Other Cycloadditions

1 [4 + 6] Cycloadditions. Secondary orbital interactions have been cited as an explanation for the stereochemistry of [4 + 6] cycloadditions such as that between cyclopentadiene and tropone 6.45 - 6.46, which favours the exo transition structure 6.360. The frontier orbitals have a repulsive interaction (wavy lines) between C-3, C-4 on the tropone and C-2 on the diene (and between C-5 and C-6 on the tropone and C-3 on the diene) in the endo transition structure 6.361. However, in this reaction the exo adduct is thermodynamically favoured, the normal repulsion between filled orbitals in the endo transition structure is an adequate explanation, and the electrostatic explanation given in Section 6.5.2.4 works just as well. There is no real need to invoke secondary orbital interactions. 

For example, the singlet trimethylenemethane 6.365 can be produced by heating the strained bicyclic hydrocarbon 6.363 or the diazene 6.364, or by photolysis of the latter. It dimerises to give a mixture of at least three hydrocarbons out of the eight possible, of which one stereoisomer of the fused-bridged product 6.366 is the major. The exocyclic methylene carbon is the unique carbon, and can be assigned to be the one with the large coefficient in ip2 and a zero coefficient in The experimental result can then be explained if the former is the HOMO and the latter the LUMO.873 

When the same intermediate is generated in methyl acrylate, only the four possible fused products 6.367 are formed, and no bridged products. This regioselectivity corresponds to that expected if ip2 is the HOMO. 

The same reaction in cyclopentadiene gives a mixture of two of the fused products 6.368 and a single bridged product 6.369. The fused products are similar to those from the reaction with acrylate, and the bridged product is allowed, whether one takes the frontier orbitals as HOMO jmethyienemethane)/ LUMO(Cycl0pentadiene) or the other way round as illustrated. One hint that the other way round is important is the endo-like selectivity, which might follow from the secondary interaction shown as dashed lines.873 874 

The oxyallyl system, another reactive intermediate usually written with two charges 6.370 instead of as a diradical, has a similar conjugated system, except that the coefficients will be different, and the central carbon atom, although close to a node in ip2 and u 3, will not have a node exactly through it. When generated on its own, it dimerises with different regioselectivity from trimethylenemethane, giving the 1,4-dioxan 6.371.875 

1 [4 + 6] Cycloadditions. Secondary orbital interactions have been cited as an explanation for the stereochemistry of the [4 + 6] cycloaddition 

2 Ketene Cycloadditions. As we saw earlier [see (Section 6.3.2.8) pages 211 and 212], ketenes undergo cycloadditions to double bonds 6.118 (repeated below) to give cyclobutanones. In practice, the reaction is faster and cleaner when the ketene has electron-withdrawing groups on it, as in dichloroketene, and when the alkene is relatively electron-rich, as in cyclopentadiene. The product from this pair of reagents is the cyclobutanone 6.249. 

The energies and coefficients of the frontier orbitals of ketene are shown in Fig. 6.39. The regioselectivity in the reaction between cyclopentadiene and dichloroketene giving the cyclobutanone 6.249 is explained by the overlap from the large LUMO coefficient on the central atom of the ketene and the larger coefficient at C-l in the HOMO of the diene. 

When the two substituents on the ketene are different, as in methylketene 6.253, the stereoselectivity is usually in favour of the product 6.254 with the larger substituent in the more hindered endo position. This follows from the approach 6.255, in which the ketene is tilted so that both bonds can develop simultaneously (solid lines), and tilted so that the smaller substituent, the hydrogen atom, is closer to the C=C bond. As the bonds develop further, the methyl group moves down into the more hindered environment, but this must only become perceptible after the transition structure has been passed. 

The cycloaddition of ketenes to carbonyl compounds also shows the expected regioselectivity. Both HOMO,keI() c/LlJMO(kctcnc) and LUMO(ketone)/ HOMO(ketcnc) interactions may be important, but they lead to the same conclusions about regioselectivity. Lewis acid catalysis is commonly employed in this reaction presumably the Lewis acid lowers the energy of the LUMO of the ketene (or that of the ketone) in the same way that it does with dienophiles. Ketenes also dimerise with ease, since they are carbonyl compounds. The regiochemistry, whether it is forming a /3-lactone 6.256, 6.257 or a 1,3-cyclobutanedione 6.258, is that expected from the frontier orbitals of Fig. 6.39. 

In recent years, nitrile oxides have also undergone cycloadditions enan-tioselectively in the presence of N/ -dioxide ligands, for example, to 3-arylideneoxindoles to provide regioselectively the corresponding chiral spiro[isoxazoline-3,3 -oxindoles]. Along with moderate to good yields, excellent diastereo- and enantioselectivities of up 98% de and 99% ee, respectively, were reached. In addition, excellent results (up to 99% yield, 98% de, and 99% ee) have also been described for 1,3-dipolar cycloadditions of 

In the last decade, several excellent results were also published in the area of enantioselective nickel-catalysed Diels-Alder cycloadditions. Among them, the reactions of cyclopentadiene with 3-alkenoyloxazolidin-2-ones induced by (i )-BINIM-2QN provided cycloadducts in up to 99% yield, 98% de, and 96% ee. Another excellent result was achieved by using a chiral iV,iV -oxide-derived nickel catalyst in Diels-Alder cycloadditions of 3-vinylindoles with methyleneindolinones for the construction of chiral spiro[carbazole-oxindoles] in up to 97% yield, 98% de, and 98% ee. Moreover, the use of the chiral DBFOX-Ph ligand has allowed an inverse-electron-demand Diels-Alder reaction of a range of Af-sulfonyl-l-azadienes with vinyl ethers to be achieved, providing highly functionalised piperidines in up to 75% yield, 96% de, and 92% ee. 

Evans and J. S. Johnson, in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer-Verlag, New York, 1999, ch. 33.1. 

Andronova, A. Kollarovic, S. Vyskocil, S. Juge, G. C. Lloyd-Jones, P. J. Guiry and I. Stary, Collect. Czech. Chem. Commun., 2011, 76, 2005-2022. 

Enantioselective Nickel(ii)-Catalysed Conjugate Addition Reactions 

3-Dipoles react with alkenes and alkynes (dipolarophiles) in 1,3-dipolar cycloadditions (a.k.a. [3 -I- 2] cycloadditions) to give five-membered heterocycles. Many agrochemicals and pharmaceuticals contain five-membered heterocycles, and the dipolar cycloaddition is an important synthetic route to these compounds. 

The three-atom component of the cycloaddition, the 1,3-dipole, is a compound for which a relatively stable resonance structure can be drawn in which one terminus has a formal positive charge (and is electron-deficient) and the other terminus has a formal negative charge. All the common 1,3-dipoles have a heteroatom (N or O) in the central position in order to stabilize the electron-deficient terminus. 

The five-membered heterocyclic product is the key to identifying a 1,3-dipo-lar cycloaddition. Many 1,3-dipoles are not stable, so they are generated by a series of polar reactions and then react in situ without being isolated. 

The reaction produces a five-membered heterocycle, suggesting a 1,3-dipolar cycloaddition. What penultimate intermediate would undergo a 1,3-dipolar cycloaddition to give the observed product The two-atom component of the dipolar cycloaddition is the C=C tt bond, so the three-atom component must be C—N—O. The C is likely to be the (+) terminus and the O the (—) terminus of the dipole. The 1,3-dipole in this reaction is a nitrile oxide, an unstable functional group that must be generated in situ. 

How is the nitrile oxide formed The elements of water must be eliminated from the nitro compound, and an N—O bond must be cleaved. The O of the NO2 group is not a leaving group, so the role of ArNCO must be to convert it into one. Nitro compounds are quite acidic (p Tg = 9), so deprotonation by EtaN is the first step. Attack of 0 on the electrophilic C of the isocyanate, protonation of N, and then E2 elimination gives the nitrile oxide, which undergoes the [3 + 2] cycloaddition to give the product. 

Few other qfdoaddition reactions with microwave irradiation have appeared in the literature since the first applications were published. In particular, the [2+2+1] reaction, known as the Pauson-Khand reaction, [6+4], and tandem [6+4]-[4+2] cycloadditions have been reported as being performed successfully under micro-wave conditions. A range of examples is described below. 

This chapter emphasizes recent applications of microwave technology in the synthesis of carbocycles and heterocycles by cycloaddition reactions. In these applications, it is clearly demonstrated that it is possible to use two different types of 

The benefits of microwave heating, in conjunction with polar solvents and sealed-vessel systems, are diverse  

The authors work in microwave chemistry has been generously supported by the CNRST-Morocco [convention France-Morocco, CHIMIE 04105) Fund, PROTARS III financial support [Programme Thematique d Appui a la Recherche Scientijique, ref. number D13/57) (KB and MS), by the CNRS, and by the French Ministry of Education (GB). We thank all our former and present coworkers for their dedication, enthusiasm, and for their essential contributions. 

1 (a) S. Kobayashi, K. A. Jorgensen, Cydoaddition in Organic Synthesis, Hardcover, 2002 (b) B. E. Hanson, Comm. Inorg. Chem. 2002, 23, 289-318 (c) H. SuGA, Angew. Chem. Int. 

An unusual influence of water on the rate of 1,3-dipolar cydoadditions was first observed when 2,6-dichlorobenzonitrile N-oxide was allowed to react with 2,5-di-methyl-p-benzoquinone [50]. Likewise, bromonitrile oxide, generated in water at acidic pH, gave cycloadducts effidendy with water-soluble alkenes and alkynes [51]. In highly aqueous media remarkable accelerations for the cycloaddition of phenyl azide to norbomene were observed [52]. 

Whereas cycloaddition of azomethine ylids were usually conducted with careful exclusion of water, it was recently shown that the cydoaddition in water-tetra-hydrofuran solution of stabilized ylids derived from ethyl sarcosinate with several dipolarophiles can occur in excellent yields [53]. 

The cycloaddition of a,a -dibromo (or dichloro) ketones with furan (or cyclopen-tadiene) gave very good yields when the reaction was conducted in pure water with iron powder. Furthermore, in the presence of triethylamine as the base, monobro-mo (or chloro) ketones react to furan (or cyclopentadiene) in water to afford the corresponding cycloadducts in near-quantitative yields (Eq. 5). In both cases, 2-oxy-allyl cation, the formation of which is favored in water, was considered as the reactive intermediate [54]. 

R4 = C02Me, C02Et, CHO, COMe R5 = C02Me, C02Et, C4H9, Ph, TMS 

The proposed mechanism involves silver-catalyzed attack by the imine function on the cyclopropyl system. This is followed by conjugate addition of the intermediate silver species on the tropone ring system and subsequent isomerization to afford 171. 

With the relative air and water stability of silver phosphine complexes in mind, the Frost and Weller groups reported the use of a silver(I) carborane triphenylphosphine complex as a catalyst for the aza-Diels-Alder reaction.82,83 These unique catalyst complexes were able to catalyze the reaction of Danishefsky s diene (195) with 196 in 

Complexation of the three silver salts Ag(CBnH12), Ag(CBnH6Br6), and Ag(OTf) to polymer bound triphenylphosphine also yielded active catalyst systems. The polymer-bound catalyst could be recycled 3 times with no loss of activity. Dimeric complexes [e.g., [Ag(PPh3)2(CBnH12)]2] were significantly poorer catalysts. 

SCHEME 109. Asymmetric homo-Diels-Alder reaction. 

ASYMMETRIC CATAI YSIS VIA CHIRAL METAL COMPLEXFS 

SCHEME 110. Fe-catalyzed codimerization of isoprene and trans- 1,3-pentadiene. 

A similar tethering strategy was more recently used by Inouye et al. in their formal, racemic synthesis of precapnelladiene 94 [37]. The reacting enone and cyclopentene were linked through an ether tether. Irradiation of 95 in hexane effected cyclization. 

It has been reported that nickel catalyzed the reactions of 6-amino- 

3-dimethyluracil with substituted alkynylketones in water to give substituted 2,4-dioxopyrido[2,3- 7]pyiimidine derivatives in quantitative yields at room temperature (Eq. 4.70). The products have potential pharmacological and biological activities. The reaction may have proceeded through an ionic process. 

Poly-(acetylene)s are widely used in different fields, such as organic light-emitting diodes (OLEDS), solar cells, and lasers.Synthesis 

The insertion reaction between an isocyanide and a sulfenyl chloride generates an intermediate (e.g. equation 4.42), which can undergo 1,3-cycloaddition reactions with electron-deficient species to form pyrroles and pyrrolines. Potassium fluoride supported on alumina is a mild basic catalyst for this process [161]. 

Iron-exchanged montmorillonite KIO catalyses the cycloaddition of N-benzylidineaniline to vinyl esters [162]. Two types of cycloaddition, [2 + 4] and [2 + 2], occur in competition (e.g. equation 4.43). 

The iron(III)-exchanged clay raises both the rate and selectivity of this process whereas iron(III) chloride raises only the rate. The selectivity depends on the nature of the ether and reactions are both regio and stereospecific. Reaction only occurs with activated ethers. 

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Let us now examine the Diels-Alder cycloaddition from a molecular orbital perspective Chemical experience such as the observation that the substituents that increase the reac tivity of a dienophile tend to be those that attract electrons suggests that electrons flow from the diene to the dienophile during the reaction Thus the orbitals to be considered are the HOMO of the diene and the LUMO of the dienophile As shown m Figure 10 11 for the case of ethylene and 1 3 butadiene the symmetry properties of the HOMO of the diene and the LUMO of the dienophile permit bond formation between the ends of the diene system and the two carbons of the dienophile double bond because the necessary orbitals overlap m phase with each other Cycloaddition of a diene and an alkene is said to be a symmetry allowed reaction... 

Vinylboranes are interesting dienophiles in the Diels-Alder reaction. Alkenylboronic esters show moderate reactivity and give mixtures of exo and endo adducts with cyclopentadiene and 1,3-cyclohexadiene (441). Dichloroalkenylboranes are more reactive and dialkylalkenylboranes react even at room temperature (442—444). Dialkylalkenylboranes are omniphilic dienophiles insensitive to diene substitution (444). In situ formation of vinyl-boranes by transmetaHation of bromodialkylboranes with vinyl tri alkyl tin compounds makes possible a one-pot reaction, avoiding isolation of the intermediate vinylboranes (443). Other cycloadditions of alkenyl- and alkynylboranes are known (445). 

