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®138 C.F. Lane The reductions are conveniently carried out in meth- anolic hydrogen chloride at 25°. Some specific examples are summarized in Table 2 The reduction of cyclopentenone with sodium eyano- borohydride, under the conditions described in Table 2, gives mainly cyclopentanol®, However, this may not be a general result for 2,f-unsaturated systems Recently, it was shown that, for the reduction of a seties of conjugated ketones of the cholestenone type with sodium cyanoborohydride in tetrahydro- furan, the major product was usually the correspond ing allylic alcohol? For sodium cyanoborodeuteride reductions. the recommended solvent is tetrahydrofuran/deuterium oxide and the pH is maintained by adding a solution of deuterium chloride/acetic acid-OD in tetrahydro- furan/deuterium oxide’. High yields of deuterated alcohols are possible as shown in Table 3. Table 3. Reduction of Aldehydes and Ketones with Sodium Cyanoborodeuterde” Compcind pit” Time” Pua Wi ea i ‘a oy go oO oc” 3 1b on a wtitom 3 th weeilonom st & be 25°. pH maintained by addition of deuterium chloride dente este acid in tetrahydrofuranjdeuterium oxide. Results a from Lit® 33.DimethyIbuian-2-04-24" [8 trace of methyl orange is dissolved in deuterium oxide (0.1 mi and added tocetrahydrofuran (2 mlb. Pinacolone (300 mg. 3m and sodium cyanoborodeuteride (190 mg. 3 mmol) are added, and 4 solution of deuterium chloride/aoati aci-OD in tetahydro- Taran is added dropwise with siting to maintain the red color. Mer Smin, the Fed color persists. Stirring i then continued for 2h, The solution is poured anto water (100m), saturated with sodium chloride, and extracted with ether (3% 10m, The combined extracts are dried (MgSO4) and evaporated in rac aiving GLC. pore \3dimethylbutan-2-L-2d; yield: 265mg (81,1 NIMGR. and mas speetal analysis show >96%, deuterium incorporation. The mild conditions employed for these reductions with sodium cyanoborohydride should result in many applications for the selective reduction of aldehydes The effet that alkyl and alkoxy substituents exert on the reactivity and selectivity of the borohydride ion was reviewed in a recent technical bulletin: “Triubstitwed Borokvaride Reducing gens", Aldcich Chemical Company, Ine. Mil: rakes, Wisconsin, 58238, USA, © G, Drea E. Kei J. Pro. Chem. 6,80 1958, and ketones. Recently, a specific example was reported which showed that an aldehyde group can be selectively reduced with sodium cyanoborohy- dride in the presence of a thiol ester group!”. Ho-gs HO-CH, eae aaa) Ho By changing the cation and solvent it is possible to carry out an even more selective reduction. Thus, tetrabutylammonium eyanoborohydride in acidified hexamethylphosphoric triamide selectively reduces aldehydes in the presence of almost all other func- tional groups including cyano, ester, amido, nitro, and even the keto group'®, 52. Reduction of Oximes Under acid conditions, the reduction of ketoximes proceeds smoothly to the corresponding N-alkylhy- droxylamine with no trace of the amine which would result from overreduction® Non RE-Re HOH NeBHOUCHHOHMHEL 25, gy I pe The reduction of aldoximes is very pH dependent. When the reduction is carried out at pH 4, the major product is the dialkythydroxylamine, while at pH 3, the major product is the monoatyydroytimine’. b-N-CH, LCHOHIY, ao” ro C ? Jemowc, oH 3 (cHy-NH-O# ee 73% Reduction with sodium cyanoborohydride provides ‘what is apparently the only known method for the conversion of O-alkylbenzaldoximes to the corres- ponding N,O-dialkylhydroxylamines". an NaBHcN SAISCNIOONICL OS pec naeOR W The reduction of oximes with borane/tetrahydro- furan providesan alternative method for the prepara- tion of N-alkylhydroxylamines?