Highly Efficient Selective Benzylation of Carbohydrates Catalyzed by Iron(III) with Silver Oxide and Bromide Anion as Co-catalysts

Article abstract of DOI:10.1002/cctc.201601558

A highly efficient, green, and regioselective method for the benzylation of diols and polyols was developed. With the use of Ag₂O (0.6 equiv.) and tetrabutylammonium bromide (0.1 equiv.) as co-catalysts, the iron(III)-catalyzed benzylation reaction proceeded to completion at 40 °C within 2–3 h and gave the products in high yields with high regioselectivities. A mechanism involving the principle of enhanced basicity of Ag₂O by soft anions was proposed.

Full text of DOI:10.1002/cctc.201601558

Accepted Article
Title: Highly Efficient Selective Benzylation of Carbohydrates Catalyzed
by Iron(III) with Ag2O and Bromide Anion as Co-catalysts
Authors: Bo Ren, Jian Lv, Yu Zhang, Jun Tian, and Hai Dong
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10.1002/cctc.201601558
ChemCatChem
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Highly Efficient Selective Benzylation of Carbohydrates Catalyzed
by Iron(III) with Ag2O and Bromide Anion as Co-catalysts
Bo Ren,[a] Jian Lv,[a] Yu Zhang,[a] Jun Tian,[a] and Hai Dong*[a]
KI in Ag2O-mediated reactions was disclosed, and a principle of
the enhanced basicity of Ag2O through the coordination of soft
anion to silver was proposed.7 The enhanced basicity of Ag2O
depends on the initial additive amount of anions and remains
unchanged until Ag2O is depleted. In the proposed mechanism,
AgOH is formed with the deprotonation of hydroxyl group by
strong base AgO-. It is well known that AgOH cannot exist stably
under normal circumstances and instead immediately
decomposes into Ag2O and water once it forms. Thus, we start
to suspect that excess amounts of Ag2O have been used in all
previous reports. A little more than 0.5 equivalents of Ag2O may
be only required in Ag2O-mediated reactions since Ag2O is
partially recycled. Strong basicity is often worried to be the major
cause of poor selectivities in selective protections. For Ag2O-
mediated reaction, however, the basicity during the whole
process can be enhanced and controlled by the addition of soft
anions, which may lead to improved reaction efficiency without
causing poor selectivity. Consequently, highly regioselective
protections with both mild temperature and high efficiency could
be developed through the assistance of 0.6 equivalents of Ag2O
and a catalytic amount of bromide anion.
Abstract: It was firstly reported a green regioselective benzylation
method with both mild reaction temperature and high reaction
efficiency (short reaction time). With the use of 0.6 equiv. of Ag2O
and 0.1 equiv. of TBABr as co-catalysts, an iron(III)-catalyzed
benzylation can proceed to completion at 40 oC in 2 - 3 hours with
high regioselectivities and isolated yields. The mechanism was
proposed involving the principle on enhanced basicity of Ag2O by
soft anions.
Regioselective protections play important roles in carbohydrate
chemistry where well-designed selective protection and
deprotection strategies remain fundamental to the synthesis of
saccharide building blocks.1 Selective benzylation is one of the
most important protection methods, in which organotin species
used to be the most widely used reagents in order to obtain
good selectivities.2 Recently, several environment-friendly
methods have been developed to substitute the traditional
organotin methods, including the use of oranoboron,3 organotin4
and organoiron5 as catalysts, all of which with their respective
advantages and shortcomings. For example, the alkylations
where K2CO3 is used as
a base require high reaction
temperatures (70
–
90 oC) (Figure 1a).4a-c,5 Temperature
sensitive substrates may not tolerate in high temperature
conditions. For the alkylations where Ag2O is used as a base,
although the reactions can proceed at mild temperature (r.t. – 40
oC), their reaction efficiencies are quite poor (24 – 48 hours’
reaction time) (Figure 1b).3,4d To the best of our knowledge, a
regioselective alkylation method with both mild reaction
temperature and high reaction efficiency (short reaction time)
has never been reported. In the present study, under the
guidance of the principle on enhanced basicity of Ag2O by the
coordination of soft anions to silver, we firstly developed a
regioselective benzylation with both mild reaction temperature
and high efficiency (Figure 1c). With the use of 0.6 equivalents
of Ag2O and 0.1 equivalents of tetrabutylammonium bromide
(TBAB) as co-catalysts, an iron(III)-catalyzed benzylation can
proceed to completion at 40 oC in 2 - 3 hours in comparison with
all previous reported methods. All used reagents are associated
with lower toxicity and environment-friendly.
Figure 1 Comparison of the present method with previous reported methods.
