B-Protected Boronic Acids: Methodology Development and Strategic

Chapter 12

B-Protected Boronic Acids: Methodology Development and Strategic Application Downloaded by PURDUE UNIV on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch012

John J. Molloy and Allan J. B. Watson* Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom *E-mail: [email protected]

Boron reagents are among the most heavily used and studied class of synthetic components throughout the chemical sciences, with essential roles in organic synthesis, sensing, drug design, and materials. Historically, in synthetic chemistry, the use of an organoboron unit generally quickly followed its installation, due to the perceived reactivity of these functional groups to the reaction conditions associated with common transformations. This lack of flexibility over when an organoboron residue is used in a synthetic route has inspired the development of several protecting group strategies. These methods have now enabled the practitioner to carry a boronic acid derivative through synthetic sequences, and releasing it for use when desired. This chapter will discuss several ‘gold standard’ B-protecting groups (BMIDA, BDAN, and BF3K) with a focus on their use in methodological development and target molecule synthesis.

Introduction The chemoselective manipulation of two (or more) ostensibly equivalent functional groups or those with unfavorable reactivity gradients is often encountered within synthetic chemistry. To ensure selectivity, protecting group strategies are often employed to render one group unreactive under the prevailing reaction conditions (1). Functionalisation can then take place without concern over chemoselectivity and the protecting group can then be removed. Careful selection of a protecting group for a particular functionality is therefore crucial: © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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this must be straightforward to install, inert under the planned reaction conditions, and facile to remove. In the context of organoboron compounds, many boron functionalities can be intolerant of the reaction conditions associated with routine organic transformations. As such, organoboron residues have typically been used as soon as possible after installation to avoid potential unwanted degradation, limiting synthetic flexibility. Indeed, prior to the advent of B-protecting groups, carrying a boronic acid through a multi-step synthetic sequence was relatively rare (2–4). Organoboron reactivity is principally driven by the interaction of a nucleophilic species with the Lewis acidic empty p-orbital of boron (5). Accordingly, in order to inhibit the reactivity of an organoboron residue, the Lewis acidity of this orbital must be tempered. This has been the focus of numerous investigations over the last 30 years leading to a series of strategically designed reagents and methods that render organoboron species inert to potential nucleophiles. This now allows protected organoboron residues to be tolerant of a broad range of standard organic chemistry transformations and thereby provides the synthetic chemist the ability to choose the stage at which an installed organoboron functionality is manipulated. Based on their widespread use and accessibility, several of these protecting group methods have now become ‘gold standard’ (Figure 1). These include: N-methyliminodiacetic acid (MIDA) boronic esters, often called MIDA boronates (BMIDA, 1) (6); diaminoboranes, often called boronamides, derived from 1,8-diaminonaphthalene (BDAN, 2) (7); and potassium trifluoroborates (BF3K, 3) (8, 9). As the most prolific protecting groups throughout this area, these three protecting groups will be the basis for the following discussion.

Figure 1. Common organoboron protecting groups.

Preparation and General Information General details for the preparation of BMIDA, BDAN, and BF3K species are provided here; however, for a more detailed discussion of the interconversion of organoboron species, see the chapter by Hutton and co-workers. Boronic Acid N-Methyliminodiacetic Acid (BMIDA) Esters The BMIDA protecting group was initially discovered by Contreras and Mancilla in 1986 (10). This protecting group is derived from Nmethyliminodiacetic (MIDA) acid to which the boron forms two B-O bonds. A strong dative interaction of the ligand’s tertiary amine backbone with the boron p-orbital renders boron sp3 hybridized and provides a hindered tetrahedral structure. It is this occupation of the p-orbital that provides the stability of this 380 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


motif, rendering it inert to many common organic transformations. After synthetic manipulations of other functionalities are complete, the BMIDA unit can be easily hydrolyzed under aqueous basic conditions to reveal the boronic acid (6, 11). BMIDA reagents can be easily synthesized from the parent boronic acids by heating with MIDA acid with extrusion of water (Scheme 1) (6, 11). In addition, BMIDA reagents can also be synthesized from other organoboron species such as pinacol esters (12) and potassium organotrifluoroborates (13).

Scheme 1. General Preparation and Deprotection of BMIDA Species. Boronic Acid Diaminonaphthalene (BDAN) Boronamides Over the past decade, the BDAN motif, pioneered by Suginome, has emerged as a robust boronic acid protecting group (7, 14). 1,8-Diaminonaphthalene forms two strong B-N bonds, but unlike other B-protecting groups, the boron remains neutral and sp2 hybridized: donation of electron density from the lone pairs of the adjacent N atoms is sufficient to lower the reactivity of the boron p-orbital, providing ample protection towards many common reagents. In contrast to BMIDA, BDAN tolerates aqueous basic reaction conditions and is deprotected using aqueous acidic conditions. Similar to BMIDA, BDAN reagents can be readily synthesized through condensation reactions: the boronic acid and 1,8-diaminonaphthalene are heated in toluene with azeotropic removal of water (Scheme 2) (7). BDAN motifs can also be installed using transition metal-catalyzed borylation of aryl halides (15).

