Asymmetric Michael addition of aldehydes to maleimides in primary amine-based aqueous ionic liquid-supported recyclable catalytic system

Article abstract of DOI:10.1016/j.mencom.2017.09.014

A primary amine-based aqueous ionic liquid-supported recyclable catalytic system for asymmetric Michael addition of aldehydes to maleimides has been developed. The best enantioselectivity (up to 84% ee) was attained at the [bmim]BF₄/water 2: 1 (v/v) ratio.

Full text of DOI:10.1016/j.mencom.2017.09.014

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 473–475
Asymmetric Michael addition of aldehydes to maleimides
in primary amine-based aqueous ionic liquid-supported
recyclable catalytic system
Sergei V. Kochetkov, Alexander S. Kucherenko and Sergei G. Zlotin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: zlotin@ioc.ac.ru
DOI: 10.1016/j.mencom.2017.09.014
O
O
N
Me
+
A primary amine-based aqueous ionic liquid-supported
recyclable catalytic system for asymmetric Michael addi-
tion of aldehydes to maleimides has been developed. The
best enantioselectivity (up to 84% ee) was attained at the
[bmim]BF4 /water 2:1 (v/v) ratio.
N
O
N
O
N
R3
O
4
(S)
PF6
H
NH2
R1
20 mol%
R3
+
N
R2
9 examples
up to 84% ee
over 9 cycles
O
R1
[bmim]BF4 / H2O (2 : 1 v/v)
room temperature, 20 h
R2
O
Asymmetric organocatalysis is a mainstream of modern organic
chemistry.1 Many organocatalysts exhibit high level of stereo-
induction and are tolerant to highly polar media, such as ionic
liquids (ILs)2 and water.3 Usage of mixed IL/water solvent systems
for catalytic reactions4 is especially attractive as it allows one to
significantly reduce IL consumption and, in some cases, enhance
chemical yield and/or enantiomeric excess of products. More-
over, optimal combination of organocatalyst and aqueous IL
may facilitate catalyst recovery and reuse in the same or similar
catalytic reactions.5
amines 1, 2 bearing primary amino group (Figure 1).17 Recently,
IL-supported analogues 3 and 418 of these catalysts were prepared
and used in asymmetric reactions of hydroxycoumarin with a,b-
unsaturated ketones in an organic solvent. Herein, we report the
first application of catalysts 3 and 4 for asymmetric additions
of aldehydes to maleimides in IL/water solvent systems. This
reaction has not been carried out in the presence of recyclable
organocatalysts so far.
Asymmetric addition of isobutyraldehyde 5a to N-phenyl-
maleimide 6a was chosen as model reaction (Scheme 1). In the
presence of catalyst 3 (20 mol%), this reaction affords adduct
7a in nearly quantitative yield with moderate enantioselectivity
(60–72% ee) both in traditional organic solvents (CHCl3 or
DMF) and in IL, 1-butyl-3-methylimidazolium tetrafluoroborate
([bmim]BF4) (Table 1, entries 1–3). Unlike a majority of
molecular organic solvents, the IL does not leach into organic
solution (Et2O) during workup allowing convenient recycling of
the catalytic system to be accomplished. Compound 4 appeared
significantly less active and stereoselective catalyst under com-
parable conditions (entry 4). Interestingly, changing of solvent
resulted in enantioselectivity switching: the product (S)-7a was
Organocatalytic Michael reactions are extensively used for
