One-step chemoselective conversion of tetrahydropyranyl ethers to silyl-protected alcohols

Article abstract of DOI:10.1039/c4ra00655k

Aluminium trichloride catalyses the expeditious direct conversion of tetrahydropyranyl ethers to silyl ethers. This one-step transformation is chemoselective versus deprotection of the acetal and hydrosilylation of unsaturated carbon-carbon bonds, and can also be applied to linear acetals. A possible mechanism is tentatively proposed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00655k

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One-step chemoselective conversion of
tetrahydropyranyl ethers to silyl-protected
Cite this: RSC Adv., 2014, 4, 14475
alcohols†
a
b
b
´
a
*
*
Julian Bergueiro, Javier Montenegro, Carlos Saa and Susana Lopez
´
´
Received 22nd January 2014
Accepted 12th March 2014
Aluminium trichloride catalyses the expeditious direct conversion of tetrahydropyranyl ethers to silyl ethers.
This one-step transformation is chemoselective versus deprotection of the acetal and hydrosilylation of
unsaturated carbon–carbon bonds, and can also be applied to linear acetals. A possible mechanism is
tentatively proposed.
DOI: 10.1039/c4ra00655k
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obtained with phenolic ethers than with aliphatic ethers,
conversion of only primary and secondary examples of the
Introduction
latter being reported. The desired conversion also resulted
from Sn(OTf)2-catalysed reduction of THP ethers with a tri-
alkylsilane, at least in the case of simple primary and
secondary protected alcohols.
Despite their usefulness, both the above methods suffer
from drawbacks (the use of noxious dimethylsulde, or Lewis
acid containing toxic tin, or competitive O-silylation of free
hydroxyls by silyltriate donors) and both afford unsatisfactory
yields for sterically demanding aliphatic substrates. There is
clearly a need for a “greener” and more generally applicable
method.
AlCl3 is one of the most powerful Lewis acids, and is also
probably the most commonly used7 in synthetic laboratories
and in the chemical industry as a catalyst for Friedel–Cras
reactions, polymerizations, acetal cleavage,8 and the hydro-
silylation9 of unsaturated carbon–carbon bonds. Here we
report the use of aluminum trichloride catalyst for the expe-
dient, direct conversion of acetals into silyl ethers. In
addition to being effective with primary, secondary, and
tertiary alkyl THP ethers, and for a wide range of different
silyl protecting groups (including some of the more
commonly employed), this reaction is applicable to substrates
with unprotected functional groups that are known to be
reactive under AlCl3/R3SiH conditions, including alkenes
and alkynes. It can be also applied to linear acetals
(Scheme 1).
The replacement of one protecting group with another, a
common process in the synthesis of polyfunctional mole-
cules, usually requires two separate steps: deprotection
and re-protection.1 One-step conversion of one protecting
group to another, when possible, saves time, material, and
energy.
Hydroxyl-protecting groups have been extensively explored
and are generally classied as giving rise to alkyl ethers, silyl
ethers, acetals, or esters; among the most popular are those
producing silyl ethers2 (–SiR3) or acetals (tetrahydropyranyl
(THP), ethoxyethyl (EE), methoxymethyl (MOM), etc.). A
number of methods are now available for direct conversions
among the various types,3 yet only a couple concern the
formation of silyl ethers from the widely used cyclic acetal
(THP) ether.1,4 Kim et al.5 transformed THP ethers into tert-
butyldimethylsilyl (TBDMS) ethers by treatment with
TBDMSOTf and dimethyl sulde in dichloromethane. Using
Ph3P instead of Me2S afforded just slightly decreased yields,
but pyridine and Et3N were ineffective. Primary and
secondary alkyl or benzylic THP ethers responded well,
yielding the corresponding TBDMS ethers in high yields
ꢀ
under very mild conditions (À50 C), but allylic and tertiary
alkyl THP ethers were less responsive. Oriyama6 later reported
that a mixture of trialkylsilyl triuoromethanesulfonate and
triethylamine converts THP ethers to the corresponding tri-
alkylsilyl ethers at room temperature. Better yields were
a
´
´
´
Departamento de Quımica Organica, Facultade de Quımica, Universidad de Santiago
de Compostela, 15782, Santiago de Compostela, Spain. E-mail: susana.lopez.estevez@
usc.es; Fax: +34 981 591 014
b
´
´
´
Centro Singular de Investigacion en Quımica Biologica y Materiales Moleculares
(CIQUS), Universidad de Santiago de Compostela, 15782, Santiago de Compostela,
Spain. E-mail: javier.montenegro@usc.es
Scheme 1 Direct conversion of acetals to silyl ethers.
† Electronic supplementary information (ESI) available: Detailed experimental
procedures. See DOI: 10.1039/c4ra00655k
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Scope, chemoselectivity and limitations
Results and discussion
To evaluate the scope of the reaction on the silyl side we ran the
reactions of 1-(2-tetrahydropyranyloxy)octane (1a1) with an
assortment of commercially available silanes (Table 2). Direct
conversion proceeded smoothly in all cases, regardless of the
steric and/or electronic properties of the silane: although
slightly longer reaction times (1 h) were needed for silanes that
were bulky (entries 7, 9 and 10) or oxygenated (entries 3 and 8),
the yield of the silyl ether 2ax was always excellent. From
among all the silanes tested, PhMe2SiH was selected for use
thereaer in view of its excellent yield, easy visualization by
TLC, and low cost.
To evaluate the scope of the reaction we tested a collection of
THP ethers that included different functional groups (Tables 3, 4).
Primary, secondary and even tertiary alkyl acetals (1x1) were
all converted to the corresponding dimethylphenylsilyl ethers
2x1 in short time and excellent yields, as were allylic, benzylic
and propargylic acetals, although an extra equivalent of
hydrosilane was required for sterically demanding substrates,
entries 6 and 8.
Optimization of reaction conditions
With Oriyama's6 Sn(OTf)2-catalysed reaction in mind, we initi-
ated our study by screening a representative set of Lewis acids.
We chose the conversion of 1-(2-tetrahydropyranyloxy)octane
(1a1) to 1-(dimethylphenylsilyloxy)octane (2a1) as the model
reaction (Table 1). Silane and catalyst (5 mol%) were mixed in
CH2Cl2 at 0 C, and the acetal was then added.10 As expected,
ꢀ
Sn(OTf)2 worked well for this simple THP-protected substrate,
giving a yield of 81% (Table 1, entry 1). The titanium-based
Lewis acids CpTiCl2 and Ti(iOPr)2 had no effect, while TiCl4 led
to decomposition of the starting material in less than 1 h
(entries 2–4). BF3$Et2O produced a complex mixture, and InCl3
afforded but a poor yield, the main product being deprotected
octanol (3a) (entries 5 and 6). FeCl3 gave a better yield (60%,
entry 7), though inferior to that of Sn(OTf)2; and EtAlCl2 yet a
better (74%, entry 8), but required a reaction time of 8 h. Finally,
with AlCl3 an excellent 91% yield was obtained in just half an
hour (entry 9), and we proceeded to optimize the experimental
conditions for this catalyst.
Decreasing the concentration of AlCl3 to 2.5 mol% slowed
the reaction and lowered the yield (entry 10), while increasing it
to 10 mol% favoured deprotection over the desired conversion
(entry 11). At this point we also noticed that the absence of water
was critical for avoiding THP cleavage, and dried solvent and
freshly sublimated AlCl3 were accordingly used in all subse-
quent experiments. Trials with alternative solvents identied
none better than dichloromethane: the reaction was slightly
slower in toluene, and failed to occur to any detectable extent in
the coordinating solvents THF and DMF (entries 12–14).
Of particular note, the reaction was compatible with halide,
alkene, alkyne and aromatic functional groups, being
completely chemoselective for conversion of the protecting
group despite these same experimental conditions having
been shown to effect the regio- and stereoselective hydro-
silylation of alkenes and alkynes.9 Substrates with free
hydroxyl groups were more problematic under standard
ꢀ
conditions (PhMe2SiH, AlCl3, CH2Cl2, 0 C), the THP-monop-
rotected 1,7-heptanediol 1k1 evolved within minutes to
deprotected 1,7-heptanediol (3k) instead of giving the desired
7-(phenyldimethylsilyloxy)-1-heptanol (2k1); see Table 4, entry
1. The use of the bulky silane iPr3SiH in toluene allowed useful
yields of the corresponding silyl ether to be obtained – 58% in
the case of 7-(triisopropylsilyloxy)-1-heptanol (2k6)11 (entry 2)
and 70% in that of the bispropargylic substrate 4-(triisopro-
pylsilyloxy)-but-2-yn-1-ol (2l6) (entry 3). In this last case the
Table 1 Optimization of Lewis acid and reaction conditions
Table 2 Hydrosilane screening
Entry
Lewis acid
mol%
Time (h)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Sn(OTf)2
CpTiCl2
Ti(iOPr)2
TiCl4
BF3$Et2O
InCl3
FeCl3
EtAlCl2
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
5
5
5
5
5
5
5
5
5
2.5
10
5
5
5
2
5
5
1
2
2
2
8
0.5
1
0.5
2
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
81
—
—
Entry
R3SiH
Time (h)
Product number
Yielda (%)
Decomp.
