Asymmetric hydrogenation of quinoxalines with diphosphinite ligands: A practical synthesis of enantioenriched, substituted tetrahydroquinoxalines

Article abstract of DOI:10.1002/anie.200904518

An easily accessible chiral lr/H₈-binapo catalyst exhibits unprecedented reactivity and excellent enantioselectivity in the hydrogenation of quinoxalines at a high ratio of substrate to catalyst (from 100 to 20000). This new method provides a p

Full text of DOI:10.1002/anie.200904518

Angewandte
Chemie
DOI: 10.1002/anie.200904518
Asymmetric Hydrogenation
Asymmetric Hydrogenation of Quinoxalines with Diphosphinite
Ligands: A Practical Synthesis of Enantioenriched, Substituted
Tetrahydroquinoxalines**
Weijun Tang, Lijin Xu,* Qing-Hua Fan,* Jun Wang, Baomin Fan, Zhongyuan Zhou,
Kim-hung Lam, and Albert S. C. Chan*
The 1,2,3,4-tetrahydroquinoxaline ring system is an important
structural unit in many bioactive compounds.[1–3] Optically
pure tetrahydroquinoxaline derivatives have shown great
potential for pharmaceutical applications. For example, chiral
compound A has been pursued as a potent vasopressin V2
receptor antagonists,[1d] and optically pure compound B is a
promising inhibitor of cholesteryl ester transfer protein.[1e] In
both cases, the chirality of the compounds was found to play a
very important role in the relevant bioactivity of these
compounds.
The most convenient and straightforward route to chiral
tetrahydroquinoxalines is the asymmetric hydrogenation of
quinoxalines. Although several kinds of heteroaromatic
compounds,[4] such as quinolines,[5] indoles,[6] furans,[7] pyr-
idines,[8] and pyrazines[9] have been successfully hydrogenated
with good to excellent enantioselectivities and yields in the
presence of chiral transition-metal catalysts, the enantiose-
lective hydrogenation of substituted quinoxaline derivatives
has been less extensively studied.[3] In 1987, Murata et al. first
reported the rhodium-catalyzed asymmetric hydrogenation of
2-methylquinoxaline with only 3% ee.[3a] Later Bianchini
et al. enantioselectively hydrogenated 2-methylquinoxaline
with an orthomelated dihydride iridium complex to produce
the product with up to 90% ee,[3b,c] but the reduction suffered
from
lower
conversions.
The
performance
of
[RuCl2(diphosphine)(diamine)] complexes[3d,e] and Ir/PQ-
phos[3f] (PQ-phos = (R)-[6,6-(2S,3S-butadioxy)]-(2,2’)-bis(di-
phenylphosphino)-(1,1’)-biphenyl) was also investigated, but
only gave medium to low ee values. Given the importance of
chiral tetrahydroquinoxalines and in view of the lack of
efficient methods for the preparation of these compounds,[2,3]
the development of a practical and highly efficient catalytic
asymmetric synthetic method appeared to be of great
importance. Herein we describe the asymmetric hydrogena-
tion of quinoxalines with an easily accessible Ir/diphosphinite
catalyst. Good to excellent enantioselectivity (up to 98% ee),
unprecedented high catalytic activity (TOF up to 5620 hÀ1),
and productivity (TON up to 18140) were observed for a wide
range of substrates.
[*] Dr. W. Tang, J. Wang, Dr. B. Fan, Prof. Z. Zhou, Dr. K.-h. Lam,
Prof. A. S. C. Chan
Department of Applied Biology and Chemical Technology and
Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis
The Hong Kong Polytechnic University, Hong Kong (China)
E-mail: bcachan@polyu.edu.hk
Recently, the combination of transition metals and chiral
phosphinite ligands has led to efficient catalysts for the
asymmetric hydrogenation of prochiral olefins.[10] In compar-
ison with diphosphines, diphosphinites offer the advantages of
easy preparation and derivatization. Recently, we have
demonstrated that the easily accessible chiral diphosphinite
ligands derived from (R)-H8-binol (binol = (1,1’-bi-2-naph-
thyl)) and (R)-1,1-spirobiindane-7,7-diol provided excellent
catalytic activity and/or enantioselectivity in the Ir-catalyzed
asymmetric hydrogenation of quinolines.[5f,g] Based on our
previously optimized reaction conditions, we first investigated
the performance of the [{IrCl(cod)}2] (cod = 1,5-cycloocta-
diene)/(R)-H8-binapo or the (R)-sdpo/I2 catalyst system in
THF for the asymmetric hydrogenation of 2-methylquinoxa-
line (1a). To our delight, both catalysts worked efficiently
with full conversions and good enantioselectivities (Table 1,
entries 1 and 2), and (R)-H8-binapo gave the desired product
in somewhat better enantiomeric excess. In sharp contrast to
Prof. L. Xu
Department of Chemistry, Renmin University of China
Beijing 100872 (China)
E-mail: xulj@chem.ruc.edu.cn
Prof. Q.-H. Fan
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190 (China)
E-mail: fanqh@iccas.ac.cn
[**] Financial support from the Hong Kong Research Grants Council
(Polyu 5001/07P), the Hong Kong UGC AoE Scheme (AoE P/10-01),
the Hong Kong Polytechnic University Areas of Strategic Develop-
ment Fund, the National Natural Science Foundation of China
(20873179, 20532010), the Ministry of Science and Technology
(nos. 2007CB935904 and 2010CB833305), the Renmin University of
China, and the Chinese Academy of Sciences is greatly acknowl-
edged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904518.
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Communications
to similar catalytic activity but lower enantioselectivity
(Table 1, entries 3–6). Considering the crucial role of the
additive in the asymmetric hydrogenation of heteroaromatic
compounds,[5] we also evaluated the effects of additives. For
example, only 28% conversion and 32% ee were obtained in
the absence of the iodine additive (Table 1, entry 7). Replac-
ing iodine with other additives gave lower ee values or even
racemic product.[11] With iodine as the additive and THF as
the solvent, further investigations focused on the effect of
hydrogen pressure and temperature. Increasing the hydrogen
pressure had no effect on the reactivity and enantioselectivity
(Table 1, entry 8), but decreasing the hydrogen pressure led to
a lower ee value (83%; Table 1, entry 9). Lowering the
reaction temperature resulted in a marked increase in
enantioselectivity, and the best ee value of 93% was obtained
at À58C (Table 1, entries 10 and 11). To the best of our
knowledge, this ee value represents the highest enantioselec-
tivity attained so far in the catalytic asymmetric hydrogena-
tion of 2-methylquinoxaline.[3]
Having established a highly enantioselective hydrogena-
tion of 1a, we turned to examine the catalyst loading (Table 1,
entries 12–16). Pleasingly, we were able to decrease the
catalyst loading to 0.005 mol% without any loss in enantio-
selectivity. Even with 0.005 mol% of Ir catalyst, the reaction
proceeded smoothly in only slightly lowered conversion and
with the same enantioselectivity (Table 1, entry 15). Remark-
ably, under the same reaction conditions, 1a was hydro-
genated in 1 h to give 28% conversion, providing a TON of
18140 and a TOF of 5620 hÀ1 (Table 1, entry 16). Notably, this
TOF value is the best result reported so far in the asymmetric
hydrogenation of heteroaromatic compounds.[3–9]
Table 1: Optimization of the reaction conditions for asymmetric hydro-
genation of 2-methyl-quinoxaline 1a.[a]
Entry Solvent H2 [psi]; T [8C]; S/C T [h] Conv. [%][b] ee [%][c]
1
THF
THF
700; 20; 100
700; 20; 100
20
20
20
20
20
20
20
1
100
100
100
100
100
100
28
89(S)
83(R)
70(S)
80(S)
87(S)
61(S)
38(S)
89(S)
83(S)
91(S)
93(S)
93(S)
93(S)
93(S)
93(S)
93(S)
2[d]
3
toluene 700; 20; 100
4
5
6
CH2Cl2
DCE
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
700; 20; 100
700; 20; 100
700; 20; 100
700; 20; 100
1500; 20;100
300; 20; 100
700; 0; 100
700; À5; 100
700; À5; 1000
700; À5; 5000
700; À5; 10000
700; À5; 20000
700; À5; 20000
7[e]
8
100
100
9
1
10
11
12
13[f]
14[f]
15[g]
16[g]
1.5 100
1.5 100
20
20
20
20
1
100
100
100
91
28
[a] All reactions were carried out with 2-methylquinoxaline (0.15 mmol),
I2 (2 mol%), solvent (0.6 mL). [b] The conversion was determined by
1H NMR spectroscopy of the crude reaction mixture. [c] The enantio-
meric excess was determined by HPLC on a chiral stationary phase
according to previously reported methods.[3b] [d] (R)-SDPO was used as
the ligand. [e] Without I2 as an additive. [f] 0.3 mmol of 2-methylquinoxa-
line was used. [g] 0.6 mmol of 2-methylquinoxaline was used. DCE=1,2-
dichloroethane, S/C=substrate/catalyst molar ratio, THF=tetrahydro-
furan.
Next, we explored the scope of the iridium-catalyzed
asymmetric hydrogenation of substituted quinoxalines under
the optimized reaction conditions. The results are listed in
Table 2, which showed that all the substrates were smoothly
reduced with good enantioselectivities and full conversions
even at an S/C ratio of 5000. It was found that the reaction
system was sensitive to steric effect, and the presence of a less
sterically demanding alkyl group at the 2-position led to
better enantioselectivities (compare Table 2, entries 1–4 with
entry 5). The presence of substituents at the 6- and 7-positions
of the quinoxaline framework slightly lowered the enantio-
selectivity (Table 2, entries 6 and 7). Lower ee values were
also observed in the case of aryl-substituted quinoxalines
(Table 2, entries 8 and 9). In the hydrogenation of 2-styryl-
substituted quinoxalines, the substituents on the phenyl ring
showed no influence on the catalytic activity, but slightly
affected the enantioselectivity (Table 2, entries 10–14). The
best results were obtained with substrates bearing phenyl or
p-tolyl groups (Table 2, entries 10 and 13).
the excellent performance of the commercially available
chiral bidentate phosphine ligands in the iridium-catalyzed
asymmetric hydrogenation of quinolines,[5] lower enantiose-
lectivities of tetrahydroquinoxaline were observed when Ir/
binap (18% ee; binap = 2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl),
Ir/MeO-biphep
(59% ee;
biphep = 2,2’-
bis(diphenylphosphino)-1,1’-biphenyl), Ir/P-Phos (49% ee;
P-Phos = 2,2’,6,6’-4,4’-bis(diphenylphosphino)-3,3’-bipyri-
dine), or Ir/synphos (77% ee; synphos = (5,6),-(5’,6’)-bis-
(ethylenedioxy)-2,2’-bis(diphenylphosphino)-1,1’-biphenyl)
were used. In addition, the other sterically demanding (R)-H8-
binapo derivatives bearing substituents on the 3- and 3’-
positions of the ligand framework resulted in much lower
enantioselectivities.[11]
The absolute configuration of the 2-substituted styryl
tetrahydroquinoxalines (2j) was determined to be S based on
single-crystal X-ray analysis of 4-N-tosyl-2-styryl-tetrahydro-
quinoxaline (2o; Scheme 1).[11] The configurations of the
other compounds are proposed by analogy.
