Enamines electron-poor, cycloaddition

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

The first stereocontrolled syntheses of juvabione are described in Schemes 13.11 and 13.12. Scheme 13.10 is a retrosynthetic analysis corresponding to these syntheses. These syntheses have certain similarities. Both start with cyclohexenone. There is a general similarity in the fragments that were utilized, but the order of construction differs. In the synthesis shown in Scheme 13.11, the crucial step for stereochemical control is step B. The first intermediate is constructed by a [2 + 2] cycloaddition between reagents of complementary polarity, the electron-rich enamine and the electron-poor enone. The cyclobutane ring is then opened in a process which corresponds to retrosynthetic step Ha => Ilia in... 

Nitroalkenes can also be converted to nitronates by direct combination with an alkene. The nitronate is formed as a result of a [4 + 2] cycloaddition of the electron-deficient nitroalkene, wherein one of the N—O bonds of the nitro group participates as part of the 4n fragment (Eq. 2.19) (89). Because of the electron-deficient nature of the heterodiene, alkenes react in the order electron rich > electroneutral > electron poor. Therefore, the majority of dienophiles investigated are enamines (52,71,199-207) and vinyl ethers (99,208-213). 

A simple preparation of electron-poor 2-azadienes and the preliminary study of their ability to participate in [4 + 2] cycloadditions was done almost simultaneously by out group (87CC1195) (Scheme 49). The preparation of 2-azadienes 212 with two appended methoxycarbonyl groups was achieved, in a multigram scale and in nearly quantitative yield, by the insertion reaction of N- trimethylsilyl imines 210 into the carbon—carbon triple bond of dimethyl acetylenedicarboxylate to give 211 followed by protodesilylation with CsF/MeOH. Azadienes 212 underwent at room temperature inverse-electron demand [4 + 2] cycloaddition with cyclic enamines to give exclusively exo-cycloadducts 213 in 82-95% yield. Acid hydrolysis of them resulted in their aromatization to yield 2-pyrindine (n = 1] and isoquinoline (n = 2) derivatives 214. 

Theoretical analysis of this [4% + 27r]-cycloaddition reaction by consideration of frontier-orbital interactions between the electron-rich olefin (highest occupied molecular orbital, HOMO) and the electron-poor 5-nitropyrimidine (LUMO) has shown that the FMO perturbation theory correctly predicts an exclusive regiospecific addition of the enamine to N-l and C-4 of the pyrimidine ring (86JOC4070). 

One of the classic approaches toward cyclobutanes and cyclobutenes, [2+2] cycloaddition between electron-rich and electron-poor alkenes or alkynes, is mirrored by the in situ reaction of [W(CO)5] adducts of electron-deficient phosphaalkenes with enamines, enol ethers, ynamines, and ethoxyacetylene to yield the corresponding phosphetanes and 1,2-dihydrophosphetes.21 Prior... 

Thennal [2 + 2] cycloadditions proceed to give cyclobutenes either when an alkyne bearing an electron-withdrawing group is reacted with an electron-rich alkene such as an enamine or enol ether (equation 5), or when the alkyne substituted with an electron-donating group, such as dimethylamino, is heated with electron-poor alkenes (equation 6). Crood to excellent yields of cyclobutenes are generally obtained. 

The opposite type of reaction has also been reported, viz. one in which the heterocyclic molecule reacts via an electron-rich double bond with electron-poor olefins, in particular with tetracyanoethylene. Tanny and Fowler43 found that 2-azabicyclo[3.1.0]hex-3-enes reacted with tetracyanoethylene via a (2 + 2)-cycloaddition of the enamine double bond to give 13. Other electron-deficient reactants, such as JV-phenyl-maleimide, reacted differently, yielding an 8-azabicyclo[3.2.1]oct-2-ene (16). This type of reaction possibly occurs via a concerted [ 2 +ff2 +n2]-cycloaddition.43 At room temperature tetracyanoethylene also readily formed (2 + 2)-cycloadducts with heterocycles that contained a vinyl ether group for instance, 3,4-dihydro-2ff-pyran, 2,3-dihydrofuran, and 2,2-dimethyi-l,3-dioxole afforded the adducts 17-19 in yields of... 

The asymmetric 3 + 2-cycloaddition of cyclic azomethine ylides with Oppolzer s acryloyl camphor sultam has been used for the construction of X-azabicyclo[7M.2.1] alkenes in optically pure form. The non-stereospeciflc 1,3-dipolar cycloaddition of electron-poor azomethine ylides and electron-rich enamines proceeds by a two-step mechanism via zwitterionic intermediates. The 1,3-dipolar cycloaddition of 4,6-diazaphenanthrene 6-phenacylide with a variety of dienophiles readily produces the fused heterocycles tetrahydrobenzo[/]pyrrolo[l,2-/z][l,7]naphthyridines. Sequential... 

When reacted with electron-rich enamines f ,)-R12N-CH=CH-Me, stable azomethine ylides 214 <1999T9515> undergo regioselective 1,3-dipolar cycloadditions giving rise to tetrahydropyrrolizines 215 as mixtures of cis- and trans-isomers with poor diastereoselectivity, which is an argument in favor of a two-step instead of a concerted mechanism (Scheme 51) <1999T9535>. 

Other dienes, even cyclopentadiene, perform poorly with this dienophile 38 but the azadiene 39 that does so well here is a very special case. It is stabilised by the phenyl groups at both ends of the molecule and it cannot tautomerise into an enamine. More generally useful 1-azadienes must be stabilised by conjugating substituents that are definitely electron-donating or withdrawing so that the HOMO or the LUMO is unambiguously selected for cycloaddition. 

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