IODOPHENOLS WITH TERMINAL ALKYNES

CLAIM OF PRIORITY

[001] This application claims priority to U.S. Patent Application No. 17/094,140, filed on November 10, 2020, the entire contents of which are hereby incorporated by reference.

TECHNICAL FIELD

[002] This document relates to palladium-carbenes complexes and cyclocarbonylative Sonogashira cross-coupling reactions.

BACKGROUND

[003] Chromones and aurones are useful precursors to pharmacological compounds, and new and efficient methods and catalysts for producing chromones and aurones are needed.

SUMMARY

[004] This disclosure describes palladium catalysts, methods of synthesizing palladium-carbene catalysts, and methods of producing chromones and aurones using palladium-N-heterocyclic carbene (NHC) catalysts.

[005] In some implementations, a compound of Formula C3 has the following structure: [006] In some implementations, a method of synthesizing a palladium catalyst includes reacting a benzimidazole with a halogenated hydrocarbon in the presence of a base and acetonitrile to produce an alkyl-7H-benzo[d]imidazole, reacting the alkyl- 7H-benzo[d] imidazole with a halogenated crosslinking chain to produce a bridged N- heterocyclic carbene salt precursor, and reacting the bridged N-heterocyclic carbene with palladium acetate.

[007] In some implementations, a method of synthesizing chromones or aurones includes reacting a 2-iodophenol and an aryl alkyne in the presence of a palladium catalyst, wherein the palladium catalyst includes at least one of Formula Cl, Formula C2, or Formula C3, where Formula Cl has the structure

[008] In some implementations, a method of synthesizing chromones or aurones includes reacting a 2-iodophenol and an alkyl alkyne in the presence of a palladium catalyst, wherein the palladium catalyst includes at least one of Formula Cl, Formula

[009] The details of one or more implementations of the disclosure are set forth in the accompanying drawings and the description that follows. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

[010] FIG. 1 shows an example of Sonogashira cross-coupling reaction.

[Oi l] FIG. 2 shows an example of carbonylative Sonogashira cross-coupling reaction.

[012] FIG. 3 shows an example of cyclocarbonylative Sonogashira cross-coupling reaction.

[013] FIG. 4 shows examples of chromones.

[014] FIG. 5 shows a bridged bis(N-Heterocyclic Carbene) palladium(II) [bis(NHC)Pd(II)] catalyst.

[015] FIG. 6 shows the structure of three bis(NHC)Pd(II)Br2 catalysts. [016] FIG. 7 is a flow chart of an example method of synthesizing a palladium bridged bis(NHCs) catalyst.

[017] FIG. 8 is a flow chart of an example method of synthesizing chromones or aurones.

[018] FIG. 9 is a flow chart of a second example method of synthesizing chromones or aurones.

[019] FIG. 10 shows an example of a reaction between a benzimidazole and an alkyl halide.

[020] FIG. 11 shows an example of a reaction between a 1 -alkyl benzimidazole produced in FIG. 10 and a halogenated crosslinking alkyl chain.

[021] FIG. 12 shows an example reaction of a bridged NHC salt precursor with palladium acetate.

[022] FIG. 13 shows an example ORTEP diagram of the molecular structure of complex C 1.

[023] FIG. 14 shows an example ORTEP diagram of the molecular structure of complex C3.

[024] FIG. 15 shows an example reaction between a substituted 2-iodophenol and an aryl alkyne.

[025] FIG. 16 shows an example reaction between a substituted 2-iodophenol and an alkyl alkyne.

[026] Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

[027] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[028] Provided in this disclosure, in part, are palladium catalysts, methods of synthesizing palladium catalysts, and methods of producing chromones and aurones using palladium bridged bis(NHCs) catalysts. [029] In some implementations, a catalyst containing palladium is complexed with one or more N-heterocyclic carbenes (NHC). For example, palladium can be complexed with benzimidazole. The palladium-NHC complex (Pd-NHC) can be used to catalyze Sonogashira reactions.

[030] Sonogashira reactions can be exemplified by three types of reactions. In a first type of Sonogashira cross-coupling reaction, a carbon-carbon bond is formed between a terminal alkyne and an aryl or vinyl halide, resulting in an aryl alkyne. This type of reaction uses both a palladium catalyst and a copper catalyst. FIG. 1 shows an example of this type of a Sonogashira cross-coupling reaction.

[031] In a carbonylative Sonogashira cross-coupling reaction, a carbonyl -carbon bond is formed between a terminal alkyne and an aryl halide under carbon monoxide, resulting in an alkynone. Alkynones are known to be bioactive. Carbonylative Sonogashira cross-coupling reactions employ a palladium catalyst and a copper cocatalyst in the presence of carbon monoxide (CO). FIG. 2 shows an example of a carbonylative Sonogashira cross-coupling reaction.

[032] In a cyclocarbonylative Sonogashira cross-coupling reaction, carbonylative coupling reactions occur in the presence of carbon monoxide to form carbonyl-carbon bonds. The reaction products include five- or six-membered ring ketones. Cyclocarbonylative Sonogashira cross-coupling reactions employ palladium catalysts, and can employ copper co-catalysts. The carbonyl -carbon bonds are formed via cyclocarbonylative coupling reactions between a terminal alkyne and a halogenated phenol. Five-membered ring products of this reaction are referred to as aurones, and six-membered ring products are referred to as chromones. FIG. 3 shows an example of a cyclocarbonylative Sonogashira cross-coupling reaction that yields an aurone or a chromone. Chromones and aurones have industrial and pharmaceutical applications, for example as precursor compounds. FIG. 4 illustrates a number of different chromones, which have uses in anticancer, anti-microbial, anti-inflammatory, and anti-viral applications, among others. Accordingly, there is a need for new chromones and new methods of producing chromones.

