Lewis Base-Catalyzed Mannich-type Reaction between Aldimine and Trimethylsilyl Enolate

Article abstract of DOI:10.1246/cl.2003.1036

Lithium benzamide- or potassium phthalimide-catalyzed Mannich-type reaction between trimethylsilyl enolates and aldimines proceeded smoothly in a DMF solvent to afford the corresponding β-amino esters in good to high yields.

Full text of DOI:10.1246/cl.2003.1036

1036
Chemistry Letters Vol.32, No.11 (2003)
Lewis Base-Catalyzed Mannich-type Reaction between Aldimine and Trimethylsilyl Enolate
Hidehiko Fujisawa,y;yy Eiki Takahashi,y;yy Takashi Nakagawa,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 August 8, 2003; CL-030738)
Lithium benzamide- or potassium phthalimide-catalyzed
Ts
Ts
H
Mannich-type reaction between trimethylsilyl enolates and aldi-
mines proceeded smoothly in a DMF solvent to afford the corre-
sponding ꢀ-amino esters in good to high yields.
Catalyst
OSiMe3
OMe
HN
Ph
O
N
(10 mol%)
H+
+
OMe
Ph
DMF, rt, 6 h
1
2 (1.4 eq)
O
Mannich-type reaction of silyl enolate with aldimine is one
of the most important and versatile tools in constructing ꢀ-ami-
no carbonyl compounds. It provides useful routes for the synthe-
sis of ꢀ-amino esters which are employed as immediate precur-
sors of ꢀ-lactams and ꢀ-amino acids. Mannich-type reaction
generally proceeds via the electronphilic activation step of Man-
O
NK
Ph
NHLi
O
3(99%)
4(96%)
Scheme 1.
nich acceptor with Lewis acids1 such as TiCl4 and lanthanoid
2
triflate.3 On the other hand, it is also known that Mannich-type
reaction proceeds via the nucleophilic activation step of nucleo-
philes such as silyl enolate. For example, Sodeoka and co-work-
ers reported the reactions of imines with nucleophilic transition
metal enolate formed by the addition of Pd complex to silyl eno-
late.4 In most cases, a Lewis acid activator was often trapped by
the nitrogen atom of starting aldimines or that of produced ami-
no esters, and therefore, more than stoichiometric amounts of the
Lewis acids are needed to complete the reaction. It was expected
then that the reaction would proceed alternatively in the presence
of a catalytic amount of Lewis base which would work to acti-
vate the silyl enolates and that the above-mentioned undesirable
interactions of acids should be eliminated. Recently, Hosomi and
co-workers reported that Lewis base-catalyzed Mannich-type re-
action was carried out by using dimethyl silyl enolate which
readily formed hypervalent silicate with Lewis base such as dii-
sopropylethylamine and calcium chloride.5 In our previous re-
ports, commonly used trimethylsilyl (TMS) enolate was success-
fully activated with Lewis bases such as lithium diphenylamide
and lithium pyrrolidone, and worked as a strong nucleophile in
aldol and Michael reactions.6 In this communication, we would
like to report on a catalytic Mannich-type reaction between TMS
enolates and aldimines by using the nitrogen anions generated
from amides or imides as Lewis base catalysts.
In the first place, a reaction between N-tosylaldimine and
TMS enolate 2 was tried in the presence of 10mol % of lithium
pyrrolidone at ꢁ45 ꢂC in N,N-dimethylformamide (DMF) and
the corresponding ꢀ-amino ester was obtained in 37% yield. Af-
ter screening Lewis bases and reaction conditions, anions gener-
ated from lithium benzamide (3) and pottasium phthalimide (4)
turned out to be effective base catalysts in accelerating the pres-
ent Mannich-type reactions between silyl enolates and aldi-
mines, and the corresponding ꢀ-amino ester was afforded in
quantitative yields.7 In the absence of the catalyst, the reaction
also proceeded slowly at room temperature, however, the yield
of the corresponding ꢀ-amino ester was 24% after 6 h. These re-
sults indicated that Lewis base such as lithium benzamide 3 or
pottasium phthalimide 4 effectively catalyzed Mannich-type re-
action between TMS enolates and aldimines.
Next, the reactions of TMS enolate 2 with various aldimines
were tried by using 10mol % of 3 or 4 in DMF (Table 1). Var-
ious aromatic aldimines smoothly reacted with 2 to afford the
corresponding ꢀ-amino esters in high yields. When aromatic al-
