Reaction of C2-symmetrical dialkoxysilanes R1O-Si(R2)2-OR1 with the two Vilsmeier-Haack complexes POCl3·DMF and (CF3SO2)2O·DMF: An efficient one-step conversion to the

Article abstract of DOI:10.1055/s-2001-18395

The two electrophilic Vilsmeier-Haack complexes POCl₃·DMF 1 and (CF₃SO₂)₂O·DMF 2 react with C2-symmetrical dialkoxysilanes R₁O-Si(R₂)₂-OR₁ (R₁=(-)-menthyl o

Full text of DOI:10.1055/s-2001-18395

LETTER
1543
Reaction of C2-Symmetrical Dialkoxysilanes R1O-Si(R2)2-OR1 with the two
Vilsmeier-Haack Complexes POCl3 DMF and (CF3SO2)2O DMF: An Efficient
One-Step Conversion to the Corresponding Formates R1-OCHO
R
eactionof C2
-
Sy
a
m
metrical
D
r
ialkoxy
i
silanes
v
w
ithVilsmeier-H
aC
ackComplexes ohen, Vadim Kotlyar, Sylvain Koeller,1 Jean-Paul Lellouche*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Fax +972(3)5351250; E-mail: lellouj@mail.biu.ac.il
Received 1 August 2001
DMS/O-TIPS/O-TBDPS ethers R4-OSi(R5)3 to the
corresponding formates R4-OCHO (anhydrous DMF,
0 °C to 20 °C, yield range 50-91%).30,31 This mild one-
step interconversion of OH-protecting groups would ful-
Abstract: The two electrophilic Vilsmeier-Haack complexes
POCl3 DMF 1 and (CF3SO2)2O DMF 2 react with C2-symmetrical
dialkoxysilanes R1O-Si(R2)2-OR1 (R1 = (-)-menthyl or 3 -choles-
teryl, R2 = Me, Ph or i-Pr: 5a-c/6a-c) affording the formates R1-
OCHO 7 and 8 in medium to good yields depending on conditions. fill the above requirement if applicable to both alkoxy
The scope and limitations of this novel one-step deprotection of C2-
symmetrical silaketals to formates are described.
groups of alkoxysilanes. As simple models, we first inves-
tigated the easily accessible C2-symmetrical dialkoxysi-
Key words: Vilsmeier-Haack complexes, protecting group inter-
conversion, deprotection, formates, formylation
lanes R1O-Si(R2)2-OR1. Interestingly and to the best of
our knowledge, no similar conversion has been reported
in the current literature.
We hereby report our findings, emphasizing the scope and
limitations of this unique and mild transformation.
Reacting pre-organized species intramolecularly using a
neutral and removable “silicon temporary connection”
has been developed quite successfully in various fields of
synthetic organic chemistry.2–4 Expectedly, the intramo-
lecular character of this process involving silaketals of the
type R1O-Si(R2)2-OR3 would allow an enhanced predict-
able control of the attachment regio- and stereoselectivity.
Significant examples can be found in the recent literature
dealing with glycosidation,5–7 with ring-closure metathe-
sis,8–10 with [4+2]-Diels–Alder reactions,11–14 with photo-
chemical ene-ene or ene-yne [2+2]-cycloadditions,15–17
with azomethine ylide [3+2]-cycloadditions,18,19 with
[3+2]-nitrone cycloadditions,20 with benzoannulation re-
actions of chromium siloxycarbene complexes,21 with Pd-
catalyzed Heck reactions,22 and with radical cycliza-
tions.23–27 Following reaction, resulting cyclic O-silylated
diethers must be further manipulated to eliminate the sili-
con tether and liberate the latent OH-functionalities. The
conditions needed for that may not always be compatible
with other functional groups present.
The symmetrical (–)-menthol- and 3 -cholesterol-based
dialkoxysilanes 5a-c and 6a-c were prepared uneventfully
using the Hanessian’s silylation conditions (anhydrous
DMF, imidazole, appropriate dichlorosilane: 2.1 equiv.,
0–20 °C, 18 h, unoptimized yields of purified substrates
36-96%, Scheme 1 and Table).32 Different silyl connec-
tors (R2 = Me, Ph and i-Pr) were included in our reactivity
studies to provide information regarding the influence of
growing steric hindrance at silicon. The two electrophilic
VH-complexes 1 and 2 were prepared classically by slow
addition of freshly distilled POCl3 or (CF3SO2)2O to anhy-
drous DMF under nitrogen at 0 °C and stirring over 30
min at this temperature. The complexes were then imme-
diately reacted with the model dialkoxysilanes 5a-c/6a-c
following the reported protocol35 and subsequent modifi-
cations registered in the Table of results. Furthermore, the
influence of different molar ratios between the VH-com-
plexes and substrates (1 or 2 versus 5a-c or 6a-c, molar
equivalents: 0.3/1.0, 1.0/1.0 and 2.0/1.0) has been exam-
ined.
Synthetically speaking, the overall concept would be even
more attractive if a non-fluoride-based elimination of the
silyl tether were available to liberate O-protected rather
than OH-products, in only one-step. This approach would
save synthetic steps with the potential advantage of in-
creasing overall yield. During recent exploratory works
on glycal-based peptidomimetics, we discovered that the
two electrophilic Vilsmeier-Haack (VH) complexes
POCl3 DMF 1 (equilibrium mixture of the two salts 3 and
4, Scheme 1) and (CF3SO2)2O DMF 228,29 are able to me-
diate the one-step conversion of diverse O-TES/O-TB-
Several valuable conclusions may be drawn (Scheme 1
and Table). As expected, the O-formylation of the di-
alkoxysilanes 5a-c and 6a-c may be operated under mild
conditions leading to the formates 7 and 8, using either of
the two VH-complexes 1 or 2 (entries 4-9 and 10-15, see
