Unified Strategy to Access 6H-Benzofuro[2,3-b]indoles and 5,6-Dihydroindolo[2,3-b]indoles via UV Light-Mediated Diradical Cyclization

Article abstract of DOI:10.1002/adsc.201701270

A unified protocol for the construction of 6H-benzofuro[2,3-b]indoles and 5,6-dihydroindolo[2,3-b]indoles via UV light-mediated diradical cyclization was developed and preliminary efforts were also made to functionalize at C10b position of 6H-benzofuro[2,3-b]indoles. This mild and facile strategy may have great potential in the syntheses of natural products and functional materials. (Figure presented.).

Full text of DOI:10.1002/adsc.201701270

Title: Unified strategy to access 6H-benzofuro[2,3-b]indoles and 5,6-
dihydroindolo[2,3-b]indoles via UV light-mediated diradical
cyclization
Authors: Bin cheng, Bing Zu, Yuntong Li, Shengxian Zhai, Wei Xu, Yun
Li, and Hongbin Zhai
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701270
Link to VoR: http://dx.doi.org/10.1002/adsc.201701270

10.1002/adsc.201701270
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201
Unified strategy to access 6H-benzofuro[2,3-b]indoles and 5,6-
dihydroindolo[2,3-b]indoles via UV light-mediated diradical
cyclization
Bin Cheng,*,a Bing Zu,a,‡ Yuntong Li,a,‡ Shengxian Zhai,a Wei Xu,a Yun Lia and
Hongbin Zhai*,a,b,c
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, People’s Republic of China
E-mail: chengb@lzu.edu.cn or zhaihb@pkusz.edu.cn
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School
b
of Peking University, Shenzhen 518055, People’s Republic of China
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of
c
China
‡
These authors contributed equally to this work
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
In contrast, only a few methods for the construction
of 6H-benzofuro[2,3-b]indoles and 5,6-
Abstract: A unified protocol for the construction of
6H-benzofuro[2,3-b]indoles and 5,6-dihydroindolo[2,3-
b]indoles via UV light-mediated diradical cyclization
was developed and preliminary efforts were also made to
functionalize at C10b position of 6H-benzofuro[2,3-
b]indoles. This mild and facile strategy may have great
potential in the syntheses of natural products and
functional materials.
dihydroindolo[2,3-b]indoles have been reported. The
major synthetic approaches to 5,6-dihydroindolo[2,3-
b]indoles include two classes: (i) Pd-mediated C-I/C-
H or oxidative C-H/C-H coupling reaction (Scheme 1,
path (a)),[3,5] (ii) electrophilic amination of arene C-H
bond,[6] Cadogan cyclization,[7] and iodine-mediated
cyclization (path b).[8] As for 6H-benzofuro[2,3-
b]indoles, there are only two synthetic routes via
copper-mediated coupling reaction[9] or oxidative
cycloamination reaction[10] in literature. Given these
approaches often require high temperatures,
prefunctionalized substrates, and/or multi-step
manipulation, developing a simple and practical
method to access these heterocycle-fused indoles is
still highly desirable.
Keywords: UV light-mediated; diradical cyclization;
6H-benzofuro[2,3-b]indole; 5,6-dihydroindolo[2,3-
b]indole.
Indole derivatives are one of the most important
nitrogen-containing heterocycles with wide-spectrum
bioactivities and diverse structures.[1] Among them,
6H-benzofuro[2,3-b]indoles
and
5,6-
dihydroindolo[2,3-b]indoles, two intriguing classes of
heterocycle-fused indoles, have attracted tremendous
attention owing to their wide applications in
functional
materials
(such
as
OLED),[2]
pharmaceutical/medicinal chemistry[3] and other
scientific fields. Especially, C10b functionalized
5a,10b-dihydro-6H-benzofuro[2,3-b]indoles widely
distributed in quite a number of natural products such
as diazonamide A and azonazine (Figure 1), had
raised broad interest from organic community, and a
variety of efficient approaches to build this
framework were developed, including intramolecular
[3+2] annulation, intramolecular electrosynthesis, and
iminium-catalyzed cascade process, among others.[4]
Figure 1. Representative natural products
diazonamide
A
and azonazine with C10b
functionalized
5a,10b-dihydro-6H-benzofuro[2,3-
b]indole structural unit.
