Inverse electron demand using enols

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Hanessian and Compain have also reported a Lewis acid-promoted inverse electron demand hetero-Diels-Alder reaction between dihydrofurans and dihydropyrans with a-keto-/3,7-unsaturated phosphonates to give stmcturally related products <2002T6521>. High-pressure OTr/o-selective hetero-Diels-Alder reactions between a,/3-unsaturated aldehydes and enol ethers in the presence of lanthanide catalysts have also been reported and give 3,4-dihydro-27/-pyrans. Examples include the use of cyclic enol ethers to give 2,3,4,4a,5,8a-hexahydro-277,577-pyrano[2,3-. ]pyrans <1995T8383>. 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

Alternatively, the inverse electron-demand hetero IEDARs of ,( >-unsalur-ated carbonyl compounds with enol ethers serve as a short and attractive route to dihydropyrans. For instance, the use of Lewis acids such as Eu(fod)3 along with high-pressure afforded a high yield of the dihydropyran 56, as shown in Scheme 17 [47]. Analogous and more synthetically extensive results including dihydrothiopyrans were also reported [48-52],... 

Arjona and Plumet recently contributed to the study of the use of non-aromatic enol and thioenol ethers as dienophiles with inverse electronic demand [140]. Cydoadditions using 76a also proved to be endo-selective and regiospecific (Figure 25). The regioisomers obtained were those having the heteroatom of the dienophile component adjacent (ortho) and anti to the carbonyl function, rather than ortho and anti to the dimethyl ketal function, as in the... 

Enamino ketones, e.g. 1. react with various enol ethers in hetero-Diels Alder reactions, with inverse electron demand - yields are high. Reactions are regioselective, but not stereoselective. Although the endo approach is favored, stereoselectivity also depends on the EjZ configuration of the heterodiene. The use of high pressure (3.75 MTorr) improves the endo selectivity. ... 

Enol ethers have often been used as the olefinic component in inverse electron demand Diels Alder reactions. De Meijere and co-workers reported a novel approach to the synthesis of racemic 2-deoxy-z rz2Z,z o-hexopyranoside skeleton by a pressure-promoted hetero-Diels Alder reaction between the cyclopropa-nated enol ether 61 and p,Y-unsaturated a-ketoesters 62 (Scheme 7.14). 

A conceptually different [4-1-2] cycloaddition catalyzed by a chiral lanthanide complex has been disclosed. The inverse electron demand Diels Alder reaction of 3-methoxycarbonyl-2-pyrone (67) and enol ethers or sulfides [135] was catalyzed by a chiral ytterbium(III) triflate-binaphthol complex in the presence of diisopropylethylamine (Scheme 51) [136]. Thermal decarboxylations of bicyclic lactones such as 68 are known to yield dienes which may undergo subsequent pericyclic reactions [137] thus, the adducts of this process are potentially useful chiral building blocks. The nature of the substituent on the 2k component was found to be crucial for the realization of high enantioselectivity. 

Inverse electron demand in the dienophile is shown in Scheme 5.5, where an enol ether is used as the dienophile. 

Another valuable approach to 1,2-oxazines makes use of the N=0 group as part of the diene. Thus, nitroso ethylene (5.10) is reactive to an enol ether in another case of cycloaddition with inverse electron demand (Scheme 5.12). 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

Inverse-electron-demand DA cycloaddition reactions retain the top position in synthetic research on 1,2,4-triazines (12CHC1153). There are several new examples of the use of the reaction for 1,2,4-triazine ring transformation. Thus, a new route to prepare pyridine derivatives 23 and 24 based on inverse-electron-demand DA/retro-DA reactions of ketones with 1,2,4-triazines 25 using the enolates of methyl ketones direcdy as a dienophile without enamine intermediates is reported, which is complementary to the classical Boger procedure (14RSCA59218). 

In addition to metal-based catalysts, organocatalysts are also selective promoters of asymmetric Diels-Alder reactions. Several groups reported the use of cinchona alkaloid catalysts in standard Diels-Alder reactions. Deng combined 2-pyrones with a,P unsaturated ketones, while Bernard and Ricci focused on the reactions of vinylindoles with quinones and maleimides. Lectka reported enantioselective inverse electron demand hetero Diels-Alder reactions of ketene enolates and o-benzoquininone diimides catalyzed by a combination of benzoylquinidine and zinc triflate. For example, subjecting diimide 51 to the standard reaction conditions yields cycloadduct 52 as a single stereoisomer, which can be easily converted to... 

Nitroalkenes 1 behave as heterodienes in [4+2] inverse electron demand cycloadditions with simple unactivated alkenes, enamines, or enol ethers (2) as dieno-philes. These reactions require the presence of a Lewis acid to enhance the reactivity of the nitroalkene and accelerate the process. The products obtained in such reactions are six-membered cyclic compounds called nitronates (3) (Scheme 22.1). These compounds can be used in turn, as 1,3-dipoles in [3+2] cycloaddition reactions. 

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