Cycloaddition reactions solved problems

Cycloaddition reactions often require the use of harsh conditions such as high temperatures and long reaction times. These conditions are not compatible with sensitive reagents or products such as natural products. The applicability of Diels-Alder cycloadditions is, moreover, limited by the reversibility of the reaction when a long reaction time is required. The short reaction times associated with microwave activation avoid the decomposition of reagents and products and this prevents polymerization of the diene or dienophile. All these problems have been conveniently solved by the rapid heating induced by microwave irradiation, a situation not accessible in most classical methods. With the aid of microwave irradiation, cydoaddition reactions have been performed with great success [9, 10]. 

Achiral ester-substituted nitrones as well as chiral nitrones can be employed in diastereoselective asymmetric versions of tandem transesterification/[3 + 21-cycloaddition reactions, as shown in Scheme 11.54 (174). High diastereoselectivity and excellent chemical yields have been observed in the reaction with a (Z)-allylic alcohol having a chiral center at the a-position in the presence of a catalytic amount of TiCl4- On the other hand, the reaction with an ( )-allylic alcohol having a chiral center at the a-position, under similar conditions, affords very low selectivities. Tamura et al. has solved this problem with a double chiral induction method. Thus, high diastereoselectivity has been attained by use of a chiral nitrone. 

To solve this problem, bisoxygenation or dihydroxylation of the model tetracycle 61 was carried out followed by removal of the more activated secondary oxygen functionality in 62 or 63 using reductive methods that we had developed for these specific systems [Scheme 13].59,60 The effort in developing this methodology [61 —> 64] turned out to be significant not only in this synthetic endeavor, but also for future total syntheses employing the formal [3 + 3] cycloaddition reaction. 

The nature of the iminic nitrogen substituent influences the cycloaddition pathway (4 + 2 versus 3 + 2) followed in the reactions of a-nitrosoalkenes with alkyl/aryl-substituted acyclic imines.4 The problem of rotamer control in Lewis acid-catalysed 3 + 2- and 4 + 2-cycloaddition reactions of a./S-disubstituted acryloylimides was solved by the use of N-H imide templates.5... 

The Pauson-Khand reaction is a well-known method for preparing cydopente-nones by the [2 + 2 + 1] cycloaddition reaction of alkyne, alkene and CO. While reactions using stoichiometric amounts of Co2(CO)g were initially examined, catalytic versions with cobalt, titanium, rhodium, iridium, and ruthenium complexes have recently been developed. Whilst the intramolecular version is rather easy, the inter-molecular version is a very difficult problem that has not yet been solved [76]. 

However, there are still a number of problems that will have to be solved Synthetic equivalents will have to be found for those cosubstrates that do not undergo this cycloaddition. The possibilities of inversion the polarity (e.g. by the introduction of a nitro-group at the unsaturated cosubstrate) remain to be examined as does the extension of these cycloaddition reactions to an intramolecular version leading to cyclopentane annulation. Although the regioselectivity may be manipulated by changing the catalyst (e.g. Pd(0) versus Ni(0)), there is still room for improvement and a deeper understanding of the mechanistic details of these reactions is needed. But the activity and the interest in this field assure that most of these problems will be solved in the near future. 

Cycloaddition reactions have been performed with great success with the aid of microwave irradiation (Chapter 11). All the problems associated with these reactions have been conveniently solved by the rapid heating achieved with microwave irradiation, a situation not accessible by classical methods [4a, 6]. In some examples the selectivity of the reaction has also been modified. Langa described the cydoad-dition of N-methylazomethine ylides to C70 to give three regioisomers (83a-c) by attack at the 1-2, 5-6, and 7-21 bonds (Scheme 5.24) [68]. Under the action of conventional heating the 7-21 83c isomer was formed in only a low proportion... 

Regardless of the precise structure of the chosen half southern synthon, the two main problems to be solved are the establishment of the carbon skeleton and the introduction of the necessary chirahty into the molecule. The published approaches have introduced chirality either by resolution, by starting with a chiral precursor, or via use of asymmetric synthesis techniques. The carbon skeleton has been established by use of a wide variety of techniques including the Diels-Alder and other cycloaddition reactions, heteroatom induced cyclizations, intramolecular Michael or Aldol cyclizations, intramolecular ether formation, and radical cyclization. 

Electrocyclic, sigmatropic, and cycloaddition reactions are subsequently described in Chapters 2, 3, and 4, respectively. Chapter 5 is devoted to a study of cheletropic and 1,3-dipolar cycloaddition reactions as examples of concerted reactions. Many group transfer reactions and elimination reactions, including pyrolytic reactions, are included in Chapter 6. There are solved problems in each chapter that are designed for students to develop proficiency that can be acquired only by practice. These problems, about 450, provide sufficient breadth to be adequately comprehensive. Solutions to all these problems are provided in each chapter. Finally, in Chapter 7, we have compiled unworked problems whose... 

Building on the shoulders of these predecessors, we continued our own efforts and developed a more general solution to render acyclic enals useful in this formal cycloaddition reaction. To solve the competing reaction pathway problem or to improve the pathway leading to the desired... 

In early studies of these reactions, the turnover efficiency was not always high, and stoichiometric amounts of the promoters were often necessary to obtain reasonable chemical yields (Scheme 105) (256). This problem was first solved by using chiral alkoxy Ti(IV) complexes and molecular sieves 4A for reaction between the structurally elaborated a,/3-unsaturated acid derivatives and 1,3-dienes (257). Use of alkylated benzenes as solvents might be helpiul. The A1 complex formed from tri-methylaluminum and a C2 chiral 1,2-bis-sulfonamide has proven to be an extremely efficient catalyst for this type of reaction (258). This cycloaddition is useful for preparing optically active prostaglandin intermediates. Cationic bis(oxazoline)-Fe(III) catalysts that form octahedral chelate complexes with dienophiles promote enantioselective reaction with cyclopentadiene (259). The Mg complexes are equally effective. 

The structure of the reaction product of 2-aminopyridine and diethyl malonate, described by Chichibabin as 2,4-dioxo-3,4-dihydro-2//-pyrido-[l,2-<7]pyrimidine,96 was first questioned by Snyder and Robison253 on the basis of the high melting point and poor solubility of the compound. They suggested the tautomeric 2-hydroxy-4-oxo-4H-pyrido[l,2-a]pyrimidine structure. The problem was solved by Katritzky and Waring273 who compared the UV spectrum of the product with that of fixed tautomers and found that the product may best be described as anhydro- 2-hydroxy-4-oxo-4/f-pyrido[l,2- ]pyrimidinium)hydroxide (63). Because of the chemical behavior of these compounds, however, the contribution of other mesomeric forms to the structure has also been considered.122 Thus, PPP-SCF quantum chemical calculations suggest that 1,4-dipolar cycloadditions to the C-3 and C-9a atoms are to be expected.352 This type of reaction does in fact occur (see Section III,C,10). Katritzky and Waring273 estimated the ratio of the mesomeric betaine (63 R = H) and the 2-hydroxy-4-oxo tautomers to be about 20 1. 

Although this strategy had solved the problem of pyrrolidine ring formation, the unexpected incorporation of the oxygen functions in both products presented a new one. Strenuous measures to eliminate air from the reaction mixture failed to avoid this complication, suggesting that the reaction intermediates (which may be either zwitterionic or radical in nature) were remarkably efficient scavengers of O2. Thus, faced with additional steps required to manipulate these groups in a productive way and the already poor yield of the dipolar cycloaddition, this approach was abandoned. 

High pressure has been applied successfully to Diels-Alder reactions of furans, which are notoriously troublesome due to low activation barriers and low or even negative AC values. For example, attempts to synthesize the potent vesicant cantharidin (232) via reaction of furan (228) with dimethylmaleic anhydride (234) date back to 1928. The failure of this approach has been attributed to a thermodynamic preference for cycloreversion over cycloaddition. More than SO years later the problem was solved by employing high pressures and either a modified dienophile (229) or diene paitner (233). Interestingly, product (235) reverts to reactants (233) and (234) in solution at atmospheric pressure and room temperature (Scheme S4). 

The two Pd(0) or Ni(0) catalyzed [3+2]-cycloadditions starting with the readily accessible trimethylenemethane -precursors [2-(acetoxymethyl)-3-allyl]trimethyl-silan, methylenecyclopropane, and their substituted derivatives are important new methods for the synthesis of methylenecyclopentanes. Because of the simplicity with which many problems of cyclopentane-syntheses can be solved in a convenient one pot reaction this new methodology may be compared with the synthesis of six-membered rings by the powerful 4+2]-cycloaddition of the Diels-Alder reaction. 

Isomeric adducts can also derive from concurrent reactions at different positions of a reactant a common case is the occurrence of both Diels-Alder and 1,2-cycloaddition products in photochemical and sometimes in thermal reactions between simple olefins and dienes. The analytical problem is usually solved by gas chromatography . ... 

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