Synthesis and characterization of 2-Alkyl -5-{4-[(3-nitrophenyl- 5isoxazolyl)methoxy]phenyl}-2H-tetrazoles

Article abstract of DOI:10.1007/BF03246058

Heteroaryl substituted analogs of antirhnoviral (A), was prepared by a convergent approach. 3-Nitrophenyl-5bromooromethylisoxazoles 5a-b were synthesized by [3+2] cycloaddition of 3-(benzoyloxy)-propyne 2 to in situ generated arylnitrile oxides followed by deprotection of cycloadducts 3a-b and bromination of the resulting alcohols 4a-b. Coupling of 3nitrophenyl-5- bromooromethylisoxazoles (5a-b) with 4-[5-(2-alkyl-2H-tetrazolyl)]phenols (6a-d) in N-methylpyrrolidinone under mild conditions afforded a new series of 2-alkyl-5-{4-[1-(3-nitrophenyl-5-isoxazolyl)methyloxy]phenyl}-2H-tetrazoles (7a-h) in high yields. The structures of the synthesized compounds were confirmed by their ¹H NMR, Mass spectral, and Elemental Analysis data.

Full text of DOI:10.1007/BF03246058

J. Iran. Chem. Soc., Vol. 7, No. 3, September 2010, pp. 685-694.
JOUIRrNaAnLiaOnF THE
Chemical Society
Synthesis and Characterization of 2-Alkyl -5-{4-[(3-nitrophenyl-5-
isoxazolyl)methoxy]phenyl}-2H-tetrazoles
Y.R. Mirzaeia,* and L. Edjlalib
aDepartment of Chemistry, University of Wisconsin-Eau Claire,Eau Claire, WI 54702, USA
bDepartment of Applied Chemistry, Faculty of Science, Islamic Azad University-Tabriz Branch, P. O. Box 1655
Tabriz, Iran
(Received 24 April 2009, Accepted 29 October 2009)
Dedicated to Prof. Dr. J. M. Shreeve for her great contribution to chemistry
Heteroaryl substituted analogs of antirhnoviral (A), was prepared by a convergent approach. 3-Nitrophenyl-5-
bromooromethylisoxazoles 5a-b were synthesized by [3+2] cycloaddition of 3-(benzoyloxy)-propyne 2 to in situ generated
arylnitrile oxides followed by deprotection of cycloadducts 3a-b and bromination of the resulting alcohols 4a-b. Coupling of 3-
nitrophenyl-5-bromooromethylisoxazoles (5a-b) with 4-[5-(2-alkyl-2H-tetrazolyl)]phenols (6a-d) in N-methylpyrrolidinone under
mild conditions afforded a new series of 2-alkyl-5-{4-[1-(3-nitrophenyl-5-isoxazolyl)methyloxy]phenyl}-2H-tetrazoles (7a-h) in
1
high yields. The structures of the synthesized compounds were confirmed by their H NMR, Mass spectral, and Elemental
Analysis data.
Keywords: Isoxazolyl-Tetrazolyl ethers, [3+2] Cycloaddition, Isoxazole, Nitro compounds, Tetrazole
INTRODUCTION
The chemistry of tetrazoles as well as their medicinal
applications have been covered in the literature [8,9].
Tetrazoles have attracted considerable attention in recent years
[8-16]; they have applications in photography and information
recording systems [10], pharmaceutical [11-13] and material
sciences and as ligands in coordination chemistry [14]. The
most direct method to synthesize tetrazoles is via the formal
[3+2] cycloaddition [15] of azides and nitriles [16]. Biological
activity in tetrazoles is due to the special metabolism of the
disubstituted tetrazole system and because tetrazole ring is
isosteric with a carboxylic acid group and of comparable
acidity [8b,17]. Hence, for all biologically active molecules
possessing a carboxylic group (-CO2H), there is a theoretical
nitrogen analogue possessing a tetrazolic group (-CN4H), and
since tetrazole moiety appears to be the metabolically more
In this study we prepared analogs of antirhnoviral (A)
where the oxazoline ring was replaced with 2-alkyltetrazoles,
and alkylisoxazole with nitrophenylisoxazoles. Isoxazoles
functionalized with an additional nitrogen-containing group
have had applications in medicinal chemistry [1-7]. They
possess interesting medicinal or crop protection properties as
well as other industrial utility [1a]. Various pharmacologically
important isoxazoles with antibacterial, antiviral, anti-
inflammatory,
antidiabetic,
antifungal,
antiparkinson,
antihypertensive and antitumor activity have been reported
[1b].
*Corresponding author. E-mail: mirzaeyr@uwec.edu

Mirzaei & Edjlali
stable of the two, an extensive study of these molecules is
ongoing [17].
The antipicornaviral activity of compounds related to
CH3
CH3
O
N
(CH2)7O
compound (A) (Fig. 1) is well-documented [18]. However,
compound (A) and the related compounds suffer from having
a very short half-life, particularly due to the acid liability of
the oxazoline ring. The preparation of several isoxazoles with
potential antipicornavirus activity has also been investigated
[19,20].
O
N
Disoxaril, (A)
CH3CH2CH2
CH3
CH3
N
In view of the chemical instability associated with the
oxazoline ring of the compound (A), we examined the
heterocyclic replacements with groups having comparable or
enhanced antirhnovirus activity and which were considerably
more stable to acid hydrolysis. It was found that one of the
most promising replacements for the oxazoline ring is 2-
methytetrazole [19].
N
N
N
(CH2)3O
O
N
CH3
WIN 61605, (B)
Fig. 1
In pursuit of our continuing interest in isoxazole chemistry
[4-6,27] to improve antirhinovirus activity, and increase the
possibility of the hydrophobic interactions in the binding site,
we prepared a series of analogues of compound (A), where
oxazoline ring was replaced with 2-alkyltetrazole, 3-
spectrophotometer. Mass spectra were taken with a Finnigan-
MAT 8400 at 70 eV. Elemental analyses were performed by
Heareus CHN-O-RAPID analyzer. The solvents DMF,
CH3CN and N-methyl pyrrolidine (NMP) were dried over
molecular sieves.
methylisoxazole
ring
was
replaced
with
3-
nitrophenylisoxazole, and the ether linkage between the
isoxazole and the phenyl ring was modified. We chose 2-
regioisomer of 6 because it was more potent than the
Synthesis of 1-[3-(3-nitrophenyl)isoxazole-5-yl]methyl
benzoate (3a). To a suspension of 3-nitrobenzaldehyde (1.52
g, 10 mmol) in a 1:5 mixture of H2O/EtOH (20 ml) was added
hydroxylamine hydrochloride (1.41 g, 20.04 mmol). To this
solution was added sodium acetate (4.09 g, 30 mmol), and the
mixture was allowed to stir for 1 h at room temperature. The
ethanol was then removed by rotary evaporation, and
methylene chloride and water were added. The layers were
separated, and the aqueous layer was extracted twice more
with methylene chloride. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated in vacuo.
Recrystallization of solid residue from EtOAc and petroleum
ether afforded 3-nitrobenzaldoxime 1a (1.58 g, 95%), m.p.:
122 °C, (116-118 °C [20f], 121-123 °C reported for E-m-
nitrobenzaldoxime [20g]); IR (KBr, cm-1) 3200-3500 (OH
stretch), 1615 (C=C, C=N stretch), 1530 (NO2 stretch), 1520,
1460, 1345 (NO2 stretch), 1300, 1100, 960, 835 (oop bending
stretch), 800, 730, 700; 1H NMR (CDCl3) 1 7.62 (m, 1H), 8.06
(s, 1H), 8.16 (m, 2H), 8.52 (s, 1H), 8.70-9.12 (m, 1H). To a
mixture of 3-butyn-1-ol (1.3 ml, 16.9 mmol), Et3N (3.0 ml,
corresponding 1-regioisomer [19f].
A second approach
modified the electronic and steric environment about the
tetrazole moiety, varying substituents in 2-position of the
heterocycle, incorporating nitrophenyl-isoxazole moiety as
well as decreasing the length of the ether linkage connecting
the two heterocycles of WIN 61605 (B). Herein, we report the
synthesis of tetrazole derivatives 7a-h with possible
antirhinovirus activity.
EXPERIMENTAL
Melting points were determined with an Electrothermal
1
9100 apparatus and are uncorrected. H NMR, and 13C NMR
spectra were acquired on a Bruker AC-80, a General
ElectricQE-300, or a Bruker FTNMR (400 MHz) spectrometer
in CDCl3 or DMSO-d6. Chemical shifts are reported in ppm
values relative to TMS as an internal standard. IR spectra were
run on
a
Shimadzu IR-408 and Mattson FTIR
686

Synthesis and Characterization of Tetrazole Derivatives
21.6 mmol) and benzene (5.0 ml) at 0-5 °C was added
ether. The ethereal extracts were combined and dried over
(Na2SO4), and concentrated to dryness. The crude product was
purified on column chromatography (Silica Gel 100, CH2Cl2-
petroleum ether 2:3, Rf = 0.32) to give 1-[3-(4-nitrophenyl)
isoxazole-5-yl]methyl benzoate 3b as a yellow solid (1.37 g,
70%), m.p.: 136 °C; IR (KBr, cm-1)ꢁmax 3100, 3050, 2950,
2850, 1725 (C=O stretch), 1590 (C=N ring stretch), 1525
(NO2 stretch), 1445, 1425 (N-O stretch), 1340 (NO2 stretch),
1305, 1260 (C-O stretch), 1170, 1100 (C-O stretch), 845, 700;
1H NMR (CDCl3) 1 5.16 (s, 2H), 6.57 (s, 1H, Isox C4-H),
7.35-7.52 (m, 3H); 7.56 (m, 1H, Ar-H), 7.95-8.05 (m, 2H),
8.16 (m, 2H, Ar-H), 8.55 (s, 1H, Ar-H); 13C NMR (CDCl3, 75
MHz) 1 60.7, 102.2, 124.2, 127.05, 127.3, 128.6, 129.7, 129.9,
133.2, 137.3, 147.6, 161.3, 165.5, 171.6; Anal. Calcd. for
(C17H12N2O5): C, 62.96; H, 3.73; N, 8.64. Found: C, 62.94; H,
3.72; N, 8.66.
3-(3-Nitrophenyl)-isoxazol-5-ylmethanol (4a). A mixture
of compound 3a (1.50 g, 4.39 mmol), ammonia (5.0 ml), and
MeOH (15.00 ml) was refluxed for 80 h. The reaction mixture
was concentrated and the residue was partitioned between H2O
and Et2O. The combined ethereal extracts were dried and
concentrated in vacuo, the crude product was purified on
column chromatography (Silica Gel 100, EtOAc-CHCl3; 4:1,
Rf = 0.20) to give 4a as a yellow solid (0.73 g, 75%), m.p.: 118
°C; IR (KBr, cm-1)ꢁmax 3500-3200 (OH stretch), 3150 (ArC-H
stretch), 2954 (CH stretch), 2850 (CH stretch), 1605 (C=N
ring stretch), 1570, 1525 (NO2 stretch), 1495, 1470, 1420 (N-
O stretch), 1340 (NO2 stretch), 1030 (C-O stretch), 895, 760,
690; 1H NMR (CDCl3) 1 2.08 (br, s, 1H), 4.83 (s, 2H), 6.60 (s,
1H, Isox C4-H), 7.58 (m, 1H, Ar-H), 8.18 (m, 2H, Ar-H), 8.58
(s, 1H, Ar-H); 13C NMR (CDCl3, 75 MHz) 1 55.8, 100.1,
124.2, 126.9, 135.2, 148.7, 161.4, 171.7; MS m/z (rel. int.)
220.04 (M+, 100), 202 (8), 177 (26), 191 (56), 174 (42), 123
(44), 78 (14), 93 (8), 77 (81), 69 (12), 68 (14), 67 (27), 65 (7),
59 (65), 43 (64), 41 (23), 26; Anal. Calcd. for (C10H8N2O4): C,
54.55; H, 3.66; N, 12.72. Found: C, 55.44; H, 3.61; N, 12.65.
3-(4-Nitrophenyl)-isoxazol-5-ylmethanol (4b). The same
procedure as described for compound 4a from 3-(4-
nitrophenyl)-5-[5-(phenyl carboxylate)]isoxazole 3b to give
4b after column chromatography (Silica Gel 100, EtOAc-
CHCl3; 4:1, Rf = 0.22) as yellow solid (0.74 g, 68%), m.p.: 120
°C; IR (KBr, cm-1)ꢁmax 3600-3300 (OH stretch), 3100 (ArC-H
stretch), 2950 (CH2 stretch), 2850 (CH2 stretch), 1610 (C=N
PhCOCl (3.0 ml, 18 mmol) dropwise. The mixture stirred at
room temperature for 2 h, filtration and evaporation gave a
residue which was distillated at reduced pressure (12 mmHg,
37 °C) to yield 3-butynyl benzoate 2 as colorless oil (2.42 g,
94%) [20a-d]; IR (neat, cm-1) 3295 (ꢀC-H), 3100, 2950, 2120,
1720 (C=O), 1600, 1450, 1260, 1100. To an ice-cooled
solution of the 3-nitrobenzaldoxime 1a (1.32 g, 8 mmol) and
3-butynyl benzoate 2 (0.74 g, 10 mmol) in CH2Cl2 (12 ml) was
added 10% NaOCl (14.00 ml, 19 mmol) dropwise, and the
solution was stirred at room temperature for 48 h [7,21a-c].
