Imidoyl halides, alkylation

Since the electrophilic character of carbonyl groups in acid halides is more pronounced than in carboxylic anhydrides, the former are better suited for aza-Wittig reactions. Zbiral et al. studied the reaction of imino-phosphoranes with acid halides and obtained imidoyl halides (69LA29 72PS35). A -alkyl and A -aryl iminophosphoranes can be set to use in this reaction (72PS35). 

Imidoyl halides react with NH- and NHa-containing compounds to give amidinium salts, which were sometimes isolated,but the hree amidine bases were usually prepared from them. Since amid-ines are converted by water-free acids to the corresponding amidinium salts, amidinium salts with nearly every desired anion are accessible by this procedure. The alkylation of A/A(, -trisubstituted amidines, as well as those of symmetrically IV.lV -disubstituted, IV-monosubstituted and A(-unsubstituted amidines are unambigous reactions. By this method a lot of amidinium salts, e.g. (145), (146) and (147) (equation 87), have been prepared. The alkylation of A -monosubstituted and N,Ar-unsymmetrrcally substituted amidines can give rise to product mixtures of amidinium salts. 

The NMR spectra of imidoyl halides are not too well investigated. We have utilized NMR spectroscopy to elucidate the structure of arylsulfonyl-chloroformamidines ( ), but no data with regard to the chemical shift of alkyl groups attached to the carbon or nitrogen atom of the —C(X)=N— system is available. Of course, differentiation of the imidoyl halide structure in a-hydrogen containing compounds from the corresponding tautomeric enamine structures is easily accomplished by NMR spectroscopy, provided that the system contains olefinic protons. 

The reactions of carbonimidoyl dihalides can be divided into nucleophilic substitution reactions, whereby the halo groups are replaced stepwise by other nucleophiles, and addition reactions. The substitution reactions are often accompanied by elimination, depending upon the stability of the formed imidoyl derivatives. For example, the monosubstitution products can eliminate hydrogen halide, alkyl halide, or sulfenyl chloride, i.e.,... 

Phosphanes are widely used as reagents in organic synthesis, triphenylphos-phane being the most commonly applied due to its stability towards oxidation. The polymer-supported analog has so far found use in the transformation of alcohols into alkyl halides and acids into acid halides, using either carbon tetrachloride or carbon tetrabromide as the halogen source (Scheme 6.4) [7, 11-14], This system can also successfully transform primary amides and oximes into nitriles, whereas secondary amides are transformed into imidoyl chlorides (Scheme 6.5) [15],... 

A halo group attached to a carbon which has a heteroatom attached to it has increased reactivity. This concept is amply explained by the electronic assistance of the heteroatom. For example, the halogen groups in a-haloethers and a-chloroamines are considerably more reactive than halo groups attached to aliphatic carbon atoms. The reactivity of halo groups is further enhanced if the halo group is directly attached to a C=0 double bond. For example, acid chlorides (III) are considerably more reactive than alkyl or aryl halides. Likewise, halo groups directly attached to C=N double bonds have an increased reactivity, quite comparable to that of acid chlorides. Thus imidoyl chlorides (IV) resemble acid chlorides in their chemical reactions. 

The classical example of this type of reaction is the v. Braun method of degradation, by which a secondary amine can be transformed into a primary amine, and finally into ammonia, via the imidoyl chloride intermediates. This reaction has been used for the structure elucidation of alkaloids. Although degradative studies are not conducted to any extent today due to the convenience of spectral methods, the v. Braun elimination is still used in organic synthesis to prepare nitriles as well as alkyl halides. 

The reaction of iminium chloride with alcohols affords imidoyl ester hydrochlorides LXXXVI as intermediates, which eliminate alkyl halides upon heating, thereby regenerating the corresponding carboxylic acid amide... 

The thermal elimination of alkyl halides to form nitriles is perhaps the best known reaction of imidoyl chlorides. J. v. Braun investigated this reaction in detail over a period of 40 years, and he developed a host of useful new synthetic procedures for the synthesis of compounds, which are otherwise more difficult to obtain. Unfortunately, most of his work has been written up in detailed form in Chemische Berichte and it requires some effort to retrieve this information. However, he wrote one review article in 1934 which is most informative. The elimination of alkyl halides on heating of imidoyl chlorides was recognized by Wallach in 1877 and v. Pechmann and Ley and Holzweissig reported examples of this reaction prior to the work of J. v. Braun. The elimination reaction, in its most general terms, can be described by the following sequences ... 

The Grignard reaction of imidoyl chlorides with alkyl and arylmag-nesium halides has been investigated corresponding ketones... 

It is believed that this reaction proceeds via initial formation of hydrochloric salts of imidoyl chloride when POCI3, PCI5, or SOCI2 is used as a reagent, followed by the formation of imidoyl chloride by the loss of hydrogen chloride, which is in equilibrium with nitrilium salt. Then the 3,4-dihydroisoquinoline is formed via the ring closure of nitrilium salt, as indicated in the direct formation of such dihydroisoquinoline via alkylation of nitrile with phenylethyl halide in the presence of a Lewis acid. An exemplary mechanism of the Bischler-Napieralski reaction is illustrated here. 

Among other reactions, the bis-metallated species (151) derived from nitroalkanes condense with dialkyl carbonates to give comp>ounds (152), in 60—80% yield, which can serve as precursors of both a-amino-acids and a-hydroxyamino-esters as well as a-keto-esters. Oxazolin-5-ones (153) can be alkylated at the 4-position by alkyl halides in hot DMF containing HMPA and ethyldi-isopropylamine. Yields are good (60—90%) for allylic, benzylic, and propargylic halides but otherwise poor (e.g. 32% with EtI) under these conditions acid hydrolysis of the products affords substituted a-amino-acids. Mesoionic l,3-oxazol-5-ones (154), obtained from imidoyl chlorides and acyl-tetracarbonylferrates, react with alcohols to give N-acyl-a-amino-acid esters. ... 

For example, the sensitive imidoyl chloride moiety at the C-3 position of the pyrazinone scaffold is known to vmdergo Stille reactions with a variety of tetraaryltin reagents, generating the corresponding 3-substituted pyrazi-nones (Scheme 10) [26]. Furthermore, the transition-metal-catalyzed stannyl-ation at the C-3 position is also documented in the literature, in view of cross-coupHng with a variety of alkyl and (hetero)aryl halides [26]. However, this strategy is completely restricted to the C-3 position, while the Cl atom of C-5 position was found to be inert under these conditions. 

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