MOJ Bioorganic & Organic Chemistry Review Article Open Access Boron trifluoride etherate in organic synthesis Abstract Volume 3 Issue 1 - 2019 The Lewis acid boron trifluoride etherate has played an important role in organic Ajoy K Banerjee,1 Alexis Maldonado,1 Dioni synthesis. To accomplish the hydroxylation of double bond, cleavage of epoxides, A Arrieche,1 Liadis Bedoya,1 William J Vera,1 esterification of acids and many cyclization reaction boron trifluoride etherate proved 2 3 very useful compared to other Lewis acids. These organic reactions are frequently Elvia V Cabrera, Po S Poon 1 employed to achieve the synthesis of natural products. In addition, boron trifluoride Chemistry Center, Venezuelan Institute of Scientific Research (IVIC), Venezuela etherate has also been utilized to realize ketalization, thioketalization, alkylation and 2Faculty of Chemical Engineering, Central University of Ecuador, many others organic reactions. Quito, Ecuador 3 Keywords: boron trifluoride etherate, hydroboration-oxidation, epoxides, Technological Development Unit (UDT), University of Concepcion, Chile esterification, thioketalization, cyclization Correspondence: Ajoy K Banerjee, Centro de Química, IVIC, Apartado- 21827, Caracas-1020A, Venezuela, Tel +5802 1250 4132 4, Fax +5802 1250 4135 0, Email Received: November 06, 2018 | Published: January 21, 2019 Me Introduction Me H H The innumerable application of boron trifluoride etherate in + B organic synthesis1,2 encouraged us to write a micro review on this H H B H reagent. The commercially available boron trifluoride etherate (b.p. 1 H 126oC), a brown liquid, is very toxic by inhalation, causes severe burns, reacts violently with water, hot alkali or alkaline earth (not Mg) metals Me Me with incandescence. It can be purified by distillation. This review would discuss only four principal use of boron trifluoride etherate: H H B (a) hydroboration–oxidation reaction, (b) cleavage and rearrangement B H H of epoxides, (c) esterification (d) cyclization. In addition, some other O - OH minor uses of boron trifluoride etherate will be briefly described. OOH (H2O2 + NaOH) Applications of boron trifluoride etherate Me Me -OH Hydroboration–oxidation reaction OH BH2 BH2 The cis addition of diborane to an alkene bond provides an O O extremely useful method of hydration. Diborane can be generated by the addition of sodium borohydride to boron trifluoride etherate in Me Me tetrahydrofuran or ether at 0o-5oC. Diborane is the dimer of borane (BH3) and is stable form of this reagent (Scheme1). THF O OH NaBH + BF B H 4 3 2 6 2 0 - 5 °C Scheme 1 Obtention of Diborane from sodium borohydride Scheme 2 Reaction mechanism for the formation to trans-2-methylcyclo- The addition of diborane to the alkene is extremely rapid and hexanol 2 generally, the reagent adds from the less hindered of the two faces of the π system. The cis addition has been rationalized by a four center Synthesis of (±) junenol and (±) acalomone transition state. The borane complex resulting from the addition of The use of hydroboration-oxidation reaction was observed diborane to an alkene is converted, with retention of stereochemistry, by Banerjee and coworkers during the synthesis3 of eudesmone to an alcohol by treatment with basic hydrogen peroxide. Thus sesquiterpenes (±) junenol and (±) acalomone. In order to achieve the 1-methylcyclohexene 1 on hydroboration-oxidation leads the synthesis of these sesquiterpenes the alkene 3, was selected as starting formation of trans-2-methylcyclo-hexanol 2. The mechanistic path material and subjected to hydroboration-oxidation to yield the alcohol has been depicted in (Scheme 2). The method for the conversion of 4 (Scheme 3). Ketone 5, obtained by the oxidation of the alcohol with alkene to alcohol by hydroboration-oxidation has been applied for Jones reagent4 was made to react with diethyl carbonate. The resulting the synthesis of many natural products. Few examples are illustrated product was treated with methyl lithium to obtain the ketol 6 whose below. conversion to the isopropyl ketone 7 was effected by dehydration Submit Manuscript | http://medcraveonline.com MOJ Biorg Org Chem. 2019;3(1):1‒9. 1 ©2019 Banerjee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. Copyright: Boron trifluoride etherate in organic synthesis ©2019 Banerjee et al. 2 and hydrogenation respectively. Metal hydride reduction of the The ester 17 was converted into pisiferic acid 18 by heating with ketone followed by oxidation with lead tetraacetate5 in cyclohexane aluminium bromide and ethane thiol. afforded the cyclic ether 8, which was converted to ketoacid 9 by The hydroboration-oxidation reaction has been applied for oxidation with chromic acid and acetic acid. Decarboxylation with the synthesis of (±) eudes-4(14),7(11)-diene-8-one,9 taxodione,10 lead tetraacetate in benzene and pyridine followed by purification norditerpene alcohols11 and many other terpenes.12 These examples over 10% AgNO impregnated silica gel afforded (±) acolamone 10. 