Efficient synthesis of piperazinediones using potassium iodide catalysis in aqueous media

Article abstract of DOI:10.2174/157017811799304098

A simple and efficient synthetic approach to 1,4-disubstituted piperazine-2,5-diones was developed. A series of symmetrical 1,4-disubstituted piperazine-2,5-diones was prepared from chloroacetamides using potassium iodide catalysis in acetone/water. The structures of two products were confirmed by single crystal X-ray diffraction analysis.

Full text of DOI:10.2174/157017811799304098

732
Letters in Organic Chemistry, 2011, 8, 732-736
Efficient Synthesis of Piperazinediones Using Potassium Iodide Catalysis
in Aqueous Media
Yong-Hong Wen*, Xiao-Na Chen, Hui-Ling Wen and Xiao-Fang Tang
College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042,
P. R. China
Received May 23, 2011: Revised June 30, 2011: Accepted August 09, 2011
Abstract: A simple and efficient synthetic approach to 1,4-disubstituted piperazine-2,5-diones was developed. A series of
symmetrical 1,4-disubstituted piperazine-2,5-diones was prepared from chloroacetamides using potassium iodide catalysis
in acetone/water. The structures of two products were confirmed by single crystal X-ray diffraction analysis.
Keywords: Chloroacetamide, cyclization reaction, diketopiperazine, piperazinedione.
INTRODUCTION
RESULTS AND DISCUSSION
Piperazinediones (diketopiperazines) are the smallest
structural cyclodipeptides and represent an important class of
biologically active natural products [1]. Piperazinediones are
now an important core for the expression of biological
activity. Recently, piperazinediones have gained importance
in drug discovery [2], as inhibitors of various enzymes,
including e.g. topoisomerases, collagenase-1, glutathione-S-
transferase [3], as well as bradykinin antagonists, modulators
of plasminogen activator inhibitor-1, and opioid receptor
agonists and antagonists [4]. In addition, piperazinediones
represent important precursors for the synthesis of peptides
and non-natural amino acids [5]. The synthetic methods for
the preparation of piperazinediones are now being exploited
by use of various strategies, such as phase transfer catalysis,
and multicomponent reactions [6, 7]. The synthesis of the N-
substituted piperazinediones has been difficult directly from
N-alkylation of piperazinediones and much effort has been
carried out using the acyclic chloroacetamides [8-11]. Water
possesses many advantages over traditional organic solvents:
simple operation, safety, low cost, the minimization of
tedious protection and deprotection, etc., so growing interest
has been focused on synthetic organic reactions in aqueous
media in the past decades. Many organic reactions have been
successfully carried out in aqueous media, such as Diels-
Alder reactions, Claisen rearrangements and aldol reactions
[12-15]. We report herein a simple and efficient method for
the synthesis of 1,4-disubstituted piperazine-2,5-diones by
the cyclization reactions of the N-substituted chloroac-
etamides using potassium iodide catalysis in aqueous media.
Thirteen piperazine-2,5-diones were synthesized and
Firstly, to optimize the reaction conditions, we chose the
cyclization of 2-chloro-N-(3-methylphenyl) acetamide (1c)
as our model reaction. 1,4-Bis(3-methylphenyl)piperazine-
2,5-dione (2c) was obtained only in low yield of 46% when
1c was refluxed 24 h in acetone in the absence of catalyst
(Table 1, entry 1), while the yield of 2c (75% and 85%)
increased enormously when NaI or KI was added (Table 1,
entries 2 and 3), meanwhile the reaction time decreased from
24 h to 5 h. It is supposed that chloroacetamides are
transformed by KI to more reactive iodoacetamides, and then
iodoacetamides carry out the cyclization reaction quickly.
