Biobased Spiroimides from Itaconic Acid and Formamides: Molecular Targets for a Novel Synthetic Application of Renewable Chemicals

Article abstract of DOI:10.1055/s-0040-1707318

Spiroimides exhibit a wide range of biological activities, such as anticonvulsant, antiarrhythmic, and antihyperglycemic activities. Herein, a novel synthetic application of renewable chemicals, itaconic acid and formamides, is described. Proper exploitation of the reactivity of itaconic acid and formamide allows for the development of an efficient synthetic approach for the production of several new biobased spiroimides, spiro[dihydroquinolin-2-one-succinimides] and spiro[indolin-2-one-glutarimides], in excellent overall yields (up to 98%).

Full text of DOI:10.1055/s-0040-1707318

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–M
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M. M. Hornink et al.
Feature
Synthesis
Biobased Spiroimides from Itaconic Acid and Formamides:
Molecular Targets for a Novel Synthetic Application of Renewable
Chemicals
Milene Macedo Hornink
Alice Uva Lopes
Leandro Helgueira Andrade*
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Institute of Chemistry, University of São Paulo,
Av. Prof. Lineu Prestes, 748, São Paulo,
SP 05508-000, Brazil
leandro@iq.usp.br
LIeneMsataniitCdluorlteorearHeonsefdplCrgoohun@eedmiiqrnai.usgAtsrApnyu.d,btUrrhanodireversity of São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
Received: 17.06.2020
Accepted after revision: 08.09.2020
Published online: 20.10.2020
peratures, long reaction times, and halogenated solvents,
which are not attractive from a green chemistry perspec-
tive. Additionally, the lack of concern regarding the applica-
tion of renewable compounds is apparent in those method-
ologies.
Considering the need for greener synthetic methodolo-
gies designed from renewable feedstocks,9 we developed a
novel synthetic pathway to obtain new biobased spiroimid-
es, exploiting the reactivity of itaconic acid and formamide
(Scheme 1).
DOI: 10.1055/s-0040-1707318; Art ID: ss-2020-z0330-fa
Abstract Spiroimides exhibit a wide range of biological activities,
such as anticonvulsant, antiarrhythmic, and antihyperglycemic activi-
ties. Herein, a novel synthetic application of renewable chemicals,
itaconic acid and formamides, is described. Proper exploitation of the
reactivity of itaconic acid and formamide allows for the development of
an efficient synthetic approach for the production of several new
biobased spiroimides, spiro[dihydroquinolin-2-one-succinimides] and
spiro[indolin-2-one-glutarimides], in excellent overall yields (up to
98%).
Key words spiroimides, itaconic acid, formamides, renewable build-
ing blocks, photochemistry
Spiro compounds are a class of rigid scaffolds with
unique structural features, which are often relevant for
drug discovery.1 In this context, spirosuccinimide and
spiroglutarimide scaffolds are found in compounds of bio-
logical interest, such as anticonvulsant,2 antiarrhythmic,3
and antihyperglycemic4 agents, sedatives,5 and inhibitors of
the enzyme aldose reductase6,7 (Figure 1).
O
H
N
O
O
NH
R
O
N
O
O
R1
N
R2
Scheme 1 Biobased spiroimides as molecular targets for the synthetic
O
application of renewable materials
O
Sedative and
Anticonvulsant
Antihyperglycemic
hypnotic activities
Figure 1 Selected examples of bioactive spiroimides
Itaconic acid is a renewable chemical used in the syn-
thesis of biobased polymers (polyesters and poly-
amides),10,11 and can be produced from the fermentation of
sugars or starch by Aspergillus terreus.12 Moreover, forma-
mide (HCONH2) has been considered a key prebiotic pre-
cursor of relevant organic compounds.13 There are studies
Despite these important biological activities of spiroim-
ides, the development of general synthetic routes to obtain
these compounds is quite scarce in the literature.7,8 Most of
the methods employ harsh conditions, such as high tem-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. M. Hornink et al.
Feature
Synthesis
dedicated to understanding its role in the origin of life on
our planet.14 In addition, formamide is ubiquitous in the
universe and has been found in molecular clouds,15 com-
ets,16 interstellar medium,17 and also in protostellar cores.13
Industrially, formamide is a well-known solvent. There are
different synthetic routes for formamide, which include
carbon monoxide (CO), carbon dioxide (CO2), formic acid
(HCO2H), and methyl formate (HCO2Me) as C1 starting ma-
terials.18,19
Our successful synthetic strategy to obtain new
biobased spiroimides relies on the structural features of
itaconic acid and formamide. Proper exploitation of both
carboxyl groups of itaconic acid can result in two key inter-
mediates, 1 and 2 (Scheme 2). Carbamoyl radical, which can
be generated from formamide using Fenton’s reaction,20 can
react with ,-unsaturated esters 1 and amides 2 to pro-
duce 3,4-dihydroquinolin-2-one 3 and indolin-2-one 4
cores, respectively. Finally, succinimide and glutarimide
frameworks can be generated via a cyclization reaction un-
der basic conditions, yielding new biobased spiroimides 5
and 6.
Initially, biobased amides 1a–j were prepared through a
selective ring-opening reaction of itaconic anhydride with
N-alkylated aromatic amines, followed by an esterification
reaction (Scheme 3). After three steps, compounds 1a–j
were obtained in high overall yields. It is worth mentioning
that only one purification step by column chromatography
was needed.
For the synthesis of methyl 3-(alkyl(aryl)carbam-
oyl)but-3-enoates 2a–d, methyl 3-(chlorocarbonyl)but-3-
enoate was prepared from itaconic acid methyl ester21 and
then reacted with N-alkylated aromatic amines (Scheme 4).
Having obtained the biobased amides 1a–j and 2a–d,
the next step was the exploitation of their reactivity toward
carbamoyl radicals. We employed Fenton’s reaction (hydro-
gen peroxide, H2SO4, Fe2+)20b for a fast hydroxyl radical
Biographical Sketches
Milene M. Hornink was born
in 1995 in Piracicaba, São Paulo,
Brazil. She received her bache-
lor’s degree in chemistry from
the Federal Institute of Educa-
tion, Science and Technology of
São Paulo in 2017. Currently,
she is working on her PhD re-
search under the direction of
Prof. Leandro H. Andrade. Her
PhD research focuses on the de-
velopment of catalytic methods
employing haloperoxidases and
on the exploitation of biomass-
derived chemicals for the syn-
thesis of nitrogen-containing
spiro compounds.
Alice U. Lopes was born in
1998 in São Paulo, São Paulo,
Brazil. Currently, she is an un-
dergraduate student at the
School of Pharmaceutical Sci-
ences (University of São Paulo)
in São Paulo. In 2018/2019, she
spent one year in Prof.
Andrade’s lab working on the
synthesis of spiro compounds
from biobased chemicals.
Leandro H. Andrade was
born in Santo Antônio das
Missões, Brazil. He received his
M.S. degree in chemistry (1998)
and his PhD degree in chemistry
(2002) from the Federal Univer-
sity of Santa Maria (RS, Brazil),
working under the direction of
Professor A. L. Braga. In 2002,
postdoctoral fellowship to work
with Professor J. V. Comasseto
at São Paulo University. In 2005,
he joined the Institute of Chem-
istry at São Paulo University as
Professor of Chemistry. He
served as the Chair of the Brazil-
ian Chemical Society, Organic
Chemistry Division (2011–
2014). In 2013/2014, he spent a
sabbatical year in the Depart-
ment of Chemistry at the Mas-
sachusetts
Institute
of
Technology, USA working with
Professor Timothy F. Jamison.
He is an Associate Editor of the
journal Química Nova. His cur-
rent research interests include
sustainable synthesis, catalysis,
and flow chemistry.
he was awarded
a one-year
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

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M. M. Hornink et al.
Feature
Synthesis
O
O
1
OH
OH
HO
HO
4
2
3
O
O
itaconic acid
ref. 21
R1
N
R1
R1
O
CO2Me
CO2Me
TEA
EtOAc
R2
+
Cl
N
H
N
R2
2a–d
(24–89%)
O
0 °C to rt
O
O
R2
R1 = H, p-OMe, p-CF3
R2 = Me, Bn
OMe
MeO
R2
N
O
O
Scheme 4 Synthesis of methyl 3-(alkyl(aryl)carbamoyl)but-3-enoates
2a–d
1
2
R1
O
R3
N
O
NH2
H
MeO
Fe2+, H2O2, H2SO4
65 °C, 2 h
NH2
O
O
CO2Me
O
+
NHR3
O
NHR3
O
N
O
N
O
MeO
R1
MeO
R1
O
1a
3a
O
N
R2
N
R2
O
Scheme 5 Exploitation of carbamoyl radical generation under batch
conditions for the synthesis of dihydroquinolin-2-ones
4
3
Base
employs a photochemical flow reactor. Moreover, the incor-
poration of flow chemistry into our synthetic approach
could offer some advantages, including safety, efficiency,
and productivity.24 Photochemical reactions performed un-
der continuous flow conditions offer important advantages
over batch conditions, especially regarding the issues asso-
ciated with scale-up and efficient exposure of the whole re-
action solution to irradiation.24e,f
MeOH
R1
MeOH
R3
O
R3
O
O
N
N
O
R1
O
N
N
O
R2
R2
5
6
The photochemical flow reactor utilized a UV lamp
(medium-pressure, mercury vapor lamp, 450 W), a tube re-
actor (1 mL), and a syringe pump. The synthesis of dihydro-
quinolin-2-one 3a under continuous flow conditions was
evaluated at room temperature and with a short residence
time (tR). As shown in Table 1, the desired product, dihydro-
quinolin-2-one 3a, was successfully obtained from
biobased amide 1a employing 10 minutes of residence time
and different catalyst concentrations (10, 5, and 1 mol%
Fe2+). All reactions resulted in full conversion of amide 1a
(entries 1–4). Finally, as a control assay to verify the exis-
tence of a photochemical process, a reaction in the absence
of UV light was carried out, and no product was observed
(entry 5).
Scheme 2 Our synthetic strategy to obtain new biobased spiroimides
generation, a powerful oxidant22 which produces carbamoyl
radical in the presence of formamide. Our exploratory ex-
periment under batch conditions, containing the biobased
amide 1a, successfully resulted in the full conversion of 1a
into dihydroquinolin-2-one 3a after 2 hours at 65 °C
(Scheme 5).
Although dihydroquinolin-2-one 3a was successfully
synthesized, we decided to use a photo-Fenton process for a
faster generation of carbamoyl radical.23 This methodology
In comparison to batch conditions (Scheme 5; full con-
version, 2 h, 65 °C), flow photochemistry enabled us to de-
crease the reaction time and temperature for the produc-
tion of dihydroquinolin-2-one 3a (Table 1; full conversion,
10 min, 25 °C). In addition to the above-mentioned advan-
tages of flow chemistry, another key component in its per-
formance relies on the fact that photochemistry applied to
the Fenton reaction can increase the production of hydroxyl
and carbamoyl radicals in a very short reaction time, conse-
quently increasing the production of dihydroquinolin-2-
one 3a.
R1
R1
CO2Me
(a), (b)
R2
+
O
N
O
N
H
O
O
O
R2
1a–j
ref. 10b
(32–63%)
OH
O
HO
R1 = H, p-CH3, p-OMe, p-F, p-Cl, p-Br, p-CF3, p-CO2Me
R2 = Me, Bn, Ph
Scheme 3 Synthesis of biobased amides 1a–j. Reagents and conditions:
(a) toluene, 70–80 °C, 1.5 h; (b) SOCl2, MeOH, reflux, 2.5 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

D
M. M. Hornink et al.
Feature
Synthesis
Table 1 Synthesis of Dihydroquinolin-2-one 3a Using a Photochemical Flow Reactora
O
Hg Lamp
450 W
NH2
O
CO2Me
FeSO4 (1–10 mol%)
H2SO4 (0.2 mol L–1
MeO
+
N
O
BPR
75 psi
)
1a (0.2 mol L–1
)
N
O
50 μL min–1
O
t
R = 10 min
V = 1 mL
25 °C
3a
H2O2 (0.2–0.4 mol L–1
)
= Solvent
NH2
50 μL min–1
Entry
FeSO4 (mol%)
H2O2 (mol·L–1
)
3a (%)b
1
10
5
0.2
0.2
0.2
0.1
0.2
>99
>99
>99
>99
0
2
3
1
4
1
5c
1
a Reaction conditions inside the reactor: 1a (0.1 mol·L–1), H2SO4 (0.1 mol·L–1), FeSO4 (1–10 mol%), H2O2 (0.1–0.2 mol·L–1; 30% aqueous solution), formamide as
solvent; residence time (tR) = 10 min; 25 °C; back-pressure regulator (BPR) set to 75 psi.
b Conversion was determined by GC/MS analysis.
c Hg lamp off.
With the optimized conditions established for carbam-
O
(a)
O
NH2
O
NH
oyl radical generation (Table 1, entry 3), we carried out the
continuous production of 3,4-dihydroquinolin-2-one 3a
and indolin-2-one 4a using a photochemical flow reactor
(Scheme 6). After 2 hours of production, formamide was re-
moved by vacuum distillation, and 3,4-dihydroquinolin-2-
one (3a) was isolated in high yield (83%). We also obtained
indolin-2-one 4a in excellent yield (87%).
MeO
O
O
K2CO3 (1 equiv)
toluene
reflux, 2 h
N
N
O
3a
5a (95%)
(b)
H
N
O
O
NH2
O
K2CO3 (1 equiv)
O
MeO
toluene
reflux, 2 h
O
O
O
N
N
NH2
NaH (1 equiv)
THF, rt, 1 h
91%
MeO
O
4a
6a
Amides 1a, 2a (0.2 mol L–1
)
Hg Lamp
450 W
FeSO4 (1 mol%)
N
O
H2SO4 (0.2 mol L–1
)
Scheme 7 Base-promoted cyclization of intermediates 3a and 4a
3a (83%)
50 μL min–1
H2O2 (0.4 mol L–1
BPR
75 psi
O
)
NH2
O
50 μL min–1
MeO
t
R = 10 min
3,3-disubstituted indolin-2-one 4a, but spiro[indolin-2-
one-glutarimide] 6a could not be obtained. Therefore, a
stronger base (sodium hydride) was employed, and spiro-
imide 6a was obtained in excellent yield (91%) after 1 hour
at room temperature (Scheme 7b).
O
V = 1 mL
25 °C
O
= Solvent
NH2
N
4a (87%)
CO2Me
CO2Me
Amides 1a, 2a:
A final setup for the production of biobased spiroimides
was designed to avoid multiple steps, mainly aqueous
workup and chromatographic purifications. The first step
was the continuous production of dihydroquinolin-2-ones
3a–i using a photochemical flow reactor. Then, formamide
was recovered by vacuum distillation, and the crude mate-
rial was treated with K2CO3 to produce spiro[dihydroquino-
lin-2-one-succinimides] 5a–i (Scheme 8). Biobased amides
1 were fully converted into the corresponding 3,4-dihydro-
quinolin-2-ones 3a–i using the photochemical flow reactor.
A reaction time of 2 hours was chosen for the imide forma-
tion, and several spiro[dihydroquinolin-2-one-succinimid-
es] 5 were produced in excellent overall yields (Scheme 8).
It is noteworthy that the biobased amide 1 containing a
N
O
N
O
2a
1a
Scheme 6 Production of dihydroquinolin-2-one 3a and indolin-2-one
4a using a photochemical flow reactor
After the construction of 3,4-dihydroquinolin-2-one
and indolin-2-one cores, succinimide and glutarimide
frameworks were generated by a cyclization reaction under
basic conditions. As depicted in Scheme 7, an inexpensive
base, K2CO3, was employed in the imide formation. The con-
version of dihydroquinolin-2-one 3a into spiro[dihydro-
quinolin-2-one-succinimide] 5a was excellent (Scheme 7a;
95% isolated yield, 2 h). The same protocol was applied to
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

E
M. M. Hornink et al.
Feature
Synthesis
R1
CO2Me
R3
O
FeSO4 (1 mol%)
H2SO4 (0.2 mol L–1
+
N
R2
O
Hg Lamp
450 W
N
)
NHR3
O
O
N
R2
3a–o
R1
O
MeO
1 (0.2 mol L–1
)
R1
(a) distillation
(b) K2CO3
Δ
, 2 h
BPR
75 psi
50 μL min–1
H2O2 (0.4 mol L–1
50 μL min–1
N
O
)
O
R2
O
5a–o
t
R = 10 min
R3
= Solvent
(Overall isolated yields
are given in parentheses)
N
H
V = 1 mL
25 °C
(not isolated)
O
O
O
O
O
NH
NH
NH
NH
O
NH
O
O
O
O
O
O
O
O
N
N
N
N
O
O
N
5d (90%)
5e (50%)
5a (91%)
5b (61%)
5c (74%)
O
N
O
O
O
O
NH
NH
NH
NH
O
O
O
O
O
O
Cl
F3C
Br
F
N
N
O
O
N
N
N
O
O
5j (43%)
5i (98%)
5g (67%)
5f (77%)
5h (75%)
O
N
O
N
O
N
O
O
N
N
O
O
O
O
O
O
O
O
O
Cl
F3C
N
N
N
N
O
N
O
5n (51%)
5o (49%)
5m (20%)
5l (43%)
5k (33%)
Scheme 8 Synthesis of spiro[dihydroquinolin-2-one-succinimides] 5a–o
strong electron-donating group (methoxy) attached to the
aromatic ring produced spiroimide 5e in moderate overall
yield. We assume that such an aromatic ring containing a
strong electron-donating group is susceptible to degrada-
tion by the photo-Fenton process applied for fast carbamoyl
generation.25
N-Methylformamide was also used to produce N-meth-
ylated spiroimides (Scheme 8). The carbamoyl radical gen-
erated from N-methylformamide was very efficient in pro-
ducing 4,4-disubstituted dihydroquinolin-2-ones 3j–o un-
der continuous flow conditions. N-Methylformamide was
recovered by vacuum distillation, and K2CO3 was added to
the crude mixture to promote imide formation. Some N-
methylated spirosuccinimides 5j–o were obtained in good
overall yields; however, some 4,4-disubstituted dihydro-
quinolin-2-ones were not fully transformed, resulting in
moderate overall yields.
Next, we focused on spiro[indolin-2-one-glutarimides]
6a–e with the biobased amides 2a–d as key intermediates
(Scheme 9). Carbamoyl radicals were generated from for-
mamide and N-methylformamide in the presence of 2a–d
using the photochemical flow reactor. All reactions were
carried out at 25 °C with tR = 10 min, yielding 3,3-disubsti-
tuted indolin-2-ones 4, which were purified by column
chromatography prior to imide formation. Then, com-
pounds 4a–e were treated with sodium hydride at room
temperature for 1 hour, affording spiro[indolin-2-one-glu-
tarimides] 6a–e in high overall yields.
As a proof of concept, we decided to synthesize one ex-
ample of a spiroimide from renewable chemicals using all-
biobased carbons (Scheme 10). We chose pABA (4-amino-
benzoic acid), which is one of the few abundant anilines26
found in nature. pABA is produced by plants and fungi and
stored for the production of folate.27 We applied pABA to
produce amide 1h in high yield (47%). The continuous gen-
eration of carbamoyl radicals in the presence of amide 1h
afforded the corresponding 4,4-disubstituted dihydroquin-
olin-2-one. Formamide was removed by distillation, and
the crude material was treated with K2CO3 to give the im-
ide. Finally, biobased spiro[dihydroquinolin-2-one-succin-
imide] 5p was isolated in excellent overall yield (75%).
A plausible reaction mechanism for the formation of the
3,4-dihydroquinolin-2-one core is suggested in Scheme 11.
Hydroxyl radical generation is driven by the photo-Fenton
process. Once formed, hydroxyl radical can remove formyl
hydrogen from formamide, producing carbamoyl radical.
Then, carbamoyl radical can react with the C–C double
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

F
M. M. Hornink et al.
Feature
Synthesis
R1
CO2Me
R3
N
N
R2
O
+
O
Hg Lamp
450 W
O
FeSO4 (1 mol%)
NHR3
O
H2SO4 (0.2 mol L–1
)
O
2a–d (0.2 mol L–1
50 μL min–1
H2O2 (0.4 mol L–1
)
MeO
R1
R1
NaH
BPR
75 psi
O
O
THF, rt, 1 h
)
N
R2
N
R2
50 μL min–1
O
6a–e
t
R = 10 min
R3
4a–e
= Solvent
(Overall isolated yields
are given in parentheses)
N
H
V = 1 mL
25 °C
H
N
O
H
N
O
N
O
H
H
N
O
O
N
O
O
O
O
O
O
O
F3C
O
O
O
O
N
N
N
N
N
6a (79%)
6d (87%)
6e (36%)
6c (62%)
6b (46%)
Scheme 9 Synthesis of spiro[indolin-2-one-glutarimides] 6a–e
(a) Dihydroquinolin-2-one formation
R1
CO2Me
N
R2
O
O
R1
O
NHR3
O
O
R3HN
H2O
N
CO2Me
R2
I
R3HN
HO
O
NHR3
MeO
H
Fe3+ + H2O
R1
O
O
UV
light
HO
N
Fe2+
+ H+
R2
II
H2O2
Y
HY
O
NHR3
MeO
R1
O
O
N
R2
Scheme 10 Synthetic pathway for the production of spiroimide 5p us-
ing all-biobased carbons. Reagents and conditions: (a) SOCl2, MeOH, rt
to reflux, 2 h; (b) NaOMe, HCOH, NaBH4, MeOH, rt to reflux, 1.6 h; (c)
itaconic anhydride, toluene, 70–80 °C, 1.5 h; (d) SOCl2, MeOH, reflux,
2.5 h; (e) photochemical flow reactor: 1h (0.2 mol·L–1), H2SO4 (0.2
mol·L–1), FeSO4 (1 mol%), H2O2 (30% aqueous solution; 0.4 mol·L–1),
formamide as solvent, tR = 10 min, 25 °C; (f) K2CO3 (1.0 equiv), reflux,
Dean–Stark apparatus, 2 h.
III
(b) Imide formation
O
O
NR3
O
NHR3
MeO
R1
R1
B–
O
N
R2
O
N
O
R2
MeOH
IV
III
Scheme 11 Proposed reaction mechanism for dihydroquinolin-2-one
and imide formation
bond of the unsaturated amide, generating intermediate I
that undergoes cyclization and rearomatization to produce
the dihydroquinolin-2-one core. The reaction mechanism
for indolin-2-one formation should follow a similar path.
During imide formation, a cyclization reaction occurs due
to the presence of a primary amide and an ester group un-
der basic conditions, yielding spiroimides.
In summary, a novel synthetic application of renewable
chemicals, itaconic acid and formamides, has been de-
scribed for the production of biobased spiroimides. A pho-
tochemical flow reactor was used to generate carbamoyl
radicals from formamides, which enabled the fast synthesis
of dihydroquinolin-2-one and indolin-2-one cores. Finally,
spiro[dihydroquinolin-2-one-succinimides] and spiro[indo-
lin-2-one-glutarimides] were synthesized in excellent over-
all yields.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

G
M. M. Hornink et al.
Feature
Synthesis
13C NMR (125 MHz, CDCl3):  = 170.1, 167.0, 141.4, 137.9, 135.2,
130.4, 127.6, 127.1, 51.9, 37.7, 37.4, 21.1.
MS (EI+): m/z (%) = 247 (M+, 5), 121 (100), 91 (15).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H17NO3: 248.1287; found:
Formamides, itaconic acid, and itaconic anhydride were purchased
from Sigma-Aldrich. Solvents were purified by standard procedures.
Reactions were monitored using a GC/MS instrument (QP-2010 SE,
Shimadzu) with low-resolution electron impact (EI, 70 eV) equipped
with an Rtx-5MS capillary column (conditions: injector 260 °C, detec-
tor 110 °C, pressure 100 kPa, column temperature range 80 °C to 280
°C at 1 °C/min). Flash column chromatography was performed with
silica gel (200–300 mesh). 1H NMR spectra were recorded with 500
MHz and 300 MHz Bruker spectrometers. TMS was used as an inter-
nal standard (CDCl3,  7.26 ppm; DMSO-d6,  2.51 ppm; MeOD,  3.31
ppm). Coupling constants, J, are reported in hertz (Hz). Proton-decou-
pled 13C NMR spectra were recorded with 500 MHz and 300 MHz
Bruker spectrometers (CDCl3,  77.0 ppm; DMSO-d6,  40.0 ppm;
MeOD,  47.6 ppm). High-resolution mass spectra were recorded with
a Bruker Daltonics micrOTOF spectrometer using ESI-TOF techniques.
Infrared spectra were recorded with an FTIR spectrometer (Nexus
670 Nicolet). Melting points were determined with a Büchi apparatus
(B-545). N-Methylanilines, N-benzylanilines, and itaconic acid mono-
ester were prepared according to the methods described previously
(for more details, see the Supporting Information).
248.1283.
Methyl 4-((4-Methoxyphenyl)(methyl)amino)-2-methylene-4-
oxobutanoate (1c)
White solid; yield: 0.434 g (33%); Rf = 0.34 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 7.17 (d, J = 8.8 Hz, 2 H), 6.93 (d, J = 8.8
Hz, 2 H), 6.24 (s, 1 H), 5.59 (s, 1 H), 3.83 (s, 3 H), 3.73 (s, 3 H), 3.24 (s, 3
H), 3.08 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 170.3, 167.0, 159.0, 136.7, 135.2,
128.4, 127.6, 114.9, 55.5, 51.9, 37.7, 35.5.
MS (EI+): m/z (%) = 263 (M+, 10), 137 (100), 122 (69).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H17NO4: 264.1236; found:
264.1238.
