Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst

Article abstract of DOI:10.1002/chem.201600732

The iridium catalyst [IrCl(cod)]₂–phosphine–I₂(cod=1,5-cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H₂. The iridium-catalyzed hydrogenation proceeded in high-to-good enantioselectivity when an optically active phosphine–oxazoline ligand was used. The 3-substituted 5-arylisoxazolium salts were transformed into 4-isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5-position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. Meanwhile, in the selective formation of 4-isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5-aryl substituent.

Full text of DOI:10.1002/chem.201600732

DOI: 10.1002/chem.201600732
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Synthetic Methods |Hot Paper|
Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral
Iridium Catalyst
Ryuhei Ikeda and Ryoichi Kuwano*[a]
Abstract: The iridium catalyst [IrCl(cod)]2–phosphine–I2
(cod=1,5-cyclooctadiene) selectively reduced isoxazolium
triflates to isoxazolines or isoxazolidines in the presence of
H2. The iridium-catalyzed hydrogenation proceeded in high-
to-good enantioselectivity when an optically active phos-
phine–oxazoline ligand was used. The 3-substituted 5-aryl-
isoxazolium salts were transformed into 4-isoxazolines with
up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines
were obtained in up to 89:11 e.r., with no formation of their
trans isomers, when the substrates had a primary alkyl sub-
stituent at the 5-position. The mechanistic studies indicate
that the hydridoiridium(III) species prefers to deliver its hy-
dride to the C5 atom of the isoxazole ring. The hydride
attack leads to the formation of the chiral isoxazolidine via
a 3-isoxazoline intermediate. Meanwhile, in the selective for-
mation of 4-isoxazolines, hydride attack at the C5 atom may
be obstructed by steric hindrance from the 5-aryl substitu-
ent.
Introduction
Catalytic asymmetric hydrogenation of heteroarenes offers
a versatile method to synthesize optically active five- or six-
membered heterocycles.[1] During the past decade, many
chemists, including us,[2] have devoted great effort to develop
chiral catalysts for the reduction of prochiral heteroarenes.
Nowadays, various heteroarenes, for example, pyrroles,[2d,3] pyr-
idines,[4] indoles,[2a–c,5,6] and quinolines,[7] are reduced with H2 to
yield the corresponding chiral heterocycles with high enantio-
selectivities.[8–10] However, many heteroarene substrates still
remain unexplored or strenuous targets for asymmetric hydro-
genation.
Scheme 1. Possible reactions of isoxazoles with H2.
lines or isoxazolidines is a formidable task in organic chemis-
try.[16]
The asymmetric hydrogenation of isoxazoles is a useful
method to prepare optically active isoxazolines or isoxazoli-
dines. These compounds are often used as intermediates in
the syntheses of useful compounds.[17,18] The isoxazoline or
isoxazolidine framework is found in some biologically active
molecules.[19,20] Furthermore, the isoxazolidine structural motif
is useful for designing DNA intercalators.[21]
To our knowledge, the asymmetric hydrogenation of isoxa-
zoles remains unexplored, although we previously reported
a ruthenium-catalyzed asymmetric hydrogenation of benzisox-
azoles to give chiral a-substituted o-hydroxybenzylamines.[11]
Based on the resonance energy of the aromatic p system,[12]
the dearomatization of isoxazoles is considered to be compara-
ble in difficulty to the dearomatization of pyrroles and more
difficult than the dearomatization of furans or oxazoles. More-
over, isoxazole reduction is commonly accompanied by a ring-
opening reaction[13] because the NÀO bond is amenable to
cleavage with a low-valence transition metal (Scheme 1).[14,15]
Therefore, the selective transformation of isoxazoles to isoxazo-
In this study, we found a useful chiral catalyst for the hydro-
genation of isoxazolium salts. The asymmetric reaction pro-
vides isoxazolines or isoxazolidines with high stereoselectivity
in the presence of an iridium complex that bears a chiral phos-
phine–oxazoline ligand.[5] Use of the iridium complex allows
the hydrogenation to proceed without formation of the ring-
opening side product.
[a] R. Ikeda, Prof. R. Kuwano
Department of Chemistry, Faculty of Science and
International Research Center for Molecular Systems (IRCMS)
Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395 (Japan)
E-mail: rkuwano@chem.kyushu-univ.jp
Results and Discussion
Optimization of the reaction conditions
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201600732. It
contains details of the preparation of compounds 7, assignment of the ste-
reochemistry of compound 9q, and details of the mechanistic studies.
First, the hydrogenation of 3-methyl-5-phenylisoxazole (1a)
was attempted with [RuCl(p-cymene){(R,R)-(S,S)-PhTRAP}]Cl (2,
PhTRAP=(R,R)-bis[(S)-(diphenylphosphino)ethyl]-1,1’’-biferro-
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cene),[2c] which catalyzed the transformation of benzisoxazoles
to o-hydroxybenzylamines with moderate enantiomeric ratio
(e.r.) values in our previous study.[11] As with the benzisoxa-
zoles, the isoxazole ring of 1a opened to yield achiral enami-
none 3 in 39% yield (Scheme 2a). Enaminone 3 was further re-
Table 1. Effect of additives on the hydrogenation of 7a.[a]
Entry
Additive/s (mol%)
Yield [%][b]
e.r.[c]
1[d]
2
–
–
0
0
–
–
3
4
5
I2 (8.0)
KHCO3 (110)
KHCO3 (110), I2 (8.0)
0
–
61[e]
96
56:43
41:59
[a] Reactions were conducted on 0.20 mmol scale in THF (1.0 mL) under
H2 (5.0 MPa) at 708C for 4 h. The ratio of 7a/[IrCl(cod)]2/(R)-BINAP was
100:1.0:2.2. [b] Determined by 1H NMR spectroscopic analysis. [c] Deter-
mined by chiral HPLC analysis. [d] Isoxazole 1 was used in place of 7a.
[e] Enaminone 3’ was also formed in 18% yield.
Scheme 2.
duced with H2 to give a mixture of products 3–6 when the re-
action was carried out in the presence of stoichiometric
(Boc)2O (Scheme 2b; Boc=tert-butoxycarbonyl). The formation
of further saturated products 4–6 may be enabled by in situ N-
Boc protection of the b-amino ketone intermediate. It is note-
worthy that 4 was obtained in moderate yield with 96:4 e.r.,
and that the e.r. might be enhanced by kinetic resolution in
the further reduction of 4 to 5.
