Note pubs.acs.org/joc
Regioselective Bromination of Thieno[2′,3′:4,5]pyrrolo[1,2‑d][1,2,4]triazin-8(7H)‑one and Sequential Suzuki Couplings Chunliang Lu,† Minyu Dong,‡ and Hugh Y. Zhu*,† †
Novartis Institutes for BioMedical Research (China), Zhangjiang Hi-Tech Park, Shanghai 201203, China Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, China
‡
S Supporting Information *
ABSTRACT: Regioselective bromination of thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one at the 2- or 9-position was achieved by modulating the basicity of the reaction conditions. An anion-directed site-specific bromination mechanism was proposed. In addition, a one-pot bromination− Suzuki coupling protocol was developed for quick access of analogues at the 9-position.
A
developing a more convergent synthesis for our SAR study as well as a new chemistry to approach the 9-position of the core structure. Herein, we report the first regioselective modification on the thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one core structure. The bromine atom was introduced selectively as a handle for modification to the 2- or 9-position of the tricyclic core. The mechanism of regioselective bromination at the 9-position under basic conditions was proposed to explain the regioselectivity. In addition, a one-pot bromination−Suzuki coupling protocol was developed for quick construction of 9-substituted analogues. Thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one 2 was synthesized according to the literature.6 Because of the low solubility of 2, DMF was tested as solvent. When it was subjected to 1 equiv of NBS at rt, the bromine atom mainly went to the 2-position (Table 1, entry 1). When 3 equiv of NBS was used, the bromine atom was introduced to both the 2-position and the 9-position (Table 1, entry 2). We proposed that the 9-position could be more favored if the electron density on the rings was modulated. Therefore, different bases were tested (entries 3−11), and the process of the reaction was monitored by LC-MS. To our delight, 2 equiv of K2CO3 and 3 equiv of NBS gave 87% of the 9-bromothieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one 3a with a small amount of 3b and 3c (entry 11). Extending the reaction time to 24 h did not change the ratio of the products. Stronger and weaker inorganic bases, such as KOH (entry 3), NaOH (entry 4), NaH (entry 5), KOtBu (entry 6), Cs2CO3 (entry 9), and KOAc
nnulated thieno[3,2-b]pyrroles are useful pharmacophores for drug discovery.1,2 One of these compounds, thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one 1 (Figure 1),
Figure 1. Structure of UHRF1 hit compound 1.
was recently identified as a hit during our screening for binders with the tandem tudor domain (TTD) of UHRF1 (TTDUHRF1).3 UHRF1 is a multidomain 90 kDa protein that is essential for maintaining the DNA methylation pattern and found to be overexpressed in various cancer types.4,5 Therefore, there is great interest to develop small-molecule inhibitors against UHRF1 as potential cancer therapeutic agents. The crystal structure of compound 1 in complex with TTD-UHRF1 revealed that the thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one core played a central role in binding with TTDUHRF1. The tricyclic core buries deep in a primary aromatic cage, and the 9-position of the core structure has a potential for extension.3 We then planned to improve the binding of the hit compound 1 through structure-based core modification. Ivachtchenko and co-workers first synthesized thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones and 2-substituted analogues.6 In their studies, 2-substitutions were introduced in the beginning of core structure construction. Meanwhile, there was no report on the modification of the 9-position of this tricyclic core. Thus, there is a demand for © 2017 American Chemical Society
Received: June 22, 2017 Published: July 20, 2017 9229
DOI: 10.1021/acs.joc.7b01542 J. Org. Chem. 2017, 82, 9229−9234
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In contrast, the conversion of 4 to 5 was much slower when K2CO3 was used as additive. 5 was obtained in 35% yield (92% brsm) under 2 equiv of K2CO3 and 3 equiv of NBS over 8 h (Scheme 1, method B). This observation implied that the reactivity of NBS was greatly decreased in the presence of K2CO3. The interaction between NBS and bases has been studied and applied for different reactions.7−9 This K2CO3mediated NBS deactivation effect could also explain why the more reactive 2-position was difficult to be brominated even with excess amounts of NBS under basic conditions (Table 1, entry 14). Based on the above observation, we proposed the following mechanism (Scheme 2). Upon addition of the base, N−H of 2 was deprotonated to give anion 6, which was demonstrated by the disappearance of the N−H proton in NMR (inset of Scheme 2). However, the chemical shifts of the protons on the