Design, synthesis and antiviral evaluation of novel acyclic phosphonate nucleotide analogs with triazolo[4,5-b]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-b]pyridin-2(3H)-one systems

Article abstract of DOI:10.1080/15257770.2019.1669046

A new series of phosphonylated triazolo[4,5-b]pyridine (1-deaza-8-azapurine), imidazo[4,5-b]pyridine (1-deazapurine) and imidazo[4,5-b]pyridin-2(3H)-one (1-deazapurin-8-one) were synthesized from 2-chloro-3-nitropyridine and selected diethyl ?-aminoalkylp

Full text of DOI:10.1080/15257770.2019.1669046

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: https://www.tandfonline.com/loi/lncn20
Design, synthesis and antiviral evaluation of novel
acyclic phosphonate nucleotide analogs with
triazolo[4,5-b]pyridine, imidazo[4,5-b]pyridine and
imidazo[4,5-b]pyridin-2(3H)-one systems
Anna Hartwich, Nee Zdzienicka, Dominique Schols, Graciela Andrei, Robert
Snoeck & Iwona E. Głowacka
To cite this article: Anna Hartwich, Nee Zdzienicka, Dominique Schols, Graciela Andrei,
Robert Snoeck & Iwona E. Głowacka (2019): Design, synthesis and antiviral evaluation of novel
acyclic phosphonate nucleotide analogs with triazolo[4,5-b]pyridine, imidazo[4,5-b]pyridine and
imidazo[4,5-b]pyridin-2(3H)-one systems, Nucleosides, Nucleotides and Nucleic Acids, DOI:
10.1080/15257770.2019.1669046
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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
https://doi.org/10.1080/15257770.2019.1669046
Design, synthesis and antiviral evaluation of novel
acyclic phosphonate nucleotide analogs with
triazolo[4,5-b]pyridine, imidazo[4,5-b]pyridine and
imidazo[4,5-b]pyridin-2(3H)-one systems
a
a
b
b
Anna Hartwich , Nee Zdzienicka , Dominique Schols , Graciela Andrei ,
b
a
Robert Snoeck , and Iwona E. Głowacka
a
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ł ꢀo d ꢀz , Ł ꢀo d ꢀz , Poland;
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
b
ABSTRACT
ARTICLE HISTORY
A new series of phosphonylated triazolo[4,5-b]pyridine (1-
deaza-8-azapurine), imidazo[4,5-b]pyridine (1-deazapurine) and
imidazo[4,5-b]pyridin-2(3H)-one (1-deazapurin-8-one) were
synthesized from 2-chloro-3-nitropyridine and selected diethyl
W-aminoalkylphosphonates followed by reduction of the nitro
group and cyclization. In the final step O,O-diethylphospho-
nates were transformed into the corresponding phosphonic
acids. All synthesized compounds were evaluated in vitro for
inhibitory activity against a broad variety of DNA and RNA
viruses and their cytotoxic potencies were also established.
Compound 12f showed marginal activity against cytomegalo-
virus Davis strain (EC50 ¼ 76.47 lM) in human embryonic
lung (HEL) cells while compounds 10g (EC ¼ 52.53 lM) and
Received 10 April 2019
Accepted 12 September 2019
KEYWORDS
Aminoalkylophosphonates;
acyclonucleotides; synthesis;
antiviral activity
5
0
1
2l (EC50 ¼ 61.70 lM) were minimally active against the
varicella-zoster virus Oka strain in HEL cells. Compounds under
investigation were not cytotoxic at the maximum concentra-
tion evaluated (100mM).
1
. Introduction
Acyclic nucleoside phosphonates (ANPs) are structural analogs of nucleo-
side monophosphates in which aliphatic chain plays the role of a furanose
ring and the isosteric and isoelectronic oxymethylphosphonate (phosphoryl-
methoxy) moiety [(HO) P(O)–CH –O] replaces the naturally occurring
2
2
0
[1,2]
labile phosphate moiety [(HO) P(O)–O–C(5 )].
ANPs are known since
986 when (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-
HPMPA] (Figure 1) has been synthesized and its promising antiviral activ-
2
1
[
3]
ity towards DNA and RNA viruses was revealed. Since then various
ANPs have been obtained and several compounds have been recognized to
CONTACT Iwona E. Glowacka
iwona.glowacka@umed.lodz.pl
Bioorganic Chemistry Laboratory, Faculty of
Pharmacy, Medical University of Ł ꢀo d ꢀz , Muszy nꢀ skiego 1, Ł ꢀo d ꢀz 90-151, Poland.
ß 2019 Taylor & Francis Group, LLC

2
A. HARTWICH ET AL.
NH
2
NH
2
NH
2
NH
2
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
N
(HO)
2
(O)P
O
(HO)
2
(O)P
O
2
(HO) (O)P
O
2
(HO) (O)P
OH
OH
Cidofovir
(S)-HPMPA
Adefovir
Tenofovir
Figure 1. Acyclic nucleoside phosphonates with antiviral activity.
Figure 2. Acyclic nucleoside phosphonates (ANPs) with modified carbon linkers.
possess a broad spectrum of antiviral and cytostatic activities with already
[
4–9]
proved mechanism of action.
Among them, adefovir, tenofovir
and cidofovir (Figure 1) as well as their prodrugs are currently applied
[
6–11]
as pharmaceuticals in the treatment of viral infections.
However, emergence of mutant viruses after long-term treatment with anti-
viral drugs may result in lower sensitivity of viruses to chemotherapeutics
(
drug resistance) which is an important problem in the treatment of viral
[
11–13]
infections.
For this reason, a search for new antiviral compounds has
been continuing for many years. Many acyclic nucleotide analogs have been
synthesized and both the aliphatic chain and the nucleobase unit were altered.
Modifications of the aliphatic chain are possible through carbon-chain
lengthening, branching and incorporation of nitrogen, oxygen, sulfur, fluorine
[
14–19]
atoms, or the unsaturated bonds into their structures (Figure 2).
On the other hand, modifications a purine unit were accomplished
in several ways, for example, by construction of 8-azapurine analogs [1,2,3-
triazolo[4,5-d]pyrimidines] via replacement of C8 with the nitrogen
[
20–24]
atom.
Various 1-, 3-, or 7-deazapurine analogs were obtained by sub-
stitution of the respective nitrogen atoms of purine moiety by the methine

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Figure 3. Examples of 8-aza and deazapurine nucleotides.
group without changes of the steric demands in the newly formed systems
[
25–27]
(
Figure 3).
For example, compound 1 exhibited inhibitory effect on the DNA viruses
herpes simplex virus 1 (HSV-1), HSV-2, cytomegalovirus (CMV)
IC ¼ 0.4–3.5 mg/mL), varicella zoster virus (VZV) (IC ¼ 0.01–0.06 mg/
(
50
50
mL), vaccinia virus (IC ¼ 0.7–2.0 mg/mL), and against the retroviruses
50
Moloney murine sarcoma virus (MSV) (IC ¼ 0.57–0.03 mg/mL), human
5
0
[
22]
immunodeficiency virus type 1 (HIV-1) and HIV-2 (IC >0.8 mg/mL).
Compound 2 was active against thymidine kinase deficient (TK ) HSV-
50
–
þ
–
1
0
and HSV-2, CMV (IC ¼ 2–7 mg/mL) and TK and TK VZV (IC ¼
50
50
.04–0.4 mg/mL) as well as the retroviruses MSV (IC ¼ 0.32 ± 0.1 mg/mL)
50
[
21,22]
and HIV-1 and HIV-2 (IC ¼ 2 mg/mL).
Aza-nucleotide 3 is a potent
50
inhibitor of PfHGXPRT [Plasmodium falciparum (Pf) hypoxanthine-guanine-
xanthine phosphoribosyltransferase (HGXPRT)].
[
27]
Moreover, compounds possessing 1,2,3-triazolo[4,5-b]pyridines, imidazo
4,5-b]pridines and imidazo[4,5-b]pyridin-2-ones units exhibited interesting
pharmacological and biological activities.
[
[
28–33]
These achievements prompted us to design and synthesize new acyclic
phosphonate nucleoside analogs in which the natural purine nucleobase
was replaced by triazolo[4,5-b]pyridine (1-deaza-8-azapurine), imidazo
[
4,5-b]pyridine (1-deazapurine) and imidazo[4,5-b]pyridin-2(3H)-one
(
1-deazapurin-8-one) moieties with intention to evaluate their antiviral and
cytotoxic properties (Scheme 1).
2
. Results and discussion
For the purpose of this project, known diethyl x-aminoalkylphosphonates
4
a–i (Scheme 1) were synthesized according to the procedures previously
[
16,27,34–39]
described.
Pure racemic diethyl 2-amino-1-hydroxyethylphosphonate 4g and diethyl
-amino-2-hydroxypropylphosphonate 4i were synthesized via slightly
3
modified procedures which relied on the reacting the epoxyalkylphospho-
nate with dibenzylamine and subsequent hydrogenolytic removal of benzyl
group (Scheme 2). Earlier procedure for the transformation of 13b into
3-dibenzylamino-2-hydroxypropylphosphonate 14b required heating of the

4
A. HARTWICH ET AL.
Scheme 1. Retrosynthesis of the designed acyclic nucleotides 7–12.
ꢀ
ꢀ
Scheme 2. Reagents and conditions: (a) NHBn , MW, 60 C, 5 hours and (b) NHBn , 60 C,
2
2
2
0 hours; H , 10% Pd(OH) /C, EtOH, r.t., 5 days.
2 2
Scheme 3. Reagents and conditions: (a) 2-chloro-3-nitropyridine, TEA, THF, or CH Cl , r.t.,
2
2
2
4 hours and (b) SnCl , 36% HCl, 95% CH COOH, r.t., 1.5 hours.
2 3
ꢀ
[40]
reaction mixture at 60 C for 20 hours.
carried out under microwave irradiation, a full conversion of the epoxide
3b into 3-dibenzylamino-2-hydroxypropylphosphonate 14b was achieved
after 5 hours. After hydrogenolysis of 14b racemic diethyl 3-amino-
-hydroxypropylphosphonate 4i was obtained in good overall yield (77%).
However, when the reaction was
1
2
In the similar way, racemic diethyl 2-amino-1-hydroxyethylphosphonate 4g
was obtained from epoxyethylphosphonate 13a (93%).
Aminoalkylphosphonates 4a–i were then reacted with 2-chloro-3-nitro-
[41]
pyridine (Scheme 3)
to give the respective diethyl [(3-nitropyridin-2-yl)
amino]alkylphosphonates 5a–i in 39%–91% yields. The reduction of the nitro
[41]
group
in 5a-i led to the formation of the diethyl [(3-aminopyridin-2-yl)
amino]alkylphosphonates 6a–i (Scheme 3) which were subsequently applied

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
ꢀ
Scheme 4. Reagents and conditions: (a) NaNO , H SO , 0 C, 1 hour; (b) HC(OEt) , p-TsOH,
2
2
4
3
THF, r.t., 24 hours; (c) CDI, THF, r.t., 72 hours; and (d) TMSBr, CH Cl , r.t., 24 hours.
2
2
as key substrates in the synthesis of the designed nucleotide analogs
(Scheme 1).
Diazotization of diethyl [(3-aminopyridin-2-yl)amino]alkylphosphonates
[
42]
6a–i followed by spontaneous intramolecular cyclization
led to the for-
mation of diethyl {1,2,3-triazolo[4,5-b]pyridin-3-yl}alkylphosphonates 7a–i
in 47%–96% yields. 1-Deazapurine-containing analogs 8a–i were synthe-
sized by the reaction of 6a–i with triethyl orthoformate in the presence of
[
43]
p-toluenesulphonic acid
in 32%–99% yields. In order to obtain imidazo-
lone analogs 9a–i, diethyl [(3-aminopyridin-2-yl)amino]alkylphosphonates
0
[44]
6
a–i were treated with 1,1 -carbonyldiimidazole
(Scheme 4). However,
under these conditions only diethyl [(3-aminopyridin-2-yl)amino]alkyl-
phosphonates 6a–f were effectively transformed into the compounds 9a–f.
In the case of racemic phosphonates 9g–i containing the hydroxy group
0
in phosphonoalkyl chain reaction with 1,1 -carbonyldiimidazole led to the
formation of complex mixture of products. Several attempts at separating
of the crude reaction mixture on silica gel columns failed.
We concluded that in case of phosphonates 6g–i transformation into the
respective imidazolones required prior protection of hydroxyl groups in
[
45,46]
the phosphonoalkyl chain.
For this reason, the O-methyl-amino-
phosphonates 4j–l were synthesized as depicted on Schemes 5 and 6.
Transformation of 2-dibenzylamino-1-hydroxyethylphosphonate 14a and

6
A. HARTWICH ET AL.
Scheme 5. Reagents and conditions: (a) H , 10% Pd(OH) /C, Boc O, EtOH, r.t., 72 hours; (b)
2
2
2
CH I, Ag O, CH Cl , r.t., 7 days; and (c) TFA, CH Cl , r.t., 5 hours.
3
2
2
2
2 2
Scheme 6. Reagents and conditions: (a) CH I, Ag O, CH Cl , r.t., 7 days and (b) H , 10%
3
2
2
2
2
Pd(OH) /C, EtOH, r.t., 72 hours.
2
Scheme 7. Reagents and conditions: (a) CDI, THF, r.t., 72 hours and (b) TMSBr, CH Cl , r.t., 24 hours.
2
2
3-dibenzylamino-2-hydroxypropylphosphonate 14b into the respective
O-methyl-aminophosphonates 4g and 4i was accomplished in three steps
[47,48]
[49]
involving catalytic hydrogenation in the presence of Boc O,
O-methylation
2
and hydrolysis (Scheme 5).
On the other hand, the synthesis of diethyl 3-amino-1-methoxypropyl-
phosphonate 4k was achieved by reaction sequence including methylation
of the hydroxy group at C(1) in 17 and catalytic hydrogenation in diethyl
3-[N-(benzyloxycarbonyl)amino]-1-hydroxypropylphosphonate 18 (Scheme 6).
The racemic O-methylated alkylphosphonates 6j–l were applied in the
0
reaction with 1,1 -carbonyldiimidazole to afford the respective phospho-
noalkyl imidazolones 9j–l (Scheme 7).
All diethyl phosphonates 7a–i, 8a–i, and 9a–f, j–l were finally trans-
formed into the respective phosphonic acids 10a–i, 11a–i and 12a–f, j–l
[
50]
with trimethylsilyl bromide
(Schemes 4 and 7).
The structure and purity of all synthesized compounds were verified by
H, P, and C NMR and IR techniques as well as by elemental analysis.
1
31
13
2
.1. Antiviral activity and cytotoxicity evaluation
All the synthesized diethyl phosphonates 7–9 as well as the respective
phosphonic acids 10–12 were evaluated for their antiviral activities against

