Rapid synthesis of the indole-indolone scaffold via [3+2] annulation of arynes by methyl indole-2-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2009.04.047

The reaction of methyl indole-2-carboxylates and arynes affords a very efficient, high yielding synthesis of a novel indole-indolone ring system, which tolerates considerable functionality, is broad in scope, and proceeds under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2009.04.047

Tetrahedron Letters 50 (2009) 4003–4008
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid synthesis of the indole-indolone scaffold via [3+2] annulation of arynes
by methyl indole-2-carboxylates
*
Donald C. Rogness, Richard C. Larock
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of methyl indole-2-carboxylates and arynes affords a very efficient, high yielding synthesis
of a novel indole-indolone ring system, which tolerates considerable functionality, is broad in scope, and
proceeds under mild reaction conditions.
Received 27 March 2009
Accepted 8 April 2009
Available online 14 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aryne
Annulation
Indole
Nitrogen-containing heterocycles exhibit a diverse array of
favorable biological and pharmacological properties. The indole
core, in particular, is the foundation for many well-known medic-
inally active compounds.1 Convenient methods for constructing
fused indoles are of great value to medicinal chemists.1,2 In addi-
tion, indolone derivatives possess potent biological activities. Thus,
new methodologies for their synthesis contribute significantly to
the pursuit of new drugs.3 Of considerable current interest to
medicinal chemists is the synthesis of new drug-like compounds
in which two separate biologically interesting scaffolds, both inde-
pendently known for their favorable activities, are fused.2,4 Since
both indoles and indolones are relevant core structures for phar-
maceuticals, a hybrid thereof could potentially lead to a series of
biologically active compounds (Fig. 1).
Arynes have been used extensively in recent years in the con-
struction of many heteroaromatic structures.5 The highly electro-
philic nature of benzyne is most suitable for cross coupling with
various nucleophilic heteroatoms. If the substrate containing the
nucleophilic heteroatom is tethered with a neighboring electro-
phile, such as a carbonyl group, intramolecular annulations often
take place.6 Recently, our group has reported annulations between
ortho-heteroatom (N, O, and S) benzoates with arynes, producing a
diverse array of medicinally relevant acridones, xanthones, and
thioxanthones in good to excellent yields.7 The proven success
and utility of this novel methodology led us to envision a related
[3+2] annulation involving the reaction of indole-2-carboxylate es-
ters and arynes. Herein, we report the synthesis of a novel indole-
O
N
Indole
Indolone
Figure 1. Indole-indolone scaffold.
indolone hybrid, a previously unexplored scaffold with respect to
biological activity and materials applications, via the annulation
of arynes by methyl indole-2-carboxylates (Scheme 1).
Initial experiments began with ethyl indole-2-carboxylate as
our test substrate, but little success was realized using conditions
similar to those of our previous annulation chemistry.7 Switching
to the methyl ester, however, produced a slight increase in yield
of the desired product (Table 1, entry 1). It was not until we
switched to 1,2-dimethoxyethane (DME) as a solvent that decent
results were obtained (entry 3). The addition of various bases
was examined and a significant improvement in yield was realized
when 2 equiv of Cs2CO3 was utilized (entry 6). The success of this
base over others (entries 7–9) may be attributed to its superior sol-
ubility in DME. The success of aryne annulation chemistry often
depends heavily on the relative rate of aryne formation versus
bimolecular coupling of the substrate and the aryne. For that rea-
son, both the quantity and the nature of the fluoride source, as well
as the solvent and temperature, are often critical. CsF has generally
been the most popular source of fluoride used in benzyne chemis-
try and, in fact, it seems to work best for our methodology. Other
sources of fluoride, such as tetrabutylammonium reagents have
* Corresponding author. Tel.: +1 515 294 4660; fax: +1 515 294 0105.
E-mail address: larock@iastate.edu (R.C. Larock).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.047

4004
D. C. Rogness, R. C. Larock / Tetrahedron Letters 50 (2009) 4003–4008
R2
R2
O
R1
OTf
F
R1
R3
N
CO2Me
N
TMS
H
R3
1
2
3
Scheme 1. General reaction of arynes with methyl indole-2-carboxylates.
Table 1
Optimization studies of the reaction between methyl indole-2-carboxylate and o-(trimethylsilyl)phenyl triflate (Scheme 1, R1 = R2 = R3 = H)a
Entry
Aryne precursor (equiv)
Fluoride sourceb (equiv)
Base (equiv)
Solvent
Temp. (°C)
% Yieldc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.2
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.5
1.5
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
TBAT (2)
TBAF (2)
—
—
—
THF
65
80
90
90
90
90
90
90
90
90
120
90
rt
22
34
44
52
55
70
34
34
39
<10
62
62
33
19
MeCN
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
Cs2CO3 (1.1)
Cs2CO3 (1.1)
Cs2CO3 (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
CsOPiv (2.0)
NaH (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
rt
a
Reaction conditions: 0.5 mmol of 1, 5 mL of solvent, 24 h. optimized conditions are indicated in bold.
Per 1 equiv of benzyne precursor.
Isolated yields.
b
c
been examined. However, the overall yields declined (entries 13
that the overall yields depend greatly on the electronics of the ar-
yne precursors. Thus, electron-rich aryne precursor 2c gave the
highest yield (entry 2), whereas electron-poor aryne precursor 2d
gave the lowest yield (entry 3). Unsymmetrical benzyne precursors
present an issue of regioselectivity, since a nucleophile can attack
either one of the two reactive aryne carbons. Some unsymmetrical
benzyne precursors display higher regioselectivity than others. For
example, it has been reported in the literature that benzyne pre-
cursor 2f undergoes nucleophilic attack at the meta-position for
both steric and electronic reasons.9 As expected, our observations
were consistent with the previous reports. Utilizing a 2D-NOESY
experiment, the structure of product 3t was established as shown
(entry 6). Benzyne precursor 2g also presents regioselectivity is-
sues. Here a single product was formed. Although a 2D-NOESY
experiment was not performed on the major isolated product, it
is assumed that the nitrogen nucleophile would attack at the beta
position based on steric hindrance. In addition, previous literature
has shown that benzyne precursor 2g preferably undergoes attack
at the beta position.10,6b
A possible mechanism for formation of the [3+2] annulated
product parallels what has been proposed previously in the litera-
ture (Scheme 2).7 First, immediately following formation of the
benzyne, a negatively charged indole nucleophilically attacks the
aryne, resulting in intermediate A. The newly formed aryl carban-
ion then intramolecularly attacks the neighboring ester, displacing
a methoxy group, which can also aid in deprotonation of the indole
starting material.
and 14), even though these fluorides are more soluble in DME.
With optimized conditions in hand (Table 1, entry 6), we have
explored the scope and limitations of our methodology. Suitable
indole substrates were easily prepared by the esterification of
commercially available 2-indolecarboxylic acids. It was found that
indoles containing electron-donating groups generally resulted in
lower yields than the unsubstituted indole (Table 1, entries 2–6).
Possibly, the electron-donating groups decrease the acidity of the
indole, resulting in a weaker nucleophile. In fact, for all substrates
containing a methoxy group, it has been observed that a signifi-
cant amount of the starting material remains after 24 h. Low
yields are also obtained with indole 1g, a substrate containing a
highly electron-withdrawing group. It is believed, however, that
steric crowding of the nitro group around the nucleophilic nitro-
gen center is the main reason for the observed decrease in yield
(entry 7). On the other hand, a variety of 5-haloindole-2-carbox-
ylates have afforded good yields of the desired products (entries
8–10).8 Interestingly, even better results were observed when
the halogen occupies the 3-position of the indole (entries 11–
13). This trend is also observed in substrates 1n and 1o, whose
3-positions are substituted (entries 14 and 15) and near quantita-
tive yields are observed. This may be attributed to steric effects,
in that a substituent at the 3-position can better help direct the
electrophilic ester moiety for intramolecular attack by the inter-
mediate aryl carbanion. As expected, replacement of the N–H
with a N-methyl group prevented any formation of the desired
N-annulated product (entry 16).
In conclusion, we have demonstrated a new and novel ben-
zyne methodology for the synthesis of a previously unexplored
indole-indolone scaffold, which provides good to excellent yields.
The reaction involves a [3+2] annulation of arynes by methyl in-
dole-2-carboxylates under mild conditions, producing a variety
of functionally diverse compounds. In addition, a variety of
substituted benzyne precursors, both symmetrical and unsym-
After a number of methyl indolecarboxylates were examined,
we turned our attention toward screening various benzyne precur-
sors. Substrate 1l was chosen for these reactions due to its favor-
able performance with benzyne precursor 2a (Table 2, entry 12).
A series of symmetrical benzyne precursors were examined first
(Table 3, entries 1–4) and good yields were obtained. It was found

D. C. Rogness, R. C. Larock / Tetrahedron Letters 50 (2009) 4003–4008
4005
Table 2
[3+2] Annulations of methyl indole-2-carboxylatesa
R2
R2
4
3
OTf
O
R1
5
CsF, Cs2CO3
2
R1
CO2Me
N
6
DME
90 °C, 24 h
1
N
TMS
7
R3
1
2a
3
Entry
Substrate
Product
% Yieldb
O
N
1
R1 = R2 = R3 = H, 1a
70
3a
Me
O
N
2
3
4
R
1 = 5-Me, R2 = R3 = H, 1b
62
28
45
3b
MeO
O
R1 = 5-OMe, R2 = R3 = H, 1c
N
3c
OMe
O
R
1 = 4-OMe, R2 = R3 = H, 1d
N
3d
O
N
MeO
5
6
7
8
R1 = 6-OMe, R2 = R3 = H, 1e
33
39
40
3e
3f
MeO
MeO
O
R
R
R
1 = 5,6-(OMe)2, R2 = R3 = H, 1f
1 = 7-NO2, R2 = R3 = H, 1g
1 = 5-F, R2 = R3 = H, 1h
N
O
N
NO2
3g
F
O
N
64
3h
(continued on next page)

4006
D. C. Rogness, R. C. Larock / Tetrahedron Letters 50 (2009) 4003–4008
Table 2 (continued)
Entry
Substrate
Product
% Yieldb
Cl
O
O
N
N
9
R1 = 5-Cl, R2 = R3 = H, 1i
78
3i
Br
10
R
1 = 5-Br, R2 = R3 = H, 1j
76
3j
Cl
O
11
R
1 = R3 = H, R2 = Cl, 1k
83
N
3k
Br
O
O
12
R1 = R3 = H, R2 = Br, 1l
88
N
3l
I
13
R1 = H, R2 = I, R3 = H, 1m
85
N
3m
O
14
R1 = R3 = H, R2 = Ph, 1n
94
N
3n
3o
CO2Me
O
15
R1 = R3 = H, R2 = CO2Me, 1o
88
N
16
R1 = R2 = H, R3 = Me, 1p
—
0
a
Reaction conditions: 0.50 mmol of 1, 0.75 mmol of 2, 2.25 mmol of CsF, 1.00 mmol of Cs2CO3, DME (5 mL) at rt for 1 d.
Isolated yields.
b

D. C. Rogness, R. C. Larock / Tetrahedron Letters 50 (2009) 4003–4008
4007
Table 3
Reactions of indole 1l with various benzyne precursors
Br
Br
6
O
1
OTf
5
4
CsF, Cs2CO3
CO2Me
N
R
DME
90 °C, 24 h
N
H
2
TMS
3
R
1l
2
3
Entry
Benzyne precursor
Product
% Yielda
Br
O
N
1
R = 4,5-Me2, 2b
67
Me
Me
3p
Br
O
N
2
R = 4,5-(OMe)2, 2c
87
OMe
MeO
Br
3q
O
N
3
R = 4,5-F2, 2d
37
F
F
3r
Br
O
N
4
R = 4,5-(CH)4–, 2e
67
3s
Br
N
O
5
R = 3-OMe, 2f
82
OMe
3t
Br
N
O
6
R = 3,4-(CH)4–, 2g
74
3u
a
Isolated yields.

4008
D. C. Rogness, R. C. Larock / Tetrahedron Letters 50 (2009) 4003–4008
OTf
O
CsF, Cs2CO3
CO2Me
N
DME
90 °C, 24h
N
TMS
H
O
O
N
OMe
N
OMe
Cs
A
Scheme 2. Proposed mechanism.
4. (a) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed. 2003, 42,
3996–4028; (b) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem.
2005, 7, 813–815; (c) Meunier, B. Acc. Chem. Res. 2008, 41, 69–77; (d) Bajorath,
J. Mol. Diversity 2002, 5, 305–313.
5. Chen, Y.; Larock, R. C. In Modern Arylation Methods; Ackerman, J., Ed.; Wiley/
VCH: New York, 2009; pp 401–473.
6. (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2006, 128, 13112–13122; (b)
Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002,
41, 3247–3249; (c) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5340–5341.
metrical, undergo smooth annulations. Single regioisomers have
been obtained in good yields for the unsymmetrical benzyne
precursors studied. This novel indole-indolone scaffold holds
great promise for biological activity. In addition, compounds 3j,
3l, 3m, and 3p–u are suitable for further elaboration via palla-
dium chemistry if a combinatorial library of these compounds
is desired.
7. (a) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583–588; (b) Zhao, J.; Larock, R.
C. Org. Lett. 2005, 7, 4273–4275.
Acknowledgments
8. Representative procedure (3i, Table 2, entry 9): An oven dried 6-dram vial
equipped with a stirrer bar was charged with 107.4 mg of 1i (0.50 mmol) and
223.8 mg of 2a (0.75 mmol), followed by 2.5 mL of dry DME. The mixture was
briefly stirred and 325.8 mg of dry Cs2CO3 and 341.8 mg of dry CsF were added
sequentially, followed by an additional 2.5 mL of DME, washing the sidewalls
of the vial. The vial was sealed and placed in an oil bath at 90 °C and allowed to
stir for 1 d. The resultant mixture was cooled and eluted through a plug of silica
gel with ethyl acetate and DCM. The filtrate was dried with anhydrous Na2CO3,
decanted, and evaporated. The residue was impregnated with silica gel and
purified by column chromatography (35:1–10:1 hexane/ethyl acetate),
affording 98.3 mg of the desired product 3i as a light orange solid; mp 203–
204 °C; 1H NMR (400 MHz, CDCl3) d 7.62 (d, J = 7.6 Hz, 1 H), 7.57 (s, 1 H), 7.50 (t,
J = 7.6 Hz, 1 H), 7.31–7.39 (m, 2 H), 7.26 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1
H), 6.99 (s, 1 H); 13C NMR (100 MHz CDCl3) d 181.4, 145.3, 136.8, 135.8, 133.6,
132.5, 129.3, 128.5, 127.7, 125.5, 124.4, 124.4, 112.3, 111.4, 107.0; HRMS (EI):
calcd for C15H8ClNO 253.0294, found 253.0301.
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593) and the National Institutes of Health
Kansas University Center of Excellence in Chemical Methodology
and Library Development (P50 GM069663) for their generous
financial support. We also thank Dr. Feng Shi for his help in the
preparation of some of the aryne precursors.
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