Synthesis of triazole and isoxazole based novel unsymmetrical bis-heterocycles

Article abstract of DOI:10.1002/jhet.1587

Novel unsymmetrical bis-heterocyclic compounds encompassing triazole and isoxazole moieties were synthesized by employing 1,3-dipolar cycloaddition/click chemistry approach using 5-butynyl-1,2,3-triazoles and 5-butynyl isoxazoles.

Full text of DOI:10.1002/jhet.1587

Month 2013
Synthesis of Triazole and Isoxazole Based Novel Unsymmetrical
Bis-heterocycles
Syed Shafi,a,b S. Singh, S. Haider, D. Mahendhar Reddy, M. S. Alam, G. Narayana Swamy, and H. M. S. Kumar
b
a
b
a
c
d
*
aDepartment of Chemistry, Faculty of Science, Jamia Hamdard, New Delhi 110062, India
bSynthetic and Biological Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, India
cDepartment of Chemistry, Sri Krishnadevaraya University, Anantpur, India
dIndian Institute of Chemical Technology-Hyderabad, India
*
E-mail: shafirrl@gmail.com
Received April 21, 2011
DOI 10.1002/jhet.1587
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Novel unsymmetrical bis-heterocyclic compounds encompassing triazole and isoxazole moieties
were synthesized by employing 1,3-dipolar cycloaddition/click chemistry approach using 5-butynyl-1,2,3-
triazoles and 5-butynyl isoxazoles.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
bis, tris, or multiple heterocycles to exploit the pharmaco-
logical and altered physical properties of the resulting
multivalent ligands [7].
Organic compounds bearing heteroaromatic moieties
are valuable synthetic templates for the preparation of
new molecules with useful material and pharmacological
properties. The synthesis of such constructs is possible
either through rapid assembly and variation of multiple
pendant substituents on the heteroaromatic core or through
the construction of diverse aromatic heterocycles with
defined substitution patterns. In recent years, attention has
been increasingly paid to the synthesis of aromatic hetero-
cycles and bis-heterocyclic compounds, which exhibit
various biological activities [1] including antibacterial, fun-
gicidal, tuberculostatic, and plant growth regulative proper-
ties. Bis-heterocyclic compounds have found numerous
applications as electrical materials [2], biologically active
molecules [3], chelating agents, and metal ligands [4] owing
to which have attracted great deal of attention in recent years.
Of particular interest would be the bis-heterocycles that
encompass isoxazoles and triazoles as their components,
which gained importance because of their diverse applica-
tions and pharmacological activities. Bis-triazole-based
size-specific mRNA hairpin loop-binding agents have been
developed to target mRNAs coding for proteins [5]. Recent
studies have disclosed a series of 1,2,3-triazole-based
bis-heterocycles as potent HIV-1 protease inhibitors for
the inhibition of viral replication [6]. Efforts are being made
to combine the variety of multiple heterocyclic cores in a sin-
gle molecular framework as symmetrical or unsymmetrical
RESULTS AND DISCUSSION
With the wide range of pharmacological activities and
applications of bis-heterocyclic systems with particular
emphasis on their mRNA hairpin loop-binding potential,
we envisaged the design and synthesis of a focused library
of novel 1,2,3-triazole-isoxazole hybrids. Herein, we report
the synthesis of such novel unsymmetrical bis-heterocyles
encompassing biologically active isoxazole and triazole
moieties separated by two carbon flexible spacers by
employing stepwise approach involving combination of
domino addition and 1,3-dipolar cycloaddition strategy.
One of the most frequently used methods to synthesize
isoxazoles is 1,3-dipolar cycloaddition involving a nitrile
oxide, and the usual dipolarophile for this process is an
alkyne [8]. Further, the bio-orthogonality has allowed the
use of the copper-catalyzed azide–alkyne [3 + 2] cycloaddi-
tions in various biological applications, which has been
termed the “cream of the crop” of click reactions [9] afford-
ing 1,2,3-triazoles with high regiospecificity.
The acetylenic dipolarophiles that are used as precursors of
bis-heterocycles were prepared through the domino addition
of allenylmagnesium bromide to azides/nitrileoxides [10].
Several in situ generated nitrile oxides were reacted with
© 2013 HeteroCorporation

Vol 000
S. Shafi, S. Singh, S. Haider, D. Mahendhar Reddy, M. S. Alam,
G. Narayana Swamy, and H. M. S. Kumar
EXPERIMENTAL
1,5-disubstituted 1,2,3-triazoles at ambient temperature to
afford novel bis-heterocyclic compounds that are sepa-
rated by two carbon spacer (Scheme 1). The reaction was
found to be general with regard to various substituted
nitrile oxides and butynyltriazoles bearing electron-donating
or electron-withdrawing groups on the aromatic ring.
