Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp3)−H bonds with alkynes

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)—C(sp) coupling of unactivated C(sp3)−H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp3)—H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P-ligand catalyst for asymmetric oxidative cross-coupling of unactivated C(sp3)—H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N-fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C(sp3)−H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C(sp3)—C(sp), C(sp3)—C(sp2), and C(sp3)—C(sp3) bonds when allied with follow-up transformations.


Supplementary
Mechanistic studies of Sonogashira-type enantioselective oxidative cross-coupling reaction. a The reaction was significantly inhibited by addition of common radical inhibitors TEMPO and BHT. b and c An intramolecular KIE of 1.94 and an intermolecular KIE of 1.16 were observed, respectively, on substrate 1aa and its corresponding deuterated derivatives, thus indicating the HAA step might not be involved in the rate-determing step(s).
The absolute configuration of 3a was determined by comparing the HPLC spectrum and specific rotation of prepared 5 with those reported in literature, as shown below. [1][2][3][4] The product 3a was determined to be of an "S" absolute configuration according to the "R" absolute configuration of 5.

Supplementary Methods
Most of reactions were carried out under argon atmosphere using Schlenk techniques. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. CuI was purchased from Sigma-Aldrich. Analytical thin layer chromatography (TLC) was performed on precoated silica gel 60 GF254 plates. Flash column chromatography was performed using Tsingdao silica gel (60, particle size 0.040-0.063 mm). Visualization on TLC was achieved by use of UV light (254 nm) or iodine. NMR spectra were recorded on Bruker DRX-400 and DPX-500 spectrometers at 400 or 500 MHz for 1

General synthesis of N-(tert-butyl)benzamides S-1a-S-1l.
Supplementary Figure 237 General synthesis of N-(tert-butyl)benzamides S-1a-S-1l According to the literature procedures. 5,6 To a stirred solution of 2-iodobenzoic acid in THF (0.33 M) in an oven-dried flask was added MeMgBr (1 equiv.) at 30 °C under argon and the reaction mixture was stirred under the same conditions for 5 mins. Next, iPrMgCl (1.2 equiv.) was added slowly and the stirring was continued under the same conditions for another 1 h. Then, the reaction mixture was cooled to 40 °C and a solution of CuCNꞏ2LiCl in THF (5 mol%, 0.34 M) was added slowly. The reaction mixture was stirred for 10 mins while being warmed to 30 °C. Subsequently, alkyl bromide or alkyl iodide (3.0 equiv.) was added in one portion and the reaction was allowed to warm to ambient temperature overnight while stirring. Upon completion, the reaction was diluted with EtOAc, acidified with 1 M HCl to pH = 3, and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The crude mixture was concentrated and purified by column chromatography on silica gel to yield 2-subsituted benzoic acid. To a solution of 2-subsituted benzoic acid (1.0 equiv.) and DMF (0.05 equiv.) in DCM (0.3 M) was added oxalyl chloride (1.50 equiv.) dropwise at rt. The reaction was stirred under the same conditions until bubbling stopped. Then, volatiles were removed by rotary evaporation under high vacuum. The crude reaction product was dissolved in DCM (0.3 M) and tert-butylamine (1.5 equiv.) as well as triethylamine (2.0 equiv.) were sequentially added at room temperature. The reaction was stirred for 1 to 3 h before being quenched with 1.0 M aqueous HCl. The crude mixture was diluted with DCM (0.1 M) and water (0.1 M). The organic layer was removed and then, the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried with NaSO4, filtered, and concentrated by rotary evaporation. The residue thus obtained was purified by silica gel column chromatography (typically 20% EtOAc in hexanes) to afford the pure amide.

