Pd(II)-catalyzed selective β-C–H functionalization of azobenzene carboxamides

Abstract

We report a Pd(II)-catalyzed bidentate directing group 8-aminoquinoline-aided, site-selective β-C–H functionalization protocol for assembling modified azobenzene carboxamides. Considering the importance of azobenzenes in chemical sciences, this paper reports a new route for enriching the library of modified azobenzene motifs.

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The transition metal-catalyzed C–H activation and functionalization, especially, the Pd(II)-catalyzed C–H functionalization of organic substrates has transpired as one of the cornerstone strategies.^1,2 The site-selective C–H activation and functionalization of organic substrates have been accomplished by using appropriate directing groups (DGs).^1,2

Azobenzenes are a phenomenal class of photochromic molecules and have found a wide range of applications in chemical sciences.³ Azobenzene-based molecules have been found to exhibit a wide range of biological activities, used as drug molecules and as tools to study the pharmacology of various bioactive compounds (Fig. 1).^3,4 There have been constant efforts to synthesize novel and functionalized azobenzenes. Notably, the inherent –N=N– (azo) group-aided C–H functionalization strategy has been extended to functionalize the ortho position of azobenzene motif 1a (Scheme 1).⁵ Thus, there is immense scope for investigating the C–H bonds of other positions of azobenzenes via different C–H functionalization strategies.

Scheme 1 Pd(II)-catalyzed DG-aided C–H functionalization of azobenzenes.

Fig. 1 Examples of bioactive azobenzene compounds.

The Pd(II)-catalyzed, site-selective C–H functionalization of aromatic carboxamides assisted by the bidentate directing groups (e.g., 8-aminoquinoline (8-AQ) and picolinamide (PA)) has emerged as a benchmark strategy.^2,6 Taking an impetus from this strategy, we herein report the Pd(II)-catalyzed 8-aminoquinoline DG-assisted, selective β-C–H arylation and alkylation of azobenzene motif 1c and synthesis of modified azobenzene carboxamides (Scheme 1).

To commence with the Pd(II)-catalyzed aminoquinoline-assisted, site-selective β-C–H arylation and alkylation of azobenzene carboxamides, we prepared the azobenzene carboxamide 5 from its carboxylic acid and 8-AQ DG. Table 1 shows the optimization of reaction conditions for the β-C–H arylation of substrate 5 with 2-iodothiophene (6a) involving the Pd- or Ni-based catalysts and an iodide ion scavenger (e.g., AgOAc, Ag₂CO₃, K₂CO₃, etc.).^2,6

Table 1 Pd(II)-catalyzed, 8-AQ DG-aided site-selective β-C–H arylation of 5

Entry	Substrate (mmol)	6a (mmol)	Catalyst (mol%)	Additive (mmol)	Yield (%)	Yield (%)
a 36 h. b Toluene (2–3 mL). c p-Anisyl iodide (6b). d 4-Acetyliodobenzene (6c), toluene (1 mL), 160 °C, sealed tube, 40 h.
1	5 (0.15)	0.3	Pd(OAc)2	AgOAc (0.30)	7a′ : —	7a : 35
2	5 (0.15)	0.6	Pd(OAc)2	AgOAc (0.38)	7a′ : —	7a : 50
3	5 (0.15)	0.6	Nil	AgOAc (0.38)	7a′ : —	7a : —
4	5 (0.15)	0.6	Pd(OAc)2 (5 mol%)	AgOAc (0.38)	7a′ : —	7a : 40
5	5 (0.15)	0.6	Pd(OAc)2	AgOAc (0.30)	7a′ : —	7a : 38
6	5 (0.15)	0.6	Pd(OAc)2	Ag2CO3 (0.30)	7a′ : —	7a : 35
7	5 (0.15)	0.6	Pd(OAc)2	NaHCO3 (0.30)	7a′ : —	7a : —
8	5 (0.15)	0.6	Pd(OAc)2	K2CO3 (0.30)	7a′ : —	7a : 43
9	5 (0.15)	0.45	Pd(OAc)2	AgOAc (0.30)	7a′ : —	7a : 67
10^a	5 (0.2)	0.8	Ni(OTf)2	Na2CO3 (0.4)	7a′ : 47	7a : —
11^b	10c (0.2)	0.8	Pd(OAc)2	AgOAc (0.44)	11e′ : —	11e : 32
12^b	10d (0.25)	1	Pd(OAc)2	AgOAc (0.55)	11f′ : —	11f : 51
13	10e (0.2)	0.6^c	Pd(OAc)2	AgOAc (0.4)	11g′ : —	11g : 41
14^a^,^b	10f (0.15)	0.6^c	Pd(OAc)2	AgOAc (0.33)	11h′ : —	11h : —
15^a	10f (0.15)	0.45^d	Ni(OTf)2	Na2CO3 (0.45)	11i′ : —	11i : —
16^a^,^b	10g (0.15)	0.6^c	Pd(OAc)2	AgOAc (0.33)	11j′ : —	11j : —

