Synthesis and antimicrobial activity of novel 1,2,3-triazole-conjugates of quinazolin-4-ones

Article abstract of DOI:10.1002/ardp.201800302

A novel series of diethyl{4-[(4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates 9aa–aj and their respective derivatives substituted at C6 of the quinazolinone moiety with a bromine atom (9ba–bj) or a nitro group (9ca–cj) were synthesized and assessed for the antibacterial activity toward selected Gram-positive and Gram-negative bacteria. Their antifungal activity was also screened. Compound 9ac was found to be the most active against Staphylococcus aureus ATCC 6535 (MIC 0.625 mg/mL, MBC 1.25 mg/mL), phosphonates 9ab–ai showed promising activity against Enterococcus faecalis ATCC 29212 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL), while compounds 9ac–j appeared the most active toward Pseudomonas aeruginosa ATCC 27853 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL). Antifungal assays of compounds 9aa–aj, 9ba–bj, and 9ca–cj were conducted on Candida albicans ATCC 10231 and Aspergillus brasiliensis ATCC 16404 and revealed noticeable activity of 9aa–aj (MIC = 1.25 mg/mL).

Full text of DOI:10.1002/ardp.201800302

Received: 12 October 2018
Revised: 22 November 2018
Accepted: 27 November 2018
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DOI: 10.1002/ardp.201800302
FULL PAPER
Synthesis and antimicrobial activity of novel
1,2,3-triazole-conjugates of quinazolin-4-ones
Iwona E. Głowacka1
Łukasz Kalinowski2
Piotr Grzonkowski1
Dorota G. Piotrowska1
Paweł Lisiecki2
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1 Bioorganic Chemistry Laboratory, Faculty of
Pharmacy, Medical University of Lodz, Lodz,
Poland
Abstract
A novel series of diethyl{4-[(4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-
alkylphosphonates 9aa–aj and their respective derivatives substituted at C6 of the
quinazolinone moiety with a bromine atom (9ba–bj) or a nitro group (9ca–cj) were
synthesized and assessed for the antibacterial activity toward selected Gram-positive
and Gram-negative bacteria. Their antifungal activity was also screened. Compound
9ac was found to be the most active against Staphylococcus aureus ATCC 6535 (MIC
0.625 mg/mL, MBC 1.25 mg/mL), phosphonates 9ab–ai showed promising activity
against Enterococcus faecalis ATCC 29212 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL),
while compounds 9ac–j appeared the most active toward Pseudomonas aeruginosa
ATCC 27853 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL). Antifungal assays of com-
pounds 9aa–aj, 9ba–bj, and 9ca–cj were conducted on Candida albicans ATCC 10231
and Aspergillus brasiliensis ATCC 16404 and revealed noticeable activity of 9aa–aj
(MIC = 1.25 mg/mL).
2 Faculty of Pharmacy, Department of
Pharmaceutical Microbiology and
Microbiological Diagnostics, Medical
University of Lodz, Lodz, Poland
Correspondence
Iwona E. Głowacka, Bioorganic Chemistry
Laboratory, Faculty of Pharmacy, Medical
University of Lodz, Muszyńskiego 1, 90-151
Lodz, Poland.
Email: iwona.glowacka@umed.lodz.pl
Funding information
Medical University of Lodz, Grant numbers:
503/3-014-01/503-31-001, 503/3-012-03/
503-31-001
K E Y W O R D S
1,2,3-triazoles, antibacterial, antifungal, phosphonates, quinazolin-4-ones
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1
INTRODUCTION
substituents located at C2 and C3. On the other hand, modification or
improvement of the biological potency can be also achieved by
Quinazolines and their carbonyl derivatives, namely quinazolinones,
are important structural motifs present in many natural and synthetic
compounds exhibiting diverse biological activities like soporific,
sedative, antidiabetic, antibacterial, antifungal, anticancer, anticonvul-
sant, antimalarial, antiinflamatory, antiviral, etc.[1–7] A list of already
approved marketed drugs includes several compounds containing
quinazoline pharmacophore, e.g., 6,7-dimethoxyquinazolin-4-amine
derivatives such as prazosin, terazosin, alfuzosin, and doxazosin.[8,9] It
has also been proven that even slight structural modifications in
functional groups present in a quinazoline skeleton significantly
change pharmacological properties of the compounds. Many substi-
tuted derivatives of quinazolin-4-one were obtained so far with
intention to test their activity, among them analogues with additional
combination of two or more pharmacophores. Based on this idea
various hybrids were designed and screened (Figure 1).
(1,2,4-Triazol-1-yl)-conjugate of quinazolin-4-one 1, a fungicide
known as Albaconazole (UR-9825), shows a broad-spectrum antifungal
activity.[10,11] Among substituted 3-(pyrazol-3-yl)aminoquinazolin-4-
one derivatives tested for their antibacterial activity, compound 2 was
the most active against Staphylococus aureus, Bacillus subtilis as well as
Escherichia coli.[2,12] Recently, compounds 3 and 4 were synthesized
based on combination of an 1,2,3-triazole moiety with a quinazolin-4-
one pharmacophore andshowed promising antibacterial activity against
Klebsiella pneumoniae, Escherichia coli, Staphylococus aureus, and Bacillus
subtilis. Moreover, they exhibited relatively high antifungal properties
against tested species.[13] (1,2,3-Triazole)-containing quinazolin-4-ones
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Arch Pharm Chem Life Sci. 2019;e1800302.
wileyonlinelibrary.com/journal/ardp
© 2019 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.201800302

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FIGURE 1 Examples of biologically active quinazoline-4-ones
havingfluorinatedaliphaticsidechainshowedsignificantactivityagainst
Gram-positive and Gram-negative bacteria. Among all tested analogues,
compounds5–7werethe mostpotent.[14] Rao and co-workersdesigned
and synthesized series of new 1,2,3-triazole derivatives of quinazolin-4-
ones 8 having an additional halogen atom incorporated into the
quinazolin-4-one skeleton.[15] Among them several compounds ex-
hibited a broad-spectrum activity against Gram-positive and Gram-
negative bacteria comparable to ciprofloxacin used as a standard drug.
Furthermore, a few of them showed also the antifungal activity toward
Candida albicans and Aspergillus niger higher than fluconazole used as a
reference compound.
application of a one-pot procedure starting from anthranilic acid 12a
or its derivative 12b and N,N-dimethylformamide dimethylacetate
have been already described.[40] Furthermore, Lazrek and co-workers
as well as Scriba described the synthesis of C2-substituted N3-
propargylquinazolin-4-ones in
a two-step procedure, however,
formation of N3- and O-substituted products was observed when
potassium tert-butoxide/potassium carbonate was used for propargy-
lation of the quinazolinone moiety.[41,42]
For the purpose of this paper a two-step procedure was applied
(Scheme 2).[41,42] Thus, anthranilic acid 12a or its substituted
derivatives 12b,c were transformed into quinazolin-4-ones 13a–c
which were subsequently alkylated with propargyl bromide in the
presence of potassium carbonate. Selective formation of N3-prop-
argylquinazolin-4-ones 10a–c was noticed without traces of
O-alkylated products. Structures of compounds 10a–c were confirmed
based on analysis of the 1H NMR data, since the respective chemical
On the other hand, a phosphonate residue is present in several
molecules recognized as inhibitors of certain biosynthetic pathways
and are degraded by prokaryotic microorganisms.[16] Following these
observations several compounds containing C–P bond attracted a
considerable interest in medicinal chemistry.[17–19] Among them
substituted alkylphosphonates[20–22] as well as derivatives with
various heterocyclic systems should be mentioned.[23–30]

shifts for CH2 (doublet in the range of 4.85–4.80 ppm) and CH
(triplet in the range of 2.50–2.60 ppm) protons were observed. At the
same time no additional signals at δ ca. 5.3 and 2.1 ppm were noticed,
which according to the literature data are expected for O-alkylated
products.[41,42]
In continuation of our search for biologically active 1,2,3-
triazoles,[31–36] a new class of (1,2,3-triazol-1-yl)quinazolin-4-ones 9
was proposed. The aim of these studies was the preparation of a series
of compounds having additional phosphonoalkyl group located at C4 in
the 1,2,3-triazole ring (Scheme 1). We assumed that incorporation of a
phosphonoalkyl residue as an additional pharmacophore may have a
positive impact on the antimicrobial activity of obtained compounds.
The alternative synthetic strategy for the synthesis of compounds
10a,b relies on the transformation of the respective isatoic anhydrides
14a,b into N-propargyl 2-amino-benzamides 15a,b and subsequent
cyclization to quinazolin-4-ones 10a,b with triethyl orthoformate in
the presence of acetic acid (Scheme 3).[42,43] Since installation of a
propargyl residue at N3 of the quinazolin-4-one moiety in 10a,b
requires prior formation of the respective N-propargyl benzamides 15,
structures of the products 10a,b were unambiguously established.
All synthesized N3-propargylquinazolin-4-ones 10a–c were then
subjected to the Cu(I)-catalyzed Hüisgen dipolar cycloaddition with the
selected ω-azidoalkyphosphonates 11a–j to produce the respective
1,2,3-triazoles 9aa–aj, 9ba–bj, and 9ca–cj (Scheme 1) in good to
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2
RESULTS AND DISCUSSION
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2.1 Chemistry
Optimized preparative procedures for all ω-azidoalkylphosphonates
11a–j were previously elaborated in our research groups.[31,32,34,37–39]
Synthesis of N3-propargylquinazolin-4-ones 10a and 10b via

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SCHEME 1 Retrosynthesis of quinazolin-4-ones 9
excellent yields after chromatographic purification and/or crystalliza-
tion. Their structures and purity were determined by 1H, 13C and
31P NMR and IR spectra as well as by elemental analyses.
(MIC = 0.625 mg/mL, MBC = 1.25 mg/mL). Moreover, the compound
9ac exhibited the most promising activity against S. aureus ATCC 6535
(MIC 0.625 mg/mL, MBC 1.25 mg/mL).
A significant decrease in activity toward all tested Gram-positive
and Gram-negative bacteria was noticed when a bromine atom
(9ba–bj) or the nitro group (9ca–cj) were incorporated at C6 of the
quinazolinone moiety (MIC > 5 mg/mL).
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2.2 Antimicrobial activity
The antimicrobial activity of the 1,2,3-triazole conjugates of quinazo-
lin-4-ones 9aa–aj, 9ba–bj, and 9ca–cj was evaluated toward selected
bacterial strains: B. subtilis ATCC 6633, S. aureus ATCC 6535, E. faecalis
ATCC 29212, E. coli ATCC 8739, P. aeruginosa ATCC 27853 and two
fungal strains: C. albicans ATCC 10231 and Aspergillus brasiliensis ATCC
16404 (Supporting Information Tables S1–S3). The antimicrobial
activity of the compounds was assessed according to their minimal
inhibitory concentrations (MIC) and minimal bactericidal concentra-
tions (MBC). Gentamicin and fluconazole were used as antimicrobial
standards.
Compounds 9aa–aj having an unsubstituted quinazolinone moiety
showed antifungal activity against C. albicans ATCC 10231
(MIC = 1.25 mg/mL, MBC = 1.25 mg/mL) and A. brasiliensis ATCC
16404 (MIC = 1.25 mg/mL, MBC = 2.5 mg/mL), while analogous com-
pounds substituted at C6 of the quinazolinone skeleton with a bromine
atom (9ba–bj) or the nitro group (9ca–cj) appear inactive in
concentrations up to 5 mg/mL.
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CONCLUSIONS
All synthesized compounds (9aa–aj, 9ba–bj, and 9ca–cj) showed
inhibitory activity toward all tested Gram-positive (B. subtilis ATCC
6633, S. aureus ATCC 6535, Enterococcus faecalis ATCC 29212) and
Gram-negative (E. coli ATCC 8739, P. aeruginosa ATCC 27853)
bacteria. Compounds 9aa–aj showed potency against all tested
bacteria (MIC < 1.25 mg/mL and MBC < 2.5 mg/mL). The most active
toward E. faecalis ATCC 29212 were compounds 9ab–ai
(MIC = 0.625 mg/mL, MBC = 1.25 mg/mL), while 9ac–aj showed
noticeable activity against P. aeruginosa ATCC 27853
A novel series of diethyl {4-[(4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}alkylphosphonates 9aa–aj, as well as their deriva-
tives substituted at C6 of the quinazolin-4-one moiety with a bromine
atom (9ba–bj) and the nitro group (9ca–cj) have been synthesized via
Cu(I)-catalyzed dipolar cycloaddition of N3-propargylquinazolin-4-
ones 10a–c with the respective ω-azidoalkylphospontates 11a–j
under microwave irradiation.
SCHEME 2 Synthesis of N3-propargylquinazolin-4-ones 10a–c. Reagents and conditions: (a) formamide 150°C, MW, 30 min, (b) propargyl
bromide, K2CO3, r.t. 24 h

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SCHEME 3 Synthesis of N3-propargylquinazolin-4-ones 10a,b. Reagents and conditions: (a) propargyl amine, DMF, 50°C, 3 h or propargyl
amine, H2O, r.t., 3 h; (b) (EtO)3CH, CH3COOH, ethanol, 78°C, 4 h
From all synthesized compounds phosphonate 9ac was the most
active against S. aureus ATCC 6535 (MIC 0.625 mg/mL, MBC 1.25 mg/
mL), quinazoline-4-ones 9ab–ai were the most active toward E. faecalis
ATCC 29212 (MIC = 0.625 mg/mL, MBC = 1.25 mg/mL), while 9ac–j
showed the highest activity against P. aeruginosa ATCC 27853
(MIC = 0.625 mg/mL, MBC = 1.25 mg/mL). Quinazolin-4-ones 9aa–aj
exhibited potency toward all tested Gram-positive and Gram-negative
bacteria, whereas their derivatives having additional substituents at C6
(the nitro group or a bromine atom) in the quinazoline-4-one moiety
appeared less active (9a vs. 9b or 9c).
5-Bromoisatoic anhydride was prepared according to the
literature.[45]
Commercially available anthranilic acid (≥98%), 5-bromoanthra-
nilic acid (97%), and 5-nitroanthranilic acid (95%) were used without
further purification.
The InChI codes of the investigated compounds together with
some biological activity data are provided as Supporting Information.
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4.1.2 General procedure for the synthesis of
quinazolin-4(3H)-ones 13a–c
The antifungal activity against C. albicans ATCC 10231
(MIC = 1.25 mg/mL, MBC = 1.25 mg/mL) and A. brasiliensis ATCC
16404 (MIC = 1.25 mg/mL, MBC = 2.5 mg/mL) was observed for
compounds 9aa–aj, while their analogous possessing a bromine
atom (9ba–bj) or the nitro group (9ca–cj) at C6 of the quinazolin-4-
one skeleton were inactive in concentrations up to 5 mg/mL.
The mixture of anthranilic acid or 5-bromoanthranilic acid or
5-nitroanthranilic acid (1 mmol) and formamide (1 mmol) was irradi-
ated in the microwave reactor (Discover SP CEM) at 150°C for 30 min.
Then the mixture was cooled to room temperature and water (5 mL)
was added. The suspension was filtered and crystallized from ethanol
to give pure quinazolin-4(3H)-ones 13a–c.
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4
EXPERIMENTAL
Quinazolin-4(3H)-one 13a[41]
From anthranilic acid 12a (5.00 g, 36.5 mmol) and formamide (1.5 mL,
36.5 mmol) the quinazolin-4(3H)-one 13a (4.553 g, 86%) was obtained
as a white powder. M.p.: 218–220°C (lit.[41] m.p.: 217–219°C);
1H NMR (200 MHz, CDCl3): δ = 11.52 (brs, 1H, NH), 8.34–8.30 (m,
1H, Haromat.), 8.14 (s, 1H, Haromat.), 7.89–7.75 (m, 2H, Haromat.), 7.56
(ddd, J = 8.1 Hz, J = 6.2 Hz, J = 2.1 Hz, 1H, Haromat.).
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4.1 Chemistry
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4.1.1 General
1H NMR spectra were taken in CDCl3 on the following spectrometers:
Varian Mercury-200 and Bruker Avance III (600 MHz) with TMS as an
internal standard; chemical shifts δ in ppm with respect to TMS;
coupling constants J in Hz. 13C NMR spectra were recorded for CDCl3
or DMSO-d6 solutions on a Bruker Avance III (600 MHz) spectrometer
at 151 MHz. 31P NMR spectra were taken in CDCl3 on Varian Mercury-
200 at 81 MHz. IR spectral data were measured on a Bruker Alpha-T
FT-IR spectrometer. Melting points were determined on a Boetius
apparatus and were uncorrected. Elemental analyses were performed
by the Microanalytical Laboratory of this faculty on a Perkin Elmer PE
2400 CHNS analyzer.
6-Bromoquinazolin-4(3H)-one 13b[46]
From 5-bromoanthranilic acid 12b (2.00 g, 9.26 mmol) and formamide
(0.368 mL, 9.26 mmol) the 6-bromoquinazolin-4-one 13b (1.946 g,
93%) was obtained as a yellowish solid. M.p.: 271–273°C (lit.[46] m.p.:
273–275°C); 1H NMR (200 MHz, DMSO-d6): δ = 12.41 (brs, 1H, NH),
8.20–8.18 (m, 1H, Haromat.), 8.13 (s, 1H, Haromat.), 7.98–7.91 (m, 1H,
Haromat.), 7.62 (d, J = 8.7 Hz, 1H, Haromat.).
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.[44]
All microwave irradiation experiments were carried out in
microwave reactors Plazmartonika RM 800 or Discover SP CEM.
The reaction was carried out in a 50 mL glass vial.
6-Nitroquinazolin-4(3H)-one 13c[47]
From 5-nitroanthranilic acid 12c (2.01 g, 11.0 mmol) and formamide
(0.436 mL, 11.0 mmol) the 6-nitroquinazoline-4-one 13c (1.809 g,
86%) was obtained as a yellow powder. M.p.: 279–281°C (lit.[47] m.p.:
283–285°C); 1H NMR (200 MHz, DMSO-d6): δ = 12.65 (brs, 1H, NH),
8.70 (dd, J = 2.7 Hz, J = 0.3 Hz, 1H, Haromat.), 8.45 (ddd, J = 9.0 Hz,
J = 2.7 Hz, J = 0.3 Hz, 1H, Haromat.), 8.23 (s, 1H, Haromat.), 7.77 (d,
J = 9.0 Hz, 1H, Haromat.).

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4.1.3 General procedure for the synthesis of
and stirred at 50°C for 3 h. Then the mixture was cooled to room
temperature, water (5 mL) was added and the precipitated product was
filtered and dried on air to give pure 2-amino-N-(prop-2-yn-1-yl)
benzamide 15a,b.
N3-propargylquinazolin-4(3H)-ones 10a–c
To a solution of quinazolin-4-one 13a–c (1 mmol) in DMF (3 mL),
K2CO3 (1.2 mmol) and propargyl bromide (1.2 mmol) were added. The
suspension was stirred at room temperature for 24 h. Then N,N-
dimethylformamide was co-evaporated with toluene (5 × 10 mL). The
residue was partitioned between brine (5 mL) and ethyl acetate
(10 mL). The aqueous layer was extracted with ethyl acetate
(4 × 10 mL). The organic layer was dried (anhydrous MgSO4),
concentrated in vacuo and the residue was crystallized to give pure
N3-propargylquinazolin-4-ones 10a–c.
Method B: To a solution of the respective isatoic anhydride 14a,b
(1.00 mmol) in water (2 mL) propargyl amine (1.00 mmol) was added
and stirred to room temperature for 3 h. The solid was filtered and
dried on air to give pure 2-amino-N-(prop-2-yn-1-yl)benzamide
15a,b.
2-Amino-N-(prop-2-yn-1-yl)benzamide 15a
According to the general procedure (method A) from the isatoic
anhydride 14a (0.600 g, 3.68 mmol) and propargyl amine (0.256 mL,
3.60 mmol) pure 2-amino-N-(prop-2-yn-1-yl)benzamide 15a (0.461 g,
72%) was obtained as a white powder. M.p.: 85–87°C (lit.[48] m.p.: 86–
88°C).
3-(Prop-2-yn-1-yl)quinazolin-4(3H)-one 10a[42]
From quinazolin-4-one 13a (1.00 g, 6.89 mmol) the 3-(prop-2-yn-1-yl)
quinazolin-4-one 10a (1.202 g, 95%) was obtained as a creamy solid
after crystallization from ethyl acetate–hexane mixtures. M.p.: 118–
120°C (lit.[42] m.p.: 115–116°C); 1H NMR (200 MHz, CDCl3): δ = 8.31–
8.26 (m, 2H, Haromat.), 7.80–7.65 (m, 2H, Haromat.), 7.49 (ddd, J = 8.2 Hz,
J = 6.5 Hz, J = 1.9 Hz, 1H, Haromat.), 4.80 (d, J = 2.6 Hz, 2H, CH2), 2.49 (t,
J = 2.6 Hz, 1H, CH).
According to the general procedure (method B) from the isatoic
anhydride 14a (1.066 g, 6.53 mmol) and propargyl amine (0.418 mL,
6.53 mmol) 2-amino-N-(prop-2-yn-1-yl)benzamide 15a (0.953 g,
84%) was obtained as a white powder. M.p: 85–87°C (lit.[48] m.p.:
86–88°C).
1H NMR (200 MHz, CDCl3): δ = 8.31–8.26 (m, 2H, Haromat.), 7.80–
7.65 (m, 2H, Haromat.), 6.10 (brs, 1H, NH), 5.51 (brs, 2H, NH2), 4.06 (dd,
J = 5.1 Hz, J = 2.5 Hz, 2H, CH2), 2.25 (t, J = 2.5 Hz, 1H, CH).
6-Bromo-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 10b[40]
From 6-bromoquinazolin-4-one 13b (1.00 g, 4.44 mmol) the 6-bromo-
3-(prop-2-yn-1-yl)quinazolin-4-one 10b (1.202 g, 85%) was obtained
as a yellow solid after crystallization from methanol. M.p.: 132–
134°C (lit.[40] m.p.: 134–136°C.); 1H NMR (200 MHz, CDCl3): δ = 8.45–
8.42 (m, 1H, Haromat.), 8.31 (s, 1H, Haromat.), 7.85 (ddd, J = 8.7 Hz,
J = 2.3 Hz, J = 0.3 Hz, 1H, Haromat.), 7.60 (d, J = 8.7 Hz, 1H, Haromat.),
4.81 (d, J = 2.6 Hz, 2H, CH2), 2.51 (t, J = 2.6 Hz, 1H, CH).
2-Amino-5-bromo-N-(prop-2-yn-1-yl)benzamide 15b
According to the general procedure (method A) from 5-bromoisatoic
anhydride 14b (0.150 g, 0.620 mmol) and propargyl amine (0.041 mL,
0.620 mmol), 2-amino-5-bromo-N-(prop-2-yn-1-yl)benzamide 15b
(0.101 g, 64%) was obtained as
a yellow powder. M.p.: 126–
127°C (lit.[49] m.p.: 125–126°C).
6-Nitro-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 10c
According to the general procedure (method B) from 5-
bromoisatoic anhydride 14b (0.100 g, 0.413 mmol) and propargyl
amine (0.027 mL, 0.413 mmol), 2-amino-5-bromo-N-(prop-2-yn-1-yl)-
benzamide 15b (0.079 g, 75%) was isolated as a yellowish powder.
M.p. = 126–127°C (lit.[49] m.p.: 125–126°C).
From 6-nitroquinazolin-4-one 13c (0.624 g, 3.26 mmol) the 6-nitro-3-
(prop-2-yn-1-yl)quinazolin-4-one 10c (0.657 g, 88%) was obtained as a
pale solid after crystallization from methanol. M.p.: 132–134°C; IR
(KBr): ν = 3258, 3099, 3073, 2962, 2927, 1699, 1613, 1601, 1517,
1349, 893 cm−1 1H NMR (200 MHz, CDCl3): δ = 9.19 (dd, J = 2.6 Hz,
;
1H NMR (200 MHz, CDCl3): δ = 7.43 (d, J = 2.1 Hz, 1H, Haromat.),
J = 0.4 Hz, 1H, Haromat.), 8.56 (dd, J = 9.0 Hz, J = 2.6 Hz, 1H, Haromat.),
8.46 (s, 1H, Haromat.), 7.87 (d, J = 9.0 Hz, 1H, Haromat.), 4.85 (d, J = 2.6 Hz,
2H, CH2), 2.57 (t, J = 2.6 Hz, 1H, CH); 13C NMR (151 MHz, CDCl3):
7.31 (d, J = 8.7 Hz, J = 2.1 Hz, 1H, Haromat.), 6.57 (d, J = 8.7 Hz, 1H,
Haromat.), 6.14 (brs, 1H, NH), 5.55 (brs, 2H, NH2), 4.19 (dd, J = 5.2 Hz,
J = 2.6 Hz, 2H, CH2), 2.30 (t, J = 2.6 Hz, 1H, CH).

