Letter
a
Table 1. Screening of Optimal Reaction Conditions
Figure 1. Selected indoline-based natural products containing a C2
quaternary centers.
successively disclosed palladium- and nickel-catalyzed intra-
molecular asymmetric dearomatization via reductive Heck
reactions of N-(2-halobenzoyl)indoles.
Considering the high importance of the asymmetric
dearomatization of indoles and the facility of thioester in the
metal-catalyzed transformations, we proposed that the
oxidative addition of the Pd(0) to thioesters and subsequently
the intramolecular reductive Heck reaction of indoles could
construct a stereocenter at the C2 position. To date, the
asymmetric construction of valuable cyclic motifs bearing
quaternary carbon centers from carbonyl functionalities (for
example, thioesters, amide, and ester) is still a big
b
c
entry
variations from the standard conditions
yield (%)
ee (%)
1
2
3
4
5
6
7
8
none
89
86
28
78
81
91
60
79
92
96
90
15
0
91
88
26
85
92
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
L7 instead of L1
L8 instead of L1
HCOOH + TMEDA instead of HOONa
without HCOONa
1
9,20
challenge.
Previously, Du Bois and coworkers reported
an intramolecular nondecarbonylative Heck-type reaction of
thioester, forming terminal alkenes with prochirality (Scheme
2
1
1
C). In this Letter, we disclose a palladium-catalyzed ligand-
d
9
promoted asymmetric dearomatization of indoles via the
decarbonylative Heck-type reaction of thioesters, constructing
C2 aza-quaternary centers with high enantioselectivities.
We commenced our investigation by choosing S-ethyl 2-(2-
methylindole-1-carbonyl)benzothioate (1a) as the model
substrate. After careful optimization of the reaction conditions,
including chiral phosphines, the solvent, and the reaction time,
we obtained the desired product 2a in 89% yield with 96% ee
10
11
12
without Pd(OAc)2
without CuTC
<5
a
Reaction conditions: 1a (0.1 mmol), Pd(OAc) (10 mol %), ligand
(12 mol %), HCOONa (2.0 equiv), CuTC (1.5 equiv), MeOH (1.0
mL), 120 °C (oil bath), N , 12 h. Yield was determined by H NMR
analysis of crude reaction mixture using CH Br as the internal
standard. Determined by chiral HPLC. CuTC: copper(I) thiophene-
-carboxylate. 2.0 equiv. HCOOH and 2.0 equiv. TMEDA were
2
b
1
2
2
2
c
by treating 1a with Pd(OAc) (10 mol %), (R)-BINAP (12
2
d
2
mol %), CuTC (1.5 equiv), and HCOONa (2 equiv) in
methanol at 120 °C for 12 h (Table 1, entry 1). A lower
catalyst loading led to decreased yields of 1a (Table S1).
Phosphine ligands are often required in the decarbonylation of
separately added.
18e
hindrance (2g, 2h, 2l). Substrates bearing a naphthyl group
at the C2 position of the indole furnished the desired product
in 67% yield with 96% ee (2n). To our delight, the protocol
could be extended to heterocycle-containing substrates,
including furan and thiophene, giving the asymmetric
dearomatization products with excellent enantioselectivities
(2o and 2p). Moreover, benzyl and ester groups at the C2
position of indoles were also proven to be favorable in the
transformation, affording the desired products 2q and 2r in
good yields with 92 and 91% ee, respectively.
5
d,e10
thioesters.
phosphines gave good to excellent yields (Table 1, entries 2−
), and L1 ((R)-BINAP) delivered the best ee value (Table 1,
Among the various chiral ligands, bidentate
8
entry 1). Although HCOONa gave the best result among the
with HCOOH was also employable (Table S2). A higher yield
was obtained by using HCOOH/TMEDA as the hydride
source with 92% ee (Table 1, entry 9). A hydride source,
palladium catalyst, and CuTC are indispensable in the reaction
(
Table 1, entries 10−12). Lowering the reaction temperature
Substituents at other positions of indoles were also
investigated (Table 3). A substrate bearing electron-donating
groups such as methyl, methoxyl, and t-butyl would proceed
efficiently, giving the desired products in good yields with high
ee values (2s, 2v, 2w, 2aa). The halogen -substituted substrates
(2t and 2u) could also be converted into the desired products
in satisfactory yields along with excellent enantioselectivities.
For those substrates with electron-withdrawing groups, such as
trifluoromethyl (2x, 2ab) and nitrile (2y), the reaction
proceeded with relatively lower yields due to the decom-
position of starting material. When the C5 position of the
indole moiety was substituted by a phenyl group, the reaction
could also give the desired product in moderate yield, despite
the extended π-conjugation (2z). To our delight, the protocol
could be extended to the asymmetric dearomative alkenylation
With the optimized reaction conditions in hand, we
subsequently explored the substrate scope by examining the
substituents at the C2 position of the indoles (Table 2). To
our delight, various alkyl groups, including methyl, n-butyl,
cyclohexyl, and cyclopropyl were compatible, delivering the
corresponding products 2a−d in good yields (69−86%) with
excellent enantioselectivities (90−96% ee). Aryl groups with
various substituents at the C2 position of the indoles were also
examined, and corresponding products 2e−m could be
obtained with good results. Substrates with an ortho- and
meta-substituted benzene ring gave the desired products in
relatively lower yields, possibly due to the unfavorable steric
B
Org. Lett. XXXX, XXX, XXX−XXX
Han, Ming-Liang
