Generation of Diversity Sets with High sp3 Fraction Using the

Dec 27, 2017 - We have developed a generally useful, continuous flow Csp3–Csp2 coupling procedure for the synthesis of diverse product sets that is ...
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Generation of Diversity Sets with High sp3 Fraction Using the Photoredox Coupling of Organotrifluoroborates and Organosilicates with Heteroaryl/Aryl Bromides in Continuous Flow Kevin D. Raynor, Gregory D. May, Upul K. Bandarage, and Michael J. Boyd* Vertex Pharmaceuticals Inc., 50 Nothern Avenue, Boston, Massachusetts 02210, United States S Supporting Information *

ABSTRACT: The photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3−Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluoroborates. We have developed a generally useful, continuous flow Csp3−Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborates and silicate reagents. This universal protocol provides diversity sets from both primary and secondary coupling partners. This easily scalable procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high sp3 fraction.

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reactions are not easily scalable. These limitations could potentially be addressed by using continuous flow.3 Previously, we have shown that such transformations can be used to generate analogues using a continuous flow procedure which addresses all of the limitations mentioned above (Figure 1).4

n medicinal chemistry, cross-couplings that work through a two-electron transmetalation mechanism, such as the Suzuki− Miyaura coupling, have been extensively used to generate diversity. In general, this transformation forms sp2−sp2 bonds, which leads to compounds with relatively lower sp3 fractions (Fsp3). It has reported that compounds that have lower Fsp3 have higher rates of attrition in drug development.1 Therefore, a similar transformation that could efficiently generate compounds with a higher Fsp3 would be highly desirable. One such transformation is the photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates developed by Molander et al., which is a very effective means to form Csp3−Csp2 bonds. This procedure, which occurs through a single-electron transmetalation mechanism,2 has great potential for increasing product diversity in medicinal chemistry library generation. However, limitations in reported procedures render parallel chemistry and library synthesis a challenge for the following reasons: (1) in batch reactions, the sensitivity of the reaction necessitates thorough exclusion of oxygen;2 (2) the need to remove THF after preforming the ligated nickel complex2 (preformation of the Ni complex is required for efficient reactivity) results in reactions that are operationally inconvenient, in parallel; (3) traditional batch photochemistry is impractical in parallel as space and effective irradiation are limiting (additionally, these reactions are typically cooled with fans or circulating water, which makes for further complications); (4) reactions are often run at high dilution (e.g., 0.05 M), and therefore, larger volumes further increase space requirements; (5) batch photochemical © 2017 American Chemical Society

Figure 1. Generation of analogues with higher sp3 fractions using a photoredox cross-coupling in continuous flow.

Despite the utility of this powerful chemistry to generate diverse sets of compounds with higher Fsp3, the cross-coupling of potassium alkyl trifluoroborates with aryl halides has two limitations. The first is that the procedure is limited to secondary and activated primary alkyl trifluoroborates, and the second is that the presence of hydrogen bond donors can be problematic.2 Recently, Fensterbank et al. and Molander et al.5 have shown that using hypervalent silicon reagents (catechol silicates), instead of potassium alkyl trifluoroborates, addresses both of these issues. Although the cross-couplings of silicates and aryl bromides Received: October 23, 2017 Published: December 27, 2017 1551

DOI: 10.1021/acs.joc.7b02680 J. Org. Chem. 2018, 83, 1551−1557

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The Journal of Organic Chemistry

was interfering with the silicate coupling. However, the coupling did not proceed in a mixture of dioxane/DMA, with the exclusion of 2,6-lutidine (Table 1, entry 2). It appears that dioxane completely suppresses the cross-coupling of silicates with aryl halides. Reported conditions for silicate couplings employ DMF as solvent,5 which is not an option for our library protocol because, as mentioned previously, trifluoroborate couplings do not work efficiently in DMF or DMA without dioxane. Interestingly, when the silicate coupling was performed in pure DMA (without dioxane or 2,6-lutidine), good yield of coupled product was obtained in both batch and flow (Table 1, entries 3 and 4). Using this new procedure, reactions were shown to be significantly faster in flow: 40 min vs 24 h. Interestingly, only trace amounts of solvent addition product was observed in flow, which was somewhat surprising because solvent addition was problematic when running trifluoroborate couplings in flow without dioxane. To overcome these apparent incompatibilities, while minimizing manipulations, we envisioned a protocol that required the preparation of only one stock solution that contains all reagents except the variable silicates or trifluoroborates (Figure 2).

