Chiral Indolizidine Synthesis through the Ir-Catalyzed Asymmetric Hydrogenation of Cyclic Pyridinium Salts

Article abstract of DOI:10.1021/acs.joc.1c00958

The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)py

Full text of DOI:10.1021/acs.joc.1c00958

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Chiral Indolizidine Synthesis through the Ir-Catalyzed Asymmetric
Hydrogenation of Cyclic Pyridinium Salts
Wenkuan Li, Sheng Zhang,* Xiaoqiang Yu, Xiujuan Feng, Yoshinori Yamamoto, and Ming Bao*
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ABSTRACT: The Ir-catalyzed asymmetric hydrogenation of cyclic
pyridinium salts is presented as a new strategy for the convenient and
efficient synthesis of chiral indolizidines. The asymmetric hydro-
genation of cyclic pyridinium salts derived from 2-(2-acylphenyl)-
pyridines proceeded smoothly in the presence of [Ir(cod)Cl]2 and
(R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines
6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The
enantiomeric purity of 6j was increased to 92:8 through recrystallization.
he development of convenient and efficient methods for
the synthesis of chiral piperidines has elicited consid-
T
erable attention. Chiral piperidines can be utilized as versatile
and key synthetic intermediates for preparing several natural
products and biologically active compounds.1 Among the
methods developed for the synthesis of chiral piperidines,2 the
transition-metal-catalyzed asymmetric hydrogenation of sub-
stituted pyridines is an atom-economic and direct approach.3
Three main methods were developed over the past years to
circumvent the inherent problems (i.e., the strong coordination
capability of pyridine substrates and corresponding piperidine
products may deactivate the catalysts, and the thermodynamic
stability of the aromatic pyridine ring may impede the
reduction) that occur in the direct catalytic asymmetric
hydrogenation of simple pyridines.4 One of these methods
involves the N-protonation of substituted pyridines to form
pyridinium salts.5 Another method involves the N-amination of
substituted pyridines to prepare N-imino pyridinium ylides.6
The last method involves the N-benzylation of substituted
pyridines to generate N-benzylpyridinium salts.7 The third
method is frequently utilized to obtain chiral piperidines due to
the simple operation of pyridine activation and the high
enantioselectivity (Figure 1a).
Figure 1. Asymmetric hydrogenation of pyridinium salts.
Figure 2. Representative natural products and drugs containing a 7,8-
benzoindolizidine scaffold.
We recently succeeded in cleaving the amide C−N bond
with a Ru catalyst for the first time, obtaining ortho-acylation
products via the C−H bond activation of 2-arylpyridines.8 In
the current work, 2-(2-acylphenyl)pyridines were successfully
transformed into cyclic pyridinium salts to obtain chiral
indolizidines via catalytic asymmetric hydrogenation (Figure
1b). The indolizidine moiety is the most common N-
heterocycle structure; it exists in a wide range of natural
products, pharmaceuticals, and biologically active molecules,9
such as valmerin, mAChR modulator, and antiplasmodial
inhibitor (Figure 2).10 Although numerous synthetic methods
have been developed for assembling this important structural
motif,11 as far as we know, only one study has constructed
chiral 7,8-benzoindolizidine molecules.12 Therefore, the
development of a convenient and efficient method is highly
desirable. To the best of our knowledge, no successful example
of the direct catalytic asymmetric hydrogenation of achiral
Received: April 24, 2021
Published: July 8, 2021
https://doi.org/10.1021/acs.joc.1c00958
J. Org. Chem. 2021, 86, 10773−10781
© 2021 American Chemical Society
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Note
cyclic pyridinium salts has been reported. In the current study,
we present the first example of Ir-catalyzed asymmetric
hydrogenation of cyclic pyridinium salts to produce chiral
7,8-benzoindolizidines.
Table 2. Screening of Reaction Conditions for Synthesis of
Chiral 7,8-Benzoindolizidine
a
In accordance with our research objectives, C−H bond
acylation products, 2-(2-acylphenyl)pyridines 1, were initially
transformed into cyclic pyridinium salts 2 for the synthesis of
chiral 7,8-benzoindolizidine. The results are summarized in
Table 1. Cyclic pyridinium salts 2 were readily synthesized
yield
b
cd
,
entry
ligand
Y
solvent
(%)
er
a b
,
1
2
3
4
5
6
7
8
9
(R)-SegPhos
(R)-SynPhos
(R)-DifluorPhos
(R)-BINAP
(R)-MeO-BIPHEP
(R,R)-DIOP
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
toluene
THF
dioxane
DMF
MeOH
iPrOH
acetone
acetone
acetone
acetone
acetone
acetone
94
89
80
92
96
85
92
18
92
28
15
21
25
89
trace
trace
78
NR
NR
23
87
92
63:37
61:39
64:36
54:46
57:43
56:44
55:45
56:44
70:30
61:39
58:42
67:43
59:41
67.5:32.5
Table 1. Formation of Various Cyclic Pyridinium Salts 2
(R)-DM-BINAP
(R)-DTBM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
(R)-DM-SegPhos
10
11
12
13
14
15
16
17
18
19
Br
75:25
e
OTf
SbF6
OTf
F
e
f
20
50:50
82:18
84:16
21
22
Cl
a
Reaction conditions: 2a−5a (0.2 mmol), [Ir(COD)Cl]2 (2 mol%),
ligand (4.4 mol%), H2 (3 MPa) in solvent (2 mL) at 28 °C for 24 h.
b
c
Isolated yield. The ratio of enantiomers (er) was determined by
d
chiral HPLC. The ratio of diastereomers (dr) was determined by 1H
NMR spectroscopy to be >20:1 in all cases. No reaction was
observed; the starting materials were recovered. NaCl (20 mol%) was
e
f
added as an additive.
8). Surprisingly, the diastereoselectivity of the target reaction
was extremely high (>20:1 dr) even when an achiral ligand was
utilized. This finding implies that this type of asymmetric
hydrogenation involves a change in the configuration of the
achiral benzylic sp3 carbon atom. The results of solvent
screening showed that, even though the yield of 6a was slightly
decreased, the enantioselectivity was improved to 75:25 when
the hydrogenation of 2a′ was performed in acetone in the
presence of (R)-DM-SegPhos (entry 17 vs entries 9−16). The
effects of counterions were finally investigated using (R)-DM-
SegPhos and acetone as the ligand and solvent, respectively. It
is worth noting that counterions have a significant effect on the
catalytic activity and enantioselectivity. No desired product
a
Reaction conditions: first step: 1 (5 mmol), NaBH4 (3 equiv.) in
MeOH (15 mL) at room temperature for 6 h; second step: 4 mol/L
of HCl in dioxane (1 equiv.) in AcOH (1 mL) at 90 °C for 3 h.
b
c
Isolated yield. Second step: 33 wt % HBr in AcOH (1 equiv.) at 90
d
°C for 3 h. Second step: 120 °C for 6 h.
with good to excellent yields (84−95%) through a simple two-
step procedure, including the reduction reaction of 1 with
NaBH4 and the cyclization reaction of the resulting alcohols
with HX (X = Br, Cl).13 The cyclic pyridinium salts 3a−5a
with other counterions were also easily obtained from
pyridinium bromide salt 2a′ via a counteranion exchange
reaction with corresponding silver salts (see details in the
Experimental Section).14
The reaction conditions of the asymmetric hydrogenation of
cyclic pyridinium salts for chiral 7,8-benzoindolizidine syn-
thesis were optimized using [Ir(COD)Cl]2 as the precatalyst.
The results are shown in Table 2. The asymmetric hydro-
genation of 2a′ was initially chosen as the model reaction to
screen chiral ligands and solvents. Among the chiral phosphine
ligands examined,15 the use of (R)-DM-SegPhos led to the
formation of product 6a in excellent yield (92%) with a
relatively high enantioselectivity (70:30, entry 9 vs entries 1−
was obained when the OTf− and SbF6 salts were examined.
