792
Bull. Chem. Soc. Jpn. Vol. 84, No. 7 (2011)
© 2011 The Chemical Society of Japan
Table 2. Thermal Reaction of Several Isocyanides 1a)
Ph
I
Ph
I
R
E
+
I2
R
E
Δ
CDCl3, 4 h
40 °C
NC
N
4a, 14%
36%
+
E2
CDCl3, 4 h
1a, 0.05 mmol
1 equiv
NC
N
60 °C
80 °C
80 °C
1
44%
Entry
1
E
Product
Yield/%b)
0.10 mmol
43%
)
(
(
(
(
(
E
1
2
3c)
PhTe-
PhSe-
I-
2a
3a
4a
73
84
44
Scheme 3. The reaction of isocyanide 1a with iodine.
1a
1b
1c
1d
1e
N
E
E
E
E
E
E
afforded 2,4-ditellurated quinoline 2a in 78% yield (Entry 1).
When the reaction was performed at 60 and 40 °C, quinoline 2a
was obtained in 74% and 73% yields, respectively (Entries 2
and 3). The thermal reaction with (PhSe)2 at 40 °C afforded 2,4-
diselenated quinoline 3a in 85% yield, successfully (Entry 4).
Increasing the temperature (60 and 80 °C) resulted in the
decrease in the yields of quinoline 3a (62% and 57%,
respectively). In these cases, the starting isocyanide was not
recovered (Entries 5 and 6). This is probably due to side-
reactions, e.g., a thermal addition of (PhSe)2 to aromatic
acetylenes, which proceeds at 80 °C to produce the corre-
sponding vicinally diselenated alkenes.14 Next the synthesis of
2,4-dithiolated quinoline 5a was attempted, but the thermal
reaction of 1a with (PhS)2 did not proceed (Entries 7-9).
The thermal reaction of 1a with iodine was also examined
(Scheme 3). The reaction of isocyanide 1a with iodine at 40 °C
provided 2,4-diiodoquinoline 4a in 14% yield.12b,15 The yields
of 2,4-diiodoquinoline 4a increased to 44% by increasing the
reaction temperature to 80 °C.
Scope and limitation of this thermal reaction was examined
and the results are summarized in Table 2. Isocyanides 1b and
1c, which bear 4-methylphenyl and 4-methoxyphenyl groups,
underwent the ditellurated and diselenated cyclization to afford
the corresponding quinolines 2b, 3b, 2c, and 3c in 78%, 55%,
67%, and 62% yields, respectively (Entries 4, 5, 7, and 8).
Halide substituents such as chloride and fluoride are tolerant of
the reaction conditions, and the corresponding quinolines 2d,
3d, 2e, and 3e were obtained successfully (Entries 10, 11, 13,
and 14). In the case of isocyanide 1f, low yields of quinolines
2f and 3f were obtained (the oligomerization of 1f proceeded
preferentially) (Entries 16 and 17). 2-(1-Hexynyl)phenyl iso-
cyanide (1g) could also afford quinolines 2g and 3g in 78% and
72% yields, respectively (Entries 19 and 20). The reactions of
isocyanides 1a, 1b, 1c, 1d, 1e, and 1g with iodine at 80 °C gave
the corresponding 2,4-diiodoquinolines 4a, 4b, 4c, 4d, 4e, and
4g, respectively (Entries 3, 6, 9, 12, 15, and 21). Unfortunately,
the reaction of 1f with iodine formed a trace amount of 4f.
Instead, the oligomer of 1f was obtained as the major product
(Entry 18). In general, the thermal Bergman cyclization of (Z)-
3-hexen-1,5-diyne derivatives requires heating at approximate-
ly 200 °C.16 It is noteworthy that the present thermal aza-
Bergman cyclization proceeds upon heating at 40-80 °C.
A possible reaction pathway for the thermal reaction of
o-alkynylaryl isocyanides 1 is shown in Scheme 4.17 Upon
heating, o-alkynylaryl isocyanides 1 undergo aza-Bergman
cyclization to generate the corresponding 2,4-biradical species
A. Then, the 2,4-biradical species A is captured by diphenyl
ditelluride,18 diphenyl diselenide,18 or iodine19 to form the
corresponding 2,4-disubstituted quinolines.
Me
OMe
Cl
)
)
)
)
4
5
6c)
PhTe-
PhSe-
I-
2b
3b
4b
78
55
49
N
E
7
8
9c)
PhTe-
PhSe-
I-
2c
3c
4c
67
62
46
N
E
10
11
12c)
PhTe-
PhSe-
I-
2d
3d
4d
51
60
44
N
E
F
13
14
15c)
PhTe-
PhSe-
I-
2e
3e
4e
74
82
25
N
E
CN
)
)
(
(
16
17
18c)
PhTe-
PhSe-
I-
2f
3f
4f
18
7
1f
trace
N
E
E
E
19
20
21c)
PhTe-
PhSe-
I-
2g
3g
4g
78
72
67
1g
N
a) Reaction conditions: isocyanide (1, 0.05 mmol), dichalco-
genide (0.10 mmol), CDCl3 (0.5 mL), 40 °C, 4 h. b) Isolated
yield. c) Iodine (0.05 mmol) was used in place of organic
dichalcogenides, and the reaction was carried out at 80 °C.
E
R
E_E
R
E
R
Δ
E = PhTe
N
NC
N
A
PhSe
I
1
2, 3, 4
Scheme 4. A possible reaction pathway.
In summary, a novel thermal aza-Bergman cyclization of
o-alkynylaryl isocyanides with diphenyl diselenide, diphenyl
ditelluride, and iodine has been developed. These reactions
provide the corresponding 2,4-difunctionalized quinolines
selectively. It is noteworthy that the present aza-Bergman
cyclization proceeds at lower temperatures than the thermal
Bergman cyclization of 1,2-diethynylbenzene derivatives.
Experimental
Typical Procedure for the Synthesis of 2,4-Difunctional-
ized Quinolines, e.g., 2,4-Ditellurated Quinolines.
mixture of 2-(phenylethynyl)phenyl isocyanide (1a, 0.05
mmol) and diphenyl ditelluride (0.10 mmol) in CDCl3 (0.5
mL) was heated at 40 °C for 4 h. After the reaction was
A
Mitamura, Takenori
