Selective synthesis of allylated oxime ethers and nitrones based on palladium-catalyzed allylic substitution of oximes

Article abstract of DOI:10.1021/jo050632+

The viability of oximes as nucleophiles in transition-metal-catalyzed allylic substitution was examined. The oxygen atom of oxime acted as a reactive nucleophile in the reaction of a π-allyl palladium complex. In the presence of Pd(PPh₃)₄, the allylic substitution of oximes with allylic carbonate afforded the linear O-allylated oxime ethers selectively without a base. In contrast, the palladium-catalyzed reaction with allylic acetate proceeded smoothly in the presence of K₂CO₃ or Et₂Zn as a base. Selective formation of nitrones was achieved by using palladium(II) catalyst. In the presence of Pd(cod)Cl₂, the allylic substitution of oximes with allylic acetate afforded the N-allylated nitrones under solvent-free conditions, as a result of the reaction with the nitrogen atom of oximes.

Full text of DOI:10.1021/jo050632+

Selective Synthesis of Allylated Oxime Ethers and Nitrones Based
on Palladium-Catalyzed Allylic Substitution of Oximes
Hideto Miyabe, Kazumasa Yoshida, Valluru Krishna Reddy, Akira Matsumura, and
Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received March 31, 2005
The viability of oximes as nucleophiles in transition-metal-catalyzed allylic substitution was
examined. The oxygen atom of oxime acted as a reactive nucleophile in the reaction of a π-allyl
palladium complex. In the presence of Pd(PPh3)4, the allylic substitution of oximes with allylic
carbonate afforded the linear O-allylated oxime ethers selectively without a base. In contrast, the
palladium-catalyzed reaction with allylic acetate proceeded smoothly in the presence of K2CO3 or
Et2Zn as a base. Selective formation of nitrones was achieved by using palladium(II) catalyst. In
the presence of Pd(cod)Cl2, the allylic substitution of oximes with allylic acetate afforded the
N-allylated nitrones under solvent-free conditions, as a result of the reaction with the nitrogen
atom of oximes.
Introduction
Oximes are attractive synthetic reagents for allylic
substitution since they have both nitrogen and oxygen
atoms as nucleophiles (Figure 1). However, the utility of
oximes in transition-metal-catalyzed allylic substitution
has not been investigated, except for the palladium-
catalyzed reaction of oximes with butadiene.1,2 Therefore,
the viability of oximes as nucleophiles in allylic substitu-
tion is our initial focusing efforts. Particularly, our
laboratory is interested in controlling the reactivity of
the nitrogen and oxygen atoms of oxime by simply
changing the reaction conditions. As our first successful
result, we have recently reported the utility of oximes
as oxygen nucleophiles in transition-metal-catalyzed
allylic substitution to give oxime ethers selectively.3 In
FIGURE 1. Allylic substitution of oximes.
this paper, we describe the in detail study of the selective
synthesis of oxime ethers and nitrones by changing the
palladium catalysts.
Results and Discussion
Synthesis of Oxime Ethers Based on Palladium-
(0)-Catalyzed Allylic Substitution. Oxime ether has
recently emerged as a valuable substrate for nucleophilic
addition of organometallic reagents or radical species.4,5
In general, oxime ether is prepared from O-alkyl hy-
droxylamine and its corresponding aldehyde. The direct
preparation of oxime ethers from oximes has been com-
monly limited to the reaction of oxime with alkyl halide
* FAX: +81-75-753-4569.
(1) Baker, R.; Nobbs, M. S. Tetrahedron Lett. 1977, 3759.
(2) In a related study, the palladium-catalyzed deprotection of
O-allyl oxime ethers and its application were reported. See:
(a) Yamada, T.; Goto, K.; Mitsuda, Y.; Tsuji, J. Tetrahedron Lett. 1987,
28, 4557. (b) Suzuki, O.; Hashiguchi, Y.; Inoue, S.; Sato, K. Chem. Lett.
1988, 291.
(3) (a) Miyabe, H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.;
Takemoto, Y. Synlett 2004, 2123. (b) Miyabe, H.; Matsumura, A.;
Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6, 4631.
