Ruthenium-catalyzed enantioselective C-H functionalization: A practical access to optically active indoline derivatives

Article abstract of DOI:10.1021/jacs.9b07251

Ru(II)-catalyzed enantioselective C-H activation/hydroarylation has been developed for the first time, allowing for highly enantioselective synthesis of indoline derivatives via catalytic C-H activation. Commercially available Ru(II) arene complexes and chiral α-methylamines were employed as highly enantioselective catalysts. Based on a sterically rigidified chiral transient directing group, multisubstituted indolines were produced in up to 92% yield with 96% ee. Further transformation of the resulting 4-formylindoline enables access to an optically active tricyclic compound that is of potential biological and pharmaceutical interest.

Full text of DOI:10.1021/jacs.9b07251

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Communication
Ruthenium-Catalyzed Enantioselective C–H Functionalization:
A Practical Access to Optically Active Indoline Derivatives
Zhongyuan Li, Hetti Handi Chaminda Lakmal, Xiaolin Qian, Zhenyu
Zhu, Bruno Donnadieu, Sarah J. McClain, Xue Xu, and Xin Cui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07251 • Publication Date (Web): 19 Sep 2019
Downloaded from pubs.acs.org on September 19, 2019
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Journal of the American Chemical Society
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Ruthenium-Catalyzed Enantioselective C–H Functionalization:
A Practical Access to Optically Active Indoline Derivatives
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Zhong-Yuan Li, Hetti Handi Chaminda Lakmal, Xiaolin Qian, Zhenyu Zhu, Bruno Donnadieu, Sarah J.
McClain, Xue Xu, Xin Cui*
Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, United States
Supporting Information Placeholder
the square planar Pd center are key to the superior enantiocontrol.
Moreover, Rh(III)-catalyzed enantioselective processes have been
accomplished by the Cramer group with chiral Cp* ligands13 and
the Rovis group with engineered enzymes,14 respectively (Scheme
1, B). While Rh(III) serves as the major focus of d6 metal catalysts
with continued development,9a,15 the scope was also extended to
Ir(III)1b,16 and very recently, Co(III)17. Sharing the general C–H
metalation step, each metal species has shown distinct
stereoselectivity and reactivity profiles, which have brought in new
opportunities for the enantioselective access to various target
molecules.18
ABSTRACT: Ru(II)-catalyzed enantioselective C–H activation/
hydroarylation has been developed for the first time, allowing for
highly enantioselective synthesis of indoline derivatives via
catalytic C–H activation. Commercially available Ru(II) arene
complexes and chiral α-methylamines were employed as highly
enantioselective catalysts. Based on a sterically rigidified chiral
transient directing group, multi-substituted indolines were
produced in up to 92% yield with 96% ee. Further transformation
of the resulting 4-formylindoline enables access to an optically
active tricyclic compound that is of potential biological and
pharmaceutical interest.
During the past two decades, Ru(II) arene complexes have
emerged as effective and favorable catalysts for C–H activation
owing to their cost-effectiveness, easy preparation, versatile and
Development of new catalytic systems for enantioselective C–H
functionalization has been growing rapidly with multidisciplinary
impacts.1 Among different approaches,2 directed C–H bond
activation has emerged as a general and effective tool.3 Beyond the
C–H oxidative addition-based pathways,1b,2b,4 mechanistically new
reactivities and selectivities by high-valent metals, including
Pd(II),3a-c,5 Ru(II),6 Rh(III),7 and others,8 have emerged via
metalation/deprotonation pathways. Unlike low-valent metal-
catalyzed systems,1b their enantioselective versions encounter
mechanistic complication and intrinsic challenges that make many
“privileged” ligands incompatible.5a,9
distinct
reactivity
and
selectivity.2i,6b-f,19
Nevertheless,
enantioselective C–H activation with Ru(II) remains unknown
(Scheme 1, C).1b,20 With only three coordination sites, Ru(II) arene
catalysts are not readily compatible with the design of ligands or
bidentate CTDGs for Pd.9b Meanwhile, the inactivity of the
Ru(II)Cp complexes in C–H activation has limited the application
of chiral Cp* ligands.21 While Ru(II) continues to advance as an
active metal catalyst for C–H activation, developing
enantioselective versions as new synthetic tools is highly desirable
as this would unlock practical and inexpensive access to meet the
increasing need for new optically pure structures.
Scheme 1. Transition Metal Catalysts for Enantioselective
C–H Activation via Directed Metalation/Deprotonation
Scheme 2. Indoline Formation via C–H Functionalization
enantioselective?
A. Pd(II)-Catalyzed Enantioseletive C–H Activation:
3a
7a
3
Carbene C–H Alkylation
Nitrene C–H Amination
C–H Activation/Hydroarylation
R
H
2
H
L
DG
H
DG
mediator
C–H Activation/Amination
MPAA
MPAAM
MPAO...
N
H
Bidentate
CTDG
1
Pd
N
Pd
L
*
C
*
L
X
L
*
C
H
Pd
O
3,4-Disubstitution
for Building ABC Tricyclic Systems
R
FG
L
Precursor for CTDG
Y
D
X
X
B. Rh(III), Ir(III), Co(III)-Catalyzed
Enantioseletive C–H Activation:
C. Ru(II)-Catalyzed Enantio-
seletive C–H Activation:
H
O
R1
H
O
Z
*
Ru(II)
H
C
CTDG
4
*
C
H
R
R'
*
*
M = Rh, Ir, Co
H
2R
X
2R
3
2R
Biotin
B
N
2R
A
B
A
R1
N
N
Ru
N
L
Rh
DG
engineered
streptavidin
3
2
1
H
4
R3
PG
PG
M
PG
DG
H
C
H
Ergoline
C
H
Enabling Ru-catalyzed enantioselective C–H activation
Enabling enantioselective access to chiral indolines via C–H activation
DG
Alkaloids
C
A Missing Tool
During the past decade leading efforts by the Yu group have
enabled successful application of monoprotected amino acids
(MPAA) and related ligands in Pd(II)-catalyzed enantioselective
C–H activation (Scheme 1, A).5a,10 Pioneered by Yu recently,
bidentate chiral transient directing groups (CTDGs)10e,11 and chiral
transient mediators12 have been developed to address major
challenges. The conformationally organized intermediates
resulting from the chelation of the MPAA ligands and CTDGs at
Optically active indolines are important motifs in both synthetic
and medicinal chemistry.22 C–H activation and functionalization
have enabled approaches that are capable of constructing any of the
four non-aromatic bonds (Scheme 2). The enantioselective
formation of C2–C3 and C2–N1 bonds can rely on carbene C–H
alkylation23 and nitrene C–H amination,24 respectively. While the
Pd(II)-catalyzed C–H activation was successful for making the
C7a–N1 bond,25 which does not generate chirality, the
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Journal of the American Chemical Society
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hydroarylation via C–H activation provides a pathway to
enantioselectively construct the C3–C3a bond. While
enantioselective hydroarylation has been successfully developed
for the syntheses of other related cyclic skeletons, the
10).
A
mixed solvent system with toluene and
1
2
3
4
5
6
7
8
hexafluoroisopropanol (HFIP) turned out to be effective in
conjunction with KH2PO4 as an additive. This condition requires
only catalytic amount of the carboxylic acid, thus making the
employment of some functionalized acids practical.15f,16,17b,31 A 30
mol % of bulky acids A1 and A2 effectively increased both yield
and ee, respectively (entries 11 and 12). Examination of other N-
protected amino acids (entries 13–19) afforded 2aa in 76% yield
and 84% ee (entry 17). With protected L-tert-leucine (A7), further
optimization resulted in 88% yield of 2aa in 94% ee in PhCl/HFIP
solvent at 60 oC (entries 20 and 21). Notably, the sense of the chiral
induction is predominantly determined by the chiral amine, as
evidenced by the resulting -85% ee with ent-CA8 and A7 (entry
22).
enantioselective
synthesis
of
indolines
has
been
underdeveloped.1b,7b,7c,26,27 Of particular relevance, Bergman and
Ellman demonstrated a synthesis of a functionalized dihydrofuran
in 45% ee using 30 mol% of a chiral amine co-catalyst in a Rh(I)-
catalyzed intramolecular hydroarylation.27c Recent disclosure of
Ru(II) as an effective catalyst for intramolecular hydroarylation
encourages the development of the potential enantioselective
processes.28 Considering the cost-effectiveness and the availability
of the simple Ru(II) arene complexes, identifying a suitable imine-
based CTDG strategy seems practical. Starting with benzaldehyde
1, the resulting 3,4-disubstituted indolines 2 are particularly
desirable as they allow for cyclization with the 4-formyl group,
which produces tricyclic skeleton 3 that is relevant to the synthesis
of ergot analogs (4).22c,29
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Table 1. Ru(II)-Catalyzed Enantioselective Hydroarylation
under Various Conditionsa
Ph
CHO
CHO
[Ru(p-cymene)Cl2]2 (5 mol %)
H
H
CTDG (50 mol %), Additive
Scheme 3. Postulated Asymmetric Induction Model
AgBF4, solvent, 70 oC, 24 h
N
N
-Branched
Chiral Amines
H
Ph
arene
arene
1aa
2aa
Ts
Ts
Enantiomeric
Differentiation
by Potential
H
H
2R
3R
Ru
NH2
~3.1 Å
Ru
H
Standard conditions:
Additive: AcOH (5 equiv.); Solvent: ClCH2CH2Cl
H
A. Effect of -Branched Chiral
Amines as CTDGs:

*
CA
CHR
RHC
N
N
1
Sterically Rigidified
Conformation
H
Me
H
H
H
R
A
B
CA2
NH2
OH
entry 2:
0% y, ee: -
H
CA1
NH2
CA4
NH2
CA3
NH2
Ts
N
Ts N
Ru
Favored
Disfavored
H
H
Ph
Ph
entry 4
entry 1
35% y, ee: 17%
entry 3:
0% y, ee:-
:
:
H
Since only monodentate TDGs may work with Ru(II) arene
10% y, ee: 33%
H
catalysts, we envisioned chiral α-branched amines CA with an α-
hydrogen would be adaptable (Scheme 3). Suggested by the
measurement on a known structure,30 the distance between the
nearly parallel C–N bond and arene unit in a proposed key
intermediate A may be ~3.1Å. The limited distance would restrict
the free rotation of the C–N bond in the postulated intermediates A
and B, with the hydrogen briefly facing the top arene. This amine-
arene rigidified conformation would make a stationary arrangement
of the big and small substituents on two sides of the ruthenacycle.
