Synthesis of 2,5-diketopiperazine derivatives using 2-isocyanophenyl 4-methylbenzoate as a fragrant convertible isocyanide

Article abstract of DOI:10.1002/jhet.1684

A new protocol in which 2-isocyanophenyl 4-methylbenzoate is used as a convertible isocyanide for Ugi/deprotection + activation/cyclization synthesis of 2,5-diketopiperazine derivatives has been developed. This operational simple procedure displays good functional group tolerance and avoids treatment of typically known offensive isocyanides.

Full text of DOI:10.1002/jhet.1684

September 2014 Synthesis of 2,5-Diketopiperazine Derivatives Using 2-Isocyanophenyl
4-Methylbenzoate as a Fragrant Convertible Isocyanide
1287
*
Fei Ji, Wen-Bin Yi, and Chun Cai
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, China
*
E-mail: c.cai@mail.njust.edu.cn
Received November 3, 2011
DOI 10.1002/jhet.1684
Published online 18 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
A new protocol in which 2-isocyanophenyl 4-methylbenzoate is used as a convertible isocyanide for Ugi/
deprotection + activation/cyclization synthesis of 2,5-diketopiperazine derivatives has been developed. This
operational simple procedure displays good functional group tolerance and avoids treatment of typically
known offensive isocyanides.
J. Heterocyclic Chem., 51, 1287 (2014).
INTRODUCTION
Among the different postcondensation approaches known,
the versatile ones are the so-called Ugi-4CR/deprotection/
cyclization procedures and those that include convertible
isocyanides as a manner to activate the terminal isocyanide-
derived carbonyl amide (Ugi-4CR/activation/cyclization)
[6,10]. To date, 1-isocyano-2-(2,2-dimethoxyethyl)benzene,
also known as an indole isocyanide, (b-isocyano-ethyl)-
alkyl-carbonates, and 1-isocyanocyclohexene as convertible
isocyanides have been utilized in the Ugi-4CR/deprotection +
activation/cyclization synthesis of 2,5-diketopiperazine deriva-
tives [11]. The indole isocyanide and (b-isocyano-ethyl)-alkyl-
carbonates overcame the limit of 1-isocyanocyclohexene
that it is only stable for a few months if it is stored
under argon at À30ꢀC, but still could not avoid the treat-
ment of typically known offensive isocyanides.
Recently, a new promising convertible isocyanide, 2-
isocyanophenyl 4-methylbenzoate, was introduced to pro-
duce methyl esters using Ugi reaction in combination
with acyl substitution process by Pirrung et al. [12]. It is
stable and does not have the offensive odors for which
isocyanides are typically known, making it more accessible
as reagents for organic synthesis. As part of our interest in
the research about applications of this new convertible
isocyanide, herein, we developed a new routine of the
synthesis for 2,5-diketopiperazine derivatives based on 2-
isocyanophenyl 4-methylbenzoate via Ugi/deprotection +
activation/cyclization (Scheme 1).
Many diketopiperazine derivatives are among the most
important backbones in modern drug discovery industries.
The compounds containing these core templates have
widespread biological applications, such as being utilized
as antagonists of the platelet glycoprotein IIb/IIa [1], anti-
convulsant agents [2], serine protease inhibitors [3], and
CNS agents [4]. In addition, the diketopiperazine scaffold
often occurs in complex nature products [5]. Consequently,
research that focused on the synthesis of diketopiperazine
derivatives has been receiving more and more attention [6].
Multicomponent reactions (MCRs) are useful tools
for generating high levels of diversity, as they allow more
than two building blocks to be combined in a practical,
time-saving, one-pot operation, affording the complex
structures by simultaneous formation of two or more bonds
[7]. MCRs that involve isocyanides (IMCRs) are important
for modern drug discovery and allow rapid, automated,
high-throughput generation of organic compounds [8].
Of all the IMCRs, the most noticeable reaction is Ugi
four-component condensation of an aldehyde, or a ketone,
an amine, an acid, and an isocyanide. In recent years, the
combination of Ugi four-component condensation with
efficient postcondensations, typically ring formation process
or nucleophilic addition, has been proven to be a powerful
method to synthesize diketopiperazine derivatives [9].
