135 REVIEWS Sodium Cyanoborohydride — A Highly Selective Reducing Agent for Organic Functional Groups Clinton F. LANE Aldrich-Boranes, Inc., Milwaukee, Wisconsin 53233, U.S.A. The wilty of sodium eyanoborohydride as a selective vvcing 52. Reduction of Oximes agen for organic synthesis is resiewed. Firstly a summary of 53. Reduction of Enamines the preparation and properties of sodium eyanoborohydride is S4. Resluctive Amination of Aklehydes and Ketones given. Then some examples of sodium cyanoborohydrde reduc 55. Reductive Aliglation of Amines and Hydrazines tions of various systems are given including some applications $6, Reductive Displacement of Halides and Tosylates of sodium cyanoborodeuteride 53. Deoxygenation of Aldehydes and Ketones 1. Preparation In ciner Uhersicht werden die Anvendungsmigichkciten des se 2 Patification lektivwirkenden Reduktionsmitels Natriumeyanoboriydrid bei 4. hysial Properties ‘orpanischen Synthesen aulgezcit. Zunichst werden Herstllung 4 Chemical Propertin und Eigenschften des Reagenzes zusammengealt. U's folgt dann 4 Hydrolysis «ine Reihe von Redktionsbeispelen mit Natriumeyanoborhydrid 42 Exchange an verschiedenen Systemen einsehleBlich einiger Anwendungen 5. Selective Reducing Properties ‘om Natriumeyanobordetterd 5.1. Reduction of AMchydes and Ketones ‘The synthetic organic chemist, being faced with the shown that, under the proper conditions, sodium need to prepare compounds of ever-increasing com- _ cyanoborohydride is an extremely useful reagent for plexity. has had the problems confronting him greatly the selective reduction of organic functional groups. simplified by the development of numerous selective reducing agents’. Reagents that are capable of redue- inga given functional group in the presence of various other sensitive functional groups, have been prepared by modifying the reducing power of complex metal hydrides. For example, substituted borohydrides are a particularly successful modification. The steric and clectronic effects of the substituents greatly influence the teactivity of the borohydride ion?. Thus, sodium The first synthesis of a cyanoborohydride was cyanoborohydride with its strongly electron-with- reported by Wittig in 19514 The lithium salt was drawing cyano group is a milder and more selective prepared by reacting lithium borohydride with excess reducing agent than sodium borohydride. hydrogen cyanide under pressure. Subsequently, an improved synthesis was reported for the correspond- ing sodium salt§ Within the last year the number of reported explor- atory investigations of this reagent has decreased while the number of reported applications has increased substantially. Consequently. the time seems appropriate to review this interesting new reagent. |. Preparation The initial exploratory work on the utility of an alkali metal eyanoborohydride as a reducing agent resulted in almost totally negative results, Of all the functional groups studied only aldehydes were “1 org recat exon review of sects redutioas, sx H reported to be reduced’. Fortunately, the reagent Crown,“ Borunes in Ongnie Chem” Cornell Universi was not forgotien and recent investigations have Yew Ithaca, New York 172 chaps [an Th136 C.F. Lane Sodium Cyanoboroby ide To. rapidly stcred slurry of sodium borohydride (802 g, 209 ‘mol in tetrahydrofuran (1000 ml) in a2 Nask is add & solution of hydrogen eyanide in tecrahydroturan 29 g contuming S88 ¢ ‘of hydrogen cyanide) at 25°. Evolution of hydrogen vxcurs slowly ring the addition. Following the adlition, the reation mixture is tired for 1h at 25° and then heated at eefloy until hydrogen evolution has ceased. Filtration followed by vacuum removal ‘ofthetetrahsdrofiran gives white solid sodium eyanoboroby rid: old: 120 g 1% The direct reaction of borane with sodium cyanide might appear (0 offer a more convenient method for preparing sodium cyanoborohydride. However, the reaction of diborane with sodium cyanide in {.2-dimethoxyethane gave a diborane adduct that was precipitated and isolated as the etherate 1° 1 niconcrcrt- Os Oo Pe NaCN + Bolg => na 2 Bate Napiscnars 24 9 1 The infrared spectrum and "'B-N.M.R. spectrum were only consistent with the structure [HsBCNBH,]®. A similar reaction of sodium cyanide with borane-tetrahydrofuran also resulted ion of NaBHsCNBH*. The sodium cyanoborohydride prepared by the above procedure’, and the product available com- ‘mercially is usually of sufficient purity for most appli cations. However, if ultra-pure material is required, then one of the following purification procedures should be used. The sodium cyanoborohydride is dissolved in tetrahydrofuran (20% w/v), filtered, and reprecipitated bya four-fold volume of dichlorometh- ane*. The sodium cyanoborohydride is then collected and dried in vacuo, Alternatively, the compound is dissolved in dry nitromethane and filtered. and the filtrate is poured into a ten-fold volume of tetrachlo- romethane with vigorous string’. The white precipi- tate of sodium cyanoborohydride is filtered, washed several times with tetrachloromethane, and dried in racuo. A third method for the purification of sodium, cyanoborohydride is described below in detail and is necessary when the above procedures fail to improve the purity Purification of Sodium Cyanoborohydtie": Sodium cyanoborohydride (10g) is dissolved in tetrahydrofuran {80 mi) and 11N mthanolic hydtochlorc aid is added until the pu reaches 8. The solution is then poured with string into Aioxan (250 mh. The precipitate & collected and sited for 2h in ethyl