Iron triflate catalyzed reductive amination of aldehydes using sodium borohydride

Article abstract of DOI:10.1016/j.tetlet.2012.06.018

An efficient and convenient procedure for the reductive amination of aldehydes using NaBH₄ in the presence of catalytic amount of Fe(OTf)₃ is described.

Full text of DOI:10.1016/j.tetlet.2012.06.018

Tetrahedron Letters 53 (2012) 4354–4356
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Tetrahedron Letters
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Iron triflate catalyzed reductive amination of aldehydes using
sodium borohydride
N. Uday Kumar a, B. Sudhakar Reddy a, V. Prabhakar Reddy b, Rakeshwar Bandichhor a,
⇑
a Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur, R.R. Dist. 500072, Andhra Pradesh, India
b Department of Chemistry, Osmania University, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient procedure for the reductive amination of aldehydes using NaBH4 in the pres-
ence of catalytic amount of Fe(OTf)3 is described.
Received 13 April 2012
Revised 1 June 2012
Accepted 6 June 2012
Available online 12 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Reductive amination
Iron triflate
Sodium borohydride
Direct reductive amination of aldehydes in one pot is an impor-
tant transformation in organic synthesis from process efficiency
standpoint. Wherein, alternatively, indirect or two step reductive
amination involves isolation of imine derivative with impeded
efficiency (Scheme 1).
complex,16 FeII/EDTA complex,17 LiBH4,18 ammoniaborane/
Ti(OiPr)4,19 bis(triphenylphosphine)copper(I) tetrahydroborate,20
molybdenum dioxide dichloride and phenylsilane21 etc. have been
reported.4f Moreover, reagents containing zinc and Ti(OiPr)4 medi-
ated are not suitable for chemoselective reductions.22 Usage of tin
hydrides is not suitable due to toxicity in large scale production as
the removal of residual tin is found to be extremely difficult. Re-
cently, Hantzsch method that involves dihydropyridine as reduc-
tant (removal of toxic pyridine is found to be extremely difficult)
in the presence of scandium triflate as a catalyst,23 S-benzyl isothio-
uronium chloride as a recoverable organocatalyst along with dihy-
There are two types of reducing agents employed for direct
reductive amination of aldehydes with amines. These two strate-
gies are mainly based on metal catalyzed hydrogenation and
hydride reducing agents. The metal catalyzed hydrogenation has
limitations to many substrates which has reducible functionalities
apart from imines.1 There is another excellent Borch reduction
approach, one of the early methods that involves sodium cyano-
borohydride.2a In addition to this, derivatives of cyano borohydride
in combination with other reagents2b–f are also being used but the
cyanoborohydride derivatives suffer from the formation of highly
toxic byproducts such as HCN and NaCN. Numerous alternative
reagents such as NaBH(OAc)3,3a TiCl(OiPr)3/NaBH(OAc)3,3b NiCl2/
NaBH4,4a NaBH4/ZnCl2,4b NaBH4/ZrCl4,4c Ti(OiPr)4/NaBH4,4c NaBH4/
dropyridine,24
Pd(PhCN)2Cl2/2,20-biquinoline-4,40-dicarboxylic
acid dipotassium salt (BQC)25 and Leuckart type reductive amina-
tion26 are also reported for reductive amination.
Metal triflate catalyzed reductive amination procedures are
well documented. In most of the cases, the metals as part of cata-
lysts are not suitable for the synthesis of active pharmaceutical
ingredients (APIs) due to regulatory requirements as one has to
limit the traces of them in the order of ppms (parts per millions).27
H2SO4,4d NaBH4/wet clay,4e solid acid activated NaBH4,4f NaBH4/
4g
H3PW12O40
,
NaBH4/Bronsted acidic ionic liquid,4h NaBH4/(GuH-
Cl),4i borohydride exchange resin,5 pyridine/borane,6 picoline/bor-
ane,7 diborane/MeOH,8 decaborane,9 ZnBH4,10a ZnBH4/ZnCl2,10b
ZnBH4/SiO2,10c Zn/AcOH,11 PMHS/Ti(OiPr)4,12a PMHS/ZnCl2,12b
PMHS/BuSn(OCOR)3,12c Et3SiH/CF3CO2H,12d PhMe2SiH/(C6F6)3,12e
Direct
H
NHR1
catalyst
O
reagent
R
R
Cl3SiH/DMF,12f PhSiH3/Bu2SnCl2,12g PMHS/TFA,12h nBu3SnH/DMF or
13b
reagent
HMPA,13a nBu3SnH/SiO2
and nBu2SnIH or nBu2/SnClH,13c,d
catalyst
H
Zr(BH4)4/piperazine,14 hydrio-iridium(III) complex,15 iridium
NR1
R
Indirect
⇑
Corresponding author.
E-mail address: rakeshwarb@drreddys.com (R. Bandichhor).
Scheme 1. Direct and indirect reductive amination.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.018

N. Uday Kumar et al. / Tetrahedron Letters 53 (2012) 4354–4356
4355
Class 1 (toxic)
Pt, Pd, Ir, Rh, Ru, Os
Mo, Ni, Cr, V
Class 2 (less toxic)
Class 3 (non-toxic)
OLA
LA
H
O
O
Cu, Mn, Ti, Sc
Zn, Fe
R
H
R
R
H
R1
Fe(OTf)3
(TfO)3Fe
N
Figure 1. Comparative toxicological classification of the metals.
H
H
NH2
R1
H
NR1
(a-t)
1 mol% Fe(OTf)3
1 eq. NaBH4
H
O
O
OLA
H2NR1
R
R
H
NaBH4
H
R
3
R
1
R
H
2
NH
N
N
R1
R1
R, R1 = alkyl,aryl or heterocyclic
R1
H
H2O
Ph
N
H
N
H
Scheme 3. Possible mechanism for direct amination.
N
Ph
H
3a 90%
3d 90%
3b 90%
3c 92%
NHPh
most widely recommended due to its non-toxic nature. Such a
strategy that features Fe(OTf)3/NaBH4 reducing system provides
very efficient and workable protocol to address the associated
industrial problems up to great extent from three standpoints;
(1) reduced duration of the reaction, (2) high conversion and (3) re-
laxed specification for metal content as Fe in pharmaceutical prod-
ucts is relatively much safer as per the US FDA guidelines.27 This
adds to a better process efficiency as one can avoid purifications
and thereby increase the isolated yield in comparison to hitherto
known procedures.
NHPh
N
H
Ph
O
CF3
3f 88%
Cl
3e 80%
NHPh
NHPh
NHPh
EtO
F
3i 82%
3h 90%
3g 90%
NHPh
In our endeavor, catalytic quantity of iron triflate (Fe(OTf)3
along with NaBH4 was opted for direct reductive amination.
Sodium borohydride is an inexpensive reducing agent which
stands alone known to reduce imines and other functionalities
limiting its application in broader sense. Moreover, it is under-
stood that the poor electrophilic carbonyls, poor nucleophilic
amines, and sterically crowded reactive centers do not favor the
completion of imine formation. Thus, it is quite apparent that
NaBH4 alone may not afford excellent yields. Strategically, we em-
ployed the combination of 1 mol % Fe(OTf)3 along with stoichiom-
etric amount of NaBH4 for the first time in the direct reductive
amination. This strategy was demonstrated with various alde-
hydes and amines.
H3CO
OCH3
N
H
C2H5O
3j 87%
3l 89%
3k 88%
N
H
Ph
N
H
Ph
C2H5O
NO2
3m 92%
N
Ph
N
H
Ph
H
O2N
Cl
3n 89%
3o 90%
The reaction of aldehydes 1 with amines 2 proceeded smoothly
in CH2Cl2 with excellent yields as shown in Scheme 2.30 In most of
the cases, we obtained pure products hence there was no need to
involve column chromatography. The catalytic activity of Fe(OTf)3
in reductive amination, was probed by conducting the control
experiment without the catalyst. In this control experiment, we
found that only NaBH4 did not afford clean imine rather we
encountered incomplete reaction as well as alcohol as a byproduct.
This strategy was extended not only to model substrates but it
has found application in the synthesis of pharmaceutically relevant
intermediates for example, Cinacalcet (3s)28 and Aliskiren (3t).29
Mechanistically, iron triflate as a Lewis acid activates the car-
bonyl functionality and provides very reactive electrophile source.
Amine that was used as substrate reacts with the activated alde-
hyde to afford hemiaminol equivalent. Thereafter, dehydration
event regenerates the catalyst. In situ generated imine can further
be reduced with sodium borohydride affording the products as
shown in Scheme 3. Our approach allowed us to have quick access
of the products as the rate of the reaction was found to be very fast
(in the order of minutes) in comparison with the non-catalytic
reactions for example, NaBH(OAc)3,3a mediated reactions take
2 h–10 d for such type of reductive amination.
O2N
N
H
Ph
N
H
OH
Ph
H3CO
OCH3
3p 90%
3q 90%
H
N
N
H
Ph
CF3
CF3
3r 89%
3s Cinacalcet 80%
O
O
O
O
HN
Ph
O
3t Aliskiren intermediate 88%
Scheme 2. Fe(OTf)3 catalyzed reductive amination of carbonyl compounds.
We have developed and demonstrated novel method by involv-
ing catalytic quantity of iron triflate and sodium borohyderide
(1 equiv) which can be considered as synthetically useful reagent
system for reductive amination in one pot.
In order to do so, a tedious workup is required that becomes costly
affair due to material loss. Therefore, we attempted to develop
non- or less toxic metal triflate which is readily and cheaply avail-
able in the market. In comparison to other metals (Fig. 1),27 Fe is

4356
N. Uday Kumar et al. / Tetrahedron Letters 53 (2012) 4354–4356
12. (a) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett 2000, 1655; (b)
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We are grateful to the management of Dr. Reddy’s Laboratories
Ltd for supporting this work. We are thankful to NMR group of DRF
for their assistance.
Dr. Reddy’s communication number IPDO IPM-00327.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.018.
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