Redox-neutral indole annulation cascades

Article abstract of DOI:10.1021/ja110713k

Aminobenzaldehydes react with indoles in an unprecedented cascade reaction. This acid-catalyzed redox-neutral annulation proceeds via a condensation/1,5-hydride shift/ring-closure sequence. Polycyclic azepinoindoles and related compounds are obtained in a single step with good to excellent yields.

Full text of DOI:10.1021/ja110713k

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pubs.acs.org/JACS
Redox-Neutral Indole Annulation Cascades
Michael C. Haibach, Indubhusan Deb, Chandra Kanta De, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
S Supporting Information
b
ABSTRACT: Aminobenzaldehydes react with indoles in an
unprecedented cascade reaction. This acid-catalyzed redox-
neutral annulation proceeds via a condensation/1,5-hydride
shift/ring-closure sequence. Polycyclic azepinoindoles and
related compounds are obtained in a single step with good to
excellent yields.
Figure 1. Redox-neutral C-H bond functionalization.
irect functionalization of unactivated and relatively unreactive
D
C-H bonds continues to be a major focus of inquiry.1 Exciting
progress in this intensely active research area has been achieved and
many more advances can be anticipated. Much of the current research
efforts are focused on the development of C-H bond func-
tionalization processes by means of oxidative methods that require
(super)stoichiometric amounts of oxidant. Fundamentally different
from a mechanistic point of view and comparatively unexplored are
reactions that lead to C-H bond functionalization through redox-
neutral processes (e.g., Figure 1).2,3 In these reactions, the C-H
bond to be functionalized serves as a hydride source for a pendant
acceptor moiety. After hydride transfer, the reduced and oxidized
portions of the molecule recombine to form a new ring system.
Previously reported hydride shift-initiated C-H bond func-
tionalizations often follow the general reaction sequence shown
in Figure 1.4,5 In the first step, aldehyde 1 is allowed to react with
a nucleophile (H2Nu) to form intermediate 2. Thermal or
catalyst promoted activation of 2 facilitates hydride shift/ring-
closure to form 4 via the intermediacy of dipolar species 3. In the
majority of cases, this sequence is conducted in a stepwise
manner that requires isolation and purification of intermediate
2. Many of these reactions involve 1,5-hydride shifts and result in
the formation of products that contain six-membered rings.6
As part of a program aimed at developing redox-neutral
reaction cascades for the rapid buildup of molecular complexity,7
we considered a new reaction cascade design in which an initial
1,5-hydride shift would ultimately result in the formation of
larger rings. As outlined in Figure 2, the acid-catalyzed reaction of
aldehyde 1 with a doubly nucleophilic compound is envisioned
to initially result in the formation of the activated species 5.
Subsequent to intramolecular hydride transfer, the resulting
intermediate 6 could react with the pendant nucleophile. Proton
loss would then result in the formation of product 7.
Figure 2. Design of a new redox-neutral reaction cascade.
(partially) saturated rings onto simple indoles is relatively rare in
cases where indole retains its aromaticity. This is particularly true for
annulations with larger than six-membered rings.11
Given the importance of indole in medicinal chemistry,12 the
prospect of rapidly generating new indole-containing molecular
frameworks appeared particularly appealing. Reaction of an appro-
priate aminobenzaldehyde with indole should result in one-step
formation of azepinoindoles such as 8. The azepinoindole sub-
structure is found in a numberofnatural products (e.g., arboflorine
and subincanadine F) and biologically active drug candidates.13
We initiated our studies by investigating the reaction of in-
dole with aminobenzaldehyde 9a under a variety of conditions. Not
surprisingly, a reaction conducted in ethanol at room temperature led
to the formation of the bis(indolyl)methane 10a in 62% yield
(eq 1).14 As outlined in eq 2, using very similar conditions but higher
reaction temperatures (reflux in n-butanol) resulted in the unexpected
formation of the reduced product 11a (vide infra). Gratifyingly, the
Due to its known nucleophilic properties, it occurred to us that
indole should be able to serve as a double nucleophile in the proposed
sequence.8 Such a reaction would constitute a new one-step indole
annulation. Whereas indole annulations to form carbazoles are
numerous9 and indole annulations that lead to dearomatization of
the indole nucleus have been reported,10 direct annulation of
Received: November 29, 2010
Published: January 31, 2011
r
2011 American Chemical Society
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desired product 12a could be obtained in a reaction conducted in toluene
under reflux and in the presence of catalytic amounts of p-toluenesulfonic
acid (p-TSA). However, the azepinoindole 12a was obtained in only 24%
yield, and its formation was accompanied by the generation of product
11a in 29% yield (eq 3). In addition, small amounts (7%) of the
bis(indolyl)methane 10a were isolated as well (not shown).
Table 1. Evaluation of Reaction Parametersa
entry
catalyst (equiv)
solvent yield of 12a (%) yield of 11a (%)
1
2
3
4
5
6
7
8
9
p-TSA (0.1)
PhMe
PhMe
PhMe
PhMe
PhMe
56
20
trace
54
trace
0
13
CF3COOH (1.2)
CH3SO3H (0.2)
CSA (0.1)
30
trace
9
HBF4 OEt2 (0.1)
trace
3
4-Br-pyr HCl (0.1) PhMe
0
0
0
4
4
4
6
6
4
3
H3PO4(1.2)
PhCOOH (0.2)
DPP (0.1)
PhMe
PhMe
PhMe
xylenes
C2H4Cl2
PhMe
PhMe
PhMe
0
0
81
69
40
79
73
83
10b DPP (0.1)
11 DPP (0.1)
12c DPP (0.1)
13d DPP (0.1)
14
DPP (0.2)
a Reactions were performed on a 0.25 mmol scale. b Reaction was
run at 170 °C. c Reaction was run with 1.1 equiv of indole. d Reaction
was run with 1.3 equiv of indole.
Various other reaction conditions were evaluated in order to im-
prove the overall efficiency of this reaction and to maximize the yield
of the desired product 12a. As part of this study, we found that reac-
tions conducted under microwave irradiation produced particularly
promising results and allowed for conveniently short reaction times.
Different acid additives are summarized in Table 1. Optimal
results were obtained with 20 mol % of diphenyl phosphate
(DPP) in toluene (entry 14).15 Under these conditions, the
indole annulation product 12a was obtained in 83% yield, and
formation of the undesired product 11a was almost completely
suppressed. A reaction conducted at reflux in toluene but in
otherwise identical conditions went to completion within 3 h. In
this instance, 12a was obtained in 57% yield in addition to 10a
(25%) and 11a (10%). The corresponding reaction in refluxing
xylenes gave 12a (60%), 10a (13%) and 11a (11%) after 2 h.
With the optimized reaction conditions at hand, a number
of other readily available indoles were allowed to react with
aminobenzaldehyde 9a, including relatively electron-rich and
electron-poor indoles. As summarized in Chart 1, the corre-
sponding annulation products 12 were obtained in good yields.
The structure of the N-methylindole-derived product 12f was
confirmed further by X-ray crystallography.
Chart 1. Scope of the Indole Componenta
The scope of the indole annulation with regard to the amino-
benzaldehyde is shown in Chart 2. A number of aminobenzaldehydes
underwent reaction with indole to yield the expected products 14
in good to excellent yields. Minor amounts of the corresponding
reduced products were isolated in some instances. In case of
the 2-methylpyrrolidine-derived aminobenzaldehyde 13e (not
shown), the resulting product 14e was obtained as a single regio-
isomer. The fact that the more substituted of the two possible
regioisomers was isolated is consistent with earlier observa-
tions7b,c and with the notion that a tertiary C-H bond is a
better hydride donor than a secondary C-H bond. Interestingly,
the corresponding 2-methylpiperidine-derived product 14f was
obtained as a 4:1 mixture of regioisomers. However, the preference
for the formation of the more substituted product was main-
a Reactions were performed on a 0.25 mmol scale.
tained (minor regioisomer not shown, dr = 3:2). The structure of
14h was confirmed by X-ray crystallography.
The new cascade reaction was successfully extended to double
nucleophiles other than indole. As shown in eq 7, reaction of amino-
benzaldehyde 9a with 2,5-dimethylpyrrole resulted in formation
of the 3,4-pyrrole annulated benzazepine 15 in 59% yield.16
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Chart 2. Scope of the Aminobenzaldehyde Componenta
obtained in 33% yield as the only isolable product. As we have thus
far been unable to isolate the corresponding oxidation product of
12a, presumably due to its rapid decomposition, we devised an
alternative experiment to establish the potential of 12a to act as an
intermolecular hydride delivery agent. Indeed, as shown in eq 9, 12a
readily promoted the reduction of imine 17 to the corresponding
amine 18 in 70% yield (yield based on 12a).17 The product resulting
from the oxidation of 12a could not be isolated, and the reduced 11a
was not formed in this process.
Lastly, we wanted to establish that formation of the well-known
and easily formed bis(indolyl)methanes14 (e.g., 10a) does not nec-
essarily represent a dead end in this reaction. Rather, we speculated
that under acid-catalyzed conditions, compounds such as 10a might
be in equilibrium with the corresponding azafulvenium ions (e.g.,
19), presumed intermediates in the formation of the annulation
products. Indeed, exposure of 10a to the original reaction conditions
gave rise to the formation of annulation product 12a in 85% yield,
accompanied by the expected recovery of indole in 84% yield
(Scheme 1). In addition, 11a was formed in 5% yield (not shown).
Scheme 1. Transformation of a Bis(indolyl)methane into an
Azepinoindole
a Reactions were performed on a 0.25 mmol scale.
In preliminary work, we considered entirely different double nucleo-
philes. For instance, substrate 9a readily underwent reaction with
N,N0-diphenylhydrazine to form the interesting triaza-heterocycle 16
in 72% yield (eq 8). A reduced catalyst loading of 5 mol % was beneficial
in this case. The X-ray crystal structure of 16 was also obtained.
Here we have shown that reactions of doubly nucleophilic species such
as indoles with aminobenzaldehydes lead to unprecedented reaction
cascades. In this new redox-neutral process, a 1,5-hydride shift results in
formation of seven-membered ring products. The resulting indole-fused
benzazepines can be obtained in just two steps from commercially
available materials. Current studies are aimed at developing other redox-
neutral reaction cascades for rapid buildup of molecular complexity.
As outlined before, under certain reaction conditions, the forma-
tion of the desired annulation products was accompanied by varying
amounts of apparently reduced product (i.e., 11a) which in some
cases was the only isolable material. Considering that products such
as 12a could potentially act as hydride donors, we proposed that 12a
might promote its own reduction in an interesting type of dis-
proportionation reaction. In fact, we have observed that prolonged
reaction times under microwave irradiation led to reduced yields of
annulation products and the buildup of increased amounts of the
reduced products. Furthermore, when 12a was exposed to the
reaction conditions outlined in eq 2, the reduced product 11a was
’ ASSOCIATED CONTENT
S
Supporting Information. Complete ref 13e, experimen-
b
tal procedures, characterization data, and X-ray crystal structures
of 10a, 12f, 14h, and 16. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
seidel@rutchem.rutgers.edu
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’ ACKNOWLEDGMENT
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We are grateful to the National Science Foundation for support
of this research (Grant CHE-0911192). M.C.H. acknowledges
Celgene for generous support through a Celgene Drug Discovery
Fellowship. We thank Dr. Tom Emge for crystallographic analysis.
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(15) While the results in Table 1 indicate that the catalyst pKa is
certainly important, there appears to be no direct correlation between
catalyst activity and acidity. Acids with similar pKa’s (e.g., DPP and
phosphoric acid) gave vastly different results. We thus speculate that
catalyst reactivity might be partially dependent on catalyst solubility in
the nonpolar reaction medium (or on the corresponding solubility of
protonated starting material/product).
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(17) No reduction of 17 was observed in the absence of 12a.
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