The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker

Article abstract of DOI:10.1016/j.ejmech.2013.10.057

The efficient synthesis of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker is described starting from diethyl azidomethyl-, 2-azidoethyl-, 3-azidopropyl-, 4-azidobutyl-, 2-azido-1-hydroxyethyl-, 3-azido-2-hydroxypropyl- and 3-azido-1-hydroxypropylphosphonates and selected alkynes under microwave irradiation. Several O,O-diethylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and cytostatic activity against murine leukaemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Acyclonucleotide 22e exhibited activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC₅₀ = 17 μM) and feline herpes virus (EC ₅₀ = 24 μM) in CRFK cell cultures, while compounds 20k, 21k, 22k and 23k preferentially inhibited proliferation of human T-lymphocyte CEM cells at IC₅₀ in the 2.8-12 μM range.

Full text of DOI:10.1016/j.ejmech.2013.10.057

Accepted Manuscript
The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new series of
acyclonucleotide analogues with a 1,2,3-triazole linker
Iwona E. Głowacka, Jan Balzarini, Andrzej E. Wróblewski
PII:
S0223-5234(13)00698-3
10.1016/j.ejmech.2013.10.057
EJMECH 6520
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 5 July 2013
Revised Date: 16 October 2013
Accepted Date: 23 October 2013
Please cite this article as: I.E. Głowacka, J. Balzarini, A.E. Wróblewski, The synthesis, antiviral,
cytostatic and cytotoxic evaluation of a new series of acyclonucleotide analogues with a 1,2,3-triazole
linker, European Journal of Medicinal Chemistry (2013), doi: 10.1016/j.ejmech.2013.10.057.
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ACCEPTED MANUSCRIPT
Graphical abstract
The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new
series of acyclonucleotide analogues with a 1,2,3-triazole linker
Iwona E. Głowacka*, Jan Balzarini and Andrzej E. Wróblewski
N
N
(
EtO) (O)P
X
N
2
B
X = CH , (CH ) , (CH ) , (CH ) ,
2
2 2
2 3
2 4
CH(OH)CH , CH CH(OH)CH ,
2
2
2
CH(OH)CH CH2
2
B - nucleobases or their mimetics
The 1,2,3-triazoloacyclonucleotides were evaluated in vitro for activity against a broad
variety of DNA and RNA viruses and cytostatic activity against murine leukemia L1210,
human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Diethyl 3-{4-[(3-
benzoyl-2,4-dioxoquinazolin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
exhibited activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell
cultures (EC = 17 µM) and feline herpes virus (EC = 24 µM) in CRFK cell cultures.
5
0
50
Several compounds preferentially inhibited proliferation of human T-lymphocyte CEM
cells at IC in the 2.8–12 µM range.
5
0
1

ACCEPTED MANUSCRIPT
The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new series of
acyclonucleotide analogues with a 1,2,3-triazole linker
a
b
a
Iwona E. Głowacka* , Jan Balzarini and Andrzej E. Wróblewski
a
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, 90-
51 Łódź, Muszyńskiego 1, Poland
1
b
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven,
Belgium
Corresponding author: Tel: +48 42 677 92 37; fax: +48 42 678 83 98. E-mail address:
iwona.glowacka@umed.lodz.pl
Keywords: Aziodophosphonates / Acyclonucleotides / 1,2,3-Triazoles / Synthesis / Antiviral /
Cytostatic
Abstract
The efficient synthesis of a new series of acyclonucleotide analogues with a 1,2,3-triazole
linker is described starting from diethyl azidomethyl-, 2-azidoethyl-, 3-azidopropyl-, 4-
azidobutyl-,
2-azido-1-hydroxyethyl-,
3-azido-2-hydroxypropyl-
and
3-azido-1-
hydroxypropylphosphonates and selected alkynes under microwave irradiation. Several O,O-
diethylphosphonate acyclonucleotides were transformed into the respective phosphonic acids.
All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA
viruses and cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM
and human cervix carcinoma HeLa cells. Acyclonucleotide 22e exhibited activity against both
herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 = 17 µM) and feline
herpes virus (EC50 = 24 µM) in CRFK cell cultures, while compounds 20k, 21k, 22k and 23k
preferentially inhibited proliferation of human T-lymphocyte CEM cells at IC50 in the 2.8-12
ꢀM range.
1
. Introduction
Several acyclic nucleosides and nucleotides exhibit antiviral or anticancer activities.
However, in most cases, the clinical use of antiviral nucleosides is hampered by the drug
resistance and/or toxicity problems. Under these circumstances intensive search for new drugs
1

ACCEPTED MANUSCRIPT
effective in the chemotherapy of viruses such as HIV, herpes virus, hepatitis viruses and
cytomegalovirus has been conducted by many laboratories. A large number of modifications
has been introduced to both the nucleobase and the sugar moieties of natural nucleosides.
Consequently, several analogues like adefovir [1,2], tenofovir [3] and cidofovir [4] (Figure 1)
were synthesised in which the furanose ring and the readily hydrolysable phosphate ester
linkage present in natural nucleotides have been replaced by an acyclic chain and phosphonate
moiety, respectively.
Figure 1. Acyclic nucleoside phosphonates used in the treatment of viral infections.
In drug discovery replacement of canonical nucleobases [5] by substituted five-membered
heterocyclic rings such as imidazole or triazole has been particularly successful. Ribavirin
[
6−12], AICA [13,14], Bredinin [15,16] and TSAO analogues [17,18] are the best known
examples among these analogues (Figure 2).
Figure 2. Ribavirin, AICA, Bredinin and TSAO analogues.
Further efforts in this field led to the synthesis of several analogues containing both modified
nucleobases and 1,2,3-triazole moieties [19–37]. Among them compounds 1−11 [27–37] in
which nucleobases or their mimetics and substituted triazoles are linked by the methylene
group are of special interest (Figure 3).
Figure 3. Nucleoside analogues having natural nucleobases connected to the 1,2,3-triazole
ring by a methylene linker.
Moreover, several compounds possessing the 1,2,3-triazole ring show cytostatic [38–45],
antiviral [46–49], antibacterial [50–56] or antifungal activities [57–60]. The conventional
synthesis of 1,2,3-triazoles relies on the Hüisgen [3+2] cycloaddition between alkynes and
organic azides and usually provides a mixture of 1,4- and 1,5-disubstitued regioisomers
[
61,62]. Recent discovery of copper(I) as an efficient and regiospecific catalyst for this
2

ACCEPTED MANUSCRIPT
transformation [63,64] provides a general and mild approach for the preparation of 1,4-
disubstituted 1,2,3-triazole derivatives.
In continuation of our studies on nucleotide analogues [65–70] a new series of modified
phosphonylated 1,2,3-triazoloacyclonucleosides bearing selected nucleobases or their
mimetics at C-4 of the 1,2,3-triazole moiety (Scheme 1) has been synthesised and subjected to
biological evaluation.
Scheme 1. Synthesis of phosphonylated 1,2,3-triazoloacyclonucleosides 20−26 a−m.
2
. Results and discussion
2
.1. Chemistry
Compounds 20–26 a–l were obtained by the 1,3-dipolar cycloaddition of
9
azidoalkylphosphonates 12−18 with propargylated nucleobases 19a−l: N -propargyladenine
1
1
4
1
1
9a [27], N -propargylthymine 19b [27], N -propargyluracil 19c [17] and N -acetyl-N -
3
1
propargylcytosine 19d [71] and mimetics of nucleobases: N -benzoyl-N -
1
7
propargylquinazoline-2,4-dione 19e, N -propargyl-6-azauracil 19f [30], 8-chloro-N -
1
7
propargyltheophylline
19g
[72],
N -propargyltheobromine
19h
[73,74],
N -
1
propargyltheophylline 19i [75], 5,6-dimethyl-N -propargylbenzimidazole 19j [76], 3-acetyl-
N-propargylindole 19k [77], N-propargyl-2-pyridon 19l [76]. The required
azidoalkylphosphonates 12−18 were synthesised according to the procedures described
previously [65,66,69,78,79].
3
1
Except for N -benzoyl-N -propargylquinazoline-2,4-dione 19e all alkynes used in this paper
3
1
have already been described in the literature. N -Benzoyl-N -propargylquinazoline-2,4-dione
1
9e was synthesised in 19% overall yield in three steps from quinazoline-2,4-dione 27
1
3
1
beginning with bis-N ,N -benzoylation to 28 followed by the selective N -debenzoylation to
3
2
9 and propargylation (Scheme 2). The N -benzoylquinazoline-2,4-dione 29 was previously
obtained from 2-benzoylaminobenzoxazinone in less than 5% yield [79].
3

ACCEPTED MANUSCRIPT
3
Scheme 2. Reagents and conditions: a. benzoyl chloride (2.2 equiv.), pyridine, CH CN, r.t,
1
2 3
2 h., 87%; b. 1N K CO aq., dioxane, r.t., 24 h., 23%; c. propargyl bromide (1.2 equiv.),
K
2
CO (1.1 equiv.), DMF, r.t., 24 h., 97%.
3
3
1
The structure of N -benzoyl-N -propargylquinazoline-2,4-dione 19e was confirmed on the
1
13
basis of H, C NMR and IR spectral data and finally proved by 2D COSY and NOESY
experiments (Figure 4).
Figure 4. NOESY correlations in 19e.
All 1,2,3-triazoles 20−26 were obtained in good yields in 1,3-dipolar cycloadditions which
were carried out in a microwave oven at 40–45°C. This approach caused significant
improvements in purity of the final products and allow to shorten the reaction time from 48
hours at room temperature to 10 minutes of irradiation. Since syntheses of phosphonylated
1
,2,3-triazoles 20a–d, 21a–d, 22a–d, 24a–d and 25a–d have already been described and their
9
1
1
biological activity evaluated [32,69], N -propargyladenine 19a, N -propargylthymine 19b, N -
4
1
propargyluracil 19c and N -acetyl-N -propargylcytosine 19d were reacted with two
azidophosphonates 15 and 18, only. However, mimetics of nucleobases 19e–19l were applied
in cycloadditions with all seven azidophosphonates 12–18 (Scheme 3 and 4).
Scheme 3. Reagents and conditions: a. CuSO
4 2
×5H O (0.05 equiv.), sodium ascorbate (0.1
equiv.), H O−EtOH (1:1), MW, 40–45°C, 10 min.
2
Scheme 4. Reagents and conditions: a. CuSO ×5H O (0.05 equiv.), sodium ascorbate (0.1
4
2
equiv.), H
2
O−EtOH (1:1), MW, 40–45°C, 10 min.
Since the preliminary experiments have demonstrated antiviral activity of compound 22e
against herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50 = 17 µM) and
feline herpes virus (EC50 = 24 µM) in CRFK cell cultures, phosphonate 22m was synthesised
in order to establish the influence of the fused phenyl ring in 22e on the observed activity
(Scheme 5).
4

ACCEPTED MANUSCRIPT
Scheme 5. Reagents and conditions: a. CuSO
4
×5H
2
O (0.05 equiv.), sodium ascorbate (0.1
equiv.), H O−EtOH (1:1), MW, 40–45°C, 10 min.
2
3
1
3
Our synthesis of N -benzoyl-N -propargyluracil 19m by propargylation of N -benzoyluracil
with propargyl bromide (Scheme 6) appeared more efficient (95%) in comparison to the
3
previously described approach from N -benzoyluracil and propargyl alcohol via the
Mitsunobu reaction (76% yield) [81].
2 3
Scheme 6. Reagents and conditions: a. propargyl bromide (1.2 equiv.), K CO (1.1 equiv.),
DMF, r.t., 24 h, (95%).
Finally, using bromotrimethylsilane [82] selected diethyl phosphonates 22e, 22g, 22j, 22m,
2
3a–c and 24i were transformed into the respective phosphonic acids in good yields (Scheme
7
).
Scheme 7. Reagents and conditions: a. TMSBr, CH Cl , r.t., 24 h.
2
2
2
.2. Conformational analysis
Conformational preferences of phosphonates described in this paper were ascertained by
1
1
31
13
analyses of H, H{ P} and C NMR spectra. Since all vicinal proton-proton couplings
within the H C–CH fragment in phosphonates 21e–l were observed around 7 Hz, it was
2
2
2 2
concluded that the rotation around the PCH –CH N bond is fully unrestricted. On the other
3
3
hand, based on the values of JH1−H2a = 10.0 Hz, JH1−H2b = 2.9 Hz [83] and small values of
3
3
JP−H2a and J
(ca. 5.5 Hz) [84,85] one may deduce that phosphonates 24e–l exist in the
P−H2b
antiperiplanar conformation 34 which is probably stabilised by the intramolecular hydrogen
bond (Figure 5). Conformational behaviour of the three-carbon linkers between the
diethoxyphosphoryl and substituted 1,2,3-triazole groups in phosphonates 22e–l, 25e–l and
2
6e–l is primarily governed by the presence of the hydroxy groups. Thus, values of vicinal
proton-proton couplings within PCH –CH and CH –CH N subunits in 22e–l (ca. 7 Hz) can
only be observed when free rotation around these bonds is allowed. 2-Hydroxyphosphonates
5e–l adopt the H-bond stabilised antiperiplanar conformation 35 along the PCH –CH bond
2
2
2
2
2
2
3
3
3
3
[
J
H1a−H2 = 3.9 Hz, JH1b−H2 = 8.6 Hz, JP−H2 = 12.0 and JP−C3 = 14–18 Hz [85,86,87], while
5

