Expedient mukaiyama-type mannich reaction catalyzed by lithium chloride

Article abstract of DOI:10.1055/s-2008-1078424

The Mannich reaction of methylsilyl enol ether with arylaldimine proceeded in the presence of a catalytic amount of lithium chloride in dimethylformamide at room temperature. The reaction was mild enough to apply to aldimines having the AcO, TBDMSO, or MeS group. Microwave irradiation accelerated the reaction substantially to reduce reaction time.

Full text of DOI:10.1055/s-2008-1078424

1520
LETTER
Expedient Mukaiyama-Type Mannich Reaction Catalyzed by Lithium
Chloride
LiCl-Catalyzed
Mu
kaiya
m
s
a-Type
M
a
annich
R
e
h
action iro Hagiwara,*a Daiki Iijima,a Bahlul Z. S. Awen,b Takashi Hoshi,c Toshio Suzukic
a
b
c
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
Department of Medicinal and Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Fateh University, Seedi Elmasry, P. O. Box 13610,
Tripoli, Libya
Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Received 11 March 2008
R2
H
Abstract: The Mannich reaction of methylsilyl enol ether with
arylaldimine proceeded in the presence of a catalytic amount of lith-
ium chloride in dimethylformamide at room temperature. The reac-
tion was mild enough to apply to aldimines having the AcO,
TBDMSO, or MeS group. Microwave irradiation accelerated the re-
action substantially to reduce reaction time.
N
R2
R1
HN
O
1
LiCl (0.2 equiv), DMF, r.t.
+
OMe
Keywords: Mannich reaction, aldimines, trimethylsilyl ketene ace-
R1
tal, microwave heating, lithium chloride
OTMS
3
OMe
2 (1.5 equiv)
The development of environmentally benign synthesis of
an organic substance is currently of great interest in the
chemical community for applications to promote a sus-
tainable society.1 The Mannich reaction and its related re-
actions are among the most basic C–C bond-forming
reactions, especially for the synthesis of biologically ac-
tive b-amino acids along with b-lactams,2 and thus more
benign reaction conditions are always desired. Recently,
nucleophilic reaction via a hypervalent silicate intermedi-
ate has attracted much attention in the aldol3 or Mannich
reaction,4 which directly activates silyl enol ether differ-
ently from the activation of the carbonyl group with Lewis
acid in the original Mukaiyama reaction.5
Scheme 1 Mukaiyama-type Mannich reaction catalyzed by lithium
chloride
catalyzed by lithium chloride in dimethylformamide
(DMF).
Employing the Mannich reaction of N-tosyl-p-chloro-
phenylaldimine 1 (R1 = Cl, R2 = Ts) with trimethylsilyl
ketene acetal 2 as a probe to optimize the reaction condi-
tions, an optimum catalyst was investigated initially
(Scheme 1).
Based on our previous result on the aldol reaction, N-
methylimidazole or pyridine N-oxide in combination
with lithium chloride was employed in initial attempts
(Table 1, entries 1–4). However, during the course of our
investigation, we found that only lithium chloride was
sufficient to catalyze the Mannich reaction more efficient-
ly at room temperature (Table 1, entries 5 and 6).
The new Mukaiyama aldol and Mannich reaction
protocols3,4 employ a catalytic amount of Lewis base such
as lithium carboxylate or lithium amide, and thus are
much more mild, general and environmentally benign,
since a stoichiometric amount of a strong Lewis acid is not
required. Based on the concept on the new Mukaiyama re-
action, we previously reported the practical and benign al-
dol reaction of silyl ketene acetal with aldehyde catalyzed
by a Lewis basic organomolecular catalyst such as pyri-
dine N-oxide or N-methylimidazole in the presence of
lithium chloride,6 in which the role of lithium chloride
was proposed to replace the organomolecular catalyst on
a hypervalent alkoxysilicate intermediate after the aldol
reaction, thereby facilitating turnover of a catalytic cycle.
Subsequently, employing lithium chloride as the catalyst,
an optimum solvent was investigated and DMF exhibited
better results among the other solvents tested (Table 2, en-
tries 5 and 6). The addition of H2O afforded lower yield
(Table 2, entry 6) due to hydrolysis of aldimine 1, which
is different from the results obtained by Mukaiyama et al.3
Although the reaction takes a longer time at room temper-
ature, microwave irradiation was effective in accelerating
the reaction substantially (Table 2, entry 7), while con-
ventional heating in an oil bath provided lower yield
(Table 2, entry 8).
In this letter, we report a new environmentally benign
Mannich reaction of arylaldimine 1 with silyl enol ether 2
The optimum reaction conditions (Table 2, entries 5 and
7) were general for various substrates, as shown in
Table 3. Since the catalyst (lithium chloride) is a neutral
salt, acid- or base-sensitive groups on aldimine 1 re-
mained intact in product 3 (Table 3, entries 9–12). The
SYNLETT 2008, No. 10, pp 1520–1522
Advanced online publication: 19.05.2008
DOI: 10.1055/s-2008-1078424; Art ID: U01708ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

