Contributions to the chemistry of 3-cyanoacetylhydrazono-2-indolinones and x-ray structure of z-3-cyanoacetylhydrazono-2-indolinone monohydrate

Article abstract of DOI:10.1002/hc.20531

The tendency of acylhydrazones to undergo a spontaneous cyclization into 1,3,4-oxadiazolines has been investigated. Contrary to the literature data, an attempted transformation of isatin cyanoacetylhydrazone in solution generates stereoisomers and not the

Full text of DOI:10.1002/hc.20531

Heteroatom Chemistry
Volume 20, Number 4, 2009
Contributions to the Chemistry
of 3-Cyanoacetylhydrazono-2-indolinones and
X-ray Structure of Z-3-Cyanoacetylhydrazono-
2-indolinone Monohydrate
La´szlo´ Somogyi1 and Attila Csaba Be´nyei2
1Department of Organic Chemistry, University of Debrecen, P.O. Box 20,
H-4010 Debrecen, Hungary
2Department of Physical Chemistry, Laboratory for X-ray Diffraction, University of Debrecen,
P.O. Box 7, H-4010 Debrecen
Received 28 January 2009
INTRODUCTION
ABSTRACT: The tendency of acylhydrazones to
undergo
a spontaneous cyclization into 1,3,4-
It is always a challenging problem to verify the
exact structure and electron distribution when
several functional groups capable of conjugation
(C C, C O, aromatic ring) are present in the
same molecule. Cyclic N,O-acetals 3-acyl-1,3,4-
oxadiazolines are 3-acyl derivatives of the cyclic
isomers of aldehyde or ketone acylhydrazones and
represent an interesting example for conjugation.
They can be prepared by cycloaddition of 3,3-
disubstituted diazirenes to diacyldiazenes [1–12],
that of aldehydes to nitrilimines [13], or a ketene to
a ketone acylhydrazone [14]. Other methods to pre-
pare such compounds include Pb(OAc)4 oxidation
of aldazines [15], treating silver salt of acylhydra-
zones with acid chloride [16]. More conveniently,
a reaction of (acyl)hydrazones with acid chlorides
[10,11], as well as with acid anhydrides—either
by itself or in the presence of a base and Lewis
or protic acid, respectively [17–20]—also gives
3-acyl-1,3,4-oxadiazoline derivatives.
oxadiazolines has been investigated. Contrary to the
literature data, an attempted transformation of isatin
cyanoacetylhydrazone in solution generates stereoiso-
mers and not the reported structural isomer oxa-
diazoline. A similar behavior of the corresponding
l-methyl- and l-acetylisatin derivatives even under
acetylation conditions has been found. The crystal
structure of the Z isomer of 3-cyanoacetylhydrazono-
2-indolinone monohydrate is reported. It contains
strong intramolecular hydrogen bond between the hy-
drazone N H and oxygen atom of the indolinone
carbonyl, and in this way the Z isomer over the
ꢀ
C
C N bond is stabilized.
2009 Wiley Periodicals, Inc.
Heteroatom Chem 20:183–193, 2009; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20531
By considering the sulfur analogs, it is known
that some of the thioacylhydrazones cyclize in
the solution spontaneously into the isomeric 2,3-
dihydro-1,3,4-thiadiazoles [21], probably due to
the greater nucleophilicity of S in comparison to
O. For 1,3,4-oxadiazolines, the presence of an acyl
Correspondence to: La´szlo´ Somogyi; e-mail: somoladeszerv@
freemail.hu.
Contract grant sponsor: Hungarian Scientific Research Fund.
Contract grant number: OTKA T037201.
c
ꢀ
2009 Wiley Periodicals, Inc.
183

184 Somogyi and Be´nyei
group at position 3 is essential for the stabilization
of the heterocycle. The 3-acyl-1,3,4-oxadiazolines
are known to transform (sometimes reversibly)
into the isomeric open-chain diacylhydrazones
or substituent-isomeric 3-acyl-1,3,4-oxadiazolines
[9–11,22,23] or to be transacylated [24] via an open-
chain transitional azomethine imine form especially
in polar solvents of high dielectric constant or under
acetylating conditions.
SCHEME 1
Recently, a number of 1,3,4-oxadiazoline deriva-
tives also with free endocyclic NH group have been
published [25–31] and the cyclic structure was
to repeat this questionable reaction converting A
into B and check the structure of the product.
1
suggested on the basis of IR and H NMR spectral
data. Ring-opening transformation into aldehyde
acylhydrazones has also been observed [26] when
1,3,4-oxadiazoline derivatives were simply dissolved
in dimethyl sulfoxide. According to our earlier expe-
RESULTS AND DISCUSSION
In our work, compounds 1–5, the isomers of lower
R (thin layer chromatography, TLC), will be desig-
f
1
riences in the chemistry of oxadiazolines, H NMR
spectra are less informative and comprehensive.
13C NMR investigations are needed for proving
the cyclic structure of 2,2-disubstituted 1,3,4-
oxadiazolines with free NH group, whereas the final
proof for the structure determination could be a
single crystal X-ray diffraction measurement. The
tendency to cyclize even under acylating conditions
depends on the electron distribution of the C N
and NH C O moieties of acylhydrazones and on
steric factors, as well. Thus, in some cases, under
acylating conditions acylhydrazones are transacy-
lated rather than to cyclize into 3-acyloxadiazolines
or transform into diacylhydrazones. Even the
partial deacetylation of a diacetylhydrazone under
acetylating conditions has been described [32].
Isatin aroylhydrazones have been reported
to resist cyclization and gave acetylhydrazones
via transacetylation [33] when they were treated
with boiling Ac2O for 1–36 h. Successful cycliza-
tion of both isatin aroyl- and acetylhydrazones
into the corresponding 1,5ꢁ-disubstituted 3ꢁ-
acetylspiro[oxindole-3,2ꢁ-[1,3,4]oxadiazolines] has
been achieved [20] in Ac2O in the presence of acid
(trifluoroacetic acid, TFA) or base (pyridine, NaOAc)
additives.
nated as a, those of higher ones as b (see Scheme 2).
To perform a valid and comprehensive com-
parison, not only the reported [34] isatin 3-
cyanoacetylhydrazone (la) but the analogous
l-methyl and l-acetyl derivatives (2a and 3a) were
prepared too. To distinguish the isomeric acyl-
hydrazone from the oxadiazoline structures, a
1
detailed analysis of IR-, H-, and 13C NMR spectra
was performed. As it was mentioned earlier for
structure elucidation, the IR spectra of analogous
3-acylhydrazono-2-indolinones were found to be
less informative [20], and because of the lack of an
azomethine or O CHR N acetalic hydrogen also
1
the H NMR spectra are inferior than in the case of
the corresponding aldehyde derivatives [35].
