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Synlett 2023; 34(18): 2071-2084
DOI: 10.1055/a-2106-1799
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Modern Boron Chemistry: 60 Years of the Matteson Reaction

Transition-Metal-Free Insertion of Diazo Compounds, N-Arylsulfonylhydrazones or Ylides into Organoboronic Acids or Their Derivatives

Zhicheng Bao
a   Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China
,
Jianbo Wang∗
a   Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China
b   The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
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The project is supported by the Natural Science Foundation of China (21871010) and the Laboratory for Synthetic Chemistry and Chemical Biology of Health@InnoHK, the Innovation and Technology Commission (ITC), Government of the Hong Kong Special Administrative Region (HKSAR).
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Abstract

Insertion reactions of carbenes or ylides with organoboronic acids or their derivatives have emerged as valuable methods for coupling or homologation of organoboron compounds under metal-free conditions. The crucial steps of these reactions are coordination of the electron-rich carbon centers of the carbene precursors or ylides to the electron-poor boron center, followed by 1,2-migration of the corresponding tetracoordinated boron intermediates. This type of unique transformation provides an efficient method for the construction of C–C or C–X (X = H, B) bonds. Moreover, the C–B bonds generated by such transformations can be utilized as a handle for further derivatization or iterative homologations. In this Account, we summarize the developments in this arena according to the reactive diazo compound, N-arylsulfonylhydrazone or ylide species involved.

1 Introduction

2 Reactions with Diazo Compounds

3 Reactions with N-Arylsulfonylhydrazones

4 Reactions with Ylides

5 Conclusion


#

Key words

diazo compounds - ylides - N-tosylhydrazones - organoboronic acids - 1,2-migration

Biographical Sketches

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Zhicheng Bao obtained his B.S. degree in 2019 in Jianbo Wang’s group at Peking University. He is currently pursuing his Ph.D. in the same research group, with a focus on the reactions of organoboron compounds.

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Jianbo Wang received his B.S. degree from Nanjing University of Science and Technology in 1983, and his Ph.D. from Hokkaido University (under the supervision of Prof. H. Suginome) in 1990. He was a postdoctoral associate at the University of Geneva from 1990 to 1993, working with Prof. C. W. Jefford. He then moved to the University of Wisconsin-Madison, where he was a postdoctoral associate from 1993 to 1995, working with Prof. H. E. Zimmerman and Prof. F. A. Fahien. He began his academic career at Peking University in 1995. His research interests are focused on catalytic metal carbene transformations.

1

Introduction

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Scheme 1 Early studies on the reactions of organoboron compounds involving 1,2-migration

Organoboron compounds are an important class of reaction substrates. Their rich reactivity is mainly due to the presence of an empty p orbital in the tri-coordinated boron center. In addition to the common transmetalation with the aid of bases for participation in cross-coupling reactions, there is another important type of reaction, namely 1,2-migration based on tetracoordinated organoboron species.[1] The earliest organoboron compounds explored for such transformations were boranes, due to their easy availability and higher Lewis acidity as compared with organoboronic acids or their derivatives.[2] The classic application of organoboron compounds is undoubtedly the hydroboration/oxidation developed by Brown (Scheme [1a]).[3] In this powerful transformation, which converts an olefin into an alcohol with anti-Markovnikov selectivity, coordination of the borane generated through hydroboration with the hydroperoxide forms a tetracoordinated boron intermediate, which is followed by 1,2-migration with hydroxide as the leaving group. Formally, it can be viewed as an insertion of oxygen into the C–B bond of the organoboron intermediate. Similarly, insertion of carbon is also common starting from a tetracoordinated boron complex, resulting in homologation of the corresponding organoboron compound. The first carbon insertion with a tetracoordinated boron complex dates back to 1962. Hillman and co-workers reported that carbon monoxide was complexed with a trialkylborane and then migrated to form an acylboron intermediate. This was followed by rehydration to form a series of organoboron compounds (Scheme [1b]).[4]

