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Organic Letters
Letter
75% yield. Furthermore, α-substituted MBH adducts 2e and 2f
tolerated in this transformation to afford C3- and C4-
disubstituted carbazoles 6ae (45%) and 6af (32%), respec-
tively.
Scheme 6. Possible Pathways and Electronic Effect for the
Formation of Carbazoles
To gain mechanistic insight into this process, a series of
deuterium-labeling and kinetic isotope effect (KIE) experi-
ments was performed (Scheme 5). First, treatment of 1a with
Scheme 5. Deuterium-Labeling and Kinetic Isotope Effect
Experiments
CD3CO2D resulted in a remarkable H/D exchange (51% D
incorporation) at the ortho-position of recovered deuterio-1a,
indicating that the C−H cleavage step might be reversible (eq
1). In addition, the reaction of deuterio-1a′ with 2a gave
deuterio-3aa in 65% yield, and no scrambling of benzylic
deuterium was observed. Partial hydrogenation (17% H) at the
ortho-position on the aryl ring suggests the reversibility of the
C−H activation (eq 2). Next, the intermolecular competition
reaction between 1a and deuterio-1a′ in the presence of 2a
resulted in a KIE value of 1.02, suggesting that the C−H
cleavage might not be involved in the turnover-limiting step
(eq 3).
We considered several plausible pathways. One involved
allylated intermediate Int1 undergoing deprotonation to form
anionic species Int2, which would undergo intramolecular
addition to the iminium moiety to give hydroxyamine Int3
(Scheme 6, eq 1). The difficulty in this pathway lies in the high
energy barrier of the annulation under the experimentally
details). As an alternative reaction pathway (eq 2), it is
conceivable that the carbazole product could be formed from
the [3 + 2] bicyclic adduct Int4, and the enamine-like
reactivity of the indole could trigger further C−N bond
cleavage of bridged bicyclic intermediate. To test our
hypothesis, a series of control experiments was carried out.
We found that N-acetyl indolinyl nitrone 7a was coupled with
MBH carbonate 2b to furnish a separable mixture of carbazole
8ab (11%) and bridged bicycle 9ab (50%) (eq 3). A similar
phenomenon was observed when using C7-nitro indolinyl
nitrone 7b, which afforded 8bb (10%) and 9bb (83%) (eq 4).
Intriguingly, 9bb can be converted into 8bb upon treatment
with AgSbF6 as a Lewis acid in the absence of a Rh(III)
catalyst. Furthermore, a kinetic reaction profile between 8bb
and 9bb was determined by monitoring the conversion of 9bb
into 8bb under the standard reaction conditions (Figure S1).
Within 2 h, bicyclic product 9bb was formed (approximately
95%), and carbazole 8bb was subsequently generated with
concomitant disappearance of 9bb, which indicates the
intermediacy of 9bb in the overall process. Interestingly, no
deuterium was incorporated into product 6ab (eq 5), which is
in good agreement with our initial calculations that anionic
species Int2 may not be involved in the carbazole formation
process.
Preliminary mechanistic studies indicate that the [3 + 2]
cycloaddition adducts are initially formed as common
intermediates, and only electron-rich indolinyl or aniline
substrates can undergo subsequent C−N bond cleavage of
the bridged bicyclic intermediate. We sought to better
understand the origin of this unusual reactivity through
density functional theory (DFT) studies and the energy
profiles comparing the different substrates (Scheme 7). We
started with allylated intermediates A1, B1, and C1 generated
from Rh-catalyzed C−H activation and migratory insertion.
The energy barriers for the [3 + 2] cycloaddition were less
than 22 kcal/mol, indicating that bridged bicyclic intermedi-
ates can be readily formed in all cases. The main reaction
energy pathway continues to the formation of AcOH
complexes A3, B3, and C3, which were located at 3.6, 0.6,
and −2.5 kcal/mol, respectively. To push the reaction forward
and form aromatic rings, A3, B3, and C3 should proceed
through the C−N bond cleavage, followed by deprotonation
by the acetate anion to give intermediates A4, B4, and C4.
Whereas the transition state for this step, C3-TS is found at
34.4 kcal/mol, resulting in a barrier of 38.4 kcal/mol as
highlighted in red, the analogous transition states A3-TS and
B3-TS are located at 25.1 and 22.7 kcal/mol, giving rise to
barriers of 22.9 and 26.1 kcal/mol, respectively (see the
Supporting Information for details). Once intermediates A3
and B3 are formed, the reaction pathways become essentially
irreversible, leading to the construction of carbazole and
naphthalene after facile elimination of the nitroso group and
aromatization. In the case of indolinyl and aniline substrates,
the electron-rich enamine systems in A3 and B3 could trigger
the C−N bond cleavage of the bridged bicyclic intermediate.
In accordance with the experimental observations that the
C
DOI: 10.1021/acs.orglett.8b01910
Org. Lett. XXXX, XXX, XXX−XXX