ACCEPTED MANUSCRIPT
3
3
the rotation around the CH–CH
2
N bond is unrestricted [ JH2−H3a = 3.0 Hz, JH2−H3b = 7.0 Hz].
To establish a conformational behaviour of 1-hydroxyphosphonates 26a–l the extensive NMR
studies on 1-hydroxyphosphonate 26i were conducted at 600 MHz. From the values of
3
3
3
3
3
J
H1−H2a = 3.3 Hz, JH1−H2b = 10.9 Hz as well as JP−H2a = 6.1 and JP−H2b = 6.4 JP−C3 = 15–18
2
Hz, it is evident that along the PCH–CH bond, this phosphonate exists in the antiperiplanar
3
3
3
conformation 36, while based on the values of J
= J
= 8.0 Hz, J
= 5.9
H2b−H3a
H2a−H3a
H2a−H3b
3
Hz and JH2b−H3b = 5.9 Hz one may suggest that along the CH
2
–CH
2
N bond in 26i the rotation
is almost free.
The anticipated full conformational freedom along the tetramethylene linker in the
3
butylphosphonates 23a–l is confirmed by the values of JH−H = 7.1 Hz between all methylene
groups (Figure 5).
Figure 5. Preferred conformations of phosphonates investigated in this paper
2
.3. Antiviral activity and cytotoxicity evaluation
All the synthesised compounds 20−26 a–m, 31e, 31g, 31j, 31m, 32a–c and 33i were
evaluated for their antiviral activities against a wide variety of DNA and RNA viruses, using
the following cell-based assays: (a) human embryonic lung (HEL) cells: herpes simplex virus-
−
r
1
(KOS), herpes simplex virus-2 (G), herpes simplex virus-1 (TK ACV KOS), vaccinia
virus and vesicular stomatitis virus; (b) CEM cell cultures: human immunodeficiency virus-1
HIV-1] and HIV-2; (c): Vero cell cultures: para-influenza-3 virus, reovirus-1, Sindbis virus,
[
Coxsackie virus B4, Punta Toro virus; (d): HeLa cell cultures: vesicular stomatitis virus,
Coxsackie virus B4 and respiratory syncytial virus; (e): Crandell-Rees Feline Kidney (CRFK)
cell cultures: feline corona virus (FIPV) and feline herpes virus (FHV); (f): Madin Darby
Canine Kidney (MDCK) cell cultures: influenza A virus H1N1 subtype (A/PR/8), influenza A
virus H3N2 subtype (A/HK/7/87) and influenza B virus (B/HK/5/72). Ganciclovir, cidofovir,
acyclovir, brivudin, (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA], Hippeastrum hybrid
agglutinin (HHA), Urtica dioica agglutinin (UDA), dextran sulfate (molecular weight 5000,
DS-5000), ribavirin, oseltamivir carboxylate, amantadine and rimantadine were used as the
reference compounds. The antiviral activity was expressed as the EC50: the compound
6

ACCEPTED MANUSCRIPT
concentration required to reduce virus plaque formation (VZV) by 50% or to reduce virus-
induced cytopathogenicity by 50% (other viruses).
The cytotoxicity of the tested compounds toward the uninfected host cells was defined as the
minimum cytotoxic concentration (MCC) that causes a microscopically detectable alteration
of normal cell morphology. The 50% cytotoxic concentration (CC50), causing a 50% decrease
in cell viability was determined using a colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay system.
Among all the 1,2,3-triazole derivatives tested, compound 22e having a three carbon fragment
3
between the phosphorus atom and the 1,2,3-triazole ring substituted at C4′ with N -benzoyl-
1
N -methylquinazoline-2,4-dione showed a moderate activity against both herpes simplex
viruses (HSV-1, HSV-2) (EC50 = 17 µM) in HEL cell cultures, and feline herpes virus (EC50
=
24 µM) in CRFK cell cultures.
2
.4. Evaluation of cytostatic activity
The cytostatic activity of the tested compounds was defined as the 50% cytostatic inhibitory
concentration (IC50), causing a 50% decrease in cell proliferation was determined against
murine leukaemia L1210, human lymphocyte CEM and human cervix carcinoma HeLa cells.
Most compounds were not cytostatic at 200 µM.
Several compounds showed very moderate inhibitory against the proliferation of tumour cell
lines (Table 1), although in a few cases, the compounds seemed to be preferentially cytostatic
against human tumour cell lines (esp. lymphocyte CEM cells) than murine (L1210) cells. In
particular, compound 20k, 21k, 22k and 23k were antiproliferative at IC50 values ranging
between 2.8 and 12 µM.
Table 1. Inhibitory effect of tested compounds against the proliferation of murine leukemia
(L1210), human T-lymphocyte (CEM) and human cervix carcinoma cells (HeLa).
2
.5. Structure-activity relationship
7

ACCEPTED MANUSCRIPT
Structure-activity relationship studies on a series of 1,2,3-triazoloacyclonucleotides 20−26 a-
m and 30e, g, j, m, 31a–c and 32i revealed cytostatic activity of compounds substituted at C4′
3
of the 1,2,3-triazole ring with 3-acetylindole, N -benzoylquinazoline-2,4-dione and 5,6-
dimethylbenzimidazole. Regardless of the length of the linker (1–4 carbon atoms) all
derivatives of the 1,2,3-triazoles with 3-acetylindole were the most active towards CEM cell
lines (e.g. IC50 = 2.78±1.4 ꢀM for 20k) and also some of them against HeLa cells.
Furthermore, compounds 21j, 22e, 23k, 24k, 25e and 26e selectively inhibited the
proliferation of human T-lymphocyte (CEM).
As could be expected the phosphonic acids were found inactive in all biological tests
including these acids for which the corresponding diethyl esters displayed significant activity
(22e vs. 31e and 22j vs. 31j). This is in full agreement with observation that lipophilic
phosphonate esters better penetrate through membranes in comparison with phosphonic acids
and thus the sufficient concentration of the ester is achieved in cells to undergo further
reactions.
For compound 22e containing a three methylene linker between the phosphorus atom and the
3
1
1
,2,3-triazole ring substituted at C4′ with N -benzoyl-N -methylquinazoline-2,4-dione activity
against both herpes simplex viruses (HSV-1, HSV-2) (EC50 = 17 µM) in HEL cell cultures,
and feline herpes virus (EC = 24 µM) in CRFK cell cultures was established. The presence
50
of the quinazoline ring appeared necessary for 22e to display antiviral activity, since its
structural analogue lacking the condensed phenyl ring (compound 22m) was found inactive
EC50 > 200 µM.
3
. Conclusion
A new series of 1,2,3-triazoloacyclonucleotides 20−26 a−m has been efficiently obtained
from diethyl azidomethyl-, 2-azidoethyl-, 3-azidopropyl-, 4-azidobutyl-, 2-azido-1-
hydroxyethyl-, 3-azido-2-hydroxypropyl- and 3-azido-1-hydroxypropylphosphonates and
9
selected N-propargyl alkynes including N-propargyl nucleobases (N -propargyladenine
1
1
4
1
1
9a,
N -propargylthymine
19b,
N -propargyluracil 19c
and
N -acetyl-N -
3
1
propargylcytosine 19d) and several mimetics (N -benzoyl-N -propargylquinazoline-2,4-
1
7
1
dione 19e, N -propargyl-6-azauracil 19f, 8-chloro-N -propargyltheophylline 19g, N -
7
1
propargyltheobromine
19h,
N -propargyltheophylline
19i,
5,6-dimethyl-N -
8

ACCEPTED MANUSCRIPT
propargylbenzimidazole 19j, 3-acetyl-N-propargylindole 19k, N-propargyl-2-pyridon 19l
3
1
and N -benzoyl-N -propargyluracil 19m) via 1,3-dipolar cycloadditions carried out under
microwave irradiation.
3
1
The N -benzoyl-N -propargylquinazoline-2,4-dione 19e was synthesised from quinazoline-
1
3
2
,4-dione 27 in the sequence of reactions including bis-N ,N -benzoylation followed by the
1
selective N -debenzoylation and propargylation.
Under standard conditions (TMSBr, ethanol) several O,O-diethylphosphonates 22e, g, j, m,
2
3a-c and 24i were transformed into their respective phosphonic acid.
All synthesised compounds were evaluated against a variety of DNA and RNA viruses.
Compound 22e containing a three carbon linker between the phosphorus atom and the 1,2,3-
3
1
triazole ring substituted at C4′ with N -benzoyl-N -methylquinazoline-2,4-dione showed a
moderate activity (EC50 = 17 µM) against both herpes simplex viruses (HSV-1, HSV-2) in
HEL cell cultures and feline herpes virus (EC50 = 24 µM) in CRFK cell cultures.
All synthesised compounds were also evaluated for their anti-proliferative activity against
three tumour cell lines (L1210, CEM and HeLa) and several compounds, i.e. 20k, 21j–k, 22j–
k, 23j–k and 24k were found to be the most active (and preferentially inhibitory) towards T-
lymphocyte CEM cell proliferation.
4
. Experimental
4
.1. Chemistry
1
3 3 2
H NMR were taken in CDCl , CD OD or D O on the following spectrometers: Varian
Mercury-300 and Bruker Avance III (600 MHz) with TMS as an internal standard; chemical
1
3
shifts δ in ppm with respect to TMS; coupling constants J in Hz. C NMR spectra were
recorded for CDCl , CD OD, DMSO-d or D O solutions on a Varian Mercury-300 and
3
3
6
2
31
Bruker Avance III (600 MHz) spectrometer at 75.5 and 150.5 MHz, respectively. P NMR
spectra were taken in CDCl , CD OD or D O on Varian Mercury-300 at 121.5 MHz.
3
3
2
IR spectral data were measured on an Infinity MI-60 FT-IR spectrometer. Melting
points were determined on a Boetius apparatus and are uncorrected. Elemental analyses were
performed by the Microanalytical Laboratory of this Faculty on a Perkin Elmer PE 2400
CHNS analyzer.
The following adsorbents were used: column chromatography, Merck silica gel 60
(
70-230 mesh); analytical TLC, Merck TLC plastic sheets silica gel 60 F . TLC plates were
254
9

ACCEPTED MANUSCRIPT
developed in chloroform−methanol solvent systems. Visualization of spots was effected with
iodine vapours. All solvents were purified by methods described in the literature.
All microwave irradiation experiments were carried out in microwave reactor
Plazmartonika RM 800. The reaction carried out in 50 mL glass vial.
4
.1.1. Synthesis of 1,3-dibenzoylquinazoline-2,4-dione 28
The benzoyl chloride (6.48 mL, 0.056 mol) was added to a stirred suspension of quinazoline-
,4-dione (4.00 g, 0.025 mol) in dry acetonitrile (25 mL) containing dry pyridine (10 mL) at
2
room temperature. After 24 h the products were concentrated under reduced pressure. The
residue was partitioned between dichloromethane (100 mL) and water (100 mL). The organic
4
layer was dried (MgSO ), concentrated in vacuo and the residue was crystallised from ethanol
to give 1,3-dibenzoylquinazoline-2,4-dione 28 (7.985 g, 87%) as a white powder; m.p.: 159–
–1 1
1
60°C; IR (KBr): ν = 3040 1753, 1723; 1674, 1605, 1472, 974; 866; 753, 688 cm ; H NMR
300 MHz, CDCl ): δ = 8.28 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H, H5); 8.02–7.98 (m, 4H, 4×o-
CH); 7.73–7.63 (m, 3H, 2×p-CH, H7); 7.56–7.48 (m, 4H, 4×m-CH); 7.36 (dt, J = 7.9 Hz, J =
(
3
1
3
0
1
1
.7 Hz, 1H, H6); 7.10 (d, J = 8.4 Hz, 1H, H8); C NMR (151 MHz, CDCl
67.8; 160.9; 147.9; 138.6; 136.1; 135.7; 135.3; 131.8; 131.4; 130.6; 130.5; 129.5; 129.3;
29.1; 124.8; 115.2; 114.9; Anal. Calcd. for C22 : C, 71.35; H, 3.81; N, 7.56. Found:
3
): δ = 169.2;
14 2 4
H N O
C, 71.49; H, 3.76; N, 7.44.
3
4
.1.2. Synthesis of N -benzoylquinazoline-2,4-dione 29
A mixture of 1,3-dibenzoylquinazoline-2,4-dione 28 (1.73 g, 4.67 mmol), dioxane (50 mL)
and 1N K CO aq. (25 mL) was stirred at room temperature. After 24 h glacial acetic acid was
2
3
added to pH 5. The products were concentrated under reduced pressure and the residue was
stirred with saturated aqueous sodium bicarbonate (200 mL) at room temperature for 2 h. The
solid was filtered off, washed with cold water and dried on air. The crude product was
chromatographed on a silica gel column with chloroform–methanol (200:1, 100:1, v/v) and
crystallised from ethyl acetate−petroleum ether to give the compound 29 (0.255 g, 23%) as
white needles; m.p.: 209–211°C; IR (KBr): ν = 3436, 3063, 2937, 1753, 1707, 1668, 1400,
–
1 1
7
1
60, 687 cm ; H NMR (300 MHz, CDCl
3
): δ = 9.34 (brs, 1H, NH); 8.13 (dd, J = 7.9 Hz, J =
.5 Hz, 1H); 8.03–7.99 (m, 2H, 2×o-CH); 7.71–7.62 (m, 2H); 7.55–7.49 (m, 2H); 7.29 (dd, J
1
0

ACCEPTED MANUSCRIPT
1
3
=
7.9 Hz, J = 0.9 Hz, 1H); 7.31 (ddd, J = 8.2 Hz, J = 0.9 Hz, J = 0.5 Hz, 1H); C NMR (151
MHz, DMSO-d ): δ = 170.3; 162.3; 149.3; 140.9; 136.4; 135.9; 132.0; 130.9; 129.9; 127.7;
23.6; 116.4; 114.3; Anal. Calcd. for C15 : C, 67.67; H, 3.79; N, 10.52. Found: C,
6
1
6
10 2 3
H N O
7.48; H, 3.91; N, 10.45.
3
1
4
.1.3. Synthesis of N -benzoyl-N -propargylquinazoline-2,4-dione 19e
3
A suspension of N -benzoylquinazoline-2,4-dione 29 (0.239 g, 0.898 mmol), potassium
carbonate (0.135 g, 0.978 mmol) and propargyl bromide (0.081 mL, 1.08 mmol) in DMF (3
mL) was stirred at room temperature for 24 h. The mixture was co-evaporated with toluene
(5×10 mL). The residue was dissolved in chloroform (10 mL) and washed with brine (2×5
mL). The organic phase was dried over MgSO , concentrated in vacuo and the residue was
4
crystallised from methanol–diethyl ether to give compound 19e (0.265 g, 97%) as a white
powder; m.p.: 180–182°C; IR (KBr): ν = 3256, 3002, 2925, 1751, 1697, 1659, 1482, 756, 684
–1 1
cm ; H NMR (600 MHz, CDCl ): δ = 8.26 (dd, J = 7.9 Hz, J = 1.3 Hz, 1H, H5); 8.12–7.99
3
(m, 2H, 2×o-CH); 7.83 (dt, J = 7.3 Hz, J = 1.4 Hz, 1H, H7); 7.69–7.67 (m, 1H, p-CH); 7.54–
7
3
.50 (m, 3H, 2×m-CH, H8); 7.31 (brt, J = 7.6 Hz, 1H); 4.96 (d, J = 2.5 Hz, 2H, CH≡CCH
2
);
1
3
.74 (t, J = 2.5 Hz, 1H, CH≡CCH ); C NMR (151 MHz, CDCl ): δ = 168.4 (s, C=O); 160.9
2
3
(s, C=O); 148.8 (s, C=O); 139.6; 136.1; 135.1; 131.7; 130.5; 129.2; 129.2; 123.9; 115.8;
1
14.7; 73.8; 32.8; Anal. Calcd. for C18 : C, 71.05; H, 3.97; N, 9.21. Found: C, 70.92;
12 2 3
H N O
H, 4.05; N, 9.14.
3
1
4
.1.4. N -benzoyl-N -propargyluracil 19m
3
A suspension of N -benzoyluracil 30 (0.506 g, 0.234 mmol), potassium carbonate (0.356 g,
0
.257 mmol) and propargyl bromide (0.211 mL, 0.281 mmol) in DMF (4 mL) was stirred at
room temperature for 24 h. The mixture was co-evaporated with toluene (5×10 mL). The
residue was dissolved in chloroform (10 mL) and washed with brine (2×5 mL). The organic
phase was dried over MgSO , concentrated in vacuo and crystallised from methanol–diethyl
4
1
ether to give compound 19m (0.562 g, 95%) as a white solid; m.p.: 139–140°C; H NMR
(
600 MHz, CDCl
Hz, 1H, HC=CH); 7.55–7.48 (m, 2H, m-CH); 5.89 (d, J = 8.1 Hz, 1H, HC=CH); 4.59 (d, J =
.6 Hz, 2H, CH≡CCH ); 2.55 (t, J = 2.6 Hz, 1H, CH≡CCH ).
3
): 7.95–7.92 (m, 2H, 2×o-CH); 7.69–7.63 (m, 1H, p-CH); 7.58 (d, J = 8.1
2
2
2
1
1

ACCEPTED MANUSCRIPT
4
.1.5. General procedure for the preparation of 1,2,3-triazoles
To a solution of azidoalkylphosphonate (1.00 mmol) in EtOH (1 mL) and H
added CuSO ×5H O (0.05 mmol), sodium ascorbate (0.10 mmol) and alkynes (1.00 mmol).
The suspension was microwave irradiated in the microwave reactor (Plazmatronika RM 800,
00 W) at 40–45°C for 10 min. After cooling the solvent was removed by vacuum
2
O (1 mL) were
4
2
8
evaporation. The residue was suspended in dry chloroform (5 mL) and filtered through a layer
of Celite. The solution was concentrated in vacuo and the crude product was purified on a
silica gel column with chloroform–methanol mixtures (50:1, 20:1 or 10:1, v/v) to give the
appropriate 1,2,3-triazoles.
4
.1.5.1.
Diethyl
{4-[(3-benzoyl-2,4-dioxoquinazolin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}methylphosphonate 20e
3
1
From azide 12 (0.095 g, 0.492 mmol) and N -benzoyl-N -propargylquinazoline-2,4-dione 19e
0.150 g, 0.492 mmol) the phosphonate 20e (0.199 g, 81%) was obtained as a colourless oil
after purification on a silica gel column with chloroform–methanol (50:1, v/v). IR (film): ν =
(
–1 1
3
030, 2982, 1750, 1700, 1662, 1021, 757, 671 cm ; H NMR (600 MHz, CDCl
dd, J = 7.9 Hz, J = 1.6 Hz, 1H, H5); 7.99–7.95 (m, 2H, 2×o-CH); 7.88 (brd, J = 8.5 Hz, 1H,
H8); 7.86 (s, 1H, HC5′); 7.76 (ddd, J = 8.5 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H, H7); 7.68–7.64 (m,
3
): δ = 8.20
(
1
2
H, p-CH); 7.52–7.49 (m, 2H, 2×m-CH); 7.31 (dt, J = 7.9 Hz, J = 0.6 Hz, 1H, H6); 5.42 (s,
H, CH ); 4.73 (d, J = 13.1 Hz, 2H, PCH ); 4.17–4.06 (m, 4H, 2×POCH CH ); 1.25 (t, J = 7.2
CH ); 1.24 (t, J = 7.2 Hz, 3H, POCH ); C NMR (75.5 MHz, CDCl ): δ
168.6 (s, C=O); 161.1 (s, C=O); 149.5 (s, C=O); 142.8 (s, HC=C); 140.2; 136.2; 135.2;
31.6; 130.6; 129.4; 129.0; 124.8 (s, HC=C); 123.9; 116.0; 115.3; 63.7 (d, J = 6.5 Hz, POC);
2
2
2
3
13
Hz, 3H, POCH
2
3
2
CH
3
3
=
1
4
3
1
6.1 (d, J = 154.9 Hz, PC); 38.9; 16.5 (d, J = 5.7 Hz, POCC); P NMR (121.5 MHz, CDCl ):
3
24 5 6
δ = 16.49 ppm. Anal. Calcd. for C23H N O P: C, 55.53; H, 4.86; N, 14.08. Found: C, 55.24;
H, 4.73; N, 13.86.
4
.1.5.2.
Diethyl
{4-[(3,5-dioxo-1,2,4-triazin-2-yl)methyl]-1H-1,2,3-triazol-1-
yl}methylphosphonate 20f
1
2

ACCEPTED MANUSCRIPT
1
From azide 12 (0.132 g, 0.683 mmol) and N -propargyl-6-azauracil 19f (0.103 g, 0.683 mmol)
the phosphonate 20f (0.184 g, 78%) was obtained as a white solid after purification on silica
gel with chloroform–methanol (50:1, v/v); m.p.: 139–140°C; IR (KBr): ν = 3344, 2988,
–1 1
1
7
2
697,1668, 1235, 1025 cm ; H NMR (300 MHz, CDCl
.40 (s, 1H); 5.22 (s, 2H, CH ); 4.76 (d, J = 13.3 Hz, 2H, PCH
×POCH CH ); 1.30 (t, J = 6.9 Hz, 3H, POCH CH ); 1.29 (t, J = 6.9 Hz, 3H, POCH CH );
3
): δ = 10.6 (s, 1H, NH); 7.94 (s, 1H);
2
2
); 4.18–4.07 (m, 4H,
2
3
2
3
2
3
1
3
C NMR (75.5 MHz, CDCl
3
): δ = 155.9 (s, C=O); 149.1 (C=O); 142.2 (s, HC=C); 134.8 (s,
HC=N); 125.1 (s, HC=C); 66.9 (d, J = 6.6 Hz, POC); 46.0 (d, J = 155.5 Hz, PC); 34.7; 16.5
31
(
d, J = 5.8 Hz, POCC); P NMR (121.5 MHz, CDCl ): δ = 16.83 ppm. Anal. Calcd. for
3
11 17 6 5
C H N O P: C, 38.38; H, 4.98; N, 24.41. Found: C, 38.50; H, 4.80; N, 24.55.
4
.1.5.3. Diethyl {4-[(8-chloro-1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-1-
yl}methylphosphonate 20g
7
From azide 12 (0.100 g, 0.518 mmol) and 8-chloro-N -propargyltheophylline 19g (0.131 g,
.518 mmol) the phosphonate 20g (0.210 g, 91%) was obtained as a white solid after
purification on silica gel with chloroform–methanol (50:1, v/v); m.p.: 156–157°C; IR (KBr): ν
0
–
1 1
=
2996, 2955, 1707, 1667, 1251, 1025, 757 cm ; H NMR (300 MHz, CDCl
H, HC5′); 5.65 (s, 2H, CH ); 4.74 (d, J = 13.1 Hz, 2H, PCH ); 4.18–4.07 (m, 4H,
×POCH CH ); 3.54 (s, 3H, CH ); 3.40 (s, 3H, CH ); 1.30 (t, J = 7.2 Hz, 3H, POCH CH );
.28 (t, J = 7.2 Hz, 3H, POCH ); C NMR (75.5 MHz, CDCl ): δ = 154.3 (s, C=O);
51.1 (s, C=O); 147.3; 142.0; 138.9; 124.5; 107.5; 63.7 (d, J = 6.5 Hz, POC); 46.0 (d, J =
3
): δ = 7.98 (s,
1
2
1
1
1
2
2
2
3
3
3
2
3
13
2
CH
3
3
3
1
54.9 Hz, PC); 41.0; 30.0; 28.1; 16.4 (d, J = 5.7 Hz, POCC); P NMR (121.5 MHz, CDCl
3
):
7 5
δ = 16.48 ppm. Anal. Calcd. for C15H21ClN O
P: C, 40.41; H, 4.75; N, 21.99. Found: C,
4
0.53; H, 4.60; N, 21.80.
4
.1.5.4.
Diethyl
{4-[(3,7-dimethyl-2,6-dioxopurin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}methylphosphonate 20h
1
From azide 12 (0.116 g, 0.601 mmol) and N -propargyltheobromine 19h (0.131 g, 0.601
mmol) the phosphonate 20h (0.194 g, 79%) was obtained as a white solid after purification on
silica gel with chloroform–methanol (50:1, v/v); m.p.: 139–140°C; IR (KBr): ν = 2984, 2944,
–1 1
2
3
830, 1706, 1663, 1237, 1028 cm ; H NMR (300 MHz, CDCl ): δ = 7.83 (s, 1H); 7.52 (s,
1
3

