Angewandte
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Chemie
Table 1: Electrophilic aromatic iodination of unsubstituted isoxazole 1.
Table 2: Preparation of the 4-oxazolyl anion by halogen–metal exchange
of 2.
Entry
Reagent
Solvent
T [8C]
Yield [%][a]
Entry
Reagent
Conc. of 2 [m]
T [8C]
Yield [%][a]
1
2
3
4
5
6
7
8
NIS
NIS
TFA
50
50
50
50
50
50
9
13
2
29
3
[b]
TfOH
TfOH
TFA
TfOH
TFA
1
2
3
4
nBuLi
0.3
1.0
0.1
0.1
À78
À78
À78
À20
–
[b]
DIH
DIH
NISac
NISac
NIS
iPrMgCl·LiCl
iPrMgCl·LiCl
iPrMgCl·LiCl
–
quant.
quant.
trace
70
[a] Yield of isolated product. [b] Complex mixture was obtained.
TFA
TFA
120 (M.W.)
120 (M.W.)
NIS
69[b]
[a] Yield of isolated product. [b] The reaction was carried out at gram
scale (ca. 2 g of product). M.W.=microwave, TFA=trifluoroacetic acid.
using nBuLi produced a complex mixture (entry 1). Then,
turbo Grignard reagent (iPrMgCl·LiCl)[19] was used for the
iodine–metal exchange reaction. The use of a 1.0m solution of
2 again afforded a complex mixture (entry 2). However,
surprisingly, the use of a lower concentration (0.1m) of 2 and
iPrMgCl·LiCl resulted in a dramatic improvement of the yield
of 4c (entry 3). The reaction was carried out as follows: to
a stirred 0.1m solution of 2 in THF, a 0.63m solution of
iPrMgCl·LiCl in THF (1.10 equiv) was added dropwise at
À788C under an argon atmosphere. After being stirred at the
same temperature for 30 minutes, the vessel was filled with
CO2 gas, which was collected in a balloon by sublimation of
dry ice. After being stirred at room temperature for
15 minutes, a standard workup procedure afforded the
desired product 4c quantitatively. We speculated that heat
generated when a higher concentration solution was used
induced undesired reactions. However, even if the reaction
was carried out at À208C, the desired product 4c was
obtained quantitatively (entry 4). Although the exact reason
why the concentration of 2 was critical for this reaction is not
clear, we suppose that the undesired ring opening of 2, by the
generated anion species 3,[20] might be suppressed under the
lower concentration conditions.
microwave irradiation conditions, and 2 was obtained in 70%
yield (entry 7). To our delight, the yield of 2 was reproducible,
even on a gram scale (entry 8). It should be noted that this is
the first report of the electrophilic halogenation of 1 in such
good yields.
With the establishment of a practical protocol for the
synthesis of 2, we next examined various chemical modifica-
tions of 2, which should be valuable for functionalization at
the 4-position using transition metal-catalyzed cross-coupling
reactions. Therefore, we conducted typical palladium-cata-
lyzed cross-coupling reactions, Suzuki–Miyaura coupling[15]
and Sonogashira coupling,[16] with 2 (Scheme 2). As has been
Additional functionalizations using 3 were investigated, as
shown in Table 3. Various functional groups were introduced
at the 4-position of isoxazole in good to excellent yields (52%
to quant.). The nucleophilic addition reactions of 3 proceeded
with various electrophiles, such as aldehyde (entry 1), ketone
(entry 2), anhydride (entry 3), formamide (entry 4),[21] and
isocyanate (entry 5) to give corresponding adducts 4d–h in
55–88% yields. Acylation and allylation of 3 also proceeded
in the presence of a catalytic amount of CuCN·2LiCl
(0.2 equiv) to give 4-benzoylisoxazole (4i; 52%) and 4-
allylisoxazole (4j; 84%), respectively (entries 6 and 7). Not
only the nucleophilic additions but also Negishi cross-
coupling[22] with ethyl 4-iodobenzoate proceeded in the
presence of ZnCl2 (1.1 equiv) to afford ethyl 4-(4’-isoxazolyl)
benzoate (4k) in 61% yield (entry 8). Furthermore, 3 under-
went carbon–heteroatom bond formation reactions. 4-
Aminoisoxazole (4l)[23] and 4-phenylthioisoxazole (4m)
were obtained from propan-2-one O-tosyl oxime (64%)[24]
and PhSO2SPh (82%), respectively (entries 9 and 10). The
conversion of 3 into more stable organometallic species was
also possible and the corresponding boronate ester 4n,[25]
Scheme 2. Introduction of substituents at the 4-position of 4-iodoisox-
azole (2) by palladium-catalyzed cross-coupling reactions. a) 5 mol%
[Pd2(dba)3],[17] 10 mol% P(tBu)3·HBF4,[18] Na2CO3, THF/H2O (1:1), RT,
1 h, 88%; b) 2 mol% [PdCl2(PPh3)2], 4 mol% CuI, 1.1 equiv NEt3, THF,
RT, 1 h, 64%. dba=dibenzylideneacetone, THF=tetrahydrofuran.
described before, 3,5-unsubstituted isoxazole is extremely
labile under basic conditions. To suppress ring opening,
Suzuki–Miyaura coupling was performed under two-phase
conditions using Na2CO3 in THF and H2O. As a result, the
desired coupling product 4a was obtained in a high yield
(88%). Similarly, Sonogashira coupling using 1.1 equivalents
of NEt3 afforded the desired product 4b in 64% yield.
We next examined the generation of the carbanion 3 from
2 and subsequent electrophilic trapping with CO2 to obtain 4-
isoxazolyl carboxylic acid (4c) for structurally diverse func-
tionalization (Table 2). The iodine–metal exchange reaction
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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