aromatic ring did not change. This implied that the electron density of the two aromatic rings was not much affected, and hence, the switch of the regioselectivity was not driven by the electronic effect. The anion 6 was then quickly brominated by NBS to give 7a, which was in equilibrium with 7b. Because bromine on 7b was in close contact with the 9-position of the tricyclic core, the bromination of the 9-position was more favored. After proton transfer and tautomerization, 3a was obtained as the final product. Even though NBS was deactivated by K2CO3 as we observed previously, the bromination of 9-position was still favored through the mechanism proposed here. Similar results were observed by Orentas and co-workers on N-iodosuccinimide-mediated iodination, where the iodination on the aromatic ring was suppressed by K2CO3 while N-iodination was still operating.10 There are reports on transition-metal-mediated regioselective bromination through C−H activation,11−14 but the aniondirected bromination as we disclosed here is unprecedented to the best of our knowledge. In accord with our interest to explore the SAR of the 9-position of the thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one core, we attempted to apply a one-pot bromination−Suzuki coupling protocol to quickly access the analogues. Müller and co-workers previously developed a one-pot bromination−Suzuki coupling reaction by using 0.1 equiv excess of NBS for bromination.15 They noticed that without the catalytic amount of triphenylphospine (0.08 equiv), the Suzuki coupling reaction did not work. An excess amount of triphenylphosphine was first applied to our reaction to neutralize the excess amount of NBS. However, the coupling reaction still did not work. Unlike Müller’s reaction, which only used 1.1 equiv of NBS, our protocol used a significant amount of NBS (3 equiv). Thus, removal of the excess NBS became the prerequisite to the following coupling reaction. Inspired by Pinnick oxidation, which has to remove the excess amount of hypochlorous acid,16−18 we tried 2-methyl-2butene to eliminate the excess amount of NBS. Gratifyingly, the subsequent Suzuki coupling reaction worked well with phenylboronic acid. After a quick screening of catalysts, PdCl2(dppf)·CH2Cl2 was determined as the optimal one (Table S1, Supporting Information). Without further optimization of other conditions, the substrate scope was expanded to explore functional group compatibility (Table 2). Halogens such as fluorine (10b) and chlorine (10c) were tolerated under the reaction conditions. Phenylboronic acids with electronwithdrawing and electron-donating groups, such as trifluoromethyl (10d) and methoxy group (10e), could also be used.
Table 1. Regioselectivity of 2 with NBS under Different Conditionsa
product HPLC area (%)b entry
base (equiv)
NBS (equiv)
3a
3b
3c
1 2d 3 4 5 6 7 8 9 10 11 12 13 14
none none KOH (2) NaOH (2) NaH (2) KOtBu (2) DBU (2) Et3N (2) Cs2CO3 (2) KOAc (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2)
1 3 3 3 3 3 3 3 3 3 3 1 2 7
6 0 81 67 63 47 60 0 80 70 88(87)c 33 72 79
84(80)c 4 5 9 11 31 5 0 2 7 4 0 6 4
2 94(83)c 7 6 7 1 1 0 5 14 4 0 1 1
a
See Experimental Section for conditions. bUncalibrated HPLC area. Yield in the parentheses. Refer to Supporting Information for HPLC tracer. dOvernight reaction. c
(entry 10), gave decreased yield and regioselectivity. Organic bases, such as DBU (entry 7) and TEA (entry 8), also showed inferior yield and selectivity. Reducing the amount of NBS led to decreased yield of 3a because of incomplete conversion (entries 12 and 13). Additionally, double the amount of NBS did not lead to dibrominated product 3c, and 9-bromo product 3a was still the major product (entry 14). Therefore, this K2CO3-mediated 9-position bromination reaction is a robust process. Three brominated products, 3a, 3b, and 3c, could be obtained regioselectively with excellent yield under different conditions. The excellent regioselectivity promoted us to further explore the reaction mechanism. We proposed that the N−H of 2 played a vital role in reverting the selectivity from the 2-position to the 9-position. Thus, N-methylated compound 4 was synthesized and subjected to the optimum conditions for 3a and 3b. As expected, both cases gave 2-bromo product 5 as the major product. Without K2CO3, 1 equiv of NBS converted 4 to 5 in 1 h with 79% yield (90% brsm) (Scheme 1, method A). Scheme 1. Bromination of Methylated Compound 4a
a
Yields are based on HPLC area. Refer to the Supporting Information for HPLC tracer; brsm: based on recovered starting material. 9230
DOI: 10.1021/acs.joc.7b01542 J. Org. Chem. 2017, 82, 9229−9234
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The Journal of Organic Chemistry Scheme 2. Proposed Mechanism for Regioselective Bromination of 2 under Basic Conditionsa
a
Inset: (a) DMSO-d6 solution of 2. (b) DMSO-d6 solution of 2 treated with K2CO3 (2 equiv).