© 2014 HeteroCorporation

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F. Ji, W. B. Yi, and C. Cai
Vol 51
Scheme 1. Synthesis of 2,5-diketopiperazine derivatives. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
RESULTS AND DISCUSSIONS
when heated to 40ꢀC in methanol. Increasing the tem-
perature of Ugi reaction to 60ꢀC could not improve
the total yield (Table 1, entries 1–2, 5). In the following
reaction, anhydrous hydrogen chloride was formed with
addition of acyl chloride into methanol and was respon-
sible for deprotection of Boc group and activation of
carbonyl amide bond. Therefore, the model reaction in
methanol at 55ꢀC was studied using different amounts
of acyl chloride. The reaction yield increased as amount
of acyl chloride was raised. The best yield was obtained
We began this study by subjecting 2-isocyanophenyl 4-
methylbenzoate, 4-bromobenzaldehyde, benzylamine and
N-Boc-phenylglycine to the synthesis of 2,5-diketopiperazine
derivatives in methanol via Ugi/deprotection + activation/
cyclization. For optimization of this reaction, we investigated
the effect of the temperature of Ugi reaction, amount of
acyl chloride, and the reaction time of cyclization (Table 1).
It was found that reactants could be dissolved completely
Table 1
Optimization of the synthesis of 2,5-diketopiperazine derivatives.a
Entry
Temperature of Ugi reaction (ꢀC)
Amount of acyl chloride (mmol)
Time (h)b
Yield (%)c
1
2
3
4
5
6
7
8
50
60
40
40
40
40
40
40
40
40
40
4
4
2
3
4
5
4
4
4
4
4
48
48
48
48
48
48
12
24
36
60
36
60
63
37
53
63
62
36
55
61
62
59d
9
10
11
aReaction conditions: methanol 2 mL; 2-isocyanophenyl 4-methylbenzoate 1 mmol; 4-bromobenzaldehyde 1 mmol; N-Boc-phenylglycine 1 mmol;
benzylamine 1 mmol; triethylamine 6 mmol.
bTime of cyclization.
cTotal isolated yield (one-pot).
dTotal isolated yield (Ugi products were isolated for next step).
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One-Pot Synthesis of 2,5-Diketopiperazine Derivatives
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with 4 equivalents of acyl chloride (Table 1, entries 3–6).
Next, we studied cyclization reaction at room temperature
with excess amount of Et3N at different reaction times
(Table 1, entries 5, 7–10). The optimum results were
obtained in 36 h. Further lengthening the reaction time of
cyclization failed to improve the yield significantly. At
last, we examined the multistep version of this sequence.
Ugi product was isolated for the next step after Ugi
reaction. Under these conditions, compound A2 could be
obtained in 59% yield over three steps (Table 1, entry 11).
Compared with the one-pot method (Table 1, entry 9), it
demonstrated that the by-product of Ugi reaction would not
affect the subsequent reaction yield significantly.
electron-rich aldehydes stabilized the intermediate enamines
in Ugi reaction. Thereafter, 4-methylbenzylamine, 4-fluoro-
benzylamine, and cyclohexylamine were utilized to replace
benzylamine to furnish the expected 2,5-diketopiperazine
derivatives in moderate to excellent yields. The substituted
benzylamine with different electronic effects on aromatic
ring showed marginal effect on the reactivity. Other
commercial N-Boc-amino acids such as N-Boc-glycine and
N-Boc-phenylalanine were also examined. Generally,
corresponding products were obtained in moderate yields.
Comparatively, N-Boc-phenylglycine showed better reactiv-
ity than others. There was no obvious difference in yield
between the two methods.
With optimized conditions established, we next attempted
to extend the process to different aromatic aldehydes, amines,
and N-Boc-amino acids. The results are summarized in
Table 2. All present aromatic aldehydes bearing electron-
donating group (methoxyl), electron-withdrawing group
(nitro), and halogen groups (such as bromo, chloro) were
smoothly transformed to target compounds in moderate to
good yields (40–70%). Impressively, electron-rich aromatic
aldehydes were more favorable for the transformation
compared with electron-deficient ones. We envisioned that
A proposed reaction mechanism for this synthesis
strategy is outlined in Scheme 2. The first step involves
Ugi reaction of isocyanides, amines, aldehydes, and Boc-
amino acids leading to the formation of dipeptide B. In
the presence of acyl chloride, dipeptide B undergoes a
deprotection and activation process, giving the Ugi conver-
sion product F and the observed benzoxazoles. Two
pathways of deprotection and activation process are possible
following the generation of C. One is subjected to direct
reaction with a nucleophile (path a), the other proceed
Table 2
Synthesis of 2,5-diketopiperazine derivatives.a
Entry
R1
R2
R3
Product
Yield (%)b
Yield (%)c
1
2
3
4
5
6
7
8
H
C6H5
C6H5CH2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-CH3OC6H4
4-ClC6H4
C6H5
4-NO2C6H4
1-naphthyl
4-BrC6H4
4-BrC6H4
4-BrC6H4
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
52
61
45
60
55
45
40
41
43
66
60
51
59
42
61
56
43
38
43
45
65
59
9
10
11
4-FC6H4CH2
4-CH3C6H4CH2
Cyclohexyl
aReaction conditions: methanol 2 mL; 2-isocyanophenyl 4-methylbenzoate 1 mmol; aldehyde 1 mmol; N-Boc-amino acid 1 mmol; amine 1 mmol; acyl
chloride 4 mmol; triethylamine 6 mmol.
