Triflimide-Promoted Nucleophilic C-Arylation of Halopurines to Access N⁷-Substituted Purine Biaryls

Abstract

Functionalized nucleobases are utilized in a wide range of fields; therefore, the development of new synthesis methods is essential for their continued application. With respect to the C⁶-arylation of halopurines, which possess a substituent at the N⁷-position, only a small number of successful cases have been reported, which is predominately a result of large steric hinderance effects. Herein, we report efficient and metal-free C⁶-arylations and S_NAr reactions of N⁷-substituted chloropurines in aromatic and heteroatom nucleophiles promoted by triflimide (Tf₂NH) in fluoroalcohol.

Introduction

Nucleobase derivatives are used in a wide range of fields, such as pharmaceuticals, pesticides, and functional organic materials.^1–6) Compounds containing purine nucleobase as the biaryl unit are of particular interest as they exhibit unique biological functions; for example, a CRH-R₁ modulator, contains physiologically active substances which exhibit human immunodeficiency virus (HIV) and tuberculosis suppressing functions.^7,8) Therefore, the development of efficient synthesis methods, in particular the cross-coupling reaction of nucleobases,^9,10) is critical for further drug discovery studies.

Several studies have reported a method of purine biaryl synthesis achieved through oxidative coupling of purines using excess Grignard reagents and potassium ferricyanide (K₃Fe(CN)₆).¹¹⁾ However, the versatility of this method has not yet been extensively studied; thus, there is progress to be made regarding the potential substrate scope on the synthesis of purine biaryl compounds. Recently, transition metal-catalyzed Suzuki, Stille, Kumada, and Negishi coupling reactions making use of boron, tin, magnesium, or zinc-functionalized aromatic compounds have been proposed as versatile methods for synthesizing N⁹-substituted purine biaryl from 6-halopurine constituents^12–19) (Chart 1). An alternative coupling strategy has also been reported; it utilized stoichiometric quantities of aluminum chloride (AlCl₃) as a Lewis acid to induce a reaction between halopurines and aromatic nucleophiles.²⁰⁾ In addition to these approaches, purinyl radical-induced arylations were demonstrated in 1980s.^21–23) Furthermore, with respect to the coupling reaction of N⁷-substituted 6-halopurines, only a limited number of substrate reports have been published; this is likely because of the challenges in the synthesis of corresponding purine biaryls, which is attributed to the steric hindrance between the purine N⁷-substituent and the C⁶-introduced aryl group.

Chart 1. Synthesis of 6-Arylpurines

(A) General methods for N⁹-substituted purines. (B) This work for N⁷-substituted purines.

It has previously been established that several N⁷-substituted purine biaryls and related compounds exhibit advantageous biological properties. Two such compounds are, N-(4-(7-methyl-7H-purin-6-yl)benzyl)sulfamide²⁴⁾ and 3-(3-(4-(9H-purin-6-yl)phenyl)ureido′)-N-isopropylbenzamide,²⁵⁾ which successfully act as ENPP1 and Rho kinase inhibitors. While the biological activities of the N⁷-substituted purine biaryls were well documented in these studies, their synthesis methods were not investigated in detail. One such method concerns Stille-type coupling utilizing phenyl tributyltin (PhSnBu₃). In this process N⁷-benzylpurine was reacted with the phenylating agent (PhSnBu₃) in N,N-dimethylformamide (DMF) at 100–110 °C in the presence of a palladium catalyst¹²⁾ (Chart 1, Eq. 1). In this reaction, the phenyl and thienyl groups were only introduced, and the substrate scope was not investigated. Other methods for the C⁶-arylation of N⁷-substituted halopurines rely on the Suzuki cross-coupling reaction using a variety of organoboron compounds¹⁵⁾ (Chart 1, Eq. 2); however, the introduction of sterically hindered aryl groups, such as the naphthalene and indole rings, have not yet been examined in this method. To broaden the scope for obtaining rarely prepared N⁷-substituted arylpurine derivatives with structural and steric diversities, the development of a new practical method for the coupling reaction of N⁷-substituted purine electrophiles is imperative. In the ongoing development of a new method for the synthesis of functionalized nucleobases,²⁶⁾ we are pleased to report the metal-free arylation of N⁷-substituted purine derivatives through a S_NAr process initiated by triflimide (Tf₂NH) in fluoroalcohol ((CF₃)₂CHOH, hexafluoroisopropanol (HFIP)).

