Synthesis of (1,2,3‐triazol‐4‐yl)methyl phosphinates and (1,2,3‐Triazol‐4‐yl)methyl phosphates by copper‐catalyzed azide‐alkyne cycloaddition

Article abstract of DOI:10.3390/molecules24112085

An efficient and practical method was developed for the synthesis of new (1,2,3‐triazol‐4‐yl)methyl phosphinates and (1,2,3‐triazol‐4‐yl)methyl phosphates by the copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) of organic azides and prop‐2‐ynyl phos

Full text of DOI:10.3390/molecules24112085

Article
Synthesis of (1,2,3‐triazol‐4‐yl)methyl Phosphinates
and (1,2,3‐Triazol‐4‐yl)methyl Phosphates by
Copper‐Catalyzed Azide‐Alkyne Cycloaddition
1
2
2
1,
Anna Tripolszky , Krisztina Németh , Pál Tamás Szabó and Erika Bálint *
1
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary; tripolszky.anna@mail.bme.hu
MS Metabolomics Laboratory, Instrumentation Center, Research Centre for Natural Sciences,
2
Hungarian Academy of Sciences, Magyar Tudósok Krt. 2., H‐1117 Budapest, Hungary;
nemeth.krisztina.94@ttk.mta.hu (K.N.); szabo.pal@ttk.mta.hu (P.T.S.)
*
Correspondence: ebalint@mail.bme.hu; Tel.: +36‐1‐463‐3653
Received: 21 May 2019; Accepted: 30 May 2019; Published: 31 May 2019
Abstract: An efficient and practical method was developed for the synthesis of new
(1,2,3‐triazol‐4‐yl)methyl phosphinates and (1,2,3‐triazol‐4‐yl)methyl phosphates by the
copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) of organic azides and prop‐2‐ynyl
phosphinate or prop‐2‐ynyl phosphate. The synthesis of (1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl
diphenylphosphinate was optimized with respect to the reaction parameters, such as the
temperature, reaction time, and catalyst loading. The approach was applied to a range of organic
azides, which confirmed the wide scope and the substituent tolerance of the process. The method
elaborated represents a novel approach for the synthesis of the target compounds.
Keywords: 1,2,3‐triazol; triazolylmethyl phosphinate; triazolylmethyl phosphate; copper‐catalyzed
azide‐alkyne cycloaddition; click reaction
1
. Introduction
The family of 1,2,3‐triazoles has attracted considerable attention in the last decades due to the
wide range of their applications in medicine and biochemistry, as well as in materials science [1–3].
Several 1,2,3‐triazoles proved to be effective antibacterial, antifungal, anticancer, antiviral, or anti‐
inflammatory agents [4]. The 1,4‐disubstituted 1H‐1,2,3‐triazoles also have important applications as
agrochemicals, photostabilizers, dyes, or anticorrosives [5–8].
Organophosphorus compounds also present significant importance as biologically active agents
[9]. The 1,2,3‐Triazolyl phosphonates combine the advantages of the triazole and the phosphonate
moieties [10]. Additionally, several triazolylphosphonate derivatives were found to be suitable for
bioconjugation [11,12] or showed an anti‐HIV effect [13].
The most convenient synthetic method for the preparation of 1,4‐disubstituted 1H‐1,2,3‐triazoles
is the Cu(I)‐catalyzed 1,3‐dipolar (Huisgen) cycloaddition of azides with alkynes (CuAAC) (the “click
reaction”), which was developed by Meldal and Sharpless [14,15]. The 1,2,3‐Triazolyl phosphonates
may be synthesized by the reaction of azides with phosphorus‐containing acetylenes [12,13,16–20] or
by the cycloaddition of azides incorporating a phosphonate moiety with alkynes [21–24]. In this
paper, reports of the former method will be presented in detail.
The 1,3‐dipolar cycloaddition of benzyl azide and ethyl ethynylphosphonate (1) was carried out
in the absence of any catalyst at reflux temperature in toluene (Scheme 1) [16]. The reaction was not
Molecules 2019, 24, 2085; doi:10.3390/molecules24112085
www.mdpi.com/journal/molecules

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selective, two regioisomers, 1,2,3‐triazolyl‐4‐phosphonate (2a) and 1,2,3‐triazolyl‐5‐phosphonate (2b)
were formed.
Ar
Bn
O
1
10 °C, 24 h
N
N
N
N
N
+
N
BnN3
+
(EtO) P
2
toluene
Bn
P(OEt)2
O
P(OEt)2
1
O
2
a
2b
33%
4
0%
Scheme 1. Cycloaddition of benzyl azide and diethyl ethynylphosphonate (1).
Bisphosphonates incorporating a triazole ring (4) were prepared by the CuAAC reaction of a
propargyl‐substituted bisphosphonate (3) and organic azides (Scheme 2) [17,18]. The reactions were
performed using different methods. According to method A, copper iodide was applied as a catalyst
in the presence of N,N‐diisopropylethylamine (DIPEA) as a base in tetrahydrofuran (THF) [17]. In
another case, the Cu(I) catalyst was formed in situ from copper(II) sulfate pentahydrate and sodium
ascorbate in the mixture of tert‐butanol and water [18].
Scheme 2. Synthesis of bisphosphonates bearing a triazole ring (4) via CuAAc reaction.
Röschenthaler and co‐workers performed the synthesis of triazole‐containing α‐CF ‐α‐
3
aminophosphonates (6) by the Cu(I)‐catalyzed cycloaddition of azides and ethynyl‐ or propargyl‐
substituted phosphonate (5) (Scheme 3) [19].
Scheme 3. Synthesis of triazole‐containing α‐CF ‐α‐aminophosphonates (6).
3
The click reaction of 2‐azidoethanol and triprop‐2‐ynyl phosphate (7) was also reported, in
which a triazole‐functionalized phosphate flame‐retardant monomer (8) was synthesized (Scheme 4)
[20].
Scheme 4. Synthesis of a triazole‐functionalized phosphate monomer (8).

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To the best of our knowledge, there is no example for the azide‐alkyne cycloaddition of simple
azides and prop‐2‐ynyl phosphinate or diethyl prop‐2‐ynyl phosphate. The reaction of prop‐2‐ynyl
diphenylphosphinate was reported only with steroidal azides [25]. Hence, we set a sight on building
a phosphinate or phosphate side‐chain on position 4 of the triazole ring by the click reaction with
simple azides.
In this paper, we report on an efficient and fast synthesis of (1,2,3‐triazol‐4‐yl)methyl
phosphinates and (1,2,3‐triazol‐4‐yl)methyl phosphates by the copper(I)‐catalyzed 1,3‐dipolar
(Huisgen) cycloaddition of organic azides and prop‐2‐ynyl phosphinates or diethyl prop‐2‐ynyl
phosphate.
2
. Results and Discussion
At first, the starting materials of the cycloadditions were prepared. The synthesis of azides was
carried out based on the literature data [26,27] (Scheme 5). The benzyl or substituted benzyl bromides
were reacted with 1.5 equivalents of sodium azide at room temperature for 24 h in a mixture of
acetone/water in a ratio of 4:1, and the corresponding azides (9a–f) were obtained in yields of 80–93%
(
Scheme 5/I, Method A). The synthesis of octyl‐, i‐octyl‐ and cyclohexyl azides (9g–i) was performed
using 1.2 equivalents of sodium azide at 70 °C in dimethylformamide (DMF) (Scheme 5/I, Method B).
For the preparation of phenyl azide (11), aniline was reacted with sodium nitrite in HCl/H O solution
2
at 0 °C for 15 min, and the diazonium salt (10) formed was further reacted with sodium azide at
ambient temperature (Scheme 5/II). After workup, phenyl azide (11) was obtained in a yield of 65%.
Scheme 5. Synthesis of organic azides (9a–i and 11).
The synthesis of the prop‐2‐ynyl diphenylphosphinate (12a) and the diethyl prop‐2‐ynyl
phosphate (12b) was carried out by the reaction of diphenylphosphinic chloride or diethyl
chlorophosphate with propargyl alcohol in the presence of triethylamine in diethyl ether (Scheme 6).
The phosphorus‐containing alkynes (12a and 12b) were isolated in yields of 88% and 72%,
respectively.
Scheme 6. Synthesis of prop‐2‐ynyl phosphinate (12a) and diethyl prop‐2‐ynyl phosphate (12d).
As the next step of our work, the 1,3‐dipolar cycloaddition of benzyl azide (9a) and prop‐2‐ynyl
diphenylphosphinate (12a) was investigated in the presence of copper(II) sulfate pentahydrate and
sodium ascorbate in the mixture of tert‐butanol/water (4:1) (Table 1). Performing the reaction at room

