Mannich-type reactions in a colloidal solution
formed by sodium tetrakis(3,5-trifluoromethylphenyl)borate
as a catalyst in water
Chi-Tsing Chang, Bei-Sih Liao and Shiuh-Tzung Liu
* Department of Chemistry, National Taiwan University, Taipei 106, TaiwanReceived 22 August 2006; revised 18 October 2006; accepted 25 October 2006 Available online 13 November 2006
Abstract—Sodium tetrakis(3,5-trifluoromethylphenyl)borate½NaBArF4 efficiently catalyzed the one-pot, three-component Mannich
reaction of ketones with aromatic aldehydes and different anilines in water at an ambient temperature and afforded the correspond-ing b-amino carbonyl compounds in good to excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The Mannich reaction is one of the most important car-bon–carbon bond forming reactions in organic synthesis, Eq.1.1This reaction provides the formation of b-amino carbonyl compounds, which are important intermediates for the construction of various nitrogen-containing nat-ural products and pharmaceuticals.2However, the dras-tic reaction conditions for the classical intermolecular Mannich reaction limit its synthetic usefulness. There-fore, numerous modifications of this reaction have been developed to overcome the drawbacks.1,3 Many metal complexes have been used as Lewis acid catalysts to pro-mote the reaction under anhydrous conditions,1–3 and few water-compatible Lewis acids were reported.4
In recent years, organic reactions in an aqueous medium have received enormous attention, because the use of water has several advantages as it is the easiest obtain-able solvent, is an environmentally friendly substance, and can be easily separated from organic products.5–7 In this context, researches focusing on the development of new catalysts to promote organic reactions in water have become highly desirable. In an early report
Koba-yashi and Manabe, they found that dodecylbenzenesulf-onic acid could catalyze the Mannich reaction at an ambient temperature in water to give various b-amino ketones in good yields.6 In these surfactant-aided sys-tems, organic substrates form emulsion droplets that function as reaction media in water. However, the pres-ence of a Brønsted acid is still required to carry out the reaction in most of the instances. Here, we offer an efficient method for the preparation of Mannich type products in water by using sodium tetrakis(3,5-trifluoro-methyl-phenyl)borate (½NaBArF4) as a catalyst under mild and nearly neutral conditions.
Initially, the two-component Mannich reaction of N-benzylideneaniline (1.0 mmol) and various nucleophiles (2 mmol) was examined (Table 1). As a preliminary study, we found that½NaBArF
4 did not catalyze the reac-tion of acetophenone with benzylideneaniline in most of the organic solvents such as THF, dichloromethane or DMF. It was revealed that the present Mannich-type reaction proceeded only in aqueous media. Running the reaction of benzylideneaniline with ketone in water at an ambient temperature gave the desired product in an excellent yield (Table 1, entry 4). Encouraged by the results, we examined various ketones and silyl eno-lates to screen the scope of this new protocol. The silyl R1CHO + R2NH2+ O R4 R3 R1 R4 NH O R2 R3 catalyst ð1Þ F3C F3C B Na NaBArF4 4
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* Corresponding author. Tel.: +8862 23660352; fax: +8862 23636359; e-mail:[email protected]
enolate as the nucleophile in the reaction appeared to be more reactive than the corresponding ketone com-pounds as evidenced by the shorter reaction time and better yields (Table 1, entries 5 and 6).
With the success of the above coupling reaction, we examined the feasibility of the three-component Mannich reaction. The reaction of benzaldehyde, aniline, and acetophenone in the presence of½NaBArF4 as the catalyst in water provided the desired compound in an 81% isolated yield (Table 2, entry 1). Again, this efficient catalyst was not observed in the reactions car-ried out in the organic solvents. Several of the substi-tuted anilines underwent the reaction smoothly except for p-nitroaniline (Table 2, entry 9). By using 1H NMR to monitor the reaction, we realized that the imine intermediate, 4-nitrobenzylidenephenylamine, was not formed during the reaction.
The reactions proceeded not only for acetophenone but also for other dialkyl ketones in good yields. As illus-trated inScheme 1,½NaBArF4 did catalyze the Mannich reaction of cyclohexone, substituted benzaldehydes, and anilines to yield the desired b-amino ketone products. The stereoselectivity was determined by1H NMR spec-troscopy and by comparison with known compounds.
The selectivity for anti-isomers is slightly favored. In addition, the reaction of cyclohexanone and p-chloro-aniline with 1-naphthalenecarbaldehyde yielded the coupling product, 2-[(4-chlorophenylamino)naphtha-len-1-ylmethyl]-cyclohexanone, in 65% (anti:syn = 1:1). For unsymmetric ketone, the regioselectivity of the less hindered site is observed. Thus, the reaction of 2-buta-none, benzaldehyde, and aniline in the presence of ½NaBArF
4 in water provided Mannich products I and II, Eq.2. The ratio of I:II is about 85:15, indicating that the reaction takes place at the less substituted carbon center.
It should be noted that the addition of organic substrates to this sodium salt in water readily formed a milky sus-pension, indicating that borate anions acted as surfac-tants.8 In an early work, we found this salt did not completely dissociate into free ions in dichloromethane, with the formation of aggregation instead.9 From the dynamic light scattering measurement, the average size of aggregated particles of ½NaBArF
4 and organic substrates is in the range of 1 lm. Thus the addition of organic substrates readily forms a colloidal disper-sion, which is similar to that of a mixture of dodecyl-benzenesulfonic acid (DBSA) and organic reagents in water reported by Kobayashi and Manabe.6Apparently, the formation of colloid particles plays an essential role in the acceleration of the coupling reaction. In our early study, the crystal structure of ½NaBArF4 reveals that the fluorine atoms of trifluoromethyl groups do coordinate toward the metal center.9We believe that such coordina-tion might partially persist in an aqueous environment, which thus increases the Lewis acidity of metal ions. In conclusion, this procedure offers several advantages for the Mannich reaction such as low loading of cata-lyst, mild conditions, high yields, clean reactions, which make it a useful and attractive methodology for organic synthesis. Quite a number of products are solid and insoluble in water, which can be obtained by filtration and recrystallization. This simple work-up procedure is also beneficial to this method. Further applications of this catalyst to other transformations are currently under investigation.
Table 1. Results of Mannich reaction catalyzed by½NaBArF4 a
Entry Ketone or silyl enol ether Solvent Time Yield (%) 1 Acetophenone CH2Cl2 96 h 0
2 Acetophenone THF 96 h 0 3 Acetophenone DMF 96 h Trace 4 Acetophenone Water 96 h 96 5 C6H5C(OSiMe3)@CH2 Water 30 min 91
1 h 100 6 C6H5C(OSiMe3)@CHCH3 Water 30 min 77
1 h 100 7 C6H5C(O)CH2CH3 Water 144 h 32
8 Cyclohexone Water 3 h 100
a
Reaction conditions: ½NaBArF
4 (0.005 mmol), ketone or silyl enol
ether (2 mmol), N-benzylideneaniline (1 mmol) at 30°C.
Table 2. Results of the three-component Mannich reactiona
O CHO R1 NH2 R2 + + NH O R2 R1 H2O NaBArF4
Entry R1 R2 Time (h) Yield (%)
1 H H 48 81 2 F H 48 51 3 Cl H 48 74 4 Br H 48 85 5 i-Propyl H 48 53 6 CH3O H 48 21 7 H I 24 100 8 H Me 24 51 9 H NO2 48 — aReaction conditions: ½NaBArF 4 (0.005 mmol), acetophenone
(2 mmol), aniline (1 mmol), aldehyde (1 mmol) in H2O (2 mL) at
30°C. CHO Y O NH2 Z NH O Z Y Y = -COOMe = -COOMe Z = I = Cl 63 % (anti:syn = 7:4) 57 % (anti:syn = 8:5) NaBAr4F H2O Scheme 1. Ph NH Ph O C6H5CHO + C6H5NH2 + O Ph NH Ph O + I II ð2Þ
Acknowledgment
This research was supported by the funding of National Science Council (NSC94-2113-M002-035).
Supplementary data
Supplementary data (spectroscopic data for the Man-nich reaction products) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet. 2006.10.125.
References and notes
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