Facile synthesis of phosphorylated azides in ionic liquids and their use in the preparation of 1,2,3-triazoles

Article abstract of DOI:10.1002/hc.20420

The facile general synthetic route to azidoalkylphosphonates by the nucleophilic substitution reaction in a series of bromoalkylphosphonates was elaborated, using 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF₆]) as a recyclable rea

Full text of DOI:10.1002/hc.20420

Heteroatom Chemistry
Volume 19, Number 3, 2008
Facile Synthesis of Phosphorylated Azides in
Ionic Liquids and Their Use in the Preparation
of 1,2,3-Triazoles
Oleg I. Artyushin,1 Daria V. Vorob’eva,1 Tamara P. Vasil’eva,1
Sergey N. Osipov,1 Gerd-Volker Ro¨schenthaler,2
and Irina L. Odinets1
1A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova, 119991 Moscow, Russia
2Institute of Inorganic & Physical Chemistry, University of Bremen, Leobener Strasse,
D-28334 Bremen, Germany
Received 19 July 2007; revised 28 August 2007
acting low-molecular weight molecules. That is why
ABSTRACT: The facile general synthetic route to azi-
simple methods that can quickly and easily gener-
doalkylphosphonates by the nucleophilic substitution
ate large libraries of compounds have emerged and
reaction in a series of bromoalkylphosphonates was
are more and more used [1]. The so-called “click”
elaborated, using 1-butyl-3-methylimidazolium hex-
methodology recently introduced by Sharpless
afluorophosphate ([bmim][PF6]) as a recyclable re-
et al. [2] is one of these methods based on reac-
action medium. These azidoalkylphosphonates were
tions that are of wide scope, give high yields, and
used as intermediates for copper(I)-catalyzed re-
use highly energetic reactants to form irreversible
gioselective 1,3-dipolar cycloaddition with a vari-
carbon–heteroatom bonds. The Huisgen 1,3-dipolar
ety of alkynes to afford 4-substituted (1H-1,2,3-
cycloaddition of azides with terminal alkynes per-
triazol-1-yl)alkylphosphonates as potential drug can-
fectly illustrates this kind of reactions. The discov-
ꢀ
C
didates. 2008 Wiley Periodicals, Inc. Heteroatom Chem
ery of catalytic properties of copper(I), which al-
lows high rate and control of regioselectivity of
this cycloaddition to give 1,4-disubstituted 1,2,3-
19:293–300, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20420
triazoles, stimulated the investigations in this field
over the last 5 years. The above methodology of 1,2,3-
triazole ring formation has been successfully used
INTRODUCTION
Modern drug discovery requires the identification
and optimization of synthetic routes to specifically
for the synthesis of a wide range of novel biologically
active compounds including triazole-linked glyco-
conjugates [3] and glycopeptides [4], 1,2,3-triazole-
modified nucleic acids [5], 1,2,3-triazole-containing
dendrimers [6], and nucleoside analogs [7]. It should
be noted that despite the 1,2,3-triazole structural
moiety does not occur in nature a wide range of com-
pounds containing this functionality have exhibited
diverse biological activities [8] such as anti-HIV [9],
Correspondence to: Irina L. Odinets; e-mail: odinets@ineos.
ac.ru.
Contract grant sponsor: Deutschen Forschungsgemeinschaft.
Contract grant number: 36 RUS 113/905/0-1.
Contract grant sponsor: Russian Foundation of Basic Research.
Contract grant number: 06-03-04003.
c
ꢀ
2008 Wiley Periodicals, Inc.
293

294 Artyushin et al.
anti-epileptic [10], and antimicrobial [11] and act as
selective β3-adrenergic receptor agonists [12].
At the same time, it is well recognized that
organophosphorus compounds also exhibit different
types of bioactivity and, therefore, form an impor-
tant series of compounds in the search for new drugs
[13]. Phosphorylated compounds may be used as
prodrugs to improve drug delivery to particular tar-
gets, and solubility of drugs could be modified by
attaching phosphorus groups; for example, phos-
phorylation significantly increases the solubility of
steroidal drugs in water. Therefore, phosphorylated
1,2,3-triazoles possessing the advantages both of tri-
azole and phosphonate moieties may be useful as
potential drug candidates.
Taking into account that some RTILs, namely
[bmim][PF6], [bmim][NTf2], and [hpyr][NTf2], are
an efficient promoting medium for nucleophilic dis-
placement reactions [23] to give the corresponding
substituted products with a considerable increase in
conversion comparing the reactions performed in
traditional solvents, we investigated the possibility of
using ILs as promoting reaction media for the syn-
thesis of azidoalkylphosphonates by azide/halogen
exchange.
