The chiral diamine mediated asymmetric Baylis-Hillman reaction

Article abstract of DOI:10.1002/adsc.200404069

A chiral diamine, easily prepared from proline, is an effective, asymmetric organic catalyst for the Baylis-Hillman reaction of aldehydes and methyl vinyl ketone, affording adducts with enantio-selectivities up to 75%.

Full text of DOI:10.1002/adsc.200404069

COMMUNICATIONS
The Chiral Diamine Mediated Asymmetric Baylis–Hillman
Reaction
Yujiro Hayashi,* Tomohiro Tamura, Mitsuru Shoji
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo
162-8601, Japan
Fax: (þ81) 3-5261-4631, e-mail: hayashi@ci.kagu.tus.ac.jp
Received: March 8, 2004; Accepted: July 10, 2004
[
9]
Abstract: A chiral diamine, easily prepared from
proline, is an effective, asymmetric organic catalyst
for the Baylis–Hillman reaction of aldehydes and
methyl vinyl ketone, affording adducts with enantio-
selectivities up to 75%.
which affords the product in up to 81% ee, while
Schaus reported that the combined use of chiral BINOL
derivatives with PEt realized enantioselectivities of up
to 96% in the reaction of aldehydes and cyclohexe-
3
[
10]
none.
The generally accepted concept used in designing ef-
fective catalysts for the Baylis–Hillman reaction is that
they should possess both a nucleophilic moiety and an
Keywords: asymmetric synthesis; Baylis–Hillman re-
action; diamines; enones; Lewis base catalysts; or-
ganic catalysis
[
2,5,7]
acidic part,
or that two molecules, one acting as a nu-
cleophile and the other as an acid, should be employ-
[
3b,6,8–10]
[5]
ed.
Marko reported that a hydroxy group suita-
bly positioned on an amine catalyst exerts a marked ef-
fect on rate acceleration as well as improving asymmet-
The Baylis–Hillman reaction is a synthetically useful ric induction by stabilizing the oxyanion intermediate
method for the preparation of b-hydroxy-a-methylene through hydrogen bonding.
carbonyl compounds in one-step from electrophilic al-
Chiral diamines have been developed by Mukaiyama
kenes and carbonyl compounds by using a tertiary et al. as effective ligands with various uses as asymmetric
[
1]
[11]
amine or tertiary phosphine as an organic catalyst.
catalysts; such compounds are also excellent organic
As chiral b-hydroxy-a-methylene carbonyl compounds catalysts for the kinetic optical resolution of alcohols
[
12]
are useful intermediates in natural product synthesis, as developed by Oriyama et al. In our continuing in-
several enantioselective versions of this reaction involv- vestigation of asymmetric reactions using organic cata-
[
13]
ing chiral catalysts have been developed. For the Baylis– lysts, we have discovered that a chiral diamine can
Hillman reaction of acrylate esters as electrophilic al- promote the Baylis–Hillman reaction enantioselective-
[2,3]
kenes, excellent enantioselectivities of up to 99% ee ly, even though the catalyst does not possess an acidic
have been attained using b-isocupreidine (b-ICD) by moiety, as disclosed in this communication.
[2]
Hatakeyama. For the asymmetric Baylis–Hillman re-
The reaction of p-nitrobenzaldehyde and methyl vinyl
action of a,b-unsaturated ketones as electrophilic al- ketone (MVK) was selected as a model. The reaction
kenes, however, although there were several precedents was carried out in the presence of (S)-1-methyl-2-(1-pyr-
[
14]
until recently, the enantioselectivity achieved has been rolidinylmethyl)-pyrrolidine (1) as organic catalyst
[
4]
[5]
moderate: Hirama and Marko developed chiral and using i-PrOH as solvent at room temperature, af-
DABCO-type and quinidine- or cinchonine-based cata- fording the Baylis–Hillman adduct in 28% yield with
lysts, respectively, which afforded modest enantioselec- 54% ee. As moderate enantioselectivity was attained
tivities (47% ee, 45% ee) under high pressure condi- in spite of the low yield, the reaction conditions were in-
tions. The combination of a chiral calcium catalyst and vestigated further. First, the diamine was examined. Be-
tributylphosphine developed by Ikegami gave moderate cause of their ready preparation, we focused on pyrroli-
enantioselectivity (56% ee) in the reaction of cyclopen- dine-based diamines, the effects of which on the yield
[6]
tenone. Good enantioselectivity (72% ee) has been at- and the enantioselectivity are summarized in Table 1.
tained using a chiral pyrrolizidine catalyst developed by It was found that the diamineꢀs structure affects both re-
[7]
Barrett. The combination of a chiral sulfide with TiCl
activity and enantioselectivity a great deal, and the fol-
4
promoted the Baylis–Hillman reaction of 3-phenylpro- lowing features were observed: 1) The substituent on
panal, affording the product in 74% ee, though an equi- the nitrogen of the pyrrolidine derived from proline is
[
8]
molar amount of the chiral sulfide had to be employed.
very important. Moderate enantioselectivity with low
Just recently, Miller et al. have reported a dual catalyst yield (28%, 54% ee) was obtained with N-methyldi-
composed of a nucleophile-loaded peptide and proline, amine 1, while moderate yield and low enantioselectiv-
1106
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DOI: 10.1002/adsc.200404069
Adv. Synth. Catal. 2004, 346, 1106–1110

