Synthesis of Oxindoles and Benzofuranones via Oxidation of 2-Heterocyclic BMIDAs

Article abstract of DOI:10.1055/s-0035-1562619

The synthesis of functionalized oxindoles and benzofuranones via oxidation of 2-BMIDA indoles and benzofurans, respectively, is described. Interconversion of boron species (BMIDA→BF₃K) was necessary to enable oxidation and overcome boronic acid stability issues associated with a difficult BMIDA hydrolysis. Overall, a robust process was developed that allowed access to a small library of oxindole and benzofuranone products and facilitated the step-efficient synthesis of biologically active compounds containing the oxindole pharmaco-phore.

Full text of DOI:10.1055/s-0035-1562619

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
C. P. Seath et al.
Paper
Synthesis
Synthesis of Oxindoles and Benozfuranones via Oxidation of
2-Heterocyclic BMIDAs
Ciaran P. Seath
12 examples
up to 99% yield
R
BMIDA
R
O
BS
Ox
James W. B. Fyfe
John J. Molloy
X
X
• Controlled oxidation via interconversion of boron species
• Rapid access to bioactive heterocyclic templates
X = O, NTs
Allan J. B. Watson*
Department of Pure and Applied Chemistry, WestCHEM,
University of Strathclyde, 295 Cathedral St., Glasgow, G1
1XL, UK
allan.watson.100@strath.ac.uk
Received: 14.06.2016
Accepted after revision: 22.07.2016
Published online: 12.08.2016
preparation of oxindoles beginning from the corresponding
indole starting materials are comparatively limited,4 with
oxidative methods often suffering from the problem of
over-oxidation to deliver isatins (Scheme 1b).5 Hydrolysis of
2-oxyindoles gives the corresponding oxindoles; however,
this requires a pre-oxygenated indole as a starting material
(Scheme 1c).6 We recently disclosed a one-pot synthesis of
2-heterocyclic BMIDA derivatives,7 which are bench-stable,
free-flowing solids that can be stored indefinitely without
degradation.8 Here, we present the utility of 2-BMIDA in-
doles and benzofurans as readily accessible precursors to
oxindoles and benzofuranones, respectively, and the scope
and limitations of this process (Scheme 1d).
DOI: 10.1055/s-0035-1562619; Art ID: ss-2016-z0431-op
Abstract The synthesis of functionalized oxindoles and benzofura-
nones via oxidation of 2-BMIDA indoles and benzofurans, respectively,
is described. Interconversion of boron species (BMIDA→BF3K) was nec-
essary to enable oxidation and overcome boronic acid stability issues
associated with a difficult BMIDA hydrolysis. Overall, a robust process
was developed that allowed access to a small library of oxindole and
benzofuranone products and facilitated the step-efficient synthesis of
biologically active compounds containing the oxindole pharmacophore.
Key words boron, oxidation, heterocycles, lactams, lactones
a) Building the pyrrole nucleus
The oxindole motif is present in the core of numerous
biologically active natural products as well as pharmaceuti-
cals such as tenidap, coreulescine, and semaxanib (Figure
1).1 Consequently, numerous methods have been and con-
tinue to be developed to allow access to this privileged
chemotype.
b
Y
X
a
b
CO2H
NH2
O
N
N
H
O
H
a
b) C2-Oxidation of indole
[Ox]
O
O
O
N
H
N
H
N
Me
H
Me
S
N
OH
O
c) Hydrolysis of 2-oxyindoles
hydrolysis
Cl
Me
N
H
OR
O
O
O
N
N
N
N
H
H
H
N
H
NH2
O
d) This work: Brown-type oxidation via boron species interconversion
1) KHF2
2) Oxone®
tenidap
coerulescine
semaxanib
Figure 1 Pharmaceutically relevant oxindoles
O
BMIDA
N
N
R
R
Scheme 1 Methods for the synthesis of oxindoles
The most common synthetic approaches towards the
oxindole framework forge the pyrrole nucleus either via
disconnection at the amide C–N bond to provide a phenyl-
acetic acid precursor,2 or at the C-3 position to afford an an-
ilide precursor (Scheme 1a).3 Despite significant research,
Oxidation of 2-borylated indoles is limited to two single
examples using two specific 2-BPin indole substrates.9 This
class of compounds is generally difficult to access and han-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
C. P. Seath et al.
Paper
Synthesis
dle due to issues with protodeboronation.10 Consequently, a
BMIDA-based process would offer significant synthetic ad-
vantages due to the accessibility and stability of these orga-
noboron derivatives.8
DA→BF3K interconversion on this template was unknown.
Accordingly, we evaluated conversion of BMIDA 1 into the
BF3K derivative 5.
Our initial studies commenced with N-Ts-indole-2-BMIDA
1, using well-established Brown-type reaction conditions:
H2O2 in a range of solvent/water mixtures and in the pres-
ence of base (Scheme 2; see the Supporting Information for
full details).11
aq KHF2 (4.5 M), MeOH
70 °C, 4 h
BF3K
BMIDA
(a)
N
N
Ts
Ts
5: quant.
1
Oxone® (1.1 equiv), acetone
rt, 18 h
O
BF3K
(b)
N
N
Ts
Ts
H2O2 or Oxone®
3a: quant.
