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Synthesis 2013; 45(4): 507-510
DOI: 10.1055/s-0032-1318108
paper
© Georg Thieme Verlag Stuttgart · New York

One-Step Synthesis of 5-Substituted 1H-Tetrazoles from an Aldehyde by Reaction with Acetohydroxamic Acid and Sodium Azide under Bi(OTf)3 Catalysis

Madabhushi Sridhar*
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India   Fax: +91(40)27160387   Email: smiict@gmail.com
,
Kishore Kumar Reddy Mallu
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India   Fax: +91(40)27160387   Email: smiict@gmail.com
,
Raveendra Jillella
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India   Fax: +91(40)27160387   Email: smiict@gmail.com
,
Kondal Reddy Godala
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India   Fax: +91(40)27160387   Email: smiict@gmail.com
,
China Ramanaiah Beeram
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India   Fax: +91(40)27160387   Email: smiict@gmail.com
,
Narsaiah Chinthala
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India   Fax: +91(40)27160387   Email: smiict@gmail.com
› Author Affiliations
Further Information

Publication History

Received: 23 November 2012

Accepted after revision: 27 December 2012

Publication Date:
17 January 2013 (online)

 
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One-Step Synthesis of 5-Substituted 1H-Tetrazoles from an Aldehyde by Reaction with Acetohydroxamic Acid and Sodium Azide under Bi(OTf)3 CatalysisSynthesis 2013; 45(04): e1-e1
DOI: 10.1055/s-0032-1316853

Abstract

An efficient one-step method for the synthesis of 5-substituted 1H-tetrazoles from aldehydes by reaction with aceto­hydroxamic acid and sodium azide using bismuth(III) triflate as the catalyst is described.


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Key words

aldehydes - 5-substituted 1H-tetrazoles - sodium azide - bismuth(III) triflate - catalysis

5-Substituted 1H-tetrazoles are an important class of nitrogen heterocycles that have applications as propellants[ 1 ] and specialty explosives.[ 2 ] These compounds also exhibit important pharmacological properties as antiviral,[ 3 ] anti-inflammatory,[ 4 ] antifungal,[ 5 ] and antiulcer[ 6 ] agents. In medicinal chemistry, the tetrazole functionality is a known bioisosteric replacement for the carboxylic group[ 7 ] and also exhibits good metabolic stability and high lipophilicity. Hence, the presence of this functionality was often found to improve in vivo half-life, oral bioavailability, and cell penetration ability of several bioactive molecules.[ 8 ]

The synthesis of 5-substituted 1H-tetrazoles is a widely studied subject in the literature,[ 9 ] and in existing studies 5-substituted 1H-tetrazoles are generally prepared from nitriles by reaction with a metal azide in the presence of a base or acid catalyst. However, there are no methods in the literature for the preparation of 5-substituted 1H-tetrazoles directly from aldehydes in a single step. We consider that development of a simple method for preparation of 5-substituted 1H-tetrazoles from aldehydes is highly desirable as it reduces the number of steps and minimizes ­effluents.

Acetohydroxamic acid (AHA) is simple organic compound that can be easily prepared by reaction of hydroxylamine and ethyl acetate in the presence of a base. Acetohydroxamic acid, which is also known as Lithostat®, is a known drug for treatment of urinary tract infections.[ 10 ] Acetohydroxamic acid is a widely used chelating agent in the UREX process for the separation of uranium from spent nuclear fuel.[ 11 ] However, acetohydroxamic acid has not received much attention in organic chemistry and its applications in organic synthesis are scarcely known. Recently, we developed new methods for the selective preparation of oximes[ 12 ] and nitriles[ 13 ] from aldehydes using acetohydroxamic acid. In continuation of our research interest in the development of new synthetic applications of acetohydroxamic acid, we report here an efficient and simple method for the preparation of 5-substituted 1H-tetrazoles in high yields (60–87%) directly from aldehydes by reaction with acetohydroxamic acid and sodium azide using bismuth(III) triflate as the catalyst as shown in Scheme [1].

Zoom Image
Scheme 1 One-step synthesis of 5-substituted 1H-tetrazoles from aldehydes

In our preliminary experiments, we found benzaldehyde (1a) reacted with acetohydroxamic acid and sodium azide under bismuth(III) triflate catalysis upon heating in N,N-dimethylformamide at 120 °C producing 5-phenyl-1H-tetrazole (2a) in 87% yield. Under similar conditions, this reaction was found to proceed well also with aldehydes 1b–l, which gave the corresponding 5-substituted 1H-tetrazoles 2b–l in 60–87% yields; the results are shown in Table [1]. Tetrazoles 2a–c,e–g,k,l are known compounds and they gave characteristic and spectroscopic data identical to that reported in the literature (Table [1]). Tetrazoles 2d,h–j are novel compounds and their characteristic and spectroscopic data are provided.

