Catalyst-Switchable Regiocontrol in the Direct Arylation of Remote C–H Groups in Pyrazolo[1,5-a]pyrimidines**

The regiodivergent palladium-catalyzed C–H arylation of pyrazolo[1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. A phosphine-containing palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas a phosphine-free catalyst targets the most electron-rich position (C3).


General Conditions
All reagents were purchased from commercial suppliers and used as received, without further purification. Pyrazolo [1,5--a]pyrimidine was purchased from Combi--Block Chemicals. Reactions were performed using anhydrous solvents under an atmosphere of air. NMR spectra were acquired at the indicated field strengths on either a Varian 500 MHz, 400 MHz, an ECP 400 MHZ or a Jeol ECP 300 MHz spectrometer. 1 H and 13 C NMR spectra were referenced to the residual protio solvent. ESI--MS were performed on a Daltonics Apex IV spectrometer. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT--IR spectrometer with an ATR diamond cell.

Reaction Optimisation
Reaction optimisation was carried out in a glass--tube fitted with a Young's valve (nominal volume ~ 20 mL) under air. Pyrazolo[1,5--a]pyrimidine (0.25 mmol) and bromobenzene were combined with catalyst, ligand, base, additive, solvent and heated to the desired temperature for the required duration (see Tables S1--S3). The reaction mixture was filtered through Celite washing exhaustively with ethyl acetate and 1,3,5--trimethoxybenzene (internal standard, 0.25 mmol) was added to the washings. The solution was concentrated in vacuo, redissolved in CDCl 3 and analysed by 1 H NMR. Table S1. Catalyst, Ligand, Base and Solvent Screen. [
Larger Scale Examples. The procedures above were repeated on a larger scale (1.0 mmol of 1) using bromobenzene. Conditions A gave 2a in 79% isolated yield, while conditions b afforded 2b in 70% spectroscopic yield. Table S4 shows the selectivities for the reactions summarised in Figures 2 and 3, as determined by 1 H NMR spectroscopy. The diarylated products 4 were not isolated, but there presence or otherwise was confirmed by UHPLC--MS analysis.

Relative acidities
The relative acidities for each of the C--H bonds of 1 was calculated by considering the deprotonation of 1 by the acetate ion, according to equation S1: The relative acidities were expressed as the free energies of the exchange processes, as defined in equation S2: For each species, the structure was optimized and a frequency calculation was performed at the B3LYP level of theory, using the 6--31G(d) basis set and the Cartesian coordinates for these species and electronic energies are given below. All calculated structures showed no imaginary frequencies,

Time (h)
Run 1 Run 2 1 + Ac -toluene (1 -H) -+ AcH (S1) Reaction appearance 6 hours (from run 1) Reaction appearance 0 -5 hours (from run 1) showing that they are intermediates. The Gibbs free energy for each species (ΔG sol in Table  S5) was determined by (a) running a single point calculation at the B3LYP level of theory, based on the results of the prior optimizations with the smaller basis set, using the 6--311++G(2df,2p) basis set with solvent (toluene) effects included using the PCM model (E sol , Table  S5), [S6] and then (b) adding the thermal correction obtained from the calculation from the smaller basis set. [S7] These values were then substituted into equation S2 to give the values for the exchange energies, summarized in Figure S3. Figure S3. Exchange energies (as defined in Eqs. S1 and S2) for the various C--H residues of 1.

Electrophile Affinities (Eα)
The recently introduced concept of electrophile affinity (Eα) is defined according to equation S3. [S8] Good to excellent correlations are observed between Eα values and relative rates and regioselectivities in chlorination, bromination, nitration and benzylation of simple aromatics and, in principle, this correlation should hold for any S E Ar process which proceeds via the rate--limiting formation of a Wheland--like intermediate. [S8] Eα (kcal/mol) = [E arene + E electropile ] -E arenium ion (S3) In this case the Eα were calculated in the gas--phase, with arene = 1; electrophile = Br + ion and arenium = the sigma--complexes [1--Br] + with the site of Br + substitution varied between the C2, C3, C5, C6 and C7 positions, using the B3LYP functional, [S3] combined with 6--311+G(2d,2p) basis set. [S9] Cartesian coordinates and energies of all optimized structures are given below. All calculated S29 structures showed no imaginary frequencies, showing that they are intermediates. Figure S4 shows a representative example of an arenium complex, namely that of the C3--brominated sigma--complex [1--3Br] + , and summarizes the values obtained for Eα at all the carbon--positions.