Development of Organic Transformations Based on

Chapter 15

Development of Organic Transformations Based on Protodeboronation Downloaded by UNIV OF FLORIDA on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch015

Chun-Young Lee and Cheol-Hong Cheon* Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea *E-mail: [email protected]; Phone: +82-2-3290-3147; Fax: +82-2-3290-3121

Although protodeboronation has been considered as an uncontrollable side reaction in metal-catalyzed cross-coupling and/or a decomposition pathway of unstable organoboron compounds, the synthetic organic community has not recognized the importance of protodeboronation and the underlying mechanism, and thus few organic transformations have been developed based on the protodeboronation of organoboron compounds until recently. However, recently the synthetic community has started to understand the reaction mechanism and reaction parameters for protodeboronation, which enabled us to develop methods in which carbon-boron bonds in organoboron compounds can be converted into carbon-hydrogen bonds under mild conditions. Based on this finding several synthetic protocols have been developed recently. In this chapter, recent progress in the development of novel organic transformations based on protodeboronation will be described.

Introduction Organoboron compounds, such as organoboranes and organoboronic acids and their derivatives, are widely used in organic synthesis because of their ready availability, versatile reactivity, low toxicity, and high stability (1). The most widespread application of these compounds is in metal-catalyzed cross-coupling reactions, such as Suzuki–Miyaura (2, 3) and Chan–Lam reactions (4). In © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Downloaded by UNIV OF FLORIDA on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch015

addition, these compounds have been used as precursors for various functional groups. For example, carbon–boron bonds in organoboron compounds can be converted into other functional groups, such as alcohols (5), amines (6–8), and halogens (9–11), and a number of synthetic protocols have been developed based on these oxidative transformations. On the other hand, the importance of reductive transformations of organoboron compounds, i.e., the conversion of carbon–boron bonds into carbon–hydrogen bond known as protodeboronation, has not been recognized by the synthetic community until fairely recently. Hence, few organic transformations have been developed based on this reductive conversion of organoboron compounds until recently, despite the fact that protodeboronation has long been known as an unwanted side reaction in transition metal-catalyzed cross-coupling reactions and/or a decomposition pathway of unstable organoboron compounds (Scheme 1) (12, 13). This lack of progress in the development of novel transformations based on protodeboronation would be ascribed to the fact that harsh conditions are usually required, such as strong acids or bases, depending on the substrate. Furthermore, poor understanding of the reaction mechanism and reaction parameters for the protodeboronation precludes the development of novel transformations based on this route.

Scheme 1. Oxidative and Reductive Transformations of Organoboron Compounds

Recently, the synthetic organic community has recognized the importance of protodeboronation and the underlying mechanism, and proposed various controlling parameters for the protodeboronation, albeit with limited substrates (14–17). Furthermore, applications of protodeboronation to organic synthesis have been demonstrated by several groups. In this chapter, we will describe recent progress on the development of synthetic protocols based on protodeboronation. We initially considered covering the protodeboronation mechanism in this chapter. However, since protodeboronation is strongly substrate-dependent, and the proposed reaction mechanisms are therefore not general and can only be applied to specific substrates, we decided instead to focus on the development of new synthetic protocols based on protodeboronation in this chapter.

Synthetic Applications of Protodeboronation Reduction of Alkenes and Alkynes One of the early but rare examples of organic transformations based on protodeboronation is the reduction of alkenes or alkynes to the corresponding alkanes or alkenes, respectively, as an alternative to the reduction of π-bonds via 484 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


hydrogenation. Hydroboration of alkenes or alkynes with hydroborating agents provides the corresponding alkylboranes or alkenylboranes, and subsequent cleavage of carbon–boron bonds via protodeboronation affords the corresponding alkanes or alkenes, respectively (18). Based on this idea, in 1959 Brown et al. reported a protocol for the reduction of alkenes 1 into corresponding alkanes 3 via hydroboration, followed by protodeboronation of the resulting carbon–boron bond in trialkylboranes 2 with a relatively strong acid, such as propionic acid (Scheme 2) (19, 20).

Scheme 2. Reduction of Alkenes into Alkanes via Hydroboration/ Protodeboronation

A few years later, the same group further developed a protocol for the reduction of alkynes 4 to alkenes 6 via hydroboration/protodeboronation (Scheme 3) (21, 22). Hydroboration of alkynes 4 generated cis-alkenyl boranes 5 and subsequent protodeboronation of the resulting vinylboranes 5 with acetic acid provided cis-alkene compounds 6 with high stereoselectivity. Furthermore, the resulting alkenylboranes 5 provided deuterium-incorporated alkenes 6-D with high selectivity when subjected to protodeboronation conditions with deuterioacetic acid, proving that hydroboration/protodeboronation of alkynes is a simple, stereospecific method for the preparation of cis-substituted alkenes. However, the reduction of π-bonds based on this alternative, non-hydrogenative protocol (hydroboration of π-bonds, followed by protodeboronation) has not been widely utilized, presumably due to the relatively harsh reaction conditions required to cleave the carbon–boron bond in the resulting organoboranes.

Scheme 3. Stereospecific Reduction of Alkynes 4 to Alkenes 6 via Hydroboration/ Protodeboronation 485 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The Renaud group discovered that B-alkylcatecholboranes 8 generated by hydroboration of alkenes 7 with catecholborane are a very efficient source of alkyl radicals in the presence of molecular oxygen or peroxide as the radical initiator (23, 24). Based on these findings, in 2005, the authors successfully developed a method for the reduction of alkenes 7 via hydroboration with catecholborane to afford the corresponding B-alkylcatecholboranes 8, followed by protodeboronation of 8 with alcohol under mild conditions (Scheme 4) (25).