δ = 159.27 (s, C O), 151.94, 147.94, 146.24, 129.37, 128.54, 123.38,
122.00, 76.15, 75.62, 35.64. Anal. calcd. for C11H7N3O3: C, 57.65; H,
3.08; N, 18.33. Found: C, 57.48; H, 3.12; N, 18.32.
4.1.5 Synthesis of N3-propargylquinazolin-4-ones
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10a,b from 2-amino-N-(prop-2-yn-1-yl)benzamides
15a,b, general procedure
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4.1.4 Synthesis of 2-amino-N-(prop-2-yn-1-yl)-
To
a solution of 2-amino-N-(prop-2-yn-1-yl)benzamides 15a,b
benzamides 15a,b from the respective isatoic
anhydrides 14a,b
(1.00 mmol) in ethanol (5 mL) acetic acid (1.7 mmol) and triethyl
orthoformate (1.1 mmol) were added and stirred at 78°C for 4 h.
Then the mixture was cooled at room temperature and was
extracted with dichloromethane (4 × 10 mL). The organic layer was
dried (anhydrous MgSO4), concentrated in vacuo and the residue
was crystallized to give pure N3-propargylquinazolin-4-ones
10a,b.
Synthesis of 2-amino-N-(prop-2-yn-1-yl)benzamides 15a,b,
general procedure
Method A: To a solution of the respective isatoic anhydride 14a,b
(1.00 mmol) in DMF (2 mL) propargyl amine (1.00 mmol) was added

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3-(Prop-2-yn-1-yl)quinazolin-4(3H)-one 10a
(100:1, v/v). IR (film): ν = 3364, 3143, 3072, 2987, 2932, 1676, 1611,
According to the general procedure from 2-amino-N-(prop-2-yn-1-yl)-
benzamide 15a (0.500 g, 2.87 mmol), acetic acid (0.284 mL, 4.88 mmol,
1.7 eq.) and triethyl orthoformate (0.600 mL, 3.16 mmol, 1.1 eq.) N3-
propargylquinazolin-4-one 10a (0.444 g, 84%) was obtained after
crystallization from ethyl acetate–hexane mixtures as a creamy solid.
1474, 1224, 1049, 754 cm−1
1H), 8.29–8.24 (m, 1H, Haromat.), 7.81 (s, 1H, HC5′), 7.80–7.66 (m, 2H,
aromat.), 7.54–7.45 (m, 1H, Haromat.), 5.25 (s, 2H, CH2), 4.64–4.50 (m,
;
1H NMR (200 MHz, CDCl3): δ = 8.34 (s,
H
2H, PCH2), 4.12–3.98 (m, 4H, 2 × POCH2CH3), 2.47–2.30 (m, 2H,
PCCH2), 1.25 (t, J = 7.0 Hz, 6H, 2 × POCH2CH3); 13C NMR (151 MHz,

CDCl3): δ = 160.97 (s, C O), 148.19, 146.22, 142.29, 134.43, 127.68,
6-Bromo-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 10b
127.39, 126.50, 124.10, 121.98, 62.18 (d, J = 6.5 Hz, POC), 44.69,
41.68, 27.18 (d, J = 141.5 Hz, PC), 16.30 (d, J = 6.0 Hz, POCC);
31P NMR (81 MHz, CDCl3): δ = 26.01 ppm. Anal. calcd. for
According to the general procedure from 2-amino-6-bromo-N-(prop-
2-yn-1-yl)benzamide 15b (0.100 g, 0.359 mmol), acetic acid (0.035 mL,
0.610 mmol, 1.7 eq.) and triethyl orthoformate (0.066 mL, 0.395 mmol,
1.1 eq.) pure 6-bromo-3-(prop-2-yn-1-yl)quinazolin-4(3H)-one 10b
(0.089 g, 86%) was obtained after crystallization from methanol.
C17H22N5O4P: C, 52.17; H, 5.67; N, 17.89. Found: C, 51.98; H,
5.88; N, 18.12.
Diethyl 3-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-
triazol-1-yl}propylphosphonate 9ac
|
4.1.6 General procedure for the preparation of
From diethyl 3-azidopropylphosphonate 11c (0.065 g, 0.294 mmol)
and N3-propargylquinazolin-4(3H)-one 13a (0.054 g, 0.294 mmol), a
phosphonate 9ac (0.099 g, 83%) was obtained as a colorless oil after
purification on a silica gel column with chloroform–methanol mixtures
(100:1, v/v). IR (film): ν = 3285, 3144, 2985, 2909, 1676, 1612, 1475,
1,2,3-triazoles 9aa–cj
To a solution of ω-azidoalkylphosphonate 11 (1.00 mmol) in EtOH
(1 mL) and H2O (1 mL), CuSO4 × 5H2O (0.05 mmol), sodium ascorbate
(0.10 mmol) and alkynes 13 (1.00 mmol) were added. The suspension
was microwave irradiated in the microwave reactor (Plazmatronika RM
800, 800 W) at 35–45°C for 2 min. After cooling the solvent was
removed by vacuum 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 (100:1, v/v) or by
crystallization to give the respective 1,2,3-triazoles 9.
1225, 1026, 777 cm−1 1H NMR (200 MHz, CDCl3): δ = 8.34 (s, 1H),
;
8.30–8.25 (m, 1H, Haromat.), 7.80–7.60 (m, 3H, 2H, Haromat., HC5′),
7.54–7.50 (m, 1H, Haromat.), 5.26 (s, 2H, CH2), 4.42 (t, J = 7.0 Hz, 2H,
PCCCH2), 4.16–3.95 (m, 4H, 2 × POCH2CH3), 2.31–2.09 (m, 2H,
PCCH2), 1.79–1.61 (m, 2H, PCH2), 1.29 (t, J = 7.1 Hz, 6H,
2 × POCH2CH3); 13C NMR (151 MHz, CDCl3): δ = 160.99 (s, CO),
148.20, 146.26, 142.34, 134.41, 127.68, 127.36, 126.52, 123.94,
122.01, 61.84 (d, J = 6.6 Hz, POC), 50.15 (d, J = 15.2 Hz, PCCC), 41.71,
23.58 (d, J = 4.5 Hz, PCC), 22.63 (d, J = 143.2 Hz, PC), 16.40 (d,
J = 5.9 Hz, POCC); 31P NMR (81 MHz, CDCl3): δ = 30.65 ppm. Anal.
calcd. for C18H24N5O4P: C, 53.33; H, 5.97; N, 17.28. Found: C, 53.58;
H, 6.19; N, 17.52.
Diethyl {4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-triazol-
1-yl}methylphosphonate 9aa
From diethyl azidomethylphosphonate 11a (0.072 g, 0.373 mmol) and
N3-propargylquinazolin-4(3H)-one 13a (0.068 g, 0.373 mmol) a phos-
phonate 9aa (0.090 g, 64%) was obtained as a white powder after
purification on a silica gel column with chloroform–methanol mixtures
(100:1, v/v). M.p.: 131–132°C; IR (KBr): ν = 3423, 3145, 3081, 2987,
Diethyl 4-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-
triazol-1-yl}butylphosphonate 9ad
2937, 1675, 1611, 1475, 1248, 1023, 776, 756 cm−1
;
1H NMR
From diethyl 4-azidobutylphosphonate 11d (0.054 g, 0.230 mmol)
and N3-propargylquinazolin-4(3H)-one 13a (0.042 g, 0.230 mmol), a
phosphonate 9ad (0.068 g, 71%) was obtained as a colorless oil after
(200 MHz, CDCl3): δ = 8.33 (s, 1H), 8.29–8.25 (m, 1H, Haromat.), 7.95 (s,
1H, HC5′), 7.80–7.65 (m, 2H, Haromat.), 7.55–7.45 (m, 1H, Haromat.),
5.27 (s, 2H, CH2), 4.74 (d, J = 13.1 Hz, 2H, PCH2), 4.19–4.06 (m, 4H,
2 × POCH2CH3), 1.26 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR
(151 MHz, CDCl3): δ = 160.89 (s, CO), 148.18, 146.19, 142.70, 134.38,
127.68, 127.34, 126.50, 124.73, 122.01, 63.50 (d, J = 6.6 Hz, POC),
45.95 (d, J = 155.3 Hz, PC), 41.61, 16.23 (d, J = 5.6 Hz, POCC);
31P NMR (81 MHz, CDCl3): δ = 16.27 ppm. Anal. calcd. for
purification on
mixtures (100:1, v/v). IR (film): ν = 3286, 3144, 2985, 2985, 1677,
1612, 1475, 1225, 1052, 1026, 777, 754 cm−1 1H NMR (200 MHz,
a silica gel column with chloroform–methanol
;
CDCl3): δ = 8.34 (s, 1H), 8.30–8.24 (m, 1H, Haromat.), 7.79–7.67 (m,
3H, 2H, Haromat., HC5′), 7.53–7.45 (m, 1H, Haromat.), 5.25 (s, 2H, CH2),
4.32 (t, J = 7.1 Hz, 2H, PCCCCH2), 4.14–3.96 (m, 4H,
2 × POCH2CH3), 2.07–1.92 (m, 2H, PCCCH2), 1.84–1.50 (m, 4H,
PCH2, PCCH2), 1.27 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR
(151 MHz, CDCl3): δ = 161.00 (s, CO), 148.22, 146.27, 142.33,
134.40, 127.70, 127.35, 126.51, 123.60, 122.02, 61.61 (d,
J = 6.6 Hz, POC), 49.83, 41.72, 30.65 (d, J = 15.3 Hz, PCCC); 25.0
(d, J = 142.1 Hz, PC); 19.69 (d, J = 4.7 Hz, PCC); 16.41 (d, J = 5.9 Hz,
POCC); 31P NMR (81 MHz, CDCl3): δ = 31.65 ppm. Anal. calcd. for
C16H20N5O4P: C, 50.93; H, 5.34; N, 18.56. Found: C, 50.95; H,
5.22; N, 18.32.
Diethyl 2-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-
triazol-1-yl}ethylphosphonate 9ab
From diethyl 2-azidoethylphosphonate 11b (0.069 g, 0.333 mmol) and
N3-propargylquinazolin-4(3H)-one 13a (0.061 g, 0.333 mmol), a phos-
phonate 9ab (0.101 g, 78%) was obtained as a colorless oil after
purification on a silica gel column with chloroform–methanol mixtures
C
19H26N5O4P: C, 54.41; H, 6.25; N, 16.70. Found: C, 54.68; H, 6.02;
N, 17.00.

GŁOWACKA ET AL.
7 of 14
|
Diethyl 2-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-
triazol-1-yl}ethoxymethylphosphonate 9ae
5.26 (AB, J = 14.8 Hz, 1H, CHaHb), 5.23 (AB, J = 14.8 Hz, 1H, CHaHb),
4.76 (ddd, J = 14.6 Hz, J = 5.1 Hz, J = 2.6 Hz, 1H, PCCHaHb), 4.53–4.38
(m, 1H, PCCHaHb), 4.35–4.07 (m, 5H, PCH(OH), 2 × POCH2CH3), 1.30
(t, J = 7.0 Hz, 3H, POCH2CH3), 1.29 (t, J = 7.0 Hz, 3H, POCH2CH3);
13C NMR (151 MHz, CDCl3): δ = 160.83 (s, CO), 147.83, 146.45,
141.97, 134.42, 127.41, 127.38, 126.49, 125.48, 121.87, 67.03 (d,
J = 164.7 Hz, PC), 63.51 (d, J = 7.4 Hz, POC); 63.32 (d, J = 7.4 Hz, POC),
51.72 (d, J = 9.3 Hz, PCC), 41.57, 16.41 (d, J = 5.37 Hz, POCC);
31P NMR (81 MHz, CDCl3): δ = 20.90 ppm. Anal. calcd. for
From diethyl (2-azidoethoxy)methylphosphonate 11e (0.080 g,
0.337 mmol) and N3-propargylquinazolin-4(3H)-one 13a (0.062 g,
0.337 mmol), a phosphonate 9ae (0.128 g, 78%) was obtained as a
colorless oil after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). IR (film): ν = 3436, 3128, 2984, 2931,
1678, 1612, 1475, 1230, 1027, 777 cm−1; 1H NMR (200 MHz, CDCl3):
δ = 8.36 (s, 1H), 8.30–8.25 (m, 1H, Haromat.), 7.88 (s, 1H, HC5′), 7.80–
7.67 (m, 2H, Haromat.), 7.54–7.46 (m, 1H, Haromat.), 5.27 (s, 2H, CH2),
4.53 (t, J = 4.8 Hz, 2H, OCH2CH2N), 4.17–4.02 (m, 4H,
2 × POCH2CH3), 3.97 (t, J = 4.8 Hz, 2H, OCH2CH2N), 3.75 (d,
J = 8.1 Hz, 2H, PCH2O), 1.29 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3);
13C NMR (151 MHz, CDCl3): δ = 160.88 (s, CO), 148.16, 146.32,
142.30, 134.37, 127.65, 127.33, 126.54, 124.68, 122.04, 71.10 (d,
J = 10.0 Hz, OCH2CH2N), 65.35 (d, J = 166.5 Hz, PC), 62.52 (d,
J = 6.6 Hz, POC), 50.18 (s, OCH2CH2N), 41.47, 16.42 (d, J = 5.6 Hz,
POCC); 31P NMR (81 MHz, CDCl3): δ = 21.12 ppm. Anal. calcd. for
C17H22N5O5P: C, 50.12; H, 5.44; N, 17.19. Found: C, 50.27; H,
5.48; N, 17.30.
Diethyl 2-hydroxy-3-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylphosphonate 9ah
From diethyl 3-azido-2-hydroxypropylphosphonate 11h (0.072 g,
0.304 mmol) and N3-propargylquinazolin-4(3H)-one 13a (0.055 g,
0.304 mmol), a phosphonate 9ah (0.121 g, 96%) was obtained as a
white powder after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). M.p.: 132–133°C; IR (KBr): ν = 3267,
C18H24N5O5P: C, 51.30; H, 5.74; N, 16.62. Found: C, 51.55; H, 6.02; N,
16.39.
3159, 2910, 1676, 1613, 1476, 1217, 1048, 756 cm−1 1H NMR
;
(600 MHz, CDCl3): δ = 8.36 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H, Haromat.),
7.95 (s, 1H, HC5′), 7.76–7.69 (m, 2H, Haromat.), 7.45 (t, J = 7.3 Hz, 1H,
Diethyl 2-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-
triazol-1-yl}ethoxyethylphosphonate 9af
Haromat.), 5.29 (AB, J = 15.1 Hz, 1H, CHaHb), 5.26 (AB, J = 15.1 Hz, 1H,
From diethyl 2-(2-azidoethoxy)ethylphosphonate 11f (0.063 g,
0.251 mmol) and N3-propargylquinazolin-4(3H)-one 13a (0.046 g,
0.251 mmol), a phosphonate 9af (0.090 g, 88%) was obtained as a
colorless oil after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). IR (film): ν = 3384, 3118, 2986, 2925,
1676, 1613, 1475, 1135, 1027, 777 cm−1; 1H NMR (200 MHz, CDCl3):
δ = 8.35 (s, 1H), 8.31–8.26 (m, 1H, Haromat.), 7.89 (s, 1H, HC5′), 7.80–
7.67 (m, 2H, Haromat.), 7.53–7.45 (m, 1H, Haromat.), 5.27 (s, 2H, CH2),
4.50 (t, J = 5.0 Hz, 2H, OCH2CH2N), 4.13–3.98 (m, 4H,
2 × POCH2CH3), 3.79 (t, J = 5.0 Hz, 2H, OCH2CH2N), 3.67 (dt,
J = 11.9 Hz, J = 7.3 Hz, 2H, PCH2CH2O), 2.05 (dt, J = 18.7 Hz,
CHaHb), 4.54 (dd, J = 17.0 Hz, J = 6.1 Hz, 1H, PCCCHaHb), 4.42–4.36
(m, 2H, PCCH(OH), PCCCHaHb), 4.15–4.07 (m, 4H, 2 × POCH2CH3),
2.00 (ddd, 1H, J = 18.9 Hz, J = 15.4 Hz, J = 3.5 Hz, PCHaHb), 1.97 (ddd,
2H, J = 16.7 Hz, J = 15.4 Hz, J = 8.3 Hz, PCHaHb), 1.32 (t, J = 7.1 Hz, 3H,
POCH2CH3), 1.31 (t, J = 7.1 Hz, 3H, POCH2CH3); 13C NMR (151 MHz,

