A simple procedure for the synthesis of 4-aza-podophyllotoxin derivatives in water under microwave irradiation conditions

Article abstract of DOI:10.1055/s-2006-950279

4-Aza-podophyllotoxin derivatives were synthesized via the three-component reaction of an aldehyde, an aromatic amine, and either tetronic acid or 1,3-indanedione in water under microwave irradiation conditions. This new protocol has the advantages of hig

Full text of DOI:10.1055/s-2006-950279

LETTER
2785
A Simple Procedure for the Synthesis of 4-Aza-podophyllotoxin Derivatives in
Water under Microwave Irradiation Conditions
Synthesis of
4
h
-Aza-podoph
u
yllotoxin D
e
j
rivativ
i
es ang Tu,*a Yan Zhang,a Junyong Zhang,a Bo Jiang,a Runhong Jia,a Jinpeng Zhang,b Shunjun Ji*b
a
Department of Chemistry, Key Laboratory of Biotechnology for Medicinal Plants, Xuzhou Normal University, Xuzhou, Jiangsu 221116,
P. R. of China
Fax +86(516)83403164; E-mail: laotu@xznu.edu.cn
College of Chemistry and Chemical Engineering, Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou University, Suzhou,
b
Jiangsu 215006, P. R. of China
Received 8 June 2006
H
N
Abstract: 4-Aza-podophyllotoxin derivatives were synthesized via
the three-component reaction of an aldehyde, an aromatic amine,
and either tetronic acid or 1,3-indanedione in water under micro-
wave irradiation conditions. This new protocol has the advantages
of higher yield, lower cost, reduced environmental impact, and
convenient procedure.
O
O
O
O
O
O
O
O
O
Key words: multicomponent reactions, heterocycles, indenoquino-
MeO
OMe
MeO
OMe
line, 4-aza-podophyllotoxin, microwave irradiation
OMe
OMe
1
2
Figure 1 Structures of podophyllotoxin 1 and 4-aza-podophyllo-
toxin 2
Multicomponent reactions, in which multiple reactions
are combined into one synthetic operation, have been used
extensively to form carbon–carbon bonds in synthetic
chemistry.1 Such reactions offer a wide range of possibil-
ities for the efficient construction of highly complex
molecules in a single procedural step, thus avoiding com-
plicated purification operations and allowing savings of
both solvents and reagents. Organic reactions accelerated
by microwave irradiation have attracted considerable
attention over the past number of years for the efficient
synthesis of a variety of organic compounds.2 The use of
microwave irradiation for the formation of carbon–het-
eroatom and carbon–carbon bonds has been successfully
demonstrated.3
via the sequence condensation, cyclization, and reduction.
However, this method was less efficient and the scope was
limited. Tratrat et al.7c also reported the synthesis of
4-aza-podophyllotoxin derivatives by the one-pot reaction
of an aldehyde, tetronic acid, and an aniline in refluxing
ethanol with the limitation that the aniline must be substi-
tuted in the meta-position by an electron-donating group.
In continuation of our recent interest in the synthesis of
heterocyclic compounds,8 we herein developed a green
multicomponent reaction consisting of aldehyde 3, aro-
matic amine 4, and tetronic acid 5 in water under micro-
wave irradiation conditions without using any catalyst to
afford a new series of 4-aza-podophyllotoxin derivatives
6 (Scheme 1).
