A facile and efficient synthesis of N-substituted furo[3,4-b] indeno[2,1-e]pyridine analogues of azapodophyllotoxin via microwave-assisted multicomponent reactions

Article abstract of DOI:10.1002/jhet.187

(Chemical Equation Presented) The efficient and facile synthesis of N-substituted furo[3,4-b]indeno[2,1-e]pyridine analogues of azapodophyllotoxin was achieved via microwave-assisted multicomponent reactions of aldehyde, 2H-indene-1,3-dione and 4-(arylami

Full text of DOI:10.1002/jhet.187

September 2009
A Facile and Efficient Synthesis of N-Substituted Furo[3,4-b]
indeno[2,1-e]pyridine Analogues of Azapodophyllotoxin via
Microwave-Assisted Multicomponent Reactions
965
Feng Shi,a,b Ge Zhang,a,b Yan Zhang,c Ning Ma,a,b Bo Jiang,a,b
and Shu-Jiang Tua,b
*
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, Jiangsu
221116, People’s Republic of China
bKey Laboratory of Biotechnology for Medicinal Plant, Xuzhou Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China
cCollege of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093,
People’s Republic of China
*E-mail: laotu2001@263.net
Received December 28, 2008
DOI 10.1002/jhet.187
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
The efficient and facile synthesis of N-substituted furo[3,4-b]indeno[2,1-e]pyridine analogues of
azapodophyllotoxin was achieved via microwave-assisted multicomponent reactions of aldehyde, 2H-in-
dene-1,3-dione and 4-(arylamino)furan-2(5H)-one in glycol without catalyst. This method has the
obvious advantages over traditional heating ones on short reaction time, high yield, operational
simplicity as well as being environmental friendly.
J. Heterocyclic Chem., 46, 965 (2009).
INTRODUCTION
(GT) [23], and proliferation of vascular smooth muscle
cells [24] but also antagonists of adenosine A2a receptor
[25] and human fatty acid synthase thioesterase [26]. It is
promising that the modifications on ring A of azapodo-
phyllotoxin, changed into indenole ring, may bring about
novel or improved significant bioactivities.
Tetronic acid derivatives and their metabolites are
interesting and intriguing compounds because of their
antibiotic [1], anticoagulant [2], antiepileptic [3], anti-
fungal [4], anti-inflammatory [5], and anti-HIV [6]
activities. Among them, azapodophyllotoxin (Fig. 1)
derivatives are also well-known anticancer agents [7]
besides their cardiotonic [8], inotropic [9], pesticidal
[10], potassium channel opening [11], and calcium chan-
nel agonistic [12] activities. Moreover, more potent and
less toxic azapodophyllotoxin derivatives with antitumor
activities have also been obtained by extensive structural
modifications [13]. However, most modifications were
performed on ring B and C (Fig. 1), and the modifica-
tions both on ring A and on nitrogen atom were not
well documented.
However, survey of the literature reveals only two
typical methods on synthesizing N-unsubstituted
furo[3,4-b]indeno[2,1-e]pyridine analogues of azapodo-
phyllotoxin. One method is a multistep reaction com-
posed by cyclocondensation of arylideneindandione with
3-aminocrotonic acid ester, both of which should be pre-
pared beforehand, and subsequently intramolecular cy-
clization treated with NBS to give the target compounds
(Scheme 1) [27]. Evidently, this method suffers from
the drawbacks of long route, low yields, as well as com-
plicated operation.
Indenopyridine skeletons, existed in many natural prod-
ucts, such as, onychine and oracin (Fig. 2) as well as lots
of synthesized heterocyclic compounds, possess numer-
ous significant bioactivities, namely, anticancer [14], anti-
infective [15], anti-inflammatory [16], calcium antagonis-
tic [17], DNA-damaging [18], antimicrobial [19] and anti-
candidal activities [20]. In addition, not only they are
inhibitors against phosphodiesterase [21], cyclic nucleo-
tide synthesis [22], bovine liver glutathione S-transferase
Another method is Hantzsch condensation of 1,3-
indandione, ammonium acetate, and 3-benzylidenefuran-
2,4(3H,5H)-dione (Scheme 2), which was prepared in
advance by condensation of tetronic acid with aromatic
aldehyde [21]. However, this method still has some disad-
vantages such as long reaction time and moderate yields.
In addition, these two methods did not offer the syn-
thesis of N-substituted furo[3,4-b]indeno[2,1-e]pyridine
C
V
2009 HeteroCorporation

966
F. Shi, G. Zhang, Y. Zhang, N. Ma, B. Jiang, and S.-J. Tu
Vol 46
Scheme 1
furan-2(5H)-one 3c was used to optimize the reaction con-
ditions. To find the best suitable solvent, we compared the
synthesis of 4c in different solvents, such as, water, glycol,
DMF, glacial acetic acid, and ethanol. The mixture of
4-bromobenaldehyde 1c (1 mmol), 2H-indene-1,3-dione 2
(1 mmol), 4-(phenylamino)furan-2(5H)-one 3c (1 mmol),
and corresponding solvent (2 mL) was irradiated under
MW at 90ꢀC and 200 W for a given time, then the crude
product was purified by recrystallization from EtOH.
