Sulfoxide-mediated oxidative cross-coupling of phenols

Abstract

A metal-free, oxidative coupling of phenols with various nucleophiles, including arenes, 1,3-diketones and other phenols, is reported. Cross-coupling is mediated by a sulfoxide which inverts the reactivity of the phenol partner. Crucially, the process shows high selectivity for cross-versus homo-coupling and allows efficient access to a variety of aromatic scaffolds including biaryls, benzofurans and, through an iterative procedure, aromatic oligomers.

---

Introduction

Metal-catalyzed cross-coupling, involving an aryl halide and an organometallic partner, is a powerful tool for biaryl synthesis (Scheme 1A).¹ However, oxidative, C–H/C–H couplings, involving non-prefunctionalized partners, have recently come to the fore as an attractive alternative (Scheme 1B).² Their development remains a challenge, as the reactivity of one partner must be inverted, and known processes are compromised by the requirement for expensive, supply risk, metal oxidants or metal catalysts.² The development of selective, metal-free C–H/C–H coupling reactions is, therefore, an important goal.³

Scheme 1 (A and B) Types of cross-coupling. (C and D) Metal-free, oxidative coupling of phenols. (E) Sulfoxide-mediated, oxidative coupling of phenols.

Phenols, in particular unsymmetrical phenol-derived biaryls, are ubiquitous in nature, biomaterials and ligand collections for catalysis.⁴ Approaches to these compounds generally require multiple steps – prefunctionalization of partners or manipulation of protecting groups – and/or the use of metals.⁵ Metal-free oxidative coupling of unprotected phenols is therefore of interest, however, avoiding homocoupling is a challenge (Scheme 1C).⁶ Nevertheless, metal-free cross-coupling of phenols has been described, most notably using electroorganic synthesis⁷ or hypervalent iodine reagents,⁸ amongst other approaches⁹ (Scheme 1D).

We proposed that sulfoxides^10,11 could be used to invert the reactivity of a phenol partner, thus providing an alternative approach to their oxidative coupling (Scheme 1E). Capture of phenols by sulfoxides will deliver aryloxysulfonium intermediates I that are electrophilic and capable of coupling with various nucleophiles (e.g. Ar²).^12–14 The major challenge in such an approach is the avoidance of homocoupling.¹³ Furthermore, alternative Pummerer chemistry of the sulfoxide¹⁵ and rearrangement of sulfonium intermediates I^9a,10,16 must be by-passed.

Here we describe the metal-free, oxidative cross-coupling of phenols with various carbon nucleophilic partners, including other phenols, arenes, and 1,3-diketones (Scheme 1E). Couplings deliver biaryls, 2-aryl 1,3-dicarbonyl compounds and benzofurans. An iterative procedure allows selective double functionalization of phenols and the preparation of aryl oligomers.

Results and discussion

Oxidative cross-coupling of phenols with phenols, phenol derivatives and arenes

Guided by our previous studies, phenol 1a in CH₂Cl₂ was treated with sulfoxide 4a, activated using trifluoroacetic anhydride (TFAA), before subsequent addition of 2a (1.5 equivalents), to give the product of cross-coupling 3a in 91% isolated yield (see the ESI† for optimisation).

2-Naphthols bearing bromo (3c, 3e, 3h), methoxy (3b), phenyl (3d), cyano (3f) and ester (3g, 3i) groups at the 3-, 6- and 7-positions were found to be compatible with the coupling (Scheme 2). The process also embraced 1-naphthol (3j), phenols (3k–3m) and their methyl ether derivatives (3n–3q). Of particular note, pyrene (3r) underwent coupling with 1a to give 3r. The structure of 3r was confirmed by X-ray crystallographic analysis.¹⁷

Scheme 2 Oxidative cross-coupling of phenols with phenols, phenol derivatives and arenes. Reaction conditions: to sulfoxide 4a (0.11 mmol) in CH₂Cl₂ (1 mL, 0.1 M) in an oven-dried tube flushed with N₂ at −40 °C was added TFAA (0.17 mmol, 1.7 equiv.). After 5 min, phenol 1 (0.1 mmol in 0.5 mL CH₂Cl₂) was added in one portion. Arene 2 (0.15 mmol in 0.5 mL CH₂Cl₂) was then added immediately. After 15 min at −40 °C, the mixture was warmed to room temperature and stirred for 2 h. ^a CH₂Cl₂/TFA (1 : 1) as solvent. ^b Larger scale: (1.2 g of 1 was used). ^c 2 equiv. of 2 and 2.2 equiv. of 4a.