also the general O-formylation protocol).35 Depending on
the VH-complex, conversion yields vary in a low/medium
(20-78%, 2: entries 4-9, 10-14) to good range ( 80%, 1:
entries 5-7, 9-10, and 15). Uniformly, unreacted starting
material and/or hydrolyzed (–)-menthol/3 -cholesterol
accounts for mass balance. Almost under all conditions,
the VH-complex 1 is the more efficient (entries 4-12 and
14-15). Except for one entry (entry 13), this same reactiv-
ity feature is observed for any molar ratio, 1.0/1.0 or 2.0/
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1543,1546,ftx,en;D18001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1544
Y. Cohen et al.
LETTER
Scheme 1
Table Reaction of Dialkoxysilanes R1O-Si(R2)2-OR1 with the VH-Complexes POCl3 DMF 1 and (CF3SO2)2O DMF 2
Entry
Substrate (1.0 equiv.) POCl3 DMF 1 or
(CF3SO2)2O DMF 2
Formate 7
1: (%)a,c
Formate 8
1: (%)a,c
2: (%)a,c
2: (%)a,c
(equiv.)b
1
2
5a
5b
5c
5a
5b
5c
5a
5b
5c
6a
6b
6c
6a
6b
6c
0.3
1.0
2.0
42
38
22
73
80
80
82
77
82
–
–
–
–
–
–
–
3
–
–
–
4
20
30
36
68
56
66
–
–
–
5
–
–
6
–
–
7
–
–
8
–
–
9
2
–
–
10
11
12
13
14
15
1.0
82
75
46
75
76
83
50
50
30
78
59
5
–
–
2
–
–
2.0
–
–
–
–
–
–
a Yields of isolated purified compounds.
b Number of molar equivalents versus substrate (1.0 equiv.).
c Averaged yields for at least two trials except for entries 1 and 15 (VH-complex 2) (3 trials).
1.0, between VH-complexes and starting dialkoxysilanes capable of formylating electronically deficient aromat-
(1.0/1.0, entries 4-6 and 10-12; 2.0/1.0: entries 7-9 and 14- ics,33 the VH-complex 2 does not follow the efficiency
15). Thus, although it is the more electrophilic, since it is trend observed for the O-formylation of simple O-silylat-
Synlett 2001, No. 10, 1543–1546 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Reaction of C2-Symmetrical Dialkoxysilanes with the two Vilsmeier-Haack Complexes
1545
ed ethers by the same VH-complexes.31 Regarding re- First, it has been possible to isolate and partially charac-
agent 1, comparison of entries 4-6 and 10-11 (ratio 1.0/10: terize the chromatographically labile silanol ether 12 (Ta-
73-82%) versus entries 7-9 and 13-15 (2.0/1.0: 75-83%) ble, entry 9, VH-complex 1, R1 = (–)-menthyl, R2 = i-Pr)
shows that conversion yields are very similar for those implying the hydrolysis of the intermediate 11 (high-field
two different ratios. It seems likely that, at least, one an- 1H NMR, 300 MHz, CDCl3; EI-MS/DCI-MS (NH3 and
other VH-reagent, different from 1, has been generated CH4)). Moreover, depending on the VH-complex, the sec-
able of the same conversion. This unexpected result needs ond step 11 13 should be disfavored when involving a
clarification and will be the object of future works. Inter- less nucleophilic intermediate 11 (X = OTf) versus 11
estingly, when the VH-complex 2 is used in a 1.0/1.0 mo- (X = Cl). Indeed, this factor rationalizes well the marked
lar ratio, the two formates are obtained in yields inferior difference of conversion efficiency observed for 1 and 2.
or equal to 50% (Table, entries 4-6 and 10-12: 20-50%).
In conclusion, we have demonstrated that the two VH-
In the case of the VH-complex 1 and, except for the result complexes 1 and 2 can react cleanly with C2-symmetrical
of entry 12, increasing steric hindrance at silicon in 5a-c/ dialkoxysilanes R1O-Si(R2)2-OR1 affording the corre-
6a-c (R2 = Me, Ph and i-Pr) has no major effect on the sponding formates R1-OCHO in low/medium to high
transformation yields (entries 4-9: 73-82%; entries 10-11 yields depending on conditions and substrates. In any
and 13-15: 75-83%). Again, this reactivity trend differs case, the VH-complex 1 is the most efficient reagent to
fundamentally from previous data obtained with the simi- perform this mild one-step transformation, which, inter-
lar O-formylation of simple O-silylated ethers.30,31 On the estingly, is rather insensitive to steric hindrance at sili-
contrary, marginal steric effect can be detected when the con.35,36
VH-reagent 1 is reacted with 5a-c in a sub-molar ratio
(0.3/1.0, entries 1-3: 22-42%). The following scaling of
steric hindrance at silicon Me << Ph << i-Pr has been
References and Notes
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Scheme 2
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A stepwise mechanism appears likely in view of some
previous results.30,31 The electrophilic VH-complexes 1 or
2 can add the dialkoxysilanes 5a-c/6a-c affording the ox-
onium cation 9 (first Si-O bond, Scheme 2). Thermody-
namically strong Si-Cl/Si-O bonds (111.0 kcal/mole and
128.2 kcal/mole),34 favor its decomposition toward the
neutral species R1O-Si(R2)2-X 11 (X = Cl or TfO) and the
imidate salt 10 (first equiv.). Subsequent hydrolysis of 10
furnishes the formates 7-8. The second Si-O bond in the
silylated intermediate 11 can react similarly, giving a sec-
ond equivalent of the same imidate 10 accompanied re-
spectively by the dichlorosilane or bistriflated silane 14 or
15. Indirect evidence is afforded by two observations.
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Synlett 2001, No. 10, 1543–1546 ISSN 0936-5214 © Thieme Stuttgart · New York

1546
Y. Cohen et al.
LETTER
anhydrous DMF (1.0 mL, –5 °C) under nitrogen, and
agitated for 30 min at the same temperature affording a
homogeneous DMF solution of the two VH-reagents 1 and 2
for immediate use. Depending on conditions (Table), the
VH-reagent was added dropwise to a cold solution of the
requisite substrate 5a-c/6a-c (1.0 mmol, 1.0 mL of
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(35) Representative experimental protocol (exemplified for a
1.0/1.0 ratio between VH-reagents and substrates).
Freshly distilled phosphorus oxychloride POCl3 or triflic
anhydride Tf2O (1.0 mmol) was dissolved in cooled
anhydrous DMF, –5 °C). The medium was stirred overnight
at 20 °C. After medium hydrolysis at –5 °C (saturated
aqueous solution of NaHCO3, 10 mL), the aqueous layer was
extracted with ether (4 10 mL). The combined organic
layers are washed to neutrality with water (2 10 mL), dried
over anhydrous MgSO4, filtered (5 m Buchner filter)and
evaporated under reduced pressure. The resulting crude
formates are purified by preparative flash chromatography
on a silica gel column (silica gel Merck Si-60, 43-60 m)
eluted by a hexane–CH2Cl2, 60:40 mixture. They are
obtained as an homogeneous pale oil (7) or solid (8)
(reaction conditions and yields are registered in the Table).
(36) The new compounds have been fully characterized
spectroscopically (FT-IR, 1H/13C NMR, EI/DCI-MS) and
their homogeneities checked by TLC and/or HPLC.
Synlett 2001, No. 10, 1543–1546 ISSN 0936-5214 © Thieme Stuttgart · New York