A Highly Efficient Microwave-Assisted Suzuki Coupling Reaction of Aryl Perfluoro-octylsulfonates with Boronic Acids

Abstract

A new strategy to improve the efficiency of Suzuki coupling reactions is introduced by combining fast microwave reaction with easy fluorous separation. Aryl perfluorooctylsulfonates derived from the corresponding phenols are coupled with aryl boronic acids to form biaryls under general microwave conditions. Both intermediates and products are purified by solid-phase extraction over FluoroFlash silica gel. Application of this tagging strategy to multistep synthesis of biaryl substituted hydantoin is also described.

The palladium-catalyzed cross-coupling of aryl halides with aryl boronic acids (Suzuki coupling) is a powerful reaction for the construction of biaryls.¹ Its scope has been extended through the use of aryl triflates (ArOSO₂CF₃) or aryl nonaflates (ArOSO₂(CF₂)₃CF₃) as halide equivalents.2 Aryl perfluoroalkylsulfonates prepared from a wide range of commercially available phenols have shown high reactivity, good stability for room temperature storage, chromatography, and resistance towards hydrolysis.³

Application of Suzuki coupling reactions for parallel and combinatorial synthesis has been explored by conducting the reaction under microwave irradiation⁴ or on solid support⁵ with a linker such as perfluoroalkylsulfonyl.⁶ However, the microwave reaction does not directly address the separation issue, which is usually the bottle-neck of high-throughput synthesis. Microwave-assisted solid-phase reactions have limitations on solvent selection due to resin swelling and thermostability issues.⁷ We report here a new strategy which significantly improves the efficiency of Suzuki coupling reactions by combining fast microwave reaction with easy fluorous separation.

Fluorous synthesis unites the attractive features of solution-phase chemistry with the convenient workup of solid-phase chemistry.⁸ Molecules attached with a perfluoroalkyl “phase tag” can be easily isolated from the reaction mixture by fluorous separation techniques such as fluorous solid-phase extraction (F-SPE).⁹ The fluorous Suzuki coupling reaction employs aryl perfluorooctylsulfonates (ArOSO₂(CF₂)₇CF₃) as precursors. The perfluorooctylsulfonyl group has enough fluorines (17) to serve as a fluorous tag for F-SPE. Recently we reported the use of aryl perfluorooctylsulfonate tag in palladium-mediated cross-coupling reactions for the formation of C-S bond.^10,11 We now extend the application of this fluorous tag to the synthesis of C-C bond of biaryls.

A variety of phenols were converted to the corresponding aryl perfluorooctylsulfonates by reacting with commercially available perfluorooctylsulfonylfluoride under mild conditions, using K₂CO₃ as a base in dimethylformamide (DMF) at 70 °C for 5 h (Scheme 1).¹² The crude aryl perfluorooctylsulfonate 1 has greater than 90% purity and is used directly for the next step reaction. If further purification is needed, this can be accomplished by crystallization from MeOH or by F-SPE purification on FluoroFlash cartridges.¹³ Two F-SPE fractions need to be collected; the first elution with 80:20 MeOH/H₂O contains unreacted phenol and other non-fluorous compounds; the second elution with MeOH contains the desired aryl perfluorooctylsulfonate 1. After F-SPE, the purity is greater than 95% (Figure 1).¹⁴

Scheme 1.

Fluorous Synthesis of Biaryls

Figure 1.

¹H NMR (CDCl₃) of 1a after F-SPE

Suzuki coupling is a substrate dependent reaction, which is reflected by numerous publications on the optimization of catalyst, base, solvent, and other reaction conditions.^1,5 Lack of a general procedure suitable for a broad range of substrates limits the application of Suzuki reactions in high-throughput synthesis. As a powerful and easily controllable heating source, microwave irradiation can generate more consistent results than the conventional heating source.⁴ In our development of fluorous Suzuki coupling reactions, a literature procedure¹⁵ for the coupling of triflates was adapted for the reaction of aryl perfluorooctylsulfonates.¹⁶ Thus, we used [Pd(dppf)Cl₂] (dppf = 1,1’-bis(dipenylphospanyl)ferrocene) as a catalyst, K₂CO₃ as a base, and 4:4:1 toluene/acetone/H₂O as a co-solvent. The reactions were conducted in a sealed-tube under single-mode microwave irradiation at 100–130°C for 10 min. This general condition is compatible with a range of functionalized aryl perfluorooctylsulfonates such as methoxy, aldehyde, ketone, and heterocyclic groups. It is also compatible with a broad range of boronic acids including sterically hindered ortho-isopropoxy substituted boronic acid and electron-deficient 3,4-dichlorophenylboronic acid (Table 1).¹⁷ The purification of the final product is straightforward; the organic layer of the reaction mixture was directly loaded onto a FluoroFlash SPE cartridge. The biaryl product was collected in the fraction of 80:20 MeOH/H₂O, while the cleaved fluorous tag remained on the cartridge until the wash with MeOH was done. To avoid the other organic component to co-eluting in the MeOH/H₂O fraction, the boronic acid was used as the limiting agent (~0.95 equiv.). After F-SPE, biaryl compounds were isolated in 75–95% yields with purity greater than 90%.¹⁴ No detectable amount of dppf ligand was observed by ¹H NMR analysis.¹⁸

Table 1.

Structures and Yields of Biaryls

entry	aryl perfluorooctylsulfonate1		boronic acid	biaryl 2		yield
1		1a			2a	90%
2		la			2b	89%
3		1a			2c	93%
4		1a			2d	87%
5		1a			2e	87%
6		1b			2f	95%
7		1b			2g	75%
8		1b			2h	78%
9		1c			2i	95%
10		1c			2j	88%
11		1d			2k	81%

We also demonstrated the use of the fluorous sulfonyl tag in multistep synthesis of a biaryl substituted hydantoin 7 (Scheme 2). The hydroxyl group of 4-hydroxybenzaldehyde was protected by converting it to a fluorous sulfonate. The tagged benzaldehyde 3 underwent a reductive amination reaction. The resulting amine 4 was treated with an isocyanate to form urea 5, which spontaneously cyclized to form hydantoin 6. In the last step, the fluorous sulfonyl group was detagged by the Suzuki coupling reaction to form the C-C bond of biaryl 7. The efficiency of this multistep synthesis is facilitated by easy F-SPE purification of the reaction intermediates 4 and 6. The perfluorosulfonyl tag has been demonstrated to be tolerant to reductive amination and isocyanate reactions. The tagged intermediates were also found to be stable during F-SPE separations.

Scheme 2.

Fluorous Synthesis of Biaryl-Substituted Hydantoin 7

In this fluorous multistep synthesis, the tagging is accomplished at the phenol derivatization and the detagging at the Suzuki cross-coupling step. No synthetic steps are added just for the sake of putting in and taking off the fluorous tag. In addition to simplifying the intermediate purification, the perfluorosulfonyl group has the functions of protecting the hydroxyl group in the early steps and activating the phenol for cross-coupling at the last step. The high solubility of aryl perfluorooctylsulfonates in common organic solvents and high thermostability of the perfluorosulfonyl tag render the fluorous molecules good substrates for solution-phase microwave reactions. Other than formation of C-C and C-S bonds, the perfluorooctylsulfonate moiety is amenable to other kinds of cross-coupling reactions to form C-H, C-N, C-O, C-P, and C-CN bonds. We believe this readily available, highly efficient, and synthetically versatile fluorous tag will have broad applications in solution-phase parallel and combinatorial syntheses.