Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction

Abstract

A regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane is reported. A series of 2-aryltetrazoles were obtained in good to moderate yields with wide functional group compatibility. Furthermore, this cycloaddition reaction opens the way to build up the versatile intermediate 2-aryl-5-bromotetrazole.

Graphical abstract

Introduction

Tetrazoles are an important class of five-membered ring heterocycles broadly used in pharmaceuticals, agrochemicals and material science. Surprisingly, the synthesis of simple unsubstituted 2-aryltetrazoles is almost non-existent in the literature. Lippmann et al. has developed a regioselective method for the construction of 2-aryl tetrazoles employing 2-(2-arylhydrazono)acetic acid and 1-azido-2,4,6-tribromobenzene¹. Ito’s synthesis employs arylsulfonylhydrazones and arene diazonium salts but both of these strategies afford 2-aryl-5-carboxylatetetrazole and must be decarboxylated at 160 °C². Genin et al. and Kitazaki et al. reported a nucleophilic aromatic substitution between 4-nitrofluorobenzene or 3,4-difluoronitrobenzene and tetrazole but these non-regioselective transformations gave poor yields and require the nitro group for activation (10% to 25%)^3,4. Very recently, Ramanathan et al. reported a cyclisation between an aryldiazonium salt and formamidine in the presence of iodide⁵.

There are more examples of 2-aryl-5-substituted tetrazoles in the primary literature. This scaffold has recently acquired increasing attention from the medicinal chemistry community. For example, this substitution pattern has recently appeared in Breast Cancer Resistance Protein inhibitors⁶, DNA methyltransferases 1 inhibitors⁷, α₄β₂α₅ nicotinic acetylcholine receptors modulators⁸, FAAH inhibitors⁹ and MDR1 inhibitors¹⁰. In addition to Lippmann’s and Ito’s synthetic methods, Han and co-workers reported the synthesis of 2-aryl-5-substituted tetrazoles through the coupling of 5-substituted tetrazoles with arylboronic acids in the presence of copper(II)¹¹. Onaka et al. also reported a regioselective 2-arylation of 5-substituted tetrazoles catalyzed by [Cu(OH)(TMEDA)]₂Cl₂.¹²

We recently had the need for the synthesis of substituted N-linked tetrazoles with versatility for substitution at the 5-position (H or aryl) wherein none of the current published methods proved useful. Therefore we embarked upon a search for a facile and robust method to generate these molecules. Chen et al. recently reported a cycloaddition between an arene-diazonium salt and 2,2,2-trifluorodiazoethane with a catalytic amount of silver salt¹³. This method was attractive, however the tetrazole products formed were CF₃-substituted at the 5-position wherein we needed a hydrogen atom or aryl ring. We envisioned that a silver salt might also be utilized to promote the cyclization of an arenediazonium salt with trimethylsilyldiazomethane. This would provide for TMS-substituted tetrazoles, which could either be desilylated to produce the unsubstituted tetrazole or converted to the bromo-tetrazole for further functionalization (Figure 1). Herein, we report a [3+2] cycloaddition between an arenediazonium salt and trimethylsilyldiazomethane with a silver salt catalyst. This cycloaddition affords 2-aryl-5-trimethylsilyltetrazoles, a key intermediate which can be easily cleaved in one pot with CsF to provide 2-aryltetrazoles.

Figure 1.

Tetrazole Formation

Results and discussion

To optimize reaction conditions, phenyl diazonium tetrafluoroborate 1a was employed as a substrate using trimethylsilyldiazomethane with various silver salts and one copper salt (widely used in click chemistry) in THF at −78 °C (entries 1–7, Table 1). To our delight, CF₃CO₂Ag was found to be optimal, and the cycloaddition proceeded smoothly to furnish the desired cycloadduct 2a in 75% yield (entry 1).

Table 1.

Optimization of reaction conditions^a

Entry	Catalyst	Base (equiv)	Solvent	Yieldb (%)
1	CF3CO2Ag	Et3N(1.5)	THF	82 (75)
2	AgBF4	Et3N(1.5)	THF	70(61)
3	AgNO3	Et3N(1.5)	THF	69
4	AgOTf	Et3N(1.5)	THF	70 (62)
5	AgOAc	Et3N(1.5)	THF	42
6	Ag2CO3	Et3N(1.5)	THF	<10
7	Cu(OAc)2	Et3N(1.5)	THF	<10
8	CF3CO2Ag	Cs2CO3(1.5)	THF	36
9	CF3CO2Ag	Na2CO3(1.5)	THF	<10
10	CF3CO2Ag	Lutidine (1.5)	THF	<10
11	CF3CO2Ag	DBU(1.5)	THF	71
12	CF3CO2Ag	DABCO (2.0)	THF	49
13	CF3CO2Ag	Et3N (2.0)	THF	79
14	CF3CO2Ag	Et3N(2.5)	THF	74
15b	CF3CO2Ag	Et3N (3.0)	THF	77
16c	CF3CO2Ag	Et3N (3.0)	THF	79
17d	CF3CO2Ag	Et3N(1.5)	THF	<10
18e	CF3CO2Ag	Et3N(1.5)	THF	<10
19f	CF3CO2Ag	Et3N(1.5)	THF	23
20	CF3CO2Ag	Et3N(1.0)	THF	54
21	—	Et3N(1.5)	THF	<10
22	CF3CO2Ag	—	THF	<10
23	CF3CO2Ag	Et3N(1.5)	CH3CN	<10
24	CF3CO2Ag	Et3N(1.5)	DCM	<10
25	CF3CO2Ag	Et3N(1.5)	DMF	<10
26g	CF3CO2Ag	Et3N(1.5)	THF/DMF	23
27	CF3CO2Ag	Et3N(1.5)	Toluene	77 (69)

^aGeneral reaction conditions: 1a (0.2 mmol), Me₃SiCHN₂ (1.1eq), catalyst (1.2 eq), base (x equiv) in 2 mL of solvent under Ar at −78°C for 1 h. Yields were determined by HPLC with 3,5-Dimethoxybromobenzene as an internal standard. The values in parentheses represent the yields of isolated products.

^b2 eq CF₃CO₂Ag;

^c2 eq CF₃CO₂Ag and 1.5 eq Me₃ SiCHN₂;

^d10 mol% of CF₃CO₂ Ag was used;

^ereaction at 4°C;

^freaction at −20°C;

^gTHF/DMF = 10/1.

The use of 2 equivalents of CF₃CO₂Ag did not improve the yield (entries 15 and 16). In sharp contrast, the reaction did not proceed without the silver catalyst or with only 10 mol% of CF₃CO₂Ag (entries 17 and 21). The control of the temperature is a critical parameter: a mixture of uncharacterized by-products is obtained when the reaction is conducted at 4°C and poor yield was obtained at −20°C (entries 18 and 19). Note that 1-aryl-1H-Tetrazole has never been detected. Next, we turned our attention to testing a range of mineral and organic bases. Triethylamine was found to be the base of choice for this cycloaddition reaction (entries 8–12). The yield substantially decreased with only 1 equivalent of trimethylamine (entry 20) and no reaction was observed without any base (entry 21), but 2.0 equivalents of Et₃N did not improve the yield when compared to that obtained with 1.5 equivalent of Et₃N (entries 1 and 13). A solvent screen was conducted in order to explore this parameter further (entries 23–27). THF was identified as the optimal solvent from those screened.

Having established optimal conditions, we set out to explore the scope of this silver-mediated cycloaddition reaction, and the results are summarized in Scheme 1. In the case of phenyl diazonium salts, the cycloaddition reaction tolerates various substitution patterns and a range of different substituents on the phenyl ring. Alkyl-, alkoxy-, amino-, cyano-, nitro-, acid-, halo- and phenyl-substituted phenyldiazonium salts all undergo the desired reaction to give the cycloadducts 2a–l in moderate to good yields. It is worth noting that anilines bearing a free phenol group (2h) or carboxylic acid (2g) are tolerated as are electron poor (2c,2e–f,2m) or electron rich (2d,2h–i,k) aromatics. Note that in these reactions, only the 2-aryl tetrazole was formed and the 1-aryltetrazole was not observed.

Scheme 1.

Substrate scope of cycloaddition reaction of TMSCHN₂ with aryl diazonium salts

To be synthetically useful, this new method also needed to scale well. Hence we conducted this reaction sequence on a 1g scale. As shown in Scheme 2, the diazotation step from the commercial aniline afforded 1k in 91% yield which does not require purification. Intermediate 1k reacted with TMSCHN₂ to give the corresponding 2-substituted tetrazole 2k with a 67% yield in two steps.

Scheme 2.

Gram scale reaction

Finally, we turned our attention to the key intermediate 2-aryl-5-trimethylsilyl tetrazole (3k, Scheme 3). This reaction could be carried out without the addition of CsF and, under these conditions, we were able to isolate the trimethylsilyl derivate 3k in good yield. With this compound in hand, we demonstrated the versatile properties by substitution of the trimethylsilyl group with a bromine on the 5-position to afford 4k. From this compound, introduction of many other groups and functionalities are possible via metal-mediated coupling reactions. This route offers an approach for rapid structure-activity relationship studies (SAR) of the 5-position of the tetrazole ring. This strategy complements that of Ramanathan et al. and offers a new synthetic method for the synthesis of functionalized tetrazoles.

Scheme 3.

Access to the 2-aryl-5-bromo-tetrazole

Conclusions

In summary, we have successfully disclosed a quick and general method to synthesize 2-aryltetrazoles by a [3+2] regioseletive cycloaddition reaction of trimethylsilyldiazomethane with various aryl and heteroaryl diazonium salts. A broad range of 2-substituted tetrazoles were obtained in moderate to good yields. The practicality of this methodology was further demonstrated by the facile synthesis of a gram scale sequence. We believe this motif has the potential for use in drug discovery programs as a valuable synthetic building block, which is now readily available via this methodology.

Research highlights.

• ►Regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane.
• ►Best catalyst to perform this reaction was silver trifluoroacetate.
• ►A large set of diazonium salt was used under optimized conditions.
• ►Gram scale have been successfully accomplished