Efficient Mannich reaction using iminium salts generated from glycine derivatives

Article abstract of DOI:10.1246/cl.2011.351

Iminium salts generated by the oxidation of amino ketene silyl acetals underwent a facile Mannich reaction with another ketene silyl acetal to give aspartic acid derivatives in good yields. The diastereoselectivities were controlled to some extent by usin

Full text of DOI:10.1246/cl.2011.351

doi:10.1246/cl.2011.351
Published on the web March 2, 2011
351
Efficient Mannich Reaction Using Iminium Salts Generated from Glycine Derivatives
Makoto Shimizu,* Toshiki Kusunoki, Mari Yoshida, Koichi Kondo, and Isao Mizota
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507
(Received December 27, 2010; CL-101094; E-mail: mshimizu@chem.mie-u.ac.jp)
NBn
2O
OSi
OR
Iminium salts generated by the oxidation of amino ketene
silyl acetals underwent a facile Mannich reaction with another
ketene silyl acetal to give aspartic acid derivatives in good
yields. The diastereoselectivities were controlled to some extent
by using an appropriate isomer of ketene silyl (thio)acetals.
EtO2C
EtO2C
OR
NBn2
+
DDQ
NBn2
EtO
EtO2C
NBn
2O
-OAr
TBSO
OSi
SR
SR
Increasing interest in controlling the reactivity of imino
derivatives involving iminium salts1 coupled with the need to
construct amino diacid skeletons such as aspartic acid2 in an
efficient manner prompted us to report our recent approach to
this class of compounds using iminium salts generated by the
oxidation of glycine derivatives. We have recently disclosed a
simple and useful approach to alkoxycarbonyl iminium salts3
using the oxidation of the ketene silyl acetals derived from N,N-
dibenzylglycinate with DDQ4 or BPO (benzoyl peroxide). The
alkoxycarbonyl iminium salts are excellent acceptors of electro-
philes such as alkylaluminums, Grignard reagents, allylmetals,
and metal cyanides. For the preparation of amino esters and
amino ketones, the Mannich reaction offers one of the most
straightforward methods. To the best of our knowledge, little is
known about the diastereoselectivity of the Mannich reaction
(addition to iminium salts), although stereocontrol in the
addition reactions to imines has been achieved using several
promoters.5
We have now found that the alkoxycarbonyl iminium salts
prepared as above work in an efficient manner in the Mannich
reaction to give aspartic acid derivatives and ¡-amino-£-
ketoesters in good yields with good diastereoselectivities
(Scheme 1). Table 1 summarizes the reaction of the iminium
salts with a variety of ketene silyl (thio)acetals and silyl enol
ethers.
The reactions were carried out either in the presence of
BF3¢Et2O in DME (conditions A) or in its absence in DMF
(conditions B). In general, although better product yields were
obtained under conditions A, use of silyl enol ethers recorded
comparable results under both conditions (Entries 23-26).
Regarding the alkoxy group of the ketene silyl acetal 2, only
slight differences in the product yields were observed among the
methoxy, ethoxy, and tert-butoxy derivatives (Entries 1-6). On
the other hand, use of their ethylsulfanyl counterpart resulted in
an enhanced product yield (Entry 7), although a prominent
effect was not observed under conditions B (Entry 8). Among
the substituents at the nitrogen, the dibenzyl and morpholino
derivatives gave better results (Entries 3 and 17). In terms of
further functional group transformations, dibenzyl or diallyl
derivative appeared to be the substrate of choice. Under similar
conditions, diastereoselectivity was next examined using trisub-
stituted ketene silyl acetals.
Scheme 1. The present strategy.
Table 1. Addition of TMS-enolatesa
R2N
EtO2C
O
NR2
+
OTMS
DDQ (1.0 equiv)
R1
R2
EtO
R2
R1 R1
Solvent, −55 °C to rt, 17.0 - 18.0 h
R1
TBSO
Condns A: with BF3.OEt2 (2.0 equiv) in DME
3
1
2 (2.0 equiv)
.
Condns B: without BF3 OEt2 in DMF
Entry R, R
R1 R2
Conditions 3/%b
1
2
3
4
5
6
7
8
9
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Me, Me
Me, Me
Allyl, Allyl
Allyl, Allyl
-(CH2)4-
-(CH2)4-
-(CH2)5-
-(CH2)5-
Me OMe
Me OMe
Me OEt
Me OEt
Me OtBu
Me OtBu
Me SEt
Me SEt
Me OEt
Me OEt
Me OEt
Me OEt
Me OEt
Me OEt
Me OEt
Me OEt
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
68
59
81
59
66
54
81
60
57
55
69
52
46
50
70
64
78
49
66
50
71
56
70
74
67
65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-(CH2)2O(CH2)2- Me OEt
-(CH2)2O(CH2)2- Me OEt
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
Bn, Bn
H
H
H
H
H
H
H
H
OEt
OEt
SEt
SEt
tBu
tBu
Ph
Ph
aSee a typical procedure in the Supporting Information (SI).9
bIsolated yields.
mixtures of diastereomers (Entries 1, 2, 4, and 7). However, the
use of ketene silyl thioacetal with BF3¢Et2O in CH2Cl2 recorded
good diastereoselectivity, where noteworthy is the fact that
CH2Cl2 appears to be the solvent of choice for syn-selectivity
(Entry 8). Regarding the ester group in the ketene silyl acetal 2,
use of the methyl propionate derivative gave a better result
As can be seen from Table 2, better diastereoselectivities
were observed with (Z)-ketene silyl acetals (Entries 9-18),
whereas use of their (E)-counterparts usually gave almost 1:1
Chem. Lett. 2011, 40, 351-353
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

