Pure &AppI. Chem., Vol. 59, No. 8, pp. 10051010, 1987.

Printed in Great Britain.

1987 IUPAC

Selective reductions with complex hydride

reducing agents
Sunggak Kim

Department

of Chemistry, Korea Advanced Institute of Science and

Technology, Seoul 131, Korea

Abstract -

This

paper describes the selective reductions with

thioborane derivatives, zincmodified cyanoborohydride, and the ate

complex from diisobutylaluminum hydride and n-butyllithium. Reaction

of carboxylic acids with 1,3,2-dithiaborinane in the presence of

stannous chloride or boron trifluoride etherate in tetrahydrofuran
The reaction of acids with
gives 1,3-dithianes in high yields.
thexylphenylthioborane in dichloromethane gives S,S'-diphenyl acetais,
whereas esters are converted into phenyl sulfides in the presence of
Zinc-modified cyanoborohydride in ether selectively
zinc iodide.
reduces allylic, benzylic, tertiary alkyl halides without reducing
primary and secondary alkyl, vinyl, and aryl halides. Furthermore, the
reagent in ether reduces aldehydes, ketones, and acid chlorides to
alcohols and the reagent in methanol is very effective in the reduction

of enamines, reductive amination of aldehydes and ketones, and

The ate complex from
deoxygenation of aldehdyes and ketones.
diisobutylaluminum hydride and n-butyllithium, capable of reducing most
reducible functional groups, is found to be a highly selective reducing
agent.
The reagent rapidly reduces simple primary alkyl bromides,
benzylic, and allylic halides but slowly primary alkyl chlorides and
Tertiary amides are cleanly reduced to
secondary alkyl bromides.
aldehydes and various selective reductions can be achieved by the use
of the reagent.

INTRODUCTION
The development of numerous selective reducing agents, capable of reducing a certain
functional group in the presence of various other reducible functional groups has attracted a
great deal of recent attention (ref. 1).
In general, selective reducing agents have been
prepared by modifying the steric and electronic effects of substituents on the boron atom or

the aluminum atom.

For instance, sodium cyanoborohydride containing a strong electron

withdrawing cyano group is a milder and more selective reducing agent than sodium borohydride
(ref. 2), whereas lithium trisecbutylborohydride having sterically bulky three sec-butyl
groups is a stronger and highly stereoselective reducing agent than lithium borohydride (ref.
3). As our continuous efforts toward the development of new hydride reducing agents, we have

recently developed new types of hydride reducing agents, namely 1,3,2-dithiaborinane and
thexylphenylthioborane, which are capable of transferring hydride and mercapto moities to
We have further modified the
carboxylic acids by one step procedure (ref S. 4 and 5).
reducing properties of sodium cyanoborohydride by the addition of metal salts, especially
zinc chloride (ref s. 6 and 7). Finally, we have investigated the reducing properties of the
ate complex generated from diisobutylaluminum hydride (Dibah) and n-butyllithium and found
that the reagent is a powerful and highly selective reducing agent for the reduction of
various functional groups (ref. 8).

1,3,2-DITHIABORINANE AND THEXYLPHENYLTHIOBORANE

A new method for direct conversion of carboxylic acids into synthetically useful thioacetals
consists of the sequence of two steps, partial reduction of acids to the aldehyde stage (ref.
9) and the subsequent protection as thioacetals (ref. 10). As far as we are aware, this is

the first example among various partial reductions using various complex hydride reducing
agents where partial reduction and subsequent protection are achieved by one step procedure.
1,3,2-Dithiaborinane(1) was readily prepared by treating borane-dimethyl sulfide with 1 e9uiv

of 1,3-propanedithio in tetrahydrofuran and subsequent stirring at room temperature for a

week (eq. 1). The 1BNMR spectrum of the reagent (1) exhibited a doublet (JH=16u Hz) at
62.4 ppm relative to boron trifluoride etherate. Reaction of phenylacetic acid with 2 equiv
of the reagent (1) in tetrahydrofuran at room temperature gave a 60:25 mixture of benzyi 1,3-

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SKIM

1006

HS_.\

Me2SBH3 +

H\,S\

THF

Me2S '
1

RCOOH

r.t.

CH2=CH(CH2)8COOH

rt

(1)

SnC12 or BF3Et20

2.

