Manganese(iii)-promoted tandem phosphinoylation/cyclization of 2-arylindoles/2-arylbenzimidazoles with disubstituted phosphine oxides

Article abstract of DOI:10.1039/d0ob00877j

A simple and practical method for the synthesis of phosphoryl-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and benzimidazo[2,1-a]isoquinolin-6(5H)-ones through manganese(iii)-promoted tandem phosphinoylation/cyclization of 2-arylindoles or 2-arylbenzimidazoles with disubstituted phosphine oxides was developed. In this transformation, new C-P bond and C-C bond were constructed simultaneously under silver-free conditions, exhibiting a broad substrate scope. It was noted that not only diarylphosphine oxides but also dialkyl and arylalkyl-phosphine oxides were compatible with the conditions. This journal is

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Dynamic Article Links►
Journal Name
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
FULL PAPER
Manganese(III)-Promoted
Tandem
Phosphinoylation/Cyclization
of
2-
Arylindoles/2-Arylbenzimidazoles with Disubstituted Phosphine Oxides
a
a
a
a
a
ab
Shuai-Shuai Jiang, Yu-Ting Xiao, Yan-Chen Wu, Shu-Zheng Luo , Ren-Jie Song* and Jin-Heng Li*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A simple and practical method for the synthesis of phosphoryl-
However, the reaction substrates are difficult to synthesize.
substituted indolo[2,1-a]isoquinolin-6(5H)-ones and 40 Thus, the development of a new and efficient synthetic strategy
benzimidazo[2,1-a]isoquinolin-6(5H)-ones
through
for the construction of C-P bond is still highly attractive.
Radical alkenes difunctionalization reaction has been
considered as one of the most effective methods for the
manganese(III)-promoted tandem phosphinoylation/cyclization
of 2-arylindoles or 2-arylbenzimidazoles with disubstituted
phosphine oxides was developed. In this transformation, new C-
1
0
formation multifunctional products with highly atom-economical
3
P bond and C-C bond were constructed simultaneously under 45 and step-economical (Scheme 1a).
Recently, alkene
silver-free conditions, exhibits a broad substrate scope. It was
noted that not only diarylphosphine oxides but also dialkyl and
arylalkyl-phosphine oxides were compatible with the conditions.
carbophosphinoylation was became a useful tool for the
4
-5
synthesis of phosphorus-containing heterocycles. For instance,
in 2013, the Yang group have described a silver-catalyzed
reaction between alkenes and diarylphosphine oxides for the
synthesis of diphenylphosphoryl oxindoles in the presence of
1
5
Organophosphorous compounds, especially heterocycle-
containing organophosphorus, as important structural moieties
are widespread in drugs, active molecules, functional materials
5
0
6
2 3 3 2 2
Ag CO /Mg(NO ) ·6H O system (Scheme 1b). Sequentially,
Chen, Lv, Yu and co-workers also developed a two-component
alkene carbophosphinoylation for the preparation of
1
and pesticides. In addition, the introduction of phosphorus
2
0
substituents to organic molecule would improve the biological
phosphoryl-substituted
benzimidazo[2,1-a]isoquinolin-6(5H)-
2
and physical properties. Much efforts have been developed to
1c).4i
5
5
ones
(Scheme
However,
most
of
those
synthesis of organophosphorous. For example, the group of
phosphinoylation/cyclization reactions mediated by silver
catalysts or additives, which might limit its further synthetic
applications.
2
g
Nevado in 2015 reported a multi-step radical reaction for the
construction of Ph (O)P-containing indolo[2,1-a]isoquinolin-
2
2
5
6(5H)-ones from N-[(2-ethynyl)arylsulfonyl]acrylamides.
6
0
CHO
N
N
OMe
a) Radical alkene carbophosphinoylation
OH
(MeO)2
N
C
N
O
N
O
O
R2
R4
R3
HO
[O]
R2
H
P
R4
P
R4
+
R1
H
C
Difunctionalization
R1
O
n-Bu
+
n-Bu
P
Benzimidazo-
isoquinoline-6H(5H)-one
Inhibitor of tubulin
polymerization
Against human
cancer cell lines
R3
R3
O
b) Two-component alkene carbophosphinoylation for heterocycles construction
R4
R3
PR R6
5
Ar
N
H
N
N
Cl
N
N
O
R1 Ar
AgNO3
O
Mg(NO3)2·6H2O
O
N
R4
+
H
P
R6
R1
Ar
o
CH3CN, 100 C
N
Cl
R2
R3
R5
R2
O
Ar
O
c) Silver-catalyzed two-component carbon phosphonylation of alkenes
Hemoglobinpathies
ATMs
Antidiabetic agents
R1
N
N
R1
N
O
Ar
Figure 1. Important biologically indolo[2,1-a]isoquinolin-6(5H)-
ones and benzimidazo[2,1-a]isoquinolin-6(5H)-ones.
