Multi-product classes obtained from allylation of α-halo ketones with allylzinc bromide

Article abstract of DOI:10.1002/chem.200901487

An efficient, one-pot synthesis procedure for the preparation of allylic epoxides, aldehydes and homoallylic alcohols (see scheme) has been described. The three industrial products were synthesized by the reaction of allylzinc bromide with a-halo ketones

Full text of DOI:10.1002/chem.200901487

DOI: 10.1002/chem.200901487
Multi-Product Classes Obtained from Allylation of a-Halo Ketones with
Allylzinc Bromide
Min Zhang, Yuanyuan Hu, and Songlin Zhang*[a]
Selectivity in organic synthesis is of particular significance
due to the high probability of potential parallel (side)reac-
tion pathways or the generation of intermediates, which lead
to different product classes. Although several examples have
successfully demonstrated this synthesis strategy,[1] little at-
tention has actually been paid to this challenge.
rangement products aldehydes or ketones were afforded
when the reaction was catalyzed with a Brønsted acid as the
catalyst; and the third product class, homoallylic alcohols,
were formed under Lewis acid catalysis (Scheme 1).
Epoxides—being important building blocks and inter-
mediates[2] in organic synthesis—attracted our attention due
to their high reactivity, which allows easy transformation
into different products.[3] One of the useful transformations
is the Meinwald rearrangement from epoxides to afford al-
dehydes or ketones.[4]
Zinc is a relatively non-toxic metal available at low cost.
Although almost ignored for more than 100 years after their
discovery, organozinc reagents are today one of the most
useful class of organometallic reagents for organic and or-
ganometallic synthesis.[5] The lower reactivity of organozinc
compounds, once considered a major impediment, has now
become one of their greatest assets.[6] Intrigued by the palla-
dium-catalyzed reaction of a-halo ketones with allyl-substi-
tuted tin compounds such as allytributyltin or diallyldibutyl-
tin to allylic epoxides,[7] and the indium-mediated allylation
of a-chlorocarbonyl compounds[8] to afford homoallylic
chlorohydrins which transferred to the corresponding epox-
ides in the second-step under basic conditions, we tried to
investigate the possible epoxide formation from the allyl-
Scheme 1. Reactions of a-halo ketones with allylzinc bromide.
In the context of our recent investigation on the reaction
of allylzinc bromide (2) toward a-bromoacetophenone (1a)
in THF at room temperature, we found that allylic epoxide
(3a) was formed in 2 h. The best ratio 1a/2 was 1:1.2
(Scheme 2). Under the best optimized conditions, a variety
of a-halo ketones are discussed herein and the results are
shown in Scheme 3.
ACHTUNGTRENNUNGation of a-halo ketones with allylzinc bromide. We also an-
ticipated that the reaction system could afford different
product classes only by changing the reaction conditions.
Herein, we reported that allylic epoxides could be ob-
tained in high yields without any additive; Meinwald rear-
Scheme 2. Reaction of a-bromoacetophenone and allylzinc bromide.
[a] M. Zhang, Y. Hu, Prof. S. Zhang
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Dushu Lake Campus, Soochow University
Suzhou, 215123 (PR China)
Fax : (+86)512-65880352
E-mail: zhangsl@suda.edu.cn
Generally, the a-halo ketones were treated with allylzinc
bromide at room temperature in THF and the correspond-
ing allylic epoxides 3a–j were obtained in good yields
except for 3e. We investigated the factors of the electronic
effect and steric hindrance at the phenyl- and halo-substitut-
ed compounds. Electron-deficient groups at the para posi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901487.
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Chem. Eur. J. 2009, 15, 10732 – 10735

COMMUNICATION
Scheme 5. Reaction of a-bromoacetophenone and allylzinc bromide cata-
lyzed by TsOH·H2O.
Table 1). It is worth mentioning that the use of TsOH·H2O
as the catalyst is more advantageous than TfOH both in
terms of safety and convenience considerations.
Table 1. Reactions of a-bromoacetophenone and allylzinc bromide cata-
lyzed by acids (by Lewis acids or protic acids).
Entry
Cat.[a]
Yb(OTf)3
InCl3·4H2O
Mn(OAc)3·2H2O
BiBr3
CeCl3·7H2O
HCl
Cat./Sub.
t [h]
Yield [%]
1
2
3
4
5
6
7
8
G
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.4
0.8
1.0
1.0
1
1
1
20
20
1
1
1
1
1
1
0.67
none
none
none
none
none
12
20
18
60
75
G
Scheme 3. Products obtained by the allylation of a-halo ketones 1 with
allylzinc bromide 2. Overall isolated yields based on a-halo ketones after
silica gel chromatography. The ratio of cis/trans was given.
TfOH
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
9
10
11
12
90
78
tion of phenyl ring were well tolerated in good yields (3b,
ca, d), except for 3cb, which was formed in lower yields be-
cause of the lower leaving ability of Cl atom compared with
Br. Electron-donating groups at the para-position of phenyl
ring resulted in relatively diminished efficiency (3e). Sub-
strates bearing more sterically hindered groups still yielded
the corresponding epoxides (3 f–h) in good yields; the ratio
(cis/trans) was up to 94:6, 72:28, 71:29, respectively. Epox-
ides 3i (R1 =tBu) and 3j (R1 =2-thienyl) were also obtained
in good yields. When R2 =Ph, 3k (cis) was obtained in
lower yield.
We discovered that the addition of allylzinc bromide to w-
halo ketones at room temperature in THF provided a mix-
ture of expected allylic tetrahydrofurans (6m) along with
non-cyclized products (5m) and non-cyclized product 5n
(Scheme 4).
[a] Catalyst and a-halo ketone were added in one portion to the solution
of allylzinc bromide (entries 1–5), and catalyst was added to the reaction
mixture of a-halo ketone with allylzinc bromide (entries 6–12).
Under the above-optimized conditions, a variety of sub-
strates were investigated and the results were compiled in
Scheme 6. We found that aldehydes could be conveniently
formed (7a–e, 7i, 7j) from a-halo ketones via the rearrange-
ment of epoxides. The yields of aldehydes were influenced
by the formation of the epoxides and consistent with epox-
ides. When R2 is CH3 ketone (7 f) as Meinwald rearrange-
ment product was obtained in lower yield.
To our surprise, when the reaction catalyst was replaced
with Lewis acid, a sterically hindered homoallylic alcohol
was obtained in good yield (Scheme 7, Table 2).
Various a-halo ketones were treated with allylzinc bro-
mide under the best reaction condition and the correspond-
ing homoallylic alcohols were obtained (Scheme 8). The al-
lylation of substrates bearing electron-donating groups was
highly efficient (1e) in contrast to those bearing electron-de-
ficient groups (1b–d).
Scheme 4. Reactions of w-halo ketones and allylzinc bromide.
The possible mechanism illustrated in Scheme 9 showed
the mutual relations of forming allylic epoxides, aldehydes
and homoallylic alcohols.
In summary, we have encountered a novel environmental-
ly benign reaction of allyl bromide with a-halo ketones lead-
ing to three different products depending on the different
reaction conditions: allylic epoxides were obtained without
Based on the Meinwald rearrangement, the initial screen-
ing showed that a-bromoacetophenone (1a) reacted
smoothly and economically at room temperature with allyl-
zinc bromide (2) in THF catalyzed by 1 equiv TsOH·H2O
affording the aldehyde (7a) in good yields (Scheme 5,
Chem. Eur. J. 2009, 15, 10732 – 10735
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S. Zhang et al.
Scheme 8. Products obtained by the YbACHTUNRGTNEUNG(OTf)3-catalyed reaction of a-
bromo ketones 1 with 2. Isolated yields based on a-bromo ketones. [a]
The reaction was completed within 5 h.
Scheme 6. Products obtained by the TsOH·H2O-catalyed reaction of a-
halo ketones 1 with 2. Isolated yields based on a-halo ketones. [a] The
reaction was carried out at 508C.
Experimental Section
General procedure for the synthesis of epoxides 3: Allyl bromide (51 mL,
0.6 mmol) and zinc power (0.04875 g, 0.75 mmol) in dry THF (3 mL)
under a nitrogen atmosphere at room temperature. The mixture was
stirred for about 15 min, and zinc power was disappeared. The stirring
was continued to 1 h. Then the solution (3 mL) of substrate (a-halo ke-
tones, 0.5 mmol) was added (the reaction was monitored by TLC). The
reaction mixture was stirred for 2 h and then was quenched with water.
The resulting mixture was extracted with diethyl ether (3ꢁ10 mL), and
dried over anhydrous Na2SO4. The solvent was removed by evaporation
under reduced pressure. Purification by column chromatography on silica
gel afforded epoxides 3 (300–400 mesh, petroleum ether and ethyl ace-
tate).
Scheme 7. Reaction of a-bromoacetophenone and allylzinc bromide cata-
lyzed by YbACHTUNGTRENNUNG(OTf)3.
Table 2. Reactions of a-bromoacetophenone and allylzinc bromide cata-
lyzed by Lewis acids.
Entry
Cat.[a]
Cat./Sub.
Yield [%]
1
2
3
4
5
6
7
InCl3·4H2O
CeCl3·7H2O
BiBr3
0.2
0.2
0.2
0.2
0.2
0.2
0.15
50
30
25
50
trace
95
85
Acknowledgements
Mn
RuCl3·xH2O
Yb(OTf)3
Yb(OTf)3
(OAc)3·2H2O
We thank the Program for Hi-Tech Research of Jiangsu Science and
Technology Department (BE2008063), Innovation Fund for Small Tech-
nology-based Firms (08C26223201851), Innovator Fund of Suzhou Gov-
ernment (ZXJ0726), Suzhou LAC Co., Ltd., and Suzhou Chiral Chemis-
try Co., Ltd. (www.suzhoulac.com) for financial support.
ACHTUNGTRENNUNG
C
[a] Catalyst and a-halo ketone were added in one portion to the solution
of allylzinc bromide.
any additive and the addition of
TsOH·H2O or YbACHTUNGTRENNUNG(OTf)3 as cat-
alyst afforded aldehydes or ho-
moallylic alcohols, respectively.
The different products were
thus obtained in one reaction,
under mild experimental condi-
tions, high yields and a one-pot
procedure. Further investiga-
tions using other organozinc re-
agents are currently in progress.
Scheme 9. Mechanism of the reaction of a-halo ketones and allylzinc bromide.
10734
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Chem. Eur. J. 2009, 15, 10732 – 10735

Asymmetric Synthesis
COMMUNICATION
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A. E. Graham, Tetrahedron Lett. 2006, 47, 5919–5921.
Keywords: allylation
ketones · selectivity
· allylzinc bromide · epoxides ·
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Received: June 3, 2009
Published online: September 11, 2009
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