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XtalFluor® Reagents

New fluorinating reagents for alcohols and carbonyls

Xtalfluor® – New fluorinating reagents for alcohols and carbonyls

XtalFluor Reagents Structures

Manchester Organics in partnership with OmegaChem have developed and commercialised a new safer and crystalline fluorinating reagent.
In the past, organic chemists needed DAST, Deoxo-Fluor® and more recently Fluolead to perform fluorination, but XtalFluor®reagentscome today with a long list of advantages over all of them.

Many advantages over DAST & Deoxo-Fluor®

XtraFluor e
 
XtraFluor Saftey Margins

Superior Safety Margin

Overlapped DSC thermograms indicate that XtalFluor® reagents are more stable and provide greater safety than DAST and Deoxo-Fluor® by showing a higher decomposition temperature and a lower exothermic heat.

XtraFluor Saftey Margins

 

In depth analyses of overlapped ARC thermograms clearly show higher onset temperatures for XtalFluor® reagents. Whereas DAST and Deoxo-Fluor® show an onset of self accelerated decomposition at 60°C, XtalFluor-E® and XtalFluor-M® start decomposing at much higher temperatures, i.e. 119°C and 141°C respectively.

 
Examples of increased selectivity:

Fluorination of hydroxyls

Fluorination of carbonyls

 

Using XtalFluor® reagents allows chemists to vary several reaction conditions, such as the nature of the reagent, temperature, additives and stoichiometry to obtain optimal results.

 
Research quantities available through Sigma-Aldrich Co.Sigma Aldrich logo

XtalFluor-E® : Aldrich catalog # 719439
XtalFluor-M® : Aldrich catalog # 719447

 
Multi-kilo quantities available through Manchester OrganicsManchester Organics logo

XtalFluor-E® : Manchester catalog # J11026
XtalFluor-M® : Manchester catalog # K11027



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XtalFluor-E® and XtalFluor-M® are registered trademarks of OmegaChem, Inc.
Since the discovery in 2009 of new crystalline fluorinating reagents, the following scientific papers have been published. These publications should allow a full understanding of their benefits over DAST, Deoxo-Fluor® and Fluolead™.
A provisional US Patent Application has been filled along with Trademarks for XtalFluor-E® and XtalFluor-M®.

Publications:

April, 2015, ACS Publications
Asymmetric Synthesis of Substituted anti-β-Fluorophenylalanines
Stephen G. Davies, Ai M. Fletcher, Aileen B. Frost, Paul M. Roberts, and James E. Thomson

March, 2015, Royal Society of Chemistry
Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones
Lynne Gilfillan, Raik Artschwager, Alexander H. Harkiss, Rob M. J. Liskampa, and Andrew Sutherland

March, 2015, ACS Publications
Utilizing CYP2D6 and BACE1 Structure Complexes to Reduce Risk of Drug Series of Centrally Efficacious BACE1 Inhibitors
Michael A. Brodney, Elizabeth M Beck, Christopher R. Butler, Gabriela Barreiro, Eric F. Johnson, David Riddell, Kevin Parris, Charlie E Nolan, Ying Fan, Kevin Atchison, Cathleen Gonzales, Ashley Robshaw, Shawn D Doran, Mark W Bundesmann, Leanne M Buzon, jason K Dutra, Kevin E Henegar, Erik A LaChapelle, Xinjun Hou, Bruce N. Rogers, Jayvardhan Pandit, Ricardo Lira, Luis A Martinez, John C Murray, Kevin Ogilvie, Loren Price, Subas Sakya, Aijia Yu, yong Zhang, and Brian T. O'Neill

February, 2015, Tetrahedron Letters
Synthesis and use of N-Fmoc-L-fluoroalanine
Claudia Carpentier, Raphaël Godbout, François Otis, Normand Voyer

February 16, 2015, ACS Publications
A Novel and Selective Fluoride Opening of Aziridines by XtalFluor-E. Synthesis of Fluorinated Diamino Acid Derivatives
Nonn M., Kiss L., Haukka M., Fustero S., Fülöp F. Org. Lett. DOI: 10.1021/acs.orglett.5b00182..

2015, Journal of Organic Chemistry
Synthesis of 2-Oxazolines by in Situ Desilylation and Cyclodehydration of β-Hydroxyamides
Brandstatter M., Roth F., Luedtke N.W., J. Org. Chem. 80(1), 40-51 (2015)..

