Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C–X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.


Disclosure
One important fact to disclose was that the formation of the alpha triflate from the corresponding alpha hydroxyamide proved to proceed in consistently higher yields when 2,6-lutidine was used as a base. For instance, when 2-I-Pyridine was used the yield was significantly lower and the 1 H-NMR analysis became less straightforward.
In order to access whether the intermediate (-triflate) could be transformed to the intramolecular fridelcraft product we scoped a wide array of conditions. We soon realized that forcing conditions, such as the one encountered previously in the literature (enolnium ref paper) where ideal. After careful examination we became aware that 2-I-Pyridine as a base, combined with extreme temperatures (110 °C) in acetonitrile were crucial for the reaction to take place (vide infra). To a solution of the amide 2m (0.2 mmol, 1 equiv.) and distilled 2,6-lutidine (1 equiv.) in DCM (0.1 M, 2 mL) at 0 °C, triflic anhydride (35 µL, 1.1 equiv.) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature while stirring for 1 hour. TBAI (0.6 mmol, 3 equiv.) was added and the reaction mixture was stirred at room temperature for 3 h before being quenched with NH4Cl solution. The layers were separated and the aqueous extracted with DCM. The combined organic layers were washed with brine before being dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (EtOAc in heptane 10% -40%) to afford the product as a yellow oil in 69% (47.1 mg) yield.
To a solution of the amide 2m (0.2 mmol, 1 equiv.) and distilled 2,6-lutidine (1 equiv.) in DCM (0.1 M, 2 mL) at 0 °C, triflic anhydride (35 µL, 1.1 equiv.) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature while stirring for 1 hour. Then, a solution of the deprotonated nucleophile was generated from addition of the N-Methyl-p-toluenesulfonamide (0.6 mmol, 3 equiv.) to a suspension of NaH (0.6 mmol, 3 equiv.) in DMF (3.0 mL) was added. The reaction mixture was stirred at room temperature for 3 h before being quenched with NH4Cl solution. The layers were separated and the aqueous extracted with DCM. The combined organic layers were washed with brine before being dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (EtOAc in heptane 20% -40%) to afford the product as a yellow oil in 82% (65.9 mg) yield. Addition of 3 mL dioxane, 10 eq. Bu4NOH 69 0 a Using 1,3,5-trimethoxybenzene as an internal standard in 1 H NMR.

S16
General procedures for the synthesis of carboxamides and sulfonamides

Carboxamides -Procedure A
To a solution of the amine (1.0 equiv.) and triethylamine (2.0 equiv.) in DCM (0.1 M) at 0 °C, the corresponding acyl chloride (1.2 equiv.) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature while stirring overnight (14 h). After this time, a saturated aqueous solution of sodium bicarbonate was added and the biphasic system was separated. The aqueous phase was extracted with DCM (1×) and the organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel (heptane/ethyl acetate) to afford the desired compound.

Carboxamides -Procedure B
To

S18
The product was prepared according to general procedure B from 1.42 g (7.0 mmol) monomethyl azelate and 0.50 g (0.57 mL, 7.0 mmol) pyrrolidine in 99% (1.77 g) yield. All spectroscopic properties are in good accordance with reported data. [1] 1-(Pyrrolidin-1-yl)undecane-1,10-dione Prepared according to the procedure reported in the literature. [3] All analytical data were in good accordance with data reported in the literature.

N,N-dibenzyl-4-phenylbutanamide
The product was prepared according to general procedure A. Purification by flash column chromatography yielded the product as a yellow oil (84%).
General procedures for the -functionalization of amides

-dimethylbenzenesulfonamide
The product was prepared according to general procedure E. Purification by column chromatography on silica gel (EtOAc: heptane = 1:1) yielded the product (60.0 mg, 69%) as a pale yellow liquid.

butan-2-yl)-L-cysteinate
The product was prepared according to general procedure E. Purification by flash column chromatography

X-ray Analysis
The X-ray intensity data were measured on Bruker X8 APEX2 diffractometer equipped with multilayer monochromator, Mo K/a INCOATEC micro focus sealed tube and Cryoflex cooling device. The structure was solved by direct methods and refined by full-matrix least-squares techniques. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were inserted at calculated positions and refined with riding model. The following software was used: Bruker SAINT software package b using a narrow-frame algorithm for frame integration, SADABS c for absorption correction, OLEX2 d for structure solution, refinement, molecular diagrams and graphical user-interface, Shelxle e for refinement and graphical user-interface SHELXS-2015 f for structure solution, SHELXL-2015 g for refinement, Platon h for symmetry check. Experimental data and CCDC-Codes Experimental data and CCDC-Code (Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html) can be found in Table S1. Crystal data, data collection parameters, and structure refinement details are given in Tables S2 and S3. Crystal structure is visualized in Figure S1.   2-(Methylamino)-2-(4-nitrophenyl)-3-phenyl-1-(pyrrolidin-1-yl)propan-1-one 7b Figure S1 Crystal structure, drawn with 50% displacement ellipsoid. The bond precision for C-C single bonds is 0.0048Å. The chiral orientation could not be determined (visualized R).

Computational details
The conformational space of all flexible molecules has been initially searched using the OPLS_2005 force field 1 and the systematic Monte Carlo conformers search routine implemented in MACROMODEL 11.5. 2 To consider the flexibility of the complexes composed of individual fragments (e.g. the complex of a cation with the negatively charged TfOcounterion), the electrostatic potential of the ions has been studied applying natural bond orbital (NBO) population analysis. The reciprocal positions of the fragments have been determined based on the calculated NBO charges. The obtained complexes have been used to restrict further the conformational search and obtain the set of complexes that will be reoptimized using density functional theory (DFT) methods.
Accordingly, the structures located at force field level have then been subjected to B3LYP-D3/def2-SVP 3-8 (using def2-ECP 9 for iodine atom) geometry optimization. The "Ultrafine" integration grid has been applied. The nature of all stationary points (minima and transition states) was verified through the computation of the vibrational frequencies.
The density-based solvation model SMD 12