Synthesis of Dihydroanthracenes via Palladium-Catalyzed Tandem Mizoroki–Heck/Reductive Heck Reactions Using Cyclic Diaryliodoniums and Alkenes

Abstract

An efficient Pd-catalyzed domino Mizoroki–Heck and reductive Heck reaction of terminal alkenes with six-membered cyclic diaryliodoniums is reported for the facile access to a diverse set of novel dihydroanthracenes. The scope of alkenes is general, leading to concise generation of 30 dihydroanthracenes which are not easily accessed by conventional methods. Furthermore, one of the newly synthesized dihydroanthracene displayed excellent antiproliferative activity against PANC-1 cancer cells (IC₅₀ = 11.74 μM).

Anthracene-based derivatives are essential structural motifs in a great number of anticancer drugs,[1] organic functional materials,[2] and natural products.[3] For instance, rhein (1a) possesses an anthracene scaffold and exhibits an excellent anti-inflammatory activity[4] (Figure [1]). Just like other anthracene-based compounds, there are several anthracene-based drugs such as mitoxantrone (1b), topopyrone C (1c), and doxorubicin (1d) with anticancer activities probably due to their noncovalent binding to DNA duplexes and these drugs are used for treatment of various cancers[5] (Figure [1]). In recent years, some studies have found that anthracene-based derivatives can also be used as an effective antidepressant with similar pharmacological properties to tricyclic antidepressants (TCAs).[6]

Thus, the synthesis of various anthracenes had attracted extensive attention by organic chemists and medicinal chemists. A variety of synthetic methods have been developed to construct dihydroanthracene scaffolds over the past few years, including benzylation of arenes,[7] modification of the existing dihydroanthracenes core,[8] and Friedel–Crafts alkylation[9] (Scheme [1a] and 1b). However, these present methods still have some challenges that need to be addressed, including harsh conditions, limited substrate scopes, poor accessibility of starting materials, and low yields. In the past decades, cyclic diaryliodonium salts have found numerous applications as electrophilic arylating reagents in both transition-metal-catalyzed and metal-free reactions to construct diverse arenes or heterocycles due to their high reactivity and environmentally benign nature.[10]

In our previous study, we demonstrated that dual arylation of dicarbonyl and C–N Buchwald coupling of nitriles with cyclic diaryliodonium salts could lead to the construction of fluorenes and acridines conveniently.[11] To continue our interest in constructing libraries of complex molecules with cyclic diaryliodonium salts, we envisioned that the careful modulation of two tandem Mizoroki–Heck reactions including one conventional Mizoroki–Heck reaction and one reductive Heck reaction between terminal alkenes and six-membered cyclic diaryliodonium salts could provide an alternative route to dihydroanthracenes. Herein, we report an efficient access to modularly generate 9,10-dihydroanthracenes from six-membered cyclic diaryliodonium salts with terminal alkenes, catalyzed by Pd(PPh₃)₄ (Scheme [1c]).

To test our hypothesis, we initiated the investigation by reacting the readily available methyl acrylate 3a with six-membered cyclic diaryliodonium salts 2a using Pd(OAc)₂ as a catalyst and Na₂CO₃ as the base in DMF under an argon atmosphere at 120 °C (Table [1]). The reaction provided the desired dihydroanthracene 4a albeit in 6% yield (entry 1). We then undertook some optimization mainly by changing different palladium species (entries 2–4). When Pd(PPh₃)₄ was employed, to our delight the desired compound 4a was obtained with a relatively high yield (16%). Next a base screening was carried out to optimize the yield (entries 5–8), and it was found that the yield could be improved to 39% with trimethylamine as the base source. From these observations, the base has an apparently influence on the reaction. Due to the reductive property of HCOONa to accelerate reductive Heck reaction, not surprisingly, its addition increased the yield significantly (entries 9 and 10). Thus, the Et₃N/HCOONa system was selected for further optimization of reaction conditions (entry 10). The influence of the solvents was then studied (entries 11–14). We found the yield was improved to 69% by using 1,2-dichloroethane (DCE) as the solvent, and we were surprised to observe that no desired product was generated in the presence of MeOH as solvent (entry 13 vs. 14). A further jump in yield could be attained by reducing the temperature to 100 °C (78%, entry 15).