bTotal isolated yield (one-pot).
cTotal isolated yield (Ugi products were isolated for next step).
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F. Ji, W. B. Yi, and C. Cai
Vol 51
Scheme 2. Mechanism evoked for the formation of products A1–A11 derivatives.
analyzed qualitatively by high performance liquid chromatography
(HPLC) on Agilent 1120 (Eclipse XDB-C18, G1214B VWD;
Waldbornn, Germany). Mass spectra were taken on Shimadzu
LCMS-2020 (Kyoto, Japan). The IR spectra were recorded on
KBr pellets on Shimadzu IR Prestige-21 spectrophotometer. 1H
and 13C NMR spectra were recorded at 500 and 125 MHz, respec-
tively, in DMSO-d6 and CDCl3, and chemical shifts were reported
in parts per million from internal TMS (d). Elemental analyses were
performed on a Yanagimoto MT3CHN recorder (Saitama, Japan).
Typical procedure for the synthesis of 1-benzyl-6-(4-
bromophenyl)-3-phenylpiperazine-2,5-dione (A2). Benzylamine
(1 mmol) and 4-bromobenzylaldehyde (1 mmol) were dissolved in
methanol (2 mL). This mixture was stirred at room temperature for
0.5 h. Then, N-Boc-phenylglycine (1 mmol) and 2-isocyanophenyl 4-
methylbenzoate (1 mmol) were added into the solution and stirred for
48 h at 40ꢀC. After the reaction was completed, acyl chloride
(4 mmol) was added and stirred at 55ꢀC overnight. To this solution,
triethylamine (5 mmol) was added in sequence and stirred at room
temperature for 36 h. The crude mixture was applied directly to flash
column chromatograph on silica gel, eluting with EtOAc/hexane
(1:6) to afford the white solid. The purity of the corresponding
product was high up to 98% based on the analysis of HPLC
(MeCN : H2O=9:1).
involves intramolecular nucleophilic substitution via the
intermediate münchnones E (path b). At last, Ugi conversion
product F undergoes the intramolecularly nucleophilic reac-
tion with amino group catalyzed by Et3N to afford 2,5-dike-
topipeprazine derivatives.
In conclusion, we have developed a new and efficient
approach for the synthesis of 2,5-diketopiperazine deriva-
tives through the use of a fragrant and stable isocyanide,
avoiding the offensive odors for which isocyanides are
typically known and the instability of 1-isocyanocyclohexene.
It is the first time that this new convertible isocyanide was
applied in the synthesis of 2,5-diketopiperazine derivatives
and this simple and efficient process will help accelerate the
research about 2,5-diketopiperazines derivatives.
EXPERIMENTAL
Starting isocyanide, 2-isocyanophenyl 4-methylbenzoate was
prepared according to the literatures [12a]. Water was removed
out of THF, and other materials were obtained from commercial
supplier and used without further purification. The purity was
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One-Pot Synthesis of 2,5-Diketopiperazine Derivatives
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(m, 2H), 8.25–8.26 (m, 2H), 8.90 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) d: 48.27, 58.68, 63.80, 124.31, 127.90, 128.16, 128.60,
128.87, 128.95, 129.38, 136.47, 139.20, 144.52, 147.96, 164.66,
166.24; MS (ESI) m/z 355 [M-H]; Anal. Calcd for C23H20N2O2:
C, 77.51; H, 5.66; N, 7.86; found C, 77.52; H, 5.65; N, 7.84.
1-Benzyl-6-(4-nitrophenyl)-3-phenylpiperazine-2,5-dioÀn1e
All of the products have been fully characterized by 1H NMR,
13C NMR, IR, mass, and elemental analysis.