The phenol coupling partner (Ar¹) could also be varied and products of ortho-coupling with a range of nucleophilic partners gave products 3s–3ac (30–90% yield). Interestingly, treatment of 4-methoxyphenol with 1,2,4-trimethoxybenzene, under our standard conditions, gave the product of double arylation 3ab′ in 46% yield. The yield of 3ab′ could be increased by using 2.2 equivalent of the sulfoxide 4a and 2.0 equivalents of 1,2,4-trimethoxybenzene (80%). Diarylated compound 3ac′ could also be obtained. Interestingly, the couplings could be tuned to favour products of mono- or bis-coupling; using CH₂Cl₂/TFA (1 : 1) as solvent favoured formation of the mono-arylated products 3ab and 3ac. Finally, the oxidative coupling could be carried out on a gram scale; the use of 1.2 g of 4-methoxyphenol produced 1.6 g of 3ab (55% isolated yield). In all cross-couplings, 3-methyl benzothiophene was recovered in high yield by chromatography and could be reused.

Oxidative coupling of phenols with 1,3-diketones

1,3-Dicarbonyl compounds could be used as the second nucleophilic partner (Scheme 3). For example, treatment of 1a with 1,3-diphenylpropane-1,3-dione afforded 6a in 85% yield. The products of ortho coupling underwent cyclization to give benzofuran products; for example, the use of 4-methoxyphenol gave aroyl[b]benzofuran¹⁸6e in 55% isolated yield.

Scheme 3 Oxidative coupling of phenols with 1,3-diketones. Reaction conditions: to sulfoxide 4a (0.11 mmol) in CH₂Cl₂ (1 mL, 0.1 M) in an oven dried tube flushed with N₂ at −40 °C was added TFAA (0.17 mmol, 1.7 equiv.). After 5 min, phenol 1 (0.1 mmol in 0.5 mL CH₂Cl₂) was added in one portion. 1,3-Dicarbonyl 5 (0.15 mmol in 0.5 mL CH₂Cl₂) was then added immediately. After 15 min at −40 °C, the mixture was warmed to room temperature and stirred for 2 h. ^a CH₂Cl₂/TFA (1 : 1) as solvent.

Iterative coupling of three nucleophiles

Intrigued by the formation of the triaryl products 3ab′ and 3ac′ (Scheme 2), we considered an iterative process that would allow the sequential, metal-free, oxidative coupling of phenols with two different nucleophilic partners (Scheme 4). For example, 4-methoxy phenol was first coupled with 1,2,4-trimethoxybenzene to afford 3ab. Subsequent treatment of 3ab with 1,3-dimethoxybenzene gave the unsymmetrical, diarylated phenol 7a in 68% yield. 1,3-Diphenylpropane-1,3-dione could also be used as the third nucleophilic partner and gave C7-arylated benzofurans 7c and 7h.¹⁹

Scheme 4 Iterative coupling of three nucleophiles. Reaction conditions: to sulfoxide 4a (0.11 mmol) in CH₂Cl₂ (1 mL, 0.1 M) in an oven dried tube flushed with N₂ at −40 °C was added TFAA (0.17 mmol, 1.7 equiv.). After 5 min, 3 (0.1 mmol in 0.5 mL CH₂Cl₂) was added in one portion. A third nucleophile (0.15 mmol in 0.5 mL CH₂Cl₂) was then added immediately. After 15 min at −40 °C, the mixture was warmed to room temperature and stirred for 2 h. ^a Compound 3z was used as the substrate. ^b CH₂Cl₂/TFA (1 : 1) as solvent.

Mechanistic studies

Based on the above results, and our previous studies,^10,13 a possible mechanism for the oxidative cross-coupling is shown in Scheme 5A.¹³ Activation of sulfoxide 4a with TFAA gives acyloxysulfonium salt II and interrupted Pummerer reaction with a phenol coupling partner gives aryloxysulfonium salt I. Subsequent attack of the second partner, at the ortho or para position of the first, results in C–C bond formation and expulsion of 3-methylbenzothiophene. The control experiments in Scheme 5B highlight the important role of the hydroxy group in the first partner and suggest that activation of the phenol occurs via intermediate I. However, we were unable to detect or isolate this intermediate and further studies are needed to confirm the exact mechanism for phenol activation. Scheme 5C shows that the order in which the two nucleophilic partners are combined can be critical, suggesting that rapid and irreversible, aryloxysulfonium salt formation takes place between the activated sulfoxide I and the first phenol partner, and that aryloxysulfonium salt intermediates have very different reactivities.²⁰

Scheme 5 Proposed mechanism and support for the intermediacy of an aryloxysulfonium salt.

Conclusions

In summary, a metal-free, sulfoxide-mediated, oxidative cross-coupling unites phenols and various nucleophilic partners, including phenols, 1,3-diketones and arenes. The capture and inversion of reactivity of the first nucleophilic partner, using an interrupted Pummerer reaction, prior to coupling with the second nucleophile, is key to the cross-coupling. Homocoupling is not observed and alternative Pummerer and rearrangement processes are avoided. Iterative sulfoxide-mediated couplings allow the construction of polyaryl compounds.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank EPSRC (EP/M005062/1; Postdoctoral Fellowship to Z. H.; Established Career Fellowship to D. J. P.) and The University of Manchester (Lectureship to G. J. P.·P.) for their generous support.

Notes and references

1. (a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062–5085; (b) G. Bringmann, R. Walter and R. Weirich, Angew. Chem., Int. Ed., 1990, 29, 977–991; (c) I. Hussain and T. Singh, Adv. Synth. Catal., 2014, 356, 1661–1696.
2. (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215–1292; (b) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068–5083; (c) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780–1824; (d) C. Liu, J. Yuan, M. Gao, S. Tang, W. Li, R. Shi and A. Lei, Chem. Rev., 2015, 115, 12138–12204; (e) Y. Yang, J. Lan and J. You, Chem. Rev., 2017, 117, 8787–8863; (f) H. Wang, X. Gao, Z. Lv, T. Abdelilah and A. Lei, Chem. Rev., 2019, 119, 6769–6787.
3. (a) C.-L. Sun and Z.-J. Shi, Chem. Rev., 2014, 114, 9219–9280; (b) R. Narayan, K. Matcha and A. P. Antonchick, Chem.–Eur. J., 2015, 21, 14678–14693.
4. (a) S. Quideau, D. Deffieux, C. Douat-Casassus and L. Pouységu, Angew. Chem., Int. Ed., 2011, 50, 586–621; (b) G. Bringmann, T. Gulder, T. A. M. Gulder and M. Breuning, Chem. Rev., 2011, 111, 563–639; (c) D. Parmar, E. Sugiono, S. Raja and M. Rueping, Chem. Rev., 2014, 114, 9047–9153; (d) R. Maji, S. C. Mallojjala and S. E. Wheeler, Chem. Soc. Rev., 2018, 47, 1142–1158; (e) M. A. Rahim, S. L. Kristufek, S. Pan, J. J. Richardson and F. Caruso, Angew. Chem., Int. Ed., 2019, 58, 1904–1927; (f) J. Guo, T. Suma, J. J. Richardson and H. Ejima, ACS Biomater. Sci. Eng., 2019, 5, 5578–5596.
5. Z. Huang and J.-P. Lumb, ACS Catal., 2019, 9, 521–555.
6. (a) H. Eickhoff, G. Jung and A. Rieker, Tetrahedron, 2001, 57, 353–364; (b) G. Bringmann and S. Tasler, Tetrahedron, 2001, 57, 331–343; (c) C. Boldron, G. Aromí, G. Challa, P. Gamez and J. Reedijk, Chem. Commun., 2005, 5808–5810; (d) A. Kirste, M. Nieger, I. M. Malkowsky, F. Stecker, A. Fischer and S. R. Waldvogel, Chem.–Eur. J., 2009, 15, 2273–2277; (e) A. Kirste, G. Schnakenburg and S. R. Waldvogel, Org. Lett., 2011, 13, 3126–3129; (f) A. Kirste, S. Hayashi, G. Schnakenburg, I. M. Malkowsky, F. Stecker, A. Fischer, T. Fuchigami and S. R. Waldvogel, Chem.–Eur. J., 2011, 17, 14164–14169.
7. (a) A. Kirste, G. Schnakenburg, F. Stecker, A. Fischer and S. R. Waldvogel, Angew. Chem., Int. Ed., 2010, 49, 971–975; (b) A. Kirste, B. Elsler, G. Schnakenburg and S. R. Waldvogel, J. Am. Chem. Soc., 2012, 134, 3571–3576; (c) B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke and S. R. Waldvogel, Angew. Chem., Int. Ed., 2014, 53, 5210–5213; (d) A. Wiebe, D. Schollmeyer, K. M. Dyballa, R. Franke and S. R. Waldvogel, Angew. Chem., Int. Ed., 2016, 55, 11801–11805; (e) S. Lips, A. Wiebe, B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke and S. R. Waldvogel, Angew. Chem., Int. Ed., 2016, 55, 10872–10876; (f) A. Wiebe, S. Lips, D. Schollmeyer, R. Franke and S. R. Waldvogel, Angew. Chem., Int. Ed., 2017, 56, 14727–14731; (g) S. Lips, D. Schollmeyer, R. Franke and S. R. Waldvogel, Angew. Chem., Int. Ed., 2018, 57, 13325–13329.
8. K. Morimoto, K. Sakamoto, T. Ohshika, T. Dohi and Y. Kita, Angew. Chem., Int. Ed., 2016, 55, 3652–3656.
9. For other selected metal-free C–H/C–H couplings of phenols, see: (a) S. Sharma, S. K. R. Parumala and R. K. Peddinti, J. Org. Chem., 2017, 82, 9367–9383; (b) K. Liu, S. Tang, P. Huang and A. Lei, Nat. Commun., 2017, 8, 775; (c) L. Bering, M. Vogt, F. M. Paulussen and A. P. Antonchick, Org. Lett., 2018, 20, 4077–4080.
10. For the reactions of benzothiophene S-oxides with phenols, see: (a) H. J. Shrives, J. A. Fernández-Salas, C. Hedtke, A. P. Pulis and D. J. Procter, Nat. Commun., 2017, 8, 14801; (b) Z. He, H. J. Shrives, J. A. Fernández-Salas, A. Abengózar, J. Neufeld, K. Yang, A. P. Pulis and D. J. Procter, Angew. Chem., Int. Ed., 2018, 57, 5759–5764; (c) K. Yang, A. P. Pulis, G. J. P. Perry and D. J. Procter, Org. Lett., 2018, 20, 7498–7503.
11. For examples of interrupted Pummerer and related reactions, see: (a) T. Kobatake, D. Fujino, S. Yoshida, H. Yorimitsu and K. Oshima, J. Am. Chem. Soc., 2010, 132, 11838–11840; (b) K. Murakami, H. Yorimitsu and A. Osuka, Angew. Chem., Int. Ed., 2014, 53, 7510–7513; (c) T. Yanagi, S. Otsuka, Y. Kasuga, K. Fujimoto, K. Murakami, K. Nogi, H. Yorimitsu and A. Osuka, J. Am. Chem. Soc., 2016, 138, 14582–14585; (d) X. Huang and N. Maulide, J. Am. Chem. Soc., 2011, 133, 8510–8513; (e) X. Huang, M. Patil, C. Farès, W. Thiel and N. Maulide, J. Am. Chem. Soc., 2013, 135, 7312–7323; (f) B. Peng, D. Geerdink, C. Farès and N. Maulide, Angew. Chem., Int. Ed., 2014, 53, 5462–5466; (g) B. Peng, X. Huang, L.-G. Xie and N. Maulide, Angew. Chem., Int. Ed., 2014, 53, 8718–8721; (h) D. Kaiser, L. F. Veiros and N. Maulide, Chem.–Eur. J., 2016, 22, 4727–4732; (i) D. Kaiser, L. F. Veiros and N. Maulide, Adv. Synth. Catal., 2017, 359, 64–77; (j) D. Kaldre, I. Klose and N. Maulide, Science, 2018, 361, 664–667; (k) A. J. Eberhart and D. J. Procter, Angew. Chem., Int. Ed., 2013, 52, 4008–4011; (l) J. A. Fernández-Salas, A. J. Eberhart and D. J. Procter, J. Am. Chem. Soc., 2016, 138, 790–793; (m) M. Šiaučiulis, S. Sapmaz, A. P. Pulis and D. J. Procter, Chem. Sci., 2018, 9, 754–759; (n) M. H. Aukland, F. J. T. Talbot, J. A. Fernández-Salas, M. Ball, A. P. Pulis and D. J. Procter, Angew. Chem., Int. Ed., 2018, 57, 9785–9789; (o) D. Chen, Q. Feng, Y. Yang, X.-M. Cai, F. Wang and S. Huang, Chem. Sci., 2017, 8, 1601–1606; (p) M. Šiaučiulis, N. Ahlsten, A. P. Pulis and D. J. Procter, Angew. Chem., Int. Ed., 2019, 58, 8779–8783; (q) L. Zhang, J.-N. He, Y. Liang, M. Hu, L. Shang, X. Huang, L. Kong, Z.-X. Wang and B. Peng, Angew. Chem., Int. Ed., 2019, 58, 5316–5320; (r) X. Meng, D. Chen, X. Cao, J. Luo, F. Wang and S. Huang, Chem. Commun., 2019, 55, 12495–12498; (s) X. Huang, S. Klimczyk and N. Maulide, Synthesis, 2012, 44, 175–183; (t) D. Kaiser, I. Klose, R. Oost, J. Neuhaus and N. Maulide, Chem. Rev., 2019, 119, 8701–8780.
12. For examples of interrupted Pummerer reactions involving alkene and alkyne nucleophiles, see; (a) B. Waldecker, F. Kraft, C. Golz and M. Alcarazo, Angew. Chem., Int. Ed., 2018, 57, 12538–12542; (b) Z. Zhang, Y. Luo, H. Du, J. Xu and P. Li, Chem. Sci., 2019, 10, 5156–5161 . See also ref. 11l, 11n and 11p.
13. For the homocoupling of 2-naphthols using a benzothiophene catalyst, see: Z. He, A. P. Pulis and D. J. Procter, Angew. Chem., Int. Ed., 2019, 58, 7813–7817.
14. A cross-coupling procedure was low yielding and not general, see: K. Higuchi, T. Tago, Y. Kokubo, M. Ito, M. Tayu, S. Sugiyama and T. Kawasaki, Org. Chem. Front., 2018, 5, 3219–3225.
15. L. H. S. Smith, S. C. Coote, H. F. Sneddon and D. J. Procter, Angew. Chem., Int. Ed., 2010, 49, 5832–5844.
16. T. Yanagi, K. Nogi and H. Yorimitsu, Tetrahedron Lett., 2018, 59, 2951–2959.
17. X-ray crystallographic data for 3r, 3ab′, 6b, 6g, and 7d can be found at the Cambridge Crystallographic Data Centre (CCDC); 1944706–1944710.†.
18. 3-Aroyl[b]benzofurans are found in bioactive molecules. (a) T. Kálai, G. Várbiró, Z. Bognár, A. Pálfi, K. Hantó, B. Bognár, E. Ősz, B. Sümegi and K. Hideg, Bioorg. Med. Chem., 2005, 13, 2629–2636; (b) C. C. Felder, K. E. Joyce, E. M. Briley, M. Glass, K. P. Mackie, K. J. Fahey, G. J. Cullinan, D. C. Hunden, D. W. Johnson, M. O. Chaney, G. A. Koppel and M. Brownstein, J. Pharmacol. Exp. Ther., 1998, 284, 291–297; (c) R. C. Heel, R. N. Brogden, T. M. Speight and G. S. Avery, Drugs, 1977, 14, 349–366.
19. In some cases, when lower yields were obtained (e.g. formation of 7d, 7e, 7f, 7h), unreacted starting material was recovered (10–15% of the phenol 3 and 20–35% of the other coupling partner – naphthol or diketone) and some decomposition took place (side products could not be isolated).
20. When reversing the order of addition of the coupling partners (Scheme 5C, bottom), the phenol could be recovered (85% recovery), however, only a trace of the naphthol component was observed. We have been unable to detect any other side products and are currently investigating possible decomposition pathways.

---

Footnote

† Electronic supplementary information (ESI) available: Full experimental details, NMR spectra, CCDC numbers for X-ray structures. CCDC 1944706–1944710. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9sc05668h

---