Synthesis of macrocyclic cyclophane-based unusual α -amino acid derivatives

Alkylation of ethyl isocyanoacetate with 1,2-bis(4-bromomethylphenyl)ethane under phase transfer catalysis (PTC) as well as phosphazene base [2-tert -butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP)] conditions gave the macrocyclic cyclophane based unusual α -amino acid derivatives

It is reported that the dibromide 4 can form radical intermediates under thermal or photochemical reaction conditions that undergo a disproportion/polymerization reaction. 12The low yield of the coupling product 10 can be explained due to possibility of this unwanted side reactions.To confirm this, dibromide 4 was treated in absence of ethyl isocyanoacetate under PTC conditions and obtained poor recovery (28%) of dibromide 4.
Several other conditions have been tried to improve the yield of 10, for instance NaH/DMSO conditions gave much lower yield compare to PTC conditions.It is known that the phosphazene bases improve the yields of coupling product when sensitive substrates are involved by minimizing the unwanted side-reactions.In this respect, 2-tert-butylimino-2-diethylamino-1,3dimethylperhydro-1,3,2-diazaphosphorine (BEMP) 13 was used as a base in acetonitrile at 0 °C.The coupling product 10 was isolated in 14% yield (4-fold increase as compared to PTC conditions) as a mixture of isomeric products.Hydrolysis of coupling product 10 in presence of HCl/diethyl ether at RT gave the N-formyl derivative 11 (mp.220 °C decomp.)and another isomeric product 12 (mp 210 °C decomp.) in 40% and 48% isolated yields respectively.The structure of 12 has been established by X-ray studies. 14The structure of 11 could not be established by crystallographic analysis because suitable crystals could not obtained.After successful synthesis of macrocyclic cyclophane-based AAAs 11 and 12 under PTC and BEMP conditions, we decided to extened this methodolgy to the corresponding benzo analogues such as 14 starting from dibromide 13 (Eq 1).(1)   Towards this goal, the precursor of dibromide 13 was prepared by an alternative method.Thus, the Suzuki coupling reaction 15 of 1,2-dibromobenzene with p-methylphenylboronic acid in presence of Pd(PPh 3 ) 4 catalyst gave the cross-coupling product 15 in 86% yield.Benzylic bromination of 15 was performed according to the known procedure 16

Conclusions
We were able to synthesize macrocyclic cyclophane-based AAA derivatives (racemic) 11, 12 and 17 by using ethyl isocyanoacetate as a glycine equivalent.Using phosphazene base (BEMP) the yields of the coupling step has been improved considerably.Use of phosphazene bases may also find applications in synthesis of cyclophane dertivatives.

Experimental Section
General Procedures.Dry diethyl ether, benzene and toluene have been obtained by distillation over sodium benzophenone ketyl.Chloroform, dichloromethane, carbon tetrachloride and acetonitrile were distilled over P 2 O 5 .BEMP and 4-vinylbenzyl chloride were purchased from Aldrich Chemical Co, Milwauke, WI, U. S. A. Grubbs' catalyst was purchased from Strem Chemical Co, Newburyport, MA.U. S. A. 1 H NMR spectra were recorded on Bruker 300 MHz or Hitachi FT-60 MHz Instrument. 13C NMR spectra were recorded on Bruker 75.4 MHz instrument.High resolution mass spectra were obtained on JEOL JMS-DX 303 GC-MS instrument.The FAB mass spectra were obtained on JEOL SX 102/DA-6000 mass spectrometer.

ISSN 1424-6376
Page 61 © ARKAT USA, Inc UV Spectra were obtained on Shimadzu UV-2100 instrument.Room temperature IR spectra were obtained on Nicolet Impact-400 FT IR spectrometer.

Synthesis of compound (7b).
To a stirred solution of isonitrile derivative 6 (180 mg, 0.52 mmol) in absolute ethanol (5 ml) was added concd HCl (5 drops) at 0 o C.After 30 minutes at RT, solvent was removed under reduced pressure, water (5 ml) was added, extracted with diethyl ether (20 ml) and ether layer was discarded to remove organic residues.The aqueous layer was basified with NH 3 solution to pH~10, extracted with ethyl acetate (20 ml × 3), dried over MgSO 4 and evaporated.The residue gave pure amino ester derivative (18 mg, 10%) as a thick liquid which was directly acetylated with acetic anhydride in the next step.