One-pot cross double-Mannich reaction of acetaldehyde catalyzed by a binaphthyl-based amino sulfonamide

Article abstract of DOI:10.1039/c2cc38370e

A one-pot cross double-Mannich reaction of acetaldehyde was developed, and densely functionalized 1,3-diamines were obtained as a single stereoisomer by use of axially chiral amino sulfonamide (S)-1 as catalyst. Using this catalyst, the one-pot Mannich reaction-aminoxylation was also realized.

Full text of DOI:10.1039/c2cc38370e

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One-pot cross double-Mannich reaction of acetaldehyde catalyzed by a
binaphthyl-based amino sulfonamide
Taichi Kano, Ryu Sakamoto, Yukako Yamaguchi, Ken-ichi Itoh and Keiji Maruoka*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An one-pot cross double-Mannich reaction of acetaldehyde
was developed, and densely functionalized 1,3-diamines were
obtained as a single stereoisomer by use of an axially chiral
amino sulfonamide (S)-1 as catalyst. With this catalyst, the
10 one-pot Mannich reaction-aminoxylation was also realized.
Asymmetric enamine catalysis has proven to be a powerful
strategy for the stereoselective αꢀfunctionalization of carbonyl
compounds and synthesis of highly valuable building blocks in
the past decade.1,2 Among carbonyl compounds, an abundant
15 carbon source acetaldehyde would be a potentially valuable
nucleophile, and has been utilized in various asymmetric
organocatalytic reactions such as aldol, Mannich and Michael
reactions for the past several years.3ꢀ7 With acetaldehyde the
double αꢀfunctionalization leading to the complex molecule with
20 a dense array of functionality would be possible. To the best of
our knowledge, however, only two examples of double αꢀ
functionalization, doubleꢀMannich reaction5d and Mannich
reactionꢀamination,5f as oneꢀpot multiple functionalization of
acetaldehyde have been reported. While the homo doubleꢀ
25 Mannich reaction was realized by using proline catalyst (Scheme
1A), attempted oneꢀpot cross doubleꢀMannich reactions with two
different imines by their sequential addition resulted in a complex
mixture including undesired singleꢀ and homo doubleꢀMannich
products (Scheme 1B).5d This result could be explained by the
30 incomplete consumption of the first imine. Recently we have
reported the Mannich reaction of acetaldehyde catalyzed by a
binaphthylꢀbased amine sulfonamide (S)ꢀ1.5c,8 Since most imines
are converted to the singleꢀMannich adducts without forming any
byꢀproducts in this condition, the oneꢀpot cross doubleꢀMannich
35 reaction would be expected by addition of the second imine
without the formation of the homo doubleꢀMannich products.
Herein we report the oneꢀpot cross doubleꢀMannich reaction of
acetaldehyde and the related reaction.
40
Scheme 1 DoubleꢀMannich reaction of acetaldehyde.
We first investigated oneꢀpot doubleꢀMannich reaction of
acetaldehyde with a Bocꢀprotected imine 2a. In the presence of 2
45 mol% of (S)ꢀ1, a mixture of 2a (1 equiv) in acetaldehyde was
stirred for 4 h at 0 °C to give the singleꢀMannich adduct 3, and an
excess amount of acetaldehyde was then removed by an
evaporator. The residue containing the singleꢀMannich adduct 3
was dissolved in CHCl3, and a solution of another equivalent of
50 NꢀBocꢀimine 2a in CHCl3 was slowly added using a syringe
pump over 4 h.9 After 2 h of stirring, the desired doubleꢀMannich
adduct 4 was obtained in low yield along with a substantial
amount of the unreacted singleꢀMannich adduct 3 (Scheme 2A).
This result indicated that catalyst (S)ꢀ1 was deactivated during the
55 first Mannich reaction. Thus, another 5 mol% of catalyst (S)ꢀ1
was added for the second Mannich reaction, and consequently,
the doubleꢀMannich adduct
4 was formed as a single
diastereomer in good yield with excellent enantioselectivity
(Scheme 2B). With this procedure for the oneꢀpot doubleꢀ
60 Mannich reaction in hand, we then turned our attention toward
the cross doubleꢀMannich reaction with two different imines,
which gives a densely functionalized 1,3ꢀdiamine.
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Table 2 Oneꢀpot doubleꢀMannich reaction of two different iminesa
Boc
A
O
HN
2 mol%
(S)-
Boc
+
Boc
Ph
O
N
O
HN
1
2a
Ph
+
3
0 °C
CHCl3
0 °C
Me
Ph
Boc
Ph
N
H
2a
3
4
8%
52%
Boc
B
O
HN
5 mol%
5 mol%
(S)- ,
1 2a
Yield (%)b
ee (%)c
Entry
Ar
Boc
+
Boc
Ph
O
N
O
HN
(S)-
1
1
2
3
4
5
6
Ph
Ph
54
55
47
46
45
57
99
99
99
99
98
99
0 °C
CHCl3
0 °C
Me
Ph
Boc
4ꢀMeOꢀC6H4
4ꢀMeꢀC6H4
2ꢀMeꢀC6H4
4ꢀClꢀC6H4
2ꢀnaphthyl
Ph
N
H
2a
3
4
75%, >99% ee
Scheme 2 DoubleꢀMannich reaction of acetaldehyde.
When the oneꢀpot doubleꢀMannich reaction was examined
using equiv of NꢀBocꢀimine 2a and NꢀPMPꢀimine 5,
respectively, the desired cross doubleꢀMannich adduct 6a was
obtained as a single diastereomer in moderate yield with virtually
perfect enantioselectivity (Table 1, entry 1).10 Use of 1.5 equiv of
5 resulted in an increase in the yield (entry 2).
