Patent Application
20210323987
The current disclosure is directed to methods for the synthesis of polycyclic aromatic hydrocarbons and heteroatom-containing polycyclic aromatic hydrocarbons, and more particularly to methods for the modular synthesis thereof by an expedient ring assembly, and to the heteroatom-containing polycyclic aromatic hydrocarbon products thereof.
Polycyclic aromatic hydrocarbons (PAHs) are important molecules in the fields of materials science and molecular electronics (see, for example, M. J. Allen, et al., Chem. Rev. 2010, 110, 132-145; and A. C. Grimsdale, et al., Chem. Commun. 2005, 2197-2204, the disclosure of which are incorporated herein by reference). Specifically, PAHs have been employed in many widely-used devices, such as organic light emitting diodes (OLEDs), field effect transistors (OFETs), and photovoltaics (OPVs) (for example, P. M. Beaujuge, et al., J. Am. Chem. Soc. 2011, 133, 20009-20029, the disclosure of which is incorporated herein by reference). However, synthetic methods to rapidly generate heterocyclic PAHs, and especially non-symmetric heteroatom-containing PAHs, remain limited. For example, the assembly of non-symmetric PAHs that possess multiple functional groups usually requires long synthetic sequences (M. Stepien, et al., Chem. Rev. 2017, 117, 3479-3716, the disclosure of which is incorporated herein by reference). In addition, synthetic approaches to PAHs often necessitate harsh reaction conditions (e.g., high temperatures and strongly acidic or basic conditions), and/or use of strongly basic organometallic reagents, or transition metal catalyzed cross-coupling reactions, and, still, typically result in low overall yields (T. C. McMahon, et al., Am. Chem. Soc. 2015, 137, 4082-4085; J. T. Markiewicz, F. Wudl, ACS Appl. Mater. Interfaces 2015, 7, 28063-28085; J. L. Marshall, et al., ChemPlusChem 2017, 82, 967-1001, the disclosure of which are incorporated herein by reference). Accordingly, new straightforward synthetic strategies allowing rapid access to a diverse range of unsymmetrical, heteroatom-containing PAHs are highly sought after.
The application is directed to methods for the synthesis of heteroatom-containing polycyclic aromatic hydrocarbons, and more particularly to methods for the modular synthesis of heteroatom-containing polycyclic aromatic hydrocarbons via in situ generated strained heterocylic alkynes or arynes, and to the heteroatom-containing polycyclic aromatic hydrocarbon products thereof.
Many embodiments are directed to methods for forming heteroatom-containing polycyclic aromatic hydrocarbons including:
In still many embodiments, the plurality of sequential Diels-Alder reactions includes a first Diels-Alder reaction, between the first cyclic alkyne and the oxadiazinone, to yield an intermediate pyrone; and a second Diels-Alder reaction, between the intermediate pyrone and the second cyclic alkyne or aryne, to yield the polycyclic aromatic hydrocarbon comprising a 9,10-diarylanthracene scaffold.
In yet many embodiments, the first cyclic alkyne includes in its ring at least one substituted or unsubstituted heteroatom selected from: N, O, S, Se, Si, B, P; and further comprises any number of substitutions and functional groups, each individually selected from: H, halide, alkyl, aryl, heteroaryl, alkoxy, PEG.
In still yet many embodiments, the first cyclic alkyne is 3,4,-piperidyne comprising an N-substitution selected from: H, alkyl, including Me, aryl, including phenyl, benzyl, carbamates, including Cbz and Boc, N-oxide, N-Borane.
In yet still many embodiments, the rings C and D, independently, include one or more functionality selected from: an electron-donating functional group, including para-methoxyphenyl, an electron-withdrawing functional group, including para-NO2, and a halogen atom, including F, CI, Br, and I, heterocycles, including thiophene, alkenes, alkynes.
In still yet many embodiments, one or both of the rings C and D include a functional handle and wherein the functional handle is used to further extend, including polymerize, the polycyclic aromatic hydrocarbon comprising a 9,10-diarylanthracene scaffold and at least one heteroatom.
In yet still many embodiments, the second cyclic alkyne or aryne includes at least one feature selected from:
In still yet many embodiments, the second cyclic alkyne or aryne is selected from: benzyne, naphthalyne, indolyne, and cyclohexyne, including cyclohexyne with at least one heteroatom, wherein the at least one heteroatom may be further functionalized.
In yet still many embodiments, the reaction conditions include additional reagents, reagent stoichiometry, and physical conditions selected to promote an elimination of silyl triflate from the first and the second corresponding silyl triflates, and to promote Diels-Alder reactions between the first cyclic alkyne and the oxadiazinone, and between an intermediate pyrone and the second cyclic alkyne or aryne.
In still yet many embodiments, the reaction conditions comprise an additional reagent providing F−, a solvent, a temperature, and a period of time.
In yet still many embodiments, the additional reagent providing F− is selected from: CsF, LiF, KF, NaF, N(nBu)4F, HF, HF.pyridine, Poly[4-vinylpyridinium poly(hydrogen fluoride)], tetrabutylammonium difluorotriphenylsilicate.
In still yet many embodiments, the solvent is selected from: acetonitrile, toluene, tetrahydrofuran, chloroform, dichloromethane, any other ethereal and halogenated solvents, and any mixture thereof.
In yet still many embodiments, the temperature is selected from: ambient, 30 to 60° C.
In still yet many embodiments, the period of time is 12 to 24 hours.
In yet still many embodiments, reacting the first cyclic alkyne, the oxadiazinone, and the second cyclic alkyne or aryne is conducted in a stepwise manner, wherein:
In still yet many embodiments, wherein:
In yet still many embodiments, the intermediate pyrone is isolated and purified prior to being reacted with the second cyclic alkyne or aryne.
In still yet many embodiments, the reacting of 1 equivalent of the first cyclic alkyne, 1 to 5 equivalents of the oxadiazinone, and 1 to 5 equivalents of the second cyclic alkyne or aryne is conducted in a one-pot manner, with addition of 1 to 10 equivalents of CsF in acetonitrile as 0.1 M solution relative to the first cyclic or heterocyclic alkyne for 12 to 24 hours.
In yet still many embodiments, the reacting of 1 equivalent of the first cyclic alkyne, 1 equivalent of the oxadiazinone, and 1 equivalent of the second cyclic alkyne or aryne is conducted in a one-pot manner, with addition of 3 equivalents of CsF in acetonitrile as 0.1 M solution relative to the first cyclic alkyne for 14 hours.
In still yet many embodiments, the polycyclic aromatic hydrocarbon comprising a 9,10-diarylanthracene scaffold further includes at least one heteroatom.
In yet still many embodiments, at least one heteroatom is nitrogen.
Various embodiments are directed to heteroatom-containing polycyclic aromatic hydrocarbon selected from the group consisting of:
Some embodiments are directed to a method for forming polycyclic aromatic hydrocarbons including:
In still some embodiments, the cyclic alkyne or aryne comprises at least one feature selected from:
In yet some embodiments, the cyclic alkyne or aryne is selected from: naphthalyne, indolyne, carbazolyne, and cyclohexyne, including cyclohexyne with at least one heteroatom, wherein the at least one heteroatom may be further functionalized.
In still yet some embodiments, the halo-biaryl is of formula:
In yet still some embodiments, the halo-biaryl is selected from:
In still yet some embodiments, the reaction conditions include additional reagents, reagent stoichiometry, and physical conditions selected to promote an elimination of silyl triflate from the corresponding silyl triflate, and to promote the transition metal-catalyzed cross-coupling reaction between the cyclic alkyne or aryne and the halo-biaryl.
In yet still some embodiments, the reaction conditions include an additional reagent providing F−, the group 10 metal catalyst, a ligand, a solvent, reflux conditions, and a period of time.
In still yet some embodiments, the additional reagent providing F− is selected from: CsF, LiF, KF, NaF, N(nBu)4F, HF, HF.pyridine, Poly[4-vinylpyridinium poly(hydrogen fluoride)], tetrabutylammonium difluorotriphenylsilicate.
In yet still some embodiments, the cyclic alkyne or aryne is a cyclic or heterocyclic alkyne and an amount of CsOPiv is added.
In still yet some embodiments, the group 10 metal catalyst is Pd0 selected from: Pd(dba)2 and Pd(OAc)2; and the ligand including P(o-tolyl)3.
In yet still some embodiments, the reflux conditions include a single or a mixture of solvents that can be heated to 90-150° C.
In still yet some embodiments, the period of time is 0.5 to 24 hours.
In yet still some embodiments, the reaction conditions comprise: 1 equivalent of the halo-biaryl, 2 equivalents of the cyclic alkyne or aryne, 1 to 20 equivalents of CsF, 5 to 100 mol % Pd0, 1:1 ratio of Pd0 to its ligand, a solvent or solvent mixture allowing heating to 90-150° C., 0.5 to 24 hours.
In still yet some embodiments, the reaction conditions comprise: 1 equivalent of the halo-biaryl, 2 equivalents of the cyclic alkyne or aryne, 10 equivalents of CsF, 5 mol % Pd(dba)2, 5 mol % P(o-tolyl)3, 1:1 acetonitrile/toluene 0.075M relative to halo-biaryl solvent mixture, 110° C., 24 hours.
In yet still some embodiments, the halo-biaryl is a part of a transition metal organometallic complex and the reaction conditions comprise: 1 equivalent of the halo-biaryl, 2 equivalents of the cyclic alkyne or aryne, 10 equivalents of CsF, 10 mol % Pd(OAc)2, 10 mol % P(o-tolyl)3, 1:1 acetonitrile/toluene 0.075M relative to halo-biaryl solvent mixture, 110° C., 0.5 hours.
In yet still some embodiments, the transition metal organometallic complex comprises a transition metal selected from: Co, Ir, Rh, Ni, Pd, Pt, Zn, Cu, Fe, Mn, Os.
In still yet some embodiments, at least one heteroatom is employed to further decorate or otherwise extend the polycyclic aromatic hydrocarbon comprising a triphenylene scaffold and at least one heteroatom.
In still yet some embodiments, the halo-biaryl is bromo-biaryl.
Certain embodiments are directed to a A heteroatom-containing polycyclic aromatic hydrocarbon selected from the group consisting of:
Additional embodiments and features are set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the disclosure. A further understanding of the nature and advantages of the present disclosure may be realized by reference to the remaining portions of the specification and the drawings, which forms a part of this disclosure.
The description will be more fully understood with reference to the following figures, which are presented as exemplary embodiments of the invention and should not be construed as a complete recitation of the scope of the invention, wherein:
Turning now to the drawings, methods for the syntheses of polycyclic aromatic hydrocarbons (PAHs) and heteroatom-containing PAHs and platforms for performing such syntheses are provided. In many embodiments methods and platforms are provided that allow for the synthesis of aza-polycyclic aromatic hydrocarbons by an expedient ring assembly. Various such embodiments employ modular approaches that rely on the controlled generation of transient cyclic and heterocyclic alkynes, arynes and heteroarynes to provide multiple new C—C bonds in predetermined sequential reactions, thus giving access to diverse compounds with multiple axes of substitution. In some embodiments, four new C—C bonds are formed via sequential pericyclic reactions. In other embodiments, two new C—C bonds are formed via transition metal catalyzed couplings. In many embodiments, the synthetic sequences disclosed in the instant application are performed in a stepwise fashion, while in other embodiments, the same is achieved in a one-pot fashion. In many embodiments, previously inaccessible PAHs and new valuable organic materials are produced.
An important subset of PAHs are 9,10-diphenylanthracene derivatives. The parent compound, 9,10-diphenylanthracene (1a in
Some synthetic strategies towards PAHs rely on small, alkyne-containing aromatic rings-arynes (A. V. Dubrovskiy, et al., Org. Biomol. Chem. 2013, 11, 191-218; D. Perez, et al., Eur. J. Org. Chem. 2013, 5981-6013; X. Xiao, T. R. Hoye, Nat. Chem. 2018, 10, 838-844; S. E. Suh, et al., Chem. Sci. 2015, 6, 5128-5132; and Y. Mizukoshi, et al., J. Am. Chem. Soc. 2015, 137, 74-77, the disclosure of which are incorporated herein by reference). In recent years, strained cyclic alkynes, such as those depicted in
This application is directed to embodiments of modular and rapid methods for syntheses of a diverse range of PAHs, including heteroatom-containing PAHs and PAHs that comprise both aromatic and non-aromatic rings, and further including small molecule fluorophores and conductive polymers. More specifically, in many embodiments, the synthetic methods of the instant application rely on trapping of in situ generated strained intermediates, that are transient cyclic and heterocyclic alkynes, arynes and heteroarynes, to furnish a multitude of diverse PAH scaffolds, including unsymmetrical, heteroatom-containing, and otherwise highly complex structures. In many embodiments, the PAH scaffolds resulting from the methods of the instant application comprise a plurality of aromatic and non-aromatic rings. In many embodiments, the transient intermediates are cyclic and heterocyclic hexynes. In many embodiments, the methods of the application allow for facile installation of heteroatoms and other desired molecular segments or functionalities into the PAH scaffold via judicious selection of simple reactive components. In some embodiments the full synthetic sequence is conducted stepwise, while in other embodiments, the desired PAHs are produced in a one-pot manner.
