Diarylprolinol in the direct asymmetric aldol reaction of trifluoromethylacetaldehyde ethyl hemiacetal with aldehyde

Article abstract of DOI:10.1055/s-0030-1259543

Asymmetric direct aldol reaction of trifluoromethylacetaldehyde with aldehyde using diarylprolinol as a catalyst, to afford a synthetically useful β-trifluoromethyl-β-hydroxy aldehyde with excellent enantioselectivity, was developed. Commercially availabl

Full text of DOI:10.1055/s-0030-1259543

CLUSTER
485
Diarylprolinol in the Direct Asymmetric Aldol Reaction of
Trifluoromethylacetaldehyde Ethyl Hemiacetal with Aldehyde
D
iarylprolinol in th
u
e
Direct
A
sy
j
mmetr
i
ic
A
ldo
r
l
Reacti
o
on Hayashi,* Yusuke Yasui, Tsuyoshi Kawamura, Masahiro Kojima, Hayato Ishikawa
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Fax +81(3)52614631; E-mail: hayashi@ci.kagu.tus.ac.jp
Received 12 December 2010
hyde generated is a versatile synthetic intermediate. Since
MacMillan’s discovery of the proline-mediated reaction,8
many cross-aldol reactions catalyzed by organocatalysts
have been reported.9 However, there is no example of
Abstract: Asymmetric direct aldol reaction of trifluoromethylacet-
aldehyde with aldehyde using diarylprolinol as a catalyst, to afford
a synthetically useful b-trifluoromethyl-b-hydroxy aldehyde with
excellent enantioselectivity, was developed. Commercially avail-
able trifluoromethylacetaldehyde ethyl hemiacetal was used direct- cross-aldol reaction of trifluoromethylacetaldehyde with
ly as a precursor of trifluoromethylacetaldehyde without acid
pyrolysis or distillation prior to use.
aldehyde. Recently, our group found that diarylprolinol is
an effective organocatalyst for the cross-aldol reactions of
acetaldehyde as a nucleophilic aldehyde10 and polymer
Key words: asymmetric synthesis, aldol reactions, organocatalyst,
ethyl glyoxylate as an electrophile.11
diarylprolinol, trifluoromethylacetaldehyde
R1
Fluorinated molecules show interesting biological activity
R2O
catalyst R1
R2
and physical properties because of the unique character of
fluorine. Thus, the synthesis of chiral fluorinated com-
pounds is an important topic in organofluorine chemistry.1
O
R1
R1
1
2
3
4
CF3
H
CF3
H
H
H
TMS
TMS
N
N
OH
H
H
Trifluoromethylacetaldehyde is a versatile reagent for
preparation of molecules containing trifluoromethyl
groups. In particular, for the asymmetric aldol reaction,2
Iseki and co-workers reported diastereoselective synthesis
of syn-b-trifluoromethyl-b-hydroxy amide using Evans
aldol reaction.3
R1
Figure 1 Organocatalysts investigated in the present study
When we applied this catalyst to the aldol reaction of tri-
fluoromethylacetaldehyde using trifluoromethylacetalde-
hyde ethyl hemiacetal as a precursor, we found that the
cross-aldol product was obtained with excellent enantio-
selectivity, as described in this communication.
Trifluoromethylacetaldehyde is a reactive aldehyde that is
prepared from its hemiacetal or hydrate by treatment with
concentrated sulfuric acid just prior to use. It would be a
synthetic advantage if commercially available and stable
trifluoromethylacetaldehyde ethyl hemiacetal could be We chose 3-phenylpropanal as a nucleophilic model alde-
used directly as a precursor of trifluoromethylacetalde- hyde, and investigated the reaction with trifluoromethyl-
hyde.
acetaldehyde ethyl hemiacetal (containing up to 10%
EtOH)12 in toluene. Because the desired product was eas-
ily isomerized,13 the aldol product was treated with Wittig
reagent in situ to transform it into a,b-unsaturated ester,
which was isolated and characterized.
On the other hand, after the discovery of a proline-medi-
ated intermolecular aldol reaction by List et al. in 2000,4
the field of organocatalysis has been developing very rap-
idly.5 Many kinds of organocatalysts have been developed
and applied to various organic reactions. For the aldol re- First, the catalyst was investigated (Figure 1, Table 1).
action of trifluoromethylacetaldehyde, Yamamoto6 and When diarylprolinol with trifluoromethyl moiety 1 was
Funabiki7 independently reported reactions with ketones employed, the desired ester was obtained in 42% yield
as nucleophiles catalyzed by proline tetrazole and proline, with moderate diastereoselectivity (anti/syn = 5:1) and
respectively. These are the first reports of the use of tri- excellent enantioselectivity (96% ee, entry 1). Diphenyl-
fluoromethylacetaldehyde ethyl hemiacetal as a precursor prolinol (2) was also an efficient catalyst, affording the
of trifluoromethylacetaldehyde in the asymmetric aldol product with excellent enantioselectivity and moderate di-
reaction.
astereoselectivity (entry 2). The silyl ethers 3 and 4 of di-
arylprolinol and diphenylprolinol were not suitable
catalysts, affording the opposite enantiomer with lower
enantioselectivities (entries 3 and 4). Proline was an inef-
fective catalyst as it gave low enantioselectivity in tolu-
ene, DMF, and DMSO, the last of which is a common
solvent in proline-mediated aldol reactions (entries 5–7).
Cross-aldol reaction of two different aldehydes is one syn-
thetically useful reaction, because the b-hydroxy alde-
SYNLETT 2011, No. 4, pp 0485–0488
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259543; Art ID: Y02510ST
x
x.
x
x.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

486
Y. Hayashi et al.
CLUSTER
Table 1 The Effects of Organocatalyst and Solvent in the Aldol Reaction of Trifluoromethylacetaldehyde Ethyl Hemiacetal and 3-Phenyl-
propanala
catalyst
O
OH
OH
OEt
O
(10 mol%)
Ph3P=CHCO2Et
r.t., 2 h
+
OEt
F3C
solvent, r.t.
F3C
Ph
H
Bn
Entry
1
Catalyst
Solvent
Yield (%)b
anti/sync
5:1
ee (%)d
96
1
toluene
toluene
toluene
toluene
toluene
DMF
42
40
95
86
32
27
27
40
27
50
40
65
2
2
3.4:1
2.7:1
2.4:1
2:1
94
3
3
–47
–37
67
4
4
5
proline
6
proline
1.7:1
1.5:1
1:1
68
7
proline
DMSO
EtOH
40
8
1
1
1
1
1
85
9
DMF
1.2:1
2.8:1
3.2:1
5:1
94
10
11
12e
THF
97
benzene
toluene
93
96
a Reaction conditions; first step: trifluoromethylacetaldehyde ethyl hemiacetal (0.6 mmol), 3-phenylpropanal (0.5 mmol), catalyst (0.05 mmol),
solvent (0.5 mL), r.t., 48 h; second step: Ph3P=CHCO2Et (0.75 mmol), r.t., 2 h.
b Isolated yield of a,b-unsaturated ester (2 steps).
c Determined by 1H NMR.
d The ee of the anti isomer, which was determined by chiral HPLC analysis.
e Toluene (0.25 mL) was employed.
Table 2 Asymmetric Aldol Reaction of Trifluoromethylacetaldehyde Ethyl Hemiacetal with Various Aldehydes Catalyzed by Diarylprolinol
catalyst 1
(10 mol%)
O
O
OH
OH
OEt
X equiv
Ph3P=CHCO2Et
r.t., 2 h
+
OEt
H
F3C
toluene
r.t., time
F3C
R
R
Y equiv
Entry
Product
x (equiv)
1.2
y (equiv)
1
Time (h)
40
Yield (%)a
65
anti/synb
ee (%)c
96
O
OH
1
2
3
5:1
OEt
F3C
Bn
O
OH
1
1
3
3
50
75
68
71
1.1:1
2.5:1
90
88
OEt
F3C
F3C
O
OH
OEt
Et
OH
O
4
1
1
3
2
80
62
69
2.1:1
4.9:1
89
93
OEt
F3C
n-Pr
O
OH
5d
112
OEt
F3C
i-Pr
Synlett 2011, No. 4, 485–488 © Thieme Stuttgart · New York

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Diarylprolinol in the Direct Asymmetric Aldol Reaction
487
Table 2 Asymmetric Aldol Reaction of Trifluoromethylacetaldehyde Ethyl Hemiacetal with Various Aldehydes Catalyzed by Diarylprolinol
(continued)
catalyst 1
(10 mol%)
O
O
OH
OH
OEt
X equiv
Ph3P=CHCO2Et
r.t., 2 h
+
OEt
H
F3C
toluene
r.t., time
F3C
R
R
Y equiv
Entry
Product
x (equiv)
1.2
y (equiv)
Time (h)
96
Yield (%)a
anti/synb
ee (%)c
91
O
OH
OEt
F3C
6e
1
1
71
3.6:1
O
OH
7e
1.2
96
71
3:1
90
OEt
F3C
Ph
a Isolated yield.
b The diastereoselectivity was determined by 1H NMR.
c The enantioselectivity of the anti isomer was determined by chiral HPLC analysis.
d The catalyst (20 mol%) was employed.
e The catalyst (15 mol%) was employed.
Next, the solvent was investigated (Table 1). As trifluo- a catalytic amount of TsOH in a one-pot operation
romethylacetaldehyde ethyl hemiacetal contains about (Scheme 1).
10% EtOH, the reaction was performed in EtOH. The re-
The absolute configuration was determined by compari-
action proceeded with lower enantioselectivity (entry 8).
son of the optical rotation with that in the literature after
While excellent enantioselectivity was observed in DMF,
conversion of the aldol product into a known acetal,3 pre-
THF, benzene, and toluene (entries 1 and 9–11), we se-
pared according to Scheme 2: 1) aldol reaction of trifluo-
lected toluene as a solvent based on the higher diastereo-
romethylacetaldehyde ethyl hemiacetal and 3-
selectivity. When the reaction was conducted in 2 mol/L,
phenylpropanal; 2) reduction with NaBH4; and 3) acetal
a better yield (65%) was obtained (entry 12).
formation by reaction with benzaldehyde dimethyl acetal.
After optimization of the reaction conditions, the general-
ity of the reaction was examined, and the results are sum-
catalyst 1
OH
OH
O
(10 mol%)
NaBH4
marized in Table 2. In addition to 3-phenylpropanal,
propanal, butanal, pentanal, and isovaleraldehyde could
be successfully employed as nucleophiles to provide aldol
products with excellent enantioselectivity (entries 1–5).
Double bonds and triple bonds did not interfere with the
reaction, providing the desired product with moderate
diastereoselectivity and excellent enantioselectivity (en-
tries 6 and 7).
+
MeOH
0 °C, 1 h
toluene
r.t., 40 h
F3C
F3C
OEt
Ph
H
Ph
Bn
PhCH(OMe)2
cat. TsOH
O
O
OH
CH2Cl2
r.t., 1 h
F3C
Bn
63%, anti/syn = 5:1
57%
The aldol product was not only converted into a,b-unsat-
urated ester, but also transformed into dimethyl acetal by
treatment of the crude aldol product with HC(OMe)3 and
Scheme 2
The absolute configuration could be explained by the tran-
sition state shown in Figure 2, similar to the one proposed
OH
Ar
HC(OMe)3
cat. TsOH
catalyst 1
OH OMe
OMe
F3C
OEt
O
(10 mol%)
Ar
N
O
+
F3C
toluene
r.t., 40 h
r.t., 1 h
H
O
Bn
Ph
H
H
F3C
R
66%, anti/syn = 3.5:1
93% ee (anti isomer)
Figure 2 Transition state of intermediate enamine and trifluoro-
methylacetaldehyde; Ar = 3,5-bis(trifluoromethyl)phenyl
Scheme 1
Synlett 2011, No. 4, 485–488 © Thieme Stuttgart · New York

488
Y. Hayashi et al.
CLUSTER
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group of the catalyst via hydrogen bonding.
In conclusion, we have developed an asymmetric direct
aldol reaction of trifluoromethylacetaldehyde with alde-
hyde catalyzed by diarylprolinol 1, to afford a synthetical-
ly useful b-trifluoromethyl-b-hydroxy aldehyde. There
are several noteworthy features in this reaction: 1) com-
mercially available trifluoromethylacetaldehyde ethyl
hemiacetal was used directly as a precursor of trifluoro-
methylacetaldehyde without acid pyrolysis or distillation
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ized. The trifluoromethyl-substituted product is an impor-
tant synthetic intermediate, and this method offers an
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(13) When the reaction was performed in 72 h, the yield increased
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indicates that the partial isomerization occurred during the
reaction.
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