Reaction of amidrazones with 2,3-diphenylcyclopropenone: Synthesis of 3-(aryl)-2,5,6-Triphenylpyrimidin-4(3H)-ones

Article abstract of DOI:10.3184/174751916X14743924874916

Amidrazones react with 2,3-diphenylcyclopropenone to give 3-Aryl-2,5,6-Triphenylpyrimidin-4(3H)-one derivatives in good yields. The synthesised compounds were characterised by spectroscopic tools and their structures confirmed by X-ray crystallography. A rational mechanism of formation of the products is presented.

Full text of DOI:10.3184/174751916X14743924874916

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 OCTOBER, 637–639
RESEARCH PAPER 637
Reaction of amidrazones with 2,3-diphenylcyclopropenone: Synthesis of
3-(aryl)-2,5,6-triphenylpyrimidin-4(3H)-ones
Ashraf A. Alya*, Mohamed Ramadanb, Mohamed Abd Al-Azizc, Hazem M. Fathyb, Stefan Bräsed,
Alan B. Browne and Martin Niegerf
aChemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
bOrganic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 71526 Assiut, Egypt
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-El-Minia, Egypt
dInstitute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
eChemistry Department, Florida Institute of Technology, Melbourne, FL 32901, USA
fLaboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, PO Box 55 (A.I. Virtasenaukio I), 00014 Helsinki, Finland
Amidrazones react with 2,3-diphenylcyclopropenone to give 3-aryl-2,5,6-triphenylpyrimidin-4(3H)-one derivatives in good yields. The
synthesised compounds were characterised by spectroscopic tools and their structures confirmed by X-ray crystallography. A rational
mechanism of formation of the products is presented.
Keywords: amidrazones, cyclopropenone, pyrimidine-4(3H)-one, ammonia extrusion, X-ray structure analysis
Cyclopropenones are reactive towards dipolar reagents and
compounds having a reactive π-system.1–3 They undergo
several interesting cycloaddition reactions, and they may
be useful starting materials for a variety of compounds.4,5
There is systematic interest in the use of cyclopropenone
chemistry to construct a wide variety of heterocycles.6,7
2,3-Diphenylcyclopropenone (1) has been found to react with a
wide range of imines and other compounds containing the C=N
moiety, usually to form azacyclopentenones (pyrrolinones) via
formal [2π + 3π] cycloaddition reactions.8–13 In contrast, the
reaction of 1 with guanidine and its alkyl and/or aryl derivatives
gives the corresponding 5,6-dihydropyrimidin-4(1H)-ones
via a formal [3π + 3π] cycloaddition reaction.14 In general,
cyclopropenones are strained ring ambident electrophiles with
a tendency to form ring-opened products; their reaction with
nucleophiles can involve carbonyl or conjugate addition.15,16 It
is expected that the use of cyclopropenones as C-3 synthetic
blocks will find a broader applicability in the field of synthetic
chemistry in the future. 2,3-Diphenylcyclopropenone (1) can be
represented by the resonance structures 1a–d,1−3 which contain
a three-membered ring of sp2 carbons coupled to the electron-
donor substituents on the phenyls, which seem to stabilise these
structures (Fig. 1).
triazin-6(4H)-ones (R = H, Me, MeO, Cl) are formed in
one step via the reactions of amidrazones with benzo- and
naphtho-1,4-quinones. In contrast, the reactions of amidrazones
with 2,3,5,6-tetrachloro-1,4-benzoquinone or 2,3-dichloro-
1,4-naphthoquinone gave indazoles.17 Recently, we reacted
amidrazones with 2-cyano-3,3-bis(methylthio)acrylate to give
mercapto pyrazole derivatives.18
We have also investigated the chemistry of 1 in heterocyclic
synthesis, such as pyridazinethiones, 1,2,4-triazolo[4,3-b]
pyridazinethiones19 and [2.2]paracyclophane-based pyrroles.20
Compound 1 also reacted with ylidene-N-phenylhydrazine-
carbothioamides to give the pyrrolo[2,1-b]-1,3,4-oxadiazoles.21
On the other hand, 1 reacted with N-imidoylthioureas 2a–e to
form the pyrimidin-4(3H)-ones 3a–e.22 The reaction mechanism
can be described as being due to stepwise addition accompanied
by elimination of phenyl isothiocyanate (Scheme 1).22
Depending upon the encouraging aforementioned results,
compound 1 can react with different nucleophiles to produce
various heterocycles. We herein investigate the reactivity of
amidrazones 4a–f towards 1.
