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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Bis(pinacolato)diborane is used as a biomaterial or organic compound in life science-related research.
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Discovery of a selective α2C-AR scaffold from a molecular hybridization approach
Patra, Sandip ; Namballa, Hari K ; Gudipally, Ashok R ; Xie, Li ; Xie, Lei ; Harding, Wayne W
Abstract: We undertook the rational design and synthesis of a novel series of ligands intended to function as selective dual dopamine D1 receptor (D1R) partial agonists and D3 receptor (D3R) antagonists. The molecular architecture of these compounds was derived by integrating key pharmacophoric features from established D1R partial agonists and D3R antagonists. Specifically, the 6-(2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione scaffold was employed as the core “tail” region associated with D1R partial agonism, while various substituted phenyl piperazine moieties were introduced as “head” groups to confer D3R antagonistic activity. A pyridine ring was utilized as a central linker across the series. Contrary to the intended dopaminergic profile, these compounds exhibited markedly higher binding affinities for α2-adrenergic receptors (α2-ARs) relative to their activity at dopamine receptor subtypes. Several analogues demonstrated potent α2C-AR binding affinities in the low nanomolar range (Ki = 7-30 nM), with moderate selectivity (up to 17-fold) over other α2-AR subtypes. Notably, compounds bearing ortho-substituted aryl groups within the “head” domain generally displayed enhanced α2C-AR binding compared to their para-substituted counterparts. Molecular docking studies conducted at both α2A-AR and α2C-AR suggested that multiple receptor-ligand interactions contribute to the observed binding profiles. In particular, an anion–pi interaction between Asp131 of α2C-AR and the phenyl ring of the phenyl piperazine “head” moiety was identified as a possible determinant of the increased α2C-AR affinity observed in ortho-substituted analogues. Given the therapeutic potential of selective α2C-AR targeting in treating various disorders, coupled with the limited availability of clinically approved selective α2C-AR ligands, the discovery of this new scaffold offers new prospects for drug discovery targeting α2C-ARs.
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Keywords: Adrenergic ; α2C ; α2A ; D1R ; D3R ; Hybridization ; AlphaFold3 ; AutoDock
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Exploration of Novel CH Functionalization Methodologies via Organic Photoredox Catalysis
Boley, Alexander Joseph ;
Abstract: The selective and facile functionalization of C-H bonds - the most abundant bonds in all chemical space - remains a key driving factor for innovation in modern chemistry. Chapter 1 provides an overview of C-H functionalization research and its importance; discussion of C-H functionalization necessitates an analysis of subjects such as organometallic chemistry, radical generation and functionalization, and the synthetic benefits and challenges presented therein. Intersecting with discussion of C-H functionalization and radical chemistry, photoredox catalysis has played a major role in modern C-H functionalization methodologies, and as such is discussed in detail. Distinct and impactful C-H functionalization works from the Nicewicz lab are explored, providing a basis for the exploratory photoredox catalysis chemistry discussed in subsequent chapters. Chapter 2 explores attempts at generating and functionalizing azaallyl radical species via organic photoredox catalysis. Using the extreme oxidizing power of acridinium photoredox catalysts for novel modes of C-H functionalization circumvents the typically harsh conditions needed for azaallyl radical formation. While methods for α-amino functionalization are abundant, azaallyl radicals are uniquely long-lived, allowing for radical cascade and cyclization reactivity. While some success was afforded C-H functionalization with typical radical traps, control of the reactivity remains tenuous and the desired cascade-like cyclization remains elusive. Chapter 3 details a completed C-H functionalization methodology for the programmable synthesis of decorated piperazine cores via organic photoredox catalysis. The synthetic and medicinal importance piperazines is highlighted, as are the typical shortcomings of both traditional and state-of-the-art approaches for their synthesis. Optimization and scope of the cyclization reaction are explored in depth, and a complementary hydroamination strategy for the synthesis of complex diamine backbones from enecarbamates via organic photoredox catalysis is demonstrated. Chapter 4 serves as a conceptual successor to the piperazine methodology, establishing the foundation of a synthetic approach for an organic photoredox-catalyzed morpholine synthesis via a C-H functionalization strategy. Initial optimization of the desired reactivity is detailed in full, exploring somewhat divergent results based on seemingly innocuous changes to the reaction system. While the yield in either iteration of the model system remains low, significant options for future optimization remain in terms of catalyst choice and substrate design.
