Reaction mechanism of vinamidinium salts and cyanoacetamide derivatives

Article abstract of DOI:10.3184/174751915X14197029812826

The mechanism of formation of a pyridin-2(1H )-one synthesised from vinamidinium salts and cyanoacetamide derivatives is illustrated through the preparation and characterisation of a key intermediate.

Full text of DOI:10.3184/174751915X14197029812826

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 JANUARY, 41–43
RESEARCH PAPER 41
Reaction mechanism of vinamidinium salts and cyanoacetamide derivatives
Jiabin Yanga, Guoqiang Sub, Yu Renb and Yang Chena*
aState Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu 210096,
P. R. China
bNanjing Zhongrui Pharmaceutical Co., Ltd., Nanjing, Jiangsu 211100, P.R. China
The mechanism of formation of a pyridin-2(1H)-one synthesised from vinamidinium salts and cyanoacetamide derivatives is
illustrated through the preparation and characterisation of a key intermediate.
Keywords: pyridin-2(1H)-ones, vinamidinium salt, reaction mechanism, heterocycles, cyanoacetamide derivatives
Pyridin-2(1H)-ones are important building blocks in organic
syntheses,1–4 and are found in many biological compounds.5–8
Therefore, their preparation has been of great interest in
organic chemistry.9–13 The reaction of vinamidine reagents
(such as vinamidinium salts, enaminones) with cyanoacetamide
derivatives have been successfully utilised for this purpose.14,15
Vinamidinium (1,5-diazapentadienium) salts, important
three-carbon building blocks, have been widely utilised to
construct substituted benzenes16 and heterocyclic compounds17.
Because this kind of salt has a quaternary ammonium group
with strong electron-withdrawing ability, it easily reacts
with various nucleophilic reagents. While investigating
therapeutic agents, we successfully used the reaction of 2-aryl
vinamidinium salts with N-aryl cyanoacetamides to synthesise
the key intermediates 1,5-diaryl pyridin-2(1H)-ones.18
Although a simple and efficient method for the synthesis of
pyridin-2(1H)-ones, the exact mechanism of this reaction is
unclear because the structure of an intermediate has not been
confirmed. So far, the structure of the intermediate in this
reaction has been based on supposition from similar reactions.
The structure of an intermediate of this reaction was proposed
by Church et al. in 1995.16 In their studies, 2-aryl vinamidinium
perchlorate salts and t-butyl cyanoacetate afforded intermediate
t-butyl 2-cyano-5-(dimethylamino)-4-aryl-2,4-pentadienoates
under base conditions. This was used as a basis to speculate
the likely structure of the intermediate in the reaction of
vinamidine with cyanoacetamide. These studies suggested
that the intermediate in this reaction underwent a Knoevenagel
condensation pathway. However, in 2011, Chikhalikar et al.19
proposed another mechanism of generation for the intermediate
of this reaction. They used the reaction of 3-dimethylamino-
2-formyl acrylonitrile with malononitrile/ethyl cyanoacetate
to produce an intermediate through a nucleophilic vinylic
substitution pathway (SNV). According to these studies, there
might be two different and conflicting reaction mechanisms in
this reaction. (Scheme 1).
The identification of the reaction intermediate is crucial to
the confirmation of the reaction mechanism. To investigate the
reactionmechanismofvinamidiniumsaltswithcyanoacetamide
derivatives,
we
selected
(E)-N-(3-(dimethylamino)-2-
phenylallylidene)-N-methylmethanaminium perchlorate (1) as
a model vinamidinium salt considering that it could be easily
prepared from phenylacetic acid and detected by HPLC with an
UV detector.
Results and discussion
The acquisition of the intermediate product with high purity
was our first challenge. Different reaction conditions were
tried. In most cases, no target compound appeared, either no
reaction or only pyridin-2(1H)-one 2 (Table 1, entries 1–5)
was obtained. The mild bases Et3N and K2CO3 cannot trigger
the reaction even with heating to reflux in DMF (Table 1,
entries 1 and 2). The high purity cyclisation product 2 can
be obtained at different temperatures using NaOEt as the
base (Table 1, entries 3–5). When the reaction temperature
was reduced to 5 °C, a new compound 3 appeared (Table 1,
entry 6). Compound 3 disappeared with an increase in the
reaction temperature. We tried different reaction temperatures
and controlled the temperature fluctuation within ±1°C range
(Table 1, entries 7–9). It was found that the highest purity of 3
(98.7%) can be obtained in the presence of NaOEt after stirring
for 40 min under 0 °C (Table 1, entry 7).
High-resolution mass spectrometry (HRMS) was applied
to determine the molecular weight of this compound. In the
HRMS spectrum, the experimental value (242.1282) for
[M+H]+ of this compound matches the calculated value of 3
(242.1288). 1H NMR was used to further confirm its structure.
Fifteen hydrogens were found in the 1H NMR spectrum, which
Knovenagel Condensation
O
NC
r
NHA '
O
N
O
NC
N
NHAr'
N
r
A
NC
NAr'
+
Ar
ClO4
N
O
Ar
ClO4
NHAr'
Ar
CN
Nucleophilic Vinylic Substitution
Scheme 1 Possible reaction mechanisms to generate the intermediate.
* Correspondent. E-mail: yc@seu.edu.cn