Furthermore, in many embodiments, and further according to
More specifically, the synthetic methods of the instant application provide a means to allow for the controlled generation and trapping of fragments 8 and 10 to ultimately deliver scaffolds 7 through the cascade of events suggested in
Here, it should be noted, that Steglich (W. Steglich, et al., Synthesis 1977, 252-253, the disclosure of which is incorporated herein by reference) had previously demonstrated the double addition of benzyne into oxadiazinones, in addition to the syntheses of conjugated materials by Nuckolls (Q. Miao, et al., J. Am. Chem. Soc. 2006, 128, 1340-1345, the disclosure of which is incorporated herein by reference) and Wudl (D. Chun, et al., Angew. Chem. Int. Ed. 2008, 47, 8380-8385; Angew. Chem. 2008, 120, 8508-8513, the disclosure of which is incorporated herein by reference) employing the same. However, an important limitation in all these cases is the inability to incorporate two different strained alkynes, instead delivering symmetric products with respect to building blocks A and B. It should also be noted, that DA reactions using substituted tetrazenes or isobenzofurans are also known, and also suffer from the inability to introduce two different strained intermediates in a controlled fashion. (For examples, see: S.-E. Suh, et al., Chem. Sci. 2018, 9, 7688-7693, the disclosure of which are incorporated herein by reference.) In contrast, the synthetic methods of some embodiments of the instant application allow a facile diversification of all four quadrants of the 9,10-diphenylanthracene scaffolds, as depicted, for example, in
In order to further demonstrate and explain some of the principles of the methods of the instant application,
As mentioned above, arynes, such as benzyne, are known to undergo oxadiazinone trapping. However, the resulting intermediate benzopyrone directly undergoes trapping with a second equivalent of the same aryne, precluding the opportunity to add two different strained alkyne fragments into the desired scaffold. Therefore, reacting benzyne with a simple model oxadiazinone 12 (wherein 12 is oxadiazinone 9 with phenyls for blocks C and D) produces only a double benzyne addition product—symmetric 9,10-diphenylanthracene 1a. Accordingly, although not to be bound by any theory, it is hypothesized, that the intermediate benzopyrone is more reactive than the initial oxadiazinone, and, therefore, prevents isolation or second addition of a different aryne. Nevertheless, Sauer and co-workers were able to trap non-aromatic cyclooctyne with an oxadiazinone to produce a pyrone intermediate (J. Balcar, et al., Tetrahedron Lett. 1983, 24, 1481-1484 the disclosure of which is incorporated herein by reference). However, no further reactions of this pyrone were described. Also of note, the cyclooctyne used by Sauer is stable and does not have to be generated in situ and furthermore cannot subsequently be transformed to an aromatic PAH. Accordingly, the methods of the instant application employ cyclic alkynes and optimized stoichiometry to trap the intermediate pyrone 90, yet avoid the second addition of the same alkyne. In many preferred embodiments, and in contrast to Sauer, the cyclic alkynes comprise 6-membered rings and are cyclohexynes or heterocyclohexynes. In many such embodiments, 6-membered ring alkynes possess a host of advantageous properties, including very good stability, which allows them to be isolated and makes them easier to use. In addition, in many embodiments, 6-membered ring alkynes yield PAHs with advantageous electronic and materials properties. However, in many other embodiments, the methods of the application may also rely on trapping of fleeting intermediates, which cannot be isolated, including cycloalkynes and heterocycloalkynes of various other ring sizes.
In many embodiments, cycloalkynes 8 further optionally comprise any number of desired functional groups and substitutions and any number of ring heteroatoms selected from: N, P, O, S, Se, B, Si; which, in turn, may be further substituted. In many embodiments 8 comprises at least one nitrogen atom. In many embodiments, 8 further comprises any number of substitutions and functional groups, including groups selected from: H, halide, alkyl, aryl, heteroaryl, alkoxy, PEG. In many embodiments, 8 is 3,4-piperidyne. In many such or other embodiments, 8 also comprises an N-substitution selected from: H, alkyl, including Me, aryl, including phenyl, benzyl, carbamates, including Cbz and Boc, N-oxide, N-Borane. However, in some embodiments 8 is a simple cyclohexyne (
In addition, other reaction conditions of the instant methods, such as additional reagents, concentration, solvent choice, temperature, and duration can also be optimized according to many embodiments to improve the yield of the single-adduct intermediate pyrone and, therefore, of the desired PAH scaffolds. For example, by increasing the concentration of silyl triflate of 8 to 0.1 M, in accordance with various embodiments, it is possible to obtain pyrones (13a and 13b) in 74% yield (entry 4 of the Table in
Furthermore, it should be noted, that although CsF reagent is used in many examples of the instant application to promote Kobayashi elimination of silyl triflate, any reagent that promotes elimination of silyl triflate to produce alkyne may be used according to embodiments. For example, in some embodiments, any reagent selected from: CsF, LiF, KF, NaF, N(nBu)4F, HF, HF.pyridine, Poly[4-vinylpyridinium poly(hydrogen fluoride)], tetrabutylammonium difluorotriphenylsilicate, is used to generate a cycloalkyne or heterocycloialkyne in situ from the corresponding alkene silyl triflate. However, as mentioned above, in some embodiments, pyrone intermediate is produced as a mixture of regioisomers, such as 13a and 13b in
In summary,
Next,
Furthermore,
Alternatively,
In many embodiments, the reaction conditions of the methods of the instant application comprise excess of silyl triflate 15 relative to bromo-biaryl 80. In some such embodiments 2 equivalents of silyl triflate are provided for each equivalent of bromo-biaryl. However, in some embodiments, only 1 equivalent of 15 relative to bromo-biaryl 80 is provided and such conditions still generate the desired PAH product, albeit with a lower yield. In many embodiments, the reaction conditions further comprise, 1 to 20 equivalents of CsF (or another Kobayashi elimination reagent), 5 to 100 mol % (but optimally 5 mol %) of Pd0 catalyst, the same amount of an appropriate ligand, and reflux conditions, including appropriately chosen solvent or solvent mixture, for 0.5 to 24 hours. In some such embodiments, the reaction conditions comprise: 1 equivalent of bromo-biaryl, 2 equivalents of cyclohexyne or aryne 10, 10 equivalents of CsF, 5 mol % Pd(dba)2, 5 mol % P(o-tolyl)3, a 1:1 acetonitrile/toluene solvent mixture, wherein the concentration of bromo-biaryl is 0.075M, 110° C., and 24 hours. In some embodiments, especially wherein ring B is non-aromatic, it has been noticed that, unexpectedly, addition of CsOPiv significantly improves the overall yield of the desired PAH (
In addition,
Experiments were conducted to demonstrate the capabilities of the methods and platforms in accordance with embodiments. These results and discussion are not meant to be limiting, but merely to provide examples of operative methods and platforms and their features.
Furthermore, as depicted in
In addition
Accordingly,
Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen using anhydrous solvents (freshly distilled or passed through activated alumina columns). All commercially obtained reagents were used as received unless otherwise specified. Cesium fluoride (CsF) and manganese (IV) oxide (MnO2) were obtained from Strem Chemicals. Benzyl 4-(trifluoromethylsulfonyloxy)-3-(trimethylsilyl)-5,6-dihydropyridine-1(2H)-carboxylate (11), Garg 4,5-indolyne precursor (precursor to 21), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (32), sodium hydride (NaH, 60% dispersion in mineral oil), palladium hydroxide on carbon (20% wt. loading, Pd(OH)2/C), bis(pinacolato) diboron (B2(pin)2), SPhos, and 4-bromo-benzothiadiazole (46) were obtained from Sigma Aldrich. Triisopropylsilyl chloride (TIPSCI) 4,7-dibromo-benzothiadiazole (48), and RuPhos-Pd-G3 were obtained from Combi-Blocks. 1-(Trimethylsilyl)-2-naphthyl trifluoromethanesulfonate (precursor to 19) was obtained from TCI America. Potassium acetate (KOAc) was obtained from Fisher Scientific and ground up and dried in an oven overnight prior to use. Potassium phosphate (K3PO4) was obtained from Acros. TIPSCI was freshly distilled before use. 1,4-Dioxane was dried overnight with 10% wt/wt 5 Å molecular sieves and sparged with nitrogen for 30 min immediately before use. Reaction temperatures were controlled using an IKAmag temperature modulator and, unless stated otherwise, reactions were performed at room (i.e, ambient) temperature (approximately 23° C.). Thin layer chromatography (TLC) was conducted with EMD gel 60 F254 pre-coated plates (0.25 mm) and visualized using a combination of UV light, anisaldehyde, and potassium permanganate staining. Silicycle Siliaflash P60 (particle size 0.040-0.063 mm) was used for flash column chromatography. For some chromatographic purifications, an automated Biotage Isolera™ with SNAP Ultra™ cartridges, Teledyne Isco CombiFlash® with RediSep Rf cartridges, or Yamazen Smart Flash AKROS with ELS detector and Universal columns were used. 1H-NMR spectra were recorded on Bruker spectrometers (at 400, 500, and 600 MHz) and are reported relative to the residual solvent signal. Data for 1H-NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz) and integration. 13C-NMR spectra were recorded on Bruker spectrometers (at 100 and 125 MHz) and are reported relative to the residual solvent signal. Data for 13C-NMR spectra are reported in terms of chemical shift and, when necessary, multiplicity, and coupling constant (Hz). IR spectra were obtained on a Perkin-Elmer UATR Two FT-IR spectrometer and are reported in terms of frequency of absorption (cm−1). Uncorrected melting points were measured using a Digimelt MPA160 melting point apparatus. DART-MS spectra were collected on a Thermo Exactive Plus MSD (Thermo Scientific) equipped with an ID-CUBE ion source and a Vapur Interface (lonSense Inc.). Both the source and MSD were controlled by Excalibur software v. 3.0. The analyte was spotted onto OpenSpot sampling cards (IonSense Inc.) using CDCl3 as the solvent. Ionization was accomplished using UHP He (Airgas Inc.) plasma with no additional ionization agents. The mass calibration was carried out using Pierce LTQ Velos ESI (+) and (−) Ion calibration solutions (Thermo Fisher Scientific). Separation of compounds 40a and 40b was carried out by Scott Virgil at California Institute of Technology on a Jasco 2000 SFC (supercritical fluid chromatography) Preparative System using a Chiral Technologies AD-H column. UV-Vis spectra were recorded using an JASCO C-770 UV-Visible/NIR spectrophotometer. Fluorescence spectra were recorded using a Horiba Instruments PTI Quanta Master Series Fluorometer. The UV-Vis and fluorescence spectra were recorded using a 1-cm quartz cuvette, with freshly distilled tetrahydrofuran (THF), methylene chloride (DCM), diethyl ether, and acetonitrile. Gel permeation chromatography (GPC) was conducted on a Shimadzu HPLC Prominence-i system equipped with a UV detector, Wyatt DAWN Heleos-II Light Scattering detector, Wyatt Optilab T-rEX RI detector, one MZ-Gel SDplus guard column, and two MZ-Gel SDplus 100 Å 5 μm 300×8.0 mm columns. Tetrahydrofuran (THF) at 40° C. was used as the eluent (flow rate: 0.70 mL/min). For polymer 49 near-monodisperse poly(styrene) standards (Polymer Laboratories) were employed for calibration and molecular weights were calculated from refractive index.
Oxadiazinone SI-13, hydrazones SI-3, SI-5 and SI-8 (see M. L. Tintas, et al., J. Mol. Struct. 2014, 1058, 106-113, the disclosure of which is incorporated herein by reference), and silyl triflates SI-15 (A. S. Devlin, et al., Chem. Sci. 2013, 4, 1059-1063, the disclosure of which is incorporated herein by reference) and SI-16 (T. K. Shah, et al., J. Am. Chem. Soc. 2016, 138, 4948-4954, the disclosure of which is incorporated herein by reference) are known compounds and were prepared following literature procedures. 1H-NMR spectral data matched those reported in the literature. Silyl triflate precursors to 17, 19, 21, and 25 are all commercially available from Sigma-Aldrich (www.sigmaaldrich.com) or TCI (www.tcichemicals.com). The Sigma-Aldrich product numbers are as follows: 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (precursor to 17): 470430; Garg 4,5-indolyne precursor (precursor to 21): 795569; benzyl 4-(trifluoromethylsulfonyloxy)-3-(trimethylsilyl)-5,6-dihydropyridine-1(2H)-carboxylate (precursor to 25): 803928. The TCI product number for 1-(trimethylsilyl)-2-naphthyl trifluoromethanesulfonate (precursor to 19) is T2465.
A. Syntheses of Oxadiazinones.
General Procedure A (Preparation of Oxadiazinone 12 is Used as an Example of Embodiments).
Oxadiazinone 12. To a 60° C. solution of benzohydrazide SI-1 (7.00 g, 51.4 mmol, 1.00 equiv) in deionized water (640 mL) and open to air, was added a solution of glyoxylic acid SI-2 (7.72 g, 51.5 mmol, 1.00 equiv) dissolved in deionized water (645 mL) dropwise over 2 h. After stirring for 2.5 h at 60° C., the reaction flask was cooled to 23° C. and the products were allowed to crystallize overnight. Filtration afforded hydrazine SI-3 (15.5 g crude mass) as a white solid, which was carried forward to the next reaction without purification.
To a solution of hydrazine SI-3 (15.5 g, 57.8 mmol, 1.00 equiv) in THF (580 mL) was added EDC.HCl (12.2 g, 63.6 mmol, 1.10 equiv). After stirring at 23° C. for 16.5 h, the reaction was concentrated under reduced pressure. The crude reaction mixture was transferred to a separatory funnel using Et2O (200 mL), H2O (200 mL), and a minimal amount of THF to dissolve precipitates (150 mL). The layers were then separated and the organic layer was washed successively with deionized water (3×100 mL) and brine (1×100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to yield oxadiazinone 12 (10.1 g, 78% yield based on SI-1) as a yellow solid. Oxadiazinone 12: mp 137-138° C.; Rf 0.41 (9:1 EtOAc:MeOH); 1H-NMR (400 MHz, CDCl3): δ 8.36-8.32 (m, 2H), 8.32-8.27 (m, 2H), 7.68-7.62 (m, 1H), 7.60-7.49 (m, 5H); 13C-NMR (100 MHz, CDCl3): δ 157.8, 153.0, 148.4, 133.9, 132.3, 131.2, 129.3, 129.2, 128.9, 128.4, 127.7; IR (film): 3061, 1685, 1578, 1480, 1257 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C15H11N2O2+, 251.0815; found, 251.0797. Melting point matched those previous reported (see, W. Steglich, et al., Synthesis 1977, 252-253, the disclosure of which is incorporated herein by reference).
Oxadiazinone SI-6. Followed General Procedure A using hydrazide SI-4 (3.00 g, 18.1 mmol) to afford oxadiazinone SI-6 (2.00 g, 49% yield over two steps) as a yellow solid after recrystallization from hot EtOAc. Oxadiazinone SI-6: mp 178-180° C.; Rf 0.46 (9:1 EtOAc:MeOH); 1H-NMR (500 MHz, CDCl3): δ 8.33-8.29 (m, 2H), 8.26-8.21 (m, 2H), 7.57-7.53 (m, 1H), 7.53-7.48 (m, 2H), 7.06-7.02 (m, 2H), 3.91 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 164.3, 157.9, 152.0, 148.6, 131.9, 131.4, 130.5, 129.0, 128.7, 119.7, 114.8, 55.8; IR (film): 3075, 2846, 1763, 1604, 1258 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C16H13N2O3+, 281.0921; found, 281.0916. IR and HRMS matched those previously reported (see M. Christl, et al., Chem. Ber. 1985, 118, 2940-2973, the disclosure of which is incorporated herein by reference).
