Aryl–aryl cross-coupling reactions without reagents or catalysts: photocyclization of ortho-iodoaryl ethers and related compounds via triplet aryl cation intermediates

Abstract

Cyclisations of benzyl ortho-iodoaryl ethers to benzo[c]chromenes can be effected without reagents or catalysts by irradiation with UVC under flow. Reactions proceed via triplet aryl cation generation, 5-exo and 3-exo-cyclisations, and rearomatisation. They have wide scope, are easy to effect and extend to a myriad of related ring systems.

---

Cyclisations of benzyl ortho-iodoaryl ethers to benzo[c]chromenes, e.g.5 → 4 or 7 (Scheme 1) are typically achieved by radical cyclisation,¹ or palladium catalysed cross-coupling reactions.² The products given by the two approaches can differ when cyclisation involves addition to a substituted arene. Thus, while the Pd catalysed cyclisation occurs ortho- to the tethering chain, giving benzoisochromene 7,² cyclisation via aryl radical intermediate 1 principally gives benzoisochromene 4 through a neophyl rearrangement via ipso-cyclisation to 2 and fragmentation to 3.^1,3 Herein we show how it is possible to induced cyclisation without reagents or catalysts through irradiation with UVC.⁴ Notably, reactions give ortho-addition products 7 rather than those derived by a radical-induced neophyl rearrangement 4, implicating the intermediacy of triplet aryl cations ³[9] and ³[10],⁵ as supported by TD-DFT calculations.⁶

Scheme 1 Regiochemical outcomes for the common cyclisation reactions of benzyl ortho-iodoaryl ethers [R = H for calculated relative ΔG values via triplet aryl cation 9].

Our investigation began with benzyl ortho-iodophenyl ether 5a which, on irradiation with UVC under continuous flow in acetonitrile at ambient temperature, gave benzoisochromene 7a in 78% yield (Scheme 2). To determine if the reaction proceeded via radical intermediate 1, the method was extended to substrates 5b–d with a para-substituent on the benzyl ether residue. In each case cyclisation gave regioisomer 7 rather than 4 indicating that they did not proceed via aryl radical intermediates 1b–d (see ESI† for further discussion).¹ We next examined the reaction by TD-DFT,⁶ and found that the 5-exo-trig cyclisation mode also appeared to be favoured by the corresponding triplet aryl cation ³[9], with 6-exo/endo-trig cyclisation to ³[8] having a higher activation energy. However, relaxation of the thus formed intermediate ³[10] led to spontaneous cyclisation to tetracycle 11, setting up a facile double aromatisation with loss of HI to give the observed product 7. The yields attained in these early experiments indicated that benzyl residues carrying an electron withdrawing substituent (5c) were poorer substrates than those carrying electron donating substituents (5b,d). To probe the impact of substituents further, a series of benzyl o-iodoaryl ethers were prepared with substituents on the iodinated arene, 5e–h, and with substituents on both arenes, 5i–l (Table 1). These experiments showed that yields were enhanced by electron donating substituents on the iodinated arene (7e,f,i–k) and were supressed by electron withdrawing substituents (7g,h). Notably, the reaction was also given in modest yield by benzyl 2-iodo-3-methoxyphenyl ether 5l. In this case we believe a complex product mixture was given due to the sensitivity of the starting material and product 7l towards the HI formed as a by-product of the reaction.⁷

Scheme 2 Regiochemistry observed for cyclisations to substituted benzyl ethers.

Table 1 Photocyclisations of benzyl ortho-iodoaryl ethers to benzoisochromenes

† 1 equiv. pyridine added.

---

Indeed, while the method was being developed, several starting materials and products proved susceptible to benzyl ether cleavage by HI.⁷ For example, photolysis of p-nitrobenzyl o-iodophenyl ether led to a complex product mixture from which p-nitrobenzyl iodide was isolated in low yield. Similarly, 3,5-dimethylbenzyl ether 5m gave the anticipated product 7m in 32% isolated yield together with biaryl 12 as a significant by-product (Scheme 3). Its formation implicates benzoisochromene cleavage to benzyl iodide 13 followed by a Ritter reaction with acetonitrile.⁸ Such side reactions were attenuated by an expeditious work-up and/or the addition of an equivalent of pyridine to the reaction mixture (e.g.Table 1).