Click chemistry approach was applied for the generation
of sugar triazole as one of the heteromer in bis-heterocyclic
system.
Sugar azides were reacted with 1,5-disubstituted isoxa-
zoles to form the novel bis-heterocyclic compounds
regiospecifically, and two heterocyclic moieties are
separated by two methylene flexible spacers to facilitate
effective target interaction. In the case of sugar-substituted
compounds, deacetylation of the click product affords the
final bis-heterocycle in quantitative yields (Scheme 2).
In conclusion, we present in this communication the
synthesis of novel bis-heterocycles encompassing triazole
and isoxazole moieties designed for effective target
binding, which might find application as pharmacologically
active ligands for future lead discovery.
All chemicals (reagent grade) used were commercially avail-
able. Melting points were measured on a Boetius micro melting
point apparatus.
General procedure for the 1,3-polar cycloaddition between
alkynyl 1,2,3-triazole and nitrile oxides (synthesis of bis-
heterocycles).
5-Butynyl triazole (20 mg, 0.088 mmol) was
added to the in situ generated p-tolylbenzonitrileoxide (using
corresponding chlorooxime and triethylamine) (0.88 mmol) in
THF (10 ml) at 0ꢀC. After stirring at this temperature for 0.5 h,
the reaction mixture was continually stirred for further 22 h at
room temperature. Excess of water (100 mL) was charged, and the
organic compound was extracted with ethyl acetate (2ꢁ 20 mL).
Combined organic layers were dried over anhydrous sodium
sulfate and evaporated under reduced pressure to afford the crude
product, which was subjected to column chromatography (basic
alumina, elution; n-hexane: EtOAc gradient) to afford pure bis-
heterocycle.
1-(4-Methoxy-phenyl)-5-[2-(3-p-tolyl-isoxazol-5-yl)-ethyl]-
1H-[1,2,3]triazole (Table 1, entry 1).
White solid; mp
120–121ꢀC; IR (KBr, cmꢂ1): 3063, 2963, 2920, 2857, 2360,
2119, 1602, 1514, 1438, 1363, 1222, 1105, 1020, 813, 774;
1H-NMR (200 MHz, CDCl3): d 2.38 (s, 3H), 3.08 (s, 4H),
3.85 (s, 3H), 6.21 (s, 1H), 7.01–7.06 (m, 2H), 7.21–7.34
(m, 4H), 7.60–7.74 (m, 3H); 13C-NMR (200 MHz, CDCl3): d
20.43, 21.14, 24.53, 54.49, 98.64, 113.67, 124.56,
125.12, 125.48, 125.58, 127.67, 128.10, 128.46, 130.58,
131.16, 139.07, 155.15, 161.00, 169.50. ESI–MS: 361
(M+ 1)+, 383 (M+ Na)+; Anal. Calcd for C21H20N4O2: C, 69.98;
H, 5.59; N, 15.54. Found: C, 69.91; H, 5.64; N, 15.60.
Scheme 1
N
N
Dry THF
+
N3
Ar
N
Ar
5-(2-(3-(4-Chlorophenyl)isoxazol-5yl)ethyl)-1-(4-nitrophenyl)-
1H-1,2,3-triazole (Table 1, entry 2). Light yellow solid; mp
188–190ꢀC; IR (KBr, cmꢂ1): 2923, 2853, 2361, 2337, 1598, 1402,
MgBr
N
1
3
2
1
1343, 1258, 1021, 858, 800, 672; H-NMR (200 MHz, CDCl3): d
Ar'
N+ O-
4
3.15 (s, 4H), 6.26 (s, 1H), 7.43 (d, 2H, J=8.38Hz), 7.65–7.71
(m, 5H), 8.44 (d, 2H, J= 8.75); 13C-NMR (50 MHz, CDCl3): d
22.50, 26.14, 100.47, 125.65, 126.06, 128.38, 129.70, 133.73,
136.61, 136.4, 136.64, 141.02, 148.67, 161.98, 170.81; ESI–
MS: m/z = 396.5 (M + 1)+; Anal. Calcd for C19H14ClN5O3: C,
Ar'
N
N
THF, 0 0C-RT
N
O
5
Ar
Scheme 2
OAc
OAc
OAc
O N3
OAc
OAc
H3C
OAc
OAc
7
O
O
N
N
N
N
N
O
OAc
H3C
8
CuSO4.5H2O
Sodium ascorbate
Dry MeOH/ NaOMe
OH
6
Water:t' BuOH
N
O
O
OH
N
N
H3C
N
OH
HO
9
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Synthesis of Triazole and Isoxazole Based Novel Unsymmetrical Bis-heterocycles
Table 1
Synthesis of novel bis-heterocycles.
