Polyfunctionalization of vicinal carbon centers and synthesis of unsymmetric 1,2,3,4-tetracarbonyl compounds

The synthesis and characterization of organic compounds with unusual atom or functional group connectivity is one of the main driving forces in the discovery of new synthetic methods that has raised the interest of chemists for many years. Polycarbonyl compounds are such compounds wherein multiple carbonyl groups are directly juxtaposed and influence each other’s chemical reactivity. While 1,2-dicarbonyl or 1,2,3-tricarbonyl compounds are well-known in organic chemistry, the 1,2,3,4-tetracarbonyl motif remains barely explored. Herein, we report on the synthesis of such 1,2,3,4-tetracarbonyl compounds employing a synthetic strategy that involves C-nitrosation of enoldiazoacetates, while the diazo functional group remains untouched. This strategy not only leverages the synthesis of 1,2,3,4-tetracarbonyl compounds to an unprecedented level, it also accomplishes the synthesis of 1,2,3,4-tetracarbonyl compounds, wherein each carbonyl group is orthogonally masked. Combined experimental and theoretical studies provide an understanding of the reaction mechanism and rationalize the formation of such 1,2,3,4-tetracarbonyl compounds.


General procedure for the synthesis of enoldiazo compounds
Step 1: Following the reported procedure, 1 to a 100-mL oven-dried flask containing a magnetic stirring bar, the ethyl 3-oxobutanoate (10 mmol, 1.16g), the corresponding alcohol (11 mmol, 1.1 eq.) and DMAP (4-dimethylaminopyridine, 0.5 mmol, 5 mol%) were dissolved in toluene (30 mL), and the reaction mixture was stirred at 110-120 ℃ overnight (monitored by TLC until all of the starting material was consumed). After cooling to room temperature and removing the solvent in vacuo, the residue was purified by column chromatography on silica gel using a 10:1 to 4:1 gradient of hexane/ethyl acetate (v/v) as eluent to afford the S-1 in >80% yield.
Step 2: Following the reported procedure, 1 to a stirred solution of an oxobutanamide S-1 (10 mmol, 1.0 equiv.) and p-acetamidobenzenesulfonyl azide (p-ABSA), (12 mmol, 1.2 equiv.) in acetonitrile (5 ml/mmol), triethylamine (15 mmol, 1.5 equiv.) was added dropwise at 0 ℃ over 3 min. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. Acetonitrile was then removed under reduced pressure, and the residue was redissolved in dichloromethane. The sulfonamide precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel using a 9:1 to 4:1 gradient of hexane/ethyl acetate (v/v) as eluent to afford the corresponding diazo S-2 in 60-90% yield.
Step 3: Following the reported procedure, 1 to a 100-mL oven-dried round bottom flask containing a magnetic stirring bar, S-2 (2.0 mmol) and Et3N (3.0 mmol, 1.5 eq) in DCM (10 mL), was added SiOTf [TIPSOTf or TBSOTf (2.2 mmol, 1.1 eq)] slowly at 0 ℃. After the reaction mixture was stirred for 0.5-1 h under these conditions, hexanes (30 mL) were added, followed by saturated aqueous NaHCO3 (40 mL). The organic phase was separated and washed two more times with saturated aqueous NaHCO3 (40 mL X 2) and dried with anhydrous Na2SO4. After evaporating the solvents the residue was purified by column chromatography on silica gel which was pre-treated with 5 vol.% triethylamine/hexanes (eluent: pure hexanes) to give the desired products 6 in 90-95% yield.  of TBN  nd  5  THF, rt  nd  6  DCM, rt  18  7  CHCl3, rt  23  8  acetone, rt  nd  9  cyclohexane, rt  nd  10  toluene, rt  nd  11 hexane, rt nd a Reaction conditions: t BuONO (3.5 equiv.) was added dropwise to a 2.0 mL solution containing 6 (0.20 mmol, 0.10 M) at 0 ℃ under N2. The reaction was continued for 12 h at room temperature. Another 1.0 equiv. of TBN was added after 24 h. b The percentage of 7 compared with the initial amount of 6 was determined by proton NMR spectral analysis using CHBr3 as internal standard. nd = not detected. Parenthesis isolated yield. Concentration 0.1M. [Cu(CH3CN)4]PF6 (5 mol%) complex m a Reaction conditions: using a syringe pump, diazo compound 7 (0.1 mmol) in 1 mL of DCE was added to a DCE solution (1 mL) containing H2O (5.0 equiv.) and Rh2(esp)2 (1.0 × 10 −3 mmol) over 1 h. The reaction was continued for the indicated time at room temperature. b Isolated yield. c The 8:14 ratio was determined by 1 H-NMR analysis. d 40% of 7 was unreacted. e 92% of 7 was unreacted. f 96% of 7 was unreacted. g 82% conversion. h 99% of 7 was unreacted. j 85% of 7 was unreacted. k 98% of 7 was unreacted. l 100% conversion. m 100% conversion. nd = not detected. Rh2(hfb)4 = rhodium(II) heptafluorobutyrate dimer. Supplementary Fig. 3. Time course of reaction between t BuONO and enoldiazo 6a. t BuONO (3.5 equiv.) was added dropwise to a 0.6 mL CD3CN solution containing 6a (0.1 mmol) at 0 ℃ under N2. The reaction was continued and monitored during the time for 4 h at room temperature. Supplementary Fig. 4. Time course reaction between t BuONO, tBuOH and enoldiazo 6a. t BuONO (3.5 equiv.) was added dropwise to a 0.6 mL CD3CN solution containing 6a (0.2 mmol) and tBuOH (2.0 equiv.) at 0 ℃ under N2. The reaction was continued and monitored during the time for 4 h at room temperature. and Cyclic voltammetry (CV) were performed in acetonitrile/water and dimethylformamide (DMF) at 23°C on a CH Instruments 620D electrochemical workstation. In entry 1 a 9:1 ratio of ACN to deionized (DI) water was used to improve solubility of the compound. A three-electrode setup was employed comprising a 2 mm diameter glassy carbon working electrode, a platinum wire auxiliary electrode, and a Ag/AgCl quasi-reference electrode. Triply recrystallized Bu4NPF6 was used as the supporting electrolyte. All electrochemical data were referenced to the ferrocene/ferrocenium couple at 0.00 V.

General procedures
Formation of 1-Ester-2-diazo-3-keto-4-protected Oximes. tert-Butyl nitrite (3.5 equiv., 1.4 mmol) was added dropwise over 1 min in a round bottom flask containing a solution of enoldiazo compound 6 (0.4mmol, 0.10 M in MeCN) at 0℃ under a N2 atmosphere. The reaction solution was slowly warmed to room temperature, and the progress of the reaction was followed by TLC until consumption of the vinyldiazo compounds was complete. The color of solution went from orange/yellow to colorless. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography (hexane/ethyl acetate = 5/1) to give the desired diazo product 7.

Formation of 1-Ester-2-diazo-3-keto-4-oximes.
To a solution of the protected oxime 7 (0.1 mmol, 0.20 M in THF) in a dry 8-mL vial was added TBAF (1.5 equiv., 0.15 mmol) at 0 ℃ all at once. The progress of the reaction was followed by TLC until consumption of the protected oxime was complete, and the residue was purified by flash chromatography (dichloromethane/methanol = 9/1) to give the desired product 10.
Formation of Dioxolene Carboxylate 11. To solution of Rh2(OAc)4 (5 mol%) in 2 mL of acetone in a dry 8-mL tube, diazo-oxime 10 (0.1 mmol,) was added at room temperature. The temperature was increased to 45 ℃ and the solution was stirred for 24 h. The residue was then purified by flash chromatography (hexane/ethyl acetate = 5/1) to give the desired dioxolene product 11 (16.1 mg, 50%).

Formation of Enediol and α-Hydroxycarbonyl Compounds.
In a dry 8-mL tube, to solution of Rh2(esp)2 (1 mol%) in 1 mL of dichloroethane with H2O (5.0 equiv., 0.5 mmol), diazo protected oxime 7 (0.1 mmol, 0.10 M in DCE) was added over 1 h with a syringe pump at room temperature under N2. The color of the solution changed from light blue/green to light brown after 24 h. The vial was moved into a glove box, and the solvent was then removed. Deuterated solvent was added S10 under N2 to determine the equilibrium between α-hydroxy carbonyl (13a) and enediol (12a) compounds. The enediol 12 is stable under N2, but in the presence of air 12 is rapidly converted to 2,3-diketo oxime 8 and its hydrate form 14.

Crystallographic data
Crystallographic data and structure refinement for compound 9h Supplementary Fig. 8. ORTEP drawing of 10h showing thermal ellipsoids at the 50% probability level.
Single crystals of C14H12F3N3O4(1) were prepared by slow evaporation of a MeOH/DCM solution. A suitable colorless plank-like crystal, with dimensions of 0.191 mm × 0.120 mm × 0.042 mm, was mounted in paratone oil onto a nylon loop. All data were collected at 100.0(1) K, using a XtaLAB Synergy/ Dualflex, HyPix fitted with CuKα radiation (λ = 1.54184 Å). Data collection and unit cell refinement were performed using CrysAlisPro software. 2 The total number of data were measured in the 5.7° < 2θ < 153.0° for compound 10h, using ω scans. Data processing and absorption correction, giving minimum and maximum transmission factors (0.655, 1.000 for compound 10h were accomplished with CrysAlisPro 2 and SCALE3 ABSPACK 3 . The structure, using Olex2 4 , was solved with the ShelXT 5 structure solution program using direct methods and refined (on F2) with the ShelXL 6 refinement package using full-matrix, least-squares techniques. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atom positions were determined by geometry and refined by a riding model.  Fig. 9. ORTEP drawing of 11 showing thermal ellipsoids at the 50% probability level.

Supplementary
Single crystals of of C16H19NO6 were prepared by slow evaporation of a DCM/hexane solution. A suitable colorless plank-like crystal, with dimensions of 0.123 mm × 0.090 mm × 0.033 mm, was mounted in paratone oil onto a nylon loop. All data were collected at 100.0(1) K, using a XtaLAB Synergy/ Dualflex, HyPix fitted with CuKα radiation (λ = 1.54184 Å). Data collection and unit cell refinement were performed using CrysAlisPro software. 2 The total number of data were measured in the 6.2° < 2θ < 152.8° for compound 11, using ω scans. Data processing and absorption correction, giving minimum and maximum transmission factors (0.808, 1.000 for compound 11) were accomplished with CrysAlisPro 2 and SCALE3 ABSPACK 3 . The structure, using Olex2 4 , was solved with the ShelXT 5 structure solution program using direct methods and refined (on F2) with the ShelXL 6 refinement package using full-matrix, least-squares techniques. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atom positions were determined by geometry and refined by a riding model. the hydroxyl hydrogen atom on the oxygen atom, O6, was determined by electron density plot.

Computational Details
All calculations were performed using the Gaussian 16, Revision B.01 package. 7 All structures were optimized in gas phase at the (U)BP86 level 8 of theory in combination with D3(BJ) dispersion corrections, 9 and the 6-31G(d) basis set 10

Computed Reaction Pathways
Supplementary Fig. 10. Relative free-energy profile for the reaction of enol diazoacetate 6a with TBN.

Computed Energy of all Stationary Points
Supplementary