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AcO

Sodium borohydride in carboxylic acid media: a phenomenal reduction system


Ph

OAc

H O O

Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA

The union of sodium borohydride and carboxylic acids has yielded an amazingly versatile and efficient set of reducing reagents. These acyloxyborohydride species reduce and N-alkylate indoles, quinolines, isoquinolines, related heterocycles, imines, enamines, oximes, enamides, and similar 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 aldehydes and ketones in a novel reductive amination process. 1 Introduction Like an artist without paint, the synthetic chemist is impotent without the necessary chemical reagents to synthesize molecules of interest. As synthetic targets increase in complexity, so must the tools of the chemist increase in efficiency and selectivity. The present article summarizes the enormous range of chemical transformations available through the use of the relatively new reagent combination of sodium borohydride in carboxylic acids, leading to the generation of sodium acyloxyborohydrides [eqns. (1) and (2)]. The less reactive sodium triacyloxyborohydrides 1 form with 3 equivalents of a carboxylic acid (or excess), and the more reactive sodium acyloxyborohydrides 2 form with one equivalent of a carboxylic acid.1,2 NaBH4 + 3RCO2H ? NaBH(OCOR)3 + 3H2 NaBH4 + RCO2H ? NaBH3OCOR + H2 (1)

Following a report by Marshall and Johnson on the compatibility of NaBH4 and acetic acid (HOAc) in the reduction of enamines,3 we investigated this unlikely chemical combination as a possible new indole (3) reduction method. Surprisingly, not only is the indole double bond rapidly and efficiently reduced, presumably via indolenium ion 4, but the nitrogen is alkylated by the acetic acid solvent to afford N-ethylindoline (6) (Scheme 1).4 Further study of this novel transformation revealed that the N-alkylation can be circumvented using NaBH3CNHOAc to afford indoline (5) in essentially quantitative yield.4,5
H
NaBH4

H
+ N H 4

3 94%

N H

HOAc 86%

N H
5

NaBH3CN HOAc NaBH4 NaBH4

N H
5

HOAc 88% 6

N CH2CH3

HOAc 86% 7

N CH2CH3

Scheme 1

(2)

These fascinating results sparked our further studies with the NaBH4RCO2H reagent system, an odyssey that has continued for 25 years and has led to an extraordinarily versatile, unique, and efficient set of reducing agents.1,2 Throughout this presentation uncited reactions can be found in the reviews.1,2 2 Chemistry of acyloxyborohydrides 2.1 Reduction of indoles The reduction and N-alkylation of indoles with NaBH4RCO2H to give N-alkylindoles (Scheme 2)4 and the reduction of indoles with NaBH3CNHOAc to give indolines are quite general
NaBH4 HCO2H N CH3

Gordon 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, with Frank A. L. Anet. Professor Gribble has been at Dartmouth since 1968. In addition to his research program on heterocyclic chemistry and natural product synthesis, he has a fascination with naturally occurring organohalogen compounds, and he has published more than 160 papers in these areas. As an amateur winemaker, he also has a strong interest in the chemistry of wine and winemaking.

53%

NaBH4 N H 3 NaBH4 (CH3)2CHCO2H N CH3CH2CO2H N CH2CH2CH3

69%

49%

CH2CH(CH3)2

Scheme 2

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processes. The latter reaction is the preeminent method for reducing the indole double bond, provided that electronwithdrawing groups are not present to retard the initial indole protonation (i.e., 3?4). Thus, an indole double bond containing an ester group at C-2 or C-3 (810) is inert to the action of NaBH3CNHOAc. Likewise, 5-nitroindole is not reduced to 11 under these conditions. Such selectivity has been of great utility in the synthesis of the antitumor agent CC-1065 and analogues. However, at higher temperatures one may encounter N-ethylation with NaBH3CNHOAc.
CO2Me MeO N H 98% H O N H H 98% Me N Et N N Me N BnO2C N H O OBn OMe N H MeO MeO HN O TMS CO2Et N Me O2N N H 11 (0%) NH OBn OMe MeO N H 8 (0%) 9 (96%) CO2Me EtO2C HN

