Iridium-difluorphos-catalyzed asymmetric hydrogenation of 2-alkyl- and 2-aryl-substituted quinoxalines: A general and efficient route into tetrahydroquinoxalines

Article abstract of DOI:10.1002/adsc.201000513

A highly efficient and general iridium-difluorphos-catalyzed asymmetric hydrogenation of diverse 2-alkyl- and 2-aryl-substituted quinoxalines into biologically and pharmaceutically relevant 2-substituted-1,2,3,4- tetrahydroquinoxaline units has been developed. High isolated yields and excellent enantioselectivities of up to 95% for 2-alkyl-substituted quinoxalines and of up to 94% for 2-aryl-substituted quinoxalines were obtained.

Full text of DOI:10.1002/adsc.201000513

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DOI: 10.1002/adsc.201000513
Iridium-Difluorphos-Catalyzed Asymmetric Hydrogenation of
2-Alkyl- and 2-Aryl-Substituted Quinoxalines: A General and
Efficient Route into Tetrahydroquinoxalines
Damien Cartigny,a Takuto Nagano,b Tahar Ayad,a Jean-Pierre GenÞt,a
Takashi Ohshima,b,* Kazushi Mashima,b,* and Virginie Ratovelomanana-Vidala,*
a
Laboratoire Charles Friedel, UMR CNRS 7223, ꢀcole Nationale Supꢁrieure de Chimie de Paris, Chimie ParisTech, 11 rue
P. et M. Curie, 75231 Paris cedex 05, France
Fax : (+33)-1-4407-1062; e-mail: virginie-vidal@chimie-paristech.fr
Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8631, Japan
b
Fax : (+81)-6-6850-6245; e-mail: ohshima@chem.es.osaka-u.ac.jp, mashima@chem.es.osaka-u.ac.jp
Received: June 30, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000513.
Abstract: A highly efficient and general iridium-di-
fluorphos-catalyzed asymmetric hydrogenation of
diverse 2-alkyl- and 2-aryl-substituted quinoxalines
into biologically and pharmaceutically relevant 2-
substituted-1,2,3,4-tetrahydroquinoxaline units has
been developed. High isolated yields and excellent
enantioselectivities of up to 95% for 2-alkyl-substi-
tuted quinoxalines and of up to 94% for 2-aryl-sub-
stituted quinoxalines were obtained.
hydroquinoxalines, few examples of asymmetric hy-
drogenation of the corresponding quinoxaline deriva-
tives have been reported so far in the literature. Since
the first report by Murata et al. in 1987 using Rh-
DIOP catalyst (3% ee),[7] the substrate scope was
mainly limited to 2-methylquinoxaline (MeQ) as a
model substrate. Bianchini described in 1998 and 2001
the hydrogenation of MeQ using either fac-exo-(R)-
ACHNTURGENU{NG IrH2ACHUTNGTREN[NUGN C6H4C*H(Me)N(CH2CH2-PPh2)2]} (90% ee,
53.7% yield)[8] and iridium- or rhodium-[(R)-(R)-
Keywords: asymmetric catalysis; difluorphos; hy-
drogenation; iridium; quinoxaline; tetrahydroqui-
noxalines
BPP-BzP] catalysts (11–23% ee, 40.7–93.2 yields).[9] In
2003, Henschke et al.
used
Noyoriꢂs
[RuCl2(diphosphine)ACHTUNGTERNN(UNG diamine)] complexes with ee up
to 73% and 99% conversion when HexaPHEMP de-
2-Substituted-1,2,3,4-tetrahydroquinoxalines are use-
ACHTUNGTRENNUNGful key structural units for drug development and
have attracted significant attention over the years.[1]
They exhibit a variety of biological activities and have
found applications as cholesteryl ester transfer protein
inhibitors 1 (CETP),[2] M2 acetylcholine receptor ago-
nists 2,[3] prostagladin D2 receptor antagonists 3,[4] or
therapeutic agents for increasing renal fluid flow[5]
(Figure 1).
Therefore, a practical, convenient and atom-eco-
nomical route to access tetrahydroquinoxaline core is
highly desirable. Asymmetric hydrogenation consti-
tutes one of the most direct and viable strategy for
the synthesis of such compounds. Over the past few
years, significant progress in the development of tran-
sition-metal catalyzed asymmetric hydrogenation of
heteroaromatic compounds has been made.[6] How-
Figure 1. Representative bioactive compounds with the 2-
ACHTUNGTRENNUNGever, despite the obvious biological potential of tetra- substituted-1,2,3,4-tetrahydroquinoxaline framework.
1886
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Adv. Synth. Catal. 2010, 352, 1886 – 1891