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
Figure 4. Structures of active compounds.
a wide variety of DNA and RNA viruses, using the following cell-based
assays: (a) human embryonic lung (HEL) cells: Herpes simplex virus-1
(
(
KOS strain), Herpes simplex virus-2 (G strain), Herpes simplex virus-1
TK ACV KOS), Vaccinia virus, Adenovirus-2, human coronavirus,
–
r
cytomegalovirus (AD-169 strain and Davis strain), varicella-zoster virus
þ
–
(
TK VZV strain OKA and TK VZV strain 07-1); (b) HeLa cell cultures:
vesicular stomatitis virus, Coxsackie virus B4 and respiratory syncytial virus
RSV); (c): Vero cell cultures: Parainfluenza-3 virus, Reovirus-1, Sindbis
(
virus, Coxsackie virus B4, Punta Toro virus, yellow fever virus; and (d)
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,
zalcidabine, alovudine, Urtica dioica agglutinin (UDA), dextran sulfate
(
molecular weight 10,000, DS-10000), zanamivir, mycophenoic acid, riba-
virin, amantadine, and rimantadine were used as the reference compounds.
The antiviral activity was expressed as the EC : the compound concentra-
5
0
tion required to reduce virus-induced cytopathogenicity by 50% (other
viruses). Among the synthesized compounds, phosphonic acid 12f showed
marginal activity only against the CMV Davis strain (EC ¼ 76.47 lM) but
5
0
not against the AD-169 strain in HEL cells, while compounds 10g
(
EC ¼ 52.53 lM) and 12l (EC ¼ 61.70 lM) showed also very minor
50
50
activity against the VZV Oka strain but not against the 07-1 strain of VZV
in HEL cells (Figure 4). None of the other compounds showed any activity
against the different DNA and RNA evaluated.
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.
None of the compounds proved cytotoxic up to 100 mM, the highest
concentration tested.
3
. Conclusion
New series of phosphonylated triazolo[4,5-b]pyridine (1-deaza-8-azapurine),
imidazo[4,5-b]pyridine (1-deazapurine) and imidazo[4,5-b]pyridin-2(3H)-one

8
A. HARTWICH ET AL.
(1-deazapurin-8-one) were successfully obtained from diethyl [(3-aminopyri-
din-2-yl)amino]alkylphosphonates 6a–l by three different approaches: diazoti-
zation and spontaneous intramolecular cyclization (7a–i), cyclization with
0
triethyl orthoformate (8a–i) and reaction with 1,1 -carbonyldiimidazole (9a–i).
The corresponding diethyl [(3-aminopyridin-2-yl)amino]alkylphosphonates
6a–l were efficiently prepared via reaction W-aminoalkylphosphonates with 2-
chloro-3-nitropyridine and reduction nitro group. All synthesized compounds
were tested for their antiviral activity against DNA and RNA viruses and cyto-
toxicity properties. Antiviral activity against cytomegalovirus (EC ¼ 76.47 mM;
50
MCC > 100 mM) in human embryonic lung (HEL) cells has been observed for
compound 12f. Phosphonic acids 10 g and 12l indicated marginal activity
against VZV (EC ¼ 52.53 mM for 10g and EC ¼ 61.70 mM for 12l;
50
50
MCC > 100 mM) in HEL cells. None of the compounds were not cytotoxic at
the maximum concentration evaluated (100 mM).
4
. Experimental
1
H NMR were taken in CDCl , D O, or DMSO-d on the following
3
2
6
spectrometers: Varian Mercury-300, Varian Mercury-200 and Bruker Avance
III (600 MHz) with TMS as an internal standard; chemical shifts d in ppm
1
3
with respect to TMS; coupling constants J in Hz. C NMR spectra were
recorded for CDCl , D O, or DMSO-d solutions on a Varian Mercury-300
3
2
6
and Bruker Avance III (600 MHz) spectrometer at 75.5 and 151 MHz, respect-
31
ively. P NMR spectra were taken in CDCl , D O, or DMSO-d on Varian
3
2
6
Mercury-300, Varian Mercury-200 and Bruker Avance III (600 MHz) at
121.5, 80.9, and 242 MHz using 85% phosphoric acid as an external standard.
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,
(
Perkin-Elmer Corp., Norwalk, CT, USA).
The following adsorbents were used: column chromatography, Merck
silica gel 60 (70–230 mesh); analytical TLC, Merck TLC plastic sheets silica
gel 60 F254. TLC plates were developed in chloroform–methanol solvent
systems. Visualization of spots was effected with iodine vapors. All solvents
were purified by methods described in the literature.
4
.1. Synthesis of diethyl 2-amino-1-methoxyethylphosphonate 4j
4
.1.1. Diethyl-2-(tert-butoxycarbonylamino)-1-hydroxyethylphosphonate 15a
A solution of diethyl 2-dibenzylamino-1-hydroxyethylphosphonate 14a
2.670 g, 7.08 mmol) and di-tert-butyl dicarbonate (1.545 g, 7.08 mmol) in
(

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
anhydrous ethanol (15 mL) was kept under hydrogen atmosphere over 10%
Pd(OH) /C (0.020 g, 0.01 mmol) at room temperature for 72 hours. The
2
suspension was filtered through a pad of Celite and washed with ethanol.
After evaporation of the solvent, the residue was chromatographed on
a silica gel column with a chloroform–methanol (100:1, v/v) mixture to
give diethyl-2-(tert-butoxycarbonylamino)-1-hydroxyethylphosphonate 15a
1
(
1.490 g, 71%) as a pale yellow oil. H NMR (600 MHz, CDCl ) d [ppm]:
3
5
.22 (brs, 1 H, NH), 4.27–4.09 (m, 5 H, 2 ꢁ POCH CH , OH), 4.01 (ddd,
2
3
J ¼ 7.8 Hz, J ¼ 6.6 Hz, J ¼ 3.6 Hz, 1 H, PCH), 3.71–3.29 (m, 2 H, PCCH ),
2
3
1
1
.44 (s, 9 H, 3 ꢁ CH ), 1.35 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ). P NMR
3
2
3
13
(
243 MHz, CDCl ) d [ppm]:23.17. C NMR (151 MHz, CDCl ) d [ppm]:
3 3
1
56.97, 79.67, 68.00 (d, J ¼ 127.2 Hz, PC), 62.93 (d, J ¼ 6.4 Hz, POC), 62.89
(
d, J ¼ 6.4 Hz, POC), 42.29, 28.35, 16.46 (d, J ¼ 5.2 Hz, POCC), 16.44
(
d, J ¼ 5.5 Hz, POCC).
4
A
.1.2. Diethyl-2-(tert-butoxycarbonylamino)-1-methoxyethylphosphonate 16a
suspension of diethyl-2-(tert-butoxycarbonylamino)-1-hydroxyethyl-
phosphonate 15a (1.000 g, 3.36 mmol), methyl iodide (0.400 mL, 6.73 mmol)
and silver(I) oxide (1.247 g, 5.38 mmol) in dichloromethane (20 mL) was
stirred vigorously at room temperature for 7 days. The reaction mixture
was filtered through a layer of Celite, concentrated and the crude product
was chromatographed on a silica gel column with a chloroform–methanol
(
100:1, v/v) mixture to give a diethyl-2-(tert-butoxycarbonylamino)-1-
methoxyethylphosphonate 16a as a colorless oil (0.882 g, 84%). IR (film,
–1
1
cm ) v : 3331, 2981, 2930, 1767, 1266, 1224, 1028, 964, 762; H NMR
max
(
600 MHz, CDCl ) d [ppm]: 5.09 (s, 1 H, NH), 4.25–4.16 (m, 4 H,
3
2
3
ꢁ POCH CH ), 3.72–3.50 (m, 2 H, PCCH ), 3.58 (s, 3 H, PCOCH ),
2
3
2
3
.39–3.29 (m, 1 H, PCH), 1.47 (s, 9 H, 3 ꢁ CH ), 1.38 (t, J ¼ 7.1 Hz, 3 H,
3
1
3
POCH CH ), 1.36 (t, J ¼ 7.1 Hz, 3 H, POCH CH ); C NMR (151 MHz,
2
3
2
3
CDCl ) d [ppm]: 155.80 (s, C ¼ O), 79.46 (s, CCH ), 76.28 (d, J ¼ 153.4 Hz,
3
3
PC), 62.61 (d, J ¼ 6.7 Hz, 2 ꢁ POC), 60.20 (s, PCOCH ), 40.18 (s, PCC),
3
3
1
2
8.37 (s, 3ꢁCH ), 16.49 (d, J ¼ 5.5 Hz, 2 ꢁ POCC); P NMR (243 MHz,
3
CDCl ) d [ppm]: 21.06; Anal. Calcd. for C H NO P: C, 46.30; H, 8.42;
3
12 26
6
N, 4.50; Found: C, 46.43; H, 8.44; N, 4.39.
4
.2. Diethyl 2-amino-1-methoxyethylphosphonate 4j
To a solution of diethyl-2-(tert-butoxycarbonylamino)-1-methoxyethyl-
phosphonate 16a (0.832 g, 2.80 mmol) in dichloromethane (15 mL),
trifluoroacetic acid (3.00 mL, 40.00 mmol) was added. The reaction mixture
was stirred at room temperature for 5 hours. Washed with saturated
sodium bicarbonate (2 ꢁ 5 mL) and organic layer was dried over anhydrous

1
0
A. HARTWICH ET AL.
MgSO . The crude product was purified on a silica gel column with a
4
chloroform–methanol (100:1, v/v) mixture to give diethyl 2-amino-1-
methoxyethylphosphonate 4j (0.288 g, 51%) as a colorless oil. IR (film,
–1
1
cm ) v : 3333, 2988, 2935, 1270, 1223, 1029, 964, 762; H NMR
max
(
3
600 MHz, CDCl ) d [ppm]: 4.28–4.15 (m, 4 H, 2 ꢁ POCH CH ), 3.63 (s,
3
2
3
H, OCH ), 3.60–3.56 (m, 2 H, PCCH ), 3.27–2.94 (m, 1 H, PCH), 2.54
3 2
(
3
brs, 2 H, NH ), 1.38 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.37 (t, J ¼ 7.1 Hz,
2
2
3
1
3
H, POCH CH );
C NMR (151 MHz, CDCl ) d[ppm]: 78.48 (d,
3
2
3
J ¼ 161.9 Hz, PC), 62.59 (d, J ¼ 6.9 Hz, POC), 62.52 (d, J ¼ 7.1 Hz, POC),
6
2
0.41 (d, J ¼ 3.9 Hz, PCOC), 41.57 (s, PCC), 16.52 (d, J ¼ 5.5 Hz,
31
ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]: 21.40; Anal. Calcd. for
3
C H NO P ꢁ 0.8H O: C, 37.27; H, 8.76; N, 6.21; Found: C, 37.30; H, 8.46;
7
18
4
2
N, 5.98.
4
.3. Synthesis of diethyl 3-amino-2-methoxypropylphosphonate 4l
4
.3.1. Diethyl-3-(tert-butoxycarbonylamino)-2-hydroxypropylphosphonate 15b
A suspension of diethyl 3-dibenzylamino-2-hydroxypropylphosphonate 14 b
1.600 g, 4.09 mmol), di-tert-butyl dicarbonate (0.893 g, 4.09 mmol) and
0% Pd(OH) /C (0.030 g, 0.01 mmol) in anhydrous ethanol (15 mL) was
(
1
2
stirred under hydrogen atmosphere at room temperature for 72 hours. The
catalyst was filtered off through a layer of Celite, the solution concentrate-
din vacuo and the residue was chromatographed on a silica gel column
with a chloroform–methanol (100:1, v/v) mixture to give diethyl-3-(tert-
butoxycarbonylamino)-2-hydroxypropylphosphonate 15b (1.031 g, 81%) as
–1
a pale yellow oil. IR (film, cm ) vmax: 3340, 2982, 2933, 1769, 1222, 1022,
1
9
66, 766; H NMR (600 MHz, CDCl ) d [ppm]: 5.08 (brs, 1 H, NH),
3
4
.25–4.07 (m, 6 H, 2 ꢁ POCH CH ), 3.39 (brs, 1 H, OH), 3.21–3.18 (m, 1 H,
2
3
PCCH), 2.00–1.94 (m, 2 H, PCH ), 1.47 (s, 9 H, 3 ꢁ CH ), 1.38 (t,
2
3
1
3
J ¼ 7.1 Hz, 3 H, POCH CH ), 1.36 (t, J ¼ 7.1 Hz, 3 H, POCH CH );
C
2
3
2
3
NMR (151 MHz, CDCl ) d [ppm]: 156.60, 79.62, 66.28, 62.05 (d, J ¼ 6.5 Hz,
3
2
ꢁ POC), 46.71, 30.77 (d, J ¼ 139.4 Hz, PC), 28.37, 16.41 (d, J ¼ 5.6 Hz,
31
POCC), 16.37 (d, J ¼ 5.7 Hz, POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
2
9.71 Anal. Calcd. for C H NO P ꢁ 0.1H O: C, 46.03; H, 8.43; N, 4.47;
1
2
26
6
2
Found: C, 46.12; H, 8.53; N, 4.43.
4
.3.2. Diethyl-3-(tert-butoxycarbonylamino)-2-methoxypropylphosphonate 16b
A suspension of diethyl-3-(tert-butoxycarbonylamino)-2-hydroxypropylphosph-
onate 15b (0.915 g, 2.94 mmol), methyl iodide (0.816 g, 3.52 mmol) and silver(I)
oxide (0.400 mL, 5.87 mmol) in CH Cl (10 mL) was vigorously stirred at room
2
2
temperature for 7 days. The reaction mixture was filtered through a layer of
Celite, concentrated and the crude product was purified on a silica gel column

