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April 28, 2010

Deoxofluorination Reagents Proliferate

Fluorine Chemistry: New generation of safer compounds will benefit pharmaceuticals and agrochemicals

Stephen K. Ritter

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Image of XtalFluor-E crystals Courtesy of Michel Couturier

A pair of crystalline fluorinating reagents that are easily handled and significantly more stable than the current workhorse reagents they are designed to replace are being reported by a team led by Michel Couturier of Canadian custom chemicals firm OmegaChem (J. Org. Chem., DOI: 10.1021/jo100504x).

Omegachem's XtalFluor-E (crystals shown) and XtalFluor-M, which have [R2N=SF2]+ as the key structural feature, are founding members of a new generation of deoxofluorination reagents. They join Fluolead, a crystalline phenylsulfur trifluoride compound introduced last fall by Denver-based IM&T Research (C&EN, Oct. 12, 2009, page 45).

Deoxofluorination is a key reaction in organic synthesis for converting the hydroxyl group in alcohols to –CH2F and the carbonyl in aldehydes to –CHF2, in ketones to –CF2–, and in carboxylic acids to –COF or –CF3. Currently, (CH3CH2)2NSF3 (DAST) and (CH3OCH2CH2)2NSF3 (Deoxo-Fluor) are the reagents of choice for these transformations.

As liquids, DAST and Deoxo-Fluor are safer than the sulfur tetrafluoride gas they replaced more than a decade ago. But they react vigorously with water and are thermally unstable, which precludes using them in larger scale industrial processes. Hazardous distillation is also required to purify them.

Like Fluolead, the XtalFluor reagents go a step further: They are crystalline solids that don't fume in air, don't react violently with water, and have enhanced thermal stability. In addition, the XtalFluor compounds don't generate free HF as a side product, so regular glassware can be used for handling.

OmegaChem prepares the compounds from DAST derivatives by using BF3 as an irreversible fluoride-ion acceptor to extract fluorine from SF3. When carrying out deoxofluorination reactions, the XtalFluor reagents require DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or an additional fluoride source, such as (CH3CH2)3 N•3HF, to promote reactivity.

Stéphane Caron, director of chemical R&D at Pfizer, lauds the XtalFluor reagents for addressing the shortcomings of DAST and Deoxo-Fluor, given the importance of fluorine in influencing the pharmacokinetics of biologically active molecules. "They provide the opportunity to incorporate deoxofluorination at any point of a synthesis using standard equipment, rather than relying on fluorinated starting materials," he says.

Couturier and coworkers have hit a "grand slam" for deoxofluorinations with their XtalFluor reagents, comments Robert P. Discordia, Bristol-Myers Squibb's group director of process R&D and head of the department's outsourcing efforts. "These compounds have properties that discovery and process chemists desire, including ease of isolation, good yields, and selectivity," Discordia says. "In addition, they don't react violently with water and are storable solids with no shipping restrictions. Add to this that reactions can be run in simple borosilicate glassware, and you have clearly improved deoxofluorinating reagents."

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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