Highly N²-Selective Palladium-Catalyzed Arylation of 1,2,3-Triazoles

Abstract

Highly N²-selective arylation of 4,5-unsubstituted and 4-substituted 1,2,3-triazoles was achieved for the first time by Pd/L1 catalyst system. A wide range of N²-aryl-1,2,3-triazoles were prepared from aryl bromides, chlorides and triflates with excellent (95–99%) N²-selectivity. DFT calculations suggest that formation of N²-arylated 1,2,3-triazoles is favored kinetically.

N-Substituted-1,2,3-triazoles have found widespread applications in material science and medicinal chemistry.^[1–2] Due to the importance of this structural motif, many practical synthetic methods have been developed. Among them, the Huisgen azide-alkyne dipolar cycloaddition (AAC) is perhaps the most commonly utilized method for the synthesis of N¹-substituted 1,2,3-triazoles.^[3] In particular, recent developments in Cu-^[4] and Ru-catalyzed^[5] AAC reactions have provided a general and regioselective access to 1,4- and 1,5-substituted 1,2,3-triazoles, respectively. On the other hand, regioselective synthesis of N²-substituted 1,2,3-triazoles remains a challenging issue. A particulary interesting subset of these compounds are N²-aryl-1,2,3-triazoles, which are found in biologically active compounds including an orexin receptor antagonist (MK4305), ^[2a–b] JAK kinase inhibitors^[2c] and 2,3-oxidosqualene cyclase inhibitors.^[2d] Ideally, the most direct route to N²-aryl-1,2,3-triazoles involves N-arylation of 1,2,3-triazoles.^{[2a–c, 6–7]} However, S_NAr and Cu-catalyzed arylation reactions of simple 1,2,3-triazoles generally give mixtures of regioisomers with poor to moderate N²-selectivity.^[8] Recently, Shi^[9] and Wang^[10] reported the highly N²-selective S_NAr and Cu-catalyzed arylation reactions using 4,5-disubstituted 1,2,3-triazoles, where C⁴- and C⁵-substituents prevent substitution on the N¹- and N³-position by steric hindrance.^[11] Despite these advances, a highly (>90%) N²-selective arylation method of 4-substituted and 4,5-unsubstituted 1,2,3-triazoles is still lacking. Herein, we report that exceptional levels of N²-selectivity can be obtained in the Pd-catalyzed N-arylation of simple 1,2,3-triazoles by the use of a very bulky biaryl phosphine ligand L1. This method enabled the first highly N²-selective arylation of 4-substituted and 4,5-unsubstituted 1,2,3-triazoles with aryl bromides, chlorides and triflates.

We initiated our study by examining the N-arylation of 1,2,3-triazole with bromobenzene in the presence of Pd₂(dba)₃ (0.75 mol%) with series of biaryl phosphine ligand L1–L4 (1.8 mol%), (Table 1). Gratifyingly, the Pd-catalyzed reaction of 1,2,3-triazole using L1 furnished N²-arylated product in 90% yield with excellent N²-selectivity (N²:N¹ = 97:3) (entry 1).^[12] To the best of our knowledge, this is the first Pd-catalyzed and highly N²-selective arylation of 4,5-unsubstituted 1,2,3-triazole. It was important to pre-heat a solution of Pd₂(dba)₃ and L1 before they were exposed to 1,2,3-triazole, bromobenzene and K₃PO₄. The reaction was significantly less efficient without catalyst pre-heating (entry 2), presumably due to inhibitory effect of 1,2,3-triazole on the in situ formation of catalytically active Pd(0)-ligand complex. The use of less sterically hindered biaryl phosphines L2–L4 provided, at best, 16% yield of N-arylated product (entries 3–5). This suggests that the nature of the both upper-ring substituents and lower-ring isopropyl groups of L1 are crucial to the present catalyst system.

Table 1.

Ligand effects on the Pd-catalyzed N-arylation of 1,2,3-triazole ^[a]

entry	ligand	GC conv. (%)	GC yield of N2- arylated product (%)	N2:N1 [b]
1	L1	100	93 (90)c	97:3
2[d]	L1	9	7	N.D. [e]
3	L2	<5	<5	N.D.
4	L3	20	16	96:4
5	L4	<5	<5	N.D.

^[a]Conditions: bromobenzene (1 mmol), 1,2,3-triazole (1.2 mmol), K₃PO₄ (2 mmol), Pd₂(dba)₃ (0.75 mol%), ligand (1.8 mol%), toluene (1 mL), 120 °C, 5 h. Pd₂(dba)₃ and ligand were premixed in toluene (0.5 mL) at 120 °C for 3 min.

^[b]N²-N¹ ratio was determined by GC.

^[c]Isolated yield.

^[d]Reaction was performed without premixing Pd₂(dba)₃ and L1.

^[e]Not determined.

The substrate scope of the N-arylation of 1,2,3-triazole is shown in Scheme 1. A variety of aryl bromides, chlorides and triflates with ester, ketone, aldehyde, acetal, nitro and cyano groups could be employed in the N-arylation reactions. While slightly decreased N²-selectivity was observed for the reactions of aryl chlorides with para-electron withdrawing groups (entries 9 and 10), excellent N²-selectivity (>95% N²-selective) was observed in all other substrates examined. The yield was diminished when the aryl halide bearing an ortho-substituent was employed (46% yield, entry 11) probably due to unfavorable steric interaction between the bulky ligand and the ortho-substituent (entry 11). Lower (0.3–0.7 mol%) Pd loadings could be employed for the electron deficient aryl halides and triflate (entries 3–4, 9–10 and 13).

Scheme 1.

Substrate scope of N²-selective arylation of 4,5-unsubstituted 1,2,3-triazole; Ar-X (1 mmol), 1,2,3-triazole (1.2 mmol), K₃PO₄ (2 mmol), Pd₂(dba)₃ (0.25–0.75 mol%), L1 (0.5–1.8 mol%), toluene (1 mL), 120 °C, 5 h. Yields are isolated yield of N²-arylated product (average of two runs). ^[a] Determined by GC analysis.

To expand the generality of this process, we examined the N-arylation of 4-substituted 1,2,3-triazoles (Scheme 2). The N-arylation of 4-phenyl-1,2,3-triazole with bromobenzene gave excellent N²/N¹ selectivity; the N³-arylated product was not detected by GC-MS or ¹H NMR analysis of the crude reaction mixture (entry 1). Similarly, N-arylation of other 4-aryl-substituted 1,2,3-triazoles gave products with 98% N²-selectivity (entries 2–3). These N²-selectivity are higher than selectivity reported for Cu-catalyzed N-arylation (N²:N¹=4:1) and S_NAr reaction (N²:N¹=1.6:1) of 4-aryl-1,2,3-triazoles.^7a Reactions of primary alkyl, functionalized primary alkyl and secondary alkyl substituted 1,2,3-triazole also showed excellent N²-selectivities (entries 4–7, 98–99% N²-selective).

Scheme 2.

Substrate scope of N²-selective arylation of 4-substituted 1,2,3-triazoles; Ar-X (1 mmol), 4-substituted 1,2,3-triazole (1.2 mmol), K₃PO₄ (2 mmol), Pd₂(dba)₃ (0.5–0.75 mol%), L1 (1.0–1.8 mol%), toluene (1 mL), 120 °C, 5 h. Yields are isolated yield of N²-arylated product (average of two runs). ^[a] Determined by GC analysis.

While excellent N²-selectivity was observed for the reactions of 4,5-unsbstituted and 4-substituted 1,2,3-triazoles, we obtained near 1:1 mixture of N¹- and N²-aryl isomers for the reaction of benzotriazole with bromobenzene (Scheme 3).

Scheme 3.

Pd-catalyzed N-arylation of benzotriazole

In order to gain insight into the origin of regioselectivity, we performed DFT calculation of the presumed intermediates. For the N-arylations of benzotriazole and 1,2,3-triazole with bromobenzene, transmetallation of the triazolate to the L1Pd(Ph)(Br) complex could provide tautomeric species A/A' and B/B' respectively.^[13–14] The relative energies of the key intermediates and the transition states (TSs) are shown in Figure 1. In the benzotriazole case, a small energetic preference (ΔG = 1.6 kcal/mol) for the N²-benzotriazolate complex A over the N¹-benzotriazolate A' was observed. Comparison of the two isomeric transition states for the reductive elimination from the benzotriazolate complexes A and A' showed only an insignificant energetic preference exist between the A-TS and A'-TS (ΔΔG^‡ = 0.1 kcal/mol). The poor regioselectivity (N²:N¹=47:53) observed for the benzotriazole system can be explained by the close relative energies of the A-TS and A'-TS. In the 1,2,3-triazole system, the transition states for the reductive elimination (B-TS and B'-TS) are significantly different (ΔΔG^‡ = 3.3 kcal/mol) in favor of the transition state leading to the N²-arylated product, which is in agreement with the observed regioselectivity.

Figure 1.

Energy diagrams for the reductive elimination of benzotriazolate-Pd and 1,2,3-triazolate-Pd complexes

In summary, we have established a highly N²-selective Pd-catalyzed arylation of 4,5-unsubstituted and 4-substituted 1,2,3-triazoles with aryl bromides, chlorides and triflates. Theoretical calculations suggested that highly N²-selective arylation of 1,2,3-triazoles is due to rapid reductive elimination from N²-1,2,3-triazolate-Pd complex B. Together with the well established Cu- and Ru-catalyzed AAC, present Pd-catalyzed system allows straightforward and regioselective preparation of N-aryl-1,2,3-triazoles.

Experimental Section

General procedure: An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ and L1. The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of 3 times). Toluene (0.5 mL) was added to the vial via syringe. The resulting dark purple mixture was stirred at 120 °C for 3 min, at this point the color of the mixture turned to dark brown. A second oven-dried vial, which was equipped with a stir bar, was charged with K₃PO₄ (424 mg, 2.0 mmol) (aryl halides and 1,2,3-triazoles that were solid at room temperature were added at this point). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of 3 times) and then 1,2,3-triazole (1.2 mmol) and aryl halide (1.0 mmol) were added via syringe and the premixed catalyst solution and toluene (0.5 mL) was added by syringe to the second vial (total 1.0 mL toluene). The reaction mixture was heated at 120 °C for 5 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄, concentrated in vacuo and purified via flash chromatography to give pure products.