Pd-Catalyzed Homologation of Arylboronic Acids as a Platform for the Diversity-Oriented Synthesis of Benzylic C–X Bonds

Dedicated to Prof. Donald S. Matteson on the 60^th anniversary of the reaction that bears his name.

Abstract

We report a synthetic platform for the formation of benzylic C–X bonds. Benzylboronic acid pinacol (Bpin) esters are useful synthetic intermediates but are commercially uncommon, leading to preparations that typically rely upon stoichiometric metalation. Pd-catalyzed formal homologation of arylboronic acids provides access to these compounds that, in turn, allow the formation of C–C, C–O, and C–N bonds from Pd- and Cu-mediated cross-coupling or oxidative processes. This affords a wide variety of benzylic alcohols, diarylmethanes, benzyl amines, and benzyl ethers. Limitations are disclosed, and the utility is further demonstrated by the generation of analogues of meclizine.

Key words

boron - catalysis - chemoselectivity - homologation - diversity-oriented synthesis

Scheme 1 (a) General catalytic strategies towards C(sp²)–C(sp²) and C(sp²)–X bond formation. (b) General strategies towards benzylic C–C, C–N, and C–O bond formations. (c) This work: a diversity-oriented approach towards benzylic C–C, C–N, and C–O bonds via a catalytic arylboronic acid homologation using a halomethyl Bpin reagent.

Diarylmethanes, benzyl ethers, and benzyl amines are common motifs found in bioactive molecules. Typical organometallic approaches towards the synthesis of diarylmethanes involve nucleophilic displacement of benzylic halides or the reduction of acetophenones/benzhydrols;[1] however, reactions are often limited to the availability of the organometallic reagent or the preparation of symmetric diarylmethane products. Catalytic approaches – including Suzuki–Miyaura couplings[2] – are known using either benzylic halides and arylboron reagents[3] [4] or aryl (pseudo)halides and typically benzylic BF₃Ks,[5,6] although other organoborons have been used.[7] Among other Pd-catalyzed methods,[8] [9] [10] [11] [12] [13] Shibata has reported the synthesis of unsymmetrical diarylmethanes using diborylmethane and 10 mol% Pd(P-tBu₃)₂.[14] These methods are supplemented by similar Ir- or Ni-catalyzed processes.[15] [16] Classical alkylation or reductive amination reactions to prepare benzylic ethers or amines often require harsh conditions and limit functional group compatibility (Scheme [1b]).[17] Catalytic approaches towards C–X bond formation, including Buchwald–Hartwig,[18] Ullmann–Goldberg,[18] and Chan–Lam couplings,[19] have traditionally focused on C(sp²)–X bond formation (Scheme [1a]). C(sp³)–X bond formations using Buchwald–Hartwig and Chan–Lam approaches are becoming more common but can require the use of bespoke ligands or long reaction times. [18] [19]

While historically utilized in C(sp²)–C(sp²) cross-coupling reactions, contemporary work has employed C(sp³)–B organoboron reagents as a method to prepare more C(sp³)-rich scaffolds for improved biological characteristics in medicinal chemistry.[20] As such, both the preparation and utilization of C(sp³)–B bonds remains a strategic focal point within academic and industrial research settings. Several benzyl boronic acids are known; however, very few are commercially available likely due to their propensity to degrade (protodeboronation).[21] Approaches to prepare the respective benzylic boronic esters typically require the use of stochiometric organometallic reagents from halides,[1] [22] hydroboration,[1,23] C–H activation,[24] or photoredox[25] methods. As a conceptual alternative to the classical Matteson homologation,[26] which inserts a metalated carbenoid into an organoboron reagent,[27] we have recently disclosed an approach using Pd catalysis, arylboronic acids, and a halomethylboronic acid pinacol ester.[28]

Scheme 2 Example scopes. Yields determined by ¹H NMR spectroscopy using an internal standard, isolated yields in brackets. a) ArB(OH)₂ (1 equiv), BrCH₂BPin (1.5 equiv), Pd(PPh₃)₄ (1.5 mol%), K₃PO₄ (3 equiv), H₂O (10 equiv), DCE, Ar, 60 °C, 24 h. b) Arylbromide (1 equiv), BnBpin (3 equiv), Pd(dppf)Cl₂ (1 mol%), K₃PO₄ (3 equiv), H₂O (50 equiv), PhMe, Ar, 90 °C, 24 h. c) Aq. H₂O₂/2 N aq. NaOH/THF (3:2:1), air, 0 °C to rt, 15 min. d) BnBpin (1 equiv), alcohol (5 equiv), Cu(OAc)₂ (2 equiv), (t-BuO)₂ (2 equiv), PhMe, Ar, 100 °C, 16 h. e) BnBpin (1 equiv), amine (4 equiv), Cu(OAc)₂ (2 equiv), Cs₂CO₃ (0.5 equiv), MeOH/pyridine (4:1), Ar, 50 °C, 16 h.

