One-step diketopiperazine synthesis using phase transfer catalysis

Article abstract of DOI:10.1016/j.tetlet.2009.01.146

A simple and efficient one-step procedure is described for the synthesis of a number of symmetrical 1,4-disubstituted piperazine-2,5-diones under phase transfer conditions. The reactions are carried out at room temperature, starting from a suitable N-chloroacetamide in the presence of an aqueous solution of sodium hydroxide. Piperazine-2,5-diones were obtained with excellent selectivity in yields of up to 90%.

Full text of DOI:10.1016/j.tetlet.2009.01.146

Tetrahedron Letters 50 (2009) 1748–1750
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One-step diketopiperazine synthesis using phase transfer catalysis
*
Elaine O’Reilly, Elena Lestini, Daniele Balducci, Francesca Paradisi
UCD School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient one-step procedure is described for the synthesis of a number of symmetrical 1,4-
disubstituted piperazine-2,5-diones under phase transfer conditions. The reactions are carried out at
room temperature, starting from a suitable N-chloroacetamide in the presence of an aqueous solution
of sodium hydroxide. Piperazine-2,5-diones were obtained with excellent selectivity in yields of up to
90%.
Received 18 December 2008
Revised 20 January 2009
Accepted 28 January 2009
Available online 1 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diketopiperazine
Chloroacetamide
Phase transfer catalyst
TEBA
Diketopiperazines (DKPs) are a class of compounds which are of
significant interest in biology and drug discovery.1,2 These com-
pounds are present in biologically active natural products2, and
because of their embedded amino acid structures, they represent
an important alternative to common peptides. The synthesis of
DKPs is described extensively in the literature.3 Here we report
the synthesis of 1,4-disubstituted piperazine-2,5-diones by direct
cyclization of N-substituted chloroacetamides in a two-phase med-
ium (CH2Cl2/alkaline solution) in the presence of the phase transfer
catalyst, triethylbenzylammonium chloride (TEBA) (Scheme 1).
Phase transfer catalysis (PTC) is a convenient method which
generally allows for the rate increase of a reaction under mild con-
ditions. The catalytic amount of base which is transferred into the
organic layer at any given time appears to be totally selective
towards the cyclization rather than polymerization of the chloro-
acetamides. Bifunctional molecules such as chloroacetamides or
amino acids are known to polymerize in highly concentrated solu-
tions, and cyclization is merely a side reaction.4 Quaternary ammo-
nium salts have been investigated widely and successfully used in
several areas of organic chemistry since their discovery as PT cat-
alysts.5,6 A single example of their use in the synthesis of DKPs
was reported in 1981.7 Compound 4b was prepared using this
methodology in only 50% yield and no other example was
reported.7 Considering the rising demand for peptide alternatives
such as DKPs, due to their potential industrial and medical applica-
tions,8 there is great interest in the development of efficient routes
to the synthesis of peptide precursors, such as the synthesis of
symmetrical disubstituted piperazine-2,5-diones as presented
here. In contrast to the most common step-wise procedures which
consist of construction of head-to-tail dipeptides, followed by their
cyclization at elevated temperatures,9,10 the one-step synthesis
reported here is carried out at room temperature and in the pres-
ence of a catalytic amount of TEBA. Following this procedure, a ser-
ies of symmetrical 1,4-disubstituted piperazine-2,5-diones was
synthesized (Table 1).
The chiral DKP 3b has been employed extensively in the asym-
metric synthesis of both enantiomers of 2,6-diaminopimelic acid
and its derivatives as well as non natural amino acids.11–13 As a
result, it can be considered an important building block in the syn-
thesis of various molecules. Under PT conditions, compound 3b
was isolated successfully in 90% yield. Similar results were
obtained for the chiral derivative 5b (88%). This molecule is cur-
rently under investigation as a precursor in the synthesis of non-
natural amino acids. Cyclization of aromatic, non-chiral chloroace-
tamides 1a and 4a afforded the corresponding diketopiperazine
products 1b and 4b, both in 85% yield. 2-Chloro-N-(1-ethylphe-
R
O
O
R
O
R1
TEBA (10%), aq. NaOH
CH2Cl2, rt, 48 h
N
N
N
H
R1
R
Cl
R1
R
R = H, Me
R1 = H, OMe
O
O
O
R
TEBA (10%), aq. NaOH
N
N
N
H
Cl
R
CH2Cl2, rt, 48 h
O
R = Cy, Ph, p -EtC6H4,
* Corresponding author. Tel.: +353 1 716 2967; fax: +353 1 716 2501.
