Phenanthroline- tBuOK Promoted Intramolecular C-H Arylation of Indoles with ArI under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.8b03449

The first example of phenanthroline-^tBuOK promoted intramolecular radical C-H arylation of N-(2-iodobenzyl)indoles without involvement of transition metals has been developed. A variety of substituted 6H-isoindolo [2, 1-a] indoles were prepared by a simple and efficient intramolecular cyclization using 1,10-phenanthroline in the presence of potassium tert-butoxide and chlorobenzene. This strategy provides a fast and versatile access to isoindolo[2,1-a]indole derivatives for the synthesis of pharmaceuticals and organic electroluminescent (EL) materials.

Full text of DOI:10.1021/acs.orglett.8b03449

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phenanthroline‑tBuOK Promoted Intramolecular C−H Arylation of
Indoles with ArI under Transition-Metal-Free Conditions
Xiang-Huan Shan,† Bo Yang,† Hong-Xing Zheng,† Jian-Ping Qu,*,‡ and Yan-Biao Kang*,†
†Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
S
* Supporting Information
ABSTRACT: The first example of phenanthroline-tBuOK promoted intramolecular radical C−H arylation of N-(2-
iodobenzyl)indoles without involvement of transition metals has been developed. A variety of substituted 6H-isoindolo [2, 1-a]
indoles were prepared by a simple and efficient intramolecular cyclization using 1,10-phenanthroline in the presence of
potassium tert-butoxide and chlorobenzene. This strategy provides a fast and versatile access to isoindolo[2,1-a]indole
derivatives for the synthesis of pharmaceuticals and organic electroluminescent (EL) materials.
soindolo[2,1-a]indole represents an important and ubiq-
intramolecular five-membered radical cyclization,7 especially
in the case of 6H-isoindolo [2, 1-a] indole synthesis, suffered
from low yield due to the direct reductive dehalogenation of
the staring materials (Scheme 1).7b
I
uitous heterocyclic frameworks in the medical chemistry1
and material chemistry (Figure 1).2 The preparation of
The base-promoted homolytic radical aromatic substitution
(BHAS)8−10 approach has recently emerged since Itami8a
Scheme 1. Transition-Metal-Free Synthesis of 6H-
Isoindolo[2,1-a]indoles via Intramolecular Radical
Cyclization
Figure 1. Selected examples for pharmaceuticals, biologically active
compounds, and organic electroluminescent (EL) materials.
isoindolo[2,1-a]indoles has gained considerable research
interest. Catalytic intramolecular direct arylation of N-(2-
iodobenzyl)indoles involving transition metals3−5 provides a
fast access to isoindolo[2,1-a]indoles albeit with the problem
of removal heavy metals residues in the products limiting its
application in pharmaceutical synthesis. Therefore, a tran-
sition-metal-free cyclization is highly desired.
Tributyltin hydride promoted intramolecular six- and seven-
membered radical cyclization afforded the corresponding
heterocycles in moderate to good yield.6 However, the
Received: October 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reported that potassium tert-butoxide could effect the addition
of haloarenes to electron-deficient aromatic rings in 2008.
1,10-Phenanthrolines have been proved to be a useful additive
to assist the potassium tert-butoxide induced intramolecular
radical cross coupling of arenes and alkenes to construct fused
heterocycles, but they normally focused on the electron-rich
arenes or simple arenes.9 Moreover, despite the fact that
intermolecular transition-metal-free C−H arylation of hetero-
cycles have been reported,11 intramolecular transition-metal-
free C−H arylation of heterocycles is scarce.
On the basis of our studies on self-hydrogen transferring
rearrangement12a and hydrodehalogenation12b promoted by
potassium tert-butoxide, we developed the first example of
intramolecular C−H arylation of indoles and azaindoles, in
which 1,10-phenanthroline assists intramolecular cyclization of
the aryl radical onto C2 of indoles to give fused isoindolo [2,1-
a] indoles in up to 90% yield (Scheme 1, down), while the
reported intermolecular transition-metal-free arylation of
indoles normally occurred on the C311 or N-position11c of
indoles. Herein, we present our result in details.
chlorobenzene at 90 °C for 24 h afforded the optimal yield
(83%, entry 13).
After establishing the standard reaction conditions, the
substrate scope of radical cyclization was then investigated.
Several N-(2-iodobenzyl) indoles bearing an electron -donat-
ing group on the benzyl group have been subjected to the
standard conditions, and generally good yields were obtained
(Scheme 2, 2b−2d). The effect of substituted groups on the
indole was also investigated (Scheme 2, 2f−2v). High yields
were achieved with N-(2-iodobenzyl) indoles bearing both
electron-donating groups and electron-withdrawing groups
except that when 4-CN indole was employed 2p was obtained
in moderate yield. Bromide, chloride, and fluoride are tolerated
a
Scheme 2. Substrate Scope
The reaction conditions were first investigated as shown in
Table 1. In our early work, we noted that 10−40% of 1,10-
Table 1. Reaction Conditions
b
entry
L
x
base
y
M
2a (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
−
L1
L1
L1
L1
L1
L1
L1
L1
0.4
0.4
0.4
0.4
−
0.4
0.4
0.4
0.4
0.4
0.4
0.1
0.1
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuONa
tBuOLi
KOH
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
2.0
2.0
2.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
48
0
47
47
0
-
0
0
62
70
75
74
83
c
9
10
11
c
0.1
c
0.05
0.05
0.05
c
12
c d
,
13
a
Conditions: 1a (0.5 mmol), L (x mol %), base (y mol %), 90 °C,
b
1
toluene, argon, 12 h. Determined by H NMR using dibenzyl ether
as internal standard. PhCl instead of toluene as solvent. For 24 h.
c
d
phenanthroline L1 could assist the radical allylic isomerization
of allylic alcohol.11a By screening the organic additives L1−L4
(entries 1−4), 1,10-phenanthroline turned out to be the best
in current radical cyclization of 1-(2-iodobenzyl)-1H-indole
(1a). Without additive, the reaction could not occur (entry 5).
We also investigated other bases, such as lithium tert-butoxide,
sodium tert-butoxide, and potassium hydroxide, but they were
ineffective for the radical cyclization (entries 6−8). Using
chlorobenzene as solvent, yield improved from 48% to 62%
(entry 1 vs 9). Finally, using 10 mol % L1 (1,10-Phen) and 2.0
equiv of potassium tert-butoxide in the presence of
a
t
Reaction conditions: 1 (0.5 mmol), 1,10-Phen (10 mol %), BuOK
b
(1 mmol), PhCl (10 mL), 90 °C, under argon. PhCl (5 mL).
c
d
tBuOK (1.5 mmol). tBuOK (1.25 mmol), 100 °C.
B
DOI: 10.1021/acs.orglett.8b03449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tBuOK generates an electron donor L1-dianion with the
formation of A, followed by the intramolecular radical addtion
to afford intermediate B.10 The deprotonation of radical B
affords radical anion C. The SET between C and 1 yields target
product 2 with the regeneration of radical A.
In conclusion, an efficient radical C−H functionalization of
C2 on N-(2-iodobenzyl) indoles has been developed with the
assistant of 1,10-phenanthroline in the presence of potassium
tert-butoxide. A variety of substituted 6H-isoindolo[2,1-a]-
indoles were prepared by this simple intramolecular cycliza-
tion. This strategy provides a fast and versatile access to
isoindolo[2,1-a]indole derivatives. We anticipate that this
approach could be applied in other organic transformations,
especially in a transition-metal-free radical process for the
synthesis of pharmaceuticals and EL materials.
though there are competing dehalogenation reactions (2h−i,
2l−o, 2q, 2v).
A comparison of the optimized transition-metal-free reaction
conditions with previously reported Pd-catalyzed methods,
which was successful in intermolecular C−H arylation, was
investigated using 1a as model substrate (Table 2). However,
poor yields were obtained using Pd-catalysts in previous
reports.15−17
§
Table 2. Comparison of Catalyst Systems
e
entry
conditions
2a (%)
ref
a
1
1,10-Phen/tBuOK/90 °C
Pd(OAc)2/PPh3/MgO/150 °C
Pd(OAc)2/PPh3/ Et3N/100 °C
83
6
21
49
this work
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03449.
■
b
2
15
16
17
S
c
3
d
4
Pd(OAc)2/Et3N/80 °C
§
a
Reaction conditions: 1a (0.5 mmol), 1,10-Phen (10 mol %),
b
tBuOK (1 mmol), PhCl (10 mL), 24 h, 90 °C, under argon. 1a (0.5
Experimental procedures and NMR spectra (PDF)
mmol), Pd(OAc)2 (5 mol %), PPh3 (20 mol %), MgO (1.2 equiv),
c
dioxane, DMF, 12 h, 150 °C, under argon. 1a (0.5 mmol), Pd(OAc)2
Accession Codes
(6 mol %), PPh3 (6 mol %), Et3N (2.0 equiv), DMF, 5 h, 100 °C,
d
CCDC 1875985 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
under argon. 1a (0.5 mmol), Pd(OAc)2 (30 mol %), Et3N (3.0
e
equiv), CH3CN, 40 h, 80 °C, under argon. Isolated yield.
A gram-scale synthesis of 2a is demonstrated in eq 1. In a
typical procedure,18 1.23 g of 2a was obtained in 75% as a
white solid.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ybkang@ustc.edu.cn.
*E-mail: ias_jpqu@njtech.edu.cn.
ORCID
A radical process of this cyclization was confirmed by radical
trapping experiments. Radical scavengers such as TEMPO
totally inhibit the cyclization of 1a to 2a (Scheme 3). TEMPO
was recovered quantitatively after the control reaction,
indicating TEMPO was not destroyed by KOtBu.
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Notes
The authors declare no competing financial interest.
Scheme 3. Radical Trapping Experiments
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21672196, 21602001, 21831007, U1463202), and the
Fundamental Research Funds for the Central Universities of
China (WK2060190086) for financial support.
A proposed mechanism is illustrated in Scheme 4 on the
basis of former reports.8,10,13,14 The reaction of 1,10-Phen and
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DOI: 10.1021/acs.orglett.8b03449
Org. Lett. XXXX, XXX, XXX−XXX