Based on this, we sought to deliver a unified approach towards the synthesis of unsymmetrical diarylmethanes, benzyl amines, and benzyl ethers using benzylic Bpins as common synthetic precursors via a series of Suzuki–Miyaura and Chan–Lam couplings. Oxidation of the Bpin would also provide a convenient method for the synthesis of benzyl alcohols (Scheme [1c]). This divergent strategy would lead to an array of C(sp³)–X products from a commercially abundant pool of arylboronic acids, without the requirement for stoichiometric metalation.

Table [ 1 ] Summary of Reaction Development

Entry	Product	Conditions	Yield (%)a
		Suzuki–Miyaura Benzylation
1	4	Pd(dba)2 (8 mol%), PPh3 (96 mol%), Ag2O (2 equiv), THF, 70 °C	19
2	4	Pd(dppf)Cl2 (1 mol%), K3PO4 (3 equiv), H2O (50 equiv), PhMe, 90 °C	99 (99)b
3	4	entry 2, Pd(PPh3)4 instead of Pd(dppf)Cl2	30
		Chan–Lam Etherification
4	5	Cu(OAc)2 (5 mol%), (tBuO)2 (2 equiv), PhMe, 100 °C	22
5	5	entry 4, 2 equiv Cu(OAc)2	63 (62)b
		Chan–Lam Amination
6	6	see entry 5	4
7	6	Cu(OAc)2 (2 equiv), Cs2CO3 (0.5 equiv), MeOH/pyridine (4:1), 50 °C	75 (71)b
		Methanolation
8	7	H2O2/NaOH, THF, rt	99 (93)b

^a Determined by ¹H NMR analysis using an internal standard (see the Supporting Information for details).

^b Isolated yield. dppf, 1,1′-bis(diphenylphosphino)ferrocene; rt, room temperature.

We established benchmark systems for the development of a Suzuki–Miyaura benzylation, Chan–Lam etherification, and Chan–Lam amination using benzyl Bpins prepared via Pd-catalyzed formal homologations of arylboronic acids (Table [1]). Suzuki–Miyaura cross-coupling of 3-Me and bromobenzene was contingent on controlling the hydrolysis of the Bpin ester to generate limiting quantities of the unstable benzyl boronic acid. Yields were improved using a K₃PO₄/stoichiometric H₂O system,[29] rather than Ag₂O,[7] and low loadings of Pd catalyst (1 mol%) were operative (entries 1 and 2). The switch from Pd(PPh₃)₄ to Pd(dppf)Cl₂ was essential (entry 3). A Chan–Lam etherification of benzyl Bpin with seven phenols has been reported by Kuninobu;[30] however, in our hands these conditions were ineffective (entry 4) and required stoichiometric quantities of Cu(OAc)₂ for an efficient reaction (entry 5, see the Supporting Information for full details). These conditions provided a more diverse range of phenols (vide infra) but did not translate to the analogous amination reaction (entry 6); however, conditions reported by Partridge were effective (entry 7),[31] with further optimization delivering no further improvement (see the Supporting Information for details). Oxidation of the homologated intermediate under Brown conditions provided the desired benzyl alcohol in quantitative yield (entry 8).

