Hosomi-Sakurai reaction - acetals - organocatalysis - Brønsted acid catalysis - allylsilanes
<P>Acetals are useful intermediates in organic synthesis and undergo coupling reactions
with different nucleophiles via carbon-carbon bond formation. Successfully used nucleophiles
include silyl enol ethers, allyl transfer reagents, vinyl ethers, and also common
olefins as well as cyanide sources. A valuable example is the Hosomi-Sakurai reaction
[
1 ]
of acetals
with allyltrimethylsilane,
[
2 ]
which furnishes homoallylic ethers. Catalysts that have been employed for this transformation
include Lewis acids such as NbCl
5 /AgClO
4 ,
[
3 ]
AlBr
3 /CuBr,
[
4 ]
FeCl
3 ,
[
5 ]
TMSOTf,
[
6 ]
Bi(OTf)
3 ,
[
7 ]
Sc(OTf)
3 ,
[
8 ]
BiBr
3 ,
[
9 ]
TMSNTf
2 ,
[
10 ]
TMSN(SO
2 F)
2 ,
[
11 ]
TiCp
2 (CF
3 SO
3 )
2 ,
[
12 ]
montmorillonite,
[
13 ]
trityl perchlorate,
[
14 ]
diphenylboryl triflate,
[
14 ]
and TMSI.
[
15 ]
Alternatively, stoichiometric Lewis acidic activators that have been used include
TiCl
4 ,
[
16 ]
AlCl
3 ,
[
17 ]
BF
3 ·Et
2 O,
[
17 ]
[
18 ]
liquid SO
2 ,
[
19 ]
and CuBr/microwave.
[
20 ]
Several of these methods suffer from drawbacks such as the involvement of compounds
that are corrosive, difficult to handle, expensive, or toxic. Others require strictly
anhydrous conditions or less practical reaction temperatures. Surprisingly, Brønsted
acids have not been studied for this important reaction despite their great potential
as easily tunable, economic, and environmentally acceptable catalysts.
[
21 ]
[
22 ]
We reasoned that a catalytic cycle could be readily initiated via the reaction of
a strong Brønsted acid (HX) with an acetal (
1 ) to give an oxonium ion (
2 ). Its reaction with allyltrimethylsilane (
3 ) would lead to the silicon-stabilized carbocation (
4 ). This intermediate in turn should readily collapse to the desired product (
5 ) and volatile methoxytrimethylsilane (
6 ) upon reaction with methanol, generated in the initializing step of the catalytic
cycle (Scheme
[
1 ]
).
[
23 ]
</P>
Scheme 1
Table 1 Catalyst Screening for the Allylation of Acetal 1a
<TD VALIGN="TOP" COLSPAN="6">
<TD VALIGN="TOP">
Entry
</TD><TD VALIGN="TOP">
Acid a (%)
</TD>
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
PPA
</TD><TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
21
</TD><TD VALIGN="TOP">
20
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
PPA
</TD><TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
60 °C
</TD><TD VALIGN="TOP">
21
</TD><TD VALIGN="TOP">
25
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
TFA
</TD><TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
>99
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
TFA
</TD><TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
21
</TD><TD VALIGN="TOP">
60
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
CSA
</TD><TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
40
</TD>
<TD VALIGN="TOP">
6
</TD><TD VALIGN="TOP">
p -TsOH
</TD><TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
12
</TD><TD VALIGN="TOP">
>99
</TD>
<TD VALIGN="TOP">
7
</TD><TD VALIGN="TOP">
p -TsOH
</TD><TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
15
</TD><TD VALIGN="TOP">
>99
</TD>
<TD VALIGN="TOP">
8
</TD><TD VALIGN="TOP">
H2 SO4
</TD><TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
95b
</TD>
<TD VALIGN="TOP">
9
</TD><TD VALIGN="TOP">
DNBA
</TD><TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
r.t.
</TD><TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
>99
</TD>
<TD COLSPAN="20">
a Conversion was determined by GC.b By-products were formed.
<TD COLSPAN="20">
<P>With this reaction design in mind, we have studied several different Brønsted acids
for the reaction of benzaldehyde acetal
1a with allylsilane
3 to give homoallylic ether
5a (Table
[
1 ]
). In initial experiments, acetonitrile was found to be the best solvent. While the
modestly acidic diphenyl phosphate) (PPA) gave some conversion (entries 1 and 2),
stronger acids such as trifluoroacetic acid (TFA; entries 3 and 4) and in particular
sulfonic acids as well as sulfuric acid (entries 5-9) proved to be much more useful.
Dinitrobenzenesulfonic acid (DNBA) turned out to be a powerful catalyst for the reaction.
Compared to sulfuric acid, which is also an active catalyst, it mediates the allylation
very cleanly without by-product formation and was therefore chosen for further studies.