R4
AgNO3, K2S2O8
CH3CN, 80 o
Ar
H
P
N
R2
R3
O
O
C
R2
O
P
R4
R3
d) This work: Mn(III)-promoted oxidative phosphinoylation/cyclization of 2-arylbenzoindoles with P(O)H
a
3
3
0
5
Key Laboratory of Jiangxi Province for Persistent Pollutants
R3
X
X
N
R3
O
P
Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, China
R1
Ar
Mn(OAc)3·2H2O
HOAc, 60 oC, Ar
R5
R1
Ar
+
H
N
R4
O
b
R4
O
R6
State Key Laboratory of Chemo/Biosensing and Chemometrics,
Ag-free
O
P
R5
Hunan University, Changsha 410082, China
E-mail: srj0731@hnu.edu.cn, and jhli@hnu.edu.cn
R6
X = C, N
†
Electronic Supplementary Information (ESI) available: [details
Scheme 1 Alkene carbophosphinoylation toward phosphorus-
of any supplementary information available should be included
here]. See DOI: 10.1039/b000000x/
containing molecules.
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Inspired by previous reports and our interest in radical alkene
(2a) in the presence of Mn(OAc)
3
·2H
2
O and HOAc at 60 oC
difunctionalization reactions, we herein present an efficient
manganese mediated tandem reaction of 2-arylindoles or 2-
arylbenzoimidazoles with disubstituted phosphine oxides to
prepare the phosphoryl-substituted indolo[2,1-a]isoquinolin-
under argon atmosphere (Table 1). To our delight, 90%
25 isolated yield of product 5-((diphenylphosphoryl)methyl)-5-
methyl-12-indolo[2,1-a]isoquinolin-6(5H)-one 3aa was
obtained under this conditions for 12 h (entry 1). The other
7
5
0
5
manganeses such as MnO
were tested, and the results showed that MnO
2
, Mn(OAc)
2
, MnCl
2
and KMnO
2
and KMnO
4
6
(5H)-ones and benzimidazo[2,1-a]isoquinoline-6(5H)-ones
8
4
(Scheme 1d). In this transformation, new C-P bond and C-C
3
3
4
4
5
0
5
0
5
0
were promoted the reaction although with lower yields
while only trace yield of product 3aa were detected by the
use of Mn(OAc) or MnCl catalysts (entries 2-5). This result
2 2
bond were constructed in one step through C-H bond
cleavage/phosphinoylation/cyclization pathway. Notably, diaryl,
dialkyl and arylalkyl-phosphine oxides were compatible with the
conditions. Importantly, indolo[2,1-a]isoquinolin-6(5H)-one and
benzimidazo[2,1-a]isoquinoline-6(5H)-one derivatives represent
an important class of N-heterocycles with valuable
1
suggested that the manganese reagent may act as an
oxidant in the reaction. Two other phosphorus radical
1
0
initiation conditions were tested, and the results showed
that only 23% yield of product 3aa was obtained under
9
pharmacological and biological activities (Figure 1).