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Catalytic asymmetric synthesis of meta benzene isosteres
Zhang, Mingkai ; Chapman, Matthew ; Sarode, Bhagyesh R ; Xiong, Bingcong ; Liang, Hao ; Chen, James K , et al.
Abstract: Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical confguration of the isosteric replacements may ofer an added opportunity to improve the afnity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for metadisubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scafold, will render this platform a useful foundation for the assembly of new biologically active agents.
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Synthetic Elaboration of β-Carbonyl Alkylboronic Esters
Hamilton, Mason D ;
Abstract: Organoboron compounds are some of the most synthetically versatile compounds in organic chemistry due to the many valuable transformations of the C-B bond. This synthetic versatility combined with the pharmacophoric nature of carboxylic acids has led to an increased interest in the one-pot difunctionalization of vinyl arenes using CO2 and pinacol boranes. Recently, much progress has been made to improve the scope and versatility of boracarboxylation reactions to now include electron-deficient and α-methyl substituted vinyl arenes. However, the potential transformations of boracarboxylated products have remained unexplored. Here, methodologies to transform the β-aryl alkylboronic ester into new C-C, C-N, and C-X bonds will be described. Medically relevant 2,3-diarylpropionic acids can now be accessed via a two-step protocol consisting of boracarboxylation of a vinyl arene followed by a palladium(0)-catalyzed Suzuki cross-coupling. This methodology provides access to both the α- and β-regioisomers independently whereas traditional strategies to access these compounds afford only one regioisomer, and in most cases, a mixture of regioisomers. Interesting biaryl and heterocyclic products can be accessed and to demonstrate the synthetic utility of this protocol, a glucagon receptor antagonist was synthesized in 4 less steps than the previously reported method while maintaining similar yields. The transformative capability of boracarboxylated products is further demonstrated through a base-_x005f_x0002_and external oxidant-free copper(II)-catalyzed amination to generate β2-amino acid derivatives. While the β-carboxylic acid was intolerable to the conditions, protection via esterification or amidation allowed for successful amination of the alkylboronic ester to occur. Amination of two bora-NSAIDs, bora-ibuprofen and bora-naproxen, was successful and a number of cyclic and acyclic amines are suitable for the transformation. Preliminary mechanistic work suggests that this amination does not proceed through a free-radical intermediate but rather a two-electron pathway. Finally, a novel halogenation of boracarboxylated products is achieved to generate the corresponding β-aryl alkyl halides. This methodology is performed in a base, metal, and additive free manner that utilizes cheap and readily available sources of electrophilic halide. Both bromination and iodination are demonstrated and can be achieved on a variety of electron-rich and electron-poor boracarboxylated products and can subsequently undergo amination to provide an alternative route to β2-amino acid derivatives. Mechanistic experiments suggest that the β-carboxylic acid is required to achieve the activation of the C-B bond. Radical trapping experiments also indicate that this transformation may occur through the formation of an alkyl radical although this is unlikely.
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Keywords: Boracarboxylation ; alkylboronic ester ; Suzuki cross-coupling ; oxidative amination ; 2,3-diarylpropionic acid ; β2-amino acid
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PROTACs Targeting MLKL Protect Cells from Necroptosis
Rathje, Oliver H. ; Perryman, Lara ; Payne, Richard J. ; Hamprecht, Dieter W. ;
Abstract: Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chem. means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC mol. that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quant. relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.
