Introduction, Interconversion and Removal of Boron Protecting Groups

Chapter 11

Introduction, Interconversion and Removal of Boron Protecting Groups Downloaded by MONASH UNIV on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch011

Quentin I. Churches and Craig A. Hutton* School of Chemistry, Bio21 Institute Building, The University of Melbourne, 30 Flemington Rd, Parkville, Victoria 3010, Australia *E-mail: [email protected]

Boronic acid protecting groups have revolutionized the use of organoborons in synthetic chemistry, enabling organoboron functional groups to be carried through multistep protocols, no longer limited to introduction of boron at a late stage or subject to immediate transformation. The development of novel B-protecting groups and methods for their orthogonal introduction and deprotection has enabled chemoselective transformations of organoboron compounds, including those with multiple organoboron functional groups. The arsenal of B-protecting groups and methods for their introduction, interconversion and removal is outlined in this chapter.

Introduction The utility of organoboron compounds in organic synthesis has flourished in recent years (1), particularly through developments in the Suzuki–Miyaura coupling reaction (2). Boronic acids are also extremely valuable substrates for the Petasis reaction (3, 4) and Chan-Evans-Lam coupling reaction (5, 6). Free boronic acids are often unstable, difficult to handle, or are prone to dehydration to give the corresponding boroxine. As such, organoboronic acids and esters have typically been installed as late as possible in a synthetic sequence, rather than carried through multiple steps, to avoid decomposition or protodeboronation. Bulky boronate esters such as pinacol boronates have been used extensively as ‘blocking groups that are resistant to hydrolysis through steric effects and improve the ease of handling of such organoboron reagents. In some cases these groups can be selectively removed to unveil the boronic acid, © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Downloaded by MONASH UNIV on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch011

but such transformations are not general. In most cases the boronate esters are reactive in metal-catalyzed cross-couplings and the generated organoboronates are transformed through such processes soon after they are formed. In the past decade a number of true ‘protecting’ groups for boronic acids have been introduced that enable organoboron functional groups to be carried through multistep transformations. To function as true protecting groups, such systems must be able to be introduced and removed under mild conditions, preferably in an orthogonal manner, and be stable to a broad range of reaction conditions experienced in standard synthetic procedures. In addition to facilitating the carriage of organoborons through multi-step synthetic sequences, the development of modern boronic acid protecting groups has also enabled chemoselective reactions of di- and tri-boronated compounds, which ultimately enables iterative cross-coupling protocols to build complex molecules through straightforward and efficient processes. Several boronic acid protecting groups have been developed (Figure 1). The most commonly used of these are the N-methyliminodiacetyl (MIDA) and diaminonaphthalenyl (DAN) B-protecting groups. Burke developed the MIDA group as a boronic acid protecting group that abolishes the reactivity of an organoboron toward metal-catalyzed cross-couplings or degradation (7, 8). Suginome developed the DAN group that similarly renders the organoboron unreactive toward cross-coupling reactions (9). Both the DAN and MIDA B-protecting groups require removal to regenerate the boronic acid in order to re-establish reactivity of the organoboron in cross-coupling reactions. Other N- and O-based protecting groups have also been developed, including the anthranilamide (AAM) (10) and 2-(pyrazol-5-yl)aniline (PZA) (11) groups, which act as both directing and protecting groups.

Figure 1. Common organoboron protecting groups. Organotrifluoroborates have also been employed as ‘protected’ boronic acids (12, 13). Organotrifluoroborates are generally easily handled, stable crystalline solids. In the absence of protic solvents they have limited reactivity, though they are readily hydrolyzed to the boronic acid in the presence of water (14). In this chapter, the preparation of protected boronic acids will be described, focusing on methods for the introduction and removal of the boronic acid protecting groups and their interconversion to activate or deactivate organoboron 358 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

reactivity. Transformation of the C–B bond to C–C or C–heteroatom bonds is covered in detail elsewhere in this book.

Boronate Esters as B-Protecting Groups


While a large number of boronate esters have been employed in organoboron chemistry, cyclic boronate esters are most commonly used due to their stability towards hydrolysis (2). Such boronate esters are easily prepared from the parent boronic acid by addition of a diol, typically a 1,2- or 1,3-diol (1). Examples include boronate esters derived from pinacol, neopentylglycol, pinanediol and hexylene glycol. Introduction of Boronate Esters Boronate esters are perhaps the most commonly generated organoborons, usually through Miyaura borylation of the an organohalide (15, 16), or direct borylation of arenes (17), with a diboron or borane reagent. For example, pinacol boronate esters are readily derived from aryl halides by treatment with bispinacolatodiboron (Pin–BPin) (Scheme 1).

Scheme 1. Miyaura borylation to generate boronate esters. Boronate esters can be easily prepared from the parent boronic acid by treatment with a diol to generate a stable cyclic boronate ester. This form of ‘protection’ of a boronic acid is not commonly employed, as the boronic acid and boronate ester tend to have similar reactivity profiles. One exception is the preparation of pinanediol boronate esters 2, which are used extensively in Matteson asymmetric chloromethylation reactions to generate functionalized alkylboronic acids in a stereoselective manner (Scheme 2) (18).

Scheme 2. Pinanediol boronate esters for Matteson chloromethylation. Though usually used as a stable organoboron reagent for cross-coupling procedures, the pinacol boronate has been shown act as a ‘protecting’ group in some circumstances. For example, the bromination of an arylboronate 3 proceeded when ‘protected’ as a pinacol boronate ester, whereas no reaction of 359 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

the corresponding boronic acid occurred (19). The BDAN protected version similarly did not react, whereas the corresponding BMIDA and BF3K compounds gave a complex mixture of products (Scheme 3).


Scheme 3. BPin as a B-protecting group. Whiting has shown that the hexyleneglycol boronate ester group acts as a ‘protecting group’ against Suzuki–Miyaura cross couplings, promoting selective Heck reactions of vinylboronates 5 to give styrenylboronates 6 (Scheme 4) (20).

Scheme 4. Vinyl hexylene glycol boronate for Heck-selective processes. Deprotection of Boronate Esters The utility of the pinacol boronate ester is due to it’s resistance to hydrolysis, and as such hydrolytic cleavage of pinacol boronate esters to generate the boronic acid is rarely performed. Nonetheless, for systems that require the free boronic acid, deprotection of pinacol boronate esters can be performed through oxidative cleavage with periodate (21, 22), or through transesterification in the presence of an excess of a sacrificial boronic acid (23) or solid-supported boronic acid (Scheme 5) (24).

Scheme 5. Deprotection of BPin by oxidative cleavage or transesterification. Neopentylglycol boronate esters are more readily hydrolyzed to the boronic acid than the corresponding pinacol boronates. Accordingly, Miyaura borylation with the corresponding diboron reagent 7, followed by deprotection through aqueous hydrolysis, can be used to generate an aryl boronic acid 9 where the boronate ester 8 is not suitable for subsequent reactions (e.g., Scheme 6) (25). 360 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Scheme 6. Hydrolysis of neopentylglycol boronate ester.


Overall hydrolysis of pinacol boronate esters to boronic acids has also been achieved through conversion to the intermediate trifluoroborate and subsequent treatment with TMS-Cl/H2O (Scheme 7) (26).

Scheme 7. Conversion of BPin to boronic acid through BF3K intermediate. Interconversion of Boronate Esters Deprotection of chiral diol boronate esters has been achieved through initial conversion to a triol boronate species, which is subsequently hydrolyzed to give the boronic acid (Scheme 8) (27). Pinanediol boronate esters have also been deprotected through initial conversion to the corresponding trifluoroborate, followed treatment with TMS-Cl and pinacol to generate the pinacol boronate ester (28). Both of these processes can be followed by (trans)esterification with the antipode of the initial chiral diol for subsequent asymmetric chloromethylation reactions with inverted stereochemistry (Scheme 8).

Scheme 8. Interconversion of chiral diol boronate esters to their antipodes, via triol boronates or trifluoroborates. Triol Boronate Complexes Triol boronate complexes 12 are generated as stable, activated forms of boronic acids that do not require addition of base to facilitate cross-coupling reactions (27, 29). These species can be generated directly from organolithium reagents by treatment with a trialkylborate (30). More commonly, triol boronate derivatives are prepared by reaction of the boronic acid with a triol under 361 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Dean–Stark conditions to generate a diol boronate intermediate 11, which is then treated with base to generate the tetracoordinate ate-complex 12 (Scheme 9) (31). The most common triol used in this process is trimethylolethane (TME, 10). TME-ate complexes 12 have been shown to be more reactive than boronic acids, boronate esters and trifluoroborates in cross-coupling reactions (32, 33). Further, they have been used to prepare stable derivatives of 2-heteroaryl boronic acids (e.g. 2-pyridyl, 2-furyl) and methylboronic acid, which are unstable as the free boronic acids (34–36).

Scheme 9. Conversion of boronic acids to diol esters to triol boronates.

scyllo-Inositol 13 is a hexol that has been employed in the preparation of bis-triolboronates 14. Interestingly, scyllo-inositol bis-boronates are less reactive than the corresponding boronic acids toward cross coupling, which enables chemoselective Suzuki–Miyaura reactions of these species with arylboronic acids to generate biaryl boronic acids, e.g. 15 (Scheme 10) (37).

Scheme 10. sycllo-Inositol bis(triolboronate) complexes.

Triolboronates are not usually deprotected as they are normally used directly in cross coupling reactions. However, triolboronates have been prepared as intermediates in the deprotection of pinanediol boronates, with final hydrolysis under aqueous acidic conditions (see Scheme 8) (27).

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


The MIDA B-Protecting Group MIDA-protected boronic acids (38) are inert to cross-coupling reactions due to their overall neutral charge and tetracoordinate nature, which prevents transmetallation (8). MIDA boronates have been employed as one of the first examples of true protecting groups for boronic acids, where the BMIDA species remains intact and inert in cross-coupling reactions of other organoboron derivatives. Chemoselective cross-couplings of BMIDA derivatives are detailed elsewhere in this book. BMIDA compounds uniformly possess a highly unusual binary affinity for silica gel with certain eluents. This binary elution profile has enabled the development of a ‘catch-and-release’ protocol that simplifies the purification of MIDA boronates and has enabled automation of iterative cross-couplings (39).