During the enantio-determining insertion step,13 the alkene would
approach with the less substituted side toward the top arene, and
the double bond would approach from the less hindered side of the
stereogenic carbon center to form the favored enantiomer.
CA9
NH2
CA5
CA6
NH2
CA7
H
Ph
CA8
H
H
H
Me
NH2
NH2
NH2
Me
Me
Me
Me
Me
entry 5
58% y, ee: 27%
entry 6
entry 7
entry 8
entry 9
:
:
:
:
:
28% y, ee: 48% 44% y, ee: 18%
66% y, ee: 51%
10% y, ee: 65%
Standard conditions: CTDG: CA8
B. Effect of Additives and Solvents:
A1-9
(30 mol%) & KH2PO4 (2 equiv.)
entry
additive
AcOH
solvent
PhMe
yield (%)b ee (%)
iPr
10
11
12
37
52
50
66
75
79
O
O
O
O
CO2H
A1
N
N
N
N
CO2H
A1
& KH2PO4 PhMe:HFIP
& KH2PO4 PhMe:HFIP
CO2H
A2
Ph3C
O
A6
A2
tBu
13
A3 & KH2PO4 PhMe:HFIP
27
35
O
CO2H
A3
N
H
CO2H
14
15
16
17
18
19
20
21
A4 & KH2PO4 PhMe:HFIP
A5 & KH2PO4 PhMe:HFIP
A6 & KH2PO4 PhMe:HFIP
A7 & KH2PO4 PhMe:HFIP
A8 & KH2PO4 PhMe:HFIP
A9 & KH2PO4 PhMe:HFIP
17
52
74
76
53
44
89
88
68
40
79
81
84
81
76
91
94
-85
A7
O
O
O
O
As an initial study, herein we report the first Ru-catalyzed
enantioselective C–H activation/hydroarylation reaction and its
synthetic application for an ergot alkaloid-relevant tricyclic
structure. It enables a highly enantioselective synthesis of indolines
via catalytic C–H activation. Readily available Ru(II) complexes
and chiral α-methylamines are employed as catalysts and afforded
various chiral 4-formylindolines in up to 96% ee.
P
Cy
OH
A4
Me
CO2H
O
O
A8
N
CO2H
Bn
O
H
A5
CO2H
A7 & KH2PO4
A7 & KH2PO4
PhCl:HFIP
PhCl:HFIP
PhCl:HFIP
(S)
O
NH2
A9
22c A7 & KH2PO4
Me
ent-CA8
Initial efforts focused on the hydroarylation of m-
amidobenzaldehyde 1aa with [Ru(p-cymene)Cl2]2 and AgBF4 in
1,2-dichloroethane (DCE) (Table 1). Acetic acid (5 equiv) was used
for accelerating both the C–H activation and the reversible imine
formation. At 70 oC, chiral cyclic amine CA1 afforded indoline 2aa
in 35% yield and 17% ee (entry 1). Chiral amines CA2 and CA3
were shown to be ineffective, presumably due to additional
coordination by the OH and NH units (entries 2 and 3). With a
protected NH (CA4), the reaction occurred with 33% ee, however,
in low yield (entry 4). Productive reactions were observed with α-
methylbenzylamine analogs CA5–CA9, and a general trend in
enantiocontrol has emerged (entries 5–9). Increased steric
hindrance at the ortho-position of the phenyl, presumably orienting
toward the reaction center, led to increases in enantioselectivity.
Notably, all (R)-amines gave the same sense of asymmetric
induction, which is consistent with the proposed model (Scheme
3).
Standard conditions:
C. Effect of Arene Ligands:
, A7
CTDG: CA8
(30 mol %) & KH2PO4 (2 equiv.), PhCl:HFIP
Ru
Ru
Ru
Cl
Ru
Ru
Ru
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Ru1
Ru2
Ru3
Ru4
Ru5
Ru6
2
entry 28:
trace, ee: -
entry 23
17% y, ee:
entry 24
52% y, ee:
entry 25
87% y, ee:
entry 27:
96% trace, ee: -
:
:
:
entry 26
41% y, ee:
:
45%
90%
94%
a1aa (0.05 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), AgBF4 (20 mol %), acid
(30 mol %), chiral amine (50 mol %),32 KH2PO4 (2.0 equiv), solvent 0.4
mL, 24 h. bDetermined by 1H NMR with PhNO2 as internal standard. cent-
CA8 was used.
