B-3-Pinanyl-9-borabicyclo[3.3.1]nonane

(R)

[173624-47-2]  · C18H31B  · B-3-Pinanyl-9-borabicyclo[3.3.1]nonane  · (MW 258.30) (S)

[42371-63-1]

(asymmetric reducing agent which is particularly effective for aldehydes1 and alkynic ketones2)

Alternate Name: Alpine-Borane®.

Solubility: sol most organic solvents.

Form Supplied in: 0.5 M solution in THF. (R)-Alpine-Borane is prepared from (+)-a-pinene, and (S)-Alpine-Borane from (-)-a-pinene. High purity a-pinene is available commercially.

Preparative Methods: readily prepared by hydroboration of either (+)- or (-)-a-pinene4 with 9-Borabicyclo[3.3.1]nonane (9-BBN) (eq 1).

Since the neat reagent is most effective, the solvent is usually removed before reduction of the ketone. Brown has reported a synthesis using neat a-pinene and solid 9-BBN.5 The deuterium- or tritium-labeled compound may be prepared by hydroboration with labeled 9-BBN.6 Alternatively B-methoxy-9-BBN may be reduced with LiAlD4 (see Lithium Aluminum Hydride) in the presence of a-pinene.7,8

Handling, Storage, and Precautions: organoboranes are spontaneously flammable in air and must be handled under an inert atmosphere. They are generally stable to moisture. Alpine-Borane can slowly undergo dehydroboration.3 Use in a fume hood.

Reduction of Aldehydes.

Stereospecificially labeled primary alcohols are useful in biochemical and physical organic studies. Such compounds may be prepared by enzymatic reduction of a labeled aldehyde using yeast.9 However, isolation of the product is often tedious. Alpine-Borane greatly simplifies the process and provides compounds of high enantiomeric purity. It is the most efficient reagent available for reduction of aldehydes. The limiting factor is often the enantiomeric purity of the starting a-pinene. Either enantiomer of the labeled primary alcohol may be obtained by using either (+)- or (-)-a-pinene or by placing the label either on the aldehyde or on the reducing agent (eq 2).

The reduction is bimolecular and thus the rate is dependent on concentration. Running the reaction neat provides the fastest rates. Usually an excess of Alpine-Borane is used to insure that the reaction does not become excessively slow at the end of the reduction. The excess organoborane may be destroyed by addition of an aldehyde such as Acetaldehyde. The resulting alkoxy-9-BBN may be treated with Ethanolamine to liberate the alcohol and precipitate the majority of the 9-BBN. Any remaining borane impurities may be removed by oxidation with basic Hydrogen Peroxide.

The absolute configuration of the product may be predicted by using a simple six-membered ring transition state model (structures 1 and 2). In this model the predicted transition state resembles a boat cyclohexane with the small group occupying an axial-like position.

Alkynic Ketones.

The reagent is very sensitive to the steric requirements of the carbonyl group. Ketones are reduced at considerably slower rates than aldehydes.10 Alkynic ketones are reduced at somewhat slower rates than aldehydes, but generally proceed at 25 °C. An alkynic ketone may be reduced in the presence of a methyl ketone (eq 3).

Aromatic, n-alkyl, and branched alkyl alkynic ketones are effectively reduced (eq 4).

Methyl alkynic ketones are reduced with slightly lower efficiency and t-butyl alkynic ketones are reduced very slowly. In the latter case, dehydroboration of Alpine-Borane to give 9-BBN competes with the rate of reduction and the liberated 9-BBN reduces the ketone to give products of lower enantiomeric purity. This problem may be overcome by using high pressure11 or by using B-10-cis-myrtanyl-9-BBN (eqs 5 and 6).12

a-Keto Esters.

In general, electron-withdrawing groups enhance the rate of reduction of ketones with Alpine-Borane. Thus a-keto esters are generally good substrates for reduction. Methyl pyruvate is reduced within 4 h at rt with neat Alpine-Borane.13 The use of t-butyl pyruvate increases the efficiency (eq 7).

Methyl, n-alkyl, and isobutyl behave as small groups in the transition state model for reduction, while isopropyl or aromatic groups behave as large groups (eq 8).

Other Ketones.

Ketones such as acetophenone are reduced rather slowly by THF solutions of Alpine-Borane (eq 9). A competing dehydroboration process leads to reduction via 9-BBN (eq 10).

At 65 °C, Alpine-Borane undergoes 50% dehydroboration in 500 min.3 At rt there is approximately 1-2% dehydroboration per day. Running the reaction neat increases the rate of the favorable bimolecular reduction.5 Alternatively, high pressure may be used to increase the rate of the bimolecular process and retard the rate of the dehydroboration reaction (eq 11).11

The simple steric model for the transition state may be used to predict the absolute configuration of the product. The related reagent (+)-B-Chlorodiisopinocampheylborane reduces ketones with greater ease and efficiency (eq 12).14

Related Reagents.

2-[2-[(Benzyloxy)ethyl]-6,6-dimethylbicyclo[3.3.1]-3-nonyl]-9-borabicyclo[3.3.1]nonane.


1. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. JACS 1979, 101, 2352.
2. (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. JACS 1980, 102, 867. (b) Midland, M. M.; Tramontano, A.; Kazubski, A.; Graham, R.; Tsai, D. J-S.; Cardin, D. B. T 1984, 40, 1371. (c) Midland, M. M; Graham, R. S. OS 1984, 63, 57. (d) Midland, M. M.; Graham, R. S. OSC 1990, 7, 402. (e) Midland, M. M. CRV 1989, 89, 1553.
3. Midland, M. M.; Petre, J. E.; Zderic, S. A.; Kazubski, A. JACS 1982, 104, 528.
4. a-Pinene of high optical purity may be obtained from Aldrich or by enrichment: Brown, H. C.; Yoon, N. M. Isr. J. Chem. 1976/1977, 15, 12.
5. Brown, H. C.; Pai, G. G. JOC 1985, 50, 1384.
6. (a) Midland, M. M.; Tramontano, A.; Zderic, S. A. J. Organomet. Chem. 1978, 156, 203. (b) Midland, M. M.; Greer, S. S 1978, 845.
7. Althouse, V. E.; Feigl, D. M.; Sanderson, W. A.; Mosher, H. S. JACS 1966, 88, 3595.
8. Midland, M. M.; Asirwatham, G; Cheng, J. C.; Miller, J. A.; Morell, L. A. JOC 1994, 59, 4438.
9. Singaram, B.; Cole, T. E.; Brown, H. C. JACS 1985, 107, 460.
10. Midland, M. M.; Tramontano, A. JOC 1978, 43, 1470.
11. Midland, M. M.; McLoughlin, J. I.; Gabriel, J. JOC 1989, 54, 159.
12. Midland, M. M.; McLoughlin, J. I. JOC 1984, 49, 4101.
13. Brown, H. C.; Pai, G. G.; Jadhav, P. K. JACS 1984, 106, 1531.
14. Brown, H. C., Chandrasekharan, J.; Ramachandran, P. V. JACS 1988, 110, 1539.

M. Mark Midland

University of California, Riverside, CA, USA



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