Dichlorocarbene reaction with secondary amines

Scheme 5.1 Reaction of secondary amines with dichlorocarbene generated in situ.

Sol 9. (d) Aldehydes and ketones having a-protons react with secondary amines to form enamines. The enamine formed in the first step undergoes cyclopropanation reaction at the double bond with dichlorocarbene that is generated by a-elimination of HCl from chloroform. This product undergoes ring expansion to furnish 2-chlorocyclohex-2-en-l-one (I). 

One example of the reaction of dichlorocarbene with a tertiary amine under phase transfer conditions has been reported [20]. 5,7-Diphenyl-1,3-diazaadamantan-6-one is transformed into l,5-diphenyl-N,N-diformylbispidin-9-one in 23% yield. This unusual reaction may be rationalized as follows. Coordination of dichlorocarbene with a nitrogen lone pair yields a zwitterion (VI). Neighboring nitrogen assists fragmentation and the iminium zwitterion VII results. Protonation and hydrolysis of VII followed by dichlorocarbene reaction with the resulting secondary amine yields the bis-formamide VIII. The sequence is formulated in equation 3.13. 

When the reaction with substituted benzaldehydes is conducted in the presence of ammonia, the a-amino carboxylic acids are formed [11], The corresponding reaction involving bromoform is less effective and, for optimum yields, the addition of lithium chloride, which enhances the activity of the carbonyl group, is required. In its absence, the overall yields are halved. The reaction of dichlorocarbene with ketones or aryl aldehydes in the presence of secondary amines produces a-aminoacetamides [12, 13] (see Section 7.6). 

When ketones are reacted with dichlorocarbene in the presence of secondary amines, a-aminoacetamides are obtained via the ring opening of the intermediate oxiranes by the amine [19]. Similar products are obtained from the corresponding reactions with aniline and also with aldehydes (see Section 7.4). 

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]. 

Under favourable circumstances, the initially formed /V-ylid reacts further through C-N cleavage. Thus, in the presence of a strong nucleophile, such as a phenoxide anion, the quaternary dichloromethylammonium cation forms an ion-pair with the phenoxide anion (Scheme 7.27), which decomposes to yield the alkyl aryl ether and the /V-formyl derivative of the secondary amine [22, 23]. Although no sound rationale is available, the reaction appears to be favoured by the presence of bulky groups at the 4-position of the aryl ring. In the absence of the bulky substituents, the Reimer-Tiemann reaction products are formed, either through the breakdown of the ion-pair, or by the more direct attack of dichlorocarbene upon the phenoxide anion [22,23],... 

Chloroindolizine is formed in a reaction of 2-vinylpyridine with dichlorocarbene (77ACS(B)224). Af,(V-Disubstituted 3-aminoindolizines have been obtained from a reaction of 2-bromopyridine, propanol and secondary amines (79CL24 l). Irradiation of N- phenylpyr-role and N-methyldibromosuccinimide in benzene gave 18% of the indolizine (187) (80CB2884). 

Secondary amines react readily with dichlorocarbene to yield secondary formamides in good yield [17, 18]. Apparently, the secondary amine coordinates with dichlorocarbene, and after proton transfer a dialkylaminodichloromethane is produced. The latter undergoes basic hydrolysis under phase transfer conditions which evidently stops before appreciable cleavage of the formamide occurs. The reaction is formulated in equation 3.12 and several examples are tabulated in Table 3.5. 

Reactions of carbenes other than cyclopropanation can also be performed, and recent examples include the ring expansion of five-ring heterocycles, such as the indoles (18), to their six-membered counterparts (19), and the production of formamides from secondary amines (Scheme 7), both with dichlorocarbene. The latter method is of interest because of its relation to the catalysis of dichlorocarbene generation by tertiary amines in two-phase systems. Recent work indicates that such catalysis is possible because the carbene, after generation at the phase boundary, is transferred into the organic phase (to undergo reaction) in the form of the N-ylid adduct (20). 

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