William R. Dolbier

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Name: Dolbier, William R.

Organization: University of Florida , USA

Department: Department of Chemistry

Title: Professor(PhD)

TOPICS

Organic Chemistry

Difluoromethylation Metal Hydride

Chemicals
References

Synthesis of 3-phenylsulfonyl-2-trifluoromethyl-1H-indoles: A copper catalyzed cyclization approach

Co-reporter:Simon E. Lopez, Reese Gallagher, Robert J. Gilliland, Ion Ghiviriga, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2017 Volume 193() pp:118-125

Publication Date(Web):January 2017

DOI:10.1016/j.jfluchem.2016.11.009

•3-phenylsulfonyl-2-trifluoromethyl-1H-indoles have interest as potentially bioactive compounds.•3-phenysulfonyl-2-trifluoromethyl-1H-indoles have been prepared in two steps from methyl phenylsulfones.•Copper (II) catalysis is used in the final cyclization to form the indoles.3-Sulfonyl and 3-aroylindoles have attracted special attention because of their interesting biological activities, particularly for the development of antiviral and anticancer compounds. Based on the importance of the trifluoromethyl group in biological active molecules, we have developed a synthetic pathway for the preparation of a series of 3-phenylsulfonyl-2-trifluoromethyl-1H-indoles in two steps starting from readily available methyl-phenylsulfones. The starting methylsulfones underwent reaction with trifluoroacetimidoyl chlorides using LDA/THF at −40 °C to produce a mixture of trifluorometylimino/enamino-β-sulfonylphenyl intermediates, which were then cyclized using a copper (II) catalyst to give the title compounds in moderate to good yield.

Photoredox Catalyzed Intramolecular Fluoroalkylarylation of Unactivated Alkenes

Co-reporter:Zuxiao Zhang, Henry Martinez, and William R. Dolbier

The Journal of Organic Chemistry 2017 Volume 82(Issue 5) pp:

Publication Date(Web):February 10, 2017

DOI:10.1021/acs.joc.6b03012

The first example of photoredox catalyzed difluoromethylation of unactivated alkenes coupled with C–C bond formation to an aryl ring is reported. The reactions are conducted under mild conditions and afford tetralin derivatives bearing difluoromethyl as well as other fluoroalkyl groups in good to high yields. In addition, the study indicates that 6-exo radical cyclization of an alkyl radical to a phenyl ring is faster than the respective 5-exo radical cyclization. A computational study provides insights to the experimental results.

Photoredox-Catalyzed Intramolecular Difluoromethylation of N-Benzylacrylamides Coupled with a Dearomatizing Spirocyclization: Access to CF2H-Containing 2-Azaspiro[4.5]deca-6,9-diene-3,8-diones

Co-reporter:Zuxiao Zhang, Xiao-Jun Tang, and William R. Dolbier Jr.

Organic Letters 2016 Volume 18(Issue 5) pp:1048-1051

Publication Date(Web):February 11, 2016

DOI:10.1021/acs.orglett.6b00168

A visible light-mediated difluoromethylation of N-benzylacrylamides with HCF2SO2Cl as the HCF2 radical precursor is described. The reaction incorporates a tandem cyclization/dearomatization process to afford various difluoromethylated 2-azaspiro[4.5]deca-6,9-diene-3,8-diones bearing adjacent quaternary stereocenters under mild conditions in moderate to excellent yields.

Generation of ortho-SF5-Benzyne and Its Diels–Alder Reactions with Furans: Synthesis of 1-SF5-Naphthalene, Its Derivatives, and 1,6(1,7)-Bis-SF5-naphthalenes

Co-reporter:Oleksandr S. Kanishchev and William R. Dolbier Jr.

The Journal of Organic Chemistry 2016 Volume 81(Issue 22) pp:11305-11311

Publication Date(Web):October 27, 2016

DOI:10.1021/acs.joc.6b02276

Generation of ortho-SF5-benzyne was achieved by a lithiation/elimination sequence starting from 2-fluoro-SF5-benzene. The highly reactive ortho-SF5-benzyne intermediate was trapped by furan or 2-methylfuran in situ, and the obtained stable Diels–Alder adducts were subjected to the series of further chemical transformation, which led to the formation of previously unknown 1-SF5-naphthalene and its derivatives with bromo, amino, hydroxy, and methyl substituents, including bis-SF5-substituted naphthalenes. NMR spectroscopy experiments revealed characteristic through-space coupling between the SF5-group’s equatorial fluorines and proton/carbon nuclei of −H, −CH3, and −OH substituents in the peri-position to the SF5-group of 1-SF5-naphthalenes.

Photoredox-Catalyzed Tandem Insertion/Cyclization Reactions of Difluoromethyl and 1,1-Difluoroalkyl Radicals with Biphenyl Isocyanides

Co-reporter:Zuxiao Zhang, Xiaojun Tang, and William R. Dolbier Jr.

