Highly regio-, diastereo- and enantioselective one-pot gold/chiral Bronsted acid-catalysed cascade synthesis of bioactive diversely substituted tetrahydroquinolines

Article abstract of DOI:10.1039/c2ob25753j

One-pot sequential asymmetric reactions of aminobenzaldehydes or aminophenones with alkynes catalysed by a gold(i)/Bronsted acid cooperative system are reported. This process provides a highly efficient method for the synthesis of optically active tetrahydroquinolines, with one or two chiral centres at different positions as well as highly divergent functional groups, in good to excellent yields and with high regio-, diastereo- and enantioselectivities. A preliminary study on the effect of stereochemistry on biological activity suggests a potential application of these optically active tetrahydroquinolines in drug discovery processes.

Full text of DOI:10.1039/c2ob25753j

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Biomolecular
Chemistry
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Volume 10 | Number 35 | 21 September 2012 | Pages 7017–7228
ISSN 1477-0520
PAPER
Chi-Ming Che et al.
Highly regio-, diastereo- and enantioselective one-pot gold/chiral
Brønsted acid-catalysed cascade synthesis of bioactive diversely
substituted tetrahydroquinolines
1477-0520(2012)10:35;1-9

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PAPER
Highly regio-, diastereo- and enantioselective one-pot gold/chiral Brønsted
acid-catalysed cascade synthesis of bioactive diversely substituted
tetrahydroquinolines†
Xin-Yuan Liu, Ya-Ping Xiao, Fung-Ming Siu, Li-Chen Ni, Yong Chen, Lin Wang and Chi-Ming Che*
Received 19th April 2012, Accepted 11th June 2012
DOI: 10.1039/c2ob25753j
One-pot sequential asymmetric reactions of aminobenzaldehydes or aminophenones with alkynes
catalysed by a gold(I)/Brønsted acid cooperative system are reported. This process provides a highly
efficient method for the synthesis of optically active tetrahydroquinolines, with one or two chiral centres
at different positions as well as highly divergent functional groups, in good to excellent yields and with
high regio-, diastereo- and enantioselectivities. A preliminary study on the effect of stereochemistry on
biological activity suggests a potential application of these optically active tetrahydroquinolines in drug
discovery processes.
Introduction
Chiral tetrahydroquinolines with multiple chiral centres and
functional substituents are ubiquitous structural motifs in numer-
ous naturally occurring alkaloids and biologically active pharma-
ceuticals.1 For example (Fig. 1), (S)-flumequine exhibits potent
antibacterial activity and is used for treating bacterial infec-
tions.1e Martinella alkaloids, containing multiple-chiral tetra-
Fig. 1 Examples of biologically active chiral tetrahydroquinoline
derivatives.
hydroquinoline scaffold, are bradykinin receptor antagonists.1b
Dynemicin A (a member of the enediyne family of antibiotics),
isolated from a fermentation broth of Micromonospora chersina,
has anticancer activity in a number of cancer cell lines.1d The
to “hard-to-remove” aliphatic or aryl groups lacking function-
ality. 2,3-Disubstituted quinolines with reducible groups, such as
carbonyls, remain challenging substrates for such asymmetric
reduction, although these functional molecules are valuable
building blocks for further synthetic transformations. To the best
of our knowledge, there are no reports describing asymmetric
reduction of 2,4-disubstituted quinolines with high diastereo-
and enantioselectivities. On the other hand, a general limitation
for the existing asymmetric quinoline reduction systems with
transition metal catalysts3 or organocatalysts4 is the requirement
of prior preparation of starting quinolines by tedious chemical
resolution.5 The overall atom economy of such reduction
systems could be increased through cascade processes.6 There-
fore, the development of new cascade reactions employing
simple and readily available starting materials for construction of
chiral diversely substituted tetrahydroquinolines through simul-
taneous formation of two chiral centres at different positions
with readily transformable functional groups and with high
diastereo- and enantioselectivity would be highly desirable.
Cooperative catalysis combining transition metal catalysis and
organocatalysis can lead to new strategies to use readily available
precursors for rapid synthesis of organic compounds with
significant biological activities of these enantiomerically pure
backbones have led to a demand for efficient protocols for their
synthesis.2
The asymmetric reductions of quinolines using transition
metal catalysts3 or organocatalysts4 are powerful methods widely
used to synthesize chiral tetrahydroquinolines. Most of these
methods are mainly applied to 2- or 3-substituted quinolines,
thus giving products with only one chiral centre.3,4 Enantio-
enriched tetrahydroquinolines bearing two chiral centres could
be synthesized diastereoselectively either by asymmetric hydro-
genation or transfer hydrogenation of 2,3-disubstituted quinoli-
nes,3h–j,4f,g but the 2,3-substituents in these products are limited
Department of Chemistry, State Key Laboratory of Synthetic Chemistry,
and Open Laboratory of Chemical Biology of the Institute of Molecular
Technology for Drug Discovery and Synthesis, The University of Hong
Kong, Pokfulam Road, Hong Kong, P.R. China. E-mail: cmche@hku.hk;
Fax: (+852)2857-1586
†Electronic supplementary information (ESI) available: Tables S1 and
S2, Chart S1, and 1H NMR, 13C NMR and HPLC spectra. CCDC
812057 (3Dm) and 812056 (3Nb). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob25753j
7208 | Org. Biomol. Chem., 2012, 10, 7208–7219
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Scheme 1 Regio-, diastereo- and enantioselective one-pot reactions
catalysed by a cooperative catalytic system composed of a gold(I)
complex and chiral Brønsted acid.
complexity.7,8 The cooperation of homogeneous gold catalysts9
with organocatalysts has been shown to be an efficient approach
for a variety of organic transformations.10,11,12d During our
studies on gold-catalysed cascade reactions,12 we recently
reported a method for preparing highly substituted quinolines
from 2-aminophenones and alkynes.12a We envisioned that a
one-pot reaction could be established by starting with a gold-
catalysed cascade reaction of 2-aminobenzaldehyde or 2-amino-
phenone with alkyne, to furnish a quinoline intermediate, which
should undergo asymmetric transfer hydrogenation with a
Hantzsch ester (HEH) catalysed by chiral Brønsted acid13 to give
optically active tetrahydroquinoline 3 (Scheme 1). This one-pot
reaction could be a useful method for synthesizing chiral tetrahy-
droquinolines. In addition, employing various 2-aminobenzalde-
hydes, 2-aminophenones or terminal/internal alkynes bearing
diverse functional groups would allow the desired chiral pro-
ducts to undergo further synthetically useful transformations.
Herein, we describe the results on such one-pot asymmetric reac-
tions catalysed by a gold(I)/Brønsted acid cooperative system.
Using this system, a series of enantio-enriched tetrahydroquino-
lines with one or two chiral centres and functional groups were
prepared in up to 98% yields and with excellent regio-, diastereo-
and enantioselectivities from simple starting materials. After
we completed this work and during our preparation of this
manuscript, Gong and co-workers reported related asymmetric
synthesis of tetrahydroquinolines through reaction of 2-amino-
benzaldehydes or 2-aminophenyl ketones with β-keto esters and
Hantzsch esters catalysed by Mg(OTf)2 and chiral phosphoric
acids.14
Fig. 2 Binol-based chiral phosphoric acids or phosphoramide 5a–5e.
Table 1 Investigating the scope of alkynes and aminobenzaldehydes
in asymmetric one-pot reactionabc
a Reaction conditions: aminobenzaldehyde (0.4 mmol), alkyne
(0.48 mmol), ethyl Hantzsch ester (1.0 mmol), (tBu)2(o-diphenyl)PAu-
(CH3CN)SbF6 (2 mol%), 5a (3 mol%), benzene (6 mL), 5 Å MS (1 g),
60 °C. b Isolated yield based on aminobenzaldehyde. c Determined by
chiral HPLC analysis.
Results and discussion
After optimizing the reaction conditions, we investigated the
scope of the reaction using different types of terminal alkynes
and aminobenzaldehydes (Table 1). Regardless of the position
and nature of the substituent, various alkynes reacted efficiently
with 1A to afford the desired products in high yields with
excellent ee values. Aryl alkynes possessing electron-donating
ortho, meta, or para substituents were smoothly transformed
into 3Aa–3Af in 73–94% yields and with ee values of 90 to
>99%. Substrates bearing electron-withdrawing para substituents
were converted to 3Ag–3Ai with up to >99% ee, albeit in yields
(67–78%) lower than those for the substrates bearing electron-
donating substituents. When 2-ethynyl-6-methoxynaphthalene
(2j) was treated with 1A, product 3Aj was obtained in >99% ee
with 97% yield. We then evaluated the scope of the reaction with
a wide range of aminobenzaldehydes. The 2-aminobenzalde-
hydes possessing electron-withdrawing substituents at 4-, 5- or
6-positions were transformed into 3Bb–3Gb in 74–97% yields
with 97 to >99% ee. Notably, functional groups including ester
and cyano groups could be well-tolerated under the reaction
Highly enantioselective synthesis of 2-substituted chiral
tetrahydroquinolines
To validate the feasibility of the proposed one-pot sequential
process, we began with the reaction of 2-amino-5-chlorobenzal-
dehyde (1A) with phenylacetylene (2a) in benzene at 60 °C in
the presence of 3 mol% of (tBu)2(o-diphenyl)PAu(CH3CN)SbF6
15
for the first step. After completion of this reaction (6 h),
10 mol% of Brønsted acid 5a (Fig. 2) and 2.5 equivalents of
Hantzsch ester 4 were added to the reaction mixture. To our
delight, the desired product 3Aa was obtained in 87% yield with
90% ee after 20 h; upon varying counteranions (for (tBu)2-
(o-diphenyl)PAu+), catalyst loadings, solvent and additives, we
identified the following conditions as optimal: 2 mol% of
(tBu)2(o-diphenyl)PAu(CH3CN)SbF6 and 3 mol% of 5a in the
presence of 5 Å MS with benzene as solvent at 60 °C, and
product 3Aa was obtained in 90% yield and 97% ee (see
Table S1 in the ESI† and Table 1).