Oxadiazinone SI-9. Followed General Procedure A using hydrazide SI-7 (3.00 g, 16.6 mmol) to afford oxadiazinone SI-9 (1.32 g, 27% yield over two steps) as a yellow solid after recrystallization from hot EtOAc. Oxadiazinone SI-9: mp 220-224° C.; Rf 0.58 (9:1 EtOAc:MeOH); 1H-NMR (500 MHz, CDCl3): δ 8.48 (d, J=8.8, 2H), 8.41 (d, J=8.8, 2H), 8.35 (d, J=7.9, 2H), 7.62 (dd, J=7.3, 7.3, 1H), 7.54 (dd, J=7.6, 7.6, 2H); 13C-NMR (125 MHz, CDCl3): δ 155.8, 153.9, 150.9, 147.5, 133.4, 132.9, 130.7, 129.4, 129.3, 129.0, 124.4; IR (film): 3079, 1775, 1563, 1521, 1350 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C15H10N3O4+, 296.0658; found, 296.0666. Melting point and IR spectrum matched those previously reported (see E. Feineis, et al., Chem. Ber. 1993, 126, 1743-1748, the disclosure of which is incorporated herein by reference).
Hydrazone SI-11. Followed General Procedure A using hydrazide SI-10 (3.00 g, 21.1 mmol) to afford hydrazone SI-11 (3.80 g, 66% yield) as a white solid. Hydrazone SI-11: mp 186-187° C.; Rf 0.24 (9:1 EtOAc:MeOH); 1H-NMR (600 MHz, DMSO-d6, 55° C.): δ 12.14 (br s, 1H), 7.97-7.93 (m, 2H), 7.76-7.72 (m, 2H), 7.48-7.44 (m, 3H), 7.24 (dd, J=4.9, 3.8, 1H); 13C-NMR (151 MHz, DMSO-d6, 65° C.): δ 164.5, 163.2, 134.2, 129.4, 128.9, 128.5, 128.2, 127.9, 127.8, 127.09, 127.05; IR (film): 3247, 3109, 3029, 1699, 1404 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C13H11N2O3S+, 275.0485; found, 275.0475.
Oxadiazinone SI-12. Followed General Procedure A using hydrazone SI-11 (3.00 g, 10.9 mmol) to afford oxadiazinone SI-12 (2.30 g, 82% yield) as a yellow solid after recrystallization from hot Et2O. Oxadiazinone SI-12: mp 142-143° C.; Rf 0.70 (9:1 EtOAc:MeOH); 1H-NMR (500 MHz, CDCl3): δ 8.32-8.28 (m, 2H), 8.00 (dd, J=3.8, 1.2, 1H), 7.72 (dd, J=5.0, 1.2, 1H), 7.58-7.54 (m, 1H), 7.52-7.48 (m, 2H), 7.22 (dd, J=5.0, 3.8, 1H); 13C-NMR (125 MHz, CDCl3): δ 155.0, 152.1, 147.8, 134.4, 133.2, 132.1, 131.3, 130.7, 129.1, 128.9, 128.8; IR (film): 3096, 1767, 1561, 1422, 1152 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C13H9N2O2S+, 257.0379; found, 257.0371.
B. Syntheses of Pyrone Intermediates.
General Procedure B (Preparation of Pyrones 13a and 13b is Used as an Example of Embodiments).
Pyrones 13a and 13b. To a stirred solution of silyl triflate 11 (66 mg, 0.15 mmol, 1.0 equiv) and oxadiazinone 12 (75 mg, 0.30 mmol, 2.0 equiv) in acetonitrile (1.5 mL) was added CsF (46 mg, 0.30 mmol, 2.0 equiv) in one portion. The reaction was purged with nitrogen for ten minutes before being sealed with a Teflon cap and left to stir at 23° C. After 15 h, the reaction mixture was filtered through celite (monster pipette, ˜4 cm tall) with EtOAc (˜10 mL) as the eluent and then concentrated under reduced pressure. Purification of the crude material via flash chromatography (Yamazen, 8 g SiO2, 100% hexanes→3:2 hexanes:EtOAc) afforded pyrones 13a and 13b (48.4 mg, 74% yield) as a light yellow foam. Pyrones 13a and 13b: Rf 0.13 (5:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.66-7.59 (m, 5H), 7.57-7.52 (m, 6H), 7.50-7.41 (m, 7H), 7.37-7.28 (m, 12H), 5.07 (s, 4H), 4.53 (s, 2H, 13a), 4.35 (s, 2H, 13b), 3.57-3.49 (m, 4H), 2.82 (t, J=6.4, 2H, 13b), 2.72 (t, J=6.5, 2H, 13a); HRMS-APCI (m/z) [M+H]+ calcd for C28H24NO4+, 438.1700; found, 438.1683.
General Procedure C (Preparation of Pyrone 13a is Used as an Example of Embodiments).
Pyrone 13a. To a solution of silyl triflates 13a and 13b (66 mg, 0.15 mmol, 1:1 ratio of regioisomers, 1.0 equiv) in acetonitrile (0.4 mL) was added CsF (57 mg, 0.37 mmol, 5.0 equiv) in one portion. The reaction was purged with nitrogen for ten minutes before being left to stir at 23° C. After 12 h, the reaction mixture was filtered through celite (monster pipette, ˜4 cm tall) with EtOAc (˜10 mL) as the eluent and then concentrated under reduced pressure. Purification of the crude material via flash chromatography (Isco, 12 g SiO2, 100% hexanes→100% EtOAc) afforded pyrone 13a (29.8 mg, 45% recovery) as a light yellow foam. Pyrone 13a: Rf 0.13 (5:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.62-7.53 (m, 5H), 7.50-7.30 (m, 10H), 5.07 (s, 2H), 4.53 (s, 2H), 3.52 (t, J=6.4, 4H), 2.72 (t, J=6.4, 2H); 13C-NMR (125 MHz, CD3CN): δ 162.6, 156.2, 152.5, 138.4, 135.3, 133.1, 131.6, 131.3, 130.0, 129.9, 129.7, 129.6, 129.3, 129.1, 128.8, 125.1, 118.3, 113.5, 68.0, 42.3, 42.1, 28.2; IR (film): 3062, 3029, 2952, 1700, 1234 cm−1; HRMS-APCI (m/z) [M+H]30 calcd for C28H24NO4+, 438.1700; found, 438.1691.
Note, that substantial amount of insoluble white solid was formed during the reaction. Not to be bound by any theory, it is hypothesized that isomer 13b decomposes under the reaction conditions to give this amorphous polymeric material. The mechanism of decomposition is not known at this time. % recovery is defined as follows:
Pyrones 28a and 28b. Followed General Procedure B using silyl triflate 11 (66 mg, 0.15 mmol, 1.0 equiv) afforded pyrones 28a and 28b (62% yield, average of two experiments) as a yellow foam. Pyrones 28a and 28b: Rf 0.52 (1:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C):δ 7.60-7.52 (m, 5H), 7.50-7.39 (m, 6H), 7.37-7.28 (m, 11H), 7.18-7.13 (m, 2H), 7.09-7.04 (m, 4H), 5.09-5.04 (m, 4H), 4.55-4.51 (m, 3H), 4.34 (s, 1H), 3.89-3.86 (m, 7H), 3.56-3.48 (m, 4H), 2.95 (t, J=6.5, 2H), 2.71 (t, J=6.5, 2H); HRMS-APCI (m/z) [M+H]+ calcd for C29H26NO5+, 468.1806; found, 468.1774.
Pyrone 28a. Followed General Procedure C using pyrones 28a and 28b (90 mg, 0.193 mmol, 2.4:1 ratio of regioisomers) afforded pyrone 28a (65.0 mg, 72% recovery) as a yellow foam. Pyrone 28a: Rf 0.52 (1:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.58-7.52 (m, 2H), 7.49-7.44 (m, 2H), 7.43-7.39 (m, 1H), 7.36-7.24 (m, 7H), 7.10-7.04 (m, 2H), 5.07 (s, 2H), 4.54 (s, 2H), 3.89 (s, 3H), 3.51 (t, J=6.4, 2H), 2.71 (t, J=6.4, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): δ (22 of 23 signals observed) 162.62, 162.59, 156.2, 152.6, 138.4, 135.3, 131.5, 131.3, 129.6, 129.5, 129.2, 129.1, 128.8, 125.3, 124.4, 115.6, 112.8, 68.0, 56.5, 42.3, 42.1, 28.2; IR (film): 3032, 2937, 2837, 1697, 1255 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C29H26NO5+, 468.1806; found, 468.1784.
Pyrones 29a and 29b. Followed General Procedure B using silyl triflate 11 (66 mg, 0.15 mmol, 1.0 equiv) afforded pyrones 29a and 29b (68% yield, average of two experiments) as a yellow foam. Pyrones 29a and 29b: Rf 0.17 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 70° C.): δ 8.36-8.28 (m, 4H), 7.89-7.79 (m, 4H), 7.52-7.41 (m, 7H), 7.37-7.27 (m, 13H), 5.07 (s, 4H), 4.53 (s, 2H, 29a), 4.37 (s, 2H, 29b), 3.58-3.52 (m, 4H), 2.84 (t, J=6.3, 2H, 29b), 2.75 (t, J=6.6, 2H 29a); HRMS-APCI (m/z) [M+H]+ calcd for C28H23N2O6+, 483.1551; found, 483.1538.
Pyrone 29a. Followed General Procedure C using pyrones 29a and 29b (115 mg, 0.236 mmol, 1.5:1 ratio of regioisomers) afforded pyrone 29a (71 mg, 62% recovery) as a yellow foam. Pyrone 29a: Rf 0.17 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 70° C.): δ 8.35-8.28 (m, 2H), 7.86-7.79 (m, 2H), 7.52-7.41 (m, 4H), 7.37-7.30 (m, 6H), 5.07 (s, 2H), 4.54 (s, 2H), 3.57-3.52 (m, 2H), 2.78-2.72 (m, 2H); 13C-NMR (125 MHz, CD3CN, 70° C.): (17 of 22 signals observed) δ 160.7, 150.8, 137.5, 133.7, 129.88, 129.87, 128.4, 128.3, 128.2, 127.9, 127.6, 125.1, 123.8, 66.9, 41.0, 40.7, 27.0; IR (film): 3061, 2948, 1699, 1520, 1342 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C28H23N2O6+, 483.1551; found, 483.1546.
Pyrones 30a and 30b. Followed General Procedure B using silyl triflate 11 (66 mg, 0.15 mmol, 1.0 equiv) afforded pyrones 30a and 30b (66% yield, average of two experiments) as a yellow foam. Pyrones 30a and 30b: Rf 0.18 (5:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.72-7.69 (m, 3H), 7.56-7.54 (m, 2H), 7.53-7.45 (m, 8H), 7.44-7.40 (m, 3H), 7.36-7.29 (m, 12H), 5.07 (s, 4H), 4.50 (s, 2H, 30a), 4.35 (s, 2H, 30b), 3.56-3.49 (m, 4H), 2.80 (t, J=6.3, 2H, 30b), 2.72 (t, J=6.6, 2H, 30a); HRMS-APCI (m/z) [M+H]+ calcd for C28H23BrNO4+, 516.0805; found, 516.0796.
Pyrone 30a. Followed General Procedure C using pyrones 30a and 30b (40.0 mg, 0.0775 mmol, 1.3:1 ratio of regioisomers) afforded pyrone 30a (17 mg, 43% recovery) as a yellow foam. Crystals suitable for X-ray diffraction studies were obtained by concentration of pyrone 30a from a mixture of hexanes and EtOAc (CCDC #1876924). Pyrone 30a: mp 71-74° C.; Rf 0.18 (5:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.72-7.67 (m, 2H), 7.54-7.45 (m, 4H), 7.45-7.40 (m, 1H), 7.38-7.23 (m, 7H), 5.07 (s, 2H), 4.51 (s, 2H), 3.52 (t, J=6.5, 2H), 2.72 (t, J=6.5, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): (20 of 27 observed) δ 162.3, 154.8, 152.3, 135.1, 134.3, 133.2, 132.1, 131.7, 131.2, 129.6, 129.5, 129.32, 129.27, 129.1, 128.8, 125.4, 113.9, 68.0, 42.3, 41.9; IR (film): 3057, 2924, 2854, 1700, 1417, 1235 cm−1; HRMS-APCI (m/z) [M +H]+ calcd for C28H23BrNO4+, 516.0805; found, 516.0772.
Pyrones 31a and 31b. Followed General Procedure B using silyl triflate 11 (66 mg, 0.150 mmol, 1.0 equiv) afforded pyrones 31a and 31b (84% yield, average of two experiments) as a yellow foam. Pyrones 31a and 31b: Rf 0.62 (1:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): 31a: δ 7.72 (dd, J=5.1, 1.1, 1H), 7.56-7.52 (m, 1H), 7.49-7.44 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.27 (m, 7H), 7.26-7.22 (m, 1H), 5.13 (s, 2H), 4.71 (s, 2H), 3.54 (t, J=6.2, 2H), 2.66 (t, J=6.2, 2H); 31b: δ 7.70 (dd, J=5.1, 1.1, 1H), 7.61 (dd, J=3.8, 1.1, 1H), 7.49-7.44 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.27 (m, 7H), 7.26-7.22 (m, 1H), 5.07 (s, 2H), 4.32 (s, 2H), 3.65 (t, J=6.2, 2H), 2.95 (t, J=6.2, 2H); HRMS-APCI (m/z) [M+H]+ calcd for C26H22NO4S+, 444.1264; found, 444.1254.
Pyrone 31a. Followed General Procedure C using pyrones 31a and 31b (160 mg, 0.361 mmol, 2.1:1 ratio of regioisomers) afforded pyrone 31a (81 mg, 51% recovery) as a yellow foam. Pyrone 31a: Rf 0.62 (1:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.72 (dd, J=5.0, 0.9, 1H), 7.56-7.52 (m, 1H), 7.49-7.44 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.29 (m, 7H), 7.26-7.22 (m, 1H), 5.13 (s, 2H), 4.71 (s, 2H), 3.54 (t, J=6.2, 2H), 2.66 (t, J=66.2, 2H); 13CNMR (125 MHz, CD3CN, 60° C.): δ 161.6, 152.2, 150.4, 138.4, 135.2, 135.0, 131.2, 131.0, 130.8, 129.7, 129.5, 129.4, 129.3, 129.1, 128.8, 125.0, 112.4, 68.1, 42.8, 41.8, 28.7; IR (film): 3032, 2925, 2854, 1700, 1418 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C26H22NO4S+, 444.1264; found, 444.1240.
C. Syntheses of Tricyclic Products.
General Procedure D (Preparation of Cycloadduct 18 is Used as an Example of Embodiments).
Cycloadduct 18. To a stirred solution of pyrone 13a (44 mg, 0.10 mmol, 1.0 equiv) and silyl triflate 32 (60 mg, 0.20 mmol, 2.0 equiv) in acetonitrile (1.0 mL) was added CsF (76 mg, 0.50 mmol, 5.0 equiv) in one portion. The reaction was purged with nitrogen for ten minutes before being sealed with a Teflon cap and left to stir at 23° C. After 14 h, the reaction mixture was filtered through celite (monster pipette, ˜4 cm tall) with EtOAc (˜10 mL) as the eluent and then concentrated under reduced pressure. Purification of the crude material via flash chromatography (7:3 hexanes:EtOAc) afforded cycloadduct 18 (83% yield, average of two experiments) as a light yellow foam. Cycloadduct 18: Rf 0.57 (5:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.61-7.50 (m, 6H), 7.41-7.30 (m, 12H), 5.05 (s, 2H), 4.48 (s, 2H), 3.59 (t, J=6.3, 2H), 2.77 (t, J=6.3, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): δ 140.2, 139.5, 138.9, 138.6, 137.5, 132.9, 132.8, 132.6, 131.5, 131.4, 131.2, 130.0, 129.8, 129.6, 129.0, 128.9, 128.7, 127.2, 127.1, 126.8, 126.6, 67.7, 45.9, 43.1, 28.8; IR (film): 3062, 2935, 2887, 1698, 1233 cm−1; HRMS-APCI (m/z) [M+Na]+ calcd for C33H27NO2Na+, 492.1934; found, 492.1898.
Cycloadducts 20a and 20b. Followed General Procedure D using pyrone 13a (44 mg, 0.100 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Biotage 10 g SiO2, 19:1→2:3 hexanes:EtOAc), cycloadducts 20a and 20b (89% yield, 1.4:1 ratio of regioisomers, average of two experiments) as a yellow foam. Cycloadducts 20a and 20b: Rf 0.37 (5:2 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.79 (dd, J=7.5, 1.6, 2H), 7.63-7.48 (m, 18H), 7.42-7.38 (m, 2H), 7.37-7.28 (m, 18H), 7.05-7.00 (m, 2H), 5.08-5.03 (m, 4H), 4.45 (s, 4H), 3.63-3.56 (m, 4H), 2.75-2.69 (m, 4H); 13C-NMR (125 MHz, CD3CN): δ (52 of 62 signals observed) 156.3, 144.3, 143.6, 140.8, 140.4, 140.1, 139.7, 138.7, 138.6, 134.8, 134.6, 134.5, 133.6, 133.5, 132.23, 132.16, 131.8, 131.7, 131.4, 131.2, 131.00, 130.95, 130.83, 130.80, 130.1, 130.0, 129.7, 129.64, 129.60, 129.3, 129.1, 129.01, 128.97, 128.9, 128.70, 128.68, 128.5, 128.3, 128.2, 127.2, 127.1, 126.3, 126.19, 126.18, 126.0, 67.7, 46.6, 46.2, 43.0, 42.7, 29.4, 29.0; IR (film): 3055, 2939, 2889, 1698, 1235 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C37H30NO2+, 520.2271; found, 520.2242. Note: All peaks in the 1H-NMR spectrum of 20a and 20b were overlapping. However, the ratio of the two compounds was determined via deconvolution of the peaks at 5.06 and 5.04 ppm.
Cycloadducts 22a and 22b. Followed General Procedure D using pyrone 13a (44 mg, 0.100 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Isco 4 g gold SiO2, 100% hexanes→100% EtOAc), cycloadducts 22a and 22b (70% yield, average of two experiments) as a yellow foam. Cycloadducts 22a and 22b: Rf 0.38 (5:2 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 9.44 (br s, 2H), 7.63-7.41 (m, 15H), 7.38-7.21 (m, 17H), 7.11 (dd, J=9.0, 6.1, 2H), 6.91 (dd, J=2.9, 2.9, 2H), 5.08-5.02 (m, 6H), 4.46 (s, 2H), 4.44 (s, 2H), 3.60 (t, J=6.1, 4H), 2.75-2.68 (m, 4H); 13C-NMR (125 MHz, CD3CN, 60° C.): (47 of 58 signals observed) δ 156.4, 143.4, 142.6, 141.7, 141.0, 139.9, 138.6, 138.3, 137.8, 134.6, 134.4, 132.5, 131.4, 131.23, 131.19, 131.2, 131.1, 130.5, 130.3, 129.9, 129.8, 129.6, 129.3, 129.0, 128.94, 128.89, 128.63, 128.62, 128.58, 128.4, 128.2, 127.5, 127.1, 122.9, 122.74, 122.68, 122.0, 121.9, 114.4, 114.3, 105.9, 105.8, 67.7, 46.2, 46.1, 43.12, 43.08; IR (film): 3321, 3054, 2937, 1681, 1239 cm−1; HRMS-APCI (m/z) [M−Cbz+H]+ calcd for C27H23N2+, 375.1856; found, 375.1834. Note: All peaks in the 1H-NMR spectrum of 22a and 22b were overlapping. However, the ratio of the two compounds was determined via deconvolution of the peaks at 4.46 and 4.44 ppm.
Cycloadduct 24. Followed General Procedure D using pyrone 13a (44 mg, 0.100 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Biotage 10 g SiO2, 19:1→2:3 hexanes:EtOAc), cycloadduct 24 (71% yield, average of two experiments) as a yellow foam. Cycloadduct 24: Rf 0.54 (5:2 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.51-7.45 (m, 4H), 7.44-7.29 (m, 6H), 7.28-7.24 (m, 1H), 7.17-7.13 (m, 4H), 5.03 (s, 2H), 4.16 (s, 2H), 3.49 (t, J=6.0, 2H), 2.42 (t, J=6.0, 2H), 2.36-2.31 (m, 4H), 1.64-1.59 (m, 4H); 13C-NMR (125 MHz, CD3CN, 60° C.): (24 of 27 signals observed) δ 156.3, 141.9, 141.5, 140.8, 134.8, 134.4, 131.3, 130.4, 130.24, 130.17, 130.0, 129.8, 129.6, 128.9, 128.3, 128.0, 67.6, 46.0, 42.7, 31.0, 29.7, 29.4, 23.88, 23.85; IR (film): 3054, 2932, 2857, 1702, 1434 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C33H32NO2+, 474.2428; found, 474.2318.
Cycloadducts 14a and 14b. Followed General Procedure D using pyrone 13a (44 mg, 0.100 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Biotage 10 g SiO2, 19:1→2:3 hexanes:EtOAc), cycloadducts 14a and 14b (60% yield, 1.4:1 ratio of regioisomers, average of two experiments) as a yellow foam. Cycloadducts 14a and 14b: Rf 0.27 (5:2 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 70° C.): δ 7.54-7.41 (m, 12H), 7.38-7.22 (m, 20H), 7.21-7.14 (m, 8H) 5.04 (s, 8H), 4.23 (s, 4H), 4.21 (s, 4H), 3.51 (t, J=6.0, 8H), 2.52-2.44 (m, 8H); 13C-NMR (125 MHz, CD3CN, 70° C.): (31 of 37 signals observed) δ 156.4, 141.8, 140.6, 140.0, 139.9, 139.2, 138.7, 138.3, 132.9, 132.5, 131.7, 131.2, 130.6, 130.4, 130.3, 130.2, 130.1, 129.9, 129.6, 129.1, 129.01, 128.96, 128.70, 128.68, 128.5, 67.7, 46.1, 45.9, 42.7, 28.6, 28.3; IR (film): 3057, 3030, 2937, 1697, 1232 cm−1; HRMS-APCI (m/z) [M−Cbz]⋅− calcd for C32H29N2O2⋅−, 473.2224; found, 473.2201. Note: All peaks in the 1H-NMR spectrum of 14a and 14b were overlapping. However, the ratio of the two compounds was determined via deconvolution of the peaks at 4.23 and 4.21 ppm.
Cycloadduct 27a and 27b. Followed General Procedure D using pyrone 13a (28 mg, 0.065 mmol, 1.0 equiv) afforded, after purification via preparative thin layer chromatography (5:2 hexanes:EtOAc), cycloadducts 27a and 27b (62% yield, average of two experiments) as a yellow foam. Cycloadducts 27a and 27b: Rf 0.57 (9:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.53-7.46 (m, 8H), 7.46-7.39 (m, 4H), 7.36-7.29 (m, 6H), 7.28-7.22 (m, 3H), 7.21-7.15 (m 8H), 5.03 (s, 4H), 4.31 (s, 2H), 4.30 (s, 2H), 4.21 (s, 2H), 4.20 (s, 2H), 3.77-3.73 (m, 4H), 3.51 (t, J=6.1, 4H), 2.49-2.43 (m, 4H), 2.42-2.37 (m, 4H); 13C-NMR (125 MHz, CD3CN, 70° C.): (44 of 52 signals observed) δ 156.4, 142.0, 140.6, 140.2, 139.9, 139.5, 139.0, 138.8, 138.7, 137.2, 132.8, 132.6, 132.3, 132.1, 131.5, 131.4, 131.0, 130.9, 130.5, 130.4, 130.3, 130.2, 130.14, 130.12, 130.0, 129.9, 129.6, 129.0, 128.9, 128.7, 128.63, 128.62, 128.4, 68.2, 68.0, 67.7, 65.89, 65.88, 46.0, 45.7, 42.70, 42.68, 28.7, 28.5; IR (film): 3057, 2954, 2850, 1698, 1231 cm−1; HRMS-APCI (m/z) [M+K]+ calcd for C32H29NO3K+, 514.1779; found, 514.1752. Note: All peaks in the 1H-NMR spectrum of 27a and 27b were overlapping. However, the ratio of the two compounds was determined via deconvolution of the peaks at 4.22 and 4.20 ppm.
Cycloadduct 33. Followed General Procedure D using pyrone 28a (21 mg, 0.045 mmol, 1.0 equiv) afforded, after purification via preparative thin layer chromatography (4:1 hexanes:EtOAc), cycloadduct 33 (87% yield, average of two experiments) as a yellow foam. Cycloadduct 33: Rf 0.41 (4:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.60-7.55 (m, 2H), 7.53-7.49 (m, 1H), 7.46-7.42 (m, 1H), 7.40-7.26 (m, 10H), 7.25-7.21 (m, 2H), 7.15-7.09 (m, 2H), 5.06 (s, 2H), 4.50 (s, 2H), 3.92 (s, 3H), 3.58 (t, J=6.2, 2H), 2.76 (t, J=6.2, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): (25 of 28 signals observed) δ 160.6, 156.3, 140.2, 138.7, 138.6, 137.2, 132.9, 132.8, 132.4, 131.9, 131.4, 129.8, 129.6, 129.0, 128.7, 128.6, 127.2, 127.1, 126.7, 126.5, 115.5, 67.7, 56.3, 45.9, 43.1; IR (film): 3063, 3031, 2934, 1697, 1243 cm−1; HRMS-APCI (m/z) [M+K]+ calcd for C34H29NO3K+, 538.1779; found, 538.1752.
Cycloadduct 34. Followed General Procedure D using pyrone 29a (27 mg, 0.056 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Isco 4 g gold SiO2, 1:1 hexanes:EtOAc), cycloadduct 34 (69% yield, average of two experiments) as a yellow foam. Cycloadduct 34: Rf 0.63 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 70° C.): δ 8.41-8.33 (m, 2H), 7.62-7.50 (m, 5H), 7.46-7.41 (m, 1H), 7.40-7.25 (m, 10H), 5.05 (s, 2H), 4.46 (s, 2H), 3.60 (t, J=6.1, 2H), 2.79 (t, J=6.1, 2H); 13C-NMR (125 MHz, CD3CN, 70° C.): (22 of 27 observed) δ 146.8, 140.0, 139.9, 133.04, 132.97, 132.8, 131.9, 131.8, 131.4, 129.9, 129.6, 129.1, 128.82, 128.80, 127.5, 127.1, 126.7, 125.1, 67.9, 45.7, 43.1, 28.7; IR (film): 3062, 2839, 2862, 1699, 1518, 1348 cm−1; HRMS-APCI (m/z) [M−Cbz]− calcd for C25H19N2O2−, 379.1441; found, 379.1432.
Cycloadduct 35. Followed General Procedure D using pyrone 30a (21 mg, 0.041 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Biotage 10 g SiO2, 5:1 hexanes:EtOAc), cycloadduct 35 (92% yield, average of two experiments) as a yellow foam. Cycloadduct 35: Rf 0.50 (4:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.76-7.71 (m, 2H), 7.60-7.51 (m, 3H), 7.42-7.23 (m, 13H), 5.05 (s, 2H), 4.47 (s, 2H), 3.62-3.57 (m, 2H), 2.79-2.74 (m, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): δ 156.3, 140.0, 139.3, 138.6, 138.5, 136.0, 133.3, 133.1, 132.9, 132.8, 132.3, 131.7, 131.6, 131.3, 129.8, 129.6, 129.0, 128.7, 127.3, 126.91, 126.90, 126.8, 122.6, 67.8, 45.7, 43.1, 28.7; IR (film): 3062, 3032, 2929, 1700, 1215 cm−1; HRMS-APCI (m/z) [M−Cbz]− calcd for C25H19BrN−, 412.0695; found, 412.0669.
