Regioselective benzylation of diols and polyols by catalytic amounts of an organotin reagent

Article abstract of DOI:10.1002/adsc.201301152

An efficient one-pot method for the selective benzylation of diols and polyols using 0.1 equiv. of organotin reagents and tetrabutylammonium bromide as catalyst has been developed. The diols and polyols containing a cis-vicinal diol were regioselectively

Full text of DOI:10.1002/adsc.201301152

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DOI: 10.1002/adsc.201301152
Regioselective Benzylation of Diols and Polyols by Catalytic
Amounts of an Organotin Reagent
Hengfu Xu,a Yuchao Lu,a Yixuan Zhou,b Bo Ren,b Yuxin Pei,a Hai Dong,b,*
and Zhichao Peia,c,*
a
State Key Laboratory of Crop Stress Biology in Arid Areas and College of Science, Northwest A&F University, Yangling,
712100 Shaanxi, Peopleꢀs Republic of China
Fax : (+86)-29-8709-2769; phone: (+86)-29-8709-1196; e-mail: peizc@nwafu.edu.cn
School of Chemistry & Chemical Engineering, Huazhong University of Science & Technology, Luoyu Road 1037, Wuhan
b
430074, Peopleꢀs Republic of China
E-mail: hdong@mail.hust.edu.cn
Attana AB, SE-11419, Stockholm, Sweden
c
Received: December 19, 2013; Revised: February 25, 2014; Published online: May 7, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301152.
Abstract: An efficient one-pot method for the se-
lective benzylation of diols and polyols using
0.1 equiv. of organotin reagents and tetrabutyl-
tential inherent toxicity of organotin compounds.[5]
Thus, developing non-toxic reagents[6] or employing
catalytic amounts of organotin reagents[7] is desirable,
provided that they result in the same/better regiose-
lectivities with similar/higher yields as when employ-
ing stoichiometric amount of organotins. Although
catalytic amounts of organotins have been successful-
ly applied in regioselective acylation,[8] sulfonyla-
tion,[9] silylation[10] and glycosylation,[11] it is hard to
find their application in benzylation. The reason
might be the requirement for a large amount of bro-
mide or iodide.[4] Recently, it is reported that two hy-
droxy groups in polyols are selectively benzylated
when 1 equiv. of dibutyltin oxide and 0.6 equiv. of tet-
rabutylamonnium bromide (TBAB) are used.[12]
ACHTUNGTRENNUNGammonium bromide as catalyst has been developed.
The diols and polyols containing a cis-vicinal diol
were regioselectively benzylated in 70–94% isolated
yields. A catalytic reaction mechanism was also pro-
posed.
Keywords: benzylation; carbohydrates; catalysis;
organotin reagents; regioselectivity
Benzyl ethers as ether protecting groups play very im- During the period after we submitted this paper, an-
portant roles in carbohydrate chemistry due to their other tin-catalyzed regioselective benzylation and al-
particular stability and resistance to basic and acidic lylation of polyols was published, using a moderate
conditions, as well as being easily removed by catalyt- excess of diisopropylACTHNUTRGNEU(GN ethyl)amine (DIPEA) and
ic hydrogenation.[1] Regioselective benzylations are benzyl bromide, and 0.3 equiv. of TBAI. However,
often the most important part in synthesis strategies moderate yields were generally obtained under these
towards saccharide building blocks that are used as solvent-free conditions.[13] Herein, we report an effi-
donors or acceptors in the synthesis of oligosacchar- cient one-pot method for the selective benzylation of
ides.[2] Many methods have been developed to achieve diols and polyols using 0.1 equiv. of tetrabutylamonni-
selective benzylation, including employment of re- um bromide (TBAB) and 0.1 equiv. of organotin re-
agents such as tin(IV), boron(IV), silicon(IV), cop- agent as catalyst (Figure 1). In this method, 0.1 equiv.
per(II), mercury(II), silver(I) and nickel(II) based of dibutyltin oxide (or dibutyltin dichloride, dimethyl-
complexes.[3] Organotin species have become the most
widely used reagents in selective benzylation for
higher regioselectivities and convenient manipula-
tion.[4] The regioselectivity originates from the genera-
tion of a dibutylstannylene acetal or stannyl ether be-
tween vicinal diol groups of the substrates and a stoi-
chiometric amount of the organotin reagent. Howev-
er, the main drawback with these reagents is the po- a catalytic amount of organotin reagent.
