Plausible reaction path for haval-argade contrathermodynamic rearrangement in synthesis of farinomalein

Article abstract of DOI:10.14233/ajchem.2018.21142

This work reports, the plausible reaction path in context of the farinomalein (1) and isofarinomalein (2) synthesized via Stobbe condensation and Haval-Argade Contrathermodynamic Rearrangement.

Full text of DOI:10.14233/ajchem.2018.21142

Asian Journal of Chemistry; Vol. 30, No. 4 (2018), 901-903
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21142
Plausible Reaction Path for Haval-Argade Contrathermodynamic
Rearrangement in Synthesis of Farinomalein
1,*
2
2
3
NARAYAN P. FIRKE , ANIL G. MARKANDEYA , RAJENDRA S. KONDE DESHMUKH and SHIRISH S. PINGALE
1Department of Chemistry, Willingdon College, Sangli-416 415, India
2Department of Chemistry, Fergusson College, Pune-411 004, India
3Department of Chemistry, Gramonnati Mandal's Arts, Commerce and Science College, Narayangaon-410 504, India
*Corresponding author: E-mail: npfirke@gmail.com
Received: 21 November 2017;
Accepted: 11 January 2018;
Published online: 28 February 2018;
AJC-18808
This work reports, the plausible reaction path in context of the farinomalein (1) and isofarinomalein (2) synthesized via Stobbe condensation
and Haval-Argade Contrathermodynamic Rearrangement.
Keywords: Cyanuric chloride, Maleimide, Stobbe condensation, Regioselectivity, Enthalpy.
1H NMR and 13C NMR spectra were recorded on a Bruker®
AC-200 and Varian Mercury Spectrometer 400 MHz unless
stated otherwise using CDCl3. Mass spectra were recorded on
Agilent® G6540B MS Q-TOF at 70 eV with Electron Spray
Ionization technique. The optimized geometries and the enthalpy
data of intermediate obtained from semi-empirical calculation
INTRODUCTION
The compound farinomalein (1) is first reported by Putri
et al. [1]. This compound is isolated from an entomopatho-
genic fungus P. farinosus HF599. The structure of maleimide-
bearing farinomalein (1) is determined by spectroscopic analysis
using CS MOPAC® pro version 8.0, wherein structure were
viewed in Chem3D® Molecular Modeling and Analysis.
The isofarinomalein (2) was subjected to HA contra-
thermodynamic rearrangement [10] and yielded 33 % the
mixture of farinomalein (1) and isofarinomalein (2) (Scheme-
I). None of the intermediates were isolated. Isofarinomalein (2)
regioselectively hydrolyzed by LiOH quantitatively gave 3-
(2-carboxyethylcarbamoyl)-4-methylpent-3-enoic acid (3).
The reaction with cyanuric chloride and triethyl amine at lower
temperature led to β-alkyl isomaleimide (4) which on further
refluxed with acetic acid resulted in farinomalein (1) and
isofarinomalein (2).
and chemical conversion [1]. Farinomalein (1) has been evaluated
for its potent antifungal activity with (MIC value 5 µg/disk)
against the plant pathogenic P. sojae P6497, wherein the positive
control, amphotericin B used in the assay remarkably shows
(MIC value 10 µg/disk) [1-3]. There are three derivatives of the
farinomalein (1) are reported thereafter along with isoindoline
[4]. Synthesis of farinomalein (1) started from γ-hydroxy-
butenolide [5] and ethyl-3-methyl-2-oxobutyrate [6,7] are
reported in date. In present study, the synthesis of farinomalein
is attempted started from dimethyl succinate [8,9] yield
pseudonym: isofarinomalein (2), which then further subjected
to HA contrathermodynamic rearrangement [10] yield
farinomalein (1) and isofarinomalein (2). These observations
are studied with the thermodynamic parameter of the comp-
ounds involved in the Scheme-I. The significance of the present
studies also due to the fact that transformation of dialkylidene-
succinimide to alkylmaleimide is practical difficult to achieve
by many reagents and reaction conditions [10].
RESULTS AND DISCUSSION
Farinomalein (1) and isofarinomalein (2) were found in
ratio 15:85 (calculated from 1H NMR spectral integration and
the area under the peaks in mass spectrogram). The highly
regioselective aqueous lithium hydroxide hydrolysis of com-
pound 2 exclusively delivered β-alkylidenesuccinanillic acid
(3) in almost quantitative yield [10]. The diacid 3 obtained was
subjected to kinetic dehydration in order to achieve β-dialkyl-
isosuccinimide (4). Cyanuric chloride is a fine dehydrating
reagent for such kinetic dehydration reactions [11,12].Although
the cyanuric chloride was used in excess the diacid at this
EXPERIMENTAL
The chemical and solvents reagents used for synthesis
were analytical grade with minimum purity 99.5 %. The
structures of the compounds were confirmed chromatographic
and spectroscopic method the details of which are as follows.

902 Firke et al.
Asian J. Chem.
TABLE-1
O
O
O
O
THE OPTIMIZED GEOMETRIES AND THE ENTHALPY DATA
OF INTERMEDIATES OBTAINED FROM SEMI-EMPIRICAL
CALCULATION USING CS MOPAC® PRO VERSION 8.0
i-iii
+
OH
2
N
N
OH
O
O
2
1
O
O
Scheme-I: Reagents, conditions and yields: (i) Aq. LiOH, THF, 0 °C to
RT, 5 h (ii) Cyanuric chloride, Et3N, DCM, 0 °C to room tempe-
rature, 8 h (iii) Acetic acid, reflux, 5 h (three steps) 33 %
N
OH
1
O
∆H = -144.61 kcal/mol
stage there were two choices to form desired intermediate 4
and other 6 with different proportion. The ring size in ring closure
reaction followed by Baldwin rules [13-15]. In this reaction
with cyanuric chloride thermodynamically less favoured com-
pound 6 was preferentially formed. The six member cyclic
compound with intra-molecular hydrogen bonding distancing
by 2.141 Å bears more thermodynamic stability than that of
compound 4. The compound 4was then subjected to triethylamine
wherein exocyclic double bond was dragged into the ring by
abstraction of active methylene hydrogen in β-dialkyliso-
succinimide (4). Thus carbon-carbon double bond migration
took place due to extension of π-cloud to butyrioimidolide
carbonyl group. The abstraction of the α-methylene proton
from the intermediate 4 to form β-alkyl isomaleimide 5 took
place in presence of triethyl amine. The kinetically controlled
β-alkyl isomaleimide 5 was converted to the desired, thermody-
namically more stable alkylmaleimide, farinomalein (1) in almost
quantitative yield. The transformation 6 to 7 was forbidden
due to lack of driving force for migration of carbon-carbon double
bond. In compound 6, six membered ring open and reclosed
to formed isofarinomalein (2) in acetic acid reflux conditions.
After obtaining spectroscopic data we confirmed the structures
and the ratio of the compounds in the reaction sequence and to
shed some light on the reaction path the additional thermodyna-
mic data Table-1 was obtained from semi-empirical calculation
using CS MOPAC® pro version 8.0.
O
O
N
OH
2
O
∆H = -160.20 kcal/mol
O
N
OH
O
4
O
∆H = -151.51 kcal/mol
O
N
OH
O
5
O
∆H = -138.54 kcal/mol
2.141 Å
O
O
6
HO
N
O
∆H = -147.93 kcal/mol
O
O
HO
Aq. LiOH, THF,
0 °C to RT, 5 h
N
H
OH
2
O
3
Cyanuric chloride, Et3N,
DCM, 0 °C to RT, 8 h
k2
k1
k1>>k2
O
O
N
O
O
O
OH
HO
O
AcOH
N
OH
N
O
4
reflux, 5 h
O
6
O
2
H = -148.06 kcal/mol
H = -151.51 kcal/mol
Et3N
H = -160.20 kcal/mol
x
Et3N
O
O
O
N
O
O
OH AcOH
O
HO
N
OH
N
reflux, 5 h
O
7
5
O
1
O
H = -144.61 kcal /mol
H = -138.54 kcal /mol
Fig. 1. Plausible reaction path for the formation of farinomalein (1) and isofarinomalein (2)

Vol. 30, No. 4 (2018)
Haval-Argade Contrathermodynamic Rearrangement in Synthesis of Farinomalein 903
The detailed reaction coordinate of formation of farino-
malein (1) and isofarinomalein (2) has been showed in Fig. 1.
The number of intermediates encountered in the HA contra-
thermodynamic rearrangement were also learned, although the
enthalpy values of those intermediate were numerically less
negative but the overall trend was similar to present study. The
scalar values the enthalpy of compounds 2-7 are relatively
high this may be due to the presence of acid functional group
and intramolecular hydrogen bonding present in it.
Conclusion
The present study gives a rational explanation on the
reaction path and the mechanism followed in formation of
farinomalein (1) and isofarinomalein (2). It also demonstrates
that kinetic conditions and thermodynamic stability plays an
important role in the reaction coordinate.
ACKNOWLEDGEMENTS
The authors thank UGC, New Delhi, Board of College &
University Development, Pune, India of Savitribai Phule Pune
University for research fund and Deccan Education Society’s
Fergusson College, Pune, India for their encouragement.
The obtained data utilized for the theoretical interpretation
viz. The compound 3 is converted to intermediate 6 with rate
k1 and compound 4 is converted to intermediate 5 with rate k2.
The intermediate 4 and 6 have enthalpies -151.51 and -148.06
kcal/mol, respectively. The reaction with cyanuric chloride and
triethylamine led to kinetically controlled and thermodynami-
cally less product. The practically isolated yields and enthalpies
rationally led to plausible fact that k1 >> k2. Fig. 2 explicitly
indicates change in enthalpies with reaction coordinate. The
intermediate 6 has intra-molecular hydrogen bonding, which
could be agitated by rotation of C-C bond of dihydro-1,3-oxazin-
one ring with rest of the moiety. The absence of intra-molecular
hydrogen bond elevated the ∆H towards less negative and that
too favour k1 >> k2. On the other hand, the intermediate 6 is
not having any butyrioimidolide carbonyl group which would
shift the allylic hydrogen and overruled the possibility of for-
mation of likely intermediate 7. The acetic acid reflux coverts
the intermediate 4 and 6 to farinomalein (1) and isofarinomalein
(2). The theoretically calculated enthalpy of isofarinomalein
and farinomalein are -160.20 and -144.61 kcal/mol, respec-
tively. In conclusion, the intermediates 4 and 6 played crucial
role in determining the fate of the HA contrathermodynamic
rearrangement in the reaction.
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0
1
2
3
4
5
-138.54
-140.00
-145.00
-150.00
-155.00
-160.00
-165.00
-144.61
-148.06
-151.13
k1
k2
-160.20
-160.20
Fig. 2. Graph of enthalpy vs. reaction coordinate