Generally, compounds containing a basic nitrogen atom, such as 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 16 is reduced with NaBH3CNHOAc [eqn. (5)]. Under the influence of NaBH4TFA, indole (3) is converted to a mixture of indoline (5), N-trifluoroethylindoline (17), and the Baeyer condensation product 18 [eqn. (6)].8
NaBH4 + N H 3 CF3CO2H rt N H 5 (40%) CF3 N CH2CF3 17 (5%) (6) +

N H

N CH2CF3 18 (13%)

N CH2CF3

75%

N H

10 (61%)

2.2 N-Alkylation of amines Our observation that NaBH4HOAc gives N-ethylation of indoline (5) (Scheme 1) led us to explore the scope of this unprecedented amine N-alkylation reaction. Reactions of aniline with NaBH4RCO2H are shown in Scheme 3.4 One can
Et N

A remarkable illustration of the selectivity of this indole reduction method is seen in 12 ? 13 [eqn. (3)],6 in which the protonated basic nitrogen presumably prevents a second protonation of the proximal indole double bond.
Me N NaBH3CN N H 12 Me N (3) N H 13 N H HOAc CF3CO2H (3:1) 71%

nPr
NaBH4 EtCO2H 50 C 70%

NHEt

NEt2

NaBH4 88% HOAc 20 C

NaBH4 HOAc 5060 C 74% 1. PhCHO 2. NaBH4 HOAc 20 C

N H

HN

iPr 1. acetone 2. NaBH4 HOAc


68%

NH2

NHCH2Ph

1. PhCHO 1. acetone NaBH4 NaBH4 2. NaBH4 2. NaBH4 80% Me3CCO2H HOAc 69% HOAc 80% HOAc 5055 C 5060 C 50-55 C 4045 C 79% iPr Et CH2Ph Et N N NHCH2C(CH3)3

H NaBH4 N H 14 O H N N H N Ph 16 N H HN Ph Cl NaBH3CN HOAc 10 C 15 min O H N (5) N H CF3CO2H 0 C 90% 15 N H H N (4)

Scheme 3

Cl

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 reductive amination of added aldehydes or ketones increases the versatility of the method. Pivalic acid affords N-neopentylaniline in 80% yield. Similar chemistry is observed with benzylamine and other aliphatic amines.9 Control experiments revealed that the mechanism of this Nalkylation does not involve reduction of a precursor amide,4 and gas evolution measurements and isolation studies10 indicated that 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 NaBH4 with glacial HOAc. Therefore, we believe that the NaBH(OCOR)3 species undergoes self-reduction to free aldehyde (or a synthetic equivalent) which then reacts with the amine in a typical reductive amination sequence (Scheme 4).

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HO2CR

:OH RCO H B(OCOR)3

O RCH N H 71% amines reduction NaBH3CN HOAc

50 C, 1 h N NaBH4 HOAc 68% N NaBH3CN HOAc HCO2H 52% N CH3 NaBH4 CH2CH3

RCO HB(OCOR)2

N-alkylation
RCH2OH trapped as 2,4-DNP (R = CH3, CF3) ester formation N

acetone 59%

Scheme 6

Scheme 4

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


N NaBH4 N N CF3CO2H THF rt Ph NaBH4 O + NO2 NH2 NaBH(OAc)3 HOAc ClCH2CH2Cl 23 h 66% NaBH(OAc)3 N H + NH2 O HOAc ClCH2CH2Cl 87% N H HN O O N SO2Ph NaBH3CN (9) CF3CO2H 75% N SO2Ph HN NO2 Me O + Me HOAc 40 C 99% Me O Me (8) 75% Ph N N H H N (7)

Using the isolated reducing reagent NaBH(OAc)3, AbdelMagid has extended this amine N-alkylation method into a powerful, general reductive amination protocol for aldehydes and ketones.11 Some recent examples are shown in Scheme 5.1113

2.4 Reduction of imines, enamines and related compounds A wide range of imines, enamines, enamides, vinylogous amides, and carbamates can be reduced using NaBH4RCO2H (Scheme 7).
NaBH(OAc)3 CH2Cl2 80% H N Ph CO2Me

Ph CHO +

H2NCH2CO2Me

Scheme 5

Obviously, these amine N-alkylations (reductive aminations) succeed because NaBH(OAc)3 only slowly reduces aldehydes and ketones relative to the rapid reduction of iminium and immonium ions. 2.3 Reduction of other heterocycles The facile reduction of indole (3) (Scheme 1) with NaBH4 RCO2H portended that other nitrogen-containing heterocycles that are susceptible to protonation would undergo a similar reduction/alkylation sequence. Indeed, quinolines, isoquinolines, acridines, quinazolines, quinoxalines, phthalazines, pteridines, benzoxazines, adenines, some pyrroles, and pyrylium salts are reduced by NaBH4RCO2H.1,2 More aromatic pyridines are normally unaffected by NaBH4RCO2H. Illustrative of the versatility of this methodology is the chemistry shown in Scheme 6 involving quinoline.14

2.5 Reduction of oximes Oximes are reduced and reductively alkylated with NaBH3CN HOAc and NaBH4RCO2H, respectively (Scheme 8).15 Whereas at room temperature cyclohexanone oxime is reduced to cyclohexylhydroxylamine with NaBH4HOAc, at higher temperatures the reaction proceeds to afford N,N-diethylcyclohexylamine. Similarly, oxime ethers are reduced to O-alkylated hydroxylamines under these conditions. Such an example involving a hydroxy-directed reduction is illustrated in eqn. (10).
OH N OBn

Me4NBH(OAc)3 CH3CN HOAc 35 C 95%


OH NH OBn

(10)

anti/syn : 95 : 5

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Et NaBH4 NaBH4

Et

F F O CN Br N H N Me O

N O

CO2

BHNa
3

F F O 95% ee NH
NHOH

HOAc 20 C 3.5 h 63% OH N

HOAc CH3CN 45 C NaBH4 Pr Pr 46%

i-Bu

CH2Cl2 -40 C -5 C 92% Br NaBH3CN

NaBH3CN

CH3CH2CO2H CH3CN 50 C

H
HOAc 20 C 3 h

30%

N MeO2C

CF3CO2H Cl 45%

N H CO2Me (+ aziridine)

Cl

81%

Scheme 8

OMe NaBH3CN N OMe Bn HOAc MeCN rt 56%

OMe

OMe MeO Bn NH O NaBH4 HOAc dioxane 97% MeO

OMe

N OMe (+ 3% trans)

NH

O S + NHBn NaBH4 HOAc THF 20 C 62% O EtO NHBn NaBH(OAc)3 HOAc 10 C 89% NaBH3CN O N Ph HCO2H 90% O EtO

O S + NHBn

BOC N H

H N O H N

H N BOC

NaBH3OCOCF3 THF 20 C

BOC N H O NHBn H N O O N H

H N BOC

65%

NaBH4 TFA THF 73%

H N

N H

O N Ph O N O O Ph HOAc MeCN 25 C 63% N Ts (22% cis) O OH O N H H H MeO2C (+ trans, 1 : 1) N O H N O Ph NaBH3OCOCF3 O 2S dioxane 82% O N N NaBH4 H N TFA dioxane 100 C 66% HO OH (CH2)10CH3 H N O H N O OH Me4NBH(OAc)3 O

OH OH N Ph O > 98% de

NaBH3CN N Ts (CH2)10CH3 CH2Cl2 TFA -45 C 76% NaBH4 N H N O HOAc 10 C 90%

NaBH4

OH

O2S

MeO2C

Ph

Scheme 7

2.6 Reduction of amides to amines Although NaBH(OCOR)3 (1) does not reduce amides, Umino discovered that NaBH3OCOR does reduce amides and lactams to the corresponding amines.16 Some examples of this useful reaction are listed in Scheme 9. Note that carbamates and sultams are unaffected by these conditions. Interestingly, the indole double bond in the last example is not reduced.17 2.7 Reduction of nitriles to primary amines Umino also discovered that NaBH3OCOR, particularly NaBH3OCOCF3, reduces nitriles to primary amines.18 A selection of 398 Chemical Society Reviews, 1998, volume 27

H CF3CO2H dioxane 90% N

Scheme 9

examples is shown in Scheme 10. Noteworthy is that this reduction reaction occurs in the presence of nitro and 1,2-oxazine functionalities.

Me

N N

Cl CN NO2 CN CH3 NaBH3OCOCF3 THF rt 70% NaBH3OCOCF3 THF 10-15 C 57%

Me

N N

Cl NH2 NO2
OH NaBH4 CF3CO2H +

NH2 CH3 BnO O O Ar O Ar = p-tolyl Ar


OH

1520 C 19 20

BnO O Ar O Ar O O

NO2

NO2

CN

NaBH3OCOCF3 THF rt 70%

CH2NH2
93% (11)

21

CN O N CO2Bn NaBH3OCOCF3 THF rt 48%

CH2NH2 O N CO2Bn
O I

NaBH4 CF3CO2H CH2Cl2 rt NEt2 86% I (12)

F F F F F CN NaBH3OCOCF3 THF rt 67% F F

F NH2 F F
O I NEt2

Scheme 10

2.8 Reduction of alcohols to hydrocarbons Early in our studies we thought that NaBH4CF3CO2H (TFA) might serve to reduce certain alcohols to hydrocarbons, in view of the propensity of TFA to stabilize carbocations. Indeed, this reagent combination provides an efficient and general method for 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 conditions.19
OH NaBH4 CF3CO2H
Ph

NaBH4 S OH O CF3CO2H Et2O rt 68% (13) S O Ph NaBH4 N CF3CO2H 90% major (87:13) MeS MeS N (14)

OH

15-20 C 93%

NaBH4 COH 3 CF3CO2H 15-20 C 94%

OH O N NaBH3OCOCF3 THF 4h >75%

OH (15) N

Scheme 11

In the case of carbinol 19, the intermediate carbocation 20 is ambushed by the o-phenyl group prior to reduction, affording only 9-phenylfluorene (21) [eqn. (11)].19 The generality and selectivity of this reduction method is illustrated by the examples in eqns. (12)(16). The chea moselectivity exhibited by NaBH(OCOCF3)3 vis-` -vis NaBH3OCOCF3 in eqns. (14)(15) is remarkable. 2.9 Reduction of ketones to hydrocarbons Diarylketones are smoothly reduced to diarylmethanes with NaBH4TFA.20 As we have seen, a wide range of functional

NH

N NaBH4

NH

N (16)

HN

TFA CH2Cl2 20 C 100%

HN

HO

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groups will tolerate these reaction conditions (Scheme 12). The mechanism presumably involves reduction to the diarylmethanol, solvolysis to the carbocation, and reduction to the hydrocarbon. Only in the case of strong electron-withdrawing groups (e.g., p-NO2) is the reaction incomplete. The last reaction appears to be the first reduction of a formyl group to a methyl group using this methodology. This method provides for a very useful synthesis of 3-alkylindoles [eqn. (17)] and alkyl-substituted ferrocenes [eqn. (18)].21
O Ac2O N SO2Ph AlCl3 CH2Cl2 N SO2Ph CH3

O NaBH4 R CF3CO2H 15-20 C R H Me OMe OH F Br S NaBH4 S O O Cl Cl NaBH4 CF3CO2H CH2Cl2 66% Me NaBH3CN N CO2Me O CF3CO2H 60% O O N N N HO CF3CO2H THF 89% Cl Cl O CO2Et CO2Me CO2Me O S % yield 92 89 88 90 82 94 R CN NMe2 NHPh CO2H CO2Me NO2 % yield 90 82 93 73 93 43 (+57% alcohol) S R

25 C 98%

NaBH4 CF3CO2H 15 C 25 C 99% N SO2Ph

CH3 (17)
HO

CO2Et OHC CO2Me

CO2H O Fe CF3CO2H CH2Cl2 rt 90% NaBH4 Fe

CO2H

(18)

Scheme 12

The combination of NaBH4TFA converts enones to alkenes [eqns. (19) and (20)],22,23 and isopropylidene acylmalonates, 5-acylbarbituric acids, and 3-acyl-4-hydroxycoumarins are all reduced to the corresponding methylene derivatives with NaBH3CNHOAc [e.g., eqn. (21)].
O NaBH4 (19) O CF3CO2H CH2Cl2 93% O NaBH4 (20) CF3CO2H CH2Cl2 CH3CN 69% O O Bn O 85% O O NaBH3CN HOAc rt Bn O O O O (21) OH

droarenes is particularly useful for the synthesis of polycyclic aromatic hydrocarbons. 2.11 Alkylation of arenes (Baeyer condensation) As noted earlier, indole (3) with NaBH4TFA gives some of the Baeyer condensation product 18 [eqn. (6)]. Indeed, this alkylation reaction of arenes, involving the generation of trifluoroacetaldehyde, is reminiscent of the synthesis of DDT from chlorobenzene, trichloroacetaldehyde (chloral), and sulfuric acid. We have found that several arenes give analogous products under these conditions (Scheme 14).27 Congested arenes like durene and mesitylene stop at the carbinol stage. 2.12 Selective reduction of aldehydes The reduction of aldehydes and ketones to alcohols is one of the most important reactions in organic chemistry. Although many reagents are available for this reaction, few are chemoselective for 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 relatively slowly by these acyloxyborohydrides. Indeed, this is precisely why the N-alkylation of amines works! Thus, although benzaldehyde is completely reduced to benzyl alcohol after 1 hour at 15 C with a large excess of NaBH4 in glacial acetic acid, acetophenone is only reduced to the extent of 60% at 25 C after 40 hours! By comparison, in alcoholic solution both reductions are complete in seconds. These and related observations paved the way for the chemoselective reduction of aldehydes in the presence of ketones.10,28 The isolated reagents NaBH(OAc)310 and n-Bu4NBH(OAc)328 work extremely well and some examples with the latter reagent are depicted in Scheme 15.28 Some additional examples with NaBH(OAc)3 are listed in eqns. (22)(25). Notable is the selective reduction of the aldehyde in the presence of a trifluoromethyl ketone [eqn. (24)]

2.10 Reductive cleavage of acetals, ketals, ethers, and related compounds The action of NaBH4TFA serves to reductively cleave a variety of acetals, ketals, ethers and ozonides as summarized in Scheme 13.2426 The deoxygenation of 1,4-epoxy-1,4-dihy400 Chemical Society Reviews, 1998, volume 27

O O O NaBH4 TFA THF 20 C 83% F CH3 NaBH4 O F CH3 TFA THF 15 C 92% F CH3 O CH3 O N PhO2S CH3 Mg 93% Br F O N PhO2S CH3 1. NaBH4TFA 2. NaOH 77% N H CH3 N CH3 O OHC CF3 HOAc PhH 95% NaBH4 HO N CH3 O CH3 O OH F CH3 O O O CHO O OH NaBH(OAc)3

OH (22) PhH rt

83%

NaBH(OAc)3 HOAc PhH 76% (23)

CF3 O

(24)

CH3 O O H

CHO

NaBH(OAc)3 PhH 67% O O H

CHO OH (25)

CHO

MeO MeO O

NaBH4 TFA 0-5 C 38% Cl O

MeO MeO OH

AcO H Cl Ph O O CHO Ph O

OAc

O Ph

OH OH
23 (26)

Ar O BnO

O OBn NHAc

NaBH3CN CF3CO2H DMF 84%

Ar HO BnO

O OBn NHAc

22

Ar = p-Methoxyphenyl

n-C5H11
O O NaBH4 O CF3CO2H

n-C5H11
O

ten years a very large number of hydroxy-directed carbonyl reductions using triacetoxyborohydride have been described.2a,30 A few examples are shown in Scheme 16. Several a-hydroxyketones have also been reported to undergo this intramolecular reduction.
OMe

n-C5H11

CH2Cl2 33%

n-C5H11
Arene + NaBH4CF3CO2H O O CF3

Scheme 13

and the selective reduction of the less sterically encumbered aldehyde in a dialdehyde [eqn. (25)].29 2.13 Hydroxy-directed reduction of ketones During our study of the chemoselective reduction of aldehydes in the presence of ketones, we observed the reduction of ketoaldehyde 22 to diol 23, presumably involving internal hydride delivery as shown in eqn. (26).28 Saksena independently discovered this same reaction and observed excellent stereoselectivities in the reduction of steroidal b-hydroxy ketones. Evans thoroughly explored the scope of this powerful methodology and he fully characterized several BH(OAc)3 species for the first time.30 In the intervening

53%

CF3 OMe 78%

CF3 Me CF3 Me

Me 65% 48%

Me

Scheme 14

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H O + excess n-Bu4NBH(OAc)3 PhH O 96% OH +

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


recovered ketone 94% 2. H2O2, OH 89% O CH3 1. NaBH4 HOAc OH

CHO +

CH3 excess n-Bu4NBH(OAc)3 PhH

CH2OH + 95%

OTMS 1. NaBH3OAc 2. H2O2, OH 83%

OTMS

OH

96%

O CHO

excess n-Bu4NBH(OAc)3 PhH 77%

O OH 1. NaBH3OAc 2. NaOMe CHCl3 OH OH 3. H2O2, OH 67% 98:2 anti/syn 1. NaBH3OAc O OH OH OTIPS 2. PCC 85% O O

Scheme 15
OH O Me4NBH(OAc)3 HOAc MeCN -20 C 92% O MeO O OH OTIPS Me4NBH(OAc)3

HOAc MeCN MeO 13:1 anti/syn -40 C 93% O Me4NBH(OAc)3 HOAc MeCN rt 81% O N Bn > 99:1 OH O

Scheme 17

O O N

OH

OH OH

Bn

2.15 Miscellaneous reductions Alkenes that yield stable carbocations upon protonation can be reduced to alkanes with NaBH4TFA [eqn. (27)],19 but such examples are exceedingly rare. It seems likely that NaBH4 CF3SO3H may work in this regard with other alkenes.
O O OH CF3CO2H 0 C 93% NaBH4 (27)

OH OBOM

O O OH

Me4NBH(OAc)3 75%

OH OBOM

O OH N EtO2C BnO O O NaBH(OAc)3 HOAc CH2Cl2 rt 82% N EtO2C

OH OH O O BnO Ph

Enones and enals give primarily 1,2-reduction with NaBH3OAc [eqns. (28) and (29)]. Small amounts of the 1,4-reduction products were also found.
NaBH3OAc Ph O THF 25 C 70% + OH 96% 4% O Ph (28)

O OH O OMe O

OBn

Me4NBH(OAc)3 HOAc MeCN -20 C 84% OBn

OH OH OMe 97% ds

CHO

NaBH3OAc THF 25 C 86%

CH2OH

CHO (29)

Scheme 16
99% 1%

2.14 Hydroboration of alkenes One of the first applications of the NaBH4HOAc reagent system was the hydroboration of alkenes as described by Marshall and Johnson.3 The actual reagent is the more reactive NaBH3OAc, which can also be generated from NaBH4 and 402 Chemical Society Reviews, 1998, volume 27

Twenty years ago we observed that both 1- and 2-naphthol yielded 1020% naphthalene upon treatment with NaBH4TFA (Scheme 18). In fact, when the crude reaction products were

OH NaBH4 CF3CO2H rt

+ OH

OH HN

CO2Me BOC

NaBH4 HOAc dioxane 80 C 90% HN

OH BOC (31)

H2O CO2Me 10% HN FMOC

NaBH4 HOAc dioxane 80 C 98% HN

OH FMOC (32)

