Direct aldol reaction of trifluoromethyl ketones with ketones catalyzed by Et2Zn and secondary amines

Article abstract of DOI:10.1055/s-0030-1260560

The direct catalytic aldol reaction of trifluoromethyl ketones with ketones has been accomplished. The reaction was achieved in the presence of 10 mol% Et₂Zn and N,N-dimethylethylenediamine at ambient temperature to give the expected aldol-type

Full text of DOI:10.1055/s-0030-1260560

LETTER
1431
Direct Aldol Reaction of Trifluoromethyl Ketones with Ketones Catalyzed by
Et2Zn and Secondary Amines
D
irec
t
Aldol
R
h
e
action of
T
i
rifluor
o
g
m
ethyl
K
eto
e
nes ru Sasaki, Kasumi Kikuchi, Takayasu Yamauchi, Kimio Higashiyama*
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan
Fax +81(3)54985768; E-mail: kimio@hoshi.ac.jp
Received 2 March 2011
effort has been focused on the development of this ap-
Abstract: The direct catalytic aldol reaction of trifluoromethyl
ketones with ketones has been accomplished. The reaction was
achieved in the presence of 10 mol% Et2Zn and N,N¢-dimethyleth-
ylenediamine at ambient temperature to give the expected aldol-
type products in high yields (up to 99%).
proach. Although the direct catalytic aldol reaction re-
quired to introduce the trifluoromethylated moiety has
been studied with various synthetic groups using fluoral,5
to our knowledge, there are few reports to date that have
employed the organocatalytic aldol reaction with
TFMKs.6 The latter reaction has been reported for methyl
ketones, with tri- and bimetallic zinc-catalyzed aldol reac-
tions.7 Therefore, here, we explore a new method for the
direct catalytic aldol reaction of TFMKs by applying
modified zinc complexes.
Key words: direct aldol reaction, trifluoromethyl ketone, methyl
ketone, diethylzinc, secondary amine
In recent years, organofluorine compounds have received
much attention in medicinal chemistry.1 It is well-known
that the introduction of fluorine into drugs can change
their properties, including physical properties, binding in-
teractions, and bioavailability. However, synthesizing or-
ganofluorine compounds is generally difficult because of
their unique reactivities. Therefore, methods for efficient
syntheses of organofluorine compounds have been devel-
oped by numerous research groups.2 Among such com-
pounds, the trifluoromethyl group is readily introduced
into organic compounds and has been employed in phar-
maceuticals.
As shown in Table 1, in order to evaluate the behavior of
zinc complexes and to optimize the reaction conditions,
we chose to investigate the reaction of 2,2,2-trifluoroace-
tophenone (1; 1.1 equiv) with acetophenone (2; 1.0 equiv)
and a catalytic amount of Et2Zn (10 mol%) with several
readily available catalysts (Figure 1; 10 mol%) in anhy-
drous n-hexane for 20 hours, as a model. First, we exam-
ined the aldol reaction using a mixture of diethylzinc and
methanol as a catalyst under reflux. This gave the corre-
sponding aldol adduct 3 in 8% yield, without any reduc-
tion of 1 (Table 1, entry 1). On the other hand, when 1 and
2 were treated with a catalytic amount of diethylzinc–
methanol and triethylamine as a catalyst, 3 was obtained
with an increased yield of 25% (Table 1, entry 2). This re-
sult led us to examine a complex of diethylzinc and 2-
(dimethylamino)ethanol that contained both OH and NR3
moieties in the same molecule, which gave 3 in 80% yield
(Table 1, entry 3). In addition, we carried out the aldol re-
action in the presence of benzylamine (5) as a catalyst to
give 3 in 27% yield at room temperature (Table 1, entry
4). We then examined the utilization of primary, second-
ary (N-methylbenzylamine; 6), and tertiary (N,N-dimeth-
ylbenzylamine; 7) amines. We performed the aldol
reaction in the presence of 10 mol% secondary amine 6 to
give 3 with considerably higher yield (88%) without the
formation of byproducts (Table 1, entry 5). In contrast, the
reaction with tertiary amine 7 gave a low yield of 3 with a
small amount of the reduced product of 1 (Table 1, entry
6). These results showed that a secondary amine was a
suitable catalyst for the aldol reaction. Moreover, a sec-
ondary diamine, such as N,N¢-dimethylethylenediamine
(9) gave an even higher yield than the monoamine 6
(Table 1, entry 8). We then examined the aldol reaction
with various ratios of diethylzinc and additive 9. For low-
er ratios of 9 (Table 1, entry 9; 5 mol%) and diethylzinc
(entry 10; 5 mol%), the results gave lower yields of aldol
product 3.
O
OH
Ph
CF3
Ph
CF3
99%
O
1
+
F3C
Ph
OH
Et2Zn, r.t.
+
Ph
O
OH
3
Ph
Ph
not detected
2
Scheme 1 Our previous work
In our previous work,3 we reported the chemoselective re-
duction of trifluoromethyl ketones (TFMKs) and an
equimolar mixture of methyl ketones (Scheme 1). When
we treated this mixture with Et2Zn, only TFMKs were re-
duced with good yields, leaving a small amount of aldol-
type byproduct 3.
We then focused on the aldol product 3 and found that its
formation could be catalyzed with zinc alkoxide, which is
generated in the reduction process. The aldol reaction is
one of the most important reactions available for carbon–
carbon bond formation in organic syntheses,4 and much
SYNLETT 2011, No. 10, pp 1431–1434
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260560; Art ID: U02211ST
© Georg Thieme Verlag Stuttgart · New York

1432
S. Sasaki et al.
LETTER
OH
R2
H
The diethylzinc–N,N¢-dimethylethylenediamine (9) mix-
ture was found to be a useful catalyst for the aldol reaction
of 1 with 2. We next investigated the scope and limitations
of the reaction by applying the optimized conditions de-
scribed above to various aromatic ketones (10) with 1 for
the aldol reaction as shown in Table 2. The results demon-
strated that the aldol reaction provided the desired prod-
ucts 11a–e in all cases. Compared to substrates with an
electron-withdrawing group (R = 4-Cl-Ph-; Table 2, entry
1), which had a beneficial effect, the presence of electron-
donating groups (R = 4-MeO-Ph- and 4-Me-Ph-; Table 2,
entries 4 and 5) in the para-position of the aromatic ring
appear to result in lower reactivity and required longer re-
action times (48 h). The yield decreased for 4¢-(trifluo-
romethyl)acetophenone, which has electron-withdrawing
groups in the para-position (Table 2, entries 2 and 3),
which was attributed to the lower solubility of the sub-
strate in n-hexane. The reaction with propiophenone gave
a lower yield of the aldol product 11e as an inseparable di-
astereomeric mixture (Table 2, entry 6), because 11e
caused a retro-aldol reaction to yield the starting materials
with moderate diastereoselectivity (de = 70%).
Me2N
Ph
N
R1
R3
N
N
H
R3
4
5; R1 = R2 = H
8; R3 = H
6; R1 = Me, R2 = H
7; R1 = R2 = Me
9; R3 = Me
Figure 1
Table 1 Optimization of the Reaction Conditions
O
Ph
CF3
10 mol% Et2Zn
10 mol% additive
O
1 (1.1 equiv)
F3C
Ph
OH
+
solvent, r.t., 20 h
Ph
O
3
Ph
2 (1.0 equiv)
Entry
1b
2b
3b
4
Additive
Solvent
Yield of 3 (%)a
MeOH
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
THF
8
MeOH, Et3N
25
80
27
88
17
59
92
50
66
74
73
62
44
4
Table 2 Direct Catalytic Aldol Reaction of 1 with Various Aromat-
ic Ketones
5
5
6
O
6
7
Ph
CF3
1 (1.1 equiv)
10 mol% Et2Zn
O
7
8
F3C
Ph
OH
R3
10 mol% diamine 9
+
R1
n-hexane, r.t.
8
9
O
R1
R2
9
9 (5 mol%)
11a–e
10 (1.0 equiv)
10c
11
12
13
14
9
9
9
9
9
Entry R1
R2
R3
Time Product Yield
(h)
20
20
48
48
48
72
(%)a
Et2O
1
4-Cl-C6H4
4-CF3-C6H4
Me
Me
Me
Me
Me
Et
H
11a
11b
11b
11c
11d
11e
91
toluene
2
3
4
5
6
H
66b
86
CH2Cl2
4-CF3-C6H4
4-MeO-C6H4
4-Me-C6H4
Ph
H
a Isolated yield.
H
83
b The reaction was carried out under reflux.
c The reaction was carried out in the presence of 5 mol% Et2Zn.
H
90
Me
20c
When the reaction was performed with a catalytic amount
of N,N¢-dimethylethylenediamine (9; 10 mol%) in various
solvents, the reaction in n-hexane provided the aldol prod-
uct 3 in 92% yield (Table 1, entry 8). The employment of
THF or diethyl ether for the aldol reaction resulted in
moderate yields (Table 1, entries 11 and 12). When we
carried out the reaction in toluene or CH2Cl2, the yield of
3 decreased (Table 1, entries 13 and 14). We determined
that treatment of the mixture of 1 and 2 with n-hexane so-
lution in the presence of 10 mol% diethylzinc–N,N¢-di-
methylethylenediamine (9) catalyst at room temperature
for 20 h, which gave the aldol product 3 in 92% yield,
were the best reaction conditions.
a Isolated yield.
b The lower yield was due to the lower solubility of 4¢-(trifluorometh-
yl)acetophenone in n-hexane.
c Inseparable diastereomeric mixture (70% de).
We also applied the diethylzinc–N,N¢-dimethylethylene-
diamine catalyst to various TFMK derivatives 12; the re-
sults are summarized in Table 3. In all cases, the reaction
provided the corresponding products 13a–e. TFMKs with
electron-withdrawing substituents directly linked to the
aromatic ring showed higher reactivity (R = 4-Cl-C6H4
and 4-CF3-C6H4; Table 3, entries 1 and 2). On the other
hand, TFMKs with strong electron-donating substituents
directly linked to the para-position of the aromatic ring
Synlett 2011, No. 10, 1431–1434 © Thieme Stuttgart · New York

