Thermal -Cycloadditions

As seen in Section 11.3, thermal [2+2]-cycloaddition reactions that form cyclobutane derivatives such as 310 are symmetry forbidden, but photochemically allowed.25 MOa There are, however, several examples of 

Ketenes (R2C=C=0) react at the C=C unit via thermal [2+2]-cycloaddition reactions to give cyclobutanone derivatives. Ketenes are highly electrophilic due to a low-lying LUMO (jt C=0), and the HOMO is relatively 

Cl2C=C=0 is -9.15 eV. Clearly, the presence of these groups raises the energy of the HOMO and would be expected to increase the rate of a cycloaddition driven by the LUMO of an alkene. This has been noted in many intermolecular reactions of ketenes and alkenes.259 xhis rate enhancement is apparent in the attempted intramolecular cyclization (see below) of 316 (X = H), which failed. When the a-chloro analog (316, X = Cl) was prepared, however, treatment with triethylamine led to 317, which cyclized to give a 55% yield of the [2+2]-cycloadduct (318), along with 19% of the ene adduct (319-see sec. 11.13) where X = Cl. 

The intramolecular version of this reaction is usually more efficient than the intermolecular version. When 327 (R = Me) was treated with triethylamine (0.2% solution of acid chloride in refluxing dichloromethane), ketene 328 (R = Me) was formed and the intramolecular [2+2]-cycloaddition gave 80% of 329.265 Ghosez reported, however, that reaction of 327 (R = H) under the same conditions gave only 3% of 329 (R = H). As 

Ketenes react with imines via [2+2]-cycloaddition to produce P-lactams.278 An example is the reaction of the acid chloride of phenylacetic acid with Proton Sponge to give ketene 340, which reacted with the tosyl imine shown and a quinuclidine catalyst to give a 65% yield of P-lactam 341, in 96% ee.229 A-Substituted isocyanates also undergo thermal [2+2]-cycloaddition reactions with alkenes, generating P-lactams.280 

To understand why these reactions work, we need to consider a new and potentially fruitful way for two alkenes to approach each other. Thermal cycloadditions between two alkenes do not work because the HOMO/LUMO combination is antibonding at one end. 

If one alkene turns at 90 to the other, there is a way in which the HOMO of one might bond at both ends to the LUMO of the other. First we turn the HOMO of one alkene so that we are looking down on the p orbitals. 

Now we add the LUMO of the other alkene on top of this HOMO and at 90 to it so that there is the possibility of bonding overlap at both ends. 

This arrangement looks quite promising until we notice that there is antiboding at the other two corners Overall there is no net bonding. 

We can tilt the balance in favour of bonding by adding a p orbital to one end of the LUMO and at a right angle to it so that both orbitals of the HOMO can bond to this extra p orbital. There are now four bonding interactions but only two antibonding. The balance is in favour of a reaction. This is also quite difficult to draw  

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DIELS - ALDER Cyclohexene synthesis A 2 Thermal cycloaddition between a diene and an activated alkene or alkyrte, sometimes catalyzed by Lewis acids. 

Thermal cycloadditions of butadiene to 3-bromo- 133 and 3-methoxy-5-methylene-2(5//)-furanones 220 were studied (95TL749). These systems contain substituents at C3 capable of stabilizing also a possible radical intermediate, influencing hereby the rate and/or the course of the reaction. Thus, the reaction of 133 and 220, respectively, with butadiene at 155°C afforded mixtures of the expected 1,4-cycloadducts 221 and 222, respectively, and of the cyclobutane derivatives... 

In contrast with the [4 + 2]- --electron Diels-Alder reaction, the [2 + 2 thermal cycloaddition between two alkenes does not occur. Only the photochemical [2 + 2] cycloaddition takes place to yield cyclobutane products. 

Trichlorinated tropones [10] have been prepared by a one-pot procedure based on thermal cycloaddition of tetrachlorocyclopropene 9 with electron-rich butadienes (Scheme 2.6) followed by spontaneous ring-expansion/dehydro-chlorination of the resulting cycloadducts. 

Aromatic fluoro-compounds have been prepared by thermal cycloaddition of fluorinated 1,3-butadienes 10-12 (Figure 2.1) with several dienophiles. Fluorophenols were obtained by cycloaddition of diene 10 with quinones [11]... 

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

Although 1-vinylnaphthalene thermally reacts with 4-acetoxy-2-cyclopenten-1-one (98) to regioselectively afford 99, the isomer 2-vinylnaphthalene gives the same thermal cycloaddition with low yield (30 %) and reacts satisfactorily only with 98 at 10 kbar (Scheme 5.10). Both products 99 and 101 were converted into the cyclopenta[a]phenanthren-15-one (100) and cyclopenta[c]phenanthren-l-one (102) isomers. Acetoxyketone 98 acts as a synthetic equivalent of cyclo-pentadienone (114 in Scheme 5.14) in cycloaddition reactions [33]. 

Interestingly, the cycloaddition of 2-azadiene 44 with N-methylmaleimide in 2.5m LT-DE gave predominantly exo-adduct in contrast to the thermal cycloaddition that is mainly enJo-selective (Scheme 6.27). A similar but not so dramatic increase in cxo-selectivity was also observed [47] for the cycloaddition of 44 with N-phenylmaleimide. The reaction is kinetically controlled, but the origin of the high cxo-selectivity observed in LT-DE is unclear the polar medium probably favors the more polar exo transition state. 

The same azide 67 was utiUzed to study the microwave-assisted synthesis of triazoles using the thermal cycloaddition with acetylenes. To achieve high yields in a short time and avoiding side reactions, the authors analyzed the effects of time, temperature, and concentration (in toluene) on the synthesis of triazoles [55]. 

Scheme 15. Thermal cycloaddition of a-pyrone to sila[3]pericycline 74...

Scheme 37. Thermal cycloaddition of tetrachlorothiophene-1,1-dioxide 192 to the cyclic pentayne 181...

Photocycloaddition of Alkenes and Dienes. Photochemical cycloadditions provide a method that is often complementary to thermal cycloadditions with regard to the types of compounds that can be prepared. The theoretical basis for this complementary relationship between thermal and photochemical modes of reaction lies in orbital symmetry relationships, as discussed in Chapter 10 of Part A. The reaction types permitted by photochemical excitation that are particularly useful for synthesis are [2 + 2] additions between two carbon-carbon double bonds and [2+2] additions of alkenes and carbonyl groups to form oxetanes. Photochemical cycloadditions are often not concerted processes because in many cases the reactive excited state is a triplet. The initial adduct is a triplet 1,4-diradical that must undergo spin inversion before product formation is complete. Stereospecificity is lost if the intermediate 1,4-diradical undergoes bond rotation faster than ring closure. 

Triazole derivatives are very interesting compounds that can be prepared by 1,3-dipolar cycloadditions between azides and alkynes. Loupy and Palacios reported that electron-deficient acetylenes react with azidoethylphosphonate 209 to form the regioisomeric substituted 1,2,3-triazoles 210 and 211 under microwaves in solvent-free conditions (Scheme 9.65) [114]. This procedure avoids the harsh reaction conditions associated with thermal cycloadditions (toluene under reflux) and the very long reaction times. 

A variety of other highly-strained electron-rich donors also form colored complexes (similar to homobenzvalene) with various electron acceptors, which readily undergo thermal cycloadditions (with concomitant bleaching of the color).209 For example, Tsuji et al.210 reported that dispiro[2.2.2.2]deca-4,9-diene (DDD), with an unusually low ionization potential of 7.5 eV,211 readily forms a colored charge-transfer complex with tetracyanoquinodimethane (TCNQ). The [DDD, TCNQ] charge-transfer complex undergoes a thermal cycloaddition to [3,3]paracyclophane in excellent yield, i.e.,... 

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 thermal cycloaddition of azides to acetylenes is the most versatile route to 1,2,3-triazoles, because of the wide range of substituents that can be incorporated into the acetylene and azide components. The accepted mechanism for the reaction is a concerted 1,3-dipolar cycloaddition. The rates of addition of phenyl azide to several acetylenes have been measured the rates of formation of the aromatic triazoles are not appreciably different from the rates of cycloaddition to the corresponding olefins, indicating that the transition-state energy is not lowered significantly by the incipient generation of an aromatic system. 

Subsequently to the intermolecular Diels-Alder reaction, a new diene is produced which can then be utilized in a second cycloaddition process. The feasibility of the second Diels-Alder process was demonstrated by the thermal cycloaddition of 44 with a variety of dienophiles to afford the cycloadducts 47 in high yields, albeit with moderate diastereoselectivity (Scheme 8.8). Additional investigations will be necessary to delineate further the scope and limitations of this rapid increase in molecular complexity. 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

Scheme 13.5 Representative thermal cycloadditions for seven-membered ring synthesis.

Cyclobutanes, synthesis (Continued) by thermal cycloaddition reactions, 12, 1... 

Photochemical cycloadditions provide a method that is often complementary to thermal cycloadditions with regard to the types of compounds that can be prepared. The theoretical basis for this complementary relationship between thermal and photochemical modes of reaction lies in orbital symmetry relationships, as discussed in Chapter 13 of Part... 

Amino-5-aryl-l,3,4-thiadiazole was treated with thionyl chloride in dry benzene to yield the N-sulfinylamine (93) an unstable compound, characterized by NMR and further derivatization. The sulfinylamine moiety caused an upheld shift on C(2) (4 6 ppm) comparable to a carbonyl or sulfonyl group, indicating the double-bond character of the N—S bond. Reaction of (93) with 2,3-dimethylbuta-1,3-diene yielded (94) via thermal cycloaddition <89JCS(P2)i855>. 

The thermal cycloaddition generally takes place at room temperature over extended periods of time, however, it was found that this process can be promoted by stoichiometric amounts of a Lewis acid (208). To engage unactivated dienophiles at reasonable temperatures, Lewis acid activation was found to be essential (74). 

The reaction of vinyl ethers and enamines with nitroalkenes is highly regiose-lective, with only the head-to-head adduct observed. The endo approach of the dienophile is preferred in the thermal cycloaddition, however, the mode of approach can be controlled by the choice of the Lewis acid promoter (214). Facial discrimination has been obtained by the use of chiral groups on the both the nitroalkene (215,216) and the enamine (217) or vinyl ether (218), as well as with chiral Lewis acids (46,66,94,219,220). 

Enders et al. (53) reported the use of chiral l,3-dioxan-5-ylamines in condensation reactions with aromatic aldehydes to form ylides in situ, which underwent thermal cycloaddition reactions with excellent yields. Treatment of 193 with benzaldehyde or p-fluorobenzaldehyde in the presence of excess dimethyl fumarate or fumaronitrile gave rise to the expected adducts in 85% yield with a >96% diastereomeric excess. For nitriles (R = CN), the endo/exo selectivity was higher at 70 30 than for the esters (R = C02Me) at 55 45 (Scheme 3.56). 

The reaction protocol was further extended to the concise synthesis of poly-oxamic acid, the unique polyhydroxyamino acid side-chain moiety of the antifungal polyoxin antibiotics (63). Treatment of the template 205 under standard thermal cycloaddition conditions with (5)-glyceraldehyde acetonide led to the formation of a single diastereoisomer 208 in 53% yield. Subsequent template removal released polyoxamic acid 209 in essentially quantitative yield. This represents a matched system, with the mismatched system leading to more complex reaction mixtures (Scheme 3.70). 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

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