Scheme 2. General Preparation and Deprotection of BDAN Species. Potassium Trifluoroborates (BF3K) Potassium organotrifluoroborates (BF3Ks) were first isolated in the 1960s by Chambers (16). However, application of these groups as B-protected boronic acids did not follow until the 1990s. BF3Ks exist as a negatively charged tetrahedral trifluoroborate with an associated potassium countercation and can demonstrate stability in the presence of largely anhydrous basic, acidic, and neutral reaction conditions (8, 9). 381 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


BF3Ks can be prepared using a variety of approaches but perhaps the most notable of these methods is Vedejs’ direct formation of BF3Ks from their boronic acid counterparts using KHF2 (Scheme 3) (17). Treating a boronic acid with a saturated aqueous solution of KHF2 will usually provide good yields of the corresponding BF3K adduct, which are generally isolated by precipitation (8, 9). BF3Ks are readily hydrolyzed using aqueous base to yield the parent boronic acid. However, if the BF3K group is unintentionally hydrolyzed during a reaction, the BF3K group can be restored using KHF2 in the work up procedure (18).

Scheme 3. General Preparation and Deprotection of BF3K Species.

The BMIDA Protecting Group Following their initial discovery in 1986 (10), the BMIDA protecting group received little attention until pioneering studies by Burke and coworkers beginning in the late 2000s (19). Burke has shown that the inert nature of the BMIDA group allows tolerance of an array of standard organic transformations, in particular its retention through cross-coupling processes, allowing for so-called ‘iterative’ cross-coupling (6, 11). BMIDA compounds are typically bench stable solids that can be purified by column chromatography or precipitation (6, 11). While tolerant of relatively mild reaction conditions, they are generally intolerant of relatively hard nucleophiles (organometallics) or high pH media (bases), especially at elevated temperatures (6, 11, 20). However, this property can also be beneficial, permitting in situ cleavage to the latent boronic acid to allow reaction of this residue. Accordingly, BMIDA reagents have two main applications: those that retain the BMIDA unit and those that use the BMIDA unit via in situ hydrolysis.

Synthetic Utility of BMIDAs: Retaining the BMIDA Unit In 2008, Burke demonstrated the stability of aryl BMIDAs to a range of common organic transformations (Scheme 4) (21). Benzylalcohol BMIDA 4 was shown to be resistant to Swern and Jones oxidations, silyl protection and deprotection, and Appel reaction conditions (21). Similarly, the benzaldehyde BMIDA 5 was shown to be tolerant of mild reductive conditions using NaBH4, olefination reactions (Takai and Horner-Wadsworth-Emmons), reductive amination, and Evans aldol processes (21). Besides the reaction conditions themselves, the BMIDA withstood the associated work-up and purification procedures involving brine, aq. HCl, aq. NH4Cl, and aq. NaHCO3 as well as column chromatography (21). 382 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 4. BMIDA Tolerance of Standard Organic Transformations. In addition to their stability towards standard organic transformations, Burke demonstrated the stability of aryl BMIDAs towards Suzuki-Miyaura cross-coupling (under controlled basic conditions) and, in so doing, established a platform for iterative cross-coupling (Scheme 5) (6, 11, 19). Cross-coupling of boronic acid 6 and haloaryl BMIDA 7 delivered biaryl BMIDA 8. Hydrolysis using aq. NaOH revealed the latent boronic acid 9, primed for further cross-coupling. Burke has used this iterative cross-coupling strategy to effect the rapid synthesis of a series of structurally diverse natural products (vide infra). In addition, haloaryl BMIDA species, such as 7, can undergo Miyaura borylation to provide diboryl aryls (13). For a more detailed discussion of the preparation and utility of diboron compounds, see the chapter by Li and co-workers. While aryl boronic acids and esters are readily available, vinyl and ethynyl boronic acids can be unstable and are therefore not generally commercially accessible. However, the corresponding BMIDA reagents are considerably more inert. These are readily prepared allowing a collection of vinyl (22) (eq 1, 10) and ethynyl (23) (eq 2, 11) BMIDA to become commercialized (Scheme 6). 383 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 5. Haloaryl BMIDA Within Iterative Cross-Coupling Reactions.

Scheme 6. Preparation of Vinyl and Ethynyl BMIDA. Similar to the aryl BMIDA counterparts, Burke has shown that bromovinyl BMIDA 12 is a competent electrophile within cross-coupling reactions. Under controlled reactions conditions, 12 efficiently underwent Heck, Stille, SuzukiMiyaura, Sonagashira, and Negishi cross-couplings (Scheme 7) (24).

