Asymmetric hydrogenation of quinoxalines catalyzed by iridium/PipPhos

Article abstract of DOI:10.1002/adsc.200900522

A catalyst made in situ from the (cyclooctadiene)iridium chloride dimer, [Ir(COD)Cl]₂, and the monodentate phosphoramidite ligand (S)-PipPhos was used in the enantioselective hydrogenation of 2- and 2,6-substituted quinoxalines. In the presence

Full text of DOI:10.1002/adsc.200900522

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DOI: 10.1002/adsc.200900522
Asymmetric Hydrogenation of Quinoxalines Catalyzed by
Iridium/PipPhos
a
a
a,
a,
ˇ
ˇ ´
Natasa Mrsic, Thomas Jerphagnon, Adriaan J. Minnaard, * Ben L. Feringa, *
and Johannes G. de Vriesa,b,*
University of Groningen, Stratingh Institute for Chemistry, Nijenborgh 4, 9747 AG Groningen, The Netherlands
a
E-mail: B.L.Feringa@rug.nl, A.J.Minnaard@rug.nl
DSM Pharmaceutical Products – Innovative Synthesis & Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
b
Fax : (+31)-46-476-1572; e-mail: Hans-JG.Vries-de@dsm.com
Received: July 27, 2009; Published online: October 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900522.
Abstract: A catalyst made in situ from the (cyclooc-
tadiene)iridium chloride dimer, [Ir(COD)Cl]2, and
lysts (RuPPNNCl2) in the enantioselective hydrogena-
tion of imines.[8] The highest enantioselectivity in the
hydrogenation of 2-methylquinoxaline (73% ee) was
obtained using (S)-Xyl-HexaPHEMP as ligand with
the addition of (S,S)-cyclohexanediamine and potassi-
um tert-butoxide as base. The use of a tethered
BIPHEP-type ligand in combinatioin with [Ir-
AHCTUNGTRENNUNG
the monodentate phosphoramidite ligand (S)-Pip-
Phos was used in the enantioselective hydrogena-
tion of 2- and 2,6-substituted quinoxalines. In the
presence of piperidine hydrochloride as additive
full conversions and enantioselectivities of up to
96% are obtained.
AHCTUNGRTEN(GNUN COD)Cl]2 and I2 was reported by Chan, who ach-
ieved up to 80% ee in the asymmetric hydrogenation
Keywords: asymmetric catalysis; heterocycles; ho-
mogeneous catalysis; hydrogenation; iridium; phos-
phoramidites
of 1a.[9]
So far, only bidentate ligands were reported in the
asymmetric hydrogenation of prochiral substituted
quinoxalines. In the last decade, several papers have
reported on the excellent results obtained with the
use of chiral monodentate phosphines, phosphonites,
phosphoramidites and phosphites in rhodium-cata-
Catalytic asymmetric hydrogenation of heteroaromat- lyzed asymmetric hydrogenations.[10] We recently re-
ic compounds represents a valuable method for the ported the asymmetric hydrogenation of quinolines[11]
synthesis of enantiopure saturated heterocyclic com- and N-arylimines[12] catalyzed by iridium compounds
pounds.[1] Numerous chiral heterocyclic compounds, and monodentate phosphoramidite ligands with full
including quinoxalines, are prominent among various conversion and excellent enantioselectivity. Notably,
classes of pharmaceuticals.[2,3] Substituted tetrahydro- compared to bidentate ligands, monodentate phos-
quinoxalines are of interest as models for tetrahydro- phoramidites are readily accessible, structurally highly
folic acid[4] as well as potent CETP (cholesteryl ester diverse, air-stable and inexpensive. They have found
transfer protein) inhibitors for the treatment of athe- many applications in asymmetric hydrogenation.[13] In
rosclerosis and obesity.[5] A synthetic approach to tet- addition, they are amenable to parallel synthesis.[14]
rahydroquinoxalines comprising catalytic asymmetric
hydrogenation would be highly useful.
Herein we report the highly enantioselective hydro-
genation of 2- and 2,6-substituted quinoxalines using
The first asymmetric hydrogenation of 2-methyl- an iridium catalyst with the monodentate phosphor-
quinoxaline (1a) was reported in 1987 using Rh- amidite (S)-PipPhos and piperidine hydrochloride as
DIOP as a catalyst, however with only 3% ee.[6] In additive.
A
ACHTUNGTRENNUNG
1998 Bianchini reported an iridium-based catalyzed
As a starting point, we used the best catalysts and
asymmetric hydrogenation of the same substrate with conditions employed in the asymmetric hydrogenation
high enantioselectivity using an interesting ortho- of 2-substituted quinolines.[11] Optimization of the re-
metalated PPNC iridium dihydride complex (up to action conditions was achieved using the asymmetric
90% ee).[7] In 2003 Henschke et al. reported the use hydrogenation of 2-methylquinoxaline 1a as a test re-
of a diverse library of ruthenium Noyori-type precata- action. Our results are presented in Table 1. Employ-
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Table 1. Asymmetric hydrogenation of 2-methylquinoxaline
(1a)[a]
chloromethane (entries 6 and 7). The addition of
10 mol% of the hydrochloride salt increased the ee by
19%, however the reaction was slower. We have
shown previously that addition of chloride salts en-
hances the enantioselectivity of the iridium/phosphor-
amidite-catalyzed hydrogenation of quinolines.[11] In
the previous work, we also showed that addition of
tri-o-tolylphosphine increased the ee somewhat, but
this effect was found to be negligible in the present
case (result not shown in Table 1). Lowering the cata-
lyst loading to 0.5 mol% influenced the reaction time
but only a small effect was observed with respect to
the enantioselectivity (entry 8).
Various 2- and 2,6-disubstituted quinoxalines (1a–
12a) were subjected to our best asymmetric hydroge-
nation conditions in order to study the scope of the
reaction. The substrates were synthesized according
to a known method by the iron-catalyzed Kumada re-
action on the 2-chloroquinoxaline.[17] The results are
presented in Table 2. All substrates were hydrogenat-
ed with high to excellent enantioselectivities, with 2-
methylquinoxaline 1a providing the product with the
highest ee (96% ee, Table 2, entry 1). Changing from
the methyl- to the ethyl-substituted quinoxaline sub-
strate resulted in a decrease of enantioselectivity in
the hydrogenation of 2-ethylquinoxaline (80% ee,
entry 2). Similar enantioselectivities (80–85% ee)
were obtained with all 2-alkylquinoxaline substrates
(entries 3–7). 2-Phenyl-1,2,3,4-tetrahydroquinoxaline
was obtained with 86% ee (entry 8). Low enantiose-
lectivity was obtained with phenethyl-substituted sub-
strate 9a (75% ee, entry 9). The presence of a hetero-
Entry Solvent 10 mol%
piperidine·HCl [h]
Time[b]
ee[c] Config.[d]
[%]
1
2
3
4
5
6
7
8
MeOH
TFE
toluene
EtOAc
THF
DCM
DCM
DCM
+
+
+
+
+
À
+
+
nd (<24) 17
nd (<24) 10
4
6
14
3
(S)
(R)
(S)
(S)
(S)
(S)
(S)
55
70
73
77
96
8
15
91[e] (S)
[a]
Reaction conditions: 1 mmol scale, quinoxaline/
[Ir(COD)Cl]2/(S)-PipPhos/piperidine hydrochloride=
ACHTUNGTRENNUNG
100/1/4/10, 4 mL of solvent, 608C, 25 bar H2, 24 h.
[b]
Time to achieve full conversion. Conversion was deter-
1
mined by H NMR.
[c]
[d]
Enantiomeric excess was determined by HPLC.
The absolute configuration was determined by determin-
ing the optical rotation and comparing it with literature
data.[15]
AHCTUNGTREGUNaNN tom in the structure such as oxygen did not have a
significant effect on the enantioselectivity (80% ee,
entry 10). A chloride substituent in the 6-position also
did not influence the selectivity (entry 11). The prod-
uct of this reaction can be further functionalized, for
instance, via a Suzuki or a Sonogashira coupling. Un-
fortunately, attempted hydrogenation of the methyl
ester of quinoxaline-2-carboxylic acid 12a failed,
[e]
0.5 mol% [IrACHTUNGTRENNUNG(COD)Cl]2 was used.
ing 1 mol% of the dimeric iridium precursor, 4 mol% which might be due to a strong bidentate coordina-
of phosphoramidite ligand (S)-PipPhos and 10 mol% tion of the substrate to the metal (entry 12).
of piperidine hydrochloride at 608C and 25 bar of H2
pressure, low enantioselectivities were obtained in a tion of [IrAHCTUNTGRENNUNG
In conclusion, we have shown that using a combina-
(COD)Cl]2 as metal source, PipPhos as a
protic solvent such as methanol (Table 1, entry 1). It ligand and piperidine hydrochloride as additive in the
should be noted that the opposite configuration of the asymmetric hydrogenation of 2- and 2,6-substituted
product, however with low ee, was obtained in 2,2,2- quinoxalines, full conversions and ees from 75 to 96%
trifluoroethanol as solvent (entry 2). In aprotic sol- were obtained. These results represent the highest se-
vents such as toluene and ethyl acetate higher enan- lectivity reached for this class of heterocyclic com-
tioselectivities were obtained (55% and 70% ee, re- pounds reported as yet. The highly enantioselective
spectively) with a complete conversion within 6 h (en- hydrogenation of imines and quinolines using this cat-
tries 3 and 4). The use of THF slightly increased the alytic system is now extended to another class of het-
enantioselectivity to 73% yet the reaction was slower erocycles in high yields and ees.