Cycloadduct 36. Followed General Procedure D using pyrone 31a (38 mg, 0.086 mmol, 1.0 equiv) afforded, after purification via flash chromatography (Isco gold 4 g SiO2, 1:1 hexanes:EtOAc), cycloadduct 36 (87% yield, average of two experiments) as a yellow foam. Cycloadduct 36: Rf 0.78 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.68-7.66 (m, 1H), 7.61-7.55 (m, 3H), 7.53-7.49 (m, 1H), 7.42-7.33 (m, 5H), 7.32-7.29 (m, 2H), 7.10-7.07 (m, 1H), 5.08 (s, 2H), 4.62 (s, 2H), 3.59 (t, J=6.2, 2H), 2.74 (t, J=6.2, 2H); 13CNMR (125 MHz, CD3CN, 60° C.): δ 156.3, 140.2, 139.9, 139.1, 138.5, 134.2, 133.7, 132.8, 132.7, 131.2, 129.9, 129.8, 129.6, 129.5, 129.0, 128.8, 128.72, 128.69, 128.2, 127.2, 127.00, 126.98, 126.8, 67.7, 45.9, 43.0, 28.8; IR (film): 3064, 2939, 2888, 1697, 1420 cm−1; HRMS-APCI (m/z) [M−Cbz]− calcd for C23H18NS−, 340.1155; found, 340.1133.
D. One-Pot Three-Component Coupling.
Cycloadduct 18. A solution of silyl triflate 11 (25.0 mg, 0.057 mmol, 1.0 equiv), oxadiazinone 12 (14.3 mg, 0.057 mmol, 1.0 equiv), and silyl triflate 32 (17.0 mg, 0.057 mmol, 1.0 equiv) in acetonitrile (5.7 mL) was purged with nitrogen for 10 min. Then, CsF (26.0 mg, 0.171 mmol, 3.0 equiv) was added and the reaction was allowed to stir at 23° C. for 14 h. Upon completion of the reaction, it was filtered through celite (monster pipette, ˜4 cm tall) using CH2Cl2 (˜10 mL) as the eluent and concentrated under reduced pressure. The crude residue was purified using preparative thin layer chromatography (100% benzene) to afford cycloadduct 18 (15.0 mg, 56% yield) as a yellow oil. Spectral data matched those already reported herein for 18.
E. Synthesis of Four Coordinate Products.
Hydrazone SI-18. Followed General Procedure A using hydrazide SI-4 (0.500 g, 3.20 mmol) to afford hydrazone SI-18 (0.820 g, 84% yield) as a tan solid. Hydrazone SI-18: mp 172-173° C.; Rf 0.26 (9:1 EtOAc:MeOH); 1H-NMR (500 MHz, DMSO-d6): δ 12.88 (br s, 1H), 7.86-7.82 (m, 2H), 7.67 (dd, J=3.6, 1.0, 1H), 7.63 (dd, J=5.0, 1.1, 1H), 7.13-7.08 (m, 3H), 3.85 (s, 3H); 13CNMR (125 MHz, DMSO-d6): (9 of 12 signals observed) δ 163.1, 162.5, 139.0, 129.4, 128.9, 127.8, 124.7, 114.2, 55.5; IR (film): 3210, 3012, 2838, 1691, 1483 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C14H13N2O4S+, 305.0591; found, 305.0595.
Oxadiazinone 37. Followed General Procedure A using hydrazone SI-18 (0.750 g, 3.20 mmol) to afford oxadiazinone 37 (0.550 g, 78% yield) as a yellow solid after recrystallization from hot EtOAc. Oxadiazinone 37: mp 146-147° C.; Rf 0.67 (5:2 hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 8.31 (dd, J=3.8, 1.1, 1H), 8.22-8.18 (m, 2H), 7.61 (dd, J=5.1, 1.1, 1H), 7.19 (dd, J=5.1, 3.8, 1H), 7.04-7.00 (m, 2H), 3.90 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 164.2, 156.9, 147.9, 147.8, 135.0, 133.3, 132.5, 130.3, 128.8, 119.9, 114.8, 55.7; IR (film): 3123, 3076, 2847, 1750, 1603 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C14H11N2O3S+, 287.0485; found, 287.0470.
Pyrones 38 and SI-19. Followed General Procedure B using silyl triflate 11 (680 mg, 1.55 mmol, 1.0 equiv) afforded pyrones 38 and SI-19 (69% yield, 1.4:1 ratio of regioisomers) as a yellow oil. Pyrones 38 and SI-19: Rf 0.24 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.61-7.52 (m, 5H), 7.50-7.38 (m, 10H), 7.37-7.27 (m, 16H), 7.09-7.04 (m, 5H), 5.08-5.04 (m, 4H), 4.54 (s, 2H), 4.34 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.56-3.48 (m, 4H), 2.83 (t, J=6.4, 2H), 2.71 (t, J=6.4, 2H); HRMS-APCI (m/z) [M+H]+ calcd for C27H24NO5S+, 474.1370; found, 474.1362.
Pyrone 38. Followed General Procedure C using pyrones 38 and SI-19 (85 mg, 0.179 mmol, 1.0 equiv) afforded pyrone 38 (64% yield) as a yellow oil. Pyrone 38: Rf 0.24 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.57-7.52 (m, 3H), 7.36-7.24 (m, 5H), 7.17 (dd, J=3.6, 1.3, 1H), 7.16-7.13 (m, 1H), 7.09-7.04 (m, 2H), 5.07 (s, 2H), 4.53 (s, 2H), 3.88 (s, 3H), 3.54 (t, J=6.5, 2H), 2.95 (t, J=6.5, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): (21 of 23 observed) δ 162.7, 162.1, 156.4, 153.9, 138.4, 135.4, 131.5, 130.6, 129.6, 129.1, 128.8, 128.6, 127.8, 125.1, 117.6, 115.5, 112.9, 68.0, 56.5, 42.14, 42.10, 28.7; IR (film): 3072, 2937, 1699, 1507, 1257 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C27H24NO5S+, 474.1370; found, 474.1334. Note: Pyrone 38 could be directly accessed in one step from silyl triflate 11 and oxadiazinone 37 using 5.0 equiv of CsF. This reaction results in a 41% yield (as previously shown herein) of pyrone 38 as a single regioisomer.
Cycloadducts SI-20a and SI-20b. Followed General Procedure D using pyrone 38 (200 mg, 0.422 mmol, 1.0 equiv) afforded, after purification via flash chromatography (7:3 hexanes:EtOAc), cycloadducts SI-20a and SI-20b (78% yield, 1:1 ratio of regioisomers) as a yellow oil. Cycloadducts SI-20a and SI-20b: Rf 0.25 (3:1 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 9.48 (br s, 2H), 7.69 (dd, J=5.2, 1.2, 1H), 7.63 (dd, J=5.2, 1.2, 1H), 7.52 (dd, J=9.2, 0.8, 1H), 7.48 (dd, J=9.1, 1.0, 1H), 7.37-7.25 (m. 12H), 7.23-7.19 (m, 4H), 7.17-7.08 (m, 5H), 7.06-7.04 (m, 2H), 7.03-7.01 (m, 1H), 6.96-6.94 (m, 1H), 5.31-5.29 (m, 1H), 5.16-5.13 (m, 1H), 5.08-5.04 (m, 4H), 5.48-5.42 (m, 4H), 3.94 (s, 3H), 3.91 (s, 3H), 3.65-3.60 (m, 4H), 2.92-2.80 (m, 4H); 13C-NMR (125 MHz, CD3CN, 60° C.): (57 of 60 observed) δ 159.7, 159.3, 155.1, 142.5, 140.5, 138.2, 134.1, 133.6, 133.3, 133.2, 131.4, 131.00, 130.97, 130.71, 130.70, 130.6, 130.4, 130.3, 129.1, 128.6, 128.37, 128.36, 128.2, 128.1, 127.86, 127.85, 127.8, 127.73, 127.69, 127.54, 127.53, 127.44, 127.44, 127.43, 127.36, 126.6, 126.4, 126.3, 121.9, 121.7, 121.3, 120.8, 120.4, 114.8, 114.2, 113.6, 113.1, 104.7, 104.3, 66.46, 66.45, 55.2, 55.1, 44.9, 44.8, 41.8, 41.7; IR (film): 3416, 3032, 2931, 1678, 1244 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C34H29N2O3S+, 545.1893; found, 545.1887.
Cycloadducts 40a and 40b. To a solution of NaH (33.0 mg, 60% w/w dispersion in mineral oil, 0.826 mmol, 3.0 equiv) in THF (5.0 mL) at 0° C., was cannula transferred a 0° C. solution of cycloadducts SI-20a and SI-20b (150 mg, 0.275 mmol, 1.0 equiv) in THF (14.0 mL) dropwise over 3 minutes. The reaction was allowed to warm to 23° C. and stirred for 1 h before being cooled back down to 0° C. Then, TIPSCI (0.880 mL, 0.413 mmol, 1.5 equiv) was added to the reaction mixture dropwise over 5 minutes at 0° C. The reaction was allowed to warm 23° C. and stirred for 18 h, before being quenched with saturated ammonium chloride (2.0 mL) and deionized water (10.0 mL). The layers were transferred to a separatory funnel and the aqueous layer was extracted with diethyl ether (3×10 mL). The combined organic layers were then washed with brine (1×10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified via flash chromatography (7:3 hexanes:EtOAc) to afford cycloadducts 40a and 40b (155 mg, 80% yield, 1:1 ratio of regioisomers) as a clear oil. Cycloadducts 40a and 40b: Rf 0.69 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.69 (dd, J=5.1, 1.2, 1H), 7.65 (dd, J=9.3, 1.0, 1H), 7.63-7.59 (m, 2H), 7.37-7.25 (m, 13H), 7.23-7.19 (m, 4H), 7.16-7.08 (m, 6H), 7.06-7.04 (m, 3H), 5.45 (dd, J=3.2, 0.9, 1H), 5.30 (dd, J=3.3, 0.9, 1H), 5.08-5.04 (m, 4 H), 4.47-4.42 (m, 4H), 3.93 (s, 3H), 3.91 (s, 3H), 3.64-3.58 (m, 4H), 2.92-2.85 (m, 2H), 2.83 (t, J=6.1, 2H), 1.75-1.65 (m, 6H), 1.10 (d, J=2.9, 18H), 1.08 (d, J=2.9, 18H); 13C-NMR (125 MHz, CD3CN, 60° C.): (56 of 64 observed) δ 160.9, 160.6, 156.3, 143.9, 141.7, 139.6, 139.3, 139.2, 138.6, 137.4, 135.5, 134.4, 132.5, 132.3, 132.23, 132.20, 131.9, 131.8, 131.3, 130.33, 130.27, 130.1, 129.6, 129.4, 129.14, 129.14, 129.02, 128.98, 128.92, 128.88, 128.8, 128.7, 128.6, 127.9, 127.6, 127.5, 126.8, 126.4, 121.6, 121.2, 117.0, 116.6, 116.1, 115.5, 108.5, 108.0, 67.71, 67.69, 56.41, 56.35, 46.2, 46.0, 43.1, 43.0, 18.7, 13.8; IR (film): 3066, 2947, 2867, 1701, 1243 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C43H49N2O3SSi+, 701.3228; found, 701.3213.
Cycloadduct 40a. Crystals suitable for X-ray diffraction studies were obtained by slow concentration of cycloadduct 40a from EtOAc (CCDC #1876925). Cycloadduct 40a: Rf 0.69 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.70 (dd, J=5.2, 1.1, 1H), 7.61 (dd, J=9.4, 0.8, 1H), 7.37-7.25 (m, 6H), 7.25-7.20 (m, 2H), 7.16-7.09 (m, 4H), 7.06 (dd, J=3.4, 1.2, 1H), 5.45 (3.2, 0.8, 1H), 5.07 (s, 2H), 4.46 (s, 2H), 3.94 (s, 3H), 3.65-3.59 (m, 2H), 2.93-2.86 (m, 2H), 1.71 (sep, J=7.5, 3H), 1.10 (d, J=7.5, 18H); 13C-NMR (125 MHz, CD3CN, 60° C.): (27 of 32 observed) δ 160.6, 156.4, 143.8, 139.6, 135.5, 132.5, 132.2, 130.3, 129.6, 129.1, 129.01, 128.96, 128.9, 128.8, 128.7, 127.9, 126.3, 121.6, 116.6, 115.5, 108.0, 67.7, 56.3, 46.0, 43.1, 18.6, 13.8; IR (film): 3030, 2947, 2868, 1702, 1245 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C43H49N2O3SSi+, 701.3228; found, 701.3217.
Cycloadduct 40b. Cycloadduct 40b: Rf 0.69 (7:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.68-7.62 (m, 2H), 7.38-7.20 (m, 9H), 7.19-7.13 (m, 2H), 7.08-7.05 (m, 2H), 5.30 (dd, J=3.2, 0.8, 1H), 5.07 (s, 2H), 4.46 (s, 2H), 3.94 (s, 3H), 3.63 (t, J=6.2, 2H), 2.84 (t, J=6.2, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): (31 of 32 observed) δ 160.9, 156.3, 141.7, 139.3, 138.6, 137.4, 134.4, 132.2, 131.9, 131.8, 131.3, 130.3, 130.1, 129.6, 129.4, 129.0, 128.7, 128.6, 127.6, 127.5, 126.8, 121.2, 117.0, 116.1, 108.5, 67.7, 56.4, 46.2, 43.0, 18.6, 13.8; IR (film): 3030, 2947, 2868, 1702, 1245 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C43H49N2O3SSi+, 701.3228; found, 701.3216.
