Chemoselective o-benzylation of the propargylic hydroxy group in polyols

Article abstract of DOI:10.1002/ejoc.201201086

We have discovered the highly chemoselective benzylation of propargylic hydroxy groups in the presence of other hydroxy groups under very usual conditions involving benzyl bromide and sodium hydroxide in DMF at room temperature. This methodology has a hig

Full text of DOI:10.1002/ejoc.201201086

Job/Unit: O21086
/KAP1
Date: 11-09-12 16:59:00
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201086
Chemoselective O-Benzylation of the Propargylic Hydroxy Group in Polyols
Ji Ho Lee[a] and Chang Ho Oh*[a]
Keywords: Chemoselectivity / Protecting groups / Alkynes / Alcohols / Benzyl ether
We have discovered the highly chemoselective benzylation
of propargylic hydroxy groups in the presence of other hy-
droxy groups under very usual conditions involving benzyl
bromide and sodium hydroxide in DMF at room temperature.
This methodology has a high synthetic utility for the selective
protection of hydroxy groups at the propargylic position
among various other hydroxy groups in complex molecules.
groups over primary OH groups are known.[9] Benzylation
is one of the most widely used methodologies for the pro-
tection of OH groups because the benzylated products are
quite stable and easy to debenzylate by hydrogenation.[10]
Although many benzylation reactions occur under a wide
variety of mild conditions, their chemoselectivities have re-
mained unsolved.
Recently, while exploring Au- and Pt-catalyzed reactions
of enynal systems like 4 bearing a propargylic ether group,
we faced a problem in the selective protection of a proparg-
ylic OH group in the presence of other hydroxy groups
(Scheme 2).[11]
Introduction
Hydroxy groups are present in a number of biologically
and synthetically interesting carbohydrates, steroids, nu-
cleosides, and other natural products,[1] and the chemoselec-
tive differentiation of several hydroxy groups within a mole-
cule has long been a major issue for synthetic chemists.[2,3]
In the majority of cases reported so far, the selective O-
protection of polyols generally occurs faster for primary
OH groups than for secondary or tertiary OH groups,
mainly as a result of steric reasons.[4] For instance, most the
commonly used protecting groups, such as the tert-butyldi-
methylsilyl,[5] acetyl,[6] or benzoyl group,[7] tend to form the
corresponding silyl ether, acetate ester, or benzoate ester
smoothly on the primary hydroxy group despite the pres-
ence of other hydroxy groups (Scheme 1). There have also
been a few reports on the chemoselective silylation of prop-
argylic alcohols in the presence other hydroxy groups.[8]
Scheme 1. Selective protection of OH groups.
Scheme 2. Pt-catalyzed cyclization of 4 to 4p.
The most important protecting groups for alcohols are
ethers, which vary from the very stable methyl ether to the
highly elaborate trityl ether. Although there are many re-
ports on the chemoselective O-alkylation of primary OH
groups over other OH groups, only a few methods for the
chemoselective O-alkylation of secondary and tertiary OH
The Lichtenthaler group and the Grice group reported
the very selective benzylation of the axial OH group of
carbohydrate 5a in the presence of a primary alcohol to
afford 5a-B by using sodium hydride as a base [Equa-
tion (1)].[12] This is an example of a reversal of polarity be-
tween the primary and secondary hydroxy groups. To our
best knowledge, there has been only one report on the
chemoselective benzylation of propargylic hydroxy groups
over other hydroxy groups [Equation (2)].[13] Wipf and Gra-
ham carried out the benzylation of 5b by controlling the
equivalents of NaH (1.0 equiv.) and BnBr (1.0 equiv.) in the
[a] Department of Chemistry, Hanyang University,
Sungdong-Gu, Seoul 133-791, Korea
Fax: +82-(2)22200762
E-mail: changho@hanyang.ac.kr
Homepage: http://gos.hanyang.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201086.
Eur. J. Org. Chem. 0000, 0–0
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J. H. Lee, C. H. Oh
SHORT COMMUNICATION
presence of nBu4NI (0.5–2.0 equiv.) as an additive in THF Table 1. Benzylation of 5-hexyne-1,4-diol (1a).
and isolated benzylated product 5b-B along with unreacted
starting material in 82 and 12% yield, respectively.
Entry
Base
(1.3 equiv.)
Solvent
T
[°C]
Time
[h]
Product
(% yield)[a]
1
2
3
4
5
6
7
8
NaH
NaH
LiOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
THF
dioxane
toluene
DMF
DMF
–42
r.t.
r.t.
–42
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
3
1
10
4
1
1
2a (92)
2a (91)
2a (87), 3a (11)
2a (96)
NaOH
NaOH
NaOH[b]
NaOH[c]
NaOH
NaOH
NaOH
NaOH
K2CO3
iPr2NEt
2a (94)
2a (92)
8
6
2a (41)[d]
These reports prompted us to find a chemoselective
method for the benzylation of specific OH groups. We have
postulated that reversal of nucleophilicity of the propargylic
OH group might facilitate benzylation and result in a faster
reaction than with other hydroxy groups. To test this hy- 12
pothesis, we examined the pKa values of various hydroxy
2a (82), 3a (15)
2a (75), 3a (21)
2a (72)
2a (trace)
2a (trace)
2a (trace)
9
10
11
12
24
24
12
12
13
groups, where propargyl alcohol, allyl alcohol, and ethyl
alcohol have pKa values of 13.6, 15.5, and 16.0, respec-
tively.[14] This implies that selective deprotonation at the
propargylic hydroxy group may be possible by judicious
choice of the base and its number of equivalents. Herein,
we wish to report our results on the chemoselective O-benz-
ylation of propargylic alcohols.
[a] Isolated yield. [b] Three equivalents of benzyl bromide were
used. [c] Six equivalents of base was used. [d] Dibenzylated product
was isolated as a byproduct in about 20% yield.
were delighted to find an effective, inexpensive, and chemo-
selective method for the benzylation of propargylic alcohols
in the presence of other hydroxy groups.
To explore the scope of the present chemistry, diverse
substrates for selective O-benzylation were prepared. Suc-
cessful chemoselective benzylation of these substrates was
Results and Discussion
We first designed substrate 1a as a simplified model com- observed in most cases. We prepared propargylic alcohols
pound and examined its benzylation under a variety of con- 1b–j bearing primary, secondary, and/or allylic OH groups
ditions (Table 1). First, we surveyed bases under the stan- (Figure 1) and carried out selective benzylations under the
dard conditions: benzyl bromide as the alkylating reagent optimized conditions. Products 2b–j were obtained, and
and DMF as a solvent. The reaction of 1a with NaH pro- these products were benzylated exclusively at the proparg-
ceeded well at –42 °C (dry ice in acetonitrile) and at room ylic OH group even though various other primary, second-
temperature to furnish product 2a in 92 and 91% yield, ary, and allylic hydroxy groups were present in the sub-
respectively, without forming product 3a (Table 1, en- strates. Substrates 1b and 1c gave the expected products in
tries 1 & 2). Next, lithium hydroxide was explored as a base, 92 and 86% yield, respectively. Excellent chemoselectivity
but 3a was formed as a minor product after a prolonged toward 1d and 1e bearing an allylic OH group was also
reaction time (Table 1, entry 3). The best base turned out obtained. Notably, when 1d was protected with p-meth-
to be sodium hydroxide (Table 1, entries 4 & 5). Both the oxybenzyl chloride (PMBCl) under our conditions, 2d-
reactions at –42 °C and at room temperature furnished de- PMB was isolated in 88% yield. This implied that our pro-
sired product 2a almost quantitatively. It is noteworthy that, tocol would extend to similar benzylations. More function-
when the benzylation reaction of 1a was carried out with alized substrates 1f and 1g worked as expected. Substrate
an excess amount of benzyl bromide, benzylic ether 2a was 1h bearing primary, secondary, and propargylic hydroxy
selectively formed without sacrificing the yield (Table 1, en- groups was benzylated only at the propargylic position in
try 6). However, the use of an excess amount of NaOH had 98% yield. From the 1H NMR spectrum of each of the
a negative effect leading to dibenzylation (Table 1, entry 7). crude products, the chemoselectivity was able to be deter-
Next, with the use of NaOH as the base, solvents ranging mined easily by observing the coupling partner of a leaning
in polarity from very polar DMSO to THF and 1,4-dioxane doublet due to the benzylic protons. The high chemoselec-
to nonpolar toluene were explored (Table 1, entries 8–11). tivity for the benzylation of propargylic alcohols is greatly
In terms of the yield and the selectivity, these solvents were important. The preference for benzylation at a propargylic
not better than DMF. This indicates that the solvent po- hydroxy group could serve as a very useful tool for a selec-
larity is very important for the improvement in the reactiv- tive protecting group that could be applied to the develop-
ity and selectivity of the O-benzylation of polyols. Other ment of efficient organic syntheses. Although this selectivity
weak bases such as K2CO3 and organic bases such as is not unambiguously explained, it should be pointed out