Table 1 Optimization of Reaction Conditions^a

Entry	Catalyst	Base	Solvent	Temp (°C)	Yield (%)b
1	Pd(OAc)2	Na2CO3	DMF	120	6
2	PdCl2(dppf)2	Na2CO3	DMF	120	8
3	PdCl2(PPh3)2	Na2CO3	DMF	120	11
4	Pd(PPh3)4	Na2CO3	DMF	120	16
5	Pd(PPh3)4	K2CO3	DMF	120	19
6	Pd(PPh3)4	NaHCO3	DMF	120	6
7	Pd(PPh3)4	Cs2CO3	DMF	120	trace
8	Pd(PPh3)4	Et3N	DMF	120	39
9	Pd(PPh3)4	Et3N/MeCOONa	DMF	120	35
10	Pd(PPh3)4	Et3N/HCOONac	DMF	120	48
11	Pd(PPh3)4	Et3N/HCOONac	DMSO	120	39
12	Pd(PPh3)4	Et3N/HCOONac	toluene	120	25
13	Pd(PPh3)4	Et3N/HCOONac	MeOH	120	trace
14	Pd(PPh3)4	Et3N/HCOONac	DCE	120	69
15	Pd(PPh3)4	Et3N/HCOONac	DCE	100	78
16	Pd(PPh3)4	Et3N/HCOONac	DCE	80	51
17	Pd(PPh3)4	Et3N/HCOONac	DCE	60	32
18	Pd(PPh3)4	Et3N/HCOONac	DCE	rt	trace

^a Unless otherwise stated, 2a (1.0 equiv), 3a (2.0 equiv), catalyst (0.1 equiv), base (3.0 equiv), 15 h, Ar (using sealed tube).

^b HPLC yield.

^c Et₃N (3.0 equiv), HCOONa (2.0 equiv); note: DCE, 1,2-dichloroethane.

However, the yield was dropped to 51% and 32% by decreasing the temperature to 80 °C and 60 °C, respectively (entries 16, 17). And no reaction occurred at room temperature (entry 18). Thus, the optimal catalytic system for this transformation was 0.1 equiv Pd(PPh₃)₄ and 3 equiv of Et₃N with 2.0 equiv of HCOONa in DCE at 100 °C for 15 h (using sealed tube).

With the optimal reaction conditions in hand, we next examined the scope of this novel tandem process using a range of commercially available terminal alkenes 3 with different electron-withdrawing groups (Scheme [2]). Yields were generally good for terminal alkenes while alkyls in acrylate esters were varied, in a range of 65–78% (4a–e). In our method, other important materials acrolein and acrylamides were tolerated to give the corresponding products in good yields (4f–i). Furthermore, acrylonitrile successfully provided dihydroanthracenes 4j which could undergo further transformations to build complex molecular scaffolds. Importantly, we were also pleased to find that the sulfone functional group was suitable in the formation of dihydroanthracenes 4k, albeit with lower yields. 2-Methylacrylaldehyde also worked smoothly and delivered the corresponding product 4l. Our results demonstrated a broad substrate generality of alkenes, and a variety of unique dihydroanthracenes could be quickly afforded.

To fully establish the scopes of this one-pot C–C coupling procedure, other types of alkenes were further investigated (Scheme [3]). To our delight, generally the styrene derivatives with either simple alkyl (4m) or halogen (4o,p) substituents all gave excellent yield. Importantly, the substitution of halogens (F, Cl) in dihydroanthracenes would provide opportunities to further functionalize the incorporated arene if needed. In addition, due to the special properties of fluorine in drug metabolism, the incorporation of fluorine in arene (4o) might show higher metabolic stabilities and better pharmacokinetic properties. Synthetically, both fluorinated and chlorinated species (4o,p) could undergo further modifications to broaden the structural complexity. Gratifyingly, even pyridine-substituted alkene also reacted as well under the optimum conditions (4q). The motifs of this heterocycle compound are frequently found in polycyclic heteroarenes and natural products. More strikingly, we were also pleased to find that alkyl alkenes such as 4-penten-1-ol, methallyl alcohol, and vinyl carbamate were equally effective as the alkenes with electron-withdrawing substituents (4r–t). The tethered hydroxyl functional group was compatible and provided opportunities for further transformation.