Scheme 18

allowed to stand undisturbed for six months, pure naphthalene had sublimed onto the upper part of the flask. Presumably this transformation involves ring protonation, carbonyl reduction, and dehydration. More recently this novel deoxygenation of phenols has been reported for a hydroxyphenanthrene [eqn. (30)].31
OH

CON3 NaBH4

N(CH2CF3)2

(33) CF3CO2H NaBH4 CF3CO2H rt 20% (F3CH2C)2N CF3 N(CH2CF3)2 24 (30) 91% Cl rt Cl

These results are consistent with our earlier observations that 9,10-phenanthrenequinone and 2-methyl-1,4-naphthoquinone undergo reduction to the corresponding aromatic hydrocarbons albeit in low yield (Scheme 19).1
O NaBH4 CF3CO2H O 72% NaBH4 O CF3CO2H OMe O Me HgOAc CO2Me THF 0 C 82% O O NaBH4 CF3CO2H 23% O NaBH4 CF3CO2H O 57% 12% OH NaBH4 H

NaBH(OAc)3

H CO2Me + OMe 80% 20% OAc (35) CO2Me (34)

Me

OMe

HOAc 95%

Scheme 19

Esters are not normally reduced to primary alcohols by NaBH4CO2H, but such a reduction is observed at higher temperatures 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 to aldehydes with NaBH4 in the course of the reductive amination sequence (vide supra), it is not surprising that complete reduction to primary alcohols has been found (Scheme 20). Turnbull has recently described the reduction and subsequent N-trifluoroethylation of aroyl azides with NaBH4TFA [eqn. (33)].33 The parent compound yielded the Baeyer condensation product 24 in 87% yield. Organomercurials can be reduced to alkanes with NaBH(OAc)3 [eqn. (34)],34 and the NaBH(OCOR)3 reagents can also acylate alcohols, phenols, and thiophenols [eqns. (35)(38)], presumably by direct acylation of an acyloxyborohydride intermediate.

SH

NaBH4 HOAc 95%

SAc (36)

CH2OH O2N

NaBH4 EtCO2H 90% O2N

CH2OCOEt (37)

NH2

NaBH4 EtCO2H 95%

NHCOEt (38)

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NaBH4 CO2H THF 90%

OH

Hoffman, Sandy Emery, Joe Jasinski, John Pellicone, and Steve Wright. 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. 167200; (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. Fabr and S. Iwasa, Tetrahedron Lett., 1995, 36, e 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. Gonz lez and A. Rojas, Tetrahedron, a 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.

O NaBH4 MeO (CH2)8CO2H TFA THF 25 C 78% MeO

O (CH2)9OH

Scheme 20
Indole reduction Amine alkylation Aryl carbinol reduction

-Hydroxyketone reduction NaBH4 RCO2H Oxime reduction, alkylation

Selective aldehyde reduction

Quinoline, Isoquinoline reduction Arene alkylation Amide and nitrile reduction

Acetal, ketal reductive cleavage

Scheme 21

3 Concluding remarks As summarized in Scheme 21 the combination of NaBH4 RCO2H, leading to acyloxyborohydrides, is a remarkably versatile and unique chemical system. These chemical species have emerged as the preeminent reagents of choice for a wide spectrum of chemical transformations. The ability to control chemoselectivity, regioselectivity, and stereoselectivity by adjusting the carboxylic acid, borohydride reagent, stoichiometry, and temperature has no parallel in the repertoire of the organic chemist. Nevertheless, much work remains to be done with acyloxyborohydrides, particularly with regard to understanding the mechanisms of some of the reactions, in applying these reagents to asymmetric synthesis, and in uncovering new applications. 4 Acknowledgements I am especially grateful to my many co-workers on this project over the past 25 years. In particular, graduate students Jerry Skotnicki at the beginning and Charlie Nutaitis in later years. But, my deepest appreciation goes out to the many Dartmouth undergraduates who explored and developed much of the chemistry presented here. These include Steve Dietz, Duncan Ferguson, Peter Heald, Bud Leese, Myles Sheehan, Joe

Received 16th June 1998 Accepted 26th June 1998

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Chemical Society Reviews, 1998, volume 27