Asymmetric Cycloisomerization of o-Alkenyl-N-Methylanilines to Indolines by Iridium-Catalyzed C(sp3)?H Addition to Carbon–Carbon Double Bonds

Article abstract of DOI:10.1002/anie.201708578

Highly enantioselective cycloisomerization of N-methylanilines, bearing o-alkenyl groups, into indolines is established. An iridium catalyst bearing a bidentate chiral diphosphine effectively promotes the intramolecular addition of the C(sp³)?H bond across a carbon–carbon double bond in a highly enantioselective fashion. The reaction gives indolines bearing a quaternary stereogenic carbon center at the 3-position. The reaction mechanism involves rate-determining oxidative addition of the N-methyl C?H bond, followed by intramolecular carboiridation and subsequent reductive elimination.

Full text of DOI:10.1002/anie.201708578

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Asymmetric Cycloisomerization of o-Alkenyl-N-methylanilines to
Indolines through Iridium-Catalyzed C(sp3)-H Addition to Carbon-
Carbon Double Bonds
Authors: Takeru Torigoe, Toshimichi Ohmura, and Michinori Suginome
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708578
Angew. Chem. 10.1002/ange.201708578
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10.1002/anie.201708578
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Cycloisomerization of o-Alkenyl-N-methylanilines to
Indolines through Iridium-Catalyzed C(sp3)–H Addition to
Carbon–Carbon Double Bonds
Takeru Torigoe,[a] Toshimichi Ohmura,*[a] and Michinori Suginome*[a]
Abstract: Highly enantioselective cycloisomerization of N-
methylanilines bearing o-alkenyl groups to indolines is established.
An iridium catalyst bearing a bidentate chiral diphosphine effectively
promotes the intramolecular addition of the C(sp3)–H bond across a
carbon–carbon double bond with highly enantioselective fashion.
The reaction gives indolines bearing quaternary stereogenic carbon
centers at the 3-positions. The reaction mechanism involves rate-
determining oxidative addition of the N-methyl C–H bond, followed
by intramolecular carboiridation and subsequent reductive
elimination.
enantioselective cycloisomerization of conjugated dienes
tethered to an allylamino group has successfully shown the
potential of catalytic addition of the N-alkyl C(sp3)–H bond
7
across C=C bonds in organic synthesis [Scheme 1(c)].[ It
should be noted that, in all of those examples, activation of the
α-C(sp3)–H bonds of N-alkyl groups required additional
structural setups, such as a N–H bond, a pyridyl directing group,
and an allyl group, to facilitate the C(sp3)–H activation process.
To expand the substrate scope and to make this strategy more
applicable, it is truly important to establish a corresponding
process devoid of such additional structural requirements. We
]
herein
describe
the
iridium-catalyzed
asymmetric
Asymmetric catalysis based on transition-metal-catalyzed
C–H functionalization can provide the most atom- and step-
cycloisomerization of 2-alkenyl-N-methylanilines to 3-substituted
indolines, where the N-methyl C(sp3)–H bond undergoes direct
activation and addition to an intramolecular C=C bond in a highly
enantioselective fashion [Scheme 1(d)]. We show wide reaction
scope and propose a reaction mechanism in which activation of
the methyl C(sp3)–H bond α to the nitrogen atom is involved as
the rate-determining step, based on labeling experiments.
1
]
economical synthetic accesses to chiral organic molecules.[
Particular attention has focused on the asymmetric C–C bond
forming reactions via addition of the C–H bond across C–C
multiple bonds, since such a process allows 100% atom-
economical transformations with use of unelaborated starting
2
]
materials.[ Therefore, high demand is seen for the exploration
of such C–H addition reactions in order to realize sustainable
chemical processes for the production of enantioenriched chiral
organic materials.
(a) Schafer (2009), Zi (2010, 2011),
Hultzsch (2011, 2012)
(b) Shibata (2010, 2011, 2015)
R1
R2
R1
N
H
N
N
H
N
C
R2
Chiral nitrogen-containing molecules are recognized as a
highly important class of organic compounds in the exploration
of drugs and agrochemicals. Transition-metal-catalyzed
asymmetric addition of the C(sp3)–H bond of a N-alkyl group
across C=C bonds via a C–M intermediate is expected to be a
highly efficient strategy for the synthesis of chiral amines. Indeed,
the asymmetric addition of the α-C(sp3)–H bond of N-alkyl
groups of secondary amines has been reported, using tantalum
Ir cat.
