C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Amination Using F+ As an Oxidant
chiral indolines from natural amino acids is of particular synthetic
importance (2j, 2v). The gram-scale, one-pot synthesis of 4-bromoin-
dole (5), a key precursor for ergot alkaloid synthesis,11 demonstrates
the efficiency of this approach (eq 3). This new route offers a valuable
alternative to the most broadly used synthesis of 4-bromoindole
developed by Hegedus (eq 4).11a
In summary, we have developed a catalytic C-H amination reaction
using either Ce(SO4)2 or a F+ source as the oxidant. This amination
reaction provides a concise route to substituted indolines.
Acknowledgment. We thank The Scripps Research Institute,
the U.S. National Science Foundation (NSF CHE-0615716), and
Pfizer for financial support; the Camille and Henry Dreyfus
Foundation for a New Faculty Award; and A. P. Sloan Foundation
for a Fellowship. We wish to thank Dr. L. Truesdale for advice.
Supporting Information Available: Experimental procedure and
characterization of all new compounds. This material is available free
References
a 15 mol % Pd(OAc)2 was used in the reactions.
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Extensive screening of single-electron oxidants led us to identify
anhydrous Ce(SO4)2 as a selective oxidant for amination (Table 1, entry
14). As anticipated, the use of Ce(OAc)4 resulted in significant
formation of the corresponding acetoxylation product (35% isolated
yield). It is noteworthy that the commonly used oxidant, (NH4)2Ce-
(NO3)6, was ineffective for this reaction. Presumably, the poor solubility
of Ce(SO4)2 is important as the initial oxidation of Pd(OAc)2 by Ce(IV)
prior to C-H activation may lead to unreactive Pd species.
With this catalytic system in hand, we examined the substrate scope.
Substrates 1a-1d, 1f, 1i, and 1j worked well to give the corresponding
indolines in 60-80% yield. Although OMe and OTf were tolerated,
electron-withdrawing groups such as halides and esters lowered the
yield.
We hypothesized that the presence of SO42- anions could be
detrimental to the reaction by forming unreactive PdSO4 over the course
of the reaction. We therefore decided to test if a previously established
F+ oxidant10 could oxidize the same C-H insertion intermediate to
Pd(IV) yet still allow selective reductive elimination to form the
aminated product as a consequence of the notorious strength of the
Pd-F bond. We were pleased to find that F+ source 3 is an excellent
oxidant for this amination reaction and that the substrate scope could
be substantially expanded. A broad range of functional groups including
several of the strongest electron-withdrawing groups (halo, acetyl,
cyano, nitro, etc.) were tolerated. Excellent regioselectivity in the
presence of meta-substitution was also observed (Table 2, 2c-2e, 2p).
In these cases, exclusive formation of the new C-N bond at the
sterically less hindered site was found. With highly electron-rich arenes,
indole 2u was formed as the major product via a subsequent
dehydrogenative oxidation of the indoline. We further attempted to
use phenylpropylamines as substrates. Unfortunately, the corresponding
quinolines were formed in lower yields (2w, 2x).
These indoline products are highly valuable building blocks for
medicinal chemistry and natural product synthesis. The formation of
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