Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by

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Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis Kenneth Arrington, Gregg A. Barcan, Nicholas A Calandra, Greg A. Erickson, Ling Li, Li Liu, Mark G. Nilson, Iulia I. Strambeanu, Kelsey Faith VanGelder, John L. Woodard, Shiping Xie, C. Liana Allen, John A. Kowalski, and David C. Leitch J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02269 • Publication Date (Web): 19 Oct 2018 Downloaded from http://pubs.acs.org on October 19, 2018

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The Journal of Organic Chemistry

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis Kenneth Arrington, Gregg A. Barcan, Nicholas A. Calandra, Greg A. Erickson, Ling Li, Li Liu, Mark G. Nilson, Iulia I. Strambeanu, Kelsey F. VanGelder, John L. Woodard, Shiping Xie, C. Liana Allen, John A. Kowalski,* and David C. Leitch* API Chemistry, GlaxoSmithKline, King of Prussia PA 19406. ABSTRACT: A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multi-day SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3 / pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Introduction. Hepatitis C is a potentially life-threatening viral infection that afflicts ~2% of the world’s population, with >500,000 deaths per year attributed to complications from the disease.1 While there is currently no vaccine for the Hepatitis C virus (HCV), there are several approved treatments for the condition, some of which are able to achieve cure rates of >90%.2 Because of the need for increasing patient access, particularly in developing nations, and to combat potential viral resistance to current medicines, development of alternative treatments is imperative. One important class of HCV therapeutics is the NS5B inhibitors, which operate by blocking the RNA polyermase activity of the NS5B viral enzyme.3 There are both nucleoside analog2a,4 and non-nucleoside analog5 Active Pharmaceutical Ingredients (APIs) either in development or approved for use. Previously, we reported the synthesis of a non-nucleoside analog NS5B inhibitor based on a substituted benzofuran scaffold (GSK852A, 1, Figure 1).6 A key structural feature of this compound is a boronic acid moiety,7 which contributes to the compound’s potency. Here we report on the synthesis of a more advanced benzofuranbased NS5B inhibitor, GSK8175 (2), which retains the boron-containing functionality, but removes the metabolically labile methylene linker between the sulfonamide nitrogen and the pendant arene.8

Figure 1. Structures of two benzofuran-derived NS5B inhibitors containing boronic acid motifs.

The initial synthesis of 2 is shown in Scheme 1. The first half is based heavily on our previously reported route to 1, and is identical up to the common intermediate 8. At this point in the synthesis of 1, a reductive amination and mesylation of the aryl/alkyl secondary amine completes the sequence.6b For the preparation of 2, the aniline 8 is first mesylated prior to installation of the final arene via SNAr substitution using 10; this affords the advanced intermediate 11, which contains all of the carbon atoms present in the API. From this point, there are seven more transformations required to complete the synthesis, including a Sandmeyer halogenation and use of the potent carcinogen chloromethyl methyl ether (MOMCl).

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Scheme 1. Initial synthesis of GSK8175 (2); half of the steps occur after assembling the entire carbon framework.

Due to this highly atom, step, and redox inefficient sequence to convert 11 into 2, we sought an alternative endgame that would avoid this series of functional group interconversions. Of particular importance was removing the Sandmeyer sequence, which could be achieved by directly coupling an appropriately halogenated aromatic substrate with 9 (or analog thereof). Unfortunately, SNAr reactions between 9 and fluoroaromatics without the para-nitro functionality have been unsuccessful. Even the initial SNAr is difficult, requiring multiple days to reach completion with HMPA as the solvent; alternative conditions that replace HMPA with less toxic solvents are considerably lower yielding. Palladium- or copper-catalyzed arylation of 9 was also considered; however, chemoselectivity in the presence of multiple halides was a significant concern, especially given the reactivity trends established by Buchwald for biarylphosphine-based Pd catalysts.9 Furthermore, catalytic C-N coupling using secondary sulfonamides is not well developed, particularly with N-arylsulfonamides.10 Initial attempts to couple even simple aryl-halides to 9 were not successful. Finally, while we were able to arylate 8 using Pd-catalysis, mesylation of the resulting diarylamines proved low yielding due to the propensity of the diarylmethanesulfonamides to demesylate when using strong base.11

