N-Alkylation-Initiated Redox-Neutral [5 + 2] Annulation of 3-Alkylindoles with o-Aminobenzaldehydes: Access to Indole-1,2-Fused 1,4-Benzodiazepines

Article abstract of DOI:10.1021/acs.orglett.9b03011

Described herein is an unprecedented N-Alkylation-initiated redox-neutral [5 + 2] annulation of 3-Alkylindoles with o-Aminobenzaldehydes via a cascade N-Alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. A series of indole-1,2-fused 1,4-benzodiazepines are facilely constructed in moderate to good yields in one step. This protocol features excellent regioselectivity, metal-free conditions, high step economy, and wide substrate scope.

Full text of DOI:10.1021/acs.orglett.9b03011

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N‑Alkylation-Initiated Redox-Neutral [5 + 2] Annulation of
3‑Alkylindoles with o‑Aminobenzaldehydes: Access to Indole-1,2-
Fused 1,4-Benzodiazepines
Shuai Wang,†,∥ Yao-Bin Shen,†,∥ Long-Fei Li,† Bin Qiu,† Liping Yu,*,§ Qing Liu,⊥ and Jian Xiao*,†,‡
†Shandong Province Key Laboratory of Applied Mycology, College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural
University, Qingdao 266109, China
‡College of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
§College of Landscape Architecture and Forestry, Qingdao Agricultural University, Qingdao 266109, China
⊥College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao 266590, China
S
* Supporting Information
ABSTRACT: Described herein is an unprecedented N-alkylation-
initiated redox-neutral [5 + 2] annulation of 3-alkylindoles with o-
aminobenzaldehydes via a cascade N-alkylation/dehydration/[1,5]-
hydride transfer/Friedel−Crafts alkylation sequence. A series of
indole-1,2-fused 1,4-benzodiazepines are facilely constructed in
moderate to good yields in one step. This protocol features excellent
regioselectivity, metal-free conditions, high step economy, and wide substrate scope.
ndole-fused polycyclic architectures are attractive synthetic
and acceptors. Among the elegant approaches in which the
hydride acceptors are fabricated in situ, an acid-catalyzed
redox-neutral indole annulation cascade was developed for the
synthesis of polycyclic azepinoindoles under microwave
irradiation.10c It is observed that o-aminobenzaldehydes can
serve as five-membered annulation synthons bearing two
electrophilic sites, one aldehyde moiety, and another potential
iminium ion species. Thus, we assume that the acid-catalyzed
redox-neutral [5 + 2] annulation of o-aminobenzaldehydes
with 3-alkylindoles might occur via a cascade N-alkylation/
dehydration/[1,5]-hydride transfer/Friedel−Crafts alkylation
process, thus delivering indole-1,2-fused 1,4-benzodiazepines.
Nevertheless, the main challenge of this transformation lies in
the regioselectivity of the initial alkylation step, since the
intrinsically weaker nucleophilicity of N1 position than that of
the C2 and C3 positions would render the acid-catalyzed N1-
alkylation much more difficult.13 As a result of our continuous
interest in the construction of bioactive complex molecules via
hydride transfer,6 herein, we report the facile synthesis of
indole-1,2-fused 1,4-benzodiazepines via N-alkylation-initiated
redox-neutral [5 + 2] annulation between 3-alkylindoles and o-
aminobenzaldehydes under the catalysis of a Brønsted acid
(see Scheme 1d).
1,2 In
Itargets in the organic community and medical industry.
particular, indole-1,2-fused 1,4-benzodiazepines and their
derivatives, comprising privileged indole and benzodiazepine
skeletons, have drawn tremendous attention as pharmaceuti-
cally important molecules (see Scheme 1a).3 For instance,
compound I has been identified as a type of antihypertensive.3a
Despite their bioactive significance, only sporadic synthetic
routes have been disclosed to access these scaffolds over the
past decades.4 Unfortunately, these limited examples are
largely dependent on burdensome multistep operations and
harsh reaction conditions, resulting in low efficiency and
unsatisfactory step economy and atom economy, which sets a
barrier for their practicability in synthetic chemistry and drug
discovery (see Scheme 1b). As is well-known, the annulation of
indole derivatives has been a powerful tool for the assembly of
indole-fused polyheterocycles.2 Therefore, an ideal way to
construct indole-1,2-fused 1,4-benzodiazepines would be to
explore a new class of five-membered annulation reagents
carrying two electrophilic sites to undergo [5 + 2] annulation
with the N1 and C2 positions of indoles in a one-step manner
(see Scheme 1c). However, to the best of our knowledge, such
annulation reaction remains quite challenging and has never
been documented to date.
Initially, we commenced our investigation of the [5 + 2]
annulation between 3-methylindole 1a and 2-(pyrrolidin-1-
yl)benzaldehyde 2a in the presence of 20 mol % of
trifluoromethanesulfonic acid (TfOH) in CHCl3 at 80 °C.