10
19b
60
1
2
3
4
5
6
7
8
9
10
PhMe2SiH
BnMe2SiH
(EtO)Me2SiH
tBuMe2SiH
Ph3SiH
Et3SiH
iPr3SiH
(EtO)3SiH
tBu2MeSiH
tBu3SiH
0.5
0.5
1
0.5
0.5
0.5
1
1
1
1
2a1
2a2
2a3
2a4
2a5
2a6
2a7
2a8
2a9
2a10
91
89
80
83
79
86
93
78
80
79
74
91
9
10
11
12
13
14
82
50b
85
—
—
AlCl3
DMF
a
b
Isolated yield aer column chromatography. Deprotected octanol
(3a) was also obtained.
a
Isolated yield aer column chromatography.
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Table 3 Scope of the reaction for THP ethers with no unprotected Table
4
Optimization of chemoselectivity for THP ethers with
hydroxyl groups
unprotected hydroxyl groups
Entry
1
R–OTHP
Product number
Yielda,b (%)
2a1
91
Entry HO–R–OTHP
R3SiH
Solvent
Producta (%)
1
2
PhMe2SiH CH2Cl2
3k (100)
iPr3SiH
iPr3SiH
Toluene 2k6 (58)b
2
3
2b1
2c1
90
89
3
Toluene 2l6 (70)
a
b
Isolated yield aer column chromatography. 1,7-Heptanediol (3k)
was also obtained.
4
5
2d1
2e1
88
85
alternative cleavage of the acetals, the 4ax : 2a1 ratio being
greater for the a-substituted acetal 1a3 (27%) than for the a-
unsubstituted 1a2 (16%) (Table 5, entries 2 and 3). In both cases
the global yield of 2a1 and 4ax exceeded 90%.
6
7
2f1
80c
81
Mechanism
2g1
On the basis of the above experimental evidence, the tentative
mechanism shown in Scheme 2 is proposed. Since pre-mixing
of catalyst and silane seems to be critical for the efficiency of
the reaction, the activation of the silane by aluminium
through hydride abstraction appears to be a key step.13
Following that, two pathways are possible (Routes A and B),
corresponding to the two ways in which the reactive silyl-
aluminium species can coordinate to the acetal oxygen atoms
to form the six-membered cyclic transition structure of a
concerted mechanism14 in which charge pushing by one of the
oxygens drives cleavage of the other acetal bond. Cleavage
releases a silyl ether (2a1 or 6ax) and a carbocation (I or II) that
subsequently evolves to compound 5ax or 4ax.15 For THP ethers
only Route A proceed well, Route B requiring the opening of
the pyrane ring; but for the linear acetals both pathways may
proceed well, leading to the observed mixtures of compounds
2a1 and 4ax.
8
9
2h1
2i1
80c
97
81
10
2j1
a
b
Isolated yield aer column chromatography. Standard conditions:
c
0.05 eq. of AlCl3, 1.25 eq. of PhMe2SiH, 0.5 h. 2.00 eq. of PhMe2SiH,
1.25 eq. of PhMe2SiH, 0.5 h.
Conclusions
nal reaction mixture showed no traces of silane alcoholysis,
reduction of the alcohol,12 hydrosilylation of the alkyne, or Summing up, we have developed an expedient procedure for the
cleavage of the acetal.
direct transformation of tetrahydropyranyl-protected alcohols
Finally, to explore the possible extension of the method to into the corresponding silyl ethers by their reaction with
linear acetals, we subjected the methoxymethyl ether (MOM) hydrosilanes in the presence of catalytic amounts of AlCl3. The
1a2 and the ethoxyethyl ether (EE) 1a3 to the standard condi- advantages of this protocol – mild reaction conditions, short
tions (Table 5). In these cases the desired product, silyl ether reaction times, applicability to a variety of substrates (including
2a1, was accompanied by the alkyl ethers 4ax due to the tertiary alcohols), high yield, and total chemoselectivity even in
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Table 5 Extension to linear acetals
Entry
1
Substrate
2a1 (%)
4ax (%)
Total yielda (%)
91
91
2
78
68
93
93
3
a
Isolated yield aer column chromatography.
Scheme 2 Tentative reaction mechanism.
the presence of free hydroxyls or unsaturated functional groups the Xunta de Galicia for nancial support. J. M. is a Juan de la
– make it an attractive and useful addition to the present Cierva fellow.
methodological armamentarium.
References
Acknowledgements
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14478 | RSC Adv., 2014, 4, 14475–14479
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RSC Advances
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