Highly efficient construction of pentacyclic benzo[b]indeno-[1,2,3-de][1,8] naphthyridine derivatives via four-component domino reaction

Article abstract of DOI:10.1039/c3cc43489c

A series of new octahydrobenzo[b]indeno[1,2,3-de][1,8] naphthyridine and decahydropyrido[2,3,4-gh]phenanthridine derivatives were synthesized via a four-component domino reaction under microwave irradiation. This one-pot transformation, which involved multiple steps and did not require the use of a catalyst, constructed four new C-C bonds, two new C-N bonds, and three new rings, with efficient use of all reactants.

Full text of DOI:10.1039/c3cc43489c

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Highly efficient construction of pentacyclic
benzo[b]indeno-[1,2,3-de][1,8]naphthyridine
Cite this: DOI: 10.1039/c3cc43489c
derivatives via four-component domino reaction†
Received 10th May 2013,
Accepted 20th June 2013
Cheng-Pao Cao, Wei Lin, Ming-Hua Hu, Zhi-Bin Huang* and Da-Qing Shi*
DOI: 10.1039/c3cc43489c
www.rsc.org/chemcomm
A series of new octahydrobenzo[b]indeno[1,2,3-de][1,8] naphthyridine heterocyclic skeletons of chemical and pharmaceutical interest.8
and decahydropyrido[2,3,4-gh]phenanthridine derivatives were As part of our ongoing research on the development of domino
synthesized via a four-component domino reaction under micro- reaction approaches to the synthesis of heterocycles,9 we report
wave irradiation. This one-pot transformation, which involved the efficient construction of octahydrobenzo[b]indeno[1,2,3-de]-
multiple steps and did not require the use of a catalyst, constructed [1,8]naphthyridine and decahydropyrido[2,3,4-gh]phenanthridine
four new C–C bonds, two new C–N bonds, and three new rings, derivatives via a four-component domino reaction under micro-
with efficient use of all reactants.
wave irradiation.
We began our studies with the four-component domino
The efficient construction of polyheterocyclic skeletons is a reaction of a 1 : 2 : 1 mixture of 5,5-dimethyl-3-(4-methoxyphenyl-
challenging theme in organic synthesis.1 1,8-Naphthyridine amino)cyclohex-2-enone (1a), malononitrile (2), and o-phthal-
derivatives have rich photochemical properties due to their aldehyde (3a) in ethanol at 100 1C for 20 min under microwave
rigid planar structure. Based on the bridging coordination irradiation, without the use of a catalyst. This afforded 7-amino-
mode they could form two centers by the two nitrogen atoms 5-(4-methoxyphenyl)-3,3-dimethyl-1-oxo-1,2,3,4,5,5a1,8a,12b-octa-
on positions, and auxiliary chelating groups could be incorpo- hydrobenzo[b]indeno[1,2,3-de][1,8] naphthyridine-5a1,8-dicarbonitrile
rated using a special cage-like receptor as potential multi- (4a) in 43% LC yield. The polyhydronaphthyridine derivative 4a
dentate ligands, which made naphthyridine derivatives useful was fully characterized using IR, 1H NMR, 13C NMR, and HRMS
as luminescence materials in molecular recognition.2 According spectroscopies. Only a single diastereoisomer of 4a was
1
to an extensive literature search, we found that naphthyridines detected using H NMR spectroscopy. The structure of 4a was
were not only used in photochemical,3 but also used as new further confirmed using single-crystal X-ray diffraction analysis10
drug leader4 and anti-cancer active screening agents in new (see ESI†). The usefulness of these domino reactions is shown
drug discovery.5
by the fact that up to six new bonds (four C–C bonds and two
During the past few years, multicomponent domino reac- C–N bonds) and three new rings (a tricyclic 5-6-6 skeleton
tions (MDRs), in which multiple reactions are combined into a consisting of cyclopentene and two pyridines) were readily
single synthetic operation, have been extensively used in formed in domino fashion. This work represents the first
organic synthesis, as well as in combinatorial and medicinal example of the construction of these special types of poly-
chemistry. Obviation of the need for isolation and purification hydronaphthyridine skeletons in one pot. To optimize the
of the intermediates results in maximization of yields and reaction conditions, the model reaction was investigated under
reduction of waste, making these protocols ecofriendly.6 These different reaction conditions. The results are summarized in
features make MDRs well suited for the construction of Table 1. The addition of catalysts such as L-proline, CAN,
complex molecules from readily available starting materials.7
piperidine, p-toluenesulfonic acid, and silica sulfuric acid did
Recently, we and others have been developing a series of multi- not improve the yields (Table 1, entries 2–6). DMF provided
component reactions that offer easy access to polyfunctionalized higher yields than did other organic solvents and water
(compare entry 7 with entries 8–11), so DMF was chosen as
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China. E-mail: zbhuang@suda.edu.cn, dqshi@suda.edu.cn
the solvent for all further reactions. When the reaction was
carried out at 90 1C, 100 1C, 110 1C, and 120 1C, 4a was obtained
in yields of 79%, 80%, 84%, and 80% (entries 7 and 12–14),
respectively. These experiments showed that conditions of
110 1C in DMF, without a catalyst, under microwave irradiation
provided the highest yield.
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization and spectral data of the Strecker-type reaction products.
CCDC 938367. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc43489c
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Table
1
Optimization of reaction conditions for synthesis of 4a under
Table 3 Synthesis of compounds 6 under microwave irradiation
microwave irradiation
Catalyst
(mol%)
Temp.
(1C)
Time
(min)
Yielda
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
CH3CN
CH3OH
HOCH2CH2OH
H2O
DMF
DMF
—
100
100
100
100
100
100
100
100
100
100
100
90
20
20
20
20
20
20
20
20
20
20
20
20
20
20
43
43
40
Trace
Trace
Trace
80
15
6
51
21
79
84
L-Proline (10)
CAN (10)
Piperidine (10)
p-TsOH (10)
SSA (10)
—
—
—
—
—
—
—
—
9
10
11
12
13
14
110
120
DMF
80
a
The yields were determined by HPLC-MS.
Table 2 Synthesis of compounds 4 under microwave irradiation
Using the optimal conditions, we investigated the substrate
scope of the transformation. The results are summarized in
Table 2. As shown in Table 2, n-butyl and phenyl groups bearing
either electron-withdrawing or electron-donating groups on
the enaminone ring were well tolerated under the reaction
conditions, leading to the final products in satisfactory yields
(up to 93%).
To expand the scope of the current method, glutaraldehyde
(5) was examined as a replacement for o-phthalaldehyde (3).
The desired products, decahydropyrido[2,3,4-gh]phenanthridine
derivatives (6) were obtained. The results are summarized in
Table 3. Phenyl groups bearing either electron-withdrawing or
Scheme 1 Proposed mechanism for formation of compound 4.
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A proposed mechanism for this new four-component domino
reaction is shown in Scheme 1. An initial Knoevenagel conden-
sation of o-phthalaldehyde (3a) with two malononitrile (2) mole-
cules gives the intermediate A. The intermediate B is formed by
Michael addition of enaminone (1) to intermediate A and
cyclization. Intermediate A to B may be a reversible process.
Therefore, from A to B, there may be two isomers formed. One is
syn-B, the other is anti-B. The syn-B is more stable than anti-B
(see ESI†). Moreover, syn-B is favored over anti-B to cyclize the
third ring, so anti-B will go back to A. Finally all A is transformed
to B. The syn-B undergoes imine–enamine tautomerization to
give intermediate C, which subsequently reacts in an intra-
molecular cyclization to give intermediate D. In the last step,
intermediate D undergoes imine–enamine tautomerization to
give the product 4.
In conclusion, we have developed a procedure for the facile
synthesis of various potentially biologically active octahydrobenzo-
[b]indeno[1,2,3-de][1,8]naphthyridine and decahydropyrido[2,3,4-gh]-
phenanthridine derivatives, based on a novel four-component
domino reaction. Using this method, a diverse collection of
benzo[b]indeno[1,2,3-de][1,8]naphthyridine and pyrido[2,3,4-gh]-
phenanthridine derivatives were rapidly constructed with
excellent yields in short reaction times by simply heating a
mixture of enaminones, malononitrile, and o-phthalaldehyde
or glutaraldehyde in DMF, without a catalyst, under microwave
irradiation.
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We are grateful for financial support from the Major Basic
Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049), the
Natural Science Foundation of the Jiangsu Higher Education
Institutions (No. 11KJB150014), a project fund from the Priority
Academic Project Development of the Jiangsu Higher Educa-
tion Institutions and the Foundation of the Key Laboratory of
Organic Synthesis of Jiangsu Province (No. JSK1210).
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0.21 mm), T = 293(2) K, l (Mo-Ka) = 0.71073 Å, monoclinic, space
group: P21/C, a = 14.6432(17) Å, b = 7.6244(9) Å, c = 23.275(3) Å,
b = 104.693(2)1, V = 2513.6(5) Å3, R1 = 0.0840, wR2 = 0.1996.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.