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in the isomerization of isoxazole 1a. The reaction proceeded
without any supporting ligand to afford racemic 2a (Table 1,
entry 1). Chiral bisphosphine and monophosphine ligands
drene.[15] The dialkyl-substituted diene L3 resulted in almost
the same ee value as observed with L2 (entry 10). The
hydroxyalkyl-substituted diene L4 and methoxycarbonyl-
resulted in poor conversion and enantioselectivity (entries 2– substituted diene L5 gave moderate enantioselectivity (58
6). The cyclooctadiene-coordinates complex [RhCl(cod)]2
effectively catalyzed the reaction to afford racemic 2a in
good yield (entry 7). Encouraged by this result, we then
utilized chiral diene ligands, which are known to as efficient
ligands for rhodium-catalyzed conjugate addition reactions.[14]
Simple C2-symmetric chiral diene ligands, such as Ph-bod (L1)
and Bn-bod (L2), afforded the products, but with low
enantioselectivity (3% ee with L1 and 30% ee with L2;
entries 8 and 9). To further vary the substituents on the
and 59% ee; entries 11 and 12). Use of the more hindered
tert-butoxycarbonyl-substituted diene ligand L6 improved the
enantioselectivity (67% ee; entry 13). 2-Naphthyl ester sub-
stituted L7 also provided moderate enantioselectivity
(69% ee; entry 14). Finally, with ligand L8, bearing a bulky
aromatic ester moiety, and DCE as the solvent, the catalyst
loading could be decreased to 5 mol% Rh, and the product
was obtained in 86% yield with 94% ee (Table 1, entry 18).
An iridium catalyst with ligand L8 exhibited higher catalytic
ligands, we then employed a series of chiral diene ligands L3– activity and comparable enantioselectivity (the reaction
L10 readily prepared from commercially available a-phellan-
reached completion even at 08C; 91% yield, 92% ee;
entry 19). The presence of two ester moieties on ligand L9
did not improve the ee value of the product further (84% ee;
entry 20),[16] and the use of amide-substituted ligand L10
resulted in lower enantioselectivity (53% ee; entry 21).
The present asymmetric isomerization method was
applied to the reaction of various 5-alkoxy isoxazoles 1 and
afforded the corresponding azirine-2-carboxylates 2 in good
yields with high enantioselectivity (Table 2). p-Methoxy- and
p-trifluoromethylphenyl groups were suitable as the R1
substituent (products 2b,c). 5-Ethoxy and 5-isopropoxy isox-
azoles also reacted to form ethyl ester 2d and isopropyl ester
2e with high ee values. n-Propyl and benzyl groups were
suitable as the R2 substituent (products 2 f,g). Azirine 2h, with
a phenyl group as the R2 substituent, was obtained with low
enantioselectivity (40% ee), probably owing to a steric effect
of the phenyl group. In this case, the use of the corresponding
iridium catalyst in the reaction at 08C improved the ee value
to 70%. 2H-Azirines with halogen substituents at the R2
position were obtained with high ee values (2i–k).
Table 1: Rhodium-catalyzed enantioselective isomerization of isoxazole
1a to give 2H-azirine 2a.[a]
Entry
Ligand
Conv. [%][b]
Yield [%][c]
ee [%][d]
1
2
none
(R)-binap
86
22
75
9
–
8
3
4
5
6
(R)-segphos
(R)-phanephos
(R)-mop
(R)-monophos
10
33
31
0
100
71
94
98
100
76
83
89
99
100
98
100
100
100
93
(9)
(14)
(21)
(0)
68
50
79
77
85
38
64
51
89
82
84
86
91
91
83
nd
nd
nd
nd
–
3
30
31
58
59
67
69
88
53
85
94
92
84
53
Table 2: Scope of the enantioselective synthesis of 2H-azirines 2.[a]
7[e]
8
cod
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L9
L10
9
10
11
12
13
14
15
16[f]
17[g]
18[g,h]
19[i]
20
21
[a] The reaction was carried out with isoxazole 1a (0.20 mmol), [RhCl-
(C2H4)2]2 (5 mol%), and a ligand (10 mol%) in toluene (1.5 mL).
[b] Conversion was determined by 1H NMR spectroscopy of the crude
product. [c] Yield of the isolated product. Yields in parentheses were
1
determined by H NMR spectroscopy. [d] The ee value was determined
by HPLC analysis on a chiral stationary phase. [e] [RhCl(cod)]2 (5 mol%)
was used as the catalyst. [f] The reaction was carried out at 808C. [g] The
reaction was carried out with 2.5 mol% of [RhCl(C2H4)2]2 and 5.5 mol%
of the ligand. [h] 1,2-Dichloroethane (DCE) was used instead of toluene.
[i] [IrCl(C2H4)2]2 was used at 08C instead of [RhCl(C2H4)2]2. Ar*=2,6-
diisopropylphenyl, cod=1,5-cyclooctadiene.
[a] The reaction was performed with isoxazoles 1 (0.10 mmol), [RhCl-
(C2H4)2]2 (2.5 mol%), and L8 (5.5 mol%) in DCE (1.0 mL) at 408C for
17 h. Yields are for the isolated product. HPLC analysis on a chiral
stationary phase was used to determine ee values. [b] [IrCl(C2H4)2]2 was
used instead of [RhCl(C2H4)2]2. The reaction temperature was 08C.
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1039 –1043