Enediamines

Enediamines, also known as ketene A/,iV-acetals or ketene aminals, are members of the enamine family. They can be divided into simple 1,1-enediamines1,2 and conjugated... 

In contrast to enamines1,2, the chemistry of 1,1-enediamines have been only briefly studied although the earliest reports3,4 of such compounds may date back to the 1940s. This has been partly due to the relative difficulty of the synthesis of simple 1,1-enediamines 1 in earlier years. A convenient method for the preparation of conjugated... 

In this chapter we will survey the chemistry of 1,1-enediamines. Their structural and physical properties will be first reviewed in Section II. We will see that their reactivity is critically dependent on their structures. Simple and conjugated or acyclic and cyclic 1,1-enediamines may lead to substantially different results and the correlation between structure and reactivity will be discussed. Spectroscopic characteristics will also be displayed in this section. Preparative methods of 1,1-enediamines will be summarized in Section III, which is arranged in order of importance of the methods and their scope of applicability. The reactions of 1,1-enediamines are presented in Sections IV-VI. Emphasis will be placed on the synthetic applications of these versatile synthons in the construction of heterocyclic compounds. 

The electronic structure of simple 1,1-enediamines can be simply described by the contributing resonance forms (A-C). Several physical properties as well as the chemical reactivities, e.g. the strong nucleophilicity of the /7-carbon atom of 1,1-enediamines, indicate the important contribution of the mesomeric forms B and C, which indicate the presence of an appreciable negative charge on the /7-carbon atom. 

With an electron-withdrawing group at the /7-carbon atom, the nucleophilic reactivity of the 1,1-enediamine is decreased. A systematic study on the influence of different... 

Tautomerism is another interesting feature of 1,1-enediamines. Secondary and primary... 

Except for 12 and 13 b-d, the isolation of the amidine tautomer has been reported only recently. Spectral data show that alkylated 1,1-enediamines such as 16 tautomerize predominantly to 4,5-dihydroimidazole derivatives 16 3 6 (equation 4). More interestingly, the adducts of enediamines and diethyl diazenedicarboxylate exist exclusively as the enediamine tautomer when R2 = H (17) and as the amidine tautomer when R2 = Et (17 )37 (equation 5). Since 17 and 17 differ only in an ethyl group, it appears that the steric effect plays an important role in determining the tautomeric equilibrium. 

The E- or Z-configuration about the carbon-carbon double bond in asymmetric 1,1-enediamines is determined according to the ability to form an intramolecular hydrogen bond. Thus, 1,1-enediamines 18 are present in the. E-form due to such hydrogen bonding. 

In the ultraviolet spectrum simple 1,1-enediamine 3 absorbs at 227 nm18 while the conjugated enediamine 8 shows two absorption bands at longer wavelengths of 240 and 320 nm29. The mass spectra of 1,1-enediamines display M and M-l ions and the molecular ion is usually the most abundant peak in the spectra of conjugated en-ediamines18,29. 

The olefinic chemical shift (<5) of a number of acyclic and cyclic, simple and conjugated 1,1-enediamines are listed in Tables 1 and 218,29,38-44. These values reflect... 

Although this methodology is widely applicable for the preparation of many 1,1-enediamines, 2-(aroylmethylene)benzimidazolines (29) cannot be obtained from the reaction of benzoyl-substituted ketene dithioacetals 30 and o-phenylenediamine. Instead of 29, 3H- 1,5-benzodiazepines 31 are isolated from the reaction64. Similar results have been reported for the reaction of 30 and other primary aromatic diamines70,71. A recent study64 has revealed that an enamine-imine tautomeric equilibrium is involved in the reaction process (Scheme 2). This equilibrium between 33A and 33B is affected by the... 

In general, the reaction of ketene dithioacetals and amines serves well to prepare the conjugated 1,1-enediamines. 

The reaction of amines and ketene acetals was used as a main synthetic approach to 1,1-enediamines in earlier years72. Both simple and conjugated 1,1-enediamines can be obtained by this route. Displacement reaction of ketene acetal 34 with two equivalents of piperidine furnishes 1,1-dipiperidinoethene (35) in 62% yield (equation 9)73. Primary amines and ammonia react with 34 to give amidine derivatives. Cyano-74 and trifluor-oacetyl-substituted enediamines75 have been synthesized from the corresponding ketene acetals in good to excellent yields (e.g. equation 10). 

Cyclic ketene acetals can also react with amines to give 1,1-enediamines with elimination of ethylene glycol76. Treatment of 2-[(methoxycarbonyl)cyanomethylene]-1,3-dioxolane (38) with 1,3-diaminopropane or with 4,5-dimethyl-1,2-phenylenediamine gives the hexahydropyrimidine and the benzimidazoline derivatives 39 and 40, respectively (equation 11). Similarly to the reaction of ketene dithioacetals with amines, the reaction between ketene acetals and amines proceeds via monoamino-substituted intermediates and ketene 7V,Oacetals can be isolated when one molar amine is used72. 

As we have mentioned above, ketene N9S- and N,0-acetals are the intermediates in the preparation of 1,1-enediamines from ketene dithioacetals and ketene acetals, respectively, and they can be isolated from the reactions5,51,52,72. Further substitution of the methylthio or the alkoxy groups by amines yields 1,1-enediamines. 

A few asymmetric 1,1-enediamines, i.e. with different a-amino substituents, have been prepared from ketene A S-acetals and amines5,51,52,79,80. For example, the primary 1,1-enediamines 45 are obtained by treating ketene N,5-acetals 44 with ammonia... 

Ketene N, O-acetals are converted to 1,1-enediamines when reacted with amines. For example, compound 45 has been prepared by substitution of the methoxy with amine (equation 16)79. Symmetric 1,1-enediamines are obtained when both the alkoxy and the amino substituents are displaced by the amine employed81. In this way, the reaction between ketene N, O-acetals 50 and piperidine leads to 1,1-dipipefidinoethylene (35) (equation 17)81. Alternatively, 35 can be prepared from the reaction of piperidine with triethyl orthoacetate82,83 or with ethoxyacetylene84, reactions which probably proceed via a ketene TV, 0-acetal intermediate. 

The reaction of 2-amino-4,5-dihydro-3-furancarboxylic esters (51) with amines appears interesting85. In contrast to the structure assigned earlier86-88, the reaction products have been later identified as 1,1-enediamines attached to a lactone moiety85. Thus, substrate 51 reacts with methylamine to give acyclic 1,1-enediamines 52 with an approximate E/Z ratio of 40 60. The reaction involves 4,5-dihydrofuran ring-opening and lactone-formation steps (Scheme 3). In the case of ethylenediamine and 1,3-diaminopropane, the reaction of 51 leads to the formation of cyclic 1,1-enediamine... 

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