A new way to do an old reaction: highly efficient reduction of organic azides by sodium iodide in the presence of acidic ion exchange resin

Article abstract of DOI:10.1039/c6cc08574a

Organic azides are readily reduced to the corresponding amines by treatment with sodium iodide in the presence of acidic ion exchange resin. The process, optimal when performed at 40 °C and 200 mbar pressure on a rotatory evaporator, is extremely efficient, clean, and tolerant of a variety of functional groups.

Full text of DOI:10.1039/c6cc08574a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: K. Suthagar and A.
J. Fairbanks, Chem. Commun., 2016, DOI: 10.1039/C6CC08574A.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 3
View Article Online
DOI: 10.1039/C6CC08574A
Journal Name
COMMUNICATION
A new way to do an old reaction: highly efficient reduction of
organic azides by sodium iodide in the presence of acidic ion
exchange resin
Received 00th January 20xx,
Accepted 00th January 20xx
Kajitha Suthagar,a and Antony J. Fairbanks*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
Organic azides are readily reduced to the corresponding water and filtered through a column of acidic ion exchange
amines by treatment with sodium iodide in the presence of resin (Amberlite IR 120, H+ form) to remove residual imidazole.
acidic ion exchange resin. The process, optimal when Surprisingly analysis of the final reaction product revealed the
o
performed at 40 C and 200 mbar pressure on a rotatory complete absence of any azide functionality; the major
evaporator, is extremely efficient, clean, and tolerant of a product was purified and identified as 6-amino mannose 2.14
variety of functional groups.
Ph3P, I2, imidazole, DMF
H2N
HO
HO
HO
OH
O
OH
O
Azide is a highly versatile functional group,1 which has surged
in prominence over recent years due to the burgeoning utility
of the the Cu-catalysed2 and strain-promoted3 Huisgen
cycloadditions, and the highly useful Staudinger ligation;4 all
processes which have found wide application under
biocompatible conditions.5 More long-standing interest has
centred on the highly useful reduction of azides to amines; one
of their most effective means of amine synthesis. Indeed the
literature abounds with different methods of azide reduction.6-
then NaN3, DMF
then filter through
Amberlite IR 120 (H+ form)
56%
HO
HO
OH
OH
1
2
Scheme 1. Unexpected azide reduction and direct production of 6-amino mannose.
We reasoned that the azide must have been reduced by
residual iodide, which was either left over from the Appel
reaction or produced during the nucleophilic substitution
process. However, we were intrigued by the ease and
11
Although it may appear that sufficient synthetic methods
efficiency with which the azide reduction had occurred.
A
already exist for this highly useful functional group
interconversion, each of the above methods has limitations,
either with respect to other functional group tolerance, or
associated issues of product purification, for example removal
of the phosphine oxide by-product from the Staudinger
reduction. Occasionally situations still arise in which the more
traditional methods of azide reduction do not work well.12
During investigations into the use of a series a carbohydrate-
based azides for the production of sugar-sulfamides,13 we
unexpectedly observed the in situ reduction of an
intermediate azide. During this process (Scheme 1) mannose 1
was first subjected to an Appel reaction. Following removal of
the triphenylphosphine and triphenylphosphine oxide (by
washing with dichloromethane), the crude material was
carried through to the next step of azide displacement. At the
end of that process the reaction product was dissolved in
search of the literature revealed several reports of the
reduction of azide by iodide, but in all cases such reactions had
required the use of strong Lewis acids, for example BF3.OEt2,15
16
FeCl3 , CeCl317 or Al or Gd triflates.18
Intrigued by the apparent simplicity and efficiency of the
iodide-mediated reduction process in the absence of strong
Lewis acids, we undertook a series of investigations to further
probe this unexpectedly facile reaction. Our motivation was to
arrive both at an optimised procedure in terms of practicality,
and to investigate reaction scope with respect to applicability
to a variety of different substrates.
In order to arrive at an optimised procedure, azide 3a was
used as a substrate for variation of reaction parameters (Table
1). In previously reported procedures15-18 typically nine
equivalents of sodium iodide had been used, although from a
redox perspective only two equivalents of iodide should be
required. Studies therefore commenced with the use of two
equivalents of iodide. In addition to iodide, the reduction of an
azide to an amine additionally requires two protons. Reasoning
that acidic ion exchange resin, which may be separated from
polar reaction products simply by filtration, may be the most
practically convenient proton source, we selected Amberlite IR
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 3
COMMUNICATION
Journal Name
120 (H+ form) as the source of acid. Reactions were performed that the beneficial effect was not due to the removal of iodine
View Article Online
in CD3OD to enable monitoring of reaction progress by 1H from the reaction mixture was confirmeDdObI:y10a.n10e39x/pCe6rCimC0e8n5t74inA
NMR (Table 1).
which 6 equivalents of I2 were added to a reaction performed
at atmospheric pressure (Entry 13); no change in either
conversion or reaction time were observed, indicating that
iodine did not inhibit the reaction. Secondly a series of
experiments was performed at atmospheric pressure at
increasing iodide concentration (Supporting information, Table
S1). These experiments clearly indicated that increasing iodide
concentration accelerated the reaction, implying that the rate
determining step is perhaps bimolecular involving attack by
iodide. Thus we conclude that the rotatory evaporator ‘effect’
is a concentration effect.
Table 1. Variation of reaction parameters for the for the reduction of azide 3a
conditions
O
N3
O
NH2
BnO
O
BnO
O
3a
3b
Entry
Iodide/
Acid/
Solvent
Time
Temp
/oC
rt
Conversion
equiv.
2
4
equiv.a
/%b
0
1
2
2
2
0
2
2
2
2
2
2
2
2
2
2
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3CN
CD3OD
CD3OD
1 h
1 h
1 h
1 h
1 h
16 h
1 h
1 h
16 h
1 h
1 h
rt
rt
40
rt
rt
40
rt
rt
rt
rt
20
0
3
4
4
4
45
46
82
50
65
94
100
90
100
100
Table 2. Variation of acid for the reduction of azide 3a
5
8
4 equiv. NaI
2 equiv. acid
6
8
O
N3
O
NH2
7
8
BnO
O
BnO
O
CD3OD
40 oC, 200 mbar, 15 min.
8
9
10
11
12c
13d
10
10
12
12
4
3a
3b
Entry
Acid
Conversion / % a
pKa
-
-8.0
-0.25
4.76
Amberlite (IR-120 H+)
100
100
54
0.25 h
1h
40
rt
1
2
3
4
12
HCl
CF3CO2H
AcOH
a
Equivalents calculated using a wetted bed volume (MeOH) for Amberlite IR120
b
c
0
of 1.8 mequiv./mL. Assessed by 1H NMR Performed at 200 mbar on a rotary
evaporator. The reaction was complete when evaporated to dryness in approx.
15 minutes. d Reaction performed in the presence of six equivalents of I2.
a Assessed by 1H NMR
A brief survey of the strength of the acid that was required for
this process was undertaken (Table 2) using the optimised
reaction conditions from above. Whilst the use of HCl resulted
in complete conversion of azide 3a to amine 3b (Entry 2), the
use of weaker acids was sequentially less effective:
trifluororacetic acid gave only 54% conversion to 3b (Entry 3),
whilst the use of acetic acid did not result in any reaction
(Entry 4). These results imply that a strong acid is essential,
perhaps indicating that pre-protonation is required before
subsequent attack by iodide. Given the ease with which ion
exchange resin may be removed by filtration, Amberlite IR 120
(H+ form) was used as the acid in all subsequent reactions.
Additionally it may be recycled and re-used (Supporting
Information Table S2).
The reaction scope was next investigated using a variety of
different organic azides (Table 3). In contrast to the
assessments of reaction conversion using 1H NMR, in these
cases the amine products were isolated, and yields refer to
quantities of materials produced following purification. Whilst
MeOH was used as the solvent for reaction of the more polar
substrates (Table 3, Entries 1-3), solubility issues necessitated
the use of a less polar solvent system for the less polar azides;
in these cases a CHCl3/MeOH mixed solvent system was used
(Table 3, Entries 4-10).
The use of 2 equivalents of sodium iodide and 2 equivalents of
acid did not produce any amine after 1 h at room temperature
(Entry 1). Increasing the number of equivalents of sodium
iodide to 4 did result in the formation of some amine 3b, but
with a very modest 20% conversion (Entry 2). In the absence of
added acid no reaction was observed at all (Entry 3).
Performing the reaction at 40 oC accelerated the process (45%
conversion after 1h, Entry 4). The use of a larger excess of
iodide (ranging from 8 equivalents to 12 equivalents) and
longer reaction times also further improved the efficiency of
the process (entries 5-9). Indeed complete conversion of azide
to amine was achievable in one hour at room temperature by
using 12 equivalents of iodide (Entry 10). Changing the solvent
from CD3OD to CD3CN had a minor effect of the reaction
efficiency (90% conversion, Entry 11).
Although conditions had been arrived at which led to complete
conversion of azide into product, the use of such a large excess
(e.g. 12 equivalents) of iodide was undesirable. Additionally we
were mindful of the original observation (Scheme 1) in which
almost quantitative azide reduction had followed
concentration of the crude reaction product on a rotatory
evaporator. We therefore investigated whether performing
the reaction under reduced pressure increased the efficiency
of the process. Pleasingly it was found that, with only 4
equivalents of iodide and 2 equivalents of acid, simply
performing the entire process on a rotary evaporator at 40 oC
and 200 mbar pressure resulted in complete conversion to
amine 3b as soon as the solvent had been evaporated to
dryness (approximately 15 minutes, Entry 12). The effect of
the use of a rotary evaporator was investigated further. Firstly
Azide reduction was found to be highly efficient; in all cases
reaction reaction analysis indicated that the amines 3b-12b
were the sole reaction products. Good functional group
tolerance was observed, for example the glycosidic linkages of
nucleosides 4a/b and glycosides 5a/b and 8a/b, the benzyl
ethers of 8a/b, and the alkene of 9a/b. Double reduction of di-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 3
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
azide 11a was efficiently achieved using a total of 4 conversion to product is observed as soon as the solvent has
View Article Online
DOI: 10.1039/C6CC08574A
equivalents of acid and 8 equivalents of sodium iodide (Entry fully evaporated; typically within 15 minutes. Although other
9). The reaction products could be purified very simply by ion sources of strong acid may be used, the process is
exchange chromatography; the process involving the addition experimentally extremely simple as the ion exchange resin
of more acidic ion exchange resin after the reaction was may then be used to directly purify the product. This highly
complete, and then elution on a column with 2.5 M ammonia practically rapid and clean procedure, which does not require
in MeOH. In the case of reduction of ester 10a (entry 8) it was the use of Lewis acids and/or transition metal salts in addition
found that the intermediate amine spontaneously cyclised to to iodide, may prove a useful addition to the methods of
produce lactam 10b during purification by ion exchange amine synthesis from azides where either functional group
chromatography.
tolerance or product purification hamper the use of more
common processes, such as catalytic hydrogenation or
Staudinger reaction.
Table 3. Reaction Scope
The authors thank the University of Canterbury (PhD
Scholarship to KS) and the Bimolecular Interaction Centre for
financial support.
Entry
1
Substrate
Product
Solvent
MeOH
Yield
/%
O
N3
O
NH2
89
BnO
O
BnO
O
3a
3b
O
O
2
MeOH
93
91
Notes and references
NH
NH
1
S.Bräse, C. Gil, K. Knepper and V. Zimmermann, Angew.
Chem. Int. Ed., 2005, 44, 5188.
a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B.
Sharpless, Angew. Chem, Int. Ed., 2002, 41, 2596; b) C. W.
Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002,
67, 3057.
O
O
O
O
N3
H2N
2
4a
4b
HO
HO
N3
H2N
OH
O
OH
O
3
MeOH
HO
HO
HO
HO
5b
5a
3
4
J. C. Jewett and C. R. Bertozzi, Chem. Soc. Rev., 2010, 39,
1272
a) S. S. van Berkel, M. B. van Eldijk and J. C. M. van Hest,
Angew. Chem. Int. Ed., 2011, 50, 8806; b) B. L. Nilsson, L. L.
Kiessling and R. T. Raines, Org. Lett., 2000, 2, 1939; c) E.
Saxon, J. I. Armstrong and C. R. Bertozzi, Org. Lett., 2000, 2,
2141.
E. Sletten and C. R. Bertozzi, Acc. Chem. Res., 2011, 44, 666.
H. Staudinger and J. Meyer, Helv. Chim. Acta 1919, 2, 635.
a) Y. G. Gololobov, I. N. Zhmurova and L. F. Kasukhin,
Tetrahedron, 1981, 37, 437; b) J. E. Leffler and R. D. Temple,
J. Am. Chem. Soc., 1967, 89, 5235.
E. J. Corey, K. C. Nicolaou, R. D. Balanson and Y. Machida,
Synthesis, 1975, 590, and references contained therein.
a) F. Rolla, J. Org. Chem., 1982, 47, 4327; b) F. Fringuelli, F.
Pizzo and L. Vaccaro, Synthesis, 2000, 646.
OMe
OMe
4
5
CHCl3:
MeOH
3:2
85
95
N3
NH2
6a
6b
SO2N3
SO2NH2
CHCl3:
MeOH
3:2
7b
5
6
7
7a
N3
NH2
O
6
CHCl3:
MeOH
3:2
93
O
BnO
BnO
BnO
BnO
8
9
BnO
BnO
OMe
OMe
8a
8b
N3
NH2
7
8
CHCl3:
MeOH
3:2
87
9
9
10 A. K. Bose, J. F. Kistner and L. Farber, J. Org. Chem., 1962, 27,
2925.
9a
9b
O
O
11 L. Benati, G. Bencivenni, R. Leardini, M. Minozzi, D. Nanni, R.
Scialpi, P. Spagnolo, G. Zanardi and C. Rizzoli, Org. Lett.,
2004, 6, 417 and references contained therein.
12 J. W. Lee and P. Fuchs, Org. Lett., 1999, 1, 179.
13 K. Suthagar, A. J. A. Watson, B. L. Wilkinson and A. J.
Fairbanks, Eur. J. Med. Chem., 2015, 102, 153.
14 D. Horton and A. E. Luetzow, Carbohydr. Res. 1968, 7, 101.
15 A. Kamal, N. Shankaraiah, N. Markandeya and C. S. Reddy,
Synlett, 2008, 1297.
16 a) A. Kamal, B. R. Prasad, A. V.Ramana, A. H. Babu and K. S.
Reddy, Tetrahedron Lett., 2004, 45, 3507; b) A. Kamal, K. V.
Ramana, H. B. Ankati and A. V. Ramana, Tetrahedron Lett.,
2002, 43, 6861; c) D. Pathak, D. D. Laskar, D. Prajapathi and
J. S. Sandhu, Chem. Lett., 2000, 816.
CHCl3:
MeOH
3:2
quant.
N3
MeO
NH
10a
10b
N3
N3
H2N
NH2
9
CHCl3:
MeOH
3:2
92
10
10
11b
11a
N3
NH2
10
CHCl3:
MeOH
3:2
quant.
NO2
NO2
12b
12a
17 G. Bartoli, G. Di Antonio, R. Giovannini, S. Giuli, S. Lanari, M.
Paoletti and E. Marcantoni, J. Org. Chem., 2008, 73, 1919.
18 A. Kamal, N. Markandeya, N. Shankaraiah, C. R. Reddy, S.
Prabhakar, C. S. Reddy, M. N. Eberlin and L. Silva Santos,
Chem. Eur. J., 2009, 15, 7215.
In summary investigation into the formation of an anomalous
reaction product has revealed that organic azides are readily
reduced in polar solvents simply by treatment with four
equivalents of sodium iodide in the presence of two
equivalents of acidic ion exchange resin. The reaction is highly
o
efficient when performed at 40 C and 200 mbar on a rotary
evaporator, due to a concentration effect, and complete
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins