Enantioselective synthesis of succinimides by michael addition of 1,3-dicarbonyl compounds to maleimides catalyzed by a chiral bis(2-aminobenzimidazole) organocatalyst

Article abstract of DOI:10.1002/ejoc.201201046

A wide variety of chiral succinimides have been prepared in high yields and enantioselectivities by asymmetric conjugate addition of 1,3-dicarbonyl compounds to maleimides under very mild reaction conditions using a bifunctional benzimidazole-derived orga

Full text of DOI:10.1002/ejoc.201201046

FULL PAPER
DOI: 10.1002/ejoc.201201046
Enantioselective Synthesis of Succinimides by Michael Addition of
1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis(2-
aminobenzimidazole) Organocatalyst
Eduardo Gómez-Torres,[a] Diego A. Alonso,*[a] Enrique Gómez-Bengoa,[b] and
Carmen Nájera*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Michael addition / Hydrogen bonds / Transition states
A wide variety of chiral succinimides have been prepared in
high yields and enantioselectivities by asymmetric conjugate
addition of 1,3-dicarbonyl compounds to maleimides under
very mild reaction conditions using a bifunctional benzimid-
azole-derived organocatalyst. Computational and NMR stud-
ies support the hydrogen-bonding activation role of the cata-
lyst and the origin of the stereoselectivity of the process.
ides[8] has emerged as a powerful tool for the synthetic
chemist, especially using chiral organocatalysts.[9] Thus,
very high enantioselectivities have been obtained in the con-
jugate addition of ketones,[10] aldehydes,[11] and a wide vari-
ety of activated methylenes and methines,[12] to N-substi-
tuted maleimides. Regarding activated nucleophiles, 1,3-di-
Introduction
Cyclic imides play a vital role in polymer, biological, me-
dicinal, and synthetic chemistry.[1] In particular, suc-
cinimides are important building blocks that are often pres-
ent in natural products and drugs such as phensuximide,[2]
ethosuximide,[3] and andrimid[4] (Figure 1).
ketones,[12a]
malonates,[12c]
β-keto
esters,[12a,12c,12d]
anthrones,[12b,12g] oxindoles,[12f] α-cyanoacetates,[12j,12k] α-
nitroacetates,[12l] α-isocyanoacetates,[12m] azlactones,[12i]
pyrazolones,[12n] and oxazolones,[12o] have been successfully
used as Michel donors, typically employing bifunctional
chiral Brønsted base/hydrogen-bonding organocatalysts
(Figure 2).[9f]
Very recently, the utility of chiral 2-aminobenzimidazoles
as organocatalysts for the asymmetric conjugate addition to
nitroolefins has been disclosed by our group[13] and
others,[14] which benefits from 2-aminobenzimidazole’s
characteristic dual hydrogen-bonding catalysis.[15] Thus, cat-
alyst 5b (Figure 2), in which the distance between hydrogen
atoms Ha and Hb is between the reported distances for the
highly enantioselective thiourea[16] and squarimide-derived
organocatalysts,[17] is a very active and general catalyst for
the enantioselective conjugate addition of malonates, β-keto
esters, and 1,3-diketones to a wide range of conjugated ni-
troalkanes in the presence of trifluoroacetic acid (TFA) as
cocatalyst.[13]
Regarding the addition to maleimides, we have recently
demonstrated that the recyclable chiral 2-aminobenzimid-
azole catalyst 5f efficiently catalyzes the direct conjugate ad-
dition of different 1,3-dicarbonyl compounds to maleimides
to give the corresponding chiral (S)-succinimides with very
high enantiocontrol.[18] For this process, we tentatively pro-
posed a transition state model in which the benzimidazole-
derived organocatalyst 5f carried out a bifunctional acti-
vation of the nucleophile and the electrophile.[18]
Figure 1. Succinimides in pharmaceuticals and drugs.
