Step-economy etherification of acylated alcohols

Article abstract of DOI:10.1016/j.tetlet.2014.10.077

An efficient and convenient protocol has been developed for ether bond formation in mild conditions. A mixture of primary/secondary ester and allylic/benzylic halide in tetrahydrofuran was treated with KO^tBu at room temperature to give ether in high yield. This step economic method enabled direct alkylation of the acyl group masked O-nucleophiles. Application of this method in carbohydrate synthesis was feasible and chemo-selectivity can be achieved.

Full text of DOI:10.1016/j.tetlet.2014.10.077

Accepted Manuscript
Step-Economy Etherification of Acylated Alcohols
Hua-Dong Xu, Ke Xu, Qing Zheng, Wei-Jie He, Mei-Hua Shen, Wen-Hao Hu
PII:
S0040-4039(14)01771-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.077
TETL 45306
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
29 July 2014
8 October 2014
14 October 2014
Please cite this article as: Xu, H-D., Xu, K., Zheng, Q., He, W-J., Shen, M-H., Hu, W-H., Step-Economy
Etherification of Acylated Alcohols, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.077
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Graphical Abstract
Step-Economy Etherification of Acylated
Alcohols
Leave this area blank for abstract info.
Hua-Dong Xua, Ke Xua, Qing Zhengb, Wei-Jie Heb, Mei-Hua Shen a, and Wen-Hao Hub

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Step-Economy Etherification of Acylated Alcohols
Hua-Dong Xua,, Ke Xua, Qing Zhengb, Wei-Jie Heb, Mei-Hua Shena, and Wen-Hao Hub
aSchool of Pharmaceutical Engineering and Life Science Changzhou University, 1 Gehu Road, Changzhou 213164, China
bDepartment ofChemistry, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and convenient protocol has been developed for ether bond formation in mild
conditions. A mixture of primary/secondary ester and allylic/benzylic halide in tetrahydrofuran
was treated with KOtBu at room temperature to give ether in high yields. This step economic
method enabled direct alkylation of acyl group masked O-nucleophiles. Application of this
method in carbohydrate synthesis was feasible and chemo-selectivity can be achieved.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Etherification
Step Economy
O-alkylation
Ether
Potassium tert-Butoxide
Ether groups are widely found in a variety of bioactive
molecules1-4 and functional materials.5-7 It also serves as an
important class of protecting groups for hydroxyl group in
organic synthesis.8 Accordingly, many methods for ether
synthesis have been developed,9-25 and new methodology
mixed in dry tetrahydrofurane (THF) for 2 hours and, out our
expectation, butyl ether 3aa was identified as the sole product in
84% isolated yield (Scheme 1).
development is always highly valuable.
However, the
Williamson ether synthesis involving the coupling of an alkali
metal alkoxide and an alkyl halide still dominates ether bond
construction due to its generality and practicability,26 and has
experienced many improvements and modifications in terms of
conditions and leaving groups.27-30 In 2005, Misra research group
Scheme 2. Etherification without NHC
Replacement of potassium tert-butoxide with DBU, which is a
common base in NHC catalyzed reactions, shut off the reaction.
Further studies on this unexpected etherification ruled out a
mechanism involving NHC and implied the potential of this
reaction to be a general protocol for ether synthesis. Therefore,
optimization of this reaction was carried out, using 1a/2b as
reacting combination. It was found that using two equivalents of
KOtBu is optimal to afford allyl ether 3ab in 86% yield (Scheme
2). A screening of solvents revealed that etherification occurred
more efficiently in THF than in toluene or methylene chloride.
This reaction reduced the conventional two-step-two-pot
operations, i.e. removal of acetyl group and O-allylation, to a
single one-pot operation. Additionally, regarding to the
frequently used transformation of acetyl ester to ether in organic
synthesis, the mild reaction conditions together with the bench
available inexpensive reagents employed for this reaction further
highlight the advantage of this method.
developed
a convenient one-pot protocol for the direct
benzylation of acyl-protected carbohydrates by using solid
sodium hydroxide as base and TBAI as phase transfer catalyst.31
In this letter, we present a step-economic transformation of alkyl
carboxylate to corresponding alkyl ether, which normally
necessitates two separated reaction operations.
Scheme 1. Observation of ally ether formation from ester
During the course of our research on NHC catalyzed
reactions, trans-Cinnamyl bromide 1a (1 eq), butyl acrylate 2a (1
eq), potassium tert-butoxide (3 eq) and catalytic NHC were
———
 Hua-Dong Xu. Tel.: +86-519-8633-4597; fax: +86-519-8633-4598; e-mail: hdxu@cczu.edu.cn, huadongxu@gmail.com
 Mei-Hua Shen. Tel.: +86-519-8633-4597; fax: +86-519-8633-4598; e-mail: shenmh@cczu.edu.cn, meihuashen@gmail.com