appear to have significant advantages over the cross-couplings of potassium alkyl trifluoroborates, a further important limitation remains. Unlike potassium alkyl trifluoroborates that are commercially available or conveniently prepared under mild conditions from alkyl bromides,6 to our knowledge, no catechol silicates are presently commercially available, and their preparation is less straightforward from readily available sources. In light of this, we set out to develop a convenient and effective flow procedure for library/diversity generation that could use both trifluoroborates and catechol silicates. The resulting “universal” protocol could use potassium trifluoroborates in cases where the reagent is either commercially available or straightforward to prepare, and the gaps could then be filled with catechol silicates. As in our previous report,4a the flow procedure would ideally possess the following characteristics: (1) allows for the rapid synthesis of small sets of molecules in parallel with minimal exclusion of oxygen (ideally, only a rapid replacement of atmosphere with a nitrogen blanket would be required); (2) provides consistent supply of highly pure material for initial screening purposes from small amounts of aryl bromides (∼5 mg product from ca. 80 μmol aryl bromide); (3) demonstrates broad substrate scope (for both coupling partners), and (4) requires no aqueous workup. We have already shown that trifluoroborate cross-couplings can be effectively performed in flow using a 4:1 mixture of dioxane/DMA that is crucial for keeping the reactions homogeneous while minimizing side products.4 The catechol silicate cross-couplings should be easier to adapt to continuous flow conditions because the reaction requires no base and the silicates are soluble in organic solvents such as dioxane, DMA, and DMF. The most straightforward approach to a universal protocol using either potassium alkyl trifluoroborates or silicates would be to simply apply our previously reported conditions developed for trifluoroborates (Figure 1). In this procedure, a homogeneous stock solution containing all reagents (including 2,6-lutidine, in 4:1 dioxane/DMA) is prepared and simply added to each trifluoroborate (with minimal protection from atmosphere). Unfortunately, as demonstrated in Table 1, entry 1, the reaction

Figure 2. Continuous flow protocol for the universal coupling of alkyl trifluoroborates and alkyl silicates with aryl bromides.

Table 1. Solvent Screen for a Universal Silicate/ Trifluoroborate Protocol

entry 1 2 3 4

additive/solvent 2,6-lutidine (1.5 equiv), 4:1 dioxane/DMA 4:1 dioxane/DMA DMA DMA

method

In this protocol, trifluoroborate couplings would be performed in a 4:1 mixture of dioxane/DMA (containing 2,6-lutidine), and the silicate couplings would be dissolved in DMA (without 2,6-lutidine). Another important consideration in developing a universal protocol was the choice of catalysts. Several published procedures for silicate couplings use Ni(cod)2, an airsensitive reagent, or a Ru photocatalyst,5 which is unsuitable for the coupling of trifluoroborates.2 This protocol uses NiCl2· DME (an air-stable reagent) and [Ir{dFCF3ppy}2(bpy)]PF6 as catalysts, which are suitable for coupling both trifluoroborates and silicates. This universal protocol is illustrated in Figure 2. A single stock solution containing the aryl halide, Ni source, ligand, and photocatalyst is prepared in DMA (preformation of the ligand Ni complex in THF is not required). This solution is then added to vessels charged with solid silicate or alkyl trifluoroborate. The silicate reaction solutions are then diluted with pure DMA, whereas the trifluoroborates are diluted with a solution of 2,6-lutidine in dioxane. Each reaction is then injected sequentially into the blue LED flow reactor at a flow rate of 0.5 mL/min (40 min reaction time) using a liquid handler. Product-containing fractions are collected and solvents directly evaporated. The crude residues are dissolved in DMSO and purified by automated mass-directed reversed-phase purification, where the fraction containing the

yield (reaction time)

batch and flow

0%

batch and flow batch flow

0% 84% (18 h) 83% (40 min)

between 4-bromoindazole derivative 1 with silicate 2 failed to give coupled product under these conditions. This was not surprising as Molander et al.5b have reported that silicate couplings do not work in the presence of additives required for the trifluoroborate couplings, so we hypothesized that 2,6-lutidine 1552

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select set of reactions in batch and flow. The batch reaction mixtures were placed in a blue LED bath containing eight 4 W blue LED strips,7 and the yield was compared to the that of the reaction performed with our flow protocol. To ensure accurate yields, the flow reactions were injected manually and purification was performed on silica gel rather than automated massdirected reversed-phase chromatography, which is not optimized for maximal recovery.8 As with trifluoroborate couplings, we have found that difficult silicate couplings can be significantly improved or completely rescued in flow (18 and 20) (Figure 4)

largest mass signal was used to obtain desired compounds in pure form (>95% by LCMS). Reaction injection into the flow system can be done manually or by automation. The automated protocol uses a liquid handler and HPLC pump. This avoids having to manually inject reactions in sequence. Product-containing fractions are also conveniently collected using a UV detector. With this protocol, the reaction mixtures were stable over the time course of the injection sequence, even though minimal effort was used to keep atmosphere out of the reaction mixtures (possibly a result of the relatively high Ni loading). To evaluate the protocol, a small diversity set was prepared using six alkyltrifluoroborates and six silicates (Figure 3). Similar

Figure 4. Effect of continuous flow on silicate couplings.

(generally, improvements in yield were due to improvement in conversion). This clearly demonstrates the advantage of performing these diversity sets in continuous flow as these conditions significantly expand the effective substrate scope of this reaction. Furthermore, this flow protocol is useful for performing individual reactions that show poor conversion in batch. As previously concluded, these observations also suggest that light exposure is a particularly important consideration for difficult couplings. Although we have shown that these silicate couplings can be accomplished efficiently and in high yield in flow conditions, the described protocol was optimized for diversity set generation and compatibility with alkyl trifluoroborates. Consequently, this procedure may not be optimal for individual silicate couplings or for library synthesis with only silicates as coupling partners. Therefore, we attempted to further develop flow reaction conditions for the silicate cross-coupling procedure that had shown modest, but acceptable, yields in our library synthesis procedure. One such example was the formation of 20, which showed a yield of 53% (Figure 4). Switching the solvent to DMF resulted in a significant decrease in yield (17%). Another parameter that we examined was the photocatalyst. Using [Ru(bpy)3]PF6 in place of [Ir{dFCF3ppy}2(bpy)]PF6 gave only trace conversions with this procedure (data not shown). However, changing the catalyst to the organic photocatalyst 4CzIPN5c,9 (2.5 mol %) resulted in a significant improvement in yield to 85%. Based on these results, the use of the organophotocatalyst 4CzIPN may be a better choice for silicate couplings in flow. The Ni loading was also explored, and we found that reducing Ni loading to 5% mol decreased yield to 65%.

Figure 3. Diversity set prepared from potassium alkyl trifluoroborates and catechol silicates.

to our previous work,4a our goal of obtaining at least 5 mg of product from 80 μmol aryl bromide was achieved for all compounds. The average recovery was 10 mg. The examples shown in Table 1, entries 3 and 4, suggested that, unlike alkyl trifluoroborates, flow conditions may have little effect on the coupling yield of alkyl silicates with an aryl bromide, relative to batch conditions. In our previous work,4a we have shown how application of flow conditions can rescue reactions that only gave trace amounts of product in batch. Presumably, this is due to the higher light exposure to the reaction mixture. We wanted to establish whether the same might be observed for silicate couplings. To determine if continuous flow improved conversions, we compared the efficiency of a 1553

DOI: 10.1021/acs.joc.7b02680 J. Org. Chem. 2018, 83, 1551−1557

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The Journal of Organic Chemistry We have developed a generally useful, continuous flow Csp3−Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborate and silicate reagents. This procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high Fsp3. We have also shown that our continuous flow procedure can be used to rescue reactions that work poorly in batch, thereby increasing the number and range of products that can be generated using this procedure. Finally, we have shown that, under flow conditions, DMA is a superior solvent to DMF for the coupling of alkyl silicates to aryl and heteroaryl bromides, and that the use of 4CzIPN may be superior to [Ir{dFCF3ppy}2(bpy)]PF6 in these flow reactions.

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The residue was then purified on silica gel eluting with a gradient of heptane/EtOAc. Flow. The reaction mixture was then run through a Vaportec E-series flow reactor fitted with a UV-150 photoreactor (10 mL) at a flow rate of 500 μL/min irradiating with a Vaportech 12 W LED at 450 nm at 30 °C chasing with 1:4 DMA/dioxane. The reaction was diluted with 3 times the volume of the reaction with water and extracted with ether. The reaction was extracted three times with ether; the ether layer was washed with water and dried over MgSO4. The residue was then purified on silica gel eluting with a gradient of heptane/EtOAc. General Procedure B (Diversity Set). To a flask containing a Teflon-coated stir bar were added dichloronickel/1,2-dimethoxyethane (48 mg) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (58 mg) dissolved in DMA (12 mL). The reaction was capped and sparged with N2 for 15 min. To the same vial were added 1-(benzenesulfonyl)-5bromo-pyrrolo[2,3-b]pyridine (2.06 g, 0.87 mmol) and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (19.2 mg, 0.022 mmol). The vial was stirred and sparged with N2 for 15 min or until the solution was homogeneous. Then 1 mL aliquots of the solution were pipetted into separate vials, eachvial containing one of the libraries of potassium trifluoroborates (0.11 mmol) or alkyl silicates (0.16 mmol). The vials containing potassium trifluoroborates were diluted with 4 mL of a dioxane (24 mL) solution with 2,6-lutidine (156 μL, 1.35 mmol). The vials containing alkyl silicates were diluted each with 4 mL of DMA. The headspace of each reaction was briefly sparged with N2 and capped with a rubber septum. Each reaction was run through the flow reactor as in general procedure A. Each reaction was concentrated down and was purified using automated mass-directed purification in order to obtain products in pure form. General Procedure C (Optimized Procedure for Silicate Couplings). To a 16 × 100 mm Pyrex tube were added a Teflon-coated stir bar, dichloronickel/1,2-dimethoxyethane (0.12 equiv), 4-tert-butyl2-(4-tert-butyl-2-pyridyl)pyridine (0.12 equiv), and inhibitor-free tetrahydrofuran (2 mL). The reaction was sparged with N2 and stirred to dissolve the solids, and a green solution formed after 10 min. The solution was then evaporated on the rotovap, leaving a coating of nickel complex. To the vial of nickel complex were added 2,4,5,6-tetra(carbazol-9yl)benzene-1,3-dicarbonitrile (3 mg, 0.0036 mmol) (4CzIPN), aryl bromide (1 equiv, 0.08 mmol), and alkyl silicate (2 equiv, 0.16 mmol). The tube was sealed with a septum and parafilm. A vacuum was pulled three times and backfilled with N2. The reaction then was dissolved in DMA (0.033 M). Batch. The reaction was stirred for 5 min before being placed in a water-cooled bath illuminated with 8 × 4 W blue LED light strips and stirred while being cooled with a fan from above for 18 h. The reaction was diluted with 3 times the volume of the reaction with water and extracted with ether. The reaction was extracted three times with ether; the ether layer was washed with water and dried over MgSO4. The residue was then purified on silica gel eluting with a gradient of heptane/EtOAc. Flow. The reaction mixture was then run through a Vaportech E-series flow reactor fitted with a UV-150 photoreactor (10 mL) at a flow rate of 500 μL/min irradiating with Vaportec 12 W LED at 450 nm at 30 °C chasing with 1:4 DMA/dioxane. The reaction had a residence time of 40 min. The reaction was diluted with 3 times the volume of the reaction with water and extracted with ether. The reaction was extracted three times with ether; the ether layer was washed with water and dried over MgSO4. The residue was then purified on silica gel eluting with a gradient of heptane/EtOAc. Compound Characterization. 4-Cyclohexyl-1-methylindazole (3):

