Transition-metal-free Chemoselective Oxidative C?C Coupling of the sp3 C?H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3-Aryl Oxindoles, and Benzofuro- and Indoloindoles

Article abstract of DOI:10.1002/asia.201601647

A transition-metal (TM)-free and halogen-free NaOtBu-mediated oxidative cross-coupling between the sp³ C?H bond of oxindoles and sp² C?H bond of nitroarenes has been developed to access 3-aryl substituted and 3,3-aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C?H bond of oxindoles could also react with styrene under TM-free conditions for the practical synthesis of quaternary 3,3-disubstituted oxindoles. The synthesized 3-oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C?H bond of oxindole by tert-butoxide base in DMSO. The addition of nitrobenzene to the in-situ generated carbanion leads to the 3-(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3-(nitro-aryl) oxindole by DMSO.

Full text of DOI:10.1002/asia.201601647

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: TM Free Chemoselective Oxidative C-C Coupling of sp3 C-H
Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis
of 3-Aryl Oxindoles, Benzofuro- and Indolo-indoles
Authors: Sangit Kumar, Moh. Sattar, Vandana Rathore, and Ch. Durga
Prasad
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TM Free Chemoselective Oxidative C-C Coupling of sp3 C-H Bond
of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3-
Aryl Oxindoles, Benzofuro- and Indolo-indoles
Moh. Sattar,[a] Vandana Rathore,[a] Ch. Durga Prasad,[a] and Sangit Kumar[a]*
Abstract:
A
transition-metal (TM) and halogen free NaOtBu–
from acidic carbon-hydrogen bond. The generated carbanion
substitutes the carbon-halogen bond of electron-deficient arenes
by following SNAr pathway and also substitution of C-H bond by
VNSH pathway.[6] Nitroarenes are the viable aromatic substrates
as they are readily available aromatic molecules and also many
of them are economical than other substituted benzenes.
Moreover, the nitro group has broad potential in synthetic
chemistry and the chemical industry as this can be easily
transformed into various functionalities and manipulated by
various methods into important indole and carbazole heterocyclic
rings.[6b-6i]
3-Substituted and 3,3-disubstituted oxindoles are the prominent
structural motifs that feature in many biologically active natural
products and pharmaceutical compounds.[7] Various 3-substituted
oxindoles consisting unprotected N-H bonds, display biological
activities against a variety of neurodegenerative disorders,[7c]
tumors,[7d] HIV,[7e] and anticancer.[7f]
mediated oxidative cross coupling between sp3 C-H bond of oxindoles
and sp2 C-H bond of nitroarenes has been developed to access 3-aryl
substituted and 3,3-aryldisubstituted oxindoles in DMSO at room
temperature in short time. Interestingly, sp3 C-H bond of oxindoles has
also been added to styrene under TM-free conditions for the practical
synthesis of quaternary 3,3-disubstituted oxindoles. Synthesized 3-
oxindoles have also been further transformed into advanced
heterocycles, benzofuroindoles, indoloindoles, and substituted
indoles. Mechanistic understanding of the reaction suggests the
formation of an anion intermediate from sp3 C-H bond of oxindole by
tert-butoxide base in DMSO. The addition of nitrobenzene to in-situ
generated carbanion led to the 3-(nitrophenyl)oxindolyl carbanion in
DMSO which subsequently oxidizes to 3-(nitro-aryl) oxindole by
DMSO.
Introduction
Transition metal (TM)-free strategy for C-C coupling reactions has
brought considerable interest in the scientific community since
last decade.TM-free oxidative cross coupling of C-H bonds is a
straightforward and atom-economical approach for the
construction of C-C bond.[1] This approach avoids expensive
metal catalysts, ligands, toxic waste, pre-functionalized
substrates, additional steps[2] and generates water as only by
product in the reactions. Moreover, mild reaction conditions
tolerate sensitive functional groups namely halogens, NH, CN
which are crucial for the late stage elaboration for the synthesis of
complex molecules.
tert-Butoxide with or without organic additives has been used for
the coupling of aryl halides with inactive arenes, and heteroarenes
leading a new carbon-carbon bond and thus produce pivotal
biaryls as studied by various research groups.[3-5]
This
methodology has been further extended to Heck type coupling of
aryl halides with alkenes,[5a-5b] intramolecular cyclization of aryl
halides with sp2 C-H, sec and tert-sp3 C-H bonds.[4a-4b, 5c-5f] Also
strong bases such as tert-butoxide known to generate carbanion
[a]
M. Sattar, V. Rathore, C. D. Prasad, Dr. S Kumar
Department of Chemistry
Indian Institute of Science Education and Research, Bhopal
Bhopal Bypass Road, Bhauri Bhopal, Madhya Pradesh, 462066
India
E-mail: sangitkumar@iiserb.ac.in
Scheme 1. Literature reports for the synthesis of 3-arylated and 3,3-
disubstituted oxindoles.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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In this context, arylation of oxindoles via inter[8a-8k] and intra
molecular[8l-8p] C-C coupling using aryl halide partners catalyzed
by TM-catalysts have been well explored (Scheme 1). Hg(II)-
Catalyzed Friedel-Crafts reaction of N-protected-3-substituted-3-
hydroxyoxindoles with electron rich N-methyl indoles and electron
rich phenols,[8e] Fe(III)-catalyzed cross coupling reaction of an
excess amount of activated arenes such as anisole and
thiophenes with 3-benzyl/phenyl substituted oxindoles,[8i] Rh-
catalyzed arylation of imines based oxindoles with arylboronic
acid have been reported in the literature.[8j]
Under TM-free conditions, the synthesis of 3-aryl-oxindoles have
been exploited, [8h-8k] where prefunctionalized oxindoles such as
3-diazo-2-oxindoles,[8h] 1,3-diacyloxy[8k] were coupled with
activated arenes. Despite the enlisted achievements, they suffer
from harsh reaction conditions and/or involve prefunctionalized
coupling partners. Also, the reported methodologies involve the
protection of N-H bond in order to achieve desired C-C coupled
product, as the protons of nitrogen-1 and carbon-3 atoms in
oxindole moiety have almost similar pKa (~18.5).[8l] Therefore,
unprotected N-H oxindoles may give N-arylated products with aryl
halides and boronic acids, instead of C-arylated products in
presence of metal catalysts.[8a,8d]
In continuation of our work on TM-free C-C coupling reactions[4]
herein, we disclose; a) the chemoselective coupling of sp3 C-H
bond over unprotected N-H bond of oxindole with sp2 C-H bond
of nitroarenes by the generation of a carbanion from carbon-
hydrogen bond of oxindole utilizing tert-butoxide base in DMSO
at room temperature for the synthesis of 3-arylated and 3,3-
diarylated oxindoles having a quaternary carbon center, b) an
addition of sp3 C-H bond of oxindole to the sp2 C-H bond of
styrene to obtain quaternary carbon centered 3-oxindoles in
practical yields, c) 3-substituted oxindoles have been further
transformed into benzofuroindoles, indoles and indoloindoles.
Scheme 3 Scope for N-Me-oxindoles with nitrobenzenes
With the optimized conditions in our hand, initially we explored N-
methyl-substituted oxindoles with substituted nitrobenzenes and
resulted 3-aryl oxindoles 2a-2v are summarized in Scheme 3. A
variety of substituents on nitrobenzene having electron
withdrawing groups such as CN, CF3, NO2, electron donating OMe
substituent showed the compatibility with the optimized reaction
conditions to provide 3-(nitrophenyl)oxindoles 2b-2d, and 2g in
58 to 75% yields. Furthermore, meta-fluoro/ chloro substituted
nitrobenzenes also underwent C-H coupling reaction with
oxindoles chemoselectively to give chloro and fluoro substituted
3-aryloxindoles in 82 and 72% yields, respectively (2e-f, 2o-p).