LETTER
Direct Aldol Reaction of Trifluoromethyl Ketones
1433
and aliphatic TFMKs showed lower reactivity (R = 4- creased to 87% (Table 4, entry 3). Unsymmetrical ketones
MeO-C6H4, 4-Me-C6H4, and c-hex; Table 3, entries 3–5). reacted at the less hindered a-position with 1, which di-
The low reactivity was overcome with a longer reaction rected the regioselectivity through kinetic control of eno-
time and the use of 20 mol% catalyst to obtain the prod- late formation (Table 4, entries 4 and 5). Ketones
ucts 13c–e in high yields.
substituted with a bulky group, such as the tert-butyl
group (Table 4, entry 6), reacted in the presence of 20
mol% diethylzinc–N,N¢-dimethylethylenediamine cata-
lyst to yield 16d (77%).
Table 3 Direct Catalytic Aldol Reaction of Various Trifluorometh-
yl Ketones with 2
O
In summary, we have achieved the direct catalytic aldol
reaction of TFMKs with ketones by applying a diethylz-
inc–secondary amine complex under mild conditions, af-
fording aldol adducts with a trifluoromethyl-substituted
tertiary alcohol moiety in high yields. This reaction can be
applied to a wide range of substrates. In ongoing work, we
are exploring the direct asymmetric aldol reaction of
TFMKs with methyl ketones. In addition, we are screen-
ing catalysts with complexes of diethylzinc and optically
active secondary amines.
R
CF3
10 mol% Et2Zn
O
12 (1.1 equiv)
F3C
R
OH
10 mol% diamine 9
+
n-hexane, r.t.
Ph
O
13a–e
Ph
2 (1.0 equiv)
Entry
R
Time (h)
Product
13a
Yield (%)a
1
4-Cl-C6H4
4-CF3-C6H4
4-MeO-C6H4
4-Me-C6H4
c-Hex
20
20
48
48
72
97
98
99
89
77
2
13b
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
3
13c
4
13d
5b
13e
Acknowledgment
a Isolated yield.
This work was supported in part by the Open Research Center Pro-
ject.
b The reaction was carried out in the presence of 20 mol% catalyst.
References and Notes
Next, we conducted a crossover experiment in the pres-
ence of 1 and various aliphatic ketone derivatives 14, as
shown in Table 4. As a result, the reaction of acetone with
1 (1.0 or 2.1 equiv) to yield the desired product 16a was
accompanied by the formation of a double aldol reaction
product 15 (41 or 61% yield with low diastereoselectivity;
Table 4, entries 1 and 2). When the amount of acetone was
increased from 1 to 10 equivalents, the yield of the bis-
aldol product 15 decreased to 7% and the yield of 16a in-
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Table 4 Direct Catalytic Aldol Reaction of 1with Various Aliphatic Ketones
O
O
O
O
10 mol% Et2Zn
F3C
Ph
OH HO
CF3
Ph
F3C
R
OH
10 mol% diamine 9
+
+
Ph
CF3
n-hexane, r.t.
R
Ph
1 (1.1 equiv)
14 (1.0 equiv)
15
16a–d
Entry
R
Time (h)
20
Yield of 15 (%)a
Yield of 16a–d (%)a
10 (16a)
1
2
3
4
5
6c
Me
Meb
41 (de = 0%)
20
61 (de = 7%)
9 (16a)
Me (10 equiv)
20
7 (de = 0%)
87 (16a)
n-Pr
i-Pr
48
–
–
–
80 (16b)
48
84 (16c)
t-Bu
48
77 (16d)
a Isolated yield.
b The reaction was performed with 2.1 equiv of 1.
c The reaction was carried out in the presence of 20 mol% catalyst.
Synlett 2011, No. 10, 1431–1434 © Thieme Stuttgart · New York

1434
S. Sasaki et al.
LETTER
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Synlett 2011, No. 10, 1431–1434 © Thieme Stuttgart · New York