General asymmetric hydrogenation of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by iridium-difluorphos: Unusual halide effect and synthetic application

Article abstract of DOI:10.1021/jo300455y

A general asymmetric hydrogenation of a wide range of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by an iridium-difluorphos complex has been developed. Under mild reaction conditions, the corresponding biologically relevant 2-substit

Full text of DOI:10.1021/jo300455y

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General Asymmetric Hydrogenation of 2-Alkyl- and 2-Aryl-
Substituted Quinoxaline Derivatives Catalyzed by Iridium-
Difluorphos: Unusual Halide Effect and Synthetic Application
Damien Cartigny,†,‡ Farouk Berhal,†,‡ Takuto Nagano,§,∥ Phannarath Phansavath,†,‡ Tahar Ayad,†,‡
Jean-Pierre Genet,†,‡ Takashi Ohshima,*,§ Kazushi Mashima,*,∥ and Virginie Ratovelomanana-Vidal*,†,‡
̂
†ENSCP Chimie ParisTech, Laboratoire Charles Friedel (LCF), 75005 Paris, France
‡CNRS, UMR 7223, 75005 Paris, France
§Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
∥Graduate School of Engineering Sciences, Osaka University, Toyonaka, Osaka 560-8631, Japan
S
* Supporting Information
ABSTRACT: A general asymmetric hydrogenation of a wide
range of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives
catalyzed by an iridium−difluorphos complex has been devel-
oped. Under mild reaction conditions, the corresponding bio-
logically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline
units were obtained in high yields and good to excellent enantio-
selectivities up to 95%. With a catalyst ratio of S/C = 1000 and
on a gram scale, the catalytic activity of the Ir−difluorphos complex was maintained showing its potential value. Finally, we
demonstrated the application of our process in the synthesis of compound (S)-9, which is an inhibitor of cholesteryl ester transfer
protein (CETP).
conversion of 54%. Three years later, the same group reported
the synthesis of new iridium and rhodium complexes bearing
(R,R)-BPP-BzP as a ligand, which allowed the formation of 2a
in excellent yields up to 93% but with considerably lower ee
values of 23 and 11%, respectively.9c In 2003, Henschke et al.9d
showed that a wide range of ruthenium complexes of the type
[RuCl2(diamine)(diphosphine)] can be efficiently used to hydro-
genate 1a. For example, complete conversion and 73% ee were
obtained when the electron-rich (S)-Xyl-HexaPHEMP ligand was
used in combination with the chiral (S,S)-DACH diamine. Similar
results were subsequently described in 2006 by Chan et al.9e using
the [Ir(μ-Cl)(cod)]2/PQ-Phos/I2 catalyst system (99% conv,
80% ee). As can be seen from the above examples, the substrate
scope for the asymmetric hydrogenation of quinoxaline deriva-
tives described so far in the literature was restricted to 2-
methylquinoxaline 1a. During the course of our study, Xu, Fan,
and Chan9f reported in 2009 the first general asymmetric
hydrogenation of a wide range of 2-alkyl-substituted quinoxa-
line derivatives, with good to excellent enantioselectivities ranging
from 85 to 98%, using the [Ir(μ-Cl)(cod)]2/H8−Binapo/I2
catalyst generated in situ. Simultaneously, de Vries, Minnaard,
and Feringa9g described comparable results in terms of both
reactivity and selectivity using a combination of [Ir(μ-Cl)(cod)]2
and their monodentate phosphoramidite PipPhos ligand in the
presence of piperidine hydrochloride as additive (75 to 96% ee).
INTRODUCTION
■
Asymmetric hydrogenation of prochiral unsaturated compounds
using inexpensive, clean molecular hydrogen and small amounts of
a chiral catalyst is considered as one of the most efficient and atom
economical ways to produce a wide range of enantioenriched
compounds on large scale without forming any waste.1
Asymmetric hydrogenation of ketones, imines and olefins, has
been intensively studied and usually provided high levels of
selectivity, whereas asymmetric hydrogenation of heteroaromatic
compounds has been much less explored until very recently,
because of the high stability of heteroarenes and deactivation and/
or poisoning of the catalysts by the presence of heteroatoms.
Despite these challenges, significant progress in the development
of transition-metal-catalyzed asymmetric hydrogenation of hetero-
aromatic compounds2 such as quinolines,3 indoles,4 pyrroles,5
furanes,6 pyridines,7 and pyrazines8 has been made in the past
decade. In sharp contrast, asymmetric hydrogenation of quinoxa-
line derivatives9 has been rarely explored, despite the fact that
tetrahydroquinoxaline cores are subunits of many biologically
active compounds (Figure 1).10 In 1987, Murata et al.9a described
the first example of asymmetric hydrogenation of 2-methylqui-
noxaline 1a using an hydridorhodium catalyst containing the
(+)-DIOP ligand, resulting in the formation of 2-methyl-
tetrahydroquinoxaline 2a in 72% yield but with only 3% of ee.
A great improvement for the same substrate was reported by
Bianchini et al.9b in 1998, using an orthometalated iridium
dihydride complex, providing the hydrogenated product 2a
in good enantioselectivity, up to 90%, but with a modest
Received: March 8, 2012
© XXXX American Chemical Society
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Figure 1. Previous ligands used for the asymmetric hydrogenation of quinoxalines.
Although the above catalytic systems showed high selectivity
for asymmetric hydrogenation of 2-alkyl-substituted quinoxa-
lines, they turned out to be less efficient for the reduction of 2-
aryl-substituted quinoxaline derivatives. Indeed, 84% ee was
obtained for the hydrogenation of 2-phenylquinoxaline and 2-
o′-MeO-phenylquinoxaline substrates using [Ir(μ-Cl)(cod)]2/
H8−Binapo/I2,9f whereas an enantiomeric excess of 86% was
achieved with [Ir(μ-Cl)(cod)]2/PipPhos/piperidine·HCl.9g
Using [Ir(μ-Cl)(cod)]2/SegPhos as catalyst in the presence
of Brønsted acid, a moderate ee of 65% was obtained for the
hydrogenation of 2-phenylquinoxaline by Zhou et al.9h,i In
2011, Zhou and Fan disclosed an efficient metal/Brønsted acid
relay catalysis for asymmetric reduction of 2-aryl quinoxalines
through convergent disproportionation of dihydroquinoxalines
with good to excellent enantioselectivities ranging from 83 to
96%.9k Fan and co-workers9l also reported a highly efficient
asymmetric transfer hydrogenation of 2-alkyl- and 2-aryl-
substituted quinoxalines by using a cationic Ru(η6-cymene)-
(monosulfonylated diamine)(BarF) system under 80 atm of H2
pressure (94 to 99% ee). In addition to metal-catalyzed asym-
metric hydrogenation, a highly enantioselective organocatalyzed
transfer hydrogenation of 2-aryl quinoxalines using Hantzsh
esters as a hydride source has also been developed by Rueping
et al. (80 to 98% ee).9j
reaction temperature, catalyst loading, and substrates. At first,
we examined the effect of the counterion.13 Several cationic
iridium precursors bearing weakly coordinating counterions
such as BF4 , NO3 , OTf−, PF6 , SbF6 , and BarF− were pre-
pared and tested in the hydrogenation of 2-methylquinoxaline
1a (Table 1). The reaction was carried out in toluene, at 50 bar
−
−
−
−
a
Table 1. Iridium Precursor Effect
b
c
entry
iridium precursor
conv (%)
ee (%)
1
2
3
4
5
6
7
[Ir(μ-Cl)(cod)]2
>99
63
89
40
40
50
73
76
86
[Ir(cod)2]+BF4
−
[Ir(cod)2]+NO3
71
−
[Ir(cod)2]+OTf−
>99
>99
>99
>99
[Ir(cod)2]+PF6
−
[Ir(cod)2]+SbF6
−
[Ir(cod)2]+BarF−
a
b
Reaction conditions: 1a (1.0 mmol). Conversion was determined by
c
1H NMR of the crude product. Enantiomeric excess (ee) was de-
termined by chiral stationary phase-supercritical fluid chromatography
(CSP-SFC) on a Chiralcel AD-H column.
In previous communications,11,12 we demonstrated that
Difluorphos was an efficient ligand for the iridium-catalyzed
asymmetric hydrogenation of 2-substituted quinoxaline11 and
quinoline12 derivatives. In the present study, we wish to report
the full details of both our investigations in designing an
optimized Ir/ligand catalyst for the enantioselective hydro-
genation of a full set of 2-alkyl- and 2-aryl-substituted quinoxalines
and a straightforward synthesis of an inhibitor of cholesteryl ester
transfer protein (CETP) developed by Pfizer for the treatment of
diverse diseases including atherosclerosis and obesity.10a
of hydrogen pressure and 30 °C, using 1 mol % of catalyst, pre-
pared in situ from [Ir(cod)2]+X− with (S)-Difluorphos ligand in
the presence of 2 mol % of I2 as additive.
The results listed in Table 1 clearly indicated that the stereo-
chemical outcome of the reaction is strongly dependent on the
nature of the cationic iridium precursor. When [Ir(cod)2]+BF4
−
or [Ir(cod)2]+NO3 were used, both conversions and enantio-
−
selectivities decreased significantly compared to the results
obtained with the neutral [Ir(μ-Cl)(cod)]2 complex (Table 1,
compare entries 1 vs 2, 3). The [Ir(cod)2]+OTf− precursor gave
full conversion but with only a moderate enantioselectivity of
50% (Table 1, entry 4). A better catalytic activity was achieved
RESULTS AND DISCUSSION
■
On the basis of the good results previously obtained with
Difluorphos for the asymmetric hydrogenation of heteroaromatic
compounds,11,12 we started our investigation by searching for
the best catalyst system using Difluorphos as chiral auxiliary to
perform asymmetric hydrogenation of 2-methylquinoxaline 1a
as a model substrate. We focused on optimizing a few param-
eters such as metal precursor, additive, solvent, H2 pressure,
when [Ir(cod)2]+PF6 , [Ir(cod)2]+SbF6 , and [Ir(cod)2]+BarF−
were used, providing the 2-methyl tetrahydroquinoxaline 2a
in 73, 76, and 86% ee respectively, with complete conversion
(Table 1, entries 5−7). Finally, from this iridium catalyst
−
−
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screening, [Ir(μ-Cl)(cod)]2 emerged as the most suitable metal
precursor in terms of both reactivity and selectivity (Table 1,
entry 1).