Figure 1. Regioselective benzylation of diols and polyols by
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Figure 2. Proposed mechanism for the benzylation catalyzed by an organotin reagent and TBAB.
tin dichloride) was used to form a dibutylstannylene tin atom. A catalytic amount of bromide was chosen
acetal with two vicinal OH groups of the substrates, as the best activation additive in the reaction owing
0.1 equiv. of TBAB was used to coodinate the tin to its regeneration since benzyl bromide (BnBr) has
atom of the dibutylstannylene acetal thus activating always been used as benzylation reagent. For benzyla-
the reaction, and an excess amount of potassium car- tion using a stoichiometric amount of organotin, after
bonate was used to deprotonate the hydroxy group the formation of dibutylstannylene acetals through
and recycle the reaction. The diols and polyols con- the treatment of dibutyltin oxide with vicinal OH
taining cis-vicinal diol units were regioselectively ben- groups in toulene, the reaction mixture was allowed
zylated in 70–94% isolated yields, better than report- to react with an excess amount of BnBr in the pres-
ed methods. Furthermore, unlike the above-men- ence of 0.5 equiv. of TBAB at 90–1008C.[15] The coor-
tioned solvent-free approach, this method is apparent- dination of the bromide to the tetracoordinate tin
À
ly compatible with the broadly adopted thioglycoside atom enhances the selective Sn O bond cleavage to
building blocks.
give a reactive oxygen species, followed by a nucleo-
It had been a general concept that the regioselectiv- philic attack of this oxygen species to an electrophile
ity of the dibutylstannylene-mediated protection ori- (BnBr), finally leading to a selective benzylation. The
ginated from complex stannylene structures.[4] Howev- bromide regenerates from the substitution of BnBr.
er, we recently suggested that the regioselectivity is These results inspired us to propose a benzylation
more likely to be controlled by stereoelectronic ef- mechanism when using a cataytic amount of dibutyl-
fects of the parent substrate structure.[14] Under the tin oxide, such as 0.1 equiv. of dibutyltin oxide
guidance of this principle, we studied the activation (Figure 2). After the formation of dibutylstannylene
ability of halides on organotin-mediated benzylation acetal intermediate
a
between substrates and
of carbohydrates and the results initially revealed the 0.1 equiv. of organotin, the intermediate a would fur-
mechanism of this halide-promoted benzylation.[15] ther react with BnBr in the presence of 0.1 equiv. of
The activated benzylation by halides was attributed to TBAB, leading to intermediate c where one position
coordination of the halide anion to a tetracoordinate is benzylated and the other occupied by the tin spe-
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Regioselective Benzylation of Diols and Polyols
Table 1. Comparison of results by variation from the “standard” conditions.
Entry
Reaction conditions
Time
NMR yield [%]
1
2
3
4
5
6
7
8
optimized conditions[a]
no Bu2SnO
no K2CO3
no TBAB
0.05 equiv. Bu2SnO
3 h
8 h
8 h
3 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
3 h
3 h
96
25
11
86
84
56
1.5 equiv. BnBr
react at 408C
no reaction
low conversion
low conversion
low conversion
THF only as solvent instead
toluene only as solvent instead
toluene/DMF (10:1)
toluene/MeCN (1:1)
MeCN only as solvent instead
DMF only as solvent instead
MeCN/DMF (1:1) as solvent instead
Me2SnCl2 instead of Bu2SnO
Bu2SnCl2 instead of Bu2SnO
9
10
11
12
13
14
15[b]
16[b]
low conversion
70
52
56
96
95
[a]
Conditions: 1) methyl b-d-galactoside 1 (100 mg), Bu2SnO (0.1 equiv.), toluene (6 mL), 1008C, 1 h. 2) K2CO3 (1.5 equiv.),
TBAB (0.1 equiv.), BnBr (2 equiv.), MeCN:DMF (10:1) (2 mL), 808C.
Methyl b-d-galactoside 1 (100 mg), Bu2SnCl2 or Me2SnCl2 (0.1 equiv.), K2CO3 (1.5 equiv.), TBAB (0.1 equiv.), BnBr
(2 equiv.), MeCN:DMF (10:1) (2 mL), 808C.