asymmetric synthesis of chiral bioactive compounds.6 In parti-
cular, asymmetric addition of various nucleophiles to maleimides7
in the presence of organocatalysts affords enantiomerically enriched
succinimide scaffolds, which are incorporated into a number of
natural compounds and pharmaceutical ingredients.8 Further-
more, chiral succinimides are useful building blocks for asymmetric
synthesis of other pharmaceutically relevant molecules bearing
g-lactam units,9 which are applicable for treating of epilepsy,10
HIV,11 degenerative illnesses and depressions.12
1,3-Dicarbonyl compounds,13 2-mercaptobenzaldehydes,14 aza
lactones,15 and various carbonyl compounds16 may serve as nucleo-
philes in these reactions. Asymmetric addition of aldehydes to
maleimides is efficiently catalyzed by simple chiral trans-1,2-di-
O
O
O
O
O
O
R1
i
R3
+
N
R3
N
(R)
(S)
+
N
R3
R2
O
R2
O
R2
O
R1
R1
PF6
O
6a–c
(R)
(R)
N
H
N
+
+
R1
R1
NHR2
NH2
N Me
5a–g
7a–i
Novel
approach
(S,S)
or
(R,R)
NH2
Ph
3
4
*
*
7a R1 = R2 = Me, R3 = Ph
5a R1 = R2 = Me
5b R1 = H, R2 = Me
7b R1 = R2 = Me, R3 = Bn
7c R1 = R2 = Me, R3 = Cy
7d R1 = H, R2 = Me, R3 = Bn
O
PF6
5c R1 = H, R2 = n-C5H11
5d R1 = H, R2 = n-C6H13
5e R1 = H, R2 = Bn
(S)
Ph
1, 2
(S)
N
H
N
N Me
Reactions in
organic solvents
7e R1 = H, R2 = n-C5H11, R3 = Bn
7f R1 = H, R2 = n-C6H13, R3 = Bn
7g R1 = H, R2 = Bn, R3 = Bn
7h R1 = H, R2 = 4-MeOC6H4CH2,
R3 = Bn
NH2
5f R1 = H, R2 = 4-MeOC6H4CH2
5g R1 = H, R2 = Pri
Reactions in IL/water
solvent system
1a R1 + R1 = (CH2)4, R2 = H
1b R1 + R1 = (CH2)4, R2 = Boc
1c R1 + R1 = (CH2)4, R2 = NHC(S)NHAr
R1 = Ph, R2 = H
6a R3 = Ph
6b R3 = Bn
6c R3 = Cy
2
7i R1 = H, R2 = Pri, R3 = Bn
Figure 1 Unsupported and IL-supported primary amine-derived organo-
catalysts.
Scheme 1 Reagents and conditions: i, catalyst 3 or 4, solvent, 20°C, 20 h.
© 2017 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 473 –

Mendeleev Commun., 2017, 27, 473–475
Table 1 Optimization of model reaction between compounds 5a and 6a.a
ee of 7aa (%)
ambiphilic catalyst 3 within these micro-domains or on their
surface in the transition state.
Catalyst
(mol%)
Conver-
Under the optimal conditions, isobutyraldehyde 5a reacted
with maleimides 6a–c bearing various groups at the imide nitrogen
atom to afford the corresponding Michael adducts 7a–c with
enantioselectivity 80–84% ee (Scheme 1, Table 2, entries 1–3).†
A variability of the aldehyde component was demonstrated by
asymmetric reactions of 6b with linear (5b–f) and b-branched
(5g) aldehydes. In these cases, mixtures of diastereomeric com-
pounds 7d–i were generated with enantiomeric enrichment 70–77%
ee for major isomer (entries 4–9). Absolute (S)-configuration was
assigned to compounds 7a and 7b based on comparison of their
specific optical rotations [a]2D0 = –4.1 (c 0.6, CH2Cl2) for 7a and
[a]2D0 = +4.2 (c 0.6, CHCl3) for 7b with reported data19(a) subject
to different enantiomeric enrichment of compared samples.
Configurations of adducts 7c–i were assigned analogously.
Unlike reported catalysts 1 and 2, the 3/[bmim]BF4 /H2O
(2:1 v/v) catalytic system appeared recoverable and multiply
reusable in asymmetric Michael reaction [see also ref. 17(i)].