Iridium-catalyzed isoxazole ring reduction proceeds without
NÀO bond cleavage. Although isoxazole 1a remained intact
when a solution of 1a in THF was heated at 708C under H2
(5.0 MPa) for 4 h in the presence of an [IrCl(cod)]2–(R)-BINAP
complex[22] (cod=1,5-cyclooctadiene, BINAP=2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl) the iridium catalyst could convert
isoxazolium triflate 7a into 4-isoxazoline 8a in good yield
(Table 1, entry 1 versus 4).[23,24] The reduction of the isoxazoli-
um salt required a stoichiometric amount of KHCO3 to neutral-
ize the triflic acid byproduct. The absence of the base resulted
in no formation of 8a (Table 1, entries 2 and 3). The ring-open-
ing reaction of 7a was observed as a side reaction (Table 1,
entry 4). This undesired NÀO bond cleavage was suppressed
by the addition of I2 (Table 1, entry 5). The I2 additive allowed
the BINAP–iridium catalyst to produce 8a quantitatively, but
the enantioselectivity was low.
R1 substituent for the asymmetric hydrogenation (L5). Bulkier
ligand L6 was comparable in enantioselectivity to L5, but its
tert-butyl group caused a decreased yield of 8a. Both the yield
and enantioselectivity decreased when either electron-donat-
ing or electron-withdrawing substituents were present on the
diarylphosphino group (Table 2, entries 7 and 8). Sterically con-
gested aryl or secondary alkyl substituents on the phosphorus
atom disturbed the stereochemical control (Table 2, entries 9
and 10). Substituents R2 and R3 scarcely impacted the stereose-
lectivity (Table 2, entries 11–13). The e.r. of 8a was only margin-
ally affected by replacing the oxazoline ring with an imidazo-
line ring (Table 2, entries 14 and 15). Use of ferrocene-tethered
ligand L16 gave almost racemic 8a (Table 2, entry 16).
The reaction conditions were further optimized with the L5–
iridium catalyst (Table 3). No change of the enantioselectivity
was observed when K2CO3 was used as the base in place of
KHCO3 (Table 3, entry 2 versus 1), but the base did affect the
efficiency of the iridium catalyst (Table 3, entries 1–6). No sig-
nificant decrease in the stereoselectivity was observed even in
the reaction using KOAc (Table 3, entry 6). Use of the strong
base KOtBu induced the undesired ring-opening reaction
(Table 3, entry 7). Meanwhile, the solvent remarkably affected
the e.r. as well as the yield of the hydrogenation product
(Table 3, entries 8–13). The solvent of choice for the hydroge-
nation of 7a was 2-methyl-2-butanol (tert-amyl alcohol; t-
AmOH); the reaction in t-AmOH gave the isoxazoline product
8a with 92:8 e.r. (Table 3, entry 13). Notably, racemic 8a was
obtained from the reaction in acetonitrile (Table 3, entry 12).
The enantioselectivity was slightly improved by conducting
the hydrogenation reaction at a lower temperature (Table 3,
entry 14). Under the optimized condition, the catalyst loading
can be reduced to 1.0 mol% without loss of the enantioselec-
tivity (Table 4, entry 1). Although we tried to evaluate the
counteranion of the substrate, we failed to prepare the isoxa-
The enantioselectivity remained low when chiral biaryl bis-
phosphine ligands were used. To improve the low stereoselec-
tivity, a variety of chiral phosphine ligands were evaluated for
the iridium-catalyzed hydrogenation of 7a. A series of phos-
phine–oxazoline ligands[5,25] exhibited higher enantioselectivity
than other types of chiral ligand (Table 2). The R1 substituent at
the C4 carbon atom of the oxazoline ring affects the catalytic
activity and stereoselectivity. The iridium complex prepared
from [IrCl(cod)]2, I2, and ethyl-substituted ligand L1 yielded 8a
with a 73:27 e.r. (Table 2, entry 1). Increasing the size of sub-
stituent R1 improved the yield as well as the e.r. of the hydro-
genation product (Table 2, entries 2–6). Isopropyl is the optimal
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Table 2. Evaluation of phosphine–oxazoline ligands L for the hydrogena-
tion of 7a.[a]
Table 3. Effect of the base and solvent on the hydrogenation reaction of
7a.[a]
Entry
Base
Solvent
Temp [8C]
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
KHCO3
THF
THF
THF
THF
THF
THF
THF
toluene
ClCH2CH2Cl
CPME[f]
EtOAc
MeCN
t-AmOH
t-AmOH
70
70
70
70
70
70
70
70
70
70
70
70
70
50
91
63
13
40
23
37
13[e]
30
17
8
71
33[e]
86[g]
94[g]
83:17
83:17
–
77:23
–
81:19
–
84:16
71:29
–
[d]
K2CO3
Li2CO3
Na2CO3
[d]
[d]
[d]
Cs2CO3
KOAc
KOtBu
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
9
10
11
12
13
14
85:15
50:50
92:8
93:7
[a] Unless otherwise noted, reactions were conducted on 0.20 mmol scale
in the specified solvent (1.0 mL) under H2 (5.0 MPa) at 708C for 4 h. The
ratio of 7a/[IrCl(cod)]2/L5/I2/base was 100:1.0:2.2:8.0:110. [b] Determined
Entry
Ligand
Yield [%][b]
e.r.[c]
1
by H NMR spectroscopic analysis. [c] Determined by chiral HPLC analysis.
[d] The ratio of 7a/base was 100:55. [e] A small amount of 3’ was detect-
ed. [f] CPME=cyclopentyl methyl ether. [g] Isolated yield.
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
33
34
51
91
83
68
52
45
43
63
53
69
87
55
79
64
73:27
76:24
84:16
83:17
85:15
86:14
83:17
69:31
43:57
52:48
81:19
79:21
83:17
80:20
73:27
48:52
Table 4. Asymmetric hydrogenation of 5-arylisoxazolium salts 7a–7p.[a]
9
L9
10
11
12
13
14
15
16
L10
L11
L12
L13
L14
L15
L16
Entry Substrate R1
Ar
R2 Product Yield e.r.[c]
[%][b]
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
7 f
7g
7h
7h
Me
Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me 8a
Me 8b
Me 8c
Me 8d
Me 8e
Me 8 f
Me 8g
Me 8h
Me 8h
Me 8i
Me 8j
Me 8k
Me 8l
Me 8m
84
97
98
97
99
94
85
34
81
84
93:7
93:7
93:7
93:7
95:5
93:7
62:38
94:6
93:7
94:6
nC7H15
iBu
CH2tBu
CH2Ph
cHex
Ph
[a] Reactions were conducted on 0.20 mmol scale in THF (1.0 mL) under
H2 (5.0 MPa) at 708C for 4 h. The ratio of 7a/[IrCl(cod)]2/ligand/I2/KHCO3
was 100:1.0:2.2:8.0:110. [b] Determined by H NMR spectroscopic analysis.