on 1, we intended to retain/adapt as much of that chemistry as possible. Second, because our initial scoping studies indicated mesylation of a diarylamine would be overly difficult, mesylation must precede N-arylation. Third, N-arylation would need to be achieved with a reaction that could function with both a sulfonamide and a multiply-halogenated aromatic; for this we investigated a Cu-catalyzed Chan-Lam coupling, which is orthogonal to redox-neutral C-N coupling reactions.12 Finally, Pd-catalyzed borylation must occur at the end of the synthesis due to the instability of arylboronate esters toward many reaction and work-up conditions.13 This borylation would need to be performed at a hindered position, in the presence of an Ar-Cl group, with a benzyl alcohol protecting group other than MOM.

Thus, we envisioned a new synthetic sequence with four general attributes (Figure 2). First, given the efficiency of the benzofuran synthesis from previous development work Figure 2. Key disconnection sequence in a new synthesis of 2.


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The Journal of Organic Chemistry Results and Discussion.

Preparation of Chan-Lam coupling partners. In order to effect the difficult N-arylation chemistry required for our improved synthesis of 2, we focused our efforts on a Chan-Lam coupling strategy. The Chan-Lam reaction is an oxidative C-N coupling between an arylboronic acid (or boronate ester) and a nitrogen nucleophile that operates under much milder conditions than redox neutral Pd- or Cu-catalyzed N-arylations.12 The Chan-Lam is thus an orthogonal coupling strategy, allowing use of a halogenated coupling partner. Our goal was to intercept the current chemistry at intermediate 14, and therefore we needed to access the appropriate substrates (equation 1).

While coupling sulfonamide 9 would provide the most direct method, concerns regarding chemoselectivity of the N-arylation in the presence of two N-H nucleophiles prompted the synthesis of the carboxylic acid analogue 19. This was achieved in >78% yield over two steps from 6 by hydrogenation of the nitro group to 18, followed by a onepot mesylation / saponification sequence (Scheme 2). Scheme 2. Three-step, two-pot sequence for the preparation of 19.

Initially, we planned to adapt the existing hydrogenation conditions for the conversion of 7 to 8 to the reduction of 6 (Scheme 1); however, using the previously identified 5% Pt/Al2O3 catalyst required long reaction times to reach completion (>48 hours). We therefore screened twenty different Pt-based hydrogenation catalysts on 0.1 mmol scale under a number of reaction conditions, and identified several Pt/C alternatives capable of achieving completion in 95% isolated yield. This three-step, two-pot sequence allows rapid, reliable, and high-yielding access to the key sulfonamide coupling partner for the ensuing Chan-Lam chemistry. For the aryl boronate coupling partner, we envisioned a selective Ir-catalyzed C–H borylation14 of methyl-3-bromo2-chlorobenzoate (20) as the most efficient synthetic method. This enables formation of the C-B bond in the presence of both Ar-Cl and Ar-Br groups, with the required regiochemistry, in a single step. While the use of an Ir-catalyst is of concern from a cost perspective, the low catalyst loadings needed for C-H borylation coupled with the lack of attractive alternative syntheses gave us confidence in our approach to this material. As a proof of concept, we first evaluated standard literature15 borylation conditions: 1 mol% [Ir(cod)OMe]2, 2 mol% 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbipy), with B2pin2 as the boron source, and a heptane/TBME solvent system to ensure complete dissolution of 20. After only one hour at 50 °C, conversion to 21 was complete, and no other borylated products were observed. In order to turn these initial conditions into a scalable process, we first evaluated replacing [Ir(cod)OMe]2 with the more widely available [Ir(cod)Cl]2, and dtbbipy with 2,2’-bipyridine (bipy). Previous reports have indicated that preactivation of [Ir(cod)Cl]2/ligand mixtures with B2pin2 at elevated temperature in the absence of substrate leads to an active catalyst system.16 Thus, heating [Ir(cod)Cl]2/ dtbbipy/B2pin2 at 85 °C in heptane for 30 minutes prior to introduction of 20 (as a heptane solution) is highly effective; unfortunately, we did not achieve comparable success with bipy as the ligand. At these temperatures, TBME (or another co-solvent) is not required to maintain solubility of 20, enabling maximum catalyst efficiency (various co-solvents were observed to decrease reactivity). Notably, we observed that grinding the crystalline [Ir(cod)Cl]2 into a fine powder prior to use resulted in a more active catalyst, likely due to faster solubilization in heptane during the activation period.17 This allowed us to reduce the catalyst loading to 0.4



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mol% [Ir(cod)Cl]2 and 0.8 mol% dtbbipy. The optimized reaction conditions are shown in equation 2, and have been demonstrated on >225 g scale with 91% isolated yield after crystallization from acetonitrile/water. Development of the Chan-Lam coupling. With reliable synthetic routes to both 19 and 21 in place, we focused considerable effort on developing the Chan-Lam coupling reaction. Figure 3 summarizes the key findings of a series of preliminary small-scale screening experiments that explored the effect of Cu source, base, and reaction solvent on the conversion of 19 into 22. In all cases, an excess of the arylboronate 21 was required, generally ≥2 equivalents. From these experiments, we selected acetonitrile and triethylamine as the preferred solvent and base, and established that the reaction must be run in the presence of O2. We also discovered that cationic Cu(I) salts generally outperform other Cu(I) or Cu(II) sources in the Chan-Lam arylation of secondary sulfonamides.18 Standard Chan-Lam conditions typically employ a stoichiometric amount of Cu(OAc)2, which acts as both catalyst and oxidant. In the coupling of 19 and 21, all Cu(II) sources achieved relatively poor conversion.

Figure 4. Potential byproducts of Chan-Lam couplings resulting from decomposition of 21.

We attribute the superiority of cationic Cu(I) sources to the absence of potentially competing X-type ligands (AcO-, Cl-, etc.) that could inhibit coordination of the sulfonamide. Subsequent experiments indicated that both [Cu(ACN)4]OTf and [Cu(ACN)4]PF6 can be used interchangably in this transformation. Adding ligands (such as 2,2’-bipyridine), reducing the Cu loading below 0.5 equivalents, and using alternative oxidants (such as Ag2CO3 or H2O2/urea) all led to lower conversions of 19.

es correspond to biaryl 24 and/or the diarylether 25 (such oxidative coupling products are commonly observed in Chan-Lam couplings12). These protonolytic or oxidative byproducts explain both the need for excess 21, and for the premature termination of reaction progress. Reducing the reaction temperature to ≤10 °C improved the solution yield to 70%; however, the reaction time needed increased to >48 hours (equation 3).

Figure 3. Summary of preliminary screening experiments, with most effective materials highlighted in blue. See Supporting Information for further details.

Even using the best reaction conditions identified from screening, we were unable to achieve >60% conversion of 19 into 22 before the reaction progress stalled. We did observe that in many cases all of the boronate ester 21 was consumed despite the excess charge, and that multiple byproducts were formed during the course of the reaction. We observed both compound 20 and the phenol 23, and hypothesize that non-polar byproducts seen in HPLC trac-