LETTER
LiCl-Catalyzed Mukaiyama-Type Mannich Reaction
1521
Table 1 Investigation of Optimum Catalyst in the Reaction of Ald-
imine 1 (R1 = Cl, R2 = Ts) and Silyl Ketene Acetal 2a
Table 3 Generality of the Reaction Conditions at Room Tempera-
ture with Various Types of Aldimine 1 and Silyl Ketene Acetal 2a
Entry
Additive
Temp Time Yield
Entry
R1
R2
Temp Time Yield
(°C)
(h)
(%)
(°C)
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
(h)
40
3
(%)
1
N-Methylimidazole (0.1 equiv)
+ LiCl (0.2 equiv)
r.t.
19
71
1
2b
H
Ts
84
H
Ts
75
2b
3
N-Methylimidazole (0.1 equiv)
+ LiCl (0.2 equiv)
70
r.t.
70
1.5
19
87
83
86
3
NO2
NO2
Cl
Ts
1
95
4b
Ts
0.25 83
Pyridine N-oxide (0.1 equiv)
+ LiCl (0.2 equiv)
5
Ts
13
1.5
72
4
91
87
76
77
70
51
90
89
74
77
70
74
93
86
58
51
76
4b
Pyridine N-oxide (0.1 equiv)
+ LiCl (0.2 equiv)
1.5
6b
Cl
Ts
7
MeO
MeO
TBDMSO
TBDMSO
AcO
AcO
MeS
MeS
H
Ts
5
LiCl (0.2 equiv)
LiCl (0.2 equiv)
r.t.
70
13
91
87
8b
Ts
6b
1.5
a Reaction was carried out as described in ref.8 in DMF. Yield is an
isolated pure product based on aldimine 1.
9
Ts
24
2
10b
11
12b
13
14b
15
16b
17
18b
19
20b
21
Ts
b Heated by microwave irradiation (300 W).
Ts
72
5
Table 2 Investigation of Optimum Solvent in the Reaction of Ald-
imine 1 (R1 = Cl, R2 = Ts) and Silyl Ketene Acetal 2a
Ts
Ts
120
10
29
2.5
12
3.5
23
1.5
38
Entry
1
Solvent
THF
Temp (°C)
Time (h)
24
Yield (%)
Ts
r.t.
50
r.t.
50
r.t.
r.t.
70
70
70
–
SO2Ph
SO2Ph
SO2Ph
SO2Ph
Bz
2b
3
THF
4
–
H
MeCN
MeCN
DMF
18.5
4
79
74
91
62
87
73
75
Cl
4b
5
Cl
13
H
6
DMF–H2Od
DMF
12
H
Bz
7b
8c
9e
1.5
1.5
1.5
H
Boc
DMF
a Reaction was carried out as described in ref.8 employing 0.2 equiv
of LiCl. Yield is an isolated pure product based on aldimine.
b Heated by microwave irradiation (300 W).
DMF
a Reaction was carried out as described in ref.8 in the presence of LiCl
(0.2 equiv). Yield is an isolated pure product based on aldimine 1.
b Heated by microwave irradiation (300 W).
c Conventional heating in an oil bath.
Silyl enol ether of methyl propionate 5 (R2 = Me,
R3 = OMe, E/Z = 3:1) provided Mannich product 6 in
good yield (Scheme 2 and Table 4, entries 1–4). The reac-
tion of silyl enol ether of acetophenone 5 (R2 = H,
R3 = Ph) or propiophenone 5 (R2 = Me, R3 = Ph, Z-iso-
mer) proceeded in the same manner to afford Mannich
product 6 (Table 4, entries 5–8). Moderate anti selectivity
might be explained by an acyclic transition-state model
proposed by Mukaiyama et al.4 The low yield in entry 6
was due to the b-elimination of N-tosylamine at elevated
temperature to afford 4-aryl-3-buten-2-one as a side prod-
uct. In the reaction of enol ether of propiophenone 5, un-
desired b-elimination was suppressed to proceed with
moderate anti selectivity4 (Table 4, entries 7 and 8).
d Volume ratio of DMF and H2O was 50:1.
e An equivalent amount of aldimine 1 and silyl ketene acetal 2 was
employed.
aldimine 1 having a coordinative methylthio group toward
Lewis acid afforded Mannich product 3 for the first time
(Table 3, entries 13 and 14). Not only aldimine 1 bearing
electron-withdrawing substituents (Table 3, entries 3–6)
but also electron-donating substituents (Table 3, entries
7–10) provided b-amino ester 3 in satisfactory yields.
The present reaction condition is applicable to N-phenyl-
sulfonyl-, N-benzoyl- or N-tert-butoxycarbonyl aldimine
1 (Table 3, entries 15–21), while the yield was moderate
due to low stability of the starting N-benzoylaldimine 1
(Table 3, entries 19 and 20).
The reaction of the sterically less demanding dimethylsi-
lylketene acetal 7,7 which was anticipated to facilitate the
formation of
a
hypervalent silicate intermediate
Synlett 2008, No. 10, 1520–1522 © Thieme Stuttgart · New York

1522
H. Hagiwara et al.
LETTER
Ts
N
Table 5 Mukaiyama-Type Mannich Reaction of Dimethylsilyl
Ketene Acetal 7a
H
Entry
R
Time
5 h
Yield (%)
Ts
R1
HN
O
1
2
3
4
H
73
87
89
76
1
LiCl (0.2 equiv), DMF
R3
+
Cl
75 min
15 min
5.5 h
R2
R1
OTMS
R3
NO2
MeO
6
R2
5 (1.5 equiv)
a Reaction was carried out as described in ref.8 employing 0.2 equiv
of LiCl under microwave irradiation at 70 °C. Yield is an isolated
pure product based on aldimine 1.
Scheme 2 Mukaiyama-type Mannich reaction of various types of
silyl enol ether
boxylate or amide which requires methyllithium for its
preparation,4 the present reaction offers a mild, practical,
environmentally and economically benign method for
synthesizing b-amino carbonyl compounds, which are
versatile building blocks for the synthesis of various bio-
logically important products.
Table 4 Mukaiyama-Type Mannich Reaction of Silyl Enol Ether 5a
Entry R1
R2
R3
Temp Time
(°C)
Yield anti/syn
(%)
1
Cl
Cl
H
Me OMe r.t.
Me OMe 70
Me OMe r.t.
Me OMe 70
2 h
25 min 90
1 h 91
20 min 80
88
3.9:1
3.3:1
3.4:1
2.5:1
2b
3
Acknowledgment
B. Z. S. Awen thanks Al-Fateh University for granting him sabbati-
cal leave.
4b
5
H
Cl
Cl
Cl
Cl
H
H
Ph
Ph
r.t.
70
r.t.
70
42 h
3
80
45
78
80
6b
7
References and Notes
(1) Green Chemistry: Theory and Practice; Anastas, P. T.;
Warner, J. C., Eds.; Oxford University Press: Oxford, 1998.
(2) For reviews on Mannich and Mannich-type reactions, see:
(a) Kleinman, E. F. In Comprehensive Organic Synthesis,
Vol. 2; Trost, B. M.; Fleming, I., Eds.; Oxford: Pergamon,
1991, 893. (b) Arend, M.; Westermann, B.; Risch, N.
Angew. Chem. Int. Ed. 1998, 37, 1045. (c) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
Me Ph
Me Ph
5 d
2.3:1
1.6:1
8b
9.5 h
a Reaction was carried out as described in ref.8 employing 0.2 equiv
of LiCl. Yield is an isolated pure product based on aldimine 1.
b Heated by microwave irradiation (300 W).
(3) Fujisawa, H.; Nagata, Y.; Sato, Y.; Mukaiyama, T. Chem.
Lett. 2005, 34, 842; and earlier references cited therein.
(4) Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem. Eur. J.
2006, 12, 5082; and earlier references cited therein.
(5) For example: (a) Ojima, I.; Inaba, S.; Yoshida, K.
Tetrahedron Lett. 1977, 3643. (b) Ojima, I.; Inaba, S.;
Nagai, M. Synthesis 1981, 545.
Ts
N
H
Ts
R
HN
O
1
LiCl (0.2 equiv), DMF, 70 °C
+
OMe
(6) (a) Hagiwara, H.; Inoguchi, H.; Fukushima, M.; Hoshi, T.;
Suzuki, T. Tetrahedron Lett. 2006, 47, 5371. (b) Hagiwara,
H.; Inoguchi, H.; Fukushima, M.; Hoshi, T.; Suzuki, T.
Synlett 2005, 2388.
OSiMe2H
R
3
OMe
(7) (a) Miura, K.; Tamaki, K.; Nakagawa, T.; Hosomi, A.
Angew. Chem. Int. Ed. 2000, 39, 1958. (b) Miura, K.;
Nakagawa, T.; Hosomi, A. J. Am. Chem. Soc. 2002, 124,
536.
7 (1.5 equiv)
Scheme 3 Mukaiyama-type Mannich reaction of dimethylsilyl ke-
tene acetal 7 under microwave irradiation
(8) Typical Experimental Procedure
To a stirred solution of N-p-toluenesulfonyl-p-chlorophenyl-
aldimine (1, 118 mg, 0.4 mmol) and LiCl (3.4 mg, 0.08
mmol) in DMF (1.5 mL) was added trimethylsilyl ketene
acetal 2 (130 mL, 0.6 mmol) at r.t. under nitrogen
atmosphere. After stirring for 13 h, the reaction was
quenched by adding H2O. The product was extracted with
EtOAc twice and the combined organic layer was washed
with H2O and brine, and then evaporated to dryness. Column
chromatography of the residue (eluent, EtOAc–n-hexane,
1:2) afforded b-amino ester 3 (145 mg, 91%).
(Scheme 3) proceeded more readily than the reaction of
trimethylsilyl ketene acetal 2, as shown in Table 5.
In summary, we have demonstrated a new Mannich reac-
tion of readily available and stable methylsilyl enol ether
with various arylaldimines catalyzed by lithium chloride
in DMF. Since lithium chloride is a neutral, cheap, non-
toxic, and shelf-stable catalyst compared to lithium car-
Synlett 2008, No. 10, 1520–1522 © Thieme Stuttgart · New York

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