The use of water as a solvent has many advantages in
organic synthesis from both economic and environmental
points of view.4 Water has therefore become an attractive
medium for many organic reactions, not only as one can
avoid to use drying reactants and expensive catalysts and
solvents, but also for its unique reactivity and selec-
tivity.5,6
R
NH2
O
O
H2O
MW
O
RCHO +
R'
+
O
O
N
H
Podophyllotoxin 1 (Figure 1) is an anti-tumor lignan that
inhibits microtubule assembly. Attempts to use it for the
treatment of human neoplasia were mostly unsuccessful
and were complicated by side effects. Extensive structural
modifications have been performed in order to obtain
more potent and less toxic anticancer agents. Among
them, 4-aza-podophyllotoxin (2, Figure 1) has attracted
much attention recently.7 Takeya and co-workers7a,b re-
ported the synthesis of 4-aza-podophyllotoxin derivatives
R'
3
4
5
6
Scheme 1
Choosing an appropriate solvent is of crucial importance
for the successful microwave-assisted synthesis. To
search for the optimal solvent, the reaction of 4-bro-
mophenyl aldehyde (3b), p-toluidine (4b), and tetronic
acid (5) was examined using water, glycol, DMF, glacial
acetic acid, and ethanol as solvents, respectively, at 80 °C
under microwave irradiation conditions. All the reactions
were carried out at the maximum power of 300 W
(Table 1).
SYNLETT 2006, No. 17, pp 2785–2790
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950279; Art ID: W11506ST
© Georg Thieme Verlag Stuttgart · New York

2786
S. Tu et al.
LETTER
As shown in Table 1, the reactions using glycol or water delight, under the above optimized conditions, the reac-
as the solvent resulted in higher yields and shorter reac- tions proceeded smoothly. The indeno[1,2-b]quinoline
tion times than those using acetic acid, DMF, and ethanol derivatives 8 were obtained (Scheme 2) in excellent yields
as solvents. Water was used as the solvent for all further (Table 3).11
microwave-assisted reactions as it is environmentally
friendly and the use of toxic organic reagents can be
R
NH2
O
O
avoided.
H2O
MW
+
+
RCHO
Table 1 Solvent Optimization for the Synthesis of 6c under Micro-
N
H
wave Irradiation Conditions at 80 °C
R'
R'
O
3
4
7
8
Entry
Solvent
glycol
H2O
Power (W) Time (min) Yield (%)
Scheme 2
1
2
3
4
5
300
300
300
300
300
12
12
15
16
18
86
85
71
63
60
As shown in Table 2 and Table 3 this protocol could be
applied not only to aromatic aldehydes with either elec-
tron-withdrawing or electron-donating groups, but also to
heterocyclic and aliphatic aldehydes. A wide range of
aromatic amines including phenylamine, p-toluidine, 1-
naphthylamine, and 2-naphthylamine were employed
successfully in this reaction with excellent results.
AcOH
DMF
EtOH
To optimize the reaction temperature, the synthesis of 6c
was performed using water as the solvent at temperatures
ranging from 80 to 120 °C, with an increment of 10 °C
each time. The yield of product 6c was increased and the
reaction time was shortened when the temperature was
increased from 80 °C to 100 °C. The yield levelled off
when the temperature was further increased to 110 and
120 °C. Therefore, the most suitable temperature should
be 100 °C.
Moreover, the synthesis of 6j was performed under both
microwave irradiation and classical heating conditions at
100 °C. The reaction was efficiently promoted by micro-
wave irradiation and the reaction time was strikingly
shortened to four minutes, from the six hours required
under traditional heating conditions, and the yield was
increased to 97% from 72%. Therefore, microwave irradi-
ation exhibited several advantages over conventional
heating by significantly reducing the reaction time and
dramatically improving the reaction yield.
The power of microwave irradiation was optimized by
carrying out the same reaction for the synthesis of 6c at
50, 100, 150, 200, 250, and 300 W respectively, using
water as the solvent. At 50 W and 100 W, the time taken
for the temperature to reach 100 °C was too long. Micro-
wave irradiation at 150 W generated the highest yield, and
the highest temperature reached during the reaction was
103 °C. Therefore, microwave power of 150 W was
chosen as the optimal power.