It is well-known that additives could play a crucial role in
improving the reactivity and selectivity of many asymmetric
reactions.14 We and others have recently reported that acids can
be used as additives to improve the stereochemical outcome in
ruthenium-catalyzed asymmetric hydrogenation of α-ketoest-
ers15 and β-ketoesters.16 Accordingly, we decided to evaluate
the effect of such additives for the asymmetric hydrogenation of
1a under the above reaction conditions. As demonstrated in
Table 2, good to excellent conversions were obtained, but the
a
Table 2. Effect of Acids as Additives
b
c
d
entry
additive
conv (%)
ee (%)
e
1
I2
>99
7
89
19
74
81
84
85
86
89
89
90
2
PPTS
HI
3
>99
>99
>99
>99
>99
90
4
HCl
HBr
TsOH
5
6
Figure 2. Ligands L1−L11 used in this study.
7
CH3CO2H
H2SO4
a
8
Table 3. Screening of Ligands
9
HBF4
>99
10
Piperidine·HCl
>99
a
b
Reaction conditions: 1a (1.0 mmol). 10 mol % of additive.
c
Conversion was determined by 1H NMR of the crude product.
d
Enantiomeric excess (ee) was determined by chiral stationary phase-
b
c
d
supercritical fluid chromatography (CSP-SFC) on a Chiralcel AD-H
column. 2 mol % of iodine were used.
entry
ligand
ee (%)
ee (%) with I2
e
1
L1 (S)-Ship
62
76
33
82
33
49
82
77
81
84
90
14
12
12
18
13
38
48
58
67
74
89
2
L2 (S)-Siphos
3
L3 (S)-Siphos-PE
L4 (R)-Monophos
L5 (S)-tol-SDP
L6 (S,S)-Diop
selectivity of the reaction was greatly influenced by the nature
of the acids. Very low reactivity and enantiomeric excess were ob-
tained with PPTS, while the use of aqueous HX (X = Br, Cl, I),
TsOH, or CH3COOH slightly decreased the ee values of the
hydrogenated product 2a (Table 2, compare entries 1 vs 2−7).
When the reaction was performed in the presence of H2SO4 or
HBF4, no difference was observed regarding the selectivity
compared to the result obtained with iodine (Table 2, entries 8,
9 vs 1). Finally, piperidine·HCl salt was found to be an efficient
additive, since it afforded the best result in terms of enantio-
selectivity, providing the desired 2-methyl-tetrahydroquinoxaline
2a in 90% ee, with complete conversion (Table 2, entry 10).
These results were in agreement with those previously re-
ported by de Vries, Minnaard, and Feringa9g considering the
asymmetric hydrogenation of quinoline and quinoxaline
derivatives using the [Ir(μ-Cl)(cod)]2/PipPhos/piperidine·HCl
catalytic system. We therefore performed a screening of a range
of chiral ligands (Figure 2) and a comparative study between
piperidine·HCl and I2 as additives (Table 3). The reactions
were conducted in dichloromethane at 60 °C under 25 bar of
hydrogen pressure and with either 10 mol % of piperidine·HCl
salt or 2 mol % of I2 using 1 mol % of catalyst, prepared in situ
by mixing [Ir(μ-Cl)(cod)]2 and the corresponding L1−L11
ligands (Figure 2). Excellent conversions were obtained with an
enantioselectivity depending on the nature of the considered
ligand. This screening demonstrated that spiromonodentate
4
5
6
7
L7 (S,R)-Josiphos
L8 (S)-Binap
8
9
L9 (S)-MeO-Biphep
L10 (S)-Synphos
L11 (S)-Difluorphos
10
11
a
b
Reaction conditions: 1a (1.0 mmol). Conversion was determined by
1H NMR of the crude product. All conversions were complete except
c
for L3 (35%). Enantiomeric excess (ee) was determined by chiral
stationary phase-supercritical fluid chromatography (CSP-SFC) on a
Chiralcel AD-H column. Absolute configuration was determined to be
S by comparison of the specific rotation with reported data. With 2
d
mol % of iodine as additive instead of piperidine HCl.
phosphorus ligands L1−L317 led to moderate enantioselectiv-
ities (Table 3, entries 1−3, 33−76%). When the reaction was
carried out with Monophos L4,18 an increased enantioselectivity
up to 82% ee was observed (Table 3, entry 4). With the exception
of (S)-tol-SDP L5,17 which provided 33% ee, better results were
obtained with bidentate phosphorus ligands compared to
monodentate phosphorus ligands (Table 3, entries 5−11). (S,S)-
Diop L619 and (S,R)-Josiphos L720 afforded the reduced product
2 with respectively 49 and 82% ee (Table 3, entries 6−7).
C
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The data of Table 3 clearly show that among all the tested
bidendate ligands, atropisomeric diphosphines were found to be
the more effective. The (S)-Binap L821 and (S)-MeO-Biphep
L922 diphosphines gave 77 and 81% ee, respectively, while (S)-
Synphos L1023 and (S)-Difluorphos L11,24 developed in our
group, resulted in an enhancement of the enantioselectivity up to
90% with the electron deficient Difluorphos ligand (Table 3,
entries 8−11), so this ligand was selected for further studies. For
this comparative study, a dramatic improvement of enantio-
selectivity was observed when using piperidine·HCl instead of
iodine (Table 3). One exception was the result obtained with
Difluorphos ligand L11, for which no significant difference was
observed in terms of both reactivity and enantioselectivity
(Table 3, entry 11).
reaction between NaPF6 and the corresponding chloride and
bromide complexes 3c and 3b, respectively. Initial experiments
were performed under the standard set of reaction conditions
(30 °C, 50 bar of H2, S/C = 100, toluene) and the results are
depicted in Table 4. In almost all cases, complete conversions were
obtained, but the selectivity of the reaction was greatly influenced
by the nature of the catalyst.
When the reaction was carried out with {[IrH((S)-Synphos)]2-
(μ-I)3}+I− catalyst 3a, the desired hydrogenated product 2a was
obtained in 72% ee (Table 4, entry 1). The use of catalysts
{[IrH((S)-Synphos)]2(μ-Br)3}+Br− 3b and {[IrH((S)-Synphos)]2-
(μ-Cl)3}+Cl− 3c did not improve the selectivity of the reaction,
since it resulted in the formation of 2a in 75% ee (Table 4,
entries 2−3). In contrast, a marked decrease in enantiose-
lectivity was observed when the reaction was conducted in the
Recently, we have reported a new class of cationic dinuclear
triply halogen-bridged iridium complexes {[Ir(H)((S)-diphos-
phine)]2(μ-X)3}X (Table 4, 3a−3h), which proved to be highly
−
presence of catalysts {[IrH((S)-Synphos)]2(μ-Cl)3}+PF6 3d
and {[IrH((S)-Synphos)]2(μ-Br)3}+PF6− 3e bearing the weakly
−
coordinating PF6 counterion instead of chloride or bromide.
This result indicated that the counterion associated with the
catalyst had a significant impact on the enantioselectivity
(Table 4, entries 4, 5). When the (S)-Synphos ligand was
replaced by (S)-Difluorphos, comparable results in terms of both
conversion and enantioselectivity were obtained for the triply
iodide-bridged catalyst {[IrH((S)-Difluorphos)]2(μ-I)3}+I− 3f.
Finally, we were pleased to find that the use of {[IrH((S)-
Difluorphos)]2(μ-Br)3}+Br− catalyst 3g greatly improved the
selectivity of the reaction, giving (S)-2a in 87% ee (Table 4,
entry 7). An even higher enantioselectivity was obtained with
{[IrH((S)-Difluorphos)]2(μ-Cl)3}+Cl− catalyst 3h bearing chlor-
ide ligand, providing the 2-methyl-tetrahydroquinoxaline (S)-2a
with an ee up to 92% (Table 4, entry 8). It should be noted that
this unprecedented halide dependence was once again in good
agreement with our earlier observations on the asymmetric
hydrogenation of 2-aryl- and 2-alkyl-substituted quinolinium salts
for which chloro- and bromo-iridium catalysts gave better catalytic
performance than the corresponding iodo-iridium catalyst.12
With the optimal catalyst 3h in hand, we then decided to
study other parameters that might improve the enantioselec-
tivity of the reaction. To this end, the effects of solvent, tem-
perature, and hydrogen pressure were examined using 1 mol %
of catalyst {[(IrH((S)-Difluorphos)]2(μ-Cl)3}+Cl− 3h. As illu-
strated in Table 5, complete conversions were obtained for all
tested solvents, but the selectivity of the reaction was found to
be strongly solvent-dependent (Table 5, entries 1−7). The use
of MeOH resulted in the formation of the hydrogenated
product 2a in a low 19% ee with the opposite (R) configura-
tion, whereas running the reaction in i-PrOH provided (S)-2a
in a moderate ee of 53% (Table 5, entries 1 and 2). The reac-
tion proceeded well in dichloromethane, tetrahydrofuran,
dioxane, diethylether with enantioselectivities ranging from 85
to 90% ee (Table 5, entries 3−6), but from this solvent screen-
ing, toluene proved to be the solvent of choice, providing the
desired 2-methyl-tetrahydroquinoxaline 2a in 92% ee (Table 5,
entry 7). The data in Table 5 also illustrated that variation of
the temperature and the hydrogen pressure had only little effect
on the catalytic activity in terms of both conversion and
selectivity (Table 5, entries 8−13). A temperature increase led
to a decrease in selectivity, giving 2a with 90% ee, whereas an
excellent ee, up to 93%, was obtained when the reaction was
carried out at 10 °C, but with a lower conversion of 86% (Table 5,
compare entries 8 vs 9 and 10). A change in the hydrogen
pressure from 10 to 70 bar had little impact on the stereo-
chemical outcome of the reaction, since an excellent catalytic
Table 4. Asymmetric Hydrogenation of 1a Using
{[Ir(H)((S)-diphosphine)]2(μ-X)3}Y Catalysts
a
b
c
entry
catalyst
conv (%)
ee (%)
1
2
3
4
5
6
7
8
{[IrH((S)-Synphos)]2(μ-I)3}+I−
{[IrH((S)-Synphos)]2(μ-Br)3}+Br−
{[IrH((S)-Synphos)]2(μ-Cl)3}+Cl−
{[IrH((S)-Synphos)]2(μ-Cl)3}+PF6
{[IrH((S)-Synphos)]2(μ-Br)3}+PF6
{[IrH((S)-Difluorphos)]2(μ-I)3}+I−
{[IrH((S)-Difluorphos)]2(μ-Br)3}+Br−
{[IrH((S)-Difluorphos)]2(μ-Cl)3}+Cl−
>99
>99
>99
>99
93
72
75
75
48
64
69
87
92
−
−
>99
>99
>99
a
b
Reaction conditions: 1a (1.0 mmol). Conversion was determined by
c
1H NMR of the crude product. Enantiomeric excess (ee) was
determined by chiral stationary phase-supercritical fluid chromatog-
raphy (CSP-SFC) on a Chiralcel AD-H column.
