molecules

Review Recent Synthesis Developments of Organoboron Compounds via Metal-Free Catalytic Borylation of Alkynes and Alkenes

Yanmei Wen, Chunmei Deng, Jianying Xie and Xinhuang Kang *

Faculty of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China; [email protected] (Y.W.); [email protected] (C.D.); [email protected] (J.X.) * Correspondence: [email protected]; Tel.: +86-759-2383728



Academic Editor: Igor V. Alabugin
 Received: 28 October 2018; Accepted: 19 December 2018; Published: 28 December 2018

Abstract: Diboron reagents have been traditionally regarded as “Lewis acids”, which can react with simple Lewis base to create a significant nucleophilic character in one of boryl moieties. In particular, bis(pinacolato)diboron (B2pin2) reacts with simple Lewis bases, such as N-heterocyclic carbenes (NHCs), phosphines and alkoxides. This review focuses on the application of trivalent nucleophilic boryl synthon in the selective preparation of organoboron compounds, mainly through metal-free catalytic diboration and the β-boration reactions of alkynes and alkenes.

Keywords: organoboron compound; metal-free catalytic boration; nucleophilic boron; alkyne; alkene

1. Introduction Organoboron compounds play an important role in organic chemistry as they can be converted into a wide variety of functional groups [1–13]. Thus, the synthesis of different types of organoboron compounds continues to be an important research field [14–20]. Conventional methods for their preparation are based on either reactive organometallic reagents or transition-metal-mediated processes [21–37]. Recently, great effort has been made towards the development of transition-metal-free methods with high chemoselectivity or regioselectivity and environmental sustainability [38–48]. The transition-metal-free catalyzed borylation reaction of alkynes and alkenes offers an attractive method for generating valuable organoboron compounds. The interaction of a diboron reagent, in particular bis(pinacolato)diboron (B2pin2), with a simple Lewis base, such as N-heterocyclic carbenes (NHCs), phosphines and alkoxides, generates Lewis acid-base adducts, in which the formally intact sp2 boryl moiety becomes the important source of nucleophilic boryl species, resulting in an appropriate approache towards transition-metal-free selective preparation of organoboron compounds. This review focuses on the application of trivalent nucleophilic boryl synthon in the selective preparation of organoboron compounds, mainly through diboration and β-boration reactions of alkynes and alkenes.

2. Organoboron Compounds via Transition-Metal-Free Catalytic Diboration of Unsaturated Hydrocarbons In recent years, the preparation of 1,2-diborated or 1,1-diborated products has rapidly grown due to the addition of diboryl compounds to unsaturated organic compounds in the transition metal-free catalysis. The first diboration reaction of non-activated alkenes in the absence of transition metal complexes was reported by Fernández and coworkers (Scheme1a) [ 49]. The diboration of non-activated olefins, such as terminal and internal alkenes, allenes and vinylarenes, can be produced via the formation of a 1,2-diborated product in a tetrahydrofuran (THF) solvent at 70 ◦C for ~6–16 h.

Molecules 2019, 24, 101; doi:10.3390/molecules24010101 www.mdpi.com/journal/molecules Molecules 2018, 23, x 2 of 16 Molecules 2018, 23, x 2 of 16 Molecules 2019, 24, 101 2 of 15 activated olefins, such as terminal and internal alkenes, allenes and vinylarenes, can be produced via the formation of a 1,2-diborated product in a tetrahydrofuran (THF) solvent at 70 °C for ~6–16 hours. The interaction of B2pin2 (1) and a methoxide anion, derived from the combination of Cs2CO3 and The interaction of B22pin2 ((11)) and a methoxide anion, derived fromfrom thethe combinationcombination ofof CsCs22CO3 and MeOH, can generate in situ the adduct [B2pin2OMe]−−. This adduct reacts with the unsubstituted MeOH, can generate inin situsitu thethe adductadduct [B[B2pin2pin22OMe]OMe]−. .This This adduct adduct reacts reacts with with the unsubstitutedunsubstituted 1 carbon atom (C 1)) of of the the C=C C=C double double bond bond via via the the transition transition state state (TS1), (TS1), which which is is the the overlap overlap between between the strongly polarized B-B B-B σ orbital of the activated diboron reagent reagent and and the the C–C C–C ππ* orbital of the 2 olefin.olefin. When the B–B bond weakens, the negative charge density onon thethe CC22 of the C=C double bond increases. The The negatively negatively charged charged olefin-boryl olefin-boryl olef olefin-B(pin)in-B(pin) fragment fragment attacks attacks the the boron boron atom atom with with an electrophilican electrophilic character character to form to form the thesecond second transition transition state state (TS2), (TS2), which which then then protonates protonates to form to form the diborated product (Scheme 2). The adduct [B2pin2OMe]− has− been fully characterized by both 11B- diboratedthe diborated product product (Scheme (Scheme 2). 2The). The adduct adduct [B2pin [B 22pinOMe]2OMe]− has beenhas beenfully fullycharacterized characterized by both byboth 11B- NMR11B-NMR spectroscopy spectroscopy and and ESI-MS. ESI-MS. A Alater later report report extended extended the the methodology methodology using using unsymmetrical Bpin–Bdan (dan(dan represents represents 1,8-diaminonaphthalene) 1,8-diaminonaphthalene) (2) as(2 the) as diboron the diboron reagents, reagents, where the where methoxide the methoxideselectively selectively interacted interacted with the stronger with the Lewisstronger acid Lewis Bpin acid moiety. Bpin moiety. The Bdan The moiety Bdan moiety appears appears in the ininternal the internal position position (Scheme (Scheme1b) [50 ].1b) [50].

B(OR)2 1.1 equiv B2(OR)2 B(OR)2 1.1 equiv B2(OR)2 B(OR) 15 mol% Cs2CO3 B(OR)2 15 mol% Cs2CO3 2 a) 5.0 equiv MeOH a) 5.0 equiv MeOH THF, 70 oC, 6 h THF, 70 oC, 6 h

O O O O O O O O B OR = B B B B B OR = B B B B OR O O O O O1 O O O 1 Isolated yield: 71% 59% 56% 82% Isolated yield: 71% 59% 56% 82% -OMe -OMe NH O NH O B B OMe B B NH OMeO O NH B O NH 2 O B B O NH O b) NH 2 B O NH O O b) N -OMe HN B B O Cs CO , MeOH NH - HN B B Cs2CO3, MeOH H OMe 70 2oC, 123 h 70 oC, 12 h

Isolated yield: 38% Isolated yield: 38% Scheme 1. (a) Transition-metal-free diboration reaction of non-activated olefins; (b) Mixed Scheme 1.1.( a)(a Transition-metal-free) Transition-metal-free diboration diboration reaction re ofaction non-activated of non-activated olefins; (b) Mixedolefins; organocatalytic (b) Mixed organocatalytic diboration of non-activated olefins. organocatalyticdiboration of non-activated diboration olefins.of non-activated olefins.

O O O O BB BB - O O O O O - O O O O O BB BB O O MeO- O O R MeO- R

O O O - base + O O O - base -H+ BB -H BB TS1 O O TS1 O O - - R H R H O O O MeOH O O O MeOH B + O B B + O B O O O R O O O B O R O B - O - - O O O - B + O O O O B H+ O O O BB O H O O B O BB R B O O O R O B O HO O B H R TS2 R R TS2 R Scheme 2. Suggested catalytic cycle for the dibo diborationration of non-activated olefins.olefins. Scheme 2. Suggested catalytic cycle for the diboration of non-activated olefins.

Molecules 2019, 24, 101 3 of 15 Molecules 2018, 23, x 3 of 16 Molecules 2018, 23, x 3 of 16 In 2015, Sawamura reported the formation of α,β-diboryl acrylates through trialkylphosphine In 2015, SawamuraSawamura reportedreported thethe formationformation ofof αα,,ββ-diboryl-diboryl acrylatesacrylates throughthrough trialkylphosphinetrialkylphosphine catalyzed anti-selective diboration of the C≡C triple bond (Scheme 3a) [51]. Through cross-coupling catalyzed anti-selectiveanti-selective diboration ofof thethe CC≡≡CC triple triple bond bond (Scheme 33a)a) [[51].51]. Through cross-coupling reaction of the differentiated heteroatom substituents of the α,β-diboryl acrylates in a stepwise reaction of the differentiateddifferentiated heteroatom substituents of the α,,β-diboryl acrylates in a stepwisestepwise manner, a diverse array of unsymmetrical tetrasubstituted alkenes can be accessed. Very recently, manner, a diverse array of unsymmetrical tetrasubstituted alkenes can can be be accessed. Very Very recently, recently, Santos employed an unsymmetrical Bpin–Bdan 2 as a diboron reagent for the direct diboration of Santos employed an unsymmetrical Bpin–Bdan 22 as a diboron reagent for the direct diboration of alkynamides, which display broad functional group tolerance. The transition-metal-free catalyzed alkynamides, which display broad functionalfunctional groupgroup tolerance.tolerance. The transition-metal-freetransition-metal-free catalyzed diboration of alkynamides with Bpin–Bdan, where the Bdan and Bpin moiety install α- and β-carbon diboration of alkynamides with Bpin–Bdan, where the Bdan and Bpin moiety install α-- and β-carbon atoms respectively. (Scheme 3b) [52]. atoms respectively. (Scheme(Scheme3 3b)b) [ 52[52].].

10 mol% PBu3 Ph Bpin Isolated yield 1.010 equivmol% BPBupin3 Ph Bpin Isolated yield a) 1.0 equiv B2pin2 a) Ph CO2Et o 2 2 Ph CO2Et THF, 80 C, 8 h 64% THF, 80 oC, 8 h pinB CO2Et 64% pinB CO2Et 1.4 equiv pinB-Bdan O 1.4 equiv pinB-Bdan O 1.1 equiv NaH Bpin O 1.11.0 equiv NaH15-crown-5 Bpin O N Me 1.0 equiv 15-crown-5 Me 67% b) N Me Ph N Me 67% b) Ph H THF, RT, Ph N Ph H THF, RT, Bdan H 0.5 h-1 h Bdan H 0.5 h-1 h Scheme 3. (a) Phosphine-Catalyzed 1,2-diboration of alkynoate; (b) 1,2-diboration of N-substituted Scheme 3. (a) Phosphine-CatalyzedPhosphine-Catalyzed 1,2-diboration of alkynoate; (b) 1,2-diboration1,2-diboration of N-substitutedN-substituted phenylpropiolamides. phenylpropiolamides. In 2014, Uchiyama and coworkers reported that the diboration of propargylic alcohols with In 2014, Uchiyama and coworkers reported that the diboration of propargylic alcohols with diboron reagents in the presence of aa stoichiometricstoichiometric amountamount ofof n-BuLin-BuLi enablesenables thethe trans-diborationtrans-diboration diboron reagents in the presence of a stoichiometric amount of n-BuLi enables the trans-diboration of alkynes through aqueous workup. The present trans-diborylation gave oxaborole moieties which of alkynes through aqueous workup. The present trans-diborylation gave oxaborole moieties which are key structuralstructural platforms and potentpotent pharmacophorespharmacophores in materialmaterial andand pharmaceuticalpharmaceutical sciences are key structural platforms and potent pharmacophores in material and pharmaceutical sciences (Scheme4 4))[ [53].53]. Very recently,recently, thethe directdirect diborationdiboration ofof alkynesalkynes using a more reactivereactive unsymmetricalunsymmetrical (Scheme 4) [53]. Very recently, the direct diboration of alkynes using a more reactive unsymmetrical pinB-Bmes2 ((33)) as as the the diboron diboronreagent reagent was was reported reported by by Yamashita’ Yamashita’ss group. group. The The mixture mixture of two of twocis- pinB-Bmes2 (3) as the diboron reagent was reported by Yamashita’s group. The mixture of two cis- cis-isomersisomers and and one one trans-isomer trans-isomer was was obtained obtained when when the the base-catalyzed base-catalyzed diboration diboration reaction reaction of of the isomers and one trans-isomer was obtained when the base-catalyzed diboration reaction of the terminal alkynesalkynes was was conducted conducted in thein the system system consisting consisting of n-BuLi of n-BuLi and 1,2-dimethoxyethane and 1,2-dimethoxyethane in toluene in terminal alkynes was conducted in the system consisting of n-BuLi and 1,2-dimethoxyethane in (Schemetoluene (Scheme5)[54]. 5) [54]. toluene (Scheme 5) [54].

O 1) 1.0 equiv n-BuLi O O 1) 1.0r.t., equiv30 min n-BuLi B O r.t., 30 min B Isolated yield: 77% 2) 1.1 equiv B pin Isolated yield: 77% HO 2) 1.1 equiv B2pin2 B HO THF, 75 oC,2 24 2h HO B THF, 75 oC, 24 h HO O workup O workup Scheme 4. Trans-selectiveTrans-selective diborylation reaction of propargylic alcohols.alcohols. Scheme 4. Trans-selective diborylation reaction of propargylic alcohols. In 2015, Sawamura revealed a new methodBnip forBmes the synthesis of 1,1-diborylalkenes through Bnip Bmes2 NMR yield a Brönsted base catalyzed reaction between bis(pinacolato)diboron2 NMR yield and various terminal alkynes H 5% containing propiolates, propiolamides and 2-ethynylazolesH (Scheme5%6a) [ 55]. In 2018, the Brönsted base catalyzed diboration1.0 equiv of pinB-Bmes strong electron deficient alkynes, including various propiolates, ynones 1.0 equiv pinB-Bmes2 and propiolamides,3 mol% was developedn-BuLi 2 by Song’s group (Scheme+ 6b) [ 56]. The terminal and internal 3 mol% n-BuLi1,2-dimethoxyethane + alkynes were allowed3 mol% to react1,2-dimethoxyethane under the “optimal”Bnip conditions,Bmes2 and good to excellent yields of the H Bnip Bmes2 6% O B B H toluene 6% O B B corresponding gem-diborylalkanestolueneo were obtained. H O 100 oC, 4-72 h H The asymmetric organocatalytic100 C, 4-72 h 1,2-diboration of alkenes has been accomplished3 3 utilizing economically accessible chiral alcohols as+ additives to form the Lewis acid-base * - + RO →bis(pinacolato)diboron adduct that is added to cyclic and non-cyclicpinB-Bmes alkenes, providing2 pinB-Bmes2 moderate enantioselectivity. The authors reported moderateBmes conversions and moderate levels of Bmes2 84% enantioselectivity for the synthesis of the 1,2-diborated product2 84% (Scheme7a) [ 57]. Alternatively, the enantioselective diboration of alkenes can be achievedBpin usingH inexpensive chiral carbohydrates, such Bpin H Scheme 5. Reaction of pinB–BMes2 with terminal alkynes. Scheme 5. Reaction of pinB–BMes2 with terminal alkynes.

Molecules 2018, 23, x 3 of 16

In 2015, Sawamura reported the formation of α,β-diboryl acrylates through trialkylphosphine catalyzed anti-selective diboration of the C≡C triple bond (Scheme 3a) [51]. Through cross-coupling reaction of the differentiated heteroatom substituents of the α,β-diboryl acrylates in a stepwise manner, a diverse array of unsymmetrical tetrasubstituted alkenes can be accessed. Very recently, Santos employed an unsymmetrical Bpin–Bdan 2 as a diboron reagent for the direct diboration of alkynamides, which display broad functional group tolerance. The transition-metal-free catalyzed diboration of alkynamides with Bpin–Bdan, where the Bdan and Bpin moiety install α- and β-carbon atoms respectively. (Scheme 3b) [52].

10 mol% PBu3 Ph Bpin Isolated yield 1.0 equiv B2pin2 a) Ph CO Et 2 THF, 80 oC, 8 h 64% pinB CO2Et 1.4 equiv pinB-Bdan O 1.1 equiv NaH Bpin O 1.0 equiv 15-crown-5 N Me b) Ph N Me 67% Ph H THF, RT, Bdan H 0.5 h-1 h Scheme 3. (a) Phosphine-Catalyzed 1,2-diboration of alkynoate; (b) 1,2-diboration of N-substituted phenylpropiolamides.

In 2014, Uchiyama and coworkers reported that the diboration of propargylic alcohols with diboron reagents in the presence of a stoichiometric amount of n-BuLi enables the trans-diboration of alkynes through aqueous workup. The present trans-diborylation gave oxaborole moieties which are key structural platforms and potent pharmacophores in material and pharmaceutical sciences (Scheme 4) [53]. Very recently, the direct diboration of alkynes using a more reactive unsymmetrical pinB-Bmes2 (3) as the diboron reagent was reported by Yamashita’s group. The mixture of two cis- isomers and one trans-isomer was obtained when the base-catalyzed diboration reaction of the terminal alkynes was conducted in the system consisting of n-BuLi and 1,2-dimethoxyethane in toluene (Scheme 5) [54].

Molecules 2019, 24, 101 4 of 15 O 1) 1.0 equiv n-BuLi O r.t., 30 min B as the pseudoenantiomeric glycol 6-tertbutyldimethylsilyl-1,2-dihydroglucalIsolated (4) yield: and dihydrorhamnal77% 2) 1.1 equiv B pin (5) (SchemeMolecules 20187b), [2358, x ]. TheHO alkoxide-catalyzed2 directed2 diborationB of alkenyl alcohols through4 of 16 the THF, 75 oC, 24 h HO intramolecular activation of the diboron reagent and the selectiveO delivery of the nucleophilic boryl workup unit offersIn access2015, Sawamura to the diboration revealed a ofnew cyclic method and for acyclic the synthesis homoallylic of 1,1-diborylalkenes and bishomoallylic through alcohol a Brönsted base catalyzed reaction between bis(pinacolato)diboron and various terminal alkynes substrates (SchemeScheme7c) [59 ].4. Trans-selective diborylation reaction of propargylic alcohols. containing propiolates, propiolamides and 2-ethynylazoles (Scheme 6a) [55]. In 2018, the Brönsted base catalyzed diboration of strong electron deficient alkynes, including various propiolates, ynones Bnip Bmes2 and propiolamides, was developed by Song’s group (Scheme 6b)NMR [56]. yield The terminal and internal alkynes were allowed to react under the “optimal”H conditions, and 5%good to excellent yields of the corresponding gem-diborylalkanes were obtained. 1.0 equiv pinB-Bmes2 3 mol% n-BuLi 1.0 equiv B2pin2 + OMe 3 mol%O 1,2-dimethoxyethane Isolated yield 10 mol% LiOBniptBu OBmes2 Bpin Molecules 2018, 23, x H H 6% O B 4 of 16 a) toluene o 83% B MeO CH3CN, 40 C, 5-12 h O 100 oC, 4-72 h H H Bpin In 2015, Sawamura revealed a new method for the synthesis of 1,1-diborylalkenes through3 a Brönsted base catalyzedO reaction between2.0 equiv Bbis(pi2pin2 nacolato)diboron+O and various terminal alkynes 0.3 equiv K2CO3 Bpin containing propiolates, propiolamides and 2-ethynylazoles1 (Scheme 6a) [55]. InpinB-Bmes 2018, the2 Brönsted b) 1 R R R2 10 equiv CH OH Bpin base catalyzed diboration of strong electron defi3 cient alkynes,Bmes including2 various propiolates, ynones Et O, N , 50 oC, 12 h R2 84% and propiolamides, was developed 2by Song’s2 group (Scheme 6b) [56]. The terminal and internal R1 = aryl, alkyl, OR, NR alkynes were allowed to react under the2 “optimal”Bpin conditions,H and good to excellent yields of the corresponding Schemegem-diborylalkanes 6. (a) Synthesis of were 1,1-diborylalkenes, obtained. (b) Synthesis of functionalized geminal- SchemeScheme 5.5. Reaction ofof pinB–BMespinB–BMes22 with terminal alkynes. diborylalkanes.

1.0 equiv B2pin2 OMe Isolated yield The asymmetricO organocatalytic10 mol% 1,2-diboration LiOtBu of Oalkenes hasBpin been accomplished utilizing economicallya) accessible chiralH alcohols aso additives to form the Lewis83% acid-base *RO- CH3CN, 40 C, 5-12 h →bis(pinacolato)diboronMeO adduct that is added to cyclic and non-cyclicH Bpin alkenes, providing moderate enantioselectivity. The authors reported moderate conversions and moderate levels of enantioselectivityO for the synthesis2.0 of equiv the 1,2-dibo B2pin2rated productO (Scheme 7a) [57]. Alternatively, the 0.3 equiv K2CO3 Bpin enantioselective diboration of alkenes can be achieved using1 inexpensive chiral carbohydrates, such b) R1 2 R as the pseudoenantiomericR 10 equivglycol CH 36-tertbutyldimethylsilyl-1,2-dihydroglucalOH Bpin (4) and o R2 dihydrorhamnal (5) (Scheme 7b)Et [58].2O, TheN2, 50alkoxide-catalyzed C, 12 h directed diboration of alkenyl alcohols through the intramolecular1 activation of the diboron reagent and the selective delivery of the R = aryl, alkyl, OR, NR2 nucleophilic boryl unit offers access to the diboration of cyclic and acyclic homoallylic and SchemebishomoallylicScheme 6. (a) Synthesis alcohol6. (a) Synthesis substrates of 1,1-diborylalkenes, of (Scheme1,1-diborylalkenes, 7c) ([59].b) Synthesis (b) Synthesis of functionalized of functionalized geminal-diborylalkanes. geminal- diborylalkanes.

OH The asymmetric organocatalytic 1,2-diboration Oof alkenesO has been accomplished utilizing 1.1 equiv B2pin2 B O * - economically accessible 1.0chiral equiv Csalcohols2CO3 as additives to form the Lewis acid-base RO 2.0 equiv Chiral alcohol B O →bis(pinacolato)diboron adduct that is added to cyclic and non-cyclic alkenes, providing moderate a) o DCM, 45 C, 16 h 40% ee Chiral alcohol enantioselectivity. The authors reported moderate Yield:87%conversions and moderate levels of enantioselectivity for the synthesis of the 1,2-diborated product (Scheme 7a) [57]. Alternatively, the TBSO 1.0 equiv B2(neo)2 OH O enantioselective diboration10% of TBS-DHG/DBU alkenes can beH achiO eved using inexpensive chiral carbohydrates,4 such 2 2 OH OH as the pseudoenantiomericor 20% DHR/DBU glycol NaOH6-tertbutyldimethylsilyl-1,2-dihydroglucal (4) and b) OH dihydrorhamnal (5) (SchemeTHF, 22-607b) [58]. oC, 24-48 The halkoxide-catalyzed directed diborationO of alkenyl alcohols HO Me 5 through the intramolecular activation of the diboron 4: 68%, reagent97:3 er and the selective delivery of the 5: 50%, 4:96 er HO nucleophilic boryl unit offers1.2 accessequiv B2 pinto2 the diboration of cyclic and acyclic homoallylic and OH 30% Cs2CO3 NaOH OH OH bishomoallylic alcohol substrates17 equiv (Scheme CH OH 7c) [59]. c) Ph 3 H2O2 Ph OH THF, 70 oC, 12 h Yield: 74%,13:1 dr OH Scheme 7. EnantioselectiveScheme diboration 7. Enantioselective of olefins. diboration (Oa) synthesisO of olefins. of the 1,2-diborated product; 1.1 equiv B pin (b) synthesis of pseudoenantiomeric2 2 glycol 6-tertbutyldimethylsilyl-1,2-dihydroglucalB O (4) and 1.0 equiv Cs2CO3 dihydrorhamnal (5);2.0 (c) equiv synthesis Chiral of alcohol diboration of cyclic and acyclicB O homoallylic and bishomoallylic alcohola) substrates. o DCM, 45 C, 16 h 40% ee Chiral alcohol Yield:87% TBSO 1.0 equiv B2(neo)2 OH O 10% TBS-DHG/DBU H O 4 2 2 OH OH or 20% DHR/DBU NaOH b) OH THF, 22-60 oC, 24-48 h O HO Me 5 4: 68%, 97:3 er 5: 50%, 4:96 er HO 1.2 equiv B2pin2 OH 30% Cs2CO3 NaOH OH OH 17 equiv CH OH c) Ph 3 H2O2 Ph OH THF, 70 oC, 12 h Yield: 74%,13:1 dr Scheme 7. Enantioselective diboration of olefins.

Molecules 2018, 23, x 5 of 16 Molecules 20192018,, 2423,, 101x 55 of of 1516 Molecules 2018, 23, x 5 of 16

3. Organoboron Compounds via Transition-Metal-Free Catalytic β-boration of α,β-Unsaturated 3. Organoboron Compounds via Transition-Metal-Free CatalyticCatalytic ββ-boration-boration ofof α,β-Unsaturated Compounds αCompounds,β-Unsaturated Compounds 3.1. N-Heterocyclic Carbene Catalysis 3.1. N-Heterocyclic Carbene Catalysis In 2009, Hoveyda and coworkers firstly reported that an imidazolium salt 6 in the absence of a In 2009, 2009, Hoveyda Hoveyda and and coworkers coworkers firstly firstly reported reported that that an animidazolium imidazolium salt salt 6 in6 thein absence the absence of a transition metal was able to promote the boron conjugation addition of cyclic and acyclic α,β- oftransition a transition metal metal was able was ableto promote to promote the boro then boron conjugation conjugation addition addition of cyclic of cyclic and acyclic and acyclic α,β- unsaturated ketones and esters, providing β-boryl carbonyls (Scheme 8) [60]. It is noteworthy that in αunsaturated,β-unsaturated ketones ketones and andesters, esters, providing providing β-borylβ-boryl carbonyls carbonyls (Scheme (Scheme 8) 8[60].)[ 60 It]. is It noteworthy is noteworthy that that in the presence of a base (NaOtBu) only, the borylation reaction did not take place. It was proposed that inthe the presence presence of ofa base a base (NaOtBu) (NaOtBu) only, only, the the borylation borylation reaction reaction did did not not take take place. place. It It was was proposed proposed that in this process a nucleophilic N-heterocyclic carbene (NHC) could associate with the diboron reagent in this process a nucleophilic N-heterocyclic carbene (NHC) could associate with the diboron reagent in presence of a base and an in situ generated NHC·B2(pin)2 complex. The diboron reagent becomes in presence of a base and an in situ generated NHC·B2(pin)2 complex. The diboron reagent becomes in presencepresence ofof aa basebase andand anan inin situsitu generatedgenerated NHCNHC·B·B2 22(pin)(pin)22 complex. The diboron reagent becomes nucleophilic and is able to transfer the “intact” sp2 boryl group to the activated olefins in boron nucleophilic and is able to transfer the “intact” sp2 boryl group to the activated olefins olefins in boron conjugate additions. A proton from alcohol additives or aqueous workup served as the electrophilic conjugate additions. A proton from alcohol additives or aqueous workup served as the electrophilic counterpart of the boron nucleophile (Scheme 9). Density functional theory (DFT) calculations and counterpart11 of the boronboron nucleophilenucleophile (Scheme(Scheme9 9).). DensityDensity functionalfunctional theorytheory (DFT)(DFT) calculationscalculations2 3 andand 11B-NMR studies were carried out to determine the exact structure of the proposed sp2–sp3 hybridized 1111B-NMRB-NMR studies studies were carried out to determine the exact structure ofof the proposed spsp22–sp33 hybridized NHC·B2(pin)2 adduct. The DFT calculations showed polarization of the B–B bond and diminished NHC·B2(pin)2 adduct. The DFT calculations showed polarization of the B–B bond and diminished NHCNHC·B·B2(pin)(pin)22 adduct.adduct. The The DFT DFT calculations calculations showed showed polarization polarization of of the the B–B bond and diminisheddiminished electrophilic character of the two boron atoms, where the electron density was strongly polarized electrophilic character of the two boron atoms, wherewhere the electronelectron densitydensity was stronglystrongly polarizedpolarized2 2 towards the unbound boron center. However, due to the weak association of the NHC to the sp2–sp2 towards thethe unboundunbound boronboron center.center. However,However, duedue toto thethe weakweak associationassociation ofof thethe NHCNHC toto thethe spsp22–sp–sp22 diboron, causing dynamic exchange, the 11B-NMR signal for B2pin2 disappeared within five minutes diboron, causing dynamic exchange, the 1111B-NMR signal for B2pin2 disappeared within five minutes diboron, causingcausing dynamicdynamic exchange,exchange, thethe 11B-NMR signal for BB2pin2 disappeareddisappeared within five five minutes after treatment with the NHC. In 2012, the crystal structure of the2 neutral2 NHC adduct 7 was reported after treatment with the NHC. In 2012, the crystal structure of the neutral NHC adduct 7 was reported by Marder and coworkers (Scheme 10) [61]. by Marder and coworkers (Scheme(Scheme 1010))[ [61].61]. O O O O 2.5 mol% NHC salt O 2.5 mol% NHC salt CyN NCy BF4 2.5 mol% NaOt-Bu CyN NCy BF4 2.5 mol% NaOt-Bu CyN NCy BF4 Cy = cyclohexyl 6 1.1 equiv B2pin2 Cy = cyclohexyl 6 1.1 equivo B2pin2 Bpin Cy = cyclohexyl THF, 22 oC,2 2 h2 Bpin NHC salt THF, 22 oC, 2 h NHC salt Isolated yield: 91% Isolated yield: 91% Scheme 8. The β-borylation of α,β-unsaturated carbonyl compounds. Scheme 8.8. The β-borylation of α,β-unsaturated-unsaturated carbonyl carbonyl compounds.

