Copper-catalyzed radical cascade cyclization for synthesis of CF3-containing tetracyclic benzimidazo[2,1-: A] iso-quinolin-6(5 H)-ones

Article abstract of DOI:10.1039/d0ob02210a

Here, a general copper-catalyzed radical cascade carbocyclization reaction with 2-arylbenzoimidazoles and a Togni reagent was realized. Structurally diverse CF3-containing tetracyclic core benzimidazo[2,1-a]isoquinoline-6(5H)-ones were obtained in moderat

Full text of DOI:10.1039/d0ob02210a

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DOI: 10.1039/D0OB02210A
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Copper-Catalyzed Radical Cascade Cyclization for Synthesis of CF3-
Containing Tetracyclic Benzimidazo[2,1-a]iso-quinolin-6(5H)-ones
Kai Sun,*,a,b Guofeng Li,a Sa Guo,a Zhiguo Zhang,*,a and Guisheng Zhang*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here, a general copper-catalyzed radical cascade carbocyclization these polycyclic frameworks with high levels of atom and step
reaction with 2-arylbenzoimidazoles and a Togni reagent was economy.6 In the very recent past few years, Yu,7 Song,8 Li,9 He,10
realized. Structurally diverse CF3-containing tetracyclic core and their colleagues as well as our group11 have independently
benzimidazo[2,1-a]isoquinoline-6(5H)-ones were obtained in developed efficient radical cascade carbocyclization reactions that
moderate to good yields. The wide substrate scope, good were used to access some structurally diverse benzimidazo[2,1-
functional group tolerance, and ease of scale-up of this method a]isoquinoline-6(5H)-ones. Besides, a few reports on the synthesis
are expected to promote its potential applications in pharmacy of CF3-containing isoquinolinediones, enabled by peroxidate,
and biotechnology.
electrochemical technique or others, were disclosed.12 However,
the practical methods for the synthesis of CF3-containing tetracyclic
Organofluorine compounds display unique physical properties core benzimidazole[2,1-a]isoquinolines, is still highly appealing. In
that make them indispensible for applications such as view of the considerable progress that has been made in the
agrochemicals, pharmaceuticals, polymers, and organic materials.1 development
of
transition
metal-mediated/-catalyzed
Incorporating trifluoromethyl groups into organic molecules can trifluoromethylation reactions for introducing CF3 groups into
dramatically alter many of the physical properties of such organic molecules,13 we reasoned that similar CF3-containing
compounds, including lipophilicity, metabolic stability, and tetracyclic core benzimidazole[2,1-a]isoquinolines, each with a
conformational behavior.2 As a consequence, the development of proper catalytic system and trifluoromethyl radical precursor, might
general methods for introducing CF3 groups into organic molecules be realized by deploying a radical-based cascade carbocyclization
has been a subject of intense research.3 On the other hand, strategy. Herein, we developed a copper-catalyzed radical cascade
structurally diverse benzimidazole[2,1-a]isoquinolines, containing cyclization for the purpose of synthesizing structurally diverse CF3-
fused five-membered and six-membered rings, are privileged containing tetracyclic core benzimidazo[2,1-a]iso-quinolin-6(5H)-
structural elements in chemical biology and material sciences.4 ones, some of which are expected to find use in synthetic chemistry,
However, many established methods are heavily dependent on pharmaceuticals and organic electronics.
multi-step condensation reactions with pre-functionalized starting
To find suitable reaction conditions for this cascade reaction,
materials, with limited functional group tolerability and low overall various metal catalysts, trifluoromethyl radical precursors, and
yields.5 Therefore, the development of new and general methods, solvents were screened (Table 1). Here, N-methacryloyl-2-
especially one-pot strategies, for producing these polycyclic phenylbenzoimidazole 1a was chosen as the model substrate to
structures from readily available starting materials is highly access the target product 3a. The N-methacryloyl-2-
desirable.
phenylbenzoimidazole 1a was initially treated for 12 h with
A strategy involving radical-based cascade carbocyclization CF3SO2Na in one experiment (entry 1) and TMSCF3 in another (entry
initiated by intermolecular addition of a carbon-centered radical to 2), in each case combined with (diacetoxyiodo)benzene (PIDA), to
a π system has been used to conveniently and rapidly construct form the desired 3a, respectively, only 33% and 16% yields. When
1a was treated instead with just Togni I (CAS: 887144-97-0) in one
experiment (entry 3) and Togni II (CAS: 887144-94-7) in another
a
(entry 4), these two reactions furnished product 3a in 39% and 47%
yields, respectively. Previous reports demonstrated the potential of
using copper salts as catalysts for activating Togni reagents;14
therefore, CuCl, CuBr, CuI and Cu(OAc)2 were each also included in
tests. Pleasingly, in this screening, the presence of each of these
copper salts was associated with an improvement in the reaction
School of Chemistry and Chemical Engineering, Henan Normal University,
453007, P. R. China. E-mail: sunk468@nenu.edu.cn;
zhangzg@htu.edu.cn; zgs@htu.cn
Xinxiang,
b School of Chemistry and Chemical Engineering, YanTai University, Yantai, 264005,
Shandong, P. R. China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of reaction conditionsa
We next set out to investigate the scope of the N-methacryloyl-2-
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phenylbenzoimidazole substrate 1 in reactiDoOnsI: w10i.t1h03T9o/Dgn0iOIBI0(2T2a1b0lAe
N
N
2). Both compounds containing electron-donating substituents and
Table 2. Substrate scopea
Catalyst, "CF3" source
N
Solvent, Temp.
O
N
CF3
O
CF3
I
O
R
N
N
R
N
1a
3a
CuI (10 mol%)
N
+
entry
catalyst
“CF3”
source
CF3SO2Na
TMSCF3
Togni I
oxidant solvent Yield (%)b
DCE, 120 o
C
CF3
O
O
O
1
Togni II
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
20
no
no
no
PIDA
PIDA
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhCl
EtOAc
DCM
DMSO
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
33
16
39
47
55
54
75
68
51 c
50 d
37
45
48
50
47
74e
51f
48g
40
47
46
43
N
N
N
N
N
OBn
O
N
N
N
CF3
CF3
CF3
CF3
O
O
O
O
no
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
Togni II
3a
3b
3c
3d
: 67%, 2 h
: 74%, 0.5 h
: 72%, 0.5 h
: 74%, 0.5 h
O
CuCl
CuBr
CuI
O
N
N
N
N
N
N
N
OMe
N
CF3
CF3
CF3
CF3
O
O
O
O
3e
3f
3g
: 63%, 1 h
3h
: 72%, 0.5 h
: 68%, 1 h
: 70%, 1 h
Cu(OAc)2
CuI
N
N
N
N
N
F
Cl
CN
CF3
N
O
N
N
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CF3
CF3
CF3
CF3
O
O
O
3i
3j
3k
3l
: 61%, 2 h
: 64%, 2 h
: 56%, 2 h
: 53%, 2 h
F
Cl
O2N
N
N
N
N
N
N
Br
N
O
N
CF3
CF3
CF3
CF3
O
O
O
[b]
3m:
3n
3o:
75%, 2 h
52%, 2 h
: 53%, 2 h
0%, 1.5 h
O
N
N
N
N
N
N
O
N
O
CuI
I2
KI
O
N
CF3
CF3
O
CF3
O
(1.4 : 1)
O
CF3
O
3p
3q + 3q':
3r
: 79%, 0.5 h
: 55%, 1.5 h
70%, 2 h
Cl
Cl
N
NaI
nBu4NI
N
S
N
N
N
Cl
N
N
22
a
N
N
CF3
Cl
CF3
CF3
O
Reaction conditions: 1a (0.2 mmol), “CF3” source (0.4 mmol),
copper salt (10 mol%) and oxidant (0.4 mmol) in solvent (2.0 mL) at
120 °C for 12 h under air. b Yield of the isolated product. c 5% CuI
was added. 1% CuI was added. Reaction performed at 120 C for
0.5 h. Reaction performed at 90 °C for 12 h. Reaction performed
at 60 °C for 12 h.
O
O
O
CF3
[b]
3s
3t
3u
: 53%, 2 h
3v
: 56%, 3 h
: 68%, 3 h
: 69%, 5 h
a
Reaction conditions: 1 (0.3 mmol), Togni II (2.0 equiv), CuI (10
mol%), DCE (2.0 mL), 120 °C. Isolated yields are shown. CuI (30
mol%) was used.
d
d
o
b
e
g
those containing electron-withdrawing substituents readily
underwent the radical cascade reactions smoothly, providing the
desired benzimidazo[2,1-a]iso-quinolin-6(5H)-ones 3 in moderate to
good yields (3b−3o). The experiments showed that the established
conditions can bear a variety of functional groups, including –Me, -
OMe, -OBn, -COOMe, -CN, -CF3, -F, -Cl and -Br, (3b−3o, 52−75%
yields). While when ortho-NO2 substituted substrate was tested, no
desired parduct was detected. Substrates bearing multiple
substituents on the benzene ring also reacted well to give the
corresponding products 3p−3t in satisfactory yields (55–79%).
(entries 5-8), and when CuI was included, the yield of product 3a
was 75% (entry 7). When the amount of copper salt was 5 mol%,
the yield of 3a was significantly reduced to 51%; While when 1% CuI
was added, the yield of 3a was 50% (entries 9 and 10). A series of
solvents including PhCl, EtOAc, DCM, DMSO and DMF were each
also tested, but they were not as efficient as DCE (Table 1, entries
11-15). Additionally, control experiments revealed that a 74% yield
of 3a was obtained when the reaction was performed for 0.5 h
(entry 16), while decreases in the yield were observed when the
reaction temperature was decreased to 90 C and 60 C (entries 17
and 18). In order to further improve the yield of 3a, the role of
some other iodide reagents, such as I2, KI, NaI and nBu4NI were
added in place of CuI, however, the reaction efficiency did not
improve obviously (entries 19-22). Therefore, the optimized
conditions are as follows: CuI (10 mol%) as the catalyst, Togni II (2.0
equiv) as the CF3 source, and DCE (2.0 mL) as the solvent, carrying
out at 120 °C for 0.5 h.
o
o
Notably,
when
1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-
benzo[d]imidazol-1-yl)prop-2-en-1-one 1q was deployed under the
standard conditions, two isomerically related products denoted as
3q and 3q' were obtained, with a 1.4:1 molar ratio of 3q to 3q'. We
unexpectedly yet fortunately delivered the thiophene-containing
and pyridine-containing heteroaryl products 3u and 3v in moderate
53% and 56% yields, respectively, which might broaden the
opportunity for further application. Further substrate test found
when acrylamide was used as substrate, no radical cascade
cyclization occurred, with all substrate recovered, which indicated
2 | J. Name., 2012, 00, 1-3
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that the methyl group attached to the double bond is important for
cyclization process.
CF3
View Article Online
CF3
R
N
I
[CuI]
I
1
DOI: 10.1039/D0OB02210A
CO2[CuII]
N
O
To illustrate the synthetic utility of this radical cascade cyclization
protocol, we also investigated the ability to scale up this reaction.
Conducting the reaction with substrate 1a on a gram scale provided
3a in a satisfactory 72% yield; While when 1% CuI was added, the
yield of 3a was 43%. (Scheme 1, detailed procedure provided in ESI).
O
O
CF3
B
A
Togni II
Cyclization
R
[CuII]
[CuI]
R
R
N
N
N
N
- H
N
N
Scheme 1. The gram-scale synthesis of 3a
CF3
H
H
O
O
O
CF3
CF3
3
D
C
CF3
N
N
N
I
CuI (10 mol%)
DCE, 120 o
O
+
N
C
CF3
O
O
O
Conclusions
1a
Togni II
1.5 equiv
3a
(72%, isolated yield)
, 1 g
3.82 mmol
In conclusion, a practical copper-catalyzed radical cascade
carbocyclization reaction was developed for the preparation of a
variety of structurally diverse CF3-containing tetracyclic core
benzimidazo[2,1-a]isoquinoline-6(5H)-ones. This simple radical
cascade strategy features easy-handling, a wide substrate scope,
and good functional group compatibility, and is easily scaled up. The
developed understanding of the mechanism of this type of reaction
and the potential applications of its products might garner more
research interest in this area. Research and development of
bioactive products are currently in progress in our group.
In each of two control experiments involving adding
stoichiometric amounts of a radical inhibitor, in one experiment
2,2,6,6-tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv, equation
1) and in the other 1,1-diphenylethylene (2.0 equiv, equation 2), the
reaction of 1a with Togni II to form 3a was completely suppressed.
Meanwhile, an obvious decrease in the yield was observed when
butylated hydroxytoluene (BHT, 2.0 equiv) was added (equation 3).
Notably, the products 4 and 5 did form from Togni II with 1,1-
diphenylethylene and BHT (equations 2 and 3). These results
suggested that this radical cascade carbocyclization is in general
initiated by the formation of a CF3 radical from Togni II.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21801007).
N
N
CF3
N
(1)
TEMPO (2.0 equiv)
I
N
O
CF3
Standard conditions
O
Notes and references
O
O
1a
2
3a
(0%)
trace
1
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CF3
N
N
CF3
N
N
1,1-Diphenylethylene
(2.0 equiv)
(2)
I
O
Standard conditions
CF3
O
O
O
1a
2
3a
4
5
(63%)
OH
N
N
CF3
N
(3)
I
BHT (2.0 equiv)
N
O
CF3
Standard conditions
O
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CF3
1a
2
3a
(41%)
(28%)
On the basis of the present results and previous reports,6,13
a
2
3
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derived, and is shown in Scheme 2. Initially, according to this
proposed mechanism, decomposition of Togni II occurs to deliver
the CF3 radical with the assistance of CuI under heating and release
of the CuII species A. Then, the addition of the CF3 radical to a C-C
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double bond in an N-methacryloyl-2-phenylbenzoimidazole
1
produces the radical intermediate B, which then undergoes
intramolecular cyclization to afford the radical intermediate C.
Subsequent reaction of intermediate C with the CuII species A leads
to the cationic intermediate D. And finally according to the
proposed mechanism, loss of a proton from D affords the desired
product 3.
4
Scheme 2. Proposed reaction mechanism
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB02210A
R
N
N
CF3
I
O
R
N
CuI (10 mol%)
DCE, 120 oC
N
CF3
O
O
O
+ Multistep radicals relay
+ Privileged structural motifs
+ Ease scale up operation
A practical copper-catalyzed radical cascade carbocyclization reaction was
developed for the preparation of a variety of structurally diverse CF3-containing
tetracyclic core benzimidazo[2,1-a]isoquinoline-6(5H)-ones.