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COMMUNICATION A Directing Group Free Pd(II)-Catalysed Desulfitative C6-Arylation of 2-Pyridone using Arylsulfonyl Chloride Received 00th January 20xx, Accepted 00th January 20xx
Ujjwal Karmakar,a and Rajarshi Samanta*a
DOI: 10.1039/x0xx00000x
A Pd(II)-catalysed direct desulfitative arylation was realized at the C6-position of 2-pyridone scaffolds. Aryl sulfonyl chlorides were used as the alternate arylating agent. The required site-selectivity occured without the strategic installation of heteroatom containing directing group. Preliminary mechanistic studies revealed that radical species were involved during this process. Transition metal catalysed introduction of functional groups in the electron deficient heterocycles via C-H bond functionalizations becomes an important area of research.1 Recently, among various electron deficient heterocycles, 2pyridone scaffold gathers significant attention from the synthetic chemists due to its often presence in pharmaceuticals, bio-active natural products and organic materials.2 Arylated 2-pyridones, especially C6-arylated 2pyridone scaffolds are omnipresent in various bioactive molecules (Figure 1). The classical approaches to prepare these scaffolds mostly deal with multi-step synthesis, harsh reaction conditions or treatment with prefunctionalized coupling partners. Arguably, one of the most straightforward approach could be the direct introduction of functional groups via siteselective manner. Notable advancement was observed during the last few years in the direct site-selective introduction of functional groups at the various position of this core through transition metal catalysed C-H bond functionalizations.3 Subsequently, significant progress was realized in the direct site-selective arylations at the various position of this core.4-5 C6-position, being the most electron deficient center of this core offers an important synthetic task towards the direct arylation at this site. Strategically, the challenge was overcome with the aid of robust and well-proven directing group based strategies.6-10 Hirano and Miura’s group elegantly developed a general two-steps protocol for the Rh(I)-catalysed C6borylation and its subsequent arylation under Pd(0)-catalysis.6a In another important development, Liu’s group reported a a. Department
of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India. Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1 Transition metal catalysed C6-selective arylation of 2-pyridone
Figure 1 Bioactive C6 arylated 2-pyridone
direct C6-arylation of 2-pyridone under Rh(III)-catalysed mild conditions using commercially available organotrifluoroborates.7 Subsequently, our group also developed a mild Rh(III)-catalysed direct introduction of phenol moieties at the C6-position of 2-pyridone with quinone diazides.8 In another advancement, the C6-arylation of 2pyridones was developed by Das’s group under Ru(II)catalysed conditions using aryl boronic acids.9 The related heteroarylaton at this position was also explored with the aid of nitrogen containing directing group by Hirano, Miura’s and Waser’s group.6b,10 Tactically, 2-pyridine was used in these methods as a directing group to obtain the required siteselectivity. However, as per our best of knowledge there is no report on direct C6-arylation of 2-
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Table 1 Optimization of reaction conditionsa
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En
Catalyst
Solvent
Oxidant
Additive (mol%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Pd(OAc)2 Pd(OAc)2 PdCl2 PdCl2(PPh3)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2
dioxane DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE
Ag2O Ag2O Ag2O Ag2O AgOAc Ag2CO3 Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O
17 18
Pd(OAc)2 Pd(OAc)2
DCE DCE
Ag2O Ag2O
NaOAc (100) Li2CO3 (100) PivOH (100) PivOH (50) AcOH (50) TFA (50) BzOH (50) 4-OMeBzOH (50) 4-MeBzOH (50) 2,6-(OMe)2BzOH (50) Mesitoic acid PivOH (20)
Yield (%)b 12 27 22 15 14 traces 30 34 46 52 n.d. n.d. 34 50 36 30 22 37
Scheme 2 Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), Pd(OAc)2 (10 mol%), Ag2O (0.2 mmol), pivalic acid (50 mol%), DCE (0.1 M), 110 °C. aReaction was done at 2 mmol scale
aReaction
conditions: 1a (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol%), Ag2O (0.2 mmol), solvent (0.1 M), 12 h, 110 °C. bIsolated yield. n.d. = not detected.