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Purchased from AmBeed: 30100-16-4 ; 4530-20-5 ; 1703808-53-0 ; 2840-26-8 ; 234081-98-2 ; 108466-89-3 ; 138563-68-5 ; 1005342-46-0 ; 154775-43-6 ; 214360-73-3 ; 31108-57-3 ; 57294-38-9 ; 234081-98-2 ; 73183-34-3 ; 462100-06-7 ; 187389-52-2 ; 191732-72-6 ; 173405-78-2 ; 154590-35-9 ; 6404-29-1 ; 1807518-63-3 ; 62595-74-8 ; 77383-17-6 ; 1310949-97-3 ; 138563-69-6 ; 2704620-74-4 ; 2284453-73-0 ; 191732-72-6 ; 181073-79-0
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| CAS No. : | 73183-34-3 |
| Formula : | C12H24B2O4 |
| M.W : | 253.94 |
| SMILES Code : | CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1 |
| MDL No. : | MFCD00799570 |
| InChI Key : | IPWKHHSGDUIRAH-UHFFFAOYSA-N |
| Pubchem ID : | 2733548 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H315-H319-H335 |
| Precautionary Statements: | P261-P264-P271-P280-P302+P352-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 45% | With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine In hexane at 20℃; for 16 h; | Example 2 illustrates the sp2-carbon borylation and hydrogenation of a furan substrate to form a corresponding 2-substituted sp3-carbon borylated tetrahydrofuran. Scheme 12 illustrates sp2-carbon borylation of furan with an iridium-based catalyst ([IrOMe(cod)]2 and dtbpy) in hexane (rt for 16 h). The sp2-carbon borylated product is hydrogenated using hydrogen with a rhodium-based catalyst (Rh/Al2O3) in ethanol (rt for 15 h) to form the corresponding hydrogenated, 2-substituted sp3-carbon borylated tetrahydrofuran product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With iron(III)-acetylacetonate; magnesium In tetrahydrofuran at 0℃; for 3 h; Inert atmosphere | Example 7: In the condition of adding magnesium turnings in situ,The boron esterification of ortho-fluorobenzyl chloride and bis-boronic acid pinacol ester catalyzed by Fe(acac)3 was followed by the addition of the catalyst (3.5 mg, 0.010 mmol, 2 molpercent) under argon atmosphere.Bis(pinacolato)boronic acid ester (127.0 mg, 0.5 mmol),Magnesium turnings (16.8 mg, 0.7 mmol), tetrahydrofuran (1 mL),After addition of o-fluorobenzyl chloride (160 μl, 1.35 mmol) at 0°C,The reaction was carried out for 3 hours, and the reaction was terminated with the addition of water. The reaction product was extracted with ethyl acetate and the yield was 82percent as calculated by gas chromatography. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 23% | With copper(l) iodide; lithium methanolate; triphenylphosphine In N,N-dimethyl-formamide at 20℃; for 14 h; Inert atmosphere | 2-Fluorobenzyl bromide (3000 mg, 15 mmol), boronic acid pinacol ester (6000 mg, 24 mmol),CuI (320 mg, 1.5 mmol), LiOMe (1200 mg, 32 mmol), PPh3 (540 mg, 2 mmol) and DMF (50 mL) were placed in a 250 mL reaction flask and replaced with nitrogen three times and then reacted for 14 h at room temperature. The reaction solution was poured into 200 mL of water, and the CuI was removed by filtration and washed three times with EA. The filtrate was collected and separated, and the aqueous extracted with EA (150 mL×3). After concentrating the EA layer, the title compound 52b (980 mg, 23percent) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel In 1,4-dioxane at 100℃; for 12 h; Inert atmosphere; Sealed tube | Under an argon atmosphere,To the reaction vessel, 1.4 mg (0.005 mmol) of dichlorobis (trimethylphosphine) nickel,77.4 mg (0.5 mmol) of 4-chlorobenzamide,152 mg (1.0 mmol) of cesium fluoride,140 mg (0.55 mmol) of 4,4,5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl)180 mg (1.05 mmol) of trimethyl (2,2,2-trifluoroethoxy) silane and 0.5 mL of 1,4-dioxane were added and sealed,And the mixture was stirred at 100 ° C. for 12 hours.After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined.The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 4: 1: 0 to 4: 1: 1)92 mg (white solid, yield 75percent) of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide was obtained. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 79% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 95℃; | A mixture of 2-70 (1.0 g, 5 mmol), (PinB)2 (2.28 g, 9 mmol), Pd(dppf)C12DCM (408 mg, 0.5 mmol), KOAc (980 mg, 10 mmol) and dioxane (5 mL) was degassed with N2 and stirred at 95 °C overnight. The resulting mixture was filtered and the filtrate was concentrated and purified via column chromatography on silica gel eluting with DCM/MeOH from 20/1 to 10/1 to give intermediate 2-71 (yellow solid, 975 mg, 79percent yield). LCMS (m/z):248 [M+Hj . |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 74% | With potassium acetate In 1,4-dioxane for 8.33333 h; Inert atmosphere | A mixture of 5-bromo-4-methylpyrimidine-2-ylamine (5.0g, 26 mmol), potassium acetate (7.83g, 79.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2- dioxaborolane (7.43 g, 29.2 mmol) in dioxane (140 mL) was stirred for 20 min under nitrogen. 1, 1 '-bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane adduct (1.08 g, 1.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 115 °C for 18 h under nitrogen. Upon completion, the mixture was cooled and EtOAc was added. The resulting mixture was sonicated and filtered. Additional EtOAc was used to wash the solid. The combined organic extracts were washed with water, dried over MgS04, filtered and concentrated. The crude was purified by chromatography eluting with 20-100percent EtO Ac/hex ane to yield 4.5 g of 4-methyl-5-(4,4,5,5-tetramethyl (l,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine (yield: 74percent). 1H-NMR (DMSO, 400 MHz): δ 8.28 (s, 1H), 6.86 (br s, 2H), 2.35 (s, 3 H), 1.25 (s, 12 H). MS (ESI) m/e (M+H+) 236.15, 154.07. |
| 74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 115℃; for 18 h; Inert atmosphere | A mixture of 5-bromo-4-methylpyrimidine-2-ylamine (5.0 g, 26 mmol), potassium acetate (7.83 g, 79.8mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.43 g,29.2 mmol) in dioxane (140 mL) was stirred for 20 min under nitrogen. 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane adduct (1.08 g, 1.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 115° C. for 18 h under nitrogen. Upon completion, the mixture was cooled and EtOAc was added. The resulting mixture was sonicated and filtered. Additional EtOAc was used to wash the solid. The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated. The crude was purified by chromatography eluting with 20~100percent EtOAc/hexane to yield 4.5 g of 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine 26 (yield: 74percent). 1H-NMR (DMSO, 400 MHz): δ 8.28 (s, 1H), 6.86 (br s, 2H), 2.35 (s, 3H), 1.25 (s, 12H). MS (ESI) m/e (M+H+) 236.15, 154.07. |
