Tandem 4 + 2/3 + 2-cycloaddition cascade

A domino Diels-Alder reaction (the term was chosen from the well-known game) is a one-pot process involving two or more Diels-Alder reactions carried out under the same reaction conditions without adding additional reagents or catalyst such that the second, third, etc., cycloaddition is the consequence of the functionality generated in the previous reaction. A historical example is illustrated in Equation 1.28 [60]. This type of transformation is sometimes named tandem or cascade, but these terms seem less appropriate for describing a time-resolved transformation. 

A systematic exploration of a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was conducted in which the tethered initiating dienophile, the tethered... 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

Tandem carbonyl ylide generation from the reaction of metallo carbenoids with carbonyl continues to be of great interest both mechanistically and synthetically. Effective carbonyl ylide formation in transition metal catalyzed reactions of diazo compounds depends on the catalyst, the diazo species, the nature of the interacting carbonyl group and competition with other processes. The many structurally diverse and highly successful examples of tetrahydrofuran formation cited in this mini-review clearly indicate that the tandem cyclization/cycloaddition cascade of metallo carbenoids has evolved as an important strategy in both carbo- and heterocyclic synthesis. 

The Diels-Alder reaction has a rich history of applications in tandem and cascade processes. Many of the transformations already discussed have a cascade-like nature since processes like retro-Diels-Alder reactions and aromatization reactions often occur after the initial Diels-Alder step. Clearly, the triple Diels-Alder reaction of [4]dendralene described by Sherbum (97—>98) involves a beautiful cascade of cycloaddition reactions. 

Coldham and coworkers reported a tandem condensation/cyclization/intramolec-ular cycloaddition cascade process to form fused tricychc amines, using azomethine ylides (derived from a-amino-acids or esters). This chemistry was apphed for the constmction of the pyrrolo[l,2-a]azepine ring system of the Stemona alkaloids (Scheme 4.20) [39]. Condensation of the aldehyde 96 bearing a dipolarophile (an... 

An important feature of these tandem processes is the complementary electronic nature of the [4 + 2] and the [3 + 2] cycloadditions. The former operates under inverse-electron-demand and as such requires an electron-rich dienophile. The latter operates under normal-electron-demand and is more facile with an electron-deficient dipolarophile. As a consequence, both the dienophile and the dipolarophile may be simultaneously present in the reaction mixture or linked to each other and will not lead to cross-reactivity. Tandem cycloadditions that are initiated by the thermal or pressure activated [4 + 2] cycloadditions usually require an excess of the dienophile. Even though this 27t component is electron-rich, it can react further with the nitronate intermediate unless a more reactive, electron-deficient dipolarophile is also present. As a consequence, such tandem cycloadditions may be conducted as cascade tandem processes if all three components are present firom the beginning and react under the same conditions. On the other hand, tandem processes initiated with a Lewis acid activated [4 + 2] cycloaddition often require a work up to decomplex the Lewis acid li om the nitronate, which otherwise would inhibit the next [3 + 2] step. Because this work up constitutes a change of reaction conditions, such processes are usually run as consecutive or even sequential tandem processes, if the dipolarophile is added later. 

Compared to the cycloadditions of nitroalkenes, tandem cycloadditions of 1,3,4-oxadiazoles consist not of two, but of three elementary reactions. In the first step, a 1,3,4-oxadiazole 428 serves as an electron-poor heterodiene (4jt-component) and reacts thermally with an alkene dienophile (2jt-componait) by a [4-1-2] cycloaddition reaction. The preferred dienophile is electron-rich, unhindered, and strained. At the elevated temperatures required for the first step [169], the immediate product of this reaction, 430, is unstable and undergoes extrusion of dinitrogen by a [3 + 2] cycloreversion to form dipole 431 [170]. At the high temperatures required for its formation, 431 cannot be directly observed either and reacts by a [3 + 2] cycloaddition with an available dipolarophUe, which can be the same 27i-component that served as the dienophile or something else. Because none of the intermediates is isolated and no change in reaction conditions is required, tandem [4-f 2]/[3- -2] cycloadditions of 1,3,4-oxadiazoles are tandem cascade processes as defined earlier in this chapter. 

To improve the stereocontrol of the [4 + 2] cycloaddition, the tether is shortened leading to substrate 533 (Scheme 16.114) [206]. The tandem cycloaddition with 533 provides the desired product 534 in 72% yield. The relative configuration of the cycloadduct is set following the usual trends and the stereogenic center at C(7) serves admirably to establish the C(5) stereogenic center during the [4 + 2] cycloaddition, which is transmitted throughout the cascade. The selectivity of the [4 + 2] cycloaddition may be... 

To rapidly construct complex structures, a recent synthetic strategy uses the Diels-Alder cycloaddition in sequence with another Diels-Alder reaction or with other reactions without isolating the intermediates (domino, tandem, cascade, consecutive, etc., reactions) [4-6]. Scheme 1.2 illustrates some examples. 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

Keyword Carbocycles a Cascade Reactions a Cycloadditions a Combinatorial Chemistry a Domino Reactions a Enantioselective Transformations a Ene Reactions a Eieterocydes a Natural products a Preservation of Resources and Environment a Sigmatropic Rearrangements a Tandem Reactions a Transition Metal-Catalyzed Transformations... 

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

Furans are also useful 4ji components for tandem Ugi condensation/intra-molecular Diels-Alder cascade reactions. For example, stirring a methanolic mixture of compounds 127-129 and benzylamine at rt provided the Ugi condensation product 130 that underwent a subsequent intramolecular Diels-Alder cycloaddition to furnish 131 in 70-90% yield (Scheme 23) (99TL1851). This methodology also allowed for a solid phase synthesis by using an ArgoGel-Rink resin as the amine component, providing cycloadducts 131 (after cleavage from the resin) in ca. 90-95% yields. 

Triazole Derivatives. Triazole derivatives are known to possess tumor necrosis factor-a (TNF-a) production inhibitor activity. The synthesis of triazole derivatives can be achieved from alkynes or diynes by a tandem cascade reaction involving 1,3-dipolar cycloaddition, anionic cyclization and sigmatropic rearrangement on reaction with sodium azide. Some of the benzoyl triazole derivatives were considered to be potent local anaesthetics and are comparable with Lidocaine. The triazoles can also be prepared from benzoyl acetylenes,triazoloquina-zoline derivatives, 2-trifluoromethyl chromones, aliphatic alkynes, 2-nitroazobenzenes, ring opening of [ 1,2,4]triazolo [5,1-c] [2,4]benzothiazepin-10 (5//)-one, alkenyl esters and dendrimers. A number of these reactions are outlined in eqs 44 8. 

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

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