efficient catalysts for asymmetric hydrogenation of quinoline
derivatives.12 On the basis of our previous work,11 we therefore
decided to evaluate the catalytic potential of these complexes in
the hydrogenation of 1a. Several catalysts bearing (S)-Synphos23
(3a−3e) and (S)-Difluorphos24 (3f−3h) ligands were prepared
by reacting the free ligands with [IrCl(coe)2]2 in toluene at room
temperature in the presence of an excess of aqueous HX (X = Cl,
Br, I).25 Complexes 3d and 3e were obtained by anion metathesis
D
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a
derivatives in high enantiomeric excesses and excellent yields
(Table 6, entries 7−13, 94−98% yield and 86−92% ee). Com-
parable results in terms of both chemical yield and enantioselec-
tivity were obtained with 2-alkyl-substituted quinoxalines bearing a
methyl substituent at the 6- and 7-positions of the aromatic ring,
regardless of the size of the alkyl chain (Table 6, entries 14−16,
97−98% yield and 90−91% ee).
The absolute configuration of the 2-phenethyl-1,2,3,4-tetra-
hydroquinoxaline 2g was determined to be S on the basis of a
single-crystal X-ray structure analysis27 of the corresponding 4-
N-tosyl-2-phenethyl-1,2,3,4-tetrahydroquinoxaline 6 (Figure 3).
The configurations of the other products were then assigned by
analogy and by comparison with literature data.
Table 5. Optimization of the Reaction Conditions
b
c
entry
solvent
H2 (bar)
T (°C)
conv (%)
ee (%)
1
MeOH
i-PrOH
CH2Cl2
THF
50
50
50
50
50
50
50
50
50
50
70
30
10
50
50
30
30
30
30
30
30
30
10
50
70
30
30
30
50
>99
>99
>99
>99
>99
>99
>99
86
19 (R)
53 (S)
88 (S)
85 (S)
85 (S)
90 (S)
92 (S)
93 (S)
90 (S)
90 (S)
92 (S)
94 (S)
94 (S)
94 (S)
94 (S)
2
3
4
5
dioxane
Et2O
6
7
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
To broaden the scope of this reaction, we challenged the
hydrogenation of 2-aryl-substituted-quinoxalines 4a−4t.28 The
results are presented in Table 7. In contrast to 2-alkyl-quinoxaline
derivatives, the reaction conducted in toluene under 30 bar of H2
at 30 °C using catalyst 3h gave complete conversion but a
disappointingly low enantiomeric excess of 60%. A rapid screening
of solvents revealed that dioxane gave the best results, providing
the desired 2-phenyl-tetrahydroquinoxaline 5a in 89% ee (Table 7,
entries 1−4). Using these new reaction conditions, all substrates
were hydrogenated in high chemical yields and with moderate to
excellent asymmetric inductions (Table 7, entries 4−23, 89−99%
yield and 60−94% ee). The electron-withdrawing or electron-
donating substituents on the phenyl ring influenced the selectivity
of the reaction. A slight improvement in enantioselectivity was
observed with arylquinoxaline derivatives 4b, 4d, and 4f bearing
methyl or methoxy groups at the ortho or para positions
compared to the 2-phenylquinoxaline 4a, resulting in the
formation of the hydrogenated products 5b, 5d, and 5f in 90−
91% ee (Table 7, entries 5, 7 and 9). The same substituents at the
meta position (4c and 4e) showed lower enantiomeric excesses
(Table 7, entries 6 and 8, 86% and 87% ee). A similar trend was
observed for 2-aryl-substituted quinoxalines containing electron-
withdrawing groups irrespective of the nature of the substituents.
Indeed, hydrogenation of compounds 4h, 4i, and 4j with p-NO2,
p-F, and p-Cl groups gave good to excellent enantioselectivities
ranging from 89 to 94% (Table 7, entries 11−13), whereas the
bromide derivative 4l provided 5l with 86% ee (Table 7, entry 15).
The same reaction conducted with m-NO2 and m-Br quinoxaline
derivatives 4g and 4k gave slightly lower selectivities, 85 and 88% ee,
respectively (Table 7, entries 10 and 14). The results depicted in
Table 7 also illustrated that the asymmetric hydrogenation of 2-
aryl substituted quinoxalines bearing a methyl substituent at the 6-
and 7-positions of the aromatic ring proceeded well but led to a
significant decrease in the catalytic activity (Table 7, compare
entries 4, 7, 9, 13, and 15 vs 16, 18, 20, 22, and 23). Furthermore,
the reaction appears to be sensitive to the electronic nature of the
substituent attached to the 2-substituted aromatic ring. Indeed,
substrates bearing electron-donating groups were reduced in
lower enantioselectivities (Table 7, entries 17−20, 60−66% ee)
than those with electron-withdrawing substituents (Table 7,
entries 21−23, 72−79% ee).
8
9
>99
>99
>99
>99
95
10
11
12
13
d
14
>99
>99
e
15
50
a
b
Reaction conditions: 1a (1.0 mmol). Conversion was determined by
c
1H NMR of the crude product. Enantiomeric excess was determined
by chiral stationary phase-supercritical fluid chromatography (CSP-
SFC) on a Chiralcel AD-H column. Reactions run with S/C = 500
d
e
for 36 h. Reactions run with S/C = 1000 for 36 h.
activity was still maintained, with enantiomeric excesses ranging
from 92 to 94% (Table 5, entries 11−13). Interestingly, the
catalyst loading could be reduced from 1 to 0.2 or 0.1% without
erosion of the enantioselectivity, although the reaction was
required to be conducted at 50 °C and 50 bar of H2 for 36 h to
reach completion (Table 5, entries 14, 15).
Through these screenings, the best reaction conditions for
asymmetric hydrogenation of 1a were therefore set as the
following: 1 mol % of {[(IrH((S)-Difluorphos)]2(μ-Cl)3}+Cl−
3h as catalyst, toluene as solvent, under 30 bar of H2 at 30 °C.
Under these optimized conditions, we then investigated the
scope of the reaction. To this end, several 2-alkyl-substituted
quinoxalines were prepared according to known procedures26
and subsequently hydrogenated. As outlined in Table 6, all
2-alkyl-quinoxaline derivatives 1a−p were quantitatively con-
verted to their corresponding tetrahydroquinoxaline derivatives
2a−p in excellent chemical yields and good to excellent
enantioselectivities (Table 6, entries 1−16, 94−99% yield and
82−95% ee). The length of the alkyl chain had a significant
effect on the ee values (Table 6, entries 1−6). When the methyl
group at the 2-position was replaced by an ethyl group as in 1b,
a slight increase in enantioselectivity up to 95% was observed,
while substrate 1d bearing an isopropyl substituent gave similar
results to those obtained with the 2-methylquinoxaline 1a
(Table 6, entries 1, 2, and 4). The n-butyl- and phenethyl-
substituted derivatives 1c and 1f resulted in an enantiomeric
excess of 91% (Table 6, entries 3 and 6), whereas the bulky t-
butyl group 1e led to a drastic drop in selectivity (Table 6,
entry 5, 82% ee). In the case of 2-styryl-substituted quinoxa-
lines 1g−m, the reaction proceeded well, and the position and
the nature of the substituent on the phenyl ring of the styryl
moiety seem to have no significant effect on the stereochemical
outcome of the reaction. However, as already observed by
Fan et al.,9l both the double bond and the quinoxaline ring were
simultaneously reduced, giving 2-phenethyl-tetrahydroquinoxaline
Finally, in the context of the importance of tetrahydroqui-
noxaline derivatives as biologically relevant molecules,10 we
demonstrated the application of our process in the synthesis of
compound (S)-9, which is an inhibitor of cholesteryl ester transfer
protein (CETP), developed by Pfizer for the treatment of diverse
diseases including atherosclerosis and obesity.10a Thus, the
hydrogenation of 6,7-dimethyl-2-ethylquinoxaline 1o was
carried out on a gram scale using the optimized reaction condi-
tions to give (S)-2o in a quantitative chemical yield with 91% ee.
E
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a
Table 6. Asymmetric Hydrogenation of 2-Alkyl-quinoxalines
a
b
c
Reaction conditions: 1 (1.0 mmol). Yield after flash column chromatography on silica gel. In each case, complete conversion was achieved.