EXPERIMENTAL SECTION

General Considerations. Dioxane (99.8%, extra dry) was sparged with N2 gas for 15 min upon receipt and then stored under N2. Nickel(II) chloride ethylene glycol dimethyl ether complex (98%), 4,4′-di-tertbutyl-2,2′-dipyridyl (98%) (dtbbpy), and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (dFCF3 ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine) were purchased from Sigma-Aldrich and used as received. 2,4,5,6Tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile (4CzIPN) was synthesized using the experimental procedure from the original journal source.9 Catechol silicates were prepared using previously reported procedures.5b Thin layer chromatography (TLC) was performed using 250 μm silica gel plates. TLC plates were visualized using an ultraviolet lamp. 1H NMR and 13C NMR spectra were recorded on a 400 MHz spectrometer. Spectra are internally referenced to residual solvent signals. Data for 1 H NMR are reported according to the following conventions: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quintet, br = broad, and combinations thereof), coupling constant J (Hz), integration. Automated mass-directed purification was carried out using a binary pump and an injector/fraction collector with a C8 30 × 150 mm column. Mobile phase A was 10 mM NH4OH (pH ∼10) in water; mobile phase B was acetonitrile. Compounds were purified using an 8 min focused gradient based on the retention time observed in a prepreparative analytical screen. The largest fraction-containing product was isolated. High-resolution mass spectra were acquired on a Orbitrap mass spectrometer following chromatography on a UPLC system or by direct transfusion. The samples were dissolved in DMSO at a concentration of approximately 0.2 mg/mL and infused with a flow rate of 5 μL/min. Electrospray ionization in positive ion mode was employed with a spray voltage of 4.0 kV. The mass resolution was set to 35 000. Liquid Handler Information. Waters OpenLynx was used for sample submission and to control a Waters 2767 sample manager for automated sampling of reaction mixtures, as well as fraction collection postreaction. Collection was based on UV response at 254 nm using a Waters 2489 UV/vis detector. A Waters 2545 quaternary gradient module was used to provide the 0.5 mL/min flow rate, utilizing two of the channels to avoid having premixed solvents. General Procedure A. To a 16 × 100 mm Pyrex tube were added a Teflon-coated stir bar, dichloronickel/1,2-dimethoxyethane (0.12 equiv), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.12 equiv), and inhibitor-free tetrahydrofuran (2 mL). The reaction was sparged with N2 and stirred to dissolve the solids, and a green solution formed after 10 min. The solution was then evaporated on the rotovap, leaving a coating of the nickel complex. To the vial of nickel complex were added [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (0.03 equiv), aryl bromide (1 equiv, 0.08 mmol), and alkyl silicate (1.5 equiv, 0.16 mmol). The tube was sealed with a septum and parafilm. A vacuum was pulled three times and backfilled with N2. The reaction then was dissolved in DMA (0.033 M). Batch. The reaction was stirred for 5 min before being placed in a water-cooled bath illuminated with 14 × 4 W blue LED light strips and stirred while being cooled with a fan from above for 18 h. The reaction was diluted with 3 times the volume of the reaction with water and extracted with ether. The reaction was extracted three times with ether; the ether layer was washed with water and dried over MgSO4.

Prepared using General Procedure A from 35 mg of 4-bromo-1methylindazole4b (1) and triethylammonium cyclohexylbis(catecholato)silicate (3); batch, 30 mg (84%); flow, 29 mg (83%); 1H NMR 1554

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The Journal of Organic Chemistry (400 MHz, chloroform-d) δ 7.97 (d, J = 1.0 Hz, 1H), 7.24 (dd, J = 8.4, 7.0 Hz, 1H), 7.23−7.06 (m, 1H), 6.89 (dt, J = 7.1, 0.8 Hz, 1H), 3.97 (s, 3H), 2.89 (tt, J = 11.9, 3.3 Hz, 1H), 1.92 (ddq, J = 11.5, 3.2, 1.8 Hz, 2H), 1.85−1.78 (m, 1H), 1.73 (ddtd, J = 14.5, 4.9, 3.1, 1.5 Hz, 1H), 1.59−1.34 (m, 5H), 1.31−1.18 (m, 1H); 13C NMR (101 MHz, chloroform-d) δ 141.8, 140.0, 131.4, 126.5, 123.2, 116.7, 106.5, 42.3, 35.6, 33.8, 27.0, 26.4; HRMS (ESI) m/z [M + H]+ calcd for C14H18N2+H+ 215.1543, found 215.1541. 1-(Benzenesulfonyl)-5-cyclobutyl-pyrrolo[2,3-b]pyridine (4):

6.63 (d, J = 4.0 Hz, 1H), 2.55 (td, J = 10.0, 7.9 Hz, 1H), 2.21−1.62 (m, 6H), 1.37 (dtd, J = 12.3, 9.1, 7.9 Hz, 1H), 0.93 (d, J = 6.4 Hz, 3H). tert-Butyl 4-[1-(Benzenesulfonyl)pyrrolo[2,3-b]pyridin-5-yl]piperidine-1-carboxylate (8):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and potassium (1-(tert-butoxycarbonyl)piperidin-4-yl)trifluoroborate (literature compound4b); 1H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 2.1 Hz, 1H), 8.24−8.18 (m, 2H), 7.73 (d, J = 4.0 Hz, 1H), 7.69 (dd, J = 2.2, 0.5 Hz, 1H), 7.63−7.56 (m, 1H), 7.55−7.46 (m, 2H), 6.58 (d, J = 4.0 Hz, 1H), 4.28 (d, J = 13.3 Hz, 2H), 2.91−2.72 (m, 3H), 1.84 (d, J = 13.1 Hz, 2H), 1.72−1.58 (m, 2H), 1.51 (s, 9H). 1-(Benzenesulfonyl)-5-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine (9):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium cyclobutyltrifluoroborate (literature compound4b); 1H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 2.1 Hz, 1H), 8.20−8.15 (m, 2H), 7.78 (dd, J = 2.1, 0.8 Hz, 1H), 7.72 (d, J = 4.0 Hz, 1H), 7.62−7.56 (m, 1H), 7.53−7.47 (m, 2H), 6.60 (d, J = 4.0 Hz, 1H), 3.71−3.61 (m, 1H), 2.48−2.37 (m, 2H), 2.23−2.05 (m, 3H), 1.97−1.87 (m, 1H). 1-(Benzenesulfonyl)-5-cyclopentyl-pyrrolo[2,3-b]pyridine (5):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium trifluoro(tetrahydro-2H-pyran-4-yl)borate (literature compound4b); 1H NMR (400 MHz, chloroform-d) δ 8.37 (d, J = 2.1 Hz, 1H), 8.23−8.14 (m, 2H), 7.80−7.70 (m, 2H), 7.65−7.58 (m, 1H), 7.55−7.46 (m, 2H), 6.62 (d, J = 4.0 Hz, 1H), 4.16 (ddt, J = 10.5, 3.2, 1.5 Hz, 2H), 3.60 (td, J = 11.6, 2.6 Hz, 2H), 2.92 (tt, J = 11.6, 4.3 Hz, 1H), 1.94−1.80 (m, 4H). 1-(Benzenesulfonyl)-5-hexyl-pyrrolo[2,3-b]pyridine (10):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and potassium cyclopentyltrifluoroborate (literature compound4b); 1H NMR (400 MHz, chloroform-d) δ 8.40 (d, J = 2.0 Hz, 1H), 8.20−8.15 (m, 2H), 7.84 (dd, J = 2.1, 0.6 Hz, 1H), 7.72 (d, J = 4.0 Hz, 1H), 7.64−7.57 (m, 1H), 7.56−7.47 (m, 2H), 6.63 (d, J = 4.0 Hz, 1H), 3.12 (tt, J = 9.7, 7.5 Hz, 1H), 2.20−2.08 (m, 2H), 1.92−1.81 (m, 2H), 1.79−1.70 (m, 1H), 1.67−1.55 (m, 2H). 1-(Benzenesulfonyl)-5-cyclohexyl-pyrrolo[2,3-b]pyridine (6):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and triethylammonium cyclohexylbis(catecholato)silicate; 1 H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 2.0 Hz, 1H), 8.21−8.11 (m, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 4.0 Hz, 1H), 7.64−7.57 (m, 1H), 7.56−7.47 (m, 2H), 6.63 (d, J = 4.0 Hz, 1H), 2.76−2.67 (m, 2H), 1.71−1.58 (m, 2H), 1.41−1.24 (m, 6H), 0.94−0.85 (m, 3H); 13C NMR (101 MHz, chloroform-d) δ 144.2, 138.2, 134.2, 130.8, 129.2, 127.7, 127.1, 123.8, 105.7, 32.9, 31.6, 28.8, 22.5, 14.0; HRMS (ESI) m/z [M + H]+ calcd for C19H22N2O2S+H+ 343.1475, found 343.1475. 3-[1-(Benzenesulfonyl)pyrrolo[2,3-b]pyridin-5-yl]propyl Acetate (11 and 19):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium cyclohexyltrifluoroborate (literature compound4b); 1H NMR (400 MHz, chloroform-d) δ 8.42 (d, J = 2.0 Hz, 1H), 8.19−8.13 (m, 2H), 7.91 (dd, J = 2.0, 0.5 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.66−7.60 (m, 1H), 7.53 (ddt, J = 8.2, 6.8, 1.2 Hz, 2H), 6.68 (d, J = 4.0 Hz, 1H), 2.68 (ddd, J = 11.8, 7.2, 4.1 Hz, 1H), 1.98−1.86 (m, 4H), 1.84−1.76 (m, 1H), 1.52−1.39 (m, 4H), 1.34−1.23 (m, 1H). 1-(Benzenesulfonyl)-5-[(1S,2S)-2-methylcyclopentyl]pyrrolo[2,3-b]pyridine (7):