[033] Pd-NHC complexes can be used for Sonogashira cross-coupling and carbonylative Sonogashira cross-coupling reactions. However, bridged bis(NHC)Pd(II)Br2 complexes that include N-heterocyclic carbenes (NHCs) have not previously been used for cyclocarbonylative Sonogashira cross-coupling reactions. The bridged bis(NHC)Pd(II)Br2 catalysts described herein can be used in a cyclocarbonylative Sonogashira cross-coupling reaction to yield chromones and aurones. Advantageously, these catalysts can be used for cyclocarbonylative Sonogashira cross-coupling reactions in the absence of phosphines or any other ligands or co-catalysts.

[034] In some implementations, the catalyst for cyclocarbonylative Sonogashira cross-coupling reaction is a bridged palladium complex shown in FIG. 5. The catalyst contains a bridged palladium with specific stereochemistry. As shown by X-ray diffraction analysis, the Pd(II) complexes shown in FIG. 5 can have distorted square planar geometries around the center palladium atom.

[035] The alkyl bridge between N-heterocyclic carbene units can vary in length.

The alkyl bridge is shown in FIG. 5 with n number of repeating methylene units. In some implementations, n is 1, 2, or 3.

[036] The N-heterocyclic carbenes can be functionalized with a functional group R. In some implementations, R is a straight or branched alkyl group, for example - CH(CH ₃ )2. In some implementations, R includes a carbon ring structure or aromatic group, for example -CFEPh. The functional group R can alter the steric hindrance around the palladium center and alter the functionality of the catalyst. FIG. 6 shows the structure of three palladium catalysts Cl, C2, and C3, which were used in cyclocarbonylative Sonogashira cross-coupling reactions. The synthesis of these catalysts is discussed in Examples 1-3.

[037] Catalysts Cl, C2, and C3 are stable complexes. For example, Cl, C2, and C3 are stable at temperatures as high as 120°C. These catalysts are efficient and selective. In addition, the catalysts have low loading requirements, wide substrate applications, and high yields. The geometry and configuration of Cl, C2, and C3 yields a specific catalytic activity that is advantageous for cyclocarbonylative Sonogashira cross-coupling reactions. Further, the regioselectivity of the catalysts can be controlled using specific solvents and a base, for example dimethyl formamide (DMF) as a solvent and diethylamine (Et2NH) as a base. The selectivity of the catalysts is shown in Table 6. In addition, the catalysts can be used with catalyst loading as small as 0.50 mol%, and in the absence of phosphines or any co-ligands. [038] FIG. 7 is a flow chart of an example method 700 of synthesizing palladium catalysts Cl, C2, and C3. At 702, a benzimidazole is reacted with a halogenated hydrocarbon to produce an alkyl-7H-benzo[d] imidazole. At 704, the alkyl -1H- benzo[d] imidazole is reacted with a halogenated crosslinking chain to produce a bridged N-heterocyclic carbene salt precursor. At 706, the bridged N-heterocyclic carbene salt precursor is reacted with acetylated palladium.

[039] FIG. 8 is a flow chart of an example method 800 of synthesizing chromones or aurones. At 802, a 2-iodophenol is reacted with an aryl alkyne in the presence of a palladium catalyst Cl, C2, or C3.

[040] FIG. 9 is a flow chart of a second example method 900 of synthesizing chromones or aurones. At 902, a 2-iodophenol is reacted with an alkyl alkyne in the presence of a palladium catalyst Cl, C2, or C3.

[041] Example 1 : Synthesis of Benzimidazole Precursors

Bis-NHC-Pd(II) catalysts as shown in FIG. 5 were synthesized using alkylated benzimidazole precursors. FIG. 10 shows an example of a reaction between a benzimidazole with a halogenated alkyl group in the presence of base and acetonitrile to generate alkyl-7H-benzo[d]imidazoles. The functional group R can include branched alkyl or aromatic groups. For example, R can be -CH(CH3)2 or -CFEPh. [042] The synthesis of benzimidazole precursors is described herein. A dry and clean round bottom flask was charged with benzimidazole (10.0 mmol), excess amount of alkyl bromide (12.2 mmol), an appropriate base (20.0 mmol), and 1.00 mmol of tetrabutylammonium bromide (TBAB). For the synthesis of 1 -isopropyl- 1H- benzo[d]imidazole, the alkyl bromide is 2-bromopropane and the base is potassium hydroxide. For the synthesis of l-benzyl-lH-benzo[d]imidazole, the alkyl bromide is benzyl bromide and the base is cesium carbonate. 100 m of acetonitrile was used to dissolve the prepared mixture with continuous stirring at 80 °C for 24 h. Thin layer chromatography (TLC) (l/l=hexane/ethyl acetate) was used for monitoring the reaction until no free benzimidazole was observed. After the completion of the reactions, the solvents were removed under vacuum by rotary evaporator. The oily products were collected as residues, and the purification of the products was conducted by extraction twice with 30 mL ethyl acetate and 20 mL distilled water. The aqueous layers were separated then washed with ethyl acetate. The separated organic layers were dried and washed several times with n-hexane.

[043] The synthesized compounds were analyzed by ³ H NMR (nuclear magnetic resonance) analysis and ¹³ C { ¹ H } NMR analysis. For the NMR analyses, ‘s’ denotes a singlet, ‘d’ denotes a doublet, ‘dd’ denotes a doublet of doublets, ‘t’ denotes a triplet, ‘q’ denotes a quartet, ‘qui’ denotes a quintet, and ‘sept’ denotes a septet. The coupling constant is given as J.

[044] Synthesis of l-isopropyl-lH-benzo[d]imidazole resulted in a 77% yield by mass of a sticky brown oil. ³ H NMR analysis (400 MHz, CDCh) yielded the following spectra in 5 (ppm): 7.85 (s, 1H, NC//N). 7.64-7.62 (1H, m, Ar-H). 7.25- 7.22 (1H, m, Ar-H), 7.11-7.08 (2H, m, Ar-H), 4.42 (1H, sept, ³ J= 6. 76 Hz, NCH), 1.40 (6H, d, ³ J= 6. 76 Hz, NC(CH ₃ ) ₂ ).

[045] ¹³ C{ ¹ H [ NMR analysis (500 MHz, CDCh) yielded the following spectra in 5 (ppm): 143.5 (NCN), 139.8, 132.7, 122.1, 121.5, 119.8, 109.7, (Ar-H), 47.2 (NCH), 22.02 [NC(CH ₃ )2],

[046] The theoretical composition calculated for this compound (C10H12N2, molecular weight 160) is 74.97% carbon by mass, 7.55% hydrogen by mass, and 17.48% nitrogen by mass. Elemental analysis found 74.84% carbon by mass; 7.23% hydrogen by mass; and 17.23% nitrogen by mass.

[047] Synthesis of l-benzyl-lH-benzo[d]imidazole resulted in an 87% yield by mass of a light yellow solid. ³ H NMR analysis (500 MHz, CDCh) yielded the following spectra in 5 (ppm): 7.98 (1H, s, NCHN), 7.83 (1H, d, ³ J=7.63 Hz, Ar-H), 7.34-7.24 (6H, m, Ar-H), 7.18 (2H, d, ³ J=7.02 Hz, Ar-H), 5.36 (2H, m, NCH2-PI1).

[048] ¹³ C{ ³ H} NMR analysis (500 MHz, CDCh) yielded the following spectra in 5 (ppm): 143.1 (NCN), 135.4, 129, 128.3, 127.06, 123.1, 122.3, 120.3, 110.04 (Ar-H), 48.8 (NCH2).

[049] The theoretical composition calculated for this compound (C14H12N2, molecular weight 208) is 80.74% carbon by mass, 5.81% hydrogen by mass, and 13.45% nitrogen by mass. Elemental analysis found 80.89% carbon by mass, 6.03% hydrogen by mass, and 13.73% nitrogen by mass.

[050] Example 2: Synthesis of Precursors LI, L2, and L3

The alkylated benzimidazoles were reacted with a crosslinking halogenated alkyl chain. The alkyl chain will form the bridge of the bridged palladium catalysts. FIG. 11 shows an example reaction between the benzimidazole produced in FIG. 10 and a halogenated crosslinking alkyl chain to yield a bridged NHC salt precursor. The alkyl chain can vary in length. The alkyl chain can include n number of repeating methylene units, for example where n is 1, 2, or 3.

[051] The 1-alkyl benzimidazoles synthesized in Example 1 (5.0 mmol) and 2.5 mmol of dibromoalkane (1,3 -dibromopropane or 1,4-dibromobutane) were introduced into a dried 100 mL round bottom flask. The mixture was refluxed in 35 mb of 1,4- dioxane with stirring at 103 °C for 12 h. The products appeared as white precipitates. The products were collected by fdtration and washed three times with 15 mL of 1,4- dioxane and then with 15 mL of toluene to remove any traces of the starting materials. The products were dried under vacuum then collected as a white precipitate. Characterization of the alkylene bridged N-heterocyclic dicarbene salts was conducted with different spectroscopic techniques including ^J H NMR, ¹³ C NMR, elemental analysis, and electrospray ionization. The resulting NHC salts are precursors LI, L2, and L3 for the palladium catalysts Cl, C2, and C3.

[052] 3,3’-(propane-l,3-diyl)-bis(l-isopropyl-lH-benzo[d]imidazo le-3-ium) bromide (precursor LI) was synthesized with l-isopropyl-lH-benzo[d]imidazole and 1,3 -dibromopropane as above. The synthesis resulted in a 91% yield by mass of a white solid. ¹ H NMR analysis (500 MHz, DMSO-de) yielded in the following spectra in 5 (ppm): 9.83 (2H, s, NC//N). 8.15-8.11 (4H, m, Ar-77), 7.71-7.69 (2H, m, Ar-77), 5.05 (2H, sept, ³ J=6. 71 Hz, NC77), 4.67 (4H, t, ³ J=7.01Hz, CHi), 2.67 (2H, qui, ³ J=7.02 Hz, C i), 1.61 (12H, d, ³ J=6. 7Hz, NC(CH ₃ ) ₂ ). ¹³ CpH} NMR analysis (125 MHz, DMSO) yielded the following spectra in 5 (ppm): 140.7 (NCN), 131.3, 130.5, 126.7, 126.6, 114.1, 113.7, (Ar-H), 50.7 (NCH), 44.1 (NCH ₂ ), 28.0 (CH ₂ ), 21.6 (NC(CH ₃ ) ₂ ). [053] The theoretical composition of precursor LI (C23H3oN4Br2, molecular weight

522.3) is 52.89% carbon by mass, 5.79 % hydrogen by mass, 10.73% nitrogen by mass. Elemental analysis found 52.37% carbon by mass, 5.8% hydrogen by mass, and 10.97% nitrogen by mass. Electrospray ionization analysis revealed a mass-to- charge ratio (m/z) of 442 with positive ionization and an m/z ratio of 441 with negative ionization.

