Y. Tang, M. Yang, F. Wang et al.
Tetrahedron Letters 67 (2021) 152845
Table 1
a
Optimization of reaction conditions.
Entry
Oxidant
Solvent
Yield(%)b
1
2
3
4
5
6
7
8
9
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
2
I O
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(2.0 eq.)
5
(1.0 eq.)
5
(3.0 eq.)
5
(2.0 eq.)
MeCN
1,4-Dioxane
Toluene
THF
28
54
37
72
46
0
33
42
Trace
Trace
65
38
67
59
DCE
MTBE
CPME
2-MeTHF
DMSO
DMF
THF
THF
THF
THF
10
11
12
13
14
c
d
a
(2.0 equiv, 0.5 mmol) and solvent (2.0 mL) at 80 °C for 8 h. bIsolated yield based on 1a. c1.5 eq. of TsNHNH
Reaction conditions: 1a (0.25 mmol), 2a (2.0 eq., 0.5 mmol), I
2
O
5
2
.
d
6
0 °C.
[
2,1-a]isoquinolin-6(5H)-ones 3aa in 72% yield, and other solvents
fin (R1 = H) did not undergo the cyclization (product 3as).
Attempts to construct seven-membered ring fused-benzimidazo
framework by this radical relay reactions were fruitless, which
might due to the ring strain (product 3at). To further show the
practical application of this method, N-methacryloyl-2-phenylben-
zoimidazole (1a, 5 mmol) was employed in a gram-scale reaction
and delivered 3aa in 61% yield.
such as 1,4-dioxane, toluene, CPME (cyclopentyl methyl ether), 2-
MeTHF and DCE gave low to moderate yields (Table 1, entries 2–8).
By contrast, MTBE (methyl tert-butyl ether), DMF and DMSO were
ineffective under the same conditions (Table 1, entries 6, 9–10).
Further screening of the amount of p-toluenesulfonylhydrazide
and oxidant revealed that either increasing or reducing the amount
of TsNHNH
2
and I
2
O
5
had no positive effect on the reaction effi-
Next, a series of other sulfonylhydrazides with N-methacryloyl-
2-phenylbenzoimidazole 1a were investigated (Table 3). We were
pleased to find that benzenesulfonyl hydrazide was able to furnish
the desired product 5-methyl-5-((phenylsulfonyl)methyl)benzo
[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one (3ba) in 70% yield. Fur-
thermore, benzenesulfonyl hydrazides 2, bearing either electron-
ciency (Table 1, entries 11–13). Finally, decreasing the reaction
temperature also resulted in a lower yield of 3aa (Table 1, entry
1
4).
With the optimized conditions in hand, the substrate scope for
this I induced addition/cyclization to access sulfonylated benz-
2 5
O
imidazo[2,1-a]isoquinolin-6(5H)-ones was investigated, as illus-
trated in Table 2. Initially, the suitability of various N-
methacryloyl-2-phenylbenzoimidazole was studied under the
standard conditions. It was found that various functional groups
3
donating (–OMe) or electron-withdrawing (–F, –Cl, –Br, –CF )
groups at the ortho- or para- positions of the aromatic ring were
compatible with the optimized conditions, delivering the desired
products in 45%~58% yields, respectively (products 3bb–3bg).
Finally, the reaction of naphthalene-2-sulfonohydrazide and thio-
phene-2-sulfonohydrazide with N-methacryloyl-2-phenylben-
zoimidazole 1a could also occurred smoothly and gave the
cyclization products in good yield (products 3bh ~ 3bi).
2
at the para-position of Ar , not only for the electron-donating
groups (–Me, –OMe) but also for those electron-withdrawing sub-
stituents (–F, –Cl, –Br, –I, –CN), were tolerated well delivering the
corresponding products 3ab–3ah in moderate to good yields (40–
7
0%). To investigate the regioselectivity of the transformation, the
Ar bearing a meta-bromo or meta-methyl substituent was treated
with TsNHNH under the optimized conditions, and a mixture of
two regioisomers were generated in the ratio of 6:1 and 12:1,
respectively (products 3ai–3aj). When Ar simultaneous bearing
To probe the mechanism of the reaction, we conducted several
control experiments. Initially, we added 3.0 equiv of radical scav-
enger TEMPO (2,2,6,6-tetramethylpiperidine) or BHT (2,6-di-tert-
butyl-4-methylphenol) in the reaction under standard conditions
gave product 3aa with trace amount and 10% yield, respectively
(Scheme 2, eq 1). Whereafter, we researched whether sulfonyl rad-
ical produced in the reaction by adding 2.0 equiv 1,1-dipheny-
2
2
2
nitro and methyl substituents on the meta- and para-position, an
obvious two regioisomers was generated in the ratio of 33:1 (pro-
duct 3ak). The reaction also proceeded smoothly with ortho-sub-
lethylene and vinyl sulfone
4 was detected in 19% yield
stituent on the Ar
2
affording the desired products 3al and 3am in
(Scheme 2, eq 2).
moderate yields. In addition, heteroatom and naphthalene derived
substrates 1 were also viable substrates to provide the correspond-
ing benzimidazo[2,1-a]isoquinolin-6(5H)-ones 3an–3ap in good
yields. Moreover, Substrate 1 with multiple substituents on the
Based on the experimental results and previous reports
[6–9,11,12a,13], a plausible mechanism for this transformation is
proposed in Scheme 3. Initially, The single-electron oxidation of
2 5
sulfonylhydrazide by I O leads to the formation of sulfonyl radical
Ar
yield (product 3aq). The substituent effect at R
evaluated. The CH CO Me substituent was compatible with the
optimal conditions (product 3ar), whereas monosubstituented ole-
1
occurred smoothly and gave the cyclization product in 66%
A. Then, the addition of sulfonyl radicals to the C@C bond of 1
produce carbon radical intermediate B, which undergoes an
intramolecular cyclization to deliver radical intermediate C.
Following that, intermediate C was further oxidized via an
1
position was also
2
2
3