Prepared using General Procedure A and B from 5-bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium 3-acetoxypropylbis(catecholato)silicate. For 19 (General Procedure A): batch, from 50 mg from 5-bromo-1-(phenylsulfonyl)-1H-indole, 15 mg (28%); flow, from 200 mg from 5-bromo-1-(phenylsulfonyl)-1H-indole 140 mg (64%); 1 H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 2.1 Hz, 1H), 8.20−8.16 (m, 2H), 7.72 (dd, J = 4.9, 3.1 Hz, 2H), 7.62−7.57 (m, 1H),

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium trifluoro(2-methylcyclopentyl)borate (literature compound4b); 1H NMR (400 MHz, chloroform-d) δ 8.36 (d, J = 2.0 Hz, 1H), 8.22−8.10 (m, 2H), 7.81 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.66−7.57 (m, 1H), 7.57−7.47 (m, 2H), 1555

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The Journal of Organic Chemistry

7.59−7.54 (m, 1H), 7.50−7.45 (m, 2H), 6.54 (d, J = 4.0 Hz, 1H), 2.74−2.67 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, chloroform-d) δ 146.0, 145.3, 138.5, 134.7, 133.9, 129.0, 128.5, 127.9, 126.5, 122.8, 105.3, 26.1, 16.0; HRMS (ESI) m/z [M + H]+ calcd for C15H14N2O2S+H+ 287.0849, found 287.0847. 4-Isobutyl-1-methylindazole (18):

7.51 (dd, J = 8.6, 7.0 Hz, 2H), 6.59 (d, J = 4.0 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 2.82−2.74 (m, 2H), 2.06 (s, 3H), 2.03−1.94 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 171.3, 145.6, 145.1, 138.4, 134.0, 132.0, 129.6, 129.1, 127.9, 127.8, 127.0, 123.1, 105.4, 63.5, 30.3, 29.3, 20.9; HRMS (ESI) m/z [M + H]+ calcd for C18H18N2O4S+H+ 359.1060, found 359.1061. 1-(Benzenesulfonyl)-5-propyl-pyrrolo[2,3-b]pyridine (12):

Prepared using General Procedure A from 25 mg 7-bromo-1-methyl1H-indazole and triethylammonium isobutylbis(catecholato)silicate; batch, trace; flow, 14 mg (61%); 1H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 1. 0 Hz, 1H), 7.08 (dd, J = 8.4, 6.9 Hz, 1H), 7.01 (dt, J = 8.4, 1.0 Hz, 1H), 6.68 (dq, J = 6.8, 0.7 Hz, 1H), 3.84 (s, 3H), 2.56 (d, J = 7.3 Hz, 2H), 1.84 (dq, J = 13.6, 6.8 Hz, 1H), 0.72 (d, J = 6.6 Hz, 6H); 13 C NMR (101 MHz, chloroform-d) δ135.5, 131.7, 126.2, 120.5, 106.5, 42.8, 35.6, 29.9, 22.8; HRMS (ESI) m/z [M + H]+ calcd C12H16N2+H+ 189.1386, found 189.1386. 2-(3-Isobutyl-4-methoxyphenyl)-5-methyl-1,3,4-oxadiazole (16):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and triethylammonium propylbis(catecholato)silicate; 1 H NMR (400 MHz, chloroform-d) δ 8.32 (d, J = 2.0 Hz, 1H), 8.21−8.14 (m, 2H), 7.73 (dd, J = 8.4, 3.0 Hz, 2H), 7.65−7.57 (m, 1H), 7.51 (dd, J = 8.5, 7.1 Hz, 2H), 6.60 (d, J = 3.9 Hz, 1H), 2.72−2.64 (m, 2H), 1.69 (dt, J = 15.0, 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 144.9, 144.8, 138.3, 134.1, 133.5, 130.2, 129.1, 127.8, 126.9, 123.4, 105.6, 34.9, 24.7, 13.6; HRMS (ESI) m/z [M + H]+ calcd for C16H16N2O2S+H+ 301.1005, found 301.1004. 1-(Benzenesulfonyl)-5-isobutyl-pyrrolo[2,3-b]pyridine (13):

Prepared using General Procedure A from 25 mg 2-(3-bromo-4methoxyphenyl)-5-methyl-1,3,4-oxadiazole4a and triethylammonium isobutylbis(catecholato)silicate; batch, 2.9 mg (13%); flow, 14 mg (59%); 1H NMR (400 MHz, chloroform-d) δ 7.77 (dd, J = 8.6, 2.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 6.88−6.79 (m, 2H), 3.80 (s, 3H), 2.53 (s, 3H), 2.46 (d, J = 7.2 Hz, 2H), 1.88 (dt, J = 13.6, 6.8 Hz, 1H), 0.84 (d, J = 6.6 Hz, 7H); 13C NMR (101 MHz, chloroform-d) δ165.1, 163.0, 160.4, 131.2, 129.2, 126.1, 115.7, 155.3, 110.4, 55.5, 39.3, 28.5, 22.5, 11.1; HRMS (ESI) m/z [M + H]+ calcd for C14H18N2+H 247.14, found 247.1441. 3-[2-Methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]propyl Acetate (17):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and triethylammonium isobutylbis(catecholato)silicate; 1 H NMR (400 MHz, chloroform-d) δ 8.29 (d, J = 2.0 Hz, 1H), 8.19−8.14 (m, 2H), 7.75−7.70 (m, 2H), 7.63−7.57 (m, 1H), 7.54−7.48 (m, 2H), 6.61 (d, J = 4.0 Hz, 1H), 2.58 (d, J = 7.2 Hz, 2H), 1.88 (dh, J = 13.4, 6.7 Hz, 1H), 0.93 (d, J = 6.6 Hz, 6H); 13C NMR (101 MHz, chloroform-d) δ 145.1, 144.8, 138.3, 134.1, 132.5, 131.0, 129.2, 127.8, 126.9, 123.4, 105.6, 42.2, 30.4, 22.1; HRMS (ESI) m/z [M + H]+ calcd for C17H19N2O2S+H+ 315.1162, found 315.1161. 1-(Benzenesulfonyl)-5-(3,3,3-trifluoropropyl)pyrrolo[2,3-b]pyridine (14):

Prepared using General Procedure A from 25 mg 2-(3-bromo-4methoxyphenyl)-5-methyl-1,3,4-oxadiazole and triethylammonium 3-acetoxypropylbis(catecholato)silicate; batch, 11 mg (40%); flow, 27 mg (98%); 1H NMR (400 MHz, chloroform-d) δ 7.88 (dd, J = 8.5, 2.2 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.91 (s, 3H), 2.83−2.72 (m, 2H), 2.62 (s, 3H), 2.08 (s, 3H), 2.03−1.93 (m, 2H); 13C NMR (101 MHz, chloroform-d) δ 171.2, 164.9, 163.1, 160.1, 130.6, 128.3, 126.5, 116.2, 110.4, 64.1, 55.5, 28.3, 26.7, 21.0, 11.1; HRMS (ESI) m/z [M + H]+ calcd for C15H18N2O4+H+ 291.1339, found 291.1339. 3-(1-Methylindazol-4-yl)propyl Acetate (20):

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and triethylammonium (3,3,3-trifluoropropyl)bis(catecholato)silicate; 1H NMR (400 MHz, chloroform-d) δ 8.35 (d, J =2.1 Hz, 1H), 8.18−8.13 (m, 2H), 7.78 (dd, J = 11.3, 3.0 Hz, 2H), 7.64−7.58 (m, 1H), 7.51 (dd, J = 8.6, 7.0 Hz, 2H), 6.63 (d, J = 4.0 Hz, 1H), 3.03−2.96 (m, 2H), 2.50−2.37 (m, 2H); 13C NMR (101 MHz, chloroform-d) δ 145.4, 144.4, 138.2, 134.2, 130.1, 130.0, 129.2, 127.8, 127.7, 127.5, 125.0, 123.6, 105.4, 35.6, 25.5; HRMS (ESI) m/z [M + H]+ calcd for C16H13F3N2O2S+H+ 355.0723, found 355.0721. 1-(Benzenesulfonyl)-5-ethyl-pyrrolo[2,3-b]pyridine (15):

Prepared using General Procedure A from 25 mg 7-bromo-1-methyl1H-indazole and 3-acetoxypropylbis(catecholato)silicate; batch, trace; flow, 25 mg (53%); 1H NMR (400 MHz, chloroform-d) δ 8.03 (d, J = 1.0 Hz, 1H), 7.34 (dd, J = 8.4, 6.8 Hz, 1H), 7.29−7.25 (m, 1H), 6.96 (dq, J = 6.8, 0.8 Hz, 1H), 4.13 (t, J = 6.5 Hz, 2H), 4.10 (s, 3H), 3.09−2.99 (m, 2H), 2.23−2.10 (m, 2H), 2.09 (s, 3H); 13C NMR (101 MHz, chloroform-d) δ171.2, 140.0, 134.7, 131.1, 126.5, 123.8,

Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)1H-indole and triethylammonium ethylbis(catecholato)silicate; 1 H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 2.1 Hz, 1H), 8.20−8.17 (m, 2H), 7.68 (d, J = 4.0 Hz, 1H), 7.66−7.64 (m, 1H), 1556

DOI: 10.1021/acs.joc.7b02680 J. Org. Chem. 2018, 83, 1551−1557

Note

The Journal of Organic Chemistry 119.7, 107.0, 63.8, 35.6, 29.5, 29.3, 21.0; HRMS (ESI) m/z [M + H]+ calcd for C13H16N2O2+H+ 233.1285, found 233.1284.

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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.joc.7b02680. All 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Upul K. Bandarage: 0000-0002-9456-6181 Michael J. Boyd: 0000-0003-3732-7878 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Professor Gary Molander of the University of Pennsylvania for the generous gift of silicate samples for preliminary experiments, and Dr. Michael P. Clark and Dr. Jeremy Green for helpful discussions. The authors also thank Dr. Barry Davis for high-resolution mass spectra.

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REFERENCES

(1) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752−6756. (2) (a) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014, 345, 433−436. (b) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res. 2016, 49, 1429−1439. (3) (a) Garlets, Z. J.; Nguyen, J. D.; Stephenson, C. R. J. Isr. J. Chem. 2014, 54, 351−360. (b) Tucker, J. Y.; Zhang, Y.; Jamison, T. F.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2012, 51, 4144−4147. (c) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. Rev. 2016, 116, 10276. (d) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796−11893. (4) (a) DeLano, T. J.; Bandarage, U. K.; Palaychuk, N.; Green, J.; Boyd, M. J. J. Org. Chem. 2016, 81, 12525−12531. (b) Palaychuk, N.; DeLano, T. J.; Boyd, M. J.; Green, J.; Bandarage, U. K. Org. Lett. 2016, 18, 6180−6183. (5) (a) Corce, V.; Chamoreau, L.-M.; Derat, E.; Goddard, J.-P.; Ollivier, C.; Fensterbank, L. Angew. Chem., Int. Ed. 2015, 54, 11414− 11418. (b) Jouffroy, M.; Primer, D. N.; Molander, G. A. J. Am. Chem. Soc. 2016, 138, 475−478. (c) Leveque, C.; Chenneberg, L.; Corce, V.; Ollivier, C.; Fensterbank, L. Chem. Commun. 2016, 52, 9877−9880. (d) Leveque, C.; Chenneberg, L.; Corce, V.; Goddard, J.-P.; Ollivier, C.; Fensterbank, L. Org. Chem. Front. 2016, 3, 462−465. (e) Vara, B. A.; Jouffroy, M.; Molander, G. A. Chem. Sci. 2017, 8, 530−535. (6) (a) Sandrock, D. L.; Molander, G. A. Curr. Opin. Drug Discovery Dev. 2009, 12, 811−823. (b) Presset, M.; Fleury-Bregeot, N.; Oehlrich, D.; Rombouts, F.; Molander, G. A. J. Org. Chem. 2013, 78, 4615− 4619. (7) Wang, H.; Yu, S. Org. Lett. 2015, 17, 4272−4275. (8) Accurate yields are not obtained when automation is used due to variation in injection volume, fraction collection and pooling, and differences in individual purification protocols (ref 4). (9) Luo, J.; Zhang, J. ACS Catal. 2016, 6, 873−877.

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DOI: 10.1021/acs.joc.7b02680 J. Org. Chem. 2018, 83, 1551−1557