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Heating a mixture of carboxamide 5, 2-iodothiophene (3 equiv.), Pd(OAc)₂ (10 mol%) and AgOAc additive yielded the bis β-C–H arylated azobenzene carboxamide 7a in 67% yield (entry 9, Table 1). The column chromatography purification of the crude reaction mixtures (entries 1–9, Table 1) gave the bis β-C–H arylated product 7a. We did not obtain the mono β-C–H arylated product 7a′ or any other by-product such as the azo functionality-aided ortho C–H arylated product 7aa. We also tested the efficiency of other DGs. The C–H arylation of substrate 10c possessing the 4-amino-2,1,3-benzothiadiazole DG yielded the product 11e in 32% yield (Table 1). The C–H arylation of substrates 10d and 10e possessing the 2-(methylthio)aniline DG yielded the products 11f and 11g in 41–51% yields. However, the arylation of carboxamides 10f and 10g containing the corresponding simple amide moieties did not yield corresponding products 11h–j (Table 1). Treatment of azobenzene 10h with aryl iodides under the experimental conditions did not provide the other expected azo group-directed by-products 11k or 11l (Table 1). We then continued with optimization reactions to obtain the mono β-C–H arylated azobenzene product (e.g., 7a′) in good yield. Treatment of the carboxamide 5 with 6a or 6c in the presence of the Ni(OTf)₂ catalyst and Na₂CO₃ additive in toluene gave the corresponding mono β-C–H arylated azobenzene carboxamides 7a′ or 7b′ in 47 and 50% yields (entry 10, Table 1 and entry 6, Table 2).

Table 2 Ni(II)-catalyzed, 8-AQ DG-aided site-selective mono β-C–H arylation of 5

Entry	5 (mmol)	6c (mmol)	Catalyst (mol%)	Additive (mmol)	7b’ : yield (%)	7b : yield (%)
a p-Xylene. b 36 h (in RB flask). c 5 (0.2 mmol), ArI (0.6 mmol), Na2CO3 (0.6 mmol), 36 h. d 5 (0.15 mmol), ArI (0.45 mmol), Na2CO3 (0.45 mmol), 36 h. e 5 (0.2 mmol), ArI (0.8 mmol), Na2CO3 (0.4 mmol), 36 h. f 5 (0.2 mmol), ArI (0.8 mmol), Na2CO3 (0.4 mmol), 36 h.
1	0.15	0.45	Ni(OTf)2	KHCO3 (0.45)	30	—
2	0.15	0.45	Ni(OTf)2	NaHCO3 (0.45)	26	—
3	0.15	0.45	Ni(OTf)2	K2CO3 (0.45)	39	—
4	0.15	0.45	Ni(OTf)2	Cs2CO3 (0.45)	—	—
5	0.15	0.45	Ni(OTf)2	KOAc (0.45)	11	—
6	0.15	0.45	Ni(OTf)2	Na2CO3 (0.9)	50	—
7^a	0.15	0.45	Ni(OTf)2	Na2CO3 (0.45)	40	17
8	0.15	0.45	Ni(acac)2	Na2CO3 (0.6)	7	—
9	0.15	0.45	NiCl2	Na2CO3 (0.6)	—	—
10	0.15	0.45	Ni(OAc)2·4H2O	Na2CO3 (0.6)	18	—
11^b	0.125	0.5	Pd(OAc)2	AgOAc (0.28)	—	40
12	0.15	0.45	Ni(OTf)2	AgOAc (0.3)	—	—