[c] Determined by chiral HPLC analysis.
1
8
9[d]
10[d] 7i
11[d] 7j
12
13
14
15
16
17
Ph
4-MeOC6H4 Ph
4-CF3C6H4 Ph
(50)[e] 88:12
zolium iodide from 1a because the isoxazole did not react
with iodomethane.
7k
7l
7m
7n
7o
7p
Me
Me
Me
Me
Me
Me
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-MeO2CC6H4 Me 8n
2-MeC6H4
Ph
67
81
93
77
56
96
81:19
91:9
86:14
83:17
51:49
95:5
Substrate scope of the asymmetric hydrogenation of 5-aryl-
isoxazolium triflates
Me 8o
Et 8p
A variety of 5-arylisoxazolium triflates 7 were converted into
chiral isoxazolines 8 in high yields. Under the conditions opti-
mized above, 3-alkylisoxazolium triflates 7b–7 f were reduced
with H2 to yield 8b–8 f with 93:7–95:5 e.r. (Table 4, entries 2–
6). Branching at the b-position of the alkyl substituent scarcely
affected the enantioselectivity (Table 4, entries 4–6). The hydro-
genation of 7g gave the product 8g in high yield, but the sec-
ondary alkyl substituent caused a significant decrease in the
stereoselectivity (Table 4, entry 7). 3,5-Diphenylisoxazolium salt
7h was converted into 8h with a high e.r., but the reaction
was slow because of the low solubility of 7h in t-AmOH
(Table 4, entry 8). However, the chiral product was successfully
obtained in high yield by conducting the reaction at 708C in
[a] Unless otherwise noted, reactions were conducted on 0.40 mmol scale
in t-AmOH (1.0 mL) under H2 (5.0 MPa) at 508C for 24 h. The ratio of 7/
[IrCl(cod)]2/L5/I2/base was 100:0.5:1.1:4.0:110. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis. [d] The reactions were conducted on
0.20 mmol scale with a 2% catalyst loading in THF at 708C for 4 h.
[e] Compound 8j was obtained as a mixture with 5-phenyl-3-[4-(trifluoro-
methyl)phenyl]isoxazole (1j); the yield in the parentheses was estimated
by 1H NMR spectroscopic analysis.
THF (Table 4, entry 9). The enantioselectivity was slightly en-
hanced by installing an electron-donating group on the 3-aryl
group (Table 4, entry 10). The trifluoromethyl group of 7j
caused elimination of methyl group from the substrate and de-
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creased the e.r. of the hydrogenation product (Table 4,
entry 11). The para substituent on the 5-aryl group in 7k–7n
affected the enantioselectivity, but there was no clear pattern
(Table 4, entries 12–15). The o-tolyl group of 7o disturbs the
enantiodiscrimination by the chiral L5–iridium catalyst (Table 4,
entry 16). Replacing the N-methyl group by an N-ethyl group
increased the enantioselectivity of the reaction (Table 4,
entry 17 versus 1).
1
Scheme 3. Yields were determined by H NMR analysis.
Asymmetric hydrogenation of 5-alkylisoxazolium triflates
(S)- and (R)-O-methylmandelate derivatives (S)- and (R)-10.[26]
Compound 9q was transformed into g-amino alcohol 11 by re-
ductive NÀO bond cleavage with zinc powder (Scheme 4).
Crude 11 was treated with (Boc)2O to give the N-Boc-protected
amino alcohol 12 in 52% yield. Furthermore, the hydroxyl
The L5–iridium catalyst was applied to the asymmetric hydro-
genation of 5-methyl-3-phenylisoxazolium triflate (7q), but the
reaction did not yield isoxazoline 8q (Table 5, entry 1). To our
surprise, the isoxazole ring in 7q was fully saturated to give
cis-isoxazolidine 9q without any formation of the trans isomer.
Table 5. Asymmetric hydrogenation of 5-alkylisoxazolinium salts 7q–
7u.[a]
Entry
Substrate R1
R2
Product Yield [%][c] e.r.[d]
1[d]
2
3[d]
4[f]
5[f]
6
7q
7q
7r
7s
7t
Ph
Ph
Ph
Ph
Me
Me
nBu
9q
9q
9r
98
96
94
96
86
98
82:18[e]
87:13[e]
89:11
88:12
84:16
70:30
Scheme 4. Assignment of the absolute configuration of 9q: The preparation
of O-methylmandelates 10 and the difference in chemical shifts between (S)-
and (R)-10 (Dd=dSÀdR).
CH2CH2Ph 9s
Me CH2CH2Ph 9t
Ph 9u
7u
H
[a] Unless otherwise noted, reactions were conducted on 0.40 mmol scale
in t-AmOH (1.0 mL) under H2 (5.0 MPa) at 508C for 24 h. The ratio of 7/
[IrCl(cod)]2/L4/I2/base was 100:0.5:1.1:4.0:110. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis. [d] L5 was used in place of L4. [e] The ab-
solute configuration of the major enantiomer of 9q is (3S,5S). [f] The reac-
tion was conducted on 0.20 mmol scale with a 2% catalyst loading.
group of 12 was esterified with (S)- or (R)-O-methylmandelyl
chloride to form 10. The differences in chemical shifts between
(S)- and (R)-10 are summarized in Scheme 4 and indicate that
the absolute configuration at the 5-position of 9q is S. The rel-
1
ative configuration of 9q was assigned as cis by H NOE analy-
sis and NOESY spectroscopy. Consequently, (3S,5S)-9q was
preferentially obtained from the hydrogenation reaction of 7q
with the L5–iridium catalyst.
The e.r. of the product was improved to 87:13 by using L4 as
the chiral ligand (Table 5, entry 2). The 5-alkylisoxazolium trif-
lates 7r and 7s were also exclusively converted into isoxazoli-
dines 9r and 9s with good enantioselectivity (Table 5, entries 3
and 4). The hydrogenation of 5-isopropyl substrate 7v was
sluggish: isoxazoline 8v was obtained in less than 10% yield
and isoxazolidine 9v was not formed. Reduction of the hetero-
arene would be hampered by the low solubility of 7v as well
as the steric hindrance from the secondary alkyl group. In THF,
the L4–iridium catalyst promoted hydrogenation of 7v, and
a mixture of 8v and 9v was obtained in high combined yield
(Scheme 3). The phenyl group at the 3-position is not crucial
for selective formation of the isoxazolidine product. The 3,5-di-
alkylisoxazolium triflate 7t also selectively gave 9t with good
enantioselectivity (Table 5, entry 5). The L4–iridium catalyst is
capable of reducing mono-substituted isoxazolinium 7u to
isoxazolidine 9u, but with a moderate e.r. (Table 5, entry 6).