Table 2. Substrate Scope of One-Pot Bromination−Suzuki Coupling Reaction
m-Tolylboronic acid (10g) gave comparable yield to less bulky o-tolylboronic acid (10f). In addition to phenylboronic acids, other heterocyclic boronic acids, such as pyrazole (10h),
thiophene (10i), and pyridine (10j), were also compatible with the reaction conditions, though the yield for pyridine boronic acid (10j) was decreased to some extent. 9231
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NMR (100 MHz, DMSO-d6) δ 153.5, 135.1, 133.6, 129.5, 129.0, 121.7, 114.2, 90.0, 18.0; LC-MS, rt, 1.45 min; HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H7BrN3OS 285.9473, found 285.9475. 2-Bromo-5-methylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one (3b).
In summary, we have developed a regioselective bromination method for thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)ones. Unlike previously reported transition-metal-directed C−H activation/bromination reactions, this reaction probably went through an anion-directed process. This discovery might be found useful in other regioselective bromination reactions. In addition, a one-pot bromination−Suzuki coupling protocol was developed for synthesis of 9-substituted thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones. The key to the success was to use 2-methyl-2-butene to remove an excess amount of NBS, which made the subsequent Suzuki coupling possible. As far as we know, this is the first one-pot bromination−Suzuki coupling reaction where an excess amount of NBS was used. These two new discoveries greatly expanded the chemical space of thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-ones and facilitated our SAR studies. The biological activity of these compounds will be reported in separate publications at the appropriate time.
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To a DMF solution (1 mL) of substrate 2 (50 mg, 0.24 mmol) in a 5 mL vial was added NBS (43 mg, 0.24 mmol) at room temperature. The reaction was stirred for 1 h, and the process was monitored by LC-MS. The reaction mixture was diluted with water and filtered. The resulting solid was washed with water and dried under reduced pressure to afford 3b (55 mg, 80%) as an off-white solid, which was further purified by prep-HPLC for characterization purposes: mp 280.2−281.7 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.84 (s, 1H), 7.39 (s, 1H), 2.70 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 155.0, 136.0, 133.8, 128.6, 126.8, 117.8, 115.1, 103.6, 19.0; LC-MS, rt, 1.49 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H7BrN3OS 283.9493, found 283.9487. 2,9-Dibromo-5-methylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (3c).
EXPERIMENTAL SECTION
General Methods. Unless otherwise specified, all commercially available reagents were used as received. The reactions were monitored by analytical TLC using silica gel G/GF 254 plates and LC-MS (Agilent 6110; column type: SunFire C18, 4.6 × 50 mm, 3.5 μmm; mobile phase A: water (0.01% TFA), B: MeCN (0.01% TFA); gradient: 5% B increase to 95% B within 1.2 min, 95% B for 1.3 min, back to 5% B within 0.01 min). The column chromatography was performed on a Biotage flash system with SepaFlash columns (Ultrapure irregular silica, 40−63 μm, 60 Å). NMR (1H and 13C) spectra were recorded on 400 and 500 MHz spectrometers, and the data are included as follows: chemical shifts (δ ppm) (multiplicity, coupling constant (Hz), integration). The abbreviations for multiplicity are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets. Chemical shifts (δ) are reported relative to residual solvent signals (DMSO, 2.50 ppm for 1H NMR and 39.52 ppm for 13C NMR). Mass spectra were recorded on a ESI-MS TOF instrument. Melting points were determined with TA Instruments DSC Q2000. General Procedure for Bromination of 2 under Different Conditions. To a DMF solution (1 mL) of substrate 2 (50 mg, 0.24 mmol) in a 5 mL vial was added base (0.48 mmol) at room temperature. The reaction mixture was stirred for 10 min, and NBS (128 mg, 0.72 mmol) was then added. The reaction was stirred for 1 h, and the results were determined by LC-MS. For entries 1, 2 and 11, the reaction mixture was diluted with water and filtered. The resulting solid was washed with water and dried under reduced pressure to afford 3a, 3b, and 3c as the isolated product. They were further purified by prep-HPLC (Gilson 281 instrument, column: Boston Green ODS 21.2 × 250 mm, 10 μm, mobile phase: water/10 mM NH4HCO3/MeCN, gradient: 25 to 55% MeCN in 9 min stop at 15 min, flow rate: 25 mL/min) for characterization purposes. 9-Bromo-5-methylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one (3a).