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Subsequently, additional examples of mono β-C–H arylated azobenzene carboxamides 7e′ (44%), 7c′ (20%) and 7j′ (28%) were obtained in 20–50% yields (Table 2). Towards exploring the generality, the azobenzene carboxamides 5/8/10a,b were subjected to the Pd(II)-catalyzed 8-AQ DG-aided C–H arylation with various aryl iodides. These reactions yielded the corresponding bis and mono β-C–H arylated azobenzene carboxamides 7a–i,k,l (Scheme 2), 9a–n (Scheme 3) and 11a–d (Scheme 4) in 25–78% yields. The arylation of 5 with 6a was performed on a gram scale, which afforded 7a in 55% (1.04 g).

Scheme 2 Pd(II)-catalyzed, 8-AQ DG-aided β-C–H arylation of 5. ^aGram scale reaction using 5 (1.29 g, 3.66 mmol), 6a (3 equiv.), Pd(OAc)₂ (10 mol%), AgOAc (2 equiv.), toluene (3 mL), 110 °C, 12 h.

Scheme 3 Pd(II)-catalyzed, 8-AQ DG-aided β-C–H arylation of 8.

Scheme 4 Pd(II)-catalyzed, 8-AQ DG-aided β-C–H arylation of 10a,b.

We then attempted the Pd(II)-catalyzed β-C–H alkylation of azobenzene carboxamides. Table 3 shows the optimization of reaction conditions for the C–H alkylation of 5/10b with 1-iodobutane (12a). Markedly, the Pd(II)-catalyzed, 8-AQ DG-aided β-C–H alkylation of 5 with 1-iodobutane in the presence of K₂CO₃ and NaOTf as additives in t-amylOH at 125 °C for 22–42 h successfully afforded the corresponding bis β-C–H alkylated azobenzene carboxamides 13a and 13b in 88 and 64% yields (entries 4 and 5, Table 3). Next, we performed the Pd(II)-catalyzed, 8-AQ DG-aided β-C–H alkylation of carboxamides 5/8/10a,b with various alkyl iodides, ethyl 2-iodoacetate and p-nitrobenzyl bromide. These reactions afforded the corresponding bis β-C–H alkylated azobenzene carboxamides 13a–j, 16a, 18a–c and mono β-C–H alkylated azobenzene carboxamide 13k, 15a and 18d in 24–88% yields (Schemes 5 and 6).

Scheme 5 Pd(II)-catalyzed, 8-AQ DG-aided β-C–H alkylation of 5/8/10a,b.

Scheme 6 Pd(II)-catalyzed, 8-AQ DG-aided β-C–H alkylation of 5/8/10a,b.

Table 3 Pd(II)-catalyzed, 8-AQ DG-aided site-selective β-C–H alkylation of 5/10b

Entry	Substrate (mmol)	Additive (mmol)	Solvent (mL)	Conditions	Yield (%)
a Catalyst = Ni(OTf)2.
1	5 (0.1)	Ag2CO3 (0.20), (BnO)2POOH (0.2)	t-AmylOH	110 °C, 40 h	13a : 0
2	5 (0.1)	KHCO3 (0.20), o-toluic acid (0.2)	1,2-DCE	110 °C, 40 h	13a : 0
3	5 (0.1)	Ag2CO3 (0.40), CuBr2 (0.04)	H2O	120 °C, 48 h	13a : 0
4	5 (0.1)	K2CO3 (0.20), NaOTf (0.3)	t-AmylOH	125 °C, 42 h	13a : 88
5	10b (0.15)	K2CO3 (0.30), NaOTf (0.45)	t-AmylOH	125 °C, 22 h	13b : 64
6^a	10b (0.15)	Na2CO3 (0.30), PPh3 (20 mol%)	Toluene	150 °C, 50 h	13b : 0

