Cu(I)-catalyzed alkyne–azide ‘click’ cycloaddition (CuAAC): a clean, efficient, and mild synthesis of new 1,4-disubstituted 1H-1,2,3-triazole-linked 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile–crystal structure

Article abstract of DOI:10.1007/s11164-018-03723-x

Cu(I)-catalyzed alkyne–azide ‘click’ cycloaddition (CuAAC) is an important ‘‘click chemistry’’ reaction that is widely known in materials science, chemical biology, and pharmaceutical chemistry. The CuAAC reaction of terminal alkynes affords an efficient and mild production of triazolic 1,4-disubstituted compounds. In this work, a green and valuable method was introduced for the synthesis of the category of different new 1,4-disubstituted 1,2,3-triazole swapped with a 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-cyano moiety. These triazolic derivatives were produced by treatment of various 2-amino-6-(azidomethyl)-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles with phenylacetylene in the presence of CuI as a catalyst with excellent yields (because CuAAC is selective to 1,4-disubstituted triazole derivatives) in a green solvent (ethanol/water). All structures were evaluated by ¹³C, ¹H NMR, and FT-IR spectroscopy and a compound was analyzed by crystallography (X-ray) technique.

Full text of DOI:10.1007/s11164-018-03723-x

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-03723-x
Cu(I)‑catalyzed alkyne–azide ‘click’ cycloaddition
(CuAAC): a clean, efcient, and mild synthesis of new
1,4‑disubstituted 1H‑1,2,3‑triazole‑linked 2‑amino‑4,8‑dihy
dropyrano[3,2‑b]pyran‑3‑carbonitrile–crystal structure
Khadijeh Ojaghi Aghbash1 · Nader Noroozi Pesyan1 · Ertan Şahin2
Received: 17 September 2018 / Accepted: 24 December 2018
© Springer Nature B.V. 2019
Abstract
Cu(I)-catalyzed alkyne–azide ‘click’ cycloaddition (CuAAC) is an important
‘‘click chemistry’’ reaction that is widely known in materials science, chemical
biology, and pharmaceutical chemistry. The CuAAC reaction of terminal alkynes
afords an efcient and mild production of triazolic 1,4-disubstituted compounds.
In this work, a green and valuable method was introduced for the synthesis of the
category of diferent new 1,4-disubstituted 1,2,3-triazole swapped with a 2-amino-
4,8-dihydropyrano[3,2-b]pyran-3-cyano moiety. These triazolic derivatives were
produced by treatment of various 2-amino-6-(azidomethyl)-4,8-dihydropyrano[3,2-
b]pyran-3-carbonitriles with phenylacetylene in the presence of CuI as a catalyst
with excellent yields (because CuAAC is selective to 1,4-disubstituted triazole
derivatives) in a green solvent (ethanol/water). All structures were evaluated by 13C,
1H NMR, and FT-IR spectroscopy and a compound was analyzed by crystallography
(X-ray) technique.
Keywords 4H-pyrans · 2-Amino-6-(azidomethyl)-4,8-dihydropyrano[3,2-b]pyran-
3-carbonitrile · Azide-alkyne 1,3-dipolar cycloaddition · Click reaction · Copper
catalysis · 1,2,3-Triazoles · Dimeric form · Co-crystal
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-018-03723-x) contains supplementary material, which is available to authorized users.
*
Nader Noroozi Pesyan
n.noroozi@urmia.ac.ir; nnp403@gmail.com
1
2
Department of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia 57159, Iran
Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey
Vol.:(0123456789)
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K. Ojaghi Aghbash et al.
Introduction
In the past decades, the synthesis of diferent heterocyclic structures owing to
their wide applicability has been a subject of great interest. Heterocyclic com-
pounds are necessary to life and found very widely in nature. 1,2,3-Triazoles,
important fve-membered nitrogen heterocycles, occupy a singular dwelling
in heterocyclic chemistry. The triazole ring as a slice of the structure of many
compounds has various biological, chemical and technical characteristics. The
1H-1,2,3-triazole derivatives category has displayed various industrial applica-
tions such as dyes, corrosion inhibitors, optical brighteners, and agrochemicals
[1–7]. In addition, many of the 1,2,3-triazole compounds indicate a wide spec-
tra of biological applications such as antifungal [8], anticancer [9], antibacterial
[10], anti-HIV [11], antiallergic [12], antitubercular [13], hypotensive medica-
tions, pesticides, neuroleptics and anti-infammatory [7, 14].
4H-pyrans heterocyclic scafolds are one of the very interesting and biologi-
cally important structures that formed key motifs of the numerous natural com-
pounds [15–24]. Among the many frameworks, 4H-pyrans and their derivatives
are receiving great attention owing to their medicinal activities such as antican-
cer, analgesic, etc. [25–30]. Also, 4H-pyrans are convenient intermediates in
the production of diferent compounds [31–33]. Furthermore, 4H-pyrans repre-
sent structure blocks of categories of natural compounds [34, 35]. In addition,
a number of 2-amino-4H-pyrans exemplify a signifcant series of compounds.
They are employed as photoactive materials [36], pigments [37], cosmetics and
potential biodegradable agrochemicals [25, 36]. 2-Amino-4H-pyrans, in particu-
lar 2-amino-3-cyano-4H-pyrans, also possess noteworthy photochemical features
[36] and have interested synthetic organic chemists as these show biological prop-
erties such as anticancer [38–46], antifungal, antibacterial [25, 43, 47, 48], anti-
rheumatic [49], anti-oxidant, antimicrobial, fungicidal, antiviral, herbicidal, and
antitumor [50–52]. These are key precursors for the preparation of compounds
with medicinally activities such as imidoesters 1,4-dihydropyridines, pyridones,
lactones, pyranopyrazoles, and aminopyrimidines [25, 53]. The most general and
useful method used thus far for the synthesis of 1,2,3-triazoles relies on the Huis-
gen thermal 1,3-dipolar cycloaddition of azides with alkynes [54]. The disadvan-
tages of this method include a high temperature requirement, the formation of
two isomeric products (non-selectivity), and long reaction time. In recent dec-
ades, the copper (I)-catalyzed modifcation reaction introduction has allowed the
1,3-dipolar reaction to be carried out at low temperatures (RT, etc.) leading to the
selecte formation of 1,4-disubstituted triazolic products with the shortest purif-
cation steps [55].
Recently, we have reported a new category of hybrid molecules of 1H-1,2,3-
triazole coupled to kojic acid (KA) and which we have evaluated for antioxidant
activity [56]. In the light of the above-mentioned facts, our research has been
dedicated to the improvement of a new category of heterocyclic systems which
incorporate the various pharmacophoric groups of biological relevance such as
1,2,3-triazole and 2-amino-3-cyano-4H-pyrans moieties into a single molecule,
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Cu(I)‑catalyzed alkyne–azide ‘click’cycloaddition (CuAAC):…
with the hope that they may be biologically active and pave a way to drug dis-
covery. Therefore, in this study, we present a clean, efcient, and safe method
for the construction of new 1,2,3-triazole derivatives from various 2-amino-6-
(azidomethyl)-8-oxo-4-aryl-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile with
phenylacetylene in ethanol:water (2:1) as a green solvent.
Experimental
Materials
All utilized material was purchased from Fluka or Merck. Melting points were meas-
ured with an electrothermal digital melting point apparatus and were uncorrected.
FT-IR spectra were measured on a NEXUS 670 FT-IR spectrometer in the region
4000–400 cm−1 by preparing KBr pills (Urmia University, Urmia, Iran). The 1H and
13C NMR spectra at 300 and 75 MHz on a Bruker 300 FT NMR (Urmia University)
were recorded. TLC (silica gel-coated plates) was used to control all the reactions.
General procedure for the preparation of the variety of 2‑amino‑6‑(azidomethyl)‑
8‑oxo‑4‑aryl‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitriles
Various Knoevenagel adducts (1 mmol) and azido-KA (1 mmol) in ethanol (5 mL)
were solved and, following the addition of ammonium chloride (30 mol%), were
refuxed for 12–24 h. After the achievement of the reaction, the mixture was evap-
orated and the resultant precipitate was recrystallized from acetonitrile:methanol
(1:1) for purifcation [57].
General procedure for the synthesis of variety
2‑amino‑4‑(phenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4a–4m)
Copper (I) iodide (10 mol%) and phenylacetylene (2 mmol) were added to a stirred
solution of azide (0.5 mmol) in ethanol:water (2:1) solvent (6.0 mL). The reaction
mixture was then heated to 80 °C and monitored by TLC. After completion of the
reaction, the mixture solvent was removed. The resulting crude product was purifed
by recrystallization from methanol:acetonitrile (1:1) to aford the desired substituted
1,2,3-triazole.
Spectral data
2‑Amino‑8‑oxo‑4‑phenyl‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4a, C24H17N5O3)
Cream solid: yield 0.2 g (94%); m.p.: 205–207 °C; FT-IR (KBr): ν=3369, and 3309
(–NH2), 3192, 3052, 2855, 2197 (–CN), 1645 (pyrone-CO), 1596, 1441, 1408, 1365,
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K. Ojaghi Aghbash et al.
1
1254, 1206, 1074, 1014, 856, 768 cm−1; H NMR (300 MHz, DMSO-d6): δ=4.77
(s, 1H, –CH-chiral), 5.53–5.70 (dd, 2H, –CH2N–), 6.54 (s, 1H, pyrone-H) and 7.08
(m, 1H, H-Ph), 7.16 (m, 4H, NH2, H-Ph), 7.26 (m, 2H, H-Ph), 7.33–7.38 (m, 1H,
H-Ph), 7.44–7.49 (m, 2H, H-Ph), 7.78–7.80 (m, 2H, H-Ph), 8.40 (s, 1H, triazole-H)
ppm; 13C NMR (75 MHz, DMSO-d6): δ=50.2 (C-chiral), 55.4 (–CH2N–), 114.7,
115.8, 119.6, 121.2, 123.5, 124.6, 126.8, 127.1, 128.2, 128.5, 128.9, 129.2, 130.0,
130.8, 136.8, 140.4, 147.1, 150.1, 159.8, 160.7, 162.3, 169.8 (pyrone-CO) ppm.