The mixture was poured into water (100 ml) and extracted
with ether. The ethereal extracts were combined and dried
over (Na2SO4), and concentrated to dryness. The crude
product was purified on column chromatography (Silica Gel
100, CH2Cl2-petroleum ether 2:3, Rf = 0.30) to give 1-[3-(3-
nitrophenyl)isoxazole-5-yl]methyl benzoate 3a as a yellow
solid (1.74 g, 67%), m.p.: 71 °C; IR (KBr, cm-1)ꢁmax 3100,
3055, 2950, 2850, 1720 (C=O stretch), 1605 (C=N ring
stretch), 1525 (NO2 stretch), 1445, 1420 (N-O stretch), 1340
(NO2 stretch), 1265 (C-O stretch), 1170, 1100 (C-O stretch),
1
800, 700; H NMR (CDCl3) 1 5.23 (s, 2H), 6.61 (s, 1H, Isox
C4-H), 7.35-7.52 (m, 3H); 7.59 (m, 1H, Ar-H), 7.99-8.02 (m,
2H, Ar-H), 8.18 (m, 2H, Ar-H), 8.57 (s, 1H, Ar-H); 13C NMR
(CDCl3, 75 MHz) 1 61.9, 103.2, 124.2, 126.8, 128.4, 129.7,
129.8, 133.3, 137.1, 148.7, 161.3, 165.6, 171.6; Anal. Calcd.
for (C17H12N2O5): C, 62.96; H, 3.73; N, 8.64. Found: C, 62.92;
H, 3.70; N, 8.61.
1-[3-(4-Nitrophenyl)isoxazole-5-yl]methyl
benzoate
(3b). The same procedure as described for oxime 1a from 4-
nitrobenzaldehyde to give 4-nitrobenzaldoxime 1b as yellow
crystals (1.60, 96%), m.p.: 130 °C, (128.5-129 °C [20e], 129-
130 °C reported for E-p-nitrobenzaldoxime [20g]); IR (neat,
cm-1) 3500-3200 (OH stretch), 1600 (C=C, C=N stretch), 1530
(NO2 stretch), 1345 (NO2 stretch), 1100, 840 (oop bending
1
3
stretch), 745; H NMR (CDCl3) 1 7.74 (s, 1H), 8.02 (d, J =
3
7.99 Hz, 2H, Ar-H), 8.28 (d, J = 7.99 Hz, 2H, Ar-H), 8.54-
8.85 (b, var., 1H). To an ice-cooled solution of the 4-
nitrobenzaldoxime 1b (0.99 g, 6 mmol) and 3-butynyl
benzoate 2 (0.59 g, 7.5 mmol) in CH2Cl2 (10 ml) was added
10% NaOCl (10.0 ml, 14 mmol) dropwise, and the solution
was stirred at room temperature for 48 h [7,21a-c]. The
mixture was poured into water (100 ml) and extracted with
687

Mirzaei & Edjlali
ring stretch), 1510 (NO2 stretch), 1465, 1340 (NO2 stretch),
1107, 830, 758; H NMR (CDCl3) 1 2.30 (bs, 1H), 5.07 (s,
(CDCl3, 75 MHz) 1 19.2, 100.1, 124.2, 131.3, 137.2, 147.7,
161.4, 171.7; MS m/z (rel. int.) 283.98 (M+, 92), 281.92 (98),
253 (12), 237 (15), 204 (100), 203 (10), 202 (34), 159 (30),
123 (44), 94 (8), 93 (9), 77 (78), 69 (9), 65 (12), 43 (12), 41
(9), 28 (9). Anal. Calcd. for (C10H7BrN2O3): C, 42.43; H, 2.49;
N, 9.90. Found: C, 42.34; H, 2.58; N, 9.82.
1
2H), 6.85 (s, 1H, Isox-C4H), 8.18 (d, 3J = 7.99 Hz, 2H, Ar-H),
8.53 (d, 3J = 7.99 Hz, 2H, Ar-H); 13C NMR (CDCl3, 75 MHz)
1 56.7, 101.03, 124.4, 127.07, 135.41, 148.9, 161.35, 171.64;
MS m/z (rel. int.) 220.05 (M+, 100), 202 (27), 191 (44), 190
(8), 177 (38), 174 (33), 123 (42), 96 (23), 93 (10), 78 (12), 77
(75), 69 (18), 68 (16), 67 (37), 65 (4), 59 (55), 43 (74), 41
(22), 26; Anal. Calcd. for (C10H8N2O4): C, 54.55; H, 3.66; N,
12.72. Found: C, 55.64; H, 3.56; N, 12.60.
2-Methyl-5-{4-[(3-(3-nitrophenyl)-5-isoxazolyl)
methoxy]phenyl}-2H-tetrazole (7a). A mixture of 6a (0.20 g,
1.14 mmol) [6,27], milled K2CO3 (0.30 g, 2.17 mmol), KI
(0.10 g, 0.6 mmol), 5a (0.40 g, 1.41 mmol) and N-
methylpyrrolidinone (10.0 ml) was magnetically stirred at 60
°C for 24 h. The cooled mixture was diluted with H2O (20 ml)
and extracted with EtOAc (3 ꢀ 20 ml). The combined EtOAc
extracts were washed with H2O, dried over Na2SO4 and
concentrated in vacuo. The crude product was purified on
column chromatography (Silica Gel 100, CHCl3-petroleum
ether 2:1, Rf = 0.2) to give 7a as a pure solid (0.37 g, 87%),
m.p.: 175 °C; IR (KBr, cm-1)ꢁmax 3110 (ArC-H stretch) , 2950,
1610 (C=N ring stretch), 1580, 1530 (NO2 stretch), 1495,
5-Bromomethyl-3-(3-nitrophenyl)-isoxazole (5a). To a
stirred solution of 4a (1.50 g, 6.8 mmol) in CHCl3 (35.0 ml)
was added dropwise PBr3 (11.0 ml, 11.46 mmol) at -10 °C.
Stirring was continued for 16 h at room temperature. The
reaction mixture was concentrated and partitioned between 5%
NaHCO3 (100 ml) and CH2Cl2 (3 ꢀ 20 ml). The combined
CH2Cl2 extracts were washed with H2O, dried over Na2SO4
and concentrated in vacuo. The crude product was purified on
column chromatography (Silica Gel 100, EtOAc-CHCl3 1:5, Rf
= 0.7) to give 5a as a yellow solid (1.20 g, 80%), m.p.: 88 °C
(83-85 °C [29]); IR (KBr, cm-1)ꢁmax 3150 (ArC-H stretch),
3050 (ArC-H stretch), 2920 (CH2 stretch), 2820 (CH2 stretch),
1605 (C=N ring stretch), 1575, 1530 (NO2 stretch), 1490,
1460 (CH2 bending), 1420 (N-O stretch), 1345 (NO2 stretch),
1270 (CH2Br bending), 1070, 900, 790, 685; 1H NMR
(CDCl3) 1 4.60 (s, 2H, -CH2Br), 6.67 (s, 1H, Isox-C4H), 7.58
1
1455, 1345 (NO2 stretch), 1290, 1230, 1100, 810; H NMR
(CDCl3) 1 4.3 (s, 3H, N-CH3), 5.3 (s, 2H, CH2O), 6.71 (s, 1H,
Isox-H), 7.04 (t, J = 6.70 Hz, 2H, Ar-H), 7.58 (m, 1H, Ar-H),
8.08 (m, 4H, Ar-H), 8.54 (s, 1H, Ar-H); 13C NMR (CDCl3,
100.61 MHz) 1 48.34, 81.38, 101.40, 115.11, 121.67, 121.88,
124.76, 128.55, 130.11, 132.52, 159.12, 160.76, 164.62,
169.24; MS m/z (rel. int.) 378.12 (M+, 88), 351 (16), 350 (M+-
N2, 100), 349 (65), 333 (34), 322 (M+-2N2, 35), 138 (22), 123
(45), 93 (9), 77 (82), 69 (20), 68 (24), 67 (12), 65 (8), 44 (19),
43 (55), 41 (23), 26 (17). Anal. Calcd. for (C18H14N6O4): C,
57.14; H, 3.73; N, 22.21. Found: C, 56.58; H, 3.71; N, 22.13.