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To reveal the synthetic utility, we attempted the removal of the 8-aminoquinoline DG after performing the Pd(II)-catalyzed β-C–H alkylation/arylation of azobenzene carboxamides. While we faced some issues in establishing the conditions for removing the 8-aminoquinoline DG, out of various attempts carried out, we succeeded in removing the 8-aminoquinoline DG from the bis β-C–H alkylated azobenzene carboxamide 13a by treating it with TfOH in toluene/H₂O at 110 °C. This reaction yielded the azobenzene carboxylic acid 19a in 95% yield (Scheme 7). We also succeeded in removing the 8-aminoquinoline DG from the mono β-C–H arylated azobenzene carboxamides 7e′ by treating it with KOH in MeOH at 100 °C and this reaction yielded the azobenzene carboxylic acid 19b in 66% yield.

Scheme 7 DG removal and synthetic transformations using 13a, 7e′ and 19b.

Finally, we also attempted the conversion of carboxylic acid 19b into the azobenzene lactone derivative 20via the δ-C–H lactonization of the azobenzene carboxylic acid 19b. Accordingly, treatment of 19b with K₂S₂O₈ in MeCN/H₂O at 60 °C for 24 h yielded the azobenzene-based lactone derivative 20 in 61% yield (Scheme 7). It may be noted that the synthesized azobenzene-based lactone derivative 20 is structurally similar to the lactone motifs of naturally occurring urolithin derivatives.⁷

The structure of the azobenzene-based lactone derivative 20 was unequivocally assigned based on the X-ray analysis. The X-ray structure of 20 also validates the following; (a) the Pd(II)-catalyzed C–H alkylation and arylation of azobenzene carboxamides selectively occurred at the β-C–H bonds next to the 8-AQ DG-linked carboxamide moiety, (b) based on the observed products from the arylation/alkylation of azobenzene carboxamides and the control experiment using 10h, the N=N functionality is intact and also the azo group-directed arylation did not occur under the experimental conditions used for the arylation of β-C–H bonds of azobenzene carboxamides containing a directing group (e.g., 8-AQ). Accordingly, the azo group-assisted ortho C–H functionalization or any other by-products were not obtained in characterizable amounts.

Conclusions

In summary, in this communication paper, we have shown the preliminary results comprising of the Pd(II)-catalyzed bidentate directing group 8-aminoquinoline-aided, site-selective β-C–H functionalization of azobenzene carboxamides. We have exemplified the usefulness of the Pd(II)-catalyzed 8-aminoquinoline DG-assisted C–H functionalization route for the synthesis of a wide range of novel and modified azobenzene carboxamides by negating the N=N (azo) group assistance.⁵ Considering the importance of azobenzenes in chemical sciences, this method comprising of the Pd(II)-catalyzed 8-aminoquinoline-assisted site-selective β-C–H functionalization of azobenzene carboxamides would serve as a useful method for enriching the libraries of azobenzene derivatives. Further studies to elaborate on the DG-assisted functionalization of azobenzenes and investigation of the photophysical properties of the synthesized compounds are in progress in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank IISER-M for funding, analytical facilities (NMR, HRMS and X-ray). Ms. Sonam Suwasia of our lab is thanked for helping in performing a few reactions during revision of this article.

