Copper‐Catalyzed Enantioselective Markovnikov Protoboration of α‐Olefins Enabled by a Buttressed N‐Heterocyclic Carbene Ligand

Abstract

Reported is ah ighly enantioselective copper-catalyzed Markovnikovp rotoboration of unactivated terminal alkenes.Avariety of simple and abundant feedstock a-olefins bearing ad iverse arrayo ff unctional groups and heterocyclic substituents can be used as substrates,a nd the reaction proceeds under mild reaction conditions at ambient temperature to provideexpedient access to enantioenriched alkylboronic esters in good regioselectivity and with excellent enantiocontrol. Critical to the success of the protocol was the development and application of an ovel, sterically hindered N-heterocyclic carbene,( R,R,R,R)-ANIPE, as the ligand for copper.The asymmetric hydro-and protoboration of alkenes has long been recognized as an important stereoselective transformation in chemical synthesis. [1] Thep reparative value of this transformation stems from its conversion of widely available alkenes into synthetically versatile enantioenriched alkyl boronates under generally mild reaction conditions.The C À Bb onds in the resulting organoboron compounds are readily transformed into ab road array of valuable products with high enantiospecificity,including those containing CÀO, CÀN, CÀC, and CÀX(X= F, Cl, Br, I) bonds. [2] However,over the past several decades and since Brownsf irst asymmetric hydroboration, [1a] and despite the considerable progress made in the development of stoichiometric [1b] and metal-catalyzed processes, [1c-e] the substrate scope of this transformation remains largely limited to styrenes, [3] alkenes bearing directing groups, [4] and electronically biased or activated alkenes. [5][6][7] Theapplication of asymmetric hydro-and protoboration to simple unactivated a-olefins abundantly found in petrochemical feedstocks has proven to be al ongstanding challenge,and even astoichiometric process remains elusive. Indeed, this class of substrates continues to pose substantial challenges for asymmetric catalysis as aw hole,w ith only ah andful of reactions developed, so far,t hat provide satisfactory levels of enantiocontrol. [8] We have recently become interested in the development of ac opper-catalyzed asymmetric protoboration of a-olefins (Figure 1a). [9] As illustrated in the proposed catalytic cycle (Figure 1b), ar egio-and enantioselective borylcupration of the terminal alkene B by the copper boryl A would afford aprimary alkylcopper intermediate D via the p-complex Ca. Abulky ligand would facilitate the selective formation of Ca by avoiding the steric interaction between the ligand and the alkene substituent as shown in Cb.Subsequent protonation of the transient alkylcopper species D with an alcohol as the proton donor would furnish the chiral protoboration product E and release the copper alkoxide F.As-metathesis reaction between F and the diboron reagent G would regenerate A and close the catalytic cycle.T he regio-and enantiocontrol of the olefin borylcupration step is the key event that determines the regio-and stereochemical outcome of the transformation. However,d espite recent advances in copper-catalyz...

Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes

“…On the other hand, a-chiral boronate-substituted compounds are an important family of target molecules, because the C-B linkage provides an extremely useful stereogenic center. [20][21][22][23][24][25][26][27][28][29] They have been shown to participate in C-C coupling reactions with excellent enantioselectivity. 30,31 Furthermore, the formed chiral C-B bond may be readily converted into a C-O, C-N, and other C-heteroatom bond with retention of the configuration, allowing access to a wide array of functional groups that are common in valuable synthetic targets.…”

A Bulky Chiral N‐Heterocyclic Carbene Nickel Catalyst Enables Enantioselective C−H Functionalizations of Indoles and Pyrroles

“…Nakao,H artwig, and co-workers reported an undirected C2-functionalization of electron-rich heterocycles using an achiral nickel-NHC catalyst system for anti-Markovnikov hydroarylations. [22] We recently reported [19,23] achiral NHC [24] family that offers large modulation opportunities based on Gawleysc arbene. [25] Herein, we introduce new members of this ligand family and apply them as steering ligands in Nicatalyzed directing-group-free enantioselective CÀHf unctionalizations of indoles and pyrroles (Scheme 1).…”

Ligand-Free Iron-Catalyzed Regiodivergent Hydroboration of Unactivated Terminal Alkenes

“…The regioselectivity reduced from excellent (2w, 2x) to good (2y), and then to moderate (2z, 2aa), when the alkyl substituent was changed from 3 to 2 and to 1, respectively. In contrast, for the Cu-and Rhcatalyzed versions, 1 alkyl substituted alkenes usually gave good regioselectivities, whereas 2 and 3 alkyl substituted alkenes reacted with lower regioselectivities [9][10][11][12][13] . Furthermore, the reaction tolerated a variety of functional groups, including phenyl ether (2a, 2e-h), benzyl ether (2b, 2c), silicon ether (2d), fluoro (2e), trifluoromethyl (2f), trifluoromethoxy (2g), phenylborate (2h), sulfonamide (2l), amide (2m, 2q, 2r), amine (2u), thioether (2n), sulfone (2o), and ketone (2p) groups, as well as some pharmaceutically important cycles, such as indole (2i), furan (2r), cyclopropane (2q), and amantadine (2v, 2w).…”

“…Next, we submitted alkene diboration substrate 5 to the reaction under both two standard conditions and observed no protodeboration products (Scheme 4b); thus, a diboration-protodeboration mechanism was excluded 34 . Different from Cu-or Rh-catalyzed hydroboration in which alcohols just acted as proton sources [9][10][11][12][13] , in iron-catalyzed version, additional H2O or alcohols have significant effects on the yield and regioselectivity (Scheme 4c): a) on the whole, both of yield and Markovnikov regioselectivity decreased when proton sources were added; b) the less steric hindrance of the proton source, the more the yield and Markovnikov regioselectivity decreased (entries 1-5); c) the more proton source was added, the more the yield decreased (entries 5, 6). The result indicates that the proton source can undergo anion exchange with the reaction intermediate, and the steric hindrance of anion influences yield and regioselectivity significantly.…”