Ketones cycloaddition with alkenes

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Strained n/d/ -Bredt alkenes as well as -cycloalkenes will undergo [2 + 2] cycloadditions with alkenes. The bridgehead bicyclo[3.3.1]nonenones 16, produced as a transient species by the dehydrobromination of the corresponding bridgehead bromoketone, undergo cycloaddition with 1,1-dimethoxyethenc (15) to give the tricyclic ketones 17 in quantitative yields.7... 

Cycloadditions.1 Acyclic enones do not usually undergo photochemical l2+2]cycloaddition with alkenes, but this Ti(lV) Lewis acid does promote this cycloaddition in the case of methoxymethyl vinyl ketone and, to a less extent, of methyl vinyl ketone. Usually 2 equiv. of 1 or of TiCl2(0-/-Pr)2 is required. 

Ozonolysis is widely used both in degradation work to locate the position of double bonds and in synthesis for the preparation of aldehydes, ketones, and carboxylic acids. Ozone is a 1,3-dipole and undergoes 1,3-dipolar cycloadditions with alkenes. 

The [2 -I- 2] cycloadditions of the Wittig reaction are allowed by the Woodward-Hoffmann rules because the ylide (Ph3P=CH2) has a tt bond that is made up of a P(d) orbital and a C(p) orbital, and therefore the termini of the HOMO are antisymmetric, not symmetric as they would be if the tt bond were made up of two p orbitals. The ylide s antisymmetric HOMO allows there to be bonding interactions between the termini of the ylide HOMO and the ketone LUMO in the TS for the [2 -I- 2] cycloaddition. The [2 + 2] retro-cycloaddition that completes the Wittig reaction is allowed for the same reason. Metal alkylidenes (M=CR2), which similarly have tt bonds made up of a M(d) orbital and a C(p) orbital, also undergo thermally allowed [2 + 2] cycloadditions with alkenes during olefin metathesis (see Chapter 6) and other reactions. 

The formation of 5-membered ring carbonyl ylides from a 5-keto fimc-tionality was shown to undergo the intramolecular [3+2]-cycloaddition with alkenes or alkynes. An illustrative example [79] is the reaction of acyclic diazo ketone 71 with a catalytic quantity of rhodiiun(ll) acetate at room temperature to afford the polycyclic adduct 72 in 50% yield with complete diastereoselectivity (Scheme 21). This example shows that the intramolecular cycloadditions of 5-membered ring carbonyl ylide can take place across the unactivated 1-hexenyl zr-bond. 

As one would expect, conjugated ketones are mostly poor hydrogen abstractors. This is a fortunate circumstance, because it leaves room for a variety of reactions that are quite useful from the preparative point of view. These include rearrangements [24], addition reactions and 2+2 cycloaddition with alkenes. An example of rearrangement of a cross-conjugated cyclohexadienone is shown above. This gives a cyclopropylcyclopentenone that opens up in the reaction medium (see Scheme 2.13). 

MO studies have shown that the Diels-Alder reaction of substituted selenocar-bonyl compounds with buta-1,3-diene or 2-methoxybuta-1,3-diene proceeds through a concerted, asynchronous transition state. Q ,jS-Unsaturated seleno ketones and seleno aldehydes readily undergo 4 - - 2-cycloaddition with alkenes and 4 - - 2-dimerization. The reaction of phosphaacetylene (138) with buta-1,3-diene produces triphosphatri-cyclooctenes (139) through a sequence involving Diels-Alder, ene, and intramolecular 4 -I- 2-cycloadditions (Scheme 53). The 4 + 2-cycloaddition of phosphaalkynes with 5,8-bis(trimethylsilyl)cycloocta-l,3,6-triene (140) readily yields the tricyclodecadiene (142) via the bicyclic intermediate (141) (Scheme 54). "... 

Some ketones undergo a cycloaddition reaction with alkenes to form oxetanes ... 

Catalytic cyclopropanation of alkenes has been reported by the use of diazoalkanes and electron-rich olefins in the presence of catalytic amounts of pentacarbonyl(rj2-ris-cyclooctene)chromium [23a,b] (Scheme 6) and by treatment of conjugated ene-yne ketone derivatives with different alkyl- and donor-substituted alkenes in the presence of a catalytic amount of pentacarbon-ylchromium tetrahydrofuran complex [23c]. These [2S+1C] cycloaddition reactions catalysed by a Cr(0) complex proceed at room temperature and involve the formation of a non-heteroatom-stabilised carbene complex as intermediate. 

In addition to undergoing cycloaddition reactions with alkenes and al-kynes, silenes readily undergo cycloaddition reactions with heteroatom multiple bonds such as C=0 and C=N, most commonly when the trapping reagent for the silene is either an aldehyde, ketone, or imine. In many... 

Primary nitro ketones, ethyl nitroacetate, and (phenylsulfony l)nitromethane react with alkenes in the presence of Lewis acids to give nitrile oxide cycloaddition.61a Similarly, the reaction of a-nitro ketones with TeCl4 generates the corresponding nitrile oxides, as shown in Eq. 6.36.61b... 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Cyano-substituted ethylenes react in a different way with aliphatic ketones. The orientation of photochemical cycloaddition (4.661 is the opposite of that found for electron-rich alkenes, and the reaction is highly stereoselective (4.69) in the early stages. These processes involve the formation and subsequent decay of an excited complex (exciplex) from the (n,n ) singlet state of the ketone and the alkene. Aryl ketones undergo intersystem crossing so efficiently that such a singlet-state reaction is rarely observed, but the reaction of a benzoate ester with an electron-rich alkene 14.70 rnay well be of this type, with the ester acting as electron-acceptor rather than electron-donor. 

The addition of ZnBi 2 to die tandem 1,3-azaprotio cyclotransfer-cycloaddition of a ketoxime with divinyl ketone results in rate enhancement and the exclusive formation of l-aza-7-oxabicyclo[3.2.1]octan-3-ones.79 The 1,3-dipolar cycloaddition of 1-aza-l-cyclooctene 1-oxide with alkenes produces the corresponding isoxazolidines in high yields with a minimum of polymeric material.80 The cycloaddition of thiophene-2 -carbaldehyde oxime with acetonitrile and methyl acrylate produces the 1,3-dipolar adduct, substituted isoxazolidines, and not the previously reported 4 + 2-adducts.81 Density functional theory and semi-empirical methods have been used to investigate the 3 + 2-cycloaddition of azoxides with alkenes to produce 1,2,3-oxadiazolidines.82 The 3 + 2-cycloaddition of a-nitrosostyrenes (62) with 1,3-diazabuta-l,3-dienes (63) and imines produces functionalized cyclic nitrones (64) regioselectively (Scheme 22).83... 

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