Zinc Borohydride1


[17611-70-0]  · B2H8Zn  · Zinc Borohydride  · (MW 95.09)

(mild reducing agent for carbonyl groups;1 can be used in the presence of base-sensitive functional groups; stereoselective reducing agent2)

Solubility: sol ether, DMF, CH2Cl2, toluene, THF.

Preparative Method: commercially available anhydrous Zinc Chloride (ca. 10 g) in a 200 mL flask was fused three or four times under reduced pressure and then anhydrous ether (ca. 100 mL) was added. The mixture was refluxed for 1-2 h under argon and allowed to stand at 23 °C. The supernatant sat. solution of ZnCl2 (0.69 M) in ether (80 mL; 55 mmol) was added to a stirred suspension of Sodium Borohydride (4 g; 106 mmol) in anhydrous ether (300 mL). The mixture was stirred for 2 d and stored at rt under argon. The supernatant solution was used for reduction.3

Handling, Storage, and Precautions: the solutions are sensitive to moisture and must be flushed with N2 or argon. However, it is preferable to use freshly prepared reagent.

Mild Reducing Agent.

Zn(BH4)2 is a mild reducing agent and only aldehydes, ketones, and azomethines4 are reduced to the corresponding alcohols and amines under normal conditions. Moreover, the ether solutions are almost neutral and thus can be used for the chemoselective reduction of aldehydes and ketones in the presence of nitrile,5 ester,5,6 g-lactone,7 aliphatic nitro,8 and base-sensitive functional groups (eqs 1 and 2).5,9 Selective reduction of saturated ketones and conjugated aldehydes over conjugated enones can also be effected with Zn(BH4)2 in DME (eq 3).10

Although Zn(BH4)2 is usually unreactive towards carboxylic acids and esters, activated esters (eq 4)11 and thiol esters (eq 5)12 undergo reduction, giving alcohols. Even carboxylic acids can be reduced to alcohols with this reagent in the presence of Trifluoroacetic Anhydride (TFAA) (eq 6)13 and acid chlorides undergo reduction by the addition of N,N,N,N-Tetramethylethylenediamine (eq 7).14 Acetals are reductively cleaved to ethers when Chlorotrimethylsilane is added (eq 8).15

Reduction of aliphatic carboxylic esters takes place under ultrasonic activation to give alcohols.16 The reducing ability of this system is enhanced by the addition of a catalytic amount of N,N-dimethylaniline and thus aromatic esters which are unaffected under the normal conditions undergo reduction (eqs 9 and 10).16

Unsymmetrical epoxides are reductively cleaved to the less substituted alcohols by the use of silica gel-supported Zn(BH4)2 (eq 11).17,18 The same reagent is effective for regioselective 1,2-reduction of conjugated ketones and aldehydes to give allylic alcohols (eq 12).19 Zn(BH4)2 supported on cross-linked Poly(4-vinylpyridine) (XP4) reduces aldehydes in the presence of ketones with high chemoselectivity (eqs 13 and 14).20 This polymer-supported reagent can be stored at rt without appreciable change in its reactivity.

Tertiary and benzylic halides are reductively dehalogenated with Zn(BH4)2 (eq 15).21 This process has been applied for the selective reduction of the distant double bond(s) in geranyl farnesyl and geranyl geranyl derivatives.22

Stereoselective Reductions.

syn-a-Methyl-b-hydroxy esters or their equivalents which repeatedly appear in the framework of polyoxomacrolide antibiotics are synthesized stereoselectively by the reduction of the corresponding a-methyl-b-keto esters23,24 or a-methyl-b-hydroxy ketones25 with Zn(BH4)2 in ether. Excellent selectivities are obtained when the carbonyl group is conjugated with phenyl or vinyl groups (eq 16)23-25 or the esters in a-methyl-b-keto esters are replaced by the amides (eq 17).26 Ketones having a phosphine oxide group in place of esters or amides produce syn products by the Zn(BH4)2 reduction, while reduction with Lithium Triethylborohydride gives the anti isomer stereoselectively (eq 18).27 The syn-directing reduction is presumed to proceed through a metal-mediated cyclic transition state and thus the use of a complex hydride like Zn(BH4)2, whose metal possesses a high coordinating ability, is advantageous for producing excellent selectivity.

