C4-Alkylamination of C4-Halo-1H-1-tritylpyrazoles Using Pd(dba)2 or CuI

Alkylamino coupling reactions at the C4 positions of 4-halo-1H-1-tritylpyrazoles were investigated using palladium or copper catalysts. The Pd(dba)2 catalyzed C-N coupling reaction of aryl- or alkylamines, lacking a β-hydrogen atom, proceeded smoothly using tBuDavePhos as a ligand. As a substrate, 4-Bromo-1-tritylpyrazole was more effective than 4-iodo or chloro-1-tritylpyrazoles. Meanwhile, the CuI mediated C-N coupling reactions of 4-iodo-1H-1-tritylpyrazole were effective for alkylamines possessing a β-hydrogen atom.


Introduction
Synthetic methodologies towards a range of substituted pyrazoles have been developed, as they commonly exhibit bioactivities such as antitumor, antiviral, and antifungal activities. Furthermore, the synthetic study of pyrazoles provides diverse building blocks for the discovery of new drugs, biological probes, herbicides, and other new useful materials [1][2][3]. Therefore, introduction of various functional groups at specific positions on a pyrazole ring is an important and attractive endeavor in synthetic organic chemistry. In particular, the synthesis of C4-aminated pyrazoles has become a prominent research topic, due to the important bioactivities exhibited by this compound class, as shown in Figure 1.
The well-known and widely utilized Buchwald-Hartwig coupling reaction is one of the most powerful methods for the amination of aromatic rings. Moreover, the applicability and efficiency of the reaction are continually being improved with the design and development of efficient palladium catalysts, precatalysts, and bulky ligands. Numerous combinations of catalysts and ligands exist that are suitable for specific coupling reactions [11][12][13][14][15][16][17][18].
In spite of such developments, there have been only a few reports of Buchwald-Hartwig coupling at the C4 position of pyrazoles. In 2011, the first example involving the C4 coupling of pyrazoles with aromatic amines was reported by Buchwald, as shown in Scheme 1, Equation (1) [19]. In the following year, the same group described the amidation of five-membered heterocycles with aromatic amides, wherein three examples using 1-benzyl-4-bromopyrazoles and one example using 4-bromo-1-methylpyrazole were reported (Equation (2)) [20]. In their subsequent study on the amination of unprotected five-membered bromoheterocycles, Pd-catalyzed coupling reactions of 4-bromopyrazole with eleven aromatic amines, as well as one benzylic amine, were disclosed (Equation (3)) [21]. Recently, Buchwald et al. described visible-light-mediated amination of aryl halides in the presence of nickel and photoredox catalysts, for which one example of the reaction between 1-benzyl-4-bromopyrazole and pyrrolidine was included (Equation (4)) [22].
Molecules 2020, 25, x FOR PEER REVIEW 2 of 12 catalysts, precatalysts, and bulky ligands. Numerous combinations of catalysts and ligands exist that are suitable for specific coupling reactions [11][12][13][14][15][16][17][18]. In spite of such developments, there have been only a few reports of Buchwald-Hartwig coupling at the C4 position of pyrazoles. In 2011, the first example involving the C4 coupling of pyrazoles with aromatic amines was reported by Buchwald, as shown in Scheme 1, Equation (1) [19]. In the following year, the same group described the amidation of five-membered heterocycles with aromatic amides, wherein three examples using 1-benzyl-4-bromopyrazoles and one example using 4-bromo-1-methylpyrazole were reported (Equation (2)) [20]. In their subsequent study on the amination of unprotected five-membered bromoheterocycles, Pd-catalyzed coupling reactions of 4bromopyrazole with eleven aromatic amines, as well as one benzylic amine, were disclosed (Equation (3)) [21]. Recently, Buchwald et al. described visible-light-mediated amination of aryl halides in the presence of nickel and photoredox catalysts, for which one example of the reaction between 1-benzyl-4-bromopyrazole and pyrrolidine was included (Equation (4)) [22].
In the course of our continuing studies on the functionalization at the C4 position of pyrazoles, we recently reported the synthesis of pyrazole-containing heterobicyclic molecules via ring-closing metathesis [23,24]. Our engagement in pyrazole chemistry has been focused on metal-catalyzed coupling reactions, such as Kumada-Tamao, Suzuki-Miyaura, and Sonogashira couplings, and the Heck-Mizoroki reaction [25][26][27][28]; while the Buchwald-Hartwig coupling reaction for the C4 amination In the course of our continuing studies on the functionalization at the C4 position of pyrazoles, we recently reported the synthesis of pyrazole-containing heterobicyclic molecules via ring-closing metathesis [23,24]. Our engagement in pyrazole chemistry has been focused on metal-catalyzed coupling reactions, such as Kumada-Tamao, Suzuki-Miyaura, and Sonogashira couplings, and the Heck-Mizoroki reaction [25][26][27][28]; while the Buchwald-Hartwig coupling reaction for the C4 amination of pyrazoles has remained unchallenged. Encouraged by the above-mentioned successful results, our interest has shifted to Buchwald coupling between 4-halo-1H-1-tritylpyrazoles and alkyl amines, which has not been investigated in detail, with readily accessible palladium or copper catalysts, such as bis(benzylideneacetone) palladium(0) (Pd(dba) 2 ), or copper (I) iodide (CuI). Herein, we report C4-alkylamino coupling reactions using Pd(dba) 2 or CuI with 4-halo-1H-1-tritylpyrazoles.
For this purpose, the reaction of allylamine with 4-iodopyrazole 1 I (X = I), which could be got easier than 4-bromopyrazole, was investigated, as presented in Table 3. First, the reaction was performed using the conditions similar to those used in Buchwald's procedure [32]: CuI (5 mol%), 2-isobutyrylcyclohexanone (L5: 20 mol%) as the ligand, N,N-dimethylformamide (DMF), 100 • C, 24 h, and t-BuOK (2 eq). Although the desired 4-allylaminopyrazole 2d was obtained in only 17% yield (entry 1), increasing the amount of CuI from 5 to 20 mol% improved the chemical yield of 2d to 72% (entry 2). The use of 2-acetylcyclohexanone (L6) as an alternative ligand, which is nearly 10-fold cheaper than L5, afforded a good yield (68%, entry 3), while the use of 3,4,7,8-tetramethyl-1,10-phenanthroline (L7) resulted in a poor yield (12%, entry 4). Hence, L6 was applied in the following experiments (entries 5-15 in Table 3). The reaction temperature was varied in entries 5-7, however 100 • C proved optimal (entry 3). Furthermore, various copper catalysts were investigated in entries 9-13, and it was found that the use of the high-cost (CuOTf) 2 ·C 6 H 6 catalyst (entry 13) furnished a comparable yield (70%) to that of CuI (72%) (entry 2). In addition, while the use of 4-bromopyrazole 1 (X = Br) provided 2i in 66% yield (entry 14), chloropyrazole 1 Cl (X = Cl) did not react (entry 15).  Therefore, to evaluate the scope of this transformation, additional coupling reactions between iodopyrazole 1I and various amines were performed, by applying the optimized reaction conditions (entry 3 of Table 3), as shown in Table 4. It should be noted that there were a number of distinct contrasts between the outcomes of the CuI-catalyzed ( Table 4) and those of the Pd-catalyzed coupling reactions (Table 2). In the case of CuI coupling, reactions of 1i with piperidine and morpholine afforded 2a and 2b (21% and 22%, respectively) in lower yields (Table 4, entries 1 and 2) than those obtained (60% and 67%, respectively) in the corresponding Pd-catalyzed reaction of 1Br (entries 1 and 2 in Table 2). The CuI catalyst provided the pyrrolidine derivative 2c in 43% yield (Table 4, entry 3), while the Pd catalyst yielded 2c in only 7% yield (Table 2, entry 3). CuI-catalyzed reactions with primary alkylamines gave moderate to good yields of products 2d-2l (entries 4-12), while reactions with adamantyl, tert-butyl, and aromatic amines did not afford the desired products (entries [13][14][15][16][17], and only aniline furnished a low yield of 2o (15%) (entry 15); these trends were reversed in the case of Pd-catalyzed processes. These negative results may be ascribed to the increase in bulkiness as well as a decrease in the basicity of the amine sources.  Therefore, to evaluate the scope of this transformation, additional coupling reactions between iodopyrazole 1I and various amines were performed, by applying the optimized reaction conditions (entry 3 of Table 3), as shown in Table 4. It should be noted that there were a number of distinct contrasts between the outcomes of the CuI-catalyzed ( Table 4) and those of the Pd-catalyzed coupling reactions (Table 2). In the case of CuI coupling, reactions of 1i with piperidine and morpholine afforded 2a and 2b (21% and 22%, respectively) in lower yields (Table 4, entries 1 and 2) than those obtained (60% and 67%, respectively) in the corresponding Pd-catalyzed reaction of 1Br (entries 1 and 2 in Table 2). The CuI catalyst provided the pyrrolidine derivative 2c in 43% yield (Table 4, entry 3), while the Pd catalyst yielded 2c in only 7% yield ( Table 2, entry 3). CuI-catalyzed reactions with primary alkylamines gave moderate to good yields of products 2d-2l (entries 4-12), while reactions with adamantyl, tert-butyl, and aromatic amines did not afford the desired products (entries 13-17), and only aniline furnished a low yield of 2o (15%) (entry 15); these trends were reversed in the case of Pd-catalyzed processes. These negative results may be ascribed to the increase in bulkiness as well as a decrease in the basicity of the amine sources. Table 4. CuI-catalyzed coupling of 1I with various amines.
Therefore, to evaluate the scope of this transformation, additional coupling reactions between iodopyrazole 1 I and various amines were performed, by applying the optimized reaction conditions (entry 3 of Table 3), as shown in Table 4. It should be noted that there were a number of distinct contrasts between the outcomes of the CuI-catalyzed ( Table 4) and those of the Pd-catalyzed coupling reactions (Table 2). In the case of CuI coupling, reactions of 1i with piperidine and morpholine afforded 2a and 2b (21% and 22%, respectively) in lower yields (Table 4, entries 1 and 2) than those obtained (60% and 67%, respectively) in the corresponding Pd-catalyzed reaction of 1 Br (entries 1 and 2 in Table 2). The CuI catalyst provided the pyrrolidine derivative 2c in 43% yield (Table 4, entry 3), while the Pd catalyst yielded 2c in only 7% yield ( Table 2, entry 3). CuI-catalyzed reactions with primary alkylamines gave moderate to good yields of products 2d-2l (entries 4-12), while reactions with adamantyl, tert-butyl, and aromatic amines did not afford the desired products (entries [13][14][15][16][17], and only aniline furnished a low yield of 2o (15%) (entry 15); these trends were reversed in the case of Pd-catalyzed processes. These negative results may be ascribed to the increase in bulkiness as well as a decrease in the basicity of the amine sources.

Conclusions
We have studied the C4 amination of pyrazole derivatives using readily accessible Pd(dba)2 or CuI catalysts. The Pd(dba)2-catalyzed reaction of 4-bromo-1H-1-tritylpyrazole proved to be suitable for aromatic or bulky amines lacking β-hydrogen atoms, but not for cyclic amines (piperidine and morpholine); additionally it was not suitable for alkylamines possessing β-hydrogen atoms. On the other hand, the CuI-catalyzed amination using 4-iodo-1H-1-tritylpyrazole was revealed to be favorable for alkylamines possessing β-hydrogen atoms, and not suitable for aromatic amines and bulky amines lacking β-hydrogens, indicating the complementarity of the two catalysts. Although further improvements are required for practical synthesis, such as the reduction of catalyst or ligand loading, the findings of the present study offer a useful synthetic method for the construction of 4functionalized pyrazoles. Further application of the methodology developed in this study to the C-O coupling reaction of halopyrazoles with alkylated alcohols will be evaluated and reported in the near future.

Conclusions
We have studied the C4 amination of pyrazole derivatives using readily accessible Pd(dba) 2 or CuI catalysts. The Pd(dba) 2 -catalyzed reaction of 4-bromo-1H-1-tritylpyrazole proved to be suitable for aromatic or bulky amines lacking β-hydrogen atoms, but not for cyclic amines (piperidine and morpholine); additionally it was not suitable for alkylamines possessing β-hydrogen atoms. On the other hand, the CuI-catalyzed amination using 4-iodo-1H-1-tritylpyrazole was revealed to be favorable for alkylamines possessing β-hydrogen atoms, and not suitable for aromatic amines and bulky amines lacking β-hydrogens, indicating the complementarity of the two catalysts. Although further improvements are required for practical synthesis, such as the reduction of catalyst or ligand loading, the findings of the present study offer a useful synthetic method for the construction of 4-functionalized pyrazoles. Further application of the methodology developed in this study to the C-O coupling reaction of halopyrazoles with alkylated alcohols will be evaluated and reported in the near future.
CuI-catalyzed coupling reaction with 1 and amines (Tables 3 and 4

)
Typical procedure (Table 3,  . The reaction vial was sealed and heated at 100 • C with stirring in an oil bath for 24 h. The reaction mixture was quenched by the addition of sat. aq. NH 4 Cl (1 mL) and extracted with CH 2 Cl 2 (1 mL × 3). The combined organic layers were dried over MgSO 4 , filtered, and evaporated to give a crude residue, which was purified by silica gel column chromatography (eluent: Hexane/AcOEt = 4:1) to afford 2d (28.6 mg, 68%).