CuSO4-Catalyzed dual annulation to synthesize O, S or N-containing tetracyclic heteroacenes

Article abstract of DOI:10.1039/d0cc01172j

In this work, CuSO₄ is utilized as a practical redox catalyst for tandem dual annulation in the synthesis of indole-fused tetracyclic heteroacenes, which are important skeletons in both medicinal chemistry and materials chemistry. The preparation of such skeletons in a convenient and efficient manner is in high demand. This method realizes the modular synthesis of benzofuro-, benzothieno-, and indoloindoles from abundant feedstocks such as 2-halobenzyl halides and nitrile derivatives in up to 99% yields, providing a rapid access to diverse indole-fused heteroacenes with biological or optoelectronic properties.

Full text of DOI:10.1039/d0cc01172j

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DOI: 10.1039/D0CC01172J
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CuSO4-Catalyzed Dual Annulation to Synthesize O, S or N-
Containing Tetracyclic Heteroacenes
Xiang-Huan Shan,†a, Bo Yang,†a Jian-Ping Qu,b and Yan-Biao Kang *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
In this work, CuSO4 is utilized as a practical redox catalyst for a cleavage of benzylic C-H bond, and the resulting carbanion can
tandem dual annulation in the synthesis of indole-fused tetracyclic pass through a radical addition to unsaturated bonds like C-O
heteroacenes, important skeletons in both medicinal chemistry and double bonds which is followed by an intramolecular alkoxy
materials chemistry. Preparation of such skeletons in a convenient radical addition to haloarenes.37 Recently, a catalytic approach
and efficient manner is in high demand. This method realizes has been reported for the generation of substituted indoles
modular synthesis of benzofuro-, benzothieno-, and indoloindoles with naturally abundant cupric sulfate.38 As part of our ongoing
from abundant feedstocks such as 2-halobenzyl halides and nitrile research interest in potassium tert-butoxide promoted
derivatives in up to 99% yields, providing a rapid access to diverse heterocycles synthesis, we envisaged that a strategy through
indole-fused heteroacenes with biological or optoelectronic benzylic C-H addition and iminyl radical relay can enable the
properties.
cyclization of 2-halobenzyl halides and nitriles to indole-fused
heteroacenes. Herein, we report our recent results in details.
Reaction conditions were first investigated using 2-((2-
iodobenzyl)oxy)benzonitrile 3a, generated from 2-halobenzyl
halides 1a and nitrile 2a, as a model substrate and potassium
tert-butoxide as a base. The cyclization of 3a in the absence of
any catalyst affords the corresponding product benzofuro[3,2-
b]indole 4a in 18% of yield (Table 1, entry 1). However, the
addition of 5 mol% of cupric sulfate improves the yields of 4a
dramatically, and decreasing the concentration results in the
increase of yield up to 98% (entries 2-4). The reaction in the
presence of toluene or DMF could also progress smoothly albeit
with slightly decreased yields (entries 5-6), while the reaction in
dioxane affored the desired product in only 44% yield (entry 7).
In addition, other copper salts such as CuCl2, CuO, Cu2O could
also catalyze the cyclization reaction of 3a giving 4a in moderate
to good yields (entries 8-10). Moreover, the study of the effects
of base indicates that the involvement of tBuOK is necessary for
Indole-fused heteroacenes, such as benzofuro-,1,2
benzothieno-,3,4 and indolo[3,2-b]indoles,5,6 are important
skeletons in both medicinal chemistry and materials chemistry.
They are usually utilized to develop pharmaceutical agents
exhibiting promising biological activities as well as in the
engineering organic materials possessing attractive optical or
electronic properties. However, the reported indole-fused
heteroacenes are often prepared by multiple step procedures
and are usually involved with noble metal reagents.1-11 Several
reports have been known for the synthesis of indole-fused
heteroacenes, such as benzofuro-,12 benzothieno-,13-15 or
indolo[3,2-b]indoles,16,17 respectively, but divergent access to a
variety of indole-fused heteroacenes directly from simple
starting materials is scarce.18-24 Given the importance of
functionalized indole-fused heteroacenes, the development of
a concise, efficient and environmentally benign method
towards their synthesis is in high demand.
t
the the cyclization of 3a as no reaction occured when BuONa,
tBuOLi, or NaH was utilized as the base (entry 11). The reaction
conditions in entry 4 were chosen as the standard conditions
with 5 mol % CuSO4.
Potassium tert-butoxide plays a key role in a variety of organic
reactions as a powerful base or a reagent for electron transfer
t
reactions.25-36 It was found that BuOK could promote the
Various substituted halides 3, including iodides, bromides as
well as chlorides, were subjected to the standard reaction
conditions to prepare benzofuro[3,2-b]indole 4 and the desired
products could be obtained in moderate to high yields (Schemes
1 and 2). Halogen such as bromides (4b-d, 4j, and 4n-p),
chlorides (4e, 4k, 4t, and 4u), and fluoride (4f) can survive under
this basic conditions. Starting materials with either electron
a. Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China
E-mail: ybkang@ustc.edu.cn
b. Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering,
Nanjing Tech University, Nanjing 211816, China
† X.H.S and B.Y. contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Scheme 1. Synthesis of Benzofuro[3,2-b]indoles
donating groups (4g-i, and 4l) and electron withdrawing groups
(4r and 4s) can undergo the cyclization in moderate yields. The
selectivity sequence is I>Br>Cl. For example, 4t is afforded
without the formation of 4n (X = Br).
View Article Online
DOI: 10.1039/D0CC01172J
O
R2
R2
CuSO4 (5 mol %)
R1
O
R1
Standard conditions
N
H
CN
Table 1. Reaction Conditions
X
4
3
O
Br
Br
Br
O
O
O
cat. (5 mol %), base
O
N
CN
solvent
N
H
N
N
H
I
H
H
3a
4a
4a, X = Br, 12 h, 77%
4n, X = Br, 16 h, 80%
4o, X = Br, 12 h, 66%
O
Br
O
O
entrya
cat.
base
4a(%)
18
solvent(mL)
N
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
other
PhCl(1)
PhCl(1)
N
H
N
H
1
2
none
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuCl2
CuO
N
Br
H
O
62
4p, X = Br, 12 h, 90%
(10 mol % CuSO4)
4q, X = Br, 13 h, 68%
4r, X = Br, 13 h, 69%
3
PhCl(5)
70
4
PhCl(10)
Toulene(10)
DMF(10)
Dioxane(10)
PhCl(10)
PhCl(10)
PhCl(10)
PhCl(10)
98
Cl
O
O
O
F3C
5
81
N
N
H
6
86
N
H
H
Cl
7
44
4s, X = Br, 16 h, 56%
4t, X = Cl, 13 h, 98%
4u, X = Cl, 15 h, 78%
X = Br, 10 h, 95%
8
90
Scheme 2. Synthesis of Benzofuro[3,2-b]indoles
9
77
10
11b
Cu2O
73
This reaction was further explored in the construction of
benzothienoindoles. Products 6a-i were obtained in up to 98%
yields (Scheme 3). Halogen are tolerated (6c-g). These groups
are leaving groups for cross coupling reactions, ensuring these
products can be further converted to functionalized
benzothienoindoles. Hydroxyl needs no protecting groups (6h).
CuSO4
n.r.
a Conditions: 3a (0.5 mmol), catalyst (5 mol %), 90 °C, N2,12 h, isolated yields.
b Other base refers to tBuONa, tBuOLi, or NaH, n.r. = no reactions.
O
R2
R2
S
CuSO4 (5 mol %)
R2
R2
O
R1
CuSO4 (5 mol %)
R1
S
R1
R1
Standard conditions
CN
N
I
H
Standard conditions
CN
N
X
H
3
4
6
5
O
O
O
MeO
Cl
Br
S
S
S
N
N
H
N
Br
Cl
H
H
N
N
H
N
H
H
4a, 12 h, 98%
4b, 13 h, 80%
4c, 15 h, 83%
6a, X = I, 12 h, 98%
6b, X = I, 14 h, 90%
6c, X = I, 13 h, 98%
O
O
Br
Br
S
S
S
N
H
N
H
N
H
N
H
Br
N
H
Cl
4d, 12 h, 86%
(20 mol % [Cu])
4e, 14 h, 86%
CCDC 1952777
O
6d, X = I, 13 h, 98%
6e, X = Br, 13 h, 94%
6f, X = Cl, 16 h, 77%
Cl
S
O
O
HO
F
H3C
MeO
S
S
N
H
N
H
N
H
N
H
N
N
H
H
6i, X = Br, 12 h, 68%
4f, 16 h, 90%
4h, 16 h, 86%
(10 mol % [Cu])
(20 mol % [Cu])
4g, 13 h, 72%
6g, X = Cl, 15 h, 92%
6h, X = I, 14 h, 84%
(20 mol % CuSO4)
Scheme 3. Synthesis of Benzothieno[3,2-b]indoles
Br
CH3
O
O
N
H
The N-containing analogues are indoloindole derivatives,
which are also useful EL materials or natural products as well as
pharmaceuticals. Indoloindoles 8 were obtained in 74-99%
yields under the standard conditions (Scheme 4). Either N-aryl
or N-alkyl indoloindoles (R3) are accessible (8g and 8a, 8h-l).
Removable N-protecting groups can be tolerated (8h and 8i).
N
H
4j, 16 h, 68%
(20 mol % [Cu])
CCDC 1952778
O
4i, 16 h, 97%
O
O
Cl
O
N
N
H
N
H
N
H
4l, 15 h, 84%
4m, 15 h, 60%
(20 mol % [Cu])
4k, 16 h, 70%
(10 mol % [Cu])
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
through 5 steps. By current method, 8j was obtained in 78%
yield. This method is also applied in the formal synthesis of
4H4TIDID (Scheme 7).39
View Article Online
DOI: 10.1039/D0CC01172J
R3
N
R2
CuSO4 (5 mol %)
R2
N
R3
R1
R1
Standard conditions
CN
X
N
H
7
Ph
N
8
Br
Me
N
Me
Me
N
Cl
F
N
N
Ph
N
N
CuSO4 (5 mol %)
9
N
N
Ph
N
8g
(11.8 g)
7g
Ph
N
N
N
N
H
tBuOK (2.2 equiv)
PhCl, 90 °C
NaH (2.2 equiv)
H
H
8a, X = I, 12 h, 98%
8b, X = I, 12 h, 99%
8c, X = Br, 10 h, 80%
DMF, 60 o
84%
C
Ph
(20 mol % CuSO4)
10 (20.7 g)
93%
Me
N
Me
Me
N
Scheme 6. 20-Gram Scale One-Pot Synthetic Application
F
MeO
O
N
O
N
H
N
N
H
C6H13
H
R
N
CuSO4 (20 mol%)
8d, X = I, 12 h, 99%
8e, X = I, 12 h, 83%
8f, X = I, 12 h, 58%
7j
4H4TIDID
(10 mol % CuSO4)
(20 mol % CuSO4)
(20 mol % CuSO4)
tBuOK (2.2 equiv)
N
PhCl, 90 o
C
R =
S
C6H13
Ph
N
Bn
N
PMB
N
R
H
8j (R = Br, 74%, 2.15 g)
S
Scheme 7. Two-Gram-Scale Synthesis of 4H4TIDID
N
H
N
H
N
H
8g, X = I, 12 h, 95%
8h, X = I, 12 h, 74%
8i, X = I, 16 h, 86%
A proposed reaction mechanism is demonstrated in Scheme
8. This mechanism is based on the experimental study of our
previous work. After deprotonation of benzylic proton, 3 passes
through an anion-radical relay with CuSO4 to radical A, which
transforms to C or C' via B or B′. Products 4 or 6 or 8 is afforded
through a SRN1-type process via radical anion E. The radical
process is supported by the radical inhibiting experiments (eq
1) as well as the previous report.38
(20 mol % CuSO4)
I
N
N
N
Br
Br
N
H
N
H
N
H
8j, X = Br, 3 h, 78%
(20 mol % CuSO4)
8k, X = I, 8 h, 65%
8l, X = I, 8 h, 85%
Scheme 4. Synthesis of Indolo[3,2-b]indolesa
The synthesis of tetracyclic heteroacenes 4, 6 and 8 directly
from 1 and 2-hydroxybenzonitriles 2 is also feasible. Halides 1
and nitriles 11 were treated under standard reaction conditions
with 10 mol % CuSO4 and 4a-j were obtained in moderate yields
(Scheme 5). Benzothienoindoles 6a-6k were also achieved.
Potassium salts of 13 are not available with tBuOK and KHMDS
was used for in situ deprotonation. Indoloindoles 8 were
obtained in moderate to good yields.
TEMPO
CuSO4 (20 mol%)
TEMPO (3 equiv)
CuSO4 (5 mol%)
tBuOK (2.2 equiv.)
O
3a
4a (eq 1)
tBuOK (2.2 equiv)
PhCl, 90 oC, 4 h
CN
PhCl (10 mL), 90 °
C
I
1a-OTEMP
HRMS (ESI) [M+H]+
491.1183
TEMPO (3 equiv)
or O2 (balloon)
Y
Z
X
R1
3
CuSO4 (10 mol %)
tBuOK (2.2 equiv)
Br
R1
R2
+
CuII
R2
tBuOK
I
NC
N
N
DMF, 90 o
C
- e
- X
+ e
H
H
CuI
4/6/8
11, Z = OK
12, Z = SK
13, Z = NHR
1
4, X = O
6, X = S
8, X = NR
Y
Y
Y
4c, 80%a
6d, 88%
8b, 85%b
4f, 70%a
6c, 91%
8g, 75%b
4j, 66%a
4a, 83%
6a, 90%
4e, 77%
4i, 85%
6j, 75%
8l, 80%a,b
Cl
X
N
N
X
X
H
NC
A
C
6b, 80%a
8e, 71%a,b
F
6k, 85%a
8m, 67%b
C'
8a, 86%a,b
Y
Y
N
Ph
N
S
S
X
X
NH
B
Br
B'
N
N
N
Scheme 8. Proposed Mechanism
H
8m
6j
6k
H
H
Scheme 5. Selected Examples for One-Pot Synthesis.
a With 20 mol % CuSO4. b 13
was in situ deprotonated with KHMDS (1.2 equiv) at 0 oC for 1 hr before the
addition of CuSO4 and tBuOK.
Conclusions
In conclusion, we have developed a method for the synthesis
of various O, S, or N-containing indole-fused heteroacenes via
CuSO4-catalyzed carbanion-radical redox relay, providing a
rapid access to biological or optoelectronic heteroacenes.
Compound 8g is a key intermediate for the synthesis of an EL
material 10 (Scheme 6). By our method, 10 was obtained in two
steps in over 20 gram scale. Dibromo indoloindole 8j is a key
intermediate for the synthesis of LED polymers. In previous
work, such compounds are prepared in low overall yield
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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(25) J. P. Barham, G. Coulthard, K. J. Emery, E. Doni,VFie.wCAurmticlienOen,liGne.
We thank the National Natural Science Foundation of China
(21602001, 21922109, 21672196, and 21831007) for financial
support.
Nocera, M. John, L. E. A. Berlouis, T. McGuire, T. Tuttle, J. Murphy,
DOI: 10.1039/D0CC01172J
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC01172J
R2
Tria-phIDID
Y
Y
X
CuSO4 (cat.)
N
N
N
CN
R1
N
N
R2
R1
N
H
 Synthetically practical
 X= Cl, Br, I
 20 gram-scale
 up to 99% yield
 natural abundant salt as catalyst
Y = O, S, NR
20.7 g, 78% for two steps