Entry
1
Butynyl triazole
Nitrile oxide
Bis-heterocyclea
Reaction time (h)
22
Yieldsb (%)
92
2
3
4
5
20
28
26
20
94
90
94
94
6
28
96
7
8
22
22
91
91
(Continued)
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S. Shafi, S. Singh, S. Haider, D. Mahendhar Reddy, M. S. Alam,
G. Narayana Swamy, and H. M. S. Kumar
Table I.
(Continued)
Entry
9
Butynyl triazole
Nitrile oxide
Bis-heterocyclea
Reaction time (h)
22
Yieldsb (%)
91
10
22
91
aAll products were characterized by IR, 1H-NMR, 13C-NMR, DEPT, and mass spectroscopy.
bYields obtained after column chromatography.
57.66; H, 3.57; Cl, 8.96; N, 17.69. Found: C, 57.74; H, 3.48;
Cl, 9.06; N, 17.75.
5-(2-(3-(4-Fluorophenyl)isoxazol-5yl)ethyl)-1-(4-nitrophenyl)-
(200 MHz, CDCl3): d 3.17-3.27 (s, 4H), 3.95 (s, 3H), 6.21
(s, 1H), 6.94–7.01 (m, 2H), 7.60–7.75 (m, 5H), 8.41–8.46
(dd, 2H, J = 6.98 and 2.90Hz); 13C-NMR (200MHz, CDCl3): d
22.51, 26.15, 56.69, 100.31, 112.61, 123.58, 126.67, 128.51,
129.01, 138.72, 141.30, 146.34, 148.46, 156.88, 161.64, 170.17;
ESI–MS: m/z = 391 (M+); Anal. Calcd for C20H17N5O4: C, 61.38;
H, 4.38; N, 17.89. Found: C, 61.48; H, 4.31; N, 17.84.
1H-1,2,3-triazole (Table 1, entry 3).
Light yellow solid; mp
173–174ꢀC; IR (KBr, cmꢂ1): 3063, 2963, 2920, 2857, 2360, 1602,
1514, 1438, 1363, 1222, 1105, 1020, 774, 738; 1H-NMR
(200 MHz, CDCl3): d 3.15–3.28 (m, 4H), 6.24 (s, 1H), 7.15 (t, 2H,
J= 8.82 Hz), 7.65–7.76 (m, 5H), 8.42–8.46 (dd, 2H, J =4.89 and
2.01 Hz); 13C-NMR (200 MHz, CDCl3): d 20.47, 24.09, 98.46,
114.44, 114.61, 123.18, 123.62, 124.03, 126.98, 127.05, 131.70,
134.48, 139.23, 146.40, 160.03, 161.27, 163.26, 168.63: ESI–MS:
379(M+); Anal. Calcd for C19H14FN5O3: C, 60.16; H, 3.72; F,
5.01; N, 18.46. Found: C, 60.09; H, 3.77; F, 5.11; N, 18.36.
1-(4-Nitro-phenyl)-5-(2-(3-o-tolylisoxazol-5-yl)-ethyl)-1H-
1,2,3-triazole (Table 1, entry 4). Light brown solid; mp 128–
130ꢀC; IR (KBr, cmꢂ1): 2923, 2853, 2361, 2337, 1598, 1524, 1402,
1344, 1256, 1020, 767, 725; 1H-NMR (200 MHz, CDCl3): d 2.43
(s, 3H), 3.16–3.29 (s, 4H), 6.16 (s, 1H), 7.25–7.43 (m, 4H), 7.67–
7.72 (m, 3H), 8.42–8.47 (dd, 2H, J = 4.99 and 2.03Hz); 13C-
NMR (200 MHz, CDCl3): d 21.30, 22.34, 25.85, 103.00, 125.47,
125.90, 126.27, 128.55, 129.51, 129.87, 131.38, 133.50, 136.44,
137.01, 141.14, 148.31, 163.46, 169.37; ESI–MS: m/z = 375
(M+); Anal. Calcd for C20H17N5O3: C, 63.99; H, 4.56; N, 18.66.
