Copper-Catalyzed N,N-Diarylation of Amides for the Construction of 9,10-Dihydroacridine Structure and Applications in the Synthesis of Diverse Nitrogen-Embedded Polyacenes

Article abstract of DOI:10.1021/acs.orglett.0c01775

We reported herein CuI/DMEDA catalyzed N,N-diarylation reaction of amides with various di(o-bromoaryl)methanes to produce diverse 9,10-dihydroacridine derivatives. The resulting 9,10-dihydroacridine derivatives were oxidized selectively under mild conditions to afford acridine, acridinone, and acridinium derivatives. The copper-catalyzed N,N-diarylation reaction coupled with oxidative aromatization reaction enabled the facile construction of nitrogen atom-embedded tetracenes and pentacenes of different ortho-fused patterns. The luminescence properties, especially the effect of fusion pattern on fluorescence emission of acquired N-polycenes, were also demonstrated.

Full text of DOI:10.1021/acs.orglett.0c01775

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Letter
Copper-Catalyzed N,N-Diarylation of Amides for the Construction of
9,10-Dihydroacridine Structure and Applications in the Synthesis of
Diverse Nitrogen-Embedded Polyacenes
Mei-Ling Tan, Shuo Tong,* Sheng-Kai Hou, Jingsong You, and Mei-Xiang Wang*
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ABSTRACT: We reported herein CuI/DMEDA catalyzed N,N-diarylation
reaction of amides with various di(o-bromoaryl)methanes to produce diverse
9,10-dihydroacridine derivatives. The resulting 9,10-dihydroacridine derivatives
were oxidized selectively under mild conditions to afford acridine, acridinone,
and acridinium derivatives. The copper-catalyzed N,N-diarylation reaction
coupled with oxidative aromatization reaction enabled the facile construction
of nitrogen atom-embedded tetracenes and pentacenes of different ortho-fused
patterns. The luminescence properties, especially the effect of fusion pattern on
fluorescence emission of acquired N-polycenes, were also demonstrated.
9,10-Dihydroacridine occurs as a privileged heterocyclic
structure in material science.1 It serves as well as the
intermediate for the synthesis of acridones, acridines, and
acridinium salts and, thus, has wide applications in the
pharmaceutical industry,2 catalysis,3 and dye chemistry.4
Simple 9,10-dihydroacridines are obtained predominantly by
means of the reduction of the corresponding acridines or
acridones.5 For the synthesis of functionalized 9,10-dihydroa-
cridine derivatives, however, multistep reactions involving
functional group transformations are generally required. They
suffer from either tedious stepwise chemical manipulations,
narrow substrate scope, poor functional group tolerance, or
low overall chemical yields, restricting their application in the
synthesis.1,6 New and efficient methods of general synthetic
applicability are therefore highly desirable. We report herein a
novel strategy to construct the 9,10-dihydroacridine structure
and its wide synthetic applications. We envisioned that the
copper-catalyzed double N,N-arylation of primary amides with
di(2-bromophenyl)methane derivatives would provide a
straightforward route to a wide variety of N-acyl-9,10-
dihydroacridine derivatives. The acyl functionality would not
only stabilize the products but offer a versatile handle allowing
the development of molecular diversity. Coupled with
oxidative aromatization, the method would enable the
synthesis of diverse N-embedded extended π-systems that are
inaccessible by other means.
development, Cu-catalyzed arylation reactions of amines,
aromatic nitrogen heterocycles, amides, and lactams have
become powerful and spectacular synthetic tools widely used
in both academia and industry.7 However, despite a plethora of
N-arylation reactions documented in literature, the copper-
catalyzed N,N-diarylation of primary amides is virtually
unknown.8,9 This is not surprising because the until now
existing method was normally designed for mono N-arylation.
The development of a catalyst system which could combine
the coupling reactions of both the primary and secondary
amides still remains a big challenge and is of great importance.