Scheme 7. Pd-catalyzed Cross-Couplings of Bromovinyl BMIDA 12. 384 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


In addition, vinyl BMIDA 10 can participate in a further series of transformations without disruption of the BMIDA unit (Scheme 8). BMIDA 10 is a competent olefin for Heck and oxidative Heck reactions, whilst cyclopropanation and epoxidations of the pendant olefin are also readily achieved (22). Similarly, the olefinic unit participates readily in cross-metathesis reactions (22) and can take part in radical addition reactions (25).

Scheme 8. Functionalization of Vinyl BMIDA 10. In the context of epoxidation, Burke has developed a chiral derivative of MIDA with pinene replacing the N-methyl group (26). This chiral auxiliary, termed PIDA (13), is able to direct diastereoselective epoxidation as well as being viable as a protecting group with properties similar to MIDA (Equation 1).

Alkynyl BMIDA 11 has been shown to be a competent alkyne for Sonogashira cross-coupling (Scheme 9a) (23). In addition, Toste has shown the generated aryl alkynyl BMIDA products to be compatible with Au-catalyzed heterocycle syntheses to deliver indoles, benzofurans, and phthalans (Scheme 9b) (27). Similar to the vinyl BMIDA 10, alkynyl BMIDA 11 has been shown to be tolerant of a range of reaction conditions (Scheme 10) (23). Specifically, 11 can undergo hydroboration and partial or complete reduction via hydrogenolysis (23). Radical hydrostannylation and Diels-Alder chemistries can also be applied to 11 (23). Glorius also reported a Rh-catalyzed C-H activation and annulation protocol using alkynyl BMIDAs to allow the synthesis of borylated heterocycles (28). 385 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 9. Sonogashira Cross-Coupling of 11 and Heterocycle Formation.

Scheme 10. Further Transformations of Alkynyl BMIDA 11. Accordingly, alkenyl and alkynyl BMIDA species are not only robust protected organoboron reagents but the BMIDA unit is still capable of undergoing a broad range of olefin-based transformations. These reagents therefore provide powerful and synthetically flexible units for the installation of organoboron residues. Building on developments by Burke, Yudin has demonstrated the utility of sp3-hybridized BMIDA systems towards the construction of borylated peptides via the Ugi reaction (Scheme 11a) (29) and heterocycles via a series of condensation reactions (Scheme 11b) (30). Yudin has also shown that α–BMIDA aldehydes are a key intermediate that can participate in a diverse series of synthetic 386 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


transformations including olefinations, nucleophilic additions, enolizations, and Tsuji-Trost processes, amongst others (31). In addition to building useful frameworks, these applications further demonstrate the resilience of the BMIDA unit towards synthetic manipulations.

Scheme 11. sp3-Hybridized BMIDA: Access to Borylated Peptides and Heterocycles.

Synthetic Utility of BMIDAs: Using the BMIDA Unit Many boronic acids are known to have issues with stability (5, 32). This primarily manifests in problems associated with protodeboronation and is common to, for example, 2-heterocyclic (5, 33, 34) and alkenyl/alkynyl boronic acids (5, 35). As noted above, alkenyl and alkynyl BMIDAs are significantly more stable than the parent boronic acid. This not only provides a useful method for introducing a boron motif but also provides a method for stabilizing a potentially unstable organoboron compound. With a suitable in situ release strategy, hydrolysis of the BMIDA to reveal the parent boronic acid may then enable more effective control over protodeboronation-prone substrates. In this regard, in 2009 Burke developed a general solution to the problem of using unstable boronic acids in the Suzuki-Miyaura reaction (33, 34). By using a carefully designed slow-release strategy using a mild aqueous base, hydrolysis of BMIDA reagents was effected in situ to provide the parent boronic acid, which underwent Suzuki-Miyaura cross-coupling with substantially improved efficiency than conventionally achieved using the corresponding boronic acid (Scheme 12a) (33). Alkynyl boronic acids can be harnessed using this approach (Scheme 12b) (23) as well as sp3-hybridized species (Scheme 12c) (36). Lipshutz has also shown that in situ hydrolysis of aryl BMIDA can be used to enable Suzuki-Miyaura reactions in aqueous media (37). 387 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 12. In Situ Hydrolysis of BMIDA During Suzuki-Miyaura Cross-Coupling. However, in situ hydrolysis and use of the BMIDA motif is not limited to the Suzuki-Miyaura cross-coupling reaction. In 2010, Ellman developed a Rhcatalyzed asymmetric 1,2-addition of BMIDAs to N-tert-butylsulfinyl aldimines (Ellman imines, Equation 2) (38).

Beyond the transition metal catalysis arena, Bode has developed acyl BMIDA species that are capable of amidation under very mild reaction conditions and in the absence of any additional promoter (Equation 3) (39). A similar process is achievable from acyl BF3Ks, the precursor from which the acyl BMIDAs are accessed (40).

