Synthesis of the complex bridged 1,5-oxazabicycles via one-pot reactions of 4,5-diazafluoren-9-one, alkyl halides, and cyclic 1,3-diketone

Article abstract of DOI:10.1007/s10593-012-1040-0

An efficient and practical procedure for the preparation of the complex bridged 1,5-oxazabicycles was developed via a one-pot domino reaction of 4,5-diazafluoren-9-one, reactive alkyl halides, and cyclic 1,3-dicarbonyl compounds.

Full text of DOI:10.1007/s10593-012-1040-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 4, July, 2012 (Russian Original Vol. 48, No. 4, April, 2012)
SYNTHESIS OF THE COMPLEX BRIDGED
1,5-OXAZABICYCLES via ONE-POT REACTIONS
OF 4,5-DIAZAFLUOREN-9-ONE, ALKYL HALIDES,
AND CYCLIC 1,3-DIKETONE
L. Hui1, S. Gao1, and C. G. Yan1*
An efficient and practical procedure for the preparation of the complex bridged 1,5-oxazabicycles was
developed via a one-pot domino reaction of 4,5-diazafluoren-9-one, reactive alkyl halides, and cyclic
1,3-dicarbonyl compounds.
Keywords: 4,5-diazafluoren-9-one, dimedone, heterocycle, oxazabicycle, domino reactions, one-pot
reaction.
The N,O-containing heterocycles are among the principal heterocyclic skeletons, which are widely
found in natural alkaloids, biologically active compounds, and pharmaceutical agents [1–3]. Although versatile
synthetic methods for obtaining N,O-containing normal-ring heterocycles such as oxazole, isoxazole, oxazine,
and their benzo-annelated derivatives have been developed [4–9], the easy and efficient synthesis of medium-
ring oxazabicycles from simple starting materials with milder reaction conditions and fewer preparative steps
still remains an attractive goal [10–13]. Some examples on the synthesis of the bridged oxazabicycles from the
tandem reactions involving reaction of bifunctionalized nucleophiles with N-alkylquinolinium and
N-alkylisoquinolinium salts have been shown to be the very convenient methods [14–27]. Recently, we reported
an efficient approach to bridged 1,3-oxazabicycles via the reactions of N-(p-nitrobenzyl)- or
N-phenacylphenanthrolinium bromides with a series of cyclic 1,3-dicarbonyl compounds [28]. This successful
experience prompted us to explore the scope and limitations of this reaction and to establish an oxazabicyclic
library. Thus, the reactions of the quaternary ammonium salts of 4,5-diazafluoren-9-one with cyclic 1,3-di-
carbonyl compounds were investigated, and we are pleased to find that a series of 1,5-oxazabicycles was
obtained in satisfactory yields.
The quaternary ammonium salts [29, 30] can be easily obtained by the reactions of 4,5-diazafluoren-
9-one with reactive halides, such as p-nitrobenzyl bromide, benzyl bromide, methyl iodide, phenacyl bromide,
and ethyl bromoacetate, which were not separated from the solution and could be utilized in sequential reactions
with cyclic 1,3-diketones. The reaction conditions were similar to those described in [28]: a mixture of the
quaternary ammonium salt 1a, dimedone, and triethylamine as base in acetonitrile was stirred at room
_______
*To whom correspondence should be addressed, e-mail: cgyan@yzu.edu.cn.
1Yangzhou University, 188 Daxue St., Yangzhou 225002, China.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 706-714, April, 2012. Original
article submitted January 10, 2012.
658
0009-3122/12/4804-0658©2012 Springer Science+Business Media, Inc.

temperature for a long time or at elevated temperature overnight. TLC analysis showed that nearly no reaction
took place. We suggested that triethylamine is relatively weak base, which could not deprotonate the quaternary
ammonium salt 1a to give the active pyridinium ylide intermediate. Thus K2CO3 was used to replace
triethylamine in the reaction. A mixture of the quaternary ammonium salts 1a, dimedone (2a), and potassium
carbonate in acetonitrile was stirred at room temperature overnight. After workup, we found that the expected
oxazabicycle 3a was obtained in 78% yield. Under these conditions, the reactions of salt 1a, 1,3-cyclo-
hexanedione, and 4-hydroxycoumarin gave the corresponding products 3b,c in good yields (Table, entries 1-3).
These results indicated that a practical procedure for the preparation of oxazabicycles was established by using a
one-pot domino reaction. We noticed that a C,O-dinucleophilic substitution reaction took place at the
2,4-position of the pyridine ring, not the benzyl position of the quaternary ammonium salt 1a, which indicated
that a stronger electron-withdrawing nitro group is not necessary for the reaction. Thus, the quaternary
ammonium salts 1b,c, which were obtained by the reaction of benzyl bromide or p-methylbenzyl bromide with
4,5-diazafluoren-9-one, reacted further with dimedone, 1,3-cyclohexanedione, and 4-hydroxycoumarin under
similar conditions. The corresponding oxazabicycles 3d-g were prepared in moderate yields (entries 4-7). The
quaternary ammonium salt 1d derived from methyl iodide also reacted smoothly with dimedone and 1,3-cyclo-
hexanedione to give the expected 1,5-oxazabicycles 3h,i, respectively. Lastly, the quaternary ammonium salts
1e,f, which were prepared by the reaction of 4,5-diazafluoren-9-one with phenacyl bromide or ethyl
bromoacetate, reacted similarly with cyclic 1,3-dicarbonyl compounds to give the desired products 3j-m in good
yields (entries 8-13). Due to the effect of stronger electron-withdrawing nitro and carbonyl groups, the reactions
of quaternary ammonium salts 1a,e gave relatively higher yields of products than those of other quaternary
ammonium salts.