2‑Amino‑4‑(3‑nitrophenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4b, C24H16N6O5)
Brown solid: yield 0.24 g (98%); m.p.: 217–219 °C; FT-IR (KBr): ν=3404, and
3329 (–NH2), 3149, 3071, 2859, 2195 (–CN), 1651 (pyrone-CO), 1591, 1528,
1
1437, 1347, 1219, 1077, 1011, 908, 764 cm−1; H NMR (300 MHz, DMSO-d6):
δ=5.08 (s, 1H, –CH-chiral), 5.48–5.62 (dd, 2H, –CH2N–), 6.58 (s, 1H, pyrone-
H), 7.35–7.45 (m, 6H, NH2, H-Ph), 7.62–7.64 (m, 1H, H-Ph), 7.68–7.71 (m, 2H,
H-Ph), 7.82–7.85 (m, 1H, H-Ph), 8.04 (s, 1H, H-Ph), 8.30 (s, 1H, triazole-H) ppm;
1H NMR (300 MHz, DMSO-d6 +D2O): δ=5.01 (s, 1H, –CH-chiral), 5.42–5.56 (dd,
2H, –CH2N–), 6.56 (s, 1H, pyrone-H), 7.34–7.39 (m, 4H, NH2, H-Ph), 7.53–7.61
(m, 3H, H-Ph), 7.71–7.73 (m, 1H, H-Ph), 7.93 (s, 1H, H-Ph), 8.19 (s, 1H, triazole-
H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=50.1 (C-chiral), 54.7 (–CH2N–), 114.3,
116.7, 119.3, 120.9, 122.0, 123.3, 124.4, 126.6, 128.4, 130.6, 137.1, 142.5, 147.0,
148.2, 148.7, 148.79, 149.1, 159.8, 160.6, 162.4, 169.8 (pyrone-CO) ppm.
2‑Amino‑4‑(2,4‑dichlorophenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4c, C24H15Cl2N5O3)
Cream solid: yield 0.24 g (98%); m.p.: 248–250 °C; FT-IR (KBr): ν=3377, and
3320 (–NH2), 3203, 3078, 3005, 2952, 2192 (–CN), 1640 (pyrone-CO), 1592,
1
1431, 1368, 1211, 1092, 1014, 865, 741 cm−1; H NMR (300 MHz, DMSO-d6):
δ=5.22 (s, 1H, –CH-chiral), 5.51–5.63 (dd, 2H, –CH2N–), 6.57 (s, 1H, pyrone-H),
7.26–7.38 (m, 6H, NH2, H-Ph), 7.44–7.49 (m, 2H, H-Ph), 7.76–7.78 (m, 2H, H-Ph),
8.35 (s, 1H, triazole-H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=50.0 (C-chiral),
54.4 (–CH2N–), 114.1, 116.3, 119.1, 123.5, 124.4, 126.7, 127.4, 128.4, 129.4, 130.7,
131.6, 133.8, 136.4, 137.3, 146.9, 148.5, 159.8, 160.7, 163.1, 169.7 (pyrone-CO)
ppm.
2‑Amino‑4‑(4‑nitrophenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4d, C24H16N6O5)
Dark brown; yield 0.24 g (98%); m.p.: 185–187 °C; FT-IR (KBr): ν=3458, and
3285 (–NH2), 3154, 3070, 2924, 2193 (–CN), 1668 (pyrone-CO), 1590, 1519, 1439,
1
1346, 1221, 1023, 861, 765 cm−1; H NMR (300 MHz, DMSO-d6): δ=5.01 (s,
1H, –CH-chiral), 5.50–5.62 (dd, 2H, –CH2N–), 6.59 (s, 1H, pyrone-H), 7.35–7.45
(m, 7H, NH2, H-Ph), 7.68–7.70 (m, 2H, H-Ph), 7.97–7.99 (m, 2H, H-Ph), 8.34 (s,
1H, triazole-H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=49.8 (C-chiral), 54.6
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Cu(I)‑catalyzed alkyne–azide ‘click’cycloaddition (CuAAC):…
(–CH2N–), 114.3, 119.2, 123.0, 124.2, 125.3, 126.5, 127.5, 128.5, 129.4, 130.5,
131.7, 137.1, 138.8, 147.6, 148.6, 159.7, 160.7, 169.7 (pyrone-CO) ppm.
2‑Amino‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)methyl)‑4‑(3,4,5‑trimethoxypheny
l)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4e, C27H23N5O6)
Cream solid: yield 0.24 g (93%); m.p.: 108–110 °C; FT-IR (KBr): ν=3120 and
3098 (–NH2), 2933, 2838, 2188 (–CN), 1649 (pyrone-CO), 1598, 1504, 1421, 1325,
1
1214, 1125, 1094, 1005, 847, 769 cm−1; H NMR (300 MHz, DMSO-d6): δ=2.71
(s, 3H, –OMe), 2.77 (s, 3H, –OMe), 3.48 (s, 2H, –CH2N–) 3.67 (s, 3H, –OMe),
4.71 (s, 1H, –CH-chiral), 5.58 (s, 1H, pyrone-H), 6.51 (s, 2H, NH2), 7.22 (s, 1H,
H-Ph), 7.32–7.33 (m, 1H, H-Ph), 7.40–7.44 (m, 2H, H-Ph), 7.75–7.77 (m, 2H,
H-Ph), 7.95–7.96 (m, 1H, H-Ph), 8.45 (s, 1H, triazole-H) ppm; 13C NMR (75 MHz,
DMSO-d6): δ=50.9 (C-chiral), 52.3 (–OMe), 54.5 (–OMe), 55.6 (–CH2N–), 114.1,
119.6, 120.9, 121.0, 123.4, 124.51, 124.58, 126.7, 128.2, 128.4, 129.4, 130.7, 136.1,
136.9, 137.4, 147.0, 149.8, 153.4, 159.7, 160.7, 169.8 (pyrone-CO) ppm.