General synthesis of N-alkylbenzamides S-1m-S-1q
Supplementary Figure 238 General synthesis of N-alkylbenzamides S-1m-S-1q According to the literature procedures. 5,7 To a solution of freshly distilled diisopropylamine (1.05 equiv.) in anhydrous THF (0.33 M) was added n-butyllithium (2.4 M, 1.05 equiv.) dropwise at 78 °C under argon. Upon completion, the reaction mixture was allowed to warm to 0 °C and stirred for 0.5 h. Next, the reaction solution was cooled to 78 °C and ethyl isobutyrate (1.0 equiv.) was added dropwise. The stirring was continued for 1 h at 78 °C and then, alkyl iodide (1.0 equiv.) was added. The stirring was continued overnight at room temperature. Upon completion, the reaction mixture was poured into ice-water and extracted with diethyl ether. The combined organic phase was washed with brine and dried over anhydrous MgSO4. Evaporation of organic solvent gave the crude product ester without further purification for the next step. The crude ester was dissolved in methanol (1.0 M) and 30% aqueous NaOH (2.5 equiv.) was added. The reaction solution was then refluxed for 2 h. After being cooled, the mixture was diluted with water and extracted once with diethyl ether. Then, the aqueous solution was acidified with 10% HCl at 0 °C until pH = 1. The mixture was extracted with diethyl ether. The combined organic phase was washed with brine and dried over anhydrous Na2SO4. Evaporation of organic solvent gave the crude acid without further purification for the next step. To a stirred solution of the crude acid (1.0 equiv.) and triethylamine (1.05 equiv.) in dry toluene (0.2 M) was added diphenylphosphoryl azide (DPPA) (1.05 equiv) at 0 °C for 1 h under argon. The reaction was stirred for 1 h at rt and then refluxed for 12 h (evolution of N2) under argon. Upon completion, the solution was cooled and washed with water. The toluene phase was separated and dried over anhydrous Na2SO4. Next, toluene was removed by evaporation and a mixture of 15 % HCl (10 mL) and acetic acid (10 mL) was added. After about 10 mins of a rapid evolution of CO2, the reaction mixture was stirred at rt overnight. Upon completion, the mixture was extracted once with diethyl ether and then, the aqueous solution was basified by a cooled 10% aqueous solution of NaOH until pH =13. The mixture was extracted with diethyl ether. The combined extracts were washed with water and brine and dried over anhydrous Na2SO4. Evaporation of organic solvent gave the crude amine without further purification for the next step. To a solution of the crude amine in DCM (0.3 M) were sequentially added benzoyl chloride (1.5 equiv.) and triethylamine (1.5 equiv.) at rt. The reaction mixture was stirred for 1 to 3 h under the same conditions. Upon completion, the mixture was quenched with 1 M aqueous HCl and transferred to a separatory funnel. The crude mixture was diluted with DCM and water. The organic layer was removed and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 and then brine. The organic layer was dried with NaSO4, filtered, and concentrated by rotary evaporation. The residue thus obtained was purified by silica gel column chromatography (typically 20% EtOAc in hexanes) to afford the pure amide.

Supplementary Figure 239 General synthesis of [D 1 ]-S-1aa and [D 2 ]-S-1aa
To a flame-dried 50 mL round-bottom flask with a stir bar was added S-1aa (10 mmol). The contents were evacuated and backfilled three times with argon. THF (20 mL, 0.2 M) was added via syringe and the flask was cooled on an ice bath for 15 minutes. n-Butyllithium (2.8 mL, 2.1 equiv., 2.2 M in hexanes) was added dropwise. The blood-red solution was stirred at 0 °C for 45 minutes, and then quenched with D2O (4 mL). The biphasic mixture was transferred to a separatory funnel and diluted with DCM and brine. The organic layer was removed, and the aqueous layer was extracted with DCM. The combined organic layers were dried with MgSO4, filtered, and concentrated by rotary evaporation to afford [D 1 ]-S-1aa. 1 H NMR analysis showed >95% D-incorporation. The compound [D 2 ]-S-1aa was prepared following the same procedure described above using [D 1 ]-S-1aa (5 mmol) as substrate, and 1 H NMR analysis showed >95% D-incorporation after the procedure was repeated twice.  General procedure for the synthesis of N-fluoro-N-alkylcarboxamides.

Supplementary Figure 240 General synthesis of N-fluoro-N-alkylcarboxamides.
All the N-fluoro-N-alkylcarboxamides were prepared by N-fluorination of their parent carboxamides according to conventional methods. 5,8 To a flame-dried round-bottom flask with a stir bar was added amide (1.0 equiv.). The contents were evacuated and backfilled three times with argon. Anhydrous THF (0.13 M) was added and the stirred solution was cooled on an ice bath for 15 min. n-Butyllithium (1.1 equiv., 2.4 M in hexanes) was added dropwise. The reaction was maintained at 0 °C for 1.5 h. NFSI (1.5 equiv., 0.6 M in THF) was added dropwise. The reaction was left overnight in the ice bath and allowed to warm to rt. After 10 to 14 h, the reaction was quenched with 1 M aqueous HCl and transferred to a separatory funnel. The crude mixture was diluted with DCM (0.1 M) and water (0.1 M). The organic layer was removed, and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 and then brine, dried with MgSO4, filtered, and concentrated by rotary evaporation. The residue thus obtained was purified by silica gel column chromatography (15% EtOAc in hexanes) to afford pure fluoroamides.

General procedure for enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp 3 )-H bonds with terminal alkynes
Supplementary Figure 241 General procedure for enantioselective reaction

General procedure A:
Under argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with CuI (3.8 mg, 0.020 mmol, 10 mol%), L5 (12.2 mg, 0.020mmol, 10 mol%), Cs2CO3 (65.2 mg, 0.20 mmol, 1.0 equiv.), and anhydrous THF (2.4 mL). Then, Nfluorocarocarboxamide (0.20 mmol, 1.0 equiv.) and alkyne (0.40 mmol, 2.0 equiv.) were sequentially added into the mixture and the reaction mixture was stirred at rt for 16 h. Upon completion (monitored by TLC), the precipitate was filtered off and washed by DCM. The filtrate was evaporated and the residue was purified by column chromatography on silica gel to afford the desired product. General procedure B: Under argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with CuTc (5.7 mg, 0.030 mmol, 15 mol%), L5 (12.2 mg, 0.020mmol, 10 mol%), Cs2CO3 (130.4 mg, 0.40 mmol, 2.0 equiv.), and anhydrous THF (2.4 mL). Then, Nfluorocarocarboxamide (0.20 mmol, 1.0 equiv.) and alkyne (0.40 mmol, 2.0 equiv.) were sequentially added into the mixture and the reaction mixture was stirred at rt for 24 h. Upon completion (monitored by TLC), the precipitate was filtered off and washed by DCM. The filtrate was evaporated and the residue was purified by column chromatography on silica gel to afford the desired product.