a
b
c
See Supporting Information for datails.
Isolated yield.
1
30 Enantiomeric excess determined by HPLC analysis using chiral column.
5
The above mentioned oneꢀpot procedure was also applicable to
the other electrophile such as nitrosobenzene.11ꢀ13 When 1ꢀ
methylꢀ2ꢀnitrosobenzene14 was employed instead of NꢀPMPꢀ
imine 5, the Mannich reactionꢀaminoxylation products were
35 obtained in excellent diastereoꢀ and enantioselectivity (Scheme
3).15 In this oneꢀpot reaction, use of 1ꢀmethylꢀ2ꢀnitrosobenzene as
an aminoxylating agent and benzaldehyde as an additive was
important to improve the reaction yield, since the Mannich
product 7 as the starting material for the aminoxylation could be
40 consumed by undesired formation of aminals with the Mannich
reactionꢀaminoxylation product 8 having an amino and aminoxyl
group. In the case of the reaction using 1ꢀmethylꢀ2ꢀ
nitrosobenzene, the sterically hindered oꢀtolyl group on 8
prevents or slows such aminal formation. Additionally, excess
45 amounts of benzaldehyde (5 equiv) instead of 7 can form the
Table 1 Oneꢀpot doubleꢀMannich reaction of two different iminesa
10
Yield (%)b ee (%)d
Entry
Temp (°C)
Imine 5 (equiv)
1
0
1
42
54
36
26
40
32
99
99
99
99
99
99
2
0
1.5
2
3
0
corresponding aminal with the product
consumption of 7.
8
to inhibit the
4
r.t.
–20
0
1.5
1.5
1.5
5
6d
P
O
HN
a
b
c
5 mol%
(S)-
5 mol% (S)-
1
Ar'NO, PhCHO
P
P
See Supporting Information for datails.
Isolated yield.
O
N
O
HN
1
d
Ar
NHAr'
Enantiomeric excess determined by HPLC analysis using chiral column.
+
Use of 10 mol% of (S)ꢀ1 for the first Mannich reaction and no additional
catalyst for the second Mannich reaction.
0 °C
CHCl3, 0 °C
O
Me
Ar
Ar
Ar' = 2-Me-C6H4
7
8
15
Under the optimized conditions, the cross doubleꢀMannich
reaction of various NꢀBocꢀimines 2 was examined, and the results
are summarized in Table 2. All reactions examined proceeded
smoothly to give the cross doubleꢀMannich adducts 6 as a single
diastereomer in moderate yield with excellent enantioselectivity.
Ar = 4-MeO-C6H4, P = Boc: 47%, dr = >20/1, 99% ee
Ar = Ph, P = Cbz: 44%, dr = >20/1, 99% ee
Scheme 3 Oneꢀpot Mannich reactionꢀaminoxylation catalyzed by (S)ꢀ1.
50
The absolute configuration of doubleꢀMannich product 4 was
determined by comparison with that obtained by the reaction
catalyzed by
20 With this method, three contiguous stereocenters could be
constructed in oneꢀpot operations.
L
ꢀproline.5a,5d Based on the observed
stereochemistry, transition state models can be proposed as
shown in Scheme 4. First, the Si face of NꢀBocꢀimine approaches
55 the sꢀcisꢀenamine intermediate as oriented by the acidic proton of
triflamide group (TS1).5c,8b The resulting Mannich product 9 then
forms Eꢀsꢀcisꢀenamine. The Si face of the second imine
approaches the enamine intermediate in a similar manner (TS2),
and consequently, the CꢀC bond forming reaction takes place on
60 the Si face of the s-cisꢀenamine, giving the doubleꢀMannich
adduct. Since only a single stereoisomer was detected, both
Mannich reactions were found to proceed in virtually perfect
stereoselectivity.
25
2
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8
60
65
70
75
80
85
9
Since an excess amount of NꢀBocꢀimine 2a is prone to deactivate (S)ꢀ
1 by formation of the aminal, a syringe pump was used for the slow
addition of 2a.
Scheme 4 Plausible transition state models.
10 In our previous study on the Mannich reaction between aldehydes
and NꢀPMPꢀimine 5 catalyzed by (S)ꢀ1, the reaction using ethereal
solvents showed excellent diastereoꢀ and enantioselectivity, and
therefore, THF was selected as the optimal solvent; see, ref 8a.
11 For reviews, see: (a) W. Adam and O. Krebs, Chem. Rev., 2003, 103,
4131; (b) P. Merino and T. Tejero, Angew. Chem., Int. Ed., 2004, 43,
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In summary, we have developed oneꢀpot cross doubleꢀMannich
reaction of acetaldehyde with two different imines catalyzed by
the axially chiral amino sulfonamide (S)ꢀ1. In the present doubleꢀ
Mannich reaction, densely functionalized diamines having three
contiguous stereocenters could be obtained as
stereoisomer in oneꢀpot operations. Related oneꢀpot Mannich
reactionꢀaminoxylation of acetaldehyde has also been achieved
5
a single
10 and the utility of the present method was demonstrated.
Notes and references
Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto 606-8502, Japan. Fax: +81-75-753-4041; Tel: +81-75-753-
4041; E-mail: maruoka@kuchem.kyoto-u.ac.jp
15 † Electronic Supplementary Information (ESI) available: Experimental
details. See DOI: 10.1039/b000000x/
1
2
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90 15 The oneꢀpot Mannich reactionꢀaminoxylation products
8 were
20
25
30
35
40
45
isolated as the corresponding alcohol after reduction by NaBH4.
3
4
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5
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