Enamine-aldehyde cyclization

The epimerization likely occurs through an enamine retro-aAAol reaction after formation of the initial cyclized product (92) (Scheme 6.16) [47]. First, a ring opening of 92 forms the enamine-aldehyde (93a). Rotation about the C-C a-bond in 93a provides intermediate 93b in which enamine addition to the aldehyde to reclose the ring would give 93c. After protonation of the enolate, 91 would result with an overall epimerization of the spirocyclic carbon. In addition to the 2D NMR data, we also planned a complement of experiments to support the epimerization assignment. 

Aminochromans also arise from the reaction of phenolic Mannich bases with enamines (70JHC1311). The route is attractive for a number of reasons the starting materials are readily available its scope is considerable since the enamines may be aldehyde or ketone based and the Mannich bases may be aromatic or heteroaromatic and the products themselves are precursors of hydroxychromans and 4//-chromenes. Mechanistically, the synthesis proceeds through a quinone methide followed by addition to the enamine and cyclization, which may be a concerted process (Scheme 71). 

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). 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

The Conrad-Limpach reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with the ketone or aldehyde of a 3-ketoester or a-formylester 2 providing enamine 3, and (b) cyclization with loss of alcohol to yield 4-hydroxy-quinoline 4. 

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. 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

Fig. 24 Cyclic imines/enamines from post-Ugi cyclization of amino ketones or amino aldehydes...

Based on the previous findings by Koomen [21], the Hiemstra group subsequently reported the Pictet-Spengler reaction of N-tritylsulfenyl tryptamines and various aliphatic and aromatic aldehydes by 11 (Scheme 5.11) [22]. Notably, the authors found that stabilization of the N-sulfenyliminium ion by the sulfenyl substituent facilitated preferential cyclization over enamine formation. 

Hydrolytic conditions are tolerated by dihydrobenzoxazines, and this allows the selective hydrolysis of the ester group of 243 into the free acid with 10% sodium hydroxide <1983JHC45>. The nitrile of 244 was converted into the iminium salt followed by hydrolysis to give the ester 70 <1987M273>. Conversion of 245 into an iminium salt followed by base treatment to give the a-ethoxy enamine then allows cyclization with an aldehyde to give product 246 as shown in Scheme 27 <1986H(24)3483>. 

BSB451). Metalated enamines (in the a-methyl group) easily react with aldehydes, and the new enamines thus formed undergo an intramolecular cyclization giving 2-pyrone derivatives (84T733) (Scheme 41). 

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). 

TL627>. Other metal-catalyzed reactions include the CdC -mediated cyclization of enamines in the presence of a cyano substituent (Scheme 98) <1995JOC5243>. Zinc and copper (i) salts can be used in place of the cadmium however, organocadmium promoters allow room temperature cyclization. A two-step process involving tungsten alkynols, aldehydes, and nitriles in the presence of a Lewis acid yields pyridines (Scheme 99) <1998JA4520>. 

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. 

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