2‑Amino‑4‑(2‑methoxyphenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4f, C25H19N5O4)
Cream solid: yield 0.21 g (93%); m.p.: 180–182 °C; FT-IR (KBr): ν=3143, and
3045 (–NH2), 2839, 2192 (–CN), 1643 (pyrone-CO), 1596, 1489, 1440, 1405, 1248,
1
1210, 1110, 1077, 1022, 861, 761 cm−1; H NMR (300 MHz, DMSO-d6): δ=3.63
(s, 3H, –OMe), 4.97 (s, 1H, –CH-chiral), 5.48–5.59 (dd, 2H, –CH2N–), 6.49 (s, 1H,
pyrone-H), 6.81–6.83 (m, 2H, H-Ph), 7.06–7.11 (m, 4H, NH2, H-Ph), 7.35–7.37
(m, 1H, H-Ph), 7.43–7.47 (m, 2H, H-Ph), 7.73–7.75 (m, 2H, H-Ph), 8.30 (s, 1H,
triazole-H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=36.2 (–OMe), 50.2 (C-chiral),
55.3 (–CH2N–), 113.4, 121.0, 123.2, 123.6, 124.6, 126.8, 127.5, 128.1, 128.5, 128.8,
128.9, 129.4, 130.4, 130.7, 137.3, 147.1, 150.6, 157.3, 160.0, 160.5, 169.7 (pyrone-
CO) ppm.
2‑Amino‑4‑(4‑hydroxyphenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4g, C24H17N5O4)
Yellow solid: yield 0.2 g (91%); m.p.: 237–239 °C; FT-IR (KBr): ν=3404 and 3301
(–NH2, OH), 3203, 3186, 2925, 2855, 2195 (–CN), 1641 (pyrone-CO), 1598, 1511,
1
1444, 1413, 1356, 1271, 1206, 1103, 1034, 838, 761 cm−1; H NMR (300 MHz,
DMSO-d6): δ=4.63 (s, 1H, –CH-chiral), 5.54–5.63 (m, 2H, –CH2N3), 6.47 (s, 1H,
pyrone-H), 6.63–6.66 (m, 2H, H-Ph), 6.98–7.01 (m, 2H, H-Ph), 7.19 (s, 2H, NH2),
7.35–7.37 (m, 1H, H-Ph), 7.44–7.49 (m, 2H, H-Ph), 7.80–7.82 (m, 2H, H-Ph), 8.44
(s, 1H, triazole-H) and 9.41 (s, 1H, OH) ppm; 13C NMR (75 MHz, DMSO-d6):
δ=50.2 (C-chiral), 55.9 (–CH2N–), 114.8, 119.7, 121.2, 123.7, 124.6, 126.8, 128.3,
128.5, 130.2, 130.9, 136.5, 147.1, 150.7, 157.5, 159.7, 160.7, 169.8 (pyrone-CO)
ppm.
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K. Ojaghi Aghbash et al.
2‑Amino‑4‑(3‑hydroxyphenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4h, C24H17N5O4)
Dark brown solid: yield 0.2 g (91%); m.p.: 176–178 °C; FT-IR (KBr): ν=3379,
3317 and 3196 (–NH2, OH), 2963, 2852, 2199 (–CN), 1645 (pyrone-CO), 1596,
1
1443, 1410, 1361, 1260, 1211, 1078, 1011, 869, 763 cm−1; H NMR (300 MHz,
DMSO-d6): δ=4.65 (s, 1H, –CH-chiral), 5.55–5.61 (m, 2H, –CH2N–), 6.49 (s, 1H,
pyrone-H), 6.54–6.62 (m, 3H, H-Ph), 6.93–6.99 (m, 1H, H-Ph), 7.25 (s, 2H, NH2),
7.35–7.37 (m, 1H, H-Ph), 7.44–7.59 (m, 2H, H-Ph), 7.78–7.81 (m, 2H, H-Ph), 8.43
(s, 1H, triazole-H), 9.49 (s, 1H, OH) ppm; 13C NMR (75 MHz, DMSO-d6): δ=50.3
(C-chiral), 55.7 (–CH2N–), 114.6, 119.6, 121.1, 124.64, 124.67, 126.9, 128.4, 128.5,
130.4, 130.5, 130.7, 132.3, 136.8, 142.1, 147.2, 150.3, 158.2, 159.7, 160.8, 169.7
(pyrone-CO) ppm.
