Lithium pyrrole

A modestly enantioselective pyrrole carbinol formation has been investigated <05SL2420>. Treatment of lithium pyrrolate with a ketoaldehyde in the presence of a chiral ligand preferentially led to the formation of pyrrole carbinol 49 (50% ee). A hydroxy-directed reduction of the ketone in the side chain by the addition of zinc borohydride provided 50 (88% de). Pyrrole carbinols serve as convenient precursors to aldehydes. A subsequent deprotective Horner-Wadsworth-Emmons reaction involving 50 and phosphonate ester 51 gave unsaturated ester 52. 

I = cyclopentadiene II = pyrrole III = 2,5-dimethylpyrrole IV = 2,5-di(trifluoromethyl)pyrrole V = 2,5-diformylpyrrole VI = 2,5-disulfonylpyrrole VII = 1-methylpyrrole VIII = 1-trifluoromethylpyrrole IX = 1-formylpyrrole X = 1-sulfonylpyrrole XI = l-formyl-2,5-dimethylpyrrole XII = lithium-pyrrole XIII = pyrrolium ion A = LUMOgcetylene HOMOdienel B = LUMOdiene HOMOacetylene 0 = LUMOdiformylacetylene HOMOdiene D = LUMOdiene HOMOdiformylacetylene E = LUMOdimethoxyacetylene HOMOdienei F = LUMOdiene HOMOmethoxyacetylene. 

C-Acylation and -carboxylation also occur with pyrrole Grignard reagents (p. 106). Whilst lithium pyrrole and lithium 2,4-dimethylpyrrole react with ethoxycarbonyl chloride to give ethyl pyrrole-2- and 2,4-dimethylpyrrole-5-carboxylate, respectively the corresponding potassium salts give the N-substituted pyrroles (p. 81). 

Methylpyrroles have been converted into pyridines by hydrochloric acid under severe conditions, and also by pyrolysis (p. 109). The formation of a 3-chloropyridine derivative from a pyrrole under Reimer-Tiemann conditions has been mentioned (p. 63). This type of reaction was discovered by Ciamician and Dennstedt treated pyrrole with chloroform in ether and isolated a small yield of 3-chloropyridine. Subsequently, similar reactions were realized with bromoform, carbon tetrachloride, methylene iodide and benzal chloride. Those of several of these reagents with lithium pyrrole in ether and sodium pyrrole under various conditions have been compared. The yields of pyridine derivatives were always low. In submitting 2,5-dimethylpyrrole to the Reimer-Tiemann reaction, Plancher and Ponti23 isolated a pyrrolenine (7). This and its analogues are not intermediates in the conversion of pyrroles into 3-chloropyridines. The idea that dichlorocarbene is the active reagent in reactions using chloroform is supported by recent work 22 ... 

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

The unsaturated tetraoxaquaterene (accompanied by linear condensation products) was first synthesized in 18.5% yield by the acid-catalyzed condensation of furan with acetone in the absence of added lithium salts. Other ketones also condensed with furan to give analogous products in 6-12% yield.A corresponding macrocycle was also prepared in 9% yield from pyrrole and cyclohexanone. The macrocyclic ether products have also been obtained by condensation of short linear condensation products having 2, 3, or 4 furan rings with a carbonyl compound. ... 

The Michael additkin of Lithium etiolates to tiitroalkenes folbwed by reaction with acetic anhydnde gives acetic niironic anhydndes, which are good precursors for 1,4-diketones, pyrroles, and pyrrolidines fEq. 10.73. ... 

In a related reaction, heating ketones in the presence of TlClsOTf leads to 1,3,5-trisubstituted arenes. " Nitriles react with 2 mol of acetylene, in the presence of a cobalt catalyst, to give 2-substituted pyridines. " Triketones fix nitrogen gas in the presence of TiCU and lithium metal to form bicyclic pyrrole derivatives. " ... 

Other examples of nucleophilic attack on the oxirane ring include the formation of (3-halohydrins with silica-gel supported lithium halides <96TL1845>, the addition of amines catalyzed by lithium triflate, an ersatz for lithium perchlorate <96TL7715>, and the addition of pyrroles, indoles and imidazoles under high pressure i.e., 91 —> 93) <96JOC984>. 

Alternatively, Cushman has devised a facile route to pyrroles by the reaction of Boc-a-amino aldehydes or ketones 14 with the lithium enolates of ketones 15 to afford aldol intermediates 16 which cyclize to pyrroles 17 under mild acidic conditions <96JOC4999>. This method offers several advantages over the Knorr since it employs readily available Boc-a-amino aldehydes or ketones and utilizes simple ketones instead of the p-diketo compounds or p-keto esters normally used in the Knorr. 

For an electrochemical preparation, dissolve pyrrole (to concentrations of 0.1 to 0.5M) in propylene carbonate containing traces of water and 0.2 M lithium salt... 

Two unique type Had syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles <06SL2339>. In the event, treatment of stannylcyclopropane 25 with -BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 

Tertiary A-allylthioamides have been converted into thioamidium salts by the formation of complexes with Lewis acid. Further treatment with lithium hexamethyldisilazide (LiHMDS) affords the corresponding 1,2-disubstituted pyrroles (Scheme 25).52... 

In this method, Furstner converts N-BOC protected pyrrole to the 2,5-dibromo compound (122) with NBS and this is followed by metalation and carbomethoxylation with t-butyl lithium in THF and subsequent trapping of the metalated species with methyl chloroformate to yield a pyrrole diester (123). Bromination of this diester at positions 3 and 4 with bromine in water followed by Suzuki cross-coupling with 3,4,5-trimethoxyphenyl boronic acid yields the symmetrical tetrasubstituted pyrrole (125). Base-mediated N-alkylation of this pyrrole with 4-methoxyphenethyl bromide produces the key Boger diester (126) and thereby constitutes a relay synthesis of permethyl storniamide A (120). 

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