Results and discussion
Thus, on reacting cyclopropenone 1 with amidrazones 4a–f23
in ethanol and catalysed by a few drops of triethylamine, the
reaction proceeded, surprisingly, to give 3-aryl-5,6-
We have examined the reactivity of amidrazones towards
π-acceptors. For example, various benzo- and naphtho-1,2,4-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
1
1a
1b
1c
1d
Fig. 1 Resonance structures of 2,3-diphenylcyclopropenone (1).
Ph
Ar
H
O
O
N
Ph
Ph
Ar
Ph
Ph
Ph
Ph
S
H
N
–
PhNCS
1
N
H
N
O
N
N
Ph
Ar
N
Ph
PhHN
S
Ph
2a–e
3a–e
Scheme 1 Pyrimidin-4(3H)-ones 3a–e from reaction of N-imidoylthioureas 2a–e with 1.
* Correspondent. E-mail: ashrafaly63@yahoo.com

638 JOURNAL OF CHEMICAL RESEARCH 2016
diphenylpyrimidin-4(3H)-ones 5a–f in 67–87% yields
(Scheme 1). We chose compounds 4a–f having aryl groups with
electron-donating and withdrawing substituents on the benzene
ring in order to examine their reactivity. The structure proof of
5a–f was based on the mass, 1H NMR, 13C NMR and IR spectra
as well as X-ray structure analysis, together with elemental
analyses. For example, the reaction of compound 4a with 1 for
7 h yielded yellow crystals of 5a in 83% yield (Scheme 2). The
NMR spectroscopic data of compounds 5a and other derivatives
5b, 5d and 5e were found to be similar to those reported in the
literature22. The structure was unambiguously proved during
X-ray structure analysis of compound 5e (Fig. 2). However, the
structures of the newly prepared pyrimidin-4-one derivatives,
as found in 5c and 5f, were proved by NMR, mass and IR
spectra and elemental analyses (see Experimental section). In
the case of 5c, the mass spectrum and elemental analysis proved
the molecular formula to be C30H24N2O. The 1H NMR spectrum
of 5c showed a singlet at δH = 2.06. The di-ortho-substituted
phenyl group showed a broad doublet δH = 6.92 (J = 7.5; 2H) and
a triplet at δH = 6.81 (J = 7.3 Hz, 1H) (see Experimental section).
Characteristic resonances representing the carbonyl carbon (C-
4) and C-6 resonated in the 13C NMR spectrum at δC =166.6 and
155.3, respectively. Besides, the azomethine carbon of N=C–N
which appeared in the 13C NMR spectrumatδC = 156.2, whereas
the carbon of N–C–Ar appeared at δC = 144.2. In the case of 5f,
the 13C NMR spectrum revealed C-4, N=C–N, C-6 and N–C–
Ar at δC = 161.6, 157.31, 157.26 and 137.9, respectively. The
N-3 resonates in 15N NMR at δN = 187.3 (N-3). Interestingly,
the product formation excluded the formal [2 + 3] cycloaddition
pathways proposed by Eicher.8–13 The reaction mechanism can
be simply described as due to the hydrazine addition to C-2 of
1 leading to intermediate 6. Thereafter amidine-like reaction
of N-3 to the carbonyl might occur to form salt 7 (Scheme 3).
