Glucose promoted facile reduction of azides to amines under aqueous alkaline conditions

Article abstract of DOI:10.1039/c7gc01593c

A quick and efficient method for the reduction of azides to amines in water using d-glucose and KOH as green reagents is reported. The protocol is simple, inexpensive, scalable, and can be applied to different aromatic, heteroaromatic and sulphonyl azides. A high level of chemoselectivity is observed for azide reduction in the presence of other reducible functionalities like cyano, nitro, ether, ketone, amide and acid. The reaction gets completed in a short time (5-20 minutes), and furnishes the amines in high yield (85-99%). Unlike conventional hydrogenations, this reduction protocol does not require any metal catalyst, elaborate experimental setup or use of high-pressure equipment.

Full text of DOI:10.1039/c7gc01593c

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Glucose promoted facile reduction of azides to amines in aqueous alkaline conditions
Nisha Chandna, Fatehjeet Kaur, Shobhna Kumar and Nidhi Jain*
Department of Chemistry, Indian Institute of Technology, New Delhi-110016
*E-mail: njain@chemistry.iitd.ac.in; Fax: +91 11 26581102; Tel: +91 11 26591562
Abstract:
A quick and efficient method for reduction of azides to amines in water using D-glucose and KOH
as a green reagent is reported. The protocol is simple, inexpensive, scalable, and can be applied to
different aromatic, heteroaromatic and sulphonyl azides. A high level of chemoselectivity is
observed for azide reduction in presence of other reducible functionalities like cyano, nitro, ether,
ketone, amide and acid. The reaction gets completed in short time (5-20 minutes), and furnishes
the amines in high yield (85-99%). Unlike conventional hydrogenations, this reduction protocol
does not require any metal catalyst, elaborate experimental setup or use of high-pressure
equipment.
Introduction:
Organic azides are versatile and useful synthons which find wide applications in the synthesis of
heterocycles.1,2 They can be prepared with good regio, stereo, and enantioselectivity and their
transformation to amines provides an access to a variety of organic intermediates, particularly
useful in the synthesis of pharmaceuticals, carbohydrates and nucleosides.3, 4 Although there are
several methods available in the literature for preparation of amines, their synthesis through
reduction of azides is one of the important protocols since azides can be easily prepared5-8 from
halides and sulfonates. A number of reagents have been developed over the years to bring about
this reductive transformation, and can be typically classified as: (i) hydride donors9 such as LiAIH4
or NaBH4; (II) H2 gas or its source in the presence of transition metals and their oxides (MOs) as
catalyst;10-12 (iii) low-valent metal ions13 such as SnCl2, CrCl2, TiCl3 / boranes14, 15 / silanes;16 (iv)
phosphine reagents17 as in Staudinger reaction; (v) sulphur reagents18 e.g thiolates etc. Though
useful, these methods suffer from limitations with regard to chemo-selectivity in presence of other
reducible functionalities, use of transition metals, harsh reagents, and cost efficiency. Thus, it is
highly desirable to develop reduction protocols for azides which are transition metal free,
chemoselective, and do not involve toxic hydrogen source.

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Carbohydrates are chiral organic molecules readily available from natural and renewable
resources. They are inexpensive, eco-friendly, compatible with biological systems, and soluble in
water. All these properties encouraged us to explore their capability as a hydrogen source for
reduction of azides. Continuing our efforts towards greener and economical chemical protocols,19-
22
we herein report the reduction of aromatic, heteroaromatic and sulfonyl azides to the
corresponding amines using D-glucose and KOH in aqueous conditions.
Scheme 1 Various methods for reduction of azides to amines.
Results and Discussion:
The aim to develop a transition metal-free reduction of azides motivated us initially to investigate
the reaction of 4-azidobenzonitrile (1a) with 2 equiv. of D-glucose and KOH in DMF at 110 °C.
As desired, 4-aminobenzonitrile (2a) was formed (Scheme 1), albeit in moderate yield (72%)
(Table 1, entry 1). In a quest to improve the yield of product, reaction conditions were optimized.
Screening of solvents showed that switching from DMF to DMSO (Table 1, entry 2) dropped the
yield of 2a to 30% along with formation of other undesired products. Further, either no conversion
or trace conversions took place in 1,4-dioxane, toluene, [Bmim]PF6, and N-methyl-2-pyrrolidone
as solvents. In DMF: H2O (1:1), the yield of 2a increased to 80% (Table 1, entry 3). To eliminate

