Regiochemistry of Cycloaddition Reactions

An important aspect of photocycloaddition consists of its regio- and stereoselectivity. Thus, dimerization of substituted olefins generally yields head-to-head adducts 61a and 61b in a regiospecific reaction, while head-to-tail dimers 63 are obtained from 9-substituted anthracenes (62) in polar solutions (Applequist et al., 1959 cf. Kaupp and Teufel, 1980). 

The portion of the head-to-head product increases in nonpolar solvents and in micelles (Wolff et al., 1983). The regioselectivity of 9-methylanthracene is temperature dependent, and a photochemical equilibrium exists between the two isomers (Wolff, 1985). 

Singlet acenaphthylene (64) stereospecifically gives the syn dimer 65a, while in the T, reaction the anti dimer 65b predominates. The syn-anti ratio can be influenced by solvents with heavy-atom effect (Cowan and Drisco, 1970b), as well as by micellar solvents (Ramesh and Ramamurthy, 1984). 

Triplet quenchers such as Oj or ferrocene inhibit formation of the anti dimer, while the formation of the syn dimer is hardly affected. The syn-anti ratio in the triplet reaction was determined by comparing the outcome of the reaction with and without use of a quencher (Cowan and Drisco, 1970a). 

The formation of head-to-tail dimers such as those of 9-substituted anthracenes and similar species can be rationalized by the conjecture that in this case it is not the most favorable excimer that determines the stereochemical outcome of the reaction but rather, the most readily reached peri-cyclic funnel. This can be understood if the effect of substituents on the pericyclic funnel is first considered at the simple two-electron-two-orbital model level (3x3 Cl, Section 4.3.1). The discussion of cyclodimerization of an olefin is restricted to the four orbitals directly involved in the reaction. 

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Application of DFT Concepts to Reactivity and Regiochemistry of Cycloaddition Reactions... 

Such a stepwise reaction would not be expected to change the regiochemistry of cycloaddition, but it could lead to loss of stereospecificity if the zwitterionic intermediate has a long enough lifetime. In most reactions where only carbon-carbon bonds are being formed, the D-A reaction remains stereospecific. 

Cycloaddition of CO2 with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiochemistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /J-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

The first photochemical [3 + 2] cycloadditions of arenes with aikenes were reported by two groups in 1966 [76, 77]. This is one of three types of cycloaddition reaction ortho, meta, and para) of arenes with aikenes, and is referred to as the meta-cydoaddition reaction. There are many combinations of arenes and aikenes and, indeed, a large number of reports and reviews have been made on the regiochemistry and stereochemistry [78]. Because this reaction can be used easily to construct a tricyclo[3.3.0.02,8]oct-3-ene framework, the organic syntheses of many natural compounds using this method have been attempted [79], in which the photochemical [3 + 2] cydoaddition plays a key role. 

Cycloaddition between thiocarbonyl derivatives as hetero dipolarophiles and various 1,3-dipoles provides easy entry to five-membered thiaheterocycles. The reaction of thiobenzoyltrimethylsilane lb and thiobenzoyltriphenylsilane la with benzonitrile oxides, diphenylnitrilimine, and benzonitrile-4-nitroben-zylide gave regiospecifically 5H-1,4,2-oxathiazoles 12a,b, 1,3,4-thiadiazoline 13, and 4,5-dihydrothiazole 1430 (Scheme 11). The regiochemistry of this reaction was assigned through the protiodesilylation of the adducts (vide infra). 

The regiochemistry of the reaction between an n. T-unsaturated ketone and a ketene is the opposite, even in an intramolecular reaction 8.53 —> 8.54, which involves substantial twisting and ring strain. This time it is in the sense easily explicable by the frontier orbitals. The LUMO of the unsaturated ketone and the LUMO of the ketene show that the initial bonding will be between the [3 carbon of the enone and the carbonyl carbon of the ketene, and there is an orthogonal orbital on the other carbon atom of the ketene able to complete the cycloaddition, just as we saw earlier (see pages 212 and 253) for thermal reactions. 

The regiochemistry of the cycloadditions of allenes is not easily explained by these frontier orbitals. Penta-2,3-diene and acrylonitrile give the adducts Z- and -6.404 in which the central carbon of the allene, with the smaller HOMO coefficient, has bonded to the / carbon of the Z-substituted alkene.894 Equally unexplained is the regiochemistry of the reaction between allene itself and diazomethane, which gives more of the adduct 6.405 than of its regioisomer 6.406.893... 

DeShong (Scheme 20). Thus, reaction of nitrones with vinyl silanes followed by reduction provides Peterson - type intermediates which can then be eliminated to either Z- or E-products. Homoallylic amines were also prepared using allylsilane in the initial cycloaddition. Substitution reactions of allylic nitro compounds have received considerable attention and some examples are outlined in Scheme 21. In each case, examination of the regiochemistry of the reaction was of paramount concern, the results using palladium being superior to the SnCl mediated process. Allylic sulphides constitute yet another group of... 

The approximate representation of the transition state 6.33 demonstrates that the principally also conceivable reverse cycloaddition could result in a strained ring system. More important than this explanation is the conclusion that the wrong regiochemistry of this reaction does not need much more activation energy than that of the expected cyclization. If, for example, the regioisomer ratio in intramolecular cycloadditions were 98 2, i. e., when the minor product can be detected only with much analytical effort, the activation energy for the minor product is only 10 kJ mol higher than that of the main product. 

A firm understanding of concerted cycloaddition reactions developed as a result of the formulation of the mechanism within the framework of molecular orbital theory. Consideration of the molecular orbitals of reactants and products revealed that in some cases a smooth transformation of the orbitals of the reactants to those of products is possible. In other cases, reactions that appear feasible if no consideration is given to the symmetry and spatial orientation of the orbitals are found to require high-energy transition states when the orbitals are considered in detail. (Review Section 11.3 of Part A for a discussion of the orbital symmetry analysis of cycloaddition reactions.) These considerations permit description of various types of cycloaddition reactions as allowed or forbidden and permit conclusions as to whether specific reactions are likely to be energetically feasible. In this chapter, the synthetic applications of cycloaddition reactions will be emphasized. The same orbital symmetry relationships that are informative as to the feasibility of a reaction are often predictive of the regiochemistry and stereochemistry of the process. This predictability is an important feature for synthetic purposes. Another attractive feature of cycloaddition reactions is the fact that two new bonds are formed in a single reaction. This can enhance the efficiency of a synthetic process. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Bis(tnfluoromethyl)-4,5-dihydrooxazin-6-ones [28] and their O-acetylated dcnvatives [96] are formed on treatment of acyl imines with acetyl chloride-hiethylamine at room temperature. The reaction was interpreted as a cycloaddition reaction involving a ketene [28] However, the periselectivity and regiochemistry of this reactwn-are not in agreement with results obtained from the reaction of... 

The A-benzenesulfonyl imines of hexafluoroacetone readily react with nitrile oxides to give [3-1-2] adducts, apparently in a multistep reaction [151] (equation 36) Although only a few examples of [3-1-2] cycloaddition reactions of this type have been descnbed so far, most 1,3-dipoles should react in this way with predictable regiochemistry [5 146, ISO 151]... 

In contrast, when ot,P-unsaturated multiple bond systems act as dienophiles in concerted [4+2] cycloaddition reactions, they react across the C=C double bond Periselectivity as well as regiochemistry are explained on the basis of the size of the orbital coefficients and the resonance integrals [25S]... 

An interpretation based on frontier molecular orbital theory of the regiochemistry of Diels Alder and 1,3-dipolar cycloaddition reactions of the triazepine 3 is available.343 2,4,6-Trimethyl-benzonitrile oxide, for example, yields initially the adduct 6.344... 

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