The structures of oxazabicycles 3a-m were fully characterized by spectroscopy and were confirmed by
single-crystal X-ray structural studies performed for two representative compounds 3i (Fig. 1) and 3j (Fig. 2).
From the molecular structure, it is clearly seen that a 1,5-oxazabicyclic system was formed by the oxygen atom
Synthesis of the bridged 1,5-oxazabicycles 3a-m
O
O
O
O
E
O
MeCN
O
+ RCH2X
E
+
N
50°C
4 h
MeCN, K2CO3
room temp., 10–18 h
N
N
N
N
N
X–
R
1a–f
R
O
3a–m
Entry Salt
R
Diketone
E
Product
Yield, %
1
2
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1e
1f
4-O2NC6H4 Dimedone
CH2C(CH3)2CH2
3a
3b
3c
3d
3e
3f
78
70
84
54
49
54
59
58
50
80
74
76
58
4-O2NC6H4 1,3-Cyclohexanedione CH2CH2CH2
3
4-O2NC6H4 4-Hydroxycoumarin
o-OC6H4
4
Ph
Dimedone
CH2C(CH3)2CH2
5
Ph
1,3-Cyclohexanedione CH2CH2CH2
6
4-MeC6H4
4-MeC6H4
H
Dimedone
CH2C(CH3)2CH2
o-OC6H4
7
4-Hydroxycoumarin
Dimedone
3g
3h
3i
8
CH2C(CH3)2CH2
9
H
1,3-Cyclohexanedione CH2CH2CH2
Dimedone CH2C(CH3)2CH2
1,3-Cyclohexanedione CH2CH2CH2
10
11
12
13
COPh
COPh
COPh
CO2Et
3j
3k
3l
4-Hydroxycoumarin
Dimedone
o-OC6H4
CH2C(CH3)2CH2
3m
659

of the enolate unit connected to the 4-position of the pyridyl ring, which is different from the results of
formation of 1,3-oxazabicyclic system in our previously reported reactions of N-alkylphenanthrolinium salts [28].
This difference is obviously due to the strong electron-withdrawing effect of the carbonyl group in 4,5-diaza-
fluoren-9-one.
To explain the formation of 1,5-oxazabicycles in the reaction of the quaternary ammonium salts of
4,5-diazafluoren-9-one, we outlined a plausible reaction mechanism based on the similar reaction of
N-alkylphenanthrolinium salts [28], which is shown below. Firstly, the ammonium salt of 4,5-diazafluoren-9-one
1 was deprotonated to yield the expected pyridinium ylide A, in which the positive charge is spread to the C-1
and C-3 atoms in its resonance hybrid forms A' and A". So C-1 and C-3 atoms become more susceptible to
attack by nucleophilic reagent. Secondly, the in situ formed carbanion of cyclic 1,3-dicarbonyl compound, such
as dimedone, attacks C-3 atom of ammonium salt A' to give the intermediate B. Due to the strong electron-
withdrawing effect of two carbonyl groups in intermediate B, a new enolate C was formed by proton migration.
Then the enolate, in turn, attacks the relatively positive C-1atom to give the final 1,5-oxazabicyclic compound
3. In this reaction, the cyclic 1,3-dicarbonyl compounds acted as a C,O-bifunctionalized nucleophile to
accomplish sequentially the C-alkylation and intramolecular O-alkylation. If the dimedone carbanion first
attacks the resonance hybrid form A", the sequential reaction would results in a 1,3-oxazabicyclic system. Here
the relative stability of resonance hybrid forms A' and A" determines the direction of reaction. In the hybrid form
A', the positive charge is far away from the electron-withdrawing carbonyl group, which makes the hybrid form
A' more stable than hybrid form A''. Thus, only nucleophilic reaction to hybrid form A' and formation of
1,5-oxazabicycles were observed.
O
O
O
O
+
base
+
N
+
N
N
N
+
N
N
N
N
X–
R
–
R
–
–
R
R
1
A
A''
A'
O
Me
–
Me
O
O
O
O
O
Me
Me
O
N
N
N
N
O
–
R
N
N
R
O
O
3
Me
R
B
O
Me
Me
C
Me
In summary, we have developed a practical method for preparation of the complex bridged 1,5-oxaza-
bicycles via the reactions of quaternary ammonium salts of 4,5-diazafluoren-9-one with cyclic 1,3-dicarbonyl
compounds. The reaction mechanism involves the domino C-alkylation and intramolecular O-alkylation of the
enolate of cyclic 1,3-dicarbonyl compound. This protocol has the advantages of mild reaction conditions, easily
accessible starting material, and easy purification of the products, which makes it a useful and attractive method
for the synthesis of the complex N,O-containing heterocycles in synthetic and medicinal chemistry.