The absolute configuration of the hydrogenation product
Mechanistic study
Initially, we supposed that the hydrogenation of 5-alkylisoxazo-
lium triflates 7q–7u (Table 3) proceed via 4-isoxazoline 8 to
give isoxazolidine 9 (Scheme 5a). To confirm the reaction path-
way, the hydrogenation of 8v was attempted with the L5–iridi-
um catalyst (Scheme 6a). However, 8v remained almost intact
after the reaction mixture was heated at 708C under H2
(5.0 MPa) for 6 h. This result suggested that 8v is not involved
in the production of 9v. Meanwhile, the L5–[IrCl(cod)]2–I2 cata-
lyst fully converted racemic 3-isoxazoline 13r into cis-isoxazo-
line 9r within 4 h in high yield (Scheme 6b). These observa-
tions indicate that the isoxazolidine products are formed via
the 3-isoxazoline intermediate 13 (Scheme 5b).
Some reactions were carried out with D2 to investigate the
pathway from the cyclic enamine 13 to 9. Prior to the labeling
1
9q was assigned by comparison to the H NMR spectra of the
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Scheme 5. Possible pathways of the iridium-catalyzed hydrogenation of
isoxazoles 7 to give isoxazolidine 9.
Figure 1. 1H NMR spectrum (400 MHz, CDCl3) of [D3]-9r.
product shown in Scheme 7b contains four deuterated prod-
ucts: 3,5-di, 3,4,5-tri- (two isomers), and 3,4,4,5-tetradeuterated
9r. Furthermore, 30% of the deuterium atoms were incorpo-
rated at the a-position of the butyl group. The H/D scrambling
might occur independently of the hydrogenation and proceed
through iridium-catalyzed CÀH bond activation. As with isoxa-
zole 7r, 3-isoxazoline 13r was saturated with D2 to give [D2]-
9r, in which H/D scrambling took place on the C4 atom
(Scheme 8).
Scheme 6.
experiments, the hydrogenation of 7r was attempted in THF
under H2 (1.0 MPa). From the reaction, the desired product 9r
was obtained with 76:24 e.r. in good yield. A small amount of
isoxazole 1r was detected from the crude reaction mixture
(Scheme 7a). In the deuteration of 7r under identical condi-
Scheme 8.
Based on the above experimental results, the iridium-cata-
lyzed hydrogenation of isoxazolium salts could proceed
through the pathway shown in Scheme 9. It has been pro-
posed that a hydridoiridium(III) species is involved in the cata-
lytic cycle of the hydrogenation with the [IrCl(cod)]2–bisphos-
phine–I2 catalyst.[27] The hydridoiridium(III) species A is generat-
ed by deprotonation of an iridium(III) dihydrogen[28] or dihydri-
doiridium(V) complex.[29] When the isoxazolium substrate has
Scheme 7.
tions, the substrate was fully transformed into a mixture of
[D3]-9r and 1r (Scheme 7b). The use of D2 instead of H2 scarce-
ly affected the enantioselectivity and the yield of the isoxazoli-
dine product. In [D3]-9r almost complete deuterium incorpora-
tion was observed at the 3- and 5-positions. About 50% of the
deuterium atoms were incorporated at each face of the C4
atom. The resonances of the protons on the C4 carbon atom
1
in the H NMR spectrum of [D3]-9r are shown in Figure 1. The
splitting patterns of these peaks indicate that the isoxazolidine
Scheme 9. A possible pathway for the iridium-catalyzed hydrogenation of 7.
[Ir]=(L4 or L5)Ir+X2 (X=I or Cl).
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phere. THF was purged with nitrogen for 30 min, and then dried
with an alumina and copper column system (GlassContour). [IrCl-
(cod)]2 was prepared according to a literature procedure.[30] Chiral
ligands L4 and L5, I2, and KHCO3 were purchased and used without
further purification.
a proton or primary alkyl group at its 5-position, A delivers its
hydride to the C5 atom through a 1,4-addition-like pathway.
The resulting cyclic enamine 13 is protonated at its 4-position
by cationic iridium(III) dihydrogen species C or dihydridoiri-
dium(V) species C’ to form 2-isoxazolinium 14 and A. The hy-
dride in A reduces the C=N double bond of 14 to give isoxazo-
lidine 9. The cationic iridium(III) species B is converted into A
through formation of C or C’, followed by deprotonation with
KHCO3. The H/D scrambling shown in Schemes 7b and 8
would be caused by rapid intermolecular proton transfer be-
tween intermediates 13 and 14. In the case of 5-arylisoxazoli-
um salts 7a–7p, the aryl substituent may sterically hinder the
access of iridium hydride A to the C5 atom in 7. Therefore, the
hydride on iridium selectively attacks the C3 atom to give 4-
isoxazoline 8 and create the new stereogenic center.
In summary, the chiral iridium catalyst prefers to deliver the
hydride to the C5 carbon atom of the isoxazole ring rather
than the C3 carbon atom. However, hydride attack on the C5
atom may be obstructed by steric hindrance of the 5-substitu-
ent when a 5-arylisoxazolium salt is used as the substrate. The
iridium hydride selectively reduces the N2=C3 double bond to
give 4-isoxazoline 8. In the case of 5-alkylisoxazolium salts, the
C5 carbon atom is attacked by hydridoiridium(III) species A
without steric hindrance from the alkyl group. The formation
of the 3-isoxazoline intermediate 13 leads to selective forma-
tion of the chiral isoxazolidine product 9.
Typical procedure for the asymmetric hydrogenation of 7
Under a nitrogen atmosphere, a solution of [IrCl(cod)]2 (1.3 mg,
2.0 mmol) and L5 (1.6 mg, 4.3 mmol) in dry t-AmOH or THF (1.0 mL)
was stirred at ambient temperature for 10 min. The solution of the
iridium–ligand complex was transferred via cannula to a mixture of
7
(0.40 mmol), KHCO3 (44.0 mg, 0.44 mmol), and I2 (4.0 mg,
16 mmol). The reaction mixture was stirred under H2 (5.0 MPa) at
508C or 708C. The resulting mixture was evaporated under re-
duced pressure, and then the residue was passed through a short
column of silica gel (EtOAc/hexane) to give the desired chiral
4-isoxazoline 8 or isoxazolidine 9.
