Scientific paper
Synthesis of Novel 2-Alkyl-5-{4-[(3-alkylisoxazol -5-yl)methoxy]phenyl}-2fl^-tetrazoles
Yousef Rastgar Mirzaei,1* Samad Bavili Tabrizi2 and Laden Edjlali2
1 Organic Synthesis Laboratory, Faculty of Chemistry, University of Tabriz, Tabriz 51664, Iran
' Department of Applied Chemistry, Faculty of Science, Islamic Azad University-Tabriz, P. O. Box 1655 Tabriz, Iran
* Corresponding author: E-mail: mirzaeyr@uwec.edu; mirzaeiyousef@yahoo.com
Fax: +(715) 836-4979
Received: 30-03-2008
Dedicated to Prof. Dr. Nicholas R. Natale on the occasion of his 57'h birthday.
Abstract
Several alkyl(isoxazolylmethoxyphenyl)tetrazoles were synthesized and characterized. 3-Alkyl-5-(chloromethyl)isoxa-zoles 9 were prepared by the reaction of corresponding (3-alkylisoxazol-5-yl)methanols with thionyl chloride. 4-(2-AIkyl-2ff-tetrazol-5-yl)phenols 8 were synthesized from the corresponding aldehyde 3 in five steps, which then reacted with 3-alkyl-5-(chloromethyl)isoxazoles 9 to produce the corresponding 2-alkyl-5-{4-[(3-alkylisoxazol-5-yl)met-hoxy]phenyl}-2ff-tetrazoles 10a-h in high yields.
Keywords: Cycloaddition, Isoxazole, Nitro compounds, Tetrazole.
1. Introduction
Tetrazoles are an important functionality1 with wide-ranging applications in photography and information recording systems,2 pharmaceutical3a-f and material sciences and appealing ligands in coordination chemistry.4a-e All aspects of the chemistry of tetrazoles as well as medicinal application of tetrazoles were covered in the literatu-re.1 The most direct method to form tetrazoles is via the formal [3 + 2] cycloaddition5a-d of azides and nitriles.6a-c Biological activity in tetrazoles is encountered due to the special metabolism of the disubstituted tetrazole system and also because in 5-substituted tetrazole compounds the tetrazole ring is isosteric with a carboxylic acid group and of comparable acidity.1b'7 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 stable of the two a considerable exploration of these molecules is ongoing.7
Isoxazoles may show interesting medicinal or crop protection properties or have some other industrial uti-lity.8a Various pharmacologically important isoxazoles with antibacterial, antiviral, anti-inflammatory, antidiabe-
tic, antifungal, antiparkinson, antihypertensive and antitumor activity have already been reported.8b Isoxazoles are unique in their chemical behavior, not only among hete-rocyclic compounds in general, but also among related azoles. Isoxazoles functionalized with an additional nitrogen-containing group have seen application.8,9
The antipicornaviral activity of compounds related to disoxaril (1) (Figure 1) has been well documented.10 However, disoxaril and related compounds suffer from the fact they have a very short half-life, particularly due to the acid lability of the oxazoline ring. The preparation of several isoxazoles with antipicornavirus activity has also been achieved11 and the structure and reactivity of these compounds against human picornavirus have been investigated using various physical and statistical methods.10,11 Recently, extensive studies have been focused on the antiviral activities of these types of compounds, mainly by determination of their minimum inhibitory concentration (MIC).11
Encouraged by the intense recent research activity in the tetrazole field and in pursuit of our continuing interest in isoxazole chemistry9 we envisioned the combination of these attractive functional groups by the synthesis of various 2-alkyl-5-{4-[(3-alkylisoxazol-5-yl)methoxy]
phenyl}-2H-tetrazoles 10. Other variations of the isoxazo-line ring were synthesized with the intent of discovering analogues being more stable towards hydrolysis but with comparable activity. To improve activity and decrease the side effects a series of new tetrazole-containing compounds with various functionality were synthesized via modification on the length of side chains of both hete-rocycles and also by decreasing the length of the ether link connecting the two heterocycles of WIN 61605 (2). The biological properties and structure-activity relationship (SAR) of the prepared compounds will be published upon completion.