10.1021/jo050632+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/09/2005
5630
J. Org. Chem. 2005, 70, 5630-5635

Pd-Catalyzed Allylic Substitution of Oximes
SCHEME 1
FIGURE 2. Oximes as oxygen atom nucleophiles.
under basic conditions.6 We have newly investigated an
alternative direct approach based on transition-metal-
catalyzed allylic substitution of oximes to address the
O-allylated oxime ethers under basic reaction conditions
(Figure 2).
TABLE 1. Palladium(0)-Catalyzed Reaction of 1A with
Carbonate 2aa
Transition-metal-catalyzed allylic amination and alkyl-
ation have been developed as fundamentally important
cross-coupling reactions.7 In contrast, the corresponding
reaction with oxygen nucleophiles has received much less
attention due to the poor nucleophilic property of the
oxygen atom,8 although the useful allylic substitutions
with alcohols under basic conditions have been recently
reported.9 We recently reported the utility of hydroxy-
lamines having an N-electron-withdrawing substituent
as oxygen nucleophiles in allylic substitution.10 These
ratio
entry
solvent
time (h)
yield (%)b
3Aa:4Aa:5Aa
1
2
3
4
EtOH
MeCN
THF
12
1
0.5
0.2
97
98
99
99
87:7:6
84:7:9
86:6:8
85:10:5
CH2Cl2
a Reactions were carried out using 1A (1 equiv) and carbonate
2a (1.5 equiv) in the presence of Pd(PPh3)4 (4 mol %) at 20 °C.
b Combined yields.
results indicate that oxime would act as a soft nucleophile
due to enhancing the acidity by a CdN bond.
(4) For some examples of the addition of organometallic nucleophiles
to the oxime ethers, see: (a) Cooper, T. S.; Laurent, P.; Moody, C. J.;
Takle, A. K. Org. Biomol. Chem. 2004, 2, 265. (b) Moody, C. J.;
Lightfoot, A. P.; Gallagher, P. T. Synlett 1997, 659. (c) Marco, J. A.;
Carda, M.; Murga, J.; Gonza´lez, F.; Falomir, E. Tetrahedron Lett. 1997,
38, 1841. (d) Hanessian, S.; Lu, P.-P.; Sanceau, J.-Y.; Chemla, P.;
Gohda, K.; Fonne-Pfister, R.; Prade, L.; Cowan-Jacob, S. W. Angew.
Chem., Int. Ed. 1999, 38, 3160. (e) Hanessian, S.; Yang, R.-Y.
Tetrahedron Lett. 1996, 37, 5273. (f) Miyabe, H.; Yamaoka, Y.; Naito,
T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6745. (g) Dieter, R. K.; Datar,
R. Can. J. Chem. 1993, 71, 814.
(5) For some examples of radical addition to oxime ethers, see:
(a) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002, 4,
131. (b) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569.
(c) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron Lett. 1998,
39, 631. (d) Miyabe, H.; Ushiro, C.; Naito T. Chem. Commun. 2000,
1789. (e) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631.
For reviews, see: (f) Friestad, G. K. Tetrahedron 2001, 57, 5461.
(g) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140.
(6) (a) Bull, S. D.; Davies, S. G.; Domingez, S. H.; Jones, S.; Price,
A. J.; Sellers, T. G. R.; Thomas, G. R.; Smith, A. D. J. Chem. Soc.,
Perkin Trans. 1 2002, 2141. (b) Davies, S. G.; Fox, J. F.; Jones, S.;
Price, A. J.; Sanz, M. A.; Sellers, T. G. R.; Smith, A. D.; Teixeira, F. C.
J. Chem. Soc., Perkin Trans. 1 2002, 1757. (c) Koenig, S. G.; Leonard,
K. A.; Lowe, R. S.; Austin, D. J. Tetrahedron Lett. 2000, 41, 9393.
(7) For some reviews, see: (a) Frost, C. G.; Howarth, J.; Williams,
J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (b) Trost, B. M. Chem.
Rev. 1996, 96, 395. (c) Johannsen, M.; Jorgensen, K. A. Chem. Rev.
1998, 98, 1689. (d) Pfaltz, A.; Lautens, M. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, pp 833-884. (e) Trost, B.
M.; Lee, C. B. In Catalytic Asymmetric Synthesis II; Ojima, I., Ed.;
Wiley-VCH: Weinheim, Germany, 2000; pp 593-650. (f) Trost, B. M.
Chem. Pharm. Bull. 2002, 50, 1. (g) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 103, 2921.