Scheme 4. Reduction of Alkenes 7 into Alkanes 9 via Hydroboration/ Protodeboronation

Since the protodeboronation proceeded very sluggishly under extremely strict exclusion of molecular oxygen (Scheme 5A) and the reduction of 2-carene 7e leads to monocyclic cis-para-menthyl-6-ene 9e via opening of the cyclopropane ring (Scheme 5B), it was proposed that a radical intermediate is involved in protodeboronation. Furthermore, when the pure organoborane intermediate 8a generated by hydroboration of 7a with catecholborane was treated with methanol, only a trace amount of cis-pinane 9a was obtained (Scheme 5C). Based on these results, it was initially proposed that ate complex A, which might be generated by coordination of methanol to methoxycatecholboronate B, could be responsible for protodeboronation of the resulting B-alkylcatecholborane species 8. 486 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 5. Control Experiments and Initial Postulation of the Active Species for Protodeboronation

To verify whether complex A might be the actual species responsible for protodeboronation, several experiments were carried out (Scheme 6). However, when compound B was treated with methanol, the formation of ate complex A was not observed; instead, trimethyl borate was obtained along with the free catechol. These results strongly suggested that the active species in the protodeboronation of B-alkylcatecholboranes 8 could not be ate complex A. Since catechol is liberated from the reaction, catechol was investigated as the active species for protodeboronation. When pure B-alkylcatecholborane 8a was treated with catechol using air as the radical initiator, the protodeboronation proceeded smoothly to generate cis-pinane 9a in similar yield, even in the absence of methanol (26).

Scheme 6. Protodeboronation of B-Alkylcatecholborane 8a with Catechol 487 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Based on these results, the reaction mechanism for this protodeboronation was proposed (Scheme 7). Rather than the initially proposed complex A, catechol was in fact the active species for protodeboronation. Radical species, generated from B-alkylboranes 8, abstract a hydrogen atom from catechol to produce corresponding alkanes 9 and catechol radical. The resulting catechol radical attacks B-alkylboranes 8 to generate Meulenhoff’s free acids 10 and radical species, which propagate the chain reaction.

Scheme 7. Proposed Mechanism

Synthesis of Tertiary Chiral Centers from Secondary Chiral Alcohols In 2008, Aggarwal and co-workers developed an excellent method to generate chiral tertiary alcohols 13 from chiral secondary alcohols via the addition of chiral carbanions 15 to boron reagents, leading to chiral tertiary organoboronic esters 12, followed by oxidation of the carbon–boron bond in 12 (eq a, Scheme 8) (27, 28). Since the research group developed a method for the synthesis of tertiary boronic esters 12 with high enantioselectivity, they attempted to develop a protocol which would allow access to a range of chiral building blocks 14 containing tertiary alkyl stereogenic centers by converting the carbon–boron bond of 12 into a carbon–hydrogen bond (eq b, Scheme 8) (29).

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


Scheme 8. Divergent Synthesis of Chiral Building Blocks

Since carboxylic acids, such as propionic acid, have been utilized in the protodeboronation of alkylboranes, a carboxylic acid was initially considered as the reagent of choice for protodeboronation of tertiary organoboronic esters 12. However, the treatment of tertiary organoboronic esters with propionic acid did not turn out to be promising; the desired protodeboronation product 14a was obtained as the minor product along with alkene 16 in a 1:3 ratio (Equation 1).

Considering the thermodynamic aspect between the boron–carbon and boron–fluorine bonds, where the high free bond enthalpy of the newly formed boron–fluorine bond would provide the driving force for the reaction, several fluoride sources were tested in combination with H2O as reagents for protodeboronation. CsF in combination with 1.1 equivalents of H2O led to complete protodeboronation of chiral diarylalkylboronic esters 12a–d with essentially complete retention of stereochemistry, while chiral dialkylarylboronic esters 12e–h required TBAF·3H2O to produce chiral tertiary alkanes 14e–h with excellent stereoselectivity (Scheme 9). Under these optimized conditions, several diarylalkylboronic esters and dialkylarylboronic esters 12 underwent protodeboronation to provide tertiary chiral stereogenic centers with excellent enantioselectivity.



Scheme 9. Synthesis of Chiral Tertiary Stereogenic Centers 14 via Protodeboronation of Chiral Tertiary Boronic Esters 12

Mechanistic studies suggested that the protodeboronation might proceed via coordination of an F- anion to an empty p orbital on the boron atom in chiral organoboronic ester 12. Subsequent protolysis of ate complex 17 with water would then provide the protodeboronation product 14 and FBpin (Scheme 10).

Scheme 10. Proposed Protodeboronation Mechanism of Chiral Tertiary Boronic Esters 12

With this excellent protocol in hand, the Aggarwal group applied this protocol to the synthesis of biologically important (S)-turmerone 22. When chiral secondary carbamate 18 was subjected to the lithiation–borylation protocol, the expected chiral pinacol boronate 19 was obtained in good yield and excellent enantioselectivity. The resulting chiral boronate 19 was treated with TBAF·3H2O in pentane to provide protodeboronation product 20 in good yield. Dihydroxylation, followed by oxidative cleavage of the resulting diol with NaIO4, afforded aldehyde 21. The addition of a vinyl Grignard reagent followed by oxidation of the resulting allylic alcohol completed the total synthesis of (S)-turmerone 22 (Scheme 11).



Scheme 11. Total Synthesis of (S)-Turmerone 22

Subsequently, the group further extended the methodology to the synthesis of several biologically important compounds bearing a chiral gem-diarylalkyl substructure, such as sertraline 23 and indatraline 24 (30). The retrosynthetic analysis of these two compounds is shown in Scheme 12. Both products could be prepared from the same intermediate 25, which was generated by lithiation–borylation of chiral secondary carbamate 26 with aryl boronate 27 followed by the protodeboronation protocol.

Scheme 12. Retrosynthetic Analysis of Sertraline 23 and Indatraline 24

When chiral carbamate 26 derived from a homoallylic alcohol was subjected to the standard conditions, no borylation product was obtained via a 1,2-aryl shift, despite the formation of a boron-ate complex between compounds 26 and 27 (Scheme 13). In order to determine whether the unexpected lower reactivity in 1,2-aryl shift was related to steric effects, carbamate 29 bearing a saturated moiety was subjected to the lithiation–borylation protocol. With this substrate, the 1,2-aryl shift smoothly proceeded to afford borylation product 30 in 72% yield and excellent enantioselectivity. These results suggested that the lower reactivity of the homoallylic carbamate 26 in the lithiation–borylation protocol was not due to steric effects.



Scheme 13. Reactivity Difference between Homoallylcarbamate 26 and Butylcarbamate 29

Based on these results, the authors considered the possibility that Li–π-bond coordination in complex C might be the reason for the lower reactivity of homoallylic carbamate 26. In particular, complexation of Li metal with the π-bond makes the 1,2-metalate rearrangement less favored in complex C, since the migrating group cannot be aligned antiperiplanar to the carbamate leaving group. On the other hand, in the absence of any π-bond, Li could coordinate both oxygen atoms in the pinacol ester, as shown in complex D, which allowed the aryl group to be aligned to the antiperiplanar position to the leaving group (Figure 1).