How do orbital symmetry requirements relate to [4tc - - 2tc] and other cycloaddition reactions Let us constmct a correlation diagram for the addition of butadiene and ethylene to give cyclohexene. For concerted addition to occur, the diene must adopt an s-cis conformation. Because the electrons that are involved are the n electrons in both the diene and dienophile, it is expected that the reaction must occur via a face-to-face rather than edge-to-edge orientation. When this orientation of the reacting complex and transition state is adopted, it can be seen that a plane of symmetry perpendicular to the planes of the... 

Oxetanes are present in several biologically active natural compounds as, for example, the taxol ring skeleton. An interesting method used to obtain this particular ring is the thermal [2 -i- 2] cycloaddition reaction. Longchar and co-workers reported a novel [2-1-2] cycloaddition of /1-formil enamides 5, often used in other cycloaddition and condensation processes, with acetylenic dienophiles 6 under microwave irradiation (in a domestic oven) to afford ox-etenes 7 in 80% yields [29]. This reaction was directed towards the synthesis of D-ring annelated heterosteroids (Scheme 2). 

This review has attempted to bring together the reactions of ADC compounds which are useful in heterocyclic synthesis, and to develop the general trends that have so far appeared in their reactivity. Thus, in general, ADC compounds are more powerful dienophiles than the corresponding C=C compounds, particularly when the azo bond is in the cis configuration. However, they are also more reactive as enophiles and electrophiles, and may react as such even in cases where Diels-Alder (or other) cycloaddition is formally possible, and where the corresponding C=C compounds do react as dienophiles. Nevertheless, despite this added complication, the major use of ADC compounds has been as dienophiles in the synthesis of pyridazines... 

Several relevant papers and review articles have appeared recently. These contain reports on the mechanism and kinetics of the ene reaction of ADC compounds,243-245 examples of four-membered ring formation,246-247 other cycloadditions of ADC compounds,248-252 the synthesis of azoalkanes,253 the use of chiral l,2,4-triazole-3,5-diones,254 and the use of the DEAZD/PI13P reagent in organic synthesis.255... 

Dienes do not react with carbonyl compounds unless the latter are activated by electron-withdrawing substituents such as carboxyl groups. Cyclohexa-1,3-diene, for example, adds diethyl mesoxalate (1) at 120 °C to form 2 (equation 2)2. Other cycloadditions of this ester with various dienes, which were carried out in a sealed tube at 130-135 °C, are shown in equations 3 and 43. It is noteworthy that no product was isolated from the action of diethyl mesoxalate on cyclopentadiene it was suggested3 that the cycloadduct reverted to its components at the high temperature required for the reaction. 

Diels-Alder reactions (and other cycloadditions) are accelerated in water due to a combination of enforced hydrophobic interactions and hydrogen bonding, their relative contributions depending on the nature of the diene and dienophile. Subsequent work has shown that a large variety of other organic reactions show comparable favorable characteristics in aqueous media. 

Isosydnones (146) react with alkynes to give pyrazoles (150). For example, 4,5-diphenylisosydnone (146, R = R = Ph) and ethyl phenyl propiolate gives 4-ethoxycarbonyl-l,3,5-triphenylpyrazole (150, R = R = R = Ph, R = CO Et) identical with the product from 4,5-diphenylsydnone (1, R = R = Ph). The rate of 1,3-cycloaddition for isosydnones (146) is relatively slow in comparison with sydnones (1).2o, 04 number of other cycloaddition reactions of isosydnones with alkenes, alkynes, and carbonyl compounds have been reported. ... 

One of the most successful auxiliaries for ot,p-unsaturated carbonyl compounds for not only 1,3-dipolar but also other cycloadditions is Oppolzer s chiral sultam (276). In particular, the acrylate 165 of Oppolzer s chiral sultam is one of the most frequently used substrates for asymmetric 1,3-dipolar cycloadditions, as shown in Scheme 12.52. 

Other cycloadditions were reported. The intramolecular cycloaddition of alkenylnitrones was 2q>phed to the synthesis of piperidines <99TL1397, 99JCS(P1)185>. Cycloaddition of an alkenyl azide afforded piperidines after reduction of the bicyclo triazole <99T1043, 99EJOC1407>. Similar to the cyclization of the diazo imide 2 in section 6.1.2.1, isomiinchnone intermediates can rearrange to functionalized piperidines <99JOCS56>. 

Ring Synthesis via 1,3-Dipolar and Other Cycloaddition Reactions... 

Expansion of heterocyclic rings upon treatment with carbenes 5-52 Other cycloaddition reactions... 

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