E-mail address: francesca.paradisi@ucd.ie (F. Paradisi).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.146

E. O’Reilly et al. / Tetrahedron Letters 50 (2009) 1748–1750
1749
Table 1
is substantially higher than that previously reported in homophase
conditions.14
Among the various amides tested, 2-chloro-N-(2-nitro-
phenyl)acetamide 8a was the only example which did not undergo
cyclization under these conditions. This is likely to be due to the
electron withdrawing effect of the nitro group.
Cyclization of N-substituted chloroacetamides under phase transfer conditions to give
the corresponding diketopiperazinea,b
Amide
Diketopiperazine
Yield (%)
85
O
O
N
In conclusion, we have developed an efficient one-step procedure
for the synthesis of 1,4-disubstituted piperazine-2,5-diones15,16
employing a phase transfer catalyst. This method results in good
to very good yields in most cases, and in complete selectivity to-
wards cyclization even in the presence of a high concentration of
reactants. Generally, high dilution favours cyclization, whereas high
concentrations favour polymerization of polymerizable mono-
mers.17 In our case, the selectivity towards cyclization can be attrib-
uted to the low concentration of base which reacts with the
chloroacetamide at any given time due to the PTC employed.
The ratio of TEBA/chloroacetamide was also investigated, and
optimal results were achieved with the addition of 10% wt/wt of
catalyst/amide. This study has demonstrated that slow addition
of the catalyst, ideally over a 48-h period, gives high, reproducible
yields.
N
H
1a
N
Cl
O
1b
O
O
N
N
N
N
70
90
85
88
70
80
__
H
Cl
O
2b
2a
O
O
N
H
3a
N
Cl
Cl
O
3b
O
Acknowledgements
O
N
N
H
N
We express our gratitude to Sustainable Energy Ireland, admin-
istered by the Irish Research Council for Science, Engineering and
Technology (IRCSET) for funding Elaine O’Reilly. We would also like
to acknowledge the facilities of the Centre for Synthesis and Chem-
ical Biology (CSCB), funded by the Higher Education Authority’s
Programme for Research in Third-Level Institutions (PRTLIs).
O
4b
4a
O
O
O
N
N
N
H
O
Cl
O
O
5a
References and notes
5b
1. Gomez-Monterrey, I.; Campiglia, P.; Carotenuto, A.; Stiuso, P.; Bertamino, A.;
Sala, M.; Aquino, C.; Grieco, P.; Morello, S.; Pinto, A.; Ianelli, P.; Novellino, E. J.
Med. Chem. 2008, 51, 2924–2932.
2. Boger, D. L.; Zhou, J. J. Am. Chem. Soc. 1993, 115, 11426–11433.
3. (a) Martins, M. B.; Carvalho, I. Tetrahedron 2007, 63, 9923–9932; (b) Dinsmore,
C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297–3312.
O
O
O
N
N
H
6a
N
Cl
Cl
O
6b
4. Remias, J. E.; Elia, C.; Grove, L. E.; Sen, A. Inorg. Chim. Acta 2006, 359, 2956–
2965.
O
5. Takashi Ooi, K. M. Angew. Chem., Int. Ed. 2007, 46, 4222–4266.
6. Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc. 2003, 125, 7596–7601.
7. Okawara, T.; Noguchi, Y.; Matsuda, T.; Furukawa, M. Chem. Lett. 1981, 185–188.
8. Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Hatley, R. J. D.; Hughes, J. A.; Irving, W.
R.; Livermore, D. G.; Sollis, S. L.; Nerozzi, F.; Valko, K. L.; Allen, M. J.; Perren, M.;
Shabbir, S. S.; Woollard, P. M.; Price, M. A. J. Med. Chem. 2006, 49, 4159–4170.
9. Estevez, J. C.; Burton, J. W.; Estevez, R. J.; Ardron, H.; Wormald, M. R.; Dwek, R.
A.; Brown, D.; Fleet, G. W. J. Tetrahedron: Asymmetry 1998, 9, 2137–2154.
10. Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992, 57, 6532–6536.
11. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron: Asymmetry 2000, 11,
1259–1262.
O
N
O
N
H
7a
N
O
O
7b
O
O
N
NO2
NO2
N
N
H
NO2
8a
Cl
12. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron: Asymmetry 2000, 11,
4617–4622.
13. Paradisi, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 2002, 13,
497–502.
O
8b
a
Catalyst loading (10%) in each case was in wt/% based on the weight of the
amide. Reaction time was 48 h.
14. Cho, S. D.; Song, S. Y.; Kim, K. H.; Zhao, B. X.; Ahn, C.; Joo, W. H.; Yoon, Y. J.;
Falck, J. R.; Shin, D. S. Bull. Korean Chem. Soc. 2004, 25, 415–416.
15. Compounds 1a–4a and 6a–8a are commercially available.
(S)-2-Chloro-N-(1-(4-methoxyphenyl)ethyl)acetamide 5a: Off-white solid: mp:
243–245 °C; 1H NMR (600 MHz, CDCl3) d 7.29–7.21 (m, 2H), 6.93–6.86 (m, 2H),
6.70 (s, 1H), 5.09 (p, J = 7.0 Hz, 1H), 4.04 (q, J = 15.2 Hz, 2H), 3.80 (s, 3H), 1.52
(d, J = 6.9 Hz, 3H); 13C NMR (151 MHz, CDCl3) d 164.80, 159.06, 134.42, 127.31,
114.15, 55.29, 48.70, 42.63, 21.51; HRMS (EI): m/z calcd for C11H14ClNO2:
b
Compound 7a afforded the corresponding diketopiperazine 7b in 80% crude
yield as a mixture of isomers. The meso isomers were purified by chromatography
and characterized. The other isomers however, co-eluted on silica gel with unre-
acted starting material 7a, hence full characterization of these is not provided.
227.0713, found: 227.0711; ½a D20
ꢁ89 (c 0.35, CHCl3).
ꢀ
nyl)acetamide 2a afforded the corresponding diketopiperazine 2b
in 70% yield.
16. General procedure for the synthesis of 1,4-disubstituted piperazine-2,5-diones
(1b–8b).
Chloroacetamides 1a–8a (18 mmol) were dissolved in CH2Cl2 (23 mL) and a
50% aqueous NaOH solution (8 equiv, 144 mmol, 11.5 mL) was added at room
temperature. TEBA was added gradually over a 48-h period to a total of 10%
(based on starting chloroacetamide weight), under vigorous stirring. The
reaction was quenched, firstly with H2O (20 mL) and then with 6 M HCl
(45 mL). The CH2Cl2 was removed in vacuo and the aqueous phase extracted
with EtOAc (3 ꢂ 15 mL). The organic layers were combined, washed with brine
and dried over MgSO4. After removal of the solvent in vacuo, the resulting solid
was purified by column chromatography using silica gel (cyclohexane/ethyl
Cyclization of the non-aromatic chloroacetamides 6a and 7a
was also investigated. It was found that these amides also under-
went cyclization under PT conditions, affording the desired prod-
ucts 6b and 7b in good yields. Specifically, reaction of 6a gave
the corresponding diketopiperazine 6b in 70% yield. The racemic
2-chloro-N-[(tetrahydrofuran-2-yl)methyl] acetamide 7a afforded
the corresponding diketopiperazine 7b in 80% crude yield, which

1750
E. O’Reilly et al. / Tetrahedron Letters 50 (2009) 1748–1750
acetate = 2:1), affording the 1,4-disubstituted piperazine-2,5-dione in the
1,4-Bis[(S)-1-(4-methoxyphenyl)ethyl]piperazine-2,5-dione (5b): Off-white solid;
mp: 98–99 °C; 1H NMR (500 MHz, CDCl3) d 7.20–7.15 (m, 4H), 6.89–6.82 (m, 4H),
5.88 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 16.5 Hz, 2H), 3.78 (s, 6H), 3.49 (d, J = 16.5 Hz,
2H), 1.50 (d, J = 7.2 Hz, 6H); 13C NMR (126 MHz, CDCl3) d 163.67, 159.25, 130.19,
128.52, 114.05, 55.20, 49.61, 44.45, 15.21; Anal. Calcd for C22H26N2O4: C, 69.09;
specified yield.
1,4-Diphenylpiperazine-2,5-dione (1b): White solid; mp: 267–268 °C; 1H NMR
(300 MHz, CDCl3) d 7.36 (m, 10H), 4.55 (s, 4H); 13C NMR (75 MHz, CDCl3) d
163.96, 139.58, 129.47, 127.57, 124.97, 53.48; Anal. Calcd for C8H14N2O2: C,
72.16; H, 5.30; N, 10.52. Found: C, 72.36, H, 5.26, N, 10.14.
H, 6.85; N, 7.32. Found: C, 68.95; H, 6.93; N, 7.13. ½a D20
ꢁ383.5 (c 0.65, CHCl3).
ꢀ
1,4-Bis(4-ethylphenyl)piperazine-2,5-dione (2b): White solid; mp: 243–245 °C;
1H NMR (300 MHz, CDCl3) d 7.17–7.23 (m, 8H), 4.44 (s, 4H), 2.60 (q, J = 7.6 Hz,
4H), 1.18 (t, J = 7.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 164.0, 143.8, 137.1,
128.9, 124.9, 53.5, 28.5, 15.5; Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N,
8.69. Found: C, 74.71; H, 6.79; N, 8.53.
1,4-Dicyclohexylpiperazine-2,5-dione (6b):White solid; mp: 227–228 °C; 1HNMR
(300 MHz, CDCl3) d 4.37 (m, 2H), 3.88 (s, 4H), 1.82 (m, 4H), 1.67 (m, 6H), 1.39 (m,
8H), 1.10 (m, 2H); 13C NMR (75 MHz, CDCl3) d 163.6, 52.2, 45.2, 29.3, 25.4, 25.3;
HRMS (EI): m/z calcd for C16H27N2O2: 278.1194, found: 279.2074 [M+H]+.
1,4-Bis[(tetrahydrofuran-2-yl)methyl]piperazine-2,5-dione (7b): Beige waxy
solid; 1H NMR (500 MHz, CDCl3) d 4.31 (dd, J = 17.1, 5.9 Hz, 2H), 4.18–3.98
(m, 4H), 3.86 (dd, J = 14.6, 7.4 Hz, 2H), 3.80 (ddd, J = 13.9, 5.7, 2.9 Hz, 2H),
3.73 (dd, J = 14.5, 7.5 Hz, 2H), 3.19–3.06 (m, 2H), 2.07–1.97 (m, 2H), 1.95–
1,4-Bis[(S)-1-phenylethyl]piperazine-2,5-dione (3b): Off-white solid; mp: 109–
110 °C(lit. mp: 109–110);18 1H NMR (500 MHz, CDCl3) d7.56–7.16 (m, 10H), 5.95
(q, J = 7.1 Hz, 2H), 3.86 (d, J = 16.7 Hz, 2H), 3.52 (d, J = 16.7 Hz, 2H), 1.54 (d,
J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) d 163.81, 138.27, 128.78, 128.05,
127.32, 50.14, 44.67, 15.10; Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69.
1.82 (m, 4H), 1.59–1.47 (m, 2H); 13C NMR (126 MHz, CDCl3)
d 164.05,
164.02, 77.42, 77.40, 67.92, 51.58, 49.88, 49.85, 29.07, 29.05, 25.38. Anal.
Calcd for C14H22N2O4: C. 59.56; H, 7.85; N, 9.92. Found: C, 59.54; H, 7.82; N,
9.71.
Found: C, 74.02; H, 7.05; N, 8.66. ½a D20
ꢀ
ꢁ318.2 (c 2.1, CHCl3) (lit. ½a D20
ꢀ
ꢁ323.2).18
1,4-Dibenzylpiperazine-2,5-dione (4b): White solid; mp: 175–176 °C; 1H NMR
(300 MHz, CDCl3) d 7.28 (m, 10H), 4.58 (s, 4H), 3.93 (s, 4H); 13C NMR (75 MHz,
CDCl3) d 163.2, 134.9, 128.9, 128.5, 128.2, 49.3, 49.2; Anal. Calcd for C18H18N2O2:
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.38; H, 6.27; N, 9.43.
17. Sundarrajan, S.; Sabdham, K.; Srinivasan, V. Macromol. Rapid Commun. 2004, 25,
1406–1409.
18. Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1994, 5, 453–464.