Chiral Diamine Mediated Asymmetric Baylis–Hillman Reaction
COMMUNICATIONS
Table 1. Effect of diamine on the enantioselectivity of the
Baylis–Hillman reaction.
Table 2. Solvent effects for the Baylis–Hillman reaction be-
tween p-nitrobenzaldehyde and methyl vinyl ketone.
[a]
[a]
Entry
Diamine
Yield
Optical
Entry
Solvent
Yield
[%]
Optical Yield
[% ee]
[
b]
[b]
[c]
[%]
Yield
[
c]
[
% ee]
1
2
3
4
5
6
7
8
9
DMF
6
10
7
5
2
7
1
2
28
61
54 (S)
4 (S)
DMSO
toluene
CH Cl
8
5
2
2
hexane
44
46
12
51
28
46
14
17
33
40
29
62
54
61
21
8
CH CN
3
MeOH
EtOH
i-PrOH
n-PrOH
t-BuOH
CF CH OH
3
4
6
43 (S)
7 (S)
10
11
12
3
2
30
[
a]
The reaction conditions; p-nitrobenzaldehyde:MVK:di-
amine 1¼1.2: 1.0: 0.3, 238C.
[
b]
Yield of isolated product.
5
6
5
5
3 (R)
5 (R)
[c]
Determined by HPLC using a Chiralcel OD-H column.
Table 3. Effects of molar ratio of the reagents and tempera-
ture for the Baylis–Hillman reaction between p-nitrobenzal-
dehyde and methyl vinyl ketone.
[
a]
Entry
X
Y
Temp. Yield Optical
[d]
[
a]
[
b]
[c]
The reaction conditions; p-nitrobenzaldehyde:MVK: di-
amine¼1.2: 1.0: 0.3, solvent: i-PrOH, temperature: 238C.
Yield of isolated product.
[
equivs.]
[equivs.]
[ 8C]
[%]
Yield
[
e]
[% ee]
[
[
b]
c]
1
2
3
4
5
6
7
8
9
5
3
1
1
1
1
1
1
1
1
1
23
23
23
82
72
51
31
12
2
62
71
70
57
59
62
64
65
68
58
63
65
Determined by HPLC using a Chiralcel OD-H column.
1.2
1.2
1.2
1.2
3
0
ꢀ20
ꢀ40
23
23
0
5
5
Scheme 1. The chiral diamine-mediated asymmetric Baylis–
Hillman reaction.
[a]
The reaction was performed in EtOH for 48 h in the pre-
sence of 30 mol % of the diamine 1.
Equivalents of p-nitrobenzaldehyde.
Equivalents of methyl vinyl ketone.
Yield of isolated product.
[
[
[
[
b]
c]
d]
e]
ity were observed with N-H diamine 2, and the reaction
scarcely proceeded with the corresponding N-ethyldi-
amine 3. 2) The amine moiety not derived from proline
is also very important. Minorchanges in this aminemoiety
Determined by HPLC using a Chiralcel OD-H column.
also affect the reactivity and enantioselectivity a great protic solvents. As protic solvents gave promising re-
deal. The enantioselectivity with piperidine catalyst 4 sults, alcoholic solvents have been investigated in detail:
is lower than that with pyrrolidine catalyst 1 in spite of The yield in MeOH was low, because 4-hydroxy-3-me-
their having the same reactivity, while the catalysts con- thoxymethyl-4-(p-nitrophenyl)-2-butanone, the Mi-
taining a morpholine 5 or dibenzylamine group 6 hardly chael adduct of MeOH with the desired Baylis–Hillman
promote the reaction at all. As the diamine 1 was found product, was obtained in substantial amounts. t-BuOH
to be the best catalyst examined, further investigations and acidic alcohols such as CF CH OH gave low yields
3
2
were performed using it as the organic catalyst.
of the product. EtOH, however, gave good results, af-
Next, the solvent was examined with the results sum- fording the Baylis–Hillman product in moderate yield
marized in Table 2. While the reaction is slow in DMF, and enantioselectivity (51%, 62% ee).
DMSO, toluene and CH Cl , affording the product in
In order to increase the yield and enantioselectivity,
2
2
low yield, the reaction is fast in hexane, CH CN and further optimization of the reaction conditions such as
3
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ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1107