During the following years, a series of organoboron homologation reactions was established, providing powerful tools for C–C bond construction. Notably, the key process of such homologations, namely 1,2-migration of the boronate complex, is stereospecific, which enables the formation of C–C bonds in a stereoselective manner.[5] In 1963, Matteson and Mah reported the reaction of α-haloalkaneboronic esters with Grignard reagents, resulting in the formation of one-carbon homologated boronate compounds (Scheme [2a]).[6] This transformation, which is known as the Matteson reaction, has been widely applied in organic synthesis. Matteson also demonstrated that when a phenylboronic ester bearing a chiral diol auxiliary was reacted with dichloromethyl lithium and a methyl Grignard reagent, a two-step homologation proceeded in a highly stereospecific manner.[7] Notably, the dichloromethyl lithium used in this transformation is considered to be carbenoid species. In recent years, Aggarwal has extensively explored this chemistry by employing chiral lithium carbenoid species. This lithium–borylation transformation represents a powerful method for the highly stereoselective homologation of boronates (Scheme [2b]).[8] As expected, carbene precursors, such as diazo compounds or ylides, also react with organoboron compounds following similar complexation and 1,2-migration (Scheme [2c]). These reactions have attracted attention and highly efficient new C–C bond-forming methodologies have emerged.[9] In this Account, we summarize the advances in this arena of organoboron chemistry.

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Scheme 2 Methods for the formation of C–C bonds based on the Matteson reaction and related processes (OCb = carbamate)

# 2

Reactions with Diazo Compounds

Diazo compounds have diverse reactivities and have found wide applications in organic synthesis.[10] From the resonance structure of the diazo group, it is easy to recognize that the carbon attached to the dinitrogen is electron-rich, while the N2 is undoubtingly an excellent leaving group. Thus, in transition-metal-catalyzed reactions, the diazo substrate coordinates to the metal center, followed by dinitrogen extrusion to generate a metal carbene species. When diazo compounds react with organoboron compounds, similar coordination occurs to generate a tetracoordinated boron complex, which is followed by 1,2-migration and dinitrogen extrusion. As shown in Scheme [2c], the net reaction outcome is formal insertion of the carbene into the C–B bond. In 1968, Hooz and Linke first reported the reaction of diazo ketones with trialkylboranes.[11] The reaction generated an α-borylketone or a boron enolate through coordination/1,2-migration, followed by protonation to afford a homologated ketone as the final product (Scheme [3]).

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Scheme 3 Reaction of a diazo ketone with a trialkylborane

Following this seminal work, further exploration of such types of reactions have been conducted.[12] [13] In particular, the electrophilic boron enolate species could be trapped by an electrophile in situ, affording a three-component reaction product.[13] Due to their sensitivity to water, the synthetic value of boranes is limited as compared with the more stable and readily available organoboronic acids and their derivatives. Thus, reactions of diazo compounds with the latter were in high demand. The first metal-free reaction of diazo compounds with organoboronic acid derivatives was reported by Wang and co-workers in 2009.[14] As shown in Scheme [4], the reactions of diazocarbonyl compounds with boroxines occurred smoothly to afford α-arylated or α-vinylated carbonyl products. Notably, diisopropylamine should be added to neutralize the reaction system in order to avoid decomposition of the diazo substrates.

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Scheme 4 Reactions of α-diazocarbonyl compounds with boroxines

Other less stable diazo compounds, such as 2,2,2-trifluorodiazoethane and trimethylsilyl diazomethane, were also explored. These diazo compounds were typically stored and used as solutions. In 2014, Wang and co-workers reported a switchable trifluoromethylation by using either ammonium chloride as the additive or difluorovinylation by combining with lithium hydroxide as the base (Scheme [5]).[15] The reaction was either terminated by protodeboronation or by β-fluorine elimination, depending on the reaction conditions, with series of trifluoromethylated or difluorovinylated products being obtained respectively.

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Scheme 5 Reactions of 2,2,2-trifluorodiazoethane with boronic acids

In order to prepare α-trifluoromethylated alkylboronates, two important criteria had to be met: (1) neutral conditions without any proton sources were required in order to avoid protodeboronation, and (2) a much lower temperature had to be applied to avoid β-fluoride elimination. In this context, Molander and co-workers developed a process to access α-trifluoromethylated organotrifluoroborates by the reaction of potassium organotrifluoroborates with 2,2,2-trifluorodiazoethane (CF3CHN2) (Scheme [6]).[16] With a silicon reagent as the additive, the reactive difluoroborane intermediate could be generated in situ, which reacted with the diazo substrate via the aforementioned reaction pathway. Quenching the reaction mixture with KHF2 gave the final product.

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Scheme 6 Reactions of 2,2,2-trifluorodiazoethane with potassium organotrifluoroborates

If no additive was employed in the reaction, the α-trifluoromethyl aryl- or vinylboron products might take part in another insertion with the diazo substrate. In other words, single or double insertion with the diazo substrate could be regulated through modification of the reaction conditions. In 2014, Molander and Ryu reported the diastereoselective synthesis of vicinal bis(trifluoromethylated) boron compounds by using boroxines as the boron substrates (Scheme [7]).[17] The double insertion occurred with high selectivity for syn-diastereomers. This syn selectivity can be rationalized by the favored conformation A for 1,2-migration, in which dipolar interactions are minimized. On the contrary, the conformation B, which leads to anti selectivity, is not favored due to dipolar interactions. It is worth mentioning that for other derivatives of boronic acids, single insertion prevails over double insertion.

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Scheme 7 Double-diazo insertion with boroxines

Trimethylsilyl diazomethane (TMSCHN2) is another type of functionalized diazo compound, which can introduce a TMS group along with homologation of the organoboron compounds. Wang and co-workers explored TMSCHN2 for the homologation reaction of arylboronic acids. The insertion of TMSCHN2 into the C–B bond occurred as expected, leading to a product bearing both boron and silicon on the same carbon. This gem-silylboronate ester could be subjected to Suzuki–Miyaura cross-coupling with aryl iodides to afford a series of organosilicon products (Scheme [8a]).[18] The TMS group of the products can be further transformed by treatment with fluoride and then reacting with various electrophiles. Relatively stable TMSCHN2 is widely used as a surrogate of less stable diazomethane, because the TMS group can be readily protonated when necessary. By treating the reaction mixture with TBAF and pinacol, pinacol benzylboronates could be isolated. This transformation can serve as a practical method for preparing benzylboronates from readily available arylboronic acids (Scheme [8b]).[19]

Ley and co-workers developed a three-component reaction using trimethylsilyl diazomethane, vinyl boronic acids and aldehydes for the synthesis of homoallylic alcohols. In this synthesis, the generated allylic boronic acid intermediates are trapped in situ by aldehydes to afford homoallylic alcohols (Scheme [8c]).[20] Ley’s group also studied the reaction mechanism by DFT calculations and experimentation. They showed that boroxines generated from the corresponding boronic acids are likely to be the reactive intermediates.[21]

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Scheme 8 Reactions of trimethylsilyl diazomethane with boronic acids

DFT calculations suggest that boronic esters, such as Bpin and BMIDA, would be unreactive toward diazo substrates. The only reactive boronic ester suggested by computation is catechol boronate. This could be attributed to the weaker electron-donating effect of catechol, which would lead to a higher Lewis acidity of the boron center as compared with other boronates. Indeed, Mioskowski and Le Gall previously reported the hydroboration of alkenes with catecholboranes to generate catechol boronic esters, which could react with trimethylsilyl diazomethane to afford homologated alcohols after oxidation and protodesilylation.[22]

Since diazo quinones can be considered as precursors of phenols in diazo insertion reactions, a series of phenylboronic acids and their derivatives were examined in reactions with diazo quinones by Che, Zhou and co-workers.[23] However, only boroxines, ethylene glycol boronic esters and catechol boronic esters were able to provide the corresponding biaryl phenols, among which catechol boronic esters afforded the optimal results (Scheme [9]). The results are consistent with the DFT computations by Ley and co-workers.[21] Alkenyl boronic esters were also applicable to generate alkenyl phenols.

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Scheme 9 Reactions of diazo quinones with boronic acids

As mentioned above, boronic esters have relatively low Lewis acidity and their reactivity toward diazo compounds is low. However, boronic esters can be activated through ester exchange to introduce a strong electron-withdrawing group at the boron center. Using such a strategy, Dilman and co-workers developed the activation of methyl boronic esters by treatment with Me3SiCF3. The resulting tetracoordinated boron complex could be further treated with Me3SiCl to generate a reactive trifluoromethyl-substituted boronate intermediate, which was further reacted with ethyl diazoacetates to give the corresponding carbonyl-containing compounds (Scheme [10]).[24]

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Scheme 10 Activation of boronic esters via trifluoromethylation for reactions with diazo compounds

