Abstract
An efficient palladium-catalyzed process has been developed for Negishi coupling of secondary alkylzinc halides and sterically and electronically demanding aryl bromides and activated aryl chlorides. The palladium catalyst composed of a new biaryldialkylphosphine ligand, CPhos, effectively promotes the reductive elimination step relative to the undesired β-hydride elimination pathway. The general substrate scope and excellent ratio of the desired secondary to the undesired primary coupling product make this method a powerful and reliable tool for C(sp3)-C(sp2) bond formation.
The transition-metal-catalyzed cross-coupling reactions involving sp2-hybridized carbon nucleophiles and aryl or vinyl halides have been extensively examined during the past three decades.1 In contrast, few comprehensive studies have been published concerning the analogous cross-coupling of secondary C(sp3)-hybridized organometallics with aryl halides.2
A simplified scheme of the course of the reaction for the coupling of an isopropyl metal with an aryl halide is shown (Scheme 1).1 Oxidative addition followed by transmetallation would produce intermediate B, which can reductively eliminate to form the desired product i-PrAr with concomitant reformation of LnPd(0). Competitive with this is the reversible β-hydride elimination to form C, from which reductive elimination can take place producing reduced arene. Additionally, C can undergo a migratory insertion reaction to produce D which can reductively eliminate to form the undesired product n-PrAr. Of obvious importance to developing a successful catalytic method is to have ligands that will facilitate the rate of reductive elimination from B relative to the rate of β-hydride elimination.
Scheme 1.
A Simplified Reaction Course for the Coupling of i-PrM with an Aryl Halide.
Pioneering work by Kumada and Hayashi demonstrated, with a limited set of substrates, that dichloro[1,3-bis(diphenylphosphino)propane] nickel(II) (NiCl2(dpppk))2h and dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) (PdCl2(dppf))2i could be used for the coupling of secondary alkyl Grignard reagents with aryl and vinyl halides. Recently, Dreher and Molander reported an elegant and more comprehensive study of the Pd-catalyzed Suzuki-Miyaura coupling of secondary alkyltrifluoroborates with aryl chlorides.2g These publications describe the formation of good ratios of secondary to primary alkyl coupling products in a number of cases. However, the product ratios obtained when electron-deficient and/or ortho-substituted aryl halide substrates were used were poor to moderate and the substrate scope reported was somewhat limited in terms of the functional groups that were demonstrated to be tolerated.
In this communication, we report a general catalyst for the palladium-catalyzed Negishi coupling of secondary alkylzinc halides with aryl bromides and chlorides in high yield with excellent ratios of secondary to primary coupling products which is based on a new biarylphosphine ligand, CPhos.
We initiated our studies by evaluating a series of biaryldialkylphosphine ligands3 with both an electron-deficient and -rich ortho-substituted aryl bromide, 2-bromobenzonitrile and 2-bromoanisole, in combination with isopropyl zinc bromide using 1 mol % Pd(OAc)2 at ambient temperature in THF (Figure 1). SPhos (L1), RuPhos (L2), and XPhos (L3), previously reported to be excellent ligands for Suzuki-Miyaura4 and Negishi coupling5 reactions, including those with primary alkyl boron and zinc reagents reported by Molander4b-d and Knochel5b-c, gave moderate results. In contrast, a new ligand (L6), CPhos, bearing ortho,ortho'-dimethylamino substituents on the lower (nonphosphine-containing) ring was found to give results superior to other biarylphosphine ligands in terms of the ratio of branched (i-Pr) to linear (n-Pr) products and the yield. The use of PdCl2(dppf)2i provided low (<10%) conversion of products under the same conditions.
Figure 1.
Ligand effects in the coupling of ortho-substituted aryl bromides with isopropyl zinc bromide.
We next examined the coupling of a range of aryl halides with isopropylzinc bromide, which was readily prepared as a THF solution by LiCl- assisted zinc insertion into isopropyl bromide according to Knochel's method6 (Table 1). Our coupling conditions at ambient temperature, were successfully applied to a series of ortho- and para-substituted aryl bromides; the selectivity for the branched product remains high (>20:1, i-Pr:n-Pr) in all cases.7 In general, the selectivity realized for ortho-substituted aryl bromides were lower than those obtained with corresponding para-substituted ones, presumably due to steric effects (entries 1-4 v.s. entries 7-10); this is consistent with what has been previously reported.2f Employing toluene as a co-solvent afforded higher yields and selectivities in the cases of electron-deficient aryl bromides (entries 3-5 and 9-10). Esters (entry 3 and 9), nitriles (entry 4 and 10), aldehydes (entry 5), and unprotected indoles (entry 12) were well tolerated.5b,c However, the coupling of 4-bromonitrobenzene provided a modest yield of the desired product due to formation of unidentified side products (entry 6). In addition, activated aryl chlorides8 (entries 3-5 and 9-10) were also suitable substrates at ambient temperature providing products in high yield and with good selectivity although longer reaction times were often needed compared to those for the reactions of the corresponding aryl bromides.
Table 1.
Negishi Cross-Coupling of Isopropylzinc Bromide with Aryl Bromides and Chlorides.
 | ||||
|---|---|---|---|---|
| entry | ArX | yielda | P1:P2 | |
| 1 | R= 4-OMe, X= Br | 92% | 37:1 | |
| 2 | R= 4-Ph, X= Br | 95% | 39:1 | |
| 3 | R= 4-CO2Me | X= Br | 94%b | 46:1 |
| X= Cl | 98%b,c | 45:1 | ||
| 4 | R= 4-CN | X= Br | 87%b | 59:1 |
| X= Cl | 94%b | 43:1 | ||
| 5 | R= 4-CHO | X= Br | 89%b | 43:1 |
| X= Cl | 93%b | 47:1 | ||
| 6 | R= 4-NO2, X= Br | 50%b,d | 28:1 | |
| 7 | R= 2-OMe, X= Br | 97% | 27:1 | |
| 8 | R= 2-Ph, X= Br | 97%c | 22:1 | |
| 9 | R= 2-CO2Me | X= Br | 91%b | 37:1 |
| X= Cl | 97%b,e | 30:1 | ||
| 10 | R= 2-CN | X= Br | 89%b | 20:1 |
| X= Cl | 94%b,c | 22:1 | ||
| 11 | R= 2-SMe, X= Br | 95%f | 30:1 | |
| 12 | 5-bromoindole | 96% | 58:1 | |
Isolated yields of mixtures of i-Pr and n-Pr products; average of at least two runs.
Toluene employed as a cosolvent.
rt, 3 h.
0 °C, 30 min.
rt, 6 h.
rt, 1 h.
To probe the generality of the coupling reaction with respect to secondary alkylzinc halide, a variety of cyclic and acyclic zinc reagents were prepared using Knochel's protocol.6,9 Coupling reactions of these alkylzinc reagents with aryl bromides and activated aryl chlorides could be performed efficiently employing 1-2 mol % catalyst (Scheme 2). The ratio of branched to linear product remained high for reactions involving acyclic zinc reagents (1e-f). Additionally, no isomeric products were observed for the reaction with the N-Boc piperazine substrate (1d).
Scheme 2.
Negishi Cross-Coupling of Secondary Alkylzinc Halides with Aryl or Heteroaryl Bromides and Chlorides.a
a Isolated yields; average of two runs. b Reaction conducted in THF. c 2 mol % Pd(OAc)2 and 4 mol % CPhos. d The alkylzinc reagent (1.5 equiv) was slowly added over 30 min. e 23:1 branched: linear.
There are two most probable scenarios to explain the differences seen with CPhos and XPhos (cf. Scheme 1): (1) The ratio of branched to linear products is determined by the relative rates of corresponding reductive elimination steps if a fast equilibrium exists between species B and D. In this case, similar product ratios should be obtained for couplings of both i-Pr and n-Pr zinc reagents; (2) The product ratio is largely dependent on the relative rates of reductive elimination versus β-hydride elimination– reinsertion. In order to distinguish between these, we examined the coupling of 2-bromobenzonitrile with n-propyl zinc bromide (eq 2) to compare the results to those obtained with isopropyl zinc bromide (eq 1). Consistent with the latter explanation are the different product distributions seen for the coupling of i-Pr versus n-Pr zinc reagents (CPhos, P1:P2=95:5 in eq 1 versus P1:P2< 1:99 in eq 2; XPhos, P1:P2=25:75 in eq 1 versus P1:P2=2:98 in eq 2). This explanation is further supported by an observed kinetic isotope effect on the product distribution (kH/kD=3.1) for the coupling of fully deuterated isopropyl zinc bromide using XPhos.9
In summary, we have established an efficient new catalyst system for Negishi coupling of secondary alkylzinc halides with a wide range of aryl bromides and activated chlorides in which the undesired β-hydride elimination pathway is effectively suppressed employing the new ligand CPhos, L6. The broad substrate scope and excellent selectivity of the coupling process provides a general and useful means for the forging of C(sp3)-C(sp2) bonds. Further, we have provided evidence that the excellent selectivity observed for branched versus linear products with secondary alkyl zincs using CPhos is due to the slow relative rates of β-hydride elimination-reinsertion versus reductive elimination.
Supplementary Material
Scheme 3.
Comparison of Product Distribution for the Coupling of Isopropyl and n-Propyl Zinc Bromide with 2-Bromobenzonitrile.
Acknowledgments
We thank the National Institutes of Health (Grant GM 46059) for funding this work. We are grateful to Merck, BASF (Pd compounds), and Nippon Chemical for additional support. We thank Dr. Tom Kinzel and Dr. Donald Watson for helpful discussions. The Varian NMR instrument used was supported by NIH (GM 1S10RR13886-01).
Footnotes
Supporting Information Available. Experimental procedures, structural proofs, and spectral data for all new compounds are provided (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
References
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- 9.See Supporting Information for experimental details.
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