Domino C-N bond formation via a palladacycle with diaziridinone. An approach to indolo[3,2- b]indoles

Article abstract of DOI:10.1021/acs.orglett.1c00466

Palladium-catalyzed C-N bond formation is one of the widely used transformations for the synthesis of structurally diverse N-heterocycles. This work describes an efficient palladium-catalyzed multiple-C-N bond formation reaction for the synthesis of highl

Full text of DOI:10.1021/acs.orglett.1c00466

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Domino C−N Bond Formation via a Palladacycle with Diaziridinone.
An Approach to Indolo[3,2‑b]indoles
Sudarshan Debnath, Lingli Liang, Mei Lu, and Yian Shi*
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ABSTRACT: Palladium-catalyzed C−N bond formation is one of the
widely used transformations for the synthesis of structurally diverse N-
heterocycles. This work describes an efficient palladium-catalyzed
multiple-C−N bond formation reaction for the synthesis of highly π-
conjugated N-heterocycles, indolo[3,2-b]indoles with di-tert-butyldiazir-
idinone. The reaction likely proceeds through the initial formation of an
indole-fused palladacycle by nucleophilic aminopalladation and
subsequent bisamination to give indolo[3,2-b]indoles.
−N bond formation is an important transformation in
detected. To our delight, when substrate 7a with NMe2 as
the nucleophile was subjected to the reaction conditions [di-
tert-butyldiaziridinone (1) (1.5 equiv), Pd(PPh3)4 (5 mol %),
and Cs2CO3 (1.5 equiv) in DMF at 110 °C for 48 h], the
envisioned indolo[3,2-b]indole 10a was formed in 62% NMR
yield (Table 1, entry 1). Encouraged by this result, we
subsequently screened various ligands with Pd(OAc)2 as the
catalyst (Table 1, entries 2−16). PPhCy2 was found to be the
best ligand, giving product 10a in 95% isolated yield (Table 1,
entry 11). With PPhCy2 as the ligand, Pd(OAc)2 appeared to
be the choice of the catalyst (Table 1, entries 11 and 17−19).
Other bases (Table 1, entries 20−22) and solvents (Table 1,
entries 23−25) were found to be less effective for the reaction.
The reaction temperature appeared to be important. A lower
yield was obtained when the reaction was carried out at a lower
(100 °C) or higher (130 °C) temperature (Table 1, entry 26
or 27, respectively).
With an optimized protocol in hand, the substrate scope was
subsequently investigated. Bromide 7a′ was also shown to be
an effective substrate, while a slightly lower yield was obtained
compared to that of iodide 7a (Table 2, entry 1). The
bromides were used as substrates in cases in which the
corresponding iodides were less accessible. As shown in Table
2, the reaction process can be extended to various substituted
iodides and bromides, giving a variety of substituted indolo-
[3,2-b]indoles in 52−93% yields. Substrates bearing sub-
stituents such as Me, Cl, and CF3 groups on the phenyl rings
containing the halogen (Br or I) were effective under the
C
organic synthesis.1 The palladium-catalyzed reaction
process plays a crucial role in this field and has constantly
received attention. In our own studies, we have found that di-
tert-butyldiaziridinone (1) is a class of versatile reagent for
amination. In addition to diamination of olefins (Scheme 1, eq
a),2 it can also effectively react with palladacycles 4 to generate
azacycles 6 likely via a Pd(IV) intermediate 5 (Scheme 1, eq
b).3−5 In this bisamination process, two C−N bonds are
simultaneously formed.
In general, most reported palladacycles are formed through
C−H activation.6 To expand the synthetic utility of our
bisamination process, there has been search for different ways
to generate palladacycles, which could be intercepted in situ by
the diaziridione to form structurally diverse azacycles. Along
this line, we have been investigating whether indole-fused
palladacycle 9 could be formed via intramolecular nucleophilic
aminopalladation of palladium species 8 and could be further
intercepted by di-tert-butyldiaziridinone (1) to form the
second indole moiety (Scheme 1, eq c). The indole synthesis
from 2-alkynylanilines has been extensively studied.7,8 For
example, when 2-alkynylanilines are treated with ArPdX, an
intermolecular nucleophilic aminopalladation leads to the
formation of the 3-palladaindoles, which give 3-aryl-substituted
indoles upon reductive elimination (Scheme 2).7 However, an
intramolecular version of this process (8 to 9) has been
unexplored. The envisioned process as described in Scheme 1
(eq c) could lead to the overall formation of indolo[3,2-
b]indoles 10, an important class of molecules that may possess
unique electronic properties and could be used for functional
materials.9,10 Herein, we report our preliminary studies of this
subject.
Received: February 8, 2021
Published: April 22, 2021
In our initial studies, various nitrogen nucleophiles,
including NH2, NHCOCF3, NHMs, NHTs, NMeMs, and
NMeTs, were examined (Scheme 3). The results were
somewhat disappointing, and no desired products were
https://doi.org/10.1021/acs.orglett.1c00466
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3237−3242
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Scheme 1. Diamination and Bisamination with Di-tert-
Scheme 3. Initial Studies of Nitrogen Nucleophiles
butyldiaziridinone
a
Table 1. Studies of the Reaction Conditions
b
entry
Pd catalyst
ligand
yield (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
PPh3
62
36
33
6
46
41
−
41
12
31
P(p-tolyl)3
P(o-tolyl)3
P(p-FPh)3
P(p-MeOPh)3
P(C6F5)3
P(p-CF3Ph)3
P(o-furyl)3
PCy3
PPhCy2
PPh2Cy
dppe
dppb
dppf
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
c
99 (95)
60
18
43
25
11
44
53
47
57
37
−
44
23
32
50
65
BINAP