Initially, reports of
a variety of Ag2O-mediated selective
protections caught our attention due to their efficiency and
environmental benefits.6 A large amount of Ag2O (More than
stoichiometric amount) are usually used in these methods. It
was also reported that a catalytic amount of potassium iodide
(KI) could largely improve reactivities in some Ag2O-mediated
protections.6c,d Based on this, we used to try to develop a
selective benzylation of carbohydrates with the use of Ag2O and
bromide anion. Although we finally failed to develop the method
due to poor selectivities, the origin of the improved reactivity by
Ye’s group reported a Ag2O-mediated selective acylation and
sulfonylation method where 1.5 equivalents of Ag2O and 0.2
equivalents of KI were used.6c We firstly started our study based
on this method to test if the reaction requires only 0.6
equivalents of Ag2O and 0.1 equivalents of NaBr practically. It is
proposed that NaOH be able to be used instead of NaBr since
bromide anions would form with the depletion of NaOH. Thus,
benzoylation and sulfonylation of methyl pyranoside 1, 3, 5, 7, 9
and 11 were tested with 0.6 equivalents of Ag2O and 0.1
equivalents of NaOH or NaBr (Entries 1 – 4 in Table 1). It can be
seen, similar results to Ye’s report were obtained, supporting our
conjecture. Then we turned our attention to Taylor’s alkylation.
Taylor’s method gives excellent selectivities where 1.1
equivalents of Ag2O were used.3 Its shortcoming is the longer
reaction time (48 h). We hypothesized that 0.6 equivalents of
Ag2O be enough for the reaction and the addition of 0.1
equivalents of bromide anion be able to shorten the reaction
time largely. However, the experimental results did not support
our hypothesis. The addition of bromide caused poor
[a]
Dr. B. Ren, J. Lv, Y. Zhang, J. Tian, Prof. H. Dong
Key Laboratory for Large-Format Battery Materials and System,
Ministry of Education, School of Chemistry & Chemical Engineering
Huazhong University of Science & Technology
Luoyu Road 1037, 430074 Hongshan, Wuhan, P.R. China.
E-mail: hdong@mail.hust.edu.cn.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201601558
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selectivities, which might be due to that the basicity did not play
a key role in the formation of the organoboron intermediate
proposed by Taylor3 and instead accelerated the direct
benzylation. Without the addition of bromide, organoboron-
catalyzed benzylation of compounds 7, 9, 11, 14, 18, 20, 22, 24
and 26 was performed with 0.8 equiv. of Ag2O, leading to
excellent isolated yields (Entries 3 – 9 in Table 1). Base on this,
we suspected that organotin/organoiron-catalyzed alkylations
should be improved by the addition of 0.6 equivalents of Ag2O
and 0.1 equivalents of bromide since basicity plays an important
role in the formation of the stannylene intermediate4b and the
organoiron intermediate5 proposed by us.
formed by the coordination of two deprotonated hydroxyl groups
to a tin atom, strong bacisity should favor the formation of this
intermediate. Consequently, the reaction can be improved by the
addition of Ag2O and bromide anion. Fortunately, the hypothesis
was supported this time (Entries 1 - 4 in table 2). The organotin-
o
catalyzed alkylation can proceed to completion at 40 C in 2 - 3
hours through the use of 0.6 equivalents of Ag2O and 0.1
equivalents of bromide as co-catalysts. Good isolated yields
(88-95%) for benzylations of compounds 7, 11, 14, 20, and 22
were obtained.
Table 2 Selective benzylation of carbohydrates with Ag2O and bromide
anion as co-catalysts.
Table 1 Selective protections with reduced amounts of Ag2O.
Entry
1
Substrate
Major Product
Isolated Yields %
Entry
Substrate
Major Product
Isolated Yields %
a88
b94
2a: a85, b85
2b: a77, b70
4: a80, b75
1
15: a85, b85
16: a87, b91
2
6a: b92
6b: b72
a90
b92
2
3
3
4
a95
b91
8: c70
10: c78
13: d86
5
6
7
b93
b90
b91
12: c95
15: d70
16: d76
4
5
31: b88
33: b89
17: d83
19: d60
8
9
6
7
d84
d90
35: b60, c66
37: b73, c82
d78
39: b63, c73
41: b64, c74
8
10
Reaction conditions: a Substrate (100 mg), CH2Cl2 (1 mL), NaOH (0.1 eq.),
Ag2O (0.6 eq.), TsCl/BzCl (1.2 eq.), rt, 24 h. b NaBr (0.1 eq.) instead of
NaOH in condition a. c MeCN (1 mL) instead of CH2Cl2 in condition b. d
substrate (100 mg), MeCN (1 mL), organoboron (0.1 eq.), Ag2O (0.8 eq.),
BnBr (1.5 eq.), 40℃, 24 - 48 h.
Reaction conditions：a substrate (100 mg), MeCN (1mL), Me2SnCl2 (0.1
eq.), Ag2O (0.6 eq.), TBAB (0.1 eq.), BnBr (1.5 eq.), 40℃, 2 - 3 h. b
Substrate (100 mg), MeCN (1 mL), Fe(dibm)3 (0.1 eq.), Ag2O (0.6 eq.),
TBAB (0.1 eq.), BnBr (1.5 eq.), 40℃, 2 - 3 h. c Similar conditions to b
except for longer reaction time (8 h.).