[054] 3,3’-(Butane-l,4-diyl)-bis(l-isopropyl-lH-benzo[d]imidazol e-3-ium) bromide (precursor L2) was synthesized with l-isopropyl-lH-benzo[d]imidazole and 1,4-dibromobutane, as above. The synthesis resulted in a 76% yield of a white solid. ^J H NMR analysis (500 MHz, DMSO-d6) yielded the following spectra in 5 (ppm): 10.05 (2H, s, NC7/N). 8.13-8.11 (4H, m, Ar-77), 7.68 (4H, dd, ³ J =6.1 Hz, ³ J ₂ =2. 75 Hz, Ar-H), 5.05 (2H, sept , ³ J=6. 71 Hz, NCH) , 4.58 (4H, m, NCH ₂ ), 2.04- 1.99 (4H, m, CH ₂ ), 1.62 [12H, d, ³ J=6. 71 Hz (CH ₃ ) ₂ ]. ¹³ C{Tf} NMR analysis (125 MHz, DMSO) yielded the following spectra in 5 (ppm): 140.7 (NCN), 131.3, 130.6, 126.7, 126.6, 114.1, 113.8, (Ar-H), 50.7 (NCH), 46.3 (NCH ₂ ), 25.6 (CH ₂ ), 21.64 [NC(CH ₃ )2],

[055] The theoretical composition of precursor L2 (C24H32N4Br2, molecular weight

536.3) is 53.74% carbon by mass; 6.01 % hydrogen by mass, and 10.45% nitrogen by mass. Elemental analysis found 52.12% carbon by mass, 5.91% hydrogen by mass, and 10.79% nitrogen by mass. Electrospray ionization analysis revealed an m/z ratio of 456 with positive ionization.

[056] 3,3’-(Propane-l,3-diyl)-bis(l-benzyl-lH-benzo[d]imidazole- 3-ium) bromide (precursor L3) was synthesized with l-benzyl-lH-benzo[d]imidazole and 1,4-dibromobutane, as above. The synthesis resulted in a 65% yield of a white solid. ^J H NMR analysis (500 MHz, DMSO-de) yielded the following spectra in 5 (ppm): 10.15 (2H, s, NC N). 8.14 (2H, d, ³ Ji =7.93 Hz, Ar-H), 7.96 (2H, d, ³ Ji=7.32 Hz, Ar- H), 7.66-7.62 (4H, m, Ar-H), 7.53 (4H, d, ³ Ji=7.02 Hz, Ar-H), 7.39-7.36 (4H, m, Arif), 5.80 (4H, s, NC/LPh). 4.62 (4H, m, NCH2CH2), 2.06 (2H, m, CH2). ¹³ C{Tf} NMR analysis yielded (125 MHz, CDCh) yielded the following spectra in 5 (ppm): 141.31, 132.99, 131.51, 130.77, 129.27, 129.10, 128.52, 127.26, 127.14, 114.08, 113.64 (C-arom), 51.95 (NCH2), 51.37 (NCH2), 22.44 2(CH ₂ CH). [057] The theoretical composition of precursor L3 (C ₃ iH ₃ oN4Br ₂ , molecular weight 618.4) is 60.61% carbon by mass; 4.89 % hydrogen by mass, 9.06% nitrogen by mass. Elemental analysis found 60.83% carbon, 5. 11% hydrogen, and 9.79% nitrogen. Electrospray ionization analysis revealed an m/z ratio of 538.5 with positive ionization.

[058] Example 3: Synthesis of bis-NHC-Pd(II) complexes Cl. C2, and C3 FIG. 12 shows an example reaction of an NHC salt precursor with palladium acetate to yield the bis-NHC-Pd(II) complexes Cl, C2, and C3.

[059] A round bottom flask (50 mL) was charged with 0.50 mmol of a bridged N- heterocyclic dicarbene ligand precursor (LI, L2 or L3), and 0.50 mmol of palladium(II) acetate. 15 mL of dimethyl sulfoxide was used as a solvent. The resulting orange solutions were heated to 70 °C for 24 h under stirring. The products were obtained as white precipitates. The precipitates were collected by fdtration and washed twice with 15 mL of distilled water and then 15 mL of hexane. The residues were purified by extraction three times with dichloromethane/ELO (5 mL/5 mL). Finally, the dichloromethane extracts were evaporated under vacuum and the products were obtained as crystalline solids. Full characterization of the three complexes was accomplished by different physical and spectroscopic techniques such as ³ H and ¹³ C NMR, electrospray ionization - mass spectrometry, elemental analysis, and single crystal X-ray diffraction analysis.

