An atypical easy reductive cleavage of the conjugated CC bond in 1,1′-disubstituted isoindigos under the action of aqueous hydrazine hydrate

Article abstract of DOI:10.1016/j.tetlet.2014.10.088

The reaction of diverse symmetrically-substituted isoindigo derivatives with 80% aqueous hydrazine hydrate is described. The influence of the structure of the substituent on either oxindole or isatin-3-hydrazone formation is discussed.

Full text of DOI:10.1016/j.tetlet.2014.10.088

Tetrahedron Letters 55 (2014) 6615–6618
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Tetrahedron Letters
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An atypical easy reductive cleavage of the conjugated C@C bond
0
in 1,1 -disubstituted isoindigos under the action of aqueous
hydrazine hydrate
⇑
Andrei V. Bogdanov , Alisa V. Petrova, Dmitry B. Krivolapov, Vladimir F. Mironov
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Ac. Arbuzov Str., 8, 420088 Kazan, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of diverse symmetrically-substituted isoindigo derivatives with 80% aqueous hydrazine
hydrate is described. The influence of the structure of the substituent on either oxindole or isatin-3-
hydrazone formation is discussed.
Received 22 August 2014
Revised 29 September 2014
Accepted 14 October 2014
Available online 22 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isoindigo
Reduction cleavage
Hydrazones
Single-crystal
Oxindoles
Isoindigo is one of three bis-indoles (indigo, indirubin, and iso-
indigo), which is closely connected with various pharmaceutical
and material applications. Recent data show that numerous sub-
stances bearing the indolin-2-on-3-ylidene motif possess strong
of the reaction mixture that could indicate a disruption of the con-
1
13
jugated double bond system. Indeed, the H and C NMR spectral
data showed presence of two reaction products, 3 and 4, as an
inseparable mixture, but not compound 2 (Scheme 1).
Thus in this case, besides hydrolysis and hydrazinolysis of the
ester units, cleavage of the central C@C double bond had occurred.
1
potencies in anticancer drug design. Important examples include
isoindigo derivatives such as meisoindigo and natura which are
already used in leukemia treatment (Fig. 1).2
It should be noted here that the reactions of
a
,b-unsaturated car-
Being a bis-heterocycle incorporating two lactam moieties
joined via a carbon–carbon double bond, isoindigo represents a
highly reactive conjugated system. Such structures allow these
molecules to behave as electron-acceptor materials in organic elec-
tronics such as in organic photovoltaics (OPVs) and organic field
H
N
O
O
H
N
O
N
H
N
H
3
O
N
H
effect transistors (OFETs). However, the utilization of these com-
O
O
N
H
pounds in organic reactions is limited to the synthesis of oligo-
or polymeric structures with an isoindigo unit for OPV and OFETs
under Stille or Suzuki reaction conditions.4
In the present work we disclose novel aspects of the chemistry
of these bis-heterocycles, namely their unusual reaction with
hydrazine hydrate. Thus, initially we were trying to obtain the
dihydrazide 2 with an isoindigo core from the corresponding
diester 1 using a standard organic synthetic approach. However,
treatment of isoindigo 1 with a fivefold excess of hydrazine
hydrate in EtOH at reflux temperature resulted in a discoloration
H
N
isoindigo
indirubin
indigo
O
H
N
O
O
N
O
O
OAc
N
CH3
OAc
OAc
meisoindigo
natura
⇑
Corresponding author. Tel.: +7 843 272 7384; fax: +7 843 273 2253.
E-mail address: abogdanov@inbox.ru (A.V. Bogdanov).
Figure 1. Examples of compounds containing the bis-indole moiety.
http://dx.doi.org/10.1016/j.tetlet.2014.10.088
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

