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resulted in 2-aminoquinolone 3aa[24] and imidazole 4aa[24,25] in
60 and 27% yield, respectively (Table 1, entry 1). The [4+2]
annulation of isocyanides 1a and 2a represents a new and
efficient protocol for the synthesis of quinolone 3aa; thus, the
reaction conditions were further optimized (Table 1). Solvent
Table 1: Optimization of the reaction conditions.[a]
Entry
Solvent
T [8C]
t [h]
Yield [%][b]
3aa
4aa
1
2
3
4
5
6
THF
DMF
1,4-dioxane
DCE
toluene
CH3CN
CH3CN
CH3CN
CH3CN
100
100
100
100
100
100
100
80
35
24
7
30
24
3
3
3
3
60
37
48
50
62
65
70
50
65
27
23
32
25
26
18
15
25
17
7[c]
8[c]
9[c]
120
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), Ag2CO3
(0.06 mmol), solvent (2 mL), air atmosphere, sealed tube. [b] Yield of the
isolated product. [c] Li2CO3 (0.06 mmol) was added.
Scheme 2. Scope of the reaction with respect to the isocyanoacetamide
2. Yields are for the isolated product. [a] The desired product was not
detected (ND). Imidazole 4aq was obtained in 54% yield. [b] Imid-
azole 4ar was obtained in 83% yield.
screening revealed that acetonitrile was the optimal reaction
medium with respect to the reaction time and yield of 3aa
(Table 1, entries 2–7). The yield of 3aa was further improved
to 70% by the addition of Li2CO3 (30 mol%) to the reaction
mixture (Table 1, entry 7). When the reaction was performed
at a lower or higher temperature, 3aa was produced in lower
yield (Table 1, entry 7 versus 8 and 9). Different catalysts and
bases were also screened (see the Supporting Information).
The scope of the reaction was examined under the
optimized conditions (Table 1, entry 7) with respect to the
isocyanoacetamide 2 (Scheme 2). In general, the reaction
tolerated a wide range of substrates 2 to produce a series of
polysubstituted 2-aminoquinolones 3aa–az in good to high
yields from isocyanides 1a and isocyanoacetamides 2. Iso-
cyanoacetamides 2 with various benzyl and alkyl R2 groups,
such as electron-rich (substrates 2a and 2b), electron-neutral
(substrate 2c), and electron-poor benzyl groups (substrates
2d–j), an a-naphthylmethyl group (substrate 2k), methyl
(substrate 2l), ethyl (substrate 2m), n-butyl (substrate 2n),
isopropyl (substrate 2o), and allyl (substrate 2p) groups were
effective isocyanide components and enabled the formation
of quinolones 3aa–ap in good to high yields. When isocya-
noacetamide 2q bearing a phenyl R2 substituent was used, 3-
phenylquinolone 3ap was not detected, but instead the
imidazole product (1-(2-benzoylphenyl)-4-phenyl-1H-imida-
zol-5-yl)(morpholino)methanone (4ap) was obtained in 54%
yield. When the a-unsubstituted isocyanoacetamide 2r was
used as a substrate, the Yamamoto-type imidazole 4ar was
obtained in 83% yield, and the corresponding quinolone 3ar
was not detected. Gratifyingly, halide substituents (in sub-
strates 2e, 2 f, 2h, and 2j) and an allyl group (2p) were
compatible with the developed reaction conditions, thus
providing handles for further transformation. Not only
a morpholino substituent was compatible with the reaction
conditions, but isocyanoacetamides 2 comprising thiomor-
pholino (substrate 2s), 4-methylpiperazin-1-yl (substrate 2t),
pyrrolidin-1-yl (substrate 2u), piperidin-1-yl (substrate 2v),
azepan-1-yl (substrate 2w), azocan-1-yl (substrate 2x), and
isoindolin-2-yl substituents (substrate 2y) on the amide part
(NR3 ) were converted into products 3as–ay in good yields.
2
Subsequently, the scope of the reaction was evaluated
with respect to the aryl isocyanide 1 (Scheme 3). The reaction
tolerated a wide range of aryl isocyanides 1 bearing various R
groups under the optimal conditions (Table 1, entry 7). Aryl
isocyanides with electron-withdrawing and electron-donating
groups at the ortho position give various 8-substituted 2-
aminoquinolones 3ba–ja in moderate to high yields. Aryl
isocyanides 1 with strongly electron withdrawing groups at the
para position, such as PhCO (substrate 1k) and CO2Et
(substrate 1l), afforded the corresponding 6-substituted
quinolones 3ka and 3la, respectively, in good yields. How-
ever, the corresponding 6-chloro- and 6-bromoquinolones
3ma and 3na were not detected when the corresponding 4-
chloro- and 4-bromophenyl isocyanides were used as the
substrate (the imidazole products 4ma and 4na were obtained
in 62 and 65% yield, respectively). When meta-substituted
aryl isocyanides, such as 3-ethylcarbonyl- (substrate 1o), 3-
chloro- (substrate 1p), 3-bromo- (substrate 1q), and 3-
methoxylphenyl isocyanide (substrate 1r), were used, mix-
tures of 5- and 7-substituted quinolones 3oa–ra’ were
obtained in varying ratios. The disubstituted aryl isocyanides
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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