Mn(OAc)
afforded by the use of CuSO
conditions (entries 6 and 7). Further exploration showed
that increasing the amount of Mn(OAc) ·2H O to 4
2
/MnO
2
system, while no desired product was
1
4
·5H O/TBHP/NH ·H O/MeCN
2
3
2
Table 1 Screening of optimal reaction conditions a
3
2
Ph
Ph
equivalents or reducing to 2 equivalents could not further
improve the reaction efficiency (entries 8 and 9). Other
oxidants, such as K S O , di-tert-butyl peroxide (DTBP) and
2 2 8
O
P
Ph
Ph
Mn(OAc)3·2H2O
HOAc, 60 oC, Ar
N
+
H
N
Ph
Ph
P
O
2a
O
O
Ag O, were less effective (entries 10-12). However, only
2
1a
3aa
35% yield of 3aa was got when we used the combination of
AgNO
such as Ac
results (entries 14-18). The reaction was also tested in
MeCN or DCE with the addition bases, such as K CO and
Et N, and the result showed they were less reactive (entries
9-21). Increasing or reducing the reaction temperature did
3
with K
2 2 8
S O (entry 13). The use of other solvents
Entry
Variation from the optimal conditions
none
Yield [%] b
90
2
O, MeCN, DCE, MeOH and toluene gave inferior
1
2
3
4
5
6
MnO instead of Mn(OAc) ·2H O
2
3
2
10
2
3
Mn(OAc) instead of Mn(OAc) ·2H O
2
3
2
trace
trace
15
3
MnCl instead of Mn(OAc) ·2H O
2
3
2
1
KMnO instead of Mn(OAc) ·2H O
4
3
2
not result in higher yields of 3aa (entries 22 and 23).
Notably, under air atmosphere product 3aa could also be
assembled in 69% yield (entry 24).
Mn(OAc) (5 mol%)/MnO (2 equiv) instead of
2
2
2
3
Mn(OAc)
3 2
·2H O
7
CuSO ·5H O/TBHP/NH ·H O/MeCN instead of
4
2
3
2
0
55
As the optimized reaction condition was estiblished, it was
applied to a series of phosphine oxides and 2-arylindoles. As
shown in Scheme 2, substrates with different electronic
properties all underwent the reaction to deliver the
corresponding phosphoryl-substituted products in satisfactory
Mn(OAc)
3 2
·2H O
8
9
Mn(OAc) ·2H O (4 equiv)
54
60
32
38
40
3
2
Mn(OAc) ·2H O (2 equiv)
3
2
1
0
1
2
3
K S O instead of Mn(OAc) ·2H O
2
2
8
3
2
1
1
1
DTBP instead of Mn(OAc) ·2H O
3
2
60 yields. As expected, diphylphosphine oxides 2 bearing electron-
donating groups (Me or OMe) and electron-withdrawing group
(F), were performed smoothly with 1-(2,3-diphenyl-1H-indol-1-yl)-
2-methylprop-2-en-1-one (1a) in the presence of Mn(OAc) ·2H O
Ag O instead of Mn(OAc) ·2H O
2
3
2
AgNO (20 mol%)/K S O (2 equiv) instead of
3
2
2
8
3
5
Mn(OAc)
3 2
·2H O
1
1
1
1
1
1
2
2
2
2
2
4
5
6
7
8
9
0
1
2
3
4
Ac O instead of HOAc
MeCN instead of HOAc
DCE instead of HOAc
MeOH instead of HOAc
toluene instead of HOAc
29
47
41
24
12
46
43
40
81
2
3
2
and HOAc, giving the corresponding polycyclic products 3ab-ad
65 in 72-95% yields. This transformation also tolerated substrates
ethyl phenylphosphinate (2e) and di-tert-butylphosphine oxide
11
(
2f). Notably, dialkyl phosphonates 2g-j were compatible with
K CO (2 equiv) in MeCN instead of HOAc
K CO (2 equiv) in DCE instead of HOAc
Et N (2 equiv) in MeCN instead of HOAc
2
3
the tandem phosphinoylation/cyclization conditions, and
delivered the products 3ag-aj in 42-70% yields. 2-Arylindoles
with different substitutions at the para position of aryl ring,
2
3
3
7
0
o
at 80
at 40
C
C
3
including OMe, Cl, F, CH , and Br, were suitable substrates,
o
55
69
·2H
giving products 3ba-ha in moderate to good yields. Ethyl 1-
methacryloyl-2-phenyl-1H-indole-3-carboxylate 1i was also a
good substrate. Furthermore, substrate 2-methyl-1-(2-phenyl-
under air
a
Reaction conditions: 1a (0.2 mmol), 2a (2 equiv), Mn(OAc)
equiv), HOAc (2.0 mL), Ar, 60 C and 12 h. DTBP = di-tert-butyl peroxide.
3
2
O (3
o
b
Isolated yield.
75 1H-indol-1-yl)prop-2-en-1-one 1j, a 2-arylindoles having no
substitution at the 3rd position, was suitable for the conditions
2
0
We started our investigation into this intermolecular
cyclization reaction between 1-(2,3-diphenyl-1H-indol-1-yl)-
-methylprop-2-en-1-one (1a) and diphenylphosphine oxide
and
methylindolo[2,1-a]isoquinolin-6(5H)-one 3ja in 53% yield.
