Asymmetric Synthesis of 2,3‐Dihydrobenzofurans by a [4+1] Annulation Between Ammonium Ylides and In Situ Generated o‐Quinone Methides

Abstract A highly enantio‐ and diastereoselective [4+1] annulation between in situ generated ammonium ylides and o‐quinone methides for the synthesis of a variety of 2,3‐dihydrobenzofurans has been developed. The key factors controlling the reactivity and stereoselectivity were systematically investigated by experimental and computational means and the energy profiles obtained provide a deeper insight into the mechanistic details of this reaction.


General Information:
1.1. General Methods 1 H-and 13 C-NMR spectra were recorded on a Bruker Avance III 300 MHz spectrometer with a broad band observe probe and a sample changer for 16 samples and on a Bruker Avance III 700 MHz spectrometer with with an Ascend magnet and TCI cryoprobe, which are both property to the Austro-Czech NMR-Research Center "RERI-uasb". All NMR spectra were referenced on the solvent peak. High resolution mass spectra were obtained using an Agilent 6520 Q-TOF mass spectrometer with an ESI source and an Agilent G1607A coaxial sprayer or a Thermo Fisher Scientific LTQ Orbitrap XL with an Ion Max API Source. Analyses were made in the positive ionization mode if not otherwise stated. Purine (exact mass for [M+H] + = 121.050873) and 1,2,3,4,5,6-hexakis(2,2,3,3tetrafluoropropoxy)-1,3,5,2,4,6-triazatriphosphinane (exact mass for [M+H] + = 922.009798) were used for internal mass calibration.
IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer with ATR unit.
Preparative column chromatography was carried out using Davisil LC 60A 70-200 MICRON silica gel. TLC probes were detected at 254 nm or stained with with an appropriate staining solution (compare section 3.1.3).
HPLC was performed using a Dionex Summit HPLC system consisting of a Dionex P-680 pump, an ASI-100 HPLC-autosampler, a STH-585 column oven and a PDA-100 detector or a Thermo Scientific Dionex Ultimate 3000 system with diode array detector with a Chiralcel OD-H (250 x 4.6 mm, 5 µm) or a YMC Cellulose-SB (250 x 4.6 mm, 5 µm)) chiral stationary phase.
Single-crystal structure analyses were carried out on a Bruker Smart X2S diffractometer operating with Mo-K α radiation (λ= 0.71073 Å).
All chemicals were purchased from commercial suppliers and used without further purification unless otherwise stated. All reactions were carried out under Argon.
The correct nature of each stationary point as minima (zero imaginary frequencies) or transition states (one imaginary frequency) has been checked by performing frequency calculations at the B3LYP/6-31G*(dichloromethane) level of theory.
Thermal and entropic contributions to free energy (at 298.15 K) and zero-point energy have been obtained from these frequency calculations. In Jaguar, the translational partition function is computed for ideal gas standard conditions, corresponding to a pressure of 1 atmosphere at 298.15 K. For solution reactions, the standard condition is instead 1 mol/L. Accordingly, the free energy value computed in Jaguar was corrected by a concentration term, equal to RT ln (V_mol_gas_1atm / V_mol_1M), i.e. 1.89 kcal/mol at 298.15 K.
For the large reaction systems there are usually several local minima or saddle points corresponding to each intermediate or transition state. This is due to the possibility of multiple conformations of substituents. We have made a systematic attempt to locate all possible local minima and saddle points, with the data presented referring to the lowest energy form unless mentioned otherwise. All species have been fully geometry optimized, and the Cartesian coordinates are supplied in Section 3.

Syntheses of Ammonium Salts 6
General procedure for achiral ammonium salts (in analogy to literature 2 ): To a solution of bromoacetophenone derivative (1 equiv.) in THF (3.3 mL per mmol starting material) trimethylamine (33% in EtOH -1 equiv.) is added and the mixture is stirred overnight. The product is filtered off and washed twice with EtOAc and dried under vacuo.

Conformational study of betaines
For trans pathway, addition occurs via a cisoid approach of reactants. The betaine formed initially is therefore in a cisoid conformation. In order for the second key step to occur, this betaine needs to undergo rotation around the newly formed carbon-carbon bond to give the corresponding transoid conformer ( Figure S1). The computed free energy of the transition state for this rotational equilibrium is 6.3 kcal.mol -1 , i.e. lower than TS to ring closure. It is thus not relevant for the reactivity and selectivity. Addition to form cis betaine occurs via a transoid approach. The betaine formed is thus in a conformation allowing cyclization. Figure S1. Computed free energy profile including conformational equilibrium for betaines.

Addition on the aromatic ring
Addition can potentially not only occur on the methylene position of the electrondeficient o-quinone methide but also onto electrophilic C3 and C5 carbon atoms of the quinone ring. Free energy barrier for these different addition mode are reported in Table S1. These data are in good agreement with the observed exclusive addition onto the methylene group.

Benchmark calculations
Free energy of key transition states has been obtained at different levels of theory (Table S2).

Epimerization process
The full computed free energy profile for epimerization of cis-A via a fully intramolecular mechanism is depicted in Figure S2. It should be noted that protonation and/or deprotonation steps may also well occur via a pathway involving an intermolecular process (through cis-C or trans-C for instance).

Figure S2
. Some potential pathways for the isomerization of cis-A into trans-A (free energies in kcal.mol -1 ). 4