Iminium ions with alkenes

Halide anions have also been employed to facilitate the cyclization of weakly nucleophilic terminal vinyl ir-nucleophiles. For example, the butenylamine (85) undergoes Mannich cyclization in the presence of excess Nal to provide the 4-iodopiperidine (87) in excellent yield. The success of this cyclization should be contrasted with the failure of related amines to cyclize in formic acid with formaldehyde (Scheme 25). A detailed study " of the effect that nucleophile concentration has on the outcome of Mannich cyclizations provides deilnitive evidence that the cyclization of iminium ions with alkenes is not a concerted process, but rather proceeds via a cationic intermediate capable of partitioning between product formation and reversal to the starting iminium ion. A bridged cation or ir-complex, e.g. (86) in equation (8), is a reasonable description of this intermediate. 

A variety of double bonds give reactions corresponding to the pattern of the ene reaction. Those that have been studied from a mechanistic and synthetic perspective include alkenes, aldehydes and ketones, imines and iminium ions, triazoline-2,5-diones, nitroso compounds, and singlet oxygen, 10=0. After a mechanistic overview of the reaction, we concentrate on the carbon-carbon bond-forming reactions. The important and well-studied reaction with 10=0 is discussed in Section 12.3.2. 

A related approach consists in the generation of endocyclic iminium ions from fV-acylaminals 209. As in the previous case, their treatment with boron trifluoride induces a diastereoselective cyclization, and thiazolo[3,4- ]pyridines 210 are isolated in good yields (Scheme 59) <2001EJ01267>. Alkenes can also participate and react well with the intermediate... 

On the other hand, iminium ion 3a has been reported to react with (E)- and (Z)-cyclooctene with complete retention of configuration of the alkene moiety in high yield (87 and 88%, respectively).5... 

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 ... 

Structural effects on the C-basicity of enamines are, however, more complex. Because of the paucity of values for pX H+, we shall anticipate our discussion of the kinetics of C-protonation (see Section III) so that some of the information presented there can be incorporated into the present section. The justification for doing so is that many of the effects that influence the stability of the iminium ion are expected to be operational in the transition state. In particular, the coplanarity of the atoms about the C=N bond in the iminium ion (already preferred for some enamines, but only when geometrically possible24) should be maintained or improved in the transition state in order to maximize p-n overlap (equation 4)25. This means that, besides the ability of the amino nitrogen to bear a positive charge, other factors such as formation of the C=N double bond (with attendant rehybridization at nitrogen), and steric interactions between groups attached to the alkene and amine moieties will be important both in the transition state and in the iminium ion product. 

The biomimetic construction of piperidine skeletons from N-methylhomoallyl-amines is performed by means of the ruthenium-catalyzed oxidation and subsequent olefm-iminium ion cyclization reaction. trans-l-Phenyl-3-propyl-4-chloropiper-idine 57 ivas obtained from N-methyl-N-(3-heptenyl)aniline stereoselectively via 56 upon treatment ivith a 2 N HCI solution (Eq. 3.72). This cyclization is the first demonstration of biomimetic formation of piperidine structure using N-methyl group, and can be rationalized by assuming the formation of iminium ion 58 by protonation of the oxidation product 56, subsequent elimination of f-BuOOH, nucleophilic attack of an alkene, giving a carbonium ion, which is trapped with Cl nucleophile from the less hindered side. 

On the basis of this rearrangement, an efficient synthetic route to pyrrolidines such as (46) was developed by Overman, starting from oxazolidine (42), via hydroxylated homoallylic imines such as (43 Scheme 22).Mechanistically, the formation of (46) may explained as a tandem-type combination of a cationic aza-Cope rearrangement with a subsequent Maimich cyclization (route a) or, alternatively, as an alkene-iminium ion cyclization/pinacolic rearrangement sequence (route b). 

Compared with the simple iminium ions, the enhanced reactivity of acyliminium salts opens up a greatly enlarged spectrum of counter-nucleophiles, which now includes alkenes and aromatic compounds possessing no donor substituents (see Section 4.2.2.2.2). 

As mentioned previously, acyliminium ions are electrophilic enough to react intramolecularly even with nonactivated alkenic ir-systems. These cyclization reactions have been recognized and elaborated as valuable tools in the stereoselective total synthesis of quinolizidine, indolizidine and pyrrolizidine alkaloids. A typical example from Speckamp s laboratory is the highly stereospecific acid-catalyzed cyclization of (81) to (83 Scheme 40), presumably via the corresponding acyliminium ion (82). Analogously, other more complex natural products, such as the antiulcerogenically active alkaloid ma-trine (85), can be built up with high stereocontrol (Scheme 41), with an enol ether function as a more electron-rich nucleophile for the intermediate iminium ion (84). ... 

Presumably the aldehyde forms an iminium ion 28 with the amine and this is attacked by the alkene. One way to draw this would be 28 — 29 but it looks better to have concerted attack by the C02H group on the cation as it is formed 30. At all events, the lactone 26 must have a 1,3-diaxial bridge 26a. 

Disconnection at alkene a gives a fragment 130 with some functional group OR for the Wittig or Peterson reaction. There is a unique carbon atom between the nitrogen atom and alkene b so disconnection to an (unstable) iminium ion and a stereochemically controlled vinyl anion synthon 131 (chapter 16) was chosen by Overman,20 who rather specialises in this kind of iminium ion. 

Now comes the critical moment. Treatment of 141 with acid (camphor sulfonic acid is used, not because it is enantiomerically pure, but because it is convenient) opens the heterocyclic ring to give the unstable iminium ion that cyclises onto the vinyl silane 142 to give the (5-silyl cation 143 with retention of configuration at the alkene. The product 144 is formed in only moderate yield (52% from 141) but contains no trace of the F-isomer. 

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. 

Recently Ahman and Somfai [43] have used an AT-sulfonyl iminium ion-alkene cyclization as a key step in an enantioselective total synthesis of the alkaloid anatoxin A (Scheme 20). a-Hydroxy sulfonamide 55 was prepared from L-pyro-glutamic acid (cf Scheme 12) and was transformed in 6 steps into enone 112. Exposure of 112 to acid led to a mixture of bridged enone 114 and /3-chloro ketone 113. The latter compound could be converted into the desired enone with DBU. Detosylation of 114 provided the natural product (+)-anatoxin A. 

An intramolecular allyl silane/N-sulfonyl iminium ion cyclization has also been used as a pivotal step in an approach to the tricyclic core of the unique marine alkaloid sarain A [46]. The starting material was aziridine ester 129 (Scheme 25) which was elaborated to amide 130. An important step in the synthetic strategy was thermolysis of 130 to an azomethine ylide, which underwent stereospecific intramolecular 1,3-dipolar cycloaddition with the Z-alkene to produce bicyclic lactam 131 [47]. This compound was then elaborated into allyl silane 132. It was then possible to replace the lactam N-benzyl functionality with a tosyl moiety, leading to 133, and subsequent reduction of the carbonyl group afforded the desired cyclization precursor a-hydroxy sulfonamide 134. Exposure of 134 to ferric chloride promoted cyclization to a single stereoisomeric tricyclic amino alkene 136 having the requisite sarain A nucleus. It is believed that the intermediate N-sulfonyl iminium ion cyclizes via the conformation shown in 135. 

As this chapter is concerned with the intramolecular variants of iminium ion initiated condensations, a brief outline of possible cyclization modes is in order (Scheme 1). Examples (a) and (b) depict the generation of monocyclic compounds by way of exocyclic-trigonal and endocyclic-trigonal cyclizations, respectively. Cases (c), (d) and (e) exemplify the construction of bicyclic compounds. Since rotational barriers for simple iminium ions are comparable to those of alkenes, all of these cyclization modes... 

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