Asymmetric hydrogenation of quinoxalines, benzoxazines, and a benzothiazine catalyzed by chiral ruthenabicyclic complexes

Article abstract of DOI:10.1002/adsc.201300604

The ruthenabicyclic complex RuCl[(R)-daipena][(R)-dm-segphos] with potassium tert-butoxide catalyzes the hydrogenation of 2-alkylquinoxalines and a 3-methyl-2H-1,4-benzoxazine in toluene under 20-100 atm of hydrogen at 40 °C to afford S-configured cyclic

Full text of DOI:10.1002/adsc.201300604

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DOI: 10.1002/adsc.201300604
Asymmetric Hydrogenation of Quinoxalines, Benzoxazines, and
a Benzothiazine Catalyzed by Chiral Ruthenabicyclic Complexes
Noriyoshi Arai,a Yu Saruwatari,a Kotaro Isobe,a and Takeshi Ohkumaa,*
a
Division of Chemical Process Engineering and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University,
Sapporo, Hokkaido 060-8628, Japan
Fax : (+81)-11-706-6598; e-mail: ohkuma@eng.hokudai.ac.jp
Received: July 8, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300604.
Abstract: The ruthenabicyclic complex RuCl[(R)-
daipena][(R)-dm-segphos] with potassium tert-but-
oxide catalyzes the hydrogenation of 2-alkylqui-
noxalines and a 3-methyl-2H-1,4-benzoxazine in tol-
uene under 20–100 atm of hydrogen at 408C to
afford S-configured cyclic amino products in greater
than 97% enantiomeric excess {DAIPENA=anion
of DAIPEN at the 2-position of an anisyl group,
system [substrate-to-catalyst molar ratio (S/C) 20,000,
48 atm of H2, À58C, 20 h, 91% conversion, 93% enan-
tiomeric excess (ee)][5e] and enantioselectivity as high
as 99% using the Ru(II)ACTHNUTRGNEUNG
(MsDPEN)(h6-p-cymene) cat-
alyst (S/C=100, 50 atm of H2, 408C, 8 h)[6d] are nota-
ble. Hydrogenation of 2H-1,4-benzoxazine substrates
with chiral Ir catalysts (e.g., S/C=200, 40 atm of H2,
room temperature, 20 h) afforded the products in up
to 95% ee.[7] The biomimetic asymmetric reduction
using a 9,10-dihydrophenanthridine/chiral Brønsted
acid system (S/C=100) followed by regeneration of
DAIPEN=1,1-diACHTUNTRGNEUNG(4-anisyl)-2-isopropyl-1,2-ethylene-
diamine, DM-SEGPHOS=(4,4’-bi-1,3-benzodiox-
ole)-5,5’-diylbis[di(3,5-xylyl)phosphine]}. The high
catalytic activity results in a turnover number as
high as 9400. Hydrogenation of the benzoimine het-
erocycles with the RuCl[(R)-daipena][(R)-segphos]/
potassium tert-butoxide system yields the R-config-
ured products in high enantiomeric excess
the reductant via [RuI2ACTHNUTRGNE(NUG p-cymene)]2-catalyzed (S/C=
50, 3 atm of H2, room temperature, 32 h) hydrogena-
tion of phenanthridine gave the 3,4-dihydro-2H-1,4-
benzoxazines in up to 92% ee.[6e] To the best of our
knowledge, no asymmetric hydrogenation of 3-substi-
tuted 2H-1,4-benzothiazines has previously been re-
ported.[8] Thus, the development of highly active and
enantioselective catalysts for hydrogenation of these
heterocyclic imines is a desirable objective.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
tion is discussed based on transition state models in-
volving six-membered pericyclic structures.
We have recently reported an extremely rapid and
enantioselective hydrogenation of ketones catalyzed
Keywords: amines; asymmetric catalysis; hydroge-
nation; imines; ruthenium
by the RuClACTHNGUTRENN(UG daipena)CATHUNGTREN(NUNG xylbinap)/base (base: t-
C4H9OK or DBU) system [XylBINAP=2,2’-bis(di-
3,5-xylylphosphino)-1,1’-binaphthyl: see the structure
illustrated in Scheme 1].[9–11] The turnover frequency
in the reaction of acetophenone (S/C=100,000,
Optically active 2-substituted 1,2,3,4-tetrahydroqui- 50 atm of H2) reached as high as 350,000 minÀ1 pro-
noxalines as well as 3-substituted 3,4-dihydro-2H-1,4- ducing 1-phenylethanol in >99% ee. The unique
À
benzoxazines and thia analogues are unique fused-bi- ruthenabicyclic structure of this complex with an Ru
cyclic N-arylamines possessing a b-heteroatom, and C bond appears to be significant for achieving high
are core structures in many useful biologically active activity. We expected that this new type of catalyst
compounds.[1,2] Asymmetric hydrogenation of 2-substi- could be useful for the enantioselective hydrogena-
tuted quinoxalines,[3–6] 3-substituted 2H-1,4-benzoxa- tion of 2-substituted quinoxalines as well as 3-substi-
zines,[7] and 3-substituted 2H-1,4-benzothiazines is tuted 2H-1,4-benzoxazines and their thia analogues.
