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. 2014 Nov 26;136(47):16588-93.
doi: 10.1021/ja508718m. Epub 2014 Nov 17.

Nickel-catalyzed Negishi arylations of propargylic bromides: a mechanistic investigation

Nathan D Schley  1 , Gregory C Fu
Affiliations

Nickel-catalyzed Negishi arylations of propargylic bromides: a mechanistic investigation

Nathan D Schley et al. J Am Chem Soc. .

Abstract

Although nickel-catalyzed stereoconvergent couplings of racemic alkyl electrophiles are emerging as a powerful tool in organic chemistry, to date there have been no systematic mechanistic studies of such processes. Herein, we examine the pathway for enantioselective Negishi arylations of secondary propargylic bromides, and we provide evidence for an unanticipated radical chain pathway wherein oxidative addition of the C-Br bond occurs through a bimetallic mechanism. In particular, we have crystallographically characterized a diamagnetic arylnickel(II) complex, [(i-Pr-pybox)Ni(II)Ph]BAr(F)4, and furnished support for [(i-Pr-pybox)Ni(II)Ph](+) being the predominant nickel-containing species formed under the catalyzed conditions as well as a key player in the cross-coupling mechanism. On the other hand, our observations do not require a role for an organonickel(I) intermediate (e.g., (i-Pr-pybox)Ni(I)Ph), which has previously been suggested to be an intermediate in nickel-catalyzed cross-couplings, oxidatively adding alkyl electrophiles through a monometallic pathway.

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Figures

Figure 1
Figure 1
Outline of one of the possible mechanisms for nickel-catalyzed cross-coupling of unactivated alkyl electrophiles: transmetalation before oxidative addition.
Figure 2
Figure 2
X-ray crystal structures of [((−)-i-Pr-pybox)NiIIPh]BArF4 (1; left; Ni–pyridine 1.898(2) Å; Ni–Ph 1.881(3) Å) and ((−)-i-Pr-pybox)NiIPh (2; right; Ni–pyridine 1.871(3) Å; Ni–Ph 1.896(3) Å) (ellipsoids are shown at 50% probability, and hydrogens, disordered fluorine atoms, and additional molecules in the asymmetric unit are omitted for clarity).
Figure 3
Figure 3
EPR spectrum of ((−)-i-Pr-pybox)NiIPh (2; black) and corresponding fit (red). Fit parameters: g1 = 2.0067, g2 = 2.0075, g3 = 1.9889, 14N coupling (MHz) = 0.0205, 0.0124, 47.2047, line width = 0.9929. X-band EPR spectra were collected at 77 K in a toluene glass at υ = 9.411 GHz at 2 mW power and a modulation amplitude of 2 G.
Figure 4
Figure 4
Two representations of a possible radical chain mechanism for the arylation of a propargylic bromide by an arylnickel(II) complex (L = pybox).
Figure 5
Figure 5
Progress of a stoichiometric arylation of a propargylic bromide: No evidence for the accumulation of an intermediate (monitored by 19F NMR spectroscopy).
Figure 6
Figure 6
A possible catalytic cycle for the nickel/pybox-catalyzed Negishi arylation of a propargylic bromide. For the sake of simplicity, all elementary steps are illustrated as being irreversible.
Figure 7
Figure 7
Analysis via UV–vis spectroscopy of the reaction of (i-Pr-pybox)NiIIBr2 with Ph2Zn to form [(i-Pr-pybox)NiIIPh]+.
Figure 8
Figure 8
Analysis via ESI-MS (positive-ion mode) of the reaction of (i-Pr-pybox)NiIIBr2 with Ph2Zn to form [(i-Pr-pybox)NiIIPh]+.
Figure 9
Figure 9
Analysis via 19F NMR spectroscopy of a catalyzed Negishi reaction in progress: (○) [(i-Pr-pybox)NiIIAr]+ as a percentage of all nickel that is present; (●) yield of cross-coupling product.
Figure 10
Figure 10
Analysis via UV–vis spectroscopy of a catalyzed Negishi reaction in progress: blue: (i-Pr-pybox)NiIIBr2; red: cross-coupling reaction in progress; purple: [(i-Pr-pybox)NiIIPh]BArF4.
Figure 11
Figure 11
Analysis via 19F NMR spectroscopy of a catalyzed Negishi reaction in progress, in the presence of TEMPO: (○) [(i-Pr-pybox)NiIIAr]+ as a percentage of all nickel that is present; (●) yield of cross-coupling product.
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References

    1. For reviews and leading references, see:Science of Synthesis: Cross-Coupling and Heck-Type Reactions; Molander G. A., Ed.; Georg Thieme Verlag: Stuttgart, 2013.
    1. For a recent overview, see:Tasker S. Z.; Standley E. A.; Jamison T. F. Nature 2014, 509, 299–309. - PMC - PubMed
    2. For an earlier overview, see:Modern Organonickel Chemistry; Tamaru Y., Ed.; Wiley–VCH: Weinheim, 2005.
    1. For leading references to mechanistic work on nickel-catalyzed cross-couplings of alkyl electrophiles, see:Hu X. Chem. Sci. 2011, 2, 1867–1886.
    1. Initial report:Zhou J.; Fu G. C. J. Am. Chem. Soc. 2003, 125, 14726–14727. - PubMed
    2. Initial report of stereoconvergent reactions:Fischer C.; Fu G. C. J. Am. Chem. Soc. 2005, 127, 4594–4595. - PubMed
    3. Most recent report of stereoconvergent reactions:Choi J.; Martín-Gago P.; Fu G. C. J. Am. Chem. Soc. 2014, 136, 12161–12165. - PMC - PubMed

    1. For overviews, see:

    2. Glasspoole B. W.; Crudden C. M. Nat. Chem. 2011, 3, 912–913. - PubMed
    3. Geist E.; Kirschning A.; Schmidt T. Nat. Prod. Rep. 2014, 31, 441–448. - PubMed

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