Interestingly, the formation of C-C coupled product by the
coupling of C-H and C-F/Cl/Br bond was not observed (Scheme
3,4). Halogen substituents are vital for post-modification of 3-aryl-
oxindoles and could be readily transformed into advanced
heterocycles (vide infra). When para-position of nitrobenzene is
blocked by suitable trifluoromethyl group, the desired ortho-
nitroaryl indoles 2h, 2s-2v were realized under the reaction
conditions.
Scheme 2. Optimized reaction scheme for C-3 arylation of oxindole
We started with KOtBu base for the optimization of reaction
conditions (SI please see S20-S21) which provided 65% yield of
the 3-arylated oxindole 2a (Scheme 2). Lithium tert-butoxide,
carbonate bases such as K2CO3, Na2CO3, Cs2CO3, hydride
bases; NaH, KH, and alkoxide bases NaOMe, NaOEt bases were
noticed to be ineffective for the coupling of oxindole with
nitrobenzene. Detailed optimization of conditions is enlisted in SI
(please see page S20-S21). NaOtBu gave better yield (78%) of
2a in DMSO.
Next, substituted oxindoles having electron donating -CH3, -OCH3,
OCF3, electron withdrawing Br and Cl functionalities afforded
coupled 3-aryl oxindoles 2i-2m, 2u-2v and 2n-2t with various
substituted nitrobenzenes in 48-80% yields.
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Scheme. 5 Substrate scope of 3-substituted oxindoles with styrenes. Reaction
was carried out using oxindole (0.44 mmol, 100 mg), styrene (5 equiv., 2.24
mmol, 256 µL), KOtBu (3 equiv., 1.34 mmol, 151 mg) and DMSO (2 mL) under
nitrogen atmosphere at 70 oC for 4h. [a] isolated yield[b]
3h are also studied by single crystal X-ray crystallography (Figure
1). Hayashi[5a] and Shi[5b] et al. have accomplished Mizoroki-Heck
type coupling reaction of aryl halides with styrene utilizing
potassium tert-butoxide base under TM-free conditions. We
envisaged the coupling of 3-C-H bond of oxindole with styrene
under optimized oxidative tert-butoxide mediated reaction
(Scheme 5). To our surprise, reaction of 3-unsubstituted oxindole
with styrene failed to yield any coupled product under various
optimized reaction conditions. However, 3-substituted oxindoles
reacted with styrene smoothly under heating conditions to yield 3-
quaternary substituted oxindole 4a. Methoxy and methyl
substituted styrenes have also been coupled with 3-benzyl
oxindoles to afford 3-benzyl-3-phenethyloxindoles 4b-4e in 64-
76% yields.
Scheme 4. Substrate scope for N-unprotected oxindoles with nitrobenzenes
Next, an exploration of C-H functionalization in N-unprotected
oxindoles have been carried out (Scheme 4). To our delight,
chemoselective C-H coupling of oxindoles over N-H coupling with
nitroarenes were observed under optimized reaction conditions.
N-unprotected oxindoles bearing halogens such as chloro, bromo
and
even
dichloro
substrates
smoothly
underwent
chemoselective C-H functionalization to afford desired 3-aryl
oxindoles 3a, 3e-3g, 3i-3j, and 3l in 42-85% yields. In addition,
tert-C-H bond of N-unprotected oxindoles can be arylated under
optimized reaction conditions. 3-Benzyl and 3-(bromo and
methoxy substituted)-benzyl oxindoles were also tolerated well
and afforded respective 3-(nitroaryl)-3-benzyloxindoles 3h-3o in
good yields (65-82%). 3-Naphthyl substituted oxindole was also
realized with low yield (42%) of 3-nitroaryl-3-naphthyl oxindole 3p.
However, 3-ferrocenyl oxindole failed to yield any 3-arylated
oxindole.
Scheme 6. Further functionalization of oxindoles
Further, transformation of synthesized 3-aryl oxindoles into
advanced heterocycles has been studied (Scheme 6). 3-Arylated
oxindoles 2c and 2f could be readily reduced into respective
indoles 5a and 5b using Schwartz’s reagent in promising yields.
3-Arylated oxindole 3c has been transformed into
benzofuroindole 6 using copper complex. Also, 3-(2-nitroaryl)-
substituted oxindoles 2h and 2u could be converted into
Figure 1. Crystal structures of 3-nitroaryl indoles 3b (CCDC No. 1474932) and
3m (CCDC No. 1474930). For crystallographic details and crystal structure of
3h (CCDC No. 1474931), please See SI, S126-S146.
Structures
of
fluoro,
trifluoromethyl
substituted
3-
(nitroaryl)oxindoles 3b and 3m and 3-(nitroaryl)-3-benzyloxindole
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indoloindoles 7a and 7b having two adjacent pyrrole rings by
heating in triethylphosphite [P(OEt)3].
Mechanistic Consideration
EPR Experiment on the NaOtBu-mediated reaction of 3-
unsubstituted oxindole in the presence of NaOtBu in DMSO
afforded a sharp singlet (SI, please see page S115-117). Addition
of nitrobenzene to the equimolar solution of unsubstituted
oxindole and NaOtBu lead to complete disappearance of EPR
singlet and a new triplet was observed. Intrigued by this finding,
1
we decided to perform H NMR on the reaction mixture using
DMSO-d6. The reddish reaction mixture of oxindole and NaOtBu
and dark blue colored reaction mixture of oxindole, NaOtBu and
nitrobenzene in DMSO-d6 provided clean NMR spectra without
any signal broadening, which generally occurs due to presence of
radicals in the sample (SI, pages S121-S123). 1H NMR
experiments on the reaction mixture indicated lack of radicals in
the reaction mixture in significant concentration and therefore,
reaction less likely to proceed by radical pathway.
Scheme 8. Proposed mechanism for C-3 arylation of oxindoles
In the proposed mechanism, we believe that oxindole provides
carbanion intermediate I in the presence of NaOtBu. The
intermediate can be stabilized via intermediates II and III. The
Intermediate
I may add to nitrobenzene to form 3-(4-
nitrocyclohexa-2,5-dien-1-yl)indolin-2-one anion IV which lead to
intermediate V by DMSO under basic conditions would furnish
desired C-C couple 3-nitroaryl oxindole and itself reduce to
dimethyl sulfide. The formation of DMS has also been established
by 1H NMR and GC-mass analysis of the reaction mixture (see SI,
page S121-SI123). Oxidation of 3-(4-nitrocyclohexa-2,5-dien-1-
yl)indolin-2-one anion IV is also possible by aerial oxygen,[4d,6f]
however, substantial decrease in the yield of desired 3-aryl
oxindole was noticed when reaction performed in an open flask.
Alternatively, intermediate IV may be deprotonated by NaOtBu or
by the dimsyl anion and the resulting polyanionic species VI,
which would be a reasonable electron donor, may be oxidised to
3-nitroaryl oxindole by electron transfer.
Scheme 7. Control experiment between nitrobenzene and oxindole
The reactivity of 3-oxindolyl carbanion was studied in SNAr vs
VNSH reaction by taking 2-chloro-nitrobenzene substrate which
could provide SNAr C-C coupled product by the substitution of C-
Cl bond and VNSH product by the substitution of hydrogen bond
in nitrobenzene.[9] The reaction of N-methyloxindole with 2-choro-
nitrobenzene in the presence of tert-butoxide base gave 3-(2-
nitro)phenyl-oxindole as the sole SNAr C-C coupled product and
even traces of the expected VNSH[6] 3-(3-chloro-4-nitro)phenyl-
oxindole product was not observed after several repeated
attempts.
Conclusion
Next, reaction was performed in deuterated nitrobenzene-d5
neither show any noticeable difference in the reaction time nor
incorporation of deuterium into 3-aryl oxindole was observed
which suggests the nitrobenzene does not involve in the rate
determining step of the reaction.