The application of BMIDA via in situ hydrolysis to release the parent boronic acid usually results in the formation of a new C-C bond and loss of the boron residue. However, recent developments by Watson and coworkers have shown that boron speciation can be controlled in situ during the Suzuki-Miyaura cross-coupling (41). Pd-catalyzed reaction of BPin species with haloaryl BMIDA 388 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


allowed formation of a new BPin in a formal homologation process (Scheme 13a) (41). This protocol also works effectively for boronic acids (Scheme 13b) (42).

Scheme 13. Formal Homologation of Organoboron Compounds via Controlled Boron Speciation. The Watson group subsequently demonstrated how this protocol could be leveraged to enable tandem chemoselective Suzuki-Miyaura cross-coupling in one-pot (Equation 4) (43). Combining chemoselective oxidative addition based on known reactivity profiles (44) with their speciation transfer process allowed two consecutive Suzuki-Miyaura reactions with control over the nucleophile-electrophile combinations.

In summary, the BMIDA protecting group enables effective protection of a boronic acid through many common transformations and in various reaction media. The robustness of this motif combined with facile cleavage under aqueous basic conditions has enabled the development of synthetically powerful processes for the generation of both borylated final products (retention of the BMIDA unit), for the effective use of sensitive boronic acids (via controlled release), and for the selective and sequential formation of multiple bonds (use of the BMIDA unit). One of the most powerful applications of the BMIDA protecting group has been its strategic application within iterative synthesis, leading to rapid syntheses of complex, highly functionalized natural products, as discussed below (6, 11, 35). Synthetic Utility of BMIDAs: Strategic Application In 2007, Burke demonstrated the utility of BMIDAs via an iterative Suzuki-Miyaura cross-coupling strategy towards the total synthesis of ratanhine (Scheme 14) (19). A series of simple building blocks were fused together through a sequence of Suzuki-Miyaura cross-coupling and deprotection to complete a short synthesis of the natural product. 389 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 14. Iterative Total Synthesis of Ratanhine.

In 2011, Burke vastly increased the complexity of the total synthesis target by application of a similar approach to synechoxanthin (Scheme 15) (45). Here, a convergent approach was used to assemble the symmetrical polyene from a single tetraene BMIDA intermediate. Burke and coworkers have further advanced the iterative synthesis approach to complex molecule synthesis by developing a robotic system capable of carrying out automated iterative synthesis at “the touch of a button” (46). The engineered system permits deprotection, cross-coupling, and purification of bifunctional haloaryl/haloalkenyl BMIDAs in a highly ordered process. For example, the synthesis of the core structure of citreofuran was accomplished using this system (Scheme 16). Based on the applicability and stability of the BMIDA unit throughout preparative chemistry processes, their ease of synthesis and commercial availability, their utility in iterative cross-coupling, and that these reagents are compatible within automated synthesis, BMIDA represents one of the most powerful and flexible organoboron protecting groups.

390 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 15. Iterative Total Synthesis of Synechoxanthin.

Scheme 16. Automated Iterative Approach Towards the Synthesis of Citreofuran.



The BDAN Protecting Group Aminoboranes have classically been studied within inorganic and main group chemistry (47). However, Suginome and others have exploited the unique protection afforded to boron functional groups by conversion to the corresponding aminoboranes. In particular, aminoboranes derived from 1,8-diaminonaphthalene (DAN) have been developed allowing the direct installation of protected boron functional groups as well as manipulation of boron-bearing molecules without adversely affecting the boron unit. As previously described, the lack of reactivity of the BDAN residue arises from deactivation of the Lewis acidic boron p-orbital achieved via partial delocalization of the adjacent N lone pairs (7, 20). In contrast to other B-protecting groups, BDANs are unique as they are neutral and they also exhibit an increased stability to basic reaction conditions, in contrast to BMIDA and BF3K. This is potentially advantageous in the context of cross-coupling since the majority of, for example, Pd-catalyzed processes are carried out in basic media. BDAN functional groups can be removed by mild acidic conditions to reveal the latent boronic acid. This step is commonly carried out during aqueous work up of a particular reaction (7). This is, again, in contrast to the relative stability of BMIDA and BF3K in acidic media. Accordingly, there is a useful orthogonality to BDAN and BMIDA/BF3K making it possible to select the preferred protecting group based on the anticipated reaction conditions of a planned synthetic sequence.

Synthetic Utility of BDANs: Retaining the BDAN Unit

In 2007, in parallel with the development of BMIDA by Burke, Suginome and co-workers demonstrated the utility of the BDAN protecting group to enable selective Suzuki-Miyaura cross-coupling of diboron systems to generate a new BDAN product (Scheme 17a) (7). Cross-coupling was followed by hydrolysis of the BDAN unit to reveal the parent boronic acid that was primed for further catalytic C-C bond formation. As discussed above, since BDAN are stable towards aqueous basic reaction conditions, Suzuki-Miyaura reactions could be conducted in more routine reaction media using co-solvent levels of H2O (7), unlike the BMIDA processes that are usually performed anhydrously to avoid premature hydrolysis (41). Similarly, symmetrical BDAN-protected diboron compounds can be prepared by exhaustive cross-coupling (Scheme 17b) (48). The BDAN protecting group is more robust than BMIDA under certain reaction conditions, especially in the presence of harder nucleophilic reagents. Consequently, BDAN protection allows extension of the range of reactions in which a protected organoboron can participate, widening the scope of organoboron products that can be accessed. 392 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 17. Selective Suzuki-Miyaura Cross-coupling Using BDAN. For example, the formation of aryne intermediates often involves the presence of hard nucleophilic species. However, in 2013, Akai and Ikawa successfully demonstrated a fluoride-mediated aryne formation in the presence of a BDAN unit followed by in situ nucleophilic amination to access substituted borylanilines (Equation 5) (49). Notably, the group also demonstrated the poor tolerance of other boron species (BPin, BMIDA) towards this protocol, identifying BDAN as the only viable boron functional group.

Similarly, Miura and Hirano exploited the base-stability of BDAN to allow Cu-catalyzed asymmetric hydroamination for the synthesis of chiral α-amino BDAN products (Equation 6) (50). Despite exposure to an excess of LiOt-Bu, the BDAN unit remains intact. This methodology generates a new C-B stereocentre but without relying on conventional approaches via, for example, hydroboration (51).


Hayashi also exploited alkenyl BDAN to generate chiral BDAN-containing products via Rh-catalyzed asymmetric addition of arylboroxines (Equation 7) (52). Products were isolated as the alcohol following conversion to the pinacol derivative and subsequent oxidation.


Synthetic Utility of BDANs: Using the BDAN Unit Despite numerous examples of reactions retaining the BDAN functionality, direct reaction of the BDAN group is limited. Direct reaction of the BDAN unit would require an in situ deprotection via hydrolysis to access the latent boronic acid. BDAN requires mild acidic conditions for complete deprotection which limits in situ transformations since the majority of boronic acid-based reactions involve basic reaction conditions. Consequently, the properties that engender BDAN reagents with increased stability to basic media preclude their in situ hydrolysis and use. As a result, BDANs are typically manipulated and deprotected before reaction of the liberated boronic acid (7). Having said this, Hosoya and coworkers reported a synthesis of dibenzoxaborins via chemoselective Suzuki-Miyaura cross-coupling and a subsequent deprotection/cyclization cascade (Equation 8) (53). Following the cross-coupling step, the proximity of the newly installed phenol leads to deprotection and cyclization to furnish the desired dibenzoxaborin.

Synthetic Utility of BDANs: Strategic Application The main strategic application of the BDAN protecting group has been through the development of methods to access diboron compounds. Several examples of this are provided below; for a more detailed discussion of the preparation and utility of diboron systems, see the chapter by Li and co-workers. Similar to the equivalent BMIDA compounds, haloaryl BDAN compounds can be borylated to provide access to useful orthogonally reactive diboron compounds (Scheme 18). This application has been well-explored for BDAN systems with Pd- (a) (48), Ni- (b) (54), and Rh-catalyzed (55) (c) methods all available and applicable to the borylation of a series of haloaryl BDANs.



Scheme 18. Preparation of Diboron Compounds by Borylation of Aryl BDANs.

Suginome developed an Ir-catalyzed regioselective alkyne diboration using an unsymmetrical diboron reagent (Scheme 19) (56). The resulting diboryl alkene products could then be chemoselectively cross-coupled at the BPin unit. The alkenyl BDAN was then shown to withstand hydrogenation to deliver an alkyl BDAN, which was hydrolyzed and oxidized to deliver alcohol products.

Scheme 19. Ir-Catalyzed Diboration of Alkynes and Subsequent Chemoselective Manipulation of the Resulting Diboryl Alkyne.

Hall and coworkers employed a Cu-catalyzed asymmetric conjugate addition protocol to generate geminal diboryl alkyl compounds with high levels of enantioselectivity (Scheme 20) (51). The resulting diboron compounds contained a reactive BPin and protected BDAN moiety allowing selective functionalization of the geminal diboryl carbon via stereoretentive Suzuki-Miyaura cross-coupling of the BF3K derivative.



Scheme 20. Regioselective Asymmetric Hydroboration and Chemoselective Suzuki-Miyaura. In summary, the BDAN functionality provides a very stable B-protected boronic acid which can be manipulated under basic or neutral conditions. Its stability to basic media presents some advantages as well as disadvantages over base-labile protecting groups such as BMIDA and BF3K. Importantly, the greater stability of BDAN serves to expand the potential scope of application of protected boronic acids, allowing boron residues to be taken through multiple transformations allowing useful C-C and C-X bond formation on borylated compounds.