2
Tetrahedron Letters
Table 1. the Scope of Electrophilesa
Aromatic esters 2e (entry 1) and 2f (entry 2) are both excellent
O-nucleophile donors to give the ethers in comparable high
yields as conjugated carboxylate 2a and 2d. Slightly lower yield
was obtained with ethyl 3-phenylpropanoate 2g (entry 3). About
20% drop-off in yield were observed with cyclohexyl acetate 2h
(entry 4) and phenyl acetate 2i (entry 5). The former may due to
the cyclic secondary hexyl ester which could undergo
competitive elimination reaction and the latter may attribute to
the weak nucleophilicity of phenonate. δ-Valerolactone 2j
reacted with cinnamyl bromide 1a to give the ring opening
product 3aj as the major isolable product in 31% yield.
Entry
RX
1
Product
3
Yieldb
88%
92%
85%
1
2
3
1a
1b
1c
3ac
3bc
3cc
4
1d
3dc
68%
5
6
7
1e
1f
3ec
3fc
-
26%
31%
N.A
Table 2. the Scope of Esters
1g
-
aThe reaction was conducted with 1 (1.0 eq.), 2c (1.2 eq.) and KOtBu (2.0
eq.) in dry THF (0.2 M, 1 mmol scale) at room temperature for 5 hrs.
Entry
R’CO2R
2
Product
3
Yieldb
90%
80%
71%
bIsolated yield.
1
2
3
2e
2f
2g
3ad
3af
3ab
PhCO2Me
PhCO2iPr
Next, with the optimized conditions in hand, the scope of the
substrate was explored. Various halides were submitted to the
reaction with phenethyl acetate 2c (Table 1). Activated halides
such as benzyl bromide 1a-c are good electrophiles to give
corresponding ethers in high yields (entry 1-3, Table 1), while p-
Methoxylbenzyl chloride 1d reacted with 2c to give an
acceptable yield (entry 4). Inactivated alkyl halides such as ethyl
iodide 1e (entry 5) and hexyl bromide 1f (entry 6) are less
effective partners under these conditions. Cinnamyl tosylate 1g
(entry 5), however, decomposed completely under these
conditions.
BnCH2CO2Et
4
5
2h
2i
3ah
3ai
66%
69%
PhOAc
6
2j
3aj
31%
a The reaction was conducted with 1a (1.0 eq.), 2 (1.2 eq.) and KOtBu
(2.0 eq.) in dry THF (0.2 M, 1 mmol scale) at room temperature for 5
hrs.
bIsolated yield.
Carbohydrate synthesis almost inevitably involves intensive
protecting group manipulations; therefore step-economic strategy
is highly appreciated in carbohydrate chemistry. We apply this
reaction to glucosides 2l to get phenylallyl protected glucoside
3al in 83% yield (Scheme 5, top). 4,6-Di-phenylallyl protected
glucoside 3am was obtained in 90% when two equivalents of 1a
and 4 equivalents of base were used in the reaction of diacetate
2m (Scheme 5, middle). 2,6-Diacetyl glycoside 2n was also a
feasible substrate for this reaction providing bis-allyl glycoside
3cn in 55% yield (Scheme 5,bottom).
Scheme 3. Reaction of Methyl (E)-cinnamate with Cinnamyl
Bromide
In order to pinpoint the fate of the carboxylate group in these
reactions, methyl (E)-cinnamate 2d was subjected to this
reaction. Upon completion, the reaction was quenched with HCl,
and cinnamic acid 4 and cinnamyl methyl ether 3ad were
obtained in 93% and 89% respectively after silica gel
chromatography (Scheme 3). Based on these observations, a
reaction mechanism was proposed (Scheme 4). Upon mixing
together, ester 2 and steric demanding nucleophile potassium
butoxide reacts to establish equilibrium between 2/KOtBu and
tert-butyl ester 5/6-K. The less hindered nucleophile alkoxide 6
can be trapped by alkyl halide to form the ether product 3, while
the tertiary butyl ester 5 underwent an E2 elimination pathway to
give the corresponding carboxylate 4-K. This mechanism also
explains why 2.0 equiv of potassium butoxide is optimal; since
the tert-butyl ether 7 was occasionally identified in case of 3
equivalents of KOtBu was used.
Scheme 5. Direct Allylation of Acylated Glycosides
In conclusion, an efficient and convenient protocol has been
developed for ether bond formation in mild conditions. This step
economic method could enable direct alkylation of an O-
nucleophile masked by carboxylate. Potential application in
carbohydrate synthesis was demonstrated as well.
Scheme 4. Proposed Mechanism for the Ether Formation
By using cinnamyl bromide 1a as electrophile, a variety of
esters were investigated, and the results are listed in Table 2.
Acknowledgments

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18.
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22.
Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.; Hu, J.;
This study was supported by the Natural Science Foundation
of China (NSFC 21272077), the Natural Science Foundation of
Jiangsu Province (SBK201321632).
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1
Supplementary data (experimental details, and copies of H
and 13C NMR spectra associated with this article can be found, in
the online version, at http://dx.doi.org xxx.
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