Chiral succinimides are valuable synthetic intermedi-
ates[5] and structural motifs in molecules with interesting
biological activities.[4,6] Among the different methodologies
available for the synthesis of chiral α-substituted suc-
cinimides,[7] the asymmetric conjugate addition to maleim-
[a] Departamento de Química Orgánica & Instituto de Síntesis
Orgánica, Universidad de Alicante,
Carretera de San Vicente del Raspeig s/n, 03690, San Vicente
del Raspeig, Alicante, Spain
Fax: +34-965903549
E-mail: diego.alonso@ua.es
cnajera@ua.es
Homepage: http://dqorg.ua.es/es/
[b] Departamento de Química Orgánica I, Universidad del País
Vasco,
Apdo. 1072, 20080 San Sebastián, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201046.
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Enantioselective Synthesis of Succinimides
studied the aptitude of catalyst 5g (Figure 2, R1 = R2 =
Me) in the process under the previously optimized reaction
conditions. As depicted in Figure 3, only 11% yield of suc-
cinimide 6a was obtained in a lower ee value (48%), which
confirms the importance of the presence of the secondary
amine for optimal hydrogen-bonding catalyst performance.
Figure 3. Conjugate addition of acetylacetone to maleimide cata-
lyzed by 5f and 5g.
Further optimization of the reaction conditions em-
ploying organocatalyst 5f (Table 1) showed a slight decrease
in the enantioselectivity of the process when the conjugate
addition was performed at 0 °C, affording 6a in a 94% ee
(Table 1, entry 2). With respect to the role of the acid cocat-
alyst TFA in the reaction, a significant decrease in the
enantioselectivity of the reaction (ee 51 %) was detected in
the absence of TFA (Table 1, entry 3). This result clearly
evidenced the greater ability of the protonated catalyst for
hydrogen-bonding activation. Notably, complete deactiva-
tion of the catalyst was observed when a twofold excess
(20 mol-%) of cocatalyst was used (Table 1, entry 4).
Furthermore, a dependence of the enantioselectivity of the
process on catalyst loading was observed (Table 1, entries
5 and 6). Finally, further optimization of catalyst loading
revealed that only 1 mol-% of 5f/TFA was able to afford a
highly efficient reaction, although the enantioselectivity of
the process slightly decreased to 93% (Table 1, entry 7).
Figure 2. Chiral bifunctional Brønsted base/hydrogen-bonding or-
ganocatalysts.
Herein, we report the results of a full study on this reac-
tion, including detailed NMR mechanistic investigations as
well as DFT calculations to elucidate the catalytic active
species and the H-bond network between catalyst, nucleo-
phile and maleimide responsible for the observed reactivity
and enantioselectivity.
Table 1. Enantioselective conjugate addition of acetylacetone to
maleimide catalyzed by chiral 2-aminobenzimidazole catalyst 5f.[a]
Results and Discussion
The synthesis of catalysts 5a–e has already been de-
scribed[18a] and involves, as a common initial step, solvent-
free aromatic nucleophilic substitution of (1R,2R)-1,2-di-
aminocyclohexane to 2-chlorobenzimidazole followed by
derivatization of the primary amine. C2-symmetric catalysts
5f[18a] and 5g were prepared by a twofold aromatic substitu-
tion with 2-chlorobenzimidazole and 1-methyl-2-chloro-
benzimidazole, respectively.
Entry
5f [mol- TFA [mol- T [°C] Yield [%] ee [%][c]
[b]
%]
%]
In our previous optimization study,[18,19] we demon-
strated the superiority of dimeric catalyst 5f over benzimid-
azole-derived catalysts 5a–e in the conjugate addition of a
range of 1,3-dicarbonyl compounds to maleimides. For in-
stance, the conjugate addition of acetylacetone (0.3 mmol)
to maleimide (0.15 mmol) catalyzed by 5f (10 mol-%) in the
presence of TFA (10 mol-%) as cocatalyst and toluene as
solvent, led to the formation of succinimide 6a in an excel-
lent 94% yield and ee = 97% (Figure 3). We also showed
that the use of hydrogen-bond-forming solvents such as
water or methanol, led to a drastic decrease in stereoselecti-
vity.[18] Accordingly, and to confirm the hydrogen-bonding
1
2
3
4
5
6
7
10
10
10
10
30
100
1
10
10
–
20
30
100
1
30
0
94
95
94
Ͻ5
85
81
96
97
94
51
–
87
83
93
30
30
30
30
30
[a] Reaction conditions: acetylacetone (0.3 mmol), maleimide
(0.15 mmol), 5f (10 mol-%, 0.015 mmol, 0.05 m), TFA (10 mol-%,
0.015 mmol), solvent (0.3 mL), room temp., 24 h. [b] Isolated yield
after flash chromatography. [c] Determined by chiral HPLC [OD-
H; hexane/iPrOH, 85:15; 1 mL/min].
