Switchable selectivity in Pd-catalyzed [3 + 2] annulations of γ-oxy-2-cycloalkenones with 3-oxoglutarates: C–C/C–C vs C–C/O–C bond formation

Two complementary [3 + 2] annulation protocols between 3-oxoglutarates and cyclic γ-oxy-2-cycloalkenones, simply differing on the reaction temperature, are disclosed. These domino transformations allow C–C/O–C or C–C/C–C [3 + 2] annulations at will, via an intermolecular Pd-catalyzed C-allylation/intramolecular O- or C-1,4-addition sequence, respectively. In particular, exploiting the reversibility of the O-1,4-addition step, in combination with the irreversible C-1,4-addition/decarboxylation path, the intramolecular conjugate addition step could be diverted from the kinetic (O-alkylation) to the thermodynamic path (C-alkylation) thanks to a simple temperature increase. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined step chronology in combination with the total chemoselectivity of the former step. This [3 + 2] C–C/O–C bond forming annulation protocol could be also extended to 1,3,5-triketones as well as 1,3-bis-sulfonylpropan-2-one bis-nucleophiles.

Procedures and analytical data for starting materials 1 and 2 S4 IV. Procedures and analytical data for bicyclic products 4-9 S6 V. 1 H and 13 C NMR spectra S12 S2

I. General remarks
All reactions were carried out under an argon atmosphere by standard syringe and septa techniques.
Glassware was flame-dried under vacuum or taken directly from the oven (100 °C) and let cool under vacuum prior to every use. Reagents and solvents were purchased from commercial sources and generally used as received. DCM, THF, CH 3 CN and DMF were dried on a MBRAUN purification system MB SPS-800. Where necessary, other organic solvents or compounds were dried and/or distilled.
NMR spectra ( 1 H, 13 C) were recorded on a Bruker AM 300 MHz or on a Bruker AVANCE 400 MHz.
NMR experiments were carried out at room temperature in deuterochloroform (CDCl 3 ). Chemical shifts are given in parts per million (ppm) using the residual non-deuterated signals as (CDCl 3 : δ 7.26, 77.0 ppm). The terms m, s, d, t and q represent multiplet, singulet, doublet, triplet and quartet, respectively. The term (br) is used when the peak is broad, and the correct multiplicity cannot be surely assigned. Coupling constants (J) are given in Hertz (Hz). For previously unknown compounds, a combination of 13 C DEPT and 2D experiments (COSY, HSQC, HMBC) were often used to complete assignment of 1 H and 13 C signals.
IR spectra were recorded with a Tensor 27 (ATR diamond) Bruker spectrometer. IR was reported as characteristic bands (cm −1 ). High-resolution mass spectra (HRMS) were recorded using a mass spectrometer MicroTOF from Bruker with an electron spray ion source (ESI) and a TOF detector or using a mass spectrometer from Thermo Fisher Scientific with an electron spray ion source (ESI) and

S7
In a Schlenk tube, under an argon atmosphere, were added Pd(OAc) 2 (0.10 equiv), dppb (0.15 equiv) and anhydrous DMSO (0.1 M). After 10 min, the cyclic electrophilic 2a-c (1.3 equiv) and the dimethyl 3-oxoglutarate (1a, 1.0 equiv) were added. The reaction was stirred at room temperature. After 1 hour, the reaction mixture was filtered on a plug of silica and washed with EtOAc. The filtrate was washed with a 10% aqueous solution of NaHCO 3 . The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel afforded the corresponding product 4a-c (or compound 6 in the case of 2b).

General procedure 2 (GP2): conditions A' in THF at rt
In a Schlenk tube, under an argon atmosphere, were added Pd(OAc) 2 (0.10 equiv), dppb (0.15 equiv) and anhydrous THF (0.1 M). After 10 min, the cyclic electrophilic 2a (1.3 equiv) and the bisnucleophile 1b-d (1.0 equiv) were added. The reaction was stirred at room temperature. After 1 hour, the reaction mixture was filtered on a plug of silica and washed with EtOAc. The filtrate was washed with a 10% aqueous solution of NaHCO 3 and brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel afforded the corresponding product 7-9.

General procedure 3 (GP3): conditions B in DMSO at 130 °C
In a sealed tube, under an argon atmosphere, were added Pd(OAc) 2 (0.10 equiv), dppb (0.15 equiv) and anhydrous DMSO (0.1 M). After 10 min, the cyclic electrophilic 2a-c (1.3 equiv) and dimethyl 3oxoglutarate (1a, 1.0 equiv) were added. The reaction was stirred at 130 C. After 6 hours or 8 hours, the reaction mixture was filtered on a plug of silica and washed with EtOAc. The filtrate was washed with a 10% aqueous solution of NaHCO 3 . The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous MgSO 4 , filtered and S8 concentrated under reduced pressure. Purification by column chromatography on silica gel afforded the corresponding product 5a-c.

General procedure 4 (GP4): conditions C in DMSO at 130 °C with microwave
In a sealed microwave tube, under an argon atmosphere, were added Pd(OAc) 2 (0.10 equiv), dppb (0.15 equiv) and anhydrous THF (0.1 M). After 10 mins, the cyclic electrophilic 2a-c (1.3 equiv) and dimethyl-3-oxoglutarate (1a, 1.0 equiv) were added. The reaction was stirred at 130 C under microwave irradiation conditions. After 1 hour, the reaction mixture was filtered on a plug of silica and washed with EtOAc. The filtrate was washed with a 10% aqueous solution of NaHCO 3 . The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel afforded the corresponding product 5a-c.