A novel synthesis of 4-pyridazineacetic acids via ring expansion of N-cyanomethylated 3-pyrazoline-4-acetic acids

Article abstract of DOI:10.1002/jhet.894

A novel synthetic route to 4-pyridazineacetic acids 10-12 has been achieved by the ring-expansion reaction of N-cyanomethylated 3-pyrazoline-4-acetic acids 7-9. 1H-Pyrazole-4-acetic acids 1-3 were reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the corresponding C-cyanomethylated 1H-pyrazole-4-acetic acids 4-6 as major products together with N-cyanomethylated 3-pyrazoline-4-acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and 3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the corresponding N-cyanomethylated 3-pyrazoline-4-acetic acids 7 and 9 as major products. Thermal treatment of 7-9 with sodium hydride in N,N-dimethylformamide caused ring expansion to yield the corresponding 4-pyridazineacetic acids 10-12.

Full text of DOI:10.1002/jhet.894

July 2012
A Novel Synthesis of 4-Pyridazineacetic Acids via Ring
893
Expansion of N-Cyanomethylated 3-Pyrazoline-4-acetic Acids
*
Eiichi Masumoto, Hiroshi Maruoka, Fumi Okabe, Sho Nishida,
Ryoko Tomita, Toshihiro Fujioka, and Kenji Yamagata
Faculty of Pharmaceutical Sciences, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan
*
E-mail: maruoka@fukuoka-u.ac.jp
Received January 30, 2011
DOI 10.1002/jhet.894
View this article online at wileyonlinelibrary.com.
A novel synthetic route to 4-pyridazineacetic acids 10–12 has been achieved by the ring-expansion
reaction of N-cyanomethylated 3-pyrazoline-4-acetic acids 7–9. 1H-Pyrazole-4-acetic acids 1–3 were
reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the
corresponding C-cyanomethylated 1H-pyrazole-4-acetic acids 4–6 as major products together with N-cyano-
methylated 3-pyrazoline-4-acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and
3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the
corresponding N-cyanomethylated 3-pyrazoline-4-acetic acids 7 and 9 as major products. Thermal
treatment of 7–9 with sodium hydride in N,N-dimethylformamide caused ring expansion to yield the
corresponding 4-pyridazineacetic acids 10–12.
J. Heterocyclic Chem., 49, 893 (2012).
INTRODUCTION
B and C (Scheme 1). It is well known that under an appropri-
ate reaction condition, an acylation of A provides the
corresponding C- or O-acylated pyrazoles D and E [30],
while we have reported the synthesis of N-acylated pyrazoles
F through Lewis acid-mediated rearrangement of O-acylated
pyrazoles E [31]. Furthermore, in our recent work, we
achieved the synthesis of functionalized pyrazoles and
dihydropyridazinones via a ring-opening reaction of
spirocyclopropanepyrazoles [32]. In keeping with our
interest in the chemical reactivity of functionalized
pyrazoles [33,34], we focused our attention on the develop-
ment of a new method for the preparation of pyridazine
derivatives starting from 1H-pyrazole-4-acetic acids, be-
cause these derivatives are easily available by established
synthetic procedures [35–37]. Thus, we, herein, wish to
report our experimental results, a cyanomethylation and
subsequent ring expansion of 1H-pyrazole-4-acetic acids in
the presence of a base such as triethylamine and sodium
hydride.
Nitrogen-containing heterocycles are of biological impor-
tance and design of newer strategies for their synthesis is an
important area of research in organic chemistry. Pyrazole
derivatives are well established in the literatures as impor-
tant biologically effective heterocyclic compounds. These
derivatives are the subject of many research studies due to
their widespread potential pharmacological activities such
as antitumor, analgesic, antidepressant, antibacterial, plant
growth regulatory, anti-inflammatory, and antihyperglyce-
mic activities [1–8]. Various methods have been reported
for the synthesis of pyrazole derivatives [9–14].
On the other hand, pyridazine derivatives are also versa-
tile pharmacophores in many biologically active molecules
of contemporary interest. For example, these molecules
have been previously reported to be platelet aggregation
inhibitor, a-adrenoceptor antagonist, and antisecretory/
antiulcer agent [15–20]. In this context, the synthesis of
pyridazine derivatives continues to attract attention and
provides an interesting challenge [21–29].
In connection with the synthesis and reactivity of pyrazole
derivatives, it seems to us of interest to examine the chemical
properties of 3H-pyrazol-3-one A (CH-form) as well as
possible tautomerization including OH- and NH-forms
RESULTS AND DISCUSSION
The starting materials, 1H-pyrazole-4-acetic acids 1–3,
were easily prepared by the condensation reaction of
© 2012 HeteroCorporation

894
E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, R. Tomita, T. Fujioka, and K. Yamagata
Vol 49
Scheme 1
Scheme 2
cyanomethylation reaction of 1–3. Thus, we examined sev-
eral reaction conditions, e.g., solvent, time, reagent, and
substrate/base molar ratio. The best results are shown in
Scheme 3 and Table 1. As a consequence, the reaction of
1a,b, 2a,b, and 3a,b with iodoacetonitrile in the presence
of triethylamine in refluxing acetonitrile led to the
corresponding C-cyanomethylated 1H-pyrazole-4-acetic
acids 4a,b, 5a,b, and 6a,b as major products together with
N-cyanomethylated 3-pyrazoline-4-acetic acids 7a,b and
8a,b as minor products. In this reaction, the N-cyano-
methylated 3-pyrazoline-4-acetic acids 9a,b were not
detected at all (entries 5 and 6 in Table 1), while we found
the reaction condition under which N-cyanomethylated 3-
pyrazoline-4-acetic acids 7a,b, 8b, and 9a,b could be iso-
lated as major products (Scheme 3 and Table 2). Indeed,
when 1a,b, 2b, and 3a,b were treated with chloro-
acetonitrile in the presence of triethylamine in refluxing
chloroform, the expected N-cyanomethylated products 7a,
b, 8b, and 9a,b were obtained in a somewhat better yields.
