Novel synthesis of O-allylated oxime ethers based on allylic substitution with oximes

Article abstract of DOI:10.1055/s-2004-831327

The palladium or iridium-catalyzed O-allylic substitution of oximes provides a new method for direct preparation of the O-allylated oxime ethers from oximes.

Full text of DOI:10.1055/s-2004-831327

LETTER
2123
Novel Synthesis of O-Allylated Oxime Ethers Based on Allylic Substitution
with Oximes
N
ovel Synthesis of
i
O
-Ally
d
lated
O
xim
e
Ethers to Miyabe,a Akira Matsumura,a Kazumasa Yoshida,a Masashige Yamauchi,b Yoshiji Takemoto*a
a
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
b
Faculty of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295, Japan
Received 6 July 2004
tigated (Table 1). Reaction using Pd(PPh3)4 in THF gave
the linear oxime ether 4Aa as a major product, as a result
of the reaction with the oxygen atom of oxime 1A (entry
1). In our previous study on allylic substitution with hy-
droxylamines,6 the hydroxylamines having an N-electron-
withdrawing substituent acted as a reactive nucleophile in
the allylic substitution. These observations suggest that
the stability of conjugate base of oxime 1A is important
for the nucleophilic property of an oxygen atom of
oximes.7 Thus, a rational hypothesis of this reaction is that
oxime 1A would be effectively activated by methoxide
generated from carbonate 2. In regard to the solvent ef-
fect, replacement of THF by CH2Cl2 was also effective
(entry 2), while the reaction in protic solvent such as
EtOH proceeded slowly. The iridium-catalyzed regiose-
lective allylic amination and alkylation giving the
branched products were recently achieved by Takeuchi’s
group.8–10 For the synthesis of the branched products, we
next investigated allylic substitution of carbonate 2 with
1A in the presence of [IrCl(cod)]2. Takeuchi reported that
iridium complex of phosphite has shown excellent regio-
selectivities in allylic amination. In this reaction, the for-
mation of branched oxime ether 6Aa and branched nitrone
7Aa was observed without phosphites (entries 3–6). In
contrast to the palladium-catalyzed reaction, the iridium-
catalyzed reaction proceeded slowly (entry 3). Under the
Abstract: The palladium or iridium-catalyzed O-allylic substitu-
tion of oximes provides a new method for direct preparation of the
O-allylated oxime ethers from oximes.
Key words: allylic substitution, palladium, iridium, oxime, oxime
ether
Oxime ethers have recently emerged as a valuable sub-
strate for nucleophilic addition of organometallic reagents
or radical species.1,2 In general, oxime ethers are prepared
from O-alkyl hydroxylamine and corresponding alde-
hyde. The direct preparation of oxime ethers from oximes
has been commonly limited to the reaction of oximes with
alkyl halides under basic conditions.3 Herein, we now re-
port an alternative direct procedure based on transition
metal-catalyzed allylic substitution with oximes to ad-
dress the O-allylated oxime ethers.
Oximes would be an attractive synthetic reagent for tran-
sition metal-catalyzed allylic substitution, since they have
both nitrogen and oxygen atoms as a nucleophile
(Scheme 1). However, the utility of oximes in allylic sub-
stitutions has not been investigated, except for the palladi-
um-catalyzed reaction of oximes with butadiene.4,5 Our
laboratory is interested in developing the effective oxygen
nucleophiles directly connected with heteroatoms for the
synthesis of functionalized allylic compounds. We recent-
ly reported the utility of hydroxylamines having an N-
electron-withdrawing substituent as an oxygen nucleo-
phile.6 On the basis of these results,6 we newly investigat-
ed the allylic substitution with oximes as an oxygen
nucleophile.
NOH
Ph
OR
Catalyst
20 °C
+
Ph
1A
2 : R = CO2Me
3a : R = Ac
O
Ph
+
O
N
Oxime ether
OH
N
Ph
Ar
N
+
or
Ph
Ph
R
4Aa
5Aa
Nitrone
M
Ph
Scheme 1
O
O
N
N
+
+
Ph
Ph
Ph
The viability of oximes as a nucleophile in allylic substi-
tutions and the selective synthesis of oxime ether or nitro-
ne are the first focus of our efforts (Scheme 2). At first, the
reaction of allylic carbonate 2 with oxime 1A was inves-
7Aa
6Aa
O
Zn
N
Et2Zn
1A
Ph
2
SYNLETT 2004, No. 12, pp 2123–2126
0
1
.1
0
.2
0
0
4
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831327; Art ID: U19404ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

2124
H. Miyabe et al.
LETTER
Table 1 Reaction of 1A with Carbonate 2
Entry
Catalyst
Additive
Solvent
Time
(h)
Yield
(%)a
Ratio
4Aa:5Aa:6Aa:7Aa
1b
2b
3c
4c
5c
6c
Pd(PPh3)4
None
None
None
None
Et2Znd
Et3Bd
THF
0.5
0.2
72
48
2
99
99
45
82
61
60
86:6:8:0
Pd(PPh3)4
CH2Cl2
THF
85:10:5:0
6:0:45:49
4:0:47:49
1:0:99:0
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
None
THF
THF
2
2:0:98:0
a Combined yields.
b Reactions were carried out with 1A (1 equiv) with carbonate 2 (1.5 equiv) in the presence of Pd(PPh3)4 (4 mol%) at 20 °C.
c Reactions were carried out with 1A (1 equiv) with carbonate 2 (1.5 equiv) in the presence of [IrCl(cod)]2 (4 mol%).
d 0.5 Equiv of Et2Zn and 1.0 equiv of Et3B were employed.
solvent-free conditions, the products 4Aa, 6Aa, and 7Aa ucts within 7 hours (entry 2). Amines such as Et3N were
were obtained in 82% combined yield in a 4:47:49 ratio, less effective for this reaction (entry 3). We also investi-
after being stirred at 20 °C for 48 hours (entry 4). Recent- gated the iridium-catalyzed reaction of acetate 3a with
ly, a mild and efficient method for allylic etherification oxime 1A. Although the iridium-catalyzed reaction did
using zinc alkoxides was reported by Lee’s group.11 To not proceeded in the absence of base (entry 4), the selec-
test viability of zinc alkoxides generated from oximes, the tive formation of the branched oxime ether 6Aa was ob-
reaction of oxime 1A was investigated in the presence of served by using Et2Zn as a base, after being stirred for
Et2Zn as shown in Scheme 2. The selective formation of only 0.2 hour (entry 5).
the branched oxime ether 6Aa was observed by using 0.5
equivalents of Et2Zn as a base (entry 5). In the presence of
Et3B, the reaction also proceeded smoothly to give the
branched oxime ether 6Aa (entry 6). In this reaction, Et3B
would effectively activate allylic carbonate 2.12
K2CO3
O
Ar
N
Pd(PPh3)4
R1
R2
CH2Cl2
20 °C
NOH
R2
Ar
4Ab–Da
+
R1
OAc
3a–e
Et2Zn
O
Table 2 Reaction of 1A with Acetate 3a
N
1A–D
[IrCl(cod)]2
Ar
R1
R2
THF
20 °C
Entry Catalyst
Base
Time Yield Ratio
(h)
24
7
(%)a 4Aa:5Aa:6Aa:7Aa
6Ab–Da
A : R1 = Ph, R2 = H
B : R1 = Ph, R2 = Ph
C : R1 = R2 = (CH2)5
a : Ar = Ph
1b
2b
3b
4c
5c
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
[IrCl(cod)]2
[IrCl(cod)]2
None
K2CO3
Et3N
27
86
38
94:3:3:0
96:2:2:0
90:5:5:0
–
b : Ar = 4-F3C-C6H4
c : Ar = 4-MeO-C6H4
d : Ar = 1-Naph
D : R1 = CO2Me, R2 = H
24
e : Ar = 2-Naph
None
Et2Zn
0.2 N.r.d
0.2 86
K2CO3
O
Ph
NOH
N
Ph
Ph
OAc
Pd(PPh3)4
2:0:98:0
Ph
4Af (82%)
+
Ph
1A
Ph
CH2Cl2
a Combined yields.
b Reactions were carried out with 1A (1 equiv) with acetate 3a
(1.5 equiv) in CH2Cl2 in the presence of Pd(PPh3)4 (6 mol%).
c Reactions were carried out with 1A (1 equiv) with acetate 3a
(1.5 equiv) in THF in the presence of [IrCl(cod)]2 (4 mol%).
d N.r. = no reaction.
3f
Scheme 3
To learn about the effect of allylic reagents and oximes,
we next examined the palladium-catalyzed reaction of
acetates 3a–f with oximes 1A–D (Scheme 3, Table 3). As
expected, allylic esters having electron-withdrawing or
electron-donating substituents on aromatic ring also
worked well (entries 1 and 2). The reaction of bulky allyl-
ic esters having 2-naphtyl or 1-naphtyl substituents gave
good yields of oxime ethers 4Ad and 4Ae, (entries 3 and
4). Additionally, the reaction of acetate 3f with 1A pro-
ceeded smoothly to give the symmetric product 4Af, al-
lowing facile incorporation of structural variety. It should
We next investigated the reaction of allylic acetate 3a
with oxime 1A (Table 2). In contrast to carbonate 2, the
palladium-catalyzed reaction of acetate 3a proceeded
slowly to give the products 4Aa–6Aa in 27% combined
yield (entry 1). This observation suggests that acetate an-
ion, generated from acetate 3a, is less effective for activa-
tion of oxime 1A as a base. Therefore, several bases were
employed. In the presence of K2CO3, the reaction pro-
ceeded smoothly to give the good yields of allylated prod-
Synlett 2004, No. 12, 2123–2126 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of O-Allylated Oxime Ethers
2125
be noted that a bulky ketoxime 1B and aliphatic ketoxime rearrangement of intermediate A. Recently, similar rear-
1C also worked under similar reaction conditions (entries rangement of hydroxylamine derivatives was studied by
5 and 6). The glyoxylic oxime 1D has shown high reactiv- Davies’s group.3 In the presence of Et3Zn, a novel
ity due to the neighboring electron-withdrawing substitu- isomerization of the branched oxime ether 6Aa to the lin-
ent to give the product 4Da after being stirred for three ear oxime ether 4Aa was observed. The O-allylated oxime
hours (entry 7). Good chemical yields were also observed ether 6aA could be converted into O-alkylated oxime
in the iridium-catalyzed reaction of 3a–e with 1A–D in ether 8, which is an excellent substrate for diastereoselec-
the presence of Et2Zn, to give the branched product 6Ab– tive addition of organometallic nucleophiles.1 Although
Da with excellent regioselectivities (Table 4). However, the modest diastereoselectivity was observed in the ethyl
the reaction of aliphatic allylic acetates did not give good radical addition to 8, the desired product 9 was obtained
results.
in 94% yield.
Table 3 Palladium-Catalyzed Reaction of 1A–D with Acetates
3a–ea
O
HO
Ph
N
Ph
N
Ph
Yield (%)b
n-Bu
7 (51%)
toluene
–78 – 0 °C
4 h
Ph
BF3·OEt2
n-Bu
Entry
Acetate
3b
Oxime
1A
Product
4Ab
4Ac
n-BuLi
A
1
2
3
4
5
6
7
80
71
81
73
67
51
75
3c
1A
O
N
Et2Zn
4Aa (78%)
Ph
3d
1A
4Ad
4Ae
toluene
-40 °C, 20 h
Ph
6Aa
3e
1A
H2, Pd-C EtOAc, 20 °C
3a
1B
4Ba
BF3·OEt2
Et3B
3a
1C
4Ca
4Da
O
O
N
HN
Ph
Ph
Ph
Ph
3a
1D
toluene
–78 °C, 1 h
Et
9 (94%, 38%de)
a Reactions were carried out with 1A–D (1 equiv) and 3a–e (1.5
equiv) in the presence of Pd(PPh3)4 (6 mol%) and K2CO3 (1 equiv) in
CH2Cl2.
8 (74%)
Scheme 4
b Isolated yields of linear oxime ethers 4Ab–Da. The regioselectivi-
ties were not less than 95:5 measured by 1H NMR analysis of crude
products.
In conclusion, the oxygen atom of oximes acted as a
reactive nucleophile in the palladium or iridium-catalyzed
allylic substitution. These reactions provided a new
method for preparation of oxime ethers from oximes.
Table 4 Iridium-Catalyzed Reaction of 1A–D with Acetates 3a–ea
Entry
Acetate
3b
Oxime
1A
Product
6Ab
6Ac
Yield (%)b
Acknowledgment
1
2
3
4
5
6
7
82
70
87
87
76
80
51
This work was supported in part by The Japan Health Sciences
Foundation and Grant-in-Aid for Scientific Research (C) (Y.T.) and
for Young Scientists (B) (H.M.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, and for Reseach
Grants, 21st Century COE Program ‘Knowledge Information Infra-
structure for Genome Science’. We thank Mitsubishi Chemical
Corporation Fund (H.M.).
3c
1A
3d
1A
6Ad
6Ae
3e
1A
3a
1B
6Ba
3a
1C
6Ca
6Da
References
3a
1D
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Synlett 2004, No. 12, 2123–2126 © Thieme Stuttgart · New York

2126
H. Miyabe et al.
LETTER
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Synlett 2004, No. 12, 2123–2126 © Thieme Stuttgart · New York