One-step synthesis of isoindolo[2,1- a]indol-6-ones via tandem Pd-catalyzed aminocarbonylation and C-H activation

Article abstract of DOI:10.1021/acs.joc.9b02008

A unified catalytic system for tandem Pd-catalyzed carbonylation and C-C cross-coupling via C-H activation was designed. The proposed cascade reaction allows a facile one-step construction of a tetracyclic isoindoloindole skeleton, in which three new C-C/C-N bonds are simultaneously formed. In detail, the carbonylation of aryl dibromides with indoles and C-H activation of in situ formed N-(2'-bromoaroyl)-indole provide biologically relevant 6H-isoindolo[2,1-a]indol-6-ones from commercially available substrates. The aminocarbonylation step in the proposed tandem reaction utilizes glyoxylic acid monohydrate as an environmentally friendly CO surrogate.

Full text of DOI:10.1021/acs.joc.9b02008

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Article
One-step Synthesis of Isoindolo[2,1-a]indol-6-ones via
Tandem Pd-catalyzed Aminocarbonylation and C-H Activation
Tomáš #arný, Martin Markovic, Tibor Gracza, and Peter Koos
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02008 • Publication Date (Web): 11 Sep 2019
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Page 1 of 11
The Journal of Organic Chemistry
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One-step Synthesis of Isoindolo[2,1-a]indol-6-ones via Tandem Pd-
catalyzed Aminocarbonylation and C-H Activation
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Tomáš Čarný,† Martin Markovič,*†‡ Tibor Gracza,† and Peter Koóš,*†‡
†Department of Organic Chemistry, Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of
Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
‡Georganics Ltd., Koreničova 1, SK-811 03 Bratislava, Slovakia
E-mail: peter.koos@stuba.sk, martin.markovic@stuba.sk
ABSTRACT: A unified catalytic system for tandem Pd-catalyzed carbonylation and C-C cross-coupling via C-H activation was
designed. The proposed cascade reaction allows a facile one-step construction of a tetracyclic isoindoloindole skeleton, in which
three new C-C/C-N bonds are simultaneously formed. In detail, the carbonylation of aryl dibromides with indoles and C-H
activation of in situ formed N-(2ʾ-bromoaroyl)-indole provides biologically relevant 6H-isoindolo[2,1-a]indol-6-ones from
commercially available substrates. The aminocarbonylation step in the proposed tandem reaction utilizes glyoxylic acid
monohydrate as an environmentally friendly CO surrogate.
INTRODUCTION
Scheme 1. Synthetic strategies toward isoindolo[2,1-
a]indol-6-one skeleton
The chemistry and biological activity of isoindolo[2,1-a]indol-
6-ones 1, many of which are important scaffold of drugs and
bioactive compounds,1 have drawn considerable interest in the
field of organic chemistry over the last years. Some of the
isoindoloindolone derivatives have been shown to be potent
melatonin MT3 and serotonine 5-HT6 ligands,2 topoisomerase-
II inhibitors,3 anticancer agents4 and potential antagonists of
human neurokinin-1 (hNK1) receptor in the central nervous
system.5 In addition, such tetracyclic system containing an
indole ring is also a valuable precursor in the organic synthesis
(e.g. for the synthesis of NorA efflux pump inhibitor6). In that
content, continuous effort in the construction of isoindolo[2,1-
a]indol-6-one skeleton has led to numerous synthetic
approaches to this class of compounds.7-13 In most cases, these
syntheses usually involve multi-step processes and can be
sorted by the disconnection of individual bonds in the
isoindoloindole skeleton (Scheme 1). Majority of the known
protocols involve C-N-lactam bond formation (path a, Pd-
catalyzed aminocarbonylation,7 lactamization2,8) and isoindolo
ring formation via C-C coupling (path b, Pd-catalyzed9 or
radical-initiated10 cross-coupling). Another approach utilizes
condensation reactions11 or Heck coupling2,4,12 in the
construction of the indole ring (path c). Furthermore, the
intramolecular cyclisation (path d) presents different access to
the indole substructure.13 However, most of these approaches
require multistep procedures and the development of effective
synthetic strategy remains the main challenge in the
construction of the tetracyclic backbone.
Previous work:
X
(H)
N
H
COOMe
N
N
H
X
a
X
= Br, I, OTs, H
a
O
b
X
(H)
d
COOMe
c
b
O
N
c
d
N
a
H
N
O
1
O
O
c
d
PPh3Br
Br
Br
c
O
N
R
X
NH
O
O
N
O
This work:
X
Pd0
R1
R
+
C O +
R
R1
N
O
N
Br
H
In our long-term project on the domino Pd-catalyzed
carbonylation of aryl halides,14 we have recently developed a
protocol for the carbonylative reactions using an alternative
CO source.14d In this procedure, two equivalents of gaseous
CO are released by dehydration of glyoxylic acid in a simple,
safe and environmentally friendly way. To demonstrate the
applicability of this method, we focus on the development of
new sustainable processes. Thus, we have proposed an
application of this protocol in the synthesis of isoindolo[2,1-
a]indol-6-ones 1. We assumed that the tandem Pd-catalyzed
aminocarbonylation of aryl dibromide and C-C cross coupling
RESULTS AND DISCUSSION
Herein we describe a facile construction of isoindolo[2,1-
a]indol-6-one framework via the tandem Pd-catalyzed
aminocarbonylation and C-H activation using one catalytic
system and glyoxylic acid as a CO surrogate.
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mmol), indole (1.1 equiv), Pd(OAc)2 (0.05 equiv) and K2CO3 (3
equiv) was used.
via C-H activation at C2 of an indole would lead to the
formation of the target isoindoloindole skeleton (Scheme 2).
1
2
3
4
5
6
7
8
9
The catalytic system based on Pd(OAc)2 (0.05 equiv) and
cataCXium A (0.06 equiv) has shown to be the most suitable
(entry 7), while the employment of other ligands (Xantphos,
dppp, PPh3, XPhos) led to less satisfactory results (entries 1-
4). We have also investigated the effect of quantity and the
composition of catalytic system on the yield of product 1b
(entries 7-14). Doubling the amount of Pd-catalyst and ligand
positively alter the yield (entry 12). However, changing the
ratio of catalyst to ligand up to 1:3 did not lead to the expected
result (entries 13, 14). Furthermore, screening of bases showed
that the reaction using K2CO3 or K3PO4 gave the product 1b in
the highest yield (entries 7, 8 and 9). Other bases, including
TEA, DBU, DIPEA, AcONa have shown to be incompatible
with this transformation (entries 1, 2 and 5, 6). Among all the
tested solvents, acetonitrile proved to be the most suitable
solvent (entry 12). Additionally, increasing the reaction
temperature up to 130 oC and reducing the concentration of the
reaction mixture (0.33 M solution of 2b in CH3CN), led to the
formation of product 1b in the highest yield (entry 12).
Scheme 2. Proposed synthesis of isoindolo[2,1-a]indol-6-
ones via tandem Pd-catalyzed aminocarbonylation and C-
C cross coupling
Br
CO
Pd(0)
PdII
C-H
Pd(0)
activation
Br
O
O
N
indole
N
N
Br
Br
O
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We began the investigation using symmetrical 4,5-dimethoxy-
1,2-dibromobenzene 2b and indole as model substrates. The
optimization reactions were carried out in two-chamber
apparatus.14a,d Gaseous CO (3 equiv) that was generated in the
development vial was introduced into the reaction chamber
filled with a mixture of substrate 2 (1 equiv), indole (1.1
equiv), base (3 equiv), Pd(OAc)2 (0.05 equiv) and ligand in
various solvents at 120 oC. At first, we conducted a series of
experiments to examine the influence of the Pd-
catalyst/ligand, base and solvent on the tandem reaction.
Selected results are listed in the Table 1 (for all the results see
Table S1 in Supporting Information).
To examine the applicability of the proposed method,
numerous dibromoarenes 2 and indole derivatives 3 were
subjected to the tandem carbonylation and C-C cross-coupling
reaction under the optimized reaction conditions (Scheme 3).
