Pyrroles pentasubstituted

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

The preparation of a pentasubstituted pyrrole (130) is accomplished by base-mediated condensation of an aminodiester (128) with dimethyl glyoxy-late to give a 3,4-dihydroxylated pyrrole (129), which is reacted with triflic... 

This route involves the conversion of a 3,4-diiodopyrrole (139) to the corresponding 3,4-diboronate ester (140) followed by a bis Suzuki cross-coupling reaction with a bromoquinoline, which generates the halitulin core (141). This pyrrole (141) is then alkylated with a tosylated cycloazadecane to generate a pentasubstituted pyrrole (143), which is converted to halitulin by debenzylation under hydrogenolysis conditions. 

Finally, reaction of 2,4-diphenyl-5(4//)-oxazolone 322 with 4-phenyl-A -tosyl-1-azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-A-tosyl-1-azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6-triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324—327. The marked differences in reactivity of 4-phenyl-A-tosyl-l-azabuta-l,3-diene relative to A-alkyl- or A-aryl-1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107). ... 

Mori has employed transmetallation, well documented in other organozirco-nium reactions [59], to form y-allylated a-silyl allyl amines (Eq. 19) [40,41] and substituted pyrroles (Eq. 20) [60] after the insertion of alkynes into the Zr-C bond of zirconaaziridines. The reaction sequence in Eq. 19 uses stoichiometric quantities of Zr, but catalytic amounts of Cu, and both the insertion and allylation steps proceed with high regioselectivity. Using an acyl halide instead of allyl chloride gives tetra- and pentasubstituted pyrroles, in a one-pot reaction (Eq. 20). 

In a similar context Amdtsen developed a new pyrrole synthesis from alkynes, acid chlorides either imines or isoquinolines, based on the reactivity of isocyanides (Scheme 35a) [197]. Although all atoms from the isocyanide are excluded from the final structure, its role in the reaction mechanism is crucial. The process takes place through the activation of the imine (isoquinoline) by the acid chloride to generate the reactive M-acyliminium salt, which is then attacked by the isocyanide to furnish a nitrilium ion. This cationic intermediate coordinates with the neighboring carbonyl group to form a miinchnone derivative, which undergoes a [3+2] cycloaddition followed by subsequent cycloelimination of the isocyanate unit, to afford the pentasubstituted pyrrole adducts 243 and 244 (Scheme 35a, b). 

The alkaloids ningalin A-D were first isolated in 1997 by Fenical and Kang from the marine ascidian of the genus Didemnum sp. collected in western Australia near Ningaloo Reef. By far the most complex of these four alkaloids is ningalin D (1) incorporating a biphenylene qui-none methide superimposed on an oxidized pentasubstituted pyrrole core that characterizes this class of natural products. 

From pentamethylpyrrole and benzyne the rearranged 1 2 adduct 77 was obtained but from some other pentasubstituted pyrroles thenaphthalen-1,4-imines 74 could be isolated, and two of these (R = n-Bu, cyclo-C6H,, )... 

The synthesis of pentasubstituted pyrroles has been reported by Mjalli and Toyonaga [46] using a multicomponent condensation. The treatment of the intermediate 10 with neat acetic anhydride or isobutylchloroformate and tri-ethylamine in toluene, followed by the addition of a series of acetylenic esters, provided the polymer-bound pentasubstituted pyrroles 12 (Fig. 4). The reaction proceeded by in situ cyclization of the intermediate via [3+2]... 

Mori has reported a route to tetra- and penta-substituted pyrroles by a sequence involving reaction of the iminosilaacyl complex 5 with an alkyne in the presence of LiEt3BH to afford an initial azazirconacyclopentene intermediate <97CL825>. Addition of acyl halides and CuCl leads to the pentasubstituted pyrrole 6 or the desilylated product 7 in this one-pot reaction. 

From pentamethylpyrrole and benzyne the rearranged 1 2 adduct 77 was obtained but from some other pentasubstituted pyrroles the naphthalen-... 

