Regioselective Synthesis of Dihydro-1 H -furo[ b ]indol-1-ones and Their Carbanionic Reactivity

Article abstract of DOI:10.1055/s-0037-1610439

A general synthesis of 3,4-dihydro-1 H -furo[ b ]indol-1-ones, representing a furanone-fused pyrrole unit, has been developed. The dehydrohalogenative cyclization of 4-aminofuranones was achieved by reaction with Pd(OAc) ₂ and DABCO in DMF. The corresponding N-protected indolones undergo alkylation at C3.

Full text of DOI:10.1055/s-0037-1610439

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
S. Jana et al.
Paper
Synthesis
Regioselective Synthesis of Dihydro-1H-furo[b]indol-1-ones and
Their Carbanionic Reactivity
Supriti Jana
O
O
Pd(OAc)2 (5 mol%)
DABCO, DMF
X
Mausumi Bandyopadhyay
R
O
R
O
Dipakranjan Mal*
0
0
0
0
0-
0
0
1
6-
6
3
4
9-
9
3
2
N
120 °C
29–67%
N
H
H
Department of Chemistry, Indian Institute of Technology
Kharagpur, 721302 India
dmal@chem.iitkgp.ernet.in
X = Br, I
R = alkyl, halo, ester
6 examples
Received: 23.04.2018
Accepted after revision: 28.05.2018
Published online: 10.07.2018
HO2C
DOI: 10.1055/s-0037-1610439; Art ID: ss-2018-t0277-op
HO
O
O
Abstract A general synthesis of 3,4-dihydro-1H-furo[b]indol-1-ones,
representing a furanone-fused pyrrole unit, has been developed. The
dehydrohalogenative cyclization of 4-aminofuranones was achieved by
reaction with Pd(OAc)2 and DABCO in DMF. The corresponding N-pro-
tected indolones undergo alkylation at C3.
O
N
H
O
O
O
OH
1
2
3
O
S
Key words γ-lactone-fused heterocycles, furoindolones, regioselec-
tivity, carbanions
O
N
H
O
O
4
5
Phthalides, a class of bicyclic heterocycles featuring a γ-
lactone fused with an aromatic ring, are common structural
motifs of numerous natural products and synthetic materi-
als. Many of these compounds possess useful medicinal
properties. For example, butylphthalide (1, Figure 1) is a
marketed drug used as an antiplatelet drug for ischemic ce-
rebral apoplexy. More importantly, phthalides have been
used as key intermediates for the synthesis of compounds
such as phthalans, isoindolinones, carbazoles, anthraqui-
nones, tetracenes, and lignans.1 A wide range of natural
products with broad, potent, and potentially path-pointing
biological activities possess a 3-substituted phthalide core.
For example, natural products like isochracinic acid, paeci-
locin A, and herbaric acid (2), which possess such a core,
have antibacterial, antifungal, and antibiotic activity.2
Therefore, the development of efficient synthetic proce-
dures for the facile construction of phthalides and their an-
alogues is an important activity in organic synthesis.
Figure 1 Some examples of important γ-lactones
lar azomethine ylide cycloaddition afforded 3 in only 5%
yield.3a Thiolactone-fused furan 4 was synthesized by cyclo-
condensation of benzylic-type thiols at the ortho position of
furancarboxylic acids.3b However, the involvement of unsta-
ble intermediates and low overall yields limit further devel-
opment as a general synthetic method.
In connection with our carbazole work, where we have
reported the total synthesis of several carbazole alkaloids
including calothrixin B, ekeberginine, clausamine E, clau-
lansine D, clausevatine D, and clausamine C,4 we embarked
upon the synthesis of furoindol-3-one 5. More interestingly,
we have developed a short synthesis of calothrixin B by the
reaction of furoindolone 5 and bromoquinoline. On the
contrary, the chemistry of the isomeric indolones, namely
those based on 3,4-dihydro-1H-furo[3,4-b]indol-1-one (6),
has not been investigated because of the problems of fusion
of a furanone to a pyrrole unit.3c Herein, we report a facile
synthesis of such furoindolones by dehydrohalogenative cy-
clization of 4-aminofuranones which are readily accessible
from anilines.
Quite strikingly, the chemistry of the heterocyclic ana-
logues of phthalides has not been studied in detail. Progress
in the synthesis of γ-lactones fused with a five- or six-
membered-ring heterocycle has been hindered due to diffi-
culties in constructing the γ-lactones. DeShong and Sidler’s
approach to the pyrrole-fused γ-lactone 3 by intramolecu-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
S. Jana et al.
Paper
Synthesis
O
O
O
O
AcOH
reflux
EtOH
reflux
concd. H2SO4
82%
O
O
O
O
+
NHNH2
15%
85%
HO
PhNHNH
N
OH
NH2
H
7
8
9
10
6
Scheme 1 Synthesis of furoindolone 6 using the Fischer indolization of 9
Our initial attempts were centered on the Fischer indol-
ization of compound 9 (Scheme 1) which was prepared
from tetronic acid (8) and phenylhydrazine (7) in 85% yield
following a literature procedure.5,6 On treatment of 9 with
concentrated H2SO4 at 0 °C, a new compound 10 was
formed in 82% yield.7 Attempted ring closure of the com-
pound 10 in acetic acid under reflux provided the desired
product 6 in only 15% yield. Further improvement in the
yield of furoindolone 6 could not be achieved, even though
various acid catalysts were examined.
Alternatively, lactonization of the indole derivative ethyl
2-(bromomethyl)-1-(phenylsulfonyl)-1H-indole-3-carbox-
ylate (11) was considered (Scheme 2). Heating compound
11 in DMSO–water provided compound 12.8 All attempts to
obtain the desired furoindolone 13 failed.
tion9 of 1410 to furoindolone 6; however, none furnished
the desired cyclized product 6.11
In an alternative approach, we considered the cycliza-
tion of bromo derivative 15,13 because intramolecular cy-
clization of aromatic compounds is known in the literature.
Various attempts were made to cyclize intermediate 15 to
furoindolone 6.12 None of these attempts14 successfully
gave 6.
Following the above failures, we thought to juxtapose
the halide from the lactone ring to the aromatic ring. To this
end, we synthesized intermediates 18 from o-haloanilines
16 by reaction with 17 (Scheme 4). The precursors 18a and
18b were treated separately with the reagents Pd(OAc)2 (5
mol%) and DABCO in DMF at 120 °C. Very interestingly, both
substrates 18a and 18b provided the desired furoindolone
6. The reaction was faster with the iodo derivative 18b.
Similar conditions were utilized by Chen and co-workers
for the preparation of indoles; however, no lactonic com-
pounds were synthesized. According to the Chen annula-
tion,15 if o-iodoaniline (16a) is reacted with tetronic acid (8)
under the previous coupling reaction conditions, com-
pound 6 could be synthesized in one step. But, when o-io-
doaniline (16a) was treated with tetronic acid (8), Pd(OAc)2,
and DABCO in DMF at 105 °C for 3 to 36 hours, unfortunate-
ly both the starting materials were recovered. There was no
indication of the formation of compound 6.
O
CO2Et
CO2Et
DMSO–H2O
Br
OH
70–80 °C
O
N
N
76%
N
SO2Ph
SO2Ph
SO2Ph
11
12
13
Scheme 2 Synthesis of precursors 11 and 12 for lactonization to fu-
roindolone 13
Next, we considered intramolecular dehydrogenative
cyclization or intramolecular dehydrohalogenative cycliza-
tion for the synthesis of furoindolone 6 (Scheme 3). Several
reagent systems were examined for the oxidative cycliza-
The probable course of the cyclization reaction is relat-
ed to the palladium-catalyzed aromatic substitution known
as the Mizoroki–Heck reaction. As illustrated in Scheme 5,
O
O
O
Br
reagents/catalyst
reagents/catalyst
solvent, base
O
O
O
N
N
solvent, base
H
N
H
H
14
6
15
Scheme 3 Precursors (arylamino)butyrolactones 14 and 15 for attempted intramolecular dehydrogenative or dehydrohalogenative cyclization11,12
O
O
NH2
X
AcOH, benzene
reflux, 2 h
Pd(OAc)2 (5 mol%),
DABCO
O
O
O
X
O
+
Cl
OEt
N
H
DMF, 120 °C
N
H
16
17
18
6
when starting material
16a, X = Br, 85%
16b, X = I, 89%
when starting material
18a, X = Br, 48 h, 52%
18b, X = I, 6 h, 64%
X= Br, I
Scheme 4 Successful synthesis of furoindolone 6 by intramolecular Mizoroki–Heck-type cyclization
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
S. Jana et al.
Paper
Synthesis
the reaction presumably proceeds by oxidative addition of
the aryl halide 18 to an in situ produced palladium(0) spe-
cies forming 19, followed by insertion of the double bond in
the enaminone system into the o-aryl–palladium bond (via
20); then, with the loss of a palladium hydride species from
21 by β-elimination, the desired product 6 is obtained. The
palladium hydride species collapses, with a base (DABCO)
used to regenerate the palladium(0) catalyst.
reluctant to undergo the condensation with 17. 4-Amino-3-
iodobenzoic acid (16h′) was not suitable for this reaction;
after treating it with 17, we recovered the starting aniline
16h′. But, very interestingly, when the carboxylic acid
group was esterified and methyl 4-amino-3-iodobenzoate
(16e′) was used as starting material, the desired product
22e was formed in 76% yield.
After the successful synthesis of the five precursors
22a–e for furoindolones 6′, we treated each precursor with
Pd(OAc)2 and DABCO in DMF at 120 °C, and the results are
presented in Scheme 7. 7-Methyl-3,4-dihydro-1H-furo[3,4-
b]indol-1-one (6a) was obtained in 67% yield, when 22a
was subjected to cyclization. The other precursors 22b–e
were also suitable for cyclization, giving the desired prod-
ucts 6b–e in moderate to good yields. The poor yield (29%)
of bromoindolone 6d is due to debromination of product 6d
en route to 6. When the reaction was allowed to undergo to
completion, only the debrominated furoindolone 6 was ob-
tained as the sole product in 62% yield.
X
X
O
O
O
O
O
O
Pd(II)
Pd(0)
Pd
X
Pd
N
H
N
H
N
H
18
19
20
O
O
HPdX
H
O
O
X = Br, I
N
H
N
H
PdX
21
6
Scheme 5 Proposed mechanism of the catalytic cyclization16
O
O
I
Pd(OAc)2 (5 mol%),
DABCO
R
O
R
O
Considering that o-iodoanilines 16 are broadly available
chemicals, we prepared a few o-iodoanilines 16 following
some literature procedures.17 To generalize the methodolo-
gy, we first synthesized the precursors 22 for the coupling
reaction. With the optimized conditions, the scope of the
reaction for various (arylamino)butyrolactones 22 was in-
vestigated, and the results are summarized in Scheme 6.
The R group in 22 can be methyl, dimethyl, chloro, bromo,
or ester.
N
H
DMF, 120 °C
N
H
22
6'
O
O
O
O
N
N
H
H
6a (67%)
6b (63%)
O
O
O
Cl
MeO2C
Br
NH2
O
O
O
O
I
O
O
O
AcOH, benzene
reflux, 2 h
I
R
R
Cl
N
H
N
+
OEt
N
N
H
22
H
H
6c (56%)
6d (29%)
6e (66%)
16
17
16f': R = 4-OH
Scheme 7 Substrate scope of the reaction towards furoindolones 6′
16a': R = 4-Me
16b': R = 2,4-(Me)2 16g': R = 4-OMe
16c': R = 4-Cl
16d': R = 4-Br
16e': R = 4-CO2Me
22a: R = 4-Me (83%)
22b: R = 2,4-(Me)2 (86%)
22c: R = 4-Cl (81%)
16h': R = 4-CO2H
16i': R = 4-NO2
As a cursory experiment, compound 6 was protected as
its N-methyl derivative and the resulting furoindolone 23
was subjected to reaction with LiHMDS followed by MeI
(Scheme 8). Methylated product 24 was obtained in 85%
yield, suggesting the formation of a carbanion of the pro-
tected furoindolone 23.
The reactivity of the furo[b]indolones 6′ towards anion-
ic annulations is currently being evaluated in our laboratory
and the results will be reported in due course.
In conclusion, a general synthesis of 3,4-dihydro-1H-fu-
roindolones in overall good yields has been developed. The
key step of the methodology is an intramolecular C–X (X =
Br, I) cross-coupling reaction catalyzed by Pd(OAc)2. Studies
are underway to explore the annulation18 reactivity of the
furoindolones 6′ with acrylates under anionic conditions.
22d: R = 4-Br (79%)
22e: R = 4-CO2Me (76%)
Scheme 6 Substrate scope of the reaction towards the intermediates 22
(Methylphenylamino)furanone 22a was obtained in 83%
yield when 2-iodo-4-methylaniline (16a′) was reacted with
ethyl 4-chloroacetoacetate (17). 2-Iodo-4,6-dimethylaniline
(16b′) also reacted smoothly with 17 and furnished 22b in
86% yield. Likewise, (4-chlorophenylamino)furanone 22c
was isolated in 81% yield, when 4-chloro-2-iodoaniline
(16c′) was subjected to the reaction with 17. 4-Bromo-2-
iodoaniline (16d′) underwent the condensation reaction
with 17 to produce (4-bromophenylamino)furanone 22d in
79% yield. 4-Hydroxy-2-iodoaniline (16f′), 2-iodo-4-me-
thoxyaniline (16g′), and 2-iodo-4-nitroaniline (16i′) were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
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Synthesis
O
O
O
NaH, MeI
LiHMDS, MeI
THF, 0 °C to r.t.
THF, –78 °C to r.t.
O
O
O
72%
85%
N
H
N
N
6
23
24
Scheme 8 Carbanionic reactivity of furoindolone 6
3-(2-Aminophenyl)-4-hydroxyfuran-2(5H)-one (10)
Melting points were determined in open-end capillary tubes on a
melting point Sunsim apparatus and are uncorrected. Solvents were
dried and distilled following standard procedures. TLC was carried
out on precoated plates (silica gel 60, GF254), and the spots were vi-
sualized with UV and fluorescent lights. Column chromatography was
performed on silica gel (60–120 or 230–400 mesh). 1H and 13C NMR
spectra were recorded at 400/600 and 100/150 MHz, respectively, on
Bruker Avance spectrometers. IR spectra were recorded on a Spec-
trum BX FT-IR instrument from Perkin Elmer using KBr pellets. A
Waters XEVO-G2QTOF mass analyzer type ‘TOF MS ES+’ was used for
recording HRMS data. The phrase ‘usual workup’ refers to washing of
the organic phase with water (2 × 1/3 the volume of the organic
phase) and brine (1 × 1/4 the volume of the organic phase), drying
(anhydrous Na2SO4), filtration, and concentration under reduced
pressure.
To cold concd H2SO4 (10 mL), phenylhydrazino derivative 9 (1 g, 5.25
mmol) was added in portions and the mixture was then allowed to
stand in a freezer overnight. The reaction mixture was then neutral-
ized with saturated NaHCO3 solution (17 mL). The floating solid was
filtered and the filtrate was extracted with EtOAc (3 × 10 mL). After
usual workup of the extract, the resulting residue was combined with
the solid and was recrystallized (EtOAc/hexane) to give 10 (0.82 g,
82% yield) as a pink solid; mp 227–229 °C.
IR (KBr): 3334, 3186, 1693, 1639, 1596, 1455, 1350, 1045, 988, 775
cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 6.99 (t, J = 8.3 Hz, 2 H), 6.78 (s, 1 H),
6.72 (d, J = 7.8 Hz, 1 H), 6.59 (t, J = 7.4 Hz, 1 H), 4.80 (s, 2 H), 4.67 (s, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 173.9, 164.0, 145.8, 130.5, 127.4,
116.4, 115.4, 91.2, 79.2, 66.3.
3,4-Dihydro-1H-furo[3,4-b]indol-1-one (6)
HRMS (ES+): m/z calcd for C10H10NO3 [M + H]+: 192.0661; found:
192.0659.
A solution of compound 10 (0.4 g, 2.1 mmol) in 10 mL acetic acid was
heated at about 100 °C for 4.5 h. It was then neutralized with NaHCO3.
The obtained solid was filtered and the filtrate was extracted with
EtOAc (3 × 10 mL). After usual workup of the extract, the resulting
residue was mixed with the previously obtained solid and was chro-
matographed (hexanes/EtOAc, 3:1) to obtain 6 (55 mg, 15% yield) as a
light brown solid; mp 188–190 °C.
(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)methanol (9a′, Figure 2)
Compound 9 (0.50 g, 2.63 mmol) and PTSA·H2O (1.1 g, 5.8 mmol)
were dissolved in ethanol (20 mL) and the solution was heated under
reflux until 9 was consumed, as determined by TLC. The reaction
mixture was cooled to r.t., diluted with Et2O, and neutralized with
aqueous NaHCO3. The aqueous layer was extracted with Et2O (3 × 10
mL), and combined organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. Purification of the crude product by flash
column chromatography (EtOAc/hexanes, 1:9) gave 9a′ (315 mg, 55%
yield) as a gummy liquid.
IR (KBr): 3319, 1718, 1510, 1451, 1325, 1243, 1041, 989, 958, 769,
757, 679, 658 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.09 (s, 1 H), 7.71–7.65 (m, 1 H),
7.58 (d, J = 8.1 Hz, 1 H), 7.29 (ddd, J = 8.3, 7.2, 1.4 Hz, 1 H), 7.22 (td,
J = 7.5, 1.2 Hz, 1 H), 5.39 (s, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 166.3, 160.0, 142.3, 123.2, 121.6,
120.6, 118.9, 113.3, 105.3, 64.7.
IR (KBr): 3343, 2930, 1665, 1534, 1437, 1320, 1222, 658 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.67 (d, J = 8.0 Hz, 2 H), 7.45 (t,
J = 7.8 Hz, 2 H), 7.27 (t, J = 7.5 Hz, 1 H), 5.84 (s, 1 H), 5.08 (br s, 1 H),
4.38 (s, 2 H), 4.20 (q, J = 7.1 Hz, 2 H), 1.37 (t, J = 7.1 Hz, 3 H).
HRMS (ES+): m/z calcd for C10H8NO2 [M + H]+: 174.0555; found:
174.0559.
13C NMR (101 MHz, DMSO-d6): δ = 154.4, 153.1, 138.5, 128.9, 125.8,
121.2, 85.5, 67.9, 58.1, 14.4.
HRMS (ES+): m/z calcd for C12H13N2O [M + H – H2O]+: 201.1028;
found: 201.1021.
4-(2-Phenylhydrazinyl)furan-2(5H)-one (9)
A mixture of tetronic acid (8) (2 g, 19.98 mmol) and phenylhydrazine
(7) (1.96 mL, 19.98 mmol) in dried EtOH (100 mL) was heated at 70 °C
for 2 h; the reaction mixture was concentrated to half-volume, and
allowed to stand to give a solid. This was further crystallized (EtOH)
to furnish compound 9 (3.22 g, 85% yield) as a red solid; mp 126–
128 °C.
IR (KBr): 3301, 1703, 1621, 1483, 1156, 1024, 761 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.20 (br s, 1 H), 8.02 (s, 1 H), 7.19 (t,
J = 7.8 Hz, 2 H), 6.79–6.72 (m, 3 H), 4.76 (s, 2 H), 4.53 (br s, 1 H).
HO
N
.
N
Ph
OEt
9a'
13C NMR (101 MHz, DMSO-d6): δ = 174.3, 170.1, 147.8, 129.0, 119.4,
Figure 2
112.4, 80.2, 65.4.
HRMS (ES+): m/z calcd for C10H11N2O2 [M + H]+: 191.0821; found
191.0815.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Synthesis
5-Ethoxy-1-phenyl-1H-pyrazole-3-carbaldehyde (9b′, Figure 3)
the reaction mixture was stirred at r.t. overnight. When the reaction
was completed (checked by TLC), water was added to the reaction
mixture and acetone was evaporated in vacuo. Next, the mixture was
extracted with EtOAc, and the organic layers were washed with water,
dried over Na2SO4, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (EtOAc/hexanes, 5:1) to
afford 10b′ (102.5 mg, 90% yield) as a white solid; mp 163–165 °C.
Compound 9a′ (20 mg, 0.092 mmol) was reacted with freshly pre-
pared PCC (40 mg, 0.2 mmol) in dried CH2Cl2 (7 mL), and the reaction
mixture was allowed to stir at r.t. overnight. Then, silica gel was add-
ed to the mixture and flash column chromatography (hexanes/EtOAc,
5:1) was done to afford DNP-active, yellowish solid compound 9b′ (19
mg, 95% yield); mp 178–180 °C.
IR (KBr): 2945, 2743, 1836, 1728, 1647, 1563, 1423, 1176, 773 cm–1
.
IR (KBr): 3303, 2936, 1696, 1628, 1593, 1457, 1350, 1201, 1058, 990,
776 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.89 (s, 1 H), 7.75 (d, J = 7.9 Hz, 2 H),
7.48 (t, J = 7.8 Hz, 2 H), 7.36 (t, J = 7.4 Hz, 1 H), 6.16 (s, 1 H), 4.21 (q,
J = 7.0 Hz, 2 H), 1.46 (t, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 187.3, 155.8, 150.4, 138.2, 129.2,
127.7, 122.8, 84.7, 68.6, 14.6.
1H NMR (400 MHz, CDCl3): δ = 7.79 (dd, J = 8.0, 1.6 Hz, 1 H), 7.25 (d,
J = 5.6 Hz, 1 H), 7.08 (dd, J = 7.8, 6.0 Hz, 2 H), 6.17 (s, 1 H), 4.70 (s, 2 H),
2.69 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 174.6, 162.0, 149.4, 131.1, 127.8,
125.1, 122.7, 117.8, 95.9, 66.2, 43.1.
HRMS (ES+): m/z calcd for C12H13N2O2 [M + H]+: 217.0977; found:
217.0969.
