A novel multicomponent reaction between amino acids, aromatic aldehydes and p-toluenesulfonylmethyl isocyanide: an efficient and green one-pot synthesis using nanosilica

ABSTRACT The novel diastereomeric sulfonylamide derivatives 4a–h were synthesized by multi-component reactions between (l)-α-amino acids, 1, aromatic aldehydes, 2 and p-toluenesulfonylmethyl isocyanide, 3 in water/methanol using nanosilica as a catalyst. The one-pot green reactions were carried out at room temperature with a quantitative yield in water/methanol. The yield of the reactions and products was determined and discussed. The reusablity of the catalyst is discussed.

There are a few reports about the α-amino acids used in the Ugi reaction (22). The Ugi reaction offers the possibility to synthesize a great number of different compounds in one reaction. These libraries can then be tested with enzymes or living organisms to find new active pharmaceutical substances. As a continuation our recent studies (23)(24)(25)(26), we report the green MCR between (L)-α-amino acids, aromatic aldehydes and p-toluenesulfonylmethyl isocyanide in water/methanol ( Figure 1).

Experimental detail
Starting materials and solvents were purchased from Merck (Germany) and Fluka (Switzerland) and were used without further purification. The reactions were monitored by TLC and NMR techniques, which indicated that there were no side products. IR spectra were measured on a Perkin-Elmer RXI, FT-IR spectrometer. 1 H and 13 C NMR spectra (CDCl 3 ) were recorded on a Bruker-Avance spectrometer at 300.0 and 75.0 MHz, respectively. Elemental analyses were performed by using a Perkin-Elmer 2400(II) CHN/O analyzer. The TLC plates were prepared from Merck silica gel powder.

General procedure for the synthesis of 4a-h
Silica nanoparticles (SNPs) (0.2 g) were added to a mixture of (L)-α-aminoacid (1 mmol) and aldehyde (1 mmol) which were stirred in 5 mL water-methanol (1:1) at the room temperature for 60 min. To this mixture, isocyanide (1 mmol) at 15°C was rapidly added and the solution was allowed to stand for 24 h at room temperature. The solvent was removed under reduced pressure and the diastereomeric products (4a-h) were obtained. Two diastereomers produced through purification with preparative thin layer liquid chromatography (PTLC) method by using petroleum ether-diethyl ether (10:1). Yield of the mixture of the diastereomers was determined after PTLC. The diastereomeric ratio was determined by 1H-NMR analysis of unpurified products ( Table 1). The characterization data of the compounds are given below.

Results and discussion
As a continuation of our studies, the aim of this work was to develop simple, one-pot, green and multi-component reactions between α-amino acids, 1, aromatic aldehydes 2 and p-toluenesulfonylmethyl isocyanide 3 in the presence of the SNPs at room temperature, leading to tosylmethylamino derivatives 4 ( Figure 1 and Table 1). The reaction occurs smoothly in the presence of the SNP at ambient temperature in water/methanol to produce the tosylmethylamino derivatives 4 in good yields ( Table 1). The diastereomeric products were obtained after purification with a quantitative yield in one pot. In   the absence of SNP, the reactions were not carried out to obtain the compounds 4a-h or obtain with low yields.
We also used silica particles as catalyst which increase slightly the yield of reactions (Table 1). The SNPs were prepared by thermal decomposition of rice hulls (27). The results from X-ray diffraction (XRD) showed that the sample was SNP as indicated by broadened peaks around 2θ = 22○ (Figure 2). The scanning electron microscopy (SEM) was used to investigate the morphology and grain size of the SNP (Figure 3) (28,29).
The 1H-decoupled 13 C-NMR spectrum of a major diastereomer in 4a showed 18 distinct signals; partial assignment of these signals is given in the experimental section. The 1 H-and 13 C-NMR spectra of compounds 4b-h were similar to those of 4a, except for the aromatic moiety, and the alkyl groups, which exhibited characteristic signals with appropriate chemical shifts.
As indicated in Table 1, the reactions proceeded efficiently with leucine 1 while lysine is not a suitable starting material in this reaction.
Although we have not established the mechanism of the reaction in an experimental manner, a plausible reaction sequence that accounts for the formation of 4 is shown in Figure 4. Thus, the condensation of amino acid 1 and aldehyde 2 gives an iminium ion intermediate 5,

Catalyst recovery
The recovered catalyst from the experiment was washed with acetone (3×5 mL). Then, it was dried and used in the synthesis of sulfonylamide derivatives 4a-h. Then, the catalyst was recycled for five times. The separated catalyst was used several times with a slightly decreased activity.

Conclusion
The novel diastereomeric sulfonylamide derivatives 4a-h were synthesized by multi-component reactions between α-amino acids, 1, aromatic aldehydes, 2 and p-toluenesulfonylmethyl isocyanide, 3 in water/methanol using nanosilica as a catalyst. The yield of these reactions was increased using SNPs as a catalyst. The electron-donating groups attached at the para position of aromatic aldehydes increased the yield of the reactions. The separated catalyst was used several times with a slightly decreased activity.