Chiral allylboronic acids, which are highly useful synthons in organic synthesis, can be synthesized by a homologation strategy. Matteson and co-workers first demonstrated that by using a chiral auxiliary the homologation of organoboron compounds could proceed in a highly stereoselective manner.[25] Asymmetric catalysis for this type of reaction would be highly desirable but it has remained a considerable challenge. A possible solution to this challenge is the catalytic generation of chiral boronic esters in situ through transesterification with a chiral alcohol as the catalyst. The key for success is to suppress the background reaction between the boronate and the diazo substrate prior to transesterification with the chiral alcohol. In 2020, Szabó and co-workers succeeded in developing an asymmetric catalytic process by using a chiral BINOL as the catalyst in the reaction of alkenyl boroxines with 2,2,2-trifluorodiazoethane (Scheme [11]).[26] Through transesterification with ethanol, the boroxines are first converted into diethoxyl boronates, which are inactive toward diazo compounds. Upon transesterification with the chiral BINOL, the boronic esters become reactive and undergo insertion with the diazo substrate.

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Scheme 11 The catalytic asymmetric reaction of 2,2,2-trifluorodiazoethane with boroxines

With the same chiral BINOL catalyst, Szabó and co-workers very recently developed a three-component reaction of alkynyl ethylboronates, 2,2,2-trifluorodiazoethane and ketones for the synthesis of tertiary chiral allenols possessing an axially chiral CF3 group (Scheme [12]).[27] The reactions proceeded with high levels of enantio- and diastereocontrol. Instead of 2,2,2-trifluorodiazoethane, other stabilized diazomethane derivatives were also explored. While N2CHSiMe3 also worked well at an elevated reaction temperature to afford the corresponding allenols with excellent enantio- and diastereocontrol, other stabilized diazo substrates, such as diazo-carbonyl, -ester, or -cyano compounds, failed to afford the corresponding allenol products.

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Scheme 12 The catalytic asymmetric three-component reaction of alkynyl boronates, diazomethanes, and ketones

# 3

Reactions with N-Arylsulfonylhydrazones

The use of diazo compounds is limited due to their unstable nature, especially for those with aliphatic substituents. A general method to circumvent this problem is to generate the unstable diazo compounds in situ using N-arylsulfonylhydrazones, which are readily available from the corresponding ketones or aldehydes. Such hydrazones have been extensively explored in carbene-based cross-coupling reactions with transition-metal catalysts in recent years.[28] N-Arylsulfonylhydrazones have also been widely utilized in transition-metal-free insertions with organoboron compounds. In 2009, Barluenga and Valdés reported the first reaction of N-tosylhydrazones with boronic acids to afford cross-coupled products (Scheme [13]).[29] This transition-metal-free protocol has been widely used in organic synthesis owing to the simple reaction procedure and the ready availability of the starting substrates.

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Scheme 13 Transition-metal-free reactions of N-tosylhydrazones with boronic acids

Following this seminal work, the scope of this reaction was extensively explored.[30] When alkenyl boronic acids were utilized, the allylic boronic acid intermediates underwent either α-protodeboronation or a 1,3-borotropic shift/γ-protodeboronation, affording the corresponding isomeric alkene products (Scheme [14a]).[31] Valdés and co-workers observed that the final product distribution was related to the substituents on the substrates to some extent. The protodeboronation favors positions which possess substituents that stabilize the negative charge. As shown in Scheme [14b], when R3 was an alkyl group, α-protodeboronation occurred, while the 1,3-borotropic shift/γ-protodeboronation occurred if R3 was an aryl group.

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Scheme 14 Reactions of N-tosylhydrazones with alkenyl boronic acids

Besides, when N-tosylhydrazones tethered with nitrile moieties were used as the substrates, a tandem intramolecular nucleophilic addition occurred, instead of direct protodeboronation, following 1,2-boron migration.[32] Other cascade reactions were also developed by Valdés and co-workers.[33] Incorporation of an azide group at a suitable position of the N-tosylhydrazone led to a formal intramolecular nitrene insertion after the formal carbene insertion with the organoboron substrate, affording pyrrolidine products (Scheme [15a]). By using o-(azidomethyl)phenylboronic acid as the organoboron substrate and N-tosylhydrazones derived from cyclic ketones, the same reaction gave spiropyrrolidines as the products (Scheme [15b]).

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Scheme 15 Cascade insertion of carbenes and nitrenes

In the aforementioned transformations, the boron moieties could be retained in the final products if the protodeboronation was avoided. If this was achieved, the boron moiety in the final products could be utilized as a useful handle for further derivatizations. In particular, in cases where stable alkyl boronic acid intermediates are formed, the protodeboronation may be readily avoided. Qin, Merchant and co-workers compared different organoboron compounds on base treatment under heating, mimicking the basic conditions during the coupling reactions.[34] They found that benzyl or allylic boronic acids decomposed in less than 10 minutes, while alkyl boronic acids remained intact after several hours of heating. Thus, by adjusting the structure of the substrates to avoid the generation of benzyl or allylic boronic acids, a practical and modular method for the construction of alkyl boron compounds was developed (Scheme [16]).

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Scheme 16 Reactions of N-mesitylsulfonylhydrazones with alkylboronic acids for the synthesis of alkyl boronates

For the boronates, due to their low reactivity as mentioned previously, the insertion reaction with diazo compounds or N-sulfonylhydrazones is difficult. However, when the two functional groups are assembled in a single molecule, the intramolecular reaction proved to be possible. Thus, in 2021, Qin and co-workers developed the intramolecular reaction between an N-sulfonylhydrazone and various boronates (Scheme [17]).[35] For the formation of bicyclo[1.1.1]pentanes, which possess about 71 kcal/mol strain energy, the intermediate A, generated by intramolecular coordination between the two functional groups, would be unstable. However, due to the large entropic drive from the loss of nitrogen, the subsequent 1,2-boron shift would be feasible. By exploring well-designed substrates, a variety of multisubstituted bicycloalkyl boronates could be synthesized using this strategy.

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Scheme 17 Intramolecular reactions of N-mesitylhydrazone with boronates for the synthesis of bicyclo[1.1.1]pentanes

With bis(boryl) methane as the boron substrate, intermolecular reactions with N-arylsulfonylhydrazones have been explored by Wang and co-workers (Scheme [18]).[36] Optimization of the conditions indicated that the protecting group on the diboronate influenced the reaction efficiency. Density functional theory (DFT) calculations showed that the Hirshfeld charges and buried volumes (%Vbur) of the boron atoms (Bpin and Bnep) were almost the same. Besides, control experiments suggested that the boronate group on the migrating side might promote the 1,2-migration. DFT calculations further confirmed this assumption and it was found that the neighboring group effect led to the difference in efficiency. The more exposed oxygen atom of Bnep has a better interaction with the diazo moiety compared with Bpin. Notably, when unsymmetric diboronates with different extents of buried volumes were used as substrates, high regioselectivity could be obtained, with the methylene bearing the sterically less bulky boronate moiety being the migrating group.

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Scheme 18 Reactions of N-trisylhydrazones with 1,1-diboronates

While substituted 1,1-diboronates were less effective due to steric effects, substituted 1,1-diboronic acids provided the corresponding products in moderate yields (Scheme [19]).

In addition to the insertion into the C–B bonds of aryl, alkenyl or alkyl boronic acids/esters, diboron compounds have also been explored as reaction partners with diazo compounds, which would lead to B–B bond insertion by the carbene. In 2012 Wang and co-workers reported the formal carbene insertion into B–B bonds and H–B bonds.[37] By using sodium methoxide as the base and methanol as the additive, the reactions of N-tosylhydrazones with bis(pinacolato)diboron (B2pin2) or pinacolborane (HBpin) afforded mono-boronates (Schemes 20 and 21). In the reaction with B2pin2, the initially generated gem-diboronates underwent protodeboronation in situ. It is reasoned that the empty p orbital of the boron of the adjacent Bpin group stabilizes the negative charge, thus facilitating the protodeboronation.

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Scheme 19 Reactions of N-trisylhydrazones with 1,1-diboronic acids
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Scheme 20 Reactions of N-tosylhydrazones with bis(pinacolato)diborons and pinacolboranes
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Scheme 21 Reactions of N-tosylhydrazones with pinacolboranes

For the reaction shown in Scheme [20], when protodeboronation is circumvented, it is possible to obtain 1,1-diboronates as the products. In this context, Wang and co-workers applied sodium hydride (NaH) as the base for this purpose because an acidic proton would not be generated during the deprotonation of N-tosylhydrazones with this base. Under such conditions, a series of N-tosylhydrazones derived from various aldehydes and ketones could be readily transformed into the corresponding gem-diboronates (Scheme [22]).[38] Meanwhile, a silylborane was also found to be applicable for this transformation, affording the corresponding 1-silyl-1-boryl products (Scheme [23]).

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Scheme 22 Reactions of N-tosylhydrazones with bis(pinacolato)diborons
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Scheme 23 Reactions of N-tosylhydrazones with a silylborane

As shown in the previous section (Schemes 5–7, 11 and 12), CF3CHN2 is very useful as a carbene precursor in the synthesis of organic compounds bearing a trifluoro group. However, the unstable nature of this reagent imposes some limitations on its application. To circumvent such limits, Bi and co-workers have extensively explored N-triftosylhydrazone as the precursor for CF3CHN2. Thus, under basic conditions, the in situ generated CF3CHN2 underwent β-fluoride elimination to give gem-difluoroalkenes. Using this protocol, a broad scope of alkyl and aryl boronic acids could be transformed into the corresponding gem-difluoroalkenes (Scheme [24]).[39]

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Scheme 24 Reactions of N-triftosylhydrazone with boronic acids

In addition to N-arylhydrazones, which typically need the assistance of a base, another method for the in situ generation of diazo substrates involves the use of hydrazones under oxidation conditions. In this context, Ley and co-workers utilized flow chemistry to control the uniform formation and delivery of the diazo substrates using a column packed with activated MnO2 (Scheme [25]).[40] Using this protocol, it was possible to separate the step involving generation of the diazo compound and the insertion reaction step. In this way, they realized the reaction of diazo compounds and boronic acids under mild conditions.

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Scheme 25 Reactions of hydrazones with boronic acids under flow conditions

Moreover, adding another flow of diazo compounds after the first reaction resulted in sequential insertion into the C–B bonds of alkyl boronic acids (Scheme [26]).[41] Thus, protodeboronation, pinacol protection, or trapping of the boronic acid intermediates with aldehydes could be adjusted by the modular combination of different flow protocols.

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Scheme 26 Iterative reactions of in situ generated diazo substrates with boronic acids
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Scheme 27 Deaminative couplings of α-aminoesters with boronic acids

Precursors other than hydrazones could also be utilized to generate diazo compounds in situ. Wang and co-workers explored a diazotization/deprotonation protocol of α-aminoesters and α-aminonitriles for the generation of diazoesters or diazonitriles. Upon diazotization of the amino group with NaNO2, the α-proton turned out to be very acidic due to the electron-withdrawing effect of the diazonium group and ester/cyano substituent, leading to ready protodeboronation under essentially neutral conditions. The in situ generated diazoesters or diazonitriles could react with arylboronic acids to afford the deaminative coupling products (Schemes 27 and 28).[42] In addition, 1,3,4-oxadiazolines were also explored by Ley and co-workers for the generation of diazo intermediates by UV irradiation. Under flow chemistry conditions, the diazo intermediates underwent a three-component reaction with vinylboronic acids and aldehydes to afford homoallylic alcohols.[43]

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Scheme 28 Deaminative couplings of α-aminonitriles with boronic acids

# 4

Reactions with Ylides

Ylides have similarities with diazo compounds in their chemical structures, as the carbon centers possess both a negative charge and a leaving group. Thus, ylides have the potential to participate in the homologation of boronic acids or their derivatives. The initial studies on the reactions of ylides with organoboron compounds date back to the 1960s.[44] A series of ylides, including sulfonium, ammonium, and phosphonium ylides, were utilized in reactions with boranes. Notably, the application of chiral sulfonium ylides to induce a stereoselective 1,2-boron shift in a substrate-controlled manner was developed by Aggarwal and co-workers.[45] In this section, we focus on the insertion reactions of ylides with boronic acids and their derivatives.

Similar to diazo compounds, upon complexation of sulfonium ylides with boronates to form tetracoordinate boron intermediates, 1,2-boron migration will be followed with the release of a thioether. Such a process can be designed as a catalytic reaction, because the released thioether can enter the catalytic cycle to regenerate the sulfonium ylide. In 2018, Huang and co-workers developed a Suzuki-type cross-coupling reaction between benzyl halides and boronic acids catalyzed by a thioether (Scheme [29]).[46] In this catalytic transformation, the reaction starts with nucleophilic substitution between the thioether and the benzyl halide to generate a sulfonium salt intermediate. The sulfur ylide is then formed upon deprotonation at the benzyl position. Subsequently, the sulfur ylide intermediate complexes with the boronic acid to form a tetracoordinated boron intermediate, which is followed by 1,2-migration to produce the benzyl boronic acid along with regeneration of the thioether catalyst. Finally, protodeboronation occurs to give the final coupling product (Scheme [30]). While insertion into the C–B bonds of boronic acids was efficient, boronic esters were not suitable substrates in this reaction system, presumably due to the increased steric hindrance and decreased acidity.

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Scheme 29 Reactions of benzyl chlorides with boronic acids catalyzed by thioethers
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Scheme 30 The proposed mechanism for the reaction of benzyl chlorides with boronic acids catalyzed by a thioether

More recently, He and co-workers reported the insertion of pyran, as its phosphonium ylide form, into the C–B bond of boronic esters (Scheme [31]).[47] Initially, lithiation of pyran-2-ol derivatives was attempted, however, a series of substrates with leaving groups, such as ethers and esters, all failed to deliver the corresponding products. Eventually, the phosphonium ylide approach was shown to be successful. The scope of the insertion could be extended to furanoses or pyranoses. When the boronate protecting group was replaced by (+)-pinanediol, high β-anomeric selectivity could be obtained in a substrate-controlled manner. The stereoselective insertion provided a method for gem-C,B-glycosylation, thus significantly expanding the toolbox for saccharide modification.

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Scheme 31 Reactions of phosphonium ylides with boronic acids

The reaction mechanism for this novel reaction is shown in Scheme [32]. Control experiments showed that replacing the pyran with an all carbon skeleton led to a failure to produce the insertion product. Thus, the adjacent oxygen atom is critical to promote the leaving of a P(III) group upon complexation with the boron compound. Finally, 1,2-migration occurs via the generated oxonium species to give the desired product.

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Scheme 32 Proposed mechanism for the reaction of phosphonium ylides with boronic acids
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Scheme 33 Deaminative reactions of tertiary amines with boronic acids via ammonium ylides

Ammonium ylides have also been recently explored as carbene precursors for insertion reactions with organoboron compounds. Recently, Song and co-workers developed a deaminative coupling of aliphatic tertiary amines with organoboron compounds via the generation of ammonium ylides (Scheme [33]).[48] In this reaction, BrCF2CO2K was found to be effective for converting the amine substrates into ammonium ylides. Series of both aryl and alkenyl boronic acids could be used as reaction partners in this transformation.

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Scheme 34 Proposed mechanism for the deaminative reaction of tertiary amines with boronic acids via ammonium ylides

The reaction mechanism for this transformation is shown in Scheme [34]. First, a difluorocarbene is generated from BrCF2CO2K. Complexation of the electrophilic difluorocarbene with the electron-rich amino group followed by proton transfer generates the ammonium ylide. Control experiments suggested that the substituents on the nitrogen had a significant impact on the reaction due to steric effects. Thus, sterically less hindered methyl groups gave the best results. Notably, due to the electron-withdrawing effect of the difluoromethyl group, the leaving ability of the ammonium moiety was significantly enhanced. Using high-resolution mass spectrometry, the key intermediates involved in this mechanism were verified.

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Scheme 35 Lithiation–borylation of azetidinium ions

With ammonium salts as the leaving groups, Aggarwal and co-workers also developed a strategy involving the lithiation of azetidinium ions to generate carbenoids for reactions with organoborons (Scheme [35]).[49] The 1,2-migration was accompanied by ring opening, affording 3-aryl-1-aminopropane derivatives.


