Cycloaddition reactions with carbonyl groups

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

Allenic ketones undergo a thermal cycloaddition reaction with 1,3-dienes. The carbon-carbon double bond proximal to the carbonyl group reacts exclusively as in the case of allenic esters [105]. 

The reaction of 1-disilagermirene 22 with ketones is similar to the benzaldehyde case. Thus, reaction with butane-2,3-dione gives a final bicyclic product 41, which also has a norbornane type skeleton (Scheme 15, Figure 13)50. Formation of this compound can be reasonably explained by the initial [2 + 2] cycloaddition of one carbonyl group across the Si=Si bond to form the three- and four-membered ring bicyclic compound 42, followed by the isomerization of disilaoxetane 42 to an enol ether derivative 43. The intramolecular insertion of the second carbonyl group into the endocyclic Si—Ge single bond in 43 completes this reaction sequence to produce the final norbornane 41. In this case, C=0 insertion occurred into the Si—Ge bond rather than the Si—Si bond, which is reasonable due to the weakness of Si—Ge bond. 

The Regioselectivity ofHetero Diels-Alder Reactions. In a few cases, carbonyl, nitrosyl, cyano, and other double bonds with one or more electronegative heteroatoms have acted as dienophiles in Diels-Alder reactions. The carbonyl group has a HOMO and a LUMO as shown in Fig. 1.51. The energies of both orbitals are relatively low, and most of their Diels-Alder reactions will therefore be guided by the interaction between the HOMO of the diene and the LUMO of the carbonyl compound. This explains the regioselectivity in the cycloaddition of dimethylbutadiene 6.176 and formaldehyde, and between 1-substitituted butadienes 6.177 and nitrosobenzenes. 

With an acceptor-substituted alkene moiety tethered to the molecule, the intermediate silyl enol ether may undergo an intramolecular [2-I-2] cycloaddition.The silyl-assisted addition of hydrogen halides to cyclopropanes is not restricted to ketones with carbonyl groups as activating function or iodide as nucleophile. Esters and other acid derivatives underwent similar reactions when treated with iodotrimethylsilane alone or in the presence of an additional catalyst such as mercury(II) or zinc(II) chloride.Subsequent treatment of the y-iodo ester with potassium carbonate in tetrahydrofuran gave the respective y-butyrolactones in good yield. 

These cycloadditions were originally considered by Woodward and Hoffmann to be allowed [ 2S + 2J cycloadditions5. More recent calculations suggest that these reactions arc quasi-per-icyclic [2 + 2 + 2] cycloadditions with very asynchronous bond formation6 8. syn Addition of the ketene to the alkene is always observed, as is required by a concerted cycloaddition. Furthermore, the carbonyl group of the ketene almost invariably adds exclusively to the least substituted, most nucleophilic end of the double bond. Similarly, the carbonyl group of the kctcnc adds to the more nucleophilic end of a conjugated diene. 

In studies extending the thermal and Lewis acid-catalyzed [2 -f 2] cycloadditions of electron-rich olefins with carbonyl groups and electron-deficient olefins, the reactions of ketene acetals with extended it systems including /J,j8-dicyano a,j3-unsaturated carbonyl compounds have been investigated.114 The reaction of 6 with ketene acetals and tetramethox-yethylene provided the regiospecific [4 + 2] cycloadducts with no apparent competing [2 + 2] cycloaddition [Eq. (29)].114... 

Evidence has accumulated that the Wittig reaction is a concerted [2 + 2] cycloaddition reaction, with the nucleophilic carbon of the ylide attacking the electrophilic carbon of the carbonyl compound. It is called a [2 -f 2] cycloaddition reaction because, of the four tt electrons involved in the cyclic transition state, two come from the carbonyl group and two come from the ylide (Section 29.4). Elimination of triphenylphosphine oxide forms the alkene product. 

The Patemo-Buchi reaction is one of the more predictable photocycloaddition reactions. Regiocontrol of the photoproduced oxetane is a function of the stepwise addition of the carbonyl chromophore to the alkene [30]. In the case of electron-rich alkenes, excitation of the carbonyl group produces a triplet species that adds to the alkene. The product regioselectivity is a result of addition that generates the most stable biradical, and the triplet lifetime of the intermediate biradical allows for substantial stereoselectivity prior to closing (see Scheme 2). Electron poor alkenes are more likely to undergo cycloaddition with carbonyl groups directly from an exciplex [31]. 

Reaction of a-diazoketones can also be catalysed by Lewis acids, and cyclization of a, y-unsaturated diazoketone has been used extensively in synthesis. The mechanism of the reaction has been investigated it is suggested that the Lewis acid adds to the carbonyl group, to give an intermediate such as 282, which cyclizes to 283 reaction is also catalysed by copper trifluoroacetate. Lewis acid catalysis has also been used to improve yields in cycloaddition reactions with nitriles, yielding oxazoles. 

In addition to alkenes and acetylenes, carbonyl-containing compounds also participate in [2+2] cycloaddition reactions with indoles. The first example of oxetane formation via the photoreaction of indoles with a carbonyl group (a type of Patemo-Biichi reaction) was reported by Machida and coworkers [34, 35] (Scheme 16), who carried out the intramolecular cyclization of iV-acetylindole with phthalimide tethered with appropriate linkers 67a-d. Interestingly, only the... 

Muthusamy and co-workers have demonstrated [82] the reactions of the bicyclic ylide 57, generated from the diazocarbonyl compoimd 56, with symmetrical and unsymmetrical dipolarophiles. Thus, exposure of the cyclohexanone-substituted a-diazocarbonyl compound 56 to DMAD in the presence of Rh2(OAc)4 as the catalyst has furnished the cycloadduct 58 (Scheme 16). This cycloaddition was diastereoselective and, in the case of unsymmetrical dipolarophiles such as methyl methacrylate and propargyl bromide, they were regioselective and afforded oxygen heterocycles 59 and 60, respectively. The same research group has reported the 1,3-dipolar cycloaddition of the bicyclic carbonyl yUde 57 with other dipolarophiles, namely fulvenes [83]. In these tandem cycUzation-cycloaddition reactions involving fulvenes, four stereocenters and two new C-C bonds are formed in a single step. Symmetrical dipolarophiles such as macrocycHc olefins were also used for diastereoselective 1,3-dipolar cycloaddition reaction with 56 [84]. 

The carbenes may also be trapped by nucleophilic groups that lack a hydrogen atom. The use of carbonyl groups, in an intramolecular fashion, in this way generates unstable, reactive oxonium ylids (Scheme 8.138). These ylids 8.511 are 1,3-dipoles and can participate in a cycloaddition reaction with an added dipolarophile. Many tandem processes can be designed around this concept. ... 

The photochemical [2 + 2]-cycloaddition reactions of carbonyl compounds with alkenes are known as the Paterno-Buchi reactions This reaction was first reported by the group of E. Patemo and G. Buchi on the reaction of benzaldehyde with 2-... 

---