Enantiomeric excess was determined by chiral stationary phase-supercritical fluid chromatography (CSP-SFC) on Chiralcel AD-H and OD-H
d
columns for 2a−p (see the Supporting Information). Absolute configuration was determined to be S by comparison of the specific rotation with
e
reported data. The CC bond was also hydrogenated.
Subsequent chemoselective N-Boc protection afforded com-
pound 7, which was then treated with ethylchloroformate to
give 8. A final Boc deprotection using neat TFA led to the
formation of the target molecule (S)-9 with 90% ee and 57%
overall yield (Scheme 1).
corresponding quinoxaline derivatives, using a cationic di-
nuclear iridium(III) chloride complex bearing Difluorphos as a
ligand. A notable feature of this catalyst system is the super-
iority of the chloro-iridium catalyst over the corresponding
iodo-iridium catalyst, which is opposite to the halide effect
usually observed. Moreover, the efficiency of our catalyst system
was demonstrated through the broad substrate scope of the
reaction. Indeed, a large variety of 2-alkyl- and 2-aryl-substituted
quinoxalines were hydrogenated in high chemical yields and with
excellent enantioselectivities up to 95% ee. Finally, to illustrate the
CONCLUSION
■
In conclusion, we have developed a convenient and efficient
protocol for the preparation of relevant chiral 2-substituted
tetrahydroquinoxalines by asymmetric hydrogenation of their
F
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CSP-SFC (Chiralcel AD-H, scCO2/MeOH 85:15, 5 mL/min, P =
100 bar, λ = 215 nm) t1 = 3.08 min (minor), t2 = 4.21 min (major,
ee = 94%); [α]24D = −34.6 (c 1.0, CH2Cl2; lit.9g −34.4, c 0.065, CH2Cl2,
93% ee (S)); mp = 80 °C.
(S)-2-Ethyl-1,2,3,4-tetrahydroquinoxaline (2b). (Known com-
9g
1
pound ), yellow oil, 0.160 g, 0.99 mmol, 99% yield: H NMR (300
MHz, CDCl3) δ 6.62−6.59 (m, 2H), 6.53−6.50 (m, 2H), 3.64 (br,
2H), 3.40 −3.36 (dd, J = 10.5, 3.0 Hz, 1H), 3.33−3.25 (m, 1H), 3.10−
3.04 (dd, J = 10.5, 7.8 Hz, 1H), 1.58−1.49 (m, 2H), 1.02 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 133.4, 133.3, 118.6, 118.4, 114.3,
114.3, 51.6, 46.2, 27.0, 10.0; CSP-SFC (Chiralcel AD-H, scCO2/
MeOH 85:15, 5 mL/min, P = 100 bar, λ = 215 nm) t1 = 3.41 min
Figure 3. Structure of N-tosyl tetrahydroquinoxaline derivative 6.
(minor), t2 = 4.08 min (major, ee = 95%); [α]24 = −37.6 (c 1.0,
D
CH2Cl2; lit.9g −30.1, c 0.105, CH2Cl2, 89% ee (S)).
(S)-2-Butyl-1,2,3,4-tetrahydroquinoxaline (2c). (Known com-
pound9g), yellow solid, 0.186 g, 0.98 mmol, 98% yield: 1H NMR
(300 MHz, CDCl3) δ 6.61−6.57 (m, 2H), 6.54−6.50 (m, 2H), 3.59
(br, 2H), 3.39−3.32 (m, 2H), 3.10−3.03 (m, 1H), 1.50−1.35 (m, 6H),
0.92−0.95 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 133.5,
133.4, 118.6, 118.5, 114.40, 114.3, 50.2, 46.6, 34.0, 27.8, 22.8, 14.0;
CSP-SFC (Chiralcel OD-H, scCO2/MeOH 85:15, 5 mL/min, P = 100
bar, λ = 215 nm) t1 = 2.84 min (minor), t2 = 4.04 min (major, ee =
applicability of the present method, we synthesized compound
(S)-9, an inhibitor of cholesteryl ester transfer protein (CETP),
developed by Pfizer for the treatment of diverse diseases such
as atherosclerosis and obesity.10a
EXPERIMENTAL SECTION
■
General Information. All reactions were run under an atmosphere
of argon. Reaction vessels were flame-dried under a vacuum and
cooled under a stream of argon. Toluene and dichloromethane
(DCM) were distilled on calcium hydride prior to use. THF, dioxane,
and diethylether (Et2O) were distilled on sodium/benzophenone prior
to use. Isopropanol and methanol were distilled on sodium prior to
use. All the solvents were degassed prior to use. Proton nuclear
magnetic resonance (1H NMR) spectra were recorded using a 300
MHz apparatus. Chemical shifts are reported in delta (δ) units, part
per million (ppm) downfield from tetramethylsilane (TMS) relative to
the singlet at 7.26 ppm for deuterochloroform. Coupling constants are
reported in Hertz (Hz). The following abbreviations are used: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad. Carbon-13 nuclear
magnetic resonance (13C NMR) spectra were recorded using a 75 MHz
apparatus. Chemical shifts are reported in delta (δ) units, part per million
(ppm) relative to the center line of the triplet at 77.0 ppm for
deuterochloroform. 13C NMR spectra were routinely run with broadband
decoupling. Analytical thin layer chromatography (TLC) was carried out
using commercial silica-gel plates, and spots were detected with UV light
and revealed with KMnO4 or Kagi−Mosher solutions (add 15 mL of
AcOH and 3.5 mL of p-anisaldehyde to 350 mL of ice cold EtOH, and
cautiously add 50 mL of concentrated H2SO4 dropwise over 60 min).
Enantiomeric excesses were determined by HPLC using Chiralcel
columns (OD-H or IB) and eluting with hexane/isopropanol mixture
as indicated or chiral stationary phase−supercritical fluid chromatography
(CSP−SFC) using Chiralcel columns (AD-H or IA) and eluting with a
scCO2/isopropanol mixture as indicated. Optical rotations were measured
on a polarimeter at 589 nm (sodium lamp). High resolution mass spec-
troscopic (HRMS) analysis were measured on LTQ-Orbitrap (Thermo
Fisher Scientific) at Pierre et Marie Curie University.
91%); [α]24 = −35.4 (c 1.0, CH2Cl2; lit.9g −30.4, c 0.150, CH2Cl2,
D
93% ee (S)); mp = 51 °C.
(S)-2-Isopropyl-1,2,3,4-tetrahydroquinoxaline (2d). (Known
11
1
compound ), brown solid, 0.172 g, 0.98 mmol, 98% yield: H NMR
(300 MHz, CDCl3) δ 6.65−6.60 (m, 2H), 6.57−6.52 (m, 2H), 3.68
(br, 2H), 3.39−3.36 (m, 1H), 3.21−3.11 (m, 2H), 1.83−1.71 (m, 1H),
1.08 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 133.7, 133.3, 118.5, 118.2, 114.1, 55.8, 43.8, 30.9, 18.6, 18.4;
CSP-SFC (Chiralcel OD-H, scCO2/MeOH 85:15, 5 mL/min, P = 100
bar, λ = 215 nm) t1 = 2.33 min (minor), t2 = 2.83 min (major, ee =
94%); HRMS (ESI) m/z calcd for C11H17N2 (MH+) 177.1392, found
177.1388; [α]24 = −36.2 (c 1.0, CH2Cl2); mp = 54 °C.
(S)-2-t-ButyDl-1,2,3,4-tetrahydroquinoxaline (2e). (Known
compound9g), brown solid, 0.186 g, 0.98 mmol, 98% yield: 1H
NMR (300 MHz, CDCl3) δ 6.63−6.56 (m, 2H), 6.54−6.49 (m, 2H),
3.53 (br, 2H), 3.40−3.32 (m, 1H), 3.19−3.11 (m, 2H), 1.00 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 134.5, 133.2, 118.8, 118.1, 114.3, 114.2,
58.9, 42.4, 33.54, 26.0; CSP-SFC (Chiralcel OD-H, scCO2/MeOH
85:15, 5 mL/min, P = 100 bar, λ = 215 nm) t1 = 1.89 min (minor),
t2 = 2.20 min (major, ee = 82%); [α]24 = −5.6 (c 1.0, CH2Cl2; lit.9g
D
−18.9, c 0.090, CH2Cl2, 85% ee (S)); mp = 73 °C.
(S)-2-Phenethyl-1,2,3,4-tetrahydroquinoxaline (2f). (Known
9f
1
compound ), brown solid, 0.230 g, 0.97 mmol, 97% yield: H NMR
(300 MHz, CDCl3) δ 7.40−7.26 (m, 5H), 6.68−6.65 (m, 2H), 6.55−
6.51 (m, 2H), 3.60 (br, 2H), 3.42−3.35 (m, 2H), 3.14−3.08 (dd, J =
9.9, 8.1 Hz, 1H), 2.78 (t, J = 7.5 Hz, 2H), 1.86 (quartet. J = 7.5 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 141.4, 133.2, 133.1, 128.3, 128.2,
125.8, 118.5, 118.4, 114.3, 114.2, 49.6, 46.1, 35.6, 31.9; CSP-SFC
(Chiralcel OD-H, scCO2/MeOH 80:20, 5 mL/min, P = 100 bar, λ =
215 nm) t1 = 5.86 min (minor), t2 = 9.58 min (major, ee = 91%);
General Procedure for the Ir-Catalyzed Asymmetric Hydro-
genation of 2-Substituted Quinoxalines. A glass tube was charged
with 2-substituted quinoxaline (1 mmol) and iridium dinuclear
complex (5 μmol, 0.50 mol %). The tube was placed in a stainless
steel autoclave, which was subjected to three vacuum/argon cycles.
Anhydrous and degassed solvent (7 mL) was then added under argon.
