Catalytic condensation for the formation of polycyclic heteroaromatic compounds

The conservation of our global element resources is a challenge of the utmost urgency. Since aliphatic and aromatic alcohols are accessible from abundant indigestible kinds of biomass, first and foremost lignocellulose, the development of novel chemical reactions converting alcohols into important classes of compounds is a particularly attractive carbon conservation and CO2-emission reduction strategy. Herein, we report the catalytic condensation of phenols and aminophenols or aminoalcohols. The overall reaction of this synthesis concept proceeds via three steps: hydrogenation, dehydrogenative condensation and dehydrogenation. Reusable catalysts recently developed in our laboratory mediate these reactions highly efficient. The scope of the concept is exemplarily demonstrated by the synthesis of carbazoles, quinolines and acridines, the structural motifs of which figure prominently in many important natural products, drugs and materials.


General Methods
Air-and moisture sensitive reactions were carried out under dry argon or nitrogen atmosphere using standard Schlenk or glove box techniques. Dry solvents were obtained from a solvent purification system (activated alumina cartridges) or purchased from Acros. Chemicals were purchased from commercial sources with purity over 95 % and used without further purification. Polysilazane "KiON HTT 1800" was purchased from Clariant Advanced Materials GmbH, Frankfurt (Germany) and used without further purification. NMR spectra were received using a

Synthesis of the Ir Catalysts
The used iridium PN5P-Ir-Pincer 1 and Ir@SiCN 2 catalysts were synthesized, characterized and used as reported.

Synthesis of the Pd@SiCN Catalyst
The Pd@SiCN catalyst was synthesized, characterized and used as reported. 3

Synthesis of the Ru@SiCN Catalyst
The Pd@SiCN catalyst was synthesized, characterized and used as reported. 3

Hydrogenation of Phenolic Compounds
Phenol could be hydrogenated at 50 °C and 3 bar H2 pressure within 24 h using only 0.03 mol% active Ru. A comparison to other commercial catalysts with a reaction time of 5 h is given in Supplementary Table 1. The conditions and results of the hydrogenation of phenolic compounds can be found in Supplementary Table 2. Up-scaling: Into a reaction glass vial fitted with a magnetic stirring bar, 121 mmol (11.4 g) phenol, 200 mg Ru@SiCN catalyst (0.01 mol% ruthenium), 3 mL tetrahydrofuran and 2 mL water were added. The reaction vial was then placed in a 300 mL Parr autoclave and flushed three times with hydrogen. The autoclave was then pressured with 20 bar hydrogen and the reaction was stirred for 20 h at 50 °C. After half of the reaction time, the hydrogen pressure was again adjusted to 20 bar. After 20 h the hydrogen pressure was released and the sample was extracted five times with diethyl ether. After removal of the solvent under reduced pressure the crude product was obtained in > 95 % yield and analyzed by GC and GC-MS. The hydrogenation of 3,5dimethylphenol required 80 °C on large scale for full conversion.

ADC Coupling:
All carbazoles were prepared by modification of a literature method using the homogeneous iridium PN5P-Ir-Pincer catalyst I.
Typical Procedure: In a glove box 2.0 mL catalyst I (0.02 mmol, 0.01 M in thf), cyclohexanol (15.22 mmol), 1,2-amino alcohol (7.61 mmol), 10 mL thf and KO t Bu (8.37 mmol) were given in a pressure tube and sealed with a semi-permeable membrane. The tube was heated at 105 °C (oil bath temperature) for 22 h. After cooling to RT 3 mL water and dodecane as internal standard were added. The product was extracted with diethyl ether (2x) and purified by column chromatography or crystallization.

Acceptorless Dehydrogenation:
Typical Procedure: In a 10 mL Schlenk tube 50 mg (0.18 mol% active metal) Pd@SiCN, 1.0 mmol substrate and 0.75 mL diglyme were evacuated and flushed with argon for three times. A slight argon flow of 4-6 mL/min was adjusted and the mixture was stirred for 20 h at 190 °C (oil bath temperature). After cooling to RT the catalyst was separated by centrifugation and washed with acetone two times. The organic phases were combined and the solvent was removed under reduced pressure at 60 °C giving the pure product. If required, further purification was achieved by either column chromatography or crystallization.

Comparison between heterogeneous and homogenous reaction conditions:
Regarding to carbazole synthesis, the homogeneous Ir pincer catalyst showed a higher activity than the reusable Ir@SiCN catalyst at 140 °C. However, the results could significantly be improved by an increase of the reaction temperature up to 160 °C (Supplementary Table 5). The overall yield combining all three steps for product 4c was 53 %.

ADC Coupling:
The conditions of the tetrahydropyrrole synthesis were adopted. The best catalyst loading was found to be 0.5 mol% active metal. At the beginning, a small temperature screening was performed resulting in 140 °C as the best reaction temperature (Supplementary Table 3). All products except 2a were synthesized using the heterogeneous Ir@SiCN catalyst.
General Procedure: In a glove box 150 mg Ir@SiCN (0.5 mol% active metal), cyclohexanol (12.0 mmol), 1,3-aminoalcohol (3.0 mmol), 3 mL diglyme and KO t Bu (673 mg, 6.0 mmol) were added in a pressure tube and the tube was closed by a pressure equalization device. The mixture was stirred at 140 °C (oil bath temperature) for 24 h. After cooling to RT 3 mL water and dodecane as internal standard were added and the product was extracted by diethyl ether (2x). The products were purified either by column chromatography or crystallization.

Acceptorless Dehydrogenation
General Procedure In a 10 mL Schlenk tube 50 mg (0.18 mol% active metal) Pd@SiCN, 1.0 mmol substrate and 0.75 mL diglyme were evacuated and flushed with argon for three times. A slight argon flow of 4-6 mL/min was adjusted and the mixture was stirred for 18 h at 200 °C (metal bath temperature). After cooling to RT the catalyst was separated by centrifugation and washed with acetone two times. The organic phases were combined and the solvent was removed under reduced pressure at 60 °C giving the pure product. If required, further purification can be achieved either by column chromatography or crystallization. The overall yield combining all three steps for product 5a was 58 %.

ADC Coupling:
General Procedure: In a glove box 150 mg Ir@SiCN (0.5 mol% active metal), cyclohexanol (12.0 mmol), 1,3-aminoalcohol (3.0 mmol), 3 mL diglyme and KO t Bu (673 mg, 6.0 mmol) were added in a pressure tube and the tube was closed by a pressure equalization device. The mixture was stirred at 140 °C (oil bath temperature) for 24 h. After cooling to RT 3 mL water and dodecane as internal standard were added and the product was extracted by diethyl ether (2x). The products were purified either by column chromatography or crystallization.

Acceptorless Dehydrogenation
General Procedure In a 10 mL Schlenk tube 50 mg (0.18 mol% active metal) Pd@SiCN, 1.0 mmol substrate and 0.75 mL diglyme were evacuated and flushed with argon for three times. A slight argon flow of 4-6 mL/min was adjusted and the mixture was stirred for 18 h at 200 °C (oil bath temperature). After cooling to RT the catalyst was separated by centrifugation and washed with acetone two times. The organic phases were combined and the solvent was removed under reduced pressure at 60 °C giving the pure product. If required, further purification can be achieved either by column chromatography or crystallization. The overall yield combining all three steps for product 6b was 87 %.
In a 10 mL Schlenk tube 0.5 mmol 1a were solved in 1.0 mL diglyme and the catalyst (0.18 mol% active metal) was added. The reaction mixture was evacuated and flushed with argon for three times and a slight argon flow of 4-6 mL/min was adjusted. The Schlenk tube was placed in a pre-heated oil bath at 180 °C for 6-24 h. After cooling to RT in an argon atmosphere, dodecane as internal standard was added and a sample for GC and GC-MS analysis was taken.

Hydrogen release experiments
The yield of H2 was quantified for the ADC coupling of cyclohexanol and 2aminobenzyl alcohol, as well as for the following dehydrogenation of 1,2,3,4tetrahydroacridine. ADC: In a glove box 160 mg Ir@SiCN (0.8 mol% active metal), cyclohexanol (8.0 mmol), 2aminobenzyl alcohol (2.0 mmol), 3 mL diglyme and 2 eq. KO t Bu (448 mg, 4.0 mmol) were added in a 25 ml Schlenk tube. The tube was connected to a reflux condenser, linked to a water column. The mixture was heated up to 140 °C and after a short equilibration time the released hydrogen was collected. The results are in good agreement with the theoretically expected values (Supplementary Table 6). To ensure a clean and selective dehydrogenation process a GC analysis of the gas phase was accomplished (Supplementary Figure 32).

Acceptorless Dehydrogenation:
In a glove box 2.0 mmol 1,2,3,4-tetrahydroacridine, 1 ml diglyme and 250 mg Pd@SiCN were given in a 25 mL Schlenk tube. The tube was connected to a reflux condenser, linked to a water column. The mixture was heated up to 200 °C and after a short equilibration time the released hydrogen was collected. The results are in good agreement with the theoretically expected values (Supplementary Table 7). To ensure a clean and selective dehydrogenation process a GC analysis of the gas phase was accomplished (Supplementary Figure 33).