Organic Letters 2015 Volume 17(Issue 18) pp:4401-4403

Publication Date(Web):September 4, 2015

DOI:10.1021/acs.orglett.5b02061

Using visible-light photoredox conditions, difluoromethylation and 1,1-difluoroalkylation of biphenyl isocyanides have allowed the synthesis of a series of 6-(difluoromethyl)- and 6-(1,1-difluoroalkyl)phenanthridines via tandem addition/cyclization/oxidation processes. The reactions are carried out in wet dioxane at room temperature using fac-Ir(ppy)3 as catalyst to form a large variety of substituted phenanthridine products in good to excellent yield.

Photoredox-Catalyzed Intramolecular Aminodifluoromethylation of Unactivated Alkenes

Co-reporter:Zuxiao Zhang, Xiaojun Tang, Charles S. Thomoson, and William R. Dolbier Jr.

Organic Letters 2015 Volume 17(Issue 14) pp:3528-3531

Publication Date(Web):June 29, 2015

DOI:10.1021/acs.orglett.5b01616

A photoredox catalyzed aminodifluoromethylation of unactivated alkenes has been developed in which HCF2SO2Cl is used as the HCF2 radical source. Sulfonamides were active nucleophiles in the final step of a tandem addition/oxidation/cyclization process to form pyrrolidines, and esters were found to cyclize to form lactones. Thus, a variety of pyrrolidines and lactones were obtained in moderate to excellent yield. In order for the cyclization reactions to be efficient, a combination of a copper catalyst (Cu(dap)2Cl) and silver carbonate was crucial to suppressing a competing chloro, difluoroalkylation process.

Use of 1-pentafluorosulfanyl-phenylacetylenes for the preparation of SF5-substituted five-membered ring heterocycles through 1,3-dipolar cycloadditions. Isoxazoles and isoxazolines

Co-reporter:Simon E. Lopez, Akira Mitani, Priscila Pena, Ion Ghiviriga, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2015 Volume 176() pp:121-126

Publication Date(Web):August 2015

DOI:10.1016/j.jfluchem.2015.06.006

•1,3-Dipolar cycloadditions of nitrile oxides and nitrones are reported.•SF5-substituted alkynes are used in 1,3-dipolar cycloaddition reactions.•Preparations of SF5-substituted isoxazoles and isoxazolines are reported.A synthetic methodology utilizing 1,3-dipolar cycloadditions was developed for the preparation of pentafluorosulfanyl-substituted heterocycles using SF5-substituted arylacetylenes as key building block dipolarophiles. A group of 4-SF5-isoxazoles were prepared in moderate yields using in situ generated nitrile oxides, and 4-SF5-substituted isoxazolines were obtained when nitrones were used as the 1,3-dipole.1,3-Dipolar cycloadditions of nitrile oxides and nitrones with SF5-substituted alkynes.

Chloro, Difluoromethylation and Chloro, Carbomethoxydifluoromethylation: Reaction of Radicals Derived from RfSO2Cl with Unactivated Alkenes under Metal-Free Conditions

Co-reporter:Charles S. Thomoson, Xiao-Jun Tang, and William R. Dolbier Jr.

The Journal of Organic Chemistry 2015 Volume 80(Issue 2) pp:1264-1268

Publication Date(Web):December 16, 2014

DOI:10.1021/jo502595g

Difluoromethyl and carbomethoxydifluoromethyl radicals were generated from their respective sulfonyl chlorides under mild, metal-free conditions leading to efficient atom transfer radical additions (ATRA) to unactivated alkenes to form chloro, difluoromethylated and chloro, carbomethoxydifluoromethylated products.

Efficient Cu-catalyzed Atom Transfer Radical Addition Reactions of Fluoroalkylsulfonyl Chlorides with Electron-deficient Alkenes Induced by Visible Light

Co-reporter:Dr. Xiao-Jun Tang;Dr. William R. Dolbier Jr.

Angewandte Chemie International Edition 2015 Volume 54( Issue 14) pp:4246-4249

Publication Date(Web):

DOI:10.1002/anie.201412199

Abstract

Fluoroalkylsulfonyl chlorides, R_fSO₂Cl, in which R_f=CF₃, C₄F₉, CF₂H, CH₂F, and CH₂CF₃, are used as a source of fluorinated radicals to add fluoroalkyl groups to electron-deficient, unsaturated carbonyl compounds. Photochemical conditions, using Cu mediation, are used to produce the respective α-chloro-β-fluoroalkylcarbonyl products in excellent yields through an atom transfer radical addition (ATRA) process. Facile nucleophilic replacement of the α-chloro substituent is shown to lead to further diverse functionalization of the products.

Synthesis and Characterization of 2-Pyridylsulfur Pentafluorides

Co-reporter:Dr. Oleksr S. Kanishchev ; William R. Dolbier Jr.

Angewandte Chemie International Edition 2015 Volume 54( Issue 1) pp:280-284

Publication Date(Web):

DOI:10.1002/anie.201409990

Abstract

Current approaches to prepare SF₅-substituted heterocycles during the synthesis of targeted heterocyclic compounds require the use of SF₅-functionalized aryl or alkyne reagents or SF₅Cl as a source of the SF₅ functional group. Herein we report that excess oxidative fluorination of 2,2′-dipyridyl disulfide with a KF/Cl₂/MeCN system leads to the formation of thirteen new 2-pyridylsulfur chlorotetrafluorides (2-SF₄Cl-pyridines). These molecules are found to undergo further chlorine–fluorine exchange reactions by treatment with silver(I) fluoride enabling ready access to a series of ten new substituted 2-pyridylsulfur pentafluorides (2-SF₅-pyridines). This is the first preparatively simple and readily scalable example of the transformation of an existing heterocyclic sulfur functionality to prepare SF₅-substituted heterocycles.

Efficient Cu-catalyzed Atom Transfer Radical Addition Reactions of Fluoroalkylsulfonyl Chlorides with Electron-deficient Alkenes Induced by Visible Light

Co-reporter:Dr. Xiao-Jun Tang;Dr. William R. Dolbier Jr.

Angewandte Chemie 2015 Volume 127( Issue 14) pp:4320-4323

Publication Date(Web):

DOI:10.1002/ange.201412199

Abstract

Synthesis and Characterization of 2-Pyridylsulfur Pentafluorides

Co-reporter:Dr. Oleksr S. Kanishchev ; William R. Dolbier Jr.

Angewandte Chemie 2015 Volume 127( Issue 1) pp:282-286

Publication Date(Web):

DOI:10.1002/ange.201409990

Abstract

Direct Photoredox-Catalyzed Reductive Difluoromethylation of Electron-Deficient Alkenes

Co-reporter:Dr. Xiao-Jun Tang;Zuxiao Zhang ;Dr. William R. Dolbier Jr.

Chemistry - A European Journal 2015 Volume 21( Issue 52) pp:18961-18965

Publication Date(Web):

DOI:10.1002/chem.201504363

Abstract

Photoredox-catalyzed reductive difluoromethylation of electron-deficient alkenes was achieved in one step under tin-free, mild and neutral conditions. This protocol affords a facile method to introduce RCF₂ (R=H, Ph, Me, and CH₂N₃) groups at sites β to electron-withdrawing groups. It was found that TTMS (tris(trimethylsilyl)silane) served nicely as both the H-atom donor and the electron donor in the catalytic cycle. Experimental and DFT computational results provided evidence that RCF₂ (R=H, Ph, Me) radicals are nucleophilic in nature.

Photoredox-Catalyzed Tandem Radical Cyclization of N-Arylacrylamides: General Methods To Construct Fluorinated 3,3-Disubstituted 2-Oxindoles Using Fluoroalkylsulfonyl Chlorides

Co-reporter:Xiao-Jun Tang, Charles S. Thomoson, and William R. Dolbier Jr.

Organic Letters 2014 Volume 16(Issue 17) pp:4594-4597

Publication Date(Web):August 19, 2014

DOI:10.1021/ol502163f

Fluorinated radicals were generated from RfSO2Cl by photoredox catalysis under mild conditions, where Rf = n-C4F9, CF3, CF2H, CH2F, CH2CF3, and CF2CO2Me. This method provided a general way to construct fluorinated 2-oxindoles from reaction with N-arylacrylamides via a proposed tandem radical cyclization process.

Use of fluoroform as a source of difluorocarbene in the synthesis of N-CF2H heterocycles and difluoromethoxypyridines

Co-reporter:Charles S. Thomoson, Linhua Wang, William R. Dolbier

Journal of Fluorine Chemistry 2014 Volume 168() pp:34-39

Publication Date(Web):December 2014

DOI:10.1016/j.jfluchem.2014.08.015

•Preparation of N-difluoromethylimidazoles and benzimidazoles.•Use of fluoroform as a source of difluorocarbene.•Preparation of difluoromethoxypyridines.Fluoroform is used as a source of difluorocarbene to convert various N-, O-, and C-nucleophiles to their difluoromethylated derivatives. Imidazole, benzimidazole, benztriazole, hydroxypyridines, and their derivatives underwent reaction at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/acetonitrile) process to provide moderate to good yields of the respective products. Nitrophenols required addition of a co-solvent (methanol) to obtain good yields of products.Difluorocarbene source, CHF3, can be used as a diverse difluoromethylating agent.

Preparation of 1,1-difluoroalkanes from aldehydes via 1,1-bistriflates: Advantageous use of HF–Lewis base reagents

Co-reporter:William R. Dolbier Jr., Masamune Okamoto

Journal of Fluorine Chemistry 2014 Volume 167() pp:96-100

Publication Date(Web):November 2014

DOI:10.1016/j.jfluchem.2014.06.020

•1,1-Alkane bistriflates are readily prepared from aldehydes.•1,1-Difluoroalkanes are readily prepared from 1,1-bistriflates.•Triethylaminetrishydrofluoride is an excellent fluorinating reagent.Alkane-1,1-bistriflates, prepared in excellent yields by reaction of aldehydes with triflic anhydride, are converted to their respective 1,1-difluoroalkanes in good to excellent yield through reaction with fluorinating agent, triethylaminetrishydrofluoride. Straight chain 1,1-bistriflates are more reactive than those substituted at the 2-position, but the latter are also converted successfully, without evidence of any rearrangement products.1,1-Difluoroalkanes are readily prepared from their respective 1,1-bistriflates by treatment with Et3N-3HF.

Three step procedure for the preparation of aromatic and aliphatic difluoromethyl ethers from phenols and alcohols using a chlorine/fluorine exchange methodology

Co-reporter:William R. Dolbier Jr., Fei Wang, Xiaojun Tang, Charles S. Thomoson, Linhua Wang

Journal of Fluorine Chemistry 2014 160() pp: 72-76

Publication Date(Web):

DOI:10.1016/j.jfluchem.2014.01.018

Cis-selective preparation of 2,2-difluorocyclopropyl ketones via non-metal hydride reduction of 2,2-difluorocyclopropenyl ketones

Co-reporter:Zhaoyun Zheng, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2013 Volume 149() pp:119-124

Publication Date(Web):May 2013

DOI:10.1016/j.jfluchem.2013.02.003

Diastereoselective reduction of gem-difluorocyclopropenyl ketones was accomplished by their Brønsted acid catalyzed reactions with the non-metal based hydride transfer reagent, Hantzsch ester (diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate) (HEH). The high yield reactions produced a significantly cis-enriched product mixture, from which the cis-isomer could be readily separated by column chromatography.Graphical abstractAn efficient procedure for cis-selective reduction of gem-difluorocyclopropenyl ketones, using Hantzsch ester as the hydride transfer reagent, is reported.Highlights► Cis-selective reduction of gem-difluorocyclopropenyl ketones to form 3-substituted-2,2-difluorocyclopropyl ketones. ► Hantzsch ester is a potent hydride donor under acid catalysis. ► Cis-3-substituted-2,2-difluorocyclopropyl ketones are prepared in very good yield.

The use of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate as the difluorocarbene source to generate an in situ source of difluoromethylene triphenylphosphonium ylide

Co-reporter:Charles S. Thomoson, Henry Martinez, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2013 150() pp: 53-59

Publication Date(Web):

DOI:10.1016/j.jfluchem.2013.02.026

Use of Fluoroform as a Source of Difluorocarbene in the Synthesis of Difluoromethoxy- and Difluorothiomethoxyarenes

Co-reporter:Charles S. Thomoson and William R. Dolbier Jr.

The Journal of Organic Chemistry 2013 Volume 78(Issue 17) pp:8904-8908

Publication Date(Web):August 9, 2013

DOI:10.1021/jo401392f

Fluoroform, CHF3, a non-ozone-depleting, nontoxic, and inexpensive gas can be used as a difluorocarbene source in a process for the conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives. The reactions are carried out at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/dioxane or water/acetonitrile) process to provide moderate to good yields of the respective products.

Atropisomerism of a monosubstituted perfluoro[2.2]paracyclophane. A combined synthetic, kinetic, spectroscopic and computational study

Co-reporter:Ion Ghiviriga, Henry Martinez, Christian Kuhn, Lianhao Zhang and William R. Dolbier

Organic & Biomolecular Chemistry 2012 vol. 10(Issue 4) pp:882-889

Publication Date(Web):11 Oct 2011

DOI:10.1039/C1OB06157G

The product of SNAr addition of the enolate of ethyl acetoacetate to perfluoro[2.2]para-cyclophane exists entirely as its enol tautomer 5. This enol exhibits two NMR signals for its enolic proton, and these signals were shown to derive from the presence of two, equal energy conformations that were observable as distinct, stable conformations at room temperature, but which when heated, interconverted with an energy barrier of 23.5 kcal mol−1. These atropisomers were characterized by NMR, with details of this analysis being provided. Computational work corroborated the NMR conclusions, and provided additional insight into all structural, thermodynamic and kinetic results. Enol product 5 was cyclized, under basic conditions, to form a benzofuran product 6. Its structure was confirmed by NMR, with further structural and mechanistic insights being provided by calculations.