2‑Amino‑8‑oxo‑6‑((4‑phenyl‑4,5‑dihydro‑1H‑1,2,3‑triazol‑1‑yl)methyl)‑4‑(p‑tolyl)‑4,
8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4i, C25H21N5O3)
Orange solid: yield 0.21 g (96%); m.p.: 214–216 °C; FT-IR (KBr): ν=3372, and
3325 (–NH2), 3205, 3091, 2923, 2859, 2197 (–CN), 1651 (pyrone-CO), 1598, 1511,
1
1420, 1360, 1208, 1074, 1012, 823, 765 cm-1; H NMR (300 MHz, DMSO-d6):
δ=1.98 (s, 3H, –Me), 4.69 (s, 1H, –CH-chiral), 5.51–5.63 (m, 2H, –CH2N–), 6.54
(s, 1H, pyrone-H), 6.912–6.914 (m, 2H, H-Ph), 6.93–6.99 (m, 2H, H-Ph), 7.22
(s, 2H, NH2), 7.35–7.36 (m, 1H, H-Ph), 7.44–7.46 (m, 2H, H-Ph), 7.77–7.80 (m,
2H, H-Ph), 8.38 (s, 1H, triazole-H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=21.3
(–Me), 50.5 (C-chiral), 55.4 (–CH2N–), 115.0, 119.6, 123.4, 124.4, 124.5, 126.8,
128.3, 129.2, 130.1, 130.7, 136.5, 137.3, 147.0, 150.2, 159.7, 160.5, 169.7 (pyrone-
CO) ppm.
2‑Amino‑4‑(4‑fuorophenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4j, C24H16FN5O3)
Yellow solid: yield 0.22 g (99%); m.p.: 187–189 °C; FT-IR (KBr): ν=3302, and
3189 (–NH2), 3072, 3048, 2929, 2860, 2195 (–CN), 1663 (pyrone-CO), 1594, 1506,
1
1408, 1365, 1218, 1074, 1018, 838, 761 cm−1; H NMR (300 MHz, DMSO-d6):
δ=4.79 (s, 1H, –CH-chiral), 5.52–5.62 (m, 2H, –CH2N–), 6.53 (s, 1H, pyrone-H),
6.93–6.94 (m, 2H, –NH2), 7.18–7.19 (m, 2H, H-Ph), 7.25 (s, 2H, NH2), 7.34–7.36
(m, 1H, H-Ph), 7.42–7.44 (m, 2H, H-Ph), 7.76–7.78 (m, 2H, H-Ph), 8.38 (s, 1H, tri-
azole-H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=50.2 (C-chiral), 55.4 (–CH2N–),
114.6, 119.5, 121.1, 123.5, 124.5, 126.7, 128.4, 128.5, 131.0, 133.4, 136.7, 139.1,
143.0, 147.1, 149.7, 159.7, 160.6, 169.7 (pyrone-CO) ppm.
2‑Amino‑4‑(4‑methoxyphenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4k, C25H19N5O4)
Cream solid: yield 0.21 g (93%); m.p.: 206–208 °C; FT-IR (KBr): ν=3431 (–NH2),
3065, 2925, 2853, 2196 (–CN), 1647 (pyrone-CO), 1600, 1511, 1439, 1364, 1255,
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Cu(I)‑catalyzed alkyne–azide ‘click’cycloaddition (CuAAC):…
1
1211, 1075, 1026, 835, 764 cm−1; H NMR (300 MHz, DMSO-d6): δ=3.49 (s,
3H, –OMe), 4.70 (s, 1H, –CH-chiral), 5.52–5.64 (s, 2H, –CH2N–), 6.53 (s, 1H,
pyrone-H), 6.69–6.71 (m, 2H, H-Ph), 7.05–7.08 (m, 2H, H-Ph), 7.22 (s, 2H, –NH2),
7.35–7.37 (m, 1H, H-Ph), 7.44–7.48 (m, 2H, H-Ph), 7.80–7.82 (m, 2H, H-Ph), 8.43
(s, 1H, triazole-H) ppm; 13C NMR (75 MHz, DMSO-d6): δ=35.4 (–OMe), 50.2
(C-chiral), 55.5 (–CH2N–), 115.6, 119.6, 121.1, 123.6, 124.5, 126.8, 128.3, 128.4,
130.2, 130.8, 132.3, 134.1, 136.5, 147.1, 150.3, 159.7, 160.5, 169.8 (pyrone-CO)
ppm.
2‑Amino‑4‑(4‑chlorophenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4l, C24H16ClN5O3)
Cream solid: yield 0.22 g (96%); m.p.: 221–223 °C; FT-IR (KBr): ν=3334 and
3189 (–NH2), 3089, 2926, 2856, 2195 (–CN), 1650 (pyrone-CO), 1597, 1487, 1413,
1
1360, 1212, 1081, 1015, 828, 765 cm−1; H NMR (300 MHz, DMSO-d6): δ=4.81
(s, 1H, –CH-chiral), 5.52–5.61 (m, 2H, –CH2N–), 6.54 (s, 1H, pyrone-H), 7.19 (m,
4H, –NH2, H-Ph), 7.29–7.37 (m, 3H, H-Ph), 7.43–7.48 (m, 2H, H-Ph), 7.78–7.80
(m, 2H, H-Ph), 8.42 (s, 1H, triazole-H) ppm; 13C NMR (75 MHz, DMSO-d6):
δ=35.4 (–OMe), 51.1 (C-chiral), 55.0 (–CH2N–), 114.4, 119.4, 121.1, 122.8, 124.5,
126.7, 127.1, 128.4, 129.0, 130.2, 130.8, 132.8, 136.8, 139.3, 149.5, 159.8, 160.6,
169.7 (pyrone-CO) ppm.
