Prof. Marder: Zinc-Catalyzed Borylation of Primary, Secondary and Tertiary Alkyl Halides

Zinc-Catalyzed Borylation of Primary, Secondary and Tertiary Alkyl Halides with Alkoxy Diboron Reagents at Room Temperature

Angew. Chem. Int. Ed. 2014, 53, 1799-1803 and Angew. Chem. 2014, 126, 1829-1834.

Introduction:

Organoboronates are important in medicinal chemistry^[1] and they are often used as synthetic intermediates for transition-metal catalyzed cross-coupling, conjugate addition and many other reactions.^[2] Herein, a simple zinc-catalyzed route to primary, secondary and some tertiary alkylboronates using the diboron(4) reagents B₂pin₂ or B₂neop₂ (pin = pinacolato; neop = neopentaneglycolato) is reported. This follows the first report of any metal catalyzed borylation of alkyl halides, which used a copper catalyst,^[3a] and our report of the Cu-catalyzed borylation of aryl halides.^[3b]

Alkylboronates can be prepared easily by stirring an alkyl halide with a catalyst comprising ZnCl₂ and the readily available N-heterocyclic carbene (NHC) ligand IMes (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), in the presence of a commercially available diboron(4) reagent and an appropriate base (either KO^tBu or KOMe) in MTBE (MeO^tBu) as the solvent at room temperature.

Scope:

1- Borylation of primary alkyl halides:

Primary alkyl halides having different functional groups such as ether, ketal, ester, cyano and alcohol groups were converted to the corresponding alkylboronates in good yields, in the presence of a Zn-catalyst at room temperature (Scheme 1).

2- Borylation of secondary alkyl halides:

As illustrated in Scheme 2, unactivated secondary alkyl halides can be smoothly borylated to provide the desired alkylboronates in excellent yields.

3- Borylation of tertiary alkyl halides:

In addition to primary and secondary alkyl electrophiles, ZnCl₂/IMescan also catalyzed the borylation of some tertiary alkyl halides. Thus, reactions of 1-bromo and 1,3-dibromoadamantane gave the corresponding mono- and bis- boronates in moderate to good yields (Scheme 3).

Conclusion:

A new catalyst system, incorporating the inexpensive, earth-abundant and extremely low toxicity metal zinc, in the presence of a readily accessible NHC ligand is capable of borylating primary, secondary and even some tertiary alkyl iodides and bromides under mild conditions (room temperature). A related ZnBr₂-NHC catalyst system also borylates aryl halides^[4a] and, most recently, we have shown that ZnCl₂, in the presence of 4,4’-di-^tBu-bipyridine as ligand, borylates both aryl C-X bonds and the C-H bonds adjacent to them.^[4b]