Synergistic palladium/copper-catalyzed Csp3–Csp2 cross-couplings using aldehydes as latent α-alkoxyalkyl anion equivalents

Mitsutaka Takeda , Kenya Yabushita , Shigeo Yasuda and Hirohisa Ohmiya *
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. E-mail:

Received 7th February 2018 , Accepted 8th February 2018

First published on 14th February 2018

The first Csp3–Csp2 cross-coupling using aldehydes as latent α-alkoxyalkyl anion equivalents has been achieved. The synergistic palladium/copper-catalyzed reaction of aromatic aldehydes and aryl bromides with a silylboronate afforded the three-component coupling products, silyl-protected benzhydrol derivatives. The reaction pathway involves the catalytic formation of a nucleophilic α-silyloxybenzylcopper(I) species followed by its palladium-catalyzed cross-coupling with aryl bromides.

Transition-metal-catalyzed cross-coupling is one of the most powerful carbon–carbon bond forming methods and has contributed to the synthesis of pharmaceuticals, agrochemicals and functional materials.1 Its development is still an important and challenging issue in synthetic chemistry. For example, the Csp3–Csp2 cross-coupling, which allows the manipulation of the three-dimensional space of an organic molecule, has been actively studied. Traditionally, Csp3–Csp2 cross-coupling methods have relied on the use of Csp3-organometallic nucleophiles such as Grignard reagents, organozinc reagents, or organoboron derivatives (Fig. 1A).2 These methods require the use of stoichiometric organometallic reagents and the cumbersome preparation of these reagents. In addition, the basic and nucleophilic nature of organometallic reagents reduces the functional group compatibility of these methods. In this context, metal-catalyzed cross-coupling using widely available π-unsaturated compounds as latent alkyl anion equivalents has emerged as an alternative to the traditional cross-coupling.3,4 For instance, Nakao/Semba and Buchwald independently reported reductive cross-coupling between alkenes and aryl halides utilizing synergistic palladium/copper hydride catalysis (Fig. 1B).3 The reaction involves palladium-catalyzed arylation of nucleophilic alkylcopper species that are formed catalytically through alkene insertion into Cu–H bonds. Despite remarkable progress achieved in this area, the cross-coupling using aldehydes as latent α-alkoxyalkyl anion equivalents is underdeveloped.
image file: c8cc01055b-f1.tif
Fig. 1 Csp3–Csp2 cross-coupling reactions.

Oestreich, Kleeberg, and co-workers reported the synthesis of an α-silyloxybenzylcopper(I) complex through the stoichiometric reaction of an aromatic aldehyde and a silylcopper(I) complex, which was prepared by B/Cu transmetallation between a silylboronate and a copper(I) alkoxide coordinated with N-heterocyclic carbene ligand.5 This reaction proceeds through aldehyde insertion into the Cu–Si bond6 followed by a [1,2]-Brook rearrangement7 from the resulting α-silyl-substituted copper(I) alkoxide. However, the reactivity of the α-silyloxybenzylcopper(I) complex was not revealed. With this in mind, we questioned whether the α-silyloxybenzylcopper(I) complex could be generated catalytically and exploited in a palladium-catalyzed cross-coupling, thereby providing a new strategy for cross-coupling using aldehydes as latent α-alkoxyalkyl anion equivalents (Fig. 1C).8

Here, we report a synergistic palladium/copper-catalyzed umpolung strategy to use aldehydes as latent α-alkoxyalkyl anion equivalents for the Csp3–Csp2 cross-coupling (Fig. 1C).9 The cross-coupling of aromatic aldehydes and aryl bromides with a silylboronate delivered benzhydryl silyl ethers.10,11

After numerous studies for optimizing the reaction conditions for the synergistic palladium/copper catalysis, we found that the cross-coupling reaction of o-tolualdehyde (1a) (0.3 mmol), bromobenzene (2a) (0.2 mmol) and (dimethylphenylsilyl)boronic acid pinacol ester [PhMe2SiB(pin)]12 (0.3 mmol) occurred in the presence of catalytic amounts of palladium(II) acetylacetonate [Pd(acac)2] (5 mol%), 1,1′-bis(diphenylphosphino)ferrocene (DPPF) (10 mol%), chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) [(IPr)CuCl] (25 mol%) and a stoichiometric amount of NaOtBu (0.2 mmol) as a base in toluene at 80 °C to produce the three-component coupling product, diarylmethylsilyl ether 3aa in 70% isolated yield (based on 2a; complete conversion of 2a) (Table 1, entry 1).13,14 The expected side products, dimethyldiphenylsilane (1% based on 2a) and 2-methylbenzyl silyl ether (17% based on 1a), which are derived from Pd-catalyzed silylation of 2a15 and Cu-catalyzed nucleophilic silylation of 1a followed by [1,2]-Brook rearrangement,5 respectively, were observed in small amounts.