2‑Amino‑4‑(2‑chlorophenyl)‑8‑oxo‑6‑((4‑phenyl‑1H‑1,2,3‑triazol‑1‑yl)
methyl)‑4,8‑dihydropyrano[3,2‑b]pyran‑3‑carbonitrile (4m, C24H16ClN5O3)
Cream solid: yield 0.22 g (96%); m.p.: 142–146 °C; FT-IR (KBr): ν=3362 (–NH2),
3182, 3067, 2191 (–CN), 1651 (pyrone-CO), 1593, 1440, 1366, 1263, 1214, 1077,
1
1018, 862, 764 cm−1; H NMR (300 MHz, DMSO-d6): δ=5.21 (s, 1H, –CH-chi-
ral), 5.49–5.60 (m, 2H, –CH2N–), 6.54 (s, 1H, pyrone-H), 7.04–7.09 (m, 1H, H-Ph),
7.17–7.28 (m, 5H, NH2, H-Ph), 7.36–7.38 (m, 1H, H-Ph), 7.44–7.49 (m, 2H, H-Ph),
7.73–7.75 (m, 2H, H-Ph), 8.29 (s, 1H, triazole-H) ppm; 13C NMR (75 MHz, DMSO-
d6): δ=50.1 (C-chiral), 54.7 (–CH2N–), 115.5, 119.2, 121.0, 123.4, 124.0, 126.8,
127.3, 128.4, 129.2, 130.1, 130.8, 131.1, 132.1, 137.3, 146.9, 149.1, 153.3, 159.8,
160.7, 169.7 (pyrone-CO) ppm.
Results and discussion
In association with our attention to the synthesis of heterocyclic deriva-
tives [56–58] and the wide-ranging uses of 2-amino-4H pyran-3-cyano and
1,2,3-triazoles as biologically active compounds, we became concerned in the
synthesis
of
2-amino-4-(phenyl)-8-oxo-6-((4-phenyl-1H-1,2,3-triazol-1-yl)
methyl)-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile from diferent 2-amino-6-
(azidomethyl)-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile with phenylacetylene.
To pursue our objective, the reaction of KA (1) with SOCl2 (thionyl chloride) at room
temperature formed chloro kojic acid (2-(chloromethyl)-5-hydroxy-4H-pyran-4-one)
1 3

K. Ojaghi Aghbash et al.
Scheme 1 The reaction of azido-KA with Knoevenagel adduct to prepare 2 [57]
Scheme 2 The regio-selective reaction of 2 with phenylacetylene 3 obtained 4
[59], followed by 2-(azidomethyl)-5-hydroxy-4H-pyran-4-one in the reaction with
sodium azide (NaN3) in dry DMF [60]. The reaction of azido-KA with Knoevenagel
adducts aforded 2-amino-6-(azidomethyl)-8-oxo-4-aryl-4,8-dihydropyrano[3,2-b]
pyran-3-carbonitrile (2) (Scheme 1) [57]. Then, we subjected phenylacetylene (3) to
reaction with 2 in the presence of copper iodide (Scheme 2). Continuing this work,
the efect of temperature, mol% of CuI, and a screening of solvents in the synthesis
of 4a as representative was undertaken (Table 1).
The reaction was performed in various solvents such as H2O, EtOH, MeOH,
MeCN, acetone, and THF in the presence of 10 mol% of CuI under the refux
conditions for 24 h. However, this resulted in a trace amount of the wanted
1,4-disubstituted 1,2,3-triazole compound to be synthesized (4a) (Table 1,
entries), such as THF, MeCN, MeOH, and acetone were screened at 60, 80, 60,
and 50 °C, respectively. A good result was found in MeOH/H2O, THF/H2O, and
acetone/H2O (2:1) media (Table 1, entries 11–14). Finally, this reaction was
conducted in the presence of diferent amounts of CuI as a catalyst and at vari-
ous temperatures (RT and 80 °C) in a green solvent [EtOH/H2O (2:1)]. The best
1 3

Cu(I)‑catalyzed alkyne–azide ‘click’cycloaddition (CuAAC):…
Table 1 The efect of several factors (mol% of catalysts, temperatures, and various solvents) on the syn-
thesis of 4a
Entrya
Cat. (%)
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
H2O
EtOH
MeOH
CH3CN
Acetone
THF
EG
DMF
1,4-dioxane
DMSO
CH3CN/H2O
Acetone/H2O
THF/H2O
MeOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
Refux
Refux
Refux
Refux
Refux
Refux
100
100
100
100
80
24
24
24
24
24
24
24
24
24
24
24
6
Trace
Trace
Trace
Trace
Trace
Trace
60
40
20
70
9
10
11
12
13
14
15
16
17
18
Trace
94
50
60
4
96
60
3
24
2
2
2
95
rt
40
80
80
80
96
98
95
10
15
Bold indicates the best results
aReaction conditions: azide (0.5 mmol), phenylacetylene (2.0 mmol)
bIsolated yields
results were obtained with 2-amino-6-(azidomethyl)-4,8-dihydropyrano[3,2-b]
pyran-3-carbonitrile (0.5 mmol) and phenylacetylene (2.0 mmol) in the pres-
ence of CuI (10 mol%) and EtOH/H2O (2:1) (6 mL) as clean solvents at 80 °C
(Table 1, entries 15–18).
