C4-Alkylamination of C4-Halo-1 H -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.
Keywords: amination; 4-halopyrazole; Buchwald-Hartwig coupling; Pd(dba)2; CuI mediated coupling; aliphatic amine
1. 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], [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.
Simple 4-alkylaminopyrazoles (a and b) have been reported to exhibit weak inhibitory activities against horse lever alcohol dehydrogenase (LADH) [[4]]. Azaisoindolinone derivative (c) exhibits potent lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) inhibition, with the distinct advantage of being orally administered and central nervous system (CNS)-penetrant [[6]]. Two 4-heteroarylamidopyrazoles (d and e) have been presented as apoptosis signal-regulating kinase 1 (ASK 1) inhibitors [[7]]. 1-Acetoanilide-4-aminopyrazole-substituted quinazoles are selective Aurora B protein kinase inhibitors with potent anti-tumor activity, and structure f is the most potent among them. The 3-aminopyrazole analog of compound f is AZD1152, which was the first Aurora B selective inhibitor to enter clinical trials [[8]]. 7H-pyrrolo[2,3-d]pyrimidine-based 4-amino-(1H)-pyrazole derivative (g) and pyrimidine-based 4-amino-(1H)-pyrazole derivatives (h and i) are Janus kinase (JAK) inhibitors. Specifically, compound i, a dual inhibitor of JAK and histone deacetylase (HDAC), comprises a zinc-binding moiety (HONHCO) linked to the pyrazole N1, via a (CH2)5-aliphatic chain [[9]].
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], [13], [15], [17]].
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]].
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]]. 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], [27]]; 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.
2. Results and Discussion
2.1. Pd(dba) 2 -Catalyzed Buchwald-Hartwig Coupling for C4-Amination of 4-halo-1H-1-tritylpyr...
First, we investigated the Buchwald-Hartwig coupling between 4-halo-1H-1-tritylpyrazoles (1) and piperidine, as a representative secondary amine [[16]], in order to determine the optimum reaction conditions. The results are summarized in Table 1.
As the Buchwald–Hartwig coupling reaction for 4-halo-1H-pyrazoles requires high temperatures (>80 °C) as well as prolonged time [[19], [21]], we utilized microwave (MW) apparatus to expedite the experimental process. Ligand screening was performed with the fixed conditions of 4-iodo-1H-1-tritylpyrazole (1I, X = I), Pd(dba)2, xylene, 160 °C, and 10 min under MW irradiation (entries 1–4). In the case of commonly used bidentate ligands, namely 1,1'-bis(diphenylphosphino)ferrocene (dppf, L1), 1,2-bis(diphenylphosphino)ethane (dppe, L2), and 2,2'-bis(diphenylphosphino)diphenyl ether (DPEPhos, L3), the reaction did not proceed (entries 1–3), while with the use of the bulky tBuDavePhos ligand (L4) the desired coupled product 2a was obtained in 21% yield; hence L4 was deemed a suitable ligand for this coupling reaction (entry 4). The use of L4 with palladium(II) chloride (PdCl2), palladium(II) acetate (Pd(OAc)2), or pyridine-enhanced precatalyst preparation stabilization and initiation-isopropyl (PEPPSI-IPr) catalysts did not improve the yield of 2a (entries 5–7). Although increasing the amount of L4 to 40 mol% yielded 52% of 2a, this created an additional problem for the purification of 2a (entry 8). Solvent screening with the use of L4 (40 mol%) did not improve results upon that of entry 8 (entries 9–12). Prolonged reaction time (24 h) with L4 (20 mol%) at room temperature (rt) under MW irradiation gave 2a in only 7% yield (entry 13). Conducting the reaction at 60 °C and 90 °C afforded 2a in 19% and 48% yields, respectively (entries 14 and 15). Alternatively, when 4-bromo- and 4-chloropyrazoles (1Br: X = Br and 1Cl: X = Cl) were used as substrates at 90 °C for 24 h (entries 16 and 17), the 4-bromo analogue delivered the highest yield of 2a (60%) (entry 16). Reaction conditions using bromo compound 1Br at lower or higher temperatures (70 or 140 °C in a sealed reaction vial) delivered inferior results compared to that of entry 16 (entries 18 and 19). Based on these results, further experiments were performed employing the reaction conditions listed in entry 16.
Next, optimized reaction conditions were applied to various amines, and the results are summarized in Table 2. Reactions of 1Br (X=Br) with piperidine and morpholine afforded desired products 2a and 2b in 60% and 67% yields, respectively (entries 1 and 2), while the reactions with pyrrolidine and allylamine afforded 2c (7%) and 2d (6%) in low yields (entries 3 and 4). The coupling reactions of 1Br with various primary amines produced the corresponding 4-alkylaminopyrazoles 2e–g, 2k, and 2l in low yields (17–34%) (entries 5–8, 11, and 12). Meanwhile, in the cases of isopropylamine and benzylamine, the desired products 2i and 2j were not obtained (entries 9 and 10). The reactions of 1Br with adamantylamine or tert-butylamine afforded the corresponding products 2m and 2n in 90% and 53% yields, respectively (entries 13 and 14). Furthermore, reactions with aromatic amines (anilines and 1-naphtylamine) gave the corresponding 2o (94%), 2p (91%), and 2q (85%) in high yields (entries 15–17) as being analogous to Buchwald's findings [[21]]. As the reaction with diphenylamine afforded 2r in 45% yield, we surmised that bulkiness at the reaction center depresses the chemical yield (entry 18).