O NHC O O O O O NHC O O O O NHC: O B B O B B NHC: O B B B B Base O B B O O O Base O O O O Base B(pin) O O B(pin) O O O B(pin) O NHC O aqueous O O NHC O workupaqueous B(pin) B(pin)= B workup B(pin) B(pin)= B O B(pin) B(pin) B(pin) O B(pin) B(pin) B(pin) B(pin) B(pin) Scheme 9. Mechanism for B2pin2 activation and conjugate addition to an enone. SchemeScheme 9.9. Mechanism for B22pin2 activationactivation and and conjugate conjugate addition addition to an enone. Scheme 9. Mechanism for B2pin2 activation and conjugate addition to an enone.

O O O BBO O O O BBO O O O BBO BB + CyN NCy O O BB + CyN NCy PhMe O O PhMe CyN NCy 7 O O CyN NCy 7 7 2 3 SchemeScheme 10.10.Formation Formation ofof thethe spsp2–sp–sp3 hybridized NHCNHC·B·B2(pin)(pin)22 compound.compound. Scheme 10. Formation of the sp2–sp3 hybridized NHC·B2(pin)2 compound. Scheme 10. Formation of the sp2–sp3 hybridized NHC·B2(pin)2 compound. In a subsequent study, Hoveyda reported further work on enantioselective method for In a subsequent study, Hoveyda reported further work on enantioselective method for boron boronIn conjugate a subsequent addition study, to Hoveydaα,β-unsaturated reported carbonyls further work with on a chiralenantioselective NHC 8 in combinationmethod for boron with conjugate addition to α,β-unsaturated carbonyls with a chiral NHC 8 in combination with 1,8- 1,8-diazabicyclo[5.4.0]undec-7-enediazabicyclo[5.4.0]undec-7-eneconjugate addition to α,β-unsaturated (DBU). (DBU). carbonylsThis This method method with can acan chiraltolerate tolerate NHC a a broad8 broad in combination range range of of substrates, with 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU). This method can tolerate a broad range of substrates, including acyclic and cyclic α,β-unsaturated-unsaturated ketones, ketones, as well well as as acyclic acyclic esters, esters, amides, amides, and and aldehydes. aldehydes. including acyclic and cyclic α,β-unsaturated ketones, as well as acyclic esters, amides, and aldehydes. The desired β-boryl carbonyls are obtained in up to a 94% isolated yield and an >98:2 enantiomer The desired β-boryl carbonyls are obtained in up to a 94% isolated yield and an >98:2 enantiomer

Molecules 2019, 24, 101 6 of 15

Molecules 2018, 23, x 6 of 16 The desired β-boryl carbonyls are obtained in up to a 94% isolated yield and an >98:2 enantiomer ratio (Schemeratio (Scheme 11a) [ 6211a)]. A [62]. later A report later extended report extended this methodology this methodology to β-disubstituted to β-disubstituted enones, generating enones, productsgenerating containing products boron-substituted containing boron-substitute quaternary carbond quaternary with enantioselectivity carbon with (Schemeenantioselectivity 11b) [63]. The(Scheme use of11b) diboranes [63]. The and useN of-heterocyclic diboranes and carbenes N-heterocyclic in the absence carbenes of a in transition the absence metal of complex a transition has metalbeen reported complex byhas other been groups reported [64 by,65 ].other groups [64,65].

O 2.5-7.5 mol% NHC salt Ph Ph 20 mol% dbu Bpin O Mes BF R G 1.1 equiv B2pin2 4 R G NH NMes G = alkyl, aryl, OR, 60 equiv MeOH 8 a) N(Me)OMe, H THF, 22 oC, 14h O NHC salt O

n =1-3 n Bpin n up to 94% yield >98:2 er

BF4 5.0 mol% NHC salt Ph Ph O O i Pr 20 mol% dbu Mes N 1.1 equiv B2pin2 N b) Bpin 60 equiv MeOH R Me THF, 22 oC, 14h R 9 NHC salt 63–95% yield 91:9 to >99:1 er Scheme 11. ((aa)) NHC-catalyzedNHC-catalyzed enantioselective enantioselective boryl boryl conjugate conjugate addition addition to to unsaturated unsaturated carbonyls, carbonyls, (b) (NHC-catalyzedb) NHC-catalyzed enantioselective enantioselective boryl bo conjugateryl conjugate addition addition to enones. to enones. 3.2. Base Catalysis 3.2. Base Catalysis In 2012, Fernández reported the utility of the base-catalyzed method for the β-boration of In 2012, Fernández reported the utility of the base-catalyzed method for the β-boration of acyclic acyclic and cyclic activated olefins in cases involving α,β-unsaturated amides and phosphonates [66]. and cyclic activated olefins in cases involving α,β-unsaturated amides and phosphonates [66]. The The methodology could be applied to different diboron reagents, such as bis(pinacolato)diboron methodology could be applied to different diboron reagents, such as bis(pinacolato)diboron (B2pin2), (B2pin2), bis(catecholato)borane (B2cat2) and so on. Alternative inorganic and organic bases were bis(catecholato)borane (B2cat2) and so on. Alternative inorganic and organic bases were explored, explored, such as NaOMe, LiOMe, NaOtBu, K2CO3, CsF and Verkade’s base, the latter being the such as NaOMe, LiOMe, NaOtBu, K2CO3, CsF and Verkade’s base, the latter being the most efficient most efficient (Scheme 12). With an excess of MeOH, Verkade’s base is completely protonated and (Scheme 12). With an− excess of MeOH, Verkade’s base is completely protonated and the generated the generated MeO forms a Lewis acid-base adduct with B2pin2. Computational studies identified MeO− forms a Lewis acid-base adduct with B2pin2. Computational studies identified that there was that there was an overlap between the strongly polarized B–B σ orbital and the C–C π* orbital, and an overlap between the strongly polarized B–B σ orbital and the C–C π* orbital, and DFT calculations DFT calculations revealed that in adducts the sp2 boron atom gains a strong nucleophilic character revealed that in adducts the sp2 boron atom gains a strong nucleophilic character because the sp3 because the sp3 boron atom loses negative charge density upon the charge transfer from the Lewis base. boron atom loses negative charge density upon the charge transfer from the Lewis base. The intact The intact sp2 boron atom corresponds to a nucleophilic attack at the β-carbon atom of the activated sp2 boron atom corresponds to a nucleophilic attack at the β-carbon atom of the activated olefins, olefins, forming a transition sate (TS), which releases the “(pin)BOMe” and leads to the formation of forming a transition sate (TS), which releases the “(pin)BOMe” and leads to the formation of an an anionic intermediate, which is then protonated to provide the β-boration product (Scheme 13). anionic intermediate, which is then protonated to provide the β-boration product (Scheme 13) A later report extended the methodology to non-symmetrical diboron reagents, such as Bpin–Bdan 2, where the RO− selectively interacted with the stronger Lewis acid Bpin moiety (Scheme 14a) [67]. Experimental and theoretical investigation confirmed that the interaction of RO− and the Bpin moiety preferred to form a [RO→Bpin–Bdan]− intermediate, which then resulted in exclusively the β-carbon Bdan carbonyl compound with high yields. The adduct [MeO→Bpin–Bpin]− which efficiently mediates the β-boration of α,β-unsaturated imines formed in situ was reported by Fernández’s group (Scheme 14b) [68]. From a theoretical point of view, the mechanism of β-boration of α,β-unsaturated imines has been thought to involve quaternization of the diboron reagent with methoxide. The function of the phosphine has been regarded to the ion pair formation.

MoleculesMolecules2019 2018, 24, ,23 101, x 7 of7 16 of 15 Molecules 2018, 23, x 7 of 16 Me Me MeN O 1.1 equiv B2(OR)2 RO OR Me N PN Me 1.1 equiv B (OR) RO B ORO N P Me O 15 mol% Verkade's2 2 base B O N OEt 15 mol% Verkade's base N OEt 5.0 equiv MeOH OEt 5.0 equivo MeOH OEt N THF, 70 C,o 24 h Verkade'sN base THF, 70 C, 24 h Verkade's base

O O O O O O O O B OR = B B B OR = B BB BB B OROR O O O OO OO O

Conversion:Conversion: 95%95% 99%99% 99%99% 78%78% Isolated yield: 85%85% Isolated yield: 90%90% SchemeSchemeScheme 12. 12. 12.Verkade’s Verkade’s Verkade’s basebase base mediates mediatesmediates β-boration-boration of of of ethyl ethyl ethyl crotonate. crotonate. crotonate.

MeOH OO OO OO base BB base OO OO O - BB O MeO- BB OO OO MeOHMeOH

O O - B - - OB O O O - O O O O Ⅱ O BB Ⅱ O O BBO O O Ⅰ O Ⅰ O O - O B OMe O OO O O - O B OMe O BBO O O O OBBO O O O O TS O O TS O Scheme 13. Proposed reaction pathway for β-boration of methyl acrylate. Molecules 2018, 23, xScheme Scheme 13. 13.Proposed Proposed reactionreaction pathway for ββ--borationboration of of methyl methyl acrylate. acrylate. 8 of 16 A later report extended the methodology to non-symmetrical diboron reagents, such as Bpin– Bdan 2, where the RO− selectively interacted with the stronger Lewis acid Bpin moiety (Scheme 14a) A later report extended theNH methodologyO to non-symmetrical diboron reagents, such as Bpin– − Bdan[67]. 2,Experimental where the RO and− selectively theoreticalB interacted investigationB with confirmed the stronger that Lewis the interaction acid Bpin of moiety RO and (Scheme the Bpin 14a) NH→ O − [67].moiety Experimental preferred andto form theoretical a [RO Bpin–Bdan] investigation2 intermediate, confirmed whichthat the then interaction resulted in of exclusively RO− and the the Bpinβ- OMe − carbon Bdan carbonylO compound1.1 equiv with high yields.− TheNH adduct [MeO→Bpin–Bpin] which efficiently moiety preferred to form a [RO→Bpin–Bdan] intermediate,B whichO then resulted in HNexclusively the β- mediates the β-boration of α,β-unsaturated imines formedB in situ was reportedNaO Bpin by Fernández’sO B NH group carbon Bdana) carbonyl compound9 mol% NaO withtBu high yields. TheN adductO [MeO→Bpin–Bpin]− which efficiently (Scheme 14b) [68]. From a6 theoreticamol% PCy l point of view, Hthe mechanism of β-boration of α,β-unsaturated mediates the β-boration of α,β-unsaturated3 iminesO formed in situ was reported by Fernández’s group imines has been thoughtMeOH,70 to involve oC, 16 quaternizati h on of the diboron reagent with methoxide. The (Scheme 14b) [68]. From a theoretical point of view, the mechanism of β-boration of α,β-unsaturated function of the phosphine has been regarded to the ion pair formation. imines has been thought to involveConversion: quaternizati 99% Selectivity:on of the 99% diboronIsolated reagent yield: 74% with methoxide. The - function of the phosphine has been regarded to the ionO pairOMe formation. Bpin NBn O 1) 1.1 equiv NH2Bn B O o B THF, 25 C, 6 h O O b) 2) 1.1 equiv B2pin2 15 mol% Cs CO Ph 2 3 Conversion: 90% 10 mol% PCy BnN 3 Isolated yield: 66% 2.5 equiv MeOH THF, 70 oC, 12 h

SchemeScheme 14. 14.(a )(a The) Theβ -borationβ-boration of ofα α,β,β-unsaturated-unsaturated compounds, compounds, (b (b) )The The ββ-boration-boration of ofin insitu situ formed formed α,βα-unsaturated,β-unsaturated imines. imines.

3.3. Phosphine Catalysis In 2010, Fernández reported the β-borylation of α,β-unsaturated compounds using a trivalent phosphorus nucleophile in combination with catalytic amounts of bases and stoichiometric amounts of methanol (Scheme 15) [69]. Further screening showed that a variety of phosphorus compounds including achiral, chiral mono and bidentate phosphines could also give reasonable conversions without a transition metal. The process was proposed that the phosphine interacted with the empty orbital of one of the boron atoms to result in the heterolytic cleavage of the B–B bond of B2pin2. Upon such interaction, the other boron moiety could act as a nucleophile towards the α,β-unsaturated esters and ketones (Scheme 16) [69].

4 mol% (R)-(S)-josiphos 1.1 equiv B pin O 2 2 O O P P 15 mol% Cs2CO3 B O Fe CH3 H 2.5 mmol MeOH THF, 70oC, 6 h 95% ee (R)-(S)-Josiphos

Scheme 15. Phosphine-mediated asymmetric β-boration of α,β-unsaturated compounds.

O MeO B O O O O B O O R P BB R' R 3 O O

MeOH base

R P O 3 O O O O O B - B B B R P+ O O 3 O R R' R O 3P O O R' R B B O O O R R' Scheme 16. Plausible mechanism for the phosphine-catalyzed β-boration of α,β-unsaturated carbonyl compound.

Molecules 2018, 23, x 8 of 16 Molecules 2018, 23, x 8 of 16

NH O NH O B B B BO NH 2 O NH 2 OMe O 1.1 equiv NH OMe O 1.1 equiv NH B O HN B O Bpin O HN NH a) 9 mol% NaOtBu B NaO Bpin O B NH a) 9 mol% NaOtBu N B O NaO B 6 mol% PCy HN O 6 mol% PCy3 O H MeOH,70 oC,3 16 h O MeOH,70 oC, 16 h Conversion: 99% Selectivity: 99% Isolated yield: 74% Conversion: 99% Selectivity: 99% Isolated yield: 74% O OMe - O OMe - Bpin NBn O 1) 1.1 equiv NH2Bn B O Bpin NBn O 1) 1.1 equivo NH2Bn B B O THF, 25 oC, 6 h O B THF, 25 C, 6 h O O b) 2) 1.1 equiv B pin O b) 2) 1.1 equiv B2pin2 15 mol% Cs CO2 2 Ph 15 mol% Cs2CO3 Ph Conversion: 90% 10 mol% PCy2 3 BnN Conversion: 90% 10 mol% PCy3 BnN Isolated yield: 66% 2.5 equiv MeOH3 Isolated yield: 66% 2.5 equiv MeOH THF, 70 oC, 12 h THF, 70 oC, 12 h Scheme 14. (a) The β-boration of α,β-unsaturated compounds, (b) The β-boration of in situ formed MoleculesScheme2019, 2414., 101 (a) The β-boration of α,β-unsaturated compounds, (b) The β-boration of in situ formed8 of 15 α,β-unsaturated imines. α,β-unsaturated imines.

3.3. Phosphine Catalysis 3.3. Phosphine Catalysis In 2010, Fernández reported the β-borylation of α,β-unsaturated compounds using a trivalent In 2010,2010, FernFernándezández reportedreported thethe ββ-borylation-borylation ofof αα,,ββ-unsaturated-unsaturated compounds using a trivalenttrivalent phosphorus nucleophile in combination with catalytic amounts of bases and stoichiometric amounts phosphorus nucleophilenucleophile in combination with catalytic amounts of bases and stoichiometric amounts of methanol (Scheme 15) [69]. Further screening showed that a variety of phosphorus compounds of methanol (Scheme 1515))[ [69].69]. Further screening showed that a varietyvariety ofof phosphorusphosphorus compoundscompounds including achiral, chiral mono and bidentate phosphines could also give reasonable conversions including achiral, chiral mono andand bidentatebidentate phosphinesphosphines couldcould alsoalso givegive reasonablereasonable conversionsconversions without a transition metal. The process was proposed that the phosphine interacted with the empty without a transitiontransition metal. The processprocess was proposed that the phosphine interacted with the empty orbital of one of the boron atoms to result in the heterolytic cleavage of the B–B bond of B2pin2. Upon orbital of of one one of of the the boron boron atoms atoms to toresult result in the in theheterolytic heterolytic cleavage cleavage of the of B–B the bond B–B bondof B2pin of2 B. Upon2pin2. such interaction, the other boron moiety could act as a nucleophile towards the α,β-unsaturated esters Uponsuch interaction, such interaction, the other the boron other boronmoiety moiety could couldact as a act nucleophile as a nucleophile towards towards the α,β the-unsaturatedα,β-unsaturated esters and ketones (Scheme 16) [69]. estersand ketones and ketones (Scheme (Scheme 16) [69]. 16 )[69].

