Acid-Promoted Intramolecular Decarbonylative Coupling Reactions of Unstrained Ketones: A Modular Approach to Synthesis of Acridines and Diaryl Ketones

Article abstract of DOI:10.1021/acs.orglett.0c00304

Herein, we reported Lewis acid-or Br?nsted acid-promoted intramolecular C(sp²)-C(sp²) bond cleavage and a novel C(sp²)-C(sp²) bond-forming cascade reaction to synthesize the acridine motif. The metal-free oxidation of the alkyne motif generated the in situ ketone group extracted via a decarbonylation reaction. The mechanistic studies revealed that the electrophilic N-iodo species triggered key decarbonylation reactions via consecutive dearomatization/aromatization reactions. In addition, we exploited this acid-promoted C-C bond activation system with internal alkynes to synthesize bis(heteroaryl) ketones.

Full text of DOI:10.1021/acs.orglett.0c00304

pubs.acs.org/OrgLett
Letter
Acid-Promoted Intramolecular Decarbonylative Coupling Reactions
of Unstrained Ketones: A Modular Approach to Synthesis of
Acridines and Diaryl Ketones
Ganesh Kumar Dhandabani, Chia-Ling Shih, and Jeh-Jeng Wang*
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ABSTRACT: Herein, we reported Lewis acid- or Brønsted acid-
promoted intramolecular C(sp2)-C(sp2) bond cleavage and a novel
C(sp2)-C(sp2) bond-forming cascade reaction to synthesize the
acridine motif. The metal-free oxidation of the alkyne motif
generated the in situ ketone group extracted via a decarbonylation
reaction. The mechanistic studies revealed that the electrophilic N-
iodo species triggered key decarbonylation reactions via consec-
utive dearomatization/aromatization reactions. In addition, we
exploited this acid-promoted C−C bond activation system with
internal alkynes to synthesize bis(heteroaryl) ketones.
elective molecular editing is a state-of-the-art method in
synthetic chemistry. In the last three decades, numerous
S
methods have been developed to achieve carbon chain
elongation. However, methods for shortening carbon chains
are limited due to their inert nature and resemblance of the C−
C bonds in terms of bond strength and electronic properties.
Additionally, the carbon bonds are less accessible due to their
detrimental interaction with metals.1 These phenomena hinder
recognition of the specific C−C bond that must be activated.
Noble metals play a dominant role in C−C σ-bond activation.2
However, the volatility of noble metal prices, globally
increasing demands, and limited resources drive chemists to
find alternative sources to replace expensive metal catalysts.3
To develop a sustainable C−C bond activation method,
basic metal complexes, enzymes, peroxides, and iodine source
have been recently employed.4 Despite the success of these
reported methods, selective cleavage/activation of carbon
bonds is the main challenge that accompanies transition-
metal-free C−C bond activation, especially for unstrained C−C
bond cleavage.5 Decarbonylative C−C coupling is a powerful
tool for functionalizing bioactive molecules.6 In general,
strained rings undergo the thermodynamically favored C−C
bond scission to generate a reactive intermediate species that
can undergo various bond formations through different
mechanistic pathways (Figure 1a).7
Figure 1. Types of intramolecular decarbonylative coupling reactions.
inert nature of the C(Aryl)−C(O) bond and its hindered
structure, making these motifs unsusceptible to the installation
of a directing group.