Despite these initial promising results, we quickly identified a key issue with the conditions in equation 3. Using only 10 volumes of solvent (4:1 acetonitrile/triethylamine), the reaction mixture is heterogeneous. Both compound 21 and [Cu(ACN)4]PF6 are highly soluble in acetonitrile (>100 mg/mL), whereas 19 is poorly soluble (2.7 mg/mL). Furthermore, under these conditions the initial rates and overall extents of reaction are invariant when the charges of 19, 21, or [Cu(ACN)4]PF6 are changed. In order to improve the outcome and the scalability of this reaction, we explored the solution behavior of 19 in a series of control and solubility experiments. As noted above, 19 has only 2.7 mg/mL solubility in acetonitrile; however, in the presence of excess triethylamine it should predominantly exist as the triethylammonium carboxylate. We therefore determined the solubility of 19 in a 4:1 mixture of acetonitrile and triethylamine, mirroring the ChanLam reaction solvent system. Upon addition of triethylamine to a slurry of 19 in acetonitrile, all of the solid dissolves quickly, but a tan precipitate forms shortly thereafter. HPLC analysis of the supernatant after stirring this mixture for >1 hour reveals the solution concentration of 19 (and/or the corresponding triethylammonium carboxylate) is only 2.8 mg/mL. A series of observations during Chan-Lam reaction setup led us to investigate the solubility of 19 in the presence immediately turns dark green. We attribute this behavior


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Figure 5. Solubility of compound 19 in a 4:1 ACN/NEt3 solvent mixture versus amount of [Cu(ACN)4]PF6 added, with maxmimum possible solubilities denoted based on charge of 19. The slope of the line indicates 19 forms a 2:1 complex with Cu.

to the oxidation of Cu(I) by air to generate a 2:1 complex between the anion of 19 and a Cu(II) center. This has the effect of dramatically increasing the amount of 19 in solution: quantitative HPLC analysis of a saturated solution of 19 (250 mg) with 0.6 equiv [Cu(ACN)4]PF6 (143 mg) in ACN/NEt3 (4/1 mL) indicates 188.5 mg 19 is dissolved (solubility = 37.7 mg/mL, 0.0968 M). Notably, no color change or solubilization is observed when 19 and [Cu(ACN)4]PF6 are stirred in ACN/NEt3 under N2, confirming the necessity of O2 to oxidize the Cu(I) source to Cu(II). To further test our hypothesis of 2:1 complex formation between an in situ generated Cu(II) center and the anion of 19, we measured the solution concentration of 19 in 4:1 ACN/NEt3 in the presence of varying amounts of [Cu(ACN)4]PF6 (Figure 5). These experiments were done with two different charges of 19 (20 mg and 40 mg per mL of solvent), and each of these had three different loadings of [Cu(ACN)4]PF6. A plot of the concentration of [Cu(ACN)4]PF6 (based on amount charged) versus the concentration of 19 (obtained by quantitative HPLC of the supernatant) is linear with a slope of 1.9, clearly indicating a 2:1 ratio of 19 to Cu in solution. The highest concentration of 19 observed, 39.6 mg/mL or 0.102 M, is within experimental error of the maximum solubility (37.7 mg/mL). Given the correlation between the Cu loading and amount of dissolved 19, we also assessed the influence of Cu loading on the Chan-Lam reaction itself (Figure 6). Both the initial rate of product formation and the extent of reaction after complete consumption of 21 (8 h time point) increase with amount of [Cu(ACN)4]PF6 added up to 0.6 equiv; increasing the charge to 1.2 equiv has little impact on either the initial rate or yield. While a detailed kinetic

Figure 6. Initial rate of Chan-Lam coupling (left axis, blue points) and solution yield of 22 at 8 hours (right axis, red points) versus equiv [Cu(ACN)4]PF6.

