.
Angewandte
Communications
Table 1: Catalytic reaction between imidazolones 2–14 and nitroolefins 16.[a]
In addition to these observa-
tions, it was also found that Michael
acceptors, which are less reactive
than nitroolefins, may participate in
these reactions with equal effective-
ness (Table 2). For example, the
reaction of 2A with the acrylate
surrogate 32,[15] promoted by cata-
lyst C1, provided, after desilylation
of the intermediate adduct, the
product 33 in good yield (74%),
albeit with moderate enantioselec-
tivity (84% ee).[16] Improved selec-
tivity (91% ee) was observed using
C2, and even better selectivity was
obtained with C3[17] (94% ee) and
the new catalyst C4 (96% ee,
Table 2, entry 1). Under these
latter conditions, the enone 32 also
reacted efficiently with other imid-
azolones (entries 2–7).[18]
Entry
Prod.
R1
R2
R3
Yield [%][b]
d.r. [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
17a
17b
17c
17h
Me
Me
Me
Me
Me
Me
Me
Me
Ph
97
91
82
93:7
90:10
94:6
60:40
50:50
80:20
92:8
98:2
92:8
93:7
98:2
75:25
80:20
98:2
92:8
90:10
93:7
50:50
80:20
98:2
99
96
98
4-MeC6H4
4-BrC6H4
iPr
66[e]
77[e,f]
58[e,g]
82
96
À90
À90
95
98
86
92
98
94
18d
19a
20 f
21g
22a
22i
Bn
Me
Me
Me
Me
Bn
3-MeC6H4
Ph
2-thienyl
2-furyl
Ph
nHex
iBu
iPr
Me
Me
81
84
75
85
The chemical manipulation of
9
adducts was briefly investigated to
illustrate the synthetic potential of
this approach (Scheme 2). Thus,
nucleophilic displacement of the
thioether group served to establish
concise routes to various classes of
heterocycles of interest in medicinal
chemistry,[19] that is, imidazolidi-
nones (40, 41), 2-aryl imidazolones
(43), 2-amino imidazolones (44),
and hydantoins (45–47). Eventually,
acid hydrolysis of 41 afforded the
amino amide 42 with all the above
reactions proceeding in good yields.
Similarly, the hydantoins 48–50
could be obtained upon smooth
hydrolysis of the corresponding
adducts 33–35. Further oxidative
elaboration of the ketol moiety in
these products[9,15] led to the corre-
sponding carboxylic acids 51/52, the
aldehyde 53, and ketone 54. The
present catalytic approach thus
facilitates a novel entry for the
rapid construction of functionalized
10
11
12
13
14
15
16
17
18
19
20
21
Bn
c-C6H11
40[e]
40[e,f]
78
À90
23a
24a
Me
Me
iBu
CH2CH CH2
Ph
Ph
93
=
77
94
95
92
94
65[h]
65
25a
25j
Me
Me
Ph
Ph
Ph
nPr
51[e]
51[e,g]
83
À90
26b
27a
Me
Me
4-ClC6H4
3-MeOC6H4
4-MeC6H4
Ph
98
85
88:12
95
[a] Reactions conducted on a 0.3 mmol scale in 0.5 mL CH2Cl2 (mol ratio of imidazolone/nitroolefin/C1
catalyst 1:2:0.1) unless otherwise stated. [b] Yield of the isolated major diastereomer. [c] Determined by
1H NMR (300 MHz) analysis of the crude reaction mixture. [d] Determined by HPLC analysis using
a chiral stationary phase. [e] Reaction run at 508C in 1,2-dichloroethane. [f] Using ent-C1. [g] Using C2.
[h] Reaction run at 4 mmol scale using 5 mol% catalyst (reaction time 30 h).
were all tolerated (entries 11–17, 20, and 21). Also bicyclic
imidazolones, such as 13A and 14A, provided the corre-
sponding adducts (28a, 28e, 29a) with equal effectiveness.
These latter products represent quaternary proline and
related derivatives which cannot be accessed directly through
established catalytic methodologies.[14] Of practical interest,
the catalyst loading may be reduced from 10 to 5 mol%
without affecting the results (entry 15 versus 16). In contrast,
the nature of the S-substituent group appears to have limited
impact on stereoselectivity as results obtained from the
imidazolones 2B and 2C, to produce 30a and 31a, respec-
tively, are comparable to those obtained with 2A.
5,5-disubstituted hydantoins, a well-recognized scaffold for
drug discovery.[20] Finally, the X-ray structure analyses of
hydantoins 46 and 51 served to establish the configuration of
the adducts.[21]
On the other hand, given that the new template allows
direct access to N-substituted quaternary a-amino acid
derivatives, additional ways for the elaboration of adducts
can be envisaged in which the NR2 moiety plays a strategic
role. For instance (Scheme 3), from the common adduct 47,
the densely functionalized bi- (55) and tricyclic (56)
compounds were prepared in two and four steps, respec-
tively.[9]
2
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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