352
Table 2. Diastereoselective Mannich reaction using 1aa
Table 3. Addition of enamines: comparison of reaction con-
ditions
NBn2
OSi
NBn2O
DDQ (1.0 equiv)
EtO
R1
R3
EtO2C
R3
R1 R2
solvent, −55 °C to rt, 12.5 - 18.0 h
OTBS
R2
Conditions A: with BF3•OEt2 (2.0 equiv) in DME
Conditions B: without BF3•OEt2 in DMF
Conditions C: with Et2AlCl (2.0 equiv) in DME
3
1a
2 (2.0 equiv)
Conditions D: with BF3•OEt2 (2.0 equiv) in CH2Cl2
Conditions E: without BF3•OEt2 in DME
Entry
Solvent
Temp
Yield/%
Dra
Entry R1
R2 R3
Si
Conditions 3/%b anti:sync
1
2
3
4
5
6
7
8
9
CH2Cl2
Toluene
MeCN
EtCN
DME
rt
rt
rt
rt
rt
23
25
30
31
15
29
53
72
0
38:62
45:55
45:55
43:57
45:55
58:42
40:60
37:63
®
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
Me
Me OEt TBS
Me OEt TBS
Me OEt TMS
Me OEt TMS
Me OMe TMS
Me OMe TMS
Me SEt TMS
Me SEt TMS
A
B
A
B
A
D
A
D
A
B
A
B
C
A
B
C
A
C
A
A
A
A
E
57
47
40
55
28
23
68
74
50
51
36
38
48
61
35
66
43
52
40
57
58
60
57
37
18
13
c
56:44
51:49
39:61
46:54
40:60
28:72
50:50
30:70
81:19
75:25
88:12
77:23
84:16
82:18
79:21
85:15
90:10
83:17
49:51
47:53
42:58
14:86
27:73
47:53
39:61
8:92
DMF
rt
EtCN
EtCN
EtCN
¹78 °C to rt
0 °C to rt
reflux
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt TBS
OEt TBS
OMe TBS
OMe TBS
OMe TBS
OMe TMS
OMe TMS
OMe TBS
OEt TBS
OEt TBS
10 Me
11 Me
12 Me
13 Me
14 BnO
15 BnO
16 BnO
17 BnO
18 BnO
19 Me
20 Me
21 Me
22 Me
23 Me
24 Me
25 Me
26 Me
aDiastereomer ratio: determined on the basis of isolated
products on TLC.
Table 4. Addition of various enamines
Bn2N
OEt
DDQ (1.1 equiv), Enamine (1.0 equiv)
3
OTMS
Enamine
1
EtCN, 0 °C to rt, 10 h
Entry
Product
Yield/%
Dra
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
DMS
TMS
TBS
TIPS
DMS
TMS
TBS
NBn2O
1
2
3
72
37:63
45:55
38:62
N
36b
42c
EtO2C
NBn2O
NBn2O
O
N
EtO2C
EtO2C
E
E
E
4
5
6
83
63
76
36:64
38:62
33:67
TIPS
O
N
aSee a typical procedure in SI.9 bIsolated yields. Determined
1
by HPLC and/or H NMR (ref. 6).
O
N
(Entry 11), whereas its ethyl counterpart recorded the best
selectivity of 90:10 in the case with a glycolate derivative
(Entry 17). Interestingly, the use of the TIPS enol ether gave the
adduct with good syn-selectivity (Entry 22).
Bn
2N
EtO2C
Use of enamines as nucleophiles was next examined
(Tables 3 and 4). The addition of enamines was sensitive to
the reaction solvents and temperatures, and among the reaction
conditions screened, the reaction in propionitrile at 0 °C to rt
gave the best result (Entry 8, Table 3).
aDiastereomer ratio: determined on the basis of isolated
products on TLC. In the presence of BF3¢Et2O (1.0 equiv).
cIn the presence of AlCl3 (1.0 equiv).
b
Under these conditions the enamines screened here gave the
Mannich adducts in good yields where use of 1 equiv of the
enamine effected completion of the addition reaction, although
the diastereoselectivity was not high (Table 4).
Bn2N
CN
OEt
Bn2N
CN
OEt
Bn2N
O
OEt
OTBS
.
NC
O
NC
O
OTBS
OTBS
O
NC
NC
+
1a
Cl
O
LA
LA
1a
Cl
Cl
Cl
Cl
Cl
Since the formation of the iminium species 6 was observed
O
-
LA
by the 1H and 13C NMR spectra of the reaction mixture; i.e., the
Bn2N
O
OEt
1
signals appeared at 9.27 and 193.6 ppm in the H and 13C NMR
Bn2N
CO2Et
Cl
spectra, respectively,7 a possible reaction mechanism is shown
in Scheme 2.
OTBS
O
+
NBn2
CO2Et
-OAr
NBn2
CO2Et
Nu-
Cl
NC
Cl
H
Nu
NC
NC
Cl
3
6
NC
OMXn
First, DDQ reacts with the ketene silyl acetal 1a either via a
one-electron transfer or an ionic intermediate4 to give the N,O-
acetal 5, which collapses to the iminium salt 6. The subsequent
nucleophilic attack with ketene silyl acetals gives an addition
O
-
1H NMR: 9.27 ppm
13C NMR: 193.6 ppm
5
LA
Scheme 2. A possible reaction mechanism.
Chem. Lett. 2011, 40, 351-353
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

