Synthetic Methods for the Construction of 1,2-Azaborole-Containing Polycyclic Aromatic Hydrocarbons

Abstract

Boron-doped polycyclic aromatic hydrocarbons have emerged as a prominent class of compounds due to the unique properties that can be achieved through the incorporation of boron, often paired with another heteroatom, a combination that makes them attractive for a range of applications. The benefit of doping with these heteroatoms is also evident in 1,2-azaboroles, a subclass of B-containing compounds, consisting of five-membered unsaturated heterocycles with dative boron–nitrogen bonds. The donation of electron density from nitrogen to boron renders the molecules electronically saturated and endows them with the stability that is a prerequisite for their application in organic electronics, photovoltaics, or bioimaging. The development of these compounds, first described in the 1960s, has been particularly intensive over the past two decades, driven by their photoresponsive and luminescent properties. This review aims to provide a comprehensive overview of the synthetic methodologies employed in the construction of 1,2-azaboroles. In addition to classical approaches, such as nitrogen-directed electrophilic C – H borylation or lithiation–transmetalation of prefunctionalized substrates, we discuss less commonly used methods and protocols that are limited to specific starting materials, thus demonstrating a large available repertoire of synthetic tools to access these compounds.

1 Introduction

2 Synthetic Approaches

2.1 Lithiation-Transmetalation

2.2 Electrophilic C–H Borylation

2.3 Transition Metal-Catalyzed C–H Borylation

2.4 Cycloaddition

2.5 Photoisomerization

2.6 Hydroboration

2.7 Coordination-Cyclization

2.8 Nucleophilic Aromatic Substitution

2.9 Silicon–Boron Exchange

3 Conclusion and Outlook

 

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Key words

azaboroles - borylation - cycloaddition - electrophilic borylation - PAHs - transmetalation

1 Introduction

Boron-doped polycyclic aromatic hydrocarbons (PAHs) have emerged as a prominent class of aromatic compounds, with a growing interest in recent years and a broad spectrum of applications. They play an important role in different fields, such as organic electronics,[1] stimuli-responsive materials,[2] in biomedical applications,[3] and anticounterfeiting.[4] Their attractiveness arises from distinctive features of the boron atom possessing three valence electrons but potentially four bonding orbitals that can dramatically alter the properties of the molecular frameworks in which they are embedded. In compounds with three coordinated boron, the vacant p_z orbital is susceptible to attack by nucleophiles. Their stability against e.g. moisture and air is largely determined by the steric congestion imparted by the ligands attached to the boron atom.[5] This Lewis acidic behavior can be exploited to stabilize boron atoms through intramolecular interactions between boron and atoms possessing a lone electron pair. In heterocycles, electron-donating heteroatoms, introduced in the vicinity of the boron atoms, furnish conformationally constrained compounds with tetracoordinated boron and either planar or nonplanar geometry, depending on the ring formed.[6] Here, nitrogen atoms are of particular interest due to their comparable atomic radii and potentially strong Lewis basic character, allowing the formation of strong B–N bonds. The concept of replacing C–C double bonds with the isoelectronic B–N pair has been well established and widely reported in recent years, as this exchange profoundly changes the properties and can affect the geometry of the compound, as shown for BN-helicenes.[7] The substitution of a B–N bond for a C–C bond generates the system that possesses a (local) dipole moment. This approach has been extensively applied to six-membered rings, such as azaborines,[7e],[8] and has also been demonstrated for five-membered heterocycles, more specifically, 1,2-azaboroles containing a tetracoordinated boron atom (see [Figure 1a]), although they have been less intensively investigated than derivatives containing six-membered BN-heterocycles. Nonetheless, the studies of these compounds over the past two decades have contributed to the development of efficient synthetic protocols,[9] understanding of their reactivity and optoelectronic properties. Since then, the 1,2 azaborole ring has been incorporated into a multitude of structures, including ladder compounds,[13] helicenes,[14] boron-centered spiro compounds,[15] photoswitches, and stimuli-responsive materials.[16] These compounds due to their attractive luminescent ([Figure 1b]) and charge-transport properties have been applied e.g. in solar cells,[17] transistor devices,[11],[18] organic light-emitting diodes,[19] bioimaging,[20] and as erasable inks ([Figure 1c] and d).[12] Therefore, the existing body of literature is already considerable in this field, in particular the variety of synthetic methods, with two approaches, i.e. lithiation–transmetalation and electrophilic C–H borylation, prevailing in the literature. In this review we focus on the synthesis of this compound class, showing also less commonly used general methods and protocols limited to specific substrates. We will discuss the relationship between the reaction conditions and the regioselective outcome for substrates where potentially more than one carbon atom can form a bond with boron.

Figure 1 (a) Molecular structure of 1,2-azaborole. (b) Top: Absorption spectra in CH₂Cl₂ of the parent azaborole helicene and the laterally extended helicenes with the methyl substituents on boron (molecular structures shown above). Inset right: Photographs of the solutions of the laterally extended helicenes under visible light (top) and UV light (bottom). Inset left: Photographs of the powders of the laterally extended helicenes. Bottom: Normalized absorption (solid lines) and emission (dashed lines) spectra of these helicenes in CH₂Cl₂. Adapted from Ref. [10] published under a creative commons license (CC BY). (c) Transfer curves and square root plots of the drain-source current with corresponding linear fit (black line) for organic thin-film transistor devices based on acceptor–π-bridge–acceptor (A–π–A) molecules derived from 2-(3-boryl-2-thienyl)thiazole. Atomic force microscope morphology measured between the contacts of the corresponding devices of these molecules. Reprinted with permission from Ref. [11]. Copyright 2017 Wiley-VCH GmbH. (d) Photochromic polymer film of an azaborole-containing polymer under room light (top) and UV light (bottom). Left: before irradiation at 365 nm. Right: after a mask was placed on top of the film and the film was exposed to 365 nm UV light. The photographs show the possibility of using the photochromic polymer as invisible and switchable/erasable ink. Reprinted with permission from Ref. [12]. Copyright 2017 American Chemical Society.

The term 1,2-azaborole, or simply azaborole, as used in this review, refers to a five-membered heterocyclic unsaturated ring, containing exactly one B–N bond ([Figure 1a]). In the literature, compounds containing this ring are often referred to as N→B ladder-type structures or N,C-chelate organoboron compounds. The bonding situation between nitrogen and boron in these structures is presented inconsistently, with either a dative bond from the nitrogen to the boron or a covalent bond between both atoms with and without formal charges. Sometimes no bond is shown between nitrogen and boron, even though bond lengths determined by single crystal X-ray diffraction analysis[21] or chemical shifts in ¹¹B NMR spectroscopy[22] indicate interactions between both atoms. This lack of consistency indicates that a correct description of the bonding situation in 1,2-azaboroles is not trivial. As will be shown later, some authors even report dynamic behavior and therefore a poorly defined bonding situation in these compounds, often with an open and a closed form being in equilibrium. In this review, we consistently present the structures with a dative bond and no formal charges notation.

 

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2 Synthetic Approaches

The review is structured according to the relevance and scope of the synthetic routes. The lithiation–transmetalation cascade and electrophilic C–H borylation are discussed first in Sections 1 and 2, as these are the most commonly used methods and are abundant in the literature. While the first method requires an additional lithiation step and thus, prefunctionalized precursors or starting materials possessing C–H acidic protons, the borylation in the second method allows the direct synthesis of 1,2-azaboroles by exploiting the Lewis basicity of nitrogen atoms and the Lewis acidity of boron electrophiles. We show different lithiation reagents in the former method, and a variety of borylation reagents in both approaches. In C–H borylation, the electrophilicity of these reagents dictates the reaction conditions. The use of less reactive reagents necessitates more forcing conditions and/or using an additional reagent, which in turn may affect the regioisomeric outcome.

The role of the transition metal catalysis in the synthesis of 1,2-azaboroles is then described in Section 2.3, showcasing the use of palladium and iron catalysts. Although rarely used, this method is discussed directly after Section 2.2, because, similar to N-directed electrophilic C–H borylation, it does not require prefunctionalization of the starting materials and can potentially be applied to a broad variety of ligands. In contrast, the cycloaddition reactions shown in Section 2.4 are limited to a specific group of compounds that can act as dienes and dienophiles or 1,3-dipoles and dipolarophiles. This approach has been extensively investigated and proved suitable for various starting materials, including pyrones, triazines, tetrazines, sydnones, alkynes, azides, and nitriles.

The review also covers less common approaches, which are often substrate-specific. Thus, an overview of the synthesis of 1,2-azaboroles by photoisomerization, mainly from diarylazaborinines, and mechanistic insights are depicted in Section 2.5. The following four sections describe other synthetic routes to 1,2-azaborole-containing compounds, namely hydroboration reactions (Section 2.6), a coordination–cyclization approach (Section 2.7), examples of a nucleophilic aromatic substitution (Section 2.8) and a silicon–boron exchange (Section 2.9).

2.1 Lithiation–Transmetalation

A convenient approach to the synthesis of 1,2-azaboroles is the lithiation–transmetalation reaction sequence starting from a biaryl possessing an acidic proton or bearing a halogen at a position proximal to the biaryl axis, and an N-donor atom on the adjacent ring. Lithiation of the biaryl compound, often represented by 2-phenylpyridine moieties, is achieved by halogen–metal exchange with n-butyllithium or deprotonation of a heterocycle with n-BuLi, t-BuLi, or lithium diisopropylamide (LDA).[20d],[23] Commonly used three-coordinate boron reagents are mixed boranes bearing two aryl functionalities (Ph, C₆F₅, Mes) and a leaving group (F, Cl, Br, OMe, OEt).[13a],[18],[23c],[24] Halogen–metal exchange is typically conducted at low temperatures (−78 °C) in ethereal solvents, subsequent addition of the borane, followed by slow warming to ambient temperature. Purification can usually be carried out via column chromatography, as these azaboroles often exhibit high stability toward air and moisture. In contrast to the methods described in the following sections, there is no inherent regioselectivity involved in the transmetalation approach. Therefore, to control the position of the borylation, regioselectivity must be achieved at the level of the bromination. The powerful approaches that have the potential to circumvent the problem of regioselectivity are N-directed Ir-catalyzed borylation followed by bromination or Pd-catalyzed bromination and iodination.[20d],[25]

Among the rich variety of boranes used for the transmetalation, BFMes₂ is by far one of the most commonly used borylation reagents. An advantage of this reagent is the F⁻ leaving group, which forms lithium fluoride in situ, the driving force for this reaction. The first example of its use to generate 1,2-azaboroles was demonstrated by Yamaguchi and co-workers ([Scheme 1]).[18]

Scheme 1 Lithiation and borylation cascade established by Yamaguchi.

