Heterocycle-Heterocycle Strategy for 4,5-Disubstituted Pyrrolidine 2,3-Diones: Reductive Rearrangement Approach from Isoxazole Esters

Article abstract of DOI:10.1055/a-1492-8216

The work demonstrates the heterocycle-heterocycle interconversion strategy to access 4,5-disubstituted 3-hydroxy-2-pyrrolidinone in moderate to good yields (50-80%). The approach has a distinct advantage over a multicomponent reaction approach as it allow

Full text of DOI:10.1055/a-1492-8216

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–E
letter
A
en
P. Kamath et al.
Letter
Synlett
Heterocycle–Heterocycle Strategy for 4,5-Disubstituted Pyrroli-
dine 2,3-Diones: Reductive Rearrangement Approach from Isox-
azole Esters
Prashantha Kamatha,b
Vaibhav Jadhava
Mukul Lal*a,b
0
0
0
0
-0
0
0
1
-
8
5
3
8
-
6
3
9
2
O
R2
O
O
R2
H–H interconversion
HO
O
O
R2
O
Fe (10.0 equiv.), AcOH
reflux, 1 h
O
O
R1
R1
12 examples
50–80% yield
N
a Syngenta Biosciences Pvt. Ltd. Santa Monica Works, Corlim,
Ilhas, Goa 403110, India
N
H
R1 = Aryl and alkyl
R2 = Me
mukul.lal@syngenta.com
b Department of Chemistry, Mangalore University, Mangalag-
angothri, 574199, Karnataka, India
MSeMyunakgiuCellonmLrtrauelkBsupiolo.slnacdli@einsgcyenAsguPetvnhto.arL.ctodm. Santa Monica Works, Corlim, Ilhas, Goa 403110, India
Received: 10.04.2021
OH
Accepted after revision: 27.04.2021
Published online: 27.04.2021
DOI: 10.1055/a-1492-8216; Art ID: st-2021-l0137-l
OH
O
N
O
O
Abstract The work demonstrates the heterocycle–heterocycle inter-
conversion strategy to access 4,5-disubstituted 3-hydroxy-2-pyrrolidi-
none in moderate to good yields (50–80%). The approach has a distinct
advantage over a multicomponent reaction approach as it allows access
to unsubstituted 3-hydroxy-2-pyrrolidinone at the nitrogen position for
further functionalization.
O
O
O
NH
OH
H
N
H
NH
O
HO
i
ii
Key words isoxazoles, pyrrolidinones, reductive rearrangement, het-
erocyle–heterocyle strategy, (3+2) cycloaddition, MCR
Figure 1 Naturally occurring leopoilic acid A (i) and cytochalasin B (ii)
With our ongoing interest in heterocycle–heterocycle
(H–H) interconversion strategy[7] we became interested to
extend the H–H strategy to access 5-aryl/alkyl-substituted
3-hydroxy-2-pyrrolidinones via re-organization of the cor-
responding isoxazoles under reducing conditions (Scheme
1).
The isoxazoles needed for the study were prepared via
the (3+2) cycloaddition of the corresponding nitrile oxides
with dimethyl acetylene dicarboxylate (symmetrically sub-
stituted acetylene) at room temperature in moderate to
good yields (50–84%, Scheme 2).[8]
Access to polysubstituted nitrogen heterocycles are cru-
cial to the discovery of novel biologically active compounds
(Figure 1).[1] Pyrrolidinones, including 3-hydroxy-2-pyrro-
lidinones, are one such class of nitrogen heterocycles being
actively pursued for their biological activity ranging from
HIV-1 inhibitors,[2] antitumor oral drugs,[3] antimicrobial,[4]
and antibacterial applications.[5] Recently, they have been
accessed via a multicomponent reaction (MCR) approach
requiring an aldehyde, substituted aniline, and either acety-
lene dicarboxylates or 2-oxo-1,4-dicarboxylates. The MCR
provides a convenient approach to 2-arylated 4-hydroxy-5-
pyrrolidinones (Scheme 1).[6]
R2
R2
O
O
O
O
O
R2
O
O
R2
R
2
O
HO
O
4
MCR approach
current approach
O
O
R2
or
+
O
R
O
O
N
R1
R
R1 NH2
N
R2
O
O
3
1
6
O
O
R2
5
Scheme 1 Literature-known multicomponent reaction approach to 2-pyrrolidinones and the current planned H–H approach to 2-pyrrolidinones
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
P. Kamath et al.
Letter
Synlett
To our surprise, replacing ethanol with acetic acid as re-
action solvent, formation of 1a was observed (no additive)
at reflux, however, with conversion of only 50% even after 5
h (entry 4, Table 1). To accelerate the reaction, further opti-
mization was carried out by doubling the reductant quanti-
ty from 5 equiv. to 10 equiv., and to our delight it gave 1a in
71% yield within 1 h of the reaction time (entry 5, Table 1).
When the reaction time was extended to 2 h, a 5–10% drop
in yield was observed suggesting decomposition of product
under these conditions (entry 6, Table 1). Attempts to carry
