Palladium-Catalyzed Direct C-H Arylation of Isoxazoles at the 5-Position

Article abstract of DOI:10.1002/anie.201504552

A palladium-catalyzed direct arylation of isoxazoles with aryl iodides has been achieved. The C-H bond at the 5-position is activated selectively to give coupling products in moderate to good yields. This direct arylation was applied to the synthesis of a spiro-type chiral ligand, which proved to be most effective to the palladium-catalyzed tandem cyclization of a dialkenyl alcohol.

Full text of DOI:10.1002/anie.201504552

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504552
German Edition: DOI: 10.1002/ange.201504552
Cross-Coupling
À
Palladium-Catalyzed Direct C H Arylation of Isoxazoles at the
5-Position**
Masashi Shigenobu, Kazuhiro Takenaka,* and Hiroaki Sasai*
Abstract: A palladium-catalyzed direct arylation of isoxazoles
À
with aryl iodides has been achieved. The C H bond at the 5-
position is activated selectively to give coupling products in
moderate to good yields. This direct arylation was applied to
À
Scheme 1. Direct C H arylation at the 5-position of isoxazoles.
the synthesis of a spiro-type chiral ligand, which proved to be
FG=functional group.
most effective to the palladium-catalyzed tandem cyclization of
a dialkenyl alcohol.
To explore direct C5 arylation, the reaction of tetrahydro-
O
ver the past decade, direct transformation of ubiquitous
C H bonds promoted by a transition-metal catalyst has
benzo[c]isoxazole (1a)[14] with 4-iodotoluene (2a) was con-
ducted as a model reaction. After surveying a series of
reaction parameters,[15] we identified the reaction conditions
for formation of the desired coupling product. Specifically,
treatment of 1a with 2 equivalents of 2a in the presence of
5 mol% of [PdCl2(MeCN)2], 10 mol% of 1,2-bis(diphenyl-
phosphino) benzene (DPPBz), and 2 equivalents of AgF in
N,N-dimethylacetamide (DMA) at 1008C for 24 hours gave
3aa in 86% yield (Table 1, entry 1). No reaction was observed
À
emerged as a straightforward and atom-economical function-
alization method.[1] Among such transformations, C C bond-
À
À
forming arylation through C H bond activation (direct
arylation) has been a primary research target, and is
recognized to be an environmentally benign cross-coupling
reaction.[2] This powerful approach offers a new streamlined
strategy for the production of chemicals and is applied to the
total synthesis of natural products.[3]
Isoxazoles are a major class of five-membered hetero-
cycles embedded in a variety of pharmaceutical and agro-
Table 1: Selected optimization results.[a]
chemical products.[4] This ring system, which has an N O
À
single bond, is used as a valuable synthetic intermediate in
organic chemistry[5] and as a building block in materials
science.[6] Chiral ligands having an isoxazole donor site have
also been prepared.[7] Continuing efforts are therefore being
made to develop more efficient synthetic methods for
isoxazoles.[8] Nevertheless, in contrast to the many successful
examples of direct arylation reported for other heterocyclic
Entry
Variation from the
“standard reaction conditions”
Yield [%][b]
1
2
3
4
5
6
7
8
none
no [PdCl2(MeCN)2]
no DPPBz
no AgF
86 (84)[c]
n.r.
n.r.
n.r.
69
67
35
46
59
25
12
50
37
compounds,[9] C C bond-forming reactions of this type
À
involving isoxazoles are still scarce and are limited to their
C4-position.[10] Hence, direct C H arylation of isoxazoles at
À
the 5-position would provide an alternative and versatile
protocol for their preparation.[11] Herein we report an
unprecedented palladium-catalyzed direct C5 arylation of
the isoxazole ring (Scheme 1).[12,13]
Pd(OAc)2 instead of [PdCl2(MeCN)2]
[Pd(dba)2] instead of [PdCl2(MeCN)2]
PPh3 (20 mol%) instead of DPPBz
DPPE instead of DPPBz
EtCN instead of DMA
1,4-dioxane instead of DMA
toluene instead of DMA
AgOAc instead of AgF
Ag2CO3 instead of AgF
KOAc instead of AgF
CsF instead of AgF
Bu3N instead of AgF
at 808C
at 1208C
2.5 mol% of [PdCl2(MeCN)2]/5 mol% of DPPBz
1 mol% of [PdCl2(MeCN)2]/2 mol% of DPPBz
9
10
11
12
13
14
15
16
17
18
19
20
[*] M. Shigenobu, Dr. K. Takenaka, Prof. Dr. H. Sasai
The Institute of Scientific and Industrial Research (ISIR)
Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047 (Japan)
E-mail: takena@sanken.osaka-u.ac.jp
13
trace
n.r.
65
sasai@sanken.osaka-u.ac.jp
[**] This work was supported by the Advanced Catalytic Transformation
program for Carbon utilization (ACT-C), Core Research for Evolu-
tionary Science and Technology (CREST), a Grant-in-Aid for
Scientific Research from MEXT, and the JSPS Japanese-German
Graduate Externship. We would like to thank the technical staff at
the ISIR Comprehensive Analysis Centre at Osaka University for
their assistance.
56
74[d]
61[d]
[a] All reactions were performed on a 0.13 mmol scale at 0.25m under
a N2 atmosphere in the dark. In some cases, the formation of a dimer of
1a was observed. [b] Determined by H NMR spectroscopy using 1,3,5-
1
trimethoxybenzene as an internal standard. [c] Yield of the isolated
product. [d] 48 h. n.r.=no reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504552.
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À
in the absence of any one of these components (entries 2–4).
Use of either Pd(OAc)2 or [Pd(dba)2] (dba = dibenzylidene-
acetone) instead of [PdCl2(MeCN)2] led to a slightly dimin-
ished yield (entries 5 and 6). Rigid chelation seemed to be
important in this direct arylation. For example, with the
monodentate PPh3, and the somewhat flexible 1,2-bis(diphe-
nylphosphino)ethane (dppe), 3aa was obtained in 35 and
46% yields, respectively (entries 7 and 8). The chemical yield
of the coupling product was significantly lowered in less polar
solvents (entries 9–11). Additive salts were found to have
a large impact on the reaction efficiency (entries 12–15).
Organic bases such as Bu3N did not show any positive effects
(entry 16). Even at 808C, the 5-position of 1a was function-
alized by the 4-tolyl group to give a moderate yield of 3aa,
while no improvement was achieved at higher temperatures
(entries 17 and 18). This direct C5 arylation of the isoxazole
proceeded even with a reduced catalyst loading of 2.5 or
1 mol% to afford 3aa in good yields (entries 19 and 20).
The scope with respect to the aryl iodides in this palladium
catalysis was then examined using 1a as the coupling partner
(Table 2). Substituting the iodide 2a for the corresponding
throughout the C C bond-forming process (entries 3–5).
Reaction with iodobenzene (2e) simply gave the phenylated
isoxazole 3ae in 77% yield (entry 6). 4-Iodoanisole (2 f) was
successfully employed to afford 3af in 71% yield after
48 hours, whereas no reaction took place for the more-
electron-rich substrate 2g, which possesses a dimethylamino
group (entries 7 and 8). Carbonyl functionalities were toler-
ated under these reaction conditions to give 3ah bearing an
ester moiety, and 3ai bearing a ketone moiety (entries 9 and
10). For electron-deficient aryl iodides 2j, having a trifluoro-
methyl group, and 2k, having a nitrile group, the desired
coupling products 3aj and 3ak were obtained in moderate
yields (entries 11 and 12). A strongly electron-withdrawing
nitro unit played an adverse role in this transformation, thus
resulting in a complex mixture (entry 13). A substituent at the
meta-position exerted little influence on direct arylation. The
reaction with 3-iodotoluene (2m) led to the target product
3am in 68% yield (entry 14). Although a 2-tolyl group was
introduced despite the steric hindrance, other ortho substitu-
ents slightly retarded the cross coupling reaction (entries 15–
17). 1-Iodonaphthalene (2q) and 1-iodopyrene (2r) were also
À
able to participate, albeit sluggishly, in this C H functional-
ization (entries 18 and 19). A 2,6-xylyl group was, however,
too bulky to be installed at the 5-position of the isoxazole ring
(entry 20). A complex mixture was formed in the reaction
with 2-iodopyridine (2t), and is most likely due to the high
Table 2: Scope with respect to aryl iodides.[a]
À
reactivity of its a-C H bond (entry 21). When the alkenyl
iodide 2u was used in place of aryl iodides, the desired
product 3au was not obtained at all (entry 22).
Entry
2
Ar
3
Yield [%][b]
Next, various isoxazole substrates were subjected to the
C H arylation with 2a (Table 3). The desired reaction
product was still obtained even with an aliphatic chain and
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2a
2a’[c]
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
4-MeC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3aa
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
84
À
26[d]
63
70
62
77
Table 3: Scope with respect to isoxazoles.[a]
Ph
4-MeOC6H4
4-Me2NC6H4
4-MeOC(O)C6H4
4-MeC(O)C6H4
4-CF3C6H4
4-NCC6H4
4-NO2C6H4
3-MeC6H4
2-MeC6H4
2-MeOC6H4
2-BrC6H4
71[e]
n.r.
74
47[e]
65[e]
51[e]
3aj
3ak
3al
Entry
1
R1
R2
3
Yield [%][b]
[f]
–
1
2
3
4
1b
1c
1d
1e
1 f
1g
4-ClC6H4
4-ClC6H4
PhCH2CH2
Me
Ph
C5H11
NCCH2CH2
CO2Et
3ba
3ca
3da
3ea
3 fa
3ga
60
51
70
86
3am
3an
3ao
3ap
3aq
3ar
3as
3at
68
65
45
43
À
=
À
=
À
5
CH CH CH CH
4-ClC6H4
73
1-naphthyl
1-pyrenyl
2,6-Me2C6H3
2-pyridyl
79[e]
79[e]
n.r.
6[c]
H
64[d]
2s
2t
2u
[a] All reactions were performed on a 0.13 mmol scale at 0.25m under
a N2 atmosphere. [b] Yield of isolated product. [c] 1 equiv of 2a was used.
[d] Small amounts of C4-arylated and doubly arylated products were
detected.
[f]
–
=
(E)-C6H13CH CH
3au
n.r.
[a] All reactions were performed on a 0.13 mmol scale at 0.25m under
a N2 atmosphere in the dark. [b] Yield of isolated product. [c] 4-
Bromotoluene was used. [d] Determined by 1H NMR spectroscopy using
1,3,5-trimethoxybenzene as an internal standard. [e] 48 h. [f] Complex
mixture.
aromatic rings at the 3- and 4-positions of the isoxazoles
(entries 1 and 2). In addition, nitrile and ester functionalities
were compatible with this catalysis. The reaction of 3-(3-
phenethylisoxazol-4-yl)propanenitrile (1d) and ethyl 3-meth-
ylisoxazole-4-carboxylate (1e) afforded products 3da (70%)
and 3ea (86%), respectively (entries 3 and 4). A benzene-
fused isoxazole substrate, anthranil (1 f), exhibited similar
reactivity to that of 1a to furnish the product 3 fa in 73% yield
bromide 2a’ furnished only 26% yield of 3aa, thus indicating
2
À
low reactivity of the C(sp ) Br bond under these reaction
conditions (entry 2).[16] Fluoro, chloro, and bromo substitu-
ents at the para position of iodoarenes 2b–d remained intact
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(entry 5).[13] This direct arylation proved to take place
regioselectively at the 5-position over the 4-position. Thus,
in the reaction of 3-(4-chlorophenyl)isoxazole (1g) with
À
1 equivalent of 2a, the C5 H bond was activated to predom-
inantly produce 3ga in 64% yield (entry 6).[17]
A plausible reaction mechanism for this palladium-
catalyzed direct arylation of isoxazoles is depicted in
Scheme 2. As in the conventional cross-coupling reaction,
the formation of 3 is initiated by the oxidative addition of the
Scheme 3. Mechanistic study.
The kinetic investigation indeed demonstrated the undesir-
able possibility of such a disproportionation process. As such,
an inverse relationship between the initial rate and the
catalyst loading was observed in the reaction of 1a with 2a.[15]
The utility of the direct C5 arylation of isoxazoles was
examined in the derivatization of the spiro-type chiral ligand
7, which was developed in our laboratory (Scheme 4).[7b]
Scheme 2. Plausible catalytic cycle.
iodoarene 2 to the Pd0 complex A, which would be generated
through the reduction of the PdII precatalyst by the action of
fluoride.[18] Anion exchange of the resulting PdII species B
with AgF gives the fluoride complex C.[19] Subsequently, the
À
key C H bond activation of 1 delivers the intermediate D,
where the isoxazole ring binds to Pd at its 5-position. Finally,
À
C C bond-forming reductive elimination from D provides the
coupling product 3, and the catalytic cycle is complete.[20] To
gain insight into the reaction pathway, we carried out several
additional experiments. Firstly, the kinetic isotope effect
(KIE) was evaluated by comparison of the initial rates in
parallel reactions using substrates 1a and [D]-1a under the
standard reaction conditions (Scheme 3a). The KIE value
(kH/kD), determined to be 3.4, suggested the rate-determining
Scheme 4. Application of the direct arylation of isoxazoles.
À
step to be C H bond activation. Subsequently, we prepared
the the Pd-I intermediate Ba[21] and employed it as the
catalyst in the reaction of 1a with 2a (Scheme 3b). This direct
cross-coupling gave product 3aa in 67% yield, thus implying
the involvement of Ba in the catalytic cycle. No arylated
isoxazole (3aa) was, however, obtained in the stoichiometric
reaction of Ba with 1a and AgF. The corresponding fluoride
complex C (Ar= 4-MeC6H4) could also not be synthesized. To
elucidate this, careful attention was paid to the reaction
mixture, in which the formation of a considerable amount of
4,4’-dimethyl-1,1’-biphenyl (4) was observed (Scheme 3c).
We surmized that the key fluoride complex C would have
a substantial tendency to disproportionate into difluoride
complex 5 and diaryl complex 6, the latter of which produced
biaryl derivatives upon reductive elimination (Scheme 3d).
When we treated 7 with 2 equivalents of 2q under the
standard reaction conditions, the desired product 8, bearing
the 1-naphthyl group, was obtained in 74% yield (Scheme
4a). Considering the fact that Suzuki coupling marginally
contributed to the formation of 8 (43% yield),[7c] this C H
À
functionalization would be a promising surrogate for conven-
tional cross-coupling reactions. The arylated ligand 8 exhib-
ited better results in asymmetric catalysis compared to the
unmodified ligand 7. The palladium-catalyzed Wacker-type
tandem cyclization of the dialkenyl alcohol 9 using 7
proceeded to give bicyclic product 10 in 64% yield with
97% ee, while both the yield (72%) and the enantioselectivity
(99% ee) were improved with 8 (Scheme 4b).
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In summary, we developed a palladium-catalyzed direct
arylation of isoxazoles with aryl iodides, and it takes place at
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À
the 5-position of isoxazoles through C H bond cleavage. This
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derivatives with high levels of selectivity. Further studies on
À
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organic syntheses are now in progress.
À
Keywords: arylation · C H activation · cross-coupling ·
heterocycles · palladium
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Received: May 20, 2015
Published online: June 30, 2015
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