Following the lithiation–borylation approach, azaborole 2 was synthesized in 75% yield. In the following years, the method proved to be applicable to derivatives of 2 [11],[26] or larger systems, as shown in [Scheme 2]. For instance, Wang and co-workers synthesized 2-phenylpyridine based azaborole 4a (62%), which was later extended by a second 2-phenylpyridine unit to give azaborole 4b (25%).[23a],[27] In contrast to electrophilic C–H borylation, this method allows the regioselective introduction of boron originating from the prefunctionalization of the biaryl. Similarly, the introduction of two boron atoms proceeded smoothly to provide unsubstituted and methoxy-functionalized ladder-type molecules 4c,d in yields of 51 and 28% by diborylation of the corresponding thiazolothiazoles.[13a]

Scheme 2 Synthesis of azaboroles via the lithiation–borylation sequence with BFMes₂.

In addition to the ladder compounds, this approach is suitable for the synthesis of nonplanar and helically chiral derivatives, as demonstrated by Ros, Pischel, and co-workers.[20d],[28] A series of boron-containing [5]helicenes ([Scheme 3]) was prepared from 1-(naphthalen-1-yl)isoquinoline precursors that were subjected to a nitrogen-directed iridium-catalyzed borylation reaction in the first step.[29] This was followed by treatment with copper(II)bromide in a solution of methanol, iso-propanol and water at 90 °C, to afford the ortho-brominated products, a protocol that was initially published by Huffman et al.[30] Finally, the lithiation–borylation sequence with n-BuLi and (Mes)₂BF afforded the corresponding azaboroles 9a–c in yields of 50 – 67%. While these compounds are fluxional at room temperature, Pischel developed later configurationally stable congeners by introducing an aryl ring at the sterically hindered position of the helicene framework (marked with a blue circle in the general structure of 9).[28] The final step of lithiation–borylation provided helicenes 9d–f in yields up to 54%.

Scheme 3 Synthesis of nonplanar and chiral azaborole compounds by N-directed Ir-catalyzed borylation of 1-(naphthalen-1-yl)isoquinoline derivatives, subsequent Cu-mediated bromination followed by the lithiation–borylation sequence using BFMes₂.

The authors also showed that racemic bromide 8d can be resolved into its enantiomers and converted into enantioenriched (P)- and (M)-helicenes 9d, although the precursors partially racemized already at −60 °C due to their low configurational stability. In comparison with the synthesis of helicenes by electrophilic C–H borylation, this method requires two additional steps. Nevertheless, it may prove more effective in the introduction of certain types of boron substituents.

As mentioned above, the lithiation–transmetalation sequence does not necessarily require brominated aryl precursors. The incorporation of a second heterocyclic moiety, in addition to the pyridine ring, facilitates the lithiation through the deprotonation of an acidic proton. Wang and co-workers lithiated thiophene and pyrrole moieties at the 3- and 2-positions, respectively, by using n-butyllithium and reacted them with BFMes₂ to obtain the corresponding azaboroles 11a and 11b in yields of 61 and 83% ([Scheme 4]).[23c] A more unusual example is the incorporation of a cyclopentadienide of ferrocene into azaborole 11c.[23b] This was achieved by ortho-lithiation of one cyclopentadienide using tert-butyllithium. The compound could be isolated in ca. 60% yield. Furthermore, Wang exploited the lithiation at the C3 of an indole residue using n-butyllithium followed by the transmetalation with BFMes₂ to afford the corresponding azaborole 11d in a 36% yield. This reaction not only resulted in the formation of the azaborole ring, but also led to the functionalization of the phenyl group with BMes₂.[31] The only other product of the lithiation–borylation of a carbocycle among the selected compounds was prepared by exploiting the C–H acidity of a 2,3,4,5-tetrafluorophenyl moiety. Following the lithiation–borylation sequence, azaborole 11e was obtained in a yield of 39%.[23c] For other methods used to incorporate the ferrocene or perfluoroaryl moieties into 1,2-azaboroles, see Sections 2.2 and 2.8.

Scheme 4 Lithiation–borylation cascades with BFMes₂ through deprotonation of the ligand.

Other diarylboranes can also be used to prepare 1,2-azaboroles. For example, Kano and Kawashima successfully introduced perfluorophenyl ligands using (C₆F₅)₂BOEt with EtO⁻ as the leaving group ([Scheme 5]).[24a] Interestingly, azaborole 14 was not synthesized directly via lithiation–transmetalation in this case, but in a subsequent step by converting the boron complex of benzaldehyde 13 into an imine derivative via dehydrative cyclization with aniline. Compound 14 was obtained in 83% yield after recrystallization. Wang used a different source of (C₆F₅)₂B, i.e. B(C₆F₅)₂F with a fluoride leaving group to synthesize azaborole 15b in 16% yield.[23c] Following the same procedure, phenyl derivative 15a was obtained in 33% yield using BPh₂Cl. A quite unique example is the synthesis of 16 with two ferrocene ligands by reacting bromide 3a with diferrocenylboron bromide.[24b]

Scheme 5 Synthesis of 1,2-azaboroles with different aromatic ligands on boron by the lithiation–transmetalation approach.

When two different ligands are installed on boron, azaboroles possess a stereogenic center and are therefore chiral. This can be achieved by reacting a ligand with a borane precursor, which is a source of two different groups. Using this approach, Wang prepared a series of unsymmetrically substituted azaboroles. For example, the lithiation of 2-(2-bromophenyl)pyridine (3a) and transmetalation with [(Mes)(MeO)PhB] following the standard protocol afforded 18 in a 48% yield ([Scheme 6]).[32] The unsymmetrical boranes used in this method are accessible by a stepwise reaction of trimethyl borate with two arylmagnesium bromides. Similarly, Devillard, Alcaraz, and co-workers reacted lithiated 2-phenylpyridine with (alkyl)(mesityl)bromoboranes to obtain the corresponding azaboroles 19a–c in 28 – 48%. The herein used boranes were synthesized by hydroboration of halocycloalkenes.[33] An advantage of this methodology is the easy tailoring of the shape and properties of the azaboroles by simply altering the ligands of the boron substrates.

Scheme 6 Lithiation–borylation approach using unsymmetrical boranes leading to chiral 1,2-azaboroles.

As Hornerʼs seminal work from 1984 revealed, the treatment of ortho-lithiated N,N-dimethyl-1-arylethylamines with triphenylborane results in their conversion to the corresponding dihydro-1,2-azaboroles, accompanied by phenyllithium elimination. This finding led to the emergence of triphenylborane as a prominent reagent in the synthesis of small azaboroles and BN ladder-type compounds.[34] It is worth noting that Horner describes the incorporation of an sp³-hybridized nitrogen, whereas the following three examples show azaboroles bearing sp²-hybridized nitrogen atoms, consistent with our designation of 1,2-azaboroles. In addition to the mesityl-substituted thiazolothiazole-derived azaboroles 4c,d shown above ([Scheme 2]), Zhang synthesized phenyl complexes 21a,b in moderate to good yields using triphenylborane as the boron source ([Scheme 7]).[13a] Compared with the mesityl derivative 4c, phenyl complex 21a was obtained in a higher yield (72%). A smaller representative, compound 22, derived from 2-thienylthiazole was isolated in a yield of 85%, also higher than mesityl derivative 2 (75%),[35] although this cannot be considered as a general trend. In a similar way, Yan and co-workers synthesized a π-extended version of this compound, azaborole 24, although with a lower efficiency (40%).[36] Interestingly, this compound proved to act as a fluoride sensor that can be toggled between an open and a closed form. The addition of a fluoride anion, which binds in a reversible fashion to the boron, leads to a ring opening of the 1,2-azaborole. This process can be reversed by abstracting the fluoride with BF₃•Et₂O to restore the 1,2-azaborole ring.

Scheme 7 Synthesis of phenyl-substituted 1,2-azaboroles using the lithiation–borylation sequence with BPh₃.

The only examples of aliphatic boranes used in the borylation–transmetalation approach are presented in the work of Buchmeiser and co-workers ([Scheme 8]). In the search for a new catalyst for tandem ring-opening metathesis polymerization and vinyl-insertion polymerization, the group came up with the idea of incorporating a boryl group into the ligand, which would compete for the pyridyl lone pair and thus make the α-elimination process temperature dependent. This was achieved by lithiation of a 2-phenylpyridine moiety, and subsequent conversion into the corresponding azaborole 26 in 83% yield using BEt₂OMe. Azaborole 26 was further modified and incorporated into Zr and Hf complexes. It should be noted that in the original paper the compound was not depicted as an azaborole but in an open form, indicating that the nitrogen is not bonded to the boron. Here it is presented as an azaborole because the ¹¹B NMR spectrum gives clear evidence of the presence of a four-coordinate boron compound (3.5 ppm). However, subsequent variable-temperature NMR measurements indicated that there is an increase in B–N bond dissociation at elevated temperatures.[37] In 2017, the group developed new ligands consisting of N-bridged bis-2-phenylpyridines.[38] Starting from the two-fold brominated precursor, it was feasible to synthesize mono- or di-borylated products 28b and 28a in yields of 87 and 64%, respectively, by adjusting the equivalents of n-BuLi in the lithiation step. After deprotonation, the ligands were used for the coordination of a Ti complex.

Scheme 8 Synthesis of 1,2-azaboroles using the aliphatic borane BEt₂OMe in the transmetalation step.

In contrast to the synthetic routes shown above, which are based on lithiation mediated by halogen–metal exchange or deprotonation, Nakamuraʼs synthesis illustrates lithiation occurring during reductive cyclization induced by lithium naphthalenide ([Scheme 9]). The obtained lithioindene was reacted with BPh₃ to access azaborole 30 in 75% yield.[20b]

Scheme 9 Reductive cyclization of a dialkyne, followed by reaction with BPh₃ to produce the corresponding diazaborole.