CDCl3): δ = 160.86 (s, C O), 148.04, 146.35, 141.90, 134.36, 127.54,
127.33, 126.57, 125.37, 122.01, 65.49 (d, J = 3.5 Hz, PCC), 62.30 (d,
J = 6.4 Hz, POC), 62.23 (d, J = 6.4 Hz, POC), 55.96 (d, J = 17.7 Hz,
PCCC), 41.56, 30.77 (d, J = 140.6 Hz, PC), 16.40 (d, J = 5.7 Hz, POCC);
31P NMR (243 MHz, CDCl3): δ = 28.09 ppm. Anal. calcd. for
C18H24N5O5P: C, 51.30; H, 5.74; N, 16.62. Found: C, 51.08; H,
J = 7.3 Hz, 2H, PCH2CH2O), 1.29 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3);
13
5.95; N, 16.33.

C NMR (151 MHz, CDCl3): δ = 160.92 (s, C O), 148.15, 146.37,
142.15, 134.34, 127.62, 127.31, 126.55, 124.75, 122.05, 68.79 (s,
OCH2CH2N), 65.25 (s, PCH2CH2O), 61.71 (d, J = 6.5 Hz, POC), 50.26
(s, OCH2CH2N), 41.55, 26.81 (d, J = 140.6 Hz, PC), 16.39 (d, J = 6.3 Hz,
POCC); 31P NMR (81 MHz, CDCl3): δ = 28.64 ppm. Anal. calcd. for
Diethyl {2-[4-(4-oxoquinazolin-3(4H)-yl)methyl)-1H-1,2,3-
triazol-1-yl]acetamido}methylphosphonate 9ai
From diethyl (2-azidoacetamido)methylphosphonate 11i (0.074 g,
0.296 mmol) and N3-propargylquinazolin-4(3H)-one 13a (0.054 g,
0.296 mmol), a phosphonate 9ai (0.115 g, 90%) was obtained as a
white powder after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). M.p.: 210–211°C; IR (KBr): ν = 3289,
3070, 2993, 1680, 1612, 1475, 1218, 1051, 1027, 756 cm−1; 1H NMR
(200 MHz, CDCl3): δ = 8.37 (s, 1H), 8.28–8.24 (m, 1H, Haromat.), 7.98 (s,
1H, HC5′), 7.80–7.67 (m, 2H, Haromat.), 7.61 (brt, J = 6.0 Hz, 1H, NH),
7.53–7.44 (m, 1H, Haromat.), 5.28 (s, 2H, CH2), 5.10 (s, 2H, CH2), 4.15–
4.00 (m, 4H, 2 × POCH2CH3), 3.70 (dd, J = 12.3 Hz, J = 5.9 Hz, 2H,
PCH2), 1.26 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR (151 MHz,
C19H26N5O5P: C, 52.41; H, 6.02; N, 16.08. Found: C, 52.14; H, 6.28; N,
15.83.
Diethyl 1-hydroxy-2-{4-[4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethylphosphonate 9ag
From diethyl 2-azido-1-hydroxyethylphosphonate 11g (0.074 g,
0.332 mmol) and N3-propargylquinazolin-4(3H)-one 13a (0.061 g,
0.332 mmol), a phosphonate 9ag (0.141 g, 81%) was obtained as a
white powder after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). M.p.: 130–132°C; IR (KBr): ν = 3267,


CDCl3): δ = 165.04 (d, J = 6.1 Hz, C O), 160.97 (s, C O), 148.21,
146.27, 142.58, 134.41, 127.69, 127.373, 126.54, 125.43, 122.02,
62.98 (d, J = 6.6 Hz, POC), 52.46 (s, CH2N), 41.65, 34.92 (d,
J = 157.6 Hz, PC), 16.30 (d, J = 5.6 Hz, POCC); 31P NMR (81 MHz,
3159, 2910, 1676, 1613, 1476, 1217, 1048, 756 cm−1 1H NMR
;
(200 MHz, CDCl3): δ = 8.32 (s, 1H), 8.21–8.16 (m, 1H, Haromat.), 7.97 (s,
1H, HC5′), 7.76–7.62 (m, 2H, Haromat.), 7.49–7.41 (m, 1H, Haromat.),

8 of 14
GŁOWACKA ET AL.
|
CDCl3): δ = 22.30 ppm. Anal. calcd. for C18H23N6O5P: C, 49.77; H,
134.35, 128.63, 128.60, 128.57, 128.38, 128.15, 128.12, 128.00,
127.61, 127.31, 126.56, 125.35, 122.00, 74.73 (d, J = 5.3 Hz, PCC),
72.80, 68.52 (d, J = 7.2 Hz, POC), 68.40 (d, J = 7.2 Hz, POC), 67.86,
(d, J = 160.8 Hz, PC), 50.35 (d, J = 5.9 Hz, PCCC), 41.46; 31P NMR
(81 MHz, CDCl3): δ = 23.59 ppm. Anal. calcd. for C35H34N5O6P: C,
64.51; H, 5.26; N, 10.70. Found: C, 64.77; H, 5.34; N, 10.45.
5.34; N, 19.35. Found: C, 49.91; H, 5.15; N, 19.68.
(1S,2S)-Dibenzyl 2-benzyloxy-1-hydroxy-3-{4-[4-oxoquinazolin-
3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
(1S,2S)-9aj
From (1S,2S)-dibenzyl 3-azido-2-benzyloxy-1-hydroxypropylphosph-
onate 11j (0.050 g, 0.109 mmol) and N3-propargylquinazolin-4(3H)-
one 13a (0.020 g, 0.109 mmol), a phosphonate (1S,2S)-9aj (0.064 g,
92%) was obtained as a white solid after purification on a silica gel
column with chloroform–methanol mixtures (100:1, v/v) and crystalli-
zation from ethyl acetate–petroleum ether. ½αꢀ2D0 = −7.7 (c = 1.39 in
CHCl3); m.p.: 96–97°C; IR (KBr): ν = 3282, 3065, 3032, 2996,
Diethyl {4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}methylphosphonate 9ba
From diethyl azidomethylphosphonate 11a (0.062 g, 0.321 mmol)
and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b (0.084 g,
0.321 mmol), a phosphonate 9ba (0.124 g, 85%) was obtained as
white needles after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v) and crystallization from diethyl
ether. M.p.: 145–146°C; IR (KBr): ν = 3406, 3144, 3072, 2986,
1679, 1612, 1497, 1475, 1218, 1024, 776, 752, 698 cm−1
1H NMR (200 MHz, CDCl3): δ = 8.33 (s, 1H), 8.28–8.23 (m, 1H,
;
H
H
aromat.), 7.80–7.68 (m, 3H, Haromat., HC5′), 7.52–7.44 (m, 1H,
aromat.), 7.37–7.27 (m, 10H, Haromat), 7.22–7.13 (m, 3H, Haromat),
2933, 1666, 1608, 1468, 1238, 1023, 799 cm−1 1H NMR
;
(200 MHz, CDCl3): δ = 8.39 (dd, J = 2.3 Hz, J = 0.4 Hz, 1H, Haromat.),
8.34 (s, 1H), 7.94 (s, 1H, HC5′), 7.82 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H,
7.11–7.06 (m, 2H, Haromat), 5.23 (AB, J = 14.8 Hz, 1H, CHaHb), 5.17
(AB, J = 14.8 Hz, 1H, CHaHb), 5.06–5.00 (m, 4H, 2 × POCH2Ph),
4.60–4.37 (m, 3H, OCHaHbPh, H-3a, H-3b), 4.32–4.22 (m, 1H, H-
2), 4.19 (d, J = 10.8 Hz, 1H, OCHaHbPh), 3.86 (brd, J = 8.0 Hz, 1H,
H-1), 3.16 (brs, 1H, OH); 13C NMR (151 MHz, CDCl3): δ = 160.85
Haromat.), 7.58 (d, J = 8.7 Hz, 1H, Haromat.), 5.26 (s, 2H, CH2), 4.73 (d,
J = 13.1 Hz, 2H, PCH2), 4.20–4.05 (m, 4H, 2 × POCH2CH3), 1.28 (t,
J = 7.1 Hz, 3H, POCH2CH3), 1.27 (t, J = 7.1 Hz, 3H, POCH2CH3);
13