Very few seminal works on the decarbonylation of unstrained
ketones have been reported.9 In 2018, Wei et al. disclosed a
directing group-initiated decarbonylation reaction of simple
Recently, chemists have focused on the C−C bond activation
of unstrained motifs concomitant with a decarbonylation
reaction using directing group methods (Figure 1b). Despite
the success of intermolecular decarbonylation reactions of
aldehyde, thioesters, amides, and anhydrides, intramolecular
carbonyl group cleavage of ketone molecules remains
challenging.8 This difficulty is likely due to the substantially
Received: January 22, 2020
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© XXXX American Chemical Society
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A

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a
ketones catalyzed by a combination of a Ni/electron-rich N-
Table 1. Optimization of the Reaction Conditions
heterocyclic carbene ligand (Scheme 1a).9e Maiti’s group
Scheme 1. Previous Studies and This Work on C−C Bond
Activation
b
oxidant
(Y equiv)
yield of 3aa/
3aa′ (%)
entry acid (X equiv)
solvent/atm
1
2
3
4
5
6
7
8
9
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
DMSO
24/62
57/20
60/0
50/0
15/43
85/0
58/0
ND
18/0
10/0
50/0
0/82
c
DMSO/O2
DMSO/O2
DMSO/O2
d
e
TBHP(2.0)
DTBP (2.0)
K2S2O8 (2.0) DMSO/O2
f
PIDA (0.6)
PIFA (0.6)
PIDA (0.6)
DMSO/O2
DMSO/O2
DMSO/O2
DMSO/O2
DMSO/O2
DMF/O2
g
h
acetic acid (1.0) PIDA (0.6)
10
11
12
Sc(OTf)3 (0.3)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
PIDA (0.6)
PIDA (0.6)
PIDA (0.6)
i
DMSO/O2
a
All reactions were performed using 1a (0.5 mmol, 1 equiv), 2a (0.6
developed an imine-directed copper-catalyzed rearrangement
reaction to synthesize symmetrical and unsymmetrical diaryl
ketones (Scheme 1b).9f In this series, we disclosed a transition-
metal-free and directing-group-free cascade C(sp2)−C(sp2)
bond cleavage and new intramolecular C(sp2)−C(sp2) bond-
forming reactions to synthesize dihydrobenzo[c]acridine and
bis(heteroaryl) ketones with the generation of CO and CO2 as
traceless byproducts. To the best of our knowledge, this is the
first report of an in situ generated carbonyl group undergoing
BF3·OEt2- or TfOH-mediated decarbonylative C−C bond
activation to synthesize an acridine scaffold via dearomatiza-
tion/aromatization reaction sequences. The PMA-PdCl2 test
confirmed the CO gas liberation in the reaction medium. Our
environmentally friendly protocol can replace benchmark
expensive noble metals in unstrained C−C bond activation
reactions using abundant and low-cost acids.
Initially, our transition-metal-free decarbonylation reaction
was studied using 2-(p-tolylethynyl) aniline (1a) and α-
tetralone (2a) as model substrates (Table 1). Both starting
materials were treated in the presence of BF3·OEt2 using
dimethyl sulfoxide (DMSO) as the solvent at 110 °C. This
reaction yielded 24% of the dihydrobenzo[c]acridine product
3aa (entry 1, Table 1, closed vial). When we performed the
same reaction under an oxygen atmosphere, we observed a two
fold improvement in the reaction yield (entry 2, Table 1).
Therefore, a strong oxidant may be a necessary part of the
reaction conditions to improve the yields. Next, we screened
several different oxidants with the reaction conditions to
determine the optimal oxidizing source (entries 3−7, Table 1).
The highest yield (i.e., 85%) was obtained in the presence of
0.6 equiv of (diacetoxyiodo)benzene (PIDA) (entry 6, Table
1). Furthermore, changing the acid source in the reaction
conditions did not improve the yield (entries 9 & 10, Table 1
and see Supporting Information Table S2), and without the
acid source the reaction did not proceed (entry 8 Table 1). The
role of the solvent in these C−C bond activation reactions is
crucial, because a high yield was only obtained when polar
aprotic solvents were employed (Supporting Information Table
S1). Moreover, the DMSO played a dual role as both an
oxidant and a solvent.10 The low-temperature reaction failed to
furnish the decarbonylated product (entry 12).
mmol, 1.5 equiv), acid (X equiv), oxidant (Y equiv), and solvent (2
mL) at 110 °C stirring with the indicated atmosphere for 16 h unless
b
c
otherwise noted. Isolated yield. Reaction performed under oxygen
d
e
atmosphere. 70% aq TBHP was used. Di-tert-butyl-peroxide
(DTBP). (Diacetoxy iodo)benzene (PIDA). (Bis(trifluoroacetoxy)-
iodo)benzene (PIFA). Reaction performed without BF3·OEt2.
Reaction performed at 65 °C.
f
g
h
i
The success of our optimized reaction conditions was
demonstrated by synthesizing a library of acridine derivatives.
Both the electron-rich and electron-poor o-alkynylanilines
(1a−1d) were transformed into corresponding heterocyclic
compounds 3aa−3da with 48−85% yields (Scheme 2).19 The
o-alkynylanilines containing the 3-Me (1e) and 3,4-di-Me (1f)
functional groups underwent the reaction using our optimized
reaction conditions to afford desired products 3ea (68%) and
3fa (88%). Next, we explored the reaction efficiency with
different R1-substituted starting materials (1g−1i). In general,
the R1 group with meta-substituted o-alkynylanilines (3ga and
3ha) afforded lower yields compared to the para-substituted
one (3ia). Furthermore, the α-tetralones (2b−2j) reactivity
was examined with simple o-alkynylaniline (1a). In all these
reactions, dihydrobenzo[c]acridines were isolated in good to
moderate yield (3ab−3ai, 48−87%). 2,3-Dihydro-1H-inden-1-
one (2j) was not compatible under our reaction conditions
(3aj, Scheme 2).
When similar reaction conditions were employed with simple
o-alkynylanilines (1j), a lower yield was obtained, and a major
cyclized intermediate 3ja′ as well as oxidized intermediate 3ja″
were isolated (see Scheme 7b,c). This unsatisfactory result may
be due to coordination of the current Lewis acid, which is too
weak, to the in situ formed carbonyl group to achieve the
dearomatization step. Therefore, we screened the reaction with
a diverse array of Lewis acids and Brønsted acids (Supporting
Information Tables S6 & S7). Ultimately, 2-(phenylethynyl)-
aniline (1j) and α-tetralone (2a) reacted in the presence of 1
equiv of TfOH to afford the highest yield (i.e., 78%) for the
acridine derivative (3ja) (Scheme 3). Similarly, the 4-Me (3ka)
substituted dihydrobenzo[c]acridine was also prepared in 71%
yield. Next, the substrate scope was expanded with different
electron-donating and electron-withdrawing groups bearing α-
B
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Scheme 2. Substrate Scope of the BF3·OEt2-Promoted
Scheme 4. Substrate Scope of the BF3·OEt2-Promoted
a b
,
a b
,
Decarbonylation Reaction
Annulation Reaction
a
Reaction conditions: compound 1 (1.0 mmol), 2 (1.2 mmol), BF3·
̊
OEt2 (2.0 mmol), PIDA (0.6 mmol), and DMSO (4 mL) at 65 C for
the indicated time and atmosphere unless otherwise noted. Isolated
b
yields.
industry.11 The unsymmetrical ketone synthesis primarily
depends on the controlled addition of organometallic species
with an acid, ester, or aldehyde.12 The oxidative aryl
rearrangement of an internal alkyne is an alternative method
for the synthesis of diaryl ketones. However, these methods
demand a metal catalyst with an amine directing group or a
stoichiometric amount of oxidant, which produces hazardous
byproducts.13 Although the reported metal-free methods have
been hindered by their the selectivity issues, the development
of a sustainable metal-free reaction to activate the C−C triple
bond is necessary for the synthesis of one carbon less diaryl
ketones.13b Therefore, we employed our transition metal-free
reaction conditions with an internal alkyne to synthesize diaryl
ketones via an oxidative rearrangement reaction.
