Copper(I)-catalyzed [3+2] cycloaddition of 3-azidoquinoline-2,4(1H,3H)- diones with terminal alkynes

Article abstract of DOI:10.3390/molecules16054070

3-Azidoquinoline-2,4(1H,3H)-diones 1,which are readily available from 4-hydroxyquinolin-2(1H)-ones 4 via 3-chloroquinoline-2,4(1H,3H)-diones 5, afford, in copper(I)-catalyzed [3+2] cycloaddition reaction with terminal acetylenes, 1,4-disubstituted 1,2,3-t

Full text of DOI:10.3390/molecules16054070

Molecules 2011, 16, 4070-4081; doi:10.3390/molecules16054070
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Copper(I)-Catalyzed [3 + 2] Cycloaddition of 3-Azidoquinoline-
2,4(1H,3H)-diones with Terminal Alkynes †
Stanislav Kafka 1,*, Sylvia Hauke 2, Arjana Salcinovic 3, Otto Soidinsalo 4, Damijana Urankar 5
and Janez Kosmrlj 5,*
1
Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlin, Zlin 76272,
Czech Republic
2
Institute of Chemistry, University of Potsdam, Golm D-14476, Germany
3
Faculty of Natural Sciences and Mathematics, University of Banja Luka, Banja Luka 78000, Bosnia
and Herzegovina
4
Department of Chemistry, Faculty of Science, University of Helsinki, Helsinki FI-00014, Finland
5
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana SI-1000,
Slovenia
†
Dedicated to Professor Antonín Klásek on the occasion of his 70th birthday.
* Authors to whom correspondence should be addressed; E-Mails: kafka@ft.utb.cz (S.K.);
janez.kosmrlj@fkkt.uni-lj.si (J.K.)
Received: 18 April 2011; in revised form: 11 May 2011 / Accepted: 13 May 2011 /
Published: 18 May 2011
Abstract: 3-Azidoquinoline-2,4(1H,3H)-diones 1, which are readily available from
4-hydroxyquinolin-2(1H)-ones 4 via 3-chloroquinoline-2,4(1H,3H)-diones 5, afford, in
copper(I)-catalyzed [3 + 2] cycloaddition reaction with terminal acetylenes, 1,4-disubstituted
1,2,3-triazoles 3 in moderate to excellent yields. The structures of compounds 3 were
confirmed by 1H and 13C-NMR spectroscopy, combustion analyses and mass spectrometry.
Keywords: cycloaddition; azides; quinoline-2,4(1H,3H)-diones; terminal alkynes; 1,2,3-triazoles
1. Introduction
As a part of our continuous interest in quinolinedione chemistry, we observed that 3-azidoquinoline-
2,4(1H,3H)-diones 1 behave quite differently than normally expected for organic azides, including

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α-azido carbonyl compounds [1]. For example, the Staudinger reaction [2], the reduction of azide
with triphenylphosphine, did not yield the expected 3-aminoquinoline-2,4(1H,3H)-diones (Scheme 1)
and instead, deazidation took place to afford 4-hydroxyquinolin-2(1H)-ones. Similar behaviour of
3-azidoquinoline-2,4(1H,3H)-diones was also observed in the reaction with zinc in acetic acid [1].
Scheme 1. Previously documented unexpected reactivity of 3-azidoquinoline-2,4(1H,3H)-diones 1.
O
OH
N3
R2
R2
Ph3P
or
N
O
N
R1
4
O
Zn / AcOH
R1
1
R1: H, Me, Bn, Ph
R2: alkyl, Bn, Ph
This unexpected reactivity prompted us to continue the studies of 3-azidoquinoline-2,4(1H,3H)-diones
reactivity. For examples, we were intrigued whether these compounds could serve as partners in
copper(I)-catalyzed [3 + 2] cycloaddition reaction with terminal alkynes. This reaction, also referred to as
“Click reaction”, has been recently discovered to selectively afford 1,4-disubstituted 1,2,3-triazoles [3-5].
Its remarkably mild reaction conditions, broad scope, and exquisite selectivity are well documented,
and it has succeeded in the presence of most functional groups tested to date. It has also become a
powerful and versatile tool in nearly all areas of chemistry, including macromolecular engineering,
nanotechnology, and drug discovery [6-10].
2. Results and Discussion
Starting 3-azidoquinoline-2,4(1H,3H)-diones 1 were prepared by known chemistry from the
corresponding 4-hydroxyquinolin-2-(1H)-ones 4. Chlorination and bromination of the latter with sulfuryl
chloride and bromine, respectively, afforded the corresponding 3-chloroquinoline-2,4(1H,3H)-diones 5 and
3-bromoquinoline-2,4(1H,3H)-diones 6. The resulting 3-halogenoquinoline-2,4(1H,3H)-diones were
subsequently subjected to the substitution with sodium azide.
3-Azidoquinoline-2,4(1H,3H)-diones 1 were examined as partners in copper(I) catalyzed [3 + 2]
cycloaddition (Scheme 2). Three different terminal acetylenes 2 were chosen; phenylacetylene (2a),
propargyl alcohol (2b) and 3-ethynylaniline (2c). When screening for the optimal reaction conditions,
we initially tested the most commonly used system, copper(II) sulphate pentahydrate and ascorbic acid
as a source of copper(I) in tert-BuOH/H2O as a solvent [6]. Interestingly, no reaction could be detected
by thin-layer chromatography (TLC) analysis after 24 h and the starting azides 1 were recovered nearly
quantitatively from the reaction mixtures. Similarly unsuccessful were attempts to use a combination
of copper(II) acetate and elemental copper in acetonitrile. We assumed that the prime reasons for the
failure of these reactions were the extremely low solubilities of azides 1 in the reaction media used.
Similar difficulties were previously encountered by some of us in attempts at using sparingly soluble
propargyl functionalized diazenecarboxamides [11] or azido-appended platinum(II) complexes [12] as
click components. In those instances the use of dimethyl sulfoxide (DMSO) as a reaction solvent and a

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combination of copper(II) sulphate pentahydrate and elemental copper (CuSO4/Cu(0)) provided results
that were superior to other combinations. Conducting the cycloadditions between azides 1 and
acetylenes 2 in DMSO, in the presence of CuSO4/Cu(0) couple afforded the expected 1,4-disubstituted
1,2,3-triazoles 3 in moderate to excellent yields, as shown in Table 1.
Scheme 2. Copper(I) catalyzed cycloaddition between 3-azidoquinoline-2,4(1H,3H)-
diones 1 and terminal acetylenes into 1,2,3-triazoles 3.
N
R5
O
N
N
O
N3
R2
R3
R4
R3
R4
R5 C CH
R2
+
N
R1
O
N
R1
O
1
2
3
Table 1. Reaction conditions and yields for the formation of 1,2,3-triazoles 3 (Scheme 2) a.
Entry
Azide
R2
Alkyne
R5
Triazole R. time, Yield,
b
1
R1
H
H
H
R3
H
H
H
R4
H
H
H
2
3
h
%
1
2
3
1A
1A
1A
Ph
2a
2b
2c
Ph
3Aa
3Ab
3Ac
3.3
1.5
1.3
96 (80)
95 (67)
nd (61)
Ph
CH2OH
Ph
3-(NH2)-
C6H4
4
5
1B
1B
1C
1C
1D
1D
1E
1E
H
H
Ph MeO
Ph MeO
H
H
H
H
2a
2b
2a
2b
Ph
CH2OH
Ph
3Ba
3Bb
3Ca
3Cb
3Da
3Db
3Ea
3Eb
2.2
1.1
1.2
3
98 (64)
85 (nd)
97 (78)
nd (60)
92 (82)
nd (46)
97 (51)
94 (89)
6
H
Pr
Pr
MeO
MeO
Cl
7
H
CH2OH
Ph
8
H
Ph
Ph
Ph
Ph
MeO 2a
MeO 2b
1.2
3
9
H
Cl
CH2OH
Ph
10
11
Bn
Bn
H
H
H
2a
2b
2.5
2
H
CH2OH
a Reaction conditions: 1 (2.00 mmol), 2 (2.02 mmol), CuSO4⋅5H2O (0.2 mmol, 10 mol %), granular
copper (8.8 mmol), DMSO (6 mL), air, room temperature, darkness; Chemical yield of NMR
b
pure, crude isolated product. The value in parentheses refers to the yield of crystallized product;
nd: not determined.
In a general procedure, a mixture of 3-azidoquinoline-2,4(1H,3H)-dione (1, 2.0 mmol), terminal
alkyne (2, 2.0 mmol), CuSO4⋅5H2O (0.2 mmol, 10 mol %), and granular copper (8.8 mmol) in DMSO
(6 mL) was stirred at room temperature, in the presence of air. Since azides 1 are prone to slow
decomposition in the presence of light, we decided to perform the reactions in darkness. The
cycloadditions were completed within a few hours (Table 1), and as judged by TLC analyses, the
corresponding 1,4-disubstituted 1,2,3-triazoles 3 were formed quantitatively. In most cases the
products were isolated by simple extractive workup in excellent chemical yields and more than 95%

Molecules 2011, 16
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1
purity as judged by H-NMR and TLC analyses (Table 1, entries 1, 2, 4–6, 8, 10 and 11). The
relatively high loads of granular copper could easily be recovered and eventually reused.
1
The structures of triazoles 3 were confirmed by H- and 13C-NMR spectroscopy, combustion
analyses and mass spectrometry on the crystallized compounds. In one instance, that of 3Cb, the
expected 1,4-regiochemistry at the 1,2,3-triazole ring was confirmed by a NOESY experiment. As
demonstrated in Figure 1, the triazole hydrogen atom (Htriazole) displays five NOE cross peaks; three to
the propyl group bound to C3 of the quinolinedione core and two to the hydroxymethyl group, attached
to C4’ of the triazole ring. The most important for the assigned regiochemistry is the cross peak of
Htriazole to the C3-CH2 protons, which would not be possible for the isomeric 1,5-disubstituted product.
The absence of a cross peak between the hydroxymethyl group and C3-CH2 further corroborates the
structure of 3Cb.
Figure 1. Expansions of NOESY spectrum and chemical drawing of compound 3Cb
showing relevant NOE cross peaks.
In one instance, that of 3-phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione
(3Aa), the preparation of 3-azido-3-phenylsquinoline-2,4(1H,3H)-dione (1A) and its cycloaddition
with phenylacetylene were conducted as a one-pot multicomponent reaction, i.e., by mixing the
corresponding 3-bromoquinolinedione substrate 6A, sodium azide and alkyne (2a) in the presence of
Cu(II)/Cu(0) (Experimental section). Similar one-pot azidation-cycloaddition procedures are described
in the literature [13,14] This protocol afforded the desired product (3Aa) in modest 43% yield.
3-(4-(3-Aminophenyl)-1H-1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1H,3H)-dione (3Ac) was acetylated
into N-(3-(1-(1,2,3,4-tetrahydro-2,4-dioxo-3-phenylquinolin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-acetamide
(3Ae). Whereas α-azido-β-carbonyl lactam has previously been used as a reaction partner [15], to the
best our knowledge, this is not the case with 3-azidoquinoline-2,4(1H,3H)-diones.

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3. Experimental
3.1. General
Reagents and solvents were commercially sourced (Fluka, Aldrich, Alfa Aesar) and used as
purchased. Granular copper (particle size 0.2–0.7 mm), coating quality (99.9%, Fluka #61144) was
used. For column chromatography, Fluka Silica gel 60, 220–440 mesh was used. The course of
separation and also the purity of substances were monitored by TLC on Alugram® SIL G/UV254 foils
(Macherey-Nagel). NMR spectra were recorded at 302 K on a Bruker Avance DPX 300 spectrometer
operating at 300 MHz (1H) and 75 MHz (13C), and Bruker Avance III 500 MHz NMR instrument
operating at 500 MHz (1H) and 125 MHz (13C). Proton spectra were referenced to TMS as internal
13
standard. Carbon chemical shifts were determined relative to the C signal of DMSO-d6 (39.5 ppm).
Chemical shifts are given on the δ scale (ppm). Coupling constants (J) are given in Hz. Multiplicities
are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broadened).
Phase sensitive NOESY with gradient pulses in mixing time, of 3Cb, was recorded in DMSO-d6
(c = 21 mM) using standard pulse sequence from the Bruker pulse library (noesygpphpp in the Bruker
software) at 296 K, with mixing time of 300 ms and relaxation delay of 2 s. Mass spectra and
high-resolution mass spectra were obtained with a VG-Analytical AutospecQ instrument and Q-TOF
Premier instrument. Data are reported as m/z (relative intensity). The IR spectra were recorded on a
Perkin-Elmer 421 and 1310 and Mattson 3000 spectrophotometers using samples in potassium
bromide disks. Elemental analyses (C, H, N) were performed with FlashEA1112 Automatic Elemental
Analyzer (Thermo Fisher Scientific Inc.). The melting points were determined on a Kofler block or
Gallenkamp apparatus and are uncorrected. Starting compounds 1, 4–6 were prepared by known
procedures as shown in Scheme 3 and described below.
Scheme 3. Preparation of starting compounds 4–6. For key to substituents, please see Table 1.
CAUTION: Azides can be explosive and caution should be exercised when handling them [16,17].
Although in our hands, azides 1A–1E did not appear to be shock sensitive, the compounds should
be handled with great care.
4-Hydroxyquinolin-2-(1H)-ones: 4-Hydroxy-3-phenylquinolin-2(1H)-one (4A) [18], 4-hydroxy-6-
methoxy-3-phenylquinolin-2(1H)-one (4B) [19], 6-chloro-4-hydroxy-7-methoxy-3-phenylquinolin-
2(1H)-one (4D) [19], and 1-benzyl-4-hydroxy-3-phenylquinolin-2(1H)-one (4E) [1] were prepared by
thermal condensation of the appropriate anilines and substituted malonic acids diethyl esters neat, as
described in the literature. 1-Benzyl-3-chloro-3-phenylquinoline-2,4(1H,3H)-dione (5E) was prepared
by chlorination of compound 4E with sulfuryl chloride according to the literature procedure [1].
3-Bromo-3-phenylquinoline-2,4(1H,3H)-dione (6A) and 3-bromo-6-methoxy-3-phenylquinoline-2,4-

Molecules 2011, 16
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(1H,3H)-dione (6B) were prepared by bromination of compounds 4A and 4B, respectively, as
described in the literature [20]. 3-Azido-1-benzyl-3-phenylquinoline-2,4(1H,3H)-dione (1E) was
prepared by the reaction of 1-benzyl-3-chloro-3-phenylquinoline-2,4(1H,3H)-dione (5E) with sodium
azide as described formerly [1].
3.2. 4-Hydroxy-6-methoxy-3-propylquinolin-2(1H)-one (4C)
A mixture of 4-methoxyaniline (6.16 g, 50 mmol) and diethyl propylmalonate (10.52 g, 52 mmol)
was heated on a metal bath at 220–230 °C for 1 h and then at 260–280 °C for 3 h (the reaction was
complete when the distillation of ethanol stopped). After cooling, the solid product was crushed,
suspended in aqueous sodium hydroxide solution (0.5 M, 125 mL) and after filtration the filtrate was
washed with toluene (3 × 20 mL). The aqueous phase was filtered and acidified by concentrated
hydrochloric acid. The precipitated crude product was filtered, washed with water, air dried and
crystallized from ethanol affording white solid of 4C, yield 5.90 g (51%); mp 238–243 °C; IR (cm−1):
1
2961, 1644 (CO), 1618, 1607, 1591, 1453, 1272, 1240, 1202, 1164; H-NMR (DMSO-d6) 0.91 (t,
J = 7.3 Hz, 3H), 1.39–1.51 (m, 2H), 2.50–2.56 (m, 2H), 3.79 (s, 3H), 7.08 (dd, J = 9.0, 2.7 Hz, 1H),
13
7.19 (d, J = 9.1 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 9.89 (s, 1H), 11.14 (s, 1H); C-NMR (DMSO-d6)
13.9, 21.3, 25.0, 55.4, 104.2, 111.9, 115.7, 116.1, 118.6, 131.8, 153.7, 156.5, 163.0; MS (EI) m/z (%):
233 ([M]+, 97), 218 (92), 205 (97), 204 (100), 191 (37); Anal. Calcd for C13H15NO3 (233.26): C, 66.94;
H, 6.48; N, 6.00; Found: C, 67.07; H, 6.55; N, 6.21.
3.3. 3-Chloro-6-methoxy-3-propylquinoline-2,4(1H,3H)-dione (5C)
To a stirred suspension of 4-hydroxy-6-methoxy-3-propylquinolin-2(1H)-one (4C, 3.97 g, 17 mmol)
in dioxane (50 mL) preheated to 50 °C, sulfuryl chloride (7.8 g, 57 mmol) was added dropwise,
keeping the temperature below 55 °C. The resulting reaction mixture was stirred for additional 10 min
at 50–55 °C, cooled down to room temperature and poured into ice-water (850 mL). The precipitated
crude product was filtered, washed with water (200 mL), air dried and crystallized from benzene
affording bright yellow solid of 5C, yield 3.48 g (76%); mp 138–142 °C; IR (cm−1): 2918, 1703 (CO),
1
1672 (CO), 1504, 1430, 1288, 1203; H-NMR (DMSO-d6) 0.86 (t, J = 7.2 Hz), 1.12–1.30 (m, 2H),
2.20–2.29 (m, 2H), 3.80 (s, 3H), 7.11 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 7.2, 3.0 Hz, 1H), 7.34 (d,
J = 3.0 Hz, 1H), 11.16 (s, 1H); 13C-NMR (DMSO-d6) 13.8, 17.9, 37.9, 55.6, 66.7, 109.0, 117.6, 118.3,
125.3, 135.1, 155.1, 166.3, 188.4; MS (EI) m/z (%): 269 ([M{37Cl}]+, 17), 267 ([M{35Cl}]+, 42), 240
(48), 238 (100), 233 (33), 225 (52); Anal. Calcd for C13H14ClNO3 (267.71): C, 58.32; H, 5.27; N, 5.23.
Found: C, 58.58; H, 5.07; N, 5.36.
3.4. Chlorination of 6-chloro-4-hydroxy-7-methoxy-3-phenylquinolin-2(1H)-one (4D) into
3,6-Dichloro-7-methoxy-3-phenylquinoline-2,4(1H,3H)-dione (5D) and 3,6,8-Trichloro-7-methoxy-3-
phenylquinoline-2,4(1H,3H)-dione (5F)
Sulfuryl chloride (16.7 g; 124 mmol) was added dropwise to the stirred suspension of 6-chloro-4-
hydroxy-7-methoxy-3-phenylquinolin-2(1H)-one (4D, 10.00 g; 37.41 mmol) in dioxane at 46–47 °C
during 20 min. The resulting reaction mixture was stirred for 10 min and poured into ice-water (600 mL).

Molecules 2011, 16
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The precipitated solid was filtered, washed with water, dried on the air and crystallized from benzene
(1.3 L) affording compound 5D. The mother liquor was concentrated in vacuo to approximately
380 mL. The precipitated solid was filtered and recrystallized from benzene to give compound 5F.
3,6-Dichloro-7-methoxy-3-phenylquinoline-2,4(1H,3H)-dione (5D): White solid, yield 6.33 g (50%);
mp 236–238 °C (236 °C from acetic acid [20]); IR (cm−1): 1710 (CO), 1679 (CO), 1614, 1595, 1485,
1
1445, 1400, 1335; H-NMR (DMSO-d6) 3.93 (s, 3H, CH3), 6.84 (s, 1H), 7.29–7.38 (m, 5H), 7.66 (s,
13
1H), 11.13 (s, 1H); C-NMR (DMSO-d6) 56.8, 74.4, 100.0, 111.4, 116.7, 127.0, 128.5, 128.8, 129.3,
134.9, 141.9, 160.6, 166.6, 185.5; MS (EI) m/z (%): 339 ([M{37Cl2}]+, 6), 337 ([M{37Cl35Cl}]+, 31),
335 ([M{35Cl2}]+, 42), 303 (45), 302 (54), 301 (100), 300 (83), 186 (28), 184 (67), 183 (32); Anal.
Calcd for C16H11Cl2NO3 (336,17): C, 57.16; H, 3.30; N, 4.17. Found: C, 57.16; H, 3.26; N, 4.10.
3,6,8-Trichloro-7-methoxy-3-phenylquinoline-2,4(1H,3H)-dione (5F): White solid, yield 0.82 g (6%);
mp 183–186 °C (198 °C from pet. ether [20]); IR (cm−1): 3238 (NH), 1728 (CO), 1696 (CO), 1596,
35
1463, 1317, 1055, 966, 749, 692; MS (EI) m/z (%): 373 ([M{37Cl2 Cl}]+, 4), 371 ([M{37Cl35Cl2}]+, 11),
369 ([M{35Cl3}]+, 11), 338 (20), 337 (63), 336 (78), 335 (99), 334 (100), 220 (27), 218 (41), 89 (27).
Anal. Calcd for C16H10Cl3NO3 (370.61): C, 51.85; H, 2.72; N, 3.78. Found: C, 51.92; H, 2.70; N, 3.61.
3.5. General Procedure for the Synthesis 3-Azidoquinoline-2,4(1H,3H)-diones 1A–D
To a stirred solution of the appropriate 3-chloro- (5A,B) or 3-bromoquinoline-2,4(1H,3H)-dione
(6C,D, 10 mmol) in DMF (50 mL), sodium azide (975 mg, 15 mmol) was added in small portions in
darkness during 20 min. The reaction mixture was stirred in darkness for 2 h and then poured into
ice-water (600 mL). The precipitated product 1 was filtered, washed with water (150 mL) and dried at
50–60 °C in darkness. Products 1A, 1C, 1D were crystallized from the solvents indicated below.
3-Azido-3-phenylquinoline-2,4(1H,3H)-dione (1A): White solid, yield 2.13 g (77%); mp 173–181 °C
(benzene; 170–172 °C [1]).
