Copper-Catalyzed Borylative Aromatization of p-Quinone Methides: Enantioselective Synthesis of Dibenzylic Boronates.

In this report, we establish that DM-Segphos copper(I) complexes are efficient catalysts for the enantioselective borylation of para-quinone methides. This method provides straightforward access to chiral monobenzylic and dibenzylic boronic esters, with enantiomeric ratios up to 96:4, using a commercially available chiral phosphine. Standard manipulations of the C-B bond afford a variety of chiral diaryl derivatives.

Chiral secondary boronic esters are important intermediates in organic synthesis, because they are precursors of chiral alcohols, chiral amines, and tertiary stereocenters.[1] Among them, dibenzylic boronates such as B are especially interesting, because they can provide a variety of enantiomerically enriched diaryl derivatives (see Scheme ). The diarylmethane framework represents a privileged structural motif widely found in pharmaceuticals.[2] Most of these biologically active compounds present a chiral center at the benzylic position with a stereodefined C–O, C–N, or C–C bond. We envisioned that functionalization of the C–B bond in B could offer a unified strategy for the preparation of these compounds, from a common intermediate. However, the enantioselective synthesis of dibenzylic boronic esters is still a difficult challenge in chemical synthesis.

Scheme 1

Chiral Dibenzylic Boronic Esters

At the outset of this project, the only method available for the synthesis of boronates such as B involved the use of chiral lithiated carbamates and aryl boronic esters (Scheme ).[1b] Despite the undoubted significance of this approach, the yields were moderate, and a stoichiometric amount of a chiral ligand was required. As part of our interest in unconventional C–B bond formation,[3] we envisioned a new approach toward the synthesis of dibenzylic boronates through the enantioselective 1,6-addition of a chiral copper-(I) boryl complex to a p-quinone methide (Scheme ).[4,5] Formally, p-quinone methides are neutral entities with a zwitterionic resonance structure that enhances the electrophilic character at the δ-position. Surprisingly, while ortho-quinone methides have been broadly used in asymmetric synthesis,[6] only two catalytic enantioselective additions to para-quinone methides have been reported.[7,8] Both methods use carbon-based nucleophiles and an organocatalyst to control the enantioselectivity. Therefore, we became intrigued in exploring these compounds for several reasons:Herein, we describe the synthesis of dibenzylic boronates through the borylative aromatization of p-quinone methides with good yields and high enantiomeric ratio (er) values, under mild reaction conditions and using a commercially available chiral phosphine.[9,10]

the use of asymmetric metal catalysis to functionalize p-quinone methides remained unexplored;

the introduction of a boronic ester unit in ortho- or para-quinone methides had not been reported; and

the stereoselective addition of heteroatomic nucleophiles to p-quinone methides had not been studied to date.

While unsubstituted p-quinone methides (R2, R3 = H) are too reactive to be isolated, 2,6-disubstituted derivatives are easy to handle. We began our study with p-quinone methide 1a, which contains removable t-Bu groups at the α-positions (Table ).[11] When 1a was treated in THF with Cu(CH3CN)4PF6 (10 mol %), B2pin2 (1.5 equiv), NaOt-Bu (0.2 equiv), and methanol (MeOH) (4 equiv) in the absence of ligand, we observed the formation of product 2a with moderate yield (Table , entry 1). This background reaction showed the feasibility of the transformation but also revealed a serious handicap for the development of an asymmetric version. We soon realized that the yields and stereoselectivities were highly dependent on the ligand (Table , entries 2–7).[12] Commercially available (R)-DM-Segphos was superior to other chiral ligands affording the desired dibenzylic boronate 2a in good yield and high enantiomeric ratio at room temperature (Table , entry 7, er = 96:4). The reaction can be carried out with 5 mol % copper salt and 5.5 mol % of chiral phosphine (Table , entry 8) without affecting the enantioselectivity, although the yield observed under these conditions was slightly lower. Interestingly, in the absence of MeOH, we observed product formation but moderate er values (Table , entry 9).

Table 1

Effect of the Chiral Ligand in the Borylative Aromatization of p-Quinone Methides[a]

entry	L*	enantiomeric ratio, er[b]	yield (%)[c]
1[a]			35
2[a]	L1	54.5:45.5	47
3[a]	L2	65:35	52
4[a]	L3	77:23	76
5[a]	L4	83:17	68
6[a]	L5	66.5:33.5	41
7[a]	L6	96:4	95
8[d]	L6	94:6	79
9e	L6	74:26	54

Reaction conditions: 1 (0.2 mmol), B2pin2 (0.30 mmol), NaOt-Bu (20 mol %), Cu(CH3CN)4PF6 (10 mol %), L* (11 mol %), MeOH (0.8 mmol), THF (0.2 M).

er determined by chiral SFC previous oxidation of the C–B bond.

Yield of isolated 2.

Reaction conditions: 1 (0.2 mmol), B2pin2 (0.30 mmol), NaOt-Bu (20 mol %), Cu(CH3CN)4PF6 (5 mol %), L* (5.5 mol %), MeOH (0.8 mmol), THF (0.2 M).

The reaction was carried out in the absence of MeOH.

With the optimal conditions in hand, we studied the scope of the borylative aromatization. The catalytic system was robust for p-quinone methides with different aromatic R1 substituents at the δ-carbon (Table , structures 2a–2g). Dibenzylic boronic esters with a larger naphthyl group (2b) or with electron-rich aromatic substituents (2c and 2d) were prepared in similarly good yields and high er values.

Table 2

Substrate Scope[a],[b]

Reaction conditions: 1 (0.2 mmol), B2pin2 (0.30 mmol), NaOt-Bu (20 mol %), Cu(CH3CN)4PF6 (10 mol %), (R)-DM-Segphos (11 mol %), MeOH (0.8 mmol), THF (0.2 M).

Yield of isolated 2.

er value as determined by chiral SFC or HPLC previous oxidation of the C–B bond.

er value as determined by chiral SFC.

Diaryl derivatives with electron-withdrawing groups at the meta- (2e), para- (2f), or ortho- position (2g) were also synthesized, with excellent stereocontrol. In addition, the absolute configuration of 2g was determined by single-crystal X-ray crystallography.[13] Importantly, a p-quinone methide bearing an alkyl group at the δ-carbon afforded the monobenzylic boronic ester 2h with good yield and high er value. Alkyl groups with different steric hindrance (methyl (Me) and isopropyl (i-Pr)) can also be introduced at the α-position (R2) without affecting the yields and enantioselectivities (2i–2n).

To further explore the scope of this reaction, we studied the borylative aromatization reaction with more challenging nonsymmetric p-quinone methides (1o and 1p; see Scheme ). These substrates were synthesized as E/Z mixtures of the exocyclic double bond. Surprisingly, E/Zp-quinone methides 1o and 1p afforded dibenzylic boronic esters 2o and 2p with high enantioselectivities. This result is striking and significantly increases the potential structural scope of the method. These experiments indicate that the stereodiscrimination of the prochiral Si-face is not dependent on the geometry of the exocyclic double bond in the p-quinone methide.[14,15]

Scheme 2

Borylative Aromatization of Nonsymmetric p-Quinone Methides

Overall, commercially available DM-Segphos consistently provides high er values and overcomes some of the structural limitations found with the use of chiral sulfoxide-phosphine ligands (prepared in four steps), recently reported by Liao.[10] In the latter case, p-quinone methides with ortho- substitution on the aromatic ring (similar to 1g) and groups with less steric hindrance α to the carbonyl (similar to 1i–1n) afforded only moderate enantioselectivities (er = 84:16/75:25). Our catalyst system provides similar compounds with higher stereocontrol (compounds 2g, 2i–2n, er ≥ 95:5). More significantly, we have expanded the scope of the reaction to p-quinone methides bearing alkyl substituents at the R1 position (1h) and to the challenging nonsymmetric p-quinone methides (1o and 1p), which previously have not been studied.

Functionalization of the C–B bond provided several monobenzylic, dibenzylic, and triaryl derivatives (Scheme ). Oxidation of the C–B bond allows for the synthesis of enantiomerically enriched diarylmethanols in high yields. In addition, we have prepared triarylmethane 5 from boronate 4 with excellent stereoretention (97% specificity).[1c] To the best of our knowledge, this transition-metal-free C(sp3)–C(sp2) coupling has not been used before with secondary dibenzylic boronates. Homologation and oxidation of monobenzylic boronate 2h gave alcohol 6 in good overall yield. Finally, treatment of 6 with AlCl3 in refluxing benzene resulted in removal of the tert-butyl groups, followed by Friedel–Crafts reaction to afford phenol 7.

Scheme 3

C–B Bond Functionalization

In order to gain insight into the reaction mechanism and to ascertain the reasons for the observed enantioselectivity, we performed quantum calculations at the DFT level. For this study, we used (R)-Segphos-Cu(I) complexes and p-quinone methide 1i (R2 = Me, R1 = Ph) as models. Noteworthy, no simplification of the ligand structure was used in order to properly consider the steric effects around the metal center. As shown in Scheme , the boryl cupration is a highly exoergic and, therefore, irreversible process. Since the absolute configuration of the new stereogenic carbon is fixed in this step, enantioselectivity is kinetically controlled. Transition states for the boryl cupration (TS and TS) were located and allowed the calculation of the corresponding activation energies for the formation of both enantiomers. The free energy of TS is 0.9 kcal mol–1 lower than that corresponding to TS, because of better substrate accommodation within the complex pocket for the former. This value is in accord with the observed enantioselectivity using 1a and (R)-Segphos (Table , entry 6). Intrinsic reaction coordinate studies connect these TS with long distance association adducts formed prior to the boryl cupration step (I and I; see Scheme ).[16] Calculated energies suggest the boryl cupration reaction as the rate-limiting step, as well as the enantioselective step.

Scheme 4

Calculated Reaction Profile for Both Diastereomeric Approaches (Re and Si) of the Boryl Cupration at the B3LYP/6-31G(d) (C,H,B,O,P) LANL2DZ (Cu) Level

ΔG values are represented in kcal mol–1, considering I as 0.0.

The Cu complexes formed after the alkene insertion show a long Cu–C distance with the C atom involved in the reaction (II and II; see Scheme ). In fact, the structure is reminiscent of a (π-allyl)Cu complex. These complexes would become protonated in a subsequent step. We have also calculated the energy for isomer III corresponding to the slipping of the borylated substrate to afford a copper-phenoxide complex (Figure ). This process is highly exoergic, and for that reason, we propose that protonation most likely takes place at the Cu–O bond.[17]

Figure 1

Calculated energy difference and equilibrium geometries for the formation of the copper phenoxide complex at B3LYP/STO-3G (C,H,B,O,P) LANL2DZ (Cu) level. Δ(E +ZPE) and ΔG values (given in brackets) in kcal mol–1.

In summary, we have developed a new method for the asymmetric synthesis of useful monobenzylic and dibenzylic boronic esters via a novel copper-catalyzed borylation of p-quinone methides. For the first time, consistently high enantioselectivities are observed using a commercially available phosphine ligand. The products are versatile intermediates for the enantioselective synthesis of monoaryl, diaryl, and triaryl derivatives. Calculations at the density functional theory (DFT) level fully agree with experimental observations and provide insight for the development of new asymmetric transformations.