Organic Letters
Letter
In the past decade, progress in the field of visible-light
photoredox reactions with amines has attracted considerable
interest from the chemical community.11 As part of our
research interest in the development of C−H functionalization
at the α position to the nitrogen atom, a variety of N-aryl
pyrrole derivatives have been prepared via a [1,5]-hydride shift/
isomerization process.12 Herein, we describe an intermolecular
Diels−Alder reaction based on visible-light induced formation
of isoindoles in the presence of air as latent dienes, which react
with dienophiles to afford bridged-ring heterocycles under mild
reaction conditions.
Table 2. Visible-Light Induced Isoindole Formation/D−A
a
Reaction of Isoindolines 1 with 2a in the Presence of Air
b
entry
1
R1
R2
3
yield (%)
1
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
H
3aa
3ba
3ca
3da
3ea
3fa
83
76
73
81
71
85
74
76
70
63
72
65
64
71
41
2
4-Me
2,4-Me2
2-OMe
3-OMe
4-OMe
2-Cl
3
A dichloroethane (DCE) solution of N-phenylisoindoline 1a
and dimethyl acetylenedicarboxylate 2a was stirred at room
temperature in the presence of sunlight (entry 1, Table 1).
4
5
6
7
1g
1h
1i
3ga
3ha
3ia
a
Table 1. Evaluation of Various Reaction Conditions
8
3-Cl
9
4-Br
10
11
12
13
14
15
1j
1-naphthyl
H
3ja
1k
1l
5-Me
5-OMe
4-Cl
3ka
3la
H
1m
1n
1o
H
3ma
3na
3oa
b
entry
light
temp (°C)
solvent
time (h)
yield (%)
H
5-Cl
1
2
3
4
5
sunlight
orange
green
blue
−
blue
blue
blue
blue
blue
blue
blue
20
20
20
20
20
20
20
20
20
20
50
80
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
DMF
PhMe
DCE
DCE
107
143
84
43
72
72
71
61
48
69
48
48
44
H
4-NO2
41
a
1 (0.3 mmol) and 2 (1.2 equiv), 6 W blue LED, DCE (3 mL), rt
50
b
under an air atmosphere for 43 h. Isolated yields.
83
trace
trace
72
c
6
affording the corresponding products 3aa−3ia in 70−85%
yields (entries 1−9, Table 2). The reaction of N-(1-naphthyl)-
isoindoline 1j gave the corresponding product 3ja in a slightly
lower yield (63% yield, entry 10, Table 2). The structural
assignment of 3ia was supported by the X-ray crystallography
(see the Supporting Information for details). Next, N-
phenylisoindoline derivatives with various R2 substituents
were subjected to the visible-light triggered D−A reaction
(entries 11−15, Table 2). We found that methyl, methoxyl, and
chloro groups did not affect the reactivity, giving the
corresponding products 3ka−3na in good yields (entries 11−
14, Table 2). However, the reaction with 4-NO2 substituted
substrate 1o gave the corresponding product 3oa in only 41%
yield (entry 15, Table 2). Meanwhile, we found that N-
alkylisoindoline was an inappropriate substrate for this
conversion.
To broaden the generality of the above reaction with
isoindolines 1, maleimides 2b−2d were used as the dienophiles
(entries 1−3, Table 3). Therefore, reaction of N-phenyl-
isoindoline 1a with N-methylmaleimide 2b provided the
corresponding product 4ab in 67% yield with perfect endo-
selectivity (entry 1, Table 3).13 When N-phenylmaleimide 2c
and N-benzylmaleimide 2d were reacted with 1a, products 4ac
and 4ad were isolated in 83% and 84% yield, respectively
(entries 2, 3, Table 3), both only affording the endo-products.
The relative configuration of 4ad was confirmed by X-ray
crystallography (see the Supporting Information for details).
Reaction of 2d with 2-methoxyl, 4-methoxyl, and 4-bromide
substituted isoindolines (1d, 1f, 1i) gave products 4dd, 4fd, and
4id in 76−84% yields, respectively (entries 4−6, Table 3).
To demonstrate the practical utility of this methodology, a
gram-scale reaction (1.0 g) was carried out to furnish the
desired product 3aa in 77% yield (Scheme 2). Interestingly,
treatment of 3aa with 20 mol % TsOH·H2O in DCE at 80 °C
resulted in 1-naphthylamine derivative 5 in 78% yield (Scheme
3).
7
8
75
9
81
10
11
12
78
69
67
a
b
1a (0.3 mmol), 2a (1.2 equiv), light, solvent (3 mL). Isolated yield.
c
Under a N2 atmosphere.
After 107 h, the desired product bridged-ring heterocycle 3aa
was obtained in 44% yield. Encouraged by this result, under
other identical conditions, different types of light were
examined (entries 2−4, Table 1). To our delight, 3aa was
obtained in 83% yield after 43 h of irradiation with a 6 W blue
LED at room temperature (entry 4, Table 1). In sharp contrast,
the reaction almost did not take place in the dark (entry 5,
Table 1). When the reaction was carried out under a N2
atmosphere, only a trace amount of product was observed
(entry 6, Table 1). These results indicated that both visible-
light and air played critical roles in this reaction. Furthermore,
solvent optimization revealed that DCE was the best solvent,
enabling the reaction completion at room temperature within
43 h. Other solvents, such as DCM, THF, DMF, and toluene,
could also give satisfactory results (entries 7−10, Table 1). To
examine the temperature effect, the reaction was carried out at
50 and 80 °C under otherwise identical conditions, respectively,
providing 3aa in lower yields (entries 11, 12, Table 1).
Together, the optimized reaction conditions were determined
as follows: DCE as a solvent, under air condition, room
temperature, in the presence of blue LED.
With the optimal reaction conditions in hand, we turned our
attention to explore the reaction of various isoindolines 1 with
2a as the dienophile (Table 2). It was found that both electron-
donating and -withdrawing substituents on the benzene ring
linked to the nitrogen atom of 1 were suitable for this reaction,
B
Org. Lett. XXXX, XXX, XXX−XXX