 

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2.2 Electrophilic C–H Borylation

Metal-free, N-directed electrophilic C–H borylation is a versatile tool to access 1,2-azaboroles. Due to its simplicity, it is nowadays commonly utilized, as there is no need for costly transition-metal catalysts and ligands, and the isolation of the target compounds from relatively simple reaction mixtures is typically straightforward, even though initially harsh conditions, such as high temperatures, limited the use of this method. This subsection attempts to present only the main approaches to the preparation of 1,2-azaboroles by electrophilic borylation. For a more detailed discussion of electrophilic C–H borylation toward the synthesis of various boracycles, the reader is directed to an excellent review by Ingleson.[39]

In general, the method utilizes Lewis basicity of the nitrogen atom interacting with an electrophilic boron reagent to form a complex, subsequent generation of a reactive boron species and intramolecular ring closure. The idea goes back several decades to the early 1960s, when Letsinger and McLean[40] published the first synthesis of azaboroles. Product 32 was obtained by passing BCl₃ through molten 2-phenylbenzimidazole at temperatures of 300 – 325 °C, and the following hydrolysis ([Scheme 10]). Due to the harsh conditions of this method the synthesis of azaboroles via electrophilic borylation has not gained popularity.

Scheme 10 Electrophilic borylation reaction conducted by Letsinger and McLean.

The situation has changed in 2010, when Murakami and co-workers reported the borylation of 2-arylpyridines at room temperature, an arguably one of the most important protocols for the preparation of azaboroles via electrophilic C–H borylation.[41] In this work, they used BBr₃ as an electrophile and introduced a hindered base to scavenge the released HX by-product ([Scheme 11a]). In contrast, BCl₃ did not succeeded in forming the desired dihaloborane complexes under these conditions, which is attributed to its less electrophilic character compared with BBr₃. According to the mechanism proposed based on literature reports, the reaction starts with the formation of adduct Int1 ([Scheme 11b]). Then, the bromide is abstracted by another molecule of BBr₃ to generate highly reactive borenium species Int2, which is directly involved in electrophilic attack at the neighboring aromatic moiety. The role of the bulky tertiary amine is to facilitate deprotonation of arenium cation Int3, resulting in rearomatization of the carbocyclic ring.

Scheme 11 (a) Murakamiʼs synthesis of azaboroles by nitrogen-directed electrophilic borylation. ^[a]In the second step, Et₂O used as solvent, temperature: 0 °C to rt. ^[b]In the second step, CH₂Cl₂:toluene (1 : 1) used as solvent. (b) Proposed mechanism of nitrogen-directed electrophilic C–H borylation, based on literature reports. ^[c]The second yield is the overall yield of borylation with BBr₃ and the ligand exchange. *The amine, either Et₂N ⁱ Pr or EtN ⁱ Pr₂, is inconsistently reported in the publication and the Supporting Information.

The bromide complexes thus obtained were then functionalized with triorganylaluminum or diorganylzinc reagents at room temperature or at 70 °C, respectively, to afford azaboroles 35ab–ea and 15b ([Scheme 11a]) bearing alkyl or aryl substituents in good to excellent yields (74 – 98%) and the overall yields of two steps of 63 – 87%. When reacted with LiAlH₄, dibromoborane complex 34a furnished 35aa in 80% yield. A Grignard reagent (PhMgBr) also enabled the formation of desired product 35ae, albeit in substantially lower yield (43%). On the contrary, the PhLi, PhSnBu₃, and PhCu proved ineffective in this transformation providing either no products or complex reaction mixtures.[41] Azaboroles can also be functionalized with I, OTf and NTf by reacting boron hydride 35aa and its derivatives with I₂, TfOH, and HNTf₂, respectively.[42]

The reaction with BBr₃ in the presence of a bulky amine tolerates bromide substituents, and a less basic pyrimidine moiety compared with pyridine. In terms of regioselectivity, azaborole ring closure occurs preferably at the more nucleophilic 1-position of the naphthyl moiety to produce 34f, the product of kinetic control, and less sterically congested 34g in a ratio of 3 : 1. This regioselective outcome indicates the preference for fast and irreversible borylation under these reaction conditions.[41] This finding is in agreement with the borylation of 36 under modified Murakamiʼs conditions, which resulted in an electrophilic attack at the more nucleophilic 8 position of the naphthyl moiety, leading to the closure of a six-membered ring rather than a five-membered azaborole. The subsequent ligand exchange with HF afforded 38 in 73% yield over two steps ([Scheme 12]).[43]

Scheme 12 Electrophilic C–H borylation at the more nucleophilic naphthyl 8 position, leading to the formation of a six-membered boracycle.

Owing to its simplicity and high efficiency, Murakamiʼs protocol has attracted a widespread interest and has been applied in the synthesis of a large variety of azaboroles and other boracycle-containing compounds over the last decade.

In 2012, Yam and co-workers adapted Murakamiʼs procedure to synthesize a series of diarylethene (DAE) photoswitches fused with an azaborole ring.[44] Their synthesis involved borylation in the presence of N,N-diisopropylethylamine (DIPEA) to obtain intermediate dibromoborane complexes. These compounds were then successfully functionalized using Grignard reagents. Derivatives 41aa–ba were synthesized in moderate yields of 40 – 46% (two steps), whereas derivative 41ac was obtained in 14% yield ([Scheme 13]).

Scheme 13 Synthesis of azaborole diarylethene photoswitches by electrophilic borylation. ^[a]Yield of borylation. ^[b]Yield of borylation and ligand exchange.

Following Murakamiʼs approach, Patil and co-workers[45] synthesized a series of azaboroles (43a–k) in yields ranging from 64 up to 91% over two steps, i.e. borylation with BBr₃ in the presence of Hünigʼs base and the ligand exchange with trialkyl- or triphenylaluminium at room temperature ([Scheme 14]). It is noteworthy that the borylation of pyrene derivative 42d was regioselective, producing exclusively 43d, the product of attack at the 2-position.

Scheme 14 Scope and regioselectivity of electrophilic C–H borylation.

In 2016, Jäkle and co-workers[13b] reported double directed C–H borylation giving rise to π-extended azaborole system 45 as a single regioisomer in 47% yield ([Scheme 15]). The reaction took place preferentially at the 3 and 6 positions of the fluorene moiety due to increased steric crowding at the 1 and 8 positions. This compound was then arylated using either Ph₂Zn or C₆F₅Cu to give products 46a,b in moderate yields (53 and 44%, respectively) and combined yields of two steps of 25 and 21%. Thus, the reaction with arylcopper reagents could be successfully executed, as opposed to the attempted synthesis of 35ae with PhCu (vide supra).[41]

Scheme 15 Synthesis of BN-containing conjugated ladders by regioselective borylation at the 3,6-positions of the fluorene moiety. ^[a]Yield of ligand exchange. ^[b]Yield of borylation and ligand exchange.

To synthesize carbon-centered spiro compounds with a neighboring azaborole ring, Chan and Yam applied a modified version of Murakamiʼs procedure.[46] The incorporation of boron into ligands derived from the spiro-frameworks and substituted pyridine or quinoline was performed under harsher conditions, i.e. in refluxing 1,2-dichloroethane, with four equivalents of BBr₃, probably due to a close proximity of the voluminous spiro fragment. The N^C BBr₂ chelates bearing Me, CF₃ or CN on an N-heterocyclic moiety or synthesized from an unsubstituted ligand (R′ = H) were isolated in 53 – 71% yields and converted into the corresponding (3,5-bis(trifluoromethyl)phenyl)ethynyl derivatives. The substitution performed with the arylalkynyl Grignard reagent in refluxing THF afforded 49a–h in moderate yields of 43 – 55% and the combined yields of borylation-ligand exchange of 27 – 37% ([Scheme 16]).

Scheme 16 Spiro-compounds containing an azaborole ring. ^[a]Yield of borylation. ^[b]Yield of ligand exchange. ^[c]Yield of borylation and ligand exchange.

A modification of Murakamiʼs procedure also allowed the preparation of helically chiral compounds with one and two boron centers. The formation of two azaborole rings usually requires a prolonged reaction time and was therefore carried out for 22 – 72 hours. The ligand exchange afforded target compounds 50–62 of diverse structures, including single helicenes, truncated compounds, and multihelicenes in good to excellent yields (33 – 91%) as racemic mixtures, which were then separated by HPLC on a chiral stationary phase ([Scheme 17]).[10],[19b],[47] Our group also demonstrated the stereospecific synthesis of laterally extended helicenes 60a,b from enantioenriched biaryl ligands by axial-to-helical chirality transfer with full retention of chiral information (96 – 98% ee).

Scheme 17 Azaborole helicenes obtained by electrophilic C–H borylation.

Another classical approach to B-embedded molecules is the combination of an electrophile (most commonly BCl₃) with another Lewis acid – AlCl₃ – as a catalyst and a base. This approach was first explored by Dewar[48] and then developed further by Ingleson[49],[50] for borylation that led to six- and five-membered BN-containing rings. The reaction of 33a with BCl₃ in the presence of AlCl₃ and 2,4,6-tri-tert-Bu-pyridine afforded complex 63 in 77% yield ([Scheme 18]). Since then, these conditions have been commonly used to prepare five- and six-membered azaboracycles.[51]

Scheme 18 Electrophilic C–H borylation of 2-phenylpyridine with BCl₃ in the presence of AlCl₃ as Lewis acid activator.