4 mol% (R)-(S)-josiphos 4 mol% (R)-(S)-josiphos 1.1 equiv B2pin2 P P O 1.1 equiv B2pin2 O O P P O 15 mol% Cs2CO3 O B O O Fe CH3 15 mol% Cs2CO3 B O Fe H CH3 2.5 mmol MeOH H 2.5 mmol MeOH THF, 70oC, 6 h THF, 70oC, 6 h 95% ee (R)-(S)-Josiphos 95% ee (R)-(S)-Josiphos

Scheme 15. Phosphine-mediated asymmetric β-boration of α,β-unsaturated compounds. Scheme 15. Phosphine-mediated asymmetricasymmetric ββ-boration-boration ofof αα,,ββ-unsaturated compounds.compounds.

O MeO B O MeO B O O O O O O B O O O O B O O R P BB R' R R3 P O BBO R' R 3 O O MeOH base MeOH base

R P O R3P O O O O O O3 O O B - O O O B - B B B R P+ O B B B O R3P+ O O O 3 R O R' R R' R O R3P O 3P O O R' R O R' R B B O B B O O OO O O R R R' R' Scheme 16. 16. PlausiblePlausible mechanism mechanism for the for phosphine-catalyzed the phosphine-catalyzed β-borationβ-boration of α,β-unsaturated of α,β-unsaturated carbonyl Scheme 16. Plausible mechanism for the phosphine-catalyzed β-boration of α,β-unsaturated carbonyl Moleculescompound.carbonyl 2018, 23 compound., x 9 of 16 compound.

InIn aa further further publication, publication, Fern Fernándezández presented presented novel novel reaction reaction conditions conditions for the βfor-boration the β-boration reaction ofreactionα,β-unsaturated of α,β-unsaturated carbonyl carbonyl compounds compounds without awithout transition a transition metal. Eluding metal. theEluding use of the Brönsted use of basesBrönsted to promote bases to the promote catalytic the active catalytic species, active the specie reactions, the can reaction be carried can out be bycarried the unique out by presencethe unique of catalyticpresence amountsof catalytic of phosphine amounts inof MeOHphosphine (Scheme in MeOH17)[70 ].(Scheme The experimental 17) [70]. The and theoreticalexperimental studies and demonstratedtheoretical studies interactions demonstrated between interactions the phosphine betwee andn thethe substrate.phosphine Initially, and the the substrate. phosphine Initially, interacts the withphosphine the substrate interacts to formwith athe strongly substrate basic to zwitterionic form a strongly phosphonium basic zwitterionic enolate species, phosphonium which would enolate aid + − deprotonationspecies, which ofwould the MeOH aid deprotonation to eventually of formthe MeOH the ion to pair eventually [α-(H),β form-(PR 3the)-ketone] ion pair[B [α2pin-(H),2·βMeO]-(PR3)- (Schemeketone]+ [B182).pin2·MeO]− (Scheme 18).

O 5 mol% PCy3 O O Conversion: 99% B O 1.1 equiv B2pin2 Isolated yield: 86% o MeOH, 70 C, 2 h Scheme 17.17.Phosphine Phosphine assisted assistedβ-boration β-boration reaction reaction of α ,βof-unsaturated α,β-unsaturated carbonyl carbonyl compounds compounds in MeOH. in MeOH.

O O + BB - O O O O Me P O O 3 O BB PMe3 O O MeOH Scheme 18. Ion pair formation.

Córdova developed the first metal-free one-pot three-component catalytic selective reaction between a diboron reagent, α,β-unsaturated aldehydes, and 2-(triphenylphosphoranylidene) acetate esters for the synthesis of homoallylboronates. The multicomponent reactions undergoes a catalytic β-boration of α,β-unsaturated aldehydes to give the β-borylaldehyde. A subsequent Wittig reaction between the β-borylaldehyde and the 2-(triphenylphosphoranylidene)acetate esters yields the corresponding homoallylboronates with high chemoselectivity and regioselectivity (Scheme 19) [71].

O OEt O H O O H 50 mol% amine Ph P 10 mol% NHC salt 3 Bpin OEt Ph 35 mol% KOt-Bu 1.3 equiv Bpin CyN NCy BF 4 N Ph 1.1 equiv B2pin2 22 oC, 2 h 6 H 5.0 equiv MeOH in situ OTMS Toluene, 70 oC, 1 h NHC salt amine

61% yield. 67:33 er Scheme 19. One-pot three-component synthesis of homoallylboranes.

4. Organoboron Compounds via Transition-Metal-Free Catalytic Borylation of Allyic and Propargylic Alcohols The base-catalyzed borylation of tertiary allylic alcohols can be efficiently performed to prepare 1,1-disubstituted allyl boronates with a high yields (Scheme 20a) [72]. The reactions are performed in the presence of a catalytic amount of Cs2CO3 and MeOH to promote the formation of the Lewis acid- base adduct, [Hbase]+[MeOB2pin2]−, which may also be responsible for the tandem allylic borylation/diboration of allylic alcohols that generate 1,2,3-polyborated products (Scheme 20a). To complement the study, the scope of the metal-free allylic borylation was further expanded to 1- propargylic cyclohexanol, to form the corresponding product with a working hydroborated triple bond at 50 °C. Interestingly, by increasing the temperature to 90 °C, the alkenyl borane was selectively formed (Scheme 20b). The author suggested a possible mechanism to account for this process. First,

Molecules 2018, 23, x 9 of 16

In a further publication, Fernández presented novel reaction conditions for the β-boration reaction of α,β-unsaturated carbonyl compounds without a transition metal. Eluding the use of Brönsted bases to promote the catalytic active species, the reaction can be carried out by the unique presence of catalytic amounts of phosphine in MeOH (Scheme 17) [70]. The experimental and theoretical studies demonstrated interactions between the phosphine and the substrate. Initially, the phosphine interacts with the substrate to form a strongly basic zwitterionic phosphonium enolate species, which would aid deprotonation of the MeOH to eventually form the ion pair [α-(H),β-(PR3)- species, which would aid deprotonation of the MeOH to eventually form the ion pair [α-(H),β-(PR3)- ketone]+[B2pin2·MeO]− (Scheme 18). ketone]+[B2pin2·MeO]− (Scheme 18).

O O 5 mol% PCy3 5 mol% PCy3 O O Conversion: 99% B O Isolated yield: 86% 1.1 equiv B2pin2 Isolated yield: 86% o2 2 MeOH, 70 oC, 2 h MeOH, 70 C, 2 h Scheme 17. Phosphine assisted β-boration reaction of α,β-unsaturated carbonyl compounds in MoleculesScheme2019, 2417., 101 Phosphine assisted β-boration reaction of α,β-unsaturated carbonyl compounds in9 of 15 MeOH.

O O + BB - + BB O - Me P O O O O Me3P O O O 3 O BB PMe3 O O MeOH3 MeOH Scheme 18. Ion pair formation.

CCórdovaórdova developed the firstfirst metal-free one-pot three-component catalytic selective reaction α β between a diboron reagent, α,β-unsaturated aldehydes, and 2-(triphenylphosphoranylidene) acetate esters for the synthesis of homoallylboronates. The multicomponent reactions undergoes a catalytic β α β β β-boration-boration of α,β-unsaturated-unsaturated aldehydes aldehydes to to give the β-borylaldehyde.-borylaldehyde. A A subsequent subsequent Wittig Wittig reaction β between the β-borylaldehyde and thethe 2-(triphenylphosphoranylidene)acetate2-(triphenylphosphoranylidene)acetate esters yields the corresponding homoallylboronates with high chemoselectivitychemoselectivity and regioselectivityregioselectivity (Scheme 1919))[ [71].71].

O OEt O O H 50 mol% amine O H O H 50 mol% amine Ph3P 10 mol% NHC salt Ph3P OEt 10 mol% NHC salt Bpin OEt Ph 35 mol% KOt-Bu Bpin 1.3 equiv Bpin CyN NCy BF4 35 mol% KOt-Bu 1.3 equiv Bpin CyN NCy BF4 N Ph 1.1 equiv B2pin2 22 oC, 2 h N Ph 1.1 equiv B2pin2 22 oC, 2 h H 5.0 equiv MeOH 6 H OTMS 5.0 equiv MeOH in situ OTMS o NHC salt amine Toluene, 70 oC, 1 h NHC salt amine

61% yield. 67:33 er 61% yield. 67:33 er Scheme 19. One-pot three-component synthesis of homoallylboranes.