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temperature using 5 mol% of CuSO
4ꞏ5H
2O and 30 mol% of sodium ascorbate, it was complete after
1
h and, after column chromatography, the desired (1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl
diphenylphosphinate (13a) was obtained in a yield of 84% (Table 1, Entry 1). Decreasing the amount
of the reducing agent (sodium ascorbate) to 10 mol%, the conversion was only 78% under the
conditions applied before (25 °C, 60 min) (Table 1, Entry 2). In this case, complete conversion could
be reached after 3 h (Table 1, Entry 3). Carrying out the reaction at 60 °C for 5 min under conventional
heating, the triazolylmethyl phosphinate (13a) was formed in a conversion of 93% (Table 1, Entry 4).
Applying microwave (MW) irradiation, the result obtained was similar (Table 1, Entry 5), thus further
experiments were performed in an oil bath. Increasing the reaction time to 10 min, the cycloaddition
was complete and product 13a was isolated in a yield of 89% (Table 1, Entry 6). In the next step, the
effect of the catalyst loading was studied (Table 1/Entries 7–9). Using 3% of CuSO
4
ꞏ5H O and 5 mol%
2
of sodium ascorbate, the reaction was similar to the previous experiment (Table 1, Entries 6 and 7).
Upon decreasing the amount of the Cu(II) catalyst to 2%, the conversion was lower (90%) (Table 1,
Entry 7). Based on the results obtained, a temperature of 60 °C, a reaction time of 10 min and
application of 3 mol% of CuSO
4
ꞏ5H O, as well as 5 mol% of sodium ascorbate, were found to be the
2
optimum parameters (Table 1, Entry 7).
Table 1. Optimization of the reaction of benzyl azide (9a) and propynyl diphenylphosphinate (11a).
Catalyst [mol%]
Mode of
heating
T
[°C]
t
Conversion
[%]a
Yield
[%]b
Entry
sodium
[min]
CuSO
4
ꞏ5H O
2
ascorbate
1
2
3
4
5
6
7
8
̶
25
25
25
60
60
60
60
60
60
60
180
5
5
5
5
5
5
5
3
2
30
10
10
10
10
10
5
100
78
100
93
84
–
89
̶
̶
̶

MW



5
92
̶
10
10
10
100
100
90
89
91
5
̶
a
Based on 31P NMR (phosphorus‐31 nuclear magnetic resonance) ; Isolated yield; MW (microwave).
b
In the next series of experiments, the cycloaddition of prop‐2‐ynyl diphenylphosphinate (12a)
with a wide range of organic azides (9 and 11) was studied under the optimized conditions (Scheme
7
). The reactions were complete in all cases. Using 4‐methylbenzyl azide (9b), the [1‐(4‐
methylbenzyl)‐1H‐1,2,3‐triazol‐4‐y])methyl diphenylphosphinate (13b) was isolated in a yield of
6%. Changing for fluoro‐substituted benzyl azides (2‐, 3‐ or 4‐fluorobenzyl azide) (9c–e), the desired
8
triazolylmethyl phosphinates (13c–e) were obtained in yields of 81–83% after column
chromatography. Carrying out the reaction starting from 4‐(trifluoromethyl)benzyl azide (9f), the
product 13f was prepared in a yield of 88%. Applying octyl azide (9g), the corresponding (1‐octyl‐
1
H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinate (13g) was obtained in a yield of 89%, while using
iso‐octyl azide (9h), product 13h was isolated in a yield of 77%. The cyclohexyl azide (9i) was also
tried out as the azide component; however, the triazolylmethyl phosphinate (13i) could be obtained
in a slightly lower yield (62%) due to the steric effects of the cyclohexyl group. Finally, the click
reaction of phenyl azide (11) was performed, and the desired triazolylmethyl phosphinate (13j) was
synthesized in a yield of 82%.

Molecules 2019, 24, 2085
Scheme 7. Synthesis of (1H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinates (13).
5 of 14
a
Isolated yield.
The cycloaddition of benzyl azide (9a) and diethyl prop‐2‐ynyl phosphate (12b) was also
investigated (Table 2). Using the optimized conditions (3 mol% of CuSO ꞏ5H O and 5 mol% of sodium
4
2
ascorbate, 60 °C, 10 min), the reaction was incomplete, and the (1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl
diethyl phosphate (14a) was formed in a conversion of only 48% (Table 2, Entry 1). Increasing the
reaction time to 20 min, the conversion increased to 59%; however, after 30 min, the reaction was
complete, and the triazolylmethyl phosphate (14a) was obtained in a yield of 75% (Table 2, Entries 2
and 3). The diethyl prop‐2‐ynyl phosphate (12b) proved to be somewhat less reactive in the click
reaction as compared to the prop‐2‐ynyl diphenylphosphinate (12a).

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Table 2. Reaction of benzyl azide (9a) and diethyl prop‐2‐ynyl phosphate (12b).
t
Conversion
(%)a
Yield
(%)b
Entry
(
min)
1
2
3
10
20
30
40
59
98
–
–
75
c
a
Based on 31P NMR. b Isolated yield. No change for longer reaction time.
c
In the next round, the reaction of diethyl prop‐2‐ynyl phosphate (12b) was also carried out with
a wide range of organic azides (9 and 11) in the presence of 3 mol% of CuSO ꞏ5H O and 5 mol% of
sodium ascorbate at 60 °C for 30 min (Scheme 8). Applying substituted benzyl azides (4‐methyl‐, 2‐,
4
2
3
1
6
‐ or 4‐fluorobenzylazide and 4‐(trifluoromethyl)benzyl azide) (11b–f), the corresponding (1‐benzyl‐
H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphate derivatives (14b–f) were prepared in yields of 54–
9%. Performing the cycloaddition starting from octyl or iso‐octyl azide (11g or 11h), the desired
products (14g or 14h) were isolated in yields of 60% and 54%, respectively. The reaction of cyclohexyl
azide (11i) and diethyl prop‐2‐ynyl phosphate (12b) was also carried out, and the product 14i was
obtained in a yield of 51%. Using aromatic azide, such as phenyl azide (11), the triazolylmethyl
phosphate (14j) was synthesized in a yield of 77%.

Molecules 2019, 24, 2085
Scheme 8. Synthesis of (1H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphates (14).
7 of 14
a
Isolated yield.
3
. Materials and Methods
3
.1. General
The reactions under conventional heating were carried out in an oil bath. The microwave‐
assisted experiments were performed in a 300 W CEM Discover focused microwave reactor (CEM
Microwave Technology Ltd., Buckingham, UK) equipped with a pressure controller using 5–10 W
irradiation under isothermal conditions.
High‐performance liquid chromatography‐mass spectrometry (HPLC–MS) measurements were
performed with an Agilent 1200 liquid chromatography system coupled with a 6130 quadrupole
mass spectrometer equipped with an ESI ion source (Agilent Technologies, Palo Alto, CA, USA).
Analysis was performed at 40 °C on a Gemini C18 column (150 mm × 4.6 mm, 3 μm; Phenomenex,
Torrance, CA, USA) with a mobile phase flow rate of 0.6 mL/min. The composition of eluent A was
0
5
.1% (NH
4
)(HCOO) in water; eluent B was 0.1% (NH )(HCOO) and 8% water in acetonitrile, 0–3 min
4
% B, 3–13 min gradient, 13–20 min 100% B. The injection volume was 5 μL. The chromatographic
profile was registered at 254 nm. The MSD operating parameters were as follows: positive ionization
mode, scan spectra from m/z 120 to 1200, drying gas temperature 300 °C, nitrogen flow rate 10 L/min,
nebulizer pressure 60 psi, capillary voltage 4000 V.

Molecules 2019, 24, 2085
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High‐resolution mass spectrometric measurements were performed using a Sciex 5600+ Q‐TOF
time‐of‐flight) mass spectrometer in positive electrospray mode.
(
(
The 31P, H, C, NMR spectra were taken in CDCl
1
13
3
solution on a Bruker AV‐300 spectrometer
Bruker AXS GmBH, Karlsruhe, Germany) operating at 121.5, 75.5, and 300 MHz, respectively.
PO and TMS.
Chemical shifts are downfield relative to 85% H
3
4
3
.2. General Procedure for the Synthesis of Benzyl Azides (Method A)
To a stirred solution of 10.0 mmol alkyl halides (1.19 mL of benzyl bromide, 1.85 g of
‐methylbenzyl bromide, 1.21 mL of 2‐fluorobenzyl bromide, 1.23 mL of 3‐fluorobenzyl bromide,
.25 mL of 4‐fluorobenzyl bromide, or 1.55 mL of 4‐(trifluoromethyl)benzyl bromide) in 100 mL of
4
1
acetone/H
at room temperature for 24 h. After, the reaction was extracted with Et
Na SO , and concentrated under reduced pressure to give benzyl azides as pale yellow oils. The
following azides were thus prepared (Table 3):
2O 4:1 (v/v) was added 15.0 mmol (0.98 g) of sodium azide. The reaction mixture was stirred
2O (3 × 50 mL), dried over
2
4
Table 3. MS Data for benzyl azides (9a–f).
Compound
Benzyl azide (9a) [26]
‐Methylbenzyl azide (9b) [28]
‐Fluorobenzyl azide (9c) [29]
Yield
[M+H]+found
134.0725
148.0880
152.0632
152.0633
152.0632
202.0601
[M+H]+requires
134.0718
148.0874
152.0624
152.0624
152.0624
202.0592
93% (1.24 g)
80% (1.18 g)
68% (1.02 g)
76% (1.14 g)
83% (1.25 g)
86% (1.72 g)
4
2
3
4
‐Fluorobenzyl azide (9d) [30]
‐Fluorobenzyl azide (9e) [28]
‐(Trifluoromethyl)benzyl azide (9f) [31]
4
3
.3. General Procedure for the Synthesis of Alkyl Azides (Method B)
To a stirred solution of 10.0 mmol alkyl halides (1.76 mL of octyl bromide, 1.78 mL of iso‐octyl
bromide, or 1.23 mL of bromocyclohexane) in 20 mL of DMF, 12.0 mmol (0.78 g) of sodium azide was
added. The reaction mixture was stirred at 70 °C for 24 h in an oil bath. After, the reaction was
extracted with Et2O (3 × 50 mL), dried over Na
2
SO , and concentrated under reduced pressure to give
4
alkyl azides as pale yellow oils. The following azides were thus prepared (Table 4):
Table 4. MS Data for alkyl azides (9g–i).
Compound
Yield
[M+H]+found
156.1514
156.1514
126.1038
[M+H]+requires
156.1501
156.1501
Octyl azide (9g) [32]
Iso‐octyl azide (9h) [33]
Cyclohexyl azide (9i) [27]
67% (1.04 g)
55% (0.85 g)
52% (0.65 g)
126.1031
3
.4. General Procedure for the Synthesis of Phenyl Azide
To a stirred solution of 0.46 mL aniline (5.0 mmol) in 25 mL 17% HCl solution at 0 °C, 0.51 g (7.5
mmol) of sodium nitrite in water (3 mL) was added. After stirring for 15 min, a solution of 0.32 g
sodium azide (7.5 mmol) in water (3 mL) was carefully added. The reaction was left to stir for 1 h,
followed by extraction with Et
and carefully concentrated under reduced pressure to give phenyl azide as an orange oil.
Phenyl azide (11) [26]: Yield: 65% (0.77 g) of compound 11 as orange oil; [M+H]+found = 120.0567,
requires 120.0562.
2O (3 × 30 mL). The combined organic layers were dried over Na
2
SO
4
,
C6H6N3
3
.5. General Procedure for the Synthesis of Prop‐2‐ynyl Diphenylphosphinate and Diethyl Prop‐2‐ynyl
Phosphate
To a stirred solution of 10 mmol of diphenylphosphinic chloride (1.91 mL) or diethyl
chlorophosphate (1.44 mL) in 10 mL of Et O, 1.39 mL (10 mmol) of Et N and 0.50 mL (10.0 mmol) of
propargyl alcohol at 0 °C were added under a nitrogen atmosphere. The solution was left stirring at
2
3

Molecules 2019, 24, 2085
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room temperature for 3–6 h and the reaction mixture obtained was passed through a 1 cm silica gel
layer using Et O. After evaporating the solvent, the products were obtained as white crystals (12a) or
2
colorless oil (12b). The following products were thus prepared (Table 5):
Table 5. 31P NMR and MS Data for prop‐2‐ynyl diphenylphosphinate (12a) and diethyl prop‐2‐ynyl
phosphate (12b).
Compound
2a
2b
Yield
88% (2.25 g)
72% (1.38 g)
δP
in CDCl
34.3
–0.4
3
δP
[lit.] in CDCl
34.2 [25]
–0.7 [34]
3
[M+H]+found
257.0735
193.0639
[M+H]+requires
257.0731
193.0629
1
1
3
.4. General Procedure for the Synthesis of (1H‐1,2,3‐Triazol‐4‐yl)methyl Phosphinates or Diethyl
Phosphates
The 1.0 mmol organic azide (0.13 g of benzyl azide, 0.15 g of 4‐methylbenzyl azide, 0.15 g of
‐fluorobenzyl azide, 0.15 g of 3‐fluorobenzyl azide, 0.15 g of 4‐fluorobenzyl azide, 0.20 g of
‐(trifluoromethyl)benzyl azide, 0.16 g of octyl azide, 0.16 g of iso‐octyl azide, 0.13 g of cyclohexyl
2
4
azide or 0.12 g of phenyl azide) and 1.0 mmol acetylene (0.26 g of prop‐2‐ynyl diphenylphosphinate
t
or 0.19 g of diethyl prop‐2‐ynyl phosphate) were suspended in a mixture of BuOH/H
2O (4:1) (2 mL).
To this 7.5 mg (0.03 mmol) of CuSO
The mixture was stirred at 60 °C for 10 min. The resulting solution was extracted with ethyl acetate
3 × 30 mL) and the combined organic layers were dried over Na SO . After evaporating the solvent,
4
∙5H O and 20 mg (0.1 mmol) of sodium ascorbate were added.
2
(
2
4
the crude product was purified by column chromatography using silica gel and
dichloromethane/methanol 97:3 as the eluent. The following products were thus prepared:
(
1‐Benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinate (13a): Yield: 91% (0.35 g), white crystals;
31
1
3
Mp: 91‐92 °C; P NMR (CDCl
3
) δ 33.5; H NMR (CDCl
3) δ 5.18 (d, JHP = 9.1, 2H, CH
2O), 5.46 (s, 2H,
CH Ph), 7.20–7.27 (m, 2H, C
2
2
H), 7.32–7.37 (m, 3H, C
3
H, C H), 7.38–7.44 (m, 4H, C3’H), 7.47–7.54 (m,
4
3
3
13
2
5
H, C4’H), 7.52 (s, 1H, CH), 7.79 (dd, JHP = 11.8, JHH = 7.4, 4H, C2’H); C NMR (CDCl
3) δ 54.3 (CH
2Ph),
2
3
8.2 (d, JCP = 5.3, CH
2O), 123.8 (CH=), 128.3 (C
2), 128.7 (d, JCP = 13.3, C3’), 128.8 (C
4
), 129.3 (C ), 131.2
3
1
2
), 144.0 (d, 3JCP = 6.7, C=);
(
d, JCP = 137.0, C1’), 131.8 (d, JCP = 10.3, C2’), 132.5 (d, JCP = 2.8, C4’), 134.5 (C
1
[
M+H]+found = 390.1363., C22
H21
N3O
2P requires 390.1371.
[
1‐(4‐Methylbenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diphenylphosphinate (13b): Yield: 86% (0.34 g),
31
1
white crystals; Mp: 119‐121 °C; P NMR (CDCl
d, JHP = 9.0, 2H, CH
3
) δ 33.3; H NMR (CDCl
3
) δ 2.35 (s, 3H, CH
3
Ph), 5.18
H, C H,
Ph), 54.2
), 131.3 (d,
), 144.0 (d, 3JCP
3
(
C
2
O), 5.41 (s, 2H, CH
2
Ph), 7.07–7.24 (m, 4H, C3’H), 7.32–7.60 (m, 7H, C
2
3
3
3
13
4’H), 7.79 (s, 1H, CH), 7.80 (dd, JHP = 12.4, JHH = 7.4, 4H, C2’H); C NMR (CDCl
3
) δ 21.3 (CH
), 128.7 (d, JCP = 13.2, C3’), 129.9 (C
), 131.8 (d, 2JCP = 10.3, C2’), 132.4 (d, JCP = 2.8, C4’), 138.9 (C
.7, C=); [M+H]+found = 404.1519, C23
P requires 404.1527.
3
2
3
(
CH
2Ph), 58.2 (d, JCP = 5.3, CH
2
O), 123.6 (CH=), 128.3 (C
2
3
1
J
CP = 136.6, C1’), 131.4 (C
1
4
=
6
H
23N3O
2
[
1‐(2‐Fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diphenylphosphinate (13c): Yield: 81% (0.33 g), pale
31
1
3
yellow crystals; Mp: 91‐93 °C; P NMR (CDCl
3) δ 33.5; H NMR (CDCl
3) δ 5.18 (d, JHP = 8.9, 2H,
CH O), 5.52 (s, 2H, CH Ph), 7.03–7.17 (m, 2H, C
2
2
3
H, C
5
H), 7.18–7.26 (m, 2H, C H), 7.28–7.53 (m, 7H,
6
3
3
13
C
4
H, C3’H, C4’H), 7.60 (s, 1H, CH), 7.79 (dd, JHP = 12.3, JHH = 6.9, 4H, C2’H); C NMR (CDCl
3
) δ 47.8
), 124.0
),
d, 3JCF = 4.4, CH
2
Ph), 58.1 (d, JCP = 5.3, CH
2
2
O), 115.9 (d, JCF = 21.1, C
2
3
), 121.8 (d, JCF = 14.6, C
2
1
(
(
3
), 131.1 (d, 3JCF = 8.2, C
CH=), 124.9 (d, JCF = 3.8, C
5
), 128.7 (d, JCP = 13.3, C3’), 130.7 (d, 3JCF = 3.2, C
4
6
1
2
1
31.1 (d, JCP = 136.8, C1’), 131.8 (d, JCP = 10.4, C2’), 132.4 (d, JCP = 2.9, C4’), 144.0 (d, 3JCP = 6.6, C=), 160.0
1
); [M+H]+found = 408.1268, C22
(
d, JCF = 248.1, C
2
H
20N
3
O FP requires 408.1277.
2
[
1‐(3‐Fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diphenylphosphinate (13d): Yield: 83% (0.34 g), pale
31
1
3
yellow crystals; Mp: 93‐94 °C; P NMR (CDCl
3) δ 33.7; H NMR (CDCl
3) δ 5.20 (d, JHP = 9.3, 2H,
CH O), 5.46 (s, 2H, CH Ph), 6.87–6.96 (m, 1H, C
2
2
4
H), 6.89–7.11 (m, 2H, C
2
H, C
6
H), 7.26–7.36 (m, 1H,
3
3
13
C
5
H), 7.37–7.55 (m, 6H, C3’H, C4’H), 7.59 (s, 1H, CH), 7.79 (dd, JHP = 12.4, JHH = 6.8, 4H, C2’H); C NMR
2
O), 115.2 (d, 2JCF = 22.2, C
2
(CDCl
3
) δ 53.6 (d, JCF = 2.0, CH
2
Ph), 58.2 (d, JCP = 5.3, CH
2
4
), 116.0 (d, JCF
=
), 123.9 (CH=), 128.7 (d, JCP = 13.3, C3’), 130.9 (d, 3JCF = 8.3, C
3
5
), 131.1 (d,
2
J
1.0, C
2
), 123.8 (d, JCF = 3.1, C
6
1
CP = 136.7, C1’), 131.8 (d, JCP = 10.3, C2’), 132.5 (d, JCP = 2.8, C4’), 136.8 (d, 3JCF = 7.4, C
2
), 144.2 (d, 3JCP
=
1
1
); [M+H]+found = 408.1269, C22
6
.5, C=), 163.1 (d, JCF = 248.0, C
3
H
20N
3
O FP requires 408.1277.
2

Molecules 2019, 24, 2085
10 of 14
[
1‐(4‐Fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diphenylphosphinate (13e): Yield: 83% (0.34 g), pale
31
1
3
yellow crystals; Mp: 95‐97 °C; P NMR (CDCl
3
) δ 33.5; H NMR (CDCl
3
) δ 5.18 (d, JHP = 9.2, 2H,
3
3
3
CH
7
(
1
2
O), 5.43 (s, 2H, CH
2
Ph), 7.04 (t, JHF = JHH = 8.6, 2H, C
2H), 7.23 (dd, JHF = 8.4, JHH = 5.1, 2H, C
3H),
3
3
13
.33–7.54 (m, 6H, C3’H, C4’H), 7.55 (s, 1H, CH), 7.79 (dd, JHP = 12.4, JHH = 7.4, 4H, C2’H); C NMR
CDCl
2
2
3
3
) δ 53.5 (CH
2
Ph), 58.2 (d, JCP = 5.3, CH
2
O), 116.2 (d, JCF = 21.9, C
3
), 123.8 (CH=), 128.7 (d, JCP
=
3
1
2
3.3, C3’), 130.1 (d, JCF = 8.4, C
2
), 130.4 (d, JCF = 3.3, C
1
), 131.2 (d, JCP = 136.7, C1’), 131.8 (d, JCP = 10.3,
1
); [M+H]+found = 408.1268,
C
C
2’), 132.5 (d, JCP = 2.9, C4’), 144.2 (d, 3JCP = 6.2, C=), 163.0 (d, JCF = 248.3, C
4
22
H20
N3
O FP requires 408.1277.
2
[
1‐(4‐Trifluoromethyl)benzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diphenylphosphinate (13f): Yield: 88%
3
1
1
3
(
2
C
(
0.40 g), white crystals; Mp: 124‐125 °C; P NMR (CDCl
3) δ 33.6; H NMR (CDCl
3) δ 5.20 (d, JHP = 9.5,
3
H, CH
2
O), 5.43 (s, 2H, CH
2
Ph), 7.33 (d, JHH = 8.0, 2H, C
3
2
H), 7.39–7.46 (m, 4H, C3’H), 7.48–7.53 (m, 2H,
4’H), 7.61 (d, 3JHH = 8.0, 2H, C
H), 7.63 (s, 1H, CH), 7.79 (dd, JHP = 12.4, JHH = 6.9, 4H, C2’H); C NMR
Ph), 58.2 (d, JCP = 5.4, CH
), 128.7 (d, JCP = 13.3, C3’), 131.1 (q, JCF =32.9, C
3
3
13
2
1
3
CDCl
3.7, C
3
) δ 53.6 (CH
2
2
O), 122.8 (CH=), 123.9 (q, JCF = 272.1, CF
3
), 126.2 (q, JCF
3
2
), 131.2 (d, 1JCP = 136.7, C1’), 131.7 (d,
=
3), 128.4 (C
2
4
2
CP = 10.3, C2’), 132.5 (d, JCP = 2.9, C4’), 138.5 (C
), 144.4 (d, 3JCP = 6.0, C=); [M+H]+found = 458.1242,
J
1
C
23
H
(
20
N
3
O
2
F P requires 458.1245.
3
1‐Octyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinate (13g): Yield: 89% (0.37 g), yellow oil; 31P
) δ 33.2; 1H NMR (CDCl
CH ), 1.72–1.97 (m, 2H, CH
.21 (d, JHP = 9.1, 2H, CH O), 7.34–7.57 (m, 6H, C
H); C NMR (CDCl ) δ 14.2 (CH ), 22.7 (CH
(CH CH ), 30.3 (CH ), 31.8 (CH
3
) δ 0.87 (t,
CH (CH
H, C
CH
3
J
HH = 6.5, 3H, CH
3
), 1.10–1.41 (m, 10H,
NMR (CDCl
3
3
CH CH (CH
2
2
2)5
3
2
2
2)5
CH
3
), 4.28 (t, 2H, JHH = 7.3, CH
2
CH
2
(CH
2
)
5
CH
3
),
=
),
=
3
3
3
5
7
2
5
2
3
4
H), 7.60 (s, 1H, CH), 7.82 (dd, JHP = 12.4, JHH
13
.3, 4H, C
9.1 (CH
.3, CH
2
3
3
2
3
), 26.6 (CH
CH ), 50.5 (CH
), 131.8 (d, JCP = 10.3, C
P requires 412.2153.
2CH
2CH
3
), 29.0 (CH
2
(CH
2
)
2
CH
3
2
2
2)3
3
2
(CH
2)4CH
3
2
(CH
2
)5
3
2(CH
2)
6
CH
3), 58.3 (d, JCP
3
1
2
2
O), 123.7 (CH=), 128.7 (d, JCP = 13.2, C
3
), 131.4 (d, JCP = 136.6, C
1
2
), 132.4
), 143.6 (d, JCP = 6.9, C=); [M+H]+found = 412.2154, C23
3
H
31N3O2
(d, JCP = 2.8, C
4
(
1‐Iso‐octyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinate (13h): Yield: 77% (0.49 g), yellow oil;
3
1
1
3
P NMR (CDCl
CH(CH
HP = 9.0, 2H, CH
H);
NCH
NCH
3
) δ 33.3; H NMR (CDCl
CH
O), 7.34–7.58 (m, 6H, C
NMR (CDCl 10.5 (NCH
CH CH ), 30.4 (CH
3
) δ 0.89 (t, JHH = 6.7, 6H, CH
3
), 1.02–1.41 (m, 8H,
2
)
3
CH
3
, CHCH
2
3
), 1.74–1.97 (m, 1H, NCH
H, C H), 7.59 (s, 1H, CH), 7.82 (dd, JHP = 12.5, JHH = 7.4, 4H,
CHCH CH ), 14.0 (CH ), 22.9 (CH CH ), 23.7
(CH ), 53.6
2
CH), 4.21 (d, 2H, 3JHH = 6.9, NCH
2
CH), 5.22 (d,
3
3
3
J
2
3
4
1
3
C
(
(
2
C
3
)
δ
2
2
2
3
3
2
3
2
CHCH
2
CH
CH
3
), 28.5 (CH
2
3
2
2)2CH
3
), 40.3 (NCH
2CHCH
2
CH
3
2
3
1
2
CHCH
2
3), 58.2 (d, JCP = 5.3, CH
2
O), 124.2 (CH=), 128.6 (d, JCP = 13.3, C
3
), 131.3 (d, JCP = 136.7,
2
), 143.4 (d, JCP = 6.2, C=); [M+H]+found = 412.2154,
3
C
1
), 131.7 (d, JCP = 10.3, C
2
), 132.4 (d, JCP = 2.9, C
4
C23H31N3O
2P requires 412.2153.
(
1‐Cyclohexyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinate (13i): Yield: 63% (0.24 g), white
31
1
crystals; Mp: 122‐124 °C; P NMR (CDCl
3) δ 33.2; H NMR (CDCl
3
) δ 1.16–1.52 (m, 4H, C
3
Hax, C4Hax,
C
4
H
eq), 1.58–1.80 (m, 2H, C
3
H
eq), 1.81–1.95 (m, 2H, C
2
H
ax), 2.01–2.22 (m, 2H, C
2
H
eq), 4.29–4.45 (m, 1H,
3
3
C
J
1
H), 5.21 (d, JHP = 9.0, 2H, CH
2O), 7.32–7.56 (m, 6H, C3’H, C4’H), 7.59 (s, 1H, CH), 7.82 (dd, JHP = 12.4,
3
13
2
HH = 7.3, 4H, C2’H); C NMR (CDCl
3
) δ 25.2 (C
4
), 25.3 (C
3
), 33.6 (C
2
), 58.4 (d, JCP = 5.3, CH
2O), 60.3
3
1
2
(
J
C
1) 121.6 (CH=), 128.7 (d, JCP = 13.2, C3’), 131.4 (d, JCP = 136.9, C1’), 131.8 (d, JCP = 10.3, C2’), 132.4 (d,
CP = 2.8, C4’), 143.1 (d, JCP = 6.5, C=); [M+H]+found = 382.1677, C21
3
H
25N
3
O P requires 382.1684.
2
(
1‐Phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diphenylphosphinate (13j): Yield: 82% (0.31 g), white crystals;
31
1
3
Mp: 121‐122 °C; P NMR (CDCl
3
) δ 33.5; H NMR (CDCl
3
) δ 5.30 (d, JHP = 9.1, 2H, CH O), 7.34–7.57
2
3
3
(
8
1
m, 9H, C
3
H, C
.05 (s, 1H, CH); C NMR (CDCl
3.2, C3’), 129.0 (C ), 129.9 (C
4’), 137.0 (C
4
H, C3’H, C4’H), 7.68 (d, 3JHH = 7.7, 2H, C
2H), 7.85 (dd, JHP = 12.4, JHH = 7.4, 4H, C2’H),
1
3
2
3
3
) δ 58.2 (d, JCP = 5.3, CH
2
O), 120.7 (C
2
), 122.2 (CH=), 128.8 (d, JCP
=
1
2
4
3
), 131.2 (d, JCP = 136.6, C1’), 131.8 (d, JCP = 10.4, C2’), 132.5 (d, JCP = 2.9,
C
1
), 144.4 (d, 3JCP = 6.0, C=); [M+H]+found = 376.1210, C21
H
19N
3
O P requires 376.1214.
2
(
1‐Benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphate (14a): Yield: 75% (0.24 g), pale yellow oil;
3
1
1
3
P NMR (CDCl
3
) δ –1.0; H NMR (CDCl
3
) δ 1.27 (t, JHH = 6.9, 6H, OCH
2
CH ), 4.01–4.09 (m, 4H,
3
OCH
2
CH
H, C
3
), 5.16 (d, 3JHP = 9.4, 2H, CH
H), 7.62 (s, 1H, CH); C NMR (CDCl
2O), 5.53 (s, 2H, CH
2
Ph), 7.25–7.30 (m, 2H, C
2
H), 7.32–7.40 (m,
Ph), 60.6
), 129.2 (C ), 134.5
13
3
3
(
(
H, C
d, JCP = 6.2, CH
3
4
3
) δ 16.1 (d, JCP = 6.3, OCH
), 123.5 (CH=), 128.2 (C
2
CH
), 129.0 (C
P requires 326.1269.
3
), 54.4 (CH
4
2
2
2
2O), 64.1 (d, JCP = 6.4, OCH
2CH
3
2
3
3
C
1
), 143.8 (d, JCP = 8.2, C=); [M+H]+found = 326.1259, C14
H
21
N
3O4

Molecules 2019, 24, 2085
11 of 14
[
1‐(4‐Methylbenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diethyl phosphate (14b): Yield: 69% (0.23 g), pale
31
1
3
yellow oil; P NMR (CDCl
CH
H, C
3
) δ –1.1; H NMR (CDCl
3
) δ 1.17 (t, JHH = 6.9, 6H, OCH
2
CH
Ph), 7.10 (s, 4H,
), 21.2 (CH Ph), 54.1
), 123.3 (CH=), 128.3 (C ), 129.9 (C ),
P requires 340.1426.
3
), 2.27 (s, 3H,
3
3
Ph), 3.87–4.05 (m, 4H, OCH
2CH
3), 5.07 (d, JHP = 9.2, 2H, CH
2O), 5.40 (s, 2H, CH
2
1
3
3
C
(
1
2
3
H), 7.52 (s, 1H, CH); C NMR (CDCl
3
) δ 16.1 (d, JCP = 6.8, OCH
2CH
3
3
2
2
CH
2Ph), 60.6 (d, JCP = 5.2, CH
2
O), 64.0 (d, JCP = 5.9, OCH
2CH
3
2
3
31.5 (C
1
), 138.9 (C
4
), 143.7 (d, JCP = 6.9, C=); [M+H]+found = 340.1414, C15
3
H
23N
3
O4
[
1‐(2‐Fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diethyl phosphate (14c): Yield: 54% (0.19 g), pale
31
1
3
yellow oil; P NMR (CDCl
H, OCH
.31 (m, 1H, C
3) δ –1.0; H NMR (CDCl
3) δ 1.28 (t, JHH = 7.1, 6H, OCH
2CH
3), 3.97–4.17 (m,
3
4
7
2
CH
3
), 5.16 (d, JHP = 9.3, 2H, CH
2
O), 5.59 (s, 2H, CH
2
Ph), 7.07–7.20 (m, 2H, C
3
H, C H), 7.24–
5
3
6
H), 7.32–7.41 (m, 1H, C
4
H), 7.70 (s, 1H, CH); 13C NMR (CDCl
3) δ 16.2 (d, JCP = 6.8,
), 47.9 (d, 3JCF = 4.3, CH
2
Ph), 60.6 (d, 2JCP = 5.3, CH
2O), 64.1 (d, JCP = 5.9, OCH
2
2
CH
3
), 116.0 (d,
), 131.2
FP
OCH
2
CH
3
2
2
3
J
CF = 21.1, C
d, 3JCF = 8.3, C
requires 344.1175.
3
), 121.8 (d, JCF = 14.6, C
1), 123.6 (CH=), 125.0 (d, JCF = 3.7, C
5
), 130.8 (d, JCF = 3.2, C
4
3
1
); [M+H]+found = 344.1164, C14
(
6
), 143.9 (d, JCP = 7.0, C=), 160.7 (d, JCF = 248.0, C
2
H
20N3O4
[
1‐(3‐Fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diethyl phosphate (14d): Yield: 56% (0.20 g), pale
31
1
3
yellow oil; P NMR (CDCl
H, OCH
m, 2H, C
3
) δ –0.9; H NMR (CDCl
3
) δ 1.28 (t, JHH = 7.1, 6H, OCH
2
CH
3
), 3.95–4.15 (m,
H), 7.00–7.12
) δ 16.2 (d, 3JCP = 6.8,
CH ), 115.2 (d,
), 136.9
FP
3
4
(
2
CH
H, C
), 53.7 (d, JCF = 1.9, CH
), 116.1 (d, 2JCF = 21.0, C
3
), 5.17 (d, JHP = 9.5, 2H, CH
2
O), 5.53 (s, 2H, CH
2Ph), 6.89–7.00 (m, 1H, C
4
2
6
H), 7.26–7.42 (m, 1H, C
5
H), 7.66 (s, 1H, CH); 13C NMR (CDCl
3
Ph), 60.6 (d, 2JCP = 5.2, CH
2
O), 64.1 (d, JCP = 6.0, OCH
2
2
3
OCH
2
CH
3
2
2
3
J
CF = 22.3, C
d, 3JCF = 7.4, C
requires 344.1175.
4
2
), 123.6 (CH=), 123.7 (d, JCF = 3.1, C
6
), 131.0 (d, JCF = 8.3, C
5
3
1
); [M+H]+found = 344.1164, C14
(
1
), 144.2 (d, JCP = 6.8, C=), 163.2 (d, JCF = 248.1, C
3
H
20
N
3O4
[
1‐(4‐Fluorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl])methyl diethyl phosphate (14e): Yield: 61% (0.22 g), pale
31
1
3
yellow oil; P NMR (CDCl
3
) δ –1.0; H NMR (CDCl
3
) δ 1.28 (t, JHH = 7.1, 6H, OCH
2
CH ), 3.88–4.15 (m,
3
3
3
4
(
5
(
H, OCH
2
CH
3
), 5.16 (d, JHP = 9.5, 2H, CH
2O), 5.50 (s, 2H, CH
2
Ph), 7.06 (t, JHF = JHH = 8.6, 2H, C
2
H), 7.28
CH ),
), 123.4
);
3
3
13
3
dd, JHF = 8.0, JHH = 5.8, 2H, C
3
H), 7.63 (s, 1H, CH); C NMR (CDCl
3
) δ 16.2 (d, JCP = 6.8, OCH
), 116.3 (d, JCF = 21.8, C
2
3
2
2
2
3.6 (CH
2
Ph), 60.6 (d, JCP = 5.2, CH
2O), 64.1 (d, JCP = 6.0, OCH
2CH
3
3
3
3
1
CH=), 130.2 (d, JCF = 8.4, C
2
), 130.4 (d, JCF = 3.3, C
1
), 144.0 (d, JCP = 6.9, C=), 163.1 (d, JCF = 248.3, C
4
[
M+H]+found = 344.1163, C14
H
20N
3
O FP requires 344.1175.
4
[
1‐(4‐Trifluoromethyl)benzyl)‐1H‐1,2,3‐triazol‐4‐yl]methyl diethyl phosphate (14f): Yield: 68% (0.27 g),
31
1
3
pale yellow oil; P NMR (CDCl
.12 (m, 4H, OCH
3
) δ –0.9; H NMR (CDCl
3
) δ 1.23 (t, JHH = 7.1, 6H, OCH
2
CH
3
), 3.92–
H),
), 53.6
3
3
4
7
2CH
3
), 5.13 (d, JHP = 9.4, 2H, CH
2O), 5.57 (s, 2H, CH
2
Ph), 7.36 (d, JHH = 8.0, 2H, C
2
3
13
) δ 16.1 (d, 3JCP = 6.7, OCH
.59 (d, JHH = 8.0, 2H, C
3
H), 7.68 (s, 1H, CH); C NMR (CDCl
3
2CH
3
Ph), 60.5 (d, 2JCP = 5.2, CH
26.1 (q, 3JCF = 3.8, C
), 128.4 (C
394.1157, C15
2
O), 64.0 (d, JCP = 5.9, OCH
), 131.1 (q, JCF =32.8, C
2
2
CH
3
), 123.7 (CH=), 123.8 (q, JCF = 272.4, CF
1
3),
(CH
2
2
), 144.1 (d, JCP = 6.8, C=); [M+H]+found
3
1
=
3
2
4
), 138.6 (C
1
H
20N3O4F3P requires 394.1143.
31
(1‐Octyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphate (14g): Yield: 60% (0.21 g), pale yellow oil; P
) δ –1.3; 1H NMR (CDCl
3) δ 0.88 (t,
3
J
HH = 6.7, 3H, CH ), 1.16–1.43 (m, 16H,
3
NMR (CDCl
3
CH
2
CH
2
(CH
2
)
5
CH
3
, OCH
2
CH
CH
3
), 1.81–2.01 (m, 2H, CH
2
CH
2
(CH
2
)
5
CH
3
), 4.01–4.22 (m, 4H, OCH
2
CH ),
3
3
3
13
4
.35 (t, 2H, JHH = 7.3, CH
2
2
(CH
2)5CH
3
), 5.19 (d, JHP = 9.4, 2H, CH
2O), 7.68 (s, 1H, CH); C NMR
3
(
(
(
CDCl
CH
CH
3) δ 14.2 (CH
3), 16.2 (d, JCP = 6.8, OCH
2
CH
3), 22.7 (CH
2
CH
), 31.8 (CH
CH
3
), 26.6 (CH
2
CH
2
CH ), 29.1
3
2
(CH
(CH
2)2CH
CH
3), 29.2 (CH
2
(CH
2)3
CH
3
), 30.4 (CH
2(CH
2
)4
CH
3
2(CH
2)5CH3), 50.6
2
2
3
2
2)6
3
), 60.7 (d, JCP = 5.3, CH
2O), 64.1 (d, JCP = 6.0, OCH
2
3), 123.4 (CH=), 143.4 (d, JCP
=
+
6
.7, C=); [M+H] found = 348.2043, C15
H
31N3O
4P requires 348.2052.
(
1‐Iso‐octyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphate (14h): Yield: 54% (0.19 g), pale yellow oil;
31
1
3
P NMR (CDCl
3) δ –1.2; H NMR (CDCl
3) δ 0.91 (t, JHH = 7.4, 6H, CH
3), 1.12–1.42 (m, 14H,
CH(CH
2
)
3
CH
3
, CHCH
2
CH
3
, OCH
2
CH
3
), 1.80–1.95 (m, 1H, NCH
2
CH), 3.98–4.15 (m, 4H, OCH
2
CH
) δ
), 23.8
3
),
3
3
13
4
1
.27 (d, 2H, JHH = 6.8, NCH
2CH), 5.19 (d, JHP = 9.4, 2H, CH
2O), 7.66 (s, 1H, CH); C NMR (CDCl
3
3
0.6 (NCH
CHCH
CHCH
2CHCH
2CH
3
), 14.1 (CH
3
), 16.2 (d,
3
J
CP = 6.7, OCH
(CH CH ), 40.5 (NCH
O), 64.1 (d, JCP = 6.0, OCH CH
P requires 348.2052.
2
CH
3), 23.0 (CH
2
CH
3
(
(
NCH
NCH
2
2
CH
CH
3
), 28.6 (CH
2CH
2CH ), 30.5 (CH
2
2)2
3
2CHCH
2CH
3), 53.7
2
2
3
2
2
3), 60.7 (d, JCP = 5.3, CH
2
2
3), 124.0 (CH=), 143.3 (d, JCP
=
6.6, C=); [M+H]+found = 348.2043, C15
H
31
N3O4

Molecules 2019, 24, 2085
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(
1‐Cyclohexyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphate (14i): Yield: 51% (0.16 g), pale yellow
oil; 31P NMR (CDCl
3) δ –1.3; H NMR (CDCl
1
3
) δ 1.31 (t, JHH = 6.9, 6H, OCH
3
2
CH ), 1.17–1.55 (m, 4H,
3
C
4
3
H
ax, C
4
H
ax, C
4
H
eq), 1.67–1.82 (m, 2H, C
.16 (m, 4H, OCH CH ), 4.38–4.52 (m, 1H, C
NMR (CDCl ) δ 16.2 (d, JCP = 6.8, OCH
CH CH
O), 64.0 (d, 2JCP = 5.9, OCH
P requires 318.1583.
3
H
eq), 1.88–1.98 (m, 2H, C
2
H
ax), 2.15–2.26 (m, 2H, C
2
H
eq), 4.02–
3
13
2
3
1H), 5.18 (d, JHP = 9.2, 2H, CH
2O), 7.70 (s, 1H, CH);
C
3
2
3
2
CH
3
), 25.2 (C ), 25.3 (C ), 33.7 (C
4
3
2
), 60.3 (C1), 60.8 (d, JCP = 5.2,
), 121.3 (CH=), 142.9 (d, JCP = 6.8, C=); [M+H]+found = 318.1575,
3
2
2
3
C13
H
25N
3
O
4
(
1‐Phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl diethyl phosphate (14j): Yield: 73% (0.23 g), pale yellow oil;
3
1
1
3
P NMR (CDCl
3
) δ –1.0; H NMR (CDCl
3
) δ 1.33 (t, JHH = 7.1, 6H, OCH
2
CH ), 3.99–4.20 (m, 4H,
3
3
3
OCH CH
2
3
), 5.28 (d, JHP = 9.2, 2H, CH
2O), 7.37–7.61 (m, 9H, C
3
H, C
4
H), 7.74 (d, JHH = 7.8, 2H, C
2H),
3
2
8
.16 (s, 1H, CH); 13C NMR (CDCl
3
) δ 16.2 (d, JCP = 6.8, OCH
), 121.8 (CH=), 129.1 (C ), 129.9 (C
P requires 312.1113.
2
CH
3), 60.5 (d, JCP = 5.1, CH
2O), 64.2 (d,
2
3
J
CP = 6.0, OCH
2
CH
3
), 120.7 (C
2
4
3
), 137.0 (C
1
), 144.1 (d, JCP = 7.0, C=);
[
M+H]+found = 312.1104, C13
H
19N
3O4
4
. Conclusions
In summary, we have developed a facile, efficient method for the synthesis of new (1‐alkyl/aryl‐
H‐1,2,3‐triazol‐4‐yl)methyl phosphinates or (1‐alkyl/aryl‐1H‐1,2,3‐triazol‐4‐yl)methyl diethyl
1
phosphates by the copper(I)‐catalyzed azide‐alkyne cycloaddition of organic azides and prop‐2‐ynyl
phosphinate or diethyl prop‐2‐ynyl phosphate. This method, which has the advantages of simple
operation and mild reaction conditions, is a novel approach for the synthesis of the target products.
Altogether, 20 new derivatives were synthesized and fully characterized.
Supplementary Materials: Supplementary data associated with this article are available online. Copies of 31P,
1
13
H, and C NMR spectra for all compounds synthesized are presented.
Author Contributions: Conceptualization, E.B.; methodology, E.B. and A.T.; validation, K.N. and P.T.S.; formal
analysis, K.N. and P.T.S.; investigation, A.T.; writing—original draft preparation, E.B.; writing—review and
editing, A.T.; visualization, E.B. and A.T.; supervision, E.B.; project administration, A.T.; funding acquisition,
E.B.
Funding: The project was supported by the Hungarian Research Development and Innovation Office
(
(
FK123961). E.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences
BO/00278/17/7), and by the ÚNKP‐18‐4‐BME‐131 New National Excellence Program of the Ministry of Human
Capacities. A.T. was supported by the ÚNKP‐18‐3‐I‐BME‐119 New National Excellence Program of the Ministry
of Human Capacities.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
Katritzky, A.R.; Rees, C.W.; Scriven, C.W.V. (Eds.), Comprehensive heterocyclic chemistry, vol. 4, Elsevier
Science, 1996, pp. 1–126.
Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click chemistry for drug development and diverse chemical‐
biology applications. Chem. Rev. 2013, 113, 4905–4979. doi:10.1021/cr200409f.
Lauria, A.; Delisi, R.; Mingoia, F.; Terenzi, A.; Martorana, A.; Barone, G.; Almerico, A.M. 1,2,3‐Triazole in
heterocyclic compounds, endowed with biological activity, through 1,3‐dipolar cycloadditions. Eur. J. Org.
Chem. 2014, 3289–3306. doi:10.1002/ejoc.201301695.
4.
5.
6.
Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3‐triazoles: Current developments. Bioorg.
Chem. 2017, 71, 30–54. doi:10.1016/j.bioorg.2017.01.010.
Williams, A. Opportunities for chiral agrochemicals. Pestic. Sci. 1996, 46, 3–9. doi:10.1002/(sici)1096‐
9063(199601)46:1<3::aid‐ps337>3.0.co;2‐j.
Ali, G.Q.; El‐Hiti, G.A.; Tomi, I.H.; Haddad, R.; Al‐Qaisi, A.J.; Yousif, E. Photostability and performance of
polystyrene films containing 1,2,4‐triazole‐3‐thiol ring system schiff bases. Molecules. 2016, 21, 1699–1711.
doi:10.3390/molecules21121699.
7.
Bouchemella, K.; Fauché, K.; Anak, B.; Jouffret, L.; Bencharif, M.; Cisnetti, F. Click 1,2,3‐triazole derived
fluorescent scaffold by mesoionic carbene–nitrene cyclization: an experimental and theoretical study. New
J. Chem. 2018, 42, 18969–18978. doi:10.1039/c8nj04070b.

Molecules 2019, 24, 2085
13 of 14
8
9
1
.
Srividhya, D.; Manjunathan, S.; Thirumaran, S.; Saravanan, C.; Senthil, S. Synthesis and characterization of
1,2,3]‐triazole containing liquid crystals through click reaction. J. Mol. Struct. 2009, 927, 7–13.
doi:10.1016/j.molstruc.2009.01.035.
Tajti, Á.; Keglevich, G. The importance of organophosphorus compounds as biologically active agents. In:
Organophosphorus Chemistry, Keglevich, G., Ed.; Walter de Gruyter GmbH: Berlin, Germany, 2018; pp.
[
.
53 65. ISBN:978‐3‐11‐053453‐5.
0. Li, L.; Hao, G.; Zhu, A.; Fan, X.; Zhang, G.; Zhang, L. A copper(I)‐catalyzed three‐component domino
process: assembly of complex 1,2,3‐triazolyl‐5‐phosphonates from azides, alkynes, and H‐phosphates.
Chem. Eur. J. 2013, 19, 14403–14406. doi:10.1002/chem.201303324.
1
1
1
1
1. Kee, J.M.; Villani, B.; Carpenter, L.R.; Muir, T.W. Development of stable phosphohistidine analogues. J. Am.
Chem. Soc. 2010, 132, 14327–14329. doi:10.1021/ja104393t.
2. Mukai, S.; Flematti, G.R.; Byrne, L.T.; Besant, P.G.; Attwood, P.V.; Piggott, M.J. Stable triazolylphosphonate
analogues of phosphohistidine. Amino acids. 2012, 43, 857–874. doi:10.1007/s00726‐011‐1145‐2.
3. Radi S.; Lazrek, H. B. Synthesis and biological activity of new 1,2,3‐triazole acyclonucleosides analogues of
ACV. J. Chem. Res., Synop. 2002, 264–266. doi: 10.3184/030823402103172149.
4. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise huisgen cycloaddition process:
Copper(I)‐catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002,
41, 2596–2599. doi:10.1002/1521‐3773(20020715)41:14<2596::aid‐anie2596>3.0.co;2‐4.
1
1
1
5. Tornøe, C.W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]‐Triazoles by regiospecific
copper(I)‐catalyzed 1,3‐dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 2002, 67, 3057–
3064. doi:10.1021/jo011148j.
6. Thiery, E.; You, V.; Mora, A.‐S.; Abarbri, M. Synthesis of 5‐substituted 1,2,3‐triazolyl‐4‐phosphonate
through cross‐coupling reactions of 5‐iodo‐1,2,3‐triazolyl‐4‐phosphonate. Eur. J. Org. Chem. 2016, 529–534.
doi:10.1002/ejoc.201501266.
7. Skarpos, H.; Osipov, S.N.; Vorobʹeva, D.V.; Odinets, I.L.; Lork, E.; Roschenthaler, G.V. Synthesis of
functionalized bisphosphonates via click chemistry. Org. Biomol. Chem., 2007, 5, 2361–2367.
doi:10.1039/b705510b.
1
8. Zhou, X.; Hartman, S.V.; Born, E.J.; Smits, J.P.; Holstein, S.A.; Wiemer, D.F. Triazole‐based inhibitors of
geranylgeranyltransferase II. Bioorg. Med. Chem. Lett. 2013, 23, 764–766. doi:10.1016/j.bmcl.2012.11.089.
9. Vorobyeva, D.V.; Karimova, N.M.; Vasilyeva, T.P.; Osipov, S.N.; Shchetnikov, G.T.; Odinets, I.L.;
Röschenthaler, G.‐V. Synthesis of functionalized α‐CF3‐α‐aminophosphonates via Cu(I)‐catalyzed 1,3‐
dipolar cycloaddition. J. Fluorine Chem. 2010, 131, 378–383. doi:10.1016/j.jfluchem.2009.12.003.
0. Sykam, K.; Meka, K.K.R.; Donempudi, S. Intumescent phosphorus and triazole‐based flame‐retardant
polyurethane foams from castor oil. ACS Omega. 2019, 4, 1086‐1094, doi:10.1021/acsomega.8b02968.
1. Artyushin, O.I.; Vorobʹeva, D.V.; Vasilʹeva, T.P.; Osipov, S.N.; Röschenthaler, G.‐V.; Odinets, I.L. Facile
synthesis of phosphorylated azides in ionic liquids and their use in the preparation of 1,2,3‐triazoles.
Heteroat. Chem. 2008, 19, 293‐300, doi:10.1002/hc.20420.
1
2
2
2
2. Artyushin, O.I.; Matveeva, E.V.; Bushmarinov, I.S.; Odinets, I.L. Water as a promoting media for 1,3‐dipolar
cycloaddition of phosphorylated azides to internal alkynes. Arkivoc 2012, (iv), 252–263.
doi:10.3998/ark.5550190.0013.419.
23. Glowacka, I.E.; Balzarini, J.; Wroblewski, A.E. Design, synthesis, antiviral, and cytotoxic evaluation of novel
phosphonylated 1,2,3‐triazoles as acyclic nucleotide analogues. Nucleosides Nucleotides Nucleic Acids. 2012,
31, 293–318. doi:10.1080/15257770.2012.662611.
2
4. Veliscek‐Carolan, J.; Rawal, A. Zirconium bistriazolylpyridine phosphonate materials for efficient, selective
An(iii)/Ln(iii) separations. Chem. Commun. 2019, 55, 1168–1171. doi:10.1039/c8cc07892k.
5. Erzunov, D.A.; Latyshev, G.V.; Averin, A.D.; Beletskaya, I.P., Lukashev, N.V. CuAAC synthesis and anion
binding properties of bile acid derived tripodal ligands. Eur. J. Org. Chem. 2015, 6289‐6297.
doi:10.1002/ejoc.201500835
2
26. Gann, A.W.; Amoroso, J.W.; Einck, V.J.; Rice, W.P.; Chambers, J.J.; Schnarr, N.A. A photoinduced, benzyne
click reaction. Org. Lett. 2014, 16, 2003–2005. doi:10.1021/ol500389t.
2
7. Womble, C.T.; Coates, G.W.; Matyjaszewski, K.; Noonan, K.J.T. Tetrakis(dialkylamino)phosphonium
polyelectrolytes prepared by reversible addition–fragmentation chain transfer polymerization. ACS Macro
Lett. 2016, 5, 253–257. doi:10.1021/acsmacrolett.5b00910.

Molecules 2019, 24, 2085
14 of 14
2
8. Bao, M.; Lu, W.; Su, H.; Qiu, L.; and Xu, X. A convergent formal [4 + 2] cycloaddition of 1,6‐diynes and
benzyl azides: construction ofspiro‐polyheterocycles. Org. Biomol. Chem. 2018, 16, 3258–3265.
doi:10.1039/c8ob00735g.
2
3
9. Wang, X.; Mei, T.‐S.; Yu, J.‐Q. Versatile Pd(OTf)
2
∙ 2H O‐catalyzed ortho‐fluorination using NMP as a
2
promoter. J. Am. Chem. Soc. 2009, 131, 7520–7521. doi:10.1021/ja901352k.
0. Colombano, G.; Albani, C.; Ottonello, G.; Ribeiro, A.; Scarpelli, R.; Tarozzo, G.; Daglian, J.; Jung, K.‐M.;
Piomelli, D.; Bandiera, T. O‐(Triazolyl)methyl carbamates as a novel and potent class of fatty acid amide
gydrolase (FAAH) inhibitors. Chem. Med. Chem. 2014, 10, 380–395. doi:10.1002/cmdc.201402374.
1. Tesch, M.; Kudruk, S.; Letzel, M.; Studer, A. Orthogonal click postfunctionalization of alternating
copolymers prepared by nitroxide‐mediated polymerization. Chem. Eur. J. 2017, 23, 5915–5919.
doi:10.1002/chem.201605639.
2. Colombano, G.; Travelli, C.; Galli, U.; Caldarelli, A.; Chini, M.G.; Canonico, P.L.; Sorba, G.; Bifulco, G.;
Tron, G.C.; Genazzani, A.A. A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized
via click chemistry. J. Med. Chem. 2010, 53, 616–623. doi:10.1021/jm9010669.
3
3
3
3
3. Swetha , M.; Ramana, P.V.; Shirodkar, S.G. Simple and efficient method for the synthesis of azides in water‐
THF solvent system. Org. Prep. Proced. Int. 2011, 43, 348–353. doi:10.1080/00304948.2011.594002.
4. Jones, S.;, Smanmoo, C. Phosphorylation of alcohols with N‐phosphoryl oxazolidinones employing
copper(II) triflate catalysis. Org. Lett. 2005, 7, 3271–3274. doi:10.1021/ol051104n.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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