In summary, a regioselective NaOtBu mediated protocol for
the synthesis of C-3 arylated oxindoles and 3,3-disubstituted
oxindoles has been developed at room temperature in short time
without employing external oxidant, TM-catalytic system, and
halogen. This reaction was chemoselective towards sp3 C-H bond
over N-H bond even in 3-substituted oxindoles. The presented
methodology tolerates various functionalities such as bromo,
chloro, fluoro, methyl, methoxy, trifluoromethyl groups, on the
framework of nitrobenzene. Moreover, substituted oxindoles and
3-alkylated oxindoles having functionalities on the benzene ring
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3-(2-Fluoro-4-nitrophenyl)-1-methylindolin-2-one (2e) Sienna solid;
yield: 160 mg (82%); Rf 0.32 in 3:7 (EA:Hex) 1H NMR (400 MHz, CDCl3)
δ 7.97 (dd, J = 9.7, 1.9 Hz, 6H), 7.39 – 7.31 (m, 3H), 7.24 (t, J = 7.9 Hz,
4H), 7.06 (q, J = 7.6 Hz, 6H), 6.92 (d, J = 7.8 Hz, 3H), 4.95 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 173.9, 161.9, 159.4, 148.2 (d, J = 8.7 Hz), 144.3,
132.1 (d, J = 15.4 Hz), 130.8 (d, J = 4.2 Hz), 129.1, 126.8, 124.4, 123.1,
119.6 (d, J = 3.7 Hz), 111.8 (d, J = 27.1 Hz), 108.6, 46.5, 26.6; HRMS
(ESI) m/z calcd for C15H11FN2O3 [M+H]+ 287.0826, found 287.0851.
such as 5-chloro, bromo, methoxy, methyl, OCF3 groups were
compatible in the metal free oxidative coupling. Oxindoles have
also been coupled with styrene to form quaternary carbon
containing 3,3-disubstituted oxindoles. Synthesized 3-aryl-
oxindoles can be further functionalized into indoles by using
Schwartz’s reagent in an excellent yield. Further, 3-Aryl oxindoles
can be transformed into benzofuroindole and indoloindoles.
Overall, we have developed a metal free, eco-friendly and
sustainable method for the synthesis of biologically active
substituted oxindoles which could serve as building blocks in
pharmaceuticals, agrochemicals and drug chemistry.
3-(2-Chloro-4-nitrophenyl)-1-methylindolin-2-one (2f) Firebrick solid;
yield: 144 mg (70%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (500 MHz, CDCl3) δ
8.36 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.27 – 7.01
(m, 3H), 6.96 (d, J = 7.9 Hz, 1H), 5.24 (s, 1H), 3.34 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 174.05, 147.67, 144.27, 142.54, 135.77, 129.14, 127.16,
127.14, 125.22, 124.36, 123.17, 122.21, 108.63, 49.85, 26.70; HRMS
(ESI) m/z calcd for C15H11ClN2O3 [M+H]+ 303.0535, found 303.0531.
Experimental Section
Typical Procedure for C-3 Arylation of Oxindole. Oxindoles and their
precursors were prepared by following known methods and synthesis and
analytic data are presented in SI (page S2-S19).[10] Oxindole (100 mg, 0.68
mmol) was dissolved in dry DMSO in a 10 mL round bottom flask having
stirrer bar under nitrogen atmosphere. Nitrobenzene (1.2 equiv., 84 µL,
0.82 mmol) was added to the mixture, after that NaOtBu (2 equiv., 130 mg,
1.36 mmol) portion wise dissolved to the reaction mixture. Reaction
progress was checked through silica gel thin layer chromatography. After
completion of the reaction, the mixture was dissolved in 20 mL of water
and 5 mL x 3 of ethyl acetate, further the organic layer was separated and
treated with Na2SO4 and dried over rotary evaporator. Then, the crude
product was purified through flash column chromatography using 3:7
(EA:Hex) solvent mixture as a eluent.
3-(3-Methoxy-4-nitro-5-(trifluoromethyl)phenyl)-1-methylindolin-2-
one (2g) Sienna solid; yield: 144 mg (58%); Rf 0.18 in 3:7 (EA:Hex) 1H
NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.81 (s, 1H), 7.30 (t, J = 7.5 Hz,
1H), 6.96 (t, J = 7.3 Hz, 1H), 6.92 – 6.82 (m, 2H), 4.94 (s, 1H), 3.61 (s, 3H),
3.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.7, 159.0, 147.9, 144.6,
132.9, 132.6, 132.2, 128.5, 126.8, 123.3, 122.6, 113.5 (q, J = 6.0 Hz),
109.8, 107.8, 56.9, 46.2, 26.5; HRMS (ESI) m/z calcd for C17H13F3N2O4
[M+H]+ 367.0900, found 367.0912.
1-Methyl-3-(2-nitro-5-(trifluoromethyl)phenyl)indolin-2-one (2h) Light
yellow solid; yield: 155 mg (68%); Rf 0.27 in 3:7 (EA:Hex) 1H NMR (400
MHz, CDCl3) δ 8.11 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 8.4, 1.0 Hz, 1H), 7.47
(s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.4
Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.41 (s, 1H), 3.27 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 173.8, 151.5, 144.4, 135.0, 134.7, 132.3, 129.2, 128.5,
126.1, 126.06 – 125.9 (m), 124.4, 123.1, 121.3, 108.8, 48.7, 26.7; HRMS
(ESI) m/z calcd for C16H11F3N2O3 [M+H]+ 337.0795, found 337.0788.
1-Methyl-3-(4-nitrophenyl)indolin-2-one (2a) Light yellow solid; yield:
142 mg (78%); Rf 0.25 in 3:7 (EA:Hex). 1H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 8.7 Hz, 2H), 7.38 (t, J = 8.8 Hz, 3H), 7.15 (d, J = 7.2 Hz, 1H), 7.10
(t, J = 7.4 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 4.71 (s, 1H), 3.25 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 174.4, 147.4, 144.4, 143.8, 129.4, 129.1, 127.2,
125.0, 124.0, 123.1, 108.6, 51.6, 26.6; HRMS (ESI) m/z calcd for
C15H12N2O3 [M+H]+ 269.0921, found 269.0909.
5-Methoxy-1-methyl-3-(4-nitrophenyl)indolin-2-one (2i) Orange red
solid; yield: 118 mg (70%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz,
CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 6.89 (dd, J =
8.5, 2.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 4.68 (s,
1H), 3.75 (s, 3H), 3.22 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 174.1, 156.3,
147.4, 143.8, 137.9, 129.4, 128.4, 124.0, 113.4, 112.4, 108.9, 55.8, 52.0,
26.7; HRMS (ESI) m/z calcd for C16H14N2O4 [M+H]+ 299.1026, found
299.1021.
5-(1-Methyl-2-oxoindolin-3-yl)-2-nitrobenzonitrile (2b) Yellow solid;
yield: 150 mg (75%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz, CDCl3) δ
8.28 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 11.2, 2.6 Hz, 1H), 7.46 – 7.39 (m,
1H), 7.18 – 7.11 (m, 1H), 6.96 (d, J = 7.9 Hz, 1H), 3.25 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 173.3, 147.6, 144.5, 144.2, 135.2, 133.9, 129.8, 125.9,
125.6, 125.1, 123.5, 114.7, 109.1, 108.5, 50.9, 26.8; HRMS (ESI)- m/z
calcd for C15H12N2O3 [M-H]- 292.0717, found 292.0704.
1,5-Dimethyl-3-(4-nitrophenyl)indolin-2-one (2j) Red solid; yield: 119
mg (68%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J
= 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 6.95 (s,
1H), 6.81 (d, J = 7.9 Hz, 1H), 4.67 (s, 1H), 3.23 (s, 3H), 2.31 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 174.50, 147.40, 144.14, 142.06, 132.82, 129.46,
127.33, 125.82, 124.03, 121.99, 108.38, 51.77, 26.68, 21.08; HRMS (ESI)
m/z calcd for C16H14N2O3 [M+H]+ 283.1077, found 283.1089.