C NMR (151 MHz, CDCl3): δ = 159.72 (s, C O), 147.02, 146.51,

(s, C O), 148.11, 146.40, 142.12, 136.83, 135.95 (d, J = 5.6 Hz,
142.37, 137.59, 129.51, 129.33, 124.77, 123.38, 121.01, 63.54 (d,
J = 6.6 Hz, POC), 45.99 (d, J = 155.4 Hz, PC), 41.72, 16.26 (d, J = 5.6 Hz,
POCC); 31P NMR (81 MHz, CDCl3): δ = 16.25 ppm. Anal. calcd. for
C
ipso), 135.80 (d, J = 5.6 Hz, Cipso), 134.37, 128.66, 128.64, 128.58,
128.35, 128.27, 128.18, 128.12, 128.04, 127.62, 127.32, 126.56,
125.24, 121.99, 74.08 (s, PCC), 68.58 (d, J = 6.8 Hz, POC), 68.37
(d, J = 162.0 Hz, PC), 68.28 (d, J = 6.8 Hz, POC), 50.78 (d,
J = 11.7 Hz, PCCC), 41.50; 31P NMR (81 MHz, CDCl3):
δ = 22.51 ppm. Anal. calcd. for C35H34N5O6P: C, 64.51; H, 5.26;
N, 10.70. Found: C, 64.60; H, 5.03; N, 10.77.
C16H19BrN5O4P: C, 42.12; H, 4.20; N, 15.35. Found: C, 42.15; H, 4.01;
N, 15.09.
Diethyl 2-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethylphosphonate 9bb
From diethyl 2-azidoethylphosphonate 11b (0.067 g, 0.323 mmol)
and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b (0.085 g,
0.323 mmol), a phosphonate 9bb (0.102 g, 67%) was obtained as a
white solid after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v) and crystallization from diethyl
ether. M.p.: 103–105°C; IR (KBr): ν = 3386, 2984, 2928, 1678,
(1R,2S)-Dibenzyl 2-benzyloxy-1-hydroxy-3-{4-[4-oxoquinazolin-
3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate
(1R,2S)-9aj
From (1R,2S)-dibenzyl 3-azido-2-benzyloxy-1-hydroxypropylphosph-
onate 11j (0.050 g, 0.109 mmol) and N3-propargylquinazolin-4(3H)-
one 13a (0.020 g, 0.109 mmol), a phosphonate (1R,2S)-9aj (0.056 g,
80%) was obtained as a white solid after purification on a silica gel
column with chloroform–methanol mixtures (50:1, v/v) and crystalli-
zation from ethyl acetate–petroleum ether. ½αꢀ2D0 = +2.7 (c = 1.08 in
CHCl3); m.p.: 76–78°C; IR (KBr): ν = 3282, 3065, 3032, 2996,
1608, 1443, 1226, 1025, 835, 785 cm−1 1H NMR (200 MHz,
;
CDCl3): δ = 8.39 (dd, J = 2.3 Hz, J = 0.3 Hz, 1H, Haromat.), 8.34 (s, 1H),
7.82 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H, Haromat.), 7.81 (s, 1H, HC5′), 7.57 (d,
J = 8.7 Hz, 1H, Haromat.), 5.24 (s, 2H, CH2), 4.64–4.51 (m, 2H, PCCH2),
4.13–3.99 (m, 4H, 2 × POCH2CH3), 2.47–2.30 (m, 2H, PCH2), 1.26 (t,
J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR (151 MHz, CDCl3):
δ = 159.79 (s, CO), 147.03, 146.54, 141.96, 137.06, 129.51, 129.12,
124.10, 123.36, 121.02, 62.18 (d, J = 6.4 Hz, POC), 44.73, 41.77, 27.19
(d, J = 141.9 Hz, PC), 16.33 (d, J = 5.7 Hz, POCC); 31P NMR (81 MHz,
CDCl3): δ = 26.02 ppm. Anal. calcd. for C17H21BrN5O4P: C, 43.42; H,
4.50; N, 14.89. Found: C, 40.41; H, 4.22; N, 15.05.
1679, 1612, 1497, 1475, 1218, 1024, 776, 752, 698 cm−1
1H NMR (200 MHz, CDCl3): δ = 8.34 (s, 1H), 8.30–8.23 (m, 1H,
;
H
H
aromat.), 7.82–7.68 (m, 3H, Haromat., HC5′), 7.52–7.44 (m, 1H,
aromat.), 7.36–7.24 (m, 10H, Haromat), 7.21–7.13 (m, 3H, Haromat),
7.11–7.03 (m, 2H, Haromat), 5.23 (AB, J = 14.6 Hz, 1H, CHaHb), 5.18
(AB, J = 14.6 Hz, 1H, CHaHb), 5.06–4.99 (m, 4H, 2 × POCH2Ph),
4.70 (dd, J = 14.6 Hz, J = 3.7 Hz, 1H, H-3a), 4.59 (dd, J = 14.6 Hz,
J = 6.5 Hz, 1H, H-3b), 4.39 (AB, J = 11.3 Hz, 1H, OCHaHbPh), 4.28
(d, J = 11.3 Hz, 1H, OCHaHbPh), 4.19–4.07 (m, 1H, H-2), 3.97 (dd,
J = 8.9 Hz, J = 5.7 Hz, 1H, H-1), 3.61 (brs, 1H, OH); 13C NMR
Diethyl 3-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylphosphonate 9bc
From diethyl 3-azidopropylphosphonate 11c (0.063 g, 0.285 mmol)
and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b (0.075 g,
0.285 mmol), a phosphonate 9bc (0.100 g, 72%) was obtained as

(151 MHz, CDCl3): δ = 160.85 (s, C O), 148.12, 146.44, 141.95,
136.77, 135.92 (d, J = 5.5 Hz, Cipso), 135.83 (d, J = 5.5 Hz, Cipso),

GŁOWACKA ET AL.
9 of 14
|
white needles after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v) and crystallization from diethyl ether–
petroleum ether. M.p.: 92–94°C; IR (KBr): ν = 3485, 3143, 2984, 1675,
129.48, 129.14, 124.73, 123.42, 120.92, 71.09 (d, J = 9.9 Hz,
OCH2CH2N), 65.34 (d, J = 166.4 Hz, PC), 62.50 (d, J = 6.6 Hz, POC),
50.20 (s, OCH2CH2N), 41.57, 16.44 (d, J = 5.5 Hz, POCC); 31P NMR
(81 MHz, CDCl3): δ = 21.13 ppm. Anal. calcd. for C18H23BrN5O5P: C,
43.21; H, 4.63; N, 14.00. Found: C, 42.86; H, 4.64; N, 13.70.
1607, 1467, 1226, 1025, 787 cm−1 1H NMR (200 MHz, CDCl3):
;
δ = 8.39 (dd, J = 2.3 Hz, J = 0.4 Hz, 1H, Haromat.), 8.34 (s, 1H), 8.82 (dd,
J = 8.7 Hz, J = 2.3 Hz, 1H, Haromat.), 7.78 (s, 1H, HC5′), 7.57 (d,
J = 8.7 Hz, 1H, Haromat.), 5.24 (s, 2H, CH2), 4.42 (t, J = 7.0 Hz, 2H,
PCCCH2), 4.16–3.98 (m, 4H, 2 × POCH2CH3), 2.31–2.09 (m, 2H,
PCCH2), 1.78–1.61 (m, 2H, PCH2), 1.29 (t, J = 7.1 Hz, 6H,
2 × POCH2CH3); 13C NMR (151 MHz, CDCl3): 159.82 (s, CO),
147.06, 146.56, 142.00, 137.57, 129.52, 129.14, 123.96, 123.39,
120.99, 61.83 (d, J = 6.6 Hz, POC), 50.17 (d, J = 14.9 Hz, PCCC), 41.81,
23.59 (d, J = 4.5 Hz, PCC), 22.65 (d, J = 143.7 Hz, PC), 16.42 (d,
J = 6.0 Hz, POCC); 31P NMR (81 MHz, CDCl3): δ = 30.64 ppm. Anal.
calcd. for C18H23BrN5O4P: C, 44.64; H, 4.79; N, 14.46. Found: C,
44.54; H, 5.14; N, 14.40.
Diethyl 2-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethoxyethylphosphonate 9bf
From diethyl 2-(2-azidoethoxy)ethylphosphonate 11f (0.070 g,
0.279 mmol) and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b
(0.069 g, 0.279 mmol),
a phosphonate 9bf (0.112 g, 78%) was
obtained as a white solid after purification on a silica gel column
with chloroform–methanol mixtures (100:1, v/v) and crystallization
from ethyl acetate–petroleum ether. M.p.: 102–103°C; IR (KBr):
ν = 3406, 3146, 2985, 2907, 2876, 1681, 1608, 1468, 1228, 1027,
755 cm−1
;
1H NMR (200 MHz, CDCl3): δ = 8.40 (d, J = 2.3 Hz, 1H,
H
aromat.), 8.36 (s, 1H), 7.90 (s, 1H, HC5′), 7.82 (dd, J = 8.7 Hz,
Diethyl 4-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}butylphosphonate 9bd
J = 2.3 Hz, 1H, Haromat.), 7.57 (d, J = 8.7 Hz, 1H, Haromat.), 5.26 (s, 2H,
CH2), 4.50 (t, J = 4.9 Hz, 2H, OCH2CH2N), 4.14–3.99 (m, 4H,
2 × POCH2CH3), 3.77 (t, J = 5.0 Hz, 2H, OCH2CH2N), 3.69 (dt,
J = 12.2 Hz, J = 7.4 Hz, 2H, PCH2CH2O), 2.05 (dt, J = 14.8 Hz,
From diethyl 4-azidobutylphosphonate 11d (0.063 g, 0.268 mmol)
and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b (0.070 g,
0.268 mmol), a phosphonate 9bd (0.124 g, 93%) was obtained as a
colorless oil after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). IR (film): ν = 3346, 3128, 3076, 3059,
2989, 2955, 2872, 1680, 1606, 1467, 1247, 1209, 1057, 1028, 836,
J = 7.4 Hz, 2H, PCH2CH2O), 1.30 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3);
13

C NMR (151 MHz, CDCl3): δ = 159.75 (s, C O), 147.04, 146.67,
141.85, 137.50, 129.48, 129.15, 124.76, 123.45, 120.91, 68.77 (s,
OCH2CH2N), 65.29 (s, PCH2CH2O), 61.69 (d, J = 6.6 Hz, POC), 50.29
(s, OCH2CH2N), 41.64, 26.85 (d, J = 140.3 Hz, PC), 16.42 (d,
J = 6.5 Hz, POCC); 31P NMR (81 MHz, CDCl3): δ = 28.66 ppm. Anal.
calcd. for C19H25BrN5O5P: C, 44.37; H, 4.90; N, 13.62. Found: C,
44.67; H, 4.80; N, 13.43.
780 cm−1
;
1H NMR (200 MHz, CDCl3 δ = 8.39 (d, J = 2.3 Hz, 1H,
H
aromat.), 8.35 (s, 1H), 7.82 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H, Haromat.), 7.73
(s, 1H, HC5′), 7.57 (d, J = 8.7 Hz, 1H, Haromat.), 5.24 (s, 2H, CH2), 4.33 (t,
J = 7.1 Hz, 2H, PCCCCH2), 4.15–3.96 (m, 4H, 2 × POCH2CH3), 2.08–
1.93 (m, 2H, PCCCH2), 1.83–1.53 (m, 4H, PCH2, PCCH2), 1.28 (t,
J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR (151 MHz, CDCl3):
Diethyl 2-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}-1-hydroxyethylphosphonate 9bg

C O), 147.06, 146.58, 141.98, 137.60, 137.56,
δ = 159.83 (s,
129.52, 129.13, 123.63, 123.39, 120.97, 61.61 (d, J = 6.5 Hz, POC),
49.87, 41.82, 30.65 (d, J = 15.3 Hz, PCCC); 25.00 (d, J = 142.5 Hz, PC);
19.71 (d, J = 5.0 Hz, PCC); 16.43 (d, J = 5.9 Hz, POCC); 31P NMR
(81 MHz, CDCl3): δ = 31.66 ppm. Anal. calcd. for C19H25BrN5O4P: C,
45.80; H, 5.06; N, 14.05. Found: C, 45.96; H, 4.88; N, 14.22.
From diethyl 2-azido-1-hydroxyethylphosphonate 11g (0.065 g,
0.291 mmol) and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b
(0.077 g, 0.291 mmol), a phosphonate 9bg (0.132 g, 93%) was obtained
as white needles after purification on a silica gel column with
chloroform–methanol mixtures (100:1, v/v) and crystallization from
ethyl acetate. M.p.: 72–73°C; IR (KBr): ν = 3261, 2985, 2931, 2910,
Diethyl 2-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethoxymethylphosphonate 9be
2868, 1681, 1609, 1469, 1224, 1048, 1023, 733 cm−1 1H NMR
;
(200 MHz, CDCl3): δ = 8.34 (d, J = 2.3 Hz, 1H, Haromat.), 8.33 (s, 1H),
7.97 (s, 1H, HC5′), 7.80 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H, Haromat.), 7.54 (d,
J = 8.7 Hz, 1H, Haromat.), 5.28 (AB, J = 14.8 Hz, 1H, CHaHb), 5.22 (AB,
J = 14.8 Hz, 1H, CHaHb), 4.78 (ddd, J = 14.1 Hz, J = 5.5 Hz, J = 2.6 Hz,
1H, PCCHaHb), 4.47 (ddd, J = 14.1 Hz, J = 9.9 Hz, J = 5.5 Hz, 1H,
PCCHaHb), 4.33–4.08 (m, 5H, PCH(OH), 2 × POCH2CH3), 1.33 (t,
From diethyl (2-azidoethoxy)methylphosphonate 11e (0.071 g,
0.299 mmol) and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b
(0.076 g, 0.299 mmol), a phosphonate 9be (0.114 g, 76%) was obtained
as a colorless oil after purification on a silica gel column with
chloroform–methanol mixtures (100:1, v/v). IR (film): ν = 3442, 3147,
3070, 2985, 2909, 1681, 1609, 1469, 1231, 1028, 835, 755 cm−1
;
J = 7.0 Hz, 3H, POCH2CH3), 1.31 (t, J = 7.0 Hz, 3H, POCH2CH3);
13
1H NMR (200 MHz, CDCl3): δ = 8.39 (d, J = 2.2 Hz, 1H, Haromat.), 8.35 (s,
1H), 7.89 (s, 1H, HC5′), 7.81 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H, Haromat.),
7.57 (d, J = 8.6 Hz, 1H, Haromat.), 5.25 (s, 2H, CH2), 4.53 (t, J = 4.9 Hz,
2H, OCH2CH2N), 4.18–4.03 (m, 4H, 2 × POCH2CH3), 3.97 (t,
J = 4.9 Hz, 2H, OCH2CH2N), 3.75 (d, J = 8.1 Hz, 2H, PCH2O), 1.30 (t,
J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR (151 MHz, CDCl3):
C NMR (151 MHz, CDCl3): δ = 159.69 (s, C O), 146.79, 141.64,

137.54, 129.30, 129.00, 125.58, 123.21, 120.95, 66.95 (d,
J = 164.3 Hz, PC), 63.53 (d, J = 6.9 Hz, POC); 63.36 (d, J = 6.9 Hz,
POC), 51.74 (d, J = 9.8 Hz, PCC), 41.65, 16.43 (d, J = 5.8 Hz, POCC),
16.39 (d, J = 5.8 Hz, POCC); 31P NMR (81 MHz, CDCl3): δ = 20.74 ppm.
Anal. calcd. for C17H21BrN5O5P: C, 41.99; H, 4.35; N, 14.40. Found: C,
42.07; H, 4.65; N, 14.49.

C O), 147.02, 146.64, 141.97, 137.52, 137.52,
δ = 159.71 (s,

10 of 14
GŁOWACKA ET AL.
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Diethyl 3-{4-[6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}-2-hydroxypropylphosphonate 9bh
propargylquinazolin-4(3H)-one 13b (0.034 g, 0.128 mmol), a phos-
phonate (1S,2S)-9bj (0.078 g, 83%) was obtained as a white powder
after purification on a silica gel column with chloroform–methanol
mixtures (100:1, v/v). ½αꢀD20 = −4.2 (c = 1.59 in CHCl3); m.p.: 105–
107°C; IR (KBr): ν = 3278, 3075, 3030, 2988, 1682, 1610, 1477,
From diethyl 3-azido-2-hydroxypropylphosphonate 11h (0.065 g,
0.274 mmol) and 6-bromo-N3-propargylquinazolin-4(3H)-one 13b
(0.072 g, 0.274 mmol), a phosphonate 9bh (0.113 g, 82%) was
obtained as a white solid after purification on a silica gel column
with chloroform–methanol mixtures (50:1, v/v) and crystallization
from ethyl acetate–diethyl ether. M.p.: 134–136°C; IR (KBr):
ν = 3336, 3151, 3087, 2985, 2929, 2910, 2869, 1681, 1609, 1469,
;
1465, 1211, 1027, 788, 752, 698 cm−1 1H NMR (200 MHz,
CDCl3): δ = 8.36 (d, J = 2.3 Hz, 1H, Haromat.), 8.35 (s, 1H), 7.80 (dd,
J = 8.7 Hz, J = 2.3 Hz, 1H, Haromat.), 7.71 (s, 1H, HC5′), 7.56 (d,
J = 8.7 Hz, 1H, Haromat.), 7.35–7.28 (m, 10H, Haromat), 7.25–7.15 (m,
3H, Haromat), 7.14–7.04 (m, 2H, Haromat), 5.22 (AB, J = 14.8 Hz, 1H,
CHaHb), 5.18 (AB, J = 14.8 Hz, 1H, CHaHb), 5.11–4.95 (m, 4H,
2 × POCH2Ph), 4.62–4.39 (m, 3H, OCHaHbPh, H-3a, H-3b), 4.33–
4.22 (m, 1H, H-2), 4.17 (d, J = 10.8 Hz, 1H, OCHaHbPh), 3.88 (dd,
J = 11.5 Hz, J = 3.0 Hz, 1H, H-1), 3.02 (brs, 1H, OH); 13C NMR
1227, 1027, 732 cm−1 1H NMR (200 MHz, CDCl3): δ = 8.39 (dd,
;
J = 2.3 Hz, J = 0.3 Hz, 1H, Haromat.), 8.35 (s, 1H), 7.93 (s, 1H, HC5′),
7.80 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H, Haromat.), 7.56 (d, J = 8.7 Hz, 1H,
H
aromat.), 5.28 (AB, J = 14.8 Hz, 1H, CHaHb), 5.25 (AB, J = 14.8 Hz,
1H, CHaHb), 4.58–4.29 (m, 3H, PCCHCH2), 4.21–4.00 (m, 4H,
2 × POCH2CH3), 2.08–1.67 (m, 3H, PCH2, OH), 1.32 (t, J = 7.1 Hz,
3H, POCH2CH3), 1.31 (t, J = 7.1 Hz, 3H, POCH2CH3); 13C NMR
(151 MHz, CDCl3): δ = 159.69 (s, CO), 146.86, 146.75, 141.73,
137.49, 129.34, 129.06, 125.43, 123.27, 120.91, 65.42 (d,
J = 5.0 Hz, PCC), 62.31 (d, J = 6.4 Hz, POC), 62.20 (d, J = 6.4 Hz,
POC), 56.04 (d, J = 16.9 Hz, PCCC), 41.63, 30.84 (d, J = 140.6 Hz,
PC), 16.34 (d, J = 5.6 Hz, POCC), 16.30 (d, J = 5.6 Hz, POCC);
31P NMR (81 MHz, CDCl3): δ = 29.06 ppm. Anal. calcd. for

(151 MHz, CDCl3): δ = 159.66 (s, C O), 146.95, 146.64, 141.81,
137.54, 136.75, 135.89 (d, J = 5.9 Hz, Cipso), 135.74 (d, J = 5.9 Hz,
Cipso), 129.45, 129.17, 128.70, 128.67, 128.64, 128.39, 128.20,
128.15, 128.09, 125.23, 123.36, 125.23, 123.38, 120.97,
74.11 (s, PCC), 68.61 (d, J = 7.3 Hz, POC), 68.38 (d, J = 161.9 Hz,
PC), 68.29 (d, J = 7.3 Hz, POC), 50.82 (d, J = 12.0 Hz, PCCC), 41.63;
31P NMR (81 MHz, CDCl3): δ = 22.52 ppm. Anal. calcd. for
C35H33BrN5O6P: C, 57.54; H, 4.55; N, 9.59. Found: C, 57.82; H,
C
18H23BrN5O5P: C, 43.21; H, 4.63; N, 14.00. Found: C, 43.32;
4.33; N, 9.73.
H, 4.60; N, 13.93.
(1R,2S)-Dibenzyl 2-benzyloxy-3-{4-[6-bromo-4-oxoquinazolin-3
(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-1-hydroxypropylphosphonate
(1R,2S)-9bj
Diethyl {2-[4-(6-bromo-4-oxoquinazolin-3(4H)-yl)methyl)-1H-
1,2,3-triazol-1-yl]acetamido}methylphosphonate 9bi
From diethyl (2-azidoacetamido)methylphosphonate 11i (0.067 g,
0.268 mmol) and 6-bromo-N3-propargylquinazolin-4(3H)-one
13b (0.070 g, 0.268 mmol), a phosphonate 9bi (0.101 g, 73%)
was obtained as a white solid after purification on a silica gel
column with chloroform–methanol mixtures (50:1, v/v) and
crystallization from diethyl ether–petroleum ether. M.p.: 193–
194°C; IR (KBr): ν = 3252, 3136, 3070, 2987, 2937, 1692, 1674,
From (1R,2S)-dibenzyl 3-azido-2-benzyloxy-1-hydroxypropylphosph-
onate (1R,2S)-11j (0.060 g, 0.128 mmol) and 6-bromo-N3-propargyl-
quinazolin-4(3H)-one 13b (0.034 g, 0.128 mmol),
a phosphonate
(1R,2S)-9bj (0.082 g, 87%) was obtained as a white powder after
purification on a silica gel column with chloroform–methanol mixtures
(100:1, v/v). ½αꢀ2D0 = +1.6 (c = 1.40 in CHCl3); m.p.: 116–117°C; IR
(KBr): ν = 3189, 3054, 2998, 2886, 1660, 1612, 1464, 1446, 1230,
1469, 1211, 1054, 1022, 879, 756 cm−1
;
1H NMR (200 MHz,
1025, 757, 699 cm−1
8.35 (d, J = 2.2 Hz, 1H, Haromat.), 7.79 (dd, J = 8.7 Hz, J = 2.2 Hz, 1H,
aromat.), 7.71 (s, 1H, HC5′), 7.57 (d, J = 8.7 Hz, 1H, Haromat.), 7.35–
7.24 (m, 10H, Haromat), 7.22–7.12 (m, 3H, Haromat), 7.11–7.01 (m,
2H, aromat), 5.23 (AB, J = 14.8 Hz, 1H, CHaHb), 5.16 (AB,
;
1H NMR (200 MHz, CDCl3): δ = 8.37 (s, 1H),
CDCl3): δ = 8.40 (d, J = 2.4 Hz, 1H, Haromat.), 8.39 (s, 1H), 7.96 (s,
1H, HC5′), 7.82 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H, Haromat.), 7.59 (d,
J = 8.8 Hz, 1H, Haromat.), 7.05 (brs, 1H, NH), 5.28 (s, 2H, CH2), 5.08
(s, 2H, CH2), 4.17–4.02 (m, 4H, 2 × POCH2CH3), 3.69 (dd,
J = 12.1 Hz, J = 5.9 Hz, 2H, PCH2), 1.28 (t, J = 7.1 Hz, 6H,
2 × POCH2CH3); 13C NMR (151 MHz, CDCl3): δ = 164.82 (d,

H
H
J = 14.8 Hz, 1H, CHaHb), 5.06–4.99 (m, 4H, 2 × POCH2Ph), 4.71
(dd, J = 14.7 Hz, J = 3.5 Hz, 1H, H-3a), 4.60 (dd, J = 14.7 Hz,
J = 6.4 Hz, 1H, H-3b), 4.40 (AB, J = 11.0 Hz, 1H, OCHaHbPh),
4.26 (d, J = 11.0 Hz, 1H, OCHaHbPh), 4.20–4.06 (m, 1H, H-2),
3.98 (dd, J = 9.2 Hz, J = 6.0 Hz, 1H, H-1), 3.01 (brs, 1H, OH);
13C NMR (151 MHz, CDCl3): δ = 159.65 (s, CO), 146.91, 146.71,
141.85, 137.54, 136.72, 135.86 (d, J = 5.5 Hz, Cipso), 135.78 (d,
J = 5.5 Hz, Cipso), 129.42, 129.18, 128.67, 128.63, 128.43, 128.18,
128.15, 128.09, 128.07, 125.42, 123.38, 120.97, 77.66 (d,
J = 4.5 Hz, PCC), 72.86, 68.54 (d, J = 6.7 Hz, POC), 68.42 (d,
J = 6.7 Hz, POC), 67.86 (d, J = 161.8 Hz, PC), 50.33 (d, J = 6.0 Hz,
PCCC), 41.60; 31P NMR (81 MHz, CDCl3): δ = 23.69 ppm. Anal.
calcd. for C35H33BrN5O6P: C, 57.54; H, 4.55; N, 9.59. Found: C,
57.46; H, 4.23; N, 9.80.
J = 5.7 Hz,
C
O), 159.80 (s, CO), 146.98, 146.56, 142.31,
137.64, 129.47, 129.18, 125.49, 123.37, 121.07, 62.95 (d,
J = 6.6 Hz, POC), 52.57 (s, CH2N), 41.77, 35.02 (d, J = 157.3 Hz,
PC), 16.32 (d, J = 5.9 Hz, POCC); 31P NMR (81 MHz, CDCl3):
δ = 22.23 ppm. Anal. calcd. for C18H22BrN6O5P: C, 42.12; H, 4.32;
N, 16.37. Found: C, 42.17; H, 4.38; N, 16.52.
(1S,2S)-Dibenzyl 2-benzyloxy-3-{4-[6-bromo-4-oxoquinazolin-3
(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-1-hydroxypropylphosphonate
(1S,2S)-9bj
From (1S,2S)-dibenzyl 3-azido-2-benzyloxy-1-hydroxypropyl-
phosphonate (1S,2S)-11j (0.060 g, 0.128 mmol) and 6-bromo-N3-

