Cycloadditions with Heterodienophiles

Tfctcro-Diels Alder reaction is a powerful methodology in the synthesis of heterocyclic compounds. Using the high pressure technique has greatly extended the synthetic applications of this methodology. 

Pyran derivatives, useful intermediates in the total synthesis of many monosaccharides and other natural products, have been synthesized by hetero-Dish-Alder reaction by using carbonyl compounds as dienophiles [9, 23]. 

A convenient synthetic route to obtain these compounds is the thermal Diels Alder cycloaddition of 1 -methoxybutadiene (18b) with carbonyl compounds, but this route is limited to aldehydes activated by an electron-withdrawing substituent. Non-activated carbonyl compounds require drastic conditions or fail to react. Application of high pressure overcomes this limitation. 

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Examples of the 477- participation of simple a,/3-unsaturated carbonyl compounds in Diels-Alder reactions and their application to the total syntheses of natural products are summarized in Table 7-1. Reports of simple a,/3-unsaturated carbonyl compounds participating in [4 + 2] cycloadditions with heterodienophiles have been detailed [Eq. (9)].73b 75... 

The formation of heterocycles by cycloaddition reactions of conjugated dienes is the subject of this chapter. Almost the entire account is devoted to the Diels-Alder reaction of dienes with heterodienophiles to yield six-membered ring compounds (equation 1). Many such reactions have been reported and there is a plethora of reviews. Somela p are general others are cited at appropriate places in the text. This account is highly selective, concentrating on recent work with particular regard to the stereochemistry of these processes. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

The [4+2] cycloaddition of 2-substituted-l,2-dihydropyridines 109 with heterodienophile nitrosobenzene gives unstable cycloadducts 110 as single diastereomers in 98% ee. Adducts 110 can be reduced with alane to give 3-aminosubstituted-l,2,3,6-tetrahydropyridines 111 with a /razw-relationship between the 2-substituent and 3-amino group (Scheme 30) <2005JOC2368>. 

Cycloadditions with these heterodienophiles are usually regioselective and are in accord with FMO theory. The reactions are syn selective with the diene component. Other stereochemical features of the process are outlined in some of the examples described below, as well as in previous reviews. -" It should also be mentioned that only aldehydes and some ketones act as dienophiles. Except for rare exceptions, other types of carbonyl compounds apparently do not participate in Diels-Alder cycloadditions. 

A few examples of cycloadditions with the thiophosgene equivalent (189) have been reported (equation 94). In addition, methyl cyanodithioformate (190) has also been utilized several times as a heterodienophile (equation 95). ... 

In the nineteen-eighties stoichiometric amounts of conventional Lewis acids such as TiCl4, AICI3, SnCU, BFs-Olt,., Mgl r, and ZnCU were frequently used for HDA reactions of siloxy-substituted dienes with heterodienophiles [286, 287]. Danishefsky et al., however, found that a lanthanide shift reagent such as Eu(fod)3 can promote the cycloaddition catalytically [294]. Several Bronsted and Lewis acids have recently been shown to have high catalytic activity in the DA reaction of siloxy-substituted dienes in non-aqueous or aqueous media, and elaboration of Lewis acids has achieved unique chemo- and regioselectivity. 

Two recent reports have detailed the [4 + 2] cycloadditions of o-quinone methides with heterodienophiles, thiones [Eq. (43)]168... 

Two reports of the use of heterodienophiles, amidines100 and aldehyde N,N-dimethylhydrazones,l00b in [4 + 2] cycloadditions with 1,2,4-triazines have been detailed (Table 10-IX). 

Scheme 2.15 DTHDA cycloaddition of cross-conjugated carbotrienes with heterodienophiles.

The P-nitroso phosphine oxide 406 behaves as an N-O heterodienophile and reacts with the 1,3-diene part of the molecule in a cycloaddition reaction to form the 2,4 ,5,6,7,8-hexahydro-8-phenyl-[l,2]azaphosphorino[l,6-3][l,2]oxa-zine 8-oxide 407 containing an stereogenic cyclic phosphorus atom (Scheme 64). 31P NMR spectroscopy shows one single peak indicating the formation of only one diastereomer <2002JOG6174>. 

Examples of the use of heterodienophiles under the action of microwave irradiation are not common. Soufiaoui [84] and Garrigues [37] used carbonyl compounds as die-nophiles. The first example employed solvent-free conditions the second is an example of the use of graphite as a susceptor. Cycloaddition of a carbonyl compound provided a 5,6-dihydro-2H-pyran derivative. These types of reaction proceed poorly with aliphatic and aromatic aldehydes and ketones unless highly reactive dienes and/or Lewis acid catalysts are used. Reaction of 2,3-dimethyl-l,3-butadiene (31) with ethyl glyoxylate (112) occurred in 75% yield in 20 min under the action of microwave irradiation. When conventional heating is used it is necessary to heat the mixture at 150 °C for 4 h in a sealed tube to obtain a satisfactory yield (Scheme 9.33). 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

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