−
However, the desired product 6a was obtained in 23% yield
with 50:50 er when additive NaCl was added to the reaction
mixture of OTf− salt (entry 20). The desired product 6a was
obtained in excellent yield (92%) again, and the enantiose-
lectivity was further improved to 84:16 when the chloride salt
2a was examined (entry 22 vs entries 17−21). These results
indicated that a halide anion plays an important role for the
current asymmetric hydrogenation reaction. Finally, additives
I2, phthalimide, and HI were examined in order to enhance the
enantioselectivity.16 However, no satisfactory results were
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obtained (see details in the Supporting Information). There-
fore, the subsequent asymmetric hydrogenation of various
cyclic pyridinium chloride salts 2 was conducted in the
presence of [Ir(COD)Cl]2 (2 mol %) and (R)-DM-SegPhos
(4.4 mol %) in acetone at 28 °C for 24 h.
The scope and limitation of this type of asymmetric
hydrogenation were explored using the optimized reaction
conditions, and the results are summarized in Table 3. The
benzylic position was also examined, and the same good result
was obtained as the above-mentioned substrates were tested
(6f: 82% yield, 81:19 er, and >20:1 dr). Notably, no
dehalogenation and no reduction were observed when Cl,
Br, and CO2Me group-containing substrates 2g, 2h, and 2k
were involved in the current asymmetric hydrogenation,
respectively. As expected, the asymmetric hydrogenation
reaction of substrate 2m containing a naphthalene ring
proceeded also smoothly to furnish the corresponding product
6m in 92% yield with 82:18 er and 19:1 dr. However,
significantly decreased er and dr were observed when the
substrate 2n with a Me group on the pyridine ring was
examined (6n: 95% yield, 61:39 er, and 1.7:1 dr). The absolute
configuration of 6j was determined to be (6S,10bR) based on
X-ray crystallographic analysis in combination with Nuclear
Overhauser Effect measurement. The X-ray structure of 6j
hydrochloride (6j·HCl) is shown in Table 3. Finally, the
enantiomeric purity of 6j was increased to 92:8 by
recrystallization of the resulting 6j·HCl salt. The substrate 2g
was also scaled-up to 2 mmol to verify the usefulness of the
current Ir-catalyzed asymmetric hydrogenation reaction. The
scaled-up experiment provided the desired product 6g in 81%
yield with 88:12 er and >20:1 dr.
Table 3. Ir-Catalyzed Asymmetric Hydrogenation of
a b
,
Various Cyclic Pyridinium Salts 2
Control experiments were conducted to gain insights into
the underlying mechanism of Ir-catalyzed asymmetric hydro-
genation of cyclic pyridinium salts (Scheme 1). The formation
Scheme 1. Control Experiments of Ir-Catalyzed Asymmetric
Hydrogenation
of deuterium-labeled product 6j-d was observed when the
asymmetric hydrogenation of 2j was performed under a D2
atmosphere at standard conditions (Scheme 1a). The
incorporation of 54% deuterium at the benzylic position (i.e.,
2′-position) indicated that this type of asymmetric hydro-
genation involves removal of the benzylic hydrogen atom.
Furthermore, the incorporation of 100% deuterium at the
benzylic position was observed when the cyclic pyridinium
chloride salt 2a was dissolved in CD3COOD or CD3OD
(Scheme 1b). The reason was attributed to the acidic effect of
the benzylic hydrogen atom.
A plausible mechanism for this kind of asymmetric
hydrogenation is shown in Scheme 2.7e,17 First, the iridium
hydride complex A is formed through the reaction of the
precatalyst [Ir(COD)Cl]2 with a C2-symmetric chiral bi-
sphosphine ligand and hydrogen molecule (H2). The
interaction between iridium hydride complex A and
pyridinium chloride salt 2a and the 1,4-hydrogenation of 2a
generates intermediate B and iridium hydride complex C. The
coordination of H2 with iridium hydride complex C leads to
a
Reaction conditions: 2 (0.2 mmol), [Ir(cod)Cl]2 (2 mol%), (R)-
DM-SegPhos (4.4 mol%), and H2 (3 MPa) in acetone (2 mL) at 28
b
°C for 24 h; X = Cl. Isolated yield; er and dr were determined by
c
chiral HPLC and 1H NMR, respectively. CH2Cl2/acetone (1/1, total
d
2 mL); X = Br. The reaction was conducted at 40 °C.
reactions of cyclic pyridinium halides 2 bearing electron-
donating groups (Me and MeO) or electron-withdrawing
groups (F, Cl, Br, CF3, and CO2Me) on the benzene rings
proceeded smoothly to offer the desired products 6 in high to
excellent yields (70−95%) with moderate enantioselectivity
(72:28−86:14 er) and excellent diastereoselectivity (>20:1 dr).
The results indicated that the electronic property of the
substituent linked to the benzene ring of starting materials 2
did not considerably influence the reactivity and enantiose-
lectivity. The substrate 2f bearing a cyclohexyl group on the
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Scheme 2. Proposed Mechanism of Ir-Catalyzed
Asymmetric Hydrogenation
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere unless otherwise noted. Solvents were purified
by standard techniques without special instructions. An aluminum
heating block placed on a stirring plate was used as the heating source
for the synthesis of 1 and 2. An oil bath was used as the heating
source for the synthesis of 6. 1H and 13C NMR spectra were recorded
on either a Bruker AvanceII-400 spectrometer (400 MHz for 1H, 100
MHz for 13C) or a Varian Inova-500 spectrometer (500 MHz for 1H,
125 MHz for 13C); CDCl3 and TMS were used as a solvent and an
internal standard, respectively. The chemical shifts are reported in
ppm downfield (δ) from TMS, the coupling constants J are given in
Hz. The peak patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. IR spectra were recorded on a
NEXUS FT-IR spectrometer. High resolution mass spectra were
recorded on either a Q-TOF mass spectrometry or a LTQ Orbitrap
XL mass spectrometry. TLC was carried out on SiO2 (silica gel 60
F254, Merck), and the spots were located with UV light. Flash
chromatography was carried out on SiO2 (silica gel 60, 200−300
mesh). The enantiomeric excesses were determined by HPLC with
Daicel CHIRALCEL HPLC columns. The X-ray diffraction data for
the crystallized compound were collected on a Bruker Smart APEX
CCD area detector diffractometer (graphite monochromator, Mo Kα
radiation, λ = 0.71073 Å) at 200(2) K.
General Procedure for the Synthesis of 2-(2-Acylphenyl)-
pyridines 1. All of the 2-(2-acylphenyl)pyridines 1 are known
compounds. The detailed synthesis procedures were shown in
previous reports.8,18
General Procedure for the Synthesis of Cyclic Pyridinium
Salts 2a−2n. An oven-dried 50 mL round-bottom flask was charged
with phenyl(2-(pyridin-2-yl)phenyl)methanone deravatives (1a−1n,
5 mmol) and methanol (15 mL). To the reaction mixture was slowly
added NaBH4 (3 equiv.) in portions within 1 h. The reaction mixture
was stirred at room temperature for 6 h. The reaction was quenched
by a saturated NH4Cl aqueous solution, and then the resulting
mixture was extracted by EtOAc three times, dried over Na2SO4, and
evaporated in vacuum to afford an alcohol product. The obtained
alcohol product was directly treated with 33 wt% HBr in AcOH (1
equiv.), or the obtained alcohol product was dissolved in AcOH (1
mL), and then reacted with 4 mol/L HCl in dioxane (1 equiv.) at
90−120 °C for 3−6 h. The mixture was concentrated in vacuum to
give the crude cyclic pyridinium salts 2a−2n. Except for 2f,
purification of the crude product was carried out by washing three
times with ether.13
General Procedure for the Synthesis of Cyclic Pyridinium
Salts 3a, 4a, and 5a. An oven-dried 50 mL round-bottom flask was
charged with 6-phenyl-6H-pyrido[2,1-a]isoindol-5-ium bromide (2a′,
1 mmol) and methanol (15 mL). To the mixture was added 1 equiv.
of AgY (Y = OTf, SbF6, or F). The reaction mixture was allowed to
stir at room temperature for 1 h. After filtration, the solvent was
removed under reduced pressure to give the desired cyclic pyridinium
salts 3a, 4a, and 5a in quantitative yields.14
the regeneration of iridium hydride complex A. Intermediate B
transforms to a more stable intermediate D through 1,3-proton
migration. Then, intermediate E would be easily formed by
releasing HCl from intermediate D owing to the strong acidity
of the benzylic hydrogen atom. The asymmetric proton
transfer between intermediate E and iridium hydride complex
A subsequently takes place to produce intermediate F and an
anionic iridium hydride complex G, which then delivers one
hydride to intermediate F to form intermediate I and
regenerates iridium hydride complex C. Intermediate J is
finally formed via 1,3-proton migration from intermediate I.
Similarly, the iridium hydride complex A is regenerated from
iridium hydride complex C by coordinating one H2 molecule.
Complex A then undergoes asymmetric 1,2-hydrogenation
with intermediate J to afford hydrochloride salt 6a·HCl and
finally regenerates iridium hydride complex A again by
coordinating one H2 molecule.
General Procedure for the Ir-Catalyzed Asymmetric Hydro-
genation. A mixture of [Ir(COD)Cl]2 (2.7 mg, 0.004 mmol), (R)-
DM-SegPhos (6.4 mg, 0.0088 mmol), and acetone (2 mL) was stirred
at room temperature for 20 min in a glovebox and then was
transferred by a syringe into a stainless steel autoclave, in which cyclic
pyridinium salts (2, 0.2 mmol) were placed beforehand. The
autoclave was purged with H2 (3 times) and filled with H2 to 3
MPa pressure, and the reaction mixture was stirred at 28 °C for 24 h.
After the H2 gas was carefully released, a saturated NaHCO3 aqueous
solution was added and the resulting mixture was stirred for 15 min.
The mixture was extracted with CH2Cl2 three times, and the
combined organic layers were concentrated in vacuum. The crude
product was purified by column chromatography (eluent: PE/EtOAc
= 50/1) to afford the desired indolizidine products 6a−6n. The er
In summary, we developed a convenient and efficient
method for the synthesis of chiral 7,8-benzoindolizidines. To
the best of our knowledge, the current paper presents the first
successful example of Ir-catalyzed asymmetric hydrogenation
of cyclic pyridinium salts. The desired chiral 7,8-benzoindo-
lizidines were obtained in good to excellent yields with
moderate enantioselectivity (up to 86:14 er) and excellent
diastereoselectivity (>20:1 dr). The enantiomeric purity of the
resulting products can be enriched through recrystallization.
The mild reaction conditions, good functional group tolerance,
and experimental simplicity render the proposed method as
highly useful for the synthesis of chiral heterocycle-fused
compounds. Further study on the theoretical explanation of
the reaction mechanism is currently underway to understand
the origin of the extremely high diastereoselectivity.
1
and dr were determined by chiral HPLC and H NMR, respectively.
General Procedure for Large Scale Synthesis of 6g. An oven-
dried 50 mL stainless steel autoclave was charged with a mixture of
[Ir(COD)Cl]2 (27 mg, 0.04 mmol), (R)-DM-SegPhos (64 mg, 0.088
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mmol), 6-(4-chlorophenyl)-6H-pyrido[2,1-a]isoindol-5-ium chloride
2g (0.628 g, 2 mmol), and acetone (20 mL) in a glovebox. Then the
autoclave was purged with H2 (3 times) and filled with H2 to 3 MPa
pressure. The reaction mixture was stirred at 28 °C for 24 h. After the
H2 gas was carefully released, a saturated NaHCO3 aqueous solution
was added and the resulting mixture was stirred for 15 min. The
mixture was extracted with CH2Cl2 three times, and the combined
organic layers were concentrated in vacuum. The crude product was
purified by column chromatography (eluent: PE/EtOAc = 50/1) to
afford the desired indolizidine product 6g (0.46 g, 81% yield, 88:12 er,
>20:1 dr).
6-Phenyl-6H-pyrido[2,1-a]isoindol-5-ium Chloride (2a). White
solid (1.26 g, 90% yield). 1H NMR (400 MHz, CD3COOD) δ 9.11−
9.01 (m, 1H), 8.89−8.82 (m, 2H), 8.58−8.49 (m, 1H), 8.17 (s, 1H),
8.01−7.85 (m, 2H), 7.75 (d, J = 5.6 Hz, 2H), 7.69−7.53 (m, 5H);
13C{1H} NMR (100 MHz, CD3COOD) δ 150.8, 148.3, 144.4, 139.6,
136.8, 134.2, 131.6, 130.4, 129.6, 129.2, 126.7, 125.7, 124.8, 124.4,
121.5; Hydrogen-deuterium exchange occurred in the presence of
CD3COOD. IR (KBr): υmax 3057, 2923, 1663, 1626, 1586, 1501,
1448, 1313, 1282, 779, 747, 731, 699 cm−1; HRMS (ESI) m/z calcd
for C18H14N+: 244.1121 [M+]; found: 244.1121.
8-Methyl-6-phenyl-6H-pyrido[2,1-a]isoindol-5-ium Chloride
(2b). White solid (1.35 g, 92% yield). 1H NMR (400 MHz,
CDCl3) δ 9.10 (d, J = 5.3 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.43−
8.39 (m, 1H), 8.28 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.65−7.61 (m,
1H), 7.46 (d, J = 6.9 Hz, 2H), 7.39−7.32 (m, 4H), 7.22 (s, 1H), 2.41
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.6, 145.5, 145.4,
144.2, 142.2, 134.4, 131.2, 130.4, 129.8, 129.3, 127.5, 124.9, 123.9,
123.4, 120.0, 75.5, 22.2; IR (KBr): υmax 3006, 2920, 1625, 1567, 1505,
1475, 1350, 1291, 779, 755, 729, 699 cm−1; HRMS (ESI) m/z calcd
for C19H16N+: 258.1277 [M+]; found: 258.1282.
1H), 2.82−2.72 (m, 1H), 2.43−2.33 (m, 1H), 1.89−1.80 (m, 1H),
1.63 (d, J = 12.5 Hz, 1H), 1.53−1.41 (m, 3H), 1.17−1.06 (m, 1H),
1.03−0.92 (m, 1H), 0.64 (d, J = 12.2 Hz, 1H), 0.39−0.27 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 152.6, 145.5, 142.1, 141.4,
133.0, 130.5, 129.8, 124.9, 124.0, 123.9, 120.3, 76.5, 44.8, 29.1, 26.2,
25.7, 25.3, 24.9; IR (KBr): υmax 3030, 2927, 1608, 1529, 1451, 1373,
1238, 1018, 957, 791, 766, 731, 699 cm−1; HRMS (ESI) m/z calcd for
C18H20N+: 250.1590 [M+]; found: 250.1592.
6-(4-Chlorophenyl)-6H-pyrido[2,1-a]isoindol-5-ium Chloride
(2g). White solid (1.45 g, 92% yield). 1H NMR (400 MHz,
CDCl3) δ 9.20 (d, J = 5.8 Hz, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.57−
8.53 (m, 1H), 8.41 (s, 1H), 8.38 (d, J = 6.7 Hz, 1H), 7.80−7.77 (m,
1H), 7.68−7.62 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.45−7.43 (m,
1H), 7.35 (d, J = 8.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
152.3, 146.1, 143.2, 142.1, 136.7, 134.0, 132.6, 130.8, 130.3, 130.03,
130.01, 124.8, 124.4, 123.9, 120.7, 74.8; IR (KBr): υmax 3017, 2918,
1628, 1567, 1500, 1463, 1299, 1164, 1034, 809, 772, 750, 729 cm−1;
HRMS (ESI) m/z calcd for C18H13ClN+: 278.0731 [M+]; found:
278.0733.
6-(4-Bromophenyl)-6H-pyrido[2,1-a]isoindol-5-ium Chloride
(2h). White solid (1.58 g, 88% yield). 1H NMR (400 MHz,
CDCl3) δ 9.12 (d, J = 5.9 Hz, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.51−
8.46 (m, 1H), 8.31 (d, J = 6.7 Hz, 1H), 8.27 (s, 1H), 7.72−7.68 (t, J =
6.7 Hz, 1H), 7.62−7.55 (p, J = 7.1 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H),
7.38−7.33 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.4,
146.1, 143.1, 142.1, 134.0, 133.1, 133.0, 131.0, 130.4, 130.0, 125.1,
124.7, 124.3, 123.9, 120.7, 74.8; IR (KBr): υmax 3030, 2917, 1626,
1501, 1488, 1461, 1291, 1069, 1012, 802, 777, 754 cm−1; HRMS
(ESI) m/z calcd for C18H13BrN+: 322.0226, 324.0206 [M+]; found:
322.0226, 324.0201.
6-(p-Tolyl)-6H-pyrido[2,1-a]isoindol-5-ium Chloride (2i). White
solid (1.32 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J =
6.0 Hz, 1H), 8.83 (d, J = 8.1 Hz, 1H), 8.58−8.56 (m, 1H), 8.41−8.39
(m, 1H), 8.09 (s, 1H), 7.82−7.79 (m, 1H), 7.61−7.58 (m, 2H),
7.42−7.39 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz,
2H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.2, 146.1,
143.5, 141.8, 140.7, 133.7, 131.1, 130.4, 130.1, 130.1, 129.0, 124.9,
124.2, 123.9, 120.8, 75.6, 21.3; IR (KBr): υmax 3012, 2921, 1627,
1567, 1500, 1463, 1352, 1298, 1026, 801, 767, 747 cm−1; HRMS
(ESI) m/z calcd for C19H16N+: 258.1277 [M+]; found: 258.1275.
6-(4-Methoxyphenyl)-6H-pyrido[2,1-a]isoindol-5-ium Chloride
8-Methoxy-6-phenyl-6H-pyrido[2,1-a]isoindol-5-ium Chloride
1
(2c). White solid (1.41 g, 91% yield). H NMR (400 MHz, CDCl3)
δ 8.92 (d, J = 4.8 Hz, 1H), 8.62 (d, J = 7.1 Hz, 1H), 8.36−8.31 (m,
1H), 8.28 (d, J = 9.2 Hz, 1H), 8.21 (s, 1H), 7.52−7.49 (m, 1H), 7.43
(d, J = 6.8 Hz, 2H), 7.35−7.28 (m, 3H), 7.03 (d, J = 7.8 Hz, 1H),
6.80 (s, 1H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
164.5, 152.6, 146.5, 145.5, 141.5, 134.4, 130.4, 129.8, 129.2, 125.6,
122.8, 122.5, 119.9, 117.5, 108.6, 75.1, 56.0; IR (KBr): υmax 3009,
2934, 1625, 1563, 1478, 1292, 1234, 1031, 778, 754, 730, 700 cm−1;
HRMS (ESI) m/z calcd for C19H16NO+: 274.1226 [M+]; found:
274.1226.
1
(2j). White solid (1.44 g, 93% yield). H NMR (400 MHz, CDCl3)
8-Fluoro-6-phenyl-6H-pyrido[2,1-a]isoindol-5-ium Chloride (2d).
White solid (1.33 g, 89% yield). 1H NMR (400 MHz, CD3OD) δ 8.93
(d, J = 6.2 Hz, 1H), 8.82 (d, J = 8.2 Hz, 1H), 8.74−8.70 (m, 1H),
8.56 (dd, J = 8.6, 4.7 Hz, 1H), 7.98−7.95 (m, 1H), 7.57−7.48 (m,
4H), 7.39−7.32 (m, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ
166.18 (d, JC‑F = 254.9 Hz), 152.73, 146.58, 146.36 (d, JC‑F = 10.4
Hz), 141.2, 133.8, 130.5, 129.8, 128.5, 126.7 (d, 6JC‑F = 2.3 Hz), 126.4
(d, 5JC‑F = 10.0 Hz), 124.9, 120.8, 118.0 (d, 3JC‑F = 24.3 Hz), 111.6 (d,
2JC‑F = 25.8 Hz), 75.7; Hydrogen-deuterium exchange occurred in the
presence of CD3OD. IR (KBr): υmax 3026, 2920, 1627, 1505, 1475,
1354, 1276, 1215, 777, 753, 731, 700 cm−1; HRMS (ESI) m/z calcd
for C18H13FN+: 262.1027 [M+]; found: 262.1026.
δ 9.09 (d, J = 4.4 Hz, 1H), 8.72 (d, J = 7.1 Hz, 1H), 8.45−8.40 (m,
1H), 8.31 (d, J = 7.0 Hz, 1H), 8.18 (s, 1H), 7.67−7.63 (m, 1H),
7.59−7.52 (m, 2H), 7.38−7.35 (m, 3H), 6.80 (d, J = 8.3 Hz, 2H),
3.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.1, 152.1,
145.7, 143.7, 142.0, 133.8, 130.9, 130.1, 130.1, 125.7, 124.4, 123.9,
120.7, 115.1, 75.5, 55.4; IR (KBr): υmax 3012, 2936, 1628, 1610, 1513,
1501, 1463, 1252, 1178, 1028, 818, 790, 766, 748 cm−1; HRMS (ESI)
m/z calcd for C19H16NO+: 274.1226 [M+]; found: 274.1226.
1
4
6-(4-(Methoxycarbonyl)phenyl)-6H-pyrido[2,1-a]isoindol-5-ium
1
Chloride (2k). White solid (1.51 g, 89% yield). H NMR (400 MHz,
CD3OD) δ 8.95 (d, J = 6.1 Hz, 1H), 8.79−8.70 (m, 2H), 8.45−8.40
(m, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.99−7.93 (m, 1H), 7.82−7.77 (m,
2H), 7.61−7.56 (m, 1H), 7.47−7.41 (m, 2H), 3.91 (s, 0.64H);
13C{1H} NMR (100 MHz, CD3OD) δ 167.2, 153.9, 146.6, 143.1,
141.1, 138.7, 134.0, 132.7, 130.8, 130.6, 130.3, 128.5, 125.3, 124.0,
123.6, 120.8, 51.6 (50.6). It is worth noting that an unexpected
hydrogen-deuterium exchange occurred in the presence of CD3OD;
the incorporation of 100% deuterium at the benzylic position was
observed. Furthermore, it was found that 79% of COOMe was
replaced by COOCD3. IR (KBr): υmax 2922, 1720, 1628, 1567, 1502,
1437, 1283, 1109, 1022, 765, 748, 698 cm−1; HRMS (ESI) m/z calcd
6-Phenyl-8-(trifluoromethyl)-6H-pyrido[2,1-a]isoindol-5-ium
1
Bromide (2e). White solid (1.65 g, 84% yield). H NMR (400 MHz,
CDCl3) δ 9.03 (d, J = 5.9 Hz, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.66−
8.61 (m, 2H), 8.29 (s, 1H), 7.95−7.90 (m, 1H), 7.86 (d, J = 8.0 Hz,
1H), 7.65 (s, 1H), 7.45−7.34 (m, 5H); 13C{1H} NMR (100 MHz,
CDCl3) δ 150.9, 146.9, 143.7, 142.1, 135.2 (q, 2JC‑F = 32.8 Hz), 133.3,
4
132.9, 131.0, 130.1, 129.1, 127.4 (q, JC‑F = 3.4 Hz), 126.2,
1
3
125.1,123.0 (q, JC‑F = 270.3 Hz), 122.1, 121.4 (q, JC‑F = 3.6 Hz),
76.0; IR (KBr): υmax 3020, 2929, 1625, 1597, 1503, 1434, 1328, 1168,
1126, 754, 738, 701 cm−1; HRMS (ESI) m/z calcd for C19H13F3N+:
312.0995 [M+]; found: 312.0995.
+
for C20H16NO2 : 302.1176 [M+]; found: 302.1175.
6-(2-Methoxyphenyl)-6H-pyrido[2,1-a]isoindol-5-ium Chloride
(2l). White solid (1.41 g, 91% yield). 1H NMR (400 MHz,
CD3OD) δ 8.88 (d, J = 6.1 Hz, 1H), 8.77 (d, J = 8.1 Hz, 1H),
8.72−8.67 (m, 1H), 8.45−8.40 (m, 1H), 7.96−7.91 (m, 1H), 7.79−
7.73 (m, 2H), 7.58−7.48 (m, 2H), 7.11 (s, 2H), 4.87 (s, 1.52H);
13C{1H} NMR (100 MHz, CD3OD) δ 173.6, 157.7, 153.7, 146.0,
6-Cyclohexyl-6H-pyrido[2,1-a]isoindol-5-ium Chloride (2f).