dehyde 3 via oxime formation, followed by dehydration with acetic anhydride. Treatment of nitrile 5 with sodium azide3g provided tetrazole 6 in 89% yield.3'-j Alkylation of 6 with alkyl halide and potassium carbonate in acetonitri-le gave a mixture of 1- and 2-substituted tetrazoles 7 in a ratio of approximately 65 : 35 (R = Me), 82 : 18 (R = Et), 87 : 13 (R = n-Pr), 88 : 12 (R = n-Bu), which shows that C-5 aryl substituents tend to favor N(2)-alkylation.15 The position of alkylation was also influenced by the steric requirement of the alkylating agent, as alkyl group gets bulkier, N(2) alkylation increases. When ethyl group is substituted at N(1) position of tetrazole it forces aromatic
2. Results and Discussion
Tetrazoles 8 were synthesized using an efficient process in short reaction time and good yield as outlined in Scheme 1. The requisite nitrile 5 was prepared from al-
protons adjacent to the tetrazole ring to the diamagnetic region of the heterocyclic ring current and hence chemical shift becomes lower, this being a diagnostic criterion for characterization of the two isomers. Furthermore, besides the anisotropy, electron-donating resonance effect of the
Scheme 1. Synthesis of 4-(2-alkyl-2ff-tetrazol-5-yl)phenols 8a-d
tetrazole ring in N(2) alkyl isomer can contribute to the downfield shifts, which are not possible or at least greatly diminished in the N(1) alkyl isomer. The chemical shifts of the N(1) and N(2) isomers become 5 7.58 and 5 7.99 with J = 6.69 Hz and 7.10 Hz, respectively. Tetrazole 8 was prepared16 from 7 by selective deprotection of the methoxy group by HBr-AcOH.17 It must be mentioned that under the deprotection condition N(1) dealkylation also occurred while N(2) alkyl group resisted (Scheme 1).
3-Alkyl-5-(chloromethyl)isoxazoles 9 were prepa-red9f,9h by the reaction of corresponding (3-alkylisoxazol-5-yl)methanols9f'9h12-14 with thionyl chloride.18 Treatment of the 3-alkyl-5-(chloromethyl)isoxazoles 9a,b with the 4-(2-alkyl-2-H-tetrazol-5-yl)phenols 8a-d provided compounds 10a-h, which we previously reported9g their electrochemical behavior in dimethylformamide (Scheme 2).
mol), and pyridine (25 mL, 0.310 mol) was heated to reflux for 2 h, and then concentrated to dryness. The reaction mixture was dissoled in water and the aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4), and concentrated in vacuo. Recrystallization of solid residue from EtOAc and petroleum ether afforded (8.93 g, 80%) oxime 4, mp 60 °C. IR (KBr, cm-1) vmax 3200-3500 (OH), 1610, 1570, 1520, 960; 1H NMR (CDCl3) 53.65 (s, 3H, OCH3), 6.73 (d, 3J = 8.82 Hz, 2H, Ar-H), 7.37 (d, 3J = 8.87 Hz, 2H, Ar-H), 7.97 (s, 1H), 9.0 (s, 1H). A solution of oxime 4 (14.00 g, 0.987 mol) in acetic anhydride (300 mL) was refluxed for 20 h. The solution was concentrated to dryness and the resiue was partitioned between H2O and EtOAc. The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo, leaving a dark solid. Recrystallization from et-


8a,	R = CH3
8b,	R = C2H5
8c,	R = n-CjH7
8d,	R = n-C4H9
OH + CIH^C
K2CO3, Kl, NMP
Scheme 2. Synthesis of 2-alkyl-5-{4-[(3-alkyliso-xazol-5-yl)methoxy]phenyl}-2H-tetrazoles 10
10a,	R	= CH3;	R'	= n-C4H9
10b,	R	^CHj,	R'	= n-C6Hi7
10c,	R		R'	= n-C,4H9
lOd,	R	= C2H5;	R'	= n-CaHiy
10e,	R	^n-CjHy,	R'	= n-C+Hg
lOf,	R	= r\-C3H^	R'	= n-CgH,;
log,	R	= n-C4H9;	R'	= n-C4Hg
lOh	R	= n-C^Hg;	R'	= n-CgHi;
9a, R' = n-C4H9 9b, R' = n-CgH,7
.R'
3. Experimental
Melting points were determined with an Electrothermal 9100 apparatus and are uncorrected. 1H 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-rfg. 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 spectrophotometer. Mass spectra were taken with a Finnigan-MAT 8400 at 70eV. Elemental analyses were performed by Heareus CHN-O-RAPID analyzer. The solvents DMF, CH3CN and ^-methylpyrrolidine (NMP) were dried over molecular sieves.