After obtaining reaction optimal conditions, various azides and phenylacety-
lene were utilized for evaluation of the scope of the reaction. For this purpose,
we frst examined the reaction with diferent azides and the results are given in
Table 2, in which it is shown that in general a wide range of azides could react
1 3

K. Ojaghi Aghbash et al.
Table 2 Scope of the reaction with a variety of azides and phenylacetylene
4a (94%)
4b (98%)
4c (98%)
4d (98%)
4e (93%)
4f (93%)
4g (91%)
4h (91%)
4k (93%)
4i (96%)
4j (99%)
4l (96%)
4m (96%)
smoothly with phenylacetylene and gives compounds 4a–m in good to excellent
yields.
X‑ray difraction analysis of 4j
To determine the crystal structure, single-crystal of compound 4j was measured
by a Rigaku R-AXIS RAPID-S difractometer (a four-circle instrument equipped
with a two-dimensional area IP detector) for data collection. Also, the oscilla-
tion scans technique with Δw=5° and graphite-monochromated Mo-Kα radiation
(λ=0.71073 Å) for one image were utilized. The lattice parameters were determined
1 3

Cu(I)‑catalyzed alkyne–azide ‘click’cycloaddition (CuAAC):…
by the least-squares procedure based on all refections with F2 >2σ(F2). Correction
for polarization and Lorentz efects, cell refnement, and integration of the intensi-
ties that had been received outdoors was by way of Crystal Clear software (Rigaku/
MSC, 2005) [61]. The frameworks were solved using direct methods by SHELXS-97
[62], which allowed a place for most of the heaviest atoms, with the rem residual
non-hydrogen atoms being located from various Fourier-calculated maps from con-
secutive perfect-matrix least-squares refnement circles on F2 by SHELXL-97 [62].
All atoms except hydrogen were refned by anisotropic replacement parameters. The
location of hydrogen bonded to carbon was determined at their geometric place in
SHELXL by suitable HFIX instructions.
The end diference Fourier maps displayed no peaks regarding chemical impor-
tance. Crystal data for 4j were: C24H16FN5O3, C2H6OS, crystal system, space group:
triclinic, P-1; (no:2); unit cell dimensions: a=10.0128 (12), b=11.5310 (11),
c=11.5802 (14) Å, α=98.943 (5), β=94.587 (6), γ=103.174 (5)º; volume: 1276.7
(3) Å3; Z=2; calculated density: 1.352 g/cm3; absorption coefcient: 0.176 mm−1;
F(000)=540; θ-range for data collection 2.2–26.6º; refnement method: full matrix
least-square on F2; data/parameters: 3214/336; goodness-of-ft on F2: 1.199; fnal
R-indices [I>2σ(I)]: R1 =0.085, wR2 =0.191; largest dif. peak and hole: 0.741
and −0.605 e Å−3 (See supporting information and crystal structure data section
for more information). Crystallographic data for the structure of 4j presented in this
study have been preserved with the Cambridge Crystallographic Data Center as sup-
plementary publication No. CCDC-1858846. Copies of these data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
FAX: (+44) 1223 336033, or online via www.ccdc.cam.ac.uk/data_request/cif, or
by emailing data_request@ccdc.cam.ac.uk.
X-ray analysis of the molecule 2-amino-4-(4-fuorophenyl)-8-oxo-6-[(4-phenyl-
1H-1,2,3-triazol-1-yl)methyl]-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile dime-
thyl sulfoxide solvate (4j.DMSO) were performed to confrm the structure. The
crystal structure of the molecule with the atom labeling is shown in Fig. 1a, and
dimeric H-bonding geometry is indicated in Fig. 1b. Compound 4j was crystallized
with two molecules in the unit cell (Z=2). In the triclinic P-1 space group, the struc-
ture contains an asymmetric carbon atom (C4) and has a (S) confguration stereo-
genic center. The crystal structure indicated that the molecule of 4j formed a dimeric
form with two intermolecular hydrogen bonds (dN1⋯N5 =3.059 Å,
dN5⋯H1H =2.222 Å) and a 12-membered centrosymmetric Ci form. One of the inter-
esting phenomena is the sticking of a dimethyl sulfoxide molecule to the 4j with an
intermolecular hydrogen bond between the O4 atom of dimethyl sulfoxide with the
amino group (dN1⋯O4 =2.927 Å, dH1B⋯O4 =2.136 Å). The selected bond length,
angles and torsion angles for 4j are shown in Table 3. The two hydrogen atoms of
the amino group (H1A and H1B) displayed intermolecular H-bonds with N5 of the
nitrile and O4 of the sulfoxide groups, respectively. In other words, the amino group
showed a di-hydrogen bridge H-bond
).