660

Fig. 1. Molecular structure of compound 3i.
Fig. 2. Molecular structure of compound 3j.
EXPERIMENTAL
IR spectra were obtained on a Bruker Tensor 27 spectrometer (KBr disc). 1H and 13C NMR spectra were
recorded with a Bruker AV-600 (600 and 150 MHz, respectively) spectrometer with CDCl3 as solvent and TMS
as internal standard. HPLC/MS were recorded on a Finnigan LCQ Deca XP MAX instrument. Melting points
were determined on a hot-plate microscope apparatus. All reactions were monitored by TLC, eluent light
petroleum ether–EtOAc, 3:1. Silica gel GF254 (100 mesh) purchased from Qingdao Haiyang Chemical Co.,
661

Ltd. was used for column chromatography. 4,5-Diazafluoren-9-one, cyclic 1,3-dicarbonyl compounds, alkyl
halides, and other reagents were commercial reagents and used without additional purification. Solvents were
purified by standard techniques.
Crystallographic data for compounds 3i,j have been deposited at the Cambridge Crystallographic Data
Center (CCDC 827897 and 827898).
Reaction of 4,5-Diazafluoren-9-one, Alkyl Halides, and Cyclic 1,3-Dicarbonyl Compounds
(General Method). A solution of 4,5-diazafluoren-9-one (0.364 g, 2 mmol) and f alkyl halide (2 mmol) in
MeCN (20 ml) was heated at 50°C for 4 h. Then cyclic 1,3-dicarbonyl compounds (2 mmol) and K2CO3 (0.138
g, 1 mmol) were added to the system. The solution was stirred at room temperature for 10-18 h until completion
of the reaction. After removing the solvent, the crude oily mixture was purified using column chromatography,
eluent petroleum ether–EtOAc, 1:1, to give a pure product for analysis.
16,16-Dimethyl-2-(4-nitrobenzyl)-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetra-
ene-10,18-dione (3a). Yield 78%; yellow solid, mp 162-164°C. IR spectrum, ν, cm-1: 2960 (m), 1680 (s), 1643
(s), 1608 (vs), 1554 (s), 1522 (s), 1453 (w), 1426 (w), 1375 (s), 1343 (s), 1305 (w), 1260 (w), 1175 (m), 1112
1
(m), 1081 (w), 1044 (m), 951 (w), 893 (w). H NMR spectrum, δ, ppm (J, Hz): 8.40 (1H, d, J = 5.4, H Ar); 8.23
(2H, d, J = 7.8, H Ar); 7.76 (1H, d, J = 7.2, H Ar); 7.65 (2H, d, J = 8.4, H Ar); 7.28-7.24 (1H, m, H Ar); 6.95
(1H, d, J = 15.0) and 5.10 (1H, d, J = 15.0, CH2); 5.56 (1H, s, CH); 4.69 (1H, s, CH); 2.37 (1H, d, J = 17.4) and
2.32-2.23 (3H, m, 2 CH2); 1.94 (1H, d, J = 13.2) and 1.71 (1H, d, J = 13.2, CH2); 1.05 (3H, s, CH3); 1.01 (3H, s,
CH3). 13C NMR spectrum, δ, ppm: 197.3; 185.1; 172.3; 160.3; 158.3; 149.7; 147.6; 144.9; 132.4; 129.2; 128.1;
124.7; 124.1; 111.0; 106.3; 63.7; 52.6; 50.5; 46.0; 42.0; 32.4; 29.5; 27.3; 27.0. Mass spectrum (ESI-), m/z:
456.44 [M-1]-. Found, %: C 67.97; H 5.44; N 8.84. C26H23N3O5. Calculated, %: C 68.26; H 5.07; N 9.18.
2-(4-Nitrobenzyl)-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetraene-
10,18-dione (3b). Yield 70%; yellow solid, mp 184-186°C. IR spectrum, ν, cm-1: 2945 (m), 1675 (s), 1640 (s),
1601 (vs), 1556 (s), 1523 (s), 1432 (w), 1384 (m), 1349 (s), 1301 (w), 1176 (m), 1117 (w), 1081 (w), 1028 (m),
1
963 (w), 893 (w). H NMR spectrum, δ, ppm (J, Hz): 8.40 (1H, d, J = 4.8, H Ar); 8.23 (2H, d, J = 8.4, H Ar);
7.76 (1H, d, J = 7.2, H Ar); 7.65 (2H, d, J = 8.4, H Ar); 7.25 (1H, t, J = 6.0, H Ar); 6.94 (1H, d, J = 15.0) and
5.15 (1H, d, J = 15.0, CH2); 5.56 (1H, s, CH); 4.68 (1H, s, CH); 2.47 (2H, t, J = 6.0, CH2); 2.41 (2H, t, J = 6.0,
13
CH2); 1.99-1.94 (3H, m) and 1.71 (1H, d, J = 13.2, 2CH2). C NMR spectrum, δ, ppm: 197.5; 185.1; 174.1;
160.3; 158.3; 149.7; 147.7; 145.0; 132.4; 129.2; 128.1; 124.7; 124.0; 112.2; 106.3; 63.5; 52.6; 46.2; 36.5; 28.5;
27.2; 20.6. Mass spectrum (ESI-), m/z: 428.62. Found, %: C 66.85; H 4.77; N 9.56. C24H19N3O5. Calculated, %:
C 67.13; H 4.46; N 9.78.
