Miyaura Borylation Reaction

What Is Miyaura Borylation Reaction?

Miyaura borylation reaction refers to a type of reaction that uses aromatic or alkenyl halides or trifluorosulfonate derivatives to couple with bis(pinacolato)diboron in the presence of palladium catalysts to prepare the corresponding boric acid pinacol esters. Its product is the raw material of another important reaction, Suzuki coupling reaction. This reaction has the characteristics of mild conditions and good functional group tolerance, which to a certain extent makes up for the shortcomings of using more active Grignard reagents or lithium reagents to prepare such compounds.

• Reagents: Palladium catalyst [such as Pd(PPh₃)₄ or PdCl₂(dppf)]; base [such as potassium acetate (KOAc)] is used to activate the diboron reagent.
• Reactants: Aryl or vinyl halides, diboron reagents [typically bis(pinacolato)diboron (B₂pin₂)].
• Products: Aryl or vinyl boronic esters.
• Reaction type: Formation of C-B bonds.
• Related reactions: Suzuki coupling reaction.
• Experimental tips:
  a) Aromatic halides with functional groups such as ester, cyano, nitro, and carbonyl can be synthesized into the corresponding aromatic boronic acids by this method;
  b) Polar solvents can increase the yield of the reaction;
  c) KOAc and KOPh are more suitable bases for this reaction, and other more alkaline bases are prone to further coupling of the product and reduce the yield;
  d) In addition to B₂pin₂, other boron sources can also be used, such as HBpin.

Fig 1. Miyaura borylation reaction and its mechanism. [1]

Mechanism of Miyaura Borylation

Based on the experimental results, the Miyaura team proposed a possible mechanism for the reaction:

• First, the zero-valent palladium species A generated on site in the system undergoes oxidative addition to the aryl halide to form a divalent palladium species B;
• B then undergoes ligand exchange to generate C;
• C undergoes metal exchange with biboronic acid pinacol ester to generate D;
• D then undergoes isomerization and reduction elimination to generate products and regenerate zero-valent palladium species A, thus completing the catalytic cycle.

Selection and Role of Base

The choice of base in this reaction is crucial: too strong alkalinity will cause the product to undergo Suzuki coupling reaction and reduce the yield. As for the role of the base in this reaction, the author believes that since the Lewis acidity of the raw material biboronic acid pinacol ester is very weak, it will not be activated by the base used, so the base mainly acts by activating the palladium complex generated after ligand exchange (Pd-O is more active than Pd-X) to make it easy to undergo metal exchange with biboronic acid pinacol ester.

In addition, the good affinity of boron atoms is also one of the driving forces for the metal exchange step. Based on the understanding of the role of bases, the Miyaura group successfully developed a one-pot method for preparing 1,3-conjugated dienes from olefin trifluorosulfonate compounds by adding different catalysts and bases at different stages of the reaction.

Application Examples of Miyaura Borylation

• Example 1: Chenrui Fan et al. achieved asymmetric conjugate addition of aryl halides or aryl trifluoromethanesulfonates to electron-deficient olefins through Miyaura borylation and Hayashi-Miyaura conjugate addition. [2]
• Example 2: Sing R. Gurung et al. replaced bis(pinacol)diboron with tetrahydroxydiboron to develop an efficient Miyaura borylation process, which was successfully expanded to 65 kg in a pilot plant. [3]

Fig 2. Synthetic examples via Miyaura borylation reaction.

Related Products

CAS No.	Structure	Product
214360-76-6		3-Hydroxyphenylboronic acid pinacol ester
1003845-08-6		2-Chloropyrimidine-5-boronic acid pinacol ester
1003845-08-6		2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine
864770-82-1		1-N-Boc-3-methyl-indazole-5-boronic acid pinacol ester
303006-90-8		2,2'-(2,5-Difluoro-1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)
945256-29-1		1H-Pyrrolo[2,3-b]pyridine,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
961-29-5		Isoliquiritigenin
1577-18-0		Trans-3-Hexenoic Acid
73183-34-3		Bis(pinacolato)diboron
127-08-2		Potassium acetate
100-67-4		potassium phenolate
72287-26-4		[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
14221-01-3		Tetrakis(triphenylphosphine)palladium(0)
13675-18-8		Tetrahydroxydiboron

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 362-365.
2. Fan, Chenrui, et al. Organic letters, 2019, 21(22), 8888-8892.
3. Gurung, Sing R., et al. Organic Process Research & Development, 2017, 21(1), 65-74.