Table 1 Synthesis of 5-Substituted 1H-Tetrazoles from Aldehydes Using Acetohydroxamic Acid

Entry

Aldehyde

Time (h)

Tetrazole

Yielda (%)

Mp (°C)

 1

1a

24

2a

87

215–216[ 9e ]

 2

1b

24

2b

85

264–266[ 9g ]

 3

1c

24

2c

70

218–219[ 9o ]

 4

1d

24

2d

80

198–200

 5

1e

28

2e

60

219–220[ 9e ]

 6

1f

24

2f

83

234–235[ 9o ]

 7

1g

24

2g

79

154–156[ 9o ]

 8

1h

25

2h

76

120–121

 9

1i

28

2i

65

145–146

10

1j

24

2j

79

127–128

11

1k

22

2k

86

204–205[ 9g ]

12

1l

15

2l

84

242–244[ 9e ]

a Isolated yields. All products gave satisfactory 1H and 13C NMR, IR, and mass spectral data.

In this study, the solvent was found to play an important role in promoting the reaction. For example, in acetonitrile, the reaction proceeds only up to the stage of the formation of the intermediate nitrile and no tetrazole formation was observed. Whereas in N,N-dimethylformamide we observed efficient completion of the reaction with exclusive formation of tetrazoles in high yields (Scheme [1]).

In conclusion, this work shows an efficient and simple one-step method for the preparation of 5-substituted 1H-tetrazoles from aldehydes by reaction with acetohydroxamic acid and sodium azide under bismuth(III) ­triflate catalysis.

All reagents were procured from commercial sources and used without further treatment. Melting points were recorded on CasiaeSiamia (VMP-AM) melting point apparatus and are uncorrected. IR spectra were recorded on a PerkinElmer FT-IR 240-C spectrophotometer using KBr optics. 1H NMR spectra were recorded on Bruker AV 300 MHz in CDCl3–DMSO using TMS as internal standard. Electron Spray Ionization (ESI) and HRMS were recorded on QSTARXL hybrid MS/MS system (Applied Biosystems, USA) ­under electrospray ionization.

All the reactions were monitored by TLC on precoated silica gel 60 F254 (mesh); spots were visualized with UV light. Merck silica gel (100–200 mesh) was used for column chromatography.


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5-Phenyl-1H-tetrazole (2a); Typical Procedure

Benzaldehyde (1a, 0.5 g, 4.7 mmol), acetohydroxamic acid (0.42 g, 5.7 mmol), NaN3 (0.4 g, 6.1 mmol), DMF (5 mL), and Bi(OTf)3 (0.15 g, 0.23 mmol) were taken into a 25-mL round-bottomed flask fitted with a condenser and CaCl2 guard tube. The mixture was heated at 120 °C for 24 h. After completion of the reaction (TLC), the mixture was cooled to r.t. and neutralized (pH 7) with 5% HCl. Next, the mixture was extracted with EtOAc and the organic layer was separated, dried (anhyd Na2SO4), and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (silica gel 100–200 mesh, EtOAc–hexane, 1:2) to obtain 2a as a white solid; yield: 0.6 g (87%); mp 215–216 °C (Lit.[ 9e ] 215–216 °C).

IR (KBr): 3448, 3128, 3055, 1853, 1638, 1562, 1485, 1407, 1254, 1056 cm–1.

1H NMR (300 MHz, DMSO): δ = 8.10–8.05 (m, 2 H), 7.57–7.50 (m, 3 H).

13C NMR (75 MHz, DMSO): δ = 154.2, 129.5, 127.7, 125.6, 123.0.

MS (ESI): m/z = 147 [M + H].

HRMS (ESI): m/z [M + H] calcd for C7H7N4: 147.0671; found: 147.0665.


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5-(4-Chlorophenyl)-1H-tetrazole (2b)

Brown solid; yield: 0.55 g (85%); mp 264–266 °C (Lit.[ 9g ] 265–266 °C)

IR (KBr): 3423, 3066, 2924, 1908, 1608, 1558, 1433, 1256, 1094 cm–1.

1H NMR (300 MHz, DMSO): δ = 10.20 (br s, 1 H), 8.10 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H).

13C NMR (75 MHz, DMSO): δ = 155.7, 135.0, 129.3, 128.4, 124.5.

MS (ESI): m/z = 181 [M + H].

HRMS (ESI): m/z [M + H] calcd for C7H6ClN4: 181.0281; found: 181.0279.


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5-(4-Nitrophenyl)-1H-tetrazole (2c)

Yellow solid; yield: 0.44 g (70%); mp 218–219 °C (Lit.[ 9o ] 220 °C).

IR (KBr): 3443, 3106, 2924, 1604, 1514, 1452, 1347, 1292, 1102 cm–1.

1H NMR (300 MHz, DMSO): δ = 8.36 (d, J = 9.0 Hz, 2 H), 7.89 (d, J = 9.0 Hz, 2 H).

13C NMR (75 MHz, DMSO): δ = 149.8, 146.6, 126.7, 115.1, 113.6.

MS (ESI): m/z = 192 [M + H].

HRMS (ESI): m/z [M + H] calcd for C7H6N5O2: 192.0521; found: 192.0524.


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5-(3,4-Dimethoxyphenyl)-1H-tetrazole (2d)

Brown solid; yield: 0.50 g (80%); mp 198–200 °C.

IR (KBr): 3445, 3013, 2923, 2737, 1566, 1434, 1322, 1272, 1143, 1023 cm–1.

1H NMR (300 MHz, DMSO): δ = 7.69–7.67 (m, 2 H), 6.99 (d, J = 8.3 Hz, 1 H), 3.96–3.94 (6 H).

13C NMR (75 MHz, DMSO): δ = 154.9, 150.6, 119.7, 116.2, 110.7, 109.5, 55.4, 55.3.

MS (ESI): m/z = 207 [M + H].

HRMS (ESI): m/z [M + H] calcd for C9H11N4O2: 207.2092; found: 207.2097.


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5-[4-(Trifluoromethyl)phenyl]-1H-tetrazole (2e)

White solid; yield: 0.37 g (60%); mp 219–220 °C (Lit.[ 9e ] 220–221 °C).

IR (KBr): 3422, 3021, 2965, 1597, 1450, 1386, 1296, 1125, 1098 cm–1.

1H NMR (300 MHz, DMSO): δ = 8.14 (d, J = 8.5 Hz, 2 H), 7.69 (d, J = 8.5 Hz, 2 H).

13C NMR (75 MHz, DMSO): δ = 166.3, 133.8, 129.4, 126.9, 124.5.

MS (ESI): m/z = 215 [M + H].

HRMS (ESI): m/z [M + H] calcd for C8H6F3N4: 215.0545; found: 215.0549.


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4-(1H-Tetrazol-5-yl)phenol (2f)

White solid; yield: 0.55 g (83%); mp 234–235 °C (Lit.[ 9o ] 234–236 °C).

IR (KBr): 3442, 3397, 3227, 2983, 2839, 1544, 1459, 1322, 1232, 1141, 1028 cm–1.

1H NMR (300 MHz, DMSO): δ = 9.80 (s, 1 H), 7.72 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 8.6 Hz, 2 H).

13C NMR (75 MHz, DMSO): δ = 162.2, 132.5, 130.7, 127.3, 114.6.

MS (ESI): m/z = 163 [M + H].

HRMS (ESI): m/z [M + H] calcd for C7H7N4O: 163.0620; found: 163.0614.


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(E)-5-Styryl-1H-tetrazole (2g)

White solid; yield: 0.51 g (79%); mp 154–156 °C (Lit.[ 9o ] 155–156 °C).

IR (KBr): 3391, 3058, 2991, 1617, 1586, 1494, 1345, 1208, 1145 cm–1.

1H NMR (300 MHz, DMSO): δ = 7.71 (d, J = 16.6 Hz, 1 H), 7.59–7.57 (m, 2 H), 7.45–7.37 (m, 3 H), 7.16 (d, J = 16.6 Hz, 1 H).

13C NMR (75 MHz, DMSO): δ = 136.1, 133.2, 127.7, 127.1, 125.5, 108.6.

MS (ESI): m/z = 173 [M + H].

HRMS (ESI): m/z [M + H] calcd for C9H9N4: 173.0827; found: 173.0822.


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5-(1-Phenylethyl)-1H-tetrazole (2h)

Yellow solid; yield: 0.49 g (76%); mp 120–121 °C.

IR (KBr): 3444, 2979, 1885, 1652, 1553, 1451, 1382, 1248, 1120, 1053 cm–1.

1H NMR (300 MHz, DMSO): δ = 7.33–7.23 (m, 5 H), 4.50–4.46 (q, J = 7.8 Hz, 6.8 Hz, 1 H), 1.77 (d, J = 6.8 Hz, 3 H).

13C NMR (75 MHz, DMSO): δ = 128.2, 127.7, 127.3, 126.8, 126.2, 34.4, 19.4.

MS (ESI): m/z = 175 [M + H].

HRMS (ESI): m/z [M + H] calcd for C9H11N4: 175.0984; found: 175.0989.


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5-(Bicyclo[2.2.1]hept-5-en-2-yl)-1H-tetrazole (2i)

Yellow solid: yield: 0.43 g (65%); mp 145–146 °C.

IR (KBr): 3451, 3065, 1861, 1633, 1571, 1452, 1338, 1260, 1133, 1024 cm–1.

1H NMR (300 MHz, DMSO): δ = 6.33–6.31 (m, 1 H), 6.19–6.15 (m, 1 H), 3.04–3.19 (m, 1 H), 2.86–2.82 (m, 1 H), 2.20–2.11 (m, 1 H), 1.57–1.49 (m, 2 H), 1.33–1.29 (m, 1 H), 1.21–1.19 (m, 1 H).

13C NMR (75 MHz, DMSO): δ = 138.8, 137.2, 122.9, 47.7, 45.7, 42.3, 32.4, 27.02.

MS (ESI): m/z = 163 [M + H].

HRMS (ESI): m/z [M + H] calcd for C8H11N4: 163.0984; found: 163.0988.


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5-(Cyclohex-3-enyl)-1H-tetrazole (2j)

Yellow solid; yield: 0.54 g (79%); mp 127–128 °C.

IR (KBr): 3445, 3117, 3030, 1868, 1654, 1557, 1431, 1353, 1252, 1114 cm–1.

1H NMR (300 MHz, DMSO): δ = 5.85– 5.71 (m, 2 H), 3.32–3.20 (m, 1 H), 2.58–2.32 (m, 2 H), 2.21–2.12 (m, 3 H), 1.91–1.81 (m, 1 H).

13C NMR (75 MHz, DMSO): δ = 159.0, 126.0, 124.0, 28.9, 28.7, 26.1, 23.5.

MS (ESI): m/z = 151 [M + H].

HRMS (ESI): m/z [M + H] calcd for C7H11N4: 151.0984; found: 151.0979.


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5-(Thiophen-2-yl)-1H-tetrazole (2k)

Pale yellow solid; yield: 0.58 g (86%); mp 204–205 °C (Lit.[ 9g ] 205–206 °C).

IR (KBr): 3432, 3074, 2950, 1592, 1407, 1238, 1137, 1047 cm–1.

1H NMR (300 MHz, DMSO): δ = 8.45 (br s, 1 H), 7.81 (d, J = 3.7 Hz, 1 H), 7.55 (d, J = 5.3 Hz, 1 H), 7.17 (t, J = 3.7, 4.9 Hz, 1 H).

13C NMR (75 MHz, DMSO): δ = 150.8, 127.9, 127.6, 127.0, 125.1.

MS (ESI): m/z = 153 [M + H].

HRMS (ESI): m/z [M + H] calcd for C5H5N4S: 153.0235; found: 153.0231.


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3-(1H-Tetrazol-5-yl)pyridine (2l)

White solid; yield: 0.58 g (84%); mp 242–244 °C (Lit.[ 9e ] 241–242 °C).

IR (KBr): 3445, 3071, 2928, 1537, 1428, 1387, 1238, 1140, 1073, 1017 cm–1.

1H NMR (300 MHz, DMSO): δ = 9.32 (s, 1 H), 8.74–8.73 (m, 1 H), 8.44–8.42 (m, 1 H), 7.55–7.51 (m, 1 H).

13C NMR (75 MHz, DMSO): δ = 155.7, 125.2, 120.4, 116.3.

MS (ESI): m/z = 148 [M + H].

HRMS (ESI): m/z [M + H] calcd for C6H6N5: 148.0623; found: 148.0619.


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Acknowledgment

K.K.R.M., J.R., K.R.G., and C.R.B. are thankful to C.S.I.R., New Delhi for the award of Senior Research Fellowship. N.C. is thankful to U.G.C., New Delhi for the award of Senior Research Fellowship.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information


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Zoom Image
Scheme 1 One-step synthesis of 5-substituted 1H-tetrazoles from aldehydes