With the Ir/H8-binapo catalyst in hand, a systematic study
of the hydrogenation of 1a was performed to establish the
optimum reaction conditions. The solvent effect was exam-
ined, and changing the solvent from THF to other solvents led
Finally, we applied this new protocol to the synthesis of
compound 2b, an inhibitor of cholesteryl ester transfer
protein,[1f] as an example of the quinoxaline class of biolog-
ically active compounds. Asymmetric hydrogenation of 2-
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Angewandte
Chemie
method provides a practical synthetic
approach to the preparation of opti-
cally active chiral tetrahydroquinoxa-
line derivatives.
Experimental Section
A mixture of [{IrCl(cod)}2] and (R)-H8-
binapo (M/L* = 0.5/1.1) in THF was stir-
red at room temperature for 10 min in a
glove box, the mixture was transferred by a
syringe to a stainless steel autoclave, in
which I2 (2 mol%) and the substrate were
already placed. The hydrogenation was
performed at À58C under H2 (700 psi)
from 1–20 h. After carefully releasing the
hydrogen gas, saturated sodium carbonate
was added and the mixture was stirred for
10 min. The organic layer was separated
Scheme 1. Derivatization of 2j and solid-state structure of 2o showing the stereogenic center at C8
to have an S configuration. DMAP=4-dimethylaminopyridine.
Table 2: Asymmetric hydrogenation of substituted quinoxalines 1.[a]
and extracted with diethyl ether twice, and the combined organic
extracts were dried over Na2SO4 and concentrated in vacuo. Purifi-
cation of the residue by column chromatography on silica gel (eluent:
CH2Cl2 or EtOAc) gave the pure products. The enantiomeric excess
values were determined by HPLC on a chiral stationary phase using a
Chiralcel OJ-H, OD-H, or AS-H column.
Entry
1
R1/R2
Conv. [%][b,c]
ee [%][c,d,e]
Received: August 13, 2009
Published online: October 28, 2009
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
methyl/H
ethyl/H
n-butyl/H
isobutyl/H
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99
>99 (>99)
>99 (>99)
>99 (>99)
>99 (>99)
>99 (99)
93 (93)
89 (89)
93 (93)
94 (94)
85 (81)
87
89 (91)
84 (85)
84 (84)
96 (97)
92 (92)
92 (93)
96 (98)
93 (93)
Keywords: asymmetric catalysis · diphosphinite ligands ·
.
hydrogenation · tetrahydroquinoxalines
t-butyl/H
methyl/methyl
ethyl/methyl
phenyl/H
o’-MeO-phenyl/H
styryl/H
3’-NO2-styryl/H
2’-Cl-styryl/H
4’-CH3-styryl/H
2’-(naphth-1-yl)vinyl/H
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9
10
11
12
13
14
>99 (99)
>99 (99)
>99 (99)
[a] Reaction conditions: substrate (0.15 mmol), Ir/H8-binapo catalyst
(1 mol%), H2 (700 psi), I2 (2 mol%), THF (0.6 mL), stirred at À58C for
20 h. [b] The conversion was determined by 1H NMR spectroscopy of the
crude reaction mixture. [c] The results in bracket were obtained at a
substrate (0.3 mmol) to catalyst ratio of 5000. [d] The enantiomeric
excess was determined by HPLC on a chiral stationary phase using a
Chiralcel OD-H (2a–2i), AS-H (2j, 2m), and OJ-H (2k, 2l, 2n) column.
[e] The absolute configuration was assigned as S for all products
according to a previously reported method[2f,3] (entries 1–4) or based on
the optical rotation in comparison with a derivative of 2j, which was
characterized by single-crystal X-ray analysis (entries 5–13).
ethylquinoxaline (1b) was carried out on a gram scale (1.9 g)
at a low catalyst loading (Ir/H8-binapo (0.01 mol%)), thus
providing tetrahydroquinoxaline 2b in 95% yield with
89% ee. After transformation of 2b into its N-tosylated
derivative and recrystallization from Et2O, up to 99.9% ee
was obtained.[12]
In conclusion, we have developed a highly efficient
iridium-catalyzed asymmetric hydrogenation of quinoxalines
at low catalyst loading (as low as 0.005 mol%). This new
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