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A Method for Identifying and Developing Functional Group Tolerant Catalytic Reactions: Application to the Buchwald-Hartwig Amination Jeffery Richardson, J. Craig Ruble, Elizabeth A Love, and Simon Berritt J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00201 • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on March 3, 2017

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The Journal of Organic Chemistry

A Method for Identifying and Developing Functional Group Tolerant Catalytic Reactions: Application to the Buchwald-Hartwig Amination Jeffery Richardson1*, J. Craig Ruble2, Elizabeth A. Love3, and Simon Berritt4 1 Discovery Chemistry Research and Technologies, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, United Kingdom. 2 Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United States. 3 Translational Research Office Drug Discovery Group, University College London School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom. 4 Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States. ABSTRACT: Transition metal catalysis has revolutionized organic synthesis but difficulties can often be encountered when applied to highly functionalized molecules, such as pharmaceuticals and their precursors. This results in discovery collections that are enriched in substances possessing less desirable properties (high lipophilicity, low polar surface area). Masking groups are often employed to circumvent this problem, which is in opposition to the inherent ideality of these methods for green chemistry and atom economy. A general screening methodology, related to robustness screening described by Glorius et al., builds a broad understanding the impact of individual functional groups on the success of a transformation under various conditions and provides a simple framework for identifying new conditions that tolerate challenging functional groups. Application of this approach to profile the conditions for the Buchwald-Hartwig amination and rapidly identify bespoke conditions for challenging substrate classes is described.

1. Introduction Drug discovery programs frequently call upon compound libraries to establish structureactivity relationships, testing hypotheses around binding affinity and efficacy, in addition to absorption, distribution, metabolism and excretion properties of potential drug candidates. The ability to efficiently prepare these diverse libraries is vital to the success of drug discovery programs, so robust and reliable methods that tolerate the presence of diverse functional groups are essential. In spite of the many “general” reaction conditions that are described in the literature, the preparation of diverse libraries of compounds for determination of structureactivity relationships best demonstrates some important challenges for new methodologies, especially in catalysis. Cernak, Dreher and co-workers at Merck recently disclosed an analysis of 2149 metal-catalyzed C-N couplings performed in the synthesis of highly functionalized drug leads.1 This revealed that 55% of reactions failed to deliver any product at all and pointed to the “growing recognition that the tendency of polar, highly functionalized compounds to fail in catalysis may actually enrich compound sets in hydrophobic molecules that are less likely to become successful drug candidates.”2 Similarly, the increased number of protecting group manipulations that appears in the pharmaceutical patent literature over the

last 30 years has been attributed to increased use of catalytic methods that frequently do not tolerate drug-like functional groups without protection.3 This opposes the goals of green chemistry,4 atom economy5 and protecting group free manipulations6 that are becoming increasingly important in modern organic chemistry. One of the challenges in preparing a library of compounds seeking to explore different dimensions of property space is that the chemistry used to prepare each library member is likely to perform differently. Ideally, for any given transformation, a single set of reaction conditions would exist that is effective for all conceivable substrates. Since the various starting materials are likely to have different properties (reactivity, stability and solubility) and purities, this is extremely unlikely. Although synthetic methodology publications typically describe the scope of a new method and presents several examples of the tolerance of certain functional groups, it is often the case that there is not enough directly comparable data in the literature to draw conclusions as to which method might work when applied to a highly functionalized substrate. Indeed, a key issue with literature mining and reaction databases is that hits are inherently enriched in older conditions, leading

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Figure 1. Model Buchwald-Hartwig amination reaction and overview of approach to identify functional group tolerant conditions. to the possible conclusion that newer conditions do not tolerate certain functional groups due to lack of exemplification. Furthermore, negative results are not always reported. Therefore, a systematic approach is required that compares the numerous existing conditions for a particular transformation in order to quickly identify those that are most appropriate for a new substrate and also to find and overcome gaps in the existing methodologies. Glorius and co-workers have developed a “Robustness Screen”7 designed to assess the scope of a given set of conditions in an unbiased manner by performing a reaction in the presence of an intermolecular functional group additive (FGA). To date, this methodology has only been applied to single reaction conditions i.e. “Will this reaction work for my substrate?” and has not been used as a comparative tool to facilitate method selection, “Which conditions will work for my substrate?” To answer this broader question, a variant of this protocol was conceived where a large number of known conditions for a transformation could be compared on a model reaction in the presence of a series of FGAs. The results can thus be extrapolated to substrates containing the various functional groups, allowing preselection of different conditions for individual family members in a synthetic library (Fig. 1). Additionally, for FGAs that are poorly tolerated across all conditions, it was envisaged that optimization of the model reaction in the presence of the FGA would allow rapid development of alternate conditions that overcome this substrate incompatibility. Therefore, for a given library, several sets of known conditions could be “tailored” for certain family members, while bespoke conditions could be sought in an expedited fashion for those library members that are deemed problematic from the initial assessment. Screening several known reaction conditions against a panel of FGAs develops a picture of the functional groups

that are inherently tolerated by each set of conditions. For those that are not well tolerated, optimization of the model reaction in the presence of the FGA generates new conditions that are expected to perform well in substrates containing those functional groups. This approach quickly generates uniform understanding of the effect of various FGAs, and highlights appropriate reaction conditions for molecules containing the corresponding functional group. Limiting the initial screen to conditions known to have a broad scope of reactivity increases the likelihood of effectiveness when applied to a broad range of substrates. The Buchwald-Hartwig amination reaction exemplifies this problem well; it is a highly versatile method for the conversion of aryl and vinyl halides and pseudohalides to the corresponding amino derivatives and has become a central tool for the construction of C-N bonds in drug discovery. In a recent analysis of the medicinal chemistry literature it was shown around 6% of the reactions used in the pursuit of drug candidates were amine arylations, making it the most popular C-N bond forming reaction after amide formation8 and one of a limited number of recently developed reaction types that is frequently used in medicinal chemistry.9 Since the early reports by Buchwald10 and Hartwig,11 the scope of this reaction continues to expand to encompass a wide variety of coupling partners, driven by the development of new ligand classes,12 deeper understanding of reactivity12h and advances in catalyst activation.13 The success of a given amination reaction is dependent on many factors; the properties of the amine and aryl halide/pseudohalide, catalyst activation/deactivation, competing side reactions, and poisoning from low level impurities are all possible contributors to reaction performance.12h To overcome these hurdles, the nature of the catalyst, solvent and base can be addressed, as well as concentration and reaction temperature. In spite of numerous significant advances, it remains


