2
T. Kano et al. / Tetrahedron Letters xxx (2014) xxx–xxx
PMP
PMP
Br
N
Ph
27 mol%
O
N
O HN
5 (93% ee)
Ph
a
d
b,c
CO2Et
CO2Et
MeO
MeO
MeO
MeO
1,4-dioxane
rt, 4.5 h
N
N
i-Pr
i-Pr
4
5
7% (anti/syn = >20/1)
8% ee
Br
Br
(
)-6
( )-7
S
S
Scheme 2. Autocatalytic Mannich reaction of 3-methylbutanal with 4.
NH2
N
NHTf
N
design the more nucleophilic amino sulfonamide catalyst with the
biphenyl-based amine scaffold, whose nucleophilicity can be read-
ily tuned by introduction of electron-donating groups. It is known
that the high acidity of the triflamide group is crucial to obtain high
reactivity and stereoselectivity.2b Accordingly, both high nucleo-
philicity and acidity would be requirements of the catalyst design
along with high performance. As shown in Figure 1, since introduc-
tion of electron-donating groups on one phenyl ring having a trifla-
mide group would decrease the acidity of the triflamide group,10 it
seemed reasonable to introduce the electron-donating group on
the other phenyl ring. Thus we designed and synthesized a novel
amino sulfonamide, (S)-3, bearing a pyrrolidinyl group as an
electron-donating group.
e
MeO
MeO
MeO
MeO
(S)-3
N
N
(
)-8
( )-9
S
S
Scheme 3. Synthesis of (S)-3. Reagents and conditions: (a) benzophenone imine,
Pd2(dba)3, rac-BINAP, NaOt-Bu, toluene, 110 °C, 10 h, 68%; (b) pyrrolidine, Pd(OAc)2,
rac-BINAP, Cs2CO3, 1,4-dioxane, 100 °C, 36 h, 20%; (c) 1 M HCl, THF, 70 °C, 2 h, 89%;
(d) Tf2O, CH2Cl2, 0 °C to rt, 14 h, 58%; (e) NDMBA, Pd(OAc)2, PPh3, CH2Cl2, 30 °C,
10 h, 97%. NDMBA = 1,3-dimethylbarbituric acid.
Table 1
The requisite catalyst (S)-3 was prepared from (S)-6, mostly
according to the procedure for (S)-2 as shown in Scheme 3.9a Intro-
duction of a nitrogen atom was achieved by a palladium-catalyzed
coupling reaction of (S)-6 with benzophenone imine (1.5 equiv).
The palladium-catalyzed amination of (S)-7 with pyrrolidine
(10 equiv) and subsequent hydrolysis gave the triamine (S)-8.11
Treatment of (S)-8 with Tf2O afforded the triflamide (S)-9. Finally,
palladium-catalyzed deallylation of (S)-9 provided the biphenyl-
based amino sulfonamide (S)-3.12
The efficiency of this new catalyst (S)-3 was evaluated in the
asymmetric Mannich reaction.13 Thus, in the presence of (S)-3
(0.1 mol %), the reaction of 3-methylbutanal with 4 in 1,4-dioxane
at room temperature afforded the Mannich product 5 in moderate
yield with high enantioselectivity (Table 1, entry 3). Although the
yield was still not satisfactory, an unprecedentedly high catalytic
turnover number for this type of Mannich reaction was achieved.
The significant erosion of enantioselectivity could also be sup-
pressed as expected. Both the yield and enantioselectivity were
slightly improved at higher concentration (2 M) (entry 5). Only
0.4 mol % of (S)-3 was sufficient to obtain the desired Mannich
adduct 5 in high yield and enantioselectivity (entry 7). These
results suggested that the rate of the highly enantioselective
reaction catalyzed by (S)-3 was much faster than that of the less
enantioselective autocatalysis, and that catalyst (S)-3 furnished
Mannich reaction of 3-methylbutanal with 4a
PMP
PMP
O
N
O HN
0.1 mol% cat
CO2Et
CO2Et
solvent
rt, 4.5 h
i-Pr
i-Pr
4
5
Entry
Catalyst
Solvent
Yieldb (%)
anti/sync
eed (%)
1
2
3
4
(S)-1
(S)-2
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
1,4-Dioxane (1 M)
1,4-Dioxane (1 M)
1,4-Dioxane (1 M)
Toluene (1 M)
1,4-Dioxane (2 M)
1,4-Dioxane (4 M)
1,4-Dioxane (1 M)
1,4-Dioxane (1 M)
20
19
39
20
46
42
87
30
>20/1
14/1
18/1
12/1
12/1
12/1
12/1
15/1
64
79
91
56
93
71
98
24
5
6
7e
8f
a
Unless otherwise specified, the reaction of 3-methylbutanal (0.45 mmol) with 4
(0.15 mmol) was carried out in a solvent (150 L) in the presence of a catalyst
(0.15
l
l
mol) at room temperature (18ꢀ22 °C) for 4.5 h.
b
Isolated yield.
Determined by 1H NMR spectroscopy.
c
d
e
f
Determined by HPLC analysis using a chiral column. See Ref. 14 for details.
Use of 0.4 mol % of (S)-3.
Reaction performed at 30 °C.
the almost optically pure adduct in a sufficient amount before
the catalyst consumption or deactivation.
The reaction of hexanal (as a more reactive linear aldehyde)
with 4 also proceed to completion within one hour to give the
Mannich adduct 10 with high enantioselectivity in the presence
of 0.3 mol % of (S)-3 (Table 2, entry 1). Upon further investigation
of the catalyst loading, it was found that even 0.2 mol % of (S)-3
was sufficient to obtain a satisfactory yield and enantioselectivity
(entry 2). While the reaction catalyzed by only 0.1 mol % of (S)-3
proceeded gradually to give 10 in moderate yield with decreased
enantioselectivity, an exceptionally high catalytic turnover
number in the amine-catalyzed Mannich reaction was achieved
(entry 3). The reaction with 3-phenylpropanal also gave the
desired Mannich product 11 in high enantioselectivity (entry 4).
In summary, we have synthesized a novel biphenyl-based chiral
amino sulfonamide catalyst, (S)-3, and demonstrated its effective-
ness for the asymmetric Mannich reactions, in which a high cata-
lytic turnover number for this type of reaction was achieved. We
believe that the results obtained in this study are a valuable guide
EDG
acidity decreases
NHTf
NH
MeO
MeO
nucleophilicity increases
NHTf
NH
EDG
MeO
MeO
NHTf
NH
MeO
MeO
nucleophilicity increases
EDG
Figure 1. Design of the amino sulfonamide catalyst with increased nucleophilicity.
EDG = electron-donating group.