Methyl 4-((4-Fluorophenyl)(methyl)amino)-2-methylene-4-
oxobutanoate (1d)
Biobased Amides 1a–j; General Procedure28,29
Step 1: A solution of N-alkylaniline (5 mmol) in toluene (2 mL) was
added to a stirred suspension of itaconic anhydride (0.68 g, 6 mmol)
in toluene (5 mL) via a syringe pump at 70 °C (this addition was per-
formed over 1 h). Then, the reaction mixture was stirred for 30 min at
80 °C. The solvent was removed under reduced pressure to yield the
crude product, 4-(alkyl(aryl)amino)-2-methylene-4-oxobutanoic ac-
id, which was used in the next step without further purification.
White solid; yield: 0.578 g (46%); Rf = 0.35 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 7.27–7.24 (m, 2 H), 7.12 (t, JH,F = 8.4 Hz,
2 H), 6.26 (s, 1 H), 5.62 (s, 1 H), 3.74 (s, 3 H), 3.26 (s, 3 H), 3.07 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 170.0, 166.9, 161.8 (d, JC,F = 246 Hz),
140.0 (d, JC,F = 1.3 Hz), 134.9, 129.2 (d, JC,F = 8.5 Hz), 127.8, 116.7 (d,
JC,F = 23 Hz), 52.0, 37.7, 37.5.
MS (EI+): m/z (%) = 251 (M+, 3), 125 (100), 95 (23).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H14FNO3: 252.1036; found:
Step 2: Thionyl chloride (1.3 mL, 17.5 mmol) was added dropwise to
MeOH (10 mL) at 0 °C, followed by addition of a solution of the 4-(al-
kyl(aryl)amino)-2-methylene-4-oxobutanoic acid in MeOH (10 mL).
The mixture was stirred for 2.5 h under reflux. The volatiles were re-
moved under reduced pressure. Sat. aq K2CO3 was added to the mix-
ture to obtain pH 7, and the mixture was then extracted with CHCl3 (3
× 20 mL). The combined organic layers were dried over MgSO4 and fil-
tered, and the solvent was removed under reduced pressure. The
crude mixture was purified by silica gel column chromatography
(EtOAc/hexanes, 1:1).
252.1025.
Methyl 4-((4-Chlorophenyl)(methyl)amino)-2-methylene-4-
oxobutanoate (1e)
White solid; yield: 0.709 g (53%); Rf = 0.36 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 7.40 (d, J = 8.5 Hz, 2 H), 7.23–7.20 (m, 2
H), 6.26 (s, 1 H), 5.62 (s, 1 H), 3.74 (s, 3 H), 3.26 (s, 3 H), 3.07 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 169.9, 166.9, 142.5, 134.9, 133.8,
130.0, 128.8, 127.9, 52.0, 37.7, 37.4.
MS (EI+): m/z (%) = 267 (M+, 3), 141 (100), 99 (38).
Methyl 4-(Methyl(phenyl)amino)-2-methylene-4-oxobutanoate
(1a)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H14ClNO3: 268.0740;
Yellow syrup; yield: 0.560 g (48%); Rf = 0.41 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 7.43 (t, J = 7.5 Hz, 2 H), 7.35 (t, J = 7.4
Hz, 1 H), 7.28–7.26 (m, 2 H), 6.23 (s, 1 H), 5.60 (s, 1 H), 3.74 (s, 3 H),
3.28 (s, 3 H), 3.10 (s, 2 H).
found: 268.0734.
Methyl 4-((4-Bromophenyl)(methyl)amino)-2-methylene-4-
oxobutanoate (1f)
13C NMR (125 MHz, CDCl3):  = 170.0, 166.9, 143.9, 135.1, 129.8,
White solid; yield: 0.656 g (42%); Rf = 0.42 (EtOAc/hexanes, 1:1).
127.9, 127.7, 127.4, 51.9, 37.7, 37.4.
1H NMR (500 MHz, CDCl3):  = 7.56 (d, J = 8.3 Hz, 2 H), 7.16 (d, J = 8.6
MS (EI+): m/z (%) = 233 (M+, 3), 107 (100), 77 (29).
Hz, 2 H), 6.26 (s, 1 H), 5.62 (s, 1 H), 3.74 (s, 3 H), 3.26 (s, 3 H), 3.08 (s, 2
H).
13C NMR (125 MHz, CDCl3):  = 169.8, 166.9, 143.0, 134.9, 133.1,
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H15NO3: 234.1130; found:
234.1125.
129.9, 129.2, 128.0, 52.0, 37.7, 37.4.
MS (EI+): m/z (%) = 313 (M+, 5), 185 (80), 127 (100), 99 (56).
Methyl 4-(Methyl(p-tolyl)amino)-2-methylene-4-oxobutanoate
(1b)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H14BrNO3: 312.0235;
Pale yellow solid; yield: 0.396 g (32%); Rf = 0.42 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 7.22 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.2
Hz, 2 H), 6.24 (s, 1 H), 5.59 (s, 1 H), 3.73 (s, 3 H), 3.25 (s, 3 H), 3.09 (s, 2
H), 2.38 (s, 3 H).
found: 312.0235.
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M. M. Hornink et al.
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Methyl 4-(Methyl(4-(trifluoromethyl)phenyl)amino)-2-methy-
lene-4-oxobutanoate (1g)
Methyl 3-(Methyl(phenyl)carbamoyl)but-3-enoate (2a)30
Yellow oil; yield: 1.038 g (89%); Rf = 0.51 (EtOAc/hexanes, 1:1).
Yellowish solid; yield: 0.452 g (30%); Rf = 0.39 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 7.70 (d, J = 8.3 Hz, 2 H), 7.42 (d, J = 8.2
1H NMR (500 MHz, CDCl3):  = 7.36–7.23 (m, 5 H), 5.27 (s, 1 H), 5.04
(s, 1 H), 3.71 (s, 3 H), 3.38 (s, 3 H), 3.30 (s, 2 H).
Hz, 2 H), 6.28 (s, 1 H), 5.64 (s, 1 H), 3.74 (s, 3 H), 3.31 (s, 3 H), 3.12 (s, 2
H).
13C NMR (125 MHz, CDCl3):  = 169.7, 166.8, 147.1, 134.7, 128.1,
127.8, 127.0, 123.7 (q, J = 270 Hz), 116.7, 52.0, 37.8, 37.4.
MS (EI+): m/z (%) = 301 (M+, 2), 127 (100), 99 (47).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14F3NO3: 302.1004;
13C NMR (125 MHz, CDCl3):  = 171.4, 169.6, 158.3, 137.7, 136.8,
127.9, 123.6, 114.4, 55.4, 51.9, 39.4.
MS (EI+): m/z (%) = 233 (M+, 3), 107 (100), 77 (29).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H15NO3: 234.1130; found:
234.1128.
found: 302.0999.
Methyl 3-((4-Methoxyphenyl)(methyl)carbamoyl)but-3-enoate
(2b)31
Methyl 4-(3-(Methoxycarbonyl)-N-methylbut-3-enamido)benzo-
ate (1h)
Yellow oil; yield: 0.684 g (52%); Rf = 0.28 (EtOAc/hexanes, 2:3).
1H NMR (500 MHz, CDCl3):  = 7.21 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 8.9
Hz, 2 H), 5.26 (s, 1 H), 5.06 (s, 1 H), 3.81 (s, 3 H), 3.70 (s, 3 H), 3.34 (s, 3
H), 3.29 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 171.4, 169.6, 158.3, 137.7, 136.7,
130.0, 127.9, 114.4, 55.4, 51.9, 39.4, 37.2.
MS (EI+): m/z (%) = 263 (M+, 19), 137 (100), 127 (74).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H17NO4: 264.1236; found:
Pale yellow solid; yield: 0.690 g (47%); Rf = 0.45 (EtOAc/hexanes, 1:1).
1H NMR (500 MHz, CDCl3):  = 8.11 (d, J = 8.5 Hz, 2 H), 7.36 (d, J = 8.5
Hz, 2 H), 6.27 (s, 1 H), 5.63 (s, 1 H), 3.94 (s, 3 H), 3.74 (s, 3 H), 3.31 (s, 3
H), 3.14 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 169.7, 166.8, 166.2, 147.9, 134.8,
131.2, 129.5, 128.0, 127.2, 52.3, 52.0, 37.8, 37.4.
MS (EI+): m/z (%) = 291 (M+, 4), 165 (100), 127 (74).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H17NO5: 292.1185; found:
264.1225.
292.1172.
Methyl 3-(Methyl(4-(trifluoromethyl)phenyl)carbamoyl)but-3-
enoate (2c)
Methyl 4-(Benzyl(phenyl)amino)-2-methylene-4-oxobutanoate
(1i)
Yellow oil; yield: 0.648 g (43%); Rf = 0.46 (EtOAc/hexanes, 2:3).
1H NMR (500 MHz, CDCl3):  = 7.62 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4
Hz, 2 H), 5.32 (s, 1 H), 5.00 (s, 1 H), 3.72 (s, 3 H), 3.42 (s, 3 H), 3.39 (s, 2
H).
Colorless oil; yield: 0.974 g (63%); Rf = 0.64 (EtOAc/hexanes, 2:3).
1H NMR (500 MHz, CDCl3):  = 7.37–7.20 (m, 8 H), 7.05 (d, J = 6.9 Hz, 2
H), 6.27 (s, 1 H), 5.61 (s, 1 H), 4.89 (s, 2 H), 3.74 (s, 3 H), 3.09 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 170.0, 166.9, 142.2, 137.4, 136.1,
129.6, 128.9, 128.5, 128.3, 128.1, 127.8, 127.4, 53.2, 51.2, 38.1.
13C NMR (125 MHz, CDCl3):  = 171.4, 169.3, 148.2, 136.3, 128.6 (q, J =
32.6 Hz), 126.9, 126.3 (q, J = 3.70 Hz), 124.2, 123.8 (q, J = 270.3 Hz),
51.9, 39.2, 38.3.
MS (EI+): m/z (%) = 309 (M+, 3), 250 (14), 183 (21), 91 (100), 77 (23).
MS (EI+): m/z (%) = 301 (M+, 2), 127 (100), 99 (54).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19NO3: 310.1443; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14F3NO3: 302.1004;
310.1435.
found: 302.1004.
Methyl 4-(Diphenylamino)-2-methylene-4-oxobutanoate (1j)
Methyl 3-(Benzyl(phenyl)carbamoyl)but-3-enoate (2d)
Colorless solid; yield: 0.753 g (51%); Rf = 0.24 (EtOAc/hexanes, 3:7).
Yellow oil; yield: 0.371 g (24%); Rf = 0.44 (EtOAc/hexanes, 2:3).
1H NMR (500 MHz, CDCl3):  = 7.47–7.17 (m, 10 H), 6.28 (s, 1 H), 5.66
1H NMR (500 MHz, CDCl3):  = 7.28–7.17 (m, 10 H), 5.25 (s, 1 H), 5.06
(s, 1 H), 3.76 (s, 3 H), 3.27 (s, 2 H).
(s, 1 H), 5.02 (s, 2 H), 3.69 (s, 3 H), 3.33 (s, 2 H).
13C NMR (125 MHz, CDCl3):  = 170.1, 166.9, 142.7, 140.6, 135.1,
13C NMR (125 MHz, CDCl3):  = 171.2, 169.2, 143.5, 137.4, 136.8,
128.9, 127.9, 126.4, 52.0, 39.1.
129.1, 128.4, 128.3, 127.7, 127.2, 127.1, 124.0, 53.8, 51.8, 39.6.
MS (EI+): m/z (%) = 295 (M+, 3), 169 (100), 127 (26).
MS (EI+): m/z (%) = 309 (M+, 7), 250 (45), 127 (28), 91 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H17NO3: 296.1287; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19NO3: 310.1443; found:
296.1285.
310.1473.
Biobased Amides 2a–d; General Procedure
Spiro[dihydroquinolin-2-one-succinimides] 5a–p; General Proce-
dure
A solution of methyl 3-(chlorocarbonyl)but-3-enoate (0.975 g, 6
mmol) (for its preparation, see the Supporting Information) in EtOAc
(20 mL) was added dropwise to a stirred solution of N-alkylaniline (5
mmol) and triethylamine (0.84 mL, 6 mmol) in anhydrous EtOAc (10
mL) at 0 °C. The mixture was stirred overnight at room temperature.
Sat. aq NaHCO3 (10 mL) was added, and the resulting mixture was ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
dried over MgSO4 and filtered, and the solvent was removed under re-
duced pressure. The crude mixture was purified by silica gel column
chromatography (EtOAc/hexanes, 1:1).
Step 1: Carbamoyl radical generation using the photo-Fenton reaction
under continuous flow conditions
Photochemical flow reactor assembly (also see the Supporting Infor-
mation): A UV lamp (medium-pressure, mercury vapor lamp, 450 W,
Ace Glass Inc., 7825-35) was inserted into a filter sleeve (Pyrex). Both
were inserted into a quartz immersion well, which was placed in a
water bath. A tube reactor (1 mL; high-purity perfluoroalkoxyalkane
tubing, 1/16 in. o.d. × 0.030 in. × 7.25 ft) was wrapped around the
quartz immersion well. The coil reactor was connected to syringes via
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

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M. M. Hornink et al.
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a Y-adapter. A photochemical reaction cabinet (46 × 64 × 44 cm, W ×
H × D) was built and can be maintained on a lab bench. A syringe
pump (Harvard Apparatus PHD ULTRA) was used to infuse the solu-
tions into the photochemical reactor. A back-pressure regulator (BPR,
75 psi) was connected to the end of the coil reactor, and the exiting
stream was collected into a flask.
1′-Benzyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-2,2′,5(3′H)-trione
(5b)
White solid; yield: 78.2 mg (61%); mp 263 °C (dec); Rf = 0.36
(CHCl3/MeOH, 95:5).
IR (neat): 3043, 2916, 2752, 1780, 1712, 1651, 1595, 1392, 759, 731
cm–1
.
Two solutions containing the starting materials were prepared as fol-
lows. Solution 1: Biobased amide 1a–j (0.2 mol·L–1), FeSO4·7 H2O (1
mol%), and H2SO4 (0.2 mol·L–1) were added to a volumetric flask, and
formamide (or N-methylformamide) was added to fill the remaining
volume of the flask. Nitrogen bubbling was employed for 5 min. Solu-
tion 2: Aq H2O2 (30 wt %, 0.4 mol·L–1) was added to a volumetric flask,
and formamide (or N-methylformamide) was added to fill the re-
maining volume of the flask. Nitrogen bubbling was employed for 5
min. These solutions were used to load two 8 mL stainless steel sy-
ringes that were attached to the syringe pump. For reactor equilibra-
tion, both solutions were infused at a flow rate of 50 L/min for 0.5 h;
the resulting collected mixture was discharged. After this stabiliza-
tion, a sample of the reaction solution was collected every 5 min for
analysis by GC/MS. This analysis was repeated three times. For
extraction of the samples, sat. aq NaHCO3 (0.5 mL) and CHCl3 (1 mL)
were added to the flask, and the organic layer was removed. The
aqueous layer was washed with CHCl3 (1 mL) in the same flask. The
combined organic layers were dried over MgSO4, filtered, and ana-
lyzed by TLC and GC/MS. The infusion of the solutions was main-
tained for an additional 45 min. The exiting stream was collected in a
glass flask containing NaHCO3 (0.038 g, 0.45 mmol) and Na2SO3
(0.113 g, 0.9 mmol). The resulting mixture was stirred for approxi-
mately 15 min for gas evolution. Then, 4 mL was transferred to a
round-bottom flask for formamide removal by vacuum distillation to
yield the crude product, 4,4-disubstituted dihydroquinolinone 3.
1H NMR (500 MHz, CD3OD):  = 7.32–7.29 (m, 4 H), 7.22 (t, J = 6.5 Hz,
2 H), 7.16 (d, J = 6.8 Hz, 1 H), 7.08–7.05 (m, 2 H), 5.25 (m, 2 H), 3.19 (d,
J = 15.9 Hz, 1 H), 3.06–3.00 (m, 2 H), 2.86 (d, J = 18.1 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 180.6, 176.5, 167.6, 139.3, 137.4,
129.3, 129.0, 127.4, 127.0 (2 C), 125.4, 123.0, 116.8, 47.5, 44.9, 42.9,
38.7.
MS (EI+): m/z (%) = 320 (M+, 10), 106 (20), 91 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H16N2O3: 321.1239; found:
321.1245.
1′-Phenyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-2,2′,5(3′H)-trione
(5c)
Pale yellow solid; yield: 22.7 mg (74%); mp 231–234 °C; Rf = 0.39
(CHCl3/MeOH, 95:5).
IR (neat): 2935, 2910, 2841, 1770, 1708, 1681, 1595, 1356, 761, 713
cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 10.76 (br s, 1 H), 7.55 (t, J = 7.4 Hz,
2 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.26 (d, J = 7.4 Hz, 2 H), 7.19–7.15 (m, 2
H), 7.06 (t, J = 7.4 Hz, 1 H), 6.30 (d, J = 8.0 Hz, 1 H), 3.11–2.99 (m, 4 H).
13C NMR (125 MHz, DMSO-d6):  = 180.6, 176.7, 167.1, 141.7, 138.9,
130.2, 129.7, 129.1, 128.7, 126.6, 125.2, 123.7, 117.9, 49.1, 47.6, 42.5.
MS (EI+): m/z (%) = 306 (M+, 100), 234 (63), 206 (43).
Step 2: Imidation reaction
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H14N2O3: 307.1083; found:
307.1077.
K2CO3 (55.3 mg, 0.4 mmol) and toluene (6 mL) were added to the
crude 4,4-disubstituted dihydroquinolinone 3 (0.4 mmol). The result-
ing mixture was heated under reflux (Dean–Stark apparatus) for 2 h
(5a–i and 5p) or 5 h (5j–o). Toluene was removed under reduced
pressure. Aq 2 M HCl (5 mL) was added and then the mixture was ex-
tracted with CHCl3 (3 × 5 mL). The organic layers were dried over
MgSO4, and the solvent was removed under reduced pressure. The
spiro[dihydroquinolin-2-one-succinimides] were purified by silica
gel column chromatography (5a–i: CHCl3/MeOH, 95:5; 5j–o: CHCl3).
1′,6′-Dimethyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-2,2′,5(3′H)-
trione (5d)
Yellowish solid; yield: 93.0 mg (90%); mp 227–229 °C; Rf = 0.39
(CHCl3/MeOH, 95:5).
IR (neat): 3211, 2931, 2907, 1775, 1715, 1643, 1611, 1344, 1179, 812
cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.45 (br s, 1 H), 7.16 (d, J = 8.2 Hz, 1 H),
6.97 (d, J = 8.3 Hz, 1 H), 6.88 (s, 1 H), 3.39 (s, 3 H), 3.16 (d, J = 15.8 Hz,
1 H), 2.97 (d, J = 18.4 Hz, 1 H), 2.81 (d, J = 18.4 Hz, 1 H), 2.77 (d, J = 15.8
Hz, 1 H), 2.31 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 178.6, 173.8, 166.4, 137.2, 133.7,
129.9, 126.0, 125.3, 115.9, 47.9, 43.2, 40.1, 29.7, 20.7.
1′-Methyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-2,2′,5(3′H)-trione
(5a)
White solid; yield: 92.8 mg (91%); mp 201–204 °C; Rf = 0.35 (CHCl3/
MeOH, 95:5).
IR (neat): 3129, 3063, 2943, 2911, 1767, 1705, 1643, 1593, 1577,
MS (EI+): m/z (%) = 258 (M+, 98), 187 (95), 144 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N2O3: 259.1083; found:
1138, 764 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.78 (br s, 1 H), 7.39–7.35 (m, 1 H),
7.11–7.08 (m, 3 H), 3.41 (s, 3 H), 3.17 (d, J = 15.8 Hz, 1 H), 2.98 (d, J =
18.4 Hz, 1 H), 2.83 (d, J = 18.6 Hz, 1 H), 2.80 (d, J = 16.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 178.4, 173.7, 166.5, 139.7, 129.5,
126.1, 124.8, 123.9, 116.0, 47.9, 43.1, 40.0, 29.7.
MS (EI+): m/z (%) = 244 (M+, 73), 173 (84), 144 (67), 130 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H12N2O3: 245.0926; found:
259.1085.
6′-Methoxy-1′-methyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5e)
White solid; yield: 54.8 mg (50%); mp 216–218 °C; Rf = 0.33
(CHCl3/MeOH, 95:5).
IR (neat): 3210, 2932, 2913, 2883, 1778, 1717, 1649, 1581, 1503,
245.0930.
1036, 800 cm–1
.
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M. M. Hornink et al.
Feature
Synthesis
1H NMR (500 MHz, CDCl3):  = 8.62 (br s, 1 H), 7.01 (d, J = 8.9 Hz, 1 H),
6.88 (dd, J = 8.9, 2.8 Hz, 1 H), 6.64 (d, J = 2.8 Hz, 1 H), 3.79 (s, 3 H), 3.28
(s, 3 H), 3.15 (d, J = 15.8 Hz, 1 H), 2.97 (d, J = 18.5 Hz, 1 H), 2.81 (d, J =
18.4 Hz, 1 H), 2.77 (d, J = 15.8 Hz, 1 H).
MS (EI+): m/z (%) = 324 (M+, 100), 322 (98), 251 (84).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11BrN2O3: 323.0031;
found: 323.0018.
13C NMR (125 MHz, CDCl3):  = 178.4, 173.7, 166.1, 155.9, 133.2,
127.5, 116.9, 113.5, 111.5, 55.7, 48.0, 43.1, 40.1, 29.9.
MS (EI+): m/z (%) = 274 (M+, 100), 203 (48), 188 (52).
1′-Methyl-6′-(trifluoromethyl)-1′H-spiro[pyrrolidine-3,4′-quino-
line]-2,2′,5(3′H)-trione (5i)
White solid; yield: 93.7 mg (98%); mp 254–256 °C; Rf = 0.32
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N2O4: 275.1032; found:
(CHCl3/MeOH, 95:5).
275.1036.
IR (neat): 3344, 3332, 2943, 2908, 1776, 1695, 1637, 1589, 1379,
1138, 817 cm–1
.
1H NMR (500 MHz, CD3OD):  = 7.70 (d, J = 8.4 Hz, 1 H), 7.41–7.39 (m,
2 H), 3.42 (s, 3 H), 3.10 (d, J = 16.0 Hz, 1 H), 3.00 (d, J = 18.2 Hz, 1 H),
2.95 (d, J = 17.0 Hz, 1 H), 2.91 (d, J = 18.4 Hz, 1 H).
6′-Fluoro-1′-methyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5f)
White solid; yield: 80.8 mg (77%); mp 229–232 °C; Rf = 0.26
(CHCl3/MeOH, 95:5).
13C NMR (125 MHz, DMSO-d6):  = 180.1, 176.2, 167.2, 144.1, 128.0,
126.7 (m), 124.5 (q, J = 290 Hz), 123.6, 122.2 (m), 117.0, 47.4, 42.3,
38.9, 29.8.
IR (neat): 3210, 3065, 2947, 2913, 2830, 1778, 1717, 1649, 1582,
1503, 1177, 1036, 799 cm–1
.
1H NMR (500 MHz, CD3OD):  = 7.25–7.23 (m, 1 H), 7.14 (td, J = 8.9,
2.8 Hz, 1 H), 6.94 (dd, J = 8.9, 2.8 Hz, 1 H), 3.38 (s, 3 H), 3.04 (d, J = 16.0
Hz, 1 H), 2.96 (d, J = 18.3 Hz, 1 H), 2.88 (d, J = 15.9 Hz, 1 H), 2.88 (d, J =
18.2 Hz, 1 H).
MS (EI+): m/z (%) = 312 (M+, 72), 241 (100), 198 (90).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H11F3N2O3: 313.0800;
found: 313.0805.
13C NMR (125 MHz, DMSO-d6):  = 180.1, 176.2, 166.7, 158.2 (d, JC,F
239 Hz), 137.2 (d, JC,F = 2.1 Hz), 128.6 (d, JC,F = 6.7 Hz), 118.0 (d, JC,F
8.0 Hz), 115.6 (d, JC,F = 22.1 Hz), 112.6 (d, JC,F = 24.3 Hz), 47.4, 42.3,
=
=
1,1′-Dimethyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-2,2′,5(3′H)-
trione (5j)
Due to low solubility of biobased amide 1j, it was necessary to de-
crease its concentration (1j, 0.025 mol·L–1).
39.0, 29.9.
MS (EI+): m/z (%) = 262 (M+, 74), 191 (67), 148 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11FN2O3: 263.0832;
White solid; yield: 44.4 mg (43%); mp 170–173 °C; Rf = 0.60
(CHCl3/MeOH, 95:5).
found: 263.0828.
IR (neat): 2951, 2916, 2848, 1780, 1693, 1666, 1597, 1365, 1286,
1053, 767 cm–1
.
6′-Chloro-1′-methyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5g)
1H NMR (500 MHz, CDCl3):  = 7.36 (td, J = 7.6, 1.4 Hz, 1 H), 7.09–7.06
(m, 2 H), 6.94 (dd, J = 7.6, 1.1 Hz, 1 H), 3.42 (s, 3 H), 3.18 (d, J = 15.8 Hz,
1 H), 3.14 (s, 3 H), 2.91 (d, J = 18.2 Hz, 1 H), 2.80 (d, J = 18.2 Hz, 1 H),
2.71 (d, J = 15.8 Hz, 1 H).
White solid; yield: 74.7 mg (67%); mp 266–269 °C; Rf = 0.35
(CHCl3/MeOH, 95:5).
IR (neat): 3224, 3074, 2931, 2912, 1774, 1724, 1645, 1591, 1415,
13C NMR (125 MHz, CDCl3):  = 178.7, 174.1, 166.5, 139.6, 129.4,
126.5, 124.7, 123.8, 115.9, 46.6, 42.2, 40.2, 29.7, 25.5.
1176, 819 cm–1
.
1H NMR (500 MHz, CD3OD):  = 7.39 (dd, J = 8.8, 2.3 Hz, 1 H), 7.22 (d,
J = 8.8 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 3.37 (s, 3 H), 3.05 (d, J = 16.0
Hz, 1 H), 2.96 (d, J = 18.2 Hz, 1 H), 2.88 (d, J = 16.1 Hz, 1 H), 2.88 (d, J =
18.2 Hz, 1 H).
MS (EI+): m/z (%) = 258 (M+, 93), 173 (87), 130 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N2O3: 259.1083; found:
259.1076.
13C NMR (125 MHz, DMSO-d6):  = 180.1, 176.2, 166.8, 139.7, 129.1,
128.7, 127.3, 125.1, 118.2, 47.4, 42.3, 38.9, 29.7.
MS (EI+): m/z (%) = 278 (M+, 58), 207 (64), 44 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11ClN2O3: 279.0536;
1′-Benzyl-1-methyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5k)
White solid; yield: 44.1 mg (33%); mp 146–148 °C; Rf = 0.68
(CHCl3/MeOH, 95:5).
found: 279.0525.
IR (neat): 2953, 2912, 2845, 1772, 1697, 1664, 1600, 1373, 1282, 777,
715 cm–1
.
6′-Bromo-1′-methyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5h)
1H NMR (500 MHz, CD3OD):  = 7.31–7.30 (m, 4 H), 7.24–7.19 (m, 2
H), 7.08–7.03 (m , 3 H), 5.28 (d, J = 16.4 Hz, 1 H), 5.23 (d, J = 16.4 Hz, 1
H), 3.19 (d, J = 15.9 Hz, 1 H), 3.04 (s, 3 H), 3.01 (d, J = 18.1 Hz, 1 H),
3.00 (d, J = 15.8 Hz, 1 H), 2.90 (d, J = 18.0 Hz, 1 H).
White solid; yield: 126.7 mg (75%); mp 240–243 °C; Rf = 0.43
(CHCl3/MeOH, 95:5).
IR (neat): 3180, 2939, 2914, 1774, 1712, 1658, 1614, 1330, 1280,
13C NMR (125 MHz, CD3OD):  = 179.1, 175.0, 168.2, 138.8, 136.6,
128.8, 128.4, 126.9 (2 C), 126.4, 124.7, 123.6, 116.8, 46.2, 45.3, 41.2,
38.9, 24.1.
MS (EI+): m/z (%) = 334 (M+, 11), 306 (20), 91 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H18N2O3: 335.1396; found:
1187, 1114, 829 cm–1
.
1H NMR (500 MHz, CD3OD):  = 8.04 (br s, 1 H), 7.53 (d, J = 8.7 Hz, 1
H), 7.26 (s, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 3.36 (s, 3 H), 3.04 (d, J = 16.0
Hz, 1 H), 2.97 (d, J = 18.2 Hz, 1 H), 2.88 (d, J = 16.0 Hz, 1 H), 2.87 (d, J =
18.2 Hz, 1 H).
335.1397.
13C NMR (125 MHz, DMSO-d6):  = 180.1, 176.2, 166.8, 140.1, 132.0,
129.1, 127.8, 118.5, 115.1, 47.4, 42.4, 38.9, 29.7.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

K
M. M. Hornink et al.
Feature
Synthesis
1,1′,6′-Trimethyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-2,2′,5(3′H)-
trione (5l)
1H NMR (500 MHz, CDCl3):  = 7.63 (d, J = 8.6 Hz, 1 H), 7.18–7.17 (m, 2
H), 3.44 (s, 3 H), 3.17 (d, J = 16.0 Hz, 1 H), 3.16 (s, 3 H), 2.95 (d, J = 18.2
Hz, 1 H), 2.82 (d, J = 18.3 Hz, 1 H), 2.76 (d, J = 15.9 Hz, 1 H).
White solid; yield: 46.8 mg (43%); mp 195–197 °C; Rf = 0.68
13C NMR (125 MHz, CDCl3):  = 177.8, 173.5, 166.3, 142.9, 126.9, 126.7
(q, J = 3.6 Hz), 125.8 (q, J = 33.1 Hz), 123.6 (q, J = 270 Hz), 122.0 (q, J =
3.6 Hz), 116.0, 46.4, 41.8, 40.1, 29.9, 25.7.
MS (EI+): m/z (%) = 326 (M+, 81), 241 (100), 198 (87).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H13F3N2O3: 327.0956;
(CHCl3/MeOH, 95:5).
IR (neat): 2938, 2911, 2830, 1778, 1715, 1649, 1580, 1177, 1036, 797
cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.14 (d, J = 8.2 Hz, 1 H), 6.96 (d, J = 8.3
Hz, 1 H), 6.71 (s, 1 H), 3.39 (s, 3 H), 3.15 (d, J = 15.8 Hz, 1 H), 3.14 (s, 3
H), 2.93 (d, J = 18.2 Hz, 1 H), 2.78 (d, J = 18.2 Hz, 1 H), 2.68 (d, J = 15.8
Hz, 1 H), 2.29 (s, 3 H).
found: 327.0961.
13C NMR (125 MHz, CDCl3):  = 178.8, 174.2, 166.4, 137.4, 133.5,
129.8, 126.4, 125.3, 115.8, 46.6, 42.3, 40.3, 29.7, 25.5, 20.7.
Methyl 1′-Methyl-2,2′,5-trioxo-2′,3′-dihydro-1′H-spiro[pyrroli-
dine-3,4′-quinoline]-6′-carboxylate (5p)
MS (EI+): m/z (%) = 272 (M+, 79), 187 (84), 144 (100).
White powder; yield: 90.7 mg (75%); mp 219–220 °C; Rf = 0.29
(CHCl3/MeOH, 95:5).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H16N2O3: 273.1239; found:
IR (neat): 3022, 2945, 2905, 1773, 1707, 1657, 1599, 1252, 772, 642
273.1241.
cm–1
.
6′-Methoxy-1,1′-dimethyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5m)
1H NMR (300 MHz, DMSO-d6):  = 11.64 (br s, 1 H), 7.95 (dd, J = 14.2,
3.15 Hz, 1 H), 7.61 (d, J = 3.15 Hz, 1 H), 7.31 (d, J = 14.4 Hz, 1 H), 3.83
(s, 3 H), 3.33 (s, 3 H), 2.90 (m, 4 H).
Light brown powder; yield: 23.0 mg (20%); mp 180–182 °C; Rf = 0.45
(CHCl3/MeOH, 95:5).
13C NMR (75 MHz, DMSO-d6):  = 180.2, 176.4, 167.3, 165.9, 144.5,
130.8, 127.1, 125.8, 124.1, 116.6, 52.6, 47.4, 42.7, 38.4, 29.8.
MS (EI+): m/z (%) = 302 (M+, 96), 231 (100), 200 (49).
IR (neat): 2930, 2918, 1778, 1679, 1665, 1595, 1364, 1288, 812, 692
cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.00 (d, J = 8.9 Hz, 1 H), 6.86 (d, J = 8.9
Hz, 1 H), 6.48 (s, 1 H), 3.77 (s, 3 H), 3.39 (s, 3 H), 3.15 (d, J = 15.2 Hz, 1
H), 3.13 (s, 3 H), 2.92 (d, J = 18.2 Hz, 1 H), 2.78 (d, J = 18.3 Hz, 1 H),
2.68 (d, J = 15.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 178.5, 174.1, 166.1, 155.8, 133.3,
127.9, 116.8, 113.2, 111.7, 55.7, 46.7, 42.1, 40.2, 29.8, 25.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H14N2O5: 303.0981; found:
303.0987.
Spiro[indolin-2-one-glutarimides] 6a–e; General Procedure
Step 1: Carbamoyl radical generation using the photo-Fenton reaction
under continuous flow conditions
MS (EI+): m/z (%) = 288 (M+, 100), 203 (40), 160 (39).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H16N2O4: 289.1188; found:
The same protocol described above to obtain compounds 5a–o was
employed. However, prior to the imidation reaction, 3,3-disubstituted
indolin-2-ones 4 were purified as follows: Formamide was removed
by vacuum distillation. The crude product was mixed with silica gel
and CHCl3. The solvent was removed under reduced pressure, and the
crude material adsorbed onto silica gel was transferred to a glass col-
umn for chromatography (CHCl3/MeOH, 95:5).
289.1193.
6′-Chloro-1,1′-dimethyl-1′H-spiro[pyrrolidine-3,4′-quinoline]-
2,2′,5(3′H)-trione (5n)
White solid; yield: 59.7 mg (51%); mp 232–235 °C; Rf = 0.64
(CHCl3/MeOH, 95:5).
Step 2: Imidation reaction
NaH (9.6 mg, 0.4 mmol) was added carefully to a stirred solution of
3,3-disubstituted indolin-2-one 4 (0.4 mmol) in THF (6 mL) at 0 °C.
The reaction mixture was stirred for 1 h at room temperature. The
solvent was removed under reduced pressure, and 2 M aq HCl (5 mL)
was added. The mixture was extracted with CHCl3 (3 × 5 mL). The or-
ganic layers were dried over MgSO4 and filtered, and the solvent was
removed under reduced pressure. The spiro[indolin-2-one-glutarim-
ides] were purified by silica gel column chromatography (CHCl3/
MeOH, 95:5).
IR (neat): 2930, 2918, 1778, 1679, 1665, 1595, 1364, 1288, 812, 692
cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.33 (dd, J = 8.7, 2.0 Hz, 1 H), 7.01 (d, J =
8.8 Hz, 1 H), 6.92 (d, J = 2.0 Hz, 1 H), 3.39 (s, 3 H), 3.16 (d, J = 15.8 Hz, 1
H), 3.15 (s, 3 H), 2.93 (d, J = 18.3 Hz, 1 H), 2.78 (d, J = 18.4 Hz, 1 H),
2.71 (d, J = 15.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 178.0, 176.1, 166.1, 138.5, 129.3,
129.0, 128.0, 125.0, 117.1, 46.5, 41.9, 40.0, 29.8, 25.6.
MS (EI+): m/z (%) = 294/292 (M+, 31/92), 207 (100), 164 (69).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H13ClN2O3: 293.0693;
1-Methylspiro[indoline-3,4′-piperidine]-2,2′,6′-trione (6a)32
found: 293.0690.
White solid; yield: 88.9 mg (79%); mp 199–200 °C; Rf = 0.22
(CHCl3/MeOH, 95:5).
1,1′-Dimethyl-6′-(trifluoromethyl)-1′H-spiro[pyrrolidine-3,4′-
quinoline]-2,2′,5(3′H)-trione (5o)
IR (neat): 3209, 3078, 2953, 2918, 1707, 1681, 1652, 1610, 1265,
1128, 738 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.47 (br s, 1 H), 7.37 (td, J = 7.8, 1.2 Hz,
1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.10 (td, J = 7.6, 0.9 Hz, 1 H), 6.93 (d, J =
7.8 Hz, 1 H), 3.26 (s, 3 H), 2.99 (d, J = 17.2 Hz, 2 H), 2.66 (d, J = 17.3 Hz,
2 H).
White solid; yield: 64.0 mg (49%); mp 182–184 °C; Rf = 0.61
(CHCl3/MeOH, 95:5).
IR (neat): 2938, 2911, 2830, 1778, 1715, 1649, 1582, 1177, 1036, 799,
671 cm–1
.
13C NMR (125 MHz, CDCl3):  = 176.2, 169.9 (2 C), 142.6, 129.8, 129.7,
123.6, 122.5, 109.1, 45.0, 38.7 (2 C), 26.7.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

L
M. M. Hornink et al.
Feature
Synthesis
MS (EI+): m/z (%) = 244 (M+, 100), 159 (39), 130 (61).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H12N2O3: 245.0926; found:
1H NMR (500 MHz, CDCl3):  = 8.23 (br s, 1 H), 6.88–6.82 (m, 3 H),
3.78 (s, 3 H), 3.22 (s, 3 H), 2.98 (d, J = 17.2 Hz, 2 H), 2.65 (d, J = 17.2 Hz,
2 H).
245.0920.
13C NMR (125 MHz, CDCl3):  = 175.8, 169.7 (2 C), 156.6, 135.9, 131.1,
113.3, 110.6, 109.5, 55.9, 45.3, 38.7 (2 C), 26.7.
MS (EI+): m/z (%) = 274 (M+, 100), 259 (65), 174 (18).
1-Benzylspiro[indoline-3,4′-piperidine]-2,2′,6′-trione (6b)
White solid; yield: 29.4 mg (46%); mp 181–183 °C; Rf = 0.54
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N2O4: 275.1032; found:
(CHCl3/MeOH, 95:5).
275.1037.
IR (neat): 3199, 2943, 2899, 2841, 1710, 1697, 1647, 1610, 1351,
1267, 750 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.43 (br s, 1 H), 7.35–7.22 (m, 7 H),
7.05 (t, J = 7.4 Hz, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 4.93 (s, 2 H), 3.04 (d, J =
17.2 Hz, 2 H), 2.72 (d, J = 17.2 Hz, 2 H).
13C NMR (125 MHz, CDCl3):  = 176.4, 169.8 (2 C), 141.7, 135.1, 129.8,
129.6, 129.0, 128.0, 127.2, 123.6, 122.5, 110.2, 45.0, 44.1, 38.8 (2 C).
MS (EI+): m/z (%) = 320 (M+, 5), 91 (100).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H16N2O3: 321.1239; found:
Funding Information
We thank the Conselho Nacional de Desenvolvimento Científico e
Tecnológico (National Council for Scientific and Technological Devel-
opment, CNPq, grant no. 312751/2018-4), Coordenação de Aper-
feiçoamento de Pessoal de Nível Superior (Coordination for the
Improvement of Higher Education Personnel, CAPES), and Fundação
de Amparo à Pesquisa do Estado de São Paulo (The São Paulo Research
Foundation, FAPESP, grant nos. 2017/02854-8, 2018/07152-4, and
321.1238.
2019/10762-1) for financial support.
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1,1′-Dimethylspiro[indoline-3,4′-piperidine]-2,2′,6′-trione (6c)
White solid; yield: 64.0 mg (62%); mp 215–217 °C; Rf = 0.58
(CHCl3/MeOH, 95:5).
Acknowledgment
IR (neat): 2956, 2918, 2912, 2841, 1710, 1703, 1672, 1610, 1257,
1089, 794 cm–1
.
We thank Prof. Liane M. Rossi and Lais R. Borges for helping with in-
frared analyses. We also thank Prof. Alcindo A. Santos and Marcos V. L.
R. Archilha for helping with melting point determinations.
1H NMR (500 MHz, CDCl3):  = 7.37–7.34 (m, 1 H), 7.09–7.03 (m, 2 H),
6.92 (d, J = 7.7 Hz, 1 H), 3.32 (s, 3 H), 3.24 (s, 3 H), 3.05 (d, J = 16.9 Hz,
2 H), 2.74 (d, J = 16.9 Hz, 2 H).
13C NMR (125 MHz, CDCl3):  = 176.3, 170.1 (2 C), 142.7, 130.0, 129.6,
123.4, 122.3, 109.1, 44.2, 39.5 (2 C), 26.7, 26.5.
Supporting Information
Supporting information for this article is available online at
MS (EI+): m/z (%) = 258 (M+, 100), 159 (76), 130 (63).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N2O3: 259.1083; found:
https://doi.org/10.1055/s-0040-1707318. Su
p
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ortingInformatio
n
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ortingInformatio
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259.1083.
References
1-Methyl-5-(trifluoromethyl)spiro[indoline-3,4′-piperidine]-
2,2′,6′-trione (6d)
(1) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett. 2014,
24, 3673.
White solid; yield: 108.7 mg (87%); mp 190–192 °C; Rf = 0.36
(2) (a) Hauck, F. P.; Demick, J. A.; Fan, J. J. Med. Chem. 1967, 10, 611.
(b) Tarver, M. L.; Nicholson, J. M.; Scott, K. R. J. Pharm. Sci. 1985,
74, 785. (c) Borenstein, M. R.; Doukas, P. H. J. Pharm. Sci. 1987,
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(CHCl3/MeOH, 95:5).
IR (neat): 3208, 3061, 2936, 2911, 2898, 1776, 1715, 1649, 1580,
1503, 1039, 799 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.46 (br s, 1 H), 7.67 (d, J = 8.2 Hz, 1 H),
7.44 (m, 1 H), 7.02 (d, J = 8.2 Hz, 1 H), 3.29 (s, 3 H), 2.98 (d, J = 17.2 Hz,
2 H), 2.73 (d, J = 17.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 176.3, 170.1 (2 C), 145.7, 130.3, 127.6
(q, J = 3.9 Hz), 125.9 (q, J = 32.9 Hz), 123.8 (q, J = 270 Hz), 119.6 (q, J =
3.6 Hz), 109.0, 44.9, 38.4 (2 C), 26.9.
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MS (EI+): m/z (%) = 312 (M+, 100), 227 (38), 198 (39).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H11F3N2O3: 313.0800;
found: 313.0803.
5-Methoxy-1-methylspiro[indoline-3,4′-piperidine]-2,2′,6′-trione
(6e)
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White solid; yield: 39.5 mg (36%); mp 208–210 °C; Rf = 0.45
(6) (a) Park, Y. H.; Barker, R.; Griffin, B.; Barratt, D.; Dupriest, M.;
Brazzell, K.; York, B.; Mayer, P. Xenobiotica 1992, 22, 543.
(b) Negoro, T.; Murata, M.; Fujitani, B.; Ono, Y.; Kuromiya, A.;
(CHCl3/MeOH, 95:5).
IR (neat): 3174, 3074, 2956, 2912, 2839, 1714, 1681, 1629, 1600,
1257, 1029, 798, 692 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M

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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–M