(8) For some selected examples, see: (a) Stork, G.; Poirier, J. M. J.
Am. Chem. Soc. 1983, 105, 1073. (b) Stanton, S. A.; Felman, S. W.;
Parkhurst, C. S.; Godleski, S. A. J. Am. Chem. Soc. 1983, 105, 1964.
(c) Keinan, E.; Sahai, M.; Roth, Z. J. Org. Chem. 1985, 50, 3558.
(d) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2931. (e) Goux,
C.; Massacret, M.; Lhoste, P.; Sinou, D. Organometallics 1995, 14, 4585.
(f) Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M. J. Org. Chem. 1997,
62, 4877. (g) Trost, B. M.; Tang, W.; Schulte, J. L. Org. Lett. 2000, 2,
4013. (h) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012.
(i) Labrosse, J.-R.; Lhoste, P.; Sinou, D. J. Org. Chem. 2001, 66, 6634.
(j) Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org. Chem.
2002, 67, 1768.
As a preliminary experiment, the transition metal of
choice was Pd(PPh3)4 since it has shown an excellent
reactivity in allylic substitution of various nucleophiles.7
We employed the E-oximes, after the separation of E- and
Z-isomers. In the presence of Pd(PPh3)4 (4 mol %), a
reaction of aldoxime 1A with allylic carbonate 2a was
run at 20 °C (Scheme 1). As expected, oxime 1A exhibited
an excellent reactivity toward an electrophilic π-allyl
palladium complex. The reaction in EtOH proceeded
slowly to give linear oxime ether 3Aa, linear nitrone 4Aa,
and branched oxime ether 5Aa in 97% combined yield
in an 87:7:6 ratio, after being stirred for 12 h (Table 1,
entry 1). While in the case of the reaction in MeCN, the
formation of products 3Aa-5Aa was observed after being
stirred for only 1 h (entry 2). With regard to the solvent
effect, the replacement of EtOH by THF and CH2Cl2 also
gave good results (entries 3 and 4). In our previous
studies, the oxygen atom of hydroxylamines having an
N-electron-withdrawing substituent and the nitrogen
atoms of guanidine derivatives having two N-electron-
withdrawing substituents acted as a reactive nucleophile
in allylic substitution.10,11 On the basis of these observa-
tions, it is noted that the stability of the conjugate base
of oxime 1A would be an important criteria for the
nucleophilic property of an oxygen atom. Thus, a rational
hypothesis of this reaction is that oxime 1A would be
effectively activated by methoxide generated from the
carbonate 2a.12
We next investigated the palladium-catalyzed reaction
of oxime 1A with allylic acetate 6a (Scheme 2). The
reaction with allylic acetate 6a in THF proceeded slowly
to give the products 3Aa-5Aa in 20% combined yield,
(9) For some selected examples, see: (a) Keinan, E.; Sahai, M.; Roth,
Z. J. Org. Chem. 1985, 50, 3558. (b) Trost, B. M.; McEachern, E. J.;
Toste, F. D. J. Am. Chem. Soc. 1998, 120, 12702. (c) Trost, B. M.; Tang,
W.; Schulte, J. L. Org. Lett. 2000, 2, 4013. (d) Evans, P. A.; Leahy, D.
K. J. Am. Chem. Soc. 2002, 124, 7882. (e) Kim, H.; Lee, C. Org. Lett.
2002, 4, 4369. (f) Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem.
Soc. 2002, 124, 1590. (g) Evans, P. A.; Leahy, D. K.; Slieker, L. M.
Tetrahedron: Asymmetry 2003, 14, 3613. (h) Nakagawa, H.; Hiraba-
yashi, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 3474.
(10) (a) Miyabe, H.; Yoshida, K.; Matsumura, A.; Yamauchi, M.;
Takemoto, Y. Synlett 2003, 567. (b) Miyabe, H.; Yoshida, K.; Yamauchi,
M.; Takemoto, Y. J. Org. Chem. 2005, 70, 2148.
(11) Miyabe, H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.; Take-
moto, Y. Lett. Org. Chem. 2004, 1, 119.
(12) The equilibrium acidities of oximes have been measured in
DMSO. The pKHA values for bezaldoxime 1A and cyclohexanone oxime
1F were 20.2 and 24.3, respectively. See: Bordwell, F. G.; Ji, G.-Z.
