Hetero intramolecular

Scott Denmark of the University of Illinois reports (J. Org. Chem. 68 8015,2003) a hetero intramolecular Diel-Alder reaction of a nitro alkene 5, followed by intramolecular dipolar cycloaddition of the resulting nitronate 6, to give the tricycle 7. Raney nickel reduction effected cleavage of the N-0 bonds and reductive amination of the liberated aldehyde, to give, after acetylation, the angularly substituted cis-decalin 8. 

Lewis acid catalysts have been used in this approach.225-236-238 There are also a number of examples of hetero intramolecular Diels-Alder reactions.225 238-241... 

Hetero-intramolecular Diels-Alder reactions are defined here as those of substrates with a heteroatom (i.c., not carbon or hydrogen) in either the diene or the dienophile, or both. The present discussion has been subdivided according to the location of the heteroatom in either of the reacting 7t-systems. 

Hetero-Intramolecular Diels- Alder Reactions Heterodiene-Homodienophile Reactions... 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

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. 

The versatility of the Diels-Alder reaction becomes especially obvious, when considering the hetero-variants. One or more of the carbon centers involved can be replaced by hetero atoms like nitrogen, oxygen and sulfur. An illustrating example is the formation of the bicyclic compound 31, by an intramolecular hetero-Diels-Alder reaction ... 

A sequence of two thermal intramolecular cycloadditions has been used to develop a short synthetic approach to tetrahydrothiopyrans [122], The multiple process includes an m m-hetero- and an intramolecular-carbon Diels-Alder reaction. An intramolecular /zctcro-Diels-Alder reaction of divinyl-thioketone 134 afforded a 9 1 mixture of cycloadducts 135 and 136 which then underwent a second intramolecular cycloaddition which syn o H-2)-exo-diastereoselectively led to hexacyclic tetrahydrothiopyrans 137 and 138, respectively (Scheme 2.51). 

Enhanced stereoselectivity in aqueous intramolecular hetero-Diels-Alder cycloaddition of chiral acyinitroso compounds [17c, d, 99]... 

By the radical pathway l, -diesters, -diketones, -dienes or -dihalides, chiral intermediates for synthesis, pheromones and unusual hydrocarbons or fatty acids are accessible in one to few steps. The addition of the intermediate radicals to double bonds affords additive dimers, whereby four units can be coupled in one step. By way of intramolecular addition unsaturated carboxyhc acids can be converted into five raembered hetero- or carbocyclic compounds. These radical reactions are attractive for synthesis because they can tolerate polar functional groups without protection. 

The domino reaction consists of a Knoevenagel condensation giving an intermediate which immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [18]. 

Mukai, C., Yoshida, T., Sorimachi, M., Odani, A. (2006) Co2(CO)8-Catalyzed Intramolecular Hetero-Pauson-Khand Reaction of Alkynecarbodiimide Synthesis of ( )-Physostigmine. Organic Letters, 8, 83-86. 

Tietze, L. F., Pfeiffer, T., Schuffenhauer, A., 1998, Stereoselective Intramolecular Hetero Diels-Alder Reactions of Cyclic Benzylidenesulfoxides and DFT Calculations on the Transition Structures , Eur. J. Org. Chem., 2733. 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

A new noncarbohydrate-based enantioselective approach to (—)-swainsonine was developed in which the key step was an aqueous intramolecular asymmetric hetero-Diels-Alder reaction of an acylni-troso diene (Eq. 12.57).128 Under aqueous conditions there was significant enhancement of the trans stereoselectivity relative to the reaction under conventional nonaqueous conditions. 

Scheme 2.140. Domino transetherification/intramolecular hetero-Diels-Alder reaction.

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

Scheme 4.27. Intramolecular domino hetero-Diels-Alder/[3+2] cycloaddition.

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

A diastereoselective intramolecular hetero-Diels-Alder reaction of optically active 428 gave unstable 1,3,4,8,9,9a-hexahydropyrido[2,l-f][l,3]oxazin-l-one 429 (X = 0), and l,3,4,8,9,9a-hexahydropyrido[l,2-(z]pyrazin-l-one 429 (X = NTs) (Equation 80) <2003JA4970, 2004T10277>. In the case of pyrido[l,2- ]pyrazine, the reaction was carried out in the presence of 2,6-di- /-butyl-4-methylphenol. 

Ab initio Hartree-Fock and density functional theory (DFT) calculations were performed to study transition geometries in the intramolecular hetero-Diels-Alder cycloaddition reactions of azoalkenes 20 (LJ = CH2, NFI, O) (Equation 1). The order of the reactivities was predicted from frontier orbital energies. DFT calculations of the activation energies at the B3LYP level were in full agreement with the experimental results described in the literature <2001JST(535)165>. 

A new synthesis of pterins based on the acylation of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-yielding intramolecular hetero DA cycloaddition and cleavage of the N—O bond has been reported <06HCA1140>. Several new substituted pterins have been obtained in an efficient one-pot procedure using N,N dimethyldichloromethyleniminium chloride (phosgeniminium chloride) and a suitable pyrazine <06H933>. 

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

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