Moreover, substrates 1k-m, with Br, CF and CN groups
afforded
the
5-((diphenylphosphoryl)methyl)-5-
2
3
2
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substituted at the 5-position of 2-arylindoles, were found to be
suitable substrates for the reaction, producing the
corresponding 3ka-ma. In addition, other substituted alkenes
Subsequent to the exploration of 2-arylbenzimidazoles 1p and
1q, and the result showed that the two substrates could also
translated to the corresponding phosphoryl-substituted
such as 1-(2,3-diphenyl-1H-indol-1-yl)-2-phenylprop-2-en-1-one 15 benzimidazo[2,1-a] isoquinolin-6(5H)-ones 3pa and 3qa in 77%
5
1n and 1-(2,3-diphenyl-1H-indol-1-yl)-2-(trifluoromethyl)prop-2-
en-1-one 1o underwent the reaction smoothly to provide 3na
and 3oa in 70% and 56% yields, respectively.
and 60% yields, respectively. Two other benzimidazoles, such as
1-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)-2-
methylprop-2-en-1-one 1r and 1-(2-(4-bromophenyl)-1H-
benzo[d]imidazol-1-yl)-2-methylprop-2-en-1-one
1s
were
Table 2. Variation of phosphine oxides (2) and 2-arylindoles/2- 20 compatible with the optimal conditions and afforded the
1
0
arylbenzimidazoles (1)a
corresponding products 3ra and 3sa in 81% and 50% yields.
To elucidate the mechanism of the current reaction, some
control experiments were carried out (Scheme 2). Firstly, 3
equivalents of three different types of radical trapping agents,
25 named 2,2,6,6-tetramethylpiperidine oxide (TEMPO), butylated
hydroxytoluene (BHT) and hydroquinone, were added to this
reaction system under the standard conditions, respectively. As
we expected, the reaction was completely inhibited under this
condition, and only trace yield of 3aa was detected. Importantly,
30 When the C-H phosphinoylation/cyclization of 2-arylindoles with
P(O)H was set up in the presence of 3 equivalents of BHT, radical
coupling product 4 was isolated with 31% yield, which suggested
that the reaction may involve a radical pathway
R3
R3
X
X
N
R1
O
P
R5
R6
Mn(OAc)3·2H O
HOAc, 60 oC, Ar
2
R5
H
R1
N
+
R6
P
R4
2
X = C, N
O
O
O
R4
3
1
OMe
F
Ph
Ph
Ph
O
O
P
O
P
P
N
N
N
O
O
O
OMe
F
3
ab, 95%
Ph
3ac, 85%
3ad, 72%
Ph
N
Ph
N
tBu
tBu
OEt
P
P
O
O
Ph
Ph
O
O
3ae, 74%
3af, 30%
X-ray single-crystal diffraction of 3af
Additive (3 equiv)
Mn(OAc)3·2H2O
O
P
Ph
Ph
Ph
Ph
+
H
Ph
N
HOAc, 60 oC, Ar
N
Ph
P
Ph
O
2a
O
O
N
O
OBn
OBn
N
OCH2iPr
OCH2iPr
P
N
EtO
1a
3aa
OH
OEt
P
P
O
Additive
Yield of 3aa
O
O
O
O
3
ah, 42%
3ai, 68%
TEMPO
,6-di-tert-butyl-4-methylphenol (BHT)
hydroquinone
trace
trace
trace
3ag, 70%
2
Ph
Ph
Ph
POPh2
OMe
Ph
Cl
4, 31% yield
Ph
N
OnBu
OnBu
N
Ph
N
Ph
Ph
Ph
P
P
P
O
O
O
O
O
O
N
3
aj, 62%
3ba, 67%
3ca, 80%
Mn2+
N
O
P
O
P
O
Ph
Ph
Ph
O
Ph
Ph
1a
O
H
F
OMe
Ph
P
Ph Ph
Mn3+
N
O
Ph
2a
A
N
Ph
N
O
Ph
B
Ph
Br
Ph
P
P
P
O
O
O
O
3ea, 45%
3da, 45%
3fa, 74%
COOEt
Ph
Ph
Ph
Mn2+
Cl
-
H+
+
N
O
Ph
N
O
Ph
N
Ph
N
N
N
O
P
O
P
O
Ph
P
Ph
P
Ph
P
O
O
O
Mn3+
P
O
Ph
O
O
O
Ph
Ph
3ha, 42%
3ia, 43%
Ph
Ph
Ph
3ga, 55%
E
D
C
Ph
Ph
3
5
Scheme 2 Control experiments and possible mechanism
Br
F3C
N
Ph
N
O
N
O
Ph
Ph
Ph
Ph
Ph
P
P
P
Based on the above control experiments and pervious
reports,4,12 the possible mechanism for the efficient
O
O
O
O
3ja, 53%
3ka, 62%
3la, 80%
Ph
Ph
Ph
manganese(III)-promoted tandem phosphinoylation/cyclization
NC
N
O
Ph
N
Ph
40 of 2-arylindoles with P(O)H was shown in Scheme 2. The reaction
was initiated by Mn(III) oxidant to provide the phosphinyl radical
A through a single electron transfer, and then the phosphinyl
radical A reacted with substrate 1a to form a radical
intermediate B. Subsequently, the alkyl radical B selectively
45 added to the aromatic ring of 1a to form the intermediate C.
N
Ph
Ph
Ph
Ph
P
P
P
Ph
O F3C
O
O
O
O
3
na, 70%
3oa, 56%
3
ma, 61%
R
N
N
N
N
Ph
N
Ph
N
Ph
Ph
P
Ph
Ph
P
P
O
O
O
Bn
O
O
O
R3 = OMe, 3ra, 81%
R3 = Br, 3sa, 50%
3
pa, 77%
3qa, 60%
Intermediate radical
C could be converted to cationic
intermediate D via a single electron oxidation process (SET) with
the aid of Mn(III) species, and finally deprotonation of D to
observed product 3aa.
a
Reaction conditions: 1a (0.2 mmol), 2a (2 equiv), Mn(OAc)
3
·2H
2
O (3
o
equiv), HOAc (2.0 mL), Ar, 60 C and 12 h.
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In summary, we have successfully developed a Mn-mediated
oxidative cascade cyclization of 2-arylindoles with disubstituted
phosphine oxide, providing direct access to various phosphoryl-
6
7
7
8
8
9
9
5
0
5
0
5
0
5
(i) K. Sun, Y.-F. Si, X.-L. Chen, Q.-Y. Lv, Y.-Y. Peng, L.-B. Qu, B. Yu,
substituted
indolo[2,1-a]isoquinolin-6(5H)-one
derivatives
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5
involve phosphinoylation/cyclization tandem process. This
process could be performed without silver reagents, giving the
target compounds in moderate to excellent yields. This novel
reaction occurred smoothly with a C-P bond and C-C bond
constructed simultaneously. Additionally, the synthetic utility of
this cascade reaction has been demonstrated by the applicability
to 2-arylbenzoimidazoles. The preparation of other useful
heterocycles is currently underway in our laboratory.
5
.
1
0
1
0, 3592; (f) W.-J. Yoo, S. Kobayashi, Green Chem., 2013, 15, 1844; (g)
Acknowledgment
Y. Li, Y. Zhu, S.-D. Yang, Org. Chem. Front., 2018, 5, 822; (h) H. Wang,
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financial support. Ren-Jie Song was also supported by the China
Scholarship Council (contract 201908360088).
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB00877J
Manganese(III)-Promoted Tandem Phosphinoylation/Cyclization
of 2-Arylindoles/2-Arylbenzimidazoles with Disubstituted
Phosphine Oxides
Shuai-Shuai Jiang, Yu-Ting Xiao, Yan-Chen Wu, Shu-Zheng Luo, Ren-Jie Song* and Jin-Heng Li*
R2
X
R2
R3
X
O
P
R3
O
R1 Ar
R5
Ar
+
H
Mn
R1
N
N
H
R4
O
O
P
R5
R4
X = C, N
28 examples, up to 95% yield
A simple and practical method for the synthesis of phosphoryl-substituted indolo[2,1-
a]isoquinolin-6(5H)-ones and benzimidazo[2,1-a]isoquinolin-6(5H)-ones through
manganese(III)-promoted tandem phosphinoylation/cyclization of 2-arylindoles/2-
arylbenzimidazoles with disubstituted phosphine oxide was developed.