Chinese Chemical Letters  2017, Vol. 28 Issue (7): 1607-1612   PDF    
Chemo-selective Suzuki-Miyaura reactions: Synthesis of highly substituted [1, 6]-naphthyridines
Suneel Kumar Yadavalli, Nawaz Khan Fazlur-Rahman    
Organic and Medicinal Chemistry Research Laboratory, School of Advanced Sciences, VIT-University, Vellore 632 014, India
Abstract: The Suzuki-Miyaura reaction of methyl-5-bromo-8-(tosyloxy)-1, 6-naphthyridine-7-carboxylate (5), with 2 equiv. of arylboronic acids gave diarylated product, 5, 8-diaryl-1, 6-naphthyridine-7-carboxylate (7), whereas 1 equiv. of arylboronic acid resulted in site-selective formation of 5-aryl-8-(tosyloxy)-1, 6-naphthyridine-7-carboxylate (8). The reactions proceeded with excellent chemo-selectivity in favor of the bromide group. Likewise, one-pot reaction with completely different boronic acids by sequential addition produced 1, 6-naphthyridine-7-carboxylates, (10) containing two different aryl groups at 5 and 8 positions.
Key words: Chemo-selective     Suzuki-Miyaura     [1, 6]-Naphthyridines     Site selective reaction     Diarylation Monoarylation    
1. Introduction

Among nitrogen heterocycles, the naphthyridines occur widely in natural products, such as amaroridine, curtisin, aaptamine and isoaaptamine [1]. Extremely functionalised [1, 6]-naphthyridines have an extensive scope of biological activities including antibacterial [2], anticonvulsant [3], anti-human cytomegalovirus inhibitory [4], antitumor, anticancer [5], antiviral, HIV-1 integrase [6] and antiproliferative activities. Naphthyridines are selective antagonists of 5-HT4 receptors [7]. The versatility of these compounds provoked us to synthesize highly substituted [1, 6]-naphthyridines.

Numerous routes for synthesis of substituted [1, 6]-naphthyridine derivatives were reported [8]. For instance, one-pot catalyst free, multi component, domino synthesis of 1, 2-dihydro[1, 6]-naphthyridines in water medium [9], 5, 6, 7, 8-tetrahydro-1, 6-naphthyridine through intermolecular and intramolecular cyclization [10], benzo[b][1, 6]naphthyridine-4-carboxylic acids through (3-carboxy-quinolin-2-yl)acetate and Vilsmeier reagent [11], palladium-catalysed Sonogashira coupling and annulation [12], mono-and diarylated naphthyridine derivatives by site-selective Suzuki-Miyaura cross-coupling reactions [13]. Yet, these strategies involve multistep [14], expensive catalysts [15-18], inert atmosphere [19-21], stringent conditions, prolonged reaction times and laborious workup procedure.

Regioselective Suzuki-Miyaura cross reactions of dihalogenated, triflates of pyridines, quinolines have been reported [22-44], and those containing bromide and triflate are uncommon. The Suzuki-Miyaura reactions, by and large, occur first at the bromide group and therefore, the site-selectivity of these reactions is mostly influenced by electronic and steric parameters. Along these lines, supported by the above facts and on our research interests and accomplishments [45-50], in palladium-catalyzed crosscoupling reactions, currently the chemo-selective Suzuki-Miyaura reactions are envisioned in the synthesis of highly substituted [1, 6]-naphthyridines.

2. Results and discussion

The starting material 5-bromo-8-(tosyloxy)-1, 6-naphthyridine-7-carboxylate (5) required for the present study was acquired through the already reported procedure (Scheme 1) [51].

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Scheme 1. Synthesis of 5-bromo-8-(tosyloxy)-1, 6-naphthyridine 7-carboxylate (5). (a) NaOMe, CH3OH, 0 ℃ to r.t., 3 h, 72% (b) NBS, CH2Cl2, r.t., 1 h, 82%; (c) TsCl, TEA, CH2Cl2, 5 h, 90%.

The chemo-selective Suzuki-Miyaura reaction of 5 investigated in the present work is delineated as Scheme 2.

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Scheme 2. Synthesis of 7, 8 and 10. Reagents and conditions: ⅰ. 5 (1.0 equiv.), 6 (2.3 equiv.), PdCl2(PPh3)2 (10 mol%), Sphos (10 mol%), K3PO4 (3.0 equiv.), DMF: n-butanol (9:1), 120 ℃, 3 h; ⅱ 5 (1.0 equiv.), 6 (1.2 equiv.), PdCl2(PPh3)2 (10 mol%), PPh3 (10 mol %), K3PO4 (3.0 equiv.), DMF:H2O (9:1), 80 ℃, 1 h; ⅲ a. 5 (1.0 equiv.), 6 (1.2 equiv.), PdCl2(PPh3)2 (10 mol%), Sphos (10 mol%), K3PO4 (3.0 equiv.), DMF: n-butanol (9:1), 80 ℃, 1 h, b. 9 (1.1 equiv.) at 120 ℃ 2 h.