[b]
cies coordinated by a bromide. Deprotonated by Table 1). With 0.05 equiv. of dibutyltin oxide or
a base, such as potassium carbonate, the un-benzylat- 1.5 equiv. of BnBr separately, it took 8 h to obtain an
ed substrate would also coordinate to the tetracoordi- 84% or 56% yield of 2 (entries 5 and 6 in Table 1).
nate tin atom to form pentacoordinate tin intermedi- The reaction did not appear to operate at lower tem-
ate d. After tin species exchange through intermedi- perature (entry 7 in Table 1).
ates e and f, the final benzylated product would be
Since the boiling point of THF is 668C, THF alone
generated from intermediate f, leading to the regener- as solvent led to low conversion (entry 8 in Table 1).
ation of dibutylstannylene acetal a from the un-benzy- When using toluene or toluene mixed with DMF or
lated substrate and further starting the next cycle.
acetonitrile as solvent, the poor solubility of 1 led to
In light of this proposed mechanism, we started to very low conversion (entries 9, 10 and 11 in Table 1).
investigate if this organotin and TBAB-catalyzed re- It took 8 h to obtain only 70% yield of 2 when using
gioselective benzylation method is valid. Firstly, solely MeCN as solvent, indicating the necessity of
methyl b-d-galactoside 1 was chosen to verify this the addition of DMF (entry 12 in Table 1). However,
method (Table 1). The galactoside 1 (100 mg) was al- an excessive amount of DMF hindered the reaction
lowed to react with 0.1 equiv. of dibutyltin oxide (entries 13 and 14 in Table 1). The stannylene acetal
(12.7 mg) in toluene (6 mL) at 1008C for 1 h. After intermediate may also be formed by the treatment of
removal of toluene, the residue was added into a mix- vicinal OH groups with Bu2SnCl2 or Me2SnCl2 in the
ture of MeCN (2 mL) and DMF (0.2 mL). The addi- presence of K2CO3. Thus, direct treatment of galacto-
tion of DMF was necessary to improve the solubility side 1 with 2.0 equiv. of BnBr in the presence of
of non-protected glycosides. After reacting with 0.1 equiv. of TBAB, 1.5 equiv. of K2CO3 and 0.1 equiv.
2.0 equiv. of benzyl bromide in the presence of of Bu2SnCl2 or 0.1 equiv. of Me2SnCl2 in acetonitrile
0.1 equiv. of TBAB and 1.5 equiv. of K2CO3 at 808C (MeCN/DMF=10/1) gave a similar result ( entries 15
for 3 h, the expected product 2 was formed in 96% and 16 in Table 1).
NMR yield (entry 1 in Table 1). Without dibutyltin
These experiments indicate that the mechanism
oxide or K2CO3, the reactivity was dramatically de- proposed in Figure 2 is valid and this regioselective
creased (entries 2 and 3 in Table 1), whereas, without benzylation method can be applied to more sub-
TBAB the reactivity was slightly decreased (entry 4 in strates. Although the employment of Bu2SnCl2 or
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Table 2. Selective benzylation of 1,2-diols and carbohydrates
containing cis-diol groups.[a]
Table 2. (Continued)
[a]
Conditions: 1) Bu2SnO (0.1 equiv.), toluene (6 mL),
1008C, 1 h. 2) K2CO3 (1.5 equiv.), TBAB (0.1 equiv.),
BnBr (2 equiv.), MeCN:DMF (10:1) (2 mL), 808C, 3 h.
Isolated yields.
The yields in brackets were obtained in experiments run
on a larger scale.
[b]
[c]
[d]
MeCN alone as solvent.
Me2SnCl2 was also efficient and more convenient, we
still chose Bu2SnO as catalyst in order to make sure
of the role of the dibutylstannylene acetal intermedi-
ate in the reaction. Thus, this method was further
tested with diols and polyols containing cis-diol
groups (entries 1–14 in Table 2). It can be seen that
the equatorial hydroxy groups adjacent to an axial hy-
droxy group in all the substrates were selectively ben-
zylated in 70–94% isolated yields. For the dibutylstan-
nylene acetals formed by cis-diols, the equatorial SnO
bond preferentially breaks due to a stereoelectronic
effect, thus leading to a product benzylated in an
equatorial position.[14] Benzylation of non-protected
glycosides could lead to a small amount of 3,6-di-ben-
zylation products. Thus, when the 6-postion of these
glycosides (compounds 1, 5, 9 and 19) was protected
by a TBS group (compounds 3, 7, 11 and 21), better
yields of 3-position benzylated products were ob-
tained (entries 2, 4, 6 and 11 in Table 2). Since 4,6-O-
benzylidenemannopyranosides 13 and 23 appear to
show good solubility in MeCN, the employment of
DMF is not necessary in these two cases (entries 7
and 12 in Table 2). The method could be further ap-
plied in the benzylation of the primary hydroxy group
of 1,2-diols 29 and 31 (entries 15 and 16 in Table 2).