The BF3K Protecting Group Organotrifluoroborates were initially described in the 1940’s by Fowler and Kraus who prepared tetramethyl- and tetrabutylammonium (TBA) salts (57). However, isolation and characterization of the potassium trifluoroborate (BF3K) species did not follow until some 20 years later by Chambers (16). Since then, BF3Ks have grown exponentially in popularity, becoming one of the most widely used organoboron reagents within synthetic chemistry. A wide variety of BF3Ks are commercially available – many more than BMIDA and BDAN. In addition, the applications of BF3Ks have been and continue to be thoroughly investigated. As described above, the BF3K functional group serves as a B-protected boronic acid through formation of a tetracoordinate boronate in which the reactive p-orbital is occupied by a fluoride ligand. Unlike BMIDAs, BF3Ks are salts and are therefore incompatible with column chromatography; purification/isolation is typically achieved by precipitation or crystallization (8, 9). The stability of BF3Ks is one of their most attractive features – they are usually bench (i.e., air and moisture) stable at room temperature, and therefore provide a convenient solution for the storage of unstable boronic acids. Similar to BMIDAs, BF3Ks are base labile, allowing for similar reactions based on in situ hydrolysis. Synthetic Utility of BF3Ks: Retaining the BF3K Unit In 2006, the Molander group successfully demonstrated the stability of potassium and tetra-n-butylammonium (TBA) trifluoroborates under oxidative 396 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


conditions (58). The oxidation of hydroxy-substituted TBA trifluoroborates proceeded in excellent yields under TPAP, Swern, and Dess-Martin conditions with complete retention of the trifluoroborate salt (Scheme 21a). Oxidation of non-benzylic alcohols was also shown to be viable using TPAP (Scheme 21b).

Scheme 21. Alcohol Oxidation in the Presence of BF3K. BF3Ks were also shown to tolerate Upjohn dihydroxylation using catalytic OsO4 and NMO, ensuring the integrity of the B-protected boronic acid under otherwise incompatible reaction conditions (Equation 9) (59).

The BF3K group is also generally tolerant of mild olefination processes including Wittig (Scheme 22a), stabilized Wittig (Scheme 22b), and Horner-Wadsworth-Emmons (Scheme 22c) reactions (60).

Scheme 22. Olefination of Aryl and Heteroaryl BF3Ks. 397 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Perhaps more impressively in the context of protecting group robustness, Molander demonstrated the stability of the BF3K unit towards lithium-halogen exchange (Scheme 23) (18). Lithiation of haloaryl BF3K 13 using n-BuLi at -78 °C generated the expected aryl lithium reagent 14, which could react with a selection of electrophiles. It is important to note that KHF2 was used in the quench of these reactions to ensure quantitative BF3K recovery, in the event of any unwanted hydrolysis.

Scheme 23. Lithiation and Subsequent Electrophile Trapping of Haloaryl BF3Ks. While the above examples showcase how BF3Ks can be used to protect the latent boronic acid, the primary application of BF3Ks is to provide a bench stable reservoir of boronic acid. This is especially important in the context of unstable boronic acid derivatives and enables the effective use of species which are otherwise difficult to handle/use. The section below describes several applications where the BF3K is used in situ. Synthetic Utility of BF3Ks: Using the BF3K Unit Batey demonstrated that allyl and crotyl BF3K species perform effectively in nucleophilic 1,2-addition processes to give the expected products with the anticipated diastereoselectivity (Equation 10) (61).

Batey also showed that Rh-catalysis enables nucleophilic 1,2- and 1,4-addition processes, using aryl BF3Ks as the requisite nucleophile, with both aldehydes (Scheme 24a) and α,β-unsaturated carbonyl compounds (Scheme 24b), respectively (62). 398 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 24. Rh-Catalyzed 1,2- and 1,4-Addition of RBF3K. Metal catalysis is typically required to enable nucleophilic addition of RBF3Ks based on activation of the nucleophile (i.e., the BF3K). However, MacMillan has shown that aryl and vinyl BF3Ks are sufficiently nucleophilic to participate in asymmetric bond forming reactions using organocatalysis. Here, the electrophile substrate is activated, with iminium catalysis facilitating Friedel-Crafts alkylations of aryl BF3Ks (Scheme 25a) (63). and singly occupied molecular orbital (SOMO) catalysis generating a platform for vinylation of aldehydes (Scheme 25b) (64).

