Catalyzed reduction of organofunctional groups with sodium borohydride

Journal o f Molecular Catalysis, 18 (1983) 273 - 297

273

Review

CATALYZED REDUCTIONS OF O R G A N O F U N C T I O N A L GROUPS WITH SODIUM B O R O H Y D R I D E ROBERT C. WADE Thiokol/Ventron Division, 150 Andover Street, Danvers, MA 01923 (U.S.A.)

Summary Sodium borohydride is a widely used reducing agent for synthesis of organic compounds. Non-catalyzed reductions are generally limited to carbonyl, imino and hydroperoxide moieties. Systems based on catalyzed reductions have greatly extended the scope of these reductions. The chemical properties of sodium borohydride, its reaction with inorganic cations, anions and organometallic complexes are important to these systems. There are several different types of catalysts or co-reagents and the mechanisms by which they. work vary. Slight variations in these systems can greatly affect the chemo- or regio-selectivity of the reductions and resulting products. These are pointed out. Catalyzed borohydride reductions are presented by the functional groups which are reduced. Also reviewed are some of the photocatalyzed borohydride reductions and reductions by supported borohydride reagents in inert solvents.

Introduction For over thirty years sodium borohydride (NaBH4) has been widely recognized as the reagent of choice for the selective reduction of aldehydes, ketones, quinones, acid chlorides, imines and hydroperoxides in solvents such as water, alcohols and ethers. Over the past fifteen to t w e n t y years, the utility of NaBH4 has been greatly expanded b e y o n d this traditional role as techniques have been developed to effect reduction of a broad range of organofunctional groups in a wide variety of solvents. Of particular interest is the use of c a t a l y s t s or co-reagents with NaBH4 to accomplish these reductions. It is the purpose of this review to summarize some of the representative systems which have appeared in the international chemical literature. Not covered, however, are those systems which involve the metathesis of sodium borohydride into other non-transition metal hydrides such as lithium, calcium, magnesium and aluminum borohydrides. Nor are those systems covered which involve the alteration of the BH4 anion -- examples of which are the numerous references to acid-catalyzed borohydride reductions. In 0304-5102/83/0000-0000/$03.00

© Elsevier Sequoia/Printed in The Netherlands

274

these systems, acyloxy borohydrides, BH4-n(OOCR)n, are formed and are the active reducing agent.

Properties of sodium borohydride It is important to know the properties of NaBH4 in order to determine the optimum stoichiometry, solvents, catalysts, reaction temperatures and atmosphere for the desired reactions. The following Tables summarize some of these properties. TABLE 1 Important properties of NaBH4 Mol. wt. - 37.84 Reducing equivalents/tool = 8 e Reducing eq. wt. = 4.73 ~ 1 e - ~ 1 H Decomposes above 400 °C in vacuUm Does not ignite at 300 °C on hot plate

TABLE 2 Selected solubilities of NaBH4 Solvent

Temp. (°C)

Solubility (g/100 g solvent)

H20 H20 H20

0 25 60

25 55 88.5

Isopropyl amine Ethylene diamine

28 75

6.0 22.0

Methanol Ethanol Isopropanol

20 20 25

16.4 (reacts) 4.0 (reacts slowly) 0.37 (stable)

Diglyme Diglyme Diglyme

25 45 75

5.5 8.0 0

Dimethyl acetamide Dimethyl sulfoxide Acetonitrile Tetrahydrofuran

20 25 28 20

14 5.8 2.0 0.1

A word of c a u t i o n - - d i m e t h y l f o r m a m i d e has been used in m a n y instances as a solvent for NaBH4 reductions. In the absence of a reducible substrate, greater than 2 molar solutions of NaBH4 in DMF can produce violent runaway reactions. Dimethylacetamide does not react in this manner and is recommended as a substitute.

275 Sodium b o r o h y d r i d e hydr ol yz e s in water according t o the equation: NaBH4 + 2H20

H+

~ NaBO 2 + 4H 2

Thus from 1 gram o f NaBH4, 2.37 liters of h y d r o g e n can be produced. The rate of hydrolysis is p H - d e p e n d e n t as shown in Table 3.

TABLE 3 NaBH4 hydrolysis time v s . pH (20 °C) pH

NaBH4 completely hydrolyzed in

4.0 5.0 6.0 6.5 7.0 8.0 9.0 10.0

0.02 0.22 2.2 7.0 22.1 3.7 36.8 6

sec sec sec sec sec min min h 8 min

As expected, the hydrolysis rate increases with temperature. Certain finely divided transition metals, which are precipitated from their salts by NaBH4, catalyze the hydrolysis reaction irrespective of t h e pH of the solution. The metals are, in decreasing order of catalytic activity: Ru = Rh > Pt > Co > Ni > OS > Ir > Fe Thus, those systems which might involve these metals or their salts can consume excess NaBH4 to p r o d u c e hydrogen. The precipitates are also excellent h y d r o g e n a t i o n catalysts and the c o m b i n a t i o n of NaBH4, which is the source o f H2, and catalyst m a y well serve to reduce the substrate of interest. Examples o f these systems are discussed later.

Inorganic reductions Representative cations reduced by NaBH4 are shown in Table 4. Very often the best t e c hni que for carrying out these reductions is to add NaBH4 to the solution of the metal salt. This minimizes the hydrolysis of NaBH4. In metal salt-catalyzed NaBH4 reducing systems, the choice of the anion can be very important. For instance, in the presence of h y d r o g e n a t i o n catalysts, nitrate ions can be reduced to ammonia. It is also very interesting to n o t e t h a t the bisulfite anion is reduced to dithionite at pH 2 - 7, but that no reaction occurs with the sulfite anion at pH > 9.