Once a complete conversion was attained (20 h), product 7a was
extracted with Et2O, and fresh portions of reactants 5a and 6a
were added to the remaining 3/aqueous [bmim]BF4 mixture
Entry
Solvent
(absolute
configuration)
sion (%)b
1
2
3 (20) CHCl3
3 (20) DMF
3 (20) [bmim]BF4
4 (20) DMF
3 (20) DMF / H2O (2:1)
3 (20) [bmim]BF4 /H2O (95:5 v/v) 99
3 (20) [bmim]BF4 /H2O (80:20 v/v) 99
3 (20) [bmim]BF4 /H2O (67:33 v/v) 99
3 (20) [bmim]BF4 /H2O (50:50 v/v) 99
3 (20) [bmim]BF4 /H2O (33:67 v/v) 99
3 (20) [bmim]BF4 /H2O (20:80 v/v) 99
99
99
99
34
99
68 (R)
72 (S)
60 (S)
28 (R)
76 (S)
76 (S)
78 (S)
84 (S)
80 (S)
75 (S)
64 (S)
25 (S)
60 (S)
75 (S)
78 (S)
84 (S)
80 (S)
82 (S)
80 (S)
3
4
5
6
7
8
9
10
11
12
3 (20) H2O
99
13d 3 (20) [bmim]BF4
12
14d 3 (20) [bmim]BF4 /H2O (95:5 v/v) 28
15d 3 (20) [bmim]BF4 /H2O (80:20 v/v) 46
16d 3 (20) [bmim]BF4 /H2O (67:33 v/v) 68
17
18
19
3 (15) [bmim]BF4 /H2O (67:33 v/v) 99
3 (10) [bmim]BF4 /H2O (67:33 v/v) 99
3 (5)
[bmim]BF4 /H2O (67:33 v/v) 20
Table 2 Enantioselective addition of aldehydes 5 to maleimides 6 under
optimized conditions.a
aThe reactions were carried out with isobutyraldehyde 5a (354 µmol),
N-phenylmaleimide 6a (118 mmol) and organocatalyst 3 or 4 in the specified
1
solvent (300 ml) at room temperature for 20 h. b Determined by H NMR
Reactants
Product
spectroscopic analysis of the crude product. cDetermined by HPLC (Chiralpak
OD-H). d The reactions were carried out for 6 h.
ee (major) /
ee (minor)
(%)d
Entry
Conversion
(%)b,c
5
6
7
R1 R2
R3
drb
formed in DMF or [bmim]BF4 whereas (R)-7a was generated in
CHCl3 (similar stereoswitching was reported17(a) for catalyst 1b).
Addition of water improved enantioselectivity, this effect was
more pronounced in aqueous IL medium (entries 5, 6 vs. 2, 3).
Moreover, the plot ee vs. water content (Figure 2) has a maxi-
mum (84% ee), which corresponds to IL/H2O ratio of 2:1 (v/v)
(see Table 1, entries 7–12). Further increasing of water amount led
to a less efficient stereoinduction (25% ee in ‘pure’water), which
testifies to synergistic action of the solvent system ingredients
in the corresponding transition state. Water content affected the
reaction rate as well: the conversion over 6 h was only 12% in
anhydrous IL, whereas in the IL/H2O (2:1) solvent system
it reached 68% for the same period (Table 1, entries 13–16).
A reduction of catalyst 3 loading resulted in a somewhat lower
enantioselectivity and/or a reduced conversion (entries 17–19).
It is known that even a small amount of water may dramatically
influence the liquid properties of ILs such as diffusion coefficient,
viscosity, polarity, and surface tension and this may have an effect
on reaction rates (see ref. 4 and papers cited therein). Moreover,
the formation of invisible-to-the-naked-eye self-organized micro-
structures and nanostructures of water molecules (the diameters
of channels varied from hundreds of nanometers to 5–10 mm)
in unrestrictedly miscible with water [bmim]BF4 were recently
detected by means of transmission electron microscopy (TEM).20
Most likely, the extreme character of the plot ee vs. water content
may be attributed to favorable localization and self-organization of
1
2
3
4
5
6
7
8
5a 6a 7a Me Me
5a 6b 7b Me Me
Ph 99 (90)
Bn 63
–
–
–
84
82
80
5a 6c
7c Me Me
Cy 73
5b 6b 7d
5c 6b 7e
5d 6b 7f
5e 6b 7g
5f 6b 7h
H
H
H
H
H
Me
Bn 99
55:45 72/65
40:60 75/68
44:56 77/65
60:40 70/60
65:35 74/55
n-C5H11 Bn 99 (90)
n-C6H13 Bn 99 (92)
Bn
Bn 99 (92)
4-MeO- Bn 99 (93)
C6H4CH2
9
5g 6b 7i
H
Pri
Bn 29 (21)
30:70 58/70
a The reactions were carried out with organocatalyst 3 (10 mg, 24 mmol),
aldehyde 5 (354 mmol) and maleimide 6 (118 mmol) in [bmim]BF4 (200 ml)/
water (100 ml) solvent system at ambient temperature for 20 h. b Calculated
from 1H NMR spectra of the crude material. c Isolated yields (flash chromato-
graphy) are given in parentheses. d From chiral HPLC.
†
Succinimides 7 (general procedure). A mixture of aldehyde 5 (354 mmol),
maleimide 6 (118 mmol), catalyst 3 (10 mg, 24 mmol), [bmim]BF4 (200 ml)
and water (100 ml) was stirred at ambient temperature for 20 h. Product 7
was extracted with Et2O (5×3 ml), the combined organic extracts were
filtered through a silica gel pad (1 g) and evaporated under reduced
pressure (15 Torr). Reactant 6 conversions and dr values of product 7
were derived from 1H NMR spectroscopy data. Values ee of 7 were
determined by HPLC [chiral phases: Chiralcel OD–H or Chiralpak AD–H,
hexane–propan-2-ol (75:25), 1.0 ml min–1, 220 nm]. NMR data for
succinimides 7a–c are available in the literature.19
2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)propanal 7d. Light yellow oil,
yield 26 mg (90%), Rf = 0.26 (light petroleum–EtOAc, 2:1). H NMR
1
100
80
60
40
20
0
(300 MHz, CDCl3) d: 1.13*/1.31 (d, 3H, J 7.5 Hz), 2.35–2.55 (m, 1H),
2.73–3.25 (m, 3H), 4.60–4.80 (m, 2H), 7.22–7.51 (m, 5H), 9.60/9.70*
(s, 1H). 13C NMR (100 MHz, CDCl3) d: 9.25/11.24*, 31.10/31.72*,
39.43/40.76*, 42.56/42.60*, 46.13/46.57*, 127.88, 128.03, 128.61, 128.70,
135.69, 175.73, 178.11*/178.26, 201.13*/201.47. HRMS (ESI), m/z:
245.1059 [M]+ (calc. for C14H15NO3, m/z: 245.1052). HPLC analysis:
major diastereomer: tR (major) 12.8 min, tR (minor) 31.8 min; minor
diastereomer: tR (major) 14.4 min, tR (minor) 17.3 min.
0
10 20 30 40 50 60 70 80 90 100
Water content (vol%)
For characteristics of compounds 7e–i, see Online Supplementary
Materials.
Figure 2 The plot ee vs. water content for the reaction between com-
pounds 5a and 6a in aqueous [bmim]BF4.
– 474 –

Mendeleev Commun., 2017, 27, 473–475
9 (a) J. Nöth, K. J. Frankowski, B. Neuenswander, J. Aubé and O. Reiser,
J. Comb. Chem., 2008, 10, 456; (b) E. Fenster, D. Hill, O. Reiser and
J. Aubé, Beilstein J. Org. Chem., 2012, 8, 1804.
Table 3 Recycling of the catalystic system 3/[bmim]BF4 /H2O (2:1 v/v)
in the reaction between compounds 5a and 6a.
10 (a) P.A. Reddy, B. C. H. Hsiang, T. N. Latifi, M. W. Hill, K. E. Woodward,
S. M. Rothman, J. A. Ferrendelli and D. F. Covey, J. Med. Chem., 1996,
39, 1898; (b) K. Das Sarma, J. Zhang,Y. Huang and J. G. Davidson, Eur.
J. Org. Chem., 2006, 3730.
11 (a) A. Spaltenstein, M. R. Almond, W. J. Bock, D. G. Cleary, E. S.