At high catalyst concentrations (Table 1, entries 5 and 6),
activation mode of catalyst 5f in this reaction, we initially product racemization due to thermodynamic control of the
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D. A. Alonso, C. Nájera et al.
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process was discharged, since the enantioselectivity of the
Under the optimized reaction conditions (Table 1, en-
reaction remained constant within the course of the experi- try 1), the generality of the conjugate addition reaction with
ment when a 0.1 m catalyst concentration was used in the respect to the nucleophile and the maleimide acceptor was
conjugate addition (Figure 4). This was also confirmed then investigated. As depicted in Figure 5, the conjugate ad-
when succinimide 6a (ee = 97 %) was submitted to the opti- dition of acetylacetone to different N-alkyl- and N-aryl ma-
mal reaction conditions [5f (10 mol-%), TFA (10 mol-%), leimides afforded the corresponding 1,4-adducts 6b–g in
toluene, 30 °C] in the presence of a different nucleophile good yields and excellent enantioselectivities. All the
such as 3-acetyldihydrofuran-2(3H)-one; under these condi- studied substrates afforded similar levels of ee to those with
tions, compound 6a was only detected in the crude reaction maleimide (ee = 95–97 %). The 5f-catalyzed conjugate ad-
1
mixture (TLC and H NMR analyses) with the same op- dition reaction was also applicable to α-substituted 3-meth-
tical purity (Scheme 1).
ylpentane-2,4-dione, which afforded, after addition to N-
phenylmaleimide, compound 6h in 50% yield and ee =
91 %. Regarding non-symmetrical β-diketones, the addition
of 1-phenylbutane-1,3-dione to maleimide afforded com-
pound 6i in 97% yield as a 58:42 mixture of diastereomers,
both of which were obtained with excellent enantio-
selectivity. Likewise, addition of the cyclic 2-acetylcy-
clopentanone to N-phenylmaleimide afforded 6j in 93%
yield as a 97:3 mixture of diastereomers, both of which were
also obtained with very high enantioselectivity (Figure 5).
Figure 4. The ee vs. time for the conjugate addition of acetyl-
acetone to maleimide catalyzed by 5f/TFA.
Scheme 1. Racemization study with 6a.
Additional studies on catalyst concentration were per-
formed with the model reaction. The ee values obtained at
different catalyst concentrations (Table 2) were fairly consis-
tent with the diffusion coefficients (D) of 5f/TFA, strongly
indicating that the degree of hydrogen-bonded self-associa-
tion of bifunctional organocatalyst 5f/TFA in solution plays
a crucial role in determining the enantioselectivity of the
process.[20]
Figure 5. Conjugate addition of 1,3-diketones to maleimides cata-
lyzed by 5f.
The optimized catalytic system also proved to be effective
for β-keto esters, giving the expected products in high
yields, moderate to good diastereoselectivity, and very high
levels of enantioselectivity (Figure 6). The synthesis of com-
pounds 6j–n was especially interesting because the results
demonstrated the applicability of the catalytic system for
the synthesis of adjacent quaternary/tertiary stereogenic
centers with excellent enantioselectivities.
We finished investigating the nucleophile scope with ma-
lonates. Interestingly, catalyst 5f performed better in the ab-
sence of TFA for these nucleophiles. When dimethyl malon-
ate reacted under the optimized reaction conditions with
maleimide, compound 6o was obtained in 81% ee but in
Table 2. Diffusion coefficients of 5f/TFA (10 mol-%) at different
concentrations vs. enantioselectivities in the asymmetric addition
of acetylacetone to maleimide.