We began our study with the examination of copper-
catalyzed reaction using di(2-bromophenyl)methane (1a) and
acetamide (2a) as testing substrates. Inspired by Buchward’s
pionieering work of the copper-catalyzed N-arylation of N-aryl
amide derivatives,9a,b we first heated a toluene solution of 1a
and 2a (c = 0.2 M) under the standard Buchwald amidation
conditions (CuI, DMEDA, K2CO3) at 100 °C for 24 h. To our
delight, 9,10-dihydroacridine 3a indeed formed albeit in a very
low yield (20%). From the reaction mixture, mono N-arylation
product 4a was also isolated in 10% yield as the only
byproduct. The preliminary results indicated that the
Received: May 26, 2020
Copper-catalyzed C−N bond forming reactions have been
drawing substantial attention because of the cost-effectiveness
and increased environmentally friendliness of copper in
comparison to noble metals. After more than a century of
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intermolecular mono N-arylation of 1a and the subsequent
intramolecular N-arylation of the resulting secondary amide
intermediate 4a were compatible under the copper-catalyzed
coupling conditions employed (Scheme 1). To channel the
Scheme 2. Scope of the Double N,N-Arylation Reaction for
the Synthesis of 9,10-Dihydroacridine Derivatives 3
Scheme 1. Reaction Design and Optimized Reaction
Conditions
reaction toward the formation of 3a, we carried out a
systematic survey of the reaction conditions by varying the
copper salts, ligands, bases, reaction media, and the temper-
ature (cf. the Supporting Information for details). Overall, the
optimum conditions included heating a solution of 1a (1
equiv) and 2a (1 equiv) in toluene (c = 0.2 M) at 140 °C in
the presence of CuI (0.1 equiv), L (0.3 equiv), and K2CO3 (3
equiv). Under these conditions, 3a was isolated in 91% yield. It
is worth noting that neither compound 4a from mono N-
arylation of 1a nor compound 5 from the competing double
intermolecular N-arylation of 1a was formed, suggesting the
consecutive intramolecular N-arylation of 4a proceeded
preferentially and much faster than the mono N-arylation step.
With the optimized conditions in hand, the scope of this
copper-catalyzed N,N-diarylation reaction was examined. As
shown in Scheme 2, bis(2-bromophenyl)methane moieties 1
bearing an electron-donating (Me, MeO) and electron-
withdrawing group (F, Cl, CO2Me, CN) at different positions
were well accepted as substrates, leading to 9,10-dihydroacri-
dine derivatives 3b−g in 70−93% yields. Symmetrically (1h,
1i) and asymmetrically (1j) disubstituted 1 participated in the
reaction smoothly to afford the desired products 3h, 3i, and 3j
in good to excellent yields. Bis(2-bromophenyl)benzyloxyl-
methylene (1k) was also accepted as an excellent substrate,
and the reaction furnished 3k in 90% yield. It was truly
remarkable that a range of various functional groups such as
halide, ester, cyano, and benzyl ether group (OBn) were
compatible with the reaction conditions, rendering the method
valuable in the synthesis of diverse functionalized 9,10-
dihydroacridines. In addition, besides acetamide (2a), primary
aliphatic amides with a benzyl (2l), an n-pentanyl (2m), and a
sterically bulky t-Bu (2n) group followed the same reaction
route to produce the corresponding N-acylated heterocyclic
products in 43−86% yields.
a
L (40 mol %).
further validated by the reaction of aniline with 1a under the
otherwise identical conditions, in which no formation of 10-
phenyl-9,10-dihydroacridine was observed. It is worth
emphasizing that the aniline moiety in the resulting product
3u provides a very versatile transformable functional group for
further functionalization (Scheme 2).
The advantage of using primary amides as the building
blocks to construct 9,10-dihydroacridines was evident, as the
N-acetyl group provided a versatile handle for postcyclization
modifications. As depicted in Scheme 3, removal of the acetyl
group of 3j under basic conditions (NaOMe, MeOH) afforded
the N-substituent-free 9,10-dihydroacridine 6 in nearly
quantitative yield. When acquired compound 6 was exposed
to air, it gradually underwent spontaneous oxidative aromatiza-
tion to form acridine 7. In order to accelerate this process, 2
equiv of ammonium ceric nitrate (CAN) were used as an
oxidant. The reaction proceeded rapidly to produce acridine 7
in 98% yield. Notably, the synthesis of 7 was conveniently
accomplished from a one-step direct oxidation from N-acetyl
9,10-dihydroacridine 3j under the same conditions using 2
