Organometallic-type reactivity of stable organoboronates for selective (hetero)arene C-H/C-halogen borylation and beyond

Abstract

Organometallic reagents are essential tools in both academic and industrial laboratories and the polarity separation within the carbon-metal bonds endows them with exceptional reactivities, but also imposes limitations, including air- and moisture-sensitivity, and flammability. Here, we demonstrate that stable and easily accessible benzylic (or allylic) boronate with alkali-metal alkoxide as the activator can act as reactive organometallic reagents. This strategy enables transition metal-free deprotonative C-H borylation of diverse (hetero)arenes. The polar organometallic nature of this process enables predictable and site-selective borylation by targeting the arenes's most acidic C-H bond. This approach can be coupled with Suzuki-Miyaura reaction to produce C-H arylation products. We have also applied this strategy to the dehalogenative borylation of aryl bromides and anionic polymerization of styrenes. Given the unique stability and structural diversity of organoboronates, their organometallic-type reactivities show promise as a powerful alternative to synthetic methodologies that rely on sensitive organometallic reagents.

Fig. 1. Multifaceted reactivity of organometallic reagents.

a Representative elementary reactions of polarized organometallic reagents (e.g., organolithium, organomagnesium reagents, etc.) and exemplified strategies for delivering sensitive organometallic reagents. b Organoboronates are typically used as a cross-coupling partner for C−C bond constructions with boron unit [B] as a leaving group. c In the presence of alkali-metal alkoxides, benzylic (or allylic) boronates might be considered as both superbase precursors and boron sources through the in situ heterolysis of the C−B bond. d Outline of the possible transformations using organoboronates/alkali-metal alkoxides combinations as reactive organometallic reagents via deprotonative metalation, metal-halogen exchange or anionic polymerization, in analogy to sensitive organolithiums, organomagnesiums, etc.

Fig. 2. Exploration of the superbase reactivity of organboronates, application for aromatic C−H borylation reaction, and mechanistic insight.

a Computational screening for the possible organoboronates/KO^tBu combination, which could undergo C−B bond heterolysis to generate carbanion species (∆G^ǂ: activation barrier; ∆G: reaction energy). b Experimental evaluation of the reactivity of different organoboronates for the C−H borylation of N-methylindole 2. c ¹H and ¹¹B NMR (400 MHz, THF-d₈) studies on the model reaction. Numbers within the parentheses are the boron resonances. d Computed pathways [M06-2X/def2-TZVPP, SMD(THF)//M06-2X/def2-SVP, SMD(THF)] for C−H borylation of N-methylindole with benzylic boronate 1c/KO^tBu combination. The Gibbs free reaction energies (relative to 1c) and barriers (labeled with an asterisk, relative to Int1) are in kcal mol^-1. KIE: Kinetic Isotope Effect (KIE_exp.: experimental measured KIE; KIE_cal.: computed KIE with TS_2-3). Color code: H, white; C, gray; B, pink; O, red; N, blue; K, purple.

Fig. 3. Substrate scope for the C–H borylation of (hetero)arenes.

The numbers labeled on the arenes are the calculated pK_a values of the related C−H bonds. Reaction conditions: substrates (0.2 mmol), 1c or 1d (1.5 equiv.), KO^tBu (1.5 equiv.) in 1.0 mL of THF at 80 °C, 2.5 h, under Ar. ^a5 mmol scale. ^bYield determined by ¹H NMR due to the product decomposition during the purification. ^cCascade C–H borylation/hydroxylation: NaBO₃·4H₂O (3.0 equiv.), THF/H₂O = 1:1 at room temperature, 3 h. ^d1c or 1d (3.0 equiv.) and KO^tBu (3.0 equiv.). ^e1c (4.2 equiv.) and KO^tBu (4.2 equiv.). ^fWithout further purification by column chromatography on silica gel. ^g1d (1.1 equiv.) was used. ^h1d (2.2 equiv.) and KO^tBu (2.5 equiv.). ⁱAt 60 °C, 2.5 h. Color code: H, white; C, gray; B, yellow; O, red; N, blue; S, green.

Fig. 4. Development, analysis, and predictive application of a machine learning model for borylation reactivity.

a Model performance (training and validation) across iterative data augmentation rounds. b Comparative performance of different ML algorithms leading to the selection of SVR. c Feature importance analysis identifying critical descriptors for the final SVR model. d Performance of the final SVR model for reactivity prediction. e Machine learning predictions for external examples and experimental verification. Reaction conditions: substrates (0.2 mmol), 1c, 1b or 1d (1.5 equiv.), KO^tBu (1.5 equiv.) in 1.0 mL of THF at 80 °C, 2.5 h, under Ar. ^aYield determined by ¹H NMR. The numbers labeled on the arenes are the calculated pK_a values of the related C−H bonds. (Pred.: Predicted yield; Exp.: Experimental yield).

Fig. 5. Application of the (hetero)arenes C(sp²)−H borylation and scope extension to borylation of aryl bromides and anionic polymerization.

a Borylation of methoxylmethyl (MOM)-protected (R)-BINOL and a comparison to the previous strategy. b Cascade C(sp²)−H borylation/Suzuki-Miyaura cross-coupling for the structural diversification of drug-relevant substrates. c Cascade borylation of aryl bromides/Suzuki-Miyaura cross-coupling for the synthesis of biaryls. d Benzylic boronate/KO^tBu combination-initiated polymerization of 4-chlorostyrene under different conditions. ^aWithout further purification by column chromatography on silica gel. ^bS47 (0.2 mmol), 1d (1.1 equiv) and KO^tBu (1.5 equiv) in 1.0 mL of THF at 40 °C, 5 h, under Ar. ^cS48 (0.1 mmol), 1d (1.5 equiv) and KO^tBu (1.5 equiv) in 1.0 mL of THF at 60 °C, 5 h, under Ar. ^dWith KO^tBu. ^eWith NaO^tBu.