Carbocations iminium ions

Pyrrolidine itself is not sufficiently activated to allow direct C—C bond formation at positions 2 or 3. However, under certain conditions the nitrogen atom may stabilize a reactive carbanion or carbocation (iminium ion). Both approaches have been fruitful. 

A plausible mechanism for this new alkyne aza-Prins cyclization is outlined in Scheme 27. Thus, reaction of the homopropargyl tosyl amine with an aldehyde promoted by ferric halide generates the W-sulfonyl iminium ion. This intermediate evolves to the corresponding piperidine, via the vinyl carbocation. Ah initio theoretical calculations support the proposed mechanism. 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

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 cationic-cationic domino process of a 3-hydro-xytetrahydro-P-carboline which leads to a stereo-seledive preparation of ( )-ulein was described by Blechert et al.1151 Although the intermediates of this fast proceeding sequence could not be identified definitely, it is acceptable to assume that the process is initiated by the formation of a 2-indolyl carbocation, which cyclizes after tautomerization to a more stable iminium ion. 

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 similar mechanism can be drawn if 08 is protonated first (not shown). Cleavage of the 08-C6 bond gives a C6 carbocation to which Oil adds. After cleavage of the N1-C6 bond, H+ transfer from C7 to C3 occurs to give an enol and an iminium ion. C7 then attacks C2, and elimination of the amine follows to give the products. 

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. 

Examples for frequently encountered intermediates in organic reactions are carbocations (carbenium ions, carbonium ions), carbanions, C-centered radicals, carbenes, O-centered radicals (hydroxyl, alkoxyl, peroxyl, superoxide anion radical etc.), nitrenes, N-centered radicals (aminium, iminium), arynes, to name but a few. Generally, with the exception of so-called persistent radicals which are stabilized by special steric or resonance effects, most radicals belong to the class of reactive intermediates. 

Evidence that this reduction proceeds mainly via an N-acyl iminium ion intermediate 120 was obtained by carrying out the triethylsilane reduction of 108 in deuterated trifluoroacetic acid (Scheme 49). As before, two C-4 epimeric protected kainoid analogues 121 and 122 were obtained, H NMR showing loss of the C-4 proton in both products accompanied by a simplification in the spin-spin coupling pattern of the C-5 protons.73 A close examination of the 2H NMR spectrum of each diastereoisomer did, however, reveal a trace of deuteration at C-5 indicating that a small percentage of the reduction also occurs via a benzylic carbocation intermediate 123 (Figure 12). 

When the hemiaminals A (Figure 9.12, Nu = NR3R4) are formed in a neutral or weakly basic solution, they also have the possibility to react further by an SN1 reaction albeit in a different manner than just described for the corresponding hemiacetals (Nu = OR3) and hemithioacetals (Nu = SR3). The OH group of hemiaminals A is then ejected without prior protonation (i.e., simply as an OH ion). This is possible because an especially well-stabilized carbocation is produced at the same time, that is, the iminium ion C (Nu = NR3R4). It reacts with the second equivalent of the N nucleophile. Proton loss affords the jVW-acetal B (Nu = NR3R4). 

An interesting example of a formal [4 + 2]-cycloaddition has been found to occur on condensing A-substituted anilines with co-unsaturated aldehydes in the presence of Lewis Acids. In this study, A-phenylamines 162 underwent condensation with 163 to provide acridine products 165 in ca. 60-75% yields (Scheme 29) (96CC1213). The intermediate iminium ions 164 that are first formed either participate in a concerted [4 + 2]-cycloaddition (followed by proton transfer) or else undergo polar addition to the pendant alkene by addition of the resultant benzylic carbocation onto the aniline ring. 

An iminium ion-alkene cyclization has been employed to assemble the phenylmorphan ring system (Scheme 26). The conversion of enamine (64) to (66) was suggested to arise by 1,5-hydride migration of an initially formed bicyclic cation (65). Direct intramolecular ene cyclization of the iminium ion (67) produced by protonation of (64) provides an alternative rationale for the net cis addition to the terminal alkene that occurs in this transformation, and avoids postulating the intervention of a relatively unstable fully formed secondary carbocation. 

Iminium ion-alkene cyclizations accomplished under standard Eschweiler-Clarke methylation conditions have been employed to prepare five-, six- and seven-membered azacycles (Scheme 25).57,58 It is important to note that under identical conditions amines (62) and (63) did not cyclize but afforded the corresponding IVjV-dimethylamines. With regard to the alkene participant these results are in full accord with Baldwin s rules for ring formation.2 However, the formation of pyrrolidine (61) demonstrates that 5-endo-trig cyclizations2 can take place with respect to the iminium ion n-participant. The observed regioselectivity and the failure of (63) to cyclize are in accord with obligatory formation of an intermediate with tertiary carbocation character. 

It is useful to recognize that the dissociation of tetrahedral intermediates in carbonyl chemistry is closely related to the generation of carbocations by ionization processes. The protonated carbonyl compounds or iminium ions that... 

Mannich condensations of pyrroles and indoles are especially useful examples of alkylation by stabilized carbocations, in this case iminium ions. The traditional conditions involve reaction between the heterocycle, formaldehyde and a dialkylamine in acidic solution, as in the preparation of gramine (Equation (75)) <37CB567>. 

H H J Base Enamine iminium ion to give an enamine is exactly like deprotonation of a carbocation to give an alkene. 

In 1999, the cation pool method debuted for the first time in a CDC reaction (Scheme 8.55). Yoshida carried out the electrolysis of carbamate (109) at low temperature, and the generated cation pool of carbocations (or iminium ions) (110) was further reacted with various nucleophiles, affording pipelidine derivatives 111 in moderate yields. This is the conventional and direct method for oxidative C-C bond formation. 

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