The scope of six-membered cyclic diaryliodonium salts was finally investigated for this transformation (Scheme [4]). Acrylonitrile was used as alkenes source since the attached nitriles could be further transformed. Under the standard reaction conditions, the iodoniums with either electron-donating or electron-withdrawing groups attached were all transformed to the desired dihydroanthracenes at modest to good yields. Initially we tested the reactions of symmetrical cyclic diaryliodonium salts with acrylonitrile, which afforded the corresponding dihydroanthracenes in moderate to good yields (5a–c). Next, a series of unsymmetrical cyclic diaryliodonium salts were examined (5d–l). It was found that both electron-donating groups and electron-withdrawing substituents on cyclic diaryliodonium salts reacted smoothly, although the yield was decreased when the electronically poor substituted unsymmetrical cyclic diaryliodonium salts were employed (5d–h).

Based on our observation and previous literature, a possible reaction mechanism was proposed in Scheme S1 (see the Supporting Information). As mentioned above, many dihydroanthracene-containing motifs possess anticancer properties due to their noncovalent binding to DNA duplexes. Therefore, the biological applications of the products were also investigated using a well-established MTT assay (Table [2]). To our delight, several new synthesized compounds displayed potent antiproliferative activities against the human cancer cell lines. Among them, 4j displayed the highest cytotoxicity against PANC-1 cell (IC₅₀ = 11.74 μM). Further structural optimization and structure–activity relationship study of these new scaffolds are currently in progress.

In summary, we have successfully achieved a general and efficient one-pot procedure with six-membered cyclic iodoniums and various commercially available terminal alkenes for the construction of structurally diverse dihydroanthracenes derivatives.[12] Two C–C bonds were formed and involved one conventional Mizoroki–Heck reaction and one reductive Heck reaction between cyclic iodoniums and terminal alkenes. Except traditional acrylates and alkenes with γ-electron-withdrawing functional groups, both aryl alkenes and alkyl alkenes are suitable. The present method is straightforward for the diversified synthesis of dihydroanthracenes, providing a complementary strategy to the reported synthetic routes. More importantly, the screening of our new synthetic dihydroanthracenes successfully leads to the discovery of several novel compounds with potent antiproliferative activities.

• References and Notes

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• 5a Ye MY, Yao GY, Wei JC, Pan YM, Liao ZX, Wang HS. Int. J. Mol. Sci. 2013; 14: 9424
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• 6 Karama U, Sultan MA, Almansour AI, El-Taher KE. Molecules 2016; 21: 61
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• 8a von Grotthuss E, Prey SE, Bolte M, Lerner HW, Wagner M. J. Am. Chem. Soc. 2019; 141: 6082
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• 10a Hu T, Ye Z, Zhu K, Xu K, Wu Y, Zhang F. Org. Lett. 2020; 22: 505
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• 10d Liu Z, Zhu D, Luo B, Zhang N, Liu Q, Hu Y, Pi R, Huang P, Wen S. Org. Lett. 2014; 16: 5600
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• 11b Peng XL. H, Wu F, Zhu D, Genesan A, Huang P, Wen S. Adv. Synth. Catal. 2017; 359: 1152
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• 11c Peng X, Sun Z, Kuang P, Li L, Chen J, Chen J. Org. Lett. 2020; 22: 5789
  CrossrefPubMedSearch in Google Scholar
• 12 Procedure to Synthesize Dihydroanthracene 4a To a seal tube was added cyclic diaryliodonium salt 2a (0.1 g, 0.226 mmol, 1.0 equiv), methyl acrylate 3a (0.039 g, 0.45 mmol, 2.0 equiv), Pd(PPh₃)₄ (0.026 g, 0.022 mmol, 0.1 equiv), Et₃N (0.069 g, 0.67 mmol, 3.0 equiv), HCOONa (0.031 g, 0.45 mmol, 2.0 equiv), and DCE (3.0 mL). Then the tube was sealed, degassed, and recharged with argon. The reaction proceeded at 100 °C for 15 h under argon atmosphere. The remained mixture was extracted with DCM (20 mL), the combined organic layers were washed with H₂O (3 × 2 mL) and brine, dried over anhydrous Na₂SO₄, and evaporated in vacuo. The residue was purified by column chromatography on a silica gel (PE/EtOAc = 50:1 to 20:1) to provide compound 4a (0.036 g, 78%). ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.6 Hz, 2 H), 7.51 (d, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.33–7.29 (m, 2 H), 4.46 (t, J = 7.2 Hz, 1 H), 4.07 (s, 2 H), 3.81 (s, 3 H), 2.80 (d, J = 7.2 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 173.14, 146.39, 140.91, 127.63, 127.33, 124.47, 120.10, 51.99, 43.72, 41.79, 38.63. HRMS (ESI): m/z calcd for C₁₇H₁₇O₂ [M + H]⁺: 253.1150; found: 253.1146. Procedure to Synthesize Dihydroanthracene 5a To a seal tube was added cyclic diaryliodonium salt 2 (0.1 g, 0.213 mmol, 1.0 equiv), acrylonitrile 3 (0.022 g, 0.426 mmol, 2.0 equiv), Pd(PPh₃)₄ (0.024 g, 0.021 mmol, 0.1 equiv), Et₃N (0.065 g, 0.639 mmol, 3.0 equiv), HCOONa (0.029 g, 0.426 mmol, 2.0 equiv), and DCE (3.0 mL). Then the tube was sealed, degassed, and recharged with argon. The reaction proceeded at 100 °C for 15 h under argon atmosphere. The remained mixture was extracted with DCM (20 mL), the combined organic layers were washed with H₂O (3 × 2 mL) and brine, dried over anhydrous Na₂SO₄, and evaporated in vacuo. The residue was purified by column chromatography on a silica gel (PE/EtOAc = 50:1 to 20:1) to provide compound 5a (0.033 g, 67%). ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 7.6 Hz, 2 H), 7.45 (d, J = 0.4 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 4.10 (t, J = 7.2 Hz, 1 H), 4.01 (s, 2 H), 2.79 (d, J = 7.2 Hz, 2 H), 2.44 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 144.22, 138.37, 137.19, 129.22, 125.09, 119.82, 118.73, 42.79, 41.75, 22.24, 21.78. HRMS (ESI): m/z calcd for C₁₈H₁₈N [M + H]⁺: 248.1361; found: 248.1375.