J. Org. Chem. 1992, 57, 3019.
J. Org. Chem, Vol. 70, No. 14, 2005 5631

Miyabe et al.
SCHEME 2
SCHEME 3
TABLE 2. Palladium(0)-Catalyzed Reaction of 1A with
Acetate 6a
base
ratio
entry solvent (1 equiv) time (h) yield (%)a 3Aa:4Aa:5Aa
1b
2b
3b
4b
5b
6c
THF
none
20
6
20
20
10
24
7
24
24
24
20
82
23
21
89
27
86
38
48
74
88:6:6
90:4:6
85:7:7
88:0:2
100: 0:0
94:3:3
96:2:2
90:5:5
92:8:0
92:8:0
TABLE 3. Palladium(0)-Catalyzed Reaction of 1A-G
with Acetates 6a-i in the Presence of Et2Zna
entry reagent substrate time (h) product yield (%)b
THF
K2CO3
Et3N
DBU
Et2Zn
none
THF
THF
1
2
6b
6c
6d
6e
6f
6g
6h
6i
6a
6a
6a
6a
6a
6a
1A
1A
1A
1A
1A
1A
1A
1A
1B
1C
1D
1E
1F
1G
10
10
10
10
10
10
10
10
5
10
20
15
20
5
3Ab
3Ac
3Ad
3Ae
3Af
3Ag
3Ah
3Ai
3Ba
3Ca
3Da
3Ea
3Fa
3Ga
89
79
91
94
92
89
79
89
78
95
37
88
78
53
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7c
K2CO3
Et3N
DBU
Et2Zn
3
8c
4
9c
5
10c
6
7
a Combined yields. b Reactions were carried out using 1A (1
equiv) and acetate 6a (1.5 equiv) in THF in the presence of
Pd(PPh3)4 (8 mol %). c Reactions were carried out using 1A (1
equiv) and acetate 6a (1.5 equiv) in CH2Cl2 in the presence of
Pd(PPh3)4 (6 mol %).
8
9
10
11
12
13
14
after being stirred for 20 h in the absence of base (Table
2, entry 1). This observation suggested that an acetoxy
anion, generated from acetate 6a, is less effective for
activation of oxime 1A as a base. Thus, several bases
were employed to study the effect of bases (entries 2-5).
In the presence of K2CO3, the reaction proceeded smoothly
to give good yield of allylated products 3Aa-5Aa within
6 h (entry 2). Amines, such as Et3N and DBU, were less
effective for this reaction (entries 3 and 4). Recently, a
mild and an efficient method for allylic etherification
using zinc alkoxides was reported by Lee’s group.9e To
test the viability of zinc alkoxides generated from oximes
(Scheme 2), the reaction of oxime 1A was investigated
in the presence of Et2Zn. As expected, the selective
formation of the linear oxime ether 3Aa was observed
by using Et2Zn as a base (entry 5). With regard to the
solvent effect, the reactions also proceeded smoothly in
CH2Cl2, and the similar trend was observed (entries
6-10).
To examine the effect of allylic reagents, we next
investigated the palladium-catalyzed reactions of 1A with
allylic acetates 6b-i bearing a variety of substituents
(Scheme 3). The reactions were carried out in THF in
the presence of Et2Zn (Table 3, entries 1-8). As expected,
allylic reagents having electron-withdrawing or electron-
donating substituents on the aromatic ring also worked
well. The reaction with bulky allylic reagents having
2-naphthyl or 1-naphthyl substituents also gave good
yields of oxime ethers 3Ad and 3Ae, allowing a facile
incorporation of structural variety (entries 3 and 4). To
access the scope of the allylation, we also studied the
reaction with aliphatic allylic acetates. Although 1H NMR
analysis of the roughly purified product seemed to
indicate the formation of oxime ether, the corresponding
oxime ether was not isolated as a pure form after
a Reactions were carried out using 1A-G (1 equiv) and acetate
6a-i (1.5 equiv) in the presence of Pd(PPh3)4 (8 mol %) and Et2Zn
(1 equiv) in THF. b Isolated yields of linear oxime ethers 3Ab-
Ga.
purification. We next studied the effect of oximes (entries
9-14). The reaction of aldoxime 1B containing an
electron-withdrawing substituent proceeded smoothly to
give the product 3Ba after being stirred for only 5 h,
probably due to the extra stabilization of conjugate base
of 1B by an electron-withdrawing substituent (entry 9).
The aldoxime 1C containing an electron-donating sub-
stituent, which was assumed to be less reactive than 1A,
also produced an excellent yield of oxime ether 3Ca (entry
10). However, a modest yield was observed in the reaction
of aldoxime 1D containing a basic 2-pyridinyl group
(entry 11). It should be noted that a bulky ketoxime 1E
also worked well under similar reaction conditions to give
the product 3Ea in 88% yield (entry 12). Additionally,
aliphatic ketoxime 1F, which would be the most un-
reactive,12 also worked well to give 78% yield of the
product 3Fa, after being stirred for 20 h (entry 13). These
results supported the idea that the nucleophilic property
and reactivity of oximes were dependent on the stability
of the conjugate base of oximes. Although glyoxylic oxime
1G has shown high reactivity due to a neighboring
(13) Ryu and Komatsu reported that Et2Zn can serve as a radical
initiator in the absence of O2. See: (a) Ryu, I.; Araki, F.; Minakata,
S.; Komatsu, M. Tetrahedron Lett. 1998, 39, 6335. For studies on
Et2Zn-induced radical reactions, see: (b) Bertrand, M. P.; Feray, L.;
Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189. (c) Bertrand,
M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron
2000, 56, 3951. (d) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.;
Naito T. J. Org. Chem. 2000, 65, 176. (e) Miyabe, H.; Konishi, C.; Naito,
T. Org. Lett. 2000, 2, 1443.
5632 J. Org. Chem., Vol. 70, No. 14, 2005

Pd-Catalyzed Allylic Substitution of Oximes
TABLE 4. Palladium(0)-Catalyzed Reaction of 1A-G
a
with Acetates 6a-f in the Presence of K2CO3
entry
reagent
substrate
product
yield (%)b
1
2
3
4
5
6b
6c
6f
6a
6a
1A
1A
1A
1E
1G
3Ab
3Ac
3Af
3Ea
3Ga
80
71
72
67
75
FIGURE 3. Oximes as nitrogen atom nucleophiles.
SCHEME 4
a Reactions were carried out using 1A-G (1 equiv) and acetate
6a-f (1.5 equiv) in the presence of Pd(PPh3)4 (6 mol %) and K2CO3
(1 equiv) in CH2Cl2 for 7 h. b Isolated yields of linear oxime ethers
3Ab-Ga.
substituted hydroxylamine.16 The nitrogen lone pair on
the oxime is considered to be more nucleophilic than the
oxygen lone pairs; however, mixtures of N-alkylated and
O-alkylated products are often still obtained.20 Recently,
Kanemasa reported that the conjugate addition of oximes
took place at a nitrogen atom of oxime in the presence of
Lewis acid to afford the nitrones.21 Therefore, we con-
sidered that the selective synthesis of nitrones would be
achieved under the acidic reaction conditions (Figure 3).
Palladium(II)-catalyzed reactions are important in
organic transformations.22 Palladium(II) catalysts form
a complex with π-electrons of alkene or alkyne multiple
bonds, facilitating the nucleophilic attack to carbon-
carbon multiple bonds to give an organopalladium inter-
mediate.23 Recently, the novel palladium(II)-catalyzed
intramolecular allylic substitution was reported.24 Thus,
the palladium(II)-catalyzed intermolecular allylic sub-
stitution is a challenging problem. Next, the allylic
substitution of oxime 1A was examined by using a
palladium(II) catalyst having a Lewis acidic property,
and the selective formation of nitrones was observed.
(Scheme 4).
electron-withdrawing substituent, a modest yield was
observed in the presence of Et2Zn, as a result of competi-
tive ethyl radical addition to product 3Ga (entry 14).13
Several examples of the palladium-catalyzed reactions
using K2CO3 as a base in CH2Cl2 are shown in Table 4.
Allylic reagents 6b, 6c, and 6f having electron-withdraw-
ing or electron-donating substituents and a bulky ke-
toxime 1E worked well (entries 1-4). Compared to the
reaction of glyoxylic oxime 1G using Et2Zn, the reaction
of 1G using K2CO3 afforded a good yield of product 3Ga
because no competitive radical addition reaction occurred
(entry 5). All oxime ethers 3 and 5 were obtained as
E-isomers. According to our previous studies on oxime
ethers,5,14 E- and Z-configurations of oxime ethers were
assigned by 1H NMR spectroscopy. In general, the signals
due to the imino hydrogen of the E-oxime ethers are
shifted downfield by the influence of the alkoxy group of
the oxime ether moiety.15
Synthesis of Nitrones Based on Palladium(II)-
Catalyzed Allylic Substitution. Nitrones are well-
known to be reactive substrates for 1,3-dipolar cycload-
dition reactions, nucleophilic addition of organometallic
reagents, and so on.16,17 Nitrones have also evolved as a
useful trap for short-lived reactive radicals.18 Recently,
the synthetically useful radical reactions of nitrones have
been reported.19 For the selective synthesis of nitrones,
we have next focused our efforts toward N-allylic sub-
stitution of oximes.
At first, several palladium(II) catalysts were tested
(Table 5). In the presence of Pd(MeCN)2Cl2 (10 mol %),
treatment of oxime 1A with allylic acetate 6a at 20 °C
(20) (a) Buehler, E. J. Org. Chem. 1967, 32, 261. (b) Torsell, K. B.
G. In Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis;
Feuer, H., Ed.; Wiley-VCH: Weinheim, Germany, 1988; p 88.
(21) (a) Nakama, K.; Seki, S.; Kanemasa, S. Tetrahedron Lett. 2002,
43, 829. (b) Nakama, K.; Seki, S.; Kanemasa, S. Tetrahedron Lett. 2001,
42, 6719.
(22) For some reviews, see: (a) Tsuji, J. In Palladium Reagents and
Catalysts; John Wiley & Sons: Chichester, U.K., 1995; p 19. (b) Stahl,
S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (c) Sigman, M. S.; Schultz,
M. J. Org. Biomol. Chem. 2004, 2, 2551.
(23) For some examples of the palladium(II)-catalyzed reactions,
see: (a) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. J. Org. Chem.
2003, 68, 9496. (b) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892. (c) Timokhin, V.
I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 12996.
(d) Miyakoshi, N.; Mukai, C. Org. Lett. 2003, 5, 2335. (e) Kato, K.;
Tanaka, M.; Yamamura, S.; Yamamoto, Y.; Akita, H. Tetrahedron Lett.
2003, 44, 3089. (f) Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetra-
hedron Lett. 2002, 43, 7631. (g) Kato, K.; Yamamoto, Y.; Akita, H.
Tetrahedron Lett. 2002, 43, 4915. (h) Asao, N.; Nogami, T.; Takahashi,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (i) Okumoto, H.;
Nishihara, S.; Nakagawa, H.; Suzuki, A. Synlett 2000, 217. (j) Uozumi,
Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063. (k) Larock,
R. C.; Hightower, L. A.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem.
1996, 61, 3584. (l) Ro¨nn, M.; Ba¨ckvall, J.-E.; Andersson, P. G.
Tetrahedron Lett. 1995, 36, 7749. (m) Fukuda, Y.; Shiragami, H.;
Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816. (n) Imi, K.; Imai,
K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127. (o) Hegedus, L. S.;
McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444.
N-Alkylation of oximes has been found to be the most
useful for the synthesis of nitrones as well as the
condensation between a carbonyl compound and N-
(14) (a) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;
Naito, T. J. Org. Chem. 1998, 63, 4397. (b) Miyabe, H.; Kanehira, S.;
Kume, K.; Kandori, H.; Naito, T. Tetrahedron 1998, 54, 5883.
(c) Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito, T. J. Org.
Chem. 2003, 68, 5618.
(15) McCarty, C. G. In The Chemistry of Functional Groups: The
Chemistry of the Carbon-Nitrogen Double Bond; Patai, S., Ed.; John
Wiley & Sons Inc.: New York, 1970; pp 383-392.
(16) For reviews on the reaction of nitrones, see: (a) Osborn, H. M.
I.; Gemmell, N.; Harwood, L. M. J. Chem. Soc., Perkin Trans. 1 2002,
2419. (b) Lombardo, M.; Trombini, C. Synthesis 2000, 759. (c) Merino,
P.; Franco, S.; Merchan, F. L.; Tejero, T. Synthesis 2000, 442.