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The Journal of Organic Chemistry Reaction condition A 47 additives + 1 control 48 reactions

O

Br +

Reaction condition B 47 additives + 1 control 48 reactions

N H 1

69 general conditions assessed

2

O N 3

96-well plate 3312 reactions

N (29%)

N

Cl

(49%)

Competitive N-H

Ph O (57%)

(55%)

Ph NH2

O Ph Ph

(30%) OH

O (50%)

(55%)

H (27%) O

SH

Ph NH2 (16%)

(60%)

N

O

O S

S

NH2

N (15%) H

(26%)

NH2

(18%)

Ph

NH2 (6%)

(63%)

N H

(11%)

(15%)

(35%) O

N (33%) H

(6%)

N H

O

N N

N N H (9%)

N

(61%) (7%)

S

(47%)

NH

Ph Cl

Ph OH

O (21%)

(6%)

O

O

S

O Ph

(34%)

H N

N

O

O

S

(15%) O

Average yield for control reaction = 59% (Std Dev = 35%)

NH

(13%)

Heterocycles/Competitive N-H

(25%) Functional Groups

O

S

N N

O

N (40%)

(59%)

Bn N

N

(51%)

N (42%)

(50%) N N

N

N

(32%)

(12%) N

N

(39%)

N

Cl

O

nBu

(9%) S

nBu

S (56%)

(39%)

(58%)

N Cl N (26%)

O HO O (15%) O

(50%)

N+ O-

(34%)

N (46%)

Heterocycles

Figure 2. Generalized high throughput screening (HTS) protocol and summary of FGAs employed. Additives employed in HTS of model Buchwald-Hartwig amination reaction. Numbers in parentheses are the mean yield of 3 in the various amination conditions tested in the presence of that FGA (see Supporting Information Tables S2-S70) determined by UPLC analysis against internal standard. All reactions were performed for the length of time described in the original publication. difficult to rationally preselect conditions for application to highly functionalized substrates. A recent study of the patent literature linked the increased use of protecting groups to the rise in application of catalytic methods, and also revealed that the Buchwald-Hartwig amination of both aryl bromides and chlorides were 2 of the 10 worst performing reactions in terms of median yield.3 2. Results and Discussion. To combat this problem, a study was designed to assess a number of general conditions for the Buchwald-Hartwig amination reaction (Supporting Information Table S1) against a matrix of 47 FGAs,

representing commonly occurring functional groups and heterocycles, in a high throughput screening format (Fig. 2). Across all conditions the mean yield (determined by UPLC analysis vs internal standard) for the model reaction in the absence of any FGA was 59.6%, which reflects that some conditions selected were not optimized for the chosen model reaction. A number of additive classes did not adversely affect the model reaction with average yields close to that of the control. Bioactive molecules and pharmaceuticals invariably contain hydrogen bond donors and acceptors especially N-H groups, with 17 of the top 25 best-selling small molecule drugs from 2013 con-



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taining this moiety.14 Interestingly, of the 15 worst performing FGAs in this model reaction, 11 contain the N-H moiety (average yield for the bottom 15 = 11.5%). Histogram plots (Supporting Information Figures S3-S97) further demonstrate the tendency for these FGAs to be clustered at the lowest end of the yield range, but also facilitate the identification of conditions that are outliers and could represent good starting points for further optimization. The mechanism by which different classes of FGA prevent the desired reaction can be understood to some extent. Many additives prevent the desired reaction without forming any discernible byproducts, suggesting that catalyst poisoning or inhibition of active catalyst formation is occurring. In contrast certain FGAs create strongly competing side reactions. Several products of potential side reactions were prepared as analytical standards to allow the quantitative assessment of these competing processes (Supporting Information Figure S2). Focusing on those FGAs that led to the lowest average yields, we confirmed that thiophenol, indole, indoline, aniline and 2phenylethanamine were all readily arylated under numerous reaction conditions (see Supporting Information Tables S2-S70). Conversely, carbazole, a byproduct of the reductive elimination in 2nd and 3rd generation Buchwald palladacycles,13d, 13f was rarely arylated but still had a significant detrimental effect on the yield of the model reaction (Supporting Information Figure S56). This is consistent with recent observations in amination reactions13g and potentially explains the relatively poor results obtained when using a 3rd generation palladacycle (Supporting Information Table S57). To apply this screening data to the selection of Buchwald-Hartwig amination conditions for highly functionalized substrates, conditions could be chosen where the yield of the model reaction is high, the additive is unconsumed and the literature suggests that the coupling partners are sterically and electronically compatible. This approach can be used to systematically evaluate the effect of a given functional group on the coupling across a wide range of conditions, but substrate specific influences such as changes in solubility, metal chelation, steric or electronic effects caused by other groups or by the functional group itself should also be considered when selecting conditions for application to novel targets.7a 2.1 Using the data to generate functional group tolerant conditions. Across the broad spectrum of conditions studied, several FGAs caused significant inhibition of the model reaction and certain FGAs afforded no suitable hits whatsoever. The significant negative impact of benzenesulfonamide, benzamide and indole (Supporting Information Figures S26, S44 and S52) on the performance of the majority of catalyst systems was striking, particularly given the frequency with which these substructures are encountered in medicinal chemistry efforts. There were also stark differences between certain N-H containing additives and their N-methylated derivatives. Specifically, indole was far more inhibitory than Nmethylindole (Supporting Information Fig. S52 versus