276 TABLE 4 C a t i o n s r e d u c e d b y NaBH4 Reactant

Lower Valence

Element

Fe3+ Ru 3+ p d :+ p t 2+ Cu 2+ Ag 1+ Hg2 + p b 2+

Fe 2+

Fe 0 Ru o pd°

Ce 4+

Ce 3+

Boride

pt 0

Cu ° Ag o Hg ° pb 0

Cu(B)

Ni 2+ Co 2+

Ni2B(H ) Co2B(H)

TABLE 5 A n i o n s r e d u c e d b y NaBH4 Reactant

Product

Remarks

NO3OC1Fe(CN)63HSO31SO32-

NH3 C1Fe(CN)64S2042no reaction

(Ni, Co c a t a l y s t )

pH = 5 - 7 pH = 9

Organometallic reductions Sodium borohydride has been used to prepare a large number of reduced organometallic complexes. The various types of reactions are summarized in the generalized equations shown in Table 6. Where borohydride is ligand, coordination with the metal can be monodentate, bidentate or tridentate. Monodentate

Bidentate

H M--H--B--H

, H

H M

Tridentate

H

H

H

\ /H

B

%H , 4 \

H

--H

The use of organometallic complexes catalyzes some very interesting selective reductions with NaBH4, as is shown later.

277 TABLE 6 O r g a n o m e t a l l i c r e a c t i o n s w i t h NaBH4 L = ligand, M = m e t a l , X = a n i o n , a n d n + m = v a l e n c e o f M. NaBH~ LnMX m NaBH

LnMXm

> L n + mM °

(metal precipitate)

> Ln+IMXm-1

(lower valent metal c o m p l e x )

4

excess L NaBH 4

LnMX m

> LnMXm_IH

-> L n M H m

(complexed metal hydride)

excess a NaBH 4 LnMX m - - - ' > excess L

LnMXn_IBH4

LnMHBH4

(complex metal hydrideborohydride)

/72

LnM(BH4)m

Organic reductions

Non-catalyzed reductions The carbonyl group reduction best illustrates the classical organic reductions accomplished by NaBH4 in protic solvents. In these reductions, NaBH 4 attacks the carbon atom with the largest positive charge:

+ BH4-

4 L

•

J

>4 H20

--C-OH I

H In these reactions, I mole of NaBH4 will reduce 4 moles of the compound containing the carbonyl group; aldehydes, ketones, quinones, acid chlorides and imines are all easily reduced by NaBH4 in protic or aprotic solvents. Obviously, the above equation reveals nothing about how sodium borohydride really works. This question has been addressed over the past ten years and some answers are slowly emerging. Wigfield has summarized these answers in a very interesting article [1] published recently. The most probable mechanism for ketone reductions is shown in the acyclic mechanism for the reduction of cyclohexanone.

OPr

278

4 moles of ketone are reduced directly to the alcohol (not a boron complex) by a molecule of NaBH4, with the protic solvent (isopropanol) participating in the reduction.

Catalyzed reductions Many of the reducing systems which have been developed to increase the scope and selectivity of reductions with sodium borohydride involve metals or metal compounds. In some cases, the true catalyst is formed in situ by reduction of the metal c o m p o u n d with NaBH4. Most of these catalyzed reductions can be carried out in protic solvents at room temperature and pressure. Where the co-reagent is attacked b y protic solvents, ether-type solvents may be required. Systems are n o w known which will reduce alkyl and aryl halides, nitro, nitrile, nitroso, amide, lactam, oxime, azide, indole, carb o n - c a r b o n double and triple bonds, aromatic rings, ester, lactone, carboxylic acid, tosylates and acid chlorides selectively to aldehydes. Furthermore chemo-, regio-, and stereoselectivity can be built into these systems. Obviously, the mechanism of these catalyzed reductions varies markedly from system to system. Little definitive work exists in this area. In some cases, a heterogeneous hydrogenation catalyst is probably formed in situ via NaBH4 reduction, or the co-reactant is in itself such a catalyst (e.g. Pd/C). Hydrogen is provided by BH4-/solvent reactions. In other cases, the co-reactant may be reduced to a lower-valent metal complex which can serve as a homogeneous hydrogenation catalyst or can complex with the substrate to provide a path for hydride transfer from borohydride. In any event, these systems are characterized by their simplicity and ease of h a n d l i n g - most reactions occurring under very mild conditions when c o m p a r e d to catalytic hydrogenation a t high pressures. The various organofunctional groups amenable to reduction by catalyzed borohydride reducing systems are illustrated in the following selected examples.

Organic halides a. Normally NaBH4 will n o t reduce non-activated organic halides. Howe v e r , a r a p i d and simple m e t h o d has been developed for assaying organic b o u n d halogen based on the reaction:

4RI + NaBH4

Pd(NO3)2/H:O

) 4 R H + 4HI + NaBO:

[21

Or

5% Pd/C in DMF

This m e t h o d h a s proved its usefulness and versatility for assaying aqueous solutions of X-ray contrasters, the organic-bound iodine being split off by NaBH4 in the presence of palladium as a catalyst within 10 min while

279 stirring at room temperature. Water-soluble substances need dimethylformamide (better -- dimethylacetamide) as a solvent. For the more stable bromides and chlorides, a more active palladium on charcoal is needed, together with 10 min boiling while stirring. Alkyl chlorides are only partially reduced. b. A powerful nucleophilic reagent, the zero-valent Ni(Ph3P)3, used in catalytic amounts together with NaBH4 will reduce aryl bromides [3]. The solvent must be DMF (caution!) as ethanol, methanol and T H F proved ineffective. R NaBH~

Ni (Ph3P)3 DMF/70*C 3 - 20 h Br The Ni(0} complex was prepared by NaBH 4 reduction of Ni(Ph3P)2C12 together with excess PPh3 in DMF at 70 °C for 30 - 45 min. An excess of NaBH4 was employed to maintain t h e catalyst in the zero-valent state and also to serve as the hydrogenolysis reagent. Typical mole ratios were 4.8 NaBH4/0.2 Ni(0)/0.4 PPh3/4.0 ArBr. This system reduced nitro and nitrile on aromatic rings in preference to the dehydrohalogenation reaction.

Br

B r ~ C N

Ni (0) ~' •Br ~ NO2 NaBH4

NaBH4Ni(O) , Br'~

NH 2

CH2NH 2

c. Aromatic halides are reduced in high yields by their reaction with NaBH4 activated by a catalytic amount of Cp2TiC12 in DMF in the presence of air [4]. Strangely, the reduction does not occur under a rigorously inert atmosphere. This suggests a radical mechanism.