With conditions for the homologation/C–X bond formation platform in place, the generality of the four diversifications was assessed using a variety of boronic acids, bromides, amines, and alcohols (Scheme [2]). For the Suzuki–Miyaura benzylation (top left), a variety of electronic and steric substitution was tolerated at very good to excellent yields. Of note was the tolerance towards heterocycles from either the Bpin (e.g., 9, 17) or bromide (15) counterparts, and the tolerance towards functional groups such as aldehyde (e.g., 12, 18), ester (14), and sulfonate (16). Electrophile chemoselectivity was observed, leading to chloroarene products, useful for onward cross-coupling (e.g., 17, 19). Substitution at the ortho position was well tolerated (e.g., 4, 12, 16, 17), although o-vinyl was a notable exception (see the Supporting Information for other limitations). All oxidation reactions proceeded smoothly (bottom left), and the yields generally reflected the homologation reaction, with more sensitive functional groups (e.g., 23) unaffected. Upon examining the Chan–Lam amination (top right), primary (32, 35, 37) and secondary anilines (33, 38) and secondary aliphatic amines (6, 34, 36) were accommodated. From the Bpin ester component, ortho substitution was generally poor throughout (e.g., 29 and 38, for other examples see the Supporting Information) although the substituted pyridine 36 was an exception. Assessing the corresponding Chan–Lam etherification (bottom right), the reaction was effective with electron-withdrawing (e.g., 5, 39–41) or neutral (e.g., 42) phenols; however, electron-rich substrates (e.g., 44) tended to give lower yields along with a series of unidentified side products. While benzyl alcohol was tolerated to deliver product 43, this was generally an exception and other alkyl alcohols were recalcitrant at either stoichiometric loading or when used as the solvent (see the Supporting Information for full limitations).

The developed homologation–benzylation Suzuki–Miyaura process uses low loadings of widely available and simple Pd catalysts, which we envisioned would serve as a straightforward route to nonsymmetrical diarylmethane pharmacophores. These chemotypes are found extensively throughout medicinal chemistry,[1] such as bifonazole, meclizine, fenofibrate, and bedaquiline (Scheme [3], top). To highlight the utility of this process, we undertook an SAR-style derivatization of meclizine (Scheme [3], bottom).

The homologation–benzylation process provided intermediate 51, which was brominated to yield 52.[31] This could be used without purification for alkylation reactions to afford the meclizine core (57) or ‘scaffold hopping’[32] alternatives appropriate for further SAR investigation in generally excellent yields (57–60).

Scheme 3 Top: selected examples of substituted diarylmethanes in medicinal chemistry. Bottom: derivatization of meclizine. Yields determined by ¹H NMR spectroscopy using an internal standard, isolated yields in brackets. a) 53 (5 equiv), K₂CO₃ (3 equiv), MeCN, 80 °C, 12 h. b) 54 (3 equiv), Pd(dppf)Cl₂ (1 mol%), K₃PO₄ (3 equiv), H₂O (50 equiv), PhMe, Ar, 90 °C, 24 h. c) 55 (5 equiv), K₂CO₃ (3 equiv), MeCN, 80 °C, 12 h. d) 56 (5 equiv), K₂CO₃ (3 equiv), MeCN, 80 °C, 12 h. NBS, N-bromosuccinimide; AIBN, azobisisobutyronitrile. For full experimental details, see the Supporting Information.

In summary, a diversity-oriented approach towards the platform synthesis of unsymmetrical diarylmethanes and benzylic ethers, alcohols, and amines has been developed via a catalytic formal homologation of arylboronic acids. These processes give straightforward access to a range of C(sp³)–C(sp²) and C(sp³)–X scaffolds from a previous synthetic bottleneck of benzyl Bpin esters and where stoichiometric metalation is avoided. All Pd-catalyzed manipulations take place at very low catalyst loadings, and complex ligand systems were avoided. The synthetic potential was further evaluated via an SAR-style derivatization of meclizine.[33]

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

• 1a Meindl WR, Angerer EV, Schoenenberger H, Ruckdeschel G. J. Med. Chem. 1984; 27: 1111
• 1b Gulati U, Gandi R, Laha JK. Chem. Asian J. 2020; 15: 3135
• 2a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
• 2b Lennox AJ. J, Lloyd-Jones GC. Angew. Chem. Int. Ed. 2013; 52: 7362
• 2c Lennox AJ. J, Lloyd-Jones GC. Chem. Soc. Rev. 2014; 43: 412
• 3 Chahen L, Doucet H, Santelli M. Synlett 2003; 1668
• 4 Burns MJ, Fairlamb IJ. S, Kapdi AR, Sehnal P, Taylor JK. Org. Lett. 2007; 9: 5397
• 5 Molander GA, Ito T. Org. Lett. 2001; 3: 393
• 6 Sandrock D, Jean-Gérard L, Chen C, Dreher SD, Molander GA. J. Am. Chem. Soc. 2010; 132: 17108
• 7a Imao D, Glasspoole BW, Laberge VS, Crudden CM. J. Am. Chem. Soc. 2009; 131: 5024
• 7b Matthew SC, Glasspoole BW, Eisenberger P, Crudden CM. J. Am. Chem. Soc. 2014; 136: 5828
• 8 McLaughlin M. Org. Lett. 2005; 7: 4875
• 9 Singh R, Viciu MS, Kramareva N, Navarro O, Nolan SP. Org. Lett. 2005; 7: 1829
• 10 Zhang P, Xu J, Gao Y, Li X, Tang G, Zhao Y. Synlett 2014; 25: 2928
• 11 Srimani D, Bej A, Sarkar A. J. Org. Chem. 2010; 75: 4296
• 12 Yoon S, Hong MC, Rhee H. J. Org. Chem. 2014; 79: 4206
• 13 Tang SQ, Schmitt M, Bihel F. Synthesis 2020; 52: 51
• 14 Endo K, Ishioka T, Ohkubo T, Shibata T. J. Org. Chem. 2012; 77: 7223
• 15a Podder S, Choudhury J, Roy S. J. Org. Chem. 2007; 72: 3129
• 15b Tellis JC, Primer DN, Molander GA. Science 2014; 345: 433
• 16a Tobisu M, Yasutome A, Kinuta H, Nakamura K, Chatani N. Org. Lett. 2014; 16: 5572
• 16b Tobisu M, Takahira T, Chatani N. Org. Lett. 2015; 17: 4352
• 16c Suga T, Ukaji Y. Org. Lett. 2018; 20: 7846
• 16d Chen Y, Wang X, He X, An Q, Zuo Z. J. Am. Chem. Soc. 2021;  143: 4896
• 17 Afanasyev OI, Kuchuk E, Usanov D. Chem. Rev. 2019; 119: 11857
• 18a Ruiz-Castillo P, Buchwald SL. Chem. Rev. 2016; 116: 12564
• 18b Dorel R, Grugel CP, Haydl AM. Angew. Chem. Int. Ed. 2019; 58: 17118
• 18c Seifinoferest B, Tanbakouchian A, Larijani B, Mahdavi M. Asian J. Org. Chem. 2021; 10: 1319
• 19a Qiao JX, Lam PY. S. Synthesis 2011; 829
• 19b Qiao JX, Lam PY. S. Recent Advances in Chan–Lam Coupling Reaction: Copper-Promoted C-Heteroatom Bond Cross-Coupling Reactions with Boronic Acids and Derivatives. In Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, Chap. 6. Hall DG. Wiley-VCH; Weinheim: 2011: 315-361
• 19c Munir I, Zahoor AF, Rasool N, Naqvi SA. R, Zia KM, Ahmad R. Mol. Diversity 2019; 23: 215
• 19d West MJ, Fyfe JW. B, Vantourout JC, Watson AJ. B. Chem. Rev. 2019; 119: 12491
• 19e Vijayan A, Rao DN, Radhakrishnan KV, Lam PY. S, Das P. Synthesis 2021; 53: 805
• 20a Fyfe JW. B, Watson AJ. B. Chem 2017; 3: 31
• 20b Volochnyuk DM, Gorlova AO, Grygorenko OO. Chem Eur. J. 2021; 27: 15277
• 20c Yang Y, Tsien J, David AB, Hughes JM. E, Merchant RR, Qin T. J. Am. Chem. Soc. 2021; 143: 471
• 20d Koo SM, Vendola AJ, Momm SN, Morken JP. Org. Lett. 2020; 22: 666
• 20e Blair DJ, Chitti S, Trobe M, Kostyra DM, Haley HM. S, Hansen RL, Ballmer SG, Woods TJ, Wang W, Mubayi V, Schmidt MJ, Pipal RW, Morehouse GF, Ray AM. E. P, Gray DL, Gill Burke MD. Nature 2022; 604: 92
• 20f Ghosh S, Ghosh A, Pyne P, Hajra A. Org. Biomol. Chem. 2022; 20: 4496
