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Synlett 2020; 31(19): 1857-1861
DOI: 10.1055/s-0040-1707241
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© Georg Thieme Verlag Stuttgart · New York

Metal-Free Catalytic Aromatic C–H Borylation

Hua Zhang  ∗
a   College of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang, 330031, P. R. of China
b   Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education and Hubei Key Laboratory of Catalysis and Materials Science, School of Chemistry and Materials Science, South-Central University for Nationalities, Wuhan, 430074, P. R. of China   Email: huazhang@scuec.edu.cn
,
Li Wang
a   College of Chemistry, Nanchang University, 999 Xuefu Avenue, Nanchang, 330031, P. R. of China
› Author Affiliations

This work was supported by the grants from the National Natural Science Foundation of China (21602096).
Further Information

Publication History

Received: 19 June 2020

Accepted after revision: 10 July 2020

Publication Date:
11 August 2020 (online)

 
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Abstract

In recent decades, C–H borylation has undergone rapid development and has become one of the most important and efficient methods for the synthesis of organoboron compounds. Although transition-metal catalysis dominates C–H borylation, the metal-free approach has emerged as a promising alternative strategy. This article briefly summarizes the history of metal-free aromatic C–H borylation, including early reports on electrophilic C–H borylation and recent progress in metal-free catalytic intermolecular C–H borylation; it also highlights our recent work on BF3·Et2O-catalyzed C2–H borylation of hetarenes. Despite these recent advances, comprehensive mechanistic studies on various metal-free catalytic aromatic C–H borylations and novel processes with a wider substrate scope are eagerly expected in the near future.


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Key words

C–H activation - borylation - metal-free reaction - catalysis - organoboron compounds

Organoboron compounds are important building blocks in organic synthesis and have been widely applied in various areas, such as pharmaceutical science and materials science.[1] Because of the importance of organoboron compounds, research on C–B bond formation has undergone rapid development and has become a hot topic in organic chemistry. Early examples of ipso-borylation involved carbon–metal borylation with active and air- or moisture-sensitive organometal reagents. Later, C–heteroatom and C–C borylations were developed by using C–halo, C–O, C–N, C–S, and activated C–C bond electrophiles. Evidently, C–H borylation for converting C–H bonds into C–B bonds provides an ideal and straightforward route for the synthesis of organoboron compounds.

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Hua Zhang obtained his B.Sc. (2008) and Ph.D. (2013) from Wuhan University under the supervision of Professor Aiwen Lei. After working as a postdoctoral scholar with Professor Kenichiro Itami at Nagoya University and Professor Vy Dong at University of California, Irvine, Hua took up a position at Nanchang University in 2016. In late 2019, he joined South-Central University for Nationalities, and became a professor in the School of Chemistry and Materials Science.

In the past two decades, transition-metal catalysts, especially noble-transition-metal catalysts, have played a central role in aromatic C–H borylation.[2] Although transition-metal catalysis exhibits high efficiency in these processes, metal-free aromatic C–H borylation is attractive for several good reasons. Early in 1948, Hurd reported the reaction of benzene with highly reactive and toxic diborane in sealed tubes at 100 °C to afford a borylated benzene product.[3] A decade later, the Friedel–Crafts C–H borylation of alkylated aromatics with BX3 (X = Cl, Br, I) in the presence of AlX3 (X = Cl, Br) or Al as activator was independently reported by the groups of Muetterties and Lappert (Scheme [1]A).[4] However, intermolecular electrophilic C–H borylation has received little attention[5] until the recent progress[6] made by the groups of Vedejs[7] and Ingleson[8], who achieved an intermolecular electrophilic C–H borylation of aromatic substrates by employing stoichiometric, readily synthesized, boron cations as electrophiles (Scheme [1]B).[9] As pioneered by Dewar[10] and Köster[11] and their respective co-workers (Scheme [1]C), intramolecular (directed) electrophilic aromatic C–H borylation has undergone rapid development[12] and has been widely applied in syntheses of BN-fused and boron-doped polycyclic aromatics (Scheme [1]D).[13]

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Scheme 1 Electrophilic aromatic C–H borylation

Although significant progress had been made in metal-free intermolecular aromatic C–H borylation,[14] a catalytic process using simple and mild boron sources was highly desirable.[15] In 2010, Ingleson and co-workers reported the first intermolecular electrophilic C–H borylation of alkyl aromatics with catecholborane (HBcat) by employing Ph3C[HCB11H5Br6]/Et3SiH/catBBr as catalyst (Scheme [2]).[16] A transient [catB]+[HCB11H5Br6]– (1) active species generated by halide abstraction from catBX by [Et3Si]+[HCB11H5Br6]– was proposed to be the probable catalytic species.

