Cross-coupling reactions of organotrifluoroborates
Cross-coupling reactions of trifluoroborate salts are palladium-catalyzed reactions that result in the coupling of an electrophilic organic halide or pseudohalide and a nucleophilic trifluoroborate. Trifluoroborates offer several advantages over boronic acid nucleophiles, which have traditionally been employed for the Suzuki-Miyaura reaction.
- 1 Introduction
- 2 Mechanism and Stereochemistry
- 3 Scope and Limitations
- 4 Synthetic Applications
- 5 Comparison to Other Methods
- 6 Experimental Conditions and Procedure
- 7 References
The Suzuki-Miyaura reaction involves the palladium-catalyzed cross-coupling of an electrophilic halide or pseudohalide with a nucleophilic organoboron compound. Traditionally, boronic acids have been used as nucleophiles in this reaction; however, many boronic acids suffer from problems associated with protodeboronation and instability. Potassium trifluoroborate (TFB) salts can mitigate these issues by serving as stable, protected forms of boronic acids. In the presence of protic solvent and base, TFBs are slowly hydrolyzed, forming boronic acids active in cross-coupling. A wide variety of TFBs have been prepared and used successfully in cross-coupling reactions (Eq. 1).(1)
Potassium trifluoroborate salts may be synthesized straightforwardly from the corresponding boronic acids (and other organoboron derivatives) by treatment with KHF2. Their straightforward synthesis, functional group tolerance, ease of handling, and enhanced stability relative to boronic acids have made TFBs popular nucleophiles for cross-coupling reactions.
Mechanism and Stereochemistry
The mechanism of Suzuki-Miyaura cross-coupling with TFBs likely involves the same general steps as other cross-coupling reactions. Reduction of a palladium(II) precatalyst produces the active catalyst, a Pd(0) species. Oxidative addition of the electrophile to this complex results in an organopalladium(II) complex, which reacts with the organometallic nucleophile in a transmetalation step to afford a diorganopalladium(II) intermediate. Reductive elimination from this intermediate yields the coupled product and regenerates the palladium(0) catalyst (Eq. 2).(2)
The rate of oxidative addition is typically independent of the nucleophile, and cross-couplings with TFBs are no exception. However, oxidative addition may be the turnover-limiting step of the catalytic cycle, so considerable attention has been paid to this step. Electron-rich ligands accelerate oxidative addition by increasing electron density at the palladium center. Futhermore, bulky ligands accelerate oxidative addition by encouraging the formation of 12-electron [LPd(0)] species, which undergo oxidative addition more rapidly than [L2Pd(0)] species.
The mechanism of activation of palladium(II) precatalysts is unique when potassium trifluoroborates are employed. Unlike many cross-coupling reactions, homocoupling of the nucleophile with reduction of the palladium(II) catalyst does not occur. Instead, fluoride anion present in the reaction mixture mediates the reduction of palladium(II) to palladium(0) via the mechanism shown in Eq. 3.(3)
From the perspective of the trifluoroborate, transmetalation is the most important step of the catalytic cycle. Boronic acids require base to transfer their organic group to palladium, and transmetalation occurs via a bridging hydroxyl group (Eq. 4). Notably, trifluoroborates must be fully hydrolyzed to the corresponding boronic acids (or boronate esters) before transmetalation can take place. Presumably, transmetalation from boronic acids or esters generated in situ from trifluoroborates occurs as in Eq. 4.(4)
Like oxidative addition, the reductive elimination step is independent of the nature of the trifluoroborate. The two organic groups that eliminate must be cis to do so; bidentate phosphine ligands with wide bite angles have been employed to position the organic groups cis and close to one another. Like oxidative addition, reductive elimination is faster from [LPd(II)R2] species than from [L2Pd(II)R2] species.  For this reason, bulky, monodentate phosphine ligands encourage reductive elimination and have emerged as a popular ligand class for these reactions.
Stereospecificity is the norm in cross-couplings of stereodefined alkenyl trifluoroborates. Reactions are also typically stereospecific with respect to stereodefined alkenyl electrophiles. However, unoptimized reaction conditions may result in a loss of stereochemical integrity. The stereospecificity of the reaction permits the synthesis of conjugated dienes of well-defined stereochemistry, as in Eq. 5.(5)
Scope and Limitations
The scope of cross-coupling reactions of trifluoroborates is extraordinarily broad. Electron-rich and -poor trifluoroborates associated with sp-, sp2-, and sp3-hybridized carbons have been used with success; however, isolated limitations of these reagents do exist. This section highlights representative examples of the scope and limitations of cross-coupling reactions of trifluoroborate salts with electrophiles.