In this communication, we report the general
facile route to azidoalkylphosphonates based on our
recent results and demonstrate their application in
the synthesis of phosphorylated triazoles.
Despite a few azidoalkylphosphonates obtained
by traditional substitution of an appropriate leav-
ing group were previously described in the literature
[14], until now they did not attract much attention
in synthetic and medicinal chemistry in general and
in the synthesis of phosphorylated 1,2,3-triazoles via
1,3-dipolar cycloaddition with azides in particular.
To the best of our knowledge, the above approach
was used only for the synthesis of a phosphory-
lated analog of ribavirin [15] and for the transforma-
tion of bromoethylphosphonate to 4-carbomethoxy-
1,2,3-triazole by a two-step one-pot procedure using
the polymer-supported azide [16].
We believe that the fewer number of publica-
tions concerning the reactivity of ω-azidoalkyl phos-
phonates may be related to the fact that their syn-
thesis had no general character, sometimes required
rather drastic reaction conditions and resulted in
the target compounds with poor yields. At the same
time, it is well known that room temperature ionic
liquids (RTILs), due to their potential for recycla-
bility, ability to dissolve a variety of organic, inor-
ganic, and metal complex materials, and promote
a variety of chemical transformations, are of inter-
est in chemistry in the search for green alternatives
to traditional organic solvents [17]. Phosphorus-
containing ILs (phosphonium salts having different
anions and imidazolium hexafluorophosphates) are
of special importance [18]. However, successful ex-
amples of ILs applications as activating media for
organophosphorus synthesis are rather scare and
restricted to the Wittig–Horner [19], Arbuzov [20],
and Kabachnik–Fields [21] reactions and the es-
terification of phosphonic(phosphinic) acids by tri-
ethyl(methyl) orthoacetate [22]. A few numbers of
publications in this area may be explained by easy
dealkylation of phosphorus esters observed in a vari-
ety of ILs [20] instead of desired reactions involving
other functionalities in the molecules. Nevertheless,
the proper choice of IL in use gives the possibility to
avoid such drawback.
RESULTS AND DISCUSSION
The transformation of bromoalkylphosphonates
1a–c to the corresponding azides 2a–c was found
to give the best results in terms of both conver-
sion and reaction rate in [bmim][PF6] compared
with [bmim][NTf2]. When the [bmim][PF6]/H2O sys-
tem was applied, the reaction proceeded smoothly
at room temperature to give the desired compounds
in 95%–98% yield and no side products including
dealkylated phosphonous acids were observed in
these reactions (Scheme 1). The time required for
the complete azide 2a–c formation strongly depends
on the alkylene chain length in the starting substrate.
For the less reactive 2-bromoethylphosphonate 1a,
it took about 5 days (120 h) to afford 2a in 95% yield,
whereas in the case of 1b (n= 3) and 1c (n= 4) simi-
lar high-yielding results were obtained over 40 h and
48 h, respectively.
Increasing the reaction temperature to 80◦C re-
sulted in a reduction in the reaction time up to 2 h
for 1a and to about 30 min for more reactive 1b,c.
Nevertheless, diethyl(bromomethyl)phosphonate 1d
(n= 1) did not undergo azide/halide exchange nei-
ther under prolonged reaction time at room temper-
ature nor under elevated temperature. The workup
procedure involved the removal of the aqueous
phase, extraction with Et2O (twice), and evaporation
of the combined ether extract to result in the de-
sired azides 2a–c in the yield of 95%–98% as slightly
yellowish oils having purity more than 98% accord-
1
ing the H NMR data. The 31P NMR spectrum of
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of Phosphorylated Azides in Ionic Liquids and Their Use in the Preparation of 1,2,3-Triazoles 295
TABLE 1 Reaction of 2a–c with Alkynes via Scheme 2
azido-substituted phosphonate 2a shows a singlet at
δ ∼26.9 ppm, whereas the signals for compounds
2b,c were slightly downfield shifted (ca. 31 ppm).
The IR spectra of 2a–c (KBr) show characteristic ab-
sorption bands at 1244–1248 (P O) and 2098–2104
cm−1 (N3).
Using 1b as a starting representative example,
we demonstrated that [bmim]PF6 can be recycled
and reused at least five times without any decrease in
activity. Moreover if the first reaction cycle provided
the desired 2b in the yield of 97% (purity ca. 98%),
the isolated yield and purity were even higher (quan-
titative yield, >99% purity) for subsequent reaction
cycles. The only limitation was a slight reduction in
the volume of IL phase, arising from its partial solu-
bility in water and diethyl ether (cf. [19b]).