Energetic materials containing fluorine. Design, synthesis and testing of furazan-containing energetic materials bearing a pentafluorosulfanyl group

Co-reporter:Henry Martinez, Zhaoyun Zheng, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2012 Volume 143() pp:112-122

Publication Date(Web):November 2012

DOI:10.1016/j.jfluchem.2012.03.010

The advantageous impact of a pentafluorosulfanyl substituent on the properties of furazan-containing energetic materials was demonstrated by the synthesis and study of the energetic properties of ten new compounds. The thermal stability of these compounds was evaluated by DSC and TGA, whereas densities, heats of formation, pressures of detonation and speeds of detonation were obtained computationally. On the basis of these data, it was concluded that the combination of the SF5 substituent with the furazan ring led to materials of higher density and predicted detonation properties than other known furazans or SF5-containing materials. In addition, the synthetic studies provided insight regarding the electron-withdrawing nature of the furazan ring, in particular its effect on the basicity and nucleophilic reactivity of amino furazans.Graphical abstractTen new SF5-containing furazan materials have been synthesized and their energetic properties examined.Highlights► Pentafluorosulfanylacetic acid is a useful building block for preparation of new furazan energetic materials. ► SF5-substituted furazans have densities greater than materials containing either moiety alone. ► SF5-substituted furazans have enhanced energetic properties when compared to materials containing either moiety alone. ► The low nucleophilicity of aminofurazans makes synthesis of derivatives challenging.

Impact of fluorine substituents on the rates of nucleophilic aliphatic substitution and β-elimination

Co-reporter:Henry Martinez, Adele Rebeyrol, Taylor B. Nelms, William R. Dolbier Jr

Journal of Fluorine Chemistry 2012 Volume 135() pp:167-175

Publication Date(Web):March 2012

DOI:10.1016/j.jfluchem.2011.10.008

A measure of the quantitative effect of proximate fluorine substituents on the rates of SN2 and E2 reactions has been obtained through a study mainly of reactions of fluorinated n-alkyl bromides with weak base, strong nucleophile azide ion and strong base/nucleophile methoxide ion in the protic solvent methanol and the aprotic solvent, DMSO. The order of reactivity for SN2 reactions of azide in methanol at 50 °C was found to be: n-alkyl-Br > n-alkyl-CHFBr > n-perfluoroalkyl-CH2CH2Br ≫ n-perfluoroalkyl-CH2Br > n-alkyl-CF2Br. Approximate relative rates of reaction were: 1, 0.20, 0.12, 1 × 10−4, <7.7 × 10−5. The order of reactivity for E2 reactions was found to be: n-perfluoroalkyl-CH2CH2Br ≫ n-alkyl-CF2Br > n-alkyl-CHFBr > n-alkyl-Br. The approximate relative rates for reaction of methoxide in methanol at 50 °C were: 1100, 4.4, 1.9, 1.Graphical abstractα,α or -Fluorine substitution can have a profound effect upon the rates of substitution or elimination of an alkyl halide.Highlights► Rates of bimolecular substitution by azide and methoxide are reported for a series of partially fluorinated alkyl bromides. ► Rates of β-elimination by methoxide are reported for a series of partially fluorinated alkyl bromides. ► Rates of substitution by azide and methoxide are reported for bromodifluoromethylbenzene. ► Fluorine in the vicinity of a carbon–halogen bond has a significant effect on its rates of either substitution or elimination.

Methyl 2,2-Difluoro-2-(fluorosulfonyl)acetate, a Difluorocarbene Reagent with Reactivity Comparable to That of Trimethylsilyl 2,2-Difluoro-2-(fluorosulfonyl)acetate (TFDA)

Co-reporter:Steffen Eusterwiemann, Henry Martinez, and William R. Dolbier Jr.

The Journal of Organic Chemistry 2012 Volume 77(Issue 12) pp:5461-5464

Publication Date(Web):May 21, 2012

DOI:10.1021/jo300876z

Under specific high concentration, high temperature conditions, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA) has been found to act as a very efficient source of difluorocarbene, exhibiting carbene reactivity characteristics comparable to those exhibited by trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA). For example, in reaction with highly unreactive n-butyl acrylate and using only 2 equiv of MDFA, a yield of 76% of difluorocyclopropane product was obtained after 2 days.

Use of 1,3-dipolar reactions for the preparation of SF5-substituted five-membered ring heterocycles. Pyrroles and thiophenes

Co-reporter:William R. Dolbier Jr., Zhaoyun Zheng

Journal of Fluorine Chemistry 2011 Volume 132(Issue 6) pp:389-393

Publication Date(Web):June 2011

DOI:10.1016/j.jfluchem.2011.03.017

In situ-generated unsubstituted, “parent” azomethine and thiocarbonyl ylides are used to prepare a large variety of 3-aryl- and alkyl-substituted, 4-pentafluorosulfanylpyrroles and 3-aryl-substituted, 4-pentafluorosulfanylthiophenes, the latter of which are to our knowledge the first reported SF5-substituted thiophenes. The 1,3-cycloadditions of these ylides with aryl and alkyl, SF5-alkynes produce dihydro-pyrroles and thiophenes, which without isolation can then be oxidatively aromatized to the respective pentafluorosulfanylpyrroles and thiophenes in good yield.Graphical abstractSynthesis of pentafluorosulfanyl pyrroles and thiophenes via 1,3-dipolar cycloadditions of azomethine ylide and thiocarbonyl ylide.Highlights► Synthesis of pentafluorosulfanyl pyrroles. ► Synthesis of pentafluorosulfanyl thiophenes. ► 1,3-Dipolar cycloadditions of thiocarbonyl ylide. ► 1,3-Dipolar cycloadditions of azomethine ylide.