pyridone core with-out the strategic placement of 2-pyridine or related nitrogen containing directing group. Among recent various alternative arylation sources, one of the most promising is RSO2Cl derivatives due to their easy preparation, simple handling, commercial availability and ability to provide the alternate regioisomers.11,12 They are used as suitable aryl coupling partners with the liberation of SO2 under the transition metal catalysis via C-H bond functionalizations.13 In continuation with our interest in site-selective functionalizations of 2-pyridone scaffolds under transition metal catalysis,5b,8,14 we hypothesized that the proper choice of transition metal catalyst and arylating source which has ability to proceed via different mechanistic pathway might trigger the C6-arylation with-out the guidance from the nitrogen containing directing group. We realized that the palladium catalysts could be the desirable choice due to its wide application in known desulfitative cross-coupling reactions.11a,13,15 Herein, we report a Pd(II)-catalysed direct desulfitative C6-arylation of 2-pyridone scaffolds using arylsulfonylchloride as coupling partner with-out the help of pyridine directing group. Our initial investigation was started with N-methyl 2-pyridone (1a) and p-toluenesulfonyl chloride (2a) as an aryl coupling partner in the presence of catalytic amount of Pd(OAc) 2. Initially, the reaction mixture was stirred in dioxane solvent at the 110 °C for 12 h in the presence of 10 mol% of Pd(OAc) 2 catalyst and 2 equiv of Ag2O oxidant to obtain the C6-arylated product 3a in 12% yield (Table 1, entry 1). The yield of the
desired product 3a was further decreased when the lower amount of Ag2O was utilised (see ESI detail optimization table). Next, the yield was improved to 27% when DCE was used as the reaction solvent (Table 1, entry 2). Further screening of other catalysts and oxidants did not improve the yield (Table 1, entries 3-6). For the betterment of the yield of the 3a, several additives were tested. The yield was marginally improved by the use of additives like NaOAc and Li2CO3 (Table 1, entries 78). Next, various carboxylic acids were screened. Among various carboxylic acids, pivalic acid was found to be the best with its 50 mol% amount (Table 1, entries 9-10). Other tested carboxylic acids either afforded comparable yield of the desired product 3a or decreased yield (Table 1, entries 11-17). The yield of 3a was getting lowered when there was decrease in pivalic acid amount to 20 mol% (Table 1, entry 18). After several screening of other parameters, there was no additional improvement observed in the yield of the desired product. Finally, the synthetically acceptable yield of 3a under 10 mol% Pd(OAc)2, 2 equiv of Ag2O and 50 mol% pivalic acid in DCE solvent at 110 °C was considered as the optimized conditions. After having the optimized conditions in hand, 2-pyridones with different steric and electronic properties were explored towards the C6-arylation reactions (Scheme 2). Initially, the C3-substituted 2-pyridones were screened for the desired reaction. The developed protocol worked efficiently with the electron-rich substituents present at the C3-position of 2pyridone and provided moderate to good yields of the corresponding C6-arylated products (Scheme 2, 3b-3d). The
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Scheme 4 Plausible mechanism
Scheme 3 Control experiments
reaction proceeded successfully with C4-substitution also (Scheme 2, 3e). Pleasingly, the substitution like thiophenyl group at the C5-position survived during the reaction (Scheme 2, 3f). Another important heterocyclic scaffold, isoquinolone also reacted to provide the desired product under the optimized reaction conditions (Scheme 2, 3g). Further, various N-alkyl groups were explored to obtain the desired products (Scheme 2, 3h-3k). When the N-benzyl-6-methylpyridin-2(1H)one was screened under the optimized conditions, there was no desired product formation realized. Next, the developed protocol was further extended with the various arylsulfonyl chlorides bearing different steric and electronic properties (Scheme 2, 4a-4g). The reaction worked efficiently with benzenesulfonyl chloride and provided a good yield of the corresponding arylated product (Scheme 2, 4a). It is important to mention that the structure of the product with the C6-aryl group was unequivocally determined by the comparison of the NMR data of 4a and 4b with known literature data.16 Electron rich substituents like -OCH3, -tBu groups present at the paraposition of the arylsulfonyl chloride reacted effectively with 1a and afforded the good yields of the desired C6-arylated products (Scheme 2, 4b-4c). The developed method worked smoothly with halogen substituent like –Br group attached to the para-position and furnished a good yield of the product (Scheme 2, 4d). In the presence of para-fluoro substituted arylsulfonyl chloride, the reaction was sluggish and afforded lower yield of the corresponding product (Scheme 2, 4e). Further, the C6-arylation reaction was tested with arylsulfonyl chlorides having substituents at the meta-position. The developed procedure worked efficiently with electron-rich substituents like -CH3 group present at the meta-position of arylsulfonyl chloride and furnished a good yield of corresponding product (Scheme 2, 4f). Next, a bulky naphthylsulfonyl chloride worked effectively and provided a good yield of corresponding C6-arylated product (Scheme 2, 4g).