HRMS (ES+): m/z calcd for C12H14NO3 [M + H]+: 220.0974; found:
220.0967.
CHO
N
O
O
N
Ph
N
OH
OEt
9b'
10b'
Figure 3
Figure 5
N-(2-(4-Hydroxy-2-oxo-2,5-dihydrofuran-3-yl)phenyl)acetamide
(10a′, Figure 4)
Ethyl 2-(Hydroxymethyl)-1-(phenylsulfonyl)-1H-indole-3-carbox-
ylate (12)
Compound 10 (50 mg, 0.26 mmol) was treated with Et3N (0.2 mL) and
acetyl chloride (0.2 mL, 2.6 mmol) with a pinch of DMAP in 12 mL
dried acetone. The reaction mixture was allowed to stir at 0 °C to r.t.
for 5–6 h. After reaction completion, acetone was evaporated, and the
remainder was extracted with water and EtOAc. The organic layer was
further washed with water and dried over Na2SO4, and the solvent
was evaporated. The crude residue was chromatographed (hex-
anes/EtOAc, 6:1) to furnish 10a′ (55.7 mg, 92% yield) as a white solid;
mp 170–172 °C.
A mixture of compound 11 (1 g, 2 mmol), DMSO (25 mL), and water (5
mL) was heated at 70–80 °C with stirring for 10–12 h. Then, it was
cooled, poured into water (250 mL), and extracted with Et2O (4 × 25
mL), and the combined extract was subjected to the usual workup.
The resulting solid was crystallized (CH2Cl2/petroleum ether) to give
12 (0.65 g, 76% yield) as a white solid; mp 99–101 °C.
IR (KBr): 3496, 1692, 1381, 1209, 1178, 1093, 994 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 8.21–8.17 (m, 1 H), 8.05 (m, 1 H), 7.97–
7.92 (m, 2 H), 7.58–7.24 (m, 5 H), 5.38 (d, J = 6.0 Hz, 2 H), 4.44 (ABq,
J = 7.2 Hz, 2 H), 3.7 (br s, 1 H), 1.44 (t, J = 7.2 Hz, 3 H).
IR (KBr): 3431, 3286, 1665, 1593, 1434, 1323, 1145, 725 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.87 (br s, 1 H), 7.89 (d, J = 8.1 Hz, 1
H), 7.27–7.18 (m, 2 H), 7.10 (t, J = 7.5 Hz, 1 H), 7.05 (br s, 1 H), 4.71 (s,
2 H), 2.00 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 174.1, 168.1, 165.3, 136.4, 130.5,
126.9, 123.8, 123.1, 90.4, 66.7, 24.0.
Ethyl 2-Formyl-1-(phenylsulfonyl)-1H-indole-3-carboxylate (12a′,
Figure 6)
To a stirred solution of compound 12 (0.5 g, 1.45 mmol) in dried CH2-
Cl2 (50 mL), PCC (1.24 g, 5.79 mmol) was added. After overnight stir-
ring, the reaction mixture was filtered. The filtrate was concentrated
and dissolved in Et2O (50 mL). The ether layer was washed repeatedly
with water (5 × 10 mL) and, after usual workup, gave a solid which
was chromatographed (hexanes/EtOAc, 5:1) to give 12a′ (0.31 g, 60%
yield) as an off-white solid; mp 79–81 °C.
HRMS (ES+): m/z calcd for C12H11NO4 [M + H]+: 233.0688; found:
233.0693.
O
O
IR (KBr): 2977, 2889, 1713, 1679, 1533, 1368, 1230, 1177, 1085 cm–1
.
NH
OH
1H NMR (400 MHz, CDCl3): δ = 10.57 (s, 1 H), 8.17–8.04 (m, 4 H),
7.63–7.38 (m, 5 H), 4.43 (q, J = 7.2 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H).
O
10a'
13C NMR (101 MHz, CDCl3): δ = 184.8, 163.2, 139.2, 138.0, 136.5,
Figure 4
134.7, 129.5, 128.1, 127.7, 126.4, 125.3, 123.3, 118.3, 114.7, 61.8, 14.3.
HRMS (ES+): m/z calcd for C18H16NO5S [M + H]+: 358.0749; found:
358.0741.
3-(2-(Dimethylamino)phenyl)-4-hydroxyfuran-2(5H)-one (10b′,
Figure 5)
Compound 10 (100 mg, 0.52 mmol) in 7 mL acetone, excess K2CO3,
and excess MeI were charged in a 25-mL round-bottom flask. Then,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
S. Jana et al.
Paper
Synthesis
4-((2-Iodo-4,6-dimethylphenyl)amino)furan-2(5H)-one (22b)
Yield: 2.8 g (86%); brown solid (hexanes/EtOAc, 5:1); mp 179–181 °C.
CO2Et
IR (KBr): 3227, 3044, 2919, 1706, 1615, 1589, 1558, 1539, 1469, 1303,
CHO
N
1124, 1042, 896, 784, 700, 667 cm–1
.
SO2Ph
1H NMR (400 MHz, CDCl3): δ = 7.53 (s, 1 H), 7.24 (s, 1 H), 7.03 (s, 1 H),
4.81 (s, 2 H), 4.40 (s, 1 H), 2.28 (s, 3 H), 2.24 (s, 3 H).
12a'
13C NMR (101 MHz, CDCl3): δ = 176.3, 167.2, 140.1, 137.9, 136.9,
136.1, 132.3, 99.3, 84.6, 68.0, 20.6, 19.1.
Figure 6
HRMS (ES+): m/z calcd for C12H13INO2 [M + H]+: 329.9991; found:
329.9989.
Synthesis of the Cyclization Precursors; General Procedure
An o-haloaniline 16 (11 mmol) and glacial acetic acid (2 mmol) were
added to a solution of ethyl 4-chloroacetoacetate (17) (1.65 g, 10
mmol) in dried benzene (40 mL), and the resulting mixture was heat-
ed under reflux for 2 h. After cooling, the solid precipitate was collect-
ed, washed with benzene, and triturated with ethanol to give the 4-
((2-halophenyl)amino)furan-2(5H)-one. In cases where a solid depo-
sition of product was not obtained, benzene was evaporated in vacuo
and the reaction mixture was extracted with EtOAc and water. The
water layer was washed several times with EtOAc. Then, the com-
bined organic extracts were concentrated and purified by flash col-
umn chromatography (EtOAc/hexane) to obtain the solid product.
4-((4-Chloro-2-iodophenyl)amino)furan-2(5H)-one (22c)
Yield: 2.7 g (81%); yellow solid (hexanes/EtOAc, 4:1); mp 175–177 °C.
IR (KBr): 3059, 1700, 1608, 1589, 1495, 1329, 1161, 1044, 825, 784,
707 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 2.3 Hz, 1 H), 7.32 (dd, J = 8.6,
2.3 Hz, 1 H), 7.24–7.16 (m, 1 H), 6.42 (br s, 1 H), 5.17 (s, 1 H), 4.80 (s, 2
H).
13C NMR (101 MHz, CDCl3): δ = 174.7, 162.1, 139.1, 138.6, 131.2,
130.0, 121.7, 92.0, 87.8, 68.3.
HRMS (ES+): m/z calcd for C10H8ClINO2 [M + H]+: 335.9288; found:
335.9280.
4-((2-Bromophenyl)amino)furan-2(5H)-one (18a)
Yield: 2.15 g (85%); yellow solid (hexanes/EtOAc, 8:1); mp: 171–173 °C.
IR (KBr): 3140, 2983, 1738, 1591, 1561, 1507, 1402, 1260, 1140, 1047,
4-((4-Bromo-2-iodophenyl)amino)furan-2(5H)-one (22d)
760 cm–1
.
Yield: 3.0 g (79%); yellow solid (hexanes/EtOAc, 5:1); mp 140–142 °C.
1H NMR (400 MHz, CDCl3): δ = 7.63–7.57 (m, 1 H), 7.41–7.33 (m, 2 H),
7.07–7.02 (m, 1 H), 6.75 (s, 1 H), 5.36 (s, 1 H), 4.89 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 175.8, 163.4, 137.4, 133.5, 128.7,
126.3, 121.9, 116.0, 86.5, 68.7.
HRMS (ES+): m/z calcd for C10H9BrNO2 [M + H]+: 253.9817; found
253.9811.
IR (KBr): 3238, 3122, 2933, 1717, 1655, 1616, 1586, 1459, 1372, 1228,
1167, 1043, 1031, 829, 786, 710, 667 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 9.18 (br s, 1 H), 8.11 (s, 1 H), 7.61–
7.60 (m, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 4.84 (s, 2 H), 4.81 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 174.8, 165.9, 141.5, 141.2, 132.8,
126.4, 118.9, 96.4, 84.1, 68.2.
HRMS (ES+): m/z calcd for C10H8BrINO2 [M + H]+: 379.8783; found:
379.8775.
4-((2-Iodophenyl)amino)furan-2(5H)-one (18b)
Yield: 2.55 g (89%); white solid (hexanes/EtOAc, 5:1); mp: 175–177 °C.
IR (KBr): 3246, 1718, 1615, 1576, 1541, 1437, 1310, 1156, 1049, 895,
Methyl 3-Iodo-4-((5-oxo-2,5-dihydrofuran-3-yl)amino)benzoate
(22e)
769 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.0 Hz, 1 H), 7.45–7.31 (m, 2
H), 7.02 (br s, 1 H), 6.99–6.77 (m, 1 H), 5.16 (s, 1 H), 4.89 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 175.5, 163.5, 140.0, 139.9, 129.7,
127.1, 122.1, 92.5, 86.6, 68.5.
HRMS (ES+): m/z calcd for C10H9INO2 [M + H]+: 301.9678; found:
301.9669.
Yield: 2.7 g (76%); reddish solid (hexanes/EtOAc, 10:1); mp 187–
189 °C.
IR (KBr): 3238, 3122, 2933, 1717, 1655, 1616, 1586, 1459, 1372, 1356,
1303, 1285, 1177, 1043, 1031, 786, 667 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.51 (d, J = 2.4 Hz, 1 H), 8.08 (dd, J = 1.8,
8.4 Hz, 1 H), 7.40–7.38 (m, 1 H), 6.75 (br s, 1 H), 5.51 (s, 1 H), 4.94 (s, 2
H), 3.95 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 174.2, 164.8, 160.4, 143.2, 141.2,
131.2, 127.4, 118.2, 89.7, 68.4, 52.5.
4-((2-Iodo-4-methylphenyl)amino)furan-2(5H)-one (22a)
Yield: 2.6 g (83%); brown solid (hexanes/EtOAc, 5:1); mp 183–185 °C.
HRMS (ES+): m/z calcd for C12H11INO4 [M + H]+: 359.9733; found:
359.9721.
IR (KBr): 3246, 1710, 1610, 1594, 1444, 1308, 1163, 1046, 897, 786,
657 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 1.7 Hz, 1 H), 7.20–7.11 (m, 2
H), 6.57 (s, 1 H), 5.07 (s, 1 H), 4.79 (s, 2 H), 2.25 (s, 3 H).
Cyclization; General Procedure
13C NMR (101 MHz, CDCl3): δ = 175.4, 163.4, 140.1, 137.5, 130.5,
121.8, 100.1, 92.6, 86.5, 68.3, 20.5.
HRMS (ES+): m/z calcd for C11H11INO2 [M + H]+: 315.9834; found:
315.9826.
A mixture of a 4-((2-iodophenyl)amino)furan-2(5H)-one 22 (10
mmol), DABCO (3.36 g, 30 mmol, 3 equiv), and Pd(OAc)2 (112 mg, 0.5
mmol, 5 mol%) in dried DMF (30 mL) was degassed via vacuum/nitro-
gen purges and heated to 105 °C. The mixture was heated at 120 °C
for 6 h (for the bromo derivative 18a, 36 h) or until the reaction was
complete (usually, less than 8 h). The reaction mixture was cooled to
r.t. and partitioned between EtOAc (150 mL) and water (50 mL). The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
S. Jana et al.
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Synthesis
organic layer was separated, washed with brine (5 × 20 mL), and con-
centrated under reduced pressure to dryness. The residue was chro-
matographed to give the furoindol-1-one 6′ in moderate to good
yield.
Methyl 1-Oxo-3,4-dihydro-1H-furo[3,4-b]indole-7-carboxylate
(6e)
Yield: 1.52 g (66%); brown solid (hexanes/EtOAc, 5:1); mp 190–
192 °C.
IR (KBr): 3338, 1753, 1715, 1634, 1548, 1527, 1508, 1472, 1347, 1236,
7-Methyl-3,4-dihydro-1H-furo[3,4-b]indol-1-one (6a)
1056, 959, 826, 665 cm–1
.
Yield: 1.25 g (67%); brown solid (hexanes/EtOAc, 5:1); mp 195–
197 °C.
1H NMR (600 MHz, DMSO-d6): δ = 12.44 (br s, 1 H), 8.29 (s, 1 H), 7.91
(dd, J = 1.8, 9.0 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 5.43 (s, 2 H), 3.87 (s, 3
H).
IR (KBr): 3447, 3186, 2924, 2851, 1713, 1456, 1046 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.96 (br s, 1 H), 7.64–7.32 (m, 2
H), 7.10 (dd, J = 8.3, 1.9 Hz, 1 H), 5.36 (s, 2 H), 2.40 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 167.1, 166.5, 162.4, 145.5, 124.7,
123.6, 121.1, 120.7, 114.0, 106.7, 65.6, 52.5.
13C NMR (101 MHz, DMSO-d6): δ = 166.5, 159.9, 140.6, 130.7, 124.6,
HRMS (ES+): m/z calcd for C12H10NO4 [M + H]+: 232.0610; found:
120.9, 118.9, 113.0, 104.9, 64.7, 21.1.
232.0602.
HRMS (ES+): m/z calcd for C11H10NO2 [M + H]+: 188.0712; found:
188.0718.
4-Methyl-3,4-dihydro-1H-furo[3,4-b]indol-1-one (23)
To a stirred solution of compound 6 (173 mg, 1.0 mmol) in dried THF
(10 mL), NaH (24 mg, 1.0 mmol) was added at 0 °C. After 30 min, MeI
(0.30 mL, 5.0 mmol) was added. Then, the reaction mixture was
stirred for another 6–10 h at r.t. After reaction completion (checked
by TLC), saturated ammonium chloride solution was added and THF
was evaporated under reduced pressure. The mixture was extracted
with EtOAc, and the extracts were washed with brine (3 × 1/3 vol),
dried (Na2SO4), and concentrated to provide the crude product. The
crude product was purified by column chromatography on silica gel
(hexanes/EtOAc, 3:1) to obtain 23 (135 mg, 72% yield) as a semi-solid.
5,7-Dimethyl-3,4-dihydro-1H-furo[3,4-b]indol-1-one (6b)
Yield: 1.27 g (63%); brown solid (hexanes/EtOAc, 5:1); mp 184–
186 °C.
IR (KBr): 3278, 1763, 1726, 1597, 1518, 1420, 1317, 1206, 1026, 979,
828, 675 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.05 (s, 1 H), 7.29 (s, 1 H), 6.91 (s,
1 H), 5.37 (s, 2 H), 2.46 (s, 3 H), 2.37 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 166.5, 159.6, 140.0, 130.7, 125.4,
122.0, 120.6, 116.4, 105.1, 64.5, 21.0, 16.6.
HRMS (ES+): m/z calcd for C12H12NO2 [M + H]+: 202.0868; found:
IR (KBr): 3342, 1734, 1534, 1444, 1325, 1223, 1047, 967, 929, 752,
745, 638, 627 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.87 (d, J = 7.8 Hz, 1 H), 7.37–7.30 (m, 3
202.0859.
H), 5.15 (s, 2 H), 3.76 (s, 3 H).
7-Chloro-3,4-dihydro-1H-furo[3,4-b]indol-1-one (6c)
13C NMR (150 MHz, CDCl3): δ = 166.5, 159.6, 143.1, 123.7, 122.4,
Yield: 1.16 g (56%); brown solid (hexanes/EtOAc, 5:1); mp 191–
193 °C.
121.4, 120.4, 110.4, 105.9, 63.4, 31.6.
HRMS (ES+): m/z calcd for C11H10NO2 [M + H]+: 188.0712; found:
IR (KBr): 3332, 1723, 1653, 1547, 1514, 1426, 1357, 1236, 1136, 945,
188.0710.
856, 654 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.25 (br s, 1 H), 7.65 (s, 1 H), 7.61
(dd, J = 8.7, 2.8 Hz, 1 H), 7.48–7.17 (m, 1 H), 5.40 (s, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 167.6, 161.9, 141.2, 127.1, 124.1,
121.9, 118.9, 115.4, 105.4, 65.6.
HRMS (ES+): m/z calcd for C10H7ClNO2 [M + H]+ 208.0165; found:
3,4-Dimethyl-3,4-dihydro-1H-furo[3,4-b]indol-1-one (24)
To a stirred solution of compound 23 (34 mg, 0.18 mmol) in dried THF
(5 mL), 1 M LiHMDS in hexanes (0.3 mL, 1.6 mmol) was added at
–78 °C. After 30 min, excess MeI (0.19 mL, 3.0 mmol) was added.
Then, the reaction mixture was stirred for another 6–10 h at r.t. After
reaction completion (checked by TLC), saturated ammonium chloride
solution was added and THF was evaporated under reduced pressure.
The mixture was extracted with EtOAc, and the extracts were washed
with brine (3 × 1/3 vol), dried (Na2SO4), and concentrated to provide
the crude product. The crude solid product was purified by column
chromatography on silica gel (EtOAc/hexanes, 2:1) to obtain 24 (31
mg, 85% yield) as a brown solid; mp 163–165 °C.
IR (KBr): 2925, 1743, 1618, 1550, 1451, 1398, 1081, 963, 913 cm–1
1H NMR (600 MHz, CDCl3): δ = 7.91 (d, J = 7.8 Hz, 1 H), 7.40–7.32 (m, 3
H), 5.54 (q, J = 6.6 Hz, 1 H), 3.82 (s, 3 H), 1.75 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 165.8, 162.6, 143.1, 123.7, 122.5,
121.3, 120.7, 110.3, 106.2, 71.7, 31.3, 19.3.
208.0172.
7-Bromo-3,4-dihydro-1H-furo[3,4-b]indol-1-one (6d)
In this case, there was a mixture of compound 6d and its dehaloge-
1
nated derivative 6, from the H NMR spectrum in a ratio 6d/6 of 1:2.
From the starting material 22d (3.8 g, 10 mmol), 1.73 g product was
obtained, with the mixture of compounds 6d/6 in a 1:2 ratio. Thus,
we calculated the yield of 6d as 29%. Compound 6d isolated (0.73 g,
29% yield) was obtained as a brown solid (hexanes/EtOAc, 5:1).
1H NMR (400 MHz, DMSO-d6): δ (6 and 6d) = 12.26 (br s, 0.54 H),
12.10 (br s, 1 H), 7.78 (s, 0.54 H), 7.68–7.13 (m, 6.50 H), 5.40 (s, 1.40
H), 5.38 (s, 2 H).
13C NMR (101 MHz, DMSO-d6): δ (6 and 6d) = 166.4, 165.9, 161.1,
160.1, 142.3, 141.1, 126.0, 123.3, 122.3, 121.7, 121.2, 120.7, 119.0,
115.4, 114.3, 113.4, 105.3, 105.0, 65.0, 64.8.
.
HRMS (ES+): m/z calcd for C12H12NO2 [M + H]+: 202.0868; found:
202.0862.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
S. Jana et al.
Paper
Synthesis
Funding Information
(7) The structure of compound 10 was further confirmed by syn-
thesis of the N-acetyl-protected compound 10a′ and the N,N-
dimethyl derivative 10b′ (see experimental section).
(8) The structure of compound 12 was further confirmed by oxida-
tion of its primary alcohol to give aldehyde derivative 12a′ (see
experimental section).
We gratefully acknowledge the Council of Science & Industrial Re-
search, New Delhi, India for financial support. S.J. is thankful to IIT
KHARAGPUR for her research fellowship and contingency grant. We
are also thankful to the DST-FIST for financial support for establishing
an NMR facility.
)(
(9) Momose, T.; Toyooka, N.; Nishi, T.; Takeuchi, Y. Heterocycles
1988, 27, 1907.
(10) (a) Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Florius, F.
Angew. Chem. Int. Ed. 2008, 47, 7230. (b) He, Z.; Li, H.; Li, Z.
J. Org. Chem. 2010, 75, 4636.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610439.
(11) Several reagents were examined for the oxidative cyclization of
14; however, the desired cyclized product, furoindolone 6, was
not furnished: either starting material (SM) was recovered or an
intractable reaction mixture (IRM) was obtained. We tried the
following combinations: Cu(OAc)2·H2O/Pd(OAc)2, K2CO3, DMF,
80 °C (SM recovered); PdCl2(PPh3)2, TEA, DMF, 110 °C (SM
recovered); I2, K2CO3, DMF, 100 °C (SM recovered);
Ag2O/Pd(OAc)2, KOAc, DMF, 140 °C (IRM); PPh3/Pd2(dba)3/
Cu(OAc)2·H2O, TEA, DMF, 140 °C (IRM); I2, K2CO3, DMF, 100–
140 °C (IRM).
(12) We tried the dehydrohalogenative cyclization of 15 with the
following combinations: Cu(OAc)2, Cs2CO3, DMF, 125 °C;
TBAB/Pd(OAc)2, K2CO3, DMF, 100 °C; CuI, Cs2CO3, DMF, 125 °C;
PdCl2(PPh3)2, Cs2CO3, 1,4-dioxane, 100 °C; Pd(PPh3)4, TEA, DMF,
140 °C; PPh3/Pd2(dba)3, K3PO4, toluene, 120 °C; AcOH/Pd(OAc)2,
140 °C; LiCl/Pd(PPh3)4, Na2CO3, MeCN, 140 °C; LiCl,
PPh3/Pd(OAc)2, K2CO3, DMF, 140 °C; PdCl2(PPh3)2, TEA, DMF,
110 °C.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H