Abstract
Boronic acids which quickly deboronate under basic conditions, such as polyfluorophenylboronic acid and five-membered 2-heteroaromatic boronic acids, are especially challenging coupling partners for Suzuki-Miyaura reactions. Nevertheless, being able to use these substrates is highly desirable for a number of applications. Having found that monodentate biarylphosphine ligands can promote these coupling processes, we developed a precatalyst that forms the catalytically active species under conditions where boronic acid decomposition is slow. With this precatalyst, Suzuki-Miyaura reactions of a wide range of (hetero)aryl chlorides, bromides, and triflates with polyfluorophenyl, 2-furan, 2-thiophene and 2-pyrroleboronic acids and their analogs proceed at room temperature or 40 °C in short reaction times to give the desired products in excellent yields.
The Suzuki-Miyaura cross-coupling (SMC) reaction is arguably the most important and widely used method for the construction of sp2-sp2 carbon-carbon bonds.1 However, since SMCs are typically performed at elevated temperatures and require several hours reaction time, the scope of usable boronic acids is limited to those that do not significantly decompose under standard conditions. Consequently, the SMCs of quickly deboronating2 2,6-difluorophenylboronic acid (1) and analog 2 as well as the SMCs of five-membered 2-heterocyclic boronic acids 3–8 (Chart 1) are problematic.3,4,5,6 Being able to couple these boronic acids with functionalized aryl and heteroaryl substrates would be of great interest for the synthesis of pharmaceutical and agrochemical candidates, natural products, and materials.
Chart 1.
Boronic acids that easily undergo protodeboronation in aqueous base to give the parent arene.
One viable solution to this problem is the masking of the boronic acids as MIDA boronates,7 cyclic triolborates,8 or trifluoroborate salts9,10 which slowly hydrolyze11 to the free boronic acid under the reaction conditions. The ratio of the concentration of catalyst and the boronic acid is relatively high and, as a result, transmetalation is favored over protodeboronation. Nevertheless, these surrogates are typically prepared from the free boronic acids, and often, high palladium loadings and/or long reaction times are required for efficient coupling. Another solution, albeit limited to aryl bromides and iodides, allows the coupling of 2 and pentafluorophenylboronic acid by using stoichiometric amounts of Ag2O in addition to the palladium catalyst.12,13
Herein, we report the fast and efficient SMC of the free boronic acids 1–8 at room temperature or 40 °C in short reaction times of 30 minutes to 2 hours. Key to the success was the development of a new precatalyst that generates the catalytically active LPd(0) species quickly under mild conditions under which the deboronation of the boronic acid is significantly slowed down.
In the course of mechanistic investigations, we prepared complex SPhosPdPhCl (9) that results from oxidative addition of SPhosPd(0) with chlorobenzene,14 and treated it with 1 in the presence of aqueous K3PO4 (Scheme 1). Rapid formation of product 10 demonstrated that transmetalation and reductive elimination occur with 1 at room temperature.15
Scheme 1.
Initial observation of the coupling of 1 with a stoichiometric amount of an oxidative-addition complex 9.
Using 2 mol% of 9 as precatalyst, 4-chloroanisole was coupled with 1 to give the desired product in 93% yield in less than 30 minutes using a 1:2 mixture of THF and 0.5 M aqueous K3PO4. Kinetics studies showed that product formation stopped abruptly, indicating that the remainder of 1 was consumed by competing base- and/or metal-catalyzed deboronation.2 Increasing the temperature resulted in a lower conversion. However, full conversion of 4-chloroanisole at room temperature was achieved by using the oxidative-addition complex 11 in which the SPhos ligand is replaced by XPhos (Chart 2).
Chart 2.
XPhos-containing precatalysts used in this study.
The syntheses of complexes 9 and 11 are difficult, and their use as precatalysts for the SMC of 1 with any aryl halide necessarily results in the formation of biaryl 10 in addition to the desired product. The preparation and isolation of an individual oxidative-addition complex for each substrate is clearly impractical and often impossible. Because using Pd(OAc)2 or Pd(dba)2 with XPhos gave unsatisfactory results, we sought another solution to provide the catalytically active XPhosPd(0) species which undergoes oxidative addition in situ.
Previously, we developed precatalyst 12 which, upon deprotonation by a base, forms XPhosPd(0) and indoline via C-N reductive elimination.16 While it is an excellent source of the catalytically active Pd species, its activation with weak bases is slow and occurs only at elevated temperatures. Moreover, its synthesis requires several steps. In the process of addressing these issues, we found that both drawbacks could be overcome with a new class of precatalysts where the parent aliphatic amine in 12 is replaced by 2-aminobiphenyl in 13: First, the higher acidity of the palladium-bound aromatic amine compared to the aliphatic amine allows activation of 13 to occur almost instantaneously with weak base at room temperature. Second, 13 is easily obtained in a one-pot procedure by combining Pd(OAc)2 with 2-aminobiphenyl, followed by addition of LiCl and the ligand (XPhos) (Scheme 2).17
Scheme 2.
Synthesis of precatalyst 13.
For the SMC reaction between 4-chloroanisole and 1 in the presence of aqueous 0.5 M K3PO4 as base, the use of precatalysts 12 and 13 was tested. As expected, only the latter promoted the reaction, leading to full conversion to product.
Initially, several aryl halides or pseudohalides were subjected to the SMC reaction with polyfluorophenylboronic acids. We observed that aryl chlorides, bromides, and triflates are good substrates for the coupling with 1 while only low conversions were observed with aryl iodides18 (Table 1). Substrates with coordinating groups in the ortho position, such as esters or ketones, could also not be coupled efficiently. However, even large non-coordinating ortho substituents, as in 15b, were well tolerated. Heteroaromatic compounds readily underwent the SMC to form the desired products in excellent yields, but five-membered chloro- or bromoheteroarenes with multiple heteroatoms remained problematic.
Table 1.
Coupling of polyfluoroboronic acids to aryl chlorides, bromides, and triflates.a
|
ArX (1 mmol), ArB(OH)2 (1.5 mmol), 13 (2 mol %), degassed THF (2 mL), degassed 0.5 M aq. K3PO4 (4 mL), rt, 30 min; isolated yields, average of two runs.
13 (3 mol%).
Interestingly, we found that while trisubstituted polyfluorophenylboronic acids 2 and 14 could be employed to give products 16 and 17, very low conversion was observed with 2,3,6-trifluorophenylboronic acid. To understand this result, we studied both the deboronation rates19 and apparent transmetalation rates20 of (poly)fluorophenylboronic acids (Table 2). Transmetalation efficiency increases with the number of fluorine substituents, with ortho substitution having the greatest impact. Thus, 1 reacts about 150 times faster than simple phenylboronic acid, and almost 4 times faster than 2-fluorophenylboronic acid. In the series of 1→2→14, the loss in stability is counterbalanced by higher transmetalation rates, thus allowing the coupling of 2 and 14 under essentially the same reaction conditions. In contrast, the coupling of 2,3,6-trifluorophenylboronic acid is more problematic because the deboronation rate is dramatically increased while transmetalation rate does not change relative to 1.21
Table 2.
Deboronation rates and apparent relative transmetalation rates of polyfluorophenylboronic acids.
| Entry | Boronic acid | Deboronation rate, t1/2 (min)a | Relative transmetalation rate, krel |
|---|---|---|---|
| 1 | PhB(OH)2 | 1 | |
| 2 | 2-F | 42 | |
| 3 | 3-F | 2 | |
| 4 | 4-F | 5 | |
| 5 | 2,6-F2 (1) | 28 | 155 |
| 6 | 2,4,6-F3 (2) | 10 | 202 |
| 7 | 2,6-F2-3-OnBu (14) | 6 | 536 |
| 8 | 2,3,6-F3 | 2 | 156 |
Deboronation due to the presence of base was measured via calorimetry at room temperature in a mixture of THF and 0.5 M K3PO4. The values in the column are the half-lives of the observed first-order kinetic profiles.
It is important to note that the coupling of these polyfluorophenylboronic acids proceeds using established ligands (SPhos, XPhos) that exhibited excellent results in other SMC reactions. Thus, the previously reported unsuccessful attempts3 to couple 1 and 2 in the presence of these ligands were not due to their structure, but to the reaction conditions which were necessary to provide the active catalytic species. Using precatalyst 13, the catalytically active XPhosPd(0) species is formed rapidly at room temperature, thereby allowing the successful coupling of these unstable boronic acids.
Next, we turned our attention to heteroaryl boronic acids and found that by using 2 mol% of 13, 2-heterocyclic boronic acids 3–8 could be coupled efficiently with a wide array of aryl and benzyl halides, mostly within 30 minutes at room temperature or 40 °C (Table 3). The higher stability of the 2-heterocyclic boronic acids relative to the polyfluorophenylboronic acids allowed the transformations of challenging substrates that could not be used with the latter. Therefore, performing the reaction at 40 °C for 2 h allowed the conversion of 4- and 5-halopyrazoles, 2-chlorobenzoxindole as well as 2-chloroacetanilide to give the coupled products 19a, 20c, 22b, and 20b in excellent yields.
Table 3.
Coupling of 2- and 3-heterocyclic boronic acids to aryl and benzyl chlorides and aryl bromides.b
|
ArX (1 mmol), ArB(OH)2 (1.5 mmol), 13 (2 mol %), degassed THF (2 mL), degassed 0.5 M aq. K3PO4 (4 mL), rt, or 40 °C, 30 min or 2 h; isolated yields, average of two runs.
The fast generation of XPhosPd(0) from precatalyst 13 is a prerequesite for the successful coupling of unstable boronic acids 1–8, but also increases the rate of reaction for other SMC reactions, as illustrated by the fast coupling of 3-furan and 3-thiopheneboronic acids to give 24 and 25.
In summary, we have developed a procedure for very fast SMC reactions at room temperature or 40 °C that allows the coupling of a wide range of (hetero)aryl halides and triflates with excellent functional group tolerance. The fast catalytic process and the extremely mild reaction conditions make the coupling of unstable polyfluorophenyl and five-membered 2-heterocyclic boronic acids with a wide range of aryl (pseudo)halides possible. The rate increase in comparison to typical SMC reactions relies on fast generation of the catalytically active species from an easy to prepare, air- and moisture-stable precatalyst.
Supplementary Material
Acknowledgement
We thank the NIH for financial support of this project (GM46059) and BASF for a gift of palladium compounds. T.K. thanks the Alexander von Humboldt Foundation for a Feodor Lynen postdoctoral fellowship. We also thank Dr. Jaclyn Henderson for assistence with some experiments. The Varian NMR instrument used was supported by the NSF (grants CHE 9808061 and DBI 9729592).
Footnotes
Supporting Information Available. Complete ref. 4a and 4b, experimental procedures and product characterization. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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