Heteroatom-substituted Diels-Alder reactions

Grignard reagent reactions, 233 halogen substitution, 60 handling-shipping-storage, 15 health considerations, 15 heat of polymerization, 244 heteroatom diene Diels-Alder reaction, 110, 111 heterocycles photochemical reactions, 182, 190 heterocycles radical reaction, 203, 204 heterocyclics-Diels-Alder reactions, 117, 127-131, 145... 

Fluorinated heterodienophiles and heterodienes Diels-Alder reactions in which the dienophiles have perfluoroalkyl-substituted multiple bonds between carbon and a heteroatom are quite common Reported earlier were reactions of perfluoroketones, thiones, ketimines, thioesters, nitroso compounds, and nitriles [9] Examples of a-fluoroimines [107], co-hydroperfluorothioaldehydes [108], perfluorosulfines [109, IIO], and selenocarbonyidifluoride [III] (equations 89-92) have been reported recently... 

In most of the successful Diels-Alder reactions reported, dienes containing no heteroatom have been employed, and enantioselective Diels-Alder reactions of multiply heteroatom-substituted dienes, e.g. Danishefsky s diene, are rare, despite their tremendous potential usefulness in complex molecular synthesis. Rawal and coworkers have reported that the Cr(III)-salen complex 15 is a suitable catalyst for the reaction of a-substituted a,/ -unsubstituted aldehydes with l-amino-3-siloxy dienes [21] (Scheme 1.28, Table 1.12). The counter-ion of the catalyst is important and good results are obtained in the reaction using the catalyst paired with the SbFg anion. 

Ab initio calculation of Diels-Alder reactions of a series of 5-heteroatom substituted cyclopentadienes Cp-X (65 X = NH, 50 X = NH, 64 X = NH3, 67 X = O", 54 X = OH, 68 X = OH3% 69 X = PH, 51 X = PH, 70 X = PH3% 71 X = S, 55 X = SH, 72 X = SH/) with ethylene at HF/6-31++G(d)//HF/6-31-i i-G(d) level by BumeU and coworkers [37] provided counterexamples of the Cieplak effect. The calculation showed that ionization of substituents has a profound effect on the n facial selectivity deprotonation enhances syn addition and protonation enhances anti addition. The transition states for syn addition to the deprotonated dienes are stabilized relative to those of the neutral dienes, while those for anti addition are destabilized relative to those of the neutral dienes. On the other hand, activation energies for syn addition to the protonated dienes are similar to those of the neutral dienes, but those for anti addition are very much lowered relative to neutral dienes (Table 6). 

The hetero-Diels-Alder reaction can also employ dienes containing heteroatoms. Cycloaddition of substituted styrenes with di-(2-pyridyl)-1,2,4,5-tetrazine was investigated by Engberts (Eq. 12.56).127 Again, the rate of the reaction increased dramatically in water-rich media. Through kinetic studies, they showed that the solvent effects on the... 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

Heteroatom-substituted vinylcarbene complexes are also excellent dienophiles, which usually undergo Diels-Alder reactions under very mild reaction conditions (see Experimental Procedure 2.2.7). Unfortunately the outcome of reactions between Fischer-type vinylcarbene complexes and dienes is difficult to predict ([256] compare, e.g.. Experimental Procedures 2.2.7 and 2.2.9). The course of... 

Outstanding properties are the transformation to 1H- or 2/f-phosphirenes after carbene addition (9->- i0),12b 21 22 [3 + 2]-cycloadditions of 1,3-dipoles leading to a wide variety of heteroatom-substituted phospholes (9 — ll)18 and Diels-Alder reactions (9 - 12) that make not only the phosphinines but also their valence isomers accessible.23,24 In ene reactions phosphaalkynes... 

Although the early examples of the 4ir participation of heterodienes in [4 + 2] cycloaddition reactions describe their reactions widi electron-deficient aJkenes, e.g. the thermal dimerization of a,3 unsaturated carbonyl compounds, the introduction of one or more heteroatoms into the 1,3-butadiene framewoiic does convey electrophilic character to the heterodiene. Consequently, such systems may be expected to participate preferentially in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, or simple alkene and alkyne dienophiles. The complementary substitution of the heterodiene with one or more electron-withdrawing substituents further lowers the heterodiene Elumo, accelerates the rate of heterodiene participation in the LUMOdioie-conn-olled Diels-Alder reaction, and enhances the observed regioselectivity of the [4 + 2] cycloaddition reaction. ... 

There are a few reports of hetero-Diels-Alder Reactions promoted by LPDE. Intriguing stereoselectivity is observed for the [4 + 2] cyclization between Danishefsky s diene 77 and a-heteroatom-substituted aldehydes. For example, reaction of 77 with N-Boc-protected a-aminoaldehyde with 76 gave the threo isomer selectively, a result in keeping with a chelation-controUed process. In contrast, the threo diastereoselectivity observed could be reversed by changing the amino protecting group from A-Boc to A,A(-dibenzyl. In this instance, the erythro isomer was generated exclusively via a non-chelation-controlled transition state (Sch. 38) [89]. 

The 3,3 -bis-triarylsilyl BINOL ligands 98 were first introduced by Maruoka, Itoh, Shirasaka, and Yamamoto for the heteroatom Diels-Alder reaction of electron-rich dienes with unactivated aldehydes [76,77], The catalyst was prepared by treating the BINOL 97 with trimethylaluminum in dichloromethane at room temperature for 1.5 h. The catalyst is pink to wine red and was found, by freezing point depression, to be a monomer. A typical procedure for the Diels-Alder reaction is illustrated for the reaction of the trisubstituted diene 371 and cyclohexylcarboxaldehyde. The reaction is complete with 10 mol % catalyst at -20 °C in 2 h in toluene and, after treatment with TFA to effect elimination of the methoxyl group, the product of the reaction is predominately the cii-pyrone 373. The triphenylsilyl substituted catalyst gives the product in 93 % ee (Sch. 47). 

Dienes substituted with heteroatoms, X or Y in 145, give allyl (Y in 146) or vinyl (X in 146) derivatives by the Diels-Alder reaction. The heteroatom(s) not only provide latent functionality in the product but also control the regiochemistry of the Diels-Alder reaction itself86. In Danishefsky s vemolepin synthesis87, a compound of type 146 was converted into an enone 147 by hydrolysis since 146 is a 1,3-disub-stituted allyl compounds like the enone precursors in the last section. 

This discussion allows an explanation of the ortho effect presented earlier, in connection with the Diels-Alder reaction. When a C=X or a CsX unit (where X is a heteroatom) reacts with a 1-substituted diene, the ortho product is generally preferred. Ortho selectivity is explained by the size of the orbital coefficients. When coefficient size is combined with secondary orbital interactions (sec. 11.4.C), 3 >84 indicated in the transition state shown in Figure 11.10, the carbonyl orbital is responsible for a secondary interaction that stabilizes the ortho transition state. If the meta transition state is involved, then orbital symmetry dictates an exo mode and there is no possibility of secondary orbital interactions. Secondary orbital interactions such as this are possible only in an endo transition state. It should be noted that the application of secondary orbital interactions to this problem has been questioned. 5... 

The hetero-Diels-Alder reaction can also employ dienes containing heteroatoms. Cycloaddition of substituted styrenes with di-(2-pyiidyl)-... 

The two a-bonds that are cleaved in the retro Diels-Alder reaction need not necessarily be the same as those formed in the initial forward reaction. Many valuable retro Diels-Alder reactions involve the cleavage of one carbon-carbon and one carbon-heteroatom bond, or two carbon-heteroatom bonds, that were not set up in a forward Diels-Alder reaction. For example, the otherwise relatively inaccessible 3-substituted and 3,4-disubstituted furans can be prepared by way of a tandem Diels-Alder then retro Diels-Alder reaction of 4-phenyloxazole and substituted alkynes, as illustrated in Scheme 3.87. 

Scope and Mechanism. In principle, replacing a carbon of a conjugated diene with a heteroatom does not prevent the Diels-Alder reaction from occurring. Some of the possible heterodienes based on N or O substitutions are shown in Figure 5.6 derivatives of most of these have been used in cycloadditions. 

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