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conditions. Reactions of aminobenzaldehydes having electron-
neutral and -rich substituents on the aryl rings also worked well,
furnishing 3Hb–3Kb in 71–78% yields and with 96 to >99% ee.
high diastereo- and enantioselectivity (Table 3, entry 2). It is
noteworthy that when the substituent R2 on the internal alkynes
was changed from ester to ketone, both the diastereo- and
enantioselectivity were significantly improved. For example, 2m
or 2n bearing methyl or phenoxymethylene substitution at the
α position of carbonyl group resulted in product yields of
80–96% with enantioselectivities of 93–94% ee and diastereo-
selectivities of d.r. > 20 : 1 (Table 3, entries 3 and 4). The reac-
tion also worked well for substrate 2o bearing phenyl substituent
at the α position of carbonyl group, affording 3Ao in 93% yield
Highly regio-, diastereo- and enantioselective formation of
2,3-disubstituted chiral tetrahydroquinolines
To assess the regio-, diastereo- and enantiocontrol, we extended
the substrates to include internal alkynes 2k. Treatment of
methyl 3-phenylpropiolate (2k) with 1A gave 2,3-disubstituted
tetrahydroquinoline 3Ak in 91% yield with almost complete
regioselectivity, albeit with low diastereoselectivity (2 : 1) and
moderate enantioselectivity (58% ee) (Table 2, entry 1).
Additional binol-based chiral phosphoric acids or phosphora-
mide 5b–5d (Fig. 2) were screened for this one-pot reaction of
2k with 1A, and the phosphoric acid 5c was the best catalyst,
giving 3Ak in 80% yield with good diastereo- and enantio-
selectivity (10 : 1 d.r.; 77% ee) (Table 2, entry 3). A control
experiment revealed that (tBu)2(o-diphenyl)PAu(CH3CN)SbF6
can catalyse non-enantioselective transfer hydrogenation of the
corresponding quinoline intermediate with Hantzsch ester 4 to
give 3Ak in 87% yield. To minimize this non-enantioselective
background reaction catalysed by the gold(I) complex, we
explored alternative reaction conditions that employed 4 mol%
of triethylamine16 to help deactivate gold(I) catalyst after com-
pletion of the first step reaction, which, to our delight, enhanced
the enantioselectivity from 77 to 87% ee (Table 2, entry 5),
suggesting that the non-enantioselective background reaction
could be well suppressed by adding appropriate amount of
triethylamine.
Table 3 Scope of internal alkynes and 2-aminobenzaldehydes in
asymmetric one-pot reaction catalysed by the gold(I)/chiral Brønsted
acid cooperative systema
We next set out to explore the scope of this new protocol for
the synthesis of 2,3-disubstituted chiral tetrahydroquinolines
(Table 3). Changing the substituent of the ester in 2k from a
methyl to an ethyl group did not have an appreciable effect on
the enantioselectivity, and 3Al was obtained in 95% yield with
Table 2 Optimization of reaction conditions for regio-, diastereo- and
enantioselective synthesis of 2,3-disubstituted tetrahydroquinolinea
Entry
Phosphoric acid
Yieldb (%)
d.r.c
eed (%)
1
2
3
(R)-5a
(R)-5b
(S)-5c
(S)-5d
(S)-5c
(S)-5c
91
73
80
93
87
2 : 1
58
39
77
71
87
—
1 : 1.1
10 : 1
11 : 1
10 : 1
—
4
5e
6f
g
—
a Reaction conditions: 2-amino-5-chlorobenzaldehyde (0.2 mmol),
methyl phenylpropiolate (0.24 mmol), ethyl Hantzsch ester (0.5 mmol),
(tBu)2(o-diphenyl)PAu(CH3CN)SbF6 (3 mol%), 5 (5 mol%), benzene
a Reaction conditions: 2-aminobenzaldehyde (0.4 mmol), internal alkyne
(0.48 mmol), ethyl Hantzsch ester (1.0 mmol), (tBu)2(o-diphenyl)PAu-
(CH3CN)SbF6 (3 mol%), Et3N (4 mol%), 5c (5 mol%), benzene (6 mL),
(4 mL),
5
Å
MS (0.5 g). b Isolated yield based on 2-amino-
5
Å
MS (1.0 g) at 60 °C. b Isolated yield based on
5-chlorobenzaldehyde. c Diastereomeric ratio determined by 1H NMR
2-aminobenzaldehyde. c Diastereomeric ratio determined by 1H NMR
spectroscopy; major isomer shown. d Determined by chiral HPLC
spectroscopy. d Determined by chiral HPLC analysis. e 4 mol% of Et3N
was added after first step. 15 mol% of Et3N was added after first step.
f
e
analysis. (tBu)2(o-diphenyl)PAu(CH3CN)SbF6 (5 mol%), Et3N (6 mol
g Product was not detected.
%) and 5c (7 mol%) were required.
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Table 4 Scope of 2-aminophenones and alkynes in asymmetric one-
pot reaction catalysed by gold(I)/chiral Brønsted acid cooperative
systema
Fig. 3 Molecular structure of 3Dm with 30% thermal ellipsoid
probability.
with 82% ee (d.r. = 5 : 1, Table 3, entry 5). A range of functiona-
lized 2-aminobenzaldehydes, including those with electron-with-
drawing groups (Table 3, entries 3 and 6) and electron-donating
groups (Table 3, entry 7), were found to react with 2m to give
the corresponding products (3Am, 3Dm and 3Km) selectively
with 93–97% ee (d.r. > 20 : 1). Investigations into the effect of
substitution on the phenyl ring of the internal alkynes revealed
that the reaction is highly efficient for both electron-rich and
-deficient groups at the para position, furnishing 3Ap–3As and
3Dq in 72–84% yields (d.r. > 20 : 1) and with 89–97% ee
(Table 3, entries 8–12). The absolute configuration of 3Dm was
determined as (2R,3S) by X-ray crystallographic analysis
(Fig. 3),17 and those of other 2,3-disubstituted tetrahydro-
quinolines were surmised by analogy.
Highly diastereo- and enantioselective formation of 2,4-
disubstituted chiral tetrahydroquinolines
2,4-Disubstituted tetrahydroquinolines could be synthesized
from one-pot sequential reactions of 2-aminophenones with
alkynes using the gold(I)/Brønsted acid cooperative catalytic
system. We screened a series of chiral phosphoric acids for the
reaction of 2-aminobenzophenone (1L) with 4-ethynylbiphenyl
(2f) under the optimal conditions (see the ESI, Table S2†). The
corresponding product 3Lf was formed in 73% yield with 86%
ee and with a diastereomeric ratio of 20 : 1 by using (R)-VAPOL
hydrogenphosphate (5e) as a catalyst (Table 4, entry 5).
a Reaction conditions: 2-aminophenone (0.4 mmol), alkyne
(0.48 mmol), ethyl Hantzsch ester (1.0 mmol), (tBu)2(o-diphenyl)PAu-
(CH3CN)SbF6 (3 mol%), 5e (5 mol%), benzene (6 mL), 5 Å MS
(1.0 g). b Isolated yield based on 2-aminophenones. c Diastereomeric
ratio determined by 1H NMR spectroscopy; major isomer shown.
d Determined by chiral HPLC analysis.
We then extended the reaction to various 2-aminophenones
and alkynes. For substituted 2-aminobenzophenones 1M and
1N, their reaction with 4-methoxy-phenylacetylene (2b) gave
3Mb and 3Nb, respectively, also in high enantioselectivities
(88–94% ee) and diastereoselectivities (d.r. > 20 : 1, Table 4,
entries 2 and 3). Substrate 1O with a methyl group at the α pos-
ition of the ketone unit was converted to 3Ob in 94% yield and
85% ee with d.r. > 20 : 1 (Table 4, entry 4). Similar d.r. values of
>20 : 1 and higher enantioselectivities of 88–94% ee were
obtained for the desired products (79–93% yields) in the reac-
tions of 1M with terminal alkynes 2a, 2b, 2f and 2u bearing
electron-rich or -neutral or -deficient aryl groups (Table 4, entries
2, and 6–8). The absolute configuration of 3Nb is (2R,4S), as
determined by X-ray crystallographic analysis (Fig. 4);17 those
of other 2,4-disubstituted tetrahydroquinolines were determined
in reference to 3Nb. These results underscore the synthetic
utility of the present protocol for the synthesis of 2,4-disubsti-
tuted tetrahydroquinolines with high diastereo- and enantio-
selectivities from readily available precursors.
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species could demonstrate different activity towards the
purinergic (P2Y1) receptor.
Conclusions
A gold(I)/chiral Brønsted acid cooperative catalytic system for
efficient one-pot asymmetric synthesis of tetrahydroquinolines
from reaction of 2-aminobenzaldehydes or 2-aminophenones
with alkynes has been developed. This system not only results in
the synthesis of 2-substituted tetrahydroquinolines with excellent
enantioselectivity, but also allows access to 2,3- or 2,4-disubsti-
tuted functionalized tetrahydroquinolines through simultaneous
formation of two chiral centres, with high regio-, diastereo- and
enantioselectivities. The present work highlights a highly
efficient and sustainable process in which optically active tetra-
hydroquinolines with one or two chiral centres at different
positions as well as highly divergent functional groups can be
formed from simple starting materials via independent tunability
of catalyst components. A preliminary study on the effect of
stereochemistry on biological activity suggests a potential appli-
cation of this class of optically active tetrahydroquinolines in
drug discovery processes. Further studies are under way to
expand the substrate scope and to probe the origin of stereocon-
trol in the tetrahydroquinoline formation reactions catalysed by
the gold(I)/chiral Brønsted acid cooperative system.
Fig. 4 Molecular structure of 3Nb with 30% thermal ellipsoid
probability.
Table 5 Chemical similarity between 3Lb with chemical modulators
of known targets
Rank
Targets
1
2
3
4
5
6
7
8
9
Tubulin chains, alpha-1
Norepinephrine transporter
Tubulin chains, beta-1
Dopamine transporter
Serotonin transporter
Histamine H1 receptor
Acetylcholine receptor protein alpha chain
Neurokinin 1 receptor
Purinergic receptor (P2Y1)
Experimental
Biological activity of chiral tetrahydroquinolines
General
The synthesis of a library of optically active tetrahydroquinolines
with one or two chiral centres at different positions by the proto-
col reported herein may provide an abundant resource for drug
discovery research. As many of the biological targets in the cells
are chiral,18 the effect of stereochemistry on biological activity is
of importance for medicinal application. Therefore, we were
interested in studying the stereochemistry-biological activity
relationships involving the chiral tetrahydroquinolines obtained
in this work because of the diverse biological activities of such
compounds.