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Scheme 2 Metal-free catalytic aromatic C–H borylation: catalysts and boron sources

By utilizing an ambiphilic aminoborane 2 as catalyst,[17] Fontaine and co-workers achieved an efficient metal-free C–H borylation of various hetarenes (furans, pyrroles, indoles, or thiophenes) with pinacolatoborane (HBpin) (Scheme [2]).[18a] [b] A regioselectivity similar to that of electrophilic C–H borylation was observed, while a frustrated Lewis pair (FLP) mechanism involving C–B/H–B metathesis step was proposed based on theoretical calculations (Scheme [3]A). Furthermore, the fluoroborate derivatives,[18c,e] smaller analogues,[18d] and polymeric versions[18f] of the previous aminoborane compound were developed by the same group and employed as efficient (pre)catalysts in the C–H borylation of hetarenes. They also recently reported the first transfer C–H borylation of hetarenes with the furylborane 9 with 2-sulfanylpyridine (8) as a catalyst.[18g] Repo and co-workers reported the catalytic C–H borylation of N-methylindole and 3-methylthiophene with HBcat by using the robust air- and moisture-stable 2-(dimethylamino)pyridinium salt 3 as a catalyst (Scheme [2]).[19]

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Scheme 3 Generally proposed mechanisms in metal-free catalytic aromatic C–H borylation

In continuation of their studies on the ruthenium(II) thiolate complex-catalyzed aromatic C–H borylation,[20] Oestreich and co-workers developed a catalytic Friedel–Crafts C–H borylation of electron-rich arenes [aniline derivatives, N-(triisopropylsilyl) indoles, and pyrroles] with HBcat by employing B(C6F5)3 (4) as catalyst (Scheme [2]).[21] Mechanistic studies revealed a classical SEAr mechanism involving boronium/borenium ions as reactive intermediates (Scheme [3]B). Remarkably, the addition of catalytic amounts of alkenes permitted this transformation to become the first catalytic electrophilic C–H borylation to proceed at room temperature. Almost simultaneously, Uchiyama and co-workers developed an electrophilic C–H borylation of electron-rich (het)arenes in the presence of catalytic amounts of B(C6F5)3 (4) and the sulfur Lewis base 5 (Scheme [2]).[22] Shortly afterwards, Zhang and co-workers also reported a B(C6F5)3-catalyzed C–H borylation permitting various substituted N-methylindoles to be used as substrates with HBcat as the boron source affording C3-borylated indoles (Scheme [2]).[23] The C–H borylation of substituted N-methylindoles, 1,2,5-trimethylpyrrole, and N,N-dialkylanilines with HBcat or HBpin was also achieved at room temperature by Erker and co-workers, who used a geminal chelate bisborane catalyst 6 containing strongly electrophilic BC6F5 moieties (Scheme [2]).[24]

By employing the N-heterocyclic carbene–borane 7 as a boron source, Ingleson and co-workers demonstrated an I2-catalyzed C–H borylation of hetarenes, in which a C2-regioselectivity was observed in contrast to the C3-regioselectivity reported in the previous catalytic electrophilic C–H borylation (Scheme [2]).[25] Mechanistic studies supported an SEAr mechanism and indicated that the C2-regioselectivity might arise as a result of the presence of a competent Brønsted acid, the higher thermodynamic stability of C2-isomers, and the ready protodeboronation of C3 isomers.

Inspired by recent progress in C–H borylation, and in continuation of our interest in borylation reactions,[26] we became interested in developing novel and efficient metal-free catalytic aromatic C–H borylation reactions. Due to their stability and ease of handling, tetraalkoxydiboron compounds especially bis(pinacolato)diborane (B2pin2), have been widely used as boron sources in numerous catalytic borylation reactions.[27] In addition, borylated products containing a Bpin group are basically stable to air, moisture, and column chromatography. We therefore embarked on an investigation of metal-free catalytic aromatic C–H borylation employing B2pin2 as a boron source. We initially attempted the C–H borylation of N-methylindole (10a) with B2pin2 in the presence of various initiators. To our great surprise and delight, the C2-borylated N-methylindole 11a was obtained predominantly by using boron-based Lewis acid catalysts. After extensive screening, the optimal conditions for this transformation were found to involve cheap and simple BF3·Et2O as a catalyst with octane–THF as a solvent (Scheme [4]).[28]

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Scheme 4 BF3·Et2O-catalyzed C2–H borylation of N-methylindole with B2pin2

This BF3·Et2O-catalyzed C–H borylation permitted the use of a variety of substituted indoles or other hetarenes as suitable substrates, affording the corresponding C2-borylated products in moderate to good yields (Scheme [5]).[29] N-Butylindole (10b) and N-benzylindole (10c), as well as the C3-substituted indole 10d worked well under the optimized conditions. Indoles bearing a methyl group at various positions (10e, 10f, 10g, and 10h) or electron-donating and electron-withdrawing groups [methoxy (10i), triisopropylsilyl (10j), phenyl (10k), fluoro (10l), chloro (10m), or bromo (10n and 10o)] were well tolerated. Indole (10p), N-methyl-7-azaindole (10q), and N-benzylpyrrole (10r) also reacted with B2pin2 to form C2-borylated products, albeit in relatively low yields. The synthetic versatility of 2-borylindole products in the synthesis of important C2-functionalized indoles was therefore demonstrated (Scheme [5]).

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Scheme 5 BF3·Et2O-catalyzed C2–H borylation of hetarenes

Various experiments were conducted to reveal the possible mechanism of this borylation. Radical-clock and trapping experiments ruled out the possibility of a radical process (Scheme [6]A). The reversibility and stability of C2- and C3-borylated indoles were probed, which ruled out the possibility of mutual reversibility and revealed that C2 isomers were more stable than C3 isomers under the present reaction conditions, which might be one of the reasons for the dominant C2 regioselectivity (Scheme [6]B). A reverse kinetic-isotope effect was observed in the intermolecular competition experiment, indicating that C–H bond cleavage is not the rate-determining step (Scheme [6]C). An electrophilic C–H borylation mechanism was proposed based on the results obtained and related reports. However, we must stress that extensive studies are needed to elucidate the mechanism of this C–H borylation.

In summary, the history of metal-free aromatic C–H borylation has been briefly summarized. Recent advances have been made by various groups who have developed metal-free catalytic aromatic C–H borylations promoted by various catalysts. We recently disclosed a novel metal-free C–H borylation of indoles and other hetarenes by using simple and cheap BF3·Et2O as a catalyst and stable B2pin2 as a boron source. Remarkably, a C2 regioselectivity was achieved, supplementing the C3 regioselectivity reported in most cases of electrophilic C–H borylation. A comprehensive mechanistic investigation of this process, and studies on the further development of novel metal-free catalytic C–H borylation reactions with a wider substrate scope, are underway in our group.

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Scheme 6 Preliminary mechanistic studies

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Hua Zhang obtained his B.Sc. (2008) and Ph.D. (2013) from Wuhan University under the supervision of Professor Aiwen Lei. After working as a postdoctoral scholar with Professor Kenichiro Itami at Nagoya University and Professor Vy Dong at University of California, Irvine, Hua took up a position at Nanchang University in 2016. In late 2019, he joined South-Central University for Nationalities, and became a professor in the School of Chemistry and Materials Science.
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Scheme 1 Electrophilic aromatic C–H borylation
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Scheme 2 Metal-free catalytic aromatic C–H borylation: catalysts and boron sources
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Scheme 3 Generally proposed mechanisms in metal-free catalytic aromatic C–H borylation
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Scheme 4 BF3·Et2O-catalyzed C2–H borylation of N-methylindole with B2pin2
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Scheme 5 BF3·Et2O-catalyzed C2–H borylation of hetarenes
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Scheme 6 Preliminary mechanistic studies