Asymmetric conjugate addition of ketones to maleimides using diaminomethyleneindenedione organocatalyst

Article abstract of DOI:10.1055/s-0034-1380382

Abstract A novel diaminomethyleneindenedione (DMI) organocatalyst efficiently promotes the asymmetric conjugate addition of a ketone to a maleimide to afford the corresponding addition product in a high yield with up to 99% enantiomeric excess.

Full text of DOI:10.1055/s-0034-1380382

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1248–1252
letter
1248
K. Nakashima et al.
Letter
Synlett
Asymmetric Conjugate Addition of Ketones to Maleimides Using
Diaminomethyleneindenedione Organocatalyst
Kosuke Nakashima
Masahiro Kawada
PhCO2H
Shin-ichi Hirashima
Mana Kato
(0.1 equiv)
O
O
Yuji Koseki
F3C
N
N
Tsuyoshi Miura*
H
H
O
O
NH2
(0.2 equiv)
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, Japan
tmiura@toyaku.ac.jp
O
CF3
N
R
N
R
O
+
p-xylene, 40 °C, 48 h
O
O
up to 95% ee
Received: 29.01.2015
Accepted after revision: 22.02.2015
Published online: 19.03.2015
methylenemalononitrile (DMM) motif, which has an excel-
lent double-hydrogen-donating functional group for use
instead of the thiourea and squaramide motifs.8–11 Organo-
catalyst 1, which bears the DMM motif and a primary
amine group, accelerates reactions between aldehydes and
vinyl sulfone, giving the corresponding adducts with a high
degree of stereoselectivity.8 Furthermore, 1 promotes the
conjugate addition of a malonate to an α,β-unsaturated ke-
tone without requiring a reaction solvent, and Michael ad-
ducts with excellent enantioselectivities are produced.9 We
also reported that the pyrrolidine–DMM organocatalyst 2 is
a good catalyst for asymmetric conjugate additions of ke-
tones to nitroalkenes and stereoselective direct aldol reac-
tions of ketones with aromatic aldehydes.10 In addition, we
have described a cinchona–DMM organocatalyst for the
asymmetric conjugate addition of a 1,3-diketone to ni-
troalkenes.11 To demonstrate further benefits of the DMM
motif in organocatalysts, we attempted to use organocata-
lysts 1 and 2 (each have a DMM skeleton, Figure 1) to cata-
lyze the asymmetric conjugate additions of simple ketones
to maleimides.
We examined the abilities of the DMM organocatalysts
1 and 2 to catalyze the asymmetric conjugate addition of
acetone to N-phenylmaleimide (4a), as shown in Table 1.
Organocatalyst 1, which has a primary amine group, pro-
vided the desired product 5a in a low yield with moderate
enantioselectivity (Table 1, entry 1). Organocatalyst 2,
which has a secondary amine group, promoted the conju-
gate addition reaction, and no 5a was produced (Table 1,
entry 2). Unfortunately, neither 1 nor 2 was a good catalyst
for the Michael reaction of maleimides with acetone. How-
ever, a tendency was found for organocatalysts with prima-
ry amine groups, such as 1, to be suitable for catalyzing
conjugate addition. We presumed that introducing a more
powerful electron-withdrawing group than the cyano
DOI: 10.1055/s-0034-1380382; Art ID: st-2015-u0069-l
Abstract A novel diaminomethyleneindenedione (DMI) organocata-
lyst efficiently promotes the asymmetric conjugate addition of a ketone
to a maleimide to afford the corresponding addition product in a high
yield with up to 99% enantiomeric excess.
Key words organocatalyst, maleimide, conjugate addition, asymmet-
ric reaction, ketone
Asymmetric conjugate additions of nucleophiles to ma-
leimides using organocatalysts have attracted a great deal
attention,1 because organocatalysis is an environmentally
benign method, and the substituted succinimide derivative
addition products are valuable intermediates for synthesiz-
ing natural products and some candidates for use as clinical
drugs.2 Melchiorre and coworkers described their pioneer-
ing work in this area using natural cinchona alkaloids to
catalyze enantioselective conjugate additions of 1,3-dicar-
bonyl compounds to maleimides,3 and Michael additions of
various nucleophiles to maleimides have been devel-
oped.1,4–6 There have been several reports of asymmetric
conjugate additions of aldehydes to maleimides using or-
ganocatalysts,4 but successful conjugate additions of simple
ketones, such as acetone or cyclohexanone, to maleimides
have rarely been reported.5 Therefore, the development of a
novel organocatalyst for Michael reactions between ma-
leimides and simple ketones remains a challenging research
theme in organic chemistry.
Conversely, thiourea and squaramide are excellent mo-
tifs for efficient organocatalysts, and they function as dou-
ble-hydrogen-bonding donors that offer highly efficient
catalytic activities in various asymmetric reactions, allow-
ing the production of enantiomerically enriched mole-
cules.7 In recent years, we have developed the diamino-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1248–1252