5
BMIDA
O
H
base
N
N
N
Ts
Ts
3a
Scheme 3 Conversion of BMIDA 1 into BF3K 5
Ts
1
4
[O]
PDB
B(OH)2
A short survey of reaction conditions revealed that 1
could be quantitatively converted into 5 upon treatment
with aq KHF2 in MeOH at 70 °C (Scheme 3a). In addition, 5
could be quantitatively converted into the desired oxindole
product 3a using Oxone. Combining these two events
proved to be straightforward (Table 1). Oxidation of inter-
mediate 5 was found to be sluggish in MeOH; however, a
solvent switch to acetone before addition of the oxidant
was more effective (entry 1 vs. entry 2). A short optimiza-
tion of reaction time and KHF2 stoichiometry (entries 2–5)
revealed that the overall two-step process could be com-
pleted in 6 hours by using 5 equivalents of KHF2 to facilitate
conversion into 5, ultimately delivering 99% conversion into
3a. Interestingly, whereas oxidation of the intermediate
BF3K 5 was facile with Oxone, NaBO3 and H2O2 were ineffec-
tive for oxidation of this intermediate (entries 6 and 7, re-
spectively).
N
Ts
2
Scheme 2 Attempted direct hydrolysis/oxidation of 2-BMIDA indole 1.
PDB = protodeboronation; MIDA = N-methyliminodiacetate
Based on the base lability of BMIDA and the well studied
slow or fast release of the parent boronic acid,10 we planned
an in situ hydrolysis of 1 to deliver 2 that would then be ox-
idized to deliver 3a. To our surprise, when using a base/oxi-
dant system of NaOH/H2O2 at room temperature (fast hy-
drolysis conditions), the BMIDA group remained intact, i.e.,
no hydrolysis was observed, even in the presence of excess
aqueous NaOH. In an attempt to drive the hydrolysis step,
the reaction mixture was heated to 50 °C with increasing
quantities of NaOH. However, although hydrolysis could be
induced, these reactions returned the protodeboronated
product 4 in quantitative yields in all cases, presumably due
to the sensitivity of 2 under these reaction conditions. At-
tempting to temper the reaction conditions by using a slow
hydrolysis protocol with either K3PO4 or K2CO3 in the pres-
ence of H2O2 returned starting material 1 only. Changing
the oxidant to Oxone had a small positive effect; hydrolysis
remained sluggish, requiring extended reaction times or el-
evated temperatures and, although trace quantities of 3a
were observed under these conditions, protodeboronation
product 4 dominated along with degradation of 3a.
These initial investigations highlighted a compatibility
issue between the conditions required to hydrolyze the
BMIDA unit and the stability of the intermediate boronic
acid (as well as the oxindole product). To overcome these is-
sues, we postulated that a simple boron species intercon-
version process might be achieved under mild reaction con-
ditions to deliver an organoboron derivative that could then
be oxidized under conditions sufficiently mild to inhibit
degradation of the organoboron intermediate or product. In
particular, BMIDA species can be converted into the potas-
sium organotrifluoroborate (BF3K) derivative under rela-
tively mild reaction conditions12 and BF3K species can also
be oxidized under mild conditions.13 However, BMI-
Table 1 Oxidation of Indole BMIDA via Speciation
i) aq KHF2 (4.5 M), MeOH
O
BMIDA
70 °C, x h
N
N
ii) Oxone® (1.1 equiv), acetone
rt, x h
Ts
Ts
3a
1
Entry
Conditions
3a (%)a
1
2
3
4
5
6
7
aq KHF2 (3 equiv), 2 h / Oxone, 18 hb
aq KHF2 (3 equiv), 2 h / Oxone, 18 hc
aq KHF2 (5 equiv), 2 h / Oxone, 18 hc
aq KHF2 (5 equiv), 4 h / Oxone, 18 hc
aq KHF2 (5 equiv), 4 h / Oxone, 2 hc
aq KHF2 (5 equiv), 4 h / NaBO3, 4 hc
aq KHF2 (5 equiv), 4 h / H2O2, 4 hc
27
44
92
99
99
0
0
a Determined by HPLC analysis against an internal standard.
b Oxidant added directly.
c Solvent switch to acetone before addition of oxidant.
With optimum conditions in hand, the scope of the re-
action was investigated by application to a range of substi-
tuted 2-BMIDA indole architectures (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
C. P. Seath et al.
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Synthesis
Table 2 Deprotection of N-Ts Oxindole 3a
i) aq KHF2 (4.5 M), MeOH
70 °C, 4 h
O
BMIDA
X
X
ii) Oxone® (1.1 equiv), acetone
rt, 2 h
conditions
O
O
3a–l
1
N
N
H
Ts
3a
6
O
O
N
O
N
N
Cl
6 (%)a
Ts
Me
Ts
Entry
Conditions
3a: 92%
3b: 54%
3c: 90%
3f: 66%
3i: 62%
1
2
3
4
5
6
6 M NaOH, 1,4-dioxane, r.t.
1 M NaOH, 1,4-dioxane, r.t.
1 M TBAF, THF, r.t.
0
0
F
Cl
Br
O
O
O
N
N
N
0
Ts
Ts
Ts
3d: 92%
3e: 90%
3h: 80%
Mg, MeOH, r.t.
0
MeO
O2N
F3CO
MeO2C
SmI2, pyrrolidine, H2O, r.t.
Na, naphthalene, –78 °C
0
O
O
O
O
90
N
N
N
Ts
Ts
Ts
a Isolated yield.
3g: 88%
F
O
O
To limit exposure to basic reaction conditions, we evalu-
ated several single-electron methods. Mg powder in MeOH
resulted in solvolysis of 3a.17b SmI2 conditions led to full
consumption of the starting material within five minutes of
addition; however, none of the desired oxindole was ob-
served, delivering only an unidentifiable mixture of prod-
ucts.18 Fortunately, application of sodium naphthalenide at
–78 °C led to clean conversion into the desired oxindole
product in 90% isolated yield.19
With effective conditions for the deprotection now
available, we were able to prepare several biologically ac-
tive products (Scheme 5 and Scheme 6). Both the natural
product (±)-coerulescine20 and kinase inhibitor semaxan-
ib21 could be quickly accessed via common oxindole 3a fol-
lowing tosyl deprotection (Scheme 5). From this common
intermediate, condensation with commercially available
pyrrole 7 afforded semaxanib in excellent yield, while C3
alkylation followed by ring expansion22 enabled access to
(±)-coerulescine in moderate overall yield. Although the di-
alkylation to form the cyclopropane proceeded with good
conversion (ca. 60%) based on NMR spectroscopic analysis,
the desired spirocycle 8 was found to be highly unstable on
silica, thereby limiting the yield of this process.
N
O
N
O
Ts
3j: 0% (42%)a
3k: 100%
3l: 98%
Scheme 4 Substrate scope of the oxidation process. Isolated yields. a
Determined by 1H NMR analysis.
The reaction was found to be tolerant of both electron-
donating and electron-withdrawing groups (3g, 3h, 3i). Ha-
logenated substrates were also effective, providing a syn-
thetic handle for further functionalization (3c–f). In addi-
tion, azaindoline 3j was delivered in moderate yield (42%)
based on by NMR spectroscopic analysis, with the mass bal-
ance consisting of the product of protodeboronation; how-
ever, this product was found to be labile to hydrolysis on
silica. The N-tosyl group could be replaced with a methyl
unit but this resulted in a decrease in the yield of the corre-
sponding oxindole 3b. Other N-protecting groups were not
assessed. Lastly, in addition to oxindoles, the oxidation pro-
cess was applicable to 2-BMIDA benzofurans to allow ac-
cess to benzofuranones 3k and 3l in excellent yields.
In keeping with our interests in medicinal chemistry,14
we sought to utilize the oxindole products as building
blocks in the synthesis of biologically active molecules. In
particular, the ubiquity of the oxindole motif in kinase drug
discovery15 led us to target compounds of this class. First
steps into derivatization of our oxindole products quickly
identified an issue with deprotection of the N-tosyl group.
Specifically, the lactam was found to be readily hydrolyzed
under both acidic and basic conditions.16 To our knowledge,
no methods exist for the deprotection of N-Ts-oxindole, al-
though sulfonamides have been removed from C3-substi-
tuted oxindoles by using several approaches.17 Accordingly,
we surveyed reaction conditions commonly used for sul-
fonamide cleavage; however, neither NaOH nor tetra-
butylammonium fluoride (TBAF) afforded any of the de-
sired product 6 (Table 2, entries 1–3);17d these conditions
all resulted in hydrolysis of the lactam at room tempera-
ture.
Tenidap, a potent COX inhibitor,23 was efficiently syn-
thesized in five steps from oxindole 3e (Scheme 6). Tosyl
deprotection gave the free oxindole 9, which, upon treat-
ment with phenyl chloroformate followed by ammonium
carbonate, gave oxindole 10 in 73% yield. Condensation
with 2-thiophenecarbonyl chloride and subsequent expo-
sure to ammonium carbonate afforded tenidap in excellent
yield.
In conclusion, we have reported a novel method for the
preparation of oxindoles from 2-BMIDA indoles. A boron
species (BMIDA→BF3K) interconversion was used to over-
come the instability of the intermediate indole 2-boronic
acid towards the conditions required for hydrolysis of an
unusually robust BMIDA species. The BF3K species was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
C. P. Seath et al.
Paper
Synthesis
ing potassium permanganate solution. Normal-phase flash chroma-
tography was carried out using ZEOprep 60 HYD 40–63 μm silica gel.
FTIR spectra were obtained with a Shimadzu IRAffinity-1 machine.
19F NMR spectra were obtained with either a Bruker AV 400 at 376
MHz or a Bruker DRX 500 at 471 MHz. 11B NMR spectra were ob-
tained with a Bruker AV 400 spectrometer at 128 MHz. 1H and 13C
NMR spectra were obtained with either a Bruker AV 400 at 400 MHz
and 100 MHz, respectively, or Bruker DRX 500 at 500 MHz and 126
MHz, respectively. Chemical shifts are reported in ppm and coupling
constants are reported in Hz with CDCl3 referenced at δ = 7.26 (1H)
and 77.0 ppm (13C) and DMSO-d6 referenced at δ = 2.50 (1H) and
39.5 ppm (13C). 11B NMR spectra are referenced to BF3·Et2O. High-res-
olution mass spectra were obtained through analysis at the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
Me
Me
Me
H
N
O
H
Me
N
N
7
H
O
R
O
3a: R = Ts
6: R = H, 90%
piperidine
N
Na/naph
EtOH, 80 °C
H
semaxanib
97%
1,2-dibromoethane
NaH, DMF
Me
N
Me
N
MeN
NMe
O
O
MgI2
THF
N
N
H
H
Synthesis of Oxidation Products (Scheme 4); General Procedure
(
)-coerulescine
8: 14%
An oven-dried 10 mL microwave vial was charged with R-BMIDA (0.1
mmol, 1 equiv) before the addition MeOH (4 mL). The vial was capped
before the addition of KHF2 (100 μL, 4.5 M aq. solution, 0.5 mmol, 5
equiv). The solution was then heated to 70 °C for 4 h, then cooled,
vented, decapped, and the MeOH solution was transferred to a clean
flask and concentrated under reduced pressure to provide a white
solid. The residue was diluted with hot acetone and the BF3K solution
was transferred to a 5 mL flask (2 × 2 mL acetone) and concentrated
under reduced pressure. The resulting residue was diluted with ace-
tone (0.5 mL) before the addition of Oxone (35 mg, 0.11 mmol, 1.1
equiv) in H2O (0.5 mL). The reaction was stirred for 2 h before the ad-
dition of 1 M HCl (2 mL). The reaction mixture was then diluted with
H2O (2 mL) and extracted with CH2Cl2 (2 × 5 mL). The organic layers
were filtered through 2 cm of silica gel and washed with CH2Cl2 (20
mL). The resulting solution was concentrated under vacuum to afford
the desired product.
55%
Scheme 5 Synthesis of semaxanib and (±)-coerulescine (isolated
yields)
i) PhCOCl, Et3N
THF, 0 °C
O
Cl
Cl
O
N
N
R
ii) (NH4)2CO3
DMF, 0 °C
O
PhO
10: 73%
3e: R = Ts
Na/naph
9: R = H, 80%
DMAP
DMF, 0 °C
COCl
S
HO
HO
S
S
Cl
Cl
(NH4)2CO3
DMF, 80 °C
1-Tosylindolin-2-one (3a)
O
N
O
Prepared according to the general procedure from (1-tosyl-1H-indol-
2-yl)boronic acid MIDA ester (43 mg).
N
O
O
H2N
PhO
Yield: 27 mg (92%); off-white amorphous solid.
IR (solid): 3092, 3058, 2962, 2947, 1768, 1595, 1478, 1465, 1377 cm–1
.
11 (not isolated)
tenidap: 75% (2 steps)
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.3 Hz, 2 H), 7.83 (d, J =
8.3 Hz, 1 H), 7.29–7.20 (m, 3 H), 7.13 (d, J = 7.4 Hz, 1 H), 7.06 (t, J =
7.5 Hz, 1 H), 3.47 (s, 2 H), 2.34 (s, 3 H).
Scheme 6 Synthesis of tenidap (isolated yields)
13C NMR (101 MHz, CDCl3): δ = 172.3, 145.2, 139.9, 134.8, 129.3,
128.1, 127.5, 124.2, 124.1, 122.7, 113.2, 35.6, 21.2.
HRMS (NSI): m/z [M + H]+ calcd for C15H14NO3S: 288.0689; found:
288.0690.
readily oxidized to the corresponding oxindole under mild
conditions, allowing one-pot access to oxindole products.
The scope of the reaction was evaluated by application to a
series of substrates and further exemplified in the context
of the synthesis of kinase inhibitors semaxanib and teni-
dap, and the natural product coerulescine.
1-Methylindolin-2-one (3b)
Prepared according to the general procedure from (1-methyl-1H-in-
dol-2-yl)boronic acid MIDA ester (29 mg).
Yield: 8 mg (54%); dark-green liquid.
IR (solid): 3060, 2924, 2855, 1698, 1614, 1496, 1470, 1370, 1349 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.31–7.26 (m, 1 H), 7.26–7.22 (m, 1 H),
7.05 (dd, J = 7.5, 0.9 Hz, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 3.52 (s, 2 H), 3.21
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.6, 144.7, 127.4, 123.8, 121.9,
107.6, 35.3, 25.7.
HRMS (NSI): m/z [M + H]+ calcd for C9H10NO: 148.0757; found:
148.0753.
All reagents and solvents were obtained from commercial suppliers
and used without further purification unless otherwise stated.
Where necessary, purification was carried out according to standard
laboratory methods.24 Reactions were carried out either using con-
ventional glassware (preparation of intermediates) or in capped 5 mL
microwave vials. Room temperature (rt) was generally ca. 18 °C. Reac-
tions were carried out at elevated temperatures by using a tempera-
ture-regulated hotplate/stirrer. Thin-layer chromatography was car-
ried out using Merck silica plates coated with fluorescent indicator
UV254. These were analyzed under 254 nm UV light or developed us-
.
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C. P. Seath et al.
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Synthesis
6-Chloro-1-tosylindolin-2-one (3c)
Yield: 28 mg (88%); light-brown amorphous solid.
IR (solid): 2950, 2924, 2855, 1757, 1601, 1483, 1470, 1372 cm–1
Prepared according to the general procedure from (6-chloro-1-tosyl-
.
1H-indol-2-yl)boronic acid MIDA ester (46 mg).
1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 8.3 Hz, 2 H), 7.82 (d, J =
9.0 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 2 H), 6.85 (dd, J = 9.0, 2.4 Hz, 1 H), 6.79
(s, 1 H), 3.79 (s, 3 H), 3.53 (s, 2 H), 2.42 (s, 3 H).
Yield: 29 mg (90%); white amorphous solid.
IR (solid): 2924, 2857, 1768, 1610, 1595, 1424, 1372, 1333, 1236 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.07–7.88 (m, 3 H), 7.35 (d, J = 8.1 Hz,
2 H), 7.14 (d, J = 1.1 Hz, 2 H), 3.52 (s, 2 H), 2.43 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 172.3, 146.0, 141.2, 135.0, 134.4,
.
13C NMR (101 MHz, CDCl3): δ = 172.7, 157.0, 145.6, 135.2, 133.8,
129.8, 127.9, 124.5, 114.5, 113.2, 111.2, 55.7, 36.5, 21.7.
HRMS (NSI): m/z [M + H]+ calcd for C16H16NO4S: 318.0795; found:
318.0796.
129.9, 128.1, 125.5, 125.4, 124.7, 121.5, 114.4, 35.7, 21.7.
HRMS (TOF): m/z [M + H]+ calcd for C15H13ClNO3S: 322.0305; found:
322.0304.
1-Tosyl-5-(trifluoromethoxy)indolin-2-one (3h)
Prepared according to the general procedure from (1-tosyl-5-(trifluo-
romethoxy)-1H-indol-2-yl)boronic acid MIDA ester (51 mg).
5-Fluoro-1-tosylindolin-2-one (3d)
Yield: 30 mg (80%); off-white amorphous solid.
IR (solid): 2958, 2928, 2857, 1761, 1601, 1480, 1374 cm–1
Prepared according to the general procedure from (5-fluoro-1H-
indol-2-yl)boronic acid MIDA ester (44 mg).
.
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 8.3 Hz, 2 H), 7.87 (d, J =
8.9 Hz, 1 H), 7.27 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 8.9 Hz, 1 H), 7.04 (s,
1 H), 3.51 (s, 2 H), 2.36 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 172.0, 146.0, 138.9, 135.0, 129.9,
128.1, 124.8, 121.6, 119.4, 118.2, 114.7, 36.1, 21.7. Trifluoromethyl
carbon not observed.
Yield: 28 mg (92%); off-white amorphous solid.
IR (solid): 3073, 2973, 2924, 1761, 1610, 1599, 1476, 1368 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.06–7.93 (m, 2 H), 7.88 (dd, J = 9.0,
4.5 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.04 (td, J = 9.0, 2.8 Hz, 1 H),
6.98–6.94 (m, 1 H), 3.55 (s, 2 H), 2.43 (s, 3 H).
.
13C NMR (101 MHz, CDCl3): δ = 172.3, 159.9 (d, JC–F = 244.0 Hz),
1
19F NMR (471 MHz, CDCl3): δ = –58.21.
HRMS (TOF): m/z [M + H]+ calcd for C16H12F3NO4S: 372.0517; found:
3
2
145.8, 135.1, 129.8, 128.0, 124.9 (d, JC–F = 8.6 Hz), 115.1 (d, JC–F
=
23.3 Hz), 114.9 (d, 3JC–F = 7.9 Hz), 112.4 (d, 2JC–F = 24.9 Hz), 36.2, 21.7.
19F NMR (471 MHz, CDCl3): δ = –117.57.
372.0527.
HRMS (TOF): m/z [M + H]+ calcd for C15H12FNO3S: 306.0600; found:
306.0602.
Methyl 2-Oxo-1-tosylindoline-5-carboxylate (3i)
Prepared according to the general procedure from (5-(methoxycar-
bonyl)-1-tosyl-1H-indol-2-yl)boronic acid MIDA ester (48 mg).
5-Chloro-1-tosylindolin-2-one (3e)
Yield: 22 mg (62%); white amorphous solid.
Prepared according to the general procedure from (5-chloro-1H-
indol-2-yl)boronic acid MIDA ester (46 mg).
IR (solid): 2956, 2924, 2855, 1766, 1711, 1623, 1601, 1483, 1450,
1374 cm–1
.
Yield: 29 mg (90%); white amorphous solid.
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.6 Hz, 1 H), 7.92 (d, J =
7.0 Hz, 3 H), 7.83 (s, 1 H), 7.27 (d, J = 8.2 Hz, 2 H), 3.84 (s, 3 H), 3.53 (s,
2 H), 2.36 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.9, 165.8, 145.6, 143.6, 134.4,
130.2, 129.4, 127.6, 126.1, 125.5, 122.8, 112.8, 51.8, 35.3, 21.3.
IR (solid): 2956, 2922, 1755, 1599, 1470, 1370, 1232 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.99–7.94 (m, 2 H), 7.86 (d, J = 8.8 Hz,
1 H), 7.36–7.29 (m, 3 H), 7.22–7.19 (m, 1 H), 3.55 (s, 2 H), 2.43 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 172.0, 145.9, 138.9, 135.0, 130.2,
129.8, 128.6, 128.0, 125.0, 124.9, 114.8, 35.9, 21.7.
HRMS (NSI): m/z [M + H]+ calcd for C15H13ClNO3S: 322.0299; found:
322.0302.
.
HRMS (NSI): m/z [M + H]+ calcd for C17H16NO5S: 346.0744; found:
346.0746.
Benzofuran-2(3H)-one (3k)25a
5-Bromo-1-tosylindolin-2-one (3f)
Prepared according to the general procedure from benzofuran-2-yl-
boronic acid MIDA ester (27 mg).
Prepared according to the general procedure from (5-bromo-1-tosyl-
1H-indol-2-yl)boronic acid MIDA ester (51 mg).
Yield: 14 mg (100%); white amorphous solid.
IR (solid): 2956, 2926, 1798, 1779, 1616, 1601, 1480, 1465, 1299 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.26–7.19 (m, 2 H), 7.06 (t, J = 7.5 Hz,
1 H), 7.03 (d, J = 8.0 Hz, 1 H), 3.66 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 173.6, 154.2, 128.4, 124.1, 123.6,
Yield: 24 mg (66%); light-brown amorphous solid.
IR (solid): 3088, 2958, 2924, 2854, 1757, 1599, 1469, 1455, 1375 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.01–7.96 (m, 2 H), 7.83 (d, J = 8.8 Hz,
1 H), 7.51–7.46 (m, 1 H), 7.39–7.33 (m, 3 H), 3.58 (s, 2 H), 2.45 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.4, 145.5, 138.9, 134.4, 131.0,
129.4, 127.5, 127.4, 124.7, 117.2, 114.7, 35.3, 21.3.
.
.
122.6, 110.3, 32.5.
HRMS (NSI): m/z [M + H]+ calcd for C15H13BrNO3S: 365.9794; found:
365.9798.
5-Fluorobenzofuran-2(3H)-one (3l)
Prepared according to the general procedure from (5-fluorobenzo-
furan-2-yl)boronic acid MIDA ester (29 mg).
5-Methoxy-1-tosylindolin-2-one (3g)
Yield: 15 mg (98%); white amorphous solid.
Prepared according to the general procedure from (5-methoxy-1H-
indol-2-yl)boronic acid MIDA ester (46 mg).
IR (solid): 3081, 2958, 2926, 2855, 1796, 1634, 1610, 1483, 1400,
1388 cm–1
.
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C. P. Seath et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.07–6.82 (m, 3 H), 3.69 (s, 2 H).
EtOAc (5 mL). The organic layers were then washed with H2O (2 × 5
mL) and brine (2 × 5 mL) and passed through a hydrophobic frit and
concentrated under vacuum before being purified (silica gel; EtO-
Ac/petroleum ether, 20–40%) to afford the desired product.
1
13C NMR (500 MHz, CDCl3): δ = 173.6, 159.4 (d, JC–F = 242.5 Hz),
150.6, 124.4 (d, 3JC–F = 9.5 Hz), 115.5 (d, 2JC–F = 24.3 Hz), 112.2 (d, 2JC–F
25.6 Hz), 111.7 (d, 3JC–F = 8.4 Hz), 33.5.
=
Yield: 23 mg (14%); red/brown amorphous solid.
IR (solid): 3200, 1701, 1684, 1671, 1627, 1474, 1357 cm–1
19F NMR (471 MHz, CDCl3): δ = –118.2.
HRMS (TOF): m/z [M + H]+ calcd for C8H5FO2: 153.0352; found:
.
153.0354.
1H NMR (400 MHz, CDCl3): δ = 8.34 (s, 1 H), 7.19 (t, J = 7.7 Hz, 1 H),
7.01 (t, J = 7.5 Hz, 1 H), 6.96 (d, J = 7.7 Hz, 1 H), 6.83 (d, J = 7.4 Hz, 1 H),
1.76 (d, J = 3.0 Hz, 2 H), 1.54 (d, J = 2.9 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 179.1, 140.6, 131.3, 126.7, 122.0,
118.6, 109.7, 27.4, 19.5.
Oxindole (6)25b
A 10 mL flask was charged with sodium metal (138 mg, 6 mmol, 60
equiv) and naphthalene (385 mg, 3 mmol, 30 equiv) before the addi-
tion of DME (5 mL) and the reaction mixture was stirred at r.t. for 30
min to form a blue/green solution. A solution of 1-tosylindolin-2-one
(28 mg, 0.1 mmol, 1 equiv) in DME (0.5 mL, 0.2 M) was cooled to
–78 °C and the Na-naphthalenide solution was then added dropwise
until an orange/red color persisted (1.5 mL). The solution was then
warmed to r.t. and further naphthalenide solution (0.5 mL) was add-
ed. The reaction was quenched with H2O (2 mL), and the mixture was
extracted with EtOAc (5 mL), and washed with brine (5 mL). The or-
ganic layers were then passed through a hydrophobic frit and concen-
trated under vacuum before being purified (silica gel; EtOAc–petro-
leum ether, 10–40%) to afford the desired product.
HRMS (NSI): m/z [M + H]+ calcd for C10H10NO: 160.0757; found:
160.0753.
Coerulescine
A 5 mL microwave vial equipped with a stirrer bar was charged with
spiro[cyclopropane-1,3′-indolin]-2′-one (20 mg, 0.125 mmol, 1 equiv)
and MgI2 (1.74 mg, 6.25 μmol, 5 mol%) before being capped and
purged with N2. THF (0.6 M, 0.2 mL) and trimethyl triazinane (18 μL,
0.125 mmol, 1 equiv) were then added and the reaction mixture was
heated to 125 °C in a sand-bath for 60 h. The reaction mixture was
then cooled to r.t. before being diluted with EtOAc (5 mL) and washed
with H2O (5 mL) and brine (5 mL). The organic layers were then
passed through a hydrophobic frit and concentrated under vacuum
before being purified (silica gel; EtOAc–petroleum ether, 50% then
MeOH–CH2Cl2, 20%) to afford the desired product.
Yield: 12 mg (90%); beige amorphous solid.
IR (solid): 3161, 1692, 1618, 1469, 1332 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.20 (s, 1 H), 7.24 (t, J = 7.4 Hz, 2 H),
7.05 (d, J = 7.5 Hz, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 3.57 (s, 2 H).
.
Yield: 14 mg (55%); pale-yellow oil.
IR (solid): 3192, 3060, 2943, 2787, 1707, 1619, 1472, 1336, 1195 cm–1
.
13C NMR (101 MHz, CDCl3): δ = 177.7, 142.1, 127.4, 124.8, 124.1,
121.8, 109.3, 35.8.
1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1 H), 7.41 (d, J = 7.3 Hz, 1 H),
7.19 (td, J = 7.7, 1.2 Hz, 1 H), 7.04 (td, J = 7.6, 1.0 Hz, 1 H), 6.89 (d, J =
7.7 Hz, 1 H), 3.11–3.00 (m, 1 H), 2.91 (s, 2 H), 2.88–2.74 (m, 1 H), 2.49
(s, 3 H), 2.41 (ddd, J = 12.5, 7.7, 4.7 Hz, 1 H), 2.12 (dt, J = 12.9, 7.5 Hz,
1 H).
13C NMR (101 MHz, CDCl3): δ = 182.7, 140.1, 136.0, 127.8, 123.4,
122.9, 109.5, 66.2, 56.7, 53.6, 41.8, 38.0.
Semaxanib
A 25 mL flask was charged with oxindole (133 mg, 1 mmol, 1 equiv)
and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (148 mg, 1.2 mmol, 1.2
equiv) before the addition of EtOH (0.5 M, 10 mL). Piperidine (12 μL,
0.01 mmol, 0.01 equiv) was then added and the flask was equipped
with a condenser before heating to reflux for 4 h. The reaction mix-
ture was then cooled to r.t. and concentrated under vacuum to afford
a red/orange solid. The precipitate was collected by filtration and
washed with chloroform to afford the desired product.
HRMS (NSI): m/z [M + H]+ calcd for C12H15N2O: 203.1179; found:
203.1177.
Yield: 230 mg (97%); red/orange amorphous solid.
5-Chloroindolin-2-one (9)
IR (solid): 3166, 3122, 2917, 2842, 1668, 1617, 1565, 1554, 1539,
To a 10 mL flask charged with sodium metal (83 mg, 3.6 mmol, 60
equiv) and naphthalene (231 mg, 1.8 mmol, 30 equiv) was added
DME (5 mL) and the reaction mixture was stirred at r.t. for 30 min to
form a blue/green solution. A solution of 5-chloro-1-tosylindolin-2-
one (20 mg, 0.06 mmol, 1 equiv) in DME (0.3 mL, 0.2 M) was cooled to
–78 °C and the Na-naphthalenide solution was then added dropwise
until an orange/red color persisted (1.5 mL). The solution was then
warmed to r.t. and further Na-naphthalenide solution (0.5 mL) was
added. The reaction was then quenched with H2O (2 mL), and the
mixture was extracted with EtOAc (5 mL), and washed with brine
(5 mL). The organic layers were then passed through a hydrophobic
frit and concentrated under vacuum before being purified (silica gel;
EtOAc–petroleum ether, 10–40%) to afford the desired product.
1463, 1455, 1340, 1316, 1204 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 13.12 (s, 1 H), 8.00 (s, 1 H), 7.49 (d, J =
7.6 Hz, 1 H), 7.40 (s, 1 H), 7.13 (td, J = 7.6, 1.2 Hz, 1 H), 7.05 (td, J = 7.6,
1.1 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 5.98 (d, J = 2.5 Hz, 1 H), 2.39 (s,
3 H), 2.34 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.8, 137.0, 136.9, 132.6, 127.1,
126.6, 125.6, 123.6, 121.5, 117.4, 112.7, 111.8, 109.2, 13.9, 11.6.
HRMS (NSI): m/z [M + H]+ calcd for C15H15N2O: 239.1179; found:
239.1177.
Spiro[cyclopropane-1,3′-indolin]-2′-one (8)
An oven-dried flask was charged with oxindole (133 mg, 1 mmol, 1
equiv) before the addition of anhydrous DMF (0.8 M, 1.25 mL) and di-
bromoethane (94 μL, 1.1 mmol, 1.1 equiv). The solution was then
cooled to 0 °C before the addition of NaH (60% dispersion in mineral
oil, 180 mg, 4.5 mmol, 4.5 equiv) portionwise over 20 min. The mix-
ture was then warmed to r.t. and stirred overnight, then the reaction
was quenched with H2O (3 mL) and the mixture was extracted with
Yield: 8 mg (80%); off-white amorphous solid.
IR (solid): 3159, 3047, 2960, 2926, 2855, 1699, 1621, 1478, 1379,
1316 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.20 (d, J = 11.5 Hz, 2 H),
6.80 (d, J = 8.1 Hz, 1 H), 3.54 (s, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
C. P. Seath et al.
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 175.5, 139.8, 127.0, 126.7, 125.9,
Step 2
124.1, 109.4, 35.0.
HRMS (NSI): m/z [M + H]+ calcd for C8H7ClNO: 168.0211; found:
168.0207.
To a solution of phenyl (E)-5-chloro-3-[hydroxy(thiophen-2-yl)meth-
ylene]-2-oxoindoline-1-carboxylate (12 mg, 0.03 mmol, 1 equiv) in
anhydrous DMF (0.15 M, 0.2 mL) was added ammonium carbonate
powder (3 mg, 0.03 mmol, 1 equiv). The resulting solution was then
stirred at 80 °C for 4 h, then the reaction mixture was cooled to r.t.
before being diluted with EtOAc (5 mL) and washed with H2O (5 mL).
The organic layers were then passed through a hydrophobic frit and
concentrated under vacuum before being purified (silica gel; MeOH–
CH2Cl2, 0–100%) to afford the desired product.
Phenyl 5-Chloro-2-oxoindoline-1-carboxylate (10)
Step 1: Synthesis of Phenyl 5-Chloro-2-[(phenoxycarbonyl)oxy]-1H-
indole-1-carboxylate
To a flask charged with 5-chloro-2-oxindole (1 g, 6 mmol, 1 equiv)
was added anhydrous THF (20 mL) followed by triethylamine (1.75
mL, 12.6 mmol, 2.1 equiv). The reaction mixture was cooled to 0 °C
before the dropwise addition of phenyl chloroformate (1.6 mL, 13.2
mmol, 2.2 equiv). The mixture was stirred at 0 °C for 1 h, the resulting
precipitate was then removed by filtration and the filter cake was
washed with THF (2 × 20 mL). The filtrate was concentrated under
vacuum to obtain a pink solid which was stirred in H2O (20 mL) to
form an emulsion, which was then filtered, washed with H2O (2 × 20
mL), and dried by drawing air through the filter cake to afford the de-
sired product phenyl 5-chloro-2-((phenoxycarbonyl)oxy)-1H-indole-
1-carboxylate (2.4 g crude weight) as a white solid. The product was
used directly in the next step without further purification.
Yield: 9 mg (75% over two steps); yellow amorphous solid.
IR (solid): 3330, 2254, 1694, 1627, 1595, 1571, 1457, 1424 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 9.35 (s, 1 H), 8.59 (d, J = 3.3 Hz,
1 H), 8.16 (d, J = 1.8 Hz, 1 H), 8.01 (d, J = 8.5 Hz, 1 H), 7.59 (d, J =
4.9 Hz, 1 H), 7.11–7.04 (m, 2 H), 6.79 (dd, J = 8.5, 2.3 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 176.8, 165.7, 154.7, 149.1, 132.0,
130.1, 129.5, 129.1, 126.9, 126.0, 118.3, 117.3, 113.9, 94.3.
HRMS (NSI): m/z [M + H]+ calcd for C14H10ClN2O3S: 321.0095; found:
321.0099.
Step 2
Acknowledgment
A solution of phenyl 5-chloro-2-[(phenoxycarbonyl)oxy]-1H-indole-
1-carboxylate (1.11 g, 2.75 mmol, 1 equiv) in anhydrous DMF (10 mL)
was cooled to 0 °C, followed by the portionwise addition of ammoni-
um carbonate powder (300 mg, 3.16 mmol, 1.15 equiv). The resulting
solution was stirred for 1 h at 0 °C. Upon consumption of the starting
material, the pale-yellow solution was then poured into ice water (30
mL) to provide a white precipitate. The suspension was then stirred
for 30 min before being filtered, washed with H2O (2 × 10 mL) and
dried by pulling air through the filter cake to afford the desired prod-
uct 10.
We thank the Carnegie Trust for a PhD studentship (CPS) and the
EPSRC UK National Mass Spectrometry Facility at Swansea University
for analyses.
Supporting Information
Optimization data, and 1H and 13C NMR spectra for all new com-
pounds. Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562619.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Yield: 585 mg (73% over two steps); white amorphous solid.
IR (solid): 3137, 3060, 2956, 2932, 1770, 1737, 1595, 1478 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 8.7 Hz, 1 H), 7.47 (t, J =
7.9 Hz, 2 H), 7.37–7.29 (m, 5 H), 3.80 (s, 2 H).
References
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288.0423.
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Step 1: Synthesis of Phenyl (E)-5-Chloro-3-[hydroxy(thiophen-2-
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To a 50 mL flask charged with phenyl 5-chloro-2-oxoindoline-1-car-
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H