Radical-based syntheses of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (ketorolac)

Artis, Dean R.; Cho, In-Seop; Muchowski, Joseph M.

doi:10.1139/v92-228

Cited by 63 publications

(28 citation statements)

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“…for m-Chloroperbenzoic acid (80 wt.%, 0.60 g, 2.8 mmol) was added to a stirred solution of the above sulfoxide (0.83 g, 2.8 mmol) in dichloromethane (20 mL) at 25OC. After stimng for 2 h at 25"C, the reaction mixture was worked up as for lc to give material that was purified by flash chromatography on silica gel using hexane -ethyl acetate to elute pure 7 a (0.70 g, 80%) as a solid that on crystallization from hexaneethyl acetate had mp 122-124°C; nmr (300)s: 2.81 (s, 3H, S02Me), 5.16 (s, 2H, CH2), 6.54 (dd, lH, J2,5 = 1.8 HZ, J4,5 = 2.6 HZ, H-5), 6.80 (t, lH, H-4), 6.89 (dd, lH, H-6'), 7.11 (t, lH, H-2), 7.19 (td, lH, H-5'). 7.27 (td, lH, H-4'), 7.59 (dd, lH, H-3').…”

Section: -(2-bromobenzy1)-3-methylsulfonylpyrroe (7a)mentioning

confidence: 99%

“…After 20 min at this temperature, this mixture was added to a stirred solution of 3-benzoylpyrrole (ref. 16,6.0 g, 35 mrnol) in rnethan01 at -78°C. The reaction mixture was warmed to 4 0°C and after 0.5 h it was poured into water.…”

Section: -(4-brornobuty1)-2-methanesulfonylpyrrole (8a)mentioning

confidence: 99%

“…1 for a summary of these studies). Recently, Gravel et al (3) and we (4)(5)(6) have reported synthetically useful examples of oxidative radical substitution of pyrrole derivatives in the intra- (3,4,6) and intermolecular (5) modes. This article describes our first studies on the intramolecular addition of radicals, generated with tri-n-butyltin hydride, to the pyrrole nucleus.…”

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confidence: 99%

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Oxidative radical cyclization to pyrroles under reducing conditions. Reductive desulfonylation of α-sulfonylpyrroles with tri-n-butyltin hydride

Antonio¹,

Cruz²,

Galeazzi³

et al. 1994

Can. J. Chem.

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, 15 (1994) 1-(2-Bromobenzy1)-2-alkanesulfonylpyrroles (lc, 16) and 1-(4-bromobuty1)-2-methylsulfonfylpyrrols (8) undergo oxidative radical cyclization with partial or complete reductive desulfonylation to the pyrrolizidine derivatives 5 and 9 by an AIBN initiated reaction with tri-n-butyltin hydride. These cyclizations are suggested to proceed via a pseudo SRNl process involving radical addition to the a position of the pyrrole nucleus not bearing the sulfonyl group. Reductive removal of the alkylsulfonyl moiety is proposed to occur in a second process after completion of the oxidative radical cyclization. The site of the radical addition is supported by deuterium labelling studies. Consistent with the timing of the loss of the sulonyl group is that 2-alkysulfonylpyrroles 11 are reductively desulfonylated under the same conditions that effect the oxidative radical cyclizations. 15 (1994) Lorsqu'ils sont soumis une reaction initiee par 1'AIBN et l'hydrure de tri-n-butyletain, les 1-(2-bromobenzy1)-2-alcanesulfonylpyrroles (lc,ld) et les 1 -(4-bromobuty1)-2-m~thylsulfonylpyrroles (8) subissent une cyclisation radicalaire oxydante accompagnee d'une dCsulfonylation reductrice partielle ou complkte conduisant aux derives pyrrolizidine 5 et 9. I1 y a des indications i l'effet que ces cyclisations se produisent par le biais d'un processus pseudo S 1 impliquant une addition radicalaire sur la position RN, , . a du noyau du pyrrole ne portant pas le groupe sulfonyle. I1 est suggCrC que 1 elimination reductrice de la portion alkylsulfonyle se produit au cours d'un deuxikme processus, aprks la cyclisation radicalaire oxydante. Le site de l'addition radicalaire est en accord avec les etudes de marquage au deuterium. En accord avec la sequence des reactions, il faut noter que les 2-alkylsulfonylpyrroles (11) sont dCsulfonylCs d'une fa~on reductrice dans les conditions conduisant aux cyclisations radicalaires rkductrices.[Traduit par la redaction]Several years ago we embarked on a research program, the objective of which was to study the reactions of pyrroles with alkyl and aryl radicals. Although both radical addition and radical substitution reactions of pyrrole derivatives had been reported at that time (1, 2), only arylation had been systematically studied and was of preparative significance (see ref.