Compound 8a:[31] Compound 8a (84%, 93:7 e.r.) was obtained as
1
a colorless oil. [a]2D5 = +145.4 (c=1.14 in CHCl3); H NMR (400 MHz,
CDCl3): d=1.28 (d, J=6.2 Hz, 3H), 2.83 (s, 3H), 3.86 (br, 1H), 5.24
(d, J=2.4 Hz, 1H), 7.28–7.38 (m, 3H), 7.54 ppm (d, J=7.4 Hz, 2H);
13C NMR (100 MHz, CDCl3, 508C): d=21.7, 46.4, 68.8, 97.0, 125.6,
128.3, 128.7, 129.3, 152.0 ppm.
Compound 8b: Following the typical procedure, compound 8b
(97%, 93:7 e.r.) was obtained as a colorless oil. [a]2D7 = +145.5 (c=
1
1.15 in CHCl3); H NMR (400 MHz, CDCl3): d=0.94 (t, J=7.2 Hz, 3H),
1.32–1.64 (m, 4H), 2.82 (s, 3H), 3.73 (br, 1H), 5.23 (d, J=2.7 Hz,
1H), 7.27–7.37 (m, 3H), 7.54 ppm (dd, J=1.6, 8.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 508C): d=14.0, 19.0, 38.6, 47.2, 73.5, 95.3, 125.6,
128.3, 128.7, 129.4, 152.1 ppm; IR (neat): n˜ =2956, 2930, 2872,
1651, 1494, 1448, 1270, 765, 724, 690 cmÀ1; elemental analysis
calcd (%) for C13H17NO: C 76.81, H 8.43, N 6.89; found: C 76.82, H
8.44, N 6.84.
Conclusion
We have developed a method for the enantioselective hydro-
genation of isoxazolium triflates 7 to give chiral 4-isoxazolines
8 or isoxazolidines 9. Although the reaction of an isoxazole
ring with H2 is commonly accompanied by NÀO bond cleav-
age, the undesired bond cleavage was suppressed by the use
of an iridium catalyst. With the chiral catalyst prepared from
[IrCl(cod)]2, chiral phosphine–oxazoline ligand L5, and I2 the hy-
drogenation of 5-arylisoxazolium triflates exclusively provided
the corresponding 4-isoxazolines 8 with good or high e.r.
values (up to 95:5 e.r.). Meanwhile, 5-alkylated substrates were
selectively converted into cis-3,5-disubstituted isoxazolidines 9
by using the L4–iridium or L5–iridium catalysts. Furthermore,
mechanistic studies indicated that the selectivity between 8
and 9 is strongly affected by steric hindrance from the 5-sub-
stituent on the isoxazole ring.
Compound 8c: Following the typical procedure, compound 8c
(98%, 93:7 e.r.) was obtained as a colorless oil. [a]2D5 = +120.2 (c=
1
1.30 in CHCl3); H NMR (400 MHz, CDCl3): d=0.88 (t, J=6.8 Hz, 3H),
1.20–1.64 (m, 12H), 2.81 (s, 3H), 3.71 (br, 1H), 5.23 (d, J=2.4 Hz,
1H), 7.27–7.37 (m, 3H), 7.54 ppm (d, J=7.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 508C): d=14.0, 22.6, 25.8, 29.3, 29.6, 31.8, 36.4,
47.2, 73.8, 95.3, 125.6, 128.3, 128.7, 129.4, 152.1 ppm; IR (neat): n˜ =
2954, 2926, 2854, 1652, 1494, 1449, 1266, 1022, 768, 721, 690 cmÀ1
;
elemental analysis calcd (%) for C17H25NO: C 78.72, H 9.71, N 5.40;
found: C 78.25, H 9.57, N 5.43.
Compound 8d: Following the typical procedure, compound 8d
(97%, 93:7 e.r.) was obtained as a colorless oil. [a]2D7 = +136.9 (c=
1.14 in CHCl3); 1H NMR (400 MHz, CDCl3): d=0.94 (d, J=6.4 Hz,
3H), 0.95 (d, J=6.5 Hz, 3H), 1.31–1.40 (m, 1H), 1.49–1.59 (m, 1H),
1.81 (nonet, J=6.7 Hz, 1H), 2.81 (s, 3H), 3.79 (br, 1H), 5.24 (d, J=
2.4 Hz, 1H), 7.28–7.37 (m, 3H), 7.53 ppm (d, J=7.7 Hz, 2H);
13C NMR (100 MHz, CDCl3, 508C): d=22.6, 22.9, 25.0, 45.5, 46.9,
71.8, 95.7, 125.6, 128.3, 128.7, 129.4, 152.1 ppm; IR (neat): n˜ =2955,
2925, 2870, 1651, 1494, 1448, 1271, 1014, 770, 720, 690 cmÀ1; ele-
mental analysis calcd (%) for C14H19NO: C 77.38, H 8.81, N 6.45;
found: C 77.47, H 8.80, N 6.34.
Experimental Section
NMR spectra were recorded with a Bruker AVANCE 400 or AVAN-
CE III HD 400 Nanobay (9.4 T magnet) spectrometer at ambient
1
temperature. In the H and 13C NMR spectra the chemical shift (d)
values [ppm] are referenced to internal tetramethylsilane (d=
0.00 ppm) in CDCl3 or the residual proton (d=2.05 ppm) in
[D6]acetone and the carbon atom resonance of the deuterated sol-
vent (d=77.0 ppm (CDCl3), 30.0 ppm ([D6]acetone), respectively. IR
spectra, optical rotations, and melting points were measured with
a JASCO FT/IR-4100 spectrometer, JASCO P-1020 polarimeter, and
Büchi Melting Point B-545 apparatus, respectively. t-AmOH was
dried with calcium hydride and distilled under a nitrogen atmos-
Compound 8e: Following the typical procedure, compound 8e
(99%, 95:5 e.r.) was obtained as a colorless oil. [a]2D5 = +119.3 (c=
1.02 in CHCl3); H NMR (400 MHz, CDCl3): d=0.98 (s, 9H), 1.41 (dd,
J=14.2, 5.2 Hz, 1H), 1.66 (dd, J=6.7, 14.2 Hz, 1H), 2.81 (s, 3H), 3.80
(br, 1H), 5.22 (d, J=2.2 Hz, 1H), 7.27–7.38 (m, 3H), 7.53 ppm (d, J=
7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, 508C): d=30.1, 30.3, 46.2,
50.0, 70.7, 96.9, 125.6, 128.3, 128.7, 129.4, 151.8 ppm; IR (neat): n˜ =
2954, 2871, 1651, 1494, 1448, 1364, 1274, 1250, 1009, 718,
1
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689 cmÀ1; elemental analysis calcd (%) for C15H21NO: C 77.88, H
9.15, N 6.05; found: C 77.89, H 9.11, N 5.94.