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the use of organic solvent completely, we treated 1a with 2 equiv. of D-glucose and KOH in
minimum amount of water at 110 °C in a pressure tube. We found that the reaction completed in
ten minutes, and was indicated by a change in color of the reaction mixture from yellow to brown
(Table 1, entry 4). Next, we optimized the conditions with respect to base, catalyst, and temperature
in water. Use of other inorganic bases like NaOH and K2CO3 gave lower yields of 2a (Table 1,
entries 5 and 6). Similar low yields were seen with Na2CO3, NaOtBu, KOtBu, and CH3COONa.
Control reaction in the absence of base did not yield any product even after prolonged heating for
24 h (Table 1, entry 7). Reducing the amount of KOH to 1 equiv., or raising it to 5 equiv. resulted
in incomplete conversion. However, with 3 equiv. of KOH, 2a was formed in almost 99% yield
(Table 1, entry 8). Optimizing the temperature revealed that reaction performed equally well at 85
°C (Table 1, entry 9), and conversion was complete in ten minutes. Amount of D-glucose was also
varied (1-3 equiv.), and it was found that 2 equivalents were necessary and sufficient for the
reaction (Table 1, entry 10). To establish the role of sugars in promoting the reaction, other sugars
such as maltose, fructose, D-mannose, sucrose and cellulose were tested (Table 1, entries 11-15);
of which only D-mannose was found to be effective. Further, no conversion took place in the
absence of added sugar (Table 1, entry 16).
Table 1 Optimization of reaction conditions for reduction of 1a
Carbohydrate
(equiv.)
Base
(equiv.)
Temp
(° C)
Yieldb
(%)
Entry
Solvent
Time
D-Glucose
(2)
D-Glucose
(2)
KOH
(2)
KOH
(2)
1.
2.
110
110
DMF
10 min
10 min
72%
30%
DMSO
D-Glucose
(2)
KOH
(2)
DMF:Water
(1:1)
3.
4.
110
110
10 min
10 min
80%
90%
D-Glucose
(2)
KOH
(2)
Water

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D-Glucose
(2)
NaOH
(2)
5.
6.
110
110
Water
Water
10 min
62%
D-Glucose
(2)
K2CO3
(2)
10 min
54%
NR
D-Glucose
(2)
D-Glucose
(2)
D-Glucose
(2)
D-Glucose
(1 & 3)
D-Maltose
(2)
D-Fructose
(2)
D-Mannose
(2)
Sucrose
(2)
Cellulose
(2)
7.
-
110
110
85
85
85
85
85
85
85
85
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
24 h
KOH
(1-5)
KOH
(3)
KOH
(3)
KOH
(3)
KOH
(3)
KOH
(3)
KOH
(3)
KOH
(3)
KOH
(3)
70c, 99d,
65e
8.
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
9.
99%
50% &
98%
10.
11.
12.
13.
14.
15.
16.
60%
58%
95%
NR
NR
-
NR
aReaction conditions: 1a (1 mmol, 1 equiv.), D-Glucose (2 mmol, 2 equiv.), KOH (3 mmol, 3
equiv.) were taken in water (100 휇퐿), and stirred for 10 min at 85 °C, bYield of 2a as determined
by HPLC conversion, c1 equiv. KOH, d3 equiv. KOH, e5 equiv. KOH, NR= No Reaction
Next, we investigated the generality and scope of this reaction by reacting a range of azides under
the optimized conditions in water. Though the azides were partly soluble in water at the beginning
of the reaction; but as the reaction proceeded at 85 °C, the solution turned homogeneous. Notably,
a rapid completion of reaction was observed in most cases (Table 2). Further, the work-up was
simple and clean. The amines, partly soluble in water, could be easily isolated from the reaction
mixture by extracting it with ethyl acetate. In most cases, the product was free from any associated
impurities, and no column was required for further purification. The reduction of halogenated aryl
azides yielded the corresponding amines 2c-2g in high yields without suffering any dehalogenation
(Table 2). In few cases (Table 2, compounds 2d, 2j and 2k), the reaction was found to perform
better in DMF: H2O (0.5:1), though these reactions took longer time (18-120 min) to complete.
High chemoselectivity with excellent yields was observed with 4-nitro and 3-nitrophenylazides as

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the azide group reduced exclusively in presence of nitro yielding the corresponding nitro anilines
(2h, 2i). Notably, even on using excess (6 equiv.) of D-glucose and KOH, azido group reduced
selectively in presence of nitro. Aryl azides substituted with methoxy and methyl groups (1j and
1k) were successfully reduced though much longer reaction times were required. 4-
Azidoacetophenone, 4-azidobenzoic acid and 4-azidobenzamide gave the corresponding anilines
(2l-2n) without reducing the carbonyl functionality. The methodology also worked very well for
reduction of azides in presence of sulphonamide group (1o) as well as with 1-azidonaphthalene
(1p). Further, the protocol was equally facile for heterocyclic azides, and clean reactions were
observed in all the cases without affecting the heterocyclic ring (2q-2s). Unfortunately, the reaction
did not work with alkyl azides, and no amine formation was seen with n-butyl azide as the
substrate. In addition to aryl and heteroaryl azides, the sulphonyl azides (1t-1v) could also be
reduced efficiently to the corresponding amines (2t-2v) in near quantitative yields within minutes.
Reduction of biologically relevant azides, 5-phenylthiazol-2-azide (1w) and 5-(4-
chlorobenzyl)thiazol-2-azide (1x) yielded the corresponding aminothiazoles (2w, 2x) in 95 and
96% yields respectively. These compounds are known to display potent antifungal, antibacterial,
antitubercular, and anticancer activities.23 It is noteworthy to reiterate that the reaction time
required for conversion of azides to amines is much lower compared to any of the previous
methods discussed above in Scheme 1.
Table 2 Scope of reduction of azides to aminesa,b

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aReaction conditions: 1 (1 mmol, 1 equiv.), D-Glucose (2 mmol, 2 equiv.), KOH (3 mmol, 3
equiv.) were taken in water (100 휇퐿) in a pressure tube, and stirred at 85 °C, bisolated yield, csolvent
was DMF: H2O (0.5:1, 100 휇퐿)
Next, the synthetic utility of the developed protocol was ascertained by carrying out the
reaction on a gram scale. The reduction of 4-azidobenzonitrile (1a), 2-azidoquinoline (1r) and p-
toluenesulphonyl azide (1o) starting from 10 mmol of these substrates under the optimized reaction
conditions yielded the corresponding amines 2a, 2r and 2o in 95%, 93% and 97% yields
respectively.

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Further, we also applied this protocol successfully to 5-(azidomethyl)-3-(3-fluoro-4-
morpholinophenyl) oxazolidin-2-one (1y) which is an intermediate in the preparation of the
antibiotic Linezolid. The azide could be reduced using the general reaction conditions and the
desired amine (2y) was isolated in 50% yield. However, K2CO3 was used instead of KOH to avoid
the ring opening of oxazolidinone. Increasing the amount of glucose to 3 mmol and K2CO3 to 5
mmol enhanced the yield of 2y upto 60%.
Scheme 2 Azide reduction step in synthesis of linezolid.
To identify the source of hydrogen and understand the mechanism, the reaction of 1a was carried
out in D2O instead of water (Scheme 3a). A single non-deuterated product 2a was obtained which
indicated that hydrogens of amine were being provided by glucose which acted as a reducing agent
in the reaction. Based on literature reports24-26 and D2O experiment, we believe that the reduction
of azide to amine is mediated through a hot alkaline degradation of glucose which generates
hydrogen in situ along with formation of lactate, acetate, formate and glycolate ions (Scheme 3b).
To confirm this, a model reaction of 1a was carried out in D2O, and NMR analysis of the reaction
mixture was performed (supporting info). The NMR data revealed that along with the formation
of reduced product 2a, lactate, acetate and formate ions were also being produced in the reaction.
These findings support our proposed pathway for hydrogen generation in this reaction (Scheme
3b).

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Scheme 3 a) Reaction in D2O; b) Proposed mechanism for reduction.
Conclusions
In conclusion, a highly efficient method for the reduction of aryl(heteroaryl)azides and aryl
suphonyl azides to corresponding amines and sulphonamides employing D-glucose as the
hydrogen source along with KOH in water is reported for the first time. The reagents are
inexpensive, non-stinking and non-toxic. The protocol is highly chemoselective and challenging
functional groups such as CN, NO2, COR, and SO2NH2 are well tolerated. The reaction is a rapid
and practical way of accessing amines from aryl, heteroaryl, and suphonyl azides under metal-free
conditions. The present method compares favorably to most of the earlier literature reported
procedures.
Acknowledgments
Dr. N. C. thanks DST for SERB-National Post-Doctoral Fellowship. The authors thank DST-FIST
for funding the ESI-HRMS facility at IIT Delhi.
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Ar/
HetAr
N3/SO2N3
Y
10-15 min
1. Upto 99% yield
2. Highly chemoselective
3. Cheap reagents
4. Water as medium
Y= F, Cl, Br, CH3, OCH3, CN, NO2, COCH3, CONH2, COOH, SO2NH2