Corresponding Author

Publication History

Received: 31 October 2020

Accepted after revision: 28 December 2020

Accepted Manuscript online:
28 December 2020

Article published online:
27 January 2021

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1a Pommier Y, Leo E, Zhang H, Marchand C. Chem. Biol. 2010; 17: 421
  CrossrefPubMedSearch in Google Scholar
• 1b Tikhomirov AS, Shtil AA, Shchekotikhin AE. Recent Pat. Anticancer Drug Discov. 2018; 13: 159
  CrossrefPubMedSearch in Google Scholar
• 1c Malik EM, Müller CE. Med. Res. Rev. 2016; 36: 705
  CrossrefPubMedSearch in Google Scholar
• 1d Badria FA, Ibrahim AS. Drug Discov. Ther. 2013; 7: 84
  CrossrefPubMedSearch in Google Scholar
• 2a Matsuo Y, Okada H, Kondo Y, Jeon I, Wang H, Yu Y, Matsushita T, Yanai M, Ikuta T. ACS Appl. Mater. Interfaces 2018; 10: 11810
  CrossrefPubMedSearch in Google Scholar
• 2b Haldar S, Chakraborty D, Roy B, Banappanavar G, Rinku K, Mullangi D, Hazra P, Kabra D, Vaidhyanathan R. J. Am. Chem. Soc. 2018; 140: 13367
  CrossrefPubMedSearch in Google Scholar
• 2c Fonari A, Corbin NS, Vermeulen D, Goetz KP, Jurchescu OD, McNeil LE, Bredas JL, Coropceanu V. J. Chem. Phys. 2015; 143: 224503
  CrossrefPubMedSearch in Google Scholar
• 3a Singh AJ, Gorka AP, Bokesch HR, Wamiru A, O’Keefe BR, Schnermann MJ, Gustafson KR. J. Nat. Prod. 2018; 81: 2750
  CrossrefPubMedSearch in Google Scholar
• 3b Liang YK, Yue ZZ, Li JX, Tan C, Miao ZH, Tan WF, Yang CH. Eur. J. Med. Chem. 2014; 84: 505
  CrossrefPubMedSearch in Google Scholar
• 3c Mariani A, Mai TT, Zacharioudakis E, Hienzsch A, Bartoli A, Caneque T, Rodriguez R. Chem. Commun. 2016; 52: 1358
  CrossrefPubMedSearch in Google Scholar
• 4 Cannon CP, Bhatt DL, Oldgren J, Lip GY. H, Ellis SG, Kimura T, Maeng M, Merkely B, Zeymer U, Gropper S, Nordaby M, Kleine E, Harper R, Manassie J, Januzzi JL, Ten Berg JM, Steg PG, Hohnloser SH. N. Engl. J. Med. 2017; 377: 1513
  CrossrefPubMedSearch in Google Scholar
• 5a Ye MY, Yao GY, Wei JC, Pan YM, Liao ZX, Wang HS. Int. J. Mol. Sci. 2013; 14: 9424
  CrossrefPubMedSearch in Google Scholar
• 5b Yang X, Sun G, Yang C, Wang B. ChemMedChem 2011; 6: 2294
  CrossrefPubMedSearch in Google Scholar
• 5c Tan JH, Zhang QX, Huang ZS, Chen Y, Wang XD, Gu LQ, Wu JY. Eur. J. Med. Chem. 2006; 41: 1041
  CrossrefPubMedSearch in Google Scholar
• 5d Shchekotikhin AE, Shtil AA, Luzikov YN, Bobrysheva TV, Buyanov VN, Preobrazhenskaya MN. Bioorg. Med. Chem. 2005; 13: 2285
  CrossrefPubMedSearch in Google Scholar
• 5e Huang Q, Lu G, Shen HM, Chung MC, Ong CN. Med. Res. Rev. 2007; 27: 609
  CrossrefPubMedSearch in Google Scholar
• 5f Donnelly S, Scott DL, Emery P. Baillieres Clin. Rheumatol. 1992; 6: 251
  CrossrefPubMedSearch in Google Scholar
• 6 Karama U, Sultan MA, Almansour AI, El-Taher KE. Molecules 2016; 21: 61
  CrossrefPubMedSearch in Google Scholar
• 7 Wang F, Ueda W. Chem. Eur J. 2009; 15: 742
  CrossrefPubMedSearch in Google Scholar
• 8a von Grotthuss E, Prey SE, Bolte M, Lerner HW, Wagner M. J. Am. Chem. Soc. 2019; 141: 6082
  CrossrefPubMedSearch in Google Scholar
• 8b Chatterjee A, König B. Angew. Chem. Int. Ed. 2019; 58: 14289
  CrossrefPubMedSearch in Google Scholar
• 9 Zhu J, Perez M, Caputo CB, Stephan DW. Angew. Chem. Int. Ed. 2016; 55: 1417