The hydrogenation was performed at 30 °C under an atmosphere of
hydrogen (30 bar) for 20 h. After the careful release of the hydrogen
gas, the resulting mixture was filtrated through a short pad of silica gel
and concentrated under reduced pressure. The conversion was deter-
[α]24 = −46.3 (c 1.0, CH2Cl2; lit.9f −30.5, c 0.98, CHCl3, 75% ee
D
(S)); mp = 64 °C.
(S)-2-(2-p-Tolyl-ethyl)-1,2,3,4-tetrahydroquinoxaline (2h).
(Known compound9f), yellow solid, 0.244 g, 0.97 mmol, 97% yield:
1H NMR (300 MHz, CDCl3) δ 7.10−6.95 (m, 4H), 6.55−6.35 (m,
4H), 3.60−3.32 (brs, 2H), 3.30−3.20 (m, 2H), 3.05−2.90 (m, 1H),
2.70−2.55 (m, 2H), 2.23 (s, 3H), 1.70 (quartet, J = 7.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 137.4, 134.5, 132.3, 128.2, 127.2, 117.7,
117.6, 113.5, 113.4, 48.8, 45.4, 34.9, 30.6, 20.0; CSP-SFC (Chiralcel
OD-H, scCO2/MeOH 80:20, 5 mL/min, P = 100 bar, λ = 215 nm)
t1 = 5.64 min (minor), t2 = 9.91 min (major, ee = 91%); mp = 55 °C.
(S)-2-(2-o-Tolyl-ethyl)-1,2,3,4-tetrahydroquinoxaline (2i). Or-
ange solid, 0.241 g, 0.96 mmol, 96% yield: 1H NMR (300 MHz,
CDCl3) δ 7.20−7.10 (m, 4H), 6.65−6.55 (m, 2H), 6.54−6.46 (m,
2H), 3.50−3.40 (m, 2H), 3.20−3.13 (m, 1H), 2.80−2.70 (m, 2H),
2.33 (s, 3H), 1.85−1.74 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
139.9, 135.9, 133.4, 130.5, 128.9, 126.4, 126.3, 118.9, 118.8, 114.7,
114.6, 50.3, 46.6, 34.7, 29.6, 19.5; CSP-SFC (Chiralcel IB, scCO2/
1
mined by H NMR analysis of the crude product, and the enantio-
meric excess was determined by chiral SFC/HPLC analysis of the
filtrate using a Chiralcel OD-H, AD-H, IA or IB column.
(S)-2-Methyl-1,2,3,4-tetrahydroquinoxaline (2a). (Known
compound9g), orange solid, 0.147 g, 0.99 mmol, 99% yield: 1H
NMR (300 MHz, CDCl3) δ 6.61−6.58 (m, 2H), 6.54−6.48 (m, 2H),
3.55−3.49 (m, 1H), 3.34−3.30 (dd, J = 10.5, 3.0 Hz, 1H), 3.07−3.01
(dd, J = 10.5, 8.1 Hz, 1H), 1.19 (d, J = 6.30 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 133.5, 133.1, 118.6, 114.4, 114.3, 48.2, 45.6, 19.8;
G
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a
Table 7. Asymmetric Hydrogenation of 2-Aryl-Substituted Quinoxalines
a
b
Reaction conditions: 4 (1.0 mmol). In each case, complete conversion was achieved. Yield after flash column chromatography on silica gel.
c
Enantiomeric excess was determined by HPLC or SFC on a Chiralcel OD-H column for 5a−t (see the Supporting Information). Absolute
d
configuration was determined to be S by comparison of the specific rotation with reported data. 77% conversion was obtained.
MeOH 80:20, 4 mL/min, P = 150 bar, λ = 215 nm) t1 = 4.19 min
(minor), t2 = 6.02 min (major, ee = 88%); HRMS (ESI) m/z calcd for
C17H21N2 (MH+) 253.1699, found 253.1697; [α]24 = −26.0 (c 1.23,
CHCl3); mp = 54 °C.
D
H
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(75 MHz, CDCl3) δ 131.3, 130.9, 126.4, 126.3, 116.3, 48.5, 46.0, 19.8,
18.8; CSP-SFC (Chiralcel OD-H, scCO2/MeOH 80:20, 5 mL/min,
P = 100 bar, λ = 215 nm) t1 = 2.26 min (minor), t2 = 3.47 min (major,
Scheme 1. Asymmetric Synthesis of Pfizer’s CETP Inhibitor
(S)-9
ee = 90%); [α]24 = −29.7 (c 1.0, CH2Cl2; lit.9g −26.5, c = 0.150,
D
CH2Cl2, 87% ee (S)); mp = 74 °C.
(S)-2-Ethyl-6,7-dimethyl-1,2,3,4-tetrahydroquinoxaline (2o).
(Known compound9g), brown solid, 0.186 g, 0.98 mmol, 98% yield:
1H NMR (300 MHz, CDCl3) δ 6.32 (s, 1H), 6.31 (s, 1H), 3.47 (br,
2H), 3.33−3.28 (dd, J = 10.8, 3.0 Hz, 1H), 3.24−3.17 (m, 1H), 3.02−
2.96 (dd, J = 10.8, 8.1 Hz, 1H), 2.10 (s, 6H), 1.53−1.42 (m, 2H), 0.98
(t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 131.2, 131.1, 126.2,
126.0, 116.1, 51.8, 46.4, 26.9, 18.7, 9.9; CSP-SFC (Chiralcel OD-H,
scCO2/MeOH 80:20, 5 mL/min, P = 100 bar, λ = 215 nm) t1 = 2.28
min (minor), t2 = 3.81 min (major, ee = 91%); [α]24D = −36.2 (c 1.0,
CH2Cl2; lit.9g −35.5, c 0.150, CH2Cl2, 91% ee (S)); mp = 74 °C.
(S)-2-Butyl-6,7-dimethyl-1,2,3,4-tetrahydroquinoxaline (2p).
(Known compound11), yellow solid, 0.211 g, 0.97 mmol, 97% yield:
1H NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 6.40 (s, 1H), 3.62 (br,
2H), 3.40−3.37 (m, 2H), 3.12−3.05 (dd, J = 10.8, 8.4 Hz, 1H), 2.23
(s, 6H), 1.56−1.48 (m, 6H), 1.06 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 131.1, 131.0, 125.9, 125.7, 116.02, 50.2, 46.7, 33.7, 27.6,
22.67, 18.8, 13.8; CSP-SFC (Chiralcel OD-H, scCO2/MeOH 80:20,
5 mL/min, P = 100 bar, λ = 215 nm) t1 = 2.64 min (minor), t2 =
5.29 min (major, ee = 91%) HRMS (ESI) m/z calcd for C14H23N2
(S)-2-(2-Naphthalen-1-yl-ethyl)-1,2,3,4-tetrahydroquinoxa-
line (2j). Orange solid, 0.270 g, 0.94 mmol, 94% yield: 1H NMR (300
MHz, CDCl3) δ 8.03 (d, J = 7.43 Hz, 1H), 7.92−7.85 (m, 1H), 7.72
(d, J = 7.45 Hz, 1H), 7.60−7.50 (m, 2H), 7.45−7.35 (m, 2H), 6.65−
6.50 (m, 4H), 3.60−3.45 (m, 2H), 3.25−3.15 (m, 3H), 2.05−1.90 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 137.7, 134.1, 133.3, 131.8, 129.0,
127.1, 126.1, 125.7, 123.7, 119.1, 118.9, 114.8, 114.7, 50.3, 46.6, 35.2,
29.4; CSP-SFC (Chiralcel IA, scCO2/MeOH 80:20, 4 mL/min, P =
150 bar, λ = 215 nm) t1 = 11.26 min (minor), t2 = 11.81 min (major,
ee = 86%); HRMS (ESI) m/z calcd for C20H21N2 (MH+) 289.1699,
(MH+) 219.1861, found 219.1856; [α]24 = −38.4 (c 1.0, CH2Cl2);
D
mp = 54 °C.
(S)-2-Phenyl-1,2,3,4-tetrahydroquinoxaline (5a). (Known
compound9g), yellow solid, 0.206 g, 0.98 mmol, 98% yield: 1H
NMR (400 MHz, CDCl3) δ 7. 42−7.33 (m, 5H), 6.67−6.58 (m, 4H),
4.48 (d, J = 5.6 Hz, 1H), 3.82 (br s, 2H), 3.47 (dd, J = 10.4, 2.0 Hz,
1H), 3.34 (t, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.9,
134.1, 132.7, 128.7, 127.8, 126.9, 118.8, 118.7, 114.7, 114.4, 54.7, 49.1;
HPLC (Chiralcel OD-H, hexane/iPrOH 90:10, 1 mL/min, λ =
254 nm) t1 = 21.5 min (minor), t2 = 32.8 min (major, ee = 89%);
HRMS (EI) m/z calcd for C14H14N2 (M+) 210.1157, found 210.1180;
found 289.1702; [α]24 = −22.3 (c 1.10, CHCl3); mp = 70 °C.
D
(S)-2-[2-(2-Chloro-phenyl)-ethyl]-1,2,3,4-tetrahydroquinoxa-
1
line (2k). Yellow solid, 0.265 g, 0.97 mmol, 97% yield: H NMR
[α]24 = −23.8 (c 0.17, CHCl3; lit.9g −10.5, c 0.10, CH2Cl2, 85% ee
(300 MHz, CDCl3) δ 7.36 (dd, J = 3 Hz, 9 Hz, 1H), 7.25−7.15 (m,
3H), 6.65−6.50 (m, 4H), 3.54 (brs, 2H), 3.45−3.40 (m, 2H), 3.15
(dd, J = 6 Hz, 9 Hz, 1H), 2.90−2.85 (m, 2H), 1.90−1.80 (m, 2H); 13C
NMR (CDCl3, 75 MHz) δ 139.2, 133.9, 133.4, 133.3, 130.4, 129.7,
127.7, 127.1, 119.0, 118.9, 114.8, 114.7, 49.9, 46.4, 34.3, 29.8; CSP-
SFC (Chiralcel IA, scCO2/MeOH 80:20, 4 mL/min, P = 150 bar, λ =
215 nm) t1 = 6.07 min (minor), t2 = 6.52 min (major, ee = 90%);
HRMS (ESI) m/z calcd for C16H18N2Cl (MH+) 273.1153, found
D
(S)); mp = 109 °C.