Table 1. Optimization of the reaction conditionsa
Scheme 3. Scope for the synthesis of 6H-isoindolo[2,1-
a]indol-6-one derivatives 1
H
N
(1.1 equiv)
Br
Br
MeO
MeO
Pd(OAc)2 (0.05 equiv)
OMe
OMe
+
CO
ligand, base (3 equiv)
solvent, 120 oC, 18 h
N
2b
O
1b
H2SO4 (conc.),
130 oC, 30 min
HO
HO
O
OH
glyoxylic acid (1.5 equiv)
entry
ligand (equiv)
base
solvent
dioxane
yieldb
(%)
1
xantphos (0.06)
dppp (0.06)
TEA
0
2
DBU
dioxane 11
dioxane 12
3
PPh3 (0.06)
K2CO3
K2CO3
4
XPhos (0.06)
dioxane
DMF
5
0
0
5
cataCXium A (0.06) DIPEA
cataCXium A (0.06) AcONa
cataCXium A (0.06) K2CO3
cataCXium A (0.06) K3PO4
cataCXium A (0.06) K2CO3
cataCXium A (0.10) K2CO3
cataCXium A (0.10) K2CO3
6
DMF
7
dioxane 41
8
DMF
50
50
55
52
60
46
59
9
DMF
10c
11c,d
DMF
DMF
12c,d,e cataCXium A (0.20) K2CO3
13c,d
14c,d
CH3CN
CH3CN
toluene
cataCXium A (0.15) K2CO3
cataCXium A (0.20) K2CO3
aReaction conditions: 4,5-dimethoxy-1,2-dibromobenzene 2b
(1.62 mmol, 480 mg, 1 equiv), indole (1.78 mmol, 209 mg, 1.1
equiv), Pd(OAc)2 (0.08 mmol, 18 mg, 0.05 equiv) and base (4.86
c
mmol, 3 equiv). bIsolated yield. 0.10 equiv of Pd(OAc)2 was
d
o
e
loaded. Reaction was conducted at 130 C. 250 mg of 2b (0.85
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and amino functions attached to both reaction partners. The
CO
(3 equiv)
Br
Br
Pd(OAc)2 (0.1 equiv)
1
2
3
4
5
6
7
8
9
yields of products were not significantly affected by the
position of electron donating substituents either attached to
isoindolo or indole moiety. However, the reaction of indols
bearing electron accepting groups did not provide expected
products 1aa and 1ab. In addition, 11-(2ʾ-N,N-
+
R1
cataXCium A (0.2 equiv)
R
R
R1
N
N
H
K2CO3 (3 equiv)
CH3CN, 130 oC, 18 h
3
2
(1.1 equiv)
O
(0.85 mmol)
1
MeO
OMe
OMe
OMe
OMe
dimethylaminoethyl)-6H-isoindolo[2,1-a]indol-6-one
1p,
N
O
N
N
dimethyl-6H-isoindolo[2,1-a]indol-6-ones 1u, 1w and 2-
fluoro-6H-isoindolo[2,1-a]indol-6-one 1x, which have proven
biological activity, were prepared in 40-64% yields by using
this protocol. Apparently, moderate yields of the products are
still higher than overall yields of known multi-step methods
for the construction of required isoindoloindole skeleton.4,7,9
O
O
(48%, Lit.7c 80%)
1b
(60%,a Lit.11c 18%)
1a
1c (55%)
Boc
F
Me
HN
OMe
OMe
OMe
OMe
OMe
10
11
12
13
14
15
16
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N
O
N
O
N
O
OMe
b
1f
1e
(40%)
(52%)
1d
(59%)
In all examined reactions (Scheme 3), various symmetrical
bromoarenes were used, eliminating the problems with the
regioselectivity of this tandem reaction. To extend the
generality of this method, the reactions of unsymmetrically
substituted aromatic derivatives were examined. The
regioisomeric (2-bromo-5-methoxyphenyl) 4 and (2-bromo-4-
methoxyphenyl) triflate 5 were chosen as model substrates.
Such substituted benzene derivatives ensure the selective
formation of corresponding products via different reactivity of
Br and TfO leaving group in the aminocarbonylation step. In
both cases, the tandem Pd-aminocarbonylation of
bromobenzene moiety and subsequent C-C cross coupling of
aryl triflate provided corresponding 9-methoxy- 1y and 8-
methoxy-6H-isoindolo[2,1-a]indol-6-ones 1z with high
regioselectivity (95:5) (Scheme 4).
Me
Me
Me
N
OMe
OMe
OMe
OMe
N
O
MeO
N
OMe
N
O
OMe
1g
(63%)
1h
(40%)
O
1i
(64%)
Me
Me
Me
Me
N
N
N
O
O
O
(41%)
(43%, Lit.7c 75%)
1j
1l
1k
(40%)
F
MeO
MeO
MeO
OMe
OMe
N
N
N
O
O
O
(40%, Lit.7a 46%)
(52%,c Lit.7a 45%)
Me
1m
1o
1n
(45%, Lit.11c 3%)
Scheme 4. Synthesis of 6H-isoindolo[2,1-a]indol-6-ones 1
from unsymmetrical arene derivatives
Me
Me
Me
N
Me
N
Me
N
CO
(3 equiv)
Me
Me
O
O
Pd(OAc)2 (0.1 equiv)
cataCXium A (0.2 equiv)
N
O
OTf
Br
MeO
OMe
N
N
O
N
indole (1.1 equiv)
K2CO3 (3 equiv)
CH3CN, 130 °C, 18 h
O
1p
1q
1r
(63%)
(64%)
(59%)
O
4
Me
1y
(40%)
1y/1z
(95/5)
O
O
N
O
N
N
MeO
Me
O
O
CO
(3 equiv)
(44%, Lit.4 38%)
1s
1t (51%)
(42%)
1u
Pd(OAc)2 (0.1 equiv)
cataCXium A (0.2 equiv)
OTf
Br
Me
Me
N
O
1z
1z/1y
F
Me
indole (1.1 equiv)
K2CO3 (3 equiv)
CH3CN, 130 °C, 18 h
MeO
OMe
N
5
N
N
O
(44%)
O
O
(95/5)
(35%, Lit.9a 14%)
O
(46%, Lit.7e 38%)
(40%, Lit.7e 40%)
1v
1w
1x
Based on these results and previous reports,15 a plausible
mechanism for the selective tandem reaction was proposed
(Scheme 5).
O2N
OMe
OMe
OMe
OMe
OMe
OMe
N
N
N
N
Scheme 5. Proposed reaction pathway for the selective
formation of 6H-isoindolo[2,1-a]indol-6-one framework
O
O
O
1ac (0%)d
d
d
1aa
(0%)
1ab
(0%)
a large scale reaction provided 2.49 g product in 60% yield.
b large scale reaction provided 2.70 g product in 46% yield.
c large scale reaction provided 2.22 g product in 60% yield.
d no conversion of starting materials was observed
Generally, the reactions provided corresponding products and
the isoindolo[2,1-a]indol-6-one derivatives 1a-x were obtained
in 35% to 64% yield. Also, large scale experiments using 15
mmol of various dibromoarenes were tested and products 1b,
1n and 1f were isolated in similar or better yields,
respectively. Based on these results, the tandem
transformation tolerated the presence of alkyl, alkoxy, halogen
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TfO
OMe
δC 77.16 ppm) or tetramethylsilane as internal standard. FTIR
1
2
3
4
5
6
7
8
N
spectra were obtained on a Nicolet 5700 spectrometer
(Thermo Electron) equipped with a Smart (diamond crystal
ATR) accessory, using the reflectance technique (4000 – 400
cm-1). High resolution mass spectra (HRMS) were recorded on
an OrbitrapVelos mass spectrometer (Thermo Scientific) with
a heated electrospray ionization source (HESI). The mass
spectrometer was operated with full scan (50 – 2000 amu) in
positive or negative FT mode (at a resolution of 100 000). The
analyte was dissolved in MeOH and infused via a syringe
pump at a rate of 5 mL/min. The heated capillary was
maintained at 275 °C with source heater temperature of 50 °C.
The sheath, auxiliary and sweep gases were at 10, 5 and 0
units, respectively. Source voltage was set to 3.5 kV
N
H
TfO
PdII
O
OMe
B
TfO
PdII
O
OMe
N
O
HBr
Br
Pd0-catalyzed
aminocarbonylation
PdII-catalyzed
C-H activation
HOTf
Pd0
CO
PdII
OMe
O
9
N
OMe
O
F3C
S
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13
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O
O
PdII
Br
A
OMe
TfO
Br
OMe
N
General procedure
O
1y
4
The reactions were performed in a system constructed out of
two 9 mL Ace pressure tubes capped with the Michel-Miller
Swagelok® Adapter (NPTF 1/8 in., Nylon/PTFE, Ace-Thread
#7) equipped with stainless steel Swagelok® connector (male
1/8 NPT to 1/8 in.). The vials were connected to each other
through the Omnifit® connector using the HPLC tubes (PTFE,
1/8 in. O.D. x 1/16 in. I.D.) (Figure S1, Supporting
Information). The reaction vial was loaded with Pd-catalyst,
ligand, substrate, base and solvent. The development vial was
loaded with glyoxylic acid monohydrate and concentrated
sulfuric acid. Both vials were closed, and development vial
was heated in oil bath at 130 °C for 30 min. After 30 min, the
reaction vial was placed into the oil bath at 130 °C for 18
hours. Vials were then cooled to a room temperature and
opened in a fume hood. The reaction mixture was then
filtrated using a Büchner funnel through a glass fiber paper
and filter cake was washed with DCM. After removal of
solvents in vacuo, the crude product was adsorbed onto a silica
gel and purified by MPLC.
In
detail,
a
standard
Heck-type
Pd-catalyzed
aminocarbonylation of aryl bromide 4 and indole is followed
by intramolecular-dehydrogenative cyclization of aryl triflate
B trough the C-H activation, most probably via Pd0/PdII
mechanism. The regioselectivity of this reaction can be
explained by the ability of triflate group to stabilize Pd(II)-
species in the -aryl palladium(II) bromide A.
CONCLUSION
In summary, we have developed a one-step protocol for the
construction of isoindolo[2,1-a]indol-6-one framework
through tandem Pd-catalyzed aminocarbonylation and
intramolecular cross-coupling reaction via C-H activation.
Notably, this transformation is promoted by a common
catalytic system with ex situ generation of gaseous CO. The
reported reaction proceeded in two-chamber apparatus14a using
1.5 equivalents of glyoxylic acid as an environmentally
friendly CO supplier.14d A series of 6H-isoindolo[2,1-a]indol-
6-ones have been obtained in moderate to good yields.
Compared to the other synthetic methods, this transformation
offers an effective way to create complex molecular system in
Large scale reactions were performed using 120 and 210 mL
Ace pressure tubes capped with the Michel-Miller Swagelok®
Adapter (NPTF 1/8 in., Nylon/PTFE, Ace-Thread #25). The
210 mL Ace pressure was used for the development of CO
(Figure S2, Supporting Information).
a
single reaction step by combining simple and/or
commercially available fragments.
EXPERIMENTAL SECTION
General information
All products were prepared according to the general
procedure.
6H-Isoindolo[2,1-a]indol-6-one (1a). Reaction vial: Pd(OAc)2
(19 mg, 0.08 mmol, 0.1 equiv), cataCXium A® (60 mg, 0.17
mmol, 0.2 equiv), 1,2-dibromobenzene (195 mg, 100 μL, 0.83
mmol, 1 equiv), indole (106 mg, 0.91 mmol, 1.1 equiv),
K2CO3 (343 mg, 2.48 mmol, 3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (115 mg, 1.25
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic Hex:DCM = 75:25)
providing desired product (82 mg, 48% yield, yellow solid).
All physical and spectral data were in good agreement with the
literature.9c Rf = 0.11 (Hex:DCM = 70:30); mp 149.9–151.2
°C; IR (ATR) νmax 3057, 2918, 1719, 1607, 1442, 1308, 609
Commercial reagents were used without further purification.
All solvents were distilled before use. Hexanes refer to the
fraction boiling at 60 – 65 °C. Flash column liquid
chromatography was performed on silica gel Kieselgel 60 (40
− 63 μm, 230 − 400 mesh) and analytical thin-layer
chromatography (TLC) was performed on aluminum plates
precoated with either 0.2 mm (DC-Alufolien, Merck) or 0.25
mm silica gel 60 F254 (ALUGRAM® SIL G/UV254,
Macherey-Nagel). The compounds were visualized by UV
fluorescence and by dipping the plates in an aqueous H2SO4
solution of cerium sulfate/ammonium molybdate followed by
charring with a heat gun. Melting points were obtained using a
1
cm-1; H NMR (300 MHz, CDCl3) δH 7.89 (ddd, J = 8.0, 1.8,
0.8 Hz, 1 H), 7.76 (dt, J = 7.5, 1.0 Hz, 1 H), 7.54 – 7.47 (m, 2
H), 7.51 (dt, J = 7.8, 1.0 Hz, 1 H), 7.38 – 7.25 (m, 2 H), 7.18 –
7.11 (dt, J = 7.7, 1.0 Hz, 1 H), 6.61 (d, J = 0.7 Hz, 1 H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 162.8, 139.0, 134.8,
134.7, 134.1, 133.9, 133.8, 129.0, 126.5, 125.5, 124.0, 122.4,
BUCHI Melting Point B-540 and are uncorrected. H and 13C
1
NMR spectra were recorded on either 300 (75) MHz
MercuryPlus or 600 (151) MHz Unity Inova spectrometers
from Varian. Standard chemical shifts are referenced to the
corresponding solvent residual peak (CDCl3: δH 7.26 ppm,
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121.4, 113.5, 103.6 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for
C15H10NO: 220.0757; Found: 220.0761.
2837, 1717, 1610, 1455, 1307, 582 cm-1; H NMR (300 MHz,
CDCl3) δH 7.71 (ddt, J = 4.6, 4.1, 0.6 Hz, 1 H), 7.20 (s, 1 H),
7.06 (dd, J = 8.9, 2.3 Hz, 1 H), 6.95 (s, 1 H), 6.94 (ddd, J =
9.3, 8.7, 2.5 Hz, 1 H), 6.39 (d, J = 0.7 Hz, 1 H), 3.98 (s, 3 H),
3.94 (s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 162.6,
1
1
2
3
4
5
6
7
8
8,9-Dimethoxy-6H-isoindolo[2,1-a]indol-6-one
(1b).
Small scale reaction: reaction vial: Pd(OAc)2 (19 mg, 0.08
mmol, 0.1 equiv), cataCXium A® (61 mg, 0.17 mmol,
0.2 equiv), 1,2-dibromo-4,5-dimethoxybenzene (250 mg, 0.85
mmol, 1 equiv), indole (110 mg, 0.94 mmol, 1.1 equiv),
K2CO3 (353 mg, 2.55 mmol, 3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.28
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic Hex:DCM = 20:80)
providing desired product (137 mg, 60% yield, yellow solid).
Large scale reaction: reaction vial: Pd(OAc)2 (336 mg, 1.50
mmol, 0.1 equiv), cataCXium A® (1.073 g, 3.00 mmol,
0.2 equiv), 1,2-dibromo-4,5-dimethoxybenzene (4.430 g,
15.00 mmol, 1 equiv), indole (1.929 g, 16.47 mmol, 1.1
equiv), K2CO3 (6.206 g, 44.90 mmol, 3 equiv) and acetonitrile
(45 mL). Development vial: glyoxylic acid monohydrate
(2.067 g, 22.45 mmol, 1.5 equiv) and concentrated sulfuric
acid (45 mL). Crude mixture was purified by MPLC (isocratic
Hex:DCM = 20:80) providing desired product (2.490 g, 60%
yield, yellow solid). All physical and spectral data were in
good agreement with the literature.11c Rf = 0.12 (DCM); mp
185.0 – 186.0 °C; IR (ATR) νmax 3115, 2839, 1725, 1609,
159.8 (d, JCF = 239.5 Hz), 154.1, 150.3, 140.7, 135.6, (d, JCF
9.9 Hz), 130.4 (d, JCF = 1.3 Hz), 128.8, 126.2, 113.4 (d, JCF
=
=
16.2 Hz), 113.3 (d, JCF = 18.4 Hz), 108.3 (d, JCF = 24.6 Hz),
107.7, 104.2, 102.0 (d, JCF = 4.0 Hz), 56.5, 56.5 ppm; 19F
NMR (282 MHz, CDCl3) δF -119.67 (td, J = 9.1, 4.6 Hz) ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for C17H13FNO3: 298.0874;
Found: 298.0879.
8,9-Dimethoxy-2-methyl-6H-isoindolo[2,1-a]indol-6-one
(1e). Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethoxybenzene (250 mg, 0.85 mmol, 1 equiv), 5-
methylindole (122 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic EtOAc:DCM =
0:100) providing desired product (128 mg, 52% yield, yellow
solid). Rf = 0.13 (DCM); mp 198.7 – 201.0 °C; IR (ATR) νmax
1
3003, 2831, 1716, 1611, 1455, 1304, 580 cm-1; H NMR (300
1
1444, 1315, 649 cm-1; H NMR (300 MHz, CDCl3) δH 7.81
MHz, CDCl3) δH 7.67 (d, J = 8.1 Hz, 1 H), 7.20 (d, J = 0.9 Hz,
1 H), 7.17 (d, J = 0.7 Hz, 1 H), 7.07 – 7.02 (m, 1 H), 6.95 (d, J
= 1.0 Hz, 1 H), 6.37 (d, J = 0.5 Hz, 1 H), 3.97 (s, 3 H), 3.93 (s,
3 H), 2.37 (s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC
162.8, 153.9, 150.0, 139.2, 134.9, 133.1, 132.2, 129.1, 127.2,
126.4, 122.3, 112.5, 107.5, 104.0, 102.5, 56.5, 56.4, 21.5 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for C18H16NO3: 294.1125;
Found: 294.1123.
(ddd, J = 8.0, 1.8, 0.8 Hz, 1 H), 7.43 – 7.37 (dt, J = 7.7, 1.0
Hz, 1 H), 7.28 – 7.20 (m, 2 H), 7.14 – 7.06 (m, 1 H), 6.99 (s, 1
H), 6.47 (d, J = 0.7 Hz, 1 H), 3.99 (s, 3 H), 3.95 (s, 3 H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 162.9, 154.1, 150.2,
139.1, 134.7, 134.1, 129.1, 126.4, 126.2, 123.6, 122.2, 113.0,
107.7, 104.1, 102.6, 56.5, 56.5 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for C17H14NO3: 280.0968; Found: 280.0975.
2,8,9-Trimethoxy-6H-isoindolo[2,1-a]indol-6-one
(1c).
2-(N-Boc)-8,9-dimethoxy-6H-isoindolo[2,1-a]indol-6-one
(1f). Small scale reaction: reaction vial: Pd(OAc)2 (19 mg,
0.08 mmol, 0.1 equiv), cataCXium A® (60 mg, 0.17 mmol,
0.2 equiv), 1,2-dibromo-4,5-dimethoxybenzene (250 mg, 0.85
mmol, 1 equiv), 5-(NH-Boc)indole (122 mg, 0.94 mmol, 1.1
equiv), K2CO3 (353 mg, 2.55 mmol, 3 equiv) and acetonitrile
(3 mL). Development vial: glyoxylic acid monohydrate (117
mg, 1.27 mmol, 1.5 equiv) and concentrated sulfuric acid
(3 mL). Crude product was purified by MPLC (isocratic
EtOAc:DCM = 2:98) providing desired product (134 mg, 40%
yield, yellow solid). Large scale reaction: reaction vial:
Pd(OAc)2 (336 mg, 1.50 mmol, 0.1 equiv), cataCXium A®
(1.073 g, 3.00 mmol, 0.2 equiv), 1,2-dibromo-4,5-
dimethoxybenzene (4.430 g, 15.00 mmol, 1 equiv), 5-(NH-
Boc)indole (3.825 g, 16.48 mmol, 1.1 equiv), K2CO3 (6.206 g,
44.90 mmol, 3 equiv) and acetonitrile (45 mL). Development
vial: glyoxylic acid monohydrate (2.067 g, 22.45 mmol, 1.5
equiv) and concentrated sulfuric acid (45 mL). Crude mixture
was purified by MPLC (isocratic EtOAc:DCM = 2:98)
providing desired product (134 mg, 40% yield, yellow solid).
Rf = 0.12 (EtOAc:DCM = 2.5:97.5); mp 234.0 – 235.8 °C; IR
(ATR) νmax 3365, 2835, 1726, 1698, 1458, 1308, 595 cm-1; 1H
NMR (300 MHz, CDCl3) δH 7.68 (d, J = 8.3 Hz, 1 H), 7.22 (s,
1 H), 6.99 (dd, J = 8.6, 2.1 Hz, 1 H), 6.49 (s, 1 H), 6.40 (s, 1
H), 3.99 (s, 3 H), 3.94 (s, 3 H), 1.53 (s, 9 H) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δC 162.7, 154.0, 153.2, 150.2, 139.9,
135.4, 134.4, 130.3, 129.0, 126.4, 117.6, 112.9, 112.6, 107.6,
104.1, 102.7, 80.6, 56.5, 56.5, 28.5 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for C22H23N2O5: 395.1602; Found: 395.1605.
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethoxybenzene (250 mg, 0.85 mmol, 1 equiv), 5-
methoxyindole (138 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353
mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic DCM:EtOAc =
90:10) providing desired product (144 mg, 55% yield, yellow
solid). Rf = 0.13 (DCM); mp 215.0 – 216.5 °C; IR (ATR) νmax
1
3109, 2933, 1721, 1606, 1434, 1313, 651 cm-1; H NMR (300
MHz, CDCl3) δH 7.68 (dt, J = 8.7, 0.6 Hz, 1 H), 7.21 (s, 1 H),
6.96 (s, 1 H), 6.90 (d, J = 2.1 Hz, 1 H), 6.83 (dd, J = 8.7, 2.5
Hz, 1 H), 6.39 (d, J = 0.7 Hz, 1 H), 3.98 (s, 3 H), 3.94 (s, 3 H),
3.83 (s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 162.6,
156.6, 153.9, 150.1, 140.0, 135.6, 129.0, 128.8, 126.5, 113.6,
113.4, 107.6, 106.2, 104.1, 102.5, 56.5, 56.5, 55.9 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for C18H16NO4: 310.1074;
Found: 310.1075.
2-Fluoro-8,9-dimethoxy-6H-isoindolo[2,1-a]indol-6-one
(1d). Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethoxybenzene (250 mg, 0.85 mmol, 1 equiv), 5-
fluoroindole (126 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353 mg,
2.55 mmol, 3 equiv) and acetonitrile (3 mL). Development
vial: glyoxylic acid monohydrate (117 mg, 1.27 mmol, 1.5
equiv) and concentrated sulfuric acid (3 mL). Crude product
was purified by MPLC (isocratic Hex:DCM = 0:100)
providing desired product (150 mg, 59% yield, yellow solid).
Rf = 0.25 (DCM); mp 225.0 – 227.0 °C; IR (ATR) νmax 3068,
3,8,9-Trimethoxy-6H-isoindolo[2,1-a]indol-6-one
(1g).
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
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Page 6 of 11
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethoxybenzene (250 mg, 0.85 mmol, 1 equiv), 6-
methoxyindole (138 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353
0.91 mmol, 1.1 equiv), K2CO3 (343 mg, 2.48 mmol, 3 equiv)
1
2
3
4
5
6
7
8
and acetonitrile (3 mL). Development vial: glyoxylic acid
monohydrate (115 mg, 1.25 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic Hex:DCM = 80:20) providing desired
product (80 mg, 41% yield yellow, solid). All physical and
spectral data were in good agreement with the literature.9c Rf =
0.10 (Hex:DCM = 60:40); mp 168.8 – 170.0 °C; IR (ATR)
mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic DCM:EtOAc =
90:10) providing desired product (165 mg, 63% yield, yellow
solid). Rf = 0.20 (DCM); mp 200.2 – 201.3 °C; IR (ATR) νmax
1
νmax 3057, 2914, 1708, 1608, 1445, 1305, 627 cm-1; H NMR
1
3109, 2939, 1726, 1609, 1441, 1315, 619 cm-1; H NMR (300
(300 MHz, CDCl3) δH 7.86 (dt, J = 7.9, 0.9 Hz, 1 H), 7.75 (dt,
J = 7.6, 0.9 Hz, 1 H), 7.58 – 7.54 (m, 1 H), 7.49 (td, J = 7.5,
1.1 Hz, 1 H), 7.37 (ddd, J = 7.7, 1.2, 0.8 Hz, 1 H), 7.33 – 7.25
(m, 2 H), 7.16 (dt, J = 7.6, 1.1 Hz, 1 H), 2.42 (s, 3 H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 162.4, 135.9, 135.2,
134.7, 134.1, 133.7, 133.6, 128.2, 126.6, 125.4, 123.7, 121.3,
120.3, 115.5, 113.4, 9.6 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for C16H12NO: 234.0913; Found: 234.0919.
9
MHz, CDCl3) δH 7.39 (d, J = 2.4 Hz, 1 H), 7.27 (d, J = 8.6 Hz,
1 H), 7.24 (s, 1 H), 6.96 (s, 1 H), 6.71 (dd, J = 8.6, 2.4 Hz, 1
H), 6.41 (d, J = 0.7 Hz, 1 H), 3.99 (s, 3 H), 3.95 (s, 3 H), 3.88
(s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 163.1,
159.5, 154.2, 149.8, 137.8, 135.3, 129.6, 128.0, 126.0, 122.7,
112.1, 107.6, 103.6, 102.8, 97.7, 56.5, 56.5, 56.0 ppm; HRMS
(ESI): m/z [M+H]+ Calcd. for C18H16NO4: 310.1074; found:
310.1083.
8,9-Dimethoxy-11-methyl-6H-isoindolo[2,1-a]indol-6-one
(1h). Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethoxybenzene (250 mg, 0.85 mmol, 1 equiv), 3-
methylindole (122 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8,9-Dimethyl-6H-isoindolo[2,1-a]indol-6-one
(1k).
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethylbenzene (223 mg, 0.85 mmol, 1 equiv), indole
(109 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353 mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL). Development vial: glyoxylic
acid monohydrate (117 mg, 1.27 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic Hex:DCM= 75:25) providing desired
product (90 mg, 43% yield, pale yellow solid). All physical
and spectral data were in good agreement with the literature.7c
Rf = 0.23 (Hex:DCM = 50:50); mp 209.2 – 211.3 °C; IR
(ATR) νmax 3115, 2972, 1721, 1625, 1444, 1331, 629 cm-1; 1H
NMR (300 MHz, CDCl3) δH 7.85 (ddd, J = 8.0, 1.8, 0.8 Hz, 1
H), 7.50 (s, 1 H), 7.41 (dt, J = 7.7, 0.9 Hz, 1 H), 7.28 – 7.21
(m, 2 H), 7.12 (td, J = 7.6, 1.1 Hz, 1 H), 6.50 (d, J = 0.7 Hz, 1
H), 2.32 (s, 3 H), 2.29 (s, 3 H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 163.2, 143.4, 139.3, 138.0, 134.7, 133.7, 132.8,
131.9, 126.3, 126.1, 123.7, 122.6, 122.2, 113.3, 102.6, 20.7,
20.2 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for C17H14NO:
248.1070, Found: 248.1077.
mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic EtOAc:DCM =
0.03:99.97) providing desired product (100 mg, 40% yield,
yellow solid). Rf = 0.22 (EtOAc:DCM = 2.5:97.5); mp 208.7 –
210.0 °C; IR (ATR) νmax 3055, 2835, 1711, 1607, 1447, 1306,
582 cm-1; 1H NMR (300 MHz, CDCl3) δH 7.78 (d, J = 7.9 Hz,
1 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.24 (dd, J = 8.7, 5.2 Hz, 2 H),
7.12 (t, J = 7.5 Hz, 1 H), 6.98 (s, 1 H), 4.00 (s, 3 H), 3.94 (s, 3
H), 2.38 (s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC
162.5, 153.9, 149.6, 135.9, 134.7, 134.0, 129.5, 126.5, 126.4,
123.3, 120.1, 114.2, 112.9, 107.6, 103.9, 56.5, 56.4, 9.7 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for C18H16NO3: 294.1125;
Found: 294.1125.
11-(2-(Dimethylamino)ethyl)-8,9-dimethoxy-6H-
2-Methyl-6H-isoindolo[2,1-a]indol-6-one (1l). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromobenzene (195 mg,
100 μL, 0.83 mmol, 1 equiv), 5-methylindole (119 mg,
0.91 mmol, 1.1 equiv), K2CO3 (343 mg, 2.48 mmol, 3 equiv)
and acetonitrile (3 mL). Development vial: glyoxylic acid
monohydrate (115 mg, 1.25 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic Hex:DCM = 75:25) providing desired
product (77 mg, 40% yield, yellow solid). All physical and
spectral data were in good agreement with the literature.7c Rf =
0.10 (Hex:DCM = 70:30); mp 125.1 – 127.5 °C; IR (ATR)
isoindolo[2,1-a]indol-6-one (1i). Reaction vial: Pd(OAc)2 (19
mg, 0.08 mmol, 0.1 equiv), cataCXium A® (60 mg, 0.17
mmol, 0.2 equiv), substrate (250 mg, 0.85 mmol, 1 equiv),
tryptamine (175 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353 mg,
2.55 mmol, 3 equiv) and acetonitrile (3 mL). Development
vial: glyoxylic acid monohydrate (117 mg, 1.27 mmol, 1.5
equiv) and concentrated sulfuric acid (3 mL). Crude product
was purified by MPLC (isocratic DCM:MeOH = 97.5:2.5)
providing desired product (180 mg, 64% yield, yellow solid).
Rf = 0.25 (DCM:MeOH = 96:4); mp 137.2 – 139.0 °C; IR
(ATR) νmax 3053, 2937, 1719, 1605, 1441, 1338, 652 cm-1; 1H
NMR (300 MHz, CDCl3) δH 7.79 (dt, J = 7.9, 0.9 Hz, 1 H),
7.36 (dt, J = 7.8, 0.9 Hz, 1 H), 7.28 – 7.20 (m, 1 H), 7.23 (s, 1
H), 7.11 (dd, J = 7.6, 1.1 Hz, 1 H), 7.01 (s, 1 H), 3.98 (s, 3 H),
3.94 (s, 3 H), 3.02 – 2.93 (m, 2 H), 2.69 – 2.59 (m, 2 H), 2.38
(s, 6 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 162.5,
154.0, 149.8, 135.1, 135.0, 134.1, 129.2, 126.5, 126.4, 123.3,
120.2, 116.6, 113.1, 107.7, 104.0, 59.5, 56.5, 56.4, 45.6, 23.6
ppm; HRMS (ESI): m/z [M+H]+ Calcd. for C21H23N2O3:
351.1703; Found: 351.1699.
1
νmax 3016, 2910, 1721, 1620, 1443, 1309, 586 cm-1; H NMR
(300 MHz, CDCl3) δH 7.75 (d, J = 8.1 Hz, 1 H), 7.73 (dt, J =
7.5, 0.9 Hz, 1 H) 7.52 – 7.44 (m, 1 H), 7.36 – 7.26 (m, 1 H),
7.24 – 7.20 (m, 1 H), 7.08 (ddd, J = 8.2, 1.6, 0.6 Hz, 1 H), 6.53
(d, J = 0.6 Hz, 1 H), 2.39 (s, 1 H) ppm; 13C{1H} NMR (75
MHz, CDCl3) δC 162.7, 139.1, 134.9, 134.9, 134.1, 133.7,
133.6, 131.9, 128.8, 127.6, 125.3, 122.5, 121.2, 113.1, 103.5,
21.6 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for C16H12NO:
234.0913; Found: 234.0921.
2-Fluoro-6H-isoindolo[2,1-a]indol-6-one (1m). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromobenzene (200 mg,
102 μL, 0.85 mmol, 1 equiv), 5-fluoroindole (126 mg,
11-Methyl-6H-isoindolo[2,1-a]indol-6-one (1j). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromobenzene (195 mg,
100 μL, 0.83 mmol, 1 equiv), 3-methylindole (119 mg,
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The Journal of Organic Chemistry
1
0.93 mmol, 1.1 equiv), K2CO3 (352 mg, 2.54 mmol, 3 equiv)
cm-1; H NMR (300 MHz, CDCl3) δH 7.36 (s, 1 H), 7.20 (s, 1
1
2
3
4
5
6
7
8
and acetonitrile (3 mL). Development vial: glyoxylic acid
monohydrate (117 mg, 1.27 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic Hex:DCM = 70:30) providing desired
product (80 mg, 40% yield yellow, solid). All physical and
spectral data were in good agreement with the literature.7a Rf =
0.11 (Hex:DCM = 70:30); mp 162.5 – 163.5 °C; IR (ATR)
H), 6.91 (s, 1 H), 6.88 (s, 1 H), 6.34 (d, J = 0.6 Hz, 1 H), 3.98
(s, 3 H), 3.97 (s, 3 H), 3.94 (s, 3 H), 3.90 (s, 3 H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 162.9, 153.9, 149.4,
149.2, 146.5, 137.7, 129.6, 128.6, 126.7, 125.7, 107.6, 104.5,
103.4, 102.6, 96.8, 56.4, 56.3, 56.3, 56.3 ppm; HRMS (ESI):
m/z [M+Na]+ Calcd. for C19H17NNaO5: 362.0999; Found:
362.0999; [M+K]+ Calcd. for C19H17KNO5: 378.0738; Found:
378.0739.
1
νmax 3059, 3018, 1721, 1620, 1444, 1138, 596 cm-1; H NMR
(300 MHz, CDCl3) δH 7.80 (dd, J = 8.7, 4.6 Hz, 1H), 7.75 (dt,
J = 7.5, 0.9 Hz, 1H), 7.55 – 7.47 (m, 2H), 7.40 – 7.30 (m, 1H),
7.11 (dd, J = 8.9, 2.3 Hz, 1H), 6.99 (ddd, J = 9.0, 2.5, 0.4 Hz,
1H), 6.56 (d, J = 0,7 Hz, 1H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 162.5, 160.0 (d, JCF = 240.2 Hz), 140.6, 135.6 (d,
JCF = 10.0 Hz), 134.6, 133.9, 133.8, 130.1 (d, JCF = 1.2 Hz),
11-(2-(Dimethylamino)ethyl)-6H-isoindolo[2,1-a]indol-6-
one (1p). Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1
equiv), cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-
dibromobenzene (200 mg, 0.85 mmol, 1 equiv), tryptamine
(175 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353 mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL). Development vial: glyoxylic
acid monohydrate (117 mg, 1.27 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic DCM:MeOH = 98.5:1.5) providing
desired product (155 mg, 63% yield, yellow solid). Rf = 0.18
(DCM:MeOH = 97:3); mp 101.2 – 102.1 °C; IR (ATR) νmax
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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58
59
60
129.3, 125.5, 121.5, 114.0 (d, JCF = 2.3 Hz), 113.9 (d, JCF
=
32.5 Hz), 108.5 (d, JCF = 24.5 Hz), 103.1 (d, JCF = 4.0 Hz),
ppm; 19F NMR (282 MHz, CDCl3) δ F -118.94 (td, J = 9.1, 4.5
Hz) ppm; HRMS (ESI): m/z [M+H]+ Calcd. for C15H9FNO:
238.0663; Found: 238.0669.
2-Methoxy-6H-isoindolo[2,1-a]indol-6-one (1n). Small
scale reaction: reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1
equiv), cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-
1
3051, 2939, 1716, 1608, 1444, 1361, 641 cm-1; H NMR (300
MHz, CDCl3) δH 7.87 (dt, J = 7.9, 0.9 Hz, 1 H), 7.76 (dt, J =
7.5, 0.9 Hz, 1 H), 7.58 – 7.54 (m, 1 H), 7.51 (td, J = 7.4, 1.1
Hz, 1 H), 7.42 (dt, J = 7.75, 0.9 Hz, 1 H), 7.34 – 7.25 (m, 2 H),
7.16 (td, J = 7.7, 1.1 Hz, 1 H), 3.08 – 3.00 (m, 2 H), 2.68 –
2.62 (m, 2 H), 2.38 (s, 6 H) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 162.4, 135.1, 135.0, 134.9, 134.1, 133.8, 133.7,
128.4, 126.7, 125.5, 123.8, 121.3, 120.4, 118.1, 113.6, 59.4,
45.6, 23.6 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for
C19H19N2O: 291.1492; Found: 291.1499.
11-(2-(Dimethylamino)ethyl)-8,9-dimethyl-6H-isoindolo
[2,1-a]indol-6-one (1q). Reaction vial: Pd(OAc)2 (19 mg, 0.08
mmol, 0.1 equiv), cataCXium A® (60 mg, 0.17 mmol,
0.2 equiv), 1,2-dibromo-4,5-dimethylbenzene (223 mg, 0.85
mmol, 1 equiv), tryptamine (175 mg, 0.93 mmol, 1.1 equiv),
K2CO3 (350 mg, 2.54 mmol, 3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic DCM:MeOH = 98:2)
providing desired product (175 mg, 64% yield, yellow solid).
Rf = 0.15 (DCM:MeOH = 97:3); mp 128.7 – 129.5 °C; IR
(ATR) νmax 3051, 2748, 1727, 1621, 1447, 1380, 629 cm-1; 1H
NMR (300 MHz, CDCl3) δH 7.85 (dd, J = 7.9, 0.7 Hz, 1 H),
7.51 (s, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.33 (s, 1 H), 7.29 –
7.22 (m, 1 H), 7.14 (m, 1 H), 3.03 (dd, J = 9.7, 6.7 Hz, 2 H),
2.64 (dd, J = 9.6, 6.8 Hz, 2 H), 2.39 (s, 6 H), 2.35 (s, 3 H),
2.31 (s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 162.8,
143.3, 137.4, 135.3, 135.1, 133.8, 133.0, 132.0, 126.4, 126.3,
123.5, 122.5, 120.2, 116.8, 113.4, 59.4, 45.6, 23.7, 20.8, 20.2
ppm; HRMS (ESI): m/z [M+H]+ Calcd. for C21H23N2O:
319.1805; Found: 319.1803.
dibromobenzene (200 mg, 0.85 mmol,
methoxyindole (137 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353
mg, 2.55 mmol, equiv) and acetonitrile (3 mL).
1 equiv), 5-
3
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic DCM:Hex = 50:50)
providing desired product (110 mg, 52% yield, yellow solid).
Large scale reaction: reaction vial: Pd(OAc)2 (337 mg, 1.50
mmol, 0.1 equiv), cataCXium A® (1.076 g, 3.00 mmol,
0.2 equiv), 1,2-dibromobenzene (3.539 g, 15.00 mmol, 1
equiv), 5-methoxyindole (2.428 g, 16.50 mmol, 1.1 equiv),
K2CO3 (6.219 g, 45.00 mmol, 3 equiv) and acetonitrile (45
mL). Development vial: glyoxylic acid monohydrate (2.071 g,
22.50 mmol, 1.5 equiv) and concentrated sulfuric acid
(45 mL). Crude mixture was purified by MPLC (isocratic
DCM:Hex = 50:50) providing desired product (2.226 g, 60%
yield, yellow solid). All physical and spectral data were in
good agreement with the literature.7a Rf = 0.11 (Hex:DCM =
50:50); mp 160.3 – 162.0 °C; IR (ATR) νmax 3105, 2839, 1720,
1
1618, 1437, 1330, 617 cm-1. H NMR (300 MHz, CDCl3) δH
7.68 (dt, J = 8.7, 0.7 Hz, 1 H), 7.65 (dt, J = 7.5, 1.0 Hz, 1 H),
7.44 – 7.36 (m, 2 H), 7.28 – 7.19 (m, 1 H), 6.86 (d, J = 2.2 Hz,
1 H), 6.79 (dd, J = 8.7, 2.5 Hz, 1 H), 6.45 (d, J = 0.7 Hz, 1 H),
3.76 (s, 3 H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 162.5,
156.9, 139.9, 135.6, 134.8, 134.1, 133.7, 128.9, 128.4, 125.3,
121.2, 114.1, 114.0, 106.1, 103.5, 55.9 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for C16H12NO2: 250.0863; Found: 250.0867.
2,3,8,9-Tetramethoxy-6H-isoindolo[2,1-a]indol-6-one
(1o). Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-dimethoxybenzene (250 mg, 0.85 mmol, 1 equiv), 5,6-
dimethoxyindole (165 mg, 0.94 mmol, 1.1 equiv), K2CO3 (353
11-(2-(Dimethylamino)ethyl)-5H-[1,3]dioxolo[4',5':5,6]
isoindolo[2,1-a]indol-5-one (1r). Reaction vial: Pd(OAc)2 (19
mg, 0.08 mmol, 0.1 equiv), cataCXium A® (60 mg, 0.17
mmol, 0.2 equiv), 1,2-dibromo-4,5-(methylenedioxy)benzene
(235 mg, 0.84 mmol, 1 equiv), tryptamine (174 mg, 0.92
mmol, 1.1 equiv), K2CO3 (350 mg, 2.54 mmol, 3 equiv) and
acetonitrile (3 mL). Development vial: glyoxylic acid
monohydrate (117 mg, 1.27 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic DCM:MeOH = 97.5:2.5) providing
desired product (165 mg, 59% yield, yellow solid). Rf = 0.12
(DCM:MeOH = 97:3); mp 218.2 – 219.0 °C; IR (ATR) νmax
mg, 2.55 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic DCM:EtOAc= 97:3)
providing desired product (128 mg, 45% yield, orange solid).
All physical and spectral data were in good agreement with the
literature.11c Rf = 0.11 (DCM:EtOAc = 95:5); mp 249.6 – 250.5
°C; IR (ATR) νmax 3564, 2931, 1720, 1608, 1474, 1311, 654
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1
2813, 2757, 1711, 1602, 1450, 1342, 620 cm-1; H NMR (300
J = 0.6 Hz, 1 H), 7.53 – 7.42 (m, 2 H), 7.30 – 7.19 (m, 2 H),
1
2
3
4
5
6
7
8
MHz, CDCl3) δH 7.79 (d, J = 7.9 Hz, 1 H), 7.38 (d, J = 7.8 Hz,
1 H), 7.28 – 7.21 (m, 1 H), 7.16 (s, 1 H), 7.12 (td, J = 7.6, 1.0
Hz, 1 H), 6.98 (s, 1 H), 6.07 (s, 2 H), 3.00 – 2.93 (m, 2 H),
2.65 – 2.57 (m, 2 H), 2.36 (s, 6 H) ppm; 13C{1H} NMR (75
MHz, CDCl3) δC 161.9, 152.7, 148.3, 134.9, 134.7, 134.1,
131.0, 128.2, 126.6, 123.4, 120.3, 117.3, 113.1, 105.9, 102.4,
102.1, 59.4, 45.6, 23.5 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for C20H19N2O3: 335.1392; Found: 335.1391.
6.95 (d, J = 7.9 Hz, 1 H), 2.43 (s, 3 H), 2.37 (d, J = 2.4 Hz, 3
H) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 162.4, 137.1,
135.3, 134.1, 134.0, 134.0, 133.6, 133.4, 127.9, 125.3, 124.9,
121.0, 119.9, 115.7, 113.9, 21.9, 9.6 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for C17H14NO: 248.1070; Found: 248.1076.
6H-Benzo[5,6]isoindolo[2,1-a]indol-6-one (1v). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 2,3-dibromonaphthalene (242
mg, 0.85 mmol, 1 equiv), indole (110 mg, 0.94 mmol, 1.1
equiv), K2CO3 (353 mg, 2.55 mmol, 3 equiv) and acetonitrile
(3 mL). Development vial: glyoxylic acid monohydrate (117
mg, 1.27 mmol, 1.5 equiv) and concentrated sulfuric acid (3
mL). Crude product was purified by MPLC (isocratic
Hex:DCM = 65:35) providing desired product (80 mg, 35%
yield, yellow solid). All physical and spectral data were in
good agreement with the literature.9a Rf = 0.38 (Hex:DCM =
50:50); mp 246.9 – 248.1 °C; IR (ATR) νmax 3448, 3055, 1726,
1,3-Dioxolo-6H-isoindolo[2,1-a]indol-6-one
(1s).
9
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (61 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromo-
4,5-(methylenedioxy)benzene (240 mg, 0.86 mmol, 1 equiv),
indole (110 mg, 0.94 mmol, 1.1 equiv), K2CO3 (355 mg, 2.57
mmol, 3 equiv) and acetonitrile (3 mL). Development vial:
glyoxylic acid monohydrate (118 mg, 1.28 mmol, 1.5 equiv)
and concentrated sulfuric acid (3 mL). Crude product was
purified by MPLC (isocratic Hex:DCM = 40:60) providing
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18
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20
21
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
desired product (95 mg, 42% yield, yellow solid). Rf 0.25
1599, 1446, 1340, 623 cm-1; H NMR (300 MHz, CDCl3) δH
=
(Hex:DCM = 20:80); mp 221.0 – 222.0 °C; IR (ATR) νmax
8.25 (s, 1 H), 7.98 (dd, J = 8.0, 0.8 Hz, 1 H), 7.90 (s, 1 H),
7.81 – 7.92 (m, 2 H), 7.60 – 7.45 (m, 3 H), 7.29 (td, J = 7.8,
1.2 Hz, 1 H), 7.18 (td, J = 7.6, 1.1 Hz, 1 H), 6.69 (s, 1 H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 162.7, 138.9, 136.4,
135.0, 133.3, 133.1, 131.9, 130.4, 129.5, 129.1, 128.9, 127.3,
126.7, 126.0, 124.3, 122.2, 120.5, 113.8, 102.4 ppm; HRMS
(ESI): m/z [M+H]+ Calcd. for C19H12NO: 270.0913; Found:
270.0921.