study is required to elucidate the reaction mechanism, it is clear that the optimal amount of Cu is 0.5-0.6 equiv. After establishing the appropriate reaction concentration to produce a homogeneous solution, and the optimal Cu charge of 0.5-0.6 equivalents, several additional features of the Chan-Lam reaction required process improvements. Due to safety concerns with using air, we explored the use of 5% O2 (balance N2) as an alternative. Previous work has established the limiting oxygen concentration (LOC) for acetonitrile to be 12-13%;19 thus, a 5% O2 (balance N2) gas stream is >2-fold below the LOC for combustion of the reaction solvent. In addition, use of 5% O2 instead of air performs well on multigram scale with overhead stirring: using a 10 g charge of 19, a 75% solution yield of 22 was obtained after 20 hours (equation 4), which is a very similar extent of reaction to that achieved using air. Given these promising results, all further development work was conducted using 5% O2.20

Another issue that needed to be addressed is the use of [Cu(ACN)4]PF6, especially since large quantities are costly and only available from a few suppliers. In order to access a cationic Cu(I) species in situ, we explored a number of options with Cu(I) salts and halide abstracting reagents. Traditional means of halide abstraction using Ag(I) salts such as AgBF4 or AgOTf were deemed not suitable due to



cost issues, and the need to remove the resultant silver waste. Small-scale experiments led to the identification of KPF6 in combination with CuCl as an effective replacement for [Cu(ACN)4]PF6. This system relies on the high solubility of KPF6 in acetonitrile, and the insolubility of KCl, to drive the anion metathesis forward; accordingly, CuCl and KPF6 were typically stirred in acetonitrile for ~30 minutes to complete halide abstraction. Unfortunately, this CuCl/ KPF6 system failed to reach acceptable solution yields of 22 upon scale-up, where we suspected the poor solubility of CuCl leads to slow halide abstraction. Use of CuX2 (X = Cl, Br, I) instead of CuCl resulted in more consistent outcomes on multigram scales; however, we observed a significant new byproduct resulting from halogenation of the Ar-Bpin bond.21 Iterative optimization led us to a mixed CuCl/CuCl2 system in conjunction with KPF6, which performs well on scale without the need to pre-mix the inorganics. While the exact nature of this catalyst system is still under investigation, we postulate that in the presence of O2, 19, and NEt3, all of the Cu is oxidized to Cu(II) and complexed to anionic deprotonated 19, while the chloride counterions are brought out of solution as KCl. The final aspect of this Chan-Lam coupling that required development was the workup and isolation, particularly due to the formation of the decomposition byproducts (Figure 4). We determined that crystallization of an ammonium carboxylate salt of 22 would be the best method to reject the non-polar byproducts. Because the next synthetic step is amidation to form the N-methylamide 14 (vide infra), we targetted the N-methylammonium salt 22NH2Me; this would avoid the need to completely remove an alternative amine that could interfere with the subsequent amidation. During optimization of the workup procedure, we discovered that unreacted 19 could be extracted into aqueous ammonia, leaving 22 (likely as its ammonium salt) in the organic phase. Further optimization established that 40% methylamine in water is also capable of extracting 19 into the aqueous phase, removing residual Cu, and forming the required ammonium salt with a single wash. Crystallization of 22-NH2Me purges the remaining byproducts, providing the desired product in >60% isolated yield and >95% purity (equation 5).

Completion of the synthesis with an improved borylation protocol. In order to elaborate the Chan-Lam coupling product 22 into the API (2), several additional steps required optimization. Amidation of 22 with methyl-

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amine would intercept the existing synthetic route at intermediate 14. Initially, we employed TBTU22 (1.6 equiv) as the coupling reagent using 22 as the free acid, along with methylammonium hydrochloride (1.5 equiv) and DIPEA (3 equiv), which gave 14 in >70% isolated yield on gram scale. However, switching to 22-NH2Me as isolated from the previous stage (along with extra methylammonium chloride) led to incomplete conversion. Screening other coupling reagents identified only COMU23 as an equally effective alternate system, but still only partial conversion was observed. By charging excess NH2Me-HCl (1.7 equiv) and TBTU (3 equiv), full conversion and 90% isolated yield was obtained on gram scale. This requirement for excess coupling reagent was traced to adventitious water in the batches of 22NH2Me prepared via Chan-Lam coupling (Karl-Fisher titration indicated >6% water by weight). A simple re-slurry of 22-NH2Me in acetonitrile at 50 °C for several hours is able to dehydrate 22-NH2Me. By using dry input material, only modest excesses of NH2Me-HCl (1.5 equiv) and TBTU (1.7 equiv) are required to achieve complete conversion, giving 14 in 83% yield on 30 g scale (equation 6).

With the development of this amidation chemistry, our new synthesis has intercepted a common intermediate (14) from the previous route in only six linear steps rather than nine. From 14, the only required transformations are reduction of the methyl ester group, and installation of the boron moiety. The previously developed reduction conditions for the conversion of 14 to 15 (LiBH4 in MeOH/ THF, Scheme 1) performed well, and so we focused our attention on developing a more robust borylation protocol. Previous work had identified the methoxymethyl ether (MOM) protecting group as optimal for the borylation chemistry, which was carried out using a Pd(OAc)2/dppb catalyst system under standard Miyaura borylation conditions (excess B2pin2, KOAc as base).24 Conversion of 16 to 17 required multiple catalyst charges (up to 15 mol% Pd), and resulted in a significant degree of desbromination as a side pathway (up to 30%). Furthermore, the reaction outcome was variable even when using the same batches of input material. In order to address both the identity of the protecting group (to avoid the use of MOMCl), and the unreliable catalytic conditions, we designed a parallel-in-parallel set of screens to evaluate four different protecting groups and 48 different mono- and bidentate phosphine ligands using KOAc / toluene (Figure 7). The 48 reaction set for each of the four substrates reveals several key insights into the Miyaura borylation chemistry. First, it is clear that protecting groups other than MOM are viable, with 2-tetrahydropyranyl (THP) emerging as the most attractive from these studies: not only does 26 prove


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Figure 7. Parallel-in-parallel screening design to investigate the effect of both protecting group and phosphine ligand in the Miyaura borylation shown. The screening data are visualized with the size of the points corresponding to % product (larger is greater % product), and the color corresponding to % debromination observed (color gradient as follows: red: 100% desbromo; yellow: 25% desbromo; green: 0% desbromo). Ligands identified as hits are denoted with a-l in the visualization, with structures at right. See Supporting Information for full table of conditions and results.

more effective than the acetate (27), pivalate (28), or tertbutyldimethylsilyl (29) in the borylation, but installation and removal of the THP group can be readily achieved (vide infra). Second, while dppb is clearly the best bidentate ligand among the 24 investigated, there are several relatively simple monodentate ligands that are highly effective, including PPh3 and P(iPr)Ph2. Finally, debromination is observed in nearly every case, with many systems giving exclusively the desbromo byproduct; however, borylation of the Ar-Cl is not observed using these ligands. In a follow-up screen focused on the THP-protected substrate (26), we assessed an expanded set of 33 monodentate ligands with different solvent and base combinations drawn from standard Miyaura borylation conditions in the literature (Figure 8).25 Switching from toluene to CPME had little effect, while using NaOtBu led to undesirable reactivity regardless of the ligand used. The best ligand class emerging from these experiments is alkyldiphenylphosphine, with P(iPr)Ph2 and PCyPh2 as equally effective under screening conditions. All of the phosphines that show good reactivity are modestly electron rich, and not sterically bulky. That these features are desirable for this transformation is entirely consistent with the nature of the aryl halide substrate: the borylation must occur with high chemoselectivity for the hindered Ar-Br position over the