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
PPhCy2
d
reaction conditions, affording the corresponding products
10b−e in 70−91% yields (Table 2, entries 2−5, respectively).
Substituents like Me, Ph, F, Cl, CN, CO2Me, and NO2 groups
on the phenyl rings containing the NMe2 were found to be
compatible with the reaction, generating the corresponding
indolo[3,2-b]indoles 10f−l in 52−85% yields (Table 2, entries
6−12, respectively). Substrate 7m with N,N-dimethylnaph-
thalen-1-amine also underwent the reaction smoothly to give
product 10m in 77% yield (Table 2, entry 13). The reaction
can also effectively apply to substrates bearing different
substituents in both phenyl rings, providing various substituted
indolo[3,2-b]indoles 10n−u in 69−93% yields (Table 2,
entries 14−21, respectively). A substrate with a diethylamine
group (7v) was also effective for the reaction, giving product
10v in 78% yield (Table 2, entry 22).
e
f
g
h
i
j
k
a
All reactions were carried out with 7a (0.15 mmol), Pd (0.0075
mmol), ligand (0.015−0.030 mmol; 1:4 Pd:P), di-tert-butyldiazir-
idinone 1 (0.225 mmol), and Cs2CO3 (0.225 mmol) in DMF (2 mL)
at 110 °C under N2 for 48 h unless otherwise stated. The yields were
determined by H NMR analysis of the crude reaction mixture using
b
1
c
d
PhCH2OCH3 as the internal standard. Isolated yield. With K2CO3.
e
f
g
h
i
With Na2CO3. With KOAc. In MeCN. In 1,4-dioxane. In PhCH3.
j
k
At 100 °C. At 130 °C.
As exemplified with 7a, the reaction can be carried out on a
gram scale (Scheme 4). The removal of a tert-butyl group for
10a was achieved with trifluoroacetic acid (TFA) and n-
hexane, affording indolo[3,2-b]indole 10a′ in 86% yield
(Scheme 5). Gratifyingly, highly conjugated bisindolo[3,2-
b]indole 10w was achieved from 7w via double-reaction
processes (Scheme 6).
Scheme 2. Palladium-Catalyzed Indole Formation from 2-Alkynylanilines
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a
Table 2. Substrate Scope
Scheme 4. Gram Scale Reaction with Substrate 7a
Scheme 5. Removal of the tert-Butyl Group of Product 10a
Scheme 6. Formation of Highly Conjugated Bisindolo[3,2-
b]indole
A precise understanding of the reaction mechanism requires
further study. On the basis of earlier studies,3 a plausible
catalytic cycle is proposed in Scheme 7 (with 7a as an
example). The process starts with the coordination of the
Pd(0) to the substrate (7a), followed by the oxidative addition
of the Pd(0) to the C−I bond to give Pd(II) species 15 (path
Scheme 7. A Proposed Catalytic Cycle
a
All reactions were carried out with 7 (0.30 mmol), Pd (0.015 mol),
PPhCy2 (0.060 mmol), 1 (0.45 mmol), and Cs2CO3 (0.45 mmol) in
b
DMF (3 mL) at 110 °C under N2 for 48 h. Isolated yield (%).
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a), which undergoes nucleophilic aminopalladation and
demethylation to form indole-fused pallada(II)cycle 17. The
oxidative addition of 17 to di-tert-butyldiaziridinone (1) gives
pallada(IV)cycle 18, which is converted to pallada(IV)nitrene
species 19 with release of tBuNCO. Indolo[3,2-b]indole 10a is
formed from 19 by two consecutive reductive eliminations via
20a or 20b with regeneration of the Pd catalyst. Alternatively,
the Pd(0) could be oxidatively inserted into the N−N bond of
di-tert-butyldiaziridinone (1) to form four-membered Pd
species 21 (path b). The oxidative addition of 21 to substrate
7a gives Pd intermediate 22, which is converted to pallada-
(IV)cycle 18, upon nucleophilic aminopalladation and
subsequent demethylation.
In summary, we have developed an efficient palladium-
catalyzed nucleophilic aminopalladation and bisamination
sequence with 2-[(2-haloaryl)ethynyl]-N,N-dialkylanilines (7)
and di-tert-butyl-diaziridinone (1), affording a wide variety of
substituted indolo[3,2-b]indoles in 52−93% yields. To the best
of our knowledge, this is the first example in which an indole-
fused palladacycle is formed through intramolecular nucleo-
philic aminopalladation to form overall two rings with
generation of three C−N bonds. Highly conjugated linear
bisindolo[3,2-b]indole can also be achieved via the afore-
mentioned process. Further exploration of new reaction
processes with the indole-fused palladacycle is currently
underway.
https://pubs.acs.org/10.1021/acs.orglett.1c00466
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the National Natural
Science Foundation of China (21632005) and Changzhou
University for financial support.
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ASSOCIATED CONTENT
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Experimental procedures, characterization data, and
NMR spectra (PDF)
Accession Codes
CCDC 2051396 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.
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AUTHOR INFORMATION
Corresponding Author
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11280−11284.
Yian Shi − Institute of Natural and Synthetic Organic
Chemistry, Changzhou University, Changzhou 213164,
China; Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523, United States; orcid.org/
0000-0001-9016-2078; Email: shiyian@cczu.edu.cn,
yian.shi@colostate.edu
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Authors
Sudarshan Debnath − Institute of Natural and Synthetic
Organic Chemistry, Changzhou University, Changzhou
213164, China; orcid.org/0000-0001-7122-2135
Lingli Liang − Institute of Natural and Synthetic Organic
Chemistry, Changzhou University, Changzhou 213164,
China
Mei Lu − Institute of Natural and Synthetic Organic
Chemistry, Changzhou University, Changzhou 213164,
China
Complete contact information is available at:
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