Entry
5f/TFA conc. (molar)
D/DTol[a]
ee [%][b]
1
2
3
0.01
0.05
0.1
0.33
0.31
0.20
96
97
88
[a] Diffusion coefficients D (10–10 m2 s–1) at room temperature for
5f/TFA corrected with respect to the solvent ([D8]toluene) at dif-
ferent molar (m) concentrations. [b] Determined by chiral HPLC
[OD-H; hexane/iPrOH, 85:15; 1 mL/min].
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Enantioselective Synthesis of Succinimides
Figure 7. Gram-scale synthesis of chiral succinimides 6.
Scheme 2. Synthesis of chiral pyrazol-derived succinimides 7.
Figure 6. Conjugate addition of β-keto esters and dimethyl malon-
ate to maleimides catalyzed by 5f.
tadione) by the aminobenzimidazole catalyst to form an
enolate/protonated catalyst binary complex (Figure 8). Fur-
ther hydrogen bonding with maleimide renders a ternary
complex that evolves into the final products through the
corresponding transition state. We found that the minimum
Gibbs free energy along the reaction coordinate always cor-
responded to the sum of the energies of the free maleimide
and the binary complex, which was thus taken as the
ground G = 0 energy level.
very low isolated yield (23%; Figure 6). This was probably
due to the lower acidity of the nucleophile compared with
1,3-diketones and β-keto esters, thus requiring a catalyst
with a stronger base character. This was confirmed by per-
forming the reaction in the absence of TFA, which afforded
compound 6o in ee = 78 % and with a higher isolated yield
(74%). With respect to yield, a similar tendency was ob-
served in the reaction with N-methyl- and N-phenylmaleim-
ides, which afforded compounds 6p and 6q, in ee = 99 %
and high yields in the absence of TFA (Figure 6).
The synthetic utility of the catalytic methodology was
confirmed by gram-scale experiments (5–20 mmol of
Michael acceptor) for the synthesis of succinimides 6a, 6d,
6g, and 6k, which were obtained as optically pure com-
pounds (ee Ͼ99 %) in high yields after filtration from the
crude reaction mixture (Figure 7).[21]
The functional characteristics of the synthesized chiral
1,3-dicarbonyl compounds 6 was used for the synthesis of
optically active pyrazol-derived succinimides.[22] Thus, com-
pounds 6a (ee = 97 %) and 6e (ee = 97 %) were transformed
into succinimides 7a (ee = 99 %) and 7e (ee = 99 %), respec-
tively, by treatment with N-phenylhydrazine in the presence
of phosphotungstic acid as catalyst (1 mol-%) in water at
room temperature (Scheme 2).
DFT computational studies[23] were conducted with the
aim of detailing the H-bond network between catalyst, nu-
cleophile, and maleimide responsible for the observed reac-
tivity/enantioselectivity. It was assumed that the reaction is
Figure 8. Main structures proposed along the reaction coordinate.
Three possible mechanistic scenarios were considered:
initiated by deprotonation of the pronuclephile (2,5-pen- (1) in the absence of acid, the base catalyst deprotonates
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D. A. Alonso, C. Nájera et al.
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and binds the nucleophile (A; Figure 9). Four NH groups
are available for Nu/maleimide activation, arranged in a
flexible and open reactive site; (2) when partial protonation
(1 equiv. of acid) of the catalyst is considered, the neutral
portion of the catalyst deprotonates the nucleophile, leading
to structure B, which possesses a tighter reactive space dec-
orated with three or four NH groups for reagent activation;
(3) further protonation of the catalyst with a second mole-
cule of acid would cancel the basicity of the catalyst, and
only the enol form of the nucleophile could act as a nucleo-
phile, as in structure C, lowering its reactivity.
Figure 9. Computed mechanistic alternatives A, B, and C.
