Asymmetric cobalt catalysts for hydroboration of 1,1-disubstituted alkenes

Abstract

Chiral iminopyridine oxazoline (IPO) ligands were designed, synthesized and utilized for the first cobalt-catalyzed highly regio- and enantioselective anti-Markovnikov hydroboration of 1,1-disubstituted aryl alkenes. These novel IPO ligands will likely be of high value for asymmetric transformations with first-row transition metals.

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Introduction

Asymmetric hydroboration of alkenes is one of the most useful methods to form chiral alkylboronic acid derivatives, which are widely used in organic synthesis.¹ Hydroboration of terminal alkenes catalyzed by chiral transition metals favors Markovinov regioselectivity.² Catalytic asymmetric anti-Markovnikov hydroboration of 1,1-disubstituted alkenes remains a challenge.³ Low enantioselectivity and in some cases poor regioselectivity were obtained through Rh- and Ir-catalyzed reactions of 1,1-disubstituted alkenes with catecholborane.⁴ Recently, two catalytic systems, Iridium with chiral PN-ligand⁵ and copper with chiral NHC ligand,⁶ were reported which realized asymmetric hydroboration of 1,1-disubstituted alkenes. However, a noble transition metal was used, or B₂(pin)₂ was used which provides more waste. A few cases showed high enantioselectivity (≥90% ee). To the best of our knowledge,⁷ there is no previous report on asymmetric cobalt-catalyzed anti-Markovnikov hydroboration of 1,1-disubtituted alkenes.⁸

Noble metals play a very important role in asymmetric organic transformations in academia and industry, such as in the asymmetric hydrogenation of alkenes,⁹ however, earth-abundant metal catalysts often react via one-electron processes, which are limited to certain type of reactions. Redox-active ligands, which have been studied for their spectroscopic properties, might provide the possibility for earth-abundant metals to go through two-electron redox processes to promote bond-breaking and making events.¹⁰ The asymmetric applications of redox-active ligands are extremely rare. Recently, the Chirik group reported a highly enantioselective hydrogenation of alkenes¹¹ using C₁-symmetric bis(imino)pyridine cobalt complexes,¹² which shows that the use of a chiral redox-active ligand gives a potential good class of catalysts for asymmetric organic synthesis, however, the chiral imine on the catalyst is not stable and is easily removed. Based on bi(imino)pyridine ligands, we introduced chiral oxazoline units as stereodirecting element¹³ and designed the new iminopyridine oxazoline (IPO) cobalt complexes, in which the iminopyridine group is proposed to stabilize the cobalt and chiral oxazoline group to control the enantioselectivity (Scheme 1).

Scheme 1 Design and synthesis of chiral redox-active cobalt complexes. (a) (S)-Aminoalcohol, Zn(OTf)₂, toluene, reflux, 70–93% yield; (b) nBuLi, Et₂O, −78 °C. 2 h, then DMA, 35–40% yield; (c) 2,6-diisopropylaniline, cat. HCOOH, MeOH, reflux, 24 h, 32–41% yield; (d) CoCl₂, THF, rt, then Et₂O, 86–95% yield.

Herein we report the synthesis of a series of chiral IPO ligands from commercially available starting materials (Scheme 1). The cobalt complexes 2 could be synthesized by combining cobalt dichloride with the corresponding ligands and are bench-stable.

Results and discussion

We chose the hydroboration of styrene 6a with HBpin as our model reaction to test the reactivity of our designed chiral cobalt complexes (IPO-CoCl₂). Using only 0.5 mol% cobalt complex and 1.5 mol% of NaHBEt₃ (1 M in THF solution) as the reductant without any additive solvent, high reactivity and regio- and enantioselectivities were observed in all cases among which complex 2c gave the best yield and highest enantioselectivity (Scheme 2). The reaction was really slow using 1c with iridium catalyst, which might illustrate that IPO ligands work better with first-row transition metals than with late-transition metals. Poor reactivities were achieved when using the bisoxazoline ligand instead of IPO ligands which led us to propose that the iminopyridine group is stabilizing the cobalt.

Scheme 2 Optimizations.

With the best complex (2c) in hand, studies exploring the scope of this process are summarized in Chart 1. The reactions were operated using a Schlenk line at 2.5 mmol scale, not necessarily in a glove box. (1) The reaction showed high enantioselectivities with a variety of substituted α-methyl styrenes, including both electron-rich and electron-deficient styrene compounds; (2) Halides and protected heteroatoms can be tolerated at the para, meta and ortho-positions on the aryl rings; (3) Although slightly low ee’s were observed in the reaction of ortho-substituted styrenes, high yields were obtained; (4) Long alkyl chains at the α-position of styrenes, even with functionalized alkyl chains, were tolerated to prepare the corresponding hydroboration products with high enantioselectivities; (5) A cyclic styrene with terminal alkene was also reactive to afford 7ab in a slightly lower yield with 95% ee; (6) Gratifyingly, 1,1-dialkyl substituted alkenes 6ac and 6ad also participated in this reaction to give the desired hydroboration products in 72% yield with 33% ee and 70% ee, respectively.

Chart 1 Asymmetric anti-Markovnikov hydroboration of alkenes.^{a a} Standard conditions: unless otherwise noted, 6 (2.5 mmol), HBPin (2.5 mmol), 2c (0.5 mol%), NaBHEt₃ (1.5 mol%) at room temperature for 1 h; ^b 2 mol% 2c; ^c toluene (0.5 mL). ^d 1 mol% 2c; ^e 5 mol% 2c.

The compounds 7c and 7w can be easily oxidized and further derivatized¹⁴ to (R)-naproxen and (R)-ibuprofen, which are well-known non-steroial anti-inflammatory and analgesic drugs¹⁵ (Scheme 3).

Scheme 3 Further derivatizations.

Conclusions

In conclusion, we have developed a novel iminopyridine oxazoline cobalt-catalyzed highly enantioselective and regioselective anti-Markovnikov hydroboration of 1,1-disubstituted alkenes with hydroborate. A series of useful highly enantiopure borate compounds were easily synthesized from the simple alkenes without any directing group. Current efforts in our lab are underway to explore the applications of IPO ligands in asymmetric reactions.

Acknowledgements

Financial support was provided by the “Thousand Youth Talents Plan”, the Fundamental Research Funds for the Central Universities (2013QNA3022), the Starting Funds from Zhejiang University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00295d

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