- Preparation of the HIV Attachment Inhibitor BMS-663068. Part 3. Mechanistic Studies Enable a Scale-Independent Friedel-Crafts Acylation
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During the development of a Friedel-Crafts acylation for the preparation of a key pyrrole intermediate in the synthesis of the HIV attachment inhibitor, BMS-663068-03, a significant scale dependence was found. A precipitous drop in yield was observed for
- Beutner, Gregory L.,Albrecht, Jacob,Fan, Junying,Fanfair, Dayne,Lawler, Michael J.,Bultman, Michael,Chen, Ke,Ivy, Sabrina,Schild, Richard L.,Tripp, Jonathan C.,Murugesan, Saravanababu,Dambalas, Konstantinos,McLeod, Douglas D.,Sweeney, Jason T.,Eastgate, Martin D.,Conlon, David A.
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- Hydrogen bond donor solvents enabled metal and halogen-free Friedel–Crafts acylations with virtually no waste stream
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We have developed a metal and halogen-free Friedel–Crafts acylation protocol with virtually no waste stream generation. We propose a hydrogen bonding donor solvent will form a hydrogen bonding network and may provide significant rate enhancement for Friedel–Crafts reactions. Trifluoroacetic acid is one of the strongest H-bond donor solvents, which is also volatile and can be easily recovered by distillation without need for reaction workup. Our protocol is a ‘green’ Friedel–Crafts acylation process: 1) the catalyst can be recovered and reused; 2) using halogen free starting material (carboxylic acids anhydride or carboxylic acids); 3) no need for aqueous reaction work-up; 4) minimum or no waste steam generation.
- Liu, Guangchang,Xu, Bo
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supporting information
p. 869 - 872
(2018/02/09)
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- Synthesis of 2,2′-bipyrrole-5-carboxaldehydes and their application in the synthesis of B-ring functionalized prodiginines and tambjamines
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Facile, versatile, and cost-effective synthetic routes for the preparation of a range of new 3-alkyl-, 4-alkyl-, 3,4-dialkyl-, and 3-halo-4-alkyl-2, 2′-bipyrrole-5-carboxaldehydes have been developed. These 2,2′-bipyrrole-5-carboxaldehydes offer interesting potential as building blocks for making bioactive natural and unnatural products, as demonstrated by the synthesis of B-ring functionalized prodiginines (PGs) and tambjamines.
- Kancharla, Papireddy,Reynolds, Kevin A.
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p. 8375 - 8385
(2013/09/02)
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- Direct synthesis of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines via a catalytic asymmetric intramolecular aza-Friedel-Crafts reaction
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The direct asymmetric intramolecular aza-Friedel-Crafts reaction of N-aminoethylpyrroles with aldehydes catalyzed by a chiral phosphoric acid represents the first efficient method for the preparation of medicinally interesting chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines with high yields and high enantioselectivities. This strategy has been shown to be quite general toward various aldehydes and pyrrole derivatives.
- He, Yuwei,Lin, Maohui,Li, Zhongmin,Liang, Xinting,Li, Guilong,Antilla, Jon C.
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supporting information; scheme or table
p. 4490 - 4493
(2011/10/09)
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- Lewis Acid Catalysis in Supercritical Carbon Dioxide. Use of Poly(ethylene glycol) Derivatives and Perfluoroalkylbenzenes As Surfactant Molecules Which Enable Efficient Catalysis in ScCO2
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Lewis acid catalysis in supercritical carbon dioxide (CO2) was investigated. While solubility of most organic materials is low in scCO 2, poly(ethylene glycol) derivatives or perfluoroalkylbenzenes were found to work as surfactants to dissolve organic materials in scCO2. In the presence of these molecules, Lewis acid catalyzed organic reactions such as aldol-, Mannich-, and Friedel-Crafts-type reactions proceeded smoothly in scCO2. Formation of emulsions was observed in these reactions, and the systems were studied in detail.
- Komoto, Ichiro,Kobayashi, Shu
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p. 680 - 688
(2007/10/03)
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- Benzannulation of 3-substituted pyrroles to indoles
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In a new general indole synthesis, the anion derived from benzotriazolyl derivative 5b underwent regioselective 1,4-addition to various α,β-unsaturated ketones; subsequent acid-catalyzed cyclization formed the corresponding indoles 1a-f.
- Katritzky, Alan R.,Ledoux, Stephane,Nair, Satheesh K.