Supplementary Figure 242
General procedure for enantioselective reaction General procedure C: Under argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with CuI (3.8 mg, 0.020 mmol, 10 mol%), L6 (16.7 mg, 0.020mmol, 10 mol%), Cs2CO3 (65.2 mg, 0.20 mmol, 1.0 equiv.), and anhydrous DCM (2.4 mL). Then, N-fluorocarocarboxamide (0.20 mmol, 1.0 equiv.) and alkyne (0.40 mmol, 2.0 equiv.) were sequentially added into the mixture and the reaction mixture was stirred at rt for 24 h. Upon completion (monitored by TLC), the precipitate was filtered off and washed by DCM. The filtrate was evaporated and the residue was purified by column chromatography on silica gel to afford the desired product. General procedure D: Under argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with CuI (3.8 mg, 0.020 mmol, 10 mol%), L7 (13.9 mg, 0.020mmol, 10 mol%), Cs2CO3 (65.2 mg, 0.20 mmol, 1.0 equiv.), and anhydrous chloroform (2.4 mL). Then, Nfluorocarocarboxamide (0.20 mmol, 1.0 equiv.) and alkyne (0.40 mmol, 2.0 equiv.) were sequentially added into the mixture and the reaction mixture was stirred at rt for 24 h. Upon completion (monitored by TLC), the precipitate was filtered off and washed by DCM. The filtrate was evaporated and the residue was purified by column chromatography on silica gel to afford the desired product. Since the reaction is sensitive to water and air, Schlenk tubes and the reagents must be dried prior to use.
General procedure for preparation of the racemates: Supplementary Figure 243 General procedure for racemic reaction The racemates of products were prepared following the same procedure described above using CuI (0.020 mmol, 20 mol%) and Lrac (0.020 mmol, 20 mol%) as catalyst and ligand, respectively, at rt or 40 °C in anhydrous THF (1.2 mL) for 16 to 24 h. Upon completion (monitored by TLC), the precipitate was filtered off and washed with DCM. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel to afford the desired product.

Removing the amide group to afford indirect enantioselective oxidative C(sp 3 )-C(sp) coupling
Supplementary Figure 244 Removing the amide group In a glovebox, the Schwartz reagent (103.2 mg, 0.4 mmol) and a stir bar were added to a Schlenk tube, which was then sealed with a rubber septum and removed from the box. Next, amide 3a (30.5 mg, 0.10 mmol) in anhydrous THF (2.0 mL) was added into the tube via syringe and the heterogeneous mixture was stirred vigorously at rt for 4 h. The resulting reaction mixture was then transferred to a separatory funnel and diluted with 20 mL water. The resulting mixture was extracted with DCM and the combined organic layers were dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the crude product was purified by column chromatography on silica gel to give the corresponding aldehyde 4 (17.8 mg, 76%, 89% ee) as a colorless oil. Under argon atmosphere, an oven-dried Schlenk tube equipped with a magnetic stir bar was charged with aldehyde 4 (11.7 mg, 0.050 mmol), RhCl(PPh3)3 (55.5 mg, 0.060 mmol), and anhydrous toluene (1.0 mL). Then, the mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered through celite and washed with EtOAc. After removal of solvent, the residue was purified by silica gel column chromatography to give alkyne 5 (7.1 mg, 70%, 89% ee) as a colorless oil.
[α] D 27 = −12. 8   in EtOH (0.5 mL) was added and the reaction was stirred overnight. Solvent was evaporated and the residue was purified by column chromatography on silica gel to give product 6 (13.8 mg, 90%, 89% ee) as a colorless oil.

Control experiment with copper phenylacetylide
Supplementary Figure 250 Control experiment with copper phenylacetylide Copper phenylacetylide was synthesized according to literature procedures. 11 Under argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with copper phenylacetylide (16.5 mg, 0.10 mmol, 1.0 equiv.), Nfluorocarocarboxamide 1aa (22.3 mg, 0.10 mmol, 1.0 equiv.), L5 (61.1 mg, 0.10 mmol, 1.0 equiv.), and anhydrous THF (1.2 mL). The resulting reaction mixture was stirred at rt for 16 h. Then, the reaction mixture was filtered and washed by DCM. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 3a (18.3 mg, 61% yield, 83% ee). The procedure for the reaction without L5 was the same with that described above except that L5 was not added. No desired product 3a was observed.