3-Azido-6-methoxy-3-phenyquinoline-2,4(1H,3H)-dione (1B): Yellow solid, yield 2.76 g (90%); mp
183–185 °C (182–183 °C from ethanol [20]). Anal. Calcd for C16H12N4O3 (308.29): C, 62.33; H, 3.92;
N, 18.17. Found: C, 62.21; H, 4.09; N, 18.22.
3-Azido-6-methoxy-3-propylquinoline-2,4(1H,3H)-dione (1C): Yellow solid, yield 2.39 g (87%); mp
170–171 °C (ethanol); IR (cm−1): 2962, 2121 (N3), 1700 (CO), 1665 (CO), 1509, 1492, 1424, 1354,
1208, 826; 1H-NMR (DMSO-d6) 0.81 (t, J = 7.2 Hz, 3H), 1.20–1.32 (m, 2H), 1.80–1.97 (m, 2H), 3.78
(s, 3H), 7.06 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 7.28 (dd, J = 8.8, 3.0 Hz, 1H), 10.96 (s, 1H);
1H-NMR (CDCl3) 0.91 (t, J = 7.3 Hz, 3H), 1.37–1.49 (m, 2H), 2.04–2.22 (m, 2H), 3.85 (s, 3H), 7.00
13
(d, J = 8.7 Hz, 1H), 7.19 (dd, J = 8.9, 2.8 Hz, 1H), 7.38 (d, J = 2.8 Hz, 1H), 9.58 (s, 1H); C-NMR
(DMSO-d6) 13.4, 16.7, 39.2, 55.5, 74.5, 108.7, 118.1, 118.9, 124.5, 135.2, 154.9, 168.5, 191.2;
13C-NMR (CDCl3) 13.7, 17.1, 39.9, 55.8, 73.6, 109.4, 118.1, 119.3, 125.3, 133.9, 156.4, 170.5, 191.6;
MS (EI) m/z (%): ([M]+, 30), 218 (28), 149 (100), 121 (39), 106 (66); Anal. Calcd for C13H14N4O3
(274.28): C, 56.93; H, 5.14; N, 20.43. Found: C, 56.72; H, 5.36; N, 20.37.

Molecules 2011, 16
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3-Azido-6-chloro-7-methoxy-3-phenylquinoline-2,4(1H,3H)-dione (1D): White solid, yield 3.14 g
(92%); mp 228–232 °C dec. (ethanol); IR (cm−1): 2976, 2920, 2126 (N3), 1710 (CO), 1670 (CO), 1613,
1
1590, 1407, 1348, 1279; H-NMR (DMSO-d6) 3.91 (s, 3H, CH3), 6.73 (s, 1H), 7.35–7.41 (m, 2H),
13
7.41–7.49 (m, 3H), 7.72 (s, 1H), 11.42 (s, 1H); C-NMR (DMSO-d6) 56.7, 76.8, 100.0, 112.3, 116.5,
126.6, 128.1, 129.6, 130.0, 133.3, 141.9, 160.3, 168.1, 187.1; MS (EI) m/z (%): 344 ([M{37Cl}]+, 3),
342 ([M{35Cl}]+, 9), 318 (11), 316 (40), 314 (22), 303 (17), 302 (21), 301 (51), 300 (38), 183 (100);
Anal. Calcd for C16H11ClN4O3 (342.74): C, 56.07; H, 3.23; N, 16.35. Found: C, 56.30; H, 3.24; N, 16.45.
3.6. General Procedure for the Preparation of 1,2,3-Triazoles 3
A mixture of 3-azidoquinoline-2,4(1H,3H)-dione (1, 2.00 mmol), terminal alkyne (2, 2.02 mmol),
CuSO4⋅5H2O (0.2 mmol, 10 mol%), granular copper (8.8 mmol), and DMSO (6 mL) was stirred at
room temperature in darkness until the starting compound 1 became undetectable by TLC (The
reaction times are indicated in Table 1). Then the reaction mixture was diluted with CH2Cl2 (160–250 mL)
and filtered. The filtrate was washed with saturated aqueous NH4Cl (3 × 80 mL) until the aqueous
layer remained colourless (concentrated aqueous ammonia (0.25 mL) was added to the saturated
aqueous NH4Cl for the isolation of 3Ac. Each time the product was back-extracted from the water
layer with few millilitres of CH2Cl2. The combined organic layers were shortly dried over Na2SO4,
filtered, and the solvents were evaporated in vacuo. Residual DMSO was removed by several
consecutive co-distillations in vacuo with toluene and then ethanol. The product was suspended in
boiling cyclohexane (20 mL), cooled down to room temperature, filtered and dried to give the
corresponding triazole 3. For analyses the products were crystallized from the solvent indicated below.
Reaction times along with the yields of crude and crystallized products are indicated in Table 1.
3-Phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (3Aa): White solid; mp
274–277 °C (ethanol); IR (cm−1): 3276, 1721 (CO), 1690 (CO), 1613, 1485, 1353, 771, 756; 1H-NMR
(DMSO-d6) 7.10–7.21 (m, 2H), 7.29–7.39 (m, 1H), 7.39–7.49 (m, 4H), 7.49–7.57 (m, 3H), 7.60–7.69
(m, 1H), 7.79–7.92 (m, 3H), 8.48 (s, 1H), 11.66 (br s, 1H); 13C-NMR (DMSO-d6) 80.0, 116.7, 119.1,
123.4, 123.5, 125.1, 127.5, 127.9, 128.8, 128.9, 129.5, 129.9, 130.49, 130.52, 136.9, 140.5, 145.3,
166.7, 188.9; HRMS (ESI+) calcd for C23H17N4O2 ([M + H]+): 381.1357, found 381.1355; Anal. Calcd
for C23H16N4O2 (380.40): C, 72.62; H, 4.24; N, 14.73; Found: C, 72.59; H, 4.24; N, 14.54.
3-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1H,3H)-dione (3Ab): Yellow-brown
solid; mp 116–135 °C (benzene); IR (cm−1): 3425, 2915, 1721 (CO), 1684 (CO), 1613, 1595, 1485,
1354, 762; 1H-NMR (DMSO-d6) 4.53 (d, J = 5.4 Hz, 2H), 5.20 (br t, J = 5.4 Hz, 1H), 7.10 (d, J = 8.1 Hz,
1H), 7.16 (dd, J = 7.5, 7.5 Hz, 1H), 7.34–7.45 (m, 2H), 7.45–7.56 (m, 3H), 7.62 (dd, J = 7.5, 7.5 Hz,
13
1H), 7.75 (s, 1H), 7.84 (d, J = 7.5 Hz, 1H), 11.59 (br s, 1H); C-NMR (DMSO-d6) 55.0, 79.6, 116.6,
119.1, 123.4, 124.7, 127.5, 128.7, 129.5, 130.2, 130.5, 136.8, 140.5, 146.8, 166.8, 188.9. Anal. Calcd for
C18H14N4O3 (334.33): C, 64.66; H, 4.22; N, 16.76; Found: C, 64.86; H, 4.41; N, 16.62.
3-(4-(3-Aminophenyl)-1H-1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1H,3H)-dione (3Ac): Brown solid,
mp 273–277 °C (DMF-ethanol); IR (cm−1): 3366, 1720 (CO), 1690 (CO); 1613, 1593, 1484, 1353,
1
774, 757, 697; H-NMR (DMSO-d6) 5.16 (br s, 2H), 6.49–6.55 (m, 1H), 6.90 (d, J = 7.7 Hz, 1H),

Molecules 2011, 16
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7.01–7.13 (m, 3H), 7.17 (dd, J = 7.6, 7.6 Hz, 1H), 7.37–7.46 (m, 2H), 7.47–7.56 (m, 3H), 7.59–7.68
(m, 1H), 7.85 (dd, J = 7.8, 1.2 Hz, 1H), 8.27 (s, 1H), 11.59 (br s, 1H); 13C-NMR (DMSO-d6) 79.9, 110.3,
112.8, 113.5, 116.5, 119.1, 122.8, 123.3, 127.4, 128.8, 129.3, 129.4, 129.9, 130.4, 130.9, 136.7, 140.4,
145.9, 149.0, 166.8, 188.9; HRMS (ESI+) calcd for C23H18N5O2 ([M + H]+): 396.1460, found 396.1475.
6-Methoxy-3-phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (3Ba): Yellow solid;
mp 138–145 °C (benzene); IR (cm−1): 3077, 1720 (CO), 1681 (CO), 1502, 1419, 1345, 756, 695;
1H-NMR (DMSO-d6) 3.78 (s, 3H), 7.09 (d, J = 8.5 Hz, 1H), 7.23–7.59 (m, 10H), 7.83 (d, J = 7.4 Hz,
13
2H), 8.44 (br s, 1H), 11.51 (br s, 1H); C-NMR (DMSO-d6) 55.6, 79.7, 109.3, 118.3, 119.5, 123.3,
124.9, 125.1, 127.9, 128.8, 128.9, 129.5, 130.0, 130.48, 130.51, 134.4, 145.2, 155.2, 166.3, 188.9; MS
(EI) m/z (%): 411 ([M+1]+, 3), 410 ([M]+, 13), 277 (16), 267 (42), 266 (77), 251 (18), 223 (12), 145
(13), 117 (13), 116 (100), 106 (15), 102 (14), 89 (21), 77 (15); HRMS (ESI+) calcd for C24H19N4O3
([M + H]+): 411.1457, found 411.1444.
3-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-6-methoxy-3-phenylquinoline-2,4(1H,3H)-dione (3Bb):
Yellow solid; mp 230–235 °C (crude product); IR (cm−1): 3150, 1718 (CO), 1684 (CO), 1502, 1419,
1
1345, 1286, 1034, 761; H-NMR (DMSO-d6) 3.77 (s, 3H), 4.52 (d, J = 5.1 Hz, 2H), 5.20 (br t,
J = 5.1 Hz, 1H), 7.04–7.12 (m, 1H), 7.25–7.33 (m, 2H), 7.36–7.45 (m, 2H), 7.45–7.58 (m, 4H), 7.68 (s,
13
1H); C-NMR (DMSO-d6) 54.9, 55.6, 79.3, 109.2, 118.4, 119.5, 124.7, 124.8, 128.7, 129.5, 130.3,
130.5, 134.6, 146.7, 155.1, 166.3, 188.9; HRMS (ESI+) calcd for C19H17N4O4 ([M + H]+) 365.1250,
found 365.1267.
6-Methoxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-3-propylquinoline-2,4(1H,3H)-dione (3Ca): Yellow solid;
mp 288–315 °C (methanol-N,N-dimethylformamide); IR (cm−1): 3252, 1712 (CO), 1669 (CO), 1503,
1
1417, 1286, 1240, 1204, 763; H-NMR (DMSO-d6) 0.92 (t, J = 7.2 Hz, 3H), 1.21–1.50 (m, 2H),
2.50–2.65 (m, 2H), 3.81 (s, 3H), 7.20 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 2.9 Hz, 1H), 7.31–7.43 (m, 2H),
7.47 (dd, J = 7.5, 7.5 Hz, 2H), 7.82–7.93 (m, 2H), 8.90 (s, 1H), 11.36 (br s, 1H); 13C-NMR (DMSO-d6)
13.7, 16.7, 38.2, 55.6, 74.6, 108.6, 118.4, 118.6, 122.3, 125.1, 125.6, 127.9, 128.9, 130.5, 135.7, 145.6,
155.2, 167.3, 190.5; HRMS (ESI+) calcd for C21H21N4O3 ([M + H]+): 377.1614, found 377.1617.
3-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)-6-methoxy-3-propylquinoline-2,4(1H,3H)-dione (3Cb):
Yellow solid; mp 189–191 °C (benzene-ethanol); IR (cm−1): 3083, 2912, 1715 (CO), 1686 (CO), 1509,
1
1422, 1335, 1182, 1172, 824; H-NMR (DMSO-d6) 0.89 (t, J = 7.2 Hz, 3H), 1.17–1.49 (m, 2H),
2.37–2.62 (m, 2H), 3.80 (s, 3H), 4.55 (br s, 2H), 5.25 (br s, 1H), 7.20 (d, J = 8.9 Hz, 1H), 7.26 (d,
13
J = 3.0 Hz, 1H), 7.37 (dd, J = 8.9, 3.0 Hz, 1H), 8.24 (s, 1H), 9.50 (br s, 1H); C-NMR (DMSO-d6)
13.6, 16.7, 38.1, 54.9, 55.6, 74.4, 108.6, 118.5, 118.6, 123.6, 125.4, 135.7, 147.1, 155.1, 167.5, 190.5.;
Anal. Calcd for C16H18N4O4 (330.34): C, 58.17; H, 5.49; N, 16.96. Found: C, 57.93; H, 5.45; N, 16.81.
6-Chloro-7-methoxy-3-phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (3Da):
Yellow solid; mp 300–304 °C dec. (DMF-ethanol); IR (cm−1): 3260, 1726 (CO), 1680 (CO), 1610,
1482, 1329, 1275, 1205, 763, 691; 1H-NMR (DMSO-d6) 3.93 (s, 3H), 6.78 (s, 1H), 7.30–7.36 (m, 1H),
7.42–7.48 (m, 4H), 7.52–7.56 (m, 3H), 7.80–7.88 (m, 2H), 8.41 (s, 1H), 11.68 (br s, 1H);
13C-NMR (DMSO-d6) 56.8, 79.2, 100.0, 112.4, 116.7, 123.2, 125.1, 127.8, 128.3, 128.7, 128.8, 129.5,

Molecules 2011, 16
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130.0, 130.3, 130.5, 141.7, 145.2, 160.6, 167.0, 186.4; HRMS (ESI+) calcd for C24H18ClN4O3
([M + H]+): 445.1067, found 445.1047; Anal. Calcd for C24H17ClN4O3 (444.87): C, 64.80; H, 3.85; N,
12.59. Found: C, 64.55; H, 3.87; N, 12.35.
6-Chloro-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-3-phenylquinoline-2,4(1H,3H)-dione
(3Db): White solid; mp 279–283 °C dec. (ethanol); IR (cm−1): 2838, 1709, 1678, 1613, 1596, 1415,
1354, 1279, 1222, 1035; 1H-NMR (DMSO-d6) 3.92 (s, 3H), 4.52 (d, J = 5.0 Hz, 2H), 5.19 (br t, J = 5.0 Hz,
1H), 6.76 (s, 1H), 7.33–7.45 (m, 2H), 7.46–7.58 (m, 3H), 7.68 (s, 1H), 7.83 (s, 1H), 11.63 (br s, 1H);
13C-NMR (DMSO-d6) 54.9, 56.8, 78.9, 100.1, 112.5, 116.7, 124.6, 128.3, 128.6, 129.5, 130.3, 130.5,
141.8, 146.8, 160.6, 167.0, 186.5; Anal. Calcd for C19H15ClN4O4 (398.80): C, 57.22; H, 3.79; N, 14.05.
Found: C, 57.05; H, 3.75; N, 13.92.
1-Benzyl-3-phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione (3Ea): Yellow-brown
solid; mp 105–113 °C (benzene-cyclohexane) IR (cm−1): 3061, 1714 (CO), 1679 (CO), 1600, 1468,
1453, 1373, 1312, 759, 695; 1H-NMR (DMSO-d6) 5.34 (d, J = 16.6 Hz, 1H), 5.48 (d, J = 16.6 Hz, 1H),
7.12–7.40 (m, 10H), 7.40–7.56 (m, 5H), 7.63 (dd, J = 7.7, 7.7 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.99
13
(d, J = 7.5 Hz, 1H), 8.56 (s, 1H); C-NMR (DMSO-d6) 26.3, 46.6, 80.2, 116.6, 120.8, 123.4, 124.0,
125.1, 126.7, 127.4, 127.9, 128.3, 128.6, 128.9, 129.5, 129.9, 130.5, 130.7, 135.7, 136.9, 140.8, 145.4,
166.9, 188.4; MS (EI) m/z (%): 471 ([M+1]+, 1), 470 ([M]+, 3), 326 (10), 206 (9), 116 (32), 92 (8), 91
(100), 77 (8); Anal. Calcd for C30H22N4O2 (470.52): C, 76.58; H, 4.71; N, 11.91; Found: C, 76.33; H,
4.73; N, 11.88.
1-Benzyl-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1H,3H)-dione
(3Eb).