• 21 A survey of four commercial suppliers (Fluorochem, Alfa Aesar, Apollo, TCI Chemical) on 20/05/2023 found 2376 commercially available arylboronic acids, 1314 arylboronic esters, 9 benzyl boronic acids, and 30 benzyl boronic esters.
• 22a Khotinsky E, Melamed M. Ber. Dtsch. Chem. Ges. 1909; 42: 3090
• 22b Lawesson SO. Acta Chem. Scand. 1957; 11: 1075
• 22c Li W, Nelson DP, Jensen MS, Hoerrner RS, Cai D, Larsen RD, Reide PJ. J. Org. Chem. 2002; 67: 5394
• 23a Brown HC. Hydroboration 1962
• 23b Pelter A, Smith K, Brown HC. Borane Reagents 1988
• 23c Dhillion RS. Hydroboration and Organic Synthesis 2007
• 24a Mkhalid IA. I, Barnard JH, Marder TB, Murphy JM, Hartwig JF. Chem. Rev. 2010; 110: 890
• 24b Ros A, Fernández R, Lassaletta JM. Chem. Soc. Rev. 2014; 43: 3229
• 24c Xu L, Wang G, Zhang S, Wang H, Wang L, Liu L, Jiao J, Li P. Tetrahedron 2017; 73: 7123
• 24d Haldar C, Hoque ME, Bisht R, Chattopadhyay B. Tetrahedron Lett. 2018; 59: 1269
• 24e Iqbal SA, Pahl J, Yuan K, Ingleson MJ. Chem. Soc. Rev. 2020; 49: 4564
• 24f Guo X.-N, Braunschweig H, Radius U, Marder TB. Chem. Rev. 2021; 121: 3561
• 24g Bisht R, Haldar C, Hassan MM, Hoque ME, Chaturvedi J, Chattopadhyay B. Chem. Soc. Rev. 2022; 51: 5042
• 25a Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075
• 25b Jiang M, Yang H, Fu H. Org. Lett. 2016; 18: 5248
• 25c Shu C, Noble A, Aggarwal VK. Nature 2020; 586: 714
• 25d Wei Q, Lee Y, Liang W, Chen X, Mu B, Cui X.-Y, Wu W, Bai S, Liu Z. Nat. Commun. 2022; 13: 7112
• 26 Matteson DS, Mah RW. H. J. Am. Chem. Soc. 1963; 85: 2599
• 27a Matteson DS. Tetrahedron 1998; 54: 10555
• 27b Matteson DS. J. Org. Chem. 2013; 78: 10009
• 27c Matteson DS, Collins BS. L, Aggarwal VK, Ciganek E. Org. React. 2021; 105: 427
• 28 Bastick KA. C, Watson AJ. B. ACS Catal. 2023; 13: 7013
• 29a Fyfe JW. B, Seath CP, Watson AJ. B. Angew. Chem. Int. Ed. 2014; 53: 12077
• 29b Seath CP, Fyfe JW. B, Molloy JJ, Watson AJ. B. Angew. Chem. Int. Ed. 2015; 54: 9976
• 29c Fyfe JW. B, Watson AJ. B. Synlett 2015; 26: 1139
• 29d Muir CW, Vantourout JC, Isidro-Llobet A, Macdonald SJ. F, Watson AJ. B. Org. Lett. 2015; 17: 6030
• 29e Fyfe JW. B, Fazakerley NJ, Watson AJ. B. Angew. Chem. Int. Ed. 2017; 56: 1249
• 29f Xu C, Fyfe JW. B, Seath CP, Bennett SH, Watson AJ. B. Chem. Commun. 2017; 53: 9139
• 29g Molloy JJ, Seath CP, West MJ, McLaughlin C, Fazakerley NJ, Kennedy AR, Nelson DJ, Watson AJ. B. J. Am. Chem. Soc. 2018; 140: 126
• 30 Sueki S, Kuninobu Y. Org. Lett. 2013; 15: 1544
• 31a Wohl A. Ber. Dtsch. Chem. Ges. 1919; 52: 51
• 31b Ziegler K. Justus Liebigs Ann. Chem. 1942; 551: 1
• 32a Hu Y, Stumpfe D, Bajorath J. J. Med. Chem. 2017; 60: 1238
• 32b Grisoni F, Merk D, Consonni V, Hiss JA, Tagliabue SG, Todeschini R, Schneider G. Commun. Chem. 2018; 1: 44
• 32c Grisoni F, Merk D, Byrne R, Schneider G. Sci. Rep. 2018; 8: 16469
• 33 The research data supporting this publication can be accessed at https://doi.org/ DOI: 10.17630/df058940-8cac-4ee2-abf4-da914cbcc446

Publication History

Received: 02 June 2023

Accepted after revision: 22 June 2023

Accepted Manuscript online:
26 June 2023

Article published online:
15 August 2023