All manipulations with air-sensitive reagents were carried out
under a dry nitrogen atmosphere. Solvents were dried using stan-
dard methods and distilled before use. Starting materials and
reagents were purchased from commercial sources and used
without further purification. Sieves (5 Å powdered) were acti-
vated by flame under vacuum and stored at 180 °C. Unless other-
wise noted, all reactions were prepared in flame or oven-dried
glassware in a nitrogen-filled Vacuum Atmospheres inert atmos-
phere box and performed in sealed vessels. Analytical thin layer
chromatography (TLC) was performed on precoated silica gel 60
F254 plates. Visualization on TLC was achieved by use of UV
light (254 nm) or iodine. NMR spectra were recorded on Bruker
With the use of chemical similarity search,19 chiral tetrahydro-
quinoline 3Lb was evaluated for a potential biological activity.
As shown in Table 5, the chemical similarity between 3Lb and
the modulators of the known pharmaceutical targets in the
ChEMBL (version 10) database was analyzed and ranked,
revealing that 3Lb could display potent activity towards different
pharmaceutical targets. To further verify the hypotheses gener-
ated by the chemical similarity search and evaluate the effect of
stereochemistry on biological activity, the two pure enantiomers
3Lb and 3Lb′ (see Chart S1 in the ESI†) were subjected to the
study of binding interaction with the purinergic (P2Y1) receptor,
which is a G protein-coupled receptor involved in several
cellular functions such as vascular reactivity, apoptosis, cytokine
secretion and platelet aggregation.20 Our experimental data21
revealed that 3Lb′ could enhance the activity of P2Y1 by only
15%.22 However, in the case of the opposite enantiomer 3Lb,
the activity of P2Y1 was increased by 41%, markedly higher
than that for 3Lb′. Thus, different enantiomers of the active
1
AMX-300/400 spectrometer at 300/400 MHz for H NMR and
75/100 MHz for 13C NMR in CDCl3 with tetramethylsilane
(TMS) as internal standard. The chemical shifts are expressed in
1
ppm and coupling constants are given in Hz. Data for H NMR
are recorded as follows: chemical shift (ppm), multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coup-
ling constant (Hz), integration. Data for 13C NMR are reported
in terms of chemical shift (δ, ppm). Mass spectra were deter-
mined on a Finnigan MAT 95 mass spectrometer. Single crystals
of 3Dm and 3Nb suitable for X-ray diffraction analysis were
obtained by slow evaporation of the CH2Cl2/n-hexane solutions.
The diffraction data were collected at 296 K on a Bruker X8
PROTEUM single crystal X-ray diffractometer with MicroStar
rotating-anode X-ray source (CuKα radiation, λ = 1.54178 Å).
The gold(I) complexes,15,23 and chiral phosphoric acid 5a–5e24
catalysts were prepared following literature procedures. The
7212 | Org. Biomol. Chem., 2012, 10, 7208–7219
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starting materials 2-aminobenzaldehydes25 and internal alkynes
λ = 254 nm): tR = 51.9 min (major), tR = 56.1 min (minor). The
absolute configuration was tentatively assigned by analogy.
2m–2s26 were prepared according to literature methods.
(S)-6-Chloro-2-o-tolyl-1,2,3,4-tetrahydroquinoline (3Ad).
Yield: 73%. H NMR (CDCl3, TMS, 300 MHz): δ 7.48 (d, J =
Typical procedure for synthesis of chiral 2-substituted 1,2,3,4-
tetrahydroquinolines. To a mixture of (tBu)2(o-biphenyl)PAu-
(CH3CN)SbF6 (0.008 mmol, 2 mol%) and 5 Å molecular sieves
(1 g) in dry benzene (6.0 mL) were added 2-aminobenzaldehyde
(0.4 mmol) and terminal alkyne (0.48 mmol) at room tempera-
ture. The reaction mixture was stirred at 60 °C and the evolution
of the reaction was monitored by TLC until completion. Then
phosphoric acid 5a (0.012 mmol, 3 mol%) and ethyl Hantzsch
ester 4 (1.0 mmol) were successively added at the same reaction
temperature. The resulting reaction mixture was stirred at 60 °C
and monitored by TLC. Upon completion, the reaction mixture
was filtered through a plug of silica (eluting with CH2Cl2) to
remove the molecular sieves, and then concentrated in vacuo.
The residue was purified by silica gel chromatography (eluent:
hexane–ethyl acetate = 100 : 1) to afford the enantio-enriched
product 3.
1
5.8 Hz, 1H), 7.23 (m, 3H), 6.99 (m, 2H), 6.48 (d, J = 8.2 Hz,
1H), 4.68 (dd, J = 8.9, 3.1 Hz, 1H), 3.98 (brs, 1H), 2.91 (m,
1H), 2.74 (dt, J = 16.4, 4.8 Hz, 1H), 2.41 (s, 3H), 2.12 (m, 1H),
1.91 (m, 1H). 13C NMR (CDCl3, TMS, 75 MHz): δ 143.6,
142.2, 134.7, 130.6, 128.8, 127.2, 126.7, 126.4, 125.9, 122.3,
121.3, 114.9, 52.1, 28.7, 26.3, 19.0. MS: m/z (% relative inten-
sity) 259(M+ + 2, 33), 258(M+ + 1, 24), 257(M+, 100), 166(99);
HRMS: m/z calcd for C16H16NCl (M+) 257.0966, found
257.0964. [α]2D0 = −36.7 (c 0.98, EtOAc); Enantiomeric excess:
90%, determined by HPLC (Chiralcel OD-H, hexane–isopropa-
nol = 90 : 10, flow rate 1 mL min−1, λ = 254 nm): tR = 8.3 min
(major), tR = 13.9 min (minor). The absolute configuration was
tentatively assigned by analogy.
(S)-6-Chloro-2-p-tolyl-1,2,3,4-tetrahydroquinoline (3Ae).
1
(S)-6-Chloro-2-phenyl-1,2,3,4-tetrahydroquinoline
(3Aa).11a
Yield: 87%. H NMR (CDCl3, TMS, 400 MHz): δ 7.28 (d, J =
Yield: 90%. 1H NMR (CDCl3, TMS, 300 MHz): δ 7.33 (m, 5H),
6.96 (m, 2H), 6.46 (d, J = 8.4 Hz, 1H), 4.43 (dd, J = 9.2,
3.2 Hz, 1H), 4.07 (brs, 1H), 2.88 (m, 1H), 2.70 (dt, J = 16.4,
4.8 Hz, 1H), 2.12 (m, 1H), 1.97 (m, 1H). [α]2D0 = −45.6 (c 1.34,
EtOAc); Enantiomeric excess: 97%, determined by HPLC
(Chiralcel OD-H, hexane–isopropanol = 95 : 5, flow rate 0.5 mL
min−1, λ = 254 nm): tR = 23.9 min (major), tR = 28.9 min
(minor). The absolute configuration was determined by compari-
son with the literature.11a
8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.97 (m, 2H), 6.46 (d, J =
8.3 Hz, 1H), 4.40 (dd, J = 9.3, 3.2 Hz, 1H), 4.03 (brs, 1H), 2.89
(m, 1H), 2.71 (dt, J = 16.5, 4.8 Hz, 1H), 2.38 (s, 3H), 2.11
(m, 1H), 1.96 (m, 1H). 13C NMR (CDCl3, TMS, 100 MHz):
δ 143.3, 141.4, 137.2, 129.3, 128.8, 126.7, 126.4, 122.4, 121.4,
114.9, 55.9, 30.5, 26.2, 21.1. MS: m/z (% relative intensity) 259
(M+ + 2, 30), 258(M+ + 1, 21), 257(M+, 100), 166(52); HRMS:
m/z calcd for C16H16NCl (M+) 257.0966, found 257.0962. [α]2D0
= −30.8 (c 1.18, EtOAc); Enantiomeric excess: 99%, determined
by HPLC (Chiralcel OD-H, hexane–isopropanol = 95 : 5, flow
rate 0.5 mL min−1, λ = 254 nm): tR = 17.0 min (major), tR
=
(S)-6-Chloro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
49.3 min (minor). The absolute configuration was tentatively
(3Ab). Yield: 94%. H NMR (CDCl3, TMS, 300 MHz): δ 7.31
assigned by analogy.
(d, J = 8.6 Hz, 2H), 6.95 (m, 4H), 6.45 (d, J = 8.1 Hz, 1H), 4.38
(dd, J = 9.3, 3.1 Hz, 1H), 4.03 (brs, 1H), 3.84 (s, 3H), 2.90
(m, 1H), 2.72 (dt, J = 16.5, 4.7 Hz, 1H), 2.10 (m, 1H), 1.95
(m, 1H). 13C NMR (CDCl3, TMS, 75 MHz): δ 159.0, 143.4,
136.4, 128.8, 127.6, 126.7, 122.4, 121.4, 114.9, 114.0, 55.6,
55.3, 30.6, 26.3. MS: m/z (% relative intensity) 275(M+ + 2, 33),
274(M+ + 1, 35), 273(M+, 100), 242(28), 166(43); HRMS: m/z
(S)-2-(Biphenyl-4-yl)-6-chloro-1,2,3,4-tetrahydroquinoline (3Af)
Yield: 90%. 1H NMR (CDCl3, TMS, 400 MHz): δ 7.62 (m, 4H),
7.47 (m, 4H), 7.38 (t, J = 7.2 Hz, 1H), 7.00 (m, 2H), 6.49 (d,
J = 8.2 Hz, 1H), 4.48 (dd, J = 9.0, 2.8 Hz, 1H), 4.09 (brs, 1H),
2.92 (m, 1H), 2.74 (dt, J = 16.4, 4.7 Hz, 1H), 2.17 (m, 1H), 2.02
(m, 1H). 13C NMR (CDCl3, TMS, 100 MHz): δ 143.4, 143.2,
140.8, 140.5, 128.9, 128.8, 127.4, 127.1, 126.9, 126.7, 122.4,
121.5, 115.0, 55.8, 30.4, 26.1. MS: m/z (% relative intensity)
321(M+ + 2, 35), 320(M+ + 1, 37), 319(M+, 100), 166(57);
HRMS: m/z calcd for C21H18NCl (M+) 319.1122, found
319.1116. [α]2D0 = −6.3 (c 0.97, EtOAc); Enantiomeric excess:
>99%, determined by HPLC (Chiralcel OD-H, hexane–isopropa-
nol = 95 : 5, flow rate 0.5 mL min−1, λ = 254 nm): tR = 15.3 min
(minor), tR = 27.9 min (major). The absolute configuration was
tentatively assigned by analogy.
calcd for C16H16ONCl (M+) 273.0915, found 273.0910. [α]2D0
=
−35.1 (c 0.97, EtOAc); Enantiomeric excess: 98%, determined
by HPLC (Chiralcel OD-H, hexane–isopropanol = 95 : 5, flow
rate 0.5 mL min−1, λ = 254 nm): tR = 20.6 min (major), tR
=
43.8 min (minor). The absolute configuration was tentatively
assigned by analogy.
