Deacylative Alkylation vs. Photoredox Catalysis in the Synthesis of 3,3'-Bioxindoles

Article abstract of DOI:10.1002/ejoc.202000375

The synthesis of 3,3'-bioxindoles employing deacylative alkylations (DaA) in one-pot process, where the 3-bromooxindoles are generated in situ, is described. Good yields and moderate diastereoselections are obtained. By the modification of this procedure the synthesis of pure 3-bromooxindoles through a deacylative bromination (DaB) is achieved. These bromides are efficiently employed in a photoredox dimerization process to get the desired 3,3'-bioxindoles in good yields and low diastereoselections. In this single-electron-transfer (SET) mechanism the presence of a high quantum-yield iridium(III) complex ensures high conversions in short reaction times.

Full text of DOI:10.1002/ejoc.202000375

A Journal of
Accepted Article
Title: Deacylative alkylation versus photoredox catalysis in the
synthesis of 3,3’-bioxindoles
Authors: Cristina Moreno-Cabrerizo, Aitor Ortega-Martínez, Miguel A.
Esteruelas, Ana M. López, Carmen Nájera, and Jose Miguel
Sansano
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000375
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000375
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
Deacylative alkylation versus photoredox catalysis in the
synthesis of 3,3’-bioxindoles
Cristina Moreno-Cabrerizo,[a,b] Aitor Ortega-Martínez,[a,b] Miguel A. Esteruelas,[b,c] Ana M. López,[b,c]
Carmen Nájera,[b] José M. Sansano.*[a,b]
Abstract: The synthesis of 3,3’-bioxindoles employing deacylative
alkylations (DaA) in one-pot process, where the 3-bromooxindoles
are generated in situ, is described. Good yields and moderate
diastereoselections are obtained. By the modification of this
functional groups transformation non-symmetrically substituted
3,3’-bisoxindoles can be obtained (Scheme 1d).[ 14 ] The last
strategy consists in an intramolecular dehydrogenative coupling
(IDC) from the corresponding functionalized N-acylanilines or
the o-iodo/triflate substituted surrogates. In the first case, a
radical C-H bond activation is followed by the coupling with the
activated methylene group,[ 15 ] whilst intramolecular Mizoroki-
Heck reaction control the IDC process in the second case
(Scheme 1e).[16]
procedure the synthesis of pure 3-bromooxindoles through
a
deacylative bromination (DaB) is achieved. These bromides are
efficiently employed in a photoredox dimerization process to get the
desired 3,3’-bioxindoles in good yields and low diastereoselections.
In this single-electron-transfer (SET) mechanism the presence of a
high quantum-yield iridium(III) complex ensures high conversions in
short reaction times.
Introduction
The synthesis of 3,3’-bioxindoles has been widely documented.
There are five general strategies (Scheme 1) to achieve these
systems. The oxidative coupling between two 3-substituted
oxindoles allows the preparation of these structures with the
same substituents, via radical intermediates, employing
transition metal catalysts[1, 2] or not[3] (Scheme 1a). Isoindigo
(obtained from isatin and oxindole) is a very common starting
material for the synthesis of dimeric oxindoles as intermediates
for the construction of complex natural structures. These
isoindigo derivatives can be used as electrophilic alkenes[4] or a
bis-enolate precursor after selective hydrogenation of the
carbon-carbon double bond[5] (Scheme 1b). Electron-deficient 3-
alkylidene oxindoles have been involved in [2+2] photochemical
transformations promoted by an energy transfer mechanism,[6]
and as Michael-type acceptor with Morita-Baylis-Hillman (MBH)
systems,[7] with alkoxycarbonylmethyl-pyridinium bromides,[8] 3-
substituted oxindoles,[9] the Hantzsch ester,[10] nitromethane,[11]
and with alkyl phosphites[12] to access finally the desired dimeric
unit (Scheme 1c). 13 Starting from 3-(3-indolyl)oxindoles by
[a]
Ms. C. Moreno-Cabrerizo, Dr. A. Ortega-Martínez, Prof. J. M.
Sansano
University of Alicante, Department of Organic Chemistry, and
Instituto de Síntesis Orgánica (ISO), PO Box 99, 03080 Alicante,
Spain.
[b]
[c]
Ms. C. Moreno-Cabrerizo, Dr. A. Ortega-Martínez, Prof. M. A.
Esteruelas, Prof. A. M. López, Prof. C. Nájera, Prof. J. M. Sansano
Centro de Innovación en Química Avanzada (ORFEO-CINQA)
Scheme 1. General strategies employed for the synthesis of 3,3’-bioxindoles.
Prof. M. A. Esteruelas, Prof. A. M. López
Departamento de Química Inorgánica
Instituto de Síntesis Química y Catálisis Homogénea
Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain.
The main interest of the synthesis of 3,3’-bioxindoles is
focused on the preparation of very sophisticated natural
products (1-10, Figure 1) as, for example, pyrroloindole alkaloids
of the Calycanthaceae family such as (+)-chimonanthine
1,[3b,c,4b,c,5e-h,14a,c,d,15a] (+)-chimonanthidine 2,[5g] (+)-calycanthidine
3,[17] (+)-folicanthine 4,[3a,b,f,4b,5f,h,i,14a,b,d,e,h,15a] and (+)-calycanthine
5,[3f,4b,5f,h,14d] which exhibit diverse therapeutic properties as
analgesics, antibacterials, antifungals and antivirals.[ 18 ] (+)-
https://cvnet.cpd.ua.es/curriculum-breve/es/sansano-gil-jose-
miguel/10547
Corresponding author: jmsansano@ua.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
Perophoramidine 6[14f] exhibits cytotoxicity toward the HCT 116 Results and Discussion
human colon carcinoma cell line (IC50 = 60 μM) and induces
apoptosis via poly(ADP-ribose) polymerase (PARP) cleavage.[14f]
The initial attempt to get dimers 11 consisted in the reaction
between the 3-acetyl-3-substituted oxindoles 12 as nucleophiles
and the corresponding umpolung bromides 13 as electrophiles
(Scheme 2). The already known heterocycles 12 were prepared
from 3-acetyloxindoles 14 using tetrabutylammonium hydroxide
(Triton B) as base together with the alkylating agent (Scheme
3).[23a-c] This DaA afforded good to excellent yields of the desired
products after column chromatography.
(−)-Idiospermuline 7,[5b,c] a polypyrroloindoline natural alkaloid,
exhibits
hyperpolarization
activity
on
neurochemical
transmission in Sprague-Dawley rat cortical wedge.[18, 19 ] (+)-
Communesin F 8,[14f] for example, is a complex polycyclicindole
alkaloid with cytotoxicity against P388 lymphocytic leukemia
cells (ED50 A: 3.5 μg/mL, B: 0.45 μg/mL) and potent insecticidal
activity toward silk-worms (LD50 D: 300 μg/g, E: 80 μg/g).[20]
Tryptophan-based dimeric diketopiperazine alkaloids[ 21 ] (−)-
ditryptophenaline 9[4b,5f,j,15a] and (−)-WIN 64821 10[4b,5f,j,15a] were
isolated from Aspergillus oryzae and sp. SC319, respectively.
Specially, compound 10 is competitive substance P antagonist
with submicromolar potency against the human neurokinin 1
(NK1) receptor and also an antagonist of the cholecystokinin
type-B receptor.[5j]
Scheme 2. Retrosynthetic analysis for the ionic synthesis of 3,3’-bioxindoles.
Scheme 3. Synthesis of the starting compounds 12 by base promoted DaA.
The synthesis of the 3-bromooxindole derivatives 13 was
attempted using two different approaches (Scheme 4). The first
way consisted in a halogenation-DaA sequence following the
reaction conditions used for the preparation of the corresponding
3-fluoro-3-substituted oxindole derivatives under very mild
conditions.[23d] Thus, compound 15a was obtained almost
quantitatively using N-bromosuccinimide (NBS) and MgClO4 (20
mol%) in very short reaction time and did not require additional
purification. The DaA of 15a employing Triton B and methyl
iodide afforded a very complex reaction mixture and no evidence
Figure 1. Natural products synthesized from 3,3’-bioxindoles.
This paper describes a successful access to the bioxindole
bridge employing the deacylative alkylation (DaA)[22] studied by
our group[ 23 ] and its comparison with a photoredox version
employing 3-bromo-3-substituted oxindole derivatives, which are
obtained by an original procedure involving deacylative
bromination (DaB), and a new iridium(III) photocatalyst recently
reported.
1
of compound 13a was detected in the H NMR spectra of the
reaction crudes (Scheme 4a). Other bases, such as LiOEt and
potassium tert-butoxide, in the range from 0 ºC to room
temperature were also unsuccessfully tested. So, a second
strategy performing the bromination step at the end of the
sequence was designed (Scheme 4b). The already prepared 3-
acetyl-3-methyloxindole derivative 12a was allowed to react with
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
N-bromosuccinimide (NBS) in the presence of Triton B or LiOEt
(0.1 M solution in THF) affording a 10% or a 58% yield of
brominated species 13a, respectively.
(equiv)
1.1
1.5
1.5
1
(equiv)
1
2
3
4
5
6
7
8
9
10
1
---
3
54
50
11
56
42
12
25
12
92
95
14
12
7
19
9
1
---
15
58
44
58
88
75
88
8
1.2
1.1
1.1
1
anhTHF, Ar
anhTHF, Ar
anhTHF, Ar[b]
anhTHF, Ar[b]
anhTHF, Ar[b,c]
anhTHF, Ar[b,d]
anhTHF, Ar
anhTHF, Ar[e]
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
1
2
2
1
2
1
0.5
1
0.5
1
---
[a] Ratios/percentages determined by 1H NMR analysis of the crude mixtures.
The remaining percentage (not shown) corresponds to the recovered starting
material 12a. [b] The reaction solution was deoxygenated using freezing-pump
technique. [c] Reaction performed at 0 ºC. [d] Reaction performed in 15 min.
[e] N-Iodosuccinimide (NIS) was used instead of NBS.
Scheme 4. Two possible routes to access compound 13a.
At this point, we considered that an optimization of this
bromination step was needed (Table 1). Initially, THF was
selected as solvent because the commercially available LiOEt
was dissolved on it. In addition, DCM or toluene was added as
co-solvent. However, all attempts led to complex reaction
mixtures, which were difficult to analyze by 1H NMR
spectroscopy. The reaction using wet THF and air gave a
mixture of the four compounds shown in Table 1 (entries 1 and
2) independently of the amount of NBS. Using anhydrous THF
and running the reaction under an argon atmosphere, the
formation of both undesired deacylated oxindole 17a and the 3-
hydroxy derivative 16a was suppressed, being the amount of
bromide 13a higher when added 2 equiv of NBS and the
freezing-pump technique was applied (Table 1, entries 3-6). The
effect of lowering the temperature was not beneficial (Table 1,
entry 7), but, gratifyingly, in 15 min the reaction was completed
and the amount of the dimeric product 11a was relatively small
(Table 1, entry 8). However, the generation of 11a as major
product was achieved employing 0.5 equiv of NBS under
anhydrous conditions, without the previous freezing-pump
operation (Table 1, entry 9). Employing N-iodosuccinimide,
instead of NBS, in short reaction times (15 min) afforded very
clean reaction crude, which contained almost exclusively dimer
11a (Table 1, entry 10). In this last example a deacylative
iodination (DaI) occurred instead.
Using this last reaction conditions, the preparation of
symmetrically substituted 3,3’-bioxindoles 11 was achieved
directly, in a one pot process, where the electrophile was
generated in situ (it was not necessary to isolate the
corresponding iodide) in the presence of the enolate emulating
the classical Barbier conditions. Thus, 3,3’-bioxindoles 11a-h
were isolated in very good and modest yields (90-26%) (Scheme
5). In these examples, different substituents at 1, 3 and 5
positions of the heterocycle were evaluated and the
diastereoselection was always (R*,R*):meso 3:1 (determined by
1H NMR spectroscopy on the crude mixture). It is noticeable that
in this cascade reaction two different deacylative processes
occurred, the DaI took place and immediately, and the DaA
completed the sequence. After flash chromatography, only the
major (R*,R*)-diastereoisomer 11 was isolated as pure
diastereoisomer.
Table 1. Optimization of the deacylative bromination (DaB) of oxindole
derivative 12a.
NBS
LiOEt
Conditions
13a[a]
11a
16a
17a
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
Scheme 6. Synthesis of 3-bromooxindoles 13a-h using a DaB process.
Bromide 13a was submitted to the optimization of solvents,
source of light, catalysts, base and electron donor. We initially
took the conditions reported previously employing a blue LED
source in acetonitrile, with the base DBU as electron donor .[24]
Under these conditions, photocatalyst 18 afforded a modest yield
(45%) with high amounts of the oxidized product 16a (Table 2,
entry 1). Ruthenium(II) complex 19, as well as
organophotocatalyst Eosin B (this last example is not shown in
the Table 2) did not promote the reaction at all. In view of this
situation, we decided to employ recently reported organometallic
phosphorescent compounds as new photocatalysts (Table 2,
entries 3-6): the homoleptic osmium(II) complex 20 bearing two
equal 5-electron donor C,C,C-pincer ligands based on bis-NHC
systems,[27] the heretoleptic iridium(III) derivatives 21 and 22
containing a 6-electro donor C,C,C,C-tetradentate group and a
3-electron donor orthometalated phenylpyridine,[ 28 ] and the
heteroleptic compound 23 stabilized by a 5-electron donor
N,C,N-pincer ligand and a 4-electron donor C,N,C-group.[29] The
osmium complex 20 is a blue emitter in 2-methyl tetrahydrofuran,
which displays a quantum yield of 0.62 in the solid state. Under
the same conditions, the iridium complexes 21 and 22 are blue-
green emitters with quantum yields close to unity, whereas
complex 23 is green emissive with a quantum yield of 0.87. The
best conversion and chemical yield of 11a were achieved by
intermediacy of catalyst 23 (Table 2, entry 6).In this context, it
should be mentioned that in addition to the lower energy of its
emission, complex 23 shows two noticeable differences with
regard to 21 and 22. It displays longer lifetime in 2-
methyltetrahydrofuran, at room temperature (2.4 and 1.6 µs,
respectively, versus 7.7 µs) and the presence of an oxygen atom
between the pyridyl ring and one of the phenyl group of the
C,N,C-pincer ligand, which stabilizes the octahedral geometry of
the catalyst , due to the increase of a N-Ir-C bite angle.[30] The 24
W blue LED source afforded better conversions than the visible
light, 20 W fluorescent bulb, or 20 W white bulb (not included in
Scheme 5. Synthesis of 11a-h using a combined sequential DaI-DaA.
Such as it was described, 3-chloro-3-substituted oxindoles
were successfully homocoupled via visible light photocatalysis
(method not shown in Scheme 1) using fac-Ir(ppy)3.[24] So, we
envisaged the same transformation but using the bromides 13
instead. Turning back to the best result of the Table 1 (entry 8),
the synthesis of 3-bromo-3-substituted oxindoles 13 was
accomplished after 15-20 min, by the novel DaB; using 1 equiv
of LiOEt and 1.1 equiv of NBS, at room temperature, under an
argon atmosphere. The THF solutions (the base-containing
solution and the reaction mixture) were previously submitted to a
freezing-pump deoxygenation. After purification by flash
chromatography, bromides 13 were isolated as pure compounds
in good chemical yields (Scheme 6). These results were
completely reproducible, even the synthesis of compound 13a
was scaled up to 0.5 g (2.4 mmol). This new procedure did not
required strong basic conditions,[24] the employment of
25
]
diazocompounds[
or
hazardous
tris(dimethylamino)phosphine.[26]
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
Table 2). Despite diisopropylethylamine (DIPEA) did not give
satisfactory results in acetonitrile, in THF afforded similar results
than the obtained one in the reaction with DBU (compare entries
8-10 of the Table 2). Here, the freezing-pump operation resulted
to be crucial to diminish the percentage of the oxidized
compound 16a. DIPEA was selected as base because the crude
reaction mixture was very clean (detected by 1H NMR) unlike the
reaction crude generated from DBU. The conversion and the
yield of product 11a were improved employing freshly distilled
DIPEA (under anhydrous conditions). All 11a products identified
in the crude mixtures or isolated in this Table 2 resulted to be
15
16
17
23[c]
23
23[c]
---
THF
THF
THF
trace
79
19
---
80
52
21
20
---
---
---
DIPEA[d]
DIPEA[d][g]
trace
[a] A 1:1 (R*,R*):meso diastereomeric ratio was determined by 1H-NMR
analysis of the crude mixtures. The remaining percentage (not shown)
corresponds to the recovered starting material 12a. [b] Isolated yield after flash
chromatography. [c] The reaction solution was deoxygenated using freezing-
pump technique. [d] Freshly distilled and working under anhydrous conditions.
[e] 1 Mol% of the catalyst was added. [f] In the absence of blue-LED light. [g]
TEMPO (20 mol%) was added.
1
1:1 mixtures of (R*,R*):meso diastereoisomers according to H
The catalysis can be rationalized according to Scheme 7.
The excited state of 23 is highly reductant and could be
quenched by 13a faster than by DIEPA through a SET step. The
collision should lead to a cation radical iridium(IV) species, a
bromide ion, and a radical oxindole The iridium(III) fundamental
state would be regenerated by means of the reaction of DIPEA
with the cation radical iridium(IV) species in a second SET stage.
The resulting radical cation [DIPEA]+• should release a radical H•,
to afford an iminium cation. Then, the radical H• could be
trapped by a radical Br•, which should be generated in the
collision between the radical oxindole and a second molecule of
13a, to form the carbon-carbon bond of 11a.
NMR data.
Table 2. Optimization of the synthesis of 3,3’-bioxindole 11a via photoredox
catalysis.
Scheme 7. Mechanistic proposal for the synthesis of 11a.
The efficient dimerization took place under anhydrous
conditions, under argon atmosphere, with the catalytic complex
23 (0.5 mol%) and DIPEA (1.5 equiv), after 15 h irradiation with
24 W blue LED, at room temperature. Previously, all solutions
were submitted to the freezing-pump protocol. Products 11 were
obtained in good to moderate chemical yield and as almost 1:1
(R*,R*):meso ratios (Scheme 8). These results compare well
with those obtained from 3-chlorooxindoles and the
photocatalyst 18.[24] Compound 11e was isolated in 70% yield
and as 1.2:1 (R*,R*):meso ratio (Scheme 8), whereas a 3:1
(R*,R*):meso ratio and a 40% yield was obtained using the
combined sequential DaI-DaA methodology (Scheme 5). At this
point, (R*,R*)- and meso-diastereoisomers 11a-d were
separated as pure compounds after flash chromatography.
However, for allylated derivatives 11e-h only the (R*,R*)-isomers
were obtained as pure final compounds and the meso-
surrogates were impurified with their corresponding (R*,R*)-
diasteroisomer. Compound 11e is the key building block for the
synthesis of (-)-chimonanthine (ent-1), (+)-calycanthine (5), (-)-
Catalyst
Base
Solvent
(0.1M)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
11a[a]
13a
16a
Yield
(%)[b]
45
---
1
18
DBU
66
4
30
15
10
13
24
12
10
25
15
12
7
2
19
DBU
trace
trace
22
85
90
65
36
16
12
50
---
---
---
---
67
80
3
20
DBU
---
4
21
DBU
---
5
22
DBU
40
---
6
23
DBU
72
56
58
---
7
23[c]
23[c]
23[c]
23[c]
23[c]
23[c][e]
---
DBU
78
8
DIPEA
DIPEA
DBU
DIPEA[d]
DIPEA[d]
DIPEA[d]
DIPEA[d]
25
9
85
68
69
73
73
---
10
11
12
13
14
THF
88
THF
93
THF
93
7
THF
10
23
10
23[c][f]
THF
trace
---
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
WIN 64821 (10), and (-)-ditryptophenaline (9),[15a] and a potential
precursor of (±)-dehaloperophoramidines[4d] and certain
communesins.[9d]
higher chemical yields. However, higher diastereoselectivity of
the resulting 3,3’-bioxindoles is achieved by the DaA.
Experimental Section
General: Melting points were determined with a Marienfeld melting-point
meter (MPM-H2) apparatus and are uncorrected. For flash
1
chromatography, silica gel 60 (40–60 μm) was employed. H NMR (300,
400 MHz) and 13C NMR (75 or 101 MHz) spectra were recorded with
Bruker AV300, and Bruker AV400, respectively, with CDCl3 as solvent
and TMS as internal standard for 1H NMR spectra, and the chloroform
signal for 13C NMR spectra; chemical shifts are given in ppm. Low-
resolution electron impact (DIP-EI) mass spectra were obtained at 70 eV
with an Agilent 6890N Network GC system and an Agilent 5973Network
Mass Selective Detector. High-resolution mass spectra (DIP-EI) were
recorded with a QTOF Agilent 7200 instrument for the exact mass and
Agilent 7890B for the GC. Analytical TLC was performed using
ALUGRAM® Xtra SIL G/UV254 silica gel plates, and the spots were
detected under UV light (λ=254 nm). The synthesis of known precursors
12a,[23a] 12b,[23a] 12d,[23a] 12e,[23a,c] 12f[23c] and 12h[23c] was carried out
following the reported method in yields indicated in Scheme 3. Molecules
12c and 12g were obtained using the same procedures starting from a 1
mmol scale[23] and they have not been prepared/characterized previously.
3-Acetyl-1-benzyl-3-methylindolin-2-one (12c):[23a] 167 mg (60%), pale
yellow plates; mp 62-63 °C (n-hexane/EtOAc); RF 0.45 (n-hexane/EtOAc
9:1); IR (neat) νmax 1738, 1724, 1611, 1475, 1340 cm-1; 1H NMR (300
MHz, CDCl3) δ: 7.36–7.20 (6H, m, ArH), 7.15 (1H, dd, J = 7.7, 1.1 Hz,
ArH), 7.05 (1H, td, J = 7.5, 1.0 Hz, ArH), 6.84 (1H, d, J = 7.7 Hz, ArH),
5.05, 4.90 (2H, 2xd, J = 15.4 Hz, CH2), 1.98 (3H, s, CH3), 1.63 (3H, s,
CH3); 13C NMR (75 MHz, CDCl3) δ: 200.9, 176.0 (2xCO), 143.0, 135.7,
129.6, 129.2, 129.0, 128.0, 127.6, 123.7, 123.4, 109.7 (ArC), 62.0 (CCO),
44.2 (NCH2), 26.2 (CCH2), 19.2 (CH3); MS (EI) m/z: 280 (M++1, 1%), 279
(M+, 10), 237 (54), 147 (17), 91 (100); HRMS (ESI): calcd. for C18H17NO2:
279.1259; found: 279.1255.
Scheme 8. Synthesis of 11a-h using a photoredox catalysis from 13.
3-Acetyl-3-allyl-1-benzylindolin-2-one (12g):[23a] 177 mg (58%), pale
yellow oil; RF 0.55 (n-hexane/EtOAc 9:1); IR (neat) νmax 3050, 2966, 1735,
1722, 1621, 1474, 1340 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.37–6.99
(7H, m, ArH), 6.80 (2H, d, J = 7.8 Hz, ArH), 5.39–5.24 (1H, m, CH=CH2),
5.14–4.75 (4H, m, CH=CH2, and NCH2), 3.05–2.89 (2H, m, C=CCH2),
2.00 (3H, s, CH3); 13C NMR (101 MHz, CDCl3) δ: 200.5, 174.6 (2xCO),
143.4, 135.5, 131.5, 128.8, 128.7, 127.9, 127.3,126.9, 124.1,
123.2,119.7, 109.6 (ArC and CH=CH2), 66.4 (CCO), 44.2 (NCH2), 37.5
(CCH2), 26.6 (CH3); MS (EI) m/z: 306 (M++1, 3%), 305 (M+, 13), 263 (44),
223 (27), 173 (15), 91 (100); HRMS (ESI): calcd. for C20H19NO2:
305.1416; found: 305.1420.
Conclusion
In conclusion, the efficient synthesis of 3,3’-bioxindoles or
3-bromosubstituted oxindoles can be selectively performed
using small differences in the amount of NBS employed. This is
a clear example of diverse oriented synthesis (DOS). It should
be also noted that the deacylative alkylation (DaA) of the in situ
generated bromides constitute
a very easy and original
methodology to reach these attractive symmetrically substituted
3,3’-bioxindoles. The method improves previously reported
procedures by increasing the yields and purity of the products.
Deacylative bromination (DaB), a novel synthetic protocol to
prepare 3-bromo-3-substituted oxindoles with high yields, under
mild conditions, has been developed. In both deacylative
processes no harsh reaction conditions are required. In addition,
the photoredox catalyzed version of the dimerization has been
successfully evaluated using an unprecedented iridium(III)
photocatalyst. The results of the catalysis compare well with
those obtained from 3-chlorooxindoles and the usual
photocatalyst fac-Ir(ppy)3. Ionic and radical mechanisms
afforded complementary results in terms of chemical yields,
although, in general, photoredox catalysis allowed to obtain
General procedure for the synthesis of 3-bomooxindoles (13):
Initially, two solutions were prepared independently. Solution a): under Ar
atmosphere, N-bromosuccinimide (1.1 equiv, 0.33 mmol, 58.7 mg) was
dissolved in 1.5 mL of anhydrous THF. This solution was protected from
light. Solution b): to a solution of the 3-acetyllindolin-2-one derivative 12
(1 equiv, 0.3 mmol) in 1.5 mL of anhydrous THF (under Ar atmosphere),
1M lithium ethoxide in THF (1 eq., 0.3 mmol, 0.3 mL) was added
dropwise at room temperature and stirred for 15 min. Solution b) was
added over solution a) slowly (0.6 mL/min). Stirring was continued fro 15-
20 min at room temperature. Water (10 mL) was added and the mixture
was extracted with ethyl acetate (3×10 mL) and the combined organic
layers were washed (5x10mL H2O) and brine, dried (MgSO4) and Finally,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
concentrated under vacuo (15 Torr), and the residue was purified by
column chromatography (n-hexane/ EtOAc) obtaining pure bromides 13.
3-Allyl-3-bromo-5-methoxy-1-methylindolin-2-one (13f): 53 mg (60%),
yellow wax; RF 0.25 (n-hexane/EtOAc 9:1); IR (neat) νmax 1719, 1496,
1288, 1265, 1034, 733, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.02 (1H,
d, J = 2.5 Hz, ArH), 6.86 (1H, dd, J = 8.5, 2.6 Hz, ArH), 6.73 (1H, d, J =
8.5 Hz, ArH), 5.64–5.44 (1H, m, HC=CH2), 5.17–5.03 (2H, m, HC=CH2),
3.81 (3H, s, OCH3), 3.20 (3H, s,NCH3), 3.06 (2H, m, CH2); 13C NMR (101
MHz, CDCl3) δ: 174.0 (CO), 156.8, 136.2, 131.3, 131.1, 121.2, 115.1,
112.3, 109.6 (ArC and CH=CH2), 56.3 (OCH3), 55.7 (CBr), 43.8 (CH2),
27.2 (NCH3); MS (EI) m/z: 297 (M+, 4%), 295 (M+, 4%), 217 (46), 216
(52), 215 (100), 214 (20), 200 (36), 188 (11), 184 (11), 176 (75), 174 (17),
173 (11), 172 (40), 144 (14), 115 (40), 43 (45); HRMS (ESI): calcd. for
C13H14BrNO2: 295.0208; found: 295.0214.
3-Bromo-1,3-dimethylindolin-2-one (13a):[25] 51 mg (70%), pale yellow
prisms; mp 83-85 °C (n-hexane/EtOAc); RF 0.25 (n-hexane/EtOAc 9:1);
IR (neat) νmax 1719, 1611, 1470, 1345, 749, 663 cm-1; 1H NMR (300 MHz,
CDCl3) δ: 7.44 (1H, dd, J = 7.5, 1.1 Hz, ArH), 7.33 (1H, td, J = 7.8, 1.3
Hz, ArH), 7.12 (1H, td, J = 7.6, 0.9 Hz, ArH), 6.84 (1H, d, J = 7.8 Hz, ArH),
3.24 (3H, s, NCH3), 2.03 (3H, s, CCH3); 13C NMR (101 MHz, CDCl3) δ:
174.8 (CO), 141.9, 131.7, 130.2, 124.2, 123.4, 108.87 (ArC), 52.53
(CMe), 26.82 (NCH3), 26.46 (CCH3); MS (EI) m/z: 240 (M+, 10%), 238
(M+, 10%) 161 (13), 160 (30), 159 (41), 158 (11), 146 (10), 131 (17), 130
(42), 118 (12), 71 (14), 70 (22), 61 (15), 57 (14), 45 (13), 43 (100); HRMS
(ESI): calcd. for C10H10BrNO: 238.9946; found: 238.9950.
3-Allyl-1-benzyl-3-bromoindolin-2-one (13g):[26] 52 mg (51%), orange
wax; RF 0.25 (n-hexane/EtOAc 9.7:0.3); IR (neat) νmax 2362, 1721, 1610,
1486, 1468, 1355, 1174, 927, 749 cm-1; 1H NMR (400 MHz, CDCl3) δ:
7.45–7.41 (1H, m, ArH), 7.33–7.24 (5H, m, ArH), 7.19 (1H, td, J = 7.8,
1.3 Hz, ArH), 7.06 (1H, td, J = 7.6, 0.9 Hz, ArH), 6.67 (1H, d, J = 7.8 Hz,
ArH), 5.59–5.45 (1H, m, HC=CH2), 5.20–5.05 (2H, m, HC=CH2), 4.97,
4.88 (2H, 2xd, J = 15.8 Hz, NCH2), 3.26–3.09 (2H, m, BrCCH2); 13C NMR
(101 MHz, CDCl3) δ 174.1 (CO), 141.6, 135.2, 131.1, 130.1, 129.6, 128.9,
128.8, 127.9, 127.3, 127.2, 124.9, 123.4, 121.1, 109.9 (ArC and
CH=CH2), 55.1 (CBr), 44.2, 43.2 (2xCH2); MS (EI) m/z: 343 (M+, 2%),
341 (M+, 2%), 263 (34), 262 (28), 261 (48), 232 (15), 222 (40), 218 (13),
91 (100); HRMS (ESI): calcd. for C18H16BrNO: 341.0415; found:
341.0415.
3-Bromo-5-methoxy-1,3-dimethylindolin-2-one (13b):[25] 53 mg (65%),
brown needles; mp 107-108 °C (n-hexane/EtOAc); RF 0.25 (n-
hexane/EtOAc 8.5:1.5); IR (neat) νmax 1717, 1497, 1265, 1109, 1036, 732,
702 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.04 (1H, d, J = 2.5 Hz, ArH),
6.86 (1H, dd, J = 8.5, 2.6 Hz, ArH), 6.74 (1H, d, J = 8.5 Hz, ArH), 3.82
(3H, s, OCH3), 3.22 (3H, s, NCH3), 2.02 (3H, s, CCH3); 13C NMR (75
MHz, CDCl3) δ: 174.6 (CO), 156.6, 135.2, 132.8, 114.9, 111.2, 109.4
(ArC), 56.0 (OCH3), 52.9 (CMe), 26.9 (NCH3), 26.5 (CCH3); MS (EI) m/z:
271 (M+, 4%), 269 (M+, 4%), 191 (48), 190 (100), 189 (71), 176 (44), 175
(26), 174 (96), 148 (21), 146 (16), 118 (17), 117 (12), 90 (11), 43 (22);
HRMS (ESI): calcd. for C11H12BrNO2: 269.0051; found: 269.0053.
3-Allyl-1-benzyl-3-bromo-5-methoxyindolin-2-one (13h): 93 mg, (83%),
yellow oil; RF 0.25 (n-hexane/EtOAc 9:1); IR (neat) νmax 1717, 1492, 1435,
1178, 1042, 733, 695 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.33–7.24 (5H,
m, ArH), 7.02 (1H, d, J = 2.5 Hz, ArH), 6.71 (1H, dd, J = 8.6, 2.6 Hz, ArH),
6.55 (1H, d, J = 8.6 Hz, ArH), 5.62–5.43 (1H, m, HC=CH2), 5.23–5.04
(2H, m, HC=CH2), 4.94, 4.85 (2H, 2xd, J = 15.8 Hz, NCH2),3.76 (3H, s,
OCH3), 3.22–3.10 (2H, m, BrCCH2); 13C NMR (101 MHz, CDCl3) δ: 173.8
(CO), 156.4, 135.3, 134.9, 131.1, 130.7, 128.9, 128.8, 127.8, 127.3,
127.2, 121.1, 114.8, 111.8, 110.4 (ArC and CH=CH2), 55.9 (OCH3), 55.4
(CBr), 44.2, 43.5 (2xCH2); MS (EI) m/z: 373 (M+, 1%), 371 (M+, 1%), 292
(23), 291 (100), 200 (14), 172 (15), 91 (64); HRMS (ESI): calcd. for
C19H18BrNO2: 371.0521; found: 371.0529.
1-Benzyl-3-bromo-3-methylindolin-2-one (13c): 49 mg (52%), orange
wax; RF 0.25 (n-hexane/EtOAc 9.5:0.5); IR (neat) νmax 2359, 1720, 1610,
1486, 1468, 1356, 1182, 751 cm-1; 1H NMR (400 MHz, CDCl3) δ: 7.45
(1H, d, J = 8.2 Hz, ArH), 7.34–7.25 (5H, m, ArH), 7.19 (1H, t, J = 7.8 Hz,
ArH), 7.07 (1H, t, J = 8.0 Hz, ArH), 6.69 (1H, d, J = 7.8 Hz, ArH), 5.02,
4.84 (2H, 2xd, J = 15.7 Hz, NCH2), 2.09 (3H, s, CH3); 13C NMR (101 MHz,
CDCl3) δ: 175.10 (CO), 141.0, 135.3, 131.8, 130.1, 129.1, 129.0, 127.9,
127.3, 127.2, 124.3, 123.5, 109.9 (ArC), 52.6 (CMe), 44.1 (CH2), 26.4
(CH3); MS (EI) m/z: 317 (M+, 1%), 315 (M+, 1%), 237 (33), 236 (34), 235
(49), 91 (100); HRMS (ESI): calcd. for C16H14BrNO: 315.0259; found:
315.0257.
1-Benzyl-3-bromo-5-methoxy-3-methylindolin-2-one (13d): 47 mg (45%),
brown wax; RF 0.25 (n-hexane/EtOAc 9:1); IR (neat) νmax 1720, 1495,
1264, 1041, 895, 732, 702 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.34–7.25
(5H, m, ArH), 7.04 (1H, d, J = 2.6 Hz, ArH), 6.72 (1H, dd, J = 8.6, 2.6 Hz,
ArH), 6.58 (1H, ArH), 5.00, 4.81 (2H, 2xd, J = 15.8 Hz, CH2), 3.77 (3H, s,
OCH3), 2.08 (3H, s, CH3); 13C NMR (101 MHz, CDCl3) δ: 174.9 (CO),
156.6, 135.4, 134.3, 132.9, 129.0, 128.9, 127.9, 127.2, 127.2, 114.9,
111.1, 110.5 (ArC), 55.9 (OCH3), 52.9 (CMe), 44.2 (CH2), 26.5 (CH3); MS
(EI) m/z: 347 (M+, 1%), 345 (M+, 1%), 267 (27), 266 (31), 265 (97), 146
(14), 91 (100); HRMS (ESI): calcd. for C17H16BrNO2: 345.0364; found:
345.0356.
General procedure for the synthesis of 3,3’-bioxindoles (11).
METHOD A: In
a Schlenk tube containing 3-acetyllindolin-2-one
derivative (12) (0.3 mmol) dissolved in anhydrous THF (3 mL), lithium
ethoxide (1M solution in THF) (1 equiv, 0.3 mmol, 0.3 mL) was added
dropwise under Ar atmosphere. Then, N-iodosuccinimide (0.5 equiv, 0.15
mmol, 33 mg) was added, and the reaction was stirred 15-20 minutes at
room temperature. Water (10 mL) was added, the mixture was extracted
with EtOAc (3×10 mL) and the combined organic layers were washed
(5x10 mL H2O) and brine, dried (MgSO4) and evaporated under vacuo
(15 Torr) and the residue was purified by column chromatography (n-
hexane/ EtOAc). METHOD B: A Schlenk tube containing a solution of 3-
bromolindolin-2-one derivative (0.3 mmol), photocatalyst 23 (1 mg, 0.5
mol%) and freshly distilled anhydrous DIPEA (0.078 mL,1.5 equiv, 0.45
mmol) in THF (3 mL) was degassed by freezing-pump (3 cycles). Then,
the reaction was irradiated with blue LEDs for 15 h at room temperature.
Water (10 mL) was added, and the mixture was extracted with EtOAc
(3×10 mL) and the combined organic layers were dried (MgSO4),
concentrated under vacuo and the residue was purified by column
chromatography (n-hexane/ EtOAc).
3-Allyl-3-bromo-1-methylindolin-2-one (13e):[31] 36 mg (45%), pale yellow
prisms; mp 76-77 °C (n-hexane/EtOAc); RF 0.25 (n-hexane/EtOAc 9:1);
IR (neat) νmax 1723, 1612, 1471, 1265, 930, 732, 702 cm-1; 1H NMR (300
MHz, CDCl3) δ: 7.42 (1H, dd, J = 7.5, 1.2 Hz, ArH), 7.33 (1H, td, J = 7.8,
1.3 Hz, ArH), 7.10 (1H, td, J = 7.6, 1.0 Hz, ArH), 6.83 (1H, d, J = 7.8 Hz,
ArH), 5.60–5.44 (1H, m, HC=CH2), 5.17–5.03 (2H, m, HC=CH2), 3.23 (3H,
s, NCH3), 3.18–2.97 (2H, m, CH2); 13C NMR (101 MHz, CDCl3) δ: 173.9
(CO), 142.5, 131.1, 130.2, 129.7, 125.0, 123.4, 120.8, 108.8 (ArC and
CH=CH2), 55.1 (CBr), 43.5 (CH2), 26.8 (NCH3); MS (EI) m/z: 267 (M+,
2%), 265 (M+, 3%), 187 (12), 186 (19), 185 (33), 184 (32), 158 (12), 146
(24), 71 (10), 70 (18), 61 (17), 57 (13),45 (15), 43 (100); HRMS (ESI):
calcd. for C12H12BrNO: 265.0102; found: 265.0115.
1,1',3,3'-Tetramethyl-[3,3'-biindoline]-2,2'-dione (11a):[24] 44 mg (90%,
Method A), 35 mg (72% Method B); (R*,R*): pale yellow plates; mp 166-
167 °C (n-hexane/EtOAc); RF 0.70 (n-hexane/EtOAc 5:5); IR (neat) νmax
2925, 1697, 1609, 1348, 1096, 740, 695 cm-1; 1H NMR (300 MHz, CDCl3)
δ: 7.08–6.97 (4H, m, ArH), 6.82 (2H, t, J = 7.6 Hz, ArH), 6.45 (2H, d, J =
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
7.7 Hz, ArH), 3.09 (6H, s, 2xNCH3), 1.75 (6H, s, 2xCH3); 13C NMR (75
MHz, CDCl3) δ: 178.3 (2xCO), 142.7 (2xC), 131.2, 128.2, 122.9, 121.9,
107.5 (ArC), 51.3 (2xC), 25.8 (2xNCH3), 16.2 (2xCH3); MS (EI) m/z: 320
(M+, 19%) 161 (61), 160 (100), 130 (12), 117 (13); HRMS (ESI): calcd.
for C20H20N2O2: 320.1529; found 320.1534. Meso: pale yellow oil; RF
0.30 (n-hexane/EtOAc 5:5); IR (neat) νmax 1967, 1607, 1374, 1347, 1094,
1026, 757, 736 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.24 (2H, t, J = 7.7 Hz,
ArH), 6.86 (2H, t, J = 7.6 Hz, ArH), 6.72 (2H, d, J = 7.8 Hz, ArH), 6.61
(2H, d, J = 7.3 Hz, ArH), 2.97 (6H, s, NCH3), 1.67 (6H, s, CH3); 13C NMR
(75 MHz, CDCl3) δ: 177.8 (2xCO), 143.9, 131.2, 128.6, 123.8, 121.7,
108.0 (ArC), 51.8 (2xC), 26.0 (2xNCH3), 17.5 (2xCH3); MS (EI) m/z: 320
(M+, 8%), 194 (4), 161 (28), 160 (100), 145 (3), 132 (5), 130 (6), 117 (7),
77 (3); HRMS (ESI): calcd. for C20H20N2O2: 320.1525; found 320.1533.
CDCl3) δ: 178.4 (2xCO), 155.8, 135.8, 135.4, 132.9, 128.9, 127.6, 127.2,
112.9, 110.9, 109.5 (ArC), 55.6 (2xOCH3), 51.3 (2xC), 43.8 (2xCH2), 18.4
(2xCH3); MS (EI) m/z: 532 (M+, 6%), 267 (25), 266 (100), 265 (7), 91
(47); HRMS (ESI): calcd. for C34H32N2O4: 532.2362; found 532.2361.
Meso: could not be isolated.
3,3'-Diallyl-1,1'-dimethyl-[3,3'-biindoline]-2,2'-dione (11e):[24] 22 mg (40%,
Method A), 39 mg (70% Method B); (R*,R*): yellow solid; mp 215-216 °C
(n-hexane/EtOAc); RF 0.70 (n-hexane/EtOAc 6:4); IR (neat) νmax 2932,
1686, 1491, 1353, 1096, 924, 757 cm-1; 1H NMR (300 MHz, CDCl3) δ:
7.07–6.96 (4H, m, ArH), 6.82 (2H, td, J = 7.6, 0.9 Hz, ArH), 6.41 (2H, d, J
= 7.8 Hz, ArH), 5.05–4.98 (4H, m, 2xHC=CH2), 4.74 (2H, dd, J = 8.3, 3.9
Hz, 2xHC=CH2), 3.64 (2H, dd, J = 12.6, 5.0 Hz, CH2), 3.06 (6H, s, NCH3),
3.05–2.99 (2H, m, CH2); 13C NMR (75 MHz, CDCl3) δ: 177.0 (2xCO),
143.4, 132.6, 128.3, 128.2, 123.5, 121.8, 118.9, 107.5 (ArC and
CH=CH2), 56.0 (2xC), 33.3 (2xNCH3), 25.7 (2xCH2); MS (EI) m/z: 372
(M+, 6%), 187 (49), 186 (100), 158 (16), 144 (10), 143 (10); HRMS (ESI):
calcd. for C24H24N2O2: 372.1838; found 372.1862. Meso: pale yellow oil;
RF 0.30 (n-hexane/EtOAc 6:4); IR (neat) νmax 1704, 1608, 1469, 1348,
1097, 919,753 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.30–7.19 (2H, m,
ArH), 6.87 (2H, t, J = 8.0 Hz, ArH), 6.68 (2H, d, J = 7.8 Hz, ArH), 6.60
(2H, d, J = 7.1 Hz, ArH), 5.18–5.02 (2H, m, 2xHC=CH2), 4.94 (2H, dd, J =
17.0, 2.3 Hz, 2xHC=CHH), 4.77 (2H, dd, J = 9.8, 2.3 Hz, 2xHC=CHH),
3.47 (2H, dd, J = 13.1, 7.2 Hz, 2xCH2), 2.98–2.82 (8H, m, 2xNCH3, 2x
CH2); 13C NMR (75 MHz, CDCl3) δ: 176.2 (2xCO), 144.7, 132.1, 128.7,
128.6, 124.3, 121.6, 119.3, 107.9 (ArC and CH=CH2), 56.7 (2xC), 34.9
(2xNCH3), 25.9 (2xCH2); MS (EI) m/z: 372 (M+, 5%), 187 (45), 186 (100),
158 (16), 144 (10), 143 (11); HRMS (ESI): calcd. for C24H24N2O2:
372.1838; found 372.1850.
5,5'-Dimethoxy-1,1',3,3'-tetramethyl-[3,3'-biindoline]-2,2'-dione (11b).[24]
29 mg (51%, Method A), 31 mg (54% Method B); (R*,R*): pale orange
solid; mp 213-214 °C (n-hexane/EtOAc); RF 0.8 (n-hexane/EtOAc
4.5:5.5); IR (neat) νmax 2940, 1686, 1493, 1215, 1039, 802 cm-1; 1H NMR
(300 MHz, CDCl3) δ: 6.73 (2H, d, J = 2.5 Hz, ArH), 6.58 (2H, dd, J = 8.5,
2.6 Hz, ArH), 6.39 (2H, d, J = 8.5 Hz, ArH), 3.69 (6H, s, 2xOCH3), 3.10
(6H, s, 2xNCH3), 1.74 (6H, s, 2xCCH3); 13C NMR (75 MHz, CDCl3) δ:
177.9 (2xCO), 155.7, 136.1, 132.6, 113.1, 110.2, 107.8 (ArH), 55.9
(2xOCH3), 51.5 (2xC), 26.0 (2xNCH3), 16.6 (2xCH3); MS (EI) m/z: 380
(M+, 10%), 192 (2), 191 (16), 190 (100), 176 (2), 175 (6), 174 (3), 162 (2),
160 (2), 159 (2), 147 (5), 119 (2), 118 (3); HRMS (ESI): calcd. for
C22H24N2O4: 380.1736; found 380.1749. Meso: pale yellow oil; RF 0.30
(n-hexane/EtOAc 4.5:5.5); IR (neat) νmax 1701, 1497, 1289, 1236, 1035,
732 cm-1; 1H NMR (300 MHz, CDCl3) δ: 6.78 (2H, d, J = 10.9 Hz, ArH),
6.63 (2H, d, J = 8.4 Hz, ArH), 6.29 (2H, s, ArH), 3.65 (6H, s, 2xOCH3),
2.96 (6H, s, 2xNCH3), 1.66 (6H, s, 2xCH3); 13C NMR (75 MHz, CDCl3) δ:
177.2 (2xCO), 155.2, 137.4, 132.3, 113.0, 111.2, 108.1, 55.8 (2xOCH3),
51.9 (2xC), 26.0 (2xNCH3), 17.4 (2xCH3); MS (EI) m/z: 380 (M+, 10%),
192 (2), 191 (15), 190 (100), 176 (2), 175 (6), 174 (2), 162 (2), 160 (2),
159 (2), 147 (5), 119 (2), 118 (3); HRMS (ESI): calcd. for C22H24N2O4:
380.1736; found 380.1756.
3,3'-Diallyl-5,5'-dimethoxy-1,1'-dimethyl-[3,3'-biindoline]-2,2'-dione (11f):
26 mg (40%, Method A), 16 mg (25% Method B); (R*,R*): colorless
prisms; mp 201-202 °C (n-hexane/EtOAc); RF 0.25 (n-hexane/EtOAc
9:1); IR (neat) νmax 1687, 1498, 1433, 1235, 923, 811, 736 cm-1; 1H NMR
(300 MHz, CDCl3) δ: 6.71 (2H, d, J = 2.5 Hz, ArH), 6.56 (2H, dd, J = 8.4,
2.6 Hz, ArH), 6.35 (2H, d, J = 8.5 Hz, ArH), 5.05–4.99 (2H, m, 2x
HC=CH2), 4.76 (2H, dd, J = 8.0, 4.2 Hz, 2xHC=CH2), 3.69 (6H, s, 2x
OCH3), 3.62 (2H, dd, J = 13.2, 4.9 Hz, 2xCH2), 3.07 (6H, s, 2xNCH3),
3.01 (2H, dd, J = 13.2, 5.4 Hz, 2xCH2); 13C NMR (75 MHz, CDCl3) δ:
176.6 (2xCO), 155.7, 137.0, 132.6, 129.7, 119.0, 113.1, 110.7, 107.7
(ArC and CH=CH2), 56.3 (2xC), 55.9 (2xOCH3), 33.7 (2xCH2), 25.9 (2x
NCH3); MS (EI) m/z: 432 (M+, 11%), 217 (22), 216 (100), 174 (12);
HRMS (ESI): calcd. for C26H28N2O4: 432.2049; found 432.2061. Meso:
could not be isolated.
1,1'-Dibenzyl-3,3'-dimethyl-[3,3'-biindoline]-2,2'-dione (11c):[24] 34 mg
(48%, Method A), 33 mg (47% Method B); (R*,R*): yellow solid; mp 189-
190 °C (n-hexane/EtOAc); RF 0.70 (n-hexane/EtOAc 6:4); IR (neat) νmax
2970, 1697, 1606, 1371, 1181, 741, 694 cm-1; 1H NMR (300 MHz, CDCl3)
δ: 7.31–7.18 (10H, m, ArH), 7.05 (2H, d, J = 7.5 Hz, ArH), 6.94 (2H, td, J
= 7.7, 1.2 Hz, ArH), 6.66 (2H, td, J = 7.6, 1.0 Hz, ArH), 6.46 (1H, d, J =
7.6 Hz, ArH), 5.01, 4.68 (4H, 2xd, J = 15.6 Hz, 2xCH2), 1.84 (6H, s,
2xCH3); 13C NMR (75 MHz, CDCl3) δ: 178.6 (2xCO), 142.0, 135.8, 131.5,
128.8, 128.0, 127.7, 127.7, 123.7, 122.3, 108.7, 50.9 (2xC), 43.9 (2xCH2),
17.9 (2xCH3); MS (EI) m/z: 472 (M+, 3%), 238 (6), 237 (43), 236 (100),
235 (6), 91 (61); HRMS (ESI): calcd. for C32H28N2O2: 472.2151; found
472.2169. Meso: colorless oil; RF 0.50 (n-hexane/EtOAc 6:4); IR (neat)
νmax 1708, 1608, 1487, 1348, 1183, 731 cm-1; 1H NMR (300 MHz, CDCl3)
δ: 7.20–7.09 (10H, m, ArH), 6.99–6.91 (4H, m, ArH), 6.81 (2H, t, J = 7.5
Hz, ArH), 6.58 (2H, d, J = 7.7 Hz, ArH), 4.93, 4.65 (4H, 2xd, J = 15.9 Hz,
2xCH2), 1.80 (3H, s, 2xCH3); 13C NMR (75 MHz, CDCl3) δ: 178.2 (2xCO),
143.1, 135.9, 131.6, 128.7, 128.6, 127.3, 127.2, 124.1, 122.1, 109.4
(ArC), 51.5 (2xC), 44.0 (2xCH2), 18.8 (2xCH3); LRMS (EI) m/z: 472 (M+,
3%), 237 (38), 236 (100), 91 (58); HRMS (ESI): calcd. for C32H28N2O2:
472.2151; found 472.2169.
3,3'-Diallyl-1,1'-dibenzyl-[3,3'-biindoline]-2,2'-dione (11g):[24] 20 mg (26%,
Method A), 8 mg (13% Method B); (R*,R*): Pale yellow solid; mp 201-
202 °C (n-hexane/EtOAc); RF 0.70 (n-hexane/EtOAc 5:5); IR (neat) νmax
1696, 1606, 1485, 1366, 1178, 919, 753, 695 cm-1; 1H NMR (300 MHz,
CDCl3) δ: 7.31–7.18 (10H, m, ArH), 7.07 (2H, d, J = 8.3 Hz, ArH), 6.91
(2H, td, J = 7.7, 1.2 Hz, ArH), 6.70 (2H, td, J = 7.6, 1.0 Hz, ArH), 6.35 (2H,
d, J = 7.6 Hz, ArH), 5.12 (2H, d, J = 15.6 Hz, 2xCH2), 5.08–5.01 (4H, m,
2xHC=CH2), 4.85–4.75 (2H, m, 2xHC=CH2), 4.47 (2H, d, J = 15.6 Hz, 2x
CH2), 3.80–3.70 (2H, m, 2xCH2), 3.15–3.06 (2H, m, 2xCH2); 13C NMR
(75 MHz, CDCl3) δ: 177.2 (2xCO), 142.9, 135.6, 132.6, 128.7, 128.3,
128.2, 127.7, 127.6, 124.1, 122.1, 119.3, 108.6 (ArC and CH=CH2),
55.84 (2xC), 43.9 (2xNCH2), 34.2 (2xCCH2); MS (EI) m/z 524 (M+, 2%),
263 (54), 262 (83), 261 (4), 91 (100); HRMS (ESI): calcd. for C36H32N2O2:
524.2464; found 524.2470. Meso: could not be isolated.
1,1'-Dibenzyl-5,5'-dimethoxy-3,3'-dimethyl-[3,3'-biindoline]-2,2'-dione
(11d): 37 mg (46%, Method A), 24 mg (30% Method B); (R*,R*): yellow
plates; mp 193-194 °C (n-hexane/EtOAc); RF 0.70 (n-hexane/EtOAc 6:4);
IR (neat) νmax 2967, 1698, 1453, 1180, 1036, 730, 700 cm-1; 1H NMR
(300 MHz, CDCl3) δ: 7.29–7.22 (6H, m, ArH), 7.14 (4H, dd, J = 7.4, 2.0
Hz, ArH), 6.86 (2H, d, J = 2.5 Hz, ArH), 6.50 (2H, dd, J = 8.5, 2.6 Hz,
ArH), 6.32 (2H, d, J = 8.5 Hz, ArH), 5.07, 4.66 (4H, 2xd, J = 15.8 Hz, 2x
CH2), 3.58 (6H, s, 2xOCH3), 1.86 (6H, s, 2xCH3); 13C NMR (75 MHz,
3,3'-Diallyl-1,1'-dibenzyl-5,5'-dimethoxy-[3,3'-biindoline]-2,2'-dione (11h):
36 mg (40%, Method A), 18 mg (20% Method B); (R*,R*): red plates; mp
152-153 °C (n-hexane/EtOAc); RF 0.70 (n-hexane/EtOAc 5:5); IR (neat)
νmax 1697, 1494, 1434, 1198, 1043, 906, 727 cm-1; 1H NMR (300 MHz,
CDCl3) δ: 7.32-7.13 (10H, m, ArH), 6.84 (2H, d, J = 2.5 Hz, ArH), 6.48
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
(2H, dd, J = 8.5, 2.6 Hz, ArH), 6.23 (2H, d, J = 8.5 Hz, ArH), 5.18 (2H, d,
J = 15.7 Hz, 2xCH2), 5.13–5.04 (4H, m, 2xHC=CH2), 4.87–4.78 (2H, m,
2xHC=CH2), 4.45 (2H, d, J = 15.7 Hz, 2 x CH2), 3.82–3.70 (2H, m, 2x
CH2), 3.62 (6H, s, 2xOCH3), 3.11 (2H, dd, J = 15.4, 4.3 Hz, 2xCH2); 13C
NMR (75 MHz, CDCl3) δ: 176.9 (2xCO), 155.7, 136.3, 135.6, 132.6,
129.7, 128.7, 127.5, 127.4, 119.4, 113.0, 111.3, 109.3, 56.2 (2xC), 55.7
(2xOCH3), 43.9 (2xNCH2), 34.5 (2xCCH2); MS (EI) m/z: 584 (M+, 8%),
293 (33), 292 (96), 188 (13), 91 (100); HRMS (ESI): calcd. for
C38H36N2O4: 584.2675; found 584.2682. Meso: could not be isolated.
We gratefully acknowledge financial support from the Spanish
Ministerio de Ciencia, Innovación y Universidades (projects
CTQ2016-81893REDT, and RED2018-102387-T) the Spanish
Ministerio de Economía, Industria y Competitividad, Agencia
Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo
Regional (FEDER, EU) (projects CTQ2016-76782-P, CTQ2016-
80375-P and CTQ2017-82935-P), the Generalitat Valenciana
(PROMETEOII/2014/017), the University of Alicante, and
Gobierno de Aragón (Group E06_17R and project LMP148_18).
A. O.-M. thanks MINECO for a predoctoral fellowship.
See supporting information for additional details.
Keywords: deacylative alkylation • deacylative bromination •
bioxindoles • iridium • photoredox catalysis
Acknowledgments
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10.1002/ejoc.202000375
European Journal of Organic Chemistry
ARTICLE
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
3,3’-Bioxindoles, precursors of a wide
family of natural products, are
prepared via deacylative alkylation or
by photoredox catalysis. New
Cristina Moreno-Cabrerizo, Aitor
Ortega-Martínez, Miguel A.
Esteruelas, Ana M. López, Carmen
Nájera, José M. Sansano
deacylative bromination is reported.
Notes and references
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