Acylation of chiral N-propionyloxazolidinones gives chiral a-methyl-b-keto imides, whose Zn(BH4)2 reduction affords optically active syn-a-methyl-b-hydroxy derivatives with virtually complete stereoselectivity (eq 19).28,29 In the same way, chiral carboxamides (eq 20)30 and (R)-N-acylsultams (eq 21)31 also afford chiral syn products with high selectivities.

Selectivity of Zn(BH4)2 reductions of b-hydroxy32,33 or N-aryl-b-amino34 ketones lacking a-substituents is generally unsatisfactory. A case where an excellent result is obtained is shown in eq 22.32 For the stereoselective preparation of syn- and anti-1,3-diols the use of other reagents is recommended.35 However, in the reduction of b-keto esters, with chiral ester units, the syn selectivity is improved significantly (eq 23).36 Reduction of the same keto ester with DIBAL-BHT (Diisobutylaluminum 2,6-Di-t-butyl-4-methylphenoxide) affords the diastereomer with high selectivity (eq 24).36

Zn(BH4)2 reduction of a-hydroxy ketones gives anti products predominantly over syn products. The selectivity is dependent on the substitution pattern of the a-hydroxy ketones. When R1 is phenyl or R2 is a sterically demanding group, anti selectivity is excellent (eq 25).37 This is reasonably explained by considering a zinc-chelated five-membered transition state.1,37 Other highly selective examples of Zn(BH4)2 reductions38-42 of a-hydroxy ketones are shown in eqs 26 and 27.38,41

In the cases where two functional groups are present on the a- or b-position of the keto group, reduction proceeds through the more stable transition state. When alkoxy and alkylthio functions are present on the a-position of the keto group, Zn(BH4)2 coordinates preferentially with the former (eq 28).43 Reduction of a ketone having two alkoxy groups on the a- and b-positions produces the anti-2-alkoxy alcohol almost exclusively, showing that a five-membered transition state involving the a-alkoxy group is contributing far more than six-membered one (eq 29).44 There is also a case where the three-dimensional structure of the ketone governs the selection of the transition state (eq 30).45

Optically active a-hydroxy imines are reduced with Zn(BH4)2 to give anti-hydroxy amines (eq 31).46 a,b-Epoxy ketones produce anti-epoxy alcohols with high selectivity, irrespective of the substitution pattern of the epoxide (eq 32).47,48 The corresponding aziridino ketones and imines are also reduced with Zn(BH4)2 to the anti isomer with high selectivity (eqs 33 and 34).49

1. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic: London, 1988.
2. Oishi, T.; Nakata, T. ACR 1984, 17, 338.
3. (a) Gensler, W. J.; Johnson, F.; Sloan, A. D. JACS 1960, 82, 6074. (b) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. CPB 1984, 32, 1141. (c) Crabbe, P.; Garcia, G. A.; Rfus, C. JCS(P1) 1973, 810.
4. Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M. S 1990, 401.
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14. Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M. BCJ 1988, 61, 2684.
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28. (a) Evans, A. D. Aldrichim. Acta 1982, 15, 23. (b) Evans, D. A.; Ennis, M.; Le, T. JACS 1984, 106, 1154.
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32. Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.; Stabler, R. S.; Widler, L. HCA 1986, 69, 803.
33. Kashihara, H.; Suemune, H.; Fujimoto, K.; Sakai, K. CPB 1989, 37, 2610.
34. Pilli, R. A.; Russowsky, D.; Dias, L. C. JCS(P1) 1990, 1213.
35. Oishi, T.; Nakata, T. S 1990, 635.
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38. Takahashi, T.; Miyazawa, M.; Tsuji, J. TL 1985, 26, 5139.
39. Jarosz, S. CRV 1988, 183, 201.
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43. Matsubara, S.; Takahashi, H.; Utimoto, K. CL 1992, 2173.
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Takeshi Oishi

Meiji College of Pharmacy, Tokyo, Japan

Tadashi Nakata

The Institute of Physical and Chemical Research (RIKEN), Saitama, Japan

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