out reductive reorganization under hydrogenating condi-
tions did not yield 1a despite consumption of staring mate-
rial (entry 7, Table 1).
The optimized conditions for reductive reorganization
(entry 5, Table 1), i.e., iron as reductant (10.0 equiv.) in ace-
tic acid under reflux conditions for 1 h, were used for gen-
eral applicability of the method on other isoxazoles 6b–l.
Indeed, formation of 1b–l was observed in all the cases in
moderate to good yields (50–80%, Table 2). Interestingly,
trends in the yield after isolation of 1a–l were similar to
those observed in the synthesis of isoxazoles 6a–l, i.e., elec-
tron-withdrawing groups on aryl ring at 2-position in 6a–l
gave higher yields of rearranged product (1d–f,h, Table 2)
than alkyl/electron-donating substituents on the aryl ring
(1b,g,i,l, Table 2).
O
O
R2
1) NCS, DMF, RT, 1 h
2) DMAD, TEA, RT, 1–2 h
OH
O
R2
O
N
50–84%
R1
7a–l
O
R1
N
6a–l
Scheme 2 Synthesis of isoxazole derivatives 6a–l via a (3+2) cycloaddi-
tion on dimethyl acetylenedicarboxyalte (DMAD)
In general, the yield for isoxazole formation was rela-
tively higher for electron-withdrawing substituents on the
aryl rings than in the presence of electron-donating substit-
uents on the ring. The low yield for the (3+2) cycloaddition
in electron-donating nitrile oxide can be attributed to self-
dimerization of nitrile oxides.[9]
Attempt to carry out reductive reorganization of isoxaz-
oles 6a–l[10] to 2-pyrrolidinones 1a–l was initially opti-
mized with 6a as model substrate with iron as choice of re-
ductant (Scheme 3).[11] Reductive rearrangement of 5a to 1a
was not observed when the reaction was carried out with
ammonium chloride as additive and ethanol as solvent,
even after prolonged heating at 80 °C (5 equiv.; Table 1, en-
try 1).
Table 1 Optimization of the Reductive Rearrangement of 6 to 1
This could be due to stabilization of the developing
charge during the reduction step. It was also observed that
the yield of alkyl-substituted isoxazole gave reasonable to
good yields of 1 (1c,k, Table 2) under the reaction condi-
tions.[12]
Entry Solvent Reductant
(equiv.)
Temp
(°C)
Time
(min)
Conversion
(yield, %)
1
2
3
4
5
6
7
EtOH
EtOH
EtOH
AcOH
AcOH
AcOH
EtOH
Fe/NH4Cl (5)
Zn/NH4Cl (5)
Fe/HCl (5)
Fe (5)
80
300
300
300
300
60
no reaction
no reaction
multiple spots
50
80
A plausible mechanism for the reductive rearrangement
might be attributed to an initial SET between the reductant
and 6 followed by protonation to form an intermediate A.
Intermediate A could lead to the desired product following
either path 1 or path 2 characterized by tautomerization,
cyclization, and reduction. Path 1 involves an initial tau-
tomerization (B), cyclization (C), reduction (1′), or path 2
involves further reduction (D), tautomerization (E), cyclisa-
tion (1′) and tautomerization to yield 1 (Scheme 4).
In conclusion the present work demonstrates the con-
version of isoxazoles 6a–l[10] into polysubstituted 2-pyrro-
lidinones (1a–l, 50–80% yield) under reductive rearrange-
ment conditions with iron as reductant in acetic acid as sol-
vent. The approach has a distinct advantage in accessing
unsubstituted 2-pyrrolidinones at the nitrogen center al-
lowing further scope of derivatization. The work further
demonstrates the usefulness of heterocycle–heterocycle in-
terconversion approach to access polysubstituted 2-pyrro-
lidinones from their corresponding isoxazoles. Further
work is necessary to understand the overall mechanism and
to exploit the full potential of this methodology.
80
110
110
110
110
Fe (10)
100 (71)
Fe (10)
120
120
100 (65)
Pd/C, H2 (5
bar)
multiple spots
Replacement of either the reductant, i.e., iron with zinc,
or the additive, i.e., ammonium chloride with hydrochloric
acid, did not yield the desired product (entry 2, Table 1).
With hydrochloric acid as additive the starting material was
consumed albeit with extensive degradation of 6a within 5
h at 80 °C (entry 3, Table 1).
O
R2
O
O
R2
Fe (10 equiv.), AcOH
110 °C, 1 h
HO
O
O
R2
O
O
R1
50–80%
O
R1
N
H
N
6a–l
1a–l
Scheme 3 Reductive rearrangement of 6a–l to 1a–l in the presence of
iron as reductant and acetic acid as solvent
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

C
P. Kamath et al.
Letter
Synlett
NH2 OH
NH2
O
O
O
Tautomer
O
O
R
R
O
O
O
O
E
D
Path 2
+ 2 e–, + 2 H+
Cyclization
O
O
N
O
NH OH
HN
O
+ 2 e–, + 2 H+
HN
O
O
Tautomer
O
R
R
R
OH
R
O
O
O
O
O
O
O
O
O
1
6
1'
A
Path 1
+ 2 e–, + 2 H+
Tautomer
H
O
NH2
O
O
NH
O
N
Cyclization
O
O
Tautomer
R
R
O
R
O
O
O
O
O
O
O
B'
B
C
Scheme 4 Plausible mechanism for the reductive rearrangement of isoxazoles 5 to 2-pyrrolidinone 1 using iron as reductant in acetic acid as solvent
Table 2 Synthesis of Isoxazole Esters 6a–l by Cycloaddition of the Corresponding Oximes 7a–l and Their Reductive Rearrangement to Pyrrolidine
Diones 1a–l
Entry
Oxime 7a
Isoxazole 6
Yield of 6 (%)
Pyrrolidine dione 1 (reduction)
Yield of 1 (%)
O
O
OH
O
N
HN
N
OH
a
71
71
O
O
O
O
O
O
O
OH
O
N
HN
O
N
OH
b
68
80
74
60
77
77
O
O
O
O
O
OH
O
O
N
N
HN
OH
O
c
O
O
O
O
O
O
N
OH
HN
O
O
N
OH
d
Cl
O
Cl
O
O
O
Cl
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

D
P. Kamath et al.
Letter
Synlett
Entry
Oxime 7a
Isoxazole 6
Yield of 6 (%)
Pyrrolidine dione 1 (reduction)
Yield of 1 (%)
O
F
F
N
O
OH
OH
HN
F
N
O
OH
e
70
82
65
84
80
O
O
O
O
O
O
F
N
O
F
HN
O
F
N
F
O
OH
f
78
61
62
O
O
O
F
O
F
O
OH
N
O
N
HN
O
OH
g
h
O
O
O
O
O
O
O
O
O
O
Cl
Cl
OH
N
HN
Cl
N
O
OH
O
Cl
O
Cl
O
O
O
O
Cl
OH
N
O
N
HN
O
O
OH
i
58
55
O
O
O
O
O
O
O
O
F
F
F
F
CF3
F
F
O
OH
N
O
HN
N
OH
j
78
60
50
68
60
50
O
O
O
O
O
O
N
O
OH
O
HN
N
OH
k
O
O
O
O
O
O
OH
N
O
HN
O
N
O
OH
l
S
O
S
O
O
O
S
a Oximes 7a–l were prepared using the literature protocol.
Conflict of Interest
Funding Information
The authors declare no conflict of interest.
The authors would like to thank Syngenta Biosciences Pvt. Ltd. for the
support provided for carrying out the work under its PhD program.()
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

E
P. Kamath et al.
Letter
Synlett
Supporting Information
(9) (a) Dubrovskiy, A. V.; Larcok, R. C. Org. Lett. 2010, 12, 1180.
(b) Spiteri, C.; Sharma, P.; Zhang, F.; Macdonald, S. J. F.; Keeling,
S.; Moses, J. E. Chem. Commun. 2010, 46, 1272.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1492-8216. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
(10) General Procedure for the Synthesis of Isoxazoles 6To a solu-
tion of oxime (1.0 mmol, 1.0 equiv.) in DMF (2.0 mL) at room
temperature was added N-chlorosuccinimide (1.1 mmol, 1.1
equiv.) and stirred for 60 min. Dimethylacetylenedicarboxylate
(DMAD) was added in one portion (1.1 mmol, 1.1 equiv.). Then,
a solution of triethylamine (1.0 mmol, 1 equiv.) in DMF (1.0 mL)
was added. The solution was stirred at RT till the reaction com-
pletes. The reaction mass poured into ice water, stirred for 10
min and extracted with ethyl acetate. The combined organic
layer was washed with brine solution, dried over anhydrous
sodium sulfate, and concentrated in vacuum. Purification if nec-
essary was done by column chromatography using cyclohexane
and ethyl acetate as mobile phase. §#BLD#§Dimethyl 3-
Phenylisoxazole-4,5-dicarboxylate (6a)
(11) Prepared using the general procedure by starting with benzal-
dehyde oxime (3.0 mmol). Off-white solid, 71% yield; mp 62–64
°C. 1H NMR (400 MHz, CDCl3):  = 7.71–7.70 (d, J = 7.3 Hz, 2 H),
7.54–7.46 (m, 3 H), 4.10 (s, 3 H), 3.92 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3):  = 161.8, 161.2, 159.3, 156.4, 130.6, 128.8,
128.1, 126.8, 116.04, 53.3, 53.1 ppm. HRMS (ESI): m/z [M + H]+
calcd for C13H11NO5: 261.0637; found: 261.0634.
References and Notes
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Martino, P. A.; Dallavalle, S. Beilstein J. Org. Chem. 2016, 12,
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Bioorg. Med. Chem. Lett. 2011, 21, 6724. (b) Pendri, A.; Troyer, T.
L.; Sofia, M. J.; Walker, M. A.; Naidu, B. N.; Banville, J.; Meanwell,
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2010, 12, 84. (c) Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.;
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Chem. 2012, 55, 9630.
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2002, 36, 188. (b) Anderson, D. R.; Stehle, N. W.; Kolodziej, S. A.;
Reinhard, E. J. WO2004055015 (A1) 2014. (c) Neo, A. G.; Marcos,
C. F. Org. Lett. 2018, 20, 3875.
(12) General Procedure for the Synthesis of Pyrrolidine Diones
1a–l
(4) Gein, V. L.; Armisheva, M. N.; Rassudikhina, N. A.; Voronina, E. V.
Pharm. Chem. J. 2011, 45, 162.
To a solution of isoxazole ester (0.5 g) in acetic acid (5.0 mL) was
added portionwise Fe powder (10.0 equiv.) at 100 °C. During the
addition, the colorless solution turned to dark brown. The reac-
tion was monitored by LC–MS and after complete conversion
the reaction mass was cooled to RT and poured into saturated
aqueous sodium bicarbonate solution (50.0 mL). The mixture
was filtered over a bed of Celite and the filtrate was extracted
with diethyl ether before acidification with concd HCl to pH 1.
During acidification the color of the solution turned from pale
yellow to red and colorless at pH 1. The product was extracted
to ethyl acetate layer and concentrated to get target molecule as
solid (50–80%).
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2010, 40, 1350.
Methyl-4-hydroxy-5-oxo-2-phenyl-1,2-dihydropyrrole-3-
carboxylate (1a)
Prepared using the general procedure by starting with dimethyl
3-phenylisoxazole-4,5-dicarboxylate (3.0 mmol). Off-white
1
solid, 71% yield; decomposes above 140 °C. H NMR (400 MHz,
DMSO-d6):  = 11.44 (s, 1 H), 9.27 (s, 1 H), 7.35–7.18 (m, 5 H),
5.18 (s, 1 H), 3.53 (s, 3 H) ppm. 13C NMR (101 MHz, DMSO-d6): 
= 166.3, 162.7, 154.2, 138.4, 128.3, 127.8, 127.1, 112.1, 56.4,
50.9 ppm. HRMS (ESI): m/z [M + H]+ calcd for C12H11NO4:
233.0688; found: 233.0684.
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Harate, S. B. RSC Adv. 2015, 5, 3470.
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Synth. 2011, 8, 659. (b) Chen, Y.; Dong, H.; Zhang, H. Chem. Eng.
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© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E