Gordon W. Gribble- Sodium borohydride in carboxylic acid media: a phenomenal reduction system

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O

Ph

O

B

AcO OAc

H

–

H

NH

H

NH

NH

N

CH2CH3

NH

N

CH2CH3

34

+

7

NaBH4

NaBH4

HOAc

86%

NaBH3CN

HOAc

NaBH4

HOAc

88%

94%

5

5 6

HOAc

86%

NH

N

N

CH2CH(CH3)2

N

CH2CH2CH3

CH3

NaBH4

49%

53%

(CH3)2CHCO2H

NaBH4

69%

CH3CH2CO2H

NaBH4

HCO2H

3

Sodium borohydride in carboxylic acid media: a phenomenal

reduction system

Gordon W. Gribble

Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA

The union of sodium borohydride and carboxylic acids hasyielded an amazingly versatile and efficient set of reducingreagents. These acyloxyborohydride species reduce and

N -alkylate indoles, quinolines, isoquinolines, relatedheterocycles, imines, enamines, oximes, enamides, andsimilar functional groups. They reduce amides and nitriles,aryl alcohols and ketones, aldehydes in the presence of ketones, and b-hydroxyketones to 1,3-diols stereoselectively.This reagent is also extraordinarily useful for the

N -alkylation of primary and secondary amines with alde-hydes and ketones in a novel reductive amination process.

1 Introduction

Like an artist without paint, the synthetic chemist is impotentwithout the necessary chemical reagents to synthesize mole-cules of interest. As synthetic targets increase in complexity, somust the tools of the chemist increase in efficiency andselectivity. The present article summarizes the enormous rangeof chemical transformations available through the use of therelatively new reagent combination of sodium borohydride incarboxylic acids, leading to the generation of sodium acylox-yborohydrides [eqns. (1) and (2)]. The less reactive sodiumtriacyloxyborohydrides 1 form with 3 equivalents of a car-boxylic acid (or excess), and the more reactive sodiumacyloxyborohydrides 2 form with one equivalent of a carboxylic

acid.1,2

NaBH4 + 3RCO2H ––? NaBH(OCOR)3 + 3H2 (1)

NaBH4 + RCO2H ––? NaBH3OCOR + H2 (2)

Following a report by Marshall and Johnson on the compati-bility of NaBH4 and acetic acid (HOAc) in the reduction of enamines,3 we investigated this unlikely chemical combinationas a possible new indole (3) reduction method. Surprisingly, notonly is the indole double bond rapidly and efficiently reduced,presumably via indolenium ion 4, but the nitrogen is alkylatedby the acetic acid solvent to afford N -ethylindoline (6) (Scheme1).4 Further study of this novel transformation revealed that the

N -alkylation can be circumvented using NaBH3CN–HOAc toafford indoline (5) in essentially quantitative yield.4,5

These fascinating results sparked our further studies withthe NaBH4–RCO2H reagent system, an odyssey that hascontinued for 25 years and has led to an extraordinarilyversatile, unique, and efficient set of reducing agents.1,2

Throughout this presentation uncited reactions can be found inthe reviews.1,2

2 Chemistry of acyloxyborohydrides

2.1 Reduction of indolesThe reduction and N -alkylation of indoles with NaBH4–RCO2Hto give N -alkylindoles (Scheme 2)4 and the reduction of indoleswith NaBH3CN–HOAc to give indolines are quite generalGordon W. Gribble was born in San Francisco, California, and

received his undergraduate training at the University of California, Berkeley. He obtained his PhD at the University of Oregon with Lloyd J. Dolby in 1967, and did postdoctoral

research at the University of California, Los Angeles, withFrank A. L. Anet. Professor Gribble has been at Dartmouthsince 1968. In addition to hisresearch program on hetero-cyclic chemistry and natural

product synthesis, he has a fascination with naturally oc-curring organohalogen com-

pounds, and he has published more than 160 papers in theseareas. As an amateur wine-maker, he also has a stronginterest in the chemistry of wineand winemaking.

Scheme 1

Scheme 2

Chemical Society Reviews, 1998, volume 27 395



NH

MeO

CO2Me

NH

HN

EtO2C

NH

Me

N

CO2Et

HN OTMS

O

MeO

MeO

NH

NH

N

N

N

Et

Me

Me

BnO2C

OMe

OBn

NO

NH

NH

NH

OBn

OMe

H

H

NH

CO2Me

MeO

O2N

11 (0%)

98%

9 (96%)

98%

10 (61%)75%

8 (0%)

(3)

N

H

N

Me

N

H

NH

N

Me

NH

HOAc

CF3CO2H (3:1)

NaBH3CN

1271%

13

HOAc 10 °C

15 minNH

N

HN

O

PhCl

Ph

OHN

HNNH

Cl

NH

NN

NH

H

H

H

90%

CF3CO2H

0 °C

NaBH4

(4)

(5)

14 15

16

NaBH3CN

3

18 (13%)

+

NH

NH

N

CH2CF3

N

CH2CF3 CH2CF3

N

CF3

NaBH4

CF3CO2H

rt → ∆

+

5 (40%) 17 (5%) (6)

NH2

NHEt NEt2

NHCH2Ph

Ni –PrEt

NHCH2C(CH3)3 NCH2PhEt

HNi –Pr

Nn –PrEt

80%

1. PhCHO2. NaBH4

HOAc50–60 °C

80%NaBH4

Me3CCO2H40–45 °C50-55 °C

79%

1. acetone2. NaBH4

HOAc69%

NaBH4

HOAc50–55 °C

68%

1. acetone2. NaBH4

HOAc

20 °C

1. PhCHO2. NaBH

4HOAc

74%

50–60 °C

NaBH4

HOAc

88%NaBH4

HOAc20 °C

NaBH4

EtCO2H

50 °C

70%

processes. The latter reaction is the preeminent method forreducing the indole double bond, provided that electron-withdrawing groups are not present to retard the initial indoleprotonation (i.e., 3?4). Thus, an indole double bond containingan ester group at C-2 or C-3 (8–10) is inert to the action of NaBH3CN–HOAc. Likewise, 5-nitroindole is not reduced to 11under these conditions. Such selectivity has been of great utilityin the synthesis of the antitumor agent CC-1065 and analogues.However, at higher temperatures one may encounter

N -ethylation with NaBH3CN–HOAc.

A remarkable illustration of the selectivity of this indolereduction method is seen in 12 ? 13 [eqn. (3)],6 in which theprotonated basic nitrogen presumably prevents a secondprotonation of the proximal indole double bond.

Generally, compounds containing a basic nitrogen atom, suchas the ubiquitous indolo[2,3-a]quinolizidine alkaloids (e.g., 14),can only be reduced using NaBH4 in trifluoroacetic acid (TFA)[eqn. (4)].4,7 Thus, only the imine and not the indole bond in 16is reduced with NaBH3CN–HOAc [eqn. (5)].

Under the influence of NaBH4–TFA, indole (3) is convertedto a mixture of indoline (5), N -trifluoroethylindoline (17), andthe Baeyer condensation product 18 [eqn. (6)].8

2.2 N -Alkylation of aminesOur observation that NaBH4–HOAc gives N -ethylation of indoline (5) (Scheme 1) led us to explore the scope of thisunprecedented amine N -alkylation reaction. Reactions of ani-line with NaBH4–RCO2H are shown in Scheme 3.4 One can

effect mono- or dialkylation, depending on the temperature,and, thus, achieve the conversion of a primary amine to an

unsymmetrical tertiary amine in one pot. The reductiveamination of added aldehydes or ketones increases the versatil-ity of the method. Pivalic acid affords N -neopentylaniline in80% yield. Similar chemistry is observed with benzylamine andother aliphatic amines.9

Control experiments revealed that the mechanism of this N -alkylation does not involve reduction of a precursor amide,4 andgas evolution measurements and isolation studies10 indicatedthat the borohydride species formed under these conditions of excess acetic acid is NaBH(OAc)3 (1, R = Me) [eqn. (1)].Furthermore, we were able to isolate the 2,4-DNP derivative of acetaldehyde from the evolved gases of the reaction of NaBH 4

with glacial HOAc. Therefore, we believe that the NaBH(O-COR)3 species undergoes self-reduction to free aldehyde (or asynthetic equivalent) which then reacts with the amine in a

typical reductive amination sequence (Scheme 4).