To a DMF solution (2 mL) of substrate 2 (103 mg, 0.48 mmol) in a 5 mL vial was added NBS (256 mg, 1.44 mmol) at room temperature. The reaction was stirred overnight, and the reaction was monitored by LC-MS. The reaction mixture was diluted with water and filtered. The resulting solid was washed with water and dried under reduced pressure to afford 3c (153 mg, 83%) as an off-white solid, which was further purified by prep-HPLC for characterization purposes: 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.95 (s, 1H), 2.66 (s, 3H); 13 C{1H} NMR (125 MHz, DMSO-d6) δ 154.0, 135.6, 132.2, 129.2, 121.9, 118.5, 114.8, 90.1, 18.6; LC-MS, rt, 1.64 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C9H6Br2N3OS 363.8578, found 363.8570. 5,7-Dimethylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)one (4).
To a DMF solution (3 mL) of 2 (200 mg, 0.97 mmol) in a 10 mL vial was added K2CO3 (267 mg, 1.94 mmol), and the reaction was stirred at room temperature for 10 min. MeI (137 mg, 0.97 mmol) was then added, and the reaction was stirred at room temperature for 10 h. The reaction mixture was diluted with water (20 mL) and filtered. The resulting solid was washed with water (20 mL × 3) and dried under reduced pressure to afford the product 4 as an off-white solid (180 mg, 84% yield): mp 235.7−238.5 °C; 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, J = 5.5 Hz, 1H), 7.60 (d, J = 5.5 Hz, 1H), 7.44 (s, 1H), 3.54 (s, 3H), 2.75 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 153.9, 136.0, 130.3, 129.0, 127.2, 114.3, 103.5, 36.9, 18.9; LC-MS, rt, 1.60 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H10N3OS 220.0545, found 220.0558. 2-Bromo-5,7-dimethylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (5).
To a DMF solution (2 mL) of substrate 2 (100 mg, 0.48 mmol) in a 5 mL vial was added K2CO3 (133 mg, 0.96 mmol) at room temperature. The reaction mixture was stirred for 10 min, and NBS (256 mg, 1.44 mmol) was then added. The reaction was stirred for 1 h, and the process was monitored by LC-MS. The reaction mixture was diluted with water and filtered. The resulting solid was washed with water and dried under reduced pressure to afford 3a (120 mg, 87%) as a white solid, which was further purified by prep-HPLC for characterization purposes: 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.66 (d, J = 4.0 Hz, 1H), 2.69 (s, 3H); 13C{1H}
To a DMF solution (1 mL) of 4 (50 mg, 0.23 mmol) in a 5 mL vial was added NBS (41 mg, 0.23 mmol), and the reaction was stirred at 9232
DOI: 10.1021/acs.joc.7b01542 J. Org. Chem. 2017, 82, 9229−9234
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(125 MHz, DMSO-d6) δ 155.2, 136.3, 135.0, 132.6, 131.6, 131.4, 130.5, 128.69, 128.60, 121.5, 118.7, 115.1, 19.4; LC-MS, rt, 1.90 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11ClN3OS 316.0311, found 316.0314. 5-Methyl-9-(4-(trifluoromethyl)phenyl)thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10d).
room temperature for 1 h. The yield (78%) was determined based on HPLC area. The crude product was further purified to give a white solid by prep-HPLC for characterization purposes (41 mg, 61%): mp 262.5−262.9 °C; 1H NMR (500 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.39 (s, 1H), 3.52 (s, 3H), 2.72 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 153.8, 135.8, 133.6, 129.0, 126.5, 117.8, 115.0, 103.6, 37.0, 18.8; LC-MS, rt, 1.81 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H9BrN3OS 297.9650, found 297.9645. General Procedure for One-Pot Bromination−Suzuki Coupling Reaction. To a DMF solution (3 mL) of 2 (100 mg, 0.48 mmol) in a 10 mL microwave tube was added K2CO3 (132 mg, 0.96 mmol) at room temperature. The reaction mixture was stirred for 10 min, and NBS (256 mg, 1.44 mmol) was then added. The reaction was stirred at room temperature for 1 h and monitored by LC-MS. 2-Methyl-2butene (150 μL, 1.44 mmol) was added, and the mixture was further stirred for 30 min at room temperature. Arylboronic acid (0.96 mmol), K2CO3 (198 mg, 1.44 mmol), water (0.3 mL), and Pd(dppf)Cl2· CH2Cl2 (78 mg, 0.096 mmol) were added sequentially. The reaction tube was then flushed with N2, sealed, and submerged to the preheated oil bath (100 °C). The reaction was stirred for 16 h at 100 °C. The reaction mixture was passed through a syringe filter to remove the salts. The solvent was removed under vacuum to give a black oil. The crude product was purified by flash chromatography (6 g column) with 0−40% ethyl acetate in dichloromethane as eluent. 5-Methyl-9-phenylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one (10a).