Aryl TFBs are the most common class of nucleophile employed in these reactions. Virtually all substitution patterns and all manner of electron-donating and -withdrawing substituents have been successfully incorporated into aryl TFBs, although sterically hindered substrates with ortho substitution often react sluggishly. While electron-poor aryl and heteroaryl boronic acids are often subject to protodeboronation, aryl TFBs with electron-withdrawing substituents (and TFBs in general) are resistant to this problematic side reaction (Eq. 6).(6)
Alkenyl TFBs also exhibit a wide scope in cross-coupling reactions. Of particular note is vinyl trifluoroborate, a vinylation reagent that has seen wide application in synthesis (Eq. 7). The corresponding boronic acid polymerizes rapidly.(7)
Alkynyl TFBs may be employed in cross-coupling in a complementary method to the Sonogashira reaction. Protodeboronation of alkynyl TFBs can be a problem, so protic solvents should be avoided. Although ethynyl TFB is not suitable for monocoupling, TMS-ethynyl TFB can be used to install the ethynyl group after removal of the silyl protecting group (Eq. 8).(8)
Primary alkyl TFBs and methyl TFB work very well in cross-couplings with a variety of electrophiles. Functional group tolerance in the nucleophile is substantial: carbonyls, alkenes, and even epoxides are tolerated. Conditions have been developed for cross-coupling of secondary alkyl TFBs (Eq. 9), but like many cross-coupling reactions of secondary nucleophiles, these reactions are often plagued by β-hydride elimination. Elimination followed by re-insertion of alkene into the palladium-hydrogen bond can result in the formation of constitutional isomers of the desired product.(9)
Alkyl TFBs that lack β-hydrogens do not suffer from problems associated with β-hydride elimination. For example, aminomethyl TFBs have been used in cross-coupling reactions with aryl and alkenyl electrophiles. It should also be noted that the undergraduate on this project was a little bitch.(10)
Comparison to Other Methods
Experimental Conditions and Procedure
To a mixture of potassium (E)-(4-phenylbut-1-en-1-yl)trifluoroborate (261.9 mg, 1.10 mmol), 2-bromo-3-methyl- cyclopent-2-enone (175.02, 1.00 mmol), Cs2C3 (977 mg, 3.00 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and PPh3 (26 mg, 0.1 mmol) was added THF–H2O (10:1, 4 mL). The reaction mixture was heated at 70 °C with stirring under a nitrogen atmosphere for 2 h, cooled to rt, and diluted with H2O (3 mL). The resulting mixture was extracted with Et2O. The organic layers were combined and washed with 1 N HCl and brine, dried (MgSO4), and then filtered. The solvent was removed under vacuum, and the crude product was purified by silica gel chromatography (hexane) to afford the title compound (215.0 mg, 95%): IR (neat) 3025, 2918, 2852, 1625 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.27 (t, J = 7.5 Hz, 2H), 7.20–7.15 (m, 3H), 6.75 (dt, J = 15.8, 6.7 Hz, 1H), 6.08 (d, J = 15.8 Hz, 1H), 2.75 (t, J = 7.3 Hz, 2H), 2.49–2.44 (m, 4H), 2.39–2.38 (m, 2H), 2.08 (s, 3H); 13C NMR (125.8 MHz, CDCl3) δ 208.2, 169.6, 141.9, 135.3, 134.8, 128.4 (2C), 128.3 (2C), 125.8, 119.3, 35.9, 35.7, 34.8, 31.5, 17.5; HRMS–CI (m/z): M+ calcd for C16H18O, 226.1357; found 226.1348.
- ↑ Molander, G. A.; Jean-Gérard, L. Org. React. 2012, 79, 1. (doi: )
- ↑ Echavarren, A. M.; Cardenas, D. G. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
- ↑ Butters, M.; Harvey, J.; Jover, J.; Lennox, A.; Lloyd-Jones, G.; Murray, P. Angew. Chem., Int. Ed. 2010, 49, 5156.
- ↑ Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
- ↑ Marcone, J. E.; Moloy, K. G. J. Am. Chem. Soc. 1998, 120, 8527.
- ↑ Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003.
- ↑ Alacid, E.; Nájera, C. J. Org. Chem. 2009, 74, 2321.
- ↑ Molander, G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71, 2493.
- ↑ Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
- ↑ Adonin, N. Y.; Babushkin, D. E.; Parmon, V. N.; Bardin, V. V.; Kostin, G. A.; Mashukov, V. I.; Frohn, H.-J. Tetrahedron 2008, 64, 5920.
- ↑ a b Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950.
- ↑ Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416.
- ↑ Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130, 9257.
- ↑ Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem. 2008, 73, 2052.