# 5

Conclusion

In summary, the transition-metal-free insertion of diazo compounds, N-arylsulfonylhydrazones or ylides into organoboronic acids and their derivatives has been developed as a versatile method for the construction of C–C bonds or C–X (X = H, B) bonds. 1,2-Migration of the tetracoordinated boron species is a common key step in these transformations. Upon 1,2-migration, when the generated boronic acid or boronate possess negative-charge-stabilizing groups at the α position, protodeboronation is prone to occur. However, in some cases, it is possible to trap these unstable intermediates in situ with other electrophiles, affording three-component reaction products. Unlike strategies with lithium reagents or Grignard reagents as the precursors of carbenoids, these transformations generally proceed under mild conditions and rigorous anhydrous conditions are not necessary. Nonetheless, one of the drawbacks of this strategy is that the diazo compounds and ylides are less reactive toward organoboronic acids and their derivatives in general. In some cases, this drawback can be circumvented through activating the boron substrates. Moreover, direct reactions of diazo moieties with less reactive pinacol boronic esters were successful via intramolecular reactions. Finally, as shown in this Account, the reactions with ylides are much less developed compared to those with diazo compounds, however, some recent reports have shown the significant potential of such methods in organic synthesis.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Jianbo Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University
Beijing 100871
P. R. of China   

Publication History

Received: 16 May 2023

Accepted after revision: 05 June 2023

Accepted Manuscript online:
05 June 2023

Article published online:
09 August 2023

© 2023. Thieme. All rights reserved

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Scheme 1 Early studies on the reactions of organoboron compounds involving 1,2-migration
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Scheme 2 Methods for the formation of C–C bonds based on the Matteson reaction and related processes (OCb = carbamate)
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Scheme 3 Reaction of a diazo ketone with a trialkylborane
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Scheme 4 Reactions of α-diazocarbonyl compounds with boroxines
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Scheme 5 Reactions of 2,2,2-trifluorodiazoethane with boronic acids
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Scheme 6 Reactions of 2,2,2-trifluorodiazoethane with potassium organotrifluoroborates
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Scheme 7 Double-diazo insertion with boroxines
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Scheme 8 Reactions of trimethylsilyl diazomethane with boronic acids
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Scheme 9 Reactions of diazo quinones with boronic acids
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Scheme 10 Activation of boronic esters via trifluoromethylation for reactions with diazo compounds
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Scheme 11 The catalytic asymmetric reaction of 2,2,2-trifluorodiazoethane with boroxines
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Scheme 12 The catalytic asymmetric three-component reaction of alkynyl boronates, diazomethanes, and ketones
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Scheme 13 Transition-metal-free reactions of N-tosylhydrazones with boronic acids
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Scheme 14 Reactions of N-tosylhydrazones with alkenyl boronic acids
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Scheme 15 Cascade insertion of carbenes and nitrenes
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Scheme 16 Reactions of N-mesitylsulfonylhydrazones with alkylboronic acids for the synthesis of alkyl boronates
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Scheme 17 Intramolecular reactions of N-mesitylhydrazone with boronates for the synthesis of bicyclo[1.1.1]pentanes
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Scheme 18 Reactions of N-trisylhydrazones with 1,1-diboronates
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Scheme 19 Reactions of N-trisylhydrazones with 1,1-diboronic acids
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Scheme 20 Reactions of N-tosylhydrazones with bis(pinacolato)diborons and pinacolboranes
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Scheme 21 Reactions of N-tosylhydrazones with pinacolboranes
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Scheme 22 Reactions of N-tosylhydrazones with bis(pinacolato)diborons
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Scheme 23 Reactions of N-tosylhydrazones with a silylborane
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Scheme 24 Reactions of N-triftosylhydrazone with boronic acids
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Scheme 25 Reactions of hydrazones with boronic acids under flow conditions
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Scheme 26 Iterative reactions of in situ generated diazo substrates with boronic acids
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Scheme 27 Deaminative couplings of α-aminoesters with boronic acids
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Scheme 28 Deaminative couplings of α-aminonitriles with boronic acids
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Scheme 29 Reactions of benzyl chlorides with boronic acids catalyzed by thioethers
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Scheme 30 The proposed mechanism for the reaction of benzyl chlorides with boronic acids catalyzed by a thioether
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Scheme 31 Reactions of phosphonium ylides with boronic acids
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Scheme 32 Proposed mechanism for the reaction of phosphonium ylides with boronic acids
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Scheme 33 Deaminative reactions of tertiary amines with boronic acids via ammonium ylides
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Scheme 34 Proposed mechanism for the deaminative reaction of tertiary amines with boronic acids via ammonium ylides
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Scheme 35 Lithiation–borylation of azetidinium ions