Lowering the catalyst loading from 2 mol% to 1 mol% significantly reduced the turnover
and increasing the temperature did not result in any improvement. Consequently, 2
mol% of DNBA was used in subsequent experiments.</P>
Table 2 Substrate Scope of the Brønsted Acid Catalyzed Hosomi-Sakurai Reaction of Acetals
<TD VALIGN="TOP" COLSPAN="5">
<TD VALIGN="TOP">
Entry
</TD><TD VALIGN="TOP">
Acetal
</TD><TD VALIGN="TOP">
Product
</TD><TD VALIGN="TOP">
Time (h)
</TD><TD VALIGN="TOP">
Yield (%)
</TD>
<TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
Ar = Ph
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
99
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
Ar = p -BrC6 H4
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
95
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
Ar = p -MeOC6 H4
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
90
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
Ar = p -O2 NC6 H4
</TD><TD VALIGN="TOP">
</TD><TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
93
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
6
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
7
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
8
</TD><TD VALIGN="TOP">
a
</TD>
<TD VALIGN="TOP">
9
</TD><TD VALIGN="TOP">
a
</TD>
<TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
11
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
12
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
13
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
14
</TD><TD VALIGN="TOP">
<TD VALIGN="TOP">
15
</TD><TD VALIGN="TOP">
<TD COLSPAN="20">
a Reduced yield due to volatility of the product.
<P>After identifying an active catalyst and suitable reaction conditions, we have
explored the scope of the reaction (Table
[
2 ]
). Upon treating acetals
1 with 1.5 equivalents of allyltrimethylsilane (
3 ) in the presence of 2 mol% of DNBA at room temperature in acetonitrile, the corresponding
homoallylic ethers
5 were obtained in high yields. It turned out that the selected reaction conditions
are broadly useful for a variety of different substrates. Both aromatic acetals (entries
1-4) with electron-rich or electron-poor aryl substituents, as well as simple unbranched
or branched aliphatic acetals (entries 5 and 6) can be used with similar efficiencies.
Functional groups that are tolerated include a benzyl ether (entry 7), an alkyl bromide
(entry 8), a nitrile (entry 9), two esters (entries 10 and 11), and an α,β-unsaturated
acetal. Remarkably, even ketone-derived acetals (‘ketals’) can be employed with good
results (entries 14 and 15). The reactions are generally clean and chemoselective
and possible products of hydrolysis or aldolization were not detected in the crude
mixture. The best result was achieved with benzaldehyde acetal (entry 1), which provided
the corresponding homoallylic ether in nearly quantitative yield after only one hour.
While in almost all cases full conversion to the desired product was obtained after
2 to 3 hours, the allylation of the bromo (entry 8) as well as the cyano (entry
9) substituted aliphatic acetals was less efficient (85% conversion according to GC
after 8 hours and 7 hours, respectively). In addition, the volatility of the corresponding
ethers contributed to the moderate isolated yields (53% and 64%) in these cases. It
has been reported that the Hosomi-Sakurai reaction of cinnamaldehyde dimethyl acetal
with allyltrimethylsilane mediated by stoichiometric amounts of TiCl
4 gave only the diallylated product.
[
16 ]
In contrast, we did not observe any diallylated compound. Although the allylation
of cinnamaldehyde acetal has been expected to give a mixture of regioisomeric products
resulting from either direct or vinylogous nucleophilic attack of the presumed oxonium
ion, DNBA catalyzes the formation of the homoallylic ether regiospecifically (entry
13). Compared to the present Hosomi-Sakurai reaction of acetals, the allylation of
benzaldehyde under the same conditions was found to be extremely slow. Even after
21 hours less than 20% of the corresponding homoallylic silyl ether was formed.</P><P>Finally,
a benzyl acetal (
7 ) has also been studied. Subjecting acetal
7 to our reaction conditions provided the synthetically useful benzyl homoallylic ether
8 in good yield (Equation
[
1 ]
).</P>
Equation 1
<P>In summary, we have developed a highly efficient Brønsted acid catalyzed allylation
of acetals using allyltrimethylsilane. Significant advantages of our process include:
a) its high yields, b) its broad scope, allowing for the use of both aromatic and
aliphatic substrates c) its high tolerance towards diverse functional groups, d) its
simplicity and practicability, e) its use of an inexpensive and non-toxic Brønsted
acid, and f) its low catalyst loading. We are currently extending this methodology
to alternative variants and substrate classes.</P>
General Procedure for the Hosomi -Sakurai Reaction
<P>Acetal
1 (1.5 mmol, 1.0 equiv) and allyltrimethylsilane (
3 ; 0.36 mL, 2.25 mmol, 1.5 equiv) were added to a solution of DNBA (8.5 mg, 0.03 mmol,
0.02 equiv) in anhydrous MeCN and stirred at r.t. for 1-8 h. The mixture was poured
into brine (50 mL) and extracted with Et
2 O (2 × 50 mL). The combined organic layers were washed with aqueous NaHCO
3 (10 mL) and brine (10 mL), dried over Na
2 SO
4 , filtered and concentrated. The homoallylic ether
5 was isolated by flash chromatography (SiO
2 , pentane-Et
2 O).</P>
Acknowledgment <P>We thank Degussa, Saltigo, and Wacker for the donation of chemicals and Novartis
for a Young Investigator award to BL. Our work was supported by the Max-Planck-Gesellschaft,
the Deutsche Forschungsgemeinschaft (Priority Program 1179
Organocatalysis ), and the Fonds der Chemischen Industrie. Technical assistance by Marianne Hannappel
is gratefully acknowledged.</P>
