Synthesis of methylenebisamides using CC- or DCMT-activated DMSO

Bisamides are key fragments for the introduction of gem-diaminoalkyl residues into retroinverso pseudopeptide derivatives and in the synthesis of peptidomimetic compounds. The literature methods for these types of compounds have certain drawbacks. In particular, when amides react with electrophile-activated DMSO, the yields are rather low. We have found new electrophiles, 2,4,6-trichloro[1,3,5]triazine (CC) and 2,4-dichloro-6-methoxy[1,3,5]triazine (DCMT), which activate DMSO in the presence of amides to yield methylenebisamides in good to fair yields. The amides can be aromatic or aliphatic. The operation is simple and the reagents are inexpensive.

The amide moiety is an important constituent of many biologically significant compounds. Bisamides are of considerable interest in the synthesis of peptidomimetic compounds [15]. In particular, bisamides are key fragments for the introduction of gem-diaminoalkyl residues in retro-inverso pseudopeptide derivatives [16] by treating the corresponding amide with iodobenzene bistrifluoroacetate [17]. N,N′-Methylenebisamides are usually prepared by the reactions of amides with aldehydes [18][19][20], hexamethylenetetramine [21] or activated DMSO [6], or by the reaction of nitriles with formaldehyde [22] or activated sulfoxides [23]. However, each method has certain limitations with regards to scope and reaction conditions, for example, longer reaction time [20], lower yield [6], purification problems [21,23] and drastic reaction conditions [19,22].

Results and Discussion
Initially, we chose CC as the activation reagent and benzamide as a model substrate to optimize the reaction conditions (Scheme 1, Table 1). No product was observed when the reaction was carried out in CH 3 CN (Table 1, entry 1). The reaction proceeded in CHCl 3 , DMSO, EtOAc and toluene (

2-4).
Better results were obtained when the reactions were performed in toluene (Table 1, entry 5). Encouraged by these results, we studied the effects of temperature on the reaction in toluene. Elevating the temperature to 70 °C resulted in an improved reaction rate. As for the influence of CC and DMSO dosage on the reaction, it was found that decreasing the amount of CC to 0.9 equiv resulted in reduced yield, while increasing the amount to 1.5 equiv did not make the reaction system complex and the yield was not notably different. Excess amount of DMSO (7.0 equiv) was used partially because of its ability to dissolve the amides.
After the optimization of the reaction conditions, various substrates were subjected to the conditions (Scheme 2, Table 2). The electronic effect of the substituents on aromatic rings was observed. For example, a strong electron-donating or electronwithdrawing group on the aromatic ring resulted in decreased reaction yields (Table 2, entries 5, 8), while a substituent on the para-position or meta-position led to a moderate yield (Table 2, entries 4, 7). The effect of substituents on the reaction rate was not remarkable. However, the method was not efficient for the aliphatic amides: considerable amounts of by-products were formed, probably due to the greater nucleophilicity of the aliphatic amides.  In order to improve the yield of aliphatic amides, less active DCMT was used as activating reagent instead of CC. We also optimized the reaction conditions using benzamide as a benchmark (Scheme 3, Table 3). The reaction did not proceed when low boiling solvents such as CH 3 CN, CHCl 3 and ClCH 2 CH 2 Cl were used (Table 3, entries 1-3). It was performed efficiently in high boiling solvents (1,4-dioxane, xylene and DMSO) ( Table  3, entries 4-6). The results indicate that the effect of temperature on the reaction is remarkable. The electronic effect of the substituents on aromatic rings was similar to the results when CC was used as an activating reagent (Scheme 4, Table 4, entries 5, 8). The system of DCMT/DMSO was efficient for aliphatic amides (Scheme 4, Table 4, entries 10-13).
Based on these experiments, a possible mechanism [6,23,25] is shown in Scheme 5. Intermediate 1 reacted with amides by two pathways. When the reaction of benzamide and CC-activated DMSO was carried out in chloroform, S,S-dimethyl-N-benzoylsulfilimine (4)    The amide substitutes the thioether of 5 to form methylenebisamides 6.

Conclusion
In conclusion, we have developed a simple and efficient procedure to produce methylenebisamides in good yield via the reaction of amides with CC-or DCMT-activated DMSO. The procedure reported herein is operationally simple, and requires inexpensive and commercially available reagents. A plausible mechanism of the reaction which involves two sulfonium salt intermediates was proposed and supported by the experiments.

Experimental
All chemicals were obtained from commercial sources or prepared according to standard methods [24]. All chemicals and solvents used in the reactions were dried by standard procedures prior to use. IR spectra were recorded on a Bio-Rad Exalibur FTS3000 spectrometer. The 1 H NMR (500 MHz) and 13  A mixture of amide (121.4 mg, 1.0 mmol, 1 equiv), CC (222 mg, 1.2 mmol, 1.2 equiv) and dry DMSO (0.5 mL, 7.0 mmol, 7.0 equiv) in dry toluene (8.0 mL) was stirred for 30 min at room temperature. The reaction temperature was then kept at 70°C for 1.5 h until completion. The mixture was neutralized with saturated aqueous NaHCO 3 (20 mL), then extracted with EtOAc (3 × 20 mL). The extract was washed with brine (4 × 15 mL), dried over anhydrous Na 2 SO 4 . The solvent was concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE/EA = 1/1) to afford N,N′-methylenedibenzamide (90.1 mg, 71% yield). (Table 4,