Silyl enol ethers iminium ions

Although enol ethers have received moderate notice as nucleophiles to quench intramolecular iminium ions, silyl enol ethers have been given scant attention. The first report of a silyl enol ether participating in an intramolecular Mannich reaction is found in Oppolzer and coworkers synthesis of ( )-vincamine (Scheme 14). 2 Dihydro-3-carboline (25) and silyl enol ether (26) were mixed in DMF, then warmed to 70 C for 64 h in the presence of diisopropylethylamine to provide a 1 1 mixture of cis and trans tetracyclic aldehydes (27) in 74% yield. 

The chiral (V-camphanoyl iminium ion 7, prepared by hydride abstraction from 2-camphanoyl-l,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 6 (see Appendix) with triphenylcarbenium te-trafluoroborate, reacts with silyl enol ethers to give 1-substituted tetrahydroisoquinoline derivatives with reasonable diastereoselectivity, 0°. On addition of titanium(IV) chloride, prior to the addition of the silyl enol ether, the diastereoselectivity gradually rises to an optimum at 2.5 equivalents of the Lewis acid, but the yield drops by 20%. 

All the substrates A E introduced here are alkenes that are electron-rich. This is why they react with electrophiles. Enols (A), enol ethers (C), silyl enol ethers (D) and silylketene acetals (E) react electrophiles to form oxocarbenium or carboxonium ions, whereas the reaction of enamines (B) with electrophiles gives iminium ions ... 

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 die conjugate addition can provide the electrophilic component in a cydization reaction. Acid-catalysed hydrolysis of the f) amino-ketone liberates the amine that was used to form... 

Aliphatic amines are mainly converted to a-substituted products [99,100], whereby especially the a-methoxylation leads to valuable reagents for synthesis. The intermediate iminium salts can be directly trapped by silyl enol ethers to form Mannich bases [108]. If the a-position is blocked or steric conditions favor it, N,N coupling to hydrazo or azo compounds occurs (Table 5, numbers 17-19). 1,1-Disubstituted hydrazines are dimerized to tetrazenes in fair to excellent yields (Table 5, numbers 20-24). The intermediate diaze-nium ions can attack enolizable carbonyl compounds to form aza-Mannich bases [109]. Arylazonaphthols undergo anodic oxidation, producing radical cations. These couple to biphenylbisazo compounds (up to 34%) or can be trapped by anisidine to form azodiphe-nylamines (up to 74%) [110a]. 

Santamaria et al [42] for synthesizing a-amino nitriles in the alkaloid field and also for preparing 6-cyano-l,2,3,6-tetrahydropyridine from corresponding pyridine nucleus. A similar approach has also been used by Sundberg et al. [43a,43b] for the cyanation of Catharanthine alkaloids. In situ trapping of the iminium cation (37) by allyltrimethylsilanes or silyl enol ethers is also shown [44] recently as a direct —C-C— bond formation methodology at the a-posi-tion of tertiary amines (Scheme 8). The success of this reaction is based on the comparative correlation of ion-pair yield with the AGg, values from amines and enol ethers. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Simple silyl enol ethers have been shown to be of synthetic utility. Thus, the iminium ion generated by activation of 38 with zinc bromide could react with 39 to afford ketone 40 in good yield."... 

The class of 1,2,3-oxathiazinane-2,2-dioxide heterocycles are accessible through sulfamate ester insertion into ethereal C -H centers under [Rh2(OAc)4] catalysis. These N,0-acetals, as iminium ion equivalents, coupled smoothly with silyl enol ethers, ketene silyl acetals, and thioacetals in the presence of a catalytic amount of Sc(OTf)3 (10mol%) to give the corresponding adducts with moderate to high diastereoinduction (Scheme 12.43) [107]. It is noted that the procedure does not require purification of the intermediate oxathiazinane. 

Magnus developed also a combination of iodosyl benzene and trimethylsilyl azide to azidate the j8-carbon of silyl enol ethers (Scheme 8.22). ° ° The total synthesis of lycorane amaryllidaceae alkaloids takes advantage of this process. A tentative ionic mechanism is proposed for this process. However, involvement of radicals cannot be totally excluded. Under the same reaction conditions, anilines and amides lead to the isolation of C-H substituted products at carbon atoms adjacent to nitrogen (Scheme 8.23). These azidoamines/azidoamides are precursor of iminium/acycliminium ions that are useful intermediates for C-C bond formation. 

In Xia s light-mediated coupling of silyl enol ethers to 1 (Scheme 11.28), the absenee of the nucleophile led to the formation of the metho - (27a) and hydrojgr-substituted intermediates (27b) in yields of 43% and 57% respectively in a similar fashion to that proposed by Klussmann for the copper-mediated CDC reaction, i.e., off-cycle equilibria that trap the reactive intermediate. The use of wet methanol gave complete conversion to the hemiaminal. The authors proposed that formation of these products prevented further irreversible oxidation to the corresponding amide 84. Instead, 27a and 27b are in equilibrium with the iminium ion and this competes with the irreversible carbon-carbon bond-forming reaction to give 27e upon addition of the nucleophile. 

Carbon-carbon bonds can be similarly formed at the anomeric centerof carbohydrates. Oxonium ions, formed by the treatment of l-(2 -thiopyridyl)glycosides v/ith Silver(I) Trifluoromethanesul-fonate, can be trapped with silyl enol ethers, silyl ketene acetals, and reactive aromatic compounds, where the stereoselectivity of the addition is determined by solvent and nucleophile choice. The intramolecular version of this process has also been examined (eq 5). Similarly, bicyclic piperazinediones are available by the intramolecular trapping of iminium ions, generated from the appropriate thiopyridyl derivatives with PhHgC104 (eq 6). ... 

Mayr has extended his electrophilicity scale to benzaldehyde-derived iminium ions through measurement of rate constants for their reactions with C-nucleophiles such as enamines, silylated ketene acetals and enol ethers." With an E value of -9.27 for Ph-CH=NMe2" (in a range from -8.34 to -10.69 forpara-C j, andpura-OMe, respectively), these iminium ions are 10 orders more reactive than the parent aldehydes. However, the values are restricted to C-nucleophiles the iminium ions react 10 -10 times faster with water and amines than these E values would predict. Such reactions benefit from the anomeric stabilization of 0,Af-acetals and Af,Af-aminals. 

A procedure in which the iminium salt shown, A, N-dimethyl(methylene) ammonium trifluoroacetate, is isolated and added separately to an enolate ion allows Mannich bases to be prepared by routes other than those involving acidic media. This procedure is exemplified by entry 4. N,iV-Dimethyl(methylene) ammonium iodide is commercially available as Eschenmoser s salt and is sufficiently electrophilic so as to react directly with enol silyl ethers in neutral media. Ketone enolates have been converted to Mannich bases with Eschen-moser s salt (entry 5). 

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