®, However, this pro- cedure cannot be used to prepare N.O-dialkythydrox- ylamines because reduction of oxime ethers®" and oxime esters?-2? with borane/tetrahydrofuran pro- ceeds readily to give the corresponding amines in excellent yields. Also, catalytic hydrogenation of aryl ketoximes gives amines, while aldoximes afford N.N-disubstituted hycroxylamines®® and Q-alkyl- benzaldoximes give benzyl and dibenzylamine™.Mazer 1975 The results obtained for the reduction of a variety of oximes with sodium cyanoborohydride are sum- marized in Table 4 Table 4, Reduction of Oximes with Sodium Cyanoborohydride* xine nt Prt = warn / 0 » oO ; ov 6 ont —— 4 HICH CH oy vsc-tene-cH/ 3 he“ hs-CH-N-OH , on , oer . eee oomeey oe ore * Redustionscaried out in methanol/bydrachlorc acid at 53, Reduction of Enamines Although the enamine group itself should be resistant to reduction by sodium cyanoborohydride, rapid and reversible protonation of the f-carbon generates a readily reducible iminium salt. eee Ww Yo a T Ben, td Ay Be ie Y x, Simple enamines are rapidly reduced by sodium cyanoboroliydride at an initial pH of S in a 15:1 {etrahydrofuran/methanol solvent mixture®. © ce + G, Wittig, Liebigs Ann, Chem, 573, 209 (1951), * RC. Wade, FA. Sullivan, J. R.Berschied, Je, K.P. Purcall, Inorg. Chem. 9, 2146 (1970, NaBHCN/THFCHOM, 95,2 6% Sodium Cyanohorohydride~A Highly Selective Reducing Agent for Organic Functional Groups 139 Ifthe enamine is conjugated with a carbonyl group. the reduction becomes more difficult and acid must be added to maintain a pH of 48, Yield (3 Reference co 8 7 8 n 4 1s 8 “ 8 % ‘ 2 5 2 8 se 9 ” » o » > Oo ‘1 » Q Ft NaBH cu HETEN OH HyC—C=CH—C—OC Hs = or Q ° i f HaC~CH=CHa~C~¢ OCHS 4, Reductive Amination of Aldehydes and Ketones Since the iminium ion is reduced much faster than carbonyl group, itis possible to reductively aminate aan aldehyde or ketone by simply reacting the car- bony! compound with an amine at pH 6-8 in the presence of sodium cyanoborohydride. *V.D. Afanaiian, H.C. Miller, EL. Muctertis, J. Amer Chem. Soc. 83,2471 (1961, > IER Berschied, Jr. K. F. Pucel, Inorg. Chem, 9, 624 (1970) "RF. Borch, M. D. Bernstein, H. D. Durst, J. Amer. Chem Soe. 93,2697 (1971,140 C.F Lane a ameu Neo” suo, Re Rm co Rv Ps Re Rk DeeO HNC HN, Re “RE ‘Rt The reaction is general for ammonia, primary and secondary amines, all aldehydes and unhindered ketones. Hindered and diaryl ketones fail to react and aromatic amines react somewhat sluggishly. The full scope ofthis reductive amination process is illus- trated in Table 5, The reductive amination process is not limited to the simple amines shown in Table 5. The reaction Table &, Reductive Aminations with Sodium Cyzanoborohydride! of a ketone with hydroxylamine has been used to prepare the N-alkylhydroxylamines 3 and 4°, g HA NH-OH NaBHONCHON, HS Chern sticgaes, OF 3 q con NABHHONICHLON, oH 6-8 CHs—C—CHy + HON-OH a NH-OH CoHe—CH—CHy 4 @) 5 oO e 5 on oO on 6 i j neon » oO Ce ; 33 O On O > Oo wo 6 : od cow 8 Hee O ye 9 ; ) "Sana > & Ha, Pa ay ws “ + me" q am we nMarch 1975 Sodium Cyanoborohyride-—A High Selective Reducing Agent for Organic Functional Groups 14t Table S continued ‘Compound Amine Product Yield (% - Q a yen, a Aon wore orton % i pe our es one » 2 yon, oe sce on = ryt wewni-Eioheacts Pn HyC-em Ceo n verbo o™ reson) ® cnn oomen 7 en 7 xs 5 wor oH i uh " « Reductions in absolute methanol a 25", pH 6-8 Results taken from reference & Isolated yield of recrystallized solid derivative « Somewhat improved yield was liter reported * The use of 3A molecular sieves to absorb the water generated in the reaction resulted in the improved yield « Reaction cared out im the presence of 3A molecular sieves When dimethylamine was used, the amine product was formed in only $7, yield The reaction of a dicarbonyl compound with an JOH2e-NH2 og A amine in the presence of sodium cyanoborohydride as ote ln provides an interesting new synthesis of nitrogen- x heterocycles, as illustrated by the preparation of 58, 6°, 7°, and 877. 4 » 8 ° NABHSCN/H,0, pH 6-¢ as wey «oy mms (> ee bu 7 , ow 3 | Hom vamwewonon. on + Hyon Het ‘ ros Meo Ei G0 # oO i-CaHy 4 napincniction, os ‘CaM. 6 nyc! TDA Lyte, EH, Semen, W. A. Stuck, And. Chom, 24 8 143 95 . "9 RLF Bore H.D, Dur. dmer Chem Sr 91,396 1569, THE mild conditions that are employed for these ''-M.M, Kreevoy, J. E. C. Hutchins, J. Amer, Chem. Sor. 91, Feductive aminations obviously indicate that 4339 (1969, numerous highly selective reductions should be pos-142 C.F. Lane sible, Recently, it has been shown that reductive amination with sodium cyanoborohydride can be used to prepare each of the following functionally substituted amines: aminoester (9)°, aminoepoxide (10)?* and_aminonitroxide free radical (11). An unhindered ketone can be selectively aminated in the presence of a relatively hindered ketone to give the aminoketone 12°°. Finally, a sclective amination ofa formyllactone gave the aminolactone 1374, This was then used as the key step in a convenient and high yield synthesis of the plant antifungal agent, tulipalin A (14)°?, ° VP, My saBHnEN OH, 68 S ) 3% ‘cars HC oh Heo Roca yt 8 ° Oa 1O) + Howe, mioovenoe Ww Isolated yield of puriticd amino acid Reduction using "'NHNO3 SS. Reductive Alkylation of Amines and Hydrazines, A mild and efficient method for the synthesis of tertiary methylated amines has been developed that involves simply the reductive amination of formalde- hyde*®, The reaction of an aliphatic or aromatic amine with aqueous formaldehyde and sodium cyanoborohydride in acetonitrile results in excellent isolated yields of methylated amines, as shown in Table 7. TC. Brown, H. M. Bell, J. Org. Chom. 27, 1928 (1962, © MLM, Kreevoy, D.C. Jobason, Crout. Chem: Acta 48,511 U978}: C4. RO, 268434 (1974, 4 Thistechnigue i discussed inthe technical bulletin: "Quantia tite Analtis of Active Boron Hydrides", Aldrich Chemica Company, Inc, Milwaukos, Wisconsin 53233, US.A, 1S MLM. Kreevoy, R. F.Borch, J. EC. Hutehins, U.S. Patent 3,647,890 (1972): CA, 6, 112222 (1972) © MoH. Boutigue, RJacquesy, ¥. Petit, Bull Soe. Chin, France 1973, 3082. J, Domagal, J. Wemple,Terahedeon Lett, 1973, 1179. RO. Hutchins, D, Kundasamy. J. omer, Chom Soe. 98.6131 1978, 16, Bernhart, C-G, Wermuth, Tetrahedron Lett, 974, 2695 H, Feuer, BF. Vincent, Je, R. S. Bartlet, J. Ong. Chem, Mi, 2877 (1965) 1H. Feuer, DM, Braunstein, J. Org. Chem. 4, 1817 (1969), [A Hassne, P.Catsoulacos. Chem. Commun. 