(17) For some examples of the addition of organometallic nucleo-
philes to the nitrones, see: (a) Merino, P.; Franco, S.; Merchan, F. L.;
Tejero, T. Tetrahedron: Asymmetry 1997, 8, 3489. (b) Merino, P.;
Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron 1998,
54, 12301. (c) Merino, P.; del Alamo, E. M.; Bona, M.; Franco, S.;
Merchan, F. L.; Tejero, T.; Vieceli, O. Tetrahedron Lett. 2000, 41, 9239.
(d) Merino, P.; Franco, S.; Merchan, F. L.; Revuelta, J.; Tejero, T.
Tetrahedron Lett. 2002, 43, 459.
(18) For some examples, see: (a) Becker, D. A. J. Am. Chem. Soc.
1996, 118, 905. (b) Park, Y.-T.; Kim, K.-W. J. Org. Chem. 1998, 63,
4494.
(19) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T.
Chem. Commun. 2003, 426.
(24) Allylic substitutions using palladium(II) catalyst, see:
(a) Miyazawa, M.; Hirose, Y.; Narantsetseg, M.; Yokoyama, H.;
Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 2004, 45, 2883.
(b) Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.; Yamaguchi,
S.; Hirai, Y. Org. Lett. 2000, 2, 2427.
J. Org. Chem, Vol. 70, No. 14, 2005 5633

Miyabe et al.
TABLE 5. Palladium(II)-Catalyzed Reaction of 1A with
Carbonate 2a or Acetate 6aa
SCHEME 5
entry
catalyst
reagent T (°C) time (h) % yield (ratio)b
1
2
3
4
5
6
7
8
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(PhCN)2Cl2
Pd(OCOCF3)2
Pd(cod)Cl2
6a
6a
6a
2a
6a
6a
6a
2a
20
50
90
90
90
90
90
90
24
24
6
14 (1:1.4)
37 (1:0.9)
64 (1:0.5)
37 (1:0.2)
37 (1:0.5)
18 (1:1)
6
6
6
6
65 (1:0.5)
53 (1:0.4)
Pd(cod)Cl2
6
SCHEME 6
a Reactions were carried out using 1A (1 equiv) and reagent 6a
or 2a (1.5 equiv) in the presence of the Pd(II) catalyst (10 mol %).
b Isolated yields of 4Aa. Ratio is for Z:E-isomers.
under solvent-free conditions led to the isolation of
nitrone 4Aa in 14% yield as an Z/E mixture, and the
starting material 1A was recovered in 73% yield (entry
1). The stereochemistry of nitrone 4Aa is assigned on the
basis of nOe studies.25 The reaction temperature dra-
matically influenced the reactivity. When the reaction
was carried out at 90 °C, the reaction proceeded smoothly
to give 64% yield of 4Aa (entry 3). The reaction of 1A
with allylic carbonate 2a resulted in a decrease in
the yield of product (entry 4). Although the use of
Pd(PhCN)2Cl2 and Pd(OCOCF3)2 decreased the yield of
products (entries 5 and 6), Pd(cod)Cl2 showed good
catalytic activity (entries 7 and 8). In the case of alkyl-
ation of oximes, it is known that the geometry of the
oxime affects the stereoselectivity of the subsequent
nitrone-forming reaction, with anti-aryloximes affording
nitrones, whereas syn-aryloximes favor the formation of
oxime ethers.20a It is noteworthy that the selective
formation of nitrone 4Aa was achieved in the palladium-
(II)-catalyzed allylation of anti-aryloxime (E-oxime) 1A.
Additionally, the isomerization between E-nitrone and
Z-nitrone was observed under the reaction conditions.
Initially, the palladium(II) catalyst activated the CdC
bond of 6a, and then, the nucleophilic nitrogen of oxime
1A added to the palladium(II) complex to give nitrone
4Aa.24 O-Allylated oxime ether is known to undergo
TABLE 6. Palladium(II)-Catalyzed Reaction of 1A with
Acetates 7a
entry
additive
T (°C)
time (h)
yield (%)b
1
2
3
90
90
20
6
3
24
14
34
68
ligand 9
ligand 9
a Reactions were carried out using 1A (1 equiv) and acetate 7
(1.5 equiv) in the presence of Pd(cod)Cl2 (10 mol %). b Isolated
yields of nitrone.
obtained in 57-62% yields as Z/E mixtures, although the
reaction with acetate 6d having a bulky 1-naphthyl group
decreased the yield of product 4Ad. The aliphatic acetate
6j also worked, although a moderate yield of product 4Aj
was observed, probably due to less stability of 4Aj.
Reaction scope was assessed by employing the bulky
ketoxime 1E and diphenyl allylic acetate 7 (Scheme 6).
The overall difference in steric factor was important for
the palladium(II)-catalyzed allylic substitution of oximes.
The steric congestion around the carbon-nitrogen double
bond of oxime 1E affected the reaction time and yield of
the product. The desired nitrone 4Ea was obtained only
in 23% yield, accompanying the recovered oxime 1E in
42% yield, after being stirred at 90 °C for 15 h.
The structure of allylic acetate also had a substantial
effect on the yield of product. To test the reactivity, the
racemic substrate 7 was employed. After several inves-
tigations, it was found that the ligand was necessary for
an efficient reaction of 1A with the bulky diphenyl allylic
acetate 7 (Table 6). On the other hand, the reaction
without ligand proceeded in only 14% yield (entry 1), and
the reaction proceeded effectively in the presence of box
ligand 9 (entries 2 and 3). Notably, the use of ligand 9 at
20 °C resulted in an improvement of product yield,
furnishing a 68% yield of reaction product 8 after being
stirred for 24 h (entry 3). Although several other chiral
box ligands were tested, no enantioselectivity of 8 was
a
reversible formal [2,3]-sigmatropic shift giving
N-allylated nitrone.26 Therefore, we also tested the
[2,3]-sigmatropic rearrangement of oxime ether 3Aa
under the present reaction conditions. However, the
formation of nitrone was not observed; thus, the
[2,3]-sigmatropic rearrangement is not an important
reaction pathway giving nitrone.27
Next, the reaction of 1A with various allylic acetates
6b-j was examined in the presence of Pd(cod)Cl2 (10 mol
%) (Scheme 5). All experiments were carried out under
solvent-free conditions at 90 °C for 6 h. The palladium-
(II)-catalyzed allylic substitution tolerated substitution
on aromatic ring. The nitrones 4Ab, 4Ah, and 4Ai were
(25) The irradiation of the allylic -CH2N proton of Z-nitrone 4Aa
effected an enhancement on the imino CHdN proton. See: Figure 1
in Supporting Information.
(26) (a) Grigg, R.; Markandu, J. Tetrahedron Lett. 1991, 32, 279.
(b) Eckersley, A.; Rogers, N. A. J. Tetrahedron Lett. 1974, 1661.
(c) Ranganathan, S.; Ranganathan, D.; Sidhu, R. S.; Methrotra, A. K.
Tetrahedron Lett. 1973, 3577.
(27) The 2,3-sigmatropic shift of oxime ether 3Aa was also tested
under Grigg’s reaction conditions. However, the 2,3-sigmatropic shift
was not observed, and oxime ether 3Aa was completely recovered,
probably due to the highly stabilized cinnamyl moiety on 3Aa by
resonance effect with the phenyl group.
5634 J. Org. Chem., Vol. 70, No. 14, 2005

Pd-Catalyzed Allylic Substitution of Oximes
observed. We also tested the kinetic resolution of the
racemic substrate 7 with 0.5 equiv of oxime by using
chiral ligand 9. However, the racemic nitrone 8 was
obtained with low chemical efficiency. In the reaction
with 7, only a single Z-isomer was obtained due to steric
factors.
The selective formation of N-allylated nitrones was
observed in the reaction mainly under solvent-free condi-
tions.
Acknowledgment. This work was supported in part
by a Grant-in-Aid for Young Scientists (B) (H.M.) from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan, and Foundation for Research
Grants, 21st Century COE Program “Knowledge Infor-
mation Infrastructure for Genome Science”.
Conclusions
We have clearly demonstrated that the oxygen atom
of oxime acts as a reactive nucleophile in palladium(0)-
catalyzed allylic substitution. The O-allylated oxime
ethers were selectively obtained in the reaction with
allylic carbonates or acetates. The allylic substitution
with the nitrogen atom of oxime was achieved by using
a palladium(II) catalyst having a Lewis acidic property.
Supporting Information Available: Experimental pro-
cedure and characterization data for all obtained compounds,
and 1H and 13C NMR spectra of obtained compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050632+
J. Org. Chem, Vol. 70, No. 14, 2005 5635