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. 2012 Apr 11;134(14):6146-59.
doi: 10.1021/ja301769r. Epub 2012 Mar 30.

Replacing conventional carbon nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl bromides and chlorides

Daniel A Everson  1 , Brittany A Jones, Daniel J Weix
Affiliations

Replacing conventional carbon nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl bromides and chlorides

Daniel A Everson et al. J Am Chem Soc. .

Abstract

A general method is presented for the synthesis of alkylated arenes by the chemoselective combination of two electrophilic carbons. Under the optimized conditions, a variety of aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant (-OH, -NHTs, -OAc, -OTs, -OTf, -COMe, -NHBoc, -NHCbz, -CN, -SO(2)Me), and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture. The reaction displays different chemoselectivity than conventional cross-coupling reactions, such as the Suzuki-Miyaura, Stille, and Hiyama-Denmark reactions. Substrates bearing both an electrophilic and nucleophilic carbon result in selective coupling at the electrophilic carbon (R-X) and no reaction at the nucleophilic carbon (R-[M]) for organoboron (-Bpin), organotin (-SnMe(3)), and organosilicon (-SiMe(2)OH) containing organic halides (X-R-[M]). A Hammett study showed a linear correlation of σ and σ(-) parameters with the relative rate of reaction of substituted aryl bromides with bromoalkanes. The small ρ values for these correlations (1.2-1.7) indicate that oxidative addition of the bromoarene is not the turnover-frequency determining step. The rate of reaction has a positive dependence on the concentration of alkyl bromide and catalyst, no dependence upon the amount of zinc (reducing agent), and an inverse dependence upon aryl halide concentration. These results and studies with an organic reductant (TDAE) argue against the intermediacy of organozinc reagents.