Introduction of the MIDA B-Protecting Group The MIDA B-protecting group is commonly introduced by treatment of the boronic acid with MIDA under Dean–Stark conditions (Scheme 11) (8). High temperatures are normally required, which can result in protodeboronation of electron-rich arylboronic acids during this process (40). The use of 4Å molecular sieves has been shown to promote BMIDA formation with suppression of protodeboronation, allowing preparation of BMIDA derivatives of such systems (Scheme 12) (40).

Scheme 11. Conversion of boronic acids to BMIDA boronates under Dean-Stark conditions.

Scheme 12. Preparation of electron rich aryl-BMIDA compounds.



BMIDA derivatives have been prepared by direct transesterification of the corresponding BPin boronate esters by treatment with MIDA, but this process is generally inefficient, requiring multiple cycles to generate the BMIDA derivative in good yield (e.g., 17→18, Scheme 13) (41).

Scheme 13. A BMIDA boronate from the BPin boronate ester.

BMIDA derivatives can be prepared from the corresponding dibromoborane by treatment with MIDA or its sodium salt (42–44). They can similarly be prepared from the corresponding trifluoroborate by treatment with MIDA and a fluorophile (TMS-Cl or silica) (Scheme 14) (45, 46). BMIDA derivatives can also be prepared from trialkoxyborates by treatment with MIDA at elevated temperature (47).

Scheme 14. BMIDA boronates from dibromoboranes or trifluoroborates.

Deprotection of MIDA B-Protecting Groups Deprotection of BMIDA derivatives to the corresponding boronic acids is readily achieved by treatment with aqueous base (Scheme 15) (8, 39). However, being susceptible to reaction with hard nucleophiles, the BMIDA group is incompatible with LiAlH4, DIBAL, TBAF and some metal alkoxides (48).

Scheme 15. Deprotection of BMIDA derivatives by basic hydrolysis.



The slow hydrolysis of BMIDA derivatives under protic conditions has been exploited in the ‘slow release’ of the reactive boronic acid for cross coupling reactions of otherwise unstable or hard to handle boronic acids (Scheme 16) (49).

Scheme 16. Slow release–cross-coupling of BMIDAs.

Interconversion of MIDA B-Protecting Groups MIDA-protected boronic acids have been converted to BPin boronates by treatment with NaHCO3 in the presence of pinacol (Scheme 17) (50, 51).

Scheme 17. Conversion of BMIDA boronates to BPin boronates.

Watson has developed a procedure for the controlled speciation of BMIDA boronates to BPin boronates in cross-couplings of organo–BPin compounds (39, 52–55). First, chemoselective Suzuki–Miyaura cross-coupling of an aryl–BPin with a MIDA-protected borono-arylhalide generates the cross-coupled biaryl adduct 19 containing the BMIDA group. Under protic conditions, the HO–BPin byproduct can hydrolyze to generate pinacol and the BMIDA compound 19 can hydrolyze to the boronic acid 20. Recombination of boronic acid 20 and pinacol ultimately generates the cross-coupled biaryl–BPin 21 under finely tuned equilibrium conditions (Scheme 18). Under this protocol the initial MIDA-protected biaryl adduct 19 is converted to a reactive BPin ester 21 in one pot with no need for a separate deprotection event. Moreover, subsequent addition of a second aryl bromide results in a second Suzuki–Miyaura coupling to generate a triaryl product in one pot.



Scheme 18. Controlled speciation of BMIDA–BPin protecting groups.

Burke has developed the N-isopinocampheyl equivalent of the MIDA protecting group, known as PIDA. This BPIDA group not only acts as a protecting group, preventing oxidation of the C–B bond, but also as a chiral auxiliary in the asymmetric epoxidation of vinyl boronates such as 22 (Scheme 19). Meinwald rearrangement then generates α-boryl aldehyde 24 (39, 56). Further transformations can include transesterification of the BPIDA group with pinacol in MeOH to generate the corresponding BPin derivative, which can then undergo cross-coupling reactions.

Scheme 19. BPIDA as a protecting group and chiral auxiliary.

BMIDA compounds are only very slowly converted to the corresponding trifluoroborates derivatives under standard condition (KHF2, MeOH, room temp.), with more forcing conditions required for efficient transformation (e.g. 25→26, Scheme 20) (46). The reduced reactivity of BMIDA compounds to fluorolysis enables chemoselective formation of trifluoroborates from differentially protected diboron compounds. For example, the aryl-BMIDA/BPin compound 27 is selectively converted to the BMIDA/BF3K derivative 28 under standard conditions (Scheme 20).



Scheme 20. Conversion of BMIDA boronates to trifluoroborates.

The DAN B-Protecting Group After the MIDA protecting group, the next most common group used to attenuate reactivity of organoborons in cross-couplings is the DAN B-protecting group. The BDAN group contains a tricoordinate boron, but possesses reduced reactivity in cross-coupling reactions due to donation of electron density toward the Lewis acidic boron from the Lewis basic nitrogen atoms, thus reducing the Lewis acidity of the boron and the reactivity of the C–B bond (9). DAN-protected organoborons have been used in iterative couplings through cross-coupling–deprotection sequences (9, 57), similar to iterative processes enabled by MIDA-protected organoborons.