After an extensive conformational search, the calculated
energies for the optimal transition states in model A predict
a high reactivity and a moderate selectivity [1.7 kcal/mol
Figure 10. Main transition structures computed in models A and
B.
energy difference between TSA2(S) and TSA2(R); Fig- phile[24] in a tight, concave reaction site. This effect in-
ure 10], which is in fair agreement with the experimental creases the energy difference between the diastereomeric
results in the absence of acid (94% yield, ee = 51 %; Table 1, forms TSB(S) and TSB(R) (24.7 and 29.3 kcal/mol respec-
entry 4). The privileged transition structures for each en- tively), predicting a high reactivity and very good enantio-
antiomer [TSA2(S) and TSA2(R)] bear an intramolecular H selectivity, as experimentally found (94% yield, ee = 97 %;
bond between the protonated and the neutral benzimid- Table 1, entry 1).
azole portions of the catalyst. As a consequence, a quite
As mentioned previously, the inclusion of a second mole-
open reaction space is formed in which the remaining four cule of TFA acid in the calculation has a deleterious effect
NH bonds are involved in a low-selective binding of the on the reactivity of the catalyst (Ͻ5% conversion; Table 1,
nucleophile and electrophile, see also the 3D picture for entry 4). We also offer an explanation for this effect: The
TSA2(S) in Figure 10.
double protonation of the catalyst cancels its basic charac-
In contrast, the inclusion of one molecule of trifluoro- ter and prevents deprotonation of the nucleophile. Only the
acetic acid might produce a fast protonation of the catalyst enol form of the nucleophile is available for the attack on
(model B). The CF3COO– anion is able to bind the two the maleimide, and both enol and maleimide appear to be
imidazole units, eliminating the possibility of an intramo- single bonded to the catalyst, as in model C. In this unfa-
lecular H-bonding between them. Optimal transition struc- vorable scenario, it is not surprising to find a high com-
tures were found in which three of the NH groups are ex- puted activation energy (46.3 kcal/mol).
posed to the trifluoroacetate anion and solvent. In this
Finally, the distinct outcome shown by the malonates as
structure, the activation of the maleimide is achieved by a nucleophiles might be related to the lower acidity of di-
single NH bond, and two other NH groups bind the nucleo- methyl malonate vs. acetylacetone [pKa values in dimethyl
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Enantioselective Synthesis of Succinimides
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of new organocatalysts, general experimental pro-
cedures, physical and spectroscopic data for compounds 6 and 7,
computational data as well as HPLC and NMR spectra.
sulfoxide (DMSO) are 15.7 and 13.3, respectively]. In fact,
deprotonation of dimethyl malonate by the TFA-proton-
ated catalyst (mechanism B) is computed to be a disfavored
process (Figure 11). Thus, reactions of malonate either in
the presence or absence of TFA proceed through mecha-
nism A, with a computed ee = 86 %, in fair agreement with
the experimental results (ee = 74–78 %; Figure 6), but at
different rates, since the acid exerts a negative effect by re-
ducing the available amount of the necessary free imidazole.
Acknowledgments
Financial support from the Ministerio de Educación y Ciencia
(MEC) (project numbers CTQ2007-62771/BQU, CTQ2010-20387),
from Consolider INGENIO 2010 (grant number CSD2007-00006),
from the Generalitat Valenciana (PROMETEO/2009/038), from
Fondos Europeos para el Desarrollo Regional (FEDER), from the
University of Alicante, and from the European Union (EU)
(ORCA Action CM0905) is acknowledged. We also thank SGI/
IZO-SGIker UPV/EHU for allocation of computational resources
and Dr. Emilio Lorenzo for the DOSY NMR experiments.
[1] a) M. K. Hargreaves, J. G. Pritchard, H. R. Dave, Chem. Rev.
1970, 70, 439–469; b) S. Muthaiah, S. H. Hong, Synthesis 2011,
1481–1485; c) J. Sperry, Synthesis 2011, 3569–3580.
[2] A. M. Crider, T. M. Kolczynski, K. M. Yates, J. Med. Chem.
1980, 23, 324–326.
[3] a) T. A. Glauser, E. Perucca, in: Treatment of Epilepsy, 3rd. ed.
(Eds.: S. Shorvon, E. Perucca, J. Engel Jr.), Wiley-Blackwell,
Oxford, UK, 2009, pp. 499–509; b) P. Striano, C. Minetti, Nat.
Rev. Neurosci. 2010, 6, 420–421.
[4] a) A. Fredenhagen, S. Y. Tamura, P. T. M. Kenny, H. Komura,
Y. Naya, K. Nakanishi, J. Am. Chem. Soc. 1987, 109, 4409–
4411; b) J. Needham, M. T. Kelly, M. Ishige, R. J. Andersen, J.
Org. Chem. 1994, 59, 2058–2063.
[5] For selected examples, see: a) E. J. Yoo, M. Wasa, J.-Q. Yu, J.
Am. Chem. Soc. 2010, 132, 17378–17380; b) S. Das, D. Addis,
L. R. Knöpke, U. Bentrup, K. Junge, A. Brückner, M. Beller,
Angew. Chem. 2011, 123, 9346; Angew. Chem. Int. Ed. 2011,
50, 9180–9184.
Figure 11. Different binding properties of the computed nucleo-
philes.
[6] a) S. Ahmed, Drug Des. Discovery 1996, 14, 77–89; b) M. L.
Curtin, R. B. Garland, H. R. Heyman, R. R. Frey, M. R.
Michaelides, J. Li, L. J. Pease, K. B. Glaser, P. A. Marcotte,
S. K. Davidsen, Bioorg. Med. Chem. Lett. 2002, 12, 2919–2923;
c) J. Pohlmann, T. Lampe, M. Shimada, P. G. Nell, J. Perner-
storfer, N. Svenstrup, N. A. Brunner, G. Schiffer, C. Freiberg,
Bioorg. Med. Chem. Lett. 2005, 15, 1189–1192.
Conclusion
We have designed a chiral 2-aminobenzimidazole catalyst
5f that catalyzes the direct conjugate addition of a range of
1,3-dicarbonyl compounds to maleimide and N-substituted
maleimides to give the corresponding Michael adducts with
very high enantiocontrol. The proposed hydrogen-bonding
activation role of the catalyst and the origin of the stereose-
lectivity of the process have been confirmed by DFT calcu-
lations. Further studies are in progress to explore the scope
of organocatalyst 5f in other catalytic asymmetric reactions.
[7] For selected examples, see: a) B. Alcaide, P. Almendros, G. Ca-
brero, P. Ruiz, Org. Lett. 2004, 6, 3981–3984; b) T. Mashiko,
N. Kumagai, M. Shibasaki, Org. Lett. 2008, 10, 2725–2728; c)
A. Wilsily, E. Fillion, Org. Lett. 2008, 10, 2801–2804.
[8] a) For recent examples of the asymmetric rhodium-catalyzed
asymmetric 1,4-addition of arylboronic acids to maleimides,
see: R. Shintani, K. Ueyama, I. Yamada, T. Hayashi, Org. Lett.
2004, 6, 3425–3427; b) R. Shintani, W.-L. Duan, T. Nagano,
A. Okada, T. Hayashi, Angew. Chem. 2005, 117, 4687; Angew.
Chem. Int. Ed. 2005, 44, 4611–4614; c) R. Shintani, W.-L.
Duan, T. Hayashi, J. Am. Chem. Soc. 2006, 128, 5628–5629.
[9] a) D. Almasi, D. A. Alonso, C. Nájera, Tetrahedron: Asym-
¸
Experimental Section
metry 2007, 18, 299–365; b) S. B. Tsogoeva, Eur. J. Org. Chem.
2007, 1701–1716; c) J. L. Vicario, D. Badía, L. Carrillo, Synthe-
sis 2007, 2065–2092; d) S. Sulzer-Mossé, A. Alexakis, Chem.
Commun. 2007, 3123–3135; e) Organocatalytic Enantioselective
Conjugate Addition Reactions. A Powerful Tool for the Ste-
reocontrolled Synthesis of Complex Molecules (Eds.: J. L. Vic-
ario, D. Badia, L. Carrillo, E. Reyes), RSC, Cambridge, UK,
2010; f) D. A. Alonso, in: Enantioselective Organocatalyzed Re-
actions II. Asymmetric C–C Bond Formation Processes (Ed.: R.
Mahrwald), Springer, Heidelberg, Germany, 2011, pp. 41–185.
[10] a) F. Yu, X. Sun, Z. Jin, S. Wen, X. Liang, J. Ye, Chem. Com-
mun. 2010, 46, 4589–4591; b) J. Wang, M.-M. Zhang, S. Zhang,
Z.-A. Xu, H. Li, X.-H. Yu, W. Wang, Synlett 2011, 463–476.
Typical Experimental Procedure: To a stirred solution of catalyst 5f
(5.2 mg, 0.015 mmol, 10 mol-%) and maleimide (14.6 mg,
0.15 mmol) in toluene (185 μL), a 1% (v/v) TFA solution in toluene
(115 μL, 0.015 mmol) and acetylacetone (30.8 μL, 0.3 mmol) were
added. The reaction mixture was stirred at 30 °C for 24 h, then the
solvent was evaporated under reduced pressure to give the crude
product that was purified by flash chromatography (EtOAc/hexane)
to afford pure 6a (27.8 mg, 94% yield). The selectivity of the reac-
tion was determined by chiral HPLC before purification to be ee
= 97 % (Chiralcel OD-H; 1 mL/min; hexane/iPrOH, 85:15; λ =
210 nm): tR = 28.5, 33.4 min.
Eur. J. Org. Chem. 2013, 1434–1440
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[11]
[14] a) L. Zhang, M.-M. Lee, S.-M. Lee, J. Lee, M. Cheng, B.-S.
Jeong, H.-g. Park, S.-S. Jew, Adv. Synth. Catal. 2009, 351,
3063–3066; b) J. Lin, H. Tian, Y.-J. Jiang, W.-B. Huang, L.-Y.
Zheng, S.-Q. Zhang, Tetrahedron: Asymmetry 2011, 22, 1434–
1440; c) M. Lee, L. Zhang, Y. Park, H.-G. Park, Tetrahedron
2012, 68, 1452–1459.
[15] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–
5743; b) X. Yu, W. Wang, Chem. Asian J. 2008, 3, 516–532; c)
Y. Sohtome, K. Nagasawa, Synlett 2010, 1–22; d) Hydrogen
Bonding in Organic Synthesis (Eds.: M. Petri, M. Pihko), Wiley-
VCH, Weinheim, Germany, 2009.
a) G.-L. Zhao, Y. Xu, H. Sundén, L. Eriksson, M. Sayah, A.
Córdova, Chem. Commun. 2007, 734–735; b) F. Xue, L. Liu, S.
Zhannng, W. Duan, W. Wang, Chem. Eur. J. 2010, 16, 7979–
7982; c) F. Yu, Z. Jin, H. Huang, T. Ye, X. Liang, J. Ye, Org.
Biomol. Chem. 2010, 8, 4767–4774; d) T. Miura, S. Nishida, A.
Masuda, N. Tada, A. Itoh, Tetrahedron Lett. 2011, 52, 4158–
4160; e) T. Miura, A. Masuda, M. Ina, K. Nakashima, S. Nish-
ida, N. Tada, Tetrahedron: Asymmetry 2011, 22, 1605–1609;
f) Z.-W. Ma, Y.-X. Liu, P.-L. Li, H. Ren, Y. Zhu, J.-C. Tao,
Tetrahedron: Asymmetry 2011, 22, 1740–1748.
[12] a) G. Bartoli, M. Bosco, A. Carlone, A. Cavalli, M. Locatelli,
A. Mazzanti, P. Ricci, L. Sambri, P. Melchiorre, Angew. Chem.
2006, 118, 5088; Angew. Chem. Int. Ed. 2006, 45, 4966–4870;
b) J. Shen, T. T. Nguyen, Y.-P. Goh, W. Ye, X. Fu, J. Xu, C.-
H. Tan, J. Am. Chem. Soc. 2006, 128, 13692–13693; c) W. Ye,
Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh, C.-H.
Tan, Adv. Synth. Catal. 2007, 349, 2454–2458; d) Z. Jiang, Y.
Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang, M. W.
Wong, C.-H. Tan, Angew. Chem. 2009, 121, 3681; Angew.
Chem. Int. Ed. 2009, 48, 3627–3631; e) C. S. Cucinotta, M.
Kosa, P. Melchiorre, A. Cavalli, F. L. Gervasio, Chem. Eur. J.
2009, 15, 7913–7921; f) Y.-H. Liao, X.-L. Liu, Z.-J. Wu, L.-F.
Cun, X.-M. Zhang, W.-C. Yuan, Org. Lett. 2010, 12, 2896–
2899; g) A. Zea, G. Valero, A.-N. R. Alba, A. Moyano, R.
Rios, Adv. Synth. Catal. 2010, 352, 1102–1106; h) X. Li, S. Hu,
Z. Xi, L. Zhang, S. Luo, J.-P. Cheng, J. Org. Chem. 2010, 75,
8697–8700; i) A.-N. R. Alba, G. Valero, T. Calbet, M. Font-
Bardía, A. Moyano, R. Rios, Chem. Eur. J. 2010, 16, 9884–
9889; j) J.-J. Wang, X.-J. Dong, W.-T. Wei, M. Yan, Tetrahe-
dron: Asymmetry 2011, 22, 690–696; k) Y.-H. Liao, X.-L. Liu,
Z.-J. Wu, X.-L. Du, X.-M. Zhang, W.-C. Yuan, Adv. Synth.
Catal. 2011, 353, 1720–1728; l) S. Shirakawa, S. J. Terao, R.
He, K. Maruoka, Chem. Commun. 2011, 47, 10557–10559; m)
J.-F. Bai, L.-L. Wang, L. Peng, Y.-L. Guo, L.-N. Jia, F. Tian,
G.-Y. He, X.-Y. Xu, L.-X. Wang, J. Org. Chem. 2012, 77, 2947–
2953; n) A. Mazzanti, T. Calbet, M. Font-Bardía, A. Moyano,
R. Rios, Org. Biomol. Chem. 2012, 10, 1645–1652; o) A.-N. R.
Alba, G. Valero, T. Calbet, M. Font-Bardía, A. Moyano, R.
Rios, New J. Chem. 2012, 36, 613–618.
[16] a) H. Miyabe, Y. Takemoto, Bull. Chem. Soc. Jpn. 2008, 81,
785–795; b) S. Connon, Synlett 2009, 354–376.
[17] J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem. Soc.
2008, 130, 14416–14417.
[18] a) E. Gómez-Torres, D. A. Alonso, E. Gómez-Bengoa, C.
Nájera, Org. Lett. 2011, 13, 6106–6109; b) E. Gómez-Torres,
D. A. Alonso, E. Gómez-Bengoa, C. Nájera, Synfacts 2012, 8,
100.
[19] For the full study, see the Supporting Information.
[20] For a self-association-free dimeric cinchona alkaloid organoca-
talyst, see: J. W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang,
C. E. Song, Chem. Commun. 2009, 7224–7226.
[21] The enantioselectivity of succinimides 6 was determined to be
ee Ͼ99 % by analysis of the crude reaction mixture before fil-
tration.
[22] For the synthesis of other chiral 3-substituted heterocyclic suc-
cinimides by asymmetric organocatalyzed conjugate addition
to maleimides, see ref.[12f,12h,12i,12n,12o]
[23] Calculations carried out in a solvent model (IEFPCM, toluene)
at B3LYP/6–311++G** level. The values used in the discussion
correspond to Free Gibbs energies (G). For further details, see
the Supporting Information.
[24] Tighter H-bonding to the nucleophile than to the electrophile
during the transition state has also been observed in related
addition reactions, see: a) A. Hamza, G. Schubert, T. Soós, I.
Papai, J. Am. Chem. Soc. 2006, 128, 13151–13160; b) E.
Gómez-Bengoa, A. Linden, R. López, I. Múgica-Mendiola,
M. Oiarbide, C. Palomo, J. Am. Chem. Soc. 2008, 130, 7955–
7966.
[13] D. Almasi, D. A. Alonso, E. Gómez-Bengoa, C. Nájera, J. Org.
¸
Received: August 3, 2012
Published Online: October 30, 2012
Chem. 2009, 74, 6163–6168.
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