Pink solid (68 mg, 40% yield): mp 279.3−299.9 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.83 (m, 3H), 7.65 (d, J = 5.0 Hz, 1H), 2.51 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 155.1, 136.7, 136.3, 135.1, 130.6, 130.5, 128.7, 128.1 (q, J = 32.1 Hz), 125.4 (q, J = 3.6 Hz), 124.8 (q, J = 272.3 Hz), 121.9, 118.3, 115.0, 19.4; LC-MS, rt, 1.94 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H11F3N3OS 350.0575, found 350.0564. 9-(4-Methoxyphenyl)-5-methylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10e).
Purple solid (66 mg, 44% yield); mp 247.2−249.2 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 5.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H), 2.74 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 159.2, 155.4, 136.3, 134.9, 131.2, 130.3, 128.7, 124.7, 120.8, 120.0, 115.0, 114.0, 55.6, 19.4; LC-MS, rt, 1.78 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3O2S 312.0807, found 312.0818. 5-Methyl-9-(m-tolyl)thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one (10f).
Off-yellow solid (70 mg, 51% yield): mp 243.4−243.8 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.85 (m, 3H), 7.67 (d, J = 5.5 Hz, 1H), 7.49 (m, 2H), 7.38 (m, 1H), 2.76 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 155.3, 136.3, 135.0, 132.6, 130.4, 130.0, 128.9, 128.6, 128.0, 121.3, 120.1, 115.1, 19.4; LC-MS, rt, 1.80 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H12N3OS 282.0701, found 282.0704. 9-(4-Fluorophenyl)-5-methylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10b).
Gray solid (73 mg, 51% yield): mp 277.2−279.0 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.64 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 2.75 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 155.2, 137.5, 136.2, 134.9, 132.5, 130.5, 130.3, 128.9, 128.6, 128.4, 127.1, 121.2, 120.2, 115.0, 21.6, 19.4; LC-MS, rt, 1.86 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3OS 296.0858, found 296.0852. 5-Methyl-9-(o-tolyl)thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin8(7H)-one (10g).
Purple solid (77 mg, 53% yield): mp 254.0−256.0 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.87 (m, 3H), 7.66 (d, J = 5.5 Hz, 1H), 7.33 (m, 2H), 2.76 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 162.0 (d, J = 245.3 Hz), 155.3, 136.3, 135.0, 132.0, (d, J = 8.3 Hz), 130.4, 128.9 (d, J = 3.0 Hz), 128.7, 121.3, 119.0, 115.5, (d, J = 21.3 Hz), 115.1, 19.4; LC-MS, rt, 1.81 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11FN3OS 300.0607; found 300.0612. 9-(4-Chlorophenyl)-5-methylthieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10c).
Pink solid (70 mg, 49% yield): mp 261.4−262.4 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 7.33−7.24 (m, 4H), 2.77 (s, 3H), 2.19 (s, 3H); 13 C{1H} NMR (125 MHz, DMSO-d6) δ 155.1, 137.2, 136.2, 134.5, 132.7, 130.6, 130.29, 130.20, 130.0, 128.3, 125.8, 122.5, 118.9, 114.9,
Brown solid (62 mg, 41% yield): mp 261.4−262.8 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.85 (m, 3H), 7.66 (d, J = 5.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 2.75 (s, 3H); 13C{1H} NMR 9233
DOI: 10.1021/acs.joc.7b01542 J. Org. Chem. 2017, 82, 9229−9234
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20.3, 19.2; LC-MS, rt, 1.82 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3OS 296.0858, found 296.0865. 5-Methyl-9-(1-methyl-1H-pyrazol-4-yl)thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10h).