dimethyl and/or diethyl acetylsuccinate with phenylhydra-
zines, such as phenylhydrazine, 4-nitrophenylhydrazine,
and 4-methoxyphenyhydrazine hydrochloride, in moderate
to good yields according to the procedure for the prepara-
tion of 1a [35] and 1b [36,37] reported in literature
(Scheme 2, 1a: 87%, 1b: 88%, 2a: 70%, 2b: 80%, 3a:
75%, and 3b: 86%). The structures of 2a,b and 3a,b were
confirmed by elemental analyses and spectroscopic data
(IR, 1H-NMR, 13C-NMR, and mass). The 1H-NMR spectra
of 2a,b and 3a in deuteriochloroform indicate that 2a,b
exist almost exclusively as a single CH-form and 3a exists
as a single OH-form, whereas those of 1a,b and 3b show
the presence of a tautomeric mixture of the CH-form and
OH-form, with the following ratios observed: CH-form:
OH-form = 1:1.2 for 1a, 1:1.5 for 1b, and 1:1.3 for 3b
(Experimental section). For example, the IR spectra of
2a,b display bands near 1730 cmÀ1 due to two carbonyl
groups, whereas that of 3a shows bands at 3359 cmÀ1
due to a hydroxyl group and at 1730 cmÀ1 due to an ester
Scheme 3
1
carbonyl group. The H-NMR spectra of 2a,b exhibit a
one-proton multiplet near d 3.6 assignable to the H-4
methine proton of pyrazole ring, whereas that of 3a shows
a D2O exchangeable signal at d 10.62 attributable to the
hydroxyl proton. The 13C-NMR spectra of 2a,b show a
signal near d 49 due to the C-4 methine carbon of pyrazole
ring and a signal near d 170 and 173 due to the two car-
bonyl carbons, whereas that of 3a shows a signal at
d 97.2 due to the C-4 carbon of pyrazole ring and a signal
at d 157.2 due to the C-5 carbon of pyrazole ring.
In our initial studies, to check something about the reac-
tivity of 1H-pyrazole-4-acetic acids 1–3, we carried out
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
A Novel Synthesis of 4-Pyridazineacetic Acids via Ring Expansion of
N-Cyanomethylated 3-Pyrazoline-4-acetic Acids
895
Table 1
Reaction of 1–3 with iodoacetonitrile according to Scheme 3.
Scheme 4
Entries Substrate R1
R2
Products Yields (%)
1
2
3
4
5
6
1a
1b
2a
2b
3a
3b
Me
Et
Ph
Ph
4a/7a
4b/7b
5a/8a
5b/8b
6a/9a
6b/9b
65/28
69/9
62/15
61/12
36/0
Me 4-NO2-C6H4
Et 4-NO2-C6H4
Me 4-MeO-C6H4
Et 4-MeO-C6H4
29/0
In this reaction, the C-cyanomethylated 1H-pyrazole-4-acetic
acids 4a,b and 5a,b were not isolated at all (entries 1–4 in
Table 2). Interestingly, in the case of the reaction of 2a,b,
the 4-pyridazineacetic acid derivatives 11a,b were
produced in 8–18% low yields (entries 3 and 4 in Table 2).
The reason for this change of behavior under the appro-
priate reaction conditions, such as an iodoacetonitrile/ace-
tonitrile and chloroacetonitrile/chloroform combinations,
is not very clear at present.
The formation of 4-pyridazineacetic acids 11a,b could
be explained by the possible mechanism presented in
Scheme 4. This reaction probably proceeds through attack
of a carbanion at position C-3 of pyrazole ring of 8a,b with
intramolecular Michael addition followed by ring expan-
sion with loss of cyanide ion to yield 11a,b.
These products 4–9 and 11 gave satisfactory spectro-
scopic data consistent with their assigned structures (Ex-
perimental section). The IR spectra of 4–6 display a band
in the range of 2251–2259 cmÀ1 due to a nonconjugated
cyano group, whereas those of 7–9 show a band in the
range of 2248–2253 cmÀ1 due to a nonconjugated cyano
group. The 1H-NMR spectra of 4–6 in deuteriochloroform
exhibit two two-proton AB quartets near d 2.7 and 3.0 as-
signable to the two methylene protons, whereas those of 7–
9 show two two-proton singlets near d 3.4 and 4.3 due to
the two methylene protons. The 13C-NMR spectra of 4–6
show a signal near d 52 due to the C-4 carbon of pyrazole
ring and a signal near d 114 due to the cyano carbon,
whereas those of 7–9 show a signal near d 111 due to the
C-4 carbon of pyrazole ring and a signal near d 111 due
to the cyano carbon. The 1H-NMR spectra of 11a,b
in deuteriochloroform exhibit a one-proton singlet near
d 8.1 assignable to the H-6 proton of pyridazine ring. The
13C-NMR spectra of 11a,b show a signal near d 119 due
to the C-4 carbon of pyridazine ring and a signal near
d 146 due to the C-6 carbon of pyridazine ring.
To understand better the formation of 4-pyridazine-
acetic acids 10–11, we examined the conversion of 3-py-
razoline-4-acetic acid 7a into 4-pyridazineacetic acids 10a
in the presence of a base. After some optimization, the best
result was obtained when 7a was treated with sodium
hydride in N,N-dimethylformamide at 80ꢀC for 2 h, and
the expected compound 10a was isolated in 75% yield
(entry 1 in Table 3). The use of several other bases, e.g.,
potassium carbonate and potassium tert-butoxide, resulted
in lower yields (entries 2 and 3 in Table 3).
With the optimized reaction conditions in hand, we car-
ried out the ring expansion of 7b, 8a,b, and 9a,b under the
sodium hydride/N,N-dimethylformamide combination.
The results are listed in Table 4. In fact, the desired com-
pounds 10b, 11a,b, and 12a,b were obtained in moderate
to good yields. These products 10a,b, and 12a,b were char-
acterized by IR, 1H-NMR, 13C-NMR, mass, and elemental
analyses (Experimental section). In addition, compound
11a,b was confirmed by direct comparison with authentic
samples prepared from 2a,b and chloroacetonitrile as de-
scribed above.
Table 3
Table 2
Ring expansion of 7a into 10a in the presence of bases.
Reaction of 1–3 with chloroacetonitrile according to Scheme 3.
Entries Substrate R1
R2
Products Yields (%)
1
2
3
4
5
6
1a
1b
2a
2b
3a
3b
Me
Et
Ph
Ph
4a/7a/10a 0/36/0
4b/7b/10b 0/34/0
Entries
Base (equiv.)
Conditions
Yield (%) of 10a
Me 4-NO2-C6H4 5a/8a/11a 0/0/18
Et 4-NO2-C6H4 5b/8b/11b 0/12/8
Me 4-MeO-C6H4 6a/9a/12a 9/21/0
Et 4-MeO-C6H4 6b/9b/12b 6/24/0
1
2
3
NaH (1.0)
K2CO3 (2.0)
tBuOK (2.0)
80ꢀC, 2 h
120ꢀC, 2 h
120ꢀC, 2 h
75
63
55
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

896
E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, R. Tomita, T. Fujioka, and K. Yamagata
Vol 49
1H-NMR (deuteriochloroform): d 1.22 (t, J = 7.0 Hz, 3H,
CO2CH2Me), 2.18 (s, 3H, 3-Me), 2.93–3.02 (m, 2H,
CH2CO2CH2Me), 3.56–3.58 (m, 1H, 4-H), 4.16 (q, J = 7.0
Hz, 2H, CO2CH2Me), 8.04–8.16 (m, 2H, Ph-H), 8.25–8.28
ppm (m, 2H, Ph-H); 13C-NMR (deuteriochloroform): d 14.0
(CO2CH2Me), 15.7 (3-Me), 31.5 (CH2CO2CH2Me), 48.7 (C-4),
61.6 (CO2CH2Me), 117.9, 124.8, 143.2, 144.0 (Ph-C), 159.8
(C-3), 169.6 (CO2CH2Me), 172.7 ppm (C-5); ms: m/z 306
[M+H]+. Anal. Calcd. for C14H15N3O5: C, 55.08; H, 4.95; N,
13.76. Found: C, 55.15; H, 4.97; N, 13.71.
Table 4
Ring expansion of 7–9 into 10–12 in the presence of sodium hydride.
Entries Substrate R1
R2
Products Yield (%)
4,5-Dihydro-5-hydroxy-1-(4-methoxyphenyl)-3-methyl-1H-
pyrazole-4-acetic acid methyl ester (3a). This compound was
obtained as colorless needles (75%), mp 114–117ꢀC (acetone–
petroleum ether); IR (potassium bromide): n 3359 (OH), 1730
1
7a
7b
8a
8b
9a
9b
Me
Et
Ph
Ph
10a
10b
11a
11b
12a
12b
75
84
61
45
42
45
2
3
4
5
6
Me 4-NO2-C6H4
Et 4-NO2-C6H4
Me 4-MeO-C6H4
Et 4-MeO-C6H4
1
cmÀ1 (C=O); H-NMR (deuteriochloroform): d 2.22 (s, 3H, 3-
Me), 3.45 (s, 2H, CH2CO2Me), 3.61 (s, 3H, CO2Me), 3.75 (s,
3H, OMe), 6.81–6.84 (m, 2H, Ph-H), 741–7.43 (m, 2H, Ph-H),
10.62 ppm (br, 1H, OH); 13C-NMR (deuteriochloroform):
d 10.6 (3-Me), 27.3 (CH2CO2Me), 52.1 (CO2Me), 55.5 (OMe),
97.2 (C-4), 114.3, 124.6, 127.1 (Ph-C), 146.1 (C-3), 157.2
(C-5), 159.2 (Ph-C), 171.3 ppm (CO2Me); ms: m/z 277
[M+H]+. Anal. Calcd. for C14H16N2O4: C, 60.86; H, 5.84; N,
10.14. Found: C, 60.85; H, 5.89; N, 10.15.
In conclusion, we have demonstrated the C- and N-
cyanomethylation reaction of 1H-pyrazole-4-acetic acids
1–3. Furthermore, we have developed a novel method for
the construction of 4-pyridazineacetic acids 10–12 from
N-cyanomethylated 3-pyrazoline-4-acetic acids 7–9 via a
ring expansion. Functionalized pyrazole and pyridazine
derivatives are important synthons in organic synthesis and
for the preparation of biologically active compounds with
interest in medicinal chemistry. Further synthetic applica-
tions for pyrazole and pyridazine derivatives are in progress.
4,5-Dihydro-1-(4-methoxyphenyl)-3-methyl-5-oxo-1H-pyrazole-
4-acetic acid ethyl ester and its isomer (3b). This
compound was obtained as pale red needles (86%), mp 125–
127ꢀC (acetone–petroleum ether); IR (potassium bromide): n
1725, 1623 cmÀ1 (C=O); 1H-NMR (deuteriochloroform):
d 1.22 (t, J = 7.3 Hz, 1.3H, CO2CH2Me), 1.28 (t, J =
7.3 Hz, 1.7H, CO2CH2Me), 2.116, 2.121 (s, 3H, 3-Me),
2.85–2.95 (m, 0.86H, CH2CO2CH2Me), 3.40 (s, 1.14H,
CH2CO2CH2Me), 3.50–3.53 (m, 0.43H, 4-H), 3.79, 3.80
(s, 3H, OMe), 4.14–4.20 (m, 2H, CO2CH2Me), 6.85–6.88
(m, 1.14H, Ph-H), 6.90–6.93 (m, 0.86H, Ph-H), 7.26–7.52
(m, 1.14H, Ph-H), 7.53–7.76 (m, 0.86H, Ph-H), 9.61 ppm (br,
0.57H, OH); 13C-NMR (deuteriochloroform): d 11.8 (3-Me),
14.0 (CO2CH2Me), 15.6 (3-Me), 28.7, 31.7 (CH2CO2CH2Me),
48.4 (C-4), 55.42, 55.45 (OMe), 61.4, 61.5 (CO2CH2Me), 95.3
(C-4), 114.0, 120.8, 123.0, 130.9, 131.5 (Ph-C), 147.0 (C-3), 156.4
(C-5), 157.1, 157.7 (Ph-C), 158.4 (C-3), 169.9 (CO2CH2Me),
171.9 (C-5), 173.3 ppm (CO2CH2Me); ms: m/z 291 [M+H]+. Anal.