Found: C, 63.91; H, 4.45; N, 18.75.
1-(4-Nitrophenyl)-5-(2-(3-phenylisoxazol-5-yl)ethyl)-1H-1,2,3-
triazole (Table 1, entry 7). Light brown solid; mp 167–168ꢀC;
IR (KBr, cmꢂ1): 2923, 2852, 2360, 2342, 1613, 1597, 1519,
1
1469, 1406, 1342, 1262, 1094, 1020, 856, 771, 669; H-NMR
(200 MHz, CDCl3): d 3.13–3.31 (s, 4H), 6.28 (s, 1H), 7.45
(m, 3H), 7.65–7.75 (m, 5H), 8.44 (d, 2, J = 8.80); 13C-NMR
(200 MHz, CDCl3): d 22.15, 25.78, 100.20, 125.24, 125.67,
126.70, 128.59, 129.01, 130.25, 132.37, 135.13, 138.97,
146.71, 152.83, 161.33, 170.06: ESI–MS: m/z = 361 (M+);
Anal. Calcd for C19H15N5O3: C, 63.15; H, 4.18; N, 19.38.
Found: C, 63.19; H, 4.04; N, 19.47.
4-(5-(2-(3-(4-Fluorophenyl)isoxazol-5-yl)ethyl)-1H-1,2,3-
triazol-1yl)benzenamine (Table 1, entry 8). Light yellow
solid; mp 166–168ꢀC; IR (KBr, cmꢂ1): 3305, 3300, 2923, 2852,
2360, 2342, 1613, 1597, 1519, 1469, 1406, 1342, 1262, 1094,
1
921, 771; H-NMR (200 MHz, CDCl3): d 3.29–3.32 (s, 4H), 6.51
(s, 1H), 6.79–6.83 (m, 2H), 7.12–7.24 (m, 4H), 7.68 (s, 1H), 7.77–
7.84 (m, 2H); 13C-NMR (50 MHz, CDCl3): d 22. 46, 26.33,
100.91, 115.84, 116.93, 117.17, 126.24, 126.71, 127.74, 129.96,
130.08, 133.01, 138.72, 151.57, 163.06, 166.31, 173.52; ESI–MS:
m/z = 372 (M + Na)+; Anal. Calcd for C19H16FN5O: C,
65.32; H, 4.62; F, 5.44; N, 20.05. Found: C, 65.39; H, 4.54;
F, 5.57; N, 19.93.
1-(4-Nitro-phenyl)-5-(2-(3-m-tolyl-isoxazol-5-yl)-ethyl)-1H-
1,2,3-triazole (Table 1, entry 5). Light yellow solid; mp 101–
103ꢀC; IR (KBr, cmꢂ1): 2923, 2853, 2361, 2337, 1598, 1524, 1501,
1456, 1343, 1256, 1020, 856, 767; 1H-NMR (200 MHz, CDCl3) : d
2.43 (s, 3H), 3.16–3.29 (m, 4), 6.16 (s, 1H), 7.25–7.43 (m,
4H), 7.67–7.72 (m, 3H), 8.42–8.47 (m, 2H); 13C-NMR
(50 MHz, CDCl3): d 20.48, 21.16, 24.85, 98.64, 123.26,
124.15, 125.84, 126.05, 127.16, 128.18, 130.13, 130.75,
131.61, 139.40, 155.01, 162.91, 169.67; ESI–MS: m/z = 398
(M + Na)+; Anal. Calcd for C20H17N5O3: C, 63.99; H, 4.56;
N, 18.66. Found: C, 64.06; H, 4.48; N, 18.72.
4-(5-(2-(3-Phenylisoxazol-5-yl)ethyl)-1H-1,2,3-triazol-1yl)
benzenamine (Table 1, entry 9).
Light yellow solid; mp
146–148ꢀC; IR (KBr, cmꢂ1): 3324, 3322, 2923, 2852, 2360,
2342, 1613, 1597, 1519, 1469, 1406, 1342, 1262, 1094, 824,
1
771, 669; H-NMR (200 MHz, CDCl3): d 3.13–3.31 (m, 4H),
5-(2-(3-(4-Methoxyphenyl)isoxazol-5yl)ethyl)-1-(4-nitrophenyl)
-1H-1,2,3-triazole (Table 1, entry 6). Light brown solid; mp
182–184ꢀC; IR (KBr, cmꢂ1): 2924, 2853, 2338, 1651, 1611,
1524, 1456, 1402, 1344, 1255, 1021, 856, 668; 1H-NMR
6.28 (s, 1H), 7.45 (m, 3H), 7.65–7.75 (m, 5H), 8.44
(d, J = 8.80, 2H); 13C-NMR (50 MHz, CDCl3): d 22.11,
25.73, 100.26, 125.24, 125.63, 126.78, 128.55, 129.01,
130.22, 132.33, 135.09, 138.89, 146.72, 152.86, 161.43,
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170.10; ESI–MS: m/z =354 (M+Na)+; Anal. Calcd for C19H17N5O:
C, 68.87; H, 5.17; N, 21.13. Found: C, 68.79; H, 5.24; N, 21.18.
5-(2-(3-(4-Fluorophenyl)isoxazol-5yl)ethyl)-1-p-tolyl-1H-
1,2,3-triazole (Table 1, entry 10). Light brown solid; mp
88–90ꢀC; IR (KBr, cmꢂ1): 3074, 2954, 2925, 2855, 1715, 1611,
1519, 1434, 1388, 1230, 1158, 1015, 950, 843,821, 757; 1H-
NMR (200 MHz, CDCl3): d 2.45 (s, 3H), 3.11 (s, 4H), 6.20
(s, 1H), 7.09–7.17 (m, 2H), 7.27–7.33 (m, 4H), 7.64–7.76
(m, 3H); 13C-NMR (200 MHz, CDCl3): d 21.04, 21.84, 24.66,
100.86, 113.68, 124.85, 125.62, 126.13, 126.46, 128.76, 132.81,
133.24, 144.02, 154.35, 161.64, 163.89; ESI–MS: 372 (M+ Na)+;
Anal. Calcd for C20H18FN4O: C, 68.75; H, 5.19; F, 5.44; N,
16.04. Found: C, 68.79; H, 5.14; F, 5.40; N, 11.06.
Typical procedure for the synthesis of compound 9
(Scheme 2). In a typical procedure, 0.020-g butynylisoxazole 6
(0.095mmol) was dissolved in 5 mL of tertiary butanol and water
(1:1 mixture). Copper sulfate (0.114 mmol) followed by sodium
ascorbate (0.475 mmol) were charged into the reaction mixture.
After 15min, glucose azide 7 (0.0353g, 0.095 mmol) was added
to the aforementioned mixture, and the reaction mixture was
stirred for 8 h. The mixture was diluted with water and added with
ethyl acetate. Organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (2 ꢁ 20mL). The combined
organic layers were dried over anhydrous sodium sulfate and
evaporated under reduced pressure to afford the crude product,
which, on re-crystallization with ethyl acetate/hexane, affords pure
compound 8 as light yellow solid. Further, it was deprotected
with sodium methoxide in dry methanol to afford the titled bis-
heterocycle 9 as a light yellow solid.
(M+ Na)+; Anal. Calcd for C20H24N4O6: C, 57.69; H, 5.81; N,
13.45. Found: C, 57.72; H, 5.77; N, 13.51.
Acknowledgments. Syed Shafi thanks the Hamdard National
Foundation (HNF) for the award of fellowship. S. S. thanks the
honorable Vice Chancellor, Jamia Hamdard, for providing the
facilities.
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2-Hydroxymethyl-6-{4-[2-(3-p-tolyl-isoxazol-5-yl)-ethyl]-
[1,2,3]triazol-1yl-}-tetrahydro-pyran-3,4,5-triol (compound 9,
28
Scheme 2). ½aꢃD ꢂ 2.0 (c 0.0025, MeOH): mp 202–204ꢀC; IR
(KBr, cmꢂ1): 3384, 3063, 2920, 2846, 2399, 1603, 1508, 1444,
1384, 1363, 1238, 1223, 1143, 951, 914, 818, 775; 1H-NMR
(200MHz, CD3OD): d 2.40 (s, 3H), 3.22 (s, 4H), 3.52–3.67
(m, 3H), 3.85–3.91 (t, 3H, J = 3.91 Hz), 5.58 (d, 1H, J = 9.15Hz),
6.59 (s, 1H), 7.30 (d, 2H, J = 7.88), 7.70 (d, 2H, J = 8.07 Hz), 8.03
(s, 1H); 13C-NMR (50 MHz, DMSO-d6): d 19.7, 21.41, 26.26,
55.35, 61.20, 70.07, 72.59, 77.43, 79.11, 87.88, 99.98, 121.89,
126.89, 130.09, 140.01, 142.89, 159.03, 173.34; ESI–MS: 439
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DOI 10.1002/jhet