Green and efficient aza-Michael additions of aromatic amines to α , β -unsaturated ketones catalyzed by DBU based task-specific ionic liquids without solvent

The DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) derived task-specific ionic liquids [DBU][Lac] (1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium lactate), [DBU][Ac] (1,8-diazabicyclo[5.4.0]-undec- 7-en-8-ium acetate) and [DBU][Tfa] (1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium trifluoroacetate) were synthesized. Among the three novel ionic liquids, [DBU][Lac] was found to have the highest catalytic activity for aza-Michael addition of aromatic amines to α , β -unsaturated ketones. The protocol can give good to excellent products yields and has advantages such as readily work-up and good reusability, which makes this method quite attractive.


Introduction
The aza-Michael addition is one of the widely used reactions for carbon-nitrogen bond formation in modern organic synthetic chemistry.Conjugate reaction of various amines with α,βunsaturated carbonyl compounds provides β-amino carbonyl ingredients, which have attracted great attention for their use as key intermediates of anticancer agents, antibiotics and other drugs. 1 Generally, aza-Michael additions have been catalyzed by strong bases and acids, and some side reactions occurred.Therefore, chemical researchers have paid more attentions to the development of more mild catalytic systems for the aza-conjugate reaction.A number of alternative methodologies using Lewis acidic catalysts such as PtCl 4 •5H 2 O, 2a Cu(OTf) 2 , 2b InCl 3 , 2c Yb(OTf 3 ), 2d, 2e LiClO 4 , 2f Bi(NO 3 ) , 2g FeCl 3 .6H 2 O, 2h CeCl 3 .7H 2 O, 2i ZnO, 2j MgO assisted by microwave irradiation, 2k silica supported perchloric acid 2l and sulfated zirconia 2m have been reported.Recently, silica gel in acetonitrile, 3a β-cyclodextrin in water, 3b PEG (MW 400) and 2-

Results and Discussion
We synthesized three DBU-based task-specified ionic liquids by simply neutralization reaction of DBU and three carboxyl acids, acetic acid, lactic acid, and trifluoroacetic acid (Scheme1).The reaction of aniline with ethyl vinyl ketone (EVK) was selected as model to optimize the reaction conditions.First, using [bmim]OH which is highly efficient in Michael reaction of carbon nucleophiles and aliphatic amines as catalyst, 11 8 h was required for disappearance of the starting material (Table 1, entry 4). 6Inert ionic liquid [bmim]BF 4 (1-butyl-3-methylimidazolium tetrafluoroborate) was also tested as promoter for the reaction and only 55 % yield of the desired product was obtained in 40 min (Table 1, entry 5).For comparison, some Lewis bases such as DMAP, PPh 3 , and DBU were subjected to the model reaction and bis-adduct was formed thereby decreasing the product yield (Table 1, entries 6-8).Especially, with DBU, the bis-addition product was produced as much as 32 % yield while using its corresponding ionic liquids , and [DBU][Tfa] no bis-addition reaction was observed and 96-99 % yields were afforded within the same period, demonstrating the good chemo-and regioselectivity of these ionic liquids in the reaction of aniline with ethyl vinyl ketone (   1, entry 9).To optimize the details of the reaction conditions, solvent effect was studied in the same model reaction between aniline and EVK (Table 1, entry 1).Toluene, CH 2 Cl 2 , CH 3 OH, and CH 3 CN were all found to be effective media for the reaction and relatively lower reactant concentration in organic solvent than that under solvent-free conditions decreased the reaction rate.We then selected the solventfree conditions rather than using organic solvents from the environmental and reaction rate considerations.With the efficient catalytic system in hand, EVK was treated with other aromatic amines.The results are summarized in Table 2 (entries 1-5).Aromatic amines with electron-donating group at bezene ring were effective nucleophiles to react smoothly with EVK and excellent yields were afforded in very short reaction time (Table 2, entries 1-2), while 2-Methyl substituted amine, due to its steric hindrance, reacted relatively slowly (entry 3).p-NO 2 substituted amine could not undergo the reaction at all (entry 5).Arylamine with weakly electron-drawing substitution Cl was also tested with EVK under the above reaction conditions and 95 % GC yield was obtained in 1 h (entry 4).In order to evaluate the generality of the ionic liquid [DBU][Lac] as catalyst for aza-Michael reaction of aromatic amines, 2-cyclohexen-1-one, 2-cyclopenten-1-one and chalcone were tested under the same conditions (Table 2, entries 6-17).To our delight, 2-cyclohexen-1-one and chalcone were effective Michael acceptors to react with various arylamines, achieving good to excellent isolated yields (entries, 6-10, 14-17).However, 2-cyclopenten-1-one showed relatively lower reactivity.Accordingly, higher temperature (60 ºC) was required (entries, 11-13).For further comparison with [bmim]OH, [DBU][Lac] was used as promoter for the additions of pmethyl aniline to EVK and p-methyl aniline to 2-cyclohexen-1-one respectively (entries, 2, 10).With comparable or higher products yields obtained, the two reactions catalyzed by [DBU][Lac] proceeded much faster than those promoted by [bmim]OH.Moreover, chalcone reacted smoothly with various aromatic amines using [DBU][Lac] as catalyst (entries, 14-17) while no reaction occurred in the presence of the ionic liquid [bmim]OH. 6All cases summarized in Table 2 obviously demonstrate that the novel ionic liquid [DBU][Lac] has the excellent catalytic activity for aza-Michael reaction of aromatic amines and α,β-unsaturated ketones.

Table 2. [DBU]
[Lac] catalyzed aza-Michael reactions of various aromatic amines with α,β-unsaturated ketones at room temperature a The recyclability of the ionic liquid [DBU][Lac] was then studied using the reaction of aniline and 2-cyclohexen-1-one as a model.The results are shown in Table 3. Upon the completion of the reaction, the reaction solution was extracted with ethyl acetate and purified by flash chromatography.The addition product was identified by 1 H NMR, 13 C NMR and mass spectra.The residual ionic liquid was washed with ethyl ether, dried under vacuum at 60 ºC for 2 h and reused for subsequent reactions.As shown in Table 3, the recovered ionic liquid could be used for 8 times without obvious loss of catalytic activity of the ionic liquid.It is worthwhile to note that the ionic liquid [DBU][Lac] used for 8 runs remained intact, judging from its 1 H NMR spectrum.

Conclusions
In conclusion, we have developed three task-specific ionic liquids, [DBU][Lac], [DBU][Ac] and [DBU][Tfa].The ionic liquids were then used as catalysts for aza-Michael addition of aniline to EVK.Among the three ionic liquids, [DBU][Lac] exhibited the best catalytic activity.Using [DBU][Lac] as catalyst, various aromatic amines were subjected to 2-cyclohexen-1-one, 2cyclopenten-1-one and chalcone, and good to excellent yields were obtained.This protocol also has some advantages, such as readily work-up of the reactions and excellent reaction selectivity and good recyclability of the ionic liquid (reused for 8 times without significant loss of activity).

Experimental Section
General Procedures.All chemical were purchased from Aldrich or Fluka. 1 H and 13 C NMR were recorded on a Bruker Avance DPX 400 spectrometer at 400 MHz and 100 MHz in CDCl 3 and DMSO-d 6, respectively.Chemical shifts were reported in parts per million (δ), relative to the internal standard of tetramethylsilane (TMS).Melting points were determined usingYRT-3 apparatus and were not corrected.Mass spectrometry data were obtained on Brucker Esquire-LC for electro-spay (MS-ES) measurements.Elemental analysis was carried out on a Carlo Erba 1160.All reactions were monitored by thin layer chromatography (TLC).Flash chromatography was performed on silica gel (100-200 mesh).All Michael adducts were purified through column chromatography and were characterised by NMR analysis, melting points and MS.

General procedure for preparation of ionic liquids [DBU][Lac], [DBU][Ac] and [DBU][Tfa].
DBU (6 mmol) was added to a 50 mL three -necked flask cooled by ice bath.Carboxylic acid (6 mmol) was then added dropwise at the temperature (≤5 ºC) with thorough mixing.After dropwise addition, removed the ice bath and the reaction mixture was stirred at room temperature for 24 h.The oil residue was dried in vacuo at 60 ºC for 24 h to afford desired ionic liquid as light yellow, viscous liquid.

General procedure for aza-Michael reaction of aliphatic amines with α,β-unsaturated compounds
To a mixture of the aromatic amine (1 mmol) and Michael acceptor (1.5 mmol) in 10 mL flask equipped with a magnetic stirrer was added ionic liquid [DBU][Lac] (0.3 equiv).The reaction mixture was stirred at room temperature for the desired time until the disappearance of starting material monitored by TLC.Upon completion of the reaction, the mixture was extracted with ethyl acetate for several times.The combined organic phase was concentrated through vacuum evaporation and the resulting crude product was purified by silica column chromatography to give the desired product.These products are in good agreement with spectra data of literatures.The ionic liquid [DBU][Lac] after extraction was dried in vacuo at 60 ºC for 5 h.The recovered ionic liquid was then reused in subsequent reactions.

a
] in the Reaction between aniline and 2-cyclohexen-1Reaction conditions: 1 mmol of aniline, 1.5 mmol of 2-cyclohexen-1-one, 0.3 mmol of [DBU][Lac] without solvents at rt. b GC yields.As for the role of DBU-based ionic liquids for the activation in the aza-Michael addition of aromatic amines to α,β-unsaturated ketones, [DBU][Lac] and [DBU][Ac] were regarded as Brønsted base to promote the addition and [DBU][Tfa] played the role as Brønsted acid for the this type of aza-Michael reaction.The reason for slightly higher catalytic activity of [DBU][Lac] than those of the other two ionic liquids may be the activation of carbonyl group of Michael acceptors by the hydroxyl group at the α-position of the carboxyl in lactate anion.