To our delight, the desired indole-1,2-fused 1,4-benzodiaze-
pine product 3a was afforded in 29% yield (see Table 1, entry
Recent years have witnessed the renaissance of hydride
transfer-involved redox-neutral annulation reactions, which
enable the production of various biologically important
multiring systems via the direct functionalization of inert
C(sp3)−H bonds.5 Because of the high efficiency of this type
of annulation in building molecular complexity, our group6 and
the others7−12 have developed multifarious hydride transfer-
involved annulations by using different types of hydride donors
Received: August 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of Indole-1,2-Fused 1,4-
Benzodiazepines via N-Alkylation-Initiated Redox-Neutral
[5 + 2] Annulation
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
solvent
temperature (°C)
yield (%)
1
2
3
4
5
6
7
8
9
TfOH
MsOH
TFA
PA
Sc(OTf)3
InBr3
BF3·Et2O
PA
PA
PA
PA
PA
PA
PA
PA
PA
PA
PA
DPP
−
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
80
80
80
80
80
80
80
80
80
80
80
80
100
60
40
80
80
80
80
80
29
49
33
60
39
26
41
38
36
9
toluene
THF
10
11
12
13
14
15
c
DMSO
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
n.r.
82
79
71
38
82
d
16
e
f
17
89 (79)
g
18
e
64
84
1). Various Brønsted acids and Lewis acids then were tested,
and 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (PA)
exhibited the best efficiency to furnish 3a in 60% yield
(Table 1, entries 2−7). The subsequent screening of solvents
showed that the yield could be elevated to 82% in DCM
(Table 1, entries 8−12). However, increasing or decreasing the
temperature led to inferior outcomes (Table 1, entries 13−15).
Afterward, the additive effect was examined and it was found
that anhydrous Na2SO4 gave a higher yield (Table 1, entries
16−18). In addition, other phosphate such as diphenyl
phosphate (DPP) provided 3a in 84% yield (Table 1, entry
19). Finally, the control experiment without any catalyst
resulted in no reaction, demonstrating the vital role of catalyst
(Table 1, entry 20). Thus, the employment of 20 mol % of PA
as a catalyst and 1.2 equiv of anhydrous Na2SO4 as an additive
in DCM at 80 °C was chosen as the optimal reaction
conditions.
With the optimized reaction conditions in hand, the
substrate scope of this redox-neutral [5 + 2] annulation was
investigated (Scheme 2). Generally, the reactions of a variety
of 3-alkylindoles with o-aminobenzaldehydes proceeded
smoothly to give the desired indole-1,2-fused 1,4-benzodiaze-
pines in moderate to good yields. With respect to 3-
alkylindoles, both the electron-donating (−MeO, −BnO, and
−Me) and the electron-withdrawing (−F, −Cl, and −Br)
substituted substrates reacted readily with 2-(pyrrolidin-1-
yl)benzaldehyde 2a, providing the corresponding products
3a−3i in 34%−80% yields. Notably, the higher yields of 3b−
3d than 3e−3i might be ascribed to the fact that the electron-
donating groups would help enhance the nucleophilicity of
indole moieties and stabilize the in-situ-generated carbenium
intermediates. Moreover, 3-isopropylindole was compatible
with the reaction conditions to furnish the adduct 3j in a
relatively lower yield, presumably because of the steric
19
e
c
20
n.r.
a
Unless otherwise noted, reactions were performed with 1a (0.2
mmol), 2a (0.6 mmol), and catalyst (0.04 mmol) in 1 mL of solvent
at the indicated temperature for 24 h. Legend: PA = 1,1′-binaphthyl-
2,2′-diyl hydrogen phosphate, DPP = diphenyl phosphate, DCE =
dichloroethane, THF = tetrahydrofuran, and DCM = dichloro-
methane. GC yield. n.r. = no reaction. With the addition of
anhydrous MgSO4 (0.24 mmol). With the addition of anhydrous
b
c
d
e
f
g
Na2SO4 (0.24 mmol). Isolated yield. With the addition of 4 Å MS
(50 mg).
hindrance in the final Friedel−Crafts alkylation step.
Impressively, the symmetrical 3,3′-diindolylmethane with two
indole motifs was also applicable to this transformation,
delivering 3k in 71% yield. As for o-aminobenzaldehydes,
various substituents (−Me, −CF3, −F, −Cl, and −Br) at
different positions of the benzene ring were well-tolerated and
the expected products 3l−3p were obtained in 49%−83%
yields. To broaden the scope, different types of hydride donors
were also examined. Interestingly enough, the use of
nonsymmetrical 2-methylpyrrolidine and methyl prolinate as
hydride donors led to the production of 3q and 3r in
acceptable yields. Varying five-membered pyrrolidine to six-
membered piperidine gave rise to 3s in 56% yield. Given the
vital role of tetrahydroisoquinoline in synthetic chemistry and
drug discovery,14 2-(3,4-dihydroisoquinolin-2(1H)-yl)-
benzaldehydes carrying −OMe, −F, −Cl, or −Br substituents
were also tested, all of which worked very well to give adducts
3t−3x in 62%−81% yields. The structure of 3u has been
unambiguously confirmed by X-ray crystallography. Pleasingly,
the substrate with seven-membered hexamethylenimine was
also a good candidate for this catalytic system, furnishing
B
DOI: 10.1021/acs.orglett.9b03011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope
Scheme 3. Gram-Scale Synthesis of 3a
labeling experiment were executed, as shown in Scheme 4.