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
with a chloroform–methanol (100:1, v/v) mixture to give a diethyl-3-(tert-butox-
ycarbonylamino)-2-methoxypropylphosphonate 16b as a pale yellow oil (0.879 g,
–1
1
9
2%). IR (film, cm ) v : 3331, 2981, 2930, 1699, 1269, 1224, 1028, 964, 762; H
max
NMR (600 MHz, CDCl ) d [ppm]: 4.97 (brs, NH), 3.70–3.64 (m, 1 H, PCCH)
3
4
.22–4.04 (m, 4 H, 2 ꢁ POCH CH ), 3.42 (s, 3 H, PCOCH ), 3.4–3.22 (m, 2 H,
2
3
3
PCCCH ), 2.17–1.89 (m, 2 H, PCH ), 1.47 (s, 9 H, 3 ꢁ CH ), 1.36 (t, J¼ 7.0 Hz,
2
2
3
13
6
7
H, 2 ꢁ POCH CH ; C NMR (151 MHz, CDCl ) d [ppm]: 155.97, 79.27,
2
3
3
5.35, 61.79 (d, J¼ 6.4 Hz, POC), 61.63 (d, J¼ 6.4 Hz, POC), 56.99, 43.36, 29.11
(d, J¼ 140.2 Hz, PC), 28.37, 16.39 (d, J¼ 5.8 Hz, POCC), 16.37 (d, J¼ 5.8 Hz,
31
POCC); P NMR (243 MHz, CDCl ) d [ppm]: 28.30; Anal. Calcd. for
3
C H NO P: C, 47.99; H, 8.67; N, 4.31; Found: C, 48.00; H, 8.32; N, 4.13.
13
28
6
4
.4. 3-Amino-2-methoxypropylphosphonate 4l
A solution of diethyl-3-(tert-butoxycarbonylamino)-2-methoxypropylphospho-
nate 16b (0.910 g, 2.80mmol) and trifluoroacetic acid (3.20mL, 0.04mol) in
dichloromethane (15 mL) was stirred at room temperature for 5 hours. After
the reaction mixture was dissolved in dichloromethane and washed by satu-
rated sodium bicarbonate solution (2 ꢁ 5 mL). Organic layer was dried over
anhydrous MgSO . The crude product was purified on a silica gel column with
4
a chloroform–methanol (100:1, v/v) mixture to give diethyl 3-amino-2-
–1
methoxypropylphosphonate 4l (0.524 g, 87%) as a colorless oil. IR (film, cm )
1
vmax: 3334, 2989, 2934, 1277, 1221, 1030, 964, 763; H NMR (600MHz, CDCl )
3
d [ppm]: 4.20–4.04 (m, 4 H, 2 ꢁ POCH CH ), 3.59 (dddd, J ¼ 7.3 Hz,
2
3
J ¼ 5.8 Hz, J ¼ 5.5 Hz, J ¼ 3.7 Hz, 1 H, PCCH), 3.42 (s, 3 H, CH ), 3.04 (dd
,
3
ABX
J ¼ 13.5 Hz, J ¼ 3.7Hz, 1 H, PCCCH H ), 2.79 (dd , J ¼ 13.5 Hz, J ¼ 5.8 Hz,
A
B
ABX
1
H, PCCCH H ), 2.13 (ddd, J ¼ 19.6 Hz, J ¼ 15.4 Hz, J ¼ 5.5 Hz, 1 H,
B
A
PCH H ), 1.98 (ddd, J ¼ 18.1 Hz, J ¼ 15.4 Hz, J ¼ 7.3 Hz, 1 H, PCH H ), 1.36
A
B
B A
13
(
t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.35 (t, J ¼ 7.1 Hz, POCH CH ); C NMR
2
3
2
3
(
6
151 MHz, CDCl ) d [ppm]: 77.50 (s, COCH ), 61.74 (d, J ¼ 6.5 Hz, POC),
3
3
1.57 (d, J ¼ 6.5 Hz, POC), 56.91 (s, PCC), 45.05 (d, J ¼ 7.4 Hz, PCCC), 28.41
(d, J ¼ 139.1 Hz, PC), 16.41 (d, J ¼ 6.0 Hz, POCC), 16.39 (d, J ¼ 6.1 Hz, POCC
31
P NMR (243MHz, CDCl3); d [ppm]: 28.64. Anal. Calcd. for C H NO P: C,
8
20
4
42.66; H, 8.95; N, 6.22; Found: C, 42.58; H, 8.89; N, 6.19.
4
.5. Synthesis of diethyl 3-amino-1-methoxypropylphosphonate 4k
4
.5.1. Diethyl 3-[N-(benzyloxycarbonyl)amino]-1-methoxypropylphosphonate 18
A suspension of diethyl 3-[N-(benzyloxycarbonyl)amino]-1-hydroxypropyl-
phosphonate 17 (0.402 g, 1.64 mmol), methyl iodide (0.204 mL, 3.28 mmol)
and silver(I) oxide (0.457 g, 1.97 mmol) in CH Cl (10 mL) was vigorously
2
2
stirred at room temperature for 7 days. Then the reaction mixture was filtered

1
2
A. HARTWICH ET AL.
through a layer of Celite, concentrated and the crude product was purified on
a silica gel column with a chloroform–methanol (100:1, v/v) mixture to give a
diethyl 3-[N-(benzyloxycarbonyl)amino]-1-methoxypropylphosphonate 18 as
–1
a colorless oil (0.366 g, 91%). IR (film, cm ) vmax: 3031, 2981, 2930, 1701,
1
1
268, 1222, 1029, 966, 762; H NMR (600 MHz, CDCl ) d [ppm]: 7.45–7.31
3
(
m, 5 H, Ar–H), 5.18 (brs, 1 H, NH), 5.13 (s, 2 H, CH Ph), 4.36–4.04 (m, 4 H,
2
2
ꢁ POCH CH ), 3.55 (s, 3 H, OCH ), 3.54–3.46 (m, 2 H, PCCH ), 3.39–3.33
2
3
3
2
(
m, 1 H, PCH), 2.09–1.85 (m, 2 H, PCCH ), 1.36 (t, J ¼ 7.0 Hz, 3 H,
2
13
POCH CH ), 1.35 (t, J ¼ 7.0 Hz, 3 H, POCH CH ); C NMR (151 MHz,
2
3
2
3
CDCl ) d [ppm]: 156.41, 136.64, 128.48, 128.45, 128.06, 75.85 (d,
3
J ¼ 164.9 Hz, PC), 66.64, 62.51 (d, J ¼ 6.9 Hz, POC), 62.39 (d, J ¼ 7.2 Hz,
POC), 60.14 (d, J ¼ 3.4 Hz, PCC), 37.84, 30.46, 16.51 (d, J ¼ 5.4 Hz,
3
1
2
ꢁ POCC) P NMR (243 MHz, CDCl ) d [ppm]: 22.83. Anal. Calcd. for
3
C H NO P: C, 53.48; H, 7.29; N, 3.90; Found: C, 53.48; H, 7.37; N 4.00.
16
26
6
4
.6. Diethyl 3-amino-1-methoxypropylphosphonate 4k
A solution of diethyl 3-[N-(benzyloxycarbonyl)amino]-1-methoxypropylphosph-
onate 18 (0.535 g, 1.49 mmol) in anhydrous ethanol (10 mL) was kept under
hydrogen atmosphere over 10% Pd(OH) /C (0.015 g, 0.01 mmol) at room tem-
2
perature for 72 hours. The suspension was filtered through a pad of Celite and
washed with ethanol. After evaporation of the solvent, the residue was chromato-
graphed on a silica gel column with a chloroform–methanol (100:1, v/v) mixture
to give diethyl 3-amino-1-methoxypropylphosphonate 4k (0.285 g, 85%) as a
–1
pale yellow oil. IR (film, cm ) vmax: 3334, 2988, 2933, 1277, 1220, 1030, 966, 766;
1
H NMR (600 MHz, DMSO-d ) d [ppm]: 7.75 (brs, 2 H, NH ), 4.14–4.03 (m,
6
2
4
H, 2ꢁ POCH CH ), 3.76–3.72 (m, 1 H, PCH), 3.45 (s, 3 H, OCH ), 2.98–2.89
2
3
3
(
m, 2 H, PCCCH ), 2.03–1.83 (m, 2 H, PCH ), 1.28 (t, J¼ 7.0Hz, 3H,
2
2
13
POCH CH ), 1.27 (d, J¼ 7.0Hz, 3H, POCH CH ); C NMR (151 MHz,
2
3
2
3
DMSO-d ) d [ppm]: 74.13 (d, J¼ 163.8 Hz, PC), 62.40 (d, J¼ 6.6 Hz, POC),
6
6
2.37 (d, J¼ 6.6 Hz, POC), 59.75 (d, J¼ 3.3 Hz, PCOC), 36.11 (d, J¼ 14.4 Hz,
31
PCCC), 28.24 (d, J¼ 3.0 Hz, PCC), 16.84 (d, J¼ 5.2 Hz, 2 ꢁ POCC) P NMR
(243 MHz, DMSO-d ) d [ppm]: 22.33; Anal. Calcd. for C H NO Pꢁ 0.3H O:
6
8
20
4
2
C, 41.66; H, 9.00; N, 6.07; Found: C, 41.56; H, 8.90; N, 6.20.
4
.7. Synthesis of diethyl [(3-nitropyridin-2-yl)amino]alkylphosphonates
a–l – general procedure
5
Solution of diethyl x-aminoalkylphosphonate 4a–l (1.00 mmol) in THF or
dichloromethane (2 mL) was added to a mixture of 2-chloro-3-nitropyri-
dine (1.00 mmol) and triethylamine (1.50 mmol) in appropriate solvent the
THF or CH Cl (1 mL). The reaction mixture was stirred at room
2
2

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
13
temperature for 24 hours, concentrated and the crude product was purified
on a silica gel column with a chloroform–methanol (100:1, v/v) mixture to
give the pure compounds 5a–l.
4
.8. Diethyl [(3-nitropyridin-2-yl)amino]methylphosphonate 5a
According to the general procedure from diethyl aminomethylphosphonate
a (0.281 g, 1.68mmol) and 2-chloro-3-nitropyridine (0.266g, 1.68mmol)
diethyl [(3-nitropyridin-2-yl)amino]methylphosphonate 5a (0.379, 78%) was
4
–1
obtained as a yellow oil. IR (film, cm ) vmax: 3387, 3085, 2985, 2932, 1504,
1
1316, 761; H NMR (600 MHz, CDCl ) d [ppm]: 8.47–8.46 (m, 2 H, Ar–H),
3
8
.35 (brs, 1 H, NH), 6.75 (dd, J ¼ 8.1 Hz, J ¼ 4.6 Hz, 1 H, Ar–H), 4.27–4.12
13
(
m, 6 H, 2 ꢁ POCH CH , CH ), 1.35 (t, J ¼ 7.0 Hz, 6 H, 2 ꢁ POCH CH ); C
2
3
2
2
3
NMR (151 MHz, CDCl ) d [ppm]: 155.18, 151.87 (d, J ¼ 5.7 Hz, Ar–C),
3
1
35.25, 128.87, 112.65, 62.53 (d, J ¼ 6.5 Hz, 2 ꢁ POC), 36.36 (d, J ¼ 156.0 Hz,
31
PC), 16.32 (d, J ¼ 5.8 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
2
2.48; Anal. Calcd. for C H N O P ꢁ 0.25H O: C, 40.89; H, 5.66; N, 14.31;
10
16
3
5
2
Found: C, 40.85; H, 5.42; N, 14.14.
4
.9. Diethyl 2-[(3-nitropyridin-2-yl)amino]ethylphosphonate 5b
According to the general procedure from diethyl 2-aminoethylphosphonate
b (1.000 g, 5.52 mmol) and 2-chloro-3-nitropyridine (0.875 g, 5.52 mmol)
diethyl 2-[(3-nitropyridin-2-yl)amino]ethylphosphonate 5b (1.323 g, 79%)
4
–1
was obtained as a yellow oil. IR (film, cm ) vmax: 3392, 2984, 2932, 1572,
1
1
1
391, 1247, 1035, 961, 762; H NMR (600 MHz, CDCl ) d [ppm]: 8.49 (brs,
3
H, NH), 8.45–8.43 (m, 2 H, Ar–H), 6.69 (dd, J ¼ 8.0 Hz, J ¼ 4.7 Hz, 1 H,
Ar–H), 4.33–4.06 (m, 4 H, 2 ꢁ POCH CH ), 3.97 (ddd, J ¼ 17.0 Hz,
2
3
J ¼ 12.7 Hz, J ¼ 6.9 Hz, 2 H, PCCH ), 2.21 (dt, J ¼ 17.9 Hz, J ¼ 6.9 Hz, 2 H,
2
1
3
PCH ), 1.37 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR (151 MHz,
2
2
3
CDCl ) d [ppm]: 155.48, 152.22, 135.23, 128.40, 111.95, 61.84 (d,
3
J ¼ 6.5 Hz, 2 ꢁ POC), 35.51 (d, J ¼ 4.4 Hz, PCC), 25.96 (d, J ¼ 139.9 Hz, PC),
3
1
1
2
6.41 (d, J ¼ 5.9 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
9.12; Anal. Calcd. for C H N O P ꢁ 0.3H O: C, 42.80; H, 6.07; N, 13.61;
1
1
18
3
5
2
Found: C, 42.78; H, 6.09; N, 13.61.
4
.10. Diethyl 3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5c
According to the general procedure from diethyl 3-aminopropylphospho-
nate 4c (0.496 g, 2.54 mmol) and 2-chloro-3-nitropyridine (0.403 g,
2
.54 mmol) diethyl 3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5c
–
1
(
0.629 g, 78%) was obtained as a yellow oil. IR (film, cm ) vmax: 3395,
1
3085, 2983, 2936, 1572, 1391, 1247, 1031, 962, 762; H NMR (600 MHz,

1
4
A. HARTWICH ET AL.
CDCl ) d [ppm]: 8.37 (dd, J ¼ 4.9 Hz, J ¼ 1.8 Hz, 1 H, Ar–H), 8.34 (s, 1 H,
3
Ar–H), 8.25 (brs, 1 H, NH), 6.60 (dd, J ¼ 7.9 Hz, J ¼ 5.0 Hz, 1 H, Ar–H),
4
.23–3.89 (m, 4 H, 2 ꢁ POCH CH ), 3.68 (dd, J ¼ 12.8 Hz, J ¼ 6.8 Hz, 2 H,
2
3
PCCCH ), 2.08–1.54 (m, 4 H, PCH CH ), 1.27 (t, J ¼ 7.1 Hz, 6 H,
2
2
2
1
3
2
1
ꢁ POCH CH ) C NMR (151 MHz, CDCl ) d [ppm]: 155.64, 152.67,
2
3
3
35.25, 128.17, 111.81, 61.61 (d, J ¼ 6.5 Hz, 2 ꢁ POC), 41.28 (d, J ¼ 17.3 Hz,
PCCC), 23.25 (d, J ¼ 142.7 Hz, PC), 22.66 (d, J ¼ 4.8 Hz, PCC), 16.44 (d,
3
1
J ¼ 5.9 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]: 32.16. Anal.
3
Calcd. for C H N O P: C, 45.43; H, 6.35; N, 13.24; Found: C, 45.52; H,
1
2
20 3 5
6.07; N, 13.30.
4
.11. Diethyl 4-[(3-nitropyridin-2-yl)amino]butylphosphonate 5d
According to the general procedure from diethyl 4-aminobutylphosphonate
d (0.493 g, 2.36 mmol) and 2-chloro-3-nitropyridine (0.374 g, 2.36 mmol)
diethyl 3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5d (0.632 g, 81%)
4
–1
was obtained as a yellow oil. IR (film, cm ) vmax: 3395, 2982, 2938, 1573,
1
1
2
4
391, 1245, 1027, 761; H NMR (600 MHz, CDCl ) d [ppm]: 8.53–8.33 (m,
3
H, Ar–H), 8.25 (brs, 1 H, NH) , 6.68–6.60 (m, 1 H, Ar–H), 4.30–3.93 (m,
H, 2 ꢁ POCH CH ), 3.65–3.20 (m, 2 H, PCCCCH ), 1.88–1.38 (m, 6 H,
2
3
2
1
3
PCH CH CH ), 1.31 (t, J ¼ 6.9 Hz, 6 H, 2 ꢁ POCH CH );
C NMR
2
2
2
2
3
(
(
2
151 MHz, CDCl ) d [ppm]: 155.67, 152.67, 135.20, 128.00, 111.59, 61.49
3
d, J ¼ 6.6 Hz, 2 ꢁ POC), 40.54 (s, PCCCC), 30.21 (d, J ¼ 15.8 Hz, PCCC),
5.35 (d, J ¼ 141.4 Hz, PC), 20.02 (d, J ¼ 5.2 Hz, PCC), 16.40 (t, J ¼ 5.9 Hz,
31
2
ꢁ POCC) P NMR (243 MHz, CDCl ) d [ppm]: 32.53. Anal. Calcd. for
3
C H N O P ꢁ 0.25H O: C, 47.13; H, 6.69; N, 12.68; Found: C, 46.99; H,
13
22
3
5
2
6
.59; N, 12.63.
4
.12. Diethyl {2-[(3-nitropyridin-2-yl)amino]ethoxy}methylphosphonate 5e
According to the general procedure from diethyl (2-aminoethoxy)methyl-
phosphonate 4e (0.608 g, 2.88 mmol) and 2-chloro-3-nitropyridine (0.457 g,
2
.88 mmol) diethyl 2-[(3-nitropyridin-2-yl)amino]ethoxy}methylphospho-
–1
nate 5e (0.748 g, 78%) was obtained as a yellow oil. IR (film, cm ) vmax:
1
3397, 3085, 2984, 2933, 1573, 1391, 1246, 1027, 969; H NMR (600 MHz,
CDCl ) d [ppm]: 8.43 (dd, J ¼ 8.3 Hz, J ¼ 1.7 Hz, 1 H, Ar–H), 8.41 (dd,
3
J ¼ 4.5 Hz, J ¼ 1.7 Hz, 1 H, Ar–H), 6.67 (dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H,
Ar–H), 4.23–4.16 (m, 4 H, 2 ꢁ POCH CH ), 3.92–3.89 (m, 2 H, PCOCH ),
2
3
2
3
.87 (d, J ¼ 8.3 Hz, 2 H, PCH ), 3.86–3.84 (m, 2 H, PCOCCH ), 1.36 (t,
2
2
13
J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ) C NMR (151 MHz, CDCl ) d [ppm]:
2
3
3
1
55.41, 152.49, 135.28, 128.37, 111.81, 71.73 (d, J ¼ 10.4 Hz, PCOC), 65.33
(
d, J ¼ 166.2 Hz, PC), 62.49 (d, J ¼ 6.5 Hz, 2 ꢁ POC), 40.70 (s, PCOCC),

