Cycloaddition reactions under thermal conditions

There have been reports of a number of reactions of CPNA 73 that result in cleavage of the strained C—C o-bond under thermal conditions. The formed reactive intermediate 74 undergoes insertion and cheletropic [1+2]-, [3+2]-, and [3-1-4] cycloaddition reactions under thermal conditions (Scheme 6.13a). The reactivity profiles reported to date are consistent with such a a-delocalized singlet species 74 that can react either as a 1,1- or as a 1,3-dipole. Moreover, the 2-alkylidenecyclopropanone acetal 75 derived from a CPNA 76 is a useful precursor of dialkoxy trimethylenemethane (TMM) 77. MUd thermolysis of 75 in the presence of an electrophile generates 77, which undergoes a [3+2] cycloaddition to form cyclopentane derivative 78 (Scheme 6.13b). These results were reviewed by Nakamura and coworkers [32]. 

Several examples of [5C+1S] cycloaddition reactions have been described involving in all cases a 1,3,5-metalahexatriene carbene complex as the C5-syn-thon and a CO or an isocyanide as the Cl-synthon. Thus,Merlic et al. described the photochemically driven benzannulation of dienylcarbene complexes to produce ortho alkoxyphenol derivatives when the reaction is performed under an atmosphere of CO, or ortho alkoxyanilines when the reaction is thermally performed in the presence of an isonitrile [111] (Scheme 63). In related works, Barluenga et al. carried out analogous reactions under thermal conditions [36a, c, 47a]. Interestingly, the dienylcarbene complexes are obtained in a first step by a [2+2] or a [3S+2C] process (see Sects. 2.3 and 2.5.1). Further reaction of these complexes with CO or an isonitrile leads to highly functionalised aromatic compounds (Scheme 63). 

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. 

Frontier molecular orbital analysis of a [2 + 2] cycloaddition reaction under thermal and photochemical conditions. 

A dimer is produced in this reaction under thermal conditions is two steps a symmetry allowed [7t s+7i s] cycloaddition followed by intramolecular Diels-Alder reaction ... 

Miscellaneous Reactions. Some hydantoin derivatives can serve as precursors of carbonium—immonium electrophiles (57). 5-Alkoxyhydantoins are useful precursors of dienophiles (17), which undergo Diels-Alder cycloadditions under thermal conditions or in the presence of acid catalysis (58). The pyridine ring of Streptonigrine has been constmcted on the basis of this reaction (59). 

An explanation for the finding that concerted [4 -I- 2] cycloadditions take place thermally, while concerted [2 + 2] cycloadditions occur under photochemical conditions, is given through the principle of conservation of orbital symmetry. According to the Woodw ard-Hofmann rules derived thereof, a concerted, pericyclic [4 -I- 2] cycloaddition reaction from the ground state is symmetry-allowed. 

Fora [4 + 2 -7r-electron cycloaddition (Diels-Aldei reaction), let s arbitrarily select the diene LUMO and the alkene HOMO. The symmetries of the two ground-slate orbitals are such that bonding of the terminal lobes can occur with suprafacial geometry (Figure 30.9), so the Diels-Alder reaction takes place readily under thermal conditions. Note that, as with electrocyclic reactions, we need be concerned only with the terminal lobes. For purposes of prediction, interactions among the interior lobes need not be considered. 

The cycloaddition between norbornadiene (23 in Scheme 1.12) and maleic anhydride was the first example of a /mmo-Diels-Alder reaction [55]. Other venerable examples are reported in Scheme 1.12 [56]. Under thermal conditions, the reaction is generally poorly diastereoselective and occurs in low yield, and therefore several research groups have studied the utility of transition metal catalysts [57]. Tautens and coworkers [57c] investigated the cycloaddition of norbornadiene and some of its monosubstituted derivatives with electron-deficient dienophiles in the presence of nickel-cyclo-octadiene Ni(COD)2 and PPhs. Some results are illustrated in Tables 1.4 and 1.5. 

From 1928 when Otto Diels and Kurt Alder [1] made their extraordinary discovery until 1960 when Yates and Eaton [2] reported the acceleration of the Diels-Alder cycloadditions by Lewis acid catalysts, these reactions were essentially carried out under thermal conditions owing to the simplicity of the accomplishing thermal process. Since then a variety of methods have been developed to accelerate the reactions. The reaction between 1,3-butadiene and ethylene (Equation 2.1) is a typical example of a thermal Diels-Alder cycloaddition. 

There are many types of Diels-Alder reactions that are carried out under thermal conditions. This chapter will deal with the most significant developments, the potential and range of applications of this methodology of both the intermolecular and intramolecular cycloadditions in organic synthesis. 

Equation 2.13), undergo slow but very clean regioselective cycloaddition reactions, under carefully controlled thermal conditions with both electron-poor and electron-rich dienophiles. 

Tetraene 141 has been converted into various complex polycondensed adducts by reacting with a variety of dienophiles such as maleic anhydride, N-phenylmaleimide, N-phenyltriazolinedione,p-benzoquinone and tetracyano-ethylene carried out under thermal conditions. All cycloadditions occurred facial-diastereoselectively from an outside attack and provided monocycloadducts which had an exceptionally close relationship between diene and dieno-phile and then underwent intramolecular cycloaddition [125]. The reaction between 141 and p-benzoquinone is illustrated in Scheme 2.53. 

Lewis-acid catalysis is effective in intermolecular as well as intramolecular /zomo-Diels-Alder reactions. Thus, complex polycyclic compounds 93 have been obtained in good yield by the cycloaddition of norbornadiene-derived dienynes 92 by using cobalt catalyst, whereas no reaction occurred under thermal conditions [91] (Scheme 3.18). 

An interesting example of accelerating a reaction when high pressure is applied is the synthesis of a series of highly functionalized 4a,5,8,8a-tetrahy-dro-l,4-naphthalenediones 10 by cycloaddition of p-benzoquinone (8) with a variety of electron-poor dienic esters 9 at room temperature (Equation 5.2) reported by Dauben and Baker [6]. Using conventional methods, these heat-sensitive cycloadducts are difficult to synthesize free of the isomeric hydroquin-ones. When the reactions were carried out under thermal conditions, the primary cycloadducts were mostly converted into the corresponding hydroqui-nones. 

The product profile thus reveals impressive parallels with the reaction of diphenyl-ketene, the carbon analogue of 9, with (p-methoxybenzal)acetophenone, in which, again under thermal conditions, both cycloadditions and fragmentation of the four-membered ring product25) occur. Overall, the rate or rearrangement 7- 9 appears to be more favorable by the thermal route than by the photochemical pathway. 

The [3+2] cycloaddition of azides to double and triple bond systems has found considerable interest over the last couple of years. The reaction can either be performed under thermal conditions or by copper(i) catalysis <2001AG(E)2004, 2002AG(E)2596>. In an attempt to broaden the chemistry of such cycloaddition processes, Sharpless et al. reported the generation of tetrazole derivatives 61 by an intramolecular process (Scheme 12). In... 

In photochemical process there is an excitation of an electron from the HOMO of one component to the next higher orbital which now makes this the HOMO having the opposite symmetry. This change will permit a previously forbidden reaction to become an allowed process. Thus a (n2s + n2s) cycloaddition is symmetry allowed under photochemical conditions, which was not possible under thermal conditions. 

In practice, it was found that whereas the synthesis of hirsutene according to the dual strategy met with success under thermal conditions, but at temperatures as high as 580 °C, under photochemical conditions it afforded the unnatural cis, syn, cis configuration of some intermediates which then need further elaboration. Although the transformations 44 — 43a and 45. — 43a by a [2 + 2] -cycloaddition and a vinylcyclopropane rearrangement, respectively, may involve intermediates with a more or less biradical character, they are not typical radical reactions such as the ones we are considering here. 

The [2+2] cycloadditions can be concerted under thermal conditions provided that the interaction between the Ji-systems takes place in a supra-antara mode (Fig. 1). This [27is + 27+] mechanism [20] is sterically very demanding and, therefore, it should be facilitated by cumulenes possessing s/ -hybridized electrophilic carbon atoms. This makes ketenes and isocyanates suitable candidates for concerted symmetry-allowed thermal [2+2] cycloadditions. However, the presence of heteroatoms in both possible [2+2] reactions leads in turn to different stepwise mechanisms in which the electrophilic nature of the v/ -hybridized carbon atoms of ketenes and isocyanates plays a crucial role (Scheme 2). According to these mechanisms, zwitterionic intermediates (6) and (7) are plausible via formation of C-N or C-C bonds, respectively. 

A particularly elegant example is the application of Danishefsky s diene [107] to the total synthesis of carbohydrates and carbohydrate derivatives. While it was known that activated aldehydes undergo cycloaddition with electron-rich dienes, the process was not efficient with typical aldehydes under thermal conditions. A major breakthrough was realized [108] with the development of the Lewis acid-catalyzed diene-aldehyde cyclocondensation (LACDAC) reaction, which provided a new strategy for the synthesis of carbohydrates and other polyoxygenated natural products (Scheme 1.4) [109],... 

An ester carbonyl group is known to be generally less reactive than an aldehyde or a ketone carbonyl group. As a result, cycloaddition reactions of esters under thermal conditions are very rare. In a unique case, Chatani et al. [23] found that an ester functionality also participates in the carbonylative cycloaddition reaction of a-ketolactones (Eq. 11). The presence of a bulky group next to the keto carbonyl group is required for this selective reaction. 

A major problem in the reaction of a,/3-unsaturated carbonyl compounds and alkenes proves to be the competition between hetero Diels-Alder and ene reactions. Intramolecular cycloadditions of 1,6- and 1,7-dienes with ester and cyano groups at the double bond yield the ene product nearly exclusively, but with alkylidene- and benzylidene-ketoesters and 1,3-diketones the Diels-Alder reaction is preferred under thermal conditions, however under Lewis acid catalysis also ene reactions occur [12]. 

Trifluoromethyl-substituted sulfides, sulfoxides, and sulfones can undergo [4-F 2]-cycloaddition reactions with various dienes under thermal conditions (Table 2) sec also formation of 15 and 17. 5... 

With 1,1-disubstituted trifiuoromelhylated alkenes, such as -(trifluoromethyl)styrene, cy-doaddilion with nitrone 1 is regioselective, and a 50 50 mixture of the a. s/trani -isomers is obtained, as observed in Dicls-Alder cycloaddition reactions (see Section 2.1.1.6.2.1.1.). When the reaction is performed solvent-free under microwave irradiation, instead of under thermal conditions (boiling toluene), the yield is improved from 65% to 98% and the reaction time decreases from 48 hours to 4 minutes, however, stereoselectivity is not improved. ... 

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