/----k X~~I

+NaBH4

Cp2TiCI2

DMF/70*C/O 2

: X ~ - H

80 - 9 9 %

X = H, Cl, Br, CH30

d. Dechlorination presents a potential m e t h o d for the degradation of polychlorinated hydrocarbon pesticides to render them non-toxic. Nickel boride, nominally (Ni2B)2H 3 when produced by the NaBH4 reduction of nickel salts in water or alcohols, has been used as a catalyst together with sodium borohydride to dechlorinate several organochlorine pesticides [5].

280

Heptachlor

,

(Ni2B) 2H 3 CH3OH , C2HsOH or C3H70H

Cl~c1 C1

Chlordane

C1

C1

Compound containing 3 C1 per molecule

Cl" y C1

Cl Lindane

C

I C1

Cl ~

C1 C1

J

0 Cl (cyclohexane, cyclohexene and benzene)

In addition, the herbicide 2,4-D was extensively dechlorinated by this system in the alcohols mentioned. 2-Propanol permitted the m a x i m u m dechlorination. All dechlorinations became less efficient when water was added to the solvent. In most dechlorinations the ratio of pesticide to Ni was 2:1. It was shown in the reaction of chlordane that a ratio of 80:1 could also be used without excessive loss of efficiency. Under these conditions (Ni2B)2H3 was acting as a true catalyst. e. A unique redox system has been studied based on [Co(bipyridyl)]3 +1'+2 - - N a B H 4 in CC14. Henrici-Oliv~ and Oliv4 [6] have described the redox process by which Co +1 is oxidized to Co +2 by CC14 and reduced back to Co +1 by NaBH4, producing radicals ('CC13) suitable for the initiation of methyl methacrylate polymerization. Vl~'ek et al. had earlier used this system for the reduction of nitrobenzene to aniline and phenyl hydroxylamine [7]. It is n o w believed that most of the catalyzed dehalogenation reactions with NaBH4 systems go through free radical mechanisms. f. The reductive dimerization of benzyl chloride with NaBH4/CO +2(ethylenediamine)3 complex in ethanol to give 1,2-diphenylethane has been reported [8]. Again, it is believed that NaBH4 reduces the Co(II) complex to a Co(I) complex, which then reacts with benzyl chloride to give the benzyl radical which then dimerizes to 1,2-diphenylethane.

281

PhCH2C1

Co(II)(ethylene diamine) NaBH4, EtOH (N2)

> PhCH2CH2Ph

[Co(I) complex + PhCH2C1 -+ PhCH2" ] Consumption of NaBH4 and hydrogen evolution both were very rapid. g. The reduction of 2¢hloronaphthalene to naphthalene has been reported recently [9].

5 NaBH%/I PdCl2 20°C CH3OH

66%

Nitro groups One of the major problems in manufacturing fine organic chemicals and pharmaceuticals is the selective reduction of nitro groups. Aluminohydride and metal-acid chemical reductions have been widely studied for these reactions. However, p r o d u c t isolation, handling hazards, solvent requirements, and costs of these reagents have made them less desirable for commercial use. On the other hand, borohydrides in protolytic solvents are generally found to have insufficient reduction potential to reduce nitro groups cleanly and rapidly to the desired products, although their costs are generally much lower than the aluminohydrides. Catalytic hydrogenation of nitro groups is c o m m o n l y used for producing amines since, generally, it is the lowest cost m e t h o d of reduction. However, Selectivity may be a problem -- especially when there are other reducible groups present. The use of certain catalysts together with NaBH4 is effective in the selective reduction of nitro groups and their intermediate reduction products. a. One of the first systems reported for catalyzed NaBH4 reduction of nitro groups was the n o w familiar NaBH4-Pd/C system in protic solvents [10]. Using this system, nitrobenzene was completely reduced to aniline. Most likely this is a catalytic hydrogenation reaction with NaBH4 furnishing the H2. b. The system, NaBH4-CoBr~ or trans[aquobromobis(dimethylglyoximato)] Co(III) in methanol or ethanol was effective in the reduction of a number of the intermediates of partially reduced nitrobenzene [ 11]. Most surprising was the speed of the reductions which, of course, with NaBH4 alone are difficult or impossible to carry out. c. Sodium borohydride and COC12 in lower alcohols or dioxane at 40 °C was found to reduce substituted aromatic nitro c o m p o u n d s in low yields to the corresponding aromatic amines [12]. Only the nitrile group was coreduced. This system at 20 °C in CH3OH is far more effective for reducing substituted nitrobenzenes to the corresponding azoxy c o m p o u n d s in high yields. The procedure used suggests that a complex is formed between the nitro c o m p o u n d and COC12"6H20. Addition of NaBH4 slowly does not form

282

the black Co2B(H ) precipitate, but does reduce the nitro c o m p o u n d . Molar ratios used were 1 nitro cpd/1 COC12"6H20/3NaBH4. d. A homogeneous catalyst system KhC13pya (py = pyridine) -NaBH4 in DMF is highly active for the hydrogenation of nitroaromatics and nitrocyclohexane to the corresponding amines [13]. e. Several aromatic nitro compounds have been reduced to aromatic amino c o m p o u n d s with high yields using the system NaBH4-SnC12-ethanol [14]. This system has n o w been found to selectively reduce aromatic nitro c o m p o u n d s containing other reducible functional groups in their molecular structure, such as ester, chloro, nitrile, carbonyl and c a r b o n - c a r b o n double bonds. The process is very easy to carry out. A b o u t 1 g of the nitro comp o u n d is dissolved in 100 ml ethanol together with a five molar excess of SnC12"2HEO. The mixture is heated to 60 °C. The equivalent of 0.5 mol NaBH4 (for each nitro group) dissolved in ethanol is added to the above solution over a period of 30 min. The mixture is post-stirred for an additional 30 min. Ethanol is removed by vacuum distillation and the product isolated by conventional techniques. The yields of aniline derivatives which are obtained by the reduction: R

NO2

SnCl 2/NaBH 4 EtOH ,

R

NH 2

are good in every case tested to date. Especially interesting is the almost quantitative yield of p-aminoacetophenone from the nitro c o m p o u n d , which demonstrates the uniquely high selectivity of this system. The reducing agent might well be SnC12, which is continually regenerated by NaBH4 as it is oxidized by the nitro group. f. Cobalt(III) complexes with biguanide, salen [ethylenebis(salicylimine)], and macrocyclic Schiff base in ethanol-water mixtures catalyze the reduction of PhNO 2 with borohydride [15]. The reductions follow the path: PhNO2 -+ PhNO --> PhNHOH --> PhNH2. The catalysis is related to the ability of Co(III) ion to reduce to a lower oxidation state, and also to the weak interaction of Co{II) and strong interaction of Co(I) or hydride with the substrates. The efficiency of the catalyst depends on the nature of coordination and the stability of the low oxidation state of the metal ion in the complex. g. The reduction of aromatic nitro c o m p o u n d s with sodium borohydride in ethanol in the presence of Cu(II)AcAc gave the corresponding amines in yields of 80 - 90%. The reaction is believed to take place by way of a complex metal hydride [16].