Furfine, R. J. Hazen, W. M. Kazmierski, F. G. Salituro, R. D. Tung and
L. L. Wright, Bioorg. Med. Chem. Lett., 2000, 10, 1159; (b) W. M.
Kazmierski, W. Andrews, E. Furfine, A. Spaltenstein and L. Wright,
Bioorg. Med. Chem. Lett., 2004, 14, 5689.
12 (a) D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E.
Morton, F. A. Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger
and J. Zhang, J. Am. Chem. Soc., 2002, 124, 13097; (b) K. Tang and
J.-T. Zhang, Neurol. Res., 2002, 24, 473.
13 (a) G. Bartoli, M. Bosco,A. Carlone,A. Cavalli, M. Locatelli,A. Mazzanti,
P. Ricci, L. Sambri and P. Melchiorre, Angew. Chem. Int. Ed., 2006, 45,
4966; (b) W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh
and C.-H. Tan, Adv. Synth. Catal., 2007, 349, 2454; (c) Z. Jiang, W. Ye,
Y.Yang and C.-H. Tan, Adv. Synth. Catal., 2008, 350, 2345; (d) Z. Jiang,
Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang, M. W. Wong and
C.-H. Tan, Angew. Chem. Int. Ed., 2009, 48, 3627.
Conversion ee of
Conversion ee of
Cycle
Cycle
of 6a (%)
7a (%)
of 6a (%)
7a (%)
1
2
3
4
5
99
99
99
99
99
84
82
82
81
81
6
7
99
99
99
99
99
78
76
72
70
80
8
9
10a
a Fresh portion of water (100 µl) was added.
(Table 3). A slight reduction of enantioselectivity in each next
cycle may be attributed to gradual leaching of water from the IL
to Et2O during workup. Indeed, addition of water (100 ml) to the
nine-fold recycled catalytic system significantly improved enantio-
selectivity of the catalytic reaction (Table 3, cycle 10).
In summary, a simple and readily recyclable chiral primary
amine-based aqueous ionic liquid-supported catalytic system has
been designed and successfully applied to asymmetric addition
of aldehydes to maleimides. A significant impact of the IL/H2O
ratio on stereoselectivity of the catalytic reaction has been revealed.
14 L. Zu, H. Xie, H. Li, J. Wang, W. Jiang and W. Wang, Adv. Synth. Catal.,
2007, 349, 1882.
15 A.-N. R. Alba, G. Valero, T. Calbet, M. Font-Bardía, A. Moyano and
R. Rios, Chem. Eur. J., 2010, 16, 9884.
16 (a) F. Tanaka, R. Thayumanavan and C. F. Barbas III, J. Am. Chem. Soc.,
2003, 125, 8523; (b) F. Tanaka, R. Thayumanavan, N. Mase, C. F.
Barbas III, Tetrahedron Lett., 2004, 45, 325; (c) K. Nakashima, M. Kawada,
S. Hirashima, A. Kosugi, M. Kato, A. Yoshida, Y. Koseki and T. Miura,
Tetrahedron:Asymmetry, 2016, 27, 888; (d) G.-L. Zhao,Y. Xu, H. Sundén,
L. Eriksson, M. Sayah and A. Córdova, Chem. Commun., 2007, 734.
17 (a) J. Flores-Ferrándiz, B. Fiser, E. Gómez-Bengoa and R. Chinchilla,
Eur. J. Org. Chem., 2015, 1218; (b) F. Yu, Z. Jin, H. Huang, T. Ye,
X. Liang and J.Ye, Org. Biomol. Chem., 2010, 8, 4767; (c) F.Yu, X. Sun,
Z. Jin, S. Wen, X. Liang and J. Ye, Chem. Commun., 2010, 46, 4589;
(d) A. Avila, R. Chinchilla and C. Najera, Tetrahedron: Asymmetry, 2012,
23, 1625; (e) A. Avila, R. Chinchilla, E. Gómez-Bengoa and C. Nájera,
Tetrahedron: Asymmetry, 2013, 24, 1531; (f) J. Flores-Ferrándiz and
R. Chinchilla, Tetrahedron: Asymmetry, 2014, 25, 1091; (g) P. Vízcaíno-
Milla, J. M. Sansano, C. Nájera, B. Fiser and E. Gómez-Bengoa, Synthesis,
2015, 47, 2199; (h) T. de A. Fernandes, P. Vizcaíno-Milla, J. M. J. M.