138.7, 152.1 ppm; IR (neat): n˜ =2967, 2920, 1658, 1610, 1510, 1445,
1308, 1178, 1060, 822, 748 cmÀ1; elemental analysis calcd (%) for
C12H15NO: C 76.16, H 7.99, N 7.40; found: C 75.94, H 8.00, N 7.42.
Compound 8 f: Following the typical procedure, compound 8 f
(94%, 93:7 e.r.) was obtained as a colorless oil. [a]2D6 = +125.0 (c=
Compound 8m: Following the typical procedure, compound 8m
(93%, 86:14 e.r.) was obtained as a colorless oil; [a]2D7 = +88.8 (c=
1.09 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.29 (d, J=6.4 Hz,
3H), 2.83 (s, 3H), 3.90 (br, 1H), 5.37 (d, J=2.5 Hz, 1H), 7.59 (d, J=
8.5 Hz, 2H), 7.63 ppm (d, J=8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3,
508C): d=21.5, 46.4, 68.9, 99.4, 124.1 (q, J=272 Hz), 125.3 (q, J=
4 Hz), 125.8, 130.7 (q, J=33 Hz), 132.7, 150.9 ppm; IR (neat): n˜ =
2972, 2925, 2875, 1615, 1412, 1326, 1168, 1126, 1069, 846, 765,
722 cmÀ1; elemental analysis calcd (%) for C12H12F3NO: C 59.26, H
4.97, N 5.76; found: C 59.21, H 4.97, N 5.64.
1
1.06 in CHCl3); H NMR (400 MHz, CDCl3): d=2.76 (s, 3H), 2.82 (dd,
J=7.1, 13.3 Hz, 1H), 2.97 (dd, J=6.9, 13.3 Hz, 1H), 3.98 (br, 1H),
5.19 (d, J=2.1 Hz, 1H), 7.19–7.37 (m, 8H), 7.53 ppm (d, J=7.5 Hz,
2H); 13C NMR (100 MHz, CDCl3, 508C): d=43.0, 46.9, 75.3, 94.9,
125.7, 126.3, 128.3, 128.4, 128.9, 129.2, 129.4, 138.6, 152.7 ppm; IR
(neat): n˜ =3060, 3027, 2955, 2913, 1651, 1601, 1580, 1494, 1450,
1323, 1277, 1062, 1024, 721, 700 cmÀ1; elemental analysis calcd (%)
for C17H17NO: C 81.24, H 6.82, N 5.57; found: C 81.48, H 6.66, N
4.78.
Compound 8g: Following the typical procedure, compound 8g
(85%, 62:38 e.r.) was obtained as a colorless solid. [a]2D6 = +32.9
(c=1.02 in CHCl3); H NMR (400 MHz, CDCl3): d=0.92–1.31 (m, 5H),
1.38–1.50 (m, 1H), 1.62–1.80 (m, 4H), 1.84–1.93 (m, 1H), 2.80 (s,
3H), 3.49 (dd, J=2.0, 6.2 Hz, 1H), 5.22 (d, J=2.0 Hz, 1H), 7.27–7.37
(m, 3H), 7.54ppm (d, J=6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3,
508C): d=26.1, 26.2, 26.6, 29.0, 29.2, 43.8, 48.0, 79.0, 93.1, 125.6,
128.3, 128.7, 129.4, 152.1 ppm; IR (KBr): n˜ =2921, 2849, 1652, 1494,
1446, 1261, 1039, 1020, 754, 691, 634 cmÀ1; HRMS (FAB): m/z calcd
for C16H22NO: 244.1701; found: 244.1715 [M+H]+.
Compound 8n: Following the typical procedure, compound 8n
(77%, 83:17 e.r.) was obtained as a colorless oil. [a]2D6 = +56.7 (c=
0.60 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.29 (d, J=6.4 Hz,
3H), 2.84 (s, 3H), 3.84–3.98 (br, 1H), 3.92 (s, 3H), 5.38 (d, J=2.5 Hz,
1H), 7.59 (d, J=8.3 Hz, 2H), 8.01 ppm (d, J=8.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 508C): d=21.5, 46.4, 52.0, 68.9, 99.5, 125.5, 129.7,
130.3, 133.4, 151.3, 166.6 ppm; IR (neat): n˜ =2955, 1721, 1609,
1436, 1279, 1108, 741 cmÀ1; elemental analysis calcd (%) for
C13H15NO3: C 66.94, H 6.48, N 6.00; found: C 66.89, H 6.37, N 5.99.
1
Compound 8o: Following the typical procedure, compound 8o
Compound 8h:[31] Following a slightly modified procedure (see
Table 4, entry 9), compound 8h (81%, 93:7 e.r.) was obtained as
1
(56%, 51:49 e.r.) was obtained as a colorless oil. H NMR (400 MHz,
CDCl3): d=1.29 (d, J=6.4 Hz, 3H), 2.44 (s, 3H), 2.83 (s, 3H), 3.88
(br, 1H), 5.01 (d, J=2.4 Hz, 1H), 7.15–7.26 (m, 3H), 7.48 ppm (d, J=
7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, 508C): d=21.1, 21.9, 46.4,
68.9, 100.5, 125.7, 128.6, 128.7, 128.8, 130.7, 136.6, 151.9 ppm; IR
(neat): n˜ =2967, 2923, 1639, 1455, 1304, 741 cmÀ1; elemental analy-
sis calcd (%) for C12H15NO: C 76.16, H 7.99, N 7.40; found: C 75.97,
H 8.04, N 7.37.
a
colorless solid. [a]D25 =À162.1 (c=1.17 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=2.98 (s, 3H), 4.85 (s, 1H), 5.37 (d, J=2.4 Hz,
1H), 7.24–7.43 (m, 8H), 7.59 ppm (d, J=7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 508C): d=47.1, 77.2, 95.8, 125.8, 127.1, 127.7,
128.4, 128.6, 129.00, 129.02, 142.1, 152.7 ppm.
Compound 8i: Following a slightly modified procedure (see
Table 4, entry 10), compound 8i (84%, 88:12 e.r.) was obtained as
Compound 8p: Following the typical procedure, compound 8p
(96%, 95:5 e.r.) was obtained as a colorless oil; [a]2D7 = +194.8 (c=
a
colorless solid. [a]D28 =À126.3 (c=1.04 in CHCl3); 1H NMR
1
(400 MHz, [D6]acetone): d=2.90 (s, 3H), 3.77 (s, 3H), 4.82 (brd, J=
2.6 Hz, 1H), 5.55 (d, J=2.6 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.31 (d,
J=8.8 Hz, 2H), 7.36–7.43 (m, 3H), 7.60–7.64 ppm (m, 2H); 13C NMR
(100 MHz, [D6]acetone): d=47.3, 55.7, 77.0, 97.5, 114.7, 126.5,
129.3, 129.5, 129.9, 130.3, 135.8 (br), 152.9, 160.3 ppm; IR (neat):
n˜ =2956, 1654, 1604, 1506, 1453, 1250, 1174, 1031, 831, 768,
719 cmÀ1; HRMS (FAB): m/z calcd for C17H18NO2: 268.1338; found:
268.1339 [M+H]+.
1.38 in CHCl3); H NMR (400 MHz, CDCl3): d=1.27 (t, J=7.1 Hz, 3H),
1.29 (d, J=6.4 Hz, 3H), 2.80 (dq, J=12.4, 7.1 Hz, 1H), 3.12 (dt, J=
12.4, 7.0 Hz, 1H), 3.97 (br, 1H), 5.24 (d, J=2.6 Hz, 1H), 7.27–7.37
(m, 3H), 7.54 ppm (d, J=7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3,
508C): d=12.4, 22.3, 53.6, 66.8, 97.4, 125.6, 128.3, 128.7, 129.4,
152.1 ppm; IR (neat): n˜ =2973, 2925, 1653, 1494, 1447, 1333, 1055,
1004, 752, 731, 690 cmÀ1
; elemental analysis calcd (%) for
C12H15NO: C 76.16, H 7.99, N 7.40; found: C 76.05, H 7.93, N 7.43.
Compound 8j: Following a slightly modified procedure (see
Table 4, entry 11), compound 8j (50% by 1H NMR spectroscopy,
88:12 e.r.) was obtained as a mixture with 5-phenyl-3-[4-(trifluoro-
methyl)phenyl]isoxazole. 1H NMR (400 MHz, CDCl3): d=3.00 (s,
1.9H), 4.89 (d, J=2.6 Hz, 0.7H), 5.36 (d, J=2.7 Hz, 0.6H), 6.87 (s,
0.4H), 7.34–8.02 ppm (m, 9H).
Compound 9q: Following the typical procedure and using ligand
L4, compound 9q (96%, 87:13 e.r.) was obtained as a colorless oil.
[a]2D6 =À137.7 (c=1.23 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
1.38 (d, J=6.1 Hz, 3H), 1.99 (ddd, J=7.5, 9.1, 12.2 Hz, 1H), 2.62 (s,
3H), 2.80 (dt, J=12.2, 7.1 Hz, 1H), 3.66 (br, 1H), 4.42 (sextet, J=
6.5 Hz, 1H), 7.24–7.40 ppm (m, 5H); 13C NMR (100 MHz, CDCl3,
508C): d=21.3, 43.8, 47.5, 72.8, 73.6, 127.4, 127.5, 128.5,
140.2 ppm; IR (neat): n˜ =2975, 2872, 1454, 1370, 1216, 754,
700 cmÀ1; elemental analysis calcd (%) for C11H15NO: C 74.54, H
8.53, N 7.90; found: C 74.51, H 8.49, N 7.97.
Compound 8k: Following the typical procedure, compound 8k
(67%, 81:19 e.r.) was obtained as a colorless oil. [a]2D7 = +111.1 (c=
0.61 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.26 (d, J=6.4 Hz,
3H), 2.81 (s, 3H), 3.81 (s, 3H), 3.84 (br, 1H), 5.09 (d, J=2.6 Hz, 1H),
6.87 (d, J=9.0 Hz, 2H), 7.47 ppm (d, J=9.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 508C): d=21.8, 46.4, 55.3, 68.8, 95.2, 113.8, 122.1,
127.1, 151.8, 160.2 ppm; IR (neat): n˜ =2964, 2925, 1651, 1603, 1506,
1448, 1254, 1175, 1030, 833, 745, 706 cmÀ1; HRMS (FAB): m/z calcd
for C12H16NO2: 206.1181; found: 206.1180 [M+H]+.
Compound 9r: Following a slightly modified procedure (see
Table 5, entry 4), compound 9r (94%, 89:11 e.r.) was obtained as
1
a colorless oil. [a]2D6 =À122.8 (c=1.23 in CHCl3); H NMR (400 MHz,
CDCl3): d=0.91 (t, J=7.0 Hz, 3H), 1.26–1.64 (m, 5H), 1.76–1.87 (m,
1H), 2.01 (ddd, J=7.4, 9.5, 12.2 Hz, 1H), 2.60 (s, 3H), 2.76 (dt, J=
12.2, 7.2 Hz, 1H), 3.61 (br, 1H), 4.22 (quintet, J=6.9 Hz, 1H), 7.26 (t,
J=6.9 Hz, 1H), 7.33 (t, J=7.4 Hz, 2H), 7.37 ppm (d, J=8.1 Hz, 2H);
13C NMR (100 MHz, [D6]acetone): d=14.5, 23.5, 29.5, 36.7, 44.0,
47.0, 74.0, 77.4, 128.3, 128.4, 129.4, 142.0 ppm; IR (neat): n˜ =2956,
Compound 8l: Following the typical procedure, compound 8l
(81%, 91:9 e.r.) was obtained as a colorless oil. [a]2D6 = +125.5 (c=
0.83 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.27 (d, J=6.4 Hz,
3H), 2.35 (s, 3H), 2.81 (s, 3H), 3.85 (br, 1H), 5.17 (d, J=2.6 Hz, 1H),
7.15 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3, 508C): d=21.3, 21.7, 46.4, 68.8, 96.1, 125.6, 126.5, 129.0,
2871, 1455, 755, 699 cmÀ1
C14H21NO: C 76.67, H 9.65, N 6.39; found: C 76.64, H 9.77, N 6.48.
; elemental analysis calcd (%) for
Chem. Eur. J. 2016, 22, 8610 – 8618
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[1] Reviews: a) F. Glorius, Org. Biomol. Chem. 2005, 3, 4171–4175; b) Y.-G.
Zhou, Acc. Chem. Res. 2007, 40, 1357–1366; c) R. Kuwano, Heterocycles
2008, 76, 909–922; d) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G. Zhou,
Chem. Rev. 2012, 112, 2557–2590; e) D. Zhao, F. Glorius, Angew. Chem.
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f) Z.-S. Ye, L. Shi, Y.-G. Zhou, Synlett 2014, 25, 928–931; g) K. Mashima, T.
Nagano, A. Iimuro, K. Yamaji, Y. Kita, Heterocycles 2014, 88, 103–127;
h) B. Balakrishna, J. L. NfflÇez-Rico, A. Vidal-Ferran, Eur. J. Org. Chem.
2015, 2015, 5293–5303.
[2] a) R. Kuwano, K. Sato, T. Kurokawa, D. Karube, Y. Ito, J. Am. Chem. Soc.
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kawa, Y. Ito, Org. Lett. 2004, 6, 2213–2215; c) R. Kuwano, M. Kashiwa-
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7315.
Compound 9s: Following a slightly modified procedure (see
Table 5, entry 5), compound 9s (96%, 88:12 e.r.) was obtained as
1
a colorless oil. [a]2D6 =À93.0 (c=1.02 in CHCl3); H NMR (400 MHz,
CDCl3): d=1.84 (dddd, J=5.1, 6.6, 9.8, 13.6 Hz, 1H), 2.03 (ddd, J=
7.0, 9.4, 12.3 Hz, 1H), 2.17 (dddd, J=5.7, 8.1, 9.5, 13.6 Hz, 1H), 2.62
(s, 3H), 2.65–2.86 (m, 3H), 3.61 (br, 1H), 4.23 (dq, J=5.1, 7.4 Hz,
1H), 7.15–7.39 ppm (m, 10H); 13C NMR (100 MHz, CDCl3, 508C): d=
32.6, 37.6, 43.7, 46.0, 73.5, 76.1, 125.8, 127.5, 127.6, 128.4, 128.5,
128.6, 140.0, 142.0 ppm; IR (neat): n˜ =3026, 2915, 2856, 1494, 1449,
1023, 726, 698 cmÀ1; elemental analysis calcd (%) for C18H21NO: C
80.86, H 7.92, N 5.24; found: C 80.80, H 7.81, N 5.18.
Compound 9t: Following the typical procedure and using ligand
L4, compound 9t (86%; 84:16 e.r.) was obtained as a colorless oil.
1
[a]2D5 =À47.5 (c=0.97 in CHCl3); H NMR (400 MHz, CDCl3): d=1.16
(d, J=6.2 Hz, 3H), 1.60 (ddd, J=7.2, 8.3, 12.0 Hz, 1H), 1.73–1.83 (m,
1H), 2.01 (dddd, J=5.7, 7.8, 9.6, 13.5 Hz, 1H), 2.51 (dt, J=12.0,
7.1 Hz, 1H), 2.59–2.82 (m, 3H), 2.65 (s, 3H), 4.05–4.15 (m, 1H),
7.14–7.21 (m, 3H), 7.24–7.30 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=18.1 (br), 32.6, 37.6, 43.6 (br, 2”C), 63.9 (br), 75.3 (br),
125.7, 128.3, 128.5, 142.0 ppm; IR (neat): n˜ =2962, 2862, 1493,
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C13H19NO: C 76.06, H 9.33, N 6.82; found: C 75.71, H 9.37, N 6.76.
Compound 9u: Compound 9u (98%, 70:30 e.r.); was obtained as
1
a colorless oil. [a]2D6 =À59.4 (c=1.33 in CHCl3); H NMR (400 MHz,
CDCl3): d=2.31 (dq, J=7.3, 12.1 Hz, 1H), 2.61 (s, 3H), 2.70 (dq, J=
7.7, 12.1 Hz, 1H), 3.53 (br, 1H), 4.07 (t, J=7.4 Hz, 2H), 7.28 (t, J=
7.4 Hz, 1H), 7.34 (t, J=7.4 Hz, 2H), 7.38 ppm (d, J=7.3 Hz, 2H);
13C NMR (100 MHz, CDCl3, 508C): d=39.3, 43.3, 65.7, 72.4, 127.57,
127.61, 128.6, 140.2 ppm; IR (neat): n˜ =2957, 2872, 1492, 1453,
1033, 1012, 753, 700 cmÀ1; HRMS (FAB): m/z calcd for C10H13NO:
163.0997; found: 163.0989 [M]+.
Compounds 8v and 9v: Following the typical procedure and
using ligand L4, a mixture of compounds 8v and 9v were ob-
tained. The yields given here are of the isolated products.
Compound 8v: Compound 8v (26%, 94:6 e.r.) was obtained as
1
a colorless oil. H NMR (400 MHz, CDCl3): d=1.16 (d, J=6.9 Hz, 3H),
1.17 (d, J=6.9 Hz, 3H), 2.49 (septet, J=6.9 Hz, 1H), 2.86 (s, 3H),
4.58–4.63 (m, 2H), 7.23–7.36 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3): d=20.4, 26.1, 47.0, 76.5, 93.0, 126.9, 127.5, 128.5, 142.9,
160.7 ppm.
Compound 9v: Compound 9v (21%, 80:20 e.r.) was obtained as
a colorless oil; 1H NMR (400 MHz, CDCl3): d=0.88 (d, J=6.8 Hz,
3H), 1.03 (d, J=6.8 Hz, 3H), 1.87 (octet, J=6.9 Hz, 1H), 2.09 (dt, J=
12.1, 9.0 Hz, 1H), 2.60 (s, 3H), 2.68 (dt, J=12.1, 6.9 Hz, 1H), 3.63 (br,
1H), 3.86 (q, J=7.7 Hz, 1H), 7.24–7.39 ppm (m 5H); 13C NMR
(100 MHz, CDCl3): d=18.4, 19.5, 33.4, 43.8, 44.2, 73.4, 82.5, 127.4,
127.6, 128.6, 140.1 ppm.
Acknowledgements
This work was partly supported by the JSPS KAKENHI, grant
numbers 15K13698 and 15KT0066. R.I. thanks the JSPS for fi-
nancial support (JSPS Research Fellow). We thank the Coopera-
tive Research Program of the “Network Joint Research Center
for Materials and Devices” for performing the HRMS measure-
ments.
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Keywords: asymmetric
hydrogenation · iridium · isoxazoles
catalysis
·
heterocycles
·
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Received: February 17, 2016
Published online on April 23, 2016
Chem. Eur. J. 2016, 22, 8610 – 8618
www.chemeurj.org
8618
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim