Photochemical aryl radical cyclizations to give (E)-3-ylideneoxindoles

Article abstract of DOI:10.3390/molecules191015891

(E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initia

Full text of DOI:10.3390/molecules191015891

Molecules 2014, 19, 15891-15899; doi:10.3390/molecules191015891
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Photochemical Aryl Radical Cyclizations to
Give (E)-3-Ylideneoxindoles
Michael Gurry 1, Ingrid Allart-Simon 2, Patrick McArdle 1, Stéphane Gérard 2, Janos Sapi 2 and
Fawaz Aldabbagh 1,*
1
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland
2
Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims-Champagne-
Ardenne, Faculté de Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims Cedex, France
* Author to whom correspondence should be addressed; E-Mail: Fawaz.Aldabbagh@nuigalway.ie;
Tel.: +353-91-493120; Fax: +353-91-495576.
External Editors: John C. Walton and Ffrancon Williams
Received: 2 September 2014; in revised form: 19 September 2014 / Accepted: 24 September 2014 /
Published: 30 September 2014
Abstract: (E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as
adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported
analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that
gave reduced oxindole adducts.
Keywords: cyclization; heterocycle; oxindole; UV-light
1. Introduction
3-Ylideneoxindoles, mainly ethyl (2E)-(1-methyl-2-oxoindolin-3-ylidene)acetate (2a) have recently
become privileged precursors in organic synthesis for organocatalyzed asymmetric Michael
additions/cyclization [1], epoxidation [2,3], reduction [4], [2+2] cycloaddition using visible light
photocatalysis [5], and [3+2] cycloaddition sequences [6,7]. 2-Oxoindolin-3-ylidene acetate derivatives
are prepared via modifications of the Wittig reaction on alkylated isatin (indole-2,3-dione)
derivatives [3,7–9]. The 3-ylideneoxindole moiety is present in a number of natural products,
pharmaceuticals and biologically important derivatives [10].

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There are numerous reports of reductive radical cyclizations of aryl radicals using Bu3SnH or
tris(trimethylsilyl)silane {(Me3Si)3SiH} and azo-initiators giving 3-substituted oxindoles in good yields
(Scheme 1) [11–21].
Scheme 1. An example of oxindole prepared using reductive radical cyclization [20].
O
O
OEt
EtO
I
(Me3Si)3SiH, AIBN
O
Tol, 110 °C, 10 h
99%
N
O
N
Me
Me
1a
More recently aryl radicals were reported by Gérard and Sapi and co-workers to give
3-(2-oxopyrrolidin-3-yl)indolin-2-ones via two tandem 5-exo-trig reactions [20], while for N-methyl
sulfonylfumaramides precursors (e.g., 1b and 1c) a 5-exo-trig was followed by a reductive Smiles
rearrangement (Scheme 2) [21].
Scheme 2. Oxindoles prepared via tandem cyclization/Smiles rearrangement [21].
As part of this collaboration we became interested in forming the oxindole skeleton in the absence
of toxic and hazardous radical initiators or expensive metal catalysts [22–24]. In this article, an
“initiator and metal-free” photochemical radical pathway giving non-reduced adducts, (E)-3-ylidene-
oxindoles, after 5-exo-trig cyclization is reported (Schemes 3 and 4).
2. Results and Discussion
Treatment of iodide fumarate precursors 1a, 1d and 1e in acetonitrile using a Rayonet photochemical
reactor at 254 nm yielded in 42%–48% 3-ylideneoxindoles 2a and 2d–2e (Scheme 3). The 3-ylideneoxindole
acetates are however susceptible to a highly regioselective and diastereoselective intermolecular [2+2]
cycloaddition previously reported using a visible light photocatalytic protocol using Ru(bpy)3Cl2·6H2O
photosensitizer [5]. Diastereoselectivity was not measured in the present UV-initiated reactions, but
spectroscopic data for cycloadducts 3a, 3d and 3e (isolated in 17%–23% yield) matched the literature [5].
Aryl radical reduction products presumably formed by hydrogen abstraction from the solvent
(acetonitrile [22–24]) were also detected, but not isolated and quantified. Yields of (E)-3-ylideneoxindole
acetates 2a and 2d–2e were improved (55%–72%) when the acetonitrile reaction solvent was replaced

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by methanol (Scheme 3), which may partly be due to the absence of aryl radical reduction from the
solvent. The [2+2] cycloadducts 3a, 3d and 3e were formed (in 10%–20% yield) but could be easily
separated from the desired (E)-3-ylideneoxindoles 2a and 2d–2e using column chromatography.
Scheme 3. Preparation of 3-ylideneoxindole acetates.
The cyclization onto N,N-dimethylfumaramide 1f, and N-methyl sulfonylfumaramides 1b and 1c in
acetonitrile gave 3-ylideneoxindoles 2f, 2b and 2c, as major products in low to moderate yields
(26%–48%, Scheme 4). In these cases, there was no evidence of the photochemical cycloaddition.
The yield for the N,N-dimethylfumaramide adduct 2f was marginally improved (to 54%) using
methanol, but the yield of the N-methylsulfonylfumaramide 2c was reduced (to 24%). The instability of
(E)-3-ylideneoxindole amides 2c and 2f was confirmed by subjecting them separately to UV-light
(at 254 nm) for 3 h, which resulted in a complex intractable mixture of products.
Scheme 4. Preparation of 3-ylideneoxindole acetamides.
For N-methylsulfonylfumaramides 1b–1c the domino radical cyclization-Smiles rearrangement,
which occurred with radical initiators, was not observed (Scheme 2) [21]. Column chromatography
fractions from the irradiation of 1b were analyzed using ESI, and two major but unstable products with
m/z 484.3 were observed, which proved difficult to rigorously purify and characterize due to conversion
to the oxindole 2b. The mass fitted that of iodide adducts prior to HI-elimination to give 2b (Figure 1).

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The X-ray crystal of 2b confirmed the formation of the 5-exo-trig adduct and (E)-geometry about the
3-ylidene (Figure 2) [25].
Figure 1. Putative structure for two major isomeric intermediates detected by ESI.
Figure 2. X-ray crystal structure of (2E)-N-methyl-2-(1-methyl-2-oxo-1,2-dihydro-3H-
indol-3-ylidene)-N-(phenylsulfonyl)acetamide (2b) [25].
3. Experimental Section
3.1. General
All chemicals were obtained from commercial sources and used without further purification. Thin
layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates. Dry vacuum column
chromatography [26] was carried out on silica gel (Apollo Scientific ZEOprep 60/15–35 microns).
Melting points were measured on a Stuart Scientific melting point apparatus SMP1. Infrared spectra
were recorded using a Perkin-Elmer Spec 1 with ATR attached. 1H-NMR spectra were recorded using a
Joel GXFT 400 MHz instrument equipped with a DEC AXP 300 computer workstation. The chemical
shifts were recorded in ppm relative to tetramethylsilane. 13C-NMR data were collected at 100 MHz with
complete proton decoupling. High resolution mass spectra (HRMS) were carried out using ESI time-of-flight
mass spectrometer (TOFMS) in positive mode. The precision of all accurate mass measurements were
better than 5 ppm. Photochemical reactions were carried out at 254 nm using a RPR-100 Rayonet
photochemical reactor, encompassing sixteen mercury lamps.

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3.2. Experimental Procedures
3.2.1. Synthesis of Radical Precursors
The synthesis of radical precursors acetate 1a [20], and sulfonamides 1b and 1c [21] has been
previously reported.
Ethyl (2E)-4-[(2-iodo-4-methylphenyl)(methyl)amino]-4-oxobut-2-enoate (1d). 4-Methyl-morpholine
(1.60 g, 15.9 mmol) was added to a suspension of fumaric acid monoethyl ester (2.30 g, 15.9 mmol) and
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (4.40 g, 15.9 mmol) in THF (50 mL)
and the suspension was stirred at room temperature for 20 min. A solution of 2-iodo–p-toluidine (3.35 g,
14.4 mmol) in THF (5 mL) was added and the suspension was stirred overnight. The reaction mixture
was diluted with water, extracted with diethyl ether washed with saturated NaHCO3, water, 2%
hydrochloric acid, brine, dried (NaSO4), and evaporated. The residue was added to a mixture of sodium
hydride (0.371 g, 15.4 mmol) in THF (25 mL), which was cooled to 0 °C. The solution was stirred for
30 min at 0 °C and at room temperature for another 30 min. Methyl iodide (2.74 g, 19.3 mmol) was added
and the reaction was stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate,
washed with water, dried (MgSO4) and evaporated. The resulting crude was recrystallized from diethyl
ether to give the title compound (3.65 g, 68%) as an off-white solid; mp 76–80 °C; vmax (neat, cm−1)
2925, 1716 (C=O), 1663 (C=O), 1633, 1489, 1419, 1375, 1295, 1174, 1127, 1059, 1033; δH (400 MHz,
CDCl3) 1.24 (t, J 7.1 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 3.23 (s, 3H, NCH3), 4.15 (q, J 7.1 Hz, 2H, OCH2),
6.63 (d, J 15.3 Hz, 1H), 6.87 (d, J 15.3 Hz, 1H), 7.10 (d, J 8.0 Hz, 1H, 6-H), 7.20 (dd, J 8.0, 1.1 Hz, 1H,
5-H), 7.74 (d, J 1.1 Hz, 1H, 3-H); δC (100 MHz, CDCl3) 14.2 (CH3CH2), 20.7 (CH3), 36.7 (NCH3), 61.1
(OCH2), 99.1 (C), 128.7 (6-CH), 130.9 (5-CH), 131.6, 133.8 (CH), 140.8 (3-CH), 140.9, 142.1 (C),
164.2, 165.8 (C=O). HRMS (ESI) m/z (M+H)+, C14H17NO3I calcd. 374.0253, observed 374.0248.
Ethyl (2E)-4-[benzyl(2-iodophenyl)amino]-4-oxobut-2-enoate (1e). Same procedure as for the synthesis
of 1d was followed, except 2-iodoaniline (3.15 g, 14.4 mmol) and benzyl bromide (7.39 g, 43.2 mmol)
were used, and the crude was purified by dry vacuum column chromatography with gradient elution of
petroleum ether and ethyl acetate to give the title compound (5.07 g, 81%) as an off-white solid; Rf 0.52
(1:4 EtOAc/Pet); mp 64–66 °C; vmax (neat, cm−1) 3031, 2981, 1720 (C=O), 1662 (C=O), 1637, 1577,
1468, 1388, 1292, 1160, 1082, 1023; δH (400 MHz, CDCl3) 1.23 (t, J 7.1 Hz, 3H, CH3), 4.08 (d, J 14.2 Hz,
1H, NCHH), 4.14 (q, J 7.1 Hz, 2H, OCH2), 5.66 (d, J 14.2 Hz, 1H, NCHH), 6.58 (d, J 15.2 Hz, 1H), 6.71
(dd, J 7.8, 1.6 Hz, 1H, 6-H), 6.93 (d, J 15.2 Hz, 1H), 7.06 (td, J 7.9, 1.6 Hz, 1H), 7.18–7.27 (m, 6H),
7.93 (dd, J 7.9, 1.4 Hz, 1H, 3-H); δC (100 MHz, CDCl3) 14.2 (CH3), 52.3 (NCH2), 61.1 (OCH2), 100.3 (C),
127.9, 128.6, 129.4, 129.6, 130.5 (CH), 131.0 (6-CH), 132.2, 133.8 (CH), 136.3 (C), 140.5 (3-CH), 142.6
(C) 163.9, 165.6 (C=O). HRMS (ESI) m/z (M+H)+, C19H19NO3I calcd. 436.0410, observed 436.0414.
(2E)-N-(2-iodophenyl)-N,N',N'-trimethylbut-2-enediamide (1f). 4-((2-Iodophenyl)(methyl)amino)-4-
oxobut-2(E)-enoic acid [21] (0.300 g, 0.9 mmol), oxalyl chloride (0.15 mL, 1.8 mmol) and DMF
(0.70 mL, 9.1 mmol) were stirred in dichloromethane (10 mL) at room temperature for 12 h. The mixture
was evaporated to dryness, and the residue was dissolved in dichloromethane (10 mL), and triethylamine
(0.50 mL, 3.6 mmol) added, and stirred at room temperature for 6 h. The mixture was washed with brine

Molecules 2014, 19
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(2 × 20 mL) and the organic layer was dried (Na2SO4), evaporated to dryness, and purified by dry
vacuum column chromatography with gradient elution of petroleum ether and ethyl acetate to give the
title compound (0.227 g, 70%) as a brown solid; Rf 0.38 (EtOAc); mp 100–102 °C; vmax (neat, cm−1)
3293, 2927, 2853, 1630 (C=O), 1611 (C=O), 1468, 1370, 1057; δH (400 MHz, CDCl3) 2.93 (s, 3H, CH3),
3.08 (s, 3H, CH3), 3.24 (s, 3H, CH3), 6.52 (d, J 14.7 Hz, 1H), 7.06 (t, J 7.8 Hz, 1H), 7.22–7.25 (m, 1H),
7.36–7.42 (m, 2H), 7.88 (d, J 8.0 Hz, 1H); δC (100 MHz, CDCl3) 35.8, 36.7, 37.6 (CH3), 99.5 (C), 129.3,
130.2, 130.4, 131.0, 131.7, 140.4 (all CH), 144.9 (C) 164.8, 165.2 (C=O); HRMS (ESI) m/z (M+H)+,
C13H16N2O2I calcd. 359.0257, observed 359.0269.
3.2.2. Photochemical Radical Cyclizations
The o-iodoanilide derivative (0.5 mmol) in acetonitrile or methanol (29 mL) was irradiated in a
cylindrical quartz tube at 254 nm for 3 h. The solution was evaporated to dryness and the residue washed
with saturated NaHCO3 solution (20 mL), and extracted with dichloromethane (3 × 10 mL). The organic
layers were combined, dried (Na2SO4), evaporated to dryness, and purified by dry vacuum column
chromatography with gradient elution of petroleum ether and ethyl acetate.
Ethyl (2E)-(1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetate (2a). 55 mg (48%) using MeCN
and 83 mg (72%) using MeOH; orange solid; Rf 0.52 (1:4 EtOAc/Pet); mp 76–78 °C (mp [9] 75–76 °C);
Spectral data consistent with the literature [5].
Diethyl 1,1"-dimethyl-2,2"-dioxo-1,1",2,2"-tetrahydrodispiro[indole-3,1'-cyclobutane-2',3"-indole]-
3',4'-dicarboxylate (3a). 20 mg (17%) using MeCN and 12 mg (10%) using MeOH; off-white solid; Rf
0.61 (1:1 EtOAc/Pet); mp 132–134 °C (mp [5] 154–156 °C); Spectral data consistent with the literature [5].
Ethyl (2E)-(1,5-dimethyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetate (2d). 59 mg (48%) using
MeCN and 78 mg (64%) using MeOH; orange solid; Rf 0.55 (1:4 EtOAc/Pet); mp 110–112 °C (mp [5]
116–118 °C); Spectral data consistent with the literature [5].
Diethyl 1,1",5',5"-tetramethyl-2,2"-dioxo-1,1",2,2"-tetrahydrodispiro[indole-3,1'-cyclobutane-2',3"-
indole]-3',4'-dicarboxylate (3d). 24 mg, (20%) using MeCN and 18 mg, (15%) using MeOH; orange
solid; Rf 0.67 (1:1 EtOAc/Pet); mp 128–130 °C (mp [5] 142–145 °C); Spectral data consistent with the
literature [5].
Ethyl (2E)-(1-benzyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetate (2e). 64 mg (42%) using MeCN and
84 mg (55%) using MeOH; orange solid; Rf 0.68 (1:4 EtOAc/Pet); mp 60–62 °C (mp [5] 79–80 °C);
Spectral data consistent with the literature [5].
Diethyl
1,1"-dibenzyl-2,2"-dioxo-1,1",2,2"-tetrahydrodispiro[indolo-3,1'-cyclobutane-2',3"-indole]-
3',4'-dicarboxylate (3e). 35 mg (23%) using MeCN and 31 mg (20%) using MeOH; yellow solid, Rf 0.36
(1:4 EtOAc/Pet); mp 122–124 °C, (mp [5] 134–138 °C); Spectral data consistent with the literature [5].
(2E) N,N-dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetamide (2f). 55 mg (48%)
using MeCN and 62 mg (54%) using MeOH; yellow oil; Rf 0.47 (EtOAc); vmax (neat, cm−1) 2928, 2853,

Molecules 2014, 19
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1714 (C=O), 1634 (C=O), 1610, 1470, 1448, 1375, 1337, 1157; δH (400 MHz, CDCl3) 3.09 (s, 3H,
NCH3), 3.12 (s, 3H, NCH3), 3.23 (s, 3H, NCH3), 6.79 (d, J 7.7 Hz, 1H, 7-H), 7.00 (t, J 7.7 Hz, 1H), 7.21
(s, 1H), 7.31 (t, J 7.7 Hz, 1H), 7.79 (d, J 7.7 Hz, 1H, 4-H); δC (100 MHz, CDCl3) 26.3, 35.0, 37.7 (NCH3),
108.2 (7-CH), 120.0 (C), 122.8 (CH), 125.6 (CH), 125.8 (4-CH), 131.3 (CH), 132.8, 144.9 (C), 166.1,
167.6 (C=O); HRMS (ESI) m/z (M+H)+, C13H15N2O2 calcd. 231.1134, observed 231.1131.
(2E)-N-methyl-2-(1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-N-(phenylsulfonyl)acetamide (2b). 69
mg (39%); yellow solid; Rf 0.48 (1:1 EtOAc/Pet); mp 128–130 °C; vmax (neat, cm−1) 3058, 2928, 1715
(C=O), 1683 (C=O), 1610, 1470, 1448, 1349 (SO2), 1254, 1164 (SO2), 1087, 1038; δH (400 MHz,
CDCl3) 3.21 (s, 3H, NCH3), 3.44 (s, 3H, NCH3), 6.75 (d, J 7.7 Hz, 1H, 7-H), 6.90 (td, J 7.7, 1.0 Hz, 1H),
7.30 (td, J 7.7, 1.0 Hz ,1H), 7.39 (s, 1H), 7.46-7.50 (m, 2H), 7.56–7.58 (m, 1H), 7.66 (d, J 7.7 Hz, 1H,
4-H), 7.91–7.93 (m, 2H); δC (100 MHz, CDCl3) 26.3, 33.1 (NCH3), 108.4 (7-CH), 119.3 (C), 122.7,
123.6 (CH), 126.4 (4-CH), 127.8, 129.4, 132.3, 134.1 (all CH), 135.4, 138.6, 145.7 (C) 165.8, 167.1
(C=O); HRMS (ESI) m/z (M+H)+, C18H17N2O4S calcd. 357.0909, observed 357.0913.
Methyl-2-({methyl[(2E)-2-(1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl]amino}sulfonyl)
benzoate (2c). 54 mg (26%) using MeCN and 49 mg (24%) using MeOH; red solid; Rf 0.61 (1:4
EtOAc/Pet); mp 134–137 °C; vmax (neat, cm−1) 2954, 2925, 2853, 1735 (C=O), 1717 (C=O), 1682 (C=O),
1609, 1470, 1434, 1360 (SO2), 1298, 1265, 1167 (SO2), 1104, 1057; δH (400 MHz, CDCl3) 3.20 (s, 3H,
NCH3), 3.43 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 6.73 (d, J 7.8 Hz, 1H, 7-H), 6.92 (t, J 7.8 Hz, 1H), 7.27
(s, 1H), 7.30 (t, J 7.8 Hz, 1H), 7.63–7.65 (m, 3H), 7.77 (d, J 7.8 Hz, 1H, 4-H), 8.32–8.34 (m, 1H); δC
(100 MHz, CDCl3) 26.3, 33.2 (NCH3), 53.4 (OCH3), 108.3 (7-CH), 119.3 (C), 122.8, 123.5 (CH), 126.8
(4-CH), 129.7, 130.8, 132.3 (CH), 132.5 (C), 132.7, 133.8 (CH), 135.6, 136.9, 145.6 (C), 165.8, 166.7,
167.1 (C=O); HRMS (ESI) m/z (M + Na)+, C20H18N2O6SNa calcd. 437.0783, observed 437.0775.
4. Conclusions
A photochemical “initiator and metal-free” 5-exo-trig reaction of aryl radicals proceeds to give
3-ylideneoxindoles. Higher yields are obtained when using methanol compared to acetonitrile as the
reaction solvent. In the case of the 3-ylideneoxindole acetates a greater preponderance for the subsequent
[2+2] photochemical cycloaddition occurs in acetonitrile, as well as some reduction of the cyclizing
radical. Novel 3-ylideneoxindole acetamides are also accessed, but are found to degrade with prolonged
UV-irradiation. In contrast, the same iodide radical precursors are reported to give reduced oxindole products
when the 5-exo-trig is carried out using literature metal hydride and azo-initiator protocols [20,21].
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/10/15891/s1.
Acknowledgments
This collaborative project was funded by Ulysses 2012, with equal funding gratefully received from
the Irish Research Council (IRC) and Campus France. Michael Gurry is funded by the College of
Science, National University of Ireland Galway.

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Author Contributions
Michael Gurry and Ingrid Allart-Simon performed experimental work. Patrick McArdle performed
X-ray crystallography. Stéphane Gérard, Janos Sapi and Fawaz Aldabbagh conceived and obtained
funding for the project and oversaw the research. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
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