dimines having electron-donating groups were used as Mannich
acceptors, the reactions proceeded slowly compared with those
of using aldimines having electron-withdrawing groups. These
results indicated that reaction rates were dependent on the elec-
trophilicity of aldimines. The present Lewis base catalyzed reac-
tion is considered to have a remarkable advantage of forming ꢀ-
amino esters especially when the aldimines have basic functions
in the same molecules. Expectedly, the reactions in the presence
Table 1.
Ts
Ts
OSiMe3
OMe
Catalyst
HN
O
N
H+
(10 mol %)
+
Ar
OMe
Ar
H
DMF, rt, Time
2 (1.4 equiv.)
Entry
Ar
Catalyst
Time/h
Yielda/%
1
2
3
4
5
6
7
8
9
4-ClC6H4
4-ClC6H4
3
4
3
4
3
4
3
4
3
4
3
4
3
4
6
3
6
3
6
3
6
9
6
3
6
16
6
3
95
quant
92
4-NCC6H4
4-NCC6H4
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
77
89
80
87
92
91
84
68
104-MeC
6H4
11
12
13
14
4-Me2NC6H4
4-Me2NC6H4
4-Pyridyl
84
70
81
4-Pyridyl
aYield was determined by 1H NMR analysis (270MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.11 (2003)
1037
Table 2.
References and Notes
1
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omiyama, D. C. Oniciu, and A. R. Katrizky, Tetrahedron
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121, 5450(1999); E. Hagiwara, A. Fujii, and M. Sodeoka,
J. Am. Chem. Soc., 120, 2474 (1998).
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Typical experimental procedure is as follows (Scheme 1): to a
stirred solution of pottasium phthalimide (3.7 mg, 0.02 mmol)
in DMF (0.3 mL) were added successively a solution of silyl
enolate 2 (48.9 mg, 0.28 mmol) in DMF (0.4 mL) and a solu-
tion of N-tosylbenzaldimine 1 (52.0mg, 0.2 mmol) in DMF
(0.7 mL) at 0 ꢂC. After warmed up to room temperature, the
mixture was stirred for 6 h, and quenched with saturated aque-
ous NH4Cl. The mixture was extracted with AcOEt. Organic
layer was washed with brine and dried over anhydrous sodium
sulfate. After filtration and evaporation of the solvent, the
crude product was purified by preparative TLC to give the cor-
responding ꢀ-amino ester (69.0mg, 95%) as a white powder.
T. Muraoka, S. Kamiya, I. Matsuda, and K. Itoh, J. Chem.
Soc., Chem. Commun., 2002, 1284.
Ts
H+
N
Catalyst (10 mol %)
Silyl enolates
(1.4 equiv.)
+
Products
DMF, rt, Time
Ph
H
Entry
Silyl Enolates Catalyst Time /h Yielda /% anti:syn
OSiMe3
1
2
3
4
6
4
100
83
-
-
St-Bu
OSiMe3
OMe
3
4
3
4
6
6
70
52
1.8:1
1.6:1
(E:Z = 5:1)
OSiMe3
5
6
3
4
24
24
59
67
1.8:1
1.6:1
OMe
(E:Z = 1:9)
OSiMe3
7
8
4
4
3
3
80
72
1.6:1
2.1:1
St-Bu
OSiMe3
Ph
2
3
aYield was determined by 1H NMR analysis (270MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
of 3 or 4 proceeded smoothly at room temperature in DMF to af-
ford the corresponding ꢀ-amino esters in high yields (Table 1,
Entries 11–14).
Lewis base-catalyzed Mannich-type reaction was further ex-
amined by using other silyl enolates (Table 2). When the enolate
generated from S-tert-butyl thioisobutyrate was employed, the
corresponding Mannich adduct was obtained in high yield (En-
tries 1 and 2). Furthermore, the Mannich adducts were obtained
in good yields with moderate anti-diastereoselectivity irrespec-
tive of the geometry of the two isometric silyl enolates derived
from methyl propionate (Entries 3–6).8 The reaction of less reac-
tive Z enolate with aldimine proceeded more slowly than that of
E enolate. The observed anti-diastereoselectivities, irrespective
of the geometries of silyl enolates, indicated that the present
Lewis base-catalyzed Mannich-type reaction proceeded via acy-
clic transition states.5,6
Thus, it is noted that lithium benzamide- or potassium
phthalimide-catalyzed Mannich-type reaction between TMS
enolates and aldimines proceeded smoothly under weakly basic
conditions in DMF. This method is practically applicable for the
synthesis of various ꢀ-amino esters because the reactions are
promoted with such a mild, readily-available, and inexpensive
Lewis base catalyst. Further extension of this reaction is now
in progress.
4
5
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.
8
Published on the web (Advance View) October 13, 2003; DOI 10.1246/cl.2003.1036