| 74% | With potassium acetate In 1,4-dioxane at 115℃; for 18 h; Inert atmosphere | A mixture of 5-bromo-4-methylpyrimidine-2-ylamine (5.Og, 26 mmol ), potassium acetate (7.83g, 79.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- 1,3,2-dioxaborolane (7.43 g, 29.2 mmol) in dioxane (140 mL) was stirred for 20 min under nitrogen. 1, l'-bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane adduct (1.08 g, 1.33 mmol) was added to the reaction mixture. The reaction mixture was heated to 115 ° C for 18 h under nitrogen. Upon completion, the mixture was cooled and EtOAc was added. The resulting mixture was sonicated and filtered. Additional EtOAc was used to wash the solid. The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated. The crude was purified by chromatography eluting with 20-100percent EtOAc/hexane to yield 4.5 g of 42 (yield: 74percent). 1H-NMR (DMSO, <n="71"/>400 MHz): δ 8.28 (s, IH), 6.86 (br s, 2H), 2.35 (s, 3 H), 1.25 (s, 12 H). MS (ESI) m/e (M+H+) 236.15, 154.07. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 50% | With potassium acetate In dimethyl sulfoxide at 20 - 80℃; | To a solution of compound 4-bromo-l -phenyl- lH-pyrazo Ie (0.5 g, 2.3 mmol) in DMSO (50 mL) was added KOAc (0.66 g, 6.8 mmol), bis(pinacolato)diboron (0.63 g, 2.5 mmol) and .yen.dCb(dpp{) (0.076g, 0.11 mmol) at room temperature. The reaction mixture was stirred overnight at 8O0C. The result mixture was diluted with EA, washed with brine, dried over Na2SO4, concentrated, purified by chromatography (EA:PE=1: 12) to give l-phenyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- pyrazole (0.3 g, 50percent) as light yellow solid |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 48.15% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 8 h; Inert atmosphere | A mixture of 4-iodo-1-phenyl-1H-pyrazole (706 mg, 2.59 mmol) , potassium acetate (762 mg, 7.76 mmol) , bis (pinacolato) diboron (860 mg, 3.37 mmol) and Pd (dppf) Cl2(212 mg, 0.26 mmol) was suspended in DMSO (15 mL) . The system was exchanged with N2. The mixture was stirred at 80 for 8 h. The reaction mixture was diluted with water (60 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 20/1 to give a yellow solid product (340 mg, 48.15) .[1650]MS (ESI, pos. ion) m/z: 271.05 [M+1]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | With tris-(dibenzylideneacetone)dipalladium(0); sodium acetate; tricyclohexylphosphine In 1,4-dioxane at 115 - 120℃; for 24 h; | 20.0 g of compound vii (0.102 mol), 38.7 g of bis(pinacolato)diboron (0.152 mol), 2.85 g of tricyclohexyl phosphine (0.010 mol), 4.65 g of tris(dibenzylideneacetone)dipalladium (0.005 mol) and 25.0 sodium acetate were added to 200ml 1,4-dioxane, heated to 115 ~ 120 , incubation reaction 24h, cooling to room temperature, adding purified water 200ml. Extracted twice with 200 ml of ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a reddish brown solid. The solid was added to 30 ml of t-butyl methyl ether, stirred for 2 h. A yellowish solid, i.e. 9-azoindole-5-boronic acid (compound vi), was filtered off and weighed 11.8 g in a yield of 72.0percent. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 28% | With potassium acetate In dichloromethane; dimethyl sulfoxide at 80℃; | Example 46; 6-(2,3-Dihydro-1H-indol-5-yl)-4-morpholin-4-yl-1-(1-pyridin-3-ylmethyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Scheme 36)1 mmol (198 mg) 5-bromoindoline, 1.5 mmol (381 mg) bispinacolatodiboron, 0.1 mmol (73 mg) Pd(dppf)Cl2.CH2Cl2 and 3 mmol (296 mg) KOAc are suspended in DMSO and heated at 80 C overnight. The mixture is diluted with EtOAc, filtered over Celite and concentrated. Flash chromatography (5-20percent EtOAc in hexanes) gave 69 mg (28percent) of the boronate. This was added to a solution of 50 mg 6-Chloro-4-morpholin-4-yl-1-(1-pyridin-3-ylmethyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine in 2 mL DME and 250 uL of a 2M Na2CO3 solution. 10 mol percent Pd(PP3)4 was added and the mixture was stirred at 95C overnight. The solvents were removed and the product was purified by HPLC (TFA buffers). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 15% | With potassium acetate In N,N-dimethyl-formamide at 80℃; | AH. Methyl 2-methoxy-5-(4 A5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2- <n="105"/>vDnicotinate; To a dry flask was added methyl 5-bromo-2-methoxynicotinate (0.5 g, 2.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.61 g, 2.4 mmol), and Pd(dppf)Cl2 (82 mg, 0.10 mmol). Potassium acetate (0.6 g, 6.0 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N- dimethylformamide (10.0 mL) was added and the reaction was heated at 80 0C in an oil bath overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (10 mL) and washed with water (1OmL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography (eluting with 0-70percent ethyl acetate in hexanes) to yield the product (0.36 g, 72percent). ESI-MS m/z calc. 249.11, found 250.3 (MW+1)+. Retention time 1.84 minutes. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 30.5% | With potassium acetate In dimethyl sulfoxide at 80℃; for 4 h; | A mixture of tert-butyl 4-(4-bromo-3-methyl-pyrazol-l-yl)piperidine-l-carboxylate (2.7 g), 4,4,4',4>,5,5,5>,5>-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.98 g), 1,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(II) - CH2Cl2 adduct (0.634 g) and potassium acetate (2.31 g) in DMSO (40 ml) was stirred at 80 0C for 4 hours. The reaction mixture was allowed to cool to room temperature under stirring over a period of 1 hour, quenched with water (25 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic phases were washed with water (3 x 30 ml), brine (1 x 20 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10 to 30percent ethyl acetate in petroleum ether to afford tert-butyl 4-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)piperidine-l-carboxylate (0.937 g, 30.5 percent) as a white solid. NMR Spectrum(DMSOd): 1.24 (s, 12H), 1.41 (s, 9H), 1.71 (dd, IH), 1.76 (dd, IH), 1.89-1.96 (m, 2H), 2.22 (s, 3H), 2.85 (bs, 2H), 3.95-4.07 (m, 2H), 4.20-4.29 (m, IH), 7.82 (s, IH) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 868 mg | With potassium acetate; palladium diacetate; XPhos In acetonitrile at 75℃; for 18 h; Inert atmosphere | General procedure: Step 2: tert-butyl (2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- yl)carbamate: The product from Step 1 above (6 g, 18.52 mmol, 97percent purity), bis- (pinacolato)diboron (5.82 g, 22.91 mmol), palladium(II) acetate (0.107 g, 0.477 mmol), potassium acetate (5.62 g, 57.3 mmol) and XPhos (0.457 g, 0.955 mmol) were combined in MeCN (50 ml). The vessel was purged with N2 then heated at 75 °C for 18 h. The reaction mixture was cooled, filtered through Celite®, washing with MeCN (2 x 50 ml), and concentrated in vacuo to afford a brown oil. The residue was partitioned between DCM (50 ml) and water (50 ml). The phases were separated and the organic phase was concentrated in vacuo to afford a brown soild. The crude product was purified by columnchromatography (220 g cartridge, 0-20percent EtOAc/isohexane) to afford the title compound (5.67 g, 15.1 mmol, 96percent purity) as an off-white solid. LCMS (Method 1): m/z 306 (M+H- C4H8)+ at 2.83 min. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 110℃; for 2 h; Sealed tube; Microwave irradiation | Intermediate 114: 4-(4,4,5,5-Tetramethyl-1 ,2-dioxaborolan-2-yl)indolin-2-one (0793) A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.903 g, 7.49 mmol, commercially available from, for example, Fluorochem), 4-bromoindolin-2-one (1.038 g, 4.90 mmol, commercially available from, for example, Fluorochem), [1,1'- 7 s(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [Pd(dppf)Cl2.DCM] (0.601 g, 0.73 mmol) and potassium acetate (1.480 g, 15.08 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C for 2 h. The mixture was allowed to cool to rt before being filtered through a 10 g celite cartridge. The cartridge was washed through with ethyl acetate (3 x 30 mL) and the combined filtrates were evaporated in vacuoto give a brown liquid which was re-dissolved in DCM (ca. 10 mL), loaded onto a 100 g SNAP silica cartridge and purified by Biotage SP4 semi-automated flash column chromatography eluting with a gradient of 20 to 50percent ethyl acetate in cyclohexane. The required fractions were combined and evaporated in vacuo, this was re-dissolved in DCM (ca. 10 mL), transferred to a tarred vial and the solvent evaporated under a stream of nitrogen. The residue was triturated with ether (5 x 5 mL), decanting away the mother liquor each time, and the residue dried under a stream of nitrogen and in vacuo to give the desired product 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-2-one (941.8 mg, 3.63 mmol, 74 percent yield) as a cream solid. (0794) LCMS (2 min Formic): Rt = 0.93 min, [MH]+ = 260.3. |
| 74.2% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 110℃; for 2 h; | A mixture of 4,4,4T,4T,5,5,5T,5T-octamethyl-2,2T-bi( 1,3, 2-d ioxaborolane) (1.9025 g, 7.49 mmol), 4-bromoindolin-2-one (1.0383 g, 4.90 mmol), [1,1’-Bis(d iphenylphosphino)ferrocene]dichloropallad ium(II), complex with dichloromethane (0.6005 g,0.734 mmol) and potassium acetate (1.4802 g, 15.08 mmol) in 1,4-Dioxane (30 mL) was stirred at110 °C for 2 hr. The mixture was allowed to cool to room temperature before being filtered througha lOg celite cartridge. The cartridge was washed through with ethyl acetate (3 x 30 mL) and thecombined filtrates were evaporated in vacuo to give to give a brown liquid, which was redissolved indichloromethane (ca. 10 mL), loaded onto a bOg SNAP silica cartridge and purified by Biotage 5P4semi-automated flash column chromatography eluting with a gradient of 20 to 50percent ethyl acetate incyclohexane. The required fractions were combined and evaporated in vacuo, the residue (which was on the verge of crystallisation) was re-dissolved in dichloromethane (ca. 10 mL), transferred to a tared vial, the solvent evaporated under a stream of nitrogen. The residue was triturated with ether (5 x 5 mL), decanting away the mother liquor each time, and the residue dried under a stream of nitrogen and in vacuoto give the desired product as a cream solid (941.8 mg, 3.63 mmol, 74.2 percent yield)LCMS (2 mm Formic): Rt = 0.93 mi [MH]+ = 260 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 42.4% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 16 h; Inert atmosphere | NrV-Dimethyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]propan-l- amine N,N-Dimethyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]propan-l -amine is available commercially from several suppliers including Apollo Scientific Ltd., Whitefield Rd, Bredbury, Stockport, Cheshire, SK6 2QR, UK. CAS number [627899-90- 5], catalogue number OR12268. Alternatively, it can be prepared as follows: A 1 : 1 complex of [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (8.64 mg, 10.58 μιηο) was added to 3-(4-bromophenoxy)-N,N- dimethylpropan-1 -amine (546 mg, 2.12 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (644 mg, 2.54 mmol) and potassium acetate (830 mg, 8.46 mmol) in 1,4- dioxane (6 mL) warmed to 90°C under nitrogen. The resulting suspension was stirred at 90 °C for 16 h. The reaction mixture was evaporated to dryness and re-dissolved in DCM (25 mL), and washed with water (20 mL). The organic layer was dried with a phase separating cartridge, filtered and evaporated to afford crude product. The crude product was purified by FCC, elution gradient 0 to 10percent MeOH in DCM. Pure fractions were evaporated to dryness to afford the desired material as a brown waxy solid (274 mg, 42.4 percent). NMR Spectrum: NMR (500MHz, CDCls) δ 1.33 (12H, s), 1.89 - 2.08 (2H, m), 2.32 (6H, s), 2.53 (2H, dt), 4.05 (2H, t), 6.86 - 6.91 (2H, m), 7.71 - 7.76 (2H, m). Mass Spectrum: m/z (ES+)[M+H]+ = 258. |
| 42.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 16 h; Inert atmosphere | Dichloro [1,1 ‘-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct(0.063 g, 0.08 mmol) was added to 3-(4-bromophenoxy)-N,N-dimethylpropan-1-amine(2g, 7.75 mmol), 4,4,4’,4’,5 ,5 ,5’,5 ‘-octamethyl-2,2’-bi(1 ,3 ,2-dioxaborolane) (2.36 g, 9.30 mmol) and potassium acetate (3.04 g, 30.99 mmol) in 1,4-dioxane (35 mL) and the mixture degassed for 15 minutes. The resulting suspension was stirred at 90 °C for 16 hours under an inert atmosphere. The reaction mixture was evaporated to dryness, redissolved in DCM(25 mL), washed with water (20 mL) and the organic layer was dried with a phase separating cartridge, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10percent MeOH in DCM, to afford the desired material as a brown oil (1.000 g, 42.3 percent) which solidified on standing. NMR Spectrum: ‘H NMR (400MHz, CDC13) ö 1.33 (12H, s), 1.96 - 2.07 (2H, m), 2.34(6H, s), 2.52 - 2.65 (2H, m), 4.04 (2H, t), 6.83 - 6.94 (2H, m), 7.68 - 7.78 (2H, m).Mass Spectrum: mlz (ES+) [M+H]+ = 306 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68% | With copper(l) iodide; lithium methanolate; bis[2-(diphenylphosphino)phenyl] ether In dimethyl sulfoxide at 50℃; for 16 h; | General procedure: Phenylpropiolic acid (439 mg, 3.0 mmol), B2pin2 (763 mg, 3.0 mmol), lithium methoxide (23 mg, 0.6 mmol), copper iodide (57 mg, 0.3 mmol), and Dpe-Phos (324 mg, 0.6 mmol) were added to a vial containing DMSO (5 mL). The suspension was stirred for 16 h at 50 °C. The reaction was monitored by TLC, and after the completion of the reaction, the reaction mass was cooled to 25–28 °C and quenched into a mixture of 50 mL of water and 50 mL of ethyl acetate. The ethyl acetate layer was washed with water (2 × 25 mL), brine (2 × 25 mL), and then dried over Na2SO4. Evaporation of the solvent under reduced pressure provided the crude product, which was purified by column chromatography (hexane:EtOAc = 9.5:0.5). |
| 57% | With copper(II) trifluoroacetate; sodium carbonate In 1,4-dioxane at 80℃; for 18 h; Inert atmosphere | General procedure: A Schlenk tube with a magnetic stirring bar was charged with 3-phenylpropiolic acid (1a, 68 mg, 0.5 mmol), bis(pinacolato)diboron (2a, 152 mg, 0.6 mmol), Cu(TFA)2 (29 mg, 10 molpercent), Na2CO3 (127 mg, 1.2 mmol), and 1,4-dioxane (2 mL) under N2. The reaction mixture was stirred at 80 °C for 18 h (monitored by TLC and GC). Upon completion of the reaction, the reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate (20 mL), filtered through a plug of silica gel, and washed with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL×2) and dried over anhydrous Na2SO4. The solvents were removed via rotary evaporator and the residue was purified by flash chromatography (silica gel, ethyl acetate: petroleum ether=1:30) to give 89.7 mg of desired product 3a in 78 percent yield as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.48–7.50 (m, 2H), 7.41 (d, 1H, J=18.5Hz), 7.29–7.32 (m, 3H), 6.18 (d, 1H, J=18.4Hz), 1.32 (s, 12H). 13C NMR (100 MHz, CDCl3): δ 148.5, 136.4, 127.9, 127.5, 126.0, 82.3, 23.8 |