Introduction of the DAN B-Protecting Group Aryl–BDAN derivatives can be prepared through Miyaura borylation of organohalides with the mixed diboron reagent PinB–BDAN (Scheme 21) (58). Vinyl–BDAN derivatives can be prepared through metal-catalyzed borylation of alkynes with H–BDAN (57) or PinB–BDAN (Scheme 22) (59, 60). Hydroboration of alkynes with H–BDAN in the presence of an iridium catalyst generates predominantly the trans-vinylboronate 29. The use of the mixed diboron reagent PinB–BDAN under similar conditions results in diboration to give the PinB/BDAN-disubstituted vinyl bis-boron adduct 30. The NHC-Cu(I)-catalyzed reaction with PinB–BDAN generates the 1,1-disubstituted vinyl–BDAN adduct 31.

Scheme 21. Miyaura borylation with PinB–BDAN generates aryl–BDAN.



Scheme 22. Hydroboration or diboration of alkynes to generate vinyl–BDANs. The DAN B-protecting group can be installed onto boronic acids by treatment with diaminonaphthalene under Dean–Stark conditions (Scheme 23), similar to the introduction of the MIDA B-protecting group (9). This reaction has also been reported to proceed under ball milling of the solid reagents at 0 °C (61).

Scheme 23. Protection of boronic acids as BDAN derivatives. BDAN derivatives have also been prepared from trifluoroborates through treatment with TMS-Cl/diaminonaphthalene (46).

Deprotection of DAN B-Protecting Groups DAN B-protecting groups are stable to basic, neutral and weakly acidic conditions but are cleaved through hydrolysis with strong aqueous acid (Scheme 24) (9, 62). The DAN B-protecting group is therefore orthogonal to the MIDA B-protecting group, which is stable to acid but is cleaved with aqueous base.

Scheme 24. Hydrolysis of BDAN derivatives to boronic acids. This simple deprotection method allows for iterative couplings or aryl and vinyl–BDAN derivatives through sequential coupling–deprotection processes incorporating BDAN-protected halo-organoboronates (9, 55, 57). 368 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Interconversion of DAN B-Protecting Groups


Organo–BDAN derivatives have been converted to the corresponding BPin derivatives through treatment with pinacol under acidic conditions (Scheme 25) (63).

Scheme 25. Transesterification of an alkyl–BDAN to an alkyl–BPin.

The DAN B-protecting group is one of the most stable boronic acid protecting groups; for example, it is unreactive to conditions that convert other organoboron derivatives to the corresponding trifluoroborate (KHF2, MeOH, H2O, rt). This property has been used in the chemoselective conversion of BPin/BDAN bis-boron compounds to the corresponding BF3/BDAN analogues (Scheme 26) (46, 63).

Scheme 26. Selective conversion of BDAN–BPin bisboronates to BDAN–BF3K.

Trifluoroborates as B-Protecting Groups Organotrifluoroborates are commonly employed as bench stable, crystalline forms of organoborons where the corresponding boronic acid is unstable or difficult to handle (12, 13). While most anionic tetracoordinate boron reagents are activated towards transmetalation and are therefore reactive in cross-couplings, trifluoroborates are not due to the high electronegativity of fluorine. Thus, hydrolysis of trifluoroborates to the boronic acid is required for cross-coupling processes (14). This property enables trifluoroborates to act as slow release reagents of the reactive boronic acid, which reduces flux through unproductive routes such as homocoupling and protodeboronation. The trifluoroborate group is protected against various oxidation processes, such as epoxidation and dihydroxylation, which would otherwise oxidize aryl- or vinylboronic acids and esters (Scheme 27). 369 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Scheme 27. Oxidative functionalization in the presence of trifluoroborate.


Preparation of Trifluoroborates Organotrifluoroborates are routinely prepared from boronic acids or boronate esters by treatment with KHF2 (Scheme 28) (64, 65). They can also be prepared from dibromo- or difluoroboranes by treatment with KF (Scheme 29) (13).

Scheme 28. Conversion of boronic acids/boronate esters to trifluoroborates.

Scheme 29. Conversion of dihaloboranes to trifluoroborates.

Organotrifluoroborates can be prepared from BMIDA derivatives under slightly more forcing conditions (46). The reduced susceptibility of BMIDA compounds to the standard fluorolysis conditions enables selective formation of trifluoroborates in bis-boron compounds (see Scheme 20).

Hydrolysis of Trifluoroborates to Boronic Acids In the presence of water and a fluorophile, trifluoroborates are readily hydrolyzed to the corresponding boronic acids (Scheme 30). Examples of fluorophiles employed to facilitate this process include TMS-Cl (26, 66), silica gel (67), alumina (68) and FeCl3 (69).

