used for HPLC analysis.
Table 7. Effect of Quinone Derivatives on Etherification of
Table 8. Etherification of Phenylethyl Alcohol with 1a and 4
Phenylethyl Alcohol
1a
(equiv)
Ph(CH ) OH
(equiv)
4
yield
(%)
2 2
entry
(equiv)
1
2
3
4
5
6
7
8
9
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
2.0
1.5
1.2
1.0
1.2
1.2
1.2
1.2
1.0
1.0
1.5
1.5
1.5
1.5
1.3
1.2
1.1
1.0
72
70
87
88
92
87
92
92
85
72
10
phorus intermediate because the key step of abstraction of one
hydrogen atom from the alcohols did not take place smoothly
under the conditions. An employment of a more powerful
oxidant such as fluoranil was then considered, and the reaction
with alcohols and 1, in situ-formed from nBuLi-treated alcohols
and 2, was examined. It was considered that the intermediate
phosphonium salt would be in turn converted successfully to
the so-called pentavalent phosphorus compound by catching one
hydrogen atom from alcohols and the corresponding symmetrical
intermediate, phosphonium salt, was considered to be formed
effectively by application of oxidants such as 3 because the
alkoxy part was introduced to phosphine in advance, but the
phosphonium salt was not converted to the pentavalent phos-
9
7364 J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004

Oxidation−Reduction Condensation
A R T I C L E S
Table 9. Etherification via 4, Various Alcohols, and 1 in Situ-Formed from Primary Alcohols, 2, and nBuLi
a 1.0 equiv of fluoranil was used.
or unsymmetrical ethers would be formed in good to high yields
by just starting from two free alcohols (Scheme 1). When a
more powerful oxidizing agent such as 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) or tetrachloro-1,4-benzoquinone (chlor-
anil) was used, the corresponding ether was obtained in 18%
and 6% yields, respectively (Table 7, entries 2 and 3).
Interestingly, the desired product was obtained in 72% yield at
room temperature when an oxidant such as 4 was allowed to
react under the same conditions for 3 h (Table 7, entry 4). After
the reaction conditions were screened, it was revealed that the
ether was obtained in 92% yield when 1.0 equiv of 1a and 1.2
equiv of 4 were treated with 1.2 equiv of 2-phenylethanol at
room temperature for 3 h (Table 8, entry 8).
noted that alcohols which have a hydroxyl group at the
R-position of carboxylic esters such as ethyl glycolate afforded
the desired products also in 86% yield (Table 9, entry 7).
However, the yield of the coupling reaction lowered to 63%
when p-methoxybenzyl alcohol and alkoxydiphenylphosphine
n
in situ-formed from a BuLi-treated primary alcohol such as
n-butanol were used (Table 9, entry 11).
Etherification of 1 in situ-formed from several nBuLi-treated
bulky secondary or tertiary alcohols with 2-phenylethanol or
2-methyl-1-phenyl-2-propanol proceeded smoothly to afford the
corresponding unsymmetrical ethers in high yields when the
reaction mixture was kept standing at room temperature for 3
h (Table 10, entries 1-4). Attempted reaction between p-
methoxybenzyl alcohol and in situ-formed tert-butoxydiphen-
ylphosphine from tert-butyl alcohol and 2 for preparation of
tert-butyl 4-methoxybenzyl ether did not take place at all (Table
10, entry 5), while the desired product was obtained in 89%
yield when in situ-generated p-methoxybenzyloxydiphenylphos-
phine from p-methoxybenzyl alcohol and 2 was treated with
tert-butanol (Table 9, entry 4).
Next, the O-alkylation reaction via 4, various alcohols, and
n
1, in situ-formed from BuLi-treated primary alcohols and 2,
was examined (Tables 9-11). When benzyl alcohols which have
electron-donating or electron-withdrawing groups and primary,
secondary, and tertiary alcohols were used, the corresponding
symmetrical or unsymmetrical ethers were obtained in good to
high yields (Table 9, entries 1-10). It should particularly be
9
J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004 7365

A R T I C L E S
Shintou and Mukaiyama
Table 10. Etherification via 4, Several Alcohols, and 1 in Situ-Formed from Secondary or Tertiary Alcohols, 2, and nBuLi
Table 11. Etherification with Inversion or Retention of Stereochemistry via 4, Various Alcohols, and 1 in Situ-Formed from Various Alcohols,
2, and nBuLi
1
a DAICEL CHIRALCEL OJ column was used for chiral HPLC analysis. b Diastereoselectivities were determined by H NMR spectroscopy. c 1.0 equiv
of fluoranil was used. d DAICEL CHIRALCEL OD column was used for HPLC analysis. e DAICEL CHIRALCEL OB column was used for HPLC analysis.
9
7366 J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004

