Palladium-catalyzed N-Arylation of 1-substituted-1H-tetrazol-5-amines

A palladium-catalyzed N-arylation of 1-substituted-1H-tetrazol-5-amines has been described for the first time. The reaction provides good yields of desired products with broad substrate scope and good functional group tolerance. © 2018 Elsevier B.V. All rights reserved.

Palladium-catalyzed arylation of amines has emerged as powerful tool in organic synthesis and medicinal chemistry [16,17]. Of particular interest is palladium catalyzed arylation of primary amine derivatives of fiveand six-membered heterocyclic compounds, which have been challenging substrates [18,19]. As we have recently demonstrated, electrostatic map potential of 5aminotetrazoles shows that most of the electron density is located in the tetrazole ring while the amino group is in the blue region. This indicates that amino group is electron deficient and therefore less nucleophilic [20].

Results and discussion
In order to optimize the reaction condition, we began our study by choosing readily available 1-benzyl-1H-tetrazol-5-amine 1a and bromobenzene 2a as the model substrates with catalytic amount of Pd 2 (dba) 3 (10 mol % Pd with respect to 2a) as source of palladium and NaOt-Bu (1.2 equiv) as a base, in toluene at 105 C. An excess amount of the 5-aminotetrazole substrate was used in the reaction in order to prevent the formation of diarylated product. Using biaryl phosphane ligand JohnPhos (20 mol % with respect to 2a) the desired product 3a was obtained in 8% isolated yield after 24 h reaction time (   With the optimized reaction conditions in hand, we examined the substrate scope with respect to arylbromides. As shown in Table 2, a series of arylbromides, including those with electron-donating group (-OMe) and others with electronwithdrawing groups (-NO 2 , -CN, -CO 2 Me, -CHO, and -COCH 3 ) were transformed into the desired products in moderate to good yields ( Table 2, 3b-3g), providing a potential point for further functionalization of the coupling products. In the cases of substrates with sensitive functional groups, K 2 CO 3 was used as base ( Table 2, 3d-3g). In addition, with 1-bromo-4-chlorobenzene and 1-bromo-3chlorobenzene excellent selectivity was observed ( Table 2, 3h and 3i). Moreover, when sterically demanding 2-bromo-5-chlorotoluene was employed as substrate, the reaction provided the corresponding product 3j in good yield. The scope of this method was further investigated by utilizing heteroaryl bromides. The present method is also applicable to 3-bromopyridine and corresponding product 3l was obtained in 51% yield, while there was no reaction with 2bromothiophene (Tables 2, 3k). Notably, the reaction could be scaled up to 1 mmol scale, yielding 3a in 91% isolated yield.
The reaction conditions also proved applicable to the coupling reaction of 1-benzyl-1H-tetrazol-5-amine 1a with iodobenzene 4 and chlorobenzene 5, and to a lesser extent to the coupling reaction of 1a and phenyl trifluoromethanesulfonate 6 (Scheme 1).
Finally, as an expansion of this study, we explored the removal of benzyl group [21] in order to obtain N-phenyl-1H-tetrazol-5amine. Under hydrogen atmosphere (1atm), 3a was converted into 7a in almost quantitative yield, using Pd/C (5 mol % Pd) as a catalyst (Scheme 2).

Conclusions
In conclusion, we have successfully developed an efficient palladium-catalyzed N-arylation of 1-substituted-1H-tetrazol-5amines. The reaction exhibits broad substrate scope and good functional group compatibility. Considering the generality, this methodology could be of synthetic utility in the industry and drug discovery and development process.

General information
Unless stated otherwise, all solvents and reagents were obtained a Reactions were performed in a flame-dried closed reaction tube. Pd 2 (dba) 3 (10 mol % Pd), ligand (20 mol %) and base (1.2 equiv) were added to the reaction tube followed by the solvent. The mixture was stirred under an inert atmosphere at room temperature for 5 min, after which 2a (1.0 equiv) and 1a (1.2 equiv) were added. The tube was sealed and the mixture was heated at 105 C in an oil bath for the indicated reaction time. b Isolated yield.
from commercial sources and used without further purification. Dry-flash chromatography was performed on SiO 2 (0.018e0.032 mm). Melting points were determined on a Boetius PMHK apparatus and are not corrected. IR spectra were recorded on a Thermo-Scientific Nicolet 6700 FT-IR Diamond Crystal instrument. 1 H and 13 C NMR spectra were recorded on a Bruker Ultrashield Avance III spectrometer (at 500 and 125 MHz, respectively) using DMSO-d 6 (unless stated otherwise) as the solvent. Chemical shifts are expressed in parts per million (ppm) on the (d) scale. Chemical shifts were calibrated relative to those of the solvent. All new compounds were analyzed by high resolution tandem mass spectrometry using LTQ Orbitrap XL (Thermo Fisher Scientific Inc., USA) mass spectrometer. The sample was dissolved in MeCN and it was injected directly. Ionization was done in positive mode on heated electrospray ionization (HESI) probe. HESI parameters were: spray voltage 4.7 kV, vaporizer temperature 60 C, sheath and auxiliary gas flow 24 and 10 (arbitrary units), respectively, capillary voltage 49 V, capillary temperature 275 C, tube lens voltage 80 V, resolution (at m/z 400): 30000.

General procedure A for palladium catalyzed arylation of 1substituated-1H-tetrazol-5-amines
To a flame-dried reaction tube, Pd 2 (dba) 3 (11 mg, 0.012 mmol, 10 mol % Pd), t-BuXPhos (21 mg, 0.050 mmol, 20 mol %) and NaOt-Bu (42 mg, 0.300 mmol, 1.2 equiv) were added followed by 1,4dioxane (1 mL). The mixture was stirred at room temperature under an inert atmosphere for 5 min, after which the aryl-bromide (0.250 mmol, 1.0 equiv) and amine (0.300 mmol, 1.2 equiv) were added, the tube was sealed and the mixture was heated at 105 C in an oil bath for 24 h. The reaction mixture was cooled to room temperature and the mixture was diluted with EtOAc (30 mL). The mixture was washed with water (30 mL), brine (30 mL) and the organic solution was dried over anhydrous MgSO 4 . The mixture was filtered and the solvents were removed under the reduced pressure. The crude product was purified by dry-flash column chromatography on SiO 2 .

General procedure B for palladium catalyzed arylation of 1substituated-1H-tetrazol-5-amines
To a flame-dried reaction tube, Pd 2 (dba) 3 (11 mg, 0.012 mmol, 10 mol % Pd), t-BuXPhos (21 mg, 0.050 mmol, 20 mol %) and K 2 CO 3 (29 mg, 0.300 mmol, 1.2 equiv) were added followed by 1,4-dioxane (3.2 mL). The mixture was stirred at room temperature under an inert atmosphere for 5 min, after which the aryl-bromide (0.250 mmol, 1.0 equiv) and amine (0.300 mmol, 1.2 equiv) were added, the tube was sealed and the mixture was heated at 105 C in an oil bath for 24 h. The reaction mixture was cooled to room temperature and the mixture was diluted with EtOAc (30 mL). The mixture was washed with water (30 mL), brine (30 mL) and the organic solution was dried over anhydrous MgSO 4 . The mixture was filtered and the solvents were removed under the reduced pressure. The crude product was purified by dry-flash column chromatography on SiO 2 .
Following the general procedure A for palladium catalyzed arylation, compound 3t was obtained after dry-flash column chromatography (
Following the general procedure A for palladium catalyzed arylation, compound 3u was obtained after dry-flash column chromatography (SiO 2 : Hex/EtOAc ¼ 9/1) as a colorless solid
In a flame-dried flask, 3a (23 mg, 0.092 mmol) was dissolved in deoxygenated methanol (1 mL) and Pd/C (5 mg, 0.005 mmol, 5 mol % Pd) was added. The flask was closed with a rubber septum and the reaction mixture, connected to a balloon of hydrogen, was stirred at room temperature for 72 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (25 mL). The solvents were removed under the reduced pressure to afford the pure 7a as a colorless solid (

Notes
The authors declare no competing financial interest.