2-ISOPROPOXYL-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE 1

2-Isopropoxyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

OB

OO

[61676-62-8] C9H19BO3 (MW 186.06)InChI = 1S/C9H19BO3/c1-7(2)11-10-12-8(3,4)9(5,6)13-10/

h7H,1-6H3InChIKey = MRWWWZLJWNIEEJ-UHFFFAOYSA-N

(reagent primarily used as an electrophilic boron source in theformation of pinacol boronic esters)

Physical Data: bp 180–185 ◦C, d 0.912 g mL−1 at 25 ◦C.Solubility: soluble in aromatic hydrocarbons, ethers, chlorinated

hydrocarbons.Form Supplied in: colorless oil; widely available.Analysis of Reagent Purity: 1H NMR (400 MHz, CDCl3) δ 1.18

(d, J = 6.2 Hz, 6H), 1.23 (s, 12H), 4.31 (sept, J = 6.2 Hz, 1 H);13C NMR (25 MHz, CDCl3) δ 24.0, 24.3, 66.9, 82.0.1

Purification: may be distilled at atmospheric pressure under N2.Handling, Storage, and Precautions: 2-isopropoxyl-4,4,5,5-

tetramethyl-1,3,2-dioxaborolane is air stable in liquid form. Re-acts with water. Irritating to eyes, respiratory system, and skin.Flammable. Handle in a fume hood. Store under N2 to preventhydrolysis.

Preparation. 2-Isopropoxyl-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (aka PINBOP, isopropyl pinacol borate) can be preparedfrom isopropyl borate and pinacol.1 Lin et al. have reported adetailed procedure for the preparation of this reagent on >1 kgscale.2

General Comments. Isopropoxyl pinacol boronic ester isprimarily used in the synthesis of aryl, vinyl, and alkyl pinacolboronic esters for use in cross-coupling reactions. Most proce-dures for the formation of pinacol boronic esters that use iso-propoxyl pinacol boronic ester proceed via nucleophilic addi-tion of the substrate to the boronate, displacing the isopropox-ide ion. The subsequent boronic ester can be used directly inSuzuki–Miyaura cross-coupling reactions,3 hydrolyzed to theboronic acid,4 or transmetalated to the corresponding Sn,5 In,6 orZn7,8 reagent for further coupling reactions. Pinacol boronic es-ters are generally quite stable to protodeboronation and oxidation.Additionally, boroxine formation via dehydration of boronic acidsis circumvented by the use of pinacol boronic esters.4 They aremore amenable to purification via chromatography and in manycases can be prepared on multigram scale.

Aryl Pinacol Boronic Esters. Aryl boronic esters can beobtained from metalation of the arene, either by lithium–halogenexchange or by deprotonation, followed by treatment withPINBOP. The complexity of substrates for this reaction is quitevariable and this procedure has found widespread use in a numberof settings, ranging from materials applications to total synthesis.

The monoborylated arene was obtained by Grisorio et al. vialithium–halogen exchange on the symmetric dibrominated fluo-rene derivative followed by treatment with PINBOP (eq 1).9

Br Br

R R

R = CH2CHMe(CH2)4CHMe2

Br BPin

R R (1)

n-BuLi (1 equiv) PinB(Oi-Pr)

51%

Wong et al. synthesized a spirobifluorene with two pendantpinacolato boronic esters in a 60% yield via lithium–halogen ex-change of the corresponding aryl iodides with tert-butyllithiumand subsequent treatment with PINBOP.10 A functionalizeddithienophosphazole was prepared by Baumgartner and co-workers through LDA deprotonation and addition of isopropylpinacol borate (eq 2).11

S

P

S

Ph

LDA; PinB(Oi-Pr)

S

P

S

Ph

PinB BPin

(2)

THF, –78 °C55%

Lithiation and subsequent quench with PINBOP was demons-trated in the formation of an azulene boronic ester by Ito et al.12

Shu and coworkers synthesized a 2,2′-dibromospirobifluoreneand, upon lithium–halogen exchange followed by addition ofPINBOP, obtained the boronic ester in 40% yield.13

Hydrolytic protodeboronation under basic conditions is a prob-lem that is especially pronounced for electron-deficient hetero-aromatics.4,14 However, lithiation of trifluoromethyl-substitutedpyrazoles and subsequent quench with isopropyl pinacol borateafforded the boronic ester in good yield (eq 3).

NN

CF3

Ph

n-BuLi PinB(Oi-Pr)

NN

CF3

PhPinB

(3)THF, –78 °C to rt

92%

Nichols and coworkers15 reported the synthesis of a pinacolboronic ester via a chelate-directed lithiation followed by treat-ment with PINBOP (eq 4). This boronic ester was then useddirectly in a Suzuki–Miyaura coupling. Kim and coworkers usedisopropyl pinacol borate to make an aryl boronic ester for furtheruse in a Suzuki cross-coupling.16

MeO

MeO

O

O

n-BuLi; PinB(Oi-Pr)

MeO

MeO

O

O

BPin(4)

Et2O, – 78 °C to rt76%

Stoltz and coworkers reported the use of PINBOP in their totalsynthesis of dragmacidins D and F (eq 5).17,18

2 2-ISOPROPOXYL-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE

NSEM

OMeO

HTBSO

1. NBS, THF

NSEM

OMeO

HTBSO BPin

(5)

2. n-BuLi PinB(Oi-Pr), THF, –78 °C 70% over 2 steps

Sarpong and coworkers used isopropyl pinacol borate to form adesired cross-coupling partner (eq 6).19 This pinacol boronic esterwas found to be more easily purified than the analogous boronicacid.

Br

OMe OMOM

t-BuLi; PinB(Oi-Pr)

BPin

OMe OMOM

(6)THF, –78 °C to rt

93%

In the case of ortho-alkoxy-substituted arenes, Whiting andcoworkers observed the addition of multiple equivalents of anin situ generated aryl Grignard to the electrophilic isopropyl pina-col borate, leading to production of borinic esters and boranes asby-products (eq 7). It was found that addition at lower tempera-tures, followed by heating at 50 ◦C for 1 h, drove the equilibriumto the thermodynamically favored boronic ester.20

Cl

I

O

F

Cl

i-PrMgClPinB(Oi-Pr)

Cl

BPin

O

F

Cl

Cl

B

O

F

Cl

OR

Ar

50 °C

Cl

BPin

O

F

Cl

+

(7)

THF

The use of PINBOP was shown to be crucial in a one-potconsecutive lithium–halogen exchange reaction developed byZhichkin and coworkers.21 The authors show that an aryllithiumgenerated from a dibromoarene adds to isopropyl pinacol borateand forms an aryltrialkoxyborate anion in situ, which can then

undergo another lithium–halogen exchange for further function-alization of the arene (eq 8).

Br

Br

B

Br

PinB(Oi-Pr) t-BuLi

OO

O

Li

t-BuLi; E+

BPin

E

(8)THF

–78 ºC63–78%

THF–78 ºC

Alkenyl and Alkynyl Pinacol Boronic Esters. Treatment oftrimethylsilylacetylide with PINBOP afforded the desired boronicester in 83% yield.22 Srebnik and coworkers synthesized alkynyl-boronates via acetylide addition to the dioxaborolane.23 Lopezet al. made enynylboronates via deprotonation followed by addi-tion of isopropyl pinacol borate (eq 9).24

OTBDPS

OTBDPS

PinB(9)

2. HCl, Et2O (quant)

1. n-BuLi PinB(Oi-Pr), Et2O

Hansen and Lee synthesized a wide variety of alkynyl pina-col boronic esters as substrates in their method for the synthesisof vinyl boronates.25 A Corey–Fuchs alkyne synthesis followedby quench with PINBOP afforded the alkynylboronic ester inwork by Anderson et al.26 Fandrick and coworkers7 utilized anumber of allenyl and propargyl27 boronates for addition tocarbonyl compounds. These boronic esters were prepared in astraightforward manner via lithiation and treatment withPINBOP. Addition of vinylmagnesium bromide to isopropyl pina-col boronate gives the vinylboronic ester in good yield.28 Hall andcoworkers reported the convenient synthesis of alkenylboronic es-ters via the Shapiro reaction of cycloalkanones and subsequentaddition of PINBOP.29

Alkyl Pinacol Boronic Esters. An enantioenriched boronicester was obtained by Whiting and coworkers via a (−)-sparteine-mediated deprotonation of Boc-pyrrolidine and subsequent treat-ment with PINBOP (eq 10).30

NBoc

(–)-sparteine, s-BuLiEt2O, –78 °C

NBoc

BPin (10)PinB(Oi-Pr), –78 ºC to rt

88%

Hammerschmidt and coworkers investigated the diastereoselec-tivity of the formation of an alkyl pinacol boronic ester (eq 11).When THF was used as the solvent, a 35% yield of a mixtureof diastereomers was obtained in a 1.7:1 ratio favoring the(S)-configuration about the newly formed stereocenter. However,using hexanes as the solvent afforded the mixture of diastereomersin a 77% yield, albeit with a drop in diastereoselectivity (1.5:1).The authors note that the distal relationship to the stereocenters onthe substrate may account for the modest diastereoselectivity.31

2-ISOPROPOXYL-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE 3

TMS O N Ph

O

Ph

s-BuLi, TMEDATMS O N Ph

O

Ph

TMS O N Ph

O

Ph

+

BPin

BPin

(11)

PinB(Oi-Pr)–78 ºC77%

Hoffman and coworkers observed an interesting bias toward theformation of (Z)-pentenyl boronic esters when treating a mixtureof the corresponding Grignard reagent with PINBOP (eq 12).1

MgCl PinB(Oi-Pr) BPin BPin+

91 9:(12)

THF85%

Lithiation of allyl chloride and subsequent addition of isopropylpinacol boronate afforded the boronic ester in good yield and mod-est E/Z selectivity.32

Miscellaneous Reactions. Aminoboronic esters were syn-thesized by Shibli and Srebnik via lithiation of an aminobo-rane adduct followed by quench with PINBOP.33 Suginome andcoworkers functionalized silyllithium species through addition ofPINBOP to afford a silylboronic ester that could be further used insilylborations (eq 13).34,35 In an analogous reaction, the authorshave shown that treatment of PINBOP with the silylgermylenealso affords the germylborane in good yield.35

PhMe2SiLi + PinB(Oi-Pr) PhMe2SiBPin (13)1:1 THF/hexane

0 ºC to rt74%

Treatment of PINBOP with acetonitrile in the presence ofH2SO4 gives access to a tetramethyl-substituted oxazoline via aRitter-type reaction (eq 14).36

OB

OO

N

O(14)

MeCN

H2SO4

55%

1. Andersen, M. W.; Hildebrandt, B.; Koster, G.; Hoffmann, R. W., Chem.Ber. 1989, 122, 1777.

2. Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.;Galya, L.; Metcalf, B.; Yue, T.-Y.; Liu, P.; Zhou, J., Org. Lett. 2009, 11,1999.

3. Miyaura, N.; Suzuki, A., Chem. Rev. 1995, 95, 2457.

4. Hall, D. G., Structure, properties, and preparation of boronic acidderivatives. overview of their reactions and applications. In BoronicAcids, 1st ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2005;Chapter 1.

5. Rauniyar, V.; Zhai, H.; Hall, D. G., J. Am. Chem. Soc. 2008, 130, 8481.

6. Schneider, U.; Ueno, M.; Kobayashi, S., J. Am. Chem. Soc. 2008, 130,13824.

7. Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Johnson, C. S.;Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H., Org. Lett. 2010, 12,88.

8. Fujita, M.; Nagano, T.; Schneider, U.; Hamada, T.; Ogawa, C.;Kobayashi, S., J. Am. Chem. Soc. 2008, 130, 2914.

9. Grisorio, R.; Mastrorilli, P.; Nobile, C. F.; Romanazzi, G.; Suranna, G.P.; Meijer, E. W., Tetrahedron Lett. 2004, 45, 5367.

10. Wong, K.-T.; Liao, Y.-L.; Peng, Y.-C.; Wang, C.-C.; Lin, S.-Y.; Yang,C.-H.; Tseng, S.-M.; Lee, G.-H.; Peng, S.-M., Cryst. Growth Des. 2005,5, 667.

11. Neumann, T.; Dienes, Y.; Baumgartner, T., Org. Lett. 2006, 8, 495.

12. Ito, S.; Kubo, T.; Morita, N.; Matsui, Y.; Watanabe, T.; Ohta, A.; Fujimori,K.; Murafuji, T.; Sugihara, Y.; Tajiri, A., Tetrahedron Lett. 2004, 45,2891.

13. Shen, W.-J.; Dodda, R.; Wu, C.-C.; Wu, F.-I.; Liu, T.-H.; Chen, H.-H.;Chen, C.-H.; Shu, C.-F., Chem. Mater. 2004, 16, 930.

14. Clapham, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B., Org. Biomol.Chem. 2009, 7, 2155.

15. Grubbs, R. A.; Lewis, M. M.; Owens-Vance, C.; Gay, E. A.; Jassen, A.K.; Mailman, R. B.; Nichols, D. E., Bioorg. Med. Chem. 2004, 12, 1403.

16. Lim, B.; Hwang, J.-T.; Kim, J. Y.; Ghim, J.; Vak, D.; Noh, Y.-Y.; Lee,S.-H.; Lee, K.; Heeger, A. J.; Kim, D.-Y., Org. Lett. 2006, 8, 4703.

17. Garg, N. K.; Caspi, D. D.; Stoltz, B. M., J. Am. Chem. Soc. 2005, 127,5970.

18. Garg, N. K.; Sarpong, R.; Stoltz, B. M., J. Am. Chem. Soc. 2002, 124,13179.

19. Wood, J. L.; Pujanauski, B. G.; Sarpong, R., Org. Lett. 2009, 11, 3128.

20. Hawkins, V. F.; Wilkinson, M. C.; Whiting, M., Org. Process Res. Dev.2008, 12, 1265.

21. Jiang, Q.; Ryan, M.; Zhichkin, P., J. Org. Chem. 2007, 72, 6618.

22. Deloux, L.; Srebnik, M., Tetrahedron Lett. 1996, 37, 2735.

23. Deloux, L.; Skrzypczak-Jankun, E.; Cheesman, B. V.; Srebnik, M.;Sabat, M., J. Am. Chem. Soc. 1994, 116, 10302.

24. Lopez, S.; Montenegro, J.; Saa, C., J. Org. Chem. 2007, 72, 9572.

25. Hansen, E. C.; Lee, D., J. Am. Chem. Soc. 2005, 127, 3252.

26. Anderson, J. C.; Denton, R. M.; Hickin, H. G.; Wilson, C., Tetrahedron2004, 60, 2327.

27. Hoffmann, R. W.; Brinkman, H.; Frenking, G., Chem. Ber. 1990, 123,2387.

28. Wallace, R. H.; Zong, K. K., Tetrahedron Lett. 1992, 33, 6941.

29. Rauniyar, V.; Zhai, H.; Hall, D. G., Synth. Commun. 2008, 38, 3984.

30. Batsanov, A. S.; Grosjean, C.; Schutz, T.; Whiting, A., J. Org. Chem.2007, 72, 6276.

31. Simov, B. P.; Rohn, A.; Brecker, L.; Giester, G.; Hammerschmidt, F.,Synthesis 2004, 16, 2704.

32. Julia, M.; Verpeaux, J.-N.; Zahneisen, T., Synlett 1990, 769.

33. Shibli, A.; Srebnik, M., Eur. J. Inorg. Chem. 2006, 1686.

34. Suginome, M.; Matsuda, T.; Ito, Y., Organometallics 2000, 19, 4647.

35. Ohmura, T.; Masuda, K.; Furukawa, H.; Suginome, M., Organometallics2007, 26, 1291.

36. Kuznetsov, V. V.; Brusilovskii, Y. E.; Mazepa, A. V., Chem. Heterocycl.Compd. 2001, 37, 920.

Jessica L. Wood & Richmond SarpongUniversity of California, Berkeley, CA, USA