Scheme 3

396 Chemical Society Reviews, 1998, volume 27



O OH

H B(OCOR)3

O

– –

R—C—O

HO2CR

R—C—O

:

R—C—H

amines reduction

N -alkylation RCH2OHtrapped as

2,4-DNP

ester formation

H—B(OCOR)2

(R = CH3, CF3)

O NH2

NO2

HN

NO2

NH

NH2

O

O O

NH

HN

O

O

CHO

Ph PhHN CO2Me

+

NaBH(OAc)3

HOAc

ClCH2CH2Cl

23 h

66%

NaBH(OAc)3

87%+

NaBH(OAc)3

CH2Cl2

80%H2NCH2CO2Me

HOAc

ClCH2CH2Cl

+

52%59%

NaBH3CN

HOAc71%

NaBH4

HOAc

68%

NaBH3CNHOAc

acetone

NaBH4

HCO2H

50 °C, 1 h

N

NH

N

CH2CH3

N

CH3

N

N N

N

NH

N

HN

75%

CF3CO2H

75%

CF3CO2H

+

NaBH4

Ph

MeMe O

N

SO2Ph

N

SO2Ph

OMe Me

Ph

THF rt

NaBH3CN

NaBH4

(7)

HOAc

40 ˚C

99%

(8)

(9)

(10)

anti/syn : 95 : 5

95%

–35 ˚C

CH3CN HOAc

Me4NBH(OAc)3

N

OH

OBn

NH

OBn

OH

Using the isolated reducing reagent NaBH(OAc)3, Abdel-Magid has extended this amine N -alkylation method into apowerful, general reductive amination protocol for aldehydesand ketones.11 Some recent examples are shown in Scheme5.11–13

Obviously, these amine N -alkylations (reductive aminations)succeed because NaBH(OAc)3 only slowly reduces aldehydesand ketones relative to the rapid reduction of iminium andimmonium ions.

2.3 Reduction of other heterocyclesThe facile reduction of indole (3) (Scheme 1) with NaBH4–RCO2H portended that other nitrogen-containing heterocyclesthat are susceptible to protonation would undergo a similarreduction/alkylation sequence. Indeed, quinolines, isoquino-lines, acridines, quinazolines, quinoxalines, phthalazines, pter-idines, benzoxazines, adenines, some pyrroles, and pyryliumsalts are reduced by NaBH4–RCO2H.1,2 More aromatic pyr-idines are normally unaffected by NaBH4–RCO2H. Illustrativeof the versatility of this methodology is the chemistry shown in

Scheme 6 involving quinoline.14

2.4 Reduction of imines, enamines and relatedcompoundsA wide range of imines, enamines, enamides, vinylogousamides, and carbamates can be reduced using NaBH4–RCO2H(Scheme 7).

2.5 Reduction of oximesOximes are reduced and reductively alkylated with NaBH3CN–HOAc and NaBH4–RCO2H, respectively (Scheme 8).15

Whereas at room temperature cyclohexanone oxime is reducedto cyclohexylhydroxylamine with NaBH4–HOAc, at highertemperatures the reaction proceeds to afford N , N -diethylcy-clohexylamine.

Similarly, oxime ethers are reduced to O-alkylated hydrox-ylamines under these conditions. Such an example involving ahydroxy-directed reduction is illustrated in eqn. (10).

Scheme 4

Scheme 5

Scheme 6

Some additional examples are shown below [eqns. (7)–(9)].




O

N

F

F

Me

N CO2

O O i -Bu

BHNa

F

F

NH

O

N

MeO2C Cl

N

CN

Br

H H

Br N

ClCO2Me

NH

N

OMe

OMe

BnN

Bn

OMe

OMe

S NHBn

O

S

O

NHBn

EtO

O NHBn NHBnO

EtO

NO

Ph

NO

N (CH2)10CH3 N

TsTs

(CH2)10CH3

ONH

N

MeO2C

O

MeO2C

H

NNH H

Ph

+

HOAc

10 ˚C

89%

(+ 3% trans )56%

HOAc

MeCN rt

NaBH3CN

(+ aziridine)

45%

NaBH(OAc)3

CF3CO2H

NaBH3CN

95% ee

92%

-40 ˚C → -5 ˚C

CH2Cl2

3

(+ trans , 1 : 1)

76%

CH2Cl2TFA -45 ˚C

NaBH3CN

+

–

NaBH4

HOAc

THF 20 ˚C

62%

–

90%

HCO2H

NaBH3CN

(22% cis )

