Fluoro-Julia Olefination as a Mild, High-Yielding Route to α-Fluoro Acrylonitriles

Solar, Maria del; Ghosh, Arun K.; Zajc, Barbara

doi:10.1021/jo801235x

Cited by 37 publications

(29 citation statements)

References 54 publications

(53 reference statements)

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“…In our previous studies, we have developed a general method for the synthesis of Julia olefination reagents via heterogeneous metalation-fluorination of appropriate precursors, specifically 1,3-benzothiazol-2-ylsulfonyl (BT-sulfonyl) derivatives 9,10a,11–13. Further, to date the only reported Julia olefination reagent for the synthesis of fluoroalkylidene derivatives was the benzothiazolyl based α-fluoroethyl BT-sulfone 8.…”

Section: Resultsmentioning

confidence: 99%

“…Several approaches have been undertaken for the synthesis of fluorinated Julia-Kocienski reagents. These range from synthesis utilizing commercial fluorinated precursors,8,10b,10d,11 to halogen exchange reaction of appropriate chloroderivative,8 to metalation-electrophilic fluorination 9,10a,10c,11–13. Among these, we have extensively investigated the metalation-fluorination approach,9,10a,11–13 since it offers the most general access to fluorinated Julia-Kocienski reagents.…”

Section: Introductionmentioning

confidence: 99%

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Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General Reagents for Fluoroalkylidene Synthesis

Ghosh

Zajc

2009

J. Org. Chem.

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Julia-Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-2-propenyl and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones were prepared by metalation followed by electrophilic fluorination. Although metalation-fluorination of n-propyl, 5-hexenyl and (cyclopropyl)methyl PT-sulfones proceeded under homogeneous conditions, fluorination of 2-methyl-2-propenyl PT-sulfone required heterogeneous fluorination conditions. Condensation reactions of fluoro PT-sulfones with aldehydes resulted in fluoroalkylidenes in high yields. Screening of olefination conditions showed that stereoselectivity depended on reagent and carbonyl structure and can in many cases be tuned either towards E-or Z-selectivity. For example, LHMDS-mediated condensations of 1-fluoropropyl PT-sulfone in the presence of MgBr 2 ·OEt 2 were Z-selective with electron-rich aromatic aldehydes, a hindered aromatic aldehyde and cinnamaldehyde. Low temperature KHMDS-mediated condensations were E-selective with electron-rich and electron-deficient aromatic aldehydes and Z-selective with n-octanal. Dialkyl, aryl alkyl and diaryl ketones reacted as well to give fluoro olefin products in 71-99% yields.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General Reagents for Fluoroalkylidene Synthesis

Ghosh

Zajc

2009

J. Org. Chem.

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“…This precursor 1 was treated with potassium ethyl xanthate in presence of pyridine to afford intermediate benzo[ d ]oxazole‐2‐thiol ( 2 ) in 85% yield . Further the compound, 2 was treated with chloroacetonitrile and K 2 CO 3 as base in DMF produced, (1,3‐benzoxazol‐2‐ylsulfanyl)acetonitrile ( 3 ) in excellent yield . Next, desired starting compound 4 was achieved from compound 3 using hydroxylamine hydrochloride and triethylamine in presence of ethanol in 90% yield.…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of 2 (((5‐aryl‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazoles: New Antiinflammatory and Antioxidant Agents

et al. 2018

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The oxadiazole linked benzoxazoles derivatives were designed using scaffold hopping approach and their molecular level interactions with both isoforms of cyclooxygenases, Cyclo OXygenase‐1 (COX‐1) and CycloOXygenase‐2 (COX‐2), were carried out using docking protocols. Mini library of oxadiazole linked benzoxazoles derivatives were synthesized and tested for their COX inhibitory activity by in vitro enzyme assay. The results indicated that compound 2‐(((5‐(2,4‐dichlorophenyl)‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazole (5 h), 2‐(((5‐(4‐nitrophenyl)‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazole (5 j) and 2‐(((5‐(4‐(trifluoromethyl)phenyl)‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazole (5 k) selectively inhibited COX‐2 enzyme. The compound 5 j exhibited strong selective COX‐2 inhibition (IC50=4.83 μM) followed by compound 5 h (IC50=5.10 μM) and 5 k (IC50=6.70 μM). The in vivo anti‐inflammatory activity of compound 5 j was found to have better efficiency than the standard drug Ibuprofen at both 3 h and 5 h intervals. The significant molecular level interactions with respect to position of benzoxazole, 1,2,4‐oxadiazole and substituted aryl groups in both COX‐1 and COX‐2 active sites were discussed. Subsequently, 2,2‐diphenyl‐2‐picrylhydrazyl (DPPH) anti‐oxidant activity was also checked for all the compounds and the compound 5 j was found to be good anti‐oxidant among the series with an IC50 of 34.5 μM.

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“…Application of this reaction for preparation of fluoroalkylidenes was initially demonstrated using a single olefination precursor5. We were the first to utilize metalation-fluorination as a general approach for the preparation of novel Julia reagents for the synthesis of functionalized fluoroolefins 6–9. Variously functionalized fluoroolefins are now conveniently accessible by the Julia-Kocienski olefination 6–11.…”

Section: Introductionmentioning

confidence: 99%

“…Variously functionalized fluoroolefins are now conveniently accessible by the Julia-Kocienski olefination 6–11. In our work, we have developed a series of isolable and stable fluorinated reagents that have yielded facile access to α-fluorostilbene and styrene derivatives,6 α-fluoroacrylates,7 α-fluorovinyl sulfones8 and α- fluoroacrylonitriles 9…”

Section: Introductionmentioning

confidence: 99%

α-Fluorovinyl Weinreb Amides and α-Fluoroenones from a Common Fluorinated Building Block

et al. 2009

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Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones, to give α-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are ≥98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give α-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate in the synthesis of α-fluorovinyl Weinreb amides and α-fluoroenones has been demonstrated. Application of the Weinreb amide to α-fluoro allyl amine synthesis is also shown.

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Fluoro-Julia Olefination as a Mild, High-Yielding Route to α-Fluoro Acrylonitriles

Cited by 37 publications

References 54 publications

Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General Reagents for Fluoroalkylidene Synthesis

Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General Reagents for Fluoroalkylidene Synthesis

Design, Synthesis and Biological Evaluation of 2 (((5‐aryl‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazoles: New Antiinflammatory and Antioxidant Agents

α-Fluorovinyl Weinreb Amides and α-Fluoroenones from a Common Fluorinated Building Block

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