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S68) and N-phenylacetamide was far more inhibitory than N-methyl-N-phenylacetamide (Supporting Information Fig. S46 versus S10). In neither case could the degree of inhibition be fully explained by simple consumption of the N-H containing additive (Supporting Information Figs S53 and S47). The approach described in Fig. 1 was therefore applied to develop reaction conditions that would tolerate these functional groups. Benzenesulfonamide was selected for further study (Scheme 1) given that N-H sulfonamide groups were particularly underrepresented in the literature, with only a single example15 of the group being present as a non-reacting spectator in the various methodology papers from which our screening conditions were chosen (Supporting Information Table S72). The first iteration was to verify the small number of conditions that showed promise from the HTS. While the initial HTS data were obtained as single points with no repetition and on a small scale, the screening data translated well when repeated in a non-HTS setting. A few examples of reactions where the product was formed but the sulfonamide was degraded were also analyzed (see Supporting Information Table S71) to add certainty to this validation.16

Figure 3. Ligands and Pd complexes that were defined as hits in HTS of sulfonamide, indole and amide FGAs. Ad= 1-adamantyl. Several conditions performed well, with the AdBippyphos and PEPPSI-IPent (Fig. 3) conditions described by Hartwig17 and Organ18 respectively giving outstanding conversion to desired target with little degradation of the benzenesulfonamide additive. During the hit verification reactions with PEPPSI-IPent (9), it was noticed that those using 1,2-dimethoxyethane (DME) as solvent were somewhat capricious, giving variable conversions for all reactions when repeated. Upon switching from DME to 1,4dioxane, these reactions became very efficient and reproducible (Supporting Information Table S71). For the second iteration, the model reaction was optimized in the presence of the FGA. Even though seemingly adequate conditions had been identified in the first iteration, the second iteration allows optimization in other dimensions, for example selecting a base that might be more tolerant of other functional groups that could be present in


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Scheme 1. Optimization of model reaction in presence of benzenesulfonamide. Condition set a: Pd2(dba)3 (10 mol%), 4 (15 mol%), NaOtBu (1.4 eq), PhMe, 110 °C. Condition set b: [(cinnamyl)PdCl]2 (1.2 mol%), 5 (10 mol%), NaOtBu (1.5 eq), TPGS-750-M (2% in H2O), 65 °C. Condition set c: [(allyl)PdCl]2 (1.5 mol%), 6 (6 mol%), base, Dioxane, 100 °C. Condition set d: 7 (3 mol%), 8 (3 mol%), NaOtBu (1.5 eq), Dioxane, 110 °C. Condition set e: 9 (3 mol%), base, solvent, 80 °C.

Scheme 2. Optimization of model reaction in presence of indole. Condition set a: Pd2(dba)3 (10 mol%), 4 (15 mol%), NaOtBu (1.4 eq), PhMe, 110 °C. c: [(allyl)PdCl]2 (1.5 mol%), 6 (6 mol%), base, Dioxane, 100 °C. Condition set e: 9 (3 mol%), base, solvent, 80 °C. a) N-Arylation to form 10 competes. potential library members. In instances where the first screening hits are less successful, this second iteration is invaluable for arriving at suitable conditions. The conditions employing AdBippyphos and PEPPSI-IPent (condition sets c & e) were selected for further study, since these conditions overlapped with successful conditions for the other FGAs under consideration here. A simple screen of commonly used bases for these coupling reactions12h showed that, for both catalyst systems, cesium carbonate, potassium tert-butoxide and lithium hexamethyldisilazide were highly effective bases for the model reaction with little degradation of the benzenesulfonamide additive. Similarly, optimization was performed with indole as the FGA (Scheme 2). One of the key differences between the sulfonamide and indole as an additive in this model

reaction is the competing side product formation. Conditions were selected from the HTS data where the side Narylation to form 10, was minimized. Notably, the AdBippyphos and PEPPSI-IPent conditions (condition sets c and e) from the previous screen were also high quality starting points for indole. Further screening of bases in the second iteration showed that the AdBippyphos conditions favored the coupling of morpholine, but that coupling of indole was a significant side reaction. Interestingly, with a variety of bases PEPPSI-IPent did not afford indole arylation to an appreciable extent. A truncated set of conditions was assessed in an identical manner for N-phenylacetamide as the FGA. Conditions that had previously tolerated benzenesulfonamide and indole were selected preferentially and further study



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Scheme 3. Optimization of model reaction in presence of N-phenylacetamide. Condition set a: Pd2(dba)3 (10 mol%), 4 (15 mol%), NaOtBu (1.4 eq), PhMe, 110 °C. Condition set c: [(allyl)PdCl]2 (1.5 mol%), 6 (6 mol%), base, Dioxane, 100 °C. Condition set Condition set e: 9 (3 mol%), base, solvent, 80 °C. a) From HTS data without repeat. of bases identified several conditions where the additive was tolerated and not significantly consumed (Scheme 3). When applying these data to the selection of conditions for use with medicinally interesting substrates, conditions could either be individually selected for each FGA class or a single set of conditions that was effective for all, although perhaps not optimal for any, could be chosen. Following the latter of these paths, PEPPSI-IPent (9) was selected to prepare a small library of products from coupling partners containing sulfonamides, indoles and amides (Fig. 4). The catalyst was paired with lithium hexamethyldisilazide, which is precedented to show some NH tolerance19 in such couplings. Note that any of the successful hits using different catalysts, bases and solvents could similarly have been selected (Supporting Information Table S71). Across a wide variety of sulfonamide, indole and amide containing aryl bromides very good yields of desired product were obtained in most instances and 17 of the 18 members gave useful quantities of the target compounds. This is particularly impressive given that this library is composed entirely of substrates bearing challenging functional groups. Although optimized with a secondary alkyl amine, primary amines and aniline derivatives were also coupled effectively under these conditions. The coupling of morpholine with 4-bromobenzenesulfonamide to afford 11 and the coupling of N-(2-bromophenyl)acetamide to afford 24 both delivered product under the standard conditions, but were hindered by limited solubility of the starting material in the reaction solvent. Performing these reactions in dioxane at higher temperature and with alternate bases resulted in substantially improved yield. Using the first pass conditions, all compounds were formed in sufficient yield to be considered as successful in a parallel synthesis setting with the exception of 17. This high success rate is in stark contrast to the 55% failure rate described for Buchwald-Hartwig couplings of functionalized substrates by the Merck group.1 One limitation of this method is that the impact of the proximity of the functional groups to the reacting centers

is not predicted. For example, the low yield of 15 (relative to 11 containing the same functional group) may be due to the formation of a stable palladacycle intermediate that prevents catalyst turnover. Despite this, knowledge of the conditions that tolerate a particular functional group provides excellent starting points for focused design of follow-up experiments and more rapid development of conditions that might overcome such challenges. 3. Conclusion A simple and systematic approach for identifying and optimizing reaction conditions with high functional group tolerance is described. The application to the medicinally important Buchwald-Hartwig amination demonstrates the potential of this approach for tailoring conditions to provide libraries containing desirable functional groups without the need for protecting groups. By applying such tailored conditions an improvement in the reaction success rate can be expected with concomitant improvements in the amount of chemical space explored. Reducing the number of missed opportunities will result in diverse libraries that contain molecules with more suitable physicochemical properties and thus a higher probability of finding drug leads or candidates. This approach is equally applicable to other catalytic and non-catalytic processes and will readily generate large data sets, enabling chemists to select conditions prior to experimentation, thus accessing compound libraries with the properties required for biomedical research, rather than those dictated by the method of synthesis. The data can also be used to identify trends and new opportunities to improve these methods in a manner that does not require attempted application in the rarified circumstances of synthesizing a specific target. Applying this approach to other commonly used and high value transformations could have a significant impact on library synthesis by allowing the identification and development of bespoke conditions for challenging substrates in an efficient manner prior to working with the actual library members. Those functional groups that cannot be improved by varying the reaction parameters


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Figure 4. Application of optimized reaction conditions to functional group containing substrates. Isolated yields, average of 2 runs. a) HPLC yield vs internal std. b) Cs2CO3 (2 equiv.), dioxane, 100 °C. c) KOtBu (2 equiv.), dioxane, 100 °C. d) reaction performed at room temperature. e) Reaction performed at 30 °C. provide a foundation for future innovation in catalyst design, as chemists continue to deliver syntheses that are efficient, environmentally benign (protecting group free) and robust (i.e. tolerant of process impurities).

EXPERIMENTAL SECTION General Methods. All reagents purchased from commercial suppliers and used as received. Solvents were purchased from Aldrich, anhydrous, sure-seal quality, and used with no further purification. The ligands and bases were purchased from commercial sources and stored in the glovebox. All HTS reactions were performed inside a Vacuum Atmospheres (VAC) glovebox operating with a N2-atmosphere (oxygen typically < 5 ppm). All other experiments were performed in a conventional fume cupboard. Reaction experimental design was aided by the use of Accelrys Library Studio. 20 μmol scale reactions for the limiting reagent were carried out in 1 mL glass vials (Freeslate, Cat. No. S11500, 8 x 30 mm, 1mL, flat bottom) equipped with magnetic tumble stir bars (V&P Scientific, Cat. No. 7111D-1) in 96-well reaction plates (Analytical Sales, Cat. No. 96960) or 24-well reaction plates (Analytical-Sales, Cat. No. 24249). Liquid handling was done using single and multi-channel Eppendorf pipettors (10, 100, 200, and 1000 μL). On completion of solution dosing the plates were covered by a perfluoroalkoxy alkane (PFA) mat (Analytical-Sales, Cat. No. 96967 and 24261), followed by two silicon rubber mats (Analytical-Sales, Cat. No. 96965 and 24262), and an aluminum cover which was tightly and evenly sealed by 9

screws. Reactions were monitored using a Waters Acquity UPLC-MS. Column: Acquity UPLC HSS C18 1.7 um 2.1 x 50 mm (Part # 186002350), pH 3.5 Stock Solution: 12.6 g ammonium formate + 7.9 mL formic acid to 1 L water; Mobile Phase A: 1% pH 3.5 stock solution in H2O, Mobile Phase B: 1% pH 3.5 stock solution in water (100 mL) + acetonitrile (900 mL); Strong Wash: acetonitrile (1700 mL), water (200 mL), 2-propanol (100 mL); Weak Wash: acetonitrile (200 mL) + water (1800 mL). The instrument was equipped with an SQD detector with electrospray ionization (ESCi) source in positive and negative mode. High throughput data analysis was carried out with Virscidian Analytical Studio™ software. Flash column chromatography was carried out using silica gel columns with a Teledyne ISCO Com1 13 biFlash Companion system. H and C NMR spectra were recorded on a Bruker AV-HD 400 spectrometer. Signal positions were recorded in δ ppm with the abbreviations s, d, t, q, dd, dt and m denoting singlet, doublet, triplet, quartet, doublet of doublets, doublet of triplets and multiplet respective1 ly. All H NMR chemical shifts were referenced to SiMe4 as an 13 internal standard (0.00 ppm). All C NMR chemical shifts in CDCl3 were referenced to the residual solvent peak at 77.00 13 ppm. All C NMR chemical shifts in (CD3)2SO were referenced to the residual solvent peak at 39.52 ppm. All coupling constants, J, are quoted in Hz. Infra-red spectra were record-



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ed on a Nexus FT-IR spectrometer with Nicolet OMNI sampler using a neat sample. Melting points were obtained using a DSC 1 STARe system and high resolution mass spectrometry (HRMS) data were recorded under electrospray ionisation conditions. High performance liquid chromatography (HPLC) purification was achieved using Gilson 333/334 pumps, a Gilson 155 dual wavelength detector and a Gilson 215 autosampler with 819-injection module, where fractionation was triggered by slope of UV response. Microwave experiments were carried out using sealed vessels in a Biotage Initiator Sixty microwave reactor operating at 2.45 GHz with stirring at 600 rpm and variable power output (0-400 W), sensing temperature with an IR sensor to measure the temperature of the external surface of the glass vial. Pressure was recorded by the cavity lid, which resisted the deformation of the vial cap as pressure increased. Reactions reached their target temperature within 1 minute and cooled back to room temperature within 3 minutes upon completion. Synthesis of compounds prepared in Figure 4. 4-Morpholinobenzenesulfonamide (11). A 20 mL microwave vial equipped with a stirrer bar was charged with 4bromobenzenesulfonamide (500 mg, 2.05 mmol), PdPEPPSI-IPent (51 mg, 3 mol%) and cesium carbonate (1.34 g, 4.11 mmol). The vial was sealed and purged with 3x vacuum/nitrogen cycles. 1,4-dioxane (4 mL) and morpholine (250 µl, 2.87 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 100 °C and stirred at this temperature for 24 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a plug of silica. The silica plug was rinsed with EtOAc, the organic filtrates combined and concentrated in vacuo. Purification by column chromatography (gradient elution 0-90% EtOAc in Heptane) yielded the desired product 11 as a yellowish white solid (Run 1 = 402 mg, 1 81% yield; Run 2 = 394 mg, 79%). m.p. 213 – 216 °C; H NMR (400 MHz, DMSO): 7.63 (d, J= 9.0 Hz, 2H), 7.06-7.02 (m, 13 4H), 3.75-3.72 (m, 4H), 3.24-3.21 (m, 4H). C NMR (100 MHz, -1 DMSO): 153.5, 133.8, 127.5, 114.0, 66.3, 47.7. IR (neat, cm ): 3186, 2962, 2862, 1593. HRMS (ESI) m/z: [M+] calcd for C10H14N2O3S 242.0725 found 242.0731. N-Methyl-2-morpholino-benzenesulfonamide (12). A 20 mL microwave vial equipped with a stirrer bar was charged with 2-bromo-N-methylbenzenesulfonamide (500 mg, 1.96 mmol) and Pd-PEPPSI-IPent (50 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 7 mL, 7 mmol) and morpholine (240 µl, 2.75 mmol) were then added via a syringe and the vial purged with a further 2 x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 18 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-5% methanol in DCM), yielding the desired product 12 as a white solid (Run 1 = 480 mg, 96% yield; Run 2 = 438 mg, 87%). m.p. 174 – 177 1 °C; H NMR (400 MHz, CDCl3): 8.03 (dd, J= 1.6, 7.8 Hz, 1H), 7.61 (td, J= 7.8, 1.6 Hz, 1H), 7.42 (dd, J= 1.0, 8.0 Hz, 1H), 7.35 (td, J= 7.6, 1.0 Hz, 1H), 5.86 (d, J= 5.1 Hz, 1H), 3.88 (d, J= 3.9 13 Hz, 4H), 3.07-3.05 (m, 4H), 2.52 (d, J= 5.7 Hz, 3H). C NMR (100 MHz, CDCl3): 150.3, 134.4, 134.0, 130.7, 126.0, 123.4, 67.7, -1 54.2, 29.8. IR (neat, cm ): 3337, 3097, 2964, 1587. HRMS (ESI) m/z: [M+] calcd for C11H16N2O3S 256.0882 found 256.0887.

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N-(4-Morpholinophenyl)methanesulfonamide (13). A 20 mL microwave vial equipped with a stirrer bar was charged with N-(4-bromophenyl)methanesulfonamide (400 mg, 1.58 mmol) and Pd-PEPPSI-IPent (39 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 5.5 mL, 5.5 mmol) and morpholine (200 µl, 2.29 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The mixture was then stirred at 30 °C for 66 h. After adsorbing the reaction mixture onto silica, purification by column chromatography (gradient elution 0-10% MeOH in DCM) yielded the desired product 13 as a yellow solid (Run 1 = 399 mg, 99% yield; Run 1 2 = 398 mg, 99%). m.p. 184 – 188 °C; H NMR (400 MHz, DMSO): 9.25 (s, 1H), 7.11-7.08 (m, 2H), 6.94-6.91 (m, 2H), 13 3.73-3.71 (m, 4H), 3.06-3.04 (m, 4H), 2.86 (s, 3H). C NMR (100 MHz, MeOD): 149.4, 130.0, 123.4, 116.3, 66.5, 49.5, 37.3. IR -1 (neat, cm ): 3227, 2970, 2819, 2361, 1738, 1512. HRMS (ESI) m/z: [M+] calcd for C11H16N2O3S 256.0882 found 256.0884. N,N-Dimethyl-2-morpholino-benzenesulfonamide (14). A 20 mL microwave vial equipped with a stirrer bar was charged with 2-bromo-N,N-dimethylbenzenesulfonamide (500 mg, 1.86 mmol) and Pd-PEPPSI-IPent (46 mg, 3 mol%). The vial was sealed and purged with 3 x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 6.5 mL, 6.5 mmol) and morpholine (230 µl, 2.64 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 6 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica gel and purified by column chromatography (gradient elution 0-50% EtOAc in heptane) to afford the desired product 14 as a yellow solid (Run 1 = 397 mg, 79% yield; Run 2 = 393 1 mg, 78%). m.p. 113 – 115 °C; H NMR (400 MHz, DMSO): 7.82 (dd, J= 1.6, 8.0 Hz, 1H), 7.68-7.64 (m, 1H), 7.53 (dd, J= 1.0, 8.0 Hz, 1H), 7.36-7.32 (m, 1H), 3.73-3.71 (m, 4H), 2.96-2.93 (m, 13 4H), 2.70 (s, 6H). C NMR (100 MHz, CDCl3): 152.5, 133.8, -1 132.9, 132.2, 124.8, 123.1, 67.0, 54.4, 38.2. IR (neat, cm ): 3072, 2860, 1732, 1585. HRMS (ESI) m/z: [M+] calcd for C12H18N2O3S 270.1038 found 270.1038. N-(2-Morpholinophenyl)methanesulfonamide (16). A 20 mL microwave vial equipped with a stirrer bar was charged with N-(2-bromophenyl)methanesulfonamide (611 mg, 2.52 mmol) and Pd-PEPPSI-IPent (61 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.5 mL, 8.5 mmol) and morpholine (300 µl, 3.79 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 24 h. After cooling to room temperature, the mixture was treated with 2N HCl (8 mL) and stirred for 5 min, then neutralized with sat. aq. sodium bicarbonate (15 mL) and diluted with 2-MeTHF (50 mL). The layers were separated and the organic layer evaporated to dryness. The residue was dissolved in MeOH and purified on an SCX-2 column, eluting first with MeOH (5 column volumes) then 3.5N NH3 in MeOH (5 column volumes). The basic fraction was evaporated to dryness. Purified by preparative HPLC (Phenomenex Gemini 5 Micron 30*100mm C-18 column, 30% to 100% MeCN in ammonium hydroxide solution, over 9 minutes at 60 mL/min, detection at 220 nm) to afford the desired product 20 as a yellow oil (Run 1 = 127 mg, 20 % yield; 1 Run 2 = 146 mg, 21%). H NMR (400 MHz, CDCl3): 7.23 (t, J = 8.0 Hz, 1H), 6.81 (dd, J = 1.8, 2.1 Hz, 1H), 6.72 (dd, J = 2.1, 8.5,


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1H), 6.67 (dd, J = 1.8, 8.0, 1H), 3.88-3.83 (m, 4H), 3.19-3.15 (m, 13 4H), 3.00 (s, 3H). C NMR (100 MHz, CDCl3): 152.4, 137.4, -1 130.3, 112.3, 111.7. 107.7, 66.8, 48.8, 39.2. IR (neat, cm ): 1603, 1585, 1502, 1475, 1450, 1325, 1267, 1147, 1117, 987, 771. ES/MS: m/z 257.0 (M+H). N-Benzyl-1H-indol-5-amine (18). A 20 mL microwave vial equipped with a stirrer bar was charged with 5-bromoindole (500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and benzylamine (308 µl, 2.80 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 42 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-40% EtOAc in heptane), yielding the desired product 18 as a green solid (Run 1 = 543 mg, 97 % yield; Run 2 = 535 1 mg, 95%). m.p. 102 – 106 °C; H NMR (400 MHz, CDCl3): 7.90 (s, 1H), 7.42 (d, J= 7.4 Hz, 2H), 7.35-7.32 (m, 2H), 7.28-7.24 (m, 1H), 7.19 (d, J= 8.6 Hz, 1H), 7.09 (t, J= 2.8 Hz, 1H), 6.87 (d, J= 2.3 Hz, 1H), 6.65 (dd, J= 2.2, 8.7 Hz, 1H), 6.38-6.37 (m, 1H), 13 4.36 (s, 2H), 3.81 (s, 1H). C NMR (100 MHz, CDCl3): 142.4, 140.1, 130.6, 128.8, 128.6, 127.7, 127.1, 124.4, 112.1, 111.6, 102.3, -1 101.9, 49.7. IR (neat, cm ): 3360, 3147, 2839, 1687, 1618, 1584. HRMS (ESI) m/z: [M+] calcd for C15H14N2 222.1157 found 222.1163. 4-(1H-Indol-5-yl)morpholine (19). A 20 mL microwave vial equipped with a stirrer bar was charged with 5-bromoindole (500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and morpholine (308 µl, 3.53 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The reaction was stirred at room temperature for 72 h. After adsorbing the reaction mixture onto silica, purification by column chromatography (gradient elution 0-50% EtOAc in heptane) yielded the desired product 19 as a brick-red solid (Run 1 = 479 mg, 89% yield; Run 2 = 443 mg, 82%). 1 m.p. 132 – 135 °C; H NMR (400 MHz, CDCl3): 8.09 (s, 1H), 7.30-7.24 (m, 1H), 7.16-7.14 (m, 2H), 6.95 (dd, J= 2.3, 8.8 Hz, 1H), 6.47-6.46 (m, 1H), 3.91-3.89 (m, 4H), 3.14-3.12 (m, 4H). 13 C NMR (100 MHz, CDCl3): 145.9, 131.5, 128.4, 124.7, 115.3, 111.6, 107.5, 102.4, 67.3, 52.0. This data matched previously reported 19b data. N-Methyl-N-phenyl-1H-indol-5-amine (20). A 20 mL microwave vial equipped with a stirrer bar was charged with 5bromoindole (500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and N-methylaniline (670 µl, 6.12 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 24 h. After cooling to room temperature, the solvent was removed in vacuo and the reaction mixture dissolved in MeOH. A 10 g SCX-2 column was used to remove any of the 5-bromoindole starting material. The crude product was then adsorbed onto silica and purified by column chromatography (gradient elution 0-40% EtOAc in heptane), yielding the desired product 20 as a yellow oil (Run 1 = 337 mg, 60 % 1 yield; Run 2 = 373 mg, 66%). H NMR (400 MHz, CDCl3): 8.20-8.07 (m, 1H), 7.46 (d, J= 2.0 Hz, 1H), 7.38 (d, J= 8.6 Hz,

