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J. Flores-Ferrándiz, R. Chinchilla / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Other
a
,
a
-disubstituted aldehydes were employed for the
room temperature. Once the reaction is completed, the final adduct
can be separated by extraction, and the deep eutectic solvent
retaining the organocatalyst, can be reused up to four times after
the addition of fresh additive, while keeping its enantiodifferentia-
tion activity. These results demonstrate than the use of deep eutec-
tic solvents in enantioselective organocatalytic reactions can result
in efficient and green strategies, and afford even better enantiose-
lections than when conventional volatile organic compounds are
used.
organocatalyzed conjugate addition reaction to N-phenyl-
maleimide. Thus, 2-ethylbutanal 3b afforded succinimide (R)-4ba
with moderate yield and enantioselectivity (Table 2, entry 10).
However, cyclopentanecarbaldehyde 2c gave almost a quantitative
yield of (R)-4ca with 87% ee (Table 2, entry 11), something very dif-
ferent than when using cyclohexanecarbaldehyde 2d, which
afforded the corresponding adduct (R)-4da with an enantioselec-
tion of only 31% (Table 2, entry 12). Moreover, when a different
a,a-disubstituted aldehyde such as 2-phenylpropanal 2e was
employed, the final adduct was obtained in a 4/1 diastereomeric
ratio with an enantioselection of 85% for the diastereomer (S,R)-
4ea and 10% for (R,R)-4ea (Table 2, entry 13). Furthermore, the
4. Experimental
4.1. General
use of an
a-monosubstituted aldehyde such as propanal 2f,
allowed us to obtain the adducts as a 1.4/1 mixture of diastere-
omers, with enantioselections of 50% for (R,R)- and (S,R)-4fa
(Table 2, entry 14).
All reagents were commercially available and used without fur-
ther purification. Organocatalysts 1 were obtained as described.12r
All known adducts
4 were characterized by spectroscopic
methods.12r Enantioselectivities and absolute configurations were
determined on the reaction crude by HPLC analyses12r on an
Agilent 1100 series equipped with chiral columns (Chiralcel OD-
H: 4aa, 4ab, 4ac, 4ad, 4ca, 4da, 4ea;12l Chiralcel AD-H: 4af;
Chiralpak AS-H: 4ae, 4ah, 4ba; Chiralpak AD-H: 4ag, 4ai, 4fa),
using mixtures of n-hexane/isopropyl alcohol as the mobile
phase, at 25 °C. Analytical TLC was performed on Schleicher &
Schuell F1400/LS silica gel plates and the spots were visualised
under UV light. For chromatography we employed Merck silica
gel 60 (0.063–0.2 mm).
The possibility of reusing the deep eutectic solvent is the
cornerstone of a synthetic methodology performed using these
neoteric solvents. Therefore, we explored the reusability of the
deep eutectic solvent, and the catalytic system, by carrying out dif-
ferent reaction cycles of the model conjugate addition reaction per-
formed under the best reaction conditions depicted in Table 2,
entry 1. Thus, once the reaction was finished, a 4/1 v/v mixture
of ethyl ether/n-hexane was added and the resulting mixture was
stirred vigorously. After the two layers settled down, the upper
layer, containing the final adduct, was separated. Attempting to
directly reuse the lower deep eutectic solvent layer in other reac-
tion by adding new aldehyde and maleimide resulted in low yields
and moderate enantioselectivities of the resulting adduct (R)-4aa.
This was explained after observing the presence of acid additive
in the recovered organic layer (NMR). After several attempts, it
was found that refreshing the catalytic system by the addition of
new additive (but no new chiral organocatalyst) to the recovered
deep eutectic solvent allowed us to obtain (R)-4aa with almost
identical enantioselectivity and yield than when used for the first
time. Following this recovery procedure, the deep eutectic solvent
containing the organocatalyst 1a could be reused four times with-
out diminishing its enantioinduction (Table 3). However, a fifth
reaction cycle led to a decrease in the catalytic activity.
4.2. General procedure for the preparation of deep eutectic
solvents
A mixture of the two components, with the previously specified
molar ratio, was added to a round bottom flask and the mixture
was stirred for 60 min in a temperature range between 65 and
80 °C, obtaining the corresponding deep eutectic solvent.14
4.3. Enantioselective conjugate addition reaction. General
procedure
To a mixture of catalyst 1 (0.02 mmol), additive (0.02 mmol),
and maleimide (0.2 mmol) in the corresponding deep eutectic sol-
vent (0.5 mL) was added the aldehyde (0.4 mmol) and the reaction
was vigorously stirred during the necessary reaction time (TLC,
Table 2) at rt. Next 2 M HCl (10 mL) was added and the mixture
was extracted with AcOEt (3 Â 10 mL). The combined organics
were washed with aq NaHCO3 (2 Â 10 mL), dried (MgSO4) and
evaporated (15 torr), and the resulting crude was purified by flash
chromatography (hexane/EtOAc gradients) affording adduct 4.
Table 3
Recycle experiments. Yields and ee’s of (R)-4aa after consecutive reaction cyclesa
Reaction cycle
Yieldb (%)
eec (%)
1
2
3
4
5
97
95
93
76
60
94
94
93
92
84
4.4. Recycling experiments
a
1a (10 mol %), 3,4-(MeO)2C6H3CO2H (10 mol %), Ph3MePBr/Gly (1/2 molar
ratio), 25 °C, 8 h.
To a mixture of catalyst 1a (4.3 mg, 0.02 mmol), 3,4-dimethoxy-
benzoic acid (3,7 mg, 0.02 mmol), and N-phenylmaleimide
(34.6 mg, 0.2 mmol) in Ph3MePBr/Gly (1/2 molar ratio, 0.5 mL)
b
Isolated yield after flash chromatography.
c
Enantioselectivitity determined by chiral HPLC.
was added isobutyraldehyde (36.5 lL, 0.4 mmol) and the reaction
was vigorously stirred for 8 h at rt. After this period, a mixture of
ethyl ether/n-hexane (4/1, v/v, 3 mL) was added and the mixture
was stirred for 2 min. The stirring was stopped to allow for phase
separation and the upper organic layer was removed through set-
tling. This extractive procedure was repeated three times. The
combined organic extracts were washed (NaHCO3 aq, 10 mL), dried
(MgSO4), evaporated (15 torr) and purified by flash chromatogra-
phy on silica gel (hexane/EtOAc gradients) to yield (R)-4aa. The
deep eutectic solvent layer, where catalyst 1a remained dissolved,
was evaporated in vacuo to remove volatile solvent residues
3. Conclusions
It can be concluded that deep eutectic solvents can be used as
reusable solvents in enantioselective conjugate additions of alde-
hydes, mainly
a,a-disubstituted, to N-substituted maleimides, to
afford enantioenriched substituted succinimides. Carbamate-
monoprotected trans-cyclohexa-1,2-diamines have been employed
as enantiomerically pure organocatalysts, with the mono-Boc-sub-
stituted derivative affording the best results. The reaction can be
carried out in the presence of a carboxylic acid as an additive at
Flores-Ferrándiz, Jesús