The protocol remained unsuccessful in the cases of N-phenyl 2-pyridone, NH-free 2-pyridone and N-methyl 4-pyridone substrates (Scheme 2, 4h-4j). As a demonstration of scalability, the reaction was carried out in a 2 mmol scale under the developed conditions to obtain 41% isolated yield of the desired C6-arylated 2-pyridone product (Scheme 2, 3a). To understand the mechanism of the reaction, several control experiments were performed. The H/D scrambling experiment was performed with 1a and CD3CO2D (10 equiv) was used as the deuteration source. The result showed that no deuterium incorporation was observed at the C6-position in the absence of tosyl chloride. This result revealed that C–H metalation was irreversible in the absence of coupling partner tosyl chloride. Further, to know the participation of the radical intermediates in the reaction pathway, it was carried out in the presence of stoichiometric amount of radical trapping reagent like 2,6-ditert-butyl-4-methylphenol (BHT). The formation of the desired C6-arylated product 3a was inhibited completely and the side product 6 was formed in a significant amount. This result suggested that free aryl sulfonyl radical was generated during the progress of the reaction which was quenched by radical trapping agent BHT (Scheme 3ii). Further, few more experiments were executed to know the exact conditions of the formation of the arylsulfonyl radical species (Scheme 3iiiv). When the tosyl chloride was treated with BHT in the presence of catalytic amount of Pd(OAc)2, only trace amount of arylsulfonyl coupled BHT adduct 6 was formed (Scheme 3iii). Next, only 10% formation of adduct 6 was realized when the reaction was carried out under the 2 equiv of Ag2O (Scheme 3iv). Finally, a good yield of the adduct 6 was isolated when the reaction was carried out in the presence of catalytic Pd(OAc)2 and 2 equiv of Ag2O (Scheme 3v). These results proved that both the catalytic Pd(OAc)2 and stoichiometric Ag2O were necessary to generate the arylsulfonyl radical species. Moreover, the analysis of the GCMS data of the crude reaction mixture confirmed the formation of 4,4'-dimethyl1,1'-biphenyl (See ESI for more details). This result suggested the generation of para-methylphenyl radical which might develop from the para-methylsulfonyl radical via SO2 elimination. Based on the control experiments and previous literature reports,13 a tentative mechanism was proposed (Scheme 4). Initially, in the presence of Pd(OAc)2 and Ag2O, arylsulfonyl
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chloride provided the corresponding arylsulfonyl radical species which further reacted with Pd(OAc)2 to produce an aryl palladium species A via the extrusion of SO2. Next, the deprotonation was occurred at the most electron deficient C6position of 1a with the involvement of species A to form C6metallated intermediate B through metal-pivalate assisted C-H bond functionalization. Further, the reductive elimination of species B afforded the desired compound 3 with the generation of Pd(0) species. Finally, the oxidation of Pd(0) species by Ag2O regenerated the active Pd(II) species to continue the catalytic cycle. However, at this moment, Pd(II)/Pd(IV) catalytic cycle cannot be completely ruled out. The detail mechanistic studies are currently underway to reveal more insight.
Conclusions In conclusion, Pd(II)-catalyzed desulfitative C6-arylation of 2pyridones was reported with easily accessible, cheap arylsulfonyl chlorides as an alternative arylation source. The developed reaction was explored with wide scope and exhibited good functional group tolerance. The protocol proceeded without the strategic installation of the heteroatom-containing directing group. Preliminary mechanistic studies revealed that radical species are involved.
Conflicts of interest
3
4
5 6
7 8 9 10 11
12
There are no conflicts to declare.
Acknowledgements Authors thank the SERB, India (CRG/2018/000630), and DST, India (SR/FST/CSII-026/2013; for 500 MHz NMR), for financial support. UK thanks to IIT Kharagpur for his research fellowship. 13
References 1
2
(a) R. Das and M. Kapur, Asian J. Org. Chem. 2018, 7, 1217; (b) Y. Nakao, Synthesis 2011, 3209; (c) N. I. Nikishkin, J. Huskens and W. Verboom, Org. Biomol. Chem. 2013, 11, 3583; (d) T. Iwai and M. Sawamura, ACS Catal. 2015, 5, 5031; (e) D. E. Stephens and O. V. Larionov, Tetrahedron 2015, 71, 8683; (f) L. Théveau, C. Schneider, C. Fruit and C. Hoarau, ChemCatChem 2016, 8, 3183; (g) K. Murakami, S. Yamada, T. Kaneda and K. Itami, Chem. Rev. 2017, 117, 9302; (h) L. Ping, D. S. Chung, J. Boufard and S. Lee, Chem. Soc. Rev. 2017, 46, 4299; (i) P. Y. Choy, S. M. Wong, A. Kapdi and F. Y. Kwong, Org. Chem. Front. 2018, 5, 288; (j) E. V. Verbitskiy, G. L. Rusinova, O. N. Chupakhin and V. N. Charushin, Synthesis 2018, 193. Directing group free functionalizations: (k) C. Tian, Q. Wang, X. Wang, G. An and G. Li, J. Org. Chem. 2019, 84, 14241; (l) H. Ni, X. Shi, Y. Li, X. Zhang, J. Zhao and F. Zhao, Org. Biomol. Chem. 2020, 18, 6558. (a) H. J. Jessen and K. Gademann, Nat. Prod. Rep. 2010, 27, 1168; (b) R. M. Wilson and S. J. Danishefsky, Acc. Chem. Res. 2006, 39, 539; (c) C. Tohda, T. Kuboyama and K. Komatsu, Neurosignals 2005, 14, 34.