acetate (250 ml. This solution is ier, heated to ellux fon steam bath, and then diosan (150ml) is added slowly with swiling. This solution is slowly cooled to room temperature, chilled, and filtered. ‘The erystalline dioxan complex is dried In tacuo for 4B at room temperature, then for 4h at 80°: yield: 74g: purity 98", sediom eyanoborohydride by iodometsc 3. Physical Properties Solvent-free sodium cyanoborohydride is a white amorphous powder, m.p. 240-242° (decomp.). Con- tact with air should be kept to a minimum because the compound is very hygroscopic. Sodium eyanoborohydride is highly soluble in a va- riety of solvents including water, alcohols, amines, and tetrahydrofuran buts insolublein hydrocarbons. Complete solubility data are summarized in Table 1 Table |. Solubility of Sodium Cyanohorohydide in Various Sol Solvent Temperature Solubility {1100 g solven THE 2 372 46 410 or 422 water = 2 x it * 21 smathanol 2 very soluble ethanol a slightly soluble dialyme 2 16 isopeopylamine 25° ihtly soluble lott ether 2° insoluble benzene 2s insoluble hexane 2s insoluble 4, Chemical Properties 4. Hydrolysis The utility of sodium cyanoborohydrideasa reducing agent is greatly enhanced by its stability in acid to pH 3°, The hydrolysis of sodium eyanoborohy- drideisacid-catalyzed. However, its rate of hydrolysis is 10-* that of sodium borohydride". The decom- position of sodium cyanoborohydride in water at pH 7 as measured by hydrogen evolution at concen- trations from 107? to 0.3.M is less than 0.5 mol % alter 24h”. In. 12. hydrochloric acid, relatively rapid hydrolysis does occur’. BHCN® + 3 420 BOHN + CN + 3 He The acid stability of sodium cyanoborohydride has resulted in numerous applications of this reagent that would not be possible with sodium borohydride (vide infra, Section 5), For example, sodium borohy- dride can be used to trap carbonium ions formed in the ionization of readily ionizable organic halides in an aqueous diglyme solution'®. The rate of solvo- lysis would, of course, be enhanced in the presence of acid, but this would also rapidly destroy the sodium borohydride. This serious limitation is not present with sodium cyanoborohydride, which has been used to trap carbonium ions generated with hydrogen chloride in aqueous tetrahydrofuran”.March 1975 Measurement of the volume of hydrogen evolved upon hydrolysis in aqueous acid can be used for the quantitative analysis of sodium borohydride" However, this procedure cannot be used conveniently to analyze sodium cyanoborohydride due to its slow rate of hydrolysis even in aqueous acid. lodomettic titration has been used to determine the purity of sodium borohydride? and sodium cyanoborohy- dride*"?, The half-reaction for this redox reaction is as shown”. BHsCN® + 31,0 ——> BIOHIs + CN + GHP + Ge 42. Exchange At pH 3, the hydrogen atoms of the cyanoborohy- drideanion can be readily exchanged for either deute- rium or tritium’, thus permitting the direct synthesis of NaBDsCN and NaBHCN-i*, When deuterium oxide is used, the rate of exchange is about 15 times, faster than the rate of hydrolysis!”. In the case of sodium. borohydride, hydrolysis competes with ‘exchange, thus exchange is barely detectable. Sodium Cyanoborohydtides ‘A trace of methyl orange is added to solution of sodium eyano- borchydride(1, g)in water (10 ml) containing 100 mCi of tritium, The resulting solution i ratintained at the red color (pH~3) for M0 min by the dropwise addition of 0.2 M hyGrochloric acid Solid Sodium carbonates then added until pH.7, and the solution is evaporated to dryness in eacuo, The solid residue is stirred ‘overnight with tetrahydrofuran (30 ml) then filtered. The resulting solutions evaporated incacuo giving sodium cyanoborohydride-: yield: 075g; specific activity: 49.5 xCiimmol '5. Selective Reducing Properties Sodium eyanoborohydride is a versatile reagent that will reduce a variety or organic functional groups with remarkable selectivity. For example, many selec- Sodium Cyanohorohydride A Highly Selective Reducing Agent for Organic Functional Groups 4a tive reductions have resulted from the observation that an iminium ion (2) is reduced much faster than a carbonyl group*! Cee Sec MO hy dero e am a Deck MBO 2 meen at et yy Also, the stability of sodium cyanoborohydride in protic solvents at low pH has allowed reductions tobecarried out under conditions that would rapidly hydrolyze sodium borohydride. Finally, the solubility of sodium cyanoborohydride in polar aprotic sol- vents has further enhanced its uitity as a reducing agent Sodium eyanoborohydride is a very selective reduc- ing agent because, even under the diverse reaction conditions that have been employed, many sensitive functional groups have not been reduced. For example; amides, ethers, lactones, nitriles, nitro com- pounds and epoxides are inert toward this reagent. Si Reduction of Aldehydes and Ketones, Under neutral conditions in water or methanof there is negligible reduction of aldehydes and ketones. However, at pH 3-4, the rate of reduction is suffi- ciently rapid to be synthetically useful. Since the reduction consumes acid, a buffered system is required or acid must be added to maintain the necessary low pH, 3DC=0 + BHEN® + 3ROH + He —> 3HE-OH + BIORy + HEN ‘Table 2. Reduction of Aklehydes and Ketones with Sodium Cyanoborohydride Compound oS 6 Hac-E—torete—chy me 8 wedten be bat ol d 4 th Hyc-CHteHae— ch rs te ss eghhen - Be om 8 a * Reductionsin methanol at 2, pH maintained by addition of methanolic hydrochloric Gd. Results ate taken From Lit®