Iminium ion equivalents

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... 

The sulfamate ester variant of this chemistry has already been shown to be a very powerful protocol for the syntheses of 1,3-amino alcohols and related /3-amino acids (Equation (90)), as well as iminium ion equivalents (Equation (91)). The further showcases of this chemistry are the total syntheses of the bromopyrrole alkaloids, manzacidins A and C (Scheme 13).234 The cyclic sulfamidate 129 was obtained diastereospecifically from sulfamate 128 using intramolecular rhodium-catalyzed G-H insertion. It was then found to react with sodium azide in NfN-dimethylformamide at room temperature after introduction of the Boc-activating group to afford the 1,3-diamino precursor 130 in 78% yield over 3 steps. Four subsequent manipulations afford the target structure 131. 

Aminomethylbenzotriazoles 285, as effective MBH electrophiles, react with ethyl acrylate in the presence of TiCU at 20 °C to afford the corresponding benzotriazolated adducts 286 in 66-80% yield. The adducts 286 are readily transformed into the MBH olefins 287 by treatment with sodium hydride, demonstrating the convenience of A-(a-aminomethyl)benzotriazoles 285 as iminium ion equivalents with a-H atoms generated in situ (Scheme 2.156). ... 

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. 

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%. 

Addition of enols, enolates, or enolate equivalents to imines or iminium ions provides an important route to (3-amino ketones. 

Alternatively, the ring C/D enlargement-contraction to form the spiroin-dolenine moiety could take place via an electrophilic attack on bisindolenamine 323 to afford the iminium ion 324 or its equivalent carbinolamine 325. Ring closure to hydroxyaziridinium ion 326, followed by C—C fragmentation could... 

In the LAH reduction sequence, the C=N double bond in the iminium ion now behaves just as the C=0 bond of a carbonyl (see Section 7.7.1) and is also reduced by transfer of hydride from a further equivalent of LAH. The final product is thus an amine. 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

The primary addition products A now undergo SN1 reactions (Figure 9.12). A reversible protonation of the OH group of A leads to oxonium ions D. Water is ejected from D without the nucleophile getting involved. Thereby the intermediate oxocarbenium ions C (Nu = OR3), thiocarbenium ions C (Nu = SR3), or iminium ions C (Nu = NR3R4) are formed. These combine with the second equivalent of the nucleophile to form an 0,0-acetal B (Nu = OR3), an S,S-acetal B (Nu = SR3), or an N,N-acetal (Nu = NR3R4). 

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). 

The reaction mechanism most likely involves an initial condensation of the amino functionality of the a-amino acid 168 with the aldehyde 169 to form iminium ion 171. After a-addition, intermediate 172 is formed which is attacked by the solvent methanol, to form derivative 174 after rearrangement. This compound stiU has a free carboxylic acid, which can undergo a P-3CR in the same pot to afford 175. The drawback of this procedure is that two equivalents of the aldehyde and isonitrile inputs are used, which also limits the substituent variability. 

Formic acid is an exception among organic acids in having reducing capacity because of its combined acid/aldehyde character and the possibility for exothermic release of carbon dioxide on hydride donation. Ammonium formate, NH4CO2H, has long been used for reductive alkylation of amines. This is the Leuc-kart reaction, which has been reviewed. In this process aldehydes or ketones are used to alkylate ammonia and form a primary amine (11), as depicted in equation (11). The reductive step is the reaction of formate with an iminium ion or its equivalent (equation 12). ... 

The rate of initial electron transfer from A,7V-dimethylaniline to [Fe(phen)3] + is diffusion-limited. This is followed by the rate-determining proton transfer from the radical cation to pyridine to give the deprotonated a-amino radical which is rapidly oxidized by a second equivalent of [Fe(phen)3] + to yield the product iminium ion. Kinetic isotope effects [kii/kjf) for the proton transfer were determined from the J3/tfo ratios of the products derived from p-substituted A-methyl-A-trideuteromethylanilines. The k /kx) value first increases and then decreases with increasing pAa of p-substituted A,A-dimethylaniline. Such a bell-shaped isotope effect profile is typical of proton-transfer reactions [82, 85]. The maximum kn/fco value is determined as 8.8 which is much larger than the corresponding value for the demethylation of the same substrate by cytochrome P-450 (2.6) [79]. 

The most recent source of these iminium ion precursors is the amide derived from 3-chloropropionyl chloride. Using the procedure reported by Ruhlmann for the preparation of 1-methoxy-l-trimethylsilyloxycyclopropane, Wasserman and Dion " converted the piperidide (58) to the 1-piperidino-l-trimethylsilyloxycyclopropane (59) by treatment with sodium metal in dry ether at 0°C. This reaction, which takes place smoothly and in high yield, serves as a short, inexpensive way to form the stable cyclopropanone equivalent. Further reaction of the silyl derivative (59) with tetrabutylam-monium fluoride in THF yields the corresponding carbinol amine (60). 

There are, however, numerous organic precendents. The Cannizzaro reaction, in which two equivalents of a nonenolizable aldehyde such as bezaldehyde are reacted with hydroxide to form a primary alcohol and the salt of a carboxylic acid, is thought to involve hydride transfer to one aldehyde carbonyl from the carbonyl-addition product of the other aldehyde and hydroxide. The Leuckart reaction, formation of a tertiary amine from formic acid, a primary amine and either a ketone or an aldehyde, seems to procede via hydride transfer from formate to an iminium ion. And the Meervein-Ponndorf-Verley-Oppenauer reaction, the reversible transfer of hydrogen between ketones and secondary alcohols in the presence of excess aluminum isopropoxide, is almost certainly a hydride-transfer reaction. This latter process is of particular interest to us because it requires a metal, just as GI does. The aluminum acts as a Lewis acid, coordinating the carbonyl oxygen and... 

An alternative sequence in which an a-cyanoalkylamine is employed as an iminium ion precursor has also been described (Scheme 44). This two-step temative is attractive if the aldehyde component is scarce since only one equivalent of the aldehyde is employed. ... 

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