White solid; mp 184–187 °C (benzene-ethanol); IR (cm−1): 1721 (CO), 1691 (CO), 1601, 1468, 1453,
1373, 1311, 1027, 763, 693; 1H-NMR (DMSO-d6) 4.56 (d, J = 5.1 Hz, 2H), 5.23 (br t, J = 5.1 Hz, 1H),
5.31 (d, J = 16.7 Hz, 1H), 5.46 (d, J = 16.6 Hz, 1H), 7.15–7.39 (m, 9H), 7.41–7.55 (m, 3H), 7.61 (dd,
13
J = 7.5, 7.5 Hz, 1H), 7.88 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H); C-NMR (DMSO-d6) 46.7, 55.0, 80.0,
116.6, 121.0, 123.9, 124.9, 126.7, 127.4, 127.9, 128.6, 128.9, 129.5, 130.2, 130.6, 135.8, 136.8, 140.9,
147.0, 167.0, 188.5; MS (EI) m/z (%): 424 ([M]+, 2), 327 (16), 326 (16), 325 (9), 303 (7), 146 (7), 104
(10), 103 (7), 92 (9), 91 (100), 77 (11), 65 (10); Anal. Calcd for C25H20N4O3 (424.45): C, 70.74; H,
4.75; N, 13.20; Found: C, 70.49; H, 4.81; N, 12.91.
3.7. One-Pot Synthesis of 3-Phenyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione
(3Aa) Starting from 3-Bromo-3-phenylquinoline-2,4(1H,3H)-dione (6A)
A mixture of 3-bromo-3-phenylquinoline-2,4(1H,3H)-dione (6A, 316 mg, 1.00 mmol), pulverized
.
NaN3 (130 mg, 2.00 mmol), phenylacetylene (2a, 103 mg, 1.01 mmol), CuSO4 5H2O (25 mg, 0.10 mmol),
copper powder (280 mg, 4.41 mmol) and dimethyl sulfoxide (3.0 mL) was stirred in darkness for 20 h
and then diluted with CH2Cl2 (80 mL). The reaction mixture was filtered and the filtrate was
repeatedly extracted with saturated aqueous NH4Cl, until the aqueous phase remains colourless (totally
50 mL). The collected aqueous layer was back-extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried over Na2SO4, filtered and evaporated in vacuo. Residual DMSO was
removed by consecutive co-distillations in vacuo with toluene (2 × 15 mL) and then ethanol (2 × 15 mL).

Molecules 2011, 16
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The product was suspended in cyclohexane (10 mL). The suspension was shortly boiled, cooled down
to room temperature and the product was collected by filtration. Recrystallization from ethanol-acetic
acid afforded pure 3Aa (162 mg, 43%); mp 250–270 °C.
3.8. N-(3-(1-(1,2,3,4-Tetrahydro-2,4-dioxo-3-phenylquinolin-3-yl)-1H-1,2,3-triazol-4-yl)
phenyl)acetamide (3Ae).
A suspension of 3-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1H,3H)-dione
(3Ac, 99 mg, 0.25 mmol) in a mixture of ethyl acetate (0.5 mL) and pyridine (0.3 mL) was heated to
the boiling point. Acetic anhydride (62 mmol, 6 mL) was added portion wise under shaking. The
reaction mixture was cooled down to room temperature, left overnight and evaporated in vacuo. The
residue was suspended in hot methanol (2 mL), cooled down to room temperature and product 3Ae
(72.3 mg, 65%) was collected by filtration: light brown powder; mp 307–314 °C (dec.); IR (cm−1): 3319,
1
1719, 1678, 1615, 1594, 1485, 1446, 1369, 784; H-NMR (DMSO-d6) δ 2.06 (s, 3H), 7.11 (d,
J = 8.1 Hz, 1H), 7.17 (dd, J = 7.5, 7.5 Hz, 1H), 7.35 (dd, J = 7.8, 7.8 Hz, 1H), 7.39–7.48 (m, 3H),
7.48–7.59 (m, 4H), 7.59–7.68 (m, 1H), 7.84 (dd, J = 7.7, 0.9 Hz, 1H), 8.10 (br s, 1H), 8.46 (s, 1H), 10.03
(br s, 1H), 11.62 (br s, 1H); 13C-NMR (DMSO-d6) δ 24.0, 80.0, 115.5, 116.6, 118.4, 119.2, 119.8, 123.3,
127.4, 128.8, 129.2, 129.4, 129.9, 130.4, 130.8, 136.7, 139.8, 140.4, 145.2, 166.7, 168.3, 188.8; Anal.
Calcd for C25H19N5O3 (437.45): C, 68.64; H, 4.38; N, 16.01. Found: C, 68.58; H, 4.39; N, 15.93.
4. Conclusions
In conclusion, 3-azidoquinoline-2,4(1H,3H)-diones readily undergo copper(I)-catalyzed [3 + 2]
cycloaddition reaction with terminal alkynes to give the corresponding 1,4-disubstituted-1,2,3-triazoles.
Acknowledgements
This study was supported by the Ministry of Education, Youth and Sports of the Czech Republic
(Project MSM7088352101 and Joint Project Nr 9-06-3 of Programme KONTAKT), and the Slovenian
Research Agency (Project P1-0230-0103 and Joint Project BI-CZ/07-08-018). This work was also
partly supported through the infrastructure of the EN-FIST Centre of Excellence, Ljubljana. The
authors thank Bogdan Kralj and Dušan Žigon (Mass Spectrometry Center, Jožef Stefan Institute,
Ljubljana, Slovenia) for mass spectral measurements and Marijan Kočevar for the suport in
characterization of azides.
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Sample Availability: Samples of the compounds 1–6 are available from the authors.
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