This has been demonstrated by the cyclization reaction of 2-
iodo-N-(3-methylphenyl)acetamide: 2c was obtained in the
yield of 83% from 2-iodo-N-(3-methylphenyl)acetamide in
the reaction conditions of entry 3 in Table 1 in the absence of
KI. It is interesting to note that the yield of 2c was still high
in the presence of water. The effect of water on the yield of
cyclization reaction was specially investigated. The yield of
2c was still higher than 80% when the cyclization reactions
were carried out in the mixture solvent of acetone: water >
2:1 (Table 1, entries 4–6). When the ratios of acetone to
water were smaller than 1:1, the yield of 1c decreased
obviously (Table 1, entries 8–10). This is likely to be due to
the decrease in solubility of chloroacetamide.
Taking various factors into consideration, especially to
develop an efficient method for the synthesis of
piperazinediones in the water-containing system, which is a
very important topic in green chemistry, the conditions of
entry 6 were selected for the further study. With potassium
iodide as a catalyst and potassium carbonate as a base, a
series of piperazine-2,5-diones were prepared in the mixture
solvent of acetone : water = 2 : 1 (Table 2). All reactions
proceeded in moderate to good yields. Nitro-substituted
piperazine-2,5-diones 2j and 2k were also obtained
successfully from the electron-poor chloroacetamides 1j and
1k, which were reported to be unreactive in a recent
literature [11], in the good yields of 78% and 69%,
respectively. The meta-substituted compounds 2c and 2f
were isolated successfully in the better yields of 81% and
83%, respectively, than other products. Large naphthalenyl
1
characterized by elemental analyses, IR, H and 13C NMR
spectroscopy, of which two compounds were confirmed by
single crystal X-ray diffraction structural analysis.
*Address correspondence to this author at the College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China; Tel: +86 532 84022681; Fax: +86-532-
84023927; E-mail: yonghwen@163.com
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

Synthesis of Piperazinediones
Letters in Organic Chemistry, 2011, Vol. 8, No. 10
733
Table 1. The Optimization of the Reaction Conditions for the Synthesis of Piperazine-2,5-dione 2c
Entry
Base
Catalyst
Solvent
Time (h)
Yield (%)
1
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
NaI
KI
KI
KI
KI
KI
KI
KI
KI
Acetone
24
5
46
75
85
82
81
81
67
44
22
19
Acetone
3
Acetone
5
4
Acetone/H2O 4:1
Acetone/H2O 3:1
Acetone/H2O 2:1
Acetone/H2O 1:1
Acetone/H2O 1:2
Acetone/H2O 1:3
Acetone/H2O 1:4
5
5
5
6
5
7
5
8
5
9
5
10
5
substituent chloroacetamide 1n afforded the corresponding
product 2n in 70% yield in this reaction condition. 1,4-Bis(4-
ethoxyphenyl)piperazine-2,5-dione 2i was collected in 63%
yield, but its ortho-substituted isomer 2h could not be
obtained in the same condition. This is probably because the
relatively lower solubility and larger steric hindrance of the
ortho-ethoxy group at benzene ring prevent 1h from carrying
out the cyclization reaction.
The structures of all products obtained were established
by elemental analyses and spectroscopic methods. The
structures of 2c and 2j were confirmed by single crystal X-
ray diffraction analysis (Figs. 1 and 2). Compound 2c
contains two independent molecules in the asymmetric unit,
while 2j contains only one independent molecule in the
asymmetric unit. The piperazinedione ring in 2c is planar,
but the one in 2j is the boat conformation.
This method is not limited to the use of N-aryl
chloroacetamides, because aliphatic-substituted 2-chloro-N-
cyclohexylacetamide 1m also gave the corresponding
piperazinedione 2m in yield of 65%.
In conclusion, the present communication provides an
efficient method for the synthesis of 1,4-disubstituted
piperazine-2,5-diones by direct cyclization reaction of N-
substituted chloroacetamides using potassium iodide as a
Table 2. Synthesis of 1,4-disubstituted Piperazine-2,5-diones
O
O
K2CO3, KI
acetone/water
H
N
R
N
N
O
R
R
Cl
1
2
Entry
R
Product
Isolated yield (%)
1
2
Ph
2a
2b
2c
2d
2e
2f
75
71
81
60
67
83
72
—
63
78
69
57
65
70
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-EtOC6H4
4-EtOC6H4
2-NO2C6H4
4-NO2C6H4
2-ClC6H4
3
4
5
6
7
2g
2h
2i
8
9
10
11
12
13
14
2j
2k
2l
C6H11
2m
2n
C10H7

734 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
Wen et al.