(S)-2-o-Tolyl-1,2,3,4-tetrahydroquinoxaline (5b). (Known
compound11), pale yellow oil, 0.217 g, 0.97 mmol, 97% yield: 1H
NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 1H), 7.13−7.04 (m,
3H), 6.52−6.41 (m, 4H), 4.56 (dd, J = 8.0, 2.8 Hz, 1H), 3.66 (br, 2H),
3.29 (dd, J = 10.8, 2.8 Hz, 1H), 3.11 (dd, J = 10.8, 8.0 Hz, 1H), 2.28
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.5, 135.0, 134.3, 132.7,
130.2, 130.0, 127.2, 126.4, 118.6, 118.5, 114.5, 114.3, 50.5, 47.6, 19.0;
HPLC (Chiralcel OD-H, hexane/iPrOH 95:5, 1 mL/min, λ =
254 nm) t1 = 34.8 min (minor), t2 = 39.3 min (major, ee = 91%);
HRMS (EI) m/z calcd for C15H16N2 (M+) 224.1313, found 224.1302;
273.1156; [α]24 = +46.9 (c 1.45, CHCl3); mp = 62 °C.
D
(S)-2-[2-(2-Methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydroqui-
noxaline (2l). Red oil, 0.257 g, 0.96 mmol, 96% yield: 1H NMR (300
MHz, CDCl3) δ 7.25−7.10 (m, 2H), 6.95−6.85 (m, 2H), 6.60−6.45
(m, 4H), 3.85 (s, 3H), 3.45−3.30 (m, 2H), 3.20−3.10 (m, 1H), 2.85−
2.70 (m, 2H), 1.85−1.75 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
157.3, 133.2, 129.9, 129.8, 127.3, 120.6, 118.8, 118.6, 114.5, 110.3,
55.3, 49.4, 46.7, 34.3, 25.9; CSP-SFC (Chiralcel IA, scCO2/i-PrOH
80:20, 4 mL/min, P = 150 bar, λ = 215 nm) t1 = 5.92 min (major, ee =
87%), t2 = 6.83 min (minor); HRMS (ESI) m/z calcd for C17H21ON2
[α]24 = −18.2 (c 0.26, CHCl3).
D
(S)-2-m-Tolyl-1,2,3,4-tetrahydroquinoxaline (5c). (Known
compound11), pale yellow oil, 0.220 g, 0.98 mmol, 98% yield: 1H
NMR (400 MHz, CDCl3) δ 7.07−7.22 (m, 4H), 6.59−6.56 (m, 2H),
6.50−6.47 (m, 2H), 4.39−4.32 (m, 1H), 3.79 (s, 2H), 3.34 (d, J = 8.8
Hz, 1H), 3.23 (t, J = 9.2 Hz, 1H), 2.32 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 142.3, 138.6, 134.6, 133.2, 129.0, 128.9, 128.1, 124.5, 119.2,
119.1, 115.1, 114.8, 55.1, 49.6, 21.8; HPLC (Chiralcel OD-H, hexane/
iPrOH 90:10, 1 mL/min, λ = 254 nm) t1 = 15.9 min (minor), t2 =
22.4 min (major, ee = 86%); HRMS (EI) m/z calcd for C15H16N2
(MH+) 269.1648, found 269.1649; [α]24 = +77.4 (c 1.15, CHCl3).
D
(S)-2-[2-(4-Methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydroqui-
1
noxaline (2m). Red solid, 0.260 g, 0.97 mmol, 97% yield: H NMR
(300 MHz, CDCl3) δ 7.12 (d, J = 9 Hz, 2H), 6.84 (d, J = 9 Hz, 2H),
6.65−6.57 (m, 2H), 6.55−6.45 (m, 2H), 3.80 (s, 3H), 3.45−3.33 (m,
2H), 3.18−3.05 (m, 1H), 2.75−2.65 (m, 2H), 1.85−1.75 (m, 2H); 13C
NMR (CDCl3, 75 MHz) δ 158.1, 133.6, 133.4, 129.4, 118.8, 114.7,
114.6, 114.1, 55.4, 49.9, 46.6, 36.1, 31.3; CSP-SFC (Chiralcel OD-H,
scCO2/MeOH 80:20, 4 mL/min, P = 150 bar, λ = 215 nm) t1 = 5.88
min (major, ee = 91%), t2 = 8.74 min (minor); HRMS (ESI) m/z
(M+) 224.1313, found 224.1287; [α]24 = −3.6 (c 1.27, CHCl3).
D
(S)-2-p-Tolyl-1,2,3,4-tetrahydroquinoxaline (5d). (Known
11
1
compound ), yellow oil, 0.222 g, 0.99 mmol, 99% yield: H NMR
(400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.6 Hz,
1H), 6.58−6.55 (m, 2H), 6.49−6.46 (m, 2H), 4.33 (d, J = 6.0 Hz,
1H), 3.83 (s, 2H), 3.33 (d, J = 9.2 Hz, 1H), 3.21 (t, J = 5.2 Hz, 1H),
2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.8, 137.1, 134.0,
132.6, 129.0, 128.3, 128.2, 126.7, 118.5, 118.3, 114.4, 114.1, 54.2, 49.0,
20.8; HPLC (Chiralcel OD-H, hexane/iPrOH 90:10, 1 mL/min, λ =
254 nm) t1 = 16.8 min (minor), t2 = 24.4 min (major, ee = 91%);
HRMS (EI) m/z calcd for C15H16N2 (M+) 224.1313, found 224.1333;
calcd for C17H21ON2 (MH+) 269.1648, found 269.1649; [α]24
+37.7 (c 1.06, CHCl3); mp = 88 °C.
=
D
(S)-2,6,7-Trimethyl-1,2,3,4-tetrahydroquinoxaline (2n).
(Known compound9g), brown solid, 0.172 g, 0.98 mmol, 98% yield:
1H NMR (300 MHz, CDCl3) δ 6.34 (s, 1H), 6.33 (s, 1H), 3.50−3.43
(m, 2H), 3.31−3.26 (dd, J = 3.0, 10.8 Hz, 1H), 3.03−2.96 (dd, J =
10.8, 8.1 Hz, 1H), 2.10 (s, 6H), 1.18 (d, J = 6.3 Hz, 3H); 13C NMR
[α]24 = −4.2 (c 0.95, CHCl3).
D
I
dx.doi.org/10.1021/jo300455y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(S)-2-(3-Methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline (5e).
2H), 6.63−6.61 (m, 2H), 6.55−6.53 (m, 2H), 4.40 (br, 1H), 3.83 (br,
2H), 3.40 (d, J = 5.4 Hz, 1H), 3.24 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 141.0, 133.6, 132.6, 131.6, 128.6, 121.5, 118.9,
114.6, 114.4, 54.0, 53.4, 48.8; HPLC (Chiralcel OD-H, hexane/iPrOH
80:20, 1 mL/min, λ = 254 nm) t1 = 17.9 min (minor), t2 = 38.4 min
(major, ee = 86%); HRMS (EI) m/z calcd for C14H13BrN2 (M+)
11
1
(Known compound ), red oil, 0.233 g, 0.97 mmol, 97% yield: H
NMR (400 MHz, CDCl3) δ 7.22 (t, J = 8.0 Hz, 1H), 6.93−6.90 (m,
2H), 6.80 (ddd, J = 8.4, 2.4, 0.8 Hz, 1H), 6.59−6.56 (m, 2H), 6.51−
6.48 (m, 2H), 4.35 (d, J = 5.6 Hz, 1H), 3.80 (br, 2H), 3.74 (s, 3H),
3.36 (d, J = 9.2 Hz, 1H), 3.23 (t, J = 9.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 159.7, 143.5, 133.9, 132.6, 129.3, 119.1, 118.6, 118.5,
114.5, 114.2, 113.0, 112.3, 55.0, 54.4, 48.9; HPLC (Chiralcel OD-H,
hexane/iPrOH 90:10, 1 mL/min, λ = 254 nm) t1 = 30.4 min (minor),
t2 = 51.2 min (major, ee = 87%); HRMS (EI) m/z calcd for C15H16N2O
288.0262, found 288.0229; [α]24 = −8.6 (c 0.41, CHCl3).
D
(S)-6,7-Dimethyl-2-phenyl-1,2,3,4-tetrahydroquinoxaline
1
(5m). Yellow solid, 0.226 g, 0.95 mmol, 95% yield: H NMR (300
MHz, CDCl3,) δ 7.50−7.27 (m, 5H), 6.41 (s, 2H), 4.45 (brs, 1H),
3.70 (brs, 2H), 3.50−3.20 (m, 2H), 2.13 (brs, 6H); 13C NMR (CDCl3,
75 MHz) δ 142.2, 130.5, 128.7, 127.9, 127.1, 126.6, 116.9, 116.3, 55.2,
49.6, 19.1; CSP-SFC (Chiralcel IA, scCO2/MeOH 80:20, 4 mL/min,
P = 150 bar, λ = 215 nm) t1 = 7.26 min (major, ee = 67%), t2 =
8.92 min (minor); HRMS (ESI) m/z calcd for C16H19N2 (MH+) 239.1542,
(M+) 240.1263, found 240.1239; [α]24 = −2.8 (c 1.22, CHCl3).
D
(S)-2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoxaline (5f).
