Conjugate addition of 1,3-dicarbonyl compounds to maleimides using a chiral C2-symmetric bis(2-aminobenzimidazole) as recyclable organocatalyst

Article abstract of DOI:10.1021/ol202599h

The recyclable chiral 2-aminobenzimidazole-derived organocatalyst 1f efficiently promotes the room temperature asymmetric conjugate addition of 1,3-diketones, β-ketoesters, and malonates to maleimide and N-substituted maleimides, affording the correspondi

Full text of DOI:10.1021/ol202599h

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6106–6109
Conjugate Addition of 1,3-Dicarbonyl
Compounds to Maleimides Using a Chiral
C2-Symmetric Bis(2-aminobenzimidazole)
as Recyclable Organocatalyst
†
Eduardo Gomez-Torres, Diego A. Alonso,* Enrique Gomez-Bengoa, and
,†
‡
ꢀ
ꢀ
,†
ꢀ
Carmen Najera*
ꢀ
Departamento de Quımica Organica & Instituto de Sıntesis Organica, Universidad de
Alicante, Carretera de San Vicente del Raspeig s/n, E-03690, San Vicente del Raspeig,
ꢀ
ꢀ
Alicante, Spain, and Departamento de Quımica Organica I, Universidad del Paıs Vasco,
ꢀ
Apdo. 1072, E 20080, San Sebastian, Spain
diego.alonso@ua.es; cnajera@ua.es
Received September 26, 2011
ABSTRACT
The recyclable chiral 2-aminobenzimidazole-derived organocatalyst 1f efficiently promotes the room temperature asymmetric conjugate addition
of 1,3-diketones, β-ketoesters, and malonates to maleimide and N-substituted maleimides, affording the corresponding Michael adducts in
excellent yields and enantioselectivities even at gram scale.
In recent years, organocatalytic enantioselective conju-
gate addition reactions have been subjected to intensive
investigations,1 enals, enones, and nitroolefins generally
being used as Michael acceptors. In sharp contrast,
maleimides have been used to a lesser extent as elec-
trophiles,2À4 despite the broad synthetic and biological
utilities of chiral R-branched succinimides.5 Furthermore,
the nature of the substituent on the N atom of the
maleimide has been shown to be a critical parameter for
the stereochemical outcome of the process. In particular,
the development of a general and highly enantioselective
† Universidad de Alicante.
‡ Universidad del Paıs Vasco.
(1) (a) Almas-i, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymme-
ꢀ
try 2007, 18, 299–365. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–
1716. (c) Organocatalytic Enantioselective Conjugate Addition Reac-
tions. A Powerful Tool for the Stereocontrolled Synthesis of Complex
Molecules; Vicario, J. L., Badia, D., Carrillo, L.; Reyes, E., Eds.; Royal
Society of Chemistry: Cambridge, 2010. (d) Alonso, D. A. Organocatalyzed
Conjugate Additions. In Enantioselective Organocatalyzed Reactions II.
Asymmetric C-C Bond Formation Processes; Mahrwald, R., Ed.; Springer:
Heidelberg, 2011; pp 41À185.
(4) For representative conjugate additions of activated methylenes to
N-substituted maleimides, see: (a) Bartoli, G.; Bosco, M.; Carlone
A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.;
Melchiorre, P. Angew. Chem., Int. Ed. 2006, 45, 4966–4870. (b) Shen,
J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C.-H. J. Am.
Chem. Soc. 2006, 128, 13692–13693. (c) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma,
T.; Lee, R.; Yang, Y.; Huang, K.-W.; Wong, M. W.; Tan, C.-H. Angew.
Chem., Int. Ed. 2009, 48, 3627–3631. (d) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-
J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896–
2899. (e) Zea, A.; Valero, G.; Alba, A.-N. R.; Moyano, A.; Rios, R. Adv.
Synth. Catal. 2010, 352, 1102–1106.
(2) For the conjugate addition of ketones to N-substituted malei-
mides, see: Yu, F.; Sun, X.; Jin, Z.; Wen, S.; Liang, X.; Ye, J. Chem.
Commun. 2010, 4589–4591.
(3) For the conjugate addition of aldehydes to N-substituted mal-
ꢀ
eimides, see: (a) Zhao, G.-L.; Xu, Y.; Sunden, H.; Eriksson, L.; Sayah,
ꢀ
M.; Cordova, A. Chem. Commun. 2007, 734–735. (b) Xue, F.; Liu, L.;
(5) Ahmed, S. Drug Des. Discovery 1996, 14, 77–89. (b) Curtin, M. L.;
Garland, R. B.; Heyman, H. R.; Frey, R. R.; Michaelides, M. R.; Li, J.;
Pease, L. J.; Glaser, K. B.; Marcotte, P. A.; Davidsen, S. K. Bioorg. Med.
Chem. Lett. 2002, 12, 2919–2923.
Zhannng, S.; Duan, W.; Wang, W. Chem.;Eur. J. 2010, 16, 7979–7982.
(c) Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh, A. Tetrahedron
Lett. 2011, 52, 4158–4160.
r
10.1021/ol202599h
Published on Web 10/26/2011
2011 American Chemical Society