COMMUNICATIONS
Yujiro Hayashi et al.
Optical Yield [% ee]
[
a]
Table 4. The asymmetric Baylis–Hillman reaction of various aldehydes.
[
b]
Entry
1
Aldehyde
Product
Time [d]
2
Yield [%]
70
[
f]
p-nitrobenzaldehyde
65
[
f]
f]
2
3
o-nitrobenzaldehyde
4
3
40
72
68
75
[
2,4-dichlorobenzaldehyde
[
[
c]
[f]
4
5
6
p-chlorobenzaldehyde
p-bromobenzaldehyde
4
4
6
78
72
67
70
64
46
[
f]
d]
[f]
[
f]
7
4
67
69
[
g]
h]
8
9
o-chlorobenzaldehyde
p-cyanobenzaldehyde
4
4
96
71
45
61
[
[
e]
[g]
1
1
0
1
benzaldehyde
furylaldehyde
6
5
70
64
49
[
f]
44
[
a]
Unless otherwise shown, reactions were conducted with 30 mol % of the diamine 1, 1.0 equiv. of aldehyde, and 5.0 equivs. of
methyl vinyl ketone in EtOH at 08C.
Yield of isolated product.
The diamine 1 was used in 60 mol %.
The diamine 1 was used in 10 mol %.
[
[
[
[
[
[
[
b]
c]
d]
e]
f]
The reaction was performed at 238C.
Determined by HPLC using a Chiralcel OD-H column.
Determined by HPLC using a ChiralpakAD-H column.
Determined by HPLC using a ChiralpakAD-H column after conversion of the vinylidene species to the corresponding
epoxide.
g]
h]
molar ratio of aldehyde, methyl vinyl ketone and di- methyl vinyl ketone at lower temperature (08C) in
amine 1, and reaction temperature has been performed EtOH (entry 9) with the results summarized in Table 4.
with the results summarized in Table 3. A good yield was
Not only p-nitrobenzaldehyde, but also the reactive o-
obtained when excess aldehyde or methyl vinyl ketone nitrobenzaldehyde and 2,4-dichlorobenzaldehyde re-
was employed (entries 1–3, 7, 8). When the reaction acted at 08C, affording the Baylis-Hillman adducts in
was performed at lower temperature, the optical purity 40% and 72% yield with 68% ee and 75% ee, respective-
was increased with a decrease in the yield (entries 3–6). ly (entries 2 and 3). p-Chlorobenzaldehyde and p-bro-
Because of the low cost and the easy removal under re- mobenzaldehyde gave the Baylis–Hillman products in
duced pressure of methyl vinyl ketone, the generality of good yield with good enantioselectivity (entries 4–7),
the reaction was investigated using 5 equivalents of while lower enantioselectivity and good yield was ob-
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Adv. Synth. Catal. 2004, 346, 1106–1110

