Etherification of alkoxydialkylsilanes with carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(02)02253-0

A novel method for preparing ethers from alkoxydialkylsilanes and carbonyl compounds through reductive etherification is described. The salient feature in this method is the utilization of internal hydrogen as the hydride source for reducing the oxonium intermediate generated by using the Cl(R)₂SiBr[BiBr₃/Cl(R)₂SiH] catalytic system.

Full text of DOI:10.1016/S0040-4039(02)02253-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9225–9227
Etherification of alkoxydialkylsilanes with carbonyl compounds
Xinglong Jiang,* Joginder S. Bajwa, Joel Slade, Kapa Prasad, Oljan Repicˇ and Thomas J. Blacklock
Process R&D, Chemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza,
East Hanover, NJ 07936, USA
Received 2 August 2002; revised 1 October 2002; accepted 2 October 2002
Abstract—A novel method for preparing ethers from alkoxydialkylsilanes and carbonyl compounds through reductive etherifica-
tion is described. The salient feature in this method is the utilization of internal hydrogen as the hydride source for reducing the
oxonium intermediate generated by using the Cl(R)2SiBr[BiBr3/Cl(R)2SiH] catalytic system. © 2002 Published by Elsevier Science
Ltd.
In a previous communication1 we reported an efficient
reductive etherification of alcohols with carbonyl com-
pounds through the intermediacy of different trialkylsi-
lyl ethers using the BiBr3/Et3SiH catalytic system. The
active catalyst was deduced to be as triethylsilyl bro-
mide by NMR studies and by verifying that commercial
alcohols and chlorodiisopropylsilane using DMAP. The
triethylsilyl bromide works as the catalyst for this pur-
reductive etherification was first tried with benzyloxydi-
pose. In that method triethylsilane was used in excess as
isopropylsilane and benzaldehyde in the presence of
the reducing agent. To make the method more efficient
bismuth bromide, and the expected product was iso-
in terms of atom economy, we investigated the possibil-
lated in 57% yield after overnight at room temperature.
ity of using alkoxydialkylsilanes as intermediates in
Addition of 0.1 equiv. of chlorodiisopropylsilane accel-
these reductive etherifications using a BiBr3–Cl(R)2SiH
erated this reaction and the reaction went to 96%
conversion in 20 min. The best conditions4 for this
reductive etherification are the use of catalytic BiBr3/
chlorodiisopropylsilane in acetonitrile at room tempera-
ture followed by the addition of alkoxysilane and the
carbonyl compound. The results6 obtained using this
method are summarized in Table 1.
catalytic system.
In these alkoxysilanes, the H present in the molecule is
expected to serve as an internal reducing agent. A
recent report by Baba2 on the use of chlorodiphenyl-
silane with catalytic amount of indium trichloride for
reductive deoxygenation of secondary and tertiary alco-
hols to alkanes gave further impetus to this study. In
the present communication we report the results of our
investigations, which led to a novel method for ether
formation by hydride transfer.
Treatment of benzyloxydiisopropylsilane with aliphatic
or aromatic aldehydes and ketone (entries 1, 2 and 3)
afforded the corresponding ethers in 88–90% yield.
Under these conditions, reacting a optically pure
alkoxysilane with an aldehyde (entry 9) gave the corre-
sponding ether in good yield with complete retention of
stereochemistry. It is also noteworthy that alkoxysilane
with a halide substituent can be used for this alkylation
giving the alkylated product in 91% yield (entry 7).
However, alkylation of silane derived from (R)-(−)-pan-
tolactone (entry 10) was not successful.
Alkoxydialkylsilanes used in the present study are read-
ily prepared3,5 in high yields from the corresponding
As in the case of reductive etherification of trialkyl silyl
ethers described in the previous communication using
bismuth bromide–triethylsilane, we observed precipita-
tion of the metal during the reaction. NMR studies
confirmed the interaction of BiBr3 with alkoxydialkylsi-
Keywords: alkoxydialkylsilanes; Cl(R)2SiBr[BiBr3/Cl(R)2SiH]; reduc-
tive etherification.
* Corresponding author. Tel.: 973 781 8672; fax: 973 781 2188;
e-mail: xinglong.jiang@pharma.novartis.com
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02253-0

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X. Jiang et al. / Tetrahedron Letters 43 (2002) 9225–9227
Table 1. Ether formation from alkoxysilanes and carbonyl compounds
lane or chlorodiisopropylsilane in acetonitrile leading
to the formation of the corresponding bromodiiso-
propylsilane, Bi metal, and HBr, which adds to acetoni-
trile.7
These results are in agreement with the conclusions
drawn in the previous communication, and accordingly
the active catalyst in this case is proposed to be the
corresponding to the –SiH that was used. The mecha-
nistic details are shown in Scheme 1.
An interesting byproduct that was isolated was the
trisiloxane shown in Scheme 1, which oiled out during
the reaction. This byproduct was characterized by spec-
troscopy and authenticated by comparison with the
literature.8
In conclusion, an efficient method for reductive etherifi-
cation of alkoxydialkylsilanes via internal hydride
transfer using Cl(R)2SiBr (BiBr3–Cl(R)2SiH) as the cat-
alyst is described.
Scheme 1. Reductive etherification of alkoxydialkylsilanes.