Arylsulfur trifluorides: Improved method of synthesis and use as in situ deoxofluorination reagents

Co-reporter:Wei Xu, Henry Martinez, William R. Dolbier Jr

Journal of Fluorine Chemistry 2011 Volume 132(Issue 7) pp:482-488

Publication Date(Web):July 2011

DOI:10.1016/j.jfluchem.2011.05.001

Building on recent results of Umemoto and Winter, an improved method of synthesis of arylsulfur trifluorides, including the excellent, new deoxofluorination reagent Fluolead, is hereby reported. The method utilizes Br2 and KF as oxidizing and fluorinating reagents for efficient, high yield conversion of aryl disulfides and mercaptans to arylsulfur trifluorides. It has also been shown that both Fluolead and mesitylsulfur trifluoride may be generated in acetonitrile and used as in situ deoxofluorination reagents for conversion of either aldehydes or ketones to their respective gem-difluoro compounds. An analysis of the probable mechanism of action, including computational efforts, allows postulation of a rationale for the highly variable reactivities of different arylsulfur trifluorides as deoxofluorination reagents.Graphical abstractBr2 and KF are utilized as oxidizing and fluorinating reagents for efficient, high yield conversion of aryl disulfides and mercaptans to arylsulfur trifluorides.Highlights► Arylsulfur trifluorides are synthesized from thiophenols and aryl disulfides in very good yield. ► Arylsulfur trifluorides are effective in situ deoxofluorination reagents with aldehyde and ketone substrates. ► Calculations help explain variations in reactivity of arylsulfur trifluorides in their deoxofluorination reactions.

Friedel−Crafts Reactions of 2,2-Difluorocyclopropanecarbonyl Chloride: Unexpected Ring-Opening Chemistry

Co-reporter:William R. Dolbier Jr., Eric Cornett, Henry Martinez, and Wei Xu

The Journal of Organic Chemistry 2011 Volume 76(Issue 9) pp:3450-3456

Publication Date(Web):April 1, 2011

DOI:10.1021/jo200423y

The Friedel−Crafts reactions of 2,2-difluorocyclopropanecarbonyl chloride with various arenes did not lead to the straightforward formation of the expected aryl 2,2-difluorocyclopropyl ketones. Instead the reactions proceeded, to various degrees depending on the reactivity of the arene, via an apparent rearrangement of the initially formed acylium ion to form novel aryl 3-chloro-3,3-difluoropropyl ketones. The ring-opened product was formed exclusively, and therefore the reaction may be synthetically useful when relatively unreactive arene substrates such as benzene, toluene, and p-xylene are used. No conditions were found where ring-intact products could be formed exclusively when using substituted benzenes as substrates, with the very reactive substrate thiophene being most selective in that regard, favoring ring intact product 3 with a selectivity of 98:2. The regioselectivity of ring-opening was examined and compared with other related systems computationally.

Preface

Co-reporter:Vadim A. Soloshonok, Karel D. Klika, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2010 Volume 131(Issue 4) pp:455

Publication Date(Web):April 2010

DOI:10.1016/j.jfluchem.2010.01.011

Magnesium iodide promoted defluorinative reactions of 2,2-difluorocyclopropyl aryl ketones with aryl imines: A new, general synthesis of 2-alkylideneazetidines

Co-reporter:Wei Xu, Ion Ghiviriga, Qing-Yun Chen, William R. Dolbier

Journal of Fluorine Chemistry 2010 Volume 131(Issue 9) pp:958-963

Publication Date(Web):September 2010

DOI:10.1016/j.jfluchem.2010.06.021

Upon treatment with anhydrous MgI2, 2,2-difluorocyclopropyl aryl ketones undergo a ring-opening process leading to complete loss of fluorine. When carried out in the presence of aryl imines, the reaction leads to a novel synthesis of 2-alkylideneazetidenes. A fluorine-free allenyl ketone is proposed as an intermediate in these reactions.A novel synthesis of 2-alkylideneazetidenes via the defluorinative ring-opening reaction of 2,2-difluorocyclopropyl ketones with imines.

Highly Reactive and Regenerable Fluorinating Agent for Oxidative Fluorination of Aromatics

Co-reporter:Krishna Murthy Janmanchi and William R. Dolbier, Jr.

