Pyrrolidine, iminium salts from

The reaction from an enamine is initiated by the addition of a trace of a strong acid, e.g. /7-toluenesulfonic acid (TsOH, 4-methylbenzene-sulfonic acid), to the ketone and pyrrolidine in a solvent such as toluene. When the mixture is at reflux in a Dean-Stark apparatus, water is liberated and is removed through azeotropic distillation, leaving the enamine in the reaction vessel. After a follow-up reaction between the enamine and a suitable electrophile, an iminium salt is produced that liberates both the a-substituted ketone and pyrrolidine when it is treated with aqueous acid (Scheme 6.20). 

Enamines are intermediate in reactivity more reactive than an enol, but less reactive than an enolate ion. Enamine reactions occur under milder conditions than enolate reactions, so they avoid many side reactions. Enamines displace halides from reactive alkyl halides, giving alkylated iminium salts. The iminium ions are unreactive toward further alkylation or acylation. The following example shows benzyl bromide reacting with the pyrrolidine enamine of cyclohexanone. 

Yang and co-workers have suggested that the inherent difficulties in the preparation/isolation of unstable exocyclic iminium salts can be overcome by in situ formation of the catalytic species from chiral pyrrolidines and aldehydes. The catalytic asymmetric epoxidation of phenylcyclohexene and dihydronaphthalene mediated by the iminium salt derived from pyrrolidine 67 and aldehyde 68 has been examined (Scheme 27) <20010L2587>. 

A potentially mote interesting application of the method for asymmetric synthesis - uses chiral a-chloroiminium chlorides as starting material. Best results are obtained with iminium salts derived from (2S)-(methoxymethyl)pyrrolidine. They react with imines in the presence of triethylamine to give opti-... 

The piperidine alkaloids were mentioned in the chapter (p. 1418) where the pathway was described as similar to that of the pyrrolidine alkaloids . We can follow the same reactions starting from lysine instead of ornithine. The first stage produces the cyclic iminium salt fi om lysine by decarboxylation with pyridoxal. 

Epoxidations. A mixture of Oxone and an iminium salt derived from pyrrolidine is an effective epoxidizing agent. An imino group can also be exploited for directing epoxidation of a proximal double bond.- The oxodiazepinium salt I- and 4-oxothiane-S,S-dioxide are also general and efficient catalysts. A popular approach to asymmetric epoxidation of alkenes is based on generating dioxiranes in situ from chiral ketones and Oxone . ... 

The [3+2] cycloaddition of allylsilanes is applicable to imines and iminium salts [419, 484, 485], Highly substituted pyrrolidines can be synthesized with high diastereo and enantio control by reaction of homochiral crotylsilanes with carbon-nitrogen double bond generated in situ from acetals and methyl carbamate (Scheme 10.174) [419]. The cycloaddition to N-tosylaldimines of aromatic aldehydes proceeds with excellent 2,4-ds selectivity whereas the stereoselectivity with aliphatic aldimines is rather low [484]. With N-tosylaldimines, fhe formation of [2+2] adducts is not observed (vide infra). 

In 1987, Hill and co-workers (75) reported a clever synthesis of the pentacyclic cephalotaxine analog 246 starting from the nitrostyrene derivative 98 (Scheme 42). The Diels-Alder adduct 244, obtained by the reaction of butadiene sulfone with 98, was treated with methyl acrylate to give a single stereoisomer of the nitro ester, which was reduced with zinc in etha-nolic HCl to yield the lactam 245 and further reduced by Red-AI to the corresponding pyrrolidine. Pictet-Spengler cyclization with formaldehyde gave the pentacyclic amine 246. Alternatively, the reduced pyrrolidine obtained from 245 could be formylated, cyclized to the iminium salt by a Bischler-Napieralski protocol, and finally reduced with sodium borohy-dride to 246. Nearly identical sequences have also been reported by Bryce... 

The first step is probably the Michael addition 115 of the enamine 112 to the unsaturated ester 113. The resulting iminium salt 116 loses a proton to regenerate an enamine. But it does so on the side away from the first reaction to avoid forcing the side chain into the same plane as the pyrrolidine ring. The new enamine is 117. 