1249
K. Nakashima et al.
Letter
Synlett
NC
CN
F3C
NH2
F3C
N
H
N
H
O
O
NH2
F3C
NC
CN
O
O
CF3
7
F3C
N
CF3
SMe
1
THF, reflux, 16 h
93%
H
N
N
H
MeS
SMe
H
HN
6
8
CF3
CF3
2
NH2
O
O
F3C
O
O
NH2
N
N
H
H
F3C
9
N
NH2
N
H
H
THF, r.t., 23 h
63%
NH2
CF3
3
Figure 1 Structure of organocatalysts
CF3
3
Scheme 1 Preparation of organocatalyst 3
group would be required to develop a more reactive or-
ganocatalyst. Organocatalyst 3, which has a 2-(diamino-
methylene)indene-1,3-dione (DMI) skeleton and contains
carbonyl groups rather than the cyano groups that are pres-
ent in 1, was found to be a good catalyst, giving the desired
adduct 5a in moderate yield with a high degree of enanti-
oselectivity (Table 1, entry 3). Here, we describe efficient
conjugate additions of simple ketones to maleimides using
the DMI organocatalyst 3 rather than the DMM motif.
We performed tests to determine the optimal condi-
tions for the enantioselective conjugate addition using 3, as
shown in Table 2. The conjugate addition reactions were
conducted using acetone and 4a as test reactants in the
presence of a catalytic amount of 3 and the chosen additive
at room temperature. p-Xylene was found to be the most
suitable of the reaction solvents that were tested (Table 2,
entries 2–9). We examined the effects of the presence of
different protic acids, and benzoic acid was found to be the
most suitable additive (Table 2, entries 9–13). Adding 0.2 or
0.05 equivalents of benzoic acid resulted in a slight loss of
enantioselectivity (Table 2, entries 14 and 15). Performing
the reaction under dilute conditions tended to improve the
enantioselectivity (Table 2, entry 16). Conducting the reac-
tion at 40 °C in the presence of 0.2 equivalents of 3 gave
both a high yield and a high degree of enantioselectivity
(Table 2, entry 18).
Considering these optimal conditions, we examined the
scope and limitations of the conjugate additions between
ketones and maleimides 4 (Table 3).14 The reaction between
acetone and N-benzylmaleimide (4b) proceeded smoothly
to afford the corresponding product 5b in high yield with
excellent enantioselectivity (Table 3, entry 2). We tested
maleimides with electron-withdrawing groups, such as
halogen atoms and trifluoromethyl groups, on the aromatic
ring. The reactions between maleimides with electron-
withdrawing groups and acetone proceeded smoothly giv-
ing the corresponding adducts 5c–e in good to high yields
and with a high degree of enantioselectivity (Table 3, en-
tries 3–5).
Table 1 Selection of Organocatalystsa
O
O
catalyst
(0.1 equiv)
PhCO2H
(0.1 equiv)
O
+
N Ph
N
Ph
O
toluene, r.t.
(5 equiv)
O
O
4a
5a
Entry
Catalyst
Time (h)
Yield (%)b
ee (%)c
1
2
3
1
2
3
170
170
95
16
57
–
n.d.d
59
89
a Reactions conditions: 4a (0.20 mmol), acetone (1.0 mmol), and catalyst
(0.020 mmol) in toluene (0.2 mL) were stirred at rt.
b Isolated yields.
c Determined by HPLC analysis.
d Not detected.
Organocatalyst 3 was easily prepared from the known
compound 612 in two steps, as shown in Scheme 1. The re-
action of 6 with 3,5-bis(trifluoromethyl)benzylamine (7)
under reflux conditions in THF provided intermediate 8 in
93% yield. Intermediate 8 was then reacted with (1R,2R)-
cyclohexane-1,2-diamine (9) to afford the desired DMI
organocatalyst 313 in 63% yield.
Organocatalyst 3 promoted the reaction between ace-
tone and maleimides bearing methyl or methoxy electron-
donating groups to provide the corresponding adducts 5f–h
in good to high yields and with a high degree of enantiose-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1248–1252