Figure 1. Plausible Structures of Ate Complexes from Carbamates 26 and 29

In order to facilitate 1,2-metalate migration, 12-crown-4 and TMSCl were used to sequester the Li metal ion from complex C and the desired product 28 was obtained in 81% yield and excellent enantioselectivity. More interestingly, when the same transformation was performed in non-coordinating hydrocarbon solvents, such as CHCl3 and PhCF3, rather than ether solvent, 1,2-metalate migration took place even in the absence of any Li-sequestering reagents to afford chiral tertiary boronic ester 28 in similar enantioselectivity, presumably by making lithiated complex D more stable than complex C (Scheme 14). The resulting diarylalkylboronate 28 was subjected to protodeboronation using CsF in combination with 2.5 equivalents of water to afford the desired product 25 in the best result (87% yield, 97% ee). 492 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 14. Preparation of Key Intermediate 25 Using compound 25 as the key intermediate, the divergent total syntheses of sertraline 23 and indatraline 24 were completed (Scheme 15). Hydroboration of compound 25 followed by oxidation generated carboxylic acid 31. Subsequent intramolecular Friedel–Crafts reaction of the resulting carboxylic acid 31 using chlorosulfonic acid afforded tetralone 32. Reductive amination of the ketone in compound 32 gave the desired cis-product 23 and its trans-epimer in a 96.5:3.5 ratio. For the synthesis of indatraline 24, compound 25 was converted into carboxylic acid 33 by one-carbon dehomologation through dihydroxylation with OsO4 followed by cleavage of the resulting diol with IO4- to afford the corresponding aldehyde, which was further oxidized to carboxylic acid 33 using Pinnick oxidation. Subsequent intramolecular Friedel–Crafts reaction with chlorosulfonic acid provided indanone compound 34. Reduction of the carbonyl group to an alcohol with K-selectride, followed by mesylation, and subsequent conversion with MeNH2, provided the desired product 24 in 76% yield.

Scheme 15. Synthesis of (+)-Sertraline 23 and (+)-Indatraline 24 The same research group further extended this protocol to the stereoselective synthesis of (+)-erogorgiaene 35. The retrosynthetic analysis of the total synthesis of (+)-erogorgiaene 35 is depicted in Scheme 16 (31). Target molecule 35 could be prepared via protodeboronation of a boronate, which was prepared by reaction between chiral carbamate 36 and chiral boronate 37. The corresponding carbamate 493 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


36 could then be prepared via stereoselective reduction from tetralone compound 38, which was generated from carboxylic acid via intramolecular Friedel–Crafts cyclization. The corresponding carboxylic acid was synthesized by reaction of carbamate 39 with pinacol boronate 40.

Scheme 16. Retrosynthetic Analysis of (+)-Erogorgiaene 35

Based on this synthetic route, the selectivity of the lithiation/borylation of tetralone-based carbamate 36 was investigated using isopropyl pinacol boronate as a model substrate. However, reactions of carbamate 36 with isopropyl pinacol boronate gave a ~1:1 ratio of diastereomers 41 (Scheme 17).

Scheme 17. Model Studies on the Selectivity of Lithiation/Borylation of Tetralone-based Carbamates 36 and 42

The group also developed a method for the stereodivergent preparation of chiral tertiary organoboranes from chiral secondary carbamate 43 via the lithiation–borylation protocol depending on boron reagents (Scheme 18). For example, when pinacol boronate was used in this lithiation–borylation protocol with chiral carbamate 43, the resulting pinacol boronate 44 was obtained with retention of configuration. On the other hand, reactions with simple boranes afforded borylation products 45 with the inversion of stereochemistry (27, 28). Based on this idea, reaction of the other diastereomer 42 with dimethylisopropylborane provided a mixture of cis and trans isomers 41 in a 1:4 ratio by inversion of stereochemistry during borylation and retention of stereochemistry in protodeboronation. 494 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 18. Stereodivergent Synthesis of Chiral Building Blocks Bearing Tertiary Stereogenic Centers Depending on Boron Reagents

With these results in hand, the total synthesis of (+)-erogorgiaene 35 was completed (Scheme 19). Lithiation of EtOCb in the presence of a (+)-sparteine surrogate followed by the addition of homoallylboronic ester 46, afforded (S)-37, which was further converted into mixed borane 47 by treatment with MeMgBr. The resulting borane 47 was directly added to lithiated carbamate Li-42 without further isolation to generate the resulting borane 48 with inversion of stereochemistry. Borane 48 was subjected to protodeboronation conditions with TABF·3H2O without further purification to afford the desired (+)-erogorgiaene 35 in 73% yield. It should be noted that TBAF, previously used for stereoselective protodeboronation of tertiary boronic esters, is also suitable for the protodeboronation of tertiary boranes.

Scheme 19. Total Synthesis of (+)-Erogorgiaene 35

The lithiation–borylation protocol for chiral secondary carbamates was further extended to the enantioselective synthesis of heterocyclic boronate esters 49 with heterocyclic pinacol boronates. Subsequent oxidation of the boronic ester moiety in the resulting tertiary pinacol boronates afforded α-heterocyclic tertiary alcohols 50 in good to high yields and excellent enantioselectivity, while the resulting chiral pinacol boronates could be selectively reduced to corresponding alkanes 51 in good yields via stereoselective protodeboronation (Scheme 20) (32). 495 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 20. Asymmetric Synthesis of α-Heterocyclic Tertiary Alcohols 50 and 1-Heterocyclic-1-arylethanes 51 via Lithiation–Borylation Protocol

Application of Quinonyl-2-Boronic Acids in Organic Synthesis Although quinone and its derivatives have been utilized in various organic transformations and applied to the synthesis of complex molecular targets, the effect of a boron substituent directly linked to the quinone moiety has been poorly investigated. The electronic and steric effects of a substituent along the double bond have a strong influence on the reactivity and regioselectivity in reactions with quinones. In other words, a less substituted double bond in the quinonyl system displays higher reactivity than a more substituted double bond. However, few methods have been developed to control opposite regioselectivity in reactions with simple quinones. Recently, the Carreňo group investigated the effect of a boronic acid moiety in quinones in several organic transformations and found that the boronic acid moiety acts as 1) an activating group, i.e., a double bond bearing B(OH)2 is more reactive than the other regardless of the substituent, and 2) a traceless directing group after spontaneous removal of the boronic acid moiety via protodeboronation. Overall, incorporation of B(OH)2 into a quinonyl system can have a significant influence on the outcome of these transformations (Figure 2).