During our ongoing work for facile construction of
spiro[indazole-3,3’-indolin]-2’-ones via 1,3-dipolar
1
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10.1002/adsc.201701270
Advanced Synthesis & Catalysis
cycloaddition of arynes with 3-diazoindolin-2-ones,
we found that indazolo[2,3-c]quinazolin-6(5H)-ones
could be readily afforded from spiro[indazole-3,3’-
indolin]-2’-ones through thermal isomerization.[11] As
part of our continuous endeavour to develop other
transformations of these unique azo spirooxindoles,
we present herein a unified approach to synthesize
diazene-based bond-forming chemistry.[15] Inspired
by these advances, we wondered whether azo
spirooxindoles could be transform into other useful
scaffolds via UV light radiation. Thus, we allowed
the spirooxindole 1a to be radiated with UV lamps.
To avoid dimerization, we conducted the reaction in a
highly diluted solution. To our delight, the desired
diradical cyclization product 2a was obtained in 49%
yield in THF with a concentration of 12 mM along
with some unidentified side-products (Table 1, entry
1). Subsequent X-ray studies revealed that one of the
side pathways was dimerization.[16] Further diluting
the solution resulted in a higher yield (63%, entry 3),
while lower concentration could not raise the yield of
2a (entries 4 and 5). When the solvent was changed
from THF to DCM, PhMe, and CH3CN (entries 6−8),
it was found that DCM and PhMe afforded
comparable yields. However, CH3CN was found to
be inferior probably because the C-N triple bond of
CH3CN interfered with the radical reaction. Exposure
of the reaction system to the air lowered the yield
slightly (entry 9). When a different light source such
as LED UV lamp (15 W) was employed, the reaction
also proceeded smoothly but required longer time
(entry 10).
6H-benzofuro[2,3-b]indoles
and
5,6-
dihydroindolo[2,3-b]indoles via UV light-mediated
diradical cyclization from this class of azo
spirooxindoles and their N-analogues.
Table 1. Optimization of reaction conditions[a]
Concentration
Entry
Solvent
Yield [%][b]
(mM)
Scheme 1. Synthetic routes to 6H-benzofuro[2,3-
b]indoles and 5,6-dihydroindolo[2,3-b]indoles
1
12
9
6
3
0.8
6
6
6
THF
THF
THF
THF
49
59
63
63
63
52
60
44
50
55
2
3
4
5
6
In
modern
organic
synthesis,
chemical
THF
transformations mediated by light are thought to be
superior to conventional transition metal-catalyzed
reactions, because light is a traceless, nonpolluting
reagent,[12] and most of the current efforts are focused
on visible light photoredox catalysis.[13] Reactions
mediated by UV light are usually associated with
multiple side pathways and poor functional group
tolerance due to the high energy of UV light, but they
usually do not require additional photocatalysts to
sensitize organic molecules. Moreover, UV light-
induced extrusion of nitrogen from benzotriazole or
indazole derivatives followed by diradical cyclization
was early developed to prepare diverse
heterocycles.[14] Recently, Movassaghi reported a
series of total synthesis of dimeric alkaloids via
diazene-directed fragment assembly strategy, further
highlighting the importance and practicality of
DCM
Toluene
CH3CN
THF
7
8
9[c]
6
6
10[d]
THF
[a]
Reaction conditions: 1a (0.2 mmol), 250 W high-
pressure Hg UV lamp (365 nm), solvent, under N2.
[b] Isolated yields of 2a.
[c] Under air.
[d] 15 W LED UV lamp (365 nm) was used instead.
With the optimal reaction conditions in hand
(Table 1, entry 3), we set out to explore the substrate
scope of spirooxindoles prepared via 1,3-dipolar
cycloaddition of arynes with 3-diazoindolin-2-ones.