Inglesonʼs protocol was used by Jäkle to prepare borane complexes from 1,6-dipyridylpyrenes 64 and 66 containing two alkyl groups either at the 3 and 8 positions of pyrene or at the 2-position of the pyridyl rings ([Scheme 19]).[51d] These pyrene derivatives were borylated using BCl₃/AlCl₃ in the presence of 2,6-di-tert-butylpyridine (DTBP) and the resulting BCl₂ complexes were then reacted with the organozinc compounds to afford phenyl- and ethyl-substituted azaboroles 65a,b in yields of 23 and 73% respectively, and azaborinines 67a,b in yields of 70 and 62%. These compounds exhibited high stability in air both in the solid state and in solution. As expected, when no alkyl substituents were attached to the pyrene, the reaction proceeded preferentially to form the five-membered rings with the boron atoms attached at the 2,7-positions. Importantly, due to the presence of the tridecyl chain at the neighboring 2-pyridyl position, the B–N bonds were weakened, as indicated by the increased B–N lengths in 65b (1.658(3) Å) compared with the azaborinine derivatives 67a,b (1.623(3)–1.629(5) Å), and the low-field shift in the ¹¹B NMR spectrum. The introduction of the octyl substituents at the 3 and 8 positions of pyrene induced the borylation at the 5,10-positions of the K region, typically more difficult to functionalize, and thus the formation of the six-membered rings. The same principle was used to extend the π-system of anthracene. A similar borylation reaction (BCl₃/AlCl₃ with DTBP) of dipyridylanthracene, followed by the ligand exchange using organozinc reagents provided complexes 69a–c bearing ethyl, phenyl, or pentafluorophenyl substituents on boron ([Scheme 19]).[51e] As in the synthesis of pyrene derivatives 67a,b, the steric effect exerted by the phenyl rings at the 9 and 10 positions of anthracene directed the azaborole ring closure at the 3,7-positions.

Scheme 19 π-Extension of pyrene and anthracene by electrophilic C–H borylation.

These conditions were also effective for the double borylation of less reactive pyrazine derivatives.[52]

A less commonly used electrophile in electrophilic borylation is BI₃. In 2019, Hatakeyama and coworkers[53] demonstrated the use of this reagent in tandem double electrophilic borylation. The reaction of ligand 70 with BI₃ and N,N-dimethyl-p-toluidine (DMPT) as base at 140 °C followed by substitution using AgF or PhMgBr afforded products 71a and 71b in yields of 52 and 40%, respectively ([Scheme 20]). Contrary to expectations, the [5, 6] annulation product was formed in the first step instead of the [6, 6] annulation compound. Density functional theory (DFT) calculation revealed that the observed product is thermodynamically more stable than the [6, 6] annulation product, explaining the reaction outcome.

Scheme 20 Electrophilic borylation using BI₃.

The growing interest in various B-embedded compounds stimulates the development of new approaches. In 2015, Ingleson[49] addressed the problems encountered during the arylation of the boron center with commonly used organometallic reagents, such as organolithium, -aluminum, -zinc, or Grignard reagents, i.e. low yields, poor stability of organometallic reagents and cumbersome isolation of the desired products. His group presented a new way toward functionalized four-coordinate organoboranes (e.g. 35ae, 73, and 74) via boro-destannylation and boro-desilylation ([Scheme 21a]). According to this method, haloboron compound 75 is subjected to a reaction with R₃EAr (where E = Sn or Si) and a catalytic amount of AlCl₃. The latter subtracts a halide atom to form three-coordinate borenium cation Int4. This reactive species can then react with R₃EAr, leading to the installation of the Ar moiety on boron. The generated by-product R′₃ E⁺ can produce further borenium cations, allowing the process to be carried out using catalytic AlCl₃ ([Scheme 21b]). As in other transmetalation reactions, the success of boro-destannylation and boro-desilylation depends on the electrophilicity of the borenium cation and the nucleophilicity of the organometallic reagent. While the reactions with stannanes proceed smoothly at room temperature, leading to the two-fold substitution, analogous boro-desilylation requires prolonged reaction times and results in the installation of either a single or two groups, depending on the reactivity of the reaction partners. For instance, the reaction of 63 with PhSnBu₃ in the presence of catalytic AlCl₃ provided 35ae within minutes, whereas the same transformation using PhSiMe₃ required 10 hours for completion. In addition, the double Si–B exchange either with a less nucleophilic trimethyl(3-bromophenyl)silane or dimethylsilole was carried out at 60 °C to afford 74 and boron-centered spiro compound 73 in high yields. Importantly, for the boro-desilylation reactions at elevated temperature, CH₂Cl₂ had to be exchanged with o-dichlorobenzene to avoid Friedel–Crafts alkylation.

Scheme 21 (a) Synthesis of aryl-substituted azaboroles by boro-destannylation and boro-desilylation. (b) General mechanism of these reactions proposed by Ingleson based on experimental results, reactivity studies supported by DFT calculations for stationary points.

Aside from being convenient (no use of glovebox, mild conditions, and isolation of the product only by filtration through a plug of silica) and providing the boron complexes in good yields of up to 92%, this method, with a judicious selection of reagents, allows the subsequent functionalization of the boron center with two different moieties.

In addition to standard BX₃ (X = Cl, Br, or I) electrophiles, the use of less reactive RBX₂ or R₂BX species in N-directed electrophilic C–H borylation is reported. Whenever applicable, the reactions with RBX₂ and R₂BX allow direct access to products functionalized at the boron atom, i.e. bearing substituents other than only halides. A notable example is stereoselective borylation of stannylated and mercurated pyridylferrocene derivatives with PhBCl₂ ([Scheme 22]).[54] The reaction of this electrophile with 79 proceeded with inversion of the absolute configuration, while the configuration was retained in the borylation product of 77. These stereochemical outcomes imply different reaction mechanisms. The mercurated precursor undergoes transmetalation from mercury to boron (the C–Hg position is directly attacked by the boron electrophile) to afford compound (pS)-78 in 37% yield and with 90% ee. In contrast, the formation of the pR-enantiomer with excellent enantiomeric excess (99% ee) is favored for the organotin compound via N-directed electrophilic borylation where the postulated borenium cation attacks at the adjacent C–H position. Due to the high nucleophilicity of the ferrocene cyclopendadienyl ring both reactions proceeded readily at low temperature and with no need for a Lewis acid catalyst. Importantly, as indicated by the reaction of (pS)-79 with 1 equivalent of PhBCl₂ and the control NMR experiments, the latter transformation requires the use of 2 equivalents of PhBCl₂, as the one of the methyl groups located on tin can be substituted by chloride, resulting in the formation of the less reactive PhMeBCl species. The proposed mechanism of this reaction, investigated by a series of NMR experiments, involves the complexation of the borane to the nitrogen atom of the pyridyl group in the first step, with possible formation of a reactive borenium species. This is followed by an intramolecular electrophilic attack of the boron moiety on the neighboring carbon atom of the ferrocene cyclopendadienyl ring. Subsequently, a proton transfer to the C–Sn position, possibly mediated by the pyridine moiety, takes place, followed by the release of Me₂SnCl₂ and Me₃SnCl as by-products.[54a]

Scheme 22 Stereoselective synthesis of azaborole 78 by transmetalation (top) and electrophilic C–H borylation (bottom) using PhBCl₂.

Wang, Yu, and co-workers reported the use of TfOB ⁿ Bu₂ as a boron electrophile in S_EAr of 2-arylpyridines.[55] The reaction of 2-phenylpyridine with 1.5 equivalents of TfOB ⁿ Bu₂ (82) under optimized conditions was performed in the presence of Et₃N in toluene at 80 °C to afford azaborole 81a in 97% yield. The type of base, solvent, and temperature were found to be critical to the success of this reaction. The substrate scope was investigated for a wide range of 2-arylpyridines bearing alkyl, alkoxy, and halide substituents either at a pyridine or carbocyclic moieties, 2-(thiophen-2-yl)pyridine, and derivatives with annelated rings ([Scheme 23]). Notably, all the azaborole products possessed two ⁿ Bu substituents on boron, defined by the type of boron electrophile. The study showed that Me, OMe, and OCF₃ groups and a thienyl moiety were well-tolerated providing the target compounds in 86 – 93% yields. The fact that OMe is compatible with the reaction conditions can be correlated with the lower Lewis acidity of the borane electrophile. Not surprisingly, the introduction of electron-withdrawing groups (EWG), such as CO₂Me, CF₃ and halides had a negative effect on the reaction efficiency, with the lowest yields for strongly deactivated starting materials 80f (30%) and 80n (22%) bearing CF₃ or two fluoride substituents, respectively.

Scheme 23 Direct synthesis of 1,2-azaboroles using TfOB ⁿ Bu₂.

In contrast to the borylation of 2-(naphthalen-1-yl)pyridine with BBr₃,[43] its reaction with TfOB ⁿ Bu₂ favored five-membered azaborole 81s (52%) over the closure of a six-membered ring to give regioisomer 81s′ (20%).[55] Likewise, the product distribution in the borylation of 2-(naphthalen-2-yl)pyridine with TfOB ⁿ Bu₂ differed to that of a similar reaction with BBr₃ under Murakamiʼs conditions.[41] Here, the major product was sterically less hindered 81t obtained in 47% yield. In both cases, isomers 81s and 81t were formed preferentially over the respective borylation products of the more nucleophilic 1 and 8 napthyl positions, indicating thermodynamic control.

A more recent work by Piers reported a new borylation reagent, (C₆F₅)₂BNTf₂, allowing the introduction of pentafluorophenyl groups in the presence of DTBP. Two experiments suggested that the order of addition of the reaction components can significantly affect the efficiency and rate of the reaction, as shown for azaborole 15b. Upon addition of DTBP to the mixture of 2-phenylpyridine and the boron reagent, the reaction required heating at 100 °C to ensure high conversion. However, when DTBP and (C₆F₅)₂BNTf₂ were mixed first and then 33a was added, the reaction could be performed at room temperature and the conversion was quantitative.[56]

In 2018, Song and co-workers described an efficient method for the synthesis of four-coordinate boron compounds consisting of five- and six-membered boracycles from N-arylpyridine-2-amines or 2-arylpyridines ([Scheme 24a]).[57] In this protocol, an aryltrifluoroborate was combined with tetrachlorosilane and an amine in one reaction vessel to initiate a reaction cascade including B–Cl/C–B metathesis and C–H bond borylation of the pyridine derivatives. This reaction sequence afforded, among others, compounds 84a and 84b in moderate to good yields (72 and 42%, respectively). While the azaborole products were synthesized only with phenyl substituents on boron, the general method is also amenable to ArBF₃K bearing electron-donating and -withdrawing groups, as well as heteroaryl- and vinyltrifluoroborates. As described by Kim and Matteson,[58] SiCl₄ acts as a fluorophile in this transformation to generate aryldichloroborane 85b from ArBF₃K, a valuable intermediate in the synthesis of various boracyclic compounds.[59] This species then reacts with another molecule of ArBF₃K to provide diphenylchloroborane 85d via B–Cl/C–B cross-metathesis ([Scheme 24b]). Experimental mechanistic studies confirmed that this intermediate is the species involved in N-directed electrophilic borylation to form an azaborole ring. In principle, S_EAr can also occur between 85b and arylpyridine, followed by fluorination,[60] although the side-products were formed only in trace amounts under optimized reaction conditions. Here, the reaction temperature and addition of EtN ⁱ Pr₂ proved essential for achieving high selectivity of this transformation.