Scheme 30. Hydrolysis of trifluoroborates to boronic acids. 370 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Interconversion of Trifluoroborates with Other B-Protecting Groups


Analogous to the hydrolysis of trifluoroborates in the presence of a fluorophile and water, treatment of trifluoroborates with a fluorophile and the appropriate bis-nucleophile effects the interconversion of trifluoroborates with virtually any other boronic acid protecting group (Scheme 31 (46). For example, treatment of trifluoroborates with TMS-Cl, a base and a diol generates the corresponding boronate ester (70). Use of silica as the fluorophile (67) or the diol bis-silyl ether in place of the diol (71, 72) obviates the need for addition of base. Treatment with MIDA or DAN in place of the diol generates the BMIDA or BDAN compounds, respectively (45, 46).

Scheme 31. Conversion of trifluoroborates to a wide range of other B-protecting groups.

Miscellaneous Boron Protecting Groups Anthranilamide (AAM) (10) and 2-(pyrazol-5-yl)aniline (PZA) (11) B-protecting groups have recently been developed. AAM and PZA B-protected compounds are similar to DAN B-protected compounds in that they possess a tri-coordinate boron with two nitrogen atoms attached. However, they are much more labile than the BDAN group due to less efficient donation of the nitrogen lone pair electrons to the B-atom, due to conjugation through the carbonyl group and nitrogen aromaticity, respectively. These groups act as ortho-directing groups in addition to boron protecting groups. The B-protecting groups are introduced by treatment of the boronic acid with the corresponding bis-nucleophile under Dean-Stark conditions. Use of 2-pyrazol-5-ylaniline generates the aryl-BPZA 32 (Scheme 32) (11). The PZA group directs ortho-silylation in the presence of Et3SiH and a Ru-catalyst to generate 33. Removal of the PZA group is achieved under acidic conditions; aqueous acid generates the boronic acid 34 whereas treatment with pinacol and TsOH generates the pinacol boronate 35. Both 34 and 35 can then be used in subsequent Suzuki–Miyaura reactions. 371 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 32. PZA as a dual B-protecting group and ortho-directing group. The use of anthranilamide generates the aryl–BAAM boronate in a similar manner to preparation of Ar–BPZA (Scheme 33) (10). Removal of the AAM group is again achieved under aqueous acidic conditions to generate the boronic acid, or by treatment with pinacol and TsOH to generate the pinacol boronate ester (Scheme 33).

Scheme 33. Introduction and removal of the BAAM protecting group. The utility of the AAM group as both a B-protecting group and ortho-directing group is highlighted in Scheme 34. AAM-protected m-bromobenzeneboronic acid 36 undergoes a chemoselective Suzuki–Miyaura reaction with tolueneboronic acid to generate the biaryl–BAAM 37. Subsequent ortho-directed silylation generates the silyl arylboronate 38 (10).

Scheme 34. AAM as a B-protecting group and an ortho-directing group.

Conclusion True boronic acid protecting groups have revolutionized the use of organoborons in synthetic chemistry, enabling organoboron functional groups to be carried through multistep protocols, no longer limited to introduction of boron 372 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

at a late stage or subject to immediate transformation. B-Protecting groups enable chemoselective transformations of systems with multiple organoboron functional groups, which has facilitated the development of iterative coupling–deprotection sequences to build up complex molecules in a straightforward manner.

References 1.


2. 3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Singapore, 2011. Lennox, A. J. J.; Lloyd-Jones, G. C. Selection of Boron Reagents for Suzuki–Miyaura Coupling. Chem. Soc. Rev. 2014, 43, 412–443. Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Boronic Acids and Esters in the Petasis-Borono Mannich Multicomponent Reaction. Chem. Rev. 2010, 110, 6169–6193. Kaiser, P. F.; Churches, Q. I.; Hutton, C. A. Organoboron Reagents in the Preparation of Functionalized α-Amino Acids. Aust. J. Chem. 2007, 60, 799–810. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. New Aryl/Heteroaryl C-N Bond Cross-Coupling Reactions via Arylboronic Acid/Cupric Acetate Arylation. Tetrahedron Lett. 1998, 39, 2941–2944. Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of Diaryl Ethers Through the Copper-Promoted Arylation of Phenols with Arylboronic Acids. An Expedient Synthesis of Thyroxine. Tetrahedron Lett. 1998, 39, 2937–2940. Churches, Q. I. N-Methyliminodiacetate (MIDA): A Useful Protecting Group for the Generation of Complex Organoboron Compounds. Aust. J. Chem. 2011, 64, 1474. Gillis, E. P.; Burke, M. D. A Simple and Modular Strategy for Small Molecule Synthesis: Iterative Suzuki−Miyaura Coupling of B-Protected Haloboronic Acid Building Blocks. J. Am. Chem. Soc. 2007, 129, 6716–6717. Noguchi, H.; Hojo, K.; Suginome, M. Boron-Masking Strategy for the Selective Synthesis of Oligoarenes via Iterative Suzuki−Miyaura Coupling. J. Am. Chem. Soc. 2007, 129, 758–759. Ihara, H.; Koyanagi, M.; Suginome, M. Anthranilamide: A Simple, Removable Ortho-Directing Modifier for Arylboronic Acids Serving Also as a Protecting Group in Cross-Coupling Reactions. Org. Lett. 2011, 13, 2662–2665. Ihara, H.; Suginome, M. Easily Attachable and Detachable Ortho-Directing Agent for Arylboronic Acids in Ruthenium-Catalyzed Aromatic C−H Silylation. J. Am. Chem. Soc. 2009, 131, 7502–7503. Molander, G. A.; Ellis, N. Organotrifluoroborates: Protected Boronic Acids That Expand the Versatility of the Suzuki Coupling Reaction. Acc. Chem. Res. 2007, 40, 275–286. Darses, S.; Genet, J.-P. Potassium Organotrifluoroborates: New Perspectives in Organic Synthesis. Chem. Rev. 2008, 108, 288–325. 373 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