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p. 5728 - 5730
(2007/10/03)
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- Aromatic heterocycle compounds having HIV integrase inhibiting activities
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A compound of the formula (I): wherein X is hydroxy, protected hydroxy or optionally substituted amino; Y is —COORAwherein RAis hydrogen or ester residue, —CONRBRCwherein RBand RCeach is independently hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl; and A1is optionally substituted heteroaryl; provided that a compound wherein Y and/or A1is optionally substituted indol-3-yl is excluded, a tautomer, a prodrug, a pharmaceutically acceptable salt or a hydrate thereof has an inhibitory activity against an integrase.
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- Synthesis and Diels-Alder reactions of the furo[3,4-b]pyrrole ring system. A new indole ring synthesis
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The previously unknown furo[3,4-b]pyrrole ring system has been synthesized from the appropriate pyrrolo hydroxyketones by acid-catalyzed cyclodehydration. Diels-Alder reactions of these furo[3,4-b]pyrroles affords a new synthesis of indoles.
- Moskalev, Nikolai V.,Gribble, Gordon W.
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p. 197 - 201
(2007/10/03)
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- General Methods for Synthesizing 2,4-Diacylpyrroles and their Precursors Containing One or Two Masked Acyl Groups
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A thorough study of the synthesis of 2,4-diacylpyrroles by direct acylation of pyrrole and 2- and 3-acylpyrroles is reported.Among these, Friedel-Crafts acylation of 3-acylpyrroles is the most general and advantageous method because it utilises easily accessible starting materials.In addition it is always regiospecific and readily provides 2,4-diacylpyrroles containing identical or different acyl groups in very high yields (81-100percent) under mild conditions, Alternative procedures concern the synthesis of precursors of 2,4-diacylpyrroles containing one or two acyl groups masked by a 1,3-benzodithiolyl or 1,3-benzoxathiolyl group and subsequent hydrolysis with HgO-35percent aq.HBF4-Me2SO.Overall yields are always good (52-60percent).Indirect acylation constitutes a secure complement to direct acylation when it is necessary to operate in the presence of protected acyl groups.
- Cadamuro, Silvano,Degani, Iacopo,Dughera, Stefano,Fochi, Rita,Gatti, Antonella,Piscopo, Laura
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p. 273 - 284
(2007/10/02)
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- Regioselective Synthesis of Acylpyrroles
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The regioselective synthesis of several pyrrole derivatives is described.AlCl3-catalyzed acylation reactions of 1-(phenylsulfonyl)pyrrole (1) give 3-acyl derivatives, whereas the corresponding BF3*OEt2-catalyzed reactions give 2-acyl derivatives predominantly.Mild alkaline hydrolysis gives the corresponding acyl-1H-pyrroles in excellent yields.AlCl3-catalyzed reactions of 1 with 1,1-dichloromethyl methyl ether and oxalyl chloride give 1-(phenylsulfonyl)-2-formylpyrrole (6) and 1-(phenylsulfonyl)-2-(chlorocarbonyl)pyrrole (7), respectively. 3-Pyrrolylacetic acid (10) was prepared by thallium(III) nitrate promoted rearrangement of 1-(phenylsulfonyl)-3-acetylpyrrole (2a).Trifluoroacetic anhydride catalyzed cyclization of 4-butyric acid (14) gives 1-(phenylsulfonyl)-7-oxo-4,5,6,7-tetrahydroindole (17).Attempts to cyclize 14 at the 4-position have been unsuccessful.
- Kakushima, Masatoshi,Hamel, Pierre,Frenette, Richard,Rokach, Joshua
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p. 3214 - 3219
(2007/10/02)
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- A SIMPLE AND EFFICIENT ROUTE TO β-SUBSTITUTED PYRROLES
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N-Phenylsulfonylpyrrole undergoes Friedel-Crafts acylation exclusively at the β-position of the pyrrole ring, thus allowing a simple and efficient synthesis of β-acylated pyrroles.
- Rokach, Joshua,Hamel, Pierre,Kakushima, Masatoshi,Smith, Graham M.
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p. 4901 - 4904
(2007/10/02)
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- PYRROLE CHEMISTRY XXV: A SIMPLIFIED SYNTHESIS OF SOME 3-SUBSTITUTED PYRROLES
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A new synthesis is reported which allows the rapid preparation in good yield of 3-aroyl-, 3-acetyl- and 3-nitro- pyrroles from pyrrole utilizing the 1-benzenesulfonyl group as a blocking group.
- Xu, Ru Xun,Anderson, Hugh J.,Gogan, Niall J.,Loader, Charles E.,McDonald, Robert
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p. 4899 - 4900
(2007/10/02)
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