Results and Discussion

In our recent study, we developed an efficient method for the introduction of nucleophilic aryl groups into the 6-position of chloropurines, a process initiated by triflic acid (TfOH) in fluoroalcohol, HFIP²⁶⁾ (Chart 2). However, chloropurines bearing the substituent at the N⁷-position exhibited reduced reactivity using this method, which is likely attributed to steric hindrance around the coupling site. The effects of the steric hindrance were validated when a diverse series of N⁹-substituted C⁶-aryl purines were obtained using TfOH. However, these results could not be replicated when N⁷-substituted purines were used instead, suggesting steric hinderance affected the reaction kinetics.

Chart 2. Our Previous TfOH/HFIP Reaction System for S_NAr Reaction of Halopurines

Next, we examined the arylation between N⁷-methyl-6-chloropurine 1a and indole 2a under our previously reported conditions using TfOH,²⁶⁾ which obtained a moderate yield of the target product 3aa (Table 1, Entry 1). Meanwhile, it was found that halopurine reactivity may be influenced by altering the Brønsted acid, further broadening the substrate scope. As a result of this finding, we carried out further optimization studies of the acid initiator to induce a greater yield of the purine–indole biaryl product 3aa (Table 1). As expected, the yield of purine biaryl 3aa decreased when the reaction was performed with a weaker Brønsted acid, such as p-toluenesulfonic acid or trifluoroacetic acid, in the presence of identical substrate combinations (Entries 2 and 3). For these processes to occur, a high strength acid is required to initiate the reaction, and in this case, a super acid, Tf₂NH,^27–31) that can more effectively protonate the N⁷-substituted halopurine 1a as well as S_NAr reaction intermediates was considered. Purine–indole product 3aa yield was increased to 94% when the higher strength Brønsted acid, Tf₂NH, was used in our reaction system (Entry 4). On the other hand, this reaction did not proceed at room temperature (Entry 5), and the stoichiometric amount of Tf₂NH was necessary to obtain the good yield (Entry 6). Montmorillonite K10 (M-K10) and Nafion were also tested as recyclable solid acids, but the reaction efficiency was lower compared to the reaction with Tf₂NH (Entries 7 and 8). Furthermore, no reaction was observed in the absence of these acids at 60 °C after stirring for 24 h (Entry 9). Subsequently, we substituted HFIP with the following solvents, 1,2-dichloroethane (DCE), isopropanol, and 2,2,2-trifluoroethanol, each of which produced a low yield of the target product 3aa. Further optimization studies regarding the Brønsted acid concentration, temperature, and reaction time in HFIP indicated that the product 3aa was most efficiently obtained at 60 °C after 24 h with 1.0 M equivalent (equiv.) of Tf₂NH. Note that the desired reactions did not occur when Lewis acid, AlCl₃, was used alongside refluxing DCE²⁰⁾; the crowded S_NAr transition state with AlCl₃ and the aromatic nucleophiles is likely a result of the low reactivities of N⁷-substituted halopurines 1 (Entry 10).

Table 1. Optimization of the Reaction Conditions

The scope of aromatic nucleophiles toward N⁷-substituted halopurines 1a and 1b were then studied under the optimized conditions (Table 1, entry 4), with the chosen compounds shown in Table 2. Under the given acidic conditions N-methylindole 2b exhibited lower stability than 1H-indole 2a,^32,33) and a lower yield of the corresponding coupling product 3ab was obtained. Meanwhile, electron-rich indole 2c possessing a methoxy group at the 5-position produced the target product 3ac with an improved yield of 64%. 7-Benzylchloropurine 1b could be used with a less reactive nucleophile, N-phenylindole 2d, for this coupling. 1-Methoxynaphthalene 2e, 1-naphthol 2f, and 2-naphthol 2g, would be homogeneously distributed along the purine–naphthalene carbon–carbon bond of the biaryls 3ae–ag. In these naphthalene nucleophiles, halopurine 1b exerts a greater influence on the reaction kinetics, owing to its steric repulsion with respect to the N⁷-substituent (3bf: 71% versus 3af: 98%). Furthermore, resorcinol 2h exhibited excellent nucleophile tendencies, and the product 3ah was subsequently produced. In comparison, 1,3-dimethoxybenzene 2i and 1,3,5-trimethoxybenzene 2j also underwent the reaction with halopurine 1a, and the coupling products, 3ai and 3aj, were obtained in relatively low yields, 39 and 28%, respectively. As the reaction of 2-methoxynaphthalene did not occur in the N⁷-substituted halopurines, it was determined that the subtle change in the steric environment of the product and the aromatic nucleophiles is crucial for initiating the reaction.

Table 2. Scope of Substrates

Further, the introduction of p-substituted aniline and phenol to N⁷-substituted halopurine was also studied (Chart 3). HFIP-promoted S_NAr-type amination of halogenated heteroaromatic electrophiles was recently reported to produce C⁶-aminopurines,³⁴⁾ without the inclusion of N⁷-substituted chloropurine as the substrate. The reaction of N⁷-methyl chloropurine 1a has since been studied, and by using p-anisidine 2k as a nucleophile, a 75% of amination product 3ak was obtained (Eq. 1). Interestingly, biaryl formation was not observed in this case.^35,36) Similarly, p-methoxyphenol nucleophile 2l induced a high yield of the aryloxy–purine compound 3al, owing to the carbon–oxygen coupling, under identical conditions (Eq. 2). These reactions did not proceed when the reactions were carried out under the Kapdi’s conditions (HFIP without Tf₂NH).³⁴⁾ Therefore, our proposed method, which utilizes Tf₂NH, is not only beneficial for biaryl formation, but also for the selective introduction of extensive nucleophiles in N⁷-substituted halopurines.

Chart 3. Coupling Reactions with Aniline Nitrogen and Phenol Oxygen

A plausible mechanism for the S_NAr introduction of nucleophiles within halopurines 1 is depicted in Chart 4. Initially, Tf₂NH in the reaction system activates halopurines 1 by preferentially protonating the N¹-position^35–37) prior to the nucleophile attack. The fluoroalcohol, HFIP,^38–41) can support this protonation step through strong hydrogen bonding to Tf₂NH.⁴²⁾ Several groups including us reported that the addition of HFIP can accelerate the Brønsted acid-induced reactions by enhancing their acidities.^43–46) Next, the nucleophiles attack the C⁶-position of halopurines 1, which is the most electrophilic site, generating the tetrahedral intermediate, A. To effectively induce nucleophile introduction, strong protonation is required for the N⁷-substituted halopurines 1 throughout the S_NAr process, which produces intermediates and products with increased steric hindrances. Finally, rearomatization to the coupling product 3 occurs alongside the elimination of hydrogen chloride, which is potentially assisted by the leaving-group activation abilities of HFIP through the strong hydrogen bonding.^47,48)

Chart 4. S_NAr Reaction

In conclusion, in this study, we developed a Brønsted acid-catalyzed S_NAr coupling of N⁷-substituted chloropurines with aromatic and heteroatom nucleophiles. Biaryl compounds possessing the desired nucleobases were obtained in high yields when the reactions were carried out in the presence of triflimide (Tf₂NH), with HFIP as a solvent. The reactions were shown to proceed under metal-free conditions and can be applied to a wide range of nucleophilic aromatic substrates. The unique purine biaryl motif obtained in this study potentially falls into a new class of organocatalyses. Chiral purine biaryl atrop-compounds of similar molecular design will be reported in our future research.

Experimental

General

Melting points were measured using a Büchi B 545 apparatus and are uncorrected. ¹H- and ¹³C-NMR spectra were recorded with a JEOL JMN-400 spectrometer operating at 400 and 100 MHz in CDCl₃ at 25 °C with tetramethylsilane (δ = 0 ppm) as the internal standard. The data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br s = broad singlet, m = multiplet), coupling constant (Hz), and integration. IR spectra were recorded by using a Hitachi 270-50 spectrophotometer; intensities of absorptions are reported in reciprocal centimeters (cm⁻¹). High resolution mass spectra (HRMS) obtained by the direct analysis in real time (DART) method were recorded on a Thermo Scientific Exactive Plus Orbitrap (Thermo Fisher Scientific, Inc., Waltham, MA, U.S.A.). Flash column chromatography and analytical TLC were carried out on Merck Silica gel 60 (230–400 mesh) and Merck Silica gel F₂₅₄ plates (0.25 mm), respectively. The spots and bands were detected by UV irradiation (254, 365 nm) or by staining with 5% phosphomolybdic acid followed by heating.