~

N02

Cu(II) AcAc NaBH~ EtOH

NH2 80 - 9 0 %

283

h. Bis(triphenylphosphine)Ni(II)-NaBH4 complex in 2-propanol at 60 °C reduces --C1 or --OMe substituted aromatic nitro compound completely to the amine in high yields w i t h o u t reducing the substituent groups [17].

NaBH~ --NiX~ (PPh~)2 ~. R @ N H 2 2 -Propano i 60 °C R=Cl, OMe X = C I , Br, I (80%) i.On the other hand, a very similar Ni-triphenylphosphine complex bound to a polymeric backbone together with NaBH4 in ethanol at 60 °C gave primarily azoxybenzene [18]. This clearly illustrates the chemoselectivity that can be obtained with minor changes in these catalyzed NaBH4 systems.

R

NO2

NO2

(~--PPh2--NiCI2 : ~ ~ = N ~ NaBH~, EtOH, 55 - 60°C

55- 80%

]. Perhaps the best system for the reduction of nitrobenzene to azoxybenzene is NaBH4 catalyzed by Co(Ill) tetraethylenepentamine in water at 25 °C [19]. Tetraethylenepentamine was used in the ratio of 2 polyamines to 1 cobalt. All of the reactionswere carriedout for 60 min at 25 °C in aqueous solutions under nitrogen. Yields of nearly 100% were obtained using one mol NaBH4, one mol cobalt, and two tool tetraethylenepentamine.When large excesses of N a B H 4 were used, aniline and phenylhydroxylamine were also produced. Under optimum conditions very little(<10%) of the N a B H 4 was hydrolyzed to produce hydrogen. k. Coutts and Wibberley reduced with catalyzed (10% Pd-on-charcoal) sodium borohydride several o-nitro-esters,in which the ester group was suitably oriented with respect to the o-nitrophenyl group, and found this to be a very efficientway of producing cyc|ic hydroxarnic acids [20].

oCOO

2

NaBH4 ~ Pd/C

R I ~ X ~

~,~ "NI "." J OH

The hydroxamic acids prepared by this route were evaluated for their antimicrobial properties. Reduction of structurally related ketones with NaBH4-Pd/C also resulted in cyclization at the hydroxylamino stage of reduction of the nitro group and cyclic N-oxides were the products obtained:

~ / X Y~ ~/'~.COR NO2

NaBH~ Pd/C '

X..y ~ N / ~ R I O_

284

It should be n o t e d t hat the Pd/C catalyst m a y become p y r o p h o r i c after its use with NaBH4. Nitrile and amide groups Many of the same systems useful for the reduct i on of nitro groups are useful for r ed u ctio n of nitriles and amides to amines. In addition, two simple metal salt (which are reduced t o the metal or metal boride by NaBHa) systems have been described [ 21].

NaBH4

a. ArCN

> ArCHzNH 2

(35 - 80%)

COC12, C H 3 O H or dioxane 20 - 40 °C

b. ArCONH 2

NaBH4

> ArCH2NH 2

(30 - 70%)

CuCI 2

c. Egli has f o u n d that Raney nickel-NaBH4 in a m e t h a n o l - w a t e r solvent system will reduce bot h aromatic and aliphatic nitriles to the corresponding amines [22]. ArCN

NaBH 4

~ ArCH2NH 2

RaNi-CH3OH/H20

RCN

NaBH4

~ RCH2NH 2

RaNi-CH3OH/H20

d. Creaser and Sargeson have taken a unique approach to the reduction of nitriles [23]. T hey reasoned t hat if a substantial electron-withdrawing m o i e t y such as a metal is c o o r d i n a t e d to the nitrile, the carbon center should become more electropositive and, therefore, m ore easily attacked by H or BH4-. Th ey f o u n d t hat the acetonitrile pentaamine cobalt complex, [(NH3)sCo--N~CCH3]C104, treated with aqueous sodium b o r o h y d r i d e at pH 9 for six min at 25 °C gav e 50% yield of the amine metal complex. The u n c o o r d i n a t e d acetonitrile was n o t reduced after 10 days. A n u m b e r of o t h e r nitriles were also reduced by this technique implying general applicability o f the m e t h o d . e. Imidic esters: an interesting reduction o f an imidic ester~ prepared from benzamide and t r i e t h y l o x o n i u m fluoroborate, with NaBH4/SnCI4" 2(C2H5)20 in glyme at 0 °C gave benzylamine in high yield [24]. This is an indirect conversion of amide t o amine.

285

0

?C2H5

Glyme

0 °C

f. N-nitrosamines and amine N-oxides: nitrosamines have been used for the introduction of substituents at the a-position of secondary amines and by this method a variety of secondary amines were prepared. A key step of this synthetic operation is the denitrosation. Although several methods are available for the regeneration of secondary amines from their nitrosamines, catalytic hydrogenation with freshly activated Ni catalyst and the LiAIH 4 reduction/Ni--H 2 procedure are usually employed because of their convenience. A combination of N a B H 4 and TiCl4 in dimethoxyethane (DME) was found to be effective for reductive denitrosation of nitrosamines to the corresponding parent secondary amines [25]. N-nitroso-N-methylaniline was treated with TiC14--NaBH4, prepared by mixing 4 equimolar amounts of NaBH4 with 2 equimolar amounts of TIC14 in DME, at room temperature for 14 h. The mixture was poured into water and made basic with 28% ammonia and extracted with chloroform. Evaporation of the solvent yielded Nmethylaniline in 92% yield. In addition, this system was found to be effective for the deoxygenation of heteroaromatic amine oxides to the parent base. g. Before leaving nitrogen compounds, note should be made of the very extensive work of Schrauzer and others relating to their development of nitrogenase models for the reduction of molecular nitrogen [26]. In these systems, molecular nitrogen is complexed with various molybdenum(V) complexes and other protein-like materials and reduced to ammonia via NaBH 4 . Ketone reductions a. Normally, aft-unsaturated ketones give a substantial amount of the saturated alcohol when reduced with NaBH4 in protic solvents. A very unique system has been reported where only the allylic alcohol is obtained in quantitative yields [ 27 ]. Treatment of an equimolecular amount of saturated ketone (2hexanone, cyclohexanone, acetophenone) and samarium chloride hexahydrate in ethanol with sodium borohydride (1 molar equiv.) produces an evolution of hydrogen coupled with a quantitative yield of the corresponding alcohol in 5- 10 min. Application of this procedure (in methanol) to aft-unsaturated ketones produced high yields of the corresponding allylic alcohols, in many cases uncontaminated with the 1,4-reduction product.

NaBH4 =CH--C--

CeCl3"6H20 MeOH

?H > =C--C-- allylic alcohol (100%) !

H

286 Of the lanthanides tested, samarium and cerium appear to offer the best combination of yield and selectivity. The m e t h o d evidently offers the following advantages. First, nearly exclusive selective 1,2-reduction is obtained under conditions which do not affect carboxylic acids, esters, amides, halides, and cyano and nitro groups. Even 2-cyclopentenone, which is especially prone to undergo the 1 i4-addition reaction, can be reduced to 2-cyclopentenol with a selectivity as high as 97%. Furthermore, the reactions may be conducted at room temperature, without special exclusion of air or moisture, and excellent yields are obtained within 5 min. b. One of the most interesting reversals of the normal reduction sequence of borohydride is the ability of the lanthanide-NaBH4 s y s t e m to selectively and completely reduce ketones in the presence of aldehydes. Thus a one to one molar ratio of an aldehyde and ketone was mixed with 1.5 mol NaBH4 to 1 mol CeC13"6H20 in an ethanol-water mixture at --15 °C. The ketone was reduced to the alcohol quantitatively with only very small amounts of the aldehyde being reduced [28].

CeC13.6H20 EtOH-H20, --15 °C

H

It has been shown that the lanthanide salts catalyze the selective ketalization of the aldehyde in both alcohols and water, thus protecting t h a t group from borohydride reduction. Some hemi-acetalization together with hydrate formation cannot be completely ruled out, however. Reduction with NaBH4 followed by deprotection of the aldehyde affords the secondary alcohol and the original aldehyde. c. Aromatic ketones, hindered steroidal ketones and benzylic alcohols can be reduced to the corresponding hydrocarbons by the previously described system, NaBH4-PdC12 in methanol at 20 °C [9]. ArCOR ArCHOHR R = aryl or alkyl

NaBH4-PdC12 > ArCH2R 20 °C, MeOH

yields 40 - 90%

NaBH4/PdC12 = 5/1

In these systems, Pd can be recovered as the metal, therefore the mechanism appears to be a Pd-catalyzed hydrogenation or hydrogenolysis of the substrate. d. The reduction of/3-dialkylamino conjugated enones to the saturated ~,-amino alcohols is accomplished with sodium borohydride in the presence of iron(III) chloride [28].

287 OH

O

NaBH~-PdCl 2 ~ 20~C' T H F - H 2 O y ' L L _

~ 5

X

X O -~HO ~,,, ACO i,,, HO ~ AcO ~ o

R'

Y HO HO ACO HO AcO

Yield (%) ~'~ ,,L, ~ll ~ ~

R2

96 96 84 91 94 OH

N/ [ R4

NaBH~ , R' FeCI 3 •6H 20 MeOH

R2

N [ R4

Good to excellent yields were obtained using a mole ratio of FeC13' 6H20 to 3NaBH4 in only 20 min reaction time at 20 °C. e. Though n o t truly a catalyzed borohydride reducing system, a new, very effective, homogeneous catalytic system able to p r o m o t e the hydrogenation of several ketones to alcohols has been reported [29]. The success of the system is related to the pretreatment of the rhodium complex: RhCI(CsHa2)PPh3 with a stoichiometric amount of NaBH4 in toluene and methanol. Dark, very reactive solutions were obtained which, in the presence of strong alkali, catalyze the hydrogenation of a number of ketones including acetone, hexan-2-one, pentan-2-one, acetophenone, benzophenone, and adamantan2-one. The pre-reduction of RhCl(CsH12)PPh3 was carried o u t in the reaction cell by dissolving the complex (5 - 10 rag) in toluene (1 ml) and adding two molar equivalents of ethanolic NaBH4. After stirring for a few minutes the solvents were evaporated under reduced pressure. The reactions of hydrogen and different substrates were carried out using a themostatted Pyrex apparatus ( ~ 1 0 ml) connected to a gas burette (10 ml) containing H2 on Hg. The temperature was 25 0C and the hydrogen pressure was 1.2 - 1 arm. f. 2-Methyl- and 2,3-dimethylthiochromenes were reduced selectively to the corresponding thiochromones with NaBH4 in the presence of CeC13" 7H20 in good yields [30]. Cerium trichloride was found necessary to acti-

288

vate the carbonyl group for reduction with sodium borohydride. Reactions were carried out in methanol at room temperature for 5 h, molar ratio of substrate/NaBHa/CeC13-7H20 were 1/2.5/1.5. Standard procedure was to dissolve the thiochromone and CeC13.TH20 in methanol, then add to this mixture powdered NaBH 4 in several portions with good stirring for 5 h.

NaBH%-CeCI ~ 2

CH 3 OH

'~ H

O

H

Acid chloride to aldehydes A number of researchers have concentrated efforts on techniques to partially reduce acid chlorides to the aldehyde stage and stop there. The normal course of events with sodium borohydride in aprotic solvents such as ethers is to go all the way to the alcohol. Two distinct systems have evolved. The first of these came from two separate groups simultaneously. a. The best-studied complex to date is (Ph3P)2CuBH4 which has been shown to reduce acid chlorides to aldehydes under extremely mild conditions [31, 32]. All other functional groups are inert to reaction.

--COCI

Ph 3P

86% (gc)

~-~

(ph~p) 2 C u B H 4

'

--CHO O

nonanoyl chloride

(Ph3P)2CuBH4

~ nonanal 94% (go)

Ph3P

To perform the reduction, one adds the acid chloride to an acetone suspension of the complex at 25 °C. After stirring 1 - 2 h, the solution is filtered from the inorganic byproduct and the product is isolated. Addition of two molar equivalents of triphenylphosphine frequently increases both the rate of the reaction and the final yield of aldehyde; it is suggested that an acylphosphonium complex, RCO'PPh3, is formed which is attacked by the reducing reagent. The effects of the addition of other possible nucleophilic catalysts have been investigated. The major by-product in the reaction is tris(triphenylphosphine)copper(I) chloride which is insoluble in acetone and may be removed by filtration and efficiently recycled to (Ph3PhCuBH4. Yields of aldehydes with this reagent have been compared with those obtained by reduction of acid halides by the Rosenmund and lithium aluminum tri-t-butoxyhydride methods. Similarly, a polymer-bound phosphine-complexed copper borohydride and its use in reducing acid chlorides to aldehydes has been described [33]. The claimed advantage of this reagent over the u n b o u n d reagent is its ease of

289 removal from the product and the ease of regeneration. Aldehyde yields were equivalent to those obtained with the u n b o u n d reagent. b. The second system appears to be more economical than that just described, although it does involve handling the toxic CdC12 [ 34]. Cadmium chloride and dimethylformamide are conveniently combined by recrystallization of CdC12-2½ H20 from dry dimethylformamide to give CdC12.1-~-DMF. As an example, sodium borohydride (2.0 mmol) was dissolved in acetonitrile (10 ml) and hexamethylphosphoramide (0.5 ml) and then stirred for 5 min with CdC12" 1-12DMF (1.25 mmol) at -- 5 to 0 °C (icesalt bath). To the slightly opaque solution 4 ~ h l o r o b e n z o y l chloride (2 mml) in acetonitrile ( 2 - 3 ml) was added rapidly with stirring, which was continued for 5 min. Dilute HC1 was added slowly to the reaction mixture which was then extracted with ether to give 4-chlorobenzaldehyde. Other functional groups, chloro, cyano, nitrile, ester, and C--C double bonds are unaffected. Cadmium gives the most stable reducing solution of all the metal ions tested.

Organosulfur reductions a. No general m e t h o d was known for the facile reduction of sulfoxides to sulfides in high yields. N o w the system NaBH4/CoC12"6H20 in 95% ethanol reduces dialkyl, diaryl, arylalkyl and diaryl sulfoxides, as well as thioxanthene sulfoxide in excellent yield [35]. R2S=O -+ R2S However, dibenzyl sulfoxide and tetramethylene sulfoxide are n o t reduced appreciably. In a typical experiment, 1 molar part of NaBH4 is slowly added to 0.1 molar part of the sulfoxide and 0.2 molar parts of CoC12" 6H20 in 95% ethanol. Gas is evolved and the black Co2B precipitate forms. After 2 h stirring, the sulfide p r o d u c t is recovered. The formation of the black precipitate suggests that the reductions proceed via catalytic hydrogenation. If so, the large amount of catalyst used relative to the sulfoxide may be required to overcome the poisoning effects of the p r o d u c t sulfide on the catalyst. It is conceivable that the sulfoxide oxygen coordinates with the metal ion thus weakening the sulfur-oxygen bond and rendering it more liable to borohydride reduction. b. The second m e t h o d involves the already described system of Kano: NaBH4/TiC14/glyme [25]. Thus, for example:

~

-S-C2H5NaBH~/TiC14, ~ 0

S-C2Hs

Glyme

This system is well known to reduce many other functional groups, so that care must be exercised in its applications [36, 37].

290

Carbon-carbon unsaturation a. Acetylenes: by itself, of course, sodium borohydride will not reduce acetylenic triple bonds. However, the cluster [Fe4S4(SR)4] 2 catalyzes the reduction of diphenylacetylene to cis-stilbene in the presence of NaBH4 in CH3CN/CH3OH at room temperature and in an inert atmosphere [38]. When the reduction was carried out in CH3OD/CH3CN, only cis-C6HsCD=CHC6H5 was formed. Thus one hydrogen atom originated from the solvent (CH3OD) and the Other from NaBH4. The study on the reaction mechanism is significant for obtaining t h e characteristics of iron-sulfur proteins. Cobalt(II) p h t h a l o c y a n i n e - s o d i u m tetrasulfonate exhibits a specific catalytic effect for the selective reduction of acetylene with NaBH4 to ethylene [39]. When acetylene (0.1 - 0.7 atm) was admitted to an alkaline (pH 8 - 1 2 ) borate buffered solution of Co(II)PcTS (0.1- 1.0 mmol) and NaBH4 (1 - 10 mmol) at 27 °C, ethylene was produced at a considerable rate. Oxygen and carbon dioxide killed the catalyst completely, but activity was slowly restored by reduction of the inhibitor gases with excess NaBH4. A possible mechanism for the selective reduction of acetylene takes place through hydrogen transfer from a hydrogen adduct of CoPcTS ~which has been formed with NaBH4, a strong reductant, in alkaline solution according to the scheme: /

H

H~c~C - -

H

/

N

/co ND

(II/ N

N

N 2e+H+,,~ / C o ( I ) / N--N

N

N ]

N

HC--CH / C o ~ / N N

CH 2 = CH 2 b. Olefinic compounds: the system 2 molar parts of NaBH4 per molar part of a cobalt(II) salt in ethanol at 0 °C reduces alkenes (and some alkynes) in high yields; this system displays an extremely high stereoselectivity in the reduction of alkenes [40]. Mono-substituted a-olefins are most easily reduced by this reagent, the reactions being complete in 1 h. Disubstituted olefins are in general more slowly reduced, although reduction of norbornene and norbornadiene is exceptionally facile. The reduction rates are significantly different for cis- and trans-stilbenes, with the cis isomer being more easily reduced. While mono- and disubstituted olefins are efficiently reduced by this reagent, the more highly-substituted olefins are virtually inert to these reducing conditions. The potential synthetic utility of this reducing agent is well demonstrated in the reduction of limonene, in which

291 the disubstituted side-chain olefin is selectively reduced in the presence of the trisubstituted endocyclic double bond.

NaBHq (2 mole) Co(II) (I mole) EtOH, 0°C

It is likely that the species responsible for the selective reduction of alkenes and alkynes is a cobalt boride-hydride (Co2B)sH3 [41]. Whether this functions via a catalytic hydrogenation or hydrocobaltation reaction remains to be determined. Two systems for the reduction of methyl cinnamate to methyl hydrocinnamate have been described. The first, like the previous Co system, is most likely a heterogeneous hydrogenation system based on formation of nickel boride [(Ni2B)2H3] from NaBH4 and NiC12-6H20 in CH3OH at 20 °C [42]. The second is the homogeneously catalyzed reduction with NaBH4 and the [Co(CN)4] -2 anion in water under a nitrogen atmosphere [43]. According to the authors, the mechanism of this reaction appears to involve the intermediate formation of the cyanocobaltate hydride anion [Co(CN)sH] 3CH=CHCOOCH3

NaBH~p

Catalyst methyl cinnamate

~

CH2CH 2 COOCH 3

methyl hydrocinnamate

The chemoselective borohydride reduction of a C=C double bond in the presence of a keto group is unusual. However~ such a reduction can be accomplished with either the COC12 or NiC12/NaBH4/methanol systems described above [44]. Thus ~-sulfenylated ~fl-unsaturated ketones are reduced with NaBH4 and catalytic amounts of CoCl~ or NiC12 in methanol to give the saturated ketone in excellent yield.

Ru-C--CH=C(R2)SR 3

NaBH4/MC12 CH3OH

O I[ ~ RI--C--(CH2)2 R2

Contrast this with the system described in Ketones d. above, where both the keto and the C=C unsaturation are reduced, and one can appreciate the remarkable selectivity available. c. Aromatic rings: c o m p o u n d s containing aromatic rings are reduced to give saturated rings with sodium b o r o h y d r i d e - r h o d i u m chloride in hydroxylic solvents under mild conditions [45]. The substrates are first incubated

292

at 30 °C with rhodium chloride in a hydroxylic solvent such as ethanol prior to addition of an ethanolic solution of sodium borohydride. Reduction temperature generally must not exceed 60 °C. Water can be used as a solvent where the substrate is water soluble. About 1 mole RhC13 is required for each mole of substrate. Carboxylic acids, esters, and amides are unaffected and ketones are only partially reduced. Olefinic bonds are simultaneously completely reduced.

Catalytic hydroboration of double bonds a. The reagent system generated from Cp2TiC12 and LiBH4 promotes the catalytic hydroboration of olefins with LiBH4 to give Li alkylborohydrides [46]. These can be converted to alcohols by treating with NaOMe and H202. This system avoids the use of pregenerated diborane, which may be of considerable advantage for industrial scale operations. One wonders if the system NaBH4 + LiC1 + 4 olefin

Cp2TiCI2 THF

> LiBR4 + NaC1

might also work in a "one p o t " synthesis. Such a system would permit the use of low cost starting materials and avoid the handling of diborane. b. The catalytic reaction of molecular oxygen with alkenes to give alcohols under reductive conditions represents an example of the activation of substrate over activation of oxygen [37]. When styrene is stirred in the presence of a catalytic a m o u n t of bis(dimethylglyoximato)chloro(pyridine) cobalt(III) and an excess a m o u n t of sodium borohydride under oxygen, 1phenylethanol is obtained selectively with no detectable a m o u n t of 2-phenylethanol. Control experiments without oxygen or borohydride give no alcohol in either case.

~CH=CH2

NaBH~ + 02 Co (DH)2 (PY)C1

~CH

2CH2OH

Appreciable yields based on olefin are obtained with catalytic amounts of the cobalt complex using glyme or dimethylsulfoxide solvents. Again, it is believed that the Co(III) complex is reduced to a Co(I) species by NaBH4. The Co(I) complex reacts with olefin to give an alkylcobaloxime(III) which, in t u r n , reacts with oxygen to form an alkyl peroxo complex. BH4- reacts with the alkyl peroxo complex to form the alcohol. c. Another system for converting olefins to alcohols has been published by Kano and co-workers [48]. They have found that the treatment of alkenes with a combination of 1 equivalent of SnC14 and 4 equivalents of NaBH4 in tetrahydrofuran at room temperature followed by hydrolysis with water in air gave the corresponding alcohols. The h y d r o x y l group was introduced in the anti-Markownikov direction.

293 Photoreductions

~ arene rings

Perhaps the most surprising development in the last t w e n t y years has been the photocatalyzed reduction by NaBH4 of arenes and related compounds. These are very interesting because such reductions are proposed to involve the hydride ion attack on organic radicals or radical ions, or the generation of boron hydride radical ions. No extraneous metal or organometallic c o m p o u n d is involved in these reductions. As a result, c o m p o u n d s containing aromatic rings, previously inert to borohydride, can n o w be reduced. In 1967, Waters and Witkop described the solvent dependent ultraviolet photoreduction of 3,17~-estradiol in ethanol with sodium borohydride to give 3(~,17~-dihydroxy-5(10)-estrene and A/B, c i s - f u s e d 3~,17~-dihydroxy5~,10~-estrane and polymeric material. Photoreduction in dioxane-water led to a new isomer of 3,17fl-dihydroxy-5(10)-estrene. Earlier work by Witkop and his associates described the photoreduction of the heterocyclic systems in uridine, tryptophan and thymidine [49 - 51]. The reduction mechanism in these reactions was not established. One possibility discussed was radical attack by hydrogen atoms, since large amounts of polymers were formed in these reactions. In 1972 Barltrop and Owers described the UV photoreduction of naphthalenes with sodium borohydride in acetonitrile/water or acetonitrile/DfO [52]. The 1-CN and 1- or 2-COfMe derivatives gave the corresponding dihydronaphthalenes. Naphthalene itself gave a mixture of 1,4-dihydronaphthalene and tetralin. A mechanism involving hydride attack u p o n the excited organic molecules was proposed. Barltrop and Bradbury reported the photoreduction of chloro-, bromoand iodobenzene by sodium borohydride in aqueous acetonitrile [53]. Benzene was obtained in virtually 100% yield, and in quantum yield often in excess of unity. Bradbury and Barltrop carried o u t deuterium labelling experiments to elucidate the mechanism of the U V p h o t o r e d u c t i o n of phenols with sodium borohydride [54]. p-Cresol was reduced (in poor yield) in alkaline aqueous solutions to give the corresponding cyclohexene and cyclohexane derivatives. The results suggest the interaction of p h e n o x y radicals successively with borohydride anti with solvated electrons. Tsujimoto e t al. studied the UV photoreduction of 3- and 4-chlorobiphenyl by NaBH4 in acetonitrile-water [55]. Based on deuterium labelling experiments, they concluded that reduction takes place by a h y d r i d e proton-transfer mechanism rather than the radical chain mechanism proposed by Barltrop and Bradbury. Biphenyl was the sole product. Mizuno e t al. reported the efficient photoreduction of phenanthrene, anthracene and naphthalene by sodium borohydride in the presence of 1,4dicyanobenzene [56]. Reductions were carried out in aqueous acetonitrile and gave the dihydro derivatives of the starting hydrocarbons. When the photoreduction of phenanthrene or anthracene was carried out in the presence of deuterium oxide instead of water, a m o n o d e u t e r a t e d product was obtained. Photoreaction in the absence of 1,4-dicyanobenzene was very

