An efficient and expeditious microwave-assisted synthesis of 4-azafluorenones via a multi-component reaction

Article abstract of DOI:10.1016/j.tetlet.2006.12.102

An efficient and expeditious microwave-assisted synthesis of 4-azafluorenone derivatives and related compounds is accomplished via a multi-component reaction of an aldehyde, 1,3-indanedione, an arone and ammonium acetate. It is an efficient and promising

Full text of DOI:10.1016/j.tetlet.2006.12.102

Tetrahedron Letters 48 (2007) 1369–1374
An efficient and expeditious microwave-assisted synthesis
of 4-azafluorenones via a multi-component reaction
Shujiang Tu,* Bo Jiang, Runhong Jia, Junyong Zhang and Yan Zhang
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology for Medicinal Plant,
Xuzhou, Jiangsu 221116, PR China
Received 27 October 2006; revised 18 December 2006; accepted 19 December 2006
Available online 20 December 2006
Abstract—An efficient and expeditious microwave-assisted synthesis of 4-azafluorenone derivatives and related compounds is
accomplished via a multi-component reaction of an aldehyde, 1,3-indanedione, an arone and ammonium acetate. It is an efficient
and promising synthetic strategy to build indenopyridine skeleton.
Ó 2006 Elsevier Ltd. All rights reserved.
Multi-component reactions (MCRs) are of increasing
importance in organic and medicinal chemistry, because
the strategies of MCR offer significant advantages over
conventional linear-type syntheses. MCRs leading to
interesting heterocyclic scaffolds are particularly useful
for the creation of diverse chemical libraries of ‘drug-
like’ molecules for biological screening, since the combi-
nation of three or more small molecular weight building
blocks in a single operation leads to a high combinato-
rial efficacy.1
Several approaches have been developed for the syn-
thesis of the 5H-indeno[1,2-b]pyridin-5-ones: oxidative
thermal rearrangement of 2-indanone oxime O-ally1
ethers;7 direct cyclization of 2-aryl-3-methylpyridines
to give 5H-indeno[1,2-b]pyridines followed by oxida-
tion;8 cyclization of 2-aryl-3-nicotinic acids by the use
of polyphosphoric acid.8,9 Other ways to build 5H-
indeno[1,2-b]pyridin-5-ones are the extrusion of
organophosphorus compound.10 In addition, there are
some modern strategies to synthesize 5H-indeno[1,2-b]-
pyridin-5-ones, for example, Pummerer reaction of
imidosulfoxides11 or especially Pd(0)-catalyzed cross-
coupling reaction12 between arylboronic acids and 2-
halopyridines, which result in excellent yields of the
desired products. However, even these methods are still
not satisfactory in view of using toxic catalyst, narrow
application scope of substrates, harsh reaction condi-
tions, generality and operational complexity due to the
occurrence of several side reactions. Thus, a simple,
rapid and efficient procedure is still strongly desired for
the synthesis of these important heterocyclic compounds.
The development of efficient chemical processes for
the preparation of new biologically active molecules
constitutes a major challenge for chemists in organic
synthesis. The 4-azafluorenone (5H-indeno[1,2-b]pyridin-
5-one) alkaloids from Annonaceae species comprise a
small but biologically intriguing group of alkaloids.2
4-Azafluorenone derivatives were found to exhibit
adenosine A2a receptor binding and phosphodiesterase
inhibiting activities for the treatment of neurodegenera-
tive disorders and inflammation related diseases.3 They
also acted as calcium antagonistic activators4 and her-
bicides.5 Therefore, these compounds have distin-
guished themselves as heterocycles of profound
chemical and biological significance. As a result, the
synthesis of these molecules has attracted considerable
attention.6
With the aim to develop more efficient synthetic pro-
cesses, reduce the number of separate reaction steps,
and minimize byproducts, and in continuation of our
recent interest in the construction of heterocyclic
scaffolds,13 we herein describe a practical, inexpensive,
rapid microwave-promoted (MW) method for the prep-
aration of indenopyridine derivatives 4 via multi-com-
ponent reactions of aldehydes 1, 1,3-indanedione 2
and arones 3 in the presence of ammonium acetate
(Scheme 1).
*
Corresponding author. Tel.: +86 516 83403163; fax: +86 516
83403164; e-mail: laotu2001@263.net
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.102

1370
S. Tu et al. / Tetrahedron Letters 48 (2007) 1369–1374
Ar
N
O
O
NH4OAc / DMF
Ar'COCH3
+
Ar
+
CHO
MW
Ar'
O
1
2
3
4
Scheme 1.
