Lithium acetate-catalyzed mannich-type reaction between trimethylsilyl enolates and aldimines in a water-containing DMF

Article abstract of DOI:10.1246/cl.2004.936

Lithium acetate-catalyzed Mannich-type reaction between trimethylsilyl enolates and aldimines proceeded smoothly in dry or even in a water-containing DMF to afford the corresponding β-amino carbonyl compounds in good to high yields under mild conditions.

Full text of DOI:10.1246/cl.2004.936

936
Chemistry Letters Vol.33, No.7 (2004)
Lithium Acetate-catalyzed Mannich-type Reaction between Trimethylsilyl Enolates
and Aldimines in a Water-containing DMF
Eiki Takahashi,y;yy Hidehiko Fujisawa,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received May 13, 2004; CL-040550)
Lithium acetate-catalyzed Mannich-type reaction between
Ts
OTMS
OMe
2
Ts
H
Cat.
NH
O
trimethylsilyl enolates and aldimines proceeded smoothly in
dry or even in a water-containing DMF to afford the correspond-
ing ꢀ-amino carbonyl compounds in good to high yields under
mild conditions.
H+
O
N
(10 mol%)
+
Ph
OMe
DMF, Temp.
Ph
1
PhCOOLi, rt, 6 h, quant.
CH3(CH2)4COOLi, rt, 6 h, quant.
NLi, −45 °C, 6 h, 37%.
CH3COOLi, rt, 6 h, quant.
CH3COOLi, −45 °C, 12 h, quant.
The Mannich-type reaction of aldimine with silyl enolate is
one of the most important tools for the construction of ꢀ-amino
carbonyl compounds. Recently, several methods for the catalytic
Mannich-type reaction by using Lewis acid catalysts have inten-
sively been studied.1 Although these acids were generally em-
ployed for promotion of the above reaction, deactivation caused
by the coordination of a nitrogen atom of the starting aldimines
or of the produced amine was considered as a negative problem.
On the other hand, it is feasible to use a Lewis base catalyst for
the Mannich-type reaction since the catalyst would bring about
no undesirable interactions between substrates and catalyst.2
In the course of our investigation for the activation of trime-
thylsilyl (TMS) enolate with a Lewis base catalyst,3 nitrogen-
containing organic anions generated from amides and imides
were found to work effectively as Lewis base catalysts to accel-
erate the Mannich-type reaction.4 Accordingly, the carboxylate
anion such as lithium acetate were expected to work as an effec-
tive Lewis base catalyst as it did in the aldol reaction between
aldehydes and TMS enolates.5 The above anions are readily
available, inexpensive and could be used under mild conditions
in water-containing solvent because they are weakly-basic and
are stable toward water. In addition, they are very useful from
an environmental point of view because of their low toxicity
and are disposable without any special treatment. Then, in order
to further examine the usefulness of organic anions as Lewis bas-
es in organic reactions, the use of oxygen-containing organic
anions generated from carboxylic acids was considered. In this
communication, we would like to report on the Mannich-type re-
action between TMS enolates and aldimines by using a catalytic
amount of lithium acetate both in dry or water-containing DMF
solvent.
Scheme 1.
Table 1.
Ts
OTMS
OMe
2
Ts
H
AcOLi
(10 mol%)
NH
O
N
H+
+
Ar
OMe
DMF, rt
Ar
Yielda /%
quant
81
Entry
Ar
Time /h
p-MeOC6H4
p-MeC6H4
1
2
3
4
5
6
6
3
3
3
p-ClC6H4
p-BrC6H4
p-CNC6H4
97
quant
84
96
78
77
p-O2NC6H4
6
7
8
3
6
3
p-Me2NC6H4
4-Pyridyl
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
1
tried by using 10 mol % of lithium acetate in DMF (Table 1).
Most aromatic aldimines reacted smoothly with 2 to afford the
corresponding ꢀ-amino esters in high yields. Further, the corre-
sponding Mannich-adducts were afforded in high yields even
when aromatic aldimines having either electron-donating or hav-
ing electron-withdrawing groups were used as their acceptors. It
is noteworthy to point out that the corresponding ꢀ-amino esters
were also obtained in good yields when aldimines having basic
part such as dimethylamino- or pyridiyl-function in the same
molecule were used (Entries 8 and 9).