Cyanoacetylhydrazone la, mp 211–212◦C [re-
crystallized from EtOH; [34] mp 230–232◦C (from
EtOH)], was synthesized according to the litera-
ture method [34] by condensing isatin (10) with
cyanoacetohydrazide in EtOH. Compound 1b, mp
205–206◦C, was obtained as an AcOH solvate by
Keeping the above findings in mind, a recent re-
port [34] on the cyclization of isatin cyanoacetylhy-
drazone A (2-cyano-Nꢁ-[(3Z)-2-oxo-1,2-dihydro-3H-
indol-3-ylidene]-acetohydrazide) into the isomeric
spiro[oxindole-3,2ꢁ-[1,3,4]oxadiazoline]
B (2-oxo-
1,2-dihydro-3ꢁ H-spiro[indole-3,2ꢁ [1,3,4]oxadiazol]-
5ꢁ-yl)acetonitrile) by boiling it in acetic acid for
2 h seemed to be a very unusual chemical reaction
(see Scheme 1). Moreover, the product was claimed
to be stable for subsequent transformations with
HNO2, aldehydes, AcOH/Zn, etc. Thus, we decided
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Chemistry of 3-Cyanoacetylhydrazono-2-indolinones and X-ray Structure of Z-3-Cyanoacetylhydrazono-2-indolinone Monohydrate 185
treatment of 1a with boiling AcOH. The paper in
question reports [34] this method to transform
cyanoacetylhydrazone A into spiro-oxadiazoline
B ([34] mp 207–209◦C). According to our results,
compound 1b could also be prepared in poor yield
by condensing 10 with cyanoacetohydrazide in
hot AcOH. Contrary to 1a, isomer 1b was found
to form an AcOH and a pyridine solvate, as well.
Moreover, a partial transformation 1a → 1b in hot
MeO(CH2)2OH (2-methoxyethanol) was observed
(see the section Experimental). Similarly, 1-Me and
1-Ac analogs 2a and 3a were synthesized by con-
densing cyanoacetohydrazide with 1-methylisatin
(11) in MeOH and 1-acetylisatin (12) in EtOAc,
respectively. Transformations a → b could be ef-
fected by recrystallizing 2a from MeO(CH2)2OH or
by treating 2a with Ac2O/TFA to give 2b, as well
as by heating 3a in AcOH or more advantageously
in Ac2O/TFA (see the section Experimental). The
condensation of 12 with cyanoacetohydrazide in
warm AcOH afforded 3b in poor yield.
Although the isomerization of cyanoacetylhy-
drazones 1–3 into spiro-oxadiazolines of type B
was unsuccessful, cyclization of 3-acylhydrazono-2-
indolinones into 1,5ꢁ-disubstituted 3ꢁ-acetylspiro-
[oxindole-3,2ꢁ-[1,3,4]oxadiazolines] has been per-
formed smoothly [20] under acetylating conditions
by treatment with Ac2O in the presence of acid or
base additives. Nevertheless, the treatment with
Ac2O/ZnCl2 at room temperature left both 1a and
1b unreacted (see the section Experimental). As
mentioned above, even the Ac2O/TFA couple was not
suitable for spirocyclization into the corresponding
3-acetyl[1,3,4]-oxadiazolines as this agent generated
merely a → b isomerizations with cyanoacetylhydra-
zones 1–3. A treatment with Ac2O/py or Ac2O/NaOAc
did not affect a spirocyclization of neither 1a, 1b,
or 2a, instead by C-acetylation resulted in the
formation of 2-cyanoacetoacetylhydrazones 4a,b
and 5a,b (see the section Experimental).
subjected to X-ray diffraction studies and was found
to be the Z isomer of 3-cyanoacetylhydrazono-2-
indolinone (Fig. 1) with a strong intramolecular
hydrogen bond between N3 H3 and O1 (see below).
Unfortunately, several attempts to grow X-ray
quality single crystals of 1a remained unsuccessful.
However, its structure tentatively assigned as the E
isomer on the basis of NMR and IR data (see below).
The appearance of isomers may be promoted also
by the presence of the CH2 moiety with C H bonds
loosened by the electron-withdrawing cyano group.
This is reflected by the presence of two separate
singlets of different intensities at δ 4.17–4.41 (see
Table 1). FT-IR spectra gave additional information
as in the spectrum (Nujol) of 1a; the relative intensi-
ties of the bands at 1622 and 1606 cm−1 are different
from those of 1b at 1618 and 1606 cm−1 (NH bands).
1
The H NMR spectra (Table 1) of isomers a (i.e.,
lower Rf ) of compounds 1–5 reveal that one of the
H Ar signals (H4) is downfield shifted (δ 8.11–8.38).
This was attributed to the deshielding effect of
the 3-hydrazono moieties with E stereostructure.
The spectra of the 1-Ac compounds 3,4 show that
an additional signal (H7) is downfield shifted. In
the 1H NMR spectra of the acetylation products
4 and 5, the CH2 signals are absent. However,
because of the possibility for various chelated
mesomeric or tautomeric forms [36–38] the signal
of C(O) CH(CN) C(O) Me could not be unequiv-
ocally assigned. In the IR spectra of compounds 1–7,
the CN bands show diverse intensities (Table 3).
To further investigate the transformation A → B
in question, benzohydrazide was made to react with
diethyl acetylenedicarboxylate. This reaction could
serve as a model for the reported [31] synthesis
of 1,3,4-oxadiazolines with the free endocyclic
NH group. Such compounds are the products of
the reaction of aroylhydrazines with acetylenedi-
carboxylic acid or -dimethyl ester. However, in
our case the product turned out to be diethyl 1-
benzoylhydrazonoethane-1,2-dicarboxylate (8) and
not the 2,2,5-trisubstituted 1,3,4-oxadiazoline 13
(see Scheme 3). When 8 was treated with Ac2O/py
at room temperature (see the section Experimental)
diethyl 1-(N-acetylbenzoylhydrazono)-3-butanone-
1,2-dicarboxylate (9) could be prepared via N- and
C-acetylation and not the 3-acetylated oxadiazoline
14 or its C-acetylated derivative.
For blocking the neighboring group effect of
the CH2 moiety, p-anisylidene derivative 6 was
prepared and subjected to the transformation in
question under acetylating conditions and this led
to the formation of 1-acetyl derivative 7 instead of a
spiro-oxadiazoline derivative.
Structures for compounds 1–7 were confirmed
1
by H NMR (Table 1), 13C NMR (Table 2), and IR
spectra (Table 3). On the basis of 1H- and especially
13C NMR spectral data, the presence of C N signals
at δ 140–145 and particularly the lack of a signal
about δ 90–95 (see Table 2) characteristic [20] of the
N,O-acetalic spiro C, we suggest products b to be the
Z isomers of the corresponding compounds. To have
the final structural evidence, monohydrate of 1b was
Bond length and bond angle data are in agree-
ment with the expected values, clearly indicating
partial conjugation along the molecule. In the
hydrogen bond web, hydrogen atoms of N1 H1,
N3 H3, O1w–H11, and O1w–H12 participate. O1
forms both intramolecular hydrogen bond with H3
and intermolecular one with H1 of the next molecule
Heteroatom Chemistry DOI 10.1002/hc

186 Somogyi and Be´nyei
TABLE 1 1H NMR Spectral Data of Acylhydrazones 1a–5ba
Compound
NH/OH
H-Ar
CH2
NCH3
CH3 CO
1a
b10.83 (1H)d
11.31 (1/3 H)
11.61 (2/3 H)
6.90f
7.04
7.40
4.17 (2/3 H)
4.33 (1 1/3 H)
8.11i
6.92f
7.08g
7.37g
7.52f
1b
b11.27 (1H)d
11.92 (0.9H)
12.47 (0.1H)
12.61 (0.7H)e
13.00 (0.3H)e
b11.55 (1H)o
4.18 (0.5H)
4.38 (1.5H)
1.90 (2.6H)e
2.31 (0.2H)e
2a
2b
7.09 (2H)f ,h
7.48
4.19 (0.5H)
4.33 (1.5H)
3.17
3.20
8.13i
b12.55 (0.8H)
12.98 (0.2H)
7.08–7.18
(2H)
4.21 (0.5H)
4.41 (1.5H)
7.46–7.49
7.57–7.58f
7.34i
3a
3b
4a
b11.65
11.90
4.34k
2.62
2.62
7.56g,j
8.26f ,h
8.29i
b,l12.29
b11.13
c14.49
7.32–7.35g
7.50–7.53g
7.71f ,m
4.37 (2H)o
8.14f ,m,n
7.30–7.33g,p
7.51–7.54g,p
8.24–8.26f
8.27–8.29f
7.26–7.68
(4H)q
2.31o
2.62
4b
5a
2.15o
2.63
8.13–8.18f ,n
7.08–7.21
(2H)
c13.62 (0.8H)
14.07 (0.2H)
3.20
3.21
2.13 (2.4H)
2.30 (0.6H)
7.41–7.49g
8.35–8.38f ,r
7.10–7.17
(2H)
5b
c4.18
2.12 (0.6H)
2.24 (2.4H)
7.39–7.46g
7.55–7.58f
aIn [CD3]2SO; the frequencies are indicated before the first column.
b500 MHz.
c200 MHz.
dH1.
eAcOH solvate.
f d-shaped m.
gt-shaped m.
hJ = 8 Hz.
i s-shaped m.
j J = ∼7 Hz.
k2 br s (major/minor).
l At 320 K, because of the poor solubility.
mJ = ∼10 Hz.
nH7.
obr s.
p The signal of CH(CN) is not noticeable.
qH4,5,6, and presumably CH(CN)
r H4.
.
Heteroatom Chemistry DOI 10.1002/hc

Chemistry of 3-Cyanoacetylhydrazono-2-indolinones and X-ray Structure of Z-3-Cyanoacetylhydrazono-2-indolinone Monohydrate 187
TABLE 2 13C NMR Spectral Data of Acylhydrazones 1a–4aa
Aromatic
Compound
C O
C N
CR
CH
CN
CH2
25.8
CH3
1a
164.1
167.9
144.0
115.0
137.5
110.7
121.7
126.2
132.9
111.3
120.9
122.7
132.0
109.3
122.2
125.9
132.8
110.0
120.5
123.2
131.9
116.2
124.8
125.6
132.7
116.2
120.2
125.2
131.6
116.0
124.7
125.3
132.0
115.7
1bb
162.4
165.8
172.0b
142.7
119.3
135.5
115.5
23.9
21.0b
2a
2b
3a
3b
4a
4bj
162.8
167.9
145.0
143.9
141.2
140.5
140.7
114.3c
115.6
115.4
115.6
115.0
24.9
23.9
26.0d
25.7d
26.5
160.5
165.8
118.6
131.9
162.9e
168.2e
170.3
116.3c
25.0
f160.6
169.7
∼ 24h
26.0
g
g,i
163.3
170.3c
116.5c
–
26.5c
∼190.0e
a125 MHz, for solutions in DMSO-d6, at 23◦C if not otherwise stated before the first column.
bAcOH solvate.
c2C.
dN-Me.
eWeak.
f At 320 K, because of the poor solubility.
gNot observable.
hBarely observable.
i The IR(KBr) band, however, is observable at 2190 cm−1
.
j Because of the poor solubility, the spectrum of 4b could not be registered.
TABLE 3 IR Spectral Data of Acylhydrazones 1a–5ba
1a
1b
(KBr):
(Nujol):
(KBr):
3256 (s), 2262 (w), 1732 (s), 1654 (w), 1612 (s), 1560 (w), 1512 (m), 1472 (s/m), 1382 (m), 1344 (s)
3244 (w), 3162 (m), 2264 (w), 1732 (s), 1704 (s), 1622 (m), 1606 (s/m)
3204 (s), 2264 (w/m), 1730 (s), 1698 (vs), 1618 (s), 1598 (m/s), 1490 (w), 1470 (s), 1452 (m/s), 1382 (m),
1350 (s)
3350 (w), 3162 (w), 2264 (w), 1704 (s), 1618 (m/s), 1606 (w), 1462 (s), 3162 (w), 2262 (w), 1726 (s), 1698
(s), 1694 (s), 1682 (sh), 1674 (sh), 1620 (m), 1598 (m)
(Nujol)b:
2a
2b
3a
3b
(KBr):
(KBr):
(KBr):
(KBr):
3268 (m), 2968 (w), 2932 (w), 2260 (w), 1724 (s), 1698 (s), 1606 (s), 1556 (vw), 1490 (m), 1472 (s)
3218 (m), 2928 (w), 2262 (m), 1710 (s), 1678 (s), 1614 (s), 1560 (m)
3244 (w), 2260 (w), 1768 (m/s), 1704 (s), 1654 (w), 1648 (w), 1636 (w), 1616 (m), 1600 (m)
3218 (s), 3140 (m/w), 3058 (w), 2970 (m), 2924 (m), 2260 (m), 1772 (sh), 1708 (s), 1654 (w), 1648 (w),
1636 (w), 1606 (s)
4a
4b
5a
5b
(KBr):
(KBr):
(KBr):
(KBr):
3252 (m), 2190 (w), 1756 (s), 1716 (s), 1704 (s), 1674 (m), 1604 (s), 1586 (m/s)
3212 (w), 2216 (m), 1716 (s), 1648 (m/s), 1604 (s), 1578 (m), 1510 (s/vs), 1462 (s)
3432 (br s), 2926 (w), 2220 (m), 1702 (s), 1644 (m), 1606 (s), 1518 (s), 1494 (m), 1466 (m/s)
3438 (br s), 2930 (w), 2212 (m/s), 1696 (s), 1642 (m/s), 1614 (s), 1526 (s), 1492 (m/w), 1470 (s)
aWave numbers (cm−1).
bThe product was kept at 100◦C/0.5 Torr over P4O10 to reach constant weight.
Heteroatom Chemistry DOI 10.1002/hc

188 Somogyi and Be´nyei
Germany) instrument, acceleration voltage 19 kV,
reflection mode, nitrogen laser (337 nm), 50 μL
solution of 2,5-dihydroxybenzoic acid (DHB) matrix
(20 mg/mL MeOH) and 10 μL solution of the
substance (5 mg/mL MeOH) were mixed and 0.5 μL
of the mixture examined. Atomic emission Na
determination: Varian SpectrAA 10 spectrometer
(FES), at 589.0 nm, after HNO3/H2O2 destruction.
X-ray Data Collection and Reduction
Crystals of 1b monohydrate were grown from AcOH
by slow evaporation of the solution. A colorless
prism crystal (0.55 × 0.45 × 0.2 mm) was fixed
on a glass capillary using epoxy glue. Data were
collected at 293(1) K, Bruker–Nonius MACH3
FIGURE 1 ORTEP view of 1b monohydrate. Selected bond
distances (A): N1–C8 1.411(6); N1–C2 1.355(5); C2–O1
1.236(5); C2–C3 1.496(6); C3–N2 1.283(5); C3–C9 1.461(5);
N2–N3 1.381(5); C11–N3 1.346(5); C11–O11 1.226(5); C11–
C12 1.507(6); C13–N14 1.137(5). Torsion angles (◦): C11–
N3–N2–C3 173; N3–C11–C12–C13 177.
˚
˚
diffractometer, Mo Kα radiation λ = 0.71073 A,
ω motion, θmax = 25.4◦. The structure was solved
using the SIR-92 software [51] and refined on F2
using SHELX-97 program, publication material
was prepared with the WINGX-97 suite. Hydrogen
atoms were fixed into geometric position except
N H and O H that could be found at the difference
electron density map.
in the lattice. H11 is donated to O11, whereas H12
to oxygen atom of another solvate water molecule.
Stacking interaction of the indolinone rings further
stabilizes the layered structure.
In conclusion, the reported [34] spirocyclization
of isatin cyanoacetylhydrazone (A) into oxadiazoline
B is not a valid reaction and the real transformation
was found to be an E/Z isomerization common
[39–50] among (acyl)hydrazones. Even under
acetylating conditions, no spirocyclization could be
observed.
Crystal
data:
formula
C11H8N4O2.H2O,
M= 246.23, monoclinic, space group P21/n,
˚
˚
a = 4.7103(10) A, b= 27.057(2) A, c= 9.4354(10),
◦
3
˚
β = 101.33(1) , V = 1179.1(3) A , Z = 4, ρcalc = 1.387,
2191 measured, 995 reflections were unique
with I > 2σ(I), decay: 2%, R1 = 0.0792 and
wR2 = 0.1797 for all 2191 reflections and 117
parameters, GOF = 1.013. Residual electron density:
3
˚
0.217/−0.202 e/A .
EXPERIMENTAL
Melting points (uncorrected): Kofler block. Solu-
tions were concentrated under reduced pressure in
a rotary evaporator (<50◦C, bath). TLC: Kieselgel
60 F254 (Merck, Alurolle). IR (KBr disks and Nujol
mull): Perkin-Elmer 16 PC-FT spectrophotometer.
E and Z-3-Cyanoacetylhydrazono-2-indolinone
(1a and 1b)
(a) A mixture of isatin (2.943 g, 20 mmol), pow-
dered cyanoacetohydrazide (2.063 g, 20.4 mmol;
98%; Aldrich), and commercial anhydrous EtOH
(50 mL) was boiled with stirring for 2.5 h and
then cooled to give crude [3.676 g, 80.5%, mp
206–208◦C, [34] 230–232◦C (from EtOH)] or
recrystallized 1a, mp 211–212◦C (from EtOH).
1
200 MHz H- and 50 MHz 13C NMR: Bruker WP
200 SY, 500 MHz 1H- and 125 MHz 13C NMR:
Bruker DRX 500 spectrometers; for recording the
13C NMR spectra, J-echo techniques were used.
MALDI-TOF MS: Bruker BIFLEX III (Brehmen,
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

Chemistry of 3-Cyanoacetylhydrazono-2-indolinones and X-ray Structure of Z-3-Cyanoacetylhydrazono-2-indolinone Monohydrate 189
The mother liquor of crude 1a was con-
centrated, and the residue crystallized from
99%–100% AcOH to give 1b (0.449 g, 7.8% as
an AcOH solvate), mp 202–203◦C.
10.2 mmol; 98%; Aldrich), and MeOH (30 mL) was
stirred at 50◦C (bath) for 6 h. The solid was filtered
off at ∼30◦C to give TLC [CHCl3/EtOAc (9:1), three-
fold run] homogeneous (R 0.14) crude 2a (1.856 g;
f
76.6%), mp 205–206◦C, which when recrystallized
from MeO(CH2)2OH transformed into TLC (as men-
(b) Compound 1a (2.282 g, 10 mmol) was boiled in
99%–100% AcOH (25 mL) with stirring for 2.5 h
to give 1b (2.449 g, 84.9% as an AcOH solvate),
mp 201–202◦C [for compound B, [34] mp 207–
209◦C (from AcOH)]: TLC [CHCl3/EtOAc (9:1),
tioned above) homogeneous (R 0.74) 2b, mp 215–
f
217◦C. The mother liquor of crude 2a was concen-
trated, and the residue triturated with water in the
cold to give an amorphous solid (0.458 g; 18.9%)
consisting (TLC as mentioned above) of 2a, 2b, and
three-fold run] R ∼ 0.35, whereas compound 1a
f
remained at the start point. Product 1b (5.317 g),
mp 205–206◦C, when kept over P4O10/0.5 Torr
at 100◦C unto constant weight, sustained a de-
crease in weight 0.616 g (11.2%; calcd for 1 AcOH
solvate, 20.8%), mp 204–205◦C.
1
some 11. For H- and 13C NMR, as well as IR spec-
tral data of 2a,b, see Tables 1–3. 2b: Anal. Calcd
for C12H10N4O2 (242.23): C, 59.50; H, 4.16; N, 23.13.
Found: C, 59.38; H, 4.24; N, 23.08.
(c) Compound 1a (1.500 g) was recrystallized from
MeO(CH2)2OH to give 1a (0.270 g), mp 203–
206◦C, TLC [CHCl3/EtOAc (9:1), three-fold run]
1-Acetyl-3-cyanoacetylhydrazono-2-indolinone
(3a and 3b)
R 0.0. The mother liquor was concentrated, and
f
(a) A mixture of 1-acetylisatin [20] (12, 5.675 g,
30 mmol), powdered cyanoacetohydrazide
(3.032 g, 30 mmol; 98%; Aldrich), and EtOAc
(100 mL) was stirred at 60◦C (bath) for 22 h.
The solid was filtered off in the cold to give
crude (4.248 g, 52.4%, mp 195–197◦C) or recrys-
tallized 3a, mp 220–223◦C (from DMF). 3a: For
1H- and 13C NMR, as well as IR spectral data, see
Tables 1–3. Anal. Calcd for C13H10N4O3 (270.24):
C, 57.77; H, 3.73; N, 20.73. Found: C, 57.70; H,
3.76; N, 20.80.
the residue triturated with MeOH to give 1b
(0.638 g), with R 0.35 and traces of 1a with R
f
f
0.0; thus also in hot MeO(CH2)2OH 1a undergoes
1
a transformation into 1b. 1a,b: For H- and 13C
NMR, as well as IR spectral data, see Tables 1–3.
Pyridine-Solvate Formation of 1b
Compound 1b, previously having been kept at
100◦C/0.5 Torr over P4O10 to constant weight
(0.1212 g) was stirred in pyridine (1.2 mL) for 30 min
and then hexane (3.6 mL) was added. The solid was
filtered off and washed with hexane to give a product
(0.1564 g), mp 204–205◦C, which on the basis of the
(b) A mixture of powdered 12 [20] (2.838 g,
15 mmol), powdered cyanoacetohydrazide
(1.547 g, 15.3 mmol; 98%; Aldrich), and AcOH
(15 mL, 99%–100%) was stirred at 58◦C (bath)
for 18 h, and then cooled to give crude 3b
(0.707 g, 17.4%), mp 218–220◦C. A solution of
the crude product in hot CHCl3 was treated with
charcoal and was concentrated to a smaller vol-
ume, and hexane was added to give TLC homoge-
increase in weight could be regarded as a 1:1 solvate
1
but the 1H- and 13C NMR spectra revealed a 1b
᭹
/2py
composition: 1H NMR (500 MHz, 23◦C, DMSO-d6) δ:
4.21 (s, 0.5H) and 4.41 (s, 1.5H) (CH ), 6.95 (d, 1H,
2
1
H7), 7.10 (t, 1H, H6), 7.37–7.41 (m, 2H, H5 +/2py
H3.5), 7.54 (d, 1H, H4), 7.77–7.81 (t, 0.5H, 1/2py H4),
1
8.58 (d, 1H, /2py H2,6), 11.31 (s, 1H, H1), 12.64
neous [CHCl3/EtOAc (9:1); R 0.49] 3b, mp 232–
f
(s, 0.75H), and 13.02 (s, 0.25H)( NNH ). 13C NMR
(125 MHz, 23◦C, DMSO-d6) δ: 23.9 (CH2), 111.3 (2C,
aromatic CH), 115.5 (C N), 119.3 (aromatic CR),
120.8, 122.6 (2C), 123.9, and 132.0 (2C)(aromatic
CH), 135.5 (aromatic CR), 136.1 (aromatic CH),
142.7 (C NNH ), 149.6 (aromatic CH), 162.4, and
165.8 (2 C O). Under similar conditions, a solvate
formation of compounds 1a or 2b could not be
observed.
233◦C.
(c) A solution of pure 3a (0.540 g) in 99–100% AcOH
(20 mL) was boiled with stirring for 2 h and then
concentrated. The residue was processed as in
(b) to give pure isomer 3b (0.174 g; 32%), mp
232◦C.
(d) A mixture of Ac2O (60 mL, 640 mmol), TFA
(98%, 2 mL, 26 mmol), and pure 3a (2.702 g,
10 mmol) was stirred at 70◦C (bath) for 24 h and
then concentrated. The deep freezed residue was
triturated with commercial anhydrous EtOH
(10 mL), and after being kept at room tem-
perature for 1 h hexane (10 mL) was added
in portions to afford TLC (see above in (b))
3-Cyanoacetylhydrazono-1-methyl-2-indolinone
(2a and 2b)
A mixture of powdered 1-methylisatin (11, 1.661 g,
10 mmol), powdered cyanoacetohydrazide (1.031 g,
Heteroatom Chemistry DOI 10.1002/hc

190 Somogyi and Be´nyei
homogeneous pure isomer 3b (1.850 g; 68.5%),
mp 232–233◦C. 3b: For 1H- and 13C NMR, as well
as IR spectral data, see Tables 1–3.
a pyridine salt of 5a (1.411 g, 77.7%), mp 153–155◦C,
well soluble in cold water. 5a
py: 1H NMR (200 MHz,
᭹
23◦C, DMSO-d6) δ: 2.13 (s, 3H, CH –CO), 3.19 (s, 3H,
3
NMe), 7.09–7.22 (m, ∼2.2H), 7.39–7.49 (m, ∼1.2H),
8.01–8.08 (m, 2H), 8.36–8.40 (d, 1H), 8.51–8.61 (m,
1H), and 8.92–8.96 (m, 2H), altogether 9.4H (9 H-
Ar and probably the C(O) CH(CN) C(O) CH3). IR
(KBr, cm−1): 3416 (vw), 3066 (w), 2194 (s), 1720 (s),
1610 (s), 1562 (m), 1488 (s), 1468 (m), 1418 (m),
1378 (vs).
1-Acetyl-3-(2-cyanoacetoacetylhydrazono)-2-
indolinone (4a)
A mixture of 1a (1.141 g, 5 mmol), anhydrous pyri-
dine (12 mL), and Ac2O (12 mL) was stirred at room
temperature for 24 h. The solid was filtered off,
washed with Ac2O and hexane to give crude pyridine
A solution of 5a py (0.1817 g, 0.5 mmol) in wa-
᭹
salt of 4a (1.231 g), mp 198–202◦C. 4a
᭹
(∼0.65 py):
ter (5 mL) was filtered and acidified by addition
of 1N HCl (0.6 mL, 0.6 mmol). The yellow powder
precipitate was filtered off, washed with water, 2-
PrOH/hexane (1:2), and hexane to give 5a (0.1384 g;
97.4%), mp 132–133◦C. For 1H NMR and IR spectral
data, see Tables 1 and 3. Anal. Calcd for C14H12N4O3
(284.27): C, 59.15; H, 4.26; N, 19.71. Found: C, 59.04;
H, 4.28; N, 19.64.
1H NMR (500 MHz, 23◦C, DMSO-d6) δ: 2.15 (s, 3H,
Ac), 2.63 (s, 3H, Ac), 7.39–7.42 (t, 1H) and 7.50–7.53
(t, 1H H5.6), 8.06–8.08 (t, ∼1.3H, py H3,5), 8.30–
8.32 (d, 1H, H4?), 8.49–8.50 (d, 1H, H7?), 8.58–8.61
(t, ∼0.65H, py H4), 8.94–8.95 (d, ∼1.3H, py H2,6),
13.87 (br s, 1H, NH). The mother liquor of the crude
product was concentrated, and the residue was trit-
urated with commercial anhydrous EtOH (2 mL) in
the cold to give a solid (0.147 g), which was treated
with charcoal in hot CHCl3 and the solution concen-
trated. The residue was boiled in EtOAc to give pure
4a (0.051 g), mp 191–192◦C. For 1H- and 13C NMR, as
well as IR spectral data, see Tables 1–3. Anal. Calcd
for C15H12N4O4 (312.28): C, 57.69; H, 3.87; N, 17.94.
Found: C, 57.59; H, 3.89; N, 17.88.
3-(2-Cyanoacetoacetylhydrazono)-1-methyl-2-
indolinone (5b)
A mixture of powdered 2b (1.453 g, 6 mmol), Ac2O
(20 mL), and anhydrous pyridine (15 mL) was stirred
at room temperature for 24 h. The solid was fil-
tered off, washed with Ac2O and hexane to give crude
5b
᭹
py salt (1.744 g; 80%), mp 179–180◦C. 5b py: 1H
᭹
NMR (200 MHz, 23◦C, DMSO-d6) δ: 2.10 (s, 3H, Ac),
3.21 (s, 3H, NMe), 7.05–7.12 (t, 2H), and 7.33–7.49
(m, 2H H4-Ar), 7.93–8.00 (t, 2H, py H3.5), 8.43–8.51
(t, 1H, py H4), 8.88–8.90 (d, 2H, py H2.6), 14.52 (br
s, 1H, NH). IR (KBr, cm−1): 3436 (br s), 3062 (m),
2930 (w), 2200 (s), 1688 (s), 1614 (s), 1604 (sh), 1556
(m), 1484 (s), 1470 (s), 1380 (m).
1-Acetyl-3-(2-cyanoacetoacetylhydrazono)-2-
indolinone (4b)
A mixture of Ac2O (16 mL, 170 mmol), anhydrous
NaOAc (0.50 g, ∼6 mmol), and 1b (0.577 g, ∼2 mmol,
AcOH solvate) was stirred at 91–92◦C (bath) for 2 h,
and then concentrated. The cold residue was trit-
urated with water (∼50 mL), and the undissolved
was filtered off, washed with water and hexane and
dried in a vacuum desiccator to give crude Na-salt
of 4b (0.528 g; 79%), mp >360◦C. Anal. Calcd for
C15H11N4O4Na (334.27): Na, 6.88. Found: Na, 6.04.
The aqueous mother liquor was acidified by ad-
dition of 2 N HCl (4 mL, 8 mmol), the precipitate
was filtered off as a powder, washed with water and
hexane to give 4b (0.073 g; ∼11.7%), mp 223◦C. For
1H NMR and IR spectral data, see Tables 1–3. Anal.
Calcd for C15H12N4O4 (312.28): C, 57.69; H, 3.87; N,
17.94. Found: C, 57.76; H, 3.86; N, 17.99.
A solution of 5b py (0.1817 g, 0.5 mmol) in wa-
᭹
ter (25 mL, at ∼40◦C) was filtered and in the cold
acidified by addition of 1 N HCl (0.6 mL, 0.6 mmol).
The yellow precipitate was filtered off, washed with
water and hexane to give 5b (0.1231 g; 86.6%),
1
mp 189◦C. For H NMR and IR spectral data, see
Tables 1 and 3. Anal. Calcd for C14H12N4O3 (284.27):
C, 59.15; H, 4.26; N, 19.71. Found: C, 59.02; H, 4.25;
N, 19.77.
3-(4-Methoxybenzylidenecyanoacetylhydrazono)-
2-indolinone (6)
(a) A mixture of 1a (9.128 g, 40 mmol), anisaldehyde
(5.990 g, 43 mmol; 98%), commercial anhydrous
EtOH (160 mL), and Et3N (12 drops) was boiled
with stirring for 3 h. The solid was filtered off
in the cold, washed with EtOH and hexane to
give crude (8.045 g, 58.1%, mp 274–277◦C) or
recrystallized 6, mp 277–278◦C (from DMF).
3-(2-Cyanoacetoacetylhydrazono)-1-methyl-2-
indolinone (5a)
A mixture of 2a (1.211 g, 5 mmol), Ac2O (15 mL,
159 mmol), and anhydrous pyridine (7 mL, 87 mmol)
was stirred at room temperature for 29 h. The solid
was filtered off, washed with Ac2O and hexane to give
Heteroatom Chemistry DOI 10.1002/hc

Chemistry of 3-Cyanoacetylhydrazono-2-indolinones and X-ray Structure of Z-3-Cyanoacetylhydrazono-2-indolinone Monohydrate 191
(b) A mixture of 1b (3.195 g, ∼14 mmol, previ-
ously kept at 100◦C/0.5 Torr over P4O10 for sev-
eral hours), anisaldehyde (2.06 g, 14.8 mmol;
98%), commercial anhydrous EtOH (50 mL),
and Et3N (10 drops) was boiled with stirring for
3 h, as described above, to give crude (4.217 g.
87%, mp 281–282◦C) or recrystallized 6, mp 286–
287◦C (from DMF), identical (1H NMR, IR) with
that obtained from 1a as described in (a)). 6:
1H NMR (200 MHz, 23◦C, DMSO-d6) δ: 3.89
(b) A mixture of Ac2O (25 mL, 265 mmol), TFA
(1 mL, 13 mmol), and 1b (1.000 g, ∼ 4.4 mmol, as
an AcOH-solvate) was stirred at 70◦C (bath) for
22 h and then processed as described in (a)). A so-
lution of the crude product (0.821 g) in hot CHCl3
(170 mL) was treated with fuller’s earth and char-
coal and concentrated. Recrystallization from
EtOAc yielded 1b (0.354 g. ∼35%), mp 200◦C.
The products obtained in (a) and (b) are identi-
cal (IR, TLC [CHCl3/EtOAc (9:1), four-fold run])
with compound 1b prepared from isatin (10) and
cyanoacetohydrazide in AcOH or that obtained
by recrystallization of 1a from AcOH (see above).
(s, 3H, OCH ), 6.95–7.63 (m, 6H, H4,5,6,7 and
3
H3.5-Ph), 8.14 (d-shaped m, 2H, H2.6-Ph), 8.44
(s, 1H, C(CN) CH ), 11.35 (s, 1H, H1), 13.86
(br s, 1H, N NH). 13C NMR (50 MHz, 23◦C,
DMSO-d6) δ: 55.8 (OCH3), 98.5 ( C(CN) CH ),
116.3 (C N), 119.6 and 124.3 (2-2 aromatic
CR), 115.0 (2C), 121.2, 122.7, 132.2, 133.5
(2C) (altogether eight aromatic CH), 142.9
(C N N), 153.8 ( C(CN) CH ), 162.8 (C O),
163.6 (C O). IR (KBr, cm−1): 3224 (m/w), 2204
(m/w), 1712 (s/m), 1676 (s), 1622 (s/m), 1602
(w), 1572 (s/m), 1562 (s/m), 1510 (s), 1466 (s),
1170 (vs). Anal. Calcd for C19H14N4O3 (346.33):
C, 65.89; H, 4.07; N, 16.18. Found: C, 65.80; H,
4.10; N, 16.21.
(c) A mixture of Ac2O (3 mL, 32 mmol), TFA (0.1 mL,
1.3 mmol; >98%), and 2a (0.121 g, 0.5 mmol)
was stirred at 70◦C (bath) for 24 h, and then con-
centrated. The residue was triturated with an-
hydrous EtOH (1 mL) and, after being kept at
room temperature for 0.5 h, hexane (1 mL) was
added to give TLC [CHCl3/EtOAc (9:1)] homoge-
neous 2b (0.090 g; 74.4%), mp 220–221◦C, identi-
cal (TLC, 1H NMR) with the product obtained by
condensing l-methylisatin (11) with cyanoaceto-
hydrazide in EtOH followed by recrystallization
from 2-methoxyethanol (see above).
(d) A mixture of Ac2O (3 mL, 32 mmol), TFA (0.1 mL,
1.3 mmol; >98%), and 3a (0.135 g, 0.5 mmol)
was stirred at 70◦C (bath) for 24 h, and then con-
centrated and processed as in described (c) to
give TLC [CHCl3/EtOAc (9:1)] homogeneous 3b
(0.093 g; 69%), mp 232–233◦C, identical (TLC)
with the product obtained by condensing 1-
acetylisatin (12) with cyanoacetohydrazide in
hot AcOH or by recrystallizing 3a from AcOH
(see above).
Attempted Transformation of 1a,b by Treatment
with Ac2O/ZnCl2
To
a solution of anhydrous ZnCl2 (0.20 g,
∼1.4 mmol) in Ac2O (5 mL, 53 mmol) was added
1a (0.2282 g, 1 mmol). The mixture was stirred at
room temperature for 53 h, and then the solid was
filtered off, washed with Ac2O, water, and hexane to
give a product (0.1858 g, 81.4%, mp 199–201◦C) TLC
[CHCl3/MeOH (9:1)] identical with the substrate 1a.
An exactly the same treatment of the AcOH-
solvate 1b (0.2882 g, ∼1 mmol) afforded a product
(0.1910 g, ∼66%) TLC [CHCl3/EtOAc (9:1), three-fold
run] identical with the substrate 1b.
(e) A mixture of Ac2O (3 mL, 32 mmol), TFA (0.1 mL,
1.3 mmol; >98%), and anisylidene derivative 6
(0.173 g, 0.5 mmol) was stirred at 70◦C (bath)
for 24 h. The solid was filtered off in the cold,
washed with Ac2O and hexane to give TLC homo-
geneous product (0.163 g; 94%), mp 283–285◦C,
identical (mp, TLC, IR, 1H NMR) with 6 obtained
from 1a or 1b (see above). Thus, in (a)–(e) nei-
ther acetylation nor spirocyclization of the sub-
strates 1a,b, 2a, 3a, and 6 occurred, but 1a, 2a,
and 3a were transformed into the corresponding
Attempted Acetylation/Spirocyclization of
Acylhydrazones 1a,b, 2a, 3a, and 6 by
Treatment with Ac2O/TFA
(a) A mixture of Ac2O (12 mL, 127 mmol), TFA
(0.4 mL, 5 mmol; >98%), and 1a (0.456 g,
2 mmol) was stirred at 70◦C (bath) for 24 h and
then concentrated. The residue was triturated
with water in the cold to give a solid. A solution of
the crude product in hot EtOAc was treated with
fuller’s earth and charcoal and concentrated. Re-
crystallization form EtOAc afforded 1b (0.206 g;
45%), mp 199–200◦C.
modifications b of higher R values.
f
1-Acetyl-3-(4-methoxybenzylidenecyanoacetyl-
hydrazono)-2-indolinone (7)
(a) A mixture of crude compound 6 (0.200 g,
∼0.57 mmol, prepared from 1a), Ac2O (2 mL),
and anhydrous pyridine (2 mL) was stirred at
Heteroatom Chemistry DOI 10.1002/hc

192 Somogyi and Be´nyei
50–52◦C (bath) for 21 h and then concentrated.
The residue was triturated with water in the cold
to give a TLC [CHCl3/EtOAc (95:5)] multicompo-
nent solid (0.258 g) which when extracted with
hot CHCl3 (5 mL) left undissolved compound 7
(0.050 g; 23%), mp 254–255◦C.
(Ph C O). IR (KBr, cm−1): 3190 (m), 3016 (w), 2986
(w), 2936 (w), 1746 (s), 1716 (s), 1668 (s), 1626
(w), 1598 (w), 1580 (w), 1542 (m). MALDI-TOF MS
m/z 307.142 [M + H]+, 329.114 [M + Na]+, 345.066
[M + K]+. Anal. Calcd for C15H18N2O5 (306.31): C,
58.81; H, 5.92; N, 9.15. Found: C, 58.88; H, 5.96;
N, 9.09.
(b) A mixture of crude compound 6 (0.693 g,
2 mmol, prepared from 1b), Ac2O (4 mL), and
anhydrous pyridine (4 mL) was stirred at 70◦C
(bath) for 6 h and then was kept at room tem-
perature for 2 days. The solid was filtered off,
washed with Ac2O and hexane to give crude 7
(0.607 g; 78%), which when extracted with hot
AcOH (46 mL) left undissolved 7 (0.364 g; 47%),
mp 258◦C. From the mother liquor separated out
recrystallized 7 (0.195 g; 25%), mp 264–265◦C.
Diethyl 1-(N-Acetylbenzoylhydrazono)-3-
butanone-1,2-dicarboxylate (9)
A
mixture of benzoylhydrazone
8
(0.429 g,
1.4 mmol), Ac2O (4 mL, 42 mmol), and anhydrous
pyridine (3 mL, 37 mmol) was stirred until dis-
solution was complete (∼3 min) and was kept at
room temperature for 65 h and then concentrated.
The residue was triturated with water in the cold.
A solution of the doughy product in CHCl3 was
dried (MgSO4), treated with fuller’s earth and char-
coal and then concentrated. The amorphous residue
was dried in a vacuum desiccator to give a TLC
[CHCl3/EtOAc (95:5)] almost homogeneous glassy
(c) A mixture of Ac2O (14 mL), anhydrous NaOAc
(0.60 g, 7.2 mmol), and crude 6 (0.693 g, 2 mmol,
prepared from 1b) was heated with stirring at
110◦C (bath) for 7 h, and then was kept at
room temperature for 1 day. The solid was fil-
tered off, washed with Ac2O, hexane, and sev-
eral times with water to afford undissolved crude
(0.674 g, 86.8%, mp 258–259◦C) or recrystal-
lized 7, mp 260–261◦C (from MePh/EtOAc). The
products obtained in (a)–(c) are identical (TLC
[MePh/EtOAc (8:2)], IR, and 1H NMR). 7: 1H
NMR (200 MHz, 23◦C, DMSO-d6/CDCl3 (8:2)) δ:
1
product (9, 0.545 g, 99.7%). 9: H NMR (200 MHz,
23◦C, CDCl3) δ: 1.11–1.24 (m, 6H, 2 CH2CH ), 2.08
3
and 2.36 (each s, 3H; 2 Ac), 4.01–4.21 (m, 4H, 2
CH CH3), 5.63 (s, 1H, CH(Ac) CO2Et), 7.32–7.59
2
(m, 5H, Ph). 13C NMR (50 MHz, 23◦C, CDCl3) δ: 13.2
and 13.6 (2 CH2CH3), 20.9 and 23.4 (2 CH3 C O),
60.7 and 62.0 (2 CH2CH3), 107.1 (br low signal, de-
tectable only with bb decoupling, CH(Ac) CO2Et),
127.9–128.2 C3,4,5-Ph), 132.4 (C1-Ph), 132.7 (2C,
C2,6-Ph), 143.2 (N N C), 161.7, 163.8, 169.2, 169.4,
and 171.0 (5 C O). MALDI-TOF MS m/z 413.180
[M + Na]+, 429.129 [M + K]+. C19H22N2O7 (390.39).
2.67 (s, 3H, 1-Ac), 3.90 (s, 3H, OCH ), 7.16–7.20
3
(d, 2H, H3,5-Ph), 7.36–7.40 (t, 1H, H-Ar), 7.51–
7.55 (t, 1H, H-Ar), 7.76–7.80 (d, 1H, H-Ar), 8.13–
8.22 (m, 2H, H2,6-Ph), 8.48 (s, 1H, (CN) CH ),
13.40 (s, 1H, NH). IR (KBr, cm−1): 3434 (br),
2212 (w/m), 1718 (s), 1696 (s), 1606 (m), 1578
(vs), 1562 (m), 1514 (vs), 1460 (m/s). Anal. Calcd
for C21H16N4O4 (388.37): C, 64.94; H, 4.15; N,
14.43. Found: C, 65.04; H, 4.20; N, 14.36.
SUPPLEMENTARY DATA
Crystallographic data have been deposited with
Cambridge Crystallographic Data Centre. De-
position number CCDC-625194. Copies of
the data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge, CB2 1EZ, UK; Fax:
+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Diethyl 1-benzoylhydrazonoethane-1,2-
dicarboxylate (8)
A mixture of benzohydrazide (2.723 g, 20 mmol),
anhydrous MeOH (50 mL), and diethyl acetylenedi-
carboxylate (3.582 g, 20 mmol; 98%; Fluka) was
boiled with stirring for 2 h and then cooled to give 8
(0.890 g, 14.5%), mp 142–143◦C. The mother liquor
was concentrated to give a second crop of 8 (4.010
1
g; 65.4%). 8: H NMR (200 MHz, 23◦C, CDCl3) δ:
REFERENCES
1.23–1.30 and 1.33–1.40 (each t, 3H; 2 CH2CH ), 3.86
3
(s, 2H, CH CO2Et), 4.15–4.26 and 4.29–4.40 (each q,
[1] Schmitz, E. Angew Chem 1961, 73, 23–25.
[2] Breslow, R.; Yaroslavsky, C.; Yaroslavsky, S. Chem
Ind (London) 1961, 1961.
[3] Bettinetti, G. F.; Capretti, L. Gazz Chim Ital 1965, 95,
33–42.
[4] Bettinetti, G. F.; Gru¨nanger, P. Tetrahedron Lett
1965, 2553–2557.
2
2H; 2 CH CH3), 7.95–7.99 (d shaped m, 2H, H2,6-Ph),
2
11.14 (br s, 1H, NH). 13C NMR (50 MHz, 23◦C, CDCl3)
δ: 13.9 and 14.0 (2 CH2CH3), 33.4 (CH2CO2Et),
62.4 (CH2CH3, 2C), 128.5 (C3,4,5-Ph), 132.1 (C1-
Ph), 132.5 (C2,6-Ph), 163.9 (EtO C O, 2C), 168.8
Heteroatom Chemistry DOI 10.1002/hc

Chemistry of 3-Cyanoacetylhydrazono-2-indolinones and X-ray Structure of Z-3-Cyanoacetylhydrazono-2-indolinone Monohydrate 193
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Heteroatom Chemistry DOI 10.1002/hc