Asymmetric hydrogenation of 2-and 2,3-substituted ouinoxalines with chiral cationic ruthenium diamine catalysts

Article abstract of DOI:10.1021/ol2029096

The enantioselective hydrogenation of 2-alkyl- and 2-aryl-subsituted quinoxalines and 2,3-disubstituted quinoxalines was developed by using the cationic Ru(η⁶-cymene)(monosulfonylated diamine)(BArF) system in high yields with up to 99% ee. The counteranion was found to be critically important for the high enantioselectivity and/or diastereoselectivity.

Full text of DOI:10.1021/ol2029096

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6568–6571
Asymmetric Hydrogenation of 2- and
2,3-Substituted Quinoxalines with Chiral
Cationic Ruthenium Diamine Catalysts
Jie Qin,† Fei Chen,† Ziyuan Ding,† Yan-Mei He,† Lijin Xu,‡ and Qing-Hua Fan*,†
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry and Graduate School,
Chinese Academy of Sciences (CAS), Beijing 100190, P. R. China, and Department of
Chemistry, Renmin University of China, Beijing 100972, P. R. China
fanqh@iccas.ac.cn
Received October 27, 2011
ABSTRACT
The enantioselective hydrogenation of 2-alkyl- and 2-aryl-subsituted quinoxalines and 2,3-disubstituted quinoxalines was developed by using the
cationic Ru(η6-cymene)(monosulfonylated diamine)(BArF) system in high yields with up to 99% ee. The counteranion was found to be critically
important for the high enantioselectivity and/or diastereoselectivity.
The 1,2,3,4-tetrahydroquinoxaline ring system is a use-
ful key structural unit in many therapeutically and bio-
logically active compounds.1 Optically pure tetrahydro-
quinoxalines have shown great potential for drug
development.1cÀh Consequently, increasingresearchefforts
have been devoted to the asymmetric synthesis of these
compounds over the past decades.2À5 Among the reported
different methods, asymmetric hydrogenation (AH) of the
corresponding readily available quinoxalines represents
one of the most convenient and straightforward approaches
for attaining such optically activeheterocyclic compounds.
Inrecentyears, great progress in the metal-catalyzedAH
of heteroaromatic compounds,6 particularly quinolines,7
has been made. However, despite the great importance of
tetahydroquinoxalines, few successful examples of AH of
quinoxalines have been reported so far in the literature.5
The first AH of 2-methyl-quinoxaline with a Rh-DIOP
catalyst was reported by Murata in 1987, however with
† Chinese Academy of Sciences.
‡ Renmin University of China.
(1) (a) Sikorski, J. A. J. Med. Chem. 2006, 49, 1. (b) Jacobsen, E. J.;
Stelzer, L. S.; Belonga, K. L.; Carter, D. B.; Im, W. B.; Sethy, V. H.;
Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D. J. Med. Chem. 1996, 39,
3820. (c) Ohtake, Y.; Naito, A.; Hasegawa, H.; Kawano, K.; Morizono,
D.; Taniguchi, M.; Tanaka, Y.; Matsukawa, H.; Naito, K.; Oguma, T.;
Ezure, Y.; Tsuriya, Y. Bioorg. Med. Chem. 1999, 7, 1247. (d) Torisu, K.;
Kobayashi, K.; Iwahashi, M.; Nakai, Y.; Onoda, T.; Nagase, T.;
Sugimoto, I.; Okada, Y.; Matsumoto, R.; Nanbu, F.; Ohuchida, S.;
Nakai, H.; Toda, M. Bioorg. Med. Chem. 2004, 12, 5361. (e) Eary, C. T.;
Jones, Z. S.; Groneberg, R. D.; Burgess, L. E.; Mareska, D. A.; Drew,
M. D.; Blake, J. F.; Laird, E. R.; Balachari, D.; O’Sullivan, M.;
Allen, A.; Marsh, V. Bioorg. Med. Chem. Lett. 2007, 17, 2608. (f) Jones,
Z.; Groneberg, R.; Drew, M.; Eary, C. T. U.S. Patent 20050282812,
2005. (g) Chang, G.; Didiuk, M. T.; Finneman, J. I.; Garigipati, R. S.; Kelley,
R. M.; Perry, D. A.; Ruggeri, R. B.; Bechle, B. M. Patent WO 2004085401,
2004. (h) Kuhl, A.; Kolkhof, P.; Telan, L.; Peters, J. G.; Lustig, K.; Kast, R.;
M€unter, K.; Stasch, J.-P.; Tinel, H. Patent WO 2005028451, 2005.
(2) (a) Fisher, G. H.; Whitman, P. J.; Schultz, H. P. J. Org. Chem.
1970, 35, 2240. (b) Massacret, M.; Lhoste, P.; Sinou, D. Eur. J. Org.
Chem. 1999, 129. (c) Bunce, R. A.; Herron, D. M.; Hale, L. Y.
J. Heterocycl. Chem. 2003, 40, 1031. (d) Abdel-Jalil, R. J.; Shah,
S. T. A.; Khan, K. M.; Voelter, W. Lett. Org. Chem. 2005, 2, 238.
(e) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.; Lectka,
T. J. Am. Chem. Soc. 2006, 128, 13370. (f) Kim, J. C.; Choi, H. G.; Kim,
M. S.; Ha, H.-J.; Lee, W. K. Tetrahedron 2010, 66, 8108. (g) Wang
D.-W.; Wang, D.-S.; Chen, Q.-A.; Zhou, Y.-G. Chem.;Eur. J. 2010, 16,
1133.
(3) For organo-catalyzed asymmetric transfer hydrogenation of 2-
aryl quinoxalines, see: Rueping, M.; Tato, F.; Schoepke, F. R. Chem.;
Eur. J. 2010, 16, 2688.
(4) For metal/Brønsted acid relay catalysis for asymmetric reduction of
2-aryl quinoxalines, see: Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G.; Duan, Y.;
Fan, H.-J.; Yang, Y.; Zhang, Z. J. Am. Chem. Soc. 2011, 133, 6126.
r
10.1021/ol2029096
Published on Web 11/18/2011
2011 American Chemical Society

only 3% ee.5a Since then, much effort has been made by
several research groups to expand the substrate scope and
to improve the reactivity and enantioselectivity of such a
transformation. Most recently, Chan and Fan reported an
efficient Ir/H8-binapo system for AH of 2-alkyl-substituted
quinoxalines with high enantioselectivities (up to 96% ee)
at low catalyst loading.5g Simultaneously, Feringa and co-
workers realized the enantioselective hydrogenation of a
range of 2-substituted quinoxalines with an iridium cata-
lyst containing monodentate phosphoramidite PipPhos
ligand by using piperidine hydrochloride as an additive
with up to 96% ee.5h Later Ratovelomanana-Vidal and co-
workers described an iridium-difluorphos catalyzed AH of
2-alkyland 2-aryl-substituted quinoxalineswithup to95%
ee.5k However, all these metallic catalysts had at least one
phosphine ligand around the metal center and were often
air sensitive. Furthermore, most of these catalysts were
highly enantioselective only in the hydrogenation of 2-
alkyl-substituted quinoxalines. To the best of our knowl-
edge, AH of 2,3-disubstituted quinoxalines has not been
reported so far. Therefore, more general, efficient, and
stable catalyst systems for AH of quinoxaline derivatives
are desirable.
derivatives, providing chiral 1,2,3,4-tetrahydroquinolines
with up to 99% ee.9 Further mechanistic study indicated
that the counteranion is critically important for the high
enantioselectivity,9b which may provide a suitable plat-
form for extending the application of this Ru-diamine
catalyst in the AH of other difficult substrates. Most
recently, this catalytic system has been demonstrated to
be highly enantioselective for AH of the often-problematic
acyclic and cyclic N-alkyl imines with up to 99% ee.10 It
was found that the weakly coordinating counterions did
influence the enantioselectivity significantly. Encouraged
by these results and as our continuing interest in the AH of
heteroaromatic compounds and imines, herein, we report
the general and highly efficient asymmetric hydrogenation
of a broad range of 2-alkyl- and 2-aryl-substituted and 2,
3-dialkyl-substituted quinoxalines using a ruthenium-
diamine catalytic system to give 1,2,3,4-tetrahydroquino-
xaline derivatives in excellent enantioselectivities.
Recently, we have found that the cationic ruthenium
complexes of chiral monotosylated diamines were very
efficient catalysts for AH8 of a broad range of quinoline
(5) (a) Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26,
763. (b) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani,
M. Organometallics 1998, 17, 3308. (c) Bianchini, C.; Barbaro, P.;
Scapacci, G. J. Organomet. Chem. 2001, 621, 26. (d) Cobley, C. J.;
Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195. (e) Henschke, J. P.;
Burk, M. J.; Malan, C. G.; Herzberg, D.; Peterson, J. A.; Wildsmith,
A. J.; Cobley, C. J.; Casy, G. Adv. Synth. Catal. 2003, 345, 300. (f) Qiu,
L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.;
Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955.
(g) Tang, W.; Xu, L.; Fan, Q.-H.; Wang, J.; Fan, B.; Zhou, Z.; Lam,
Figure 1. Screened catalysts.
The study was initiated by screening the Ru catalysts
containing different chiral diamine ligands and counter-
anions using 2-methylquinoxaline (1a) as the standard
substrate (Figure 1). According to our previous reports
on the AH of quinolines,9 we examined the AH of 1a cata-
lyzed by (R,R)-7a (1 mol %) in methanol (entry 1 in
Table 1). The reaction proceeded smoothly, affording
(R)-2-methyl-1,2,3,4-tetrahydroquinoxaline in quantita-
tive yield, but with only 23% ee. Gratifyingly, a distinct
increase in enantioselectivity was observed when aprotic
dichloromethane (DCM) was used as solvent (entry 2).
Further investigation of a variety of catalysts demon-
strated that the counteranion of the catalyst had a signifi-
cant impact on the stereochemical outcome of the reaction
(entries 3À7 and Table S1 in Supporting Information (SI)).
A full conversion and excellent enantiomeric excess of
98% were obtained with the weakly coordinating coun-
terion BArFÀ (tetrakis(3,5-bis-trifluoromethylphenyl)bo-
rate) (entry7). Inaddition, for the AHof 1awith 1.0 mol %
(R,R)-8e, DCM, toluene, or ClCH2CH2Cl (DCE) all gave
excellent enantioselectivities, while DCE resulted in the
highest reactivity (entries 7À9). It was also observed that
the enantioselectivity is insensitive to hydrogen pressure
and temperature (entries 9À13). Furthermore, lowering
ꢀ ꢁ
K.-h.; Chan, A. S. C. Angew. Chem., Int. Ed. 2009, 48, 9135. (h) Mrsic,
N.; Jerphagnon, T.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G.
Adv. Synth. Catal. 2009, 351, 2549. (i) Wang, D.-S.; Zhou, Y.-G. Tetra-
ꢁ~
ꢁ
ꢁ
hedron Lett. 2010, 51, 3014. (j) Nunez-Rico, J. L.; Fernandez-Perez, H.;
Benet-Buchholz, J.; Vidal-Ferran, A. Organometallics 2010, 29, 6627.
^
(k) Cartigny, D.; Nagano, T.; Ayad, T.; Genet, J.-P.; Ohshima, T.;
Mashima, K.; Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2010, 352,
1886.
(6) For recent reviews, see: (a) Glorius, F. Org. Biomol. Chem. 2005,
3, 4171. (b) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357. (c) Kuwano, R.
Heterocycles 2008, 76, 909.
(7) For selected examples of AH of quinolines with the Ir/phosphine/
I2 system, see: (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.;
Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536. (b) Wang, D.-W.;
Wang, X.-B.; Wang, D.-S.; Lu, S.-M.; Zhou, Y.-G.; Li, Y.-X. J. Org.
Chem. 2009, 74, 2780. (c) Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.;
Lo, W.-H.; Chan, A. S. C. Chem. Commun. 2005, 1390. (d) Wang, Z.-J.;
Deng, G.-J.; Li, Y.; He, Y.-M.; Tang, W.-J.; Fan, Q.-H. Org. Lett. 2007,
9, 1243. (e) Reetz, M. T.; Li, X. Chem. Commun. 2006, 2159. (f) Tadaoka,
^
H.; Cartigny, D.; Nagano, T.; Gosavi, T.; Ayad, T.; Genet, J. P.;
Ohshima, T.; Ratovelomanana-Vidal, V.; Mashima, K. Chem.;Eur.
J. 2009, 15, 9990.
(8) For pioneering work on using chiral metal complexes of diamine
for hydrogenation, see: (a) Ito, M.;Hirakawa, M.;Murata, K.; Ikariya, T.
Organometallics 2001, 20, 379. (b) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.;
Murata, K.; Sandoval, C.; Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724.
For recent examples of AH of imines, see:(c) Li, C.; Xiao, J. J. Am. Chem.
Soc. 2008, 130, 13208. (d) Li, C.; Wang, C.; Villa-Marcos, B.; Xiao, J.
J. Am. Chem. Soc. 2008, 130, 14450. (e) Shirai, S.-y; Nara, H.; Kayaki, Y.;
Ikariya, T. Organometallics 2009, 28, 802.
(9) (a) Zhou, H.;Li, Z.;Wang, Z.;Wang, T.; Xu, L.; He, Y.; Fan, Q.-H.;
Pan, J.; Gu, L.; Chan, A. S. C. Angew. Chem., Int. Ed. 2008, 47, 8464.
(b) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.;
Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc. 2011, 133, 9878.
(10) (a) Chen, F.; Wang., T.; He, Y.; Ding, Z.; Li, Z.; Xu, L.; Fan,
Q.-H. Chem.;Eur. J. 2011, 17, 1109. (b) Chen, F.; Ding, Z.; Qin, J.;
Wang, T.; He, Y.; Fan, Q.-H. Org. Lett. 2011, 13, 4348.
Org. Lett., Vol. 13, No. 24, 2011
6569

the catalyst loading to 0.1 mol % led to a remarkable
decrease in both reactivity and enantioselectivity (entry
14), whereas increasing the substrate concentration (from
0.1 to 1.0 mol/L; 2.0 g scale) could maintain the same enan-
tioselectivity (entry 15). Remarkably, full conversion was
also observed when the hydrogenation was carried out at a
substrate/catalyst ratio of 1000 under solvent-free condi-
tions, with a slightly lower enantioselectivity (entry 16).
Table 2. AH of 2-Alkyl-Substituted Quinoxalinesa
Table 1. Optimization of Reaction Conditionsa
a Reaction conditions: 0.2 mmol of substrate (1aÀ1m) with 1.0 mol
% (R,R)-8e in 1 mL of DCE, 50 atm of H2, stirred at 40 °C for 8 h.
b Isolated yield. c Determined by chiral HPLC. d The conjugated CdC
bond was also hydrogenated.
optimization of the reaction conditions. To our delight,
hydrogenation of 3a with 1.0 mol % (R,R)-8e gave very
good enantioselectivity (Table 3, entry 1). After a survey of
a variety of catalysts (Table S2 in SI), complex (S,S)-9e
was found to be the optimal catalyst (entry 2). Further
improvement in enantioselectivity was achieved when the
reaction was carried out under ascending hydrogen pres-
sure and decreasing reaction temperature (entries 3À7).
Undertheoptimizedreactionconditions(entry7inTable3),
a variety of 2-aryl-substituted quinoxalines were enantio-
merically hydrogenated to afford the corresponding prod-
ucts in good to excellent enantioselectivities (89À96% ee,
entries 7À13). It was found that the electronic properties of
the substituents at the phenyl ring had no apparent effect
on activity and enantioselectivity. However, substrate 3g
with the substituent at the ortho position of the phenyl ring
gave low enantioselectivity (entry 13). Notably, hydroge-
nation of 3c afforded the corresponding product with
96% ee (entry 9), which is, to the best of our knowledge,
the highest ee value reported so far for the AH of 2-aryl-
substituted quinoxaline derivatives.
Finally, we expanded the substrate scope to the readily
accessible 2,3-dialkyl-substituted quinoxalines, and the
results were summarized in Table 4. Hydrogenation of 5a
was performed in DCE with 1.0 mol % (R,R)-8e, which
was the optimal catalyst for the AH of 2-alkyl-substituted
quinoxalines, giving the corresponding product with
good diastereoselectivity and excellent enantioselectivity
(entry 1). To the best of our knowledge, this is the first
time the AH of 2,3-disubstituted quinoxalines was
realized.11 Again, catalyst screening demonstrated that
a Reaction conditions: 0.2 mmol of 1a with 1.0 mol % Ru-catalyst in
2 mL of solvent, 12 h. b Determined by 1H NMR of the crude reaction
mixture. c Determined by chiral HPLC. d Value in parentheses was
related to reaction time of 1.5 h. e With 0.1 mol % catalyst, 0.5 mmol
of 1a in 5 mL of DCE, 24 h. f With 0.1 mol % catalyst, 14 mmol (2.0 g) of
1a in 14 mL of DCE, 24 h. g Isolated yield. h 114 mg of 1a (1 mmol) with
0.1 mol % catalyst under solvent-free conditions for 24 h.
Under the optimized reaction conditions (entry 9 in
Table 1), a variety of 2-alkyl-substituted quinoxalines were
efficiently hydrogenated in the presence of 1.0 mol %
(R,R)-8e to afford the corresponding chiral tetrahydroqui-
noxalines with excellent enantioselectivities (95À99% ee,
Table 2). It was found that the presence of a sterically
demanding alkyl group, such as tert-butyl and cyclohexyl,
at the 2-position led to slightly lower enantioselectivities
(entries 6 and 8). The presence of substituents at the 6- and
7-positions of the quinoxaline framework had no effect on
the enantioselectivity (entries 9À12). In the case of 2-styryl
quinoxaline, both the heteroaromatic ring and CdC double
bond of styryl were hydrogenated, producing 2-phenethyl-
tetrahydroquinoxaline with high enantiomeric excess
(entry 13).
Encouraged by these promising results, we then moved
to examine the catalytic efficiency of Ru/diamine-type
catalysts in the AH of the more challenging 2-aryl sub-
stituted quinoxalines.3,4,5k 2-Phenylquinoxaline (3a) was
used as the model substrate for catalyst screening and
(11) For recent work on the AH of the carbocyclic ring of 2,3-
disubstituted quinoxalines by using a chiral ruthenium NHC complex,
see: Urban, S.; Ortega, N.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
3803.
6570
Org. Lett., Vol. 13, No. 24, 2011

platform for extending their application in the AH of other
heteroaromatic compounds. Investigation for detailed in-
sight intothe nature of this remarkable counteranion effect
is in progress.
Table 3. AH of 2-Aryl-Substituted Quinoxalinesa
Table 4. AH of 2,3-Dialkyl-Substituted Quinoxalinesa
a Reaction conditions: 0.2 mmol of substrate (3aÀ3g) with 1.0 mol %
(S,S)-9e (except for entry 1, (R,R)-8e) in 1 mL of DCE, 16 h. b Deter-
mined by 1H NMR of the crude reaction mixture. c Determined by chiral
HPLC. d Isolated yield.
the counteranion also played an important role in the
diastereoselectivity control of this reaction (entries 1À5).
After optimization of the reaction conditions (Table S3 in
SI), a variety of 2,3-dialkyl substituted quinoxalines
were reduced at 40 °C for 8 h in toluene under 50 atm of
hydrogen using 1.0 mol % (R,R)-8e. Generally, excellent
enantioselectivities (99% ee in all cases) and moderate
diastereoselectivities (69/31À86/14) were achieved. It was
found that the electronic properties of the substituents
at the 6-position of the quinoxaline framework had an
apparent effect on diastereoselectivity. Substrates bearing
F (5g) or Cl (5h) gave low diastereoselectivities (entries 12
and 13).
In summary, the half-sandwich Ru(II) complexes of
monosulfonylated diamine bearing a weakly coordinating
bulky counterion BArFÀ have been disclosed to be highly
efficient for AH of a variety of 2- and 2,3-substituted
quinoxalines, providing a convenient access to the corre-
sponding optically active 1,2,3,4-tetrahydroquinoxalines
with biological importance. The counterion was found to
be critically important for the high enantioselectivity
and/or diastereoselectivity, which may provide a suitable
a Reaction conditions: 0.2 mmol of substrate (5aÀh) with 1.0 mol %
Ru-catalyst in 1 mL of solvent, 50 atm of H2, stirred at 40 °C for 8 h.
b Determined by 1H NMR of the crude reaction mixture. c Determined
by 1H NMR12 and/or HPLC. d Determined by chiral HPLC. e Isolated
yield.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant No.
20973178), the National Basic Research Program of China
(973 Program, No. 2010CB833300), and the Chinese
Academy of Sciences is greatly acknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization data for all compounds, de-
scriptions of stereochemical assignments, and copies of
1H and 13C NMR spectra for new compounds reported in
the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Gibson, C. S. J. Chem. Soc. 1927, 342. (b) Archer, R. A.;
Mosher, H. S. J. Org. Chem. 1967, 32, 1378.
Org. Lett., Vol. 13, No. 24, 2011
6571