Generation of Diversity Sets with High sp3 Fraction Using the

Subscriber access provided by University of Florida | Smathers Libraries

Note

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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02680 • Publication Date (Web): 27 Dec 2017 Downloaded from http://pubs.acs.org on January 1, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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* Abstract: The photoredox cross coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluroborates. 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 analogs bearing a high sp3 fraction.

In 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

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

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 pre-forming the ligated nickel complex2 (pre-formation 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 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 analogs using a continuous flow procedure which addresses all of the limitations mentioned above (Figure 1).4

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


Page 2 of 22

Page 3 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Solvent screen for a universal silicate/trifluoroborate protocol

Entry

Additive/Solvent

Method

1 2

2,6-Lutidine (1.5eq), 4:1 Dioxane/DMA 4:1 Dioxane/DMA

3

DMA

Batch and flow Batch and flow Batch

4

DMA

Flow

Yield (reaction time) 0% 0% 84% (18h) 83% (40 min)

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 these issues. Although the cross couplings of silicates and aryl bromides appears 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 alkylbromides,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 homogenous while minimizing side products.4 The catechol silicates cross couplings should be easier to adapt to continuous flow conditions since 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 homogenous 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 between 4bromoindazole derivative 1 with silicate 2 failed to give coupled product under these conditions. This was not surprising since 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


Page 4 of 22

Page 5 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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

2,6-lutidine 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 since, 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 since 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). 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 air sensitive reagent, or a Ru photocatalyst,5 which is unsuitable for the coupling of trifluroborates.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, while 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 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


Page 6 of 22

Page 7 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


injection sequence, even though minimal effort was used to keep atmosphere out of the reaction mixtures (possibly a result a the relatively high Ni loading).

To evaluate the protocol, a small diversity set was prepared using six alkyltrifluoroborates and six silicates (Figure 3). Similar to our previous work,4 a 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.

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



The examples shown in Table 1, entries 3-4 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 work4a 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 select set of reactions in batch and flow. The batch reaction mixtures were placed in a blue LED bath containing eight 4W blue LED strips7 and the yield compared to 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 mass-directed 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 (18,20) (Figure 4) (generally, improvements in yield were due to improvement in conversion). This clearly demonstrates the advantage of performing these diversity sets in continuous flow, since 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


Page 8 of 22

Page 9 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. The effect of continuous flow on silicate couplings.

for individual silicate couplings or for library synthesis with solely silicates as coupling partners. Therefore, we attempted to further develop flow reaction conditions for the silicate crosscoupling 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%.

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 analogs 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 briomides, and that the use of 4CzIPN may be superior to [Ir{dFCF3ppy}2(bpy)]PF6 in these flow reactions.


Page 10 of 22

Page 11 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Experimental Section General Considerations: Dioxane (99.8%, extra dry) was sparged with N2 gas for 15 min upon receipt then stored under N2. Nickel(II) chloride ethylene glycol dimethyl ether complex (98%), 4,4′-di-tert-butyl-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. 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile (4CzIPN) was synthesized using experimental the procedure from 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 1H 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 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 pre-preparative 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 ﬂowrate 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 254nm using a Waters 2489 UV/Vis detector. A Waters 2545 quaternary gradient module was used to provide the 0.5mL/min flowrate, utilizing two of the channels to avoid having pre-mixed solvents.

General Procedure A: To a 16 x 100 mm Pyrex tube was added a Teflon coated stir bar, dichloronickel;1,2-dimethoxyethane (0.12 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.12 eq) and inhibitor free tetrahydrofuran (2 mL). The reaction was sparged with N2 and stirred to dissolve the solids, 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 was added [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (0.03 eq), aryl bromide (1 eq, 0.08 mmol) , and alkyl silicate (1.5 eq, 0.16 mmol). The tube was sealed with a septum and parafilm. A vacuum was pulled 3 times and back filled with N2. The reaction then was dissolved in DMA (0.033M). Batch: The reaction was stirred for 5 minutes before being placed in a water-cooled bath illuminated with 14x4 W blue LED light strips and stirred while being cooled with a fan from above for 18 hours. The reaction was diluted with 3 times the volume of the reaction with water



and extracted with ether. The reaction was extracted 3 times with ether; the ether layer was washed with water and dried over MgSO4. The residue was then purified on silica gel eluting with 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 Vapourtech 12 Watt LED @ 450 nm at 30oC 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 3 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 was added dichloronickel;1,2-dimethoxyethane (48 mg) and 4-tert-butyl-2-(4-tert-butyl-2pyridyl)pyridine (58 mg) dissolved in DMA (12 mL). The reaction was capped and sparged with N2 for 15 minutes. To the same vial there was added 1-(benzenesulfonyl)-5-bromo-pyrrolo[2,3b]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 minutes or until the solution was homogenous. Then 1 mL aliquots of the solution were pipetted into separate vials, each vial containing one of the libraries 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 alkylsilicates 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 procedure. Each reaction was concentrated down and were 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 x 100 mm Pyrex tube was added a Teflon coated stir bar, dichloronickel;1,2-dimethoxyethane (0.12 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.12 eq) and inhibitor free tetrahydrofuran (2 mL). The reaction was sparged with N2 and stirred to dissolve the solids, 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 was added 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3dicarbonitrile (3 mg, 0.0036 mmol) (4CzIPN), aryl bromide (1 eq, 0.08 mmol), and alkyl silicate (2 eq, 0.16 mmol). The tube was sealed with a septum and parafilm. A vacuum was pulled 3 times and back filled with N2. The reaction then was dissolved in DMA (0.033 M). Batch: The reaction was stirred for 5 minutes before being placed in a water-cooled bath illuminated with 8x4 W blue LED light strips and stirred while being cooled with a fan from above for 18 hours. The reaction was diluted with 3 times the volume of the reaction with water and extracted with ether. The reaction was extracted 3 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. .


Page 12 of 22

Page 13 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 uL/min irradiating with Vapourtec 12 Watt LED @ 450 nm at 30oC chasing with 1:4 DMA:Dioxane. The reaction had a residence time of 40 minutes. The reaction was diluted with 3 times the volume of the reaction with water and extracted with ether. The reaction was extracted 3 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:

3. 4-cyclohexyl-1-methyl-indazole: Prepared using General Procedure A from 35 mg 4-bromo-1-methylindazole4b (1) and triethylammonium cyclohexylbis(catecholato)silicate (3). Batch 30 mg (84%) Flow 29 mg (83%). 1H NMR (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.

4. 1-(benzenesulfonyl)-5-cyclobutyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium cyclobutyltrifluoroborate. Literature Compound.4b 1 H 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).


Page 14 of 22

Page 15 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5. 1-(benzenesulfonyl)-5-cyclopentyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium cyclopentyltrifluoroborate. Literature Compound.4b 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).

6. 1-(benzenesulfonyl)-5-cyclohexyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium cyclohexyltrifluoroborate. Literature Compound.4b 1 H 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).

7. 1-(benzenesulfonyl)-5-[(1S,2S)-2-methylcyclopentyl]pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium trifluoro(2methylcyclopentyl)borate. Literature Compound.4b 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), 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).



8. tert-butyl 4-[1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-5-yl]piperidine-1-carboxylate: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium (1-(tertbutoxycarbonyl)piperidin-4-yl)trifluoroborate. Literature Compound.4b 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)

9. 1-(benzenesulfonyl)-5-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and potassium trifluoro(tetrahydro-2H-pyran4-yl)borate Literature Compound.4b 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).

10. 1-(benzenesulfonyl)-5-hexyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium cyclohexylbis(catecholato)silicate. 1H 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.


Page 16 of 22

Page 17 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


11 & 19. 3-[1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-5-yl]propyl acetate. Prepared using General Procedure A and B from 5-bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium 3acetoxypropylbis(catecholato)silicate. For 19 (General Procedure A ). Batch: from 50 mg from 5-bromo1-(phenylsulfonyl)-1H-indole, 15 mg (28%). Flow: from 200 mg from 5-bromo-1-(phenylsulfonyl)-1Hindole 140 mg (64%). 1H 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), 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). 13C 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.

12. 1-(benzenesulfonyl)-5-propyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium propylbis(catecholato)silicate. 1H 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). 13C 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.

13. 1-(benzenesulfonyl)-5-isobutyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium isobutylbis(catecholato)silicate. 1H 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.

14. 1-(benzenesulfonyl)-5-(3,3,3-trifluoropropyl)pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5-bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium (3,3,3trifluoropropyl)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.

15. 1-(benzenesulfonyl)-5-ethyl-pyrrolo[2,3-b]pyridine: Prepared using General Procedure B from 5bromo-1-(phenylsulfonyl)-1H-indole and triethylammonium ethylbis(catecholato)silicate. 1H 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), 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.


Page 18 of 22

Page 19 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


18. 4-isobutyl-1-methyl-indazole: Prepared using General Procedure A from 25 mg 7-bromo-1-methyl1H-indazole and triethylammonium isobutylbis(catecholato)silicate. Batch: (trace). Flow: 14mg (61%). (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). 13C 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.

16. 2-(3-isobutyl-4-methoxy-phenyl)-5-methyl-1,3,4-oxadiazole: Prepared using General Procedure A from 25 mg 2-(3-bromo-4-methoxyphenyl)-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.

17. 3-[2-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]propyl acetate: Prepared using General Procedure A from 25 mg 2-(3-bromo-4-methoxyphenyl)-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). 13 C NMR (101 MHz, Chloroform-d) δ171.2, 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.

20. 3-(1-methylindazol-4-yl)propyl acetate: Prepared using General Procedure A from 25 mg 7-bromo1-methyl-1H-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, 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.

Acknowledgements 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.

Supporting Information -All 1H and 13C NMR spectra.

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.


Page 20 of 22

Page 21 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


[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, 1252512531. b) Palaychuk, N.; DeLano, T. J; Boyd, M. J.; Green, J., Bandarage; U. K. Org. Lett. 2016, 18, 61806183. [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) Levesque, C.; Chenneberg, L.; Corce, V.; Ollivier, C.; Fensterbank, L. Chem. Commun. 2016, 52, 9877-9880. d) Levesque, 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. Discov. Devel. 2009, 12, 811–823. b) Presset, M.; Fleury-Bregot, 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.



Graphical abstract:


Page 22 of 22

Generation of Diversity Sets with High sp3 Fraction Using the

Recommend Documents