Scheme 24 (a) Synthesis of four-coordinate boron compounds by cascade B–Cl/C–B cross-metathesis and N-directed C–H bond borylation. (b) Proposed mechanism of target compounds and side-products based on experimental mechanistic studies and previous reports.

When two different ArBF₃K are employed, the method offers the possibility of preparing azaboroles bearing two different substituents at the boron center. To avoid the formation of side-products, i.e. the compounds substituted with two identical aryl substituents, the authors combined electron-deficient and electron-rich aryltrifluoroborates, where species 85b is generated from an electron-poor aryltrifluoroborate and reacted with an electron-rich ArBF₃K in the next step.

A noticeable implementation of this methodology is illustrated by the synthesis of borylated pyrrolo[3,2-b]pyrroles (PPs), a highly interesting class of compounds discovered by the Gryko group.[61] Treatment of the pyridine-substituted PP with BBr₃ and a base under Murakamiʼs conditions led to their complete decomposition. On the contrary, the reactions of parent 1,2,4,5-tetraarylpyrrolo[3,2-b]pyrroles (TAPPs) with aryltrifluoroborate in the presence of SiCl₄ afforded targets 87a–h in 8 – 62% yields ([Scheme 25]).

Scheme 25 Synthesis of TAPP-based azaboroles performed by Gryko.[61]

 

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2.3 Transition Metal-Catalyzed C–H Borylation

Transition metal-catalyzed direct borylation via C–H bond activation is a highly useful, versatile, and well-established approach to synthesize diverse boron-functionalized compounds, often intermediates in the synthesis of more complex molecules.[62] In contrast to the methods based on transmetalation, no prefunctionalization (vide infra) or preceding functional group manipulation is required.[63] The issue of site-selective introduction of substituents can be effectively addressed through the utilization of directing groups. Despite these advantages, transition metal-catalyzed borylation has rarely been used to form 2H-1,2-azaborole rings. One of the few examples was reported by Kuninobu and Takai who investigated the palladium-catalyzed ortho-selective C–H borylation of 2-phenylpyridine and its derivatives.[64] They tested several borane reagents, but only 9-borabicyclo[3.3.1]nonane (9-BBN) proved suitable due to its higher Lewis acidity compared with pinacolborane and bis(pinacolato)diboron, allowing the generation of azaboroles under mild conditions. Thus, the reaction of this reagent with 2-phenylpyridine in the presence of a catalytic amount of Pd(OAc)₂ in 1,2-dichloroethane at room temperature for 24 h afforded the corresponding azaborole 90a in a yield of 87% ([Scheme 27]). In contrast to the standard directed C–H activation reactions, the Lewis basic nitrogen atom is not directly coordinated to the metal atom, but forms Lewis base/Lewis acid adduct Int5 with the boron atom of 9-BBN, analogous to N-directed electrophilic C–H borylation (Section 2.2, vide infra). This step is followed by oxidative addition of the B–H bond to the Pd(0) species (Int5→Int6), σ-bond metathesis to form Int7, and reductive elimination to give an azaborole product (see [Scheme 26]).

Scheme 26 Proposed mechanism for the formation of azaboroles by palladium-catalyzed C–H borylation of phenylpyridines (not supported by experimental or theoretical mechanistic studies).

Scheme 27 Synthesis of 1,2-azaboroles by nitrogen-directed palladium catalyzed borylation. ^[a]Reaction conducted at 50 °C

The reaction tolerates both electron-donating ([Scheme 27], 90b, 90d, 90h) and -withdrawing groups at either side of the starting material, although the yield is significantly lower for the CF₃-substituted compound 90c. It is also compatible with extended aromatic scaffolds (90e, 90f), and other N-containing heterocycles, such as 4,5-dihydrooxazole (90j) and pyrazole (90i), reaching the highest yield for the latter compound. When benzo[h]quinoline was used as the starting material, the yield decreased to 19% (90g). This is probably due to the rigid scaffold of this heterocycle, which does not allow the favorable geometry of an azaborole ring to be achieved, as opposed to other derivatives in which the carbocycle and pyridine moieties are linked by a single C–C bond. It is important to note that ligands 89e and 89f can potentially give rise to two regioisomers. Yet the reaction occurred at less sterically hindered positions in each case to give 90e and 90f in 77 and 50% yields, respectively. This demonstrates the preference for thermodynamic control and orthogonal regioselectivity compared with the N-directed electrophilic borylation with BBr₃ in the presence of a tertiary amine, as is evident for ligand 89e.

The reaction was not effective for 2,6-diphenylpyridine, and less nucleophilic 2-phenylpyrimidine or 2,3-diphenylpyrazine 91. The two-fold borylation of the latter ligand was, however, successfully executed at 135 °C upon switching from Pd(OAc)₂ to a rhenium catalyst. Under these conditions, target compound 92, containing two azaborole rings, was isolated in a yield of 51% ([Scheme 28]).

Scheme 28 Synthesis of a 2,3-diphenylpyrazine-based 1,2-azaborole by rhenium-catalyzed borylation.

Interestingly, borylation also took place in the absence of a palladium catalyst when the temperature was increased to 135 °C to afford 90a in a good yield of 73%. The addition of a radical scavenger such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) or galvinoxyl completely inhibited the reaction, indicating that the metal-free reaction is likely to follow a radical mechanism. The yields were satisfactory, although generally lower. However, the reaction failed to proceed for the condensed ligand 89g and ligands containing five-membered heterocycles 89i,j. This is most likely due to the higher geometric requirements, i.e. a greater distance between the nitrogen and the ortho-carbon atom, hindering the borylation in the absence of the Pd catalyst.

Later work by Kuninobu demonstrated that an iron catalyst could also be used with great success in the nitrogen-directed borylation of 2-arylpyridines.[65] Replacing much more expensive Pd(OAc)₂ with FeBr₃ provided previously described azaborole 90a in a slightly higher yield of 93%, although the reaction temperature had to be raised to 90 °C to achieve this efficiency ([Scheme 29]).

Scheme 29 Synthesis of 1,2-azaboroles by nitrogen-directed iron-catalyzed borylation.

Changing 1,2-dichloroethane to a more polar solvent, such as THF, acetonitrile, pyridine, or acetone, completely inhibited the reaction. Furthermore, significantly reduced yields or trace amounts of the product were observed when FeBr₃ was replaced by FeF₃, FeCl₃ or Fe(0), Fe(I), and Fe(II) catalysts, thereby indicating that FeBr₃ is the optimal catalyst for this process. The reaction conditions using this catalyst were applied to different phenylpyridine derivatives substituted with electron-withdrawing and -donating groups ([Scheme 29], 90b–d and 94a–k) to afford the azaboroles in yields of 50 – 86%. The highest yield was obtained for 94k bearing a CF₃ group on the phenyl side and a para-trifluoromethylphenyl group on the pyridine ring. The reaction also tolerated the presence of a thiophene ring and a silyl group in 93p and 96n. These compounds were successfully borylated to give the corresponding products in yields of 79 and 83%, respectively.

Importantly, the regioisomeric outcome of the FeBr₃-catalyzed borylation of 90e and 90f was identical to that observed in the Pd(OAc)₂-catalyzed reactions with a markedly enhanced yield of azaborole 90f.

The plausible mechanism resembles that of the Pd(OAc)₂-catalyzed borylation. As in the latter case, the reaction is likely initiated by the complexation of boron to the Lewis basic nitrogen atom to give Int8 ([Scheme 30]). This step is followed by the formation of the boryl-iron species Int9, a subsequent iron-catalyzed C–H activation, resulting in intermediate ferrocycle Int10, and a final reductive elimination to give a target azaborole.

Scheme 30 Plausible mechanism for the formation of azaboroles by iron-catalyzed C–H borylation of phenylpyridines, deduced from some experimental results and basic DFT calculations.

Overall, iron-catalyzed borylation generally provided slightly increased yields when compared with the palladium-catalyzed reactions. However, it is important to note that this was achieved at an elevated temperature and with a higher catalyst loading.

 

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2.4 Cycloadditions

Cycloaddition reactions represent powerful and versatile tools in organic preparative chemistry for the formation of C–C bonds.[66] In particular, the ability to form multiple bonds simultaneously and stereogenic centers in a single step, often with a completely predictable outcome, renders them extremely useful. Several elegant examples of the azaborole synthesis by Diels–Alder reaction or 1,3-dipolar cycloaddition have been published to date. They rely on two general approaches. In the first approach, a boron atom is precoordinated to the nitrogen-containing aryl ring, while the cycloaddition leads to the formation of the other ring. In the second approach, the construction of a nitrogen-containing ring by cycloaddition is followed by boracyclization to give an azaborole.

An important contribution to this field was made by Harrity and co-workers who extensively investigated the directed cycloaddition of 2-pyrones with akynylboronates. These reagents in a nondirected variant of cycloaddition usually require harsh conditions for the reaction to proceed, while the reaction itself shows a low degree of regiocontrol, issues that are circumvented in directed cycloadditions.[67] The introduction of a Lewis basic pyridinyl nitrogen in a diene partner enables preassociation with a boron-containing alkyne, thereby promotes the reaction and determines its regioselectivity. The authors found that the product distribution depends on both the number of Lewis acid equivalents and the reaction temperature. When pyrone 97a was stirred with 3 equivalents of trifluoroborate 98a in the presence of 3 equivalents of BF₃•OEt₂ at 40 °C, the reaction afforded difluorinated complex 99a in a yield of 82% along with alkynylated products 100 and 101 in yields of 5% each ([Scheme 31]). Stirring at 40 °C with 1 equivalents of the Lewis acid led selectively to difluorinated product 99a although in a lower yield, while reducing the temperature increased the yields of 100 and 101.[67b]

Scheme 31 Synthesis of 1,2-azaboroles 99a-101 by cycloaddition of 2-pyrones with an in situ generated alkynylborane.

In-depth theoretical and experimental studies revealed a complex reaction mechanism and provided an explanation for the presence of mixed products bearing fluoride and/or alkynyl substituents on boron. Initially, the in situ generated alkynyldifluoroborane undergoes a rapid equilibration to generate bis- and tris(alkynyl)boranes. All these compounds engage in cycloaddition with a pyrone diene to form the three azaboroles differing in the substituents on the boron. The subsequent ligand exchanged with BF₃ leads to the exclusive or predominant formation of the difluoride complex.[67a] The latter step was confirmed by the reaction of tert-butylalkynyl-substituted azaborole 103, selectively generated from 97a and tris(alkynylborane) 102, with BF₃•OEt₂, which afforded 104 in a nearly quantitative yield ([Scheme 32]).[67a]

Scheme 32 Synthesis of compound 104 by cycloaddition with a tris(alkynylborane) and a subsequent ligand exchange with BF₃•OEt₂.

The procedure for the difluorinated products could also be applied to the precursors bearing electron-donating groups (Me, OMe) on the pyridine ring (products 99b and 99c), as well as to pyrones containing other N-heterocycles, such as thiazole and oxazole (products 99d and 99e), to give the corresponding boron complexes in good yields of 67 – 82% ([Scheme 33]).[67b]

Scheme 33 Synthesis of 1,2-azaboroles with fluoride ligands on boron by cycloaddition of 2-pyrones with an in situ generated alkynylborane.

Additionally, substituting BF₃ for BCl₃ or BBr₃ permitted the synthesis of dichloro and dibromo adducts 105 and 106 in yields of 89 and 68%, respectively. ([Scheme 34]).

Scheme 34 Synthesis of 1,2-azaboroles with chloride and bromide ligands on boron by cycloaddition of 2-pyrones with an in situ generated alkynylborane.

In particular, BCl₃ proved to be highly effective in this transformation, affording 105 in a yield of 93% when the reaction temperature was lowered to 0 °C, and in a satisfactory yield of 84% when the number of equivalents of alkyne and Lewis acid was further reduced to two ([Scheme 34]). The latter conditions enabled the synthesis of a variety of azaboroles with aryl, alkyl, or trimethylsilyl (TMS) substituents on a carbocyclic ring and a pyridine or a 2-thiazole N-heterocyclic moiety ([Scheme 35]). The reaction of 107f with the TMS-substituted alkyne was more sluggish and therefore was conducted at 40 °C. A similar problem was encountered in the synthesis of 4-azole derivatives 99d–f and 107g–i, which was consistently carried out at an elevated temperature. Compared with the 2-substituted oxazole derivatives, the reactivity of the precursors lacking the substituent at this position was significantly lower. Consequently, the reaction time had to be increased to 3 days.[67a]

Scheme 35 Synthesis of 1,2-azaboroles by cycloaddition of 2-pyrones with in situ generated alkynylboranes.

It is important to note that neither ¹¹B NMR nor X-ray diffraction analysis have been used to verify the binding mode in these compounds. However, it is reasonable to assume that the majority of the products exist in a closed azaborole forms, based on nucleophilicity of the N-heterocycle, the fully characterized examples, and other structures reported in the literature.

This synthetic approach could be extended to the Diels–Alder cycloaddition of pyridyl-1,2,4-triazines, 1,2,4,5-tetrazines, and sydnones with in situ generated alkynyldifluoroboranes.[68]

The key step in the synthesis of azaboroles from a 1,2,4-triazine was precoordination of alkynylborane to its nitrogen atom, which allowed to lower the reaction temperature from 180 °C for an alkyne lacking BF₂ to 40 °C and shorten the reaction time from 48 hours to 10 minutes, while generating the target azaborole in a significantly higher yield. The reaction tolerated alkyl and aryl substituents on the triazine ring (109a–e) and was even amenable to ester functionality (109g,h), providing fluoride-substituted products 109 in moderate to high yields ([Scheme 36]).[68a]

Scheme 36 Synthesis of 1,2-azaboroles by cycloaddition of 1,2,4-triazines with in situ generated alkynytrifluoroboranes in the presence of BF₃•OEt₂.

Interestingly, cycloadditions of 110 and 112 with 98a revealed a supportive role of the Lewis basic nitrogen.[68a] The reaction of 110 with the nitrogen atom more distant from the biaryl axis did afford the azaborole, but it was sluggish and ca. 10% of the starting material was recovered. This result was consistent with the outcome of the cycloaddition of 112 with 98a. The compounds possessing two reactive sites, preferably underwent boracyclization at the site where the triazine nitrogen atom was adjacent to the pyridine–triazine axis ([Scheme 37]).[68a]

Scheme 37 Effect of the positioning of the nitrogen directing atom and regioselectivity of the cycloaddition of 1,2,4-triazines with an in situ generated alkynytrifluoroborane.

The nitrogen-directed inverse electron demand aza-Diels–Alder (IEDDA) reaction also provided easy access to pyridazine-containing azaboroles under mild conditions. When TMSCl was used as the fluorophilic Lewis acid, the reactions of 1,2,4,5-tetrazines and generated alkynyldifluoroboranes could be carried out at room temperature in most cases, providing the cycloaddition products, such as 116a–e, in good to nearly quantitative yields and complete regioselectivity, as demonstrated for unsymmetrical tetrazines, e.g. 116e ([Scheme 38]). Both the five- and six-membered N-heterocycles (pyrazole, pyridine) performed well as N-directing groups in this reaction.[69]

Scheme 38 Synthesis of 1,2-azaboroles by cycloaddition of 1,2,4,5-tetrazines with in situ generated alkynytrifluoroboranes in the presence of BF₃•OEt₂.

Jiménez-Osés and Bernardes transferred this useful reaction to aqueous media.[20a] However neither TMSCl nor BF₃•OEt₂, commonly used activators of alkynyltrifluoroborates, are compatible with water. Screening of various salts allowed the identification of AlCl₃•6H₂O as the key component promoting the reaction. Cycloaddition of 117 with 98b in a 1 : 1 MeCN/phosphate-buffered saline (PBS) (pH 7.6) system using this reagent afforded 118 with the hydroxyl boron substituents in 96% yield ([Scheme 39]). The reaction is favored at low pH and is therefore attributed to the concentration of AlCl₃•6H₂O, since [Al(OH)₆]³⁺ acts as a weak acid. This is attributed to the protonation of the pyridine, which lowers the LUMO level of the tetrazine (diene) and thus reduces the HOMO–LUMO gap between the diene and the dienophile, critical in an IEDDA reaction. This chemistry was applied to orthogonal labelling of two different protein–dienophile conjugates with different fluorophores appended to two tetrazines.

Scheme 39 Synthesis of a 1,2-azaboroles with the hydroxyl substituents on boron by cycloaddition of a 1,2,4,5-tetrazine with an in situ generated alkynytrifluoroborane promoted by AlCl₃•6H₂O.

In contrast to the products generated from triazines or tetrazines, the reaction with sydnones furnished pyrazole-containing dialkynylboranes, with no fluoride-substituted azaboroles observed. The general principle is similar: the boron atom of the alkynylborane is coordinated to the nitrogen atom of the sydnone pyridyl substituent, which lowers the reaction temperature and determines its regioselectivity. The [4 + 2] cycloaddition of these compounds using the optimal ratio of BF₂•OEt₂ and alkyne of 2 : 5 allowed generating a variety of azaboroles usually in good to excellent yields ([Scheme 40]).[68b] Both N-alky and N-aryl sydnones, as well as alkyl, aryl, and even silyl or terminal alkynes could be successfully employed in this reaction (120a–i). Likewise, the substitution of the pyridyl directing group, i.e. the position and the electronic nature of the substituent (CF₃, OMe) provided highly satisfactory results (120j–o). The directing group could also be replaced with other heterocycles with no detrimental effect on the reaction efficiency to produce oxazine 120q in a 94% yield or providing the product in a somewhat reduced yield (65%) for quinolone derivative 120p. Compared with oxazine 120q, oxazoline led to an inferior result (yield of 20%), likely due to unfavorable ring geometry of the oxazoline, furnishing 120r with the alkyne boron substituents replaced with OH during the workup.

Scheme 40 Synthesis of 1,2-azaboroles by cycloaddition of sydnones with in situ generated alkynytrifluoroboranes in the presence of BF₃•OEt₂. ^[a]The reaction was carried out for 4 h.

Cycloaddition can also be used to synthesize products bearing perfluoroalkyl substituents from pyridine-substituted pyrones, sydnones, tri- and tetrazines, albeit BCl₃ was found to promote the reaction more effectively.[70]

Pammerʼs approach differed from these methods in that the boron atoms were preinstalled on the aryl substrate in the ortho-position to the ethynyl groups. The cycloaddition resulted in the formation of an N-heterocycle, which then directly interacted with the neighboring boron atom to form a boracycle. This appealing way of constructing azaboroles was demonstrated in a copper-catalyzed azide–alkyne cycloaddition (CuAAC). Functionalized azide aryls 122a–c were reacted with (2,5-diethynyl-1,4-phenylene)bis(dimesitylborane) (121) in the presence of a catalytic amount of copper(I) iodide and Hünigʼs base to furnish 1,4-disubstitued triazoles 123a–c with two azaborole rings. While the yield for the methyl derivative 123a was only 29%, the efficiency of the cycloaddition for the methoxy- (123b) and trifluoromethyl derivatives (123c) was much higher (68 and 81% yields, respectively) ([Scheme 41]).[71] As there is no correlation between the electronic nature of the substituents and the reaction outcome, these results may be partly due to a different way of carrying out the reactions. An interesting feature of these compounds is that under ambient conditions they exist in dynamic equilibrium between the open, the half-open with no or one B⃪N bond, respectively, and the closed azaborole forms. The lability of the B⃪N bonds can be attributed to the lower basicity of 1H-1,2,3-triazoles compared with pyridine and electron-rich, bulky boron substituents that reduce the Lewis acidity of boron. As might be anticipated, these conformations display distinctive electronic properties related to the geometry of the compound (planar for the closed and twisted for the open forms) and the electronic character of boron (Lewis acidic for tricoordinated boron in the open form and electronically saturated tetracoordinated boron in the closed form). The dynamic behavior of these compounds could potentially be exploited in frustrated Lewis pair catalysis.