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Section: -(2-bromobenzy1)-3-methylsulfonylpyrroe (7a)mentioning

confidence: 99%

Section: -(4-brornobuty1)-2-methanesulfonylpyrrole (8a)mentioning

confidence: 99%

mentioning

confidence: 99%

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Oxidative radical cyclization to pyrroles under reducing conditions. Reductive desulfonylation of α-sulfonylpyrroles with tri-n-butyltin hydride

Antonio¹,

Cruz²,

Galeazzi³

et al. 1994

Can. J. Chem.

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“…In total, 517.0 mg of the title product 5a was obtained in 91% yield [theoretical yield of two steps from compound 2 calculated with the ratio for (obtained weights in step 2)/(used weights in step 3) of compound 4a]. 106,107 . The reaction mixture was stirred at room temperature under N 2 for 5 min, warmed to 80 C, and stirred under N 2 .…”

mentioning

confidence: 99%

“…The residue was purified by flash column chromatography (silica gel, hexane/AcOEt ¼ 3:1) to afford 578.2 mg of the title product 6a in 70% yield as a brown amorphous solid. 1 107 . The reaction solution was warmed up to reflux conditions using an oil bath, stirred under N 2 for 17 h, then more TFA (451 mL, 5.85 mmol) was added, and stirred for 7 h. The reaction solution was cooled to 0 C, ice-cooled saturated aqueous NaHCO 3 (20 mL) was added, and the resulting mixture was stirred at 0 C for 15 min.…”

mentioning

confidence: 99%

Design, synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs

Hayashi

Ueno

Murase

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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Because of the pivotal role of cyclooxygenase (COX) in the inflammatory processes, nonsteroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of inflammatory diseases/syndromes; however, traditional NSAIDs exhibit serious side-effects such as gastrointestinal damage and hyper sensitivity owing to their COX-1 inhibition. Also, COX-2 inhibition-derived suppressive or preventive effects against initiation/proliferation/invasion/motility/recurrence/metastasis of various cancers/tumours such as colon, gastric, skin, lung, liver, pancreas, breast, prostate, cervical and ovarian cancers are significant. In this study, design, synthesis and structure-activity relationship (SAR) of various novel {2-[(2-, 3-and/or 4-substituted)-benzoyl, (bicyclic heterocycloalkanophenyl)carbonyl or cycloalkanecarbonyl]-(5-or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of potent and selective COX-2 inhibitors for the treatment of inflammatory diseases, resulting in the discovery of orally potent agents in the peripheral-inflammation model rats. The SARs and physicochemical properties for the analogues are described as significant findings.

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Triethylborane

Yamamoto¹,

Yoshimitsu²,

Wood³

et al. 2007

Encyclopedia of Reagents for Organic Synthesis

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Radical-based syntheses of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (ketorolac)

Abstract: Short, efficient, and convergent syntheses of ketorolac (1) based on the inter- or intramolecular oxidative addition of malonyl and substituted malonyl radicals to 2-benzoylpyrrole and derivatives thereof are described.

Cited by 63 publications

References 0 publications

Oxidative radical cyclization to pyrroles under reducing conditions. Reductive desulfonylation of α-sulfonylpyrroles with tri-n-butyltin hydride

Oxidative radical cyclization to pyrroles under reducing conditions. Reductive desulfonylation of α-sulfonylpyrroles with tri-n-butyltin hydride

Design, synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs

Triethylborane

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