X. Jiang et al. / Tetrahedron Letters 43 (2002) 9225–9227
9227
References
5. NMR data on silanes: (1) 1H l 1.00–1.06 (m, 14H), 4.25 (s,
1H), 4.80 (s, 2H), 7.24–7.34 (m, 5H). 13C l 13.3, 17.5, 67.8,
126.7, 127.5, 128.6, 141.3. (2) 1H l 0.99–1.04 (m, 14H),
2.86 (t, J=7.35 Hz, 2H), 3.89 (t, J=7.35 Hz, 2H), 4.12 (s,
1H), 7.20–7.30 (m, 5H); 13C l 13.4, 24.4, 39.7, 67.2, 125.7,
1. Bajwa, J. S.; Jiang, X.; Slade, J.; Prasad, K.; Repicˇ, O.;
Blacklock, T. J. Tetrahedron Lett. 2002, 43, 6709–6713.
2. Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J.
Org. Chem. 2001, 66, 7741–7744.
3. Typical procedure for the preparation of alkoxydiisopropyl-
silanes: A 250 mL three-necked flask, equipped with a
1
127.8, 129.4, 145.9. (3) H l 0.90–0.98 (m, 14H), 1.92–2.04
(m, 2H), 3.46 (t, J=6.4 Hz, 2H), 3.77 (t, J=5.85 Hz, 2H),
4.08 (s, 1H). 13C l 12.3, 17.7, 26.3, 35.8, 63.3. (4) 1H l 0.79
(d, J=6.6 Hz, 6H), 0.87–1.08 (m, 14H), 1.15 (d, J=6.8
Hz, 3H), 1.20–1.51 (m, 7H), 3.62–3.80 (m, 1H), 4.11 (s,
1H). 13C l 12.4, 13.6, 17.2, 18.5, 22.3, 24.2, 27.5, 28.9,
thermocouple, condenser and
a magnetic stirrer was
charged with an alcohol (30 mmol), 90 mL of THF,
DMAP (6 mmol) and triethylamine (60 mmol). Chlorodi-
isopropylsilane (36 mmol) was slowly added to the solu-
tion. The resulting solution was stirred at 25°C overnight
or heated to 50°C and maintained at this temperature for
2 h. After the reaction was completed (monitored by TLC
or HPLC), the solid was filtered, and the filtrate was
evaporated under reduced pressure. The residue was
extracted with 150 mL of TBME, washed with 50 mL of
water and 50 mL of saturated sodium chloride, and dried
over magnesium sulfate. Evaporation of organic solvent
afforded a colorless liquid, which was further purified by
silica column chromatography.
1
71.4. (5) H l 0.91–0.95 (m, 14H), 0.92–1.25 (m, 4H), 1.37
(t, J=6.9 Hz, 3H), 1.41–1.62 (m, 3H), 1.79–1.98 (m, 2H),
3.28–3.41 (m, 1H), 3.61–3.70 (m, 1H), 3.98 (q, J=6.9 Hz,
2H), 4.05 (s, 1H), 4.72 (d, J=7.5 Hz, 1H), 4.80 (d, J=7.5
Hz, 1H), 4.97 (d, J=10 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H),
7.09–7.19 (m, 2H), 7.26–7.28 (m, 3H), 7.62 (d, J=8.1 Hz,
2H). 13C l 12.8, 17.8, 26.2, 27.8, 35.0, 40.5, 60.2, 64.3,
67.7, 73.4, 114.9, 128.6, 129.0, 129.5, 129.8, 131.2, 135.1,
162.8, 171.6. (6) 1H l 1.01–1.13 (m, 14H), 1.19 (s, 3H),
1.24 (s, 3H), 3.89 (d, J=9.2 Hz, 1H), 3.99 (d, J=9.2 Hz,
1H), 4.12 (s, 1H), 4.33 (s, 1H); 13C l 12.8, 17.8, 19.5, 23.3,
41.6, 76.0, 78.9, 175.8.
4. Typical procedure for etherification: A flask was charged
with bismuth bromide (0.35 mmol) and 10 mL of acetoni-
trile, followed by the addition of chlorodiisopropylsilane
(0.45 mmol) and alkoxydiisopropylsilane (4.5 mmol) in 5.0
mL of acetonitrile. The fine black suspension was formed
within a couple of minutes. Then, the aldehyde or ketone
(5.4 mmol) was slowly added. The reaction was exother-
mic, and the formation of an oil was observed within 10
min. After the reaction was completed (monitored by TLC
or HPLC), acetonitrile was evaporated. The residue was
extracted with 100 mL of TBME and washed with 20 mL
of water. The organic layer was dried over magnesium
sulfate and evaporated under reduced pressure. The crude
was purified on a silica column with an EtOAc/hexane
eluent system to give the desired product.
6. NMR data on ethers: Compounds 7–13 and 15 are known
and the NMR data are identical to those reported in the
literature. NMR data for the two new compounds are as
follows: 14 1H l 0.80 (d, J=6.6 Hz, 6H), 1.02–1.10 (m,
2H), 1.12 (d, J=6.8 Hz, 3H), 1.20–1.51 (m, 5H), 3.40–3.42
(m, 1H), 4.32 (d, J=13 Hz, 1H), 4.43 (d, J=13 Hz, 1H),
7.15 (s, 1H), 7.16 (s, 1H), 7.18 (s, 1H); 13C l 20.0, 22.9,
23.6, 28.4, 37.2, 39.4, 69.2, 76.0, 126.1, 127.8, 135.2, 143.2;
MS C15H22OCl2, 273 (M−16).
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8. Goikhman, R.; Aizenberg, M.; Shimon, L. J.; Milstein, D.
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