Scheme 3 A side reaction promoted by HI involving benzoisochromene cleavage by HI and a Ritter reaction.

The photocyclisation was next extended to analogous pyridyl ethers 15a–d (Table 2) leading respectively to heterocycles 16a–d. It also proved effective for the synthesis of an array of polyaromatic ring systems through related photocyclisation (Scheme 4) and tandem photocyclisation reactions (Scheme 5). It is notable that lower yields were generally associated with products bearing substituents in the ‘fjord’ region (Scheme 4), indicating their increased sensitivity towards ethereal cleavage by HI due to steric strain. Nonetheless, the method was able to produce a myriad of polyaromatic ring systems, including oxahelicene 25 and terphenyls 31 and 32 (Schemes 4 and 5).

Table 2 Photocyclisations of benzyl and pyridyl 2-iodopyrid-3-yl ethers

---

Scheme 4 Photocyclisations leading to polyaromatic ring systems.

Scheme 5 Tandem photocyclisations leading to terphenyl containing ring systems.

The presence of ortho-substituents on the benzyl ether was investigated next and revealed a further subtlety (Scheme 6). When both ortho sites carried methyl substituents, 5n, cyclisation of the spirocyclic intermediate ³[10n] to 11n is presumably followed by fragmentation to oxocarbenium ion 34, as the main product given was biaryl 33a.⁹ The rearrangement pathway to 7 and fragmentation pathway to 33 compete when the benzyl residue carries a single ortho-substituent, with the o-methyl analogue 5o favouring benzoisochromene 7o while the o-methoxy analogue 5p favoured biaryl 33c. The extent to which the spirocyclic triplet aryl cation intermediate ³[10] follows each of these pathways is presumably determined by a combination of steric and electronic factors.

Scheme 6 Substrates giving biaryls by sequential cyclisation and fragmentation.

A further curiosity arose when the benzyl residue carried a meta-methoxy substituent, e.g.5q–s (Scheme 7). Photolysis under the aforementioned conditions principally followed the pathway leading to benzoisochromenes 7q–s respectively. However, these products were each accompanied by a spirocyclic enone, 35a–c, which we presume arises through H-atom abstraction from HI by ³[10q–s] to radical cation 36, then single electron transfer to dienyl ether 37, and demethylation.

Scheme 7 Substrates giving benzoisochromenes and spirocyclic enones.

A more useful observation came through extension of the methodology to homobenzyl ortho-iodophenyl ethers 38a–c. Photocyclisation of these substrates proceeded smoothly and in good yield to give the corresponding 7-ring ethers 39a–c (Scheme 8). Additionally, we have established that p-chloro- and p-methoxy- substituents on the iodoarene, 40 and 43, can also facilitate triplet aryl cation formation to ³[41] and ³[44] respectively (Scheme 9). These extensions to regioisomeric benzoisochromenes (e.g.42) and dihydrophenanthrenes (e.g.45) demonstrate ways of extending the method to systems that do not carry an ethereal linkage to the iodoarene residue.

Scheme 8 Extensions to dibenzo[b,d]oxepines and a benzo[4,5]oxepino[3,2-b]pyridine.

Scheme 9 Extension to regioisomeric benzoisochromenes and dihydrophenanthrenes.

In conclusion, we have shown that intramolecular aryl–aryl coupling reactions of benzyl ortho-iodoaryl ethers and related substrates can be effected without reagents or catalysts by irradiation with UVC under flow. Reaction proceeds via triplet aryl cation intermediates such as ³[9] and ³[10] rather than by radical cyclisation. The method can be applied to systems bearing all manner of substituents including extended aromatic ring systems. The reaction works best when the arenes carry electron donating groups, yet also gives good to excellent yields with analogous pyridyl systems. The sensitivity of both starting materials and products towards benzyl ether cleavage by HI can be resolved, in part, by employing an expeditious work-up and/or a scavenger. ortho-Substituents are tolerated on either ring but do lead to diminished yields. When the benzyl residue carries two ortho-substituents, a biaryl is given. Notably, extensions to tandem cyclisation reactions gave terphenyl containing products and extensions to homobenzyl ethers gave 7-ring ethers. Importantly, para-chloro- and para-methoxy-substituents on the iodoarene have also been shown to facilitate triplet aryl cation formation, extending these photocyclisation reactions to systems devoid of an ethereal bond ortho- to the iodide.

Wei Sun and Luke Wilding-Steele performed the synthetic chemistry under the supervision of Richard Brown and the corresponding author David Harrowven. Wei Sun performed the TD-DFT analyses. We gratefully acknowledge financial support from EPSRC [EP/P013341/1 and EP/K039466/1] and the European Regional Development Fund [ERDF Interreg Va programme (Project 121)], Dr James Pearce for the gift of compound 15a and Dr Michael I. T. Nunn for some characterisation data presented in the ESI.†

Conflicts of interest

There are no conflicts of interest to declare.

Notes and references

1. Radical cyclisations of 2-iodoaryl benzyl ethers have been induced with (i) Bu₃SnH: D. C. Harrowven, M. I. T. Nunn, N. A. Newman and D. R. Fenwick, Tetrahedron Lett., 2001, 42, 961 ; (ii) KOtBu and a nitrogen heterocycle: D. S. Roman, Y. Takahashi and A. B. Charette, Org. Lett., 2011, 13, 3242; S. Zhou, G. M. Anderson, B. Mondal, E. Doni, V. Ironmonger, M. Kranz, T. Tuttle and J. A. Murphy, Chem. Sci., 2014, 5, 476; S. Chen, W. Chen, Y. Chen, Z. Liu, T. Mu, P. Wang and Z. Yan, RSC Adv., 2020, 10, 14500; C.-L. Sun, Y.-F. Gu, W.-P. Huang and Z.-J. Shi, Chem. Commun., 2011, 47, 9813; H. Yang, L. Zhang and L. Jiao, Chem. – Eur. J., 2017, 23, 65 ; (iii) KO^tBu, DMSO and blue light: M. E. Budén, M. D. Heredia, M. Puiatti and R. A. Rossi, Org. Biomol. Chem., 2022, 20, 228 ; (iv) with boron reagents: S. Pinet, V. Liautard, M. Debiais and M. Pucheault, Synthesis, 2017, 4759; A. B. Waghamare, R. K. Raut, N. Patel and M. Majumdar, Eur. J. Inorg. Chem., 2022, E202200089 ; (v) by photocatalysis: P. Herr, F. Glaser, L. A. Büldt, C. B. Larsen and O. S. Wenger, J. Am. Chem. Soc., 2019, 141, 14394 ; (vi) with Me₄NI: K. Nozawa-Kumada, K. Nakamura, S. Kurosu, Y. Iwakawa, C. Denneval, M. Shigeno and Y. Kondo, Chem. Pharm. Bull., 2019, 67, 1042.
2. M. Kitamura, K. Ohmori, T. Kawase and K. Suzuki, Angew. Chem., Int. Ed., 1999, 38, 1229; R. Grigg, V. Savic and V. Tambyrajah, Tetrahedron Lett., 2000, 41, 3003; T. Harayama, H. Yasuda, T. Akiyama, Y. Takeuchi and H. Abe, Chem. Pharm. Bull., 2000, 48, 861; K. Ohmori, M. Tamiya, M. Kitamura, H. Kato, M. Oorui and K. Suzuki, Angew. Chem., Int. Ed., 2005, 44, 3871; D. C. Harrowven, T. Woodcock and P. D. Howes, Angew. Chem., Int. Ed., 2005, 44, 3967; L.-C. Campeau, M. Parisien, A. Jean and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581; M. Tamiya, K. Ohmori, M. Kitamura, H. Kato, T. Arai, M. Oorui and K. Suzuki, Chem. – Eur. J., 2007, 13, 9791; H. Kelgtermans, L. Dobrzanska, W. Dehaen and L. Van Meervelt, Org. Lett., 2012, 14, 5200; T. Matsukihira, T. Kida, K. Hidaka, S. Saga, M. Takemura, A. Yonoki, T. Nishimori, Y. Horino, T. Harayama, Y. Takeuchi and H. Abe, Heterocycles, 2013, 87, 2555; G. Bringmann, N. Manchala, T. Büttner, B. Hertlein-Amslinger and R. Seupel, Chem. – Eur. J., 2016, 22, 9792; R. Cano, J. M. Pérez, D. J. Ramón and G. P. McGlacken, Tetrahedron, 2016, 72, 1043; Y. Tanji, N. Mitsutake, T. Fujihara and Y. Tsuji, Angew. Chem., Int. Ed., 2018, 57, 10314; Y. An, B.-S. Zhang, Z. Zhang, C. Liu, X. Y. Gou, Y.-N. Ding and Y.-M. Liang, Chem. Commun., 2020, 56, 5933.
3. F. H. Seubold Jr, J. Am. Chem. Soc., 1953, 75, 2532; J. W. Wilt and W. W. Pawlikowski Jr, J. Org. Chem., 1975, 40, 3641; M. Weber and H. Fischer, J. Am. Chem. Soc., 1999, 121, 7381; Z.-M. Chen, X.-M. Zhang and Y.-Q. Tu, Chem. Soc. Rev., 2015, 44, 5220; A. Behnia, M. A. Fard, J. M. Blacquiere and R. J. Puddephatt, Organometallics, 2017, 36, 4759; A. Navarro-Vázquez and D. Domínguez, Tetrahedron Lett., 2020, 61, 151871.
4. For our work on flow photochemistry see: W. Sun, S. Kayal, W. A. T. Raimbach, X.-Z. Sun, M. E. Light, M. W. D. Hanson-Heine, M. W. George and D. C. Harrowven, Chem. Commun., 2022, 58, 1546; W. Sun, W. A. T. Raimbach, L. D. Elliott, K. I. Booker-Milburn and D. C. Harrowven, Chem. Commun., 2022, 58, 383; M. A. Manning, W. Sun, M. E. Light and D. C. Harrowven, Chem. Commun., 2021, 57, 4556; D. E. Collin, E. H. Jackman, N. Jouandon, W. Sun, M. E. Light, D. C. Harrowven and B. Linclau, Synthesis, 2021, 1307; M. J. Ralph, D. C. Harrowven, S. Gaulier, S. Ng and K. I. Booker-Milburn, Angew. Chem., Int. Ed., 2015, 54, 1527; D. C. Harrowven, M. Mohamed, T. P. Gonçalves, R. J. Whitby, D. Bolien and H. F. Sneddon, Angew. Chem., Int. Ed., 2012, 51, 4405.
5. R. W. Taft, J. Am. Chem. Soc., 1961, 83, 3350; W. E. Lee, J. G. Calvert and E. W. Malmberg, J. Am. Chem. Soc., 1961, 83, 1928; J. D. Dill, P. V. R. Schleyer and J. A. Pople, J. Am. Chem. Soc., 1977, 99, 1; H. Zollinger, Angew. Chem., Int. Ed. Engl., 1978, 17, 141; H. B. Ambroz and T. J. Kemp, Chem. Soc. Rev., 1979, 8, 353; H. B. Ambroz and T. J. Kemp, J. Chem. Soc., Perkin Trans. 2, 1980, 768; N. J. Bunce, J. P. Bergsma, M. D. Bergsma, W. De Graaf, Y. Kumar and L. Ravanal, J. Org. Chem., 1980, 45, 3708; H. B. Ambroz and T. J. Kemp, Chem. Commun., 1982, 172; H. B. Ambroz, T. J. Kemp and G. K. Przybytniak, J. Photochem. Photobiol., A, 1992, 68, 85; S. Gasper, C. Devadoss and G. B. Schuster, J. Am. Chem. Soc., 1995, 117, 5206; S. Steenken, M. Ashokkumar, P. Maruthamuthu and R. A. McClelland, J. Am. Chem. Soc., 1998, 120, 11925; P. S. J. Canning, K. McCrudden, H. Maskill and B. Sexton, J. Chem. Soc., Perkin Trans. 2, 1999, 2735; P. S. J. Canning, H. Maskill, K. McCrudden and B. Sexton, Bull. Chem. Soc. Jpn., 2002, 75, 789; S. Milanesi, M. Fagnoni and A. Albini, Chem. Commun., 2003, 216; M. Freccero, M. Fagnoni and A. Albini, J. Am. Chem. Soc., 2003, 125, 13182; M. Fagnoni and A. Albini, Acc. Chem. Res., 2005, 38, 713; S. Milanesi, M. Fagnoni and A. Albini, J. Org. Chem., 2005, 70, 603; M. De Carolis, S. Protti, M. Fagnoni and A. Albini, Angew. Chem., Int. Ed., 2005, 44, 1232; S. Protti, M. Fagnoni and A. Albini, Angew. Chem., Int. Ed., 2005, 44, 5675; M. Slegt, H. S. Overkleeft and G. Lodder, Eur. J. Org. Chem., 2007, 5364; V. Dichiarante and M. Fagnoni, Synlett, 2008, 787; A. B. Penenory and J. E. Argüello, Handbook of Synthetic Photochemistry, ed. A. Albini and M. Fagnoni, Wiley-VCH, Weinheim, Germany, 2010, pp. 319–352; S. Protti, V. Dichiarante, D. Dondi, M. Fagnoni and A. Albini, Chem. Sci., 2012, 3, 1330; S. Protti, D. Ravelli, B. Mannucci, A. Albini and M. Fagnoni, Angew. Chem., Int. Ed., 2012, 51, 8577; V. Dichiarante, S. Protti and M. Fagnoni, J. Photochem. Photobiol. A: Chem., 2017, 339, 103; E. Abitelli, S. Protti, M. Fagnoni and A. Albini, J. Org. Chem., 2012, 77, 3501; H. Qrareya, C. Raviola, S. Protti, M. Fagnoni and A. Albini, J. Org. Chem., 2013, 78, 6016; S. V. Bondarchuk and B. F. Minaev, J. Phys. Chem. A, 2014, 118, 3201; S. Rayne and K. Forest, Theor. Chem. Acc., 2016, 135; C. Raviola, F. Chiesa, S. Protti, A. Albini and M. Fagnoni, J. Org. Chem., 2016, 81, 6336; A. M. Mfuh, J. D. Doyle, B. Chhetri, H. D. Arman and O. V. Larionov, J. Am. Chem. Soc., 2016, 138, 2985; A. M. Mfuh, V. T. Nguyen, B. Chhetri, J. E. Burch, J. D. Doyle, V. N. Nesterov, H. D. Arman and O. V. Larionov, J. Am. Chem. Soc., 2016, 138, 8408; C. Pedroli, D. Ravelli, S. Protti, A. Albini and M. Fagnoni, J. Org. Chem., 2017, 82, 6592.
6. A. Dreuw and M. Head-Gordon, Chem. Rev., 2005, 105, 4009.
7. K. Auwers, F. A. Traun and R. Welde, Chem. Ber., 1899, 32, 3317.
8. For reviews on the Ritter reaction see: L. I. Krimen and D. J. Cota, Org. React., 1969, 17, 213; R. Bishop, Comp. Org. Synth., 2014, 6, 239; D. Jiang, T. He, L. Ma and Z. Wang, RSC Adv., 2014, 4, 64936; J. Bolsakova and A. Jirgensons, Chem. Heterocycl. Compd., 2017, 53, 1167; G. M. Ziarani, F. S. Hasankiadeh and F. Mohajer, Chem. Select, 2020, 5, 14349; M.-E. Chen, X.-W. Chen, Y.-H. Hu, R. Ye, J.-W. Lv, B. Li and F.-M. Zhang, Org. Chem. Front., 2021, 8, 4623.
9. For a related approach to encumbered biaryls by radical cyclisation see: P. Poonpatana, G. dos Passos Gomes, T. Hurrle, K. Chardon, S. Bräse, K.-S. Masters and I. Alabugin, Chem. – Eur. J., 2017, 23, 9091.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental accounts with spectral details and copies of NMR spectra are available as supplementary information. See DOI: https://doi.org/10.1039/d3cc03271j

---