[060] Synthesis of Dibromido(l,l'-diisopropyl-3,3'-propylenedibenzimidazoline- 2,2-diylidene)palladium(II) (complex Cl) was performed as described above, with a 92% yield by mass of a white solid. Single crystals for complex Cl were obtained by slow crystallization procedure using a saturated solution of dichloromethane/acetonitrile (10: 1 v/v). ³ H NMR analysis (500 MHz, DMF-d7) yielded the following spectra in 5 (ppm): 8.08 (2H, d, ³ J =8.24 Hz, Ar-H, (the signals of aromatic protons overlap with solvent signal), 7.97 (2H, d, ³ J=8.24 Hz, Ar-H), 7A5-7.37 (4H, m, Ar-H), 5.99 (2H, m, NCH). 5.43 (2H, m, C z), 5.11 (2H, m, CHi), 2.19 (2H, m, CH2C 2CH2). 1.94 [6H, M.J 6. 71Hz. NC(CH ₃ ) ₂ ], 1.78 [6H, d, ³ J=5.80Hz, NC(CH ₃ ) ₂ ], ¹³ C{ 1H} NMR analysis (125 MHz, CD ₂ C1 ₂ ) yielded the following spectra in 5 (ppm): 181 (Pd-C) /carbene signal (NCbinimN)], 135.2, 133.3, 132.3, 123.8, 123.7, 123.4, 123.1, 122.9, 113,2. 113, 110.7, 110.5 (Ar-H), 55.4 (NCH), 53.4 (NCH), 49.5 (NCH ₂ ), 47.8 (NCH ₂ ), 30.0 (CH ₂ ), 28.5 (CH ₂ ), 22.1, 21.7, 21.3 [NC(CH ₃ ) ₂ ],

[061] The theoretical composition for complex Cl (C’ ₂₃ H ₂ xN4Br ₂ Pd. molecular weight 626.74) is 44.08% carbon; 4.50% hydrogen; and 8.94% nitrogen. Elemental analysis found 43.86% carbon, 4.25% hydrogen, and 8.63% nitrogen. Electrospray ionization yielded an m/z ratio of 547 with positive ionization.

[062] Dibromido(l,l'-diisopropyl-3,3'-butylenedibenzimidazoline-2, 2- diylidene)palladium(II) (complex C2) was synthesized as above, with a 68% yield by mass of an orange solid. ³ H NMR analysis (400 MHz, CDCh) yielded the following spectra in 5 (ppm): 8.49 (2H, d, ³ J=7.28 Hz, Ar-H). 7.30 (2H, d, ³ J=7.44 Hz Ar-H), 7.17-7.14 (4H, m, Ar-H), (the signals of aromatic protons overlap with solvent signal), 6.00-5.96 (2H, m, NCH), 5.75-5.71 (2H, m, NCH ₂ ), 4.45-4.41 (2H, m, NCH ₂ ), 1.80-1.45 (4H, m, NCH2CH2) (the signals of methylene protons were not assigned due to overlap with the isopropyl methyl signals), 1.74 [6H, d, ³ J=6.56Hz (CH ₃ ) ₂ ], 1.69 [6H, d, ³ J=7.16Hz (CH ₃ ) ₂ ], ¹³ CfH} NMR analysis (125 MHz, CD ₂ Q ₂ ) yielded the following spectra in 5 (ppm): 181.1 (Pd-C) /Carbene signal (NCbinimN)], 135.9, 132.9, 122.9, 122.8, 112.9, 111.0, (Ar-H), 48.2 (NCH), 30.1 (NCH ₂ ), 27.7 (CH ₂ ), 21.2 [NC(CH ₃ ) ₂ ],

[063] The theoretical composition for this compound (C ₂ 4H ₃ oN4Br ₂ Pd, molecular weight 640.7) is 44.99% carbon, 4.72% hydrogen, and 8.74% nitrogen. Elemental analysis found 44.78% carbon, 4.89% hydrogen, and 8.53% nitrogen. Electrospray ionization yielded an m/z ratio of 561.00 with positive ionization.

[064] Dibromido(l,l'-dibenzyl-3,3'-propylenedibenzimidazoline-2,2- diylidene)palladium(II) (complex C3) was synthesized as above, with a 73% yield by mass of white crystals. ¹ H NMR analysis (400 MHz, CDCh) yielded the following spectra in 5 (ppm): 7.10-7.69 (m, 2H, C-H- pyr), 7.48 (m, 4H, C-H- arom), 7.45-7.41 (m, 6H, C-H arom), 7.35-7.29 [m, 6H, C-H-(phenyl)], 5.87 (s, 4H, CH ₂ -Ph), 5.25 (m, 4H, NCH ₂ ), 1.67 (m, 2H, NC(CH ₂ ). ¹³ C NMR analysis (125 MHz, CD ₂ C1 ₂ ) yielded the following spectra in 5 (ppm): 176.39 (Pd-C), 135.14, 134.96, 133.86, 129.08. [065] Example 4: X-rav crystallography of complexes Cl and C3: Single crystal X-ray data collection for complexes Cl and C3 were performed at 298 K on a Bruker D8 Quest diffractometer (MoKa radiation X = 0.71073 Angstroms (A)). Data were collected and integrated using Bruker APEX3 software package. Multiscan absorption correction was performed using SADABS. The structures were solved by direct methods with SHELXS using SHELXTL package and refined using full-matrix least squares procedures on F2 via the program SHELXL-2014. ORTEP3 software was used for molecular graphics. The molecular structures of complexes Cl and C3 are depicted in example ORTEP diagrams in FIG. 13 and FIG. 14, respectively. All hydrogen atoms were included at calculated positions using a riding model. The thermal ellipsoids in FIGS. 13 and 14 are drawn at 30% probability level, with a symmetry code where i = x,-y+l/2,z. The crystal data and refinement details for Cl and C3 are given in Table 1. Selected bond lengths and bond angles are given in Table 2.

