A Synthetic Route to Chiral Benzo-Fused N-Heterocycles via Sequential Intramolecular Hydroamination and Asymmetric Hydrogenation of Anilino-Alkynes

Article abstract of DOI:10.1021/acs.organomet.9b00183

An efficient sequential intramolecular hydroamination/asymmetric hydrogenation reaction under catalysis of a single chiral ruthenium complex or a binary system consisting of achiral gold complex and chiral ruthenium complex has been reported. A diverse range of enantioenriched benzo-fused N-heterocycles, including 1,2,3,4-tetrahydroquinoline, indoline, and 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives, were obtained from anilino-alkynes in high yields (up to 98%) with moderate to excellent enantioselectivities (up to 98% ee) under mild conditions. This protocol features good functional group tolerance and high atom economy. Furthermore, this catalytic protocol is applicable to gram-scale synthesis of a naturally occurring alkaloid, (-)-Angustureine.

Full text of DOI:10.1021/acs.organomet.9b00183

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
A Synthetic Route to Chiral Benzo-Fused N‑Heterocycles via
Sequential Intramolecular Hydroamination and Asymmetric
Hydrogenation of Anilino-Alkynes
Cong Xu,† Yu Feng,† Faju Li,† Jiahong Han,† Yan-Mei He,† and Qing-Hua Fan*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences (ICCAS), and University of Chinese Academy of Sciences, Beijing 100190, PR China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, PR China
S
* Supporting Information
ABSTRACT: An efficient sequential intramolecular hydro-
amination/asymmetric hydrogenation reaction under catalysis
of a single chiral ruthenium complex or a binary system
consisting of achiral gold complex and chiral ruthenium
complex has been reported. A diverse range of enantioen-
riched benzo-fused N-heterocycles, including 1,2,3,4-tetrahy-
droquinoline, indoline, and 2,3,4,5-tetrahydro-1H-benzo[b]-
azepine derivatives, were obtained from anilino-alkynes in
high yields (up to 98%) with moderate to excellent
enantioselectivities (up to 98% ee) under mild conditions.
This protocol features good functional group tolerance and
high atom economy. Furthermore, this catalytic protocol is
applicable to gram-scale synthesis of a naturally occurring alkaloid, (−)-Angustureine.
catalytic systems provide enamine or imine products.8d To
INTRODUCTION
■
achieve step-economic synthesis of such chiral nitrogen-
Benzo-fused N-heterocycles (BFNHs) are core structural
containing products, the one-pot cascade reaction strategy
elements in a large number of biologically active molecules,
involving hydroamination of alkynes and a subsequent
including natural alkaloids and pharmaceuticals.1−3 Among
asymmetric transformation has been developed.11,12 Among
these BFNHs, tetrahydroquinoline and indoline derivatives are
the reported examples, asymmetric reduction of the imine/
regarded as privileged structures in medicine chemistry.2,3
enamine intermediates is a straightforward and efficient route
Consequently, many efforts have been made to develop new
to access the chiral amines or chiral nitrogen heterocycles.12
methods for the synthesis of optically active BFNHs through
However, most catalytic systems constituted two-type catalysts
asymmetric metal- or organocatalysis.4 In the past decade,
and required stepwise addition of the second chiral catalyst
highly enantioselective catalytic reduction of the presynthe-
and/or reducing reagent. In 2009, Gong and co-workers
sized quinolines and indoles has been well established (Scheme
reported a notable example,12c in which a consecutive
1a).5,6 Alternatively, intramolecular asymmetric reductive
amination (ARA) of ketones provides another efficient and
intramolecular hydroamination/asymmetric transfer hydro-
genation of alkynes were carried out under relay catalysis of
an achiral gold(I) complex and chiral phosphoric acid binary
system, giving chiral tetrahydroquinolines with excellent
enantioselectivity (Scheme 1c). This method, however, still
suffers from some drawbacks, such as the use of stoichiometric
Hantzsch esters as reductant and the lack of substrate
direct route toward chiral tetrahydroquinolines and indolines
(Scheme 1b).7 Despite these remarkable advances, highly
efficient catalytic systems capable of furnishing structurally
diverse chiral BFNHs with different ring size remain rare and
thus highly desirable.
The metal-catalyzed asymmetric hydroamination of an
generality. Therefore, it is still highly desirable to develop a
unsaturated C−C bond has proven to be an attractive
general and more efficient atom- and step-economic approach
alternative approach for the construction of chiral nitrogen
to allow the synthesis of structurally diverse chiral BFNHs with
heterocycles because of its high atom economy.8 Recently,
various chiral pyrrolidine and piperidine alkaloids, and
different ring size.
derivatives thereof, have been prepared using asymmetric
Special Issue: Asymmetric Synthesis Enabled by Organometallic
intramolecular hydroamination of alkenes.9 Although alkynes
Complexes
are more reactive than alkenes, only a few successful examples
of asymmetric hydroamination of alkynes to access chiral
Received: March 18, 2019
nitrogen-containing compounds were reported.10 Instead, most
© XXXX American Chemical Society
A
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conditions previously reported by our research group:15
Cu(OTf)2 (10 mol %) and (R,R)-C1a (10 mol %) as a binary
metal catalysts, THF as a solvent (Table 1, entry 1).
Unexpectedly, the reaction gave the expected product 2-
propyl-1,2,3,4-tetrahydroquinoline 2a with only moderate
conversion, and poor chemoselectivity and enantioselectivity.
Then, several other π-Lewis acidic metal complexes, such as
AgOTf, PtCl2, IMesAuCl C2a, and IMesAuMe C2b were
studied (entries 2−5). It was found that C2a gave the best
result for this process, which afforded the desired product 2a in
76% yield with 73% ee (entry 4). In addition, the
enantioselectivity could not be further improved after an
examination of different solvents (Table S1, entries 6−11 in
Supporting Information). Notably, a control experiment in the
presence of only a gold catalyst C2a (10 mol %) gave the
racemic product 2a in 25% yield (entry 6), suggesting that the
achiral gold catalyst might participate in the second catalytic
hydrogenation step. To our delight, the sequential reaction
could be catalyzed by a single chiral ruthenium catalyst (R,R)-
C1a (10 mol %), affording 2a with high enantioselectivity
albeit moderate reactivity and chemoselectivity (entry 7). This
result indicated that the ruthenium catalyst can also activate
the alkyne group and realize the hydroamination reaction.16 To
achieve this sequential reaction with only a single catalyst, we
further screened several reaction solvents (entry 8 and entries
1−6 in Table S2, Supporting Information). Unexpectedly, full
conversion and excellent enantioselectivity were only observed
in neat room-temperature ionic liquid [Bmim]SbF6 (entry 9).
Notably, the enantioselectivity were influenced by the nature
of the counteranion (entries 9−13 in Table 1),14b and
[Bmim]NTf2 gave the highest enantioselectivity (97% ee).
Subsequently, several chiral ruthenium catalysts were screened
in [Bmim]NTf2 (entries 13−15 in Table 1 and entries 12−21
in Table S2, Supporting Information), and (R,R)-C1a was
found to be the optimal catalyst in terms of both catalytic
activity and enantioselectivity. In addition, the experiments of
other reaction parameters, including hydrogen pressure and
temperature, revealed that 50 atm of hydrogen gas and 25 °C
were the optimal reaction conditions (entries 22−24 in Table
S2, Supporting Information). Notably, reducing the catalyst
loading to 5 mol % still provided almost complete conversion
and the same high enantioselectivity (Table S2, entry 25).
Under the optimized reaction conditions (entry 13 in Table
1), we further investigated the substrate scope of the Ru-
catalyzed sequential hydroamination/asymmetric hydrogena-
tion of various 2-(2-propynyl)aniline derivatives in [Bmim]-
NTf2. As shown in Scheme 2, all reactions proceeded smoothly
affording the corresponding chiral 2-alkyl substituted tetrahy-
droquinolines in high yields with excellent enantioselectivities
(88−98% ee). It was found that there is no obvious effect on
either reactivity or enantioselectivity when the length of the
alkyl chain (R2) prolonged (2a−2c). However, slight lowered
yields and enantioselectivities were observed when steric
hindrance R2 group such as cyclohexyl or isopropyl introduced
(2d and 2e). Moreover, substrates bearing both electron-
donating (2h and 2i) and electron-withdrawing groups (2j−
2l) on the aniline moiety similarly provided the corresponding
chiral products in excellent reactivity and enantioselectivity.
Encouraged by these results, the aryl-substituted substrate 2-
(3-phenyl-2-propynyl)aniline was also studied. When a single
chiral ruthenium catalyst (R,R)-C1a was used, only low yield
and moderate enantioselectivity were observed (entries 1−7 in
Table S3, Supporting Information). We then investigated this
Scheme 1. Strategy for Enantioselective Synthesis of Chiral
Benzo-Fused N-Heterocycles (BFNHs)
Recently, we have demonstrated that the cationic ruthenium
complexes of chiral monosulfonated diamines13 are very
efficient catalysts for the asymmetric hydrogenation of various
challenging substrates, such as quinolines, indoles and cyclic
ketimines.5c,d,14 Most recently, we found that this catalytic
system is well compatible with some π-Lewis acidic metal
complexes like Cu(OTf)2, and could efficiently catalyzed the
asymmetric tandem reaction of ortho-(alkynyl)aryl ketones,
giving chiral 1H-isochromenes with excellent enantioselectiv-
ity.15 Intrigued by this result and inspired by the aforemen-
tioned advances achieved in the asymmetric hydroamination of
alkynes,12c we envision that alkynyl amines could be directly
transferred into chiral BFNHs under relay catalysis of a
bimetallic system (Scheme 1d). Herein, we report an efficient
route to chiral tetrahydroquinolines and indolines in high
yields (up to 98%) with moderate to excellent enantioselectiv-
ities (up to 98% ee) through sequential intramolecular
hydroamination and asymmetric hydrogenation of various
anilino-alkynes.