The results (Table 1) reveal that glycol as solvent not
only improve the yield but also shorten the time of this
reaction. Therefore, glycol was preferred as solvent for
all further microwave-assisted reactions.
Figure 1. Structure of azapodophyllotoxin.
analogues of azapodophyllotoxin, which may bring
about great changes in the bioactivities by the modifica-
tions both on nitrogen atom and on ring A of
azapodophyllotoxin.
As a result, developing a facile and efficient method
on the synthesis of N-substituted furo[3,4-b]indeno[2,1-
e]pyridine analogues of azapodophyllotoxin is of great
significance.
Multicomponent reactions (MCRs) are of increasing
importance in organic and medicinal chemistry, because
the strategies of MCR offer significant advantages over
conventional linear-type syntheses [28]. On the other
hand, microwave-assisted organic synthesis has been a
topic of continued studies as it could lead to higher
yields of pure products, easier operation, and shorter
reaction time as compared with the traditional heating
method [29]. Thus, it goes without saying that the use
of atom-economical MCRs, together with the employ-
ment of energy-efficient microwave irradiation (MW),
must be considered to be facile and efficient synthetic
strategy of heterocyclic compounds with important bio-
activities in the sense that the combination in itself
offers greater potential than the two parts in isolation.
As a continuation of our efforts on structural modifi-
cations of azapodophyllotoxin with facile and efficient
method [30], herein, we wish to report the synthesis of
N-substituted furo[3,4-b]indeno[2,1-e]pyridine analogues
of azapodophyllotoxin through three-component reac-
tions of aldehyde 1, 2H-indene-1,3-dione 2 and 4-(aryla-
mino)furan-2(5H)-one 3 in glycol under microwave irra-
diation without catalyst (Scheme 3).
To optimize the reaction temperature, the reaction of
1c (1 mmol), 2 (1 mmol), and 3c (1 mmol) was carried
out using glycol (2 mL) as solvent under MW (200 W) at
temperatures ranging from 70 to 110ꢀC, with an incre-
ment of 10ꢀC each time. Similarly, the crude product was
purified by recrystallization from EtOH. The results are
shown in Table 2. The yield of product 4c was increased
and the reaction time was shortened when the tempera-
ture was increased from 70 to 100ꢀC (Entries 1ꢁ4, Table
2), whereas the yield leveled off when the temperature
was further increased to 110ꢀC (Entry 5, Table 2). Thus,
100ꢀC is assigned as the most suitable reaction tempera-
ture. Furthermore, we found that the yield of this reaction
was affected by the volume of glycol. The synthesis of
4c was tested in different volumes of glycol at 100ꢀC.
The outcomes show that 2.0 mL of glycol is optimal as
solvent because it generates the highest yield of 4c.
Under these optimized reaction conditions (2.0 mL of
glycol, 100ꢀC), a series of novel N-substituted furo[3,4-
b]indeno[2,1-e]pyridine analogues of azapodophyllotoxin
4 were synthesized under MW, and the results were
summarized in Table 3. As shown in Table 3, this
method can be applied to various aromatic aldehydes
and enamines of tetronic acid with high yields under the
same conditions. Therefore, this synthetic approach has
wide scope of applicability.
RESULTS AND DISCUSSION
Initially, the three-component reaction of 4-bromobenal-
dehyde 1c, 2H-indene-1,3-dione 2 and 4-(phenylamino)
Moreover, we also performed the synthesis of 4 in
glycol at 100ꢀC under standard heating conditions (SC).
Scheme 2
Figure 2. Structures of onychine and oracin.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009 A Facile and Efficient Synthesis of N-Substituted Furo[3,4-b]indeno[2,1-e]-
pyridine Analogues of Azapodophyllotoxin via Microwave-Assisted Multicomponent Reactions
967
Scheme 3
Table 2
Temperature optimization for the synthesis of 4c.
Entry
T (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
70
80
15
12
10
8
77
83
88
92
92
90
100
110
8
The results (Table 3) reveal that microwave irradiation
efficiently promoted the reactions, resulting in dramatic
reduction of reaction time, from hours to minutes, and
remarkable increase in yields as well.
Melting points were determined in XT5 apparatus and are
uncorrected. IR spectra were recorded on a FTIR-Tensor 27
1
spectrometer. H NMR spectra were measured on a DPX 400
spectrometer operating at 400 MHz, using DMSO-d6 as sol-
vent and TMS as internal standard. HRMS (ESI) was deter-
mined by using micrOTOF-QII HRMS/MS instrument
(BRUKER). X-ray crystallographic analysis was performed
Although the detailed mechanism of the earlier reac-
tion remains to be fully clarified, the formation of
N-substituted furo[3,4-b]indeno[2,1-e]pyridine analogues
of azapodophyllotoxin 4 could be explained by a reac-
tion sequence of condensation, addition, cyclization, and
dehydration (Scheme 4). First, the condensation of alde-
hyde 1 and 2H-indene-1,3-dione 2 gave the intermediate
product 5. The addition of 3–5 then furnished the inter-
mediate product 6, which upon intramolecular cycliza-
tion and dehydration gave rise to 4.
with
a
diffractometer.