2-Ethyl-5-{4-[(3-(3-nitrophenyl)-5-isoxazolyl)methoxy]
phenyl}-2H-tetrazole (7b). The same procedure as described
for compound 7a to give 7b after column chromatography
(Silica Gel 100, CHCl3-petroleum ether 2:1, Rf = 0.19) as pure
yellow solid (0.35 g, 86%), m.p.: 134 °C; IR (KBr, cm-1)ꢁmax
3110 (ArC-H stretch), 2950, 1610 (C=N ring stretch), 1580,
(m, 1H, Ar-H), 8.18 (m, 2H, Ar-H), 8.53 (s, 1H, Ar-H); 13
C
NMR (CDCl3, 75 MHz) 1 19.6, 100.4, 124.2, 130.2, 136.8,
148.7, 161.4, 171.7; MS m/z (rel. int.) 283.88 (M+, 88), 281.92
(96), 253 (18), 237 (33), 204 (100), 203 (14), 202 (31), 159
(34), 123 (42), 94 (16), 93 (12), 77 (80), 69 (8), 68 (12), 67
(10), 65 (8), 43 (8), 41 (14); Anal. Calcd. for (C10H7BrN2O3):
C, 42.43; H, 2.49; N, 9.90. Found: C, 42.36; H, 2.60; N, 9.71.
5-Bromomethyl-3-(4-nitrophenyl)-isoxazole (5b). The
same procedure as described for compound 5a to give 5b after
column chromatography (Silica Gel 100, EtOAc-CHCl3 1:5, Rf
= 0.65) as yellow solid (0.84 g, 54.5%), m.p.: 136 °C; IR
(KBr, cm-1)ꢁmax 3150 (ArC-H stretch), 3050 (ArC-H stretch),
2950 (CH2 stretch), 2850 (CH2 stretch), 1610 (C=N ring
stretch), 1595, 1510 (NO2 stretch), 1450 (CH2 bending), 1421
1
1525 (NO2 stretch), 1495, 1460, 1345 (NO2 stretch), 1240. H
NMR (CDCl3) 1 1.61 (t, J = 7.35 Hz, 3H), 4.63 (q, J = 7.35
Hz, 2H), 5.25 (s, 2H, CH2O), 6.71 (s, 1H, Isox-H), 7.10 (m,
2H, Ar-H), 7.58 (m, 1H, Ar-H), 8.07 (m, 4H, Ar-H), 8.56 (s,
1H, Ar-H); 13C NMR (CDCl3, 100.61 MHz) 1 39.42, 45.71,
61.38, 101.40, 115.14, 121.89, 124.77, 128.55, 130.11,
132.52, 159.12, 160.76, 164.61, 169.24; MS m/z (rel. int.)
1
(N-O stretch), 1340 (NO2 stretch), 1230, 1100, 850; H NMR
(CDCl3) 1 4.47 (s, 2H, -CH2Br), 6.62 (s, 1H, Isox-C4H), 7.93
(d, J = 6.91 Hz, 2H), 8.40 (d, J = 6.90 Hz, 2H); 13C NMR
688

Synthesis and Characterization of Tetrazole Derivatives
392.12 (M+, 89), 364 (M+-N2, 100), 363 (55), 346 (8), 336
2-Methyl-5-{4-[(3-(4-nitrophenyl)-5-isoxazolyl)
(M+-2N2, 40), 335 (18), 138 (12), 123 (39), 93 (14), 77 (68),
69 (6), 68 (11), 67 (10), 57 (44), 44 (17), 43 (60), 41 (25), 26
(20). Anal. Calcd. for (C19H16N6O4) C, 58.16; H, 4.11; N,
21.42. Found: C, 58.01; H, 4.14; N, 21.33.
methoxy]phenyl}-2H-tetrazole (7e). The same procedure as
described for compound 7a to give 7e after column
chromatography (Silica Gel 100, CHCl3-petroleum ether 2:1,
Rf = 0.21) as pure pale yellow solid (0.35 g, 82%), m.p.: 192
°C; IR (KBr, cm-1); IR (KBr, cm-1)ꢁmax 3089 (ArC-H stretch),
3047 (ArC-H stretch), 2998, 2919, 1613 (C=N ring stretch),
1517 (NO2 stretch), 1468, 1419 (N-O stretch), 1339 (NO2
stretch), 1307, 1248, 1044, 837; 1H NMR (CDCl3, 300 MHz) 1
4.38 (s, 3H, N-CH3), 5.31(s, 2H, CH2O), 6.76 (s, 1H, Isox C4-
H), 7.09 (d, J = 8.61 Hz, 2H, Ar-H), 7.99 (d, J = 8.48 Hz, 2H,
Ar-H), 8.10 (d, J = 8.62 Hz, 2H, Ar-H), 8.31 (d, J = 8.42 Hz,
2H, Ar-H); 13C NMR (CDCl3, 75 MHz) 1 40.32, 61.36,
101.59, 115.09, 121.75, 124.25, 127.75, 128.36, 132.40,
134.76, 148.84, 159.08, 160.80, 164.53, 169.28; MS (EI, 70
ev) m/z (rel. int.) 378.11 (M+, 92), 350 (M+-N2, 100), 349
(66), 335 (23), 334 (20), 322 (M+-2N2, 22), 138, 123 (44), 93
(12), 77 (79), 69, 68, 67 (12), 65 (10), 43 (66), 41 (7), 26 (12).
Anal. Calcd. for (C18H14N6O4): C, 57.14; H, 3.73; N, 22.21.
Found: C, 57.40; H, 3.66; N, 21.67.
2-Ethyl-5-{4-[(3-(4-nitrophenyl)-5-isoxazolyl)methoxy]
phenyl}-2H-tetrazole (7f). The same procedure as described
for compound 7a to give 7f after column chromatography
(Silica Gel 100, CHCl3-petroleum ether 2:1, Rf = 0.19) as pure
yellow solid (0.34 g, 83%), m.p.: 169 °C; IR (KBr, cm-1)ꢁmax
3107 (ArC-H stretch), 2997 (C-H stretch), 1616 (C=N ring
stretch), 1583, 1532 (NO2 stretch), 1465, 1421 (N-O stretch),
1338 (NO2 stretch), 1042, 836; 1H NMR (CDCl3, 300 MHz) 1
1.80 (t, J = 6.93 Hz, 3H, N-CH2CH3), 4.76 (q, J = 7.02 Hz,
2H, N-CH2CH3), 5.30 (s, 2H, CH2O), 6.75 (s, 1H, Isox-H),
7.08 (d, J = 8.50 Hz, 2H, Ar-H), 8.03 (d, J = 8.51 Hz, 2H, Ar-
H) 8.14 (d, J = 8.50 Hz, 2H, Ar-H), 8.25 (d, J = 8.52 Hz, 2H,
Ar-H); 13C NMR (CDCl3, 75 MHz) 1 14.58, 48.34, 61.33,
101.50, 101.56, 115.06, 121.66, 124.22, 127.72, 128.52,
132.49, 134.72, 148.8, 159.1, 160.76, 164.57, 169.24; MS (EI,
70 ev) m/z (rel. int.) 392.13 (M+, 93), 364 (M+-N2, 100), 363
(67), 336 (M+-2N2, 21), 335 (43), 138 (11), 123 (46), 93 (12),
77 (80), 69 (11), 68 (8), 67 (10), 57 (60), 56 (34), 43 (67), 41
(12), 26 (10). Anal. Calcd. for (C19H16N6O4) C, 58.16; H, 4.11;
N, 21.42; Found: C, 57.79; H, 4.12; N, 21.30.
2-Propyl-5-{4-[(3-(3-nitrophenyl)-5-isoxazolyl)methoxy]
phenyl}-2H-tetrazole (7c). The same procedure as described
for compound 7a to give 7c after column chromatography
(Silica Gel 100, CHCl3-petroleum ether 2:1, Rf = 0.19) as pure
yellow solid (0.35 g, 87%), m.p.: 120 °C; IR (KBr, cm-1)ꢁmax
3110 (ArC-H stretch), 2950, 1610 (C=N ring stretch), 1575,
1525 (NO2 stretch), 1495, 1450, 1421 (N-O stretch), 1340
(NO2 stretch), 1240, 800. 1H NMR (CDCl3) 1 0.98 (t, J = 7.20
Hz, 3H), 2.03 (sext, 2H), 4.49 (t, J = 7.0 Hz, 2H), 6.71 (s, 1H,
Isox-H), 7.04 (m, 2H, Ar-H), 7.58 (t, 1H, Ar-H), 8.23 (m, 4H,
Ar-H), 8.65 (s, 1H, Ar-H); 13C NMR (CDCl3, 100.61 MHz) 1
10.98, 22.88, 55.71, 61.48, 101.39, 115.11, 121.88, 124.71,
128.56, 130.11, 132.52, 159.11, 160.72, 164.58, 169.64; MS
m/z (rel. int.) 406.14 (M+, 94), 378 (M+-N2, 100), 377 (68),
360 (15), 350 (M+-2N2, 27), 338 (19), 337 (39), 138 (15) , 123
(45), 93 (17), 77 (76), 69 (12), 68 (14), 67 (27), 65 (4), 43
(74), 41 (12), 26 (12). Anal. Calcd. for (C20H18N6O4): C,
59.11; H, 4.46; N, 20.68. Found: C, 58.51; H, 4.42; N, 20.15.
2-n-Butyl-5-{4-[(3-(3-nitrophenyl)-5-isoxazolyl)
methoxy]phenyl}-2H-tetrazole (7d).
The
same
procedure as described for compound 7a to give 7d after
column chromatography (Silica Gel 100, CHCl3-petroleum
ether 2:1, Rf = 0.25) as pure yellow solid (0.30 g, 80%), m.p.:
128 °C; IR (KBr, cm-1); IR (KBr, cm-1)ꢁmax 3080 (ArC-H
stretch), 2950, 1610 (C=N ring stretch), 1575, 1530 (NO2
stretch), 1495, 1450, 1420 (N-O stretch), 1345 (NO2 stretch),
1
1240; H NMR (CDCl3) 1 0.95 (t, J = 6.39 Hz, 3H), 1.27 (m,
2H), 1.94 (m, 2H), 4.57 (t, J = 7.05 Hz, 2H), 5.3 (s, 2H), 6.71
(s, 1H, Isox-H), 7.08 (m, 2H, Ar-H), 7.57 (m, 1H, Ar-H), 8.23
(m, J = 9.05 Hz, 4H, Ar-H), 8.60 (s, 1H, Ar-H); 13C NMR
(CDCl3, 100.61 MHz) 1 10.97, 22.88, 37.00, 54.71, 61.38,
101.49, 115.11, 121.88, 124.76, 128.56, 130.53, 132.52,
159.11, 160.76, 164.58, 169.23; MS (EI, 70 ev) m/z (rel. int.)
420.15 (M+, 92), 392 (M+-N2, 100), 391 (59), 364 (M+-2N2,
22), 337 (43), 138 (12), 123 (34), 93 (12), 83 (55), 77 (69), 69
(12), 68 (8), 67 (11), 43 (71), 26 (18). Anal. Calcd. for
(C21H20N6O4): C, 59.99; H, 4.79; N, 19.99. Found: C, 59.50;
H, 4.55; N, 20.10.
2-Propyl-5-{4-[(3-(4-nitrophenyl)-5-isoxazolyl)methoxy]
phenyl}-2H-tetrazole (7g). The same procedure as described
for compound 7a to give 7g after column chromatography
689

Mirzaei & Edjlali
(Silica Gel 100, CHCl3-petroleum ether 2:1, Rf = 0.23) as
synthesized with the intention of discovering analogues more
stable towards hydrolysis but with comparable activity.
Modifications on the isoxazole ring were made using the
procedures outlined in Scheme 1. The heteroarylethers 7a-h,
with the homologation of the alkyl group on the tetrazole ring,
and the modification of isoxazole moiety were carried out as
outlined in Scheme 2.
Isoxazoles 5a-b were synthesized under mild conditions in
a short reaction time with good overall yield as outlined in
Scheme 1. Cycloaddition of 3-(benzoyloxy)-propyne 2 [20a-d]
with in situ generated arylnitrile oxide [7,21] produced
isoxazole 5 in good yield [22-24]. Removal of the protecting
group [25] led to the primary alcohol 4. The
pure yellow solid (0.33 g, 84%), m.p.: 150 °C; IR (KBr, cm-1);
IR (KBr, cm-1)ꢁmax 3119, 2939, 1614 (C=N ring stretch), 1519
(NO2 stretch), 1422 (N-O stretch), 1339 (NO2 stretch), 1054,
1
835; H NMR (CDCl3, 300 MHz) 1 0.96 (t, J = 7.01 Hz, 3H,
N-CH2CH2CH3), 2.09 (m, 2H, N-CH2CH2CH3)), 4.54 (t, J =
6.90 Hz, 2H, N-CH2CH2CH3), 5.30 (s, 2H, CH2O), 6.75 (s,
1H, Isox-H), 7.1 (d, J = 8.50 Hz, 2H, Ar-H), 7.95 (d, J = 8.5
Hz, 2H, Ar-H), 8.14 (d, J = 8.49 Hz, 2H, Ar-H), 8.31 (d, J =
8.51 Hz, 2H, Ar-H); 13C NMR (CDCl3, 75 MHz) 1 10.9, 22.8,
54.7, 61.3, 101.5, 115.1, 121.6, 124.2, 127.7, 128.5, 134.7,
148.8, 159.0, 160.7, 164.5, 169.2; MS (EI, 70 ev) m/z (rel. int.)
406.12 (M+, 96), 378 (M+-N2, 100), 377 (59), 350 (M+-2N2,
22), 138 (24), 123 (43), 93 (12), 77 (74), 69 (12), 68 (22), 67
(8), 57 (11), 43 (75), 26 (32). Anal. Calcd. for (C20H18N6O4):
C, 59.11; H, 4.46; N, 20.68. Found: C, 58.87; H, 4.42; N,
20.38.
hydroxymethylisoxazole
4
was converted into the
bromomethylisoxazole 5 by the reaction with phosphorous
tribromide [26c] (Scheme 1). Coupling of the
bromomethylisoxazoles 5a,b with the 4-(2-alkyl-2H-tetrazol-
5-yl)phenols 6a-d provided the desired compounds 7a-h in
2-n-Butyl-5-{4-[(3-(4-nitrophenyl)-5-isoxazolyl)
1
methoxy]phenyl}-2H-tetrazole (7h). The same procedure as
described for compound 7a to give 7h after column
chromatography (Silica Gel 100, CHCl3-petroleum ether 2:1,
Rf = 0.25) as pure yellow solid (0.32 g, 82%), m.p.: 134 °C;
IR (KBr, cm-1) (KBr, cm-1)ꢁmax 3115 (ArC-H stretch), 2932
(C-H stretch), 1616 (C=N ring stretch), 1518 (NO2 stretch),
high yields (Scheme 2). A comparison of H NMR spectra
revealed that the introduction of nitro phenyl group on the
isoxazole ring had a pronounced deshielding effect and shifted
the isox-H signal of 7a-h further downfield (e.g., 6.75 ppm for
3-nitrophenylisoxazole; 6.00 ppm 3-alkylisoxazole). It is
interesting to mention that, with the same alkyl group on the
tetrazole ring of 7a-h, meta-nitro group had more deshielding
effect than did para-nitro group on aromatic protons and
shifted them further downfield (-M effect, larger shifts).
Biological and structural activity relationship (SAR) of the
prepared compounds will be determined and reported upon
completion.
1
1422 (N-O stretch), 1339 (NO2 stretch), 1040, 832; H NMR
(CDCl3, 300 MHz) 1 0.98 (t, J = 6.90 Hz, 3H), 1.40 (m, 2H),
2.04 (m, 2H), 4.14 (t, J = 7.02 Hz, 2H), 5.29 (s, 2H, CH2O),
6.77 (s, 1H, Isox C4-H), 7.08 (d, J = 8.65 Hz, 2H, Ar-H), 8.01
(d, J = 8.55 Hz, 2H, Ar-H), 8.13 (d, J = 8.52 Hz, 2H, Ar-H),
8.30 (d, J = 8.54 Hz, 2H, Ar-H); 13C NMR (CDCl3, 75 MHz) 1
13.37, 19.64, 31.33, 52.89, 61.30, 101.59, 115.09, 124.25,
127.76, 128.56, 134.76, 148.84, 159.08, 160.80, 164.53,
169.28; MS m/z (rel. int.) 420.14 (M+, 90), 392 (100, M+-N2),
391 (45), 374 (20), 364 (M+-2N2, 17), 158 (25), 144 (12), 138
(8), 123 (37), 93 (12), 91 (14), 83 (56), 82 (30), 77 (81), 69
(12), 68 (8), 67 (7), 43 (66), 41 (8), 26 (9). Anal. Calcd. for
(C21H20N6O4): C, 59.99; H, 4.79; N, 19.99. Found: C, 59.23;
H, 4.68; N, 19.67.
CONCLUSIONS
In conclusion, we have presented a facile and an efficient
route to nitrophenyl(isoxazolylmethoxyphenyl)alkyltetrazoles
7a-h which were synthesized from 4-[5(2-alkyl-2H-
tetrazolyl)]phenols
6
and 3-nitrophenyl-5-bromomethyl-
isoxazoles 5a-b in high yields. Isoxazoles 5a-b were
synthesized under mild conditions in a short reaction time with
good overall yield. Cycloaddition of 3-(benzoyloxy)-propyne
2 with in situ generated arylnitrile oxide produced isoxazole 5
in good yield. Removal of the protecting group led to the
primary alcohol 4a-b. The hydroxymethylisoxazole 4 was
RESULTS AND DISCUSSION
A convergent method was used to synthesize the
compounds described above. The isoxazole ring was
690

Synthesis and Characterization of Tetrazole Derivatives
BzO
OCOPh
HC
2
CH=NOH
O
NaOCl,
N
R
R
CH2Cl2, r.t.
1a, R = 3-NO2
1b, R = 4-NO2
3a, R = 3-NO2
3b, R = 4-NO2
Br
HO
PBr3
CHCl3
Ammonia,
MeOH
O
O
N
N
R
Reflux
R
4a, R = 3-NO2
4b, R = 4-NO2
5a, R = 3-NO2
5b, R = 4-NO2
Scheme 1
Br
R
N
N
K2CO3, KI
NMP
HO
+
N
Ar
N
O
N
6a: R = 2-methyltetrazole
6b: R = 2-ethytetrazole
6c: R = 2-propyltetrazol
6d: R = 2-butyltetrazole
5a, Ar = 3-nitrophenyl
5b, Ar = 4-nitrophenyl
R
N
N
O
N
N
O2N
O
N
7a: Ar = 3-nitrophenyl, R = CH3
7b: Ar = 3-nitrophenyl, R = C2H5
7c: Ar = 3-nitrophenyl, R = n-C3H7
7d: Ar = 3-nitrophenyl, R = n-C4H9
7e: Ar = 4-nitrophenyl, R = CH3
7f: Ar = 4-nitrophenyl, R = C2H5
7g: Ar = 4-nitrophenyl, R = n-C3H7
7h: Ar = 4-nitrophenyl, R = n-C4H9
Scheme 2
converted into the bromomethylisoxazole 5a-b by the reaction
Research Office of Tabriz University for financial support of
this project.
with phosphorous tribromide. The structures of the
1
synthesized compounds were confirmed by H NMR, Mass
spectral, and Elemental Analysis data.
REFERENCES AND NOTES
ACKNOWLEGEMENTS
aOn leave from Organic Synthesis Laboratory, Faculty of
Chemistry, University of Tabriz, Tabriz 51664, Iran.