Calcd. for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C,
62.12; H, 6.28; N, 9.67.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were
recorded on a JASCO FTIR-4100 spectrometer. The 1H and
13C-NMR spectra were recorded on a JEOL JNM-A500 spec-
trometer at 500 and 125 MHz, respectively. The 1H and 13C
chemical shifts (d) are reported in parts per million (ppm) rela-
tive to tetramethylsilane as internal standard. The positive
FAB mass spectra were obtained on a JEOL JMS-700T spec-
trometer. The elemental analyses were performed on
a
YANACO MT-6 CHN analyzer. The starting compounds, 1H-
pyrazole-4-acetic acids 1a [35], 1b [36,37], 2a,b, and 3a,b,
were prepared in this laboratory according to the procedure
reported in literature [35–37].
General procedure for the preparation of C-cyanomethylated
1H-pyrazole-4-acetic acids 4–6 from 1–3 and iodoacetonitrile
in the presence of triethylamine. A mixture of 1–3 (1 mmol),
iodoacetonitrile (0.501 g, 3 mmol), and triethylamine (0.304 g,
3 mmol) in acetonitrile (5 mL) was refluxed for 3 h. To the
reaction mixture, cold water was added with stirring and ice
cooling. The resulting mixture was extracted with ethyl
acetate (60 mL). The extract was dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue
was purified by column chromatography on silica gel with
chloroform as the eluent to give 4a,b, 5a,b, and 6a,b.
Further, the elution afforded 7a,b and 8a,b (see Table 1).
4-(Cyanomethyl)-4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-
pyrazole-4-acetic acid methyl ester (4a). This compound was
obtained as colorless prisms (0.185 g, 65%), mp 69–71ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 2255
4,5-Dihydro-3-methyl-1-(4-nitrophenyl)-5-oxo-1H-pyrazole-
4-acetic acid methyl ester (2a). This compound was obtained
as yellow needles (70%), mp 155–156ꢀC (acetone–petroleum
ether); IR (potassium bromide): n 1731, 1634 cmÀ1 (C=O);
1H-NMR (deuteriochloroform): d 2.18 (s, 3H, 3-Me), 2.98–2.99
(m, 2H, CH2CO2Me), 3.57–3.60 (m, 1H, 4-H), 3.72 (s, 3H,
CO2Me), 8.13–8.16 (m, 2H, Ph-H), 8.25–8.28 ppm (m, 2H,
Ph-H); 13C-NMR (deuteriochloroform): d 15.7 (3-Me), 31.3
(CH2CO2Me), 48.6 (C-4), 52.5 (CO2Me), 117.9, 124.8, 143.1,
144.1 (Ph-C), 159.7 (C-3), 170.2 (CO2Me), 172.7 ppm (C-5);
ms: m/z 292 [M+H]+. Anal. Calcd. for C13H13N3O5: C, 53.61; H,
4.50; N, 14.43. Found: C, 53.78; H, 4.72; N, 14.16.
4,5-Dihydro-3-methyl-1-(4-nitrophenyl)-5-oxo-1H-pyrazole-
4-acetic acid ethyl ester (2b). This compound was obtained as
brown needles (80%), mp 148–149ꢀC (acetone–petroleum
ether);IR (potassium bromide): n 1734, 1632 cmÀ1 (C=O);
1
(CN), 1739, 1715 cmÀ1 (C=O); H-NMR (deuteriochloroform):
d 2.23 (s, 3H, 3-Me), 2.72 (AB q, J = 16.8 Hz, 2H, CH2CN),
2.95 (AB q, J = 16.5 Hz, 2H, CH2CO2Me), 3.63 (s, 3H,
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DOI 10.1002/jhet

July 2012
A Novel Synthesis of 4-Pyridazineacetic Acids via Ring Expansion of
N-Cyanomethylated 3-Pyrazoline-4-acetic Acids
897
CO2Me), 7.20–7.23 (m, 1H, Ph-H), 7.39–7.42 (m, 2H, Ph-H),
7.85–7.87 ppm (m, 2H, Ph-H); 13C-NMR (deuteriochloroform):
d 14.3 (3-Me), 23.0 (CH2CN), 36.9 (CH2CO2Me), 51.7 (C-4),
52.4 (CO2Me), 114.4 (CN), 119.3, 125.7, 128.9, 137.5 (Ph-C),
158.6 (C-3), 168.3 (CO2Me), 171.7 ppm (C-5); ms: m/z 286
[M+H]+. Anal. Calcd. for C15H15N3O5Á0.5H2O: C, 61.22; H,
5.48; N, 14.28. Found: C, 61.07; H, 5.21; N, 14.17.
13C-NMR (deuteriochloroform): d 14.3 (3-Me), 23.0 (CH2CN),
37.0 (CH2CO2Me), 51.5 (C-4), 52.4 (CO2Me), 55.5 (OMe), 114.2
(Ph-C), 114.5 (CN), 121.3, 130.8, 157.6 (Ph-C), 158.4 (C-3),
168.3 (CO2Me), 171.4 ppm (C-5); ms: m/z 315 [M+H]+.
Anal. Calcd. for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33.
Found: C, 60.95; H, 5.47; N, 13.33.
4-(Cyanomethyl)-4,5-dihydro-1-(4-methoxyphenyl)-3-methyl-
5-oxo-1H-pyrazole-4-acetic acid ethyl ester (6b). This compound
was obtained as colorless scales (0.096 g, 29%), mp 95–97ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 2253
(CN), 1725, 1704 cmÀ1 (C=O); 1H-NMR (deuteriochloroform):
d 1.16 (t, J = 7.3 Hz, 3H, CO2CH2Me), 2.30 (s, 3H, 3-Me),
2.72 (AB q, J = 17.1 Hz, 2H, CH2CN), 2.93 (AB q, J = 16.5
Hz, 2H, CH2CO2CH2Me), 3.81 (s, 3H, OMe), 4.09 (q, J =
7.3 Hz, 2H, CO2CH2Me), 6.92–6.94 (m, 2H, Ph-H), 7.73–
7.75 ppm (m, 2H, Ph-H); 13C-NMR (deuteriochloroform):
d 13.9 (CO2CH2Me), 14.3 (3-Me), 23.1 (CH2CN), 37.3
(CH2CO2CH2Me), 51.6 (C-4), 55.5 (OMe), 61.6 (CO2CH2Me),
114.1 (Ph-C), 114.5 (CN), 121.2, 130.8, 157.6 (Ph-C), 158.5
(C-3), 167.8 (CO2CH2Me), 171.4 ppm (C-5); ms: m/z 329
[M+H]+. Anal. Calcd. for C17H19N3O4: C, 62.00; H, 5.81; N,
12.76. Found: C, 62.02; H, 5.81; N, 12.82.
2-(Cyanomethyl)-3-methyl-5-oxo-1-phenyl-3-pyrazoline-4-
acetic acid methyl ester (7a). This compound was obtained as
colorless prisms (0.079 g, 28%), mp 93–95ꢀC (chloroform–
petroleum ether); IR (potassium bromide): n 2251 (CN), 1738,
1676 cmÀ1 (C=O); 1H-NMR (deuteriochloroform): d 2.28
(s, 3H, 3-Me), 3.42 (s, 2H, CH2CO2Me), 3.70 (s, 3H, CO2Me),
4.29 (s, 2H, NCH2CN), 7.29–7.32 (m, 1H, Ph-H), 7.40–
7.48 ppm (m, 4H, Ph-H); 13C-NMR (deuteriochloroform):
d 11.4 (3-Me), 27.9 (CH2CO2Me), 37.4 (NCH2CN), 52.2
(CO2Me), 110.9 (C-4), 111.8 (CN), 123.3, 127.1, 129.5,
134.3 (Ph-C), 154.0 (C-3), 165.5 (C-5), 170.3 ppm (CO2Me);
ms: m/z286 [M+H]+. Anal. Calcd. for C15H15N3O5Á0.15H2O:
C, 62.56; H, 5.35; N, 14.59. Found: C, 62.56; H, 5.23; N,
14.66.
4-(Cyanomethyl)-4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-
pyrazole-4-acetic acid ethyl ester (4b). This compound was
obtained as colorless scales (0.206 g, 69%), mp 93–95ꢀC
(chloroform-petroleum ether); IR (potassium bromide): n 2252
1
(CN), 1733, 1715 cmÀ1 (C=O); H-NMR (deuteriochloroform):
d 1.15 (t, J = 7.0 Hz, 3H, CO2CH2Me), 2.25 (s, 3H, 3-Me),
2.72 (AB q, J = 16.8 Hz, 2H, CH2CN), 2.95 (AB q, J =
16.5 Hz, 2H, CH2CO2CH2Me), 4.03 (q, J = 7.0 Hz, 2H,
CO2CH2Me), 7.20–7.26 (m, 1H, Ph-H), 7.39–7.42 (m,
2H, Ph-H), 7.86–7.89 ppm (m, 2H, Ph-H); 13C-NMR
(deuteriochloroform):
d 13.9 (CO2CH2Me), 14.4 (3-Me),
23.2 (CH2CN), 37.3 (CH2CO2CH2Me), 51.8 (C-4), 61.7
(CO2CH2Me), 114.5 (CN), 119.2, 125.7, 128.9, 137.5 (Ph-C),
158.7 (C-3), 167.7 (CO2CH2Me), 171.7 ppm (C-5); ms: m/z 300
[M+H]+. Anal. Calcd. for C16H17N3O3: C, 64.20; H, 5.72; N,
14.04. Found: C, 64.21; H, 5.78; N, 14.03.
4-(Cyanomethyl)-4,5-dihydro-3-methyl-1-(4-nitrophenyl)-5-
oxo-1H-pyrazole-4-acetic acid methyl ester (5a). This compound
was obtained as yellow prisms (0.205 g, 62%), mp 160–162ꢀC
(chloroform-petroleum ether); IR (potassium bromide): n 2259
(CN), 1736, 1719 cmÀ1 (C=O); 1H-NMR (deuteriochloroform):
d 2.28 (s, 3H, 3-Me), 2.77 (AB q, J = 16.8 Hz, 2H, CH2CN),
3.02 (AB q, J = 17.1 Hz, 2H, CH2CO2Me), 3.65 (s, 3H,
CO2Me), 8.13–8.15 (m, 2H, Ph-H), 8.27–8.29 ppm (m, 2H,
Ph-H); 13C-NMR (deuteriochloroform): d 14.4 (3-Me), 23.2
(CH2CN), 37.1 (CH2CO2Me), 52.0 (C-4), 52.6 (CO2Me), 114.0
(CN), 118.3, 124.9, 142.5, 144.5 (Ph-C), 160.0 (C-3), 168.3
(CO2Me), 172.3 ppm (C-5); ms: m/z 331 [M+H]+. Anal. Calcd.
for C15H14N4O5: C, 54.55; H, 4.27; N, 16.96. Found: C, 54.35;
H, 4.37; N, 16.83.
4-(Cyanomethyl)-4,5-dihydro-3-methyl-1-(4-nitrophenyl)-
5-oxo-1H-pyrazole-4-acetic acid ethyl ester (5b). This
compound was obtained as yellow prisms (0.210 g, 61%),
mp 139–141ꢀC (chloroform–petroleum ether); IR (potassium
bromide): n 2251 (CN), 1734, 1720 cmÀ1 (C=O); 1H-NMR
(deuteriochloroform): d 1.56 (t, J = 7.0 Hz, 3H, CO2CH2Me),
2.28 (s, 3H, 3-Me), 2.76 (AB q, J = 17.1 Hz, 2H, CH2CN),
3.00 (AB q, J = 16.8 Hz, 2H, CH2CO2CH2Me), 4.09 (q, J =
7.0 Hz, 2H, CO2CH2Me), 8.13–8.16 (m, 2H, Ph-H), 8.26–
8.29 ppm (m, 2H, Ph-H); 13C-NMR (deuteriochloroform):
d 13.9 (CO2CH2Me), 14.4 (3-Me), 23.2 (CH2CN), 37.4
(CH2CO2CH2Me), 52.1 (C-4), 61.9 (CO2CH2Me), 114.0
(CN), 118.3, 124.9, 142.5, 144.5 (Ph-C), 159.8 (C-3), 167.6
(CO2CH2Me), 172.4 ppm (C-5); ms: m/z 345 [M+H]+. Anal.
Calcd. for C16H16N4O5Á0.3H2O: C, 54.95; H, 4.78; N, 16.02.
Found: C, 54.96; H, 4.64; N, 15.97.
2-(Cyanomethyl)-3-methyl-5-oxo-1-phenyl-3-pyrazoline-4-
acetic acid ethyl ester (7b). This compound was obtained as
colorless prisms (0.027 g, 9%), mp 109–111ꢀC (chloroform–
petroleum ether); IR (potassium bromide): n 2251 (CN), 1734,
1677 cmÀ1 (C=O); 1H-NMR (deuteriochloroform): d 1.26 (t,
J = 7.0 Hz, 3H, CO2CH2Me), 2.28 (s, 3H, 3-Me), 3.40 (s, 2H,
CH2CO2CH2Me), 4.16 (q, J = 7.0 Hz, 2H, CO2CH2Me), 4.29
(s, 2H, NCH2CN), 7.29–7.32 (m, 1H, Ph-H), 7.40–7.47 ppm
(m, 4H, Ph-H); 13C-NMR (deuteriochloroform):
d 11.4
(3-Me), 14.1 (CO2CH2Me), 28.1 (CH2CO2CH2Me), 37.4
(NCH2CN), 61.2 (CO2CH2Me), 111.0 (C-4), 111.8 (CN),
123.3, 127.1, 129.5, 134.3 (Ph-C), 154.0 (C-3), 165.6 (C-5),
170.0 ppm (CO2CH2Me); ms: m/z 300 [M+H]+. Anal. Calcd.
for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C,
64.19; H, 5.79; N, 14.06.
2-(Cyanomethyl)-3-methyl-1-(4-nitrophenyl)-5-oxo-1-phenyl-
3-pyrazoline-4-acetic acid methyl ester (8a). This compound
was obtained as pale yellow needles (0.050 g, 15%),
mp 187–189ꢀC (chloroform–petroleum ether); IR (potassium
bromide): n 2252 (CN), 1744, 1689 cmÀ1 (C=O); 1H-NMR
(deuteriochloroform): d 2.32 (s, 3H, 3-Me), 3.43 (s, 2H,
CH2CO2Me), 3.72 (s, 3H, CO2Me), 4.36 (s, 2H, NCH2CN),
7.63–7.65 (m, 2H, Ph-H), 8.32–8.34 ppm (m, 2H, Ph-H);
4-(Cyanomethyl)-4,5-dihydro-1-(4-methoxyphenyl)-3-methyl-
5-oxo-1H-pyrazole-4-acetic acid methyl ester (6a). This
compound was obtained as colorless scales (0.114 g, 36%),
mp 138–140ꢀC (chloroform–petroleum ether); IR (potassium
bromide): n 2259 (CN), 1720, 1703 cmÀ1 (C=O); 1H-NMR
(deuteriochloroform): d 2.26 (s, 3H, 3-Me), 2.73 (AB q, J =
17.1 Hz, 2H, CH2CN), 2.94 (AB q, J = 16.8 Hz, 2H,
CH2CO2Me), 3.64 (s, 3H, CO2Me), 3.81 (s, 3H, OMe),
6.92–6.95 (m, 2H, Ph-H), 7.71–7.74 ppm (m, 2H, Ph-H);
13C-NMR (deuteriochloroform):
d
11.6 (3-Me), 27.8
(CH2CO2Me), 38.2 (NCH2CN), 52.3 (CO2Me), 111.2 (CN),
111.6 (C-4), 121.6, 125.1, 139.9, 145.3 (Ph-C), 156.5 (C-3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

898
E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, R. Tomita, T. Fujioka, and K. Yamagata
Vol 49
165.6 (C-5), 169.8 ppm (CO2Me); ms: m/z 331 [M+H]+. Anal.
Calcd. for C15H14N4O5: C, 54.55; H, 4.27; N, 16.96. Found:
C, 54.50; H, 4.31; N, 16.96.
(5 mL), 60% of sodium hydride (0.040 g, 1 mmol) was added.
The stirring was continued at room temperature until
evolution of gas ceased, and then the mixture was stirred at
80ꢀC for 1 h. After the removal of the solvent in vacuo, cold
water was added to the residue. The resulting mixture was
extracted with chloroform (60 mL). The extract was dried
over anhydrous sodium sulfate and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel with chloroform as the eluent to afford 10a,b, 11a,b, and
12a,b.
2,3-Dihydro-5-methyl-3-oxo-2-phenyl-4-pyridazineacetic acid
methyl ester (10a). This compound was obtained as pale
yellow oil (0.194 g, 75%); IR (neat): n 1738, 1669 cmÀ1
(C=O); 1H-NMR (deuteriochloroform): d 2.36 (s, 3H, 5-Me),
3.64 (s, 2H, CH2CO2Me), 3.71 (s, 3H, CO2Me), 7.35–7.37
(m, 2H, Ph-H), 7.44–7.52 (m, 3H, Ph-H), 8.06 ppm (s, 1H,
6-H); 13C-NMR (deuteriochloroform): d 21.7 (5-Me), 31.5
(CH2CO2Me), 52.1 (CO2Me), 119.0 (C-4), 126.6, 129.2,
129.5, 137.1 (Ph-C), 147.6 (C-6), 160.8 (C-3), 160.9 (C-5),
170.8 ppm (CO2Me); ms: m/z 259 [M+H]+. Anal. Calcd. for
C14H14N2O3Á0.2H2O: C, 64.21; H, 5.54; N, 10.70. Found:
C, 64.28; H, 5.55; N, 10.73.
2,3-Dihydro-5-methyl-3-oxo-2-phenyl-4-pyridazineacetic acid
ethyl ester (10b). This compound was obtained as pale yellow
oil (0.228 g, 84%); IR (neat): n 1732, 1667 cmÀ1 (C=O);
1H-NMR (deuteriochloroform): d 1.26 (t, J = 7.0 Hz, 3H,
CO2CH2Me), 2.36 (s, 3H, 5-Me), 3.63 (s, 2H, CH2CO2CH2Me),
4.17 (q, J = 7.0 Hz, 2H, CO2CH2Me), 7.36–7.37 (m, 2H, Ph-H),
7.36–7.52 (m, 3H, Ph-H), 8.05 ppm (s, 1H, 6-H); 13C-NMR
(deuteriochloroform): d 14.1 (CO2CH2Me), 21.7 (5-Me), 31.7
(CH2CO2CH2Me), 60.9 (CO2CH2Me), 119.1 (C-4), 126.6,
129.1, 129.4, 137.1 (Ph-C), 147.5 (C-6), 160.8 (C-3), 160.9
(C-5), 170.3 ppm (CO2CH2Me); ms: m/z 273 [M+H]+. Anal.
Calcd. for C15H16N2O3Á0.3H2O: C, 64.88; H, 6.03; N, 10.09.
Found: C, 64.81; H, 5.96; N, 10.10.
2,3-Dihydro-5-methyl-1-(4-nitrophenyl)-3-oxo-2-phenyl-4-
pyridazineacetic acid methyl ester (11a). This compound was
obtained as pale brown needles (0.185 g, 61%), mp 183–185ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 1737,
1676 cmÀ1 (C=O); 1H-NMR (deuteriochloroform): d 2.38
(s, 3H, 5-Me), 3.64 (s, 2H, CH2CO2Me), 3.72 (s, 3H, CO2Me),
7.61–7.63 (m, 2H, Ph-H), 8.07 (s, 1H, 6-H), 8.37–8.39 ppm (m,
2H, Ph-H); 13C-NMR (deuteriochloroform): d 21.7 (5-Me), 31.4
(CH2CO2Me), 52.2 (CO2Me), 119.3 (C-4), 124.8, 127.7, 142.1
(Ph-C), 146.3 (C-6), 147.9 (Ph-C), 160.2 (C-3), 161.4 (C-5),
170.5 ppm (CO2Me); ms: m/z 304 [M+H]+. Anal. Calcd. for
C14H13N3O5Á0.2H2O: C, 54.79; H, 4.40; N, 13.69. Found: C,
54.79; H, 4.38; N, 13.75.
2-(Cyanomethyl)-3-methyl-1-(4-nitrophenyl)-5-oxo-1-phenyl-
3-pyrazoline-4-acetic acid ethyl ester (8b). This compound was
obtained as colorless needles (0.040 g, 12%), mp 166–168ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 2248
(CN), 1735, 1686 cmÀ1 (C=O); 1H-NMR (deuteriochloroform):
d 1.27 (t, J = 7.3 Hz, 3H, CO2CH2Me), 2.32 (s, 3H, 3-Me), 3.41
(s, 2H, CH2CO2CH2Me), 4.17 (q, J = 7.3 Hz, 2H, CO2CH2Me),
4.34 (s, 2H, NCH2CN), 7.63–7.65 (m, 2H, Ph-H), 8.32–8.34 ppm
(m, 2H, Ph-H); 13C-NMR (deuteriochloroform): d 11.6 (3-Me),
14.1 (CO2CH2Me), 28.1 (CH2CO2CH2Me), 38.2 (NCH2CN),
61.4 (CO2CH2Me), 111.2 (CN), 111.8 (C-4), 121.6, 125.2,
140.0, 145.3 (Ph-C), 156.4 (C-3), 165.6 (C-5), 169.4 ppm
(CO2CH2Me); ms: m/z 345 [M+H]+. Anal. Calcd. for
C16H16N4O5: C, 55.81; H, 4.68; N, 16.27. Found: C, 55.71; H,
4.73; N, 16.29.
General procedure for the preparation of N-cyanomethylated
3-pyrazoline-4-acetic acids 7–9 from 1–3 and chloroacetonitrile
in the presence of triethylamine. A mixture of 1–3 (1 mmol),
chloroacetonitrile (0.227 g, 3 mmol), and triethylamine (0.304 g,
3 mmol) in chloroform (5 mL) was refluxed for 3 h. To the
reaction mixture, cold water was added with stirring and ice
cooling. The resulting mixture was extracted with chloroform
(60 mL). The extract was dried over anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified by
column chromatography on silica gel with chloroform as the
eluent to yield 7a,b, 11a, 8b, and 6a,b. Further, the elution
provided 11b and 9a,b (see Table 2).
2-(Cyanomethyl)-1-(4-methoxyphenyl)-3-methyl-5-oxo-1-
phenyl-3-pyrazoline-4-acetic acid methyl ester (9a). This
compound was obtained as pale brown needles (0.067 g, 21%),
mp 132–134ꢀC (chloroform–petroleum ether); IR (potassium
bromide): n 2253 (CN), 1752, 1671 cmÀ1 (C=O); 1H-NMR
(deuteriochloroform): d 2.26 (s, 3H, 3-Me), 3.41 (s, 2H,
CH2CO2Me), 3.70 (s, 3H, CO2Me), 3.83 (s, 3H, OMe), 4.24
(s, 2H, NCH2CN), 6.97–6.99 (m, 2H, Ph-H), 7.30–7.32 ppm (m,
2H, Ph-H); 13C-NMR (deuteriochloroform): d 11.3 (3-Me), 27.9
(CH2CO2Me), 37.0 (NCH2CN), 52.2 (CO2Me), 55.6 (OMe),
110.5 (CN), 111.9 (C-4), 115.0, 126.1, 126.8 (Ph-C), 153.2
(C-3), 159.1 (Ph-C), 165.7 (C-5), 170.4 ppm (CO2Me); ms:
m/z 316 [M+H]+. Anal. Calcd. for C16H17N3O4: C, 60.94; H,
5.43; N, 13.33. Found: C, 60.80; H, 5.41; N, 13.57.
2-(Cyanomethyl)-1-(4-methoxyphenyl)-3-methyl-5-oxo-1-phenyl-
3-pyrazoline-4-acetic acid ethyl ester (9b). This compound
was obtained as colorless columns (0.079 g, 24%), mp 109–111ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 2248 (CN),
1741, 1668, 1651 cmÀ1 (C=O); 1H-NMR (deuteriochloroform):
d 1.26 (t, J = 7.3 Hz, 3H, CO2CH2Me), 2.26 (s, 3H, 3-Me), 3.40
(s, 2H, CH2CO2CH2Me), 3.83 (s, 3H, OMe), 4.16 (q, J = 7.3 Hz, 2H,
CO2CH2Me), 4.24 (s, 2H, NCH2CN), 6.97–6.99 (m, 2H, Ph-H), 7.30–
7.32 ppm (m, 2H, Ph-H); 13C-NMR (deuteriochloroform): d 11.4
(3-Me), 14.1 (CO2CH2Me), 28.1 (CH2CO2CH2Me), 37.0 (NCH2CN),
55.6 (OMe), 61.2 (CO2CH2Me), 110.6 (C-4), 111.9 (CN),
114.9, 126.1, 126.9 (Ph-C), 153.2 (C-3), 159.1 (Ph-C), 165.7
(C-5), 170.0 ppm (CO2CH2Me); ms: m/z 330 [M+H]+. Anal.
Calcd. for C17H19N3O4: C, 62.00; H, 5.81; N, 12.76. Found: C,
62.00; H, 5.81; N, 12.78.
2,3-Dihydro-5-methyl-1-(4-nitrophenyl)-3-oxo-2-phenyl-4-
pyridazineacetic acid ethyl ester (11b). This compound was
obtained as pale yellow scales (0.143 g, 45%), mp 157–159ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 1735,
1665 cmÀ1 (C=O); 1H-NMR (deuteriochloroform): d 1.28 (t,
J = 7.0 Hz, 3H, CO2CH2Me), 2.38 (s, 3H, 5-Me), 3.63 (s, 2H,
CH2CO2CH2Me), 4.19 (q, J = 7.0 Hz, 2H, CO2CH2Me), 7.27–
7.62 (m, 2H, Ph-H), 8.06 (s, 1H, 6-H), 8.37–8.39 ppm (m, 2H,
Ph-H); 13C-NMR (deuteriochloroform): d 14.2 (CO2CH2Me),
21.8 (5-Me), 31.6 (CH2CO2CH2Me), 61.2 (CO2CH2Me), 119.5
(C-4), 124.8, 127.7, 142.2 (Ph-C), 146.3 (C-6), 147.9 (Ph-C),
160.2 (C-3), 161.4 (C-5), 170.0 ppm (CO2CH2Me); ms:
m/z 318 [M+H]+. Anal. Calcd. for C15H15N3O5: C, 56.78; H,
4.76; N, 13.24. Found: C, 56.69; H, 4.77; N, 13.29.
General procedure for the preparation of 4-pyridazineacetic
acids 10–12 from 7–9 and sodium hydride. To an ice-cooled
and stirred solution of 7–9 (1 mmol) in N,N-dimethylformamide
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
A Novel Synthesis of 4-Pyridazineacetic Acids via Ring Expansion of
N-Cyanomethylated 3-Pyrazoline-4-acetic Acids
899
[10] Schmidt, D.; Smenton, A.; Raghavan, S.; Carballo-Jane, E.;
Lubell, S.; Ciecko, T.; Holt, T. G.; Wolff, M.; Taggart, A.; Wilsie, L.;
Krsmanovic, M.; Ren, N.; Blom, D.; Cheng, K.; McCann, P. E.; Waters,
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Chem 2001, 80, 73.
2,3-Dihydro-1-(4-methoxyphenyl)-5-methyl-3-oxo-2-phenyl-
4-pyridazineacetic acid methyl ester (12a). This compound was
obtained as colorless needles (0.120 g, 42%), mp 78–80ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 1732,
1
1720, 1665 cmÀ1 (C=O); H-NMR (deuteriochloroform): d 2.35
(s, 3H, 5-Me), 3.64 (s, 2H, CH2CO2Me), 3.71 (s, 3H, CO2Me),
3.84 (s, 3H, OMe), 6.98–7.00 (m, 2H, Ph-H), 7.26–7.28 (m, 2H,
Ph-H), 8.04 ppm (s, 1H, 6-H); 13C-NMR (deuteriochloroform):
d 21.7 (5-Me), 31.5 (CH2CO2Me), 52.1 (CO2Me), 55.6 (OMe),
114.7 (Ph-C), 118.9 (C-4), 127.7, 129.8 (Ph-C), 147.9 (C-6),
160.1 (Ph-C), 160.9 (C-3), 161.1 (C-5), 170.8 ppm (CO2Me);
ms: m/z 289 [M+H]+. Anal. Calcd. for C15H16N2O4: C, 62.49;
H, 5.59; N, 9.72. Found: C, 62.38; H, 5.67; N, 9.68.
[14] Elguero, J. InComprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
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S.; Strappaghetti, G. Bioorg Med Chem 2006, 14, 2828.
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Manetti, F.; Strappaghetti, G.; Botta, M. J Med Chem 2003, 46, 3555.
[17] Li, C. S.; Brideau, C.; Chan, C. C.; Savoie, C.; Claveau, D.;
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Riendeau, D.; Thérien, M.; Wong, E.; Prasit, P. Bioorg Med Chem Lett
2003, 13, 597.
2,3-Dihydro-1-(4-methoxyphenyl)-5-methyl-3-oxo-2-phenyl-
4-pyridazineacetic acid ethyl ester (12b). This compound was
obtained as colorless needles (0.137 g, 45%), mp 82–84ꢀC
(chloroform–petroleum ether); IR (potassium bromide): n 1727,
1
1665 cmÀ1 (C=O); H-NMR (deuteriochloroform): d 1.26 (t, J =
7.3 Hz, 3H, CO2CH2Me), 2.35 (s, 3H, 5-Me), 3.62 (s, 2H,
CH2CO2CH2Me), 3.84 (s, 3H, OMe), 4.17 (q, J = 7.3 Hz, 2H,
CO2CH2Me), 6.98–7.00 (m, 2H, Ph-H), 7.26–7.28 (m, 2H,
Ph-H), 8.03 ppm (s, 1H, 6-H); 13C-NMR (deuteriochloroform):
d 14.1 (CO2CH2Me), 21.7 (5-Me), 31.7 (CH2CO2CH2Me), 55.6
(OMe), 61.0 (CO2CH2Me), 114.7 (Ph-C), 119.1 (C-4), 127.7,
129.9 (Ph-C), 147.9 (C-6), 160.0 (Ph-C), 160.8 (C-3), 161.1
(C-5), 170.3 ppm (CO2CH2Me); ms: m/z 303 [M+H]+. Anal.
Calcd. for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27. Found: C,
63.46; H, 6.02; N, 9.26.
[18] Barbaro, R.; Betti, L.; Botta, M.; Corelli, F.; Giannaccini, G.;
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Acknowledgments. The authors thank Hiroshi Hanazono and
Yukiko Iwase for obtaining Mass and NMR spectra and to
Junko Honda for her valuable help with elemental analyses.
[26] Clapham, K. M.; Batsanov, A. S.; Greenwood, R. D. R.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet