One-pot green synthesis of azides from alcohols using bronsted acidic ionic liquid [HMIM][BF4] as solvent and catalyst

Article abstract of DOI:10.1002/jccs.201400046

Bronsted acidic ionic liquid, [HMIM][BF₄], has been used as a non-volatile, eco-friendly solvent, and catalytic medium for the one-pot green synthesis of azides from corresponding alcohols. The [HMIM][BF ₄] showed high reactivity than [BMIM][BF₄] and [BMIM][PF₆], affording azides in up to 97% yield, which could be easily separated from the reaction mixture. The ease of recyclability of [HMIM][BF₄] makes the reaction economically and potentially viable for practical applications. Azides are versatile substrates in organic synthesis and serve as convenient intermediate in the synthesis of pharmaceutical heterocycles and natural products. By using dual functional [HMIM][BF ₄] as solvent and catalyst, efficient synthesis of azides from their corresponding alcohols have been undertaken under eco-friendly conditions. This study may pave the way for practical application of [HMIM][BF₄] in cholesterylamine synthesis.

Full text of DOI:10.1002/jccs.201400046

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
One-pot Green Synthesis of Azides from Alcohols Using Brønsted Acidic Ionic Liquid
[HMIM][BF4] as Solvent and Catalyst
Bhaskar Garg and Yong-Chien Ling*
Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan
(Received: Jan. 27, 2014; Accepted: Mar. 25, 2014; Published Online: ??; DOI: 10.1002/jccs.201400046)
Brønsted acidic ionic liquid, [HMIM][BF4], has been used as a non-volatile, eco-friendly solvent, and cat-
alytic medium for the one-pot green synthesis of azides from corresponding alcohols. The [HMIM][BF4]
showed high reactivity than [BMIM][BF4] and [BMIM][PF6], affording azides in up to 97% yield, which
could be easily separated from the reaction mixture. The ease of recyclability of [HMIM][BF4] makes the
reaction economically and potentially viable for practical applications.
Keywords: [HMIM][BF4]; Azide; Alcohol; Green chemistry; Ionic liquid.
INTRODUCTION
Azides are probably one of the most important 1,3-di-
ings. Furthermore, the solubility associated with [HNMP]
[HSO4] also makes it difficult to separate from the reaction
mixture.20 Accordingly, the search for alternative ap-
proaches employing highly efficient, eco-friendly, and re-
cyclable catalysts is of colossal importance.
poles in organic chemistry1,2 and serve as important precur-
sor for the amino groups, which are quite essential and ver-
satile in the synthesis of natural products as well as N-con-
taining heterocycles.3 Owing to their remarkable stability
under physiological conditions and inimitable reactivity,
azides play a significant role in ‘click’ chemistry4 and in
bioconjugation.5 Additionally, azides have also been em-
ployed for the synthesis of sugar triazole derivatives as
antituberculosis agents6 and azido pyrimidines/purines as
anti HIV-1 biological agents.7
In recent years, ILs in particular based on imidazo-
lium cations (Fig. 1) have gained considerable interest as
green alternative to conventional acid catalysts.21-23 Fur-
thermore, owing to their non-volatility, heat resistance,
non-corrosiveness, and negligible vapour pressure, they
are highly advantageous in minimizing solvent consump-
tion and addressing the problem of volatile organic sol-
vents emission into the atmosphere, a key feature required
to develop economical, efficient, and green chemical pro-
cesses.24-30
In spite of the availability of a range of indirect meth-
ods, direct access of azides from corresponding alcohols is
relatively less studied. In this context, Mitsunobu displace-
ment8-11 employing hydrazoic acid as azide source for the
aforementioned transformation is especially notable. How-
ever, considering the health hazards associated with hydra-
zoic acid, modified Mitsunobu conditions have also been
surfaced from time to time.12-17 Despite this noticeable im-
provement, most of these methods are inappropriate due to
high cost, side reactions, excessive use of reagents, toxic-
ity, and separation issues. In a bid to replace Mitsunobu
conditions, the use of BF3-Et2O18 and N-methyl-2-pyrro-
lidonium hydrogen sulphate [HNMP][HSO4]19 have also
been found to be effective for the direct synthesis of azides
from alcohols. Nevertheless, the excessive use and non-
recyclability of catalysts still possess serious shortcom-
Recently, we have explored the unique catalytic po-
tential of Brønsted acidic ILs in the high yield synthesis of
N-confused calix[4]pyrrole.31 In yet other work, we have
employed them in the rapid and sensitive determination of
tertiaryalkyl amines.32 In continuation of our high interest
in green catalysis,33,34 herein, we report a practical proce-
dure for the efficient conversion of benzyl alcohols into
azides using 1-methylimidazolium tetrafluoroborate
Fig. 1. Imidazolium based ionic liquid.
Special Issue for Green & Sustainable Chemistry
* Corresponding author. Tel: +886 35715131 ext. 33394; Fax: +886 35721774; Email: ycling@mx.nthu.edu.tw
Abbreviations: [HNMP][HSO4], N-methyl-2-pyrrolidonium hydrogen sulphate; IL, Ionic liquid; [HMIM][BF4], 1-methylimidazolium
tetrafluoroborate; [BMIM][BF4], 1-butyl-3-methylimidazolium tetrafluoroborate; [BMIM][PF6], 1-butyl-3-methylimidazolium hexafluo-
rophosphate.
J. Chin. Chem. Soc. 2014, 61, 000-000
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Garg and Ling
[HMIM][BF4] (Scheme 1). The present protocol over-
comes the problems encountered with classical Lewis acids
and offers the recoverability and reusability of the catalyst.
C8H15N2PF6: C; 33.81, H; 5.32, N; 9.86. Found C; 33.83, H; 5.36,
N; 9.84.
Typical procedure for the one-pot synthesis of azides
catalyzed by [HMIM][BF4]: In a 25 mL round bottomed flask
containing [HMIM][BF4] (5.0 mL) was added a mixture of alco-
hol (2 mmol) and sodium azide (2.1 mmol). The reaction mixture
was stirred at 100 °C for appropriate time. After every 1 h inter-
val, the progress of the reaction was monitored by TLC (hexane:
ethyl acetate, 8:2, v/v). After completion of the reaction, the reac-
tion mixture was extracted with hexane-ethyl acetate (2 ´ 10 mL,
9:1, v/v) and filtered off the solid. The organic layer was washed
with water (2 ´ 10 mL). The combined organic layer was dried
over anhydrous magnesium sulfate and solvent was evaporated
under reduced pressure. The crude was column chromatographed
over silica gel using hexane-ethyl acetate as an eluent to afford
desired azides.
[HMIM][BF4] catalyzed conversion of alco-
hols into azides
Scheme 1
EXPERIMENTAL
Materials and methods: All the chemicals and reagents
were commercially available and used without further purifica-
tion. Most of the alcohols were purchased from Lancaster. 1-chlo-
robutane, potassium tetrafluoroborate and N-methyl imidazole
were purchased from Sigma-Aldrich. The Fourier transform in-
frared spectroscopy was carried out on a Perkin-Elmer system
Spectroscopic data of selected azides: 1-(azidomethyl)-
4-hydroxybenzene (2b): 1H NMR (400 MHz, CDCl3, 298K): d =
7.70 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.4 Hz), 5.62 (bs, 1H,
Ar-OH) and 4.15 (s, 2H); 13C NMR (150 MHz, CDCl3, 298K): d =
158.05 (C), 127.05 (CH), 124.80 (C), 115.29 (CH) and 54.81
(CH2); 1-(1-azidoethyl)-4-methoxybenzene (2g): 1H NMR (600
MHz, CDCl3, 298K): d = 7.57 (d, 2H, J = 8.1 Hz), 7.20 (d, 2H, J =
7.9 Hz), 4.49-4.53 (q, 1H), 3.70 (s, 3H) and 1.90 (d, 3H, J = 7.2
Hz); 13C NMR (150 MHz, CDCl3, 298K): d = 158.01, 137.04,
128.44, 113.05, 58.36, 55.22 and 18.31; 2-(azidomethyl)thio-
phene (2q): 1H NMR (600 MHz, CDCl3, 298K): d = 7.69-7.71 (m,
1H), 7.60-7.62 (m, 2H) and 4.00 (s, 2H); 13C NMR (150 MHz,
CDCl3, 298K): d = 151.75 (C), 138.44 (CH), 124.52 (CH), 122.23
(CH) and 54.01 (CH2); 1-(azidomethyl)-4-nitrobenzene (2r): 1H
NMR (600 MHz, CDCl3, 298K): d = 7.84 (d, 2H, J = 8.2 Hz), 7.62
(d, 2H, J = 8.2 Hz) and 4.60 (s, 2H); 13C NMR (150 MHz, CDCl3,
298K): d = 151.85 (C), 146.04 (C), 126.02 (CH), 122.86 (CH) and
1
2000. The H NMR (600, 400 MHz) and 13C NMR (150 MHz)
were recorded on a nuclear magnetic resonance spectrometer
(Bruker Cryomagnet, Oxford) using CDCl3 as solvent and TMS
as an internal standard, unless otherwise mentioned. The splitting
patterns are designed as s (singlet), d (doublet), t (triplet), bs
(broad singlet), and m (multiplet). The column chromatography