Iridium-Difluorphos-Catalyzed Asymmetric Hydrogenation of 2-Alkyl- and 2-Aryl-Substituted Quinoxalines
rivatives were used as chiral ligands.[10,11] Chan et al. reported so far are limited to 2-phenylquinoxaline, 2-
reported in 2006 the use of PQ-Phos ligands with ee benzoACTHUNRTGENNUG[1,3]diACHTUNGTRENoNUGN xolequinoxaline and 2-o’-MeO-phenyl-
up to 80% for asymmetric hydrogenation of MeQ,[12] quinoxaline with ee values up to 84% ee using (R)-
and later, in 2009, an efficient Ir/H8-binapo system for H8-Binapo,[13] up to 86% using (S)-PipPHOS,[14] and
asymmetric hydrogenation of 2-alkyl-substituted qui- up to 65% ee using (R)-SegPhos.[15]
noxalines derivatives with 85 to 96% ee at low cata-
We were interested in pursuing a research program
lyst loading.[13] Simultaneously, de Vries, Feringa and on the iridium-promoted asymmetric hydrogenation
Minnaard described an iridium-based catalyzed hy- of heteroaromatic compounds, and report herein the
drogenation of 2- and 2,6-substituted quinoxalines first general, highly efficient, catalytic asymmetric hy-
using the monodentate phosphoramidite PipPhos drogenation of a broad range of 2-aryl-substituted
ligand and piperidine hydrochloride as an additive quinoxalines. The hydrogenation of 2-alkyl-substitut-
with ee ranging from 75 to 96%.[14] However, these ed quinoxalines is described as well. We previously re-
catalytic systems are mostly limited to 2-alkyl-substi- ported the efficient asymmetric hydrogenation of 2-
tuted quinoxalines. In sharp contrast, asymmetric hy- alkyl-substituted quinolines[16] and 2-aryl- and 2-alkyl-
drogenation of challenging 2-aryl-substituted quinoxa- substituted quinolinium salts,[17] using various cationic
lines has scarcely been explored. The rare examples dinuclear triply halogen-bridged iridium complexes of
formula [{IrH((S)-diphosphine)}2ACTHNUTRGNEUNG
(m-X)3]+YÀ.[18] We
started our investigation by first identifying the most
appropriate cationic iridium complexes bearing either
(S)-Synphos[19] or (S)-Difluorphos[20] (Figure 2) for the
asymmetric hydrogenation of 2-methylquinoxaline 5a
as a model substrate.
Complexes 4a–4f used in this study were conven-
iently prepared by adding an excess of aqueous HX
to a mixture of [IrClACHTNUTRGNE(UGN COE)2]2 and the required chiral
diphosphine ligand in toluene at room tempera-
ture.[17,18] Initial experiments were performed under a
standard set of reaction conditions (50 bar of H2,
308C, toluene, S/C=100). The results are summarized
in Table 1. Hydrogenation of 2-methylquinoxaline 5a,
using {[IrH((S)-Synphos)]2ACTHNUTRGNEUNG
(m-I)3}+IÀ 4a, led to the de-
sired product (S)-6a with complete conversion and a
promising 72% ee (entry 1). Comparable results in
terms of both conversion and enantioselectivity were
obtained when catalysts {[IrH((S)-Synphos)] CHTUNGTRENNUNG(m-
2A
Figure 2. Cationic dinuclear triply halogen-bridged iridium
complexes [{IrH((S)-diphosphine)}
2A
N
Br)3}+BrÀ 4b and {[IrH((S)-Synphos)] (m-Cl)3}+ClÀ 4c
2ACTHNGUTERNNUG
Table 1. Catalyst screening.[a]
Entry
Catalysts
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
N
N
>99
72
75
75
69
87
92
>99
>99
>99
>99
>99
[a]
[b]
[c]
Reaction conditions: 5a (1.0 mmol).
Conversion was determined by H NMR of the crude product.
Enantiomeric excess was determined by chiral stationary phase-supercritical fluid chromatography (CSP-SFC) on a Chir-
alcel AD-H column. Absolute configuration was determined by comparison of the specific rotation with reported data.
1
Adv. Synth. Catal. 2010, 352, 1886 – 1891
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Damien Cartigny et al.
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Table 2. Optimization of the reaction conditions.[a]
Entry
Solvent
H2 [bar]
Temperature [8C]
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
MeOH
i-PrOH
CH2Cl2
THF
dioxane
Et2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
50
50
50
50
50
50
50
50
50
50
70
30
30
30
30
30
30
30
30
30
10
50
70
30
30
30
>99
>99
>99
>99
>99
>99
>99
>86
>99
>99
>99
>99
>99
(R) 19
(S) 53
(S) 88
(S) 85
(S) 85
(S) 90
(S) 92
(S) 93
(S) 90
(S) 90
(S) 92
(S) 94
(S) 94
9
10
11
12
13[d]
[a]
Reaction conditions: 5a (1.0 mmol).
Conversion was determined by H NMR of the crude product.
[b]
[c]
1
Enantiomeric excess was determined by chiral stationary phase-supercritical fluid chromatography (CSP-SFC) on a Chir-
alcel AD-H column. Absolute configuration was determined by comparison of the specific rotation with reported data.
S/C=1000.
[d]
were used (entries 2 and 3, 99% conversion, 75% ee). gen pressure were also investigated, using 1 mol% of
Finally, we were pleased to find that switching from the best catalyst {[IrH((S)-Difluorphos)]2A
(m-Cl)3}+ClÀ
CTHUNGTRENNUNG
(S)-Synphos[19] to the electron-deficient ligand (S)-Di- 4f. The results from these experiments are shown in
fluorphos,[20] developed by our group, had a significant Table 2. Excellent conversions were achieved in all
impact on the stereochemical outcome of the reac- examined solvents, either protic or aprotic, but the
tion. The high performance of the Difluorphos ligand enantiomeric excesses of the products were highly sol-
has been previously demonstrated in the asymmetric vent-dependent. While each catalytic hydrogenation
hydrogenation of various 2-substituted quinoline de- was allowed to proceed in each considered solvent,
rivatives.[16,17] Indeed, although the triply iodide- the use of MeOH resulted in the formation of the hy-
bridged catalyst {[IrH((S)-Difluorphos)]
gave (S)-6a with a moderate ee of 69%, the use of opposite configuration; whereas running the reaction
{[IrH((S)-Difluorphos)]2A
(m-Br)3}+BrÀ catalyst 4e bear- in i-PrOH provided (S)-6a in a moderate ee of 53%
(m-I)3}+IÀ 4d drogenated product (R)-6a, with a low 19% ee and an
2ACHTUNGTRENNUNG
CTHUNGTRENNUNG
ing a bromide instead of an iodide ligand led to a con- (entries 1 and 2). Tetrahydrofuran, ether, dioxane and
siderable improvement in the enantioselectivity, pro- dichloromethane gave significantly better enantiose-
viding the reduced product (S)-6a with an ee of up to lectivities (entries 3–6, 85 to 90% ee), but the best ee
87% and 99% conversion (entries 4 and 5). The best (92%) was obtained when toluene was used as solvent
result regarding both conversion and enantioselectivi- (entry 7). Data in Table 2 also illustrate that varia-
ty was reached with catalyst [{IrH((S)-Difluorphos)}2 tions of the temperature and hydrogen pressure influ-
ACHTUNGTRENNUNG
(m-Cl)3]+ClÀ 4f producing 2-methyl-1,2,3,4-tetrahydro- enced the catalytic activity in terms of both conver-
quinoxaline (S)-6a with a full conversion and an ex- sion and enantioselectivity. A temperature increase
cellent enantiomeric excess of 92% (entry 6). This un- above 308C led to a decrease in selectivity giving 6a
precedented halide dependence is once again in with 90% ee whereas an excellent ee of up to 93%,
agreement with our earlier observations on the asym- was obtained when the reaction was conducted at
metric hydrogenation of 2-aryl- and 2-alkyl-substitut- 108C, albeit at a lower conversion of 86% (entries 8
ed quinolinium salts, where chloro- and bromo-iridi- vs. 9 and 10). A change in the hydrogen pressure
um catalysts gave superior catalytic performance over from 30 to 70 bar had little effect on the stereochemi-
the corresponding iodo-iridium catalyst.[17]
cal outcome of the reaction, since an excellent catalyt-
To further improve the enantioselectivity of the re- ic activity in terms of both conversion and enantiose-
action, the effects of solvent, temperature and hydro- lectivity was still maintained with ees ranging from 92
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Adv. Synth. Catal. 2010, 352, 1886 – 1891

Iridium-Difluorphos-Catalyzed Asymmetric Hydrogenation of 2-Alkyl- and 2-Aryl-Substituted Quinoxalines
Table 3. Asymmetric hydrogenation of 2-alkyl- and 2-aryl-substituted quinoxalines.[a]
Entry
Substrate
R1
Yield [%][b,c]
ee [%][d]
R2
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
H
H
H
H
Me
Et
n-Bu
i-Pr
CH2CH2Ph
Me
Et
n-Bu
C6H5
o-Me-C6H4
m-Me-C6H4
p-Me-C6H4
m-OMe-C6H4
p-OMe-C6H4
p-NO2-C6H4
p-F-C6H4
p-Cl-C6H4
m-Br-C6H4
99
99
98
98
97
98
98
97
98
97
98
99
97
97
96
97
98
98
94 (S) 6a
95 (S) 6b
91 (S) 6c
94 (S) 6d
91 (S) 6e
90 (S) 6f
91 (S) 6g
90 (S) 6h
89 (S) 6i
91 (S) 6j
86 (S) 6k
91 (S) 6l
87 (S) 6m
90 (S) 6n
91 (S) 6o
89 (S) 6p
94 (S) 6q
88 (S) 6r
H
Me
Me
Me
H
H
H
H
H
H
H
9[e]
10[e]
11[e]
12[e]
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
H
H
H
[a]
Reaction conditions: 5 (1.0 mmol).
Isolated yield after flash column chromatography on silica gel.
In each case complete conversion was achieved.
[b]
[c]
[d]
Enantiomeric excess was determined either by chiral stationary phase-supercritical fluid chromatography (CSP-SFC) on
Chiralcel AD-H and OD-H columns for 6a-h, or by HPLC on a Chiralcel OD-H column for 6i–r (see Supporting Infor-
mation). Absolute configuration was determined by comparison of the specific rotation with reported data.
Dioxane was used as a solvent instead of toluene.
[e]
to 94% (entries 11 and 12). Moreover, the catalyst tosyl-2-phenethyl-1,2,3,4-tetrahydroquinoxaline 7 (not
loading can even be lowered to 0.1 mol% without shown). Comparable good selectivities were obtained
erosion of the enantioselectivity (entry 13).
with 2-alkyl-substituted quinoxalines bearing a methyl
Encouraged by the promising results obtained in substituent at the 6- and 7-positions on the aromatic
the hydrogenation of 2-methylquinoxaline 5a, a varie- ring (entries 6–8, 90–91% ee). The data in Table 2
ty of 2-alkyl- and 2-aryl-substituted quinoxalines, show that 2-aryl-substituted quinoxalines 5i–r, with
easily prepared according to known procedures,[21,22] either electron-withdrawing or electron-donating sub-
were reduced under the optimized reaction condi- stituents, can also be hydrogenated in high chemical
tions. As illustrated in Table 3, all quinoxaline deriva- yields and with good to excellent asymmetric induc-
tives 5a–r were successfully hydrogenated to afford tions when the reactions were conducted in dioxane
their corresponding tetrahydroquinoxaline derivatives (entries 9–18, 96–99% yield and 86–94% ee). Indeed,
6a–r in excellent isolated yields and good to excellent hydrogenation of 2-phenylquinoxaline 5i resulted in
enantioselectivities (entries 1–18, 96–99% yield and the formation of compound 6i in 89% ee, which is the
86–95% ee).
best enantioselectivity reported so far (entry 9),
For 2-alkyl-substituted quinoxalines, the length of whereas ortho-substitution afforded 6j in 91% ee
the alkyl chain had a negligible impact on the enan- (entry 10). Furthermore, high ee values were also
tioselectivity, since ee values ranging from 91% for reached with meta-substituted derivatives irrespective
the phenethyl substituent to 95% for the ethyl group of the electronic nature of the substitution pattern
were observed (entries 1–5). The absolute configura- (entries 11, 13, and 18, 86–88% ee). Finally, hydroge-
tion of the 2-phenethyl-1,2,3,4-tetrahydroquinoxaline nation of 2-aryl-substituted quinoxalines containing
6e was determined to be S based on a single-crystal either electron-donating or electron-withdrawing sub-
X-ray structure analysis[23] of the corresponding 4-N- stituents at the para position of the aromatic moiety
Adv. Synth. Catal. 2010, 352, 1886 – 1891
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1889

Damien Cartigny et al.
COMMUNICATIONS
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led to excellent selectivities with ee up to 94% (en-
tries 12, 14–17).
In conclusion, we have developed a general and ef-
ficient iridium-Difluorphos-catalyzed asymmetric hy-
drogenation of diverse 2-alkyl- and 2-aryl-substituted
quinoxalines into biologically and pharmaceutically
relevant 1,2,3,4-tetrahydroquinoxaline units, with high
chemical yields and enantioselectivities ranging from
89% ee for 2-phenylquinoxaline to up to 95% ee
which are, to the best of our knowledge, the highest
ee values reported so far for the asymmetric hydroge-
nation reactions of 2-aryl-substituted quinoxaline de-
rivatives.
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General Procedure
[7] S. Murata, T. Sugimoto, S. Matsuura, Heterocycles
A glass tube was charged with 5 (0.42 mmol) and iridium di-
nuclear complex (2.1 mmol, S/C=100). The tube was placed
in a stainless steel autoclave, which was subjected to three
vacuum/argon cycles. Anhydrous and degassed solvent
(3.0 mL) was then added under argon. The hydrogenation
was performed at 308C under an atmosphere of hydrogen
(30 bar) for 20 h. After careful releasing of the hydrogen
gas, the resulting mixture was filtered through a short pad of
silica gel and concentrated under reduced pressure. The con-
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1
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[23] See Supporting Information. CCDC 774501 contains
the supplementary crystallographic data for compound
(S)-7 of this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Adv. Synth. Catal. 2010, 352, 1886 – 1891
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