5-(4-Methoxyphenyl)-2-methyl-2H-tetrazole (7a).15
A solution of 4-methoxybenzaldehyde (9.1 mL, 0.082 mol), hydroxylamine hydrochloride (25.25 g, 0.365
her and petroleum ether afforded nitrile 5 as a white solid (12 g, 86%), mp 59 °C; IR (KBr, cm-1) vmax 3025 (Ar-H), 2955, 2200 (CN), 1600, 1505, 1300, 125^, 1170, 1020, 825; 1H NMR (CDCl3) 54.02 (s, 3H, OCH3), 7.10 (d, 3J = 9.02 Hz, 2H, Ar-H), 7.74 (d, 3J = 8.86 Hz, ^H, Ar-H). To a solution of nitrile 5 (6.00 g, 0.451 mol) in DMF (45 mL) under argon was added NaN3 (3.00 g, 0.0463 mmol) and NH4Cl (0.60 g, 0.113 mol). The mixture was shielded in a fume hood heated to ca. 110 °C for 48 h. The cooled solution was poured into H2O (150 mL) and extracted with CH2Cl2 (2 X 20 mL). The aqueous solution was chilled in ice and acidified carefully dropwise with 6 N HCl. The white solid residue was collected and dried. Recrystalliza-tion from CH3CN afforded 5-(4-methoxyphenyl)tetrazole 6 (7.00 g, 88%), mp 229.7 °C (lit.3d,g mp 227-228 °C) (lit.3h mp 238-239 °C). IR (KBr, cm-1) vmax 3130 (N-H), 2700, 1612 (C=N), 1400, 1050, 750; 1H INMR (DMSO-
d6) S 3.73 (s, 3H, OCH3), 3.90 (s, 1H), 7.02 (d, 3J = 8.93 Hz, 2H, Ar-H), 7.86 (d, 3J = 9.03 Hz, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) S 55.43, 114.82, 116.25, 128.65, 154.58, 161.44. A suspension of tetrazole 6 (1.76 g, 10 mmol), milled K2CO3 (1.58 g, 11.5 mmol), and methyl iodide (0.7 mL, 1.14 mmol) in CH3CN (28 mL) was reflu-xed for 1 h, then stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the resulting yellow oil was subjected to column chromatography (Silica Gel 100, CH2Cl2, R^ = 0.2) to give 7a15 as a pale yellow solid (1.10 g, 58%), mp 86 °C (lit.15a mp 86.5-87.5 °C, lit.15b mp 85-86 °C); IR (KBr, cm-1) vmax 3009, 2950, 1605 (C=N ring stretch), 1580 (C=C), 1540, 1400, 1246, 1170, 1100, 1020, 835, 755, 715; 1H NMR (CDCl3) S 3.77 (s, 3H, OCH3), 4.27 (s, 3H, N-CH3), 6.92 (d, 3J = 8.92 Hz, 2H, meta-H with respect to tetrazole ring), 7.99 (d, 3Jo_m = 8.89 Hz, 2H, ortho-H); 13C NMR (100 MHz, CDC13) S 40.33, 55.43, 114.78, 116.21, 128.64, 155.07, 161.41; MS (EI, 70 eV) m/z (rel. int.) 190.2 (M+), 162 (100, M+ - N2), 161 (45), 152 (65), 147 (10), 139 (21), 134 (67), 43 (3^). Anal. Calcd for C9H10N4O: C, 56.83; H, 5.30; N, 29.46. Found: C, 56.69; H, ^.24; N, 29.38.
2-Ethyl-5-(4-methoxyphenyl)-2H-tetrazole (7b).
The same procedure as described for compound 7a, from tetrazole 6 and ethyl iodide to afford 7b as a pale yellow solid (1.40 g, 68%), mp 63 °C; IR (KBr, cm-1) vmax 3010 (Ar-H), 2955, 1605 (C=N ring stretch), 1540, 134K), 1244, 1100, 1020, 835, 760, 675; 1H NMR (CDCl3) S 1.60 (t, J = 7.31 Hz, 3H, N-CH2CH3), 3.75 (s, 3H, OC//3), 4.55 (q, J = 7.4 Hz, 2H, N-CH2CH3), 6.98 (d, 3J = 8.1 Hz, 2H, Ar-H), 7.99 (d, 3J = 8.1 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) S 14.38, 48.12, 55.48, 114.85, 116.42, 128.68, 154.67, 161.43; MS (EI, 70 eV) m/z (rel. int.) 204.2 (M+), 176 (100, M+ - N2), 152 (15), 148 (55), 139 (25), 57 (40). Anal. Calcd for C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C, 58.67; 1:1, 5.85; N, 27.36.
5-(4-Methoxyphenyl)-2-(«-propyl)-2H-tetrazole (7c).
The same procedure as described for compound 7a, from tetrazole 6 and n-propyl iodide to afford 7c as yellow viscose oil (1.25 g, 58%); IR (neat, cm-1) vmax 3007 (Ar-H), 2950, 2870, 1605 (C=N ring stretch), 1^80 (C=C), 1540, 1450, 1380, 1300, 1245, 1100, 990, 840, 760; 1H NMR (CDCl3) S 0.80 (t, J = 7.13 Hz, 3H), 1.90 (m, 2H, N-CH2CH2CH3), 3.60 (s, 3H, OCH3), 4.40 (t, J = 6.99 Hz, 2H, N-CH2CH2CH3), 6.85 (d, 3J = 6.87 Hz, 2H, Ar-H), 7.95 (d, 3 J = 6.82 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) S 10.98, 22.88, 54.70, 55.49, 114.83, 116.44, 128.66, 154.62, 161.45; MS (EI, 70 eV) m/z (rel. int.) 218.2 (M+), 190 (100, M+ - N2), 162 (55), 152 (30), 69 (22), 43 (18). Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.48; 1:1, 6.44; N, 25.71.
2-(«-Butyl)-5-(4-methoxyphenyl)-2H-tetrazole (7d).
The same procedure as described for compound 7a, from tetrazole 6 and n-butyl iodide to afford 7d as yellow viscose oil (1.23 g, 53%); IR (neat, cm-1) vmax 3008 (Ar-H), 2950, 2870, 1605 (C=N ring stretch), 1^80 (C=C), 1460, 1300, 1250, 1100, 995, 835; 1H NMR (CDCl3) S 0.79 (t, J = 7.2 Hz, 3H), 1.15 (m, 2H), 1.88 (m, 2H), ^.62 (s, 3H, OCH3), 4.45 (t, J = 7.22 Hz, 2H, N-CH2CH2CH2C^3), 6.85 (d, 3J = 7.88 Hz, 2H, Ar-H), 7.95 (d, 3J = 7.95 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) S 12.12, 19.64, 33.34, 52.89, 55.49, 114.85, 116.43, 128.67, 154.65, 161.45; MS (EI, 70 eV) m/z (rel. int.) 232.3 (M+), 204 (100, M+ - N3), 176 (50), 139 (40), 99 (43), 71 (15). Anal. Calcd for C13H1gN4O: C, 62.05; H, 6.94; N, 24.13. Found: C, 62.08; 1:1, 6.98; N, 24.11.
5-(4-Hydroxyphenyl)-2-methyltetrazole (8a).
A solution of 7a, (1.00 g, 0.526 mol), HBr (5 mL), and AcOH (0.5 mL) was refluxed17 for 5 h then the reaction mixture was cautiously poured into ice-water and the resulted white precipitate was collected and recrystallized from EtOH to afford 8a as a white solid (0.85 g, 92%), mp 110 °C; IR (KBr, cm-1) vmax 3140 (OH), 3008 (Ar-H), 2950, 1605 (C=N ring strettali), 1540, 1460, 1370, 1270, 1230, 1165, 1050, 840, 720; 1H NMR (DMSO-dg) S 4.40 (s, 3H, N-CH3), 6.94 (d, 3J = 8.0 Hz, 2H, Ar-H), 7.90 (d, 3J = 8.0 Hz, 2H, Ar-H), 9.97 (s, 1H, Ar-OH); 13C NMR (100 MHz, CDCl3) S 40.35, 114.65, 116.21, 128.84, 154.77, 160.21; MS (EI, 70 eV) m/z (rel. int.) 176.2 (M+), 148 (100, M+ - N3), 147 (43), 138 (25), 119 (75.8), 118 (38). Anal. Calcd for C8H8N4O: C, 54.54; H, 4.58; N, 31.80. Found: C, 54.69; 4.48; N, 31.57.
2-Ethyl-5-(4-hydroxyphenyl)tetrazole (8b).
The same procedure as described for compound 8a, to give 8b as pure white solid (0.79 g, 69%), mp 160 °C; IR (KBr, cm-1) vmax 3145 (OH), 3007 (Ar-H), 2950, 1605 (C=N ring stretch), 1590 (C=C), 1455, 1375, 1270, 1170, 835, 760; 1H NMR (DMSO-dg) S 1.74 (t, J = 7.31 Hz, 3H, N-CH3CH3), 4.88 (q, J = 7.5^ Hz, 2H, N-CH3CH3), 7.05 (d, 3J ^ 6.84 Hz, 2H, Ar-H), 8.03 (d, 3J = 6.76 Hz, 2H, Ar-H), 10.15 (s, 1H, Ar-OH);. 13C NMR (100 MHz, CDCl3) S 14.38, 48.12, 114.64, 116.25, 128.82, 154.66, 160.21; MS (EI, 70 eV) m/z (rel. int.) 190.2 (M+), 162 (100, M+ - N3), 161 (46), 138 (25), 134 (72), 77 (52). Anal. Calcd for C9H10N4O: C, 56.83; H, 5.30; N, 29.46. Found: C, 56.80; H, 5.^6; N, 29.40.
5-(4-Hydroxyphenyl)-2-propyltetrazole (8c).
The same procedure as described for compound 8a, to give 8c as pure white solid (0.69 g, 53%), mp 142 °C; IR (KBr, cm-1) vmax 3150 (OH), 3010 (Ar-H), 2955, 1605 (C=N ring stretch), 1590 (C=C), 1540, 1450, 1378, 1270, 1230, 1160, 1100, 1040, 900, 835, 760; 1H NMR (DMSO-dg) S 0.80 (t, J = 6.50 Hz, 3H, N-CH3CH3CH3), 1.85 (m, 2H, N-CH3CH3CH3), 4.55 (t, J = 6.91 Hz, 2H, N-
CH2CH2CH3), 6.88 (d,3/ = 8.05 Hz, 2H, Ar-H), 7.85 (d, 3J = 8.05 Hz, 2H, Ar-H), 9.90 (s, 1H, Ar-OH); 13C NMR (100 MHz, CDCl3) 511.08, 23.15, 55.47, 114.64, 116.25, 128.82, 154.66, 160.21; MS (EI, 70 eV) m/z (rel. int.) 204.23 (M+), 176 (100, M+ - N2), 175 (40), 148 (74), 138 (25), 43 (26). Anal. Calcd for C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C, 58.97; H, 5.90; N, 27.39.
2-(«-Butyl-5-(4-hydroxyphenyl)tetrazole	(8d).
The same procedure as described for compound 8a, to give 8d as pure white solid (0.72 g, 58%), mp 89 °C; IR (KBr, cm-1) vmax 3150 (OH), 3010 (Ar-H), 2954, 1605 (C=N), 1590 (C:^C), 1450, 1380, 1280, 1230, 1170, 1045, 835, 760; 1H NMR (DMSO-rfg) 50.90 (t, J = 6.51 Hz, 3H, N-CH2CH2CH2CH3), 1.30 (m, 2H, N-CH2CH2CH2CH3), 1.95 (m, 2H, NN-CH2CH2CH2CH3), 4.60 (t, J = 7.13 Hz, 2H, N-CH2CH2CH2CH3), 6.10 (s, 1H), 6.90 (d, 3J = 7.89 Hz, 2H, Ar-H), 7.95 (d, 3 J = 7.76 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) 5 13.12, 19.74, 31.34, 52.89, 114.65, 116.21, 128.81, 154.76, 160.22. MS (EI, 70 eV) m/z (rel. int.) 218.26 (M+), 190 (100, M+ - N2), 189 (38), 162 (72), 125 (21). Anal. Calcd for C11H14N4O: C, 60.53; H, 6.47; N, 25.67. Found: C, 60.50; H, 6.41; N, 25.76.
3-(«-Butyl)-5-(chloromethyl)isoxazole	(9a).9f,9h
A solution of 3-(1-butyl)-isoxazol-5-ylmetha-nol9f,12-15 (1.0 g, 0.645 mol), cold thionyl chloride16 (4.68 mL, 0.645 mmol) was stirred at 0 °C overnight, the reaction mixture was concentrated and partitioned between H2O and Et2O. The ethereal extracts were combined and washed with NaHCO3 (5%), dried over Na2SO4 and concentrated to dryness. The crude product was purified on column chro-matography (Silica Gel 100, EtOAc-petroleum ether 1:10, Rf = 0.56) to give 9a as a yellow oil (0.8 g, 70%); IR (neat, cm-1) vmax 3150, 2950, 1717, 1600 (C=N ring stretch), 1469, 1420 (N-O ring stretch), 1375, 1275, 1000, 920, 870, 715; 1H NMR (CDCl3) 50.87 (t, J = 7.20 Hz, 3H), 1.22 (m, 2H), 1.45 (m, 2H), 2.60 (t, J = 7.21 Hz, 2H), 4.55 (s, 2H, CH2Cl), 6.42 (s, 1H, Isox-H); 13C NMR (75 MHz, CDCl3) 5 13.^2, 22.71, 26.89, 41.48, 44.95, 102.95, 163.68, 168.26; MS (EI, 70 eV) m/z (rel. int.) 173.64 (44, M+), 138 (100), 137 (21), 124 (45), 68 (24), 56 (82), 43 (20), 41 (65), 28 (33). Anal. Calcd for C8H12ClNO: C, 55.34; H, 6.97; N, 8.07. Found: C, 55.50; H, 6.84; N, 8.10.
5-Chloromethyl-3-(«-octyl)isoxazole (9b).
The same procedure as described for compound 9a, from 3-(1-octyl)-isoxazol-5-ylmethanol9f to give yellow oil. The crude product was purified on column chromato-graphy (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.62) to give 9b as a yellow oil (1.07g, 72%): IR (neat, cm-1) vmax 3100, 2926, 1716, 1608 (C=N ring stretch), 1422 (N-0 ring stretch), 1273, 715; 1H NMR (CDCl3) 5 0.95 (t, J = 7.11 Hz, 3H), 1.50 (m, 12H), 2.80 (t, J = 7.11 Hz, 2H), 4.60 (s, 2H, CH2Cl), 6.43 (s, 1H, Isox-H); 13C NMR (75 MHz, CDCl3) 5 11.66, 13.98, 22.50, 23.43,
27.64, 28.72, 31.67, 42.48, 44.45, 102.93, 163.78, 168.36; MS (EI, 70 eV) m/z (rel. int.) 229.75 (34, M+), 194 (100), 193 (33), 137 (32), 124 (42), 111 (22), 68 (33), 56 (41), 43 (66), 41 (72), 28 (27). Anal. Calcd for C12H20ClNO: C, 62.73; H, 8.77; N, 6.10. Found: C, 63.01; H, 8.84; N, 6.06.
5-{4-[(3-Butyl-5-isoxazolyl)methoxy]phenyl}-2-met hyl-2H-tetrazole (10a).
A mixture of 8a (0.2 g, 114 mmol), milled K2CO3 (0.3 g, 2.17 mmol), KI (0.1 g, 0.6 mmol), 9a (0.25g, 1.^3 mmol) and N-methylpyrrolidinone (10 mL) was magnetically stirred at 60 °C for 24 h. The cooled reaction mixture was concentrated and partitioned between H2O and Et2O. The combined ethereal extracts were washed with NaHCO3 (5%), dried over Na2SO4 and concentrated in vacuo. The crude product was purified on column chromato-graphy (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.1) to give pure 10a as a white solid (0.3 g, 86%), mp 88 °C. IR (KBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1580 (C^C), 1540, 1450, 1420 (N-O ring stretch), 1360, 1300, 1230, 1170, 1020; 1H NMR (CDCl3) 51.13 (t, J = 6.46 Hz, 3H), 1.75 (m, 4H), 2.89 (t, J = 6.45 Hz, 2H), 4.53 (s, 3H, N-CH3), 5.35 (s, 2H, CH2O), 6.37 (s, 1H, Isox-H), 7.22 (d, 3J = 8.9 Hz, 2H, Ar-H), 8.25 (d, 3J = 8.8 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) 5 12.48, 22.45, 26.89, 30.03, 40.33, 61.42, 102.65, 114.^8, 122.12, 123.75, 128.72, 158.64, 164.78, 167.06; MS (EI, 70 eV) m/z (rel. int.) 313.6 (M+), 285 (100), 258 (44), 147 (80), 146 (68), 91 (25), 65 (12), 43 (25). Anal. Calcd for C1gH19N5O2: C, 61.33; H, 6.11; N, 22.35. Found: C, 6^.50; H, 6.04; N, 22.10.
2-Methyl-5-{4-[(3-octyl-5-isoxazolyl)methoxy]phenyl} -2H-tetrazole (10b).
The same procedure as described for compound 10a to give 10b after column chromatography (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.14) as pure white solid (0.35 g, 84%), mp 86 °C; IR (KBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1580 (C=C), 1540, 1470, 1450, 1420 (N-O ring stretch), 1375, 1230, 1170, 1030; 1H NMR (CDCl3) 50.81 (t, J = 7.49 Hz, 3H), 1.20 (m, 10H), 1.57 (m, 2H), 2.55 (t, J = 7.51 Hz, 2H), 4.30 (s, 3H, N-CH3), 5.11 (s, 2H, CH2O), 6.12 (s, 1H, Isox-H), 6.98 (d, 3J = 9.00 Hz, 2H, Ar-H), 8.01 (d, 3J = 8.8 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) 5 13.66, 22.70, 25.23, 27.12, 27.64, 31.67, 40.48, 61.23, 102.95, 120.24, 124.88, 128.74, 158.57, 163.78, 168.35; MS (EI, 70 eV) m/z (rel. int.) 369.46 (M+), 341 (100, M+ - N)), 340 (51), 313 (67), 195 (10), 180 (22), 137 (23), 147 (^2), 57 (41). Anal. Calcd for C)0H)7N5O): C, 65.02; H, 7.37; N, 18.96. Found: C, 65.21; 7.32; IN, 19.28.
5-{4-[(3-Butyl-5-isoxazolyl)methoxy]phenyl}-2-ethyl-2H-tetrazole (10c).
The same procedure as described for compound 10a to give pure 10c after column chromatography (Silica Gel
100, EtOAc-petroleum ether 1:10, Rf = 0.13) as a white solid (0.3 g, 87%), mp 73 °C. IR (KBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1580 (C=C), 1460, 1423 (N-O ring stretch), 1360, 1230; 1H NMR (CDClj) 50.8 (t, J = 6.99 Hz, 3H), 1.41 (m, 7H), 2.50 (t, J = 7.01 Hz, 2H), 4.54 (q, J = 7.00 Hz, 2H, N-CH2CH3),
5.04	(s, 2H, CH20), 6.06 (s, 1H, Isox-H), 6.92 (d, 3J = 8.07 Hz, 2H, Ar-H), 7.90 (d, 3J = 8.34 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) 5 12.48, 15.12, 22.45, 26.89, 48.14, 61.52, 102.55, 114.76, 122.18, 123.80, 128.71, 158.62, 164.79, 167.09; MS (EI, 70 eV) m/z (rel. int.) 327.38 (M+), 299 (100, M+ - N2), 298 (55), 256 (30), 161 (77), 160 (55), 137 (18), 69 (10). Anal. Calcd for C17H21N502: C, 62.37; H, 6.47; N, 21.39. Found: C, 6^.40; H, 6.19; N, 21.30.
2-Ethyl-5-{4-[(3-octyl-5-isoxazolyl)methoxy]phenyl}-2H-tetrazole (10d).
The same procedure as described for compound 10a to give pure 10d after column chromatography (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.14) as a white solid (0.35 g, 88%), mp 59 °C; IR (K^ r, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1470, 1420 (N-0 ring stretch), 1380, 1230, 1020; 1H NMR (CDCl3) 5 0.81 (t, J = 7.02 Hz, 3H), 1.14-1.23 (m, 10H), 1.48-1.67 (m, 4H), 2.57 (t, J = 6.98 Hz, 3H, N-CH2CH3), 4.59 (q, J = 7.02 Hz, 2H, N-CH2CH3), 5.11 (s, 2H, CH20), 6.08 (s, 1H, Isox-H), 7.96 (d, 3J ^ 6.88 Hz, 2H, Ar-H), 7.98 (d, 3J = 8.93 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) 5 13.66, 22.70, 25.23, 26.98, 27.64, 31.67, 39.42, 6^.39, 102.95, 120.24, 124.88, 128.74, 158.57, 163.78, 168.35; MS (EI, 70 eV) m/z (rel. int.) 383.48 (M+), 355 (100, M+ - N2), 354 (60), 161 (78), 137(12), 124 (21), 57 (32). Anal. Calcd for C21H29N5O2: C, 65.77; H, 7.62; N, 18.26. Found: C, 65.70; H, 77.60; NN, 18.11.
5-{4-[(3-Butyl-5-isoxazolyl)methoxy]phenyl}-2-propyl -2H-tetrazole (10e).
The same procedure as described for compound 10a to give pure 10e after column chromatography (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.12) as a white solid (0.3 g, 90%), mp 54 °C; IR (KBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1570 (C=C), 1540, 1460, 1420 (N-0 ring stretch), 1380, 1250, 1160, 1100, 1055; 1H NMR (CDCl3) 5 0.81 (m, 7H), 1.34 (m, 3H), 1.95 (q, J = 7.01 Hz, 2H), 2.53 (t, J = 6.99 Hz, 2H), 4.45 (t, J = 6.99 Hz, 2H, N-CH2C), 5.04 (s, 2H, CH2O),
6.05	(s, 1H, Isox-H), 6.91 (d, ^J = 8.88 Hz, 2H, Ar7H), 7.96 (d, 3J = 8.86 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) 510.96, 12.48, 14.58, 21.61, 22.88, 29.51, 54.71, 61.55, 102.65, 114.36, 122.58, 128.51, 158.62, 164.49, 167.19; MS (EI, 70 eV) m/z (rel. int.) 342 (M + 1), 313 (100, M+ - N2), 285 (36), 176 (69), 175 (52), 137 (24), 68 (28). Anal. Calcd for C18H23N5O2: C, 63.31; H, 6.79; N, 20.52. Found: C, 63.60; 6.70; IN, 20.59.
5-{4-[(3-Octyl-5-isoxazolyl)methoxy]phenyl}-2-propyl -2H-tetrazole (10f).
The same procedure as described for compound 10a to give pure 10f after column chromatography (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.15) as a white solid (0.32 g, 82%), mp 64 °C; IR (KfBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N), 1580 (C=C), 1540, 1460, 1420 (N-0 ring stretch), 1390, 1300, 1250. 1H NMR (CDCl3) 5 0.79 (t, J = 6.95 Hz, 3H), 0.98 (t, J = 7.00 Hz, 3H), 1.07 (m, 12H), 1.89 (m, 2H), 2.46 (t, J = 7.06 Hz, 2H), 4.39 (t, J = 7.69 Hz, 2H, N-CH2C), 4.96 (s, 2H, CH20), 6.00 (s, 1H, Isox-H), 6.86 (d, 3J = 8.91 Hz, 2H, Ar-H), 7.90 (d, 3J = 8.85 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) 5 7.05, 10.96, 13.66, 19.70, 21.79, 22.82, 25.23, 27.52, 29.64, 39.27, 54.70, 61.33, 102.65, 122.24, 124.88, 128.64, 158.77, 163.98, 168.35; MS (EI, 70 eV) m/z (rel. int.) 397.52 (M+), 370 (100, M+ - N2), 341 (34), 195 (12), 180 (17), 176 (75), 175 (44), 90 (10), 71 (24), 43 (52). Anal. Calcd for C22H31N5O2: C, 66.46; H, 7.86; N, 17.63. Found: C, 66.49; 7.80; IN, 17.50.