All reagents and compounds are commercially available, and were used as received. Solvents were purchased from commercial suppliers and used for the reactions, extraction, column chromatography, and TLC without further purification. 6-Chloro-7-methylpurine 1a and 6-chloro-7-benzylpurine 1b were prepared from commercially available 6-chloro-7H-purine by the known procedures.⁴⁹⁾

General Procedure for the Tf₂NH-Promoted Arylation of N⁷-Substituted Halopurines with Aromatic Nucleophiles in Fluoroalcohol (Table 2)

To a stirred solution of N⁷-substituted chloropurine 1a or 1b (0.20 mmol) and the aromatic nucleophile 2 (0.22 mmol, 1.1 equiv.) in hexafluoroisopropanol (2 mL) in open flask was added Tf₂NH (0.20 mmol, 1 equiv.) at room temperature. Next, the reaction mixture was heated at 60 °C. and reacted for 24 h. After confirming the disappearance of chloropurine 1 by TLC, sat. sodium bicarbonate aqueous solution was added to neutralize the reaction solution. The resulting biphasic solution was extracted with ethyl acetate three times, and then the combined solvent was distilled off with a rotary evaporator. The obtained crude product 3 was purified by column chromatography on silica gel (dichloromethane : methanol = 10 : 1) to obtain the N⁷-substituted purine biaryl 3 in the yield indicated in Table 2.

6-(1H-Indol-3-yl)-7-methyl-7H-purine (3aa): A yellow liquid. IR: 3395, 1352, 1186, 1060 cm⁻¹. ¹H-NMR (400 MHz, dimethyl sulfoxide (DMSO)-d₆) δ: 3.82 (s, 3H), 7.11–7.14 (m, 1H), 7.20–7.24 (m, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 8.61 (s, 1H), 8.95 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 34.8, 112.1, 114.7, 117.9, 120.4, 121.1, 122.4, 122.5, 124.4, 126.6, 133.7, 136.2, 150.5, 151.9 ppm. HR-DART-MS: Calcd for C₁₄H₁₂N₅⁺ [M + H]⁺ 250.1087. Found 250.1085.

7-Mehyl-6-(1-methyl-1H-indol-3-yl)-7H-purine (3ab): A white solid, mp 209–211 °C. IR: 3606, 1065 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.78 (s, 3H), 3.87 (s, 3H), 7.11 (t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H), 8.56 (s, 1H), 8.88 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 33.0, 34.7, 109.9, 110.4, 120.6, 120.7, 122.4, 122.8, 126.8, 132.9, 136.9, 147.4, 150.4, 151.9, 161.2 ppm. HR-DART-MS: Calcd for C₁₅H₁₄N₅⁺ [M + H]⁺ 264.1244. Found 264.1241.

6-(5-Methoxy-1H-indol-3-yl)-7-methyl-7H-purine (3ac): A white solid, mp 64–66 °C. IR: 3393, 2921, 1662, 1513, 1353, 1247 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.73 (s, 3H), 3.81 (s, 3H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 8.59 (s, 1H), 8.94 (s, 1H), 11.7 (br s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 34.7, 55.3, 101.9, 110.7, 112.5, 112.7, 117.9, 121.1, 122.9, 124.4, 127.0, 131.4, 136.5, 151.8, 154.4 ppm. HR-DART-MS: Calcd for C₁₅H₁₄N₅O⁺ [M + H]⁺ 280.1193. Found 280.1191.

6-(1-Phenyl-1H-indol-3-yl)-7-phenylmethyl-7H-purine (3bd): A yellow powder, mp 191–194 °C. IR: 1693, 1521 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 5.54 (s, 2H), 7.26–7.39 (m, 7H), 7.49–7.74 (m, 6H), 8.72 (s, 1H), 8.91–8.95 (m, 2H), 9.14 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 46.4, 110.9, 112.8, 122.1, 123.2, 123.6, 124.5, 126.8, 127.6, 127.7, 127.9, 128.8, 130.1, 134.5, 136.0, 136.7, 138.2, 143.3, 145.0, 150.5, 152.0, 152.3 ppm. HR-DART-MS: Calcd for C₂₆H₂₀N₅⁺ [M + H]⁺ 402.1713. Found 402.1713.

6-(4-Methoxynaphthalen-1-yl)-7-methyl-7H-purine (3ae): A yellow liquid. IR: 3422, 1584, 1267 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.35 (s, 3H), 4.07 (s, 3H), 7.14 (d, J = 8.4 Hz, 1H), 7.45–7.61 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.64 (s, 1H), 9.06 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 33.6, 55.9, 103.6, 122.0, 124.6, 125.0, 125.8, 127.5, 128.8, 128.9, 132.1, 150.8 (×2), 151.5, 151.9, 155.9, 161.0 ppm. HR-DART-MS: Calcd for C₁₇H₁₅N₄O⁺ [M + H]⁺ 291.1240. Found 291.1240.

4-(7-Methyl-7H-purine-6-yl)naphthalen-1-ol (3af): A white solid, mp 242–245 °C. IR: 3620, 1069 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.23 (s, 3H), 7.02 (d, J = 8.0 Hz, 1H), 7.43–7.53 (m, 4H), 8.26 (d, J = 8.0 Hz, 1H), 8.62 (s, 1H), 9.04 (s, 1H), 10.7 (br s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 33.7, 107.1, 122.5, 123.3, 124.3, 124.7, 125.0, 125.1, 127.3, 129.2, 132.5, 150.7, 151.3, 151.9, 154.8, 160.9 ppm. HR-DART-MS: Calcd for C₁₆H₁₃N₄O⁺ [M + H]⁺ 277.1084. Found 277.1086.

1-(7-Methyl-7H-purine-6-yl)naphthalen-2-ol (3ag): A white solid, mp 230–232 °C. IR: 3625, 1073 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.30 (s, 3H), 7.12–7.17 (m, 1H), 7.31–7.35 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.88–7.93 (m, 1H), 7.99 (d, J = 9.2 Hz, 1H), 8.61 (s, 1H), 9.08 (s, 1H), 10.4 (br s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 32.1, 114.7, 118.0, 121.1, 123.2, 123.7, 125.4, 127.0, 127.7, 131.2, 132.9, 148.6, 150.3, 152.2, 153.2, 160.7 ppm. HR-DART-MS: Calcd for C₁₆H₁₃N₄O⁺ [M + H]⁺ 277.1084. Found 277.1083.

4-(7-Phenylmethyl-7H-purin-6-yl)-naphthalene-1-ol (3bf): A yellow powder, mp 259–263 °C. IR: 3613, 2980, 1697 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 4.96–5.04 (m, 2H), 6.18 (d, J = 7.3 Hz, 2H), 6.77 (t, J = 7.3 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 5.4 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.91 (s, 1H), 9.04 (s, 1H), 10.7 (br s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 49.8, 107.0, 122.2, 123.4, 123.6, 124.3, 124.7, 124.9, 125.7, 126.9, 127.3, 127.9, 128.8, 132.3, 135.6, 150.8, 151.7, 152.0, 154.9, 161.6 ppm. HR-DART-MS: Calcd for C₂₂H₁₇N₄O⁺ [M + H]⁺ 353.1397. Found 353.1395.

4-(7-Methyl-7H-purine-6-yl)benzene-1,3-diol (3ah): A white solid, mp 238–241 °C. IR: 3650, 1065 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.63 (s, 3H), 6.41 (d, J = 7.8 Hz, 1H), 6.46 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 8.55 (s, 1H), 8.89 (s, 1H), 9.85 (br s, 1H), 10.0 (br s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 33.7, 114.9, 118.0, 121.1, 125.2, 128.2, 130.8, 131.5, 135.2, 140.4, 143.7, 152.2 ppm. HR-DART-MS: Calcd for C₁₂H₁₁N₄O₂⁺ [M + H]⁺ 243.0877. Found 243.0876.