23-(4-Nitrobenzyl)-4,12-dioxa-20,23-diazahexacyclo[11.10.1.02,11.05,10.014,22.016,21]tetracosa-
2(11),5(10),6,8,16,18,20-heptaene-3,15-dione (3c). Yield 84%; yellow solid, mp 146-148°C. IR spectrum, ν,
cm-1: 2969 (w), 1697 (s), 1617 (vs), 1556 (s), 1517 (s), 1491 (w), 1456 (w), 1427 (w), 1401 (s), 1378 (m), 1343
(s), 1289 (w), 1204 (m), 1174 (m), 1105 (m), 1085 (w), 1041 (m), 951 (w), 881 (w). 1H NMR spectrum, δ, ppm
(J, Hz): 8.41 (1H, d, J = 4.8, H Ar); 8.26 (2H, d, J = 8.4, H Ar); 7.88 (1H, d, J = 7.8, H Ar); 7.76 (1H, d, J = 7.2,
H Ar); 7.69 (2H, d, J = 8.4, H Ar); 7.56 (1H, t, J = 7.8, H Ar); 7.30 (1H, d, J = 9.0, H Ar); 7.27-7.25 (2H, m, H
Ar); 7.10 (1H, d, J = 15.0) and 5.30 (1H, d, J = 15.0, CH2); 5.87 (1H, s, CH); 4.87 (1H, s, CH); 2.21 (1H, d,
J = 13.8, CH2); 1.95 (1H, d, J = 13.8, CH2). 13C NMR spectrum, δ, ppm: 185.3; 163.3; 161.8; 160.6; 158.1;
152.8; 149.9; 147.7; 144.6; 133.0; 132.1; 129.2; 128.3; 124.8; 124.3; 124.2; 123.9; 116.7; 115.1; 106.0; 100.8;
64.2; 63.1; 48.0; 27.1. Mass spectrum (ESI-), m/z: 478.41. Found, %: C 67.57; H 3.84; N 8.67. C27H17N3O6.
Calculated, %: C 67.64; H 3.57; N 8.76.
2-Benzyl-16,16-dimethyl-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetra-
ene-10,18-dione (3d). Yield 54%; yellow solid, mp 172-174°C. IR spectrum, ν, cm-1: 2959 (w), 1681 (s), 1650
(s), 1615 (vs), 1555 (s), 1489 (w), 1455 (w), 1378 (s), 1314 (w), 1279 (w), 1253 (w), 1205 (w), 1174 (m), 1154
(m), 1118 (m), 1079 (m), 1046 (m), 1024 (w), 983 (w), 896 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.41 (1H, d,
J = 3.6, H Ar); 7.75 (1H, d, J = 6.0, H Ar); 7.45 (2H, d, J = 7.8, H Ar); 7.36 (2H, t, J = 7.2, H Ar); 7.31 (1H, t,
J = 7.2, H Ar); 7.24-7.22 (1H, m, H Ar); 6.93 (1H, d, J = 14.4) and 4.92 (1H, d, J = 14.4, CH2); 5.53 (1H, d,
662

J = 1.8, CH); 4.77 (1H, s, CH); 2.36 (1H, d, J = 17.4), 2.29 (1H, d, J = 16.2) and 2.25-2.22 (2H, m, 2CH2);
1.88-1.85 (1H, m) and 1.63 (1H, d, J = 13.8, CH2); 1.04 (3H, s, CH3); 1.00 (3H, s, CH3). 13C NMR spectrum, δ,
ppm: 197.1; 184.8; 172.3; 160.5; 158.4; 149.6; 137.3; 132.9; 128.8; 128.5; 127.9; 127.8; 124.5; 111.2; 105.8;
64.0; 53.4; 50.2; 45.7; 42.1; 32.3; 29.5; 27.3; 27.0. Mass spectrum (ESI-), m/z: 411.31. Found, %: C 75.52;
H 6.13; N 6.47. C26H24N2O3. Calculated, %: C 75.71; H 5.86; N 6.79.