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
15
3
1
1
2
6.45 (d, J ¼ 5.6 Hz, 2 ꢁ POCC) P NMR (243 MHz, CDCl ) d [ppm]:
3
0.74; Anal. Calcd. for C H N O P: C, 43.25; H, 6.05; N, 12.61; Found:
1
2
20 3 6
C, 43.24; H, 6.07; N, 12.61.
4
.13. Diethyl 2-{2-[(3-nitropyridin-2-yl)amino]ethoxy}ethylphosphonate 5f
According to the general procedure from diethyl 2-(2-aminoethoxy)ethyl-
phosphonate 4f (0.849 g, 3.77 mmol) and 2-chloro-3-nitropyridine (0.598 g,
3
.77 mmol) diethyl 2-[(3-nitropyridin-2-yl)amino]ethoxy}methylphospho-
–1
nate 5f (1.191 g, 91%) was obtained as a yellow oil. IR (film, cm ) vmax:
1
3396, 2984, 2932, 1572, 1390, 1245, 1027, 969, 761; H NMR (600 MHz,
CDCl ) d [ppm]: 8.58–8.29 (m, 3 H, NH, 2 ꢁ Ar–H), 6.65 (dd, J ¼ 8.3 Hz,
3
J ¼ 4.5 Hz, 1 H, Ar–H), 4.21–4.02 (m, 4 H, 2 ꢁ POCH CH ), 3.85 (dd,
2
3
J ¼ 10.8 Hz, J ¼ 5.4 Hz, 2 H, PCCOCH ), 3.77 (dt, J ¼ 11.5 Hz, J ¼ 7.5 Hz,
2
1
H, PCCH ), 3.70 (t, J ¼ 5.4 Hz, 2 H, PCCOCCH ), 2.14 (dt, J ¼ 18.7 Hz,
2
2
13
J ¼ 7.5 Hz, 2 H, PCH ), 1.32 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ) C NMR
2
2
3
(
151 MHz, CDCl ) d [ppm]: 155.53, 152.57, 135.28, 128.30, 111.76, 69.13 (s,
3
PCCOC), 65.08 (s, PCC), 61.68 (d, J ¼ 6.4 Hz, 2 ꢁ POC), 40.88 (s,
3
1
PCCOCC), 26.99 (d, J ¼ 139.7 Hz, PC), 16.39 (d, J ¼ 6.0 Hz, 2 ꢁ POCC);
NMR (243 MHz, CDCl ) [ppm]: 29.11. Anal. Calcd. for
P
d
3
C H N O P ꢁ 0.4H O: C, 44.04; H, 6.48; N, 11.85; Found: C, 44.10; H,
13
22
3
6
2
6.43; N, 11.84.
4
.14. Diethyl 1-hydroxy-2-[(3-nitropyridin-2-yl)amino]ethylphosphonate 5g
According to the general procedure from diethyl 2-amino-1-hydroxyethyl-
phosphonate 4g (0.576 g, 2.92 mmol) and 2-chloro-3-nitropyridine (0.463 g,
2
.92 mmol) diethyl 1-hydroxy-2-[(3-nitropyridin-2-yl)amino]ethylphospho-
ꢀ
nate 5g (0.522 g, 56%) was obtained as a yellow solid. M.p. 97–98 C; IR
–1
(
KBr, cm ) vmax: 3385, 3227, 3089, 2984, 1571, 1390, 1349, 1032, 977, 757;
H NMR (600 MHz, CDCl ) d [ppm]: 8.57 (brs, 1 H, NH), 8.46 (dd,
1
3
J ¼ 8.3 Hz, J ¼ 1.8 Hz, 1 H, Ar–H), 8.37 (dd, J ¼ 4.6 Hz, J ¼ 1.8 Hz, 1 H,
Ar–H), 6.73 (dd, J ¼ 8.3, J ¼ 4.6 Hz, 1 H, Ar–H), 4.31–4.13 (m, 6 H, PCH ,
2
2
ꢁ POCH CH ), 4.12–3.85 (m, 1 H, PCH), 1.37 (t, J ¼ 7.0 Hz, 3 H,
2
3
13
POCH CH ), 1.30 (t, J ¼ 7.0 Hz, 3 H, POCH CH ). C NMR (151 MHz,
2
3
2
3
CDCl ) d [ppm]: 154.88, 152.84, 135.74, 128.88, 112.37, 68.13 (d,
3
J ¼ 161.9 Hz, PC), 62.94 (d, J ¼ 6.6 Hz, POC), 62.90 (d, J ¼ 6.6 Hz, POC),
4
3.49 (d, J ¼ 4.6 Hz, PCC), 16.48 (d, J ¼ 5.4 Hz, POCC), 16.44 (d, J ¼ 5.4 Hz,
31
POCC); P NMR (81 MHz, CDCl ) d [ppm]: 23.06; Anal. Calcd. for
3
C H N O P: C, 41.38; H, 5.68; N, 13.16; Found: C, 41.64; H, 5.70;
11
18 3 6
N, 13.18.

1
6
A. HARTWICH ET AL.
4
.15. Diethyl 1-hydroxy-3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5h
According to the general procedure from diethyl 3-amino-1-hydroxypropyl-
phosphonate 4h (0.653 g, 3.09 mmol) and 2-chloro-3-nitropyridine (0.490 g,
3
.09 mmol) diethyl 1-hydroxy-3-[(3-nitropyridin-2-yl)amino]propylphospho-
–1
nate 5h (0.907 g, 88%) was obtained as a yellow oil. IR (film, cm ) vmax:
1
3395, 3310, 3082, 2986, 1249, 1037, 967, 759; H NMR (600 MHz, CDCl ) d
3
[
ppm]: 8.49 (s, 1 H, NH), 8.48 (dd, J ¼ 8.3 Hz, J ¼ 1.7 Hz, 1 H, Ar–H), 8.40
(
dd, J ¼ 4.6 Hz, J ¼ 1.7 Hz, 1 H, Ar–H), 6.71 (dd, J ¼ 8.3 Hz, J ¼ 4.6 Hz, 1 H,
Ar–H), 4.23–4.19 (m, 4 H, 2 ꢁ POCH CH ), 4.11–4.05 (m, 1 H, PCCCH),
2
3
3
.97 (ddd, J ¼ 11.4 Hz, J ¼ 8.6 Hz, J ¼ 2.9 Hz, 1 H, PCH), 3.78–3.72 (m, 1 H,
PCCCH), 1.37 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.35 (t, J ¼ 7.1 Hz, 3 H,
2
3
13
POCH CH ); C NMR (151MHz, CDCl ) d [ppm]: 155.05, 152.81, 135.98,
2
3
3
1
28.58, 111.88, 65.19 (d, J ¼ 167.7Hz, PC), 62.74 (d, J ¼ 7.1 Hz, POC), 62.63
(
d, J ¼ 7.1 Hz, POC), 37.74 (d, J ¼ 15.8 Hz, PCCC), 31.68 (s, PCC), 16.50 (d,
31
J ¼ 5.5 Hz, POCC), 16.49 (d, J ¼ 5.5 Hz, POCC); P NMR (243 MHz, CDCl )
3
d [ppm]: 24.56; Anal. Calcd. for C H N O P ꢁ 0.3H O: C, 42.56; H, 6.13;
12
20
3
6
2
N, 12.41; Found: C, 42.40; H, 6.09; N, 12.47.
4
.16. Diethyl 2-hydroxy-3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5i
According to the general procedure from diethyl 3-amino-2-hydroxypropyl-
phosphonate 4i (0.234 g, 1.11mmol) and 2-chloro-3-nitropyridine (0.166 g,
1
.05 mmol) diethyl 2-hydroxy-3-[(3-nitropyridin-2-yl)amino]propylphospho-
–1
nate 5i (0.292 g, 79%) was obtained as a yellow oil. IR (film, cm ) vmax:
1
3373, 3274, 2982, 2930, 1225, 1027, 964, 762; H NMR (600 MHz, CDCl ) d
3
[
ppm]: 8.53 (s, 1 H, NH), 8.46 (dd, J ¼ 8.3 Hz, J ¼ 1.6 Hz, 1 H, Ar–H), 8.39
(
dd, J ¼ 4.4 Hz, J ¼ 1.4 Hz, 1 H, Ar–H), 6.70 (dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H,
Ar–H), 4.39 (d, J ¼ 3.3 Hz, 1 H, OH), 4.36–4.28 (m, 1 H, PCCH), 4.24–4.11
(
m, 4 H, 2 ꢁ POCH CH ), 4.02–3.72 (m, 2 H, PCCCH ), 2.07 (dd,
2
3
2
J ¼ 17.9 Hz, J ¼ 6.4 Hz, 2 H, PCH ), 1.37 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH );
2
2
3
1
3
C NMR (151 MHz, CDCl ) d [ppm]: 155.17, 152.94, 135.57, 128.62, 112.15,
3
6
6.31 (d, J ¼ 3.5 Hz, PCC), 62.05 (d, J ¼ 6.4 Hz, POC), 62.00 (d, J ¼ 6.6 Hz,
POC), 47.35 (d, J ¼ 15.9 Hz, PCCC), 31.39 (d, J ¼ 139.0 Hz, PC), 16.42 (d,
31
J ¼ 5.9 Hz, POCC), 16.38 (d, J ¼ 5.9 Hz, POCC); P NMR (243 MHz, CDCl )
3
d [ppm]: 29.04; Anal. Calcd. for C H N O P: C, 43.25; H, 6.05; N, 12.61;
12 20 3 6
Found: C, 43.21; H, 6.07; N, 12.70.
4
.17. Diethyl 1-methoxy-2-[(3-nitropyridin-2-yl)amino]ethylphosphonate 5j
According to the general procedure from diethyl 2-amino-1-methoxyethyl-
phosphonate 4j (0.200 g, 0.95 mmol) and 2-chloro-3-nitropyridine (0.151 g,
0.95 mmol) diethyl 1-methoxy-2-[(3-nitropyridin-2-yl)amino]ethylphosphonate

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
17
–
1
5
3
j (0.234 g, 74%) was obtained as a yellow oil. IR (film, cm ) vmax: 2294,
1
085, 2984, 2934, 1573, 1392, 1251, 1024, 966, 761; H NMR (600 MHz,
CDCl ) d [ppm]: 8.55 (brs, 1 H, NH), 8.46 (dd, J ¼ 8.3 Hz, J ¼ 1.6 Hz, 1 H,
3
Ar–H), 8.44 (dd, J ¼ 4.5 Hz, J ¼ 1.6 Hz, 1 H, Ar–H), 6.70 (dd, J ¼ 8.3 Hz,
J ¼ 4.5 Hz, 1 H, Ar–H), 4.32–4.20 (m, 5 H, 2 ꢁ POCH CH , PCH),
2
3
3
.90–3.77 (m, 2 H, PCCH ), 3.62 (s, 3 H, CH ), 1.40 (t, J ¼ 7.1 Hz, 3 H,
2
3
13
POCH CH ), 1.38 (t, J ¼ 7.1 Hz, 3 H, POCH CH ); C NMR (151 MHz,
2
3
2
3
CDCl ) d [ppm]: 155.16, 152.22, 135.46, 128.60, 111.96, 76.09 (d,
3
J ¼ 164.1 Hz, PC), 62.90 (d, J ¼ 7.1 Hz, POC), 62.59 (d, J ¼ 7.1 Hz, POC),
6
0.49 (d, J ¼ 5.0 Hz, PCOC), 40.99 (d, J ¼ 5.4 Hz, PCC), 16.53 (d, J ¼ 5.5 Hz,
31
POCC), 16.49 (d, J ¼ 5.6 Hz, POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
20.82; Anal. Calcd. for C H N O P: C, 43.25; H, 6.05; N, 12.61; Found:
12 20 3 6
C, 43.19; H, 5.83; N, 12.43.
4
.18. Diethyl 1-methoxy-3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5k
According to the general procedure from diethyl 3-amino-1-methoxypropyl-
phosphonate 4k (0.300 g, 1.33mmol) and 2-chloro-3-nitropyridine (0.211g,
1
.33 mmol) diethyl 1-methoxy-3-[(3-nitropyridin-2-yl)amino]propylphospho-
–1
nate 5k (0.180g, 39%) was obtained as a yellow oil. IR (film, cm ) vmax:
1
3395, 3086, 2984, 2933, 1573, 1392, 1251, 1024, 965, 761; H NMR
(
600 MHz, CDCl ) d [ppm]: 8.49 (brs, 1 H, NH), 8.45 (dd, J ¼ 4.7 Hz,
3
J ¼ 1.7 Hz, 1 H, Ar–H), 8.44 (s, 1 H, Ar–H), 6.67 (dd, J ¼ 7.8 Hz, J ¼ 5.0 Hz,
H, Ar–H), 4.27–4.17 (m, 4 H, 2 ꢁ POCH CH ), 3.97–3.77 (m, 2 H,
1
2
3
PCCCH ), 3.65–3.60 (m, 4 H, CH , PCH), 2.28–2.04 (m, 2 H, PCCH ), 1.39
2
3
2
13
(
t, J ¼ 7.2 Hz, 3 H, POCH CH ), 1.36 (t, J ¼ 7.2 Hz, 3 H, POCH CH );
C
2
3
2
3
NMR (151 MHz, CDCl ) d [ppm]: 155.67, 152.63, 135.26, 128.18, 111.66,
3
7
6.33 (d, J ¼ 164.9Hz, PC), 62.58 (d, J ¼ 6.9 Hz, POC), 62.34 (d, J ¼ 7.2 Hz,
POC), 60.31 (d, J ¼ 2.5 Hz, PCOC), 38.46 (d, J ¼ 14.5 Hz, PCCC), 29.89 (d,
J ¼ 2.6 Hz, PCC), 16.55 (d, J ¼ 5.4 Hz, POCC), 16.53 (d, J ¼ 5.4 Hz, POCC);
31
P NMR (243 MHz, CDCl ) d [ppm]: 22.64. Anal. Calcd. for C H N O P:
3
13 22 3 6
C, 44.96; H, 6.38; N, 12.10; Found: C, 44.95; H, 6.41; N, 12.03.
4
.19. Diethyl 2-methoxy-3-[(3-nitropyridin-2-yl)amino]propylphosphonate 5l
According to the general procedure from diethyl 3-amino-2-methoxypro-
pylphosphonate 4l (0.250 g, 1.11 mmol) and 2-chloro-3-nitropyridine
(
0.166 g, 1.05 mmol)diethyl 2-methoxy-3-[(3-nitropyridin-2-yl)amino]pro-
pylphosphonate 5l (0.332 g, 86%) was obtained as a yellow oil. IR (film,
–1
1
cm ) v : 3395, 3085, 2984, 2933, 1572, 1392, 1249, 1024, 965, 761; H
max
NMR (600 MHz, CDCl ) d [ppm]: 8.47 (brs, 1 H, NH), 8.45 (dd, J ¼ 8.3 Hz,
3
J ¼ 1.8 Hz, 1 H, Ar–H), 8.42 (dd, J ¼ 4.5 Hz, J ¼ 1.7 Hz, 1 H, Ar–H), 6.68