2 +

HO(CH2)locO

THr

(2)

CH2=CH(CH2)8CH7OH

no additive:

44%

11%

8%

BF3'Et20:

38%

13%

7%

SnC12:

78%

dithiane and phenethyl alcohol along with a small amount of several unidentified byproducts.
Encouraged by this result, we have investigated the present reaction in detail. After much

experimentation to find an optimum condition, several important observations have been

First, the addition of stannous chloride or boron trifluoride etherate is very
made.
effective for clean conversion of acids into 1,3-dithianes (2) without accompanyiny alcohols
Secondary, even more important is the observation that acids can be selectively
(eq. 1).
converted into 1,3-dithianes in the presence of alkenes using stanous chloride as an additive
(eq. 2), although it has been reported that 1,3,2-dithiaborolane hydroborates readily alkenes
The use of boron trifluoride etherate was not effective for this purpose.
(ref. 11).
Thirdly, 2 equiv of the reagent is not essentially required for this facile conversion. The
best condition found for maximum yield and functional group selectivity are to employ 1.7
equiv of the reagent (1) and 1 equiv of stannous chloride or boron trifluoride etherate tor
In the case
each mole of aliphatic carboxylic acids in tetrahydrofuran at room temperature.

of aromatic acids, the use of 2 equiv of the reagent is recommended to obtain better
yields. Carboxylic acids containing a bromo, an ester, and a tert-amide group were cleanly
converted into the corresponding 1,3-dithianes without attacking such reducible yroups by the
As shown in Table 1, various carboxylic acids including sterically hindered
reagent(l).
acids were cleanly converted into the corresponding 1,3-dithianes (2) in high yields.

Me2SBH3 +

HS

r.t.

HSJ

THF

R S

RCOOH

H\ ,i
I

Me231"S-J

SnC12

(3)

or BF3Et2O ''.J

Furthermore,

we have found that 1,3,2-Dithiaborolane (3), prepared by the reaction of boranedimethyl sulfide with 1 equiv of 1,2-ethanedithiol in tetrahydrofuran at room temperature for
24 h, was capable of converting acids into 1,3-dithiolanes (4) in the presence of stannous
In general, the efficiency, applicability,
chloride or boron trifluoride etherate (eq. 3).
and scope of this method were similar to those of using 1,3,2-dithioborinane (1).

BBr

BHBr'SMe2

Pb(SC H )

6 5 2 FHBHSC6H5

+ Me2SBBr3

CH2C12

(4)

RCOOH

_____BHSC6H5 +

RCH(SC6H5)2

(5)

RCH2SC6H5

(6)

Me2SBBr3

\..
RCOOR'

Zn12, CH2C12

7
R'=Me, Et, iC3H7, CH2C6H5

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1007

Selective reductions with complex hydride reducing agents

Table 1. Direct Conversion of Carboxylic Acids to Thioacetals.

isolated yields of
S,S1-diphenyl acetals, %b

time, h

isolated yields of
1,3-dithianes, %a

84

81

3.5

90

87

(CH3)2CHCOOH

81

87

cyclohexanecarboxyli c

3.5

82

84

1-adamantanecarboxyl ic

80

87

Br(CH2)10C00H

82

87

HOOC(CH2)4COOMe

12

83

82

C6H5COOH

20

74

71(14)c

20

71

75(14)c

20

75

acid

C6H5CH2COOH
CH3(CH2)5COOH

p-Cl-C6H4COOFI

p-MeO-C6FI4COOH

time, h

aThe reaction was carried out with 1.7 equiv of the reagent (1) for aliphatic acids and 2.0

equiv for aromatic acids in the presence of 1.0 equiv of stannous chloride in
tetrahydrofuran at room temperature.
bThe reaction was carried out with 2.2. equiv of the reagent (5) in dichloromethane at room
temperature.
cThe numbers in parentheses indicate the isolated yields of benzyl phenyl sulfide and pchlorobenzyl phenyl sulfide, respectively.

Although it has been reported the aryl- and alkylthioboranes hydroborate alkenes and reduce
acids, aldehydes, and ketones to alcohols, their synthetic utilities have been hampered due

to the facile cleavage of etheral

solvents

(ref.

12).

We have

found that

thexylphenylthioborane (eq. 4), prepared from thexylbromoborane and bis(phenylthio) lead in

dichloromethane, was also effective for conversion of acids into S.S'-diphenyl acetals (6)
The reaction was carried out with 2.2 equiv of the reagent (5) in dichloromethane
(eq. 5).
at room temperature. As shown in Table 1, various structurally different acids were cleanly
converted into S,S'-diphenyl acetals (6) in high yields. However, in the case of aromatic
acids, small amounts of the corresponding phenyl sulfides were formed as a byproduct.