Reactions of 1Br with pyrrolidine, allylamine, or primary amines bearing a β-hydrogen atom resulted in low yields (entries 3–12), while amines lacking a β-hydrogen afforded good yields (entries 13–18). These contrasting results are likely due to β-elimination occurring in the palladium complex during the coupling process.
2.2. CuI-Catalyzed Coupling for C4-Amination of 4-Halo-1H-1-tritylpyrazoles
Copper-catalyzed C-N coupling reactions have been extensively studied [[29]], and Buchwald has reportedly implemented this type of reaction using bromo- or iodobenzenes as substrates progressively, but not with five-membered heterocyclic compounds such as pyrazoles [[30], [32], [34], [36]]. As the C-N coupling reaction of 4-halopyrazoles 1 with allyl- or alkylamines bearing β-hydrogen atoms revealed low reactivities in the above investigation (Table 2, entries 4–12), the copper-catalyzed reaction of 1 was further studied.
For this purpose, the reaction of allylamine with 4-iodopyrazole 1I (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·C6H6 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 1Cl (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 13–17), 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.
3. 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.
4. Materials and Methods
General: Nuclear magnetic resonance (NMR) spectra were recorded at 27 °C on an Agilent 400-MR-DD2 spectrometer (Agilent Tech., Inc., Santa Clara, CA, USA) in CDCl3 with tetramethylsilane (TMS) as an internal standard. Abbreviations for splitting patterns in 1H-NMR spectra are noted as d = doublet; t = triplet; q = quartet; quin = quintet; sept = septet. Electron impact-high-resolution mass spectra (EI-HRMS) were measured with a JEOL JMS-700 (2) mass spectrometer (JEOL, Tokyo, Japan). Melting points were determined on a Yanagimoto micromelting point apparatus and were uncorrected. Liquid column chromatography was conducted with silica gel (FL-60D, Fuji Silysia Chemical Ltd., Kasugai, Aichi, Japan). Analytical thin layer chromatography (TLC) was performed on silica gel 70 F254 plates (Wako Pure Chemical Industries, Tokyo, Japan), and compounds were detected by dipping the plates into an EtOH solution of phosphomolybdic acid followed by heating. MW-aided reactions were carried out in a Biotage Initiator® reactor (PartnerTech Atvidaberg AB for Biotage Sweden AB, Uppsala, Sweden). Pd(dba)2, mesitylene, dppf (L2), copper (I) thiophene-2-carboxylate (CuCT), piperidine, pyrrolidine, allylamine, n-propylamine, isobutylamine, isoamylamine, isopropylamine, benzylamine, 2-phenylethylamine, 3-phenylpropylamine, adamantylamine, tert-butylamine, aniline, 2-methoxyaniline, 1-naphthylamine, and N,N-diphenylamine were purchased from Tokyo Chemical Industry (TCI) Co. (Tokyo, Japan). tBuOK, CuI, and 3,4,7,8-tetramethyl-1,10-phenanthroline (L7) were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Dry xylene, THF, 1,4-dioxane, and DMF were purchased from FUJIFILM Wako Pure Chemical Co. (Osaka, Japan). PEPSI-IPr, dppf (L1), DEPPhos (L3), tBuDavePhos (L4), morpholine, 2-isobutyrylcyclohexanone (L5), and 2-acetylcyclohexanone (L6) were purchased from Sigma-Aldrich Co. LLC (St. Louis, MI, USA).
Palladium-catalyzed coupling reaction with 1 and amines (Table 1 and Table 2)
Typical procedure (Table 1, entry 16): To a solution of 1Br (50.0 mg, 1.28 × 10−1 mmol) in xylene (2 mL) in a MW vial were added tBuDavePhos (8.8 mg, 2.56 × 10−2 mmol, 20 mol%), Pd(dba)2 (7.4 mg, 1. 28 × 10−2 mmol, 10 mol%), potassium t-butoxide (tBuOK) (28.8 mg, 2.57 × 10−1 mmol, 2.0 Equation) and piperidine (0.03 mL, 2.57 × 10−1 mmol, 2.0 Equation). The reaction vial was sealed and heated at 90 °C with stirring in an oil bath for 24 h. The reaction mixture was quenched by the addition of sat. aq. NH4Cl (1 mL) and extracted with CH2Cl2 (1 mL × 3). The combined organic layers were dried over MgSO4, filtered, and evaporated to give a crude residue, which was purified by silica gel column chromatography (eluent: Hexane/AcOEt = 4:1) to afford 1-(1-trityl-1H-pyrazol-4-yl)piperidine (2a) (30.9 mg, 60%) as a white powder.
CuI-catalyzed coupling reaction with 1 and amines (Table 3 and Table 4)
Typical procedure (Table 3, entry 3); To a solution of 1I (50.0 mg, 1.15 × 10−1 mmol) in DMF (2 mL) in a MW vial, were added 2-acetylcyclohexanone (3.0 μL, 2.30 × 10−2 mmol, 20 mol%), CuI (4.4 mg, 2.30 × 10−2 mmol, 20 mol%), tBuOK (25.7 mg, 2.30 × 10−1 mmol, 2.0 Equation) and allylamine (0.03 mL, 2.30 × 10−1 mmol, 2.0 Equation). 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. NH4Cl (1 mL) and extracted with CH2Cl2 (1 mL × 3). The combined organic layers were dried over MgSO4, 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%).
1-(1-Trityl-1H-pyrazol-4-yl)piperidine (2a): white powder; mp 170–174 °C; 1H-NMR (400 MHz, CDCl3): δ 1.49 (2H, quin, J = 5.7 Hz, -CH2CH2CH2-), 1.64 (4H, quin, J = 5.7 Hz, -CH2CH2CH2), 2.83 (4H, t, J = 5.7 Hz, -NCH2CH2) 6.88 (1H, d, J = 0.8 Hz, pyrazole-H), 7.13–7.18 (6H, m, Ph-H), 7.28–7.31 (9H, m, Ph-H), 7.39 (1H, d, J = 0.8 Hz, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 23.9, 25.5, 52.4, 78.4, 118.9, 127.5, 127.6, 129.5, 130.1, 137.7, 143.4; EI-HRMS m/z calcd. for C27H27N3 (M+) 393.2205, found 393.2210.
4-(1-Trityl-1H-pyrazol-4-yl)morpholine (2b): white powder; mp 209–211 °C; 1H-NMR (400 MHz, CDCl3): δ 2.87 (4H, t, J = 4.7 Hz, -NCH2CH2), 3.78 (4H, t, J = 4.7 Hz, -OCH2CH2-), 6.90 (1H, s, pyrazole-H), 7.14–7.17 (6H, m, Ph-H), 7.27–7.30 (9H, m, Ph-H), 7.39 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 51.4, 66.5, 78.5, 118.8, 127.7, 129.0, 130.1, 136.9, 143.3 (two signals are overlapping to give one signal); EI-HRMS m/z calcd. for C25H25N3O (M+) 395.1996, found 395.1997.
4-(Pyrrolidin-1-yl)-1-trityl-1H-pyrazole (2c): white powder; mp 189–190 °C; 1H-NMR (400 MHz, CDCl3): δ 1.90 (4H, br t, J = 6.5 Hz, -NCH2CH2-), 2.99 (4H, t, J = 6.5 Hz, -NCH2CH2), 6.74 (1H, d, J = 0.8 Hz, pyrazole-H), 7.16–7.18 (6H, m, Ph-H), 7.25–7.30 (10H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 24.7, 51.0, 78.3, 116.9, 127.5, 127.6, 128.2, 130.1, 135.1, 143.5; EI-HRMS m/z calcd. for C26H25N3 (M+) 379.2049, found 379.2048.
N-Allyl-1-trityl-1H-pyrazol-4-amine (2d): oil; 1H-NMR (400 MHz, CDCl3): δ 3.53 (2H, dt, J = 5.7, 1.6 Hz, -NHCH2CH=CH2), 5.09–5.12 (1H, dq, J = 10.1, 1.4 Hz, -NHCH2CH=CHH), 5.16–5.21 (1H, dq, J = 17.1, 1.6 Hz, -NHCH2CH=CHH), 5.86–5.96 (1H, ddt, J = 17.1, 10.1, 5.7 Hz, -NHCH2CH=CH2), 6.88 (1H, d, J = 0.8 Hz, pyrazole-H), 7.14–7.18 (6H, m, Ph-H), 7.25–7.30 (9H, m, Ph-H), 7.32 (1H, d, J = 0.8, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 50.5, 78.3, 116.3, 119.2, 127.6, 129.9, 130.1, 132.3, 135.8, 143. 4; EI-HRMS m/z calcd. for C25H23N3 (M+) 365.1892, found 365.1892.
N-Propyl-1-trityl-1H-pyrazol-4-amine (2e): white powder; mp 145–148 °C; 1H-NMR (400 MHz, CDCl3): δ 0.94 (3H, t, J = 7.4 Hz, -NHCH2CH2CH3), 1.56 (2H, sext, J = 7.4 Hz, -NHCH2CH2CH3), 2.86 (2H, t, J = 7.0 Hz, -NHCH2CH2CH3), 6.86 (1H, d, J = 0.8 Hz, pyrazole-H), 7.14–7.20 (6H, m, Ph-H), 7.26–7.35 (10H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 11.6, 23.0, 49.7, 78.2, 118.7, 127.5, 127.6, 129.7, 130.1, 132.9, 143.5; EI-HRMS m/z calcd. for C25H25N3 (M+) 367.2048, found 367.2049.
N-Butyl-1-trityl-1H-pyrazol-4-amine (2f): white amorhous; mp 112–116 °C; 1H-NMR (400 MHz, CDCl3): δ 0.91 (3H, t, J = 7.4 Hz, -CH2CH3-), 1.36 (2H, br sext, J = 7.4 Hz, -CH2CH2CH3), 1.52 (2H, br quint, J = 7.4 Hz, -CH2CH2CH2-),2.89 (2H, t, J = 7.0 Hz, -NHCH2CH2-), 6.86 (1H, s, pyrazole-H), 7.14–7.19 (6H, m, Ph-H), 7.27–7.33 (10H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 14.0, 20.2, 32.0, 47.6, 78.2, 118.7, 127.5, 127.6, 129.7, 130.1, 132.9, 143.4 EI-HRMS m/z calcd. for C26H27N3 (M+) 381.2205, found 381.2215.
N-Isobutyl-1-trityl-1H-pyrazol-4-amine (2g): white powder; mp 135–136 °C; 1H-NMR (400 MHz, CDCl3): δ 0.93 (6H, d, J = 6.6 Hz, -NHCH2CH(CH3)2), 1.78 (1H, nonet, J = 6.6 Hz, -NHCH2CH(CH3)2), 2.70 (2H, d, J = 6.6 Hz, -NHCH2CH(CH3)2), 6.85 (1H, s, pyrazole-H), 7.11–7.19 (6H, m, Ph-H), 7.25–7.32 (10H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 20.5, 28.4, 55.7, 78.2, 118.4, 127.5, 127.6, 129.6, 130.1, 133.1, 143.5; EI-HRMS m/z calcd. for C26H27N3 (M+) 381.2205, found 381.2210.
N-Isoamyl-1-trityl-1H-pyrazol-4-amine (2h): white amorphous; mp 110–113 °C; 1H-NMR (400 MHz, CDCl3): δ 0.89 (6H, d, J = 6.7 Hz, -CH(CH3)2), 1.48 (2H, q, J = 7.4 Hz, -CH2CH2CH-), 1.64 (1H, nonet, J = 6.6 Hz, -CH2CH(CH3)2), 2.89 (2H, br t, J = 7.3 Hz, -NHCH2CH2-), 6.86 (1H, s, pyrazole-H), 7.15–7.18 (6H, m, Ph-H), 7.26–7.32 (10H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 22.6, 25.9, 38.9, 46.0, 78.3, 118.7, 127.5, 127.6, 129.7, 130.1, 132.9, 143.5; EI-HRMS m/z calcd. for C27H29N3 (M+) 395.2361, found 395.2359.
N-Isopropyl-1-trityl-1H-pyrazol-4-amine (2i): white powder; mp 130–133 °C; 1H-NMR (400 MHz, CDCl3): δ 1.11 (6H, d, J = 6.3 Hz, -NHCH(CH3)2), 3.18 (1H, sept, J = 6.3 Hz, -NHCH(CH3)2), 6.88 (1H, s, pyrazole-H), 7.15–7.19 (6H, m, Ph-H), 7.26–7.35 (10H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 23.0, 48.4, 78.2, 120.5, 127.5, 127.6, 130.1, 131.1, 143.4 (two carbon signals overlapped); EI-HRMS m/z calcd. for C25H25N3 (M+) 367.2048, found 367.2046
N-Benzyl-1-trityl-1H-pyrazol-4-amine (2j): white powder; mp 148–151 °C; 1H-NMR (400 MHz, CDCl3): δ 4.06 (2H, s, -CH2Ph), 6.84 (1H, s, pyrazole-H), 7.13–7.16 (6H, m, Ph-H), 7.24–7.30 (14H, m, Ph-H), 7.32 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ52.2, 78.3, 119.2, 127.2, 127.5, 127.6, 127.9, 128.5, 129.9, 130.1, 132.4, 139.4, 143.4; EI-HRMS m/z calcd. for C29H25N3 (M+) 415.2048, found 415.2046.
N-Phenethyl-1-trityl-1H-pyrazol-4-amine (2k): white powder; mp 134–137 °C; 1H-NMR (400 MHz, CDCl3): δ 2.84 (2H, t, J = 6.9 Hz, -NHCH2CH2Ph), 3.16 (2H, t, J = 6.9 Hz, -NHCH2CH2Ph), 6.85 (1H, d, J = 0.9 Hz, pyrazole-H), 7.14–7.32 (21H, m, Ph-H and pyrazole-H); 13C-NMR (100 MHz, CDCl3) δ 35.8, 48.9, 78.3, 119.0, 126.4, 127.5, 127.6, 128.6, 128.8, 129.8, 130.1, 132.3, 139.3, 143.4; EI-HRMS m/z calcd. for C30H27N3 (M+) 429.2205, found 429.2200.
N-(3-Phenyl)propyl-1-trityl-1H-pyrazol-4-amine (2l): white powder; mp 114–117 °C; 1H-NMR (400 MHz, CDCl3): δ 1.86 (2H, br quint, J = 7.3 Hz, -CH2CH2 CH2-), 2.67 (2H, br t, J = 7.5 Hz, -CH2CH2Ph), 2.94 (2H, t, J = 7.1 Hz, -NHCH2CH2-), 6.84 (1H, s, pyrazole-H), 7.14–19 (8H, m, Ph-H and pyrazole-H), 7.24–7.30 (13H, m, Ph-H, and pyrazole-H); 13C-NMR (100 MHz, CDCl3) δ 31.4, 33.3, 47.4, 78.3, 118.8, 125.9, 127.5, 127.6, 128.3, 128.4, 129.8, 130.1, 132.6, 141.8, 143.4; EI-HRMS m/z calcd. for C31H29N3 (M+) 443.2362, found 443.2365.
N-((3s,5s,7s)-Adamantan-1-yl)-1-trityl-1H-pyrazol-4-amine (2m): white powder; mp 204–205 °C; 1H-NMR (400 MHz, CDCl3): δ 1.59 (12H, m, Ad-H), 2.05 (4H, br n, Ad-H, and -NHAd), 7.00 (1H, s, pyrazole), 7.14–7.18 (6H, m, Ph-H), 7.28–7.30 (9H, m, Ph-H), 7.34 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 29.6, 36.4, 43.2, 51.7, 78.3, 125.4, 127.2, 127.5, 127.6, 130.1, 136.8, 143.3; EI-HRMS m/z calcd. for C32H33N3 (M+) 459.2674, found 459.2673.
N-(tert-Butyl)-1-trityl-1H-pyrazol-4-amine (2n): white powder; mp 137–140 °C; 1H-NMR (400 MHz, CDCl3): δ 1.11 (9H, s, -C(CH3)3), 7.01 (1H, s, pyrazole-H), 7.15–7.18 (6H, m, Ph-H), 7.28–7.30 (9H, m, Ph-H), 7.36 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 29.5, 51.9, 78.3, 126.7, 127.0, 127.5, 127.6, 130.1, 136.2, 143.3; EI-HRMS m/z calcd. for C26H27N3 (M+) 381.2205, found 381.2206.
N-Phenyl-1-trityl-1H-pyrazol-4-amine (2o): white powder; mp 191–192 °C; 1H-NMR (400 MHz, CDCl3): δ 5.05 (1H, br, -NHPh), 6.70–6.76 (3H, m, Ph-H and pyrazole-H), 7.14–7.20 (7H, m, Ph-H), 7.24–7.32 (11H, m,Ph-H), 7.61 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 78.8, 113.4, 118.5, 123.5, 127.2, 127.8, 129.3, 130.0, 130.1, 136.0, 143.1, 146.6; EI-HRMS m/z calcd. for C28H23N3 (M+) 401.1892, found 401.1890.
N-(o-Methoxy)phenyl-1-trityl-1H-pyrazol-4-amine (2p): white powder; mp 133–136 °C; 1H-NMR (400 MHz, CDCl3): δ 3.87 (3H, s, -OCH3), 5.70 (1H, br, -NHAr), 6.70–6.76 (1H, m, Ph-H), 6.82–6.84 (2H, m, Ph-H), 7.22–7.25 (8H, m, Ph-H), 7.32–7.68 (9H, m, Ph-H, pyrazole-H), 7.68 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 55.4, 78.6, 109.8, 110.9, 117.6, 121.1, 123.3, 126.6, 127.6, 130.1, 135.7, 136.2, 143.1, 146.5; EI-HRMS m/z calcd. for C29H25N3 (M+) 431.1998, found 431.1998.
N-(Naphthalen-1-yl)-1-trityl-1H-pyrazol-4-amine (2q): white powder; mp 175–178 °C; 1H-NMR (400 MHz, CDCl3): δ 5.66 (1H, s, -NH-naphthyl), 6.82–6.84 (1H, m, naphtyl-H), 7.21–7.26 (8H, m, Ph-H and naphthyl-H), 7.28–7.36 (9H, m, Ph-H), 7.39 (1H, s, pyrazole-H), 7.43–7.48 (2H, m, naphthyl-H), 7.69 (1H, s, pyrazole-H), 7.79–7.87 (2H, m, naphthyl-H); 13C-NMR (100 MHz, CDCl3): δ 78.8, 106.9, 118.9, 119.8, 123.4, 123.6, 125.1, 125.9, 126.3, 127.6, 127.8, 128.7, 130.1, 130.4, 134.4, 136.4, 142.2, 143.1; EI-HRMS m/z calcd. for C32H25N3 (M+) 451.2049, found 451.2052.
N,N-Diphenyl-1-trityl-1H-pyrazol-4-amine (2r): white powder; mp 175–177 °C; 1H-NMR (400 MHz, CDCl3): δ6.92 (2H, t, J = 7.3 Hz, Ph-H), 7.04–7.06 (4H, m, Ph-H and pyrazole-H), 7.16–7.22 (10H, m, Ph-H), 7.29–7.33 (10H, m, Ph-H and pyrazole-H), 7.52 (1H, s, pyrazole-H); 13C-NMR (100 MHz, CDCl3): δ 78.9, 121.5, 121.9, 127.7, 127.9, 127.74, 127.78, 127.8, 128.6, 129.1, 129.2, 130.1, 130.2, 137.1, 143.0, 147.7; EI-HRMS m/z calcd. for C34H27N3 (M+) 477.2205, found 477.2197.
Figure, Scheme and Tables
Graph: Figure 1 Examples of bioactive 4-aminopyrazoles (a–i).
Graph: Scheme 1 Preceding studies on C4-amino-functionalization of 4-bromo-1H-pyrazoles.
Graph
Table 1 Buchwald-Hartwig coupling between 4-halo-1H-1-tritylpyrazoles (1) and piperidine.
Entry a | Substrate | Pd Catalyst | Ligand d | Solvent | Temperature (°C) | Time | Yield 2a (%) |
---|
1 | 1I: X = I | Pd(dba)2 | L1 | xylene | 160 (MW b) | 10 min | 0 |
2 | 1I | Pd(dba)2 | L2 | xylene | 160 (MW) | 10 min | 0 |
3 | 1I | Pd(dba)2 | L3 | xylene | 160 (MW) | 10 min | 0 |
4 | 1I | Pd(dba)2 | L4 | xylene | 160 (MW) | 10 min | 21 |
5 | 1I | PdCl2 | L4 | xylene | 160 (MW) | 10 min | 9 |
6 | 1I | Pd(OAc)2 | L4 | xylene | 160 (MW) | 10 min | 20 |
7 | 1I | PEPPSI-IPr | L4 | xylene | 160 (MW) | 10 min | 13 |
8 c | 1I | Pd(dba)2 | L4 | xylene | 160 (MW) | 10 min | 52 |
9 c | 1I | Pd(dba)2 | L4 | toluene | 160 (MW) | 10 min | 30 |
10 c | 1I | Pd(dba)2 | L4 | mesitylene | 160 (MW) | 10 min | 49 |
11 c | 1I | Pd(dba)2 | L4 | 1,4-dioxane | 160 (MW) | 10 min | 32 |
12 c | 1I | Pd(dba)2 | L4 | THF | 160 (MW) | 10 min | 0 |
13 | 1I | Pd(dba)2 | L4 | xylene | rt | 24 h | 7 |
14 | 1I | Pd(dba)2 | L4 | xylene | 60 | 24 h | 19 |
15 | 1I | Pd(dba)2 | L4 | xylene | 90 | 24 h | 48 |
16 | 1Br: X = Br | Pd(dba)2 | L4 | xylene | 90 | 24 h | 60 |
17 | 1Cl: X = Cl | Pd(dba)2 | L4 | xylene | 90 | 24 h | 40 |
18 | 1Br | Pd(dba)2 | L4 | xylene | 70 | 24 h | 43 |
19 | 1Br | Pd(dba)2 | L4 | xylene | 140 | 24 h | 23 |
a. general reaction conditions: substrate (50 mg, 0.13 mmol); solvent (2 mL), others are seen in the scheme in this table. b. MW: microwave, c. 40 mol% of L4 was used. d.
Graph
Graph
Table 2 Buchwald-Hartwig coupling of 4-bromo-1H-1-tritylpyrazole (1Br) with various amines.
Entry. | Amine | Product | Yield (%) |
---|
1 | piperidine | 2a: R = R' = -CH2CH2CH2CH2CH2- | 60 |
2 | morpholine | 2b: R = R' = -CH2CH2OCH2CH2- | 67 |
3 | pyrrolidine | 2c: R = R' = -CH2CH2CH2CH2- | 7 |
4 | allylamine | 2d: R = CH2CH=CH2, R' = H | 6 |
5 | n-propylamine | 2e: R = CH2CH2CH3, R' = H | 24 |
6 | n-butylamine | 2f: R = CH2CH2CH2CH3, R' = H | 17 |
7 | isobutylamine | 2g: R = CH2CH(CH3)2, R' = H | 28 |
8 | isoamylamine | 2h: R = CH2CH2CH(CH3)2, R' = H | 20 |
9 | isopropylamine | 2i: R = CH(CH3)2, R' = H | 0 |
10 | PhCH2NH2 | 2j: R = CH2Ph, R' = H | 0 |
11 | PhCH2CH2NH2 | 2k: R = CH2CH2Ph, R' = H | 30 |
12 | PhCH2CH2CH2NH2 | 2l: R = CH2CH2CH2Ph, R' = H | 34 |
13 a | adamantylamine | 2m: R = adamantyl, R' = H | 90 |
14 a | tert-butylamine | 2n: R = CH(CH3)3, R' = H | 53 |
15 a | aniline | 2o: R = Ph, R' = H | 94 |
16 a | 2-methoxyaniline | 2p: R = 2-MeOPh, R' = H | 91 |
17 a | 1-naphthylamine | 2q: R = naphth-1-yl, R' = H | 85 |
18 a | N,N-diphenylamine | 2r: R = R' = Ph | 45 |
a. Entries 13–18 were performed with 1.1 equivalents of amine.
Graph
Table 3 CuI-catalyzed allylamination of 4-halo-1H-1-tritylpyrazoles 1.
Entry a | Substrate | Cu Catalyst | Ligand c | Temperature (°C) | Yield 2d (%) |
---|
1 b | 1I: X = I | CuI | L5 | 100 | 17 |
2 | 1I | CuI | L5 | 100 | 72 |
3 | 1I | CuI | L6 | 100 | 68 |
4 | 1I | CuI | L7 | 100 | 12 |
5 | 1I | CuI | L6 | rt | 0 |
6 | 1I | CuI | L6 | 70 | 41 |
7 | 1I | CuI | L6 | 130 | 9 |
8 | 1I | CuI | L6 | 100 | 52 |
9 | 1I | CuI2 | L6 | 100 | 57 |
10 | 1I | Cu(OAc)2 | L6 | 100 | 58 |
11 | 1I | Cu2O | L6 | 100 | 16 |
12 | 1I | CuCT | L6 | 100 | 50 |
13 | 1I | [CuOTf]2.C6H6 | L6 | 100 | 70 |
14 | 1Br: X = Br | CuI | L6 | 100 | 66 |
15 | 1Cl: X = Cl | CuI | L6 | 100 | 0 |
a. general reaction conditions: substrate (50 mg, 0.12 mmol); solvent (2 mL), others are seen in the scheme in this table. b. CuI (5 mol%), L5 (20 mol%), Cs2CO3 (2.0 Equation). c.
Graph
Graph
Table 4 CuI-catalyzed coupling of 1I with various amines.
Entry | Amine | Product | Yield (%) |
---|
1 | piperidine | 2a | 21 |
2 | morpholine | 2b | 22 |
3 | pyrrolidine | 2c | 43 |
4 | allylamine | 2d | 68 |
5 | n-propylamine | 2e | 75 |
6 | n-butylamine | 2f | 62 |
7 | isobutylamine | 2g | 70 |
8 | isoamylamine | 2h | 62 |
9 | isopropylamine | 2i | 57 |
10 | PhCH2NH2 | 2j | 55 |
11 | Ph CH2CH2NH2 | 2k | 53 |
12 | Ph CH2 CH2CH2NH2 | 2l | 69 |
13 | adamantylamine | 2m | 0 |
14 | tert-butylamine | 2n | 0 |
15 | aniline | 2o | 15 |
16 | 1-naphthylamine | 2q | 0 |
17 | N,N-diphenylamine | 2r | 0 |
Author Contributions
Y.U. and Y.T. conceived, designed, and performed the synthetic experiments; Y.U., H.Y. and S.H. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Acknowledgments
M. Fujitake of our University is appreciated for performing MS measurements.
[
Footnotes
1
Sample Availability: Not available.
]
[
References
Li J.J. Pyrazoles, pyrazolones, and indazoles. Heterocyclic Chemistry in Drug DiscoveryLi J.J. ; Wiley-VCH: Weinheim, Germany. 2013: 198-229
2
Brown A.W. Recent developments in the chemistry of pyrazoles. Adv. Heterocycl. Chem. 2018; 126: 55-107
3
Karrouchi K., Radi S., Ramli Y., Taoufik J., Mabkhot Y.N., Al-aizari F.A., M'hammed A. Synthesis and pharmacological activities of pyrazole derivatives: A review. Molecules. 2018; 23134. 10.3390/molecules23010134. 29329257
4
Tolf B.-R., Dahlbom R., Aakeson A., Theorell H. Synthetic inhibitors of alcohol dehydrogenase. Pyrazoles containing polar groups directly attached to the pyrazole ring in the 4-position. Acta Pharm. Suec. 1985; 22: 147-156
5
Tolf B.-R., Dahlbom R., Akeson A., Theorell H. 4-Substituted pyrazoles as inhibitors of liver alcohol dehydrogenase. Structure-activity relationships. Biologically Active Principles of Natural ProductsVoelter W., Daves D.G. ; Thieme Medical Publishers: Stuttgart, Germany. 1984: 265-277
6
Come J.H., Collier P.N., Henderson J.A., Pierce A.C., Davies R.J., Le T.A., O'Dowd H., Bandarage U.K., Cao J., Deininger D. Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS). J. Med. Chem. 2018; 61: 5245-5256. 10.1021/acs.jmedchem.8b00085. 29847724
7
Gibson T.S., Johnson B., Fanjul A., Halkowycz P., Dougan D.R., Cole D., Swann S. Structure-based drug design of novel ASK1 inhibitors using an integrated lead optimization strategy. Bioorg. Med. Chem. Lett. 2017; 27: 1709-1713. 10.1016/j.bmcl.2017.02.079
8
Foote K.M., Mortlock A.A., Heron N.M., Jung F.H., Hill G.B., Pasquet G., Brady M.C., Green S., Heaton S.P., Kearney S. Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: Selective inhibitors of Aurora B kinase with potent antitumor activity. Bioorg. Med. Chem. Lett. 2008; 18: 1904-1909. 10.1016/j.bmcl.2008.02.002
9
Liang X., Zang J., Zhu M., Gao Q., Wang B., Xu W., Zhang Y. Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors. ACS Med. Chem. Lett. 2016; 7: 950-955. 10.1021/acsmedchemlett.6b00247
Liang X., Zang J., Li X., Tang S., Huang M., Geng M., Chou C.J., Li C., Cao Y., Xu W. Discovery of novel Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors for the treatment of hematological malignancies. J. Med. Chem. 2019; 62: 3898-3923. 10.1021/acs.jmedchem.8b01597
Jiang L., Buchwald S.L.. Palladium-Catalyzed Aromatic Carbon-Nitrogen Bond Formation in Metal-Catalyzed Cross-Coupling Reactions2nd ed.De Meijere A., Diederich F. ; Wiley-VCH Verlag GmbH & Co.: Weinheim, Germany. 2004; Volume 2: 699-760
Dorel R., Grugel C.P., Haydl A.M. The Buchwald–Hartwig Amination after 25 Years. Angew. Chem. Int. Ed. 2019; 58: 17118-17129. 10.1002/anie.201904795
Muci A.R., Buchwald S.L. Practical palladium catalysts for C-N and C-O bond formation. Top. Curr. Chem. 2002; 219: 131-209
Altman R.A., Fors B.P., Buchwald S.L. Pd-catalyzed amination reactions of aryl halides using bulky biarylmonophosphine ligands. Nat. Protoc. 2007; 2: 2881-2887. 10.1038/nprot.2007.414. 18007623
Hartwig J.F. Evolution of a fourth-generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 2008; 41: 1534-1544. 10.1021/ar800098p. 18681463
Hartwig J.F. "Palladium-catalyzed amination of aryl halides and related reactions". Handbook of Organopalladium Chemistry for Organic SynthesisNegishi E. ; John Wiley & Sons, Inc.: Hoboken, NJ, USA. 2002; Volume 1: 1051-1096
Louie J., Hartwig J.F. Palladium-catalyzed synthesis of arylamines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents. Tetrahedron Lett. 1995; 36: 3609-3612. 10.1016/0040-4039(95)00605-C
Ingoglia B.T., Wagen C.C., Buchwald S.L. Biaryl monophosphine ligands in palladium-catalyzed C–N coupling: An updated User's guide. Tetrahedron. 2019; 75: 4199-4211. 10.1016/j.tet.2019.05.003
Maiti D., Fors B.P., Henderson J.L., Nakamura Y., Buchwald S.L. Palladium-catalyzed coupling of functionalized primary and secondary amines with aryl and heteroaryl halides: Two ligands suffice in most cases. Chem. Sci. 2011; 2: 57-68. 10.1039/C0SC00330A
Su M., Buchwald S.L. Bulky biaryl phosphine ligands for palladium-catalyzed amidation of five-membered heterocycles as electrophiles. Angew. Chem. Int. Ed. 2012; 51: 4710-4713. 10.1002/anie.201201244
Su M., Hoshiya N., Buchwald S.L. Palladium-catalyzed amidation of five-membered heterocyclic bromides. Org. Lett. 2014; 16: 832-835. 10.1021/ol4035947
Park B.Y., Pirnot N.T., Buchwald S.L. Visible light-mediated (hetero)aryl amidation using Ni(II) salts and photoredox catalysis in flow: A synthesis of tetracaine. J. Org. Chem. 2020; 85: 3234-3244. 10.1021/acs.joc.9b03107
Usami Y., Tsujiuchi Y., Machiya Y., Chiba A., Ikawa T., Yoneyama H., Harusawa S. Synthetic challenges in the construction of 8- to 10-Membered Pyrazole-fused rings via ring-closing metathesis. Heterocycles. 2020; 101: 496-511. 10.3987/COM-19-S(F)32
Usami Y., Tatsui Y., Sumimoto K., Miyamoto A., Koito N., Yoneyama H., Harusawa S. 3-Trifluoromethansulfonyloxy-4,7-dihidropyrazolo[1,5-a]pyridine via ring-closing metathesis: Synthesis and transformation to withasomnine homologs. Heterocycles. 2020; 103in press
Ichikawa H., Ohno Y., Usami Y., Arimoto M. Synthesis of 4-Arylpyrazoles via PdCl2(dppf) catalyzed cross-coupling reaction with Grignard reagents. Heterocycles. 2006; 68: 2247-2252. 10.3987/COM-06-10863
Ichikawa H., Nishioka M., Arimoto M., Usami Y. Synthesis of 4-Aryl-1H-pyrazoles by Suzuki-Miyaura cross coupling reaction between 4-Bromo-1H-1-tritylpyrazole and arylboronic acids. Heterocycles. 2010; 81: 1509-1516. 10.1002/chin.201043119
Ichikawa H., Ohfune H., Usami Y. Microwave-assisted selective synthesis of 2H-indazoles via double Sonogashira coupling of 3,4-diiodopyrazoles and Bergman-Masamune cycloaromatization. Heterocycles. 2010; 81: 1651-1659. 10.3987/COM-10-11950
Usami Y., Ichikawa H., Harusawa H.S. Heck-Mizoroki reaction of 4-Iodo-1H-pyrazoles. Heterocycles. 2011; 83: 827-835. 10.3987/COM-11-12146
Bhunia S., Pawar G.G., Kumar S.V., Jiang Y., Ma D. Selected copper-based reactions for C-N, C-O, C-S, and C-C bond formation. Angew. Chem. Int. Ed. 2017; 56: 16136-16179. 10.1002/anie.201701690. 28544319
Kwong F.Y., Klapars A., Buchwald S.L. Copper-catalyzed coupling of alkylamines and aryl iodide: An efficient system even in an air atmosphere. Org. Lett. 2002; 4: 581-584. 10.1021/ol0171867. 11843596
Kwong F.Y., Buchwald S.L. Mild and efficient copper-catalyzed amination of aryl bromides with primary alkylamines. Org. Lett. 2003; 5: 793-796. 10.1021/ol0273396
Shafir A., Buchwald S.L.J. Highly selective room-temperature copper-catalyzed C−N coupling reactions. J. Am. Chem. Soc. 2006; 128: 8742-8743. 10.1021/ja063063b
Jiang S., Dong X., Qiu Y., Xiaoxing D.C., Wu X., Jiang S. A new ligand for copper-catalyzed amination of aryl halides to primary (hetero)aryl amines. Tetrahedron Lett. 2020; 61: 151683. 10.1016/j.tetlet.2020.151683
Luo T., Wan J.-P., Liu Y. Toward C2-nitrogenated chromones by copper-catalyzed β-C(sp2)–H N-heteroarylation of enaminones. Org. Chem. Front. 2020; 7: 1107. 10.1039/D0QO00065E
Liu W., Xu J., Chen X., Zhang F., Xu Z., Wang D., He Y., Xia X., Zhang X., Liang Y. CuI/2-Aminopyridine 1-Oxide Catalyzed Amination of Aryl Chlorides with Aliphatic Amines. Org. Lett. 2020; 22: 7486-7490. 10.1021/acs.orglett.0c02672. 32909758
Lyakhovich M.S., Averin A.D., Grigorova O.K., Roznyatovsky V.A., Maloshitskaya O.A., Beletskaya I.P. Cu(I)- and Pd(0)-catalyzed arylation of oxadiamines with fluorinated halogenobenzenes: Comparison of efficiency. Molecules. 2020; 251084. 10.3390/molecules25051084. 32121113
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By Yoshihide Usami; Yuya Tatsui; Hiroki Yoneyama; Shinya Harusawa; Vera L. M. Silva and Artur M. S. Silva
Reported by Author; Author; Author; Author; Author; Author