2015, Org. Biomol. Chem.
In situ activation of benzyl alcohols with XtalFluor-E: formation of 1,1-diarylmethanes and 1,1,1-triarylmethanes through Friedel-Crafts benzylation
Desroches J., Champagne P.A., Benhassine, Y., Paquin J.-F. Org. Biomol. Chem., 2015,13, 2243..

Jan 8, 2015, Tetrahedron Letters
Synthesis of isocyanides through dehydration of formamides using XtalFluor-E
Keita M., Vandamme M., Mahé O., Paquin J.-F. Tetrahedron Lett. 56(2), 461-464 (2015)..

August, 2013, Tekno Scienze
Dialkylaminodifluorosulfinium tetrafluoroborate salts: synthesis and applications
Turcotte-Savard M-.O., Mahé O., Paquin J.-F. Chimica Oggi-Chemistry Today, 31 (4), 14-19 (2013)..

May 23, 2013, European Journal of Organic Chemistry
Amide Formation Using In Situ Activation of Carboxylic Acids with [Et2NSF2]BF4
Mahé O., Desroches J., Paquin J.-F. Eur. J. Org. Chem. (2013), 4325-4331..

Feb 5, 2013, ACS Publications
XtalFluor-E, an Efficient Coupling Reagent for Amidation of Carboxylic Acids
Orliac A., Gomez P. D., Bombrun A., Cossy J. Org. Lett. 15(4), 902-905 (2013)..

2013, Journal of Fluorine Chemistry
Deoxofluorination Reactions Using N,N-Disubstituted Aminodifluorosulfinium Tetrafluoroborate Salts
Mahé, O.; L'Heureux, A.; Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.; Paquin, J.-F. J. Fluorine Chem. 153, 57-60 (2013)..

2013, Thieme E Journals
Dialkylaminodifluorosulfinium Salts: XtalFluor-E and XtalFluor-M
Franconetti A., Synlett, 24(7), 891-892 (2013).

September 13, 2013 C&I Magazine
Simpler fluorine chemistry
Bennett, C.; Clayton,S.; Tovell, D. (2010). C&I Magazine. Issue 17. September 13, 2012.

May 17, 2013, Journal of Fluorine Chemistry
Deoxofluorination Reactions Using N,N-Disubstituted Aminodifluorosulfinium Tetrafluoroborate Salts
Olivier Mahe, Alexandre L’Heureux, Michel Couturier, Christopher Bennett, Simon Clayton, David Tovell, Francis Beaulieu, Jean-Francois Paquin.

October 16, 2012, ACS Publications
Halogenation of Primary Alcohols Using a Tetraethylammonium Halide/[Et2NSF2]BF4 Combination
Pouliot M.-F., Mahe O., Hamel J.-D., Desroches J., Paquin J.-F. Org. Lett. 14(21), 5428-5431 (2012)

August 1, 2012 Carbohyrdrate Research
Synthesis of glycosyl fluorides from thio-, seleno-, and telluroglycosides and glycosyl sulfoxides using aminodifluorosulfinium tetrafluoroborates
Tsegay S., Williams R. J., Williams S. J. Carbohydr. Res. 357, 16-22 (2012)

February 24, 2012 European Journal of Organic Chemistry
Access to Optically Active 3-Aminopiperidines by Ring Expansion of Prolinols: Thermodynamic versus Kinetic Control
Cochi A., Pardo D. G., Cossy J. Eur. J. Org. Chem. 2012(10), 2023 (2012)

2012, Thieme
Regiocomplementary Synthesis of Fluorinated Bridged Biphenyls
Nemoto H., Takubo K., Shimizu K., Akai S. Synlett 23(13), 1978-1984 (2012)

August 8, 2012, Tetrahedron Letters
Synthesis of 2-oxazolines and related N-containing heterocycles using [Et2NSF2]BF4 as a cyclodehydration agent
Pouliot M.-F., Angers L., Hamel J.-D., Paquin J.-F. Tetrahedron Lett. 53(32), 4121-4123 (2012).

September 2, 2011, Journal of Fluorine Chemistry
Synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using [Et2NSF2]BF4 as a practical cyclodehydration agent
Pouliot M.-F., Angers L., Hamel J.-D., Paquin J.-F. Org. Biomol. Chem. 10(5), 988-993 (2012).