The lithium acetate-catalyzed Mannich-type reaction was
further tried by using various silyl enolates and the correspond-
ing Mannich-adducts were obtained in good to quantitative
yields (Table 2). When two TMS enolates derived from methyl
propionate were used, they reacted smoothly at ꢁ20 ꢂC to afford
the corresponding Mannich-adduct in quantitative yields. Fur-
thermore, the diastereomeric ratio of the anti isomer increased
with the use of (E)-enolate 5 and also the same results were ob-
serbed when silyl enolate 7 was used.
In the first place, reactions between N-tosylaldimine 1 and
TMS enolate 2 were tried in the presence of 10 mol % of lithium
carboxylates such as lithium acetate, benzoate, and hexanoate at
room temperature and the corresponding Mannich-adducts were
obtained in quantitative yields (Scheme 1). It is interesting to
note that the above reaction proceeds smoothly even at ꢁ45 ꢂC
by using lithium acetate while N-lithio-2-pyrrolidone is less ef-
fective at the same temperature in spite of weaker nucleophilic-
ity of the lithium carboxylate than that of N-lithio-2-pyrrolidone.
Because of these results, it was thought that lithium carboxylates
would be employed as favorable catalysts of this reaction.
Next, the reactions of TMS enolate 2 with aldimines were
Then, lithium acetate-catalyzed Mannich-type reaction in
water-containing DMF solvent was tried. When N-tosylaldimine
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.7 (2004)
937
Table 2.
Ts
OTMS
OMe
Ts
H
NH
O
N
Ts
AcOLi (10 mol%)
OTMS
Ts
+
NH
O
AcOLi (10 mol%) H+
DMF, Temp. Time
Ph
OMe
N
R1
DMF-H2O
(Volume ratio 50:1)
Ph
+
R
Ph
R
2 (2.0 eq)
1
Ph
H
R2
84%
24 h, −45 °C
R1 R2
1
Entry
Silyl enolates Temp. /°C Time /h Yielda /% anti :syn
Scheme 2.
containing DMF, the yield and ratio of anti isomer decreased
compared to those in dry DMF whereas the ratio increased when
silyl enolate 6 was used.
OSiMe3
quant
quant
––
1
6
3
4
rt
St-Bu
Thus, the lithium acetate-catalyzed Mannich-type reaction
between TMS enolates and aldimines in dry or water-containing
DMF solvent was established. This method is quite practical and
is applicable to the synthesis of various ꢀ-amino carbonyl com-
pounds since its reaction conditions do not have to be strictly an-
hydrous and mild, readily available yet inexpensive Lewis base
catalyst is used. Further development of this reaction is now in
progress.
OSiMe3
OMe
2
−20
24
1.6 : 1
(E : Z = 1 : 9)
OSiMe3
3
4
rt
6
84
1.6 : 1
4.2 : 1
5
OMe
quant
−20
24
(E : Z = 5 : 1)
OSiMe3
quant
85
5
6
rt
3
6
3.0 : 1
3.1 : 1
6
7
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
−45
St-Bu
OSiMe3
Ph
quant
quant
7
8
3.0 : 1
5.4 : 1
rt
−20
1
3
24
References
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
1
I. Ojima, S. Inaba, and K. Yoshida, Tetrahedron Lett., 1977,
3643; I. Ojima, S. Inaba, and M. Nagai, Synthesis, 1981,
545; T. Mukaiyama, K. Kashiwagi, and S. Matsui, Chem. Lett.,
1989, 1397; T. Mukaiyama, H. Akamatsu, and J. S. Han,
Chem. Lett., 1990, 889; S. Kobayashi, M. Araki, H. Ishitani,
and S. Nagayama, Synlett, 1995, 233; M. Shimizu, K. Kume,
and T. Fujisawa, Chem. Lett., 1996, 545; S. Kobayashi, H.
Ishitani, and M. Ueno, J. Am. Chem. Soc., 120, 431 (1998);
D. Ferraris, B. Young, T. Dudding, and T. Lactka, J. Am.
Chem. Soc., 120, 4548 (1998); R. Hayakawa and M. Shimizu,
Chem. Lett., 1999, 591; S. Yamasaki, T. Iida, and M.
Shibasaki, Tetrahedron Lett., 40, 307 (1999); H. Ishitani, T.
Kitazawa, and S. Kobayashi, Tetrahedron Lett., 40, 2161
(1999); H. Ishitani, M. Ueno, and S. Kobayashi, J. Am. Chem.
Soc., 122, 8180 (2000); K. Juhl, N. Gathergood, and K. A.
Jꢀrgensen, Angew. Chem., Int. Ed., 40, 2995 (2001); S.
Kobayashi, H. Ishitani, Y. Yamashita, M. Ueno, and H.
Shimizu, Tetrahedron, 57, 861 (2001); B. M. Trost and L. R.
Terrell, J. Am. Chem. Soc., 125, 338 (2003).
1 and TMS enolate 2 in the presence of 10 mol % of lithium ace-
tate were allowed to react at room temperature for 6 h in DMF/
H2O (50:1), the corresponding ꢀ-amino ester was obtained in
65% yield. After screening several reaction conditions, the cor-
responding Mannich-adduct was obtained in high yield when
carried out at ꢁ45 ꢂC for 24 h. It is generally known that silyl
enolates, especially those generated from carboxylic esters, are
sensitive to water and are hydrolyzed easily under acidic condi-
tions. This is the first example of the Lewis base-catalyzed Man-
nich-type reaction using silyl enolates derived from carboxylic
esters in a homogeneous water-containing solvent.6,7
The same reaction in water-containing DMF solvent by us-
ing several silyl enolates was studied next, and the diastereose-
lection of the reaction was found to be influenced by the co-ex-
isting water and also by the structures of silyl enolates employed
(Table 3). That is, when silyl enolate 5 was employed in water-
2
3
K. Miura, K. Tamaki, T. Nakagawa, and A. Hosomi, Angew.
Chem., Int. Ed., 39, 1958 (2000); K. Miura, T. Nakagawa,
and A. Hosomi, J. Am. Chem. Soc., 124, 536 (2002).
H. Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 182; H.
Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 858; T.
Mukaiyama, H. Fujisawa, and T. Nakagawa, Helv. Chim. Acta,
85, 4518 (2002); T. Mukaiyama, T. Nakagawa, and H.
Fujisawa, Chem. Lett., 32, 56 (2003).
H. Fujisawa, E. Takahashi, and T. Mukaiyama, Chem. Lett.,
32, 1036 (2003).
T. Nakagawa, H. Fujisawa, and T. Mukaiyama, Chem. Lett.,
32, 462 (2003).
T. Akiyama, J. Takaya, and H. Kagoshima, Synlett, 1999,
1045; T. Akiyama, J. Takaya, and H. Kagoshima, Tetrahedron
Lett., 42, 4025 (2001); T. Akiyama, J. Takaya, and H.
Kagoshima, Adv. Synth. Catal., 344, 338 (2002).
K. Manabe, Y. Mori, and S. Kobayashi, Synlett, 1999, 1401; T.
Akiyama, J. Takaya, and H. Kagoshima, Synlett, 1999, 1426;
T. Akiyama, J. Itoh, and K. Fuchibe, Synlett, 2002, 1269.
Table 3.
Ts
H
Ts
OTMS
R
AcOLi (10 mol%)
N
NH O
+
R1
DMF-H2O
(Volume ratio 50:1)
Temp., Time
Ph
Ph
R
(2.0 eq)
1
R1
Temp. /°C Time /h Yielda /%
Silyl enolates
OSiMe3
anti :syna
Entry
4
5
6
1
5
−20
−45
24
74
1.6 : 1
OMe
OSiMe3
St-Bu
OSiMe3
Ph
quant
quant
6
5.5 : 1
5.8 : 1
2
3
6
7
−20
12
7
1
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
Published on the web (Advance View) June 26, 2004; DOI 10.1246/cl.2004.936