Hexanes/acetonitrile: A binary solvent system for the efficient monosilylation of symmetric primary and secondary diols

Article abstract of DOI:10.1016/j.tetlet.2014.02.067

Symmetric diols are useful compounds in the synthesis of natural products, their value often dependent on their successful monoprotection. A general and simple method for the monosilylation of symmetrical primary and secondary diols is reported. The metho

Full text of DOI:10.1016/j.tetlet.2014.02.067

Tetrahedron Letters 55 (2014) 2600–2602
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Tetrahedron Letters
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Hexanes/acetonitrile: a binary solvent system for the efficient
monosilylation of symmetric primary and secondary diols
Burkhardt I. Wilke a,b, Mark H. Dornan b, Jon Yeung b, Christopher N. Boddy b, Atahualpa Pinto c,
⇑
a Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
b Department of Chemistry, Centre for Catalysis Research and Innovation, University of Ottawa, Ottawa, ON K1N 6N5, Canada
c Department of Chemistry, SUNY College of Environmental Science and Forestry, Syracuse, NY 13210, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Symmetric diols are useful compounds in the synthesis of natural products, their value often dependent
on their successful monoprotection. A general and simple method for the monosilylation of symmetrical
primary and secondary diols is reported. The method exploits the solubility differential of diols and their
monosilylated counterparts in a binary hexanes/acetonitrile solvent system.
Received 1 February 2014
Accepted 18 February 2014
Available online 25 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Symmetric diol
Monoprotection
Silylation
Binary solvent system
Symmetric diols have been employed as precursors in the
multi-step syntheses of various bioactive natural products such
as amphidinolide B, polycavernoside, spirastrellolide A, and spicu-
loic acid A among others.1–5 Their synthetic value, typically reliant
on the efficient production of monoprotected diol, is tempered by
the near-equivalent reactivity of the hydroxyls in both the diol and
monoprotected products. Under most reaction conditions, mono-
protection reactions lead to a statistical mixture of products
including a buildup of undesired diprotected product.6 A common
and attractive strategy employed to favor the statistical distribu-
tion toward the desired monoprotected product involves the
monosilylation of diol with the silylating agent as the limiting
agent and in the presence of a vast excess of diol (Scheme 1).7–9
While this approach has found widespread use its scope re-
mains limited to abundant and inexpensive diols. More atom eco-
nomical variants have been developed,10,11 however, these
methodologies often require harsh reaction conditions and careful
monitoring to avoid the undesired accumulation of disilylated
side-product.
to hypothesize that the sequestration of monosilylated product
in a non-polar solvent may lead to a practical and efficient method
for the monosilylation of symmetric diols. Herein we describe our
efforts to validate our hypothesis by employing an immiscible hex-
anes and MeCN solvent system.
Heptanediol (4a, Table 1) was selected as a test substrate for our
method development studies. The success of the proposed solvent
system would depend on both the differential solubilities of the
monosilylated product, monoTBS-heptanediol (4b), and of unre-
acted diol in hexanes and MeCN. We hypothesized the MeCN layer
R3SiX, Base
Solvent
HO
OH
n
HO
OSiR3
n
R3SiO
OSiR3
n
+
Scheme 1. General reaction scheme for the monosilylation of symmetric diols.
Table 1
The mechanism of silylether formation, while intricate, is gen-
erally thought to proceed through the rate-determining formation
of a pentacoordinate complex, consistent with a marked depen-
dency on polar solvents.12 This mechanistic feature along with
the substantial difference in the solubilities of diols and their
monoprotected counterparts in acetonitrile (MeCN), permitted us
Initial comparison of monoprotection strategies
HO
OH
7
HO
OTBS
TBSCl, Base
Solvent
7
4a
4b
Base
Solvent
% Yield
Reference
13
Imidazole
NaH
Et3N
DMF
THF
41
27
66
8
⇑
Corresponding author. Tel.: +1 315 470 6984; fax: +1 315 470 6856.
E-mail address: atpinto@syr.edu (A. Pinto).
2:1 Hexanes/MeCN
This study
http://dx.doi.org/10.1016/j.tetlet.2014.02.067
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

B. I. Wilke et al. / Tetrahedron Letters 55 (2014) 2600–2602
2601
Table 2
and 0.718, respectively, confirming the disparity in solubility be-
tween the two species, and the applicability of the hexanes/MeCN
solvent system in our method.
Reaction time study of the monosilylation of 4a and its effect on the yields of products
4b and 4ca
TBSCl, Et3N
HO
OH
7
HO
OTBS TBSO
+
OTBS
7
Early investigation into the use of biphasic hexanes/MeCN for
the preparation of 4b resulted in a 66% yield based on the diol
starting material (Table 1). Comparatively, our attempts to gener-
ate monosilylated product via a monoalkoxide intermediate in tet-
7
4:1 Hex/MeCN
4a
4b
4c
Time (h)
4b (%)
4c (%)
4b:4c
rahydrofuran
(THF)8
or
the
customary
imidazole/
6
12
24
63
66
72
10
10
10
6.3
6.5
6.7
dimethylformamide (DMF) method led to lower yields.13
To optimize conversion to the monoprotected product, we
probed both reaction times and solvent composition ratios. As Ta-
ble 2 shows, the isolated yields and monoprotected:diprotected ra-
tios remain static after 6 h, with the greatest yield at 24 h.
By systematically increasing the hexanes in the reaction we
hypothesized that sequestration of the monoprotected species
from the reactive MeCN environment would minimize formation
of the undesirable diprotected species. Table 3 shows the isolated
yields of 4b at different hexanes/MeCN ratios after 24 h. Encourag-
ingly, as the hexanes increased, the yield of monoprotected prod-
uct also increased, thus fitting our initial hypothesis.
a
Reaction conditions: rt.
Table 3
Ratio of hexanes/MeCN study with isolated yields of 4b and 4c at 24 h reaction timea
TBSCl, Et3N
Solvent
HO
OH
7
HO
OTBS TBSO
OTBS
7
+
7
4a
4b
4c
Hexanes/MeCN
4b (%)
4c (%)
4b:4c
1:1
4:1
8:1
33
69
80
17
9
10
1.9
7.7
8.0
Due to the extended reaction times, we investigated the forma-
tion of monoprotected material via silyl migration from diprotect-
ed product to diol. To test for this we performed a crossover
experiment to mimic the conditions with equal equiv of 4c and
4a in the absence of 4b (Scheme 2). If 4b were generated it would
be visible by GC, clearly demonstrating the occurrence of silyl
migration, and providing information on the thermodynamic prod-
uct ratio. No 4b was detected at 24 h indicating silyl migration was
not a relevant factor under these conditions.
a
Reaction conditions: rt, 24 h.
Et3NHCl, Et3N
4:1 Hex/MeCN
HO
OH
7
TBSO
OTBS
7
HO
OTBS
+
7
4a
4c
4b
Encouraged by these results, we investigated the scope of the
reaction with primary and secondary symmetric diols of variable
chain lengths and side chains (Table 4).14 The increasing yields
seen for the homologous series of long chain diols (Table 4, entries
1–5) correlated with the increased hydrophobicity of the com-
pounds. Conversely, the highly polar triethylene glycol (Table 4,
entry 6) is a poor substrate for monosilylation and the reaction re-
sults in a 17% yield, a result consistent with our hypothesis. The
Scheme 2. Crossover experiment at 24 h reaction time.
would effectively solvate both the diol and tert-butyldimethylsilyl
chloride (TBSCl) while the newly formed monoprotected species
would preferentially migrate to the hexanes. Partition coefficients
(P) for 4a and 4b, were measured where P = [X]hexanes/[X]MeCN. The
partition coefficients for 4a and 4b were found to be 1.21 Â 10À3
Table 4
Preparation of monosilylated diolsa
TBSCl, Et3N
3:1 Hex/MeCN
OH
OTBS
OTBS
HO
n
HO
n
Xa
Xb
Entry (X)
Diol (a)
Product (b)
Yield (%)
59
HO
HO
1
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
OTBS
2
3
4
5
51
57
72
71
OH
OTBS
OTBS
OTBS
OH
OH
O
O
6
7
8
17
79
65
O
OTBS
O
OH
HO
OH
HO
OTBS
HO
HO
OH
OH
HO
HO
OTBS
OTBS
9
NR
46
30
HO
HO
HO
HO
10
O H
OH
OTBS
OTBS
11
a
Reaction conditions: rt, 24 h.

2602
B. I. Wilke et al. / Tetrahedron Letters 55 (2014) 2600–2602
Table 5
processes capable of utilizing this non-polar sequestration tech-
nique as these reactions occur in the polar layer where charge sta-
bilization is critical.
Monosilylation of secondary diol 9a under various reaction conditionsa
TBSCl, Et3N
HO
OH
HO
OTBS
Solvent
Acknowledgments
9a
9b
Entry
Hexanes/MeCN
T (°C)
Time (h)
Yield (%)
This work was supported by NSERC, CFI, and the University of
Ottawa.
1
2
3
4
5
6
3:1
3:1
8:1
8:1
8:1
8:1
r.t.
50
r.t.
r.t.
r.t.
r.t.
96
96
24
48
72
96
39
37
43
52
71
67
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
067.
a
Reaction conditions: Et3N.
References and notes
polarity of the 6a likely prevents the compound from exchange
into the non-polar reservoir. Propanediol analogs (Table 4, entries
7–8) show the positive effect the introduction of methyl side
chains has on yields of monoprotected species when compared
to propanediol (Table 4, entry 2). Not surprisingly a yield decrease
is observed for the neopentyl variant (Table 4, entry 8) as com-
pared to entry 7.15 When the method was applied to secondary
diols (Table 4, entries 9–11) yields varied greatly on a case-by-case
basis. Curiously, when compared to the yield shown for entry 10
(Table 4), the unexpected absence of product in entry 9 (Table 4)
may be suggestive of its preferential conformation in an unreactive
cyclic arrangement, assisted furthermore by the steric bulk of both
vicinal methyl groups.
The ability to access monoprotected secondary diols was of ma-
jor concern to us, we therefore focused on further optimizing this
methodology to access the challenging product from 2,4-pentane-
diol 9a. Extended reaction times (Table 5, entries 1–2) enabled pro-
duction of the monoprotected diol 9b. Increasing the hexanes/
MeCN ratio to 8:1 facilitated the generation of synthetically useful
yields of 9b (Table 5, entries 3–6).
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14. Typical procedure for the monosilylation of symmetric diols: In a flame-dried
100 mL round-bottom flask equipped with a teflon magnetic stir bar, diol
(5.0 mmol) was added to acetonitrile (12.5 mL) and hexanes (37.5 mL).
Triethylamine
(Et3N,
0.84 mL,
6.00 mmol,
1.2 equiv)
and
tert-
butyldimethylsilyl chloride (TBSCl, 0.53 g, 5.0 mmol, 1.0 equiv) were added
to the solution and the resulting biphasic mixture was stirred vigorously at
room temperature for 24 h under a N2 atmosphere. The reaction was quenched
with saturated aqueous ammonium chloride (NH4Cl, 50 mL), and extracted
with ethyl acetate (EtOAc, 3 Â 50 mL). The combined organic phase was
washed with brine (3 Â 50 mL) and dried over anhydrous sodium sulfate
(Na2SO4). The crude product was purified by silica gel column chromatography
(10–15% EtOAc/hexanes).
A binary hexanes/MeCN solvent system for the monosilylation
of symmetric primary and secondary diols has been developed
and shown to be efficient, scalable, and avoids the use of cumber-
some precipitates or sensitive bases. Though this study has focused
on silylation, it can likely be adapted for other protecting groups.
Acylation of similar diols with the corresponding anhydrides, and
transesterification of symmetrical dicarboxylic acids are both
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