Lithium Aluminum Hydride-2,2-Dihydroxy-1,1-binaphthyl

(LiAlH4)

[16853-85-3]  · AlH4Li  · Lithium Aluminum Hydride-2,2-Dihydroxy-1,1-binaphthyl  · (MW 37.96) ((R)-BINAL)

[18531-94-7]  · C20H14O2  · Lithium Aluminum Hydride-2,2-Dihydroxy-1,1-binaphthyl  · (MW 286.34) ((S)-BINAL)

[18531-99-2]

(used for enantioselective reduction of prochiral ketones to alcohols1)

Alternate Name: BINAL-H.

Physical Data: BINAL: white solid, mp 208-210 °C. Also see Lithium Aluminum Hydride.

Solubility: sol THF.

Preparative Methods: prepared in situ from commercially available lithium aluminum hydride and BINAL.

Handling, Storage, and Precautions: sensitive to moisture (see Lithium Aluminum Hydride).

Overview and General Considerations.

This article will cover the title reagent and other chiral reducing agents derived from lithium aluminum hydride and chiral additives, with initial emphasis on the title reagent. The enantioselective reduction of prochiral ketones is a reaction of considerable importance to the synthetic organic chemist and can now be accomplished by a variety of methods and reagents.1,2 Particularly the use of chiral oxazaborolidines for the catalytic asymmetric reduction of ketones has received much recent interest. This method has been shown to be useful for the preparation of a variety of chiral alcohols with high optical purities. This transformation can also be realized using catalytic hydrogenation with a chiral catalyst or by use of chiral borane reducing agents such as (R,R)-2,5-Dimethylborolane and B-3-Pinanyl-9-borabicyclo[3.3.1]nonane. Enzyme-catalyzed transformations, for example Baker's Yeast reductions of carbonyl compounds, can also provide access to a range of chiral alcohols with high optical purities.

The use of complexes of lithium aluminum hydride (LAH) with various chiral ligands to achieve the enantioselective reduction of prochiral ketones has been extensively studied for over 40 years.1 However, this method, with some exceptions, has not found widespread use due to a number of limiting factors. These factors vary from moderate to poor enantioselectivities, often observed in these reductions, to ready availability of only one antipode of a desired chiral ligand. The recovery of the often expensive chiral ligand that is used in stoichiometric quantities to form the LAH complex is obviously an important experimental concern. Also, in some cases the LAH complex with the chiral ligand may disproportionate to achiral reducing species under the reaction conditions, resulting in poor optical purities of the desired products. Further, no single complex appears to have a sufficiently broad substrate specificity. Aromatic and unsaturated ketones are in general the better substrates and they can be reduced with good enantioselectivities using this method. A useful article comparing the merits of some of the more promising asymmetric reducing agents known for ketones has been published.3

Chiral Alcohol Modifying Agents.

Complexes of a variety of chiral alcohols (see Figure 1) with LAH have been prepared in situ and examined for their ability to effect enantioselective reduction of prochiral carbonyl compounds. However in most cases, the optical purities of the products obtained have not been satisfactory. This is in part due to the tendency of these chiral ligand-hydride complexes to disproportionate under reaction conditions yielding achiral reducing agents. An exception is the complex of LAH and (-)-menthol (1) which has been used to reduce a and b-aminoketones with good enantioselectivities.

The reduction of carbonyl compounds with LAH complexes of a number of chiral diols derived from carbohydrates and terpenes has been studied. In general, the enantioselectivities observed with such reagents have been low to moderate. Acetophenone, which is the model substrate in many of these reduction studies, is reduced by a complex of LAH and the glucose-derived diol (2) in about 71% ee under optimized conditions.

The reagent (R)- or (S)-BINAL-H, (7) developed by Noyori, is undoubtedly the most useful LAH complex reported so far for the asymmetric reduction of a variety of carbonyl compounds.4 The reagent is prepared from (R)- or (S)-2,2-dihydroxy-1,1-binaphthyl (3) (BINAL). Both enantiomers of BINAL are commercially available, although they are somewhat expensive. The chiral ligand, however, can be recovered after the reduction and reused. Equimolar quantities of BINAL and LAH are initially mixed together to form a LAH complex that has a C2 axis of symmetry, which makes the two hydrogens on the aluminum homotopic. It is interesting to note that the 1:1 complex of BINAL and LAH is a reducing agent that exhibits extremely low enantioselectivity as seen in the case of acetophenone (2% ee). Replacement of one of the hydrogens with an alcohol, like methanol or ethanol, gives a single reducing agent (7), which exhibits much higher specificity in the reduction of prochiral ketones. Another useful observation is that reduction of carbonyls with the (R)-BINAL-H reagent tends to give the (R)-alcohol while the (S)-reagent gives the (S)-alcohol. The use of lower reduction temperatures enhances optical purities of the product alcohols, but lowers the yields. Optimized conditions for reductions involve reaction of a ketone with 3 equiv of the reagent formed from LAH, BINAL, and ethanol (1:1:1) in THF for 1 h at -100 °C and then at -78 °C for 2 h.

A number of structurally diverse ketones have been reduced using BINAL-H. Some of the results are summarized in Table 1.5 Aryl alkyl ketones, alkynic ketones, and a,b-unsaturated ketones are reduced to alcohols with good to excellent % ee, while aliphatic ketones give products with lower optical purities. The asymmetric reduction of a number of acylstannanes with (7) gives synthetically valuable a-alkoxystannanes with high optical purities after protection of the initially formed unstable alcohols as their MOM or BOM ethers.6

BINAL-H has been used to prepare deuterated primary alcohols with high optical purities. For example, benzaldehyde-1-d is reduced in 59% yield and 87% optical purity. b-Ionone is reduced with this reagent to the corresponding alcohol in 100% ee and 87% yield. Simple cyclic enones like 2-cyclohexenone are not reduced by the BINAL-H reagent under standard reduction conditions.5

The chiral nonracemic enone (8) is reduced with (S)-(7) to give the (15S)-alcohol in 100% de and 88% yield. The product is a valuable intermediate in the synthesis of prostaglandins.5

The asymmetric reduction of lactone (9) to give predominantly one atropoisomer can be achieved using 10 equiv of a complex prepared from LAH and BINAL (1:1) at -40 °C.7 This reduction gives an 88:12 ratio of (10a):(10b) in good yield (80%). Reduction of the same substrate with 8 equiv of a complex of LAH with (S)-(+)-2-(anilinomethyl)pyrrolidine in ether at -40 °C leads to opposite stereochemical results (38:62 ratio of 10a:10b).

BINAL-H has also been used for the asymmetric reduction of methylaryl- and methylalkylphosphinylimines to the corresponding phosphinylamines in high % ee (Table 2).8 Similar to the reduction of ketones, reduction of the imines with (S)-(7) produces the (S)-amine and reduction with (R)-(7) gives the (R)-amine.

The complex of the biphenanthryl diol (4) with LAH has been prepared and its reduction properties have been examined.9 This reagent gives excellent enantioselectivity in the reduction of aromatic ketones. For example, acetophenone is reduced in 75% yield with 97% ee. As with Noyori's reagent, reductions with the (S)-reagent give (S)-alcohols and aliphatic ketones are reduced with low enantioselectivity. Both enantiomers of this auxiliary can be readily prepared and can also be recovered for reuse at the end of the reduction.

The LAH complex of the chiral spirodiol (5) has recently been prepared. This complex exhibits excellent enantioselectivity in the reduction of some aromatic ketones.10 Acetophenone is reduced at -80 °C in 98% ee and 80% yield. Reduction of other aryl alkyl ketones also gives excellent stereoselectivity, but the use of this reagent with a variety of ketones has not been studied. The chiral auxiliary can be recovered and reused.

Recently, the preparation of the chiral biphenyl (6) and its use as a modifying agent with LAH has been reported.11 A complex of LAH-(6)-EtOH (1:1:1) at -78 °C gives the best enantioselectivities in the reduction of prochiral ketones. Similar to Noyori's reagent, use of the LAH complex with (S)-(6) leads to the (S)-alcohol. Enantioselectivity is usually high for aromatic ketones (acetophenone 97% ee, 93% yield). This reagent reduces 2-octanone in higher enantioselectivity (76% ee) than 3-heptanone (36% ee).

Chiral Amino Alcohol Modifying Agents.

A number of chiral amino alcohols have been examined as ligands for the preparation of chiral LAH reducing agents (Figure 2). The complex of (-)-N-methylephedrine (11) with LAH has been widely studied and has shown promise for the asymmetric reduction of prochiral ketones. It has been found that addition of an achiral component such as 3,5-dimethylphenol (DMP), N-ethylaniline (NEA), or 2-ethylaminopyridine (EAP) to the complex of LAH with (11) can enhance the enantioselectivity observed in these reductions. Both enantiomers of (11) are commercially available and the ligand can be recovered subsequent to the reaction and reused.

Vigneron and co-workers have observed that a complex of LAH, (-)-(11), and DMP (1:1:2), in ether at -15 °C, appears to show the highest enantioselectivity in the reduction of a series of aromatic and alkynyl ketones to the corresponding (R)-alcohols (Figure 3).12 Interestingly, the optical purities of the products obtained were lower both at higher and lower reaction temperatures.

The complex of LAH, (-)-(11), and DMP has also been used to reduce stereoselectively a steroidal alkynic ketone. Reduction of the alkynic ketone (16) with 3 equiv of the complex at -15 °C gave a 17:1 ratio of the two diastereomers (22R/22S) in 94% yield, to provide a key intermediate for the synthesis of a vitamin D2 metabolite.13

The enantioselective reduction of cyclic conjugated enones may be best accomplished using a complex of LAH with (11) to which EAP has been added.14,15 Optimum conditions for these reductions involve treatment of the ketone with 3 equiv of a 1:1:2 complex of LAH-(-)-(11)-EAP in ether at -78 °C for 3 h (Table 3). However, under these conditions, acetophenone is reduced to the (R)-alcohol in only 54% ee.

It has been found that the addition of 2 equiv of NEA to a 1:1 complex of LAH and (-)-(11) in ether produces a reagent capable of reducing some a,b-unsaturated ketones to the (S)-alcohols in good optical purities at -78 °C (Table 4).16 It is interesting to note that, with this reagent, the (S)-alcohol is the product that is formed preferentially.

The preparation and use of a polymer supported LAH-ephedrine-DMP reducing reagent has been reported.17 In preparing this reagent, ephedrine is attached to a 1% crosslinked polystyrene backbone prior to mixing with LAH and DMP. Careful control of the degree of functionalization of the polymer gives a reducing reagent comparable in efficacy to the analogous nonpolymeric complex.

The use of the complex formed between LAH and Chirald (often called Darvon alcohol in the literature) (12) for the reduction of conjugated enones and ynones was first reported by Yamaguchi and Mosher.18 The mode of preparation of the complex, its age, and the precise experimental conditions of the reduction all appear to have significant impact on the enantioselectivities obtained using this reagent. Thus when 1.5 equiv of a freshly prepared complex of LAH and Chirald (1:2.3) is used to reduce acetophenone at 0 °C, the (R)-alcohol is obtained in 68% ee and nearly quantitative yield. If however, the reagent is allowed to stir overnight, or is refluxed in ether prior to the addition of the ketone, the (S)-enantiomer is obtained in 66% ee and 43% yield. Unfortunately, this observed reversal in stereochemical outcome is not predictable. Hence, it may be preferable to use the complex of LAH with the enantiomer of Chirald to reverse the stereoselectivity of the reduction.19

A number of alkynic ketones have been reduced with the complex of LAH and (12) (1.1:2.5 equiv, ether, -78 °C, 30-60 min) to give the corresponding (R)-alcohols (Table 5).20,21 Johnson and co-workers have reported22 the reduction of ynone (17) to the (R)-alcohol in 84% ee and 95% yield with the LAH-Chirald complex. The resulting alcohol was an intermediate in an enantioselective synthesis of 11a-hydroxyprogesterone.22 The thiophene ketone (18) is reduced by the same reagent in ether at -70 °C for 16 h to give the (R)-alcohol in 85-88% ee and 80-90% yield.23 The resulting alcohol has been used in the synthesis of LY248686, an inhibitor of serotonin and norepinephrine uptake carriers.

A macrocyclic alkynic ketone has been protected as the Co derivative and then reduced with the complex of LAH with (12) (eq 1). Deprotection gave the (R)-alcohol (71% ee) which was an important intermediate in a synthesis of (+)-a-2,7,11-cembratriene-4,6-diol.24

In general, structural variations to the backbone of the Chirald ligand have not led to the development of more selective or reliable LAH complexes for use in asymmetric reductions.25 Other complexes of amino alcohols with LAH have been studied for their ability to achieve enantioselective reduction of prochiral ketones. However, in most cases the selectivities observed have been moderate.26 The complex of LAH with the amino alcohol (15) reduces some enones, such as cyclohexenone and cyclopentenone, to the corresponding (S)-alcohols in high optical purities (100% and 82% ee, respectively).27

Chiral Amine Modifying Agents.

Some chiral amine additives (Figure 4) have also been studied for their potential to give useful chiral LAH reagents, but the results so far have not been very promising. An exception to this is the complex of LAH with the chiral aminopyrrolidine (19) (R = Me), which reduces aromatic ketones in good ee.28 This reagent reduces acetophenone in 95% ee and 87% chemical yield. LAH complexes of diamine ligands (20), analogs of BINAL-H, have also been prepared and examined.29 In general, the optical purities obtained with this reagent are significantly lower than those observed for BINAL-H in the reduction of aryl ketones.


1. (a) Nishizawa, M.; Noyori, R. COS 1991, 8, Chapter 1.7. (b) Grandbois, E. R.; Howard, S. I.; Morrison, J. D. Asymmetric Synthesis; Academic: New York, 1983; Vol. 2. (c) Nógrádi, M. Stereoselective Synthesis; VCH: Weinheim, 1986; Chapter 3. (d) ApSimon, J. W.; Collier, T. L. T 1986, 42, 5157. (e) Singh, V. K. S 1992, 605. (f) Blaser, H.-U. CRV 1992, 92, 935. (g) Haubenstock, H. Top. Stereochem. 1982, 14, 231. (h) Mukaiyama, T.; Asami, M. Top. Curr. Chem. 1985, 127, 133. (i) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. S 1992, 503.
2. (a) Tomioka, K. S 1990, 541. (b) Wallbaum, S.; Martens, J. TA 1992, 3, 1475. (c) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. CRV 1992, 92, 1071.
3. Brown, H. C.; Park, W. S.; Cho, B. T.; Ramachandran, P. V. JOC 1987, 52, 5406.
4. Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. JACS 1984, 106, 6709.
5. Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. JACS 1984, 106, 6717.
6. (a) Chan, P. C.-M.; Chong, J. M. JOC 1988, 53, 5584. (b) Chong, J. M.; Mar, E. K. T 1989, 45, 7709. (c) Chong, J. M.; Mar, E. K. TL 1990, 31, 1981. (d) Marshall, J. A.; Gung, W. Y. TL 1988, 29, 1657.
7. Bringmann, G.; Hartung, T. S 1992, 433.
8. Hutchins, R. O.; Abdel-Magid, A.; Stercho, Y. P.; Wambsgans, A. JOC 1987, 52, 702.
9. Yamamoto, K.; Fukushima, H.; Nakazaki, M. CC 1984, 1490.
10. Srivastava, N.; Mital, A.; Kumar, A. CC 1992, 493.
11. Rawson, D.; Meyers, A. I. CC 1992, 494.
12. (a) Vigneron, J. P.; Jacquet, I. T 1976, 32, 939. (b) Vigneron, J. P.; Blanchard, J. M. TL 1980, 21, 1739. (c) Vigneron, J. P.; Bloy, V. TL 1980, 21, 1735. (d) Vigneron, J.-P.; Bloy, V. TL 1979, 2683.
13. Sardina, F. J.; Mouriño, A. Castedo, L. TL 1983, 24, 4477. (b) Sardina, F. J.; Mouriño, A.; Castedo, L. JOC 1986, 51, 1264.
14. Kawasaki, M.; Suzuki, Y.; Terashima, S. CL 1984, 239.
15. Iwasaki, G.; Sano, M.; Sodeoka, M.; Yoshida, K.; Shibasaki, M. JOC 1988, 53, 4864.
16. (a) Terashima, S.; Tanno, N.; Koga, K. TL 1980, 21, 2753. (b) Terashima, S.; Tanno, N.; Koga, K. CC 1980, 1026. (c) Terashima, S.; Tanno, N.; Koga, K. CL 1980, 981.
17. Fréchet, J. M.; Bald, E.; Lecavalier, P. JOC 1986, 51, 3462.
18. (a) Yamaguchi, S.; Mosher, H. S. JOC 1973, 38, 1870. (b) Yamaguchi, S.; Mosher, H. S.; Pohland, A. JACS 1972, 94, 9254.
19. Paquette, L. A.; Combrink, K. D.; Elmore. S. W.; Rogers, R. D. JACS 1991, 113, 1335.
20. Brinkmeyer, R. S.; Kapoor, V. M. JACS 1977, 99, 8339.
21. Marshall, J. A.; Salovich, J. M.; Shearer, B. G. JOC 1990, 55, 2398.
22. Johnson, W. S.; Brinkmeyer, R. S.; Kapoor, V. M.; Yarnell, T. M. JACS 1977, 99, 8341.
23. Deeter, J.; Frazier, J.; Staten, G.; Staszak, M.; Weigel, L. TL 1990, 31, 7101.
24. Marshall, J. A.; Robinson, E. D. TL 1989, 30, 1055.
25. Cohen, N.; Lopresti, R. J.; Neukom, C.; Saucy, G. JOC 1980, 45, 582.
26. (a) Brown, E.; Penfornis, A.; Bayma, J.; Touet, J. TA 1991, 2, 339. (b) Steels, I.; DeClercq, P. J.; Declercq, J. P. TA 1992, 3, 599. (c) Morrison, J. D.; Grandbois, E. R.; Howard, S. I.; Weisman, G. R. TL 1981, 22, 2619.
27. (a) Sato, T.; Gotoh, Y.; Wakabayashi, Y.; Fujisawa, T. TL 1983, 24, 4123. (b) Sato, T.; Goto, Y.; Fujisawa, T. TL 1982, 23, 4111.
28. Asami, M.; Mukaiyama, T. H 1979, 12, 499.
29. Kabuto, K.; Yoshida, T.; Yamaguchi, S.; Miyano, S.; Hashimoto, H. JOC 1985, 50, 3013.

Aravamudan S. Gopalan & Hollie K. Jacobs

New Mexico State University, Las Cruces, NM, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.