Since carboxylic esters were generally inert to the reagent (5), we considered the
group of an ester by the addition of Lewis acids.
possibility of activating the carbonyl
Among several Lewis acids tested in this study, the use of 1 equiv of zinc iodide gave the
best result for clean conversion of acids into phenyl sulfides (7) (eq. 6).
The present
method can be successfully applied to the preparation of various phenyl sulfides from various
esters such as methyl, ethyl, benzyl, and isopropyl ester.

ZINC-MODIFIED CYANOBOROHYDRIDE
Althoughthe reducing properties of sodium borohydride/metal salts have been intensively
investigated (ref. 13), there are relatively few reports in the literature on the use of
It has been reported that the combination of socium
sodium cyanoborohydride/metal salts.
cyanoborhydirde with Cu(II) and triphenylphosphine (ref. 14) and Pd(0) (ref. 15) reduces acid
chlorides to aldehydes and allylic acetates to alkenes, respectively. We have also studied

reducing properties of sodium cyanoborohydride/metal salts to modify the usual reducing

ability of sodium cyanoborohydride alone. Among several metal salts such as zinc chloride,
cobalt (II) chloride, stannous chloride, stannic chloride, and titanium chloride tested in
Thus, we have investigated the
this study, zinc chloride gave the promising results.
reducing

properties of sodium cyanoborohydride and zinc chloride in detail.

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SKIM

1008

2 NaBH3CN +

/Br
-F

2h
r

Zincmodified Cyanoborohydride

ZnC12

LH

(7)

ONe

S .M. (8)

10

82

10

58

25

Et20:
DNE:

95

MeOH:

Zinc-modified cyanoborohydride (8) utilized in this study was prepared by mixing sodium
cyanoborohydride and zinc chloride in a 2:1 molar ratio at room temperature in several
solvents such as ethyl ether, tetrahydrofuran, and methanol (eq. 7). The reagent (8) was
relatively stable in aqueous media and its stability in aqueous media may enhance its utility
as a versatile reducing agent, while zinc borohydride decomposes rapidly with evolution of

It was found that the reayent (8) in ether reduced

hydrogen gas in alcoholic solvents.
allylic, benzylic, and tertiary halides to the corresponding alkanes without attacking
As shown in eq. 8, the tertiary
primary and secondary alkyl, vinyl, and aryl halides.
bromide was cleanly and selectively reduced in the presence of the primary alkyl bromide in

ether, whereas methyl ether was obtained as a major product in methanol.

Similarly,
selective reduction of tertiary, benzylic, and allylic halides can be achieved with zinc
It
borohydride in ether (ref. 16) and sodium cyanoborohydride/stannous chloride (ref. 17).
is assumed that benzylic, allylic, and tertiary halides and alcohols are activated by zinc
halides to generate carbocationic species which are trapped with various soft nucleophiles
such as thiol, thioacids, and selenols (refs. 18 and 19).

0H +

(9)

C1CH2CH2C1

80%

QH cicc2ci
80 C, lh

0(1

(10)

89%

On the basis of this concept, we attempted deoxygenation of allylic, benzylic, and tertiary
of
reagent (8) in ether or dichloroethane.
However, reaction
alcohols with the
-methylbenzyl alcohol with the reagent (8) in dichloroethane at room temperature gave bis
(a-methylbenzyl) ether in 80% yield (eq. 9). This result is in marked contrast with recently
reported deoxygenation of benzylic alcohols with sodium cyanoborohydride/zinc iodide (ref.
We have developed a new convenient method for direct synthesis of ethers via zinc
20).
chloride mediated etherification of benzylic, allylic, and tertiary alcohols (eq. 9 and 10)
(ref. 21).

Zinc-modified cyanoborohydride (8) in ether reduced aldehydes, ketones, and acid chlorides to
The reagent in
alcohols but did not reduce acid anhydrides, acids, esters, and amides.
methanol did not readily reduce aldehyes and ketones, though the use of an excess amount of
zinc chloride resulted in almost completion of the reduction. The reduction of enamines with
the reagent (8) in methanol proceeded smoothly and the reaction was normally complete within

1 h at room temperature.

Since the reduction of enamines with the reagent in methanol

occurred much more rapidly than that of aldehydes and ketones, it was expected that reductive

amination of aldehdyes and ketones (eq. 11) and reductive methylation of amines (eq.
could be effected by simply reacting the carbonyl compounds with amines by the use of
It is of interest to note that the present procedure does
reagent (8) in methanol.
require pH control. Furthermore, the reductive deoxygenation of aldehydes and ketones

12)
the
not
via
the intermediacy of tosylhydrazones was accomplished with the reagent in methanol at ref lux
(eq. 13).

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1009

Selective reductions with complex hydride reducing agents

r.t., 2h

KIII:= + NH2 +

(11)

KI::_.NH_-::
85%

r.t, 2h

O2N--NH2 +

HCHO

OCH32

(12)

90%
2h

+ 8

+ CH3S02NHNH2

n-C12H26

(13)

70%

THE ATE COMPLEX FROM DIUSOBUTYLALUMINUM HYDRIDE AND

n-BUTYLLITHIU M
The reducing properties of alkali metal trialkylborohydrides have been intensively studied.
However, there are only several reports in the literature on the use of lithium trialkylThus, the lack of systematic investigations of the reducing
aluminum hydrides (ref. 22).
properties of these ate complexes prompted a detailed study of the reduction of a series of
selected organic compounds containing various functional groups with the ate complex from
Dibah and n-butyllithium in tetrahydrofuran-hexane and/or toluene-hexane (eq. 14) (ref. 8).
The simple primary alkyl bromide, 1-bromododecane, was reduced with the reagent (9) in tetraat room temperature, whereas it was inert to the reagent at
hydrofuran-hexane within 10 mm
The secondary alkyl bromide was reduced much more slowly than the primary alkyl
-78C.
bromide and the tertiary alkyl bromde was essentially inert to the reagent but trace amounts

of elimination products were detected.

Furthermore, the reagent rapidly reduced simple
The reactivity of organic halides toward the reagent makes
benzylic and allylic halides.
possible elective reduction of primary bromides in the presence ut secondary bromides (eq.
Of special synthetic significance is the stoichiometric requirement of the reagent (9)
15).
in the reduction of organic halides. Essentially complete utilization of the hydride of the
reagent is in marked contrast with the results obtained from the reaction of organic halides
It has been reported that the reaction of
with several hydride reducing agents (ref. 23).
alkyl halides with equimolar amounts of lithium triethylborohydride proceeds rapidly up to

50%, with further reaction being sluggish probably due to the formation ot lithium
triethylborohydride-triethylborane complex and 2 equiv of the reagent are required for the
However, we expected that the bulkiness of lithium tri-seccomplete reduction.
butylborohydirde (10) might prevent the formation of such complex. Indeed, it was found that
the reduction of the primary alkyl bromide with a stoichiometric amount of lithium tri-secIn general, the efficiency and applicability
butylborohydride (10) proceeded to completion.
of lithium tri-sec-butylborohydride were very similar to those of the reagent (9) (ref. 24).

iBu2A1H +

nBuLl

LIA1H(nBu)(lBu)2

(14)

9
C6H5CH2Br +

C6H5CHBrCH3

r.t.

C6H5CH3 +

C6H5CH2CH3

9:

95

10:

98

OMe 2 eq. 9

NaBH4 pH (16)

78 Cr.t., lh

78 C, lh

X=CONEt2
=Br

lh

83%
95%
80%

=CN

NEt2 1

(15)

NCI
86%

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(17)

SKIM

1010

Esters and lactones were completely reduced to alcohols at room temperature, whereas they
were reduced to a mixture of alcohols and aldehdyes at -78C even with an excess amount of
Partial reduction of esters and lactones to aldehydes and lactols was not
the reagent (!).
achieved. The reagent reduced acid chlorides and acid anhydrides but did not reduce
carboxylic acids, primary, and secondary amides. Tertiary amides were cleanly reduced to
aldehydes with a stoichiometric amount of the reagent at room temperature or at 00C, whereas
they were inert to the reagent at -78C, which permitted the selective reduction of other
reducible functional groups in the presence of the tertiary amide group.
Unlike facile
reduction of nitriles with Dibah, nitriles were only slowly reduced to the corresponding
Systematic investigations of the reagent (9) toward various functional groups
aldehydes.
For instance, selective reduction of
suggest the possibility of many selective reductions.
esters in the presence of a tertiary amide, a bromide, and a nitrile can be achieved with the
Furthermore, the reagent is capable of reducing selectively a tertiary
reagent (eq. 16).
amide in the presence of a nitrile (eq. 17).

Acknowledgement

wish to thank my collaborators of this work and continuing financial support from Korea

Science and Engineering Foundation is gratefully acknowledged.

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