14. Lennox, A. J. J.; Lloyd-Jones, G. C. Organotrifluoroborate Hydrolysis: Boronic Acid Release Mechanism and an Acid–Base Paradox in Cross-Coupling. J. Am. Chem. Soc. 2012, 134, 7431–7441. 15. Ishiyama, T.; Miyaura, N. Metal-Catalyzed Reactions of Diborons for Synthesis of Organoboron Compounds. Chem. Record 2004, 3, 271–280. 16. Ishiyama, T.; Miyaura, N. Chemistry of Group 13 Element-Transition Metal Linkage — the Platinum- and Palladium-Catalyzed Reactions of (Alkoxo)Diborons. J. Organomet. Chem. 2000, 611, 392–402. 17. Ingleson, M. A Perspective on Direct Electrophilic Arene Borylation. Synlett 2012, 23, 1411–1415. 18. Matteson, D. S. Boronic Esters in Asymmetric Synthesis. J. Org. Chem. 2013, 78, 10009–10023. 19. Kamei, T.; Ishibashi, A.; Shimada, T. Metal-Free Halogenation of Arylboronate with N-Halosuccinimide. Tetrahedron Lett. 2014, 55, 4245–4247. 20. Lightfoot, A. P.; Maw, G.; Thirsk, C.; Twiddle, S. J. R.; Whiting, A. 4,4,6-Trimethyl-2-Vinyl-1,3,2-Dioxaborinane: A Superior 2-Carbon Building Block for Vinylboronate Heck Couplings. Tetrahedron Lett. 2003, 44, 7645–7648. 21. Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. One-Pot Synthesis of Arylboronic Acids and Aryl Trifluoroborates by Ir-Catalyzed Borylation of Arenes. Org. Lett. 2007, 9, 757–760. 22. Coutts, S. J.; Adams, J.; Krolikowski, D.; Snow, R. J. Two Efficient Methods for the Cleavage of Pinanediol Boronate Esters Yielding the Free Boronic Acids. Tetrahedron Lett. 1994, 35, 5109–5112. 23. Decicco, C. P.; Song, Y.; Evans, D. A. Intramolecular O-Arylation of Phenols with Phenylboronic Acids: Application to the Synthesis of Macrocyclic Metalloproteinase Inhibitors. Org. Lett. 2001, 3, 1029–1032. 24. Pennington, T. E.; Kardiman, C.; Hutton, C. A. Deprotection of Pinacolyl Boronate Esters by Transesterification with Polystyrene–Boronic Acid. Tetrahedron Lett. 2004, 45, 6657–6660. 25. Skaff, O.; Jolliffe, K. A.; Hutton, C. A. Synthesis of the Side Chain CrossLinked Tyrosine Oligomers Dityrosine, Trityrosine, and Pulcherosine. J. Org. Chem. 2005, 70, 7353–7363. 26. Yuen, A. K. L.; Hutton, C. A. Deprotection of Pinacolyl Boronate Esters via Hydrolysis of Intermediate Potassium Trifluoroborates. Tetrahedron Lett. 2005, 46, 7899–7903. 27. Matteson, D. S.; Man, H.-W. Hydrolysis of Substituted 1,3,2-Dioxaborolanes and an Asymmetric Synthesis of a Differentially Protected Syn,Syn-3Methyl-2,4-Hexanediol. J. Org. Chem. 1996, 61, 6047–6051. 28. Matteson, D.; Maliakal, D.; Pharazyn, P.; Kim, B. Cesium Alkyltrifluoroborates From Asymmetric Boronic Esters. Synlett 2006, 2006, 3501–3503. 29. Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Cyclic Triolborates: Air- and Water-Stable Ate Complexes of Organoboronic Acids. Angew. Chem., Int. Ed. 2008, 47, 928–931. 374 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


30. Oberli, M. A.; Buchwald, S. L. A General Method for Suzuki–Miyaura Coupling Reactions Using Lithium Triisopropyl Borates. Org. Lett. 2012, 14, 4606–4609. 31. Akula, M. R.; Yao, M.-L.; Kabalka, G. W. Triolborates: Water-Soluble Complexes of Arylboronic Acids as Precursors to Iodoarenes. Tetrahedron Lett. 2010, 51, 1170–1171. 32. Yu, X.-Q.; Shirai, T.; Yamamoto, Y.; Miyaura, N. Rhodium-Catalyzed 1,4Addition of Lithium 2-Furyltriolborates to Unsaturated Ketones and Esters for Enantioselective Synthesis of γ-Oxo-Carboxylic Acids by Oxidation of the Furyl Ring with Ozone. Chem. Asian J. 2011, 6, 932–937. 33. Yu, X.-Q.; Yamamoto, Y.; Miyaura, N. Aryl Triolborates: Novel Reagent for Copper-Catalyzed N-Arylation of Amines, Anilines, and Imidazoles. Chem. Asian J. 2008, 3, 1517–1522. 34. Sakashita, S.; Takizawa, M.; Sugai, J.; Ito, H.; Yamamoto, Y. Tetrabutylammonium 2-Pyridyltriolborate Salts for Suzuki–Miyaura Cross-Coupling Reactions with Aryl Chlorides. Org. Lett. 2013, 15, 4308–4311. 35. Chen, K.; Peterson, R.; Math, S. K.; Lamunyon, J. B.; Testa, C. A.; Cefalo, D. R. Lithium Trihydroxy/Triisopropoxy-2-Pyridylborate Salts (LTBS): Synthesis, Isolation, and Use in Modified Suzuki–Miyaura Cross-Coupling Reactions. Tetrahedron Lett. 2012, 53, 4873–4876. 36. Yamamoto, Y.; Ikizakura, K.; Ito, H.; Miyaura, N. Cross-Coupling Reaction with Lithium Methyltriolborate. Molecules 2013, 18, 430–439. 37. Kuno, S.; Kimura, T.; Yamaguchi, M. Scyllo-Inositol As a Convenient Protecting Group for Aryl Boronic Acids in Suzuki–Miyaura Cross-Coupling Reactions. Tetrahedron Lett. 2014, 55, 720–724. 38. Mancilla, T.; Contreras, R.; Wrackmeyer, B. New Bicyclic Organylboronic Esters Derived From Iminodiacetic Acids. J. Organomet. Chem. 1986, 307, 1–6. 39. Li, J.; Grillo, A. S.; Burke, M. D. From Synthesis to Function via Iterative Assembly of N-Methyliminodiacetic Acid Boronate Building Blocks. Acc. Chem. Res. 2015, 48, 2297–2307. 40. Ahn, S.-J.; Lee, C.-Y.; Cheon, C.-H. General Methods for Synthesis of NMethyliminodiacetic Acid Boronates From Unstable Ortho-Phenolboronic Acids. Adv. Synth. Catal. 2014, 356, 1767–1772. 41. Woerly, E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. Stereoretentive Suzuki−Miyaura Coupling of Haloallenes Enables Fully Stereocontrolled Access To (−)-Peridinin. J. Am. Chem. Soc. 2010, 132, 6941–6943. 42. Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. Simple, Efficient, and Modular Syntheses of Polyene Natural Products via Iterative Cross-Coupling. J. Am. Chem. Soc. 2008, 130, 466–468. 43. Gillis, E. P.; Burke, M. D. Iterative Cross-Couplng with MIDA Boronates: Towards a General Platform for Small Molecule Synthesis. Aldrichim. Acta 2009, 42, 17–27. 44. Uno, B. E.; Gillis, E. P.; Burke, M. D. Vinyl MIDA Boronate: A Readily Accessible and Highly Versatile Building Block for Small Molecule Synthesis. Tetrahedron 2009, 65, 3130–3138. 375 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


45. Burke, S. J.; Gamrat, J. M.; Santhouse, J. R.; Tomares, D. T.; Tomsho, J. W. Potassium Haloalkyltrifluoroborate Salts: Synthesis, Application, and Reversible Ligand Replacement with MIDA. Tetrahedron Lett. 2015, 56, 5500–5503. 46. Churches, Q. I.; Hooper, J. F.; Hutton, C. A. A General Method for Interconversion of Boronic Acid Protecting Groups: Trifluoroborates as Common Intermediates. J. Org. Chem. 2015, 80, 5428–5435. 47. Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. General Method for Synthesis of 2-Heterocyclic N-Methyliminodiacetic Acid Boronates. Org. Lett. 2010, 12, 2314–2317. 48. Gillis, E. P.; Burke, M. D. Multistep Synthesis of Complex Boronic Acids From Simple MIDA Boronates. J. Am. Chem. Soc. 2008, 130, 14084–14085. 49. Knapp, D. M.; Gillis, E. P.; Burke, M. D. A General Solution for Unstable Boronic Acids: Slow-Release Cross-Coupling From Air-Stable MIDA Boronates. J. Am. Chem. Soc. 2009, 131, 6961–6963. 50. Fujii, S.; Chang, S. Y.; Burke, M. D. Total Synthesis of Synechoxanthin Through Iterative Cross-Coupling. Angew. Chem., Int. Ed. 2011, 50, 7862–7864. 51. Woerly, E. M.; Roy, J.; Burke, M. D. Synthesis of Most Polyene Natural Productmotifs Using Just 12 Building Blocks and One Coupling Reaction. Nat. Chem. 2014, 6, 484–491. 52. Fyfe, J.; Watson, A. Strategies Towards Chemoselective Suzuki–Miyaura Cross-Coupling. Synlett 2015, 26, 1139–1144. 53. Seath, C. P.; Fyfe, J. W. B.; Molloy, J. J.; Watson, A. J. B. Tandem Chemoselective Suzuki-Miyaura Cross-Coupling Enabled by Nucleophile Speciation Control. Angew. Chem. 2015, 127, 10114–10117. 54. Fyfe, J. W. B.; Seath, C. P.; Watson, A. J. B. Chemoselective Boronic Ester Synthesis by Controlled Speciation. Angew. Chem., Int. Ed. 2014, 53, 12077–12080. 55. Xu, L.; Zhang, S.; Li, P. Boron-Selective Reactions as Powerful Tools for Modular Synthesis of Diverse Complex Molecules. Chem. Soc. Rev. 2015, 44, 8848–8858. 56. Li, J.; Burke, M. D. Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3) Boronate Building Blocks. J. Am. Chem. Soc. 2011, 35, 13774–13777. 57. Iwadate, N.; Suginome, M. Synthesis of B-Protected Β-Styrylboronic Acids via Iridium-Catalyzed Hydroboration of Alkynes with 1,8-Naphthalenediaminatoborane Leading to Iterative Synthesis of Oligo(Phenylenevinylene)S. Org. Lett. 2009, 11, 1899–1902. 58. Xu, L.; Li, P. Direct Introduction of a Naphthalene-1,8-Diamino Boryl [B(Dan)] Group by a Pd-Catalysed Selective Boryl Transfer Reaction. Chem. Commun. 2015, 51, 5656–5659. 59. Yoshida, H.; Takemoto, Y.; Takaki, K. A Masked Diboron in Cu-Catalysed Borylation Reaction: Highly Regioselective Formal Hydroboration of Alkynes for Synthesis of Branched Alkenylborons. Chem. Commun. 2014, 50, 8299–8302. 376 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