White solid (1.25 g, 87% yield). Purified by column chromatography
(CH2Cl2/MeOH = 2/1). 1H NMR (400 MHz, CDCl3) δ 10.13 (d, J
= 4.7 Hz, 1H), 8.70 (d, J = 7.8 Hz, 1H), 8.64−8.58 (m, 1H), 8.31 (d,
J = 7.5 Hz, 1H), 8.01−7.94 (m, 1H), 7.75−7.62 (m, 3H), 6.86 (s,
10777
https://doi.org/10.1021/acs.joc.1c00958
J. Org. Chem. 2021, 86, 10773−10781

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
143.4, 140.6, 133.5, 132.3, 130.7, 129.7, 124.9, 123.2, 121.3, 120.3,
112.3, 55.1−54.8 (m). It is worth noting that an unexpected
hydrogen-deuterium exchange occurred in the presence of CD3OD;
the incorporation of 100% deuterium at the benzylic position was
observed. Furthermore, it was found that 100% of OMe was replaced
by OD3. IR (KBr): υmax 3014, 2937, 1629, 1600, 1496, 1461, 1290,
1256, 1163, 1019, 757, 736 cm−1; HRMS (ESI) m/z calcd for
C19H16NO+: 274.1226 [M+]; found: 274.1223.
12-Phenyl-12H-benzo[e]pyrido[2,1-a]isoindol-11-ium Chloride
(2m). White solid (1.57 g, 95% yield). 1H NMR (400 MHz,
CD3OD) δ 8.96 (s, 1H), 8.88−8.83 (m, 2H), 8.68−8.64 (m, 1H),
8.17−8.15 (m, 1H), 7.92−7.87 (m, 3H), 7.61−7.59 (m, 2H), 7.49−
7.44 (m, 3H), 7.38−7.34 (m, 3H); 13C{1H} NMR (100 MHz,
CD3OD) δ 153.0, 146.3, 141.1, 138.2, 135.7, 135.3, 133.4, 130.3,
129.7, 129.4, 129.2, 128.5, 128.3, 127.9, 127.7, 125.7, 124.7, 123.5,
121.3, 75.7; IR (KBr): υmax 3051, 3027, 1626, 1565, 1498, 1450, 1319,
1143, 894, 779, 747, 702 cm−1; HRMS (ESI) m/z calcd for
C22H16N+: 294.1277 [M+]; found: 294.1274.
1448, 1281, 1071, 929, 746, 699, 644. HRMS (ESI) m/z calcd for
C18H14N+: 244.1121 [M+]; found: 244.1117.
(6S,10bR)-6-Phenyl-1,2,3,4,6,10b-hexahydropyrido[2,1-a]-
isoindole (6a). White solid (45.8 mg, 92% yield, 84:16 er, >20:1 dr).
25
[α]D = +91.1 (c = 0.5, CHCl3). mp 39−40 °C. Purified by column
1
chromatography (PE/EA = 100/1). H NMR (400 MHz, CDCl3) δ
7.40 (d, J = 7.2 Hz, 2H), 7.36−7.33 (m, 2H), 7.30−7.27 (m, 1H),
7.21−7.18 (m, 2H), 7.12−7.08 (m, 1H), 6.77 (d, J = 7.4 Hz, 1H),
4.46 (d, J = 2.8 Hz, 1H), 3.41 (d, J = 10.8 Hz, 1H), 2.92 (d, J = 10.6
Hz, 1H), 2.40 (td, J = 10.8, 3.2 Hz, 1H), 2.31−2.25 (m, 1H), 1.97−
1.90 (m, 1H), 1.67−1.44 (m, 4H); 13C{1H} NMR (100 MHz,
CDCl3) δ 144.9, 143.6, 141.4, 128.8, 128.4, 127.5, 126.7, 126.6, 122.7,
120.1, 77.4, 77.1, 76.8, 72.1, 67.0, 49.0, 29.1, 26.1, 24.6; IR (KBr):
υmax 2931, 2851, 2773, 1450, 1282, 1141, 1049, 983, 861, 740, 699
cm−1; HRMS (EI) calcd for C18H19N: 249.1517 [M]+; found:
249.1515. HPLC (Chiralcel OD-H column, hexane/isopropanol =
100/0, flowing rate = 0.5 mL/min, λ = 254 nm) tR= 15.6 min
(minor), 17.4 min (major).
3-Methyl-6-phenyl-6H-pyrido[2,1-a]isoindol-5-ium Chloride
(2n). White solid (1.32 g, 90% yield). 1H NMR (400 MHz,
CDCl3) δ 8.92 (s, 1H), 8.60 (d, J = 7.7 Hz, 1H), 8.29−8.24 (m, 2H),
8.16 (d, J = 7.4 Hz, 1H), 7.59−7.53 (m, 2H), 7.43 (d, J = 7.1 Hz,
2H), 7.38−7.31 (m, 4H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 150.0, 146.6, 143.3, 141.4, 135.8, 134.4, 133.3, 130.5, 130.1,
130.0, 129.8, 129.3, 124.4, 123.5, 120.0, 75.6, 18.8; IR (KBr): υmax
3051, 2921, 1632, 1514, 1497, 1464, 1348, 1298, 925, 777, 745, 726
cm−1; HRMS (ESI) m/z calcd for C19H16N+: 258.1277 [M+]; found:
258.1273.
(6S,10bR)-8-Methyl-6-phenyl-1,2,3,4,6,10b-hexahydropyrido-
[2,1-a]isoindole (6b). White solid (50.3 mg, 95% yield, 80:20 er,
25
>20:1 dr). [α]D = +71.7 (c = 0.5, CHCl3). mp 59−60 °C. Purified
1
by column chromatography (PE/EA = 50/1). H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 7.0 Hz, 2H), 7.45−7.41 (m, 2H), 7.39−7.35
(m, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.66 (s,
1H), 4.51 (d, J = 2.5 Hz, 1H), 3.44 (d, J = 10.7 Hz, 1H), 2.98 (d, J =
10.6 Hz, 1H), 2.45 (td, J = 10.7, 3.6 Hz, 1H), 2.35−2.31 (m, 1H),
2.30 (s, 3H), 2.04−1.97 (m, 1H), 1.73−1.51 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3) δ 145.1, 141.6, 140.8, 136.4, 128.9, 128.4,
127.5,127.4, 123.5, 120.0, 77.5, 77.2, 76.8, 72.1, 66.9, 49.1, 29.3, 26.2,
24.7, 21.4; IR (KBr): υmax 2931, 2851, 2773, 1489, 1450, 1249, 1176,
1141, 1048, 781, 743, 699 cm−1; HRMS (EI) calcd for C19H21N:
263.1674 [M]+; found: 263.1668. HPLC (Chiralcel OD-H column,
hexane/isopropanol = 99.5/0.5, flowing rate = 0.5 mL/min, λ = 254
nm) tR = 7.4 min (minor), 8.1 min (major).
6-Phenyl-6H-pyrido[2,1-a]isoindol-5-ium Bromide (2a′). White
1
solid (1.48 g, 91% yield). H NMR (400 MHz, CD3COOD) δ 9.05
(d, J = 6.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.78−8.74 (m, 1H),
8.50−8.48 (m, 1H), 8.05−8.01 (m, 1H), 7.82−7.80 (m, 2H), 7.64−
7.62 (m, 1H), 7.60 (s, 1H), 7.55−7.51(m, 3H), 7.46−7.44 (m, 2H);
13C{1H} NMR (100 MHz, CD3COOD) δ 154.9, 148.5, 145.3, 143.3,
(6S,10bR)-8-Methoxy-6-phenyl-1,2,3,4,6,10b-hexahydropyrido-
136.1, 135.7, 132.2, 132.1, 132.0, 131.6, 130.5, 127.3, 126.0, 125.6,
122.9, 77.8; IR (KBr): υmax 3008, 2923, 1627, 1566, 1499, 1462, 1352,
1298, 1161, 768, 746, 700 cm−1; HRMS (ESI) m/z calcd for
C18H14N+: 244.1121 [M+]; found: 244.1124.
[2,1-a]isoindole (6c). White solid (52.7 mg, 94% yield, 82:18 er,
25
>20:1 dr). [α]D = +63.6 (c = 0.5, CHCl3). mp 68−70 °C. Purified
1
by column chromatography (PE/EA = 50/1). H NMR (400 MHz,
CDCl3) δ 7.46−7.41 (m, 2H), 7.40−7.36 (m, 2H), 7.34−7.30 (m,
1H), 7.11 (d, J = 8.1 Hz, 1H), 6.76 (dd, J = 8.1, 2.2 Hz, 1H), 6.37 (d,
J = 1.7 Hz, 1H), 4.46 (d, J = 2.7 Hz, 1H), 3.70 (s, 3H), 3.38 (d, J =
10.7 Hz, 1H), 2.92 (d, J = 10.5 Hz, 1H), 2.41 (td, J = 10.7, 3.5 Hz,
1H), 2.31−2.25 (m, 1H), 1.99−1.91 (m, 1H), 1.78−1.39 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 146.4, 141.3 136.1, 128.9,
128.5, 127.6, 120.8, 112.0, 109.1, 77.5, 77.2, 76.8, 72.3, 66.6, 55.6,
49.1, 29.4, 26.1, 24.6; IR (KBr): υmax 2932, 2848, 2774, 1613, 1488,
1451, 1277, 1179, 1141, 1032, 833, 743, 700 cm−1; HRMS (EI) calcd
for C19H21NO: 279.1623 [M]+; found: 279.1624. HPLC (Chiralcel
OD-H column, hexane/isopropanol = 99/1, flowing rate = 0.5 mL/
min, λ = 254 nm) tR = 8.2 min (minor), 9.0 min (major).
6-Phenyl-6H-pyrido[2,1-a]isoindol-5-ium Trifluoromethanesul-
fonate (3a). White solid (386.3 mg, 98% yield). 1H NMR (400
MHz, CD3CN) δ 8.68 (d, J = 6.1 Hz, 1H), 8.65−8.54 (m, 2H), 8.38−
8.26 (m, 1H), 7.92−7.81 (m, 1H), 7.78 8−7.67 (m, 2H), 7.56−7.36
(m, 4H), 7.25 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz,
CD3CN,) δ 153.5, 146.7, 143.3, 141.0, 134.04, 134.01, 130.5, 130.4,
130.3, 129.9, 128.6, 125.5, 124.2, 123.7, 121.1; 19F NMR (376 MHz,
CD3CN) δ −79.3. Hydrogen-deuterium exchange occurred in the
presence of CD3CN. IR (KBr): υmax 3070, 1630, 1501, 1263, 1224,
1155, 1030, 767, 752, 736, 700, 637. HRMS (ESI) m/z calcd for
C18H14N+: 244.1121 [M+]; found: 244.1123.
6-Phenyl-6H-Pyrido[2,1-a]Isoindol-5-Ium Hexafluorostibate
(4a). White solid (474.9 mg, 99% yield). 1H NMR (400 MHz,
Acetone-d6) δ 9.06−9.04 (m, 1H), 8.87−8.78 (m, 2H), 8.51−8.44
(m, 1H), 8.15−8.06 (m, 1H), 7.87−7.81 (m, 2H), 7.68−7.64 (m,
1H), 7.54−7.42 (m, 5H), 7.33 (s, 0.53H); 13C{1H} NMR (100 MHz,
Acetone-d6) δ 153.7, 150.7, 148.6, 146.8, 144.6, 143.7, 141.4, 139.8,
136.7, 134.6, 134.4, 134.1, 131.9, 130.5, 130.44, 130.39, 129.9, 129.5,
129.4, 128.7, 127.1, 125.8, 125.7, 124.7, 124.3, 124.2, 123.7, 121.3,
121.1, 103.7, 76.2. Hydrogen-deuterium exchange occurred in the
presence of Acetone-d6. IR (KBr): υmax 3100, 1629, 1503, 1463, 1351,
1252, 1223, 1071, 767, 752, 700, 660. HRMS (ESI) m/z calcd for
C18H14N+: 244.1121 [M+]; found: 244.1119.
(6S,10bR)-8-Fluoro-6-phenyl-1,2,3,4,6,10b-hexahydropyrido[2,1-
a]isoindole (6d). White solid (50.6 mg, 95% yield, 81:19 er, >20:1
25
dr). [α]D = +85.6 (c = 0.5, CHCl3). mp 58−60 °C. Purified by
column chromatography (PE/EA = 50/1). 1H NMR (400 MHz,
CDCl3) δ 7.42−7.31 (m, 5H), 7.14−7.10 (m, 1H), 6.92−6.87 (m,
1H), 6.50 (dd, J = 8.7, 1.7 Hz, 1H), 4.47 (d, J = 2.6 Hz, 1H), 3.39 (d,
J = 10.2 Hz, 1H), 2.92 (d, J = 10.6 Hz, 1H), 2.41 (td, J = 10.9, 3.3 Hz,
1H), 2.31−2.25 (m, 1H), 1.99−1.92 (m, 1H), 1.66−1.44 (m, 4H);
1
13C{1H} NMR (100 MHz, CDCl3) δ 160.4 (d, JC‑F = 243.1 Hz),
5
6
145.1 (d, JC‑F = 8.0 Hz), 138.8, 137.1 (d, JC‑F = 2.4 Hz), 126.8,
4
3
126.6, 125.9, 119.2 (d, JC‑F = 8.6 Hz), 111.4 (d, JC‑F = 22.5 Hz),
2
7
6-Phenyl-6H-pyrido[2,1-a]isoindol-5-ium Fluoride (5a). White
108.4 (d, JC‑F = 23.3 Hz), 70.1 (d, JC‑F = 2.4 Hz), 64.5, 47.0, 27.2,
24.0, 22.6; IR (KBr): υmax 2932, 2851, 2774, 1484, 1450, 1265, 1172,
869, 827, 783, 743, 699 cm−1; HRMS (ESI) m/z calcd for C18H18NF:
[M + H+]; 268.1496, found: 268.1494. HPLC (the connection of
Chiralcel OD-H column and Chiralcel OJ-H column, hexane/
isopropanol = 99/1, flowing rate = 0.25 mL/min, λ = 254 nm) tR =
30.2 min (major), 31.3 min (minor).
1
solid (258.3 mg, 98% yield). H NMR (400 MHz, CD3COOD) δ
8.80 (d, J = 5.0 Hz, 1H), 8.65−8.58 (m, 1H), 8.51 (d, J = 7.7 Hz,
1H), 8.25 (d, J = 6.6 Hz, 1H), 7.97−7.86 (m, 1H), 7.79−7.67 (m,
2H), 7.59 (d, J = 6.7 Hz, 1H), 7.51−7.35 (m, 6H); 13C{1H} NMR
(100 MHz, CD3COOD) δ 151.2, 147.4, 143.8, 140.3, 137.0, 133.7,
131.6, 130.6, 130.3, 129.2, 126.4, 126.0, 125.2, 124.8, 121.7.
Hydrogen-deuterium exchange occurred in the presence of
CD3COOD. IR (KBr): υmax 3057, 1664, 1626, 1586, 1501, 1460,
(6S,10bR)-6-Phenyl-8-(trifluoromethyl)-1,2,3,4,6,10b-hexahydro-
pyrido[2,1-a]isoindole (6e). White solid (44.6 mg, 70% yield, 81:19
10778
https://doi.org/10.1021/acs.joc.1c00958
J. Org. Chem. 2021, 86, 10773−10781

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
25
er, >20:1 dr). [α]D = +45.9 (c = 0.5, CHCl3). mp 84−85 °C.
1283, 1078, 1049, 865, 794, 740 cm−1; HRMS (EI) calcd for
C19H21N: 263.1674 [M]+; found: 263.1675. HPLC (Chiralcel OD-H
column, hexane/isopropanol = 99.8/0.2, flowing rate = 0.5 mL/min, λ
= 254 nm) tR = 8.4 min (minor), 9.5 min (major).
Purified by column chromatography (PE/EA = 50/1). 1H NMR (400
MHz, CDCl3) δ 7.51 (d, J = 7.7 Hz, 1H), 7.47−7.33 (m, 5H), 7.30
(d, J = 7.7 Hz, 1H), 7.04 (s, 1H), 4.52 (d, J = 2.6 Hz, 1H), 3.47 (d, J =
10.6 Hz, 1H), 2.96 (d, J = 10.7 Hz, 1H), 2.43 (td, J = 10.8, 2.9 Hz,
1H), 2.37−2.30 (m, 1H), 2.02−1.96 (m, 1H), 1.71−1.46 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ 147.5, 145.7, 140.3, 129.2 (q,
(6S,10bR)-6-(4-Methoxyphenyl)-1,2,3,4,6,10b-hexahydropyrido-
[2,1-a]isoindole (6j). White solid (51.7 mg, 93% yield, 81:19 er,
25
>20:1 dr). [α]D = +80.6 (c = 0.5, CHCl3). mp 63−65 °C. Purified
1
2JC‑F = 31.7 Hz), 128.7, 128.6, 127.9, 124.4 (q, JC‑F = 270.5 Hz),
1
by column chromatography (PE/EA = 50/1). H NMR (500 MHz,
124.1 (q, 3JC‑F = 3.8 Hz), 120.5, 119.6 (q, 4JC‑F = 3.7 Hz), 71.9, 66.7,
48.9, 28.9, 25.7, 24.4; IR (KBr): υmax 2934, 2853, 2779, 1451, 1432,
1332, 1263, 1155, 1123, 833, 746, 700, 666 cm−1; HRMS (EI) calcd
for C19H18F3N: 317.1391 [M]+; found: 317.1382. HPLC (Chiralcel
OD-H column, hexane/isopropanol = 99.8/0.2, flowing rate = 0.3
mL/min, λ = 254 nm), tR = 13.4 min (major), 14.9 min (minor).
(6S,10bR)-6-Cyclohexyl-1,2,3,4,6,10b-hexahydropyrido[2,1-a]-
isoindole (6f). White solid (42.0 mg, 82% yield, 81:19 er, >20:1 dr).
CDCl3) δ 7.34−7.26 (m, 2H), 7.23−7.15 (m, 2H), 7.14−7.06 (m,
1H), 6.90−6.87 (m, 2H), 6.77 (d, J = 7.5 Hz, 1H), 4.39 (d, J = 2.9
Hz, 1H), 3.80 (s, 3H), 3.37 (d, J = 10.9 Hz, 1H), 2.90 (d, J = 10.5 Hz,
1H), 2.36 (td, J = 11.0, 3.0 Hz, 1H), 2.29−2.25 (m, 1H), 1.95−1.90
(m, 1H), 1.73−1.37 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ
159.2, 145.2, 143.7, 133.6, 130.0, 126.7, 122.8, 120.2, 113.8, 77.4,
77.2, 76.9, 71.6, 67.0, 55.4, 49.0, 29.2, 26.2, 24.7; IR (KBr): υmax 2931,
2851, 2773, 1612, 1511, 1459, 1300, 1246, 1170, 1036, 804, 741
cm−1; HRMS (EI) calcd for C19H21NO: 279.1623 [M]+; found:
279.1624. HPLC (Chiralcel OD-H column, hexane/isopropanol =
99.5/0.5, flowing rate = 0.5 mL/min, λ = 254 nm), tR = 9.7 min
(minor), 10.4 min (major).
25
[α]D = +34.9 (c = 0.5, CHCl3). mp 46−48 °C. Purified by column
1
chromatography (PE/EA = 100/1). H NMR (400 MHz, CDCl3) δ
7.33−7.30 (m, 1H), 7.22−7.16 (m, 2H), 7.13−7.11 (m, 1H), 3.46 (s,
1H), 3.25−3.18 (m, 2H), 2.33 (td, J = 11.0, 3.1 Hz, 1H), 2.21−2.19
(m, 1H), 1.92−1.12 (m, 17H); 13C{1H} NMR (100 MHz, CDCl3) δ
144.3, 142.6, 126.2, 126.1, 122.7, 120.1, 71.5, 67.6, 50.3, 40.2, 30.2,
29.1, 29.0, 27.6, 27.1, 26.3, 24.7; IR (KBr): υmax 2927, 2850, 2769,
1448, 1376, 1278, 1189, 1136, 980, 894, 857, 736 cm−1; HRMS (ESI)
m/z calcd for C18H25N: [M + H+]; 256.2060, found: 256.2056.
HPLC (Chiralcel OD-H column, hexane/isopropanol = 99.9/0.1,
flowing rate = 0.5 mL/min, λ = 254 nm), tR = 8.9 min (minor), 10.5
min (major).
Methyl 4-((6S,10bR)-1,2,3,4,6,10b-Hexahydropyrido[2,1-a]-
isoindol-6-yl)benzoate (6k). White solid (53.1 mg, 86% yield,
25
84:16 er, >20:1 dr). [α]D = +97.7 (c = 0.5, CHCl3). mp 81−83
1
°C. Purified by column chromatography (PE/EA = 30/1). H NMR
(400 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz,
2H), 7.26−7.20 (m, 2H), 7.13−7.10 (m, 1H), 6.74 (d, J = 7.4 Hz,
1H), 4.56 (d, J = 2.8 Hz, 1H), 3.93 (s, 3H), 3.47 (d, J = 10.8 Hz, 1H),
2.89 (d, J = 10.5 Hz, 1H), 2.43 (td, J = 10.7, 3.3 Hz, 1H), 2.35−2.28
(m, 1H), 1.99−1.94 (m, 1H), 1.70−1.40 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3) δ 167.2, 147.0, 144.1, 143.5, 129.7, 129.5, 128.7,
126.9, 126.7, 122.5, 120.3, 71.7, 67.0, 52.0, 49.0, 29.1, 26.0, 24.5; IR
(KBr): υmax 2934, 2848, 2770, 1723, 1607, 1435, 1277, 1112, 1019,
878, 816, 763, 741, 705 cm−1; HRMS (EI) calcd for C20H21NO2:
307.1572 [M]+; found: 307.1568. HPLC (Chiralcel OD-H column,
hexane/isopropanol = 99/1, flowing rate = 0.5 mL/min, λ = 254 nm)
tR = 11.2 min (minor), 12.6 min (major).
(6S,10bR)-6-(4-Chlorophenyl)-1,2,3,4,6,10b-hexahydropyrido-
[2,1-a]isoindole (6g). White solid (48.0 mg, 85% yield, 86:14 er,
25
>20:1 dr). [α]D = +98.4 (c = 0.5, CHCl3). mp 52−54 °C. Purified
1
by column chromatography (PE/EA = 50/1). H NMR (400 MHz,
CDCl3) δ 7.35−7.30 (m, 4H), 7.23−7.17 (m, 2H), 7.12−7.09 (m,
1H), 6.73 (d, J = 7.4 Hz, 1H), 4.44 (d, J = 2.6 Hz, 1H), 3.41 (d, J =
10.7 Hz, 1H), 2.86 (d, J = 10.7 Hz, 1H), 2.39 (td, J = 10.9, 2.7 Hz,
1H), 2.31−2.25 (m, 1H), 1.97−1.90 (m, 1H), 1.71−1.40 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ 144.4, 143.5, 140.1, 133.1,
130.1, 128.5, 126.8, 126.7, 122.6, 120.2, 71.3, 66.9, 48.9, 29.1, 26.0,
24.5; IR (KBr): υmax 2933, 2851, 2777, 1489, 1458, 1377, 1281, 1141,
1086, 1014, 870, 827, 801, 742 cm−1; HRMS (EI) calcd for
C18H18ClN: 283.1128 [M]+; found: 283.1122. HPLC (Chiralcel OD-
H column, hexane/isopropanol = 99.8/0.2, flowing rate = 0.6 mL/
min, λ = 254 nm) tR = 9.7 min (minor), 10.2 min (major).
(6R,10bR)-6-(2-Methoxyphenyl)-1,2,3,4,6,10b-hexahydropyrido-
[2,1-a]isoindole (6l). Colorless oil (51.9 mg, 93% yield, 72:28 er,
19
>20:1 dr). [α]D = +111.4 (c = 0.5, CHCl3). Purified by column
1
chromatography (PE/EA = 50/1). H NMR (400 MHz, CDCl3) δ
7.48 (d, J = 7.5 Hz, 1H), 7.27−7.22 (m, 1H), 7.19−7.13 (m, 2H),
7.11−7.05 (m, 1H), 6.98−6.92 (m, 2H), 6.86 (d, J = 7.4 Hz, 1H),
5.03 (d, J = 2.5 Hz, 1H), 3.89 (s, 3H), 3.44 (d, J = 10.9 Hz, 1H), 2.96
(d, J = 10.8 Hz, 1H), 2.42−2.34 (m, 1H), 2.32−2.26 (m, 1H), 1.98−
1.92 (m, 1H), 1.69−1.58 (m, 3H), 1.54−1.41 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 158.0, 144.5, 143.5, 129.8, 128.5, 127.9,
126.6, 126.4, 122.8, 121.0, 120.1, 110.2, 67.1, 64.4, 55.5, 49.3, 29.1,
26.1, 24.7; IR (neat): υmax 2933, 2778, 1597, 1585, 1488, 1460, 1438,
1283, 1241, 1048, 754, 741 cm−1; HRMS (ESI) m/z calcd for
C19H21NO: [M + H+]; 280.1696, found: 280.1695. HPLC (Chiralcel
OJ-H column, hexane/isopropanol = 100/0, flowing rate = 0.2 mL/
min, λ = 254 nm) tR = 31.8 min (minor), 34.9 min (major).
(6bR,12S)-12-Phenyl-6b,7,8,9,10,12-hexahydrobenzo[e]pyrido-
[2,1-a]isoindole (6m). White solid (55.1 mg, 92% yield, 82:18 er,
19:1 dr). [α]D19 = +55.2 (c = 0.5, CHCl3). mp 94−96 °C. Purified by
column chromatography (PE/EA = 50/1). 1H NMR (400 MHz,
CDCl3) δ 7.86 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 (s,
1H), 7.52−7.48 (m, 2H), 7.47−7.34 (m, 5H), 7.21 (s, 1H), 4.58 (s,
1H), 3.57−3.52 (m, 1H), 3.05−3.00 (m, 1H), 2.50−2.42 (m, 2H),
2.07−2.00 (m, 1H), 1.82−1.52 (m, 4H), 1.04−0.89 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 144.00, 142.49, 141.31, 133.10,
(6S,10bR)-6-(4-Bromophenyl)-1,2,3,4,6,10b-hexahydropyrido-
[2,1-a]isoindole (6h). White solid (59.2 mg, 90% yield, 85:15 er,
19
>20:1 dr). [α]D = +113.9 (c = 0.5, CHCl3). mp 100−101 °C.
Purified by column chromatography (PE/EA = 50/1). 1H NMR (400
MHz, CDCl3) δ 7.48−7.45 (m, 2H), 7.29−7.26 (m, 2H), 7.22−7.17
(m, 2H), 7.12−7.08 (m, 1H), 6.73 (d, J = 7.4 Hz, 1H), 4.43 (d, J =
3.1 Hz, 1H), 3.41 (d, J = 10.8 Hz, 1H), 2.85 (d, J = 10.8 Hz, 1H),
2.37 (td, J = 10.9, 3.1 Hz, 1H), 2.30−2.25 (m, 1H), 1.97−1.90 (m,
1H), 1.66−1.41 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ
144.31, 143.46, 140.66, 131.50, 130.48, 126.86, 126.71, 122.57,
121.30, 120.23, 71.41, 66.91, 48.87, 29.11, 26.04, 24.52; IR (KBr):
υmax 2932, 2770, 1617, 1486, 1454, 1372, 1278, 1076, 1010, 865, 796,
741 cm−1; HRMS (ESI) m/z calcd for C18H18BrN: [M + H+];
328.0695, 330.0675, found: 328.0698, 330.0673. HPLC (Chiralcel
OD-H column, hexane/isopropanol = 99.9/0.1, flowing rate = 0.6
mL/min, λ = 254 nm) tR = 12.4 min (minor), 14.2 min (major).
(6S,10bR)-6-(p-Tolyl)-1,2,3,4,6,10b-hexahydropyrido[2,1-a]-
isoindole (6i). White solid (50.1 mg, 95% yield, 81:19 er, >20:1 dr).
25
[α]D = +90 (c = 0.5, CHCl3). mp 52−54 °C. Purified by column
133.06, 128.97, 128.46, 128.05, 127.82, 127.63, 125.42, 125.19,
121.17, 118.26, 72.04, 66.70, 49.61, 29.18, 26.01, 24.62; IR (KBr):
υmax 2932, 2774, 1601, 1495, 1450, 1380, 1241, 1064, 833, 804, 743,
700 cm−1; HRMS (ESI) m/z calcd for C22H21N: [M + H+]; 300.1747,
found: 300.1752. HPLC (Chiralcel OD-H column, hexane/
isopropanol = 99.5/0.5, flowing rate = 0.4 mL/min, λ = 254 nm) tR
= 11.9 min (major), 12.9 min (minor).
1
chromatography (PE/EA = 50/1). H NMR (400 MHz, CDCl3) δ
7.27 (d, J = 8.0 Hz, 2H), 7.21−7.14 (m, 4H), 7.12−7.07 (m, 1H),
6.77 (d, J = 7.4 Hz, 1H), 4.42 (d, J = 2.9 Hz, 1H), 3.38 (d, J = 10.8
Hz, 1H), 2.91 (d, J = 10.6 Hz, 1H), 2.36 (td, J = 10.8, 3.2 Hz, 1H),
2.35 (s, 3H), 2.30−2.24 (m, 1H), 1.95−1.90 (m, 1H), 1.68−1.40 (m,
4H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.1, 143.6, 138.4, 137.0,
129.1, 128.8, 126.6, 126.6, 122.7, 120.1, 71.9, 67.0, 49.0, 29.1, 26.1,
24.6, 21.2; IR (KBr): υmax 2931, 2851, 2777, 1604, 1458, 1376, 1301,
(3R,6S,10bR)-3-Methyl-6-phenyl-1,2,3,4,6,10b-hexahydropyrido-
[2,1-a]isoindole (6n). White solid (50.0 mg, 95% yield, 61:39 er, 1.7:1
10779
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J. Org. Chem. 2021, 86, 10773−10781

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Note
19
dr). [α]D = +53.1 (c = 0.5, CHCl3). mp 52−54 °C. Purified by
Fundamental Research Funds for the Central Universities (No.
DUT20LK42) for their financial support. This work was also
supported by the LiaoNing Revitalization Talents Program
(XLYC1802030) and the Natural Science Foundation of
Liaoning, China (No. 2019JH3/30100001).
column chromatography (PE/EA = 50/1). 1H NMR (400 MHz,
CDCl3) δ 7.48−7.33 (m, 6H), 7.28−7.21 (m, 2H), 7.17−7.11 (m,
1H), 6.81 (d, J = 7.5 Hz, 1H), 4.50 (d, J = 2.2 Hz, 1H), 3.42 (d, J =
10.9 Hz, 1H), 2.94 (dd, J = 10.5, 3.9 Hz, 1H), 2.34 (d, J = 12.1 Hz,
1H), 2.09 (t, J = 10.5 Hz, 1H), 1.98 (d, J = 12.6 Hz, 1H), 1.86−1.65
(m, 2H), 0.90 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 145.1, 143.3, 141.4, 128.8, 128.4, 127.5, 126.6, 126.6, 122.7,
120.2, 71.8, 66.7, 56.4, 33.6, 31.7, 28.8, 19.5; IR (KBr): υmax 2926,
2765, 1597, 1478, 1454, 1380, 1352, 1249, 1070, 1020, 740, 699
cm−1; HRMS (ESI) m/z calcd for C19H21N: [M + H+]; 264.1747,
found: 264.1741. HPLC (Chiralcel OD-H column, hexane/
isopropanol = 99.9/0.1, flowing rate = 0.5 mL/min, λ = 254 nm) tR
= 12.6 min (minor), 15.0 min (major).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00958.
■
sı
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Complementary experimental details; X-ray crystallog-
raphy data of compound 6j·HCl; copies of NMR spectra
and HPLC spectra for racemic and chiral compounds
(PDF)
Accession Codes
CCDC 2049311 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 Authors
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Zhang, X., Eds.; Springer, 2014; pp 145−190.
■
Sheng Zhang − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China;
orcid.org/0000-0002-9671-7668; Email: shengzhang@
dlut.edu.cn
Ming Bao − State Key Laboratory of Fine Chemicals, Dalian
University of Technology, Dalian 116023, China;
orcid.org/0000-0002-5179-3499; Email: mingbao@
dlut.edu.cn
́
̃
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Authors
Wenkuan Li − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China
Xiaoqiang Yu − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China;
orcid.org/0000-0001-9396-3882
Xiujuan Feng − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China
Yoshinori Yamamoto − State Key Laboratory of Fine
Chemicals, Dalian University of Technology, Dalian 116023,
China; Research Organization of Science and Technology,
Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
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Complete contact information is available at:
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful to the National Natural Science
Foundation of China (No. 21573032 and 21602026) and the
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J. Org. Chem. 2021, 86, 10773−10781

The Journal of Organic Chemistry
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