To our delight, the first C−C bond activation reaction with
diphenylacetylene proceeded under BF3·OEt2/PIDA condi-
tions with 96% yield to afford the corresponding benzophe-
none (5a, Scheme 5). With the same reaction conditions, 4-
methoxy (5b) and 4-hydroxy (5c) substituted benzophenones
were prepared in moderate to excellent yields. However, a
a
Reaction conditions: compound 1 (1.0 mmol), 2 (1.2 mmol), BF3·
̊
OEt2 (2.0 mmol), PIDA (0.6 mmol), and DMSO (4 mL) at 110 C for
the indicated time and atmosphere unless otherwise noted. Isolated
yields.
b
Scheme 3. Substrate Scope of the TfOH-Promoted
Decarbonylation Reaction
a b
,
a b
,
Scheme 5. Scope of Reaction: Diaryl Ketones
a
Reaction conditions: compound 1 (1.0 mmol), 2 (1.2 mmol), TfOH
(1.0 mmol), PIDA (0.6 mmol), and DMSO (4 mL) at 110 °C for the
b
indicated time and atmosphere unless otherwise noted. Isolated
yields.
tetralones, and all these substrates were transformed into the
required products (3ja−3jl, 3ka). Some of the incompatible
substrates are listed in Scheme 3. Using the low-temperature
reaction condition (Table 1 entry 12), we synthesized seven
different benzylated acridine compounds (Scheme 4).
Ketones are a pivotal motif present in many marketed drug
molecules, and they are valuable precursors in the polymer
a
Reaction conditions: compound 4a−4e (1.0 mmol), BF3·OEt2 (2.0
mmol), PIDA (0.6 mmol), and DMSO (4 mL) at 110 °C for the
b
indicated time and atmosphere unless otherwise noted. Isolated
yields. Standard conditions except BF3·OEt2 was replaced with TfOH
(1.0 mmol).
c
C
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pyridine-containing internal alkyne (4d) only underwent the
oxidative rearrangement reaction in the presence of the TfOH/
PIDA reaction conditions. Furthermore, the compatibility of
our reaction conditions with diyne was confirmed by isolating
the corresponding product (5e) in 90% yield (for plausible
reaction mechanisms, see Supporting Information Scheme S7).
Phenstatins is a well-known tubulin polymerization inhibitor
that exhibits cytotoxicity against various cancer cell lines, and
its derivatives are undergoing clinical studies as vascular
disrupting agents and antiangiogenic agents.14 To confirm
the efficiency of our reaction conditions, we synthesized
phenstatins in 71% overall yield with two steps (Scheme 6a).
Furthermore, using the metal-free reaction conditions, we
completely oxidized the dihydrobenzo[c] acridine derivatives
(Scheme 6b).10d
annulated intermediate-I (3ja′) in 75% yield (see Supporting
Information Scheme S5). Annulated intermediate-I (3ja′),
which was introduced in our standard reaction conditions (7
h), was converted to oxidized intermediate-II 3ja″ (65% yield)
and final product 3ja (21% yield, Scheme 7b). This isolated
intermediate-II (3ja″) confirmed the participation of the
decarbonylation step in the reaction mechanism, because this
intermediate was transformed into final compound 3ja under
our optimal reaction conditions (Scheme 7c). Further, the
evolution of CO gas from the reaction system was confirmed by
a PMA-PdCl2 test (see Supporting Information Figure S4).
On the basis of previously reported literature and control
studies, we propose the plausible reaction mechanism shown in
Scheme 8. The condensation reaction of o-alkynylanilines with
Scheme 8. Plausible Reaction Mechanism
Scheme 6. Formal Synthesis of Phenstatins and Complete
Oxidation of Dihydrobenzo[c]acridine Derivatives
We performed various mechanistic studies to elucidate the
reaction mechanism (Scheme 7). Maiti et al. reported the
Scheme 7. Control Studies
tetralones produce imine intermediate A, which further
converted to D (3aa′) via imine-enamine isomerization and
acid/PIDA-promoted intramolecular nucleophilic 6-exo-dig
cyclization.10,15 In the presence of PIDA/O2, the benzylic
oxidation of D yielded E (3aa″).10,16 The acid-triggered PIDA
coordination facilitates the N-iodo species F.17 The concerted
dearomatization of F generates delocalized Wheland inter-
mediate G, which underwent aromatization-induced decarbon-
ylation to form the final product.18,19
In summary, we report the first transition-metal-free and
directing-group-free intramolecular decarbonylative C−C bond
formation reaction to synthesize the dihydrobenzo[c]acridine
motif. Furthermore, the efficiency of these methods was
evaluated with one carbon less aryl(heteroaryl) ketones
synthesis from internal alkynes. The practical use of this
method indicates good functional group tolerance, mild as well
as environmentally benign reaction conditions, and discharging
CO and CO2 as traceless byproducts. Mechanistic studies and
isolated intermediates confirmed the direct decarbonylative C−
C coupling involved in the dihydrobenzo[c]acridines synthesis.
The acid coordination with the ketone group initiates the N-
iodo species generation, which aids in converting the simple
ketones into a highly strained ring system through dearoma-
tization and then aromatization driven decarbonylation of the
in situ generated strained ring to afford the desired acridine
copper-catalyzed aerobic C−C bond activation of deoxy
benzoin to synthesize benzophenone.9f We performed the
same decarbonylation reactions with our metal-free reaction
conditions to compare the efficiency of our method. These
experiments confirmed that our rationalized benzil intermedi-
ate participated in the reaction mechanism (Supporting
Information Scheme S4), because the reaction afforded a
70% isolated yield of benzophenone (Scheme 7a). Although
the radical scavengers failed to reduce the regular reaction
yield, we ruled out a radical mechanism (see Supporting
Information Scheme S1). In the short reaction time, compound
1j reacted with 2a in the presence of triflic acid to afford the
D
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00304.
Experimental procedures, X-ray crystallographic data for
3aa & 3fa, spectroscopic data, and copies of NMR
spectra for all new compounds (PDF)
̈
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Accession Codes
CCDC 1918651−1918652 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.
AUTHOR INFORMATION
Corresponding Author
■
Jeh-Jeng Wang − Department of Medicinal and Applied
Chemistry, Kaohsiung Medical University, Kaohsiung City 807,
Taiwan; Department of Medical Research, Kaohsiung Medical
University Hospital, Kaohsiung City 807, Taiwan;
orcid.org/0000-0002-3148-1885; Email: jjwang@
kmu.edu.tw
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Decarbonylation of Aryl Ketones. Angew. Chem., Int. Ed. 2017, 56,
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by Transition Metals. Edited by Masahiro Murakami and Naoto
Chatani. Angew. Chem., Int. Ed. 2016, 55, 7291−7291. (c) Chen, F.;
Wang, T.; Jiao, N. Recent advances in transition-metal-catalyzed
functionalization of unstrained carbon-carbon bonds. Chem. Rev.
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Cleavage and Activation of C−C Single Bonds. Eur. J. Org. Chem.
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Chemistry of Cyclopropenes and Cyclopropanes. Chem. Rev. 2007,
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Authors
Ganesh Kumar Dhandabani − Department of Medicinal and
Applied Chemistry, Kaohsiung Medical University, Kaohsiung
City 807, Taiwan
Chia-Ling Shih − Department of Medicinal and Applied
Chemistry, Kaohsiung Medical University, Kaohsiung City 807,
Taiwan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00304
Notes
The authors declare no competing financial interest.
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carbon−carbon bonds by radical reactions. Chem. Soc. Rev. 2019, 48,
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cascade reactions triggered by single electron transfer. Nat. Rev. Chem.
2017, 1, 0077−0093. (c) Marek, I.; Masarwa, A.; Delaye, P.-O.;
Leibeling, M. Selective carbon-carbon bond cleavage for the
stereoselective synthesis of acyclic systems. Angew. Chem., Int. Ed.
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Z.; Zhu, L.; Fan, X.; Bi, S. Mechanism of Cu-Catalyzed Aerobic
C(CO)−CH3 Bond Cleavage: A Combined Computational and
Experimental Study. ACS Catal. 2019, 9, 1066−1080. (f) Richter, S.;
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Branched Aliphatic Aldehydes at Ambient Temperature. Chem. - Eur.
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ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the Ministry
of Science and Technology (MOST), Taiwan, and the Centre
for Research and Development of Kaohsiung Medical Univ. for
the 400 MHz NMR, LC-MS, and GC-MS analyses.
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