Science of Synthesis

DOI: 10.1055/sos-SD-230-00001

Fernández, E., Science of Synthesis: Advances in Organoboron Chemistry towards Organic Synthesis, (2019) 1, 1.

There are at least two main reasons for the impressive evolution of organoboron chemistry in recent years: the parallel development of new, accessible boron reagents and the growing application of organoboron compounds in organic synthesis, molecular receptors and sensors, novel materials, and biological probes. A testament to the enormous advances made in organoboron chemistry in the last two decades is that, despite the very diverse nature of the chapters contained within this work, the vast majority of the references cited throughout all chapters date from 2000 onwards, with most being from the current decade.

Since the discovery of the hydroboration of alkenes and alkynes as a convenient route to organoboron compounds, hydroborating reagents have become fundamental tools for the generation of new C—B bonds. Moving from borane (BH3) to more-selective mono- and disubstituted boranes, the hydroborating reagents have evolved into diboron reagents, which have now become major players in any type of borylation reaction due to their stability and accessibility. In particular, tetraalkoxydiboron reagents are nowadays considered a principal boron source, and efforts to develop innovative ways for B—B activation have stimulated their increasing use. Within the last decade, gem-diborylalkanes have erupted into the area of organoboron chemistry as a promising type of boron source, since they are also stable and provide many modes of activation and reactivity.

The rapid progress in the development of boron sources highlights their importance as pillars of organoboron chemistry; however, the intrinsic ways in which to convert these compounds into reactive species is equally important, and great efforts have been devoted to experimental and theoretical studies to generate new insights into the activation modes of B—H, B—B, and B—C—B reagents. As a natural consequence, we now have new concepts for the mechanistic understanding of C—B bond formation and Section 2, by Feliu Maseras and Jorge Carbó, provides a summary of the mechanistic aspects of several of the advanced borylation reactions covered within this volume, with a special focus on transition-metal-catalyzed reactions and also on the innovation achieved in the last two decades in transition-metal-free catalytic reactions.

Once the ground rules of the intrinsic mechanisms for C—B bond formation have been clearly established, Section 3 by Hiroto Yoshida elegantly describes the synthesis and applications of diboron compounds, covering both symmetrical and unsymmetrical reagents. The chemistry of bis(pinacolato)diboron, arguably the most commonly used diboron reagent, is covered and compared with alternative diboron reagents with complementary Lewis acidity. Since they are stable and easy to handle, diboron compounds are widely used as diborating or monoborating reagents, depending on the reaction conditions and the substrate involved. Diboron reagents can also be used for carboboration or aminoboration under controlled, selective pathways. Diversity in the C—B bond formation can be provided by unsymmetrical diboron reagents, which have great potential taking into consideration both electronic and steric factors. The author has provided a significant number of examples, the vast majority related to important achievements from the current decade, thus confirming the ongoing interest in diboron reagents.

A breath of fresh air comes from the hands of Jianbo Wang, Yifan Ping, and Chaoqiang Wu, describing in Section 4 the synthesis of gem-diborylalkanes as a new generation of boron source. The synthetic methodologies included represent straightforward protocols for the synthesis of diverse gem-diborylalkanes, including those with two identical or different boron moieties on the same carbon. The synthetic strategies described in this chapter cover transition-metal catalysis as well as transition-metal-free approaches. The scope covers a large range of products, most of them very reactive via deborylative or deprotonative pathways.

Another breakthrough in modern organoboron chemistry is based on boron addition to C—C multiple bonds that proceeds with unusual anti-stereoselectivity. In this context, in Section 5, Masaya Sawamura and Hirohisa Ohmiya describe this creative mode of activation of boron reagents to mediate anti-diboration, anti-hydroboration, anti-carboboration, and anti-silaboration processes. In each case, the authors focus on transition-metal-mediated and transition-metal-free approaches, as well as radical protocols.

The nucleophilic borylation of carbonyl groups and imines is a well-established way to functionalize polarized double bonds in a selective manner; it provides facile access to α-oxy and α-amino boronates, respectively, which are key synthons in many target syntheses. Toward this end, in Section 6, Timothy Clark and Hee Yeon Cho describe the transition-metal-catalyzed borylation of aldehydes, ketones, aldimines, and ketimines, with a particular focus on asymmetric approaches. Successful reactivity and further functionalization of the corresponding α-oxy and α-amino boronates is precisely detailed in the chapter through a significant number of examples and protocols, emphasizing the access to target products with biological activity.

Two highlights of advanced organoboron chemistry are borylative ring-opening and borylative ring-closing protocols, which are fully covered in Section 7 and Section 8, respectively. Mauro Pineschi and Cosimo Boldrini deal with the borylative attack and concomitant ring cleavage of cyclopropyl ketones, vinylcyclopropanes, vinyl epoxides, vinyl aziridines, cyclic vinyl carbonates, propargylic three- and four-membered rings, and diazabicycles. The scope covered is extensive, with detailed experimental protocols, both under transition-metal catalysis and in transition-metal-free approaches. Similarly, Koji Kubota and Hajime Ito cover borylative ring-closing reactions, with an emphasis on the incorporation of boryl groups into carbo- and heterocyclic synthons that are key intermediates in natural and useful non-natural organic compounds. The authors outline the most advanced protocols to borylate alkenes, allenes, and alkynes bearing leaving groups, as well as nonactivated unsaturated substrates, to eventually conduct the ring-closing pathway in an intramolecular fashion. The authors compile a large number of examples, including asymmetric versions, thus helping the reader to choose the metal catalyst and ligand most appropriate for the ring closing process they are interested in. In addition to metal-catalyzed methods, transition-metal-free protocols using boron electrophiles have also been included.

Section 9, by Liang Xu, tackles the impressive emerging area of decarbonylative and decarboxylative borylation in its entirety. Abundant organic feedstocks containing carbonyl and carboxylic units can be transformed into their borylated counterparts via several different catalytic or stoichiometric approaches. These methods are summarized in this chapter, with detailed information about the reaction conditions, substrate scope, and experimental procedures. Decarbonylative borylation of esters, amides, thioesters, and aroyl halides, together with the decarboxylative borylation of carboxylic acids, are the main topics developed using transition-metal catalysts and photoredox protocols.

Despite the Lewis acidity of organoboron compounds, their synthesis can be performed using water as solvent, thus fulfilling one of the main principles of green chemistry. In Section 10, Taku Kitanosono and Shu Kobayashi describe borylation reactions in aqueous conditions in extensive detail. The authors have selected recent developments from across the broad landscape of organoboron chemistry, covering a range of C—B bond-formation processes, including enantioselective reactions. Special mention of the borylation of aryl and alkyl halides is given, with a number of examples and protocols. Interestingly, the addition of boron to unsaturated compounds, such as alkenes, alkynes, and allylic alcohols is accompanied by a description of ring-opening borylation in water. This chemistry is based on transition-metal-catalyzed reactions, with a special emphasis on the tolerance of the multicomponent systems to water, even for asymmetric reactions.

Another emerging area in advanced organoboron chemistry is that of nanocatalyzed borylation reactions. In Section 11, K. Geetharani and Shubhankar Kumar Bose have appealingly described the successful use of metal nanoparticles, with high surface-area-to-volume ratio and a high density of active sites, for the catalytic synthesis of organoboron compounds. The nanocatalyzed 1,2-diboration of alkynes and alkenes is complemented by the 1,3-diboration of allenes. Furthermore, the nanocatalyzed hydroboration of alkynes and α,β-unsaturated carbonyl compounds is precisely documented. Nanocatalyzed silaboration is another case study, and a description of substrate scope together with specific protocols are provided. Nanocatalyzed C—X and C—H borylations are also included and compared with the reactivity achieved using preformed transition-metal complexes.

As in most other chapters, very recent organoboron chemistry is depicted in Section 12, which concerns reactions through radical boryl moieties, where most representative examples have been reported in the last ten years. This emerging chemistry has been greatly developed since the discovery that Lewis base ligated boryl radicals allowed the realization of new reactions through new mechanisms. Feng-Lian Zhang and Yi-Feng Wang have compiled a significant number of examples and protocols involving boryl radicals promoting reduction reactions, radical coupling reactions, radical borylative cyclizations, radical hydroboration reactions, radical borylations using diboron reagents, radical 1,2-carboboration of alkenes, and radical borylation of organic halides, among others.

The elegant chemistry of boron “ate” complexes for asymmetric synthesis is described in Section 13 from the perspective of one of the experts in the field, Varinder Aggarwal, together with two members of his team, Sheenagh Aiken and Joseph Bateman. They highlight the use of this powerful tool in asymmetric synthesis and describe the basis of the mechanism via 1,2-metalate rearrangement for substrate- and reagent-controlled homologation of boronic esters. The use of lithiation–borylation reactions for the construction of adjacent hindered stereocenters is presented. The discussion of “assembly-line synthesis” collects a large number of examples and protocols related to lithiation–borylation with substrates containing heteroatoms as well as homologation of boronic esters with cyclic carbenoids. The last part of the chapter describes the use of boronate complexes as nucleophiles, enabling the C—B bond to be converted, with reliable inversion of stereochemistry, into C—I, C—Br, C—Cl, C—N, C—O, and C—C bonds.

After considering the top organoboron chemistry developed in recent years, the last chapter of this volume is devoted to the application of selective asymmetric borylation to target compounds. In this context, Section 14 has been compiled by Tian-Jun Gong, Ebrahim-Alkhalil M. A. Ahmed, and Yao Fu to highlight how asymmetric hydroboration, diboration, and borylative difunctionalization, together with transition-metal-free catalytic asymmetric borylation, have become key steps for the synthesis of α-amino boronates and β-amino boronates, as well as their application to the synthesis of medicinal and natural compounds. Representative examples discussed include (+)-trans-dihydrolycoricidine, (−)-paroxetine, C30 botryococcene, (R)-tolterodine, and vitronectin receptor antagonist, among many others. In most cases covered, the asymmetric induction has been achieved during the C—B bond formation and stereochemical purity is maintained in further functionalizations.

The title of this work, “Advances in Organoboron Chemistry toward Organic Synthesis”, represents the spirit of the modern chemistry associated with the creation of C—B bonds. The fact that all the chapters collected in this volume are “hot topics” indicates that organoboron chemistry is at the forefront of contemporary organic synthesis and also that the innovation and creativity with regard to C—B bond formation sets the pace for future progress. There is no doubt that the great popularity of organoboron chemistry in most interdisciplinary journals is due to its infinite versatility in terms of activation and reactivity and, more remarkably, the fact that organoboron chemistry is crucial for unprecedented synthetic pathways, allowing exquisite control of chemo-, regio-, and stereoselectivity. Organoboron chemistry thus provides great opportunities for chemists to innovate and generate knowledge for real applications.

The future direction of this chemistry is probably connected to the development of new organoboron reagents and to the understanding and application of the unusual behavior of the boron atom in the presence of light, metals, nucleophiles, electrophiles, etc. The strong demand for organoboron compounds in target synthesis, molecular receptors and sensors, materials, and biochemical targets is an important driving force for the development of organoboron chemistry. Chemists around the world are invited to share in this passion and be as creative as possible to generate the need, within the next few years, for a follow-up work: “New Advances in Organoboron Chemistry towards Organic Synthesis”!