Scheme 1
.
Catalytic Enantioselective Three-Component
Synthesis of 1,3-Diamines
Table 1. One-Pot Synthesis of 1,3-Diamines: A Survey of
Reaction Conditionsa
EtOH
yield
yield
7 (%)b
yield
ee
entry
Ar
(equiv) 6 (%)b
1 (%)b c (%)g
,
1
2
3
4
5
6
7
8
9
p-MeOC6H4
Ph
17
17
17
17
17
10
5
6a (21) 7a (50) 1a (32)d
6b (77) 7b (11) 1b (51)d
77
92
92
90
93
94
95
96
p-ClC6H4
p-ClC6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
6c (85)
6d (85)
6e (72)
6e (63)
6e (55)
-
-
-
-
-
-
-
-
1c (82)d
1d (76)d
1e (70)d
1e (81)d
1e (64)d
We have recently reported a chiral phosphoric acid
5-catalyzed enantioselective Povarov reaction for the syn-
thesis of tetrahydroquinolines 7.6-8 Inspired by Lavilla’s
observation that a classic Povarov reaction pathway can be
17
17
1e (86)e
-
1e (72)e f 92
,
a General conditions: 2a/3/4/5 ) 1.1/1.0/1.5/0.1 in CH2Cl2 (c ) 0.1) at
0 °C. b Yields refer to chromatographically pure products. c Reduction
conditions: NaBH3CN (20 equiv), pTSA (10 equiv) in EtOH (c ) 0.05).
d Yields calculated from 6. 4b was used. e Sequential one-pot 4CR/reduction
process, yields calculated from 3. f Reaction performed at rt. g Enantiomeric
excess was determined by chiral HPLC analysis. For details see Supporting
Information.
(6) Phosphoric acid 5 was selected for its ability to efficiently catalyze
the Povarov reaction, see: Liu, H.; Dagousset, G.; Masson, G.; Retailleau,
P.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598
.
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interrupted by a suitable external nucleophile,9 we set out
to examine the 5-catalyzed enantioselective reaction of
benzaldehyde (2a), 4-methoxyaniline (3a), and benzyl N-
vinylcarbamate (4a) using EtOH (17 equiv) as a trapping
reagent to intercept the initial Mannich adduct.10 Under these
conditions, we did isolate the four-component adduct 6a as
a mixture of two diastereoisomers (21%), together with the
Povarov adduct 7a (R ) OMe, R1 ) Ph, R2 ) H, P ) Cbz,
50%, entry 1, Table 1). Using electron-neutral aniline (3b,
Ar ) Ph) as an input, the Mannich adduct 6a (R1 ) Ar )
Ph, R2 ) H, P ) Cbz) was isolated as a major product in
77% yield (entry 2).10 With electron-poor 4-chloroaniline
(3c, Ar ) 4-ClPh) and 4-nitroaniline (3d, Ar ) 4-NO2Ph),
the four-component Mannich adducts 6c and 6e were formed
exclusively at the expense of the tetrahydroquinolines (entries
3-5). Reducing the amount of EtOH resulted in the low yield
of 6 (entries 5-7). We stress that in the absence of EtOH
under otherwise identical conditions, only Povarov products
7 (R ) Cl or NO2) were obtained.
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