Angewandte
Chemie
Encouraged by the promising results achieved above, we
then tested the scope of a-tertiary a-amino acids by using 1H-
indole (2a) as the nucleophile (Scheme 4). We were pleased
to find that a wide range of a-substituted a-amino acids
underwent a smooth oxidative coupling. For example, the
reactions of methyl, ethyl, benzyl, and allyl phenylalanine
esters afforded the coupled products in good yields
(Scheme 4, 3a and 4a–4c). When the phenyl ring of the
phenylalanine ester substrates was functionalized with elec-
tron-donating, electron-withdrawing, sterically hindered, or
multiple groups, all of them gave the desired products (4d–
4m) in moderate to good yields (Scheme 4). The catalytic
system was highly compatible with various functional groups
on the phenyl ring (e.g. halide, nitrile, alkoxyl, and even
hydroxy groups). We subsequently applied this procedure to
other natural and non-natural a-amino acid derivatives for
the synthesis of a,a-disubstituted a-amino acids (4n–4u;
Scheme 4). It is worth noting that a variety of natural a-amino
acid substrates (e.g. phenylalanine, tyrosine, tryptophane, and
aspartic acid) and non-natural a-amino acid substrates (e.g.
naphthylalanine, phenylglycine, thienylalanine, allylglycine,
benzoylglycine, and acetylglycine) could undergo the oxida-
tive cross-coupling reactions with 1H-indole in satisfactory
yields. Notably, the reaction of the b,b-disubstituted alanine
substrate failed to produce the targeted compound (4v;
Scheme 4) under the standard reaction conditions.
To further highlight the synthetic usefulness of our
strategy we turned our attention to the scope of nucleophiles
(Scheme 5). A series of electron-rich N-heterocycles was first
investigated because of their central place in synthetic,
medicinal, and material chemistry. Besides indoles, other
types of electron-rich heteroarenes such as indolizines, 7-aza-
1H-indoles, thiophenes, furans, and N-alkyl pyrroles also
coupled smoothly with the 2-pyridinecarbonyl phenylglycine
ester to afford a,a-disubstituted a-amino acids in syntheti-
cally useful yields (5a–5g; Scheme 5). Malonates were also
suitable nucleophilic substrates. The oxidative cross-coupling
of the phenylalanine derivative with dimethyl and diethyl
malonates afforded 5k and 5l in 70% and 74% yields,
respectively (Scheme 5). Interestingly, the phenylglycine
derivative underwent a tandem reaction involving the oxida-
Scheme 5. Scope of nucleophiles. [a] Reaction conditions: 1 (0.25 mmol), 2
(2.0 equiv), FeCl3·6H2O (20 mol%), DTBP (2.0 equiv), and DCE (1.0 mL) at
1208C under air for 24 h. See the Supporting Information for details.
[b] Yield of isolated products. [c] Cu(OAc)2 (20 mol%) and dioxane (1.0 mL)
at 1108C. [d] Trimethyl(1-phenylvinyloxy)silane (4.0 equiv) was used as the
nucleophile. [e] Dimethyl malonate (4.0 equiv) and DTBP (3.0 equiv) for
24 h.
À
À
tive C H/C H cross-coupling and decarboxylation to give 5j
in 63% yield. To our surprise, 1,2,4,5-tetramethylbenzene
could couple with the phenylglycine substrate to give 5h in
34% yield. The present method also allowed for the use of
trimethyl(1-phenylvinyloxy)silane as the nucleophile to pre-
pare the benzoyl-substituted a-quaternary a-amino acid 5i.
Although the detailed mechanism of this transformation
is not clear at this stage, the possible pathway was proposed to
involve a single-electron transfer (SET), which was demon-
strated by the addition of radical inhibitors. When treated
with 2,2,6,6-tetramethylpiperidine oxide (TEMPO) or 2,6-di-
tert-butyl-4-methylphenol (BHT), the coupling reaction of
ethyl 3-phenyl-2-(picolinamido)propanoate (1a) with 1H-
indole (2a) could be suppressed (see Part V in the Supporting
Information). The plausible catalytic route is illustrated in
Scheme 6. First, 2-picolinamido a-tertiary amino acid ester
coordinates with FeIII to yield the intermediate IM1. Next, the
tert-butoxyl radical (tBuOC) generated from DTBP abstracts
3
À
Scheme 6. Possible mechanism of the a-C(sp ) H functionalization of
a-substituted a-amino acid esters.
the a-hydrogen atom of IM1 to form the radical IM2.[7k]
Subsequently, the radical species IM2 undergoes an intra-
molecular single-electron transfer (SET) to give the a-
ketimine intermediate IM3. The coordination of FeIII with
the picolinamido group activates the a-ketimine and facili-
tates the addition of nucleophile to IM3 to afford the desired
a-quaternary a-amino acid ester. Given the fact that 3a was
obtained in 39% yield in a N2 atmosphere (Table S1,
entry 28), we assumed that the released FeII is reoxidized to
FeIII by air[11] as well as DTBP[7j,12] to fulfill the catalytic cycle.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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