Organocopper cross-coupling reaction for C–C bond formation on highly sterically hindered structures

A potent cross-coupling methodology that enables efficient carbon–carbon bond formation at sterically hindered sp2- and sp3-carbons has been developed.


Introduction
Three-dimensionally (3D) bulky carbon frameworks and other bulky substrates have become important scaffolds for a broad range of functional molecules (Scheme 1A). They are useful in many elds due to features such as improved solubility, enhanced stability, and increased control of molecular stacking. 1-4 While transition metal-catalyzed cross-coupling reactions are among the most developed of C-C bond-forming reactions, 5 bond formation at sterically hindered structures remains a challenging task in cross-coupling chemistry, even with sp 2 -or sp 3 -carbon substrates. Recent improvements have focused mostly on the design of (pre)catalysts and customized ligands in order to achieve efficient generation of active palladium species, and on the oxidative addition/reductive elimination step in the catalytic cycle (Scheme 1B). 6 These "state-of-the-art" systems, in particular with customized ligands, enable bond formation on sterically hindered substrates. 7 However, transmetalation, a fundamental step in cross-coupling reactions, 8 can also be targeted to address this challenge.
Herein, we report a powerful and broadly applicable (to both sp 2 -and sp 3 -carbons) Pd-catalyzed cross-coupling reaction of organocopper reagents that enables efficient C-C bond formation even on 3D bulky carbon frameworks (Scheme 1C). Notably, this reaction proceeds under mild conditions using readily available reagents and has high functional group tolerance. Experimental and theoretical studies revealed that copper(I)-palladium(II) interaction facilitates the formation of a compact and well-organized transition state in the transmetalation step.
Scheme 1 (A) Three-dimensionally (3D) bulky carbon frameworks in a broad range of disciplines. (B) Fundamental steps in cross-coupling reactions and recent developments in the catalytic cycle. (C) Pdcatalyzed organocopper cross-coupling reaction on highly sterically hindered structures (this work).

Results & discussion
We commenced our search to develop a potent methodology by focusing on the triptycene framework, 9 due to its extremely hindered tertiary sp 3 -carbon at the bridgehead 9-position and unprecedent use in cross-coupling chemistry. The crosscoupling reactions using a boronate ester or zinc(II) complex of 9-triptycene (1a and 1b) failed to afford any coupled product under the representative palladium-catalyzed conditions (runs 1-3, Table 1). 7e,g,h On the other hand, we found that the crosscoupling reaction of 9-triptycenylcopper(I) complex 1c 10 with 2 smoothly proceeded using 5 mol% of Pd(OAc) 2 and tris(omethoxyphenyl)phosphine (L1) at 80 C to afford the coupling product 3 in 86% yield (run 4). The direct use of organocopper reagents in Pd-catalyzed cross-coupling reactions is limited, 11 and a copper co-catalyst 12 as well as relay catalysis using palladium and copper 13 have been employed. The absence of a palladium catalyst yielded no desired product (run 5). Under similar reaction conditions, other organometallic reagents (1a, 1b, 1d, and 1e) were also not competent (runs 6-9).
The optimized conditions of the present organocopper crosscoupling reaction were then applied to bond formation using a variety of electrophiles (Scheme 2A). Both electronwithdrawing and -donating groups on aryl halides, containing CO 2 Me, CF 3 , CN, acetyl, and MeO groups, were compatible with the reaction conditions, and the desired products were obtained in good yields (3)(4)(5)(6)(7)(8). Moreover, sterically demanding orthosubstituted substrates gave 9-arylated triptycene derivatives 9 and 10. X-ray crystallography of 9 conrmed the desired C-C bond formation. A straightforward, one-step synthesis of 9-ferrocenyltriptycene 11 (ref. 4b) was accomplished with the present coupling strategy. Various heteroaromatic moieties were successfully coupled (12-18), and bond formation was also achieved with sp-carbon of an alkynyl substrate 19. The coupling reaction with ethyl bromoacetate proceeded to give the product 20 in 76% yield having a C(sp 3 )-C(sp 3 ) bond. 14 Since existing syntheses of 9-functionalized triptycenes are rather lengthy, 9 the present methodology offers substantial synthetic advantages, including high functional group tolerance.
Other sterically hindered tertiary sp 3 -carbon compounds were also competent substrates for this reaction (Scheme 2B). The adamantyl group was successfully introduced not only onto a simple aryl group (21), but also onto aryl halide moieties on a sugar skeleton and into a steroid backbone, affording the corresponding products 22 and 23 in good yields. These results indicate that the present methodology would be suitable for late-stage functionalization of biologically relevant compounds and functional molecules with bulky tertiary alkyl moieties. Similarly, the introduction of a tert-butyl group having bhydrogen was achieved, affording 24 in 63% yield. A secondary 2adamantyl group was also introduced onto an aromatic ring to give 25 in 88% yield.
Further examination revealed that this methodology was also applicable to sterically hindered sp 2 -carbon using conditions essentially identical to those employed for sp 3 -substrates (Scheme 2C). The reaction between mesitylcopper(I) and 2 proceeded efficiently at room temperature, affording the coupled product 26 in quantitative yield. The same organocopper(I) reagent reacted smoothly under these conditions with various electrophiles, affording the corresponding biaryl products 27-32 in good yields, including hindered ortho-substituted substrates. Furthermore, the present protocol realized the reactions with much bulkier copper reagents, such as "supermesityl" 15 (35) and EMind 16 (36) substrates. Importantly, this reaction could also be applied to the cubane skeleton (i.e. 37). Although the cubane motif has recently attracted great attention as a bioisostere of benzene in pharmaceuticals, 17 there have only been two examples of cross-coupling chemistry, and the yields were not high with respect to the catalyst loading. 18 In contrast, the present organocopper cross-coupling reaction enabled catalytic C-C bond formation with an iodocubane derivative for the rst time, installing the sterically hindered mesityl group in 49% yield using a 10 mol% Pd catalyst. 14 Given that the nature of the metal species should have the greatest inuence on the transmetalation step (Scheme 1B), and taking into account the mechanistic implications of experimental ndings, 19 we performed theoretical calculations for the ligand transfer process from 9-metalated triptycene (boron, zinc, and copper) to an arylpalladium complex as a model of the transmetalation step (Fig. 1) at the uB97X-D/SDD & 6-31+G* level of theory. DFT calculation for the reaction of 9-triptycenylboronate with trans-Pd(Ph)OH(PMe 3 ) 20 indicated that the bulky triptycene group distorts the transition-state structure (TS B 1), resulting in a high activation energy (DG ‡ ¼ +46.4 kcal mol À1 , Fig. 1A). Although a lower activation barrier (DG ‡ ¼ +28.0 kcal mol À1 ) was observed with 9-triptycenylzinc chloride via TS Zn 1, this reaction (IM Zn 1-TS Zn 1-IM Zn 2) is thermodynamically unfavorable; the transmetalated product IM Zn 2 is quite unstable (+25.5 kcal mol À1 , compared with IM Zn 1), suggesting that efficient transmetalation is improbable (Fig. 1B). These ndings are consistent with the experimental results shown in Table 1. Scheme 2 Organocopper cross-coupling reaction of sp 3 -and sp 2 -carbon substrates with sterically hindered structures. Isolated yields are shown ( 1 H NMR yields in parentheses). a L2 was used instead of L1. b Ni(acac) 2 was used instead of Pd(OAc) 2 . c L2 was used instead of L1 and 3 eq. of TMEDA were added. d L3 was used instead of L1 at À20 C and 3 eq. of TMEDA were added. e 10 mol% Pd catalyst and 30 mol% L2 were used.
The situation with the copper reagent is completely different; the initial coordination of 9-triptycenylcopper and trans-Pd(Ph) Br(PMe 3 ) (RT Cu ) affords IM Cu 1 with a large stabilization energy (À31.4 kcal mol À1 ) (Fig. 1C). Furthermore, the distance between the copper and palladium atoms is shorter (2.69Å) than the sum of their van der Waals radii (3.03Å), supporting the existence of strong metal-metal interaction. 21 This Cu-Pd interaction results in the formation of a compact transition-state structure (TS Cu 1, Cu-Pd: 2.52Å) that facilitates delivery of the bulky triptycenyl group from the copper to the palladium center with a reasonable activation energy (DG ‡ ¼ +21.4 kcal mol À1 ). The resultant IM Cu 2 having both phenyl and triptycenyl ligands on palladium in a cis-fashion then undergoes reductive elimination. The reductive elimination also reasonably proceeds (DG ‡ ¼ +19.8 kcal mol À1 ) to achieve the C-C bond formation on the triptycene framework (IM Cu 3).
Thus, the unique observed reactivity of the copper complex, in contrast to the boron or zinc complex, is supported by the theoretical calculations. Although the possibility of a similar metal-metal interaction in transmetalation has been suggested previously, 22-24 our DFT calculations directly compare the transmetalation transition-state structures of an arylpalladium complex with these organometallic reagents. Energy decomposition analysis (EDA) 25 of these transition-state structures clearly indicates that small values of the deformation energy (DEF) are mainly responsible for the low activation barrier in the case of the copper reagent (Fig. 1D). In particular, the 9-triptycenylcopper unit involves a much lower DEF TripM than those in the cases of boron and zinc, probably due to the favorable Cu(I)-Pd(II) interaction, as well as the abundance of vacant sites around the copper center. Interestingly, the Zn(II) center also shows some interaction with Pd(II), but the DEFs of both the 9triptycenyl zinc reagent and the arylpalladium complex are much larger. In the less-distorted TS Cu 1, smooth delivery of the triptycenyl ligand is facilitated by the well-organized triangular arrangement of copper-palladium-carbon (Cu(I)-Pd(II)-C). In addition, natural bond orbital (NBO) 26 analysis showed that electron donation from Cu(I) to Pd(II) is predominant in IM Cu 1 and TS Cu 1 (Fig. 1E), while the reverse donation from the Pd(II) center to Lewis acidic Zn(II) was observed in TS Zn 1. 14,23d,e These results reect the characteristic reactivity of organocopper reagents arising from the high-energy d orbitals and vacant coordination sites of copper. Thus, transfer of the bulky triptycenyl ligand is promoted not only by the adjacency of the two metal centers, but also by the favorable electronic interaction between them.

Conclusions
In conclusion, the experimental results and DFT calculations conrm that this organocopper cross-coupling reaction is a potent C-C bond-forming methodology with unprecedented applicability to 3D bulky molecules. The unique ability of copper to facilitate efficient transmetalation via a compact transition state arising from an efficient metal-metal interaction is the key to the success of this reaction. Thus, this reaction is quite efficient with high functional group tolerance, and applicable to both sp 2 -and sp 3 -substrates. Further investigations on the substrate scope and detailed reaction mechanism are the subjects of ongoing research.

Conflicts of interest
There are no conicts to declare.