Reactions Involving Imines as Intermediates

The photochemistry of certain A-substituted heterocycles has also been studied. As part of a continuing investigation of the photolysis of A-nitroso compounds in solution, the conversion of A-nitroso-3-azabicyclo[3.2.2]nonane (65) into the oxime (66) by photolysis in the presence of acid was reported.58 N-Nitrosopyrrolidine is similarly transformed. The mechanism of this reaction is said58 to involve elimination of NOH with the formation of an imine as intermediate, and, in fact, in the photolysis of 2-ethyl-A-nitrosopiperidine (67), the tetrahydropyridine (68) is the major product. This mechanism certainly does not operate in the photolysis of iV-nitroso-2-azacyclo-octanone, which can be rationalized on the basis of an intramolecular hydrogen transfer [Eq. (16)].59 Acyclic iV-nitrosoamides behave in a similar fashion to IV-nitrosoamines.60... 

Aldehyde (166) reacted with excess hydrazine hydrochloride to afford a pyrazoline in 63% yield a mixture of pyrazoline and pyrazolidine was obtained under an inert atmosphere.83 This reaction presumably involves the hydrazone and protonated azomethine imine as intermediates. Using (166) in excess afforded a bisintramolecular adduct in 87% yield. 

Another unusual three-component coupling reaction involving an imine as intermediate has been developed by Ishii who has shown that a C-H bond adjacent to the nitrogen atom of an imine can be activated by an iridium complex. Carbo-metallation reactions of acetylenic compounds may then be achieved, which lead to unsaturated imines 155 (Scheme 8.67) [122]. 

Pyridoxal is the reagent in other reactions of amino acids, all involving the imine as intermediate. The simplest is the racemization of amino acids by loss of a proton and its replacement on the other face of the enamine. The enamine, in the middle of the diagram below, can be reprotonated on either face of the prochiral imine (shown in green). Protonation on the bottom face would take us back to the natural amino acid from which the enamine was made in the first place. Protonation on the top face leads to the unnatural amino acid after hydrolysis of the imine (really transfer of pyridoxal to a lysine residue of the enzyme). 

Other bis azo compounds give y-triazole JV-imines as intermediates. Thus, photolysis of sydnones (58) 94-97 and of 2,5-disubstituted tetrazoles98-99 gives w-triazoles (62). These reactions probably involve the primary formation of nitrilimines (60) which dimerize to the bis azoethylene derivatives (61) which in turn cyclize to form the v-triazole IV-imines. These, under the reaction conditions, cleave at the exocyclic N-N bond (see Section IV,F). 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

An interesting reaction ensues when the intermediate synthetic precursor (65) to synthon 60 is heated with phenylenediamine. The reaction can be rationalized as involving initial enamine-imine formation (66), followed by intramolecular attack on the ester carbonyl groups resulting in carbamate formation (67), which carbamate undergoes intramolecular trans-amidation to give urea 66. Other scenarios can be proposed and defended, but the net result is formation... 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

The preparation of thiiranes is most conveniently performed in solution. However, there are also protocols reported for reaction in the gas and solid phase. By using diazo and thiocarbonyl compounds in ether as solvent, both alkyl and aryl substituted thiiranes are accessible. As indicated earlier, aryl substituents destabilize the initially formed 2,5-dihydro-1,3,4-thiadiazole ring and, in general, thiiranes are readily obtained at low temperature (13,15,35). On the other hand, alkyl substituents, especially bulky ones, enhance the stability of the initial cycloadduct, and the formation of thiiranes requires elevated temperatures (36 1,88). Some examples of sterically crowded thiiranes prepared from thioketones and a macro-cyclic diazo compound have been published by Atzmiiller and Vbgtle (106). Diphenyldiazomethane reacts with (arylsulfonyl)isothiocyanates and this is followed by spontaneous N2 elimination to give thiirane-2-imines (60) (107,108). Under similar conditions, acyl-substituted isothiocyanates afforded 2 1-adducts 61 (109) (Scheme 5.23). It seems likely that the formation of 61 involves a thiirane intermediate analogous to 60, which subsequently reacts with a second equivalent... 

Tetra-r-butylpyridazine (34) is converted into its Dewar isomer (35) when irradiated in pentane with UV light of wavelength > 300 nm. Irradiation of this product at shorter wavelengths, or thermolysis, gives rise to further reaction (91TL57). Irradiation of 4-amino-2,6-dimethylpyrimidine gives the acyclic amino imine via the Dewar pyrimidine as shown in Scheme 2a. The photoisomerization of perfluoropyridazines to pyrazines is considered also to involve Dewar diazine intermediates. 

An unusual course of thermolysis occurs in 5-amino- and 5-alkoxytri-azolines, which are formed only as intermediates in the reaction of enamines and enol ethers with azides bearing electron-withdrawing groups it involves cleavage of the N-l/N-2 as well as the C-4/C-5 bonds of the triazoline ring to yield diazoalkanes and imines with one fewer carbon than in the triazolines (amidines and imino ethers) (Scheme 144)233.250 272 431-433 in a cycloelimination reaction, the reverse of diazoalkane-imine cycloaddition. The intermediate formation of a diazonium zwitterion is suggested,233,247 but whether the thermolysis occurs in a one- or two-step reaction is not established. 

In superacidic reactions, diprotonated imines form gitonic superelectrophiles.48 As described in Chapter 2, kinetic experiments have shown that diprotonated intermediates are involved in these conversions. Other experiments showed that the reaction provides higher yields in stronger acid systems (eq 32),... 

Thus, the selectivities, deactivation mechanisms, and potential transformations of alkoxo and amido intermediates in such reactions are not well understood. It is even rare for transition metal amido and alkoxo complexes to be clearly identified as intermediates in catalytic chemistry. The hydrogenation of imines and ketones presumably involves such intermediates [68], but they have not been clearly detected in these reactions [69]. The catalytic reduction of CO on surfaces may involve alkox-ides, but well-characterized homogeneous analogs are unusual [58]. 

In a variation of the Gatterman reaction an alkyl cyanide RCN is used in place of HCN as a useful way of preparing ketones from reactive aromatic species that do not react well under Friedel-Crafts conditions. The electrophile involved is effectively R—C NH+, although, perhaps, the imino chloride, R(C NH)C1, the analogue of an acyl chloride, RCOCl, is also involved. As in the Gatterman reaction, the imine is an intermediate. 

Protocol 6 involves heating Mannich compound 10 in DMSO, apparently causing elimination of dimethylamine and formation of enone 20 as a reactive intermediate. The corresponding enone has been synthesized in the 9-butyl series,6,22 but comparable yields are obtained in pyridine cyclization reactions involving either the preformed enone or the Mannich HQ salt.7 Prior to addition of 10, ketone 9 is heated with ammonium chloride in DMSO to promote the formation of imine 21. Isomerization of this imine to the enamine tautomer 22, Michael addition of this nucleophile to enone 20, and elimination of water account for the formation of product 11. Like many polycyclic terpyridyl analogues, this product is sparingly soluble in DMSO and is readily isolated by filtration of the reaction mixture. 

---