2-Benzyl-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetraene-10,18-dione
(3e). Yield 49%; yellow solid, mp 170–172°C. IR spectrum, ν, cm-1: 2952 (w), 1675 (s), 1638 (s), 1605 (vs),
1553 (s), 1492 (s), 1454 (w), 1434 (w), 1380 (w), 1301 (s), 1279 (w), 1261 (w), 1177 (m), 1156 (w), 1124 (m),
1085 (w), 1063 (w), 1046 (w), 1030 (m), 993 (w), 894 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.41 (1H, d, J = 4.2,
H Ar); 7.75 (1H, d, J = 6.6, H Ar); 7.44 (2H, d, J = 7.2, H Ar); 7.36 (2H, t, J = 7.2, H Ar); 7.31 (1H, t, J = 7.2,
H Ar); 7.23 (1H, t, J = 6.0, H Ar); 6.92 (1H, d, J = 14.4) and 4.96 (1H, d, J = 14.4, CH2); 5.53 (1H, s, CH); 4.75
(1H, s, CH); 2.42 (2H, d, J = 5.4, CH2); 2.40 (2H, d, J = 6.0, CH2); 1.99–1.90 (3H, m) and 1.62 (1H, d,
J = 13.2, 2CH2). 13C NMR spectrum, δ, ppm: 197.4; 184.9; 173.9; 160.6; 158.5; 149.6; 137.4; 132.9; 128.8;
128.5; 127.8; 124.4; 112.4; 106.0; 63.8; 53.4; 45.9; 36.6; 28.5; 27.3; 20.7. Mass spectrum (ESI-), m/z: 383.49.
Found, %: C 74.62; H 5.47; N 7.02. C24H20N2O3. Calculated, %: C 74.98; H 5.24; N 7.29.
16,16-Dimethyl-2-(4-methylbenzyl)-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-
4,6,8,14(19)-tetraene-10,18-dione (3f). Yield 54%; yellow solid, mp 194-198°C. IR spectrum, ν, cm-1: 2962
(w), 1677 (s), 1643 (s), 1610 (vs), 1555 (s), 1454 (w), 1378 (m), 1311 (w), 1176 (m), 1118 (m), 1084 (m), 1045
(m), 954 (w), 895 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.41 (1H, d, J = 4.8, H Ar); 7.74 (1H, d, J = 7.2,
H Ar); 7.33 (2H, d, J = 7.8, H Ar); 7.23-7.21 (1H, m, H Ar); 7.16 (2H, d, J = 7.8, H Ar); 6.88 (1H, d, J = 13.8)
and 4.87 (1H, d, J = 13.8, CH2); 5.52 (1H, d, J = 2.4, CH); 4.77 (1H, s, CH); 2.37 (1H, m) and 2.31-2.28 (1H,
m, CH2); 2.34 (3H, s, C6H4CH3); 2.25-2.21 (2H, m, CH2); 1.87-1.84 (1H, m) and 1.63-1.60 (1H, m, CH2); 1.03
13
(3H, s, CH3); 1.00 (3H, s, CH3). C NMR spectrum, δ, ppm: 197.1; 184.9; 172.3; 160.5; 158.4; 149.6; 137.6;
134.2; 132.9; 129.5; 128.5; 127.7; 124.4; 110.2; 105.7; 64.0; 53.1; 55.5; 45.6; 42.1; 32.3; 29.4; 27.3; 27.0; 21.2.
Mass spectrum (ESI-), m/z: 425.23. Found, %: C 75.86; H 6.40; N 6.74. C27H26N2O3. Calculated, %: C 76.03;
H 6.14; N 6.57.
23-(4-Methylbenzyl)-4,12-dioxa-20,23-diazahexacyclo[11.10.1.02,11.05,10.014,22.016,21]tetracosa-
2(11),5(10),6,8,16,18,20-heptaene-3,15-dione (3g). Yield 59%; yellow solid, mp 168-175°C. IR spectrum, ν,
cm-1: 2980 (w), 1710 (s), 1672 (m), 1616 (vs), 1549 (s), 1488 (m), 1456 (w), 1455 (s), 1380 (m), 1175 (m),
1105 (m), 1084 (m), 1040 (m), 968 (w), 879 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.43 (1H, d, J = 4.8, H Ar);
7.87 (1H, d, J = 7.8, H Ar); 7.74 (1H, d, J = 7.2, H Ar); 7.53 (1H, t, J = 7.2, H Ar); 7.37 (2H, d, J = 7.8, H Ar);
7.29 (1H, d, J = 8.4, H Ar); 7.27-7.25 (1H, m, H Ar); 7.22 (1H, t, J = 6.6, H Ar); 7.19 (2H, d, J = 7.8, H Ar);
7.03 (1H, d, J = 14.4) and 5.05 (1H, d, J = 14.4, CH2); 5.82 (1H, s, CH); 4.94 (1H, s, CH); 2.37 (3H, s,
C6H4CH3); 2.10 (1H, d, J = 13.8, CH2); 1.82 (1H, d, J = 13.8, CH2). 13C NMR spectrum, δ, ppm: 185.1; 163.1;
161.7; 160.8; 158.3; 152.8; 149.8; 137.8; 134.0; 132.7; 132.6; 129.6; 128.5; 128.0; 124.6; 124.1; 123.9; 116.6;
115.2; 105.4; 101.1; 64.5; 53.7; 47.6; 27.2; 21.2. Mass spectrum (ESI-), m/z: 447.47. Found, %: C 74.72;
H 4.81; N 5.89. C28H20N2O4. Calculated, %: C 74.99; H 4.50; N 6.25.