1
3116, 2916, 1710, 1614, 1442, 1318, 677 cm-1; H NMR (300
MHz, CDCl3) δH 7.81 (ddd, J = 8.0, 1.8, 0.8 Hz, 1 H), 7.41 (dt,
J = 7.7, 1.0 Hz, 1 H), 7.28 – 7.21 (m, 3 H), 7.17 (d, J = 0.5 Hz,
1 H), 7.11 (dt, J = 7.6, 1.1 Hz, 1 H), 6.94 (d, J = 0.4 Hz, 1 H),
6.48 (d, J = 0.7 Hz, 1 H), 6.08 (s, 2 H) ppm; 13C{1H} NMR
(75 MHz, CDCl3) δC 162.3, 152.8, 148.8, 138.7, 134.5, 134.1,
131.01, 128.2, 126.4, 123.7, 122.3, 113.0, 105.8, 103.0, 102.5,
102.2 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for C16H10NO3:
264.0655; Found: 264.0662.
2,11-Dimethyl-6H-isoindolo[2,1-a]indol-6-one
(1w).
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-
dibromobenzene (200 mg, 102 μL, 0.85 mmol, 1 equiv), 3,5-
dimethylindole (135 mg, 0.93 mmol, 1.1 equiv), K2CO3 (350
3-Methoxy-6H-isoindolo[2,1-a]indol-6-one (1t). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 1,2-dibromobenzene (200 mg,
0.85 mmol, 1 equiv), 6-methoxyindole (137 mg, 0.94 mmol,
1.1 equiv), K2CO3 (353 mg, 2.55 mmol, 3 equiv) and
acetonitrile (3 mL). Development vial: glyoxylic acid
monohydrate (117 mg, 1.27 mmol, 1.5 equiv) and
concentrated sulfuric acid (3 mL). Crude product was purified
by MPLC (isocratic DCM:Hex = 50:50) providing desired
product (108 mg, 51% yield, yellow solid). Rf = 0.11
(Hex:DCM = 50:50); mp 144.5 – 146.6 °C; IR (ATR) νmax
mg, 2.54 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (gradient Hex:DCM = 80:20 to
70:30 then isocratic Hex:DCM = 70:30) providing desired
product (96 mg, 46% yield, yellow solid). All physical and
spectral data were in good agreement with the literature.4 Rf =
0.13 (Hex:DCM = 55:45); mp 153.2 – 155.5 °C; IR (ATR)
1
1
3109, 2829, 1722, 1610, 1438, 1340, 612 cm-1; H NMR (300
νmax 3018, 2914, 1713, 1610, 1446, 1290, 593 cm-1; H NMR
MHz, CDCl3) δH 7.74 (dt, J = 7.5, 0.9 Hz, 1 H), 7.53 – 7.42
(m, 3 H), 7.32 – 7.26 (m, J = 7.6, 5.9, 2.2 Hz, 2 H), 6.75 (dd, J
= 8.6, 2.4 Hz, 1 H), 6.53 (d, J = 0.7 Hz, 1 H), 3.88 (s, 3 H)
ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 163.0, 159.7, 137.7,
135.1, 134.9, 133.9, 133.7, 128.3, 128.0, 125.4, 123.0, 120.9,
112.7, 103.9, 98.0, 55.9 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for C16H12NO2: 250.0863; Found: 250.0869.
(600 MHz, CDCl3) δH 7.73 (dt, J = 7.5, 0.9 Hz, 1 H), 7.72 (d, J
= 8.0 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.48 (td, J = 7.5, 1.1
Hz, 1 H), 7.28 (td, J = 7.5, 1.0 Hz, 1 H), 7.16 – 7.15 (m, 1 H),
7.09 (dd, J = 8.1, 0.9 Hz, 1 H), 2.40 (s, 3 H), 2.40 (s, 3 H)
ppm; 13C{1H} NMR (150 MHz, CDCl3) δC 162.3, 136.2,
135.2, 134.9, 134.2, 133.4, 133.4, 131.8, 128.1, 127.7, 125.3,
121.2, 120.5, 115.4, 113.1, 21.6, 9.6 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for C17H14NO: 248.1070; Found: 248.1067.
2-Fluoro-11-methyl-6H-isoindolo[2,1-a]indol-6-one (1x).
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-
dibromobenzene (200 mg, 102 μL, 0.85 mmol, 1 equiv), 5-
fluoro-3-methylindole (139 mg, 0.93 mmol, 1.1 equiv), K2CO3
(350 mg, 2.54 mmol, 3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (isocratic Hex:DCM = 75:25)
providing desired product (86 mg, 40% yield, yellow solid).
All physical and spectral data were in good agreement with the
literature.4 Rf = 0.13 (Hex:DCM = 60:40); mp 188.0 – 189.2
°C; IR (ATR) νmax 3097, 2858, 1716, 1611, 1447, 1336, 605
cm-1; 1H NMR (600 MHz, CDCl3) δH 7.76 (qd, J = 4.4, 0.4 Hz,
3,11-Dimethyl-6H-isoindolo[2,1-a]indol-6-one
(1u).
Reaction vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv),
cataCXium A® (60 mg, 0.17 mmol, 0.2 equiv), 1,2-
dibromobenzene (200 mg, 102 μL, 0.85 mmol, 1 equiv), 3,6-
dimethylindole (135 mg, 0.93 mmol, 1.1 equiv), K2CO3 (350
mg, 2.54 mmol,
3 equiv) and acetonitrile (3 mL).
Development vial: glyoxylic acid monohydrate (117 mg, 1.27
mmol, 1.5 equiv) and concentrated sulfuric acid (3 mL). Crude
product was purified by MPLC (gradient Hex:DCM = 80:20 to
70:30 then isocratic Hex:DCM = 70:30) providing desired
product (93 mg, 44% yield, yellow solid). All physical and
spectral data were in good agreement with the literature.4 Rf =
0.14 (Hex:DCM = 55:45); mp 146.1 – 148.3 °C; IR (ATR)
1
νmax 3055, 2858, 1704, 1609, 1438, 1357, 615 cm-1; H NMR
(300 MHz, CDCl3) δH 7.72 (dd, J = 7.6, 0.9 Hz, 1 H), 7.67 (d,
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The Journal of Organic Chemistry
1 H), 7.74 (qd, J = 7.5, 0.9 Hz, 1 H), 7.54 (dt, J = 7.6, 0.8 Hz, AUTHOR INFORMATION
1
2
3
4
5
6
7
8
1 H), 7.50 (td, J = 7.5, 1.1 Hz, 1 H), 7.31 (td, J = 7.5, 1.1 Hz, 1
H), 7.03 (dd, J = 8.7, 0.4 Hz, 1 H), 6.98 (ddd, J = 9.2, 8.7, 2.5
Hz, 1 H), 2.38 (s, 3 H) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δC 162.1, 160.0 (d, JCF = 240 Hz), 137.1 (d, JCF = 9.2
Hz), 136.3, 134.9, 133.9, 133.7, 130.0, 128.5, 125.5, 121.4,
114.9 (dd, JCF = 4.0, Hz), 114.9 (dd, JCF = 4.0, Hz), 114.0 (d,
JCF = 18.0 Hz), 113.9 (d, JCF = 34.0 Hz), 106.6 (d, JCF = 24.4
Hz), 9.6 ppm; 19F NMR (282 MHz, CDCl3) δ F -118.91 (td, J =
9.0, 4.5 Hz) ppm; HRMS (ESI): m/z [M+H]+ Calcd. for
C16H11FNO: 252.0819; Found: 252.0817.
Corresponding Author
* E-mail: peter.koos@stuba.sk
* E-mail: martin.markovic@stuba.sk
ACKNOWLEDGMENT
We thank Slovak Grant Agencies (VEGA No. 1/0552/18, APVV-
14-0147, ITMS project No. 26240120025).
9
REFERENCES
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(1) See review and citation therein: H. K. Kadam, H. K; Tilve, S.
G. Isoindoloindolones - biological activities and syntheses.
ARKIVOC, 2015 (vi), 524-539.
(2) Boussard, M. F.; Truche, S.; Rousseau, A.; Briss, S.; Descamps,
S.; Droual, M.; Wierzbicki, M.; Ferry, G.; Audinot, V.;
Delagrange, P.; Boutin, J. New ligands at the melatonin binding
site MT(3). Eur. J. Med. Chem., 2006, 41, 306-320.
9-Methoxy-6H-isoindolo[2,1-a]indol-6-one (1y). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 2-bromo-5-methoxyphenyl
trifluoromethanesulfonate (285 mg, 0.85 mmol, 1 equiv),
indole (110 mg, 0.94 mmol, 1.1 equiv), K2CO3 (350 mg, 2.54
mmol, 3 equiv) and acetonitrile (3 mL). Development vial:
glyoxylic acid monohydrate (117 mg, 1.27 mmol, 1.5 equiv)
and concentrated sulfuric acid (3 mL). Crude product was
purified by MPLC (gradient Hex:DCM = 70:30 to 50:50 then
isocratic Hex:DCM =50:50) providing desired product (85 mg,
40% yield, yellow solid). All physical and spectral data were
in good agreement with the literature.9c Rf = 0.12 (Hex:DCM =
50:50); mp 155.0 – 155.7 °C; IR (ATR) νmax 3008, 2838, 1728,
(3) (a) Guillaumel, J.; Leonce, S.; Pierre, A.; Renard, P.; Pfeiffer,
B.; Arimondo, P. B.; Monneret, C. Synthesis and biological
activity of 6H-isoindolo[2,1-a]indol-6-ones, analogues of
batracylin, and related compounds. Eur. J. Med. Chem. 2006,
41, 379-386. (b) Guillaumel, J.; Leonce, S.; Pierre, A.; Renard,
P.; Pfeiffer, B.; Peruchon, L.; Arimondo, P. B.; Monneret, C.
Synthesis and antiproliferative activity of basic ethers of 1,2-
dihydropyrrolo[1,2-a]indole, 6H-isoindolo[2,1-a]indole, and
6H-benz[5,6]isoindolo[2,1-a]indole. Oncol. Res. 2003, 13, 537-
549.
(4) Nallapati, S. B.; Adepu, R.; Ashfaq, M. A.; Sreenivas, B. Y.;
Mukkanti, K.; Pal, M. A Pd-catalyzed direct entry to 11-
substituted 6H-isoindolo[2,1-a]indol-6-one derivatives as
potential anticancer agents. RSC Adv. 2015, 5, 88686-88691.
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receptor antagonists: optimisation of the 2-Aryl ring and the
indole nitrogen substituent. Bioorg. Med. Chem. Lett. 2001, 11,
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pump in Staphylococcus aureus. Bioorg. Med. Chem. Lett.
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(7) (a) Han, Q.; Fu, S.; Zhang, X.; Lin, S.; Huang, Q. Facile
approaches toward the synthesis of 6H-isoindolo[2,1-α]indol-6-
ones via palladium-catalyzed carbonylation with carbon
monoxide. Tetrahedron Lett. 2016, 57, 4165-4169. (b) Yoo, J.
M.; Ho, S. L.; Cho, C. S. Synthesis of 6H-Isoindolo[2,1-
1
1624, 1434, 1336, 616 cm-1; H NMR (600 MHz, CDCl3) δH
7.88 (dd, J = 8.0, 0.8 Hz, 1 H), 7.67 (dd, J = 8.4, 0.3 Hz, 1 H),
7.45 (d, J = 7.8 Hz, 1 H), 7.29 – 7.26 (m, 1 H), 7.14 (td, J =
7.8, 1.0 Hz, 1 H), 7.01 (d, J = 2.2 Hz, 1 H), 6.81 (dd, J = 8.4,
2.3 Hz, 1 H), 6.60 (d, J = 0.6 Hz, 1 H), 3.90 (s, 3 H) ppm;
13C{1H} NMR (150 MHz, CDCl3) δC 164.5, 162.5, 138.4,
136.9, 134.2, 133.6, 126.9, 126.3, 126.1, 123.5, 122.2, 114.1,
113.1, 107.0, 103.2, 55.8 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for C16H12NO2: 250.0863; Found: 250.0870.
8-Methoxy-6H-isoindolo[2,1-a]indol-6-one (1z). Reaction
vial: Pd(OAc)2 (19 mg, 0.08 mmol, 0.1 equiv), cataCXium A®
(60 mg, 0.17 mmol, 0.2 equiv), 2-bromo-4-methoxyphenyl
trifluoromethanesulfonate (285 mg, 0.85 mmol, 1 equiv),
indole (110 mg, 0.93 mmol, 1.1 equiv), K2CO3 (350 mg, 2.54
mmol, 3 equiv) and acetonitrile (3 mL). Development vial:
glyoxylic acid monohydrate (117 mg, 1.27 mmol, 1.5 equiv)
and concentrated sulfuric acid (3 mL). Crude product was
purified by MPLC (gradient Hex:DCM = 70:30 to 50:50 then
isocratic Hex:DCM =50:50) providing desired product (93 mg,
44% yield, yellow solid). All physical and spectral data were
in good agreement with the literature.9f Rf = 0.11 (Hex:DCM =
50:50); mp 149.4 – 150.6 °C; IR (ATR) νmax 3115, 2850, 1725,
1618, 1446, 1334, 658 cm-1;1H NMR (300 MHz, CDCl3) δH
7.84 (ddd, J = 8.0, 1.9, 0.8 Hz, 1 H), 7.42 – 7.37 (m, 2 H), 7.28
– 7.20 (m, 2 H), 7.12 (td, J = 7.57, 1.12 Hz, 1 H), 7.01 (dd, J =
8.3, 2.5 Hz, 1 H), 6.45 (d, J = 0.8 Hz, 1 H), 3.87 (s, 3 H) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 162.7, 160.8, 139.2,
135.8, 134.9, 133.9, 127.4, 126.0, 124.0, 122.5, 122.1, 120.5,
113.2, 109.8, 102.3, 55.9 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for C16H12NO2: 250.0863; Found: 250.0868.
a]indol-6-ones
via
Palladium-Catalyzed
Carbonylative
Cyclization of 2-(2-Bromophenyl)-1H-indoles. Synlett 2016,
27, 1383-1386. (c) Huang, Q.; Han, Q.; Fu, S.; Yao, Z.; Su, L.;
Zhang, X.; Lin, S.; Xiang, S. Rhodium-Catalyzed NH-Indole-
Directed C–H Carbonylation with Carbon Monoxide: Synthesis
of 6H-Isoindolo[2,1-a]indol-6-ones. J. Org. Chem. 2016, 81,
12135-12142. (d) Guo, S.; Tao, L.; Wang, F.; Fan, X. Pd-
Catalyzed Cyclocarbonylation of 2-(2-Bromoaryl)indoles with
CO as a C1 Source: Selective Access to 6 H-Isoindolo[2,1-
a]indol-6-ones and Indeno[1,2-b]indol-10(5 H)-ones. Chem.
Asian. J. 2016, 11, 3090-3096. (e) Liu, B.; Lai, C.; Zhang, C.;
Zhou, X. Synthesis of 6H-isoindolo[2,1-a]indol-6-ones via Pd-
catalyzedcycloaminocarbonylation of2-(1H-indol-2-yl)phenyl
tosylates with CO. Tetrahedron 2018, 74, 752-757.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website.
1
Optimization of reaction conditions and H, 13C and 19F
(8) Hayashi, K.; Choshi, T.; Chikaraishi, K.; Oda, A.; Yoshinaga,
R.; Hatae, N.; Ishikura, M.; Hibino, S. A novel total synthesis
NMR spectra for all compounds (PDF).
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of isocryptolepine based on
tandemCurtius rearrangement and aza-electrocyclic reaction.
Tetrahedron 2012, 68, 4274-4279.
a
microwave-assisted
hypervalent iodine(III)-promoted cascade cyclization. RSC Adv.
2015, 5, 13102-13106.
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2579-2584. (c) Slatkovská, B.; Ondriaš, J.; Doháňošová, J.;
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Substituted Indenoisoquinolines through Carbonylative
Cycloamination with [Fe(CO)5]. ChemistrySelect 2017, 2,
3948-3951. (d) Markovič, M.; Lopatka, P.; Koóš, P.; Gracza, T.
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isoindolo[2,1-a]indol-6-ones through
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Glyoxylic Acid as
a
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C.; Castedo, L.; Estévez, R. J. Copper(I) Mediated
Intramolecular
Cyclization
of
and
2-(2-Amino-
[2-(2-
phenylethynyl)benzoic
Aminophenylethynyl)phenyl]acetic Acid Esters:
Synthetic Step towards Isoindolo[2,1-a]indoles and 5H-
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Facile synthesis of 11-aryl-6H-isoindolo[2,1-a]indol-6-ones via
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The Journal of Organic Chemistry
Commercially available substrates
Br
1
2
3
4
[Pd]
ligand, base
R1
R1
+
R
N
1,4-dioxane
N
X
130 o
C
H
R
X
Br OTf
,
=
CO
O
5
6
7
8
REACTION VIAL
29 examples
(up to 64%yield)
H2SO4
(conc.)
O
HO
OH
130 o
30 min
C
OH
9
DEVELOPMENT VIAL
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