[066] Complex Cl crystallized with one molecule, located on a mirror plane, in the asymmetric unit, as a dimethylformamide solvate while complex C3 crystallized with one molecule in the asymmetric unit as mixed hydrate/dichloromethane solvate. In both complexes the Pd(II) ion is coordinated by the chelating bridged bis-carbene ligand and two bromide ions at cis positions, in a distorted square planar geometry. The cis bond angles are in the ranges of 88.66(17) - 92.97(2)° and 87.4(3)° - 97.01(4)° in Cl and C3 respectively. The former is 1.997(3) A in Cl and in the range of (1.964(8) A - 1.985(8) A) in C3 while the latter is 2.4906(4) A in Cl and in the range of (2.4659(11) A - 2.4704(11) A) in C3. The chelate C-Pd-C bite angle values are 88.66(17)° and (87.4(3)°, 87.7(3)°) in Cl and C3, respectively. The larger bond distances in C 1 are consistent with the larger steric hindrance of the isopropyl group opposing the formation of the chelate complex.

Attorney Docket No.: 38136-1262WO1

[067] Table 1: Crystal and structure refinement data of complexes Cl and C3

[068] Table 2: Selected Bond lengths [A] and bond angles [°] for complexes Cl and C3

Symmetry codes: #1= x,-y+3/2,z #2= x,-y+l/2,z

[069] Example 5: Cyclocarbonylative Sonogashira cross-coupling reaction with bis(NHC)Pd(II)Br2 complexes Cl, C2, or C3

The bis(NHC)Pd(II)Br2 complexes Cl, C2, and C3 can catalyze a reaction between 2- iodophenols and aryl alkynes. For example, FIG. 15 shows an example reaction between a functionalized 2-iodophenol, for example functionalized 4’ -hydroxy-3 ’-iodoaryl, and an aryl alkyne. The functional groups Ri and R2 can be electron withdrawing or electron donating functional groups, for example methoxy, hydrogen, nitro, methyl, tertiary butyl, phenyl or acetyl functional groups. Advantageously, the catalysts Cl, C2, and C3 can be used with as little as 0.5 mol% in the reaction. The catalyzed reactions between a functionalized 2-iodophenol and an aryl alkyne were conducted with 0.50 mmol of functionalized 2-iodophenol, 0.55 mmol of an aryl alkyne, 1.00 mmol of diethylamine (Et2NH), 3 mL of dimethylformamide (DMF), and 0.50 mol% of complex Cl, C2, or C3. The reactants were added to a 45 mL stainless steel autoclave equipped with a glass liner, gas inlet valve and pressure gauge. The reaction was run for 16 hours at 100 °C under 100 psi of carbon monoxide gas. After the reaction, the autoclave was cooled to room temperature and excess carbon monoxide gas was discharged. The reaction products were extracted three times with 5 mL of distilled water and 10 mL of ethyl acetate. The ethyl acetate extracts were combined and concentrated in a rotary evaporator under reduced pressure. Flash chromatography was used to purify the reaction mixture using silica gel and an eluent (pentane-ethyl acetate in a 7: 1 v/v ratio). Chromones and flavones (a type of aurone) were produced at high yields, between 86-91% isolated yield by mass percent. Table 3 shows example reactants and products for cyclocarbonylative Sonogashira coupling reactions catalyzed by complex Cl, and the percent yield for these reactions. ^J H NMR spectra were taken at 300 MHz in CDCh at 24°C. ¹³ C{ ¹ H} spectra were taken at 75 MHz in CDCh at 24°C.

Attorney Docket No.: 38136-1262WO1

[070] Table 3: Cyclocarbonylative Sonogashira coupling reactions of 4'-hydroxy-3'-iodoaryls with aryl alkynes catalyzed by complex Cl

Attorney Docket No.: 38136-1262WO1

[071 ] Example 6: Cyclocarbonylative Sonogashira cross-coupling reaction with Pd- bisfNHClBn complexes Cl, C2, or C3

The bis(NHC)Pd(II)Br2 complexes Cl, C2, and C3 can each catalyze the reaction between 2-iodophenols and an alkyl alkyne. For example, FIG. 16 shows an example reaction between a functionalized 2-iodophenol and an alkyl alkyne. The functional groups Ri and R” can be electron withdrawing or electron donating functional groups, for example methoxy, hydrogen, nitro, methyl, tertiary butyl, phenyl or acetyl functional groups. Advantageously, the catalysts Cl, C2, and C3 can be used with as little as 0.5 mol% in the reaction. The catalyzed reactions between a functionalized 2-iodophenol and an alkyl alkyne were conducted with 0.50 mmol of functionalized 2-iodophenol, 0.60 mmol of an alkyl alkyne, 1.00 mmol of Et2NH, 2.5 mL of DMF, and 0.50 mol% of complex Cl. The reactants were added to a 45 mL stainless steel autoclave equipped with a glass liner, gas inlet valve and pressure gauge. The reaction was run for 24 hours at 110 °C under 100 psi of carbon monoxide. After the reaction, the autoclave was cooled to room temperature and excess carbon monoxide gas was discharged. The reaction products were extracted three times with 5 mL of distilled water and 10 mL of ethyl acetate. The ethyl acetate extracts were combined and concentrated in a rotary evaporator under reduced pressure. Flash chromatography was used to purify the reaction mixture using silica gel and an eluent (pentane-ethyl acetate in a 7: 1 v/v ratio ). Chromones and flavones were produced at high yields, between 53-90% by mass. Table 4 shows example reactants and products for cyclocarbonylative Sonogashira coupling reactions catalyzed by complex Cl, and the percent yield for these reactions.

Attorney Docket No.: 38136-1262WO1

[072] Table 4: Cyclocarbonylative Sonogashira coupling reactions of 4'-hydroxy-3'-iodoaryls with alkyl alkynes catalyzed by complex Cl.

Attorney Docket No.: 38136-1262WO1

[073] Example 6: Regioselectivity of Complexes Cl, C2, and C3:

Cyclocarbonylative Sonogashira coupling reactions of a 2-iodophenol with phenylacetylene can illustrate the selectivity of the complexes Cl, C2, and C3. An example reaction of 2-iodophenol (compound la) and phenylacetylene (compound 2a) under carbon monoxide in the presence of a catalytic amount of Cl was analyzed (Eq. 1). Table 5 shows the selectivity of the complexes under these conditions.

[074] Table 5: Cyclocarbonylative Sonogashira coupling reactions of 2-iodophenol (la) with phenylacetylene (2a). a. Reaction conditions: [Pd] (mol%), 2-iodophenol (0.5 mmol), phenylacetylene (0.6 mmol), Et ₂ NH (1.0 mmol), DMF (2.5 mL), CO (100 psi), 100 °C, 16 h. b. Determined by gas chromatography (GC) and gas chromatography - mass spectrometry (GC-MS). c. Isolated yield. d. THF was used as a solvent.

[075] The selectivity of the complexes is dependent on the reaction conditions. Table 6 shows varied conditions for the reaction in Equation 1, catalyzed by complex Cl. For example, the reactions were conducted at room temperature, 80°C, or 100°C, and the base and solvent were varied. The results of these reactions are summarized in Table 6. Only traces of 2-phenyl-4H-chromen-4-one (compound 3aa) were obtained when a neat reaction was conducted using 1.0% mol of Cl as a catalyst and di ethylamine (Et2NH) as a base at room temperature for 16 hours (Table 6, Example Reaction 15). However, a conversion of 59.5% was obtained at 80 °C and a high conversion (85.5%) was achieved at 100 °C. These reactions produced 2-phenyl-4H-chromen-4-one (compound 3aa) as a major compound. The isolated yield of compound 3aa gradually increased by increasing the temperature (Table 6, Example Reactions 16-17). When diethylamine (Et2NH) in the neat reaction was replaced by trimethylamine (EtsN) at 80°C and 100°C using Cl, the cyclocarbonylative reaction of 2-iodophenols with phenylacetylene led to a six member ring product flavone (compound 3aa) and five membered ring product aurone (compound 4aa). Moreover, the increase of the temperature from 80 °C to 100 °C increased the conversion from 85% to 100% and favored the formation of the aurone product compound 4aa (57% and 66%) (Table 6, Example Reactions 18-19). However, when tetrahydrofuran (THF) was used as a solvent at 80 °C and 100 °C, with tri ethylamine as a solvent, the conversions dropped to 69% and 93%, respectively, with only smalls changes in the regioselectivity (Table 6, Example Reactions 20 and 21). Nevertheless, the use of Et2NH as a base with THF as solvent at 80°C and 100°C led to higher conversions (68% and 84.5%) (Table 6, Example Reactions 22 and 23). Accordingly, under the same experimental conditions, triethylamine oriented the cyclocarbonylative Sonogashira reactions towards the production of aurone compound 4aa as the major product. In addition, di ethylamine in THF produced flavone compound 3aa in high isolated yields. When potassium carbonate was used as a base in THF at 100 °C (Table 6, Example Reaction 24), a full conversion was observed to produce flavone compound 3aa and aurone compound 4aa (38/62). In toluene as a solvent, the cyclocarbonylative Sonogashira reaction of 2-iodophenol with phenylacetylene under the conditions in Example Reaction 25 (Et2NH/ 1.0% mol of Cl / 100 °C / 16 h) was converted (97%) and led to the two products flavone compound 3aa and aurone compound 4aa with a ratio of 93/7. In THF as a solvent and Et2NH as a base, the catalyst’s Cl loading can be decreased from 1.0 mol% to 0.5 mol% of Cl leading to high conversion (80%) to produce flavone compound 3aa as the only product of the reaction (Table 6, Example Reaction 26). An isolated yield of 2-phenyl-4H-chromen-4-one (compound 3aa, 96%) was achieved with 98% conversion of 2-iodophenol when the DMF was used as solvent under the conditions in Example Reaction 27 [Et2NH / Cl (0.5 mol%) / 100 °C / 16 h]. Small amounts of aurone compound 4aa were also obtained (compound 3aa / compound 4aa = 96/4). A decrease in the temperature from 100°C to 80 °C and 50 °C [DMF / Et2NH / Cl(0.5 mol%) /16 h] demonstrated a gradual decline in the conversion of 2-iodophenol (83% at 80 °C and 38% at 50 °C) and the isolated yields of the flavone compound 3aa were 81% at 80 °C and 35% at 50 °C (Table 6, Example Reactions 28 and 29). Therefore, 100 °C can be considered as an optimized temperature for the subsequent catalytic reactions. The effect of the reaction time was also studied. After 16 h, 12 h and 6 h the isolated yields of the flavone compound 3aa decreased from 92% to 72% and 46%, respectively (Table 6, Example Reactions 27, 30, 31). When DMF was replaced by other solvents such as THF, toluene and in the neat Et2NH [Et2NH / Cl (0.5mol%) / 100 °C / 16 h], a significant decrease in the conversions and isolated yields in flavone were observed (Table 6, Example Reactions 32-34).

[076] Additionally, the study of the role of the base on the regioselectivity was also conducted using EtsN and K2CO3 as bases with DMF as solvent [Cl (0.5 mol%) / 100 °C / 16 h] . For example, the use of K2CO3 as a base produced a mixture of flavone compound 3aa and aurone compound 4aa (70/30) (Table 6, Example Reaction 35). Similarly, the use of trimethylamine gave lower regioselectivity, producing a mixture of flavone compound 3aa and aurone compound 4aa (60/40) (Table 6, Example Reaction 36). When EtsN was used with THF as a solvent, the isolated yield in flavone compound 3aa dropped to 30% (Table 6, Example Reaction 21) and increased with DMF to 54% (Table 6, Example Reaction 37). These results showed the importance of Et2NH and DMF as regioselective factors in the production of flavones.

[077] Table 6: Cyclocarbonylative Sonogashira coupling reactions of 2-iodophenol (compound la) with phenylacetylene (compound 2a) by complex Cl. a. Reaction conditions: complex Cl (mol%), 2-iodophenol (0.5 mmol), phenylacetylene (0.6 mmol), base (1.0 mmol), solvent (2.5 m ), CO (100 psi), 100 °C. b. Determined by GC and GC-MS. c. Isolated yield.

[078] The following units of measure have been mentioned in this disclosure:

[079] In some implementations, a compound of Formula C3 has the following structure:

[080] In some implementations, a method of synthesizing a palladium catalyst includes reacting a benzimidazole with a halogenated hydrocarbon in the presence of a base and acetonitrile to produce an alkyl-777-benzo[d]imidazole, reacting the alkyl- 1H- benzo[d] imidazole with a halogenated crosslinking chain to produce a bridged N- heterocyclic carbene salt precursor, and reacting the bridged N-heterocyclic carbene with palladium acetate.

[081] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting a benzimidazole with a halogenated hydrocarbon includes reacting at 80 °C for 24 hours.

[082] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting the alkyl-//7-benzo[d]imidazole with a halogenated crosslinking chain includes reacting at 103 °C for 24 hours in 1,4-dioxane.

[083] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting the N-heterocyclic carbene with palladium acetate includes reacting at 70 °C for 24 hours in dimethyl sulfoxide.

[084] This aspect, taken alone or combinable with any other aspect, can include the following features. The halogenated hydrocarbon is a branched halogenated alkyl group. [085] This aspect, taken alone or combinable with any other aspect, can include the following features. The branched halogenated alkyl group is isopropyl bromide.

[086] This aspect, taken alone or combinable with any other aspect, can include the following features. The halogenated hydrocarbon is benzyl bromide.

[087] This aspect, taken alone or combinable with any other aspect, can include the following features. The halogenated crosslinking chain is a di-halido unbranched alkyl chain.

[088] This aspect, taken alone or combinable with any other aspect, can include the following features. The di-halido unbranched alkyl chain is 1,3-dibromopropane, 1,4- dibromobutane, or 1,5-dibromopentane.

[089] In some implementations, a method of synthesizing chromones or aurones includes reacting a 2-iodophenol and an aryl alkyne in the presence of a palladium catalyst, wherein the palladium catalyst includes at least one of Formula Cl, Formula C2, [090] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting the 2-iodophenol and the aryl alkyne in the presence of a palladium catalyst includes reacting the 2-iodophenol and the aryl alkyne in the presence of 0.5 mol% of the palladium catalyst.

[091] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting the 2-iodophenol and the aryl alkyne in the presence of a palladium catalyst includes reacting the 2-iodophenol and the aryl alkyne with 2 equivalents diethylamine in dimethylformamide, and the reaction takes place under carbon monoxide at 100 psi for 16 hours at 100 °C.

[092] This aspect, taken alone or combinable with any other aspect, can include the following features. The 2-iodophenol is functionalized with an electron withdrawing group.

[093] This aspect, taken alone or combinable with any other aspect, can include the following features. The aryl alkyne is functionalized with an electron withdrawing group.

[094] In some implementations, a method of synthesizing chromones or aurones includes reacting a 2-iodophenol and an alkyl alkyne in the presence of a palladium catalyst, wherein the palladium catalyst includes at least one of Formula Cl, Formula C2, or Formula C3, where Formula Cl is

[095] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting the 2-iodophenol and the alkyl alkyne in the presence of a palladium catalyst includes reacting the 2-iodophenol and the alkyl alkyne in the presence of 0.5 mol% of the palladium catalyst.

[096] This aspect, taken alone or combinable with any other aspect, can include the following features. Reacting the 2-iodophenol and the alkyl alkyne in the presence of a palladium catalyst includes reacting the 2-iodophenol and the alkyl alkyne with 2 equivalents diethylamine in dimethylformamide, and wherein the reaction takes place under carbon monoxide at 100 psi for 24 hours at 110 °C.

[097] This aspect, taken alone or combinable with any other aspect, can include the following features. The 2-iodophenol is functionalized with an electron withdrawing group.

[098] This aspect, taken alone or combinable with any other aspect, can include the following features. The alkyl alkyne is functionalized with an electron withdrawing group.

[099] The term "about" as used in this disclosure can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range. [0100] The term "solvent" as used in this disclosure refers to a liquid that can dissolve a solid, another liquid, or a gas to form a solution. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0101] As used in this disclosure, “weight percent” (wt %) can be considered a mass fraction or a mass ratio of a substance to the total mixture or composition. Weight percent can be a weight-to-weight ratio or mass-to-mass ratio, unless indicated otherwise.

[0102] A number of implementations of the disclosure have been described.

Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure.