Org. Synth. 2023, 100, 382-393
DOI: 10.15227/orgsyn.100.0382
Preparation of 4-(5-(p-Tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonyl fluoride (ArSO2F)
Submitted by Lucas Wagner,
1 Clément Ghiazza,
1 and Josep Cornella*
2Checked by Haoqi Zhang, Daniel Kaiser and Nuno Maulide
1. Procedure (Note 1)
4-(5-(p-Tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonyl fluoride (3). A 250 mL Schlenk flask equipped with an oval 2.5 × 1.2 cm Teflon-coated magnetic stirring bar under air atmosphere is charged with magnesium chloride (1.049 g, 11.01 mmol, 1.5 equiv) (Notes 2 and 3), potassium fluoride (2.559 g, 44.01 mmol, 6 equiv) (Notes 3 and 4), Celecoxib (1) (2.800 g, 7.34 mmol, 1 equiv) (Note 5), pyrylium tetrafluoroborate 2 (1.849 g, 11.013 mmol, 1.5 equiv) (Note 6) and anhydrous acetonitrile (45 mL) (Note 7) (Figure 1). The flask is sealed with a glass stopper under an atmosphere of air, and the dark orange mixture is placed into a pre-heated oil bath at 60 ℃ and stirred for 2 h at 700 rpm.
Figure 1. Reaction set up A) before and B) after the addition of acetonitrile (photos provided by submitters)
The oil bath is removed and the resulting brown mixture is allowed to cool down to 20 ℃. Deionized water (36 mL) is added (Figure 2) through a funnel in one portion into the reaction flask. The mixture is stirred at 20 ℃ for 1 h.
Figure 2. Reaction A) before and B) after addition of water (photos provided by submitters)
The mixture is transferred into a 500 mL separatory funnel and diluted with deionized water (70 mL) (Figure 3A). The aqueous layer is extracted with EtOAc (1 x 120 mL then 6 x 50 mL) (Note 8). The combined organic layers are dried over anhydrous sodium sulfate (80 g) (Note 9) and filtered through a 125 mL medium-porosity (size 4) sintered glass filter (Figure 3B), which is rinsed with EtOAc (3 x 50 mL). The dark red filtrate is collected in a 1 L round-bottom flask.
Figure 3. Work up (left). Filtration set up (right) (photos provided by submitters)
Silica gel (7.2 g) (Note 10) is added to the dark red crude organic layer and the latter is concentrated by rotary evaporation (135 mmHg, 40 ℃) to form the solid deposit.
The silica gel for a chromatographic column is prepared by mixing silica gel (100 g) and the eluent system (heptane/EtOAc: 9/1, v/v, 300 mL) in an Erlenmeyer flask, and this slurry is then added to a column (diameter 4.5 cm) and the excess solvent is flushed out. The crude organic product adsorbed on silica gel is dry loaded onto the stationary phase between 2 protective layers of sand.
Fractions are monitored by TLC for the presence of product (Figure 4A), and fraction collection (20 mL fractions) starts immediately (Figure 4B). The desired product is collected in fractions 10 to 25. The fractions containing the pure product are concentrated by rotary evaporation (135 mmHg, 40 ℃) and dried in vacuo (7.5 mmHg, 25 ℃) to afford the title compound 3 (2.32 g, 82%) as a white solid (Notes 11, 12, and 13) (Figure 4C and 4D).
Figure 4. (A) Thin layer chromatography (heptane/EtOAc, 8/2, v/v); (B) Purification set up; (C) Concentrated product in round-bottom flask; (D) Final product (photos provided by submitters)
2. Notes
1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guidelines for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at
https://www.nap.edu/catalog/12654/prudent-practices-in-the-laboratory-handling-and-management-of-chemical. See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at
https://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with
magnesium chloride,
potassium fluoride,
celecoxib 1,
pyrylium tetrafluoroborate 2,
acetonitrile,
ethyl acetate,
iso-hexane,
sodium sulfate and silica gel. When heating a closed vessel, adherence to safety precautions, including the use of a blast shield, is advisable.
2.
Magnesium chloride (98%) was purchased from Sigma-Aldrich and dried under high diffusion pump (10
-3 mmHg) prior its utilization.
3. This hygroscopic reagent is stored in the glovebox after drying for practical reasons. However, other storing techniques can be used to ensure the salt is dry.
4.
Potassium fluoride (99.5%) was purchased from Sigma-Aldrich and dried under high diffusion pump (10
-3 mmHg) prior its utilization.
5. The submitters purchased
celecoxib (
1) from Sigma-Aldrich, and the checkers purchased
1 from TCI. In both cases, the compound was used as received.
6. The submitters used
pyrylium tetrafluoroborate (
2), which was prepared according to a procedure reported in
Organic Syntheses.
3 The checkers performed the 1
st run using
2 (>95%), which was purchased and used as received from Sigma-Aldrich, while the 2
nd run was performed using
2 obtained from the
Organic Syntheses procedure.
37.
Acetonitrile (99.9%, HPLC grade) was supplied by Fisher Scientific and distilled under argon from calcium hydride before use. The solvent was added by syringe.
8. Every organic phase is monitored for the presence of product (
3) by TLC on silica gel (
heptane/
EtOAc: 8/2, v/v, R
f (
3) = 0.6, visualization with UV).
9.
Sodium sulfate, anhydrous was supplied by VWR chemicals.
10. Silica gel (40 - 63 μm) was supplied by VWR chemicals.
11. Analytical data for
4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonyl fluoride (
3) as obtained by the checkers:
1H NMR
pdf (700 MHz, CDCl
3) δ: 7.99 (d,
J = 8.8 Hz, 2H), 7.60 (d,
J = 8.7 Hz, 2H), 7.22 (d,
J = 7.9 Hz, 2H), 7.13 (d,
J = 8.1 Hz, 2H), 6.76 (s, 1H), 2.41 (s, 3H);
13C NMR
pdf (176 MHz, CDCl
3) δ: 145.7, 145.0, 144.9 (q,
J = 39 Hz), 140.3, 132.0 (d,
J = 25 Hz), 130.1, 129.7, 128.9, 125.7, 125.7, 121.0 (q,
J = 269 Hz), 118.8, 107.2 (app. d,
J = 2 Hz), 21.5;
19F NMR
pdf (282 MHz, CDCl
3) δ: 66.38 (s, 1F, -SO
2F), -62.63 (s, 3F, -CF
3); mp 120.5 ℃; HRMS (ESI): calcd. for [M + H
+, C
17H
13F
4N
2O
2S]
+: 385.0629; found: 385.0633. IR (film): 1596, 1471, 1417, 1212, 1136, 786, 629 cm
-1. Purity was determined to be 97.9 wt% by qNMR
pdf using
1,3,5-trimethoxybenzene as an internal standard. Characterization data matched with a previously reported example.
412. A second reaction on the same scale provided 1.98 g (70%) of the identical product with 99% purity.
13. The product is stable for weeks on the bench top under air atmosphere without noticeable decomposition.
Working with Hazardous Chemicals
The procedures in
Organic Syntheses are intended for use only by persons with proper training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at
http://www.nap.edu/catalog.php?record_id=12654). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as published and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Sulfonyl fluorides are highly coveted compounds by practitioners of both medicinal chemistry and chemical biology. Indeed, these compounds are regarded as warheads for many applications as they allow versatile reactivity as electrophilic SuFEx (SulfurVI - Fluoride Exchange) hubs, permitting facile linkage to increase molecular complexity. Importantly, under physiological conditions aryl sulfonyl fluorides are particularly stable towards hydrolysis compared to their chlorinated analogues, thus paving the way for a plethora of applications in biological domains.
In this context, innovative methods to access this class of molecules is at the forefront of reaction development in organofluorine chemistry. Various strategies to access such compounds exist (Figure 5).
5 For example, the direct fluorosulfonylation of aromatic moieties is an appealing process as it permits the direct incorporation of the -SO
2F moiety onto the organic compound. However, these strategies rely on the use of very reactive reagents, which poses difficulties in terms of functional group tolerance and chemoselectivity, and require handling of SO
2F-containing gases (Figure 5, Path A). Other pathways were envisaged such as the oxidative chlorination/fluorination of thiols and disulfides in the presence of an oxygen source, thus affording the sulfonyl fluorides (Figure 5, Path B). Herein, the reactants are introduced in significant excess.
To address these concerns, modern strategies have emerged capitalizing on the use of transition metals, sulfur dioxide or DABSO (solid SO2 surrogate) and an electrophilic fluorine source. (Figure 5, Path C). Finally, a common strategy is the direct exchange between a leaving group and a nucleophilic fluoride on the sulfonyl moiety. For instance, sulfonyl chlorides are particularly attractive as they readily react with simple fluoride sources (Figure 5, Path D). It should be mentioned that sulfonyl chlorides are highly unstable towards hydrolysis, thus prohibiting the widespread use of this strategy.