At first, when Suzuki reaction of naphthyridine (5), was attempted in the presence of Pd(OAc)2 (10 mol%), PPh3 (10 mol %), THF (10 mL), boronic acid, 6 (2.3 equiv.), K2CO3 (3.0 equiv.) at 120 ℃ or 100 ℃, gave monoarylated naphthyridine, 8 in 49%, 57% yield, respectively (Scheme 2, Table 1, entry 1). Optimization studies were carried out in aqueous condition to acquire the desired diarylated product (7), however only monoarylated products (8) were obtained in sensible yields whereas diarylatedproduct acquired in low yield of 21% at 120 ℃ (Table 1, entries 2, 3). Further, alternative catalysts, for example PdCl2(PPh3)2, Pd2dba3 and Pd(PPh3)4, were tested. The utmost yield of just 23% was obtained with the PdCl2(PPh3)2 (Table 1, entries 4-6). Further, in the process of improving the yield of diarylated product 7, different solvents such as ethanol, n-butanol, DMF and bases such as K2CO3, K3PO4, were investigated (Table 1, entries 7-11). It is evident that n-butanol without water produced the best yield of 86% diarylated with PdCl2(PPh3)2 (10 mol%), PPh3 (10 mol%), K3PO4 (3 equiv.) at 120 ℃ (Table 1, entry 8). The other solvent system DMF: n-Butanol (9:1) gave a comparable yield of 84% (Table 1, entry 9). It is intriguing to notice that higher temperature is essential for the formation of diarylated products, since, at lower temperature, mixture of mono and diarylated products were obtained in the tested conditions (entries 8-11). Having the optimized result in hand, the effect of ligands has been studied. Among the tested ligands like PPh3, Sphos, Ruphos, Xantphos in different catalyst/ base/solvent conditions (Table 1, entries 12-19), the best one is found to be PdCl2(PPh3)2/Sphos/K3PO4/DMF:n-butanol (9:1) system with a yield of 96% diarylated product at 120 ℃ (Table 1, entry 18).

Table 1
Optimization of Suzuki–Miyaura reaction of 5-bromo-8-tosyloxy)-1, 6-naphthyridine 7-carboxylate (5)a.

Having this in mind, with the expectation of chemo-selective Suzuki reaction of bromo substituent, initially, a reaction of 5 was carried out, utilizing the above optimized conditions using 1.2 equiv. of boronic acid at 120 ℃, which demonstrated unfavorable results of mixture of mono and diarylated products. So as to accomplish the chemo-selectivity of the bromide group, when Pd (OAc)2 (10 mol%), PPh3 (10 mol%) are used alongside THF (10 mL), boronic acid (1.2 equiv.), K2CO3 (3.0 equiv., ) at 80 ℃ for 1 h gave desired moroaryl naphthyridine 8 in 67% yield (Scheme 1, Table 2, entry 1) due to the formation of stable borane-bromide bond. Optimization studies were carried out to improve the yield of the desired product (8).

Table 2
Monoarylated napththrydinesa.

Among the alternative catalysts PdCl2(PPh3)2, Pd2dba3, Pd (PPh3)4 (Table 2, entries 1-4), and solvents DMF, toluene, ethanol, n-butanol, DMF/H2O (Table 2, entries 5-10), tested, improved yield of 88% was achieved under optimized conditions of K3CO3 (3 equiv.), PdCl2(PPh3)2 (10 equiv.), boronic acid (1.2 equiv.) and DMF: H2O (9:110 mL) at 80 ℃ (Table 2, entry 10). Additional study on effect of base reveals that K3PO4 is effective in comparison to other bases; for instance, K2CO3, KHPO4, in DMF/H2O (9:110 mL) gave the best yield of 94% (Table 2, entry 13). The products derived from both the electron poor and rich arylboronic acids were obtained in good yields. It is important to mention that an exactly 1.2 equiv. of boronic acid should be used to carry out the reaction at lower temperature to induce a good site-selectivity for monoarylated product and to avoid double attack. Small amounts (approx. 5%-10%) of diarylated products were detected in the crude product mixture (by 1H NMR) before the separation. From the experimental results, it is evident that the monoarylated and the diarylated products were obtained exclusively in DMF:H2O and DMF:n-butanol (9:1) respectively giving competitive yields. By changing the ligand PPh3 to Sphos, and increasing the temperature resulted in excellent yield of diarylated products. Generally, Suzuki-Miyaura reactions of poly-halogenated or triflated arenes proceed site-selectively by initial oxidative addition of the electron rich palladium (0) catalyst and hence the arylboronic acid by reacting at more electron-deficient and less sterically-hindered site. It should be noted that among the bromides and tosylates, the bromides undergo rapid Suzuki-Miyaura coupling reactions (Fig. 1).