Good selectivities and yields were also obtained when
glycosides 5, 9 and 13 were tested in a large scale
(1 g), demonstrating the methodꢀs robustness (en-
tries 3, 5 and 7 in Table 2). However, this method
failed in the benzylation of substrates with trans-diol
groups (entries 17 and 18 in Table 2). Usually, when
using stoichiometric amounts of organotin reagents,
protection of carbohydrates with trans-diol groups
will not give selectivity if the adjacent substituents to
the diol are either both equatorial or both axial and
will give good selectivity to the hydroxy group adja-
cent to the equatorial substituent if the adjacent sub-
stituents are one equatorial and one axial.[14] Al-
though benzylation of methyl 4,6-O-benzylidene-a-d-
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Regioselective Benzylation of Diols and Polyols
Table 3. Benzylation of methyl 4,6-O-benzylidene-a-d-gluco-
to be highly efficient. The convenient protocol using
dibutyltin dichloride or dimethyltin dicholoride can
be carried out as a one-step reaction. This method ap-
peared convenient, efficient, and environmentally
friendly, and is also associated with high regioselectiv-
ity.
pyranoside by the use of various amounts of Bu2SnO.[a]
Experimental Section
General Procedure for Selective Monobenzylation of
Diols and Polyols
Entry
Bu2SnO
Yield[b]
Ratio (a:b)
Method a: Diol or polyol (100 mg) and dibutyltin oxide
(0.1 equiv.) were added in 6 mL toluene, and refluxed for
1 h. Then, after evaporation of the solvent under vacuum,
the residue was disolved in a mixture of 2 mL MeCN and
0.2 mL DMF in the presence of K2CO3 (1.5 equiv.) and
benzyl bromide (2 equiv.)
Method b: Diol or polyol (100 mg) and dibutyltin chloride
(0.1 equiv.) were added in a mixture of 2 mL MeCN and
0.2 mL DMF in the presence of K2CO3 (1.5 equiv.) and
benzyl bromide (2 equiv.). The reaction was allowed to pro-
ceed at 808C for 3 h. After the removal of the solvents, the
residue was purified by column chromatography (n-hexane/
ethyl acetate=1:1 to 0:1) to give the desired pure product;
Large scale: Diol or polyol (1 g) and dibutyltin chloride
(0.1 equiv.) were added in a mixture of 20 mL MeCN and
2 mL DMF in the presence of K2CO3 (1.5 equiv.) and benzyl
bromide (2 equiv.). The reaction was allowed to proceed at
808C for 3 h. After the removal of the solvents, the residue
was purified by column chromatography (n-hexane/ethyl
acetate=1:1 to 0:1) to give the desired pure product.
1
2
3
4
5
6
0.1 equiv.
0.2 equiv.
0.4 equiv.
0.6 equiv.
0.8 equiv.
1.1 equiv.
72%
77%
94%
90%
93%
87%
0.9:1
0.8:1
0.7:1
0.6:1
0.5:1
0.3:1
[a]
Conditions: 1) Bu2SnO, toluene (6 mL), 1008C, 1 h.
2) K2CO3 (1.5 equiv.), TBAB (0.5 equiv.), BnBr
(2.0 equiv.), MeCN (2 mL), 808C, 24 h.
Isolated yields.
[b]
glucopyranoside 33 and 4,6-O-benzylidene-b-d-galac-
topyranoside 35 gave good selectivities when using
stoichiometric amounts of organotin,[14] it did not give
selectivities in this method (entries 17 and 18 in
Table 2).
In order to explore why this method failed in the
benzylation of compounds 33 and 35, compound 33
was benzylated through the employment of various
amounts of dibutyltin oxide (Table 3). It was observed
that the yield of product 34a, where the 3-position
was benzylated, decreased with increases in the
amount of dibutyltin oxide. The experimental results
clearly indicate that the dibutylstannylene acetal ini-
tially formed with catalytic amounts of dibutyltin
oxide cannot be regenerated with trans-diol under the
prevailing conditions, thus leading to no selectivity.
Consequently, only the starting dibutylstannylene ace-
tals lead to some selectivities.
In conclusion, in light of the principle that the re-
gioselectivity in organotin-mediated protection is con-
trolled by stereoelectronic effects of the parent carbo-
hydrate structure, an organotin-catalyzed benzylation
mechanism has been proposed in this paper. Accord-
ing to the proposed mechanism, a method for the
highly regioselective benzylation of diols and polyols
employing a catalytic amount of an organotin reagent
was developed. The organotin reagents could be any
organotin reagent as long as they can form stannylene
acetals with the substrates, such as dibutyltin oxide,
dibutyltin dichloride or dimethyltin dichloride. The
method employing 0.1 equiv. of dibutyltin oxide to
substrates containing cis-diol groups has been proven
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (Nos. 31270861 and 21272083) and the
Chutian Project-Sponsored by Hubei Province.
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