An electro-synthesis method of 5-selenotetrazole

Abstract

The application discloses an electro-synthesis method of 5-selenotetrazole, which comprises the following steps: using platinum sheet as a cathode, a carbon rod as an anode, using tetrabutylammonium perchlorate or lithium perchlorate as an electrolyte under constant current catalysis, and one-pot cyclization of diaryl diselenide, isonitrile and azidotrimethylsilane to prepare 5-selenotetrazole derivatives; and after post-treatment of the obtained reaction mixture, 5-selenotetrazole pure product is separated through column chromatography. According to the application, 5-selenotetrazole can be obtained through one-step reaction, the operation steps are few, the use of oxidants and additives is avoided, the post-treatment process is simple, and the product is easy to separate.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, and specifically relates to a method for preparing 5-selenitezazole. Background Technology

[0002] 5-Selenotetrazol derivatives are a class of organic molecules with diverse biological activities and wide applications in chemistry, materials science, and drug design. To date, the synthesis of 5-selenotetrazol derivatives still requires a multi-step reaction from 5-thiotetrazolium via oxidative sulfonation followed by substitution with diaryldiselenes. In this multi-step reaction, the initial starting materials also need to be pre-synthesized, and the continuous reaction requires the use of various oxidants, metals, and additives. Therefore, the preparation of 5-selenotetrazol derivatives from simple starting materials under mild and green conditions is extremely necessary.

[0003] Electrochemical organic synthesis technology is gradually becoming a powerful synthetic tool. This is because it does not require exogenous oxidants; the gentle oxidation of the substrate can be achieved solely through electrodes. Furthermore, most electrochemical reactions can be easily operated under mild conditions, and the experiment can be started and stopped simply by controlling the current. Therefore, finding green and efficient electrochemical methods to synthesize 5-selenitezazole derivatives is a highly significant research topic. Summary of the Invention

[0004] The purpose of this invention is to provide a simple, green, and efficient method for preparing 5-selenitezazole from diaryl diselenide, isonitrile, and azidotrimethylsilane.

[0005] The technical solution to achieve the objective of this invention is:

[0006] In a first aspect, the present invention provides a method for preparing 5-selenotetrazole, comprising the step of synthesizing the target product by electrochemically reacting diaryldiselenoether, isonitrile, and azidetrimethylsilane in an electrolyte solution:

[0007]

[0008] In the formula, R 1 Including but not limited to any one of the following groups: tert-butyl, tetramethylbutyl, cyclohexyl, ester, and benzyl; R 2 Including but not limited to any of the groups phenyl or thiophene.

[0009] Furthermore, the electrolyte in the electrolyte solution is tetrabutylammonium perchlorate or lithium perchlorate, and the solvent is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 5 to 10:1, preferably 9:1.

[0010] Furthermore, the electrochemical reaction uses a carbon rod as the anode and a platinum sheet as the cathode, with a constant current of 3 mA to 20 mA, preferably 10 mA to 15 mA, and more preferably 10 mA.

[0011] Furthermore, the electrochemical reaction is carried out at 0–50°C, preferably at room temperature.

[0012] Furthermore, the electrochemical reaction time is not less than 4 hours, preferably more than 6 hours, and more preferably more than 10 hours.

[0013] Furthermore, the amount of electrolyte is 0.2-1 times the molar ratio of the amount of isonitrile, preferably 0.8 times.

[0014] Furthermore, the amount of azide-trimethylsilane used is 3-6 times the molar ratio of the amount of isonitrile, preferably 4 times.

[0015] Furthermore, the amount of diaryldiselelenide used is 0.5-2 times the molar ratio of the isonitrile used, preferably 1.5 times. Compared with the prior art, the present invention has the following significant advantages:

[0016] (1) The synthesis method of the present invention is simple and efficient. 5-Selenotetrazole can be obtained in just one reaction. There are few operation steps, avoiding the use of oxidants and additives. The post-processing is simple and the product is easy to separate, which greatly simplifies the operation requirements.

[0017] (2) The reaction conditions of the present invention are easy to achieve and do not require harsh conditions such as low temperature, high temperature, light, pressure, strong acid and strong base, thus avoiding special requirements such as biocatalysis and noble metal catalysis.

[0018] (3) The diaryl diselenide used in this invention exhibits excellent reactivity under electrochemical conditions, which cyclizes azide trimethylsilane and isonitrile into 5-selenotetraazole. In contrast, exogenous oxidants, iodine reagents, metal catalysts and the like are difficult to achieve efficient and short-time conversion. Attached Figure Description

[0019] Figure 1 This is the 1H NMR spectrum of 5-(phenylselenoyl)-1-(2,4,4-trimethylpent-2-yl)-1H-tetrazole prepared in Example 1 of this invention.

[0020] Figure 2 This is the carbon NMR spectrum of 5-(phenylselenoyl)-1-(2,4,4-trimethylpent-2-yl)-1H-tetrazole prepared in Example 1 of this invention.

[0021] Figure 3 This is the 1H NMR spectrum of 5-(phenylselenoyl)-1-(tolylmethyl)-1H-tetrazole prepared in Example 2 of this invention.

[0022] Figure 4 This is the carbon NMR spectrum of 5-(phenylselenoyl)-1-(tolylmethyl)-1H-tetrazole prepared in Example 2 of this invention.

[0023] Figure 5 This is the 1H NMR spectrum of 1-(tert-butyl)-5-((4-chlorophenyl)selenoyl)-1H-tetrazole prepared in Example 3 of this invention.

[0024] Figure 6 This is the carbon NMR spectrum of 1-(tert-butyl)-5-((4-chlorophenyl)selenoyl)-1H-tetrazole prepared in Example 3 of this invention. Detailed Implementation

[0025] The present application will be further described below with reference to specific embodiments.

[0026] It should be noted that terms such as "upper", "lower", "left", "right", and "middle" used in this specification are only for clarity of description and are not intended to limit the scope of implementation. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered as within the scope of this application.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0028] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0029] As used herein, the term “about” is used to provide for the flexibility and imprecision associated with a given term, measure, or value. Those skilled in the art can readily determine the degree of flexibility for a particular variable.

[0030] As used herein, the term “at least one of…” is intended to be synonymous with “one or more of…”. For example, “at least one of A, B, and C” explicitly includes only A, only B, only C, and combinations thereof.

[0031] Concentration, amount, and other numerical data may be presented in range format herein. It should be understood that such range format is used solely for convenience and brevity and should be flexibly interpreted to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges encompassed within the range, as if each value and subrange were explicitly stated. For example, a range of values ​​from about 1 to about 4.5 should be interpreted to include not only the explicitly stated limits of 1 to 4.5, but also individual numbers (such as 2, 3, 4) and subranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges that describe only a single value, such as “less than about 4.5,” which should be interpreted to include all the aforementioned values ​​and ranges. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic described.

[0032] The method for preparing 5-selenotetrazole according to the present invention includes the following steps:

[0033] (1) In a dry three-necked flask, under constant current, acetonitrile and hexafluoroisopropanol were used as a mixed solvent, tetrabutylammonium perchlorate as the electrolyte, a carbon rod as the anode, and a platinum sheet as the cathode. (2) The isonitrile, diaryldiselenes, and azidotrimethylsilane were added to the three-necked flask, stirred, and electrified. (3) After the reaction was completed, the resulting reaction mixture was post-treated and separated by chromatographic column chromatography to obtain pure 5-selenotetrazole.

[0034] Example 1:

[0035] A magnetic flux and tetrabutylammonium perchlorate (0.4 mmol, 1 equivalent) were added to a dry three-necked flask (20 mL) containing a graphite rod anode (φ = 6 mm, 90 mm) and a platinum cathode (10 mm × 10 mm × 0.1 mm). Acetonitrile (9 mL), hexafluoroisopropanol (1 mL), azidotrimethylsilane (4 equivalents), tetramethylbutylisocyanurate (0.5 mmol, 1 equivalent), and diphenyldiselenoether (1.5 equivalents) were then injected separately into the flasks using a syringe. The reaction mixture was stirred and electrolyzed at a constant current of 10 mA for 8 hours at room temperature (2.98 F / mol). After the reaction was complete, the solvent was removed under reduced pressure. The product was purified by flash column chromatography on silica gel using a petroleum ether / ethyl acetate mixture of 8:1 as the eluent, yielding 64% 5-selenotetrazole.

[0036] 5-(phenylselenoyl)-1-(2,4,4-trimethylpent-2-yl)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.65 (d, J = 6.8Hz, 2H), 7.35-7.28 (m, 3H), 2.02 (s, 2H), 1.78 (s, 6H), 0.71 (s, 9H). 13C NMR (126MHz, CDCl3) δ144.9,135.2,129.8,125.6,77.4,77.2,76.9,65.0,52.4,31.8,30.7,30.1.

[0037] Example 2:

[0038] Following the method of Example 1, p-methylbenzenesulfonylmethylisocyanate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenitezolate product, with a separation yield of 51%. NMR characterization is shown below. Figure 3 and Figure 4 .

[0039] 5-(phenylselenoyl)-1-(tolylmethyl)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.61 (d, J = 8.4Hz, 2H), 7.44 (d, J = 8.3Hz, 2H), 7.33-7.25 (m, 5H), 5.55 (s, 2H), 2.37 (s, 3H). 13 CNMR (126MHz, CDCl3) δ149.1,147.1,134.7,131.9,130.6,130.0,129.0,124.9,77.477.2,76.9,65.8,21.9.

[0040] Example 3:

[0041] Following the method of Example 1, tert-butylisocyanate was used instead of tetramethylbutylisocyanate, and 1,2-bis(4-chlorophenyl)diselenoether was used instead of diphenyldiselenoether, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 55%.

[0042] 1-(tert-butyl)-5-((4-chlorophenyl)seleno)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.69 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 1.83 (s, 9H). 13 C NMR (126MHz, CDCl3) δ144.2,136.4,123.6,77.4,77.2,76.9,61.7,29.6,28.6.

[0043] Example 4:

[0044] Following the method of Example 1, ethyl isonitrile was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 75%.

[0045] Ethyl acetate 2-(5-(phenylselenoyl)-1H-tetrazole-1-yl)acetate. 1 H NMR (500MHz, CDCl3) δ7.51 (d, J = 7.1Hz, 2H), 7.29-7.19 (m, 3H), 5.04 (s, 2H), 4.06 (q, J = 7.1Hz, 2H), 1.13 (t, J = 7.2Hz, 3H). 13 C NMR (126MHz, CDCl3) δ164.9,146.8,134.1,130.0,129.5,124.8,77.4,77.2,76.9,62.8,48.9,13.9.

[0046] Example 5:

[0047] Following the method of Example 1, methyl isonitrile acetate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 73%.

[0048] Methyl acetate 2-(5-(phenylselenoyl)-1H-tetrazole-1-yl)acetate. 1 H NMR (500MHz, CDCl3) δ7.48 (d, J = 7.0Hz, 2H), 7.28-7.17 (m, 3H), 5.06 (s, 2H), 3.57 (s, 3H). 13 C NMR (126MHz, CDCl3) δ165.4,146.7,134.1,129.9,129.5,124.7,77.4,77.2,76.9,53.2,48.7.

[0049] Example 6:

[0050] Following the method of Example 1, tert-butylisocyanate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 60%.

[0051] 1-(tert-butyl)-5-(phenylseleno)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.60 (d, J = 6.8Hz, 2H), 7.32-7.25 (m, 3H), 1.69 (s, 9H). 13 C NMR (126MHz, CDCl3) δ144.3,134.9,129.8,129.6,125.7,77.4,77.2,76.9,61.6,29.5.

[0052] Example 7:

[0053] Following the method of Example 1, cyclohexylisocyanate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 55%.

[0054] 1-Cyclohexyl-5-(phenylselenoyl)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.49 (d, J = 8.2 Hz, 2H), 7.28-7.19 (m, 3H), 4.30-4.22 (m, 1H), 1.75 (dd, J = 32.9, 22.4Hz, 6H), 1.30-1.10 (m, 4H). 13 C NMR (126MHz, CDCl3) δ144.5,134.0,130.0,129.4,125.4,77.4,77.2,76.9,59.1,32.6,25.2,24.8.

[0055] Example 8:

[0056] Following the method of Example 1, adamantane isonitrile was used instead of tetramethylbutyl isonitrile, with other conditions remaining unchanged, to obtain the 5-selenitezolate product with a separation yield of 67%.

[0057] 1-((2R,3aS,5R)-octahydro-2,5-methylpentadimethyl-1-yl)-5-(phenylselenoyl)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.62 (d, J = 6.9 Hz, 2H), 7.34-7.29 (m, 3H), 2.34 (d, J = 2.7 Hz, 8H), 1.73 (s, 7H). 13 C NMR (126MHz, CDCl3) δ143.9,135.0,129.9,129.7,125.9,77.4,77.2,76.9,62.4,41.8,35.7,29.7.

[0058] Example 9:

[0059] Following the method of Example 1, benzylisocyanate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenitezolate product with a separation yield of 51%.

[0060] 1-Benzyl-5-(phenylselenoyl)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.43 (d, J = 7.1Hz, 2H), 7.26-7.18 (m, 6H), 7.09 (d, J = 5.4Hz, 2H), 5.44 (s, 2H). 13C NMR (126MHz, CDCl3) δ145.8,133.9,133.1,129.9,129.3,129.0,128.8,127.9,125.0,77.4,77.2,76.9,51.9.

[0061] Example 10:

[0062] Following the method of Example 1, 4-methoxybenzonitrile was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenitezolate product with a separation yield of 62%.

[0063] 1-(4-methoxyphenyl)-5-(phenylseleno)-1H-tetrazole. 1 HNMR (500MHz, CDCl3) δ7.51 (d, J = 7.1Hz, 2H), 7.31-7.23 (m, 5H), 6.93 (d, J = 8.9Hz, 2H), 3.80 (s, 3H). 13 C NMR (126MHz, CDCl3) δ161.0,147.3135.1,129.8,126.7,126.3,124.4,114.9,77.4,77.2,76.9,55.8.

[0064] Example 11:

[0065] Following the method of Example 1, 4-fluorophenylisocyanate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 53%.

[0066] 1-(4-Fluorophenyl)-5-(phenylselenoyl)-1H-tetrazole. 1 H NMR (500MHz, CDCl3) δ7.64-7.61(m,2H),7.51-7.43(m,3H),7.38(t,J=7.5Hz,2H),7.32-7.26(m,2H). 13 C NMR (126MHz, CDCl3) δ162.5,147.3,135.2,130.0,127.1124.2,117.1,116.9,77.4,77.2,76.9.

[0067] Example 12:

[0068] Following the method of Example 1, 4-bromophenylisocyanate was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 58%.

[0069] 1-(4-bromophenyl)-5-(phenylseleno)-1H-tetrazole. 1H NMR (500MHz, CDCl3) δ7.59 (d, J = 8.7Hz, 2H), 7.51 (d, J = 7.1Hz, 2H), 7.28 (tt, J = 15.0, 7.3Hz, 5H). 13 C NMR (126MHz, CDCl3) δ147.1,135.2,133.0,130.0,126.3,124.7,124.1,77.4,77.2,76.9.

[0070] Example 13:

[0071] Following the method of Example 1, 2,6-dimethylbenzonitrile was used instead of tetramethylbutylisocyanate, with other conditions remaining unchanged, to obtain the 5-selenitezolate product with a separation yield of 45%.

[0072] 1-(2,6-Dimethylphenyl)-5-(phenylselenoyl)-1H-tetrazole. 1 HNMR (500MHz, CDCl3) δ7.60 (d, J = 7.7Hz, 2H), 7.45-7.33 (m, 4H), 7.22 (d, J = 7.6Hz, 2H), 1.91 (s, 6H). 13 C NMR (126MHz, CDCl3) δ136.1,135.9,131.2,130.0,129.9,128.9,77.4,77.2,76.9,17.6.

[0073] Example 14:

[0074] Following the method of Example 1, tert-butylisocyanate was used instead of tetramethylbutylisocyanate, and 1,2-bis(thiophen-2-yl)diselenic acid was used instead of diphenyldiselenic acid, with other conditions remaining unchanged, to obtain the 5-selenite product with a separation yield of 64%.

[0075] 1-(tert-butyl)-5-(thiophene-2-ylselenoyl)-1H-tetrazole. 1 HNMR (500MHz, CDCl3) δ7.62(d,J=5.3Hz,1H),7.53(d,J=3.5Hz,1H),7.16-7.13(m,1H),1.84(s,9H). 13 C NMR (126MHz, CDCl3) δ138.7,133.9,128.5,117.7,77.4,77.2,76.9,61.5,30.0-29.67,29.2.

[0076] The above examples were used to screen the substrate range of the present invention. Below, ethyl isonitrile and diphenyldiselenoether will be used as representative substrates, and the reaction conditions will be screened strictly using a single-variable method. (Other substrates do not affect the optimization of reaction conditions).

[0077] Example 15:

[0078] Following the method of Example 1, other electrolytes were used instead of tetrabutylammonium perchlorate, and other conditions remained unchanged, to obtain ethyl acetate of 2-(5-(phenylselenoyl)-1H-tetrazole-1-yl) 5-selenite. The separation yields are shown in Table 1.

[0079] Table 1: Effect of electrolyte type on the yield of target product

[0080]

[0081] Example 16:

[0082] Following the method of Example 1, other solvents were used instead of acetonitrile and hexafluoroisopropanol, while other conditions remained unchanged, to obtain ethyl acetate of 2-(5-(phenylselenoyl)-1H-tetrazole-1-yl) 5-selenite, with the separation yields shown in Table 2.

[0083] Table 2: Effect of organic solvents on the yield of the target product

[0084]

[0085] Example 17:

[0086] Following the method of Example 1, by changing the constant current and reaction time while keeping other conditions unchanged, ethyl acetate 2-(5-(phenylselenoyl)-1H-tetrazole-1-yl) of 5-selenite was obtained, and the separation yields are shown in Table 3.

[0087] Table 3: Yields of target products under different currents and reaction times

[0088]

[0089] The above embodiments are merely preferred embodiments of the present invention, but the implementation of the present invention is not limited to the above embodiments. Any changes, modifications, substitutions, or combinations made without departing from the spirit and principle of the present invention, such as various combinations of solutions in the embodiments, should be considered equivalent replacements and are all within the protection scope of the present invention.

Claims

1. A method for synthesizing 5-selenotetrazole, characterized in that, include: The steps for synthesizing the target product by electrochemical reaction of diaryldiselene, isonitrile, and azidetrimethylsilane in an electrolyte solution: ； In the formula, R 1 It is any one of tert-butyl, tetramethylbutyl, cyclohexyl, ester, and benzyl groups; R 2 It is any group among phenyl and thiophene; The solvent in the electrolyte solution is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 5 to 10:

1. The electrochemical reaction uses a constant current, ranging from 3 mA to 20 mA.

2. The method as described in claim 1, characterized in that, The electrolyte in the electrolyte solution is tetrabutylammonium perchlorate or lithium perchlorate.

3. The method as described in claim 1, characterized in that, The solvent in the electrolyte solution is a 9:1 mixture of acetonitrile and hexafluoroisopropanol.

4. The method as described in claim 1, characterized in that, The electrochemical reaction uses a carbon rod as the anode and a platinum sheet as the cathode.

5. The method as described in claim 1, characterized in that, The electrochemical reaction uses a constant current of 10 mA to 15 mA.

6. The method as described in claim 1 or 5, characterized in that, The current is 10 milliamps.

7. The method as described in claim 1, characterized in that, The electrochemical reaction is carried out at 0~50℃.

8. The method as described in claim 1 or 7, characterized in that, The electrochemical reaction takes place at room temperature.

9. The method as described in claim 1, characterized in that, The electrochemical reaction time shall not be less than 4 hours.

10. The method as described in claim 1 or 9, characterized in that, The electrochemical reaction time is more than 6 hours.

11. The method as described in claim 1 or 9, characterized in that, The electrochemical reaction time is more than 10 hours.

12. The method as described in claim 1, characterized in that, The amount of electrolyte used is 0.2-1 times the molar amount of isonitrile used.

13. The method as described in claim 1 or 12, characterized in that, The amount of electrolyte used is 0.8 times the molar amount of isonitrile used.

14. The method as described in claim 1, characterized in that, The amount of azidotrimethylsilane used is 3-6 times the molar amount of the isonitrile.

15. The method as described in claim 1 or 14, characterized in that, The amount of azide-trimethylsilane used is 4 times the molar amount of the isonitrile.

16. The method as described in claim 1, characterized in that, The amount of diaryl diselenide used is 0.5 to 2 times the molar amount of the isonitrile.

17. The method as described in claim 1 or 16, characterized in that, The amount of diaryl diselenide used is 1.5 times the molar amount of the isonitrile.

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