July 27, 2011, ACS Publications
Access to Optically Active 3-Azido- and 3-Aminopiperidine Derivatives by Enantioselective Ring Expansion of Prolinols
Cochi A., Pardo D. G., Cossy J. Org. Lett. 13(16), 4442-4445 (2011)

April 17, 2011 Chemical Communications
Noteworthy observations accompanying synthesis of the apoptolidin disaccharide
Srinivasarao M., Park T., Chen Y., Fuchs P. L. Chem. Commun. 47(20), 5858-5860 (2011)

2010, Aldrich ChemFiles
Aldrich ChemFiles Volume 10 Number 3 (5 MB )
Ryba,T. (2010)

April 21, 2010, Journal of Organic Chemistry
Aminodifluorosulfinum Salts: Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling
L'Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M J. Org. Chem. 2010, 75, 3401-3411
This article is available for free through the ACS AuthorChoice Program.

October 2, 2009, Organic Letters
Aminodifluorosulfinium Tetrafluoroborate Salts as Stable and Crystalline Deoxofluorinating Reagents
Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L'Heureux, A. Org. Lett. 2009, 11, 5052-5053.
This article is available for free through the ACS AuthorChoice Program.

Patents:

U.S. Patent No.: US 8,680,332 B2

Chinese Patent No.: CN 102482209 B

Disubstituted-Aminodifluorosulfinium Salts, Process for Preparing Same and Method of Use as Deoxofluorination Reagents
US Provisional Patent Application 61/218,592


European Patent No.: EP 2443087 B1

Canadian patent No.: CA 2764241 C
XtalFluor® Reagents get Coverage in the Media and Scientific Community
Since their introduction on the market in 2009, several articles have been published about the XtalFluor-E® and XtalFluor-M®. These new reagents have already retained the attention among the scientific community due to their potential in the fluorination industry.

November 19, 2010, ACS Publications, Organic Process Research & Development, Highlights from the Literature
XtalFluor® Salts are once again among the recent Highlights from the Literature in the latest published issue of Organic Process Research & Development.
Safety Notables: Information from the Literature
Barnhart, R.; Ironside, D. M.; Vogt, F.P. Org. Process Res. Dev. 2010, 14, 1480-1484
This article is available online through the ACS Publications.

October 1, 2010, Aldrich ChemFiles, Volume 10, Number 3
ChemFiles is a FREE quarterly newsletter written by Sigma-Aldrich experts within their Product Management and R&D team. XtalFluor® Deoxofluorination Reagent makes the cover page of their recent newsletter in addition to being among the latest products presented by these experts.
XtalFluor-E® and XtalFluor-M®: Convenient, Crystalline Deoxofluorination Reagents
Ryba,T. (2010). Aldrich ChemFiles. Volume 10, Number 3. Synthetic Reagents. XtalFluor-E® and XtalFluor-M®: Convenient, Crystalline Deoxofluorination Reagents.

September 13, 2010, Issue 17, Chemistry & Industry Magazine, Cover Story
C&I Magazine has recently published an article entitled "Simple fluorine chemistry" as cover story in their September 13th issue. This article describes the partnership between OmegaChem, Manchester Organics and Sigma-Aldrich in the development of the newXtalFluor® fluorinating reagents that put safety first and deliver results.
Simple fluorine chemistry
Bennett, C.; Clayton,S.; Tovell, D. (2010). C&I Magazine. Cover Story. Issue 17. September 13, 2012. Simple fluorine chemistry.

September 1, 2010, ACS Publications, Organic Process Research and Development, Highlights from the Literature
In this publication, the new XtalFluor® Reagents with Enhanced Thermal Stability and Ease of Handling are among the recent Highlights from the Literature.
Some Items of Interest to Process R&D Chemists and Engineers
McLaughlin, M; Rubio, S. G.; Wilson, I.; Zhao, W.; Laird, T.; Zlota, A. Org. Process Res. Dev. 2010, ASAP.
This article is available online through the ACS Publications.

June 7, 2010, American Chemical Society, Noteworthy Chemistry
The benefits XtalFluor® Reagents are highlighted in an article available online through the ACS website.
Aminodifluorosulfinium salts are improved fluorination reagents
American Chemical Society. (2010). Noteworthy Chemistry. June 7, 2010. Aminodifluorosulfinium salts are improved fluorination reagents.

May 26, 2010, ACS Publications, Organic Process Research and Development
In these articles written by several authors, XtalFluor-E®andXtalFluor-M® are among the Green Chemistry Highlights.
Green Chemistry Articles of interest to the Pharmaceutical Industry
Andrews, I.; Cui, J.; Dudin, L.; Dunn, P.; Hayler, J.; Hinkley, B.; Hughes, D.; Kaptein, B.; Lorenz, K.; Mathew, S.; Rammeloo, T.; Wang, L.; Wells, A.; White, D. T. Org. Process Res. Dev. 2010, 14, 770.
These articles can be accessed online through ACS Publications.