equiv of CAN. Gratifyingly, increasing the amount of CAN
from 2 equiv to 4 equiv under otherwise identical conditions
led to the generation of acridinone 8 in 88% yield. In this case,
the methylene was oxidized into a carbonyl while the
acetamide remained intact. Finally, reduction of the acetyl of
3j to the ethyl group with lithium aluminum hydride (LiAlH4,
THF) took place smoothly to afford 9 (95% NMR yield),
Furthermore, N-alkoxycarbonyl-bearing 9,10-dihydroacri-
dine derivatives 3o−q were also synthesized when less reactive
primary carbamates 2o−q were applied as substrates. In the
case of 3q, 0.4 equiv of ligand L was needed to ensure the full
conversion of the reaction. Moreover, aromatic carboxamides
(1r−t) reacted analogously with 1a, providing high yields of
N-aryl-9,10-dihydroacridines 3r−t. Finally, when 4-amino-
benzamide 2u was subjected to the reaction, N,N-diarylation
occurred specifically on the amide nitrogen with the aniline
moiety remaining intact. The inertness of aromatic amine was
B
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Scheme 3. Synthetic Transformations of the N-Acetyl 9,10-
Dihydroacridine Products
Scheme 4. Synthesis of N-Embedded Tetracenes and
Pentacenes
a
a
Conditions: (a) NaOMe (5.0 equiv), MeOH, rt, overnight, >95%
1
yield (from crude H NMR); (b) ammonium ceric nitrate (CAN)
(2.0 equiv), acetone, rt, 2 h, 98% yield from 6 to 7; 82% yield from 3j
to 7; (c) CAN (4.0 equiv), acetone, rt, 0.5 h, 88% yield; (d) LiAlH4
(5.0 equiv), THF, reflux, 2 h, 95% NMR yield; (e) CAN (2.0 equiv),
acetone, rt, overnight; then NH4PF6 (2.0 equiv), acetone, 2 h, 78%
yield (for two steps); (f) CAN (2.0 equiv), acetone, rt, overnight, 38%
yield.
which was readily oxidized under controlled conditions to
produce either acridinium salt 10 or N-ethyl acridinone 11 in a
yield of 78% and 38%, respectively.
Linearly and angularly fused [n]acenes which contain
nitrogen atoms have attracted intensive attention mainly
because of their potential applications in optoelectronic
materials such as the n-type of organic field effect transistors
(OFETs).10,11 Embedment of nitrogen atom(s) into the
polycyclic aromatic hydrocarbons can efficiently lower the
molecule’s LUMO level as well as achieve an “umpolung” of
the electronic properties.12 Moreover, the optical, electronic,
and magnetic properties are highly dependent not only on the
molecular size and edge structure but also on the position of
the nitrogen atom(s) incorporated.13 For example, pyrazine-
condensed N-acenes have been constructed by several
synthetic methods and they show pronounced hole-trans-
porting properties.11 However, acenes containing a pyridine
unit have rarely been reported as functional materials14 due to
the likley lack of reliable synthetic methods.15,16 The
structure−property relationship of the pyridine-type N-acenes
remains unknown. The copper-catalyzed N,N-diarylation of
primary amides would provide a powerful and invaluable tool
to access an array of long-sought N-doped polyacenes if
appropriate di(o-bromoaryl)methane reactants are applied. To
further explore the synthetic potential and also to showcase the
advantage of the method developed, we conducted the
synthesis of N-embedded pyridine-type extended π-conjugated
molecules 14. As presented in Scheme 4, the copper-catalyzed
N,N-diarylation of primary amide 2a proceeded smoothly with
methylene-tethered bis(2-bromoarenes) 12 to give polyfused
dihydroacridine derivatives. For instance, 5-acetyl-5,12-
dihydrobenzo[b]acridine 13a and 12-acetyl-7,12-dihydro-
benzo[c]acridine 13b were prepared in good yields from the
corresponding 12a and 12b.
slightly reduced yield (32%) likely due to its steric hindrance.
Subsequent N-deacylation and oxidative aromatization af-
forded fully conjugated N-embedded pentacenes with different
geometries in moderate yields. For example, deprotection of
actyl of 13a, 13e, or 13f with NaOMe followed by oxidation
with CAN produced 14a, 14e, and 14f. In the case of 13d,
oxidative aromatization occurred spontaneously during the
workup of the reaction to remove the acetyl group, thus
forming 14d in an incredible high yield of 95%. A similar case
occurred in the synthesis of linear type benzoteracene 14c,
which, to the best of our knowledge, has never been reported
by other means. The molecular structures of N,N-diarylation
product 13c and linearly and angularly fused N-acenes 14a,
14d, and 14e were unambiguously confirmed by single crystal
X-ray diffraction analysis (Scheme 4).
A five-ring linearly fused compound dihydrodibenzoacridine
13c and its L-, S-, and C-shape isomers (13d, 13e, 13f) were
obtained successfully in a similar manner when reactants 12c,
12d, 12e, and 12f were applied, respectively. The synthesis
showed high efficiency except for 13f which was obtained in a
The resulting N-embedded π-conjugated hydrocarbon
ribbons 14 were found indeed to exhibit interesting
luminescence properties. Their UV−vis absorption and
fluorescence emission spectra, both measured in CH3CN at
room temperature, are shown in Figure 1. Upon excitation at
C
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In other words, an enabled synthetic method of N,N-
diarylation of primary amides coupled with aromatization is
capable of producing various acridine-centered polyacenes with
tunable luminescence.
In summary, we have developed a new method to construct
diverse 9,10-dihydroacridine derivatives from copper-catalyzed
N,N-diarylation of primary amides with di(o-bromoaryl)-
methanes. Coupled with oxidation and oxidative aromatization
reactions, we have also demonstrated the application of the
method in the preparation of acridine, acridinone, and
acridinium derivatives. The method has been successfully
expanded to the synthesis of a number of N-embedded
tetracenes and pentacenes, which exhibit interesting lumines-
cence properties. The generality, high synthetic efficiency, and
excellent functional group compatibility would render the
method practically useful to access diverse extended π-
conjugated materials.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01775.
Synthetic experiments and data for compound character-
ization, crystal data, and photophysical properties (PDF)
Accession Codes
CCDC 1990814−1990817 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Figure 1. UV−vis absorption and emission spectra and optical data of
14a−f in aerated CH3CN solution at rt. a Quantum yield determined
in solution, using acridine yellow G as reference ϕ = 0.54 in water, λex
= 445 nm. b Quantum yield determined in solution, using 2-
aminopyridine as reference ϕ = 0.6 in 0.1 N H2SO4, λex = 300 nm.
c Quantum yield determined in solution, using rhodamine B as
reference ϕ = 0.31 in water, λex = 518 nm.
AUTHOR INFORMATION
■
Corresponding Authors
Shuo Tong − MOE Key Laboratory of Bioorganic Phosphorous
and Chemical Biology, Department of Chemistry, Tsinghua
University, Beijing 100084, China; orcid.org/0000-0002-
7982-2546; Email: tongshuo@mail.tsinghua.edu.cn
Mei-Xiang Wang − MOE Key Laboratory of Bioorganic
Phosphorous and Chemical Biology, Department of Chemistry,
Tsinghua University, Beijing 100084, China; orcid.org/
0000-0001-7112-0657; Email: wangmx@
455 nm, linear N-embedded tetracene 14a emitted fluo-
rescence in the green to yellow region (λem = 512 nm). The
fluorescence quantum yield (ϕf), which was measured by using
acridine yellow G as reference, was 24.7%. A noticeable
hypochromatic shift of emission (λem = 390 nm, ϕf = 17.4%)
was observed from the fluorescence spectrum of angularly
fused isomer 14b, implying the remarkable decrease of
HOMO−LUMO gap energy when the pattern of fusion was
changed. The significant effect of fusion manner on
luminescence behavior was manifested by N-embedded
pentacenes. Owing to the increase of extended π-systems,
mail.tsinghua.edu.cn
Authors
Mei-Ling Tan − MOE Key Laboratory of Green Chemistry and
Technology, College of Chemistry, Sichuan University, Chengdu
610064, China
Sheng-Kai Hou − MOE Key Laboratory of Bioorganic
Phosphorous and Chemical Biology, Department of Chemistry,
Tsinghua University, Beijing 100084, China
Jingsong You − MOE Key Laboratory of Green Chemistry and
Technology, College of Chemistry, Sichuan University, Chengdu
610064, China; orcid.org/0000-0002-0493-2388
pentacenes 14c (λem = 561 nm, ϕf = 17.7%) and 14d (λem
=
472 nm, ϕf = 18.7%) emitted fluorescence at longer
wavelengths in comparison to their tetracene homologues
14a and 14b. Apparently, the emission band of linear isomer
14c is 89 nm longer than that of the L-shaped isomer 14d.
Variation of the fusion pattern from linear isomer 14c to S-
(14e) and C-shaped (14f) isomers led to a drastic blue shift of
the emission from 561 to 396 nm. Intriguingly, N-doped
pentacenes of C- and S-shaped fusions gave almost identical
fluorescence emission spectra. However, the fluorescence
quantum yield varied dramatically from 14.7% of 14e to
95.0% of 14f. The outcomes indicate that the optoelectronic
properties of N-embedded polyacenes are dependent on the
molecular size and, more pronounced, on the edge structure.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01775
Notes
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
Financial support is from the National Natural Science
Foundation of China (21901137, 21732004, 21821001). S.T.
also thanks the Thousand Young Talents Program for support.
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