Although the detailed mechanism of the above reaction
remains to be fully clarified, the formation of 4-aza-podo-
phyllotoxin derivatives 6 could be explained by the reac-
tion sequence presented in Scheme 3. When the reactants
were added into the vessel a yellow solid product 9 from
the condensation of aldehyde and aromatic amine ap-
peared immediately, which was separated and identified
by IR and 1H NMR spectral data. We therefore proposed
that the reaction proceeded via a reaction sequence of con-
densation, addition, cyclization, and dehydration. First,
the condensation of aldehyde 3 and aromatic amine 4 gave
Schiff base 9. The addition of Schiff base 9 to tetronic acid
5 then furnished the intermediate product 14, which upon
intermolecular cyclization and dehydration gave rise to 6.
Furthermore, the volume of water was important as well
to the yields of the reactions. The synthesis of 6c was test-
ed in different volumes of water at 100 °C under micro-
wave irradiation conditions. When 2.0 mL of water was
used as solvent for the reaction [4-bromophenyl aldehyde
(3b, 1 mmol), p-toluidine (4b, 1 mmol), tetronic acid (5,
1 mmol)], the yield was the highest.
To test the mechanism described above, the reaction of in-
termediate product 9f12,13 and tetronic acid 5 was carried
out in water at 100 °C under microwave irradiation condi-
tions. The target compound 6f14 was obtained, in similar
yields by the one-pot reaction. The results supported the
proposed mechanism (Scheme 4).
Under the optimized conditions [water (2.0 mL), 100 °C,
150 W], the 4-aza-podophyllotoxin derivatives 6 were
synthesized9 (Table 2).
In order to expand the scope of the present method, the re-
placement of tetronic acid (5) with 1,3-indanedione 7 was
examined. This is particularly attractive because indeno-
quinoline is one of the most important ‘privileged scaf-
folds’. Compounds with this motif show a wide range of
biological activities such as 5-HT-receptor binding10a and
anti-inflammatory activities,10b and also act as anti-tumor
agents,10c,d inhibitors for steroid reductase,10e acetyl-
cholinesterase inhibitors,10f and antimalarials.10g To our
In this study, all the products were characterized by melt-
1
ing point, IR and H NMR spectral data, as well as ele-
mental analyses. Furthermore, the structure of 6n was
established by X-ray crystallographic analysis
(Figure 2).15
Synlett 2006, No. 17, 2785–2790 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Aza-podophyllotoxin Derivatives
2787
Table 2 Synthesis of 6 in Water under Microwave Irradiation Conditions at 100 °C
Entry
1
6
3
R
4
Amine
Time (min)
Yield (%)a
96
Mp (°C)
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
6a
6b
6c
6d
6e
6f
3a
3b
3b
3c
3d
3e
3f
4-FC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
3-NO2C6H4
Ph
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
phenylamine
5
5
6
6
3
7
4
5
7
4
3
6
3
5
7
5
3
6
3
2
phenylamine
97
3
p-toluidine
95
4
p-toluidine
95
5
p-toluidine
96
6
p-toluidine
97
7
6g
6h
6i
p-toluidine
98
8
3a
3b
3c
3d
3g
3h
3a
3b
3c
3d
3e
3i
4-FC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
thiophen-2-yl
Bu
1-naphthylamine
1-naphthylamine
1-naphthylamine
1-naphthylamine
1-naphthylamine
1-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
95
9
96
10
11
12
13
14
15
16
17
18
19
6j
97
6k
6l
97
97
6m
6n
6o
6p
6q
6r
6s
94
4-FC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
3-NO2C6H4
3,4-Cl2C6H3
93
98
93
94
96
95
a Isolated yields.
O
NH2
O
O
H
O
OH
O
– H2O
O
5
RCHO
N
CH
R
N
C
H
R
R'
R'
R'
3
9
10
4
R
O
O
R'
R'
O
R
OH
NH2
O
O
CH
R
NH
11
C
H
R
O
R'
NH
O
13
12
R
O
O
R
O
R'
– H2O
O
O
O
N
H
O
R'
N
H
OH
NH2
R'
6
14
15
Scheme 3
Synlett 2006, No. 17, 2785–2790 © Thieme Stuttgart · New York

2788
S. Tu et al.
LETTER
Table 3 Synthesis of 8 in Water under Microwave Irradiation Conditions at 100 °C
Entry
1
8
3
R
4
Amine
Time (min) Yield (%)a
Mp (°C)
8a
8b
8c
8d
8e
8f
3a
3b
3c
3d
3j
4-FC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
4-FC6H4
4-BrC6H4
4-ClC6H4
3-NO2C6H4
Ph
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
p-toluidine
7
6
5
4
7
5
4
3
5
6
6
7
6
6
4
5
3
96
93
94
97
95
97
96
93
94
95
98
96
93
93
95
97
97
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
2
p-toluidine
3
p-toluidine
4
p-toluidine
5
p-toluidine
6
3a
3b
3c
3e
3f
1-naphthylamine
1-naphthylamine
1-naphthylamine
1-naphthylamine
1-naphthylamine
1-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
2-naphthylamine
7
8g
8h
8i
8
9
10
11
12
13
14
15
16
17
8j
8k
8l
3g
3a
3b
3c
3d
3e
3f
thiophen-2-yl
4-FC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
3-NO2C6H4
Ph
8m
8n
8o
8p
8q
a Isolated yields.
NO2
NO2
H2O
MW
O
O
O
+
Me
O
O
HC
N
Me
N
H
9f
5
6f
Scheme 4
In conclusion, we have developed a three-component re-
action of an aldehyde, an aromatic amine, and either
tetronic acid or 1,3-indanedione for the synthesis of 4-aza-
podophyllotoxin derivatives in water under microwave ir-
radiation conditions. Particularly valuable features of this
method include excellent yields of the products, shorter
reaction time, reduced environmental impact, and
straightforward procedure.
Figure 2 ORTEP diagram of 6n
Synlett 2006, No. 17, 2785–2790 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Aza-podophyllotoxin Derivatives
2789
and filtered to give the crude product, which was further
purified by recrystallization (DMF–EtOH) to give pure 4-
aza-podophyllotoxin derivatives 6.
Acknowledgment
We are grateful for financial support from the National Natural
Science Foundation of China (No. 20372057), Natural Science
Foundation of the Jiangsu Province (No. BK2006033), the Natural
Science Foundation of Jiangsu Education Department (No.
01KJB15008), and the Key Lab of Biotechnology for Medicinal
Plants of Jiangsu Province (01AXL 14).
Compound 6c: Yellow solid; mp > 300 °C. IR (KBr): 3233,
3181, 3119, 3075, 2985, 2931, 1712, 1640, 1545, 810, 756,
689 cm–1. 1H NMR (DMSO-d6, 400 MHz): d = 10.01 (1 H,
s, NH), 7.46 (2 H, d, J = 8.4 Hz, ArH), 7.16 (2 H, d, J = 8.0
Hz, ArH), 6.96 (1 H, d, J = 7.6 Hz, ArH), 6.85–6.82 (2 H, m,
ArH), 5.00 (1 H, s, CH), 4.97–4.85 (2 H, m, CH2), 2.13 (3 H,
s, CH3). Anal. Calcd for C18H14BrNO2: C, 60.69; H, 3.96; N,
3.93. Found: C, 60.75; H, 3.90; N, 3.89. Compound 6h:
Yellow solid; mp >300 °C. IR (KBr): 3276, 3059, 2927,
2858, 1727, 1645, 1538, 1509, 1488, 803, 782, 758, 733, 723
cm–1. 1H NMR (DMSO-d6, 400 MHz): d = 10.28 (1 H, s,
NH), 8.22 (1 H, d, J = 8.4 Hz, ArH), 7.86 (1 H, d, J = 8.0
Hz, ArH), 7.65–7.49 (3 H, m, ArH), 7.30–7.27 (2 H, m,
ArH), 7.19–7.07 (3 H, m, ArH), 5.24 (1 H, s, CH), 5.11–4.97
(2 H, m, CH2). Anal. Calcd for C21H14FNO2: C, 76.12; H,
4.26; N, 4.23. Found: C, 76.23; H, 4.20; N, 4.16. Compound
6q: Yellow solid; mp >300 °C. IR (KBr): 3231, 3108, 3057,
2958, 2934, 1722, 1650, 1600, 1584, 1532, 814, 777, 742
cm–1. 1H NMR (DMSO-d6, 400 MHz): d = 10.27 (1 H, s,
NH), 7.86–7.79 (3 H, m, ArH), 7.39–7.27 (3 H, m, ArH),
7.11 (2 H, d, J = 8.8 Hz, ArH), 6.75 (2 H, d, J = 8.4 Hz,
ArH), 5.61 (1 H, s, CH), 4.98–4.87 (2 H, m, CH2), 3.64 (3 H,
s, OCH3). Anal. Calcd for C22H17NO3: C, 76.95; H, 4.99; N,
4.08. Found: C, 77.01; H, 4.95; N, 4.02.
References and Notes
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(9) Compounds 6; General Procedure: All reactions were
performed in a monomodal EmrysTM Creator from Personal
Chemistry, Uppsala, Sweden. In a 10-mL EmrysTM reaction
vial, aldehyde 3 (1 mmol), aromatic amine 4 (1 mmol),
tetronic acid 5 (1 mmol), and H2O (2 mL) were mixed and
then capped. The mixture was irradiated at 150 W and 100
°C for a given time. The reaction mixture was cooled to r.t.
(10) (a) Anzini, M.; Cappelli, A.; Vomero, S.; Cagnotto, A.;
Skorupska, M. Med. Chem. Res. 1993, 3, 44. (b) Quraishi,
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Kaye, A. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A.
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Andrisano, V.; Cavrini, V.; Cavalli, A.; Recanatini, M.
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(11) Compounds 8; General Procedure: In a 10-mL EmrysTM
reaction vial aldehyde 3 (1 mmol), aromatic amine 4 (1
mmol), 1:3-indanedione 7 (1 mmol), and H2O (2 mL) were
mixed and then capped. The mixture was irradiated at 150 W
and 100 °C for a given time. The reaction mixture was
cooled to r.t. and filtered to give the crude product which was
further purified by recrystallization (DMF–EtOH) to give
pure indeno[1,2-b]quinoline derivatives 8. Compound 8m:
Yellow solid; mp >300 °C. IR (KBr): 3220, 3065, 2855,
1710, 1662, 1574, 1533, 1485, 858, 738, 645 cm–1. 1H NMR
(DMSO-d6, 400 MHz): d = 10.99 (1 H, s, NH), 7.94 (1 H, d,
J = 8.8 Hz, ArH), 7.87 (2 H, t, J = 8.0 Hz, ArH), 7.63 (1 H,
d, J = 7.2 Hz, ArH), 7.53 (1 H, d, J = 8.8 Hz, ArH), 7.49–
7.34 (6 H, m, ArH), 7.27 (1 H, d, J = 8.0 Hz, ArH), 7.20 (2
H, d, J = 8.4 Hz, ArH), 5.80 (1 H, s, CH). Anal. Calcd for
C26H16BrNO: C, 71.25; H, 3.68; N, 3.20. Found: C, 71.34; H,
3.62; N, 3.10.
(12) (a) Proks, V.; Holik, M. Collect. Czech. Chem. Commun.
2004, 69, 1566. (b) Rothenberg, G.; Downie, A. P.; Raston,
C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701.
(c) Froeyen, P. Phosphorus, Sulfur Silicon Relat. Elem.
1993, 81, 37.