Organic Process Research & Development 2008 Volume 12(Issue 2) pp:349-354

Publication Date(Web):February 21, 2008

DOI:10.1021/op700266y

A newly synthesized copper aluminum fluoride of nominal composition CuAl2F8 exhibits excellent reactivity towards direct oxidative fluorination of aromatic compounds, as well as fluorodechlorination of chloroaromatics. The spent CuAl2F8 reagent can be regenerated by treatment with O2 and HF, and the fluorination process has been demonstrated to retain high conversions through 20 reaction cycles. The main advantages of this new process are safety, minimal waste, and potentially low cost.

Nucleophilic difluoromethylation and trifluoromethylation using tetrakis(dimethylamino)ethylene (TDAE) reagent

Co-reporter:Maurice Médebielle, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2008 Volume 129(Issue 10) pp:930-942

Publication Date(Web):October 2008

DOI:10.1016/j.jfluchem.2008.06.029

In an effort to find new methodologies to introduce difluoromethylene and trifluoromethyl moieties into organic molecules of synthetic and biological interest, tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of a series of good electron-acceptors such as bromodifluoromethyl heterocycles, chlorodifluoromethylated ketones as well as perfluoroalkyl iodides; the corresponding anions thus generated under very mild conditions, were successfully engaged in a number of intra- and intermolecular coupling reactions with a series of electrophiles (aldehydes, ketones, α-keto esters, N-tosyl aldimines, acyl chlorides, diol sulphates, disulfides, and diselenides). The corresponding adducts were usually obtained in moderate to good yields and the present method was found to be as good or even better as other most popular approaches. This paper gives an overview of our research efforts in this area as well as results from other groups.In an effort to find new methodologies to introduce difluoromethylene and trifluoromethyl moieties into organic molecules of synthetic and biological interest, the tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of a series of good electron-acceptors such as bromodifluoromethyl heterocycles, chlorodifluoromethylated ketones as well as perfluoroalkyl iodides; the corresponding anions thus generated under very mild conditions, were successfully engaged in a number of intra- and intermolecular coupling reactions with a series of electrophiles (aldehydes, ketones, α-keto esters, N-tosyl aldimines, acyl chlorides, diol sulphates, disulfides, and diselenides). The corresponding adducts were usually obtained in moderate to good yields and the present method was found to be as good or even better as other most popular approaches. This paper gives an overview of our research efforts in this area as well as results from other groups.

Novel fluoropolymers formed by an unprecedented SRN1 condensation polymerization mechanism

Co-reporter:William R. Dolbier Jr., Valerie Rodriguez-Garcia, Kai Wu, Alexander Angerhofer, Lotfi Hedhli, Maher Elsheikh

Journal of Fluorine Chemistry 2008 Volume 129(Issue 10) pp:991-993

Publication Date(Web):October 2008

DOI:10.1016/j.jfluchem.2008.02.010

A condensation copolymerization reaction between bis-phenol A and p-bis-(chlorodifluoro-methyl)benzene has been carried out to form a novel fluoropolymer that has excellent thermal and solubility properties. It is proposed that this polymerization reaction occurs via an unprecedented SRN1 mechanism. This demonstration of the use of SRN1 chemistry for condensation polymerizations of fluorinated monomers creates the opportunity for preparation of new fluoropolymers which are otherwise inaccessible.A condensation copolymerization reaction between bis-phenol A and p-bis-(chlorodifluoromethyl) benzene, likely proceeding via an unprecedented SRN1 mechanism, has produced a novel fluoropolymer.

A convenient and efficient method for incorporation of pentafluorosulfanyl (SF5) substituents into aliphatic compounds

Co-reporter:William R. Dolbier Jr., Samia Aït-Mohand, Tyler D. Schertz, Tatiana A. Sergeeva, Joseph A. Cradlebaugh, Akira Mitani, Gary L. Gard, Rolf W. Winter, Joseph S. Thrasher

Journal of Fluorine Chemistry 2006 Volume 127(Issue 10) pp:1302-1310

Publication Date(Web):October 2006

DOI:10.1016/j.jfluchem.2006.05.003

Both SF5Cl and SF5Br undergo smooth, high yield addition to alkenes and alkynes under the mild free radical chain reaction conditions of triethylborane initiation at low temperature, although the SF5Br chemistry is somewhat limited by its competing high electrophilic reactivity with electron rich alkenes. The SF5Cl addition reaction is relatively insensitive to a wide variety of non-allylic functionalities.Both SF5Cl and SF5Br undergo smooth, high yield addition to alkenes and alkynes under the mild free radical chain reaction conditions of triethylborane initiation at low temperature.

Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA): a new, highly efficient difluorocarbene reagent

Co-reporter:William R Dolbier Jr., Feng Tian, Jian-Xin Duan, An-Rong Li, Samia Ait-Mohand, Olivia Bautista, Saiwan Buathong, J Marshall Baker, Jen Crawford, Pauline Anselme, Xiao Hong Cai, Aneta Modzelewska, Henryk Koroniak, Merle A Battiste, Qing-Yun Chen

Journal of Fluorine Chemistry 2004 Volume 125(Issue 3) pp:459-469

Publication Date(Web):1 March 2004

DOI:10.1016/j.jfluchem.2003.12.002

TFDA is readily prepared from the reaction of fluorosulfonyldifluoroacetic acid with trimethylsilyl chloride, and it is a very effective and efficient source of difluorocarbene for use in addition reactions to alkenes of a broad scope of reactivities. Acid-sensitive substrates may require an additional purification step involving treatment of the distilled TFDA with sufficient Et3N to remove the acid impurity. Other trialkylsilyl fluorosulfonyldifluoroacetates can also be prepared, and they have been found to have reactivities similar to TFDA. The triethyl derivative, TEFDA is more convenient to prepare in a pure state and has similar reactivity to TFDA. Thus, it may prove to be a superior reagent.

The effect of fluorine substitution on the structure of oxiranes and on the energetics of the oxiranylcarbinyl radical ring opening

Co-reporter:Feng Tian, John M. Baker, Bruce E. Smart, William R. Dolbier Jr.

Journal of Fluorine Chemistry 2002 Volume 114(Issue 2) pp:107-111

Publication Date(Web):28 April 2002

DOI:10.1016/S0022-1139(02)00015-5

Fluorine substituent effects on the structure of oxirane and on the kinetic behavior of oxiranylcarbinyl radicals, as determined by DFT calculations, have been found to be similar to those observed for the analogous fluorinated cyclopropylcarbinyl radical systems. A structural and energetic analysis showed that a stereoelectronic effect involving preferential interaction of the semi-occupied atomic orbital of the radical with the weaker ring bond is the major factor that contributes to the regiochemistry of the ring opening of fluorinated oxiranylcarbinyl radicals. With low and potentially zero activation barriers, 3,3-difluorooxiranylcarbinyl radical and cation undergo ring opening with CO bond cleavage and CC cleavage, respectively.Graphic

Synthesis and reactivity of halogeno-difluoromethyl aromatics and heterocycles: Application to the synthesis of gem-difluorinated bioactive compounds

Co-reporter:Conrad R Burkholder, William R Dolbier Jr., Maurice Médebielle

Journal of Fluorine Chemistry 2001 Volume 109(Issue 1) pp:39-48

Publication Date(Web):June 2001

DOI:10.1016/S0022-1139(01)00378-5

In an effort to prepare new fluorine-containing compounds which are active against HIV, and based on the electrochemical reduction of a series of bromodifluoromethyl compounds, the tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of the 2-(bromodifluoromethyl)benzoxazole 1 and of the 5-(bromodifluoromethyl)-3-phenyl-1,2,4-oxadiazole 3. A stepwise electron transfer with a difluoromethyl radical as intermediate is assumed to take place in this reaction. Under mild conditions, the generated difluoromethyl heterocyclic anion was efficiently trapped with aromatic and heterocyclic aldehydes 7–14 and ketones 15–16. In this way the corresponding β,β-difluoro-α-heteroarylated alcohols 17–32 were obtained in moderate to good yields. The same methodology was successfully applied to the reduction of chlorodifluoromethylated ketones 4–6 and the generated α,α-difluoroacetyl anion was trapped with several aldehydes 7, 8, 10, 11, under mild conditions, to give the corresponding 2,2-difluoro-3-hydroxy ketone derivatives 33–38, in moderate yields. The SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole (1) with the anions of heterocyclic thiols and phenolic compounds were also carried out. The products 39–54, which all have a CF2 group, were tested for activity against HIV, and several were found to be active, including 44 which was very active.

The syntheses of nonnucleoside, HIV-1 reverse transcriptase inhibitors containing a CF2 group: The SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole with the anions derived from heterocyclic thiols and phenolic compounds

Co-reporter:Conrad R Burkholder, William R Dolbier Jr., Maurice Médebielle

Journal of Fluorine Chemistry 2000 Volume 102(1–2) pp:369-376

Publication Date(Web):March 2000

DOI:10.1016/S0022-1139(99)00314-0

In an effort to prepare new fluorine-containing compounds which are active against HIV, the SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole (5) with the anions of heterocyclic thiols and phenolic compounds were carried out. The products (6a–j and 7a–f), which all have a CF2 group, were tested for activity against HIV, and several were found to be active, including 6f which was very active. By comparing the activity of 6e, which contains a CF2 group, to that of 10, where the CF2 is replaced by a CH2 group, it was demonstrated that fluorine atom substitution produces a 10-fold increase in activity against HIV-1.

Atropisomerism of a monosubstituted perfluoro[2.2]paracyclophane. A combined synthetic, kinetic, spectroscopic and computational study

Co-reporter:Ion Ghiviriga, Henry Martinez, Christian Kuhn, Lianhao Zhang and William R. Dolbier

Organic & Biomolecular Chemistry 2012 - vol. 10(Issue 4) pp:NaN889-889

Publication Date(Web):2011/10/11

DOI:10.1039/C1OB06157G