Summarizing Cycloadditions

We are now ready to summarize the trends expected for cycloadditions. This is done in Table 15.1. The key is the sum of m + n, where once again we emphasize that m and represent a number of electrons, not atoms. The rules are reminiscent of aromaticity, in that for the conventional s + s geometry, a total of + 2 electrons is allowed, while a total of 4r) is forbidden. The less common s + a geometry is Mobius, so 4r/ is preferred in that case. 

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Conjugated cyclohexenones [6] have also been easily prepared by combining the cycloaddition of dimethylaminobutadiene 4 and several cyclic and acyclic dienophiles followed by the elimination of the amino group from the cycloadducts under acidic conditions. Scheme 2.3 summarizes some of these results. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

These dienes are valuable for the Diels-Alder based synthesis of dibenzofurans, dibenzothiophenes, carbazoles and other classes of complex polycyclic heterocyclic compounds. Scheme 2.32 summarizes some of the cycloadditions [81] of 2-vinylbenzofurans (80). 

Scandium triflate [33] is a more active catalyst than the lanthanide triflates and the cycloadditions can also be carried out in aqueous media (Chapter 4). The catalyst is easily recovered from the aqueous layer after the reaction is completed, and can be reused. Some of the cycloadditions carried out in DCM and catalyzed by Sc(OTf)3 are summarized in Table 3.2. 

Supported Lewis acids are an interesting class of catalysts because of their operational simplicity, filterability and reusability. The polymer-bound iron Lewis-acid 53 (Figure 3.8) has been found [52] to be active in the cycloadditions of a, S-unsaturated aldehydes with several dienes. It has been prepared from (ri -vinylcyclopentadienyl)dicarbonylmethyliron which was copolymerized with divinylbenzene and then treated with trimethylsilyltriflate followed by THF. Some results of the Diels-Alder reactions of acrolein and crotonaldehyde with isoprene (2) and 2,3-dimethylbutadiene (4) are summarized in Equation 3.13. 

Since dihydroarylethenes are more reactive than the corresponding fully aromatic compounds, their use in the cycloaddition reactions is preferred in order to carry out the reactions under mild conditions with higher yields. Some reactions of 3,4-dihydro-1-vinylnaphthalene (103) [33], 3,4-dihydro-2-vinyl-naphthalene (104) [34], and l,2-dihydro-4-vinylphenanthrene (105) [35] with 4-acetoxy-2-cyclopentenone (98) and 2-inden-l-one (106) are summarized in Schemes 5.11-5.13. 

Since aromatic substitutions, aliphatic substitutions, additions and conjugate additions to carbonyl compounds, cycloadditions, and ring expansion reactions catalyzed by Fe salts have recently been summarized [17], this section will focus on reactions in which iron salts produce a critical activation on unsaturated functional groups provided by the Lewis-acid character of these salts. 

Let us summarize briefly at this stage. We have seen that the point of degeneracy forms an extended hyperline which we have illnstrated in detail for a four electrons in four Is orbitals model. The geometries that lie on the hyperline are predictable for the 4 orbital 4 electron case using the VB bond energy (Eq. 9.1) and the London formula (Eq. 9.2). This concept can be nsed to provide nseful qualitative information in other problems. Thns we were able to rationalize the conical intersection geometry for a [2+2] photochemical cycloaddition and the di-Jt-methane rearrangement. 

This silylene formation from 27 under mild conditions permits the synthesis of a variety of interesting carbo- and heterocycles, most of which are new types of compounds. The results are summarized in Schemes 5 and 6. The reactions with benzene and naphthalene represent the first examples of [2+1] cycloadditions of a silylene with aromatic C=C double bonds.59 623 The reactions with carbon disulfide and isocyanide (Scheme 6) are also of great interest because of their unusual reaction patterns.62b... 

Disilenes react with various types of reagents to afford novel three-membered cyclic compounds that are otherwise inaccessible. Even though some are not mechanistically [2+1] cycloadditions, all the reactions in which three-membered rings are formed from disilenes are summarized in Scheme 12. 

The carbon-carbon bond forming reactions of nitro compounds by alkylation with alkyl halides or acylation with acyl halides have been encountered with difficulties of the competing O-alkylation or O-acylation, respectively. In this chapter, the recent developments of C-alkylations and C-acylations of nitro compounds are summarized. The O-alkylated compounds undergo cycloaddition reactions, which are discussed in the chapter of cycloaddition (Chapter 8). 

Nitro compounds have been converted into various cyclic compounds via cycloaddition reactions. In particular, nitroalkenes have proved to be useful in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes and react with dienes to yield 3-nitrocy-clohexenes. Nitroalkenes can also act as heterodienes and react with olefins in the presence of Lewis acids to yield cyclic alkyl nitronates, which undergo [3+2] cycloaddition. Nitro compounds are precursors for nitrile oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3+2]cycloaddition reactions. Thus, nitro compounds play important roles in the chemistry of cycloaddition reactions. In this chapter, recent developments of cycloaddition chemistry of nitro compounds and their derivatives are summarized. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

Cycloaddition of nitrile oxides to alkenes with various chiral auxiliaries are summarized in Table 8.1, which shows chiral alkenes and differential excess (de). 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

Extension of the enantioselective cycloaddition methods using chiral propenyl ethers is summarized in Scheme 8.39.179... 

Some cycloaddition reactions of 4 are summarized in Scheme 1. This shows that silylene 4 undergoes reactions with nitriles [14], phosphaalkynes [15], silyl azides [16], diazabutadienes [17], 2,2 -bipyridyl and its derivatives [18, 19], a-ketoimines [19], and pyridine-2-aldimines [19]. 

Reactions, under irradiation, involving the addition to unsaturated hydrocarbons of nitrogen and phosphorus compounds and of silanes have been summarized by Spinks and Woods (1990). Some cycloaddition reactions have also been reviewed. These will not be detailed here. 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

Intramolecular [3+ 2]-cycloaddition of six-membered cyclic nitronates was extensively studied by Prof. Denmark and coworkers for the tandem [4 + 2] [3 + 2] -cycloaddition reactions of nitroalkenes. Detailed considerations of this problem were summarized in two reviews (394a, b). Most data were comprehensively discussed in Reference 394b. It is unnecessary to repeat this information however, it is worthwhile to briefly review the available data. 

Main Aspects of Chemistry and Stereochemistry of Cyclic Nitroso Acetals Chemistry of cyclic nitroso acetals or nitrosals (the term was introduced by Prof. Seebach) has attracted interest only after the discovery of the 1,3-dipolar cycloaddition reaction of nitronates with olefins in 1962 by the research group of Prof. Tartakovsky. (Principal data on nitroso acetals up to 1990 were summarized in the review by Rudchenko (395).)... 

Another attempt to perform a general mechanistic consideration of [3 + 21-cycloaddition reactions of nitronates with olefins has been made relatively recently by Prof. Denmark and coworkers (162) using modern quantum-chemical methods, which allow one to correctly calculate the potential energy surfaces for model substrates. Since these data have been summarized in the recent review (335), it is not necessary to consider them as comprehensively as the study in (337). 

Yamamoto and co-workers found that BLA 76a is one of the best catalysts for the enantioselective and selective cycloaddition of a-substituted ajl-enals to highly reactive dienes such as cyclopentadiene. The results in the presence of (J )-76a are summarized in Table 5-2. The major enantiomer has, in several cases, been demonstrated to have the predicted absolute configuration. 

Apart from isolated reports summarized in Scheme 47, the chemistry of the fully conjugated ring systems has not been especially developed since CHEC-II(1996). In 1999, Monnier et al. reported the 1,3-dipolar cycloaddition of Reissert compound 160 with acrylates. Addition of triethylamine traps hydrofluoroboric acid and increases the proportion of milnchnone imine 160B the reaction therefore predominantly yields 1,3-adduct 161 which rearranges to 162 (Scheme 47) <1996BSB777, 1999EJ0297>. 

Table 5.8 summarizes the glycals that had been converted into 2-aminoglycosides so far. In general, photolytic ds/trans isomerization of trans-azodicarboxylates is necessary to accomplish good yields of the initial cycloadducts [335-337]. However, bis-trichloroethyl azodicarboxylate also reacts under thermal conditions and also gives a more reactive cycloaddition product [338,339]. 

So summarizing we see that in thermal [2 + 2] cycloaddition, a supra-supra process is geometrically possible but symmetry forbidden. But in supra-antar process, symmetry is allowed but geometrically difficult. Now we have to explain how the photochemical formation of cyclobutane takes place from 2n components. 

We have recently developed a novel method for the generation of alkylideneallyl cations from alkylidenecyclopropanone acetals (8, 9). This method provides a nice opportunity to examine the selectivity of reactions of the ambident cation with various nucleophiles including siloxyalkenes (10) and furans (11). The reaction of the cation with the carbon nucleophiles gives [4 + 3] and [3 + 2] cycloaddition products as well as simple nucleophilic addition products. These results are summarized in this chapter. 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

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