Hosomi-Sakurai reaction - acetals - organocatalysis - Brønsted acid catalysis - allylsilanes
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 with allyltrimethylsilane,
[2 5 /AgClO4 ,
[3 3 /CuBr,
[4 3 ,
[5 6 3 ,
[7 3 ,
[8 3 ,
[9 2 ,
[10 2 F)2 ,
[11 2 (CF3 SO3 )2 ,
[12 13 14 14 15 4 ,
[16 3 ,
[17 3 ·Et2 O,
[17 18 2 ,
[19 20 21 22 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
Scheme 1
Table 1 Catalyst Screening for the Allylation of Acetal 1a
Entry
Acid
Amount (mol%)
Temperature
Time
Conversiona (%)
1
PPA
10
r.t.
21
20
2
PPA
10
60 °C
21
25
3
TFA
10
r.t.
3
>99
4
TFA
5
r.t.
21
60
5
CSA
10
r.t.
24
40
6
p -TsOH
10
r.t.
12
>99
7
p -TsOH
3
r.t.
15
>99
8
H2 SO4
2
r.t.
2
95b
9
DNBA
2
r.t.
2
>99
a Conversion was determined by GC.b By-products were formed.
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
Table 2 Substrate Scope of the Brønsted Acid Catalyzed Hosomi-Sakurai Reaction of Acetals
Entry
Acetal
Product
Time (h)
Yield (%)
1
Ar = Ph
1
99
2
Ar = p -BrC6 H4
1
95
3
Ar = p -MeOC6 H4
2
90
4
Ar = p -O2 NC6 H4
3
93
5
2
84
6
2
87
7
7
96
8
8
53a
9
7
64a
10
3
85
11
3
88
12
1
78
13
2
87
14
1
82
15
2
91
a Reduced yield due to volatility of the product.
After identifying an active catalyst and suitable reaction conditions, we have explored the scope of the reaction (Table
[2 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 TiCl4 gave only the diallylated product.
[16
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
Equation 1
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.
General Procedure for the Hosomi -Sakurai Reaction
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 Et2 O (2 × 50 mL). The combined organic layers were washed with aqueous NaHCO3 (10 mL) and brine (10 mL), dried over Na2 SO4 , filtered and concentrated. The homoallylic ether 5 was isolated by flash chromatography (SiO2 , pentane-Et2 O).
Acknowledgment 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.