The compounds core comprises a pentasubstituted pyrrole, which results from a convergent synthesis with a Paal-Knorr reaction as its crucial step. This succeeds only under specially designed conditions the reaction faced initially a seemingly insurmountable obstacle, and therefore a range of linear syntheses had been developed as weU. Although they are scientifically very interesting, they will not be discussed here in any greater detail. [395,396]... 

Expanding upon these early results, the Odom group [322] showed that using a preformed diyne is not required but rather a four-component coupling reaction could be exploited to generate pentasubstituted pyrroles in up to 82% isolated yield (Table 15.27). In this case, the Ti(indolyl) complexes have been used to advantage to reahze this efficient synthesis. 

Beller reported a selective ruthenium-catalyzed synthesis of highly substituted pyrroles (e.g., 52). The sequence utihzes readily available starting materials benzylic ketone 49, amine 50 (ahphatic, aromatic, or ammonia), and vicinal diol 51.Tri-, tetra-, and pentasubstituted pyrroles can be easily prepared in moderate to high yields. A variety of aromatics, alkyl groups, and halogens are tolerated (13AG(I)597). 

By aza-Wittig reactions of iminophosphoranes with isocyanates, carbodiimide-mediated syntheses of pyrrole and indole derivatives [1270], pentasubstituted pyridines [1271], pyrimidine derivatives [1272-1274], bis( -ferrocenylvinyl)carbo-diimide [1274], amino-tetrazolyl-deoxythymidines [1275], the marine alkaloid leu-cettamine B [1276], and aza-analogues of aplysinopsins [1277] have also been accomplished. 

Maiti and cowoilcers have recently reported an excellent work about the synthesis of pentasubstituted pyrroles starting from three, four, and seven components of common precursors under very mild reaction conditions using CeCl3-7HjO as activator (Scheme 6.48) [108]. 

For another approach where dialkyl acetylenedicarboxylates were used in the synthesis of polysubstituted pyrroles, see N. Bhunia, B. Das, Synthesis 2013,45,1045-1050. One-pot synthesis of pentasubstituted pyrroles from propargyUc alcohols, amines, and dialkyl acetylenedicarboxylates tandem amination, propargylation and cycloisomerization catalyzed by molecular iodine. 

The first synthesis of pentasubstituted pyrroles was achieved by using PylC (Ik) in the U-4CR on a solid phase [50], According to Mjalli and coworkers, pyridine was necessary as a cosolvent in the U-4CR as it helped buffer the reaction mixture and stabilize the isocyanide. The acyclic Ugi product 108 can be directly converted to the miinchnone 109 by heating (100°C) in acetic anhydride and trapped in situ with alkynes bearing electron-withdrawing groups via 1,3-diploar cycloaddition to afford pyrrole 110 (Scheme 7.29). 

Phenyl isocyanide (PhNC) has been utilized in the U-4CR to synthesize pentasubstituted pyrroles [50]. The U-4CR product 111 was converted to the corresponding Ai-acyl-A-alkyl-a-amino acid 112 with the treatment with B0C2O -dimethylaminopyridine (DMAP) in tetrahydrofuran (THF) followed by 1 N LiOH... 

Further advancement has been made to employ Armstrong s CIC to perform U-4CR on a solid phase to synthesize pentasubstituted pyrroles [59] similar to that shown in Scheme 37. 

They were also able to synthesize pentasubstituted pyrroles 126 (Scheme 7.62) by refluxing the acyclic U-4CR product 179 in toluene at 100°C in the presence of HCl and dimethylacetylenedicarboxylate. 

SCHEME 7.62 Synthesis of pentasubstituted pyrroles 126 using dimethylacetylenedicar-... 

Alkynyl substituted ketones react with primary amines in the presence of iron(lll) chloride to form tetrasubstituted and pentasubstituted pyrroles as well as fused pyrrole derivatives in good to excellent yields (Scheme 4—287). The reaction probably proceeds via enamine formation and subsequent intramolecular 5-exo-dig aminoferration of the triple bond (Scheme 4-288). Protonation of the T -alkenyliron complex and isomerization affords the pyrrole. Iron(Ill) chloride is released to initiate a new catalytic cycle. ... 

---