4. Organoboron Compounds via Transition-Metal-Free CatalyticCatalytic BorylationBorylation ofof AllyicAllyic andand Propargylic4. Organoboron Alcohols Compounds via Transition-Metal-Free Catalytic Borylation of Allyic and Propargylic Alcohols The base-catalyzed borylation of tertiary allylic alcohols can be efficiently performed to prepare The base-catalyzed borylation of tertiary allylic alcohols can be efficiently performed to prepare 1,1-disubstituted allyl boronates with a high yields (Scheme 20a) [72 ]. The reactions are performed 1,1-disubstituted allyl boronates with a high yields (Scheme 20a) [72]. The reactions are performed in in the presence of a catalytic amount of Cs2CO3 and MeOH to promote the formation of the Lewis the presence of a catalytic amount of Cs2CO3 and MeOH to promote the formation of the Lewis acid- the presence of a catalytic amount+ of Cs2CO− 3 and MeOH to promote the formation of the Lewis acid- acid-base adduct, [Hbase] [MeOB2pin2] , which may also be responsible for the tandem allylic base adduct, [Hbase]+[MeOB2pin2]−, which may also be responsible for the tandem allylic borylation/diborationbase adduct, [Hbase]+ of[MeOB allylic2pin alcohols2]−, which that may generate also 1,2,3-polyboratedbe responsible for products the tandem (Scheme allylic 20a). borylation/diboration of allylic alcohols that generate 1,2,3-polyborated products (Scheme 20a). To Toborylation/diboration complement the study, of allylic the scopealcohols of that the metal-freegenerate 1,2,3-polyborated allylic borylation pr wasoducts further (Scheme expanded 20a). To to complement the study, the scope of the metal-free allylic borylation was further expanded to 1- 1-propargyliccomplement the cyclohexanol, study, the toscope form of the the corresponding metal-free allylic product borylation with a workingwas further hydroborated expanded tripleto 1- propargylic cyclohexanol, to form the corresponding product with a working hydroborated triple bondpropargylic at 50 ◦ C.cyclohexanol, Interestingly, to by form increasing the correspondi the temperatureng product to 90 ◦withC, the a alkenylworking borane hydroborated was selectively triple bondMolecules at 201850 °C., 23, Interestingly,x by increasing the temperature to 90 °C, the alkenyl borane10 was of 16 selectively formedbond at 50 (Scheme °C. Interestingly, 20b). The author by increasing suggested the atemperature possible mechanism to 90 °C, the to alkenyl account borane for this was process. selectively First, formed (Scheme 20b). The author suggested a possible mechanism to account for this process. First, formed (Scheme 20b). The− − author suggested a possible mechanism to account for this process. First, thethe adductadduct [B [B22pinpin2·MeO]2·MeO] waswas formed formed through through a base-mediated a base-mediated nucleophilic nucleophilic attack at attack one of atthe one Bpin of the Bpin moieties moieties of B B22pinpin2. 2Second,. Second, the the other other Bpin Bpin unit unitwith withnucleoph nucleophilicilic activity activity attacks attacksthe terminal the terminalcarbon carbon atomatom ofof thethe allylic allylic alcohol, alcohol, which which leads leads cleavage cleavage of of the the C–O C–O bond. bond. Last, Last, the the base base catalyst catalyst is regeneratedis + viaregenerated the reaction via the of thereaction conjugated of the conjugated acid of the acid base of the (BaseH base+ (BaseH) and the) and OH the group OH group (Scheme (Scheme 20). 21).

Bpin 3.0 equiv B2pin2 2.0 equiv B2pin2 Bpin OH Bpin 15 mol% Cs2CO3 15 mol% Cs2CO3 a) 10 equiv MeOH Bpin 10 equiv MeOH THF, 70 oC, 16 h Isolated yield: 53% THF, 90 oC, 16 h Isolated yield: 85%

2.0 equiv B pin 2.0 equiv B2pin2 Bpin 2 2 OH 15 mol% Cs2CO3 15 mol% Cs2CO3 OH b) Bpin 10 equiv MeOH 10 equiv MeOH Bpin THF, 50 oC, 16 h THF, 90 oC, 16 h Isolated yield: 68% Isolated yield: 91% Scheme 20. (a) Borylation of tertiary allylic alcohols, (b) Borylation of propargylic alcohols. Scheme 20. (a) Borylation of tertiary allylic alcohols, (b) Borylation of propargylic alcohols.

O B O OMe Bpin H2O

O O base O O O B BB O B - O O BaseH+ O HO MeOH

+ BaseH O O O - BB HO O O

Scheme 21. Suggested mechanism for the metal-free allylic borylation.

Another facile synthetic process for converting tertiary allylic alcohols to corresponding allylic boronates in moderate to good yields was reported. The mechanistic approach suggested that allylic boronate formation was achieved via the sequential processes of Fernández-type alkoxide-mediated diborylation of an alkene and the boron-Wittig reaction (Scheme 22) [73].

O O O OH 2.0 equiv B2pin2 B O 1.0 equiv NaOMe B O O 4.0 equiv MeOH B THF, 120 oC, 16 h O Isolated yield: 68% Scheme 22. Direct conversion of allylic alcohols to allylic boronates.

Molecules 2018, 23, x 10 of 16 Molecules 2018, 23, x 10 of 16 the adduct [B2pin2·MeO]− was formed through a base-mediated nucleophilic attack at one of the Bpin the adduct [B2pin2·MeO]− was formed through a base-mediated nucleophilic attack at one of the Bpin moieties of B2pin2. Second, the other Bpin unit with nucleophilic activity attacks the terminal carbon moieties of B2pin2. Second, the other Bpin unit with nucleophilic activity attacks the terminal carbon atom of the allylic alcohol, which leads cleavage of the C–O bond. Last, the base catalyst is atom of the allylic alcohol, which leads cleavage of the C–O bond. Last, the base catalyst is regenerated via the reaction of the conjugated acid of the base (BaseH+) and the OH group (Scheme regenerated via the reaction of the conjugated acid of the base (BaseH+) and the OH group (Scheme 21). 21). Bpin 3.0 equiv B2pin2 2.0 equiv B2pin2 Bpin Bpin 3.0 equiv B2pin2 OH 2.0 equiv B2pin2 Bpin Bpin 15 mol% Cs2CO3 OH 15 mol% Cs2CO3 Bpin a) 15 mol% Cs2CO3 15 mol% Cs2CO3 a) 10 equiv MeOH Bpin 10 equiv MeOH 10 equiv MeOH Bpin 10 equiv MeOH THF, 70 oC, 16 h Isolated yield: 53% THF, 90 oC, 16 h THF, 70 oC, 16 h Isolated yield: 85% Isolated yield: 53% THF, 90 oC, 16 h Isolated yield: 85% Molecules 2019, 24, 101 10 of 15 2.0 equiv B2pin2 2.0 equiv B2pin2 Bpin 2.0 equiv B2pin2 OH 2.0 equiv B2pin2 OH Bpin 15 mol% Cs2CO3 OH 15 mol% Cs2CO3 b) 15 mol% Cs2CO3 15 mol% Cs2CO3 OH Anotherb) facile synthetic process for converting tertiary allylic alcohols to corresponding allylic Bpin 10 equiv MeOH 10 equiv MeOH Bpin Bpin 10 equiv oMeOH Bpin boronates in moderate to good yields10 equiv was oMeOH reported. The mechanisticTHF, approach 50 oC, 16 suggested h that allylic THF, 90 oC, 16 h THF, 50 C, 16 h boronate formationIsolated yield: was 68% achievedTHF, via the90 sequentialC, 16 h processes of Fernández-type alkoxide-mediated Isolated yield: 91% Isolated yield: 68% Isolated yield: 91% diborylationScheme 20 of. an(a) alkeneBorylation and of the tertiary boron-Wittig allylic alcohols, reaction (b) Borylation (Scheme 21 of)[ propargylic73]. alcohols. Scheme 20. (a) Borylation of tertiary allylic alcohols, (b) Borylation of propargylic alcohols.

O O B O B OMe O OMe Bpin H2O Bpin H2O

O O base O O O O O base O O B O BB O B B - BB O B - O O + O O O BaseH+ O BaseH HO MeOH HO MeOH

+ BaseH+ O O O - BaseH O O O - BB BB HO O O HO O O

Scheme 21. Suggested mechanism for the metal-free allylic borylation. Scheme 21. Suggested mechanism for the metal-free allylic borylation. Scheme 21. Suggested mechanism for the metal-free allylic borylation. On the basis of “pseudo-intramolecular activation” [53] of diborons enabling the trans-selective Another facile synthetic process for converting tertiary allylic alcohols to corresponding allylic diborationAnother of alkynes,facile synthetic Uchiyama process and coworkersfor converting found te thatrtiary the allylic carboboration alcohols to reaction corresponding was enabled allylic by boronates in moderate to good yields was reported. The mechanistic approach suggested that allylic pseudo-intramolecularboronates in moderate activationto good yields of alkynylboronates was reported. The using mechanistic propargylic approach alcohols suggested to produce that oxaborole allylic boronate formation was achieved via the sequential processes of Fernández-type alkoxide-mediated productsboronate formation (Scheme 22 was) [74 achieved]. The synthetic via the sequential utility of processes this product of Fernández-type was investigated alkoxide-mediated using medicinal diborylation of an alkene and the boron-Wittig reaction (Scheme 22) [73]. diborylationchemistry and of strongan alkene blue and fluorescence the boron-Wittig emission. reaction (Scheme 22) [73].

O O O O O OH 2.0 equiv B2pin2 O B O O OH 2.01.0 equiv BNaOMe2pin2 B B O 1.0 equiv NaOMe O B O 4.0 equiv MeOH B O 4.0 equiv MeOH B THF, 120 oC, 16 h O THF, 120 oC, 16 h O Isolated yield: 68% Isolated yield: 68% Scheme 22. Direct conversion of allylic alcohols to allylic boronates. Scheme 22. Direct conversion of allylic alcohols to allylic boronates.

5. Organoboron Compounds via Transition-Metal-Free Catalytic Hydroboration of Unsaturated Hydrocarbons

In 2016, Song reported that the transition-metal-free catalytic borylation of arylacetylenes or vinyl arenes can been efficiently performed to produce alkylboronates through tandem borylation and protodeboronation (Scheme 23a) [75]. This method has high regioselectivity and chemoselectivity, good to excellent yields and can tolerate a broad range functional groups. The transition-metal-free method for borylation of alkynes and alkenes with bis(pinacolato)diboron can also easily afford vinylboronates (Scheme 23b) [76] or diboryl alkanes (Scheme 23c) [77]. In 2018, Fernández and coworkers reported that the 1,4-hydroboration of 1,3-dienes was followed by an in situ diboration reaction of the internal double bond to produce a 1,2,3-triboration product (Scheme 23d) [78]. Molecules 2018, 23, x 11 of 16

On the basis of “pseudo-intramolecular activation” [53] of diborons enabling the trans-selective diboration of alkynes, Uchiyama and coworkers found that the carboboration reaction was enabled by pseudo-intramolecular activation of alkynylboronates using propargylic alcohols to produce oxaborole products (Scheme 23) [74]. The synthetic utility of this product was investigated using medicinal chemistry and strong blue fluorescence emission.

Molecules 2018, 23, x Ph 11 of 16 1) 1.0 equiv nBuLi o R On the basis of “pseudo-intramolecular-78 C, thenactivation” rt, 30 min [53] of diborons enabling the trans-selective R diboration of alkynes, Uchiyama and coworkers2) Ph foundBpin that theB carboboration reaction was enabled HO HO O by pseudo-intramolecular activation of alkynylboronates90 oC, 16 h using propargylic alcohols to produce oxaboroleMolecules 2019 products, 24, 101 (Scheme 23) [74]. The synthetic utility of this product was investigated 11using of 15 medicinal chemistry andScheme strong 23. blueTrans-selective fluorescence alkynylboration emission. reaction of alkynes.

5. Organoboron Compounds via Transition-Metal-Free Catalytic HydroborationPh of Unsaturated Hydrocarbons 1) 1.0 equiv nBuLi -78 oC, then rt, 30 min R In 2016, Song reportedR that the transition-metal-free catalytic borylation of arylacetylenes or 2) Ph Bpin B vinyl arenes can been efficientlyHO performed to produce alkylboronatesHO O through tandem borylation 90 oC, 16 h and protodeboronation (Scheme 24a) [75]. This method has high regioselectivity and chemoselectivity, goodScheme to excellent 23. Trans-selectiveTrans-selective yields and alkynylboration can tolerate reactiona broad of range alkynes. functional groups. The transition-metal-free method for borylation of alkynes and alkenes with bis(pinacolato)diboron can 5.also Organoboron Aeasily new afford approach Compounds vinylboronates to the transition-metal-free via Transition-Metal-Free(Scheme 24b) [76] synthesis or diboryl Catalytic of alkenyl alkanes Hydroboration boronates (Scheme was24c)of Unsaturated based[77]. In on 2018, the HydrocarbonshydroborationFernández and of coworkers the distal doublereported bond that of the allenamides 1,4-hydroboration (Scheme 24 of)[ 1,3-dienes79]. In order was to followed obtain exclusively by an in thesitu completediboration stereoselective reaction of the product, internal the double acyl groups bond onto produce the amine a moiety1,2,3-triboration were crucial, product which (Scheme formed In 2016, Song reported that the transition-metal-free catalytic borylation of arylacetylenes or a24d) stable [78]. allylic anion intermediate that was further regioselectively protonated to obtain a Z-isomer. vinyl arenes can been efficiently performed to produce alkylboronates through tandem borylation and protodeboronation (Scheme 24a) [75]. This method has high regioselectivityIsolated yield and chemoselectivity, good to excellent yields and can tolerate a broad range functional groups. The transition-metal-free method for borylation of alkynes and alkenesO with bis(pinacolato)diboron85% can 3.0 equiv B2pin2 also easily afford vinylboronates (Scheme 24b) [76] or diboryl alkanesB O (Scheme 24c) [77]. In 2018, 4.0 equiv Cs2CO3 Fernández and coworkers reported that the 1,4-hydroboration of 1,3-dienes was followed by an in a) or 5.0 equiv MeOH situ diboration reaction of the internal doubleo bond to produce a 1,2,3-triboration89% product (Scheme CH3CN, 70 C, 4 h 24d) [78]. 1.5 equiv B pin 2 2 Isolated yield 0.5 equiv LiOt-Bu b) R Bpin 85% PhMe/MeOH R O 85% r.t. 3.024 hequiv B2pin2 B O 4.0 equiv Cs2CO3 1.0 equiv B2pin2 a) or 5.00.5 equiv equiv MeOH NaOMe o Bpin 89% c) CH CN, 70 oC, 4 h 86% MeOH,3 40 C, 10 h Bpin Bpin 1.5 equiv B23.0pin 2equiv B2pin2 0.5 equiv LiO30t-Bu mol% Na CO Bpin d) 2 3 Bpin b) R R 85%71% PhMe/MeOHMeOH 90 oC, 16 h Bpin r.t. 24 h

Scheme 24. ((aa)) Synthesis Synthesis of of 1.0alkylboronates alkylboronates equiv B2pin from2 from arylacetylenes arylacetylenes and and vinyl vinyl arenes, arenes, (b) ( bSynthesis) Synthesis of β of- β 0.5 equiv NaOMe vinylboronates-vinylboronates from from terminal terminal alkynes, alkynes, (c ()c Synthesis) Synthesis of of 1,2-diborylalkanes 1,2-diborylalkanesBpin from from non-activated non-activated olefins, olefins, (d) Synthesisc) of 1,2,3-triborated compoundso from 1,3-dienes. 86% d) Synthesis of 1,2,3-triboratedMeOH, compounds 40 C, from 10 h 1,3-dienes. Bpin 6. Conclusions Bpin A new approach to the transition-metal-free3.0 equiv B2pin2 synthesis of alkenyl boronates was based on the 30 mol% Na CO Bpin hydroborationIn thisd) review, of the we havedistal presented double bond numerous of2 allenamides very3 useful (Scheme processes 25) for [79]. the synthesis In71% order of to valuable obtain organoboronexclusively the compounds, complete stereoselective which involve product, transition-metal-freeo the acyl groups catalyzed onBpin the amine diboration, moietyβ-boration were crucial, and MeOH 90 C, 16 h borylwhich substitution formed a stable reactions. allylic The anion key to intermediate the success of that this reactionwas further is to useregioselectively a simple Lewis protonated base capable to ofobtain activatingScheme a Z-isomer. 24. the (a diboron) Synthesis reagent of alkylboronates to create afrom significant arylacetylenes nucleophilic and vinyl boryl arenes, synthon. (b) Synthesis The reactionsof β- tolerate vinylboronates a wide variety from ofterminal functional alkynes, groups (c) Synthesis and progress of 1,2-diborylalkanes under metal-free from reactionnon-activated conditions, olefins, thus avoidingd) Synthesis contaminating of 1,2,3-triborat the finaled compounds boron products from 1,3-dienes. with heavy metals, a problem which is frequently encountered in the manufacturing process. Although the metal-free catalyzed borylation of alkynes A new approach to the transition-metal-free synthesis of alkenyl boronates was based on the and alkenes is relatively unexplored at this time, there is no doubt that the future is promising for this hydroboration of the distal double bond of allenamides (Scheme 25) [79]. In order to obtain reaction and there will be many exciting discoveries in this field. exclusively the complete stereoselective product, the acyl groups on the amine moiety were crucial, Authorwhich Contributions:formed a stableConceptualization: allylic anion intermediate Y.W., C.D., J.X., that X.K.; was Writing-Original further regioselectively Draft Preparation, protonated Y.W., C.D., to J.X.,obtain X.K.; a Z Writing-Review-isomer. & Editing, Y.W., C.D., J.X., X.K.; Funding Acquisition, X.K. Acknowledgments: The authors of this paper appreciate the financial support from the Guangdong Natural Science Foundation (No. 2016A030313750), Project of Enhancing School with Innovation of Guangdong Ocean University (No. GDOU2017052502), Zhanjiang Natural Science Foundation (No. A15445, No. A14457). Conflicts of Interest: The authors declare no conflict of interest. Molecules 2019, 24, 101 12 of 15

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