Figure 5. State-of-the-art for the synthesis of sulfonyl fluorides
Despite many alternatives to incorporate the -SO
2F moiety on simple scaffolds, a lot of work remains for complex and highly functionalized compounds. In the context of late stage functionalization, chemoselective and generalizable strategies are highly desired by practitioners. To this end, our group reported the use of sulfonamides as ideal starting material for the synthesis of sulfonyl fluorides.
4 Indeed, sulfonamides are ubiquitous in complex scaffolds. In addition, they are typically inert solids and bench-stable. As sulfonamides are usually made from the parent sulfonyl chloride or fluoride, one can consider this approach counter-intuitive. However, the chemical stability of sulfonamides enables their incorporation at the early stages of a synthetic route and can be therefore regarded as a masked handle to selectively prepare bio-relevant sulfonyl fluorides (Figure 6).
Figure 6. Synthesis of sulfonyl fluorides from sulphonamides enabled by pyrylium tetrafluoroborate
The key to this strategy is the in situ condensation of primary sulfonamides with a commercially available reagent, namely, pyrylium tetrafluoroborate 2. In the presence of magnesium chloride, the condensation intermediate is converted to the arylsulfonyl chloride, thus releasing pyridine. The latter is finally quenched in the presence of potassium fluoride in water to afford the final sulfonyl fluoride. All these steps occur in one-pot, without any purification of the intermediates. In our previous study, 10 sulfonamide-containing drug analogues have been converted into their corresponding sulfonyl fluorides in moderate to excellent yields thus showcasing the performance and the functional group tolerance of this system in late-stage functionalization contexts.
Appendix
Chemical Abstracts Nomenclature (Registry Number)
Celecoxib (1) (169590-42-5)
Magnesium(II) chloride (7786-30-3)
Potassium fluoride (7789-23-3)
Pyrylium tetrafluoroborate (2) (80279-50-1)
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Josep Cornella (Pep) obtained his Ph.D. in 2012 from Queen Mary University of London (UK), in the group of Prof. Igor Larrosa. He then pursued postdoctoral studies in the groups of Prof. Ruben Martin at the ICIQ (Spain) and Prof. Phil S. Baran at the Scripps Research Institute (USA). In 2017, he was selected by the Max-Planck-Society to create and lead the Laboratory for Sustainable Catalysis at the Max-Planck-Institut für Kohlenforschung (Germany), as a Max Planck Research Group Leader. His work focuses on the development of sustainable catalytic strategies to streamline organic synthesis. |
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Lucas Wagner, born in 1999 in Bochum, completed his apprenticeship in synthetic chemistry in 2021 at the Max-Planck-Institut für Kohlenforschung (Germany). During this time, he worked in the group of Prof. Benjamin List (homogenous catalysis) and in the group of Dr. Josep Cornella (sustainable catalysis), where he is still working as a laboratory technician in the fields of metal catalysis and organic synthesis. |
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Clément Ghiazza obtained his Master´s degree in organic chemistry at the University of Lyon in 2016. He pursued a Ph.D. under the supervision of Dr. Anis Tlili and Dr. Thierry Billard at the same university during which he was involved in the development of new fluoroalkylselenolation methods. Clément is currently holding a postdoctoral fellowship from the Alexander von Humboldt foundation in the group of Dr. Josep Cornella at the Max Planck Institut für Kohlenforschung. Clément was awarded the Dina Surdin prize by the French Chemical Society - Organic Chemistry Division (SCF - DCO) in 2020. |
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Haoqi Zhang received his MSc degree from the University of Vienna, in the group of Prof. Nuno Maulide, in 2020, working on the formation of novel heterocycles though electrophilic umpolung of amides. For his Ph.D. studies, he stayed in the same group, where the focus of his thesis lies on the synthesis of drug candidates and natural product-like structures using challenging cyclization reactions. |
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Daniel Kaiser received his Ph.D. at the University of Vienna in 2018, completing his studies under the supervision of Prof. Nuno Maulide. After a postdoctoral stay with Prof. Varinder K. Aggarwal at the University of Bristol, he returned to Vienna in 2020 to assume a position as senior scientist in the Maulide group. His current research focusses on the chemistry of destabilized carbocations and related high-energy intermediates. |
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