6-(2,4-Dimethoxyphenyl)-7-methyl-7H-purine (3ai): A white solid, mp 133–135 °C. IR: 3625, 1073 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.46 (s, 3H), 3.69 (s, 3H), 3.82 (s, 3H), 6.68 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.90 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 33.0, 56.0 (×2), 98.7, 106.0, 118.0, 125.1, 132.2, 149.4, 150.7, 152.4, 158.0, 160.9, 162.7 ppm. HR-DART-MS: Calcd for C₁₄H₁₅N₄O₂⁺ [M + H]⁺ 271.1190. Found 271.1188.

7-Methyl-6-(2,4,6-trimethoxyphenyl)-7H-purine (3aj): A yellow solid, mp 224–226 °C. IR: 3437, 2946, 1613, 1131 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.36 (s, 3H), 3.62 (s, 6H), 3.82 (s, 3H), 6.36 (s, 2H), 8.50 (s, 1H), 8.89 (s, 1H) ppm. ¹³C-NMR (100 MHz, DMSO-d₆) δ: 32.1, 55.5, 55.7, 90.8, 105.3, 125.0, 147.0, 149.9, 152.0, 158.6, 160.2, 162.4 ppm. HR-DART-MS: Calcd for C₁₅H₁₇N₄O₃⁺ [M + H]⁺ 301.1295. Found 301.1295.

Procedure for the Tf₂NH-Promoted Coupling Reaction of N⁷-Substituted Halopurines with Phenol Oxygen and Aniline Nitrogen in Fluoroalcohol (Chart 3)

To a stirred solution of N⁷-methyl-6-chloropurine 1a (33.7 mg, 0.20 mmol) in hexafluoroisopropanol (2 mL) p-methoxyaniline 2k (27.0 mg, 0.22 mmol, 1.1 equiv.) or p-methoxyphenol 2l (27.3 mg, 0.22 mmol, 1.1 equiv.) and Tf₂NH (56.2 mg, 0.20 mmol, 1 equiv.) were successively added. The resulting mixture was stirred at 60 °C for 24 h. After completion of the reaction checked by TLC, the reaction mixture was poured into sat. NaHCO₃ aqueous. The resultant solution was extracted with ethyl acetate, dried with solid sodium sulfate, and then concentrated. The residue was purified by short-column chromatography on silica gel using dichloromethane–methanol (10 : 1) as the eluent to give N-(4-methoxyphenyl)-7-methylpurine-6-amine 3ak (38.2 mg, 0.150 mmol, 75%) or 6-(4-methoxyphenoxy)-7-methylpurine 3al (42.8 mg, 0.167 mmol, 84%), as a white powder, respectively.

N-(4-Methoxyphenyl)-7-methylpurine-6-amine (3ak): A white solid, mp 196–198 °C. IR: 3670, 1061 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.73 (s, 3H), 4.09 (s, 3H), 6.90 (d, J = 9.2 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 8.23 (s, 1H), 8.24 (s, 1H), 9.41 (br s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 34.1, 55.2, 112.5, 113.7, 114.9, 124.6, 129.2, 132.1, 146.7, 149.2, 151.7, 155.7, 160.2 ppm. HR-DART-MS: Calcd for C₁₃H₁₃N₄O₂⁺ [M + H]⁺ 257.1033 Found 257.1032.

6-(4-Methoxyphenoxy)-7-methylpurine (3al): A white solid, mp 248–251 °C. IR: 3597, 1065 cm⁻¹. ¹H-NMR (400 MHz, DMSO-d₆) δ: 3.60 (s, 3H), 4.04 (s, 3H), 6.62 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 9.2 Hz, 2H), 8.15 (s, 1H), 8.82 (s, 1H) ppm; ¹³C-NMR (100 MHz, DMSO-d₆) δ: 34.4, 55.3, 114.6, 115.2, 115.7, 142.4, 146.9, 147.0, 151.2, 152.1, 154.0 ppm. HR-DART-MS: Calcd for C₁₃H₁₄N₅O⁺ [M + H]⁺ 256.1193. Found 256.1192.

Acknowledgments

This work was supported in part by JSPS KAKENHI Grant Number JP20K06980 (N.T.), 18H02014 (K.K.), and 19K05466 (T.D.). T.D. also acknowledges support from the Ritsumeikan Global Innovation Research Organization (R-GIRO) project. We thank Central Glass Co., Ltd. for generous gift of fluoroalcohol.

Conflict of Interest

The authors declare no conflict of interest.

References and Notes

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