Scheme 41 Synthesis of azaboroles by CuAAC. PMDETA = N,N,N′,N′,N″-pentamethyldiethylenetriamine.

By reacting the same dialkyne with 1,12-diazidodecane 124 using a catalytic system of CuI and pentamethyldiethylenetriamine (PMDETA) in toluene/THF solution, they were able to synthesize azaborole-containing polymer 125 with a number-average molecular weight of M _n = 7.2 kDa in a yield of 61% ([Scheme 41]).[71] The dynamic behavior of BMes-functionalized azaboroles was investigated in more detail for a set of structurally related organoboron compounds 127a–j with a single boron center and varying functional groups on the triazole moiety from strong donors to strong acceptors. These compounds were obtained by CuAAc reactions between the corresponding aryl azides 122 and (2-ethynyl-5-methoxyphenyl)dimesitylborane (126) in yields of 80 – 93% ([Scheme 42]).[72] Extensive investigations revealed that these Mes-substituted azaboroles can adopt three main conformations, the closed form and two open forms syn and anti, depending on the orientation of the N-donor to the boron atom ([Scheme 42]). According to DFT calculations, the open-syn form is thermodynamically preferred for all compounds. The relative contribution of different forms depends on the electronic nature of the substituent on the triazole. In general, the stabilization of the open-syn is most pronounced for compounds bearing strong electron-withdrawing substitution, for which the lowest barriers to N→B dissociation were computed.

Scheme 42 Synthesis of 1,2-azaboroles by copper catalyzed azide-alkyne cycloaddition.

Another method for the construction of azaboroles, developed by Pammer and co-workers, which also relies on the generation of an N-heterocycle involved in the N→B coordination, is cobalt-catalyzed [2 + 2 + 2] cycloaddition.[9] The reaction of 128 with 1,7-octadiyne in a 2 : 1 ratio in the presence of CpCo(CO)₂ catalyst under UV irradiation at 350 – 400 nm furnished target compound 130a in a 12% yield. Microwave irradiation was found to be more effective than UV light, increasing the yield by a factor of two. When the ratio of the borane to the diyne was fixed to 1 : 4 and the catalyst loading was reduced to 2.5 mol% (relative to the diyne), 130a was isolated in a 37% yield or a 65% yield when corrected for an unreacted starting material. This method could be applied to diynes 129b–d, while 129e–h gave better results when the borane/diyne ratio was between 1.4 : 1 and 2 : 1, and a higher catalyst loading was used ([Scheme 43]). In the ¹¹B NMR spectra, all compounds showed resonances in the range of 4 – 5 ppm, indicating the closed form with tetracoordinated boron.

Scheme 43 Synthesis of 1,2-azaboroles by cobalt-catalyzed [2 + 2 + 2] cycloaddition. ^[a]Isolated yield. ^[b]Yield corrected for incomplete conversion.

Later, this general approach was extended to the synthesis of alkyl-tetrazole-functionalized compounds with a weak B⃪N bond by 1,3-dipolar [3 + 2] azide–nitrile cycloaddition starting from BMes₂-substituted precursors.[73]

 

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2.5 Photoisomerization

Among the diverse applications of organoboron compounds, their use in photosensitive systems is particularly notable, attributed to their unique photochemical behaviour. A significant contribution to the development of these materials has been made by the Wang group, which has undertaken extensive research on the photo- and thermal isomerization of various compounds containing azaborole structural motifs. Therefore, they synthesized a plethora of 2-phenylpyridin azaborole analogues with different aryl groups at the boron center and investigated their behavior under light irradiation. For instance, they observed that some azaborole derivatives upon exposure to ultraviolet light can reversibly isomerize to borabicyclo[4.1.0]hepta-2,4-diene or 4bH-azaborepins structures.[5c],[16b],[23a],[23c],[24c],[27],[31],[32],[74] Interestingly, they also reported the photoinduced generation of azaborole systems from other azaboraheterocycles. When B–N doped compounds 132, derived from the pyridyl-substituted naphthalene or acenaphthene precursors 131 by borylation with BMes₂F, were irradiated at 365 nm, the starting materials were completely consumed and borepin–azaborole systems 133a–c were produced in 40 – 60% yields ([Scheme 44]).[75] Thus, the reaction worked for both the more rigid scaffold 132c and the compound 132b with a more Lewis basic nitrogen atom. On the other hand, acenaphtylene borepin–azaborole 133d ([Scheme 44]) was not formed under these conditions, which was attributed to the existence of a low-lying excited state that quenched the photoreaction. Exposure to light of different wavelengths, i.e. 350 and 410 nm, provided comparable results.

Scheme 44 Synthesis of borepin- and azaborole-containing systems by transmetalation and subsequent photoisomerization.

According to the calculations, the photoexcitation of 132R induces the migration of one mesityl substituent to the neighboring carbon atom, which upon conical intersection leads to ground-state intermediate Int1-S₀ of a biradical character. This species is then converted into borepin–azaborole 133R via borirane–azaborole intermediate Int2-S₀ ([Scheme 45]).

Scheme 45 The plausible mechanism of the photoinduced isomerization of 132R to 133R and CASPT2//CASSCF potential-energy profile for this process. Adapted with permission from Ref. [75]. Copyright 2018 Wiley-VCH GmbH.

The following study shed more light on this process. When irradiating the analogs of 132a with different substituents on the boron atom at two different wavelengths, Wang and co-workers observed a controllable, sequential two-step photoisomerization.[76] The starting materials were again obtained by lithiation of the halogenated precursors and subsequent treatment with the respective ClBAr₂ reagent. Upon irradiation with light at 365 nm, diphenyl congener 132e underwent clean and quantitative isomerization to borirane 134e. Exposure of the same compound to light of 450 nm (LED lamp with FWHM of 50 nm) yielded a mixture of 133e and 134e in a ratio of 1 : 1.2 ([Scheme 46]). While the borepin could be isolated by column chromatography and was stable under ambient conditions, the borirane species degraded slowly when exposed to oxygen. Irradiation of this mixture or pure borepin 133e at 365 nm led to their quantitative conversion to 134e. On the other hand, when the latter compound was irradiated at 450 nm, again a 1 : 1.2 mixture of 133e and 134e was formed. Based on these results, they hypothesized, that the borepin species may be a photoisomerization intermediate. For derivatives 132f and 132h with the electron donating p-Me and p-OMe groups on the phenyl substituents, the borepin species were favored over the borirane species when irradiated at 450 nm, as opposed to the phenyl congener, whereas 133g was formed quantitatively. This effect of the substituents was also observed for irradiation at 365 nm. In contrast to the p-methoxy- and p-methylphenyl-substituted borepin species, which were quantitatively or nearly quantitatively converted into the boriranes, the equilibrium in the photostationary state for the xylyl derivative was shifted toward the borepin species. Furthermore, as shown previously, no borirane species could be observed for mesityl compound 132a, upon irradiation with light at 365 nm (and also at 450 nm), indicating that bulky substituents on the boron atom favor the formation of the borepin isomer. No photoreaction was observed for compounds equipped with electron-withdrawing groups, such as 3,5-bis(trifluoromethyl)phenyl and pentafluorophenyl derivatives, in line with their high fluorescence quantum yields.

Scheme 46 Photoisomerization of diarylazaborinines 132e–h to borepins 133e–h and boriranes 134e–h.

However, when only a single electron-withdrawing substituent was placed on boron, the compounds were not inert toward irradiation. Importantly, for mixed substituents, the migration of less bulky and more electron-donating substituents is preferred to form the corresponding borepins.[77]

The thiophene substituents on boron open up a new isomerization pathway. The generated boriranes can be converted regio- and stereoselectively at 80 °C by boravinylcyclopropane–boracyclopentene rearrangement into the corresponding unusual polycyclic structures 135i,j. These compounds can be transformed to either 133i,j or 134i,j by irradiation with light of appropriate wavelength ([Scheme 47]).[77]

Scheme 47 Photoisomerization of borepins 133i,j to boriranes 134i,j and boracyclopentenes 135i,j.

 

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2.6 Hydroboration

In addition to photoisomerization pathways of five-membered BN heterocycles, Wang and co-workers investigated alternative synthetic routes to access azaboroles. The new method involved the trans-hydroboration reaction of a variety of different internal 2-(arylethynyl)pyridines.[78] Hydroboration has been used to construct boracycles of various sizes from different types of starting materials and with a variety of HBR₂ boranes, but the reports on the use of this approach in the chemistry of azaboroles are scarce.[79] Stirring alkynes 136 in the presence of 9-BBN (88a) in toluene or benzene at room temperature furnished novel blue-fluorescent BN heterocycles 137 ([Scheme 48]). In contrast to the methods reported by Takai and Kuninobu, which required stirring at elevated temperatures when no catalyst was employed (see Section 2.3), Wangʼs catalyst-free method allowed the synthesis of 137 under mild conditions. The reaction proceeded via a trans-selective hydroboration, which proved to be versatile for a variety of 2-(ethynyl)pyridines in 40 – 75% yields. Besides the phenyl-derivative 136a, the reaction tolerated more electron-rich substrates, such as 136b, or electron-poor alkynes, bearing bromo- (136d,g,h) or trifluoromethyl (136f) groups on phenyl or pyridyl rings. Even products with a ferrocenyl (137e) or the bulky trimethylsilyl group (137c) could be obtained in good yields, although the latter reaction had to be stirred at 45 °C instead of room temperature. The reaction failed only for substrates with strong electron-donating groups, such as methoxy on the phenyl ring, as well as the TMS group at the meta-position of the pyridyl ring. The plausible mechanism involves the formation of a Lewis adduct and the migration of the borane hydride to the proximal sp-hybridized carbon of the ethylene moiety, leading to trans-hydroboration, which is energetically more feasible than cis-hydroboration according to DFT calculations.[78]

Scheme 48 Synthesis of 1,2-azaboroles by trans-hydroboration of 2-(arylethynyl)pyridines with 9-BBN.