Synlett 2006, No. 17, 2785–2790 © Thieme Stuttgart · New York

2790
S. Tu et al.
LETTER
(13) Compound 9f: In a 10-mL EmrysTM reaction vial 3-nitro-
benzaldehyde (3e, 2 mmol), p-toluidine (4b, 2 mmol), and
H2O (3 mL) were mixed and then capped. The mixture was
irradiated at 150 W and 100 °C for 2 min. The reaction
mixture was cooled to r.t. and filtered to give the crude
product which was further purified by recrystallization
(EtOH) to give pure N-(3-nitrobenzylidene)-4-methyl-
benzenamine (9f). Yellow solid; mp 87–88 °C. IR (KBr):
3092, 3026, 2879, 1622, 1572, 1440, 1268, 1044, 860, 765
cm–1. 1H NMR (DMSO-d6, 400 MHz): d = 8.76 (1 H, s, CH),
8.58 (1 H, s, ArH), 8.33 (1 H, d, J = 8.0 Hz, ArH), 8.27 (1 H,
d, J = 7.6 Hz, ArH), 7.68 (1 H, d, J = 8.0 Hz, ArH), 7.29–
7.20 (4 H, m, ArH), 2.41 (3 H, s, CH3). Anal. Calcd for
C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.09;
H, 4.95; N, 11.60.
(14) Reaction of Schiff Base 9f and Tetronic Acid (5): In a 10-mL
EmrysTM reaction vial, N-(3-nitrobenzylidene)-4-methyl-
benzenamine (9f, 1 mmol), tetronic acid (5, 1 mmol), H2O
(2 mL) were mixed and then capped. The mixture was
irradiated at 150 W and 100 °C for 7 min. The reaction
mixture was cooled to r.t. and filtered to give the crude
product, which was further purified by recrystallization
(DMF–EtOH) to give pure 7-methyl-9-(3-nitrophenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1 (3H)-one(6f). Yellow solid;
mp >300 °C. IR (KBr): 3237, 3183, 3121, 3077, 2932, 1714,
1640, 1544, 1348, 1205, 1109, 934, 861 cm–1. 1H NMR
(DMSO-d6, 400 MHz): d = 10.11 (1 H, s, NH), 8.05 (2 H, d,
J = 7.2 Hz, ArH), 7.69 (1 H, d, J = 7.6 Hz, ArH), 7.60 (1 H,
t, J = 8.0 Hz, ArH), 7.00 (1 H, d, J = 8.4 Hz, ArH), 6.89 (2
H, t, J = 8.0 Hz, ArH), 5.26 (1 H, s, CH), 5.02–4.88 (2 H, m,
CH2), 2.13 (3 H, s, CH3). Anal. Calcd for C18H14N2O4: C,
67.07; H, 4.38; N, 8.69. Found: C, 67.15; H, 4.29; N, 8.54.
(15) The single crystal growth was carried out in EtOH–DMF at
r.t. X-ray crystallographic analysis was performed with a
Siemens SMART CCD and a Semens P4 diffractometer
(graphite monochromator, Mo Ka radiation l = 0.71073 Å).
Crystal data for 6n: Empirical formula C21H14FNO2, yellow,
crystal dimension 0.23 × 0.18 × 0.16 mm, monoclinic, space
group C2/c, a = 21.010 (7) Å, b = 11.388 (4) Å, c = 15.123
(5) Å, a = 90°, b = 121.380 (5)°, g = 90°, V = 3089.3 (16)
Å3, Mr = 331.33, Z = 8, Dc = 1.425 Mg/m3, l = 0.71073 Å,
m (Mo-Ka) = 0.100 mm–1, F(000) = 1376, S = 0.991,
R1 = 0.049, wR2 = 0.136. Crystallographic data for the
structures of 6n reported in this letter have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC-608399.
Synlett 2006, No. 17, 2785–2790 © Thieme Stuttgart · New York