1967, 580. G. Vavon. M. Krajeinvie, Bull Soe: Chim, Feanee 1928, 231 snd referenees cited therein,March 1975 Sodium Cyanoborohydride A Highly Selective Reducing Agent for Organic Functional Groups 143 ‘Table 7, Reductive Methylation of Amines with Sodium Cyanoborohydride! Compound vi oar elerence ror Oo “ » myn serene irectna beats 8 8 ay 6 2 “ nye “Hy . ; an o Oren " 7 i oe othe eee a oa s » Nie wt ao one 2 2 a” ore . . ene cs $s omer ones . + o om 6 a \ 7 i a Sot © B es ae " omy 46° B ei od ee ~ Sey . : ow” on “ 3 ar eent Loom sees Eom 10 a“ bi con oe ~—b-cie-t—on “SE—CH-CH;—C-OCH)_ re tace-E-o a a He tae Nein on 8 e A Fro l om eeu we roid % M * Reduction in acetonitrile/acetic acid at 25°, pH 7, using an excess of 37% agucous formaldeh) 'e ” Isolated yields. a ed * Monomethylated prodet also formed (18%)144 CF Lane ‘The mild conditions, ease of experimental manipula- tion and the high yield of pure product appear to make this the method of choice for the reductive methylation of amines. 34p-Dimethylaminobenzoylpropanoie Acid A solution of methyl Mp-aminobenzovliprapanoate (1.49 g 7.20 mmol) and formaldehyde (62 mk of 37°, aqucous solution} inacetonitrile(30 mi) isadded to sodium eyanaborohydride (1.37 g 22mmol). Acetic acid (0.77 ml) s added to the steed mixture tnd stirng is continued for 2h, Additional acetic acid (0.7 mi Js added and string is continued for an additional Sh, The solution is then diluted. with ether (100ml) and washed with |W sodium hydroxide solution. The organic layer i dried, vapor ated, heated at reflux for 15h with 6 N HCI soltion (20 ml, filtered while hot, evaporated, and rturated with acetone (25m), to give 34palimethylaminobenzoslipopancie acid yield: 162g (000%); map. 172-175" Hydrazines can also be reductively alkylated using sodium cyanoborohydride to provide a simple syn- thesis of some interesting tetraalkylhydrazines®. _MaBHcREWHEO ae One® 9 a co Bete + He cotete 9 se t Ct wbewbs a CD ‘Table &, Rotuctive Displacements sneriesis 5.6. Reductive Displacement of Halides and Tosylates, Sodium cyanoborohydride in hexamethylphosphoric triamide provides a rapid, convenient and exceed- ingly selective system for the reductive removal of iodo, bromo and tosyloxy groups?®. The results sum- marized in Table 8 give an indication of the scope of this reductive displacement procedure. Primary alcohols may be converted by a simple two- step-in-one process to the corresponding hydrocar- bons. The process involves conversion of the alcohol to the iodide with methyltriphenoxyphosphonium iodide in hexamethylphosphoric triamide at room temperature followed by addition of sodium cyano- borohydride and stirring at 70°°*, Two examples are given below. H=CHOK ang we HOM(CHale—CN SHES Hyc~ICHlg—CN The superior selectivity possible for this reductive displacement reaction is demonstrated by the inertness toward almost all other functional groups including ester, amide, nitro, chloro, eyano, alkene and even such sensitive groups as epoxide, ketone and aldehyde”®. This selectivity becomes even more pronounced when tetrabutylammonium cyanoboro- hydride is used'*, with Sodium Cyanoborohydride! Compan Temperature Time Prods Yield a? HyC=lcHehi— 2 2s 35h “HyC-ICHpha=CHy oa wwe a Mth we-teshe=om 97 weet ‘0 Th weer eo y-oTee a 63h Wich TH i scree diem n° 2h ccm o wena bicoms a0 Mh wacoennho-oms 97 sncrtry-bn boca me an ” hecho ao w sh 16 ar Ly 10" ish as one car w ih 6 er-ei-en v0 3h mieemeN ts + Reductions in hexamethyphosphoric triamide, Results taken from ference 36 * Yield by G.LC. unless indicated otherwise * Isolated yield of $8: 90% for roc 4 uote Self 79-78 uetion of Iiododecane? Isolated yield of purified produet,March 1975 ‘51. Deoxygenation of Aldehydes and Ketones The propensity for sodium cyanoborohydride to reduce iminium ions has resulted in the development of still another useful synthetic reaction. The reduc- tion of aliphatic ketone and aldehyde tosylhydra- zones with sodium cyanoborohydride in acidic 1:1 dimethylformamide/sulfolane provides a mild, selec- tive, convenient and high-yield alternative to Wolff Kishner and Clemmensen reductions?