Siemens SMART CCD and
a
Siemens P4
General procedure for the synthesis of compounds 4
with microwave irradiation. Typically, a mixture of aromatic
aldehyde 1 (1.0 mmol), 2H-indene-1,3-dione 2 (1.0 mmol),
4-(arylamino)furan-2(5H)-one 3 (1.0 mmol), and glycol (2.0
mL) was added to the reaction vessel of the monomodal
EmrysTM Creator microwave synthesizer and allowed to react
under MW at 200 W power (initial power 100 W) and 100ꢀC
for several minutes. Upon completion, monitored by TLC, the
reaction vessel was cooled to room temperature. The solid
compound was collected by filtration and recrystallized from
EtOH (95%) to give pure azapodophyllotoxin derivatives 4.
General procedure for the synthesis of compounds 4
with conventional heating. A mixture containing aromatic
aldehyde 1 (1.0 mmol), 2H-indene-1,3-dione 2 (1.0 mmol), 4-
(arylamino)furan-2(5H)-one 3 (1.0 mmol), and glycol (2.0 mL)
was introduced into a 10 mL EmrysTM reaction vial, capped,
and then stirred at 100ꢀC (oil bath temperature) for a given
time. The subsequent work-up procedure was the same as in
the microwave irradiation reactions.
10-(4-Fluorophenyl)-4-phenyl-4,10-dihydro-3H-2-oxa-4-
aza-cyclopenta[b]fluorene-1,9-dione (4a). 1H NMR (400
MHz, DMSO-d6) (d, ppm): 7.86–7.85 (m, 1H, ArH), 7.76–
7.67 (m, 4H, ArH), 7.52–7.48 (m, 2H, ArH), 7.31–7.25 (m,
2H, ArH), 7.17–7.09 (m, 3H, ArH), 5.53 (d, 1H, J ¼ 7.2 Hz,
ArH) 4.79 (s, 1H, CH), 4.76–4.75 (m, 2H, CH2). IR (KBr, m,
cmꢁ1): 3487, 3068, 2864, 1757, 1689, 1669, 1596, 1553, 1505,
1455, 1407, 1396, 1349, 1319, 1283, 1224, 1185, 1156, 1140,
1113, 1074, 1025, 1013, 899, 861, 836, 803, 787, 775, 764,
730, 707, 620. HRMS (ESI) m/z: calc. for C26H16FNO3:
432.1007 [M þ Na]þ, found: 432.0998 [M þ Na]þ.
1
All the products were characterized by IR, H NMR,
and HRMS (ESI). Moreover, the structure of 4g was
also established by X-ray crystallography (Fig. 3) [31].
In conclusion, we have developed an efficient and
facile approach to the synthesis of N-substituted
furo[3,4-b]indeno[2,1-e]pyridine analogues of azapodo-
phyllotoxin via microwave-assisted MCRs without cata-
lyst. This method has the obvious advantages over tradi-
tional heating ones on short reaction time, high yield,
operational simplicity as well as being environmental
friendly. Besides, this method may provide a shortcut
for further investigations on the pharmacological activ-
ities of this type of compounds as important and novel
azapodophyllotoxin analogues.
EXPERIMENTAL
Microwave irradiation was carried out in a monomodal
EmrysTM Creator from Personal Chemistry, Uppsala, Sweden.
10-(4-Chlorophenyl)-4-phenyl-4,10-dihydro-3H-2-oxa-4-
aza-cyclopenta[b]fluorene-1,9-dione (4b). 1H NMR (400
MHz, DMSO-d6) (d, ppm): 7.87–7.85 (m, 1H, ArH), 7.78–
7.67 (m, 4H, ArH), 7.50 (d, 2H, J ¼ 8.4 Hz, ArH), 7.39 (d,
2H, J ¼ 8.4 Hz, ArH), 7.32–7.21 (m, 2H, ArH), 7.13–7.09 (m,
1H, ArH), 5.54 (d, 1H, J ¼ 7.6 Hz, ArH), 4.80(s, 1H, CH),
4.76–4.71(m, 2H, CH2). IR (KBr, m, cmꢁ1): 3474, 3061, 1754,
1694, 1669, 1595, 1560, 1490, 1454, 1391, 1351, 1283, 1182,
1143, 1114, 1086, 1039, 1025, 1010, 900, 846, 777, 763, 736,
724, 697, 678, 617. HRMS (ESI) m/z: calc. for C26H16ClNO3:
448.0711 [M þ Na]þ, found: 448.0703 [M þ Na]þ.
Table 1
Solvent optimization for the synthesis of 4c.
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
DMF
10
12
12
12
10
80
69
76
45
88
EtOH
HOAc
Water
Glycol
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

968
F. Shi, G. Zhang, Y. Zhang, N. Ma, B. Jiang, and S.-J. Tu
Vol 46
Table 3
Synthesis of 4 in glycol at 100°C under MW and SC.
Time (min)
MWa
Yield (%)
SCb
71
Entry
4
R1
R2
SCb
MWa
Mp (ꢀC)
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-FC6H4
4-ClC6H4
4-BrC6H4
C6H5
H
H
7
10
8
10
7
180
240
180
270
180
180
210
240
360
210
240
240
300
89
93
92
74
90
82
88
85
71
91
86
89
84
290–291
280–281
>300
297–298
>300
>300
>300
>300
285–286
>300
>300
74
73
61
76
68
71
69
58
75
70
73
72
3
4
H
H
5
6
2,4-Cl2C6H3
4-FC6H4
4-ClC6H4
4-BrC6H4
C6H5
H
CH3
CH3
CH3
CH3
CH3
Cl
8
7
10
10
13
8
8
9
10
11
12
13
4j
4k
4l
2,4-Cl2C6H3
4-BrC6H4
2,4-Cl2C6H3
4-ClC6H4
9
Cl
Cl
8
10
>300
>300
4m
a The time and yields under microwave irradiation conditions.
b The time and yields under standard heating conditions.
10-(4-Bromophenyl)-4-phenyl-4,10-dihydro-3H-2-oxa-4-
aza-cyclopenta[b]fluorene-1,9-dione (4c). 1H NMR (400
MHz, DMSO-d6) (d, ppm): 7.86–7.84 (m, 1H, ArH), 7.76–
7.66 (m, 4H, ArH), 7.52 (d, 2H, J ¼ 8.4 Hz, ArH), 7.43 (d,
2H, J ¼ 8.4 Hz, ArH), 7.31–7.25 (m, 2H, ArH), 7.13–7.09 (m,
1H, ArH), 5.53 (d, 1H, J ¼ 7.6 Hz, ArH), 4.79 (s, 1H, CH),
4.76–4.71 (m, 2H, CH2). IR (KBr, m, cmꢁ1): 3446, 3077,
3036, 2926, 2872, 1749, 1690, 1596, 1484, 1454, 1351, 1282,
1182, 1067, 1008, 838, 729, 695. HRMS (ESI) m/z: calc. for
C26H16BrNO3: 492.0206 [M þ Na]þ, found: 492.0195 [M þ
Na]þ.
10-(2,4-Dichlorophenyl)-4-phenyl-4,10-dihydro-3H-2-oxa-4-
1
aza-cyclopenta[b]fluorene-1,9-dione (4e). H NMR (400 MHz,
DMSO-d6) (d, ppm): 7.85 (d, J ¼ 7.2 Hz, 1H, ArH), 7.76 (d,
J ¼ 7.6 Hz, 1H, ArH), 7.73–7.68 (m, 3H, ArH), 7.65 (d, J ¼
8.4 Hz, 1H, ArH), 7.58 (d, J ¼ 2.0 Hz, 1H, ArH), 7.40 (dd,
J ¼ 8.4, 2.0 Hz, 1H, ArH), 7.29–7.26 (m, 2H, ArH), 7.14–
7.08 (m, 1H, ArH), 5.54 (d, J ¼ 7.6 Hz, 1H, ArH), 5.23 (s,
1H, CH), 4.80–4.70 (m, 2H, CH2); IR (KBr, m, cmꢁ1): 3060,
1758, 1691, 1668, 1595, 1557, 1497, 1469, 1454, 1407, 1392,
1354, 1283, 1185, 1144, 1038, 1025, 1011, 900, 869, 845,
763, 724, 708, 697. HRMS (ESI) m/z: calc. for C26H15Cl2NO3:
482.0322 [M þ Na]þ, found: 482.0320 [M þ Na]þ.
4,10-Diphenyl-4,10-dihydro-3H-2-oxa-4-aza-cyclopenta[b]-
1
fluorene-1,9-dione (4d). H NMR (400 MHz, DMSO-d6) (d,
10-(4-Fluorophenyl)-4-p-tolyl-4,10-dihydro-3H-2-oxa-4-
1
aza-cyclopenta[b]fluorene-1,9-dione (4f). H NMR (400
ppm): 7.85–7.84 (m, 1H, ArH), 7.76–7.67 (m, 4H, ArH), 7.45
(d, 2H, Jꢁ¼ 7.6 Hz, ArH), 7.35–7.21(m, 5H, ArH), 7.10 (t,
1H, J ¼ 7.6 Hz, ArH), 5.53(d, 1H, J ¼ 7.6 Hz, ArH), 4.77 (s,
1H, CH), 4.76–4.72 (m, 2H, CH2). IR (KBr, m, cmꢁ1): 3494,
3063, 3030, 2931, 2862, 1754, 1685, 1595, 1551, 1490, 1451,
1413, 1396, 1349, 1319, 1283, 1182, 1139, 1112, 1074, 1023,
1012, 946, 897, 835, 802, 790, 765, 727, 717, 696, 624.
HRMS (ESI) m/z: calc. for C26H17NO3: 414.1101 [M þ Na]þ,
found: 414.1108 [M þ Na]þ.