3 clearly indicate the use of boron tifluoride etherate in the conversion Reduction of acolamone 10 with sodium borohydride in methanol, of the alkenes into alcohols and subsequently their transformations followed by sublimation of the resulting product yielded junenol 11. into the terpenoid compounds. Me Me Me (i), (ii) (iii) (iv),(v) Cleavage of epoxides 95% 80% 48%; 96% H H The epoxides can be cleaved by several reagents. The Lewis Me Me Me Me OH Me Me O acid borontrifluoride etherate has also been used for the cleavage 3 4 5 of epoxides and in many cases the resulting product rearranges to Me Me ketone. The cleavage of epoxides is also accompanied by cyclization. (vi), (vii) (viii), (ix) In this review the cleavage of some epoxides with boron trifluoride Me Me etherate and the use of the resulting products in the synthesis of 64% 52% H OH H natural products have been discussed. MeMe O Me Me Me O Me 6 7 OMe Me Me Me OH Me Me Me (x) (xi) steps (i), (ii), Me Me 32% 17% H H (iii), (iv) Me Me O O O Me CO H Me H H 2 Me Me Me 19% 8 9 Me 12 13 Me Me OMe Me OMe Me (xii) Me Me Me Me Me O 28% HO H (vi) CH O Me H (v) 2 CH2 OH Me 56% 69% H 10 11 H Me Me Me Me 14 15 Scheme 3 Synthesis of eudesmone sesquiterpenes (±) junenol and (±)-acalomone OH Me OMe Me HO MeO2C Me Reagents: (i) BF3.Et2O, NaBH4, THF, 0-5°C; (ii) NaOH (10%), H2O2(30%); Me (iii) CrO /HMPT; (iv) NaH, CO(OEt) , DME; (v) MeLi, Et O, reflux, 2h; (vi) 3 2 2 (vii), (iii), (viii), (xii) HCl(conc), MeOH; (vii) H2, PtO2, MeOH; (viii) Na, EtOH, reflux; (ix) Pb(OAc)4, (ix), (x), (xi) 90% C6H12; (x) CrO3, AcOH; (xi) Pb(OAc)4, C 6H6, Py, reflux; (xii) NaBH4, EtOH. H 35% H Me Me Me Me Synthesis of pisiferic acid 16 17 The use of hydroboration-oxidation has been recorded during OH Me the synthesis of pisiferic acid,6 a tricyclic diterpene which shows HO C Me antibacterial activities against all gram-positive bacteria tested.7 2 The synthetic route has been depicted in Scheme 4. Hydroboration- oxidation of the alkene 13, prepared from the known8 ketoalcohol 12, was oxidized with jones reagent4 and reduced respectively with Me H Me 18 metal hydride to give alcohol 14. Oxidation with lead tetraacetate in benzene with 250W tungsten lamp gave the cyclic ether 15. The Scheme 4 Synthesis of pisiferic acid 18 cleavage of the cyclic ether with zinc, zinc iodide and acetic acid8 Reagents: (i) BF3.Et2O, NaBH4; (ii) NaOH (10%), H2O2 (30%), H2SO4-HCrO4; furnished pisiferol 16. The transformation of the pisiferol to the ester (iii) LiAlH4, THF; (iv) Pb(OAc)4, CaCO3, C 6H6, 250w tungsten lamp; (v) Zn, ZnI, 17 was achieved in six steps: MeCOOH; (vi) MeSO4, Me 2CO; (vii) H2SO4-HCrO4; (viii) CH2N2, Et 2O; (ix) NaBH , MeOH; (x) TsCl, Py; (xi) NaI, Zn dust, DMF; (xii) AlBr , (CH SH) . (i) Methylation with dimethyl sulfate 4 3 2 2 (ii) Oxidation with jones reagent Synthesis of 6-methoxy-2-tetralone (iii) Esterification with diazomethane The cleavage of epoxide with boron trifluoride etherate has been utilized13 for the synthesis of 6-methoxy-2-tetralone 20 (Scheme 5), an (iv) Reduction with sodium borohydride important selected starting material for the synthesis of many organic (v) Tosylation compounds. Epoxidation of the alkene13 19 followed by treatment of the crude product in dichloromethane with boron trifluoride etherate (vi) Detosylation afforded the tetralone 20 in 36% yield. When the cleavage was tried Citation: Banerjee AK, Maldonado A, Arrieche DA, et al. Boron trifluoride etherate in organic synthesis. MOJ Biorg Org Chem. 2019;3(1):1‒9. DOI: 10.15406/mojboc.2019.03.00090 Copyright: Boron trifluoride etherate in organic synthesis ©2019 Banerjee et al. 3 with sulfuric acid the yield of the teralone 20 was improved (39%) esterification of carboxylic acids. Dymicky22 prepared several formats along with the formation of other secondary products and thus the in high yield from formic acid and alcohol in the presence of a chromatographic purification was very laborious. catalytic amount of boron trifluoride -methanol complex. The other O catalysts e.g. sulfuric acid, p-toluene sulfonic acid was not so efficient (i), (ii) like boron trifluoride- methanol complex. 36% MeO MeO 19 20 TMS TMS Me Me (i) O Scheme 5 Synthesis of 6-methoxy-2-tetralone 20 CO Me CO2Me 2 Me Reagents: (i) MCPBA, CH2Cl2; (ii) BF3OEt2 Me Synthesis of cuprane 26 27 The rearrangement of epoxides by boron trifluoride etherate proved very useful during the synthesis14 of sesquiterpene cuprane.