(
All intermolecular hydrogen bond characteristics are shown in Table 4. The
fuorine atom on the phenyl ring does not interfere with the formation of the
1 3

K. Ojaghi Aghbash et al.
Fig. 1 a Molecular structure of the molecule 4j. Thermal ellipsoids are drawn at the 40% probability
level. b Dimeric structure with the H-bonding geometry. Hydrogen bonds are drawn as dashed lines
intermolecular hydrogen bond. The fused pyrano[3,2-b]pyran-4(8H)-one ring
has a planar form. Also, two aromatic rings of triazole and phenyl that are linked
together by a covalent bond have a nearly planar form (Table 3, entries 11 and 13,
respectively).
Representatively, the FT-IR spectrum of 4b displayed broad peaks at the frequen-
cies of 3404 and 3329 cm−1 corresponded to the NH2 functional group, and a sharp
peak at 2195 cm−1 corresponded to the nitrile group. A sharp peak at 1651 cm−1 is
1
assigned to the pyrone carbonyl group. The H NMR spectrum of this compound
1 3

Cu(I)‑catalyzed alkyne–azide ‘click’cycloaddition (CuAAC):…
Table 3 Selected bond length (d, Å), bond angles (θ, °) and torsion angles (φ, °) for 4j
Entry
Atom
d (Å), θ (°), φ (°)
Entry
Atom
d (Å), θ (°), φ (°)
1
2
3
4
5
6
7
N2–N3
N3–N4
C18–N4
C1–N5
C7–O2
O1–C9
F1–C13
1.337(3)
1.310(3)
1.347(3)
1.134(3)
1.222(3)
1.357(3)
1.363(3)
8
9
O4–S1–C25
O4–S1–C26
C26–S1–C25
O3–C6–C7–C8
N4–C18–C19–C20
C11–C10–C4–C2
O1–C9–C16–N2
106.5 (5)
109.2 (4)
98.2 (5)
178.9 (4)
−176.4 (7)
−29.8 (7)
−42.5 (7)
10
11
12
13
14
Table 4 Hydrogen bond
geometry (Å, °) for 4j
D–H⋯A
D–H
H⋯A
D⋯A
D–H⋯A
N1–H1A⋯N5i
0.86
0.86
0.86
0.97
0.97
2.222
2.136
2.888
2.698
2.561
3.058 (6)
2.927
3.736 (5)
3.333 (8)
3.389 (8)
164
153
169
123
144
N1–H1B⋯O4ii
N1–H1B⋯S1iii
C16–H16A⋯N5iv
C16–H16B⋯N3v
Symmetry codes: (v)−x+2,−y+1,−z+1; (iv) x+1, y, z; (iii) x,
y−1, z; (ii) x, y+1, z; (i) −x, −y, −z+1
indicated a singlet at δ=5.08 ppm corresponding to a benzylic methine proton in
the chiral center. The doublet of doublet peaks at δ =5.48–5.62 ppm are assigned
to diastereotopic methylene protons connected to the azide substituent. The peak of
amino protons is overlapped in the aromatic peaks region which was confrmed by
the 1H NMR spectrum of 4b in D2O examination. The singlet peak at δ=8.30 ppm
is connected to the proton on the carbon atom of the 1,2,3-triazole ring. Other pro-
ton peaks had good agreement with the assigned structure. The 13C NMR spectrum
of 4b showed 23 distinct peaks that confrmed the proposed structure. Two peaks at
δ=54.763 and 50.198 ppm corresponded to methylene and methine carbon atoms,
respectively. The peak at δ=169.822 ppm connected to cthe arbonyl carbon atom.
(See “Experimental” and supporting information). Representatively, a possible
mechanism for the production of 4a is shown in (Scheme 3).
The reaction of phenylacetylene 3 with the CuI catalyst forms Cu (I)-acetylide
(5) that coordinates with the azide (2a) to obtain a dicuprate complex (6). Then,
the C–N bond is formed between the end nitrogen of the coordinated azide and the
β-carbon of Cu (I)-acetylide generating intermediate 7, followed by reductive elimi-
nation from 7 leading to the 5-cuprated triazolic intermediate 8. Eventually, the fnal
product (4a) is obtained with protonolysis and reforms the Cu (I) catalyst [63–65].
1 3

K. Ojaghi Aghbash et al.
Scheme 3 A plausible mechanism for the reaction of Cu-catalyzed 2-amino-6-(azidomethyl)-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitrile 2a cycloaddition with phenylacetylene 3
Conclusions
In the current research, we have successfully developed a clean, mild, and efcient
process for the synthesis of a diferent array of 1,4-disubstituted 1,2,3-triazole-
linked 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles by the use of difer-
ent azides with phenylacetylene in the presence of the catalytic amount of CuI in
excellent yields.
Acknowledgement We much thanks to the Urmia University research council for supporting this
research.
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