was carried out using Merck silica gel (60-120 mesh). ILs,
[HMIM][BF4] and 1-butyl-3-methylimidazolium tetrafluoro-
borate [BMIM][BF4], were prepared according to an earlier re-
ported procedures21,35 while [BMIM][PF6] were prepared by
modification of known procedure.35
Synthesis of 1-butyl-3-methylimidazolium hexafluoro-
phosphate [BMIM][PF6]: To a freshly prepared [BMIM][Cl]
(37.5 g) in DI water (225 mL), hexafluorophosphoric acid (66
mL) was added drop wise at 0 °C under vigorous stirring. After
addition, two immiscible phases were formed and the stirring was
continued for 2 h. The aqueous phase was separated and organic
phase was washed repeatedly with ice cold DI water (5 ´ 100
mL). The crude was then dissolved in DCM (250 mL) and treated
with activated charcoal (5 mg) for 30 min. The solution was fil-
tered and dried over anhydrous magnesium sulfate. The solvent
was evaporated and [BMIM][PF6] was obtained as a colorless liq-
uid. The product was dried under high vacuum at 80 °C for 24 h.
The as-obtained [BMIM][PF6] was kept in polypropylene bottle
and stored in a dry box prior to use. 1H NMR (600 MHz, DMSO-
d6, 298K): d = 9.12 (s, 1H, Imidazole), 7.79 (s, 1H, Imidazole),
7.72 (s, 1H, Imidazole), 4.27 (t, 2H, -CH2), 3.94 (s, 3H, -CH3),
1.97-2.15 (m, 2H, -CH2), 1.64-1.68 (m, 2H, -CH2), 0.94 (t, 3H,
-CH3); 13C NMR (150 MHz, DMSO-d6, 298K): d = 137.72,
124.79, 123.46, 49.73, 40.69, 36.97, 29.58, 13.22; Anal Calc. for
1
55.11 (CH2); 1-(azidomethyl)-4-fluorobenzene (2s): H NMR
(600 MHz, CDCl3, 298K): d = 7.83 (d, 2H, J = 8.4 Hz), 7.58 (d,
2H, J = 8.4 Hz) and 4.30 (s, 2H); 13C NMR (150 MHz, CDCl3,
298K): d = 162.28 (C), 160.64 (C), 128.83 (CH), 114.67 (CH) and
55.52 (CH2).
RESULTS AND DISCUSSION
In order to demonstrate the practical (dual) utility of
[HMIM][BF4] as a reaction media as well as catalyst, bulk
synthesis of [HMIM][BF4], [BMIM][BF4], and [BMIM]
[PF6] was carried out by following the reported proce-
dures.21,35 The identity and purity of all derivatives was un-
ambiguously confirmed by different spectroscopic tech-
niques and elemental analysis. The spectral data and ele-
2
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Azides Synthesis via Ionic Liquid Catalysis
mental analysis results were in good agreement as reported
previously.
regardless of the presence of electron donating, hetero-
cyclic or branched chain functionalities could be directly
converted into their respective azides in 81-97% yields (Ta-
ble 1, entries 2-17). Nevertheless, in comparison to primary
alcohols (Table 1, entries 1-2, 4) except 1c (Table 1, entry
3), secondary alcohols (Table 1, entries 5, 8) reacted faster
and azides were formed in shorter reaction time. Further-
more, the reactivity of secondary alcohols having electron
donating substituents appeared much higher and azides
were isolated in > 93% yields (Table 1, entries 6-7, 9, 15).
On the other hand, the reactivity of alcohols containing
electron withdrawing substituents, in particular, -NO2 and
-F was very low and consequently poorer yield of azides
were obtained even after prolonging the reaction time (Ta-
ble 1, entries 18-21). On the contrary, secondary alcohols
appended with halogen-substituents afforded correspond-
ing azides in appreciable yields in 3-5 h (Table 1, entries
11-13). Likewise, the catalyst was found equally effective
for the conversion of 2-hydroxymethyl thiophene 1q and
afforded 2q in 94% yield.
To optimize the product distribution at room tempera-
ture, the conversion of 4-methylbenzyl alcohol 1a into 1-
(azidomethyl)-4-methyl benzene 2a was primarily screened
as a model reaction under a variety of experimental condi-
tions. Nevertheless, either the variations in reactants molar
ratio or amount of [HMIM][BF4] were all found unproduc-
tive to afford the desired azide. The qualitative TLC and 1H
NMR of recovered mixture showed only the presence of
starting alcohol. Later on, the reaction was examined under
varying temperature (50-100 °C) conditions. To our de-
light, after 4 h, the reaction of 1a and NaN3 (1: 1.1 mmol) at
100 °C in [HMIM][BF4] gave > 90% conversion of 1a as
determined by 1H NMR spectroscopy. After completion of
the reaction, the product was extracted with an ethyl ace-
tate-hexane mixture and subsequently washed with water.
The purification of crude by column chromatography af-
forded analytically pure 2a in 85% yield (Table 1, entry 1).
It has to be stressed that minimal changes in the isolated
yield were observed upon increasing the reaction time,
temperature, and molar ratio of reactants.
To study the reusability, the recovered [HMIM][BF4]
was reused for the conversion of 1-(2,4-dimethylphenyl)-
ethanol 1g. In particular, after extraction of respective
azide from the IL with an ethyl acetate – hexane mixture
(9:1, v/v), the IL was solubilized in acetonitrile and filtered
to separate any remaining NaOH. The organic layer was
evaporated and the IL was dried under vacuum for 1 h. To
this dried IL, NaN3 and 1g were added and mixture was
stirred at 100 °C for 2 h. After the reaction, the reaction
mixture was extracted by the ethyl acetate – hexane mix-
ture, washed with water and combined organic layers were
evaporated. Subsequently, 2g was isolated by column chro-
matography as mentioned before. This procedure was re-
peated at least five times. Interestingly, even after four con-
To determine whether the ionic liquid [HMIM][BF4]
was an essential factor to realize the conversion of afore-
mentioned reaction, the same reaction was performed in di-
chloromethane, acetonitrile and dimethyl sulfoxide in the
absence of [HMIM][BF4]. As expected, the reaction did not
proceed at all in the absence of [HMIM][BF4]. To further
verify the influence of [HMIM][BF4] in this reaction, the
reaction was carried out in [BMIM][BF4] and under opti-
mized conditions (4 h), the qualitative TLC showed only <
20% conversion of 1a. However, on prolonging the reac-
tion for 12 h, 2a could be isolated in 30% yield. Likewise,
though a bit improved yield, 2a was obtained in 35% yield
in the presence of more hydrophobic IL, [BMIM][PF6].
These findings are in fair agreement with that made in the
synthesis of isoxazolyl-1,3-benzoxazines.23 It is notewor-
thy that both the [BMIM][BF4] and [BMIM][PF6] are neu-
tral ILs while [HMIM][BF4] greatly influences the azida-
tion reaction, probably, by acting as proton donor as well as
effective solvent media.
Having established the essential nature of [HMIM]
[BF4], the conversion of a variety of benzylic alcohols into
their corresponding azide analogues were examined under
virtually identical conditions and the results are summa-
rized in Table 1. As demonstrated in Table 1, after reaction
with NaN3, various structurally diverse alcohols (1b-1q),
Fig. 2. Bar diagram: recyclable activity of [HMIM]
[BF4].
J. Chin. Chem. Soc. 2014, 61, 000-000
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Article
Garg and Ling
secutive uses, [HMIM][BF4] showed good catalytic activ-
ity with little deterioration in product yield (Fig. 2). Never-
theless, the yield was significantly decreased during the
fifth run which may be attributed to the decomposition or
decreased activity of IL due to release of moisture sensitive
NaOH in the reaction.
CONCLUSIONS
In summary, we have developed a simple and effi-
cient method for direct conversion of alcohol into azide.
Avoiding expensive starting materials, the use of [HMIM]
[BF4]as green solvent and catalytic system has proven to be
very effective for this conversion. The protocol showed
good selectivity in favor of benzylic hydroxyls. Further-
more, secondary –OH group at benzylic position could eas-
ily be substituted in relatively shorter reaction time. This
simple experimental set-up, remarkable reactivity towards
primary and secondary alcohols, good to excellent yields,
one-pot synthesis combined with easy recovery and re-
cyclability of IL contribute to the development of a green
strategy to synthetic chemists.
ACKNOWLEDGEMENTS
This work was supported by National Tsing Hua Uni-
versity (102N1807E1) and the Ministry of Science and
Technology (NSC101-2113-M-007-006-MY3) of Taiwan.
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Azides Synthesis via Ionic Liquid Catalysis
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