among the most direct and reliable methods to pro-
We first selected 2-methylquinoxaline (1a) as a typi-
duce these important molecules. Recently, several ef- cal substrate for optimization of the catalyst structure
ficient procedures with chiral Ir and Ru catalysts have and the reaction conditions (Scheme 1 and Table 1).
been reported for this reaction of quinoxalines.[5,6] When 1a (0.505 mmol) was hydrogenated in 2-propa-
The high activity of the Ir(I)H8-BINAPO/I2 catalyst nol, a typical solvent for this catalyzed reaction, at
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desired
(S)-1,2,3,4-tetrahydro-2-methylquinoxaline
[(S)-2a] was obtained in 91% yield and 99% ee ac-
companied by the partially hydrogenated compound
3a in 4% yield (entry 1). The yield and
enantiomeric purity of 2a decreased on using
RuCl
ACHTUGTNRENNUG(daipena)ACHTUNGTRENN(UGN xylbinap) (5) or RuCl2(dm-segphos)-
AHCTUNGTREG(NNNU daipen) (6), both of which exhibit excellent catalytic
performance in the reaction of ketones, instead of 4a
(entries 2 and 3).[9,10] The electron-donating ability of
DM-SEGPHOS and the ruthenabicyclic structure
À
with a Ru C (aryl) bond appear to be important for
achieving higher activity and enantioselectivity. Only
partially hydrogenated compound 3a in 56% yield
was observed in the hydrogenation with 4a in metha-
nol under otherwise identical conditions (entry 4).
The reaction in ethanol, tert-butyl alcohol or THF
gave 2a in approximately 90% yield and >99% ee
contaminated by a small amount of 3a (entries 5–7).
When the hydrogenation was carried out in CH2Cl2 or
toluene, the desired product 2a was obtained in 90%
and 94% yields, respectively, as a sole compound (en-
tries 8 and 9). Thus, we selected toluene as the most
preferable solvent. The reaction rate increased at
408C, resulting in complete conversion to 2a without
a loss of enantioselectivity (entry 10). A high yield of
90% was obtained in the reaction with an S/C of 100
even under 1–1.5 atm of H2 for 28 h (entry 11). The
Scheme 1. Asymmetric hydrogenation of 2-methylquinoxa-
line (1a). RN: R configuration of the nitrogen-containing
ligand (DAIPEN or DAIPENA). RP: R configuration of the
phosphorus-containing ligand (SEGPHOS, DM-SEGPHOS,
or XylBINAP).
258C under 20 atm of H2 for 20 h in the presence of substrate 1a was completely transformed into 2a in
RuCl[(R)-daipena][(R)-dm-segphos] [(RN,RP)-4a][9,12,13] the hydrogenation with an S/C of 2000 under 20 atm
(2.6 mmol, S/C=200) and t-C4H9OK (0.130 mmol), the of H2 for 21 h (entry 14). A turnover number of ap-
Table 1. Asymmetric hydrogenation of 2-methylquinoxaline (1a) catalyzed by chiral Ru complexes.[a]
Entry
Catalyst
S/C[b]
Solvent
Temperature [8C]
Time [h]
Yield of 2a/3a [%][c]
ee of 2a [%][d]
1
2
3
4
5
6
7
8
9
10
11[f]
12[g]
13[g]
14[g]
15[h]
U
200
200
200
200
200
200
200
200
200
200
100
1000
1000
2000
8000
i-PrOH
i-PrOH
i-PrOH
MeOH
EtOH
25
25
25
25
25
25
25
25
25
40
40
40
40
40
40
20
22
19
21
20
20
19
28
21
20
28
13
15
21
40
91/4
89/3
35/33
<1/56
91/4
89/4
99
G
95[e]
93
G
–
>99
>99
>99
>99
>99
>99
>99
>99
94
t-BuOH
THF
93/1
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
90/<1
94/<1
>99/<1
90/<1
>99/<1
96/<1
>99/<1
89/<1
ACHTUNGTRENNUNG
>99
>99
[a]
Unless otherwise stated, reactions were carried out using 1a (0.3–0.5 mmol) in solvent (0.7–2.5 mL) containing (RN,RP)-4,
(SN,SP)-5, or (RN,RP)-6 (2.4–3.6 mmol) and t-C4H9OK (0.12–0.18 mmol) under 20 atm of H2.
Substrate/catalyst molar ratio.
Determined by H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard.
Data of (S)-2a determined by chiral GC or HPLC analysis.
Data of (R)-2a.
Reaction at 1–1.5 atm of H2.
Reaction using 1a (2.3–5.0 mmol) with 4 (2.3–2.6 mmol) and t-C4H9OK (0.12–0.13 mmol).
Reaction using 1a (13.0 mmol) with 4a (1.4 mmol) and t-C4H9OK (0.68 mmol) under 100 atm of H2.
[b]
[c]
[d]
[e]
[f]
1
[g]
[h]
2
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Asymmetric Hydrogenation of Quinoxalines, Benzoxazines, and a Benzothiazine
proximately 7100 was obtained in the reaction with 20 atm of H2, 408C) to afford the 2-substituted
an S/C of 8000 under 100 atm of H2 for 40 h 1,2,3,4-tetrahydroquinoxalines, 2a–2c, in >99% ee
(entry 15). The bulky 3,5-xylyl groups on the phos- (entries 1–3). The reaction of 1d with a relatively
phine ligand were crucial to achieving excellent enan- bulky isobutyl group was somewhat slower, but the
tioselectivity in the reaction of 1a. Thus, the ee value benzyl-substituted compound 1e was smoothly con-
decreased to 94% with the RuClACTHUNTGRENNUG(daipena)ACHTUNGTNER(NUGN segphos) verted to 2e under the same conditions (entries 4 and
(4b: Ar=phenyl)[12] instead of 4a (entry 12 versus 13). 5). No hydrogenation of the 2-phenyl substrate 1f
Consequently, the 4a/t-C4H9OK catalyst system ach- occurred (entry 6), which may have been due
ieved both excellent activity and enantioselectivity in to the bulkiness of the phenyl group. Fortunately,
the hydrogenation of 1a.[5]
the hydrogenation of 1f proceeded by using
The 4a/t-C4H9OK catalyst system was applied to RuCl[(R)-daipena][(R)-segphos] [(RN,RP)-4b] with an
the asymmetric hydrogenation of a series of quinoxa- S/C of 100, resulting in the R (not S) enantiomer of 2f
line derivatives 1 (Table 2). The methyl-, ethyl-, and in 96% ee quantitatively (entry 7). The mode of enan-
propyl-substituted compounds at the C-2 position tioselection will be discussed below. The 6-chloro and
(1a–1c) were quantitatively hydrogenated (S/C=1000, 6,7-dichloro-2-methylquinoxalines, 1g and 1h, were
Table 2. Asymmetric hydrogenation of quinoxalines 1, benzoxazines 7a, b, and a benzothiazine 7c with the ruthenabicyclic
complex 4.[a]
Entry
Substrate
Catalyst
S/C[b]
Time [h]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1f
1g
1h
1h
1i
4a
4a
4a
4a
4a
4a
4b
4a
4a
4a
4a
4a
4a
4b
4b
1000
1000
1000
1000
1000
100
100
200
200
9400
100
13
25
28
31
29
24
16
16
16
72
23
24
23
22
36
>99 (>99)
99 (96)
>99 (96)
89 (82)
99 (96)
<1
>99 (99)
>99 (97)
>99 (95)
>99 (97)
>99 (97)
>99 (99)
>99 (98)
>99 (99)
>99 (98)
>99 (S)
>99 (S)
>99 (S)
97 (S)
98 (S)
–
96 (R)
>99 (S)
98 (S)
>99 (S)
>99 (S)
>99 (S)
98 (S)
10[e]
11
12
13
14
15
1j
100
200
200
100
7a
7b
7c
98 (R)
>99 (R)
[a]
Unless otherwise stated, reactions were carried out using 1 or 7 (0.1–2.0 mmol) in toluene with (RN,RP)-4 and t-C4H9OK
under 20 atm of H2 at 408C. 4:t-C4H9OK=1:50.
[b]
[c]
Substrate/catalyst molar ratio.
1
Determined by H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard. Isolated yield is given in paren-
theses.
[d]
[e]
Determined by chiral HPLC analysis. Absolute configuration of the product is stated in parentheses.
Reaction using 1h (8.0 mmol) under 100 atm of H2.
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quantitatively hydrogenated (S/C=200, 20 atm of H2) action of the phenyl-substituted quinoxaline 1f (see
to the tetrahydro products 2g and 2h in >99% ee and entry 7).
98% ee, respectively (entries 8 and 9). The high reac-
Our recent mechanistic studies on the asymmetric
tivity of 1h resulted in complete conversion in the hy- hydrogenation of ketones catalyzed by the ruthenabi-
drogenation with an S/C of 9400 under 100 atm of H2 cyclic complexes 4 with base revealed that the hydride
in 72 h to yield 2h in >99% ee (entry 10). The substi- complex RuHACTHNUTRGNEU(GN daipena)(diphosphine) (diphosphine=
tution with the electron-donating methyl or methoxy DM-SEGPHOS, XylBINAP) was formed under the
group at the 6 and 7 positions, 1i and 1j, decreased reaction conditions.[9,14] This RuH complex is expected
the reaction rate, but the high level of enantioselectiv- to act as the reactive species in the hydrogenation of
ity was maintained (entries 11 and 12). The products the heterocyclic imines, 1 and 7. Figure 1 illustrates
2i and 2j were readily oxidized back to the substrates molecular models of RuH[(R)-daipena][(R)-dm-
1i and 1j in open air, causing difficulty in separating segphos] [(RN,RP)-RuH] based on the X-ray structure
these products from the substrates. We therefore iso- of the RuCl precursor (RN,RP)-4a that was previously
lated 2i and 2j merely by passing the reaction mixture reported by our group.[9] The structure is fixed by the
through a silica gel pad to remove the metallic con- ruthenabicyclo
ACHTUNGTRENNUNG
tents.
axial-proton (Hax) of the complex is the most reactive
À
À
The (RN,RP)-4a/t-C4H9OK system also efficiently among the four amine protons, because the H Ru
catalyzed asymmetric hydrogenation of 7,8-difluoro-3- N Hax torsion angle is expected to be the smallest.[15]
À
methyl-2H-1,4-benzoxazine (7a). The reaction with an The hydrogenation of 3a, which is the second step of
S/C of 200 was completed in 23 h to afford (S)-8a in the reaction of 1a, proceeds through the six-mem-
98% ee (Table 2, entry 13). The product (S)-8a is bered pericyclic transition state, TSA or TSB, in which
d+
dÀ
d+
a key intermediate for the synthesis of the antibacteri- the planar arranged HdÀ Ru
N
Hax quadrupole
À
À
À
al agent levofloxacin.[2c,7a] The 3-aryl-substituted ben- of the catalyst fits well with the Cd+=NdÀ dipole of the
zoxazine and benzothiazine compounds, 7b and 7c, substrate (metal-ligand cooperative TS).[10,16] TSB suf-
were hydrogenated with the (RN,RP)-4b/t-C4H9OK cat- fers significant non-bonded repulsion between the
alyst to yield (R)-8b and (R)-8c in 98% ee and >99% fused arene ring of the substrate and the 3,5-xylyl
ee, respectively (entries 14 and 15). The senses of moieties of the catalyst. Therefore, (S)-2a is exclusive-
enantioselectivity were consistent with that of the re- ly produced through the TSA. The rigid chiral envi-
Figure 1. Structure of (RN,RP)-RuH species derived from 4a and diastereomeric transition states in the second step of hydro-
genation of 1a. Some aromatic groups and substituents are omitted for clarity. An=4-anisyl, Ar=3,5-xylyl, i-Pr=isopropyl.
4
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Asymmetric Hydrogenation of Quinoxalines, Benzoxazines, and a Benzothiazine
clave at a pressure of 8 atm before being reduced to 1 atm.
This procedure was repeated ten times. The autoclave was
then pressurized with H2 gas (20 atm), and the solution was
stirred vigorously at 408C for 13 h. After careful release of
the hydrogen, the solution was concentrated under reduced
pressure. The crude material was filtered through a short
pad of silica gel by eluting with hexane:ethyl acetate (1:1),
to give (S)-1,2,3,4-tetrahydo-2-methylquinoxaline [(S)-2a] as
a yellowish-white solid; yield: 126.1 mg (0.851 mmol, 99.9%,
99.8% ee); [a]D25: À33.8 (c 1.06, EtOH), lit.,[5k] [a]2D4: À20.1 (c
0.87, EtOH, for S enantiomer with 76% ee). IR (KBr): n=
1
3352, 3315, 2959, 2875, 1603, 1519, 1308, 741 cmÀ1; H NMR
(400 MHz, CDCl3): d=1.19 (d, J=6.3 Hz, 3H), 3.04 (dd, J=
10.8, 8.1 Hz, 1H), 3.32 (dd, J=10.8, 2.7 Hz, 1H), 3.50–3.56
(m, 1H), 3.60 (br s, 2H), 6.49–6.53 (m, 2H), 6.56–6.60 (m,
2H); 13C NMR (100 MHz, CDCl3): d=19.9 (CH3), 45.6
(CH), 48.2 (CH2), 114.35 (CH), 114.40 (CH), 118.6 (CHꢁ2),
133.1 (C), 133.5 (C). The enantiomeric excess of 2a was de-
termined by HPLC analysis [column, CHIRALCEL OD-H
Figure 2. Molecular models of diastereomeric transition
states in the second step of hydrogenation of 1f with
(RN,RP)-4b. Some aromatic groups and substituents are omit-
ted for clarity.
(4.6ꢁ250 mm);
eluent,
hexane:i-PrOH=80:20;
flow,
0.5 mLminÀ1; detector: UV 254 nm; column temp, 408C]: tR
of (R)-2a, 16.1 min (0.1%); tR of (S)-2a, 18.4 min (99.9%),
lit.,[5d] tR of (R)-2a, 16.5 min; tR of (S)-2a, 19.0 min.
ronment of the ruthenabicyclic catalyst appears to be
effective for achieving high enantioselectivity.
On the other hand, the hydrogenation of 3f derived
from 1f with the (RN,RP)-4b/t-C4H9OK catalyst pref-
erably proceeds through the TSD over the TSC to se-
lectively produce (R)-2f (Figure 2), as the steric repul-
sion between the 2-phenyl group of the substrate and
the P-phenyl(ax) moiety of the catalyst in TSC is much
greater than that between the fused arene ring of the
substrate and the P-phenyl(eq) moiety of the catalyst in
TSD.
Acknowledgements
This work was supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (No. 24350042)
and the MEXT (Japan) program “Strategic Molecular and
Materials Chemistry through Innovative Coupling Reactions”
of Hokkaido University.
In summary, RuCl[(R)-daipena][(R)-dm-segphos]
[(RN,RP)-4a] with t-C4H9OK exhibits high catalytic ac-
tivity and enantioselectivity for hydrogenation of 2-al-
kylquinoxalines 1 and a 3-methyl-2H-1,4-benzoxazine
7a in toluene, affording the heterocyclic amines (S)-2
and (S)-8a in >97% ee. A turnover number of as high
as 9400 is achieved for the catalyst. The less hindered
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RuCl[(R)-daipena][(R)-segphos]
[(RN,RP)-4b]/t-
C4H9OK system efficiently catalyzes the hydrogena-
tion of the benzoimine heterocycles, 1f, 7b, and 7c, to
yield the R products in high ee. The mode of enantio-
selection is interpreted by using transition state
models involving six-membered pericyclic structures.
Experimental Section
Typical Procedure for the Asymmetric
Hydrogenation of 1a with (RN,RP)-4a
The ruthenium complex (RN,RP)-4a (1.0 mg, 0.85 mmol) and
t-BuOK (4.4 mg, 0.039 mmol) were placed in a 100-mL glass
autoclave filled with argon. The reaction vessel was evacuat-
ed and refilled with argon. A solution of freshly distilled 2-
methylquinoxaline (1a) (122.8 mg, 0.852 mmol) in toluene
(0.85 mL) that had been degassed by three freeze-thaw
cycles was transferred to the autoclave through a Teflon
cannula. Hydrogen was initially introduced into the auto-
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À
À À
[15] The Cl Ru N Hax torsion angle of 4a was determined
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Asymmetric Hydrogenation of Quinoxalines, Benzoxazines,
and a Benzothiazine Catalyzed by Chiral Ruthenabicyclic
Complexes
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Adv. Synth. Catal. 2013, 355, 1 – 7
Noriyoshi Arai, Yu Saruwatari, Kotaro Isobe,
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