2,16,16-Trimethyl-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetraene-
10,18-dione (3h). Yield 58%; yellow solid, mp 148-150°C. IR spectrum, ν, cm-1: 2962 (w), 1660 (s), 1606 (vs),
1555 (s), 1484 (w), 1457 (w), 1398 (s), 1372 (s), 1321 (w), 1302 (w), 1286 (w), 1247 (w), 1217 (w), 1183 (m),
1150 (w), 1121 (m), 1094 (w), 1069 (w), 1045 (m), 955 (w), 851 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.40
(1H, d, J = 3.6, H Ar); 7.69 (1H, d, J = 6.0, H Ar); 7.20-7.18 (1H, m, H Ar); 5.55 (1H, d, J = 2.4, CH); 4.71
(1H, s, CH); 4.06 (3H, s, NCH3); 2.34 (1H, d, J = 17.4) and 2.28-2.20 (3H, m, 2CH2); 2.01-1.94 (2H, m, CH2);
1.02 (6H, s, 2CH3). 13C NMR spectrum, δ, ppm: 198.2; 186.0; 173.5; 162.6; 159.6; 150.6; 134.3; 129.1; 125.7;
112.5; 106.9; 65.2; 51.8; 50.8; 43.4; 40.9; 33.7; 30.8; 28.5; 28.3. Mass spectrum (ESI-), m/z: 335.36. Found, %:
C 71.20; H 6.37; N 8.16. C20H20N2O3. Calculated, %: C 71.41; H 5.99; N 8.33.
2-Methyl-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetraene-10,18-dione
(3i). Yield 50%, yellow solid, mp 150-152°C. IR spectrum, ν, cm-1: 2937 (w), 1669 (s), 1642 (s), 1612 (vs),
663

1560 (s), 1490 (w), 1453 (w), 1416 (m), 1392 (s), 1372 (s), 1342 (w), 1313 (w), 1277 (w), 1179 (m), 1147 (w),
1125 (m), 1088 (w), 1069 (m), 1045 (m), 1029 (m), 966 (w), 897 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.40
(1H, d, J = 5.4, H Ar); 7.70 (1H, d, J = 7.2, H Ar); 7.21-7.19 (1H, m, H Ar), 5.55 (1H, d, J = 1.8, CH); 4.70
(1H, s, CH); 4.08 (3H, s, NCH3); 2.44 (2H, t, J = 6.0, CH2); 2.39-2.37 (2H, m, CH2); 2.02-1.99 (1H, m) and
13
1.97-1.94 (3H, m, 2CH2). C NMR spectrum, δ, ppm: 197.1; 184.7; 173.7; 161.2; 158.3; 149.3; 132.9; 127.7;
124.3; 112.3; 105.5; 63.8; 49.6; 39.6; 36.6; 28.5; 26.8; 20.6. Mass spectrum (ESI-), m/z: 307.53. Found, %:
C 69.75; H 5.50; N 8.67. C18H16N2O3. Calculated, %: C 70.12; H 5.23; N 9.09.
16,16-Dimethyl-2-(2-oxo-2-phenylethyl)-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-
4,6,8,14(19)-tetraene-10,18-dione (3j). Yield 80%; yellow solid, mp 168-170°C. IR spectrum, ν, cm-1: 2959
(w), 1703 (s), 1678 (s), 1611 (vs), 1556 (s), 1492 (w), 1452 (w), 1427 (w), 1391 (s), 1371 (s), 1344 (w), 1316
(w), 1221 (m), 1182 (m), 1111 (m), 1081 (m), 1047 (m), 1020 (w), 979 (w), 894 (w). 1H NMR spectrum, δ, ppm
(J, Hz): 8.19 (1H, d, J = 7.8, H Ar); 8.01 (2H, d, J = 7.8, H Ar); 7.67 (1H, d, J = 7.2, H Ar); 7.64 (1H, t, J = 7.2,
H Ar); 7.53 (2H, t, J = 7.8, H Ar); 7.11 (1H, t, J = 7.2, H Ar); 6.72 (1H, m) and 5.74 (1H, d, J = 8.4, CH2); 5.63
(1H, s, CH); 4.63 (1H, s, CH); 2.38-2.27 (3H, m), 2.25-2.17 (2H, m) and 2.07-2.04 (1H, m, 3CH2); 1.03 (3H, s,
13
CH3); 1.02 (3H, s, CH3). C NMR spectrum, δ, ppm: 197.3; 195.1; 185.4; 172.0; 161.5; 158.2; 149.3; 135.0;
133.8; 132.3; 128.9; 128.1; 127.9; 124.2; 111.5; 106.6; 64.2; 58.6; 50.2; 49.3; 41.9; 32.2; 29.3; 27.3; 26.9. Mass
spectrum (ESI-), m/z: 439.53. Found, %: C 73.71; H 5.75; N 6.29. C27H24N2O4. Calculated, %: C 73.62; H 5.49;
N 6.36.
2-(2-Oxo-2-phenylethyl)-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-4,6,8,14(19)-tetra-
ene-10,18-dione (3k). Yield 74%; yellow solid, mp 156–158°C. IR spectrum, ν, cm-1: 2945 (w), 1678 (s), 1641
(s), 1607 (vs), 1556 (s), 1491 (w), 1430 (w), 1386 (s), 1314 (w), 1228 (m), 1177 (m), 1156 (w), 1120 (m), 1084
(w), 1053 (w), 1029 (w), 994 (w), 896 (w). 1H NMR spectrum, δ, ppm (J, Hz): 8.19 (1H, d, J = 4.2, H Ar); 8.02
(2H, d, J = 7.8, H Ar); 7.67-7.66 (1H, m, H Ar); 7.64 (1H, t, J = 7.2, H Ar); 7.53 (2H, t, J = 7.2, H Ar);
7.12-7.10 (1H, m, H Ar); 6.80 (1H, m) and 5.73 (1H, d, J = 17.4, CH2); 5.63 (1H, s, CH); 4.60 (1H, s, CH); 2.46
(2H, t, J = 6.0, CH2); 2.40-2.30 (3H, m) and 2.08-2.04 (1H, m, 2 CH2); 2.00-1.89 (2H, m, CH2). 13C NMR
spectrum, δ, ppm: 197.0; 195.2; 185.4; 173.6; 161.4; 158.3; 149.3; 135.0; 133.8; 132.3; 128.9; 128.1; 127.8;
124.2; 112.8; 106.5; 64.2; 58.6; 49.4; 36.4; 28.4; 26.8; 20.6. Mass spectrum (ESI-), m/z: 411.37. Found, %:
C 72.62; H 5.17; N 6.53. C25H20N2O4. Calculated, %: C 72.80; H 4.89; N 6.79.
23-(2-Oxo-2-phenylethyl)-4,12-dioxa-20,23-diazahexacyclo[11.10.1.02,11.05,10.014,22.016,21]tetracosa-
2(11),5(10),6,8,16,18,20-heptaene-3,15-dione (3l). Yield 76%; yellow solid, mp 184-186°C. IR spectrum, ν,
cm-1: 2934 (w), 1696 (vs), 1621 (s), 1556 (s), 1491 (w), 1451 (w), 1403 (m), 1375 (m), 1347 (w), 1324 (w),
1295 (w), 1273 (w), 1228 (m), 1207 (w), 1177 (m), 1160 (m), 1107 (w), 1085 (w), 1042 (m), 976 (w), 882 (w).
1H NMR spectrum, δ, ppm (J, Hz): 8.22 (1H, d, J = 4.8, H Ar); 8.05 (2H, d, J = 7.8, H Ar); 7.90 (1H, d, J = 7.2,
H Ar); 7.66 (2H, d, J = 7.2, H Ar); 7.56-7.52 (3H, m, H Ar); 7.27 (2H, d, J = 5.4, H Ar); 7.12 (1H, d, J = 6.0,
H Ar); 7.05 (1H, m) and 5.78 (1H, d, J = 15.0, CH2); 5.93 (1H, s, CH); 4.81 (1H, s, CH); 2.60 (1H, d, J = 13.8)
and 2.30 (1H, d, J = 13.8, CH2). 13C NMR spectrum, δ, ppm: 195.2; 185.6; 163.3; 161.6; 161.4; 158.1; 152.7;
146.6; 134.9; 133.9; 132.7; 132.0; 129.3; 128.9; 128.2; 128.1; 124.4; 124.2; 124.0; 116.6; 106.3; 101.4; 64.8;
59.0; 51.1; 26.8. Mass spectrum (ESI-), m/z: 461.37. Found, %: C 72.53; H 4.34; N 5.79. C28H18N2O5.
Calculated, %: C 72.72; H 3.92; N 6.06.
Ethyl {16,16-Dimethyl-10,18-dioxo-13-oxa-2,5-diazapentacyclo[10.7.1.03,11.04,9.014,19]icosa-
4,6,8,14(19)-tetraene-2-yl}acetate (3m). Yield 58%; yellow solid, mp 108–110°C. IR spectrum, ν, cm-1: 2961
(w), 1745 (s), 1676 (m), 1643 (m), 1607 (vs), 1552 (s), 1490 (w), 1463 (w), 1396 (m), 1371 (m), 1321 (w), 1279
(w), 1208 (s), 1179 (m), 1115 (w), 1084 (w), 1048 (w), 954 (w), 892 (w). 1H NMR spectrum, δ, ppm (J, Hz):
8.33 (1H, d, J = 4.2, H Ar); 7.68 (1H, d, J = 7.2, H Ar); 7.17-7.15 (1H, m, H Ar); 5.86 (1H, d, J = 17.4) and
5.03 (1H, d, J = 17.4, CH2); 5.56 (1H, s, CH); 4.67 (1H, s, CH); 4.22-4.18 (2H, m, CH2); 2.34 (1H, m) and 2.27
(1H, d, J = 13.8, CH2); 2.24-2.20 (2H, m, CH2); 2.16 (1H, d, J = 13.8) and 2.04-2.01 (1H, m, CH2); 1.29 (3H, t,
J = 7.2, CH3); 1.02 (6H, s, 2CH3). 13C NMR spectrum, δ, ppm: 197.1; 185.7; 171.7; 169.9; 161.1; 158.4; 149.5;
132.1; 127.9; 124.3; 114.4; 106.7; 63.9; 61.5; 53.0; 50.2; 49.1; 41.9; 32.2; 29.3; 27.2; 27.0; 14.2.
