COMMUNICATION
Table 1. a-Selective direct allylation reaction of 2-methylidene-N-aryl
succinimide 1a with N-Eoc imines.
hypothesized that the a-protons of these methylidene-succi-
nimides were acidic enough to be activated by an organo-
base. To support this hypothesis, a deuteration–isomeriza-
tion experiment was designed. A 1:1 mixture of N-(3,5-di-
fluorophenyl)methylidene-succinimide (1a) and triethyla-
mine was monitored in a solvent mixture of CDCl3/D2O
(3:1) by NMR spectroscopy. Results indicated that both the
a-protons and g-protons in methylidene-succinimide 1a
were deuterated under these basic conditions. Further analy-
sis of the isomerization process revealed the existence of in-
termediate 3. After 6 h, the ratio between protons a, b, and
c (see Figure 1) was observed to be 1:0.5:1 and this provid-
ed support for this intermediate. As the reaction time in-
creased, the equilibrium shifted towards maleimide 2 and
full deuteration was achieved for all protons.
Encouraged by this observation, we envisioned a Brønst-
ed-base catalyzed asymmetric allylic addition using N-aryl
alkylidene-succinimides as nucleophiles. We have shown
previously that chiral guanidine[11] can catalyze a variety of
reactions with high enantioselectivities. Herein, we demon-
strate that bicyclic guanidine can catalyze the direct asym-
metric allylic addition of N-aryl alkylidene-succinimides to
imines with high enantioselectivities.
Entry
1
2
Product
Time
[h]
Yield
[%][a]
ee
[%][b]
1
2
3
4
5
6
7
8
9
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
4a
4a
4a
4a
4b
4c
4d
4e
4 f
4g
6a
6b
6c
6d
6e
6 f
6g
6h
6i
24
48
24
10
10
10
10
10
10
10
92
80
83
92
90
90
91
90
91
91
86
84
81
87
77
77
83
87
82
81
10
6j
[a] Yield of isolated product. [b] Determined by chiral HPLC. Absolute
configurations were determined by X-ray structure analysis (see the Sup-
porting Information).
Preliminary studies using methylidene-succinimide 1a re-
vealed that direct allylic addition to N-protected imines re-
sulted in amine 6g as the only product by an a-addition fol-
lowed by a 1,3-proton shift (Scheme 1). No product resulting
background reaction, namely the isomerization of the succi-
nimides to maleimides. The substituents on the phenyl ring
affected the reaction rates as well as enantioselectivities
(Table 1, entries 1-4). Among these subsituents, 1a bearing a
3,5-difluorophenyl aryl group resulted in adducts with the
highest enantiomeric excess. Thus, methylidene-succinimide
1a was selected to investigate the reaction with a series of
N-Eoc imines (Table 1, entries 5–10). No g-addition products
were observed and good enantioselectivities were obtained
with all of the imines.
Subsequently, we examined the influence of a substituted
double bond on the succinimides towards this Mannich-type
allylic addition reaction. N-Aryl benzylidene-succinimides
7a–c (Table 2) were prepared in a simple, one-step and E-
selective protocol.[13] A 1,3-proton shift, after the initial ad-
dition, was no longer favorable due to this extra conjuga-
tion. A highly diastereoselective reaction was obtained with
a diastereomeric ratio that was generally >98:2. The anti-se-
lective reaction provided rapid entry to amines with two
contiguous chiral centers in high enantioselectivities.
When the phenyl group on the double bond was replaced
with an ester group, the reaction rate was greatly enhanced
(Table 3). Reactions were complete within 4 h even with a
lower catalyst loading. The ratio of N-Eoc imines was re-
duced to 1.5 equivalents without detecting any isomerized
product. However, the enantioselectivities were compro-
mised. Only the a-addition product was observed with a 1,3-
proton shift reaction proceeding favorably to provide malei-
mides 10a–g.
Scheme 1. Proposed reaction sequences of a-selective direct allylation re-
action of methylidene-succinimide 1a.
from the g-addition was observed. N-3-Ethylpentan-3-yloxy-
carbonyl (Eoc) imines were previously shown by our group
to be excellent electrophiles in bicyclic guanidine-catalyzed
enantioselective Mannich reactions. They were also crucial
in this experiment in improving enantioselectivities.[12]
In the presence of 10 mol% of guanidine 5, N-aryl meth-
ylidene-succinimides 1a–d added to N-Eoc imines with high
regio- and enantioselectivities (Table 1). However, three
equivalents of imines were required to compete with the
Chem. Eur. J. 2010, 16, 12534 – 12537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12535