Journal of the American Chemical Society
Communication
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(15) In all cases, the alkylation reactions were heterogeneous, which
we believe is due to the low solubility of the nitronate anions in the
apolar medium. The failure of the reactions involving lithium salts
likely stems from the very low solubility of the lithium nitronates.
(16) Screening reactions were set up inside a nitrogen-filled glovebox.
The use of NaOtBu, because of its limited hydroscopicity relative to
KOtBu, also allowed the reactions to be performed on the bench using
standard Schlenk techniques. With the exception of 38, all of the
isolated yields refer to reactions run on the bench. All of the reported
isolated yields are averages of at least two independent experiments.
(17) Lower catalyst loadings resulted in lower yields.
undergoes coupling with the nitronate anion. Electron transfer
from the resulting nitronate radical regenerates the Cu catalyst.
The observation of bibenzyl byproducts is consistent with an
SET pathway.25
In summary, we have developed a catalytic system for the
benzylation of nitroalkanes that utilizes readily available benzyl
bromides and related heteroaromatic compounds. This
protocol addresses a century-old gap in C−C bond
construction and provides the first example of alkylation of
nitroalkanes using readily available starting materials under mild
reaction conditions. This reaction allows the conversion of
simple starting materials to complex nitroalkanes, which are
important synthetic intermediates in the preparation of
bioactive molecules such as phenethylamines. The key to this
discovery was the identification of a highly electron-rich
Cu(I)−nacnac complex that can be prepared in situ and can
reduce the benzyl halide to the corresponding radical. This
thermally driven process clearly bears mechanistic resemblance
to catalytic photoredox systems, whose synthetic utility has
been elegantly demonstrated by several groups.26,27 Efforts to
apply our Cu-based system to other catalytic redox reactions
and to expand the scope of the nitroalkane alkylation to other
classes of alkyl halides are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
■
S
AUTHOR INFORMATION
Corresponding Author
■
(18) In some cases, particularly those involving more polar
substrates, preforming the catalyst in situ and using alternative
solvents (e.g., 1,4-dioxane) or weaker bases (e.g., NaOSiMe3) proved
to be superior to the standard conditions. For substrates containing
methyl esters, NaOMe was used as the base.
Notes
The authors declare no competing financial interest.
(19) (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105.
(b) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873.
(c) Chiral Amine Synthesis: Methods, Developments, and Applications;
Nugent, T. C., Ed.; Wiley-VCH: Weinheim, Germany, 2010.
(20) The reaction providing 38 was very sensitive to oxygen and was
performed in a nitrogen-filled glovebox.
(21) (a) Herman, G. A.; Bergman, A.; Liu, F.; Stevens, C.; Wang, A.
Q.; Zeng, W.; Chen, L.; Snyder, K.; Hilliard, D.; Tanen, M.; Tanaka,
W.; Meehan, A. G.; Lasseter, K.; Dilzer, S.; Blum, R.; Wagner, J. A. J.
ACKNOWLEDGMENTS
■
The University of Delaware (UD) and the University of
Delaware Research Foundation are gratefully acknowledged for
funding and other support. NMR and other data were acquired
at UD on instruments obtained with the assistance of NSF and
NIH funding (NSF MIR 0421224, NSF CRIF MU
CHE0840401, NIH P20 RR017716, NIH S10 RR02692).
Clin. Pharmacol. 2006, 46, 876. (b) Pauwels, R. A.; Lofdahl, C.-G.;
̈
Postma, D. S.; Tattersfield, A. E.; O’Byrne, P.; Barnes, P. J.; Ullman, A.
N. Engl. J. Med. 1997, 337, 1405. (c) Armstrong, H. E.; Galka, A.; Lin,
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Q.; Chang, L. L.; Quaker, G.; Colandrea, V. J.; Tong, X.; Wang, J.; Xu,
S.; Fong, T. M.; Shen, C.-P.; Lao, J.; Chen, J.; Shearman, L. P.;
Stribling, D. S.; Rosko, K.; Strack, A.; Ha, S.; Van der Ploeg, L.; Goulet,
M. T.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 2007, 17, 2184.
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(b) The Merck Index, 14th ed.; O’Neil, J. M., Ed.; Merck and Co., Inc.:
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(25) We note that radical chain pathways are also possible; detailed
studies to define the mechanism further are now underway.
(26) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527.
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