Intramolecular Ylide Additions

Alternatively, one can add a carbene source to some form of a C=N bond. This will generate bonds c and b . This model is limited by the availability of cyclic imine or imine-like structures. Several methods are available to prepare aziridines through the functionalization of a C=N bond, although formation of the fused rings will require an intramolecular addition to a pendent imido-bond. The Darzens process and ylide addition to C=N bond are generally not applicable in most cases owing to the structural requirements of the cyclic system. This requirement renders this process less useful overall than the addition to a C=C bond. 

Cyclic carbonyl ylides, formed from diazo amides or diazo anhydrides through intramolecular carbene addition to the carbonyl group, react with the triple bond of a dipolarophile to produce bicyclic adducts. The latter undergo a retrodiene reaction, splitting off an alkyl isocyanate or carbon dioxide to give furan derivatives. 

A review of the methods for the generation of cyclic carbonyl ylides from intramolecular carbene additions has recently appeared [64]. This intermediate was first exploited as the An component for cycloaddition reactions by Ibata [65]. ort/io-Disubstituted carboalkoxy aryl diazoketones such as 54 were decomposed by copper complexes, generating six-membered ring carbonyl ylides. These transient intermediates underwent subsequent intermolecular cycloadditions in the presence of ethylenic and acetylenic reagents to give predominantly exo products containing the oxabicyclo[3.2.1] nucleus, Eq. 38. 

A related approach for the synthesis of spirocyclopenteneoxindoles was developed by Barbas and coworkers. Chiral diphosphines catalyzed the [3+2] cycloaddition between the A-protected methyleneindolin-2-ones 17b and the Morita-Baylis-Hillman (MBH) carbonates 37 [18]. This reaction was initiated by the displacement of the carbonate moiety by the phosphine VI, an addition-elimination mechanism, which was followed by the deprotonation to afford ylide 39. A regioselective nucleophilic addition on 17 by 39, followed by an intramolecular conjugate addition, afforded intermediate 40 that, after elimination of PR3, delivered the corresponding spirocycle 41 (Scheme 10.11). 

The authors gave the following rationalization to explain the ylide annulation (Scheme 20.25). Triphenylphosphine reacts with bromide 26 to form a phospho-nium salt, which is deprotonated by K2CO3 to generate the corresponding phos-phonium ylide in situ. A Michael addition of the ylide to the electron-deficient olefins, followed by another intramolecular Michael addition of the zwitterionic intermediates, and then P-eHmination of triphenylphosphine completes the catalytic cycle. The formation of the two isomers can be explained by a- or y-attack of yHde to dually activated olefins 28. Of course, the possibility of migration of the double bond in cyclopentene products 30 under the reaction conditions cannot be excluded. 

The introduction of the activated allylic bromides and Morita-Baylis-HiUman acetates and carbonates pioneered the development of a number of phosphine-catalyzed reactions in subsequent years [45]. Interestingly, the asymmetric variant of this type of transformation only appeared in the literature seven years later. In 2010, Tang, Zhou, and coworkers disclosed a highly enantioselective intramolecular ylide [3-1-2] annulation using spirobiindane-based phosphine catalyst 31 (Scheme 20.27). BINAP was found inactive in this reaction even at an elevated temperature (70°C). Notably, both optically active benzobicyclo[4.3.0] compounds 32 and 32 with three continuous stereogenic centers could be obtained as major products in high yields and stereoselectivities just by a choice of an additive [Ti(OPr )4], which can block the isomerization of the double bond [46]. 

The proposed mechanism is shown in Scheme 7.41. Tetrahydrothiophene reacts with the benzyl bromide moiety to form a sulfonium salt, which is deprotonated by K2CO3 to generate the corresponding sulfonium yUde in situ. An intramolecular Michael addition of the ylide to the acrylate moiety, followed by a P-elimination and a cydative S 2 -substitution to re-liberate the sulfide completes the catalytic cycle. The stronger base Cs COj can isomerize the 2/7-chromene to 4ff-chromene. 

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

Triphenylphosphine gives Michael additions to the activated triple bond of acetylene dicarboxylic esters in presence of acidic compounds HY (Scheme 1). The reactions take place easily at room temperature, even at -10°C [1], through formation of intermediate activated vinylic phosphonium salts, which undergo a subsequent Michael addition of HY. The reactions afford various stabilized ylides which can be isolated in high yields or undergo possibly evolution, for example by intramolecular Wittig reaction [2]. 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

Compounds in which a carbonyl or other nucleophilic functional group is close to a carbenoid carbon can react to give ylide intermediate.221 One example is the formation of carbonyl ylides that go on to react by 1,3-dipolar addition. Both intramolecular and intermolecular cycloadditions have been observed. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

The intramolecular addition of sulfur ylides to imines (e.g. 72) has proven to be an excellent route to fused-ring aziridines (e.g. 73) <06AG(I)7066>. The addition of a sulfonamide to a vinylsulfonium salt leads to the formation of the sulfur ylide 72. The ylide then undergoes an intramolecular addition to form the product fused-ring aziridine 73. This method has also been used for the synthesis of fused-ring epoxides. 

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... 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

The intramolecular addition of acylcarbene complexes to alkynes is a general method for the generation of electrophilic vinylcarbene complexes. These reactive intermediates can undergo inter- or intramolecular cyclopropanation reactions [1066 -1068], C-H bond insertions [1061,1068-1070], sulfonium and oxonium ylide formation [1071], carbonyl ylide formation [1067,1069,1071], carbene dimerization [1066], and other reactions characteristic of electrophilic carbene complexes. 

In a related paper, Scheldt and co-workers described a stereoselective formal [3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130]. Ultimately this is an intermolecular addition of the homoenolate intermediate to an azomethine ylide followed by intramolecular acylation and presumably follows the same mechanistic path as described previously. Pyridazinones are obtained as single diastereomers in good to high yield from a number of aldehydes. Unfortunately no reaction occurs with the presence of electron-withdrawing groups on the aryl ring of the enal. 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

The addition to alkenes normally leads to unstable adducts that lose carbon dioxide under the reaction conditions. The intramolecular cycloaddition of the sydnone (30) takes place at room temperature, however (Equation (5)) and the cycloadduct (31) has been characterized <86HCA927>. The unstable species formed by the loss of carbon dioxide are also azomethine ylides. It is therefore possible for a second 1,3-dipolar addition to take place, as illustrated in Scheme 6 for the reaction of 3-phenylsydnone with Al-phenylmaleimide <86TL317,92JA8414>. This 2 1 addition has been used as the basis of a synthesis of polyimides. Imides of the type (32) were used as the dipolarophiles and their reaction with 3-phenylsydnone gave linear polymers <87MM726>. 

Friedrichsen and co-workers (133) approached substituted benzotropolones from an aromatic substituted carbonyl ylide with a tethered alkyne as the intramolecular dipolarophUe (Scheme 4.67). Starting from an aromatic anhydride, Friedrichsen was able to make the tethered alkyne via addition of either pentyn-ol or hexyn-ol, then transform the recovered benzoic acid to the a-diazocarbonyl cycloaddition precursor. Addition of rhodium acetate resulted in the tandem formation of cyclic carbonyl ylide followed by cycloaddition of the tethered alkyne producing the tricyclic constrained ether 252. Addition of BF3 OEt2 opened the ether bridge, forming the benzotropylium ion, which subsequently rearranged to form the tricyclic benzotropolone (253). 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

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