Based on the postulated model of enantiocontrol, the sterics of
the arene ligands would make an impact. A clear trend showed that
increasing steric bulkiness on the arene led to improved
enantioselectivity (entries 23–26), although trisubstituted arene
ligands deactivated the catalysts (entries 27 and 28).
Toluene as the solvent was later found to offer higher
enantiocontrol but decreased yield with chiral amine CA8 (entry
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R1
H
[Ru(p-cymene)Cl2]2 (5 mol %)
CA8
(R1 = Ar, Alk,
EWG)
CHO
CHO
Under the optimized conditions, various substituents on the
benzaldehyde unit of 1 were studied (Table 2). The R configuration
of 2aa was confirmed by single-crystal X-ray diffraction. The
ortho-substituents to the aldehyde would have significant
influences both sterically and electronically. As demonstrated by
2ba–2da with MeO-, F-, CF3- groups, respectively, electronically
and sterically different ortho-functional groups were well tolerated
at slightly elevated temperature. The meta-substituents, being para-
to the reacting C–H bond, would electronically influence both C–
H activation and insertion steps. Remarkably, 1 with electron-
donating and withdrawing, alkyl, and halogen groups were all
fruitfully transformed to indoline 2ea–2ha with up to 94% ee.
Moreover, when a methoxy group and a fluorine atom were located
on the para-position, catalytic reactions were also performed
smoothly and enantioselectively (2ia and 2ja). Moreover, an N-
nosyl group was successfully tolerated, as demonstrated by the
production of 2ka in 74% yield and 92% ee.
(50 mol %)
(30 mol %), KH2PO4 (2.0 equiv.)
H
A7
1
2
3
4
5
6
7
8
AgBF4 (20 mol %), PhCl/HFIP, 60 oC, 24 h
R1
N
N
1
2
Ts
ortho-
Ts
para-
meta-
FG
2ab
, 54% y,
ee: 94%
2ac
2ad
, 66% y,
ee: 96%
, 63% y,
ee: 93%
MeO
R1 = Ar
CHO
CHO
H
2ae
ee: 91%
, 61% y, 2af
2ag
ee: 91%b
, 85% y,
ee: 92%b
, 68% y,
FG
Me
F
(E)
H
N
N
FG
2ah
, 65% y,
ee: 93%
2ai
2aj
, 85% y,
ee: 90%
, 76% y,
ee: 93%
Ts
Ts
9
2ak
ee: 90%
2al, 79% y,
ee: 87%b
2am, 85% y,
ee: 87%b
, 71% y,
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NO2
Me
H
CHO
CHO
CHO
OTBDMS
H
H
OTBDMS
CHO
H
N
N
N
2aq
ee: 94%c
, 69% y,
2ap
ee: 91%c
, 76% y,
2an
2ao
, 92% y,
ee: 96%
, 59% y,
ee: 86%
Ts
Ts
Ts
N
Ts
CHO
CHO
CHO
O
Et
H
Table 2. Ru(II)-Catalyzed Enantioselective Hydroarylation
with Various Arene Moietiesa
H
H
C3H7
CHO
(E)
(Z)
OMe
H
N
N
N
C3H7
Ts
2as
Ts
Ts
2ar
, 55% y,
[Ru(p-cymene)Cl2]2 (5 mol %)
N
Ph
H
CHO
(E)-1as 2as

: 86% y, ee: 95%
CHO
b
ee: 81%c
(Z)-1as 2as
: 67% y, ee: 92%

CA8
(50 mol %)
86% y, ee: 91%b
Ts
H
A7
(30 mol %), KH2PO4 (2.0 equiv.)
2R
2R
aSame conditions as table 2. b70 oC. c48 h.
AgBF4 (20 mol %), PhCl/HFIP, 60 oC, 24 h
N
N
Ph
1
2
PG
Ph
PG
Subsequent efforts went on with amidobenzaldehyde 1 bearing
different types of internal alkene units (Table 3). Respectively, (E)-
styrenyl groups containing MeO-, Me-, F-, CF3-, NO2- groups at all
possible positions were systematically investigated and afforded
the corresponding indoline 2 in up to 85% yields with ee values
mostly above 90% (2ab–2an). Aliphatic alkenyl groups were also
Ph
H
Ph
CHO
CHO
CHO
(R)
F
MeO
H
H
N
N
N
Ts
, 76% y,
ee: 82%b
Ts
, 87% y,
ee: 94%
Ts
, 34% y,
ee: 90%b
2ca
2aa
2ba
X-ray 2aa
effective substituents for producing 2ao–2aq in good yields with
up to 96% ee. Remarkably, the catalytic system was successful with
electron-deficient alkene units, as exemplified by the formation of
2ar from the corresponding acrylate-containing benzaldehyde.
Additionally, the performances of the E and Z isomers were
Ph
Ph
H
Ph
H
Ph
CHO
CHO
CHO
CHO
F3C
H
H
N
N
N
N
F
MeO
Me
2fa
Ts
, 69% y,
Ts
Ts
Ts
, 71% y,
ee: 88%c
2da
2ea
, 86% y,
ee: 94%c
2ga
ee: 94%c
, 63% y,
ee: 82%c
o
compared. At 70 C, (E)-1as produced the same product 2as in
Ph
Ph
H
Ph
H
Ph
CHO
CHO
CHO
CHO
higher yield than (Z)-1as, while their ee values were almost the
same, indicating the configuration of the internal alkene was not
decisive for the enantiocontrol.33 Finally, slightly lower
temperature for the reaction of (E)-1as produced indoline 2as with
95% ee.
H
H
N
N
N
N
F3C
2ha
Ts
Ts
, 64% y,
ee: 69%d
Ts
, 60% y,
ee: 70%b
Ns
, 74% y,
ee: 92%e
OMe
F
2ia
2ja
2ka
, 62% y,
ee: 82%c
[Ru(p-cymene)Cl2]2
CHO
CHO
Ph
H
>98% H
>98% H
H
OHC
OHC
OHC
a1 (0.1 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), AgBF4 (20 mol %), acid (30
mol %), chiral amine (50 mol %), KH2PO4 (2.0 equiv), solvent 0.8 mL, 60
oC, 24 h. Isolated yield. b80 oC. c70 oC. d90 oC. e48 h.
(5 mol%)
(50 mol%)
H
H
H
CA5
rac-
(1)
+
AcOD (5 equiv.),
AgBF4 (20 mol%),
DCE, 30 oC, 24 h
N
N
N
Ph
Ph
Ph
Ph
1aa
92%
1aa
2aa
trace
Ts
H
Ts
Ts
Table 3. Ru(II)-Catalyzed Enantioselective Hydroarylation
to Various Alkenesa
[Ru(p-cymene)Cl2]2
CHO
CHO
Ph
60% D
41% D
H
64% D
41% D
(5 mol%)
(50 mol%)
H
H
H
CA5
rac-
(2)
+
AcOD (5 equiv.),
AgBF4 (20 mol%),
DCE, 40 oC, 24 h
N
N
N
Ph
1aa
1aa
83%
2aa
10%
Ts
Ts
Ts
[Ru(p-cymene)Cl2]2
(5 mol%)
without amine
CHO
CHO
Ph
H
>98% H
>98% H
H
H
H
H
(3)
+
AcOD (5 equiv.),
AgBF4 (20 mol%),
DCE, 40 oC, 24 h
N
N
N
Ph
1aa
1aa
80%
2aa
ND
Ts
Ts
Ts
For probing the mechanism, H/D exchange reactions were
carried out with the racemic form of amine CA5 in DCE.
Reversible H/D exchange did not occur at 30 °C. In contrast, at 40
°C, significant H/D exchange was observed in both the product and
recovered 1aa (eqs 1 and 2). Moreover, a control reaction without
amines gave neither the product 2aa nor detectable C–H activation
(eq 3).
Scheme 4. Postulated Mechanism and Enantiocontrol
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H
H
[Ru(p-cymene)Cl2]2
RCO2–, Ag+
AgCl
iPr
Scheme 6. Synthetic Applications of the Indolines
N
1aa
+
CA8
H+
N
Ph
H
Ar
H+
Ar
1
2
3
4
5
6
7
8
CHO
CHO
Me
OHC
Me
H
2aa
+
CA8
H
CHO
4
– H2O
5
H
OTBDMS
C
c)
a)
b)
H
C
H
O
N
H2O
H
N
Me
Ph
B
N
A
N
II
VI Ts
B
N
A
N
Ts
Ts
94% ee
7
Ru
Ts
PG
H+
2aq
O
3a Ts
RCO2
– RCO2H
iPr
Key Intermediate to
(±)-Lysergic Acid
O
a). TBAF, THF, RT, 1.5 h; b). PCC, DCM, RT, 3 h;
c). K2CO3, MeOH, RT, 16 h
59% overall yield,
91% ee from 2aq
–
I
HRMS [I - RCO2
]
R
Me
H
iPr
Me
H
m/z = 469.1027
Chiral indolines serve as important precursors for constructing
complex structures. ABC tricyclic aldehyde 7 is a key intermediate
for building the D ring in the synthesis of (±)-lysergic acid (Scheme
6).29e-h Terminal group modification of indoline 2aq followed by
an aldol condensation with the 4-formyl group afforded tricyclic 3a
in 91% ee. Different from the 5-formyl group in 7, 3a would open
potential asymmetric access to new non-naturally occurring ergot
analogs.22c
Ph
Ru
Ru
O2CR
–
N
N
O2CR
N
HRMS [III or IV - RCO2
]
Ar
Ar
Ph
m/z = 779.2240
Me
Me
N
Ts
III
Ts
V
Me
H
iPr
O
9
Ph
O
Ru
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
Ar
O
Me
N
Ts IV
arene
arene
Ph
H
Disfavored
Favored
CHO
In
summary,
Ru-catalyzed
enantioselective
C–H
H
H
A
Ru
H
Ru
PhHC
H
(R)
activation/hydroarylation reaction has been developed for the first
time. The cooperation of the α-methyl chiral amine has enabled an
effective application of enantioselective C–H activation for
synthesis of indoline derivatives. The new system features
practicality with the employment of the commercially available and
cost-effective Ru(II) complex and chiral amine. This method
provides opportunities for the enantioselective access to various
indoline-based bicyclic and polycyclic structures. More broadly,
the process represents a new tool that would stimulate further
exploration of enantioselective C–H functionalization reactions.
CHPh
N
N
N
Me
Me
Ts
2aa
B
(R)-
Based on data above and results from an existing study,6b
a
proposed mechanism is formulated to begin with a reversible
Ru(II)-based C–H activation of the transient imine intermediate II
in acidic media, forming ruthenacycle III (Scheme 4). Besides
assisting the metalation/deprotonation step, the bulky carboxylate
presumably forms an ion pair with the cationic part of the
intermediate IV, which would count for their observed impact on
the enantiomeric control. HRMS study on the reaction system
indicated a major species matching the intermediate I without a
carboxylate anion, and another major species matching the cationic
part of either intermediate III or IV (see SI for details). Based on
the postulated asymmetric induction model, the alkene unit should
prefer to approach the Ru center from the same side of the
conformationally rigidified methyl group on the chiral carbon
(Scheme 4, A and B). Notably, the proposed model leads to the R
configuration of the chiral center in 2aa, which is in accord with
the observation from its single crystal.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Experimental details and analytical data for
all new compounds (PDF); Crystallographic data (CIF).
AUTHOR INFORMATION
Corresponding Author
*xcui@chemistry.msstate.edu
Scheme 5. Syntheses of Intermediate-related Ruthenacycles
Ar
Me
6a
, Ar = Ph,
[Ru(p-cymene)Cl2]2
Notes
H
71%, 70:30 dr
(0.5 equiv.)
The authors declare no competing financial interests.
N
NaOAc (1 equiv.),
MeOH, 40 oC, 3 h
6b
, Ar = 1-Naph,
65%, 90:10 dr
5
R
R = 4-ClC6H4
ACKNOWLEDGMENT
X-ray
Me
iPr
Me
H
iPr
We are grateful for financial support from the Mississippi State
University Office of Research and Economic Development and
Department of Chemistry. We are also grateful for the helpful
discussion with Professor Charles Edwin Webster.
H
Ru
Cl
Ru
N
N
Cl
Cl
Ph
Me
Me
Cl
6a
6b
major diastereomer
major diastereomer
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(18) (a) Abrams, D. J.; Provencher, P. A.; Sorensen, E. J. Recent
Applications of C–H Functionalization in Complex Natural Product
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N. Catalytic Methods for C–H Bond Functionalization: Application in
Organic Synthesis. Adv. Synth. Catal. 2003, 345, 1077-1101.
(26) So far there is only one established example for the synthesis of
indoline via enantioselective hydroarylation that provides 19% ee: (a) Ye,
B.; Donets, P. A.; Cramer, N. Chiral Cp-Rhodium(III)-Catalyzed
Asymmetric Hydroarylations of 1,1-Disubstituted Alkenes. Angew. Chem.
Int. Ed. 2014, 53, 507-511. Alternatively, for palladium-catalyzed
enantioselective synthesis of indolines via C−H Activation with aryl
halides, see: (b) Anas, S.; Cordi, A.; Kagan, H. B. Enantioselective
Synthesis of 2-Methyl indolines by Palladium Catalysed Asymmetric
C(sp3)-H Activation/cyclisation. Chem. Commun. 2011, 47, 11483-11485.
(c) Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, E. P. Fused Indolines
by Palladium-Catalyzed Asymmetric C-C Coupling Involving an
Unactivated Methylene Group. Angew. Chem. Int. Ed. 2011, 50, 7438-7441.
(d) Saget, T.; Lemouzy, S. J.; Cramer, N. Chiral Monodentate Phosphines
and Bulky Carboxylic Acids: Cooperative Effects in Palladium-Catalyzed
Enantioselective C(sp3)-H Functionalization. Angew. Chem. Int. Ed. 2012,
51, 2238-2242. (e) Yang, L.; Melot, R.; Neuburger, M.; Baudoin, O.
Palladium(0)-Catalyzed Asymmetric C(sp3)-H Arylation Using a Chiral
Binol-Derived Phosphate and an Achiral Ligand. Chem. Sci. 2017, 8, 1344-
1349.
(27) (a) Thalji, R. K.; Ellman, J. A.; Bergman, R. G. Highly Efficient and
Enantioselective Cyclization of Aromatic Imines via Directed C−H Bond
Activation. J. Am. Chem. Soc. 2004, 126, 7192-7193; (b) Harada, H.; Thalji,
R. K.; Bergman, R. G.; Ellman, J. A. Enantioselective Intramolecular
Hydroarylation of Alkenes via Directed C−H Bond Activation. J. Org.
Chem. 2008, 73, 6772-6779. (c) Watzke, A.; Wilson, R. M.; O'Malley, S.
J.; Bergman, R. G.; Ellman, J. A. Asymmetric Intramolecular Alkylation of
Chiral Aromatic Imines via Catalytic C−H Bond Activation. Synlett 2007,
2383-2389.
(28) (a) Ghosh, K.; Rit, R. K.; Ramesh, E.; Sahoo, A. K. Ruthenium-
Catalyzed Hydroarylation and One-Pot Twofold Unsymmetrical C−H
Functionalization of Arenes. Angew. Chem. Int. Ed. 2016, 55, 7821-7825;
(b) Ghosh, K.; Shankar, M.; Rit, R. K.; Dubey, G.; Bharatam, P. V.; Sahoo,
A. K. Sulfoximine-Assisted One-Pot Unsymmetrical Multiple Annulation
of Arenes: A Combined Experimental and Computational Study. J. Org.
Chem. 2018, 83, 9667-9681; (c) Rit, R. K.; Ghosh, K.; Mandal, R.; Sahoo,
A. K. Ruthenium-Catalyzed Intramolecular Hydroarylation of Arenes and
Mechanistic Study: Synthesis of Dihydrobenzofurans, Indolines, and
Chromans. J. Org. Chem. 2016, 81, 8552-8560.
(29) (a) Mantegani, S.; Arlandini, E.; Bandiera, T.; Borghi, D.; Brambilla,
E.; Caccia, C.; Cervini, M. A.; Cremonesi, P.; McArthur, R. A.; Traquandi,
G.; Varasi, M. D1 Agonist and/or D2 Antagonist Dopamine Receptor
Properties of a Series of Ergoline Derivatives: a Structure–Activity Study.
Eur. J. Med. Chem. 1999, 34, 107-124; (b) Carr, M. A.; Creviston, P. E.;
Hutchison, D. R.; Kennedy, J. H.; Khau, V. V.; Kress, T. J.; Leanna, M. R.;
Marshall, J. D.; Martinelli, M. J.; Peterson, B. C.; Varie, D. L.; Wepsiec, J.
P. Synthetic Studies toward the Partial Ergot Alkaloid LY228729, a Potent
5HT1A Receptor Agonist. J. Org. Chem. 1997, 62, 8640-8653; (c)
Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.;
Kress, T. J.; Varie, D. L.; Wepsiec, J. P. Application of Palladium(0)-
Catalyzed Processes to the Synthesis of Oxazole-Containing Partial Ergot
Alkaloids. J. Org. Chem. 1997, 62, 8634-8639; (d) Ward, J. S.; Fuller, R.
W.; Merritt, L.; Snoddy, H. D.; Paschal, J. W.; Mason, N. R.; Horng, J. S.
Ergolines as Selective 5-HT1 Agonists. J. Med. Chem. 1988, 31, 1512-
1519; (e) Kurihara, T.; Terada, T.; Harusawa, S.; Yoneda, R. Synthetic
Studies of (±)-Lysergic Acid and Related Compounds. Chem. Pharm. Bull.
1987, 35, 4793-4802; (f) Kurihara, T.; Terada, T.; Yoneda, R. A New
(19) For other Ru-catalyzed C−H Functionalization, see: (a) Kilaru, P.;
Acharya, S. P.; Zhao, P. A Tethering Directing Group Strategy for
Ruthenium-Catalyzed Intramolecular Alkene Hydroarylation. Chem.
Commun. 2018, 54, 924-927; (b) Zhang, J.; Ugrinov, A.; Zhang, Y.; Zhao,
P. Exploring Bis(cyclometalated) Ruthenium(II) Complexes as Active
Catalyst Precursors: Room-Temperature Alkene-Alkyne Coupling for 1,3-
Diene Synthesis. Angew. Chem. Int. Ed. 2014, 53, 8437-8440; (c) Zhang,
J.; Ugrinov, A.; Zhao, P. Ruthenium(II)/N-Heterocyclic Carbene Catalyzed
[3+2] Carbocyclization with Aromatic N–H Ketimines and Internal
Alkynes. Angew. Chem. Int. Ed. 2013, 52, 6681-6684; (d) Yi, C. S.; Sang,
Y. Y.; Guzei, I. A. Catalytic Synthesis of Tricyclic Quinoline Derivatives
from the Regioselective Hydroamination and C–H Bond Activation
Reaction of Benzocyclic Amines and Alkynes. J. Am. Chem. Soc. 2005,
127, 5782-5783; (e) Yi, C. S.; Yun, S. Y. Scope and Mechanistic Study of
the Ruthenium-Catalyzed ortho-C–H Bond Activation and Cyclization
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127, 17000-17006; (f) Lee, D. H.; Kwon, K. H.; Yi, C. S. Dehydrative C–
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Substituted Indoles and Quinolines from the Dehydrative C–H Coupling of
Arylamines with 1,2- and 1,3-Diols. Organometallics 2016, 35, 1973-1977.
(20) Ru(0)-catalyzed C−H Functionalization has also been underdeveloped,
with only 15% yield and 15% ee reported: Kakiuchi, F.; Le Gendre, P.;
Yamada, A.; Ohtaki, H.; Murai, S. Atropselective Alkylation of Biaryl
Compounds by Means of Transition Metal-Catalyzed C–H/Olefin
Coupling. Tetrahedron: Asymmetry 2000, 11, 2647-2651.
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Reactions - A Treasure Trove of Atom-Economic Transformations. Angew.
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(22) (a) Podoll, J. D.; Liu, Y.; Chang, L.; Walls, S.; Wang, W.; Wang, X.
Bio-Inspired Synthesis Yields a Tricyclic Indoline that Selectively
Resensitizes Methicillin-Resistant Staphylococcus Aureus (MRSA) to β-
Lactam Antibiotics. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 15573-15578;
(b) Gan, Z.; Reddy, P. T.; Quevillon, S.; Couve-Bonnaire, S.; Arya, P.
Stereocontrolled Solid-Phase Synthesis of a 90-Membered Library of
Indoline-Alkaloid-like Polycycles from an Enantioenriched Aminoindoline
Scaffold. Angew. Chem. Int. Ed. 2005, 44, 1366-1368; (c) Deng, L.; Chen,
M.; Dong, G. Concise Synthesis of (−)-Cycloclavine and (−)-5-epi-
Cycloclavine via Asymmetric C–C Activation. J. Am. Chem. Soc. 2018,
140, 9652-9658.
(23) (a) Santi, M.; Müller, S. T. R.; Folgueiras-Amador, A. A.; Uttry, A.;
Hellier, P.; Wirth, T. Enantioselective Synthesis of trans-2,3-Dihydro-1H-
indoles Through C–H Insertion of α-Diazocarbonyl Compounds. Eur. J.
Org. Chem. 2017, 2017, 1889-1893; (b) Davies, H. M. L.; Morton, D.
Guiding Principles for Site Selective and Stereoselective Intermolecular C–
H Functionalization by Donor/Acceptor Rhodium Carbenes. Chem. Soc.
Rev. 2011, 40, 1857-1869; (c) Wen, X.; Wang, Y.; Zhang, X. P.
Enantioselective Radical Process for Synthesis of Chiral Indolines by
Metalloradical Alkylation of Diverse C(sp3)–H Bonds. Chem. Sci. 2018, 9,
5082-5086; (d) Wang, Y.; Wen, X.; Cui, X.; Zhang, X. P. Enantioselective
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Synthesis of (±)-Lysergic Acid. Chem. Pharm. Bull. 1986, 34, 442-443; (g)
Asymmetric Cyclopalladation of Dimethylaminomethylferrocene. J.
Organomet. Chem. 1979, 182, 537-546. (d) Shi, B. F.; Maugel, N.; Zhang,
Y. H.; Yu, J. Q. PdII-Catalyzed Enantioselective Activation of C(sp2)-H
and C(sp3)-H Bonds Using Monoprotected Amino Acids as Chiral
Ligands. Angew. Chem. Int. Ed. 2008, 47, 4882-4886.
Armstrong, V. W.; Coulton, S.; Ramage, R. A New Synthetic Route to (±)-
Lysergie Acid. Tetrahedron Lett. 1976, 17, 4311-4312; (h) Kornfeld, E. C.;
Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.;
Woodward, R. B. The Total Synthesis of Lysergic Acid. J. Am. Chem. Soc.
1956, 78, 3087-3114.
(30) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.;
Russell, D. R. Room-Temperature Cyclometallation of Amines, Imines and
Oxazolines with [MCl2Cp*]2 (M = Rh, Ir) and [RuCl2(p-cymene)]2. Dalton
Trans. 2003, 4132-4138.
(31) (a) Saget, T.; Lemouzy, S. J.; Cramer, N. Chiral Monodentate
Phosphines and Bulky Carboxylic Acids: Cooperative Effects in
Palladium-Catalyzed Enantioselective C(sp3)-H Functionalization. Angew.
Chem. Int. Ed. 2012, 51, 2238-2242. (b) Brauns, M.; Cramer, N. Efficient
Kinetic Resolution of Sulfur-Stereogenic Sulfoximines by Exploiting
CpXRhIII-Catalyzed C−H Functionalization. Angew. Chem. Int. Ed. 2019,
58, 8902-8906. For chiral amino acids employed for enantioselective C–H
activation, see: (c) Sokolov, V. I.; Troitskaya, L. L.; Reutov, O. A.
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(32) See Table S1 in the supporting information for the effect of the loading
of the chiral amine.
(33) To probe whether the (E)- and (Z)-alkene units undergo potential
isomerization, catalytic reactions with (E)-1as and (Z)-1as were performed
and were quenched at an abridged reaction time (3 h), respectively. 1H NMR
studies of the recovered 1as did not indicate detectable E/Z isomerization
in both experiments.
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