[-]  · C4HBF6O4  · Bis(trifluoroacetoxy)borane  · (MW 237.85) (THF complex)

[75626-03-8]  · C8H9BF6O5  · Bis(trifluoroacetoxy)borane  · (MW 309.96)

(useful as a selective reducing agent, especially in the presence of strong acids)

Preparative Method: involves treatment of certain complexes of borane, such as Borane-Tetrahydrofuran, Borane-Dimethyl Sulfide, or Borane-Pyridine, with Trifluoroacetic Acid in a suitable solvent such as tetrahydrofuran (THF), dichloromethane, or trifluoroacetic acid. Excess trifluoroacetic acid can be present because the title reagent is stable to protonolysis of the B-H bond.1

Handling, Storage, and Precautions: generated and employed in situ; normally not isolated and stored.1,2 Hydrogen is evolved during reagent generation. The reagent causes the cleavage and oligomerization of THF.1-3 Thus the use of borane-THF for reagent generation, or the use of THF as solvent, is not recommended for reactions at temperatures above 25 °C.2 Use in a fume hood.

General Information.

Reductions of organic compounds with borohydride reagents in carboxylic acid media have been recognized for many years for diverse applications.4 However, reductions with borane complexes in carboxylic acid media have received considerably less attention. Because the title reagent is stable to strong acids, such as trifluoroacetic acid, reductions can be performed in acidic media without the need for a large excess of boron hydride reagent.1,2 The title reagent, which has been explored in some detail,2 is applicable to a narrow class of reductions.

Reduction of Indoles to Indolines.

The reduction of indoles to indolines by use of hydride reagents is facilitated by activation of the indole, usually by protonation. The species reduced is actually the 3H-indolenium ion. Bis(trifluoroacetoxy)borane in trifluoroacetic acid,1,2 and certain borane complexes (borane-THF,1,2,5-8 borane-dimethyl sulfide,1,2,6,9 and borane-pyridine1,6,10) in trifluoroacetic acid, offer a rapid, mild, convenient, high-yield method for this conversion. The benefits of this method are particularly realized in the reduction of indoles bearing basic amine groups.1,2,5-8 High stereochemical control for the cis indoline can be obtained for the reduction of indoles bearing a 2,3-fused ring;1,2,5-8 however, under certain conditions other stereochemical results can be obtained.6,7 The mild, rapid reduction of tryptophan derivatives10a,b permits the selective reduction of Trp residues within peptides and proteins.10b-d Some representative examples are depicted in eq 1,1 eq 2,9 eq 3,5 and eq 4.10a

Reductive Deoxygenation of Carbinols.

Diaryl and triaryl carbinols are reduced to the corresponding hydrocarbon species by bis(trifluoroacetoxy)borane in trifluoroacetic acid, rapidly and in good yields (eqs 5 and 6).2,11 In certain b-aryl-b-hydroxy tertiary amines, an enammonium-iminium rearrangement mechanism occurs, which can afford surprisingly effective stereochemical control (eq 6).11 Diaryl ketones are directly deoxygenated to the corresponding diaryl hydrocarbons, via carbinol intermediates.2,12 It is also possible with borane-pyridine and trifluoroacetic acid to deoxygenate monoaryl carbinols and ketones (eq 7).12 Similarly, alkynic carbinols, in the form of dicobalt hexacarbonyl complexes, are reductively deoxygenated by using borane-dimethyl sulfide in trifluoroacetic acid; yields are moderate to good for the three steps of complex formation, reduction, and decomplexation (eq 8).13 Ethers prone to forming carbocations in trifluoroacetic acid, such as trimethyl orthobenzoate and acyliminium ion precursors (eq 9), are also readily reduced.2 By the same token, adducts from aldehydes or ketones and thiols are reduced to sulfides by using pyridine-borane and trifluoroacetic acid (eq 10).14

Reduction of Other Functional Groups.

As suggested above, the title reagent readily reduces aldehydes and ketones to alcohols.2 Imines are also readily reduced to amines (eq 11).2,15 Cyclohexanone oxime is reduced to the hydroxylamine in 70% yield;2 another example is shown in eq 12.16 Tosylhydrazones are reduced to tosylhydrazines (eq 13) or the corresponding hydrocarbon (eq 14).2 Certain diaza heterocycles, such as quinoxaline and quinazoline, are reduced (eq 15).2 Many other functional groups and organic moieties are relatively inert to the reducing conditions: nitro, aryl/benzyl ether, nitrile, ester, carboxamide, acid, acid chloride, amidine, imide, alkene, alkyne, sulfoxide, disulfide, quinoline, isoquinoline, pyrrole, and benzofuran.2,10

Related Reagents.

Bis(benzoyloxy)borane; Catecholborane; Sodium Borohydride; Sodium Tris(trifluoroacetoxy)borohydride.

1. Maryanoff, B. E.; McComsey, D. F. JOC 1978, 43, 2733.
2. Maryanoff, B. E.; McComsey, D. F.; Nortey, S. O. JOC 1981, 46, 355.
3. Brown, H. C.; Stocky, T. P. JACS 1977, 99, 8218.
4. (a) Borohydride review: Gribble, G. W.; Nutaitis, C. F. OPP 1985, 17, 317. (b) Cyanoborohydride review: Hutchins, R. O.; Natale, N. R. OPP 1979, 11, 201. (c) Also, see: Ketcha, D. M.; Lieurance, B. A. TL 1989, 30, 6833 and references cited therein.
5. Berger, J. G.; Tahbaz, P.; McPhail, A. T.; Onan, K. D. TL 1983, 24, 2469.
6. Repic, O.; Long, D. J. TL 1983, 24, 1115.
7. Elliott, A. J.; Guzik, H. TL 1982, 23, 1983.
8. Maryanoff, B. E.; McComsey, D. F.; Taylor, R. J.; Jr.; Gardocki, J. F. JMC 1981, 24, 79.
9. Warpehoski, M. A.; Bradford, V. S. TL 1986, 27, 2735.
10. (a) Kikugawa, Y. JCR(S) 1978, 184. (b) Kikugawa, Y.; Tachibana, S.; Araki, K. Peptide Chem. 1979, 16, 17. (c) Tachibana, S.; Araki, K.; Kikugawa, Y. Life Sci. 1980, 26, 1013. (d) Kurata, M.; Kikugawa, Y.; Kuwae, T.; Koyama, I.; Takagi, T. CPB 1980, 28, 2274.
11. (a) Maryanoff, B. E.; McComsey, D. F.; Mutter, M. S.; Sorgi, K. L.; Maryanoff, C. A. TL 1988, 29, 5073. (b) Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.; Graden, D. W.; Maryanoff, B. E. JACS 1990, 112, 3567. (c) Maryanoff, B. E.; McComsey, D. F.; Leo, G. C.; Almond, H. R., Jr. JOC 1992, 57, 1190.
12. Kikugawa, Y.; Ogawa, Y. CPB 1979, 27, 2405.
13. McComsey, D. F.; Reitz, A. B.; Maryanoff, C. A.; Maryanoff, B. E. SC 1986, 16, 1535.
14. Kikugawa, Y. CL 1981, 1157.
15. Häusler, J.; Schmidt, U. LA 1979, 1881.
16. Satoh, Y.; Stanton, J. L.; Hutchison, A. J.; Libby, A. H.; Kowalski, T. J.; Lee, W. H.; White, D. H.; Kimble, E. F. JMC 1993, 36, 3580.

Bruce E. Maryanoff & David F. McComsey

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA

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