Figure 2. Reactivity Difference between Quinones and Quinonyl-2-Boronic Acids

2-Boron substituted quinone derivatives 52 could be prepared from brominated 1,4-dimethoxy substituted phenyl and naphthyl derivatives 53 as starting materials (Scheme 21). Conventional metal–halogen exchange reactions of 1,4-dimethoxy substituted phenyl and naphthyl derivatives and subsequent trapping of the resulting organolithium species with a trialkoxy borate provided 1,4-dimethoxy aromatic 2-boronic acids 54. Subsequent oxidation with CAN (ammonium cerium (IV) nitrate) yielded corresponding quinone products 52.

Scheme 21. Synthesis of 2-Benzo- and 2-Naphthoquinonyl Boronic Acids 52

The Carreňo group first investigated the effect of boronic acid moieties of quinones in Diels–Alder reactions with various types of dienes (33, 34). Diels–Alder reaction of quinone boronic acids 52 with cyclopentadiene provided protodeboronated endo-adducts 55 in very short reaction times under mild conditions (Scheme 22). Furthermore, incorporation of the B(OH)2 group into the quinonyl compounds significantly increases the dienophilic reactivity. For instance, quinone 52a bearing a B(OH)2 group provided the desired Diels–Alder adduct 55a in a very short reaction time even at -20 °C, while 2,5-dimethylbenzoquinone, the boron-free quinone analogue, required a much higher reaction temperature and longer reaction time (35).



Scheme 22. Diels–Alder Reactions of Quinonyl Boronic Acids 52 with Cyclopentadiene Next, Diels–Alder reactions of quinonyl boronic acids 52 with acyclic dienes 56 were explored (Scheme 23). Reactions between boronic acids 52 and piperylene provided Diels–Alder adducts 56 in excellent yields under mild reaction conditions in short reaction times, which again demonstrated the enhanced reactivity of dienophiles by incorporation of the a boronic acid moiety. Furthermore, the boronic acid perfectly controlled the regioselectivity of the Diels–Alder reaction to provide 1,4a-dimethyl disubstituted derivatives. In addition, the trans relative configuration of the C4a and C9a stereogenic centers in adducts 56 indicated that the Diels–Alder reaction was followed by a trans-protodeboronation process. Furthermore, Diels–Alder reactions with 1-methoxy-1,3-butadiene provided adducts 57 via a domino sequence which involved the Diels–Alder reaction, protodeboronation, and elimination of methanol.

Scheme 23. Diels–Alder Reactions with 1-Substituted-1,3-butadienes 498 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The Diels–Alder reactions of quinonyl boronic acids 52 with 2-substituted1,3-butadienes occurred in a highly regioselective manner, leading to the exclusive formation of meta-regioisomers 58 (Scheme 24). Diels–Alder reaction followed by spontaneous protodeboronation provided a mixture of trans/cis fused adducts 58. Interestingly, compound 58b underwent an unexpected [2+2] cycloaddition to provide pentacyclic compound 59.

Scheme 24. Diels–Alder Reactions with 2-Substituted-1,3-dienes

Finally, 1,3-disubsituted dienes and 1,2,3-trisubstituted dienes were explored in Diels–Alder reactions with 52b as the dienophile (Scheme 25). Once again, trans-fused meta-regioisomeric cycloadducts 60 were obtained in good yields in very short reaction times.

Scheme 25. Diels–Alder Reactions with 1,3-Disubstituted or 1,2,3-Trisubstituted Butadienes

All of the Diels–Alder reactions displayed several interesting features. First, incorporation of a boronic acid moiety into a quinone significantly increases the dienophilic reactivity of the latter. Second, the regiochemistry is completely controlled by the boronic acid functional group, leading to exclusive meta-regioisomeric adducts with dienes bearing a substituent at the 2-position. Third, trans-isomeric adducts were obtained from Diels–Alder reactions with acyclic dienes. 499 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


In order to explain the high dienophilic reactivity of 2-quinonyl boronic acids 52, several control experiments were carried out (Table 1). First, the reactivity of quinonyl boronic acid was compared with that of the parent quinone lacking the B(OH)2 group in Diels–Alder reactions with piperylene (entries 1 and 2). Under identical reaction conditions, quinonyl boronic acid provided the adduct in a short reaction time and excellent yield, while no product was obtained with the parent quinone even after 3 days. In order to test whether the increase in reactivity in the Diels–Alder reaction could be ascribed to intermolecular interactions with another boronic acid, the Diels–Alder reaction of 3,5-dimethylbenzoquinone was performed in the presence of PhB(OH)2 (entry 3). However, the reaction did not proceed, even after 3 days, ruling out this possibility. In addition, when the corresponding pinacol boronate was used in place of the boronic acid, the Diels–Alder reaction did not proceed, even after a long reaction time (entry 4).

Table 1. Diels–Alder Reactions of Piperylene with Benzoquinone Derivatives

These results strongly suggested that the reactivity enhancement of quinones by introduction of the B(OH)2 group in quinones would be a consequence of the strong electron-withdrawing effect of the B(OH)2 group as well as intramolecular hydrogen bonding between B(OH)2 and the carbonyl group (Figure 3). Such interactions would lead to the increase in dienophilic reactivity of quinonyl boronic acids by decreasing the LUMO energy of the C2=C3 double bond, which in turn decreases the HOMO-LUMO energy gap. Furthermore, the origin of the regiocontrol exerted by the boronic acid could be also explained based on these interactions. Hydrogen bonding interactions increase the LUMO coefficient value at C1, which increases the electrophilicity of the C3 carbon in the dienophilic double bond, leading to meta-regioselectivity with 2-substituted-1,3-dienes.



Figure 3. Origin of Reactivity Enhancement and Regioselectivity in Diels–Alder Reactions with Quinonyl Boronic Acids 52 Furthermore, the cis-stereoselectivity with cyclopentadiene and transstereoselectivity with acyclic dienes in Diels–Alder reactions could be explained as shown in Scheme 26. Initial Diels–Alder reactions of quinonyl boronic acids produced endo-adducts, which were subsequently converted into boron enolates. Final protonation to the resulting boron enolates from the less hindered faces followed by the loss of boronic acids provided cis-isomers from Diels-Alder reactions with cyclopentadiene and trans-isomers from those with acyclic dienes, respectively.

Scheme 26. Stereoselectivity in Diels–Alder Reactions of 3-Methyl-2-quinonyl Boronic Acids with Cyclic and Acyclic Dienes With these interesting reactivity of quinonyl boronic acids, the same research group further extended the utility of these reagents to Friedel-Crafts reactions with heteroaromatic compounds. In general, Friedel–Crafts reactions of heteroaromatic compounds with substituted quinones 61 take place at the unsubstituted carbon, leading to formal aromatic alkenylation via a domino sequence where the initial 1,4-addition products 62 spontaneously enolize to aryl substituted hydroquinones 63, which subsequently undergo oxidation to quinones 64. On the other hand, since B(OH)2 incorporated into quinones can act as a regiocontrolling group, increasing electrophilicity at the C3 position, reactions of heteroaromatic compounds with 3-methyl-2-benzoquinonyl boronic acids 52 could afford 5,5-disubstituted cyclohexene-1,4-diones 65 via Friedel–Crafts reaction at the C3 position, followed by spontaneous protodeboronation (Scheme27) (36). 501 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 27. Difference in Reactivity between Quinones 61 and Quinonyl Boronic Acids 52 in Friedel–Crafts Reactions with Heteroarenes Based on this idea, the use of 2-quinonyl boronic acids 52 was was investigated in Friedel–Crafts reactions of electron-rich heteroarenes. Various types of heteroaromatic compounds provided 5-methyl-5-heteroaryl substituted cyclohexaenediones in good to excellent yields in a single step via Friedel–Crafts alkylation followed by protodeboronation (Scheme 28).

Scheme 28. Selected Examples of Friedel–Crafts Alkylation of Heteroaromatics with Benzoquinonyl-2-boronic Acid 52b Subsequently, the utility of 2-quinonyl boronic acid was further extended to the synthesis of indole substituted twistenedione 67 (Scheme 29) (37). The reaction of 3,5-dimethyl-2-quinonyl boronic acid 52b with 2-vinyl indoles 68 provided indole compounds 69 bearing a 6/6/6 twistane-like core via Friedel–Crafts reaction of indoles at the C3 position in quinonyl boronic acid 52b, followed by intramolecular Diels–Alder reaction of the resulting boron diene 502 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


enolates with the vinyl moiety in indoles 68, and subsequent protodeboronation. Once again, incorporation of the C2 boronic acid moiety into the quinones was essential for controlling the regiochemistry in the initial 1,4-addition and generating a useful diene via B(OH)2 migration.

Scheme 29. Reaction of Benzoquinonyl Boronic Acid 52b with 2-VinylIndoles 68

Regioselective Functionalization of Arenes Although several synthetic protocols have recently been developed based on protodeboronation of aliphatic boronic esters and/or boranes, protodeboronation of aromatic boronic acids and their derivatives has attracted little attention from the synthetic community and few such organic transformations have been developed. One of the main reasons for this lack of development is due to a biased opinion about the stability of aryl boronic acids and their derivatives. Although many aryl boronic acid derivatives are commercially available, some of these commercially aryl boronic acid derivatives are not stable and gradually decompose under ambient conditions. Another possible reason is poor understanding of the reaction mechanism of protodeboronation of aryl boronic acid derivatives, although protodeboronation of arene boronic acids is one of the most common side reactions in metal-catalyzed cross-coupling reactions. Very recently, Cheon et al. reported that commercially available ortho-phenol boronic acid 70 and para-phenol boronic acid 71 are unstable and gradually undergo decomposition to afford phenol 72 via protodeboronation, even in the absence of transition metal catalysts (Equation 2) (38). 503 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


As a result of these rather unexpected observations, the reaction parameters for protodeboronation of ortho- and para-phenol boronic acids 70 and 71 were investigated and the authors found several interesting features. 1) Water turned out to play a critical role in this transformation; protodeboronation took place in the presence of water, while no reaction was observed in the absence of water, i.e., in the presence of molecular sieves. 2) The solvent had a strong influence on protodeboronation; reaction in DMSO provided the protodeboronated product in quantitative yield in a few hours, while the reaction did not proceed in any other solvent. 3) The position of the phenolic hydroxy group relative to the boronic acid moiety significantly affects the reactivity in this protodeboronation; only orthoand para-phenol boronic acids undergo protodeboronation, whereas meta-phenol boronic acid are stable under these thermal conditions. 4) The phenolic hydroxy group had a strong influence on the reactivity of metal-free protodeboronation; when the phenolic hydroxy group was protected no protodeboronation was observed under similar conditions. Having obtained these interesting results, the authors investigated whether this type of metal-free thermal protodeboronation is a general phenomenon that occurs with other electron-rich arene boronic acids. In order to exclude steric influences in the reaction, protodeboronation of phenyl boronic acids bearing an electron-donating group at the para-position was explored. Interestingly, most electron-rich arene boronic acids underwent thermal protodeboronation in the absence of any transition metal catalysts (39). Furthermore, the rate of protodeboronation increased with the electron density on the arene ring system, i.e., the electron-donating power of substituents. After several reaction parameters affecting thermal protodeboronation were investigated, such as solvent, temperature, and proton source, suitable reaction conditions for the protodeboronation of different types of electron-rich arene boronic acids were obtained (Table 2). For highly electron-rich arene boronic acids, such as 4-phenol boronic acid and 4-aniline boronic acid, H2O could be utilized as the proton source for protodeboronation at elevated temperature to yield the corresponding phenols and anilines in quantitative yields, respectively. On the other hand, 4-anisole boronic acid and 4-anilide boronic acid, with moderate electron density in the arene ring, require slightly acidic proton sources such as acetic acid to promote protodeboronation. However, arene boronic acids bearing simple alkyl groups did not undergo protodeboronation without the aid of transition metals. Furthermore, arene boronic acids bearing an acidic proton at a substituent, such as phenol boronic acids and anilide boronic acids, could be converted into corresponding arenes via protodeboronation under basic conditions, presumably due to the increase in electron-density on the arene ring after removal of a proton. 504 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Table 2. Protodeboronation of Electron-rich Arene Boronic Acids

After all key reaction parameters had been investigated, the Cheon research group developed a new synthetic protocol for the synthesis of ortho- and meta-functionalized electron-rich arenes 74 and 75 from the corresponding boronic acid derivatives 73 using a boronic acid moiety as a traceless blocking group and traceless directing group, respectively (Scheme 30) (38, 39).

Scheme 30. Regioselective Functionalization of Electron-rich Arenes

When the boronic acid moiety in boronic acid 73 was utilized as a blocking group in electrophilic aromatic substitution (EAS) reactions, the electrophile could be introduced at the ortho-position relative to the electron donating substituent (R), and subsequent removal of the boronic acid moiety by thermal protodeboronation allowed access to ortho-functionalized electron-rich arene derivatives 74. Based on this idea, ortho-functionalization of phenol was tested (Scheme 31). When para-phenol boronic acid 71 was treated with NBS, however, the boronic acid did not act as a blocking group and the expected bromination product 76 was not observed at all; instead, the bromination occurred at the 505 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


ipso-position relative to the boronic acid to provide 4-bromophenol 77 (9). When pinacol boronate 71-pin was used in place of para-phenol boronic acid 71, the boronic acid moiety successfully acted as a blocking group to provide 2-bromophenol 78 in high yield after the removal of the boronic acid moiety via thermal protodeboronation in DMSO. Furthermore, the pinacol boronate moiety successfully acted as a blocking group even in the presence of an excess amount of NBS, and subsequent removal of the boronic acid moiety via thermal protodeboronation provided 2,6-dibromophenol 79 in 96% yield (38).

Scheme 31. ortho-Functionalization of Phenols Using the Boronic Acid Moiety as a Blocking Group in EAS Reactions

Next, this protocol was further extended to the preparation of orthofunctionalized electron-rich arenes from the corresponding arene boronic acid derivatives (Scheme 32) (39). Similar to para-phenol boronic acid 71, when simple boronic acids were subjected to bromination, all reactions took place at the ipso-position to afford 4-brominated electron-rich arenes in high yields (10, 11). In order to suppress competing ipso-substitution reactions with electron-rich arene boronic acids, the boronic acid moieties in these acids should be converted into the either corresponding pinacol boronates or N-methyliminodiacetate (MIDA) boronates (40), which can act as a blocking group in halogenation reactions. Reaction of para-anisole boronic acid 80 with Br2 provided 4-bromoanisole 81 via ipso-substitution, while that of corresponding pinacol boronate 80-pin with bromine afforded 2-bromoanisole 82 after removal of the boronic acid moiety by thermal protodeboronation. When this protocol was further extended to more electron-rich 4-aniline boronic acid 83, even pinacol boronate could not successfully act as a blocking group; the reaction of 4-aniline pinacol boronate 83-pin with NBS exclusively provided 4-bromoaniline 84 via bromodeboronation. When MIDA boronate 83-MIDA derived from aniline boronic acid 83 was subjected to bromination with NBS, the boronic acid moiety successfully acted as a blocking group to afford 2-bromoaniline 85 in 67% yield. Furthermore, the use of a boronic acid moiety as a blocking group could be extended to electrophiles, 506 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


other than halogens. For instance, when MIDA boronate 83-MIDA was subjected to nitration conditions, ortho-nitroaniline 86 was obtained in good yield after removal of the boronic acid moiety.

Scheme 32. ortho-Functionalization of Electron-rich Arenes Using the Boronic Acid Moiety as a Blocking Group In addition, a method for the synthesis of meta-substituted electron-rich arenes 75 was further developed using a boronic acid as a traceless directing group (38). For instance, a removable directing group (RDG) was introduced to the boronic acid moiety in 73 leading to compound 87. Subsequent ortho-functionalization of the boronic acid moiety, followed by its removal via protodeboronation, provided meta-functionalized arenes 75 (Scheme 33). Based on this idea, 2-pyrazol-5-ylaniline (pza) was introduced to the boronic acid moiety in methyl-protected phenol boronic acid 80 as a RDG (41, 42), and Ir-catalyzed ortho-C–H silylation followed by ligand exchange with pinacol provided ortho-silylated compound 89. Deprotection of the methoxy group, followed by removal of the boronic acid moiety via protodeboronation, afforded meta-silylated phenol 90 in 53% yield. In addition, after N-methylpropylenediamine was introduced as a removable ortho-directing group to the boronic acid moiety in compound 80 (43), treatment of the resulting boronate with (TMP)2Mg (TMP = 2,2,6,6-tetramethylpiperidine) facilitated ortho-metallation and subsequent trapping of the resulting organometallic species with I2 provided meta-iodoanisole boronic acid 91. Deprotection with BBr3 and subsequent protodeboronation generated meta-iodophenol 92 in 58% yield (Scheme 34). 507 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 33. meta-Functionalization of Electron-rich Arenes Using the Boronic Acid Moiety as a Directing Group

Scheme 34. meta-Functionalization of Phenol Using the Boronic Acid Moiety as a Directing Group

Regioselective Synthesis of Borylated Heteroarenes Since heteroaryl boronic acids 94 are useful compounds in organic synthesis, the incorporation of boronic acid moieties at specific positions in heteroarenes 93 is an important research area. Conventionally, these heteroarene boronic acids 94 are prepared via generation of organometallic species produced either by deprotonation of an acidic proton with a strong base or metal-catalyzed C–H activation followed by borylation reactions of the resulting organometallic species with borylation reagents, such as trialkyl boronates (Scheme 35).

Scheme 35. Conventional Methods for the Preparation of Heteroarene Boronic Acids 94 508 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


However, there are several problems associated with the preparation of such boronic acids via these conventional methods. In particular, when heteroarene compounds contain several acidic protons with similar acidity, regioselective metallation in the heteroaromatic compounds is problematic and often leads to the formation of a mixture of regioisomers. Furthermore, although a boronic acid moiety can be rather easily incorporated at the most reactive site of heteroaromatic compounds, introduction at less reactive sites is more difficult. To address these issues, novel routes to heteroaryl boronic acids involving protodeboronation have recently been developed by several research groups. In 2007, Moniz and co-workers reported an efficient and practical method to access 4-methyl-2-thiopheneboronic acid 97, which could be utilized as a key building block in pharmaceuticals, from 3-methylthiophene 95 (44). Although highly regioselective lithiation at the C5 position in 3-methylthiophene 95 was achieved at -78 °C over the C2 position (Scheme 36) (45), the authors planned to develop a more practical method to access boronic acid 95 at a more viable temperature (0 °C).