To explore the scope and versatility of this method, var-
ious reaction conditions were investigated, including sol-
vent and temperature variations. Highlighted in Table 1
for compound 4a, for example, is the influence of sol-
vent on the reaction yield. The MW-assisted reaction
of 4-nitrobenzaldehyde (1a, 1.0 mmol), 1,3-indanedione
(2, 1.0 mmol) and arones (3, 1.0 mmol) in the presence
of ammonium acetate (2.5 mmol) was examined using
glycol, glacial acetic acid (HOAc), ethanol and N,N-
dimethylformamide (DMF) as the solvent (1.0 mL)
and solvent-free at 100 °C, respectively. All the reactions
were carried out at the maximum power of 300 W.
The results are summarized in Table 1.
improve the yield of product 4a (Table 1, entries 9–
10). Therefore, 120 °C was chosen as the reaction tem-
perature for all further microwave-assisted reactions
(Scheme 2).
The maximum power of microwave irradiation was
optimized by carrying out the same reaction at powers
of 50, 100, 150, 200, 250 and 300 W, respectively, using
DMF as the solvent at 120 °C. When the power was at
50–100 W, the time taken for the temperature to reach
120 °C was too long. Microwave irradiation at 200 W
gave the highest yield and the maximum temperature
reached during the reaction was 124 °C. Therefore,
microwave power of 200 W was chosen as the optimum
power.
It is shown in Table 1 that the reaction using DMF as
solvent gave the best result (Table 1, entry 5). So
DMF was chosen as the reaction solvent. To further
optimize reaction conditions, the same reaction was car-
ried out in DMF at temperatures ranging from 90 to
140 °C, with an increment of 10 °C each time. The yield
of product 4a was increased and the reaction time was
shortened as the temperature was increased from 90 °C
to 120 °C (Table 1, entries 1–5). However, further
increase of the temperature to 130–140 °C failed to
The use of these optimal microwave experimental condi-
tions [DMF, 120 °C, 200 W (maximum power)] to the
reactions of different aromatic aldehydes afforded good
yields of indeno[1,2-b]pyridine-5-ones, with an aryl
group presenting in position 2 of the indeno[1,2-b]pyri-
dine nucleus. As shown in Table 2, at the beginning,
we made a search for the aldehyde substrate scope,
arone 3a and 1,3-indanedione were used as model sub-
strates (Table 2, entries 1–8), and the results indicated
that aromatic aldehydes bearing either electron-donat-
ing or electron-withdrawing functional groups such as
nitro, chloro, hydroxy, or methoxy were able to affect
the synthesis of compounds 4. We have also observed
delicate electronic effects: that is, aryl aldehydes with
electron-withdrawing groups (Table 2, entries 1–4)
reacted rapidly, while the substitution of electron-rich
groups (Table 2, entries 5 and 6) on the benzene ring
decreased the reactivity, requiring longer reaction times.
Moreover, the heterocyclic aldehydes such as thio-
phene-2-carbaldehyde (Table 2, entry 7) and furan-2-
carbaldehyde (Table 2, entry 8) still displayed a high
reactivity under this standard condition.
Table 1. Optimization of reaction conditions of compound 4a
Entry
Solvent
T (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
Glycol
HOAc
EtOH
None
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
90
110
120
130
140
12
10
12
10
8
10
8
6
64
35
58
69
75
61
81
89
85
88
6
6
10
NO2
OCH3
NO2
O
O
O
NH4OAc
+
+
MW
N
CHO
1a
O
H3CO
2
4a
3a
Scheme 2.

S. Tu et al. / Tetrahedron Letters 48 (2007) 1369–1374
Table 2. Synthesis of 4 and 6 under microwave irradiation at 120 °C20
1371
Entry
Product
Ar
3
Ar0
Time (min)
Yield (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4a
4b
4c
4d
4e
4f
4-NO2C6H4
3-NO2C6H4
2-ClC6H4
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3c
3d
3e
3e
3e
3e
3e
3a
3a
3a
3c
3f
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
2,4-Cl2C6H3
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-FC6H4
C6H5
2-Pyridyl
6
8
9
89
85
82
80
78
81
76
65
88
84
83
86
89
87
83
79
62
73
78
69
83
79
81
83
74
57
224–226
220–221
264–265
195–196
218–220
242–244
245–247
178–179
226–228
224–226
195–197
263–264
260–263
270–272
251–253
247–249
180–182
160–161
173–174
178–180
189–191
186–188
279–280
176–178
205–206
192–194
4-FC6H4
8
4-CH3OC6H4
3,4-OCH2OC6H3
2-Thienyl
2-Furyl
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-ClC6H4
4-OH-3-NO2C6H3
3-NO2C6H4
4-BrC6H4
4-CH3C6H4
2-Thienyl
4-CH3C6H4
2-Thienyl
2-Furyl
4-BrC6H4
4-ClC6H4
3-NO2C6H4
4-BrC6H4
3,4-OCH2OC6H3
2-Thienyl
12
12
14
15
8
9
10
8
10
12
10
14
12
15
11
12
10
12
8
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
6a
6b
6c
6d
6e
6f
3e
3e
3e
3e
6g
6h
6i
2-Pyridyl
2-Pyridyl
2-Pyridyl
8
10
10
To further expand the scope of arone substrates, differ-
ent aldehydes and 1,3-indanedione as model substrates
and examined various aromatic ketone including 3b,
3c, 3d and 3e. In all these cases, the reactions proceeded
smoothly to give the corresponding 5H-indeno[1,2-
b]pyridin-5-ones in good yields of 62–89%. It is worth
noting that this result is significant since there is no lit-
erature precedent for the synthesis of 2-(pyridin-2-yl)-
indeno[1,2-b]pyridine (Table 2, entries 13–17).
aromatic ketone 3 in the presence of ammonium acetate.
To our delight, a series of indeno[1,2-b]pyridines were
obtained in good yields without byproducts (Scheme
4). The results were summarized in Table 2. A diverse
range of 2-arylidene-2,3-dihydroinden-1-ones 9 with
either electron-withdrawing groups or electron-donating
O
O
Ar CHO
In order to further expand the scope of the present
method, the replacement of 1,3-indanedione with 1-
indenone was examined. The reaction proceeded
smoothly, too. A desired 2,4-diaryl-5H-indeno[1,2-
b]pyridine (6a) was obtained, accompanied with com-
pounds 7a and 814,20 (Scheme 3).
Ar
9
5
Ar
N
O
O
NH4OAc
120 oC
Ar'
+
DMF
Ar
Ar'
With the aim to improve the yields of indeno[1,2-b]pyr-
idines 6 and minimize the byproducts, 2-arylidene-2,3-
dihydroinden-1-ones 915 were employed to react with
3
9
6
Scheme 4.
Ar
Ar
Ar CHO
O
1
Ar'
N
Ar'
N
Ar'
NH4OAc
+
Ar'COCH3
+
7a
6a
120 °C
DMF
Ar
5
3
Ar = 4-CH3C6H4
Ar' = 4-CH3OC6H4
N
8
Scheme 3.

1372
S. Tu et al. / Tetrahedron Letters 48 (2007) 1369–1374
Ar
O
Ar
O
Ar-CHO
+
O
1
Ar'
N
Ar'
N
H
11
NH4OAc
MW
+
Ar'COCH3
7b
O
Ar
O
3
10
Ar = 4-ClC6H4
Ar' = 4-CH3OC6H4
N
H
Ar'
12
Scheme 5.
wave heating. Simultaneously, the reaction times was
strikingly shortened to minutes from hours required in
traditional heating condition, and the yields were
increased obviously too. The difference in yields
(MW > CH) may be a consequence of both thermal
effects and specific effects induced by the microwave
field.17
Table 3. The synthesis of some of compound 4 using conventional
heating
Entry
Product
Time (h)
Yield (%)
1
2
3
4
5
4a
4e
4i
2
2
2
2
2
84
69
74
79
72
4o
4p
To the best of our knowledge, the pKa value in the active
hydrogen of 1,3-indanedione (pKa = 7.2)18 is lower than
that of arones, indicating that the aldehyde was prefera-
bly condensed with 1,3-indanedione. Therefore, the
formation of 4 is expected to proceed via initial
condensation of aldehydes with 1,3-indanedione to
afford 2-arylidene-indene-1,3-dione 13, which further
undergoes in situ Michael addition with 1-arylethen-
amine 14, obtained by treating aromatic ketone with
ammonia from ammonium acetate, to yield intermediate
15, which is then cyclized and subsequently dehydro-
genated to afford the aromatized products 4 (Scheme
6). This type of hydrogen loss was well precedented.19
groups can likewise take part in this reaction, leading to
the preparation of a series of corresponding 2,4-diaryl-
5H-indeno[1,2-b]pyridines 6.
In a further study, dimedone 10 was employed instead of
1,3-indanedione 2 in this case.20 The reactions pro-
ceeded smoothly too. However, the different products
1116 and 7b were observed instead of the desired prod-
ucts 12. The reason may be attributed to the stability
of intermediate. With being greater conjugate system
than that of 2-arylidenedimedone by the reaction of
aldehyde with dimedone, intermediate 13 was easily
obtained, while the intermediate, 2-arylidenedimedone,
displayed a higher reactivity and instability, which pref-
erably reacted with dimedone and ammonia to produce
the acridine derivatives 11 (Scheme 5).
The structures of all the synthesized compounds were
established on the basis of their spectroscopic data.
The IR spectrum of compound 4k showed a strong
absorption at 1710 cmꢀ1 due to the C@O group. The
1H NMR spectrum of 4k showed a singlet at d 7.86
due to CH proton in the formed pyridine ring, and a sin-
glet at d 3.88 due to –OCH3 group.
Additionally, to demonstrate the purely nonthermal
microwave effects, the same temperature was applied
to synthesize some of the products under classical heat-
ing (CH) conditions. The results listed in Table 3
showed the specific activation of this reaction by micro-
In summary, we have developed a microwave-assisted
multi-component condensation of aldehydes, 1,3-indan-
O
O
HN
Ar
H2N
Ar'
ArCHO
NH3
Ar'
Ar'
Ar
O
O
2
O
14
13
3
Ar
O
Ar
N
O
O
-2H
Ar'
-H2O
Ar
Ar'
NH2
O
'
N
H
15
4
Scheme 6.

S. Tu et al. / Tetrahedron Letters 48 (2007) 1369–1374
1373
9. Zhang, J.; el-Shabrawy, O.; el-Shabrawy, M. A.; Schiff,
P. L., Jr.; Slatkin, D. J. J. Nat. Prod. 1987, 50, 800.
10. Nitta, M.; Ohnuma, M.; Lino, Y. J. Chem. Soc., Perkin
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11. Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T. J. Org.
Chem. 2000, 65, 2368.
12. Alves, T.; de Oliveira, A. B.; Snieckus, V. Tetrahedron
Lett. 1988, 29, 2135.
13. (a) Tu, S. J.; Jiang, B.; Jia, R. H.; Zhang, J. Y.; Zhang, Y.;
Yao, C. S.; Shi, F. Org. Biomol. Chem. 2006, 4, 3664; (b)
Tu, S. J.; Jiang, B.; Zhang, J. Y.; Jia, R. H.; Zhang, Y.;
Yao, C. S. Org. Biomol. Chem. 2006, 4, 3980.
edione or 1-indenone and aromatic ketones in the pres-
ent of ammonium acetate using DMF as a solvent and
have shown its application to the synthesis of a number
of poly-substituted indeno[1,2-b]pyridines. In light of its
operational simplicity, simple purification procedure,
good yields, and reduced environmental impact as well
as increased safety for small-scale high-speed synthesis,
this protocol is superior to the existing methods.
Acknowledgements
14. (a) Tu, S. J.; Li, T. J.; Shi, F.; Wang, Q.; Zhang, J. P.; Xu,
J. N.; Zhu, X. T.; Zhang, X. J.; Zhu, S. L.; Shi, D. Q.
Synthesis 2005, 3045; (b) Miri, R.; Javidnia, K.; Hem-
mateenejad, B.; Azarpira, A.; Amirghofran, Z. Bioorg.
Med. Chem. 2004, 12, 2529.
We are grateful to financial support from the National
Science Foundation of China (Nos. 20372057 and
20672090), Natural Science Foundation of the Jiangsu
Province (No. BK2006033) and Graduate Foundation
of Xuzhou Normal University (No. 06YL004).
15. The Meck Index, 11th ed.; Windholz, M., Ed.; Merck &
Co: Rahway (New Jersey), 1988; p 2028.
16. Tu, S. J.; Lu, Z. S.; Shi, D. Q.; Yao, C. S.; Gao, Y.; Guo,
C. Synth. Commun. 2002, 32, 2181.
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20. General procedure for the synthesis of compounds 4 and 6
with microwave irradiation (microwave reactor EmrysTM
Creator from Personal Chemistry, Uppsala, Sweden):
Preparation of compounds 4: In a 10-mL reaction vial, an
aldehyde (1 mmol), 1,3-indanedione (1 mmol), an arone
(1 mmol), ammonium acetate (2.5 mmol) and DMF
(1.0 mL) were mixed and then capped. The mixture was
irradiated for a given time at power of 200 W and 120 °C.
Upon completion as shown by TLC monitoring, the
reaction mixture was cooled to room temperature and
then poured into cold water. The solid product was
filtered, washed with water and EtOH (95%) and subse-
quently dried and then recrystallized from EtOH (95%) to
give the pure product. Preparation of compounds 6a, 7 and
8 (11 and 12): In a 10-mL reaction vial, an aldehyde
(1 mmol), 1-indaneone (1 mmol) (or dimedone (1 mmol)),
arone (1 mmol), ammonium acetate (2.5 mmol) and DMF
(1.0 mL) were mixed and then capped. The mixture was
irradiated for 10 min at power of 200 W and 120 °C. Upon
completion, as monitored by TLC, the reaction mixture
was cooled to room temperature. The solid was collected
by filtration and washed with water. The solid was purified
by column chromatography on silica gel (200–300 mesh)
using petroleum ether (bp 60–90 °C)–acetone (1:2) as the
eluent to give compounds 6a, 7 and 8 (11 and 12).
Preparation of compounds 6: In a 10-mL reaction vial, an
2-arylidene-2,3-dihydroinden-1-one (1 mmol), an arone
(1 mmol), ammonium acetate (2.5 mmol) and DMF
(1.0 mL) were mixed and then capped. The mixture was
irradiated for a given time at power 200 W and 120 °C.
When the reaction was completed (monitored by TLC),
the subsequent work-up was the same as that of the above
preparation of compounds 4. Spectra data and elemental
analyses of typical compounds were summarized as
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2834, 1710, 1600, 1508, 1362, 1252, 1149, 822, 751; 1H
NMR (400 MHz, DMSO-d6) (d, ppm): 8.42 (dd,
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1374
S. Tu et al. / Tetrahedron Letters 48 (2007) 1369–1374
J1 = 8.8 Hz, J2 = 5.6 Hz, 2H, ArH), 7.98 (d, J = 7.2 Hz,
(s, 2H, CH2), 3.87 (s, 3H, OCH3), 2.40 (s, 3H, CH3). Anal.
Calcd for C26H19NO2: C, 82.74; H, 5.07; N, 3.71. Found
C, 82.91; H, 4.92; N, 3.89. Compound 7b: mp 112–113 °C
(lit. 113.8–115.0 °C);14a Compound 8: mp >300 °C IR
1H, ArH), 7.86 (s, 1H, Py–H), 7.81 (d, J = 8.4 Hz, 2H,
ArH), 7.76 (t, J = 7.6 Hz, 2H, ArH), 7.69 (d, J = 7.2 Hz,
1H, ArH), 7.41 (t, J = 8.8 Hz, 2H, ArH), 7.09 (d,
J = 8.4 Hz, 2H, ArH), 3.88 (s, 3H, OCH3). Anal. Calcd
for C25H16FNO2: C, 78.73; H, 4.23; N, 3.67. Found C,
78.89; H, 4.38; N, 3.45. Compound 6a: IR (KBr, m, cmꢀ1):
3031, 2915, 1612, 1581, 1373, 1253, 1177, 1024, 820, 739;
1H NMR (400 MHz, DMSO-d6) (d, ppm): 8.20 (d,
J = 8.4 Hz, 2H, ArH), 8.11 (d, J = 6.4 Hz, 1H, ArH),
7.87 (d, J = 8.4 Hz, 2H, ArH), 7.86 (s, 1H, Py–H), 7.69–
7.67 (m, 1H, ArH), 7.51–7.48 (m, 2H, ArH), 7.35 (d,
J = 8.4 Hz, 2H, ArH), 7.14 (d, J = 8.4 Hz, 2H, ArH), 4.16
(KBr): 1600, 1562, 1519, 1463, 1290, 850, 770 cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6) (d, ppm): 8.17 (d,
J = 8.0 Hz, 2H, ArH), 8.12 (d, J = 8.0 Hz, 2H, ArH),
7.85 (d, J = 7.2 Hz, 2H, ArH), 7.66 (t, J = 7.2 Hz, 2H,
ArH), 7.64 (t, J = 7.2 Hz, 2H, ArH), 7.50 (d, J = 8.0 Hz,
2H, ArH), 3.97 (s, 4H, ArH), 2.35 (s, 3H, CH3). Anal.
Calcd for C26H19N: C, 90.40; H, 5.54; N, 4.05. Found: C,
90.49; H, 5.46; N, 4.12. Compound 11: mp 294–295 °C (lit.
296–298 °C).16