294

slow, suggesting that direct attack of the hydride ion on the excited hydrocarbon mechanism proposed by Barltrop and Owers is unlikely. These authors proposed the formation of a dicyanobenzene-hydrocarbon exciplex which dissociated into ion radicals in the polar solvent. Electron transfer from the excited hydrocarbon to the dicyanobenzene followed by nucleophilic attack of hydride ion on the hydrocarbon-cation radicals generated free radicals which are reduced by electron reversal from anion radicals and subsequent protonation to give the dihydro hydrocarbon. Further work by this group has shown that the photoreduction of phenanthrene, anthracene, naphthalene and several substituted naphthalenes efficiently occurs upon irradiation of 9:1 acetonitrile-water solutions in the presence of sodium borohydride and m- or p-dicyanobenzene [57]. The reduction of phenanthrene and anthracene gave the 9,10-dihydro derivatives. Naphthalene, 2,6-dimethylnaphthalene, acenaphthene, and 2-methoxynaphthalene are exclusively reduced at C1 and C4. With naphthalenes having alkyl groups on the one ring, photoreduction gives both 1,2- and 1,4:dihydronaphthalenes. And finally, another example of UV-catalyzed borohydride reductions has been reported [58]. Photolysis of aqueous solution of tetramethylpyrazine containing sodium borohydride caused complete reduction of the pyrazine ring to the hexahydro stage. H

Me

N

e

H20

Me

N

Me

N"

e

",Me

H

While the mechanism of these reductions is still being argued, it is clear that photoreductions of aromatic rings with sodium borohydride in aqueous acetonitrile and other solvents have extended the utility of this reducing agent. Utility in the pharmaceutical/fine chemical field is indicated.

Supported sodium borohydride The development of successful techniques for the impregnation of sodium borohydride on supports such as silica and alumina without excessive hydrolysis of the reagent has permitted these materials to become items of commerce. These supported borohydrides have reducing properties distinctly different from the unsupported reagent. As such one might consider the supporting material to be acting in a catalytic manner. For instance, sodium borohydride on alumina will reduce aldehydes and ketones in non-aqueous solvents, such as ether, benzene or ethylacetate in yields of over 80% [59]. Normally, sodium borohydride reduction in these solvents is impractically slow. Similarly acetone was reduced with sodium borohydride on alumina in toluene, ether, chloroform and hexane. The most interesting feature was that

295 almost no boron was detected in the solvent system after reduction [60]. Unsupported NaBH4 did n o t reduce acetone in toluene. Further studies by Santaniello et al. have shown that the reduction of difficult-to-reduce alkyl and aryl acid chlorides to the corresponding alcohols is easily accomplished by 10% NaBH4 on alumina in anhydrous diethyl ether at ambient temperature for 2 - 4 h [61]. Even a 90% yield of cinnamyl alcohol was obtained from cinnamoyl chloride where other methods gave reaction at the C=C double bond and no cinnamyl alcohol could be recovered. A number of keto steroids have been reduced to the corresponding secondary alcohols in aprotic solvents. More importantly the reduction:

O H3 C H

OH

H 3 C ~ N a B H ~ / A 1 2 0 3 ~ H3CCO0 H3CCOO-

-

_

proceeded without any significant hydrolysis of the enol acetate end group. Under the normal conditions used for borohydride reductions, enol acetates undergo rapid hydrolysis, and the ketones thus formed are reduced to alcohols [62].

Conclusions Catalyzed sodium b o r o h y d r i d e reducing systems have been developed which now permit the reduction of many organofunctional groups which normally are inert to sodium borohydride. These systems vary greatly in their compositions and mechanisms by which they work. Obviously much work remains to be done to better define the mechanisms. More important from an industrial point of view, perhaps, is the need to optimize the stoichiometry of these systems. In most cases, large excesses of NaBH4 are used which increase the cost of the reduction. Regardless, these systems n o w provide very simple and convenient techniques for reduction of organofunctional groups by NaBH4, which have greatly extended the scope and utility of this reagent.

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N o t e a d d e d in p r o o f ( F e b r u a r y 2 1 , 1 9 8 3 ) While this review was in press, an important contribution to the subject matter was published by S. W. Heinzman and B. Ganem, J. Am. Chem. Soc., 104 (1982) 6801 who have initiated studies on the mechanisms of sodium borohydride-cobaltous chloride reductions. Their communication indicates that preformed cobalt boride used in catalytic amounts (10 mol%), based on the substrate (benzonitrile, methylcinnamate, and 1-octyne) followed by portionwise addition of NaBH4 in CHsOH, afforded good yields of the reduced substrate. Among the possible mechanisms considered is the surface generation of transient quantities of highly reactive BH3. When tert-butylamine borane, a reagent normally inert to nitriles was combined with benzonitrile and an equivalent of Co2B, benzylamine was produced in high yield. A large excess of the amine borane was not required since it decomposed only sluggishly during reduction. The complete mechanism of the CoC12-NaBH4 reducing system remains to be explained.