Ti Cocatalyzed Biaryl

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Phenolate Enabled General and Selective Fe/Ti Cocatalyzed Biaryl Cross-Couplings between Aryl Halides and Aryl Grignard Reagents Rui Zhang, Yan Zhao, Kun-Ming Liu, and Xin-Fang Duan* College of Chemistry, Beijing Normal University, Beijing 100875, China

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ABSTRACT: The serendipitous addition of a phenolate to FeCl3/TMEDA/Ti(OEt)4 enables a strong Fe/Ti cooperativity that can efficiently catalyze a general and selective biarylcoupling reaction. In the absence of phosphine or NHC ligands, various aryl chlorides, bromides, and iodides can couple with a variety of common and Knochel-type aryl Grignard reagents. A wide range of sensitive functional groups in either coupling partner can be tolerated. This bimetallic cocatalysis not only remarkably extends the scope of Fecatalyzed biaryl couplings but also provides a solution to the problem of functional group compatibility of Grignard reagents.

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We herein report a highly general and chemoselective Febased catalyzed biaryl cross-coupling reaction. The salient feature is that the only addition of 20 mol % of Ti(OEt)4 and 20 mol % of PhOM (M = MgX, Li, or Na) to the common iron catalyst system, FeCl3/TMEDA,6 enables a general biaryl cross-coupling reaction between various aryl halides and Grignard reagents. Our previous investigations showed that the addition of Ti(OR)4 to the reactions of Co-catalyzed biaryl crosscouplings could suppress the side homocoupling reactions and improve the tolerance to sensitive functional groups.12 However, under similar conditions, iron salts/ligands in the presence of Ti(OEt)4 could hardly promote the desired cross coupling. We serendipitously discovered that the addition of PhOM to the system of iron salts/ligands and Ti(OEt)4 could efficiently catalyze the biaryl cross coupling (for the optimization of reactions, see Table S1). Because the phenolate group is a classic ligand for both iron and titanium,13 the participation of phenolate in the present reaction might promote a bimetallic cooperation by acting as a bridging ligand and, thus, significantly enhanced the catalytic reactivity of iron species. As illustrated in Scheme 1, the unactivated bromide

iaryls are ubiquitous structural units in natural products, pharmaceutics, organic materials, and ligands, and the transition-metal-catalyzed cross-coupling reactions have become an indispensable tool to make them.1 Palladium and nickel complexes have dominated this field for over 30 years; however, these two catalysts suffer from the disadvantage of the high price of palladium and the high toxicity of nickel.2 In this context, iron catalysts are a suitable replacement for palladium or nickel due to their high abundance and low toxicity.3 On the other hand, although Grignard reagents are readily available, their couplings remain challenging due to the unsatisfactory functional group compatibility. Thus, great efforts have been devoted to developing the coupling reactions of Grignard reagents with improved functional group tolerance.4 Although significant progress has been made in the Fecatalyzed couplings of Grignard reagents between C(sp2) and C(sp3) centers,3,5,6 the corresponding biaryl cross-couplings remain challenging, and only a few of Fe-catalyzed biaryl crosscouplings have been reported to date.7 The reported methods were mainly applicable to N-heteroaryl halides,7c,h,g chlorostyrenes,7f unfunctionalized aryl chlorides (tosylates).7d,e,i,j Due to dehalogenation and consequent homocoupling side reactions, aryl bromides or iodides are sometimes incompatible substrates.6a,7d,e,8−10 Besides, the poor functional group tolerance of Grignard reagents also limits the use of functionalized halides and Grignard reagents. Although this problem has often been solved by using the corresponding Zn or B reagents, to the best of our knowledge, only one Fecatalyzed Negishi and one Suzuki biaryl coupling have been reported so far;11 the Negishi coupling was limited to 2halopyridines or pyrimidines and meanwhile the Suzuki coupling only applied to N-pyrrole 2-chlorobenzamides. Due to these situations, a general Fe-catalyzed biaryl cross-coupling reaction between various aryl halides and aryl Grignard reagents is still highly desirable. © XXXX American Chemical Society

Scheme 1. Key Role of Phenolate to Fe/Ti-Cocatalyzed Biaryl Coupling Reaction

Received: November 2, 2018

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DOI: 10.1021/acs.orglett.8b03513 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Fe/Ti-Cocatalyzed Biaryl Coupling between Aryl Halides and Common Aryl Grignard Reagentsa,b

a

The reactions were carried out on a 2 mmol scale using PhOMgX as the ArOM unless indicated otherwise, and all ArOMgX were generated in situ by treating ArOH with an equal equivalent of Ar′MgBr. bAll of the yields were for isolated pure products, and the reaction time was about 8− 12 h. cMg salt of hydroquinone was used instead of PhOMgX. d2.4 equiv of Ar′MgBr were charged. eThe bromide was 4-BrC6H4CNPh.

and iodide 1a could couple with 2a to afford the product 3a in 85% and 89% isolated yields, respectively, with a very low level of debromination/deiodination and homocoupling side products (below 5%, see Table S1). Encouraged by these findings, we explored the scope of this coupling reaction. Initially, various aryl halides including those bearing important functional groups were coupled with common aryl Grignard reagents. As outlined in Scheme 2, this phosphine or NHC-free couplings proved to be highly general and chemoselective. The dehalogenation and homocoupling side reactions were all well suppressed; thus, the previously incompatible aryl iodides and bromides could react well to afford the products in good yields. Although the aryl chlorides bearing an electron-donating group gave low yields (3a−c), the other chlorides could obtain acceptable yields (3d−u). Interestingly, using the salt of hydroquinone instead of PhOMgBr could improve the yields of the chlorides (3b and 3c). Diarylation could also be realized smoothly where both bromine and chlorine could undergo the coupling well (3d). The selective couplings between different halides could also be

achieved (3e and 3f), demonstrating that the reactivity of different aryl halides was ArI > ArBr > ArCl. Instead, the coupling of difluorinated bromobenzene could afford 3g with fluorines being unaffected. Remarkably, a range of important functional groups could be well tolerated under the present conditions (3h−y). Such functional group compatibility of Grignard reagents under heated conditions in the presence of only a catalytic amount of FeCl3 and titanate (14 mol % Ti(OEt)4 to ArMgX) was observed for the first time and should be especially noteworthy. Although the structure of the metal reagents formed by mixing aryl Grignard reagent with a catalytic amount of titanate waits further investigation,14 the present protocol provides a simple and practical solution to the long-standing problem of functional group compatibilty of Grignard reagents in the coupling reactions.4 Thus, aryl halides bearing a styryl (3h and 3i),7f CF3 (3j), ester (3k), amide (3l and 3m), or cyano group (3n) could all couple with aryl Grignard reagents to generate the biaryls in up to 90% yields, where the positions of substituents (3h vs 3i; 3l vs 3m) had little effect on the outcome of the reaction. It should be noted B


Letter

Organic Letters that the easily enolizable ketones (3o and 3p) could also tolerate this coupling. Additionally, this coupling reaction could occur smoothly in the presence of sensitive CONHMe (3q), sulfonamide (3r), and sulfonate groups (3t). A sensitive biaryl aldehyde (3t) could also be prepared using 4BrC6H4CNPh as an aryl halide. Heteroaryl Grignard reagents and halides were likewise suitable coupling partners. 2-Thiophene-ylmagnesium bromide (3q and 3t) and the bromide of thiophene-yl amide (3u) could participate in the coupling to give the heterobiaryls with high chemoselectivity. In previous reports,7c,d,h,g,11a 2-halopyridines were well suited for Fe-catalyzed biaryl coupling, whereas 3-halopyridines were not. Our experiments indicated that 2-halopyridines (3v), 3halopyridines (3w), 3-bromoquinoline (3x), and functionalized 3-bromopyridine (3y) could all undergo this reaction smoothly. Although the seminal work from Knochel et al. on the functionalized Grignard reagents made these metal reagents readily available,15 their direct use in the transition-metalcatalyzed cross-couplings still faced some challenges because they were prepared and used at relatively low temperature.4 To the best of our knowlegde, their direct use in Fe-catalyzed biaryl cross-couplings has not been documented to date. We found that the concomitant i-PrI formed during the preparation of Knochel-type aryl Grignard reagents lowered the yields of the desired products by acting as an oxidant for the homocouplings of aryl Grignard reagents (Scheme 3);16,17

Scheme 4. Fe/Ti Cocatalyzed Biaryl Coupling between Aryl Halides and Knochel-Type Aryl Grignard Reagentsab

Scheme 3. Influence of i-PrI

therefore, we removed i-PrI or i-PrBr through distillation under reduced pressure before the cross-coupling reactions (for details, see Table S2). The fact that the combination of a catalytic amout of Ti(OEt)4 with functionalized aryl Grignard reagents made them stable at room temperature and subsequently allowed them to participate in the coupling at elevated temperature is noteworthy. Although the nature of this mixed metal reagents required further studies,14 the method presents a convenient solution to the problem of the stability and functional group compatibility of functionalized Grignard reagents, especially under heated conditions. As illustrated in Scheme 4, unactivated aryl iodides and bromides could still couple with functionalized Grignard reagents to afford the products in good yields, while the corresponding chlorides gave low yields (4b−d). The different yields of 4b and 4f showed again that the presence of i-PrI resulted in lower yields. The sterically hindered 2-functionalized aryl Grignard reagents were also competent coupling partners and could couple with 2-bromonaphthalence and hindered 2-halotoluene to furnish the functionalized biaryl compounds in good yields (4d−f). A comparison of Knochel’s two methods18 for preparing 2-NCC6H4MgX·LiCl indicated

a

The reactions were carried out on a 2 mmol scale using PhOMgX as the ArOM unless indicated otherwise; all Ar′MgX were prepared via iodine or bromine−magnesium exchange reaction with i-PrI(Br) being removed unless indicated otherwise. bAll of the yields were for isolated pure products, and the reaction time was about 8−10 h. c These reactions were conducted without removal of i-PrI. dMg salt of hydroquinone was used instead of PhOMgX. eIn these reactions, the Grignard reagents were prepared by ArBr + Mg + LiCl according to ref 18. fGrignard reagent was (PhCH = N)C6H4MgCl·LiCl.

that the method through the iodine-exchange reaction gave the best yield after removal of i-PrI (4e). The thienyl halide or functionalized thienyl Grignard reagents could both undergo C


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Organic Letters

(3) Plietker, B. Iron Catalysis in Organic Chemistry; Wiley-VCH: Weinheim, 2008. (4) For reviews, see: (a) Adrio, J.; Carretero, J. C. ChemCatChem 2010, 2, 1384−1386. (b) Knappke, C. E. I.; Jacobi von Wangelin, A. Chem. Soc. Rev. 2011, 40, 4948−4962. For selected examples, see: (c) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844− 3845. (d) Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 205−209. (e) Vechorkin, O.; Hu, X. Angew. Chem., Int. Ed. 2009, 48, 2937−2940. (f) Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756−9766. (g) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264−1266. (h) Hua, X. Y.; Masson-Makdissi, J.; Sullivan, R. J.; Newman, S. G. Org. Lett. 2016, 18, 5312−5315. (5) Selected reviews on iron-catalyzed coupling reaction: (a) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500−1511. (b) Czaplik, W. M.; Mayer, M.; Cvengros, J.; von Wangelin, A. J. ChemSusChem 2009, 2, 396−417. (c) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417−1492. (d) Bauer, I.; Knölker, H. J. Chem. Rev. 2015, 115, 3170−3387. (6) Selected examples: (a) Fürstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609−611. (b) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686−3687. (c) Martin, R.; Fürstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955−3957. (d) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem., Int. Ed. 2007, 46, 4364−4366. (e) Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Angew. Chem., Int. Ed. 2009, 48, 607−610. Sun, C.-L.; Krause, H.; Fürstner, A. Adv. Synth. Catal. 2014, 356, 1281−1291 and references cited therein . (7) Selected reviews covering biaryl cross couplings: (a) Kuzmina, O. M.; Steib, A. K.; Moyeux, A.; Cahiez, G.; Knochel, P. Synthesis 2015, 47, 1696−1705. (b) Guérinot, A.; Cossy, J. Top Curr. Chem. 2016, 374, 265−338. For representative examples, see: (c) Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856−13863. (d) Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844−9845. (e) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J. Am. Chem. Soc. 2009, 131, 11949−11963. (f) Gülak, S.; Jacobi von Wangelin, A. Angew. Chem., Int. Ed. 2012, 51, 1357−1361. (g) Kuzmina, O. M.; Steib, A. K.; Flubacher, D.; Knochel, P. Org. Lett. 2012, 14, 4818−4821. (h) Kuzmina, O. M.; Steib, A. K.; Markiewicz, J. T.; Flubacher, D.; Knochel, P. Angew. Chem., Int. Ed. 2013, 52, 4945−4949. (i) Chua, Y.-Y.; Duong, H. A. Chem. Commun. 2014, 50, 8424−8427. (j) Chua, Y.-Y.; Duong, H. A. Chem. Commun. 2016, 52, 1466−1469. (8) Czaplik, W. M.; Grupe, S.; Mayer, M.; Jacobi von Wangelin, A. Chem. Commun. 2010, 46, 6350−6352. (9) For representative examples for the Fe-catalyzed homocouplings, see: (a) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943−1946. (b) Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788−13789. (10) Only 2-bromopyridine derivatives and analogues are competent substrates for Fe-catalyzed biaryl couplings of Grignard reagents; see: ref 7c,g,h. For the related couplings of aryl iodides with copper reagents, see: Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulou, C.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 1654−1658. (11) For Fe-catalyzed biaryl Negishi coupling, see: (a) Bedford, R. B.; Hall, M. A.; Hodges, G. R.; Huwe, M.; Wilkinson, M. C. Chem. Commun. 2009, 6430−6432. For Fe-catalyzed biaryl Suzuki coupling, see: (b) O’Brien, H. M.; Manzotti, M.; Abrams, R. D.; Elorriaga, D.; Sparkes, H. A.; Davis, S. A.; Bedford, R. B. Nat. Catal. 2018, 1, 429− 437. For a related Suzuki coupling, see: (c) Guo, Y.; Young, D. J.; Hor, T. S. A. Tetrahedron Lett. 2008, 49, 5620−5621. (12) (a) Zeng, J.; Liu, K. M.; Duan, X. F. Org. Lett. 2013, 15, 5342− 5345. (b) Wei, J.; Liu, K. M.; Duan, X. F. J. Org. Chem. 2017, 82, 1291−1300. (13) The complexation of Fe3+ with phenols is well-known and usually introduced in textbooks for the detection of phenolic compounds. Meanwhile, titanium phenolate complexes are a class of important catalysts; see: Takeuchi, D.; Nakamura, T.; Aida, T. Macromolecules 2000, 33, 725−729 and references cited therein .

the coupling reaction well (4g and 4h). The amide group (CONMe2: 4d, 4g−m; CONHMe: 4j−l) could tolerate the present coupling well, providing functionalized biaryls in good yields. Additionally, the biaryl amine (4n) could be prepared in high yields through the couplings of 2-(PhCH = N)C6H4MgCl·LiCl. The previously challenging 3-bromopyridine derivative7c,d,g,h could still undergo the coupling with the Knochel-type aryl Grignard reagents in 86% yield (4o). To the best of our knowledge, there has been no report on the Fecatalyzed biaryl cross-couplings of 2-pyridinyl Grignard reagents until now. To our delight, this challenging biaryl coupling for 2-pyridinyl Grignard reagents could be achieved by using our protocol in an acceptable yield (4p). In addition, functionalized 3-pyridinyl Grignard reagents could undergo the biaryl coupling reaction to produce the 3-arylated pyridine compound (4q) in 73% yield. In conclusion, we have reported a phenolate-enabled Fe/Ticocatalyzed biaryl cross-coupling reaction by which the existing problems of Fe-catalyzed biaryl cross-couplings of aryl Grignard reagents have been well addressed. The fact that the classic phenolate ligand-mediated Fe/Ti cooperativity significantly enhances the catalytic activity of iron species without phosphine and NHC ligand is encouraging, although its specific mode is unclear at present. Furthermore, the fact that the presence of catalytic amount of Ti(OEt)4 enables the Grignard reagents to tolerate a wide range of sensitive functional groups even at elevated temperature is also noteworthy. We expect that these findings will not only provide a general solution to the problem of functional group compatibility of Grignard reagents but also provide inspiration for the other cocatalyzed or iron-catalyzed reactions.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03513.

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Experimental procedures, additional tables, characterization data, and NMR spectra for products (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xin-Fang Duan: 0000-0003-1480-853X Notes

The authors declare the following competing financial interest(s): The authors have filed two patents on this technology.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Nature Science Foundation of China (21572022 and 21372031). REFERENCES

(1) Cepanec, I. Synthesis of Biaryls; Elsevier: New York, 2004. (2) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062−5085. D


Letter

Organic Letters (14) The mixed Ti/Mg metal reagents formed by ArMgX with an amount of below 0.4 equiv of Ti(OEt)4 have never been reported to date. The ate complexes [ArTi(OR)4M] formed by ArM (M = Li, MgX) with 1 equiv of Ti(OR)4 have been known for a long time; however, their structures have not yet been clearly elucidated. See: (a) Bernardi, A.; Cavicchioli, M.; Marchionni, C.; Potenza, D.; Scolastico, C. J. Org. Chem. 1994, 59, 3690−3694. (b) Liu, K. M.; Wei, J.; Duan, X. F. Chem. Commun. 2015, 51, 4655−4658 and references cited therein . (15) For selected recent reviews, see: (a) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 583−593. (b) Klatt, T.; Markiewicz, J. T.; Sämann, C.; Knochel, P. J. Org. Chem. 2014, 79, 4253−4269. (c) Bao, R. L.-Y.; Zhao, R.; Shi, L. Chem. Commun. 2015, 51, 6884−6900. (16) For the influence of the concomitant i-PrI or i-PrBr formed in preparing Knochel-type aryl Grignard reagents on the Pd- or Nicatalyzed cross couplings, see ref 4d,f. (17) The product (C2b) resulting from the Fe-catalyzed cross coupling of aryl Grignard reagents with i-PrI was not observed; however, the yield of the homocoupling side reaction of aryl Grignard reagents (D2b) rosed to 15%. We deduced that the concomitant i-PrI (i-PrBr) should act as an oxidant somewhat like XCH2CH2X (X = I, Br, Cl) and thus resulted in the homocoupling reaction as reported in refs 9a and 12a. Such an influence of i-PrI was greater for the reactions of aryl bromides than for those of iodides. Besides, the effect of i-PrI was greater than that of i-PrBr. For details, see Table S2. (18) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802−6806.

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Ti Cocatalyzed Biaryl

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