Catalytic asymmetric hydrogenation of 3-substituted benzisoxazoles

Article abstract of DOI:10.3390/molecules17066901

A variety of 3-substituted benzisoxazoles were reduced with hydrogen using the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl. The ruthenium-catalyzed hydrogenation proceeded in high yield in the presence of an acylating agent, affording α-substituted o-hydroxybenzylamines with up to 57% ee. In the catalytic transformation, the N-O bond of the benzisoxazole substrate is reductively cleaved by the ruthenium complex under the hydrogenation conditions. The C-N double bond of the resulting imine is saturated stereoselectively through the PhTRAP-ruthenium catalysis. The hydrogenation produces chiral primary amines, which may work as catalytic poisons, however, the amino group of the hydrogenation product is rapidly acylated when the reaction is conducted in the presence of an appropriate acylating agent, such as Boc₂O or Cbz-OSu.

Full text of DOI:10.3390/molecules17066901

Molecules 2012, 17, 6901-6915; doi:10.3390/molecules17066901
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Catalytic Asymmetric Hydrogenation of 3-Substituted
Benzisoxazoles
Ryuhei Ikeda and Ryoichi Kuwano *
Department of Chemistry, Graduate School of Sciences, and International Research Center for
Molecular Systems (IRCMS), Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581,
Japan
* Author to whom correspondence should be addressed; E-Mail: rkuwano@chem.kyushu-univ.jp;
Tel./Fax: +81-92-642-2572.
Received: 17 April 2012; in revised form: 2 June 2012 / Accepted: 4 June 2012 /
Published: 6 June 2012
Abstract: A variety of 3-substituted benzisoxazoles were reduced with hydrogen
using the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl. The
ruthenium-catalyzed hydrogenation proceeded in high yield in the presence of an acylating
agent, affording -substituted o-hydroxybenzylamines with up to 57% ee. In the catalytic
transformation, the N–O bond of the benzisoxazole substrate is reductively cleaved by the
ruthenium complex under the hydrogenation conditions. The C–N double bond of the
resulting imine is saturated stereoselectively through the PhTRAP–ruthenium catalysis.
The hydrogenation produces chiral primary amines, which may work as catalytic poisons,
however, the amino group of the hydrogenation product is rapidly acylated when the
reaction is conducted in the presence of an appropriate acylating agent, such as Boc2O
or Cbz-OSu.
Keywords: ruthenium; catalytic asymmetric synthesis; hydrogenation; benzisoxazole; amine
1. Introduction
Catalytic asymmetric hydrogenation of heteroaromatics is an important issue in synthetic organic
chemistry [1–4]. The reaction offers a straightforward access to optically active heterocycles, which
are seen in various medicines as well as natural products. Thus, during the last decade the
enantioselective reduction of heteroarenes has been studied intensively. High enantioselectivities have

Molecules 2012, 17
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been achieved for the hydrogenation of quinolines [5–9], quinoxalines [10–14], pyridines [15–17],
furans, and benzofurans [18,19]. Meanwhile, we have also directed our attention to the asymmetric
hydrogenation of arenes, particularly nitrogen-containing 5-membered heteroaromatics [3]. In a series
of our studies, a trans-chelating chiral bisphosphine, PhTRAP (Figure 1) [20,21], was mainly used as the
chiral ligand. PhTRAP–rhodium or ruthenium complex allowed indoles [22–27] and pyrroles [28,29]
to be reduced with hydrogen to the corresponding chiral indolines and pyrrolidines with high
enantiomeric excesses, respectively. Moreover, the chiral ruthenium catalyst recently proved to be
useful for the asymmetric hydrogenation of imidazoles and oxazoles, which contain two heteroatoms
in their aromatic rings [30,31].
Figure 1. Structure of (R,R)-(S,S)-PhTRAP.
We conceived that PhTRAP–ruthenium complex might also catalyze the hydrogenation of
5-membered heteroarenes containing an N–O bond, such as isoxazoles and benzisoxazoles. If
the hydrogenation of 3-substituted benzisoxazoles were to proceed with high enantioselectivity, it
would provide optically active benzisoxazolines bearing a stereogenic center at the 3-position.
The benzisoxazoline products can be transformed into optically active -substituted o-hydroxy-
benzylamines, because N–O bonds are known to break through heterogeneous catalysis under
hydrogenation conditions [32,33]. Enantiomeric benzylamines are often used as chiral auxiliaries [34,35]
and constituents of catalysts for asymmetric synthesis [36–38]. Furthermore, the structural motives are
seen in many isoquinoline alkaloids [39–42]. Chiral amines are typically prepared through enzymatic [43]
or chemical resolution of their racemates [44]. The diastereoselective nucleophilic additions to
imines have been applied to the asymmetric synthesis of the chiral amines [45,46]. However, to our
knowledge there have been only a few reports on the enantioselective synthesis of -substituted
o-hydroxybenzylamines [47,48]. In this paper, we report a catalytic asymmetric hydrogenation of
3-substituted benzisoxazoles to yield chiral -substituted o-hydroxybenzylamines. The asymmetric
reaction proceeded through the PhTRAP–ruthenium catalysis, which transformed the benzo-fused
heteroaromatics into -substituted o-hydroxybenzylamines in high yields and up to 57% ee.
2. Results and Discussion
2.1. Optimization of Reaction Conditions
In our initial attempts, 3-ethylbenzisoxazole (1a) was treated with pressurized hydrogen gas
(50 atm) in toluene or isobutyl alcohol at 80 °C for 4 h in the presence of {RuCl(p-cymene)[(R,R)-
(S,S)-PhTRAP]}Cl (2) (Table 1, entries 1 and 2) [25]. A small amount of 1a reacted with hydrogen,

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but no saturation of the C–N double bond was observed in either reaction, which afforded only the
achiral imine 3a, formed through the hydrogenolytic cleavage of the N–O bond of 1a [49,50]. The
ruthenium catalyst failed to reduce the C–N double bond even in the presence of N,N,N',N'-
tetramethylguanidine (TMG) (entries 3 and 4), even though in our previous reports the base additive
brought about a remarkable acceleration of hydrogenations of heteroaromatics [22–25,28,30,31]. We
were pleased that the hydrogenation of the benzisoxazole was accompanied by the reduction of the
C–N double bond in the presence of stoichiometric Boc2O, which afforded N-Boc-protected (R)-1-(2-
hydroxyphenyl)-1-propylamine 4a with 25% ee (entry 5). To our surprise, no formation of 4a was
observed in the reaction using both Boc2O and TMG (entry 6). The base additive might inhibit the
hydrogenation of imine 3a. Various aprotic solvents were evaluated for the asymmetric hydrogenation
(entries 7–10). As a result, 4a was obtained with the highest ee value when the hydrogenation was
conducted in an ethereal solvent, such as THF or cyclopentyl methyl ether (CPME). The benzisoxazole
was fully converted to the N-protected amine 4a with 44% ee after 24 h (entry 11). The hydrogenation
of 1a was conducted by using other amino group protecting agents in place of Boc2O. Carboxylic
anhydrides, Ac2O and Bz2O, also worked as the acylating agent in the asymmetric reduction of the
benzisoxazole to give the corresponding chiral amine with 43% and 47% ee, respectively (entries 12
and 13). Use of sulfonic anhydride resulted in a complex mixture, which contained a small amount of
3a (entry 14). Various N-acylating agents other than acid anhydrides were applied to the asymmetric
reactions. No conversion of 1a took place when the reaction was conducted with Boc-ON (entry 15).
Use of O-alkoxycarbonyl-N-hydroxysuccinimide led to a remarkable increase in the reaction rate
and some improvement of the stereoselectivity (entries 16–18). The reactions with Cbz-OSu and
Fmoc-OSu in THF gave the desired products 8a and 9a with 52% and 56% ee, respectively. The
hydrogenation product 4a was formed under 10 atm of hydrogen, but the lower hydrogen pressure
caused a significant decrease in the reaction rate (entry 19). Substrate 1a and imine 3a completely
disappeared from the reaction mixture at 24 h.
Table 1. Optimization of reaction conditions for the hydrogenation of 1a a.
Entry Solvent
Acylating agent
Yield (3a), % b Yield, % b,c
ee, % d
1
2
toluene
i-BuOH
toluene
i-BuOH
toluene
toluene
–
–
–
–
23
12
9
13
39
22
0 (4a)
0 (4a)
0 (4a)
0 (4a)
22 (4a)
0 (4a)
–
–
–
–
3 e
4 e
5
Boc2O
Boc2O
25 (R)
–
6 e

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Table 1. Cont.
Yield (3a), % b Yield, % b,c
Entry Solvent
Acylating agent
ee, % d
30 (R)
40 (R)
39 (R)
21 (R)
44 (R)
43 (R)
47 (R)
–
7
8
9
ClCH2CH2Cl Boc2O
CPME
THF
63
19 (4a)
18 (4a)
31 (4a)
Boc2O
Boc2O
Boc2O
Boc2O
Ac2O
Bz2O
Ts2O
Boc-ON
Cbz-OSu
Cbz-OSu
Fmoc-OSu
Cbz-OSu
32
18
22
0
10
11 f
12
13
14
15
16
17
18
EtOAc
THF
THF
THF
THF
THF
CPME
THF
14 (4a)
>99 (93) g (4a)
87 (5a)
0
0
85 (6a)
17
0
0 (7a)
0 (4a)
–
15
0
0
58 (8a)
43 (R)
52 (R)
56 (R)
52 (R)
>99 (89) g (8a)
>99 (93) g (9a)
82 (8a)
THF
19 f,h THF
0
a Reactions were conducted on a 0.20 mmol scale in 1.0 mL of solvent. The ratio of 1a:2:acylating
b
1
c
agent was 40:1.0:44; Determined by H-NMR analysis of the crude products; Yields of 4a–9a.
d
The products are indicated in parentheses;
configuration of major enantiomer is indicated in parentheses; The reactions were conducted in
Determined by HPLC analysis. The absolute
e
f
g
the presence of TMG (25 mol %). The reactions were conducted for 24 h; Isolated yields of
h
N-protected chiral amines were indicated in parentheses; The reactions were conducted under
10 atm of hydrogenation.
Various chiral ligands other than PhTRAP were evaluated for the hydrogenation of 1a (Table 2).
Before the evaluation of ligands, we attempted the catalytic asymmetric reactions by means of a
few in-situ-generated PhTRAP–ruthenium catalysts. In our previous study on the asymmetric
hydrogenation of oxazoles, the chiral catalyst was generated in situ from Ru(3-methallyl)2(cod) and
the chiral bisphosphine [30]. However, the chiral ruthenium complex failed to catalyze the conversion
of 1a to imine 3a (entry 1). No reduction of the C–N double bond was observed in the reaction mixture.
The hydrogenation of 1a was conducted in the presence of the crude ruthenium complex, which was
prepared by mixing [RuCl2(p-cymene)]2 and (R,R)-(S,S)-PhTRAP in CH2Cl2–EtOH (1:2) at 50 °C for
1 h and then removing the solvent in vacuo. The resulting residue worked as the chiral catalyst as
with the isolated complex 2, akthough its catalyst efficiency was lower than that of 2 (entry 2). By
using the procedure for preparing the chiral catalyst from [RuCl2(p-cymene)]2, the hydrogenation of
1a was conducted with a series of chiral bisphosphines (entries 3–8). As a result of the ligand
evaluation, PhTRAP was found to be the most effective ligand for the asymmetric hydrogenation of
benzisoxazoles. The ruthenium catalysts prepared from BPPFA [51,52], Josiphos [53], and Chiraphos [54]
could cleave the N–O bond in 1a to give imine 3a under the hydrogenation conditions, while they
are ineffective for the conversion of 3a into 8a. Furthermore, the enantiomeric excesses of the
chiral products were lower than 20% ee. In contrast, [RuCl2(p-cymene)]2–BINAP [55,56] might be
competent to reduce the C–N double bond of 3a, but the catalyst failed to cleave the N–O bond of 1a
with sufficient reaction rate. Furthermore, no conversion of 1a was observed in the reactions using
DIOP [57] and Me-DuPhos ligands [58].

Molecules 2012, 17
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Table 2. Effect of chiral catalysts on the hydrogenation of 1a a.
Entry Chiral ligand
[Ru]
Yield (3a), % b Yield (8a), % b ee, % c
1 d
2
(R,R)-(S,S)-PhTRAP Ru(3-methallyl)2(cod)
(R,R)-(S,S)-PhTRAP [RuCl2(p-cymene)]2
0
25
28
67
0
0
47
6
15
8
–
53 (R)
–
3 (R)
17 (R)
16 (S)
–
3
4
5
(R)-(S)-BPPFA
(R)-(S)-Josiphos
(R)-BINAP
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
6
7
(2S,3S)-Chiraphos
(2S,3S)-DIOP
49
0
10
0
8
(R,R)-Me-DuPhos
0
0
–
a
Reactions were conducted on a 0.20 mmol scale in 1.0 mL of THF. The ratio of 1a:chiral
b
1
ligand:[RuCl2(p-cymene)]2:Cbz-OSu was 40:1.0:0.5:44; Determined by H-NMR analysis of the
crude products; c Determined by HPLC analysis. The absolute configuration of major enantiomer is
indicated in parentheses; d The reaction was conducted with 2.5 mol % of the catalyst precursor.
2.2. Asymmetric Hydrogenations of 3-Substituted Benzisoxazoles
As shown in Table 3, the PhTRAP–ruthenium catalyst 2 converted various 3-substituted
benzisoxazoles 1 to the corresponding N-Cbz-protected o-hydroxybenzylamines 8 under the optimized
conditions. Reaction rates of the catalytic transformations were affected by the bulkiness of the
substituent at the 3-position in 1. As with 1a, 3-methylbenzisoxazole 1b was converted to 8b with
moderate enantiomeric excess (entry 1). Chiral benzylamines 8c and 8d were obtained in high yields
from the benzisoxazoles bearing 2-phenethyl and isopropyl groups at their 3-position, but complete
conversions of 1c and 1d needed long reaction times as compared to 1a or 1b (entries 2 and 3).
Furthermore, the reactions of 1c and 1d were less enantioselective. The asymmetric hydrogenation of
aryl-substituted substrate 1e produced the desired chiral diarylamine 8e with 55% ee, but a small
amount of achiral diarylmethane was formed through the undesired hydrogenolysis of the benzylic
C–N bond (entry 4). The stereoselectivity of the asymmetric reaction may correlate with the electronic
property of the substituent at the 5-position of benzisoxazole. Electron-donating groups in 1f or 1g
slightly improved the enantioselectivity (entries 5 and 6). In contrast, the fluorine atom in 1h caused a
decrease in the ee value of the hydrogenation product (entry 7). The substituent at the 6-position
unsystematically affects the stereoselectivity. The reaction of 3,6-dimethylbenzisoxazole (1j)
proceeded with a comparable stereoselectivity to 1b (entry 9). However, the selectivity deteriorated in
the reaction of the substrate bearing either electron-donating or electron-withdrawing groups at the

Molecules 2012, 17
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6-position (entries 8 and 10). Steric hindrance of the methoxy group in 1l scarcely affected the yield of
the hydrogenation product, but it did cause significant decrease in enantioselectivity (entry 11).
Table 3. Catalytic asymmetric hydrogenation of 3-substituted benzisoxazoles 1 a.
Entry
1
R1
Me
CH2CH2Ph
i-Pr
Ph
Me
Me
Me
Me
R2
H
H
H
6-MeO
5-MeO
5-Me
5-F
6-MeO
6-Me
6-F
Substrate (1)
Product (8) Yield, % b ee, % c
1b
1c
1d
1e
1f
1g
1h
1i
8b
8c
8d
8e
8f
8g
8h
8i
78
87
99
74 e
82
87
76
69
87
82
76
48
35
40
55
54
57
38
40
51
23
25
2 d
3 d
4 d
5
6
7 d
8
9
Me
Me
Me
1j
1k
1l
8j
8k
8l
10 d
11 d
4-MeO
a
Reactions were conducted on a 0.20 mmol scale in 1.0 mL of THF. The ratio of 1a:2:Cbz-OSu
b
c
d
was 40:1.0:44; Isolated yield; Determined by HPLC analysis; The reaction was conducted for
24 h. e 2-Benzyl-5-methoxyphenol was obtained in 8% yield.
2.3. Reaction Pathway of the Asymmetric Hydrogenation of Benzisoxazoles
As described above, the hydrogenation of benzisoxazoles 1 proceeds through the reductive N–O
bond cleavage to form o-hydroxyphenyl imine 3, yielding -substituted N-Cbz-benzylamine 8 in the
presence of Cbz-OSu. The acylating agent is indispensable for the reduction of the imine to amine.
Furthermore, the absence of the ruthenium complex prevents the conversion of 1 to 3 as well as the
formation of 8. In light of these observations, two reaction pathways are conceivable for the catalytic
asymmetric hydrogenation of benzisoxazoles, as shown in Scheme 1. In both pathways, the ruthenium
catalyst 2 initially cleaves the N–O bond in 1, giving imine 3 [49,50]. One involves the acylation of the
imine NH with Cbz-OSu to form intermediate 10 [59,60], which is reduced to 8 by hydrogen through
the ruthenium catalysis (path a). In the other possible pathway, the hydrogenation of C–N double bond
in 3 occurs prior to the Cbz-protection of the nitrogen atom (path b) [61]. To ascertain these two
possibilities, the following reactions were conducted by using the imine 3a as the substrate. First, the
imine 3a was treated with Cbz-OSu at 80 °C for 4 h in the absence of catalyst 2 (Eq. 1). No formation
of N-Cbz-imine 10a was observed in the resulting mixture, and the substrate 3a remained intact, hence
path a can be ruled out. Next, the hydrogenation of 3a was conducted with the ruthenium catalyst in
the absence of Cbz-OSu, but the reaction produced only a small amount of the expected primary amine
11 (Eq. 2). The reduction of the imine 3a, however, proceeded in the presence of Cbz-OSu, affording
8a in high yield (Eq. 3). Consequently, the present hydrogenation of the benzisoxazoles should occur

Molecules 2012, 17
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through path b. Although the resulting primary amine 11 may strongly inhibit the catalysis of the
PhTRAP–ruthenium complex, the generated amino group is rapidly protected by the coexistent
Cbz-OSu under the hydrogenation conditions [62,63]. Thus, the rapid acylation effectively avoids the
inhibition of the ruthenium catalyst by the free amino group of 11 [64,65].
Scheme 1. Possible pathways for the asymmetric hydrogenation of benzisoxazoles.
Eq. (1)
Eq. (2)
Eq. (3)
3. Experimental
3.1. Materials
Optical rotations and NMR spectra were measured with JASCO P-1020 polarimeter and Bruker
1
AVANCE 400 (9.4 T magnet) spectrometer, respectively. In the H-NMR spectra, chemical shifts
(ppm) were referenced to internal tetramethylsilane (0.00 ppm in CDCl3). In 13C-NMR spectra,
chemical shifts (ppm) were referenced to the carbon signal of the deuterated solvents used (77.0 ppm
in CDCl3, 30.0 ppm in acetone-d6). Elemental analyses were performed by Service Centre of
Elementary Analysis of Organic Compounds. Flash column chromatographies were performed with
silica gel 60 (230–400 mesh, Merck). Benzisoxazole substrates were synthesized from the
corresponding o-hydroxyphenones through the oxime formation, followed by the O-acetylation
of the oxime and the intramolecular nucleophilic substitution on the nitrogen atom [66,67].

Molecules 2012, 17
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{RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl was prepared according to the literature procedure [25].
Tetrahydrofuran (THF) was deoxygenated by purging with nitrogen for 30 min and was dried with an
alumina and copper column system (GlassContour Co.). Other materials were purchased and used
without further purification.
3.2. Catalytic Asymmetric Hydrogenation of Benzisoxazoles 1
General Procedure
Under a nitrogen atmosphere, a benzisoxazole 1 (0.20 mmol) was added to a solution of {RuCl
(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl (5.5 mg, 5.0 mol), Cbz-OSu (54 mg, 0.22 mmol) in THF (1.0 mL).
The reaction mixture was stirred at 80 °C under 50 atm of hydrogen for 4 or 24 h. The resulting
reaction mixture was evaporated under reduced pressure. The residue was purified with a flash column
chromatography (EtOAc/hexane) to give the -substituted N-Cbz-o-hydroxybenzylamine 8.
Benzyl (R)-1-(2-hydroxyphenyl)-1-propylcarbamate (8a). Colorless oil, 89% yield, 52% ee; []D26 = +14.1
(c 0.51, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  0.97 (t, J = 7.3 Hz, 3H), 1.93 (quintet, J = 7.4 Hz,
2H), 4.77 (q, J = 7.8 Hz, 1H), 5.04 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.1 Hz, 1H), 5.14–6.24 (br, 1H),
6.90 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H),
7.29–7.38 (m, 5H), 7.68–7.88 (br, 1H); 13C {1H}-NMR (100 MHz, CDCl3, at 50 °C)  11.1, 27.5, 52.9
(br), 67.3, 117.3, 120.4, 127.2 (br), 128.1, 128.2, 128.5, 128.6, 136.2, 154.6, 157.5; Anal. Calcd for
C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.43; H, 6.64; N, 4.87.
26
Benzyl 1-(2-hydroxyphenyl)-1-ethylcarbamate (8b). Colorless oil, 78% yield, 48% ee; []D = +16.9
1
(c 0.72, CHCl3); H-NMR (400 MHz, CDCl3, TMS)  1.57 (d, J = 6.9 Hz, 3H), 5.04 (d, J = 12.1 Hz,
1H), 5.09 (quintet, J = 7.5 Hz, 1H), 5.15 (d, J = 12.1 Hz, 1H), 5.14–5.24 (br, 1H), 6.89 (t, J = 7.5 Hz,
1H), 6.93 (d, J = 8.3 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.28–7.38 (m, 5H),
13
7.90–8.10 (br, 1H); C {1H}-NMR (100 MHz, CDCl3)  20.3, 45.9 (br), 67.4, 117.7, 120.6, 126.3,
128.16, 128.25, 128.5, 128.9, 129.2, 136.1, 154.5, 157.3; Anal. Calcd for C16H17NO3: C, 70.83; H,
6.32; N, 5.16. Found: C, 70.46; H, 6.36; N, 5.18.
Benzyl 1-(2-hydroxyphenyl)-3-phenyl-1-propylcarbamate (8c). Colorless solid, 87% yield, 35% ee;
27
1
[]D = +8.5 (c 1.31, CHCl3); H-NMR (400 MHz, CDCl3, TMS)  2.22 (q, J = 7.7 Hz, 2H),
2.59–2.74 (m, 2H), 4.88 (q, J = 7.6 Hz, 1H), 5.05 (d, J = 12.1 Hz, 1H), 5.15 (d, J = 12.1 Hz, 1H),
5.20–5.36 (br, 1H), 6.87–6.94 (m, 2H), 7.11–7.22 (m, 5H), 7.24–7.38 (m, 7H), 7.61–7.78 (br, 1H);
13C {1H}-NMR (100 MHz, CDCl3, at 50 °C)  32.9, 36.1, 50.9 (br), 67.4, 117.5, 120.6, 126.0, 127.2
(br), 128.0, 128.1, 128.2, 128.36, 128.44, 128.5, 128.9, 136.2, 141.2, 154.6, 157.4; Anal. Calcd for
C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found: C, 76.27; H, 6.45; N, 3.90.
Benzyl 1-(2-hydroxyphenyl)-2-methyl-1-ethylcarbamate (8d). Colorless solid, 99% yield, 40% ee;
[]D27 = +12.9 (c 1.01, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  0.80 (d, J = 6.6 Hz, 3H), 1.10 (d,
J = 6.5 Hz, 3H), 2.21 (double septet, J = 9.8, 6.6 Hz, 1H), 4.48 (t, J = 9.7 Hz, 1H), 5.04 (d, J = 12.2 Hz,
1H), 5.13 (d, J = 12.2 Hz, 1H), 5.32–5.48 (br, 1H), 6.84–6.91 (m, 2H), 7.02–7.17 (m, 3H), 7.27–7.38
(m, 5H); 13C {1H}-NMR (100 MHz, CDCl3, at 50 °C)  19.6, 20.2, 31.9, 58.6 (br), 67.2, 116.9, 120.3,

Molecules 2012, 17
6909
127.8, 128.0, 128.1, 128.4, 128.5, 136.4, 154.3, 157.4; Anal. Calcd for C18H21NO3: C, 72.22; H, 7.03;
N, 4.68. Found: C, 71.95; H, 7.06; N, 4.71.
Benzyl (2-hydroxy-4-methoxyphenyl)phenylmethylcarbamate (8e). Colorless solid, 74% yield, 55% ee;
25
1
[]D = +30.5 (c 0.53, CHCl3); H-NMR (400 MHz, CDCl3, TMS)  3.76 (s, 3H), 5.11 (d,
J = 12.1 Hz, 1H), 5.18 (d, J = 12.1 Hz, 1H), 5.75 (br d, J = 7.6 Hz, 1H), 6.16 (d, J = 8.7 Hz, 1H), 6.40
(dd, J = 2.4, 8.5 Hz, 1H), 6.46 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.75–7.15 (br, 1H), 7.25–7.37 (m,
13
10H); C {1H}-NMR (100 MHz, acetone-d6, at 50 °C)  55.3, 55.8, 67.1, 103.2, 106.2, 122.5, 127.6,
128.0, 128.78, 128.81, 129.1, 129.4, 130.5, 138.7, 144.3, 156.6, 157.0, 161.4; Anal. Calcd for
C22H21NO4: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.63; H, 5.83; N, 3.79.
Benzyl 1-(2-hydroxy-5-methoxyphenyl)-1-ethylcarbamate (8f). Colorless oil, 82% yield, 54% ee;
[]D27 = +28.2 (c 0.99, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  1.54 (d, J = 6.9 Hz, 3H), 3.75 (s,
3H), 5.02 (d, J = 12.1 Hz, 1H), 5.05 (quintet, J = 7.5 Hz, 1H), 5.14 (d, J = 12.1 Hz, 1H), 5.18 (br d,
J = 7.8 Hz, 1H), 6.72–6.76 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 7.29–7.38 (m, 5H), 7.52–7.70 (br, 1H);
13C {1H}-NMR (100 MHz, CDCl3, at 50 °C)  20.2, 45.9, 55.8, 67.4, 112.4, 113.8, 118.4, 128.16,
128.24, 128.5, 130.3, 136.1, 148.3, 153.8, 157.2; Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N,
4.65. Found: C, 67.58; H, 6.21; N, 4.64.
Benzyl 1-(2-hydroxy-5-methylphenyl)-1-ethylcarbamate (8g). Colorless oil, 87% yield, 57% ee;
[]D26 = +27.4 (c 0.93, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  1.55 (d, J = 7.0 Hz, 3H), 2.26 (s,
3H), 5.03 (d, J = 12.1 Hz, 1H), 5.04 (quintet, J = 7.4 Hz, 1H), 5.14 (d, J = 12.1 Hz, 1H), 5.17–5.27 (br,
1H), 6.81 (d, J = 7.9 Hz, 1H), 6.95–7.00 (m, 2H), 7.25–7.38 (m, 5H), 7.48–7.80 (br, 1H); 13C {1H}-NMR
(100 MHz, CDCl3, at 50 °C)  20.3, 20.6, 45.9 (br), 67.4, 117.5, 126.8, 128.17, 128.23, 128.5, 129.0,
129.3, 129.8, 136.2, 152.1, 157.2; Anal. Calcd for C17H19NO3: C, 71.56; H, 6.72; N, 4.91. Found: C,
71.23; H, 6.74; N, 4.86.
Benzyl 1-(5-fluoro-2-hydroxyphenyl)-1-ethylcarbamate (8h). Colorless oil, 76% yield, 38% ee;
[]D26 = +6.2 (c 1.12, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  1.55 (d, J = 6.9 Hz, 3H), 5.04 (d,
J = 12.1 Hz, 1H), 5.05 (quintet, J = 7.4 Hz, 1H), 5.09–5.17 (br 1H), 5.16 (d, J = 12.1 Hz, 1H),
6.86–6.91 (m, 3H), 7.28–7.29 (m, 5H), 7.95–8.20 (m, 1H); 13C {1H}-NMR (100 MHz, CDCl3, at 50 °C)
 20.1, 45.3 (br), 67.6, 112.4 (d, J = 24 Hz), 115.2 (d, J = 23 Hz), 118.8 (d, J = 7 Hz), 128.2, 128.4,
128.6, 130.6 (d, J = 6 Hz), 135.9, 150.5 (d, J = 2 Hz), 157.1 (d, J = 238 Hz), 157.4; Anal. Calcd for
C16H16FNO3: C, 66.43; H, 5.57; N, 4.84. Found: C, 66.20; H, 5.56; N, 4.86.
Benzyl 1-(2-hydroxy-4-methoxyphenyl)-1-ethylcarbamate (8i). Colorless solid, 69% yield, 40% ee;
[]D27 = +14.9 (c 0.53, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  1.55 (d, J = 6.9 Hz, 3H), 3.76 (s,
3H), 5.02 (quintet, J = 7.4 Hz, 1H), 5.03 (d, J = 12.1 Hz, 1H), 5.10–5.19 (br, 1H), 5.15 (d, J = 12.1 Hz,
1H), 6.46 (dd, J = 2.4, 8.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.29–7.38 (m,
13
5H), 8.30–8.50 (br, 1H); C {1H}-NMR (100 MHz, CDCl3, at 50 °C)  20.3, 45.3 (br), 55.2, 67.4,
103.2, 106.5, 121.7, 126.8, 128.1, 128.2, 128.5, 136.1, 155.8, 157.4, 160.4; Anal. Calcd for
C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.56; H, 6.21; N, 4.56.

Molecules 2012, 17
6910
Benzyl 1-(2-hydroxy-4-methylphenyl)-1-ethylcarbamate (8j). Colorless oil, 87% yield, 51% ee;
[]D26 = +16.4 (c 1.15, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  1.55 (d, J = 7.0 Hz, 3H), 2.28 (s,
3H), 4.99–5.08 (m, 2H), 5.14 (d, J = 12.1 Hz, 1H), 5.13–5.25 (br 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.74 (s,
1H), 7.08 (d, J = 7.8 Hz, 1H), 7.28–7.38 (m, 5H), 7.80–8.10 (br, 1H); 13C {1H}-NMR (100 MHz,
CDCl3, at 50 °C)  20.3, 20.9, 45.6 (br), 67.4, 118.3, 121.3, 126.1, 126.3, 128.16, 128.23, 128.5, 136.2,
139.0, 154.6, 157.3; Anal. Calcd for C17H19NO3: C, 71.56; H, 6.72; N, 4.91. Found: C, 71.28; H, 6.75;
N, 4.87.
Benzyl 1-(4-fluoro-2-hydroxyphenyl)-1-ethylcarbamate (8k). Colorless oil, 82% yield, 23% ee;
26
1
[]D = –9.6 (c 0.69, CHCl3); H-NMR (400 MHz, CDCl3, TMS)  1.54 (d, J = 6.8 Hz, 3H), 5.02
(quintet, J = 7.3 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 5.16 (d, J = 12.2 Hz, 1H), 5.10–5.26 (br, 1H),
13
6.54–6.64 (m, 2H), 7.12 (t, J = 7.4 Hz, 1H), 7.28–7.39 (m, 5H), 8.62–8.74 (br, 1H); C {1H}-NMR
(100 MHz, CDCl3, at 50 °C)  20.3, 45.4 (br), 67.6, 104.9 (d, J = 24 Hz), 107.1 (d, J = 22 Hz), 125.2
(d, J = 3 Hz), 127.0 (d, J = 10 Hz), 128.2, 128.4, 128.6, 135.9, 156.1 (d, J = 12 Hz), 157.5, 163.0 (d,
J = 246 Hz); Anal. Calcd for C16H16FNO3: C, 66.43; H, 5.57; N, 4.84. Found: C, 66.23; H, 5.39; N, 4.84.
Benzyl 1-(2-hydroxy-6-methoxyphenyl)-1-ethylcarbamate (8l). Colorless solid, 76% yield, 25% ee;
[]D27 = –0.68 (c 0.59, CHCl3); 1H-NMR (400 MHz, CDCl3, TMS)  1.52 (d, J = 7.0 Hz, 3H), 3.81 (s,
3H), 5.04 (d, J = 12.3 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H), 5.39 (dq, J = 9.2, 7.0 Hz, 1H), 5.86–5.98 (br,
1H), 6.47 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 8.3 Hz, 1H), 7.24–7.38 (m, 5H);
13C {1H}-NMR (100 MHz, CDCl3, at 50 °C)  20.6, 43.2, 55.7, 66.9, 103.5, 109.8, 117.8, 128.0,
128.2, 128.5, 136.7, 154.9, 156.9, 158.1; Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.65; H, 6.29; N, 4.68.
4. Conclusions
In this study, we proved that 3-substituted benzisoxazoles 1 react with hydrogen in the presence
of the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl (2). The ruthenium-
catalyzed hydrogenation proceeds in the presence of an acylating agent such as Boc2O and Cbz-OSu,
to afford -substituted N-protected o-hydroxybenzylamines 4–9 in high yields with moderate
enantioselectivities. The conversion of 1 to the chiral amines proceeds through the imine intermediate
3, which is generated from the reductive cleavage of the N–O bond in the benzisoxazole ring. The C–N
double bond of 3 is hydrogenated in moderate enantioselectivity by the PhTRAP–ruthenium catalyst,
however, the resulting primary amine 11 causes deactivation of the catalyst 2. The deterioration of 2
can be avoided by the coexistent acylating agent, which rapidly reacts with the amino group.
Although the asymmetric hydrogenation of 1 with PhTRAP–ruthenium catalyst proceeds with
moderate stereoselectivity at the current moment, various 3-substituted benzisoxazoles are transformed
into the chiral o-hydroxybenzylamines in high yields. The products contain a molecular framework,
which is often used as a chiral source in asymmetric synthesis and seen in various biologically active
compounds. Consequently, the present catalytic asymmetric reaction may be potentially useful for
organic synthesis. Further improvement of the stereoselectivity is in progress.

Molecules 2012, 17
6911
Acknowledgments
This work was supported by a Grant-in-Aid for the Global COE Program, “Science for Future
Molecular Systems” from MEXT.
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