Pyrroles 1 - -, intramolecular cycloaddition

If secondary AAs are heated in the presence of aldehydes containing a proximate terminal double or triple bond and then condensed, decarboxylation and intramolecular cycloaddition tri-, tetra-, penta-, or hexa-cyclic cycloadducts with a condensed pyrrole ring are formed. An example is the reaction with sarcosine (Scheme 55) (88T4953). 

An intramolecular cycloaddition reaction results in the simultaneous formation of two new rings. Examples include the formation of an octahydroquinoline (Section 4.4.2.3.4) and a tetra-hydrobenzo[c]pyrrole (Section 4.4.3.1) by intramolecular Diels-Alder reactions. 

Vinyl azide intramolecular cycloaddition is further illustrated by the formation of azidotriazoline 32 as a minor product in the thermolysis of the bisvinyl azide 31 (Scheme 41).200 An analogy is provided by the formation of 2,5-diphenylpyrrole from the slow decomposition of a-azidostyrene.202 Pyrrole formation is interpreted in terms of cycloaddition of the azide onto the electron-rich double bond of a second molecule to give a triazoline that loses nitrogen and rearranges to a pyrroline followed by hydrogen azide elimination (Section IV,D).203... 

The unstable pyrrolotriazolines, derived from cis-cis and trans-cis-3-substituted 6-azidohexa-2,4-dienoate esters by intramolecular cycloaddition, decompose to 2-substituted pyrroles at rates that are both substituent and... 

Treatment of the dihydroisoquinolinium salt 699 with Hiinig s base (/-PrzNEt) produces the corresponding azomethine ylide, which can undergo intramolecular cycloaddition with the tethered alkyne to afford the chro-meno[3,4- ]pyrrol-4(3//)-one 700 in high yield. Subsequent deprotection of the isopropyl protecting groups affords the marine natural product lamellarin K (Scheme 173) <1997CC2259>. 

Starting from 2-(2-(2-aminophenylthio)-l//-pyrrol-l-yl)acetic acid 60, available through two synthetic steps from o-aminothiophenol, 9//-pyrrolo[2,l -b 1,3,6]bcnzothiadiazocine-10(l l//)-one 61 was obtained in 54% yield (Scheme 11, Section 14.08.5.4 <1995JHC683>). Azidoformate 51 derived from chiral enol ether, when irradiated, gives 3,6-dioxazocan-2-one derivative 52 by a highly diastereoselective intramolecular cycloaddition (Scheme 9, Section 14.08.5.3 <1999EJO2709>). 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

Intramolecular cycloaddition reactions of 1,2,4-triazines with the C=C double bond of pyrrole <93JOC5l6> or indole <92JOC5285> have also been observed. 

Intramolecular azide cycloaddition to a thiophene double bond leads to 4/f-thieno[3,2- >]pyrrole derivatives <89TL1655>. 1,3-Dipolar intramolecular cycloaddition of a nitrile oxide on to the thiophene moiety gives (138) <88S342>. In a similar fashion, one double bond of thiophene acts as a dipolarophile to produce derivative (139) <89JOC5277>. 

Intramolecular 1,3-dipolar cycloadditions represent a powerful synthetic tool. Kato and co-workers were apparently the first to report an intramolecular munchnone-alkyne cycloaddition. Thus munchnones 184, as generated from iV-acylamino acids 183, yield the corresponding benzopyrano[4,3-f ]pyrroles 186 after extrusion of carbon dioxide from adduct 185 (Fig. 4.65). The yields shown are for high-dilution reaction conditions. Under normal conditions of concentration, the yields are stiU about 60%. Interestingly, attempts to divert the intramolecular cycloaddition by the addition of A -phenylmaleimide had no effect on the reaction pathway. 

The ring opening of 2//-azirines to yield vinylnitrenes on thermolysis, or nitrile ylides on photolysis, also leads to pyrrole formation (B-82MI30301). Some examples proceeding via nitrile ylides are shown in Scheme 92. The consequences of attempts to carry out such reactions in an intramolecular fashion depend not only upon the spatial relationship of the double bond and the nitrile ylide, but also upon the substituents of the azirine moiety since these can determine whether the resulting ylide is linear or bent. The HOMO and second LUMO of a bent nitrile ylide bear a strong resemblance to the HOMO and LUMO of a singlet carbene so that 1,1-cycloadditions occur to carbon-carbon double bonds rather than the 1,3-cycloadditions needed for pyrrole formation. The examples in Scheme 93 provide an indication of the sensitivity of these reactions to structural variations. 

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

Fused (5 5 5) heterocycle 28, along with 342, has been synthesized in 34% yield via an intramolecular nitrone cycloaddition, using l-allyl-2-pyrrole carboxaldehyde 340 as a starting material (Scheme 72) <1998JOC9279>. 

An efficient synthesis of rigid tricyclic (5 5 5) nitrogen heterocycles 64 has been achieved via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole derivatives <2004JOC1207> and the trienes 477 were prepared by the acylaton of amines 475 with the anhydride 476. The amines 475 were in turn prepared starting from pyrrole-2-carbaldehyde. The triene 477 on heating in toluene at 80 °C for 15 h underwent the IMDA to afford the tricyclic compound 64 as a single diastereomer in quantitative yield. The sterically bulky N-substitutent on the triene 477 promoted cycloaddition under milder condition at 65 °C in toluene to provide the tricyclic compound 64 in quantitative yield (Scheme 108). 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

Scheme 6.186) [347]. The condensation of O-allylic and O-propargylic salicylalde-hydes with a-amino esters was carried out either in the absence of a solvent or - if both components were solids - in a minimal volume of xylene. All reactions performed under microwave conditions rapidly proceeded to completion within a few minutes and typically provided higher yields compared to the corresponding thermal protocols. In the case of intramolecular alkene cycloadditions, mixtures of hexa-hydrochromeno[4,3-b]pyrrole diastereoisomers were obtained, whereas transformations involving alkyne tethers provided chromeno[4,3-b]pyrroles directly after in situ oxidation with elemental sulfur (Scheme 6.186). Independent work by Pospisil and Potacek involved very similar transformations under strictly solvent-free conditions [348]. 

A more recent report has outlined the use of a-silylimidates for the construction of aromatic pyrroles (7). Treatment of the precursor 29, with trifluorophenylsilane and DMAD furnished the adduct 30 in 97% yield after purification. The reaction was rationalized via quaternization of the imidate and subsequent intramolecular desilylation by fluorine to develop the ylide, which underwent in situ cycloaddition and subsequent aromatization delivering 30 (Scheme 3.7). 

In a series of papers, Laude and co-workers (144-149) examined 1,3-dipolar cycloaddition reactions of mtinchnone imines derived from Reissert compounds. For example, mtinchnone imine 241 undergoes a smooth intramolecular 1,3-dipolar cycloaddition with the tethered alkyne unit to afford pyrrole 242 after extrusion of HNCO (144). 

Generally, cycloadditions represent powerful reactions for construction of heterocycles. Tandem intramolecular Diels-Alder/retro-Diels-Alder reaction sequences were applied in the syntheses of many A,B-diheteropentalenes <1996GHEC-II(7)1>. Gribble and co-workers <1998SL1061> reported new syntheses of pyrrolo[3,4-, ]indoles 426, benzo[4,5]furo[2,3-f]pyrroles 429, and benzo[4,5]thieno[2,3-4pyrroles 430 using the 1,3-dipolar cycloaddition... 

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