1-Benzyl-6-(4-bromophenyl)piperazine-2,5-dione (A1). Yield
52% (white solid); mp 175–177ꢀC; IR (KBr/cmÀ1) υ: 3756, 3290,
2936, 1691, 1653, 1465; 1H NMR (500 MHz, CDCl3) d: 3.56
(d, J= 14.5 Hz, 1H), 4.11–4.22 (m, 2H), 4.83 (s, 1H), 5.55
(d, J= 14.5 Hz, 1H), 6.60 (s, 1H), 7.19–7.21 (m, 4H), 7.28 (s, 1H),
7.34–7.35 (m, 2H), 7.56–7.57 (m, 2H); 13C NMR (125 MHz,
CDCl3) d: 44.92, 47.49, 62.02, 123.24, 128.25, 128.32, 128.52,
129.03, 132.54, 133.86, 134.73, 164.08, 166.32; MS (ESI) m/z
357 [M-H]; Anal. Calcd for C17H15BrN2O2: C, 56.84; H, 4.21; N,
7.80; found C, 56.82; H, 4.23; N, 7.75.
(A7). Yield 40% (white solid); mp 206–208ꢀC; IR (KBr/cm
)
1
υ: 3724, 3028, 2843, 1659, 1459; H NMR (500 MHz, DMSO-
d6) d: 3.62 (d, J = 15.0Hz, 1H), 4.95 (s, 1H), 5.10 (d, J = 15.0Hz,
1H), 5.45 (s, 1H), 7.12–7.14 (m, 2H), 7.27–7.33 (m, 3H),
7.37–7.47 (m, 9H), 8.74 (s, 1H); 13C NMR (125 MHz, DMSO-d6)
d: 48.28, 58.70, 63.81, 124.30, 127.89, 128.17, 128.59, 128.87,
128.95, 129.38, 136.47, 139.20, 144.52, 147.98, 164.66, 166.24;
MS (ESI) m/z 400 [M-H]; Anal. Calcd for C23H19N3O4: C, 68.82;
H, 4.77; N, 10.47; found C, 68.78; H, 4.73; N, 10.49.
1-Benzyl-6-(4-bromophenyl)-3-phenylpiperazine-2,5-dioÀn1e
(A2). Yield 61% (white solid); mp 237–239ꢀC; IR (KBr/cm
)
υ: 3730, 3312, 2962, 1727, 1678, 1425; 1H NMR (500 MHz,
DMSO-d6) d: 3.70 (d, J = 15.0Hz, 1H), 5.01 (s, 1H), 5.04
(d, J = 15.0Hz, 1H), 5.43 (s, 1H), 7.11–7.12 (m, 2H), 7.25–7.28
(m, 3H), 7.30–7.44 (m, 7H), 7.62–7.64 (m, 2H), 8.80 (s, 1H); 13C
NMR (125 MHz, DMSO-d6) d: 47.84, 58.68, 63.56, 122.21,
127.89, 128.06, 128.55, 128.60, 128.84, 129.01, 130.07, 132.26,
136.54, 136.61, 139.36, 165.17, 166.23; MS (ESI) m/z 433
[M-H]; Anal. Calcd for C23H19BrN2O2: C, 63.46; H, 4.40; N,
6.44; found C, 63.45; H, 4.35; N, 6.42.
1-Benzyl-6-(naphthalen-1-yl)-3-phenylpiperazine-2,5-dionÀe1
(A8). Yield 41% (white solid); mp 231–233ꢀC; IR (KBr/cm
)
υ: 3714, 3046, 1709, 1643, 1443; 1H NMR (500 MHz, DMSO-d6)
d: 2.94–2.98 (m, 1H), 3.29–3.30 (m, 1H), 3.55 (d, J = 15.5Hz, 1H),
4.58 (s, 1H), 4.65 (s, 1H), 4.85 (d, J = 15.0Hz, 1H), 6.16
(d, J= 8.0 Hz, 2H), 7.04–7.06 (m, 2H), 7.19–7.27 (m, 7H), 7.32–7.35
(m, 2H), 7.39–7.42 (m, 1H), 8.60 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) d: 47.70, 59.14, 60.80, 124.15, 125.90, 126.49,
126.71, 127.01, 127.75, 127.91, 128.32, 128.58, 128.78, 128.96,
129.13, 129.66, 131.73, 133.15, 134.15, 136.45, 139.83, 165.49,
166.31; MS (ESI) m/z 405 [M-H]; Anal. Calcd for C27H22N2O2:
C, 79.78; H, 5.46; N, 6.89; found C, 79.74; H, 5.45; N, 6.92.
6-(4-Bromophenyl)-1-(4-fluorobenzyl)-3-phenylpiperazine-2,5-
dione (A9). Yield 43% (white solid); mp 217–219ꢀC; IR (KBr/
cmÀ1) υ: 3723, 3052, 1703, 1653, 1453; 1H NMR (500 MHz,
CDCl3) d: 3.56 (d, J = 14.5 Hz, 1H), 4.94 (s, 1H) 5.24 (s, 1H),
5.46 (d, J = 14.5 Hz, 1H), 6.13 (s, 1H), 6.99–7.03 (m, 2H), 7.07–
7.10 (m, 2H), 7.25–7.28 (m, 2H), 7.35–7.39 (m, 2H), 7.42–7.48
(m, 3H), 7.60 (d, J = 8.5 Hz, 2H); 13C NMR (125MHz, CDCl3) d:
47.17, 59.44, 62.59, 115.86, 116.03, 123.38, 127.68, 128.51,
129.20, 129.30, 130.17, 130.23, 130.84, 132.58, 133.99, 137.01,
165.49, 165.82; MS (ESI) m/z 451 [M-H]; Anal. Calcd for
C23H18BrFN2O2: C, 60.94; H, 4.00; N, 6.18; found C, 60.97; H,
4.03; N, 6.21.
1,3-Dibenzyl-6-(4-bromophenyl)piperazine-2,5-dione (A3). Yield
45% (white solid); mp 232–234ꢀC; IR (KBr/cmÀ1) υ: 3680, 3078,
2828, 1643, 1693, 1443; 1H NMR (500 MHz, CDCl3) d: 3.10–3.15
(m, 1H), 3.32–3.35 (m, 1H), 3.40 (d, J= 14.5 Hz, 1H), 4.45–4.46
(m, 1H), 4.77 (s, 1H), 5.55 (d, J= 14.5 Hz, 1H), 6.31 (s, 1H),
6.77–6.78 (d, J= 8.5 Hz, 2H), 7.14–7.15 (m, 4H), 7.30–7.36
(m, 6H), 7.44–7.46 (m, 2H); 13C NMR (125 MHz, DMSO-d6) d:
38.81, 47.69, 56.03, 62.90, 121.52, 127.49, 127.68, 128.38,
128.75, 128.96, 130.12, 131.07, 131.48, 136.24, 136.39, 136.59,
164.40, 165.18; MS (ESI) m/z 447 [M-H]; Anal. Calcd for
C24H21BrN2O2: C, 64.15; H, 4.71; N, 6.23; found C, 64.18; H,
4.75; N, 6.22.
1-Benzyl-6-(4-methoxyphenyl)-3-phenylpiperazine-2,5-dioÀn1e
(A4). Yield 60% (white solid); mp 221-223ꢀC; IR (KBr/cm
)
υ: 3743, 3125, 2943, 1650,1712, 1452; 1H NMR (500 MHz,
DMSO-d6) d: 3.61 (d, J = 15.5 Hz, 1H), 3.79 (s, 3H), 4.87
(s, 1H), 5.10 (d, J = 15.5 Hz, 1H), 5.44 (s, 1H), 6.99–7.01 (m, 2H),
7.12–7.14 (m, 2H), 7.28–7.34 (m, 5H), 7.37–7.44 (m, 5H), 8.70
(s, 1H); 13C NMR (125 MHz, DMSO-d6) d: 47.41, 55.70, 58.77,
63.42, 114.83, 127.90, 128.01, 128.50, 128.60, 128.82, 129.06,
129.08, 136.63, 139.57, 159.86, 165.77, 166.21; MS (ESI) m/z
385 [M-H]; Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74; N,
7.25; found C, 74.55; H, 5.74; N, 7.28.
6-(4-Bromophenyl)-1-(4-methylbenzyl)-3-phenylpiperazine-
2,5-dione (A10). Yield 66% (white solid); mp 247–249ꢀC; IR
1
(KBr/cmÀ1) υ: 3696, 3212, 3062, 2912, 1709, 1659, 1459; H
NMR (500 MHz, CDCl3) d: 2.36 (s, 3H), 3.49 (d, J = 14.5 Hz,
1H), 4.94 (s, 1H), 5.23 (s, 1H), 5.50 (d, J = 14.5 Hz, 1H), 6.19
(s, 1H), 6.98 (d, J = 7.5 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H),
7.24–7.28 (m, 2H), 7.38–7.46 (m, 5H), 7.59 (d, J = 8.5Hz, 2H);
13C NMR (125 MHz, CDCl3) d: 21.22, 47.38, 59.47, 62.22,
123.22, 127.75, 128.43, 128.58, 129.14, 129.19, 129.67, 131.81,
132.50, 134.25, 137.24, 138.10, 165.71, 165.72; MS (ESI) m/z
447 [M-H]; Anal. Calcd for C24H21BrN2O2: C, 64.15; H, 4.71; N,
6.23; found C, 64.18; H, 4.73; N, 6.25.