1H), 7.23-7.17 (m, 3H), 7.04 (dd, J= 2.0, 8.6 Hz, 1H), 6.77-6.71 13 (m, 3H), 6.52-6.51 (m, 1H), 3.33 (s, 3H). C NMR (100 MHz, CDCl3): 150.4, 142.0, 133.5, 128.8, 124.9, 121.5, 118.0, 117.4, 114.7, -1 111.9, 111.9, 102.8, 40.9. IR (neat, cm ): 3404, 2870, 1738, 1595. HRMS (ESI) m/z: [M+] calcd for C15H14N2 222.1157 found 222.1160. 4-(1H-Indol-7-yl)morpholine (21). A 20 mL microwave vial equipped with a stirrer bar was charged with 7-bromoindole (500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and morpholine (308 µl, 3.53 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The reaction was stirred at room temperature for 18 h. After adsorbing the reaction mixture onto silica, purification by column chromatography (gradient elution 0-30% EtOAc in heptane) yielded the desired product 21 as a yellow solid (Run 1 = 502 mg, 98% yield; Run 2 = 489 mg, 96%). m.p. 143 – 1 145 °C; H NMR (400 MHz, CDCl3): 8.25 (br s, 1H), 7.40 (d, J= 7.8 Hz, 1H), 7.20-7.19 (m, 1H), 7.08 (t, J= 7.7 Hz, 1H), 6.86 (d, J= 7.0 Hz, 1H), 6.56 (dd, J= 2.1, 3.1 Hz, 1H), 3.94-3.92 (m, 4H), 13 3.13-3.10 (m, 4H). C NMR (100 MHz, CDCl3): 137.9, 130.6, -1 129.0, 123.7, 120.4, 116.5, 110.8, 103.5, 67.5, 52.1. IR (neat, cm ): 3319, 2959, 2816, 2360, 1726, 1581. HRMS (ESI) m/z: [M+] calcd for C12H14N2O 202.1106 found 202.1111. 2-Phenyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (22). A 20 mL microwave vial equipped with a stirrer bar was charged with 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 2.84 mmol) and Pd-PEPPSI-IPent (71 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 10 mL, 10 mmol) and bromobenzene (303 µL, 2.85 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 17 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica gel and purified by column chromatography (gradient elution 0-50% EtOAc in heptane), yielding the desired product 22 as a yellow solid (Run 1 = 663 mg, 94% yield; Run 2 = 638 1 mg, 90%). m.p. 179 – 182 °C; H NMR (400 MHz, CDCl3): 7.78 (s, 1H), 7.50 (d, J= 7.8 Hz, 1H), 7.32-7.25 (m, 3H), 7.17-7.09 (m, 2H), 7.03-7.01 (m, 2H), 6.86 (t, J= 7.3 Hz, 1H), 4.41 (s, 2H), 13 3.69-3.66 (m, 2H), 2.93-2.90 (m, 2H). C NMR (100 MHz, CDCl3): 150.8, 136.1, 131.4, 129.2, 127.2, 121.6, 119.6, 119.4, 118.1, 116.2, 110.8, 109.3, 48.0, 46.6, 21.4. This data matched previ20 ously reported data. N-(4-Morpholinophenyl)acetamide (23). A 20 mL microwave vial equipped with a stirrer bar was charged with 4bromoacetanilide (500 mg, 2.29 mmol) and Pd-PEPPSI-IPent (57 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8 mL, 8.0 mmol) and morpholine (280 µl, 3.21 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 16 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-100% EtOAc in Heptane), yielding the desired product 23 as a white solid (Run 1 = 480 mg, 86% 1 yield; Run 2 = 487 mg, 87%). m.p. 209 – 211 °C; H NMR (400 MHz, CDCl3): 7.40-7.36 (m, 2H), 7.15-7.05 (m, 1H), 6.89-6.86 13 (m, 2H), 3.87-3.84 (m, 4H), 3.12-3.10 (m, 4H), 2.15 (s, 3H). C