(S)-6-Chloro-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
(3Ac). Yield: 89%. H NMR (CDCl3, TMS, 400 MHz): δ 7.28
(t, J = 7.8 Hz, 1H), 6.96 (m, 4H), 6.85 (d, J = 8.3 Hz, 1H), 6.46
(d, J = 8.1 Hz, 1H), 4.40 (dd, J = 8.9, 2.3 Hz, 1H), 4.07 (brs,
1H), 3.82 (s, 3H), 2.88 (m, 1H), 2.70 (dt, J = 16.4, 4.8 Hz, 1H),
2.12 (m, 1H), 1.97 (m, 1H). 13C NMR (CDCl3, TMS,
100 MHz): δ 159.9, 146.1, 143.2, 129.6, 128.8, 126.7, 122.4,
121.5, 118.8, 114.9, 112.8, 112.1, 56.1, 55.2, 30.4, 26.1. MS:
m/z (% relative intensity) 275(M+ + 2, 35), 274(M+ + 1, 31), 273
(M+, 100), 242(16), 166(91); HRMS: m/z calcd for C16H16ONCl
(M+) 273.0915, found 273.0907. [α]2D0 = −41.2 (c 1.03, EtOAc);
Enantiomeric excess: 93%, determined by HPLC (Chiralcel
(S)-6-Chloro-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline
1
(3Ag). Yield: 76%. H NMR (CDCl3, TMS, 400 MHz): δ 7.30
(m, 4H), 6.96 (m, 2H), 6.47 (m, 1H), 4.41 (dd, J = 9.0, 3.3 Hz,
1H), 4.03 (brs, 1H), 2.86 (m, 1H), 2.67 (dt, J = 16.5, 5.0 Hz,
1H), 2.08 (m, 1H), 1.92 (m, 1H). 13C NMR (CDCl3, TMS,
100 MHz): δ 142.9, 142.8, 133.1, 128.8, 128.7, 127.8, 126.7,
122.3, 121.7, 115.0, 55.4, 30.4, 25.9. MS: m/z (% relative inten-
sity) 279(M+ + 2, 61), 278(M+ + 1, 38), 277(M+, 92), 166(100);
OD-H, hexane–isopropanol = 95 : 5, flow rate 0.8 mL min−1
,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7208–7219 | 7213

View Article Online
HRMS: m/z calcd for C15H13NCl2 (M+) 277.0420, found
277.0417. [α]2D0 = −36.1 (c 1.07, EtOAc); Enantiomeric excess:
99%, determined by HPLC (Chiralcel OD-H, hexane–isopropa-
nol = 95 : 5, flow rate 0.5 mL min−1, λ = 254 nm): tR = 20.2 min
(major), tR = 66.7 min (minor). The absolute configuration was
tentatively assigned by analogy.
4.06 (brs, 1H), 3.82 (s, 3H), 2.85 (m, 1H), 2.69 (dt, J = 16.3,
4.8 Hz, 1H), 2.08 (m, 1H), 1.93 (m, 1H). 13C NMR (CDCl3,
TMS, 100 MHz): δ 159.0, 145.7, 136.3, 132.1, 130.2, 127.5,
119.2, 116.7, 114.0, 113.3, 55.4, 55.3, 30.7, 25.9. MS: m/z (%
relative intensity) 275(M+ + 2, 33), 274(M+ + 1, 36), 273(M+,
100), 242(30), 166(42); HRMS: m/z calcd for C16H16ONCl
(M+) 273.0915, found 273.0912. [α]2D0 = −91.2 (c 1.16, EtOAc);
Enantiomeric excess: 98%, determined by HPLC (Chiralcel
OD-H, hexane–isopropanol = 95 : 5, flow rate 0.7 mL min−1, λ =
254 nm): tR = 17.4 min (major), tR = 34.9 min (minor). The
absolute configuration was tentatively assigned by analogy.
(S)-6-Chloro-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-
quinoline (3Ah). Yield: 78%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.62 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H),
6.98 (m, 2H), 6.50 (m, 1H), 4.52 (dd, J = 8.7, 3.0 Hz, 1H), 4.09
(brs, 1H), 2.88 (m, 1H), 2.68 (dt, J = 16.6, 5.1 Hz, 1H), 2.14 (m,
1H), 1.97 (m, 1H). 13C NMR (CDCl3, TMS, 100 MHz): δ
148.5, 142.8, 129.8 (q, JCF = 32.1 Hz), 128.9, 126.9, 126.8,
125.6 (m), 122.8, 122.3, 121.9, 115.1, 55.6, 30.3, 25.7. MS: m/z
(% relative intensity) 313(M+ + 2, 31), 312(M+ + 1, 25), 311
(M+, 100), 166(68); HRMS: m/z calcd for C16H13NClF3 (M+)
311.0683, found 311.0677. [α]2D0 = −65.5 (c 1.61, EtOAc);
Enantiomeric excess: 99%, determined by HPLC (Chiralcel
OD-H, hexane–isopropanol = 95 : 5, flow rate 0.5 mL min−1, λ =
254 nm): tR = 17.2 min (major), tR = 42.3 min (minor). The
absolute configuration was tentatively assigned by analogy.
(S)-5-Chloro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
(3Cb). Yield: 87%. H NMR (CDCl3, TMS, 400 MHz): δ 7.30
(d, J = 8.6 Hz, 2H), 6.93 (m, 3H), 6.73 (d, J = 7.8 Hz, 1H), 6.43
(d, J = 8.0 Hz, 1H), 4.33 (dd, J = 9.7, 2.9 Hz, 1H), 4.10 (brs,
1H), 3.83 (s, 3H), 2.92 (dt, J = 17.2, 5.3 Hz, 1H), 2.82 (m, 1H),
2.14 (m, 1H), 1.97 (m, 1H). 13C NMR (CDCl3, TMS,
100 MHz): δ 159.1, 146.4, 136.2, 134.7, 127.6, 127.3, 118.8,
117.7, 114.0, 112.3, 55.3, 55.2, 30.8, 24.4. MS: m/z (% relative
intensity) 275(M+ + 2, 35), 274(M+ + 1, 38), 273(M+, 100), 242
(34), 166(64); HRMS: m/z calcd for C16H16ONCl (M+)
273.0915, found 273.0908. Enantiomeric excess: >99%, de-
termined by HPLC (Chiralcel OD-H, hexane–isopropanol =
95 : 5, flow rate 0.7 mL min−1, λ = 254 nm): tR = 17.2 min
(major), tR = 40.0 min (minor). The absolute configuration was
tentatively assigned by analogy.
(S)-4-(6-Chloro-1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile
1
(3Ai). Yield: 67%. H NMR (CDCl3, TMS, 400 MHz): δ 7.63
(d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.98 (m, 2H), 6.50
(m, 1H), 4.52 (dd, J = 8.5, 3.6 Hz, 1H), 4.10 (brs, 1H), 2.85 (m,
1H), 2.64 (dt, J = 16.6, 5.2 Hz, 1H), 2.12 (m, 1H), 1.94 (m, 1H).
13C NMR (CDCl3, TMS, 75 MHz): δ 149.9, 142.5, 132.5,
128.9, 127.2, 126.9, 122.2, 122.0, 118.8, 115.2, 111.3, 55.6,
30.2, 25.4. MS: m/z (% relative intensity) 270(M+ + 2, 29), 269
(M+ + 1, 24), 268(M+, 85), 166(100); HRMS: m/z calcd for
C16H13N2Cl (M+) 268.0762, found 268.0761. [α]2D0 = −33.1
(c 1.06, EtOAc); Enantiomeric excess: >99%, determined by
HPLC (Chiralcel OD-H, hexane–isopropanol = 85 : 15, flow rate
(S)-6-Bromo-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
(3Db). Yield: 95%. H NMR (CDCl3, TMS, 300 MHz): δ 7.29
(m, 2H), 7.09 (m, 2H), 6.91 (m, 2H), 6.40 (d, J = 8.3 Hz, 1H),
4.37 (dd, J = 9.2, 3.2 Hz, 1H), 4.03 (brs, 1H), 3.83 (s, 3H), 2.89
(m, 1H), 2.71 (dt, J = 16.5, 4.8 Hz, 1H), 2.08 (m, 1H), 1.94
(m, 1H). 13C NMR (CDCl3, TMS, 75 MHz): δ 159.0, 143.8,
136.4, 131.7, 129.5, 127.6, 122.9, 115.4, 114.0, 108.4, 55.5,
55.3, 30.5, 26.3. MS: m/z (% relative intensity) 319(M+ + 2, 39),
318(M+ + 1, 24), 317(M+, 40), 153(52), 136(66); HRMS: m/z
1.0 mL min−1, λ = 254 nm): tR = 16.3 min (major), tR
=
37.3 min (minor). The absolute configuration was tentatively
assigned by analogy.
calcd for C16H16ONBr (M+) 317.0410, found 317.0403. [α]2D0
=
−8.8 (c 0.96, EtOAc); Enantiomeric excess: >99%, determined
by HPLC (Chiralcel OD-H, hexane–isopropanol = 95 : 5, flow
(S)-6-Chloro-2-(6-methoxynaphthalen-2-yl)-1,2,3,4-tetrahydro-
quinoline (3Aj). Yield: 97%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.73 (t, J = 10.8 Hz, 3H), 7.45 (dd, J = 8.5,
1.5 Hz, 1H), 7.17 (m, 2H), 6.99 (m, 2H), 6.49 (d, J = 8.4 Hz,
1H), 4.54 (dd, J = 9.1, 3.2 Hz, 1H), 4.12 (brs, 1H), 3.93 (s, 3H),
2.90 (m, 1H), 2.72 (dt, J = 16.4, 4.8 Hz, 1H), 2.16 (m, 1H), 2.04
(m, 1H). 13C NMR (CDCl3, TMS, 100 MHz): δ 157.7, 143.3,
139.4, 134.1, 129.3, 128.9, 128.8, 127.2, 126.7, 125.2, 124.9,
122.4, 121.4, 119.0, 114.9, 105.7, 56.1, 55.3, 30.4, 26.2. MS:
m/z (% relative intensity) 325(M+ + 2, 34), 324(M+ + 1, 38), 323
(M+, 100), 172(38); HRMS: m/z calcd for C20H18ONCl (M+)
323.1071, found 323.1067. [α]2D0 = −18.2 (c 1.16, EtOAc);
Enantiomeric excess: >99%, determined by HPLC (Chiralcel
rate 0.7 mL min−1, λ = 254 nm): tR = 17.8 min (major), tR
=
45.4 min (minor). The absolute configuration was tentatively
assigned by analogy.
(S)-6-Fluoro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
(3Eb). Yield: 92%. H NMR (CDCl3, TMS, 400 MHz): δ 7.33
(d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.74 (m, 2H), 6.46
(m, 1H), 4.34 (dd, J = 9.6, 2.9 Hz, 1H), 3.91 (brs, 1H), 3.83 (s,
3H), 2.94 (m, 1H), 2.74 (dt, J = 16.6, 4.5 Hz, 1H), 2.09 (m, 1H),
1.98 (m, 1H). 13C NMR (CDCl3, TMS, 100 MHz): δ 159.0,
156.7, 154.3, 141.1 (d, JCF = 1.4 Hz), 136.6, 127.6, 122.2 (d,
JCF = 6.5 Hz), 115.4 (d, JCF = 21.5 Hz), 114.6 (d, JCF = 7.6 Hz),
OD-H, hexane–isopropanol = 90 : 10, flow rate 1.0 mL min−1
,
113.9, 113.3 (d, JCF = 22.3 Hz), 55.8, 55.3, 30.8, 26.7. MS: m/z
(% relative intensity) 257(M+, 100), 150(46), 136(58); HRMS:
m/z calcd for C16H16ONF (M+) 257.1210, found 257.1201. [α]2D0
= −39.1 (c 0.99, EtOAc); Enantiomeric excess: >99%, deter-
mined by HPLC (Chiralcel OD-H, hexane–isopropanol = 95 : 5,
flow rate 0.7 mL min−1, λ = 254 nm): tR = 15.0 min (major), tR
= 32.5 min (minor). The absolute configuration was tentatively
assigned by analogy.
λ = 254 nm): tR = 14.6 min (major), tR = 63.2 min (minor). The
absolute configuration was tentatively assigned by analogy.
(S)-7-Chloro-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
(3Bb). Yield: 74%. H NMR (CDCl3, TMS, 400 MHz): δ 7.28
(d, J = 8.6 Hz, 2H), 6.90 (m, 3H), 6.60 (dd, J = 8.0, 2.0 Hz,
1H), 6.50 (d, J = 2.0 Hz, 1H), 4.38 (dd, J = 9.2, 3.2 Hz, 1H),
7214 | Org. Biomol. Chem., 2012, 10, 7208–7219
This journal is © The Royal Society of Chemistry 2012

View Article Online
(S)-2-(4-Methoxyphenyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydro-
quinoline (3Fb). Yield: 97%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.30 (m, 2H), 7.08 (d, J = 7.8 Hz, 1H), 6.92
(m, 2H), 6.88 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H), 4.43 (dd, J =
9.3, 3.3 Hz, 1H), 4.19 (brs, 1H), 3.83 (s, 3H), 2.93 (m, 1H), 2.78
(dt, J = 16.5, 4.7 Hz, 1H), 2.12 (m, 1H), 1.97 (m, 1H). 13C
NMR (CDCl3, TMS, 100 MHz): δ 159.1, 144.8, 136.2, 129.5,
129.2 (m), 127.5, 125.8, 124.4, 123.1, 114.0, 113.2 (m), 110.1
(m), 55.5, 55.3, 30.4, 26.3. MS: m/z (% relative intensity) 307
(M+, 100), 276(35), 198(36); HRMS: m/z calcd for C17H16ONF3
(M+) 307.1179, found 307.1170. [α]2D0 = −30.6 (c 0.94, EtOAc);
Enantiomeric excess: 97%, determined by HPLC (Chiralcel
OD-H, hexane–isopropanol = 95 : 5, flow rate 0.7 mL min−1, λ =
254 nm): tR = 11.3 min (major), tR = 22.0 min (minor). The
absolute configuration was tentatively assigned by analogy.
(d, J = 2.5 Hz, 1H), 4.36 (dt, J = 9.5, 3.1 Hz, 1H), 4.00 (brs,
1H), 3.80 (s, 3H), 3.74 (s, 3H), 2.84 (m, 1H), 2.67 (dt, J = 16.0,
4.7 Hz, 1H), 2.06 (m, 1H), 1.95 (m, 1H). 13C NMR (CDCl3,
TMS, 100 MHz): δ 158.9, 145.6, 136.8, 129.9, 127.6, 113.9,
113.5, 103.0, 99.2, 55.6, 55.3, 55.1, 31.3, 25.7. MS: m/z (% rela-
tive intensity) 269(M+, 100), 254(39), 160(35); HRMS: m/z
calcd for C17H19O2N (M+) 269.1410, found 269.1409. Enantio-
meric excess: 96%, determined by HPLC (Chiralcel OD-H,
hexane–isopropanol = 90 : 10, flow rate 0.5 mL min−1, λ =
254 nm): tR = 35.9 min (minor), tR = 40.5 min (major). The
absolute configuration was tentatively assigned by analogy.
(S)-6-(4-Methoxyphenyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]
quinoline (3Kb). Yield: 71%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.30 (m, 2H), 6.89 (m, 2H), 6.51 (s, 1H), 6.13
(s, 1H), 5.82 (q, J = 1.3 Hz, 2H), 4.30 (dt, J = 9.6, 3.0 Hz, 1H),
3.81 (s, 3H), 2.86 (m, 1H), 2.65 (dt, J = 16.3, 4.7 Hz, 1H), 2.05
(m, 1H), 1.96 (m, 1H). 13C NMR (CDCl3, TMS, 100 MHz): δ
158.9, 146.3, 139.5, 139.4, 136.8, 127.6, 113.9, 112.6, 109.0,
100.2, 96.4, 55.9, 55.3, 31.2, 26.6. MS: m/z (% relative inten-
sity) 283(M+, 100), 268(22), 174(20); HRMS: m/z calcd for
C17H17O3N (M+) 283.1203, found 283.1200. Enantiomeric
excess: 96%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 90 : 10, flow rate 0.5 mL min−1, λ = 254 nm): tR =
36.4 min (major), tR = 56.8 min (minor). The absolute configur-
ation was tentatively assigned by analogy.
(S)-Methyl 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline-
6-carboxylate (3Gb). Yield: 88%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.73 (m, 2H), 7.26 (m, 2H), 6.89 (m, 2H), 6.47
(m, 1H), 4.46 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 2.88 (m, 1H),
2.75 (dt, J = 16.2, 4.9 Hz, 1H), 2.10 (m, 1H), 1.94 (m, 1H). 13C
NMR (CDCl3, TMS, 100 MHz): δ 167.4, 159.1, 148.7, 135.9,
131.1, 129.2, 127.5, 119.7, 117.9, 114.0, 112.7, 55.5, 55.3, 51.4,
30.3, 26.0. MS: m/z (% relative intensity) 297(M+, 100), 266
(48), 238(18), 190(29); HRMS: m/z calcd for C18H19O3N (M+)
297.1359, found 297.1352. [α]2D0 = 45.8 (c 0.95, EtOAc);
Enantiomeric excess: >99%, determined by HPLC (Chiralcel
OD-H, hexane–isopropanol = 85 : 15, flow rate 1.0 mL min−1
,
Typical procedure for synthesis of chiral 2,3-disubstituted
1,2,3,4-tetrahydroquinolines. To a mixture of (tBu)2(o-biphenyl)-
PAu(CH3CN)SbF6 (0.012 mmol, 3 mol%) and 5 Å molecular
sieves (1 g) in dry benzene (6.0 mL) were added 2-aminobenzal-
dehyde (0.4 mmol) and internal alkyne (0.48 mmol) at room
temperature. The reaction mixture was stirred at 60 °C and the
evolution of the reaction was monitored by TLC until com-
pletion. Then triethylamine (0.016 mmol, 4 mol%), phosphoric
acid 5 (0.02 mmol, 5 mol%) and ethyl Hantzsch ester 4
(1.0 mmol) were successively added at the same reaction temp-
erature. The resulting reaction mixture was stirred at 60 °C and
monitored by TLC. Upon completion, the reaction mixture was
filtered through a plug of silica (eluting with CH2Cl2) to remove
the molecular sieves, and then concentrated in vacuo. The
residue was purified by silica gel chromatography (eluent:
hexane–ethyl acetate = 20 : 1 to 6 : 1) to afford the enantio-
enriched product 3.
λ = 254 nm): tR = 16.8 min (major), tR = 54.3 min (minor). The
absolute configuration was tentatively assigned by analogy.
(S)-2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline (3Hb).11a
Yield: 78%. 1H NMR (CDCl3, TMS, 300 MHz): δ 7.34 (m, 2H),
7.03 (m, 2H), 6.92 (m, 2H), 6.67 (m, 1H), 6.54 (dd, J = 8.1, 1.1
Hz, 1H), 4.40 (dd, J = 9.4, 3.2 Hz, 1H), 4.00 (brs, 1H), 3.84 (s,
3H), 2.95 (m, 1H), 2.76 (dt, J = 16.3, 4.6 Hz, 1H), 2.05 (m, 2H).
Enantiomeric excess: >99%, determined by HPLC (Chiralcel
OD-H, hexane–isopropanol = 90 : 10, flow rate 0.6 mL min−1
,
λ = 254 nm): tR = 15.4 min (major), tR = 25.7 min (minor). The
absolute configuration was determined by comparison with the
literature.11a
(S)-2-(4-Methoxyphenyl)-6-methyl-1,2,3,4-tetrahydroquinoline
1
(3Ib). Yield: 75%. H NMR (CDCl3, TMS, 400 MHz): δ 7.33
(m, 2H), 6.91 (m, 2H), 6.85 (m, 2H), 6.48 (d, J = 8.6 Hz, 1H),
4.36 (dt, J = 9.6, 3.1 Hz, 1H), 3.89 (brs, 1H), 3.83 (s, 3H), 2.93
(m, 1H), 2.73 (dt, J = 16.4, 4.7 Hz, 1H), 2.26 (s, 3H), 2.08
(m, 1H), 1.99 (m, 1H). 13C NMR (CDCl3, TMS, 100 MHz):
δ 158.9, 142.5, 137.0, 129.8, 127.6, 127.4, 126.3, 120.9, 114.1,
113.9, 55.9, 55.3, 31.3, 26.6, 20.4. MS: m/z (% relative intensity)
253(M+, 93), 166(56), 146(32); HRMS: m/z calcd for
C17H19ON (M+) 253.1461, found 253.1464. Enantiomeric
excess: 98%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 95 : 5, flow rate 1.0 mL min−1, λ = 254 nm): tR =
8.9 min (major), tR = 14.4 min (minor). The absolute configur-
ation was tentatively assigned by analogy.