Scheme 25. Organocatalytic Nucleophilic Addition of RBF3K. Perhaps the most widely known use and function of BF3Ks are as a source of boronic acid for Suzuki-Miyaura cross-coupling – an area championed primarily by Molander (8, 9). The advantages described in the previous sections have led to BF3Ks being one of the most broadly used nucleophiles for Pd-catalyzed C-C bond formation. The classic use of the Suzuki-Miyaura reaction to forge sp2-sp2 C-C bonds is readily achievable using BF3Ks as the nucleophile. This accommodates aryl (Scheme 26a) (65, 66), vinyl (Scheme 26b) (67), and, 399 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


notably, notoriously unstable heteroaryl nucleophiles (Scheme 26c) (68). This latter use is complementary to the use of BMIDA reagents to facilitate the same type of difficult C-C bond formation while avoiding side reactions (primarily protodeboronation) as much as possible.

Scheme 26. Use of sp2-Hybridized BF3Ks for Suzuki-Miyaura Cross-Coupling. BF3K nucleophiles have also been developed for use within sp2-sp3 cross-coupling. Primary BF3Ks are cross-coupled with good efficiency (Scheme 27a) (69) and while secondary nucleophiles presented issues with the generation of mixtures of branched and linear products (Scheme 27b) (70), this has seen improvement with the use of unprotected boronic acids (71). Biscoe has also developed robust reaction conditions that inhibit β-hydride elimination of secondary BF3Ks, allowing for significantly improved branched:linear product distributions (72).

Scheme 27. Use of Primary BF3Ks in sp2-sp3 Suzuki-Miyaura Cross-Coupling. A particularly useful application of BF3K Suzuki-Miyaura reactions is that heteroatom-substituted nucleophiles (i.e., carbenoids) are readily prepared and accommodated allowing for the direct installation of methylamino (73) (Scheme 28a) and methylalcohol (74) (Scheme 28b) functional groups. 400 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 28. Suzuki-Miyaura Cross-Coupling of Carbenoid BF3K Nucleophiles.

Based on the success of BF3K nucleophiles within sp2-sp3 cross-coupling, the natural step to enantioselective variants was prosecuted using chiral non-racemic BF3Ks. Molander developed reaction conditions that allowed stereoretentive sp2-sp3 cross-coupling (Scheme 29a) (75). Here, the stereochemistry from the BF3K nucleophile is relayed with high fidelity to the product. Stereoretentive cross-coupling of BF3Ks was also observed in reactions of diboron compounds developed by Hall (see Scheme 20) (51). Conversely, using their conditions developed to inhibit β-hydride elimination, Biscoe and coworkers developed a stereoinvertive Suzuki-Miyaura cross-coupling of secondary BF3K nucleophiles (Scheme 29b) (72). The stereochemical information is, once again, relayed effectively to the product but in this case with inversion. From these observations and other studies (76–82), the stereochemical course of similar sp2-sp3 cross-couplings appears to be dependent on both the substrate and reaction conditions.

Scheme 29. Use of Chiral Non-Racemic BF3Ks in sp2-sp3 Suzuki-Miyaura Cross-Coupling Reactions.

Moving beyond Pd catalysis, in 2015 Molander and co-workers designed and developed a cooperative Ir/Ni catalysis process for sp2-sp3 cross-coupling of alkyl BF3Ks (Scheme 30). Molander has shown this process to be effective for primary BF3Ks (Scheme 30a) (83), secondary BF3Ks (Scheme 30b) (84), and carbenoid BF3Ks (Scheme 30c) (85). In addition, use of a suitable ligand for the Ni catalyst permits enantioselective C-C bond formation from racemic BF3Ks, albeit with moderate levels of enantioinduction (Scheme 30d) (83). 401 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 30. Ir/Ni-Catalyzed Chemoselective sp2-sp3 Cross-Coupling.

Lastly, BF3Ks can be employed within Cu-catalyzed C-X bond forming reactions. Specifically, broadly similar to the use of boronic acids, Batey has shown that BF3Ks are effective reaction partners within Chan-Evans-Lam-type C-N (Scheme 31a and b) (86, 87) and C-O (Scheme 31c and d) (88, 89) bond formation.

Synthetic Utility of BF3Ks: Strategic Application BF3Ks have seen widespread uptake and use throughout the synthetic chemistry arena. As such, a full account of their use is beyond the scope of this chapter. However, several notable examples of the strategic use of BF3Ks are given below. For a more complete discussion of the use of BF3Ks, see current reviews (8, 9). As discussed above, BF3Ks are competent nucleophiles for allylation. Batey employed 3-methyl-2-butenyl BF3K for a diastereoselective nucleophilic allylation en route to the depsipeptides kitastatin and respirantin (Scheme 32) (90). 402 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 31. Use of BF3Ks in Cu-Catalyzed C-X Bond Formation.

Scheme 32. Diastereoselective Nucleophilic Allylation Using a BF3K Reagent.

In 2007, MacMillan used an aryl BF3K as the nucleophile for an iminiumcatalyzed enantioselective Friedel-Crafts reaction to facilitate a rapid synthesis of frondosin (Scheme 33) (91). 403 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 33. Iminium-catalyzed Friedel-Crafts Reaction of BF3K.

Similar to BMIDAs and BDANs, BF3Ks have been used to allow the installation of a second, more reactive boron functional group and thereby enable chemoselective cross-coupling. Molander and co-workers developed a sequential hydroboration/chemoselective Suzuki-Miyaura cross-coupling protocol. 4-Styrenyl BF3K underwent hydroboration with 9-BBN and, following addition of Pd catalyst, ligand, base, and electrophile, a subsequent cross-coupling of the newly installed trialkyl boron unit (Scheme 34a) (92). In this way the BF3K motif was retained, and could then be used for further bond formation. The natural extension of this process followed, allowing one-pot tandem chemoselective cross-coupling: hydroboration, trialkyl boron cross-coupling with an electrophile and then addition of a second catalyst and electrophile allowed cross-coupling of the aryl BF3K (Scheme 34b) (92). It is important to note that the integrity of the BF3K unit during the first cross-coupling step was ensured by inhibiting hydrolysis through use of KF as the base in an aprotic solvent. The second step employed an inorganic base (K2CO3) in MeOH to assist BF3K hydrolysis, which is required for effective cross-coupling. Building on his recently established platform, Molander has shown that reactive BPin units are tolerated within the Ir/Ni cooperative catalysis sp2-sp3 cross-coupling platform (Scheme 35) (93). This allows a sequential chemoselective Ir/Ni-catalyzed sp2-sp3 cross-coupling of the BF3K, which, without purification, is followed by treatment with a Pd catalyst and electrophile to allow a conventional Suzuki-Miyaura sp2-sp2 cross-coupling of the remaining BPin unit. The remaining electrophilic site can then undergo Buchwald-Hartwigtype amination to deliver a highly functionalized product. Accordingly, this Ir/Ni approach effectively reverses the observed chemoselectivity established in the above (Scheme 34) hydroboration/cross-coupling process.



Scheme 34. One-pot Hydroboration and Chemoselective Suzuki-Miyaura Cross-Coupling of BF3Ks.

Scheme 35. Chemoselective Sequential sp2-sp3 and sp2-sp2 Cross-Coupling.

BF3K-based Suzuki-Miyaura cross-coupling has also been strategically applied in the total synthesis of bioactive compounds and natural products. For example, vinyl BF3K was used for a late stage cross-coupling in the synthesis of a Raf kinase inhibitor (Scheme 36) (94). Here, the use of vinyl BF3K provides some advantages over alternative methods: vinyl boronic acid is unstable and other competent nucleophiles, such as vinyl stannanes, have greater health and safety issues.



Scheme 36. Application of Vinyl BF3K Within the Synthesis of a Raf Kinase Inhibitor. An alkenyl BF3K was also pivotal within Molander’s synthesis of oximidine II where an intramolecular Suzuki-Miyaura cross-coupling generated the macrocyclic framework (Equation 11) (95).

In summary, BF3Ks are a broadly useful class of B-protected boronic acid. Their ease of synthesis and commercial availability has rendered these reagents the most widely used class of protected organoboron reagents. Similar to BMIDA, the base lability of this species allows for in situ deprotection and use of the latent boronic acid – providing a method for the stabilization of otherwise unstable boronic acids has been the primary use of this protecting group. While its use as a protecting group has been demonstrated in a series of elegant applications, the base lability of this motif means that precautions must be taken to avoid premature hydrolysis in specific reaction media; however, this can be easily mitigated by use of KF as the requisite base reagent and/or use of a KHF2 work-up procedure to restore the BF3K unit.

Conclusion In conclusion, the organoboron functional group underpins some of the most important and widely practiced chemical reactions. The ability to ensure the integrity of an installed organoboron unit through several steps of a particular synthesis provides the practitioner with increased flexibility, potentially allowing an increase in synthetic efficiency of a chosen route or diversity at a late stage in a target molecule synthesis. Of the classes discussed above, the BF3K unit 406 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


is the most widely employed, but its uses are typically as a reservoir of boronic acid rather than a protecting group to ensure a boronic acid survives a particular transformation. BMIDA has emerged as a viable protecting group that can both guard against boronic acid decomposition as well as enable powerful iterative synthesis approaches to complex molecule synthesis. Both BF3K and BMIDA are base labile and so precautions must be taken to ensure premature hydrolysis is avoided. However, this base-lability can be advantageous by enabling in situ deprotection and subsequent bond formations using the liberated boronic acid. Although less used, the BDAN protecting group is more robust towards basic media. This ensures that the protected boronic acid can survive reaction conditions that would be incompatible with BF3K and BMIDA, and therefore extends the potential applications of B-protecting group strategies. The orthogonality of these three B-protecting groups is important as it provides the user with options – a practitioner can now choose the desired properties of the protecting group that would best serve their planned synthesis.

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