When the N1-position of 3-methylindole was protected with
Scheme 4. Control Experiments and Deuterium Labeling
Experiment
the methyl group, the initial N-alkylation step was obstructed,
resulting in no observation of the desired product (see Scheme
4a). The occupation at the C2-position of 3-methylindole by
the methyl group also led to no desired product, which might
be due to the prohibition of the final Friedel−Crafts alkylation
process (see Scheme 4b). However, it was noted that 2-
(pyrrolidin-1-yl)benzaldehyde 2a itself undertook the acid-
catalyzed domino [1,5]-hydride transfer/cyclization reaction
and gave the product benzoxazine 5 (see Schemes 4a and
4b).11d When the deuterated substrate [D]-2a was subjected to
the standard conditions, the corresponding product [D]-3a
was obtained in 70% yield (Scheme 4c). The complete transfer
of the deuterium label to the benzylic position fully
corroborated the occurrence of [1,5]-hydride transfer event.
On the basis of the above experimental results and literature
precedents, a plausible mechanism was proposed to rationalize
this redox-neutral [5 + 2] annulation reaction (see Scheme 5).
Under the catalysis of PA, the N-alkylation of 3-methylindole
1a with 2-(pyrrolidin-1-yl)benzaldehyde 2a occurs to deliver
the 1-indolylmethanol A, which subsequently undergoes
protonic acid-catalyzed dehydration to afford the carbocation
intermediate B. The carbocation intermediate B then induces
the intramolecular [1,5]-hydride transfer to give the iminium
ion intermediate C. Finally, the intramolecular Friedel−Crafts
alkylation operates to afford the desired product 3a.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), PA (0.04 mmol),
and Na2SO4 (0.24 mmol) in 1 mL of DCM at 80 °C for 24 h. Isolated
b
yields after column chromatography; n.d. = not detected. dr >20:1;
the dr was determined by H NMR analysis.
1
indole-1,2-fused 1,4-benzodiazepine 3y in acceptable yield.
Note that the success of halogen-substituted substrates would
provide a handle for further manipulation via transition-metal-
catalyzed cross-coupling reactions. However, to our disap-
pointment, 2-morpholinobenzaldehyde and indoles bearing
electron-withdrawing (−CN, −NO2, −CHO, and −Br)
substituents at the C3 position failed to give the desired
products.
To verify the synthetic practicability of the current
methodology, a gram-scale reaction of 3-methylindole 1a
with 2-(pyrrolidin-1-yl)benzaldehyde 2a was conducted, and
the desired indole-1,2-fused 1,4-benzodiazepine 3a was
obtained in 72% yield (see Scheme 3).
In summary, we have developed an unprecedented N-
alkylation-initiated redox-neutral [5 + 2] annulation of 3-
alkylindoles with o-aminobenzaldehydes via the cascade N-
alkylation/dehydration/[1,5]-hydride transfer/Friedel−Crafts
alkylation process. A variety of indole-1,2-fused 1,4-benzodia-
zepines, the antihypertensive analogues, were facilely con-
structed in moderate to good yields in one step. This step- and
atom-economical protocol featured excellent regioselectivity,
metal-free conditions, and a wide substrate scope, highlighting
In order to shed light on the mechanism of this
transformation, some control experiments and a deuterium
C
DOI: 10.1021/acs.orglett.9b03011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Proposed Mechanism
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03011.
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General experimental procedures, characterization and
NMR spectra of all compounds (PDF)
Accession Codes
CCDC 1951669 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chemjianxiao@163.com.
*E-mail: lipingyu99@163.com.
ORCID
Jian Xiao: 0000-0003-4272-6865
Author Contributions
∥S. Wang and Y.-B. Shen contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSFC (No. 21878167) and the Natural
Science Foundation of Shandong Province for Distinguished
Young Scholars (No. JQ201604). The Key Research and
Development Program of Shandong Province (No.
2017GSF218073) and Qingdao Special Research Foundation
of Science and Technology (No. 19-6-1-38 nsh) as well as The
First Class Fishery Discipline Programme of Shandong
Province are also gratefully acknowledged. We thank the Dr.
Feng-Ying Dong (Central Laboratory of Qingdao Agricultural
University) for NMR determination.
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