ACCEPTED MANUSCRIPT
1
3
3
1
2
H); 5.33 (s, 2H, CH
.99 (s, 3H, CH ); 3.56 (s, 3H, CH
H, POCH CH
44.0; 141.7; 124.3; 107.7; 63.6 (d, J = 6.6 Hz, POC); 45.9 (d, J = 154.9 Hz, PC); 36.1; 33.8;
2
); 4.73 (d, J = 13.1 Hz, 2H, PCH
); 1.29 (t, J = 7.0 Hz, 3H, POCH
); C NMR (75.5 MHz, CDCl ): δ = 154.7 (s, C=O); 151.2 (s, C=O); 148.9;
2
); 4.17–4.06 (m, 4H, 2×POCH
2 3
CH );
3
3
2
CH ); 1.28 (t, J = 7.0 Hz,
3
13
2
3
3
3
1
3
9.9; 16.5 (d, J = 5.7 Hz, POCC); P NMR (121.5 MHz, CDCl ): δ = 16.84 ppm. Anal.
Calcd. for C H N O P: C, 43.80; H, 5.39; N, 23.84. Found: C, 43.69; H, 5.21; N, 23.66.
15
22
7
5
4
.1.5.5.
Diethyl
{4-[(1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-1-
yl}methylphosphonate 20i
7
From azide 12 (0.136 g, 0.704 mmol) and N -propargyltheophylline 19i (0.154 g, 0.704
mmol) the phosphonate 20i (0.254 g, 88%) was obtained as a white solid after purification on
a silica gel column with chloroform–methanol (50:1, v/v); m.p.: 105–108°C; IR (KBr): ν =
–1 1
2
3
994, 2945, 1705, 1660, 1244, 1026 cm ; H NMR (300 MHz, CDCl ): δ = 8.02 (s, 1H); 7.80
(
s, 1H); 5.60 (s, 2H, CH ); 4.74 (d, J = 13.1 Hz, 2H, PCH ); 4.18–4.08 (m, 4H,
2
2
2
1
1
1
×POCH
2
CH
3
); 3.57 (s, 3H, CH
3
); 3.40 (s, 3H, CH
3
2 3
); 1.29 (t, J = 6.9 Hz, 3H, POCH CH );
13
.28 (t, J = 6.9 Hz, 3H, POCH
2 3 3
CH ); C NMR (75.5 MHz, CDCl ): δ = 155.3 (s, C=O);
51.6 (s, C=O); 149.0; 142.6; 141.3; 124.7; 106.5; 63.7 (d, J = 6.6 Hz, POC); 46.2 (d, J =
3
1
54.9 Hz, PC); 41.7; 30.0; 28.2; 16.5 (d, J = 5.7 Hz, POCC); P NMR (121.5 MHz, CDCl
3
):
δ = 16.50 ppm. Anal. Calcd. for C15
H
22
N
7
O
5
P: C, 43.80; H, 5.39; N, 23.84. Found: C, 43.88;
H, 5.45; N, 23.69.
4
.1.5.6.
Diethyl
{4-[(5,6-dimethylbenzimidazol-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}methylphosphonate 20j
1
From azide 12 (0.091 g, 0.471 mmol) and 5,6-dimethyl-N -propargylbenzimidazole 19j
(0.087 g, 0.471 mmol) the phosphonate 20j (0.121 g, 68%) was obtained as a white powder
after purification on silica gel with chloroform–methanol (50:1, v/v); m.p.: 100–102°C; IR
–1 1
(
KBr): ν = 3004, 2960, 2945, 1025, 846, 757 cm ; H NMR (300 MHz, CDCl ): δ = 7.93 (s,
3
1
H); 7.52 (s, 1H); 7.56 (s, 1H); 7.18 (s, 1H); 5.46 (s, 2H, CH
PCH ); 4.11–4.01 (m, 4H, 2×POCH CH ); 3.36 (s, 6H, 2×CH
×POCH CH ); C NMR (75.5 MHz, CDCl ): δ = 143.5; 142.1; 141.9; 132.4; 131.8; 131.3;
2
); 4.69 (d, J = 13.3 Hz, 2H,
2
2
3
3
); 1.22 (t, J = 7.2 Hz, 6H,
1
3
2
1
2
3
3
23.3; 120.1; 110.0; 63.6 (d, J = 6.6 Hz, POC); 46.0 (d, J = 154.9 Hz, PC); 40.5; 20.6; 20.3;
1
4

ACCEPTED MANUSCRIPT
31
1
6.3 (d, J = 5.8 Hz, POCC); P NMR (121.5 MHz, CDCl
3
): δ = 16.52 ppm. Anal. Calcd. for
17 24 5 3
C H N O
P: C, 54.11; H, 6.41; N, 18.56. Found: C, 53.97; H, 6.38; N, 18.44.
4
.1.5.7. Diethyl {4-[(3-acetylindol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}methylphosphonate 20k
From azide 12 (0.109 g, 0.564 mmol) and 3-acetyl-N-propargylindole 19k (0.111 g, 0.564
mmol) the phosphonate 20k (0.164 g, 75%) was obtained as a white solid after
chromatography on a silica gel column with chloroform–methanol (50:1, v/v); m.p.: 128–
–1 1
1
29°C; IR (KBr): ν = 3004, 2960, 2945, 1025, 846, 757 cm ; H NMR (300 MHz, CDCl ): δ
3
=
8.42–8.34 (m, 1H); 7.86 (s, 1H, HC5′); 7.62 (s, 1H); 7.45–7.36 (m, 1H); 7.33–7.24 (m, 2H);
.48 (s, 2H, CH ); 4.70 (d, J = 13.3 Hz, 2H, PCH ); 4.10–4.00 (m, 4H, 2×POCH CH ); 2.25
s, 3H, CH ); 1.21 (t, J = 6.9 Hz, 6H, 2×POCH CH ); C NMR (75.5 MHz, CDCl ): δ =
5
2
2
2
3
13
(
3
2
3
3
1
92.9 (s, C=O); 143.6; 136.6; 134.6; 126.6; 123.7; 123.3; 123.0; 122.9; 117.9; 109.9; 63.8 (d,
); 16.5 (d, J = 5.7 Hz,
J = 6.5 Hz, POC); 46.3 (d, J = 155.4 Hz, PC); 42.7; 27.9 (s, CH
3
3
1
POCC); P NMR (121.5 MHz, CDCl ): δ = 16.51 ppm. Anal. Calcd. for C H N O P: C,
3
18 23
4
4
5
5.38; H, 5.94; N, 14.35. Found: C, 55.35; H, 6.03; N, 14.21.
4
.1.5.8. Diethyl {4-[(2-oxopyridin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}methylphosphonate 20l
From azide 12 (0.120 g, 0.621 mmol) and N-propargyl-2-pyridon 19l (0.083 g, 0.621 mmol)
the phosphonate 20l (0.178 g, 88%) was obtained as a brown solid after chromatography on a
silica gel column with chloroform–methanol (50:1, v/v); m.p.: 82–85°C; IR (KBr): ν = 3080,
–
1 1
2
985, 2935, 1660, 1025, 978 cm ; H NMR (300 MHz, CDCl
6.7 Hz, J = 1.9 Hz, 1H); 7.31 (ddd, J = 9.2 Hz, J = 6.7 Hz, J = 1.9 Hz, 1H); 6.59 (d, J = 9.2
Hz, 1H); 6.17 (dt, J = 6.7 Hz, J = 1.2 Hz, 1H); 5.20 (s, 2H, CH ); 4.73 (d, J = 13.1 Hz, 2H,
3
): δ = 7.93 (s, 1H); 7.56 (dd, J
=
2
PCH ); 4.18–4.07 (m, 4H, 2×POCH CH ); 1.29 (t, J = 6.9 Hz, 3H, POCH CH ); 1.28 (t, J =
2
2
3
2
3
1
3
6
2 3 3
.9 Hz, 3H, POCH CH ); C NMR (75.5 MHz, CDCl ): δ = 162.1 (s, C=O); 142.9 (s,
HC=C); 139.9; 137.6; 124.9 (s, HC=C); 106.4; 63.5 (d, J = 6.7 Hz, POC); 45.8 (d, J = 154.5
3
1
Hz, PC); 44.4; 16.3 (d, J = 5.7 Hz, POCC); P NMR (121.5 MHz, CDCl ): δ = 16.62 ppm.
3
Anal. Calcd. for C13
7.25.
19 4 4
H N O P: C, 47.85; H, 5.87; N, 17.17. Found: C, 48.01; H, 6.00; N,
1
1
5

ACCEPTED MANUSCRIPT
4
.1.5.9.
Diethyl
2-{4-[(3,5-dioxo-1,2,4-triazin-2-yl)methyl]-1H-1,2,3-triazol-1-
yl}ethylphosphonate 21f
1
From azide 13 (0.147 g, 0.710 mmol) and N -propargyl-6-azauracil 19f (0.107 g, 0.710 mmol)
the phosphonate 21f (0.227 g, 89%) was obtained as a white solid after purification on silica
gel with chloroform–methanol (50:1, v/v); m.p.: 119–121°C; IR (KBr): ν = 3301, 2999, 2985,
–
1 1
1
688, 1220, 1045 cm ; H NMR (300 MHz, CDCl
.41 (s, 1H); 5.22 (s, 2H, CH ); 4.68–4.50 (m, 2H, PCH
.78–2.62 (m, 2H, PCCH ); 1.31 (t, J = 7.1 Hz, 6H, 2×POCH CH ); C NMR (75.5 MHz,
3
): δ = 11.80 (s, 1H, NH); 7.90 (s, 1H);
7
2
2
); 4.16–4.04 (m, 4H, 2×POCH CH );
2
3
13
2
2
2
3
3
CDCl ): δ = 155.9 (s, C=O); 149.1 (C=O); 141.6 (s, HC=C); 134.7 (s, HC=N); 124.4 (s,
HC=C); 62.5 (d, J = 6.6 Hz, POC); 44.5; 34.6; 27.2 (d, J = 140.9 Hz, PC); 16.4 (d, J = 6.0 Hz,
3
1
POCC); P NMR (121.5 MHz, CDCl ): δ = 27.15 ppm. Anal. Calcd. for C H N O P: C,
3
12 19
6
5
4
0.23; H, 5.35; N, 23.46. Found: C, 40.28; H, 5.29; N, 23.52.
4
1
.1.5.10. Diethyl 2-{4-[(8-chloro-1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-
-yl}ethylphosphonate 21g
7
From azide 13 (0.130 g, 0.628 mmol) and 8-chloro-N -propargylthephylline 19g (0.159 g,
0
.628 mmol) the phosphonate 21g (0.254 g, 88%) was obtained as a white solid after
chromatography on a silica gel column with chloroform–methanol (50:1, v/v); m.p.: 101–
–
1 1
1
03°C; IR (KBr): ν = 3426, 3139, 2953, 2903, 1703, 1661, 1250, 1043 cm ; H NMR (600
MHz, CDCl ): δ = 7.85 (s, 1H, HC5′); 5.65 (s, 2H, CH ); 4.63–4.56 (m, 2H, PCH ); 4.13–4.05
m, 4H, 2×POCH CH ); 3.56 (s, 3H, CH ); 3.43 (s, 3H, CH ); 2.45–2.39 (m, 2H, PCCH );
.32 (t, J = 7.0 Hz, 6H, 2×POCH ); C NMR (151 MHz, CDCl ): δ = 155.4 (s, C=O);
51.2 (s, C=O); 147.4; 141.8; 139.0; 123.9; 107.3; 62.2 (d, J = 6.0 Hz, POC); 44.7; 40.9;
3
2
2
(
2
3
3
3
2
1
3
1
1
2
2
CH
3
3
3
1
9.8; 28.0; 27.2 (d, J = 141.9 Hz, PC); 16.3 (d, J = 5.7 Hz, POCC); P NMR (243 MHz,
): δ = 25.20 ppm. Anal. Calcd. for C16 P: C, 41.79; H, 5.04; N, 21.32. Found:
C, 41.85; H, 4.94; N, 21.43.
CDCl
3
7 5
H23ClN O
4
.1.5.11.
Diethyl
2-{4-[(3,7-dimethyl-2,6-dioxopurin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}ethylphosphonate 21h
1
6

ACCEPTED MANUSCRIPT
1
From azide 13 (0.130 g, 0.628 mmol) and N -propargyltheobromine 19h (0.137 g, 0.628
mmol) the phosphonate 21h (0.219 g, 82%) was obtained as a white solid after
chromatography on a silica gel column with chloroform–methanol (50:1, v/v); m.p.: 100–
–
1 1
1
02°C; IR (KBr): ν = 3133, 3087, 2989, 2830, 1701, 1665, 1233, 1023 cm ; H NMR (300
MHz, CDCl ): δ = 7.67 (s, 1H); 7.52 (d, J = 0.6 Hz, 1H, HC5′); 5.32 (s, 2H, CH ); 4.62–4.52
m, 2H, PCH ); 4.14–4.00 (m, 4H, 2×POCH CH ); 3.99 (d, J = 0.6 Hz, 3H, CH ); 3.57 (s, 3H,
3
2
(
2
2
3
3
1
3
CH
3
); 2.46–2.34 (m, 2H, PCCH
): δ = 154.7 (s, C=O); 151.2 (s, C=O); 148.9; 143.6; 141.7; 123.5; 107.6; 62.2 (d,
J = 6.3 Hz, POC); 52.4; 44.6; 36.1; 31.9 (d, J = 293.7 Hz, PC); 28.3; 26.5; 16.5 (d, J = 6.0 Hz,
2 2 3
); 1.29 (t, J = 7.0 Hz, 6H, 2×POCH CH ); C NMR (75.5
MHz, CDCl
3
3
1
POCC); P NMR (121.5 MHz, CDCl
3
): δ = 26.59 ppm. Anal. Calcd. for C16
24 7 5
H N O P: C,
4
5.18; H, 5.69; N, 23.05. Found: C, 45.00; H, 5.56; N, 22.96.
4
.1.5.12.
Diethyl
2-{4-[(1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-1-
yl}ethylphosphonate 21i
7
From azide 13 (0.130 g, 0.628 mmol) and N -propargylthephylline 19i (0.137 g, 0.628 mmol)
the phosphonate 21i (0.219 g, 82%) was obtained as a colourless oil after purification on silica
gel with chloroform–methanol (50:1, v/v); IR (film): ν = 3033, 2987, 2889, 2830, 1703, 1666,
–
1 1
1
2
3
230, 1023 cm ; H NMR (600 MHz, CDCl
H, CH ); 4.63–4.55 (m, 2H, PCH ); 4.13–4.08 (m, 4H, 2×POCH
.43 (s, 3H, CH ); 2.45–2.39 (m, 2H, PCCH ); 1.31 (t, J = 7.0 Hz, 6H, 2×POCH
): δ = 155.4 (s, C=O); 151.6 (s, C=O); 149.0; 142.2; 141.4; 123.9;
06.5; 62.2 (d, J = 5.8 Hz, POC); 44.7; 41.4; 29.7; 28.0; 27.2 (d, J = 141.9 Hz, PC); 16.3 (d, J
3
): δ = 7.89 (s, 1H); 7.82 (s, 1H, HC5′); 5.60 (s,
2
2
2
CH ); 3.59 (s, 3H, CH );
3
3
13
3
2
2 3
CH ); C
NMR (151 MHz, CDCl
3
1
3
1
=
C
6.0 Hz, POCC); P NMR (243 MHz, CDCl
3
): δ = 25.15 ppm. Anal. Calcd. for
16
24 7 5
H N O
P: C, 45.18; H, 5.69; N, 23.05. Found: C, 45.30; H, 5.77; N, 23.17.
4
.1.5.13.
Diethyl
2-{4-[(5,6-dimethylbenzimidazol-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}ethylphosphonate 21j
From azide 13 (0.139 g, 0.671 mmol) and 5,6-dimethyl-N-propargylbenzimidazole 19j (0.124
g, 0.671 mmol) the phosphonate 21j (0.196 g, 75%) was obtained as a colourless oil after
chromatography on a silica gel column with chloroform–methanol (50:1, v/v); IR (film): ν =
–1 1
3
3
014, 2950, 2895, 1045, 856, 759 cm ; H NMR (600 MHz, CDCl ): δ = 7.93 (s, 1H); 7.58
1
7

ACCEPTED MANUSCRIPT
(s, 1H); 7.43 (s, 1H); 7.23 (s, 1H); 5.45 (s, 2H, CH
2
); 4.54 (dt, J = 12.7 Hz, J = 7.7 Hz, 2H,
PCH
2
); 4.06–4.00 (m, 4H, 2×POCH
); 2.38 (s, 3H, CH
): δ = 143.3; 142.4; 142.0; 132.5; 132.0; 131.4; 122.5; 120.3; 109.9; 62.2 (d, J =
.5 Hz, POC); 44.7 (d, J = 1.7 Hz, PCC); 40.4; 27.0 (d, J = 142.0 Hz, PC); 20.5; 20.2; 16.2 (d,
2
CH
3
); 2.38 (dt, J = 18.5 Hz, J = 7.7 Hz,, 2H, PCCH
2
);
13
2
.39 (s, 3H, CH
3
3 2 3
); 1.26 (t, J = 7.0 Hz, 6H, 2×POCH CH ); C NMR (151
MHz, CDCl
3
6
31
J = 6.4 Hz, POCC); P NMR (243 MHz, CDCl ): δ = 25.27 ppm. Anal. Calcd. for
3
18 26 5 3
C H N O P: C, 55.24; H, 6.70; N, 17.89. Found: C, 55.08; H, 6.84; N, 17.72.
4
.1.5.14. Diethyl 2-{4-[(3-acetylindol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}ethylphosphonate
2
1k
From azide 13 (0.100 g, 0.483 mmol) and 3-acetyl-N-propargylindole 19k (0.095 g, 0.483
mmol) the phosphonate 21k (0.144 g, 74%) was obtained as a white solid after purification on
silica gel with chloroform–methanol (50:1, v/v); m.p.: 83–84°C; IR (KBr): ν = 3430, 3110,
–
1 1
2
1
989, 1642, 1528, 1390, 1026, 753 cm ; H NMR (300 MHz, CDCl ): δ = 8.44–8.32 (m,
3
H); 7.87 (s, 1H, HC5′); 7.47 (s, 1H); 7.45–7.42 (m, 1H); 7.32–7.29 (m, 2H); 5.47 (s, 2H,
CH
.31 (m, 2H, PCCH
δ = 192.9 (s, C=O); 142.8; 136.4; 134.8; 126.3; 123.5; 122.7; 122.7; 122.6; 117.4; 109.8; 62.2
d, J = 6.6 Hz, POC); 44.7 (d, J = 2.0 Hz, PCC); 42.3; 27.7 (s, CH ); 27.1 (d, J = 141.4 Hz,
): δ = 26.39 ppm. Anal.
P: C, 56.43; H, 6.23; N, 13.85. Found: C, 56.54; H, 6.14; N, 13.72.
2
); 4.61–4.52 (m, 2H, PCH
2
); 4.05–3.94 (m, 4H, 2×POCH
2
CH
3
); 2.55 (s, 3H, CH
3
); 2.42–
1
3
2
2
); 1.22 (t, J = 6.8 Hz, 6H, 2×POCH
2
CH
3
); C NMR (75.5 MHz, CDCl
3
):
(
3
31
PC); 16.4 (d, J = 5.7 Hz, POCC); P NMR (121.5 MHz, CDCl
3
Calcd. for C19
25 4 4
H N O
4
.1.5.15. Diethyl 2-{4-[(2-oxopyridin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}ethylphosphonate
1l
2
From azide 13 (0.147 g, 0.710 mmol) and N-propargyl-2-pyridon 19l (0.095 g, 0.710 mmol)
the phosphonate 21l (0.214 g, 89%) was obtained as a brown oil after chromatography on a
silica gel column with chloroform–methanol (50:1, v/v); IR (film): ν = 3110, 2976, 2875,
–
1 1
1
1
668, 1035, 988 cm ; H NMR (300 MHz, CDCl
3
): δ = 7.84 (s, 1H); 7.59 (dd, J = 6.8 Hz, J =
.6 Hz, 1H); 7.33 (ddd, J = 9.2 Hz, J = 6.8 Hz, J = 2.0 Hz, 1H); 6.55 (dd, J = 9.2 Hz, J = 0.5
Hz, 1H); 6.19 (dt, J = 6.8 Hz, J = 1.6 Hz, 1H); 5.18 (s, 2H, CH ); 4.62–4.52 (m, 2H, PCH );
2
2
4
2 3 2
.13–4.03 (m, 4H, 2×POCH CH ); 2.46–2.35 (m, 2H, PCCH ); 1.29 (t, J = 7.0 Hz, 3H,
1
8

ACCEPTED MANUSCRIPT
1
3
POCH
2 3 2 3 3
CH ); 1.28 (t, J = 6.9 Hz, 3H, POCH CH ); C NMR (75.5 MHz, CDCl ): δ = 162.2
(s, C=O); 142.5 (s, HC=C); 140.0; 137.7; 124.3 (s, HC=C); 120.6; 106.5; 62.2 (d, J = 6.3 Hz,
3
1
POC); 44.6 (d, J = 2.8 Hz, PCC); 27.1 (d, J = 141.2 Hz, PC); 16.4 (d, J = 6.0 Hz, POCC); P
NMR (121.5 MHz, CDCl ): δ = 26.37 ppm. Anal. Calcd. for C14 P: C, 49.41; H, 6.22;
N, 16.46. Found: C, 49.24; H, 6.09; N, 16.28.
3
21 4 4
H N O
4
.1.5.16.
Diethyl
3-{4-[(3-benzoyl-2,4-dioxoquinazolin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylphosphonate 22e
3
1
From azide 14 (0.100 g, 0.452 mmol) and N -benzoyl-N -propargylquinazoline-2,4-dione 19e
0.138 g, 0.452 mmol) the phosphonate 22e (0.198 g, 83%) was obtained as a colourless oil
after purification on silica gel with chloroform–methanol (50:1, v/v); IR (film): ν = 3141,
(
–
1 1
3
064, 2939, 1799, 1606, 1481; 1220, 1025 cm ; H NMR (300 MHz, CDCl
7.9 Hz, J = 1.6 Hz, 1H); 8.00–7.95 (m, 2H, 2×o-CH); 7.91 (d, J = 8.5 Hz, 1H); 7.78 (ddd, J
8.5 Hz, J = 7.9 Hz, J = 1.6 Hz, 1H); 7.71 (s, 1H, HC5′); 7.70–7.62 (m, 1H, p-CH); 7.54–
.48 (m, 2H, 2×m-CH); 7.32 (dt, J = 7.9 Hz, J = 0.8 Hz, 1H); 5.40 (s, 2H, CH ); 4.41 (t, J =
.0 Hz, 2H, PCCCH ); 4.16–3.99 (m, 4H, 2×POCH CH ); 2.20 (dqu, J = 14.5 Hz, J = 7.0 Hz,
H, PCCH ); 1.71 (dt, J = 18.7 Hz, J = 7.0 Hz, 2H, PCH ); 1.30 (t, J = 7.1 Hz, 6H,
×POCH CH ): δ = 168.6 (s, C=O); 161.0 (s, C=O); 149.5 (s,
3
): δ = 8.20 (dd, J
=
=
7
7
2
2
2
2
2
3
2
2
13
2
3 3
); C NMR (75.5 MHz, CDCl
C=O); 142.4 (s, HC=C); 140.2; 136.2; 135.2; 131.5; 130.5; 129.2; 128.9; 123.9 (s, HC=C);
1
23.8; 115.5; 115.3; 61.8 (d, J = 6.7 Hz, POC); 50.3 (d, J = 15.7 Hz, PCCC); 38.9; 23.7 (d, J
3
1
=
4.9 Hz, PCC); 22.8 (d, J = 142.9 Hz, PC); 16.6 (d, J = 6.0 Hz, POCC); P NMR (121 MHz,
): δ = 30.82 ppm. Anal. Calcd. for C25 P: C, 57.14; H, 5.37; N, 13.33. Found:
C, 57.27; H, 5.49; N, 13.40.
CDCl
3
28 5 6
H N O
4
.1.5.17.
Diethyl
3-{4-[(3,5-dioxo-1,2,4-triazin-2-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylphosphonate 22f
1
From azide 14 (0.154 g, 0.697 mmol) and N -propargyl-6-azauracil 19f (0.105 g, 0.697 mmol)
the phosphonate 22f (0.215 g, 83%) was obtained as a white solid after chromatography on a
silica gel column with chloroform–methanol (50:1, v/v); m.p.: 96–97°C; IR (KBr): ν = 3384,
–
1
1
3
1
232, 3138, 2984, 2908, 1730, 1677, 1217, 1025 cm ; H NMR (300 MHz, CDCl ): δ =
3
2
1.51 (s, 1H, NH); 7.77 (s, 1H, HC5′); 7.40 (s, 1H,); 5.22 (s, 2H, CH ); 4.44 (t, J = 7.0 Hz,
1
9

