Iminium ions nucleophiles

The formation of 88 is postulated to be occurring by the nucleophilic attack of a hydride ion (47), abstracted from the secondary amine, on the a-carbon atom of the iminium salt (89). The resulting carbonium ion (90) then loses a proton to give the imine (91), which could not be separated because of its instability (4H). In the case of 2-methyIhexamethylenimine, however, the corresponding dehydro compound /l -2-methylazacyclo-heptene (92) was isolated. The hydride addition to the iminium ion occurs from the less hindered exo side. 

There have been extensive investigations on the reaction mechanism. In most cases the reaction proceeds via initial nucleophilic addition of ammonia 2 to formaldehyde 1 to give adduct 5, which is converted into an iminium ion species 6 (note that a resonance structure—an aminocarbenium ion can be formulated) through protonation and subsequent loss of water. The iminium ion species 6 then reacts with the enol 7 of the CH-acidic substrate by overall loss of a proton ... 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

Other methods for the synthesis of a-oxygenated A-alkylamides (or carbamates) include addition of oxygen nucleophiles to A-acyl (or A-alkoxycarbonyl) iminium ions, generated via either... 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

The (3-carbon atom of an enamine is a nucleophilic site because of conjugation with the nitrogen atom. Protonation of enamines takes place at the (3-carbon, giving an iminium ion. 

Imines and iminium ions are nitrogen analogs of carbonyl compounds and they undergo nucleophilic additions like those involved in aldol reactions. The reactivity order is C=NR < C=0 < [C=NR2]+ < [C=OH]+. Because iminium ions are more reactive than imines, the reactions are frequently run under mildly acidic conditions. Under some circumstances, the iminium ion can be the reactive species, even though it is a minor constituent in equilibrium with the amine, carbonyl compound, and unprotonated imine. 

The 2-azonia analog of the Cope rearrangement is estimated to be accelerated by 106, relative to the unsubstituted system.270 The product of the rearrangement is an isomeric iminium ion, which is a mild electrophile. In synthetic applications, the reaction is often designed to generate this electrophilic site in a position that can lead to a cyclization by reaction with a nucleophilic site. For example, the presence of a 4-hydroxy substituent generates an enol that can react with the iminiun ion intermediate to form a five-membered ring.271... 

Petasis reported an efficient addition of vinyl boronic acid to iminium salts.92 While no reaction was observed when acetonitrile was used as solvent, the reaction went smoothly in water to give allyl amines (Eq. 11.54). The reaction of the boron reagent with iminium ions generated from glyoxylic acid and amines affords novel a-amino acids (Eq. 11.55). Carboalumination of alkynes in the presence of catalytic Cp2ZrCl2 and H2O affords vinylalane intermediates, which serve as nucleophiles in the subsequent addition to enantiomerically enriched... 

The diversity of the Ugi-MCR mainly arises from the large number of available acids and amines, which can be used in this transformation. A special case is the reaction of an aldehyde 9-26 and an isocyanide 9-28 with an a-amino acid 9-25 in a nucleophilic solvent HX 9-30 (Scheme 9.5). Again, initially an iminium ion 9-27 is formed, which leads to the a-adduct 9-29. This does not undergo a rearrangement as usual, but the solvent HX 9-30 attacks the lactone moiety. Such a process can be used for the synthesis of aminodicarboxylic acid derivatives such as 9-31 [3, 30],... 

Triisopropylsilyloxyfurans were effective nucleophiles for the vinylogous Mannich addition to iminium ions that were formed by Rh2(cap)4-catalyzed oxidation of N-alkyl groups by THYDRO <06JA5648>. A stereoselective addition of 2-trimethylsilyloxyfurans to aryl aldehydes-derived aldimines employing a chiral phosphine/Ag complex as catalyst was developed <06AG(I)7230>. The prototypical example is shown below. 

The whole process, formation of the iminium ion by condensation of the aldehyde with an amine (1 min at 900 W in a domestic oven) then nucleophilic attack of the isocyanide (1 min at 450 W and 1 min cooling) takes 3 min to give yields ranging from 56 to 88% of the pure product. 

Different rate-determining steps are observed for the acid-catalyzed hydration of vinyl ethers (alkene protonation, ks kp) and hydration of enamines (addition of solvent to an iminium ion intermediate, ks increasing stabilization of a-CH substituted carbocations by 71-electron donation from an adjacent electronegative atom results in a larger decrease in ks for nucleophile addition of solvent than in kp for deprotonation of the carbocation by solvent. 

A very elegant expansion of the synthetic utility of this intramolecular amination was the insertion reactions into ethereal G-H bonds. Du Bois and co-workers have exploited this reactivity to prepare cyclic sulfamates that are then used as iminium ion equivalents. Upon treatment with a suitable Lewis acid, nucleophilic addition reactions... 

Recently, we have shown that iminium ions can induce a hydride shift to form a new carbocation which then reads with a nucleophile. By this way the novel unusual bridged steroid alkaloids 25 were prepared from the secoestron derivative 19 (scheme 5) M Treatment of 20 obtained from 19 by hydrogenation with aniline or an aniline derivative 21 containing an dedron-withdrawing group in the presence of the Lewis add BF3-OEt2 leads to the iminium... 

A hydroxy group can be introduced on this bicyclic system as a nucleophile. The pyrrolo[l,2-c]oxazole system can be hydroxylated at the 7a-position to produce in good yield the corresponding 7a-hydroxypyrrolo[l,2-c]oxazole. The diastereoselectivity of this nucleophilic addition is total, with attack at the iminium ion on the face hindered by the phenyl group at C-3. <2002TL463, 2004JOC7558, 2006TA53>. 

Perhydrooxazolo[3,2- ]pyridines 338 are excellent precursors of iminium ions 339 obtained after treatment of the oxazolidine with either a Bronsted or Lewis acid. Trapping of these intermediate iminium ions with nucleophiles then allows for substitution at the C-8a position together with ring opening, yielding functionalized piperidines 340 (Scheme 93). 

Carbinolamines are chemically unstable and, in the case of tertiary amines, dissociate to generate the secondary amine and aldehydes as products or eliminate water to generate the iminium ion. The iminium ion, if formed, can reversibly add water to reform the carbinolamine or add other nucleophiles if present. If the nucleophile happens to be within the same molecule and five or six atoms removed from the electrophilic carbon of the iminium ion, cyclization can occur and form a stable 5- or 6-membered ring system. For example, the 4-imidazolidinone is a major metabolite of lidocaine, which is formed in vivo or can be formed upon isolation of the A -deethyl metabolite of lidocaine if a trace of acetaldehyde happens to be present in the solvent used for extraction (116,118) (Fig. 4.52). 

In the presence of alcohols, the corresponding ethers are formed and added nucleophiles such as chloride ion40 or azide ion41 lead to the chloro- and azido-amine products, respectively. Rate constants are independent of the concentration of added nucleophile. Labelled 180 from the solvent is incorporated in the product42. All the evidence points to a reaction mechanism where water is lost from the O-protonated reactant to give a nitrenium ion-iminium ion intermediate which is rapidly trapped by a nucleophile (H2O in this case) to give the final product. This is shown in Scheme 7. Protonation at N- is likely to be more extensive, but there is no pathway to products from the N-protonated intermediate. 

Now the stereochemistry. Assume the thermodynamically more stable iminium ion forms (Me groups cis). The Cope rearrangement occurs from a chair conformation. This puts the Ph, H2, and HI 1 all pointing up both before and after the rearrangement. Assuming the Mannich reaction occurs without a change in conformation (a reasonable assumption, considering the proximity of the nucleophilic and electrophilic centers), the Ph, H2, and HI 1 should all be cis in the product. 

The combination of an amine and an aldehyde under weakly acidic conditions almost always gives an iminium ion very rapidly. Such a reaction forms the N1-C8 bond. Nucleophilic C7 can then attack this iminium ion to give a carbocation. Fragmentation of the C5-Si6 bond gives the product. 

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