11
1
(Known compound ), orange oil, 0.233 g, 0.97 mmol, 97% yield: H
NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.8 Hz, 2H), 6.86−6.83 (m,
2H), 6.58−6.55 (m, 2H), 6.51−6.47 (m, 2H), 4.32 (d, J = 6.0 Hz,
1H), 3.80 (br, 2H), 3.75 (s, 3H), 3.32 (dd, J = 9.2, 2.0 Hz, 1H), 3.20
(t, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 134.1,
133.9, 132.6, 127.9, 118.5, 118.6, 114.4, 114.2, 113.8, 55.0, 53.9, 49.1;
HPLC (Chiralcel OD-H, hexane/iPrOH 90:10, 1 mL/min, λ = 254
nm) t1 = 20.0 min (minor), t2 = 34.4 min (major, ee = 90%); HRMS
(EI) m/z calcd for C15H16N2O (M+) 240.1263, found 240.1234;
found 239.1535; [α]24 = −64.1 (c 0.515, CHCl3); mp = 102 °C.
D
(S)-6,7-Dimethyl-2-naphthalen-1-yl-1,2,3,4-tetrahydroqui-
1
noxaline (5n). Yellow oil, 0.276 g, 0.96 mmol, 96% yield: H NMR
(300 MHz, CDCl3) δ 7.90−7.80 (m, 4H), 7.55−7.45 (m, 3H), 6.46 (s,
2H), 4.65 (brs, 1H), 3.90 (brs, 2H), 3.60−3.30 (m, 2H), 2.15 (brs,
6H); 13C NMR (CDCl3, 75 MHz) δ 139.6, 133.5, 133.2, 128.5, 128.0,
127.8, 126.7, 126.3, 126.0, 125.8, 125.3, 116.9, 116.4, 55.3, 49.6, 19.1;
HPLC (Chiralcel IB, hexane/iPrOH 90:10, 1 mL/min, λ = 215 nm)
t1 = 21.9 min (major, ee = 60%), t2 = 32.9 min (minor); HRMS (ESI)
[α]24 = −5.3 (c = 0.81, CHCl3).
D
(S)-2-(3-Nitrophenyl)-1,2,3,4-tetrahydroquinoxaline (5g).
Yellow oil, 0.247 g, 0.97 mmol, 97% yield: 1H NMR (400 MHz,
CDCl3) δ 8.23 (t, J = 2.0 Hz, 1H), 8.14 (t, J = 1.2 Hz, 1H), 8.12 (dd,
J = 0.8, 2.4 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H),
4.60 (dd, J = 7.6, 2.8 Hz, 1H), 4.04−3.98 (m, 2H), 3.49 (dd, J = 7.2,
3.2 Hz, 1H), 3.30 (dd, J = 7.6, 11.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 148.6, 144.3, 133.2, 132.3, 129.6, 122.8, 122.0, 119.5, 119.3,
115.1, 114.8, 54.1, 48.6, 25.3; HPLC (Chiralcel OD-H, hexane/iPrOH
70:30, 1 mL/min, λ = 254 nm) t1 = 41.0 min (minor), t2 = 64.1 min
(major, ee = 85%); HRMS (EI) m/z calcd for C14H13N3O2 (M+)
m/z calcd for C20H21N2 (MH+) 289.1699, found 289.1697; [α]24
−63.2 (c 1.14, CHCl3).
=
D
(S)-2-(4-Methoxy-phenyl)-6,7-dimethyl-1,2,3,4-tetrahydro-
1
quinoxaline (5o). Yellow solid, 0.260 g, 0.97 mmol, 97% yield: H
NMR (300 MHz, CDCl3) δ 7.30 (d, J = 8.73 Hz, 2H), 6.90 (d, J =
8.71 Hz, 2H), 6.41 (d, J = 9.65 Hz, 2H), 4.40 (brs, 1H), 3.81 (s, 3H),
3.50−3.20 (m, 4H), 2.12 (brs, 6H); 13C NMR (CDCl3, 75 MHz) δ
159.4, 134.3, 132.3, 130.4, 128.2, 126.6, 116.8, 116.3, 114.1, 55.4, 54.6,
49.7, 19.1; CSP-SFC (Chiralcel IA, scCO2/MeOH 80:20, 4 mL/min,
P = 150 bar, λ = 215 nm) t1 = 9.65 min (major, ee = 60%), t2 = 14.88 min
(minor); HRMS (ESI) m/z calcd for C17H21ON2 (MH+) 269.1648,
255.1008, found 255.1001; [α]24 = −7.1 (c 0.75, CHCl3).
D
(S)-2-(4-Nitrophenyl)-1,2,3,4-tetrahydroquinoxaline (5h).
(Known compound11), pale yellow oil, 0.245 g, 0.96 mmol, 96%
1
found 269.1647; [α]24 = −50.7 (c 1.045, CHCl3); mp = 87 °C.
D
yield: H NMR (400 MHz, CDCl3) δ 8.20 (td, J = 8.8, 2.0 Hz, 2H),
(S)-2-(3-Methoxy-phenyl)-6,7-dimethyl-1,2,3,4-tetrahydro-
7.55 (td, J = 9.2, 2.0 Hz, 2H), 6.68−6.64 (m, 2H), 6.62−6.56 (m, 2H),
4.62 (dd, J = 7.2, 3.2 Hz, 1H), 3.79 (br, 2H), 3.50 (dd, J = 11.2, 4.0 Hz,
1H), 3.30 (dd, J = 11.2, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
149.6, 133.2, 132.7, 128.0, 127.8, 123.8, 119.3, 119.3, 118.6, 115.1,
115.0, 114.7, 54.3, 48.5; HPLC (Chiralcel OD-H, hexane/iPrOH
70:30, 1 mL/min, λ = 254 nm) t1 = 29.4 min (minor), t2 = 55.6 min
(major, ee = 91%); HRMS (EI) m/z calcd for C14H13N3O2 (M+)
255.1008, found 255.1000; [α]24 = −3.5 (c 0.77, CHCl3).
1
quinoxaline (5p). Orange solid, 0.257 g, 0.96 mmol, 96% yield: H
NMR (300 MHz, CDCl3) δ 7.30−7.20 (m, 2H), 6.99−6.95 (m, 2H),
6.90−6.82 (m, 1H), 6.41 (s, 2H), 4.45 (brs, 1H), 3.81 (s, 3H), 3.50−
3.20 (m, 2H), 2.18 (brs, 6H); 13C NMR (CDCl3, 75 MHz) δ 160.0,
143.9, 132.1, 130.5, 129.7, 127.1, 126.7, 119.4, 116.9, 116.3, 113.3,
112.5, 55.4, 55.2, 49.7, 19.1; CSP-SFC (Chiralcel IA, scCO2/MeOH
80:20, 4 mL/min, P = 150 bar, λ = 215 nm) t1 = 9.39 min (major, ee =
67%), t2 = 10.63 min (minor); HRMS (ESI) m/z calcd for C17H21ON2
(S)-2-(4-Chlorophenyl)-1,2,D3,4-tetrahydroquinoxaline (5j).
(Known compound11), yellow oil, 0.239 g, 0.98 mmol, 98% yield:
1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.40−7.37 (m, 1H), 7.25
(d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.61−6.57 (m, 2H),
6.52−6.48 (m, 2H), 4.33 (d, J = 5.2 Hz, 1H), 3.82 (br, 2H), 3.34 (dd,
J = 10.8, 2.4 Hz, 1H), 3.18 (t, J = 9.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 144.3, 133.6, 132.5, 130.7, 130.0, 129.9, 125.5, 122.5, 118.8,
118.7, 114.6, 114.3, 54.0, 48.7; HPLC (Chiralcel OD-H, hexane/
iPrOH 70:30, 1 mL/min, λ = 254 nm) t1 = 13.4 min (minor), t2 = 22.4
min (major, ee = 94%); HRMS (EI) m/z calcd for C14H13ClN2 (M+)
244.0767, found 244.0778; [α]24 = −12.1 (c 0.44, CHCl3).
(MH+) 269.1648, found 269.1647; [α]24 = −64.4 (c 0.900, CHCl3);
D
mp = 60 °C.
(S)-6,7-Dimethyl-2-p-tolyl-1,2,3,4-tetrahydroquinoxaline
(5q). Yellow solid, 0.224 g, 0.89 mmol, 89% yield: 1H NMR
(300 MHz, CDCl3) δ 7.27 (d, J = 8 Hz, 2H), 7.17 (d, J = 7.96 Hz,
2H), 6.41 (d, J = 6.78 Hz, 2H), 4.42 (brs, 1H), 3.80 (brs, 2H), 3.45−
3.20 (m, 2H), 2.35 (s, 3H), 2.12 (brs, 6H); 13C NMR (CDCl3, 75
MHz) δ 139.2, 137.6, 132.3, 130.5, 129.4, 127.0, 126.5, 116.8, 116.2,
54.9, 49.7, 21.3, 19.0; CSP-SFC (Chiralcel IA, scCO2/MeOH 80:20,
4 mL/min, P = 150 bar, λ = 215 nm) t1 = 7.91 min (major, ee = 66%),
t2 = 10.89 min (minor); HRMS (ESI) m/z calcd for C17H21N2 (MH+)
253.1699, found 253.1695; [α]24D = −55.2 (c 0.905, CHCl3); mp = 122 °C.
(S)-2-(3-Bromo-phenyl)-6,7-dimethyl-1,2,3,4-tetrahydroqui-
(S)-2-(3-Bromophenyl)-1,2,D3,4-tetrahydroquinoxaline (5k).