organocatalyst for the asymmetric conjugate addition to
maleimide still remains a challenging goal.6
Table 1. Enantioselective Conjugate Addition of Acetylacetone
to Maleimide Catalyzed by Catalysts 1a
The utility of chiral 2-aminobenzimidazoles as organo-
catalysts has been recently disclosed by our group7 and
others8 showing the benefits from 2-aminobenzimidazole’s
characteristic dual hydrogen-bonding catalysis.9 Thus, 1b,
in which the distance between hydrogen atoms Ha and Hb
is in between the reported distances for the thiourea10 and
squarimide-derived organocatalysts,11 is a very active and
general catalyst for the enantioselective addition of mal-
onates, β-ketoesters, and 1,3-diketones to nitroalkenes in
the presence of TFA as cocatalyst.7 Herein, we describe the
use of chiral 2-aminobenzimidazoles to promote the asym-
metric conjugate addition of 1,3-dicarbonyl compounds to
maleimides.
Initially, the challenging maleimide Michael acceptor
(0.15 mmol) was chosen to study the conjugate addition
of acetylacetone (0.3 mmol) in toluene at 30 °C using
10 mol % of chiral 2-aminobenzimidazole organocatalysts
1 (Figure 1) in the presence of TFA (10 mol %) as
cocatalyst (Table 1).
cocatalyst
(mol %)
conversion
(%)b
entry 1 (mol %)
solvent
ee (%)c
1
2
3
4
5
6
7
8
9
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
TFA (10) toluene
TFA (10) toluene
TFA (10) toluene
TFA (10) toluene
TFA (10) toluene
TFA (10) toluene
toluene
42
41
15
13
>99
90
<5
89
11
97
95
90
44
55
0
>99 (94)
99
1f TFA (10)d
3
1f (10)
1f (10)
TFA (10) benzene
TFA (10) xylene
TFA (10) MeOH
TFA (10) H2O
toluene
TFA (10) toluenee
TFA (10) tolueneg
>99
>99
68
10 1f (10)
11 1f (10)
12 1f (10)
13 1f (10)
14 1f (10)
>99
>99
>99 (81)f
45
51
>99
90
a Reaction conditions: acetylacetone (0.3 mmol), maleimide (0.15
mmol), 1 (10 mol %, 0.015 mmol, 0.05 M), TFA (10 mol %, 0.015
mmol), solvent (0.3 mL), 30 °C, 24 h. b Determined by 1HNMR on the
crude reaction mixture. In brackets: isolated yield after flash chromato-
graphy. c Chiral HPLC [OD-H, hexane/i-PrOH: 85/15, 1 mL/min].
d Carried out with 10 mol % of preformed bench stable salt 1f•TFA.
e Reaction conditions: acetylacetone (10 mmol), maleimide (5 mmol), 1f
(10 mol %, 0.5 mmol, 0.05 M), TFA (10 mol %, 0.5 mmol), toluene
(10 mL), 30 °C, 20 h. f Isolated yield of 2a after filtration of the crude
reaction mixture. g Reaction performed under MW irradiation condi-
tions (40 W, 25 °C, 1 h).
Figure 1. Hydrogen bond donor catalysts.
Regarding catalyst study, C2-symmetric catalyst 1f
proved to be the most promising and afforded the 1,4-
adduct 2a in an excellent isolated yield (94%) and enan-
tioselectivity (97% ee) (Table 1, entries 1À6). A similar
level of enantioselection (95% ee) was observed when the
led to a drastic decrease in stereoselectivity, especially H2O
that afforded racemic 2a (entry 11). Finally, a significant
decrease in the enantioselectivity of the reaction (51% ee)
was observed in the absence of TFA (Table 1, entry 12), a
result that evidenced the higher ability of the protonated
catalyst for hydrogen-bonding activation.
The synthetic utility of the catalytic approach was con-
firmed by a gram-scale experiment (5 mmol of maleimide),
which gave optically pure (>99% ee) 2a in 81% yield after
filtration of the crude reaction mixture (Table 1, entry 13).12
The reaction could be also performed at rt under microwave
irradiation conditions, affording succinimide 2a in a mod-
erate conversion and 90% ee in only 1 h (entry 14).
Under the optimized reaction conditions (Table 1, entry
6), the generality of the conjugate addition reaction with
respect to the nucleophile and the maleimide acceptor was
investigated. The conjugate addition of acetylacetone to dif-
ferent N-alkyl- and N-aryl maleimides afforded compounds
2bÀ2e in good yields and excellent enantioselectivities
preformed bench-stable salt 1f TFA was used as catalyst
3
(entry 7). Further optimization confirmed toluene for
optimal selectivity (Table 1, entries 8À11). The use of
hydrogen-bond accepting solvents such as H2O or MeOH
(6) Only one example of organocatalyzed conjugate addition to
maleimide has been reported using methyl 2-oxo-2,3-dihydro-1H-in-
dene-1-carboxylate as nucleophile and quinine as catalyst at À20 °C with
limited success in terms of diastereoselectivity and enantioselectivity (up
to 81% ee). See ref 4a.
ꢀ
ꢀ
(7) Almas-i, D.; Alonso, D. A.; Gomez-Bengoa, E.; Najera, C. J. Org.
Chem. 2009, 74, 6163–6168.
(8) Zhang, L.; Lee, M.-M.; Lee, S.-M.; Lee, J.; Cheng, M.; Jeong, B.-
S.; Park, H.-g.; Jew, S.-S. Adv. Synth. Catal. 2009, 351, 3063–3066.
(9) Hydrogen Bonding in Organic Synthesis; Petri, M., Pihko, M., Eds.;
Wiley-VCH: Weinheim, 2009.
(10) (a) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81,
785–795. (b) Connon, S. Synlett 2009, 354–376.
(11) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem.
ꢀ
Soc. 2008, 130, 14416–14417. (b) Aleman, J.; Parra, J.; Jiang, H.;
(12) The enantioselectivity of 2a was determined to be >99% ee on
the crude reaction mixture, before filtration.
Jørgensen, K. A. Chem.;Eur. J. 2011, 17, 6890–6899.
Org. Lett., Vol. 13, No. 22, 2011
6107

When dimethyl malonate was reacted with maleimide,
compound 2j was obtained in an 81% ee and a very low
23% isolated yield (Table 2, entry 10). This was probably
due to the lower acidity of the nucleophile compared to
that of 1,3-diketones and β-ketoesters, thus requiring a
catalyst with an stronger basic character. This was con-
firmed by performing the reaction in the absence of TFA,
which afforded compound 2j in a 78% eeand a higher 74%
isolated yield (entry 11). With respect to yield, a similar
tendency was observed in the reaction with N-methyl
maleimide (Table 2, entries 12 and 13), and compound
2k was quantitatively obtained in 99% ee in the absence of
TFA (entry13).
Table 2. Enantioselective Conjugate Addition of 1,3-Dicarbo-
nyl Compounds to Maleimides Catalyzed by 1f
The absolute configuration of compound 2e, generated
by the 1f-catalyzed conjugate addition of acetylacetone to
N-(4-bromophenyl)maleimide, was assigned to be S by
X-ray crystallography analysis (Figure 2).13 The same
crystal used for X-ray crystallography was analyzed by
chiral HPLC, which confirmed the presence of the major S
enantiomer in 97% ee. Since products 2 are generally solid
substances, this also demonstrated that it is possible to
obtain a single stereoisomer in essentially enantiomerically
pure form after a single crystallization.14
After the preparation of compound 2e, we also studied
the recyclability of organocatalyst 1f and were pleased to
demonstrate that 1f TFA could be easily recovered (99%)
3
from the crude reaction mixture just by washing with i-
PrOH (see Supporting Information) (Scheme 1). The
recovered 1f TFA was employed in a second run of the
3
reaction, affording 2e in 99% yield and 93% ee.
a Isolated yield after flash chromatography. b Chiral HPLC [OD-H,
hexane/i- PrOH: 85/15, 1 mL/min]. c Chiral HPLC [AD-H, hexane/i-
PrOH: 90/10, 1 mL/min]. d Reaction performed in the absence of TFA.
e Isolated yield of pure compound after washing of the crude reaction
mixture with i-PrOH. f dr: 93/7. g Chiral HPLC [IA, hexane/i-PrOH: 90/
10, 1 mL/min]. h dr: 76/24. i Chiral HPLC [IA, hexane/i-PrOH: 95/5,
1 mL/min]. j dr: 87/13. k Chiral HPLC [AD-H, hexane/i-PrOH: 95/5,
1 mL/min]. l Chiral HPLC [AD-H, hexane/i- PrOH: 85/15, 1 mL/min].
(Table 2, entries 1À5). All of the studied substrates
afforded levels of enantioselectivity similar to that of
maleimide (95À97% ee).
The reaction was also applicable to R-substituted
3-methylpentane-2,4-dione, which afforded, after addition
to N-phenylmaleimide, compound 2f in 50% yield and
91% ee (Table 2, entry 6).
Figure 2. X-ray structure for compound 2e.
The addition of 2-acetylcyclopentanone toN-phenylma-
leimide afforded compound 2g in 93% yield as a 93:7
mixture of diastereomers, both of them obtained with very
high enantioselectivity (entry 7). The protocol also proved
to be effective for cyclic and acyclic β-ketoesters, the expected
products being formed in high yields, good diastereoselec-
tivity, and very high ee’s (Table 2, entries 8 and 9). The
synthesis of compounds 2g and 2h was especially interest-
ing, since it evidenced the ability of the catalytic system to
synthesize adjacent quaternary/tertiary stereogenic centers
with excellent enantioselectivities.
In light of the performed experiments, we tentatively
propose the transition state model shown in Figure 3 for
the conjugate addition of acetylacetone to maleimide in the
presence of TFA as cocatalyst. The neutral portion of the
(13) Compound 2e, obtained in 98% yield and 96% ee, was crystal-
lized from a CH2Cl2 solution to give fine colorless crystals of a single
enantiomer with the configuration shown in Figure 2. Crystal data for
2e: CCDC 846922.
(14) Compounds 2g (89%, dr 100/0, ee 99%) and 2d (87%, ee 99%)
could be also obtained in a gram-scale experiment using, respectively,
5 mol % and 2 mol % of catalyst by just filtering off from the reaction
media.
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Org. Lett., Vol. 13, No. 22, 2011

Scheme 1. Recyclability and Reuse of Benzimidazole-Derived
Catalyst 1f
Figure 3. Plausible transition state for the 1f-catalyzed conju-
gate addition in the presence of 1equiv of TFA.
direct conjugate addition of different 1,3-dicarbonyl
compounds to maleimide and N-substituted malei-
mides to give the corresponding Michael adducts with
very high enantiocontrol. Further studies are in pro-
gress to study by computational methods the H-bond
network between catalyst, nucleophile, and maleimide
responsible for the observed reactivity/enantioselectiv-
ity and to explore the scope of organocatalyst 1f in
other catalytic asymmetric reactions.
catalyst deprotonates the nucleophile that performs a si
face attack to the maleimide electrophile, which is acti-
vated by the protonated benzimidazole moiety via single
hydrogen bonding interaction with the carbonyl group
(Figure 3). Inthis structure, the activation of the maleimide
is achieved by a single NH bond, and two other NH groups
bind the nucleophile.15
Acknowledgment. Financial support from the MEC
(Projects CTQ2007-62771/BQU, CTQ2010-20387, and Con-
solider INGENIO 2010 CSD2007-00006), from the General-
itat Valenciana (Projects GV/2007/142, PROMETEO/2009/
038, and FEDER), the University of Alicante, and EU
(ORCA Action CM0905) is acknowledged. We also thank
Dr. Tatiana Soler (SSTTI, Alicante University) for solving the
X-ray structure of 2e.
In summary, we have designed a recyclable chiral
2-aminobenzimidazole catalyst 1f, which catalyzes the
Supporting Information Available. Experimental pro-
cedures, spectroscopic data for all the products, and
X-ray structure for compound 2e. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(15) Tighter H-bonding to the nucleophile than to the electrophile
during the transition state have also been observed in related addition
ꢀ
reactions; see: (a) Hamza, A.; Schubert, G.; Soos, T.; Papai, I. J. Am.
ꢀ
Chem. Soc. 2006, 128, 13151–13160. (b) Gomez-Bengoa, E.; Linden, A.;
ꢀ
ꢀ
Lopez, R.; Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem.
Soc. 2008, 130, 7955–7966.
Org. Lett., Vol. 13, No. 22, 2011
6109