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Fig. 1. Chemo-selectivity.

Further attempt was made to carry out one pot reaction of 5 with two different boronic acids to achieve unsymmetrical diarylated products (Fig. 2). At first, the reaction was carried out with a mixture of two boronic acids, following the above optimized conditions. The results revealed inseparable mixture of monoarylated and diarylated products as identified by TLC, attributable to the identical Rf. A one-pot synthesis of 5 was then attempted by sequential addition of two different boronic acids as delineated below. The reaction was initially carried out utilizing 5 (1.0 equiv.), first boronic acid 6 (1.2 equiv.), PdCl2(PPh3)2 (10 mol%), Sphos (10 mol%), K3PO4 (3.0 equiv.), DMF:n-butanol (9:1), 80 ℃ for 1 h, monitored by TLC for its monoarylation. At this stage, the second boronic acid, 9 (1.2 equiv.) was added at 120 ℃ without an additional Pd catalyst, ligand, base and the solvent. Reaction monitored by TLC. Further, the reaction underwent neatly, extracted the product by ethyl acetate. Crude product was purified by column chromatography by using ethyl acetate: Petroleum ether (20:80) as an eluent.

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Fig. 2. Functionalized naththyrdines.

In the present study, the site-selectivity of palladium catalyzed reactions of naphthyridne containing both bromo and tosylate group is controlled by steric and electronic parameters. By and large, aryl bromides undergo Suzuki-Miyaura reactions more rapidly than aryl triflates, on account of the stability of the boranehalide bond; other parameters influence the selectivity as well. It is expected that the initial attack should take place at tosylate position which is electronically deficient and because of the additional chelation of the palladium catalyst by the carbonyl group. This may be due to the proximity of triflate to the naphthryidine nitrogen which might exert a catalyst-directing effect based on participation of the nitrogen lone pairs. However, a different site-selectivity at bromo position, sterically less hindered is noticed. Obviously, the regio-directing effect of the carbonyl group seems to be less prominent due to steric hindrance and therefore, the sterically less hindered bromine position is attacked first and also due to the better leaving group tendency of the bromine (Figs. 1 and 2). The aryl boronic acid, heteroarylboronic acids were successful. Likewise alkyl-and vinylboronic acids were investigated instead of arylboronic acids. However, the reactions were unsuccessful due to the formation of complex mixtures (decomposition).

3. Conclusion

We have reported an efficient synthesis of arylated naphthyridines by site-selective Suzuki-Miyaura reactions of napthryidines containing both the bromo and tosylate groups. The first Suzuki reaction at lower temperature proceeded with very good chemoselectivity in favor of the bromide group. Additionally, the selectivity and the yield are mainly determined by the first attack of the boronic acid, while the second attack has negligible influence on the yield because of non-existence of site-selectivity problem.

4. Experimental

5-Bromo-8-(tosyloxy)-1, 6-naphthyridine-7-carboxylate, 5 was acquired through reported procedure [51]. 1H NMR (400 MHz, CDCl3): δ 9.05 (d, 1H, J = 3.17 Hz), 8.59 (d, 1H, J = 8.35 Hz), 7.85 (d, 2H, J = 8.15 Hz), 7.70 (dd, 1H, J = 8.51, 4.21 Hz), 7.34 (d, 2H, J = 8.02 Hz), 3.84 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.2, 155.8, 146.5, 145.5, 141.9, 141.5, 139.3, 136.9, 133.5, 129.6, 128.8, 127.5, 125.5, 53.1, 21.7; UPLC-MS: m/z calcd. for C17H13BrN2O5S 437.26 found 438.95 [M].

