Post-cycloaddition

The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the forma tion of the unusual trans adducts 53, have been explained by the facts that (i) Diels-Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. 

Fischer-type carbene complexes, generally characterized by the formula (CO)5M=C(X)R (M=Cr, Mo, W X=7r-donor substitutent, R=alkyl, aryl or unsaturated alkenyl and alkynyl), have been known now for about 40 years. They have been widely used in synthetic reactions [37,51-58] and show a very good reactivity especially in cycloaddition reactions [59-64]. As described above, Fischer-type carbene complexes are characterized by a formal metal-carbon double bond to a low-valent transition metal which is usually stabilized by 7r-acceptor substituents such as CO, PPh3 or Cp. The electronic structure of the metal-carbene bond is of great interest because it determines the reactivity of the complex [65-68]. Several theoretical studies have addressed this problem by means of semiempirical [69-73], Hartree-Fock (HF) [74-79] and post-HF [80-83] calculations and lately also by density functional theory (DFT) calculations [67, 84-94]. Often these studies also compared Fischer-type and... 

Intramolecular [3+2] dipolar cycloadditions have also been employed as a post-Ugi transformation to generate heterobicyclic structures, namely fused isoxazolines [130], isoxazoles [130] and triazoles [131] (Fig. 31). Isoxazoles were obtained through intramolecular nitrile oxide cycloaddition. The precursor of the nitrile oxide (a nitro group) was introduced into the carboxylic component, while a triple bond was positioned in the starting amine. Treatment of 152 with POCl3/Et3N gave the intermediate nitrile oxide, which spontaneously cyclized to isoxazoles 153. 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Fluorous aminoesters have been employed in 3-component 1,3-dipolar cycloaddition reactions and post-condensation modifications in the synthesis of a bridged-tricyclic ring system 30 (Scheme 21) [49]. 

Pei Y, Moos WEI, Post-modification of peptoid side chains (3 + 2) cycloaddition of nitrile oxides with alkenes and alkynes on the solid-phase, Tetrahedron Lett., 35 5825-5828, 1994. 

The final paragraph in this section details carbazole syntheses that involve the formation of C-C bonds. Intramolecular Diels-Alder cycloaddition of ynamides provided a new route to [b -fused carbazoles <05OL2213>. An electrocyclization of 2,3-divinylindole intermediates produced functionalized carbazoles <05TL4045>. A domino alkynylation/palladium migration/C-H activation approach to 4-vinylcarbazoles was reported <050L701>. For example, treatment of A-arylaniline 134 with diphenylacetylene in the presence of palladium acetate, cesium pivalate (CsPv), and bis(diphenylphosphino)methane (dppm) gave carbazole 136 via post-palladium migration intermediate 135. 

Huisgen 1,3-dipolar cycloaddition (click reaction) between terminal alkynes and azides is a highly efficient approach for the post modification of polymers. This technique is tolerant to a wide rage of reaction conditions and functional groups allowing fast coupling reactions under simple reaction conditions with... 

Scheme 21 A dipolar cycloaddition-based post modification approach [74]...

Likewise, Hirao et al. applied copper free chck chemistry for RNA functionalization via the 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds) and pyrrole-2-carbalde-hyde (Pa) unnatural base pair [152], For this, an azide-modified Pa nucleobase (N3-Pa) was incorporated as triphosphate in a T7 in vitro transcription reaction using Ds as corresponding nucleobase in the DNA template (Fig. 3b, 2). Post-transcriptional modification was achieved using fluorescent dibenzocyclooctyne (DIBO) derivatives in a strain-promoted azide-alkyne cycloaddition reaction. Transcription and efficient site-specific labeling of a 260mer RNA was demonstrated. 

T3506). Similarly, 2-halobenzaldehydes, isonitriles, amines, and propar-gylic acids underwent Ugi reaction, then copper(I)-catalyzed alkyne—azide 1,3-dipolar cycloaddition, and then intramolecular Ullmann-type triazole N-arylation to afford triazolo-flised benzodiazepines such as 136 (13EJ01223). Similar reactions involving a post-Ugi lactamization or a post-Ugi intramolecular imination process delivered benzo-l,4-diazepin-2,5-dione derivatives or 4,5-dihydro-3H-l,4-benzodiazepine derivatives (13ACO202,13T9056). 

It has been proposed that these complex structures arise from various electro-cyclisation and cycloaddition reactions of linear polyene side-chains, undergone post-pyrone formation. For example, Trauner pointed out the wide variety of skeletal types that can be theoretically obtained from pericyclic transformations of a relatively simple E,Z,Z,E)-tQttait Q 21, further observing that isomerisations of the alkene geometries lead to an even greater number of potential cyclisation products (Scheme 1.4) [14],... 

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