Alkenes inverse electron demand Diels-Alder reactions

Lewis-acid catalyzed inverse electron-demand Diels-Alder reactions between conjugated carbonyl compounds and simple alkenes and enolethers also allow dihydropyranes to be prepared. SnCU-Catalyzed cycloaddition of... 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

The intramolecular inverse electron demand Diels-Alder reaction between the azadiene and the tethered alkene of compound 176 gives the corresponding benzoxazolo- and benzothiazolopyranopyridines. Terminal alkenes (RZ = H) give the tvr-products 177, whereas 1,2-disubstituted alkenes (R2 = Me or Ph) give the /ram-products 178 (Equation 46) <1995J(P1)1759>. 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

The reaction of hexachlorocyclopentadiene with electron-rich alkenes is classified as inverse electron demand Diels-Alder reaction, but its reaction with electron-poor alkenes is considered as a stepwise process based on a lack of stereospecificity. The cycloaddition of 7 with ethyl vinyl ether ... 

Calculations performed at the HF/3-21G level indicated smaller energy gaps between the HOMOs of the aforementioned electron-rich dienophiles and the LUMOs of the quinone ketals, as can be expected for inverse electron-demand Diels-Alder reactions under FMO control [141]. Regiochemical controls observed with quinone ketals such as 76a were well corroborated by the relative magnitudes of the atomic coefficients of the frontier orbitals. The highest coefficients at C-5 of the quinone ketal LUMO and at C-2 of the electron-rich alkenes would indeed promote bond formation between these centers. The results of calculations on other quinone ketals were, however, rather vague [141]. 

The reactions of p-nitrostyrene (81a) with both acyclic and cyclic enol-ethers have been studied. In general, when electron-rich alkenes interact at 1.5 GPa with p-nitrostyrene (81a), mixtures of bicyclic or tricyclic regioisomers are obtained. For example, the reaction of 81a with enol ether 86 (Scheme 7.21) led to a 7 3 mixture of compounds 87 and 88. p-Nitrostyrene (81a) first reacts as an electron-poor diene in an inverse electron demand Diels-Alder reaction with the enol ether, and then as an electron-poor dipolarophile with the formed monoadduct in a 1,3-dipolar cycloaddition. 

Recently, the inverse electron demand Diels-Alder reaction of triethyl l,3,5-triazine-2,4,6-tri-carboxylate with in-situ generated alkene-1,1-diamines has been investigated in the preparation of suitably functionalized pyrimidines to be used as key intermediates in natural product synthesis.7-9... 

Inverse electron demand Diels-Alder reactions of 3,6-bismethylthio-l,2,4,5-tetrazine with a wide range of dienophiles have been shown to give substituted 3,6-bismethylthiopyridazines (148), generally in yields of 60% to 90% (Scheme 111). The reactivity of electron-rich alkynes and alkenes shows the expected order of ynamines > enamines > ketene acetals > enamides > trimethylsilyl or alkyl enol ethers > enol acetates reaction with ynamines is complete at room temperature in one... 

The domino [4 + 2]/[3 - - 2] cycloaddition of an enol ether, a nitroalkene and a third alkene is a representative example of a multicomponent reaction in which a polycyclic N-containing system is formed in a single transformation [10, 11]. In this domino reaction, a nitroalkene reacts as a heterodiene with an electron-rich alkene such as an enol ether, in an inverse electron-demand Diels-Alder reaction, to form a cyclic nitronate, which then reacts with another alkene in a 1,3-dipolar cycloaddition to produce a nitroso acetal (Scheme 9.4). 

In general the inverse electron-demand Diels-Alder reaction is carried out using stoichiometric amounts of Lewis acid "catalysts (SnCU, TiCU, TiCl2(OR)2, MAD (methylaluminium bis(2,6-di-fert-butyl-4-methylphenoxide) and MAPh (methyl-aluminium bis(2,6-diphenylphenoxide) [15]) at low temperatures (-90 to 0 °C). Before the [3 + 2] cycloaddition with an electron-poor alkene can take place, the first-formed nitronate has to be separated from the Lewis acid catalyst by an aqueous work-up and chromatography [13, 16]. Probably complexation of the Lewis acid catalyst to the nitronate dipole inactivates the dipole and hinders the 1,3-dipolar cycloadditions from taking place [17]. 

It is significant that if an electron-poor diene is utilized, the preference is reversed and electron-rich alkenes, such as vinyl ethers and enamines, are the best dienophiles. Such reactions are called inverse electron demand Diels-Alder reactions, and the reactivity relationships are readily understood in terms of frontier orbital theory. Electron-rich dienes have high-energy HOMOs that interact strongly with the LUMOs of electron-poor dienophiles. When the substituent pattern is reversed and the diene is electron poor, the strongest interaction is between the dienophile HOMO and the diene LUMO. The FMO approach correctly predicts both the relative reactivity and regioselectivity of the D-A reaction for a wide range of diene-dienophile combinations. 

The reversibility of the DA reaction, known as the retro Diels-Alder reaction, can hamper the utilization of this chemistry for bioconjugation when the formation of thermally stable products is absolutely necessary. This limitation can be conveniently overcome by the use of dienes that form stable cycloadducts during the reaction. One such example is the inverse electron-demand Diels-Alder reaction of heterodienes with strained alkenes and alkynes. 

As the substituents on the styrene increase electron density on the alkene moiety the reaction rate increases (see Table 1). This is consistent with FMO theory associated with the inverse electron demand Diels-Alder reaction. As one increases the electron density on the dienophile, the energy of the HOMO also increases and narrows the energy gap with the LUMO of the diene. Thus allowing the reaction to proceed with greater efficiency and a concomitant increase in reaction rate. 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

It was described in Sect. 7.8 of this chapter that chain-fluorinaled diazines can be synthesized using inverse-electron-demand Diels-Alder reactions. Some of the fused pyridazines can also undergo analogous reactions with electron-rich alkenes. In particular, Diels-Alder reactions of pyridopyrazine 1259 were smdied. It was found that 1259 reacted with enamines to give quinoline derivatives (e.g. 1260) (Scheme 291) [790]. Reaction of 1259 with ketene N,S-acetal 1261 led to a mixture of regioisomers 1262 and 1263, whereas reaction with A-methylindole gave complex mixture of products 1264-1267 (Scheme 292) [791]. 

Figure 2.14 The inverse electron-demand Diels-Alder reaction between tetrazines and strained alkenes. The kinetics of the cycloaddition is greatly influenced by the solvent in which the reaction is performed (Blackman et al, 2008). (Reprinted with permission from M.L. Blackman, M. Royzen and J.M. Fox, Tetrazine ligation Fast bioconjugation based on inverse-electron-demand Diels-Alderneactivity, Journal of the American Chemical Society, 130, 41, 13518-13519, 2008. 2008 American Chemical Society.)...

Et2AlCl has been extensively used as a Lewis acid catalyst for intermolecular and intramolecular Diels-Alder reactions with a,3-unsaturated ketones and esters as dienophiles. It also catalyzes inverse electron demand Diels-Alder reactions of alkenes with quinone methides and Diels-Alder reactions of aldehydes as enophiles. ... 

V-Acyliminium ions act as dienophiles in [4 + 2] cycloaddition reactions with conjugated dienes13, while A-acylimimum ions that (can) adopt an x-cis conformation are able to act as heterodienes in an inverse electron demand Diels-Alder process with alkenes or alkynes3 (see Section D. 1.6.1.1.). 

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. 

Inverse electron demand cycloaddition of 1,2,4,5-tetrazine with alkenes and alkynes. Inverse electron demand Diels-Alder addition has also been employed for the synthesis of pyridazines and condensed pyridazines. The reaction of olefinic and acetylenic compounds with 3,6-disubstituted 1,2,4,5-tetrazines 142 to yield substituted pyridazines 144 by the intermediacy of 143 was first reported by Carboni and Lindsey (1959JA4342). Analogous reaction of 142 with a variety of aldehydes and ketones 145 in base at room temperature proceeded smoothly to yield the corresponding pyridazines 144. Compounds 146-148 are proposed nonisolable intermediates (1979JOC629 Scheme 26). 

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