Enamines, cyclization reactions

The enamine cyclization reaction has not been utilized in organic synthesis to the same extent as the corresponding enamide reaction. Schultz and Chiu have utilized this reaction in an approach to the synthesis of the aspidosperma alkaloids21. Irradiation of compound 37 produces tetracyclic compound 38 in 71% yield (equation 11). 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

Dimethyl acetylenedicarboxylate (80) undergoes initial 1,2 cycloaddition with acyclic enamines to form cyclobutene intermediates which immediately decompose into acyclic dienaminodiesters (94,95). When an acyclic n/c-enediamine is used instead of a simple acyclic enamine, a dienediamino-diester is produced via a cyclobutene intermediate (95a). A cyclization reaction of dimethyl acetylenedicarboxylate with an acyclic enaminoketone... 

This is illustrated by the reaction of enamine, 113 with sulfene to produce adduct 114 in an 80 % yield (146). The product 114 was also observed in an 18% yield from the reaction of diazomethane, sulfur dioxide, and enamine 113 (153). It was demonstrated that this cyclization reaction must involve sulfene adding to the enamine directly and not acylation of the enamine by... 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

The long known catalyses of some ketone condensation reactions by secondary amines, can be postulated to have their basis in the reactions of enamine intermediates with ketones. The unsuitability of methyl ketones for azeotropic enamine formation is based on this phenomenon. Recent studies in cyclization reactions have added further support to this concept (354). 

Thus, simple ketones or aliphatic aldehydes may be successfully used as starting materials in the CSIC (Carbanion mediated Sulfonate Intramolecular Cyclization) reaction. Ai-alkylsulfonamides could be also cyclized under CSIC conditions (99T(55)7625) affording the spiroisothiazoline 79. By treatment with TMSCl, Nal in acetonitrile at r.t., hydrolysis of the enamine and formation of the corresponding keto derivative 80 was obtained. 

An approach to isobacteriochlorins1 ln-e makes use of Pd(II) or metal-free bilatrienes 1 as starting materials. Cyclization of the corresponding bilatriene derivatives is induced by base in the presence of palladium(II) or zinc(II) which exercise a template effect. Zinc can be readily removed from the cyclized macrotetracycles by acid whereas palladium forms very stable complexes which cannot be demetalated. Prior to the cyclization reaction, an enamine is formed by elimination of hydrogen cyanide from the 1-position. The nucleophilic enamine then attacks the electrophilic 19-position with loss of the leaving group present at the terminal pyrrole ring. 

The detailed mechanism of this enantioselective transformation remains under investigation.92 It is known that the acidic carboxylic group is crucial. The cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. There is evidence that a second molecule of the catalyst is involved, and it has been suggested that this molecule participates in the proton-transfer step which completes the cyclization reaction. 

Irradiation of enamines (249) results in processes related to reduction and cyclization reactions with the participation of the enamine /3-carbon atom (82JOC482). A benzazepine derivative (250) was isolated as one of the products. Enamines (251) interact with aldehydes in a smooth reaction and give diazepines [84CPB3274 91KFZ(11)16]. Benzodiazepine derivatives can be obtained in a similar fashion (95KGS336). 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

The present section is briefly devoted to cyclization reactions to imines (in fact, to their secondary enamine tautomers), and will show some recent examples of the synthetic use of these hidden enamines in annulation reactions. 

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. 

If the enol component is an aldehyde, none of these methods will do and enamines or silyl enol ethers are the best choice. Enamines are excellent nucleophilic components and the iminium ion that is formed in the conjugate addition can provide the electrophilic component in a cyclization reaction. Acid-catalysed hydrolysis of the P amino-ketone liberates the amine that was used to form... 

This reaction forms the required pyrrole in one step First, the oxime is reduced to an amine then the amino group forms an imine with the most reactive carbonyl group (the ketone) in the keto-diester. Finally, the very easily formed enamine cyclizes on to the other ketone. 

Since previous reviews sufficiently cover the developments in this field until the beginning of the 80s, the intention with the present review is to focus principally on the recent synthetic methods for the preparation of cyclic compounds, although general and basic reactions of less recent origin will also be mentioned. The chapter has been divided into two sections describing methodologies leading to the synthesis of carbo- and heterocycloadducts of different size. Finally, a brief section has been dedicated to the use of imines in cyclization reactions which occur via their enamine tautomer. 

Enamine-mediated aldolizations offer much better prospects for a stereo-controlled process. The famous enantioselective proline-catalyzed triketone cyclization to the Wieland-Miescher ketone 43 [56], as well as the chemistry of type I aldolase enzymes [57],provide ample precedents for stereo- and enantioselective enamine-mediated reactions. 

However, the proline-catalyzed intramolecular cyclization reaction was considered to be a special reaction and the application of the catalyst to other reactions was not attempted until List, Lerner, and Barbas reported the proline-catalyzed intermole-cular aldol reaction in 2000 (Equation 10.13) [29]. The aldol reaction proceeds via an enamine intermediate through a six-membered transition state (Scheme 10.1) [30]. 

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