Scheme 36. Regioselective Lithiation of 3-Substituted Thiophene 97 at -78 °C However, when 3-methylthiophene 95 was treated at 0 °C with lithium diisopropylamide (LDA), followed by boronate quench and hydrolysis, 5-borylated product 97-iPr and 2-borylated product 98-iPr were obtained in a 12:1 ratio (Scheme 37). Despite numerous efforts to improve the ratio of 97-iPr to 98-iPr, the purity of the major product 97-iPr has never improved beyond the 12:1 ratio. Since the two resulting boronic acids are not easily separated by conventional separation techniques, the authors attempted to remove minor product 98-iPr from the reaction mixture via selective protodeboronation, which would make isolation of 97-iPr from the reaction mixture much more efficient. When the mixture of 97-iPr and 98-iPr was directly treated with 6 N HCl, only the undesired boronic acid 98-iPr underwent protodeboronation to afford the desired product 97 in 91% yield along with 3-methylthiophene 95.

Scheme 37. Preparation of 4-Methyl-2-thiopheneboronic Acid 97 509 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Although transition metal-catalyzed C–H activation/borylation of heteroarenes typically introduces the boronic acid functionality at the most reactive position, it is difficult to prepare mono-borylated heteroarenes via direct C–H activation at less reactive positions. More recently, the preparation of heteroaryl boronic acids, particularly those that are not easily accessible, has been reported via regioselective protodeboronation of diborylated heteroarenes. For example, heteroarenes undergo selective sequential diborylations to afford diborylated heteroarenes. If the relative reactivities for deborylation reactions parallel the reactivities of parent arenes toward borylation, the boronic acid moiety introduced first would be removed more rapidly via protodeboronation, leading to the preparation of complementary mono-borylation regioisomers (Scheme 38). In such a scenario, if heteroarenes 93 undergo sequential diborylation reactions, the resulting diborylated products 101 would deborylate selectively at the first site of borylation, which allowed us to prepare mono-borylated products 99 at the less reactive site, i.e., different regioisomers of products 100 obtained by direct C–H borylation.

Scheme 38. Regioselective Synthesis of Monoborylated Heteroarenes 99 at the Less Reactive Site

Based on this idea, the Movassaghi group developed a one-pot protocol for C7-borylation of 3-substituted indole derivatives 104 via C2/C7 diborylation/C2 protodeboronation (Scheme 39) (46). When 3-substituted indoles 102 were subjected to C–H borylation with 1 equivalent of a boronating reagent [HB(pin)] in the presence of an iridium catalyst, the C2-borylated product was obtained in 64% yield along with the C2/C7 diborylated product 103, which confirmed the order of borylation in 3-substituted indole derivatives 102. Careful optimization of the second borylation at the C7 position revealed that reaction in THF was crucial for the second borylation at the C7 position. When 3-substituted indole derivatives 102 were subjected to diborylation conditions in THF with two equivalents of HB(pin) in the presence of an iridium catalyst, 2,7-diborylated indole products 103 were obtained in good yields. Then, the resulting diborylated indole products 103 were treated with trifluoroacetic acid (TFA) under dilute conditions with CH2Cl2 to afford 7-monoborylated products 104 in good yields.



Scheme 39. Synthesis of C7-borylated 3-substituted Indole Derivatives 104

The authors then developed a one-pot protocol for the preparation of N-Boc protected tryptophan derivatives, which should obviate the use of TFA for protodeboronation (Scheme 40). The diborylation of N-Boc-tryptophan methyl ester 105 proceeded smoothly under the optimized conditions and C2-deborylation was achieved using acetic acid in the presence of Pd(OAc)2 without the use of strong TFA to afford 7-borylated N-Boc protected tryptophan 107 in 73% yield over two steps.

Scheme 40. One-pot Synthesis for C7 Borylation of N-Boc Protected Tryptophan 107

The Steel group also reported the preparation of C5-borylated indazole compound 110 based on the greater lability of the C3 boronate ester toward protodeboronation in C5/C3 diborylated indazole 109 (Scheme 41) (47). When 2-SEM protected indazoles 108 were subjected to the borylation with an excess of B2(pin)2, products 109 diborylated at the C5/C3 positions were obtained. However, simple treatment of the crude mixture with aqueous KOH selectively deborylated at the C3 position to afford C5-borylated compounds 110. 511 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 41. Preparation of 5-Borylated Indazoles 110 via Selective Protodeborylation

More recently, the Smith group successfully extended the C–H diborylation/ deborylation protocol to the synthesis of 2-substituted-3-borylated thiophenes 113 from 2-substituted thiophenes 111 (Scheme 42) (48). When 2-substituted thiophenes 109 were subjected to C–H borylation in the presence of excess HB(pin), 2-substituted-3,5-diborylated thiophenes 112 were obtained. However, when the resulting diborylated thiophenes 112 were subjected to the protodeboronation protocol using MeOH as the proton source in the presence of an iridium catalyst, selective C5 deborylation took place to afford the 2-substituted-3-thiophene boronic acids 113 in good to high yields.

Scheme 42. Preparation of 2-Substituted-3-borylated Thiophenes 113

Furthermore, the potential of diborylation/deborylation was demonstrated with complex substrates, such as clopidogrel 114. Clopidogrel 114 underwent smooth C-H borylation, first at the thiophene moiety and then at the arene ring, to afford diborylated isomers 115 and 116 in a 1:1 ratio. When the mixture of regioisomers 115 and 116 was subjected to deborylation conditions, regioselective deborylation occurred at the thiophene moiety to produce monoborylated isomers 117 and 118 in high yields (Scheme 43).



Scheme 43. Regioselective Borylation at the Arene Moiety in Clopidogrel 114

More recently, the same research group reported the synthesis of regioselective borylated indole compounds via C–H borylation/deborylation using Bi(OAc)3 as the selective protodeboronation catalyst (Scheme 44) (49). Interestingly, protection of the N–H bond in the indole ring significantly affected the reactivity not only toward iridium-catalyzed C–H borylation, but also toward Bi(OAc)3-catalyzed protodeboronation. Iridium-catalyzed C–H borylation of unprotected indoles proceeded in the following order: C2-, C7-, C4-borylation. However, N-Boc protected indoles underwent C3/C5-diborylation under the same conditions. Furthermore, protection of the N–H bond with a Boc group significantly diminished the reactivity toward Bi(OAc)3-catalyzed protodeboronation. The reactivity difference between unprotected and N-Boc protected indoles toward protodeboronation was further utilized for the regioselective preparation of mono-borylated indole derivatives. For instance, when triborylated indole 128 was treated with Bi(OAc)3 in the presence of MeOH (250 equivalents), bis-protodeboronation occurred to afford 4-borylated indole product 129 in 80% yield. On the other hand, Bi(OAc)3-catalyzed protodeboronation of compound 128 with 60 equivalents of MeOH afforded 4,7-diborylated indole product 130. Protection of the N–H bond with a Boc group and subsequent treatment of the resulting protected indole 131 with Ir-catalyzed protodeboronation provided 7-borylated indole product 132 in good yield (Scheme 45).



Scheme 44. Regioselective Synthesis of Polyborylated Indole Derivatives

Scheme 45. Regioselective Synthesis of 4- and 7-Borylated Indoles 129 and 132



Diastereomeric Resolution Using a Boronic Acid as a Traceless Resolving Group Since axially chiral biaryl natural products display interesting biological activities and unique structural diversities, considerable effort has gone into developing methods to access them stereoselectively. However, diastereomeric resolution in the synthesis of axially chiral compounds is far less developed compared to that in the preparation of compounds bearing central chirality. This is because most diastereomeric resolution procedures have been designed for the synthesis of one specific target molecule using an existing phenol hydroxyl group as the resolving group at a late stage, which makes application of these protocols to the synthesis of structurally diverse natural products with axial chirality difficult. One of the reasons for the structural diversity of axially chiral natural products is the different number of phenolic hydroxy groups on the arene moiety. For example, axially chiral natural products in Group A bear hydrogen atoms at the 3,3′-positions relative to the chiral axis, while those in Group B contain oxygen functionalities at the same positions (Figure 4).

Figure 4. Representative Examples of Structurally Diverse Natural Products with Axial Chirality



In 2013, the Cheon group developed a new method to access axially chiral biaryl compounds via diastereomeric resolution of rac-axially chiral biaryl boronic acids in which the boronic acid moiety acted as 1) a resolving group and 2) a masked functional group. Based on this idea, the research group successfully developed a new protocol to access BINOL derivatives via diastereomeric resolution of rac-BINOL boronic acid (±)-133, followed by Suzuki–Miyaura coupling reactions of the resulting chiral BINOL boronic acids (R)-133 and (S)-133 (Scheme 46) (50).

Scheme 46. Diastereomeric Resolution of rac-BINOL Boronic Acid rac-133

Since a boronic acid is converted into either a hydrogen atom or hydroxy group via reductive or oxidative cleavage, respectively, the authors further applied this diastereomeric resolution protocol using boronic acid as a resolving group to the divergent total synthesis of natural products. In order to demonstrate their idea, Cheon et al. chose desmethyltetramethylcupressuflavone 135 and desmethylkotanin 136 from Group A and hibarimicinone 137 from Group B as target molecules. Retrosynthetic analysis for these compounds is depicted in Scheme 47 (51). Diastereomeric resolution of rac-biaryl boronic acid rac-138 would afford axially chiral biaryl boronic acids (R)-138 and (S)-138. Protodeboronation of the resulting chiral boronic acid 138 would provide compound 139, which could be utilized as a key intermediate in the syntheses of desmethyltetramethyl-cupressuflavone 135 and desmethylkotanin 136. On the other hand, oxidation of the boronic acid moiety would afford compound 138. Subsequent transformation would generate compound 141, which was used as the key intermediate in the previous total synthesis of hibarimicinone 137. Based on this synthetic plan, rac-biaryl boronic acid rac-138, rather easily prepared from resorcinol in four steps, was subjected to diastereomeric resolution with a chiral MIDA ligand to afford the two diastereomers 142 and 143 in 46% and 41% yields, respectively, which were then easily separated by conventional column chromatography on silica (Scheme 48).



Scheme 47. Retrosynthetic Analysis for Target Molecules from Group A and B

Scheme 48. Diastereomeric Resolution of rac-Biaryl Boronic Acid rac-138

Subsequent protodeboronation of the boronic acid moieties in the resulting diastereomer 142 with acetic acid provided compound 144, which was subsequently converted into compound 145 via acetylation followed by deprotection of an adjacent methoxy group with AlCl3. Aldol reaction of compound 145 with anisaldehyde followed by cyclization afforded desmethyltetramethylcupressuflavone 135. Furthermore, reaction of compound 145 with methyl chloroformate, and cyclization under basic conditions, followed by methylation allowed the completion of the synthesis of desmethylkotanin 136 in 36% yield over three steps (Scheme 49).



Scheme 49. Enantioselective Syntheses of Desmethyltetramethylcupressuflavone 135 and Desmethylkotanin 136

After successful application of chiral boronic acid derivative 142 to the total syntheses of 135 and 136, the other chiral boronic acid 143 was further applied to the synthesis of compound 141, the key intermediate in the previous total synthesis of hibarimicinone 137. Removal of chiral MIDA moiety in the resulting axially chiral boronic acid derivative 143 under aqueous basic conditions provided chiral boronic acid, which was subjected to oxidation with hydrogen peroxide without further purification afforded compound 148 after protection of the resulting phenolic hydroxy groups with methyl iodide. Lithium–bromine exchange followed by trapping of the resulting organolithium species with methyl chloroformate generated the diester compound 149, which was further converted into the diamide compound 150. Subsequent bromination, lithium–bromide exchange reaction, followed by trapping of the resulting organolithium species with methyl iodide allowed the introduction of methyl groups at the 4,4′-positions, leading to the synthesis of compound 152. Subsequent deprotection of the adjacent methoxyl group to the amide in compound 152 followed by the conversion of the amide to esters provided compound 141, the key intermediate in the previous total synthesis of hibarimicinone 137 (Scheme 50).



Scheme 50. Synthesis of Compound 141

Conclusion Although oxidative transformation of boron functionalities in organoboron compounds has been well-documented, reductive transformation is far less developed. However, recent successful developments of several organic transformations incorporating protodeboronation demonstrate its usefulness and this chapter descirbes recent progress in the development of organic transformations based on protodeboronation. An early example of an organic transformation based on protodeboronation is the reduction of alkenes, an alternative to hydrogenation, where alkenes were converted into organoboron species via hydroboration and subsequent protodeboronation afforded the corresponding alkanes. Chiral tertiary alkanes could be prepared from chiral tertiary alkylboranes via stereoselective protodeboronation. Furthermore, boronic acid moieties could be utilized as traceless functional groups in various organic transformations, which allow the regioselective preparation of various aromatic compounds. Since recent progress in reductive transformations of organoboron compounds has successfully demonstrated the utility of these reactions, further advances in this field are expected, which will allow the development of divergent syntheses from organoboron compounds.


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