iPr2NEt were found to be nearly inactive for this reaction that it is probably due to the acidity of the propargylic OH
(Table 1, entries 12 & 13). From our systematic studies, we group over the other hydroxy groups. In contrast to acety-
2
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O-Benzylation of the Propargylic Hydroxy Group in Polyols
Figure 1. Chemoselective benzylation of various alcohol substrates.
lation, benzoylation, or silylation using amine-type bases,
selective benzylation using inorganic bases is more sensitive
to the acidity of the hydroxy group. It is worth noting that
the formation of the oxyanion prior to O-benzylation
would occur. Thus, the acidity of the various hydroxy
groups in the polyols might affect the population of each
oxyanion in solution and their reactivity. As a result, the
oxyanion from the propargylic hydroxy group would be
more reactive towards benzyl bromide than the other hy-
droxy groups, making chemoselective O-benzylation pos-
sible (Scheme 3).
A recent report by Czekelius described a Au-catalyzed
cyclization to obtain enol ether 9 and 10 through the
multistep synthesis outlined in path A (Scheme 4).[15] These
results inspired us to develop a mild and efficient method
for the chemoselective O-benzylation of polyols. Our proto-
Scheme 3. Chemoselective benzylation of propargylic alcohols.
col was successfully applied to the selective benzylation of γ-butyrolactone (6) with ethynylmagnesium bromide. When
the OH group at the propargylic position without attacking 1i was treated with benzyl bromide and sodium hydroxide
the primary OH group in 4-ethynylhex-5-yne-1,4-diol (1i) in DMF at room temperature, the reaction afforded ex-
as a dihydroxy compound, which was readily prepared from pected product 2i as the major product. This idea was
Scheme 4. Efficient reaction pathways involving chemoselective O-alkylation.
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J. H. Lee, C. H. Oh
SHORT COMMUNICATION
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Conclusions
We have discovered the highly chemoselective benz-
ylation of propargylic hydroxy groups in the presence of
other hydroxy groups under very usual conditions involving
benzyl bromide and sodium hydroxide in DMF at room
temperature. This methodology has a high synthetic utility
for the selective protection of hydroxy groups at the prop-
argylic position among various other hydroxy groups in
complex molecules.
Experimental Section
Representative Procedure: In a dried argon-flushed round bot-
tomed-flask, hex-5-yne-1,4-diol (1a; 124 mg, 1.1 mmol, 1.0 equiv.)
was dissolved in dry N,N-dimethylformamide (2.0 mL). Sodium hy-
droxide (57 mg, 1.3 equiv.) was added to this solution at 0 °C. The
mixture was stirred at room temperature for 30 min. The mixture
was then treated with benzyl bromide (1.2 equiv.) at 0 °C and
stirred for 1 h allowing to warm to room temperature. After com-
plete conversion as indicated by TLC analysis, water was added to
the reaction mixture, and the product was extracted with diethyl
ether (3ϫ). The combined organic phase was dried with MgSO4.
After evaporation of the solvent, the crude product was purified by
column chromatography (SiO2, n-hexane/EtOAc = 4:1) to afford
pure product 2a (209 mg, 94%).
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data, FTIR spectra, HRMS, and copies of
1
the H NMR and 13C NMR spectra for the products.
Acknowledgments
Financial support was provided by a grant from the National Re-
search Foundation of Korea (NRF 3|201100000000663). J. H. L. is
thankful for a fellowship from the Brain Korea 21program (BK21)
.
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O-Benzylation of the Propargylic Hydroxy Group in Polyols
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Received: August 10, 2012
Published Online: ᭿
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5

Job/Unit: O21086
/KAP1
Date: 11-09-12 16:59:00
Pages: 6
J. H. Lee, C. H. Oh
SHORT COMMUNICATION
Selective Benzylation
J. H. Lee, C. H. Oh* ........................ 1–6
Chemoselective O-Benzylation of the Prop-
argylic Hydroxy Group in Polyols
Keywords: Chemoselectivity / Protecting
groups / Alkynes / Alcohols / Benzyl ether
The chemoselective benzylation of prop-
argylic hydroxy groups in the presence of
other hydroxy groups under mild con-
ditions by using benzyl bromide and so-
dium hydroxide in DMF at room tempera-
ture is reported. This methodology has
high synthetic utility for the selective pro-
tection of hydroxy groups at the prop-
argylic position among various other
hydroxy groups in complex molecules.
6
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