The authors are grateful to the Research Counsel and
691

Mirzaei & Edjlali
[1]
a) S.A. Lang, Y.-I. Lin, in: K.T. Potts (Ed.),
(2003) 453; c) R.N. Butler, in: K.T. Potts (Ed.),
Comprehensive Heterocyclic Chemistry, Pergamon
Press, Oxford, 1984.
Comprehensive Heterocyclic Chemistry, Pergamon
Press, New York, 1984; b) N.K. Kochetkov, S.D.
Sokolov, in: A.R. Katritzky (Ed.), Advances in
Heterocyclic Chemistry, Academic Press, New York,
1963.
a) B.J. Wakefield, D.J. Wright, Adv. Heterocycl. Chem.
25 (1979) 147; b) P. Krogsgaard-Larsen, G.A.R.
Johnston, D.R. Curtis, C.J.S. Game, R.M. McGulloch,
J. Neurochem. 25 (1975) 803; c) S.R. Naik, A. Guidotti,
E. Costa, Neuropharmacol. 15 (1976) 479.
a) P. Grünanger, P. Vita-Finzi, in: E.C. Taylor (Ed.),
The Chemistry of the Heterocyclic Compounds, John
Wiley & Sons, New York, 1991; b) R.E. Sammelson,
R.B. Miller, M.J. Kurth, J. Org. Chem. 65 (2000) 2225
and references cited therein.
a) Y.R. Mirzaei, B.M. Simpson, D.J. Triggle, N.R.
Natale, J. Org. Chem. 57 (1992) 6271; b) Y.R. Mirzaei,
T.N. Balasubramaniam, B.J. Lefler, N.R. Natale, J.
Heterocycl. Chem. 27 (1990) 2001; c) T.N.
Balasubramaniam, Y.R. Mirzaei, N.R. Natale,
Synthesis 11 (1990) 1076; d) Y.R. Mirzaei, Diss. Abstr.
Int. B 51 (1991) 4848. Chem. Abstr. 115 (1991) 29180;
e) Y.R. Mirzaei, N.R. Natale, Org. Prep. Proced. Int. 25
(1993) 515.
Y.R. Mirzaei, S.B. Tabrizi, M.H. Gohareh, H.Z. Neirizi,
L. Edjlali, Org. Prep. Proced. Int. 35 (2003) 207.
L. Edjlali, S.M. Golabi, Y.R. Mirzaei, Bull.
Electrochem. 16 (2000) 354.
H. Theobald, Ger. Offen: 2754832 (C1. C07C135100),
1979; Chem. Abstr. 91 (1979) P 140372b.
a) J.A. Bladin, Ber. 18 (1885) 1544; b) F.R. Benson,
Chem. Rev. 41 (1947) 1; c) R.N. Butler, in: A.R.
Katritzky, A.J. Boulton (Eds.), Adv. Heterocyclic
Chemistry, Academic Press, New York, 1977; d) R.N.
Butler, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven
(Eds.), Comprehensive Heterocyclic Chemistry II,
Pergamon Press, New York, 1996; e) F.R. Benson, in:
R.C. Elderfield (Ed.), Heterocyclic Compounds, Wiley,
New York, 1967.
[10] a) G.I. Koldobskii, V.A. Ostrovskii, V.A. Usp. Khim.
63 (1994) 847; b) V.A. Ostrovskii, M.S. Pevzner, T.P.
Kofmna, M.B. Sheherbinin, I.V. Tselinskii, Targets
Heterocycl. Syst. 3 (1999) 467.
[11] a) H. Singh. A.S. Chawla, V.K. Kapoor, D. Paul, R.K.
Malhotra, in: G.P. Ellis, G.B. West (Eds.), Progress in
[2]
[3]
[4]
Medicinal
Chemistry,
Elsevier/North
Holland.
Biomedical Press, 1980; b) R.H. Bradbury, C.P. Allott,
M. Dennis, J.A. Girwood, P.W. Kenny, J.S. Major,
A.A. Oldham, A.H. Ratcliffe, J.E. Rivett, D.A. Roberts,
P.J. Robins, J. Med. Chem. 36 (1993) 1245; c) D.J.
Carini, J.V. Duncia, P.E. Aldrich, A.T. Chiu, A.L.
Johnson, M.E. Pierce, W.A. Price, J.B. Santella III, G.J.
Wells, R.R. Wexler, P.C. Wong, S.-E. Yoo,
P.B.M.W.M. Timmermans, J. Med. Chem. 34 (1991)
2525; d) K. Raman, S.S. Parmar, S.P. Singh, J.
Heterocycl. Chem. 17 (1980) 1137.
[12] a) R.S. Upadhayaya, S. Jain, N. Sinha, N. Kishore, R.
Chandra, S.K. Arora, Eur. J. Med. Chem. 39 (2004)
579; b) D. Moderhack, J. Prakt. Chem. 340 (1998) 687;
c) J.R. Maxwell, D.A. Wasdahl, A.C. Wolfson, V.I.
Stenberg, J. Med. Chem. 27 (1984), 1565 and reference
17 cited therein; d) R.M. Herbst, K.R. Wilson, J. Org.
Chem. 22 (1957) 1142.
[13] a) The earlier report of the synthesis of 9 using
ammonium azide instead of sodium azide gives lower
yield (43%), W.G. Finnegan, R.A. Henry, R. Lofquist,
J. Am. Chem. Soc. 80 (1958) 3908; b) Synthesis of
compound 9 is reported previously (decomp. 228 °C)
W. Lossen, J. Colman, Ann. 298 (1887) 107.
[14] a) M. Hisky, D.E. Chavez, D.L. Naud, S.F. Son, H.L.
Berghout, C. Bome, Proc. Int. Pyrotech. Semin. 27
(2000) 3; b) R.N. Butler, in: A.R. Katritzky, A.J.
Boulton (Eds.), Adv. Heterocycl. Chem., Academic
Press, New York, 1977; c) C. Matthias-Grunert, P.
Weinberger, J. Schweifer, C. Hamper, A.F. Stassen, K.
Mereiter, W. Linert, J. Molec. Struc. 733 (2005) 41; d)
Y.S. Gyoung, J.-G. Shim, Y. Yamamoto, Tetrahedron
Lett. 41 (2002) 4193; e) A.F. Stassen, E. Dova, J.
Ensling, H. Schenk, P. Gütlich, J.G. Haasnoot, J.
[5]
[6]
[7]
[8]
[9]
a) G.I. Koldobskii, V.A. Ostrovskii, V.S. Popavskii,
Chem. Heterocycl. Comp. 17 (1981) 965; b) G.I.
Koldobskii, R.B. Kharbash, Russ. J. Org. Chem. 39
692

Synthesis and Characterization of Tetrazole Derivatives
Reedijk, Inorg. Chim. Acta 333 (2002) 61.
M.J. Kurth, J. Org. Chem. 62 (1997) 6797; e) A.F.
Hegarty, P.J. Tuohey, J. Chem. Soc. Perkin Trans 2,
1980, 1313 and references cited therein (128.5-129 °C,
130 °C also reported in Beilstein for E-p-
nitrobenzaldoxime); f) M.O. Froster, F.P. Dunn, J.
