Organic Letters
Letter
with other transition metals, such as palladium, may allow for
amination of more electron-deficient systems,6 the gold-
catalyzed reaction provides significantly enhanced regioselectiv-
ities favoring para-substituted isomers. We hypothesize that this
is the result of an alternate mechanism that differs from our
previously reported metal-free radical initiated pathway and
Hartwig’s palladium-catalyzed CMD pathway.5,6 The substitu-
tion patterns observed in the gold-catalyzed reaction appear to
be governed by the same set of constraints observed in
electrophilic aromatic substitution. Moreover, the predominant
para- selectivity can be attributed to the large gold atom’s
preference to avoid positioning itself ortho to substituents.
Perhaps the most significant argument that can be made
regarding whether or not the reaction is more heavily
influenced by electronics or sterics is best illustrated by 10.
In the amination of m-xylene, a clear preference for amination
to occur para with respect to either of the methyl groups is
observed, rather than aminating at the less sterically
encumbered position.
likely the result of EAM and lead to the proposed mechanism
detailed in Scheme 2.
a
Scheme 2. Proposed Reaction Mechanism
Minor meta-substituted products were also observed in
reactions producing 4−8, 10, and 11, all of which are derived
from less electron-rich arene substrates. The exception to this
rule is the amination of chlorobenzene (6), which surprisingly
provided exclusive para-amination. We hypothesize that the
meta-substituted products originate from a competing mech-
anism, the metal-free, radical-mediated reaction pathway. The
meta-isomers are more often observed in less electron-rich
systems, where electrophilic aromatic metalation (EAM) should
be much slower. The inverse of this phenomenon is also
illustrated in the reaction of the more electron-rich anisole
substrate (3), which exhibits no meta-substitution, presumably
because EAM is the dominant reaction pathway.
Having successfully established the substrate scope, we
sought to further elucidate the reaction mechanism. To do this
we first probed the kinetic isotope effect by performing a
competition reaction using an equimolar solution of benzene/
benzene-d6. A KIE value of 1.04 was obtained, which rules out
the possibility of a gold-mediated C−H activation contributing
to the rate-determining step and demonstrates that a CMD
pathway is unlikely. In order to substantiate our claim that this
reaction proceeds via EAM, additional internal competition
reactions were performed (Table 4). By carrying out the
amination procedure in an equimolar mixture of an electron-
rich arene with a comparatively electron-deficient arene we
observed that amination of the more electron-rich system was
dramatically favored in both instances. These findings support
the hypothesis that the observed regioselectivity patterns were
a
(a) Oxidation, (b) EAM, (c) Transmetalation, (d) Reductive
elimination. EDG = electron donating group, X = OAc or Cl, L =
Cy3P.
The proposed Au(I)/Au(III) pathway is initiated by the
oxidation of the Au(I) species to form Au(III) as the active
catalyst. The para selectivity of this process is consistent with
other Au-catalyzed halogenation, oxygenation, and arylation
reactions that have been previously reported.3c−e The Au(III)
catalyst could then metalate either the ortho- or para-positions,
with the para-position being presumably more favored. The
metalated arene then proceeds to interact with an in situ
generated iodane species (14) via transmetalation. Once the
imide reagent has been incorporated onto the gold species, the
complex undergoes reductive elimination to afford the desired
N-coupled product while regenerating the gold(I) catalyst.
In order to determine if 14 was a plausible intermediate for
this reaction, we synthesized the N,N-diphthalimidoiodane, 15.8
When this iodane was subjected to the reaction (instead of
phthalimide), an isolated yield of 38% was observed with a
regioselectivity comparable to that of the parent reaction
(Scheme 3).
Scheme 3. Iodane-Mediated Amination
Table 4. Competition Reactions
The success of this reaction indicates that transmetalation
from a phthalimide-containing iodane intermediate is a viable
reaction pathway. Our hypothesis for the formation of 14 is
also supported by our observation of a moderate amount of the
acetoxylated arene as a minor reaction product. We hypothesize
that 15 allows for transfer of either the N- or O-ligand via
transmetalation. Alternatively, a nucleophilic Au−arene species
could directly attack the electrophilic nitrogen in 14 (not
shown). Future studies will be directed toward isolating N,O-
iodanes, such as 14, and studying their reactivities.
In conclusion, a regioselective gold-catalyzed protocol for the
amination of arenes has been developed. As phthalimides can
a
Mole fractions determined by GC/MS.
C
Org. Lett. XXXX, XXX, XXX−XXX