353
Bn
Bn
H
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Bn
H
Bn
N
ArO-
OEt
N
ArO-
OEt
Me
Me
H
H
O
EtO
O
O
EtO
O
Met
2
Met
TS-B
TS-A
(Z)-Enolate
(E)-Enolate
NBn2
CO2Et
NBn2
CO2Et
EtO2C
EtO2C
anti
syn
Scheme 3. Possible transition states for diastereoselectivity.
product 3. Regarding the diastereoselectivity, although there is
much room to define appropriate transition state models, we
explain the present diastereoselectivity using the following
models (Scheme 3).
Addition reactions of both (E)- and (Z)-ketene silyl acetals
would proceed via the chelated intermediates in anti-periplaner
fashions (TS-A and TS-B). Although the chelation would be
weak when the silicon-metal exchange reaction would not be
facile,8 these intermediates may lead to one of the explanations.
In conclusion, we have found that iminium salts generated
by the oxidation of amino ketene silyl acetals undergo a facile
Mannich reaction with another ketene silyl acetal to give aspartic
acid derivatives in good yields. The diastereoselectivity studied
here shows the first example where the diastereoselectivities in
the addition reaction to the iminium salts is controlled to some
extent by using the appropriate geometry of ketene silyl
(thio)acetals. In addition, enamines also act as good nucleophiles
in the present Mannich addition. This study opens a new entry
into the use of iminium salts for the diastereoselective approach
to this important class of amino esters and ketones.
3
4
5
6
This work was supported by Grant-in-Aids for Scientific
Research (B) and on Innovative Areas from JSPS and MEXT.
References and Notes
1
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For determination of the relative stereochemistry, see: a)
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7
8
For the 1H and 13C NMR spectra of iminium salts, see ref. 1j
and earlier references therein.
S. Kobayashi, K. Manabe, H. Ishitani, J.-I. Matsuo, in
Science of Synthesis, ed. by I. Fleming, Georg Thieme
Verlag KG, Stuttgart, 2002, Vol. 4, pp. 317-369, and refer-
ences therein.
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
9
Chem. Lett. 2011, 40, 351-353
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/