(2R,3S)-Methyl 6-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (3Ak). Yield: 87%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.24 (m, 3H), 7.11 (m, 2H), 7.00 (m, 2H), 6.50
(m, 1H), 4.93 (d, J = 4.3 Hz, 1H), 4.42 (brs, 1H), 3.62 (s, 3H),
3.19 (m, 1H), 2.85 (m, 2H). 13C NMR (CDCl3, TMS,
100 MHz): δ 172.1, 142.0, 141.6, 129.1, 128.4, 127.9, 127.3,
126.6, 121.6, 120.3, 114.5, 55.9, 51.6, 42.9, 24.9. MS: m/z (%
relative intensity) 303(M+ + 2, 34), 302(M+ + 1, 27), 301(M+,
100), 242(68), 227(39); HRMS: m/z calcd for C17H16O2NCl
(M+) 301.0864, found 301.0865. Enantiomeric excess: 87%,
determined by HPLC (Chiralcel OD-H, hexane–isopropanol =
95 : 5, flow rate 0.7 mL min−1, λ = 254 nm): tR = 32.7 min
(minor), tR = 69.5 min (major). The relative and absolute
configurations were tentatively assigned by analogy.
(S)-7-Methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroquinoline
1
(3Jb). Yield: 77%. H NMR (CDCl3, TMS, 400 MHz): δ 7.29
(m, 2H), 6.89 (m, 3H), 6.24 (dd, J = 8.2, 2.5 Hz, 1H), 6.09
This journal is © The Royal Society of Chemistry 2012
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(2R,3S)-Ethyl 6-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (3Al). Yield: 95%. 1H NMR (CDCl3, TMS,
300 MHz): δ 7.24 (m, 3H), 7.14 (m, 2H), 7.00 (m, 2H), 6.50
(m, 1H), 4.94 (d, J = 4.2 Hz, 1H), 4.42 (brs, 1H), 4.06 (m, 2H),
3.18 (m, 1H), 2.85 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR
(CDCl3, TMS, 100 MHz): δ 171.7, 142.1, 141.6, 129.0, 128.3,
127.8, 127.2, 126.8, 121.5, 120.4, 114.4, 60.6, 55.9, 43.0, 24.9,
14.1. MS: m/z (% relative intensity) 317(M+ + 2, 10), 316(M+ +
1, 7), 315(M+, 21), 286(87), 240(100); HRMS: m/z calcd for
C18H18O2NCl (M+) 315.1021, found 315.1023. Enantiomeric
excess: 87%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 97 : 3, flow rate 0.5 mL min−1, λ = 254 nm): tR =
47.7 min (minor), tR = 101.9 min (major). The relative and
absolute configurations were tentatively assigned by analogy.
excess: 82%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 85 : 15, flow rate 1.0 mL min−1, λ = 254 nm): tR =
14.1 min (minor), tR = 87.4 min (major). The relative and absol-
ute configurations were tentatively assigned by analogy.
1-((2R,3S)-6-Bromo-2-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-
ethanone (3Dm). Yield: 84%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.28 (m, 3H), 7.13 (m, 4H), 6.52 (d, J = 8.2 Hz,
1H), 4.90 (d, J = 3.8 Hz, 1H), 4.48 (brs, 1H), 3.18 (m, 1H), 2.92
(dd, J = 16.7, 10.1 Hz, 1H), 2.81 (dd, J = 16.7, 4.9 Hz, 1H),
2.03 (s, 3H). 13C NMR (CDCl3, TMS, 100 MHz): δ 207.9,
142.6, 141.2, 131.9, 130.1, 128.5, 128.0, 126.6, 121.1, 115.2,
108.9, 56.0, 50.3, 29.8, 25.4. MS: m/z (% relative intensity) 331
(M+ + 2, 43), 330(M+ + 1, 15), 329(M+, 45), 207(100), 91(94);
HRMS: m/z calcd for C17H16ONBr (M+) 329.0410, found
329.0407. Enantiomeric excess: 94%, determined by HPLC
(Chiralcel OD-H, hexane–isopropanol = 85 : 15, flow rate
1-((2R,3S)-6-Chloro-2-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-
ethanone (3Am). Yield: 80%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.26 (m, 3H), 7.14 (m, 2H), 7.01 (m, 2H), 6.52
(d, J = 8.5 Hz, 1H), 4.91 (d, J = 3.8 Hz, 1H), 4.41 (brs, 1H),
3.20 (m, 1H), 2.93 (dd, J = 16.7, 9.9 Hz, 1H), 2.83 (dd, J =
16.7, 5.1 Hz, 1H), 2.02 (s, 3H). 13C NMR (CDCl3, TMS,
75 MHz): δ 208.0, 142.1, 141.2, 129.0, 128.5, 127.9, 127.2,
126.6, 121.7, 120.5, 114.7, 56.0, 50.3, 29.7, 25.4. MS: m/z (%
relative intensity) 287(M+ + 2, 21), 286(M+ + 1, 15), 285(M+,
63), 242(100), 91(87); HRMS: m/z calcd for C17H16ONCl (M+)
285.0915, found 285.0914. [α]2D0 = −161.9 (c 1.21, EtOAc);
Enantiomeric excess: 93%, determined by HPLC (Chiralcel
1.0 mL min−1, λ = 254 nm): tR = 20.9 min (minor), tR
=
79.5 min (major). The relative and absolute configurations were
determined by X-ray crystallographic analysis.
1-((6R,7S)-6-Phenyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]-
1
quinolin-7-yl)ethanone (3Km). Yield: 76%. H NMR (CDCl3,
TMS, 300 MHz): δ 7.25 (m, 3H), 7.15 (m, 2H), 6.53 (s, 1H),
6.18 (s, 1H), 5.84 (s, 2H), 4.83 (d, J = 5.1 Hz, 1H), 4.17 (brs,
1H), 3.18 (m, 1H), 2.82 (m, 2H), 2.03 (s, 3H). 13C NMR
(CDCl3, TMS, 75 MHz): δ 207.9, 146.3, 141.1, 139.4, 137.5,
127.9, 127.2, 126.1, 110.1, 108.4, 99.9, 95.6, 55.8, 50.5, 29.1,
25.2. MS: m/z (% relative intensity) 295(M+, 10), 210(39), 182
(70), 84(100); HRMS: m/z calcd for C18H17O3N (M+) 295.1203,
found 295.1201. [α]2D0 = −20.0 (c 0.63, EtOAc); Enantiomeric
excess: 97%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 80 : 20, flow rate 1.0 mL min−1, λ = 254 nm): tR =
33.6 min (minor), tR = 61.1 min (major). The relative and
absolute configurations were tentatively assigned by analogy.
OD-H, hexane–isopropanol = 85 : 15, flow rate 1.0 mL min−1
,
λ = 254 nm): tR = 20.5 min (minor), tR = 66.5 min (major). The
relative and absolute configurations were tentatively assigned by
analogy.
1-((2R,3S)-6-Chloro-2-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-
2-phenoxyethanone (3An). Yield: 96%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.28 (m, 5H), 7.18 (m, 2H), 7.01 (m, 3H), 6.80 (d,
J = 7.9 Hz, 2H), 6.53 (m, 1H), 5.04 (d, J = 3.9 Hz, 1H), 4.41
(m, 3H), 3.64 (m, 1H), 2.98 (dd, J = 16.9, 9.0 Hz, 1H), 2.90
(dd, J = 16.9, 5.0 Hz, 1H). 13C NMR (CDCl3, TMS, 100 MHz):
δ 206.0, 157.6, 142.1, 141.0, 129.7, 129.0, 128.7, 128.1, 127.3,
126.6, 122.0, 121.9, 120.3, 114.9, 114.6, 73.1, 55.8, 46.4, 25.4.
MS: m/z (% relative intensity) 377(M+, 16), 284(100), 266(34);
HRMS: m/z calcd for C23H20O2NCl (M+) 377.1177, found
377.1170. Enantiomeric excess: 94%, determined by HPLC
(Chiralcel OD-H hexane–isopropanol = 85 : 15, flow rate 1.0 mL
min−1, λ = 254 nm): tR = 57.0 min (minor), tR = 123.1 min
(major). The relative and absolute configurations were tentatively
assigned by analogy.
1-((2R,3S)-6-Chloro-2-p-tolyl-1,2,3,4-tetrahydroquinolin-3-yl)-
ethanone (3Ap). Yield: 72%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.06 (m, 2H), 6.96 (m, 4H), 6.48 (m, 1H), 4.84
(d, J = 4.0 Hz, 1H), 4.40 (brs, 1H), 3.15 (m, 1H), 2.90 (dd, J =
16.7, 10.0 Hz, 1H), 2.76 (dd, J = 16.7, 4.9 Hz, 1H), 2.29
(s, 3H), 2.02 (s, 3H). 13C NMR (CDCl3, TMS, 100 MHz):
δ 208.1, 142.2, 138.2, 137.6, 129.2, 129.0, 127.2, 126.5, 121.7,
120.6, 114.8, 55.9, 50.4, 29.8, 25.5, 21.0. MS: m/z (% relative
intensity) 301(M+ + 2, 22), 300(M+ + 1, 17), 299(M+, 67), 256
(100), 164(63); HRMS: m/z calcd for C18H18ONCl (M+)
299.1071, found 299.1072. Enantiomeric excess: 94%,
determined by HPLC (Chiralcel OD-H, hexane–isopropanol =
85 : 15, flow rate 0.7 mL min−1, λ = 254 nm): tR = 21.6 min
(minor), tR = 81.7 min (major). The relative and absolute
configurations were tentatively assigned by analogy.