664

Mass spectrum (ESI+), m/z: 407.38. Found, %: C 67.70; H 6.38; N 6.65. C23H24N2O5. Calculated, %: C 67.63;
H 5.92; N 6.86.
This work was financially supported by the National Natural Science Foundation of China (Grant No.
20972132) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
L. A. Thompson and J. A. Ellman, Chem. Rev., 96, 555 (1996).
D. L. Klayman, J. P. Scovill, J. F. Bartosevich, and C. J. Mason, J. Med. Chem., 22, 1367 (1979).
E. Vedejs, R. J. Galante, and P. G. Goekjian, J. Am. Chem. Soc., 120, 3613 (1998).
D. C. Palmer and M. J. Strauss, Chem. Rev., 77, 1 (1977).
A. Deiters and S. F. Martin, Chem. Rev., 104, 2199 (2004).
P. A. Evans and B. Holmes, Tetrahedron, 47, 9131 (1991).
D. Staerk, M. Witt, H. A. Oketch-Rabah, and J. W. Jaroszewski, Org. Lett., 5, 2793 (2003).
G. Broggini, L. Bruch, L. Garanti, and G. Zecchi, J. Chem. Soc., Perkin Trans. 1, 433 (1994).
W. A. L. Van Otterlo, G. L. Morgans, S. D. Khanye, B. A. Aderibigbe, J. P. Michael, and D. G. Billing,
Tetrahedron Lett., 45, 9171 (2004).
10.
11.
12.
A. Klapars, S. Parris, K. W. Anderson, and S. L. Buchwald, J. Am. Chem. Soc., 126, 3529 (2004).
T. Yang, C. Lin, H. Fu, Y. Jiang, and Y. Zhao, Org. Lett., 7, 4781 (2005).
K. Mizuno, M. Sawa, H. Harada, I. Taoka, H. Yamashita, M. Oue, H. Tsujiuchi, Y. Arai, S. Suzuki,
Y. Furutani, and S. Kato, Bioorg. Med. Chem., 13, 855 (2005).
13.
14.
15.
J. K. Mishra, K. Samanta, M. Jain, M. Dikshit, and G. Panda, Bioorg. Med. Chem. Lett., 20, 244 (2010).
T. Ventrice, E. M. Campi, W. R. Jackson, and A. F. Patti, Tetrahedron, 57, 7557 (2001).
J. Agejas, F. Delgado, J. J. Vaquero, J. L. García-Navío, and C. Lamas, Tetrahedron Lett., 43, 8025
(2002).
16.
17.
18.
19.
A. Neogi, T. P. Majhi, R. Mukhopadhyay, and P. Chattopadhyay, J. Org. Chem., 71, 3291 (2006).
J. Rujirawanich and T. Gallagher, Org. Lett., 11, 5494 (2009).
E. Ullah, S. Rotzoll, A. Schmidt, D. Michalikc, and P. Langer, Tetrahedron Lett., 46, 8997 (2005).
F. M. Moghaddam, Z. Mirjafary, H. Saeidian, S. Taheri, M. Doulabi, and M. Kiamehr, Tetrahedron, 66,
134 (2010).
20.
21.
22.
23.
F. M. Moghaddam, S. Taheri, Z. Mirjafary, and H. Saeidian, Synlett, 123 (2010).
J. F. Wang, Y. X. Liao, P. Y. Kuo, Y. H. Gau, and D. H. Yang, Synlett, 2791 (2006).
J. T. Lai, P. Y. Kuo, Y. H. Gau, and D. Y. Yang, Tetrahedron Lett., 48, 7796 (2007).
D. H. Yang, Y. S. Chen, P. Y. Kuo, J. T. Lai, C. M. Jiang, C. H. Lai, Y. H. Liao, and P. T. Chou, Org.
Lett., 9, 5287 (2007).
24.
25.
C. H. Lin, J. L. Chen, and D. H. Yang, J. Comb. Chem., 12, 119 (2010).
F. M. Moghaddam, M. Mirjafary, H. Saeidian, S. Taheria, and B. Soltanzadeh, Tetrahedron, 66, 3678
(2010).
26.
27.
F. M. Moghaddam, Z. Mirjafary, H. Saeidian, S. Taheri, and M. R. Khodabakhshi, Tetrahedron Lett.,
51, 2704 (2010).
F. M. Moghaddam, S. Taheria, Z. Mirjafarya, H. Saeidianb, M. Kiamehra, and M. Tafazzolia, Helv.
Chim. Acta, 92, 142 (2011).
28.
29.
30.
L. Hui and C. G. Yan, Tetrahedron, 67, 2863 (2011).
J. E. Dickeson and L. A. Summers, Aust. J. Chem., 23, 1023 (1970).
A. V. Rotaru, R. P. Danac, and I. D. Druta, J. Heterocycl. Chem., 41, 983 (2004).
665