Cycloaddition iminium salts

The regiochemistry of ketene iminium salt cycloadditions can also differ from ketene cycloadditions. Whereas reaction of styrene with a series of ketene iminium salts gave 3-phenyI-cyclobutanones7 (60-70% yield) similar to the regiochemistry of ketene cycloadditions, reaction with a series of acrylates and a,/J-unsaturated ketones gave cyclobutanones 5 with regiochemistry opposite to what would be expected from electrostatic considerations of ketene cycloadditions.s... 

Unlike ketcnc cycloadditions, very few mechanistic studies have been carried out with ketene iminium salt cycloadditions. Differences in regiochemistry in the latter examples suggest that these reactions are not concerted and that a carbcne-type addition to the alkene leading to an intermediate such as 6 is responsible for these reactions.8... 

The ketene iminium salt cycloaddition route has been used to prepare a key intermediate 7 for the synthesis of grandisol.10... 

On the other hand, the known facts point to an alternative interpretation. The stereochemical course of the reaction may be explained in terms of a polar [2s + 2s] cycloaddition15 which is observed in reactions between very electron-poor and very electron-rich alkcnes. Namely, polar [2 + 2] cycloadditions usually proceed with high regioselectivity ( head to head ) and stereoselectivity under mild conditions33 35. This mechanism is also supported by the fact that a closely related reaction (between an ynamine and iminium salts) passes through a cyclic 4-membered intermediate36, which is probably the result of a polar [2 + 2] cycloaddition (see refs 10 and 37). 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

Recently, Malpass et al. reported a synthesis of epibatidine isomers also under reductive Heck conditions [134, 135]. 2-Azabicyclo[2.2.1]heptene 167 was assembled by cycloaddition of an iminium salt with cyclopentadiene. Treatment of 167 with 2-chloro-5-iodopyridine provided a mixture of exo-5-(6-chloro-3-pyridyl) derivative 168 and exo-6-(6-chloro-3-pyridyl) derivative 169. 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Azomethine ylides. The reaction of 1 with the oxime of an aldehyde results in an iminium salt 2. Desilylation of 2 (CsF) gives rise to an azomethine ylide (a) that undergoes 1,3-dipolar cycloaddition with electron-deficient alkenes (equation I). 

Electron-poor olefins with higher oxidation potentials may decrease the rate of electron transfer and other processes competing for deactivation of the iminium salt excited states may increase. Alternate reaction pathways involving olefin-arene 2 + 2 cycloaddition may take place in the photochemistry of 133 with electron-poor olefins (equation 62)120,121. 

The formation of isomeric products can be reconciled by consideration of the mechanistic pathway. Deprotonation of the more acidic methyl group leads to formation of iminium salt 88 that can then form two ylides, 89 and 90, furnishing a mixture of products after subsequent cycloaddition (Scheme 3.24). 

The stereochemistry with respect to the ketene iminium salt in cases of monosubstituted or unsymmetrically disubstituted derivatives in cycloadditions to alkenes show differences from the ketene counterpart. In contrast to ketene cycloadditions of monosubstituted ketenes with alkenes where the substituent in the bicyclic derivative ends up in the endo position, the cycloaddition of two monosubstituted ketene iminium salts with cyclopentene and cyclohexenc gives the e.wp-substituted derivatives 4.6... 

Although the ketene iminium salt route has advantages over the ketene route, limitations of this method include the nonstereospecificity of these cycloadditions in some instances because of the nonconcerted nature of these reactions. Of greater concern is the fact that the major product from alkenes which can form a tertiary carbocation is often the Friedel-Crafts product. This method is therefore largely limited to mono- and 1,2-disubstituted alkenes. 

Reaction of an alkene with keteniminium salts resulted in [2 + 2]-cycloaddition reactions (see Section 1.3.5.3). Hydrolysis of the intermediate cyclobutanone iminium salts 3 gave the cy-clobutanone 4.- 12 316 The cyclobutanone iminium salts are usually not isolated since they hydrolyze on aqueous workup. 

The usage of a,P-unsaturated iminium salts clearly represents a general and efficient solution leading to 2//-pyranyl products exclusively via the C-1,2-addition pathway. The reaction of the pyrone 22 led to the pyran product 23 in a much-improved yield relative to Moreno-Manas s study, and also gave previously unknown products 30b and 30c under these reaction conditions [Scheme 5]. The significance of using preformed a,P-unsaturated iminium salts to control regioselectivity of this formal cycloaddition reaction was recently validated in an account reported by Cravotto.39... 

First, sterically congested a,P-unsaturated iminium salts such as 11 [Scheme 2] can impede the formal [3 + 3] cycloaddition.20 Secondly, and more significantly, there had been no successful stereoselective examples36... 

However, under our conditions20,35,37 as well as a variety of other conditions,53,54 the formal [3 + 3] cycloaddition reaction of the iminium salt 51 with pyrone 12 failed to provide any desired pentacycle 52. This failure prompted us to think that 51 might be sterically too demanding, thereby obstructing the reaction pathway. 

By using pyrone 5757 under the same conditions, pentacycle 58 was obtained in 72% yield with a diastereomeric ratio of 91 9 in favor of the same major isomer. The compound 58 contains the desired E-ring of territrem B [3]. This current formal [3 + 3] cycloaddition approach also proves to be superior to another related variation of this cycloaddition using acid chlorides58 instead of a,P-unsaturated iminium salts. 

Reversibility of 67t-Electron Electrocyclic Ring-Closure. The high diastereoselectivity obtained in these reactions here is likely a result of the reversible 67t-electron electrocyclic ring-closure.20,37 41 The best evidence for the reversibility of this ring-closure is described in Scheme 12. We were able to isolate both the desired major isomer 10 and the minor isomer 44 from the formal cycloaddition reaction of the iminium salt 56 with pyrone 12. 

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