  CrossrefPubMedSearch in Google Scholar
• 10a Hu T, Ye Z, Zhu K, Xu K, Wu Y, Zhang F. Org. Lett. 2020; 22: 505
  CrossrefPubMedSearch in Google Scholar
• 10b Li Q, Zhang M, Zhan S, Gu Z. Org Lett. 2019; 21: 6374
  CrossrefPubMedSearch in Google Scholar
• 10c Xu S, Zhao K, Gu Z. Adv. Synth. Catal. 2018; 360: 5236
  Search in Google Scholar
• 10d Liu Z, Zhu D, Luo B, Zhang N, Liu Q, Hu Y, Pi R, Huang P, Wen S. Org. Lett. 2014; 16: 5600
  CrossrefPubMedSearch in Google Scholar
• 11a Peng XL. L, Ren Y, Xue H, Liu J, Wen S, Chen J. Adv. Synth. Catal. 2020; 362: 2030
  CrossrefSearch in Google Scholar
• 11b Peng XL. H, Wu F, Zhu D, Genesan A, Huang P, Wen S. Adv. Synth. Catal. 2017; 359: 1152
  CrossrefSearch in Google Scholar
• 11c Peng X, Sun Z, Kuang P, Li L, Chen J, Chen J. Org. Lett. 2020; 22: 5789
  CrossrefPubMedSearch in Google Scholar
• 12 Procedure to Synthesize Dihydroanthracene 4a To a seal tube was added cyclic diaryliodonium salt 2a (0.1 g, 0.226 mmol, 1.0 equiv), methyl acrylate 3a (0.039 g, 0.45 mmol, 2.0 equiv), Pd(PPh₃)₄ (0.026 g, 0.022 mmol, 0.1 equiv), Et₃N (0.069 g, 0.67 mmol, 3.0 equiv), HCOONa (0.031 g, 0.45 mmol, 2.0 equiv), and DCE (3.0 mL). Then the tube was sealed, degassed, and recharged with argon. The reaction proceeded at 100 °C for 15 h under argon atmosphere. The remained mixture was extracted with DCM (20 mL), the combined organic layers were washed with H₂O (3 × 2 mL) and brine, dried over anhydrous Na₂SO₄, and evaporated in vacuo. The residue was purified by column chromatography on a silica gel (PE/EtOAc = 50:1 to 20:1) to provide compound 4a (0.036 g, 78%). ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.6 Hz, 2 H), 7.51 (d, J = 7.6 Hz, 2 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.33–7.29 (m, 2 H), 4.46 (t, J = 7.2 Hz, 1 H), 4.07 (s, 2 H), 3.81 (s, 3 H), 2.80 (d, J = 7.2 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 173.14, 146.39, 140.91, 127.63, 127.33, 124.47, 120.10, 51.99, 43.72, 41.79, 38.63. HRMS (ESI): m/z calcd for C₁₇H₁₇O₂ [M + H]⁺: 253.1150; found: 253.1146. Procedure to Synthesize Dihydroanthracene 5a To a seal tube was added cyclic diaryliodonium salt 2 (0.1 g, 0.213 mmol, 1.0 equiv), acrylonitrile 3 (0.022 g, 0.426 mmol, 2.0 equiv), Pd(PPh₃)₄ (0.024 g, 0.021 mmol, 0.1 equiv), Et₃N (0.065 g, 0.639 mmol, 3.0 equiv), HCOONa (0.029 g, 0.426 mmol, 2.0 equiv), and DCE (3.0 mL). Then the tube was sealed, degassed, and recharged with argon. The reaction proceeded at 100 °C for 15 h under argon atmosphere. The remained mixture was extracted with DCM (20 mL), the combined organic layers were washed with H₂O (3 × 2 mL) and brine, dried over anhydrous Na₂SO₄, and evaporated in vacuo. The residue was purified by column chromatography on a silica gel (PE/EtOAc = 50:1 to 20:1) to provide compound 5a (0.033 g, 67%). ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 7.6 Hz, 2 H), 7.45 (d, J = 0.4 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 4.10 (t, J = 7.2 Hz, 1 H), 4.01 (s, 2 H), 2.79 (d, J = 7.2 Hz, 2 H), 2.44 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 144.22, 138.37, 137.19, 129.22, 125.09, 119.82, 118.73, 42.79, 41.75, 22.24, 21.78. HRMS (ESI): m/z calcd for C₁₈H₁₈N [M + H]⁺: 248.1361; found: 248.1375.

• Supplementary Material