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Mechanistic insight enables practical, scalable, room temperature Chan-Lam N-arylation of N-aryl sulfonamides Julien Vantourout, Ling Li, Enrique Bendito-Moll, Sonia Chabbra, Kenneth Arrington, Bela Ernest Bode, Albert Isidro-Llobet, John A. Kowalski, Mark Nilson, Katherine Wheelhouse, John L. Woodward, Shiping Xie, David C. Leitch, and Allan J. B. Watson ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03238 • Publication Date (Web): 06 Sep 2018 Downloaded from http://pubs.acs.org on September 7, 2018
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ACS Catalysis
Mechanistic insight enables practical, scalable, room temperature Chan–Lam N-arylation of N-aryl sulfonamides Julien C. Vantourout,a,b,‡ Ling Li,c,‡ Enrique Bendito-Moll,a,b Sonia Chabbra,d Kenneth Arrington,c Bela E. Bode,d Albert Isidro-Llobet,b John A. Kowalski,c Mark G. Nilson,c Katherine M. P. Wheelhouse,b John L. Woodard,c Shiping Xie,c David C. Leitch,c,* and Allan J. B. Watsond,* a b
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, U.K. GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
c
GlaxoSmithKline, Medicines Research Centre, 709 Swedeland Rd #1539, King of Prussia, PA 19406, U.S.A.
d
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, U.K.
In celebration of the 20th anniversary of the Chan–Lam reaction
ABSTRACT: Sulfonamides are profoundly important in pharmaceutical design. C-N cross-coupling of sulfonamides is an effective method for fragment coupling and SAR mining. However, cross-coupling of the important N-arylsulfonamide pharmacophore has been notably unsuccessful. Here, we present a solution to this problem via oxidative Cu-catalysis (Chan–Lam cross-coupling). Mechanistic insight has allowed the discovery and refinement of an effective cationic Cu catalyst to facilitate the practical and scalable Chan–Lam N-arylation of primary and secondary N-arylsulfonamides at room temperature. We also demonstrate utility in the large scale synthesis of a key intermediate to a clinical HCV treatment. KEYWORDS: boronic acid, boronic ester, catalysis, Chan–Lam, copper, sulfonamide The N-aryl sulfonamide functional group is ubiquitous in medicinal chemistry, with the value of this motif demonstrated in marketed drugs for many different disease indications (Scheme 1a).1 The broad utility of this group arises from the tetrahedral geometry, permitting control of H-bond donor/acceptor directionality to more effectively interact with a target ligand, and the imbued modulation of physicochemical properties that can be used to influence pharmacokinetics.1 N-Arylation of N-arylsulfonamides is an attractive approach to target synthesis, enabling an alternative fragment coupling to N-sulfonylation (which is not always straightforward due to the poor nucleophilicity of diarylamines), and also providing a platform for rapid SAR analysis. Despite its appeal, this has been a challenging process to realize via transition metal catalysis.2 To the best of our knowledge, only two examples of Pd-catalyzed arylation of N-arylsulfonamides have been reported (Scheme 1b),3 with ligand development usually required for substrates of impaired Lewis basicity.4 Ullmanbased approaches are generally limited to simple substrates based on the forcing conditions required.5 Oxidative crosscoupling using Cu-catalysis (Chan–Lam cross-coupling) offers an appealing alternative based on the generally inexpensive, ligand-free, and mild reaction conditions prevalent in this area, as well as the availability and variety of organoboron coupling partners.6 However, Chan–Lam N-arylation of Narylsulfonamides is particularly underdeveloped: only scattered examples are reported in the patent literature, with either low or no yields disclosed.7,8 Perhaps more importantly, the origin of the problem is unknown. Here, we provide a mechanistically informed rationally designed system for practical and scalable Chan–Lam N-arylation of sulfonamides at room temperature (Scheme 1c).
(a) Sulfonamides in pharmaceutical agents OMe H N
O HN
S
Me
O
O O
N
O
HO N
O
NH N
OMe
N
t-Bu
N
dasabuvir (HCV)
O O N
S
O
t-Bu
O
bosentan (cadriovascular disease)
S t-Bu
O
O S
F
N O Me
S
N H
F
F
H N
N S
O
O
N
H 2N dabrafenib (oncology)
sulfamethoxzaole (antibiotic) (b) Pd- and Cu-based N-arylsulfonamide N-arylation O O O O Pd or Cu S Ar1 S Ar1 Ar2 X R1 N R1 N H 2 Ar
R1
O S
R 2 R3 N H
B(OR) 2
NH 2
Buchwald–Hartwig (Pd, X = halogen): 56-77% yield (2 examples) Ullmann (Cu, X = halogen): harsh conditions, simple substrates Chan–Lam (Cu, X = B(OR) 2): 16-26% or unreported yield
(c) This work: Chan-Lam N-arylation by rational design O
N
Cu(MeCN)4PF 6 (0.5 equiv)
O R1
N-methylpiperidine or K 3PO 4 R3 MeCN, RT, air
O S
N
R2
24 examples (1 mmol) scalable to >20 mmol RB(OH) 2 and RBpin 37-98% yield
Scheme 1. (a) Exemplar sulfonamides in active pharmaceutical ingredients. (b) Previous Pd- and Cu-mediated N-arylsulfonamide N-arylation. (c) A mechanistically-informed Chan–Lam Narylation of N-arylsulfonamides.
We recently reported a functional description of Chan–Lam amination (Scheme 2).9 The description was based on the most common reaction conditions using Cu(OAc)2 and Et3N as a base. The process is initiated by denucleation of the paddlewheel dimer to the catalytically active monomeric Cu(II)(R2NH) complex 1. Transmetalation of the organoboron reagent delivers Cu(II)(Ar)(R2NH) complex 2, which is oxi-
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dized via disproportionation to Cu(III) complex 3.10 Reductive elimination liberates the product and Cu(I). Completion of the catalytic cycle requires oxidation of Cu(I) to Cu(II), typically achieved by O2. [Cu(pin) 2]2–
pinacol
4
R 2NH –AcOH•Et 3N S
O2 + R 2NH + AcOH•Et 3N
HO
L nCuOAc Cu(I)
Ar
NR 2
Reaction deconstruction: Major substrate-dependent events
[Cu(OAc) 2]2•2H 2O
Cu
OAc
R 2NH [Cu(OAc) 2]2•2H 2O
1
NHR 2 Cu(II)
Cu(II)
Cu(III) OAc Cu Ar NR 2 3 S
(a) Denucleation (R 2NH dependent)
AcO–
Ar
B(OR) 2
S
AcO– HO
OAc Cu 1 NHR 2 Cu(II)
HOB(OR) 2 (b) Oxidative turnover (R 2NH dependent) S Ar
Cu
OAc NHR 2
2
L nCu(II)X 2 L nCu(I)X 2 + HX
L nCuOAc
S
O 2, R 2NH AcOH•Et 3N
HO
Cu(I)
OAc Cu 1 NHR 2 Cu(II)
(c) Catalyst inhibition (Bpin specific)
pinacol [Cu(OAc) 2]2•2H 2O
[Cu(pin) 2]2–
4
Scheme 2. Key mechanistic considerations for reaction design.
From mechanistic analysis, two N-substrate-dependent events were identified as critical: (1) the initial paddlewheel denucleation is highly dependent on the Lewis basicity of the N-substrate (Scheme 2a).9 (2) Similarly, N-substrate association facilitates the oxidative turnover of the Cu catalyst (Scheme 2b).9 Efficient Cu(I) oxidation is essential not only for turnover but also to avoid organoboron oxidation, protodeboronation, and homocoupling, which are driven by Cu(I).9 (1) and (2) were anticipated to be the difficult steps in sulfonamide N-arylation based on the poor Lewis basicity of the Narylsulfonamide. From the organoboron perspective, no specific issues were anticipated with arylboronic acids; however, use of BPin derivatives could lead to catalyst inhibition by pinacol (forming 4), generated from transmetalation byproducts (Scheme 2c).9 Our reaction design was based on several considerations: (1) To aid paddlewheel denucleation, we selected a Cu(I) catalyst without competing ligating anions (e.g., AcO–); Cu(MeCN)4PF6.11 This catalyst also served to reduce the quantity of uncontrolled H2O in the system ([Cu(OAc)2]2 is usually the dihydrate), avoiding the need for rigorous drying and competing organoboron oxidation.12 (2) Bolstering substrate ligation would aid productive catalysis, avoid organoboron homocoupling, and facilitate oxidative turnover.9 NArylsulfonamide deprotonation was identified as a simple solution. However, base selection would be crucial: the base must deprotonate without causing competing processes – dimer-forming anionic bases would therefore be incompatible based on the points above. A second concern was inhibition of transmetallation by boron speciation, which would be a greater problem for boronic acids than BPin esters based on the propensities for hydroxy- and ternary boronate formation.13,14 As such, we excluded anionic O-bases for boronic acid couplings and instead focused on amine bases. Anionic O-bases have shown some potential utility for Chan–Lam amination of Bpin,9 and are anticipated to be tolerated for Bpin due to a lower propensity for boronate formation.14 A greater base strength would help to avoid catalyst inhibition by pinacol by providing a greater solution concentration of substrate anion. Finally, adventitious desiccant effects using hygroscopic inorganic bases would lower organoboron oxidation further.15 Based on all of these considerations, we selected K3PO4 for Bpin processes. This mechanistic rationalization was successful on application (Table 1). Using sulfonamide 5 as a benchmark substrate, control reactions with Cu(OAc)2 and Et3N confirmed the ary-
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lation efficiency problem under standard conditions (entry 1). Moving to Cu(MeCN)4PF6 with Et3N immediately improved the reaction to deliver 57% and 18% yield using 6a and 6b, respectively (entry 2). Use of a stronger amine base (Nmethylpiperidine) delivered a highly effective process using 6a (80%) and increasing base stoichiometry improved the yield further to 98% (entry 4). As expected from our previous work,9 amine bases gave a notably poorer performance with 6b, due to catalyst inhibition by pinacol (ca. 20%; entries 3 and 4). However, K3PO4 delivered 7a in 50% using 6b (entry 5) with increased stoichiometry improving to 80% (entry 6). As anticipated, K3PO4 was significantly detrimental to the reaction of 6a (entries 5 and 6). All of these reaction parameters were further investigated in multivariate arrays, confirming the optimal conditions from Table 1 (see Supporting Information (SI) for full details). Several points are worth noting: (1) the use of 0.5 equiv Cu was necessary for efficiency since Cu is required as catalyst and oxidant (oxidation of Cu(II)→Cu(III) and Cu(I)→Cu(II)); (2) the organoboron was required in excess to maintain efficiency with respect to the expected competing side reactions (i.e., protodeboronation, oxidation, and homocoupling); (3) selected inorganic bases were effective for reactions of 6a when used in in conjunction with Cu(OAc)2; however, these were not transferable to 6b. Table 1. Reaction optimization. O Me
O S
N H
5 1 equiv
O
conditions Ph
Ph
B(OR) 2
B(OH) 2 = 6a Bpin = 6b 2 equiv
Me MeCN, RT, air
O S
N
Ph
Ph 7a
Entry
Conditions
7a from 6a (%)a
7a from 6b (%)a
1
Cu(OAc)2 (0.5 equiv), Et3N (6 equiv)
43
13
2
Cu(MeCN)4PF6 (0.5 equiv), Et3N (6 equiv)
57
18
3
Cu(MeCN)4PF6 (0.5 equiv), methylpiperidine (6 equiv)
N-
80
21
4
Cu(MeCN)4PF6 (0.5 equiv), methylpiperidine (8 equiv)
N-
98
17
5
Cu(MeCN)4PF6 (0.5 equiv), K3PO4 (3 equiv)
40
50
6
Cu(MeCN)4PF6 (0.5 equiv), K3PO4 (8 equiv)
32
80
a
Conversion to product determined by HPLC. See SI.
The origin of the efficiency gain from a mechanistic perspective was reinforced by spectroscopy (Figure 2). EPR analysis confirmed the denucleation problem (Figure 2a). Effective denucleation only takes place upon inclusion of a base capable of deprotonating 5. N-Methylpiperidine and K3PO4 were significantly more effective than Et3N. Similarly, UV-Vis analysis showed that Cu(I) oxidation is more effective with 5 in the presence of N-methylpiperidine and K3PO4 due to greater electron-density at Cu(I) (Scheme 2b). It is worthwhile noting that the oxidation using K3PO4 is slower than N-methylpiperidine due to the formation of some Cu(I)PO4 in situ.16 This further highlights the need to consider all potential substrate-catalyst and reagent-catalyst interactions in the design of these processes (Figure 2b).
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ACS Catalysis O
(a) Denucleation event: EPR studies O
Cu(OAc) 2 Cu(OAc) 2 + 5 + K 3PO 4
Cu(OAc) 2 + 5
B(OR) 2
O S
R1
N H
Cu(OAc) 2 + 5 + Et 3N
R3
R2
1 equiv
Cu(OAc) 2 + 5 + NMP
base (8 equiv), MeCN, RT, air 2 equiv
O S
R1
Cu(MeCN) 4PF 6 (0.5 equiv)
R2
N
R3
ArB(OH)2: base = N-methylpiperidine ArBPin: base = K 3PO 4
7a-x
(a) Boronic acid scope
O
O
O S
Me
Me
N
O
O S
O
N
O
Me
O S
Me
S
N
N Me
(b) Cu(I) oxidation event: UV-vis studies
CF 3 7a, 96% O
O S
Me
Br
7b, 77%
7c, 82%
O
N
O S
Ph
O
N
Ph
O S
Me
7d, 89%
O
N
O S
Me
N
Me Cu(MeCN) 4PF 6 Cu(MeCN) 4PF 6 + 5 Cu(MeCN) 4PF 6 + 5 + Et 3N
Ph
Cu(MeCN) 4PF 6 + 5 + NMP
Ph
7e, 46%
Cu(MeCN) 4PF 6 + 5 + K 3PO 4
O
Cu(MeCN) 4PF 6 + 5 + NMP + KOAc
O S
Me
O
N
O
O S
Me
NC
F 7g, 94%
7f, 35%
S
N
N
7h, 84% Br
O N
O
Me
O S
Me
N Cl
Me N
MeO
N
7i, 68%
N
N
NHBoc
7j, 41%
7k, 78%
7l, 37%
(b) BPin scope
Figure 2. (a) Denucleation EPR analysis. (b) Cu(I) oxidation UVVis analysis. NMP = N-methylpiperidine.
O Me
O
O S
Me
N
O
O S
Me
N
O
O S
N
O S
Me
NH
N
The generality of the protocols was assessed by application to a series of substrates on 1 mmol scale (Scheme 3). Both protocols were broadly tolerant of functionality on the organoboron partner including variation of regiochemistry and electronic character, as well as the functionality on the N-aryl sulfonamide arene and the sulfonyl group. In particular, halide substituents (e.g., 7l, 7n, 7x) reinforce the orthogonality of the Chan–Lam amination with respect to redox neutral Pd and Cu methods, retaining these handles for subsequent manipulation. This key feature was important to the subsequent application of this method in target synthesis (vide infra). Notably, this protocol was chemoselective for the sulfonamide N-arylation vs. carbamate N-arylation (7k). While the focus of this study was to enable N-aryl sulfonamide N-arylation, we found the protocol amenable to arylation of both primary and N-alkyl sulfonamides, thereby establishing a broadly applicable method for sulfonamide arylation. Important to our focus on developing a practical methodology, the reaction operates at ambient temperature and using O2 from air (instead of, for example, a saturated O2 atmosphere). Yields were synthetically useful in the main, with sensitive organoborons (e.g., heterocyclic examples 7j, 7l, 7v, 7w) and primary sulfonamides (7p, 7s, 7t) the most challenging.
I 7m, 79% O Me
7n, 73%
7o, 81% O
O S
O N Me
N
N
7p, 57% O
S
O S
N
CN
O NH Me
O S
NH
Me
Me
N CO 2Me
Ph 7q, 70% O
7r, 51% O
S
N
O Me
Me
7s, 53% O
S
N
O Me
Me MeO
N
O S
Me N
7t, 47% O
N
Me
Me
O S
N
N
N Br
7u, 63%
7v, 56%
7w, 43%
7x, 69%
Scheme 3. N-Arylation scope. 1 mmol scale (sulfonamide), except for 7a and 7q, which are on 20 mmol scale. Isolated yields.
Similarly, our objectives required the development of a scalable process. To this end, the method was found to operate effectively on 20 mmol (3.4 g sulfonamide) scale for two examples (7a and 7q, Scheme 3). The products were isolated in high purity (>98% purity), with the reaction to form 7a requiring only a simple aqueous wash (NH4OH, NH4Cl) procedure. These results demonstrate the potential power of this Chan– Lam protocol not only for medicinal chemistry analogue generation and SAR, but also for eventual scale-up of potential clinical candidates. As a final demonstration of utility, we report the use of this Chan–Lam coupling as a key transformation in the synthesis of the NS5B inhibitor GSK8175 (Scheme 4).7c NS5B inhibitors block the RNA polymerase activity of the NS5B viral enzyme and are an important class of hepatitis C (HCV) therapeutics.17 HCV is a life-threatening condition with no known vaccine affecting approximately 2% of the global population,18 with the majority of cases occurring in the developing world. Accordingly, the development of effective treatments for HCV
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is a major international goal. A key structural feature of GSK8175 is the N,N-diarylsulfonamide, and the accompanying boronate ester moiety. Application of this Chan–Lam chemistry as an orthogonal coupling approach allows use of the halogenated aryl substrate 9 to access compound 10, which can be quickly elaborated to the API.7c While our general conditions were found to be broadly effective on 1-20 mmol scale (Scheme 3), some optimization was necessary on this more challenging substrate. Specifically, targeted optimization led to several modifications for this specific transformation, including use of NEt3 (to generate a soluble triethylammonium carboxylate in situ) and a dilute 5% O2 stream as the terminal oxidant (to maintain a basis of safety on large scale). With these modifications to our general protocol, we have achieved 63% isolated yield of 10 on 15 g scale after crystallization of the methylammonium salt.19
Scheme 4. N-Arylsulfonamide N-arylation en route to GSK8175. Isolated yield.
In summary, rational methodological design enabled by mechanistic insight has allowed the development of an effective protocol for Chan–Lam arylation of a variety of primary and secondary sulfonamides. The mild reaction conditions operate effectively on small (1 mmol) scale and can be readily scaled (20 mmol and above). This methodology is facilitating the large-scale production of a clinical HCV therapy and we expect similar utility to be found in other applications in pharmaceutical development.
AUTHOR INFORMATION Corresponding Author *
[email protected] *
[email protected] Author Contributions All authors have given approval to the final version of the manuscript. ‡These authors contributed equally.
Funding Sources Engineering and Physical Sciences Research Council (EPSRC). GlaxoSmithKline.
Notes The authors declare no competing financial interest.
ASSOCIATED CONTENT Supporting Information
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Experimental procedures, spectroscopic data (EPR, UV), characterization data, copies of NMR spectra. The Supporting Information is available free of charge on the ACS Publications website.
ACKNOWLEDGMENT We thank the EPSRC and GSK for a studentship (JCV). LL, KA, JAK, MGN, JLW, SX, and DCL thank all of the members of the GSK8175 team, and the members of the Global Chemical Catalysis group.
ABBREVIATIONS EPR, electron paramagnetic resonance spectroscopy; HCV, hepatitis C virus; NMP, N-methylpiperidine; pin, pinacol/pinacolate; SAR, structure-activity relationahips;
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ACS Catalysis of manufacture, WO2006103038A1, 5 October 2006; (c) Chong, P. Y.; Miller, J. F.; Peat, A. J.; Shotwell, J. B. Benzofuran compounds for the treatment of hepatitis c virus infections, WO2013028371A1, 28 February 2013. (8) The Chan–Lam N-arylation of primary and N-alkyl secondary sulfonamides is effective using stoichiometric Cu(OAc)2. See: Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. New N- and OArylations with Phenylboronic Acids and Cupric Acetate. Tetrahedron Lett. 1998, 39, 2933–2936. (9) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.; Watson, A. J. B. Spectroscopic Studies of the Chan–Lam Amination: A Mechanism-Inspired Solution to Boronic Ester Reactivity. J. Am. Chem. Soc. 2017, 139, 4769–4779. For previous studies, see: Vantourout, J. C.; Law, R. P.; Isidro-Llobet, A.; Atkinson, S. J.; Watson, A. J. B. Chan–Evans–Lam Amination of Boronic Acid Pinacol (BPin) Esters: Overcoming the Aryl Amine Problem. J. Org. Chem. 2016, 81, 3942–3950. (10) (a) King, A. E.; Brunold, T. C.; Stahl, S. S. Mechanistic Study of Copper-Catalyzed Aerobic Oxidative Coupling of Arylboronic Esters and Methanol: Insights into an Organometallic Oxidase Reaction. J. Am. Chem. Soc. 2009, 131, 5044−5045; (b) King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Kinetic and Spectroscopic Studies of Aerobic Copper(II)-Catalyzed Methoxylation of Arylboronic Esters and Insights into Aryl Transmetalation to Copper(II). Organometallics 2012, 31, 7948−7957. (11) For selected examples of highly active Cu complexes for Chan– Lam couplings, see: (a) Roy, S.; Sarma, M. J.; Kashyapa, B.; Phukan, P. A Quick Chan–Lam C–N and C–S Cross Coupling at Room Temperature in the Presence of Square Pyramidal [Cu(DMAP)4I]I as a Catalyst. Chem. Commun. 2016, 52, 1170–1173; (b) Duparc, V. H.; Bano, G. L.; Schaper, F. Chan–Evans–Lam Couplings with Copper Iminoarylsulfonate Complexes: Scope and Mechanism. ACS Catal. 2018, 8, 7308–7325. (12) (a) Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of Diaryl Ethers Through the Copper-promoted Arylation of Phenols with Arylboronic acids. An Expedient Synthesis of Thyroxine. Tetrahedron Lett. 1998, 39, 2937–2940; (b) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P. N-Arylation of α-Aminoesters with pTolylboronic Acid Promoted by Copper(II) Acetate. Tetrahedron Lett. 2003, 44, 1691–1694. (13) For general information, see: Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine; Hall, D. G., Ed., Wiley-VCH: Weinheim, 2005. (14) Molloy, J. J.; Clohessy, T. A.; Irving, C.; Anderson, N. A.; Lloyd-Jones, G. C.; Watson, A. J. B. Chemoselective Oxidation of
Aryl Organoboron Systems Enabled by Boronic Acid-selective Phase Transfer. Chem. Sci. 2017, 8, 1551–1559. (15) For use of K3PO4 as a desiccant in cross-coupling, see: (a) Fyfe, J. W. B.; Seath, C. P.; Watson, A. J. B. Chemoselective Boronic Ester Synthesis by Controlled Speciation. Angew. Chem. Int. Ed., 2014, 53, 12077–12080; (b) Molloy, J. J.; Law, R. P.; Fyfe, J. W. B.; Seath, C. P.; Hirst, D. J.; Watson, A. J. B. A Modular Synthesis of Functionalised Phenols Enabled by Controlled Boron Speciation. Org. Biomol. Chem., 2015, 13, 3093–3102; (c) Fyfe, J. W. B.; Valverde, E.; Seath, C. P.; Kennedy, A. R.; Redmond, J. M.; Anderson, N. A.; Watson, A. J. B. Speciation Control During Suzuki–Miyaura Cross Coupling of Haloaryl and Haloalkenyl MIDA Boronic Esters. Chem.–Eur. J. 2015, 24, 8951–8964; (d) Seath, C. P.; Fyfe, J. W. B.; Molloy, J. J.; Watson, A. J. B. Tandem Chemoselective Suzuki–Miyaura Cross Coupling Enabled by Nucleophile Speciation Control. Angew. Chem. Int. Ed. 2015, 54, 9976–9979; (e) Muir, C. W.; Vantourout, J. C.; Isidro-Llobet, A.; Macdonald, S. J. F.; Watson, A. J. B. One-Pot Homologation of Boronic Acids: A Platform for Diversity-Oriented Synthesis. Org. Lett. 2015, 17, 6030–6033; (f) Fyfe, J. W. B.; Fazakerley, N. J.; Watson, A. J. B. Chemoselective Suzuki–Miyaura Cross Coupling via Kinetic Transmetallation. Angew. Chem. Int. Ed. 2017, 56, 1249–1253; (g) Molloy, J. J.; Seath, C. P.; West, M. J.; McLaughlin, C.; Fazakerley, N. J.; Kennedy, A. R.; Nelson, D. J.; Watson, A. J. B. Interrogating Pd(II) Anion Metathesis Using a Bifunctional Chemical Probe: A Transmetalation Switch. J. Am. Chem. Soc. 2018, 140, 126−130. (16) Vanýsek, P. Electrochemical Series In CRC Handbook of Chemistry and Physics, 98th ed;, Rumble, J. R., Ed.; Taylor and Francis: Boca Raton, 2017; p8. (17) (a) Deore, R. R.; Chern, J. W. NS5B RNA Dependent RNA Polymerase Inhibitors: The Promising Approach to Treat Hepatitis C Virus Infections. Curr. Med. Chem. 2010, 17, 3806–3826; (b) Bowman, R. K.; Bullock, K. M.; Copley, R. C. B.; Deschamps, N. M.; McClure, M. S.; Powers, J. D.; Wolters, A. M.; Wu, L.; Xie, S. Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A. J. Org. Chem. 2015, 80, 9610–9619. (18) Manns, M. P.; Buti, M.; Gane, E.; Pawlotsky, J.-M.; Razavi, H.; Terrault, N.; Younossi, Z. Hepatitis C Virus Infection. Nat. Rev. Dis. Primers 2017, 3, 17006. (19) For the synthesis of 8 see ref 16b.
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Table of Contents artwork Poor substrate-catalyst interactions O B(OR) 2 Ar
O R
Cu(II)
O S
N H
R
O S
N
R
R Cu(I)
Cu(III) Ar
Mechanistic insight • RB(OH) 2 and RBpin • 24 examples •Scalable to >20 mmol
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