Indoloisoquinoline 41a. A solution of cycloadduct 40a (20 mg, 0.029 mmol, 1.0 equiv) and palladium hydroxide on carbon (20% wt %, 20 mg, 100% wt/wt relative to cycloadduct 40a) in methanol (4.0 mL) was purged with H2 for 20 min. After stirring at 23° C. under an atmosphere of H2 (1 atm) for 18 h, the reaction was diluted with CH2Cl2 (1.0 mL) and filtered through celite (monster pipette, ˜4 cm tall) with CH2Cl2 (10.0 mL) as the eluent, and concentrated under reduced pressure. The crude residue was added to a scintillation vial along with MnO2 (125 mg, 1.43 mmol, 50 equiv) and toluene (0.5 mL). The reaction vial was heated to 110° C. and left to stir. After 18 h, the reaction mixture was cooled to 23° C., filtered through celite (monster pipette, ˜4 cm tall) with CH2Cl2 (10.0 mL) as the eluent, and concentrated under reduced pressure. Purification of the crude residue via preparative thin layer chromatography (3:1 hexanes:EtOAc) afforded indoloisoquinoline 41a (11.0 mg, 68% yield, over 2 steps) as a yellow amorphous solid. Indoloisoquinoline 41a: Rf 0.54 (9:1 PhH:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 9.13 (d, J=0.8, 1H), 8.37 (d, J=6.2, 1H), 7.70 (dd, J=5.2, 1.2, 1H), 7.63 (dd, J=9.6, 0.8, 1H), 7.57 (dd, J=6.2, 1.0, 1H), 7.53 (d, J=9.6, 1H), 7.45-7.41 (m, 2H), 7.39 (dd, J=5.2, 3.4, 1H), 7.21 (dd, J=3.3, 1.2, 1H), 7.17-7.14 (m, 2H), 7.10 (d, J=3.2), 5.66 (dd, J=3.2, 0.9, 1H), 3.97 (s, 3H), 1.70-1.63 (m, 3H), 1.12 (d, J=7.6, 18H); 13C-NMR (125 MHz, CDCl3): δ 159.5, 153.2, 141.3, 140.9, 140.6, 138.4, 133.5, 132.5, 132.4, 130.7, 130.1, 128.9, 128.7, 128.5, 128.0, 127.2, 124.5, 124.4, 123.9, 121.8, 118.0, 117.3, 114.0, 108.8, 55.6, 18.3, 13.1; IR (film): 3068, 2949, 2928, 1392, 1247 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C35H39N2OSSi+, 563.2547; found, 563.2545.
Indoloisoquinoline 41b. A solution of cycloadduct 40b (20 mg, 0.029 mmol, 1.0 equiv) and palladium hydroxide on carbon (20% wt %, 20 mg, 100% wt/wt relative to cycloadduct 40b) in methanol (4.0 mL) was purged with H2 for 20 min. After stirring at 23° C. under an atmosphere of H2 (1 atm) for 18 h, the reaction was diluted with CH2Cl2 (1.0 mL) and filtered through celite (monster pipette, ˜4 cm tall) with CH2Cl2 (10.0 mL) as the eluent, and concentrated under reduced pressure. The crude residue was added to a scintillation vial along with MnO2 (125 mg, 1.43 mmol, 50 equiv) and toluene (0.5 mL). The reaction vial was heated to 110° C. and left to stir. After 18 h, the reaction mixture was cooled to 23° C., filtered through celite (monster pipette, ˜4 cm tall) with CH2Cl2 (10.0 mL) as the eluent, and concentrated under reduced pressure. Purification of the crude residue via preparative thin layer chromatography (3:1 hexanes:EtOAc) afforded indoloisoquinoline 41b (9.7 mg, 60% yield, over 2 steps) as a yellow amorphous solid. Indoloisoquinoline 41b: Rf 0.54 (9:1 PhH:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 9.12 (d, J=0.9, 1H), 8.35 (d, J=6.1, 1H), 7.72 (dd, J=9.6, 0.8, 1H), 7.66-7.62 (m, 2H), 7.57 (dd, J=6.2, 1.0, 1H), 7.43-7.40 (m, 2H), 7.33 (dd, J=5.2, 3.4, 1H), 7.24 (dd, J=3.3, 1.2, 1H), 7.22-7.19 (m, 2H), 7.04 (d, J=3.2), 5.52 (dd, J=3.1, 0.8, 1H), 4.01 (s, 3H), 1.66 (sept, J=7.7, 3H), 1.12 (d, J=7.7, 18H); 13C-NMR (125 MHz, CDCl3): δ 159.8, 153.0, 140.3, 139.2, 137.7, 137.2, 132.2, 131.94, 131.87, 131.0, 129.7, 128.7, 127.7, 127.4, 127.1, 126.9, 125.9, 125.5, 120.8, 119.0, 118.2, 114.8, 109.1, 55.6, 18.3, 13.1; IR (film): 3065, 2949, 2868, 1383, 1245 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C35H39N2OSSi+, 563.2547; found, 563.2537.
F. Synthesis of Donor-Acceptor Fluorophore and Polymer.
Hydrazone Sl-23. Followed General Procedure A using hydrazide Sl-21 (1.73 g, 9.37 mmol, 1.0 equiv) afforded hydrazone Sl-23 (2.00 g, 63% yield) as a white solid. Hydrazone Sl-23: mp 178-180° C.; Rf 0.56 (9:1 EtOAc:MeOH); 1H-NMR (500 MHz, DMSO-d6, 60° C.): δ 12.72 (br s, 1H), 7.87 (d, J=8.3, 2H), 7.72 (d, J=8.3, 2H), 7.62 (d, J=8.3, 2H), 7.49 (d, J=8.3, 2H); 13C-NMR (125 MHz, DMSO-d6, 60° C.): δ 163.2, 141.6, 136.9, 134.0, 133.4, 131.4, 130.5, 129.7, 129.4, 128.6, 128.0; IR (film): 3359, 3087, 1729, 1662, 1093 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C15H11Cl2N2O3+, 337.0141; found, 337.0130.
Oxadiazinone 43. Followed General Procedure A using hydrazone SI-23 (1.80 g, 5.34 mmol, 1.0 equiv) afforded oxadiazinone 43 (1.50 g, 88% yield) as a yellow solid after recrystallization from hot acetone. Oxadiazinone 43: mp 229-233° C.; Rf 0.64 (9:1 EtOAc:MeOH); 1H-NMR (500 MHz, CDCl3): δ 8.34-8.30 (m, 2H), 8.24-8.21 (m, 2H), 7.56-7.52 (m, 2H), 7.51-7.48 (m, 2H); 13C-NMR (125 MHz, CDCl3): δ 157.2, 152.0, 147.9, 140.7, 138.9, 130.5, 129.8, 129.7, 129.4, 129.2, 126.0; IR (film): 3099, 1757, 1595, 1151, 1094 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C15H9Cl2N2O2+, 319.0036; found, 319.0032.
Tricycle 44. A solution of silyl triflate 11 (25.0 mg, 0.057 mmol, 1.0 equiv), oxadiazinone 43 (36.5 mg, 0.114 mmol, 2.0 equiv), and silyl triflate 32 (85.3 mg, 0.286 mmol, 5.0 equiv) in acetonitrile (5.7 mL) was purged with nitrogen for 10 min. Then, CsF (60.8 mg, 0.400 mmol, 7.0 equiv) was added and the reaction was allowed to stir at 23° C. for 14 h. Upon completion of the reaction, it was filtered through celite (monster pipette, ˜4 cm tall) using CH2Cl2 (˜10 mL) as the eluent and concentrated under reduced pressure. The crude residue was purified using preparative thin layer chromatography (100% benzene) to afford tricycle 44 (17.9 mg, 58% yield) as a yellow oil. Tricycle 44: Rf 0.58 (17:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.60-7.55 (m, 4H), 7.42-7.23 (m, 13H), 5.06 (s, 2H), 4.46 (s, 2H), 3.59 (t, J=6.0, 2H), 2.75 (t, J=6.3, 2H); 13C-NMR (125 MHz, CD3CN, 60° C.): δ 156.3, 138.8, 138.5, 138.1, 137.9, 136.4, 134.6, 134.3, 133.1, 132.99, 132.96, 132.8, 132.4, 131.8, 130.1, 129.97, 129.97, 129.96, 129.95, 129.94, 129.63, 129.62, 129.61, 129.60, 129.59, 129.59, 129.0, 128.7, 127.1, 127.03, 127.00, 126.9, 67.8, 45.7, 43.0, 28.7; IR (film): 3065, 3033, 2935, 2891, 1699 cm−1; HRMS-APCI (m/z) [M]⋅+ calcd for C33H25Cl2NO2+, 537.1257; found, 537.1204.
Boronic Ester 45. To a vial was added tricycle 44 (20 mg, 0.037 mmol, 1.0 equiv), B2pin2 (19.8 mg, 0.078 mmol, 2.2 equiv), KOAc (21.9 mg, 0.233 mmol, 6.0 equiv), Pd(OAc)2 (0.8 mg, 0.0037 mmol, 10 mol %), and SPhos (3.8 mg, 0.0093 mmol, 25 mol %), and the vial was purged with nitrogen for 30 min. Then, 1,4-dioxane (3.7 mL) was added and the reaction was heated to 80° C. After stirring for 18 h, the reaction was cooled to 23° C. and concentrated under reduced pressure. The crude residue was purified via flash chromatography (Yamazen SiO2, 3:1 hexanes:EtOAc) to afford boronic ester 45 (25.0 mg, 93% yield) as a white foam. Boronic Ester 45: Rf 0.29 (17:3 hexanes:EtOAc); 1H-NMR (500 MHz, CD3CN, 60° C.): δ 7.95-7.88 (m, 4H), 7.40-7.20 (m, 13H), 5.04 (s, 2H), 4.46 (s, 2H), 3.57 (t, J=6.3, 2H), 2.76 (t, J=6.3, 2H), 1.42 (s, 12H), 1.40 (s, 12H); 13C-NMR (125 MHz, CD3CN, 60° C.): δ (29 of 35 signals observed) 156.3, 143.2, 142.5, 138.8, 138.5, 137.3, 136.0, 135.9, 132.7, 132.6, 132.3, 131.4, 131.0, 130.8, 129.6, 128.9, 128.6, 127.13, 127.09, 126.9, 126.7, 85.3, 85.2, 67.7, 45.8, 43.0, 28.7, 25.52, 25.48; IR (film): 3032, 2978, 2938, 1705, 1358 cm−1; HRMS-APCI (m/z) [M+K]+ calcd for C45H49B2NO6K+, 760.3378; found, 760.3376.
Donor-Acceptor 47. A vial was charged with boronic ester 45 (20 mg, 0.028 mmol, 1.0 equiv), 4-bromobenzothiadiazole (46) (17.9 mg, 0.083 mmol, 3.0 equiv), and RuPhos Pd G3 (1.2 mg, 0.0014 mmol, 5 mol %), and then evacuated and backfilled with nitrogen three times. A separate flask containing a 2.0 M solution of aqueous K3PO4 was sparged with nitrogen for 1 h. To the vial, was then added 1,4-dioxane (2.8 mL) and the reaction was heated to 80° C. After 10 min, K3PO4 (2.0 M solution, 0.28 mL) was added and the reaction was allowed to stir at 80° C. After 18 h, the reaction was cooled to 23° C., filtered over celite (monster pipette, ˜4 cm tall) using CH2Cl2 (˜10 mL) as the eluent, and concentrated under reduced pressure. The crude residue was purified via flash chromatography (Yamazen SiO2, 17:3 hexanes:EtOAc) to afford donor-acceptor 47 (19.5 mg, 95% yield) as an off-white solid. Donor-acceptor 47: mp 237-238° C.; Rf 0.42 (3:1 hexanes:EtOAc); 1H-NMR (500 MHz, DMSO-d6, 70° C.): δ 8.24 (d, J=8.2, 4H), 8.18-8.12 (m, 2H), 8.06-8.01 (m, 2H), 7.93-7.87 (m, 2H), 7.58-7.41 (m, 8H), 7.30-7.10 (m, 5H), 5.05 (s, 2H), 4.61 (s, 2H), 3.64 (t, J=6.1, 2H), 2.88 (t, J=6.1, 2H); 13C-NMR (125 MHz, DMSO-d6, 70° C.): δ (37 of 39 observed) 155.0, 154.9, 154.3, 152.59, 152.56, 138.1, 137.4, 136.6, 136.5, 135.9, 135.7, 135.2, 132.8, 132.7, 131.0, 130.9, 130.5, 130.0, 129.87, 129.86, 129.8, 129.12, 129.08, 127.9, 127.8, 127.7, 127.0, 125.51, 125.49, 125.3, 120.32, 120.27, 65.9, 44.2, 41.4, 28.6; IR (film): 3071, 3032, 2925, 2854, 1700 cm−1; HRMS-APCI (m/z) [M+K]+ calcd for C45H32N5O2S2+, 738.1992; found, 738.1983.
Polymer 49. A vial was charged with boronic ester 45 (2.01 mg, 0.0291 mmol, 1.00 equiv), 4,7-dibromobenzothiadiazole (48) (8.56 mg, 0.0291 mmol, 1.00 equiv), and RuPhos Pd G3 (0.487 mg, 0.000582 mmol, 2.00 mol %), and then evacuated and backfilled with nitrogen three times. A separate flask containing a 2.0 M solution of aqueous K3PO4 was sparged with nitrogen for 1 h. To the vial, was added 1,4-dioxane (2.91 mL) and the reaction was heated to 80° C. After 10 min, K3PO4 (2.0 M solution, 0.100 mL) was added and the reaction was allowed to stir at 80° C. After 18 h, the reaction was cooled to 23° C., filtered over celite (monster pipette, ˜4 cm tall) using CH2Cl2 (˜10 mL) as the eluent, and concentrated under reduced pressure. The crude residue was dissolved in CH2Cl2 (0.300 mL), then crashed out with methanol (5.00 mL) and filtered to afford polymer 49 (15.8 mg, 86% yield) as an off-white solid. Polymer 49: 1H-NMR (500 MHz, CDCl3): δ 8.37-7.84 (m), 7.81-7.08 (m), 5.26-5.01 (m), 4.79-4.53 (m), 3.79-3.58 (m), 3.05-2.76 (m).
Polymer Characterization. Near-monodisperse poly(styrene) standards (Polymer Laboratories) were employed for calibration and Mw, Mn, and DM were calculated from refractive index. Polymer 49 was found to have a Mw of 2.40 kDa, a Mn of 1.72 kDa, and a DM of 1.39.
Materials and Methods Related to Triphenylene Scaffold PAH scaffolds.
Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen or argon and commercially obtained reagents were used as received. Anhydrous solvents were either freshly distilled or passed through activated alumina columns, unless otherwise stated. Reaction temperatures were controlled using an IKAmag temperature modulator, and unless stated otherwise, reactions were performed at room temperature (approximately 23° C.). Cesium Fluoride (CsF), and Bis(dibenzylidenacetone)palladium(0) (Pd(dba)2), and Palladium(II) acetate (Pd(OAc)2) were obtained from Strem Chemicals and stored in a desiccator. Potassium hexafluorophosphate (KPF6) was obtained from Oakwood Chemicals and used as received. Tri(o-tolyl)phosphine (P(o-tolyl)3) and decolorizing carbon were obtained from Sigma-Aldrich. 2-Bromobiphenyl (17) was obtained from Combi-Blocks and purified by flash chromatography prior to use. Bromobiaryl SI-7 was obtained from Combi-Blocks. Bromobiaryls SI-3 (Zhang, Q.-W.; et al., Rhodium-Catalyzed Intramolecular C—H Silylation by Silacyclobutanes. Angew. Chem., Int. Ed. 2016, 55, 6319-6323, the disclosure of which is incorporated herein by reference), SI-5 (Wang, T.-F.; et al. Easily Accessible 2-(2-Bromophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane for Suzuki-Miyaura Reactions. J. Chin. Chem. Soc. 2007, 54, 811-816, the disclosure of which is incorporated herein by reference), SI-9 (Wu, D.; et al. Synthesis of 1,3-Azaphospholes with Pyrrolo[1,2-a]quinolone Skeleton and Their Optical Applications. Org. Lett. 2018, 20, 4103-4106, the disclosure of which is incorporated herein by reference), SI-11 (Wong, S. M.; et al. Preparation of 2-(2-(Dicyclohexylphosphino)phenyl)-1-methyl-1H-indole (CM-phos) Org. Synth. 2016, 93, 14-28, the disclosure of which is incorporated herein by reference), and SI-13 (Panteleev, J.; et al. C—H Bond Functionalization in the Synthesis of Fused 1,2,3-Triazoles. Org. Lett. 2010, 12, 5092-5095, the disclosure of which is incorporated herein by reference) were prepared according to literature procedures. The silyl triflate precursors to N-Me-4,5-indolyne (Bronner, S. M.; et al. Indolynes as Electrophilic Indole Surrogates: Fundamental Reactivity and Synthetic Applications. Org. Lett. 2009, 11, 1007-1010, the disclosure of which is incorporated herein by reference), N-Boc-4,5-indolyne (Im, G.-Y. J.; et al. Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions. J. Am. Chem. Soc. 2010, 132, 17933-17944, the disclosure of which is incorporated herein by reference), N-Me-5,6-indolyne, and N-Cbz-3,4,-piperidyne (McMahon, T. C.; et al. Generation and Regioselective Trapping of a 3,4-Piperidyne for the Synthesis of Functionalized Heterocycles. J. Am. Chem. Soc. 2015, 137, 4082-4085 the disclosure of which is incorporated herein by reference) were prepared following literature procedures. The synthesis of the silyl triflate precursor to N-Me-2,3-carbazolyne will not be discussed in this report. Regioisomeric ratios for annulation products were determined from 1H-NMR spectra of the crude mixtures. Thin-layer chromatography (TLC) was conducted with EMD gel 60 F254 pre-coated plates (0.25 mm for analytical chromatography and 0.50 mm for preparative chromatography) and visualized using UV. Silicycle Siliaflash P60 (particle size 0.040-0.063 mm) was used for flash column chromatography. 1H NMR spectra were recorded on Bruker spectrometers (at 400, 500 and 600 MHz) and are reported relative to residual solvent signals. Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), integration. Data for 13C NMR are reported in terms of chemical shift (at 101 and 125 MHz). IR spectra were recorded on a Perkin-Elmer UATR Two FT-IR spectrometer and are reported in terms of frequency absorption (cm−1). DART-MS spectra were collected on a Thermo Exactive Plus MSD (Thermo Scientific) equipped with an ID-CUBE ion source and a Vapur Interface (lonSense Inc.). Both the source and MSD were controlled by Excalibur software v. 3.0. The analyte was spotted onto OpenSpot sampling cards (lonSense Inc.) using CH2Cl2 as the solvent. Ionization was accomplished using UHP He plasma with no additional ionization agents. The mass calibration was carried out using Pierce LTQ Velos ESI (+) and (−) Ion calibration solutions (Thermo Fisher Scientific).
A. Scope of Methodology
Representative Procedure (Palladium-catalyzed annulation of indolyne precursor 19 with 2-bromobiphenyl (17) is used as an example). Indole 23. A 1-dram vial was charged with Pd(dba)2 (3.7 mg, 0.064 mmol, 5 mol %). Next, toluene (0.86 mL), P(o-tolyl)3 (2.0 mg, 0.064 mmol, 5 mol %), 2-bromobiphenyl (17) (30.0 mg, 0.129 mmol, 1.0 equiv), silyl triflate 19 (90.5 mg, 0.257 mmol, 2.0 equiv), and acetonitrile (0.86 mL) were added followed by an oven-dried magnetic stirbar and then CsF (195 mg, 1.29 mmol, 10.0 equiv). The vial was sealed with a Teflon-lined screw cap and stirred at 110° C. for 24 h. After allowing to cool to 23° C., the mixture was transferred with CH2Cl2 (10 mL) and H2O (2 mL) to a 150 mL separatory funnel containing brine (15 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product was purified by flash chromatography (100% Hexanes→200:1 Hexanes:EtOAc) to yield annulation product 23 (90% yield, average of two experiments) as an off-white solid. Indole 23: mp: 139-144° C.; Rf 0.41 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3): δ 9.24 (d, J=8.0, 1H), 8.78 (d, J=8.0, 1H), 8.72 (t, J=7.0, 2H), 8.57 (d, J=9.0, 1H), 7.75 (t, J=7.4, 1H), 7.73-7.62 (m, 4H), 7.53 (d, J=2.8, 1H), 7.28 (d, J=3.0, 1H), 3.92 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 136.4, 131.3, 131.2, 130.4, 128.9, 128.8, 127.17, 127.15, 126.7, 126.4, 125.9, 124.6, 124.1, 123.8, 123.6, 123.3, 123.3, 117.7, 110.5, 104.0, 33.3; IR (film): 3069, 2924, 2850, 1514, 1492, 1441, 1417, 1351, 1248, 754, 740, 718 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C21H16N+, 282.12773; found 282.12717.
Indole 26. Purification by flash chromatography (hexanes to 1:1 hexanes/benzene) afforded indole 26 (81% yield, average of two experiments) as an off-white solid. Indole 26: Rf 0.25 (9:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3): δ 8.92 (s, 1H), 8.73 (d, J=8.3, 2H), 8.62 (t, J=7.7, 2H), 8.51 (s, 1H), 7.66-7.56 (m, 4H), 7.27 (d, J=2.6, 1H), 6.70 (dd, J=0.8, 3.1, 1H), 4.00 (s, 3H); 13C NMR (125 MHz, CDCl3): (27 of 28 signals observed) δ 137.4, 132.0, 131.4, 131.2, 129.6, 129.3, 129.0, 127.3, 127.1, 126.6, 126.1, 125.7, 123.56, 123.55, 123.4, 123.22, 123.15, 115.1, 102.3, 101.1, 33.2; IR (film): 3081, 2928, 2811, 1628, 1601, 1520, 1446, 1218, 1085, 754 cm−1; HRMS-APCI (m/z) [M]+ calcd for C21H16N+, 281.11990; found 281.12065.
Carbazole 27. Purification by flash chromatography (100% Hexanes to 1:1 Hexanes:Benzene) afforded carbazole 27 (82% yield) as an off-white solid. Carbazole 27: Rf 0.74 (4:1 Hexanes:EtOAc); 1H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 8.86 (d, J=8.2, 1H), 8.81 (d, J=7.8, 1H), 8.68 (td, J=8.6, 1.5, 2H), 8.54 (s, 1H), 8.31 (dt, J=7.8, 0.9, 1H), 7.72-7.60 (m, 4H), 7.63 (td, J=7.8, 1.1, 1H), 7.58 (td, J=7.8, 1.1, 1H), 7.47 (d, J=8.1, 1H), 7.33 (td, J=7.4, 0.8, 1H), 4.03 (s, 3H); 13C NMR (100 MHz, CDCl3): (27 of 28 signals observed) δ 142.9, 141.3, 131.1, 130.6, 130.0, 128.85, 128.78, 127.4, 127.1, 127.0, 126.8, 126.1, 123.9, 123.6, 123.5, 123.4, 123.1, 123.0, 122.9, 120.8, 119.2, 114.8, 108.5, 101.1, 29.3; IR (film): 3049, 2923, 2854, 1638, 1603, 1500, 1443, 1258, 754 cm−1; HRMS-APCI (m/z) [M]+ calcd for C25H17N+, 331.13555; found 331.13609.
Indoles 30 and SI-4. Purification by flash chromatography (50:1 Hexanes:EtOAc) afforded an inseparable mixture of indoles 30 and SI-4 (60% yield, average of two experiments, 1.1:1 ratio) as a white solid. Indoles 30 and SI-4: Rf 0.27 (4:1 Hexanes:EtOAc); 1H-NMR (500 MHz, C6D6, combined): δ 9.42 (dd, J=8.3, 1.3, 1H), 8.93 (d, J=2.6, 1H), 8.69 (dd, J=7.9, 1.3, 1H), 8.57-8.50 (m, 5H), 8.48 (d, J=9.0, 1H), 8.22 (d, J=2.5, 1H), 7.60-7.47 (m, 6H), 7.30-7.26 (m, 3H), 7.21 (dd, J=9.2, 2.6, 1H), 6.72 (d, J=6.7, 1H), 6.69 (d, J=3.2, 1H), 3.61 (s, 3H), 3.55 (s, 3H), 3.001 (s, 3H), 2.995 (s, 3H); 13C-NMR (500 MHz, C6D6, combined): δ 159.6, 159.3, 136.7, 136.6, 133.32, 133.31, 131.2, 131.0, 130.8, 129.7, 128.6, 128.5, 127.6, 126.6, 126.4, 126.2, 126.0, 125.8, 125.4, 125.3, 125.2, 125.1, 125.0, 124.6, 124.5, 124.4, 124.0, 123.6, 123.27, 123.25, 118.1, 118.0, 115.5, 115.0, 110.8, 110.5, 110.1, 106.5, 104.5, 104.0, 55.0, 54.9, 32.31, 32.28; IR (film): 2934, 2834, 1614, 1510, 1414, 1246, 1227 cm−1; HRMS-APCI (m/z) [M+H+] calcd for C22H18NO+, 312.13829; found 312.13897.
Indoles 31 and SI-6. Purification by flash chromatography (50:1 Hexanes:EtOAc→20:1 Hexanes:EtOAc) afforded an inseparable mixture of indoles 31 and SI-6 (80% yield, average of two experiments, 1.4:1 ratio) as a yellow solid. Indoles 31 and SI-6: Rf 0.45 (4:1 hexanes:EtOAc); 1H-NMR (600 MHz, CDCl3, major): δ 10.10 (d, J=2.4, 1H), 8.79 (d, J=9.1, 1H), 8.71 (d, J=8.3, 1H), 8.66 (d, J=8.2, 1H), 8.55 (d, J=9.2, 1H), 8.41 (dd, J=9.0, 2.3, 1H), 7.78-7.72 (m, 2H), 7.68-7.65 (ddd, J=8.1, 7.0, 1.2, 1H), 7.54 (d, J=3.1, 1H), 7.39 (d, J=3.2, 1H), 4.00 (s, 3H); 1H-NMR (600 MHz, CDCl3, minor): δ 9.54 (d, J=2.3, 1H), 9.21 (d, J=8.3, 1H), 8.75 (d, J=9.1, 1H), 8.70 (d, J=8.3, 1H), 8.55 (d, J=8.9, 1H), 8.35 (dd, J=9.0, 2.3, 1H), 7.82 (ddd, J=8.1, 7.0, 1.3, 1H), 7.76-7.71 (m, 2H), 7.51 (d, J=3.1, 1H), 7.36 (d, J=3.2, 1H), 4.00 (s, 3H); 13C-NMR (125 MHz, CDCl3, combined): δ 146.4, 146.0, 136.8, 136.4, 134.8, 133.3, 132.51, 132.48, 131.3, 131.0, 129.9, 129.4, 129.0, 128.7, 128.6, 127.4, 127.3, 126.8, 126.4, 125.2, 124.6, 124.4, 124.21, 124.17, 124.14, 123.8, 123.60, 123.55, 123.5, 123.1, 122.8, 119.9, 119.53, 119.47, 117.5, 117.4, 111.7, 111.1, 104.0, 103.4, 33.4, 33.3; IR (film): 2919, 2852, 1597, 1515, 1346, 854, 747 cm−1; HRMS-APCI (m/z) [M+H+] calcd for C21H15NO2+, 327.11280; found 327.11387.
Indoles 32 and SI-8. Purification by flash chromatography (100% Hexanes→50:1 Hexanes:EtOAc→9:1 Hexanes:EtOAc) afforded an inseparable mixture of indoles 32 and SI-8 (76% yield, 1.4:1 ratio, average of two experiments) as a pale yellow solid. Indole 32: Rf 0.34 (4:1 hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 9.40 (ddd, J=8.2, 4.7, 1.4, 2H), 8.99 (dd, J=4.3, 1.6, 1H), 8.66 (d, 8.2, 1H), 8.54 (d, 8.5, 1H), 7.76 (ddd, J=8.1, 6.9, 1.6, 1H), 7.71 (ddd, J=8.3, 6.8, 1.2, 1H), 7.65 (d, J=9.0, 1H), 7.64-7.60 (m, 1H), 7.38 (d, J=2.9, 1H), 7.27 (d, J=3.2, 1H), 3.91 (s, 3H). Indole SI-8: Rf 0.34 (4:1 hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 9.46 (dd, J=8.1, 1.3, 1H), 9.18 (d, J=8.2, 1H), 8.95 (dd, J=4.3, 1.6, 1H), 8.89 (dd, J=8.4, 1.3, 1H), 8.41 (d, J=9.0, 1H), 7.83 (ddd, J=8.2, 7.0, 1.7, 1H), 7.77 (ddd, J=7.2, 5.6, 1.2, 1H), 7.64-7.60 (m, 1H), 7.55 (dd, J=8.3, 4.3, 1H), 7.53 (d, J=3.1, 1H), 7.29 (d, J=3.2, 1H), 3.90 (s, 3H); 13C-NMR (100 MHz, CDCl3, combined): 147.69, 147.66, 146.9, 145.6, 136.6, 136.3, 134.2, 132.8, 132.7, 131.4, 131.0, 130.1, 129.3, 129.2, 128.8, 128.4, 126.6, 126.4, 126.2, 126.1, 125.8, 125.4, 125.2, 124.6, 124.2, 124.0, 123.9, 123.2, 122.9, 122.8, 122.1, 121.5, 117.7, 117.3, 111.1, 110.6, 104.0, 103.2, 33.3 (2C); IR (film): 3059, 2920, 1739, 1609, 1579, 1513, 1477, 1444, 1418, 1399, 1349, 1290, 1241 cm−1; HRMS-APCI (m/z) [M+H+] calcd for C20H15N2+, 283.12297; found 283.11932.
