Chloroformates, addition benzyl, with amines

As mentioned before structure of 2-2 was proposed by spectral analyses, the position of methylenedioxyl group in isoquinoline of 2-2 is in position C-5—C-6, but it did not exclude its possibility in position C-7—C-8. A total synthesis was accomplished in order to confirm the structure and to derive more samples for pharmacological tests. Piperonal 2-4 was used as starting material. It was oxidized by silver oxide in basic condition to get 2-5, then amidized with dimethyl amine to 2-6 and directed ortho-lithiation with n-butyl-lithium in THF (tetrahydrofuran) to get homogeneous yellow solution, which upon treatment with methyl iodide afforded toluamide 2-7, the yield was 85%. The model synthesis study showed that lithiated toluamide 2-7 could condense with compound 2-14 to achieve the final product 2-2 through several steps (see below). The intermediate compound 2-14 could be synthesized starting from the same piperonal 2-4. It was reacted with cyclohexylamine to get Shiff base 2-8, the latter was reacted with 1.13 equiv. of n-butyllithium at -78°C, the metalated intermediate was carbethoxylated in situ by addition of excess ethyl chloroformate and the aldehyde 2-9 was obtained by extraction with dilute acid. Combination of 2-9 with equimolar of propane-1,3-dithiol a compound 2-10 was obtained, then 2-10 was reduced by lithium aluminum hydride and benzylated with benzyl bromide to 2-12. After treatment with bis(trifluoroacetoxy) iodobenzene, the obtained compound 2-13 was reacted with benzylamine to get the key compound 2-14. 

The triethylamine salt of 2,2-dimethyl-3-(3,4-methylenedioxyphenyl)-propionic acid (5.4 g amine, 11.4 g acid) was dissolved in 10 mL 11,0 and diluted with sufficient acetone to maintain a clear solution at ice-bath temperature. A solution of 6.4 g ethyl chloroformate in 40 mL acetone was added to the 0 °C solution over the course of 30 min, followed by the addition of a solution of 4.1 g sodium azide in 30 mL H20. Stirring was continued for 45 min while the reaction returned to room temperature. The aqueous phase was extracted with 100 mL toluene which was washed once with H20 and then dried with anhy drou s Mg S04. Thi s org ani c sol uti on of the azide was heated on a steam bath until nitrogen evolution had ceased, which required about 30 min. The solvent was removed under vacuum and the residue was dissolved in 30 mL benzyl alcohol. This solution was heated on the steam bath overnight. Removal of the excess benzyl alcohol under vacuum left a residue 13.5 g of l-(N-(benzyloxycarbonyl)amino)-1,1 -dimethyl-2-(3,4-methylenedioxyphenyl)ethane as an amber oil. The dimethyl group showed, in the NMR, a sharp singlet at 1.30 ppm in CDCH,. Anal. (C19H2lN04) C,H. This carbamate was reduced to the primary amine (below) or to the methylamine (see under MDMP). 

A solution of the hydroxylamine (1.73 g, 3.7 mmol) in MeOH (50 mL) was treated with a 20% w/w aqueous solution of TiClj (1.43 g, 9.2 mmol, in 5.7 mL of HjO) at room temperature for 15 min, then 5-M aqueous NaOH was added, and stirring was continued for an additional 5 min. The mixture was extracted with ethyl acetate (4 x 25 mL), the combined extracts were washed with brine, dried (MgSO,, and concentrated to afford the crude amine, which was used in the next step without purification. To a cooled (0°C) and stirred mixture of the crude amine and 7% aqueous NaHCOj (20 mL) in 1,4-dioxane (50 mL) was added benzyl chloroformate (0.57 mL, 4.0 mmol). Stirring was continued at 0°C for 20 min, then H O (80 mL) and CHjClj (50 mL) were added. The organic layer was separated, and the aqueous layer was extracted with (2 x 25 mL). The... 

Amino groups can be blocked by converting them into carbamates through simple addition-elimination reactions (p. 901).Two popular methods involve the transformation of the free amine into a carbamate by reaction with either di- -butyl dicarbonate or benzyl chloroformate. Biochemists are even more addicted to acronyms than are organic chemists, and these protecting groups are called tBoc and Cbz, respectively (Fig. 23.45). 

By analogy with the catalytic allylic alkylation performed with C-nucleo-philes described in Section 7.2.2.3, Plietker et al. used benzyl mercaptan as an S-nucleophile toward an isobutyl carbonate in the presence of an NHC-Fe complex 9. Allylic thioethers were obtained in 82% yield as a mixture of two regioisomers [eqn (7.7)]. The same group also investigated the sulfonylation of allylic carbonates with a-sulfonyl succinimides as S-nucleop-hiles. In this case, a base-free catalytic system generated in situ by thermal release of the SIMes carbene from its chloroform adduct in the presence of [Bu4N][Fe(CO)3(NO)] was adopted. Addition of DBU to the reaction mixtures allowed the one-pot synthesis of vinyl sulfones through a tandem iron-catalysed allylic sulfonylation/amine-catalysed isomerisation process. Remarkably, base-induced decomposition of the iron catalyst was not observed. 

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