(entry 5). Finally, the best results were obtained in di-
chloromethane with ees up to 96% (entries 6–8). It is
clear that the presence of piperidine hydrochloride af-
fects the enantioselectivity of this reaction in di-
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Asymmetric Hydrogenation of Quinoxalines Catalyzed by Iridium/PipPhos
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Table 2. Asymmetric hydrogenation of 2- and 2,6-substituted
quinoxalines using (S)-PipPhos as a ligand and piperidine
hydrochloride as an additive.[a]
tive to the residual solvent peak. Carbon assignments are
based on APT experiments. HPLC analysis was performed
on a Shimadzu LC-10ADVP HPLC equipped with a Shi-
madzu SPD-M10AVP diode array detector. The enantiomer-
ic excess values were determined by HPLC with an OD-H
chiral column. High resolution mass spectra were recorded
on an AEI-MS-902 mass spectrometer. Optical rotations
were measured on a Schmidt+Haensch polarimeter (Polar-
tronic MH8) with a 10 cm cell (c given in g/100 mL).
Preparation of Quinoxaline Substrates[17] (except 8a)
To a flame-dried, 3-necked flask 2-chloroquinoxaline (1.15 g,
6.99 mmol)
and
iron(II)
acetylacetonate
(125 mg,
0.35 mmol) were added. The mixture was dissolved in dry
THF (50 mL) and N-methyl-2-pyrrolidone was added
(4 mL). A Grignard solution (8.39 mmol) was added drop-
wise over 10 min. The resulting reaction mixture was stirred
for 20 min, diluted with ether (50 mL) and quenched with
1M aqueous HCl solution (15 mL). After 10 min water was
added (50 mL). The ether layer was separated, washed with
brine (50 mL), dried and the solvent was removed under
vacuum. The crude product was purified by column chroma-
tography on aluminum oxide (EtOAc/heptane=1/6). 2-
Methylquinoxaline was purchased from Aldrich and used di-
rectly in the hydrogenation reactions.
Entry
R1
R2
Time[b]
[h]
Yield
[%]
ee[c]
[%]
General Experimental Procedure for Hydrogenation
1
2
3
4
5
6
7
8
9
Me (1b)
Et (2b)
i-Bu (3b)
n-Bu (4b)
n-pentyl (5b)
2-ethylhexyl (6b)
dodecyl (7b)
Ph (8b)
H
H
H
H
H
H
H
H
H
11
5
10
8
9
12
7
85
71
74
83
96
80
80
82
85
80
81
86
75
A mixture of [IrACHTUNRGTNEUNG(COD)Cl]2 (6.72 mg, 0.01 mmol), (S)-Pip-
Phos (15.98 mg, 0.04 mmol), substrate (1 mmol) and piperi-
dine hydrochloride (12.16 mg, 0.1 mmol) was dissolved in
4 mL of solvent, in a glass vial. The vial was placed in a
stainless steel autoclave. Reaction vessels were filled under
air and then flushed with nitrogen before hydrogen pressure
was applied. Hydrogenation was performed at 608C under
25 bar of hydrogen pressure for the indicated time. After
cooling the autoclave, the hydrogen pressure was carefully
released. Solvent was removed under vacuum and conver-
sion was determined by 1H NMR. The crude product was
purified by chromatography (silica gel, heptane/EtOAc=
A
89
81
92
81
9
8
CH2CH2Ph (9b)
10
H
14
83[d]
80
11
12
Me (11b)
COOMe (12b)
Cl
H
7
16
88
0
88
–
1
4/1). Although no side products were observed by H NMR,
yields were ranging from 80 to 99%. It is assumed that in
some cases the yield is lower due to the loss of product on
the silica column.
[a]
Reaction conditions: 1 mmol scale, quinoxaline/
[Ir(COD)Cl]2/(S)-PipPhos/piperidine hydrochloride=
100/1/4/10, 4 mL of DCM, 608C, 25 bar H2.
ACHTUNGTRENNUNG
[b]
Time to achieve full conversion. Conversion was deter-
1
mined by H NMR.
[c]
[d]
Enantiomeric excess was determined by HPLC.
NMR yield.
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Adv. Synth. Catal. 2009, 351, 2549 – 2552