14
15 16
Related reviews: (a) K. Hirano and M. Miura, Chem. Sci. 2018, View Article Online 9, 22; (b) A. Biswas, S. Maity, S. Pan and R. Samanta, Chem DOI: 10.1039/D0OB01716G Asian J. 2020, 15, 2092; (c) A. M. Prendergast and G. P. McGlacken, Eur. J. Org. Chem. 2018, 6068. Arylation at the C3-position: (a) A. Nakatani, K. Hirano, T. Satoh and M. Miura, J. Org. Chem. 2014, 79, 1377; (b) A. Najib, S. Tabuchi, K. Hirano and M. Miura, Heterocycles 2016, 92, 1187; (c) E. E. Anagnostaki, A. D. Fotiadou, V. Demertzidou and A. L. Zografos, Chem. Commun. 2014, 50, 6879; (d) A. Modak, S. Rana and D. Maiti, J. Org. Chem. 2015, 80, 296; (e) P. Chauhan, M. Ravi, S. Singh, P. Prajapati and P. P. Yadav, RSC Adv. 2016, 6, 109. Arylation at the C5-position: (a) Y. Chen, F. Wang, A. Jia and X. Li, Chem. Sci. 2012, 3, 3231; (b) S. Maity, D. Das, S. Sarkar and R. Samanta, Org. Lett. 2018, 20, 5167. (a) W. Miura, K. Hirano and M. Miura, Org. Lett., 2016, 18, 3742; (b) for heteroarylation: R. Odani, K. Hirano, T. Satoh and M. Miura, Angew. Chem. Int. Ed. 2014, 53, 10784; (c) K. Takamatsu, K. Hirano and M. Miura, Angew. Chem. Int. Ed. 2017, 56, 5353. P. Peng, J. Wang, H. Jiang and H. Liu, Org. Lett., 2016, 18, 5376. D. Das, P. Poddar, S. Maity and R. Samanta, J. Org. Chem., 2017, 82, 3612. K. A. Kumar, P. Kannaboina and P. Das, Org. Biomol. Chem. 2017, 15, 5457. For heteroarylation: E. Grenet, A. Das, P. Caramenti and J. Waser, Beilstein J. Org. Chem. 2018, 14, 1208. Selected reviews: (a) K. Yuan, J. F. Soulé and H. Doucet, ACS Catal. 2015, 5, 978; (b) S. G. Modha, V. P. Mehta and E. Van der Eycken, Chem. Soc. Rev., 2013, 42, 5042; (c) J. Lou, Q. Wang, P. Wu, H. Wang, Y. -G. Zhou, Z. Yu, Chem. Soc. Rev. 2020, 49, 4307. Selected references on arylation using aryl sulfonylchlorides: (a) X. Zhao, E. Dimitrijevic and V. M. Dong, J. Am. Chem. Soc. 2009, 131, 3466; (b) S. Dubbaka and P. Vogel, J. Am. Chem. Soc. 2003, 125, 15292; (c) C. Rao and P. Vogel, Angew. Chem. Int. Ed. 2008, 47, 1305; (d) H. Li, T. Roisnel, J. -F. Soulé and H. Doucet, Tetrahedron Lett. 2020, 61, 151342; (e) A. Hfaiedh, K. Yuan, H. Ben Ammar, B. Ben Hassine, J.-F. Soulé and H. Doucet, ChemSusChem 2015, 8, 1794; (f) I. Idris, F. Derridj, S. Djebbar, J. -F. Soulé and H. Doucet, Tetrahedron 2015, 71, 9617; (g) W. Zhang, F. Liu, B. Zhao, Appl. Organomet. Chem. 2015, 29, 524; (h) K. Yuan, R. Sang, J. -F. Soulé and H. Doucet, Catal. Sci. Technol., 2015, 5, 2904; (i) B. Saoudi, A. Debache, J. -F. Soulé and H. Doucet, RSC Adv. 2015, 5, 65175. Selected references on arylation using aryl sulfonyl chlorides via C-H bond functionalizations: (a) D. Zhang, X. Cui, Q. Zhang and Y. Wu, J. Org. Chem. 2015, 80, 1517; (b) M. Zhang, S. Zhang, M. Liu and J. Cheng, Chem. Commun. 2011, 47, 11522; (c) K. Yuan and H. Doucet, Chem. Sci., 2014, 5, 392; (d) K. Yuan, J. F. Soulé, V. Dorcet and H. Doucet; ACS Catal. 2016, 6, 8121; (e) R. Jin, K. Yuan, E. Chatelain, J. -F. Soulé and H. Doucet, Adv. Synth. Catal. 2014, 356, 3831; (f) S. Mao, X. Shi, J. -F. Soulé and H. Doucet, Eur. J. Org. Chem. 2020, 91; (g) W. Hagui, K. Yuan, N. Besbes, E. Srasra, J. -F. Soulé and H. Doucet, ChemCatChem 2015, 7, 3544. (a) D. Das, A. Biswas, U. Karmakar, S. Chand and R. Samanta, J. Org. Chem. 2016, 81, 842; (b) A. Biswas, D. Giri, D. Das, A. De, S. K. Patra and R. Samanta, J. Org. Chem. 2017, 82, 10989; (c) D. Das and R. Samanta, Adv. Synth. Catal. 2018, 360, 379; (d) D. Das, G. Sahoo, A. Biswas and R. Samanta, Chem. Asian J. 2020, 15, 360. D. H. Ortgies, A. Hassanpour, F. Chen, S. Woo and P. Forgione, Eur. J. Org. Chem. 2016, 408. J. Wysocki, C. Schlepphorst and F. Glorius, Synlett 2015, 26, 1557.
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Organic & Biomolecular Chemistry rsc.li/obc
Volume 15 Number 47 21 December 2017 Pages 9945-10124
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors.
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I . J. Dmochowski et al. Oligonucleotide modifi cations enhance probe stability for single cell transcriptome in vivo analysis (TIVA)
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COMMUNICATION A Directing Group Free Pd(II)-Catalysed Desulfitative C6-Arylation of 2-Pyridone using Arylsulfonyl Chloride Received 00th January 20xx, Accepted 00th January 20xx
Ujjwal Karmakar,a and Rajarshi Samanta*a
DOI: 10.1039/x0xx00000x
A Pd(II)-catalysed direct desulfitative arylation was realized at the C6-position of 2-pyridone scaffolds. Aryl sulfonyl chlorides were used as the alternate arylating agent. The required site-selectivity occured without the strategic installation of heteroatom containing directing group. Preliminary mechanistic studies revealed that radical species were involved during this process. Transition metal catalysed introduction of functional groups in the electron deficient heterocycles via C-H bond functionalizations becomes an important area of research.1 Recently, among various electron deficient heterocycles, 2pyridone scaffold gathers significant attention from the synthetic chemists due to its often presence in pharmaceuticals, bio-active natural products and organic materials.2 Arylated 2-pyridones, especially C6-arylated 2pyridone scaffolds are omnipresent in various bioactive molecules (Figure 1). The classical approaches to prepare these scaffolds mostly deal with multi-step synthesis, harsh reaction conditions or treatment with prefunctionalized coupling partners. Arguably, one of the most straightforward approach could be the direct introduction of functional groups via siteselective manner. Notable advancement was observed during the last few years in the direct site-selective introduction of functional groups at the various position of this core through transition metal catalysed C-H bond functionalizations.3 Subsequently, significant progress was realized in the direct site-selective arylations at the various position of this core.4-5 C6-position, being the most electron deficient center of this core offers an important synthetic task towards the direct arylation at this site. Strategically, the challenge was overcome with the aid of robust and well-proven directing group based strategies.6-10 Hirano and Miura’s group elegantly developed a general two-steps protocol for the Rh(I)-catalysed C6borylation and its subsequent arylation under Pd(0)-catalysis.6a In another important development, Liu’s group reported a a. Department
of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India. Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1 Transition metal catalysed C6-selective arylation of 2-pyridone
Figure 1 Bioactive C6 arylated 2-pyridone
direct C6-arylation of 2-pyridone under Rh(III)-catalysed mild conditions using commercially available organotrifluoroborates.7 Subsequently, our group also developed a mild Rh(III)-catalysed direct introduction of phenol moieties at the C6-position of 2-pyridone with quinone diazides.8 In another advancement, the C6-arylation of 2pyridones was developed by Das’s group under Ru(II)catalysed conditions using aryl boronic acids.9 The related heteroarylaton at this position was also explored with the aid of nitrogen containing directing group by Hirano, Miura’s and Waser’s group.6b,10 Tactically, 2-pyridine was used in these methods as a directing group to obtain the required siteselectivity. However, as per our best of knowledge there is no report on direct C6-arylation of 2-
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Table 1 Optimization of reaction conditionsa
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En
Catalyst
Solvent
Oxidant
Additive (mol%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Pd(OAc)2 Pd(OAc)2 PdCl2 PdCl2(PPh3)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2
dioxane DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE
Ag2O Ag2O Ag2O Ag2O AgOAc Ag2CO3 Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O Ag2O
17 18
Pd(OAc)2 Pd(OAc)2
DCE DCE
Ag2O Ag2O
NaOAc (100) Li2CO3 (100) PivOH (100) PivOH (50) AcOH (50) TFA (50) BzOH (50) 4-OMeBzOH (50) 4-MeBzOH (50) 2,6-(OMe)2BzOH (50) Mesitoic acid PivOH (20)
Yield (%)b 12 27 22 15 14 traces 30 34 46 52 n.d. n.d. 34 50 36 30 22 37
Scheme 2 Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), Pd(OAc)2 (10 mol%), Ag2O (0.2 mmol), pivalic acid (50 mol%), DCE (0.1 M), 110 °C. aReaction was done at 2 mmol scale
aReaction
conditions: 1a (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol%), Ag2O (0.2 mmol), solvent (0.1 M), 12 h, 110 °C. bIsolated yield. n.d. = not detected.
pyridone core with-out the strategic placement of 2-pyridine or related nitrogen containing directing group. Among recent various alternative arylation sources, one of the most promising is RSO2Cl derivatives due to their easy preparation, simple handling, commercial availability and ability to provide the alternate regioisomers.11,12 They are used as suitable aryl coupling partners with the liberation of SO2 under the transition metal catalysis via C-H bond functionalizations.13 In continuation with our interest in site-selective functionalizations of 2-pyridone scaffolds under transition metal catalysis,5b,8,14 we hypothesized that the proper choice of transition metal catalyst and arylating source which has ability to proceed via different mechanistic pathway might trigger the C6-arylation with-out the guidance from the nitrogen containing directing group. We realized that the palladium catalysts could be the desirable choice due to its wide application in known desulfitative cross-coupling reactions.11a,13,15 Herein, we report a Pd(II)-catalysed direct desulfitative C6-arylation of 2-pyridone scaffolds using arylsulfonylchloride as coupling partner with-out the help of pyridine directing group. Our initial investigation was started with N-methyl 2-pyridone (1a) and p-toluenesulfonyl chloride (2a) as an aryl coupling partner in the presence of catalytic amount of Pd(OAc) 2. Initially, the reaction mixture was stirred in dioxane solvent at the 110 °C for 12 h in the presence of 10 mol% of Pd(OAc) 2 catalyst and 2 equiv of Ag2O oxidant to obtain the C6-arylated product 3a in 12% yield (Table 1, entry 1). The yield of the
desired product 3a was further decreased when the lower amount of Ag2O was utilised (see ESI detail optimization table). Next, the yield was improved to 27% when DCE was used as the reaction solvent (Table 1, entry 2). Further screening of other catalysts and oxidants did not improve the yield (Table 1, entries 3-6). For the betterment of the yield of the 3a, several additives were tested. The yield was marginally improved by the use of additives like NaOAc and Li2CO3 (Table 1, entries 78). Next, various carboxylic acids were screened. Among various carboxylic acids, pivalic acid was found to be the best with its 50 mol% amount (Table 1, entries 9-10). Other tested carboxylic acids either afforded comparable yield of the desired product 3a or decreased yield (Table 1, entries 11-17). The yield of 3a was getting lowered when there was decrease in pivalic acid amount to 20 mol% (Table 1, entry 18). After several screening of other parameters, there was no additional improvement observed in the yield of the desired product. Finally, the synthetically acceptable yield of 3a under 10 mol% Pd(OAc)2, 2 equiv of Ag2O and 50 mol% pivalic acid in DCE solvent at 110 °C was considered as the optimized conditions. After having the optimized conditions in hand, 2-pyridones with different steric and electronic properties were explored towards the C6-arylation reactions (Scheme 2). Initially, the C3-substituted 2-pyridones were screened for the desired reaction. The developed protocol worked efficiently with the electron-rich substituents present at the C3-position of 2pyridone and provided moderate to good yields of the corresponding C6-arylated products (Scheme 2, 3b-3d). The
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Scheme 4 Plausible mechanism
Scheme 3 Control experiments
reaction proceeded successfully with C4-substitution also (Scheme 2, 3e). Pleasingly, the substitution like thiophenyl group at the C5-position survived during the reaction (Scheme 2, 3f). Another important heterocyclic scaffold, isoquinolone also reacted to provide the desired product under the optimized reaction conditions (Scheme 2, 3g). Further, various N-alkyl groups were explored to obtain the desired products (Scheme 2, 3h-3k). When the N-benzyl-6-methylpyridin-2(1H)one was screened under the optimized conditions, there was no desired product formation realized. Next, the developed protocol was further extended with the various arylsulfonyl chlorides bearing different steric and electronic properties (Scheme 2, 4a-4g). The reaction worked efficiently with benzenesulfonyl chloride and provided a good yield of the corresponding arylated product (Scheme 2, 4a). It is important to mention that the structure of the product with the C6-aryl group was unequivocally determined by the comparison of the NMR data of 4a and 4b with known literature data.16 Electron rich substituents like -OCH3, -tBu groups present at the paraposition of the arylsulfonyl chloride reacted effectively with 1a and afforded the good yields of the desired C6-arylated products (Scheme 2, 4b-4c). The developed method worked smoothly with halogen substituent like –Br group attached to the para-position and furnished a good yield of the product (Scheme 2, 4d). In the presence of para-fluoro substituted arylsulfonyl chloride, the reaction was sluggish and afforded lower yield of the corresponding product (Scheme 2, 4e). Further, the C6-arylation reaction was tested with arylsulfonyl chlorides having substituents at the meta-position. The developed procedure worked efficiently with electron-rich substituents like -CH3 group present at the meta-position of arylsulfonyl chloride and furnished a good yield of corresponding product (Scheme 2, 4f). Next, a bulky naphthylsulfonyl chloride worked effectively and provided a good yield of corresponding C6-arylated product (Scheme 2, 4g).
The protocol remained unsuccessful in the cases of N-phenyl 2-pyridone, NH-free 2-pyridone and N-methyl 4-pyridone substrates (Scheme 2, 4h-4j). As a demonstration of scalability, the reaction was carried out in a 2 mmol scale under the developed conditions to obtain 41% isolated yield of the desired C6-arylated 2-pyridone product (Scheme 2, 3a). To understand the mechanism of the reaction, several control experiments were performed. The H/D scrambling experiment was performed with 1a and CD3CO2D (10 equiv) was used as the deuteration source. The result showed that no deuterium incorporation was observed at the C6-position in the absence of tosyl chloride. This result revealed that C–H metalation was irreversible in the absence of coupling partner tosyl chloride. Further, to know the participation of the radical intermediates in the reaction pathway, it was carried out in the presence of stoichiometric amount of radical trapping reagent like 2,6-ditert-butyl-4-methylphenol (BHT). The formation of the desired C6-arylated product 3a was inhibited completely and the side product 6 was formed in a significant amount. This result suggested that free aryl sulfonyl radical was generated during the progress of the reaction which was quenched by radical trapping agent BHT (Scheme 3ii). Further, few more experiments were executed to know the exact conditions of the formation of the arylsulfonyl radical species (Scheme 3iiiv). When the tosyl chloride was treated with BHT in the presence of catalytic amount of Pd(OAc)2, only trace amount of arylsulfonyl coupled BHT adduct 6 was formed (Scheme 3iii). Next, only 10% formation of adduct 6 was realized when the reaction was carried out under the 2 equiv of Ag2O (Scheme 3iv). Finally, a good yield of the adduct 6 was isolated when the reaction was carried out in the presence of catalytic Pd(OAc)2 and 2 equiv of Ag2O (Scheme 3v). These results proved that both the catalytic Pd(OAc)2 and stoichiometric Ag2O were necessary to generate the arylsulfonyl radical species. Moreover, the analysis of the GCMS data of the crude reaction mixture confirmed the formation of 4,4'-dimethyl1,1'-biphenyl (See ESI for more details). This result suggested the generation of para-methylphenyl radical which might develop from the para-methylsulfonyl radical via SO2 elimination. Based on the control experiments and previous literature reports,13 a tentative mechanism was proposed (Scheme 4). Initially, in the presence of Pd(OAc)2 and Ag2O, arylsulfonyl
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chloride provided the corresponding arylsulfonyl radical species which further reacted with Pd(OAc)2 to produce an aryl palladium species A via the extrusion of SO2. Next, the deprotonation was occurred at the most electron deficient C6position of 1a with the involvement of species A to form C6metallated intermediate B through metal-pivalate assisted C-H bond functionalization. Further, the reductive elimination of species B afforded the desired compound 3 with the generation of Pd(0) species. Finally, the oxidation of Pd(0) species by Ag2O regenerated the active Pd(II) species to continue the catalytic cycle. However, at this moment, Pd(II)/Pd(IV) catalytic cycle cannot be completely ruled out. The detail mechanistic studies are currently underway to reveal more insight.
Conclusions In conclusion, Pd(II)-catalyzed desulfitative C6-arylation of 2pyridones was reported with easily accessible, cheap arylsulfonyl chlorides as an alternative arylation source. The developed reaction was explored with wide scope and exhibited good functional group tolerance. The protocol proceeded without the strategic installation of the heteroatom-containing directing group. Preliminary mechanistic studies revealed that radical species are involved.
Conflicts of interest
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There are no conflicts to declare.
Acknowledgements Authors thank the SERB, India (CRG/2018/000630), and DST, India (SR/FST/CSII-026/2013; for 500 MHz NMR), for financial support. UK thanks to IIT Kharagpur for his research fellowship. 13
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Related reviews: (a) K. Hirano and M. Miura, Chem. Sci. 2018, View Article Online 9, 22; (b) A. Biswas, S. Maity, S. Pan and R. Samanta, Chem DOI: 10.1039/D0OB01716G Asian J. 2020, 15, 2092; (c) A. M. Prendergast and G. P. McGlacken, Eur. J. Org. Chem. 2018, 6068. Arylation at the C3-position: (a) A. Nakatani, K. Hirano, T. Satoh and M. Miura, J. Org. Chem. 2014, 79, 1377; (b) A. Najib, S. Tabuchi, K. Hirano and M. Miura, Heterocycles 2016, 92, 1187; (c) E. E. Anagnostaki, A. D. Fotiadou, V. Demertzidou and A. L. Zografos, Chem. Commun. 2014, 50, 6879; (d) A. Modak, S. Rana and D. Maiti, J. Org. Chem. 2015, 80, 296; (e) P. Chauhan, M. Ravi, S. Singh, P. Prajapati and P. P. Yadav, RSC Adv. 2016, 6, 109. Arylation at the C5-position: (a) Y. Chen, F. Wang, A. Jia and X. Li, Chem. Sci. 2012, 3, 3231; (b) S. Maity, D. Das, S. Sarkar and R. Samanta, Org. Lett. 2018, 20, 5167. (a) W. Miura, K. Hirano and M. Miura, Org. Lett., 2016, 18, 3742; (b) for heteroarylation: R. Odani, K. Hirano, T. Satoh and M. Miura, Angew. Chem. Int. Ed. 2014, 53, 10784; (c) K. Takamatsu, K. Hirano and M. Miura, Angew. Chem. Int. Ed. 2017, 56, 5353. P. Peng, J. Wang, H. Jiang and H. Liu, Org. Lett., 2016, 18, 5376. D. Das, P. Poddar, S. Maity and R. Samanta, J. Org. Chem., 2017, 82, 3612. K. A. Kumar, P. Kannaboina and P. Das, Org. Biomol. Chem. 2017, 15, 5457. For heteroarylation: E. Grenet, A. Das, P. Caramenti and J. Waser, Beilstein J. Org. Chem. 2018, 14, 1208. Selected reviews: (a) K. Yuan, J. F. Soulé and H. Doucet, ACS Catal. 2015, 5, 978; (b) S. G. Modha, V. P. Mehta and E. Van der Eycken, Chem. Soc. Rev., 2013, 42, 5042; (c) J. Lou, Q. Wang, P. Wu, H. Wang, Y. -G. Zhou, Z. Yu, Chem. Soc. Rev. 2020, 49, 4307. Selected references on arylation using aryl sulfonylchlorides: (a) X. Zhao, E. Dimitrijevic and V. M. Dong, J. Am. Chem. Soc. 2009, 131, 3466; (b) S. Dubbaka and P. Vogel, J. Am. Chem. Soc. 2003, 125, 15292; (c) C. Rao and P. Vogel, Angew. Chem. Int. Ed. 2008, 47, 1305; (d) H. Li, T. Roisnel, J. -F. Soulé and H. Doucet, Tetrahedron Lett. 2020, 61, 151342; (e) A. Hfaiedh, K. Yuan, H. Ben Ammar, B. Ben Hassine, J.-F. Soulé and H. Doucet, ChemSusChem 2015, 8, 1794; (f) I. Idris, F. Derridj, S. Djebbar, J. -F. Soulé and H. Doucet, Tetrahedron 2015, 71, 9617; (g) W. Zhang, F. Liu, B. Zhao, Appl. Organomet. Chem. 2015, 29, 524; (h) K. Yuan, R. Sang, J. -F. Soulé and H. Doucet, Catal. Sci. Technol., 2015, 5, 2904; (i) B. Saoudi, A. Debache, J. -F. Soulé and H. Doucet, RSC Adv. 2015, 5, 65175. Selected references on arylation using aryl sulfonyl chlorides via C-H bond functionalizations: (a) D. Zhang, X. Cui, Q. Zhang and Y. Wu, J. Org. Chem. 2015, 80, 1517; (b) M. Zhang, S. Zhang, M. Liu and J. Cheng, Chem. Commun. 2011, 47, 11522; (c) K. Yuan and H. Doucet, Chem. Sci., 2014, 5, 392; (d) K. Yuan, J. F. Soulé, V. Dorcet and H. Doucet; ACS Catal. 2016, 6, 8121; (e) R. Jin, K. Yuan, E. Chatelain, J. -F. Soulé and H. Doucet, Adv. Synth. Catal. 2014, 356, 3831; (f) S. Mao, X. Shi, J. -F. Soulé and H. Doucet, Eur. J. Org. Chem. 2020, 91; (g) W. Hagui, K. Yuan, N. Besbes, E. Srasra, J. -F. Soulé and H. Doucet, ChemCatChem 2015, 7, 3544. (a) D. Das, A. Biswas, U. Karmakar, S. Chand and R. Samanta, J. Org. Chem. 2016, 81, 842; (b) A. Biswas, D. Giri, D. Das, A. De, S. K. Patra and R. Samanta, J. Org. Chem. 2017, 82, 10989; (c) D. Das and R. Samanta, Adv. Synth. Catal. 2018, 360, 379; (d) D. Das, G. Sahoo, A. Biswas and R. Samanta, Chem. Asian J. 2020, 15, 360. D. H. Ortgies, A. Hassanpour, F. Chen, S. Woo and P. Forgione, Eur. J. Org. Chem. 2016, 408. J. Wysocki, C. Schlepphorst and F. Glorius, Synlett 2015, 26, 1557.
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