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Figures

Figure 1
Figure 1
Conventional transition-metal-catalyzed C–C bond formation (Cδ– + Cδ+) compared to direct reductive C–C bond formation (Cδ+ + Cδ+).
Figure 2
Figure 2
Effects of increasing the equivalents of one substrate on maximum statistical yield and waste.
Scheme 1
Scheme 1. Possible Mechanisms for the Direct Cross-Coupling of Aryl Halides with Alkyl Halides
Figure 3
Figure 3
This work: reductive coupling of aryl bromides, vinyl bromides, and aryl chlorides with alkyl bromides.
Scheme 2
Scheme 2. Substrate Scope of Aryl and Alkyl Bromides for the Nickel-Catalyzed Reductive Cross-Coupling
Reaction conditions: organic halides (0.75 mmol each), NiI2·xH2O (0.054–0.078 mmol), ligand (0.05–0.075 mmol), pyridine (0.05–0.075 mmol), sodium iodide (0.19 mmol), zinc dust (>10 μm, 1.5 mmol), and DMPU (3 mL) were assembled on the bench in a 1 dram vial and heated for 5–41 h under air. Yields are of isolated and purified product. Average of two runs. Used 1.25 equiv of alkyl bromide (0.94 mmol). The 2-bromoheptane contained 11% 3-bromoheptane (NMR). Product 3n was isolated as an 83:17 ratio of 3n:heptan-3-ylbenzene (NMR). Isolated as an inseparable mixture with benzyl butyrate; yields determined by NMR analysis of this mixture. Isolated as an inseparable mixture of (E) and (Z) isomers. Isomer ratio determined by NMR analysis. Starting material (2-bromo-2-butene) was an 88:12 ratio of (Z) and (E) isomers.
Scheme 3
Scheme 3. Substrate Scope of Aryl Chlorides for the Nickel-Catalyzed Reductive Cross-Coupling,
Reaction conditions: aryl chloride (0.75 mmol), alkyl bromide (0.94 mmol), NiI2·xH2O (0.054 mmol), ligand 6 (0.05 mmol), pyridine (0.05 mmol), zinc dust (>10 μm, 1.5 mmol), and DMPU (3 mL) were assembled on the bench in a 1 dram vial and heated for 18–23 h under air. Yields are of isolated and purified product. Average of two runs. Used 1.0 equiv alkyl bromide (0.75 mmol). Technical grade 1-chloronaphthalene was used (87:13 1-chloronaphthalene/2-chloronaphthalene).
Scheme 4
Scheme 4. Substrates That Demonstrate the Complementarity of Direct Reductive Cross-Coupling to Conventional Cross-Coupling,
Reaction conditions: organic bromides (0.75 mmol each), NiI2.xH2O (0.054 mmol), ligand (0.05 mmol), pyridine (0.05 mmol), sodium iodide (0.19 mmol), zinc dust (>10 μm, 1.5 mmol), and DMPU (3 mL) were assembled on the bench in a 1 dram vial and heated for 3.5–23 h under air. Yields are of isolated and purified product. Average of two runs. Run at 80 °C and with 1 equiv of sodium iodide. Run with 1.25 equiv of alkyl bromide (0.94 mmol). Zinc was activated in situ with TMS-Cl and 1,2-dibromoethane (6 μL each).
Figure 4
Figure 4
(a) Plot of −ln(1 – f), where f is the fraction of product as a function of time (see Supporting Information for full details and linear fits): standard conditions (□, −ln(1 – f) = 0.00327t, R2 = 0.9957); 2 equiv of bromobenzene (1) (+, −ln(1 – f) = 0.000905t, R2 = 0.9951); 2 equiv of 1-bromooctane (2) (○, −ln(1 – f) = 0.0031t, R2 = 0.9817); 4 equiv of Zn0 (Δ, −ln(1 – f) = 0.00336t, R2 = 0.9916); 20 mol % Ni/6/pyridine, (◇, −ln(1 – f) = 0.00479t, R2 = 0.9971). (b) As in panel a, but with activated zinc (TMSCl and 1,2-dibromoethane): standard conditions (□, −ln(1 – f) = 0.00502t, R2 = 0.9944); 2 equiv of bromobenzene (1) (+, −ln(1 – f) = 0.00160t, R2 = 0.9896); 2 equiv of 1-bromooctane (2) (○, −ln(1 – f) = 0.00954t, R2 = 0.9859), 4 equiv of Zn0 (Δ, −ln(1 – f) = 0.00482t, R2 = 0.9987); 20 mol % Ni/6/pyridine (◇, −ln(1 – f) = 0.0105t, R2 = 0.9945); with 1 equiv of benzene (●, −ln(1 – f) = 0.00376t, R2 = 0.9987).
Scheme 5
Scheme 5. Comparison of Reductive Cross-Coupling and Iterative Cross-Coupling for Synthesis of Functionalized Carbon Nucleophiles
Scheme 6
Scheme 6. Direct Insertion of Zinc and Activated Zinc
GC yield at 24 h based on unreacted 1 or 2, corrected vs dodecane internal standard.
Scheme 7
Scheme 7. Nickel-Catalyzed Reductive Cross-Coupling with a Nonmetallic Reducing Agent
GC yield corrected vs dodecane internal standard. TDAE = tetrakis(dimethylamino)ethylene.
Figure 5
Figure 5
Yield of product versus bromoarene substituent for 4,4′-dimethoxy-2,2′-bipyridine (6, solid bars) and 1,10-phenanthroline (7, white speckled bars). In general, ligand 6 is superior for electron-rich arenes, such as 4-methoxybromobenzene and all chloroarenes (data not on chart). Ligand 7 works best for electron-poor bromoarenes.
Figure 6
Figure 6
Hammett plots of (a) log(krel) versus σ(−) for ligand 6 (■), krel = 1.235σ(−), R2 = 0.9259; (b) log(krel) vs σ(−) for ligand 6 (■), krel = 1.635σ(−), R2 = 0.9531; (c) log(krel) vs σ(−) for ligand 7 (●), krel = 1.264σ, R2 = 0.9387; (d) log(krel) vs σ for ligand 7 (●), krel = 1.657σ, R2 = 0.9468.
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