Ravasco, A. Ortega-Martínez, J. M. Sansano, C. Nájera, P. R. R. Costa,
B. Fiser and E. Gómez-Bengoa, Tetrahedron: Asymmetry, 2016, 27, 118;
(i) J. Flores-Ferrándiz and R. Chinchilla, Tetrahedron: Asymmetry, 2017,
28, 302.
This work was supported by the Russian Science Foundation
(grant no. 16-13-10470).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2017.09.014.
References
1 (a) Science of Synthesis: Asymmetric Organocatalysis, vol. 1, eds. B. List
and K. Maruoka, vol. 2, ed. B. List, Thieme, Stuttgart, 2012; (b) Com-
prehensive Enantioselective Organocatalysis: Catalysts, Reactions, and
Applications, ed. P. I. Dalco, Wiley-VCH, Weinheim, 2013.
2 S. G. Zlotin and N. N. Makhova, Mendeleev Commun., 2010, 20, 63.
3 M. Raja and V. K. Singh, Chem. Commun., 2009, 6687.
4 P. N. Reddy, P. Padmaja, B. V. Subba Reddy and G. Rambabu, RSC Adv.,
2015, 5, 51035.
5 A. S. Kucherenko, D. E. Syutkin and S. G. Zlotin, Russ. Chem. Bull., Int.
Ed., 2008, 57, 591 (Izv. Akad. Nauk, Ser. Khim., 2008, 578).
6 O. V. Maltsev, I. P. Beletskaya and S. G. Zlotin, Russ. Chem. Rev., 2011,
80, 1067 (Usp. Khim., 2011, 80, 1119).
18 A. S. Kucherenko, D. E. Siyutkin, A. G. Nigmatov, A. O. Chizhov and
S. G. Zlotin, Adv. Synth. Catal., 2012, 354, 3078.
7 P. Chauhan, J. Kaur and S. S. Chimni, Chem. Asian J., 2013, 8, 328.
8 (a) A. Fredenhagen, S. Y. Tamura, P. T. M. Kenny, H. Komura, Y. Naya,
K. Nakanishi, K. Nishiyama, M. Sugiura and H. Kita, J. Am. Chem. Soc.,
1987, 109, 4409; (b) C. Malochet-Grivois, C. Roussakis, N. Robillard,
J. F. Biard, D. Riou, C. Débitus and J. F. Verbist, Anti-Cancer Drug Des.,
1992, 7, 493; (c) Y. Ando, E. Fuse and W. D. Figg, Clin. Cancer Res.,
2002, 8, 1964; (d) C. Freiberg, N. A. Brunner, G. Schiffer, T. Lampe,
J. Pohlmann, M. Brands, M. Raabe, D. Häbich and K. Ziegelbauer,
J. Biol. Chem., 2004, 279, 26066; (e) M. Isaka, N. Rugseree, P. Maithip,
P. Kongsaeree, S. Prabpai and Y. Thebtaranonth, Tetrahedron, 2005, 61,
5577; (f) J. Uddin, K. Ueda, E. R. O. Siwu, M. Kita and D. Uemura,
Bioorg. Med. Chem., 2006, 14, 6954.
19 (a) C. G. Kokotos, Org. Lett., 2013, 15, 2406; (b) F.Yu, Z. Jin, H. Huang,
T. Ye, X. Liang and J. Ye, Org. Biomol. Chem., 2010, 8, 4767.
20 A. S. Kashin, K. I. Galkin, E. A. Khokhlova and V. P. Ananikov, Angew.
Chem. Int. Ed., 2016, 55, 2161.
Received: 23rd January 2017; Com. 17/5156
– 475 –