Table 1 Screening of conditions for cross-coupling of 1a and 2a with PhMe2SiB(pin)a

image file: c8cc01055b-u1.tif

Entry Change from standard conditions Yieldb (%) of 3aa
a Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), PhMe2SiB(pin) (0.3 mmol), Pd (5 mol%), bisphosphine (10 mol%) or monophosphine (20 mol%), copper–carbene (25 mol%), base (0.2 mmol), toluene (1 mL), 80 °C, 3 h. b 1H NMR yield. Yield of the isolated product is in parentheses.
1 None 75 (70)
2 Without Pd(acac)2–DPPF 0
3 Without (IPr)CuCl 0
4 Pd(OCOCF3)2 instead of Pd(acac)2 73
5 Pd(OAc)2 instead of Pd(acac)2 69
6 Pd(dba)2 instead of Pd(acac)2 68
7 BINAP instead of DPPF 67
8 Xantphos instead of DPPF 32
9 DPPE instead of DPPF 0
10 PPh3 instead of DPPF 59
11 PCy3 instead of DPPF 19
12 Xphos instead of DPPF 55
13 (SIPr)CuCl instead of (IPr)CuCl 29
14 (IMes)CuCl instead of (IPr)CuCl 55
15 (SIMes)CuCl instead of (IPr)CuCl 66
16 LiOtBu instead of NaOtBu 10
17 KOtBu instead of NaOtBu 30
18 NaOMe instead of NaOtBu 0
19 Na2CO3 instead of NaOtBu 0
20 PhOTf instead of PhBr (2a) 43
image file: c8cc01055b-u2.tif

Importantly, the cross-coupling reaction did not occur at all in the absence of Pd(acac)2–DPPF or (IPr)CuCl (Table 1, entries 2 and 3). Thus, these results indicated the synergistic cooperation of the palladium and copper catalysts in the Csp3–Csp2 cross-coupling.

Results of the reaction conducted with other palladium sources are shown in Table 1, entries 4–6. Pd(OCOCF3)2 was as effective as Pd(acac)2 (entry 4). The use of Pd(OAc)2 or Pd(dba)2 slightly decreased the product yields (entries 5 and 6).

Effects of bidentate and monodentate phosphine ligands on palladium are shown in Table 1, entries 7–12. The use of BINAP instead of DPPF slightly decreased the product yield (67%) (entry 7). The use of Xantphos having a larger bite-angle decreased the yield to a low level (32%) (entry 8). DPPE ligand promoted no reaction (entry 9). The monophosphines such as PPh3 (59%) and Xphos (55%) were also useful, although the yields were moderate (entries 10 and 12). Tricyclohexylphosphine (PCy3) gave a low yield (19%) (entry 11).

Copper–N-heterocyclic carbene complexes showed marked influences on the product yield (Table 1, entries 13–15). The use of a ring-saturated (SIPr)CuCl instead of (IPr)CuCl under the optimized conditions resulted in significantly decreased product yield (29%) (entry 13). The use of sterically less demanding (IMes)CuCl gave a moderate yield (55%) (entry 14). (SIMes)CuCl performed with a similar level of yield to that of (IPr)CuCl (66%) (entry 15).

The choice of base was essential (Table 1, entries 16–19). The use of LiOtBu or KOtBu instead of NaOtBu resulted in significant reductions in the product yields (entries 16 and 17). A base with a smaller alkoxo moiety, NaOMe, resulted in no reaction (entry 18). No reaction occurred with Na2CO3 (entry 19).

When the leaving group of the aryl substrate was changed from bromide to triflate PhOTf (Table 1, entry 20), the reaction gave the coupling product 3aa albeit in moderate yield.

Table 2 summarizes the results of the reactions of various aryl substrates.16 In some cases, Pd(OCOCF3)2 was a better palladium source than Pd(acac)2 in terms of the product yield. Electron-rich and electron-deficient aryl bromides were used successfully (3ab–3ak). Various functional groups such as methoxy, trifluoromethyl, chloro, fluoro, methoxy carbonyl, trifluoromethoxy, benzyl ether, tetrahydropyranyl (THP) ether, and pivalate substituents were tolerated at the meta- or para-positions of the aromatic ring of the aryl bromide (3ab–3ak). π-Extended aryl halides such as 2-bromonaphthalene and 9-bromophenanthrene served as substrates (3al and 3am). Sterically challenging 2-bromotoluene also participated in the reaction (3bn). Heteroaryl bromides such as bromothiophene or bromopyridine were compatible with the reaction (3ao and 3ap).

Table 2 Scope of aryl bromides and aromatic aldehydesa
a Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), PhMe2SiB(pin) (0.3 mmol), Pd(acac)2 (5 mol%), DPPF (10 mol%), (IPr)CuCl (25 mol%), NaOtBu (0.2 mmol), toluene (1 mL), 80 °C, 3 h. b Pd(OCOCF3)2 (5 mol%) was used as a Pd source. c 9-Bromophenanthrene (4 mmol) was used.
image file: c8cc01055b-u3.tif

The potential for scaling up the synergistic palladium/copper catalyzed reaction was examined on a preparative scale. Thus, the reaction of o-tolualdehyde (721 mg, 6 mmol), 9-bromophenanthrene (1.03 g, 4 mmol), and PhMe2SiB(pin) (1.57 g, 6 mmol) yielded 1.33 g (77%) of 3am.

The range of aldehydes is also shown in Table 2.16 The reaction of p-tolualdehyde with 1-bromo-4-chlorobenzene gave the corresponding diarylmethylsilyl ether product (3cd). Sterically hindered aromatic aldehydes such as 3,5-dimethylbenzaldehyde and 2,5-dimethylbenzaldehyde underwent the coupling reactions (3dd and 3ed). p-Anisaldehyde and 3-fluorobenzaldehyde also served as suitable substrates (3fa and 3gd). Aliphatic aldehydes did not participate in the reaction (data not shown).

To gain understanding into the mechanism of the synergistic palladium/copper catalyzed cross-coupling, experiments using complexes that was considered to be relevant to the catalysis were conducted (Scheme 1). The reaction of the known α-silyloxybenzylcopper (4),5,17 which was prepared in situ from p-tolualdehyde, (IPr)CuCl, PhMe2SiB(pin) and NaOtBu (1/1/1/1), with 1-bromo-4-chlorobenzene (2d) was performed in the presence of Pd(acac)2 (5 mol%) and DPPF (10 mol%) in toluene at 80 °C (Scheme 1). The reaction gave the corresponding coupling product 3cd in 68% yield. In the absence of a catalytic amount of Pd(acac)2–DPPF, the coupling reaction between 4 and 2d under otherwise identical conditions did not afford 3cd with complete recovery of 2d (data not shown).

image file: c8cc01055b-s1.tif
Scheme 1 Palladium-catalyzed reaction using stoichiometric α-silyloxybenzylcopper(I) complex.

Based on the results of the catalytic reactions in Table 1 and the information obtained by the stoichiometric reaction in Scheme 1, a reaction mechanism in which two distinct catalytic cycles, namely palladium and copper catalysis, operate simultaneously can be proposed as illustrated in Fig. 2. The reaction of (IPr)CuCl (A), NaOtBu and a silylboron forms a IPr-coordinated silylcopper(I) species (B). The addition of silylcopper(I) (B) across the C[double bond, length as m-dash]O bond of aldehyde 1 followed by [1,2]-Brook rearrangement from the resulting α-silyl-substituted copper(I) alkoxide (C) occurs to form an α-silyloxybenzylcopper(I) species (D).5 Next, Cu/Pd transmetallation between D and an arylpalladium(II) (F), which is generated from the oxidative addition of aryl bromide 2 across a palladium(0)–bisphosphine complex (E), produces an organopalladium(II) complex (G), in which the α-silyloxybenzyl- and aryl ligands coordinate to the palladium center, and regenerates the copper(I)–carbene complex (A). Finally, reductive elimination from G gives the coupling product 3, regenerating the palladium(0) complex (E).

image file: c8cc01055b-f2.tif
Fig. 2 A possible catalytic cycle.

In summary, we demonstrated that readily available aldehydes can be used as latent α-alkoxyalkyl anion equivalents for Csp3–Csp2 cross-couplings. The reaction of aromatic aldehydes, aryl bromides, and a silylboronate utilizing palladium/copper catalysis in a synergistic manner delivered the three-component coupling products, benzhydryl silyl ethers. Various functional groups were tolerated in the substrates. This reaction pathway involves the catalytic formation of a nucleophilic α-silyloxybenzylcopper(I) species followed by its palladium-catalyzed cross-coupling. The synergistic palladium/copper catalysis presented here provides a new umpolung strategy for molecular transformation using aldehydes as latent α-alkoxyalkyl anion equivalents. Studies for expanding this strategy toward using different coupling partners are ongoing in our laboratory.

This work was supported by JSPS KAKENHI Grant Number JP15H03803 to Scientific Research (B) and JSPS KAKENHI Grant Number JP17H06449 in Hybrid Catalysis for Enabling Molecular Synthesis on Demand.

Conflicts of interest

There are no conflicts to declare.

Notes and references

  1. (a) Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, Germany, 2nd edn, 2004 Search PubMed ; (b) Metal-Catalyzed Cross-Coupling Reactions and More, ed. A. de Meijere, S. Brasäe and M. Oestreich, Wiley-VCH, Weinheim, Germany, 2014 Search PubMed .
  2. For a review on cross-couplings using alkylmetal reagents, see: R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417 CrossRef CAS PubMed .
  3. (a) K. Semba, K. Ariyama, H. Zheng, R. Kameyama, S. Sakaki and Y. Nakao, Angew. Chem., Int. Ed., 2016, 55, 6275 CrossRef CAS PubMed ; (b) S. D. Friis, M. T. Pirnot and S. L. Buchwald, J. Am. Chem. Soc., 2016, 138, 8372 CrossRef CAS PubMed ; (c) S. D. Friis, M. T. Pirnot, L. N. Dupuis and S. L. Buchwald, Angew. Chem., Int. Ed., 2017, 56, 7242 CrossRef CAS PubMed .
  4. For nickel-catalyzed reductive Csp3–Csp2 cross-couplings of alkenes and aryl iodides with hydrosilanes, see: (a) X. Lu, B. Xiao, Z. Zhang, T. Gong, W. Su, J. Yi, Y. Fu and L. Liu, Nat. Commun., 2016, 7, 11129 CrossRef PubMed ; (b) S. A. Green, J. L. M. Matos, A. Yagi and R. A. Shenvi, J. Am. Chem. Soc., 2016, 138, 12779 CrossRef CAS PubMed ; (c) Y. He, Y. Cai and S. Zhu, J. Am. Chem. Soc., 2017, 139, 1061 CrossRef CAS PubMed .
  5. C. Kleeberg, E. Feldmann, E. Hartmann, D. J. Vyas and M. Oestreich, Chem. – Eur. J., 2011, 17, 13538 CrossRef CAS PubMed .
  6. For copper-catalyzed carbonyl addition of silylborons to aldehydes, see: V. Cirriez, C. Rasson, T. Hermant, J. Petrignet, J. Díaz Álvarez, K. Robeyns and O. Riant, Angew. Chem., Int. Ed., 2013, 52, 1785 CrossRef CAS PubMed .
  7. (a) A. G. Brook, J. Am. Chem. Soc., 1958, 80, 1886 CrossRef CAS ; (b) A. G. Brook, Acc. Chem. Res., 1974, 7, 77 CrossRef CAS .
  8. For examples on synergistic palladium/copper catalysis, see: (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 16, 4467 CrossRef ; (b) L. S. Liebeskind and R. W. Fengl, J. Org. Chem., 1990, 55, 5359 CrossRef CAS ; (c) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D. Larsen and M. M. Faul, J. Am. Chem. Soc., 2010, 132, 3674 CrossRef CAS PubMed ; (d) F. Nahra, Y. Macé, D. Lambin and O. Riant, Angew. Chem., Int. Ed., 2013, 52, 3208 CrossRef CAS PubMed ; (e) S. Vercruysse, L. Cornelissen, F. Nahra, L. Collard and O. Riant, Chem. – Eur. J., 2014, 20, 1834 CrossRef CAS PubMed ; (f) K. Semba and Y. Nakao, J. Am. Chem. Soc., 2014, 136, 7567 CrossRef CAS PubMed ; (g) K. B. Smith, K. M. Logan, W. You and M. K. Brown, Chem. – Eur. J., 2014, 20, 12032 CrossRef CAS PubMed ; (h) T. Jia, P. Cao, B. Wang, Y. Lou, X. Yin, M. Wang and J. Liao, J. Am. Chem. Soc., 2015, 137, 13760 CrossRef CAS PubMed ; (i) K. M. Logan, K. B. Smith and M. K. Brown, Angew. Chem., Int. Ed., 2015, 54, 5228 CrossRef CAS PubMed ; (j) R. Shintani, H. Kurata and K. Nozaki, J. Org. Chem., 2016, 81, 3065 CrossRef CAS PubMed ; (k) K. M. Logan and M. K. Brown, Angew. Chem., Int. Ed., 2017, 56, 851 CrossRef CAS PubMed ; (l) S. R. Sardini and M. K. Brown, J. Am. Chem. Soc., 2017, 139, 9823 CrossRef CAS PubMed ; (m) K. B. Smith and M. K. Brown, J. Am. Chem. Soc., 2017, 139, 7721 CrossRef CAS PubMed ; (n) X. Huo, R. He, J. Fu, J. Zhang, G. Yang and W. Zhang, J. Am. Chem. Soc., 2017, 139, 9819 CrossRef CAS PubMed ; (o) B. Chen, P. Cao, X. Yin, Y. Liao, L. Jiang, J. Ye, M. Wang and J. Liao, ACS Catal., 2017, 7, 2425 CrossRef CAS ; (p) J. Mateos, E. Rivera-Chao and M. Fañanás-Mastral, ACS Catal., 2017, 7, 5340 CrossRef CAS ; (q) A. Saito, N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2017, 56, 5551 CrossRef CAS PubMed ; (r) L. Wei, S.-M. Xu, Q. Zhu, C. Che and C.-J. Wang, Angew. Chem., Int. Ed., 2017, 56, 12312 CrossRef CAS PubMed ; (s) D. R. Pye and N. P. Mankad, Chem. Sci., 2017, 8, 1705 RSC .
  9. Palladium-catalyzed cross-couplings between α-alkoxyalkyltrifluoroborates and aryl halides have been reported. See: (a) G. A. Molander and S. R. Wisniewski, J. Am. Chem. Soc., 2012, 134, 16856 CrossRef CAS PubMed ; (b) R. Karimi-Nami, J. C. Tellis and G. A. Molander, Org. Lett., 2016, 18, 2572 CrossRef CAS PubMed .
  10. For the importance of the direct synthesis of a protected secondary alcohol without the intermediacy of an unprotected derivative, see: ref. 9b.
  11. (a) D. Ameen and T. J. Snape, Med. Chem. Commun., 2013, 4, 893 RSC ; (b) F. Schmidt, R. T. Stemmler, J. Rudolph and C. Bolm, Chem. Soc. Rev., 2006, 35, 454 CAS .
  12. The use of a trialkylsilylboronate such as Et3SiB(pin) instead of PhMe2SiB(pin) under the conditions for Table 1, entry 1 resulted in no reaction.
  13. For a review on reductive cross-coupling between carbonyl-type compounds and organic halides, see: T. Moragas, A. Correa and R. Martin, Chem. – Eur. J., 2014, 20, 8242 CrossRef CAS PubMed .
  14. Cross-couplings involving the carbonyl addition of nucleophilic arylmetal species, which are derived from aryl halides, to aldehydes have been reported. These reactions require the use of an excess amount of metallic reductants such as Mn or Zn powder. See: (a) A. Fürstner and N. Shi, J. Am. Chem. Soc., 1996, 118, 2533 CrossRef ; (b) K. K. Majumdar and C.-H. Cheng, Org. Lett., 2000, 2, 2295 CrossRef CAS PubMed .
  15. H. Guo, X. Chen, C. Zhao and W. He, Chem. Commun., 2015, 51, 17410 RSC .
  16. For Table 2, small amounts of Ar1CH2OSiMe2Ph and Ar2–SiMe2Ph, which are derived from the Cu-catalyzed nucleophilic silylation of aldehydes (Ar1CHO) followed by [1,2]-Brook rearrangement and Pd-catalyzed silylation of aryl bromides (Ar2Br), respectively, were observed in the crude material.
  17. The clean conversion to α-silyloxybenzylcopper(I) complex (4) was confirmed by 1H NMR spectroscopy. See ESI for details.


Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data and copies of 1H and 13C NMR spectra. See DOI: 10.1039/c8cc01055b

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