1-Benzyl-6-(4-chlorophenyl)-3-phenylpiperazine-2,5-dioÀn1e
(A5). Yield 55% (white solid); mp 247–249ꢀC; IR (KBr/cm
)
1
υ: 3680, 3196, 3046, 1643, 1459; H NMR (500 MHz, DMSO-
d6) d: 3.71 (d, J = 15.0 Hz, 1H), 5.03 (d, J = 15.0 Hz, 1H), 5.04
(s, 1H), 5.44 (s, 1H), 7.11–7.12 (m, 2H), 7.25–7.31 (m, 3H),
7.35–7.44 (m, 7H), 7.48–7.50 (m, 2H), 8.79 (s, 1H); 13C NMR
(125MHz, DMSO-d6) d: 47.84, 58.69, 63.50, 127.89, 128.07,
128.55, 128.60, 128.84, 129.00, 129.33, 129.77, 133.63, 136.21,
136.55, 139.38, 165.23, 166.22; MS (ESI) m/z 389 [M-H]; Anal.
Calcd for C23H19ClN2O2: C, 70.68; H, 4.90; N, 7.17; found C,
70.65; H, 4.88; N, 7.20.
6-(4-Bromophenyl)-1-cyclohexyl-3-phenylpiperazine-2,5-dione
(A11). Yield 60% (white solid); mp 255–257ꢀC; IR (KBr/cmÀ1
)
υ: 3714, 3062, 2928, 2844, 1693, 1643, 1425; 1H NMR (500 MHz,
DMSO-d6) d: 0.94–0.99(m, 1H), 1.07–1.18 (m, 3H), 1.41–1.55
(m, 4H), 1.67–1.78 (m, 2H), 3.89–3.94(m, 1H), 5.24 (s, 1H), 5.24
(s, 1H), 7.31–7.40 (m, 5H), 7.45 (d, J = 8.5 Hz 2H), 7.63
(d, J= 8.5 Hz 2H), 8.58 (s, 1H); 13C NMR (125 MHz, DMSO-d6)
d: 25.19, 25.88, 25.91, 29.92, 30.13, 56.27, 58.79, 61.58, 121.82,
128.37, 128.63, 128.90, 129.65, 132.05, 138.57, 139.29, 165.98,
166.00; MS (ESI) m/z 425 [M-H]; Anal. Calcd for C22H23BrN2O2:
C, 61.83; H, 5.42; N, 6.56; found C, 61.81; H, 5.44; N, 6.58.
1-Benzyl-3,6-diphenylpiperazine-2,5-dione (A6).
Yield 45%
(white solid); mp 254–256ꢀC; IR (KBr/cmÀ1) υ: 3748, 3062, 1659,
1459; 1H NMR (500MHz, DMSO-d6) d: 3.83 (d, J= 15.0 Hz, 1H),
4.98 (d, J= 15.0 Hz, 1H), 5.29 (s, 1H), 5.45 (s, 1H), 7.10–7.11
(m, 2H), 7.22–7.28 (m, 4H), 7.36–7.44 (m, 5H), 7.66–7.77
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1292
F. Ji, W. B. Yi, and C. Cai
Vol 51
Acknowledgment. Financial support by NUST Research Funding
(2011ZDJH07) is gratefully acknowledged.
D. G.; Vercillo, O. E. Chem Rev 2009, 109, 796; (d) Rivera, D. G.;
Wessjohann, L. A. J Am Chem Soc 2006, 128, 7122; (e) Wessjohann,
L. A.; Voigt, B.; Rivera, D. G. Angew Chem Int Ed 2005, 30, 4785;
(f) Wessjohann, L. A.; Rivera, D. G.; Coll, F. J Org Chem 2006, 71,
7521; (g) Rahmati, A.; Kouzehrash, M. A. Synthesis 2011, 2193.
[8] Weber, L. Curr Med Chem 2002, 9, 1241.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet