Highly chemoselective reduction of azides to amines by Fe(0) nanoparticles in water at room temperature

Article abstract of DOI:10.1016/j.tetlet.2017.07.076

A highly chemoselective reduction of aryl, heteroaryl, acyl and sulfonyl azides to the corresponding amines has been achieved by Fe(0) nanoparticles in water at room temperature in the absence of external hydride source. Several readily reducible functionalities including alkene, alkyne, S-S linkage, OTBDMS remain unaffected during reduction.

Full text of DOI:10.1016/j.tetlet.2017.07.076

Accepted Manuscript
Highly chemoselective reduction of azides to amines by Fe(0) nanoparticles in
water at room temperature
Subir Panja, Debasish kundu, Sabir Ahammed, Brindaban C. Ranu
PII:
S0040-4039(17)30938-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.076
TETL 49158
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
27 June 2017
20 July 2017
21 July 2017
Please cite this article as: Panja, S., kundu, D., Ahammed, S., Ranu, B.C., Highly chemoselective reduction of azides
to amines by Fe(0) nanoparticles in water at room temperature, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.07.076
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Graphical Abstract
Highly chemoselective reduction of azides to
amines by Fe(0) nanoparticles in water at
room temperature
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Subir Panja, Debasish Kundu, Sabir Ahammed, Brindaban C. Ranu

1
Tetrahedron Letters
Highly chemoselective reduction of azides to amines by Fe(0) nanoparticles in water
at room temperature
Subir Panja,a Debasish kundu,a Sabir Ahammed,a and Brindaban C. Ranu*a
aDepartment of Organic chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata – 700032, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly chemoselective reduction of aryl, heteroaryl, acyl and sulfonyl azides to the
corresponding amines has been achieved by Fe(0) nanoparticles in water at room
temperature in the absence of external hydride source. Several readily reducible
functionalities including alkene, alkyne, S-S linkage, OTBDMS remain unaffected
during reduction.
Available online
Keywords:
reduction
azide
Fe(0) Nanoparticles
amines
chemoselectivity
Introduction
The organic azides are of much importance as they have
versatile applications in the synthesis of a wide variety of useful
compounds such as triazoles, tetrazoles and other heterocycles.1
The reduction of azides provides an easy access to amines which
play important role in both biology and chemistry as the amines
constitute the vital unit for many useful pharmaceuticals,
biologically active compounds, natural products, rubber and
dyes.2 As azides are easily accessible from halides and
sulfonates3 several methods are reported for the preparation of
amines from azides.4 However reduction of azide in the presence
of other reducible groups, particularly S-S linkage5 is difficult to
achieve. Notably, many biologically relevant molecules such as
DNA oligonucleotides contain S-S linkage along with amine
functionality (Figure 1) and thus reduction of azide in the
presence of S-S linkage is of much importance. Several
procedures involving hydride reducing agents,6a triphenyl
phosphine,6b radical initiators,6c Zn(BH4)2,6d Cl2InH,6e
molybdenum xanthate/PhSiH36f metal catalyzed hydrogenations6g
etc. were employed. However, these protocols are associated with
one or more of the limitations such as chemoselectivity, general
applicability, cost efficiency, harsh reaction conditions and
tedious work up procedures.7
Fig. 1. A few biologically active molecules containing S-S
bond.
the parent metals.8 Catalytic hydrogenations in the presence of
transition metal nanoparticle based on Pd,9 (Pt, Ru)10 and Cu11
have been accomplished in the presence of a co-reductant like
hydrazine hydrate,ammonium formate, methanol etc. However
the high cost and toxicity of these metals led to find alternate
economical, and environmentally benign candidates. The
consideration of Fe-catalysis receives prime importance as iron is
one of the most inexpensive, abundant and environmentally
friendly transition metals. Recently a couple of methods based on
In general, hydrogenations over transition metal nanoparticles
provide an efficient tool for reduction due to the availability of
more active surface area of the metal nanoparticles compared to
 Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33
24732805.
E-mail address: ocbcr@iacs.res.in (B.C. Ranu).

2
Tetrahedron
aReaction conditions: azidobenzene (1 mmol), rt, solvent (5 ml).
o
Fe such as Fe(acac)3/N2H4.H2O/MW(150 C)4h and Fe3O4 NPs/
N2H4.H2O/120 oC12 have been reported for the reduction of
azides to amines. However, these Fe-catalyzed procedures are
associated with use of high temperature and excess co-reductant
for efficient reduction and also poor chemoselectivity with aryl
nitro-azides.12 Thus a simpler and greener protocol with high
chemoselectivity is highly desired. In continuation of our interest
on application of metal nanoparticles4n,11,13 we report here a
highly chemoselective reduction of aryl/heteroaryl azides to
amines using Fe(0) nanoparticles14 in water at room temperature
in the absence of any external co-reductant as H-source (Scheme
1).
To standardize the reaction conditions several experiments have
been performed by varying the reaction parameters such as
solvent, time, amount of Fe(0) Nps etc for a representative
reduction of azidobenzene (Table 1). Solvents such as toluene,
dichloromethane (DCM), N,N-dimethyl formamide (DMF),
dimethyl sulfoxide (DMSO), acetonitrile failed to produce
satisfactory results (Table 1, entries 1-5). The reaction went
efficiently in water using 3 equivalents of Fe nanoparticles (Table
1, entry 6). However, the reaction furnished only 30% yield
using 2 equivalents of Fe(0) NPs in water (Table 1, entry 8).
Interestingly, a protic solvent methanol failed to initiate the
reduction process. Thus water has a decisive role in this reaction.
A wide range of substituted aromatic azides have been reduced
successfully by this procedure to produce the corresponding
aromatic amines. The result was summarized in Scheme 2. The
easily reducible functionalities such as –COPh (2n), –COOMe
(2l), –COOH (2j), -CN (2i), -CONH2 (2k), -OAc (2s) and the
halogen moieties –F (2i), -Br (2h), -I (2g), and -Cl (2f) in the
aromatic ring remained unaffected during the reaction. The
reactions went successfully with electron donating substituent in
the aromatic ring e.g –OMe, -Me and -Et (Scheme 2, 2a-2d). The
more vulnerable moieties such as O-benzyl (2m), O-Allyl (2r),
O-TBDMS (2q), cinnamyl, styrenyl double bond (2p), triple
bond (2o) etc remained unaffected during the reaction conditions.
The N-heterocyclic rings such as pyridine, quinoline etc also
produce satisfactory results.
Scheme 1. Highly selective water mediated azide reduction
by Fe(0) NPs .
Our primary consideration in selective reduction of the azide
moiety is to find a target specific reducing agent which is just
enough to reduce the azide functionality in the presence of other
reducible functionalities on the aromatic ring. As Fe(0)
nanoparticles are more reactive compared to Fe(0) powder, better
co-ordination of Fe NPs with water molecules is expected and in
this situation the electrophile hydrogens of water are likely to
attain pseudo-hydride character and such mild hydride is
considered enough to reduce the aromatic azide moieties keeping
the other reducible functionalities in the aromatic ring unaffected.
Results and Discussion
The Fe nanoparticles were obtained by a reported procedure
using FeCl3 and sodium borohydride and used as such.14 Aryl
azide (1 mmol) was stirred with Fe(0) nanoparticles (3 mmol) in
water at room temperature for a required period of time (TLC).
Extraction by ethyl acetate and standard work up provided the
product. The Fe(0) NPs obtained by a different procedure using
tea extract15 without using any hydride reducing agent also
provides the same result.
Table 1
Standardization of reaction conditions
aReaction conditions: azidobenzene (1 mmol), Fe (0) nanoparticles (3 equiv.),
Yield (%)[a]
rt, water (5 ml), 2h. b4 h was required.
Fe(0)Nps
(equiv.)
Time
(h)
Entry
Solvent
Scheme 2. (Fe(0) nanoparticles mediated reduction of
aromatic and heteroaromatic azides
1
2
3
4
5
6
7
8
3
3
3
3
3
3
3
2
toluene
dichloromethane
DMF
12
12
12
12
12
2
-
-
Interestingly, under the reaction conditions the -NO2
functionality was reduced to amine keeping -N3 intact in
aromatic ring. However, in the presence of reduced amount
(50 mol %) of Fe(0) nanoparticles and 2 equivalents of
CH3COONH4 under refluxing conditions, the azide moiety
was reduced to amine by keeping NO2 unaffected (Scheme
3). CH3COONH4 is a co-reductant and helps the selective
reduction of azide over nitro functionality under this
trace
trace
-
DMSO
CH3CN
H2O
95
MeOH
12
4
-
35
H2O

3
We have developed a simple and green procedure for the
conditions. However, the exact role of ammonium acetate is
not clear yet.
reduction of aryl/heteroaryl/acyl/sulfonyl azides to the
corresponding amines using iron nanoparticles in water at room
temperature without any external reducing agent. The significant
feature of this protocol is high chemoselectivity leaving sensitive
functionalities such as S-S linkage, alkene, alkyne and OTBDMS
unaffected during the reduction process and this quality makes
this procedure superior to the existing methods. The other
advantages include mild reaction conditions (reaction at room
temperature and neutral medium), water as reaction medium, use
of inexpensive and benign iron (0) nanoparticles as reagent and
high yield of reduced products. Certainly, this methodology will
find useful applications in organic synthesis.
Scheme 3. Fe(0) Selective reduction of aromatic nitro-azides
by Fe(0) nanoparticle.
Significantly this protocol allows selective reduction of
azide and nitro functionality in presence of each other.
Remarkably, the reduction of the aromatic azide in the
presence of di-sulfide bond is achieved under the conditions
(Scheme 4). This will be of much importance in the
reduction of bioactive azide molecules containing S-S
linkage.16 This is not addressed with conventional reducing
agents.17
Acknowledgments
We gratefully acknowledge the financial support from DST,
Govt. of India for the award of J C Bose fellowship Grant
(SR/S2/JCB-11/2008) and Indian National Science Academy,
New Delhi for the offer of INSA Senior Scientist to BCR. SP
thanks CSIR for his fellowship.
Supplementary Material
Supplementary data (1 H NMR, 13C NMR data and 1 H NMR, 13
C
NMR spectra of all compounds listed in Schemes 2, 3, 4 and 5)
associated with this article can be found, in the online version, at
References and notes
Scheme 4. Selective reduction of azide group over di-sulfide
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Highlights
 Highly chemoselective reduction of azide to
amine at room temperature in water
 Use of inexpensive and nontoxic iron
nanoparticles
 Use of no hydride reducing agent
 Tolerance to a wide spectrum of functional
groups including S-S linkage