Organic Letters
Letter
a
Decreasing the reaction temperatures from 90 to 50 °C
increases the yields from 74 to 84% (Table 1, entries 1−3).
Scheme 2. Reactions Using Aryl Iodides or Bromides
a
Table 1. Reaction Conditions
entry
base
solvent
T (°C)
3a (%)
1
2
tBuOK
tBuOK
tBuOK
tBuOK
tBuONa
tBuOLi
Cs2CO3
KOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
90
70
50
30
50
50
50
50
50
50
50
74
82
84
61
26
trace
0
3
4
5
6
7
8
9
10
11
0
18
0
NaH
none
tBuOK
b
DMA
trace
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), base (1.2
1
mmol), solvent (1 mL), argon, 4 h. Yield was determined by H
NMR. DMSO, dioxane, PhCl, and toluene were also investigated,
b
giving no desired products.
Further decreasing the temperature to 30 °C results in the loss
of yield (entry 4). Other bases such as NaOtBu, LiOtBu,
Cs2CO3, and NaH are not effective (entries 5−9). There was
no conversion in the absence of a base (entry 10). The
reactions carried out in other solvents including DMA, DMSO,
dioxane, PhCl, and toluene were also investigated, and no
desired products were obtained (entry 11). The reaction
conditions demonstrated in entry 3 were chosen as the
standard conditions for further investigations. At 50 °C for 4 h,
2-aryl indoles could be obtained in generally high yields,
t
promoted only by BuOK without oxidants, additives, or
transition metal catalysts.
With the standard reaction conditions in hand, the substrate
scope was investigated (Scheme 2). Aryl iodides or bromides
are more reactive than chloride and fluoride analogues. In
addition to 3a, from dibromo substrates, all 4- to 7-bromo-
substituted indoles 3b−3e were obtained in 73−94% yields
without loss of 4- to 7-bromo groups under such basic
conditions. These indoles are useful intermediates because
they can be converted to 4- to 7-substituted indoles with a
cross-coupling reaction. The synthesis of 4- to 7-substituted
indoles has always been a demanding mission in organic
synthesis. Chloro- and fluoro-substituted indoles 3f and 3g
were also afforded. Other groups such as cyano, ester, and
trifluoromethyl were all tolerated under these reaction
conditions (3h, 3n, 3l, 3i, and 3m). Indoles bearing fused
heterocycles or rings were achieved in up to 96% yields (3j and
3k). Both electron-withdrawing groups and electron-donating
groups on the aryl substituents of imine are tolerated, giving
3m−3p in moderate yields. ortho-Bromophenoxymethylarene
bearing electron-rich substituents were compatible with the
standard reaction conditions too, affording the corresponding
product 3q and 3r in 46−64% yields. The alkyl-substituted
imines could also react with 1a, yielding 3s in 50% yield. What
should be pointed out is that either bromo or iodo substrates
are suitable for this reaction (3d and 3f), but iodides are more
reactive than bromides.
a
t
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), BuOK (1.2
b
mmol), DMF (1 mL), argon, isolated yields. 8 mmol scale of
reaction was performed, and 1.68 g of 3a was obtained in 78% yield.
c
The reaction was performed at 90 °C.
Chloro- and fluoroarene substrates are challenging reactants
for metal-catalyzed cross-coupling reactions such as Ullman-
type C−N bond formation. Using the current method, in
addition to bromides and iodides demonstrated above in
Scheme 2, aryl halides containing chloro and fluoro were also
found to synthesize indoles. As shown in Scheme 3, various
aryl chlorides and fluorides 1 were treated with imines 2 under
standard conditions, and desired indoles were obtained in up
to 95% yields. All selected indoles 3f−3x bore a convertible
chloro-substituent that occupied the potential sites for further
transformation by the cross-coupling reaction. Challenging aryl
fluorides were also successfully utilized in the cyclization with
imines. Several representative indoles bearing functional
groups such as CF3 or Br were obtained in 73−94% yields
(Scheme 3). Therefore, one standard procedure can be applied
to cyclize imines with all four types of halides, including F, Cl,
B
Org. Lett. XXXX, XXX, XXX−XXX
Li, Ya-Wei