The structure of 32 was verified by 2D-NOESY and 2D-COSY of the mixture, as the following interactions were observed:
Pyrroles 33 and SI-10. Purification by flash chromatography (20:1 Hexanes:Benzene) afforded a mixture of pyrroles 33 and SI-10 (86% yield, 1.4:1 ratio, average of two experiments) as a yellow solid, mp: 135-140° C. Pyrroles 33 and SI-10: Rf 0.56 (4:1 Hexanes:EtOAc); 1H-NMR (500 MHz, C6D6, combined): δ 9.01 (dd, J=8.0, 1.5, 1H), 8.33-8.28 (m, 1H), 8.13 (d, J=8.9, 1H), 8.01 (d, J=8.7, 1H), 7.65 (dd, J=3.0, 1.4, 1H), 7.58 (dd, J=3.0, 1.4, 1H), 7.4 (m, 3H), 7.28 (dd, J=3.2, 0.7, 1H), 7.27-7.23 (m, 2H), 7.22-7.19 (m, 1H), 7.19-7.17 (m, 2H), 7.10 (t, J=0.9, 1H), 7.09 (m, 2H), 6.92 (dd, J=4.0, 2.9, 1H), 6.84 (dd, J=3.9, 2.8, 1H), 6.67 (d, J=3.0, 1H), 6.62 (d, J=3.3, 1H), 2.96 (s, 3H), 2.92 (s, 3H); 13C-NMR (125 MHz, C6D6, combined): δ 136.7, 136.2, 134.0, 132.9, 131.5, 129.6, 128.9, 128.8, 127.60, 127.58, 127.0, 124.3, 124.2, 124.0, 123.7, 123.5, 123.4, 122.9, 121.5, 120.4, 118.9, 118.6, 117.9, 117.0, 115.3, 115.2, 113.0, 112.9, 112.7, 112.2, 111.5, 108.8, 105.6, 102.94, 102.88, 101.0, 32.22, 32.19; IR (film): 3102, 2923, 1500, 1441, 1355 cm−1; DART-HR MS (m/z) [M+H+] calcd for C19H15N2+, 271.12297; found 271.12191.
Indoles 34 and SI-12. Purification by flash chromatography (100% Hexanes→200:1 Hexanes:EtOAc→100:1 Hexanes:EtOAc) afforded an inseparable mixture of indoles 34 and SI-12 (53% yield, 1.4:1 ratio, average of two experiments) as a yellow amorphous solid. Indole 34: Rf 0.40 (3:1 hexanes:EtOAc); 1H-NMR (500 MHz, C6D6): δ 9.74 (d, J=8.5, 1H), 9.09 (d, J=8.8, 1H), 8.92-8.88 (m, 1H), 8.48 (dd, J=8.3, 0.9, 1H) 7.70-7.65 (m, 2H), 7.59-7.43 (m, 4H), 7.29 (dd, J=7.5, 1.5, 1H), 6.81 (d, J=3.1, 1H), 3.57 (s, 3H), 3.11 (s, 3H); 13C-NMR (125 MHz, C6D6): 141.8, 134.8, 134.2, 132.7, 128.4, 128.2, 125.7, 125.3, 125.2, 124.4, 123.9, 123.8, 123.5, 123.3, 122.6, 122.1, 120.3, 118.8, 115.7, 111.4, 109.9, 103.9, 34.0, 32.4. Indole SI-12: Rf 0.40 (3:1 hexanes:EtOAc); 1H-NMR (500 MHz, C6D6): δ 9.37 (d, J=8.1, 1H), 8.92-8.88 (m, 1H), 8.68 (d, J=9.1, 1H), 8.38 (dd, 8.4, 0.9, 1H), 7.95 (d, J=3.1, 1H), 7.59-7.43 (m, 3H), 7.40 (ddd, J=7.9, 7.1, 1.1, 1H), 7.34 (dd, J=9.1, 0.6, 1H), 7.26 (d, J=8.1, 1H), 6.72 (d, J=3.1, 1H), 3.54 (s, 3H), 3.1 (s, 3H); 13C-NMR (125 MHz, C6D6, 23 of 24 signals observed): 141.5, 136.4, 136.2, 132.8, 126.3, 125.8, 125.1, 124.8, 124.54, 124.51, 124.46, 123.7, 123.6, 123.1, 121.7, 119.2, 118.3, 115.3, 109.7, 108.1, 105.8, 34.0, 32.4; IR (film, entire mixture): 3055, 2923, 2854, 1737, 1509, 1472, 1374, 1342, 1245, 1102 cm−1; HRMS-APCI (m/z) [M+H]+ calcd for C24H19N2+, 335.15428; found 335.15396.
The structure of 34 was verified by 2D-NOESY of the mixture, as the following interaction was observed:
Indoles 35 and SI-14. Purification by flash chromatography (100% Hexanes→100:1 Hexanes:EtOAc→25:1 Hexanes:EtOAc→9:1 Hexanes: EtOAc, followed by a second run of 9:1 Hexanes:EtOAc) afforded an inseparable mixture of indoles 35 and SI-14 (78% yield, 1.3:1 ratio) as a bright yellow solid. Indoles 35 and SI-14: Rf 0.32 (4:1 hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3, major): δ 8.43 (dd, J=8.2, 1.0, 1H), 8.28 (dd, J=8.0, 1.1, 2H), 8.04 (d, J=9.0, 1H), 7.98 (d, J=8.6, 1H), 7.79 (s, 1H), 7.41 (ddd, J=7.8, 6.8, 0.9, 1H), 7.36-7.31 (m, 1H), 7.30-7.17 (m, 3H), 7.08 (dd, J=8.9, 0.6, 1H), 6.63 (d, J=3.2, 1H), 2.94 (s, 3H); 1H-NMR (500 MHz, CDCl3, minor): δ 8.95 (dd, J=8.0, 1.6, 1H), 8.41 (dd, J=8.0, 1H), 8.23 (d, J=8.4, 1H), 7.98 (d, J=7.6, 1H), 7.91 (d, J=7.9, 1H), 7.41 (ddd, J=7.5, 6.9, 0.9, 1H), 7.36-7.31 (m, 1H), 7.30-7.17 (m, 4H), 7.04 (dd, J=8.7, 0.7, 1H), 6.58 (d, J=3.2, 1H), 2.92 (s, 3H); 13C-NMR (125 MHz, C6D6, combined): (45 of 46 signals observed) δ 137.6, 137.2, 136.7, 136.5, 135.6, 135.5, 134.1, 133.9, 131.7, 131.6, 129.3, 129.2, 127.6, 127.3, 124.6, 124.3, 124.0, 123.8, 123.7, 123.04, 122.95, 122.3, 122.11, 122.06, 121.6, 121.5, 121.4, 121.05, 120.98, 120.7, 119.9, 118.7, 116.8, 116.7, 116.6, 114.8, 111.3, 110.5, 103.2, 102.9, 99.8, 95.2, 32.2 (2C); IR (film): 3040, 2923, 1738, 1601, 1550, 1509, 1490, 1447, 1419, 1355; HRMS-APCI (m/z) [M+H]+ calcd for C23H17N2+, 321.13862; found 321.13951.
Indole 37. Purification by flash chromatography (100% Hexanes→200:1 Hexanes:EtOAc→10:1 Hexanes:EtOAc) afforded indole 37 (45% yield) as an orange solid. Indole 37: Rf 0.29 (4:1 hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 9.35 (d, J=8.3, 1H), 8.63 (d, J=8.3, 1H), 8.59 (d, J=8.3, 1H), 8.55 (d, J=8.2, 1H), 8.48 (d, J=8.9, 1H), 7.59-7.42 (m, 5H), 7.26 (d, J=8.9, 1H), 7.45 (br s, 1H), 6.73 (t, J=2.9, 1H).
B. Piperidyne Annulation
Piperidine 54. A flame-dried 20 mL scintillation vial was charged with Pd(dba)2 (11.3 mg, 0.064 mmol, 5 mol %). Next, toluene (4.9 mL), P(o-tolyl)3 (6.2 mg, 0.020 mmol, 5 mol %), 2-bromobiphenyl (17) (90.6 mg, 0.389 mmol, 1.0 equiv), silyl triflate 53 (331 mg, 0.757 mmol, 2.0 equiv), CsOPiv (109 mg, 0.466 mmol, 1.2 equiv), and acetonitrile (0.24 mL) were added followed by an oven-dried magnetic stirbar and then CsF (195 mg, 1.29 mmol, 10.0 equiv). The vial was sealed with a Teflon-lined screw cap and stirred at 110° C. for 24 h. After allowing to cool to room temperature, the mixture was transferred with CH2Cl2 (10 mL) and H2O (2 mL) to a 150 mL separatory funnel containing brine (15 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude oil was purified via flash chromatography (10% Triethylamine in Hexanes→10% Triethylamine in 4:1 Hexanes:EtOAc) using silica gel neutralized with triethylamine to afford piperidine 54 (69.3 mg, 49% yield) as a yellow solid. Piperidine SI-19: Rf 0.39 (4:1 Hexanes:EtOAc); 1H NMR (500 MHz, CDCl3): δ 8.72-8.68 (m, 2H), 8.04-7.84 (m, 2H), 7.67-7.61 (m, 4H), 7.47-7.32 (m, 5H), 5.27 (s, 2H), 5.10 (s, 2H), 3.95 (s, 2H), 3.23 (d, J=16.4, 2H); IR (film): 3031, 2927, 2854, 1698, 1431, 1243, 1115; HRMS-APCI (m/z) [M+H]+ calcd for C25H22NO2+, 368.16451; found 368.16218.
C. Annulations onto Ru(bpy)3 Complexes
A 1-dram vial was charged with Pd(OAc)2 (1.5 mg, 0.0067 mmol, 10 mol %). Next, bromo-Ru(bpy)3[PF6]2 55 (61.3 mg, 0.065 mmol, 1.0 equiv), P(o-tolyl)3 (202 mg, 0.006 mmol, 10 mol %), acetonitrile (0.45 mL), toluene (0.45 mL), and silyl triflate 56 (40.1 mg, 0.134 mmol, 2.0 equiv) were added followed by an oven-dried magnetic stirbar and then CsF (101 mg, 1.29 mmol, 10.0 equiv). The vial was sealed with a Teflon-lined screw cap and stirred at 110° C. for 30 min. After allowing to cool to 23° C., the mixture was filtered through celite with acetonitrile (5 mL), and the resulting crude product was purified by flash chromatography (14:2:1 CH3CN: H2O: saturated aqueous KNO3). KPF6 (20 mL) was then added to the concentrated eluent to crash out the desired product. The mixture was then transferred to a 100 mL separatory funnel with CH2Cl2 (20 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×20 mL) and the combined organic layers were dried over magnesium sulfate, concentrated under reduced pressure, and redissolved in CH3CN (5 mL). The solution was then agitated with decolorizing carbon (150 mg) and filtered, concentrated under reduced pressure, and dried on high vacuum overnight to afford the desired product in 61% yield. Ruthenium Complex 57: Rf 0.57 (7:2:1 CH3CN: H2O: saturated aqueous KNO3); 1H-NMR (500 MHz, CD3CN): δ 9.41 (s, 2H), 9.29 (dd, J=8.0, 1.2, 2H), 8.56-8.51 (m, 4H), 8.30-8.27 (m, 2H), 8.11 (td, J=10, 1.4, 2H), 8.03-7.99 (m, 4H), 7.85 (dd, J=5.5, 0.5, 2H), 7.79-7.76 (m, 4H), 7.72 (dd, J=5.6, 0.5, 2H), 7.46 (ddd, J=7.8, 5.7, 1.3, 2H), 7.27 (ddd, J=7.8, 5.7, 1.3, 2H); 13C-NMR (500 MHz, CD3CN): δ 158.1, 157.9, 152.9, 152.8, 152.3, 149.6, 138.8, 138.7, 134.0, 133.0, 132.3, 129.3, 129.1, 128.5, 128.4, 127.7, 126.4, 125.6, 125.2, 125.1 cm−1; HR-ESI-MS (m/z) calcd for C40H27N6PF6Ru+, 839.1061; found 839.1050.
Ruthenium Complex 59. Purification by flash chromatography (14:2:1 CH3CN: H2O: saturated aqueous KNO3) afforded 59 (61% yield, average of two experiments) as a red solid. Ru Complex 59: Rf 0.70 (7:2:1 CH3CN: H2O: saturated aqueous KNO3); 1H-NMR (600 MHz, CD3CN): δ 9.52 (d, J=8.7, 1H), 9.29 (d, J=8.7, 1H), 8.96 (d, J=8.3, 1H), 8.82 (d, J=8.7, 1H), 8.57-8.50 (m, 4H), 8.37 (d, J=8.8, 1H), 8.24 (d, J=7.9, 1H), 8.15-8.09 (m, 4H) 8.00 (t, J=7.8, 2H), 7.89-7.78 (m, 6H), 7.69 (d, J=5.2, 1H), 7.64 (d, J=5.6, 1H), 7.49-7.44 (m, 2H), 7.23-7.20 (m, 2H); HR-ESI-MS (m/z) calcd for C40H27N6PF6Ru+, 839.1061; found 839.1119.
Although specific combinations of method steps and specific synthetic platforms are described above, it will be understood that modifications to the methods and synthetic platforms may be made in accordance with embodiments of the invention.
Accordingly, although the present invention has been described in certain specific aspects, many additional modifications and variations would be apparent to those skilled in the art. It is therefore to be understood that the present invention may be practiced otherwise than specifically described. Thus, embodiments of the present invention should be considered in all respects as illustrative and not restrictive.
The current application claims priority to U.S. Provisional Application No. 62/720,005, filed Aug. 20, 2018, the disclosure of which is incorporated herein by reference.
This invention was made with government support under Grant Numbers GM122245 and GM008496, awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US19/47344 | 8/20/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62720005 | Aug 2018 | US |