GŁOWACKA ET AL.
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Diethyl {4-[6-nitro-4-oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-
triazol-1-yl}methylphosphonate 9ca
1H, Haromat.), 8.50 (s, 1H), 7.84 (dd, J = 8.9 Hz, J = 0.4 Hz, 1H,
aromat.), 7.82 (s, 1H, HC5′), 5.29 (s, 2H, CH2), 4.44 (t, J = 7.0 Hz,
H
From diethyl azidomethylphosphonate 11a (0.050 g, 0.259 mmol) and
6-nitro-N3-propargylquinazolin-4(3H)-one 13c (0.059 g, 0.259 mmol),
a phosphonate 9ca (0.096 g, 88%) was obtained as white solid after
purification on a silica gel column with chloroform–methanol mixtures
(100:1, v/v) and crystallization from ethyl acetate–petroleum
ether. M.p.: 187–188°C; IR (KBr): ν = 3334, 3054, 2966, 2914,
2H, PCCCH2), 4.16–4.01 (m, 4H, 2 × POCH2CH3), 2.32–2.10 (m,
2H, PCCH2), 1.81–1.59 (m, 2H, PCH2), 1.31 (t, J = 7.1 Hz, 6H,
2 × POCH2CH3); 13C NMR (151 MHz, CDCl3): δ = 159.89 (s, CO),
152.20, 149.22, 146.10, 141.45, 129.40, 128.38, 124.10, 123.21,
122.26, 61.83 (d, J = 6.6 Hz, POC), 50.20 (d, J = 15.1 Hz, PCCC),
41.92, 23.60 (d, J = 4.6 Hz, PCC), 22.64 (d, J = 143.4 Hz, PC), 16.42
(d, J = 6.1 Hz, POCC); 31P NMR (81 MHz, CDCl3): δ = 30.59 ppm.
Anal. calcd. for C18H23N6O6P: C, 48.00; H, 5.15; N, 18.66. Found:
C, 48.28; H, 5.29; N, 18.52.
1670, 1611, 1458, 1222, 1025, 844 cm−1 1H NMR (200 MHz,
;
CDCl3): δ = 9.11 (dd, J = 2.6 Hz, J = 0.4 Hz, 1H, Haromat.), 8.51 (dd,
J = 8.9 Hz, J = 2.6 Hz, 1H, Haromat.), 8.48 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H,
HC5′), 7.83 (d, J = 8.9 Hz, 1H, Haromat.), 5.30 (s, 2H, CH2), 4.75 (d,
J = 13.2 Hz, 2H, PCH2), 4.21–4.06 (m, 4H, 2 × POCH2CH3), 1.29 (t,
J = 7.1 Hz, 3H, POCH2CH3), 1.28 (t, J = 7.1 Hz, 3H, POCH2CH3);
13C NMR (151 MHz, CDCl3): δ = 159.77 (s, CO), 152.16, 149.17,
146.11, 141.82, 129.73, 128.39, 124.86, 123.17, 122.24, 63.56 (d,
J = 6.6 Hz, POC), 46.04 (d, J = 155.3 Hz, PC), 41.84, 16.28 (d, J = 5.6 Hz,
POCC); 31P NMR (81 MHz, CDCl3): δ = 16.23 ppm. Anal. calcd. for
Diethyl 4-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}butylphosphonate 9cd
From diethyl 4-azidobutylphosphonate 11d (0.100 g, 0.425 mmol) and
6-nitro-N3-propargylquinazolin-4(3H)-one 13c (0.097 g, 0.425 mmol),
a phosphonate 9 cd (0.166 g, 84%) was obtained as a colorless oil after
purification on a silica gel column with chloroform–methanol mixtures
(100:1, v/v). IR (film): ν = 3330, 3055, 2989, 2888, 1677, 1615, 1473,
1249, 1220, 1021, 840, 779 cm−1; 1H NMR (600 MHz, CDCl3 δ = 9.16
(d, J = 2.6 Hz, 1H, Haromat.), 8.55 (dd, J = 8.9 Hz, J = 2.6 Hz, 1H, Haromat.),
8.53 (s, 1H), 7.86 (d, J = 8.9 Hz, 1H, Haromat.), 7.79 (s, 1H, HC5′), 5.31 (s,
2H, CH2), 4.38 (t, J = 7.1 Hz, 2H, PCCCCH2), 4.14–4.04 (m, 4H,
2 × POCH2CH3), 2.53 (qu, J = 7.1 Hz, 2H, PCCCH2), 1.80–1.74 (m, 2H,
PCCH2), 1.70–1.63 (m, 2H, PCH2), 1.32 (t, J = 7.2 Hz, 6H,
2 × POCH2CH3); 13C NMR (151 MHz, CDCl3): δ = 159.90 (s, CO),
152.21, 149.22, 146.11, 141.44, 129.41, 128.38, 123.75, 123.22,
122.26, 61.63 (d, J = 6.6 Hz, POC), 49.94, 41.94, 30.64 (d, J = 15.0 Hz,
PCCC); 24.99 (d, J = 142.2 Hz, PC); 19.70 (d, J = 5.2 Hz, PCC); 16.43 (d,
J = 5.7 Hz, POCC); 31P NMR (243 MHz, CDCl3): δ = 30.72 ppm. Anal.
calcd. for C19H25N6O6P: C, 49.14; H, 5.43; N, 18.10. Found: C, 49.30;
H, 5.18; N, 18.37.
C16H19N6O6P: C, 45.50; H, 4.53; N, 19.90. Found: C, 45.75; H, 4.22; N,
20.12.
Diethyl 2-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethylphosphonate 9cb
From diethyl 2-azidoethylphosphonate 11b (0.068 g, 0.328 mmol)
and
6-nitro-N3-propargylquinazolin-4(3H)-one
13c
(0.075 g,
0.328 mmol), a phosphonate 9cb (0.104 g, 73%) was obtained as
white solid after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v) and crystallization from ethyl
acetate–petroleum ether. M.p.: 139–140°C; IR (KBr): ν = 3334,
3054, 2966, 2914, 1670, 1611, 1458, 1222, 1025, 844 cm−1
1H NMR (200 MHz, CDCl3): δ = 9.12 (dd, J = 2.6 Hz, J = 0.3 Hz, 1H,
aromat.), 8.53 (dd, J = 8.6 Hz, J = 2.6 Hz, 1H, Haromat.), 8.49 (s, 1H),
;
H
7.84 (s, 1H, HC5′), 7.83 (d, J = 8.6 Hz, 1H, Haromat.), 5.29 (s, 2H, CH2),
4.66–4.53 (m, 2H, PCCH2), 4.15–4.00 (m, 4H, 2 × POCH2CH3), 2.48–
2.31 (m, 2H, PCH2), 1.28 (t, J = 7.1 Hz, 6H, 2 × POCH2CH3); 13C NMR
(151 MHz, CDCl3): δ = 159.83 (s, CO), 152.17, 149.22, 146.10,
141.43, 129.39, 128.38, 124.18, 123.16, 122.21, 62.19 (d,
J = 6.5 Hz, POC), 44.79, 41.86, 27.19 (d, J = 141.9 Hz, PC), 16.33
(d, J = 6.1 Hz, POCC); 31P NMR (81 MHz, CDCl3): δ = 25.56 ppm.
Anal. calcd. for C17H21N6O6P: C, 46.79; H, 4.85; N, 19.26. Found: C,
46.66; H, 5.02; N, 19.39.
Diethyl 2-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethoxymethylphosphonate 9ce
From diethyl (2-azidoethoxy)methylphosphonate 11e (0.067 g,
0.283 mmol) and 6-nitro-N3-propargylquinazolin-4(3H)-one 13c
(0.065 g, 0.283 mmol), a phosphonate 9ce (0.086 g, 65%) was obtained
as a yellowish oil after purification on a silica gel column with
chloroform–methanol mixtures (100:1, v/v). IR (film): ν = 3423, 3147,
3094, 2986, 1688, 1617, 1345, 1231, 1026, 665 cm−1 1H NMR
;
(600 MHz, CDCl3): δ = 9.14 (d, J = 2.6 Hz, 1H, Haromat.), 8.54 (dd,
J = 8.9 Hz, J = 2.6 Hz, 1H, Haromat.), 8.53 (s, 1H), 7.96 (s, 1H, HC5′), 7.85
(d, J = 8.9 Hz, 1H, Haromat.), 5.32 (s, 2H, CH2), 4.57 (t, J = 4.9 Hz, 2H,
OCH2CH2N), 4.17–4.12 (m, 4H, 2 × POCH2CH3), 4.00 (t, J = 4.9 Hz,
2H, OCH2CH2N), 3.79 (d, J = 8.2 Hz, 2H, PCH2O), 1.34 (t, J = 7.1 Hz,
6H, 2 × POCH2CH3); 13C NMR (151 MHz, CDCl3): δ = 159.79 (s, CO),
152.19, 149.28, 146.07, 141.48, 129.36, 128.35, 124.90, 123.23,
122.29, 71.08 (d, J = 9.9 Hz, OCH2CH2N), 65.37 (d, J = 167.1 Hz, PC),
62.54 (d, J = 6.6 Hz, POC), 50.27 (s, OCH2CH2N), 41.72, 16.46 (d,
J = 5.5 Hz, POCC); 31P NMR (243 MHz, CDCl3): δ = 20.23 ppm. Anal.
calcd. for C18H23N6O7P: C, 46.35; H, 4.97; N, 18.02. Found: C, 46.04;
H, 4.84; N, 18.20.
Diethyl 3-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylphosphonate 9cc
From diethyl 3-azidopropylphosphonate 11c (0.108 g, 0.488 mmol)
and 6-nitro-N3-propargylquinazolin-4(3H)-one 13c (0.112 g,
0.488 mmol), a phosphonate 9cc (0.195 g, 89%) was obtained as
white solid after purification on
a silica gel column with
chloroform–methanol mixtures (100:1, v/v) and crystallization
from ethyl acetate–petroleum ether. M.p.: 91–92°C; IR (KBr):
ν = 3334, 3086, 2999, 2878, 1666, 1615, 1444, 1230,
1024, 789 cm−1
;
1H NMR (200 MHz, CDCl3): δ = 9.14 (dd,
J = 2.6 Hz, J = 0.4 Hz, 1H, Haromat.), 8.52 (dd, J = 8.9 Hz, J = 2.6 Hz,

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Diethyl 2-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)methyl]-1H-
1,2,3-triazol-1-yl}ethoxyethylphosphonate 9cf
1616, 1369, 1047, 1026, 752 cm−1
;
1H NMR (200 MHz, CDCl3):
δ = 9.14 (d, J = 2.6 Hz, 1H, Haromat.), 8.51 (dd, J = 8.7 Hz, J = 2.6 Hz, 1H,
From diethyl 2-(2-azidoethoxy)ethylphosphonate 11f (0.063 g,
0.251 mmol) and 6-nitro-N3-propargylquinazolin-4(3H)-one 13c
(0.058 g, 0.251 mmol), a phosphonate 9cf (0.102 g, 85%) was obtained
as a yellow oil after purification on a silica gel column with chloroform–
methanol mixtures (100:1, v/v). IR (film): ν = 3385, 3055, 2988, 2866,
1671, 1620, 1433, 1224, 1020, 785 cm−1; 1H NMR (600 MHz, CDCl3):
δ = 9.16 (d, J = 2.6 Hz, 1H, Haromat.), 8.55 (dd, J = 8.9 Hz, J = 2.6 Hz, 1H,
H
aromat.), 8.50 (s, 1H), 8.01 (s, 1H, HC5′), 7.94 (d, J = 8.7 Hz, 1H,
aromat.), 5.48 (s, 2H, CH2), 4.60–4.25 (m, 3H, PCCHCH2), 4.24–3.92
H
(m, 4H, 2 × POCH2CH3), 2.18–1.60 (m, 3H, PCH2, OH), 1.33 (t,
J = 7.1 Hz, 3H, POCH2CH3), 1.32 (t, J = 7.1 Hz, 3H, POCH2CH3);
13

C NMR (151 MHz, CDCl3): δ = 159.82 (s, C O), 152.16, 149.28,
146.08, 141.31, 129.34, 128.37, 125.49, 123.26, 122.27, 65.47 (d,
J = 4.2 Hz, PCC), 62.39 (d, J = 6.7 Hz, POC), 62.35 (d, J = 6.7 Hz, POC),
55.98 (d, J = 18.6 Hz, PCCC), 41.79, 30.68 (d, J = 140.7 Hz, PC), 16.38
(d, J = 6.4 Hz, POCC), 16.34 (d, J = 6.4 Hz, POCC); 31P NMR (81 MHz,
CDCl3): δ = 29.03 ppm. Anal. calcd. for C18H23N6O7P: C, 46.35; H,
4.97; N, 18.02. Found: C, 46.06; H, 4.84; N, 17.82.
H
H
aromat.), 8.54 (s, 1H), 7.98 (s, 1H, HC5′), 7.86 (d, J = 8.9 Hz, 1H,
aromat.), 5.33 (s, 2H, CH2), 4.54 (t, J = 5.0 Hz, 2H, OCH2CH2N), 4.12–
4.08 (m, 4H, 2 × POCH2CH3), 3.84 (t, J = 5.0 Hz, 2H, OCH2CH2N), 3.72
(dt, J = 12.7 Hz, J = 7.3 Hz, 2H, PCH2CH2O), 2.08 (dt, J = 18.7 Hz,
J = 7.4 Hz, 2H, PCH2CH2O), 1.33 (t, J = 7.2 Hz, 6H, 2 × POCH2CH3);
13

C NMR (151 MHz, CDCl3): δ = 159.83 (s, C O), 152.20, 149.34,
Diethyl {2-[4-(6-nitro-4-oxoquinazolin-3(4H)-yl)methyl)-1H-
1,2,3-triazol-1-yl]acetamido}methylphosphonate 9ci
146.07, 141.33, 129.36, 128.34, 124.93, 123.24, 122.30, 68.77 (s,
OCH2CH2N), 65.29 (s, PCH2CH2O), 61.74 (d, J = 6.6 Hz, POC), 50.35
(s, OCH2CH2N), 41.77, 26.86 (d, J = 140.7 Hz, PC), 16.42 (d, J = 6.4 Hz,
POCC); 31P NMR (243 MHz, CDCl3): δ = 27.78 ppm. Anal. calcd. for
From diethyl (2-azidoacetamido)methylphosphonate 11i (0.064 g,
0.256 mmol) and 6-nitro-N3-propargylquinazolin-4(3H)-one 13c
(0.059 g, 0.256 mmol), a phosphonate 9ci (0.075 g, 61%) was obtained
as a white solid after purification on a silica gel column with
chloroform–methanol mixtures (50:1, v/v) and crystallization from
ethyl acetate. M.p.: 198–199°C; IR (KBr): ν = 3332, 3106, 2983, 2830,
1682, 1644, 1429, 1221, 1027, 756 cm−1; 1H NMR (600 MHz, CDCl3):
δ = 9.16 (d, J = 2.8 Hz, 1H, Haromat.), 8.55 (dd, J = 8.5 Hz, J = 2.8 Hz, 1H,
Haromat.), 8.54 (s, 1H), 8.02 (s, 1H, HC5′), 7.87 (d, J = 8.5 Hz, 1H,
C19H25N6O7P: C, 47.50; H, 5.25; N, 17.49. Found: C, 47.75; H, 5.01; N,
17.11.
Diethyl 1-hydroxy-2-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)-
methyl]-1H-1,2,3-triazol-1-yl}ethylphosphonate 9cg
From diethyl 2-azido-1-hydroxyethylphosphonate 11g (0.101 g,
0.453 mmol) and 6-nitro-N3-propargylquinazolin-4(3H)-one 13c
(0.104 g, 0.453 mmol), a phosphonate 9cg (0.187 g, 91%) was obtained
as white needles after purification on a silica gel column with
chloroform–methanol mixtures (100:1, v/v) and crystallization from
ethyl acetate. M.p.: 170–171°C; IR (KBr): ν = 3261, 2985, 2931, 2910,
Haromat.), 7.02 (brs, 1H, NH), 5.34 (s, 2H, CH2), 5.12 (s, 2H, CH2), 4.16–
4.11 (m, 4H, 2 × POCH2CH3), 3.72 (dd, J = 12.4 Hz, J = 5.8 Hz, 2H,
PCH2), 1.32 (t, J = 7.0 Hz, 6H, 2 × POCH2CH3); 13C NMR (151 MHz,


CDCl3): δ = 164.42 (d, J = 5.4 Hz, C O), 159.89 (s, C O), 152.19,
149.18, 146.13, 141.41, 129.42, 128.45, 125.61, 123.24, 122.27,
62.96 (d, J = 6.5 Hz, POC), 52.67 (s, CH2N), 41.89, 35.04 (d,
J = 157.2 Hz, PC), 16.33 (d, J = 6.0 Hz, POCC); 31P NMR (243 MHz,
CDCl3): δ = 21.38 ppm. Anal. calcd. for C18H22N7O7P: C, 45.10; H,
4.63; N, 20.45. Found: C, 44.91; H, 4.39; N, 20.72.
2868, 1681, 1609, 1469, 1224, 1048, 1023, 733 cm−1 1H NMR
;
(200 MHz, CDCl3): δ = 9.11 (d, J = 2.7 Hz, 1H, Haromat.), 8.53 (dd,
J = 8.8 Hz, J = 2.7 Hz, 1H, Haromat.), 8.51 (s, 1H), 7.99 (s, 1H, HC5′), 7.84
(d, J = 8.8 Hz, 1H, Haromat.), 5.34 (AB, J = 14.8 Hz, 1H, CHaHb), 5.25 (AB,
J = 14.8 Hz, 1H, CHaHb), 4.78 (ddd, J = 16.7 Hz, J = 5.8 Hz, J = 2.8 Hz,
1H, PCCHaHb), 4.55–4.40 (m, 2H, PCCHaHb, OH), 4.34–4.10 (m, 5H,
PCH(OH), 2 × POCH2CH3), 1.35 (t, J = 7.1 Hz, 3H, POCH2CH3), 1.33 (t,
J = 7.1 Hz, 3H, POCH2CH3); 13C NMR (151 MHz, CDCl3): δ = 159.84 (s,

(1S,2S)-Dibenzyl 2-benzyloxy-1-hydroxy-3-{4-[6-nitro-4-
oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylphosphonate (1S,2S)-9cj
C
O), 152.12, 149.34, 146.07, 141.20, 129.35, 128.39, 125.64,
From (1S,2S)-dibenzyl 3-azido-2-benzyloxy-1-hydroxypropylphosph-
onate (1S,2S)-11j (0.064 g, 0.137 mmol) and 6-nitro-N3-propargylqui-
nazolin-4(3H)-one 13c (0.031 g, 0.137 mmol), a phosphonate (1S,2S)-
9cj (0.065 g, 68%) was obtained as a white powder after purification on
a silica gel column with chloroform–methanol mixtures (50:1, v/v).
½αꢀ2D0 = −7.3 (c = 1.15 in CHCl3); m.p.: 194–195°C; IR (KBr):
ν = 3280, 3066, 3022, 2984, 2883, 1672, 1620, 1457, 1223,
123.13, 122.21, 67.07 (d, J = 163.6 Hz, PC), 63.65 (d, J = 6.9 Hz, POC);
63.45 (d, J = 6.9 Hz, POC), 51.66 (d, J = 9.1 Hz, PCC), 41.82, 16.45 (d,
J = 5.6 Hz, POCC), 16.40 (d, J = 5.6 Hz, POCC); 31P NMR (81 MHz,
CDCl3): δ = 20.64 ppm. Anal. calcd. for C17H21N6O7P: C, 45.14; H,
4.68; N, 18.58. Found: C, 44.96; H, 4.88; N, 28.39.
Diethyl 2-hydroxy-3-{4-[6-nitro-4-oxoquinazolin-3(4H)-yl)-
methyl]-1H-1,2,3-triazol-1-yl}propylphosphonate 9ch
1024, 757, 699 cm−1
;
1H NMR (200 MHz, CDCl3): δ = 9.07 (d,
J = 2.6 Hz, 1H, aromat.), 8.51 (dd, J = 8.9 Hz, J = 2.6 Hz, 1H,
H
From diethyl 3-azido-2-hydroxypropylphosphonate 11h (0.066 g,
0.278 mmol) and 6-nitro-N3-propargylquinazolin-4(3H)-one 13c
(0.064 g, 0.278 mmol), a phosphonate 9ch (0.104 g, 80%) was obtained
as a white solid after purification on a silica gel column with
chloroform–methanol mixtures (50:1, v/v) and crystallization from
ethyl acetate. M.p.: 158–159°C; IR (KBr): ν = 3317, 2986, 2911, 1689,
Haromat.), 8.47 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H, Haromat.), 7.72 (s,
1H, HC5′), 7.37–7.27 (m, 10H, Haromat), 7.23–7.15 (m, 3H, Haromat),
7.14–7.05 (m, 2H, Haromat), 5.24 (AB, J = 14.6 Hz, 1H, CHaHb), 5.17
(AB, J = 14.6 Hz, 1H, CHaHb), 5.13–4.98 (m, 4H, 2 × POCH2Ph),
4.65–4.44 (m, 3H, OCHaHbPh, H-3a, H-3b), 4.32–4.20 (m, 1H,
H-2), 4.19 (d, J = 10.8 Hz, 1H, OCHaHbPh), 3.87 (ddd, J = 11.9 Hz,

GŁOWACKA ET AL.
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J = 9.1 Hz, J = 3.0 Hz, 1H, H-1), 3.11 (dd, J = 9.1 Hz, J = 6.7 Hz, 1H,
13
was used for the fungal strains. Each tested compounds was dissolved
in 10 mg/mL in sterile water. Twofold series dilutions of the different
compounds in growth medium was performed in the 96-well sterile
microtiter plates (Kartell Labware, Italy). Inocula were freshly prepared
and standardized as microbial suspensions (McFarland scale) contain-
ing 108 colony forming units (cfu/mL), added at a volume of 10 µL to
the wells of the microtiter plate together with the serial dilutions of the
compounds in the growth medium. After 24 h of incubation at 37°C,
microbial growth was evaluated spectrophotometrically at 595 nm

OH); C NMR (151 MHz, CDCl3): δ = 159.75 (s, C O), 152.14,
149.17, 146.08, 141.30, 136.67, 135.83, 135.63 (d, J = 5.5 Hz,
Cipso), 129.36, 128.77, 128.73, 128.70, 128.44, 128.37, 128.23,
128.18, 128.16, 125.28, 123.23, 122.21, 76.88 (d, J = 2.2 Hz),
74.14 (s, PCC), 68.67 (d, J = 7.5 Hz, POC), 68.37 (d, J = 161.1 Hz,
PC), 68.33 (d, J = 7.5 Hz, POC), 50.81 (d, J = 12.1 Hz, PCCC), 41.77;
31P NMR (81 MHz, CDCl3): δ = 22.45 ppm. Anal. calcd. for
C35H33N6O8P: C, 60.34; H, 4.77; N, 12.06. Found: C, 60.74; H,
4.53; N, 12.18.
using a Microplate Reader 680 (BioRad, France). The lowest
concentration of the test compounds resulting in total growth
inhibition was taken as the MIC value. To determine the MBC,
10 µL of the culture were collected from each well, where no visible
growth of microorganisms was recorded and plated onto the surface of
Brain Heart Infusion Agar (BioMerieux). The cultures were incubated
at 37°C for 24 h, and an absence of microbial growth indicated the
bactericidal activity of the tested compounds. Plates with A. brasiliensis
were incubated at 37°C for 3 days. The tests were performed in two
independent experiments. Gentamicin (Sigma) and fluconazole (Sigma)
were used as antimicrobial standard.
(1R,2S)-Dibenzyl 2-benzyloxy-1-hydroxy-3-{4-[6-nitro-4-
oxoquinazolin-3(4H)-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylphosphonate (1R,2S)-9cj
From (1R,2S)-dibenzyl 3-azido-2-benzyloxy-1-hydroxypropylphosph-
onate (1R,2S)-11j (0.065 g, 0.137 mmol) and 6-nitro-N3-propargylqui-
nazolin-4(3H)-one 13c (0.032 g, 0.137 mmol), a phosphonate (1R,2S)-
9cj (0.067 g, 69%) was obtained as a white powder after purification on
a silica gel column with chloroform–methanol mixtures (50:1, v/v).
½αꢀ2D0 = −1.9 (c = 1.34 in CHCl3); m.p.: 176–177°C; IR (KBr):
ν = 3179, 3120, 2988, 2855, 1667, 1642, 1424, 1244, 1027,
759, 699 cm−1
1H, aromat.), 8.52 (s, 1H), 8.48 (dd, J = 8.8 Hz, J = 2.6 Hz, 1H,
aromat.), 7.80 (d, J = 8.8 Hz, 1H, Haromat.), 7.75 (s, 1H, HC5′), 7.35–
;
1H NMR (200 MHz, CDCl3): δ = 9.06 (d, J = 2.6 Hz,
H
ACKNOWLEDGMENT
H
This work was supported by the Medical University of Lodz internal
funds (synthetic part: 503/3-014-01/503-31-001 and biological part:
503/3-012-03/503-31-001).
7.23 (m, 10H, Haromat), 7.22–7.14 (m, 3H, Haromat), 7.12–7.02 (m,
2H, Haromat), 5.22 (s, 2H, CH2), 5.07–4.97 (m, 4H, 2 × POCH2Ph),
4.77–4.55 (m, 2H, H-3a, H-3b), 4.43 (AB, J = 11.0 Hz, 1H,
OCHaHbPh), 4.27 (d, J = 11.0 Hz, 1H, OCHaHbPh), 4.20–4.05 (m,
1H, H-2), 4.03–3.30 (m, 2H, H-2, OH); 13C NMR (151 MHz,
CDCl3): δ = 159.75 (s, CO), 152.13, 149.31, 146.05, 141.14,
136.68, 135.80 (d, J = 5.5 Hz, Cipso), 135.72 (d, J = 5.5 Hz, Cipso),
129.33, 128.72, 128.69, 128.46, 128.34, 128.19, 128.16, 128.12,
128.06, 125.52, 123.21, 122.21, 77.62 (d, J = 4.4 Hz, PCC), 72.87,
68.58 (d, J = 6.6 Hz, POC), 68.45 (d, J = 6.6 Hz, POC), 67.80 (d,
J = 161.4 Hz, PC), 50.31 (d, J = 6.3 Hz, PCCC), 41.73; 31P NMR
(81 MHz, CDCl3): δ = 23.80 ppm. Anal. calcd. for C35H33N6O8P: C,
60.34; H, 4.77; N, 12.06. Found: C, 60.55; H, 4.83; N, 12.12.
CONFLICT OF INTEREST
The authors have declared no conflict of interest.
ORCID
Iwona E. Głowacka
http://orcid.org/0000-0001-7567-5860
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
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How to cite this article: Głowacka IE, Grzonkowski P,
Lisiecki P, Kalinowski Ł, Piotrowska DG. Synthesis and
antimicrobial activity of novel 1,2,3-triazole-conjugates of
quinazolin-4-ones. Arch Pharm Chem Life Sci. 2019;1–14.
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