Process for the electro-synthesis of alpha-aminomethyltetrazoles

Abstract

This invention discloses a α The electrosynthesis method of α-aminomethyltetrazole includes: using a platinum sheet as the cathode and a carbon rod as the anode, and employing ammonium tetrabutyltetrafluoroborate as the electrolyte under constant current catalysis, a one-pot coupling of a tertiary amine, an isonitrile, and azide trimethylsilane to prepare the α-aminomethyltetrazole. α The step involving the aminomethyltetrazole derivative, followed by post-treatment and column chromatography separation of the resulting reaction mixture, yields... α - Pure aminomethyltetrazole. This invention yields it through a single reaction step. α -Aminomethyltetrazole has fewer operating steps, avoids the use of large amounts of oxidants and additives, simplifies post-processing, and makes the product 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 α-aminomethyltetrazole. Background Technology

[0002] α-Aminomethyltetrazole derivatives are a class of organic synthetic intermediates with diverse biological activities and wide applications in chemistry, materials science, and drug design. To date, the classic Ugi-azide reaction has provided strong support for the synthesis of α-aminomethyltetrazole derivatives, in which primary or secondary amines, aldehydes or ketones, isonitriles, and azides are the four starting components. However, tertiary amines remain unsuitable for this reaction due to their structural limitations, as the key intermediate imino ion depends on the condensation reaction of primary or secondary amines with aldehydes or ketones. Therefore, the preparation of α-aminomethyltetrazole derivatives from tertiary amines is essential.

[0003] In addition, synthetic methods for preparing α-aminomethyltetrazole derivatives from tertiary amines have been reported. However, these methods use different substrates and follow different routes, which can be selected according to needs when designing different synthetic strategies. However, some routes often suffer from problems such as long reaction times, the use of additives and external oxidants, and low yields. Finding green and efficient alternative methods is an important research topic. Among these, electrochemical organic synthesis is currently an important method in green alternative technologies. Summary of the Invention

[0004] The purpose of this invention is to provide a simple, green, and efficient method for preparing α-aminomethyltetrazole from tertiary amines, isonitriles, 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 α-aminomethyltetrazole, comprising the step of synthesizing the target product by electrochemically reacting a tertiary amine, an isonitrile, and azide-trimethylsilane in an electrolyte solution.

[0007] Its general reaction formula is as follows:

[0008]

[0009] In the formula, R 1 Including but not limited to any group selected from methyl, tert-butyl, methoxy, phenyl, halogen, and trifluoromethyl; R 2 Including but not limited to any of the following groups: alkyl, benzyl, and aryl.

[0010] Furthermore, the electrolyte in the electrolyte solution is tetrabutylammonium tetrafluoroborate, and the solvent is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 5 to 10:1, preferably 7:1.

[0011] 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 a constant current of 10 mA.

[0012] Furthermore, the electrochemical reaction is carried out at 0–40°C, preferably at room temperature.

[0013] Furthermore, the electrochemical reaction time is not less than 2 hours.

[0014] Furthermore, the amount of electrolyte used is 0.2-1 times the molar ratio of the amount of tertiary amine used, preferably 1 times.

[0015] Furthermore, the amount of azide-trimethylsilane used is 1-3 times the molar ratio of the amount of tertiary amine used, preferably 1 times.

[0016] Furthermore, the amount of isonitrile used is 0.5-1 times the molar ratio of the tertiary amine used, preferably 0.5 times. Compared with the prior art, the present invention has the following significant advantages:

[0017] (1) The synthesis method of the present invention is simple and efficient. α-aminomethyltetrazole can be obtained in just one reaction step. There are few operation steps, avoiding the use of a large amount of oxidants and additives. The post-processing is simple and the product is easy to separate, which greatly simplifies the operation requirements.

[0018] (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.

[0019] (3) The tertiary amine used in this invention exhibits excellent reactivity under electrochemical conditions, which couples azide trimethylsilane, tertiary amine, and isonitrile to α-aminomethyltetrazole. In contrast, exogenous oxidants, iodine reagents, metal catalysts, etc., are difficult to achieve efficient and short-time conversion. Attached Figure Description

[0020] Figure 1 This is the 1H NMR spectrum of ethyl 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazole-1-yl)acetate prepared in Example 2 of this invention.

[0021] Figure 2 This is the carbon NMR spectrum of ethyl 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazole-1-yl)acetate prepared in Example 2 of this invention.

[0022] Figure 3 This is the high-resolution mass spectrum of ethyl acetate 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazole-1-yl)prepared in Example 2 of this invention.

[0023] Figure 4 This is the 1H NMR spectrum of N-((1-benzyl-1H-tetrazole-5-yl)methyl)-N-methylaniline prepared in Example 5 of this invention.

[0024] Figure 5 This is the carbon NMR spectrum of N-((1-benzyl-1H-tetrazole-5-yl)methyl)-N-methylaniline prepared in Example 5 of this invention.

[0025] Figure 6 This is a high-resolution mass spectrum of N-((1-benzyl-1H-tetrazole-5-yl)methyl)-N-methylaniline prepared in Example 5 of this invention. Detailed Implementation

[0026] The present application will be further described below with reference to specific embodiments.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] The method for preparing α-aminomethyltetrazole according to the present invention includes the following steps:

[0034] (1) In a dry three-necked flask, under constant current, acetonitrile and hexafluoroisopropanol were used as a mixed solvent, tetrabutylammonium tetrafluoroborate as the electrolyte, a carbon rod as the anode, and a platinum sheet as the cathode. (2) A tertiary amine, isonitrile, 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 α-aminomethyltetrazole.

[0035] Example 1:

[0036] In the presence of graphite rod anode ( A magnetic flux and 0.2 mmol of tetrabutylammonium tetrafluoroborate were added to a dry three-necked flask (20 mL) with a 90 mm diameter cathode and a platinum cathode (10 mm × 10 mm × 0.2 mm). Acetonitrile (7 mL), hexafluoroisopropanol (1 mL), azidotrimethylsilane (2 equivalents), N,N-dimethylaniline (0.4 mmol, 2 equivalents), and ethyl isonitrile (1 equivalent) were then injected separately into the flask using a syringe. The reaction mixture was stirred and electrolyzed at a constant current of 10 mA for 2.5 h (4.7 F / mol) at room temperature. 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 3:1 mixture of petroleum ether and ethyl acetate as eluent, yielding 86% of the product.

[0037] 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazole-1-yl)ethyl acetate. 1H NMR (500MHz, CDCl3) δ7.18(t,J=7.6Hz,2H),6.80(t,J=7.3Hz,1H),6.73(d,J=8.4Hz,2H ),5.02(s,2H),4.71(s,2H),4.07(q,J=6.8Hz,2H),2.80(s,3H),1.13(t,J=7.1Hz,3H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ165.4,153.5,148.8,129.5,119.9,114.6,62.6,48.6,47.8,39.9,13.9.

[0038] Example 2:

[0039] Following the method in Example 1, 4-tert-butyl-N,N-dimethylaniline was used instead of N,N-dimethylaniline, with other conditions remaining unchanged, to obtain the α-aminomethyltetrazole product, with a separation yield of 92%. Nuclear magnetic resonance and high-resolution mass spectrometry characterization are shown in [reference needed]. Figure 1 and Figure 2 .

[0040] 2-(5-((((4-(tert-butyl)phenyl)(methyl)amino)methyl)-1H-tetrazole-1-yl)ethyl acetate. 1 H NMR(500MHz, CDCl3) δ7.31(d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),5.15(s,2H),4. 78(s,2H),4.15(q,J=7.1Hz,2H),2.88(s,3H),1.31(s,9H),1.22(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ165.4,153.5,146.5,142.6,126.1,114.4,62.3,48.5,47.9,40.0,33.7,31.2,13.8.HRMS(ESI):calcd for C 17 H 25 N5O2Na[M+Na] + :354.1906; Found:354.1908.

[0041] Example 3:

[0042] Following the method in Example 1, 4-methyl-N,N-dimethylaniline was used instead of N,N-dimethylaniline, with other conditions remaining unchanged, to obtain the α-aminomethyltetrazole product, with a separation yield of 90%.

[0043] 2-(5-((methyl(p-tolyl)amino)methyl)-1H-tetrazole-1-yl)ethyl acetate. 1 H NMR(500MHz, CDCl3) δ7.04(d,J=8.5Hz,2H),6.71(d,J=8.5Hz,2H),5.09(s,2H),4. 70(s,2H),4.14(q,J=7.1Hz,2H),2.81(s,3H),2.24(s,3H),1.20(t,J=7.2Hz,3H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ165.4,153.5,146.7,129.9,129.5,115.1,62.4,48.6,48.1,40.3,20.2,13.8.

[0044] Example 4:

[0045] Following the method in Example 1, tert-butylisocyanate was used instead of ethyl isonitrile, with other conditions remaining unchanged, to obtain the α-aminomethyltetrazole product with a separation yield of 87%.

[0046] N-((1-(tert-butyl)-1H-tetrazole-5-yl)methyl)-N-methylaniline. 1 HNMR (500MHz, CDCl3) δ7.19 (t, J = 8.0 Hz, 2H), 6.79–6.76 (m, 3H), 4.69 (s, 2H), 2.85 (s, 3H), 1.67 (s, 9H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ151.8,149.4,129.3,119.2,114.6,61.4,47.7,39.3,29.4.

[0047] Example 5:

[0048] Following the method in Example 1, benzylisocyanate was used instead of ethyl isonitrile, with other conditions remaining unchanged, to obtain the α-aminomethyltetrazole product, with a separation yield of 81%. Nuclear magnetic resonance and high-resolution mass spectrometry characterization are shown below. Figure 3 and Figure 4 .

[0049] N-((1-benzyl-1H-tetrazole-5-yl)methyl)-N-methylaniline. 1H NMR (500MHz, CDCl3) δ7.25(d,J=5.6Hz,3H),7.17(t,J=8.0Hz,2H),6.98(d,J=7.7Hz,2H ),6.79(t,J=7.3Hz,1H),6.68(d,J=8.4Hz,2H),5.46(s,2H),4.52(s,2H),2.68(s,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ152.5,149.0,133.3,129.4,129.0,128.7,127.2,119.6,114.7,51.1,46.7,39.4.HRMS(ESI):calcd for C 16 H 17 N5Na[M+Na] + :302.1382;Found:302.1385。

[0050] Example 6:

[0051] Following the method in Example 1, other electrolytes were used instead of ammonium tetra-n-butyltetrafluoroborate, and other conditions remained unchanged, to obtain ethyl acetate of 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazole-1-yl) α-aminomethyltetrazole product. The separation yields are shown in Table 1.

[0052] Table 1: Effect of electrolyte type on the yield of target product

[0053]

[0054]

[0055] Example 7:

[0056] Following the method in Example 1, other solvents were used instead of acetonitrile, while other conditions remained unchanged, to obtain ethyl acetate of 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazole-1-yl) α-aminomethyltetrazole product. The separation yields are shown in Table 2.

[0057] Table 2: Effect of organic solvents on the yield of the target product

[0058]

[0059] Example 8:

[0060] Following the method in Example 1, by changing the constant current and reaction time while keeping other conditions unchanged, 2-(5-((methyl(phenyl)amino)methyl)-1H-tetrazole-1-yl)ethyl acetate, the α-aminomethyltetrazole product was obtained. The separation yields are shown in Table 3.

[0061] Table 3: Yields of target products under different currents and reaction times

[0062]

[0063] 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 preparing α-aminomethyltetrazole, characterized in that, include: The step of synthesizing the target product by electrochemical reaction of a tertiary amine, an isonitrile, and azide-trimethylsilane in an electrolyte solution. Its general reaction formula is as follows: ； In the formula, R 1 Selected from any group of methyl, tert-butyl, methoxy, phenyl, halogen, or trifluoromethyl; R 2 Selected from any group of alkyl, benzyl, or aryl groups; The electrolyte in the electrolyte solution is tetrabutylammonium tetrafluoroborate, and the solvent is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 5~10:

1. The current is a constant current of 3 mA to 20 mA.

2. The method as described in claim 1, characterized in that, The solvent is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 7:

1.

3. 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, with a constant current of 10 mA.

4. The method as described in claim 1, characterized in that, The electrochemical reaction is carried out at 0~40℃.

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

6. The method as described in claim 1, characterized in that, The electrochemical reaction time shall not be less than 2 hours.

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

8. The method as described in claim 1, characterized in that, The amount of electrolyte used is 1 times the molar amount of the tertiary amine.

9. The method as described in claim 1, characterized in that, The amount of azidotrimethylsilane used is 1-3 times the molar amount of the tertiary amine.

10. The method as described in claim 1, characterized in that, The amount of azidotrimethylsilane used is 1 times the molar amount of the tertiary amine.

11. The method as described in claim 1, characterized in that, The amount of isonitrile used is 0.5-1 times the molar amount of the tertiary amine.

12. The method as described in claim 1, characterized in that, The amount of isonitrile used is 0.5 times the molar amount of the tertiary amine.

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