MHz, DMSO-d6) (d, ppm): 7.72 (d, 1H, J ¼ 8.0 Hz, ArH),
7.61 (d, 1H, J ¼ 7.6 Hz, ArH), 7.50–7.45 (m, 4H, ArH), 7.31–
7.24 (m, 2H, ArH), 7.17–7.11 (m, 3H, ArH), 5.61 (d, 1H, J ¼
7.6 Hz, ArH), 4.78 (s, 1H, CH), 4.74–4.73 (m, 2H, CH2), 2.47
(s, 3H, CH3). IR (KBr, m, cmꢁ1): 3483, 3067, 2923, 2871,
1756, 1684, 1604, 1552, 1510, 1455, 1412, 1348, 1319, 1283,
1224, 1185, 1153, 1143, 1112, 1093, 1074, 1038, 1027, 1011,
951, 901, 867, 848, 833, 806, 790, 761, 732, 709, 695, 682,
Scheme 4
Figure 3. ORTEP diagram of 4g.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009 A Facile and Efficient Synthesis of N-Substituted Furo[3,4-b]indeno[2,1-e]-
pyridine Analogues of Azapodophyllotoxin via Microwave-Assisted Multicomponent Reactions
969
649, 606, 588. HRMS (ESI) m/z: calc. for C27H18FNO3:
446.1163 [M þ Na]þ, found: 446.1160 [M þ Na]þ.
1
penta[b]fluorene-1,9-dione (4g). H NMR (400 MHz, DMSO-d6)
IR (KBr, m, cmꢁ1): 3085, 1768, 1680, 1579, 1490, 1322, 1236,
1180, 1056, 1026, 1018, 840, 769, 698, 675, 646, 588. HRMS
(ESI) m/z: calc. for C26H14Cl3NO3: 515.9932 [M þ Na]þ,
found: 515.9918 [M þ Na]þ.
10-(4-Chlorophenyl)-4-p-tolyl-4,10-dihydro-3H-2-oxa-4-aza-cyclo-
(d, ppm): 7.72 (d, 1H, J ¼ 8.0 Hz, ArH), 7.61 (d, 1H, J ¼ 8.0
Hz, ArH), 7.50–7.37 (m, 6H, ArH), 7.31–7.25 (m, 2H, ArH),
7.13 (t, 1H, J ¼ 6.8 Hz, ArH), 5.61 (d, 1H, J ¼ 7.6 Hz, ArH),
4.78 (s, 1H, CH), 4.74–4.73 (m, 2H, CH2), 2.47 (s, 3H, CH3).
IR (KBr, m, cmꢁ1): 3446, 2869, 1751, 1682, 1552, 1486, 1349,
1283, 1141, 1086, 1011, 864, 761, 694, 682. HRMS (ESI) m/z:
4,10-Di-(4-chlorophenyl)-4,10-dihydro-3H-2-oxa-4-aza-cyclo-
1
penta[b]fluorene-1,9-dione (4m). H NMR (400 MHz, DMSO-
d6) (d, ppm): 7.72 (d, 1H, J ¼ 8.0 Hz, ArH), 7.66 (d, 1H, J ¼
8.0 Hz, ArH), 7.59–7.48 (m, 6H, ArH), 7.40–7.32 (m, 2H,
ArH), 7.26–7.19 (m, 1H, ArH), 5.72 (d, 1H, J ¼ 8.0 Hz,
ArH), 4.81 (s, 1H, CH), 4.79–4.69 (m, 2H, CH2). IR (KBr, m,
cmꢁ1): 3085, 1776, 1687, 1565, 1468, 1328, 1239, 1172, 1085,
1032, 1018, 839, 764, 688, 673, 645, 587. HRMS (ESI) m/z:
calc. for C27H18ClNO3: 462.0868 [M
462.0860 [M þ Na]þ.
1
cyclopenta[b]fluorene-1,9-dione (4h). H NMR (400 MHz,
þ
Na]þ, found:
10-(4-Bromophenyl)-4-p-tolyl-4,10-dihydro-3H-2-oxa-4-aza-
calc. for C26H15Cl2NO3: 482.0322 [M
482.0307 [M þ Na]þ.
þ
Na]þ, found:
DMSO-d6) (d, ppm): 7.72 (d, 1H, J ¼ 8.0 Hz, ArH), 7.61 (d,
1H, J ¼ 8.0 Hz, ArH), 7.53–7.41 (m, 6H, ArH), 7.31–7.25 (m,
2H, ArH), 7.15–7.11 (m, 1H, ArH), 5.61 (d, 1H, J ¼ 8.0 Hz,
ArH), 4.78 (s, 1H, CH), 4.77–4.69 (m, 2H, CH2), 2.47 (s, 3H,
CH3). IR (KBr, m, cmꢁ1): 3488, 3065, 2926, 2868, 1752, 1682,
1553, 1483, 1348, 1183, 1071, 835, 761, 695, 679, 647, 583.
HRMS (ESI) m/z: calc. for C27H18BrNO3: 506.0363 [M þ
Na]þ, found: 506.0345 [M þ Na]þ.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20672090), the Key Item of Natural
Science Foundation of Xuzhou Normal University (No.
07XLA04), the Preliminary Item of Xuzhou Normal University
on National Natural Science Foundation of China (No.
08XLY04), the Qing Lan Project (No. 08QLT001), and Science
and Technology Foundation of Xuzhou (No. XM08C027) for fi-
nancial supports.
10-Phenyl-4-p-tolyl-4,10-dihydro-3H-2-oxa-4-aza-cyclopen-
1
ta[b]fluorene-1,9-dione (4i). H NMR (400 MHz, DMSO-d6)
(d, ppm): 7.72–7.70 (m, 1H, ArH), 7.63–7.61 (m, 1H, ArH),
7.49–7.44 (m, 4H, ArH), 7.35–7.21 (m, 5H, ArH), 7.15–7.11
(m, 1H, ArH), 5.62 (d, 1H, J ¼ 7.2 Hz, ArH), 4.79 (s, 1H,
CH), 4.78–4.72 (m, 2H, CH2), 2.45 (s, 3H, CH3). IR (KBr, m,
cmꢁ1): 3378, 3054, 2922, 2858, 1747, 1686, 1543, 1319, 1180,
1045, 826, 798, 682, 669, 634, 576. HRMS (ESI) m/z: calc.
for C27H19NO3: 428.1258 [M þ Na]þ, found: 428.1260 [M þ
Na]þ.
REFERENCES AND NOTES
[1] Ley, S. V.; Trudell, M. L.; Wadsworth, D. J. Tetrahedron
1991, 47, 8285.
[2] Witiak, D.; Kokrady, S. S.; Patel, S. T.; Akbar, H.; Feller,
D. R.; Newmann, H. A. I. J Med Chem 1982, 25, 90.
[3] Zhang, C. L.; Chatterjee, S. S.; Stein, U.; Heinemann, U.
Naunyn-Schmidebergs Arch Pharmacol 1992, 345, 85.
10-(2,4-Dichlorophenyl)-4-p-tolyl-4,10-dihydro-3H-2-oxa-4-
1
aza-cyclopenta[b]fluorene-1,9-dione (4j). H NMR (400 MHz,
[4] Luk, K.; Readshaw, S. A.
1 1991, 1641.
[5] Foden, F. R.; McCormick, J.; O’Mant, D. M. J Med Chem
1975, 18, 199.
J Chem Soc Perkin Trans
DMSO-d6) (d, ppm): 7.73–7.71 (m, 1H, ArH), 7.64–7.61 (m,
2H, ArH), 7.58–7.57 (m, 1H, ArH), 7.48 (t, 2H, J ¼ 8.0 Hz,
ArH), 7.40 (dd, 1H, J ¼ 8.0, 2.0 Hz, ArH), 7.28–7.27 (m, 2H,
ArH), 7.16–7.12 (m, 1H, ArH), 5.63 (d, 1H, J ¼ 8.0 Hz,
ArH), 5.22 (s, 1H, CH), 4.78–4.69 (m, 2H, CH2), 2.46 (s, 3H,
CH3). IR (KBr, m, cmꢁ1): 3071, 1756, 1691, 1666, 1596, 1584,
1557, 1510, 1469, 1394, 1347, 1321, 1282, 1234, 1185, 1144,
1098, 1074, 1038, 1024, 1012, 901, 868, 844, 823, 792, 762,
730, 706, 692. HRMS (ESI) m/z: calc. for C27H17Cl2NO3:
496.0478 [M þ Na]þ, found: 496.0470 [M þ Na]þ.
[6] Roggo, B. E.; Petersen, F.; Delmendo, R.; Jenny, H. B.;
Peter, H. H.; Roesel, J. J Antibiot 1994, 47, 136.
[7] (a) Magedov, I. V.; Manpadi, M.; Van Slambrouck, S.;
Steelant, W. F. A.; Rozhkova, E.; Przheval’skii, N. M.; Rogelj, S.;
Kornienko, A. J Med Chem 2007, 50, 5183; (b) Hitotsuyanagi, Y.;
Fukuyo, M.; Tsuda, K.; Kobayashi, M.; Ozeki, A.; Itokawa, H.;
Takeya, K. Bioorg Med Chem 2000, 10, 315.
[8] Skrastins, I.; Vitolina, R.; Kastron, V. V.; Dubur, G. Y.
Khim-Farm Zh 1995, 29, 31.
10-(4-Bromophenyl)-4-(4-chlorophenyl)-4,10-dihydro-3H-2-
1
oxa-4-aza-cyclopenta[b]fluorene-1,9-dione (4k). H NMR
[9] Skrastins, I.; Kastron, V.; Vitolins, R.; Duburs, G.; Stivrina,
M. S.; Kaidaka, K. Khim-Farm Zh 1989, 23, 1323.
(400 MHz, DMSO-d6) (d, ppm): 7.73 (d, 1H, J ¼ 8.0 Hz,
ArH), 7.64 (d, 1H, J ¼ 8.0 Hz, ArH), 7.58–7.49 (m, 6H,
ArH), 7.39–7.28 (m, 2H, ArH), 7.22–7.17 (m, 1H, ArH), 5.69
(d, 1H, J ¼ 8.0 Hz, ArH), 4.80 (s, 1H, CH), 4.78–4.69 (m,
2H, CH2). IR (KBr, m, cmꢁ1): 3078, 1762, 1689, 1557, 1473,
1320, 1234, 1177, 1079, 1027, 1016, 838, 765, 698, 679, 643,
586. HRMS (ESI) m/z: calc. for C26H15BrClNO3: 525.9817 [M
þ Na]þ, found: 525.9783 [M þ Na]þ.
[10] (a) Velten, R.; Adelt, I.; Boehmer, J.; Frackenpohl, J.;
Schenke, T.; Loesel, P.; Malsam, O.; Arnold, C. WO 2,005,097,802
(2005); (b) Velten, R.; Adelt, I.; Boehmer, J.; Frackenpohl, J.;
Schenke, T.; Loesel, P.; Malsam, O.; Arnold, C. Chem Abstr 2005,
143, 405891.
[11] (a) Carroll, W. A.; Agrios, K. A.; Basha, F. Z.; Chen, Y.;
Kort, M. E.; Kym, P. R.; Tang, R.; Turner, S. C.; Yi, L. WO
2,000,024,741 (2000); (b) Carroll, W. A.; Agrios, K. A.; Basha, F. Z.;
Chen, Y.; Kort, M. E.; Kym, P. R.; Tang, R.; Turner, S. C.; Yi, L.
Chem Abstr 2000, 132, 308329.
10-(2,4-Dichlorophenyl)-4-(4-chlorophenyl)-4,10-dihydro-
1
(4l). H
3H-2-oxa-4-aza-cyclopenta[b]fluorene-1,9-dione
NMR (400 MHz, DMSO-d6) (d, ppm): 7.77–7.72 (m, 1H,
ArH), 7.68–7.63 (m, 2H, ArH), 7.60–7.57 (m, 1H, ArH), 7.50
(t, 2H, J ¼ 8.0 Hz, ArH), 7.43 (d, 1H, J ¼ 8.0 Hz, ArH),
7.30–7.27 (m, 2H, ArH), 7.20–7.13 (m, 1H, ArH), 5.67 (d, 1H,
J ¼ 8.0 Hz, ArH), 5.28 (s, 1H, CH), 4.79–4.71 (m, 2H, CH2).
[12] Patmore, L.; Duncan, G. P.; Clarke, B.; Anderson, A. J.;
Greenhouse, R.; Pfister, J. R. Br J Pharmacol 1990, 99, 687.
[13] (a) Pearce, H. L.; Bach, N. J.; Cramer, T. L. Tetrahedron
Lett 1989, 30, 907; (b) Tomioka, K.; Kubota, Y.; Koga, K. Tetrahe-
dron 1993, 49, 1891; (c) Lienard, P.; Quirion, J. C.; Husson, H. P.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

970
F. Shi, G. Zhang, Y. Zhang, N. Ma, B. Jiang, and S.-J. Tu
Vol 46
Tetrahedron 1993, 49, 3995; (d) Madalengoitia, J. S.; Macdonald, T.
L. Tetrahedron Lett 1993, 34, 6237; (e) Lehnert, E. K.; Miller, K. E.;
Madalengoitia, J. S.; Guzi, T. J.; Macdonald, T. L. Bioorg Med Chem
Lett 1994, 4, 2411; (f) Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.;
Kobayashi, M.; Ozeki, A.; Itokawa, H.; Takeya, K. Bioorg Med Chem
Lett 2000, 10, 315; (g) Tratrat, C.; Giorgi-Renault, S.; Husson, H. P.
Org Lett 2002, 4, 3187.
[25] (a) Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demar-
est, K. T.; Tang, Y.; Jackson, P. F. U.S. Pat. 2,004,082,578 (2004);
(b) Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demarest, K. T.;
Tang, Y.; Jackson, P. F. Chem Abstr 2004, 140, 375085.
[26] (a) Smith, J. W.; Richardson, R. D. U.S. Pat. 2,007,203,236
(2007); (b) Smith, J. W.; Richardson, R. D. Chem Abstr 2007, 147,
315119.
[14] Manpadi, M.; Uglinskii, P. Y.; Rastogi, S. K.; Cotter, K.
M.; Wong, Y. C.; Anderson, L. A.; Ortega, A. J.; Van Slambrouck, S.;
Steelant, W. F. A.; Rogelj, S.; Tongwa, P.; Antipin, M. Y.; Magedov,
I. V.; Kornienko, A. Org Biomol Chem 2007, 5, 3865.
[15] (a) Levy, S. B.; Alekshun, M. N.; Podlogar, B. L.; Ohe-
meng, K.; Verma, A. K.; Warchol, T.; Bhatia, B.; Bowser, T.; Grier,
M. U.S. Pat. 2,005,124,678 (2005); (b) Levy, S. B.; Alekshun, M. N.;
Podlogar, B. L.; Ohemeng, K.; Verma, A. K.; Warchol, T.; Bhatia, B.;
Bowser, T.; Grier, M. Chem Abstr 2005, 143, 53440.
[16] Chojnacka-Wojcik, E.; Naparzewska, A. Pol J Pharmacol
Pharm 1983, 35, 327.
[27] Kastron, V. V.; Vitolinya, R. O.; Skrastinsh, I. P.; Dubur,
G. Y. Khim-Farm Zh 1993, 27, 20.
[28] (a) Domling, A.; Ugi, I. Angew Chem Int Ed Engl 2000,
39, 3168; (b) Li, G.; Wei, H.-X.; Kim, S. H.; Carducci, M. D. Angew
Chem Int Ed Engl 2001, 40, 4277; (c) Bagley, M. C.; Dale, J. W.;
Bower, J. Chem Commun 2002, 1682; (d) Nuria, M.; Jordi, T.; Jose, I.
B.; Oliver, C. K. Tetrahedron Lett 2003, 44, 5385; (e) Simon, C.; Con-
stantieux, T.; Rodriguez, J. Eur J Org Chem 2004, 24, 4957; (f) Cui,
S. L.; Lin, X. F.; Wang, Y. G. J Org Chem 2005, 70, 2866; (g) Huang,
Y. J.; Yang, F. Y.; Zhu, C. J. J Am Chem Soc 2005, 127, 16386; (h)
Ramsn, D. J.; Yus, M. Angew Chem Int Ed Engl 2005, 44, 1602; (i)
Domling, A. Chem Rev 2006, 106, 17.
[17] Safak, C.; Simsek, R.; Altas, Y.; Boydag, S.; Erol, K. Boll
Chim Farm 1997, 136, 665.
[29] (a) Kappe, C. O. Angew Chem Int Ed Engl 2004, 43, 6250;
(b) Varma, R.S. Green Chem 1999, 1, 43; (c) Bose, A. K.; Manhas, M.
S.; Ganguly, S. N.; Sharma, A. H.; Banik, B. K. Synthesis 2002, 1578;
(d) Baghurst, D. R.; Mingos, D. M. P. Chem Soc Rev 1991, 20, 1.
[30] (a) Tu, S.; Zhang, Y.; Jia, R.; Jiang, B.; Zhang, J.; Ji, S.
Tetrahedron Lett 2006, 47, 6521; (b) Tu, S.; Zhang, Y.; Zhang, J.;
Jiang, B.; Jia, R.; Zhang, J.; Ji, S. Synlett 2006, 17, 2785; (c) Shi, F.;
Wang, Q.; Tu, S.; Zhou, J.; Jiang, B.; Li, C.; Zhou, D.; Shao, Q.; Cao,
L. J Heterocycl Chem 2008, 45, 1103.
[18] Lago, J. G.; Chaves, M. H.; Ayres, M. C.; Agripino, D. G.;
Young, M. M. Planta Med 2007, 73, 292.
[19] Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki,
Y.; Taniguchi, M. Bioorg Med Chem Lett 2005, 15, 1079.
[20] Hufford, C. D.; Liu, S.; Clark, A. M.; Oguntimein, B. O.
J Nat Prod 1987, 50, 961.
[21] (a) Heintzelman, G. R.; Averill, K. M.; Dodd, J. H. WO
2,002,085,894 (2002); (b) Heintzelman, G. R.; Averill, K. M.; Dodd, J.
H. Chem Abstr 2002, 137, 337793.
[31] The single-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographic analysis was performed with a Sie-
mens SMART CCD and a Siemens P4 diffractometer. Crystal data for
4g: C27H18ClNO3, red brown, crystal dimension 0.09 mm ꢂ 0.06 mm ꢂ
[22] (a) Guerrant, R. L.; Kots, A. Y.; Murad, F.; Choi, B. K.
WO 2,008,008,704 (2008); (b) Guerrant, R. L.; Kots, A. Y.; Murad,
F.; Choi, B. K. Chem Abstr 2008, 148, 136041.
˚
[23] Tirzite, D.; Tirzitis, G.; Vigante, B.; Duburs, G. Biochem
Pharmacol 1993, 46, 773.
0.04 mm, monoclinic, space group P2(1)/c, a ¼ 10.822(5) A, b ¼
ꢀ
ꢀ
˚
˚
10.783(6) A, c ¼ 18.355(9) A, a ¼ c ¼ 90 , ß ¼ 94.289(11) , V ¼
3
3
˚
˚
[24] Yang M.; Huang H. L.; Zhu B. Y.; Tuo Q. H.; Liao D. F.
Acta Pharmacol Sin 2005, 26, 205.
2135.8(18) A , Mr ¼ 439.87, Z ¼ 4, Dc ¼ 1.368 mg/m , k ¼ 0.71073 A,
l(MoKa) ¼ 0.209 mmꢁ1, F(000) ¼ 912, R1 ¼ 0.0892, wR2 ¼ 0.1061.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet