Key words asymmetric synthesis - aldol reaction - organocatalyst - brine - Mannich reaction
Among various types of amine-based, chiral, and bifunctional organocatalysts, amino
Tf-amide organocatalysts are very reliable in various asymmetric transformations that
include asymmetric aldol, Mannich, and conjugate addition reactions.[1 ]
[2 ] In 2005, we reported the design of chiral binaphthyl-modified secondary amino Tf-amide organocatalysts of the type 1 , which effectively promote anti -selective direct asymmetric Mannich reactions and syn -selective direct asymmetric cross-aldol reactions (Figure [1 ]).[3 ] Later, we prepared structurally similar chiral biphenyl-modified secondary amino Tf-amide organocatalysts of type 2 .[4 ] Moreover, we also designed primary amino Tf-amide organocatalysts of the type 3 and 4 for asymmetric aldol reactions and asymmetric conjugate additions.[5 ]
[6 ] Compared to primary amino aliphatic Tf-amide organocatalysts of the type 3 and 4 , which are not applicable to asymmetric Mannich-type reactions, the catalysts 1 and 2 exhibit a high nucleophilicity of the secondary amino moiety in addition to the acidic, aromatic Tf-amide hydrogen atom. However,
due to the laborious synthesis of 1 and 2 ,[3 ]
[4 ] the design and synthesis of easily accessible reactive amine Tf-amide organocatalysts
represent a desirable research target.[7 ]
[8 ] Our strategy is based on the enhancement of the reactivity of the acidic Tf-amide
moiety by introducing an aromatic Tf-amide moiety as illustrated in primary amino Tf-amide organocatalysts of type 5 , which could accelerate asymmetric aldol and Mannich reactions.
Figure 1 Previously and newly designed amino Tf-amide organocatalysts 1 –5
Initially, we prepared various types of primary amino aromatic Tf-amide organocatalysts (6 –10 ) and evaluated their reactivity and selectivity in asymmetric direct aldol reactions
(Table [1 ]). For this purpose, a series of aldol reactions between 4-nitrobenzaldehyde and
cyclohexanone was carried out in the presence of catalysts 6 –10 in aqueous THF at room temperature (Table [1 ], entries 1–5).[9 ] Among these catalysts, 9 afford the highest stereoselectivity, giving the anti -aldol product (anti -11a ) with 97% anti -selectivity and 99% ee, albeit that 120 h are required for 60% yield (Table [1 ], entry 4). Subsequently, we carried out a solvent screening in order to improve
the reactivity (Table [1 ], entries 6–11). Among the solvents tested, aqueous solvents, in particular brine,
dramatically accelerated the rate of the asymmetric aldol reactions (Table [1 ], entries 9 and 10), furnishing anti -11a in high yield with excellent stereoselectivity.[10 ] However, the low reactivity and selectivity were observed in the reaction in anhydrous
DMSO (Table [1 ], entry 11).[5b ] Lowering the catalyst loading to 5 mol% did not affect the anti - or enantioselectivity (Table [1 ], entry 12). However, carrying out the reaction with 2 mol% of 9 slightly diminished the reactivity and afforded anti -11 with lower stereoselectivities (Table [1 ], entry 13).
Table 1 Optimization of the Catalysts and Reaction Conditions in the Asymmetric Direct Aldol
Reactions between 4-Nitrobenzaldehyde and Cyclohexanonea
Entry
Catalyst
(x mol%)
Solvent
Time
(h)
Yield (%)b
anti /syn
c
ee (%)d
1
6 (10)
THF/H2 O
168
32
75:25
89
2
7 (10)
THF/H2 O
168
8
45:55
11
3
8 (10)
THF/H2 O
48
96
90:10
97
4
9 (10)
THF/H2 O
120
60
97:3
99
5
10 (10)
THF/H2 O
120
96
93:7
86
6
9 (10)
DMSO/H2 O
40
92
97:3
99
7
9 (10)
EtOH/H2 O
120
72
87:13
83
8
9 (10)
neat
24
69
94:6
99
9
9 (10)
H2 O
20
91
97:3
99
10
9 (10)
brine
12
91
97:3
99
11
9 (10)
DMSO
72
62
95:5
98
12
9 (5)
brine
24
92
97:3
99
13
9 (2)
brine
48
92
97:3
99
a Unless otherwise specified, the asymmetric direct aldol reaction between cyclohexanone
and 4-nitrobenzaldehyde was carried out in the presence of 2–10 mol% of 6 –10 at room temperature.
b Isolated yield.
c The anti /syn ratio was determined by 1 H NMR analysis.
d % ee of major anti -isomer.
Subsequently, the scope of the asymmetric direct aldol reaction between cycloalkanones
and various benzaldehydes in brine solvent was investigated under the optimized conditions
using 5 mol% of 9 (Table [2 ]).[11 ] The reactions involving benzaldehydes bearing strong electron-withdrawing substituent(s)
at any position of the phenyl group furnished the corresponding aldol products 11 in high yields, with excellent anti - and enantioselectivity (Table [2 ], entries 1–7). Especially the heteroaromatic nicotinic and isonicotinic aldehydes
afforded 11 in excellent yield and selectivity (Table [2 ], entries 8 and 9). Even though the reactivity for 4-halobenzaldehydes was slightly
lower, these reactions still showed excellent stereoselectivity (Table [2 ], entries 10 and 11). When benzaldehyde was employed, the corresponding aldol product
11l (Ar = Ph; R1 and R2 = -(CH2 )4 -) was obtained in moderate yield with high anti - and enantioselectivity (Table [2 ], entry 12). The use of cyclopentanone as the aldol donor also showed high reactivity
and stereoselectivity for the corresponding aldol product 11m (Ar = 4-NO2 -C6 H4 ; R1 and R2 = -(CH2 )3 -; Table [2 ], entry 13). Cycloheptanone and acetone provided the corresponding aldol products
in good yield with high stereoselectivity, though 10 mol% of 9 were required (Table [2 ], entries 14 and 15).
Table 2 Asymmetric Direct Aldol Reaction of Cycloalkanone and Substituted Benzaldehydes Catalyzed
by Organocatalyst 9
a
Entry
Ar, R1 , R2
11
Time (h)
Yield (%)b
anti /syn
c
ee (%)d
1
4-NO2 -C6 H4 , –(CH2 )4 –
11a
24
92
97:3
99
2
4-CF3 -C6 H4 , –(CH2 )4 –
11b
30
96
95:5
99
3
4-CN-C6 H4 , –(CH2 )4 –
11c
30
96
97:3
98
4
4-CO2 Me-C6 H4 , –(CH2 )4 –
11d
48
88
97:3
99
5
2-NO2 -C6 H4 , –(CH2 )4 –
11e
24
88
97:3
99
6
3-NO2 -C6 H4 , –(CH2 )4 –
11f
48
84
98:2
99
7
C6 F5 , –(CH2 )4 –
11g
30
88
99:1
97
8
3-pyridyl, –(CH2 )4 –
11h
36
92
96:4
99
9
4-pyridyl, –(CH2 )4 –
11i
20
98
94:6
99
10
4-Cl-C6 H4 , –(CH2 )4 –
11j
48
55
97:3
99
11
4-Br-C6 H4 , –(CH2 )4 –
11k
48
72
97:3
99
12
C6 H5 , –(CH2 )4 –
11l
48
47
94:6
98
13
4-NO2 -C6 H4 , –(CH2 )3 –
11m
18
89
91:9
99
14e
4-NO2 -C6 H4 , –(CH2 )5 –
11n
48
92
88:12
89
15e
4-NO2 -C6 H4 , CH3 , H
11o
48
80
–
87
a Unless otherwise specified, the asymmetric direct aldol reaction between cycloalkanone
and the substituted benzaldehydes was carried out in brine in the presence of 5 mol%
of 9 at room temperature.
b Isolated yield.
c The anti /syn ratio was determined by 1 H NMR analysis.
d % ee of major anti -isomer.
e 10 mol% of 9 was used.
In order to demonstrate the applicability of the catalyst 9 in asymmetric transformations, we carried out asymmetric direct Mannich reaction
between cyclic ketones and α-imino ester 12 in the presence of catalytic amounts of 9 in THF at room temperature (Scheme [1 ]), which afforded the anti -Mannich products 13a (anti /syn = 93:7; 95% ee (anti )), 13b (anti /syn = 96:4; 97% ee (anti )), and 13c (anti /syn = 97:3; 92% ee (anti )) in high yield.[12 ]
Scheme 1 Asymmetric Mannich reaction between cyclic ketone and α-imino ester 13 catalyzed by organocatalyst 9 .
Scheme 2 Reagents and conditions : (a ) Ti(OEt)4 , THF, 70 °C or 90 °C; (b ) DIBAL-H, THF, –78 °C; (c ) (i ) HCl, dioxane, MeOH, rt; (ii ) Boc2 O, CH2 Cl2 , rt; (d ) (i ) Tf2 O, Et3 N, CH2 Cl2 , –78 °C; (ii ) TFA, CH2 Cl2 , rt.