RESULTS AND DISCUSSION
■
The Sequential Intramolecular Hydroamination/
Asymmetric Hydrogenation Reaction. Synthesis of
Tetrahydroquinolines. To explore the viability of this
strategy, 2-(hex-2-yn-1-yl)aniline (1a) was chosen as the
model substrate for optimization of the reaction conditions of
the sequential intramolecular hydroamination/asymmetric
hydrogenation reaction. As a starting point, we used the
B
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a
Table 1. Optimization of Reaction Conditions
b
b
c
entry
solvent
THF
THF
THF
THF
THF
THF
THF
MeOH
[Bmim]SbF6
[Bmim]PF6
[Bmim]BF4
[Bmim]OTf
[Bmim]NTf2
[Bmim]NTf2
[Bmim]NTf2
catalyst I
catalyst II
conv [%]
ratio [%] 2a:2o:2p:2q
ee of 2a [%]
1
2
3
4
5
6
7
8
Cu(OTf)2
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
−
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1a
(R,R)-C1e
(R,R)-C1i
68
60
83
>95
67
82
75
80
>95
>95
>95
>95
>95
>95
49
43:9:48:0
31:15:54:0
32:68:0:0
76:14:10:0
29:20:51:0
25:11:0:64
36:28:37:0
56:13:31:0
95:4:1:0
95:5:0:0
94:5:1:0
93:7:0:0
94:6:0:0
92:5:3:0
30
38
10
73
87
0
89
93
95
96
93
92
97
96
98
AgOTf
PtCl2
C2a
C2b
C2a
−
−
−
−
−
9
10
11
12
13
14
15
−
−
−
−
57:24:19:0
a
Standard reaction conditions: substrate 1a (0.1 mmol), solvent (0.5 mL), catalyst I (10 mol %), catalyst II (10 mol %), H2 (50 atm), 25 °C, 24 h.
b
c
1
Determined by H NMR analysis of the crude product. Determined by HPLC analysis.
a
Scheme 2. Synthesis of Chiral 2-Substituented Tetrahydroquinolines: Substrate Scope
a
Reactions were carried out on a 0.2 mmol scale using (R,R)-C1a (10 mol %) in [Bmim]NTf2 (1.0 mL) under H2 atmosphere (50 atm) at room
b
c
temperature for 24 h. 50 °C. (R,R)-C1e (10 mol %) and C2a (10 mol %) were stirred at 0 °C in 2-propanol. Yield of isolated product given. The
absolute configurations of the products were determined by comparison with literature data.
sequential reaction by using a binary catalytic system consisting
of achiral gold catalyst and chiral ruthenium catalyst. Notably,
IMesAuCl C2a was found to be the best partner of ruthenium
catalyst (R,R)-C1a, and afforded 2m in 94% yield with 71% ee
in methanol (entries 8 in Table S3, Supporting Information).
Upon a brief screening of several ruthenium catalysts, solvents
C
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and temperature (entries 10−17 in Table S3, Supporting
Information), very good yield and enantioselectivity (87%
yield with 88% ee) were achieved.
found to be insensitive to the length of the alkyl side chain (4b,
4c), and a comparable reactivities and better enantioselectiv-
ities were observed as compared with 4a. The substrates
bearing phenyl groups (4e, 4f) or more steric isobutyl groups
(4d) on the side chain gave only slightly lower yields (81−
89%) and comparable enantioselectivities (94−97%), albeit
needing long reaction time (48 h). Moreover, the substrates
bearing methyl group and electron-donating substitution like
methoxy on the aniline moiety also gave very good yields (89−
92%) with excellent enantioselectivities (95−97%) (4g, 4h).
Notably, substrates bearing electron-withdrawing substituents
(F or Cl) on the aniline moiety gave only slightly lower
enantioselectivities (91−92% ee) and yields (83−85%) upon
prolonged reaction time (4i, 4j).
Synthesis of 2,3,4,5-Tetrahydro-1H-benzo[b]azepine
Derivatives. Benzo-fused seven-membered aza-heterocycles,
such as benzazepine, are widely present in a variety of drugs
and bioactive molecules.17 However, the direct catalytic
asymmetric synthesis of benzazepine framework is less
studied.14d,17b,c Encouraged by the excellent results obtained
above, we attempted to employ this effective approach for the
construction of 2,3,4,5-tetrahydro-1H-benzo[b]azepine deriva-
tives (Scheme 4). In contrast to anilino-alkyne 1a, substrate 5a
Synthesis of Indoline Derivatives. Encouraged by the
excellent results obtained above, we then expand this protocol
to fabricate chiral indoline derivatives. As refer to our previous
work,6c hexafluoro-2-propanol (HFIP) was the optimal solvent
in the asymmetric hydrogenation of indoles. Thus, we first
chose the sequential hydroamination/asymmetric hydrogena-
tion of 2-(pent-1-yn-1-yl)aniline (3a) in the presence of 10
mol % (R,R)-C1a in HFIP as a standard reaction. However, no
conversion was observed and all starting material were
recovered (entry 1 in Table S4, Supporting Information).
Then, we investigated this one-pot sequential reaction by using
a binary catalytic system consisting of achiral gold catalyst and
chiral ruthenium catalyst (entries 2−11 in Table S4,
Supporting Information). A series of Lewis acids and
ruthenium catalysts were screened, and the results are listed
in Table S4 in Supporting Information. It was found that
IMesAuMe C2b (10 mol %) and (R,R)-C1i (10 mol %) binary
catalytic system gave the best catalytic performance. An
examination of other reaction parameters, including hydrogen
pressure and temperature, revealed that 50 atm of hydrogen
gas and 25 °C were the optimal reaction conditions (entries
12−13 in Table S4, Supporting Information).
Scheme 4. Synthesis of Chiral 2,3,4,5-Tetrahydro-1H-
benzo[b]azepine Derivatives
With the optimized sequential reaction conditions in hand, a
variety of 2-ethynylaniline derivatives 3b−3j with different
substituents at the alkyne and the aromatic ring were
investigated. As summarized in Scheme 3, all reactions
proceeded smoothly to give full conversions and afforded the
corresponding chiral indoline derivatives with excellent
enantioselectivities (91−97% ee). Notably, the reaction was
Scheme 3. Synthesis of Chiral 2-Substituented Indolines:
a
Substrate Scope
was less reactive in [Bmim]NTf2 in the presence of (R,R)-C1a,
and the six-membered 2-ethyl-1,2,3,4-tetrahydroquinoline 2v
was found to be the main product (Table S5, entry 1 in
Supporting Information). When this reaction was carried out
under a binary catalytic system of C2a and (R,R)-C1a in
[Bmim]NTf2, full conversion of 5a was observed (Scheme 4a).
The seven-membered 2-methyl-1H-benzo[b]azepine 6a was
obtained in 50% isolated yield with 48% ee, and 2v was also
observed in 28% isolated yield with 96% ee. Notably,
sequential reaction of racemic substrate 5b bearing a hydroxyl
group proceeded smoothly in [Bmim]NTf2 in the presence of
(R,R)-C1a, affording the seven-membered ring isomers as the
main product in 53% totally isolated yield with 74% ee (trans
isomer, 6b-1) and 88% ee (cis isomer, 6b-2), respectively
(Scheme 4b). The absolute configuration of trans isomer 6b-1
was determined to be (2R,5S) based on the single-crystal X-ray
analysis (see Scheme S2, Supporting Information).
a
Reactions were carried out on a 0.15 mmol scale using (R,R)-C1i
(10 mol %) and C2b (10 mol %) in HFIP (1.0 mL) under H2
atmosphere (50 atm) at room temperature for 24 h. Yield of isolated
product given. 48 h. 72 h. 50 °C.
b
c
d
D
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Catalytic Pathway. In our initial study with this sequential
hydroamination/asymmetric hydrogenation protocol, we
proposed a catalytic reaction pathway, including hydro-
amination of anilino-alkyne, isomerization, and asymmetric
hydrogenation of imine. Despite such a general understanding,
however, some key issues of this sequential reaction were
unclear. In order to further investigate the catalytic mechanism,
several control experiments were carried out (Scheme 5).
catalytic system by our group,5d,6c a plausible mechanism was
proposed for the synthesis of tetrahydroquinolines via
sequential reaction (Scheme 7). In the hydroamination step,
the anilino-alkyne substrates 1 were activated by ruthenium
catalyst (R,R)-C1a to generate 1,4-dihydroquinoline inter-
mediate. Then, 1,4-dihydroquinoline was activated by
Brønsted acid HOTf to form the iminium cation, and the
subsequent asymmetric hydrogenation catalyzed by (R,R)-C1a
leads to the desired product.5d Considering that the D atoms
were not found at 4-position of the product (as shown in
Scheme 6b), the asymmetric disproportionation of 1,4-
dihydroquinoline intermediate do not occur in the presence
of hydrogen gas. In the case of synthesizing chiral indolines,
similar catalytic pathway can be proposed, which involves gold-
catalyzed hydroamination of anilino-alkyne to generate indoles,
followed by asymmetric hydrogenation of indoles catalyzed by
(R,R)-C1i to give the desired chiral products.6c
Scheme 5. Control Experiments
Product Elaboration. As a specific synthetic application,
we developed a gram-scale synthesis of (−)-Angustureine, a
natural product with multiple biological activities.18 Sequential
hydroamination/asymmetric hydrogenation of 1c catalyzed by
(R,R)-C1a (10 mol %) was carried out in [Bmim]NTf2 at
room temperature for 48 h, affording (R)-2c in full conversion
with 97% ee. Subsequent N-methylation of 2c under mild
reaction conditions gave (−)-Angustureine in 98% isolated
yields (1.2 g) with 97% ee (Scheme 8).
Reaction of 1a in the presence of 10 mol % (R,R)-C1a in
methanol led to the formation of chiral tetrahydroquinoline
(R)-2a in 49% yield with 79% ee and the corresponding
quinoline 2q in 51% yield (Scheme 5a). This result indicated
that the chiral ruthenium complex first functioning as a π-
Lewis acid catalyst catalyzed hydroamination of 1a, furnishing
a 1,4-dihydroquinoline intermediate, followed by asymmetric
disproportionation of 1,4-dihydroquinoline catalyzed by (R,R)-
C1a.4q In the case of synthesizing chiral indolines with a binary
catalytic system, reaction of 3a in the presence of only a π-
Lewis acid catalyst C2b resulted in the formation of 2-propyl-
1H-indole in 99% conversion (Scheme 5b). These results
demonstrated that both the ruthenium catalyst and the gold
catalyst can catalyze the hydroamination of anilino-alkyne.
To further confirm the catalytic pathway, isotope labeling
experiments using deuterated hydrogen gas and solvents were
carried out, and the concentration of deuterium in the various
positions of the targeted product was determined by 1H NMR
spectroscopy. As shown in Scheme 6a, the reaction of 1a was
CONCLUSIONS
■
In summary, we have developed an efficient and facile protocol
for the one-pot synthesis of enantioenriched benzo-fused N-
heterocycles from anilino-alkynes through the relay catalysis
using a single chiral ruthenium catalyst or using a binary
system consisting of achiral gold complex and chiral ruthenium
complex. Series of chiral benzo-fused N-heterocycles, including
tetrahydroquinoline, indoline, and benzazepine derivatives
were obtained in high yields with moderate to excellent
enantioselectivities. The chiral ruthenium catalysts worked well
for the synthesis of 2-alkyl 1,2,3,4-tetrahydroquinolines.
Instead, the Au/Ru binary catalytic system provided better
results for the synthesis of 2-phenyl 1,2,3,4-tetrahydroquino-
line and indoline derivatives. Notably, the use of ionic liquids
enhanced the chemo- and enantioselectivities. Further control
and deuteration labeling experiments demonstrated that these
sequential reactions comprise π-Lewis acid-catalyzed intra-
molecular hydroamination and ruthenium-catalyzed asymmet-
ric hydrogenation reactions. In addition, this new protocol was
further applied in the gram-scale synthesis of naturally
occurring tetrahydroquinoline alkaloid, (−)-Angustureine.
Scheme 6. Deuterium-Labeling Studies
EXPERIMENTAL SECTION
General Methods. Unless otherwise noted, all experiments were
■
carried out under an atmosphere of nitrogen using standard Schlenk
techniques or in a nitrogen-filled glovebox. H NMR and 13C NMR
1
spectra were recorded on Bruker Model Avance DMX 300
Spectrometer (1H 300 MHz and 13C 75 MHz, respectively), Bruker
Model Avance DMX 400 Spectrometer (1H 400 MHz and 13C 100
MHz, respectively) and Bruker Model Avance DMX 500
Spectrometer (1H 500 MHz and 13C 125 MHz, respectively).
Chemical shifts (δ) were given in ppm and were referenced to residual
solvent or TMS peaks. Optical rotations were measured with Rudolph
Autopl VI polarimeter. High resolution mass spectra (HRMS) were
obtained on Thermo Fisher Q Exactive Mass Spectrometer. All
organic solvents were dried using standard, published methods and
were distilled before use. All other chemicals were used as received
performed with 10 mol % (R,R)-C1a under 50 atm H2 in
CD3OD for 24 h. The isolated product 2a bearing 100% D at
1-position and 115% D at 3-position was obtained. Instead,
when the sequential reaction was carried out under 50 atm D2
in CH3OH, the D atoms were found only at 2-position of 2a
with 90% D (Scheme 6b).
On the basis of these results obtained from the above
experiments, as well as relevant study on asymmetric
hydrogenation of quinolines and indoles with this ruthenium
E
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Scheme 7. Proposed Mechanism for This One-Pot Sequential Reaction
CHCl3) (literature data5a [α]D = +79.9 (c 1.0, CHCl3) for the R-
25
Scheme 8. Ru-Catalyzed Sequential Hydroamination/
Asymmetric Hydrogenation of 1c on Gram-Scale and the
Synthesis of (−)-Angustureine1b
1
isomer 92% ee); H NMR (500 MHz, CDCl3) δ (ppm) 6.96 (t, J =
7.5 Hz, 2H), 6.60 (t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 3.80
(brs, 1H), 3.26−3.21 (m, 1H), 2.85−2.71 (m, 2H), 1.99−1.94 (m,
1H), 1.64−1.56 (m, 1H), 1.51−1.48 (m, 2H), 1.38 (s, 4H), 0.94 (t, J
= 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 144.9, 129.4,
126.8, 121.5, 117.0, 114.2, 51.7, 36.5, 28.2, 28.0, 26.6, 23.0, 14.2. The
enantiomeric excess was determined by HPLC (Chiralcel OJ-H, n-
hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 8.0 min (major), tR = 7.0 min (minor).
(R)-2-n-Pentyl-1,2,3,4-tetrahydroquinoline (2c). Colorless oil,
20
isolated yield: 84%, 31 mg. 97% ee, [α]D = +92.3 (c 0.40,
CHCl3) (literature data5a [α]D = +74.4 (c 1.03, CHCl3) for the R-
25
1
isomer 94% ee); H NMR (500 MHz, CDCl3) δ (ppm) 6.98 (t, J =
7.5 Hz, 2H), 6.62 (t, J = 7.3 Hz, 1H), 6.49 (d, J = 7.5 Hz,1H), 3.70
(brs, 1H), 3.28−3.23 (m, 1H), 2.87−2.72 (m, 2H), 2.01−1.96 (m,
1H), 1.66−1.58 (m, 1H), 1.53−1.49 (m, 2H), 1.46−1.34 (m, 6H),
0.94 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm)
144.9, 129.4, 126.8, 121.5, 117.0, 114.2, 51.7, 36.8, 32.1, 28.3, 26.6,
25.5, 22.8, 14.2. The enantiomeric excess was determined by HPLC
(Chiralcel OJ-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 6.9 min (major), tR = 6.4 min (minor).
(S)-2-Isopropyl-1,2,3,4-tetrahydroquinoline (2d). Colorless oil,
from Aldrich or Acros without further purification. The enantiomeric
excess of the chiral compounds was determined by HPLC (Varian
Prostar 210 liquid chromatography) with a chiral column using
racemic compounds as references. The absolute configuration of
1,2,3,4-tetrahydroquinoline5c,d and indoline6c,21 derivatives were
determined by comparison of optical rotation with literature data.
The catalysts5d,13b and substrates12c,d,19 were synthesized according to
the modified literature methods.
20
isolated yield: 80%, 24 mg. 88% ee, [α]D = +60.3 (c 0.33,
CHCl3) (literature data5a [α]D = +21.1 (c 0.32, CHCl3) for the S-
Typical Procedure for Sequential Hydroamination/Asym-
metric Hydrogenation Reaction: Synthesis of 2-Alkyl-tetrahy-
droquinoline Derivatives. A 30 mL glass-lined stainless-steel
reactor equipped with a magnetic stirrer bar was charged with
substrate 1a−1l (0.2 mmol), Ru-catalyst (R,R)-C1a (0.02 mmol) in
1.0 mL of [Bmim]NTf2 under N2 atmosphere in a glovebox. The
autoclave was closed, and the final pressure of the hydrogen gas was
adjusted to 50 atm after purging the autoclave with hydrogen gas
several times. The reaction mixture was stirred at room temperature
for 24 h. Then the hydrogen gas was carefully released, the reduced
product was extracted with diethyl ether (6 × 1 mL). The combined
diethyl ether layer was concentrated under vacuum to give the crude
product 2a. The conversion was determined by 1H NMR spectros-
copy of crude mixture. The crude mixture was filtered through a short
pad of silica eluted with petroleum ether and EtOAc (PE:EA = 15:1,
v/v) to give the isolated pure product 2a−2l.
25
1
isomer 94% ee); H NMR (300 MHz, CDCl3) δ (ppm) 6.97 (t, J =
7.2 Hz, 2H), 6.60 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 3.72
(brs, 1H), 3.08−3.02 (m, 1H), 2.88−2.70 (m, 2H), 1.97−1.89 (m,
1H), 1.78−1.61 (m, 2H), 1.00 (t, J = 7.4 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ (ppm) 145.1, 129.3, 126.8, 121.6, 116.9, 114.2, 57.4,
32.6, 26.8, 24.6, 18.7, 18.4. The enantiomeric excess was determined
by HPLC (Chiralcel OJ-H, n-hexane/isopropanol = 98/2, flow rate
1.0 mL/min, T = 25 °C, 254 nm) tR = 17.9 min (major), tR = 17.2
min (minor).
(S)-2-Cyclohexyl-1,2,3,4-tetrahydroquinoline (2e). Colorless oil,
20
isolated yield: 71%, 14 mg. 90% ee, [α]D = +49.9 (c 0.46, CHCl3)
(literature data20 [α]D = +56.5 (c 0.40, CHCl3) for the S-isomer
25
1
95% ee); H NMR (500 MHz, CDCl3) δ (ppm) 6.97 (t, J = 8.3 Hz,
2H), 6.61 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 4.01 (brs,
1H), 3.07−3.04 (m, 1H), 2.83−2.71 (m, 2H), 1.96−1.91 (m, 1H),
1.82(t, J = 14.5 Hz, 4H), 1.75−1.67 (m, 2H), 1.42−1.01 (m, 7H);
13C NMR (125 MHz, CDCl3) δ (ppm) 144.8, 129.3, 126.8, 121.8,
117.1, 114.4, 56.8, 42.5, 29.3, 28.9, 26.7, 26.6, 26.5, 26.5, 24.7. The
enantiomeric excess was determined by HPLC (Chiralcel OD-H, n-
hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 5.4 min (major), tR = 5.0 min (minor).
(R)-2-Propyl-1,2,3,4-tetrahydroquinoline (2a). Colorless oil, iso-
20
lated yield: 84%, 26 mg. 97% ee, [α]D = +94.7 (c 0.42, CHCl3)
(literature data5a [α]D = +72.7 (c 1.58, CHCl3) for the R-isomer
25
1
93% ee); H NMR (400 MHz, CDCl3) δ (ppm) 6.99 (t, J = 7.2 Hz,
2H), 6.64 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 3.80 (brs,
1H), 3.29−3.28 (m, 1H), 2.88−2.72 (m, 2H), 2.01−1.97 (m, 1H),
1.69−1.59 (m, 1H), 1.56−1.42 (m, 4H), 0.99 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 144.4, 129.4, 126.8, 121.8, 117.4,
114.5, 51.6, 38.8, 28.1, 26.5, 19.0, 14.3. The enantiomeric excess was
determined by HPLC (Chiralcel OJ-H, n-hexane/isopropanol = 90/
10, flow rate 1.0 mL/min, T = 25 °C, 254 nm) tR = 9.7 min (major),
tR = 7.9 min (minor).
(S)-2-Isobutyl-1,2,3,4-tetrahydroquinoline (2f). Colorless oil,
20
isolated yield: 63%, 20 mg. 98% ee, [α]D = +85.0 (c 0.30,
CHCl3) (literature data5d [α]D = +88.7 (c 0.21, CHCl3) for the S-
25
1
isomer 99% ee); H NMR (300 MHz, CDCl3) δ (ppm) 6.97 (t, J =
6.6 Hz, 2H), 6.61 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 3.38−
3.30 (m, 1H), 2.89−2.69 (m, 2H), 2.00−1.92 (m, 1H), 1.84−1.68
(m, 1H), 1.66−1.54 (m, 1H), 1.50−1.27 (m, 2H), 0.96 (d, J = 6.3 Hz,
(R)-2-n-Butyl-1,2,3,4-tetrahydroquinoline (2b). Colorless oil,
20
isolated yield: 80%, 28 mg. 97% ee, [α]D = +92.5 (c 0.40,
F
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
6H); 13C NMR (75 MHz, CDCl3) δ (ppm) 144.8, 129.4, 126.8,
121.6, 117.1, 114.3, 49.4, 46.0, 28.7, 26.6, 24.6, 23.3, 22.6. The
enantiomeric excess was determined by HPLC (Chiralcel OJ-H, n-
hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 8.1 min (major), tR = 6.3 min (minor).
6.36 (d, J = 8.4 Hz, 1H), 3.90 (brs, 1H), 3.26−3.20 (m, 1H), 2.82−
2.66 (m, 2H), 1.98−1.91 (m, 1H), 1.61−1.53 (m, 1H), 1.51−1.37
(m, 4H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 143.7, 131.8, 129.5, 123.6, 115.6, 108.5, 51.4, 38.8, 27.7, 26.3,
19.0, 14.3. HR-ESI calculated for C12H17NBr ([M + H]+): 254.05389,
found 254.05348. The enantiomeric excess was determined by HPLC
(Chiralcel OJ-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 8.6 min (major), tR = 7.8 min (minor).
Typical Procedure for Sequential Hydroamination/Asym-
metric Hydrogenation Reaction: Synthesis of 2-Aryl-tetrahy-
droquinoline Derivatives. A 30 mL glass-lined stainless-steel
reactor equipped with a magnetic stirrer bar was charged with
substrate 1m (0.1 mmol), Ru-catalyst (R,R)-C1e (0.01 mmol) and
IMesAuCl C2a (0.01 mmol) in 1.0 mL IPA under N2 atmosphere in a
glovebox. The autoclave was closed, and the final pressure of the
hydrogen gas was adjusted to 50 atm after purging the autoclave with
hydrogen gas several times. The reaction mixture was stirred at 0 °C
for 24 h. Then the hydrogen gas was carefully released. The
conversion was determined by 1H NMR spectroscopy of crude
mixture. The crude mixture was filtered through a short pad of silica
eluted with petroleum ether and EtOAc (PE:EA = 10:1, v/v) to give
the isolated pure product 2m.
(R)-2-Phenethyl-1,2,3,4-tetrahydroquinoline (2g). Colorless oil,
20
isolated yield: 91%, 22 mg. 95% ee, [α]D = +87.5 (c 0.20, CHCl3)
(literature data5d [α]D = +88.9 (c 0.27, CHCl3) for the R-isomer
25
99% ee); 1H NMR (500 MHz, CDCl3) δ (ppm) 7.31−7.28 (m, 2H),
7.24−7.18 (m, 3H), 6.95 (t, J = 7.3 Hz, 2H), 6.60 (t, J = 7.3 Hz, 1H),
6.45 (d, J = 7.5 Hz, 1H), 3.87 (brs, 1H), 3.32−3.28 (m, 1H), 2.83−
2.72 (m, 4H), 2.02−1.98 (m, 1H), 1.86−1.81 (m, 2H), 1.71−1.64
(m, 1H); 13C NMR (125 MHz, CDCl3) δ (ppm) 144.5, 142.0, 129.4,
128.6, 128.5, 126.9, 126.1, 121.5, 117.3, 114.4, 51.3, 38.3, 32.3, 28.1,
26.3. HR-ESI calculated for C17H20N ([M + H]+): 238.15903, found
238.15892. The enantiomeric excess was determined by HPLC
(Chiralcel OJ-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 22.6 min (major), tR = 21.5 min
(minor).
(R)-6-Methyl-2-propyl-1,2,3,4-tetrahydroquinoline (2h). Color-
20
less oil, isolated yield: 84%, 32 mg. 97% ee, [α]D = +61.8 (c 0.44,
1
CHCl3); H NMR (400 MHz, CDCl3) δ (ppm) 6.80 (d, J = 6.0 Hz,
(S)-2-Phenyl-1,2,3,4-tetrahydroquinoline (2m). Colorless oil,
2H), 6.49−6.47 (m, 1H), 4.03 (brs, 1H), 3.27−3.21 (m, 1H), 2.85−
2.68 (m, 2H), 2.22 (s, 3H), 2.01−1.94 (m, 1H), 1.67−1.57 (m, 1H),
1.55−1.35 (m, 4H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 142.2, 129.9, 127.4, 126.6, 121.8, 114.6, 51.7, 38.9,
28.4, 26.5, 20.5, 19.1, 14.3. HR-ESI calculated for C13H20N ([M +
H]+): 190.15903, found 190.15889. The enantiomeric excess was
determined by HPLC (Chiralcel OJ-H, n-hexane/isopropanol = 90/
10, flow rate 1.0 mL/min, T = 25 °C, 254 nm) tR = 12.3 min (major),
tR = 8.8 min (minor).
20
isolated yield: 87%, 18 mg. 88% ee, [α]D = −110.0 (c 0.40,
CHCl3) (literature data5d [α]D = +36.8 (c 0.95, CHCl3) for the R-
25
1
isomer 92% ee); H NMR (400 MHz, CDCl3) δ (ppm) 7.41−7.26
(m, 5H), 7.02−6.99 (m, 2H), 6.67 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 8.0
Hz, 1H), 4.43 (dd, J1 = 9.4 Hz, J2 = 3.4 Hz, 1H), 2.96−2.88 (m, 1H),
2.75(t, J = 4.6 Hz, 1H), 2.71 (t, J = 4.6 Hz, 1H), 2.16−2.09 (m, 1H),
2.06−1.96 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 144.5,
144.3, 129.4, 128.7, 127.6, 127.1, 126.8, 121.4, 117.8, 114.5, 56.5,
30.9, 26.5. The enantiomeric excess was determined by HPLC
(Chiralcel OD-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 9.3 min (major), tR = 11.6 min
(minor).
(R)-6-Methoxy-2-propyl-1,2,3,4-tetrahydroquinoline (2i). Color-
20
less oil, isolated yield: 94%, 39 mg. 98% ee, [α]D = +97.0 (c 0.95,
CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm) 6.61−6.57 (m, 2H),
6.47 (d, J = 8.5 Hz, 1H), 3.73 (s, 3H), 3.63 (brs, 1H), 3.22−3.17 (m,
1H), 2.86−2.69 (m, 2H), 1.98−1.93 (m, 1H), 1.63−1.55 (m, 1H),
1.52−1.38 (m, 4H), 0.97 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ (ppm) 152.0, 138.8, 123.0, 115.5, 114.8, 113.0, 55.9, 51.8,
38.9, 28.4, 26.9, 19.1, 14.3. HR-ESI calculated for C13H20ON ([M +
H]+): 206.15394, found 206.15414. The enantiomeric excess was
determined by HPLC (Chiralcel OJ-H, n-hexane/isopropanol = 90/
10, flow rate 1.0 mL/min, T = 25 °C, 254 nm) tR = 17.1 min (major),
tR = 11.8 min (minor).
Typical Procedure for Sequential Hydroamination/Asym-
metric Hydrogenation Reaction: Synthesis of Indolines
Derivatives. A 30 mL glass-lined stainless-steel reactor equipped
with a magnetic stirrer bar was charged with substrate 3a−3j (0.15
mmol), Ru-catalyst (R,R)-C1i (0.015 mmol), C2b (0.015 mmol) in
1.0 mL of HFIP under N2 atmosphere in a glovebox. The autoclave
was closed, and the final pressure of the hydrogen gas was adjusted to
50 atm after purging the autoclave with hydrogen gas several times.
The reaction mixture was stirred at room temperature for specific
time. Then the hydrogen gas was carefully released and the
conversion was determined by 1H NMR spectroscopy. The reaction
mixture was filtered through a short pad of silica (ethyl acetate/
petroleum ether/Et3N, 40/1/1, v/v) to give the pure products 4a−4j.
(R)-2-Propylindoline (4a). Colorless oil, isolated yield: 96%, 16 mg.
(R)-6-Fluoro-2-propyl-1,2,3,4-tetrahydroquinoline (2j). Colorless
20
oil, isolated yield: 93%, 36 mg. 96% ee, [α]D = +87.0 (c 0.38,
CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm) 6.68−6.65 (m, 2H),
6.41−6.39 (m, 1H), 3.64 (brs, 1H), 3.22−3.17 (m, 1H), 2.83−2.67
(m, 2H), 1.97−1.92 (m, 1H), 1.60−1.53 (m, 1H), 1.49−1.36 (m,
4H), 0.96 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm)
96% ee, [α]D = +16.7 (c 0.18, CHCl3) (literature data6c [α]D
=
20
25
155.6 (d, JC−F = 232.9 Hz), 141.0 (d, JC−F = 2.5 Hz), 122.9 (d, JC−F
=
1
+9.3 (c 0.3, CHCl3) for the R-isomer 96% ee); H NMR (500 MHz,
CDCl3) δ (ppm) 7.07 (d, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H),
6.69 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 3.89−3.83 (m, 1H),
3.13 (dd, J1 = 15.3 Hz, J2 = 8.8 Hz, 1H), 2.68 (dd, J1 = 15.5 Hz, J2 =
8.5 Hz, 1H), 1.71−1.55 (m, 2H), 1.49−1.34 (m, 2H), 0.97 (t, J = 7.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) 151.0, 129.1, 127.3,
124.8, 118.7, 109.3, 60.0, 39.1, 36.3, 19.9, 14.3. The enantiomeric
excess was determined by HPLC (Chiralcel OD-H, n-hexane/
isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254 nm)
tR = 6.3 min (major), tR = 8.0 min (minor).
6.3 Hz), 115.5 (d, JC−F = 21.4 Hz), 114.9 (d, JC−F = 7.5 Hz), 113.3 (d,
JC−F = 21.4 Hz), 51.6, 38.9, 28.0, 26.7, 19.0, 14.3. HR-ESI calculated
for C12H17NF ([M + H]+): 194.13450, found 194.13425. The
enantiomeric excess was determined by HPLC (Chiralcel OJ-H, n-
hexane/isopropanol = 99/1, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 11.0 min (major), tR = 10.1 min (minor).
(R)-6-Chloro-2-propyl-1,2,3,4-tetrahydroquinoline (2k). Colorless
20
oil, isolated yield: 87%, 28 mg. 91% ee, [α]D = +84.8 (c 0.50,
CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.92−6.89 (m, 2H),
6.39 (d, J = 8.0 Hz, 1H), 3.79 (brs, 1H), 3.26−3.20 (m, 1H), 2.82−
2.66 (m, 2H), 1.98−1.92 (m, 1H), 1.61−1.53 (m, 1H), 1.52−1.37
(m, 4H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 143.3, 128.9, 126.6, 123.1, 121.4, 115.1, 51.4, 38.8, 27.8, 26.4,
19.0, 14.3. HR-ESI calculated for C12H17NCl ([M + H]+): 210.10440,
found 210.10419. The enantiomeric excess was determined by HPLC
(Chiralcel OJ-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 7.7 min (major), tR = 7.1 min (minor).
(R)-6-Bromo-2-propyl-1,2,3,4-tetrahydroquinoline (2l). Colorless
(R)-2-Butylindoline (4b). Colorless oil, isolated yield: 98%, 25 mg.
97% ee, [α]D = +14.3 (c 0.60, CHCl3) (literature data6c [α]D
=
20
25
+11.8 (c 0.6, CHCl3) for the R-isomer 97% ee); 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.09 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H),
6.76−6.70 (m, 2H), 3.92−3.84 (m, 1H), 3.15 (dd, J1 = 15.4 Hz, J2 =
8.6 Hz, 1H), 2.71 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 1.74−1.59 (m,
2H), 1.44−1.31 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 150.7, 129.2, 127.4, 124.8, 118.8, 109.5, 60.3,
36.6, 36.3, 28.9, 22.9, 14.2. The enantiomeric excess was determined
by HPLC (Chiralcel OD-H, n-hexane/isopropanol = 90/10, flow rate
20
oil, isolated yield: 89%, 11 mg. 95% ee, [α]D = +76.0 (c 0.20,
CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.06−7.02 (m, 2H),
G
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
1.0 mL/min, T = 25 °C, 254 nm) tR = 5.5 min (major), tR = 6.8 min
(minor).
found 192.13872. The enantiomeric excess was determined by HPLC
(Chiralcel OD-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 6.6 min (major), tR = 13.8 min
(minor).
(R)-2-Pentylindoline (4c). Colorless oil, isolated yield: 93%, 26 mg.
97% ee, [α]D = +16.6 (c 0.70, CHCl3) (literature data6c [α]D
=
20
25
+16.4 (c 0.5, CHCl3) for the R-isomer 96% ee); 1H NMR (500 MHz,
CDCl3) δ (ppm) 7.08 (d, J = 7.0 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H),
6.71 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 4.10 (brs, 1H),
3.89−3.83 (m, 2H), 3.14 (dd, J1 = 15.5 Hz, J2 = 8.5 Hz, 1H), 2.70
(dd, J1 = 15.0 Hz, J2 = 8.5 Hz, 1H), 1.67−1.59 (m, 2H), 1.43−1.34
(m, 6H), 0.92 (t, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 150.6, 129.3, 127.4, 124.8, 119.0, 109.6, 60.3, 36.8, 36.3, 32.0,
26.4, 22.8, 14.2. The enantiomeric excess was determined by HPLC
(Chiralcel OD-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 5.4 min (major), tR = 6.6 min (minor).
(R)-2-Isobutylindoline (4d). Colorless oil, isolated yield: 81%, 21
mg. 96% ee, [α]D = +18.0 (c 0.50, CHCl3); H NMR (500 MHz,
CDCl3) δ (ppm) 6.94 (d, J = 7.0 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H),
6.57 (t, J = 7.3 Hz, 1H), 6.51(d, J = 8.0 Hz, 1H), 4.18 (brs, 1H),
3.85−3.79 (m, 1H), 3.00 (dd, J1 = 15.5 Hz, J2 = 8.5 Hz, 1H), 2.54
(dd, J1 = 15.5 Hz, J2 = 8.5 Hz, 1H), 1.64−1.55 (m, 1H), 1.49−1.43
(m, 1H), 1.37−1.31 (m, 1H), 0.83 (d, J = 6.5 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ (ppm) 150.6, 129.3, 127.4, 124.8, 119.0, 109.7,
58.3, 46.0, 36.6, 25.8, 23.2, 22.6. HR-ESI calculated for C12H18N ([M
+ H]+): 176.14338, found 176.14352. The enantiomeric excess was
determined by HPLC (Chiralcel OD-H, n-hexane/isopropanol = 90/
10, flow rate 1.0 mL/min, T = 25 °C, 254 nm) tR = 6.5 min (major),
tR = 7.8 min (minor).
(R)-5-Fluoro-2-propylindoline (4i). Colorless oil, isolated yield:
20
1
85%, 22 mg. 91% ee. [α]D = +9.8 (c 0.40, CHCl3); H NMR (500
MHz, CDCl3) δ (ppm) 6.80−6.78 (m, 1H), 6.71−6.67 (m, 1H),
6.51−6.49 (m, 1H), 3.90−3.84 (m, 1H), 3.10 (dd, J1 = 15.8 Hz, J2 =
8.3 Hz, 1H), 2.66 (dd, J1 = 16.0 Hz, J2 = 8.5 Hz, 1H), 1.65−1.54 (m,
2H), 1.47−1.32 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 157.1 (d, JC−F = 235.5 Hz), 146.9, 130.9 (d,
J
C−F = 8.1 Hz), 113.2 (d, JC−F = 23.1 Hz), 112.2 (d, JC−F = 23.1 Hz),
109.5 (d, JC−F = 9.1 Hz), 60.7, 39.0, 36.5, 19.9, 14.2. HR-ESI
calculated for C11H15NF ([M + H]+): 180.11830, found 180.11871.
The enantiomeric excess was determined by HPLC (Chiralcel OD-H,
n-hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 5.1 min (major), tR = 7.8 min (minor).
(R)-5-Chloro-2-propylindoline (4j). Colorless oil, isolated yield:
83%, 24 mg. 92% ee, [α]D20 = +11.5 (c 0.80, CHCl3); 1H NMR (500
MHz, CDCl3) δ (ppm) 7.02 (s, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.52
(d, J = 8.0 Hz, 1H), 3.91−3.85 (m, 1H), 3.15−3.08 (m, 1H), 2.66
(dd, J1 = 15.5 Hz, J2 = 8.5 Hz, 1H), 1.65−1.53 (m, 2H), 1.47−1.32
(m, 2H), 0.96 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
(ppm) 149.2, 131.2, 127.1, 125.0, 123.5, 110.2, 60.4, 38.9, 36.1, 19.8,
14.2. HR-ESI calculated for C11H15NCl ([M + H]+): 196.08875,
found 196.08888. The enantiomeric excess was determined by HPLC
(Chiralcel OD-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 5.4 min (major), tR = 10.4 min
(minor).
20
1
(R)-2-Phenethylindoline (4e). Colorless oil, isolated yield: 89%, 31
mg. 94% ee, [α]D20 = +14.6 (c 0.65, CHCl3), (literature data21 [α]D
25
1
= +12.0 (c 0.17, CHCl3) for the R-isomer 98% ee); H NMR (500
Typical Procedure for Sequential Hydroamination/Asym-
metric Hydrogenation Reaction: Synthesis of 2-Methyl-
2,3,4,5-tetrahydro-1H-benzo[b]azepine. A 30 mL glass-lined
stainless-steel reactor equipped with a magnetic stirrer bar was
charged with substrate 5a (0.16 mmol), (R,R)-C1a (0.016 mmol),
and C2a (0.016 mmol) in 1.0 mL of [Bmim]NTf2 under N2
atmosphere in a glovebox. The autoclave was closed, and the final
pressure of the hydrogen gas was adjusted to 50 atm after purging the
autoclave with hydrogen gas several times. The reaction mixture was
stirred at room temperature for 24 h. Then the hydrogen gas was
carefully released, the reduced product was extracted with diethyl
ether (6 × 1 mL). The combined diethyl ether layer was concentrated
under vacuum to give the crude product. the conversion was
MHz, CDCl3) δ (ppm) 7.30−7.27 (m, 2H), 7.23−7.18 (m, 3H), 7.07
(d, J = 7.0 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.69 (t, J = 7.5 Hz, 1H),
6.60 (d, J = 7.5 Hz, 1H), 3.91−3.84 (m, 1H), 3.15 (dd, J1 = 15.5 Hz,
J2 = 8.5 Hz, 1H), 2.75−2.67 (m, 3H), 2.01−1.90 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ (ppm) 150.7, 141.8, 128.9, 128.6, 128.5, 127.4,
126.1, 124.8, 118.9, 109.5, 59.7, 38.5, 36.2, 33.1. The enantiomeric
excess was determined by HPLC (Chiralcel OD-H, n-hexane/
isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254 nm)
tR = 9.9 min (major), tR = 13.9 min (minor).
(R)-2-Benzylindoline (4f). Colorless oil, isolated yield: 81%, 25 mg.
97% ee, [α]D = +77.1 (c 0.55, CHCl3) (literature data6c [α]D
=
20
25
+78.6 (c 0.5, CHCl3) for the R-isomer 97% ee); 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.35−7.31 (m, 2H), 7.26−7.22 (m, 3H), 7.08 (d, J
= 7.2 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 6.57
(d, J = 7.6 Hz, 1H), 4.12−4.05 (m, 1H), 3.16−3.08 (m, 1H), 2.93−
2.77 (m, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) 150.4, 139.2,
129.3, 128.8, 128.6, 127.5, 126.6, 124.9, 118.8, 109.4, 61.1, 42.8, 36.0.
The enantiomeric excess was determined by HPLC (Chiralcel OD-H,
n-hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 7.6 min (major), tR = 8.4 min (minor).
1
determined by H NMR spectroscopy of crude mixture. The crude
mixture was filtered through a short pad of silica eluted with
petroleum ether and ethyl acetate (PE:EA = 15:1, v/v) to give the
isolated pure product 6a.
(+)-2-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (6a).22
White solid, Melting point: 57−60 °C, isolated yield: 50%, 13 mg.
20
1
48% ee, [α]D = +15.5 (c = 0.40, CHCl3). H NMR (400 MHz,
CDCl3) δ (ppm) 7.09−7.02 (m, 2H), 6.84 (td, J1 = 7.4 Hz, J2 = 0.8
Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 3.47 (brs, 1H), 2.98−2.89 (m,
1H), 2.84−2.79 (m, 1H), 2.74−2.68 (m, 1H), 1.96−1.83 (m, 2H),
1.55−1.35 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 148.9, 134.0, 130.7, 126.7, 121.2, 120.0, 53.9, 39.4,
35.7, 26.4, 24.2. HR-ESI calculated for C11H16N ([M + H]+):
162.12827, found 162.12766. The enantiomeric excess was
determined by HPLC (Chiralcel OJ-H, n-hexane/isopropanol = 90/
10, flow rate 1.0 mL/min, T = 25 °C, 254 nm) tR = 7.9 min (major),
tR = 7.4 min (minor).
(R)-5-Methyl-2-propylindoline (4g). Colorless oil, isolated yield:
92%, 24 mg. 97% ee, [α]D20 = +22.2 (c 0.50, CHCl3); 1H NMR (500
MHz, CDCl3) δ (ppm) 6.93 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.63
(d, J = 8.0 Hz, 1H), 4.97 (brs, 1H), 3.90−3.84 (m, 1H), 3.11 (dd, J1 =
15.5 Hz, J2 = 8.5 Hz, 1H), 2.68 (dd, J1 = 15.5 Hz, J2 = 8.5 Hz, 1H),
2.26 (s, 3H), 1.71−1.58 (m, 2H), 1.51−1.36 (m, 2H), 0.98 (t, J = 7.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm) 147.2, 129.9, 129.1,
127.7, 125.6, 110.3, 60.3, 38.7, 36.3, 21.0, 19.9, 14.2. HR-ESI
calculated for C12H18N ([M + H]+): 176.14338, found 176.14395.
The enantiomeric excess was determined by HPLC (Chiralcel OD-H,
n-hexane/isopropanol = 90/10, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 5.3 min (major), tR = 7.4 min (minor).
(R)-5-Methoxy-2-propylindoline (4h). Colorless oil, isolated yield:
89%, 25 mg. 95% ee, [α]D20 = +21.6 (c 0.50, CHCl3); 1H NMR (500
MHz, CDCl3) δ (ppm) 6.71(s, 1H), 6.59−6.55 (m, 2H), 3.87−3.81
(m, 1H), 3.74 (s, 3H), 3.10 (dd, J1 = 15.3 Hz, J2 = 8.3 Hz, 1H), 2.66
(dd, J1 = 15.5 Hz, J2 = 8.5 Hz, 1H), 1.66−1.54 (m, 2H), 1.47−1.35
(m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
(ppm) 153.7, 144.5, 131.0, 112.2, 111.8, 110.2, 60.5, 56.1, 39.0, 36.8,
20.0, 14.3. HR-ESI calculated for C12H18ON ([M + H]+): 192.13829,
(R)-2-Ethyl-1,2,3,4-tetrahydroquinoline (2v). Colorless oil, iso-
20
lated yield 28%, 8 mg. 96% ee, [α]D = +100.0 (c 0.45, CHCl3)
(literature data5d [α]D = +80.3 (c 0.19, CHCl3) for the R-isomer
25
1
99% ee); H NMR (400 MHz, CDCl3) δ (ppm) 6.97 (t, J = 7.2 Hz,
2H), 6.61 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.90 (brs,
1H), 3.19−3.17 (m, 1H), 2.86−2.70 (m, 2H), 1.99−1.97 (m, 1H),
1.65−1.50 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 144.7, 129.4, 126.8, 121.6, 117.1, 114.2, 53.2, 29.5,
27.7, 26.5, 10.2. The enantiomeric excess was determined by HPLC
(Chiralcel OJ-H, n-hexane/isopropanol = 90/10, flow rate 1.0 mL/
min, T = 25 °C, 254 nm) tR = 9.4 min (major), tR = 8.6 min (minor).
H
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
15
1
Typical Procedure for Sequential Hydroamination/Asym-
metric Hydrogenation Reaction: Synthesis of 2-Phenyl-
2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol. A 30 mL glass-
lined stainless-steel reactor equipped with a magnetic stirrer bar was
charged with substrate 5b (0.2 mmol), (R,R)-C1a (0.02 mmol) in 2.0
mL of [Bmim]NTf2 under N2 atmosphere in a glovebox. The
autoclave was closed, and the final pressure of the hydrogen gas was
adjusted to 50 atm after purging the autoclave with hydrogen gas
several times. The reaction mixture was stirred at room temperature
for 18 h. Then the hydrogen gas was carefully released, the reduced
product was extracted with diethyl ether (6 × 1 mL). The combined
diethyl ether layer was concentrated under vacuum to give the crude
product. the conversion and diastereoselectivity was determined by
1H NMR spectroscopy of crude mixture. The crude mixture was
filtered through a short pad of silica eluted with petroleum ether and
EtOAc (PE:EA = 2:1, v/v) to give the isolated mixed product 6b (25
mg, 53% yield), two isomers were isolated through silica eluted with
petroleum ether, ethyl acetate and Et3N (PE:EA:Et3N = 10:2:1, v/v)
to achieve the trans isomer 6b-1 and cis isomer 6b-2, respectively.
(2R,5S)-2-Phenyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol
(6b-1). trans isomer. White solid, melting point: 124−127 °C, isolated
yield: 36%, 17 mg. 74% ee, [α]D20 = +26.0 (c 0.20, CHCl3). 1H NMR
(500 MHz, CDCl3) δ (ppm) 7.53 (d, J = 7.5 Hz, 1H), 7.42−7.37 (m,
4H), 7.32 (t, J = 7.0 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.3
Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.94 (d, J = 9.0 Hz, 1H), 3.91 (dd,
J1 = 11.0 Hz, J2 = 2.5 Hz, 1H), 3.71 (brs, 1H), 2.29 (brs, 1H), 2.22−
2.17 (m, 1H), 2.11−1.97 (m, 2H), 1.86−1.78 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ (ppm) 146.5, 145.5, 135.4, 129.0, 127.8, 127.6,
126.2, 125.9, 121.8, 120.5, 72.4, 62.8, 36.0, 34.8. HR-ESI calculated
for C16H18NO ([M + H]+): 240.13829, found 240.13861. The
enantiomeric excess was determined by HPLC (Chiralcel OD-H, n-
hexane/isopropanol = 80/20, flow rate 1.0 mL/min, T = 25 °C, 254
nm) tR = 13.1 min (major), tR = 6.4 min (minor).
data5a [α]D = −6.7 (c 1.00, CHCl3) for the R-isomer 94% ee); H
NMR (500 MHz, CDCl3) δ (ppm) 7.10 (t, J = 7.5 Hz, 1H), 6.99 (d, J
= 7.0 Hz,1H), 6.60 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H),
3.27−3.23 (m, 1H), 2.95 (s, 3H), 2.86−2.79 (m, 1H), 2.70−2.65 (m,
1H), 1.95−1.86 (m, 2H), 1.64−1.60 (m, 1H), 1.46−1.25 (m, 7H),
0.92 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ (ppm)
145.5, 128.8, 127.2, 122.0, 115.3, 110.5, 59.1, 38.1, 32.2, 31.3, 25.9,
24.5, 23.7, 22.8, 14.2. The enantiomeric excess was determined by
HPLC (Chiralcel OJ-H, n-hexane/isopropanol = 99/1, flow rate 1.0
mL/min, T = 25 °C, 254 nm) tR = 5.3 min (major), tR = 5.9 min
(minor).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00183.
■
S
Additional experiments data (Table S1−S7, Scheme
S1−S2); NMR and HPLC spectra of all substrates and
chiral products (Figures S1−S60) (PDF)
Accession Codes
CCDC 1908845 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*E-mail: fanqh@iccas.ac.cn.
■
(2R,5R)-2-Phenyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol
(6b-2). cis isomer. Yellow oil, isolated yield: 17%, 8 mg. 88% ee,
20
1
ORCID
[α]D = +83.5 (c 0.20, CHCl3). H NMR (500 MHz, CDCl3) δ
(ppm) 7.43−7.38 (m, 4H), 7.33 (t, J = 6.8 Hz, 1H), 7.22 (d, J = 7.5
Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.77 (d, J =
7.5 Hz, 1H), 4.86 (d, J = 6.5 Hz, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.79
(brs, 2H, containing NH and OH), 2.47−2.39 (m, 1H), 2.31−2.26
(m, 1H), 1.89−1.83 (m, 2H); 13C NMR (125 MHz, CDCl3) δ (ppm)
147.1, 145.4, 135.8, 129.4, 129.1, 128.6, 127.9, 126.5, 122.7, 121.4,
74.9, 64.7, 32.6, 32.6. HR-ESI calculated for C16H18NO ([M + H]+):
240.13829, found 240.13861. The enantiomeric excess was
determined by HPLC (Chiralcel OD-H, n-hexane/isopropanol =
80/20, flow rate 1.0 mL/min, T = 25 °C, 254 nm) tR = 19.9 min
(major), tR = 8.3 min (minor).
Yu Feng: 0000-0001-8659-9592
Qing-Hua Fan: 0000-0001-9675-2239
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC, 21790332 and 21521002) and CAS
(QYZDJSSWSLH023) for financial support.
Synthesis of (−)-Angustureine (2n). In a 50 mL glass-lined
stainless steel reactor with a magnetic stirring bar was charged with
(R,R)-C1a (460 mg, 0.6 mmol), substrate 1c (1.2 g, 6.0 mmol) and
[Bmim]NTf2 (5 mL). The autoclave was closed, and hydrogen was
initially introduced into the autoclave at a pressure of 50 atm, before
being reduced to 1 atm. After this procedure was repeated three times,
the autoclave was pressurized with H2 to 50 atm. Then, the mixture
was stirred under this H2 pressure at room temperature for 48 h. After
carefully releasing the hydrogen, the reaction mixture was extracted
with diethyl ether. The combined diethyl ether layer was concentrated
under vacuum to give the crude product 2c (100% conversion), which
was further purified through flash chromatography on silica gel to
afford pure 2c (1.16 g, 95% yield, 97% ee). To a solution of 2c (1.16
g, 5.7 mmol) obtained in the above step in CH3CN (50 mL) at room
temperature was added aqueous formaldehyde (37% w/w, 2.9 mL,
34.0 mmol). The mixture was stirred at room temperature for 15 min.
NaBH3CN (723 mg, 11.4 mmol) was added, and stirred for another
15 min. Then, glacial acetic acid (2 mL) was added and further stirred
at room temperature for 2 h. The reaction mixture was diluted with
2% CH3OH−CH2Cl2 (10 mL), washed with 1 M NaOH (3 × 10
mL), and dried over Na2SO4. The organic solvent was removed in
vacuo to afford pure (−)-Angustureine (2n) as a pale yellow oil (1.2
REFERENCES
■
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-
Blackwell: West Sussex, United Kingdom, 2010. (b) Aldeghi, M.;
Malhotra, S.; Selwood, D. L.; Chan, A. W. E. Two- and Three-
dimensional Rings in Drugs. Chem. Biol. Drug Des. 2014, 83, 450−
461. (c) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274. (d) Scott, J. D.; Williams, R. M.
Chemistry and Biology of the Tetrahydroisoquinoline Antitumor
Antibiotics. Chem. Rev. 2002, 102, 1669−1730.
(2) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Recent Progress in
the Synthesis of 1,2,3,4-Tetrahydroquinolines. Tetrahedron 1996, 52,
15031−15070. (b) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C.
Advances in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2011,
111, 7157−7259.
́
(3) (a) Anas, S.; Kagan, H. B. Routes toward enantiopure 2-
substituted indolines: an overview. Tetrahedron: Asymmetry 2009, 20,
2193−2199. (b) Zhang, D.; Song, H.; Qin, Y. Total Synthesis of
Indoline Alkaloids: A Cyclopropanation Strategy. Acc. Chem. Res.
2011, 44, 447−457. (c) Zi, W.; Zuo, Z.; Ma, D. Intramolecular
Dearomative Oxidative Coupling of Indoles: A Unified Strategy for
20
g, 98% yield, 97% ee). [α]D = −11.6 (c = 0.73, CHCl3) (literature
I
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
the Total Synthesis of Indoline Alkaloids. Acc. Chem. Res. 2015, 48,
702−711.
(e) Ma, W.; Zhang, J.; Xu, C.; Chen, F.; He, Y.-M.; Fan, Q.-H. Highly
Enantioselective Direct Synthesis of Endocyclic Vicinal Diamines
through Chiral Ru(diamine)-Catalyzed Hydrogenation of 2,2′-
Bisquinoline Derivatives. Angew. Chem., Int. Ed. 2016, 55, 12891−
12894. (f) Rueping, M.; Antonchick, A. P.; Theissmann, T. A Highly
Enantioselective Brønsted Acid Catalyzed Cascade Reaction: Organo-
catalytic Transfer Hydrogenation of Quinolines and their Application
in the Synthesis of Alkaloids. Angew. Chem., Int. Ed. 2006, 45, 3683−
3686. (g) Tu, X.-F.; Gong, L.-Z. Highly Enantioselective Transfer
Hydrogenation of Quinolines Catalyzed by Gold Phosphates: Achiral
Ligand Tuning and Chiral-Anion Control of Stereoselectivity. Angew.
Chem., Int. Ed. 2012, 51, 11346−11349. (h) Wang, C.; Li, C.; Wu, X.;
Pettman, A.; Xiao, J. pH-Regulated Asymmetric Transfer Hydro-
genation of Quinolines in Water. Angew. Chem., Int. Ed. 2009, 48,
6524−6528. (i) Li, B.; Xu, C.; He, Y.-M.; Deng, G.-J.; Fan, Q.-H.
Asymmetric Hydrogenation of Bis(quinolin-2-yl)methanes: A Direct
Access to Chiral 1,3-Diamines. Chin. J. Chem. 2018, 36, 1169−1173.
(6) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y.
Catalytic Asymmetric Hydrogenation of Heteroaromatic Compounds,
Indoles. J. Am. Chem. Soc. 2000, 122, 7614−7615. (b) Wang, D.-S.;
Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.; Zhang, X. Pd-Catalyzed
Asymmetric Hydrogenation of Unprotected Indoles Activated by
Brønsted Acids. J. Am. Chem. Soc. 2010, 132, 8909−8911. (c) Yang,
Z.; Chen, F.; He, Y.; Yang, N.; Fan, Q.-H. Highly Enantioselective
Synthesis of Indolines: Asymmetric Hydrogenation at Ambient
Temperature and Pressure with Cationic Ruthenium Diamine
Catalysts. Angew. Chem., Int. Ed. 2016, 55, 13863−13866.
(d) Touge, T.; Arai, T. Asymmetric Hydrogenation of Unprotected
Indoles Catalyzed by η6-Arene/N-Me-sulfonyldiamine−Ru(II) Com-
plexes. J. Am. Chem. Soc. 2016, 138, 11299−11305. (e) Xiao, Y.-C.;
Wang, C.; Yao, Y.; Sun, J.; Chen, Y.-C. Direct Asymmetric
Hydrosilylation of Indoles: Combined Lewis Base and Brønsted
Acid Activation. Angew. Chem., Int. Ed. 2011, 50, 10661−10664.
(f) Silva, T. S.; Rodrigues, M. T., Jr; Santos, H.; Zeoly, L. A.; Almeida,
W. P.; Barcelos, R. C.; Gomes, R. C.; Fernandes, F. S.; Coelho, F.
Recent advances in indoline synthesis. Tetrahedron 2019, 75, 2063−
2097.
(4) For selected reviews, see: (a) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L.
Transition Metal-Catalyzed Enantioselective Hydrogenation of
Enamines and Imines. Chem. Rev. 2011, 111, 1713−1760.
(b) Zhang, Z.; Butt, N. A.; Zhang, W. Asymmetric Hydrogenation
of Nonaromatic Cyclic Substrates. Chem. Rev. 2016, 116, 14769−
14827. (c) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G.
Asymmetric Hydrogenation of Heteroarenes and Arenes. Chem. Rev.
2012, 112, 2557−2590. (d) He, Y.-M.; Song, F.-T.; Fan, Q.-H.
Advances in Transition Metal-Catalyzed Asymmetric Hydrogenation
of Heteroaromatic Compounds. Top. Curr. Chem. 2014, 343, 145−
190. (e) Meng, W.; Feng, X.; Du, H. Frustrated Lewis Pairs Catalyzed
Asymmetric Metal-Free Hydrogenations and Hydrosilylations. Acc.
Chem. Res. 2018, 51, 191−201. (f) Wiesenfeldt, M. P.; Nairoukh, Z.;
Dalton, T.; Glorius, F. Selective Arene Hydrogenation Provides Direct
Access to Saturated Carbo- and Heterocycles. Angew. Chem., Int. Ed.
2019, DOI: 10.1002/anie.201814471. (g) Jiang, X.; Wang, R. Recent
Developments in Catalytic Asymmetric Inverse-Electron-Demand
Diels−Alder Reaction. Chem. Rev. 2013, 113, 5515−5546. (h) Chrza-
nowska, M.; Grajewska, A.; Rozwadowska, M. D. Asymmetric
Synthesis of Isoquinoline Alkaloids: 2004−2015. Chem. Rev. 2016,
116, 12369−12465. (i) Zhuo, C.-X.; Zhang, W.; You, S.-L. Catalytic
Asymmetric Dearomatization Reactions. Angew. Chem., Int. Ed. 2012,
51, 12662−12686. For selected examples, see: (j) Liu, H.; Dagousset,
G.; Masson, G.; Retailleau, P.; Zhu, J. Chiral Brønsted Acid-Catalyzed
Enantioselective Three-Component Povarov Reaction. J. Am. Chem.
Soc. 2009, 131, 4598−4599. (k) Ye, K.-L.; He, H.; Liu, W. B.; Dai, L.-
X.; Helmchen, G.; You, S.-L. Iridium-Catalyzed Allylic Vinylation and
Asymmetric Allylic Amination Reactions with o-Aminostyrenes. J. Am.
Chem. Soc. 2011, 133, 19006−19014. (l) Luo, C.; Huang, Y. A Highly
Diastereo- and Enantioselective Synthesis of Tetrahydroquinolines:
Quaternary Stereogenic Center Inversion and Functionalization. J.
Am. Chem. Soc. 2013, 135, 8193−8196. (m) Saito, K.; Shibata, Y.;
Yamanaka, M.; Akiyama, T. Chiral Phosphoric Acid-Catalyzed
Oxidative Kinetic Resolution of Indolines Based on Transfer
Hydrogenation to Imines. J. Am. Chem. Soc. 2013, 135, 11740−
11743. (n) Arnold, J. S.; Mwenda, E. T.; Nguyen, H. M. Rhodium-
Catalyzed Sequential Allylic Amination and Olefin Hydroacylation
Reactions: Enantioselective Synthesis of Seven-Membered Nitrogen
Heterocycles. Angew. Chem., Int. Ed. 2014, 53, 3688−3692.
(o) Kretzschmar, M.; Hodík, T.; Schneider, C. Brønsted Acid
Catalyzed Addition of Enamides to ortho-Quinone Methide Imines-
An Efficient and Highly Enantioselective Synthesis of Chiral
Tetrahydroacridines. Angew. Chem., Int. Ed. 2016, 55, 9788−9792.
(p) Xia, Z.-L.; Zheng, C.; Wang, S.-G.; You, S.-L. Catalytic
Asymmetric Dearomatization of Indolyl Dihydropyridines through
an Enamine Isomerization/ Spirocyclization/Transfer Hydrogenation
Sequence. Angew. Chem., Int. Ed. 2018, 57, 2653−2656. (q) Chen, Q.-
A.; Wang, D.-S.; Zhou, Y.-G.; Duan, Y.; Fan, H.-J.; Yang, Y.; Zhang, Z.
Convergent Asymmetric Disproportionation Reactions: Metal/
Brønsted Acid Relay Catalysis for Enantioselective Reduction of
Quinoxalines. J. Am. Chem. Soc. 2011, 133, 6126−6129.
(7) (a) Yang, T.; Yin, Q.; Gu, G.; Zhang, X. A one-pot process for
the enantioselective synthesis of tetrahydroquinolines and tetrahy-
droisoquinolines via asymmetric reductive amination (ARA). Chem.
Commun. 2018, 54, 7247−7250. (b) Yu, C.-B.; Wang, J.; Zhou, Y.-G.
Facile synthesis of chiral indolines through asymmetric hydrogenation
of in situ generated indoles. Org. Chem. Front. 2018, 5, 2805−2809.
(c) Lim, C. S.; Quach, T. T.; Zhao, Y. Enantioselective Synthesis of
Tetrahydroquinolines by Borrowing Hydrogen Methodology: Coop-
erative Catalysis by an Achiral Iridacycle and a Chiral Phosphoric
Acid. Angew. Chem., Int. Ed. 2017, 56, 7176−7180. (d) Park, D. Y.;
Lee, S. Y.; Jeon, J.; Cheon, C.-H. Enantioselective Synthesis of
Tetrahydroquinolines from 2-Aminochalcones via a Consecutive
One-Pot Reaction Catalyzed by Chiral Phosphoric Acid. J. Org.
Chem. 2018, 83, 12486−12495.
(8) (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
̈
M. Hydroamination: Direct Addition of Amines to Alkenes and
Alkynes. Chem. Rev. 2008, 108, 3795−3892. (b) Hannedouche, J.;
Schulz, E. Asymmetric Hydroamination: A Survey of the Most Recent
Developments. Chem. - Eur. J. 2013, 19, 4972−4985. (c) Reznichenko,
A. L.; Nawara-Hultzsch, A. J.; Hultzsch, K. C. Asymmetric
Hydroamination. Top. Curr. Chem. 2014, 343, 191−260. (d) Pohlki,
F.; Doye, S. The catalytic hydroamination of alkynes. Chem. Soc. Rev.
2003, 32, 104−114.
(5) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G.
Highly Enantioselective Iridium-Catalyzed Hydrogenation of Hetero-
aromatic Compounds, Quinolines. J. Am. Chem. Soc. 2003, 125,
10536−10537. (b) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G.
Asymmetric Hydrogenation of Quinolines and Isoquinolines
Activated by Chloroformates. Angew. Chem., Int. Ed. 2006, 45,
2260−2263. (c) Zhou, H.; Li, Z.; Wang, Z.; Wang, T.; Xu, L.; He, Y.;
Fan, Q.-H.; Pan, J.; Gu, L.; Chan, A. S. C. Hydrogenation of
Quinolines Using a Recyclable Phosphine-Free Chiral Cationic
Ruthenium Catalyst: Enhancement of Catalyst Stability and
Selectivity in an Ionic Liquid. Angew. Chem., Int. Ed. 2008, 47,
8464−8467. (d) Wang, T.; Zhuo, L.; Li, Z.; Chen, F.; Ding, Z.; He,
Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. Highly
Enantioselective Hydrogenation of Quinolines Using Phosphine-
Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and
Origin of Enantioselectivity. J. Am. Chem. Soc. 2011, 133, 9878−9891.
́
(9) For selected examples, see: (a) Gagne, M. R.; Brard, L.;
Conticello, V. P.; Giardello, M. A.; Stern, C. L.; Marks, T. J.
Stereoselection Effects in the Catalytic Hydroamination/Cyclization
of Aminoolefins at Chiral Organolanthanide Centers. Organometallics
1992, 11, 2003−2005. (b) Hong, S.; Tian, S.; Metz, M. V.; Marks, T.
J. C2-Symmetric Bis(oxazolinato)lanthanide Catalysts for Enantiose-
lective Intramolecular Hydroamination/Cyclization. J. Am. Chem. Soc.
2003, 125, 14768−14783. (c) Gribkov, D. V.; Hultzsch, K. C.;
Hampel, F. 3,3′-Bis(trisarylsilyl)-Substituted Binaphtholate Rare
J
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Earth Metal Catalysts for Asymmetric Hydroamination. J. Am. Chem.
Soc. 2006, 128, 3748−3759. (d) Wood, M. C.; Leitch, D. C.; Yeung,
C. S.; Kozak, J. A.; Schafer, L. L. Chiral Neutral Zirconium Amidate
Complexes for the Asymmetric Hydroamination of Alkenes. Angew.
Chem., Int. Ed. 2007, 46, 354−358. (e) Shen, X.; Buchwald, S. L.
Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination of
Unactivated Alkenes. Angew. Chem., Int. Ed. 2010, 49, 564−567.
(f) Zhang, X.; Emge, T. J.; Hultzsch, K. C. A Chiral Phenoxyamine
Magnesium Catalyst for the Enantioselective Hydroamination/
Cyclization of Aminoalkenes and Intermolecular Hydroamination of
Vinyl Arenes. Angew. Chem., Int. Ed. 2012, 51, 394−398. (g) Manna,
K.; Everett, W. C.; Schoendorff, G.; Ellern, A.; Windus, T. L.; Sadow,
A. D. Highly Enantioselective Zirconium-Catalyzed Cyclization of
Aminoalkenes. J. Am. Chem. Soc. 2013, 135, 7235−7250. (h) Dai, X.-
(13) (a) Noyori, R.; Hashiguchi, A. S. Asymmetric Transfer
Hydrogenation Catalyzed by Chiral Ruthenium Complexes. Acc.
Chem. Res. 1997, 30, 97−102. (b) Ohkuma, T.; Utsumi, N.;
Tsutsumi, K.; Murata, K.; Sandoval, C.; Noyori, R. The Hydro-
genation/Transfer Hydrogenation Network: Asymmetric Hydro-
genation of Ketones with Chiral η6-Arene/N-Tosylethylenediamine
-Ruthenium(II) Catalysts. J. Am. Chem. Soc. 2006, 128, 8724−8725.
(14) (a) Chen, F.; Ding, Z.; Qin, J.; Wang, T.; He, Y.; Fan, Q.-H.
Highly Effective Asymmetric Hydrogenation of Cyclic N-Alkyl Imines
with Chiral Cationic Ru-MsDPEN Catalysts. Org. Lett. 2011, 13,
4348−4351. (b) Ding, Z.; Wang, T.; He, Y.-M.; Chen, F.; Zhou, H.-
F.; Fan, Q.-H.; Guo, Q.; Chan, A. S. C. Highly Enantioselective
Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquino-
lines by Ruthenium-Catalyzed Asymmetric Hydrogenation in Ionic
Liquid. Adv. Synth. Catal. 2013, 355, 3727−3735. (c) Ding, Z.; Chen,
F.; Qin, J.; He, Y.-M.; Fan, Q.-H. Asymmetric Hydrogenation of 2,4-
Disubstituted 1,5-Benzodiazepines Using Cationic Ruthenium Dia-
mine Catalysts: An Unusual Achiral Counteranion Induced Reversal
of Enantioselectivity. Angew. Chem., Int. Ed. 2012, 51, 5706−5710.
(d) Yang, Z.; Ding, Z.; Chen, F.; He, Y.-M.; Yang, N.; Fan, Q.-H.
Asymmetric Hydrogenation of Cyclic Imines of Benzoazepines and
Benzodiazepines with Chiral, Cationic Ruthenium−Diamine Cata-
lysts. Eur. J. Org. Chem. 2017, 2017, 1973−1977. (e) Chen, Y.; He, Y.-
M.; Zhang, S.; Miao, T.; Fan, Q.-H. Rapid Construction of
Structurally Diverse Quinolizidines, Indolizidines, and Their Ana-
logues via Ruthenium-Catalyzed Asymmetric Cascade Hydrogena-
tion/ Reductive Amination. Angew. Chem., Int. Ed. 2019, 58, 3809−
3813. (f) Hu, S.-B.; Chen, M.-W.; Zhai, X.-Y.; Zhou, Y.-G. Synthesis
of Tetrahydropyrrolo/indolo[1,2-a]pyrazines by Enantioselective
Hydrogenation of Heterocyclic Imines. Huaxue Xuebao 2018, 76,
103−106.
́
J.; Engl, O. D.; Leon, T.; Buchwald, S. L. Catalytic Asymmetric
Synthesis of a-Arylpyrrolidines and Benzo-fused Nitrogen Hetero-
cycles. Angew. Chem., Int. Ed. 2019, 58, 3407−3411.
(10) (a) Lutete, L. M.; Kadota, I.; Yamamoto, Y. Palladium-
Catalyzed Intramolecular Asymmetric Hydroamination of Alkynes. J.
Am. Chem. Soc. 2004, 126, 1622−1623. (b) Patil, N. T.; Lutete, L. M.;
Wu, H.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. Palladium-
Catalyzed Intramolecular Asymmetric Hydroamination, Hydroalkox-
ylation, and Hydrocarbonation of Alkynes. J. Org. Chem. 2006, 71,
4270−4279. (c) Patil, N. T.; Wu, H.; Yamamoto, Y. A Route to 2-
Substituted Tetrahydroquinolines via Palladium-Catalyzed Intra-
molecular Hydroamination of Anilino-alkynes. J. Org. Chem. 2007,
72, 6577−6579. (d) Chen, Q.-A.; Chen, Z.; Dong, V. M. Rhodium-
Catalyzed Enantioselective Hydroamination of Alkynes with Indo-
lines. J. Am. Chem. Soc. 2015, 137, 8392−8395. (e) Shi, S.-L.;
Buchwald, S. L. Copper-catalysed selective hydroamination reactions
of alkynes. Nat. Chem. 2015, 7, 38−44.
(15) Miao, T.; Tian, Z.-Y.; He, Y.-M.; Chen, F.; Chen, Y.; Yu, Z.-X.;
Fan, Q.-H. Asymmetric Hydrogenation of In Situ Generated
Isochromenylium Intermediates by Copper/ Ruthenium Tandem
Catalysis. Angew. Chem., Int. Ed. 2017, 56, 4135−4139.
(16) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
Asymmetric Transfer Hydrogenation of -Acetylenic Ketones. J. Am.
(11) (a) Wu, H.; He, Y.-P.; Gong, L.-Z. The Combination of Relay
and Cooperative Catalysis with a Gold/Palladium/ Brønsted Acid
Ternary System for the Cascade Hydroamination/Allylic Alkylation
Reaction. Adv. Synth. Catal. 2012, 354, 975−980. (b) Patil, N. T.;
Raut, V. S.; Tella, R. B. Enantioselective cooperative triple catalysis:
unique roles of Au(I)/amine/chiral Brønsted acid catalysts in the
addition/cycloisomerization/transfer hydrogenation cascade. Chem.
Commun. 2013, 49, 570−572. (c) He, Y.-P.; Wu, H.; Chen, D.-F.; Yu,
J.; Gong, L.-Z. Cascade Hydroamination/Redox Reaction for the
Synthesis of Cyclic Aminals Catalyzed by a Combined Gold Complex
and Brønsted Acid. Chem. - Eur. J. 2013, 19, 5232−5237. (d) Li, J.;
Lin, L.; Hu, B.; Lian, X.; Wang, G.; Liu, X.; Feng, X. Bimetallic
Gold(I)/Chiral N,N’-Dioxide Nickel(II) Asymmetric Relay Catalysis:
Chemo- and Enantioselective Synthesis of Spiroketals and Spiroami-
nals. Angew. Chem., Int. Ed. 2016, 55, 6075−6078. (e) Zhao, F.; Li,
N.; Zhu, Y.-F.; Han, Z.-Y. Enantioselective Construction of Function-
alized Tetrahydrocarbazoles Enabled by Asymmetric Relay Catalysis
of Gold Complex and Chiral Brønsted Acid. Org. Lett. 2016, 18,
1506−1509.
(12) (a) Heutling, A.; Pohlki, F.; Bytschkov, I.; Doye, S.
Hydroamination/Hydrosilylation Sequence Catalyzed by Titanium
Complexes. Angew. Chem., Int. Ed. 2005, 44, 2951−2954. (b) Zhai,
H.; Borzenko, A.; Lau, Y. Y.; Ahn, S. H.; Schafer, L. L. Catalytic
Asymmetric Synthesis of Substituted Morpholines and Piperazines.
Angew. Chem., Int. Ed. 2012, 51, 12219−12223. (c) Han, Z.-Y.; Xiao,
H.; Chen, X.-H.; Gong, L.-Z. Consecutive Intramolecular Hydro-
amination/Asymmetric Transfer Hydrogenation under Relay Catal-
ysis of an Achiral Gold Complex/Chiral Brønsted Acid Binary System.
J. Am. Chem. Soc. 2009, 131, 9182−9183. (d) Du, Y.-L.; Hu, Y.; Zhu,
Y.-F.; Tu, X.-F.; Han, Z.-Y.; Gong, L.-Z. Chiral Gold Phosphate
Catalyzed Tandem Hydroamination/Asymmetric Transfer Hydro-
genation Enables Access to Chiral Tetrahydroquinolines. J. Org.
Chem. 2015, 80, 4754−4759. (e) Liu, X.-Y.; Che, C.-M. Highly
Enantioselective Synthesis of Chiral Secondary Amines by Gold(I)/
Chiral Brønsted Acid Catalyzed Tandem Intermolecular Hydro-
amination and Transfer Hydrogenation Reactions. Org. Lett. 2009, 11,
4204−4207.
́
Chem. Soc. 1997, 119, 8738−8739. (b) Varela-Fernandez, A.; Varela,
́
J. A.; Saa, C. Ruthenium-Catalyzed Cycloisomerization of Aromatic
Homoand Bis-Homopropargylic Amines/Amides: Formation of
Indoles, Dihydroisoquinolines and Dihydroquinolines. Adv. Synth.
Catal. 2011, 353, 1933−1937. (c) Watanabe, T.; Mutoh, Y.; Saito, S.
Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylanilides: Syn-
thesis of 3-Substituted Indoles by 1,2-Carbon Migration. J. Am. Chem.
Soc. 2017, 139, 7749−7752. (d) Chung, L.-H.; Wong, C.-Y.
Ruthenium-Induced Alkyne Cycloisomerization: Construction of
Metalated Heterocycles, Revelation of Unconventional Reaction
Pathways, and Exploration of Functional Applications. Chem. - Eur.
J. 2019, 25, 2889−2897.
(17) (a) Ryan, J. H.; Smith, J. A.; Hyland, C.; Meyer, A. G.;
Williams, C. C.; Bissember, A. C.; Just, J. Seven-Membered Rings.
Prog. Heterocycl. Chem. 2015, 27, 531. (b) Shen, H.-Q.; Gao, X.; Liu,
C.; Hu, S.-B.; Zhou, Y.-G. A Hydrogenation/Oxidative Fragmentation
Cascade for Synthesis of Chiral 4,5-Dihydro-1H-benzo[d]azepin-1-
ones. Org. Lett. 2016, 18, 5920−5923. (c) He, H.; Liu, W.-B.; Dai, L.-
X.; You, S.-L. Enantioselective Synthesis of 2,3-Dihydro-1H-benzo[b]
azepines: Iridium-Catalyzed Tandem Allylic Vinylation/ Amination
Reaction. Angew. Chem., Int. Ed. 2010, 49, 1496−1499.
́
(18) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.; Fouraste,
I.; Moulis, C. Two tetrahydroquinoline alkaloids from Galipea
officinalis. Phytochemistry 1999, 51, 1167−1169.
(19) (a) Kuyper, L. F.; Baccanari, D. P.; Jones, M. L.; Hunter, R. N.;
Tansik, R. L.; Joyner, S. S.; Boytos, C. M.; Rudolph, S. K.; Knick, V.;
Wilson, H. R.; Caddell, J. M.; Friedman, H. S.; Comley, J. C. W.;
Stables, J. N. High-Affinity Inhibitors of Dihydrofolate Reductase:
Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-
diaminopyrrolo[3,2-f ]quinazolines with Small Molecular Size. J.
Med. Chem. 1996, 39, 892−903. (b) Herrero, M. T.; de Sarralde, J.
D.; SanMartin, R.; Bravo, L.; Domínguez, E. Cesium Carbonate-
K
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Promoted Hydroamidation of Alkynes: Enamides, Indoles and the
Effect of Iron(III) Chloride. Adv. Synth. Catal. 2012, 354, 3054−
3064.
(20) Li, X.; Tian, J.-J.; Liu, N.; Tu, X.-S.; Zeng, N.-N.; Wang, X.-C.
Spiro-Bicyclic Bisborane Catalysts for Metal-Free Chemoselective and
Enantioselective Hydrogenation of Quinolines. Angew. Chem., Int. Ed.
2019, 58, 4664−4668.
(21) Arp, F. O.; Fu, G. C. Kinetic Resolutions of Indolines by a
Nonenzymatic Acylation Catalyst. J. Am. Chem. Soc. 2006, 128,
14264−14265.
(22) For racemic 6a, see: Hegedus, L. S.; Winton, P. M.; Varaprath,
S. Palladium-Assisted N-Alkylation of Indoles: Attempted Application
to Polycyclization. J. Org. Chem. 1981, 46, 2215−2221.
L
DOI: 10.1021/acs.organomet.9b00183
Organometallics XXXX, XXX, XXX−XXX