42 JOURNAL OF CHEMICAL RESEARCH 2015
Table 1 Reaction conditions of the preparation of intermediate 3
agree with the number of hydrogen atoms of compound 3. The
two single signals at 7.77 ppm and 7.45 ppm were assigned as
H1 and H2, respectively. The two groups of multiple signals at
7.31–7.33 ppm (3H) and 7.13–7.15 ppm (2H) belonged to the five
hydrogens of phenyl ring (Fig. 1). At 6.23 ppm, a broad singlet
(br.s.) peak is from the two hydrogens of the amide. Another
br.s. signal (6H) in the high field at 2.73 ppm is believed to be
the six methyl hydrogens of the dimethylamino group. The
characteristic hydrogen (H3) of 4, another possible intermediate
undergoing the SNV pathway in this reaction, did not appear in
the 1H NMR spectrum. These data suggest that compound 3 is
the intermediate of this reaction.
On the basis of the above results, the mechanism of formation
of the pyridin-2(1H)-one is shown in Scheme 2. First,
NaOEt removed the α-proton of cyanoacetamide resulting
in the formation of a carbanion. The carbanion attacked
nucleophilically compound 1 generating 5. Then 5 eliminated
its dimethylamino group to produce the intermediate 3. shown
also as the resonance structure 3′ which further underwent a
1,6-addition followed by an elimination of dimethylamine to
yield the pyridin-2(1H)-one 2 via intermediate 6 (route a). We
note that a temperature increase accelerates the conversion
of intermediate 3 to 2. Theoretically, compound 5 could also
O
O
N
ClO4
N
N
C
NC
base
(1.0 equiv)
NH
NH2
N
O
+
+
NC
NH2
(1.0 equiv)
1
2
3
Entry
Base/solvent
T/oC
Time/min
Purityb
1
2
3
4
5
6
7
8
9
Et3N/DMFa
Reflux
Reflux
Reflux
25
120
60
20
20
20
20
40
60
60
NR
NR
K2CO3/DMF
NaOEt/EtOH
NaOEt/EtOH
NaOEt/EtOH
NaOEt/EtOH
NaOEt/EtOH
NaOEt/EtOH
NaOEt/EtOH
2, 100%
2, 100%
2, 100%
10
5
2, 62.9%; 3, 37.1%
2, 1.3%; 3, 98.7%
3, trace
0
–5
–10
NR
aProportion of 1 to cyanoacetamide to base is 1: 1: 1.
bHPLC analysis on the crude product.
NR, no reaction.
H2 H1
O
N
NH2
N
C
3
O
H3
N
NH2
N
C
l
C O4
4
Fig. 1 1H NMR spectrum of intermediate 3.
Scheme 2 Formation mechanism of the pyridin-2(1H )-one.

JOURNAL OF CHEMICAL RESEARCH 2015 43
DMSO-d6): δ 8.31 (s, ArH, 1H), 7.84 (s, ArH, 1H), 7.50 (d, J=7.8 Hz,
ArH, 2H), 7.35 (t, J=7.8 Hz, ArH, 2H), 7.19 (t, J=7.5 Hz, ArH, 1H).
Note: the active proton of NH of compound 2 was not observed in its
1H NMR spectrum. HRMS (ESI-TOF) m/z: calcd for C12H8N2ONa
(M+Na)+ 219.0553, found 219.0553.
produce 2 through an SNV pathway (route b). However, this
possibility is not supported by our experiments because no
intermediate in this route was found.
Experimental
Unless otherwise specified, the commercial reagents were used
as-received without further purification and all solvents were
dried by standard methods prior to use. Starting material (E)-N-(3-
(dimethylamino)-2-phenylallylidene)-N-methylmethanaminium
perchlorate (1) was prepared according to the reported procedure.16
HRMS data were acquired using ESI-TOF detection. The melting
point was measured on a WRS-2A melting point apparatus and
is uncorrected. HPLC SPD-10A with a UV detector was used to
determine the reaction progression and the purity of sample 3. The
column is C18, mobile phase is 50% MeOH/water (pre-cooled
to 0–5 °C), and the measurement wavelength was set at 210 nm.
1H NMR spectra of 2 and 3 were measured on a Bruker ACF-300 or
Bruker ACF-500 spectrometer at 30 °C and referenced to TMS. For
Electronic Supplementary Information
The 1H NMR spectra of 2 and 3 are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data.
Received 20 October 2014; accepted 12 December 2014
Paper 1402967 doi: 10.3184/174751915X14197029812826
Published online: 9 January 2015
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