adjacent Ar-Cl. Therefore, the ideal Pd(0) center is relatively unhindered, and will not readily undergo oxidative addition of an Ar-Cl bond. The suitability of phosphines such as PCyPh2 and the others pictured in Figures 7 and 8 is consistent with these requirements. Further studies identified Pd2dba3-CHCl3 as the most active Pd source in combination with either P(iPr)Ph2 or PCyPh2. As observed elsewhere, the quality of the “Pd-dba” used is critical to the success of the reaction.26 Commercial sources of “Pd2dba3”, or “Pd(dba)2” lead to lower conversion of starting material, and increased debromination as well as other byproducts. The chloroform solvate outperformed the alternatives.27 Having identified a suitable set of reaction conditions from high-throughput screening, our attention turned to reaction optimization on larger scale. A borylation reaction on 4 g scale was monitored over time using the Pd2dba3CHCl3 / P(iPr)Ph2 catalyst system, with toluene and KOAc as the solvent and base respectively. A plot of reaction progress over time reveals linear kinetics for the consumption of starting material and generation of both desired product and desbromo byproduct (Figure 9). Despite a large catalyst charge (5 mol% Pd), complete conversion requires nearly 24 hours at 90 °C. Given both the linear kinetics



Figure 8. Expanded monodentate ligand screen for the conversion of 26 to 30 (THP protecting group), with additional ligand hits denoted m-p. The screening data are visualized with the size of the points corresponding to % product (larger is greater % product), and the color corresponding to % debromination observed (color gradient as follows: red: 100% desbromo; yellow: 25% desbromo; green: 0% desbromo). See Supporting Information for full table of results.

observed, and the heterogeneous nature of the reaction mixture, our hypothesis is that solid/liquid mass-transfer is rate limiting in this case. KOAc has low solubility in toluene, even at elevated temperatures, and the crystallinity of as-received KOAc likely results in slow dissolution kinetics. This hypothesis was validated by performing the reaction with KOAc that was ground in a mortar and pestle under nitrogen, resulting in a >3-fold rate increase. Given that grinding a hygroscopic solid would be undesirable on larger scale, we sought to identify an alternative base that would alleviate mass-transfer issues. A variety of acetate salts were evaluated, with only KOAc and CsOAc achieving good solution yields of product. At this point, we drew inspiration from synthetic and mechanistic studies in Pd-catalyzed direct arylation chemistry.28 The proposed mechanisms for both the Miyaura borylation and direct arylation proceed through Pd(carboxylate) intermediates,29,30 and it has been shown that pivalate ligands have a pronounced positive effect on direct arylation chemistry.31 We therefore investigated both KOPiv and CsOPiv as bases, either as the discrete carboxylate salts, or generated in situ using a mixture of pivalic acid and K2CO3 or Cs2CO3. All of these pivalate-derived bases performed very well, giving 86-89% solution yield of 30,

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Figure 9. Reaction profile for conversion of 26 to 30 on gramscale using either crystalline KOAc (conditions above arrow; light-colored points), or 325 mesh K2CO3 / PivOH (conditions below arrow; dark-colored points). The rate difference between the two sets of conditions is >10-fold.

with 10-13% debromination. While these reaction endpoint results are very similar to those obtained with KOAc, use of pivalate has a striking effect on reaction rate: simply substituting as-received KOPiv for crystalline KOAc under otherwise identical conditions results in a >4-fold increase in rate, while grinding the KOPiv leads to an even greater rate increase. With powdered KOPiv, a 90% solution yield can be obtained after only 60 minutes. In order to retain the reaction rates observed with powdered KOPiv without the need to mill the solid base, we investigated the use of a pivalic acid/K2CO3 system. In contrast to KOAc and KOPiv, K2CO3 is readily available in a number of particle sizes. We chose 325 mesh K2CO3, and validated our small-scale results on gram scale using overhead stirring (to prevent any inadvertent grinding of the base by a magnetic stir bar). The solvent system was also modified to include THF as a cosolvent in order to solubilize 26 (and avoid another potential mass-transfer issue). The reaction reached completion in 99% purity as judged by HPLC analysis. Importantly, the levels of residual Pd were determined to be

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by

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