 

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2.7 Coordination–Cyclization

Yamaguchi and co-workers investigated the intramolecular double cyclization of diphenylacetylene building blocks to synthesize novel oligo(p-phenylenevinylene) skeletons. These studies resulted in a range of ladder compounds with several types of bridging moieties.[80] Substitution of phenyl with pyridine at the acetylene bridge yielded singly and doubly cyclized B–N coordinated compounds.[81] The reaction of di(2-pyridyl)acetylene 138a with bromodibenzoborole 139 in THF and subsequent stirring with water afforded a mixture of 140a and 141a in yields of 20 and 30%, respectively ([Scheme 49]). Comparable results were achieved for di(2-thiazolyl)acetylene. BF₃ etherate and dimesitylboron fluoride used in place of bromodibenzoborole were not reactive toward 138a.

Scheme 49 Synthesis of 1,2-azaboroles by coordination-induced intramolecular double cyclization.

 

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2.8 Nucleophilic Aromatic Substitution

An interesting, but limited to certain building blocks, approach to generating azaboroles is nucleophilic aromatic substitution. This method has its origins in the work of Siebert and co-workers, who examined the deprotonation of a 1,4,5-trimethylimidazole-borane adduct with a lithium base to give the corresponding N-heterocyclic carbene, and the reactivity of the newly formed adduct.[82] Erker followed this idea by reacting N-methylimidazoles with B(C₆F₅)₃ to form the Lewis adducts 142a,b ([Scheme 50]). Their treatment with MeLi then led to the release of methane and the formation of lithiated adducts 143a,b. These unstable species further reacted by nucleophilic aromatic substitution at one of the pentafluorophenyl groups under LiF elimination to the corresponding azaboroles. The isolation involved only the removal of LiF by filtration and evaporation of the solvents to afford 144a and 144b in yields of 89 and 94%.[83] This chemistry was later extended by Erker and Yamaguchi to prepare larger systems by the formation of two azaborole rings.[84] The precursors consisted of two thiazolyl moieties linked by a π-bridge, i.e. fluorene and bithiophene. These compounds were treated with B(C₆F₅)₃ to form the corresponding adducts 146a,b. Instead of using MeLi, they applied LDA to deprotonate the thiazole rings leading to the ring closure. After recrystallization, azaboroles 147a,b were obtained in 73 and 48% yields, respectively. The attractive feature of this synthetic route is the possibility of incorporating boron and electron-poor perfluoroaryl moieties into the molecular backbone in a two-step process, which has been shown to enhance the electron-accepting character of the molecules by lowering their LUMO energy levels.

Scheme 50 Deprotonation of Lewis base-B(C₆F₅)₃ adducts leading to intramolecular nucleophilic aromatic substitution and the formation of (C₆F₅)-substituted azaboroles.

 

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2.9 Silicon–Boron Exchange

Silicon–boron exchange reactions are commonly applied in synthetic chemistry to construct a variety of different boron-containing heterocycles, macrocycles, oligomers, and polymers, or simply to convert silyl-substituted compounds into boron analogues.[49],[85] However, these reports are limited to tri- or dimethylsilyl derivatives and there has been no precedent for the use of bulkier silyl groups. Our group has introduced a new method for the construction of 1,2-azaboroles by silicon–boron exchange between triisopropylsilyl (TIPS)-substituted teraryls and boron reagents.[86] Thus, symmetrical dithienothiophene building block 148 bearing two TIPS protective groups at the 2 and 5-positions and two isoquinoline moieties at the 3 and 4 positions was treated with either boron trichloride or tribromide at room temperature for 6 hours to afford the respective azaboroles ([Scheme 51]). Due to their very low solubility these compounds were not isolated but reacted with trimethylaluminium at room temperature. Ligand exchange at the boron atom of both intermediates afforded helicene 149 in yields of 45 and 42%, respectively. This method proved superior to the reaction sequence consisting of electrophilic C–H borylation of the teraryl lacking silyl groups and the ligand exchange, which yielded the target helicene in a yield below 5%.

Scheme 51 Synthesis of azaborathia[9]helicene 149 by a silicon-boron exchange reaction.

 

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3 Conclusions and Outlook

In this review, we have summarized the synthetic methodologies for the construction of 1,2-azaboroles embedded in PAHs. By far the most prominent approaches are lithiation–transmetalation with a boron reagent and electrophilic C–H borylation. A disadvantage of the former approach is that in most cases, a functional group must be present for the lithiation step to steer the regioselectivity of the borylation. Conversely, electrophilic C–H borylation can be carried out without a leaving group, yet the challenge of regioselectivity persists in cases where more than one carbon atom is available for borylation. A large variety of boranes have been reported for both methods. Electrophilic borylation is conventionally executed using BBr₃ or BCl₃ in the presence of AlCl₃, which acts as a Lewis acid activator, and the bulky amine. Alternatively, the less reactive BRX₂, and BR₂X can be used to install the substituents on boron other than halides. Less commonly applied, yet also effective, are BI₃ and TfOB ⁿ Bu₂, the latter showing different regioselectivity to the reactions carried out with BBr₃. The boranes used in the lithiation–transmetalation approach are usually BAr₃, Ar₂BX (X = F, Br) and BR₂OE. It is important to note that the progress in this field is closely related to new and efficient synthetic protocols. These also depend on the boron reagents used.

The utilization of unsymmetrical boranes, accessible by hydroboration or transmetalation, results in the generation of a stereogenic center on boron. Consequently, this process gives rise to chiral azaboroles that are obtained as racemates, thereby necessitating the exploration of novel asymmetric synthesis methodologies. Indeed, enantio- or diastereoselective generation of boron-stereogenic compounds has been reported by Cu-catalyzed desymmetric B–H bond insertion starting from azaboroles bearing two H ligands on boron, asymmetric copper-catalyzed azide−alkyne cycloaddition (CuAAC) of diethynyl azaboroles, or lithiation–transmetallation using chiral aminoalcohol borinates.[87] However, these reports are still scarce.

We also demonstrated the richness of azaborole chemistry beyond the classical approaches. In addition to the standard methods employed to access 1,2-azaboroles, we discussed less commonly used approaches, i.e. N-directed transition metal-catalyzed borylation, cycloaddition reactions, photochemical rearrangements, coordination–cyclization, and hydroboration reactions, as well as the formation of BN-rings by silicon–boron exchange and nucleophilic aromatic substitution. This multitude of synthetic methodologies demonstrates that the scientific interest in azaboroles has flourished since the early example of 1,2-azaborole reported by Letsinger and McLean in 1960s.[40] This can be explained by the increasing interest in the implementation of boron in π-conjugated organic frameworks. Rigidification of the π-scaffold through boron-bridging paves the way to access novel compounds with unique properties, such as planar PAHs, boron-centred spiro compounds, and helically chiral derivatives.

We expect that the future work will be directed toward the development of new synthetic procedures that allow access to complex structures or compounds with previously unknown substitution patterns or ring combinations. Our own experience in this field has shown that some of our target compounds were not accessible by existing methods, prompting us to develop new protocols. In addition, the focus should be on elaborating regioselective methods that do not require prefunctionalization of the starting material as well as stereoselective syntheses for different types of boron-containing chiral materials.

Funding Information

A. N.-K. thanks the German Research Foundation (DFG) for an Emmy-Noether Fellowship (NO 1459/1-1). A. N.-K. and K. S. thank the Hector Fellow Academy (HFA) for financial support.

 

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Biosketches

Patrick T. Geppert

Patrick T. Geppert graduated in chemistry from the University of Bielefeld (Germany) in 2020. He completed his masterʼs thesis in the field of homogenous catalysis under the guidance of Prof. Dr Harald Gröger. In 2021, he joined Prof. Nowak-Królʼs group at the University of Würzburg as a doctoral candidate. He is currently developing synthetic methodology and working on boron-containing polycyclic aromatic hydrocarbons and helically chiral photoswitches.

Daniel Volland

Daniel Volland graduated from the University of Würzburg in 2019 after doing his masterʼs thesis in the group of Prof. Frank Würthner. He then joined the group of Prof. Nowak-Król where he conducted his PhD studies in the field of 1,2-azaborole-containing thiahelicenes at the Institute of Inorganic Chemistry and the Institute for Sustainable Chemistry and Catalysis with Boron.

Klaudia Szkodzińska

Klaudia Szkodzińska obtained her bachelorʼs (2020) and masterʼs (2022) degrees in chemistry from the University of Wrocław (Poland) working with Prof. Szafert. She then started her PhD studies under the supervision of Prof. Nowak-Król at the University of Würzburg (Germany), where she is working on the synthesis of helically extended and expanded azaborahelicenes.

Agnieszka Nowak-Król

Agnieszka Nowak-Król graduated from the Rzeszów University of Technology in Poland. She earned her doctorate at the Polish Academy of Sciences in Warsaw (Poland) with Prof. Daniel Gryko in 2013 and continued her career as an Alexander von Humboldt Postdoctoral Fellow with Prof. Frank Würthner at the University of Würzburg in Germany. In 2016, she started her independent career as a group leader at the Center for Nanosystems Chemistry (Germany). In 2019, she received the Emmy Noether fellowship to establish an independent research group. She was appointed junior professor at the University of Würzburg in 2020, and professor in 2024. Her main activities focus on the development of boron-containing helicenes and other chiral polycyclic aromatic hydrocarbons, photoswitches, and their applications in organic electronics and bioimaging. She is a recipient of several awards and honors including the Thieme Chemistry Journals Award, the Arnold Sommerfeld Prize of the Bavarian Academy of Sciences and Humanities, the Hector Research Career Development Award of the Hector Fellow Academy, and the Wojciech Świętosławski Prize of the Polish Chemical Society.

Conflict of Interest

The authors declare no conflict of interest.

^# These authors contributed equally to this work.

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Publikationsverlauf

Eingereicht: 05. April 2025

Angenommen: 05. Mai 2025

Accepted Manuscript online:
08. Mai 2025

Artikel online veröffentlicht:
09. Juli 2025