((2R,3S)-6-Chloro-2-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-
1
(phenyl)ethanone (3Ao). Yield: 93%. H NMR (CDCl3, TMS,
300 MHz): δ 7.93 (m, 2H), 7.60 (m, 1H), 7.50 (m, 2H), 7.16
(m, 3H), 7.05 (m, 2H), 6.84 (m, 2H), 6.57 (d, J = 8.3 Hz, 1H),
5.02 (t, J = 3.2 Hz, 1H), 4.49 (d, J = 2.9 Hz, 1H), 4.17 (m, 1H),
3.09 (dd, J = 17.0, 11.2 Hz, 1H), 2.77 (dd, J = 16.5, 4.0 Hz,
1H). 13C NMR (CDCl3, TMS, 100 MHz): δ 199.1, 142.0, 140.9,
136.9, 133.2, 129.2, 128.9, 128.3, 128.1, 127.8, 127.2, 126.6,
121.8, 121.2, 114.4, 56.9, 44.4, 24.9. MS: m/z (% relative inten-
sity) 349(M+ + 2, 17), 348(M+ + 1, 13), 347(M+, 48), 242(100),
227(71); HRMS: m/z calcd for C22H18ONCl (M+) 347.1071,
found 347.1069. [α]2D0 = −188.7 (c 1.10, EtOAc); Enantiomeric
1-((2R,3S)-2-(Biphenyl-4-yl)-6-chloro-1,2,3,4-tetrahydroquino-
1
lin-3-yl)ethanone (3Aq). Yield: 84%. H NMR (CDCl3, TMS,
400 MHz): δ 7.57 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H),
7.45 (t, J = 7.3 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.21 (d, J =
8.2 Hz, 2H), 7.04 (m, 2H), 6.53 (m, 1H), 4.93 (d, J = 3.7 Hz,
1H), 4.50 (brs, 1H), 3.21 (m, 1H), 2.96 (dd, J = 16.7, 10.2 Hz,
1H), 2.84 (dd, J = 16.7, 4.8 Hz, 1H), 2.09 (s, 3H). 13C NMR
(CDCl3, TMS, 100 MHz): δ 207.9, 142.2, 140.7, 140.4, 140.3,
7216 | Org. Biomol. Chem., 2012, 10, 7208–7219
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Typical procedure for synthesis of chiral 2,4-disubstituted
1,2,3,4-tetrahydroquinolines. To a mixture of (tBu)2(o-biphenyl)-
PAu(CH3CN)SbF6 (0.012 mmol, 3 mol%) and 5 Å molecular
sieves (1 g) in dry benzene (6.0 mL) were added 2-aminophe-
none (0.4 mmol) and alkyne (0.48 mmol) at room temperature.
The reaction mixture was stirred at 75 °C and the evolution of
the reaction was monitored by TLC until completion. Then
phosphoric acid 5 (0.02 mmol, 5 mol%) and ethyl Hantzsch
ester 4 (1.0 mmol) were successively added at the same reaction
temperature. The resulting reaction mixture was stirred at 60 °C
and monitored by TLC. Upon completion, the reaction mixture
was filtered through a plug of silica (eluting with CH2Cl2) to
remove the molecular sieves, and then concentrated in vacuo.
The residue was purified by silica gel chromatography (eluent:
hexane–ethyl acetate = 300 : 1 to 100 : 1) to afford the enantio-
enriched product 3.
129.1, 128.8, 127.5, 127.3, 127.2, 127.1, 127.0, 121.9, 120.6,
114.9, 55.8, 50.4, 29.8, 25.5. MS: m/z (% relative intensity) 361
(M+, 50), 342(100), 167(93), 149(63); HRMS: m/z calcd for
C23H20ONCl (M+) 361.1228, found 361.1224. [α]2D0 = –161.9
(c 0.90, EtOAc); Enantiomeric excess: 93%, determined by
HPLC (Chiralcel OD-H, hexane–isopropanol = 83 : 17, flow rate
1.2 mL min−1, λ = 254 nm): tR = 45.3 min (minor), tR
=
78.3 min (major). The relative and absolute configurations were
tentatively assigned by analogy.
1-((2R,3S)-6-Chloro-2-(4-chlorophenyl)-1,2,3,4-tetrahydro-
1
quinolin-3-yl)ethanone (3Ar). Yield: 74%. H NMR (CDCl3,
TMS, 300 MHz): δ 7.23 (d, J = 8.5 Hz, 2H), 7.06 (d, J =
8.5 Hz, 2H), 7.01 (m, 2H), 6.52 (m, 1H), 4.89 (d, J = 3.6 Hz,
1H), 4.45 (brs, 1H), 3.17 (m, 1H), 2.86 (m, 2H), 2.06 (s, 3H).
13C NMR (CDCl3, TMS, 75 MHz): δ 207.7, 141.8, 139.8,
133.7, 129.1, 128.6, 128.1, 127.4, 122.1, 120.3, 114.9, 55.4,
50.1, 29.8, 25.3. MS: m/z (% relative intensity) 321(M+ + 2, 37),
320(M+ + 1, 15), 319(M+, 58), 276(100), 240(49); HRMS: m/z
(2R,4S)-2-(4-Methoxyphenyl)-4-phenyl-1,2,3,4-tetrahydroqui-
1
noline (3Lb). Yield: 89%. H NMR (CDCl3, TMS, 300 MHz):
δ 7.25 (m, 7H), 6.98 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.6 Hz,
2H), 6.62 (d, J = 7.5 Hz, 1H), 6.53 (t, J = 7.8 Hz, 2H), 4.52 (dd,
J = 10.0, 3.7 Hz, 1H), 4.27 (dd, J = 11.1, 6.4 Hz, 1H), 3.98 (brs,
1H), 3.76 (s, 3H), 2.19 (m, 2H). 13C NMR (CDCl3, TMS,
75 MHz): δ 159.1, 145.4, 145.3, 136.0, 129.6, 128.7, 128.5,
127.7, 127.2, 126.4, 124.7, 117.5, 114.2, 113.9, 56.6, 55.2, 45.0,
42.1. MS: m/z (% relative intensity) 315(M+, 100), 236(74), 194
(67); HRMS: m/z calcd for C22H21ON (M+) 315.1618, found
315.1605. [α]2D0 = 49.5 (c 0.74, EtOAc); Enantiomeric excess:
87%, determined by HPLC (Chiralcel OD-H, hexane–isopropa-
nol = 95 : 5, flow rate 0.5 mL min−1, λ = 254 nm): tR = 24.9 min
(minor), tR = 35.2 min (major). The relative and absolute
configurations were tentatively assigned by analogy.
calcd for C17H15ONCl2 (M+) 319.0525, found 319.0528. [α]2D0
=
−206.3 (c 1.97, EtOAc); Enantiomeric excess: 96%, determined
by HPLC (Chiralcel OD-H, hexane–isopropanol = 85 : 15, flow
rate 1.0 mL min−1, λ = 254 nm): tR = 16.6 min (minor), tR
=
69.0 min (major). The relative and absolute configurations were
tentatively assigned by analogy.
4-((2R,3S)-3-Aceyl-6-chloro-1,2,3,4-tetrahydroquinolin-2-yl)-
benzonitrile (3As). Yield: 72%. 1H NMR (CDCl3, TMS,
300 MHz): δ 7.55 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H),
7.04 (m, 2H), 6.55 (m, 1H), 4.99 (d, J = 4.0 Hz, 1H), 3.22 (m,
1H), 2.85 (m, 2H), 2.12 (s, 3H). 13C NMR (CDCl3, TMS,
75 MHz): δ 207.2, 146.7, 141.4, 132.2, 129.2, 127.7, 127.6,
122.5, 120.0, 118.5, 115.0, 111.7, 55.5, 49.9, 29.7, 25.2. MS:
m/z (% relative intensity) 312(M+ + 2, 19), 311(M+ + 1, 9), 310
(M+, 54), 267(100), 232(47); HRMS: m/z calcd for
C18H15ON2Cl (M+) 310.0867, found 310.0864. [α]2D0 = −170.4
(c 0.90, EtOAc); Enantiomeric excess: 97%, determined by
HPLC (Chiralcel OD-H, hexane–isopropanol = 83 : 17, flow rate
(2R,4S)-6-Chloro-2-(4-methoxyphenyl)-4-phenyl-1,2,3,4-tetra-
hydroquinoline (3Mb). Yield: 93%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.32 (m, 4H), 7.23 (m, 3H), 6.93 (m, 1H), 6.87
(d, J = 6.9 Hz, 2H), 6.59 (dd, J = 2.3, 1.0 Hz, 1H), 6.46 (d, J =
8.5 Hz, 1H), 4.51 (dd, J = 11.0, 2.8 Hz, 1H), 4.22 (dd, J = 12.0,
5.6 Hz, 1H), 4.01 (brs, 1H), 3.78 (s, 3H), 2.18 (m, 2H). 13C
NMR (CDCl3, TMS, 100 MHz): δ 159.2, 144.4, 144.0, 135.5,
129.2, 128.7, 128.6, 127.7, 127.1, 126.8, 126.3, 121.9, 115.3,
114.0, 56.6, 55.3, 44.9, 41.6. MS: m/z (% relative intensity) 351
(M+ + 2, 34), 350(M+ + 1, 36), 349(M+, 100), 270(58), 193(31),
121(40); HRMS: m/z calcd for C22H20ONCl (M+) 349.1228,
found 349.1221. [α]2D0 = 43.6 (c 0.97, EtOAc); Enantiomeric
excess: 94%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 95 : 5, flow rate 0.5 mL min−1, λ = 254 nm): tR =
36.6 min (minor), tR = 67.6 min (major). The relative and absol-
ute configurations were tentatively assigned by analogy.
1.2 mL min−1, λ = 254 nm): tR = 31.3 min (minor), tR
=
96.1 min (major). The relative and absolute configurations were
tentatively assigned by analogy.
1-((2R,3S)-2-(Biphenyl-4-yl)-6-bromo-1,2,3,4-tetrahydroquino-
1
lin-3-yl)ethanone (3Dq). Yield: 83%. H NMR (CDCl3, TMS,
300 MHz): δ 7.45 (m, 7H), 7.19 (m, 4H), 6.50 (d, J = 8.2 Hz,
1H), 4.95 (d, J = 3.7 Hz, 1H), 4.50 (brs, 1H), 3.22 (m, 1H), 2.98
(dd, J = 16.7, 10.2 Hz, 1H), 2.84 (dd, J = 16.5, 4.8 Hz, 1H),
2.10 (s, 3H). 13C NMR (CDCl3, TMS, 75 MHz): δ 207.9, 142.6,
140.7, 140.3, 140.2, 132.0, 130.1, 128.8, 127.5, 127.2, 127.1,
127.0, 121.1, 115.3, 109.0, 55.7, 50.3, 29.8, 25.4. MS: m/z (%
relative intensity) 407(M+ + 2, 47), 406(M+ + 1, 22), 405(M+,
51), 362(59), 283(69), 167(100); HRMS: m/z calcd for
C23H20ONBr (M+) 405.0723, found 405.0715. [α]2D0 = –134.7 (c
0.80, EtOAc); Enantiomeric excess: 89%, determined by HPLC
(Chiralcel OD-H, hexane–isopropanol = 80 : 20, flow rate
(2R,4S)-4-(4-Bromophenyl)-2-(4-methoxyphenyl)-1,2,3,4-tetra-
hydroquinoline (3Nb). Yield: 98%. 1H NMR (CDCl3, TMS,
300 MHz): δ 7.48 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H),
7.17 (d, J = 8.4 Hz, 2H), 7.06 (m, 1H), 6.95 (d, J = 8.6 Hz, 2H),
6.64 (m, 3H), 4.58 (dd, J = 10.7, 2.7 Hz, 1H), 4.32 (dd, J =
11.8, 5.7 Hz, 1H), 4.08 (brs, 1H), 3.85 (s, 3H), 2.22 (m, 2H).
13C NMR (CDCl3, TMS, 75 MHz): δ 159.2, 145.5, 144.6,
135.8, 131.7, 130.5, 129.6, 127.8, 127.5, 124.0, 120.2, 117.7,
114.4, 114.1, 56.6, 55.4, 44.5, 42.1. MS: m/z (% relative inten-
sity) 395(M+ + 2, 50), 394(M+ + 1, 34), 393(M+, 53), 224(100),
1.2 mL min−1, λ = 254 nm): tR = 45.7 min (minor), tR
=
75.4 min (major). The relative and absolute configurations were
tentatively assigned by analogy.
This journal is © The Royal Society of Chemistry 2012
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193(44); HRMS: m/z calcd for C22H20ONBr (M+) 393.0723,
found 393.0714. [α]2D0 = 77.0 (c 0.87, EtOAc); Enantiomeric
excess: 88%, determined by HPLC (Chiralcel OD-H, hexane–
isopropanol = 98 : 2, flow rate 0.5 mL min−1, λ = 254 nm): tR =
54.2 min (minor), tR = 74.7 min (major). The relative and absol-
ute configurations were determined by X-ray crystallographic
analysis.
(2R,4S)-6-Chloro-2,4-diphenyl-1,2,3,4-tetrahydroquinoline
(3Ma). Yield: 81%. H NMR (CDCl3, TMS, 300 MHz): δ 7.30
1
(m, 10H), 6.93 (m, 1H), 6.59 (t, J = 1.2 Hz, 1H), 6.46 (d, J =
8.5 Hz, 1H), 4.55 (dd, J = 10.9, 2.9 Hz, 1H), 4.22 (dd, J = 12.0,
5.6 Hz, 1H), 4.04 (brs, 1H), 2.19 (m, 2H). 13C NMR (CDCl3,
TMS, 75 MHz): δ 143.8, 143.4, 142.9, 128.6, 128.2, 128.0,
127.3, 126.6, 126.3, 126.0, 125.8, 121.5, 114.8, 56.7, 44.3, 41.1.
MS: m/z (% relative intensity) 321(M+ + 2, 33), 320(M+ + 1,
35), 319(M+, 100), 240(74), 193(64), 71(61); HRMS: m/z calcd
for C21H18NCl (M+) 319.1122, found 319.1120. [α]2D0 = 43.6
(c 1.02, EtOAc); Enantiomeric excess: 90%, determined by
HPLC (Chiralcel OD-H, hexane–isopropanol = 97 : 3, flow rate
(2R,4R)-2-(4-Methoxyphenyl)-4-methyl-1,2,3,4-tetrahydroqui-
1
noline (3Ob). Yield: 94%. H NMR (CDCl3, TMS, 300 MHz):
δ 7.40 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 7.5 Hz, 1H), 7.07 (t, J =
7.8 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H),
6.56 (d, J = 7.9 Hz, 1H), 4.48 (dd, J = 11.4, 1.6 Hz, 1H), 3.93
(brs, 1H), 3.87 (s, 3H), 3.19 (m, 1H), 2.14 (m, 1H), 1.81 (q, J =
11.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3,
TMS, 75 MHz): δ 159.1, 144.9, 136.6, 127.7, 126.9, 126.8,
126.0, 117.5, 114.1, 114.0, 56.4, 55.3, 41.7, 31.3, 20.1. MS: m/z
(% relative intensity) 253(M+, 100), 238(37), 144(28), 132(45);
HRMS: m/z calcd for C17H19ON (M+) 253.1461, found
253.1461. [α]2D0 = 93.4 (c 1.13, EtOAc); Enantiomeric excess:
85%, determined by HPLC (Chiralcel AD-H, hexane–isopropa-
nol = 95 : 5, flow rate 0.5 mL min−1, λ = 254 nm): tR = 17.8 min
(major), tR = 26.5 min (minor). The relative and absolute
configurations were tentatively assigned by analogy.
0.5 mL min−1, λ = 254 nm): tR = 37.2 min (minor), tR
=
51.4 min (major). The relative and absolute configurations were
tentatively assigned by analogy.
(2R,4S)-2-(4-Bromophenyl)-6-chloro-4-phenyl-1,2,3,4-tetra-
hydroquinoline (3Mu). Yield: 79%. 1H NMR (CDCl3, TMS,
300 MHz): δ 7.46 (m, 2H), 7.28 (m, 7H), 6.97 (m, 1H), 6.61
(dd, J = 2.4, 1.1 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 4.56 (dd, J =
11.1, 2.8 Hz, 1H), 4.25 (dd, J = 12.1, 5.6 Hz, 1H), 4.04 (brs,
1H), 2.18 (m, 2H). 13C NMR (CDCl3, TMS, 100 MHz):
δ 144.1, 143.6, 142.5, 131.8, 129.2, 128.8, 128.5, 128.3, 127.2,
126.9, 126.3, 122.3, 121.5, 115.5, 56.7, 44.7, 41.6. MS: m/z (%
relative intensity) 399(M+ + 2, 100), 398(M+ + 1, 51), 397(M+,
92), 320(79), 228(50); HRMS: m/z calcd for C21H17NBrCl (M+)
397.0227, found 397.0238. [α]2D0 = 35.8 (c 1.25, EtOAc); Enan-
tiomeric excess: 88%, determined by HPLC (Chiralcel AS-H,
hexane–isopropanol = 97 : 3, flow rate 0.5 mL min−1, λ =
254 nm): tR = 29.7 min (minor), tR = 34.5 min (major). The rela-
tive and absolute configurations were tentatively assigned by
analogy.
(2R,4S)-2-(Biphenyl-4-yl)-4-phenyl-1,2,3,4-tetrahydroquinoline
1
(3Lf). Yield: 73%. H NMR (CDCl3, TMS, 400 MHz): δ 7.56
(m, 6H), 7.44 (m, 2H), 7.29 (m, 6H), 7.02 (t, J = 7.6 Hz, 1H),
6.61 (m, 3H), 4.67 (dd, J = 11.0, 2.9 Hz, 1H), 4.34 (dd, J =
12.0, 5.6 Hz, 1H), 4.11 (brs, 1H), 2.28 (m, 2H). 13C NMR
(CDCl3, TMS, 100 MHz): δ 145.3, 145.2, 143.0, 140.8, 140.7,
129.7, 128.8, 128.7, 128.6, 127.4, 127.3, 127.2, 127.1, 127.0,
126.5, 124.8, 117.7, 114.3, 57.0, 45.0, 42.1. MS: m/z (% relative
intensity) 361(M+, 100), 356(76), 282(77), 194(47); HRMS: m/z
calcd for C27H23N (M+) 361.1825, found 361.1834. [α]2D0 = 72.5
(c 1.25, EtOAc); Enantiomeric excess: 86%, determined by
HPLC (Chiralcel OD-H, hexane–isopropanol = 85 : 15, flow rate
Bioinformatic analysis and experimental validation. Chemical
similarity analysis19 was performed to investigate the potential
biological applications of the chiral tetrahydroquinolines studied
here. Experimental validations were performed at Cerep
Company. The human recombinant 1321N1 cells were firstly
stimulated by 3 nM of MRS2365. The activation of P2Y1 recep-
tor is known to enhance the intracellular Ca2+ level. The tested
0.7 mL min−1, λ = 254 nm): tR = 21.2 min (major), tR
=
29.7 min (minor). The relative and absolute configurations were
tentatively assigned by analogy.
compounds were subsequently added at the dose of 5 × 10−5
M
and incubated at room temperature. The intracellular Ca2+ level
was determined by fluorimetric method. The analysis was
performed using software developed at Cerep (Hill software).
(2R,4S)-2-(Biphenyl-4-yl)-6-chloro-4-phenyl-1,2,3,4-tetrahydro-
quinoline (3Mf). Yield: 91%. 1H NMR (CDCl3, TMS,
400 MHz): δ 7.56 (d, J = 8.1 Hz, 4H), 7.47 (d, J = 8.0 Hz, 2H),
7.42 (t, J = 7.6 Hz, 2H), 7.32 (m, 3H), 7.22 (m, 3H), 6.94 (m,
1H), 6.61 (t, J = 1.0 Hz, 1H), 6.47 (d, J = 8.5 Hz, 1H), 4.58 (dd,
J = 11.0, 2.4 Hz, 1H), 4.23 (dd, J = 12.0, 5.4 Hz, 1H), 4.05 (brs,
1H), 2.23 (m, 2H). 13C NMR (CDCl3, TMS, 100 MHz):
δ 144.3, 143.9, 142.5, 140.9, 140.7, 129.2, 128.8, 128.7, 128.6,
127.5, 127.4, 127.2, 127.1, 127.0, 126.8, 126.3, 122.1, 115.4,
56.9, 44.9, 41.6. MS: m/z (% relative intensity) 397(M+ + 2, 36),
396(M+ + 1, 41), 395(M+, 100), 316(74), 269(41), 178(42);
HRMS: m/z calcd for C27H22NCl (M+) 395.1435, found
395.1416. [α]2D0 = 15.5 (c 0.89, EtOAc); Enantiomeric excess:
90%, determined by HPLC (Chiralcel AD-H, hexane–isopropa-
nol = 95 : 5, flow rate 0.5 mL min−1, λ = 254 nm): tR = 31.7 min
(major), tR = 41.7 min (minor). The relative and absolute
configurations were tentatively assigned by analogy.
Acknowledgements
We are thankful for the financial support of The University of
Hong Kong (University Development Fund), Hong Kong
Research Grants Council and University Grants Committee of
Hong Kong (Areas of Excellence Scheme AoE/P-10/01).
Notes and references
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