Nucleophilic addition via ring opening to the positively charged
nitrogen followed by proton transfer would give 8. Elimination
of ammonia from 8 would ultimately give 5 (Scheme 3). In
further support, 3-substituted 5,6-diphenylpyrimidin-4-ones
were obtained from diphenylcyclopropenone and N-substituted
amide oximes. Reaction proceeded via elimination of water
from the oxime moiety.24
Interestingly, in this paper we report on the first article
dealing with the removal of ammonia from amidrazone
reactions. Clearly indicative is the first X-ray structure
analysis of substituted 2,5,6-triphenylpyrimidin-4(3H)-ones.
As amidrazones can be prepared with various aliphatic and
aromatic substituents from easily available thioamides23,
accordingly, various pyrimidine-4-ones of 5 can be prepared.
Moreover, reaction between 4a–f and 1 takes place smoothly
and the reaction can be considered as one-pot.
Conclusions
In this paper, we report another new reactivity of amidrazones
via extrusion of ammonia from N-1. Hence, further
investigation of amidrazones will be valuable. Although
2,5,6-triphenylpyrimidin-4(3H)-ones are known structures,
the above procedure is shown to be a more effective, easier and
high-yield route to these products.
Fig. 2 Molecular structure of 3-(4-chlorophenyl)-2,5,6-triphenylpyrimidin-
4(3H)-one (5e) (the minor disordered part is omitted for clarity;
displacement parameters are drawn at the 50% probability level).
Ph
R2
O
R2
H
Ph
NH2
O
Ph
N
N
Et N
EtOH/
3
N
+
R1
N
reflux 6–10h
Ph
R1
Ph
R3
Ph
R3
1
4a–f
a; R1 = CH3, R2 = R3 = H
b; R1 = CH3O, R1 = R3 = H
c; R1 = H, R2= R3 = CH3
d; R1 = NO2, R2 = R3 = H
e; R1 = Cl, R2 = R3 = H
f; R1 = Br, R2 = R3 = H
5a–f (67–87%)
5a (83%); 5b (87%); 5c (86%); 5d (60%); 5e (72%); 5f (67%)
Scheme 2 Synthesis of pyrimidine-4-ones 5a–f from reaction of amidrazones 4a–f with 2,3-diphenylcyclopropenone (1).
Ar
Ar
Ph
Ph
N
O
Ph
C
:
N
C
Ph
Ph
H2N
O
HN
HN
HN
HN
NHAr
..
N
1
Ph
4
Ph
O
H
Ph
Ph
6
7
Ar
N
Ph
O
-
NH3
5
N
H3N
Ph
Ph
8
Scheme 3 Proposed mechanism describes the formation of 5.

JOURNAL OF CHEMICAL RESEARCH 2016 639
Experimental
Single crystal X-ray structure determinations of 5e
The single crystal X-ray diffraction study was carried out on a Bruker
D8 Venture diffractometer with Photon100 detector at 123 K using Mo
Kα radiation (λ = 0.71073 Å). Direct methods (SHELXS-97)25 were
used for the structure solution, and refinement was carried out using
SHELXL-2014)26 (full-matrix least-squares on F2). Hydrogen atoms were
localised using a difference Fourier synthesis map and refined using a
riding model. A semi-empirical absorption correction was applied. The
p-chlorophenyl-group is disordered. Refinement with the listed atoms show
residual electron density due to a heavily disordered methanol around a
centre of symmetry which could not be refined with split atoms. Therefore
the ‘SQUEEZE’ option of the program package PLATON27 was used to
create an hkl file taking into account the residual electron density in the
void areas. Therefore, the atoms list and unit card do not agree (see cif-file
for more details). Compound 3e: C28H19ClN2O ∙ 0.5 CH3OH, Mr = 450.92
g mol−1, yellow blocks, size 0.32 × 0.14 × 0.12 mm, triclinic, P-1 (No. 2),
a = 9.6540(6) Å, b = 10.5370(7) Å, c = 11.6531(8) Å, α = 79.706(2)°, β =
78.519(2)°, γ = 77.126(2)°, V = 1121.23(13) Å3, Z = 2, Dcalcd = 1.336 Mg m−3,
F (000) = 470, μ = 0.197 mm−1, Τ = 123 K, 42,804 measured reflections
(2θmax = 55°), 5168 independent [Rint = 0.028], 263 parameters, 36 restraints,
R1 [for 4540 I > 2σ (I)] = 0.047, wR2 (for all data) = 0.122, S = 1.03, largest
diff. peak and hole = 0.595 e Å−3/−0.666 e Å−3. CCDC 1476780 (5e) contain
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
A Gallenkamp melting point apparatus was used to determine melting
points (Weiss-Gallenkamp, Loughborough, UK); the results are
uncorrected. The IR spectra (recorded in KBr) were recorded with an
Alpha Bruker FTIR and a Shimadzu 408 instrument. The NMR spectra
were measured using a Bruker AV-400 (Florida Institute of Technology,
USA). Chemical shifts are expressed as δ (ppm) with tetramethylsilane
(TMS) as internal reference; s = singlet, t = triplet, q = quartet, m =
multiplet, br. = broad; the 13C NMR signals were assigned on the basis
of DEPT 135/90 spectra. Chemical shifts are expressed as δ in parts per
million (ppm). The mass spectra (70 eV, electron impact mode) were
recorded with a Finnigan MAT 8430 instrument. The elemental analyses
for C, H, N and S were carried out at the Microanalytical Centre, Cairo
University, Egypt with an Elmyer 306 Analyzer. Preparative layer
chromatography was performed with air-dried 1.0 mm layers of slurry-
applied silica gel (Pf254, Merck, Germany) on glass plates 48 × 20 cm
using the solvents indicated.
General procedure
Into a 250 mL two-necked round bottom flask containing a solution
of 4a–f (2 mmol) in absolute ethanol (50 mL), a solution of 1 (0.412 g,
2 mmol) in absolute ethanol (20 mL) was added dropwise with stirring.
The mixture was stirred at room temperature for 1 h, then at reflux for
6–10 h (the reaction was monitored by TLC analyses). The solvent was
evaporated under vacuum and the solid products formed were purified
by dissolving them in dry acetone (30 mL) and then subjecting them to
preparative plate chromatography (silica gel) with toluene–ethyl acetate
(10:1). The products 5a–f obtained were recrystallised from the stated
solvents.
Acknowledgement
We thank the DFG (BR 1750) for its financial support for the
stay of Professor Aly at the Karlsruhe Institute of Technology,
Institute of Organic Chemistry, Germany.
3-(4’-Methylphenyl)-2,5,6-triphenylpyrimidin-4(3H)-one
(5a):
Compound 5a was obtained as yellow crystals (0.34 g, 83%), m.p.
Received 18 August 2016; accepted 29 August 2016
Paper 1604173 doi: 10.3184/174751916X14743924874916
Published online: 26 September 2016
263–265 °C (EtOH) [lit.22 262–264 °C].
3-(4’-Methoxyphenyl)-2,5,6-triphenylpyrimidin-4(3H)-one
(5b):
Compound 5b was obtained as yellow crystals (0.37 g, 87%), m.p.
220 °C (CH3CN) [lit.22 220–222 °C].
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7.45 (d, 2H, J = 6.8 Hz), 7.38 (m, 4H), 7.29 (m, 8H), 7.25 (m, 4H); 13C NMR:
δC = 161.6 (C-4), 157.31 (N=C–N), 157.26 (C-6), 137.9 (N–C–N), 137.0,
134.9, 134.1, 131.6 (Ar–C), 131.4), 130.8, 129.6, 129.5, 129.1, 128.8, 127.9,
127.8 (2CH), 127.4, 122.4, 121.5 (CH); IR (KBr) νmax cm−1: 3090–3010
(w, Ar–CH), 1695 (s, C=O), 1612 (s, C=N), 1560 (m, C=C); 15N NMR:
δN = 187.3 (N-3); MS (m/z, %): 480 (30), 479 (156), 478 (28), 400 (34),
322 (20), 246 (18), 170 (24), 92 (28), 77 (40). Anal. calcd for C28H19BrN2O
(479.38): C, 70.16; H, 4.00; N, 5.84; found: C, 70.00; H, 4.10; N, 5.75%.
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