Sodium Cyanoborohydride1

NaBH3CN

[25895-60-7]  · CH3BNNa  · Sodium Cyanoborohydride  · (MW 62.85)

(selective, mild reducing reagent for reductive aminations of aldehydes and ketones, reductions of imines, iminium ions, oximes and oxime derivatives, hydrazones, enamines; reductive deoxygenation of carbonyls via sulfonyl hydrazones, reductions of aldehydes and ketones, polarized alkenes, alkyl halides, epoxides, acetals, and allylic ester groups)

Physical Data: white, hygroscopic solid, mp 240-242 °C (dec).

Solubility: sol most polar solvents (e.g. MeOH, EtOH, H2O, carboxylic acids) and polar aprotic solvents (e.g. HMPA, DMSO, DMF, sulfolane, THF, diglyme); insol nonpolar solvents (e.g. ether, CH2Cl2, benzene, hexane).

Form Supplied in: widely available; the corresponding deuterated (or tritiated) reagent is available via acid-catalyzed exchange with D2O (or T2O).1a,2

Handling, Storage, and Precautions: store under dry N2 or Ar.

Functional Group Reductions: General.

The chemoselectivity available with NaBH3CN is remarkably dependent on solvent and pH. Under neutral or slightly acidic conditions (pH > 5), only iminium ions are reduced in protic and ether (e.g. THF) solvents.2 Most other functional groups including aldehydes, ketones, esters, lactones, amides, nitro groups, halides, and epoxides are inert under these conditions.

Reductive Aminations.

The relative inertness of aldehydes and ketones toward NaBH3CN at pH > 5 allows reductive aminations with amine and amine derivatives (usually in MeOH) via in situ generation of iminium ions which are then reduced to amines (eqs 1 and 2).2-4 This protocol is compatible with most other functional groups, can be used to prepare N-heterocycles with stereochemical control (eqs 3 and 4),5,6 and serves as a methylation process using CH2O as the aldehyde (eq 5).7,8 For difficult cases (e.g. aromatic amines, hindered and trifluoromethyl ketones), yields may be greatly improved by prior treatment of the carbonyl and amine with Titanium(IV) Chloride (eq 6)9 or Titanium Tetraisopropoxide.10a A reagent system prepared from NaBH3CN and Zinc Chloride also is also effective for reductive aminations10b (see also Sodium Triacetoxyborohydride and Tetra-n-butylammonium Cyanoborohydride).

Reductions of Imines and Derivatives.

Preformed imines (eq 7),2,11,12 iminium ions (eq 8),2,11,13 oximes (eq 9),2,14 oxime derivatives (eqs 10 and 11),15,16 hydrazones (eq 12),17 and other N-heterosubstituted imines (eqs 13 and 14)18,19 are reduced to the corresponding amine derivatives by NaBH3CN, usually in acidic media (see also Lithium Aluminum Hydride and Sodium Borohydride).

Also under acidic conditions, enamines are reduced to amines via iminium ions by NaBH3CN (eq 15).2,20 This type of conversion is also effected with NaBH3CN/ZnCl2.10b Pyridines and related nitrogen heterocycles are reduced by NaBH3CN/H+ to di- or tetrahydro derivatives (eq 16).1e,21 Likewise, pyridinium and related salts (e.g. quinolinium, isoquinolinium) are reduced. With 4-substituted derivatives, 1,2,5,6-tetrahydropyridine products are produced (eq 17).22

Reductive Deoxygenation of Aldehydes and Ketones.23,24

p-Toluenesulfonylhydrazones (tosylhydrazones), generated in situ from unhindered aliphatic aldehydes and ketones and tosylhydrazine, are reduced by NaBH3CN in slightly acidic DMF/sulfolane (ca. 100-110 °C) to hydrocarbons via diazene intermediates (eq 18).24 With hindered examples the tosylhydrazones must be preformed and large excesses (5-10×) of NaBH3CN used in more acidic media (e.g. pH < 4) (eq 19).24,25 Likewise, aryl tosylhydrazones are nearly inert to the reagent, but exceptions are known.26 Reduction of tosylhydrazones to hydrocarbons also occurs with NaBH3CN/ZnCl2 in refluxing MeOH. This combination also gives poor yields with aryl systems.10b

Reductive deoxygenation of most a,b-unsaturated tosylhydrazones with NaBH3CN cleanly affords alkenes in which the double bond migrates to the former tosylhydrazone carbon (eq 20).24,27,28 However, the process gives mixtures of alkenes and alkanes with cyclohexenones27 (see also Bis(triphenylphosphine)copper(I) Borohydride, Catecholborane and Sodium Borohydride).

Reduction of Other p-Bonded Functional Groups.

In acidic media (i.e. pH < 4), aldehydes and ketones are selectively reduced to alcohols (eq 21).2a,28 a,b-Unsaturated ketones are reduced primarily to allylic alcohols (eq 22)29 except cyclohexenones, which give mixtures of allylic and saturated alcohols. Allylic ethers are also produced concomitantly with substrates further conjugated with aryl rings.29

The combination of NaBH3CN/ZnCl2 in ether also reduces aldehydes and ketones to alcohols.10b With 5% H2O present, cyclohexanones are selectively reduced in the presence of aliphatic derivatives.30a With NaBH3CN/Zinc Iodide, however, aryl aldehydes and ketones are converted to aryl alkanes.30b

While isolated alkenes are inert toward NaBH3CN, highly polarized double bonds (i.e. containing an attached nitro or two other electron-withdrawing groups) are reduced to hydrocarbons in acidic EtOH (eq 23).31,32 Reductions of iron carbonyl-alkene complexes to the corresponding alkyl complexes also occurs readily with NaBH3CN in MeCN.33

Nitriles are inert toward NaBH3CN even under strongly acidic conditions. However, methylation with Me2Br+SbF6- and subsequent reduction with NaBH3CN affords the corresponding methylamine (eq 24).34

Reduction of s-Bonded Functional Groups.

In SN2 rate enhancing polar aprotic solvents (e.g. HMPA, DMSO), primary and secondary alkyl, benzylic and allylic halides, sulfonate esters (eqs 25 and 26),35a and quaternary ammonium salts36 are reduced to hydrocarbons. As expected for an SN2-type process, the order of reactivity is I > Br, RSO3 > Cl.35a In addition, primary alcohols are reduced to hydrocarbons via in situ conversion to iodides with Methyltriphenoxyphosphonium Iodide (MTPI) and subsequent reduction (eq 27).35a,37 On the other hand, the combinations NaBH3CN/Tin(II) Chloride38a or NaBH3CN/ZnCl238b reduce tertiary, allylic, and benzylic halides but are inert toward primary, secondary, and aryl derivatives (eq 28)38 (see also Lithium Aluminum Hydride, Lithium Tri-s-butylborohydride and Sodium Borohydride).

In the presence of Boron Trifluoride Etherate, NaBH3CN reduces epoxides to alcohols39 with attack of hydride at the site best able to accommodate a carbocation. Epoxide opening occurs primarily anti (eq 29).39 Acetals are also reduced to ethers by NaBH3CN in acetic media (eq 30).40

Allylic groups that are normally not displaced by hydrides (e.g. carboxylates, ethers) are effectively activated via Pd0 complexation to give p-allyl complexes which are reduced by NaBH3CN to alkenes (eq 31).41


1. (a) Hutchins, R. O.; Natale, N. R. OPP 1979, 11, 201. (b) Lane, C. F. S 1975, 135. (c) COS 1991, 8, Chapters 1.2, 1.14, 3.5, 4.1, 4.2. (d) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH: New York, 1991. (e) Gribble, G. W.; Nutaitis, C. F. OPP 1985, 17, 317.
2. (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. JACS 1971, 93, 2897. (b) Hutchins, R. O.; Hutchins M. K. COS 1991, 8, 25.
3. Mori, K.; Sugai, T.; Maeda, Y.; Okazaki, T.; Noguchi, T.; Naito, H. T 1985, 41, 5307.
4. Umezawa, B.; Hoshino, O.; Sawaki, S.; Sashida, H.; Mori, K.; Hamada, Y.; Kotera, K.; Iitaka, Y. T 1984, 40, 1783.
5. (a) Abe, K.; Okumura, H.; Tsugoshi, T.; Nakamura, N. S 1984, 597. (b) Abe, K.; Tsugoshi, T.; Nakamura, N. BCJ 1984, 57, 3351.
6. Reitz, A. B.; Baxter, E. W. TL 1990, 31, 6777.
7. Borch, R. F.; Hassid, A. I. JOC 1972, 37, 1673.
8. Jacobsen, E. J.; Levin, J.; Overman, L. E. JACS 1988, 110, 4329.
9. Barney, C. L.; Huber, E. W.; McCarthy, J. R. TL 1990, 31, 5547.
10. (a) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. JOC 1990, 55, 2552. (b) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. JOC 1985, 50, 1927.
11. Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.; Stercho, Y. P. JOC 1983, 48, 3412.
12. Orlemans, E. O.; Schreuder, A. H.; Conti, P. G. M.; Verboom, W.; Reinhoudt, D. N. T 1987, 43, 3817.
13. Van Parys, M.; Vandewalle, M. BSB 1981, 90, 757.
14. Reonchet, J. M. J.; Zosimo-Landolfo, G.; Bizzozero, N.; Cabrini, D.; Habaschi, F.; Jean, E.; Geoffroy, M. J. Carbohydr. Chem. 1988, 7, 169.
15. Bergeron, R. J.; Pegram, J. J. JOC 1988, 53, 3131.
16. Sternbach, D. D.; Jamison, W. C. L. TL 1981, 22, 3331.
17. Zinner, G.; Blass, H.; Kilwing, W.; Geister, B. AP 1984, 317, 1024.
18. Branchaud, B. P. JOC 1983, 48, 3531.
19. Rosini, G.; Medici, A.; Soverini, M. S 1979, 789.
20. Cannon, J. G.; Lee, T.; Ilhan, M.; Koons, J.; Long, J. P. JMC 1984, 27, 386.
21. Booker, E.; Eisner, U. JCS(P1) 1975, 929.
22. Hutchins, R. O.; Natale, N. R. S 1979, 281.
23. Hutchins, R. O.; Hutchins, M. K. COS 1991, 8, 327.
24. Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. JACS 1973, 95, 3662.
25. Sato, A.; Hirata, T.; Nakamizo, N. ABC 1983, 47, 799.
26. Schultz, A. G.; Lucci, R. D.; Fu, W. Y.; Berger, M. H.; Erhardt, J.; Hagmann, W. K. JACS 1978, 100, 2150.
27. Hutchins, R. O.; Kacher, M.; Rua, L. JOC 1975, 40, 923.
28. Koft, E. R. T 1987, 43, 5775.
29. Hutchins, R. O.; Kandasamy, D. JOC 1975, 40, 2530.
30. (a) Kim, S.; Kim, Y. J.; Oh, C. H.; Ahn, K. H. Bull. Korean Chem. Soc. 1984, 5, 202. (b) Lau, C. K.; Dufresne, C.; Bélanger, P. C.; Piétré, S.; Scheigetz, J. JOC 1986, 51, 3038.
31. Hutchins, R. O.; Rotstein, D.; Natale, N.; Fanelli, J.; Dimmel, D. JOC 1976, 41, 3328.
32. Schultz, A. G.; Godfrey, J. D.; Arnold, E. V.; Clardy, J. JACS 1979, 101, 1276.
33. (a) Florio, S. M.; Nicholas, K. M. JOM 1978, 144, 321. (b) Whitesides, T. H.; Neilan, J. P. JACS 1976, 98, 63.
34. (a) Borch, R. F.; Evans, A. J.; Wade, J. J. JACS 1975, 97, 6282. (b) Borch, R. F.; Evans, A. J.; Wade, J. J. JACS 1977, 99, 1612.
35. (a) Hutchins, R. O.; Kandasamy, D.; Maryanoff, C. A.; Masilamani, D.; Maryanoff, B. E. JOC 1977, 42, 82. (b) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. OSC 1988, 6, 376.
36. Yamada, K.; Itoh, N.; Iwakuma, T. CC 1978, 1089.
37. (a) Okada, K.; Kelley, J. A.; Driscoll, J. S. JOC 1977, 42, 2594. (b) Borchers, F.; Levsen, K.; Schwarz, H.; Wesdemiotis, C.; Winkler, H. U. JACS 1977, 99, 6359.
38. (a) Kim, S.; Ko, J. S. SC 1985, 15, 603. (b) Kim, S.; Kim, Y. J.; Ahn, K. H. TL 1983, 24, 3369.
39. Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. JOC 1981, 46, 5214.
40. Horne, D. A.; Jordan, A. TL 1978, 1357.
41. (a) Hutchins, R. O.; Learn, K.; Fulton, R. P. TL 1980, 21, 27. (b) Hutchins, R. O.; Learn, K. JOC 1982, 47, 4380.

Robert O. Hutchins

Drexel University, Philadelphia, PA, USA

MaryGail K. Hutchins

LNP Engineering Plastics, Exton, PA, USA



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