Entry
Azide
n
Alkyne
Product
Yielda
1
2
3
4
2a
2b
2b
2c
2
3
3
4
4a
4b
4c
4d
69
75
74
71
5
2b
3
4e
4f
79
86
6
2c
4
aIsolated yields after purification by column chromatography.
yields of individual compounds 4a–f decreased up to
48%–63%.
Therefore, [bmim]PF6 ionic liquid can be suc-
cessfully used as a reaction medium for the synthesis
of phosphonates bearing azide functionality, provid-
ing the facile route to such compounds.
To impart better lipophilic and biodegradable
properties that are advantageous in medicinal chem-
istry [26] to phosphorylated triazoles, propargyl-
substituted CF3-containing alcohol 3d [27a] and pro-
tected amino acids 3e,f [27b] were also used in the
above-mentioned cycloaddition (Scheme 3).
In the reaction with the unsaturated alcohol 3d,
the reaction performed using the method A gave the
desired compounds 5a,b in the yields of 77%–78%,
whereas for the synthesis of 6a,b CuI was used as
a catalyst either in the same t-BuOH/H2O medium
under elevated temperature (method B) or in THF
solution (method C). Comparing the yields for 6b we
may mention that organoaqueous media provided
better yields of the products.
Phosphorylated triazoles 4–6 were isolated
mostly as colorless oils (only the hydroxyl-
substituted product 5a was isolated as a white solid).
In the 31P spectra, the signals of the compounds of
1,2,3-triazole series were observed practically in the
same regions as those for their azido-containing pre-
cursors 2a–c. The structures of the compounds ob-
tained were unambiguously confirmed by IR and 1H
and 13C NMR spectra, containing characteristic sets
of signals of the corresponding structures.
The azidoalkylphosphonates 2a–c obtained were
tested as substrates for Cu(I)-catalyzed 1,2,3-triazole
formation. A few procedures were suggested for re-
actions of such type in the literature, namely direct
introduction of catalytic amount of Cu(I) salt (CuI,
CuBr, etc.) into the reaction system in conjugation
with organic or inorganic base [24] or the catalyst
can be generated in situ by the reduction of Cu(II)
salts, usually in organo-aqueous systems [25]. Esti-
mating all these variants, we concluded that the lat-
ter procedure (method A, see Experimental part) was
the most suitable in the case of the simplest alkynes
3a–c (Scheme 2). When the starting substrates were
used in equimolar amounts, the conversion was
more than 90% (according to the 31P NMR data of
the reaction mixtures) under the above-mentioned
conditions. Using a small excess of alkyne led to an
increase in the yield of crude product to 95%–96%
(69%–86% after purification). Minor impurities pre-
sented the starting reactants, and copper complexes
formed both by starting and final phosphonates. At
the same time, in experiments performed with direct
introduction of Cu(I) catalysts (methods B and C) the
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

296 Artyushin et al.
SCHEME 3
CONCLUSION
The starting ω-bromoalkylphosphonates 1a–c
were obtained via an Arbuzov reaction of the corre-
sponding α,ω-dihalogenoalkanes with triethylphos-
phite according to [29], [30] and [31] for n= 2, 3, and
4, respectively. Propargyl-substituted fluorinated al-
cohol 3d and protected amino acids 3f,e were ob-
tained via the processes reported by one of us pre-
viously, based on the Grignard reagent addition to
high-electrophilic methyl trifluoropyruvate and its
imines [27].
In summary, we reported
a
new examples
of ILs’ application as activating media for
organophosphorus synthesis and demonstrated that
1-butyl-3-methylimidazolium hexafluorophosphate
([bmim][PF6]) is a suitable recyclable medium for
efficient synthesis of azidoalkylphosphonates being
useful intermediates for the synthesis of phospho-
rylated 1,3,2-triazoles via coupling with a variety
of alkynes. Biological tests of compounds 4–6 are
under investigation.
General Procedure for the Synthesis of
ω-Azidoalkylphosphonates (2a–c)
EXPERIMENTAL
NMR spectra were recorded with a Bruker Avance-
300 spectrometer (1H, 300.13; 31P, 121.49; and 13C,
75.47 MHz) and a Bruker Avance-400 spectrome-
ter (1H, 400.13; 31P, 161.97; and 13C, 100.61 MHz)
using residual proton signals of deuterated solvent
as an internal standard (1H, 13C) and H3PO4 (31P)
as an external standard. The 13C NMR spectra were
registered using the JMODECHO mode; the signals
for the C atom bearing odd and even numbers of
protons have opposite polarities. IR spectra were
recorded on a Fourier spectrometer “Magna-IR750”
(Nicolet), with a resolution of 2 cm−1, 128 scans. The
assignment of the absorption bands in IR spectra
was made according to [28]. Mass spectrometry was
performed on a tandem Finnigan LCQ Advantage in-
strument using positive mode. Analytical TLCs were
performed with Merck silica gel 60 F254 plates. Vi-
sualization was accomplished by UV light or spray-
ing with Ce(SO4)2 solution in 5% H2SO4. Flash chro-
matography was carried out using Merck silica gel
60 (230–400 mesh ASTM). Melting points were deter-
mined with an Electrothermal IA9100 digital melt-
ing point apparatus and were uncorrected.
A solution of sodium azide (10.0 mmol, 2 eq.)
in water (1.0 mL) was added to a vigorously
stirred solution (∼1200 rpm) of ω-bromoalkyl)di-
ethylphosphonate 1 (5.0 mmol) in [bmim]PF6 (1 mL)
at room temperature. The resulting two-layer mix-
ture was stirred over 120 h (n= 2), 48 h (n= 3), and
40 h (n= 4) at room temperature or over 2 h (n = 2)
and 30 min (n = 3.4) at 80◦C, whereas the reaction
course was followed by 31P NMR. The upper water
layer was decanted, the residue was extracted with
diethyl ether (10 × 3 mL), and the combined organic
phases were dried over MgSO4, filtered, and evap-
orated in vacuo to give the desired products, which
were used in the next reaction without further purifi-
cation. Similar results were obtained using 0.1 mol
of the starting substrate 1a–c, indicating the possi-
bility of further scaling up if necessary.
For the recycling experiments, the next por-
tion of bromopropylphosphonate 1b was added
to the residue from the previous cycle followed
by a solution of NaN3 in water and the pro-
cedure was repeated as described. The spectral
data for the product obtained were identical to
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of Phosphorylated Azides in Ionic Liquids and Their Use in the Preparation of 1,2,3-Triazoles 297
those for the sample from the previous cycle.
In the case of hydrophilic aminomethyl-substituted
products 4e,f, the reaction mixture was evaporated
to dryness, acetonitrile was added to a residue, the
precipitated copper salts were filtered off, and the fil-
trate was evaporated, and purified by column chro-
matography.
ω-Azidoalkylphosphonates 2a–c were used in the re-
actions of 1,2,3-triazole formation without further
purification.
Diethyl 2-azidoethylphosphonate (2a). Yield
94% (purity 96%). 31P NMR (121 MHz, CDCl3): δ
26.88. 1H NMR (300 MHz, CDCl3): δ 1.32 (t, 6H, CH3,
3 JH−H = 7.1 Hz), 2.04 (dt, 2H, PCH2, 2 JP−H = 18.6 Hz,
Method B. To a solution of the corresponding
acetylene 3 (1.0 mmol) in the mixture of t-BuOH-
H2O (1:1 ratio) (3 mL), a solution of azide 2 (2.0
mmol) and CuI (0.1 mmol) in the mixture of t-BuOH-
H2O (1:1 ratio) (2 mL) was added. The reaction mix-
ture was stirred for 8 h at 80–90◦C until the comple-
tion of the reaction monitored by TLC. Then, water
(15 mL) was added to a reaction mixture and the
aqueous layer was extracted with methylene chlo-
ride (3 × 15 mL). The organic layer was dried over
MgSO4, evaporated, and the residue was purified by
flash chromatography on silica gel using acetone–
hexane (1.5:1) as an eluent.
3
3 JH−H = 7.7 Hz), 3.52 (dt, 2H, NCH2, JP−H = 7.8 Hz,
3 JH−H = 7.7 Hz), 4.07–4.11 (m, 4H, OCH2). IR (thin
film) ν (cm−1): 965, 1028 and 1057 (P O C), 1248
(P O), 2103 (N3), 2910, 2933, 2984, 3472. EMS: m/z
calcd for C6H14N3O3P: 207.17 [M]+; found: 208.2
[M + H]+.
Diethyl 2-azidopropylphosphonate (2b). Yield
97% (purity 95%). 31P NMR (121 MHz, CDCl3): δ
30.93. 1H NMR (300 MHz, CDCl3): δ 1.37 (t, 6H, CH3,
3 JH−H = 7.1 Hz), 1.82–1.98 (m, 4H, P(CH2)2), 3.43 (t,
2H, NCH2, 3 JH−H = 6.4 Hz), 4.12–4.17 (m, 4H, OCH2).
IR (thin film) ν (cm−1): 962, 1027, and 1054 (P O C),
1244 (P O), 2101 (N3), 2874, 2913, 2935, 2983, 3874.
EMS: m/z calcd for C7H16N3O3P: 221.2 [M]+; found:
222.0 [M + H]+.