90%

HOAc

10 ˚C

NaBH4

NOH

NHOH

NEtEt

NPr Pr

30%

50 °CCH3CN

CH3CH2CO2H

NaBH4

46%45 °C

CH3CN

HOAc

NaBH4

81%

20 °C 3 h

HOAc

NaBH3CN

20 °C 3.5 h

NaBH4

HOAc

63%

NHH

O

OMe

MeO

BOC NH

HNH

MeO

OMe

HN

HN BOC

O

HN BOC

HN

NH

BOC

HN

NH

O

O

NH

HN

N

O

O

Ph

OH

N

O

O O

O OH

Ph

O

OH

HN

OHO

O

HN

OHHO

OH

O

O2S

HN

Ph

O2S

HN

Ph

O

NN

O

NN

H

NaBH3OCOCF3

65%

THF

20 °C

97%

NaBH4

NaBH4

100 °C 66%

TFA dioxane

HOAc

dioxane

HOAc

MeCN

25 °C

Me4NBH(OAc)3

> 98% de63%

73%

TFA THF

NaBH4

82%

dioxane

NaBH3OCOCF3

90%

CF3CO2H

dioxane ∆

NaBH4

2.6 Reduction of amides to aminesAlthough NaBH(OCOR)3 (1) does not reduce amides, Uminodiscovered that NaBH3OCOR does reduce amides and lactamsto the corresponding amines.16 Some examples of this usefulreaction are listed in Scheme 9. Note that carbamates andsultams are unaffected by these conditions. Interestingly, theindole double bond in the last example is not reduced.17

2.7 Reduction of nitriles to primary aminesUmino also discovered that NaBH3OCOR, particularly NaB-

H3OCOCF3, reduces nitriles to primary amines.18 A selection of

examples is shown in Scheme 10. Noteworthy is that thisreduction reaction occurs in the presence of nitro and 1,2-ox-

azine functionalities.

Scheme 7

Scheme 8

Scheme 9




N

N

Me

CN

NO2

Cl Cl

NO2

N

NMe

NH2

CH3

NO2BnO

CN

BnO NO2

CH3

NH2

F

CN

F

F

F

F

F

F

F

F

F

NH2

Ar

O O

O

OO

Ar

CN CH2NH2

Ar

OO

O

OO

Ar

N

O

CN

CO2BnN

CO2Bn

CH2NH2

O

Ar = p -tolyl

NaBH3OCOCF3

THF rt

48%

70%

THF rt

NaBH3OCOCF3

67%

THF rt

NaBH3OCOCF3

NaBH3OCOCF3

THF rt

70%

57%

THF 10-15 °C

NaBH3OCOCF3

15-20 °C

CF3CO2H

NaBH4

OH

CF3CO2H

93%

COH

3

94%

15-20 °C

NaBH4

21

15–20 °C

CF3CO2H

NaBH4

OH

+

93% (11)

19 20

O

OH

I

I

O

NEt2

NEt2

O

I

I

O

S O

OH

OS

(12)

(13)

Et2O rt

CH2Cl2 rt

NaBH4

CF3CO2H

86%

CF3CO2H

NaBH4

68%

N

OHPhPh

N

N

O

OH OH

N

MeS MeS

NaBH4

CF3CO2H

major (87:13)

90%

NaBH3OCOCF3

THF4 h

>75%

(14)

(15)

TFA

CH2Cl2

20 °C

100%

NH N

HNN

HO

N HN

NNH

(16)NaBH4

2.8 Reduction of alcohols to hydrocarbonsEarly in our studies we thought that NaBH4–CF3CO2H (TFA)might serve to reduce certain alcohols to hydrocarbons, in viewof the propensity of TFA to stabilize carbocations. Indeed, thisreagent combination provides an efficient and general methodfor reducing di- and triarylcarbinols to di- and triarylmethanes(Scheme 11).19 Other alcohols, unless the derived carbocation is

highly stabilized, are not reduced cleanly under these condi-tions.19

In the case of carbinol 19, the intermediate carbocation 20 isambushed by the o-phenyl group prior to reduction, affordingonly 9-phenylfluorene (21) [eqn. (11)].19

The generality and selectivity of this reduction method isillustrated by the examples in eqns. (12)–(16). The che-moselectivity exhibited by NaBH(OCOCF3)3 vis-a-vis NaB-H3OCOCF3 in eqns. (14)–(15) is remarkable.

2.9 Reduction of ketones to hydrocarbonsDiarylketones are smoothly reduced to diarylmethanes with

NaBH4–TFA.20 As we have seen, a wide range of functional

Scheme 10

Scheme 11




98%

25 °C

AlCl3 CH2Cl2N

SO2Ph

O

N

CH3

SO2Ph

N

CH3

SO2Ph

Fe

Ac2O

CO2H

99%

Fe

CF3CO2H

CO2H

15 °C → 25 °C

O

NaBH4

(18)

NaBH4

90%

CF3CO2H

CH2Cl2

rt

(17)

O

O OH

O

O

O

Bn

O

O

O

93%

(19)

69%

O

O

Bn

O

O

NaBH4

CF3CO2H

CH2Cl2 CH3CN

(20)

CF3CO2H

CH2Cl2

NaBH4

(21)NaBH3CN

HOAc rt

85%

S

S

O

S

S

OHO

O Cl

Cl

CO2Et CO2Et

Cl

Cl

HO O

O

R R

N

N

CO2Me

CO2Me

Me

O O

N

N

CO2Me

CO2Me

OHC

O O

9343 (+57% alcohol)

R % yield

CNNMe2

NHPhCO2H

CO2MeNO2

90829373

92898890

8294

HMeOMeOH

FBr

R % yield

15-20 °C

CF3CO2H

NaBH4

NaBH4

CF3CO2H

CH2Cl2

89%

CF3CO2H

THF

NaBH4

66%

NaBH3CN

CF3CO2H

60%

groups will tolerate these reaction conditions (Scheme 12). Themechanism presumably involves reduction to the diaryl-methanol, solvolysis to the carbocation, and reduction to thehydrocarbon. Only in the case of strong electron-withdrawinggroups (e.g., p-NO2) is the reaction incomplete. The lastreaction appears to be the first reduction of a formyl group to amethyl group using this methodology.

This method provides for a very useful synthesis of 3-alkylindoles [eqn. (17)] and alkyl-substituted ferrocenes [eqn.(18)].21

The combination of NaBH4–TFA converts enones to alkenes[eqns. (19) and (20)],22,23 and isopropylidene acylmalonates,5-acylbarbituric acids, and 3-acyl-4-hydroxycoumarins are allreduced to the corresponding methylene derivatives with

NaBH3CN–HOAc [e.g.,

eqn. (21)].

2.10 Reductive cleavage of acetals, ketals, ethers, andrelated compoundsThe action of NaBH4–TFA serves to reductively cleave avariety of acetals, ketals, ethers and ozonides as summarized in

Scheme 13.24–26 The deoxygenation of 1,4-epoxy-1,4-dihy-

droarenes is particularly useful for the synthesis of polycyclicaromatic hydrocarbons.

2.11 Alkylation of arenes (Baeyer condensation)

As noted earlier, indole (3) with NaBH4–TFA gives some of theBaeyer condensation product 18 [eqn. (6)]. Indeed, thisalkylation reaction of arenes, involving the generation of trifluoroacetaldehyde, is reminiscent of the synthesis of DDTfrom chlorobenzene, trichloroacetaldehyde (chloral), and sulfu-ric acid. We have found that several arenes give analogousproducts under these conditions (Scheme 14).27 Congestedarenes like durene and mesitylene stop at the carbinol stage.

2.12 Selective reduction of aldehydesThe reduction of aldehydes and ketones to alcohols is one of themost important reactions in organic chemistry. Although manyreagents are available for this reaction, few are chemoselectivefor aldehydes and such methods are in great demand.

From the beginning of our work in this area, it was clear that

aldehydes and, especially, ketones were reduced relativelyslowly by these acyloxyborohydrides. Indeed, this is preciselywhy the N -alkylation of amines works! Thus, althoughbenzaldehyde is completely reduced to benzyl alcohol after 1hour at 15 °C with a large excess of NaBH4 in glacial aceticacid, acetophenone is only reduced to the extent of 60% at 25 °Cafter 40 hours! By comparison, in alcoholic solution bothreductions are complete in seconds. These and related observa-tions paved the way for the chemoselective reduction of aldehydes in the presence of ketones.10,28 The isolated reagentsNaBH(OAc)310 and n-Bu4NBH(OAc)328 work extremely welland some examples with the latter reagent are depicted inScheme 15.28

Some additional examples with NaBH(OAc)3 are listed ineqns. (22)–(25). Notable is the selective reduction of the

aldehyde in the presence of a trifluoromethyl ketone [eqn. (24)]

Scheme 12




CH3

CH3

O

OO

OOH

O

MeO

MeO

Cl Cl

MeO

MeO

OH

F

CH3

CH3

Br

N

PhO2S

OO

N

PhO2S

CH3

CH3

NH

CH3

CH3

F

F F

F CH3

CH3

O

O

O OBn

BnO NHAc

Ar O

O

HO OBn

BnO NHAc

Ar

O

OO

n -C5H11

n -C5H11

O

n -C5H11

n -C5H11

38%

NaBH4

NaBH4

TFA THF

20 °C

83%

TFA

0-5 °C

92%

TFA THF

15 °C

NaBH4

NaBH3CN

CF3CO2H

DMF

84%

Ar = p -Methoxyphenyl

77%

2. NaOH

1. NaBH4 –TFA

93%

Mg

CF3CO2H

CH2Cl2

33%

NaBH4

O

O

OH

O

O

OCHO

O

NCF3

HO

OCH3

O

O

OHO

NCF3

OHC

OCH3

PhH rt

83%

(22)