Ar
CH3
*
H2
Ta, Nb cat.
Ar
N
+
+
R3
N
*
R
R3
R
up to 98% ee
up to 99% ee
(c) Yu (2011)
(d) This Work
R1
N
R1
N
Rh cat.
TsN
Ir cat.
CH3
R4
CH2
TsN
R2
R2
*
*
*
R
R3
R3
3
]
and niobium catalysts bearing chiral ligands [Scheme 1(a)].[
The catalysis proceeds through the initial formation of metal
amides followed by β-hydrogen elimination, which affords an
R4
up to 98.7% ee
R
up to 94% ee
Scheme 1. Transition-Metal-Catalyzed Asymmetric Addition of C(sp3)–H Bond
of N-Alkyl Group across C=C Bond.
4
]
active organometallic intermediate that reacts with an alkene.[
Although up to 98% ee was attained in one example,[3e]
enantioselectivities were generally moderate. Activation of the
C(sp3)–H bond α to the nitrogen atom was also promoted by use
The new cycloisomerization was designed on the basis of
our recent study on the cycloisomerization of o-alkynylanisoles
to benzofurans, which proceeds through activation of the
5
]
of a 2-pyridyl directing group.[ This type of activation enables
the iridium-catalyzed intermolecular asymmetric addition of 2-
(alkylamino)pyridines to terminal alkenes, in which one of the
two enantiotopic hydrogen atoms of the nitrogen-bound
methylene group takes part in the reaction selectively [Scheme
8
methoxy C(sp3)–H bond.[ N,N-Dimethylaniline 1a bearing a 1-
phenylvinyl group at the ortho position was reacted in toluene at
110 °C in the presence of [IrCl(C2H4)2]2 (3 mol %, 6 mol % Ir) as
a catalyst precursor and (S)-SEGPHOS (L1, 6 mol %) as a
ligand (entry 1, Table 1). Intramolecular addition of the C(sp3)–H
bond of the methyl group on nitrogen took place to give 1,3-
dimethyl-3-phenylindoline (2a) in 11% yield after 24 h.
Enantiomeric excess (ee) of the product was appreciably high
(85% ee), indicating that enantioface discrimination of the
double bond was accomplished efficiently by L1. The ee of 2a
improved to 91% (38% yield) when (S)-DM-SEGPHOS (L2) was
used as a ligand (entry 2). The reactions with L1 and L2 gave
hydrogenated 3 as a side product in 5-14% yield (entries 1 and
]
6
]
1(b)].[
At around the same time, rhodium-catalyzed
[a]
Dr. T. Torigoe, Prof. Dr. T. Ohmura, Prof. Dr. M. Suginome
Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: ohmura@sbchem.kyoto-u.ac.jp; suginome@sbchem.kyoto-
u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708578
Angewandte Chemie International Edition
COMMUNICATION
2). We found that an iridium catalyst bearing (S)-DTBM-
SEGPHOS (L3), bearing the bulky and electron donating 3,5-di-
tert-butyl-4-methoxyphenyl group (DTBM) on the phosphorus
atoms promoted the reaction more efficiently to give 2a in 85%
yield with 97% ee, in which the formation of 3 was completely
suppressed (entry 3). The absolute configuration of the major
enantiomer of 2a was determined to be R by single crystal X-ray
diffraction of the corresponding ammonium salt prepared from
2a with iodomethane (see Supporting Information). DTBM-
substituted ligands (S)-DTBM-MeOBIPHEP (L4) and (S)-DTBM-
BINAP (L5) both afforded high yields, although L5 afforded
slightly lower ee than L4 (entries 4 and 5). The Ir-L3-catalyzed
reaction proceeded even at 80 ºC, leading to the highest ee of
2a (98.7% ee) (entry 6). Commercially available [IrCl(cod)]2 was
also an effective catalyst precursor, although the yield of 2a was
slightly low due to the formation of 3 (entry 7). Toluene was the
solvent of choice, while the reaction in THF resulted in
preferential formation of 3 through hydrogen transfer from THF
(entry 8).[8,9]
R
N
R
N
[IrCl(C2H4)2]2 (3 mol %)
(S)-L3 (6 mol %)
6
3
1
5
4
Me
R'
R'
toluene
110 ºC, 24 h
2
Me
Ar
Ar
2
1
Me
N
Me
N
Me
Me
N
N
Me
Me
Me
Me
Me
F3C
MeO
2b[a]
94% yield
98% ee
2c
88% yield
97% ee
2d
82% yield
97% ee
2e
88% yield
98% ee
Me
N
Me
N
Me
N
Me
N
Me
Me
Me
Me
B(pin)
Ac
Me
2g[b]
80% yield
97% ee
2h
89% yield
98% ee
2i
2f
89% yield
97% ee
86% yield
96% ee
Table 1. Iridium-catalyzed asymmetric cycloisomerization of o-(1-
phenylvinyl)-N,N-dimethylaniline (1a) in the presence of chiral phosphorus
ligands L1-L5[a]
Me
N
Me
N
Me
Me
N
N
CH3
N
CH3
N
CH3
Ir precursor (3 mol %)
N
L (6 mol %)
Me
Me
Me
Me
CH3
CH3
+
solvent
CH3
CH3
T (ºC), 24 h
N
N
Ph
(R)-2a
Ph
1a
Ph
3
Me
2j
Me
Me
Br
Br
2m[b]
0% yield
2k[c]
2l
93% yield
97% ee
70% yield
96% ee
81% yield
97% ee
O
Me
DM
Me
N
Me
N
Me
N
O
O
PAr2
PAr2
MeO
MeO
PAr2
PAr2
PAr2
PAr2
Me
Me
Me
MeO
DTBM
t-Bu
O
Me
Me
Me
Ph
2n
70% yield
96% ee
Ph
2o
83% yield
98% ee
Ph
2p
78% yield
96% ee
(S)-L1 (Ar = Ph)
(S)-L2 (Ar = DM)
(S)-L3 (Ar = DTBM)
(S)-L4 (Ar = DTBM) (S)-L5 (Ar = DTBM)
OMe
t-Bu
3[c]
Me
F
Me
N
Me
N
Me
N
Me
N
entry Ir precursor
L
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
T (°C)
110
110
110
110
110
80
2a[b]
F3C
1
2
3
4
5
6
7
8
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(C2H4)2]2
[IrCl(cod)]2
(S)-L1
(S)-L2
(S)-L3
(S)-L4
(S)-L5
(S)-L3
(S)-L3
(S)-L3
11[c], 85
38, 91
85, 97
88, 96
81, 91
45, 98.7
76, 97
6[c], nd
5
Me
Me
Me
Me
Me
Ph
2r
Ph
Ph
Ph
2q
Me
2s
83% yield
96% ee
2t
14
0
70% yield
96% ee
87% yield
96% ee
82% yield
97% ee
Bn
N
Ph
N
Ac
N
H
N
1
Me
Me
Me
Me
2
Ph
2u[d]
72% yield
94% ee
Ph
2v[e]
61% yield
90% ee
Ph
2w[b]
0% yield
Ph
2x[b]
0% yield
2
110
110
10
80
Scheme 2. Iridium-catalyzed asymmetric cycloisomerization of 1. Reaction
conditions: 1 (0.20 mmol), [IrCl(C2H4)2]2 (0.0060 mmol), and (S)-L3 (0.012
mmol) were stirred in toluene (0.2 mL) at 110 °C for 24 h unless otherwise
noted. Isolated yields are given. Enantiomeric excesses (ees) were
determined by SFC with chiral stationary phase column. [a] 5.0 mmol (1.2 g)
scale. [b] In p-xylene at 135 °C. [c] In p-xylene at 135 °C for 36 h with 8
mol % of Ir. [d] 0.60 mmol scale. [e] In p-xylene at 135 °C with 8 mol % of Ir.
[IrCl(C2H4)2]2
[a] 1a (0.20 mmol), an Ir precursor (0.0060 mmol), and L (0.012 mmol) were
stirred in solvent (0.2 mL) at 80-110 °C for 24 h. [b] Isolated yield (%) and ee
(%) determined by SFC with chiral stationary phase column. [c] 1H NMR
yield (%).
A range of N-methylaniline derivatives 1 were subjected to
the
iridium-catalyzed
enantioselective
cycloisomerization
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10.1002/anie.201708578
Angewandte Chemie International Edition
COMMUNICATION
(Scheme 2). The reaction of N,N-dimethylanilines 1b-f bearing
para-substituted aryl groups on the double bonds took place
efficiently in toluene at 110 ºC in the presence of Ir-(S)-L3 (6
mol %) to give indolines 2b-f in 82-94% yields with 97-98% ees.
Under these reaction conditions, 2b was obtained on a gram
scale (1.1 g, 94% yield, 98% ee). No significant influence of
either Me, Et, CF3, OMe, or B(pin) groups on the reactivity and
enantioselectivity was observed (2b-f). By contrast, the reaction
of 1g bearing an acetyl group was sluggish at 110 ºC; it required
elevation of the reaction temperature to 135 ºC to give 2g in
good yield without a significant decrease in ee. 3-Methylphenyl-
and 2-naphthyl-substituted 1h and 1i also afforded 2h and 2i in
high yields with 96-98% ees. Pyrrolyl- and pyridyl-substituted 1j
and 1k affored the corresponding products with high ees,
although the latter substrate required forced reaction conditions
(8 mol % Ir, 135 °C, 36 h). It is interesting to note that 4-
bromophenyl-substituted 1m resulted in no reaction (2m), while
3-bromo-4-methylphenyl-substituted 1l gave 2l in high yield with
97% ee, probably because of steric shielding of the Br–C bond.
Compounds 1n-q, which bear the 4-Me, 4-OMe, 5-Me, and
5-CF3 groups on the aniline ring, respectively, gave the
corresponding products 2n–q in good yields with 96-98% ees
(Scheme 2). A substituent ortho to either the dimethylamino or
the alkenyl group did not affect the reaction; 2r-t were obtained
in good yields with 96-97% ees. In the reaction of N-benzyl-N-
methylaniline 1u, selective conversion of the N-methyl C–H took
place to give 2u with slightly low ee (94% ee), where the
enantioselectively. These results indicate that even
isomerizable C=C bonds including trisubstituted C=C bonds
undergo cycloisomerization with no prior double bond
migration.
(a)
Me
N
NMe2
Ph
[IrCl(C2H4)2]2 (3 mol %)
(S)-L3 (6 mol %)
toluene
110 ºC, 24 h
Me
Ph
1z
(R)-2z (89%, 81% ee)
(b)
Me
N
NMe2
Me
same as above
Ph
Me
Ph
(E)-1aa
(S)-2z (51%, 88% ee)
Scheme 4. Asymmetric Cycloisomerization of Potentially Interconvertible
Alkenes 1z and (E)-1aa
Reaction of 1ab and 1ac bearing tri-substituted alkenes
proceeded at 135 °C to afford the corresponding indolines 2ab
and 2ac with 95 and 96% ees, respectively, with moderate
yields [Eq.(1)].
Me
N
[IrCl(C2H4)2]2 (4 mol %)
(S)-L3 (8 mol %)
NMe2
10
(1)
]
methylene C–H of the N-benzyl group left untouched.[
The
R2
p-xylene
135 ºC, 24 h
R1
R1
reaction of N-methyl-N-phenylaniline 1v proceeded slowly,
giving 2v in 61% yield with 90% ee when using 8 mol % catalyst
at 135 °C. On the other hand, no reaction took place with N-
methylanilines 1w and 1x bearing an acetyl and hydrogen on the
nitrogen atoms (2w and 2x).
R2
1ab (R1 = n-C4H9, R2 = Ph)
1ac (R1 = n-C5H11, R2 = CO2Me)
2ab (50% from 1ab, 95% ee)
2ac (45% from 1ac, 96% ee)
The asymmetric cycloisomerization of 1 enables efficient
access to enantioenriched unprotected indoline 2x and acyclic
amine 4 both containing a quaternary carbon center (Scheme
5). Although 2x could not be synthesized by the
cycloisomerization of 1x directly (Scheme 2), debenzylation of
2u by hydrogenolysis led to 2x in high yield (Scheme 5, left).
According to the procedure reported by MacMillan et al., 2b
was reacted with iodomethane in CH2Cl2 and the resulting
ammonium salt was treated with Na/NH3 (Scheme 5, right).[11]
Cleavage of the C(sp2)–N bond took place smoothly at –78 °C,
giving 4 in good total yield and with retention of enantiopurity.
Cycloisomerization of the 4-(N,N-dimethylamino)pyridine
derivative 1y was not observed under the standard conditions
(Scheme 3). It is presumed that coordination of the sp2 nitrogen
atom to the iridium center shut down the catalyst activity. This
problem was overcome by pretreatment of 1y with BF3•OEt2 to
form 1y•BF3, which was found to undergo cycloisomerization
under the standard conditions. The cyclized product was then
treated with aqueous KOH in THF at 50 °C, giving 2y in 80%
yield with 97% ee.
BF3·Et2O
2 toluene
rt, 10 min
[IrCl(C2H4)2]2 (3 mol %)
(S)-L3 (6 mol %)
toluene, 110 ºC, 24 h
Me
N
NMe
Ph
NMe2
Ph
for 2b (98% ee)
for 2u (94% ee)
NMe2
N
N
F3B
then
N
then
remove
volatiles
1. MeI, CH2Cl2
rt, 12 h
H
Me
KOH aq.
THF, 50 ºC, 2 h
H2, Pd/C
N
Ph
2
Me
1y
1y•BF3
2y (80%, 97% ee)
EtOAc
2. Na, NH3
–78 ºC, 5 min
3. i-PrOH
Me
50 ºC, 24 h
Ph
2x (84%, 94% ee)
Me
4 (72%, 98% ee)
Scheme 3. Asymmetric Cycloisomerization of 4-(N,N-Dimethylamino)pyridine
Derivative 1y
–78 ºC, 5 min
Scheme 5. Synthetic Conversion of Enantioenriched Indolines 2
We then compared the cycloisomerization of two isomeric
substrates, terminal alkene 1z and trisubstututed internal
alkene (E)-1aa, which are potentially interconvertible via
double bond migration (Scheme 4). It should be noted that they
To gain insight into the reaction mechanism, deuterium-
labeling experiments were carried out (Scheme 6). Deuterium-
labeled 1a-D gave indoline 2a-D at 135 °C in 82% yield
[Scheme 6(a)]. While almost perfect deuterium incorporation
afforded
enantiomeric
products
(R)-
and
(S)-2z
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10.1002/anie.201708578
Angewandte Chemie International Edition
COMMUNICATION
was observed at the N-methyl and the methylene group of the
product, lower deuterium incorporation at the 3-methyl group
(81%) with its delivery to the ortho-position (27%) was noticed.
A large kinetic isotope effect (kH/kD = 3.3) was observed in the
independent reactions of 1a and 1a-D [Scheme 6(b)],
suggesting that oxidative addition of the C–H bond of the N-
methyl group to iridium is the rate-determining step.
bond to iridium is followed by insertion of a C=C bond into the Ir–
C bond, i.e., carboiridation, in a 5-exo fashion, to form the Ir–H
species B. Intermediate B undergoes reductive elimination of
the C–H bond to form the cycloisomerization product 2. The
observed formation of indole 5 can only be explained by β-
elimination from B (R = H) by this mechanism, but not by an
alternative mechanism involving insertion of a C=C bond into the
Ir–H bond (hydroiridation) of intermediate A. In the (S)-L3/Ir-
catalyzed reaction of 1a (R = Ph), the carboiridation proceeds
selectively on the Re-face of the C=C bond to afford R
enantiomer through a configuration that avoids steric repulsion
between the substituent R and the DTBM groups on the
phosphorus atoms.[13 ] Partial H/D exchange at C7 shown in
Scheme 6(a) is likely to indicate existence of a non-productive
iridacycle C formed from A.
(a)
73% H
27% D
92% CD3
8% CHD2
99% D
H
CD3
[IrCl(C2H4)2]2 (3 mol %)
(S)-L3 (6 mol %)
96% D
4% H
N(CD3)2
N
D
96% D
4% H
D
p-xylene
135 ºC, 24 h
CH2D
Ph
Ph
81% CH2D
19% CH3
1a-D
2a-D (82%)
(b)
[Ir(I)]
1
2
1a
2a
[IrCl(C2H4)2]2 (1.5 mol %)
(S)-L3 (3 mol %)
H
kH/kD = 3.3
H [Ir] CH2
Me
CH2
[Ir]
Me
toluene (0.20 M), 110 ºC
NMe
N
N
1a-D
2a-D
CH2
[Ir]
H
Scheme 6. Deuterium-Labeling Experiments
R
insertion into
Ir–C bond
(carboiridation)
R
R
H
C
A
B
We also carried out the reaction of vinyl-substituted N,N-
dimethylaniline 1ad [Scheme 7(a)]. We obtained indole 5 and
ethyl-substituted aniline 6 both in 41% yield along with the
cycloisomerization product 2ad in low yield. The formation of 5
may be explained either by dehydrogenation from the
cycloisomerization product 2ad or by β-H-elimination of an
iridium intermediate in the catalytic cycle. We could exclude the
former possibility by the reaction of 1ad in the presence of an
equimolar amount of N-benzylindoline 7 as a mimic of product
Scheme 8. A Possible Mechanism
In conclusion, we established an efficient Ir-(S)-L3 catalyst
system, for cycloisomerization of N-methylanilines into
indolines 2 with the construction of quaternary stereogenic
centers in highly enantioselective fashion. Mechanistic
1
a
investigations revealed that oxidative addition of a C–H bond to
Ir(I) is the rate-determining step, and the following insertion of a
C=C bond takes place via carboiridation rather than
hydroiridation.
12
]
2ad [Scheme 7(b)].[ At 23% conversion, the reaction afforded
5 (8%) and 6 (9%) along with the cycloisomerization product 2ad
in 6% yield with formation of only a small amount of indole 8
(<1.5%), which was derived from 7. This result clearly excludes
the possibility of a dehydrogenation process after the formation
of 2ad, but suggests a β-elimination process in the catalytic
cycle.
Acknowledgements
The authors thank Dr. Takeshi Yamamoto for helping X-ray
crystallographic analysis. This work was supported by JSPS
KAKENHI Grant Numbers 26•5249 for JSPS Research Fellow
(TT), JP26288048 for Scientific Research (B) (TO), and
JP15H05811 for Scientific Research on Innovative Areas in
Precisely Designed Catalysts with Customized Scaffolding (MS).
TO also expresses his appreciation for the support by The Kyoto
University Research Fund for Senior Scientists (Core) FY2017.
(a)
Me
N
Me
N
[IrCl(C2H4)2]2 (3 mol %)
(S)-L3 (6 mol %)
NMe2
NMe2
+
+
C6D6 (0.10 M)
80 ºC, 24 h
Me
2ad (16%)
Me
5 (41%)
1ad
6 (41%)
Bn
(b)
Bn
2ad (6%)
+
[IrCl(C2H4)2]2 (3 mol %)
N
N
(S)-L3 (6 mol %)
5 (8%)
+
6 (9%)
1ad
+
+
C6D6 (0.10 M)
80 ºC, 4 h
Keywords: Asymmetric synthesis • C–H activation •
Heterocycles • Quaternary stereogenic center • Synthetic
methods
Me
7 (1 equiv)
Me
8 (<1.5%)
23% conv. of 1ad
Scheme 7. Mechanistic Study Based on the Reaction of 1ad
[1]
For recent reviews, see: a) C. González-Rodríguez, M. C. Willis, Pure
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mechanism for the present cycloisomerization (Scheme 8). The
rate-determining oxidative addition of the N-methyl C(sp3)–H
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[IrCl(C2H4)2]2 (3 mol %)
(S)-L3 (6 mol %)
N
Ph
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2
no reaction
p-xylene
135 ºC, 24 h
Ph
1ae
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Entry for the Table of Contents
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T. Torigoe, T. Ohmura,* M. Suginome*
R1
R1
[IrCl(C2H4)2]2 (3 mol %)
(S)-DTBM-SEGPHOS (6 mol %)
N
N
CH3
Page No. – Page No.
R2
R2
CH2
*
toluene
R4
Asymmetric Cycloisomerization of o-
Alkenyl-N-methylanilines to Indolines
through Iridium-Catalyzed C(sp3)–H
Addition to Carbon–Carbon Double
Bonds
R3
110 ºC, 24 h
R3
R4
Build a bridge: Highly enantioselective cycloisomerization of N-methylanilines
bearing o-alkenyl groups to indolines is established. An iridium catalyst bearing a
bidentate chiral diphosphine effectively promotes the intramolecular addition of the
C(sp3)–H bond across a carbon–carbon double bond with highly enantioselective
fashion. The reaction gives indolines bearing quaternary stereogenic carbon
centers at the 3-positions. Twenty two indolines were synthesized over 95% ees.
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