April 28, 2010, Chemical & Engineering News
The multiple benefits of XtalFluor® Reagents for the pharmaceutical and agrochemical industries have been first reported in an article written by Stephen K. Ritter on the C&EN website.
Deoxofluorination Reagents Proliferate
Ritter, K. S. (2010). Chemical & Engineering News. Latest News. April 28, 2010. Deoxofluorination Reagents Proliferate.
The article was then published in the May edition of the C&EN magazine: C&EN, Vol.88, No.18, pp.34-35

November, 2009, Scientific Update
Scientific Update was the first to cover the XtalFluor® reagents discovery in November 2009.
New Deoxofluorination Reagent
Scientific Update (2009). NewDeoxofluorination Reagent. Issue 32, November 2009.

General fluorination procedures using Xtalfluor® reagents

General Procedure A (XtalFluor®, TEA∙3HF, CH2Cl2)
To a cold solution of triethylamine trihydrofluoride (2.0 mmol) in CH2Cl2 (3.0 ml) is added XtalFluor-E® or XtalFluor –M® (1.5 mmol) followed by the substrate (1.0 mmol). After 30 min of stirring under nitrogen, the reaction mixture is allowed to warm to room temperature. Upon reaction completion, the reaction mixture is quenched at room temperature with a 5% aqueous NaHCO3 solution, stirred for 15 min, and the resulting mixture is extracted twice using CH2Cl2. The organic phases are combined, dried over MgSO4 and filtered. Solvents are evaporated and the resulting crude material is purified by standard methods.

General Procedure B (XtalFluor®, TEA∙2HF, CH2Cl2)
To a cold solution of triethylamine trihydrofluoride (2.0 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (3.0 ml) is added XtalFluor-E® or XtalFluor –M® (1.5 mmol) followed by the substrate (1.0 mmol). After 30 min of stirring under nitrogen, the reaction mixture is allowed to warm to room temperature. Upon reaction completion, the reaction mixture is quenched at room temperature with a 5% aqueous NaHCO3 solution, stirred for 15 min, and the resulting mixture is extracted twice using CH2Cl2 . The organic phases are combined, dried over MgSO4 and filtered. Solvents are evaporated and the resulting crude material is purified by standard methods.

General Procedure C (XtalFluor®, TEA∙3HF, DCE, reflux)
To a solution of triethylamine trihydrofluoride (1.0 mmol) in 1,2-dichloroethane (2.0 ml) are added XtalFluor-E® or XtalFluor-M® (1.5 mmol) followed by the substrate (1.0 mmol), and the reaction mixture is heated to reflux. Upon reaction completion, the reaction mixture is quenched at room temperature with a 5% aqueous NaHCO3 solution, stirred for 15 min, and the resulting mixture is extracted twice using CH2Cl2 . The organic phases are combined, dried over MgSO4 and filtered. Solvents are evaporated and the resulting crude material is purified by standard methods.

General Procedure D (XtalFluor®, DBU, CH2Cl2)
To a cold solution of substrate (1.0 mmol) and DBU (1.5 mmol) in CH2Cl2 (3.0 ml) is added XtalFluor-E ®or XtalFluor-M® (1.5 mmol). After 30 min of stirring under nitrogen, the reaction mixture is allowed to warm to room temperature. Upon reaction completion, the reaction mixture is quenched with a 5% aqueous NaHCO3 solution, stirred for 15 min, and the resulting mixture is extracted twice using CH2Cl2. The organic phases are combined, dried over MgSO4 and filtered. Solvents are evaporated and the resulting crude material is purified by standard methods.

Which procedure to choose:

3HF∙TEA is a good place to start (Procedure A). If conversion is problematic, 2HF∙TEA is a more reactive promoter (Procedure B). If 3HF∙TEA provides less elimination by-product than 2HF∙TEA but fails to complete, then use 3HF∙TEA in refluxing DCE (Procedure C). DBU is a good promoter for acid-sensitive substrates and works only for hydroxyls such as alcohols and carboxylic acids (Procedure D).

Examples:

XtalFluor Reagents Chemistry Examples


Manchester Organics; A Group Company of Navin Fluorine International Limited