O

O H

CHO

CHO

NaBH(OAc)3

HOAc PhH

∆ 76%

NaBH4

HOAc PhH

∆

(23)

O

O H

CHO

95%

(24)

PhH

NaBH(OAc)3

OH

67%

(25)

NaBH(OAc)3

PhCHO

O O

Ph

O

B

AcO OAc

H

OH

Ph OH

22 23

–

(26)

48%65%

78%

53%

O

CF3

O

OMe

CF3

OMe

CF3

MeMe

Me CF3 Me

Arene + NaBH4 –CF3CO2H

and the selective reduction of the less sterically encumberedaldehyde in a dialdehyde [eqn. (25)].29

2.13 Hydroxy-directed reduction of ketonesDuring our study of the chemoselective reduction of aldehydesin the presence of ketones, we observed the reduction of ketoaldehyde 22 to diol 23, presumably involving internalhydride delivery as shown in eqn. (26).28

Saksena independently discovered this same reaction andobserved excellent stereoselectivities in the reduction of steroidal b-hydroxy ketones. Evans thoroughly explored thescope of this powerful methodology and he fully characterized

several BH(OAc)3 species for the first time.30 In the intervening

ten years a very large number of hydroxy-directed carbonylreductions using triacetoxyborohydride have been descri-bed.2a,30 A few examples are shown in Scheme 16. Severala-hydroxyketones have also been reported to undergo thisintramolecular reduction.

Scheme 13

Scheme 14




O

H

O

OH

CHOO CH3 CH3O

CH2OH

CHO

O O

OH

+

excess

n -Bu4NBH(OAc)3

PhH+

recovered

ketone

+

excess

n -Bu4NBH(OAc)3

PhH+

95% 96%

excess

n -Bu4NBH(OAc)3

77%

PhH

96% 94%

OH O OHOH

MeOOTIPS

O O OH OHOHO

OTIPSMeO

NO

O O O OH

Bn Bn

OHOHOO

NO

OH

OBOM

O

O

O

OH

O

OH

O

OH

OBOM

OH

OH

O

O

BnO

N

O

EtO2C

BnO

O

O N

EtO2C

OH

OH

O OBn

OMe

OH OH

OOH

OMe

OBnO

75%

Me4NBH(OAc)3

> 99:181%

HOAc MeCNrt

Me4NBH(OAc)3

98:2 anti/syn

13:1 anti/syn

Me4NBH(OAc)3

HOAc MeCN-40 °C

93%

92%

HOAc MeCN-20 °C

Me4NBH(OAc)3

97% ds

84%

HOAc MeCN-20 °C

Me4NBH(OAc)3

82%

rt

HOAc CH2Cl2

NaBH(OAc)3

1. NaBH4

HOAc

85%

2. PCC

1. NaBH3OAc

67%

2. NaOMe CHCl3

3. H2O2, OH –

1. NaBH3OAc

89%

2. H2O2, OH –

1. NaBH3OAc

83%

2. H2O2, OH –

OH

OTMS OTMS

OH

O

O

NaBH4

CF3CO2H

0 °C

93%

(27)

Ph

O

Ph

OH

Ph

O

NaBH3OAc

THF 25 °C

70%

+

CHO

96% 4%

(28)

NaBH3OAc CH2OH

THF 25 °C

CHO

86%

(29)

99% 1%2.14 Hydroboration of alkenesOne of the first applications of the NaBH4–HOAc reagentsystem was the hydroboration of alkenes as described byMarshall and Johnson.3 The actual reagent is the more reactive

NaBH3OAc, which can also be generated from NaBH4 and

Hg(OAc)2. Some examples of alkene hydroboration are listed inScheme 17.

2.15 Miscellaneous reductionsAlkenes that yield stable carbocations upon protonation can bereduced to alkanes with NaBH4–TFA [eqn. (27)],19 but suchexamples are exceedingly rare. It seems likely that NaBH4–CF3SO3H may work in this regard with other alkenes.

Enones and enals give primarily 1,2-reduction with NaB-H3OAc [eqns. (28) and (29)]. Small amounts of the 1,4-reduc-tion products were also found.

Twenty years ago we observed that both 1- and 2-naphtholyielded 10–20% naphthalene upon treatment with NaBH4–TFA

(Scheme 18). In fact, when the crude reaction products were

Scheme 15

Scheme 16

Scheme 17




OH OH OH

NaBH4

CF3CO2H

rt

+

–H2O

10%

NaBH4

CF3CO2H

rt

OH

20%

(30)

O

O

O

O

O

O

Me

Me

O

O

NaBH4

CF3CO2H

72%

NaBH4

CF3CO2H

23%

NaBH4

CF3CO2H

CF3CO2H

12%

57%

NaBH4

(31)

NaBH4

BOCHN

CO2Me

HN BOC

OH

HOAc

dioxane

80 °C

90%

NaBH4

HOAcdioxane

80 °C

98%

FMOCHN

CO2Me

HN FMOC

OH

(32)

CON3

Cl

N(CH2CF3)2

Cl

NaBH4

CF3CO2H

(F3CH2C)2N

CF3

N(CH2CF3)2

rt

91%

(33)

24

CO2Me

OMe

HgOAc

CO2Me

OMe

H

CO2Me

OMe

H

OH

NaBH(OAc)3

OAc

THF 0 °C

82%

(34)+

80% 20%

NaBH4

HOAc

∆ 95%

(35)

CH2OH

SAcNaBH4

HOAc

∆

O2N

95%

CH2OCOEtNaBH4

O2NEtCO2H

∆

SH

90%

(36)

(37)

NaBH4

EtCO2H

NH2 NHCOEt

∆ 95%

(38)

allowed to stand undisturbed for six months, pure naphthalenehad sublimed onto the upper part of the flask. Presumably thistransformation involves ring protonation, carbonyl reduction,and dehydration.

More recently this novel deoxygenation of phenols has beenreported for a hydroxyphenanthrene [eqn. (30)].31

These results are consistent with our earlier observations that9,10-phenanthrenequinone and 2-methyl-1,4-naphthoquinoneundergo reduction to the corresponding aromatic hydrocarbonsalbeit in low yield (Scheme 19).1

Esters are not normally reduced to primary alcohols by

NaBH4–CO2H, but such a reduction is observed at highertemperatures in the case of amino acid and peptide esters [eqns.(31) and (32)].32 Importantly, racemization is not seen.

In view of the facile reduction of carboxylic acids toaldehydes with NaBH4 in the course of the reductive aminationsequence (vide supra), it is not surprising that completereduction to primary alcohols has been found (Scheme 20).

Turnbull has recently described the reduction and subsequent N -trifluoroethylation of aroyl azides with NaBH4–TFA [eqn.(33)].33 The parent compound yielded the Baeyer condensationproduct 24 in 87% yield.

Organomercurials can be reduced to alkanes with NaB-H(OAc)3 [eqn. (34)],34 and the NaBH(OCOR)3 reagents canalso acylate alcohols, phenols, and thiophenols [eqns.(35)–(38)], presumably by direct acylation of an

acyloxyborohydride intermediate.

Scheme 18

Scheme 19




78%

NaBH4

TFA THF

25 ˚C

90%

THF

NaBH4

CO2HOH

MeO (CH2)8CO2H

O O

(CH2)9OHMeO

NaBH4

RCO2H

Indole reduction

Quinoline, Isoquinolinereduction

Arene alkylation

Amide andnitrile reduction

Oximereduction,

alkylation

Aryl carbinol reductionAminealkylation

Selective aldehydereduction

β-Hydroxyketonereduction

Acetal, ketalreductivecleavage

3 Concluding remarks

As summarized in Scheme 21 the combination of NaBH4–RCO2H, leading to acyloxyborohydrides, is a remarkablyversatile and unique chemical system. These chemical specieshave emerged as the preeminent reagents of choice for a wide

spectrum of chemical transformations. The ability to controlchemoselectivity, regioselectivity, and stereoselectivity byadjusting the carboxylic acid, borohydride reagent, stoi-chiometry, and temperature has no parallel in the repertoire of the organic chemist. Nevertheless, much work remains to bedone with acyloxyborohydrides, particularly with regard tounderstanding the mechanisms of some of the reactions, inapplying these reagents to asymmetric synthesis, and inuncovering new applications.

4 Acknowledgements

I am especially grateful to my many co-workers on this projectover the past 25 years. In particular, graduate students JerrySkotnicki at the beginning and Charlie Nutaitis in later years.But, my deepest appreciation goes out to the many Dartmouthundergraduates who explored and developed much of thechemistry presented here. These include Steve Dietz, DuncanFerguson, Peter Heald, Bud Leese, Myles Sheehan, Joe

Hoffman, Sandy Emery, Joe Jasinski, John Pellicone, and SteveWright. Thank you all.

5 References

1 For a review and historical background on acyloxyborohydrides, see:G. W. Gribble and C. F. Nutaitis, Org. Prep. Proc. Int., 1985, 17,317.

2 For recent reviews of the synthetic utility of acyloxyborohydrides, see:(a) G. W. Gribble, in Reductions in Organic Synthesis, ed. Ahmed F.Abdel-Magid, ACS Symposium Series 641, American Chemical

Society, Washington, DC, 1996, pp. 167–200; (b) G. W. Gribble,Chemtech, 1996, 12, 26.3 J. A. Marshall and W. S. Johnson, J. Org. Chem., 1963, 28, 421.4 G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T. Eaton and

J. L. Johnson, J. Am. Chem. Soc., 1974, 96, 7812.5 G. W. Gribble and J. H. Hoffman, Synthesis, 1977, 859.6 M. Somei, F. Yamada and H. Morikawa, Heterocycles, 1997, 46, 91.7 G. W. Gribble, J. L. Johnson and M. G. Saulnier, Heterocycles, 1981,

16, 2109.8 G. W. Gribble, C. F. Nutaitis and R. M. Leese, Heterocycles, 1984, 22,

379.9 G. W. Gribble, J. M. Jasinski, J. T. Pellicone and J. A. Panetta,

Synthesis, 1978, 766.10 G. W. Gribble and D. C. Ferguson, J. Chem. Soc., Chem. Commun.,

1975, 535.11 A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and

R. D. Shah, J. Org. Chem., 1996, 61, 3849.

12 J. Quirante, C. Escolano, A. Merino and J. Bonjoch, J. Org. Chem.,1998, 63, 968.

13 J. Cossy and D. Belotti, J. Org. Chem., 1997, 62, 7900.14 G. W. Gribble and P. W. Heald, Synthesis, 1975, 650.15 G. W. Gribble, R. W. Leiby and M. N. Sheehan, Synthesis, 1977,

856.16 N. Umino, T. Iwakuma and M. Itoh, Tetrahedron Lett., 1976, 763.17 A. Padwa, S. R. Harring and M. A. Semones, J. Org. Chem., 1998, 63,

44.18 N. Umino, T. Iwakuma and N. Itoh, Tetrahedron Lett., 1976, 2875.19 G. W. Gribble, R. M. Leese and B. E. Evans, Synthesis, 1977, 172.20 G. W. Gribble, W. J. Kelly and S. E. Emery, Synthesis, 1978, 763.21 S. Bhattacharyya, J. Chem. Soc., Perkin Trans. 1, 1996, 1381.22 M. Beckmann, T. Meyer, F. Schulz and E. Winterfeldt, Chem. Ber.,

1994, 127, 2505.23 V. H. Rawal, A. Fabre and S. Iwasa, Tetrahedron Lett., 1995, 36,

6851.24 C. F. Nutaitis and G. W. Gribble, Org. Prep. Proc. Int., 1985, 17, 11.25 G. W. Gribble, W. J. Kelly and M. P. Sibi, Synthesis, 1982, 143.26 G. W. Gribble, M. G. Saulnier, M. P. Sibi and J. A. Obaza-Nutaitis,

J. Org. Chem., 1984, 49, 4518.27 C. F. Nutaitis and G. W. Gribble, Synthesis, 1985, 756.28 C. F. Nutaitis and G. W. Gribble, Tetrahedron Lett., 1983, 24, 4287.29 G. Stork, F. West, H. Y. Lee, R. C. A. Isaacs and S. Manabe, J. Am.

Chem. Soc., 1996, 118, 10 660.30 D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem. Soc.,

1988, 110, 3560.31 A. K. Banerjee, J. C. Acevedo, R. Gonzalez and A. Rojas, Tetrahedron,

1991, 47, 2081.32 M. Soucek, J. Urban and D. Saman, Collect. Czech. Chem. Commun.,

1990, 55, 761.33 D. M. Krein, P. J. Sullivan and K. Turnbull,Tetrahedron Lett., 1996, 37,

7213.

34 F. H. Gouzoules and R. A. Whitney, J. Org. Chem., 1986, 51, 2024.

Received 16th June 1998 Accepted 26th June 1998

Scheme 20

Scheme 21


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Gordon W. Gribble- Sodium borohydride in carboxylic acid media: a phenomenal reduction system