ACCEPTED MANUSCRIPT
2
H, PCCCH
PCCH ); 1.75 (dt, J = 19.0 Hz, J = 7.0 Hz, 2H, PCH
×POCH
2
); 4.16–4.03 (m, 4H, 2×POCH
2
CH
3
); 2.21 (dqu, J = 14.9 Hz, J = 7.0 Hz, 2H,
); 1.32 (t, J = 7.0 Hz, 6H,
2 3 3
CH ); C NMR (75.5 MHz, CDCl ): δ = 155.8 (s, C=O); 148.9 (C=O); 141.3 (s,
2
2
1
3
2
HC=C); 134.5 (s, HC=N); 124.2 (s, HC=C); 62.0 (d, J = 6.4 Hz, POC); 50.0 (d, J = 15.1 Hz,
PCCC); 34.5; 23.4 (d, J = 4.3 Hz, PCC); 22.2 (d, J = 143.0 Hz, PC); 16.4 (d, J = 6.0 Hz,
3
1
POCC); P NMR (121.5 MHz, CDCl ): δ = 31.41 ppm. Anal. Calcd. for C H N O P: C,
3
13 21
6
5
4
1.94; H, 5.69; N, 22.57. Found: C, 41.92; H, 5.52; N, 22.41.
4
1
.1.5.18. Diethyl 3-{4-[(8-chloro-1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-
-yl}propylphosphonate 22g
7
From azide 14 (0.160 g, 0.723 mmol) and 8-chloro-N -propargyltheophylline 19g (0.183 g,
0
.723 mmol) the phosphonate 22g (0.298 g, 84%) was obtained as a white solid after
purification on silica gel with chloroform–methanol (50:1, v/v); m.p.: 127–128°C; IR (KBr): ν
–
1 1
=
=
3362, 3101, 2981, 2935, 1707, 1679, 1224, 1020, 956 cm ; H NMR (600 MHz, CDCl ): δ
3
7.83 (s, 1H, HC5′); 5.66 (s, 2H, CH ); 4.46 (t, J = 7.0 Hz, 2H, PCCCH
×POCH CH ); 3.57 (s, 3H, CH ); 3.44 (s, 3H, CH ); 2.23 (dqu, J = 14.7 Hz, J = 7.0 Hz, 2H,
); 1.74 (dt, J = 18.7 Hz, J = 7.0 Hz, 2H, PCH ); 1.34 (t, J = 7.1 Hz, 6H,
2
×POCH CH ); C NMR (151 MHz, CDCl ): δ = 154.5 (s, C=O); 151.2 (s, C=O); 147.4;
2 3 3
2
2
); 4.15–4.05 (m, 4H,
2
2
3
3
3
PCCH
2
1
3
2
1
2
41.8; 139.0; 123.7; 107.4; 61.8 (d, J = 6.4 Hz, POC); 50.1 (d, J = 15.2 Hz, PCCC); 41.0;
9.8; 27.9; 23.6 (d, J = 4.8 Hz, PCC); 22.6 (d, J = 142.3 Hz, PC); 16.4 (d, J = 6.1 Hz, POCC);
3
1
3 7 5
P NMR (243 MHz, CDCl ): δ = 29.80 ppm. Anal. Calcd. for C17H25ClN O P: C, 43.09; H,
5
.32; N, 20.69. Found: C, 42.88; H, 5.44; N, 20.71.
4
.1.5.19.
Diethyl
3-{4-[(3,7-dimethyl-2,6-dioxopurin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylphosphonate 22h
1
From azide 14 (0.160 g, 0.723 mmol) and N -propargyltheobromine 19h (0.158 g, 0.723
mmol) the phosphonate 22h (0.270 g, 85%) was obtained as a white powder after
crystallisation from diethyl ether; m.p.: 175–176°C; IR (KBr): ν = 3444, 3001, 2984, 1704,
–
1 1
1
5
3
668, 1221, 1020 cm ; H NMR (600 MHz, CDCl ): δ = 7.76 (s, 1H); 7.53 (s, 1H, HC5′);
.35 (s, 2H, CH ); 4.42 (t, J = 7.0 Hz, 2H, PCCCH ); 4.15–4.05 (m, 4H, 2×POCH CH ); 4.02
2
2
2
3
(
s, 3H, CH
3
); 3.60 (s, 3H, CH
3
2
); 2.22 (dqu, J = 14.2 Hz, J = 7.0 Hz, 2H, PCCH ); 1.74 (dt, J =
2
0

ACCEPTED MANUSCRIPT
13
1
8.7 Hz, J = 7.0 Hz, 2H, PCH
MHz, CDCl ): δ = 154.8 (s, C=O); 151.4 (s, C=O); 148.9; 143.7; 141.6; 123.4; 107.7; 61.7 (d,
J = 6.5 Hz, POC); 50.0 (d, J = 16.1 Hz, PCCC); 36.0; 33.6; 29.7; 23.6 (d, J = 4.5 Hz, PCC);
2 2 3
); 1.34 (t, J = 7.0 Hz, 6H, 2×POCH CH ); C NMR (151
3
3
1
2
3
5
2.7 (d, J = 143.1 Hz, PC); 16.4 (d, J = 5.8 Hz, POCC); P NMR (243 MHz, CDCl
3
): δ =
0.03 ppm. Anal. Calcd. for C17
.90; N, 22.06.
H N O P: C, 46.47; H, 5.96; N, 22.31. Found: C, 46.36; H,
26 7 5
4
.1.5.20.
Diethyl
3-{4-[(1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylphosphonate 22i
7
From azide 14 (0.091 g, 0.412 mmol) and N -propargyltheophylline 19i (0.090 g, 0.412
mmol) the phosphonate 22i (0.181 g, 74%) was obtained as a white solid after
chromatography on a silica gel column with chloroform–methanol (50:1, v/v); m.p.: 187–
–1 1
1
90°C; IR (KBr): ν = 3440, 2996, 2984, 1704, 1668, 1225, 1018 cm ; H NMR (600 MHz,
CDCl ): δ = 7.87 (s, 1H); 7.83 (s, 1H, HC5′); 5.61 (s, 2H, CH ); 4.46 (t, J = 7.0 Hz, 2H,
3
2
PCCCH
2
); 4.16–4.05 (m, 4H, 2×POCH
2
CH
); 1.74 (dt, J = 18.7 Hz, J = 7.0 Hz, 2H, PCH
); C NMR (151 MHz, CDCl ): δ = 155.4 (s, C=O); 151.5
s, C=O); 149.0; 142.2; 141.4; 123.8; 106.4; 61.8 (d, J = 6.5 Hz, POC); 50.1 (d, J = 15.3 Hz,
3
); 3.60 (s, 3H, CH
3
); 3.44 (s, 3H, CH
3
); 2.24
(
(
(
dqu, J = 14.6 Hz, J = 7.0 Hz, 2H, PCCH
2
2
); 1.34
13
t, J = 7.0 Hz, 6H, 2×POCH
2
CH
3
3
PCCC); 41.4; 29.7; 27.9; 23.6 (d, J = 4.8 Hz, PCC); 22.6 (d, J = 142.4 Hz, PC); 16.4 (d, J =
31
5
.8 Hz, POCC); P NMR (243 MHz, CDCl
3 26 7 5
): δ = 29.75 ppm. Anal. Calcd. for C17H N O P:
C, 46.47; H, 5.96; N, 22.31. Found: C, 46.59; H, 6.11; N, 22.45.
4
.1.5.21.
Diethyl
3-{4-[(5,6-dimethylbenzimidazol-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylphosphonate 22j
1
From azide 14 (0.160 g, 0.723 mmol) and 5,6-dimethyl-N -propargylbenzimidazole 19j
(0.133 g, 0.723 mmol) the phosphonate 22j (0.221 g, 76%) as a colourless oil after
purification on silica gel with chloroform–methanol (50:1, v/v); IR (film): ν = 3446, 2990,
–1 1
2
938, 1498, 1444, 1224, 1050, 965 cm ; H NMR (600 MHz, CDCl
s, 1H,); 7.54 (s, 1H,); 7.32 (s, 1H,); 5.55 (s, 2H, CH ); 4.43 (t, J = 7.0 Hz, 2H, PCCCH
.15–4.05 (m, 4H, 2×POCH CH ); 2.41 (s, 3H, CH ); 2.40 (s, 3H, CH ); 2.21 (dqu, J = 14.6
3
): δ = 8.33 (s, 1H); 7.61
(
2
2
);
4
2
3
3
3
2 2
Hz, J = 7.0 Hz, 2H, PCCH ); 1.70 (dt, J = 19.2 Hz, J = 7.0 Hz, 2H, PCH ); 1.34 (t, J = 7.1 Hz,
2
1

ACCEPTED MANUSCRIPT
1
3
6
1
=
2 3 3
H, 2×POCH CH ); C NMR (151 MHz, CDCl ): δ = 143.4; 142.3; 142.0; 132.4; 131.4;
22.4; 120.3; 109.9; 61.8 (d, J = 6.5 Hz, POC); 50.0 (d, J = 14.5 Hz, PCCC); 40.5; 23.5 (d, J
3
1
4.5 Hz, PCC); 22.4 (d, J = 142.3 Hz, PC); 20.5; 20.1; 16.4 (d, J = 5.8 Hz, POCC); P NMR
): δ = 29.68 ppm. Anal. Calcd. for C19 P: C, 56.29; H, 6.96; N,
7.27. Found: C, 56.07; H, 7.14; N, 17.10.
(243 MHz, CDCl
3
28 5 3
H N O
1
4
.1.5.22. Diethyl 3-{4-[(3-acetylindol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
2
2k
From azide 14 (0.110 g, 0.497 mmol) and 3-acetyl-N-propargylindole 19k (0.098 g, 0.497
mmol) the phosphonate 22k (0.202 g, 97%) was obtained as a colourless oil after
chromatography on a silica gel column with chloroform–methanol (50:1, v/v); IR (film): ν =
–
1 1
3
394, 3110, 2941, 2825, 1648, 1229, 1029 cm ; H NMR (300 MHz, CDCl
3
): δ = 8.43–8.38
); 4.44
(
(
(
(
m, 1H); 7.88 (s, 1H, HC5′); 7.43–7.38 (m, 2H); 7.36–7.27 (m, 2H); 5.48 (s, 2H, CH
2
t, J = 7.0 Hz, 2H, PCCCH ); 4.10–4.01 (m, 4H, 2×POCH CH ); 2.53 (s. 3H, CH ); 2.20
2
2
3
3
dqu, J = 14.7 Hz, J = 7.0 Hz, 2H, PCCH
2
); 1.65 (dt, J = 18.4 Hz, J = 7.0 Hz, 2H, PCH
): δ = 192.9 (s, C=O); 142.9;
36.4; 134.7; 126.3; 123.5; 122.7; 122.6; 122.5; 117.5; 109.9; 61.9 (d, J = 6.3 Hz, POC); 50.0
d, J = 14.9 Hz, PCCC); 42.4; 27.8; 23.6 (d, J = 4.9 Hz, PCC); 22.1 (d, J = 142.8 Hz, PC);
2
); 1.29
13
2 3 3
t, J = 7.1 Hz, 6H, 2×POCH CH ); C NMR (75.5 MHz, CDCl
1
(
31
1
6.4 (d, J = 6.1 Hz, POCC); P NMR (121.5 MHz, CDCl
3
): δ = 30.85 ppm. Anal. Calcd. for
20 27 4 4
C H N O
P: C, 57.41; H, 6.50; N, 13.39. Found: C, 57.60; H, 6.73; N, 13.50.
4
.1.5.23. Diethyl 3-{4-[(2-oxopyridin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
2
2l
From azide 14 (0.154 g, 0.696 mmol) and N-propargyl-2-pyridon 19l (0.093 g, 0.696 mmol)
the phosphonate 22l (0.206 g, 83%) was obtained as a brown oil after purification on silica gel
with chloroform–methanol (50:1, v/v); IR (film): ν = 3426, 3144, 2986, 1657, 1226; 1026,
–1 1
9
68 cm ; H NMR (300 MHz, CDCl ): δ = 7.81(s, 1H, HC5′); 7.60 (ddd, J = 6.8 Hz, J = 2.1
3
Hz, J = 0.7 Hz, 1H); 7.32 (ddd, J = 9.2 Hz, J = 6.6 Hz, J = 2.1 Hz, 1H); 6.56 (ddd, J = 9.2 Hz,
J = 1.3 Hz, J = 0.7 Hz, 1H); 6.20 (dt, J = 6.8 Hz, J = 1.3 Hz, 1H); 5.19 (s, 2H, CH ); 4.41 (t, J
7.1 Hz, 2H, PCCCH ); 4.15–4.03 (m, 4H, 2×POCH CH ); 2.22 (dqu, J = 14.9 Hz, J = 7.1
2
=
2
2
3
2 2
Hz, 2H, PCCH ); 1.66 (dt, J = 18.2 Hz, J = 7.1 Hz, 2H, PCH ); 1.34 (t, J = 6.9 Hz, 3H,
2
2

ACCEPTED MANUSCRIPT
1
3
POCH
s, C=O); 142.5 (s, HC=C); 139.9; 137.6; 124.0 (s, HC=C); 120.4; 106.4; 61.8 (d, J = 6.4 Hz,
POC); 50.0 (d, J = 16.1 Hz, PCCC); 44.5; 23.5 (d, J = 4.4 Hz, PCC); 22.1 (d, J = 147.1 Hz,
2 3 2 3 3
CH ); 1.33 (t, J = 6.9 Hz, 3H, POCH CH ); C NMR (75.5 MHz, CDCl ): δ = 162.1
(
31
3
PC); 16.4 (d, J = 6.0 Hz, POCC); P NMR (121.5 MHz, CDCl ): δ = 31.05 ppm. Anal.
Calcd. for C15
H
23
N
4
O
4
P: C, 50.84; H, 6.54; N, 15.81. Found: C, 50.61; H, 6.39; N, 15,64.
4
.1.3.24.
Diethyl
3-(4-{[3-benzoyl-2,4-dioxopyrimidin-1-yl]methyl}-1H-1,2,3-triazol-1-
yl)propylphosphonate 22m
3
1
From azide 14 (0.201 g, 0.909 mmol) and N -benzoyl-N -propargylquinazoline-2,4-dione
9m (0.230 g, 0.909 mmol) the phosphonate 22m (0.399 g, 93%) was obtained as a colourless
oil after chromatography on a silica gel column with chloroform–methanol (100:1; 50:1, 20:1
1
–
1 1
v/v); IR (film): ν = 3020, 3005, 2963, 2899, 1669, 1664, 1220, 1020, 772, 689 cm ; H NMR
300 MHz, CDCl ): δ = 7.94–7.90 (m, 2H, 2×o-CH); 7.71 (s, 1H, HC5′); 7.69–7.63 (m, 1H, p-
CH); 7.64 (d, J = 8.0 Hz, 1H, HC=CH); 7.53–7.47 (m, 2H, 2×m-CH); 5.84 (d, J = 8.0 Hz, 1H,
HC=CH); 5.02 (s, 2H, CH ); 4.46 (t, J = 7.3 Hz, 2H, PCCCH ); 4.18–4.01 (m, 4H,
); 2.23 (dqu, J = 14.7 Hz, J = 7.3 Hz, 2H, PCCH ); 1.73 (dt, J = 18.7 Hz, J =
); C NMR (151 MHz, CDCl ): δ =
(
3
2
2
2
7
1
1
×POCH
2
CH
3
2
1
3
.3 Hz, 2H, PCH
2
); 1.31 (t, J = 7.1 Hz, 6H, 2×POCH
2
CH
3
3
68.7 (s, C=O); 162.2 (s, C=O); 144.2 (s, C=O); 141.3 (s, HC=C); 135.2; 131.3; 130.4; 129.2;
24.1 (s, HC=C); 102.5; 61.9 (d, J = 6.6 Hz, POC); 50.2 (d, J = 15.4 Hz, PCCC); 43.5; 23.7
31
(
d, J = 4.7 Hz, PCC); 22.7 (d, J = 143.0 Hz, PC); 16.6 (d, J = 6.0 Hz, POCC); P NMR (121
MHz, CDCl ): δ = 30.12 ppm. Anal. Calcd. for C21 P: C, 53.05; H, 5.51; N, 14.73.
Found: C, 52.89; H, 5,33; N, 14.58.
3
26 5 6
H N O
4
.1.5.25. Diethyl 4-(4-{[6-aminopurin-9-yl]methyl}-1H-1,2,3-triazol-1-yl)butylphosphonate
2
3a
9
From azide 15 (0.061 g, 0.259 mmol) and N -propargyladenine 19a (0.045 g, 0.259 mmol) the
phosphonate 23a (0.097 g, 92%) was obtained as a white powder after chromatography on a
silica gel column with chloroform–methanol (10:1, v/v); m.p.: 119–120°C; IR (KBr): ν =
–
1
1
3
462, 3306, 3140, 2984, 2912, 2870, 1662, 1597, 1244, 1033 cm ; H NMR (600 MHz,
CDCl ): δ = 8.41 (s, 1H); 8.02 (s, 1H); 7.68 (s, 1H); 5.59 (brs, 2H, NH ); 5.51 (s, 2H, CH );
3
2
2
4
2 2 3
.36 (t, J = 7.1 Hz, 2H, PCCCCH ); 4.14–4.04 (m, 4H, 2×POCH CH ); 2.03 (qu, J = 7.1 Hz,
2
3

ACCEPTED MANUSCRIPT
2
1
1
H, PCCCH
.32 (t, J = 7.0 Hz, 6H, 2×POCH
49.8; 142.4; 140.4; 122.8; 119.5; 61.6 (d, J = 6.6 Hz, POC); 49.9; 38.6; 30.6 (d, J = 15.1 Hz,
2
); 1.80–1.73 (m, 2H, PCH
2
); 1.65 (dqu, J = 14.1 Hz, J = 7.1 Hz, 2H, PCCH
2
);
13
2
CH
3 3
); C NMR (151 MHz, CDCl ): δ = 155.6; 153.1;
PCCC); 24.9 (d, J = 142.1 Hz, PC); 19.6 (d, J = 5.0 Hz, PCC); 16.4 (d, J = 6.2 Hz, POCC);
3
1
3 25 8 3
P NMR (243 MHz, CDCl ): δ = 30.73 ppm. Anal. Calcd. for C16H N O P: C, 47.06; H,
6
.17; N, 27.44. Found: C, 46.88; H, 6.02; N, 27.29.
4
.1.5.26.
Diethyl
4-(4-{[5-methyl-2,4-dioxopyrimidin-1-yl]methyl}-1H-1,2,3-triazol-1-
yl)butylphosphonate 23b
1
From azide 15 (0.100 g, 0.425 mmol) and N -propargylthymine 19b (0.070 g, 0.425 mmol)
the phosphonate 23b (0.165 g, 97%) was obtained as a white powder after crystallisation from
ethyl acetate–petroleum ether mixtures; m.p.: 63–65°C; IR (KBr): ν = 3425, 3132, 2986,
–1 1
2
912, 2827, 1688, 1219, 1027 cm ; H NMR (600 MHz, CDCl
3
): δ = 8.69 (brs, 1H, NH);
7
.72 (s, 1H, HC5′); 7.36 (d, J = 1.0 Hz, 1H, HC=CCH ); 4.97 (s, 2H, CH ); 4.38 (t, J = 7.1
3
2
Hz, 2H, PCCCCH
2
); 4.16–4.06 (m, 4H, 2×POCH
2
CH
3
); 2.06 (qu, J = 7.1 Hz, 2H, PCCCH
); 1.69–1.64
); C NMR (151 MHz, CDCl ): δ =
2
);
1
.93 (d, J = 1.0 Hz, 3H, HC=CCH
3
); 1.78 (dt, J = 15.7 Hz, J = 7.1 Hz, 2H, PCH
2
13
(
m, 2H, PCCH ); 1.33 (t, J = 7.0 Hz, 6H, 2×POCH
2
2
CH
3
3
1
4
1
64.2 (s, C=O); 151.2 (s, C=O); 142.1; 140.2; 123.7; 111.3; 61.6 (d, J = 6.6 Hz, POC); 49.9;
3.0; 30.6 (d, J = 15.2 Hz, PCCC); 24.9 (d, J = 142.0 Hz, PC); 19.7 (d, J = 5.2 Hz, PCC);
3
1
3 3
6.4 (d, J = 6.2 Hz, POCC); 12.2 (s, CH ); P NMR (243 MHz, CDCl ): δ = 30.84 ppm.
Anal. Calcd. for C16
26
H N
5
O
5
P: C, 48.12; H, 6.56; N, 17.54. Found: C, 47.90; H, 6.33; N,
1
7.41.
4
.1.5.27.
Diethyl
4-(4-{[2,4-dioxopyrimidin-1-yl]methyl}-1H-1,2,3-triazol-1-
yl)butylphosphonate 23c
1
From azide 15 (0.100 g, 0.425 mmol) and N -propargyluracil 19c (0.064 g, 0.425 mmol) the
phosphonate 23c (0.133 g, 81%) was obtained as a white powder after crystallisation from
ethyl acetate–petroleum ether mixtures; m.p.: 124–125°C; IR (KBr): ν = 3435, 3142, 2994,
–1 1
2
7
952, 2867, 1648, 1229, 1023 cm ; H NMR (600 MHz, CDCl
.72 (s, 1H, HC5′); 7.53 (d, J = 8.0 Hz, 1H, HC=CH); 5.73 (d, J = 8.0 Hz, 1H, HC=CH); 5.00
); 4.39 (t, J = 7.1 Hz, 2H, PCCCCH ); 4.16–4.06 (m, 4H, 2×POCH CH ); 2.06
3
): δ = 8.80 (brs, 1H, NH);
(s, 2H, CH
2
2
2
3
2
4

ACCEPTED MANUSCRIPT
(
qu, J = 7.1 Hz, 2H, PCCCH
2
); 1.82–1.76 (m, 2H, PCCH
2
); 1.71–1.64 (dqu, J = 14.3 Hz, J =
1
3
7
1
4
1
.1 Hz, 2H, PCH
2
); 1.34 (t, J = 7.0 Hz, 6H, 2×POCH CH ); C NMR (151 MHz, CDCl ): δ =
2
3
3
63.7 (s, C=O); 151.1 (s, C=O); 144.3; 141.9; 123.7; 102.7; 61.6 (d, J = 6.6 Hz, POC); 49.9;
3.2; 30.6 (d, J = 15.2 Hz, PCCC); 25.0 (d, J = 142.0 Hz, PC); 19.7 (d, J = 5.3 Hz, PCC);
31
3
6.5 (d, J = 6.0 Hz, POCC); P NMR (243 MHz, CDCl ): δ = 30.77 ppm. Anal. Calcd. for
C H N O P: C, 46.75; H, 6.28; N, 18.17. Found: C, 46.84; H, 6.36; N, 18.00.
15
24
5
5
4
4
.1.5.28. Diethyl 4-(4-{[N -acetylamino-2-oxopyrimidin-1-yl]methyl}-1H-1,2,3-triazol-1-
yl)butylphosphonate 23d
4
1
From azide 15 (0.060 g, 0.259 mmol) and N -acetyl-N -propargylcytosine 19d (0.050 g, 0.259
mmol) the phosphonate 23d (0.078 g, 72%) was obtained as a white powder after purification
on silica gel with chloroform–methanol (20:1, v/v); m.p.: 159–161°C; IR (KBr): ν = 3217,
–
1 1
3
133, 3084, 2982, 1707, 1650, 1217, 1025 cm ; H NMR (600 MHz, CDCl
H, NH); 7.96 (d, J = 7.3 Hz, 1H, HC=CH); 7.84 (s, 1H, HC5′); 7.40 (d, J = 7.3 Hz, 1H,
); 4.37 (t, J = 7.1 Hz, 2H, PCCCCH ); 4.16–4.04 (m, 4H,
); 2.25 (s, 3H, CH ); 2.05 (qv, J = 7.1 Hz, 2H, PCCCH ); 1.79 (dt, J = 15.5 Hz,
J = 7.1 Hz, 2H, PCH ); 1.71–1.63 (m, 2H, PCCH ); 1.33 (t, J = 7.0 Hz, 6H, 2×POCH CH );
C NMR (151 MHz, CD OD): δ = 163.1 (s, C=O); 157.0 (s, C=O); 149.4; 142.1; 124.1; 96.9;
1.8 (d, J = 6.6 Hz, POC); 49.3; 44.9; 30.2 (d, J = 16.2 Hz, PCCC); 23.7 (d, J = 140.4 Hz,
3
): δ = 8.83 (brs,
1
HC=CH); 5.16 (s, 2H, CH
×POCH CH
2
2
2
2
3
3
2
2
2
2
3
1
3
3
6
3
1
3
PC); 23.2; 19.1 (d, J = 5.2 Hz, POCC); 15.4; P NMR (243 MHz, CDCl ): δ = 30.90 ppm.
Anal. Calcd. for C17
27
H N
6
O
5
P: C, 47.88; H, 6.38; N, 19.71. Found: C, 47.63; H, 6.41; N,
1
9.52.
4
.1.5.29.
Diethyl
4-{4-[(3,5-dioxo-1,2,4-triazin-2-yl)methyl]-1H-1,2,3-triazol-1-
yl}butylphosphonate 23f
1
From azide 15 (0.151 g, 0.642 mmol) and N -propargyl-6-azauracil 19f (0.097 g, 0.642 mmol)
the phosphonate 23f (0.240 g, 97%) was obtained as a colourless oil after chromatography on
a silica gel column with chloroform–methanol (50:1, v/v); IR (film): ν = 3439, 3231, 3141,
–
1 1
3
1
012, 2909, 1730, 1676, 1216, 1027, 754 cm ; H NMR (300 MHz, CDCl
3
): δ = 11.58 (brs,
H, NH); 7.70 (s, 1H, HC5′); 7.39 (s, 1H, HC=N); 5.20 (s, 2H, CH ); 4.33 (t, J = 7.2 Hz, 2H,
2
2 2 3 2
PCCCCH ); 4.15–4.03 (m, 4H, 2×POCH CH ); 2.01 (qu, J = 7.1 Hz, 2H, PCCCH ); 1.83–
2
5

ACCEPTED MANUSCRIPT
1
3
1
.56 (m, 4H, PCH
CDCl ): δ = 155.9 (s, C=O); 148.9 (s, C=O); 141.5; 134.6; 123.8; 61.8 (d, J = 6.6 Hz, POC);
9.7; 34.5; 30.6 (d, J = 15.5 Hz, PCCC); 24.7 (d, J = 141.4 Hz, PC); 19.5 (d, J = 4.9 Hz,
2 2 2 3
CH ); 1.31 (t, J = 7.0 Hz, 6H, 2×POCH CH ); C NMR (75.5 MHz,
3
4
31
PCC); 16.4 (d, J = 6.1 Hz, POCC); P NMR (121.5 MHz, CDCl
3
): δ = 32.44 ppm. Anal.
Calcd. for C14 P: C, 43.52; H, 6.00; N, 21.75. Found: C, 43.65; H, 5.87; N, 21.69.
23 6 5
H N O
4
1
.1.5.30. Diethyl 4-{4-[(8-chloro-1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-
-yl}butylphosphonate 23g
7
From azide 15 (0.129 g, 0.473 mmol) and 8-chloro-N -propargyltheophylline 19g (0.119 g,
.473 mmol) the phosphonate 23g (0.242 g, 98%) was obtained as a white solid after
chromatography on a silica gel column with chloroform–methanol (20:1, v/v); m.p.: 69–70°C;
0
–
1 1
IR (KBr): ν = 3013, 2988, 2962, 1707, 1668, 1225, 1015 cm ; H NMR (600 MHz, CDCl
3
):
δ = 7.79 (s, 1H, HC5′); 5.62 (s, 2H, CH ); 4.35 (t, J = 7.3 Hz, 2H, PCCCCH ); 4.14–4.04 (m,
2
2
4
H, 2×POCH CH ); 3.55 (s, 3H, CH ); 3.42 (s, 3H, CH ); 2.04 (qu, J = 7.3 Hz, 2H,
2
3
3
3
PCCCH
2
); 1.77 (dt, J = 14.8 Hz, J = 7.3 Hz, 2H, PCH
2
2
); 1.69–1.61 (m, 2H, PCCH ); 1.32 (t, J
13
=
7.0 Hz, 6H, 2×POCH
2 3 3
CH ); C NMR (151 MHz, CDCl ): δ = 154.5 (s, C=O); 151.2 (s,
C=O); 147.4; 141.7; 139.1; 123.5; 107.3; 61.6 (d, J = 6.5 Hz, POC); 49.8; 41.0; 30.6 (d, J =
1
5.1 Hz, PCCC); 29.8; 28.0; 24.9 (d, J = 142.1 Hz, PC); 19.6 (d, J = 4.8 Hz, PCC); 16.4 (d, J
3
1
=
C
5.9 Hz, POCC); P NMR (243 MHz, CDCl
3
): δ = 30.49 ppm. Anal. Calcd. for
18
H
27ClN
7
O
5
P: C, 44.31; H, 5.58; N, 20.10. Found: C, 44.56; H, 5.44; N, 20.35.
4
.1.5.31.
Diethyl
4-{4-[(3,7-dimethyl-2,6-dioxopurin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}butylphosphonate 23h
1
From azide 15 (0.135 g, 0.573 mmol) and N -propargyltheobromine 19h (0.125 g, 0.573
mmol) the phosphonate 23h (0.224 g, 88%) was obtained as a white solid after purification on
silica gel with chloroform–methanol (20:1, v/v); m.p.: 59–61°C; IR (KBr): ν = 3432, 3115,
–1 1
2
983, 2952, 1708, 1662, 1235, 1025 cm ; H NMR (600 MHz, CDCl ): δ = 7.62 (s, 1H); 7.51
3
(
s, 1H); 5.33 (s, 2H, CH
2
); 4.33 (t, J = 7.3 Hz, 2H, PCCCCH
2
); 4.13–4.05 (m, 4H,
);
2
1
1
×POCH
2
CH
3
); 4.01 (s, 3H, CH ); 3.59 (s, 3H, CH ); 2.02 (qu, J = 7.3 Hz, 2H, PCCCH
3
3
2
.73 (dt, J = 18.0 Hz, J = 7.3 Hz, 2H, PCH ); 1.63 (dqu, J = 14.0 Hz, J = 7.3 Hz, 2H, PCCH );
2
2
1
3
.32 (t, J = 7.0 Hz, 6H, 2×POCH
2
CH
3
); C NMR (151 MHz, CDCl
3
): δ = 154.8 (s, C=O);
2
6

ACCEPTED MANUSCRIPT
1
3
51.3 (s, C=O); 148.9; 143.6; 141.7; 123.1; 107.6; 61.6 (d, J = 6.5 Hz, POC); 49.6; 36.0;
3.5; 30.7 (d, J = 15.3 Hz, PCCC); 29.7; 25.0 (d, J = 144.9 Hz, PC); 19.6 (d, J = 4.7 Hz,
3
1
PCC); 16.4 (d, J = 6.1 Hz, POCC); P NMR (243 MHz, CDCl
3
): δ = 30.91 ppm. Anal. Calcd.
28 7 5
for C18H N O
P: C, 47.68; H, 6.22; N, 21.62. Found: C, 47.74; H, 6.03; N, 21.71.
4
.1.5.32.
Diethyl
4-{4-[(1,3-dimethyl-2,6-dioxopurin-7-yl)methyl]-1H-1,2,3-triazol-1-
yl}butylphosphonate 23i
7
From azide 15 (0.146 g, 0.535 mmol) and N -propargyltheophylline 19i (0.117 g, 0.535
mmol) the phosphonate 23i (0.189 g, 72%) was obtained as a white solid after
chromatography on a silica gel column with chloroform–methanol (20:1, v/v); m.p.: 58–59°C;
–1 1
IR (KBr): ν = 3432, 3115, 2983, 2952, 1708, 1662, 1235, 1025 cm ; H NMR (600 MHz,
CDCl ): δ = 7.84 (s, 1H); 7.83 (s, 1H); 5.60 (s, 2H, CH ); 4.37 (t, J = 7.1 Hz, 2H, PCCCCH );
.15–4.05 (m, 4H, 2×POCH CH ); 3.60 (s, 3H, CH ); 3.44 (s, 3H, CH ); 2.06 (qu, J = 7.1 Hz,
3
2
2
4
2
2
1
2
3
3
3
H, PCCCH ); 1.80–1.74 (m, 2H, PCH ); 1.69–1.62 (m, 2H, PCCH ); 1.33 (t, J = 7.4 Hz, 6H,
2
2
2
1
3
×POCH
2
CH
3
); C NMR (151 MHz, CDCl
3
): δ = 155.4 (s, C=O); 151.6 (s, C=O); 149.0;
42.2; 141.4; 123.5; 106.5; 61.6 (d, J = 6.4 Hz, POC); 49.9; 41.5; 30.6 (d, J = 14.7 Hz,
PCCC); 29.8; 25.0 (d, J = 142.2 Hz, PC); 19.6 (d, J = 4.5 Hz, PCC); 16.4 (d, J = 6.4 Hz,
3
1
POCC); P NMR (243 MHz, CDCl
3
): δ = 30.79 ppm. Anal. Calcd. for C18
28 7 5
H N O P: C,
4
7.68; H, 6.22; N, 21.62. Found: C, 47.80; H, 6.00; N, 21.74.
4
.1.5.33.
Diethyl
4-{4-[(5,6-dimethylbenzimidazol-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}butylphosphonate 23j
1
From azide 15 (0.150 g, 0.549 mmol) and 5,6-dimethyl-N -propargylbenzimidazole 19j
(0.100 g, 0.549 mmol) the phosphonate 23j (0.122 g, 74%) was obtained as a yellow oil after
purification on silica gel with chloroform–methanol (50:1, v/v); IR (film): ν = 3303, 3102,
–
1 1
2
1
2
1
1
1
3
982, 1219, 1027 cm ; H NMR (600 MHz, CDCl ): δ = 8.30 (s, 1H); 7.60 (s, 1H); 7.30 (s,
H); 7.32 (s, 1H); 5.48 (s, 2H, CH ); 4.38 (t, J = 7.4 Hz, 2H, PCCCCH ); 4.16–4.04 (m, 4H,
2
2
×POCH
2
CH
3
); 2.40 (s, 3H, CH
3
); 2.39 (s, 3H, CH
3
); 1.99 (qu, J = 7.4 Hz, 2H, PCCCH
2
);
);
2
.75 (dt, J = 18.2 Hz, J = 7.4 Hz, 2H, PCH ); 1.63 (dq, J = 15.4 Hz, J = 7.4 Hz, 2H, PCCH
2
13
.31 (t, J = 7.1 Hz, 6H, 2×POCH CH ); C NMR (151 MHz, CDCl ): δ = 143.0; 132.7;
2
3
3
30.8; 122.1; 120.3; 61.6 (d, J = 6.6 Hz, POC); 49.8; 30.5 (d, J = 15.1 Hz, PCCC); 24.9 (d, J
2
7

ACCEPTED MANUSCRIPT
31
=
142.1 Hz, PC); 20.4; 20.2; 19.5 (d, J = 4.7 Hz, PCC); 16.4 (d, J = 5.8 Hz, POCC); P NMR
243 MHz, CDCl ): δ = 30.84 ppm. Anal. Calcd. for C20 P: C, 57.27; H, 7.21; N,
6.70. Found: C, 57.10; H, 7.08; N, 16.79.
(
3
30 5 3
H N O
1
4
.1.5.34. Diethyl 4-{4-[(3-acetylindol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}butylphosphonate
2
3k
From azide 15 (0.114 g, 0.485 mmol) and 3-acetyl-N-propargylindole 19k (0.096 g, 0.485
mmol) the phosphonate 23k (0.187 g, 89%) was obtained as a colourless oil after
chromatography on a silica gel column with chloroform–methanol (20:1, v/v); IR (film): ν =
–
1 1
3
8
4
1
2
1
1
283, 3110, 2983, 2872, 1797, 1231, 1045, 750 cm ; H NMR (300 MHz, CDCl
.38 (m, 1H); 7.76 (s, 1H, HC5′); 7.43–7.39 (m, 1H); 7.36–7.27 (m, 3H); 5.42 (s, 2H, CH2);
.37 (t, J = 7.0 Hz, 2H, PCCCCH ); 4.10–4.00 (m, 4H, 2×POCH CH ); 2.53 (s, 3H, CH );
.98 (qu, J = 7.0 Hz, 2H, PCCCH ); 1.85–1.50 (m, 4H, PCH CH ); 1.28 (t, J = 7.0 Hz, 6H,
×POCH CH ); C NMR (75.5 MHz, CDCl ): δ = 193.0 (s, C=O); 143.0; 136.5; 134.8;
3
): δ = 8.45–
2
2
3
3
2
2
2
1
3
2
3
3
23.5; 122.7; 122.7; 122.1; 117.5; 109.9; 61.7 (d, J = 6.4 Hz, POC); 50.0; 42.5; 30.8 (d, J =
5.2 Hz, PCCC); 27.8; 24.9 (d, J = 141.7 Hz, PC); 19.7 (d, J = 4.9 Hz, PCC); 16.6 (d, J = 6.0
31
Hz, POCC); P NMR (121.5 MHz, CDCl
3 29 4 4
): δ = 31.92 ppm. Anal. Calcd. for C21H N O P:
C, 58.32; H, 6.76; N, 12.96. Found: C, 58.48; H, 6.81; N, 13.10.
4
.1.5.35. Diethyl 4-{4-[(2-oxopyridin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}butylphosphonate
2
3l
From azide 15 (0.123 g, 0.523 mmol) and N-propargyl-2-pyridon 19l (0.070 g, 0.523 mmol)
the phosphonate 23l (0.182 g, 94%) was obtained as a brown oil after purification on silica gel
with chloroform–methanol (20:1, v/v); IR (film): ν = 3134, 2996, 2935, 1659, 1222; 1020,
–1 1
9
3
68 cm ; H NMR (300 MHz, CDCl ): δ = 7.78 (s, 1H, HC5′); 7.60 (dd, J = 6.7 Hz, J = 2.2
Hz, 1H); 7.38 (ddd, J = 9.1 Hz, J = 6.7 Hz, J = 2.2 Hz, 1H); 6.54 (d, J = 9.1 Hz, 1H); 6.19 (dt,
J = 6.7 Hz, J = 1.5 Hz, 1H); 5.18 (s, 2H, CH ); 4.33 (t, J = 7.2 Hz, 2H, PCCCCH ); 4.17–4.00
2
2
(m, 4H, 2×POCH
2
CH
3
); 2.22–1.96 (m, 2H, PCCCH
2
); 1.82–1.60 (m, 4H, PCH
2
2
CH ); 1.31 (t,
1
3
J = 6.9 Hz, 6H, 2×POCH
HC=C); 140.0; 137.8; 123.9 (s, HC=C); 120.8; 106.6; 61.7 (d, J = 6.5 Hz, POC); 49.9; 44.7;
0.8 (d, J = 15.5 Hz, PCCC); 25.1 (d, J = 141.7 Hz, PC); 19.8 (d, J = 5.2 Hz, PCC); 16.6 (d, J
2 3 3
CH ); C NMR (75.5 MHz, CDCl ): δ = 162.3 (s, C=O); 142.7 (s,
3
2
8