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K. Nakashima et al.
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Table 2 Optimization of Reaction Conditionsa
skeleton can then function as hydrogen-bonding donors,
giving a rigid interaction with the maleimide oxygen. These
interactions can control the direction (Si-face attack) from
which the enamine intermediates approach the maleimide.
This ultimately leads to the corresponding addition product
being formed with excellent enantioselectivity.
O
O
3
O
(0.1 equiv)
N
Ph
+
N
Ph
O
r.t., 48 h
(5 equiv)
O
O
5a
4a
Table 3 Conjugate Additions Using Organocatalyst 3a
Entry
Solvent
Additive (equiv)
Yield (%)b ee (%)c
O
3
PhCO
(0.1 equiv)
2H
1d
2
CH2Cl2
CH2Cl2
MeOH
MeCN
THF
none
12
32
37
44
61
58
63
60
50
70
51
trace
62
48
66
57
68
81
75
79
37
36
85
89
88
88
91
89
88
–
(0.2 equiv)
carbonyl
compound
(5 equiv)
+
N
R
product
PhCO2H (0.1)
PhCO2H (0.1)
PhCO2H (0.1)
PhCO2H (0.1)
PhCO2H (0.1)
PhCO2H (0.1)
PhCO2H (0.1)
PhCO2H (0.1)
MeCO2H (0.1)
4-O2NC6H4CO2H (0.1)
TFA (0.1)
p-xylene, 40 °C, 48 h
5
3
O
4
4
5
Entry
Product
Yield (%)b ee (%)c
6
toluene
o-xylene
m-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
O
7
8
N
Ph
1
O
81
92
92
95
90
86
92
89
86
9
10
11
12
13
14
15
16e
17e,f
18e,f,g
O
5a
O
4-MeOC6H4CO2H (0.1)
PhCO2H (0.2)
PhCO2H (0.05)
PhCO2H (0.05)
PhCO2H (0.1)
PhCO2H (0.1)
88
85
88
93
90
92
N
Bn
2
O
O
O
5b
N
Br
3
86
O
a Reaction conditions (unless otherwise noted): 4a (0.20 mmol), acetone
(1.0 mmol), and catalyst 3 (0.020 mmol) in solvent (0.2 mL) were stirred at
r.t. for 48 h.
O
O
5c
b Isolated yields.
c Determined by HPLC analysis.
Cl
d The reaction was carried out for 65 h.
e p-Xylene (0.4 mL) was used.
N
f The reaction was carried out at 40 °C.
g Catalyst 3 (0.2 equiv) was used.
4
79
O
O
O
5d
CF3
lectivity (Table 3, entries 6–8). Isobutyraldehyde reacted
with N-phenylmaleimide (4a) to afford the corresponding
adduct 5i in 74% yield with 94% enantiomeric excess (Table
3, entry 9). Cyclohexanone, another type of ketone, reacted
with 4a to provide the corresponding product 5j in 95%
yield with poor diastereoselectivity, but the enantioselec-
tivities for the syn and anti isomers were excellent (Table 3,
entry 10). The stereochemistry of the addition products
5a–j was determined by comparison with reported chiral-
phase HPLC retention times and optical rotation data.5
After considering the stereochemistry of the addition
products 5 we presumed that the conjugate addition of ace-
tone to a maleimide involving the DMI organocatalyst 3
progressed via a plausible transition state (Figure 2). The
primary amine group in 3 condenses with acetone to form
enamine intermediates. The two amine protons of the DMI
N
5d
6e
7
65
O
O
O
5e
N
51
80
O
O
O
5f
N
O
O
5g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1248–1252

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K. Nakashima et al.
Letter
Synlett
Table 3 (continued)
Acknowledgment
Entry
8
Product
Yield (%)b ee (%)c
The authors would like to thank Enago (www.enago.jp) for the En-
glish language review.
O
N
OMe
55
74
85
94
O
Supporting Information
O
Supporting information for this article is available online at
5h
http://dx.doi.org/10.1055/s-0034-1380382.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
O
H
O
References and Notes
N
Ph
9
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O
5i
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99 (anti)
10
95f
N
Ph
O
O
5j
a Reactions conditions (unless otherwise noted): 4 (0.20 mmol), carbonyl
compounds (1.0 mmol), and catalyst 3 (0.040 mmol) in p-xylene (0.4 mL)
were stirred at 40 °C for 48 h.
b Isolated yields.
c Determined by HPLC analysis.
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e The reaction mixture was stirred for 140 h.
f The ratio of syn and anti isomers was 51:49.
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O
O
F3C
N
H
N
H
NH
O
CF3
Si face attack
Ph
N
O
Figure 2 Plausible transition-state model
In conclusion, the DMI organocatalyst 3, which can easi-
ly be prepared from 6 in two steps, is an excellent catalyst
for the conjugate additions of ketones to maleimides, pro-
viding the corresponding addition products 5 in high yields
and with a high degree of enantioselectivity (up to 99% ee).
We have demonstrated that the DMI motif can function as a
more efficient double-hydrogen-bond donor than can the
DMM motif in conjugate additions to maleimides. In our
laboratory, we are currently attempting to apply organocat-
alysts with DMI motifs to other types of stereoselective re-
action and to develop additional novel DMI organocatalysts.
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(13) Organocatalyst 3
Yellow powder; mp 179–180 °C; [α]D29 –10.9 (c 1.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 9.61 (br s, 1 H), 9.02 (d, J = 9.8 Hz, 1
H), 7.87 (s, 3 H), 7.61–7.57 (m, 2 H), 7.53–7.49 (m, 2 H), 5.13
(dd, J = 6.0, 16.3 Hz, 1 H) 4.88 (dd, J = 6.5, 16.3 Hz, 1 H), 3.15–
3.06 (m, 1 H), 2.82–2.76 (m, 1 H), 1.89–0.87 (m, 10 H). 13C NMR
(100 MHz, CDCl3): δ = 192.4, 161.5, 140.3, 138.6, 132.4 (q, 2JC–F
33.7 Hz), 132.3, 127.1, 123.1 (q, JC–F = 273 Hz), 121.9, 120.5,
=
1
93.7, 61.3, 55.7, 47.7, 34.1, 33.2, 24.8, 24.2. Anal. Calcd for
C
25H23F6N3O2: C, 58.71; H, 4.53; N, 8.22. Found: C, 58.62; H,
4.52; N, 8.22.
(14) Typical Procedure of the Conjugate Additions to Maleimides
Using 3
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H. Synlett 2012, 23, 1108. (g) Serdyuk, O. V.; Heckel, C. M.;
Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051. (h) Tsakos, M.;
Kokotos, C. G. Tetrahedron 2013, 69, 10199.
To a mixture of N-phenylmaleimide (4a, 34.6 mg, 0.200 mmol)
and acetone (73.4 μL, 1.00 mmol) in p-xylene (0.4 mL) was
added organocatalyst 3 (20.5 mg, 0.040 mmol) and benzoic acid
(2.5 mg, 0.020 mmol) at r.t. After stirring in closed tube at 40 °C
for 48 h, the reaction mixture was directly purified by flash
column chromatography on silica gel with a 3:2 to 1:1 mixture
of hexane and EtOAc to afford 5a (37.3 mg, 81%) as a white
powder.
(8) Kanada, Y.; Yuasa, H.; Nakashima, K.; Murahashi, M.; Tada, N.;
Itoh, A.; Koseki, Y.; Miura, T. Tetrahedron Lett. 2013, 54, 4896.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1248–1252

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