Synthesis of N-Methyl-N-formyltyramine , a New β-Phenethylamide Derivative Isolated from Cyathobasis fruticulosa ( Bunge ) Aellen

The synthesis of N-methyl-N-formyltyramine, a novel b-phenethylamide derivative isolated from Cyathobasis fructiculosa (Bunge) Aellen, is reported. The natural product was prepared in six steps and good overall yield from 4-hydroxybenzaldehyde.


Introduction
β-Phenethylamides, exemplified by compounds 1 and 2, 1 constitute a relatively widespread family of natural products, the members of which have been found mainly as soluble constituents of cell-wall fractions of higher plants. 2Several amides, structurally related to them, have been found in different plant species, 3 and N-transferuloyltyramine (3) has demonstrated to have an ubiquitous occurrence. 4,5here is no definite conclusion yet about the functions of the β-phenethylamides; however, it has been discussed their possible role in plant growth processes, as well as their participation in self defense, due to their antimicrobial and antiviral effects. 6In addition, β-phenethylamides such as 4-7 have been informed to display interesting biological activities, ranging from DNA strand scission 7 to antimutagenic and anticarcinogenic, 8 and including inhibition of the lipopolysaccharide-induced nitric oxide production in macrophages, 9 as well as inhibition of acetylcholinesterase. 10 Noteworthy, N-acetyl tyramine ( 8) is an inducible phytoalexin found in soybean seeds, 11 while Paik and coworkers reported the isolation of the unusual compounds 9-11 from Xenorhabdus nematophilus, a bacterial strain which grows symbiotic with a nematode.These β-phenethylamides were shown to be cytotoxic against five human cancer cell lines. 12ry recently, Topçu and coworkers 13 isolated Nmethyl-N-formyltyramine (12) from the aerial parts and roots of Cyathobasis fruticulosa (Bunge) Aellen (Chenopodiaceae), the only species of the genus Cyathobasis of the Turkish flora, which grows most commonly in Central Anatolia.In view of the potential interest of this type of compounds, we decided to prepare 12, and herein we disclose a short synthesis of the natural product from commercial 4-hydroxybenzaldehyde (13).

Results and Discussion
Williamson etherification of 13 with benzyl chloride provided 99% of aldehyde 14 (Scheme), which was subjected to a Henry condensation with nitromethane in the presence of ethylenediammonium diacetate as base, 14 furnishing 90% of nitrostyrene 15.In turn, this was submitted to reduction with lithium aluminum hydride, giving β-phenethylamine 16, as an oil which easily darkened upon contact with air; therefore, this was immediately amidated in refluxing ethyl formate, providing formamide 17 in 44% overall yield.Noteworthy, the 1 H and 13 C NMR spectra of 17 exhibited signals of two conformers, even at 70 ºC in DMSO-d 6 .
Next, 17 was N-methylated with methyl iodide, and the resulting amide 18 obtained in 79% yield was subjected to a final 10% Pd/C mediated catalytic hydrogenation, furnishing 92% of synthetic 12, the spectral data of which fully agreed with those previously reported for the natural product. 13Clear signals of the two conformers of 12 and 18 were also observed in their 1 H and 13 C NMR spectra.Interestingly, despite that the use of benzyl ether intermediates required additional protection and deprotection steps, increasing the length of the sequence, it allowed convenient manipulation of amine and amide reaction intermediates.
In conclusion, a simple synthesis of 12 was achieved in six steps from commercial 4-hydroxybenzaldehyde.Protection of the starting phenol as a benzyl ether allowed convenient manipulation of the reaction intermediates without sacrificing efficiency of the synthetic sequence.

General procedures
Melting points (uncorrected) were taken on an Ernst Leitz Wetzlar model 350 hot-stage microscope.FT-IR spectra were determined with a Shimadzu IR Prestige 21 spectrophotometer.The 1 H and 13 C NMR spectra were acquired in CDCl 3 employing TMS as internal standard, with a Bruker AC200-E spectrometer operating at 200.13 and 50.33 MHz, respectively; coupling constants (J) are expressed in Hertz.HRMS data were obtained from Kent Electronics (UK).The reactions were carried out under dry argon atmospheres, employing oven-dried glassware.All new compounds gave single spots on TLC plates run in different hexane-EtOAc solvent systems.Spots were visualized by exposure to UV light (254 and 365 nm), followed by spraying with ethanolic p-anisaldehyde/ sulfuric acid reagent and careful heating.Flash column chromatographies were carried out with silica gel 60 H, eluting with hexane-EtOAc mixtures under positive pressure and employing gradient techniques.