Epoxidations. Combination of Oxone and the iminium salt derived from pyrrolidine and o-trlfluoromethylbenzaldehyde is effective for epoxidation of alkenes. In the case of an active alkene (e.g., trisubstituted alkene), pyrrolidine is an adequate catalyst. Other types of mediators include a-functionalized ketones (e.g., ot-acetaminoacetone) and the A, A -dialkylalloxans 1. ... 

A one-pot sequential hydrogenation reaction was then carried out to cyclize the diol 213 (Scheme 55). First, the pyrrolidine 214 was obtained under a 4-bar atmosphere of H2 during 3 days at room temperature. Without further isolation, HCI was added to cleave the protecting groups, allowing the second cyclization to provide the iminium salt 215. A last hydrogenation step was necessary to lead to hyacinthacine hydrochloride salt 216. A simple treatment with a basic resin afforded the desired hyacinthacine A2 7 in 39% yield from 213. 

Enamines displace halides from reactive alkyl halides, giving alkylated iminium salts. The iminium ions are unreactive toward further alkylation or acylation. The following example shows benzyl bromide reacting with the pyrrolidine enamine of cyclohexanone. 

In most of the iminium salts used for epoxidation reactions, the C-N double bond is embedded in a ring (e.g., catalyst 75, Figure 12.7). Interestingly, between 1997 and 1999, Armstrong et al. [118, 119] (and later Komatsu and co-workers [120]) found that olefins can also be epoxidized using acylic iminium salts derived from pyrrolidine (83 and 84, Figure 12.9). Unfortunately, the enantioselectivities observed were... 

Makino et al. (1977) and Baba et al. (1980e) reported the asymmetric reduction of a,3-unsaturated iminium salts that were produced from isophorone and secondary amines. Since the reduced product can be hydrolyzed to give a saturated ketone as shown in Scheme 15, reduction of this type is equivalent to the reduction of the olefinic double bond in an a,3-unsaturated ketone. Stereochemical results are listed in Table 6. It was found that the iminium salt which afforded the highest e.e. was the one that is derived from pyrrolidine. The e.e. value was independent of the kind of counter anion. 

The E-isomer is generally more stable than the Z-isomer due to diminished steric hindrance, so it is assumed that the E-isomer is the major product (shown for 83). Water, a reaction by-product, may be removed to give a better yield of product and azeotropic distillation is used as well as molecular sieves (see Section 18.6.3). Enamines are structurally related to an end (HO—C=C) in that the heteroatom is directly attached to the alkene unit. Enamines are often isolable compounds, whereas enols tautomerize spontaneously to the carbonyl form. Note that when imine 76 is formed from iminium salt 80, there is no enamine product. In fact, the C-H in 80 is much less acidic that the N-H unit, so the product is the imine rather than the enamine. It is noted that there is an equilibrium between an imine and an enamine, known as imine-enamine tautomerism, but it will be ignored in this book. Many different secondary amines can be used in this reaction, including cyclic amines (see Chapter 26, Section 26.4.1) such as pyrrolidine (90), piperidine (91), and morpholine (92). It is important to note that it is generally easier to form an enamine from a ketone than from an aldehyde. 

Another reaction type involving iminium salts led to pyrrolidines via the trapping of azomethine ylides generated from sarcosine and aqueous formaldehyde (Lubineau et al, 1995). The efficiency of [3+2] cycloaddition was related to the water content. Indeed, adding THF to the reaction medium decreased the rate of the Michael addition, which competed with the desired pyrrolidine synthesis ... 

Mariano and co-workers have employed chiral eniminium salts as surrogates for enones to control the stereoselectivity of the enone-olefin [2-1-2]-photocycloaddition. Eniminium salts have only n,n excited states and intersystem crossing to triplet excited states is therefore slow. As a consequence, the photocyclization should occur from the singlet state via a concerted mechanistic pathway. The chiral iminium salt 3, accessible by condensation of the corresponding ketone with an enantiomerically pure tra s-2,5-disubstituted pyrrolidine, cychzed in good yield. After removal of the chiral auxihary, the tricyclic ketone 4 was obtained in enantiomeric excesses of up to 82% ee (Scheme 3). 

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