Intramolecular aza-wittig reaction: A new efficient tool for the construction of piperazine 2,5-dione derivatives

Article abstract of DOI:10.1055/s-0030-1258519

A new efficient approach for the synthesis of unsymmetricaly substituted piperazine 2,5-dione derivatives is described by using intramolecular aza-Wittig reaction as the key step. The reaction conditions are very simple, offer easy isolation, and excellen

Full text of DOI:10.1055/s-0030-1258519

2122
LETTER
Intramolecular Aza-Wittig Reaction: A New Efficient Tool for the
Construction of Piperazine 2,5-Dione Derivatives
C
onstruction of Pi
.
perazine 2, 5-
C
D
ione
D
erivative
.
s
Majumdar,* Krishanu Ray, Sintu Ganai
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 4 June 2010
lecular aza-Wittig reaction as the key step, and the results
are reported here.
Abstract: A new efficient approach for the synthesis of unsymmet-
ricaly substituted piperazine 2,5-dione derivatives is described by
using intramolecular aza-Wittig reaction as the key step. The reac-
tion conditions are very simple, offer easy isolation, and excellent
yields of the products.
The precursors 3a–f required for our present study were
synthesized from the amino esters 1a–f. Treatment of 1a–
f with chloroacetyl chloride under phase-transfer-cataly-
sis conditions gave the amides 2a–f. The amide formation
reaction under the PTC conditions proceeded at a much
faster rate than any normal amide formation reaction.
Compound 2a–f were then treated with excess of sodium
azide in DMF solution at 90 °C to afford the azide com-
pounds 3a–f in good to excellent yields (Scheme 1).
Key words: piperazine 2,5-dione, intramolecular aza-Wittig reac-
tion, iminophosphorane, cyclization
2,5-Diketopiperazines, known as cyclic dipeptides, are
frequently formed from both enzymatic and nonenzymat-
ic processes of peptides/protein.1 They are also well-
known as byproducts that are formed during removal of
temporal protecting group of secondary amino acids.2 The
piperazine-2,5-dione moiety occurs in a variety of drugs
and natural products which show interesting biological
activities3 including antiviral,4 antifungal,5 antitumour,6
antithrombic,7 and antibacterial activities.8 Additionally
this heterocyclic system has found unique applications as
an acceptor for organic anions or metal cations9 and in
material science.10 While numerous approaches have been
reported11–14 for the synthesis of piperazine 2,5-diones
there is still demand for more easier synthetic pathways.
Generally, synthesis of 2,5-DKP starting from amino ac-
ids or amino esters requires protection, deprotection, and
cyclization reactions which occur either in situ or at ele-
vated temperatures.
CO2Et
CO2Et
(ii)
(i)
CO2Et
R
N
R
N
RHN
76–82%
85–90%
Cl
N3
O
O
1a–f
2a–f
3a–f
Scheme 1 Reagents and conditions: (i) chloroacetyl chloride,
CH2Cl2–H2O, K2CO3, r.t.; (ii) NaN3, DMF, 90 °C.
Initially, the intramolecular aza-Wittig reaction was con-
ducted with the substrate 3a. When 3a was treated with
triphenylphosphine in THF at room temperature, product
6a was afforded along with triphenylphosphine oxide.
The intermediate iminophosphorane 4 was not isolated
(Scheme 2).
O
N
OEt
The aza-Wittig reaction has become one of the most im-
portant synthetic method for the construction of C=N,
N=N, and S=N double bonds especially in the preparation
of nitrogen containing heterocycles. Iminophosphoranes,
nitrogen analogues of phosphorus ylides, are versatile in-
termediates in modern synthetic chemistry.15 Numerous
research papers and reviews have appeared in the litera-
ture describing the general use of iminophosphorane as re-
agent and intermediate in organic synthesis,16 including
the synthesis of heterocyclic natural products by the aza-
Wittig method.17
CO2Et
N3
(i)
R
N
R
N
R
N
O
N=PPh3
OEt
O
O
3a–f
4
5
O
N
R
NH
O
6a–f
In continuation of our research interest in the synthesis of
nitrogen heterocycles18 we have undertaken a study to
synthesize 2,5-diketopiperazine derivatives of biological
interest from N-substituted amino esters using intramo-
Scheme 2 Reagents and conditions: (i) Ph3P, THF, r.t.
In this case the iminophosphorane 4 formed during the
reaction readily underwent cyclization to form the inter-
mediate 5 followed by enol ether cleavage in moist THF
(not anhydrous) to give the final product 6a19 in 96%
yield. The other solvents, acetonitrile, dichloromethane,
and toluene, were also effective in the cyclization but THF
SYNLETT 2010, No. 14, pp 2122–2124
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258519; Art ID: G13910ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

LETTER
Construction of Piperazine 2,5-Dione Derivatives
2123
was the best choice as it gave the maximum yield of 6a.
Accordingly the other substrates 3b–f were similarly
treated to give the desired cyclized products 6b–f in 88–
96% yields. The results are summarized in Table 1.
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Table 1 Summarized Results of the Intramolecular Aza-Wittig
Reaction
Entry
1
R
Substrate Time
(min)
Product Yield
(%)
3a
3b
3c
30
30
30
6a
6b
6c
96
92
94
2
3
Me
4
5
3d
3e
30
30
6d
6e
95
92
MeO
6
3f
30
6f
88
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O
N
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Me
Although a recent report20 in the literature shows a one-
pot preparation of symmetrically 1,4-substituted pipera-
zine 2,5-diones but our methodology provides the synthe-
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from easily available amino esters using intramolecular
aza-Wittig reaction as the key step. The method allows
mild reaction conditions, easy separation of products, and
affords the products in excellent yields.
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Acknowledgment
We thank (New Delhi) and CSIR (New Delhi) for financial assis-
tance. Two of us (K.R. and S.G.) are grateful to CSIR (New Delhi)
for their research fellowships.
Synlett 2010, No. 14, 2122–2124 © Thieme Stuttgart · New York

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K. C. Majumdar et al.
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(19) General Procedure for the Preparation of Compound 6a
To a solution of compound 3a (100 mg, 0.36 mmol) in THF
(5 mL) was added Ph3P (142 mg, 0.54 mmol). The mixture
was stirred at r.t. for 30 min. After completion of the reaction
(as monitored by TLC), THF was completely evaporated,
and the crude product was purified by column chromatog-
raphy over silica gel (60–120 mesh) using PE–EtOAc (1:1)
as eluant to give the pure product 6a in 96% yield.
Yield 96%, solid, mp 208–210 °C. IR (KBr): nmax = 1655,
1689, 3243 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.27–
7.38 (m, 5 H), 6.26 (br s, 1 H), 4.61 (s, 2 H), 4.10 (s, 2 H),
3.86 (s, 2 H). 13C NMR (125 MHz, DMSO-d6): d = 44.4,
Synlett 2010, No. 14, 2122–2124 © Thieme Stuttgart · New York