*?°? > ientos > 0+ Ha-niatos —> > BHCN?, Scafitennetes 228%, Soneamenetes 2, [oneneni] > Jor + me ‘The prior preparation ofthe tosythydrazone is unnec- essary in many cases since the slow rate of carbonyl ‘eduction permits the in situ generation from tosyl- hydrazine and carbonyl compound. ‘A number of general deoxygenation procedures have been developed depending on the structure of the carbonyl compound. The otiginal investigation, in which over 60 different carbonyl compounds were studied, ‘should be consulted for experimental details, but the following examples should indicate the utility and selectivity of this useful method for the deoxygenation of carbonyl compounds Hann Tor BHSEN Di eutane, 100" 8 a Hic~€—Chahy-C-0-(CHah ch on HsC-(CH4—C—0-teHp CH Ae nekortororce aa i HsC—(CHalz-C-0-(CHz}o—CHy HyC-C-(CHab-C-0-(Hae-CN a ee t HaC-(0Hi-€-0-foHale~CN o_O W fi GH Hac SH LHNCNNATesICs0H, 7 2 rasnicnronereutaane, nor, Ms wl Dos ee HCL Sy Sodium Cyanoborohydride-A Highly Selective Reducing Agent for Organic Functional Groups 145 —CHs oo Aryl carbonyl compounds proved to be quite resist- ani to reduction by this method regardless of the procedure used"*, However, this might prove to be useful because aliphatic ketones and aldehydes could probably be selectively removed in the presence of an aryl carbonyl group. A procedure has also been developed for the deoxy- genation of sulfoxides using sodium cyanoborohy ride which involves the prior formation of an alk oxysulfonium salt using methyl fluorosulfonate* cH i orm org In conclusion, the stability and reactivity of the cyanoborohydride ion in aqueous systems at pH 6-8 indicate the potential for carrying out imine reductions and carbonyl aminations on complex bio- logical systems. Recently. such an application has been reported where the imino linkage between I1- BTW, Jones, RT. Major, J. Amer. Chem, Sov: $2,669 (1930 8 RF. Borch, Org. Syn 82, 1241972. 2 GW, Gribble, J. Org. Chem. 37,1833 (1972 2A. S. Kende, TJ. Bontley, R.A, Mader, D. Ridge. J Amer ‘Chem Sov. 96, 832 197, ‘A. Pada, P. Cimiluca, D. Eastman, J. Org. Chem. 37, 808 (9, GM. Rosen, J. Med. Chem. 17, 388 (1974, % MoH. Boutigue, R. Jacques, Bull Soc. Chim. France 1973 730. OA. D. Harmon, C. R, Hutchinson, Teahedton Lert, 1973 1293, © CR. Hutchinson, J. Org. Chom 3, 1884 (1974.146 C.F. Lane sreeesis cis-retinal and the lipoprotein opsin has been reduced under mild conditions (aqueous, pH 5, 3°) using sodium cyanoborohydride*?. Also, the observed deactivation by sodium cyanoborohydride in aqueousacid medium was used in a recent characteri- zation of an aldolase enzyme*? Reesived: August 29, 1974 RF Borch, AL Hassd, J. Org. Chom. 37, 1673 (1972) FJ. MeBvoy. G. R.Allen, tJ Med. Chem. 17,281 (1978) & SF. Nebon, G. R. Weisman, Tetrahedron Lett 1978, 321 . O, Hutchins B. E, Maryanofl.C. A. Milewski, Chom. Com mun. 1971, 1083 © RO. Hutchins, CA. Milewshi, BE, Maryanolt, Org. Sym 53,107 1973) 2% RO. Hutchins, B. E, Maryanofl, C. A, Milewski, J. Amer ‘Chem. Soe. 98, 1798 11971) RO. Hutchins, C. A. Milewski, BF, Maryanof, J. Aner Chem. Soe 9, 3663 (1973) © RO. Hutchins, M. Kacher, L. Rua. Abstracts of Papers, {67th National meeting of the American Chemical Society, Los Angeles, California, Apeil 1974, ORGN-T. HD. Durst, J. W. Zubrick, G. R. Rieezykowski, Terahedron Lert. 191477 RS Fager,P, Seinowski, E,W. Abrahamson. Biochem, Biophrs es. Commun. 47, 1244 (1972 * Stribling, RN. Perham, Biochem. J. 131. $33 (1973)