Unprecedented bridged annulation approach to the construction of 5,6-Dihydro-4H-benzo[k/]acridines

Article abstract of DOI:10.1021/ol901916p

A general and novel "bridged annulation" methodology for the synthesis of 5,6-dihydro-4H-benzo[k/|acridines has been developed via Michael addition of a conjugate base of 9-methyl-3,4-dihydroacridin-1(2H)-one to various cyclic or acyclic α,β-unsaturated c

Full text of DOI:10.1021/ol901916p

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5122-5125
Unprecedented Bridged Annulation
Approach to the Construction of
5,6-Dihydro-4H-benzo[kl]acridines†
Atul Goel,*,‡ Salil Pratap Singh,‡ Amit Kumar,‡ Ruchir Kant,§ and
Prakas R. Maulik§
DiVisions of Medicinal and Process Chemistry, Molecular and Structural Biology
Central Drug Research Institute, CSIR, Lucknow 226001, India
atul_goel@cdri.res.in
Received August 18, 2009
ABSTRACT
A general and novel “bridged annulation” methodology for the synthesis of 5,6-dihydro-4H-benzo[kl]acridines has been developed via Michael
addition of a conjugate base of 9-methyl-3,4-dihydroacridin-1(2H)-one to various cyclic or acyclic r,ꢀ-unsaturated carbonyl/nitrile compounds
under mild conditions at room temperature in a short time. To the best of our knowledge, such a general bridged annulation for the synthesis
of fused N-heterocycles has not been reported in the literature.
Quinoline, acridine, and related N-heterocyclic systems like
annulated phenanthridine are key structural motifs found in
a large number of biologically important natural alkaloids
isolated from plant and marine sources and represent
privileged scaffolds in medicinal chemistry.1,2 Among them,
those bearing an acridine moiety display a wide range of
pharmacological activities such as antiviral,3 antimalarial,4
antihelmintic,5 antifungal,6 antitumor,7 stimulative,8 and other
activities.9 As a consequence, numerous methods for the
preparation of quinolines,1,10,11 acridines,12 and phenan-
thridines13 have been described.
During our drug development program, we became
interested in preparing novel quinolines, acridines, and their
annulated compounds through our recently developed ring
transformation strategy.14 Our ring transformation approach
involves the conversion of a 2-pyranone ring into an aromatic
ring by reacting a pyranone with an active methylene
† CDRI Communication No. 7848.
‡ Division of Medicinal and Process Chemistry.
§ Division of Molecular and Structural Biology.
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5, p 245, Chapter 5.06. (b) Bhakuni, D. S.; Rawat, D. S. BioactiVe Marine
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10.1021/ol901916p CCC: $40.75
Published on Web 10/14/2009
 2009 American Chemical Society

compound under mild basic conditions at room tempera-
ture.15 Very recently, we have demonstrated that our
methodology can be applied to prepare fluorescent blue
materials for efficient organic light emitting diodes.16 To
prepare various N-heterocyclic compounds under a drug
development program, various quinoline fused cyclic ketones
were desirable that could enable us to perform unprecedented
transformations.
Among various approaches reported for the synthesis of
these N-heterocycles, Friedlaender annulation is one of the
most effective and simplest protocols.17 In this approach,
an aromatic amine having an ortho-tethered enal or enone
functionality is involved in an intramolecular cyclization
reaction to furnish the desired N-heterocycles. We found the
Brønsted acid-catalyzed Friedlaender annulation protocol to
be suitable for preparing various N-heterocyclic substrates
such as 9-methyl-3,4-dihydroacridin-1(2H)-one (1, 5).18
These reactions are advantageous since they include impor-
tant “green” chemistry factors such as atom economy,19
reduction of synthetic steps, and minimization of solvents
and waste.20
When we applied our ring transformation strategy14 to
prepare 5,6-dihydrobenzo[a]acridine (4) using substrate
9-methyl-3,4-dihydroacridin-1(2H)-one (1, 1 mmol) and 6-
(4-chlorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbo-
nitrile14 (2a, 1 mmol) in the presence of NaH (1.5 mmol) in
DMF at room temperature for 1 h, we unexpectedly obtained
3-(2-(4-chlorophenyl)-5,6-dihydro-4H-benzo[kl]acridin-3-yl)-
3-(piperidin-1-yl)acrylonitrile (3a) in 54% yield (Scheme 1).
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Scheme 1. Synthesis of 5,6-Dihydro-4H-benzo[kl]acridine (3a)
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The structure of the compound 3a was unambiguously
confirmed by single-crystal X-ray analysis (Figure 1). The
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Figure 1. ORTEP diagram of compound 3a.
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formation of the compound 3a in lieu of 4 revealed that the
reaction proceeded through a carbanion generated from a
methyl group at position 9 instead of a methylene group at
position 2 of a ketone 1 as shown in Scheme 1.
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Org. Lett., Vol. 11, No. 22, 2009
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To generalize the reaction, various functionalized 2H-
pyran-2-ones14,15 (2b-e) were reacted with the cyclic ketone
1 to furnish 5,6-dihydro-4H-benzo[kl]acridines (3b-e) in a
single step at room temperature (Scheme 2). A plausible
Scheme 3. Synthesis of N-Heterocycles (7a-f) Using Cyclic or
Acyclic R,ꢀ-Unsaturated Electron-Withdrawing Compounds
Scheme 2
.
Synthesis of 5,6-Dihydro-4H-benzo[kl]acridines
(3a-e)
mechanism for the formation of 3a-e is depicted in Scheme
2, which revealed that reaction is possibly initiated by the
attack of a carbanion of 1 at the C-6 position of 2-pyranone
(2) followed by ring opening, decarboxylation, and intramo-
lecular cyclization involving the C-5 position of 2-pyranone
and carbonyl functionality of the ketone (1) to afford 5,6-
dihydro-4H-benzo[kl]acridines (3a-e). It is interesting to
note that only C-5 and C-6 positions of the 2-pyranone (2)
are involved in the construction of an aromatic bridged ring.
With the success of this new protocol, we thus envisaged
that this unexpected new “bridged annulation” approach
would allow us to prepare a wide selection of N-heterocyclic
compounds using readily available functionalized R,ꢀ-
unsaturated electron-withdrawing compounds. Accordingly,
several R,ꢀ-unsaturated compounds (6a-d) having electron-
withdrawing carbonyl or nitrile functionality were treated
with 9-methyl-3,4-dihydroacridin-1(2H)-ones (1, 5) in the
presence of NaH in DMF at room temperature, which
furnished 5,6-dihydro-4H-benzo/naphtho[kl]acridines (7a-f)
in good yields (Scheme 3).
The plausible mechanism for the formation of one of the
compounds 7a is depicted in Scheme 4. Reaction is possibly
initiated by Michael addition of a conjugate base of 1 at the
ꢀ-position of cyclohexenone (6a) followed by intramolecular
cyclization involving the R-position of 6a and carbonyl
functionality of the ketone (1) and further aromatization in
air to afford 2,3,6,7-tetrahydro-1H-naphtho[1,2,3-kl]acridin-
4(5H)-one (7a).
From the proposed mechanism, it is evident that an “H-
atom” at the R- and ꢀ-positions of the Michael acceptor is
involved in the aromatization of a newly formed bridged ring,
and the presence of ꢀ-H favors aerial oxidation as shown in
Scheme 4. To test this observation, an independent reaction
was attempted with 4-methylpent-3-en-2-one (8) having no
“ꢀ-H” as shown in Scheme 5.
We observed that both cyclic and acyclic R,ꢀ-unsaturated
compounds (2a-e, 6a-d) displayed appreciable reactivity
under these reaction conditions delivering acridine-fused
polycycles in a single step. To the best of our knowledge,
such bridged annulation has not been reported in the literature
prior to this study.
(19) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
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5124
Org. Lett., Vol. 11, No. 22, 2009

Scheme 4
.
Plausible Reaction Mechanism for 7a
Scheme 6. Synthesis of
2-Methylsulfanyl-5,6-dihydro-4H-benzo[kl]acridines (13-15)
The isolated compound was characterized as 1-(2,2-
dimethyl-2,4,5,6-tetrahydro-1H-benzo[kl]acridin-3-yl) etha-
none 9, which indicated that ꢀ-H is essential for aromati-
zation of the newly formed bridged ring. On the contrary, if
Scheme 5. Reaction of 1 with 8 Having No ꢀ-H
applied to the synthesis of quinoline or acridine-based
alkaloids for drug development perspectives.
In summary, we have developed a novel and efficient
bridged annulation strategy for the synthesis of a variety of
5,6-dihydro-4H-benzo[kl]acridines by the base-assisted Michael
addition of a conjugate base of 1 (or 5) to the ꢀ-position of
the Michael acceptor. It is demonstrated that an H-atom at
the R- and ꢀ-positions of the Michael acceptor is involved
in the aromatization of a newly formed bridged ring, and
the presence of ꢀ-H favors aerial oxidation. In the absence
of ꢀ-H at the Michael acceptor, a good leaving group at the
ꢀ-position facilitates the reaction toward aromatization of a
newly formed bridged ring. This general methodology may
be useful to synthesize a variety of N-heterocyclic com-
pounds from readily available starting materials.
we look at the case in Scheme 2, where there is no “H” at
position 6 of the pyranone ring, we obtained the aromatized
products (3a-f). The proposed mechanism revealed that a
good “leaving group (LG)” may lead to aromatization of the
bridged ring.
Thus, a few Michael acceptors (10-12)21 with a good
leaving group at the ꢀ-position of R,ꢀ-unsaturated carbonyl
compounds were prepared to confirm this bridged annulation
reaction, and results are shown in Scheme 6. The reaction is
possibly initiated by addition of a conjugate base of 1 (or 5)
to the ꢀ-position of a Michael acceptor (10-12), followed
by elimination of the methylsulfanyl anion and intramolecular
cyclization to furnish intermediate A. This intermediate A
in the presence of the methylsulfanyl anion may undergo
elimination of thiolester to afford 2-(methylsulfanyl)-5,6-
dihydro-4H-benzo[kl]acridines (13-15) in good yields.
This new bridged annulation under mild basic conditions
provides simple access to compounds with functional group
diversity by changing the substitution pattern either on
9-methyl-3,4-dihydroacridin-1(2H)-one (1, 5) or taking dif-
ferent Michael acceptor groups. The procedure may be
Acknowledgment. We gratefully acknowledge financial
support by the Department of Science and Technology
(DST), New Delhi, India, under Ramanna Fellowship project
to A.G. (SR/S1/RFPC-10/2006). S.P.S. and A.K. are thankful
to CSIR, New Delhi, for senior research fellowships.
Supporting Information Available: Complete experi-
mental details, characterization data of the compounds 3a-e,
7a-f, 9, and 13-15 and X-ray data of 3a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Tominaga, Y. Trends Heterocycl. Chem. 1991, 2, 43.
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