As shown in Table 2, substrates bearing various N-R3
2
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10.1002/adsc.201701270
Advanced Synthesis & Catalysis
including allyl and propargyl groups were all
applicable to this radical reaction, affording
corresponding 6H-benzofuro[2,3-b]indoles (2a−f) in
41−63% yields. Next, substrates with various R1 on
the benzene moiety of the oxindole were studied and
it was found that all of them except for 1n with 9-
OMe provided the desired products in moderate
yields (2g−n). Notably, it is interesting that bromo
group could survive under this radical conditions
(2j−l), which is useful handle for derivatizing to get
OLED materials.[2] The substituent of R2 on the
benzene moiety of indazole was also examined, and it
revealed that either electron-donating group (e.g.,
1o−q) or electron-withdrawing group (e.g., 1r) had
no pronounced effect on the yields of the radical
reaction.
with N-Ms performed better than those with N-Ts for
this diradical reaction (2s versus 2v, 2u versus 2x).
Table 3. Scope of diradical reaction of
spiro[indazole-3,3’-indolin]-2’-imines[a]
Table 2. Scope of diradical reaction of
spiro[indazole-3,3’-indolin]-2’-ones[a]
[a]
Reaction conditions: 1 (0.2 mmol), 250 W high-
pressure Hg UV lamp (365 nm), THF (33 mL),
under N2, 4−10 h. Isolated yield.
Fascinated by natural products diazonamide A and
azonazine containing a C10b functionalized 5a,10b-
dihydro-6H-benzofuro[2,3-b]indole core, we set out
to explore the derivation reaction at the C10b position
of
6H-benzofuro[2,3-b]indole
(Scheme
2).
Interestingly, when 2a was treated with TsOH·H2O,
3a was obtained in 98% yield via an acid-mediated
ring-opening reaction. While using anhydrous TsOH
and allyl alcohol, 4a was obtained via an acid-
promoted ring-opening and Claisen-rearrangement
cascade process along with a small amount of 3a. 3a
and 4a could be transformed into 6a through a multi-
step manipulation according to the literature.[19] At
this stage, we have developed a novel route to C10b
[a]
functionalized
5a,10b-dihydro-6H-benzofuro[2,3-
Reaction conditions: 1 (0.2 mmol), 250 W
b]indoles through ring-opening and recyclization
strategy. However, bromination at C10b using
NBS/NaBH4 failed to deliver the desired bromination
product 5a, and an unidentified product was isolated.
high-pressure Hg UV lamp (365 nm), THF (33
mL), under N2, 4−10 h. Isolated yield.
With the successful construction
of 6H-
benzofuro[2,3-b]indoles via UV light-mediated
diradical reaction, we wondered whether 5,6-
dihydroindolo[2,3-b]indoles could be accessed in a
similar fashion. Following the same procedure, we
prepared a library of spiro[indazole-3,3'-indolin]-2'-
imines (1s−x) from 3-diazoindolin-2-imines and
benzynes.[17] Note that although 3-diazoindolin-2-
imines had been successfully applied in a range of
reactions to prepare diverse heterocycles via
transition metal-catalyzed carbene reactions,[18] there
have been no reports to date on their use as 1,3-
dipoles. Then spiro[indazole-3,3'-indolin]-2'-imines
1s−x were subjected to UV radiation and all of them
proceeded smoothly to afford 5,6-dihydroindolo[2,3-
b]indole derivatives (2s−x) in moderate yields (Table
3). As shown in Table 3, it was clear that substrates
Scheme 2. Diverse transformations.
In accordance with the previous reports,[14] the
plausible diradical mechanism for the formation of 2a
was proposed and shown in Scheme 3. Initially,
3
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10.1002/adsc.201701270
Advanced Synthesis & Catalysis
Topics in Heterocyclic Chemistry, Springer,
Heidelberg, 2010, Vol. 26; b) A. J. Kochanowska-
Karamyan, M. T. Hamann, Chem. Rev. 2010, 110,
4489; c) M. Ishikura, K. Yamada, T. Abe, Nat. Prod.
Rep. 2010, 27, 1630.
spiro[indazole-3,3’-indolin]-2’-one 1a undergoes
decomposition to release N2 under the radiation of
UV light and then forms diradical intermediate 7a.[20]
Next intramolecular diradical cyclization forms a new
C-O bond and delivers the desired 2a. On the other
hand, intermediate 7a could also undergo H-
abstraction and then dimerize to afford a dimer 9a,[21]
which has been demonstrated by X-ray studies.[16]
[2] a) H. W. Ham, B. G. Kim, H. C. An, D. J. Kim, J. W.
Han, G. T. Kim, H. J. Lee, D. W. Lim, PCT Int. Appl.
WO 2015076599, 2015; b) H.-W. Ham, H.-C. An, J.-W.
Han, D.-J. Kim, G.-T. Kim, H.-J. Lee, PCT Int. Appl.
WO 2014104797, 2014.
[3] B. Prasad, B. Y. Sreenivas, D. Rambabu, G. R. Krishna,
C. M. Reddy, K. L. Kumar, M. Pal, Chem. Commun.
2013, 49, 3970.
[4] For some representative examples, see: a) A. W. G.
Burgett, Q. Li, Q. Wei, P. G. Harran, Angew. Chem. Int.
Ed. 2003, 42, 4961; b) J.-C. Zhao, S.-M. Yu, Y. Liu,
Z.-J. Yao, Org. Lett. 2013, 15, 4300; c) R. R. Knowles,
J. Carpenter, S. B. Blakey, A. Kayano, I. K. Mangion,
C. J. Sinz, D. W. C. MacMillan, Chem. Sci. 2011, 2,
308; d) H. Ding, P. L. DeRoy, C. Perreault, A. Larivée,
A. Siddiqui, C. G. Caldwell, S. Harran, P. G. Harran,
Angew. Chem. Int. Ed. 2015, 54, 4818.
Scheme 3. Proposed mechanisms.
In summary, a facile UV light-mediated diradical
cyclization was developed to construct 6H-
benzofuro[2,3-b]indoles and 5,6-dihydroindolo[2,3-
b]indoles from azo spirooxindoles and their N-
analogues. The success of this method highlights the
importance and practicality of UV light-mediated
reactions, as it provides the core structures for further
derivatization either for natural product synthesis or
for material synthesis.
[5] K. Saito, P. K. Chikkade, M. Kanai, Y. Kuninobu,
Chem. Eur. J. 2015, 21, 8365.
[6] H. Gao, Q.-L. Xu, M. Yousufuddin, D. H. Ess, L. Kürti,
Angew. Chem. Int. Ed. 2014, 53, 2701.
[7] A. H. Jackson, D. N. Johnston, P. V. R. Shannon, J.
Chem. Soc., Chem. Commun. 1975, 911.
[8] S. Badigenchala, V. Rajeshkumar, G. Sekar, Org.
Biomol. Chem. 2016, 14, 2297.
[9] M. Sattar, V. Rathore, C. D. Prasad, S. Kumar, Chem.
Asian J. 2017, 12, 734.
Experimental Section
[10] M. Kienle, A. J. Wagner, C. Dunst, P. Knochel, Chem.
Asian J. 2011, 6, 517.
A solution of 1′-benzylspiro[indazole-3,3′-indolin]-2′-one
1 (0.20 mmol) in THF (33 mL) in schlenk quartz tube was
degassed, refilled with N2 for three times, and then radiated
with 250 W high-pressure Hg UV lamp (365 nm) for 4−10
h. The tube was surrounded with cold water to keep the
[11] B. Cheng, B. Zu, B. Bao, Y. Li, R. Wang, H. Zhai, J.
Org. Chem. 2017, 82, 8228.
[12] a) H. D. Roth, Angew. Chem. Int. Ed. 1989, 28, 1193;
b) T. P. Yoon, M. A. Ischay, J. Du, Nature Chem. 2010,
2, 527; c) N. Hoffmann, Photochem. Photobiol. Sci.
2012, 11, 1613; d) M. Oelgemꢀller, Chem. Rev. 2016,
116, 9664.
o
temperature of the solution in tube at 20-25 C. When 1
was almost completely depleted by monitoring on TLC,
the solvent was removed and the resulting residue was
purified by flash column chromatography to give 2.
[13] For reviews, see: a) J. M. R. Narayanam, C. R. J.
Stephenson, Chem. Soc. Rev. 2011, 40, 102; b) C. K.
Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev.
2013, 113, 5322.
Acknowledgements
We thank NSFC (21472072, 21302077, and 21290183), Program
for Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT_15R28), FRFCU (lzujbky-2016-ct02,
lzujbky-2017-90), and “111” Program of MOE for financial
support. We thank Dr. Hanwei Hu for his assistance in polishing
the manuscript and Prof. Qiang Liu for enlightening discussions.
[14] For some representative examples of UV light-
mediated diradical cyclization, see: a) K. Hirakawa, T.
Toki, K. Yamazaki, S. Nakazawa, J. Chem. Soc.,
Perkin Trans. 1, 1980, 1944; b) E. M. Burgess, R.
Carithers, L. McCullagh, J. Am. Chem. Soc. 1968, 90,
1923; c) N. A. Al-Jalal, M. R. Ibrahim, N. A. Al-Awadi,
M. H. Elnagdi, Y. A. Ibrahim, Molecules 2014, 19,
20695 and references therein; d) T. Yamazaki, H.
Shechter, Tetrahedron Lett. 1973, 14, 1417; e) I.
Hutchinson, A. J. McCarroll, R. A. Heald, M. F. G.
References
[1] For reviews see: a) G. W. Gribble, Ed. In Heterocyclic
Scaffolds II: Reactions and Applications of Indoles,
4
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10.1002/adsc.201701270
Advanced Synthesis & Catalysis
Stevens, Org. Biomol. Chem. 2004, 2, 220; f) E. D.
Edstrom, W. Yuan, Tetrahedron Lett. 1991, 32, 323.
[15] S. P. Lathrop, M. Pompeo, W.-T. T. Chang, M.
Movassaghi, J. Am. Chem. Soc. 2016, 138, 7763 and
references therein.
[16] The X-ray structural data of dimer 9a (shown in
mechanism part, Scheme 3) were deposited at the
Cambridge Crystallographic Data Center. CCDC
1569601 contains the supplementary crystallographic
data.
[17] The X-ray structural data of 1s were deposited at the
Cambridge Crystallographic Data Center. CCDC
1569796 contains the supplementary crystallographic
data.
[18] a) Y. Xing, G. Sheng, J. Wang, P. Lu, Y. Wang, Org.
Lett. 2014, 16, 1244; b) G. Sheng, K. Huang, Z. Chi, H.
Ding, Y. Xing, P. Lu, Y. Wang, Org. Lett. 2014, 16,
5096; c) B. Lang, H. Zhu, C. Wang, P. Lu, Y. Wang,
Org. Lett. 2017, 19, 1630 and references therein.
[19] a) S. Ghosh, L. K. Kinthada, S. Bhunia, A. Bisai,
Chem. Commun. 2012, 48, 10132; b) G. Peris, E.
Vedejs, J. Org. Chem. 2015, 80, 3050 and references
therein.
[20] A triplet quenching capture experiment with ethyl
acrylate was conducted, but failed.
[21] For homocoupling of 3-aryl-2-oxoindolin-3-yl radical,
see: a) D. Uraguchi, M. Torii, T. Ooi, ACS Catal. 2017,
7, 2765; for homocoupling of 3-alkyl-2-oxoindolin-3-yl
radical, see: b) W.-L. Jia, J. He, J.-J. Yang, X.-W. Gao,
Q. Liu, L.-Z. Wu, J. Org. Chem. 2016, 81, 7172.
5
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10.1002/adsc.201701270
Advanced Synthesis & Catalysis
COMMUNICATION
Unified strategy to access 6H-benzofuro[2,3-
b]indoles and 5,6-dihydroindolo[2,3-b]indoles
via UV light-mediated diradical cyclization
Adv. Synth. Catal. Year, Volume, Page – Page
Bin Cheng,* Bing Zu, Yuntong Li, Shengxian
Zhai, Wei Xu, Yun Li and Hongbin Zhai*
6
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