Inverse-electron-demand hetero-cycloaddition

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

Various substituted unsaturated acylphosphonates participate in highly dias-tereoselective and enantioselective cycloadditions with vinyl ethers, Eqs. 177 and 178. It is intriguing to note that catalysts [(.V,.Y)-f-Bu-box]Cu (OTf)2 (269c) and [(.V,.S )-Ph-box]Cu (OTf>2 (269d) possessing the same sense of chirality afford opposite antipodes of the cycloadduct in comparable selectivities. Cyclopentadiene was found to react with acylphosphonates to give a mixture of the normal Diels-Alder adduct and the inverse electron demand hetero-Diels-Alder adduct (35 65), Eq. 179. This result may be contrasted with crotonylimide, which furnishes the normal demand Diels-Alder adduct exclusively. 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

The inverse electron demand hetero Diels-Alder reaction of 1-oxa-l,3-butadienes and electron-rich dienophiles is an extremely versatile tool in natural product synthesis. This cycloaddition represents the key step of numerous approaches not only to carbohydrates, but also to terpenes, alkaloids, polyethers, steroid derivatives and various biologically active metabolites. 

A four-component [4 + 2]/[4 + 2]/[3 + 2] cycloaddition reaction, reported by Scheeren et is another application of multicomponent reactions. The interaction of 2-methoxy-l,3-butadiene (92) (1 equiv.) with p-nitrostyrene (81a) (3 equiv.) at 1.5 GPa led to a mixture of nitroso-acetals 93-95. In this reaction, p-nitrostyrene (81a) first reacts as a dienophile in the normal electron-demand Diels-Alder reaction, it then reacts as a heterodiene in the inverse electron-demand hetero-Diels-Alder reaction and, finally, it acts as a dipolarophile in the [3 + 2] cycloaddition (Scheme 7.23). 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

J0rgensen and Juhl reported the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of aldehydes (e.g., 71) and enones (e.g., 72) with excellent diastereo- and enantioselectivity. Scheme 3.26 [41], The reaction utilizes a chiral enamine intermediate as an alkene in catalytic asymmetric cycloaddition reactions. 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Following this route, the authors achieved the synthesis of 10 analogues of compound 58, in a high global yield, where the crucial step of this total synthesis was the efficient catalytic enantio-, regio-, EIZ-, and diastereoselective three-component inverse electron demand hetero-[4+2] cycloaddition/allylboration sequence. This key process provides a rare example of an enantioselective hetero-Diels-Alder reaction involving acyclic 2-substituted enol ethers. Additionally, these compounds were evaluated for antimicrobial activity, and two of them showed more activity than the original thiomarinol H. 

Compared to the hetero-Diels-Alder reaction of carbonyl compounds and derivatives with dienes, where only a limited number of catalytic and enan-tioselective reactions have been reported, the number of asymmetric hetero-Diels-Alder reactions in which the ketone or imine functionality is part of a heterodiene is much higher. In contrast, there are only a few examples of using a,p-unsaturated aldehydes in inverse hetero-Diels-Alder reactions. In the case of the inverse electron demand hetero-Diels-Alder reaction, the ketone or imine functionality is part of an a,(I-unsaturated system, which reacts in a cycloaddition reaction with an electron-rich alkene. The inverse electron demand hetero-Diels-Alder reaction is primarily controlled by a LUMOdiene-HOMOdienophiie interaction, which can be found, for example, in the reactions... 

Wijnen, f.W., Zavarise, S., Engberts, J.B.F.N. and Charton, M., Substituent effects on an inverse electron demand hetero Diels Alder reaction in aqueous solution and organic solvents cycloaddition of substituted styrenes to di(2 pyridyl) 1,2,4,5 tetrazine, /. Org. Chem., 1996,61, 2001-2005. 

The Lewis-acid-promoted formal inverse-electron-demand hetero-4 -i- 2-cycloaddition of cationic aryl 2-oxadieneoxocarbenium ions (96) with alkenes (97) produced endo- and ejco-3,4-dihydrobenzopyrans (98,99), respectively. The substitution pattern of the alkene controls the yield and diastereoselectivity of the chroman product (Scheme 28). ... 

While disilene 5 does not undergo Diels-Alder reactions with 1,3-dienes, the [4+2]-cycloaddition products are formed with heterodienes, e.g. 1,4-diazabutadienes [17] or a-ketoimines [19]. It can be deduced that the electron deficient properties of such dienes cause them to readily take part in hetero-Diels-Alder reactions, which have inverse electron demands. This is corroborated by theoretical calculations which predict an inverse electron demand of the Si-Si double bond it is strongly electron donating rather than electron accepting towards butadienes and other compounds [24,25]. 

Af-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4+2] cycloaddition with alkenes and alkynes.15 The reaction has been utilized as a useftil method for the construction of heterocycles and acyclic amino alcohols. The reaction can be explained in terms of an inverse electron demand Diels-Alder type process that involves an electron-deficient hetero-diene with an electron-rich dienophile. Af-Acyliminium ions generated by the cation pool method were also found to undergo [4+2] cycloaddition reaction to give adduct 7 as shown in Scheme 7.16 The reaction with an aliphatic olefin seems to proceed by a concerted mechanism, whereas the reaction with styrene derivatives seems to proceed by a stepwise mechanism. In the latter case, significant amounts of polymeric products were obtained as byproducts. The formation of polymeric byproducts can be suppressed by micromixing. 

The Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, as well as the hetero-Diels-Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative. 

In this Diels-Alder reaction with inverse electron demand the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group of the oxabutadiene at the 3-position lowers its LUMO dramatically, both the cycloaddition and the condensation usually take place at room temperature. The reaction can be performed as a two-, three- or four-component transformation. There is actually no restriction on the aldehydes thus, aromatic, hetero-aromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. In addition, ketones such as a-oxocarbocylic esters can also be employed. As 1,3-dicarbonyl compounds cyclic substances such as Meldrum s acid, barbituric acid and derivates, coumarines, any type of cycloalkane-1,3-dione and / -ketoesters, as well as their phosphorus, nitrogen or sulfur analogues and acyclic... 

The hetero Diels-Alder reaction of nitrosoalkenes with electron-rich olefins has been known for a long time [363]. A detailed mechanistic study carried out by Reissig et al. has given evidence that this inverse electron demand cycloaddition is a concerted process [364]. Recent ab initio calculations dealing with the reaction between ethylene and nitroso ethylene strongly corrobate this view [365]. In this work, Jursic and Zdravkovski have also investigated the influence of BH3 as Lewis acid catalyst. However, cycloadditions of nitrosoalkenes already pro-... 

Hetero-Diels-Alder reactions of other a, -clhylenic trifluoromethyl ketones provide a good alternative access to trifluoromethyl-substitutcd dihydropyrans (Tabic 7). These cycloadditions occur with inverse electron demand with electron-rich heterodienophiles such as vinyl ethers. They are performed under mild thermal conditions or at room temperature and are chemoselective and rcgioselective. but generally not stereoselective. 

Besides Michael additions the mild reaction conditions of CIR are also compatible with cycloadditions. Since chalcones can also be considered as heterodienes, Diels-Alder reactions with inverse electron demand are suitable elementary steps that are applicable for heterocycle synthesis. Therefore, after CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, (hetero) cyclic and acyclic morpholino enamines 98 are added and, finally, after adding... 

Hetero- Diels-Alder reactions that proceed with good to excellent asymmetric induction are well known. " Chiral 1-aza-dienes have been developed as substrates, for example. " Chiral catalysts have been developed. " Conjugated aldehydes react with vinyl ethers, with a chiral chromium catalyst, in an inverse electron demand cycloaddition that give a dihydropyran with good... 

Knoevenagel products are highly reactive compounds because of their low energy LUMO. They can act as dienophiles in the normal Diels-Alder reaction, as heterodienes in the hetero Diels-Alder reaction with inverse electron demand,- as dipolarophiles in 1,3-dipolar cycloadditions, as enophiles in the ene reaction and as acceptors for the addition of allylsilanes. Sigmatropic rearrangements and photochemical reactions have been described. 

A representative of the hetero-Diels-Alder reaction of inverse electron demand is the cycloaddition of A-sulfonyl-l-azadienes with vinyl ethers. It is amenable to asymmetric catalysis, for example, by a nickel(II) complex of 101. ... 

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