molbank Communication ( S )-Ethyl 2-( tert-butoxycarbonylamino )-3-( 2-iodo-4 , 5-methylenedioxyphenyl ) propanoate

A multistep gram-scale synthesis of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5methylenedioxyphenyl)propanoate (2) has been developed. The title compound was prepared starting from commercially available L-DOPA which was Oand N-protected before undergoing iodination by CF3CO2Ag/I2. The structure of the target compound was confirmed using IR, 1H-NMR, 13C-NMR, 2D (COSY, HSQC) NMR spectroscopy, as well as ESI-MS and HRMS.


Results and Discussion
The synthesis of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5-methylenedioxyphenyl) propanoate (2, Scheme 1) was performed starting from commercially available levodopa which was reacted with thionyl chloride in EtOH to give the corresponding ethyl ester, whose amino group was in turn protected by BOC.The protection of catechol hydroxyl groups with CH 2 I 2 in the presence of Cs 2 CO 3 gave the benzodioxole derivative 3 (see Scheme 1) which was in turn submitted to an iodination reaction at the C-6 position.A similar synthetic strategy was previously reported in a Chinese patent [17] where the iodination step was performed using PhI(O 2 CCF 3 ) 2 /I 2 .We chose CF 3 CO 2 Ag/I 2 [18] as the iodinating reagent since it is cheaper and more atom efficient than PhI(O 2 CCF 3 ) 2 /I 2 .Furthermore, CF 3 CO 2 Ag/I 2 should allow easier product purification since the chosen iodination promoter does not liberate iodobenzene in the reaction crude.Finally, the reaction time was reduced from overnight to 15 minutes in our conditions, nevertheless ensuring a comparable yield (73%, 70% [17]).

Results and Discussion
The synthesis of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5methylenedioxyphenyl)propanoate (2, Scheme 1) was performed starting from commercially available levodopa which was reacted with thionyl chloride in EtOH to give the corresponding ethyl ester, whose amino group was in turn protected by BOC.The protection of catechol hydroxyl groups with CH2I2 in the presence of Cs2CO3 gave the benzodioxole derivative 3 (see Scheme 1) which was in turn submitted to an iodination reaction at the C-6 position.A similar synthetic strategy was previously reported in a Chinese patent [17] where the iodination step was performed using PhI(O2CCF3)2/I2.We chose CF3CO2Ag/I2 [18] as the iodinating reagent since it is cheaper and more atom efficient than PhI(O2CCF3)2/I2.Furthermore, CF3CO2Ag/I2 should allow easier product purification since the chosen iodination promoter does not liberate iodobenzene in the reaction crude.Finally, the reaction time was reduced from overnight to 15 minutes in our conditions, nevertheless ensuring a comparable yield (73%, 70% [17]).Through a procedure recently proposed for the synthesis of [ 18 F]labeled compounds for PET imaging [19], a copper-mediated nucleophilic fluorination of 2 could be carried out.In order to avoid a possible hydro-dehalogenation caused by the relatively acidic NH carbamate proton, the Bocderivative of 2 should be synthesized should be previously synthesized (Scheme 2).The structure of the synthesized compound 2 has been confirmed using NMR spectroscopy and mass spectrometry.Likely as a consequence of a hindered rotation around some Csp 3 -Csp 3 and Csp 3 -Csp 2 bonds, a mixture of rotamers of 2 in 1 H and 13 C-NMR spectra were recorded in CDCl3.A variable-temperature 1 H-NMR study in CD3OD was then performed in the range of temperature 25-50 °C.In particular, at 50 °C a coalescence of signals occurred allowing more sharp and detectable signals (see 1 H-NMR spectra in Figures S3, S5).On the basis of homonuclear (COSY) and heteronuclear (HSQC) experiments, it was possible to assign all 1 H and 13 C chemical shifts of 2 (see Figures S8, S9).The 1 H and 13 C-NMR spectra recorded in CD3OD at 50 °C will be described.

General Information
Unless otherwise specified, yields refer to purified products and were not optimized.The structures of the compounds were confirmed using routine spectrometric analyses.Only spectra for compounds never previously described, to our knowledge, are given.Compounds used as starting Through a procedure recently proposed for the synthesis of [ 18 F]labeled compounds for PET imaging [19], a copper-mediated nucleophilic fluorination of 2 could be carried out.In order to avoid a possible hydro-dehalogenation caused by the relatively acidic NH carbamate proton, the Boc-derivative of 2 should be synthesized should be previously synthesized (Scheme 2).

Results and Discussion
The synthesis of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(2-iodo-4,5methylenedioxyphenyl)propanoate (2, Scheme 1) was performed starting from commercially available levodopa which was reacted with thionyl chloride in EtOH to give the corresponding ethyl ester, whose amino group was in turn protected by BOC.The protection of catechol hydroxyl groups with CH2I2 in the presence of Cs2CO3 gave the benzodioxole derivative 3 (see Scheme 1) which was in turn submitted to an iodination reaction at the C-6 position.A similar synthetic strategy was previously reported in a Chinese patent [17] where the iodination step was performed using PhI(O2CCF3)2/I2.We chose CF3CO2Ag/I2 [18] as the iodinating reagent since it is cheaper and more atom efficient than PhI(O2CCF3)2/I2.Furthermore, CF3CO2Ag/I2 should allow easier product purification since the chosen iodination promoter does not liberate iodobenzene in the reaction crude.Finally, the reaction time was reduced from overnight to 15 minutes in our conditions, nevertheless ensuring a comparable yield (73%, 70% [17]).Through a procedure recently proposed for the synthesis of [ 18 F]labeled compounds for PET imaging [19], a copper-mediated nucleophilic fluorination of 2 could be carried out.In order to avoid a possible hydro-dehalogenation caused by the relatively acidic NH carbamate proton, the Bocderivative of 2 should be synthesized should be previously synthesized (Scheme 2).The structure of the synthesized compound 2 has been confirmed using NMR spectroscopy and mass spectrometry.Likely as a consequence of a hindered rotation around some Csp 3 -Csp 3 and Csp 3 -Csp 2 bonds, a mixture of rotamers of 2 in 1 H and 13 C-NMR spectra were recorded in CDCl3.A variable-temperature 1 H-NMR study in CD3OD was then performed in the range of temperature 25-50 °C.In particular, at 50 °C a coalescence of signals occurred allowing more sharp and detectable signals (see 1 H-NMR spectra in Figures S3, S5).On the basis of homonuclear (COSY) and heteronuclear (HSQC) experiments, it was possible to assign all 1 H and 13 C chemical shifts of 2 (see Figures S8, S9).The 1 H and 13 C-NMR spectra recorded in CD3OD at 50 °C will be described.

General Information
Unless otherwise specified, yields refer to purified products and were not optimized.The structures of the compounds were confirmed using routine spectrometric analyses.Only spectra for compounds never previously described, to our knowledge, are given.Compounds used as starting The structure of the synthesized compound 2 has been confirmed using NMR spectroscopy and mass spectrometry.Likely as a consequence of a hindered rotation around some Csp 3 -Csp 3 and Csp 3 -Csp 2 bonds, a mixture of rotamers of 2 in 1 H and 13 C-NMR spectra were recorded in CDCl 3 .A variable-temperature 1 H-NMR study in CD 3 OD was then performed in the range of temperature 25-50 • C. In particular, at 50 • C a coalescence of signals occurred allowing more sharp and detectable signals (see 1 H-NMR spectra in Figures S3, S5).On the basis of homonuclear (COSY) and heteronuclear (HSQC) experiments, it was possible to assign all 1 H and 13 C chemical shifts of 2 (see Figures S8, S9).The 1 H and 13 C-NMR spectra recorded in CD 3 OD at 50 • C will be described.

General Information
Unless otherwise specified, yields refer to purified products and were not optimized.The structures of the compounds were confirmed using routine spectrometric analyses.Only spectra