ACKNOWLEDGMENTS We thank Dr. Counde Oyang (GDC, Novartis) for his support in this study. We are also very grateful for the suggestions from the anonymous reviewer on the mechanism of the basemediated bromination reaction.
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REFERENCES
(1) Ohtani, M.; Fuji, M.; Adachi, M.; Ogawa, T. U.S. Patent Appl. US6703385B1, 2004. (2) Peng, W.; Peltier, D. C.; Larsen, M. J.; Kirchhoff, P. D.; Larsen, S. D.; Neubig, R. R.; Miller, D. J. J. Infect. Dis. 2009, 199, 950. (3) Senisterra, G.; Zhu, H. Y.; Luo, X.; Zhang, H.; Xun, G.; Lu, C.; Xiao, W.; Hajian, T.; Loppnau, P.; Atadja, P.; Oyang, C.; Li, E.; Brown, P. J.; Arrowsmith, C. H.; Zhao, K.; Yu, Z.; Vedadi, M. Manuscript submitted. (4) Sidhu, H.; Capalash, N. Tumor Biol. 2017, 39, 1. (5) Du, J.; Johnson, L. M.; Jacobsen, S. E.; Patel, D. J. Nat. Rev. Mol. Cell Biol. 2015, 16, 519. (6) Ilyin, A. P.; Dmitrieva, I. G.; Kustova, V. A.; Manaev, A. V.; Ivachtchenko, A. V. J. Comb. Chem. 2007, 9, 96. (7) Senanayake, C. H.; Fredenburgh, L. E.; Reamer, R. A.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Am. Chem. Soc. 1994, 116, 7947. (8) Wei, Y.; Liang, F.; Zhang, X. Org. Lett. 2013, 15, 5186. (9) Wei, Y.; Lin, S.; Liang, F. Org. Lett. 2012, 14, 4202. (10) Javorskis, T.; Sriubaitė, S.; Bagdžiunas, G.; Orentas, E. Chem. ̅ Eur. J. 2015, 21, 9157. (11) Yu, Q.; Hu, L. a.; Wang, Y.; Zheng, S.; Huang, J. Angew. Chem., Int. Ed. 2015, 54, 15284. (12) John, A.; Nicholas, K. M. J. Org. Chem. 2012, 77, 5600. (13) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483. (14) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215. (15) Willy, B.; Müller, T. J. J. Org. Lett. 2011, 13, 2082. (16) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091. (17) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. (18) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
Gray solid (60 mg, 43% yield): mp 264.6−270.0 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.51 (s,1H), 8.11 (s, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 3.94 (s, 3H), 2.51 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 155.9, 138.8, 136.5, 135.1, 131.2, 130.5, 126.8, 120.5, 114.9, 113.4, 112.2, 19.3; LC-MS, rt, 1.55 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N5OS 286.0763, found 286.0759. 5-Methyl-9-(thiophen-3-yl)thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10i).
Yellow solid (63 mg, 45% yield): mp 266.5−267.0 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.22 (dd, J = 2.5, 1.5 Hz, 1H), 7.88 (d, J = 1.0 Hz, 1H), 7.87 (d, J = 5.5 Hz, 1H), 7.66 (m, 2H), 2.74 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 155.6, 136.4, 135.0, 132.7, 130.5, 129.4, 128.1, 126.2, 125.3, 121.3, 115.3, 115.0, 19.4; LC-MS, rt, 1.79 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H10N3OS2 288.0265, found 288.0266. 5-Methyl-9-(pyridin-3-yl)thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one (10j).
Gray solid (42 mg, 31% yield): 1H NMR (500 MHz, DMSO-d6) δ (ppm) 11.81 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.56 (dd, J = 4.5, 1.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 5.0 Hz, 1H), 7.52 (dd, J = 8.0, 5.0 Hz, 1H), 2.50 (s, 3H); 13 C{1H} NMR (125 MHz, DMSO-d6) δ 155.2, 150.2, 148.7, 137.1, 136.3, 135.3, 130.5, 128.7, 128.6, 123.6, 122.0, 116.4, 115.1, 19.3; LCMS, rt, 1.56 min, HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H11N4OS 283.0654, found 283.0656.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01542. 1
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H NMR, 13C NMR spectra, and HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hugh Y. Zhu: 0000-0002-3470-8504 Notes
The authors declare no competing financial interest. 9234
DOI: 10.1021/acs.joc.7b01542 J. Org. Chem. 2017, 82, 9229−9234
