Multicomponent Synthesis of Functionalized Tetrahydroacridinones: Insights into a Mechanistic Route

Article abstract of DOI:10.1021/acs.orglett.5b02705

A mechanistic study of three-component reactions of various aromatic amines with a number of aldehydes and 1,3-diones was achieved. The unprecedented reaction involved a nucleophilic attack of an aromatic amine on the in situ generated Michael adduct inte

Full text of DOI:10.1021/acs.orglett.5b02705

Letter
pubs.acs.org/OrgLett
Multicomponent Synthesis of Functionalized Tetrahydroacridinones:
Insights into a Mechanistic Route
†
†
&
,†,‡
Tsai-Wen Chung, Bharat D. Narhe, Chun-Cheng Lin, and Chung-Ming Sun*
†
Department of Applied Chemistry, National Chiao-Tung University, 1001 Ta-Hseuh Road, Hsinchu 300-10, Taiwan
‡
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100 Shih-Chuan First Road, Kaohsiung 807-08,
Taiwan
&
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
*
S Supporting Information
ABSTRACT: A mechanistic study of three-component reactions of
various aromatic amines with a number of aldehydes and 1,3-diones
was achieved. The unprecedented reaction involved a nucleophilic
attack of an aromatic amine on the in situ generated Michael adduct
intermediate followed by six-electron ring cyclizations. It is contrary
to the common belief that advocates involvement of coupling
reactions between a Knoevenagel adduct and an aromatic amine to
deliver substituted tetrahydroacridinones.
ulticomponent reactions (MCRs) play an important role
M
in the synthesis of small organic molecules of biological
importance. MCRs are chemical transformations that involve
three or more reactants in a one-pot operation and yield
compounds with high atom economy by incorporating all the
reactants in the final product. MCRs also deliver products with
a high degree of chemical and structural diversity. Their
efficiency and the simplicity of the reaction procedures make
MCRs cost-effective, time-efficient, and ecofriendly in compar-
Figure 1. Biologically active dihydropyridines.
1
ison to conventional multistep synthesis.
nolinediones of barbaituric acid describe the power of
multicomponent coupling reactions. All of these trans-
formations that involve 1,3-diketones, aldehydes, and amines
were proposed to proceed through a Knoevenagel adduct, but
no experimental proof of the mechanism is currently available.
We recently attempted to synthesize a Knoevenagel adduct,
Over the years, three-component reactions of aromatic
amines including 2-aminoimidazole with 1,3-dicarbonyl com-
pounds and an aromatic aldehyde have been widely used for the
synthesis of nitrogen-containing fused heterocycles owing to
their diverse biological applications. A number of heterocyclic
compounds derived from these reactions are known for their
7
2
3
-benzylidene-2,4-pentanedione (K), from benzaldehyde and
important antibacterial, antimalarial, anti-inflammatory, and
2
,3
5,5-dimethylcyclohexane-1,3-dione under a number of reaction
conditions. However, we found the Michael adduct M1 is the
sole product obtained rather than a Knoevenagel adduct. As all
of the prior literature reports that three-component reactions of
anticancer activities. These acridine derivatives have also
been found to have excellent electroluminescent properties and
4
are widely used as pigments and dyes. Recent examples of
biologically active acridinones include the potential sirtuins
inhibitor 1,8-dioxodecahydroacridine (I), the antimicrobial
compound tetrahydrobenzo[c]acridin-8(9H)-one (II), and an
1
,3-diketones, benzaldehydes, and aromatic amines proceed via
a mechanistic path involving the reactions of an amine with a
Knoevenagel adduct intermediate, we decided to investigate
these reactions in more detail.
5
aurora kinase inhibitor 1,4-dihydropyridine (III) (Figure 1).
Researchers have developed a number of variants of three-
Our study began with the synthesis of Knoevenagel adduct 3-
benzylidene-2,4-pentanedione (K) from an equimolar quantity
component reactions utilizing microwave activation, ultra6-
sonication, ionic liquid media, and solvent-free conditions.
Recent reports on diastereoselective reactions of 4-hydroxy-6-
methyl-2H-pyran-2-one to produce pyrazolopyridinones and
proline-promoted the regioselective synthesis of pyrimidoqui-
Received: September 19, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02705
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Organic Letters
Letter
of benzaldehyde (1a) and 5,5-dimethylcyclohexane-1,3-dione
only products obtained using these prior studies were the
corresponding Michael adducts.
(2a) in the presence of piperidine under ultrasonic activation
Finally, we successfully synthesized a Knoevenagel adduct in
for 60 min (Scheme 1).
1
0% yield through the slow addition of 5,5-dimethylcyclohex-
ane-1,3-dione (1 equiv) into an ethanolic solution of 4-
methoxybenzaldehyde (1.2 equiv). Once the Knoevenagel
adduct was rescued, we treated it immediately with various
aromatic amines such as 3,4-(methylenedioxy)aniline (3a), 5-
aminoindazole (3b), 5-aminoindole (3c) and 5-aminoquinoline
Scheme 1. Reaction of Aldehyde and 1,3-Diketone
(
3d) in aqueous 2-propanol with piperidine under reflux
conditions. To our surprise, none of the coupling reactions
yielded MCR products and the intermediate Knoevenagel
adduct was decomposed to aldehydes and 1,3 diketones in all
cases (Scheme 2). The very fast formation of Michael adduct
However, the only product isolated from the reaction
mixture was a Michael adduct M1 in 93% yield. In order to
trap the reaction at 3-benzylidene-2,4-pentanedione stage, we
used excess amount of benzaldehyde (2 equiv) to react with
Scheme 2. Reaction of Knoevenagel Adduct K1 and
Substituted Aniline 3a−d
5,5-dimethylcyclohexane-1,3-dione, and it was unfruitful. The
only product observed was still Michael adduct M1, as
suggested by a broad singlet at δ 11.80 (−OH) and singlet at
δ 5.50 (Ph-CH) in the proton NMR of the isolated product.
Our observation was further supported by a literature report on
8
Knoevenagel condensation. The structure of Michael adduct
M1 was further confirmed by single-crystal X-ray analysis
(Figure 2). The “Y” shape of the three-dimensional structure of
led us to speculate that it might play some roles in the three-
component reactions. This prompted us to test the feasibility of
a reaction between Michael adduct and an aromatic amine.
Heating an equimolar solution of M1 and 3,4-
Figure 2. X-ray crystal structure and intramolecular hydrogen bonding
of M1.
(
methylenedioxy)aniline (3a) under the same reaction
M1 is characterized by strong intramolecular hydrogen bonding
between the hydroxyl groups of enol with a carbonyl group on
the neighboring ring. It is clear that the benzylidene enone K is
too short-lived and instantly undergoes 1,4-conjugate addition
with enolizable ketone, i.e., 1,3-dione.
conditions to give 10-phenyl-6,7,8,10-tetrahydro[1,3]dioxolo-
[4,5-b]acridin-9-(5H)-one (4a) smoothly as the single product.
Delighted with this observation, we treated a series of
Michael adducts (M1−M6) with aromatic amines 3,4-
(methylenedioxy)aniline (3a), 5-aminoindazole (3b), 5-amino-
imidazole (3c), and 5-aminoquinoline (3d), which yielded the
corresponding tetrahydroacridines 4a−u. The results of this
study are summarized in Table 1. The reaction time required
for completion varied with the reactivity of the amines from 16
h for 3,4-(methylenedioxy)aniline to 5 days for 5-aminoquino-
line (Table 1). All reactions produced yields as shown in Table
1, including those involving Michael adduct M6, synthesized
from cyclohexane carbaldehyde, which resulted in moderate
yields of 42−66%. The structures of the obtained MCR
products were further confirmed using X-ray crystallographic
studies of 4j and 4l (Figure 4).
We reacted several aromatic aldehydes with 5,5-dimethylcy-
clohexane-1,3-dione to yield the corresponding Michael
adducts (M1−M5) in the presence of piperidine under
ultrasonication (Figure 3). Aliphatic aldehyde and cyclohexane
carbaldehyde also reacted smoothly to give Michael adduct M6.
To synthesize a Knoevenagel adduct, we treated several
aromatic aldehydes to react with 5,5-dimethylcyclohexa-1,3-
9
dione, following precedents in the literature. However, the
The success of these transformations posed a question
regarding the validity of the widely proposed and accepted
10
mechanism of three-component reactions (Scheme 3). This
widely accepted mechanistic pathway involves formation of 3-
benzylidene-2,4-pentanedione (K) via Konevengel condensa-
tion of an aldehyde with 1,3-dicarbonyl compound. Piperidine
promotes the transformation by forming an iminium hydroxide
intermediate with the aldehyde. Nucleophlic attack of amine
nitrogen on β-carbon of enone K yields intermediates 8a−c
that subsequently undergo cyclization to generate hydroxyl-
amine, which leads to observed product 4 after dehydration.
The failure of a coupling reaction between a Knoevenagel
Figure 3. Preparation of Michael adducts M1−M6.
B
DOI: 10.1021/acs.orglett.5b02705
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Table 1. Coupling Reactions of Aromatic Amines with
Michael Adducts
Scheme 3. Commonly Proposed MCR Mechanism
ring closure to produce the observed product 4 following
aromatization (Scheme 4).
Scheme 4. Mechanistic Pathway for Reaction between
Michael Adduct and Amine
a
Reactions were performed in the presence of piperidine (2 equiv).
Isolated yield after column purification.
b
Next, we performed competitive three-component reactions
between 4-methoxybenzaldehyde, 5,5-dimethylcyclohexane-1,3-
dione, and amines 3a−d. The corresponding Michael adduct
M2 was also reacted with amines 3a−d. The results of these
reactions are summarized in Scheme 5 and Table 2. To our
Scheme 5. Competitive Three-Component Reactions
Performed As Part of This Study
Figure 4. X-ray crystal structures of 4j and 4l.
adduct and aromatic amines authenticated our proposal that the
Michael adduct is a key intermediate in this MCR reaction.
The reaction involves an initial nucleophilic attack of
nitrogen of an aromatic amine on enol of M1 to yield adduct
delight, the reactions produced comparable yields under
identical conditions. These observations also support our
claim regarding the mechanistic path of these reactions. This
new understanding of reaction routes of three-compound
reactions can be expected to enhance the design of new
reaction methodologies and procedures that will allow the
synthesis of interesting molecular scaffolds.
5
that, after dehydration, gives enaminone 6a. The intra-
molecular hydrogen bonding in M1 activates the enone toward
nuleophilic attack. Imino enol 6b undergoes a retro-aldol-type
reaction via keto tautomer 6c to produce aza-triene 7 and 1,3-
diketone. The aza-triene 7 then undergoes six-electron thermal
C
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corresponding acridine derivatives. The isolation of a Michael
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ASSOCIATED CONTENT
Supporting Information
■
*
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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Experimental details plus spectroscopic and other data
for compounds M1−M4, K1, and 4a−u (PDF)
X-ray data for 4c (CIF)
X-ray data for 4d (CIF)
X-ray data for 4e (CIF)
X-ray data for 4j (CIF)
X-ray data for 4l (CIF)
X-ray data for 4r (CIF)
X-ray data for 4s (CIF)
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AUTHOR INFORMATION
Corresponding Author
■
(
2
*E-mail: cmsun@mail.nctu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Council of Taiwan for financial
support and the authorities of the National Chiao Tung
University for providing laboratory facilities. This study was
particularly supported by the “Centre for bioinformatics
research of aiming for the Top University Plan” of the National
Chiao Tung University and Ministry of Education, Taiwan.
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DOI: 10.1021/acs.orglett.5b02705
Org. Lett. XXXX, XXX, XXX−XXX