www.elsevier.nl:locate:jorganchem
Journal of Organometallic Chemistry 609 (2000) 137–151
Methods of enhancement of reactivity and selectivity of sodium
borohydride for applications in organic synthesis
Mariappan Periasamy *, Muniappan Thirumalaikumar
School of Chemistry, Uni6ersity of Hyderabad, Central Uni6ersity PO, Hyderabad 500 046, India
Received 29 February 2000; received in revised form 16 April 2000
Abstract
NaBH4 does not reduce carboxylic acids, esters, amides and nitriles under ambient conditions. However, the reactivity of
NaBH4 can be enhanced by the addition of certain additives. For example, addition of iodine to NaBH4 in THF provides
H3B–THF that is useful for hydroborations and reductions of various functional groups. The aldehydes and ketones are reduced
in a fast manner by the NaBH4 reagent. Even so, the selectivities realised in such reductions can be enhanced using NaBH4 along
with another additive. In this article, various methods used for the enhancement of reactivity and selectivity of NaBH4 in organic
synthesis are described. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Sodium borohydride; Enhancement of reactivity; Additives; Reduction of organics
1. Introduction
Metal hydrides are valuable reagents in modern or-
ganic chemistry. The most frequently used hydride is
the NaBH4 reagent. It is a mild, inexpensive and invalu-
able reagent for applications in a wide range of reduc-
tion processes. It is the reagent of choice for the
reduction of aldehydes and ketones to alcohols [1] and
imines [2] or iminium salts [3] to amines with protic
solvents [4]. The carboxylic acids, esters, amides and
nitriles are more resistant towards NaBH4 [1]. How-
ever, the reactivity of NaBH4 can be enhanced by
carrying out the reaction in the presence of certain
additives. In this article, various methods of enhance-
ment of reactivity and selectivity of NaBH4 using addi-
tives for applications in organic synthesis are described.
2. Hydroboration of alkenes and alkynes
Hydroboration of carbon�carbon multiple bonds
provides a method for the synthesis of the valuable
organoborane intermediates with high regio- and
stereospecificities [5]. Historically, Brown and Subba
Rao discovered the hydroboration reaction during their
investigation of the activation of NaBH4 for the reduc-
tion of esters using AlCl3 [6]. The use of BF3 in the
place of AlCl3 led to more effective utilisation of the
hydride for the generation of diborane, B2H6 and bo-
rane Lewis base complexes (Eqs. 1–3) [7].
9RCH�CH2�AlCl3
����
diglyme
3(RCH2CH2)3B�AlH3�3NaCl (1)
12RCH�CH2�3NaBH4�4BF3
����
diglyme
4(RCH2CH2)3B�3NaBF4 (2)
(RCH2CH2)3B�3H2O2�NaOH
3RCH2CH2OH�NaB(OH)4 (3)
Although several of these borane complexes are com-
mercially available (e.g. H3B–THF, H3B–SMe2 and
H3B–NR3), there have been sustained efforts towards
the development of alternative, simple and convenient
methods of generation of boranes in situ for hydrobo-
ration. In 1963, it was reported that a 1:1 mixture of
NaBH4 and CH3COOH hydroborates alkenes [8a].
Later, a modified procedure for hydroboranes using
NaBH4–CH3COOH was reported (Eq. (4)) [8b].
* Corresponding author. Tel.: �91-40-3010904; fax: �91-40-
3010120.
E-mail address: mpsc@uohyd.ernet.in (M. Periasamy)
0022-328X:00:$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(00)00210-2
M. Periasamy, M. Thirumalaikumar : Journal of Organometallic Chemistry 609 (2000) 137–151138
NaBH4�CH3COOHCH3COOBH3Na
�������������
1. n-C4H9CH�CH2
2. H2O2�OH�
n-C4H9CH2CH2OH
75%
(4)
Selective hydroboration of olefinic moiety in the pres-
ence of carboxylic acid group was reported from this
laboratory (Eq. (5)) [9].
(5)
Also, a new method of conversion of olefins to dialkyl
ketone was developed (Eq. (6)) [10].
NaBH4�������������
1. AcOH–THF
2. n-C8H17CH�CH2
25°C, 12 h
�������������
1. CHCl3–NaOMe
2. H2O2–OH�
(n-C8H17CH2CH2)2
80%
C�O (6)
A method of conversion of terminal alkenes to car-
boxylic acids through hydroboration of olefins was also
developed (Eq. (7)) [11]. This method provides a simple,
one-pot synthesis of carboxylic acids from terminal
alkenes.
(7)
Also, various combinations of metal salts and borohy-
drides, such as SnCl4–NaBH4 [12], TiCl4–NaBH4 [13],
TiCl4–PhCH2N�(Et)3BH4� [14] and CoCl2–NaBH4 [15]
have been reported to effect hydroboration of olefins.
Whereas the CoCl2–NaBH4 combination behaves as
a hydroborating agent when the reaction is carried out
with THF for 2 h at room temperature (r.t.) before the
addition of alkene, it works as a hydrogenating agent [15]
in methanol (Eq. (8)). This method has some advantages
over the reported method using alcoholic medium [16].
(8)
Chiral semicorrin 1–3 cobalt complexes can be pre-
pared readily using CoCl2 and the corresponding free
ligands. These complexes are efficient enantioselective
catalysts for the conjugate reduction of a,b-unsaturated
carboxylates (Eq. (9)) [17] and a,b-unsaturated carbox-
amides [18] using NaBH4.
(9)
Chalcones undergo facile reduction on reaction with
NiCl2–NaBH4 system to afford dihydrochalcones (Eq.
(10)) [19]. The use of copper or cobalt chloride in place
of NiCl2 is not as efficient for this application.
(10)
The NaBH4 reacts with I2 to give diborane (Eq. (11))
[20a].
2NaBH4�I2B2H6�H2�2NaI (11)
The reactive ‘H3B–THF’ species can be easily generated
in situ by mixing NaBH4 and I2 in THF [20b]. Hydro-
boration of alkenes using this NaBH4–I2 system in THF
followed by oxidation gives the corresponding anti-
Markovnikov alcohols (Eqs. (12) and (13)) in good yields
[21,22].
n-C8H17CH�CH2�������
NaBH4–I2
THF
�����
H2O2
NaOH
n-C8H17CH2CH2OH
92% (12)
(13)
Later, it was reported that electrochemical oxidation
of NaBH4 using catalytic amounts of sodium iodide gives
diborane that hydroborates olefins (Eq. (14)) [23].
(14)
The Me3SiCl–PhCH2N�(Et)3BH4� reagent system has
been reported to effect hydroboration of olefins to give
anti-Markovnikov alcohols after oxidation (Eq. (15))
[24].
CH3(CH2)6CH�CH2 �����������
1. PhCH2N�(Et3)B�H4
Me3SiCl, CH2Cl2
2. H2O2�OH�
CH3(CH2)7CH2OH
72%
(15)
M. Periasamy, M. Thirumalaikumar : Journal of Organometallic Chemistry 609 (2000) 137–151 139
Very recently, it has been reported that the tetrabutyl-
ammonium borohydride liberates diborane in solvents
such as CH2Cl2, CHCl3 and CCl4. A number of terminal,
internal and cyclic alkenes were hydroborated using this
borohydride (Eq. (16)) [25].
(16)
The 1-alkynes undergo dihydroboration to yield the
corresponding terminal alcohols after oxidation. Gener-
ally, the disubstituted alkynes give vinyl boranes that on
oxidation offord ketones as the major product (Eqs. (17)
and (18)) [25,26]. However, the diphenyl acetylene yields
1,2-diphenylethanol as the major product through dihy-
droboration under these conditions.
C6H5C�CC6H5�������������
NaBH4�Bu4N�Cl�
CHCl3
C6H5CH(OH)CH2C6H5
83% (17)
CH3CH2C�CCH2CH3�������������
NaBH4�Bu4N�Cl�
CHCl3
CH3CH2CO(CH2)2CH3
90%
(18)
The PdCl2–NaBH4–polyethyleneglycol (PEG)–
CH2Cl2 system is effective for hydrogenation of car-
bon�carbon triple bonds to the corresponding cis-alkenes
(Eq. (19)) [27]. This reagent has advantages of faster rates
and higher selectivity.
(19)
3. Reduction of carboxylic acids
The NaBH4 gives acyloxyborohydride species on reac-
tion with carboxylic acids in THF that hydroborate
olefins. The acyloxy moieties in such acyloxyborohydrides
remain unchanged under ambient conditions. However,
one half of the acyloxy moiety undergoes reduction upon
heating to give the corresponding alcohol (Eq. (20))
[28].
(20)
A similar reaction was also observed using NaBH4,
RCOOH and catechol at 25°C (Eq. (21)) [29].
(21)
Aliphatic carboxylic acids are reduced by NaBH4 to
the corresponding alcohols in good yields when RCOOH
and CF3COOH are used in 1:1 ratio under ambient
conditions (Eq. (22)). However, the aromatic acids give
poor yields (e.g. benzoic acid 20%). Also, the NaBH4–
CF3COOH combination is good for the reduction of
aliphatic carboxylic acids (65–95% yields). Again, aro-
matic acids give poor results under these conditions (30%).
(22)
The ZnCl2–NaBH4 reagent system readily reduces
both aliphatic and aromatic acids to the corresponding
alcohols in refluxing THF (Eq. (23)) [30]. The reaction
requires only stoichiometric quantities of hydride for this
conversion. Also, dicarboxylic acids are reduced to the
corresponding diols under these conditions.
RCOOH���������
NaBH4�ZnCl2
THF, D
RCH2OH
R�alkyl:aryl
70�95%
(23)
The reagent prepared using ZrCl4 and NaBH4 reduces
the carboxylic acids in excellent yields under mild condi-
tions (Eq. (24)) [31].
PhCOOH���������
NaBH4�ZrCl4
THF, rt, 5 h
PhCH2OH
85%
(24)
Carboxylic acids are reduced to the corresponding
alcohols under ambient conditions by the NaBH4–I2
reagent system in very good yields with some selectivities
(Eqs. (25) and (26)) [32].
CH3(CH2)8COOH��������
NaBH4–I2
THF
0–25°C
CH3(CH2)8CH2OH
95%
(25)
(26)
M. Periasamy, M. Thirumalaikumar : Journal of Organometallic Chemistry 609 (2000) 137–151140
Further, selective reduction of the carboxylic acid
group in an olefinic acid has also been achieved by
forming the corresponding acyloxyborohydride before
the addition of I2 (Eq. (27)) [32].
(27)
Cyanuric chloride–NaBH4 reagent system has also
been used to effect the reduction of carboxylic acids to
alcohols under mild conditions (Eq. (28)) [33].
(28)
Facile, chemoselective reduction of carboxylic acids to
alcohols using a phosphonium hexafluorophosphate
(BOP reagent)–NaBH4 reagent system has been reported
(Eqs. (29) and (30)) [34]. Also, this method is convenient,
rapid and chemoselective in several cases. For example,
functional groups such as nitro, nitrile, azido and ester
are unaffected under these conditions.
(29)
(30)
4. Reduction of amino acids and their derivatives
Chiral amino alcohols are important class of com-
pounds. They are useful in asymmetric transformations,
synthesis of pharmaceuticals [35], resolution of racemic
mixtures [36] and in synthesis of insecticides [37]. Obvi-
ously, several reagents are available (e.g. LiAlH4 [38],
DIBAL [39], H3B–THF [40]) for the reduction of free as
well as protected amino acids to the corresponding amino
alcohols. However, these reagents suffer from disadvan-
tages of cost, inflammability and tedious isolation proce-
dures. Meyers and coworkers examined the reduction of
amino acids using the NaBH4–I2 reagent system. The
results indicate that it is an excellent reagent system for
the conversion of amino acids to amino alcohols (Eq.
(31)) [41].
(31)
The N-acyl amino acids give the corresponding N-
alkyl amino alcohols under these conditions (Eq. (32))
[41].
(32)
However, the N-carbamate protecting group is unaf-
fected under these conditions [41]. Also, the reductions
of pentachlorophenyl esters of the Boc protected amino
acids and peptides to the corresponding alcohols have
been reported (Eq. (33)) [42].
(33)
The NaBH4–I2 reagent system is safe, simple and
inexpensive. Hence, it is useful, especially in the large
scale synthesis of chiral amino alcohols.
Amino acids are also reduced using the inexpensive
NaBH4–H2SO4 reagent system in THF (Eq. (34)) [43].
It is of interest to note that no racemization occurs in the
reduction of amino acids using NaBH4–I2 or NaBH4–
H2SO4.
(34)
5. Reduction of carboxylic acid esters
The NaBH4–ZnCl2 reagent system exhibits powerful
reducing properties in the presence of a tertiary amine.
The carboxylic esters were smoothly reduced by this
reagent to their corresponding alcohols (Eq. (35)) [44].
Further, the reduction does not take place without the
amine under these conditions.
(35)
M. Periasamy, M. Thirumalaikumar : Journal of Organometallic Chemistry 609 (2000) 137–151 141
The NaBH4–I2 reagent system has also been used for
this application. It readily reduces carboxylic acid esters
under reflux conditions in good yields (Eq. (36)) [21].
PhCH2COOEt ���������
NaBH4–I2, THF
70°C, 0.5 h
����
H2O
PhCH2CH2OH
85%
(36)
6. Reduction of carboxylic acid amides
Numerous chemicals of importance in medicinal
chemistry have been prepared through reduction of
amides [45]. It was found that the amides can be easily
reduced to primary amines using NaBH4–CoCl2 system
in good yields in hydroxylic as well as in non-hydrox-
ylic solvents (Eq. (37)) [46].
n-C3H7CONH2����������
NaBH4–CoCl2
n-C3H7CH2NH2
70%
(37)
The NaBH4–I2 system is also useful for the reduction
of amides (Eqs. (38)–(40)) [21].
PhCONH2 �������
NaBH4–I2
THF, D
����
NaOH
PhCH2NH2
70%
(38)
PhNHCOCH3PhNHCH2CH3
75%
(39)
Ph(CH3)NCOCH3Ph(CH3)NCH2CH3
74%
(40)
Further, reduction of amides containing sensitive
functional groups can also be carried out using
NaBH4–I2 reagent system under ambient conditions
(Eq. (41)) [47].
(41)
A new procedure for the highly selective reduction of
tertiary amides to amines using NaBH4–bis(2-bro-
moethyl)selenium dibromide 4 has been reported (Eq.
42) [48a,b].
(42)
At a higher temperature, this reaction takes place
smoothly in a shorter period. However, reduction of
secondary and primary amides with this system in THF
failed. Also, without the selenium compound, the reac-
tion did not take place. It has been observed that the
reaction of NaBH4 with 4 produces borane (5) and
bis(2-bromoethyl)selenide (6).
(BrCH2CH2)2Se–BH3 (BrCH2CH2)2Se
5 6
7. Reduction of nitriles
The CoCl2–NaBH4 reagent system effectively re-
duces the nitriles in good yields [46] in hydroxylic as
well as non-hydroxylic solvents (Eq. (43)).
C6H5CH(OH)CN����������
NaBH4–CoCl2
C6H5CH(OH)CH2NH2
80% (43)
Mandelonitrile is smoothly reduced using the
NaBH4–CoCl2 system [49]. It is of interest to note that
reduction by LiAlH4 gives the a-hydroxy-b-phenylethyl-
amine in low yields. Cupric salts–NaBH4 combinations
are also effective for reduction of nitriles. The halo-
genides, sulfates, carboxylates of cobalt, nickel, iridium,
rhodium, osmium and platinum were also used along
with NaBH4 in several applications. Also, ZrCl4–
NaBH4 reagent system has been used for the reduction
of nitriles in excellent yields (Eq. (44)) [31].
PhCH2CN����������
NaBH4–ZrCl4
THF, r.t.
PhCH2CH2NH2
91%
(44)
Nitriles are also reduced by NaBH4–I2 system in
THF under refluxing conditions (Eq. (45)) [21].
PhCN������
NaBH4–I2
THF
������
NaOH
PhCH2NH2
72%
(45)
Also, nitriles on reaction with a mixture of NaBH4
and bis(2-bromoethyl)selenium dibromide (4), in boil-
ing THF give the corresponding primary amines (Eq.
(46)) [48].
RCN������������
1. NaBH4–4, THF
2. HCl
RCH2NH2.HCl
R�alkyl:aryl
35–73%
(46)
This reagent system does not affect many other sub-
stituents that are susceptible to H3B–THF [48b].
8. Reduction of acid chlorides
The acyl chlorides are efficiently reduced to the cor-
responding alcohols on reaction with Zn(BH4)2 in pres-
ence of TMEDA (Eq. (47)) [50]. Electron withdrawing
group in the substrates enhances the rate of reduction.
It is of interest to note that the selective reduction of
acyl chlorides in the presence of other functional
groups, such as chloro, nitro, ester and conjugated
double bond can be achieved using this reagent system.
RCOCl���������
NaBH4–ZnCl2
TMEDA
RCH2OH
R�alkyl:aryl
86–98%
(47)
M. Periasamy, M. Thirumalaikumar : Journal of Organometallic Chemistry 609 (2000) 137–151142
9. Reduction of nitro compounds
Nitro compounds are reduced to the corresponding
amino compounds effectively using the NaBH4–CuSO4
system (Eq. (48)) [51]. It was reported that this system
also reduces ketones, aliphatic esters, olefins and
nitriles.
(48)
A novel reagent system, prepared using BiCl3 and
NaBH4, reduces aromatic nitro compounds to the cor-
responding amines in good yields (Eq. (49)) [52]. The
functional groups such as Me, OH, NH2, OMe, Cl in
the aromatic ring do not have any marked effect on the
rate of the reaction. Moreover, these functional groups
survive during the reduction, making this process fairly
general and selective.
RNO2���������
NaBH4–BiCl3
THF
RNH2
R�alkyl:aryl
35–90%
(49)
The aromatic nitro compounds are also reduced in
good yields to the corresponding N-aryl hydroxyl-
amines using NaBH4 in the presence of catalytic
amounts of metallic selenium (Eq. (50)) [53].
(50)
These selenium catalysed reductions were accelerated
by electron withdrawing groups. The aliphatic nitro
compounds gave the corresponding oximes under these
conditions. The active species in this system is the
hydrogen selenide anion [54]. Hence, this method opens
up a new way to the use of selenium as a redox catalyst
in organic synthesis.
The N-aryl hydroxylamines have been also prepared
through antimony catalysed NaBH4 reduction of ni-
troarenes (Eq. (51)) [55].
(51)
The novel NaBH4–(NH4)2SO4 reagent system has
been used for the selective, rapid reduction of nitro
compounds to the corresponding amino derivatives in
good yields (Eq. (52)) [56].
RNO2����������������
NaBH4–(NH4)2SO4
EtOH, r.t., 30–120 min
RNH2
R�aryl (70–90%)
(52)
10. Reduction of aldehydes and ketones
The NaBH4 is a reagent of choice for the reduction
of aldehydes and ketones. The reactivity of NaBH4 can
be readily modified through its reaction with acetic acid
(Eq. 53) [2,57]. With excess of acetic acid, triacyloxy
borohydride is formed. The NaBH4–CH3COOH
reagent system has been used for reductions of enam-
ines, imines, vinylogous carbamates, aromatic and
aliphatic a,b-unsaturated tosylhydrazones, pyrylium
salts [58]. It has been also used for the reduction or
reductive N-alkylation of amines, oximes [59] and ni-
trogen containing heterocycles [2].
(53)
The NaBH(OAc)3 reagent has been used for the
chemoselective reduction of aldehydes in the presence
of ketones [2]. Also, selective reduction of ketones using
NaBH4 in glacial acetic acid solvent or NaBH4 in THF
using 3 equivalents of acetic acid were reported [60].
Further, highly stereoselective reduction of ketones was
also achieved using NaBH(OAc)3 in acetic acid (Eq. 54)
[61].
(54)
In the presence of ZrCl4, NaBH4 reduces the alde-
hydes selectively in high yields (Eq. (55)) [31].
PhCHO���������
NaBH4�ZrCl4
THF, r.t., 5 h
PhCH2OH
95%
(55)
Aromatic aldehydes are more selectively reduced
than the related ketones by the reducing system consist-
ing of NaBH4 and SnCl2 in THF (Eq. (56)) [62]. It may
of interest to note that selective reduction of aldehydes
in the presence of ketones is ordinarily impracticable
using the reducing agents such as alkali metal borohy-
drides, aluminohydrides and diborane [63].
PhCHO����������
NaBH4–SnCl2
PhCH2OH
96.8%
�PhCOPh
92%
(56)
M. Periasamy, M. Thirumalaikumar : Journal of Organometallic Chemistry 609 (2000) 137–151 143
The NaBH4 in combination with anhydrous AlCl3
conveniently reduces diaryl and aryl alkyl ketones to
methylenic hydrocarbons (Eq. (57)) [64].
(57)
Although alkali metal borohydrides have received
much attention in organic synthesis, the studies on the
use of alkaline earth metals are limited. For example,
a,b-unsaturated ketones more readily converted to allylic
alcohols selectively using NaBH4 in the presence of CaCl2
(Eq. (58)) [65]. Among the alkaline earth metal chlorides
examined, CaCl2 gives the best combination of good
yields and selectivities in the NaBH4 reduction of 2-cyclo-
hexen-1-one. Further, this method provides a simple,
inexpensive alternative procedure for the selective 1,2-re-
duction of a,b-unsaturated ketones.
(58)
Metal salts mediated NaBH4 reduction of a-alkyl-b-
keto esters leads to different stereochemical control
depending on the nature of the metal atom. For example,
the strongly chelating TiCl4 led to the syn isomer while
non-chelating CeCl3 [66] gave anti isomer [67]. The keto
esters are also reduced using the ZnCl2–NaBH4 system
to afford the corresponding hydroxy ester (Eq. (59)) [68].
(59)
Stereoselective reduction of 3-keto-2-methyl esters
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