Chiral Diamine Mediated Asymmetric Baylis–Hillman Reaction
COMMUNICATIONS
tained in the reaction of o-chlorobenzaldehyde (en- Synthesis of (S)-1-Methyl-2-(1-pyrrolidinylmethyl)-
[14]
try 8). Not only electron-deficient aldehydes, but also pyrrolidine (1)
benzaldehyde and a heteroaromatic aldehyde, such as
To a CH Cl suspension (30 mL) of (S)-Boc-proline (21.5 g,
2
2
furylaldehyde, gave the Baylis–Hillman product in rea-
sonable yield with moderate enantioselectivity (en-
tries 10 and 11). Good enantioselectivity (70% ee) was
1
00 mmol) was added a CH Cl solution (60 mL) of DCC
2 2
(
20.6 g, 100 mmol) at 08C under an argon atmosphere and
the reaction mixture was stirred for 30 minutes at that temper-
attained when 60 mol % of diamine was employed, ature. To this reaction mixture was added a CH Cl solution
2
2
while a decrease in enantioselectivity (46% ee) was ob- (40 mL) of pyrrolidine (8.35 mL, 100 mmol) slowly at 08C,
served in the presence of only 10 mol % of the catalyst and the reaction temperature was increased to room tempera-
ture after 15 minutes. After 12 h, volatile materials were re-
(
entries 4 and 6). The reaction scarcely proceeded, af-
moved under reduced pressure, and ethyl acetate (100 mL)
was added to the residue. After insoluble materials had been
removed by filtration, the filtrate was washed with 1 N HCl
fording the Baylis–Hillman adducts in less than 5% yield
under the same reaction conditions when electron-rich
aromatic aldehydes such as p-anisaldehyde and aliphat-
ic aldehydes such as cyclohexanecarbaldehyde were em-
ployed.
(
20 mL), saturated NaHCO solution (20 mL) and brine suc-
3
cessively, before drying over anhydrous Na SO . After removal
2
4
of the volatile materials under reduced pressure, the residue
was purified by silica gel column chromatography
The absolute configuration of the Baylis–Hillman ad-
[
4]
ducts derived from p-nitrobenzaldehyde, o-nitroben-
zaldehyde, and furylaldehyde was determined by 21.7 g (81%).
(
CHCl :AcOEt¼10:0 to 5:1) to afford the amide; yield:
3
[9]
[9]
comparison of the optical rotations with those reported
in the literature.
In summary, we have found that the diamine 1 can pro-
mote the Baylis–Hillman reaction of methyl vinyl ke-
tone and various aldehydes, affording adducts in good
yield with moderate to good enantioselectivity (up to
To a THF suspension (73 mL) of LiAlH (7.0 g, 183 mmol)
was added a THF solution (73 mL) of the amide (19.7 g,
3 mmol) at 08C and the temperature of the reaction mixture
4
7
was raised to room temperature gradually. After refluxing
the reaction mixture for 4 h, saturated Na SO solution was
2
4
added to the reaction mixture at 08C until the evolution of
H ceased. After filtration of the inorganic materials, volatile
2
75% ee). As described above, most of the amine cata-
materials were removed under reduced pressure and the resi-
lysts for the asymmetric Baylis–Hillman reaction pos-
sess two functionalities, a basic amine part such as a nu-
cleophilic amine, and an acidic part such as a hydroxy or
phenoxy group. The present reaction is the first demon-
stration that a chiral diamine possessing two basic amine
moieties without an acidic part can promote the Baylis–
Hillman reaction enantioselectively. Although more ex-
perimentation is needed to clarify the reaction mecha-
nism, including the role of the two amine moieties, and
there is room for improvement in the enantioselectivity,
the finding that not only amino alcohols but also dia-
mines can promote the Baylis–Hillman reaction opens
the way for the design of new asymmetric organic cata-
lysts for this reaction.
due was purified by column chromatography using Al O3
2
(
hexane:AcOEt¼6:1) followed by distillation to afford the di-
amine 1; yield: 15.0 g (80%); bp 748C/6 mmHg.
Scheme 2. Synthesis of the diamine 1.
Acknowledgements
Experimental Section
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Typical Experimental Procedure (Table 4, entry 1)
To an ethanol solution (0.45 mL) of p-nitrobenzaldehyde
(
2
75.6 mg, 0.5 mmol) and methyl vinyl ketone (204 mL,
.5 mmol) was added (S)-1-methyl-2-(1-pyrrolidinylmethyl)-
References and Notes
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mixture was stirred for 2 days at this temperature. After remov-
al of the volatile materials under reduced pressure, the residue
was purified by thin-layer chromatography to afford the Bay-
lis–Hillman adduct in a yield of 77.6 mg (70%) with 65% ee,
as determined by HPLC analysis on a chiral stationary
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Adv. Synth. Catal. 2004, 346, 1106–1110
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ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1109

COMMUNICATIONS
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Adv. Synth. Catal. 2004, 346, 1106–1110