Dimethyl 2 , 2 ′-[ Carbonylbis ( azanediyl ) ] ( 2 S , 2 ′ S )-bis [ 3-( 4-hydroxyphenyl ) propanoate ]

The thus-far unknown ureic derivative dimethyl 2,2′-[carbonylbis(azanediyl)](2S,2′S) -bis[3-(4-hydroxyphenyl)propanoate] has been efficiently synthesized by enantiospecific oxidative carbonylation of readily available L-tyrosine methyl ester, using a very simple catalytic system (PdI2 in conjunction with KI) under relatively mild conditions (100 ◦C for 5 h in DME as the solvent and under 20 atm of a 4:1 mixture CO-air).


Introduction
Ureas are very important carbonyl compounds.Many ureic derivatives have shown interesting biological activities, including anticancer activity [1,2].Moreover, they find different practical applications, including their use as gelators or hydrogen-bond donors [3,4].
A very attractive method for the preparation of ureas is based on direct carbonylation of amines under oxidative conditions [5,6].In this field, we have previously reported that a very simple catalytic system, consisting of PdI 2 in conjunction with KI, is able to promote the oxidative carbonylation of primary amines to symmetrically 1,2-disubstituted ureas as well as of primary and secondary amines to trisubstituted ureas with excellent selectivities (up to 99%) and very high turnover numbers (up to 43,500 mmol of urea per mmol of palladium) [7][8][9].
According to our previous findings, the formation of urea 2 can be interpreted as occurring as shown in Scheme 2, involving the formation of a carbamoylpalladium iodide intermediate I (by the reaction between the amino group of the substrate, CO, and PdI2) followed by β-H elimination from the Pd-(CO)-NH moiety to give isocyanate II, and nucleophilic addition to the latter by a second molecule of substrate.

Materials and Methods
Solvents and chemicals were reagent grade and used without further purification.Reactions were analyzed by thin layer chromatography (TLC) on silica gel 60 F254 (Merck s.p.a., Vimodrone, Milano, Italy).Starting material L-tyrosine methyl ester was commercially available (Sigma-Aldrich Italia s.r.l., Milano, Italy).Column chromatography was performed on silica gel 60 (Merck s.p.a., Vimodrone, Milano, Italy, 70−230 mesh).Evaporation refers to the removal of solvent under reduced pressure.Melting point is uncorrected. 1H-NMR and 13 C-NMR spectra were recorded at 25 °C on a 300 MHz spectrometer (Bruker DPX Avance 300, Bruker Italia s.r.l., Milano, Italy) in DMSO-d6 solutions with Me4Si as the internal standard.Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively.IR spectrum was taken with a JASCO FTIR 4200 spectrometer.Mass spectrum was obtained using a HPLC/ESI/Q-TOF HRMS apparatus.HPLC conditions were as follows: water, acetonitrile, and formic acid were of HPLC/MS grade; the HPLC system was an Agilent 1260 Infinity; a reversed-phase C18 column (ZORBAX Extended-C18 2.1 × 50 mm, 1.8 m) with a Phenomenex C18 security guard column (4 mm × 3 mm) were used; the flow-rate was 0.4 mL/min and the column temperature was set to 30 °C; the eluents were formic acid-water (0.1:99.According to our previous findings, the formation of urea 2 can be interpreted as occurring as shown in Scheme 2, involving the formation of a carbamoylpalladium iodide intermediate I (by the reaction between the amino group of the substrate, CO, and PdI 2 ) followed by β-H elimination from the Pd-(CO)-NH moiety to give isocyanate II, and nucleophilic addition to the latter by a second molecule of substrate.
According to our previous findings, the formation of urea 2 can be interpreted as occurring as shown in Scheme 2, involving the formation of a carbamoylpalladium iodide intermediate I (by the reaction between the amino group of the substrate, CO, and PdI2) followed by β-H elimination from the Pd-(CO)-NH moiety to give isocyanate II, and nucleophilic addition to the latter by a second molecule of substrate.

Scheme 2 .
Scheme 2. Proposed mechanism for the formation of urea 2 from L-tyrosine methyl ester 1.