Amines with chloroformates

Although the extraction of primary amines from a basic medium with chloroform is an inadvisable procedure, on account of the formation of trace amounts of the pungent isonitriles, the specific synthesis of isonitriles by the two-phase reaction of primary amines with chloroform is unreliable. However, the application of the phase-transfer technique [e.g. 1 -5] for the controlled release of dichlorocarbene facilitates the synthesis of isonitriles in relatively high yields (Table 7.12). 

Compared with primary and secondary amines, tertiary amines are virtually unreac-tive towards carbenes and it has been demonstrated that they behave as phase-transfer catalysts for the generation of dichlorocarbene from chloroform. For example, tri-n-butylamine and its hydrochloride salt have the same catalytic effect as tetra-n-butylammonium chloride in the generation of dichlorocarbene and its subsequent insertion into the C=C bond of cyclohexene [20]. However, tertiary amines are generally insufficiently basic to deprotonate chloroform and the presence of sodium hydroxide is normally required. The initial reaction of the tertiary amine with chloroform, therefore, appears to be the formation of the A -ylid. This species does not partition between the two phases and cannot be responsible for the insertion reaction of the carbene in the C=C bond. Instead, it has been proposed that it acts as a lipophilic base for the deprotonation of chloroform (Scheme 7.26) to form a dichloromethylammonium ion-pair, which transfers into the organic phase where it decomposes to produce the carbene [21]. 

A,r-Benzyl groups can be removed by reaction of amines with chloroformates. This can be a useful method for protecting-group manipulation if the resulting carbamate is also easily cleaved. A particularly effective reagent is a-chloroethyl chloroformate, which can be removed by subsequent solvolysis.78... 

Very frequently the transition through urethanes is employed by treating the primary amine with chloroformate. The N-substituted urethane so obtained is nitrated by substituting the free N-hydrogen and then subjecting the product to alkaline hydrolysis which results in the formation of the salt of a primary nitramine and a base. The free nitramine is obtained by acidification. 

HOFMANN ISONITRILE SYN THESIS. Formation of isonitriles hy the read ion of primary amines with chloroform in the presence of an alkali tlic odor of the isocyanidc is a test lor a primary amine. 

Many years ago. Hofmann showed that isonitriles arc formed on reaction of primary amines with chloroform and a strong base. Yields by this method are low and the reaction has been little used. Recently, Weber and Gokel reported that isonitriles can... 

Formation of Carbamates. The reaction of amines with chloroformates bears some simUarity to amide formation and produces carbamates (Eq. 2)... 

Although some of the early work on the separation of diastereomers by GLC (71) or LC (19) involved carbamates, derivatization of chiral amines with chloroformate CDAs has received relatively little attention until recently in pharmaceutical/pharmacological applications. This is surprising, inasmuch as chiral chloroformates can be readily synthesized from chiral alcohols, many of which are commercially available. There are indications, however, that interest in the use of chloroformates is increasing, and several reports on such reagents have appeared in recent years. 

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). 

The isonitrile can be obtained by reacting ethyl amine with chloroform (note that the fume hood is required because of the overpoweringly objectionable odor of the isonitrile). 

Two classical methods based on methylamines 58a have been developed for preparation of substituted methyl isocyanides-the second component of the reaction shown in Scheme 4.28. The first method consists of one stage, namely, treatment of amines with chloroform in the presence of alkalis the second method consists of two stages. The reaction with ethyl formate leads to formamides 58b, which are then dehydrated by treating with phosphorus oxochloride in the presence of tri-ethylamine (Scheme 4.29) (Jacobsen et al. 1996a). 

Aliphatic Alcohols and Thiols. Ahphatic alcohols on reaction with chloroformates give carbonates and hydrogen chloride. Frequendy, the reaction proceeds at room temperature without a catalyst or hydrogen chloride acceptor. However, faster reactions and better yields are obtained in the presence of alkaU metals or their hydroxides, or tertiary amines. Reactions of chloroformates with thiols yield monothiolocarbonates (14). 

Heterocyclic Alcohols. Thek reactions with chloroformates lead to carbonates. Thus furan- and tetrahydrofuran-derived alcohols give the corresponding carbonates in 75% yield (15). Inorganic bases and tertiary amines as acid acceptors increase the rate and yield in this reaction. 

Caibamates ate formed from an amine with a wide variety of reagents, of which the chloroformate is the most common amides are formed from the acid chloride. -Alkyl caibamates are cleaved by acid-catalyzed hydrolysis A/-alkylamides are cleaved by acidic or basic hydrolysis at teflux. conditions that cleave peptide bonds. 

The catalytic effect of aromatic nitro groups in the substrate and product or in an added inert nitro compoimd (e.g., w-dinitrobenzene in 18) has been observed in the reaction of 2,4-dinitrochlorobenzene with an amine in chloroform. Hydrogen bonding to benzil or to dimethyl sulfone and sulfoxide also provided catalysis. It is clear that the type of catalysis of proton transfer shown in structure 18 will be more effective when hydrogen bonding is to an azine-nitrogen. 

Nucleophilic aromatic substitution of the anion from ary lace ton itrile 113 on the dichloroni-trobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsa-licylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydroly.sis, the anthelmintic agent closantel (118) [28]. 

The present method utilizes dichlorocarbene generated by the phase-transfer method of Makosza4 and Starks.5 The submitters have routinely realized yields of pure distilled isocyanides in excess of 40%.6 With less sterically hindered primary amines a 1 1 ratio of amine to chloroform gives satisfactory results. Furthermore, by modifying the procedure, methyl and ethyl isocyanides may be prepared directly from the corresponding aqueous amine solutions and bromoform.7 These results are summarized in Table I. 

The alkanephosphonic acid dichlorides obtained by these methods are converted with amines, with all reactions carried out in solvents such as acetone, benzene, or diethyl ether at 10°C with triethylamine as HC1 captor. The conversion runs quantitatively followed by a purification with the help of column chromatography with chloroform/methanol in a ratio of 9 1 as mobile phase. The alkanephosphonic acid bisdiethanolamides could be obtained as pure substances with alkane residues of C8, C10, C12, and Ci4. The N-(2-hydroxyethane) alkanephosphonic acid 0,0-diethanolamide esters were also prepared in high purity. The obtained surfactants are generally stable up to 100°C. Only the alkanephosphonic acid bismonomethylamides are decomposed beneath this temperature forming cyclic compounds. 

Berthelot et al. have already reported that the reaction of aromatic amines with tetrabutylammonium tribromide (TBA Br3) in chloroform gave p-selective bromo-substituted aromatic amines (ref. 10). We also carried out the bromination of... 

Reaction with chloroform under basic conditions is a common test for primary amines, both aliphatic and aromatic, since isocyanides have very strong bad odors. The reaction probably proceeds by an SnIcB mechanism with dichlorocarbene as an intermediate ... 

Aliphatic amines have been determined by a number of methods. Batley et al. [290] extracted the amines into chloroform as ion-association complexes with chromate, then determined the chromium in the complex colorimetri-cally with diphenylcarbazide. The chromium might also be determined, with fewer steps, by atomic absorption. With the colorimetric method, the limit of detection of a commercial tertiary amine mixture was 15ppb. The sensitivity was extended to 0.2 ppb by extracting into organic solvent the complex formed by the amine and Eosin Yellow. The concentration of the complex was measured fluorometrically. Gas chromatography, with the separations taking place on a modified carbon black column, was used by Di Corcia and Samperi [291] to measure aliphatic amines. 

The flow-cell design was introduced by Stieg and Nieman [166] in 1978 for analytical uses of CL. Burguera and Townshend [167] used the CL emission produced by the oxidation of alkylamines by benzoyl peroxide to determine aliphatic secondary and tertiary amines in chloroform or acetone. They tested various coiled flow cells for monitoring the CL emission produced by the cobalt-catalyzed oxidation of luminol by hydrogen peroxide and the fluorescein-sensitized oxidation of sulfide by sodium hypochlorite [168], Rule and Seitz [169] reported one of the first applications of flow injection analysis (FTA) in the CL detection of peroxide with luminol in the presence of a copper ion catalyst. They... 

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