References

1. (a) F. Kakiuchi and S. Murai, Acc. Chem. Res., 2002, 35, 826; (b) S. Rej, A. Das and N. Chatani, Coord. Chem. Rev., 2021, 431, 213683; (c) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960; (d) P. A. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879; (e) T. Besset, T. Poisson and X. Pannecoucke, Chem. – Eur. J., 2014, 20, 16830; (f) A. Banerjee, S. Sarkar and B. K. Patel, Org. Biomol. Chem., 2017, 15, 505; (g) M. Maraswami and T.-P. Loh, Synthesis, 2019, 51, 1049; (h) R. Mandal, B. Garai and B. Sundararaju, ACS Catal., 2022, 12, 3452; (i) M. Miura, T. Satoh and K. Hirano, Bull. Chem. Soc. Jpn., 2014, 87, 751; (j) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem. – Eur. J., 2010, 16, 2654; (k) J. He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Y. Yu, Chem. Rev., 2017, 117, 8754; (l) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (m) T. Yoshino and S. Matsunaga, Adv. Synth. Catal., 2017, 359, 1245; (n) J. J. Topczewski and M. S. Sanford, Chem. Sci., 2015, 6, 70; (o) S.-F. Ni, G. Huang, Y. Chen, J. S. Wright, M. Li and L. Dang, Coord. Chem. Rev., 2022, 455, 214255; (p) J. I. Higham and J. A. Bull, Org. Biomol. Chem., 2020, 18, 7291; (q) S. K. Sinha, S. Guin, S. Maiti, J. P. Biswas, S. Porey and D. Maiti, Chem. Rev., 2022, 122, 5682; (r) R. Manoharan and M. Jeganmohan, Asian J. Org. Chem., 2019, 8, 1949; (s) R. Das, G. S. Kumar and M. Kapur, Eur. J. Org. Chem., 2017, 5439; (t) S. V. Kumar, S. Banerjee and T. Punniyamurthy, Org. Chem. Front., 2020, 7, 1527; (u) T. Yanagi, K. Nogi and H. Yorimitsu, Tetrahedron Lett., 2018, 59, 2951; (v) M. M. Mingo, N. Rodríguez, R. G. Arrayás and J. C. Carretero, Chem. Commun., 2022, 58, 2034.
2. (a) S. Rej, Y. Ano and N. Chatani, Chem. Rev., 2020, 120, 1788; (b) O. Daugulis, J. Roane and L. D. Tran, Acc. Chem. Res., 2015, 48, 1053; (c) X. Yang, G. Shan, L. Wang and Y. Rao, Tetrahedron Lett., 2016, 57, 819; (d) C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord, T. Besset, B. U. W. Maes and M. Schnürch, Chem. Soc. Rev., 2018, 47, 6603; (e) R. K. Rit, M. R. Yadav, K. Ghosh and A. K. Sahoo, Tetrahedron, 2015, 71, 4450; (f) B. Liu, A. M. Romine, C. Z. Rubel, K. M. Engle and B.-F. Shi, Chem. Rev., 2021, 121, 14957; (g) G. He, B. Wang, W. A. Nack and G. Chen, Acc. Chem. Res., 2016, 49, 635; (h) S. A. Babu, Y. Aggarwal, P. Patel and R. Tomar, Chem. Commun., 2022, 58, 2612.
3. (a) E. Merino, Org. Biomol. Chem., 2011, 40, 3835; (b) W.-C. Geng, H. Sun and D.-S. Guo, J. Inclusion Phenom. Macrocyclic Chem., 2018, 92, 1; (c) M. Ghedini, I. Aiello, A. Crispini, A. Golemme, M. L. Deda and D. Pucci, Coord. Chem. Rev., 2006, 250, 1373; (d) C. Y. Chang, C. Fedele, A. Priimagi, A. Shishido and C. J. Barrett, Adv. Opt. Mater., 2019, 7, 1900091; (e) X. Pang, J.-a. Lv, C. Zhu, L. Qin and Y. Yu, Adv. Opt. Mater., 2019, 31, 1904224; (f) H. A. Wegner, Angew. Chem., Int. Ed., 2012, 51, 4787; (g) A. Chevalier, P.