Trimethyl Borate


[121-43-7]  · C3H9BO3  · Trimethyl Borate  · (MW 103.93)

(used for the preparation of boronic acids and esters;1a also used as Lewis acid catalyst or additive in various reactions)

Physical Data: mp -34 °C; bp 68-69 °C; n20D 1.3568; d 0.915 g cm-3.

Solubility: sol in every proportion in Et2O and MeOH; very sol EtOH; sol benzene; dec in H2O.2

Form Supplied in: colorless liquid, with purity &egt;99%; azeotrope with methanol (bp 53-58 °C); MeOH is usually present as an impurity.

Preparative Methods: an improved preparation has been recently reported.3

Purification: if necessary, the small quantities of MeOH can be removed by adding anhydrous lithium chloride to the bottle of commercial reagent; the mixture is allowed to stand with occasional stirring. The upper layer is then decanted and distilled.4

Handling, Storage, and Precautions: is moisture sensitive; must be stored under nitrogen in a cool dry place. It is extremely flammable and forms explosive mixtures in air. Container explosion may occur under fire conditions. B(OMe)3 is irritating to the skin and, as a vapor, to the eyes, mucous membranes, and upper respiratory tract.5

Synthesis of Boronic Acids and Esters.

Trimethyl borate is an inexpensive starting material for the preparation of dimethyl boronates, precursors of boronic acids. The classical synthesis involves the reaction with Grignard or alkyllithium reagents (eq 1); treatment with an aqueous acid, followed by extraction with an organic solvent, permits the direct isolation of the boronic acids (eq 2).1 Various conditions have been used to hydrolyze boronic esters: Acetic Acid,4a Hydrochloric Acid,4b,6 Sulfuric Acid,7 aqueous ammonium chloride.8 In some cases, a direct exchange of the OMe group with another alcoholic residue can be effected.9

A wide variety of boronic esters or acids can be prepared by this methodology: alkyl- and arylboronic acids are available from both Grignard and lithium reagents,1,10 allylboronic acid and esters from Allylmagnesium Bromide,6 g-substituted allylboronic acids and esters from organolithium reagents,8 and allenylboronic esters as the only product starting from propargyl Grignard reagents.11 Vinylboronic esters can be obtained in a stereospecific manner from the corresponding Grignard reagents.1a,7 The organometallic reagent which reacts with trimethyl borate can also contain an heteroatom, such as sulfur12a or silicon,12b a to the carbon-metal bond. Finally, lithium derivatives of pyrrole13a and furan13b can be transformed into the corresponding boronic esters.

For boronic acid synthesis, other electrophilic boron reagents, e.g. Fluorodimethoxyborane Diethyl Etherate or Triisopropyl Borate, can be used. In the case of substituted allylboronic acids and esters, these two reagents have been employed preferentially.14

Use of Boronic Acids and Esters.

Boronic acids and esters are versatile intermediates which have found many applications in organic synthesis, especially in the field of stereocontrolled C-C bond formation.

Dimethyl alkyl- or arylboronates react with H2O2 to give the corresponding alcohols or phenols. Coupled with the above described condensation of B(OMe)3 with Grignard or lithium reagents, this reaction allows the overall hydroxylation of organometallic compounds. Applications include the synthesis of phenols4b from aryl bromides and of 4-hydroxyisoxazolines4c from isoxazolines via the 4-lithio derivative.

Reaction of dimethyl vinylboronates with bromine furnishes the corresponding vinyl bromides with inversion of configuration, allowing the transformation of a (Z)- or (E)-vinyl bromide into the corresponding (E) or (Z) diastereoisomer.1a

Boronic acids (with R1 = allyl, substituted allyl, allenyl, and vinyl; R2 = H; eq 3), obtained from trimethyl borate, can be easily transformed into acyclic boronates, cyclic boronates, or 1,3,2-oxazaborolidines by reaction with the appropriate aliphatic alcohol,1a,6 a chiral (e.g. phenylbornanediol, diisopropyl tartrate, pinanediol) or achiral diol (pinacol, ethylene glycol)1a,6 or a chiral or an achiral 2-amino alcohol.6 This procedure allows the preparation of very pure reagents, in which the single organic group is totally differentiated from a chemical point of view from the alkoxy ligands; in this way the carbon-boron linkage can be utilized very efficiently. Chiral allylboronates can be used for enantio- and diastereoselective C-C bond forming reactions1,14 with aldehydes (eq 3); the chirality can be present either a to the boron atom (when R4 &neq; H) or in the chiral auxiliary R1; also the aldehyde can be achiral or chiral. Finally, if the reaction is carried out between a chiral allylboronic ester and a stereochemically matched chiral aldehyde, greater stereoselectivity can be obtained in taking advantage of double stereodifferentiation effects.

Allylboronates also react with C=N electrophiles such as aldoximes, imines, and sulfenimides,14 although the reactions are considerably slower than those with aldehydes.

Boronic acids or esters are also suitable reagents for cross-coupling reactions, used for the formation of a C-C single bond (eq 4); this method is especially useful for the preparation of unsymmetrically substituted biaryls. One or both components can also be heterocycles. Organoboronic acids and esters used for this kind of reaction have R1 = phenyl,15a various aryl,10,15a 2-15a and 3-furyl,13b 2-thienyl,15a N-Boc-pyrrolidin-2-yl;13a R2 is usually hydrogen except for R1 = 3-furyl, where the dimethyl boronate is used directly.13b R3 is usually an aromatic or heteroaromatic moiety, but alkenyl or allyl derivatives have also been used. X is a halogen (bromine or iodine)10,13b or a triflate.13b This coupling reaction has also been used for a new synthesis of hemispherands.15b

A stereocontrolled synthesis of terminal (E)- and (Z)-dienes can be performed by reacting pinacol (E)-1-trimethylsilyl-1-propene-3-boronate with aldehydes; the intermediate b-trimethylsilyl alcohols can then be transformed into both (E)- and (Z)-dienes.8 Vinylboronates are also prepared from the reaction of the anion of a trimethylsilyl methaneboronic ester (derived from trimethyl borate) and various aldehydes or ketones.12b

Anions prepared from cyclic bis(phenylthio)methaneboronic esters, derived from the corresponding dimethyl boronates, can be used to prepare ketene dithioacetals through homologation of carbonyl compounds (eq 5).12a

More recently, an arylboronic acid has been used as an intermediate for the preparation of 2-borono-1,3-xylyl crown ethers.16

Boronic esters can be reduced by Lithium Aluminum Hydride to the corresponding lithium alkylborohydrides, which are easily converted into monoorganylboranes,17a such as tripylborane, a compound similar to thexylborane, but considerably more stable.17b

Use of Trimethyl Borate as Catalyst or Additive.

Trimethyl borate has been used, like other boron compounds, as a catalyst for the reduction of esters to alcohols by Lithium Borohydride.18a Trimethyl borate also promotes a rapid ionic reaction of methyl hypobromite with alkenes and dienes.18b Finally, trimethyl borate, as with other boronic acids and various boranes, has been used to catalyze anti-Markovnikov hydration of alkenes in the presence of dichloroaluminum hydride under dry air.18c

Trimethyl borate has been successfully used to improve the yields in the Reformatsky reaction.19 This is due to the mildly acidic properties of the boron reagent which neutralizes the zinc alkoxides, so that base-catalyzed side reactions of starting materials are prevented.

Reactions of aldehydes with 1,3-bis(trimethylsilyl)propenyl anion are poorly stereoselective. However, when this condensation was carried out in the presence of B(OMe)3, only anti compound (1) was obtained (eq 6); (1) can in turn be stereospecifically transformed into either (1E,3E)- or (1E,3Z)-1-trimethylsilylbuta-1,3-dienes.20


Trimethyl borate has been used as an electrophilic reagent to trap the product of the regio- and stereoselective Dichlorobis(cyclopentadienyl)zirconium-catalyzed ethylmagnesation of allylic21a and homoallylic21b alcohols (eqs 7 and 8).

B(OMe)3, in the presence of Borane-Dimethyl Sulfide, has been used to promote the chemoselective reduction of a carboxylic acid to an alcohol in the presence of an ester.22

Trimethyl borate was used also to prepare other borates or tetraalkoxy boron ate compounds. For example, functionalized borate (2), obtained by in situ treatment of juglone with B(OMe)3 and a tartaric acid derived chiral diol, has been used as dienophile in an asymmetric Diels-Alder reaction (eq 9).23

Finally, in the synthesis of aplasmomycin, a boron-containing antibiotic, the boron ate unit was introduced as the last step by the reaction of deboro aplasmomycin with B(OMe)3.24

Related Reagents.

Fluorodimethoxyborane Diethyl Etherate; Triisopropyl Borate.

1. (a) Matteson, D. S. T 1989, 45, 1859. (b) Matteson, D. S. S 1986, 973.
2. Handbook of Chemistry and Physics, 55th ed.; Weast, R. C., Ed.; CRC: Cleveland, 1974/75; p C-208.
3. Masuda, Y.; Nunokawa, Y.; Hoshi, M.; Arase, A. CL 1992, 349.
4. (a) Kidwell, R. L.; Murphy, M.; Darling, S. D. OSC 1973, 5, 921. (b) Hawthorne, M. F. JOC 1957, 22, 1001. (c) Schwab, W.; Jäger, V. AG(E) 1981, 20, 603.
5. The Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Lenga, R. E. Ed.; Sigma-Aldrich: Milwaukee, 1988; Vol. 2, p 3483d.
6. Brown, H. C.; Racherla, U. S.; Pellechia, P. J. JOC 1990, 55, 1868.
7. Basile, T.; Biondi, S.; Boldrini, G. P.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. JCS(P1) 1989, 1025.
8. Tsai, D. J. S.; Matteson, D. S. TL 1981, 22, 2751.
9. Soderquist, J. A.; Brown, H. C. JOC 1980, 45, 3571.
10. Sharp, M. J.; Cheng, W.; Snieckus, V. TL 1987, 28, 5093.
11. Ikeda, N.; Arai, I.; Yamamoto, H. JACS 1986, 108, 483.
12. (a) Mendoza, A.; Matteson, D. S. JOC 1979, 44, 1352. (b) Matteson, D. S.; Majumdar, D. CC 1980, 39.
13. (a) Martina, S.; Enkelmann, V.; Wegner, G.; Schlüter, A.-D. S 1991, 613. (b) Cristofoli, W. A.; Keay, B. A. TL 1991, 32, 5881.
14. Roush, W. R. COS 1991, 2, 1.
15. (a) Huth, A.; Beetz, I.; Schumann, I. T 1989, 45, 6679. (b) Ostaszewski, R.; Verboom, W.; Reinhoudt, D. N. SL 1992, 354.
16. Tuladhar, S. M.; D'Silva, C. TL 1992, 33, 265.
17. (a) Srebnik, M.; Cole, T. E.; Ramachandran, P. V.; Brown, H. C. JOC 1989, 54, 6085. (b) Pelter, A.; Smith, K.; Buss, D.; Jin, Z. HC 1992, 3, 275.
18. (a) Brown, H. C.; Narasimhan, S. JOC 1982, 47, 1604. (b) Heasley, G. E.; Duke, M.; Hoyer, D.; Hunnicutt, J.; Lawrence, M.; Smolik, M. J.; Heasley, V. L.; Shellhamer, D. F. TL 1982, 23, 1459. (c) Maruoka, K.; Sano, H.; Shinoda, K.; Yamamoto, H. CL 1987, 73.
19. Rathke, M. W.; Lindert, A. JOC 1970, 35, 3966.
20. Chan, T.-H.; Li, J.-S. CC 1982, 969.
21. (a) Hoveyda, A. H.; Xu, Z. JACS 1991, 113, 5079. (b) Hoveyda, A. H.; Xu, Z.; Morken, J. P.; Houri, A. F. JACS 1991, 113, 8950.
22. Yamamoto, Y.; Yamamoto, K.; Nishioka, T.; Oda, J. ABC 1988, 52, 3087.
23. Maruoka, K.; Sakurai, M.; Fujiwara, J.; Yamamoto, H. TL 1986, 27, 4895.
24. Corey, E. J.; Hua, D. H.; Pan, B.-C.; Seitz, S. P. JACS 1982, 104, 6818.

Luca Banfi, Enrica Narisano & Renata Riva

Università di Genova, Italy

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