60. Iwadate, N.; Suginome, M. Differentially Protected Diboron for Regioselective Diboration of Alkynes: Internal-Selective Cross-Coupling of 1-Alkene-1,2-Diboronic Acid Derivatives. J. Am. Chem. Soc. 2010, 132, 2548–2549. 61. Kaupp, G.; Naimi-Jamal, M. R.; Stepanenko, V. Waste-Free and Facile Solid-State Protection of Diamines, Anthranilic Acid, Diols, and Polyols with Phenylboronic Acid. Chem. Eur. J. 2003, 9, 4156–4161. 62. Noguchi, H.; Shioda, T.; Chou, C.-M.; Suginome, M. Differentially Protected Benzenediboronic Acids: Divalent Cross-Coupling Modules for the Efficient Synthesis of Boron-Substituted Oligoarenes. Org. Lett. 2008, 10, 377–380. 63. Lee, J. C. H.; Mcdonald, R.; Hall, D. G. Enantioselective Preparation and Chemoselective Cross-Coupling of 1,1-Diboron Compounds. Nat. Chem. 2011, 3, 894–899. 64. Vedejs, E.; Chapman, R.; Fields, S.; Lin, S.; Schrimpf, M. Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates - Convenient Precursors of Arylboron Difluoride Lewis-Acids. J. Org. Chem. 1995, 60, 3020–3027. 65. Bagutski, V.; Ros, A.; Aggarwal, V. K. Improved Method for the Conversion of Pinacolboronic Esters into Trifluoroborate Salts: Facile Synthesis of Chiral Secondary and Tertiary Trifluoroborates. Tetrahedron 2009, 65, 9956–9960. 66. Inglis, S. R.; Woon, E. C. Y.; Thompson, A. L.; Schofield, C. J. Observations on the Deprotection of Pinanediol and Pinacol Boronate Esters via Fluorinated Intermediates. J. Org. Chem. 2010, 75, 468–471. 67. Molander, G. A.; Cavalcanti, L. N.; Canturk, B.; Pan, P.-S.; Kennedy, L. E. Efficient Hydrolysis of Organotrifluoroborates via Silica Gel and Water. J. Org. Chem. 2009, 74, 7364–7369. 68. Kabalka, G. W.; Coltuclu, V. Thermal and Microwave Hydrolysis of Organotrifluoroborates Mediated by Alumina. Tetrahedron Lett. 2009, 50, 6271–6272. 69. Blevins, D. W.; Yao, M.-L.; Yong, L.; Kabalka, G. W. Iron Trichloride Promoted Hydrolysis of Potassium Organotrifluoroborates. Tetrahedron Lett. 2011, 52, 6534–6536. 70. Hohn, E.; Paleček, J.; Pietruszka, J.; Frey, W. Enantiomerically Pure Vinylcyclopropylboronic Esters. Eur. J. Org. Chem. 2009, 3765–3782. 71. Touchet, S.; Carreaux, F.; Molander, G. A.; Carboni, B.; Bouillon, A. Iridium-Catalyzed Allylic Amination Route to α-Aminoboronates: Illustration of the Decisive Role of Boron Substituents. Adv. Synth. Catal. 2011, 353, 3391–3396. 72. Yamamoto, Y.; Hattori, K.; Ishii, J.-I.; Nishiyama, H. Synthesis of Arylboronates Via Cp*Rucl-Catalyzed Cycloaddition of Alkynylboronates. Tetrahedron 2006, 62, 4294–4305.


Introduction, Interconversion and Removal of Boron Protecting Groups

Recommend Documents