(Known compound11), orange oil, 0.282 g, 0.98 mmol, 98% yield:
1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.38 (ddd, J = 7.6, 1.6,
1.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.60−
6.57 (m, 2H), 6.52−6.48 (m, 2H), 4.33 (dd, J = 7.6, 2.4 Hz, 1H), 3.82
(br, 2H), 3.34 (dd, J = 8.4, 2.6 Hz, 1H), 3.18 (t, J = 9.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 144.3, 133.6, 132.5, 130.6, 130.0, 129.9,
125.5, 122.5, 118.8, 118.7, 114.5, 114.3, 54.0, 48.7; HPLC (Chiralcel
OD-H, hexane/iPrOH 70:30, 1 mL/min, λ = 254 nm) t1 = 12.1 min
(minor), t2 = 23.0 min (major, ee = 88%); HRMS (EI) m/z calcd for
1
noxaline (5r). Pale yellow oil, 0.300 g, 0.95 mmol, 95% yield: H
NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.43 (d, J = 9 Hz, 1H),
7.30−7.20 (m, 2H), 6.41 (s, 2H), 4.41 (brs, 1H), 3.60−3.20 (m, 4H),
2.13 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 144.7, 131.7, 130.9,
130.4, 130.3, 130.2 127.2, 126.9, 125.8, 122.8, 116.9, 116.4, 54.7, 49.4,
19.1; HPLC (Chiralcel IB, hexane/iPrOH 90:10, 1 mL/min, λ =
215 nm) t1 = 16.95 min (major, ee = 72%), t2 = 26.77 min (minor);
HRMS (ESI) m/z calcd for C16H18N2Br (MH+) 317.0647, found
C14H13BrN2 (M+) 288.0262, found 288.0247; [α]24 = −8.1 (c 0.8,
317.0643; [α]24 = −72.5 (c 0.400, CHCl3).
D
D
CHCl3).
(S)-2-(4-Chloro-phenyl)-6,7-dimethyl-1,2,3,4-tetrahydroqui-
noxaline (5s). Orange solid, 0.242 g, 0.89 mmol, 89% yield: 1H NMR
(300 MHz, CDCl3) δ 7.32 (s, 4H), 6.41 (s, 2H), 4.43 (brs, 1H), 3.70−
2.80 (m, 4H), 2.13 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 140.8,
(S)-2-(4-Bromophenyl)-1,2,3,4-tetrahydroquinoxaline (5l).
Pale yellow oil, 0.279 g, 0.97 mmol, 97% yield: 1H NMR (400
MHz, CDCl3) δ 7.48 (d, J = 7.6 Hz, 2H), 7.23 (dd, J = 8.4, 2.0 Hz,
J
dx.doi.org/10.1021/jo300455y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
133.6, 130.3, 128.9, 128.5, 127.3, 126.9, 116.9, 116.3, 54.6, 49.4, 19.1;
CSP-SFC (Chiralcel IA, scCO2/MeOH 80:20, 4 mL/min, P = 150 bar,
λ = 215 nm) t1 = 10.22 min (major, ee = 79%), t2 = 13.11 min
(minor); HRMS (ESI) m/z calcd for C16H18N2Cl (MH+) 273.1153,
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (+81)-92-642-6650 (T.O.); (+81)-6-6850-6245 (K.M.);
(+33)144071062 (V.R.-V.). E-mail: ohshima@phar.kyushu-u.ac.jp
(T.O.); mashima@chem.es.osaka-u.ac.jp (K.M.); virginie-vidal@
chimie-paristech.fr (V.R.-V.).
found 273.1153; [α]24 = −81.9 (c 0.885, CHCl3); mp = 115 °C.
D
(S)-2-(4-Bromo-phenyl)-6,7-dimethyl-1,2,3,4-tetrahydroqui-
noxaline (5t). Orange solid, 0.281 g, 0.89 mmol, 89% yield: 1H NMR
(300 MHz, CDCl3) δ 7.47 (d, J = 8.43 Hz, 2H), 7.25 (d, J = 8.28 Hz,
2H), 6.41 (d, J = 6 Hz, 2H), 4.41 (brs, 1H), 3.39 (m, 1H), 3.23 (m,
1H), 2.13 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 141.4, 131.8, 130.4,
128.8, 127.2, 126.9, 121.7, 116.9, 116.3, 54.6, 49.4, 19.1; CSP-SFC
(Chiralcel IA, scCO2/MeOH 80:20, 4 mL/min, P = 150 bar, λ = 215
nm) t1 = 13.37 min (major, ee = 77%), t2 = 19.05 min (minor); HRMS
(ESI) m/z calcd for C16H18N2Br (MH+) 317.0647, found 317.0643;
ACKNOWLEDGMENTS
■
D.C. warmly acknowledges the CNRS and the French
Minister
̀
e de l′Education et de la Recherche for the financial
support. This work was also financially supported by JSPS-
CNRS Joint program (2007 and 2008). T.N. and D.C. thank
the Global COE program “Global Education and Research
Center for Bio-Environmental Chemistry” of Osaka University.
[α]24 = −62.3 (c 0.915; CHCl3); mp = 108 °C.
D
(S)-3-Phenethyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline (6).
(Known compound11), white solid, 0.307 g, 0.784 mmol, 80% yield:
1H NMR (300 MHz, CDCl3) δ 7.68−7.65 (dd, J = 8.4, 1.5 Hz, 1H),
7.37−7.24 (m, 5H), 7.15 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H),
6.99−6.93 (m, 1H), 6.71−6.65 (m, 1H), 6.45−6.41 (dd, J = 8.1,
1.2 Hz, 2H), 4.35−4.30 (dd, J = 13.8, 3.6 Hz, 1H), 3.03−2.95 (dd, J =
13.8, 10.2 Hz, 1H), 2.79−2.55 (m, 3H), 2.35 (s, 3H), 1.68 (q, J =
7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 143.4, 140.5, 137.5, 136.3,
129.5, 128.6, 128.2, 127.1, 126.3, 126.2, 125.5, 121.9, 117.3, 114.6,
48.8, 47.0, 35.2, 31.4 21.5; HRMS (ESI) m/z calcd for
REFERENCES
■
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C23H24N2O2SNa (MNa+) 415.1456, found 415.1451; [α]24
−45.1 (c 1.0, CH2Cl2); mp = 66 °C.
=
D
(S)-t-Butyl-3-ethyl-6,7-dimethyl-3,4-dihydroquinoxaline-N1-
carboxylate (7). (Known compound10a), pale yellow oil, 0.992 g,
1
3.42 mmol, 65% yield: H NMR (300 MHz, CDCl3) δ 7.32 (br, 1H),
6.38 (s, 1H), 3.99−3.97 (m, 1H),3.78 (s, 1H), 3.25−3.22 (m, 2H),
2.15 (s, 3H), 2.14 (s, 3H), 1.53 (s, 9H), 1.52−1.43 (m, 2H), 1.01 (t,
J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.0, 134.3, 132.1,
124.6, 123.7, 121.7, 115.3, 80.0, 52.5, 45.4, 27.9, 26.5, 18.9, 18.6, 9.6;
HRMS (ESI) m/z calcd for C17H26N2O2Na (MNa+) 313.1892, found
313.1888; [α]24 = −22.4 (c 1.0, CH2Cl2).
D
(S)-N4-t-Butyl-N1-ethyl-2-ethyl-6,7-dimethyl-2,3-dihydro-
quinoxaline-1,4-dicarboxylate (8). (Known compound10a), yellow
1
solid, 1.14 g, 3.15 mmol, 92% yield: H NMR (300 MHz, CDCl3) δ
7.56 (br, 1H), 7.43 (s, 1H), 4.53−4.45 (m, 1H), 4.30−4.17 (m, 2H),
3.83−3.78 (dd, J = 12.9, 3.6 Hz, 1H), 3.74−3.68 (dd, J = 12.9, 5.1 Hz,
1H), 2.21 (s, 3H), 2.20 (s, 3H), 1.52 (s 9H), 1.49−1.32 (m, 2H), 1.31
(t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 154.0, 153.0, 131.8, 131.2, 128.6, 125.8, 125.0, 123.5, 80.8,
61.6, 53.8, 48.0, 28.0, 24.0, 19.3, 19.2, 14.3, 10.0; HRMS (ESI) m/z
calcd for C20H30N2O4Na 385.2103, found 385.2098; [α]24 = −20.3
D
(c 1.0, CH2Cl2); mp = 83 °C.
(S)-Ethyl-2-ethyl-6,7-dimethyl-3,4-dihydroquinoxaline-1-
carboxylate (9). (Known compound10a), yellow oil, 0.825 g, 3.15
mmol, 100% yield: 1H NMR (300 MHz, CDCl3) δ 7.33 (br, 1H), 6.36
(s, 1H), 4.49−4.46 (m, 1H), 4.32−4.16 (m, 2H), 3.78 (br, 1H), 3.40−
3.35 (dd, J = 11.7, 3.6 Hz, 1H), 3.27−3.23 (dd, J = 11.7, 1.8 Hz, 1H),
2.16 (s, 3H), 2.14 (s, 3H), 1.54−1.38 (m, 2H), 1.32 (t, J = 7.2 Hz,
3H), 0.91 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 154.5,
133.9, 132.9, 126.0, 124.8, 119.5, 115.5, 61.6, 50.6, 44.4, 23.1, 19.3,
19.0, 14.5, 10.5; CSP-SFC (Chiralcel OD-H, scCO2/MeOH 85:15,
5 mL/min, P = 100 bar, λ = 215 nm) t1 = 1.57 min (major, ee = 90%),
t2 = 2.11 min (minor); HRMS (ESI) m/z calcd for C15H23N2O2
(MH+) 263.1760, found 263.1757; [α]24 = −18.5 (c 1.0, CH2Cl2).
D
̌ ́
2008, 47, 759. (t) Mrsic, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A.
ASSOCIATED CONTENT
J.; Feringa, B. L.; de Vries, J. G. Adv. Synth. Catal. 2008, 350, 1081.
(u) Wang, D. W.; Wang, X. B.; Wang, D. S.; Lu, S. M.; Zhou, Y. G. J.
Org. Chem. 2009, 74, 2780. (v) Eggenstein, M.; Thomas, A.;
■
S
* Supporting Information
Experimental details, copies of H, 13C NMR, SFC/HPLC
1
̀
Theuerkauf, J.; Francio, G.; Leitner, W. Adv. Synth. Catal. 2009, 351,
spectra, and the crystal information file (CIF) for compound
(S)-6. This material is available free of charge via the Internet at
http://pubs.acs.org.
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K
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