Blue Light-Emitting Diode-Mediated in Situ Generation of Pyridinium and Isoquinolinium Ylides from Aryl Diazoesters: Their Application in the Synthesis of Diverse Dihydroindolizine

Article abstract of DOI:10.1021/acs.joc.1c01209

Blue light-emitting diode-mediated environmentally sustainable three component reactions among pyridine/isoquinoline 1/2, aryl diazoesters 3, and acrylic ester/3-alkenyl oxindoles 5/6 provide various dihydroindolizines 7 to 9 in excellent yield. The principle of the strategy is photolytic generation of nitrogen ylides from N-heteroarenes and aryl diazoesters and their subsequent [3 + 2] cycloaddition reaction with dipolarophiles. Detailed mechanistic analysis of the transformation through control experiments establishes this strategy as the foundation for the photolytic multicomponent reaction.

Full text of DOI:10.1021/acs.joc.1c01209

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Article
Blue Light-Emitting Diode-Mediated In Situ Generation of
Pyridinium and Isoquinolinium Ylides from Aryl Diazoesters: Their
Application in the Synthesis of Diverse Dihydroindolizine
Saibal Sar,† Souvik Guha,† Tejas Prabakar,† Debajit Maiti, and Subhabrata Sen*
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ABSTRACT: Blue light-emitting diode-mediated environmentally sustainable three component reactions among pyridine/
isoquinoline 1/2, aryl diazoesters 3, and acrylic ester/3-alkenyl oxindoles 5/6 provide various dihydroindolizines 7 to 9 in excellent
yield. The principle of the strategy is photolytic generation of nitrogen ylides from N-heteroarenes and aryl diazoesters and their
subsequent [3 + 2] cycloaddition reaction with dipolarophiles. Detailed mechanistic analysis of the transformation through control
experiments establishes this strategy as the foundation for the photolytic multicomponent reaction.
As a part of a natural evolutionary process in this strategy,
we thought of aryl diazoesters as appropriate and hitherto
unused reaction partners to generate the nitrogen ylides under
a blue light-emitting diode (LED), without the use of a metal
catalyst and base. Photolytic reactions that can tolerate various
functional groups to generate diverse substrates can be a
formidable solution for this.
By virtue of their presence as natural product scaffolds and
active pharmaceutical ingredients, indolizines serve a niche
position among heteroarenes to organic synthetic and
medicinal chemists.7 They have been reported to demonstrate
anticancer, anti-inflammatory, and antifungal properties.8 They
have demonstrated antituberculosis property too.9 Various
strategies had been developed to access these molecules, for
example, cyclization of C2-free pyridines, cyclization leading to
the functionalization at the C2 position of pyridines, reaction
of alkynes with pyridine triazoles, 1,3-dipolar cycloaddition of
pyridine ylides, and cycloisomerization of alkynyl pyridine
derivatives.10−12 In spite of the presence of such numerous
INTRODUCTION
■
Among nitrogen ylides, pyridinium and isoquinolinium ylides
are a class of useful reagents that are utilized in various organic
transformations.1 The facile synthesis of these ylides prompts
their utilization in 1,3-dipolar cycloaddition and Michael
addition reactions.2 They have also been used to generate
interesting heterocycles via pyridine dearomatization.3a−c
Conventionally, the synthesis of such ylides involved base-
mediated generation of pyridinium and isoquinolinium salts.3d
Unfortunately, these methods were plagued with drawbacks
such as constricted substrate scope, formation of large amount
of conjugate acid waste, and the requirement of polar solvents.
It was not until Padwa et al.’s seminal report in 1993 on
Rh(II)-catalyzed reactions of pyridine and α-diazoacetate with
dimethyl acetylenedicarboxylate which proceeded through the
in situ formation of pyridinium ylide (Scheme 1a) that the
importance of the catalytic generation of pyridinium ylides was
highlighted as a more efficient and robust strategy compared to
the conventional methods.4 Nearly two decades later,
́
Barluenga and Tomas et al. demonstrated successful examples
of metal-catalyzed cyclization of pyridine with diazoalkanes to
afford indolizines (Scheme 1b).5 Recently, several examples
have been reported involving Fe, Cu, and hemoglobin as
catalysts for the generation of quinoline, isoquinoline, and
pyridine ylides with unsubstituted or aliphatic diazoacetate
(Scheme 1c−e) and their subsequent applications in the
generation of indolizine scaffolds.6
Received: May 24, 2021
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© XXXX American Chemical Society
A

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Scheme 1. Literature Reports for the Metal-Catalyzed Pyridine, Isoquinoline, and Quinoline Ylides and Their Transformation
to Indolizine Derivatives4,5,6b−d
Scheme 2. PLatz’s Synthesis of Nitrogen Ylides that Inspired Our Blue LED-Mediated Strategy
strategies, a photoinduced synthesis of indolizine derivatives
will surely prove as a niche strategy to access these molecules.
In the early 1990s, PLatz and co-workers in a series of
pioneering work reported trapping of various carbenes
B
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generated from Laser flash photolysis of diazoalkanes,
benzoyltrimethylsilanes, phenyl-(9)-homocubene, adamantyli-
dene, and alkyl chlorodiazirines with pyridine and thiophene
(Scheme 2a).13 Taking a cue from their work herein, we report
that the blue LED induced in situ generation of pyridinium and
isoquinolinium ylides from pyridine and isoquinoline,
respectively, with aryl diazoacetates (Scheme 2b). They
subsequently underwent cycloaddition reactions with various
dipolarophiles such as methyl acrylate and 3-alkenyl oxindole
to afford a wide variety of dihydroindolizine derivatives in good
to excellent yields. The probable mechanism was realized
through control experiments (Scheme 2b).
LED for 2 to 3 h or until it indicates the completion of the
formation of the pyridine ylide 4. Subsequently, methyl
acrylate 5 was added, and the reaction gets completed in
another 5 to 6 h. Alternatively, all the three reactants were
stirred in blue LED from the beginning, and the desired
product 7 was formed after about 9 to 11 h. In either cases, the
product yield was comparable and obtained as single
regioisomers. Next, to explore whether isoquinoline 2 could
also be used as a substrate in this reaction, they were reacted
with 3 and 5 in a similar manner to 1. The desired 2,3-
dihydropyrrole[2,1-a]isoquinolines 8a−h, j−l was obtained as
a single regioisomer in moderate to good yields (Scheme 4). It
was observed that the substrates with electron-withdrawing
groups at the 4-position of the aryl moiety, that is, 3d, 3e, and
3f when reacted with methyl acrylate 5 provided the desired
products 8d, 8e, and 8f in excellent yields of 71, 86, and 69%,
respectively. On the contrary, the yield from the electron-rich
aryl diazoesters such as 3b, c, and l was moderate (61 → 71%)
(Scheme 4). Interestingly, when the optimized reaction was
tried with phenyl acetylene and 2-butyne as the dipolarophiles,
the corresponding cycloadducts were not obtained. There were
several byproduct formation in the reaction mixture.
RESULTS AND DISCUSSION
■
For the optimization of the reaction, we first examined the
reaction among pyridine 1, phenyl diazoacetate 3a, and methyl
acrylate 5 under various conditions in dichloromethane
(DCM) at r.t. (Scheme 3). As expected, the dihydroindolizine
Scheme 3. Reaction Optimization for the Photolytic In Situ
Generation of Nitrogen Ylides and Their Cycloaddition to
Dihydroindolizines
The reactions of various 3-alkylidene oxindoles 6a−c were
evaluated with pyridine and various aryl diazoesters 3a−c, f, h,
i, k, and n (Scheme 5a). The substrates 6a−c were synthesized
following the literature protocols from N-acetyl and N-Boc
isatin and the corresponding phosphonium ylide.14 With N-
acetyl and 5-Br-N-acetyl oxindoles 6a/b, the desired cyclo-
adducts 9a−g were generated as mixtures of diastereomers
(Scheme 5a). Among these, the major diastereomers of 9a, f,
and g were isolated successfully (Scheme 5a); however, 9b−e
were obtained as inseparable diastereomers in a ratio of 3:1 to
1
6:1 (from H NMR). The DFT calculation [(using Gaussian
09) where the structures were optimized for the ground-state
closed-shell system and by using B3LYP/6-31G(d) in all
calculations] for both diastereomers indicated that the S-
isomer is energetically more stable than the R-isomer by 1.6
kcal/mol (refer Supporting Information file). With N-Boc
oxindole 6c, the desired cycloadducts 9h−k were obtained as
single diastereomers with yield 63−81%. Interestingly, reaction
of 6c with ethyl/methyl diazoacetate 3p/q provided a 3-vinyl
oxindoles 10a and 10b as the unexpected product instead of
the cycloadducts (Scheme 5b). A close scrutiny of the reaction
revealed putative formation of cyclopropane intermediate A
due to the direct cyclopropanation of the 6c at C3 olefin by the
carbene generated from diazoester (instead of the formation of
the pyridine ylide). A then opens up to afford 10a and 10b
(Scheme 5b). The pathway for the formation of 10a/b was
further confirmed when 3p was reacted with 6c in the absence
of pyridine (Scheme 5c). Compound 10a was successfully
isolated in 75% yield (Scheme 5c).
To understand the mechanism of this transformation,
control experiments were performed, as depicted in Scheme
6. When pyridine 1 and phenyl diazoacetate 3a were reacted,
the desired pyridine ylide 4a was detected by high-resolution
mass spectrometry (HRMS), thereby confirming its existence
and importance in the cycloaddition (Scheme 6a). Next, after
the complete formation of the intermediate 4a, methyl acrylate
5 was added to provide the desired product 7a in 75% yield.
To understand if this was a radical-mediated transformation,
the optimized reaction of 1, 3a, and methyl acrylate 5 was
performed in the presence of the radical trapping reagent PBN
(N-tertiary-butyl nitrone) (Scheme 6b). The reaction occurred
7a was obtained in the moderate yield of 45% as a single
regioisomer, when 10 mol % of Mn(CO)5Br in the presence of
2 equivalent of sodium acetate (NaOAc) was used (Scheme
3a). The same reaction when performed in the presence of a
blue LED [5−6 W Micro Photochemical Reactor (ALD-
KIT001) with blue LED lights (435−445 nm)] along with
Mn(CO)5Br improved the yield to 58% (Scheme 3b).
Finally, the reaction under only the blue LED afforded 7a in
76% yield (Scheme 3c). However, the reaction with green and
red LEDs could not provide better yield of 7a (Scheme 3d,e).
Hence, the blue LED-mediated reaction was chosen as the
optimized protocol and used for the generic synthesis.
With the optimized protocol in hand, next pyridine 1 was
reacted with various aryl diazoacetates, 3a−m, along with
methyl acrylate 5 (Scheme 4). Products 7a−l were obtained in
excellent yields ranging from 77 to 91% with both electron-
donating and electron-withdrawing groups at the aryl moiety of
the aryl diazoacetates 3 (Scheme 4). The reaction with
thiophen-3-yl diazoacetate 3j afforded the desired compound
7j in 79% yield (Scheme 4). In a typical experiment, the aryl
diazoacetates 3 and pyridine 1 were stirred under the blue
C
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Scheme 4. Synthesis of Dihydroindolizine Derivatives 7a−l and 8a−h, 8j−l with Pyridine and Isoquinoline Ylides
Scheme 5. (a) Synthesis of Spirooxindole-Dihydroindolizine Derivatives 9a−k; (b) C3 Olefin-Substituted Oxindoles 10a/b;
and (c) Synthesis of 10a without Pyridine
smoothly to provide compound 7a in excellent yields with no
formation of the PBN intermediate, as observed in the HRMS.
This corroborated that the reaction does not proceed through
the radical pathway. Next, when the optimized cycloaddition
reaction was performed in the presence of an inert atmosphere
(argon) under a blue LED, the saturated intermediate C was
obtained as the intermediate, which indicated that the expected
final product 7 was only obtained after the air oxidation of C
(Scheme 6c).
Based on the control experiments, the probable mechanism
of this transformation is depicted in Scheme 7, with 1, 3a, and
5 as the representative participants. The blue LED facilitated
the formation of carbene B from 3a (Scheme 7). It then reacts
with pyridine 1 to afford the pyridine ylide 4a which reacts
with methyl acrylate 5 to provide the saturated intermediate C
via cycloaddition (Scheme 7). C oxidizes in the presence of air
to afford the desired product 7a (Scheme 7). Interestingly, in a
bid to observe if the cycloaddition and the remaining steps also
required blue LED, after the pyridine ylide 4a was generated in
D
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Scheme 6. Control Experiments to Understand the Mechanism of the Reaction
blue LED, it was turned off. Despite this, the final product 7a
was obtained in 74% yield, which indicated that the [3 + 2]
cycloaddition and the remaining reaction did not require any
blue LED and could be a pericyclic process.
ophiles like methyl acrylate 5 and 3-alkylidene oxindole 6a−c.
The mechanism of transformation was realized through control
experiments. The biological activity of dihydroindolizine
products is presently being evaluated.
CONCLUSIONS
GENERAL EXPERIMENTAL PROCEDURE
■
■
In summary, we have developed a blue LED-mediated reaction
for the generation of dihydroindolizine derivatives via in situ
formation of pyridine and isoquinoline ylides with aryl
diazoesters and their subsequent cycloaddition with dipolar-
All blue light-mediated reactions were carried out under air, as
specified in Photochemical ReactorAldrich Micro Photochemical
Reactor, blue LED lights (ALDKIT001-1EA). LED light is IP68
double density 12 V DC waterproof blue light with the spectral range
E
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under reduced pressure, and purifications were carried out by column
chromatography using silica gel (60−120 mesh size) in 15% ethyl
acetate in hexane.
Scheme 7. Probable Mechanism of the Pyridine/
Isoquinoline Ylide-Based Cycloaddition of the Reaction
with Dipolarophile
7a. Dimethyl 3-Phenyl-2,3-dihydroindolizine-1,3-dicarboxylate.
The crude product was purified by column chromatography (SiO2,
hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7a (160.92 mg, 79%
yield) as yellow oil. 1H NMR (400 MHz, CDCl3): δH 7.43−7.39 (t, J
= 8 Hz, 5H), 7.37−7.33 (m, 2H), 7.28 (s, 2H), 4.07−4.02 (d, J = 20
Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.16−3.12 (d, J = 16 Hz, 1H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 173.0, 162.4, 142.5,
139.2, 129.0, 128.5, 125.6, 76.0, 53.5, 52.4, 42.5, 29.8, 22.8 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C18H18NO4, 312.1230;
found, 312.1231. IR (neat) νmax: 3847, 3742, 3343, 2922, 2856, 2354,
1713, 1567, 1443, 1246, 1128, 1068, 883, 699, 630, 506 cm−1.
7b. Dimethyl 3-(4-(tert-Butyl)phenyl)-2,3-dihydroindolizine-1,3-
dicarboxylate. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford
1
pure 7b (185.66 mg, 87% yield) as yellow oil. H NMR (400 MHz,
of 435−445 nm with wall plug power supply of 500 mA with 5−6 W.
The irradiation vessel material is borosilicate glass. The distance of the
irradiation vessel from the light source is 2 cm. Reactions were
monitored through thin-layer chromatography (TLC) by visualizing
in the UV detector. All purifications were carried out in silica gel (60−
120 mesh size) column chromatography. Aryl acetates were procured
commercially from Sigma-Aldrich, TCI Chemicals, and Acros
Organics. All 1H and 13C NMR spectra were recorded taking
tetramethylsilane as an internal standard at ambient temperature
unless otherwise indicated with Bruker 400 MHz instruments at 400
MHz for 1H and 100 MHz for 13C NMR spectroscopy. Splitting
patterns are designated as singlet (s), broad singlet (br, s), doublet
(d), triplet (t), quartet (q), quintet (quin) doublet of doublets (dd),
and triplet of doublets (td). Splitting patterns that could not be
interpreted or easily visualized are designated as multiplet (m). MS
analyses were carried out using Agilent 6540 accurate-mass Q-TOF
LC/MS (Agilent Technologies, U.S.A.). MS analyses were performed
under the following operation parameters: dry gas temperature 350
°C, dry gas (N2) flow rate 10 L/min, nebulizer pressure 30 psi, Vcap
4000, and fragmentor voltage 110 V. HRMS spectra were acquired in
the positive ion mode by scanning from 100 to 1500 in the mass to
charge ratio (m/z). The mobile phase composition used for
UHPLC−QTOF MS comprised H2O (A) and acetonitrile (ACN)
(B), with optimized linear gradient elution. The injection volume was
2 μL. The flow rate was set at 0.3 mL/min. Accurate mass analysis
calibration was carried out by ESI-low concentration tuning mix
solution provided by Agilent technologies, U.S.A. The accuracy error
threshold was set at 5 ppm. Prep. High-performance liquid
chromatography experiments were carried out on the Agilent 1290
infinity series of the LC system (Agilent Technologies, U.S.A.) with a
photodiode-array/ELSD detector for purification of some of the
compounds. Fourier transform infrared spectroscopy was performed
on Thermo Scientific Nicolet iS20 equipped with iD5-ATR accessory,
in the range of 4000 to 400 cm−1 with a resolution of 4 cm−1.
Synthesis of aryl diazo esters (3a−n): All aryl diazo acetates were
prepared by the reported procedure.15 Aryl acetates (1 equiv, 5
mmol) were dissolved in ACN (10 mL) in a clean oven-dried round-
bottom flask. 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 equiv, 6 mmol)
was added and stirred for 10 min. p-ABSA (4-acetamidobenzene-
sulfonyl azide) (1.2 equiv, 6 mmol) was added and stirred for 4 h in
the dark and room temperature (r.t.); after completion, ACN was
removed under vacuum, diluted with ethyl acetate (25 mL), washed
with water, and the organic layer was dried with brine and sodium
sulfate, and purified with flash column chromatography in silica gel
(60−120 mesh size) with 5% ethyl acetate in hexane to yield 98%.
General Procedure for Synthesis of (7a−l, 8a−h, and 8j−l).
Various substituted aryl diazo esters (3a−m) (1 equiv) and pyridine/
isoquinoline (1 equiv) were taken in a 20 mL borosilicate glass vial
and dissolved in DCM (5 mL). The reaction mixtures were stirred at
r.t. under the irradiation of blue LED for 5−7 h. After that, methyl
acrylate (1 equiv, 0.58 mmol, 50 mg) was added into the reaction
mixture. Finally, the reaction mixtures were stirred at r.t. under the
irradiation of blue LED for another 5−7 h. The solvent was removed
CDCl3): δH 7.43−7.39 (d, J = 8 Hz, 3H), 7.34−7.32 (d, J = 8 Hz,
3H), 7.28−7.27 (d, J = 4 Hz, 2H), 4.03−3.98 (d, J = 20 Hz, 1H), 3.86
(s, 3H), 3.78 (s, 3H), 3.17−3.12 (d, J = 20 Hz, 1H), 1.33 (s, 9H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 173.1, 162.4, 151.5,
142.4, 136.1, 126.0, 125.3, 75.9, 53.4, 52.3, 42.3, 34.6, 31.3, 29.8 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C22H26NO4, 368.1856;
found, 368.1856. IR (neat) νmax: 3364, 2929, 2354, 1722, 1560, 1427,
1345, 1249, 1115, 1057, 957, 808, 745, 664, 567, 456 cm−1.
7c. 3-Ethyl 1-Methyl 3-(p-Tolyl)-2,3-dihydroindolizine-1,3-dicar-
boxylate. The crude product was purified by column chromatography
(SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7c (161.63
mg, 82% yield) as yellow oil. 1H NMR (400 MHz, CDCl3): δH 7.31−
7.26 (m, 5H), 7.20−7.18 (d, J = 8 Hz, 3H), 4.25−4.19 (m, 2H),
4.03−3.99 (d, J = 16 Hz, 1H), 3.86 (s, 3H), 3.13−3.09 (d, J = 16 Hz,
1H), 1.27−1.24 (t, J = 8 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δC 172.6, 162.5, 142.5, 138.3, 136.5, 129.7, 125.5, 75.8, 62.6,
52.3, 42.4, 29.8, 21.1, 14.0 ppm. HRMS (ESI+) m/z: [M + H]+ c for
C20H22NO4, 340.1543; found, 340.1549. IR (neat) νmax: 3447, 2929,
2354, 1729, 1604, 1512, 1444, 1249, 1159, 1088, 813, 491 cm−1.
7d. Dimethyl 3-(4-Bromophenyl)-2,3-dihydroindolizine-1,3-di-
carboxylate. The crude product was purified by column chromatog-
raphy (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7d
1
(190.37 mg, 84% yield) as yellow oil. H NMR (400 MHz, CDCl3):
δH 7.44−7.42 (d, J = 8 Hz, 3H), 7.23−7.21 (d, J = 8 Hz, 3H), 7.20−
7.17 (d, J = 12 Hz, 2H), 3.97−3.92 (d, J = 20 Hz, 1H), 3.77 (s, 3H),
3.69 (s, 3H), 3.02−2.97 (d, J = 20 Hz, 1H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δC 172.6, 162.2, 142.7, 138.3, 132.2, 127.4, 122.7,
75.5, 53.6, 52.4, 42.6 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C18H17BrNO4, 390.0335; found, 390.0339. IR (neat) νmax: 3340,
2951, 2354, 1724, 1576, 1438, 1245.98, 1127, 1063, 817, 753, 622,
508 cm−1.
7e. Dimethyl 3-(4-Fluorophenyl)-2,3-dihydroindolizine-1,3-di-
carboxylate. The crude product was purified by column chromatog-
raphy (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7e
1
(174.05 mg, 91% yield) as yellow oil. H NMR (400 MHz, CDCl3):
δH 7.34−7.30 (m, 3H), 7.20 (s, 2H), 7.00−6.96 (m, 3H), 3.96−3.92
(d, J = 16 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.03−2.98 (d, J = 20
Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 172.8, 163.9,
162.2, 161.4, 142.6, 135.1, 135.0, 127.6, 127.5, 116.0, 115.8, 75.4,
53.5, 52.4, 42.7 ppm. 19F NMR (376 MHz, CDCl3): δF (−)113.49
ppm. HRMS (ESI+) m/z: [M + H]+ calcd for C18H17FNO4,
330.1136; found, 330.1139. IR (neat) νmax: 3339, 2956, 2350, 1727,
1579, 1436, 1246, 1127, 1060, 821, 753, 624, 507 cm−1.
7f. Dimethyl 3-(4-Chlorophenyl)-2,3-dihydroindolizine-1,3-dicar-
boxylate. The crude product was purified by column chromatography
(SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7f (176.72 mg,
1
88% yield) as yellow oil. H NMR (400 MHz, CDCl3): δH 7.36 (s,
6H), 7.28 (s, 2H), 4.05−4.00 (d, J = 20 Hz, 1H), 3.85 (s, 3H), 3.77
(s, 3H), 3.10−3.06 (d, J = 16 Hz, 1H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δC 172.6, 162.2, 142.6, 137.8, 134.5, 129.2, 127.1,
75.4, 53.6, 52.4, 42.6 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C18H17ClNO4, 346.0841; found, 346.0863. IR (neat) νmax: 3342,
F
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2964, 2350, 1729, 1590, 1438, 1248, 1128, 1061, 822, 754, 626, 507
cm−1.
3H), 3.14−3.09 (d, J = 20 Hz, 1H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δC 173.2, 162.4, 159.7, 155.7, 142.6, 131.2, 126.9, 114.4,
75.6, 55.4, 53.4, 52.4, 42.4 ppm. HRMS (ESI+) m/z: [M + H]+ calcd
for C19H20NO5, 342.1336; found, 342.1327. IR (neat) νmax: 3341,
2922, 2854, 2337, 1723, 1598, 1511, 1444, 1244, 1170, 1033, 807,
744, 589, 527 cm−1.
7g. Dimethyl 3-(3-Fluorophenyl)-2,3-dihydroindolizine-1,3-di-
carboxylate. The crude product was purified by column chromatog-
raphy (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7g
1
(149.19 mg, 78% yield) as yellow oil. H NMR (400 MHz, CDCl3):
δH 7.36−7.31 (m, 2H), 7.26−7.24 (d, J = 8 Hz, 2H), 7.19−7.13 (m,
3H), 7.04−6.99 (m, 1H), 4.04−3.99 (d, J = 20 Hz, 1H), 3.84 (s, 3H),
3.77 (s, 3H), 3.11−3.06 (d, J = 20 Hz, 1H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δC 172.5, 164.2, 162.2, 161.8, 142.6, 141.8, 141.7,
141.6, 130.7, 130.6, 121.3, 121.2, 115.6, 115.4, 113.2, 113.0, 75.6,
75.5, 53.6, 52.4, 42.7 ppm. 19F NMR (376 MHz, CDCl3): δF
(−)111.30 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C18H17FNO4, 330.1136; found, 330.1142. IR (neat) νmax: 3339,
2946, 2351, 1724, 1572, 1439, 1250, 1124, 1062, 883, 791, 756, 686
cm−1.
8a. Dimethyl 3-Phenyl-2,3-dihydropyrrolo[2,1-a]isoquinoline-
1,3-dicarboxylate. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to afford
1
pure 8a (157.41 mg, 75% yield) as yellow oil. H NMR (400 MHz,
CDCl3): δH 9.82−9.80 (d, J = 8 Hz, 1H), 7.50−7.46 (m, 1H), 7.40−
7.36 (m, 4H), 7.33−7.31 (m, 2H), 7.28 (s, 1H), 6.65−6.63 (d, J = 8
Hz, 1H), 6.09−6.07 (d, J = 8 Hz, 1H), 4.01−3.97 (d, J = 16 Hz, 1H),
3.89 (s, 3H), 3.72 (s, 3H), 3.43−3.39 (d, J = 16 Hz, 1H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δC 172.5, 166.3, 150.7, 140.7,
135.7, 131.8, 131.1, 130.3, 129.1, 128.7, 126.5, 126.3, 125.7, 124.1,
106.3, 90.3, 75.9, 53.3, 50.8, 44.9 ppm. HRMS (ESI+) m/z: [M + H]+
7h. Dimethyl 3-(3-Methoxyphenyl)-2,3-dihydroindolizine-1,3-
dicarboxylate. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford
calcd for C22H20NO4, 362.1387; found, 362.1391. IR (neat) νmax
:
3369, 3184, 3058, 2922, 2856, 1739, 1664, 1525, 1440, 1340, 1249,
1
1193, 1075, 904, 738, 514 cm−1.
pure 7h (180.41 mg, 91% yield) as yellow oil. H NMR (400 MHz,
CDCl3): δH 7.31−7.28 (m, 3H), 6.98−6.96 (m, 3H), 6.88−6.86 (m,
2H), 4.04−3.99 (d, J = 20 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76
(s, 3H), 3.14−3.09 (d, J = 20 Hz, 1H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δC 172.8, 162.3, 160.0, 142.4, 140.7, 130.1, 117.7,
113.7, 111.5, 75.9, 55.4, 53.4, 52.3, 42.4 ppm. HRMS (ESI+) m/z: [M
+ H]+ calcd for C19H20NO5, 342.1336; found, 342.1339. IR (neat)
νmax: 3329, 3010, 2943, 2852, 2353, 1721, 1591, 1445, 1236, 1130,
1040, 956, 892, 789, 687, 604, 493 cm−1.
7i. Dimethyl 3-(3-Chlorophenyl)-2,3-dihydroindolizine-1,3-dicar-
boxylate. The crude product was purified by column chromatography
(SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7i (178.73 mg,
89% yield) as yellow oil. 1H NMR (400 MHz, CDCl3): δH 7.46−7.43
(m, 2H), 7.32−7.28 (m, 6H), 4.05−4.01 (d, J = 16 Hz, 1H), 3.85 (s,
3H), 3.78 (s, 3H), 3.12−3.07 (d, J = 20 Hz, 1H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δC 172.4, 162.1, 142.6, 141.2, 135.0, 130.3,
128.7, 128.0, 123.8, 75.5, 53.6, 52.4, 42.6 ppm. HRMS (ESI+) m/z:
[M + H]+ calcd for C18H17ClNO4, 346.0841; found, 346.0848. IR
(neat) νmax: 3338, 2946, 2351, 1722, 1572, 1437, 1248, 1123, 1062,
882, 790, 755, 685 cm−1.
8b. Dimethyl 3-(4-(tert-Butyl)phenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8b (172.16 mg, 71% yield) as yellow oil. H NMR (400
MHz, CDCl3): δH 9.86−9.84 (d, J = 8 Hz, 1H) 7.52−7.48 (m, 1H),
7.43−7.38 (m, 3H), 7.31−7.28 (m, 3H), 6.70−6.69 (d, J = 4 Hz, 1H),
6.12−6.10 (d, J = 8 Hz, 1H), 4.00−3.96 (d, J = 16 Hz, 1H), 3.90 (s,
3H), 3.75 (s, 3H), 3.46−3.42 (d, J = 16 Hz, 1H), 1.33 (s, 9H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δC 172.7, 166.4, 151.8, 150.6,
137.6, 135.7, 131.8, 131.1, 130.4, 126.2, 126.1, 126.0, 125.7, 124.1,
106.2, 90.3, 75.7, 53.2, 50.8, 44.8, 34.7, 31.3 ppm. HRMS (ESI+) m/
z: [M + H]+ calcd for C26H28NO4, 418.2013; found, 418.2017. IR
(neat) νmax: 2950, 2248, 1739, 1666, 1524, 1443, 1342, 1250, 1193,
1076, 904, 830, 728, 556 cm−1.
8c. 3-Ethyl 1-Methyl 3-(p-Tolyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8c (149.28 mg, 66% yield) as yellow oil. H NMR (400
MHz, CDCl3): δH 9.82−9.80 (d, J = 8 Hz, 1H) 7.49−7.45 (m, 1H),
7.39−7.34 (m, 1H), 7.27−7.25 (m, 1H), 7.23−7.18 (m, 4H), 6.67−
6.65 (d, J = 8 Hz, 1H), 6.08−6.06 (d, J = 8 Hz, 1H), 4.39−4.30 (m,
2H), 3.97−3.93 (d, J = 16 Hz, 1H), 3.72 (s, 3H), 3.42−3.38 (d, J = 16
Hz, 1H), 2.35 (s, 3H), 1.34−1.30 (t, J = 8 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3): δC 172.1, 166.4, 150.7, 138.6, 137.9, 135.7,
131.8, 131.1, 130.4, 129.7, 126.4, 126.2, 125.7, 124.1, 106.2, 90.2,
75.6, 62.6, 50.8, 44.7, 21.2, 14.2 ppm. HRMS (ESI+) m/z: [M + H]+
7j. 3-Ethyl 1-Methyl 3-(Thiophen-3-yl)-2,3-dihydroindolizine-1,3-
dicarboxylate. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford
1
pure 7j (152.04 mg, 79% yield) as yellow oil. H NMR (400 MHz,
CDCl3): δH 7.36−7.34 (m, 2H), 7.30−7.28 (m, 2H), 7.25 (s, 1H),
7.12−7.10 (d, J = 8 Hz, 2H) 4.29−4.23 (q, J = 8 Hz, 2H), 3.94−3.90
(d, J = 16 Hz, 1H), 3.86 (s, 3H), 3.17−3.12 (d, J = 20 Hz, 1H), 1.31−
1.28 (t, J = 8 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC
172.2, 162.4, 142.5, 140.0, 127.2, 125.6, 121.9, 73.5, 68.1, 62.8, 52.4,
42.4, 25.7, 14.1 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C17H18NO4S, 332.0951; found, 332.0964. IR (neat) νmax: 3346, 3103,
2923, 2350, 1720, 1570, 1444, 1244, 1128, 1061, 850, 789, 742, 632
cm−1.
calcd for C24H24NO4, 390.1700; found, 390.1708. IR (neat) νmax
:
3390, 3184, 2920, 2856, 1732, 1661, 1522, 1444, 1341, 1248, 1186,
1073, 1025, 897, 768, 653, 508 cm−1.
8d. Dimethyl 3-(4-Bromophenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8d (181.55 mg, 71% yield) as yellow oil. H NMR (400
7k. Dimethyl 3-(3-Bromophenyl)-2,3-dihydroindolizine-1,3-di-
carboxylate. The crude product was purified by column chromatog-
raphy (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7k
MHz, CDCl3): δH 9.80−9.78 (d, J = 8 Hz, 1H) 7.53−7.51 (m, 2H),
7.49−7.46 (m, 1H), 7.40−7.36 (m, 1H), 7.28 (s, 1H), 7.21−7.19 (m,
2H), 6.62−6.60 (d, J = 8 Hz, 1H), 6.10−6.09 (d, J = 4 Hz, 1H),
3.99−3.95 (d, J = 16 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H), 3.36−3.32
(d, J = 16 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC
172.0, 166.2, 150.6, 139.9, 135.5, 132.3, 132.0, 131.2, 129.9, 128.2,
126.5, 125.8, 124.0, 123.0, 106.6, 90.4, 75.4, 53.5, 50.9, 45.0 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C22H19BrNO4, 440.0492;
found, 440.0495. IR (neat) νmax: 3384, 3185, 2920, 2855, 1737, 1648,
1526, 1436, 1338, 1254, 1194, 1073, 1019, 787, 504 cm−1.
1
(174.51 mg, 77% yield) as yellow oil. H NMR (400 MHz, CDCl3):
δH 7.60−7.59 (t, J = 4 Hz, 1H), 7.49−7.46 (m, 2H), 7.36−7.30 (m,
2H), 7.28−7.27 (m, 2H), 7.25−7.23 (d, J = 8 Hz, 1H), 4.05−4.01 (d,
J = 16 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.12−3.07 (d, J = 20 Hz,
1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 172.4, 162.1, 142.6,
141.4, 131.6, 130.6, 128.8, 124.3, 123.1, 75.4, 53.7, 52.4, 42.6 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C18H17BrNO4, 390.0335;
found, 390.0339. IR (neat) νmax: 3338, 2946, 2351, 1723, 1571, 1436,
1249, 1124, 1062, 881, 790, 755, 683 cm−1.
8e. Dimethyl 3-(4-Fluorophenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
7l. Dimethyl 3-(4-Methoxyphenyl)-2,3-dihydroindolizine-1,3-di-
carboxylate. The crude product was purified by column chromatog-
raphy (SiO2, hexane/EtOAc = 85:15, Rf = 0.3) to afford pure 7l
1
afford pure 8e (189.49 mg, 86% yield) as yellow oil. H NMR (400
1
(162.57 mg, 82% yield) as yellow oil. H NMR (400 MHz, CDCl3):
MHz, CDCl3): δH 9.81−9.79 (d, J = 8 Hz, 1H) 7.50−7.46 (m, 1H),
7.40−7.36 (m, 1H), 7.33−7.28 (m, 3H), 7.10−7.06 (m, 2H), 6.62−
6.60 (d, J = 8 Hz, 1H), 6.10−6.08 (d, J = 8 Hz, 1H), 3.99−3.95 (d, J
δH 7.31−7.28 (m, 3H), 6.98−6.96 (m, 3H), 6.88−6.86 (m, 2H),
4.04−3.99 (d, J = 20 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76 (s,
G
https://doi.org/10.1021/acs.joc.1c01209
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
= 16 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.39−3.35 (d, J = 16 Hz,
1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 172.4, 135.6, 131.9,
131.6, 131.2, 130.4, 130.0, 128.5, 128.4, 126.4, 125.8, 116.2, 116.0,
106.6, 90.3, 75.3, 53.4, 52.4, 50.9, 45.1 ppm. 19F NMR (376 MHz,
CDCl3): δF (−)112.77 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C22H19FNO4, 380.1293; found, 380.1295. IR (neat) νmax: 3385, 3185,
2919, 2856, 1738, 1646, 1572, 1437, 1339, 1256, 1191, 1072, 1021,
787, 506 cm−1.
2 Hz, 1H) 6.64−6.62 (d, J = 8 Hz, 1H), 6.12−6.10 (d, J = 8 Hz, 1H),
4.00−3.96 (d, J = 16 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.37−3.33
(d, J = 16 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC
171.9, 166.2, 150.5, 143.0, 135.5, 132.0, 131.9, 131.2, 130.6, 129.9,
129.6, 126.5, 125.8, 125.1, 124.1, 123.2, 106.7, 90.4, 75.3, 53.6, 50.9,
45.1 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for C22H19BrNO4,
440.0492; found, 440.0490. IR (neat) νmax: 3388, 3184, 2918, 2854,
1736, 1640, 1528, 1424, 1252, 1197 1076, 1024, 787, 654, 527 cm−1.
8l. Dimethyl 3-(4-Methoxyphenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
8f. Dimethyl 3-(4-Chlorophenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
1
afford pure 8l (138.64 mg, 61% yield) as yellow oil. H NMR (400
afford pure 8f (158.62 mg, 69% yield) as yellow oil. H NMR (400
MHz, CDCl3): δH 9.82−9.80 (d, J = 8 Hz, 1H), 7.49−7.45 (m, 1H),
7.39−7.35 (m, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.91−6.89 (m, 3H),
6.63−6.61 (d, J = 8 Hz, 1H), 6.09−6.07 (d, J = 8 Hz, 1H), 3.95−3.91
(d, J = 16 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.72 (s, 3H), 3.43−
3.39 (d, J = 16 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC
172.8, 166.4, 159.8, 150.6, 135.7, 132.5, 131.8, 131.1, 130.2, 128.0,
126.2, 125.7, 114.4, 106.3, 90.2, 75.6, 55.5, 53.3, 50.8, 44.8 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C23H22NO5, 392.1492;
found, 392.1495. IR (neat) νmax: 3368, 3184, 2919, 2854, 1735, 1639,
1512, 1439, 1252, 1021, 792, 523 cm−1.
MHz, CDCl3): δH 9.80−9.78 (d, J = 8 Hz, 1H) 7.51−7.47 (m, 1H),
7.41−7.35 (m, 3H), 7.28−7.27 (m, 2H), 7.26 (s, 1H), 6.62−6.60 (d, J
= 8 Hz, 1H), 6.11−6.09 (d, J = 8 Hz, 1H), 3.99−3.95 (d, J = 16 Hz,
1H), 3.88 (s, 3H), 3.72 (s, 3H), 3.36−3.32 (d, J = 16 Hz, 1H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δC 172.1, 166.2, 150.6, 139.3,
135.5, 134.8, 132.0, 131.2, 129.9, 129.3, 127.9, 126.5, 125.8, 124.0,
106.6, 90.3, 75.3, 53.5, 50.9, 45.0 ppm. HRMS (ESI+) m/z: [M + H]+
calcd for C22H19ClNO4, 396.0997; found, 396.1050. IR (neat) νmax
:
3386, 3184, 2900, 2850, 1741, 1646, 1527, 1438, 1340, 1252, 1192,
1073, 1020, 788, 506 cm−1.
Wittig Salt Preparation Procedure. To a suspension of PPh3
(634 mg, 3.794 mmol, 1.0 equiv) in toluene (8 mL), ethyl-2-
bromoacetate was added, and the reaction was allowed to stir at r.t.
overnight. The mixture was filtered through the sinter funnel. The
precipitate was washed with toluene and dried under vacuum to
obtain phosphonium salt. Distilled water (10 mL) was added to the
solution of phosphonium salt in DCM (30 mL) and stirred
vigorously. NaOH was dropwise added to the mixture until the
reaction reaches pH > 14. The layers were separated, and the aqueous
phase was extracted with DCM. The combined organic phase was
washed with brine and dried over Na2SO4. The residue was filtered
and concentrated under reduced pressure to obtain ylide as a colorless
solid (94% yield) (791.56 mg).
8g. Dimethyl 3-(3-Fluorophenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8g (171.86 mg, 78% yield) as yellow oil. H NMR (400
MHz, CDCl3): δH 9.80−9.78 (d, J = 8 Hz, 1H), 7.51−7.47 (t, J = 8
Hz, 1H), 7.40−7.34 (m, 2H), 7.29−7.27 (d, J = 8 Hz, 1H), 7.12−7.04
(m, 3H), 6.66−6.64 (d, J = 8 Hz, 1H), 6.12−6.10 (d, J = 8 Hz, 1H),
4.00−3.96 (d, J = 16 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.38−3.34
(d, J = 8 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 172.0,
166.2, 150.63, 143.33, 135.6, 132.0, 131.2, 130.8, 130.7, 130.0, 126.4,
125.8, 124.1, 122.1, 115.9, 115.7, 114.0, 113.7, 106.6, 90.4, 75.4, 53.5,
50.9, 45.0 ppm. 19F NMR (376 MHz, CDCl3): δF (−)110.93 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C22H19FNO4, 380.1293;
found, 380.1299. IR (neat) νmax: 3389, 3213, 2903, 2855, 1736, 1641,
1527, 1424, 1251, 1190, 1077, 1023, 782, 654, 526 cm−1.
Ethyl 2-(Triphenyl-λ5-phosphanylidene)acetate. 1H NMR
(400 MHz, CDCl3): δH 7.67−7.62 (dd, J = 20 Hz, 6H), 7.55−7.52
(m, 3H), 7.47−7.43 (m, 6H), 3.98−3.93 (q, J = 20 Hz, 2H), 1.25 (s,
1H), 1.03 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 133.1,
133.0, 132.0, 132.0, 128.8, 128.7, 58.0, 14.9 ppm. HRMS (ESI+) m/z:
[M + H]+ calcd for C22H22O2P, 349.1357; found, 349.1355.
Wittig Reaction Procedure. A solution of isatin/5-bromo isatin
(1 equiv, 500 mg) and phosphonium ylide (1.1 equiv) was stirred at
r.t. for 8 h. The solvent is evaporated under vacuo, and the crude
product was purified by silica gel column chromatography (SiO2,
hexane/EtOAc = 85:15, Rf = 0.4) to give orange solid.
Ethyl (E)-2-(2-Oxoindolin-3-ylidene)acetate. The crude prod-
uct was purified by column chromatography (SiO2, hexane/EtOAc =
85:15, Rf = 0.4) to afford pure (649.6 mg, 88% yield) as an orange
solid. 1H NMR (400 MHz, CDCl3): δH 9.38 (s, 1H), 8.93−8.91 (d, J
= 8 Hz, 1H), 7.72−7.68 (t, J = 16 Hz, 1H), 7.45−7.41 (t, J = 16 Hz,
1H), 7.28−7.26 (m, 1H), 4.75−4.70 (q, J = 20 Hz, 2H), 1.78−1.75 (t,
J = 12 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 169.6,
165.7, 143.6, 138.3, 132.6, 129.1, 123.0, 122.7, 110.3, 61.3, 14.3 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C12H12NO3, 218.0817;
found, 218.0823.
N-Acetylation of 3-Alkylidene Oxindoles. Pyridine (1 equiv),
N,N-dimethyl-aminopyridine (0.2 equiv), and acetic anhydride (7
equiv) were added to a solution of 3-alkylidene oxindoles (1 equiv,
500 mg) in DCM (8 mL) and allowed to stir at r.t. under an inert
atmosphere. After completion of the reaction (monitored by TLC),
saturated aqueous NaHCO3 (8 mL) was added to the mixture and
stirred until the evolution of gas ceases (generally about 1 h). The
organic layer is collected and washed (3 × 20 mL) with saturated
aqueous CuSO4 and dried over Na2SO4. The solvent is evaporated
under vacuo, and the crude product was purified by silica gel column
chromatography (SiO2, hexane/EtOAc = 80:20, Rf = 0.4) to afford
yellow solid.
8h. Dimethyl 3-(3-Methoxyphenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8h (152.31 mg, 67% yield) as yellow oil. H NMR (400
MHz, CDCl3): δH 9.82−9.80 (d, J = 8 Hz, 1H) 7.50−7.46 (m, 1H),
7.39−7.35 (m, 1H), 7.32−7.30 (d, J = 8 Hz, 1H), 7.28 (d, J = 2 Hz,
1H), 6.90−6.85 (m, 3H), 6.68−6.66 (d, J = 8 Hz, 1H), 6.09−6.08 (d,
J = 4 Hz, 1H), 3.99−3.95 (d, J = 16 Hz, 1H), 3.87 (s, 3H), 3.79 (s,
3H), 3.72 (s, 3H) 3.42−3.38 (d, J = 16 Hz, 1H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δC 159.5, 150.3, 132.3, 131.5, 130.9, 129.9,
127.7, 125.9, 125.4, 114.1, 106.0, 75.3, 55.2, 53.0, 50.5, 44.5 ppm.
HRMS (ESI+) m/z: [M + H]+ calcd for C23H22NO5, 392.1492;
found, 392.1497. IR (neat) νmax: 3368, 3185, 2919, 2854, 1736, 1642,
1526, 1435, 1250, 1189, 1032, 777, 526 cm−1.
8j. Dimethyl 3-(Thiophen-3-yl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8j (138.70 mg, 65% yield) as yellow oil. . H NMR (400
MHz, CDCl3): δH 7.35−7.32 (q, J = 4 Hz, 2H), 7.28−7.27 (m, 2H),
7.21 (br s, 2H), 7.18−7.14 (m, 1H), 7.09−7.07 (dd, J = 4 Hz, 2H),
3.92−3.88 (d, J = 16 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.16−3.11
(d, J = 20 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC
172.7, 162.3, 142.6, 139.9, 130.0, 127.3, 126.1, 125.6, 122.0, 73.6,
53.5, 52.4, 42.4 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C21H20NO4S, 382.1108; found, 382.1107. IR (neat) νmax: 3367, 3106,
2924, 2831, 1732, 1670, 1524, 1424, 1252, 1196, 1071, 1012, 788,
660, 531 cm−1.
8k. Dimethyl 3-(3-Bromophenyl)-2,3-dihydropyrrolo[2,1-a]-
isoquinoline-1,3-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 85:15, Rf = 0.2) to
1
afford pure 8k (150.87 mg, 59% yield) as yellow oil. H NMR (400
MHz, CDCl3): δH 9.80−9.78 (d, J = 8 Hz, 1H), 7.51−7.47 (m, 3H),
7.40−7.36 (m, 1H), 7.29 (d, J = 2 Hz, 1H), 7.27 (s, 1H), 7.25 (d, J =
6a. Ethyl (E)-2-(1-Acetyl-2-oxoindolin-3-ylidene)acetate. The
crude product was purified by column chromatography (SiO2,
H
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hexane/EtOAc = 80:20, Rf = 0.4) to afford pure 6a (501.27 mg, 84%
yield) as yellow solid (mp 67 °C).·1H NMR (400 MHz, CDCl3): δH
8.68−8.66 (d, J = 8 Hz, 1H), 8.29−8.27 (d, J = 8 Hz, 1H), 7.45−7.41
(m, 1H), 7.24−7.20 (m, 1H), 6.90 (s, 1H), 4.36−4.31 (q, J = 4, 8 Hz,
2H), 2.70 (s, 3H), 1.40−1.36 (t, J = 8 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δC 170.4, 168.0, 165.2, 142.2, 136.3, 133.0,
128.2, 125.4, 123.5, 120.5, 116.5, 61.5, 26.9, 14.2 ppm. HRMS (ESI+)
m/z: [M + H]+ calcd for C14H14NO4, 260.0923; found, 260.0927.
N-Boc Protection of 3-Alkylidene Oxindoles. DMAP (0.4
equiv), Et3N (0.2 equiv), and (Boc)2O (1.5 equiv) were added to a
solution of 3-alkylidene oxindoles (1 equiv, 500 mg) in DCM (8 mL)
and allowed to stir at r.t. overnight under an inert atmosphere. After
completion of the reaction (monitored by TLC), the reaction was
quenched with saturated solution of NH4Cl. The organic layer is
collected and washed (3 × 20 mL) with brine and water and dried
over Na2SO4. The solvent is evaporated under vacuo, and the crude
product was purified by silica gel column chromatography (SiO2,
hexane/EtOAc = 85:15, Rf = 0.4) to afford yellow solid.
for C32H33N2O6, 541.2339; found, 541.2345. IR (neat) νmax: 3391,
3187, 2920, 2857, 1709, 1587, 1460, 1369, 1242, 1158, 1092, 1021,
801, 752, 652, 588 cm−1.
9c. Diethyl 1-Acetyl-2-oxo-3′-(p-tolyl)-3′H-spiro[indoline-3,2′-
indolizine]-1′,3′-dicarboxylate. The crude product was purified by
column chromatography (SiO2, hexane/EtOAc = 75:25, Rf = 0.3) to
afford pure 9c (122.57 mg, 62% yield as ∼6:1 diastereomeric mixture)
as yellow solid (mp 87 °C). 1H NMR (400 MHz, CDCl3): δH 8.56−
8.55 (dd, J = 4 Hz, 1H), 8.30−8.28 (d, J = 8 Hz, 1H), 7.92−7.90 (dd,
J = 8 Hz, 1H), 7.58−7.53 (td, J = 20 Hz, 1H), 7.42−7.38 (td, J = 16
Hz, 1H), 7.32−7.28 (td, J = 16 Hz, 1H), 7.26−7.24 (m, 2H), 7.17−
7.13 (m, 1H), 7.11−7.08 (m, 3H), 3.73−3.61 (m, 2H), 3.59−3.54
(m, 2H), 2.66 (s, 3H), 2.32 (s, 3H), 1.03−1.00 (t, J = 12 Hz, 3H),
0.68−0.64 (t, J = 16 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δC 175.1, 171.3, 167.6, 166.5, 157.6, 149.5, 140.9, 140.6,
138.4, 136.9, 133.5, 130.4, 129.2, 128.7, 128.5, 126.0, 125.5, 122.9,
122.3, 116.3, 63.6, 61.5, 61.0, 26.7, 21.3, 13.7, 13.2 ppm. HRMS (ESI
+) m/z: [M + H]+ calcd for C30H29N2O6, 513.2026; found, 513.2024.
IR (neat) νmax: 3390, 3309, 3197, 3053, 2921, 2858, 1762, 1707,
1582, 1461, 1370, 1236, 1156, 1087, 1019, 798, 745, 589, 523 cm−1.
9d. 1′-Ethyl 3′-Methyl 1-Acetyl-3′-(3-methoxyphenyl)-2-oxo-
3′H-spiro[indoline-3,2′-indolizine]-1′,3′-dicarboxylate. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc = 75:25, Rf = 0.3) to afford pure 9d (146.86 mg, 74% yield as
6c. tert-Butyl (E)-3-(2-Ethoxy-2-oxoethylidene)-2-oxoindoline-1-
carboxylate. The crude product was purified by column chromatog-
raphy (SiO2, hexane/EtOAc = 85:15, Rf = 0.4) to afford pure 6c
1
(606.27 mg, 83% yield) as yellow solid (mp 65 °C). H NMR (400
MHz, CDCl3): δH 8.68−8.66 (d, J = 8 Hz, 1H), 7.90−7.88 (d, J = 8
Hz, 1H), 7.44−7.40 (m, 1H), 7.20−7.16 (td, J = 16 Hz, 1H), 6.90 (s,
1H), 4.35−4.30 (q, J = 20 Hz, 2H), 1.64 (s, 9H), 1.38−1.35 (t, J = 12
Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 165.8, 165.5,
148.9, 141.9, 136.4, 132.8, 128.4, 124.7, 123.2, 120.2, 115.0, 84.8,
61.4, 28.2, 28.0, 14.2 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C17H20NO5, 318.1341; found, 318.1345.
1
3:1 diastereomeric mixture) as yellow solid (mp 82 °C). H NMR
(400 MHz, CDCl3): δH 8.57−8.56 (d, J = 4 Hz, 1H), 8.31−8.29 (d, J
= 8 Hz, 1H), 7.91−7.89 (dd, J = 8 Hz, 1H), 7.59−7.54 (td, J = 20 Hz,
1H), 7.43−7.39 (m, 1H), 7.33−7.29 (td, J = 16 Hz, 1H), 7.21−7.18
(m, 1H), 7.17−7.15 (m, 1H), 7.08−7.06 (d, J = 8 Hz, 1H), 6.96−6.95
(m, 1H), 6.90−6.88 (d, J = 8 Hz, 1H), 6.88−6.84 (dd, J = 16 Hz,
1H), 3.78 (s, 3H), 3.63−3.59 (m, 2H), 3.26 (s, 3H), 2.67 (s, 3H),
0.70−0.66 (t, J = 16 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δC 175.0, 171.3, 167.3, 166.6, 159.3, 157.4, 149.6, 140.5,
140.1, 138.6, 137.4, 137.0, 130.1, 129.5, 129.3, 129.1, 125.9, 125.6,
123.0, 122.2, 121.1, 116.3, 114.8, 113.7, 63.6, 61.1, 55.4, 55.1, 52.6,
52.2, 26.8, 13.7, 13.3 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C29H27N2O7, 515.1818; found, 515.1821. IR (neat) νmax: 3393, 3183,
3050, 2926, 2854, 1715, 1586, 1462, 1369, 1234, 1160, 1095, 1021,
909, 736, 590, 463 cm−1.
General Procedure for Synthesis of (9a−k and 10a−b).
Pyridine (3 equiv) and various substituted aryl/heteroaryl diazoesters
(1.5 equiv) were taken in a 20 mL borosilicate glass vial and dissolved
in DCM (6 mL). After 30 min, various substituted 3-alkylidene
oxindoles 6a−c (1 equiv) were added into the reaction mixture.
Finally, the reaction mixtures were stirred at r.t. under the irradiation
of blue light for 16−17 h. The crude reaction mixture organic layer (3
× 5 mL) was then washed with sat. aq. CuSO4, recollected, and dried
over Na2SO4. The solvent was removed under reduced pressure, and
purifications were carried out by column chromatography in silica gel
(100−200 mesh size) in 25% ethyl acetate in hexane.
9a. 1′-Ethyl 3′-Methyl 1-Acetyl-2-oxo-3′-phenyl-3′H-spiro-
[indoline-3,2′-indolizine]-1′,3′-dicarboxylate. The crude product
was purified by column chromatography (SiO2, hexane/EtOAc =
80:20, Rf = 0.2) to afford pure 9a (128.94 mg, 69% yield) as yellow
solid (mp 81 °C). 1H NMR (400 MHz, CDCl3): δH 8.52−8.51 (d, J =
4 Hz, 1H), 8.27−8.25 (d, J = 8 Hz, 1H), 7.87−7.85 (d, J = 8 Hz, 1H),
7.54−7.49 (td, J = 20 Hz, 1H), 7.38−7.36 (m, 1H), 7.34−7.28 (m,
4H), 7.26−7.24 (m, 2H), 7.13−7.10 (dd, J = 12 Hz, 1H), 7.04−7.02
(d, J = 8 Hz, 1H), 3.57−3.49 (m, 2H), 3.21 (s, 3H), 2.62 (s, 3H),
0.61−0.57 (t, J = 16 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δC 175.0, 171.2, 167.3, 166.6, 157.4, 149.6, 140.5, 140.3,
137.0, 136.3, 130.2, 129.2, 128.6, 128.5, 128.1, 125.9, 125.6, 122.9,
122.2, 116.3, 63.6, 61.1, 52.1, 26.7, 13.2 ppm. HRMS (ESI+) m/z: [M
+ H]+ calcd for C28H25N2O6, 485.1713; found, 485.1717. IR (neat)
νmax: 3847, 3742, 3343, 2922, 2856, 2354, 1713, 1568, 1443, 1246,
1129, 1068, 883, 699, 630, 506 cm−1.
9e. 1′-Ethyl 3′-Methyl 1-Acetyl-3′-(3-chlorophenyl)-2-oxo-3′H-
spiro[indoline-3,2′-indolizine]-1′,3′-dicarboxylate. The crude prod-
uct was purified by column chromatography (SiO2, hexane/EtOAc =
75:25, Rf = 0.3) to afford pure 9e (162.13 mg, 81% yield as ∼5:1
1
diastereomeric mixture) as yellow solid (mp 89 °C). H NMR (400
MHz, CDCl3): δH 8.59−8.58 (d, J = 4 Hz, 1H), 8.33−8.31 (d, J = 8
Hz, 1H), 7.91−7.89 (d, J = 8 Hz, 1H), 7.60−7.56 (td, J = 16 Hz, 1H),
7.45−7.41 (m, 2H), 7.35−7.33 (d, J = 8 Hz, 1H), 7.31−7.28 (m, 2H),
7.25 (s, 1H), 7.20−7.17 (dd, J = 12 Hz, 1H), 7.07−7.05 (d, J = 8 Hz,
1H), 3.65−3.62 (m, 2H), 3.29 (s, 3H), 2.69 (s, 3H), 0.74−0.71 (t, J =
12 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 174.8,
171.2, 166.9, 166.1, 157.4, 149.6, 140.6, 139.8, 138.7, 137.9, 137.1,
134.0, 130.0, 129.3, 128.9, 128.6, 126.9, 125.8, 125.7, 123.0, 122.1,
116.4, 63.6, 61.3, 52.4, 26.7, 13.3 ppm. HRMS (ESI+) m/z: [M + H]+
calcd For C28H24ClN2O6, 519.1323; found, 519.1321. IR (neat) νmax
:
3385, 3299, 3058, 2922, 2857, 1710, 1579, 1461, 1370, 1244, 1156,
1089, 1018, 912, 745, 693, 589 cm−1.
9f. 1′-Ethyl 3′-Methyl 1-Acetyl-3′-(3-nitrophenyl)-2-oxo-3′H-
spiro[indoline-3,2′-indolizine]-1′,3′-dicarboxylate. The crude prod-
uct was purified by column chromatography (SiO2, hexane/EtOAc =
75:25, Rf = 0.3) to afford pure 9f (138.88 mg, 68% yield) as yellow
solid (mp 81 °C). 1H NMR (400 MHz, CDCl3): δH 8.58−8.57 (d, J =
4 Hz, 1H), 8.33−8.31 (d, J = 8 Hz, 1H), 8.27 (s, 1H), 8.20−8.18 (d, J
= 8 Hz, 1H), 7.89−7.87 (d, J = 8 Hz, 1H), 7.71−7.69 (d, J = 8 Hz,
1H), 7.60−7.55 (td, J = 20 Hz, 1H), 7.53−7.49 (t, J = 16 Hz, 1H),
7.46−7.42 (m, 1H), 7.35−7.32 (t, J = 12 Hz, 1H), 7.20−7.17 (dd, J =
12 Hz, 1H), 7.01−6.99 (d, J = 8 Hz, 1H), 3.62−3.56 (m, 2H), 3.30
(s, 3H), 2.67 (s, 3H), 0.69−0.65 (t, J = 16 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3): δC 174.7, 171.2, 166.5, 165.7, 157.3, 149.7,
148.0, 140.7, 137.9, 137.7, 137.2, 135.0, 129.9, 129.5, 129.1, 125.8,
125.7, 124.0, 123.4, 123.1, 122.0, 116.5, 63.7, 61.5, 52.6, 26.7, 13.3
9b. 1′-Ethyl 3′-Methyl 1-Acetyl-3′-(4-(tert-butyl)phenyl)-2-oxo-
3′H-spiro[indoline-3,2′-indolizine]-1′,3′-dicarboxylate. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc = 75:25, Rf = 0.3) to afford pure 9b (160.56 mg, 77% yield as
1
∼3:1 diastereomeric mixture) as yellow solid (mp 85 °C). H NMR
(400 MHz, CDCl3): δH 8.57−8.55 (d, J = 8 Hz, 1H), 8.31−8.29 (d, J
= 8 Hz, 1H), 7.92−7.90 (dd, J = 8 Hz, 1H), 7.58−7.54 (td, J = 16 Hz,
1H), 7.44−7.38 (q, J = 24 Hz, 2H), 7.32−7.31 (m, 2H), 7.30−7.29
(m, 2H), 7.17−7.13 (m, 1H), 7.09−7.08 (d, J = 4 Hz, 1H), 3.61−3.55
(m, 2H), 3.25 (s, 3H), 2.67 (s, 3H), 1.28 (s, 9H), 0.61−0.57 (t, J = 16
Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 171.3, 167.6,
166.9, 157.5, 151.7, 149.6, 140.5, 137.0, 133.3, 130.8, 130.3, 129.2,
128.3, 126.0, 125.8, 125.6, 125.0, 122.9, 122.3, 117.1, 116.3, 61.0,
52.1, 34.7, 31.3, 26.7, 13.1 ppm. HRMS (ESI+) m/z: [M + H]+ calcd
I
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ppm. HRMS (ESI+) m/z: [M + H]+ calcd for C28H24N3O8, 530.1563;
found, 530.1559. IR (neat) νmax: 3394, 3078, 2930, 2859, 1716, 1589,
1528, 1462, 1343, 1233, 1096, 1018, 914, 751, 689, 590, 456 cm−1.
9g. 1′-Ethyl 3′-Methyl 1-Acetyl-5-bromo-3′-(3-bromophenyl)-2-
oxo-3′H-spiro[indoline-3,2′-indolizine]-1′,3′-dicarboxylate. The
crude product was purified by column chromatography (SiO2,
hexane/EtOAc = 75:25, Rf = 0.3) to afford pure 9g (129.16 mg,
68% yield) as yellow solid (mp 85 °C). 1H NMR (400 MHz, CDCl3):
δH 8.57−8.56 (d, J = 4 Hz, 1H), 8.23−8.21 (d, J = 8 Hz, 1H), 8.07 (d,
J = 4 Hz, 1H), 7.62−7.58 (m, 1H), 7.56−7.54 (m, 2H), 7.47−7.45 (d,
J = 8 Hz, 1H), 7.29−7.28 (m, 1H), 7.21−7.17 (m, 2H), 7.05−7.03 (d,
J = 8 Hz, 1H), 3.64−3.60 (m, 2H), 3.34 (s, 3H), 2.63 (s, 3H), 0.74−
0.70 (t, J = 16 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC
174.1, 171.0, 166.8, 166.1, 156.6, 149.8, 139.6, 138.9, 137.9, 137.3,
132.3, 131.7, 131.7, 129.6, 128.9, 127.4, 123.3, 122.2, 122.1, 118.7,
117.9, 63.4, 61.5, 52.6, 32.0, 26.7, 22.8, 14.2, 13.3 ppm. HRMS (ESI
+) m/z: [M + H]+ calcd for C28H23Br2N2O6, 642.9923; found,
642.9928. IR (neat) νmax: 3357, 3185, 3072, 2920, 2855, 1716, 1580,
1460, 1372, 1243, 1093, 1017, 800, 697, 603, 533 cm−1.
9h. 1-(tert-Butyl) 1′,3′-Diethyl 2-Oxo-3′-(p-tolyl)-3′H-spiro-
[indoline-3,2′-indolizine]-1,1′,3′-tricarboxylate. The crude product
was purified by column chromatography (SiO2, hexane/EtOAc =
80:20, Rf = 0.3) to afford pure 9h (145.65 mg, 81% yield) as yellow
solid (mp 72 °C). 1H NMR (400 MHz, CDCl3): δH 8.55−8.54 (dd, J
= 4 Hz, 1H), 8.00−7.98 (dd, J = 8 Hz, 1H), 7.92−7.90 (d, J = 8 Hz,
1H), 7.57−7.52 (td, J = 20 Hz, 1H), 7.41−7.37 (td, J = 16 Hz, 1H),
7.29−7.27 (m, 2H), 7.26−7.25 (m, 1H), 7.17−7.13 (m, 2H), 7.12−
7.08 (m, 2H), 3.79−3.73 (m, 1H), 3.65−3.54 (m, 3H), 2.31 (s, 3H),
1.61 (s, 9H), 1.09−1.06 (t, J = 12 Hz, 3H), 0.68−0.64 (t, J = 16 Hz,
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 172.6, 167.6, 166.5,
157.5, 149.5, 149.4, 140.9, 140.1, 138.2, 137.6, 136.8, 133.6, 130.2,
129.0, 128.7, 128.6, 126.6, 124.8, 122.8, 122.6, 114.8, 84.3, 61.5, 60.9,
28.2, 21.3, 13.7, 13.2 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C33H35N2O7, 571.6500; found, 571.6496. IR (neat) νmax: 3395, 2974,
2925, 1722, 1586, 1465, 1343, 1233, 1146, 1092, 1025, 910, 735, 462
cm−1.
9i. 1-(tert-Butyl) 1′-Ethyl 3′-Methyl 3′-(3-Chlorophenyl)-2-oxo-
3′H-spiro[indoline-3,2′-indolizine]-1,1′,3′-tricarboxylate. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc = 80:20, Rf = 0.3) to afford pure 9i (143.65 mg, 79% yield) as
yellow solid (mp 75 °C). 1H NMR (400 MHz, CDCl3): δH 8.56−8.54
(m, 1H), 7.95−7.91 (dd, J = 16 Hz, 2H), 7.58−7.53 (td, J = 20 Hz,
1H), 7.42−7.38 (m, 2H), 7.28−7.27 (m, 2H), 7.25−7.22 (m, 2H),
7.16−7.13 (dd, J = 12 Hz, 1H), 7.12−7.10 (d, J = 8 Hz, 1H), 3.64−
3.60 (dd, J = 16 Hz, 2H), 3.33 (s, 3H), 1.62 (s, 9H), 0.73−0.69 (t, J =
16 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 166.2,
157.3, 149.6, 140.2, 138.1, 136.9, 134.0, 129.9, 129.3, 129.1, 128.9,
128.6, 127.0, 126.4, 124.9, 122.9, 122.3, 114.9, 84.5, 61.2, 53.5, 52.3,
28.2, 13.3 ppm. HRMS (ESI+) m/z: [M + H]+ calcd for
C31H30ClN2O7, 577.1742; found, 577.1747. IR (neat) νmax: 3061,
2963, 2930, 1729, 1581, 1466, 1241, 1146, 1085, 1021, 908 728, 461
cm−1.
product was purified by column chromatography (SiO2, hexane/
EtOAc = 80:20, Rf = 0.3) to afford pure 9k (116.65 mg, 63% yield) as
yellow solid (mp 71 °C). 1H NMR (400 MHz, CDCl3): δH 8.56−8.55
(d, J = 4 Hz, 1H), 8.28−8.27 (m, 1H), 8.19−8.16 (dd, J = 12 Hz,
1H), 7.94−7.92 (d, J = 8 Hz, 2H), 7.73−7.71 (d, J = 8 Hz, 1H),
7.59−7.54 (td, J = 20 Hz, 1H), 7.51−7.47 (t, J = 16 Hz, 1H), 7.44−
7.40 (td, J = 16 Hz, 1H), 7.31−7.27 (t, J = 16 Hz, 1H), 7.17−7.14
(dd, J = 12 Hz, 1H), 7.08−7.06 (d, J = 8 Hz, 1H), 3.64−3.54 (m,
2H), 3.35 (s, 3H), 1.63 (s, 9H), 0.69−0.66 (t, J = 12 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δC 172.1, 166.5, 165.7, 157.3,
149.7, 149.4, 147.9, 141.2, 140.2, 138.1, 137.7, 137.1, 135.1, 129.7,
129.3, 129.0, 126.3, 125.0, 124.0, 123.3, 123.0, 122.1, 114.9, 84.6,
63.6, 61.3, 52.5, 28.2, 13.3 ppm. HRMS (ESI+) m/z: [M + H]+ calcd
for C31H30N3O9, 588.1982; found, 588.1979. IR (neat) νmax: 3074,
2973, 2936, 1725, 1586, 1466, 1343, 1236, 1146, 1089, 1023, 909,
727, 460 cm−1.
10a. Diethyl 2-(1-(tert-Butoxycarbonyl)-2-oxoindolin-3-yl)-
maleate. The crude product was purified by column chromatography
(SiO2, hexane/EtOAc = 80:20, Rf = 0.3) to afford pure 10a (57.21
mg, 45% yield) as yellow oil. 1H NMR (400 MHz, CDCl3): δH 7.89−
7.86 (d, J = 12 Hz, 1H), 7.41−7.37 (m, 1H), 7.30−7.28 (m, 1H),
7.17−7.13 (td, J = 16 Hz, 1H), 4.63 (s, 1H), 4.35−4.33 (q, J = 8 Hz,
2H), 3.85−3.80 (q, J = 20 Hz, 2H), 1.64 (s, 9H), 1.37−1.33 (t, J = 16
Hz, 3H), 0.87−0.83 (t, J = 16 Hz, 3H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δC 173.8, 166.0, 161.1, 148.8, 139.7, 139.1, 131.3,
125.8, 125.2, 125.1, 123.2, 115.6, 115.4, 85.4, 73.0, 62.2, 61.8, 61.7,
60.1, 29.4, 28.1, 14.3, 13.7 ppm. HRMS (ESI+) m/z: [M + H]+ calcd
for C21H26NO7, 404.1709; found, 404.1713. IR (neat) νmax: 3320,
2978, 2930, 1726, 1592, 1529, 1460, 1294, 1150, 1026, 910, 741, 465
cm−1.
10b. 1-Ethyl 4-Methyl 2-(1-(tert-Butoxycarbonyl)-2-oxoindolin-
3-yl)maleate. The crude product was purified by column
chromatography (SiO2, hexane/EtOAc = 80:20, Rf = 0.3) to afford
1
pure 10b (68.72 mg, 56% yield) as a yellow solid (mp 69 °C). H
NMR (400 MHz, CDCl3): δH 7.89−7.86 (dd, J = 12 Hz, 1H), 7.41−
7.37 (td, J = 16 Hz, 1H), 7.29−7.27 (d, J = 8 Hz, 1H), 7.17−7.13 (td,
J = 16 Hz, 1H), 4.62 (s, 1H), 3.87 (s, 3H), 3.85−3.80 (q, J = 20 Hz,
2H), 1.64 (s, 9H), 0.86−0.82 (t, J = 16 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δC 173.7, 165.9, 161.5, 148.7, 139.7, 138.7,
131.3, 131.1, 125.8, 125.2, 125.1, 124.3, 123.1, 115.6, 115.4, 85.5,
85.2, 73.1, 73.0, 62.3, 61.7, 61.6, 60.0, 52.6, 28.1, 13.6 ppm. HRMS
(ESI+) m/z: [M + H]+ calcd for C20H24NO7, 390.1553; found,
390.1555. IR (neat) νmax: 3320, 2974, 2931, 1726, 1581, 1456, 1248,
1144, 1033, 909, 740, 464 cm−1.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01209.
Complete experimental details and characterization data
for the synthesized compounds (PDF)
9j. 1-(tert-Butyl) 1′-Ethyl 3′-Methyl 3′-(4-Chlorophenyl)-2-oxo-
3′H-spiro[indoline-3,2′-indolizine]-1,1′,3′-tricarboxylate. The crude
product was purified by column chromatography (SiO2, hexane/
EtOAc = 80:20, Rf = 0.3) to afford pure 9j (140.01 mg, 77% yield) as
yellow solid (mp 73 °C). 1H NMR (400 MHz, CDCl3): δH 8.56−8.54
(dd, J = 8 Hz, 1H), 7.95−7.90 (m, 2H), 7.57−7.53 (td, J = 16 Hz,
1H), 7.42−7.37 (td, J = 20 Hz, 1H), 7.33−7.31 (m, 2H), 7.28−7.26
(m, 3H), 7.15−7.13 (dd, J = 8 Hz, 1H), 7.12−7.10 (d, J = 8 Hz, 1H),
3.63−3.58 (dd, J = 20 Hz, 2H), 3.32 (s, 3H), 1.62 (s, 9H), 0.73−0.69
(t, J = 16 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δC 172.4,
167.1, 166.4, 157.4, 149.6, 140.2, 139.4, 139.0, 136.9, 134.9, 134.7,
130.2, 130.0, 129.1, 128.3, 126.4, 124.9, 122.9, 122.3, 114.9, 84.5,
63.6, 61.2, 52.2, 28.2, 13.3 ppm. HRMS (ESI+) m/z: [M + H]+ calcd
for C31H30ClN2O7, 577.1742; found, 577.1748. IR (neat) νmax: 3369,
3184, 3058, 2922, 2856, 1739, 1664, 1525, 1440, 1340, 1249, 1193,
1075, 904, 738, 514 cm−1.
AUTHOR INFORMATION
■
Corresponding Author
Subhabrata Sen − Department of Chemistry, School of
Natural Sciences, Shiv Nadar University Dadri, Uttar
Pradesh 201314, India; orcid.org/0000-0002-4608-
5498; Email: subhabrata.sen@snu.edu.in
Authors
Saibal Sar − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University Dadri, Uttar Pradesh
201314, India
Souvik Guha − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University Dadri, Uttar Pradesh
201314, India
9k. 1-(tert-Butyl) 1′-Ethyl 3′-Methyl 3′-(3-Nitrophenyl)-2-oxo-
3′H-spiro[indoline-3,2′-indolizine]-1,1′,3′-tricarboxylate. The crude
J
https://doi.org/10.1021/acs.joc.1c01209
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Unified Synthesis of Azepines by Visible-Light-Mediated Dearomative
Ring Expansion of Aromatic N-Ylides. Org. Lett. 2021, 23, 525−529.
(d) Basavaiah, D.; Devendar, B.; Lenin, D.; Satyanarayana, T. The
Baylis-Hillman Bromides as Versatile Synthons: A Facile One-Pot
Synthesis of Indolizine and Benzofused Indolizine Frameworks.
Synlett 2009, 2009, 411−416.
Tejas Prabakar − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University Dadri, Uttar Pradesh
201314, India
Debajit Maiti − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University Dadri, Uttar Pradesh
201314, India
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01209
(5) Barluenga, J.; Lonzi, G.; Riesgo, L.; López, L. A.; Tomás, M.
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Author Contributions
†S.S., S.G., and T.P. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for funds from the Shiv Nadar University.
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