Oxidation−Reduction Condensation
A R T I C L E S
Further, etherifications of in situ-formed 1 from nBuLi-treated
various alcohols and 2 with inversion or retention of stereo-
chemistry were investigated under the above-mentioned condi-
tions (Table 11). It is noted that the desired ether was obtained
in 90% yield with 69% inversion when alkoxydiphenylphos-
phine in situ-formed from nBuLi-treated (R)-(+)-1-phenylethanol
and (R)-(+)-1-phenylethanol were used (Table 11, entry 1).
Etherifications of alkoxydiphenylphosphine in situ-formed from
nBuLi-treated p-methoxybenzyl alcohol with (1S,2S,5R)-(+)-
neomenthol or (1R,2S,5R)-(-)-(l)-menthol also proceeded to
afford the desired ethers in more than 90% yields without
racemization (Table 11, entries 2 and 3), while the corresponding
ether was obtained in 30% yield with perfect inversion by the
reaction between alkoxydiphenylphosphine in situ-formed from
nBuLi-treated (1R,2S,5R)-(-)-(l)-menthol and p-methoxybenzyl
alcohol (Table 11, entry 4). Similarly, the corresponding ether
was obtained in 83% yield with complete retention of config-
uration when alkoxydiphenylphosphine in situ-formed from
nBuLi-treated p-methoxybenzyl alcohol was allowed to react
with methyl (R)-(-)-mandelate (Table 11, entry 5). However,
the yield of the desired ether was 89% with 95% inversion when
Thus, an effective method for the etherification of chiral
alcohols with retention or inversion was established: that is,
reaction between chiral alkoxydiphenylphosphine and achiral
alcohol afforded the inverted ether, while that between achiral
alkoxydiphenylphosphine and chiral alcohol afforded the ether
with retention of configuration (Table 11, entries 3-8).
Summary
Alkyl-aryl ethers were obtained in good to high yields by
oxidation-reduction condensation using alkoxydiphenylphos-
phines, generated in situ from chlorodiphenylphosphine and
alcohols, 2,6-dimethyl-1,4-benzoquinone, and phenols (Scheme
1). Similarly, a new and efficient method was introduced for
the preparation of symmetrical or unsymmetrical dialkyl ethers
in good to high yields via fluoranil, alcohols, and alkoxydi-
n
phenylphosphine, in situ-formed from BuLi-treated alcohols
and chlorodiphenylphosphine (Scheme 1). It is interesting to
note that this method enabled the etherification of chiral
secondary or tertiary alcohols with retention or inversion of
configurations; that is, by treating chiral alkoxydiphenylphos-
phines and achiral alcohols, the inverted ethers were successfully
obtained, while the reaction of achiral alkoxydiphenylphosphines
and chiral alcohols afforded the retained ethers only.
n
alkoxydiphenylphosphine in situ-formed from a BuLi-treated
secondary alcohol such as methyl (R)-(-)-mandelate and
p-methoxybenzyl alcohol were treated under the same conditions
(Table 11, entry 6). Further, etherification of alkoxydiphenyl-
phosphine in situ-formed from a nBuLi-treated tertiary alcohol
such as (S)-2-phenyl-2-butanol with p-methoxybenzyl alcohol
proceeded smoothly to afford the corresponding unsymmetrical
ethers in 88% yields with 99% inversion (Table 11, entry 7).
The desired ether was obtained in 86% yield without racem-
ization when alkoxydiphenylphosphine in situ-formed from
p-methoxybenzyl alcohol and (S)-2-phenyl-2-butanol were used
(Table 11, entry 8).
Acknowledgment. This study was supported in part by the
Grant of 21st Century COE Program, the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT). We wish
to thank Mr. Sachiki Shimizu, Sankio Chemical Co., Ltd. (http://
www.sankio-chem.co.jp/), for his kind help with mass spec-
trometry and IR analysis.
Supporting Information Available: Experimental procedures
and characterization of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0487877
9
J. AM. CHEM. SOC. VOL. 126, NO. 23, 2004 7367