Benzyl chloroformates, from amines

The tertiary amine thus obtained was dissolved in absolute ethanol and was refluxed for two days with five molar percent excess of the appropriate bromoalkane (97% Humphrey Chemical, North Haven, Conn.). Solvent was removed and the residue in aqueous Na2C03 solution was extracted with hexane to remove any unreacted bromoalkane. Next, the N-alkyl N-benzyl N-methylglycine was extracted into chloroform from the aqueous layer. Solvent was stripped off and the crude material was recrystallized thrice from carbon tetrachloride and twice from THF/CHCl3 (60 40 v/v) mixture. The yields of the purified betaines were about 75% of the theoretical. 

Try to anticipate the formation of azeotropes when distillation and concentration occur. Unexpected azeotropes may cause unsafe operations. For instance, distillative removal of water from the reaction of an amine with benzyl chloroformate (PhCH2COCl) resulted in formation of an azeotrope of water and benzyl chloride, a common impurity in benzyl chloroformate [40]. 

An elegant approach for the preparation of secondary amines is outlined in Scheme 11. The method is based on the efficient cleavage of N-benzyl-linked tertiary amines from a solid support by treatment with a-chloroefhyl chloroformate/ methanol [30]. 

A synthesis of the intermediate 71, as aprecursor to (-)-swainsonine (1), has been reported (Scheme 8). Prolonged hydrogenation of the azide 69, obtained from D-mannose in eight steps, in methanol and then in acetic acid afforded the pyrrolidine 70 in 90% yield. Protection of the secondary amine in 70 with benzyl chloroformate followed by sodium periodate oxidation and subsequent sodium borohydride reduction gave 71. 

Removal of the methoxymethyl groups from 43 with HCl, followed by protection of the secondary amine with benzyl chloroformate afforded the carbamate 9. Selective silylation of the 4-hydroxy group of 9 by treatment with 1.2 equiv of tert-butyldimethylsilyl chloride and 2.4 equiv of imidazole in DMF at room temperature for 1 h afforded the corresponding silyl ether as a single isomer in 80% yield that was subjected to acetylation at the C-3 hydroxyl group to afford the carbamate 11, which upon removal of the Cbz and TBDMS groups furnished 1. 

Simple amides are easy to prepare from either acid chlorides or anhydrides (or for for-mamides, ethyl formate), but they are quite difficult to hydrolyze and not widely used. Urethanes, RNHCOOR, are prepared from amines and chloroformates, R 0C(=0)C1, usually benzylchlo-roformate. Urethanes can be hydrolyzed with HBr, but the presence of the benzyl group also allows the option of removal by hydrogenolysis. The summary of key points from Section 20.9 is given in Table 20.1. 

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

The interaction of alkyl halides, preferably iodides or bromides, with hexamine in chloroform or alcohol solution forms quaternary ammonium salts which on heating with hydrochloric acid are readily converted to primary amines. The procedure has been employed successfully in the reaction of primary, but not secondary or tertiary, aliphatic halides, certain benzyl halides, halo ketones, halo acids, and halo esters. The yields range from 40% to 85%. 

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. 

Reaction of a primary amine with chloroform in the presence of an alkali hydroxide gives the isocyanide. This reaction has long been known for qualitative detection of primary amines but it often gives good yields on a preparative scale. It usually occurs exothermally on mere mixing of the components. By using benzene as solvent Malatesta637 achieved yields of 80-85% from some aliphatic and arylalkyl amines (butyl, isopentyl, pentyl, benzyl). 

While the aforementioned ionophores are microbial metabolites, the crown polyethers, the depicted prototype of which is dicyclohexyl-18-crown-6 (Fig. 2D) are synthetic macrocyclic ethers. The first crown ether synthesized, dibenzo-18-crown-6, is the first multidentate synthetic macrocycle with the ability to form stable complexes with alkali and alkaline earth compounds. The complexing abilities of this crown ether led to the preparation of many others in rapid succession. Different size crown rings have been synthesized containing benzyl, cyclohexyl and naphthyl moieties Optically pure dinaphthyl crown ethers have been used to resolve asymmetric amine salts by enantioselective extraction from an aqueous solution into chloroform... 

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