1
8
A. HARTWICH ET AL.
(
dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H, Ar–H), 4.20–4.07 (m, 5 H, 2 ꢁ POCH CH ,
2
3
PCCH), 3.93–3.75 (m, 2 H, PCCCH ), 3.49 (s, 3 H, CH ), 2.19 (ddd,
2
3
J ¼ 19.3 Hz, J ¼ 15.4 Hz, J ¼ 6.0 Hz, 1 H, PCH ), 2.05 (ddd, J ¼ 18.3 Hz,
b
J ¼ 15.4 Hz, J ¼ 6.6 Hz, 1 H, PCH ), 1.37 (t, J ¼ 7.1 Hz, 3 H, POCH CH ),
a
2
3
1
3
1
[
.35 (t, J ¼ 7.1 Hz, 3 H, POCH CH ); C NMR (151 MHz, CDCl ) d
2
3
3
ppm]: 155.54, 135.28, 128.52, 127.03, 111.89, 75.05 (s, PCC) 61.89 (d,
J ¼ 6.4 Hz, POC), 61.63 (d, J ¼ 6.3 Hz, POC), 43.96 (d, J ¼ 9.1 Hz, PCCC),
2
9.29 (d, J ¼ 140.0 Hz, PC), 16.38 (d, J ¼ 6.2 Hz, POCC), 16.36 (d,
31
J ¼ 6.1 Hz, POCC); P NMR (243 MHz, CDCl3) d [ppm]: 27.87; Anal.
Calcd. for C H N O P: C, 44.96; H, 6.38; N, 12.10; Found: C, 44.62; H,
1
3
22 3 6
6.16; N, 12.08.
4
.20. Synthesis of diethyl [(3-aminopyridin-2-ylo)amino]alkylphosphonates
a–l – general procedure
6
Solution of diethyl (3-nitropyridin-2-ylo)aminoalkylphosphonate 5a–l
1.00 mmol) in 95% acetic acid (0.240 mL) was added to mixture tin(II)
(
chloride (3.30 mmol) in 36% hydrochloric acid (0.640 mL). The reaction
mixture was stirred at room temperature for 1.5 hours. Then the reaction
was neutralized with 20% NaOH and concentrated in vacuo. The residue
was dissolved in chloroform, dried over anhydrous MgSO and filtered.
4
The solution was concentrated and the residue was chromatographed on a
silica gel column with a chloroform–methanol (100:1, v/v) mixture to give
diethyl [(3-aminopyridin-2-ylo)amino]alkylphosphonates 6a–l.
4
.21. Diethyl [(3-aminopyridin-2-yl)amino]methylphosphonate 6a
According to the general procedure from diethyl [(3-nitropyridin-2-yl)ami-
no]methylphosphonate 5a (0.784 g, 2.71 mmol) in 95% acetic acid
(
0.650 ml) and tin(II) chloride (1.670 g, 8.81 mmol) in 36% hydrochloric
acid (1.710 ml) diethyl [(3-aminopyridin-2-yl)amino]methylphosphonate 6a
–
1
(
0.485 g, 69%) was obtained as a pale red oil. IR (film, cm ) vmax: 3368,
1
3
7
1
265, 2983, 2931, 1504, 1302, 785; H NMR (200 MHz, CDCl ) d [ppm]:
3
.72 (dd, J ¼ 5.0 Hz, J ¼ 1.5 Hz, 1 H, Ar–H) , 6.86 (dd, J ¼ 7.4 Hz, J ¼ 1.5 Hz,
H, Ar–H), 6.57 (dd, J ¼ 7.4 Hz, J ¼ 5.0 Hz, 1 H, Ar–H), 4.48 (brs, 1 H,
NH), 4.32–4.03 (m, 4 H, 2 ꢁ POCH CH ), 3.93 (dd, J ¼ 11.8 Hz, J ¼ 5.9 Hz,
2
3
2
H, PCH ), 3.35 (brs, 2 H, NH ), 1.30 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH );
2
2
2
3
1
3
3
C NMR (151 MHz, CDCl ) d [ppm]: 148.73 (d, J ¼ 8.7 Hz, Ar–C),
3
1
38.20, 129.20, 121.85, 114.37, 62.43 (d, J ¼ 6.6 Hz, 2 ꢁ POC), 36.89 (d,
3
1
J ¼ 156.3 Hz, PC), 16.35 (d, J ¼ 5.9 Hz, 2 ꢁ POCC); P NMR (81 MHz,
CDCl ) d [ppm]: 26.56; Anal. Calcd. for C H N O P ꢁ 0.25H O: C, 45.54;
3
10 18
3
3
2
H, 7.07; N, 15.93; Found: C, 45.74; H, 7.18; N, 15.77.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
19
4
.22. Diethyl 2-[(3-aminopyridin-2-yl)amino]ethylphosphonate 6b
According to the general procedure from diethyl 2-[(3-nitropyridin-2-yl)a-
mino]ethylphosphonate 5b (0.218 g, 0.72 mmol) in 95% acetic acid
(
0.173 ml) and tin(II) chloride (0.444 g, 2.34 mmol) in 36% hydrochloric
acid (0.454 ml) diethyl 2-[(3-aminopyridin-2-yl)amino]ethylphosphonate 6b
–
1
(
3
0.194 g, 99%) was obtained as a pale red oil. IR (film, cm ) vmax: 3372,
1
263, 2983, 2929, 1642, 1229, 987, 785; H NMR (600 MHz, CDCl ) d
3
[
ppm]: 7.72 (dd, J ¼ 5.1 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 6.84 (dd, J ¼ 7.4 Hz,
J ¼ 1.5 Hz, 1 H, Ar–H), 6.53 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz, 1 H, Ar–H), 5.00
brs, 1 H, NH), 4.20–4.06 (m, 4 H, 2 ꢁ POCH CH ), 3.79 (dt, J ¼ 20.4 Hz,
(
2
3
J ¼ 6.5 Hz, 2 H, PCCH ), 3.11 (brs, 2 H, NH ), 2.18 (dt, J ¼ 17.4 Hz,
2
2
1
3
J ¼ 6.5 Hz, 2 H, PCH ), 1.34 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR
2
2
3
(
(
151 MHz, CDCl ) d [ppm]: 149.41, 138.31, 128.97, 121.52, 113.54, 61.75
3
d, J ¼ 6.5 Hz, 2 ꢁ POC), 35.71 (d, J ¼ 5.4 Hz, PCC), 25.66 (d, J ¼ 139.0 Hz,
3
1
PC), 16.39 (d, J ¼ 6.0 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d
3
[
ppm]: 30.95; Anal. Calcd. for C H N O P ꢁ 0.6H O: C, 46.51; H, 7.52;
1
1
20
3
3
2
N, N. 14.79; Found: C, 46.50; H, 7.52; N, 14.48.
4
.23. Diethyl 3-[(3-aminopyridin-2-yl)amino]propylphosphonate 6c
According to the general procedure from diethyl 3-[(3-nitropyridin-2-yl)a-
mino]propylphosphonate 5c (0.393 g, 1.24 mmol) in 95% acetic acid
(
0.298 ml) and tin(II) chloride (0.764 g, 4.03 mmol) in 36% hydrochloric
acid (0.782 ml) diethyl 3-[(3-aminopyridin-2-yl)amino]propylphosphonate
–
1
6
3
c (0.114 g, 32%) was obtained as a pale red oil. IR (film, cm ) vmax: 3376,
1
262, 3048, 2982, 2937, 1254, 1026, 965; H NMR (600 MHz, CDCl ) d
3
[
ppm]: 7.72 (dd, J ¼ 5.1 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 6.83 (dd, J ¼ 7.4 Hz,
J ¼ 1.5 Hz, 1 H, Ar–H), 6.51 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz, 1 H, Ar–H), 4.79
brs, 1 H, NH), 4.29–3.96 (m, 4 H, 2 ꢁ POCH CH ), 3.56 (dd, J ¼ 10.7 Hz,
(
2
3
J ¼ 6.6 Hz, 1 H, PCCCH ), 3.40 (brs, 2 H, NH ), 2.04–1.98 (m, 2 H,
2
2
PCCH ), 1.93–1.88 (m, 2 H, PCH ), 1.33 (t, J ¼ 7.1 Hz, 6 H,
2
2
1
3
2
1
ꢁ POCH CH ).; C NMR (151 MHz, CDCl ) d [ppm]: 149.87, 138.52,
2
3
3
28.57, 121.23, 113.08, 61.66 (d, J ¼ 6.6 Hz, 2 ꢁ POC), 41.98 (d, J ¼ 13.7 Hz,
PCCC), 23.64 (d, J ¼ 141.5 Hz, PC), 22.43 (d, J ¼ 4.9 Hz, PCC), 16.42 (d,
3
1
J ¼ 6.0 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]: 32.86; Anal.
3
Calcd. for C H N O P ꢁ 0.5H O: C, 48.64; H, 7.82; N, 14.18; Found: C,
1
2
22
3
3
2
4
8.87; H, 7.82; N, 14.04.
4
.24. Diethyl 4-[(3-aminopyridin-2-yl)amino]butylphosphonate 6d
According to the general procedure from diethyl 4-[(3-nitropyridin-2-yl)a-
mino]butylphosphonate 5d (0.666 g, 2.01 mmol) in 95% acetic acid

2
0
A. HARTWICH ET AL.
(
0.160 ml) and tin(II) chloride (1.236 g, 6.52 mmol) in 36% hydrochloric
acid (1.26 ml) diethyl 4-[(3-aminopyridin-2-yl)amino]butylphosphonate 6d
–
1
(
0.279 g, 46%) was obtained as a pale red oil. IR (film, cm ) vmax: 3377,
1
3
7
1
4
(
2
1
262, 2983, 1254, 1027, 966, 784; H NMR (600 MHz, CDCl ) d [ppm]:
3
.73 (dd, J ¼ 5.1 Hz, J ¼ 1.2 Hz, 1 H, Ar–H), 6.83 (dd, J ¼ 7.3 Hz, J ¼ 1.2 Hz,
H, Ar–H), 6.50 (dd, J ¼ 7.3 Hz, J ¼ 5.1 Hz, 1 H, Ar–H), 4.40 (s, 1 H, NH),
.25–3.95 (m, 4 H, 2 ꢁ POCH CH ), 3.48–3.45 (m, 2 H, PCCCCH ), 3.32
2
3
2
brs, 2 H, NH ), 1.87–1.72 (m, 6 H, PCH CH CH ), 1.32 (t, J ¼ 7.1 Hz, 6 H,
2
2
2
2
1
3
ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.21, 138.74,
2
3
3
28.43, 121.48, 113.03, 61.51 (d, J ¼ 6.6 Hz, 2 ꢁ POC), 41.12, 30.30 (d,
J ¼ 15.0 Hz, PCCC), 25.25 (d, J ¼ 140.5 Hz, PC), 20.18 (d, J ¼ 5.0 Hz, PCC),
3
1
1
3
6.42 (d, J ¼ 5.9 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
3.19; Anal. Calcd. for C H N O P ꢁ H O: C, 48.89; H, 8.21; N, 13.16;
1
3
24
3
3
2
Found: C, 48.88; H, 8.36; N, 13.05.
4
.25. Diethyl {2-[(3-aminopyridin-2-yl)amino]ethoxy}methylphosphonate 6e
According to the general procedure from diethyl {2-[(3-nitropyridin-2-yl)a-
mino]ethoxy}methylphosphonate 5e (0.380 g, 1.14 mmol) in 95% acetic acid
(
0.274 ml) and tin(II) chloride (0.702 g, 3.70 mmol) in 36% hydrochloric
acid (0.717 ml) diethyl {2-[(3-aminopyridin-2-yl)amino]ethoxy}methyl-
phosphonate 6e (0.270 g, 78%) was obtained as a pale red oil. IR (film,
–1
1
cm ) v : 3373, 3267, 2982, 2929, 2907, 1226, 1027, 992, 962; H NMR
max
(
600 MHz, CDCl ) d [ppm]: 7.70 (dd, J ¼ 5.1 Hz, J ¼ 1.5 Hz, 1 H, Ar–H),
3
6
1
3
.82 (dd, J ¼ 7.4 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 6.51 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz,
H, Ar–H), 4.96 (brs, 1 H, NH), 4.27–4.10 (m, 4 H, 2 ꢁ POCH CH ),
2
3
.90–3.86 (m, 2 H, PCOCH ), 3.87 (d, J ¼ 7.8 Hz, 2 H, PCH ), 3.69 (dd,
2
2
J ¼ 10.0 Hz, J ¼ 5.1 Hz, 2 H, PCOCCH ), 3.49 (brs, 2 H, NH ), 1.35 (t,
2
2
1
3
J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]:
2
3
3
1
(
1
2
49.55, 138.19, 128.93, 121.04, 113.28, 72.83 (d, J ¼ 9.1 Hz, PCOC), 65.30
d, J ¼ 166.6 Hz, PC), 62.50 (d, J ¼ 6.6 Hz, 2 ꢁ POC), 41.24 (s, PCOCC),
3
1
6.44 (d, J ¼ 5.6 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
1.72; Anal. Calcd. for C H N O P ꢁ 0.2H O: C, 46.96; H, 7.36; N, 13.69;
1
2
22
3
4
2
Found: C, 46.95; H, 7.23; N, 13.58.
4
.26. Diethyl 2-{2-[(3-aminopyridin-2-yl)amino]ethoxy}ethylphosphonate 6f
According to the general procedure from diethyl 2-{2-[(3-nitropyridin-2-
yl)amino]ethoxy}ethylphosphonate 5f (0.493 g, 1.42 mmol) in 95% acetic
acid (0.341 ml) and tin(II) chloride (0.876 g, 4.62 mmol) in 36% hydro-
chloric acid (0.896 ml) diethyl 2-{2-[(3-aminopyridin-2-yl)amino]ethoxy}e-
thylphosphonate 6f (0.428 g, 95%)was obtained as a pale red oil. IR (film,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
21
–1
1
cm ) v : 3375, 3263, 2983, 2927, 1225, 1027, 994, 785; H NMR
max
(
6
1
600 MHz, CDCl ) d [ppm]: 7.66 (dd, J ¼ 5.1 Hz, J ¼ 1.5 Hz, 1 H, Ar–H),
3
.77 (dd, J ¼ 7.4 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 6.48 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz,
H, Ar–H), 4.17–4.04 (m, 4 H, 2 ꢁ POCH CH ), 3.80 (dt, J ¼ 19.5 Hz,
2
3
J ¼ 6.4 Hz, 2 H, PCCH ), 3.77–3.74 (m, 2 H, PCCOCH ), 3.69–3.66 (m, 2 H,
2
2
PCCOCCH ), 2.12 (dt, J ¼ 17.9 Hz, J ¼ 6.4 Hz, 2 H, PCH ), 1.33 (t,
2
2
1
3
J ¼ 7.1 Hz, 3 H, 2 ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]:
2
3
3
1
6
49.18, 137.34, 129.34, 120.22, 112.99, 69.64, 64.30 (d, J ¼ 5.6 Hz, PCC),
1.78 (d, J ¼ 6.5 Hz, 2 ꢁ POC), 41.20, 26.75 (d, J ¼ 141.8 Hz, PC), 16.36 (d,
3
1
J ¼ 6.1 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]: 29.41; Anal.
3
Calcd. for C H N O P ꢁ 0.8H O: C, 47.07; H, 7.78; N, 12.67; Found: C,
1
3
24
3
4
2
4
7.05; H, 7.78; N, 12.65.
4
.27. Diethyl 2-[(3-aminopyridin-2-yl)amino]-1-hydroxyethylphosphonate 6g
According to the general procedure from diethyl 1-hydroxy-2-[(3-nitropyri-
din-2-yl)amino]ethylphosphonate 5g (0.488 g, 1.53 mmol) in 95% acetic acid
(
(
0.367 ml) and tin(II) chloride (0.946 g, 4.99 mmol) in 36% hydrochloric acid
0.968 ml) diethyl 2-[(3-aminopyridin-2-yl)amino]-1-hydroxyethylphospho-
–1
nate 6g (0.243 g, 55%) was obtained as a pale red oil. IR (film, cm ) vmax:
3
1
373, 3265, 3059, 2983, 2930, 1230, 1024, 970, 787; H NMR (600 MHz,
CDCl ) d [ppm]: 7.50 (d, J ¼ 5.4 Hz, 1 H, Ar–H), 6.85 (dd, J ¼ 7.5 Hz,
3
J ¼ 1.4 Hz, 1 H, Ar–H), 6.55 (dd, J ¼ 7.5 Hz, J ¼ 5.4 Hz, 1 H, Ar–H), 5.90 (brs,
1
H, NH), 4.36–4.01 (m, 6 H, PCCH , 2 ꢁ POCH CH ), 3.92–3.71 (m, 3 H,
2
2
3
PCH, NH ) , 1.35 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.23 (t, J ¼ 7.1 Hz, 3 H,
2
2
3
1
3
POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 149.29, 135.30, 129.73,
2
3
3
1
21.71, 114.05, 70.10 (d, J ¼ 162.1 Hz, PC), 63.07 (d, J ¼ 7.3 Hz, POC), 62.47
(
1
d, J ¼ 7.0 Hz, POC), 45.60 (d, J ¼ 2.8 Hz, PCC), 16.44 (d, J ¼ 5.8 Hz, POCC),
3
1
6.32 (d, J ¼ 5.8 Hz, POCC); P NMR (243 MHz, CDCl ) d [ppm]: 23.06;
3
Anal. Calcd. for C H N O P ꢁ 0.7H O: C, 43.77; H, 7.15; N, 13.92; Found:
1
1
20
3
4
2
C, 43.88; H, 7.28; N, 13.65.
4
.28. Diethyl 3-[(3-aminopyridin-2-yl)amino]-1-hydroxypropylphosphonate 6h
According to the general procedure from diethyl 1-hydroxy-3-[(3-nitropyri-
din-2-yl)amino]propylphosphonate 5h (0.307 g, 0.92 mmol) in 95% acetic
acid (0.360 ml) and tin(II) chloride (0.569 g, 3.00 mmol) in 36% hydro-
chloric acid (0.583 ml) diethyl 3-[(3-aminopyridin-2-yl)amino]-1-hydroxy-
propylphosphonate 6h (0.103 g, 37%) was obtained as a pale red oil. IR
–
1
1
(
(
6
film, cm ) v : 3385, 2981, 2926, 1217, 1024, 964, 763; H NMR
max
600 MHz, CDCl ) d [ppm]: 7.60 (dd, J ¼ 5.3 Hz, J ¼ 1.4 Hz, 1 H, Ar–H),
3
.86 (dd, J ¼ 7.4 Hz, J ¼ 1.4 Hz, 1 H, Ar–H), 6.51 (dd, J ¼ 7.4 Hz, J ¼ 5.3 Hz,

2
2
A. HARTWICH ET AL.
1
4
H, Ar–H), 5.10 (brs, 1 H, OH), 4.25–4.14 (m, 5 H, 2 ꢁ POCH CH , PCH),
2
3
.01–3.88 (m, 2 H, PCCCH ) 3.47 (brs, 1 H, NH), 2.10–1.90 (m, 2 H,
2
PCCH ), 1.36 (t, J ¼ 5.9 Hz, 3 H, POCH CH ), 1.34 (t, J ¼ 5.8 Hz, 3 H,
2
2
3
1
3
POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.65, 137.29, 128.48,
2
3
3
1
22.20, 113.16, 64.01 (d, J ¼ 170.6 Hz, PC), 62.60 (d, J ¼ 7.1 Hz, POC), 62.51
(
(
d, J ¼ 6.7 Hz, POC), 37.38 (d, J ¼ 16.1 Hz, PCCC), 33.30, 16.51
3
1
d, J ¼ 5.6 Hz, POCC), 16.47 (d, J ¼ 5.5 Hz, POCC); P NMR (243 MHz,
CDCl ) d [ppm]: 26.28; Anal. Calcd. for C H N O P ꢁ 0.1H O: C, 47.24;
3
12 22
3
4
2
H, 7.33; N, 13.77; Found: C, 47.54; H, 7.43; N, 13.71.
4
.29. Diethyl 3-[(3-aminopyridin-2-yl)amino]-2-hydroxypropylphosphonate 6i
According to the general procedure from diethyl 2-hydroxy-3-[(3-nitropyri-
din-2-yl)amino]propylphosphonate 5i (0.106 g, 0.35 mmol) in 95% acetic
acid (0.087 ml) and tin(II) chloride (0.216 g, 1.14 mmol) in 36% hydro-
chloric acid (0.221 ml) diethyl 3-[(3-aminopyridin-2-yl)amino]-2-hydroxy-
propylphosphonate 6i (0.093 g, 96%) was obtained as a pale red oil. IR
–1
1
(
film, cm ) v : 3374, 3263, 2983, 1224, 1027, 966, 759; H NMR
max
(
6
1
600 MHz, CDCl ) d [ppm]: 7.64 (dd, J ¼ 5.1 Hz, J ¼ 1.1 Hz, 1 H, Ar–H),
3
.88 (dd, J ¼ 7.4 Hz, J ¼ 1.1 Hz, 1 H, Ar–H), 6.55 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz,
H, Ar–H), 6.38 (brs, 1 H, NH), 5.01 (brs, 1 H, OH), 4.28–4.21 (m, 1 H,
PCCH), 4.21–4.08 (m, 4 H, 2 ꢁ POCH CH ), 3.83 (ddd, J ¼ 14.3 Hz,
2
3
J ¼ 5.7 Hz, J ¼ 2.0 Hz, 1 H, PCCCH ), 3.61 (dt, J ¼ 14.3 Hz, J ¼ 5.7 Hz,
a
J ¼ 5.7 Hz, 1 H, PCCCH ), 3.33 (brs, 2 H, NH ), 2.11 (ddd, J ¼ 18.0 Hz,
b
2
J ¼ 6.7 Hz, J ¼ 2.4 Hz, 2 H, PCH ), 1.37 (t, J ¼ 6.9 Hz, 3 H, POCH CH ),
2
2
3
1
3
1
[
.36 (t, J ¼ 6.9 Hz, 3 H, POCH CH ); C NMR (151 MHz, CDCl ) d
2
3
3
ppm]: 150.02, 137.36, 128.92, 121.76, 113.66, 67.43, 61.86 (d, J ¼ 6.5 Hz,
POC), 61.83 (d, J ¼ 6.4 Hz, POC), 48.58 (d, J ¼ 10.0 Hz, PCCC), 31.34
3
1
(
d, J ¼ 136.1 Hz, PC), 16.37 (d, J ¼ 6.1 Hz, 2 ꢁ POCC); P NMR (243 MHz,
CDCl ) d [ppm]: 29.31; Anal. Calcd. for C H N O P: C, 47.52; H, 7.31;
3
12 22 3 4
N, 13.85; Found: C, 47.54; H, 7.56; N, 13.74.
4
.30. Diethyl 2-[(3-aminopyridin-2-yl)amino]-1-methoxyethylphosphonate 6j
According to the general procedure from diethyl 1-methoxy-2-[(3-nitropyr-
idin-2-yl)amino]ethylphosphonate 5j (0.197 g, 0.59 mmol) in 95% acetic
acid (0.216 ml) and tin(II) chloride (0.366 g, 1.93 mmol) in 36% hydro-
chloric acid (0.374 ml) diethyl 2-[(3-aminopyridin-2-yl)amino]-1-methoxye-
thylphosphonate 6j (0.140 g, 78%) was obtained as a pale red oil. IR (film,
–1
1
cm ) v : 3382, 3263, 2983, 2933, 1233, 1024, 968; H NMR (600 MHz,
max
CDCl ) d [ppm]: 7.69 (d, J ¼ 4.7 Hz, 1 H, Ar–H), 6.88 (dd, J ¼ 7.4 Hz,
3
J ¼ 1.3 Hz, 1 H, Ar–H), 6.57 (dd, J ¼ 7.4 Hz, J ¼ 4.7 Hz, 1 H, Ar–H), 5.28

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
23
(
brs, 1 H, NH), 4.28–4.17 (m, 4 H, 2 ꢁ POCH CH ), 4.09–4.00 (m, 1 H,
2
3
PCH), 3.88–3.78 (m, 2 H, PCCH ), 1.83 (brs, 2 H, NH ), 1.39 (t, J ¼ 7.1 Hz,
2
2
1
3
3
H, POCH CH ), 1.36 (t, J ¼ 7.1 Hz, 3 H, POCH CH );
C NMR
2
3
2
3
(
(
6
151 MHz, CDCl ) d [ppm]: 149.02, 144.42, 129.59, 121.57, 113.69, 76.10
d, J ¼ 163.3 Hz, PC), 62.85 (d, J ¼ 7.0 Hz, POC), 62.60 (d, J ¼ 6.9 Hz, POC),
3
0.07 (d, J ¼ 6.7 Hz, PCC), 41.36, 16.50 (d, J ¼ 6.2 Hz, POCC), 16.46 (d,
3
1
J ¼ 6.3 Hz, POCC); P NMR (243 MHz, CDCl ) d [ppm]: 22.10; Anal.
3
Calcd. for C H N O P ꢁ 0.6H O: C, 45.89; H, 7.44; N, 13.38; Found: C,
1
2
22
3
4
2
4
5.85; H, 7.45; N, 13.32.
4
.31. Diethyl 3-[(3-aminopyridin-2-yl)amino]-1-methoxypropylphosphonate 6k
According to the general procedure from diethyl 1-methoxy-3-[(3-nitropyr-
idin-2-yl)amino]propylphosphonate 5k (0.146 g, 0.42 mmol) in 95% acetic
acid (0.100 ml) and tin(II) chloride (0.258 g, 1.36 mmol) in 36% hydro-
chloric acid (0.264 ml) diethyl 3-[(3-aminopyridin-2-yl)amino]-1-methoxy-
propylphosphonate 6k (0.084 g, 63%) was obtained as a pale red oil. IR
–1
1
(
film, cm ) v : 3378, 3264, 3049, 2984, 1232, 1023, 969, 786; H NMR
max
(
600 MHz, CDCl ) d [ppm]: 7.74 (dd, J ¼ 5.1 Hz, J ¼ 1.5 Hz, 1 H, Ar–H),
3
6
1
3
1
.84 (dd, J ¼ 7.4 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 6.52 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz,
H, Ar–H), 4.79 (s, 1 H, NH), 4.24–4.16 (m, 4 H, 2 ꢁ POCH CH ),
2
3
.77–3.57 (m, 2 H, PCCCH ), 3.67 (ddd, J ¼ 8.3 Hz, J ¼ 6.7 Hz, J ¼ 4.3 Hz,
2
H, PCH), 3.58 (s, 3 H, CH ), 3.32 (brs, 2 H, NH ), 2.29–2.03 (m, 2 H,
3
2
PCCH ), 1.37 (t, J ¼ 7.0 Hz, 3 H, POCH CH ), 1.35 (t, J ¼ 7.0 Hz, 3 H,
2
2
3
1
3
POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.00, 138.73, 128.54,
2
3
3
1
(
21.35, 113.11, 76.54 (d, J ¼ 137.9 Hz, PC), 62.55 (d, J ¼ 7.0 Hz, POC), 62.43
d, J ¼ 7.0 Hz, POC), 60.06 (d, J ¼ 4.7 Hz, PCC), 38.66 (d, J ¼ 12.3 Hz,
PCCC), 29.91, 16.52 (d, J ¼ 5.2 Hz, POCC), 16.49 (d, J ¼ 5.1 Hz, POCC);
31
P NMR (243 MHz, CDCl ) d [ppm]: 23.63; Anal. Calcd. for
3
C H N O P ꢁ 0.6H O: C, 47.58; H, 7.74; N, 12.81; Found: C, 47.67; H,
13
24
3
4
2
7.68; N, 12.93.
4
.32. Diethyl 3-[(3-aminopyridin-2-yl)amino]-2-methoxypropylphosphonate 6l
According to the general procedure from diethyl 2-methoxy-3-[(3-nitropyr-
idin-2-yl)amino]propylphosphonate 5l (0.263 g, 0.83 mmol) in 95% acetic
acid (0.199 ml) and tin(II) chloride (0.514 g, 2.71 mmol) in 36% hydro-
chloric acid (0.526 ml) diethyl 3-[(3-aminopyridin-2-yl)amino]-2-methoxy-
propylphosphonate 6l (0.163 g, 68%) was obtained as a pale red oil.
–1
IR (film, cm ) vmax: 3373, 3274, 2982, 2930, 1225, 1027, 964, 762;
1
H NMR (600 MHz, CDCl ) d [ppm]: 7.71 (d, J ¼ 5.1 Hz, 1 H, Ar–H), 6.84
3
(
dd, J ¼ 7.4 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 6.53 (dd, J ¼ 7.4 Hz, J ¼ 5.1 Hz,

2
4
A. HARTWICH ET AL.
1
3
H, Ar–H), 4.86 (s, 1 H, NH), 4.20–4.07 (m, 4 H, 2 ꢁ POCH CH ),
2
3
.95–3.86 (m, 1 H, PCCH), 3.76–3.66 (m, 2 H, PCCCH ), 3.47 (s, 3 H,
2
CH ), 2.24–2.10 (m, 2 H, PCH ), 1.36 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.33
3
2
2
3
1
3
(
1
t, J ¼ 7.1 Hz, 3 H, POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]:
2
3
3
49.65, 138.31, 128.88, 121.28, 113.46, 75.09 (d, J ¼ 1.5 Hz, PCC), 61.79 (d,
J ¼ 6.4 Hz, POC), 61.76 (d, J ¼ 6.3 Hz, POC), 57.00, 44.52 (d, J ¼ 8.5 Hz,
PCCC), 29.95 (d, J ¼ 139.6 Hz, PC), 16.37 (d, J ¼ 6.1 Hz, POC), 16.36
3
1
(
d, J ¼ 6.1 Hz, POC); P NMR (243 MHz, CDCl ) d [ppm]: 29.16; Anal.
3
Calcd. for C H N O P ꢁ 0.4H O: C, 48.11; H, 7.70; N, 12.95; Found: C,
1
3
24
3
4
2
4
8.19; H, 7.68; N, 12.92.
4
.33. Synthesis of diethyl (1,2,3-triazolo[4,5-b]pyridin-3-yl)alkylphosphonate
a–i – general procedure
7
A solution of diethyl [(3-aminopyridin-2-yl)amino]alkylphosphonate 6a–i
ꢀ
(
1.00 mmol) in 98% H SO (4.40 mL) was cooled to the 0 C and a solution
2
4
of sodium nitrite (2.00 mmol) in water (7.50 mL) was added dropwise. The
reaction mixture was stirred for 1 hour. Then the reaction was neutralized
with 20% NaOH and concentrated in vacuo. The residue was dissolved
in chloroform, dried over MgSO4 and filtered. The solution was
concentrated and chromatographed on a silica gel column with a chloro-
form–methanol (100:1, v/v) mixture to give (1,2,3-triazolo[4,5-b]pyridin-
3-yl)alkylphosphonate 7a–i.
4
.34. Diethyl (1,2,3-triazolo[4,5-b]pyridin-3-yl)methylphosphonate 7a
According to the general procedure from diethyl [(3-aminopyridin-2-yl)a-
mino]methylphosphonate 6a (0.179 g, 0.69 mmol) in 98% H SO (3 mL)
2
4
and solution of sodium nitrite (0.095 g, 1.38 mmol) in water (5.50 mL) the
phosphonate 7a (0.127 g, 68%) was obtained as a pale orange amorphous
ꢀ
ꢀ
1
–1
solid. M.p. 83.5 C–84.5 C; IR (KBr, cm ) vmax: 3066, 2989, 2961, 2920,
1
591, 1241, 969, 706; H NMR (600 MHz, CDCl ) d [ppm]: 8.73 (d,
3
J ¼ 4.5 Hz, 1 H, Ar–H), 8.41 (d, J ¼ 8.3 Hz, 1 H, Ar–H), 7.40 (dd, J ¼ 8.3 Hz,
J ¼ 4.5 Hz, 1 H, Ar–H), 5.18 (d, J ¼ 12.2 Hz, 2 H, PCH ), 4.23–4.04 (m, 4 H,
2
1
3
2
(
ꢁ POCH CH ), 1.29 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR
2
3
2
3
151 MHz, CDCl ) d [ppm]: 150.57, 145.81, 136.61, 128.71, 119.98, 63.33
3
(
2
d, J ¼ 6.3 Hz, 2 ꢁ POC), 42.01 (d, J ¼ 155.8 Hz, PC), 16.23 (d, J ¼ 6.0 Hz,
3
1
ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]: 15.95; Anal. Calcd. for
3
C H N O P ꢁ 0.5 H O: C, 43.01; H, 5.78; N, 20.06; Found: C, 43.43; H,
10
15
4
3
2
5
.62; N, 20.06.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
25
4
.35. Diethyl 2-(1,2,3-triazolo[4,5-b]pyridin-3-yl)ethylphosphonate 7b
According to the general procedure from diethyl 2-[(3-aminopyridin-2-yl)a-
mino]ethylphosphonate 6b (0.049 g, 0.18 mmol) in 98% H SO (0.80 ml)
2
4
and solution of sodium nitrite (0.025 g, 0.37 mmol) in water (1.50 mL) the
phosphonate 7b (0.049 g, 96%) was obtained as a pale yellow oil. IR (film,
–1
1
cm ) v : 3474, 3062, 2985, 2930, 1739, 1257, 1054, 1025, 778; H NMR
max
(
600 MHz, CDCl ) d [ppm]: d ¼ 8.64 (dd, J ¼ 4.5 Hz, J ¼ 1.5 Hz, 1 H,
3
Ar–H), 8.33 (dd, J ¼ 8.3 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 7.32 (dd, J ¼ 8.3 Hz,
J ¼ 4.5 Hz, 1 H, Ar–H), 5.06–4.85 (m, 2 H, PCCH ), 4.10–3.98 (m, 4 H,
2
2
2
1
ꢁ POCH CH ), 2.68–2.45 (m, 2 H, PCH ), 1.24 (t, J ¼ 7.1 Hz, 6 H,
2
3
2
13
ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.24, 145.68,
2
3
3
37.06, 128.58, 119.85, 62.05 (d, J ¼ 6.5 Hz, POC), 41.40 (s, PCC), 26.28 (d,
3
1
J ¼ 141.0 Hz, PC), 16.32 (d, J ¼ 5.9 Hz, POCC); P NMR (243 MHz,
CDCl ) d [ppm]: 26.48; Anal. Calcd. for C H N O P ꢁ 0.2H O: C, 45.90;
3
11 17
4
3
2
H, 6.09; N, 19.46; Found: C, 45.76; H, 5.89; N, 19.21.
4
.36. Diethyl 3-(1,2,3-triazolo[4,5-b]pyridin-3-yl)propylphosphonate 7c
According to the general procedure from diethyl 3-[(3-aminopyridin-2-yl)a-
mino]propylphosphonate 6c (0.070 g, 0.24 mmol) in 98% H SO (1 ml) and
2
4
solution of sodium nitrite (0.034 g, 0.49 mmol) in water (1.90 ml) the
phosphonate 7c (0.068 g, 93%) was obtained as a pale red oil. IR (film,
–1
1
cm ) v : 3456, 3065, 2983, 1640, 1228, 964, 779; H NMR (600 MHz,
max
CDCl ) d [ppm]: 8.68 (dd, J ¼ 4.5 Hz, J ¼ 1.3 Hz, 1 H, Ar–H), 8.39 (dd,
3
J ¼ 8.3 Hz, J ¼ 1.3 Hz, 1 H, Ar–H), 7.37 (dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H,
Ar–H), 4.84 (t, J ¼ 6.9 Hz, 2 H, PCCCH ), 4.29–3.88 (m, 4 H,
2
2
1
ꢁ POCH CH ), 2.60–2.29 (m, 2 H, PCCH ), 1.97–1.73 (m, 2 H, PCH ),
2
3
2
2
13
.31 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d
2
3
3
[
2
(
ppm]: 150.24, 145.85, 136.95, 128.59, 119.81, 61.72 (d, J ¼ 6.5 Hz,
ꢁ POC), 46.94 (d, J ¼ 18.0 Hz, PCCC), 23.20 (d, J ¼ 143.3 Hz, PC), 23.03
3
1
d, J ¼ 4.6 Hz, PCC), 16.39 (d, J ¼ 5.9 Hz, 2 ꢁ POCC); P NMR (243 MHz,
CDCl ) d [ppm]: 30.11; Anal. Calcd. for C H N O P ꢁ 0.6H O: C, 46.63;
3
12 19
4
3
2
H, 6.59; N, 18.13; Found: C, 46.71; H, 6.53; N, 17.98.
4
.37. Diethyl 4-(1,2,3-triazolo[4,5-b]pyridin-3-yl)butylphosphonate 7d
According to the general procedure from diethyl 4-[(3-aminopyridin-2-yl)a-
mino]butylphosphonate 6d (0.078 g, 0.26 mmol) in 98% H SO (1.20 ml)
2
4
and solution of sodium nitrite (0.035 g, 0.51 mmol) in water (1.95 ml) the
phosphonate 7d (0.078 g, 96%) was obtained as a pale yellow oil. IR (film,
–1
1
cm ) v : 3066, 2983, 2940, 1227, 1025, 964, 779; H NMR (600 MHz,
max
CDCl ) d [ppm]: 8.69 (dd, J ¼ 4.4 Hz, J ¼ 1.0 Hz, 1 H, Ar–H), 8.40 (dd,
3

2
6
A. HARTWICH ET AL.
J ¼ 8.3 Hz, J ¼ 1.1 Hz, 1 H, Ar–H), 7.38 (dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H,
Ar–H), 4.79 (t, J ¼ 7.0 Hz, 2 H, PCCCCH ), 4.21–3.96 (m, 4 H,
2
2
ꢁ POCH CH ), 2.22 (qv, 2 H, J ¼ 7.0 Hz, PCCCH ), 1.87–1.79 (m, 2 H,
2
3
2
PCCH ), 1.75–1.66 (m, 2 H, PCH ), 1.31 (t, J ¼ 7.1 Hz, 6 H,
2
2
1
3
2
1
ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.12, 145.84,
2
3
3
36.95, 128.58, 119.73, 61.53 (d, J ¼ 6.5 Hz, 2 ꢁ POC), 46.20, 30.12 (d,
J ¼ 15.9 Hz, PCCC), 25.03 (d, J ¼ 141.8 Hz, PC), 19.79 (d, J ¼ 5.0 Hz, PCC),
3
1
1
3
6.40 (d, J ¼ 5.9 Hz, 2 ꢁ POCC); P NMR (243 MHz, CDCl ) d [ppm]:
3
1.06; Anal. Calcd. for C H N O P ꢁ H O: C, 47.27; H, 7.02; N, 16.96;
1
3
21
4
3
2
Found: C, 47.21; H, 7.05; N, 16.87.
4
.38. Diethyl {2-(1,2,3-triazolo[4,5-b]pyridin-3-yl)ethoxy}methylphosphonate 7e
According to the general procedure from diethyl {2-[(3-aminopyridin-2-
yl)amino]ethoxy}methylphosphonate 6e (0.079 g, 0.26 mmol) in 98% H SO
2
4
(
(
1.20 ml) and solution of sodium nitrite (0.033 g, 0.51 mmol) in water
2 ml) the phosphonate 7e (0.067 g, 82%) was obtained as a pale orange oil.
–1
1
IR (film, cm ) v : 3067, 2985, 2932, 1223, 973, 779; H NMR (200 MHz,
max
CDCl ) d [ppm]: 8.67 (dd, J ¼ 4.5 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 8.38
3
(
dd, J ¼ 8.3 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 7.36 (dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H,
Ar–H), 4.95 (t, J ¼ 5.6 Hz, 2 H, PCOCH ), 4.22 (t, J ¼ 5.6 Hz, 2 H,
2
PCOCCH ), 4.11–3.90 (m, 4 H, 2 ꢁ POCH CH ), 3.79 (d, J ¼ 8.3 Hz, 2 H,
2
2
3
1
3
PCH ), 1.21 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR (151 MHz,
2
2
3
CDCl )
d
[ppm]: 150.21, 146.14, 136.92, 128.57, 119.78, 70.50
3
(
2
d, J ¼ 10.6 Hz, PCOC), 65.18 (d, J ¼ 165.7 Hz, PC), 62.45 (d, J ¼ 6.5 Hz,
3
1
ꢁ POC), 46.28, 16.33 (d, J ¼ 5.7 Hz, 2 ꢁ POCC); P NMR (81 MHz,
CDCl ) d [ppm]: 20.12; Anal. Calcd. for C H N O P ꢁ 0.3 H O: C, 45.08;
3
12 19
4
4
2
H, 6.18; N, 17.53; Found: C, 45.10; H, 6.16; N, 17.21.
4
.39. Diethyl 2-{2-(1,2,3-triazolo[4,5-b]pyridin-3-yl)ethoxy}ethylphosphonate 7f
According to the general procedure from diethyl 2-{2-[(3-aminopyridin-2-
yl)amino]ethoxy}ethylphosphonate 6f (0.097 g, 0.32 mmol) in 98% H SO
2
4
(
(
1.40 ml) and solution of sodium nitrite (0.043 g, 0.63 mmol) in water
2.40 ml) the phosphonate 7f (0.083 g, 80%) was obtained as a pale yellow
–1
1
oil. IR (film, cm ) v : 3455, 3065, 2982, 2927, 1250, 1025, 991, 778; H
max
NMR (200 MHz, CDCl ) d [ppm]: 8.62 (dd, J ¼ 4.5 Hz, J ¼ 1.5 Hz, 1 H,
3
Ar–H), 8.33 (dd, J ¼ 8.3 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 7.40 (dd, J ¼ 8.3 Hz,
J ¼ 4.5 Hz, 1 H, Ar–H), 4.87 (t, J ¼ 5.7 Hz, 2 H, PCCOCH ), 4.03–3.90 (m,
2
6
H, 2 ꢁ POCH CH , PCCOCCH ), 3.64 (dt, J ¼ 11.2 Hz, J ¼ 7.3 Hz, 2 H,
2
3
2
PCCH ), 1.93 (dt, J ¼ 18.7 Hz, J ¼ 7.3 Hz, 2 H, PCH ), 1.21 (t, J ¼ 7.1 Hz,
2
2
1
3
6
H, 2 ꢁ POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.17,
2
3
3

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
27
1
46.13, 136.91, 128.54, 119.73, 68.24, 65.04, 61.59 (d, J ¼ 6.3 Hz, 2 ꢁ POC),
31
4
6.48, 26.82 (d, J¼ 139.6 Hz, PC), 16.34 (d, J¼ 6.0 Hz, 2 ꢁ POCC); P NMR
(81 MHz, CDCl ) d [ppm]: 28.87; Anal. Calcd. for C H N O Pꢁ 0.5H O:
3
13 21
4
4
2
C, 46.29; H, 6.57; N, 12.61; Found: C, 46.30; H, 6.45; N, 12.65.
4
.40. Diethyl 1-hydroxy-2-(1,2,3-triazolo[4,5-b]pyridin-3-
yl)ethylphosphonate 7g
According to the general procedure from diethyl [(3-aminopyridin-2-yl)a-
mino]-1-hydroxyethylphosphonate 6g (0.052 g, 0.18 mmol) in 98% H SO
2
4
(
(
0.8 ml) and solution of sodium nitrite (0.024 g, 0.35 mmol) in water
1.4 ml) the phosphonate 7g (0.025 g, 47%) was obtained as a pale yellow
–1
oil. IR (film, cm ) vmax: 3283, 3058, 3001, 2985, 1253, 1018, 965, 779;
1
H NMR (600 MHz, CDCl ) d [ppm]: 8.69 (dd, J ¼ 4.5 Hz, J ¼ 1.4 Hz, 1 H,
3
Ar–H), 8.44 (dd, J ¼ 8.3 Hz, J ¼ 1.4 Hz, 1 H, Ar–H), 7.41 (dd, J ¼ 8.3 Hz,
J ¼ 4.5 Hz, 1 H, Ar–H), 5.18 (ddd, J ¼ 14.6 Hz, J ¼ 9.0 Hz, J ¼ 2.8 Hz, 1 H,
PCH), 5.13–5.07 (m, 2 H, PCCH ), 4.66 (brs, 1 H, OH), 4.27–4.17 (m, 4 H,
2
2
3
1
ꢁ POCH CH ), 1.36 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.33 (t, J ¼ 7.1 Hz,
2
3
2
3
13
H, POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 149.97, 146.10,
2
3
3
37.24, 129.19, 119.93, 67.21 (d, J ¼ 165.2 Hz, PC), 63.26 (d, J ¼ 7.0 Hz,
POC), 63.16 (d, J ¼ 7.0 Hz, POC), 50.21 (d, J ¼ 7.2 Hz, PCC), 16.45
P
3
1
(
d, J ¼ 5.6 Hz, POCC), 16.40 (d, J ¼ 5.6 Hz, POCC); P NMR (243 MHz,
CDCl ) d [ppm]: 19.94; Anal. Calcd. for C H N O P: C, 44.00; H, 5.51;
3
11 17 4 4
N, 18.66; Found: C, 44.09; H, 5.49; N, 18.45.
4
.41. Diethyl 1-hydroxy-3-(1,2,3-triazolo[4,5-b]pyridin-3-
yl)propylphosphonate 7h
According to the general procedure from diethyl 3-[(3-aminopyridin-2-yl)
amino]-1-hydroxypropylphosphonate 6h (0.045 g, 0.15 mmol) in 98%
H SO (0.7 ml) and solution of sodium nitrite (0.020 g, 0.15 mmol) in water
2
4
(
0.6 ml) the phosphonate 7h (0.030 g, 64%) was obtained as a white
ꢀ
ꢀ
–1
powder. M.p. 65 C–66 C; IR (KBr, cm ) vmax: 3289, 3028, 2986, 1236,
1
1
021, 968, 782; H NMR (600 MHz, CDCl ) d [ppm]: 8.70 (dd, J ¼ 4.5 Hz,
3
J ¼ 1.3 Hz, 1 H, Ar–H), 8.44 (dd, J ¼ 8.3 Hz, J ¼ 1.3 Hz, 1 H, Ar–H), 7.42
dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz, 1 H, Ar–H), 5.03 (dd, J ¼ 9.6 Hz, J ¼ 5.1 Hz, 2 H,
PCCCH ), 4.29 (s, 1 H, OH), 4.24–4.16 (m, 4 H, 2 ꢁ POCH CH ), 3.81
(
2
2
3
(
ddd, J ¼ 11.9 Hz, J ¼ 9.6 Hz, J ¼ 2.9 Hz, 1 H, PCH), 2.65–2.27 (m, 2 H,
PCCH ), 1.36 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.32 (t, J ¼ 7.1 Hz, 3 H,
2
2
3
1
3
POCH CH ).; C NMR (151 MHz, CDCl ) d [ppm]: 150.19, 145.96,
2
3
3
1
37.04, 129.18, 119.95, 64.50 (d, J ¼ 168.7 Hz, PC), 62.91 (d, J ¼ 6.8 Hz,
POC), 62.74 (d, J ¼ 6.8 Hz, POC), 43.00 (d, J ¼ 15.7 Hz, PCCC),

2
8
A. HARTWICH ET AL.
3
1.68 (d, J ¼ 2.5 Hz, PCC), 16.49 (d, J ¼ 5.3 Hz, POCC), 16.46 (d, J ¼ 5.3 Hz,
31
POCC); P NMR (243 MHz, CDCl ) d [ppm]: 23.55; Anal. Calcd. for
3
C H N O P: C, 45.86; H, 6.09; N, 17.83; Found: C, 45.76; H, 6.24;
12
19 4 4
N, 17.62.
4
.42. Diethyl 2-hydroxy-3-(1,2,3-triazolo[4,5-b]pyridin-3-
yl)propylphosphonate 7i
According to the general procedure from diethyl 3-[(3-aminopyridin-2-yl)a-
mino]-2-hydroxypropylphosphonate 6i (0.148 g, 0.49 mmol) in 98% H SO
2
4
(
(
2.1 ml) and solution of sodium nitrite (0.067 g, 0.97 mmol) in water
3.7 ml) the phosphonate 7i (0.086 g, 56%) was obtained as a pale yellow
–1
1
oil. IR (film, cm ) v : 3332, 3069, 2984, 1256, 1026, 966, 778; H NMR
max
(
8
1
(
600 MHz, CDCl ) d [ppm]: 8.71 (dd, J ¼ 4.5 Hz, J ¼ 1.4 Hz, 1 H, Ar–H),
3
.42 (dd, J ¼ 8.3 Hz, J ¼ 1.4 Hz, 1 H, Ar–H), 7.40 (dd, J ¼ 8.3 Hz, J ¼ 4.5 Hz,
H, Ar–H), 4.95 (dd , J ¼ 14.1 Hz, J ¼ 4.3 Hz, 1 H, PCCCH), 4.90
ABX
ddABX, J ¼ 14.1 Hz, J ¼ 4.3 Hz, 1 H, PCCCH) 4.74–4.67 (m, 1 H, PCCH),
4
.45 (brs, 1 H, OH), 4.22–4.08 (m, 4 H, 2 ꢁ POCH CH ), 2.18–2.05 (m, 2 H,
2
3
PCH ), 1.35 (t, J ¼ 7.1 Hz, 3 H, POCH CH ), 1.34 (t, J ¼ 7.1 Hz, 3 H,
2
2
3
1
3
POCH CH ); C NMR (151 MHz, CDCl ) d [ppm]: 150.34, 146.23, 136.98,
2
3
3
1
28.91, 119.92, 65.86 (d, J ¼ 4.0 Hz, PCC), 62.23 (d, J ¼ 6.3 Hz, POC), 62.12
(
d, J ¼ 6.5 Hz, POC), 53.16 (d, J ¼ 17.5 Hz, PCCC), 31.41 (d, J ¼ 140.7 Hz,
31
PC), 16.38 (d, J ¼ 6.0 Hz, POCC), 16.37 (d, J ¼ 6.0 Hz, POCC); P NMR
243 MHz, CDCl ) d [ppm]: 28.12; Anal. Calcd. for C H N O P ꢁ 0.3H O:
(
3
12 19
4
4
2
C, 45.08; H, 6.18; N, 17.53; Found: C, 45.16; H, 6.30; N, 17.28.
4
.43. Synthesis of diethyl (imidazo[4,5-b]pyridin-3-yl)alkylophosphonate
a–i – general procedure
8
A solution of diethyl [(3-aminopyridin-2-yl)amino]alkylophosphonate
a–i (1.00 mmol), p-toluenesulphonic acid (0.50 mmol) and triethyl ortho-
6
formate (10.00 mmol) in THF (12 mL) was stirred at the room tempera-
ture for 24 hours. Then the solvent was evaporated in vacuo and the
residue was purified on a silica gel column with a chloroform–methanol
(
100:1, v/v) mixture to give diethyl (imidazo[4,5-b]pyridin-3-yl)
alkylophosphonates 8a–i.
4
.44. Diethyl (imidazo[4,5-b]pyridin-3-yl)methylphosphonates 8a
According to the general procedure from diethyl [(3-aminopyridin-2-yl)a-
mino]methylphosphonate 6a (0.161 g, 0.62 mmol), p-toluenesulphonic acid
(
0.053 g, 0.31 mmol) and triethyl orthoformate (0.739 g, 6.20 mmol) the
phosphonate 8a (0.114 g, 68%) was obtained as a pale yellow powder. M.p.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
29
ꢀ
ꢀ
–1
6
8 C–69 C; IR (KBr, cm ) vmax: 3088, 3059, 2983, 1242, 1023, 977, 776;
1
H NMR (600 MHz, CDCl ) d [ppm]: 8.43 (dd, J ¼ 4.8 Hz, J ¼ 1.3 Hz, 1 H,
3
Ar–H), 8.27 (s, 1 H, NCHN), 8.10 (dd, J ¼ 8.0 Hz, J ¼ 1.3 Hz, 1 H, Ar–H),
7
.27 (dd, J ¼ 8.0 Hz, J ¼ 4.8 Hz, 1 H, Ar–H), 4.72 (d, J ¼ 12.0 Hz, 2 H,
PCH ), 4.15–4.10 (m, 4 H, 2 ꢁ POCH CH ), 1.22 (t, J ¼ 7.1 Hz, 6 H,
2
2
3
1
3
2
ꢁ POCH CH );
C NMR (151 MHz, CDCl ) d [ppm]: 146.74 (d,
3
2
3
J ¼ 2.3 Hz, Ar–C), 144.47, 144.0, 134.75, 128.10, 118.54, 63.12 (d, J ¼ 6.6 Hz,
3
1
2
ꢁ POC), 38.29 (d, J ¼ 157.7 Hz, PC), 16.21 (d, J ¼ 5.8 Hz, 2 ꢁ POCC);
P
NMR (243 MHz, CDCl ) d [ppm]: 18.01; Anal. Calcd. for C H N O P: C,
3
11 16 3 3
49.07; H. 5.99; N. 15.61; Found: C. 48.97; H. 6.20; N. 15.77.
4
.45. Diethyl 2-(imidazo[4,5-b]pyridin-3-yl)ethylphosphonate 8b
According to the general procedure from diethyl 2-[(3-aminopyridin-2-yl)a-
mino]ethylphosphonate 6b (0.044 g, 0.16 mmol), p-toluenesulphonic acid
(
0.014 g, 0.08 mmol) and triethyl orthoformate (0.192 g, 1.61 mmol) the
phosphonate 8b (0.041 g, 96%) was obtained as a pale yellow oil. IR (film,
–1
1
cm ) v : 3444, 3058, 2985, 2932, 1725, 1233, 973, 777; H NMR
max
(
8
200 MHz, CDCl ) d [ppm]: 8.33 (dd, J ¼ 4.8 Hz, J ¼ 1.4 Hz, 1 H, Ar–H),
3
.04 (s, 1 H, NCHN), 8.01 (dd, J ¼ 8.1 Hz, J ¼ 1.4 Hz, 1 H, Ar–H), 7.19 (dd,
J ¼ 8.1 Hz, J ¼ 4.8 Hz, 1 H, Ar–H), 4.53 (dt, J ¼ 14.5 Hz, J ¼ 7.2 Hz, 2 H,
PCCH ), 4.04–3.88 (m, 4 H, 2 ꢁ POCH CH ), 2.42 (dt, J ¼ 18.2 Hz,
2
2
3
1
3
J ¼ 7.2 Hz, 2 H, PCH ), 1.16 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR
2
2
3
(
151 MHz, CDCl ) d [ppm]: 146.72, 144.41, 144.12, 135.18, 127.89, 118.51,
3
6
1.95 (d, J ¼ 6.5 Hz, 2 ꢁ POC), 38.59 (d, J ¼ 3.8 Hz, PCC), 26.27 (d,
31
J ¼ 140.9 Hz, PC), 16.25 (d, J ¼ 6.0 Hz, 2 ꢁ POCC).; P NMR (81 MHz,
CDCl ) d [ppm]:; Anal. Calcd. for C H N O P ꢁ 0.6H O: C. 49.01; H.
3
12 18
3
3
2
6.58; N. 14.29; Found: C. 49.02; H. 6.60; N. 14.12.
4
.46. Diethyl 3-(imidazo[4,5-b]pyridin-3-yl)propylphosphonate 8c
According to the general procedure from diethyl 3-[(3-aminopyridin-2-yl)a-
mino]propylphosphonate 6c (0.078 g, 0.27 mmol), p-toluenesulphonic acid
(
0.057 g, 0.33 mmol) and triethyl orthoformate (0.324 g, 2.72 mmol) the
phosphonate 8c (0.073 g, 93%) was obtained as a pale orange oil. IR (film,
–1
1
cm ) v : 3425, 3088, 3058, 2984, 1600, 1228, 965, 777; H NMR
max
(
600 MHz, CDCl ) d [ppm]: 8.40 (dd, J ¼ 4.8 Hz, J ¼ 1.5 Hz, 1 H, Ar–H),
3
8
.12 (s, 1 H, NCHN), 8.08 (dd, J ¼ 8.0 Hz, J ¼ 1.5 Hz, 1 H, Ar–H), 7.25 (dd,
J ¼ 8.0 Hz, J ¼ 4.8 Hz, 1 H, Ar–H), 4.44 (t, J ¼ 7.0 Hz, 2 H, PCCCH ),
2
4
.17–4.04 (m, 4 H, 2 ꢁ POCH CH ), 2.35–2.24 (m, 2 H, PCCH ), 1.81–1.70
2
3
2
13
(
m, 2 H, PCH ), 1.32 (t, J ¼ 7.1 Hz, 6 H, 2 ꢁ POCH CH ); C NMR
2
2
3
(151 MHz, CDCl ) d [ppm]: d ¼ 147.00, 144.27, 144.07, 135.52, 127.99,
3