Fig. (1). ORTEP plot of 2c (50% probability level). The suffix A corresponds to symmetry code (1/2-x, 1/2+y, 1/2-z).
catalyst in aqueous media. Thirteen piperazinediones
compounds were synthesized and the structures of two
compounds were confirmed by single crystal X-ray
diffraction analysis. The method has such advantages as less
steps, lower cost, mild reaction condition, high yield, simple
workup, and is environmentally friendly. The yields of the
products are influenced by the solubility and the steric
hindrance of reactants. The investigations on biological
activities of these compounds are now under way and some
positive results have been obtained in our laboratory. The
results obtained will be very useful for the further synthetic
study of piperazinediones.
spectrometer at 500 and 125 MHz, respectively. Chemical
shifts (ꢀ) were reported in ppm relative to solvent signals (ꢀ
= 2.51 and 39.5 ppm for DMSO-d6 or 7.25 and 77.0 ppm for
CDCl3). Coupling constants (J) were quoted in Hz. Melting
points were determined on a RY-1 melting point apparatus
and were uncorrected. Elemental analyses were performed
by an Elementar Vario EL III analyzer.
The N-substituted chloroacetamides, 2-chloro-N-phenyl-
acetamide (1a), 2-chloro-N-(2-methylphenyl)acetamide (1b),
2-chloro-N-(3-methylphenyl)acetamide (1c), 2-chloro-N-(4-
methylphenyl)acetamide
phenyl)acetamide (1e),
(1d),
2-chloro-N-(2-methoxy-
2-chloro-N-(3-methoxyphenyl)
acetamide (1f), 2-chloro-N-(4-methoxyphenyl)acetamide
(1g), 2-chloro-N-(2-ethoxyphenyl)acetamide (1h), 2-chloro-
N-(4-ethoxyphenyl)acetamide (1i), 2-chloro-N-(2-nitro-
phenyl)acetamide (1j), 2-chloro-N-(4-nitrophenyl)acetamide
(1k), 2-chloro-N-(2-chlorophenyl)acetamide (1l), 2-chloro-
N-cyclohexylacetamide (1m), and 2-chloro-N-(naphthalen-1-
yl)acetamide (1n), were prepared by the reactions of
corresponding amines and chloroacetyl chloride in the
presence of triethylamine according to the literature methods
[10].
Fig. (2). ORTEP plot of 2j (50% probability level). The suffix A
corresponds to symmetry code (3/2-x, 3/2-y, z).
General Procedure for the Preparation of Piperazine-2,5-
diones 2a–o
EXPERIMENTAL
To a solution of N-substituted chloroacetamide (20
mmol) in acetone (20 mL) and water (10 mL) were added
K2CO3 (22 mmol) and KI (0.3 g, 2 mmol), respectively, and
the mixture was refluxed for 5 h. After completion of the
reaction (5 h, monitored by TLC), the mixture was cooled,
diluted with water (30–50 mL) and filtered through a thin
pad of Celite. The filter cake was collected and purified by
recrystallization or by column chromatography to afford the
piperazinedione 2.
All chemicals used were of analytical reagent grade and
used directly without further purification. Crude products
were purified by column chromatography on silica gel or by
recrystallization from EtOH or acetone/water. IR spectra
were recorded on a Perkin–Elmer FT IR spectrometer (KBr).
1H and 13C NMR spectra were recorded at room temperature
in DMSO-d6 or CDCl3 solvent on Bruker Avance 500 NMR

Synthesis of Piperazinediones
Letters in Organic Chemistry, 2011, Vol. 8, No. 10
735
1,4-Diphenylpiperazine-2,5-dione (2a)
212 °C. IR (KBr): 3024 (w), 2942 (w), 2855 (w), 1673 (vs),
1595 (m), 1575 (w), 1500 (s), 1466 (s), 1380 (w), 1269 (m),
Synthesized from 2-chloro-N-phenylacetamide (1a, 3.39
g, 20.0 mmol) following the general procedure (56 °C, 5 h)
and purified by recrystallization (acetone/water). Yield: 1.99
g (75%); white solid; mp 266–267 °C. IR (KBr): 3050 (w),
3020 (w), 1654 (vs), 1594 (w), 1552 (w), 1495 (s), 1470 (m),
1431 (m), 1251 (w), 758 (s), 693 (s) cm-1. 1H NMR (500
MHz, DMSO-d6): ꢀ = 4.51 (s, 4 H, 2 ꢀ CH2), 7.31 (t, J = 7.0
Hz, 4 H, ArH), 7.42–7.47 (m, 6 H, ArH). 13C NMR (125
MHz, DMSO-d6): ꢀ = 53.39, 123.28, 125.98, 129.35, 140.67,
160.21. Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N,
10.52. Found: C, 72.21; H, 5.28; N 10.45.
1
1251 (m), 1113 (m), 761 (s) cm-1. H NMR (500 MHz,
CDCl3): ꢀ = 3.91 (s, 6 H, 2 ꢀ CH3), 4.45 (s, 4 H, 2 ꢀ CH2),
7.04 (d, J = 8.5Hz, 2 H, ArH), 7.06 (d, J = 8.2Hz, 2 H, ArH),
7.29–7.31 (m, 2 H, ArH), 7.37–7.40 (m, 2 H, ArH). 13C
NMR (125 MHz, CDCl3): ꢀ = 53.65, 56.33, 116.54, 122.10,
123.76, 124.45, 129.66, 156.78, 161.25. Anal. Calcd for
C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.09; H,
5.68; N 8.58.
1,4-Bis(3-methoxyphenyl)piperazine-2,5-dione (2f)
Synthesized
from
2-chloro-N-(3-methoxyphenyl)
1,4-Bis(2-methylphenyl)piperazine-2,5-dione (2b)
acetamide (1f, 3.99 g, 20.0 mmol) following the general
procedure (56 °C, 5 h) and purified by recrystallization
(acetone/water). Yield: 2.70 g (83%); white solid; mp 181–
182 °C. IR (KBr): 3015(w), 2946 (w), 1641(vs), 1596(s),
1495(s), 1466(m), 1426(w), 1340 (m), 1212(s) 1144 (m),
Synthesized from 2-chloro-N-(2-methylphenyl)acetamide
(1b, 3.66 g, 20.0 mmol) following the general procedure (56
°C, 5 h) and purified by recrystallization (acetone/water).
Yield: 2.10 g (71%); white solid; mp 196–197 °C. IR (KBr):
3056 (w), 3024 (w), 2973 (w), 2924 (w), 1678 (vs), 1604
(w), 1582 (w), 1493 (s), 1461 (s), 1421 (s), 1323 (s), 1378
(w), 1262 (w), 758 (vs) cm-1. 1H NMR (500 MHz, DMSO-
d6): ꢀ = 2.38 (s, 6 H, 2 ꢀ CH3), 4.40 (s, 4 H, 2 ꢀ CH2), 6.95–
7.21 (m, 8 H, ArH). 13C NMR (125 MHz, DMSO-d6): ꢀ =
22.35, 53.31, 119.68, 124.66, 127.52, 129.87, 136.63,
139.78, 159.56. Anal. Calcd for C18H18N2O2: C, 73.45; H,
6.16; N, 9.52. Found: C, 73.42; H, 6.12; N 9.56.
1
1032 (m), 859 (w), 787(s), 692(m). H NMR (125 MHz,
DMSO-d6): ꢀ = 3.78 (s, 6 H, 2 ꢀ CH3), 4.49 (s, 4 H, 2 ꢀ
CH2), 6.89 (d, J = 7.5 Hz, 2 H, ArH), 6.99 (d, J = 8.0 Hz, 2
H, ArH), 7.01 (s, 2 H, ArH), 7.35 (dd, J = 8.0 Hz, 2 H, ArH).
13C NMR (500 MHz, DMSO-d6): ꢀ = 53.75, 56.21, 112.18,
113.37, 118.34, 130.58, 142.21, 160.48, 164.94. Anal. Calcd
for C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.18;
H, 5.65; N 8.52.
1,4-Bis(4-methoxyphenyl)piperazine-2,5-dione (2g)
1,4-Bis(3-methylphenyl)piperazine-2,5-dione (2c)
Synthesized
from
2-chloro-N-(4-methoxyphenyl)
Synthesized from 2-chloro-N-(3-methylphenyl)acetamide
(1c, 3.66 g, 20.0 mmol) following the general procedure (56
°C, 5 h) and purified by recrystallization (acetone/water).
Yield: 2.38 g (81%); white solid; mp 176–177 °C. IR (KBr):
3053 (w), 2917 (w), 1664 (vs), 1605 (w), 1587 (m), 1494
(m), 1460(s), 1429(w), 1271 (w), 870 (m), 796 (s), 690 (m)
acetamide (1g, 3.99 g, 20.0 mmol) following the general
procedure (56 °C, 5 h) and purified by recrystallization
(acetone/water). Yield: 2.35 g (72%); white solid; mp 259–
260 °C. IR (KBr): 3014(w), 2957 (w), 2834 (w), 1652(vs),
1610(w), 1587(w), 1514(s), 1467(w), 1384 (w), 1337 (s),
1245(w), 1147(m), 1033 (m), 817(s) cm-1. H NMR (500
1
1
cm-1. H NMR (500 MHz, DMSO-d6): ꢀ = 2.36 (s, 6 H, 2 ꢀ
MHz, DMSO-d6): ꢀ = 3.75 (s, 6 H, 2 ꢀ CH3), 4.40 (s, 4 H, 2
ꢀ CH2), 6.87 (d, J = 8.0 Hz, 4 H, ArH), 7.11 (d, J = 8.0 Hz, 4
H, ArH). 13C NMR (125 MHz, DMSO-d6): ꢀ = 52.72, 55.23,
116.45, 121.97, 133.88, 158.31, 159.26. Anal. Calcd for
C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.30; H,
5.54; N 8.55.
CH3), 4.50 (s, 4 H, 2 ꢀ CH2), 7.15 (d, J = 7.0 Hz, 2 H, ArH),
7.24 (d, J = 8.0 Hz, 2 H, ArH), 7.27 (s, 2 H, ArH), 7.35 (dd,
J = 8.0 Hz, 2 H, ArH). 13C NMR (125 MHz, DMSO-d6): ꢀ =
20.88, 52.87, 122.21, 125.74, 127.31, 128.68, 138.30,
140.13, 164.08. Anal. Calcd for C18H18N2O2: C, 73.45; H,
6.16; N, 9.52. Found: C, 73.56; H, 6.19; N 9.42.
1,4-Bis(4-ethoxyphenyl)piperazine-2,5-dione (2i)
1,4-Bis(4-methylphenyl)piperazine-2,5-dione (2d)
Synthesized from 2-chloro-N-(4-ethoxyphenyl)acetamide
(1i, 4.27 g, 20.0 mmol) following the general procedure (56
°C, 5 h) and purified by recrystallization (acetone/water).
Yield: 2.23 g (63%); white amorphous solid; mp 249–251
°C. IR (KBr): 2976 (w), 2927 (w), 1657(vs), 1606(w),
1514(s), 1474(w), 1395 (w), 1336 (m), 1244 (m), 1146(w),
1047 (w), 822 (m) cm-1. 1H NMR (500 MHz, DMSO-d6): ꢀ =
1.33 (t, 6 H, J = 7.0 Hz, 2 ꢀ CH3), 4.04 (q, 4 H, J = 7.0 Hz, 2
ꢀ OCH2), 4.41 (s, 4 H, 2 ꢀ CH2), 6.97 (d, J = 8.5 Hz, 4 H,
ArH), 7.31 (d, J = 8.5 Hz, 4 H, ArH). 13C NMR (125 MHz,
DMSO-d6): ꢀ = 15.52, 53.65, 60.73, 123.78, 128.96, 136.62,
148.78, 162.46. Anal. Calcd for C20H22N2O4: C, 67.78; H,
6.26; N, 7.90. Found: C, 67.54; H, 6.22; N 7.85.
Synthesized from 2-chloro-N-(4-methylphenyl)acetamide
(1d, 3.66 g, 20.0 mmol) following the general procedure (56
°C, 8 h) and purified by recrystallization (acetone/water).
Yield: 1.76 g (60%); white amorphous solid; mp 255–256
°C. IR (KBr): 3040 (w), 2948 (w), 2852 (w), 1657 (vs), 1613
(w), 1575 (w), 1515 (s), 1467 (s), 1430 (w), 1381 (w), 1336
1
(s), 1279 (w), 1251 (m), 810 (s) cm-1. H NMR (500 MHz,
DMSO-d6): ꢀ = 2.32 (s, 6 H, 2 ꢀ CH3), 4.45 (s, 4 H, 2 ꢀ
CH2), 7.24 (d, J = 8.0 Hz, 4 H, ArH), 7.29 (d, J = 8.0 Hz, 4
H, ArH). 13C NMR (125 MHz, DMSO-d6): ꢀ = 21.22, 52.96,
122.66, 127.34, 133.42, 139.87, 160.46. Anal. Calcd for
C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.62; H,
6.00; N 9.63.
1,4-Bis(2-nitrophenyl)piperazine-2,5-dione (2j)
1,4-Bis(2-methoxyphenyl)piperazine-2,5-dione (2e)
Synthesized from 2-chloro-N-(2-nitrophenyl)acetamide
(1j, 4.29 g, 20.0 mmol) following the general procedure (56
Synthesized
from
2-chloro-N-(2-methoxyphenyl)
acetamide (1e, 3.99 g, 20.0 mmol) following the general
procedure (56 °C, 5 h) and purified by recrystallization
(acetone/water). Yield: 2.18 g (67%); white solid; mp 210–
°C,
5 h) and purified by column chromatography
(CH3COOEt–petroleum ether, 1:1). Yield: 2.78 g (78%);

736 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
Wen et al.
yellow solid; mp 232–233 °C. IR (KBr): 3027 (w), 2935 (w),
1675 (s), 1601 (m), 1565 (w), 1500 (s), 1463 (s), 1355 (s),
1268 (m), 852 (m), 751 (w) cm-1. 1H NMR (500 MHz,
DMSO-d6): ꢀ = 4.42 (s, 4 H, 2 ꢀ CH2), 7.33–7.68 (m, 6 H,
ArH), 8.03 (d, J = 8.0 Hz, 2 H, ArH). 13C NMR (125 MHz,
DMSO-d6): ꢀ = 56.45, 120.88, 123.55, 126.31, 125.20,
137.79, 154.68, 164.25. Anal. Calcd for C16H12N4O6: C,
53.94; H, 3.39; N, 15.73. Found: C, 53.80; H, 3.29; N 15.81.
7.61–7.76 (m, 8H, ArH), 8.02–8.17 (m, 6H, ArH). 13C NMR
(125 MHz, DMSO-d6): ꢀ = 53.73, 106.94, 117.36, 120.12,
123.47, 124.50, 125.27, 126.68, 129.86, 133.41, 147.25,
158.64. Anal. Calcd for C24H18N2O2: C, 78.67; H, 4.95; N,
7.65. Found: C, 78.69; H, 5.00; N, 7.56.
Crystallographic Data
Crystallographic data for the structural analysis of 2c and
2j have been deposited with the Cambridge Crystallographic
Data Center. CCDC reference number CCDC-675104 (2c),
and CCDC-742099 (2j) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallogra-
phic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1,4-Bis(4-nitrophenyl)piperazine-2,5-dione (2k)
Synthesized from 2-chloro-N-(4-nitrophenyl)acetamide
(1k, 4.29 g, 20.0 mmol) following the general procedure (56
°C,
5 h) and purified by column chromatography
(CH3COOEt–petroleum ether, 1:1). Yield: 2.46 g (69%);
yellow solid; mp 295–297 °C. IR (KBr): 3075 (w), 2974 (w),
1670 (vs), 1591 (m), 1517 (s), 1490 (s), 1461 (m), 1349 (s),
1266 (m), 857 (w) cm-1. 1H NMR (500 MHz, DMSO-d6): ꢀ =
4.70 (s, 4 H, 2 ꢀ CH2), 7.75 (d, J = 9.0 Hz, 4 H, ArH), 8.31
(d, J = 9.0 Hz, 4 H, ArH). 13C NMR (125 MHz, DMSO-d6):
ꢀ = 55.32, 123.30, 125.62, 148.92, 157.86, 162.48. Anal.
Calcd for C16H12N4O6: C, 53.94; H, 3.39; N, 15.73. Found:
C, 53.85; H, 3.42; N 15.68.
ACKNOWLEDGEMENT
This work was supported by the National Natural Science
Foundation of China (No. 20971076).
REFERENCES
1,4-Bis(2-chlorophenyl)piperazine-2,5-dione (2l)
[1]
Fischer, P.M. Diketopiperazines in peptide and combinatorial
chemistry. J. Peptide Sci., 2003, 9, 9–35.
Synthesized from 2-chloro-N-(2-chlorophenyl)acetamide
(1l, 3.39 g, 20.0 mmol) following the general procedure (56
°C, 5 h) and purified by recrystallization (ethanol/water).
Yield: 1.90 g (57%); yellowish solid; mp 208–210 °C. IR
(KBr): 3084 (w), 2901 (w), 1681 (vs), 1639 (w), 1585 (w),
1478 (vs), 1455 (s), 1427 (m), 1321 (s), 1064 (vs), 766 (vs),
736 (s) cm-1. 1H NMR (500 MHz, DMSO-d6): ꢀ = 4.40 (s, 4
H, 2 ꢀ CH2), 7.43–7.50 (m, 4 H, ArH), 7.54 (d, J = 7.5 Hz, 2
H, ArH), 7.63 (d, J = 8.5 Hz, 2 H, ArH). 13C NMR (125
MHz, DMSO-d6): ꢀ = 52.98, 129.02, 130.35, 130.67, 131.69,
132.90, 137.93, 164.51. Anal. Calcd for C16H12Cl2N2O2: C,
57.33; H, 3.61; N, 8.36. Found: C, 57.65; H, 3.59; N 8.28.
[2]
Krchnak, V.; Weichsel, A.S.; Cabel, D.; Flegelova, Z.; Lebl M.
Structurally
homogeneous
and
heterogeneous
synthetic
combinatorial libraries., Mol. Div. 1996, 1, 149–164.
[3]
[4]
Sanatamaria, A.; Cabezas, N.; Avendano, C. Synthesis of
tryptophan-dehydrobutyrine diketopiperazines and analogues.
Tetrahedron, 1999, 55, 1173–1186.
Acharya, A.N.; Ostresh, J.M.; Houghten, R.A. Solid-phase
synthesis of substituted imidazoline-tethered 2,3-diketopiperazines,
cyclic ureas, and cyclic thioureas. J. Comb. Chem., 2001, 3, 612–
623.
[5]
[6]
Paradisi, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Enantioselective
synthesis of 2,6-diaminopimelic acid derivatives. Part 3.
Tetrahedron: Asymmetry, 2002, 13, 497–502.
Kennedy, A.L.; Fryer, A.M.; Josey, J.A. A new resin-bound
universal isonitrile for the Ugi 4CC reaction: preparation and
applications to the synthesis of 2,5-diketopiperazines and 1,4-
benzodiazepine-2,5-diones. Org. Lett. 2002, 4, 1167–1170.
Martins, M.B.; Carvalho, I. Diketopiperazines: biological activity
and synthesis. Tetrahedron, 2007, 63, 9923–9932.
1,4-Dicyclohexylpiperazine-2,5-dione (2m)
Synthesized from 2-chloro-N-cyclohexylacetamide (1m,
3.51 g, 20.0 mmol) following the general procedure (56 °C,
5 h) and purified by recrystallization (acetone/water). Yield:
1.80 g (65%); yellowish solid; mp 226–227 °C. IR (KBr):
2933 (s), 2853 (m), 1640 (vs), 1447 (w), 1419 (w), 1325 (w),
[7]
[8]
Wen, Y.H.; Zhang, S.S.; Yu, B.H.; Liu, Q.; Li, X.M. Synthesis and
crystal structure of 1,4-di(1-naphthyl)-2,5-piperazinedione, Asian J.
Chem., 2006, 18, 201–206.
1243 (w), 1175 (m), 1153 (w), 762 (w), 706 (w) cm-1. H
1
[9]
Wen, Y.H.; Zhang, S.S.; Yu, B.H.; Li, X.M.; Liu, Q. Synthesis and
crystal structure of 1,4-bis(2-methylphenyl)-2,5-piperazinedione,
Asian J. Chem., 2006, 18, 1032–1038.
NMR (500 MHz, DMSO-d6): ꢀ = 3.59 (s, 4 H, 2 ꢀ CH2),
3.44–3.48 (m, 2 H, ArH), 1.65–1.72 (m, 8 H, ArH), 1.11–
1.52 (m, 12 H, ArH). 13C NMR (125 MHz, DMSO-d6): ꢀ =
24.25, 26.70, 30.14, 46.60, 52.15, 163.22. Anal. Calcd for
C16H26N2O2: C, 69.03; H, 9.41; N, 10.06. Found: C, 69.15;
H, 9.34; N 10.18.
[10]
[11]
Zhang, S.S.; Wen, Y.H.; Tang, X.F.; Li, X.M. Synthesis and
structural characterization of 1,4-di(2-methoxyphenyl)-2,5-
piperazinedione, Chin. J. Chem., 2007, 25, 714–717.
O'Reilly, E.; Lestini, E.; Balducci, D.; Paradisi, F. One-step
diketopiperazine synthesis using phase transfer catalysis.
Tetrahedron Lett., 2009, 50, 1748–1750.
[12]
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Chanda, A.; Fokin, V.V. Organic synthesis “on water”. Chem. Rev.,
2009, 109, 725–748.
Li, C.J. Organic reactions in aqueous media with a focus on
carbon-carbon bond formations: a decade update. Chem. Rev.,
2005, 105, 3095–3166.
Lunbineau, A.; Augé, J.; Queneau, Y. Water-promoted organic
reactions. Synthesis, 1994, 741–760.
Chan, T.H.; Isaac, M.B. Organometallic-type reactions in aqueous
media mediated by indium: application to the synthesis of
carbohydrates. Pure & Apple. Chem., 1996, 68, 919–924.
1,4-Di(naphthalen-1-yl)piperazine-2,5-dione (2n)
Synthesized from 2-chloro-N-(naphthalen-1-yl)acetamide
(1n, 4.39 g, 20.0 mmol) following the general procedure (56
°C, 5 h) and purified by recrystallization (acetone/water).
Yield: 2.56 g (70%); white solid; mp 284–285 °C. IR (KBr):
3049 (w), 2922 (w), 1643 (vs), 1593 (w), 1574 (w), 1508
[14]
[15]
(w), 1480 (s), 1332 (m), 1274 (w), 799 (s), 771 (s) cm-1. H
1
NMR (500 MHz, DMSO-d6): ꢀ = 4.45 (s, 4 H, 2 ꢀ CH2),