2-Butyl-5-{4-[(3-butyl-5-isoxazolyl)methoxy]phenyl}-
2H-tetrazole (10g).
The same procedure as described for compound 10a to give pure 10g after column chromatography (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.14) as a white solid (0.3 g, 92%), mp 64 °C; IR (KBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1580 (C=C), 1540, 1460, 1424 (N-0 ring stretch), 1390, 1250; 1H NMR (CDCl3) 5 0.79 (m, 6H), 1.17 (m, 6H), 1.90 (m, 2H), 2.45 (t, J = 7.50 Hz, 2H), 4.45 (t, J = 6.97 Hz, 2H, N-CH2C), 5.00 (s, 2H, CH20), 6.02 (s, 1H, Isox-H), 6.88 (d, 3J = 8.93 Hz, 2H, Ar-H), 7.92 (d, 3J = 8.89 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3) 512.48, 13.30, 15.12, 19.61, 21.65, 29.39, 31.22, 52.84, 61.52, 102.56, 114.76, 122.38, 123.80, 128.71, 158.62, 163.79, 167.04; MS (EI, 70 eV) m/z (rel. int.) 355.43 (M+), 327 (100, M+ - N2), 326 (43), 191 (73), 69 (11), 57 (25), 43 (42), 28 (34). Anal. Calcd for C19H25N502: C, 64.19; H, 7.09; N, 19.71. Found: C, 64.50; H, 7.11;N, 20.09.
2-Butyl-5-{4-[(3-octyl-5-isoxazolyl)methoxy]phenyl}-2H-tetrazole (10h).
The same procedure as described for compound 10a to give pure 10h after column chromatography (Silica Gel 100, EtOAc-petroleum ether 1:10, R^ = 0.16) as a white solid (0.33 g, 88%), mp 70 °C; IR (KfBr, cm-1) vmax 3005 (Ar-H), 2950, 1605 (C=N ring stretch), 1580 (C=C), 1540, 1460, 1390, 1300, 1255; 1H NMR (CDCl3) 5 0.88 (m, 6H), 1.19 (m, 12H), 1.49 (m, 2H), 2.01 (m, ^H), 2.58 (t, J = 6.96 Hz, 2H), 4.54 (t, J = 6.99 Hz, 2H, N-CH2C), 5.09 (s, 2H, CH20), 6.11 (s, 1H, Isox-H), 6.97 (d, 3J = 8.34 Hz, 2H, Ar-H), 8.01 (d, 3J = 8.69 Hz, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) 5 7.15, 12.26, 13.46, 19.68, 21.79, 23.62, 25.23, 27.52, 29.64, 31.24, 39.27, 52.80, 61.33, 102.65, 122.24, 124.88, 128.64, 158.77, 163.88,
168.45; MS (EI, 70 eV) m/z (rel. int.) 411.44 (M+), 383 (100, M+ - N2), 328 (29), 191 (70), 68 (11), 57 (22), 28 (32). Anal. Cailcd for C23H33N5O2: C, 67.11; H, 8.09; N, 17.02. Found: C, 67.20; 7.89; 16.82.
4. Conclusion
In conclusion, we have presented a facile and an efficient route to 2-alkyl-5-[4-(3-alkyl-5-isoxazolyl)met-hoxyphenyl]-2H-tetrazoles 10a-h which were synthesized from 4-[5(2-alkyl-2H-tetrazolyl)]phenols 8 and 3-alkyl-5-chloromethylisoxazole 9 in high yields. 3-Alkyl-5-chloromethylisoxazole 9 was prepared by the reaction of corresponding 3-(1-alkyl)isoxazol-5-ylmethanol with thionyl chloride. 4-[5-(2-Alkyl-2H-tetrazolyl)]phenols 8a-d were synthesized from the corresponding aldehyde 3 in five steps.
5. Acknowledgements
We would like to extend our appreciation to Research counsel and research office of Tabriz University for financial support of this project.
6. References
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Povzetek
Pripravili in karakterizirali smo več alkil(izoksazolilmetoksifenil)tetrazolov. Alkil-5-(klorometil)izoksazole 9 smo pripravili z reakcijo med ustreznimi (3-alkilizoksazol-5-il)metanoli z uporabo tionil klorida. 4-(2-Alkyl-2H-tetrazol-5-il)]fenole 8 smo v petih stopnjah pripravili iz ustreznih aldehidov 3. Dobljene produkte 8 smo nato reagirali z alkil-5-(klorometil)izoksazoli 9 pri čemer so z visokimi izkoristki nastali ustrezni 2-alkil-5-{4-[(3-alkilizoksazol-5-il)metok-si]fenil}-2H-tetrazoli 10a-h.