Chemo- and Stereoselective Transition-Metal-Free Amination of Amides with Azides

The synthesis of α-amino carbonyl/carboxyl compounds is a contemporary challenge in organic synthesis. Herein, we present a stereoselective α-amination of amides employing simple azides that proceeds under mild conditions with release of nitrogen gas. The amide is used as the limiting reagent, and through simple variation of the azide pattern, various differently substituted aminated products can be obtained. The reaction is fully chemoselective for amides even in the presence of esters or ketones and lends itself to preparation of optically enriched products.


Azides synthesis
General Procedure for the synthesis of 2a-g A solution of bromide (1 eq.) and NaN 3 (1.5 eq.) in DMF (0.2M) was heated at 80°C overnight. The reaction mixture was cooled, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated under vacuum, to afford the corresponding azide which was used without further purification.

General procedure for α-amination of amides
To a mixture of amide (0.3 mmol) and 2-fluoropyridine (0.6 mmol, 2 equiv., 58.3 mg, 51.6 µl) in DCM (1 mL) triflic anhydride was added dropwise (0.6 mmol, 2 equiv., 84 mg, 51μL.) at 0 °C under Ar. The mixture was stirred for 15 minutes at this temperature. Then a solution of azide (0.6 mmol, 2 equiv.) in 0.5 mL of DCM was added and the mixture was brought to room temperature. N 2 release was observed after addition of the azide. After 30 min, 2 mL of a saturated solution of NaHCO 3 were added and the mixture was further stirred for 1h. The biphasic mixture was then diluted with DCM and washed with a 20 mL of NaHCO 3 . The combined organic layers were dried over MgSO 4 and the solvent removed under reduced pressure. Purification through column chromatography DCM/DMA (0 to 60% DMA) afforded the products.      1

N,N-diethyl-2-(pyrrolidin-1-yl)butanamide (3oh)
To a mixture of amide 1o (0.3 mmol) and 2-fluoropyridine (0.6 mmol, 2 equiv., 58.3 mg, 51.6 µl) in DCM (1 mL) triflic anhydride was added dropwise (0.6 mmol, 2 equiv., 84 mg, 51μL.) at 0 °C under Ar. The mixture was stirred for 15 minutes at this temperature. Then a solution of azide 2h (0.6 mmol, 2 equiv) in 0.5 mL of DCM was added and the mixture was brought to room temperature. After 1 h, 2 mL of a saturated solution of NaHCO 3 were added and the mixture was further stirred for 2h. The biphasic mixture was then diluted with DCM and washed with a 20 mL of NaHCO 3 . The combined organic layers were dried over MgSO 4

Determination of the relative configuration of compounds 3xa and 3ya
The identity of major diastereoisomers for compounds 3xa and 3ya was determined by synthesizing the similar α-amino amides from isoleucine, allo-isoleucine and (R)-valine.
The substrates were prepared from the corresponding α-amino acids using known procedure.18 The αamino amides were then converted to secondary amines by reductive amination of 2-phenyl acetaldehyde using the following procedure: The amine and phenylacetaldehyde (1 equiv.) were dissolved in DCM (0.1 M) at r.t. and NaBH(OAc) 3 (1.2 equiv.) was added. The reaction was stirred for 5 hours prior to quenching with water, extraction with EtOAc drying over Na 2 SO 4 and concentration. The product was purified by column chromatography (20-50% EtOAc/heptane) to afford the pure secondary amide. The relative configuration of 3xa was determined by comparing the relative chemical shifts and coupling constants of the α-proton in (2S,3S)-and (2R,3S)-3-methyl-2-(phenethylamino)-1-(pyrrolidin-1yl)pentan-1-one with the two diasteroisomers obtained in 3xa. The chemical shift and coupling constant of the major diasteroisomer matches with the anti configuration (δ 3.00, d, J = 6.6Hz). The relative configuration of 3ya was determined by comparing the product prepared from L-valine with the crude of 3ya, and observing that it matches with the minor diastereoisomer. Therefore, the major product is the (R,R) isomer.

Computations Computational Details
All DFT (density functional theory) calculations were carried out with the Gaussian09 program package. 19 Geometry optimizations were performed using the M06-2X functional and the polarized double- basis set 6-31+G*. 20 Geometry optimizations were carried out without any constraints. Ground state minima and transition states were confirmed by frequency calculations, yielding no and one imaginary frequency, respectively. The connectivity of the transition state structures was verified by intrinsic reaction coordinate calculations. 21 The electronic energies obtained, E, were converted to relative free energies G 0 and enthalpies H 0 at 273.15 K and 1 atm by using zero point energy and thermal energy corrections obtained in the frequency calculation. Single-point energies were computed at the SMD(DCM) 22 M06-2X/def2-QZVP 23 level of theory using the geometries optimized at the M06-2X/6-31+G* level. The free energy and enthalpy values discussed in the manuscript were derived from the electronic energy values obtained at the SMD(DCM) M06-2X/def2QZVP//M06-2X/6-31+G* level, E DCM , according to the following equation: All energies are reported in hartrees/particle, unless noticed otherwise. Computed structures and molecular orbitals were visualized using the Chemcraft software. 24

Hydrolytic Liberation of Amide G
We have investigated the hydrolytic liberation of amide G from amidinium D computationally. As shown in Scheme 1-SI, the azidirine moiety in E was found to undergo a facile two-step hydrolytic opening. Accordingly, addition of water (TS E-F ), followed by water-mediated proton-transfer (TS F-G ) ultimately leads to amide G in a highly exergonic fashion (E→G: ΔG 0 DCM = -70.9 kcal mol -1 ).