-y. Renard and A. Romieu, Chem. – Asian J., 2017, 12, 2008; (h) A. S. Amrutha, K. R. S. Kumar and N. Tamaoki, ChemPhotoChem, 2019, 3, 337; (i) H. M. D. Bandara and S. C. Burdette, Chem. Soc. Rev., 2012, 41, 1809; (j) S. Crespi, N. A. Simeth and B. König, Nat. Rev., 2019, 3, 133; (k) M. Zhu and H. Zhou, Org. Biomol. Chem., 2018, 16, 8434; (l) J. Vapaavuori, C. G. Bazuin and A. Prrimagi, J. Mater. Chem. C, 2018, 6, 2168; (m) W. Wagner-Wysiecka, N. Łukasik, J. F. Biernat and E. Luboch, J. Inclusion Phenom. Macrocyclic Chem., 2018, 90, 189; (n) M. D. Martino, L. Sessa, M. D. Matteo, B. Panunzi, S. Piotto and S. Concilio, Molecules, 2022, 27, 5643.
4. (a) M. W. H. Hoorens, M. E. Ourailidou, T. Rodat, P. E. van der Wouden, P. Kobauri, M. Kriegs, C. Peifer, B. L. Feringa, F. J. Dekker and W. Szymanski, Eur. J. Med. Chem., 2019, 179, 133; (b) J. A. Frank, M. Moroni, R. Moshourab, M. Sumser, G. R. Lewin and D. Trauner, Nat. Commun., 2015, 6, 7118; (c) B. Blanco, K. A. Palasis, A. Adwal, D. F. Callen and A. D. Abell, Bioorg. Med. Chem., 2017, 25, 5050; (d) S. A. Reis, B. Ghosh, J. A. Hendricks, D. M. Szantai-Kis, L. Törk, K. N. Ross, J. Lamb, W. Read-Button, B. Zheng, H. Wang, C. Salthouse, S. J. Haggarty and R. Mazitschek, Nat. Chem. Biol., 2016, 12, 317; (e) R. S. Stoll, M. V. Peters, A. Kühn, S. Heiles, R. Goddard, M. Buhl, C. M. Thiele and S. Hecht, J. Am. Chem. Soc., 2009, 131, 357.
5. (a) D. R. Fahey, J. Organomet. Chem., 1971, 27, 283; (b) D. R. Fahey, J. Chem. Soc. D, 1970, 417a; (c) T. H. L. Nguyen, N. Gigant and D. Joseph, ACS Catal., 2018, 8, 1546; (d) N. K. Mishra, J. Park, H. Oh, S. H. Han and I. S. Kim, Tetrahedron, 2018, 74, 6769; (e) G. Li, X. Ma, C. Jia, Q. Han, Y. Wang, J. Wang, L. Yu and S. Yang, Chem. Commun., 2017, 53, 1264.
6. (a) D. Shabashov and O. Daugulis, J. Am. Chem. Soc., 2010, 132, 3965; (b) N. Hoshiya, K. Takenaka, S. Shuto and J. Uenishi, Org. Lett., 2016, 18, 48; (c) K. S. Kanyiva, Y. Kuninobu and M. Kanai, Org. Lett., 2014, 16, 1968; (d) G. He, S.-Y. Zhang, W. A. Nack, Q. Li and G. Chen, Angew. Chem., Int. Ed., 2013, 52, 11124; (e) R. Parella and S. A. Babu, J. Org. Chem., 2015, 80, 12379; (f) R. Parella and S. A. Babu, J. Org. Chem., 2017, 82, 7123; (g) B. Gopalakrishnan, S. Mohan, R. Parella and S. A. Babu, J. Org. Chem., 2016, 81, 8988; (h) R. Padmavathi, R. Sankar, B. Gopalakrishnan, R. Parella and S. A. Babu, Eur. J. Org. Chem., 2015, 3727; (i) R. Tomar, D. Bhattacharya and S. A. Babu, Asian J. Org. Chem., 2022, 11, e202100736; (j) R. Kaur, S. Banga and S. A. Babu, Org. Biomol. Chem., 2022, 20, 4391; (k) R. Tomar, S. Suwasia, A. R. Choudhury, S. Venkataramani and S. A. Babu, Chem. Commun., 2022, 58, 12967; (l) A. Seki and Y. Takahashi, Tetrahedron Lett., 2021, 74, 153130; (m) C. Wang, L. Zhang and J. You, Org. Lett., 2017, 19, 1690; (n) C. Reddy, N. Bisht, R. Parella and S. A. Babu, J. Org. Chem., 2016, 81, 12143.
7. B. Cerdá, J. C. Espín, S. Parra, P. Martínez and F. A. Tomás-Barberán, Eur. J. Nutr., 2004, 43, 205.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2226308. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2ob02261c

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