Compound 7a: In a sealed tube, a mixture of 1, 6-naphthyridine 5 (268 mg, 0.5 mmol), 4-methoxyphenylboronic acid (174.9 mg, 1.15 mmol), PdCl2(PPh3)2 (35 mg, 10 mol%), Sphos (20.5 mg, 10 mol %), DMF: n-butanol (9:1) (5 mL), K3PO4 (317.8 mg, 1.5 mmol) was kept stirring for 3 h at 120 ℃. Reaction was monitored for completion by TLC. Reaction mass was quenched in water, then the product was extracted by ethyl acetate. Crude product purified utilizing column chromatography (100-200 mesh) by using the 5%-10% ethylacetate in pet ether. Pure product, 7a (192 mg, 96%), was characterized by 1H NMR, 13C NMR and mass spectral analysis. White solid, mp 210-213 ℃, 1H NMR (400 MHz, CDCl3): δ 9.13 (dd, 1H, J = 4.02, 1.32 Hz), 8.52 (dd, 1H, J = 8.40, 1.13 Hz), 7.70 (d, 2H, J = 8.62 Hz), 7.51 (dd, 1H, J = 8.48, 4.10 Hz), 7.45 (d, 2H, J = 8.59 Hz), 7.12 (m, 4H), 3.90 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.1, 160.7, 160.3, 159.5, 154.5, 150.4, 146.2, 136.1, 131.7, 131.7, 130.4, 126.9, 122.6, 122.5, 114.2, 113.7, 55.5, 55.2, 52.6; UPLC-MS: m/z calcd. for C24H20N2O4 400.1 found 401.47 [M].

Compound 8a: In a sealed tube, a mixture of 1, 6-naphthyridine 5 (268 mg, 0.5 mmol), 4-methoxyphenylboronic acid (91.2 mg, 0.6 mmol), PdCl2(PPh3)2 (35 mg, 10 mol%), PPh3(13.1 mg, 10 mol%), DMF:H2O (9:1) (5 mL), K3PO4 (317.8 mg, 1.5 mmol) was kept stirring for 1 h at 80 ℃. Reaction monitored by TLC for completion and the reaction mass was quenched in water, Product extracted by ethyl acetate. Crude product was purified using column chromatography (100-200 mesh) utilizing 5%-10% ethyl acetate in petroleum ether. Pure product 8a (218.1 mg, 94%), was characterized by 1H NMR, 13C NMR and mass spectral analysis. White solid, mp 114-116 ℃, 1H NMR (400 MHz, CDCl3): δ 9.03 (dd, 1H, J = 4.12, 1.48 Hz), 8.45 (dd, 1H, J = 8.57, 1.48 Hz), 7.90 (d, 2H, J = 8.28 Hz), 7.65 (d, 2H, J = 8.66 Hz), 7.54 (dd, 1H, J = 8.55, 4.15 Hz), 7.34 (d, 2H, J = 8.18 Hz), 7.07 (d, 2H, J = 8.62 Hz), 3.89 (s, 3H), 3.81 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.7, 160.9, 159.5, 154.7, 146.2, 145.3, 139.9, 139.2, 135.9, 133.8, 131.7, 129.7, 129.6, 128.8, 124.5, 123.8, 114.2, 55.5, 52.8, 21.7; UPLC-MS: m/z calcd. for C24H20N2O6S, 464.1 found 465.30 [M].

Compound 10a: In a sealed tube, a mixture of 1, 6-naphthyridine 5 (268 mg, 0.5 mmol), 4-biphenylboronic acid (118.8 mg, 0.6 mmol), PdCl2(PPh3)2 (35 mg, 10 mol%), Sphos (20.5 mg, 10 mol %), DMF: n-butanol (9:1) (5 mL), K3PO4 (317.8 mg, 1.5 mmol) was kept stirring for 1 h at 80 ℃. Reaction monitored by TLC, then followed by addition of 4-methoxyphenyl boronic acid (83.6 mg, 0.55 mmol), reaction checked by TLC. Reaction mass was quenched with water. The crude product was then extracted using ethyl acetate and purified by column chromatography (100-200 mesh) utilizing 5%-10% ethyl acetate in petroleum ether. Pure product 10a (185.2 mg, 83%), was characterized by 1H NMR, 13C NMR and mass spectral analysis. White solid, mp 132-135 ℃, 1H NMR (400 MHz, CDCl3): δ 8.83 (dd, 1H, J = 4.13, 1.72 Hz), 7.78 (dd, 1H, J = 8.49, 1.72 Hz), 7.61 (dd, 1H, J = 7.15, 1.91 Hz), 7.60 (dd, 1H, J = 7.15, 1.91 Hz), 7.48 (m, 2H), 7.34 (d, 2H, J = 8.68 Hz), 7.11 (dd, 1H, J = 8.48, 4.17 Hz), 7.05 (m, 2H), 6.97 (m, 5H), 3.80 (s, 3H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.9, 161.2, 159.5, 154.4, 149.4, 145.8, 141.8, 140.6, 136.6, 135.6, 132.6, 131.6, 131.2, 129.9, 129.6, 129.2, 128.0, 127.9, 126.9, 126.8, 122.8, 122.3, 113.6, 55.2, 52.6; UPLC-MS: m/z calcd. for C29H22N2O3 446.16 found 447.07 [M].

Acknowledgments

The authors wish to express their gratitude to the VIT University Vellore for the support and facilities and SIF-VIT for their support of NMR (DST-FIST Fund).

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