Method C. A solution of the corresponding
acetylene 3 (1.0 mmol) in anhydrous THF (2 mL)
was added dropwise to a solution of CuI (1.0 mmol)
in anhydrous THF (2 mL). To the reaction mixture,
DIPEA (N,N-diisopropylethylamine) was added (10
mmol), followed by dropwise addition of azide 2 (1.5
mmol) solution in anhydrous THF (2 mL) within
10 min. The reaction mixture was stirred at room
temperature for 6–7 h until the completion of the
reaction monitored by TLC. The reaction mixture
was subsequently neutralized with 1 N HCl (15
mL), diluted with H2O (5 mL), and extracted with
ether (3 × 15 mL). The organic layer was dried over
MgSO4, evaporated, and the residue was purified by
flash chromatography on silica gel using acetone–
hexane (1.5:1) as an eluent.
Diethyl 2-azidobutylphosphonate (2c). Yield
98% (purity 100%). 31P NMR (121 MHz, CDCl3): δ
1
31.37. H NMR (400 MHz, CDCl3): δ 1.29 and 1.32
3
(2t, 3H + 3H, CH3, JH−H = 7.0 Hz), 1.66–1.75 (m,
6H, P(CH2)3), 3.23–3.32 (m, 2H, NCH2), 4.04–4.08
(m, 4H, OCH2). IR (thin film) ν (cm−1): 962, 1028
(P O C), 1055, 1244 (P O), 2098 (N3), 2829, 2874,
2916, 2982, 3465. Anal Calcd. for C8H18N3O3P: C,
40.85; H, 7.71; N, 17.86; P 13.17. Found: C, 40.70; H,
7.52; N 17.97; P, 12.86.
General Procedures for the Synthesis of
4-Substituted 1,2,3-Triazoles (4–6)
Diethyl
2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl-
Method A. A solution of azidophosphonate 2
(1.0 mmol), sodium ascorbate (0.3 mmol), and 0.5
mol% copper(II) sulfate pentahydrate (0.05 mmol)
in a mixture of t-BuOH-H2O (1:1 ratio) (2 mL) was
added to a solution of the corresponding acetylene
3 (1.0 mmol) in a mixture of t-BuOH-H2O (3 mL).
The reaction mixture was stirred at room tempera-
ture for 4–6 h until the completion of the reaction
monitored by TLC. After evaporation of the mixed
solvent under reduced pressure, water (2 mL) was
added to a residue. Then the aqueous mixture was
extracted with ethyl acetate (2 × 20 mL). The organic
layer was dried over MgSO4 and evaporated to dry-
ness. The residue was purified by flash chromatog-
raphy on silica gel eluting by EtOAc-hexane (1.5:1).
phosphonate (4a). Method A: oil, yield 69%. 31P
NMR (121 MHz, CDCl3): δ 25.78. 1H NMR (300 MHz,
3
CDCl3): δ 1.21 (t, 6H, CH3, JH−H = 7.1 Hz), 2.38 (dt,
2
3
2H, PCH2, JP−H = 7.6 Hz, JH−H = 7.7 Hz), 3.97–4.04
3
(m, 4H, OCH2), 4.58 (dt, 2H, NCH2, JP−H = 7.5 Hz,
3 JH−H = 7.7 Hz), 7.23 (t, 1H, CH , JH−H = 7.3 Hz),
4
3
7.23 (t, 2H, Ph, JH−H = 7.1 Hz), 7.67–7.78 (m, 3H,
Ph). 13C NMR (100.61 MHz, CDCl3): δ 16.32 (d,
3
1
CH3, JP−C = 6.0 Hz), 27.14 (d, PCH2, JP−C = 141.4
2
Hz), 44.57 (CH2N), 62.15 (d, POCH2, JP−C = 6.6
Hz), 120.31 (HC ), 125.64 (o-C in Ph), 128.17 (p-C
in Ph), 128.83 (m-C in Ph), 130.45 (ipso-C in Ph),
144.53 (Ph C ). IR (thin layer) ν (cm−1): 697, 768,
974, 1028, and 1030 (P O C), 1240 (br) (P O),
1610 (weak) (C C), 2907, 2983, 3464 (br). Calcd. for
Heteroatom Chemistry DOI 10.1002/hc

298 Artyushin et al.
1H NMR (300 MHz, CDCl3): δ 1.19 (t, 6H, CH3,
3 JH−H = 7.1 Hz), 1.60–1.68 (m, 2H), 2.06–2.18 (m,
2H, PCH2), 2.54 (s, 6H, NCH3), 3.93–4.06 (m,
4H, OCH2), 4.37 (c, 2H, NCH2), 7.94 (br.s, 1H,
CH). 13C NMR (100.61 MHz, CDCl3): δ 16.28
C14H20N3O3P: C, 54.36; H, 6.52; N, 13.59. Found: C,
54.27; H, 6.61; N, 13.38.
Diethyl 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl-
phosphonate (4b). Method A: oil, yield 75%. 31P
NMR (121 MHz, CDCl3): δ 30.04. 1H NMR (300
1
(CH3CH2), 22.36 (d, PCH2, JP−C = 143.1 Hz), 23.48
3
(d, PCH2CH2, 2 JP−C = 4.3 Hz), 42.58 (CH3N), 50.05 (d,
MHz, CDCl3): δ 1.24 (t, 6H, CH3, JH−H = 7.1 Hz),
3
3
1.67 (m, 2H, CH2), 2.20 (m, 2H, CH2, JH−H = 7.2
NCH2CH2, JP−C = 16.4 Hz), 51.87 (NCH2), 61.68 (d,
POCH2, 2 JP−C = 6.6 Hz), 125.85 (CH2 N C ), 139.02
(N N C ). Calcd for C12H25N4O3P: C, 47.36; H, 8.28;
N, 18.41. Found: C, 46.94; H, 8.05; N, 18.11.
Hz), 3.97–4.08 (m, 4H, OCH2), 4.44 (t, 2H, NCH2,
4
3 JH−H = 6.9 Hz), 7.26 (t, 1H, CH , JH−H = 7.5
3
Hz), 7.35 (t, 2H, Ph, JH−H = 7.6 Hz), 7.76 (d,
3
3H, Ph, JH−H = 8.5 Hz). 13C NMR (75.47 MHz,
3
CDCl3): δ 16.44 (d, CH3, JP−C = 6.0 Hz), 22.46
Diethyl 3-{4-[(dimethylamino)methyl]-1H-1,2,3-
triazol-1-yl}butylphosphonate (4f). Method A: oil,
yield 86%. 31P NMR (121 MHz, CDCl3): δ 30.86.
1H NMR (300 MHz, CDCl3): δ 1.23 (t, 6H, CH3,
3 JH−H = 7.0 Hz), 1.48–2.50 (3 br. overlapped m, 12H,
P(CH2)3 + N(CH3)2), 3.45–3.58 (m, 2H, NCH2CH2),
3.95–4.12 (m, 4H, OCH2), 4.32 (c, 2H, NCH2),
7.47 (br.s, 1H, CH). 13C NMR (75.47 MHz, CDCl3):
δ 16.41 (CH3CH2), 19.60 (PCH2CH2), 24.83 (d,
1
(d, PCH2, JP−C = 143.4 Hz), 23.70 (d, PCH2CH2,
2 JP−C = 4.3 Hz), 49.98 (d, CH2N, 3 JP−C = 14 Hz), 61.81
2
(d, POCH2, JP−C = 6.3 Hz), 119.99 (HC ), 125.66
(o-C in Ph), 128.16 (p-C in Ph), 128.84 (m-C in Ph),
130.51 (ipso-C in Ph), 143.58 (Ph-C ). IR (thin layer)
ν (cm−1): 697, 768, 964, 1030, and 1048 (P O C),
1230 and 1251 (P O), 1610 (weak) (C C), 2907,
2982, 3454 (br). Calcd for C15H22N3O3P: C, 55.72; H,
6.86; N, 13.00. Found: C, 55.54; H, 6.94; N, 12.77.
1
PCH2, JP−C = 141.9 Hz), 30.54 (d, P(CH2)2CH2,
3 JP−C = 14.6 Hz), 42.58 (CH3N), 44.82 (NCH2CH2),
2
Diethyl 3-(4-butyl-1H-1,2,3-triazol-1-yl)propyl)-
49.60 (NCH2), 61.47 (d, POCH2, JP−C = 6.6 Hz),
phosphonate (4c). Method A: light-yellow oil, yield
122.44 (CH2 N C ), 145.09 (N N C ). Calcd for
C12H25N4O3P·2H2O: C, 44.06; H, 8.82; P, 8.74. Found:
C, 44.05; H, 8.05; P, 8.66.
1
74%. 31P NMR (121 MHz, CDCl3): δ 30.0. H NMR
3
(300 MHz, CDCl3): δ 0.86 (t, 3H, CH3, JH−H = 7.3
3
Hz), 1.24 (t, 6H, CH3, JH−H = 7.0 Hz), 1.32 (m, 2H,
CH2), 1.56–1.68 (m, 4H, CH2), 2.21 (m, 2H, PCH2),
Methyl 2-({1-[2-(diethoxyphosphoryl)ethyl]-1H-
1,2,3-triazol-4-yl}methyl)-3,3,3-trifluoro-2-hydroxy-
propanoate (5a). Method A: white solid, yield 78%,
mp 84–86◦C. 31P NMR (121 MHz, CDCl3): δ 25.58.
1H NMR (300 MHz, CDCl3): δ 1.25 (two t, 6H, CH3,
3 JH−H = 7.08 Hz), 2.29–2.40 (m, 2H, CH2), 3.18 and
3.52 (AB-system, 1H + 1H, CH2C(OH), 2 JH−H = 14.85
Hz), 3.82 (s, 3H, OCH3), 3.98–4.08 (m, 4H, OCH2),
4.41 (s, 1H, OH), 4.47–4.57 (m, 2H, NCH2CH2),
7.51 (s, 1H, CH). 19F NMR (282 MHz, CDCl3): δ
–0.63 (s, CF3). 13C NMR (75.47 MHz, CDCl3): δ
3
2.64 (t, 2H, CH2, JH−H = 7.5 Hz), 3.99–4.05 (m, 4H,
OCH2), 4.36 (t, 2H, NCH2, 3 JH−H = 6.7 Hz), 7.30 (br.s,
1H, CH). Calcd for C15H22N3O3P: C, 55.72; H, 6.86;
N, 13.00. Found: C, 55.54; H, 6.94; N, 12.77.
Diethyl 3-(4-butyl-1H-1,2,3-triazol-1-yl)butylphos-
phonate (4d). Method A: light-yellow oil, yield 71%.
1
31P NMR (121 MHz, CDCl3): δ 31.0. H NMR (300
MHz, CDCl3): δ 0.68 (t, 3H, CH3, 3 JH−H = 7.2 Hz), 1.13
(t, 6H, CH3, 3 JH−H = 7.0 Hz), 1.13–1.15 (m, 2H, CH2),
1.36–1.39 (m, 4H, CH2), 1.51–1.54 (m, 2H, PCH2),
1.72–1.79 (m, 2H, PCH2), 2.45 (t, 2H, CH2, 3 JH−H = 7.4
Hz), 3.76–3.85 (m, 4H, OCH2), 4.10 (br, 2H, NCH2),
7.12 (s, 1H, CH). 13C NMR (75.47 MHz, CDCl3): δ
1
16.27 (CH3CH2), 27.03 (d, PCH2, JP−C = 141.4 Hz),
28.99 (CH2C ), 44.46 (CH2N), 54.15 (OCH3), 62.16
2
(d, POCH2, JP−C = 6.3 Hz), 77.18 (d, C(OH)CF3,
1
2 JF−C = 29.3 Hz), 123.28 (q, CF3, JF−C = 286.2 Hz),
3
13.18 (CH3(CH2)3), 15.80 (d, CH3CH2O, JP−C = 5.8
123.85 (CH ), 139.95 (CH2C ), 169.13 (CO). IR
(KBr) ν (cm−1): 976, 1033 (P O C), 1065, 1152,
1180, 1227 (P O), 1731 (C O), 3204 (br.OH). Calcd
for C13H21F3N3O6P: C, 38.74; H, 5.21; N, 10.43; P,
7.68. Found: C, 38.70; H, 5.21; N, 10.28; P, 7.53.
2
Hz), 18.99 (d, PCH2CH2, JP−C = 4.7 Hz), 21.63
1
(CH2CH3), 24.22 (d, PCH2, JP−C = 141.6 Hz), 24.68
( CCH2CH2), 30.15 (d, P(CH2)2CH2, 3 JP−C = 15.3 Hz),
30.94 (CH2C ), 48.78 (CH2N), 61.81 (d, POCH2,
2 JP−C = 6.6 Hz), 120.06 (HC ),147.67 (Bu-C ). Calcd
for C14H28N3O3P: C, 52.98; H, 8.89; N, 13.24. Found:
C, 52.65; H, 8.64; N, 12.97.
Methyl 2-({1-[3-(diethoxyphosphoryl)propyl]-1H-
1,2,3-triazol-4-yl}methyl)-3,3,3-trifluoro-2-hydroxy-
propanoate (5b). Method A: oil, yield 77%. 31P
NMR (121 MHz, CDCl3): δ 30.04. 1H NMR (300
Diethyl 3-{4-[(dimethylamino)methyl]-1H-1,2,3-
triazol-1-yl}propylphosphonate (4e). Method A: oil,
yield 79%. 31P NMR (121 MHz, CDCl3): δ 30.03.
2
MHz, CDCl3): δ 1.26 (t, 6H, CH3, JH−H = 7.1 Hz),
3
1.61 (appar. dt, 2H, PCH2CH2, JH−H = 8.0 Hz,
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of Phosphorylated Azides in Ionic Liquids and Their Use in the Preparation of 1,2,3-Triazoles 299
3 JP−H = 12.7 Hz), 2.06–2.21 (m, 2H, PCH2), 3.19 and
[4] Kuijpers, B. H. M.; Groothuys, S.; Keereweer, A. R.;
2
Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft,
F. L.; Rutjes, F. P. J. T. Org Lett 2004, 6, 3123–3126;
(b) Dondoni, A.; Giovannini, P. P.; Massi, A. Org Lett
2004, 6, 2929–2932.
3.52 (AB-system, 1H + 1H, CH2C(OH), JH−H = 14.6
Hz), 3.78 (s, 3H, OCH3), 4.00–4.06 (m, 4H, OCH2),
3
4.37 (t, 2H, NCH2, JH−H = 6.9 Hz), 4.99 (br.s, 1H,
OH), 7.55 (s, 1H, CH). 19F NMR (282 MHz, CDCl3):
δ –0.56 (s, CF3). IR (KBr) ν (cm−1): 976, 1028
(P O C), 1050 (C O C), 1136, 1188, 1228 (P O),
1753 (C O), 3202 (br.OH). Calcd for C14H23F3N3O6P:
C, 40.32; H, 5.51; N, 10.08. Found: C, 40.32; H, 5.51;
N, 9.84.
[5] Weller, R. L.; Rajski, S. R. Org Lett 2005, 7, 2141–
2144.
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Methyl
2-{[(benzyloxy)carbonyl]amino}-2-({1-
[2-(diethoxyphosphoryl)ethyl]-1H-1,2,3-triazol-4-yl}-
methyl)-3,3,3-trifluoropropanoate (6a). Method C:
oil, yield 50%. 31P NMR (121 MHz, CDCl3): δ 25.18.
1H NMR (300 MHz, CDCl3): δ 1.37 (t, 6H, CH3,
2 JH−H = 7.08 Hz), 2.31–2.42 (dt, 2H, CH2, 3 JH−H = 7.5
2
Hz, JP−H = 18.7 Hz), 3.97 (s, 3H, OCH3), 4.09–4.17
(m, 4H, OCH2), 3.71 and 4.23 (AB-system, 1H + 1H,
2
CH2, JH−H = 14.61 Hz), 4.42–4.55 (m, 2H, NCH2),
5.05 and 5.21 (AB-system, 1H + 1H, CH2C(CF3),
2 JH−H = 12.2 Hz), 6.32 (s, 1H, NH), 7.32 (s, 1H, CH),
7.42 (s, 5H, Ph). 19F NMR (282 MHz, CDCl3): δ 3.66
(s, CF3). EMS: m/z Calcd for C21H28F3N4O7P: 537.1
[M + H]+; found: 537.0 [M + H]+, 493 [M + H-OEt]+.
Methyl 2-({1-[2-(diethoxyphosphoryl)ethyl]-1H-
1,2,3-triazol-4-yl}methyl)-3,3,3-trifluoro-2-[(phenyl-
sulfonyl)amino]propanoate (6b). Method B: oil,
yield 62%. Method C: oil, yield 32%. 31P NMR
(121 MHz, CDCl3): δ 25.43. 1H NMR (300 MHz,
2
CDCl3): δ 1.38 (t, 6H, CH3, JH−H = 7.1 Hz), 2.47
3
2
(dt, 2H, PCH2, JH−H = 7.8 Hz, JP−H = 18.7 Hz),
3.70 and 4.02 (AB-system, 1H + 1H, CH2C(NH ),
2 JH−H = 14.6 Hz), 3.97 (s, 3H, OCH3), 4.12–4.22 (m,
4H, OCH2), 4.63–4.67 (m, 2H, NCH2), 6.27 (s, 1H,
NH), 7.51–7.62, 7.86–7.87 (m, 5H, Ph). 19F NMR
(282 MHz, CDCl3): δ 5.42 (s, CF3). EMS: m/z calcd
for C19H26F3N4O7PS: 543.1 [M + H]+; found: 543.0
[M + H]+, 515 [M + H-2Et]+.
[15] (a) Wroblewski, A. E.; Glowacka, I. E. Tetrahedron:
Asymmetry 2004, 15, 1457–1467; (b) Wroblewski,
A. E.; Glowacka, I. E. Tetrahedron: Asymmetry 2005,
16, 4056–4064.
[16] Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Seibel,
W. L.; Srivastava, A. Tetrahedron Lett 2003, 44, 2153–
2155.
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