Based on the mechanism studies of organotin-mediated
selective protection,8 we used to develop an organotin-catalyzed
alkylation method4b,c where the reaction proceeded at 80 oC for 3
hours. A proposed mechanism suggest that a dioxlane five or six
membered ring stannylene intermediate plays an important role
in the catalysis process. Since the stannylene intermediate is
We developed an iron(III)-catalyzed selective alkylation method
just few months ago.5 A resemble dioxlane five or six membered
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ring intermediate where iron atom displaced with tin atom has
been proposed to play an important role in the catalysis
process.5 Apparently, strong basicity should also favor the
formation of this intermediate. It is therefore easy to conclude
that the iron(III)-catalyzed selective alkylation may proceed at a
mild temperature for a short time when Ag2O and bromide are
used as co-catalysts. In order to confirm this, compounds 7, 11,
14, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 and 40 were
benzylated using iron(III)-catalyzed method where 0.6
equivalents of Ag2O and 0.1 equivalents of TBAB were used as
co-catalysts instead of 1.5 equivalents of K2CO3 (Table 2). It can
be seen that good isolated yields (66-94%) were obtained for all
cases after the reactions proceeded at 40 oC for 2 hours.
However, the cis-diols appear lower reactivity and require longer
reaction times (Entries 9 – 10 in Table 2).
oC in 2 - 3 hours. Good isolated yields were obtained in all cases.
This directly translates into high regioselectivities.
Experimental Section
General Preparation method for Fresh Ag2O: A stoichiometric amount
of saturated sodium hydroxide solution was added dropwise to a silver
nitrate aqueous solution (10 mL, 0.2 M) to form a large amount of
precipitate. After being filtered, washed with deionized water for three
times, washed with ethanol and dried at 40 oC, solid silver oxide was
obtained as brown powder.
General procedure of Ag2O-mediated organotin/Fe (III)-catalyzed
selective benzylation: Substrates (100 mg) were allowed to react with
BnBr (1.5 equiv.) in dry acetonitrile (1 mL) at 40 oC for 2 - 3 h in the
presence of Ag2O (0.6 equiv.), TBAB (0.1 equiv.) and
Me2SnCl2/Fe(dibm)3 (0.1 equiv.). The reaction mixture was filtered and
directly purified by flash column chromatography (hexanes/EtOAc = 3:1
to 1:1) to afford the pure products.
Acknowledgements
This study was supported by the National Nature Science
Foundation of China (Nos. 21272083). The authors are also
grateful to the staffs in the Analytical and Test Center of School
of Chemistry & Chemical Engineering, HUST, for support with
the NMR instruments.
Figure 2. A proposed mechanism for iron(III)-catalyzed benzylation with Ag2O
and TBABr as co-catalysts
Keywords: silver catalysis • iron(III) catalysis • Ag2O • regioselective
benzylation • green
A mechanism was proposed in Figure 2. The cyclic dioxolane-
type intermediate formed by tin or iron catalyst with two adjacent
hydroxyl groups plays key roles for the benzylation selectivity.
The resulted regioeslectivity by intrinsic reactivities of diols,
including 1,2-diols, 1,3-diols, cis-diols, and trans-diols, has been
fully discussed in our previous studies.8b In the present systems,
the regioselectivity should rely not only on the conditions but
also to some favorable intrinsic relative reactivity of diols,
notably diols exhibiting the axial-equatorial relationship (cis-
diols). Ag2O turns into a strong base after the coordination of
bromide to silver, which favors the formation of this cyclic
intermediate. Meanwhile, Ag2O as a Lewis acid can also activate
the leaving of bromide from the benzylation reagent. Ag2O is
partially recycled in the catalytic process through the
decomposing of AgOH. Consequently, the whole reaction can
be performed under mild condition with high efficiency through
the addition of catalytic amount of Ag2O and TBAB.
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protections. Some of these protections may be highly improved
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strong basicity favors these reactions. The conjecture was then
supported by tests in four types of Ag2O-mediated protections.
Finally, a green regioselective benzylation method with both mild
temperature and high reaction efficiency (short reaction time)
were firstly developed in this study. With the use of 0.6
equivalents of Ag2O and 0.1 equivalents of bromide anions as
co-catalysts, both the organotin-catalyzed benzylation and the
iron(III)-catalyzed benzylation can proceed to completion at 40
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
It was firstly reported a green
regioselective benzylation
method with both mild reaction
temperature and high reaction
efficiency. With the use of 0.6
equiv. of Ag2O and 0.1 equiv. of
TBABr as co-catalysts, an
iron(III)-catalyzed benzylation
can proceed to completion at 40
oC in 2 - 3 hours with high
regioselectivities and isolated
yields.
Bo Ren,Jian Lv, Yu Zhang, Jun
Tian,and Hai Dong*
Page No. – Page No.
Title
Highly Efficient Selective
Benzylation of
Carbohydrates Catalyzed
by Iron(III) with Ag2O and
Bromide Anion as Co-
catalysts
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