Chem. Soc. 95 (1909) 425 (also reported in Beilstein for
E-m-nitrobenzaldoxime); g) D.R. Dalton, H.G. Foley, J.
Org. Chem. 24 (1973) 4200.
[15] a) R. Huisgen, J. Org. Chem. 33 (1968) 2291; b) R.
Huisgen, Angew. Chem. Int. Ed. Engl. 2 (1963) 565; c)
R. Huisgen, J. Org. Chem. 41 (1976) 403; d) F. Himo,
Z.P. Demko, L. Noodleman, K.B. Sharpless, J. Am.
Chem. Soc. 124 (2002) 12210 and references cited
therein.
[16] a) R.N. Butler, in: K.T. Potts (Ed.), Comprehensive
Heterocyclic Chemistry, Pergamon Press, Oxford,
1984; b) S.J. Wittenberger, Org. Prep. Proc. Int. 26
(1994) 499.
[21] For conversion of aldoximes to the corresponding
nitrile oxides using sodium hypochlorite see: a) A.L.
Smith, C.-K. Hwang, E. Pitsinos, G.R. Scarlato, K.C.
Nicolaou, J. Am. Chem. Soc. 114 (1992) 3134; b) C.
Grundman, J.M. Dean, J. Org. Chem. 30 (1965) 2809
and references cited therein; c) A. Hassner, K.S.K.
Murty, J. Org. Chem. 54 (1989) 5277.
[22] P.G. Baraldi, A. Barco, S. Benetti, F. Moroder, G.P.
Pollini, D. Simmon, J. Org. Chem. 48 (1983) 1297.
[23] a) The melting point and also the NMR spectra were
consistent with the reported one. T. Isida, T. Akiyama,
K. Nabika, K. Sisido, S. Kozima, Bull. Chem. Soc. Jpn.
46 (1973) 2176 and references cited therein; b) R.N.
Butler, V.C. Garvin, T.M. McEvoy, J. Chem. Soc.
Perkin Trans 2 (1984) 721 and references cited therein;
c) R.N. Butler, V.C. Garvin, T.M. McEvoy, J. Chem.
Soc. (Synop) 6 (1981) 174; d) W. Fuhrer, F.
Ostermayer, M. Zimmermann, Eur. Pat. Appl. EP
39892 (Cl. C07D233/64), 1981; Chem. Abstr. 96
(1981) P 122404n; d) A.V. Moskvin, A.V. Ostrovskii,
I.Y. Shirobokov, G.I. Koldobskii, B.V. Gidaspov, Zh.
Org. Khim. 14 (1978) 2440.
[24] The melting point and also the NMR spectra were
consistent with the reported one.
[25] a) K. Tsuszuki, Y. Nakajima, T. Walanabe, M.
Yanajiya, T. Matsumoto, Tetrahedron Lett. 11 (1978)
989; b) I. Kawasaki, K. Matsuda, T. Kaneko, T. Bull.
Chem. Soc. Jpn. 14 (1971) 1986.
[26] a) J.J. Hansen, P. Krogsgaard-Larsen, J. Chem. Soc.
Perkin Trans. I. (1980) 1826; b) T.N. Johansen, B.
Ebert, H. Braeuner-Osborne, M. Didriksen, I.T.
Christensen, K.K. Søby, U. Madsen, P. Krogsgaard-
Larsen, L. Brehm, J. Med. Chem. 41 (1998) 930; c) Y.
Watanabe, H. Iida, C. Kibayashi, J. Org. Chem. 54
(1989) 4088; d) This compound was prepared earlier, E.
[17] a) R.M. Herbst, Essays in Biochemistry, John Wiley &
Sons, New York, 1956; b) F. Lenda, F. Guenoun, J.
Martinez, F. Lamaty, Tetrahedron Lett. 48 (2007) 805;
c) K.L. Yu, R.L. Johnson, J. Org. Chem. 52 (1987)
2051; d) J. Zabrocki, D. Smith, J.B. Dunbar, H. Iijima,
G.R. Marshal, J. Am. Chem. Soc. 110 (1988) 5875.
[18] a) G.D. Diana, M.A. Mckinlay, C.J. Brisson, E.S.
Zaloy, J.V. Mirallco, U.J. Salvador, J. Med. Chem. 28
(1985) 748; b) G.D. Diana, M.A. Mckinlay, M.J. Otto,
V. Akullian, C. Oglesby, J. Med. Chem. 28 (1985)
1906.
[19] a) G.D. Diana, P. Kowalczyk, A.M. Treasurywala, R.C.
Oglesby, D.C. Pevear, F.J. Dutko, J. Med. Chem. 35
(1992) 1002; b) G.D. Diana, D. Cutcliffe, R.C.
Oglesby, M.J. Otto, J.P. Mallamo, V. Akullian, M.A.
Mckinlay, J. Med. Chem. 32 (1989) 450; c) G.D. Diana,
D. Cutcliffe, D.L. Volkots, J.P. Mallanio, T.R. Bailey,
N. Vescio, R.C. Oglesby, T.J. Nitz, J. Wetzel, V.
Giranda, D.C. Pevear, F.J. Dutko, J. Med. Chem. 36
(1993) 3240; d) G.D. Diana, D.L. Volkots, T.J. Nitz,
T.R. Bailey, M.A. Long, N. Vescio, S. Aldous, D.C.
Pevear, F.J. Dutko, J. Med. Chem. 37 (1994) 2421; e)
E.A. Hallinan, S. Tsymbalov, C.R. Dorn, B.S. Pitzele,
D.W.J. Hansen, J. Med. Chem. 45 (2002) 1686; f) P.M.
O’Brien, D.R. Sliskovic, A. Bernabei, T. Hurley, M.K.
Anderson, R.F. Bousley, B.R. Krause, R.L. Stanfield,
Biorg. Med. Chem. Lett. 5 (1995) 295.
[20] a) Sankyo Co., Ltd. Jpn. (C1. C07D261/12), 1980;
Chem. Abstr. 94 (1981) P 139781q; b) M.J. Kurth,
L.A.A. Randall, K. Takenouchi, J. Org. Chem. 61
(1996) 8755; c) B.A. Lorsbach, R.B. Miller, M.J. Kurth,
J. Org. Chem. 61 (1996) 8716; d) E.J. Kantorowski,
693

Mirzaei & Edjlali
Mugnani, P. Grünanger, Atti Accad. Nazl. Lincei,
Rend, Classe Sci. Fis., Mat. Nat. 14 (1953) 95; Chem.
Abstr. 48 (1954) 2685.
[28] K. Hayakawa, M. Yodo, S. Ohsuki, K. Kanematsu, J.
Am. Chem. Soc. 106 (1984) 6735.
[29] This compound was prepared in a different method
without any characterization: H.G. Sen, D. Seth, D.U.N.
Joshi, P. Rajagopalan, J. Med. Chem. 9 (1966) 431.
[27] Y.R. Mirzaei, S.B. Tabrizi, L. Edjlali, Acta Chim. Slov.
55 (2008) 554.
694