Suzuki Coupling

Aldrich ChemFiles 2006, 6.2, 10.

Boronate Esters

C–C bond formation via the Suzuki–Miyaura reaction is one of the most powerful and thoroughly explored facets of Pdcatalyzed cross-coupling. The boron-based nucleophiles utilized in this reaction offer distinct advantages over other organometallic coupling reagents. Both boronic acids and boronate esters are highly nucleophilic, exhibit a broad range of functional group tolerance, and are substantially less toxic than heavy metal organometallic reagents such as organotins.

Sigma-Aldrich is pleased to offer the following boronate esters as part of our growing portfolio of reagents used in the Suzuki coupling reaction. Included in this listing are five novel 2- pyridylboronate esters. While most pyridylboronate esters readily undergo hydrolysis, those ligated to N-phenyldiethanolamine are stable reagents amenable to long-term storage. Most importantly, they exhibit high activity in cross-coupling reactions.1

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Potassium Organotrifluoroborates

Boronic acids, boronate esters, and organoboranes have typically been the boron-based reagents of choice in Suzuki–Miyaura crosscoupling reactions. While in many instances these reagents provide suitable results, each has inherent limitations. Organoboranes are limited by their hydroboration method of preparation, and hence suffer from functional group incompatibility. Boronic acids may have indeterminate stoichiometry as a result of partial cyclodehydration, and moreover can be difficult to purify. While boronate esters don’t suffer these drawbacks, they lack atom economy and are more costly.

Potassium organotrifluoroborates are an attractive alternative to other boron-based reagents. The air- and moisture-stable salts are readily accessible by a variety of high-yielding methods. The tractable, crystalline solids are suitable for storage for extended periods of time. The post-reaction byproducts (salts) are readily separated from the desired product. Most importantly, these novel nucleophiles perform as well as boronic acids and esters in cross-coupling and other important reactions. Additionally, the BF3K moiety is compatible with sensitive functional groups and is tolerant to “hostile” reaction conditions such as epoxidation,2 ozonolysis,3 osmylation,3 and metal-halogen exchange (Scheme 28).3 Sigma-Aldrich has partnered with Gary Molander at the University of Pennsylvania in a collaborative effort to provide an array of potassium organotrifluoroborates, thereby expanding the toolbox of available boron reagents.

Scheme 28


Potassium organotrifluoroborates exhibit superb behavior in the Suzuki–Miyaura reaction and provide a powerful method for the construction of important structural motifs including functionalized alkenes and arenes; 1,3-dienes; styrenes; biaryls; and complex heterocyclic natural products.

The Molander group successfully demonstrated facile bond formation between alkyltrifluoroborates and alkenyl triflates (Scheme 29).4 Presence of water was found to be essential, and use of Cs2CO3 was more effective than other bases (e.g., K2CO3, K3PO4, CsOH, NaOAc, or KOH).

Scheme 29


Application of these conditions to the cross-coupling of alkyltrifluoroborates and aryl bromides or triflates gave excellent results, providing access to a myriad of functionalized arenes (Scheme 30).4,5

Scheme 30


The stereospecificity of this reaction is illustrated by cross-coupling of alkene partners, giving synthetically versatile 1,3-dienes (Scheme 31).6 Access to any one of the four possible geometrical isomers is achieved simply by choosing the appropriate trifluoroborate nucleophile and alkenyl bromide.

Scheme 31


Vinylation of arenes by alkenyltrifluoroborates has proven to be a very general reaction. Aryl bromides, iodides, and triflates all perform well, giving functionalized styrene derivatives in good-toexcellent yields (Scheme 32).7,8

Scheme 32


Until recently, biaryl coupling of trifluoroborates was limited to the use of more reactive aryl coupling partners: aryl triflates, iodides, and bromides.9–11 Buchwald et al. were able to assemble sterically-conjested biphenyls using ordinarily unreactive aryl chlorides (Scheme 33).12 This was achieved by the use of S-Phos as a ligand additive to the reaction mixture.

Scheme 33


Kabalka and co-workers have also made headway in the field of biaryl coupling by employing microwave synthesis.13 Use of microwaves dramatically reduced reaction times relative to the thermal reaction. Aryl iodides containing electron-withdrawing groups or electron-donating groups worked equally well (Scheme 34).

Scheme 34


Lastly, the Molander group demonstrated the generality of potassium organotrifluoroborate cross-coupling in the preparation of the salicylate enamide natural product oximidine II (Scheme 35).14 The key ring-closure step utilized an intramolecular C–C bond formation between a potassium styryltrifluoroborate and a 1-bromo-1,3-diene to give the desired macrolide framework.

Scheme 35


In addition to Suzuki–Miyaura cross-coupling, potassium organotrifluoroborates participate in other synthetically useful reactions such as 1,2-addition to aldehydes15 and sulfinimines;16 conjugate addition to enones;15,17 C–N bond formation;18 halogenation;19 and allylation20 (Scheme 36).

Scheme 36


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Materials

     

References

  1. Hodgson, P. B. et al. Tetrahedron Lett. 2004, 45, 685.
  2. Molander, G. A. et al. J. Am. Chem. Soc. 2003, 125, 11148.
  3. Molander, G. A. et al. Unpublished results.
  4. Molander, G. A. et al. Org. Lett. 2001, 3, 393.
  5. Molander, G. A. et al. J. Org. Chem. 2003, 68, 5534.
  6. Molander, G. A. et al. J. Org. Chem. 2005, 70, 3950.
  7. Molander, G. A. et al. Org. Lett. 2002, 4, 107.
  8. Molander, G. A. et al. J. Org. Chem. 2002, 67, 8424.
  9. Molander, G. A. et al. Aldrichimica Acta 2005, 38, 49.
  10. Molander, G. A. et al. Org. Lett. 2002, 4, 1867.
  11. Molander, G. A. et al. J. Org. Chem. 2003, 68, 4302.
  12. Buchwald, S. L. et al. Org. Lett. 2004, 6, 2649.
  13. Kabalka, G. W. et al. Tetrahedron Lett. 2005, 46, 6329.
  14. Molander, G. A. et al. J. Am. Chem. Soc. 2004, 126, 10313.
  15. Batey, R. A. et al. Org. Lett. 1999, 1, 1683.
  16. Batey, R. A. et al. Org. Lett. 2005, 7, 1481.
  17. (a) Genêt, J.-P. et al. Tetrahedron Lett. 2002, 43, 6155; (b) Genêt, J.-P. et al. Eur. J. Org. Chem. 2002, 3552; (c) Genêt, J.-P. et al. J. Org. Chem. 2003, 4313 (d) Feringa, B. L. et al. J. Org. Chem. 2004, 69, 8045.
  18. (a) Batey, R. A. et al. Org. Lett. 2003, 5, 1381; (b) Batey, R. A. et al. Org. Lett. 2003, 5, 4397.
  19. (a) Kabalka, G. W. et al. Organometallics 2004, 23, 4519; (b) Kabalka, G. W. et al. Tetrahedron Lett. 2004, 45, 343; (c) Kabalka, G. W. et al. Tetrahedron Lett. 2004, 45, 1417; (d) Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah, G. A. Synlett 1997, 606.
  20. (a) Batey, R. A. et al. Synthesis 2000, 7, 990; (b) Batey, R. A. et al. Tetrahedron Lett. 1999, 40, 4289; (c) Batey, R. A. et al. Org. Lett. 2002, 4, 3827; (d) Szabó, K. J. et al. Org. Lett. 2005, 7, 689.

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