Synthesis of 1,4-diaryl-piperazine-2,5-diones: New behavior of N,N-dimethylformamide dimethyl acetal (DMFDMA)

Article abstract of DOI:10.1080/00397910701767098

Reactions of chloroacetamides (5) with N,N-dimethylformamide dimethyl acetal gave 1,4-diaryl-piperazine-2,5-diones 11a-e in good yield, rather than 1,5-diaryl-3,7-dimethoxy-1H,5H-[1,5]diazocine-2,6-diones (9a-e). Copyright Taylor & Francis Group, LLC.

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Synthesis of 1,4‐Diaryl‐piperazine‐2,5‐diones:
New Behavior of N,N‐Dimethylformamide
Dimethyl Acetal (DMFDMA)
Fathi A. Abu‐Shanab a , Ahmed Al‐Harrasi b & Sayed A. S. Mousa a
a Faculty of Science, Department of Chemistry, Al‐Azhar University, Assiut,
Egypt
b Department of Chemistry, College of Science, Sultan Qaboos University,
Al‐Khod, Oman
Version of record first published: 28 Jan 2008.
To cite this article: Fathi A. Abu‐Shanab , Ahmed Al‐Harrasi & Sayed A. S. Mousa (2008): Synthesis of
1,4‐Diaryl‐piperazine‐2,5‐diones: New Behavior of N,N‐Dimethylformamide Dimethyl Acetal (DMFDMA),
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:3, 376-382
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Synthetic Communicationsw, 38: 376–382, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701767098
Synthesis of 1,4-Diaryl-piperazine-2,5-diones:
New Behavior of N,N-Dimethylformamide
Dimethyl Acetal (DMFDMA)
Fathi A. Abu-Shanab,1 Ahmed Al-Harrasi,2 and Sayed A. S.
Mousa1
1Faculty of Science, Department of Chemistry, Al-Azhar University,
Assiut, Egypt
2Department of Chemistry, College of Science, Sultan Qaboos
University, Al-Khod, Oman
Abstract: Reactions of chloroacetamides (5) with N,N-dimethylformamide dimethyl
acetal gave 1,4-diaryl-piperazine-2,5-diones 11a–e in good yield, rather than 1,5-
diaryl-3,7-dimethoxy-1H,5H-[1,5]diazocine-2,6-diones (9a–e).
Keywords: a-chloroacetamides 1,4-diarylpiperazine-2,5-diones, condensation, dimer-
ization, N,N-dimethylformamide dimethyl acetal
Formamide acetals are useful reagents.[1,2] They have two sites of attack in their
structure. The first one is nucleophilic—the nitrogen atom that carries two
electron-repelling groups (methyl groups)—and the other is electrophilic—
the carbon that carries two electron withdrawing groups (methoxy groups).
We concentrate on N,N-dimethylformamide dimethyl acetals (DMFDMA) (1).
Received in the U.K. April 4, 2007
Dedicated to Dr. Basil J. Wakefield on the occasion of his 73rd birthday.
Address correspondence to Fathi A. Abu-Shanab, Faculty of Science, Department
of Chemistry, Al-Azhar University, Assiut 71524, Egypt. E-mail: fathiabushanab@
yahoo.com
376

1,4-Diaryl-piperazine-2,5-diones
377
Their main application has been functional group transformations,[3] but
they may also be regarded as one-carbon synthons in the construction of
carbon skeletons. One type of reaction that is potentially valuable for the
latter purpose involves 1,3-dicarbonyl compounds 1 to give enamines 4.[2]
We have reported that these enamines 4 were used as precursors in the
synthesis of pentasubstituted pyridines[4–6] and pentasubstituted benzene[7]
(Scheme 1).
In an extension of our studies, we now report reactions of N,N-dimethyl-
formamide dimethyl acetal (DMFDMA) (1) with chloroacetamides[8] 5. This
reaction was expected to afford the chloroenamine derivatives[4] 6, which are
important precursors that can be used for further heterocyclic syntheses. After
the addition of DMFDMA, a highly water-soluble white precipitate was
1
formed, but the H NMR spectra of the product showed the disappearance
of the -NMe2 group and the appearance of a singlet at d 4.5 ppm (Table 1).
Also, the mass spectra of the product showed a molecular ion peak at
higher values than compounds 5 and the absence of chlorine, so the product
of these reactions is not 6 (Scheme 2). One possible pathway for further
reaction of 6 is shown in Scheme 2, in which nucleophilic attack on 6 by
the produced MeOH gives 7. Protonation by the relased HCl affords the salt
8, and subsequent dimerization with the elimination of dimethylamine hydro-
chloride leads to the formation of 1,5-diaryl-3,7-dimethoxy-1H,5H-
[1,5]diazocine-2,6-diones 9.[9]
However, the mass spectra of the products did not show the molecular ion
1
corresponding to structure 9, and their H NMR spectra showed a singlet
signal at about dH ¼ 4.5 ppm and aromatic protons only. The proton of the
diazocine ring does not appear. Also, 13C NMR showed the presence of a
methylene group, not a methoxy group, which indicates that the products
are not 9. Scheme 3 shows a possible alternative pathway, in which N,N-
dimethylformamide dimethyl acetal (DMFDMA) (1) act as a nucleophile
that attacks the carbon carrying the chlorine in chloroacetamides (5a–e) to
afford the salt (10a–e),[10] dimerization with elimination of DMFDMA then
gives 1,4-diarylpiperazine-2,5-diones 11.
The identity of the main product 11 was established by MS, 1H NMR, and
elemental analysis as shown in Tables 1 and 2. We have found that Okawara
et al.[11] reported the syntheses of various 1,4-disubstituted 2,5-diketopipera-
zines by intermolecular condensation of halocarboxamides using a reaction
Scheme 1.

Table 1. Physical and spectroscopic data of 1,4-diaryl-piperazine-2,5-diones (11a–e)a
Molecular
formula
Molecular
weight
Product
Yield (%)
60
Mp (8C)
242
IR (KBr) n(cm21
)
1H NMR (CDCl3/TMS) d, J (Hz)
5a
C16H12Cl2N2O2
335.18
1656, 1590
4.43 (s, 4H), 7.22–7.24 (d, 4H,
J ¼ 7.1 Hz), 7.35–7.37 (d, 4H-
Ar AB, J ¼ 7.2 Hz) equal
integrals
5b
5c
58
54
275 (267[11]
262
)
C16H14N2O2
C18H18N2O2
266.29
294.35
1656, 1612, 1582
1656, 1590
4.53 (s, 4H), 7.3–7.46 (m,10H-Ar)
2.64 (s, 6H), 4.59 (s, 6H), 7.49–
7.63, 7.81–7.95 (m, 8H-Ar)
4.42 (s, 4H), 7.15–7.18 (d, 4H,
J ¼ 6.95 Hz), 7.50–7.52 (d, 4H-
Ar AB, J ¼ 6.93 Hz) equal
integrals
5d
62
144
C16H12Br2N2O2
424.09
1692, 1656, 1582
5e
42
168
C20H18N2O4
350.37
1653, 1580
2.63 (s, 6H), 4.49 (s, 4H), 7.27–7.95
(m, 8H-Ar).
aSatisfactory microanalysis obtained: C, H, N + 0.3.

1,4-Diaryl-piperazine-2,5-diones
379
Scheme 2.
system comprising a mixture of dichloromethane and 50% aqueous sodium
hydroxide solution in the presence of a solid phase-transfer catalyst. Among
the compounds whose syntheses are reported in Okawara et al. are 1,4-diben-
zylpiperazine-2,5-dione (11f), 1,4-diphenylpiperazine-2,5-dione (11b), and
1,4-diphenyl-3,6-dimethylpiperazine-2,5-dione (11g). The reference does
not report any use for the products synthesized.
Cavicchioni et al.[12] reports the preparation of both N,N0-dialkylpipera-
zines and 2-amino-2-haloalkyloxazolidones by intermolecular condensations
of the same reactants used in the syntheses described by Okawara et al. Cavic-
chioni et al. do not give much detail on the reaction system utilized, but appar-
ently employed a polar organic solvent system rather than a two-phase system
with a phase-transfer catalyst. Also, several 1,4-diaryl-2,5-piperazinediones
were prepared from halogen-substituted acetamide derivatives.[13]

380
F. A. Abu-Shanab, A. El-Harrasi, and S. A. S. Mousa
Scheme 3.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded on a Perkin-
Elmer 17100 FTIR spectrometer as KBr disks. NMR spectra were recorded
on Bruker AC300 spectrometer at 400 MHz for solutions in CDCl3 with tetra-
methylsilane (TMS) as an internal standard unless otherwise recorded at the
Department of Chemistry, Sultan Qaboos University, Al-Kha, Oman. Mass
spectra were obtained on Finnigan 4500 (low-resolution) spectrometers
using electron impact (EI) assay at the Micro-analytical Center, Cairo Univer-
sity, Giza, Egypt. Chloroacetamides (5a–e) were prepared according to litera-
ture procedure.[8] N,N-Dimethylformamide dimethyl acetal (DMFDMA) was
purchased from Merck.
General Procedure for 1,4-Diaryl-piperazine-2,5-diones 11a–e
A mixture of a-chloroacetamides (5a–e) (10 mmol) and dimethylformamide
dimethyl acetal (1.19 g, 10 mmol) in dry dioxane (20 mL) was refluxed for

Table 2. 13C NMR and DEPT 13C NMR data of 1,4-diaryl-piperazine-2,5-diones 11c–e
Product
13C NMR (DMSO) d C
DEPT 135
DEPT 90
DEPT 45
5c
21.49 (CH3), 53.93 (CH2), 125.54,
130.47, 137.47, 137.94 (CH-Ar),
164.45 (CO)
21.06 (CH3), 253.49 (CH2) 125.17, 129.77 (CH-Ar)
124.86, 130.04 (CH-Ar)
5d
5e
53.50, 9 (CH2), 120.53, 126.81, 133, 253.06 (CH2), 126.38,
126.43, 132.62 (CH-Ar)
53.50 (CH2), 126.81, 133 (CH-Ar)
138.78 (CH-Ar), 164.05 (CO)
27.07 (CH3), 53.55 (CH2), 12470,
127.79, 129.98, 130.12, 133.75,
140.47 (Ar), 164.35(CO), 197.31
(CO)
132.56 (CH-Ar).
26.66 (CH3), 253.15 (CH2) 124.32, 127.45, 129.71,
124.34, 127.40, 129.66,
129.70 (CH-Ar)
27.09 (CH3), 53.58 (CH2), 124.70,
127.8 129.99, 130.13 (CH-Ar)
129.75 (CH-Ar)

382
F. A. Abu-Shanab, A. El-Harrasi, and S. A. S. Mousa
6 h. The solution was filtered while hot. After cooling, the solid obtained was
collected by filtration and purified by recrystallization from ethanol to
afford the corresponding 11a–e. Yields and other data are compiled in
Tables 1 and 2.
ACKNOWLEDGMENT
The authors thank Dr. Basil Wakefield for advice on preparing this article.
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