1-Methyl-3-(4-nitro-3-(trifluoromethyl)phenyl)indolin-2-one (2c) Light
1
yellow; yield: 160 mg (70%); Rf 0.27 in 3:7 (EA:Hex) H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.58 (dd, J = 8.3, 1.5 Hz,
1H), 7.45 – 7.36 (m, 1H), 7.19 – 7.08 (m, 2H), 6.95 (d, J = 7.9 Hz, 1H),
4.73 (s, 1H), 3.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.8, 147.3,
144.5, 142.1, 133.0, 129.5, 128.0 (q, J = 5.2 Hz), 126.1, 125.6, 125.0,
124.0, 123.3, 120.4, 108.9, 51.2, 26.7; HRMS (ESI) m/z calcd for
C16H11F3N2O3 [M+H]+ 337.0795, found 337.0813.
5-(1,5-Dimethyl-2-oxoindolin-3-yl)-2-nitrobenzonitrile (2k) Dark brown
solid; yield: 107 mg (56%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz,
CDCl3) δ 8.29 (d, J = 8.5 Hz, 1H), 7.80 – 7.67 (m, 2H), 7.21 (d, J = 7.9 Hz,
1H), 6.96 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.69 (s, 1H), 3.23 (s, 3H), 2.34
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.30, 144.44, 142.11, 135.16,
133.96, 133.28, 130.04, 125.93, 125.84, 125.72, 122.95, 114.81, 108.81,
108.53, 51.05, 26.81, 21.10; HRMS (ESI) m/z calcd for C17H13N3O3 [M+H]+
308.1030, found 308.1047.
3-(2,4-Dinitrophenyl)-1-methylindolin-2-one (2d) Dark brown solid;
yield: 158 mg (74%); Rf 0.18 in 3:7 (EA:Hex) 1H NMR (400 MHz, CDCl3) δ
8.87 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 8.5, 2.0 Hz, 1H), 7.40 (dd, J = 17.5,
8.7 Hz, 1H), 7.11 (dt, J = 14.9, 7.3 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.56
(s, 1H), 3.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 173.3, 149.6, 147.3,
144.4, 138.1, 132.5, 129.5, 127.3, 125.8, 124.5, 123.3, 121.0, 108.9, 48.7,
26.7; HRMS (ESI) m/z calcd for C15H11N3O5 [M+H]+ 314.0771, found
314.0785.
3-(2,4-Dinitrophenyl)-1,5-dimethylindolin-2-one (2l) Yellow solid; yield:
106 mg (52%); Rf 0.18 in 3:7 (EA:Hex) 1H NMR (400 MHz, CDCl3) δ 8.86
(s, 1H), 8.34 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.2
Hz, 1H), 6.94 (s, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.51 (s, 1H), 3.24 (s, 3H),
2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.37, 147.24, 142.03, 138.42,
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10.1002/asia.201601647
Chemistry - An Asian Journal
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133.07, 129.71, 127.38, 126.87, 125.94, 125.36, 120.98, 120.26, 108.67,
48.78, 26.79, 21.07; HRMS (ESI) m/z calcd for C16H13N3O5 [M+H]+
328.0928, found 328.0936.
49.1, 26.8; HRMS (ESI) m/z calcd for C16H10BrF3N2O3 [M+H]+ 414.9900,
found 414.9897.
5-Chloro-1-methyl-3-(2-nitro-5-(trifluoromethyl)phenyl)indolin-2-one
(2t) Peru solid; yield: 98 mg (48%); Rf 0.24 in 3:7 (EA:Hex) 1H NMR (400
MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.47 (s,
1H), 7.34 (dd, J = 8.3, 1.3 Hz, 1H), 7.10 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H),
5.30 (d, J = 16.2 Hz, 1H), 3.28 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
173.43, 156.37, 142.99, 137.92, 135.06 (q, J = 33.7 Hz), 132.37, 131.71,
129.21, 128.49, 127.27, 126.40, 113.48, 109.67, 109.15, 55.83, 26.84;
HRMS (ESI) m/z calcd for C16H10ClF3N2O3 [M+H]+ 393.0224, found
393.0210.
1-Methyl-3-(4-nitrophenyl)-5-(trifluoromethoxy)indolin-2-one
(2m)
orange solid; yield: 85 mg (56%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz,
CDCl3) δ 8.20 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 9.5
Hz, 1H), 7.05 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.73 (s, 1H), 3.26 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 174.14, 147.65, 145.02 (q, J = 1.9 Hz),
143.17, 142.77, 129.36, 128.50, 124.21, 122.39, 121.77, 119.11, 109.09,
51.64, 26.83; HRMS (ESI) m/z calcd for C16H11F3N2O4 [M+H]+ 353.0744,
found 353.0759.
5-Bromo-1-methyl-3-(4-nitrophenyl)indolin-2-one (2n) Dark goldenrod
solid; yield: 114 mg (74%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz,
CDCl3) δ 8.19 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.6
Hz, 2H), 7.25 (d, J = 4.7 Hz, 1H), 6.80 (t, J = 8.5 Hz, 1H), 4.70 (s, 1H), 3.23
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.8, 147.6, 143.5, 142.9, 132.0,
129.4, 129.1, 128.2, 124.1, 115.7, 110.0, 51.4, 26.7; HRMS (ESI) m/z
calcd for C15H11BrN2O3 [M-H]- 344.9869, found 344.9875.
5-methoxy-1-methyl-3-(2-nitro-5-(trifluoromethyl)phenyl)indolin-2-
one (2u) Brown solid; yield: 145 mg (70%); Rf 0.22 in 3:7 (EA:Hex) 1H
NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H),
7.46 (s, 1H), 6.97 – 6.81 (m, 2H), 6.74 (s, 1H), 5.38 (s, 1H), 3.74 (s, 3H),
3.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.47, 156.39, 137.95, 134.94
(q, J = 33.2 Hz ), 132.39, 127.28, 126.17, 126.01 (q, J = 3.8 Hz ), 124.05,
121.33, 113.49, 111.91, 109.14, 55.84, 49.12, 26.78; HRMS (ESI) m/z
calcd for C17H13F3N2O4 [M+Na]+ 389.0720, found 389.0725.
5-Bromo-3-(2-fluoro-4-nitrophenyl)-1-methylindolin-2-one (2o) Peru
solid; yield: 129 mg (80%); Rf 0.24 in 3:7 (EA:Hex) 1H NMR (400 MHz,
CDCl3 δ 7.98 (dd, J = 11.6, 4.4 Hz, 2H), 7.47 (dd, J = 8.2, 1.0 Hz, 1H), 7.27
(dd, J = 9.4, 4.5 Hz, 1H), 7.18 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.93 (s,
1H), 3.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.38, 160.53 (d, J =
252.4 Hz), 148.43 (d, J = 8.0 Hz), 143.32, 132.04 (s), 131.20 (d, J = 15.2,
Hz), 130.93 (d, J = 4.1, Hz), 128.75, 127.62, 119.79 (d, J = 3.7 Hz), 115.71
(s), 111.96 (d, J = 26.95 Hz), 110.03, 46.45, 26.81; HRMS (ESI) m/z calcd
for C15H10BrFN2O3 [M+H]+ 364.9932, found 364.9938.
1,5-Dimethyl-3-(2-nitro-5-(trifluoromethyl)phenyl)indolin-2-one (2v)
Peru solid; yield: 148 mg (68%); Rf 0.22 in 3:7 (EA:Hex) 1H NMR (500 MHz,
CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 8.4, 1.1 Hz, 1H), 7.50 (s,
1H), 7.20 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.40
(s, 1H), 3.30 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 173.82,
151.51, 142.07, 135.06, 134.80, 132.87, 132.64, 129.50, 126.14, 125.93
(q, J = 3.54 Hz), 125.26 – 125.04 (m), 123.79, 121.62, 108.51, 49.17, 26.73,
21.08; HRMS (ESI) m/z calcd for C17H13F3N2O3 [M+H]+ 351.0951, found
351.0945.
5-Chloro-3-(2-fluoro-4-nitrophenyl)-1-methylindolin-2-one (2p) Dark
goldenrod solid; yield: 110 mg (62%); Rf 0.24 in 3:7 (EA:Hex) 1H NMR (400
MHz, CDCl3) δ 8.07-7.93 (m, 2H), 7.33-7.25 (m, 2H), 7.05 (s, 1H), 6.84 (d,
J = 8.4 Hz, 1H), 4.93 (s, 1H), 3.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
173.47, 161.86, 159.35, 148.43 (d, J = 8.7 Hz), 142.84, 131.22 (d, J = 15.4
Hz), 130.91 (d, J = 4.1 Hz), 129.13, 128.47 (d, J = 15.4 Hz), 124.90, 119.78
(d, J = 3.7 Hz), 111.94 (d, J = 27.1 Hz), 109.54, 46.52 (d, J = 1.5 Hz),
26.83; HRMS (ESI) m/z calcd for C15H10ClFN2O3 [M+H]+ 321.0437, found
321.0451.
5-Bromo-3-(4-nitrophenyl)indolin-2-one (3a) Dark blue green solid;
yield: 108 mg (69%); Rf 0.18 in 3:7 (EA:Hex) 1H NMR (500 MHz, CDCl3) δ
8.96 (s, 1H), 8.29 – 8.23 (m, 2H), 7.49 – 7.39 (m, 3H), 7.27 (s, 1H), 6.90
(d, J = 8.3 Hz, 1H), 4.78 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 176.56,
147.70, 142.70, 140.55, 132.13, 129.96, 129.45, 128.48, 124.30, 115.81,
111.87, 52.14; HRMS (ESI) m/z calcd for C14H9BrN2O3 [M+H]+ 332.9869,
found 332.9878.
3-(2-Fluoro-4-nitrophenyl)indolin-2-one (3b) Yellow solid; yield: 168 mg
(82%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H),
8.13 – 8.04 (m, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 6.98
– 6.87 (m, 3H), 5.14 (s, 1H); 13C NMR (100 MHz, DMSO) δ 176.00, 160.27
(d, J = 250.5 Hz), 148.21 (d, J = 9.1 Hz), 143.23, 133.23 (d, J = 15.1 Hz),
132.77 (d, J = 4.6 Hz), 128.83 (d, J = 38.8 Hz), 123.45 (d, J = 232.1 Hz),
120.35 (d, J = 3.3 Hz), 111.96 (d, J = 26.89 Hz), 110.16, 47.66; HRMS
(ESI) m/z calcd for C14H9FN2O3 [M+H]+ 273.0970, found 273.0653.
5-Bromo-1-methyl-3-(4-nitro-3-(trifluoromethyl)phenyl)indolin-2-one
(2q) Bisque solid; yield: 114 mg (62%); Rf 0.22 in 3:7 (EA:Hex) H NMR
1
(400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 7.7
Hz, 2H), 7.27 (s, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.73 (s, 1H), 3.24 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 173.2, 147.5, 143.5, 141.3, 132.9, 132.4,
128.1 – 127.8 (m), 125.7, 124.6, 124.2, 123.0, 120.3, 115.9, 110.3, 51.1,
26.8; HRMS (ESI) m/z calcd for C16H10BrF3N2O3 [M-H]- 412.9743, found
412.9749.
3-(2-Bromo-4-nitrophenyl)indolin-2-one (3c) Brown solid; yield: 160 mg
(64%); Rf 0.18 in 3:7 (EA:Hex) 1H NMR (400 MHz, DMSO) δ 10.75 (s, 2H),
8.63 – 7.81 (m, 5H), 7.22 (s, 2H), 7.20 – 6.51 (m, 8H), 5.27 (s, 2H); 13C
NMR (126 MHz, CDCl3) δ 180.54, 152.35, 150.32, 148.04, 141.03, 135.12,
134.01, 132.91, 130.36, 129.57, 128.56, 127.26, 115.14, 56.81; HRMS
(ESI) m/z calcd for C14H9BrN2O3 [M+H]+ 332.9869, found 332.9869.
5-Chloro-1-methyl-3-(4-nitro-3-(trifluoromethyl)phenyl)indolin-2-one
(2r) White solid; yield: 106 mg (52%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.53 (dd, J = 8.3, 1.5
Hz, 1H), 7.38 (dd, J = 8.3, 1.4 Hz, 1H), 7.14 (s, 1H), 6.88 (d, J = 8.4 Hz,
1H), 4.73 (s, 1H), 3.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.35,
143.05, 141.33, 132.91, 129.58, 128.78, 128.06 (q, J = 5.4 Hz), 127.80,
125.77, 125.47, 120.35, 109.86, 51.17, 26.87; HRMS (ESI) m/z calcd for
C16H10ClF3N2O3 [M+H]+ 371.0405, found 371.0396.
3-(2-Methyl-4-nitrophenyl)indolin-2-one (3d) Firebrick solid; yield: 137
mg (68%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (500 MHz, CDCl3) δ 9.04 (s, 1H),
8.15 (s, 1H), 7.99 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.09 – 7.02
(m, 2H), 6.99 (d, J = 7.8 Hz, 1H), 5.00 (s, 1H), 2.87 – 2.30 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 177.41, 147.31, 142.61, 141.54, 139.42, 128.96,
125.71, 124.79, 123.99, 123.20, 121.48, 112.49, 110.36, 49.64, 19.97;
HRMS (ESI) m/z calcd for C15H12N2O3 [M+H]+ 269.0921, found 269.0926.
5-Bromo-1-methyl-3-(2-nitro-5-(trifluoromethyl)phenyl)indolin-2-one
(2s) Tan solid; yield: 121 mg (66%); Rf 0.24 in 3:7 (EA:Hex) 1H NMR (400
MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.56 –
7.38 (m, 2H), 7.22 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.31 (s, 1H), 3.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 173.3, 151.0, 143.4, 133.25 (q, J = 33.9
Hz), 132.1, 131.7, 128.0, 127.3, 126.4, 123.9, 121.2, 118.5, 115.7, 110.1,
5-Bromo-3-(2-methyl-4-nitrophenyl)indolin-2-one (3e) Brown solid;
yield: 103 mg (63%); Rf 0.2 in 3:7 (EA:Hex) 1H NMR (500 MHz, DMSO) δ
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10.1002/asia.201601647
Chemistry - An Asian Journal
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10.82 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.2 - 6.8
(m, 3H), 6.92 (d, J = 8.3 Hz, 1H), 5.27 (s, 1H), 2.84 – 2.17 (m, 3H); 13C
NMR (125 MHz, DMSO) δ 176.23, 168.85, 151.05, 147.10, 143.85, 142.63,
140.08, 131.64, 127.67, 125.52, 121.74, 114.03, 112.09, 55.35, 19.63;
HRMS (ESI) m/z calcd for C15H11BrN2O3 [M+H]+ 344.9869, found
344.9895.
3-Benzyl-5-bromo-3-(2-fluoro-4-nitrophenyl)indolin-2-one (3l) Yellow
solid; yield: 114 mg (78%); Rf 0.21 in 2:8 (EA:Hex) 1H NMR (500 MHz,
DMSO) δ 10.54 (s, 1H), 8.27 – 8.14 (m, 2H), 8.05 (dd, J = 11.1, 2.1 Hz,
1H), 7.42 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.3, 1.9 Hz, 1H), 7.15 – 7.07
(m, 3H), 6.82 (d, J = 6.6 Hz, 2H), 6.54 (d, J = 8.3 Hz, 1H), 3.88 (d, J = 12.2
Hz, 1H), 3.47 (d, J = 12.2 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 177.53,
170.80, 159.55 (d, J = 247.07 Hz), 148.25 (d, J = 9.7 Hz), 142.23, 135.87
(d, J = 13.0 Hz), 134.42, 133.81, 131.73, 130.80 (d, J = 4.1 Hz), 130.48,
128.00, 127.33 (d, J = 7.6 Hz), 120.07 (d, J = 2.9 Hz), 113.70, 111.88 (d,
5-Bromo-3-(2-fluoro-4-nitrophenyl)indolin-2-one (3f) Brown solid;
yield: 141 mg (85%); Rf 0.22 in 3:7 (EA:Hex) 1H NMR (400 MHz, DMSO)
δ 10.85 (s, 1H), 8.09 (t, J = 7.0 Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.40 (d, J
= 7.9 Hz, 1H), 7.14 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.21 (s, 1H); 13C NMR
(100 MHz, DMSO) δ 176.60, 176.22, 155.02, 147.09, 142.63, 137.47,
131.63, 127.52, 125.51, 121.73, 113.04 (d, J = 195.38 Hz), 112.26 (d, J =
71.63 Hz), 109.78, 46.25 (d, J = 46.25 Hz); HRMS (ESI) m/z calcd for
C14H8BrFN2O3 [M-H]- 348.9619, found 348.9601.
J
= 2.9 Hz), 111.55, 60.22, 55.50; HRMS (ESI) m/z calcd for
C21H14BrFN2O3 [M+H]+ 441.0245, found 441.0256.
3-Benzyl-3-(4-nitro-3-(trifluoromethyl)phenyl)indolin-2-one
(3m)
1
Antique white solid; yield: 120 mg (65%); Rf 0.2 in 2:8 (EA:Hex) H NMR
(400 MHz, CDCl3) δ 8.18 (s, 1H), 8.00 (s, 1H), 7.93 – 7.79 (m, 2H), 7.27 –
7.22 (m, 1H), 7.21 – 6.98 (m, 5H), 6.84 (d, J = 7.1 Hz, 2H), 6.76 (d, J = 7.7
Hz, 1H), 3.66 (d, J = 12.9 Hz, 1H), 3.44 (d, J = 12.9 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 178.13, 147.15, 145.19, 140.68, 134.19, 132.16, 130.09,
129.34, 127.91, 127.18, 126.98 (q, J = 5.5 Hz), 125.88, 125.32, 124.03,
123.69, 122.92, 120.52, 110.57, 58.31, 44.33; HRMS (ESI) m/z calcd for
C22H15F3N2O3 [M+H]+ 413.1108, found 413.1115.
4,7-Dichloro-3-(4-nitrophenyl)indolin-2-one (3g) Dark brown solid;
yield: 88 mg (55%); Rf 0.14 in 3:7 (EA:Hex) 1H NMR (400 MHz, CDCl3) δ
8.51 (s, 1H), 8.19 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.27 (d, J =
8.7 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.82 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 174.51, 147.72, 140.83, 140.75, 130.47, 129.97, 129.29, 126.39,
124.35, 124.16, 114.00, 52.97; HRMS (ESI) m/z calcd for C14H8Cl2N2O3
[M-H]- 320.9828, found 320.9854.
3-(2-Bromobenzyl)-3-(4-nitrophenyl)indolin-2-one (3n) Yellow solid;
yield: 91 mg (65%); Rf 0.18 in 2:8 (EA:Hex) 1H NMR (400 MHz, DMSO) δ
10.67 (s, 1H), 8.20 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 7.39 (dd,
J = 7.9, 1.0 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.14 (td, J = 7.7, 0.9 Hz, 1H),
7.08 (td, J = 7.5, 1.1 Hz, 1H), 7.00 (td, J = 7.7, 1.7 Hz, 1H), 6.92 (dd, J =
7.6, 6.8 Hz, 2H), 6.74 (d, J = 7.7 Hz, 1H), 3.78 (q, J = 13.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 182.93, 152.90, 151.87, 147.02, 140.57, 137.85,
135.42, 134.98, 134.10, 134.08, 133.58, 132.46, 131.30, 130.59, 128.89,
126.80, 115.03, 62.86, 46.13; HRMS (ESI) m/z calcd for C21H16BrN2O3
[M+H]+ 423.0339, found 423.0320.
3-Benzyl-3-(4-nitrophenyl)indolin-2-one (3h) Light yellow solid; yield:
127 mg (82%); Rf 0.2 in 2:8 (EA:Hex) H NMR (500 MHz, CDCl3) δ 8.22
1
(d, J = 8.9 Hz, 3H), 7.72 (d, J = 8.9 Hz, 2H), 7.25 (td, J = 7.7, 1.1 Hz, 1H),
7.20 (d, J = 7.0 Hz, 1H), 7.17 – 7.09 (m, 2H), 7.05 (t, J = 7.4 Hz, 2H), 6.90
(d, J = 7.2 Hz, 2H), 6.78 (d, J = 7.7 Hz, 1H), 3.71 (d, J = 12.9 Hz, 1H), 3.52
(d, J = 12.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 178.75, 147.24, 146.86,
140.72, 134.69, 130.39, 130.14, 128.93, 128.39, 127.82, 127.00, 125.91,
123.71, 122.66, 110.29, 58.65, 43.87; HRMS (ESI) m/z calcd for
C21H16N2O3 [M+H]+ 345.1234, found 345.1233.
3-(4-Methoxybenzyl)-3-(4-nitrophenyl)indolin-2-one (3o) Light yellow
solid; yield: 108 mg (73%); Rf 0.19 in 2:8 (EA:Hex) 1H NMR (400 MHz,
DMSO) δ 10.43 (s, 1H), 8.18 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H),
7.35 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H),
6.77 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 7.7 Hz, 1H), 6.57 (d, J = 8.6 Hz, 2H),
3.58 (s, 3H), 3.54 – 3.44 (m, 2H); 13C NMR (100 MHz, DMSO) δ 178.28,
158.33, 148.75, 146.95, 142.37, 131.46, 131.39, 128.95, 128.75, 127.86,
126.06, 124.00, 122.13, 113.40, 110.20, 58.96, 55.24, 41.78; HRMS (ESI)
m/z calcd for C22H18N2O4 [M+H]+ 375.1339, found 375.1330.
3-Benzyl-5-bromo-3-(4-nitrophenyl)indolin-2-one (3i) Yellow solid;
yield: 101 mg (72%); Rf 0.2 in 2:8 (EA:Hex) 1H NMR (400 MHz, CDCl3) δ
8.21 (d, J = 8.9 Hz, 2H), 8.02 (s, 1H), 7.66 (t, J = 11.6 Hz, 2H), 7.33 (dd, J
= 8.3, 1.8 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.14 – 7.02 (m, 3H), 6.86 (d, J =
6.9 Hz, 2H), 6.63 (d, J = 8.3 Hz, 1H), 3.66 (d, J = 12.9 Hz, 1H), 3.46 (d, J
= 12.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.90, 147.42, 145.97,
139.62, 134.19, 132.62, 131.84, 130.09, 128.95, 128.26, 128.02, 127.24,
123.89, 115.25, 111.61, 58.80, 43.83; HRMS (ESI) m/z calcd for
C21H15BrN2O3 [M+H]+ 423.0339, found 423.0320.
3-(Naphthalen-1-ylmethyl)-3-(4-nitrophenyl)indolin-2-one (3p) Yellow
solid; yield: 61 mg (42%); Rf 0.2 in 2:8 (EA:Hex) 1H NMR (400 MHz, CDCl3)
δ 8.35 (s, 1H), 8.18 (d, J = 8.9 Hz, 2H), 7.95 – 7.89 (m, 1H), 7.76 – 7.66
(m, 3H), 7.60 (d, J = 8.2 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.14 – 7.04 (m, 2H),
6.98 (dd, J = 14.5, 7.2 Hz, 2H), 6.87 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 7.8 Hz,
1H), 4.21 (d, J = 13.8 Hz, 1H), 3.94 (d, J = 13.8 Hz, 1H); 13C NMR (125
MHz, DMSO) δ 178.51, 149.00, 147.02, 142.34, 133.61, 132.53, 132.45,
131.24, 129.01, 128.96, 128.55, 128.39, 127.78, 126.67, 125.73, 125.27,
125.11, 124.03, 121.92, 110.04, 58.87, 37.78; HRMS (ESI) m/z calcd for
C25H18N2O3 [M+H]+ 393.1234, found 393.1257.
3-Benzyl-5-chloro-3-(4-nitrophenyl)indolin-2-one (3j) Yellow solid;
yield: 110 mg (75%); Rf 0.2 in 2:8 (EA:Hex) 1H NMR (400 MHz, DMSO) δ
10.59 (s, 1H), 8.21 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.54 (d, J
= 1.9 Hz, 1H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 – 7.02 (m, 3H), 6.95 –
6.87 (m, 2H), 6.65 (d, J = 8.3 Hz, 1H), 3.67 (d, J = 12.8 Hz, 1H), 3.55 (d, J
= 12.8 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 178.01, 148.04, 147.13,
141.23, 135.86, 133.50, 130.39, 128.91, 128.76, 128.14, 127.17, 126.28,
126.27, 124.19, 111.55, 59.24, 41.99; HRMS (ESI) m/z calcd for
C21H15ClN2O3 [M+Na]+ 401.0663, found 401.0671.
Typical procedure for reductive addition of styrene with 3-substituted
oxindoles. 3-Benzyl oxindole (0.44 mmol, 100 mg) was dissolved in dry
DMSO (2 mL) in a 15 mL well dried sealed tube having magnetic bead.
Styrene (5 equiv, 2.2 mmol, 256 µL) was added to the mixture, after that
KOtBu (3 equiv, 1.32 mmol, 148 mg) was added over portion wise.
Reaction progress was checked through thin layer chromatography, after
completion of the reaction, reaction mixture was dissolved in 20 mL of
water and organic layer was extracted with (5 mL × 3) of ethyl acetate,
treated with Na2SO4 and dried over rota evaporator. Purified through flash
column chromatography using 3:7 (EA:Hex) solvent mixture as a eluent.
3-Benzyl-3-(2-fluoro-4-nitrophenyl)indolin-2-one (3k) Light goldenrod
solid; yield: 136 mg (84%); Rf 0.22 in 2:8 (EA:Hex) 1H NMR (500 MHz,
CDCl3) δ 8.31 (s, 1H), 8.15 (dd, J = 8.7, 1.8 Hz, 1H), 7.93 – 7.85 (m, 2H),
7.19 – 7.10 (m, 3H), 7.06-7.02 (m, 3H), 6.83 (d, J = 7.2 Hz, 2H), 6.63 (d, J
= 7.8 Hz, 1H), 5.31 (s, 1H), 3.70 – 3.63 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 178.04, 160.22 (d, J = 253.6 Hz), 148.07 (d, J = 9.3 Hz), 141.26,
135.73 (d, J = 13.1 Hz), 133.45, 130.88, 130.23, 129.20 (d, J = 4.4 Hz),
128.84, 127.70 , 127.06 , 123.86 (d, J = 1.6 Hz), 122.65, 119.36 (d, J = 3.5
Hz), 111.98 (d, J = 27.55 Hz), 109.86, 54.60 (d, J = 292.8 Hz), 41.65;
HRMS (ESI) m/z calcd for C21H15FN2O3 [M+H]+ 363.1139, found 363.1163.
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10.1002/asia.201601647
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3-Benzyl-3-phenethylindolin-2-one (4a) Bisque solid ; yield: 122 mg
(83%) Rf 0.5 in 3:7 (EA:Hex) 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H),
7.27 – 7.17 (m, 5H), 7.14 – 7.04 (m, 6H), 6.94 – 6.90 (m, 2H), 6.82 (d, J =
7.6 Hz, 1H), 3.20 (d, J = 13.1 Hz, 1H), 3.11 (d, J = 13.1 Hz, 1H), 2.48 –
2.39 (m, 2H), 2.23 – 2.15 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 181.58,
141.49, 141.20, 135.72, 131.40, 130.04, 128.36, 128.33, 128.00, 127.66,
126.56, 125.93, 123.88, 122.27, 109.77, 55.19, 44.13, 39.31, 30.83;
HRMS (ESI) m/z calcd for C23H21NO [M+H]+ 328.1696, found 328.1705.
δ 8.06 (d, J = 1.1 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.92 (dd, J = 13.9, 5.0
Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.38 – 7.32 (m, 1H), 7.32 – 7.25 (m, 1H),
3.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 144.58, 141.55, 137.84, 129.48,
128.62, 126.39, 125.43 (q, 5.8 Hz ), 124.86, 124.52, 123.04, 123.62,
121.40, 119.25, 113.46, 110.24, 33.27; HRMS (ESI) m/z calcd for
C16H11F3N2O2 [M+H]+ 321.0845, found 321.0822.
3-(2-Chloro-4-nitrophenyl)-1-methyl-1H-indole (5b) Orange solid; yield:
75 mg (79%); Rf 0.3 in 1:9 (EA:Hex) 1H NMR (500 MHz, CDCl3) δ 8.43 (d,
J = 2.4 Hz, 1H), 8.20 (dd, J = 8.6, 2.4 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H),
7.73 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.39 – 7.35
(m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 145.68, 140.93, 136.91, 132.90, 131.28, 130.38, 126.48, 125.75, 122.66,
121.80, 120.83, 119.71, 111.18, 109.96, 33.26.
3-Benzyl-3-(4-methylphenethyl)indolin-2-one (4b) Green yellow solid;
yield: 116 mg (76%) Rf 0.5 in 3:7 (EA:Hex). 1H NMR (500 MHz, CDCl3) δ
8.24 (s, 1H), 7.21 (dd, J = 11.7, 4.3 Hz, 2H), 7.13 – 7.04 (m, 6H), 6.98 (d,
J = 7.9 Hz, 2H), 6.91 (dd, J = 7.7, 1.5 Hz, 2H), 6.78 (d, J = 7.6 Hz, 1H),
3.19 (d, J = 13.1, Hz, 1H), 3.10 (d, J = 13.1 Hz, 1H), 2.44 – 2.36 (m, 2H),
2.32 (s, 3H), 2.19 – 2.10 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 181.30,
141.05, 138.42, 135.73, 135.38, 131.43, 130.04, 129.01, 128.22, 127.95,
127.64, 126.53, 123.90, 122.26, 109.63, 55.14, 44.13, 39.52, 30.35, 20.99;
HRMS (ESI) m/z calcd for C24H23NO [M+H]+ 342.1852, found 342.1868.
Synthetic procedure for the synthesis of benzofuroindole (6) To a
sealed tube containing stirrer bar oxindole (3c, 1 equiv, 0.30 mmol, 100
mg), Cu(I)TC (Copper(I)-thiophene-2-carboxylate, 1.1 equiv, 0.33 mmol,
63 mg) and K2CO3 (2 equiv, 0.60 mmol, 83 mg) were dissolved in
dimethylacetamide (DMA) under inert atmosphere. The resulted reaction
mixture was stirred at 130 oC for 3h. Upon completion of the reaction, the
mixture was cooled to room temperature, passed through celite pad, and
poured into H2O and extracted with ethyl acetate (15 mL×4). The combined
organic layers were dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified by column chromatography by
using ethyl acetate/hexane as an eluent.
3-(4-Methoxybenzyl)-3-(4-methoxyphenethyl)indolin-2-one (4c) Light
yellow solid; yield: 106 mg (69%); Rf 0.5 in 3:7 (EA:Hex) 1H NMR (500 MHz,
CDCl3) δ 7.97 (s, 1H), 7.23 – 7.16 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.99
(d, J = 8.4 Hz, 2H), 6.79 (dt, J = 16.2, 8.1 Hz, 5H), 6.59 (d, J = 8.3 Hz, 2H),
3.78 (s, 3H), 3.68 (s, 3H), 3.11 (d, J = 13.3 Hz, 1H), 3.03 (d, J = 13.3 Hz,
1H), 2.41 – 2.30 (m, 2H), 2.15 – 2.07 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 181.20, 158.18, 157.82, 141.03, 133.61, 131.59, 131.00, 129.24, 127.88,
127.81, 123.86, 122.23, 113.71, 113.03, 109.59, 55.24, 55.20, 55.00,
43.35, 39.48, 29.90; HRMS (ESI) m/z calcd for C25H25NO3 [M+H]+
388.1907, found 388.1904.
3-Nitro-6H-benzofuro[2,3-b]indole (6) Brown solid; yield: 36 mg (48%);
Rf 0.5 in 4:6 (EA:Hex) 1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.91 (d,
J = 2.0 Hz, 1H), 8.05 (dd, J = 8.5, 2.0 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.10
(d, J = 7.3 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.68 (dd, J = 11.8, 8.2 Hz, 2H);
13C NMR (100 MHz, DMSO) δ 174.67, 148.61, 143.03, 141.67, 135.77,
130.36, 128.50, 127.08, 125.15, 124.34, 122.83, 119.88, 110.47, 57.72.
3-(4-methoxybenzyl)-3-(4-methylphenethyl)indolin-2-one (4d) Antique
white solid; yield: 110 mg (75%); Rf 0.5 in 3:7 (EA:Hex) 1H NMR (500 MHz,
CDCl3) δ 8.62 (s, 1H), 7.25 – 7.19 (m, 2H), 7.14 – 7.10 (m, 1H), 7.06 (d, J
= 7.9 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 – 6.80 (m, 3H), 6.60 – 6.55
(m, 2H), 3.64 (s, 3H), 3.12 (d, J = 13.3 Hz, 1H), 3.05 (d, J = 13.3 Hz, 1H),
2.42 – 2.34 (m, 2H), 2.32 (s, 3H), 2.18 – 2.09 (m, 2H); 13C NMR (126 MHz,
CDCl3) δ 181.73, 158.17, 141.25, 138.51, 135.33, 131.66, 131.00, 129.00,
128.23, 127.91, 127.82, 123.83, 122.23, 113.04, 109.78, 55.31, 54.95,
43.30, 39.41, 30.36, 21.00; HRMS (ESI) m/z calcd for C21H16NO2 [M+H]+
372.1958, found 372.1969.
General procedure for the synthesis of indolo indoles Triethyl
phosphite P(OEt)3 (0.5 mL) and oxindole (100 mg, 1 equiv) were added to
a sealed tube (10 mL) containing stirrer bar. The resulted reaction mixture
was stirred at 150 oC for 16-20 h, Progress of the reaction was monitored
by TLC. Upon completion of the reaction, the mixture was cooled to room
temperature, poured into 5N HCl solution and extracted with ethyl acetate
(15 mL×4). The combined organic layers were dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was purified by
column chromatography by using ethyl acetate/hexane as an eluent.
3-(2-Bromobenzyl)-3-(4-methylphenethyl)indolin-2-one
(4e)
Goldenrod solid; yield: 89 mg (64%); Rf 0.5 in 3:7 (EA:Hex) 1H NMR (500
MHz, CDCl3) δ 8.70 (s, 1H), 7.40 (dd, J = 5.4, 2.6 Hz, 1H), 7.22 – 7.15 (m,
3H), 7.09 – 7.03 (m, 4H), 7.00 – 6.94 (m, 3H), 6.86 (d, J = 7.7 Hz, 1H),
3.47 (d, J = 13.9, Hz, 1H), 3.38 (d, J = 13.8, Hz, 1H), 2.49 – 2.36 (m, 2H),
2.31 (s, 3H), 2.26 - 2.19 (m, 1H), 2.13 – 2.07 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 181.73, 140.89, 138.32, 135.99, 135.40, 132.80, 131.23, 130.80,
129.02, 128.25, 128.23, 128.07, 126.91, 125.87, 124.67, 122.23, 109.58,
54.58, 42.04, 39.45, 30.18, 21.00; HRMS (ESI) m/z calcd for C24H22BrNO
[M+H]+ 420.0958, found 420.0947.
6-Methyl-2-(trifluoromethyl)-5,6-dihydroindolo[2,3-b]indole
(7a)[4d]
Cream viscous liquid; yield: 37 mg (43%); Rf 0.34 in 3:7 (EA:Hex) 1H NMR
(400 MHz, CDCl3) δ 8.21 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.45 – 7.28 (m,
4H), 3.84 (s, 3H); HRMS (ESI) m/z calcd for C16H11F3N2 [M+H]+ 289.0947,
found 289.0971.
2-Methoxy-5-methyl-9-(trifluoromethyl)-5,6-dihydroindolo[2,3-
b]indole (7b)[4d] Brown viscous liquid; yield: 45 mg (52%); Rf 0.34 in 3:7
(EA:Hex) 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.05 (s, 1H), 7.36 (d,
J = 14.6 Hz, 3H), 7.19 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 3.95 (s,
3H), 3.73 (s, 3H); HRMS (ESI) m/z calcd for C17H15F3N2O [M-H]- 319.1053,
found 319.1070.
General procedure for the synthesis of indoles. To a single neck round
bottom flask, Schwartz’s reagent (Cp2Zr(H)Cl, 1.1 equiv) was added to the
solution of oxindole (100 mg, 1 equiv) in dry THF under inert atmosphere
at 0 oC temperature. After addition, reaction mixture was kept at room
temperature for 15-20 min and reaction progress was checked by thin layer
chromatography. After completion of the reaction, saturated aqueous
NaHCO3 solution (15 mL) was added and the resulting mixture was
extracted with ethyl acetate (20 mL×3). The organic layers were combined,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by column chromatography by using ethyl
acetate/hexane (10/90).
1-Methyl-3-(4-nitrophenyl-2,3,5,6-d4)indolin-2-one (8a) Brown solid;
yield: 124 mg (67%); Rf 0.25 in 3:7 (EA:Hex) 1H NMR (500 MHz, CDCl3) δ
7.41 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H), 7.14 (td, J = 7.5, 0.7 Hz,
1H), 6.97 (d, J = 7.9 Hz, 1H), 4.75 (s, 1H), 3.29 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 174.51, 147.33, 144.49, 143.70, 129.16, 129.03 (t, J = 25.4
Hz), 127.19, 125.07, 123.67 (t, J = 26.0 Hz), 123.14, 108.67, 51.55, 26.65.
1-Methyl-3-(4-nitro-3-(trifluoromethyl)phenyl)-1H-indole (5a) Red
solid; yield: 78 mg (82%); Rf 0.3 in 1:9 (EA:Hex) 1H NMR (400 MHz, CDCl3)
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Acknowledgements
SK thanks IISER Bhopal and DST-SERB New Delhi
(EMR/2015/000061) for generous funding. MS and VR, CDP,
acknowledge CSIR and CSIR-UGC New Delhi, respectively for
fellowship .
Keywords: TM-free C-C Coupling • Oxindole • nitrobenzene •
styrene • tert-butoxide • carbanion
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M. Sattar, V. Rathore, C. D. Prasad, Dr.
S Kumar *
Page No. – Page No.
TM Free Chemoselective Oxidative C-
C Coupling of sp3 C-H Bond of
Oxindoles with Arenes and Addition
to Alkene: Synthesis of 3-Aryl
Oxindoles, Benzofuro- and Indolo-
indoles
Table of Contents
A transition-metal (TM) and halogen free NaOtBu–mediated oxidative cross coupling between sp3 C-H
bond of oxindoles and sp2 C-H bond of nitroarenes has been developed to access 3-aryl substituted and
3,3-aryldisubstituted oxindoles in DMSO at room temperature in short time. Interestingly, sp3 C-H bond
of oxindoles has also been added to styrene under TM-free conditions for the practical synthesis of
quaternary 3,3-disubstituted oxindoles. Synthesized 3-oxindoles have also been further transformed into
advanced heterocycles; benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic
understanding of the reaction suggests the formation of an anion intermediate from sp3 C-H bond of
oxindole by tert-butoxide base in DMSO. The addition of nitrobenzene to in-situ generated carbanion led
to the 3-(nitropheny)oxindolyl carbanion in DMSO which subsequently oxidizes to 3-(nitro-aryl)
oxindole by DMSO.
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