Palladium-Catalyzed Direct C=H Functionalization of Benzoquinone**

A direct Pd-catalyzed C=H functionalization of benzoquinone (BQ) can be controlled to give either mono- or disubstituted BQ, including the installation of two different groups in a one-pot procedure. BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents.


Table of Contents Experimental Supporting Information -Pages S3-S90
stir bar, distilled water (12 mL) was then added, the solution briefly sonicated to disperse the reagents where necessary and the reaction was stirred at room temperature for 18-24 h. Upon completion, as determined by thin layer chromatography, EtOAc (20 mL) and water (10 mL) were added. The layers were separated and the aqueous layer was washed with a EtOAc (3 × 20 mL). The organic layer was then washed with brine (20 mL), dried over MgSO 4 and concentrated under reduced pressure. To the resultant solid, toluene (5 mL) and enough acetone to dissolve the heterogeneous mixture (0.5-1 mL) was added. The slurry was then purified directly by flash column chromatography to afford the monofunctionalized product.
Where benzoquinone coeluted with the monofunctionalized product, it was removed by sublimation using a Kugelrohr distillation apparatus.
Where monofunctionalized products have been synthesised using both procedures 1 and 2, the procedure which gives the highest yield is that which is mentioned with the characterisation data for each compound.

General procedure 3 -Palladium(II)-catalysed C-H monofunctionalization of benzoquinone using cycloalkyl boronic acids:
Benzoquinone (3 equiv., 1.5 mmol), the corresponding boronic acid (1 equiv., 0.5 mmol) and Pd(OTFA) 2 (7.5 mol%) were added to a 5 mL round bottomed flask with stirrer bar. Acetone (3.3 mL) was added and the reaction was stirred at 40 °C for 24 h after which a further portion of Pd(OTFA) 2 (7.5 mol%) was added and the reaction stirred for another 24 h. Upon completion, as determined by thin layer chromatography, the mixture was evaporated to dryness, toluene (5 mL) and enough acetone to dissolve the heterogeneous mixture (0.5-1 mL) was added. The slurry was then purified directly by flash column chromatography to afford the monofunctionalized product.
Cyclobutyl and cyclopentyl boronic acid were found to be unstable in air (but stable once in solution) and were therefore weighed out under a nitrogen atmosphere in a glove box.
The products formed using cyclobutyl and cyclopentyl boronic acids (compounds 3t and 3s) were found to be unstable when subjected to very low pressure. In these cases, after column chromatography, the majority of solvent was removed using the rotary evaporator to form a concentrated solution and the remaining solvent evaporated by placing the solution under a steady flow of nitrogen.

2-(Cyclobutyl)-1,4-benzoquinone (3t)
General procedure 3 for cycloalkyl boronic acids was followed, except that the second portion of catalyst was added after 19 h, to give the product 3t in 67% yield as a yellow amorphous solid; R f 0.22 (

2,5-Bis-(4-ethoxycarbonylphenyl)-1,4-benzoquinone (4g)
General procedure 4 was followed using an elevated temperature of 35 °C and 3 equivalents (0.300 mmol) of 2,6-dichloro-1,4-benzoquinone. After 24 h, a second portion of boronic acid (0.051 mmol, 0.5 equiv.) and Pd(OTFA) 2 (0.005 mmol, 5 mol%) were added and after a further 7 h, FeCl 3 (0.272 mmol, 2.7 equiv.) was added as an additional oxidant. Upon purification by column chromatography, evidence of reduced product was observed so 2,6dichloro-1,4-benzoquinone (0.250 mol, 2.5 equiv.) was added to the fraction tubes and the resulting solution stirred for 72 h. After evaporation under reduced pressure, the residue was purified by column chromatography to give 4g in 25 % yield. General procedure 4 was followed to give 4h and 5h in 41% combined yield and an approximate 1:1 ratio. The products were not easily separable but a small amount of material was isolated of each isomer just for characterisation purposes.

benzoquinone (4i)
General procedure 4 was followed to yield 5i and 4i in an approximate 1:1 ratio.  General procedure 5 was followed to give the products 5j and 4j in >10:1 ratio.

2-(3-Nitrophenyl)-5-(3-thienyl)-1,4,benzoquinone (4q)
General procedure 5 was followed, using 2.5 equivalents of 3-thienyl boronic acid and FeCl 3 (1.25 equiv.) was added for 1 h at the end of the reaction. Column chromatography yielded the 2,5 isomer 4q as the major product but evidence of reduced product was observed following washing of the column with ethyl acetate. FeCl 3 (2.5 equiv.), was added as an additional oxidant to the column wash and left to stir at room temperature for 18 h, after which the solution was evaporated under reduced pressure and purified by column chromatography to yield further 2,5 product 4q. Another product, believed to be the 2,6 isomer was observed but only in trace amounts. 5. Diacetylation of 2,5-and 2,6-diaryl-1,4-hydroquinones [11] Acetylation of 5n and 4n was carried out in order to differentiate between 2,5 and 2,6 isomers. 4 J coupling could be observed in the 1 H NMR spectrum of the 2,6 isomer once acetylation had been carried out, which was absent in the 1 H NMR spectrum for the 2,5 isomer. The procedure for the diacetylation of 2,5-and 2,6-diaryl-1,4-hydroquinones was

Control reactions: Reaction to ascertain if isomerization occurs between the 2,5 and 2,6 isomers in the C-H difunctionalization of benzoquinone
In order to ascertain if isomerization occurs during the C-H difunctionalization reactions, 2 control experiments were carried out. Separate samples of the 2,5 and 2,6 isomers of bisphenyl-1,4-benzoquinone were subjected to the homo-difunctionalization reaction conditions (see scheme below) and the reactions monitored to see if formation of the other isomer was evident. Both reactions did not show any change from starting material to the other isomer, or other side products. were then added and the reaction stirred for a further 24 h. Further 1 H NMR analysis again confirmed no formation of the 2,5 isomer.

Crystal structures of difunctionalized products
Crystal structures were obtained of a number difunctionalized benzoquinone products in order to confirm their conformation as either 2,5 or 2,6 isomers.
For hetero-difunctionalizations, 2,5 and 2,6 products were distinguished by observation of 4 J coupling in the 1 H NMR spectrum for the 2,6 isomer, corresponding to the alkenyl protons as shown in the diagram below. To confirm that those compounds with 4 J coupling were in fact the 2,6 isomer, a crystal structure was grown of one example which confirmed our hypothesis as correct.
Although 4 J coupling is not always observed in 1 H NMR for 2,6 homo-difunctionalized products, the 2,5 and 2,6 isomers can be successfully assigned via 13 C NMR data. We did however grow crystals of 2 homo-difunctionalized products to confirm their identity.

Reducing the Equivalents of BQ
Attempts to reduce the amount of BQ required in the first step are shown in Table 4.
Reducing the amount of BQ from 3 to the minimum 2 equiv. (1 equiv. as substrate, 1 equiv. as oxidant) resulted in a much lower 40% yield of 3a (Entry 2). The lower yield is due to the formation of the undesired difunctionalized product 5. Using only 1 equiv. of BQ, and adding 1 equiv. of 2,6-DCBQ as oxidant results in a moderate 54% of desired monofunctionalized product 3a, but also evidence of the undesired homo-difunctionalized product 5 (Entry 3). To our delight, using 1.5 equiv. of BQ and 2,6-DCBQ respectively produces a good 71% yield of the desired 3a (Entry 4). Adopting these new conditions allows for a successful one-pot C-H hetero-difunctionalization procedure (Scheme 2).
[b] Diarylated product 5 also present in crude mixture.

Oxidant Screens
Representative initial oxidant screen: Unidentified Products -complex mixture. 10 p-Chloranil Full conversion to mono-(3a) and difunctionalised products. However, hydroquinone present and reduced oxidant co-elutes with product upon column chromatography. 11 2,6-DCBQ Full conversion to mono-(3a) and difunctionalised products. No hydroquinone present. Reduced oxidant does not co-elute. a Determined by 1 H NMR analysis of the crude mixture.
Presence of hydroquinone in this screen indicates that BQ (1) is still acting as an oxidant in the reaction (i.e. added oxidant is not the preferred oxidant over BQ). Of the oxidants screened, 2,6-DCBQ emerged as the best sacrificial oxidant and was thus used in the C-H difunctionalization reactions of BQ. The C-H difunctionalizations were later also evaluated with p-chloranil, p-fluoranil, FeCl 3 and 2,6-DCBQ as added oxidants, with 2,6-DCBQ emerging as the optimal sacrificial oxidant.

Computational Supporting Information
DFT calculations probing the migratory insertion step suggest the factors controlling selectivity are subtle. Representative results with a [Pd(Ar)(3)(acetone) 2 ] + model system showed that electron donating substituents, R (the BQ substituent, Table 3 in the main text) = Ar = p-C 6 H 4 -OMe, kinetically favor migratory insertion to the 2,6-product, but only by 0.5 kcal/mol; when R = Ar = p-C 6 H 4 -CF 3 the two transition states have the same energy.
Similar trends were obtained with other model systems featuring CF 3 CO 2 and acetone coligands. The small energy differences are consistent with the similar charge distribution and LUMO coefficients of these two BQ substrates. Full details are given below and future work will consider the overall mechanism of this direct C-H functionalization of BQ, and the factors controlling selectivity.

Computational Details and References.
Calculations were run with Gaussian 03 Revision D.01 1 with PCM solvent corrections run with Gaussian 09, Revision A.02. 2 Geometry optimisations were performed using the BP86 functional 3 with Pd described with the Stuttgart RECPs and associated basis set 4 and 6-31G** basis sets for all other atoms. 5 All stationary points were fully characterized via analytical frequency calculations as either minima (all positive eigenvalues) or transition states (one negative eigenvalue) and IRC calculations and subsequent geometry optimizations were used to confirm the minima linked by each transition state. Frequency calculations also provided a free energy in the gas-phase, computed at 298.15 K and 1 atm. Correction for dispersion effects using Grimme's D3 parameter set 6 (i.e. BP86-D3) as well as solvation in acetone (PCM approach) were applied. NBO charge distributions were calculated within Gaussian 09 using NBO 5.9. 7

Computed Charge Distributions in 3 R = p-C 6 H 4 CF 3 and p-C 6 H 4 OMe
NBO atomic charges were computed for substrates 3 with R = p-C 6 H 4 CF 3 and p-C 6 H 4 OMe with a focus on the C6 and C5 positions. In both cases C5 bears a slightly lower negative and no significant change in charge distribution is seen when comparing the two substrates. Thus the change in regioselectivity in moving from combinations of electron donating to electron withdrawing substituents cannot be simply rationalised by changes in the charge distribution.

Orbital Distributions in the LUMOs of 3 (R = p-C 6 H 4 CF 3 and p-C 6 H 4 OMe)
Orbital distributions were computed for the LUMO of substrates 3 with R = p-C 6 H 4 CF 3 and p-C 6 H 4 OMe. As shown in Figure S1 only a minor asymmetry in 2p z contribution is computed with both substituents, with the larger contribution being at C5 in both cases. The LUMO+1 was also considered in each case, although this is significantly higher in energy. A larger asymmetry is seen here, although the greater contribution is associated with C5, suggesting that changes in regioselectivity as a function of the electronic character of the substituent cannot be attributed to orbital overlap arguments. Figure S1. Orbital Distributions in the LUMOs and LUMOs+1 of 3 (R = p-C 6 H 4 CF 3 and p-C 6 H 4 OMe). The total 2p z orbital contributions at the C6 and C5 positions are indicated in each case and the orbital energy is given in atomic units.

Product Stability
Computed energies are reported as E (uncorrected SCF), H 298 (enthalpy at 298.15 K), G (free energy at 298.15 K), G-D3 (free energy corrected for dispersion using Grimme's D3 parameter set) and G-D3 (acetone) (as for G-D3 now corrected for acetone solvent via the PCM approach). Table S2. Computed Product Energies The similar energies of the alternative 2,6-and 2,5-disubstituted benzoquinoline products suggests that any change in regioselectivity in moving from combinations of electron donating to electron withdrawing substituents cannot be simply rationalised by product stability.

Computed reaction profiles for migratory insertion.
Reaction profiles were computed for the insertion of substrates 3 (with R = p-C 6 Thus the trend os for the 2,5-regioisomer to become relatively more accessible upon moving from the electron donating p-C 6 H 4 OMe substituent to the electron withdrawing p-C 6 H 4 CF 3 .