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NMR (100 MHz, CDCl3): 168.1, 148.3, 130.6, 121.526, 116.3, 66.9, 19d 49.8, 24.4. This matched previously reported data. N-(2-Morpholinophenyl)acetamide (24). A 5 mL microwave vial equipped with a stirrer bar was charged with 2bromoacetanilide (100 mg, 0.448 mmol), Pd-PEPPSI-IPent (11 mg, 3 mol%) and cesium carbonate (293 mg, 0.898 mmol). The vial was sealed and purged with 3x vacuum/nitrogen cycles. 1,4-dioxane (0.9 mL)and morpholine (55 µl, 0.631 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 100 °C and stirred at this temperature for 20 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a plug of silica. The silica plug was rinsed with EtOAc, the organic filtrates combined and concentrated in vacuo. Purification by column chromatography (gradient elution 0-60% EtOAc in Heptane) yielded the desired product 24 as a white solid (Run 1 = 76 mg, 69% yield; Run 2 = 81 1 mg, 74%). m.p. 86 – 88 °C. H NMR (400 MHz, CDCl3): 8.48 (s, 1H), 8.35 (d, J= 7.8 Hz, 1H), 7.17-7.14 (m, 2H), 7.09-7.05 (m, 13 1H), 3.88-3.86 (m, 4H), 2.88-2.86 (m, 4H), 2.21 (s, 3H). C NMR (100 MHz, CDCl3): 168.0, 140.6, 133.5, 125.8, 123.8, 120.5, -1 119.6, 67.6, 52.6, 25.0. IR (neat, cm ): 3343, 2964, 2845, 2360, 1739, 1674, 1587. HRMS (ESI) m/z: [M+] calcd for C12H16N2O2 220.1212 found 220.1217. 4-Morpholinobenzamide (25). A 20 mL microwave vial equipped with a stirrer bar was charged with 4bromobenzamide (500 mg, 2.42 mmol) and Pd-PEPPSI-IPent (61 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.5 mL, 8.5 mmol) and morpholine (300 µl, 3.44 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 16 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-10% methanol in DCM), yielding the desired product 25 as a white solid (Run 1 = 420 mg, 84% 1 yield; Run 2 = 457 mg, 91%). m.p. 216 – 220 °C; H NMR (400 MHz, DMSO): 7.77-7.70 (m, 3H), 7.02-6.93 (m, 3H), 3.74-3.72 13 (m, 4H), 3.21-3.19 (m, 4H). C NMR (100 MHz, DMSO): 168.1, 153.4, 129.3, 124.4, 113.8, 66.4, 47.9. This matched previously 21 reported data. 2-Morpholinobenzamide (26). A 20 mL microwave vial equipped with a stirrer bar was charged with 2bromobenzamide (500 mg, 2.42 mmol) and Pd-PEPPSI-IPent (61 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8.6 mL, 8.6 mmol) and morpholine (300 µl, 3.44 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 72 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-10% methanol in DCM), yielding the desired product 26 as a yellow solid (Run 1 = 415 mg, 82% 1 yield; Run 2 = 403 mg, 80%). m.p. 117 – 121 °C; H NMR (400 MHz, DMSO): 8.37 (s, 1H), 7.68 (dd, J= 1.6, 7.6 Hz, 1H), 7.507.41 (m, 2H), 7.18-7.10 (m, 2H), 3.76-3.73 (m, 4H), 2.94-2.91 13 (m, 4H). C NMR (100 MHz, DMSO): 168.9, 151.1, 131.9, 130.7, 129.5, 123.5, 119.7, 66.8, 53.1. This matched previously reported 22 data.

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N-Methyl-2-morphilino-benzamide (27). A 20 mL microwave vial equipped with a stirrer bar was charged with 2-bromo-Nmethylbenzamide (500 mg, 2.29 mmol) and Pd-PEPPSI-IPent (57 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8 mL, 8 mmol) and morpholine (280 µl, 3.21 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 21 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-5% methanol in DCM), yielding the desired product 27 as a white solid (Run 1 = 433 mg, 86% 1 yield; Run 2 = 430 mg, 85% yield). m.p. 99 - 102 °C; H NMR (400 MHz, CDCl3): 9.38 (s, 1H), 8.14 (dd, J= 1.8, 7.8 Hz, 1H), 7.44 (td, J= 7.7, 1.7 Hz, 1H), 7.27-7.16 (m, 2H), 3.87-3.85 (m, 13 4H), 3.03-2.99 (m, 7H). C NMR (100 MHz, CDCl3): 167.2, 150.5, 132.0, 131.7, 128.0, 124.9, 119.8, 67.5, 53.4, 26.0. IR (neat, -1 cm ): 3283, 2999, 2361, 1649, 1593, 1548. HRMS (ESI) m/z: [M+] calcd for C12H16N2O2 220.1212 found 220.1206. 4-Phenyl-1,3-dihydroquinoxalin-2-one (28). A 20 mL microwave vial equipped with a stirrer bar was charged with 3,4dihydro-1H-quinoxalin-2-one (500 mg, 3.21 mmol) and PdPEPPSI-IPent (80 mg, 3 mol%). The vial was sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in THF, 11 mL, 11 mmol) and bromobenzene (341 µL, 3.20 mmol) were then added via a syringe and the vial purged with a further 2x vacuum/nitrogen cycles. The vial was placed in a pre-heated aluminium block at 60 °C and stirred at this temperature for 17 h. After cooling to room temperature, the reaction mixture was adsorbed onto silica and purified by column chromatography (gradient elution 0-70% EtOAc in heptane), yielding the desired product 28 as a white solid (Run 1 = 654 mg, 91% yield; Run 2 = 623 mg, 87%). m.p. 180 – 1 184 °C; H NMR (400 MHz, CDCl3): 8.51-8.44 (m, 1H), 7.407.36 (m, 2H), 7.21-7.12 (m, 3H), 6.95-6.89 (m, 4H), 4.28 (s, 13 2H). C NMR (100 MHz, CDCl3): 167.2, 144.4, 133.5, 129.5, -1 127.3, 124.0, 123.8, 122.2, 121.0, 116.2, 116.0, 52.5. IR (neat, cm ): 3337, 3032, 2908, 2332, 1739, 1668, 1589. HRMS (ESI) m/z: [M+] calcd for C14H12N2O 224.0950 found 224.0949.

ASSOCIATED CONTENT Supporting Information. Materials, general methods, HTS data and broader analysis, experimental procedures, analytical data, literature analysis. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * [email protected].

ACKNOWLEDGMENT Funding (EL) was provided by EPSRC UCL IAA allocation. Thanks to Iván Collado and Magnus Walter for support of the program, Stephanos Ghilagaber, Jason Howe and Giovanni Giuliano for synthesis of compounds B3, B5-B13 and Lewis Vidler and David Evans for helpful discussions around data analysis.

REFERENCES


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