6
616
A. V. Bogdanov et al. / Tetrahedron Letters 55 (2014) 6615–6618
H NHN(O)C
2
N
O
O
EtO C
2
N
N
H NHN(O)C
O
2
2
O
a)
NNH2
N
O
2
CO Et
N
1
COOH
+
3
O
N
Figure 3. ORTEP view (thermal ellipsoids at the 50% probability level) of 5-bromo-
H NHN(O)C
2
1-methylindolin-2-one (6c). Selected bond lengths [Å] and angles [°]: C2–O2
4
1.215(4), C5–Br1 1.902(3), N1–C2 1.379(4), C7a–N1 1.393(5), C2–C3 1.528(5),
C3–C3a 1.499(4), O2–C2–N1 125.1(3), C2–N1–C7a 111.3(3), C3a–C3–C2 103.5(3),
C3a–C7a–N1 110.1(3), C3–C3a–C7a 107.3(3), O2–C2–C3 127.5(3).
Scheme 1. Hydrazinolysis of ester-containing isoindigo 1. Reagents and condition:
a) aqueous N (85%), EtOH, reflux.
(
2 4
H
to undergo facile C@C bond cleavage to give oxindoles 6a–c
R'
(Scheme 2) as the main reaction products under conditions much
O
R
R'
8
0% aq. N H
2 4
milder than those used in the above reaction.
N
O
N
The fact that the double bond underwent reduction-cleavage
N
EtOH, 45 °C, 1 h
6-98%
R
O
1
13
R
was proved from the H and C NMR data that showed the pres-
ence of the methylene and amide carbonyl fragments in the mole-
cule. Exemplifying on 6a, the signal corresponding to the C3
9
R'
6a-c
5
a-c
R' = H, R = Me (a); R' = H, R = 4-FC H CH (b);
methylene appeared in
a
characteristic high-field region
6
4
2
R' = Br, R = Me (c)
13
(d = 26.1) in the C NMR spectrum while C2 appeared at d 175.1,
being consistent with an amide carbonyl (Fig. 2).
Scheme 2. Substituted oxindoles from the corresponding isoindigos.
Finally, the structure of one of the reaction products (6c) was
unequivocally confirmed by X-ray crystallographic analysis
bonyl compounds with N
2 4
H are characterized by the formation of
9
either the corresponding pyrazolidinones or the products of C@C
(Fig. 3).
5
,6
bond reduction.
A plausible reaction mechanism for the formation of 6a–c
shown in Scheme 3 may be presented to rationalize the reaction
outcome. In the first stage of the reaction a conjugate addition of
hydrazine to the C@C bond to form intermediate A takes place.
Keeping in mind such an unexpected result, we decided to
examine the behavior of other symmetrically substituted isoindi-
gos 5–7 toward hydrazine hydrate.7,8 Compounds 5a–c were found
Figure 2. 13C–{ H} NMR spectrum of 1-methyloxindole 6a in CDCl
1
3
.

A. V. Bogdanov et al. / Tetrahedron Letters 55 (2014) 6615–6618
6617
R
Then redistribution of electron density and the C–C bond cleavage
lead to the formation of hydrazone B and enol C. Further, hydra-
zone B under the action of hydrazine generates anionic intermedi-
ate D, which tautomerizes to N@N containing species E. This
intermediate eliminates dinitrogen to form an anionic enolate,
which undergoes protonation with hydrazinium to give the second
molecule of final product 6.
A distinctive feature of this reaction is the sensitivity of the syn-
thetic result to the structure of the substituent at the nitrogen
atom of the bis-indole. It was found that aminomethyl-containing
isoindigos 7a–c (the so-called isoindigo N-Mannich bases) reacted
R
N
O
H
N
O
N
R' H
N NH
2
2
R'
R'
R'
O
H
N
R
NH2
N
O
5
R
A
N
NH2
R'
R'
OH
O
+
N
N
R
R
R
B
C
2 4
with aqueous N H to afford isatin-3-hydrazone 8 in almost quan-
N H
2
4
R'
titative yield (Scheme 4). In this reaction, besides the formation of
a hydrazone function and C@C bond cleavage, an elimination of an
aminomethyl moiety occured.
O
N
NH
O
N
R'
6
(c = 20% w/w), the 1H NMR spectrum of
6
At 25 °C in DMSO-d
compound exhibited four signals in the aromatic region
(d = 6.86–7.35) and two broad signals due to the NH -group
d = 9.50 and 10.52). It is interesting that the exchangeable signal
N
8
N H
2
5
R
D
2
(
N H
- N
2
H
4
2
5
of the lactam proton appeared as a singlet at d 8.04 only at a lower
solution concentration (c = 5% w/w) (Fig. 4).
H
N
N
The absence of doubling of the signals in these spectra indicated
the formation of only one Z-isomer. Its structure was finally estab-
lished by XRD analysis which data were in good agreement with
R'
R'
OH
O
N
N
- N2
R
R
10
those reported earlier.
E
F
In summary, the reaction of isoindigo derivatives with aqueous
hydrazine hydrate has been studied. It was found that in all cases,
reductive cleavage of the central C@C bond took place under mild
Scheme 3. A plausible mechanism of the formation of 6a–c.
0
R
conditions. It was revealed that 1,1 -dialkylisoindigos in this reac-
N
tion afforded the corresponding oxindoles, whereas aminomethyl
examples gave isatin-3-hydrazone. Furthermore, this reaction
may serve as a promising approach for the synthesis of difficult
to prepare 1-substituted oxindoles.
N
NH2
O
80% aq. N H4
2
O
O
N
EtOH, 45 °C, 1 h
N
H
∼
100%
R
a-c
8
7
Acknowledgement
N
N
,
O
R = Et NH ,
2
We are grateful for the financial support of the Russian Founda-
tion for Basic Research (Grant no. 14-03-31717-mol_a).
Scheme 4. Substituted oxindoles from the corresponding isoindigos.
Figure 4. Low-field fragments of the 1H spectra of isatin-3-hydrazone 8 in DMSO-d
at 25 °C: (a) c = 5% w/w; (b) c = 20% w/w.
6

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(
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Supplementary data (detailed experimental procedures, NMR
spectra and X-ray analysis (CIF-files)) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.10.088.
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