Palladium-catalyzed Heck-type reaction of oxime ether bearing a pendant vinyl iodide moiety

Article abstract of DOI:10.1039/c1cc15257b

A Pd(0)-catalyzed intramolecular Heck-type reaction of oxime ether has been developed, providing convenient access to heterocyclic oximes. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc15257b

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COMMUNICATION
Palladium-catalyzed Heck-type reaction of oxime ether bearing a
pendant vinyl iodide moietyw
Hui Liu, Limin Wang and Xiaofeng Tong*
Received 24th August 2011, Accepted 23rd September 2011
DOI: 10.1039/c1cc15257b
A Pd(0)-catalyzed intramolecular Heck-type reaction of oxime
ether has been developed, providing convenient access to hetero-
cyclic oximes.
Pd(0) catalyst and compound 1 bearing vinyl iodide and oxime
ether would also be capable of the CQN bond insertion.
Herein, we report the Pd(0)-catalyzed intramolecular Heck-
type reaction of oxime ether 1 with a pendant vinyl iodide
moiety to give heterocyclic oxime 2 (eqn (1)).
In the past decades, oxime derivatives have been widely
employed as starting materials in palladium catalysis, providing
great opportunities to develop numerous novel transformations.
For example, various oxime esters can readily undergo oxidative
addition to the Pd(0) center to realize amino-Heck reactions1
or amination of aromatic C–H bonds.2 Oxime ethers have
been proved to be efficient directing groups to achieve various
Pd-catalyzed ortho-functionalizations via C–H activation.3
Other Pd-catalyzed reactions of oxime, such as allylation of
oxime,4 deprotection of allyl oxime5 and conversion of oxime
into nitrile,6 have also been well developed.
We chose to initiate our investigation by using the same
system8 established by Ohno and co-workers with compound
1a as the model substrate (Table 1, entry 1). To our delight, the
Heck-type cyclisation of 1a did take place, affording azahetereo-
cyclic oxime 2a in 23% yield. When the solvent was switched
to toluene the isolated yield of 2a was increased to 35%
(Table 1, entry 2). With toluene as solvent, Ag2O (2 equiv.)
as the base was found to be more efficient, affording 2a in 46%
yield (Table 1, entry 3). Interestingly, the combination of
Ag2O (1 equiv.) and K2CO3 (1 equiv.) as base additive gave
Table 1 Optimization of reaction conditionsa
ð1Þ
Entry Cat.
Base (equiv.) Solvent Yieldb (%)
In sharp contrast, the oxime-involving Heck-type reactions
are extremely limited. Only two examples, to the best of our
knowledge, have been reported till now, which employed an
intramolecular strategy to get around the issue7 of CQN bond
insertion successfully. In 2007, Ohno et al. realized the first
Pd-catalyzed Heck-type reaction of oxime ethers with an
intramolecular aryl halide moiety.8 Later, Cheng et al.
reported a Pd-catalyzed cascade sequence from aromatic
aldoxime ether and aryl iodide.9 Those precedents elegantly
demonstrated that the CQN bond of oxime ether could
readily insert into the aryl palladium(II) intermediate. With
the combination of those pioneering results and our continuous
effort on Pd-catalyzed transformation of (Z)-vinyl iodide,10 we
envisioned that the vinyl palladium(II) analogue from the
1
2
3
4
Pd(PPh3)4
K2CO3 (2)
K2CO3 (2)
Ag2O (2)
Ag2O (1)
K2CO3 (1)
Ag2O (1)
K2CO3 (1)
Ag2O (1)
K2CO3 (1)
Ag2O (1)
K2CO3 (1)
Ag2O (1)
K2CO3 (1)
Ag2O (1)
K2CO3 (1)
Ag2O (1)
K2CO3 (1)
Dioxane 23
Toluene 35
Toluene 46
Toluene 45
c
Pd(OAc)2 + PPh3c
Pd(OAc)2 + PPh3c
Pd(OAc)2 + PPh3
5
Pd(OAc)2 + BINAPd
Pd(OAc)2 + dpped
Pd(OAc)2 + dpppd
Pd(OAc)2 + dppbd
Pd(OAc)2 + dppfd
Toluene
7
6
Toluene 38
Toluene 11
Toluene 24
Toluene 40
Toluene 51
Toluene 69
Toluene 81
7
8
9
c
10
11
12
Pd(dba)2 + PPh3
c
PdCl2(MeCN)2 + PPh3 Ag2O (1)
K2CO3 (1)
Pd(PPh3)2Cl2
Shanghai Key Laboratory of Functional Materials Chemistry, East
China University of Science and Technology, Shanghai 200237,
P. R. China. E-mail: tongxf@ecust.edu.cn; Fax: +86-21-64253881;
Tel: +86-21-64253881
w Electronic supplementary information (ESI) available: Experimental
procedures and copies of NMR spectra for all new products. See DOI:
10.1039/c1cc15257b
Ag2O (1)
K2CO3 (1)
a
Reaction conditions: 1a (0.3 mmol), palladium source (0.03 mmol),
b
solvent (4 mL), 24 hours. Isolated yield. 40 mol% PPh3 was used.
d
c
20 mol% ligand was used.
c
12206 Chem. Commun., 2011, 47, 12206–12208
This journal is The Royal Society of Chemistry 2011

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almost the same result (Table 1, entry 4). On the basis of these
results, we next examined a variety of biphosphine ligands,
such as 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP),
1,2-bis(diphenylphosphino)ethane (dppe), and 1,3-bis-(diphenyl-
phosphino)propane (dppp), 1,2-bis(diphenylphosphino)-
benzene (dppb) as well as 1,10-bis(diphenylphosphino)ferrocene
(dppf), which, however, did not show any superior performance
than PPh3 (Table 1, entries 5–9) in terms of yield. Fortunately,
the use of Pd(dba)2 and PPh3 as a catalyst system enabled a
promising result with a 51% isolated yield (Table 1, entry 10).
This result implied that the palladium source imposed a strong
effect on the reaction performance. Indeed, when
PdCl2(MeCN)2 was used, product 2a was obtained in 69%
yield (Table 1, entry 11). Finally, PdCl2(PPh3)2 without any
additional ligand was identified as the best choice, delivering
2a in 81% yield (Table 1, entry 12).
Table 3 Hydrolysis of 2
Entry
2 (R1, R2)
3
Yielda (%)
1
2
3
4
5
2a (H, Et)
2b (H, Ph)
2c (Bu, Et)
2d (Ph, Ph)
2e (Ph, Et)
3a
3b
3c
3d
3e
70
65
66
68
71
6
50
With the optimized conditions in hand, we then investigated
the scope of this transformation (Table 2). Firstly, various
substituted (Z)-vinyl halide oxime ethers with a nitrogen-
functionalized tether were tested. Both alkyl and aryl substi-
tuents at the C2-position are well tolerated (Table 2, entries 1
and 2). But the reaction of substrate 1c bearing a butyl group
at the C1-position gave lower yield possibly due to steric
hindrance (Table 2, entry 3). However, substrates with phenyl
substituted at the C1-position, such as 1d and 1e, show good
reactivity, delivering products with good yield (Table 2, entries
4 and 5). Interestingly, the reaction of substrate 1f gave
five-membered cycle 2f in 50% yield (Table 2, entry 6). This
protocol was also suitable for synthesis of a 7-membered cyclic
oxime. Indeed, compound 2g could be readily obtained albeit
in 37% yield (Table 2, entry 7). On the contrary, substrates
a
Isolated yield.
with oxygen-functionalized tether, such as 1h and 1i, show
much less reactivity (Table 2, entries 8 and 9), implying that
nitrogen in tether might impose a positive effect on the
reaction performance, probably via coordination to stabilize
the vinyl palladium intermediate. Additionally, a steric effect
of the bulky tosylamide group might be important to promote
the cyclization by approximating the reaction sites.
To further demonstrate the value of this Heck-type reaction
of oxime 1, the formed aza-cyclic oxime was converted into
1,2-dihydropyridin-3(6H)-one. Indeed, this transformation
can be readily achieved via hydrolysis with the use of aqueous
HCl and the results are summarized in Table 3. Moreover,
3-hydroxypyridine derivative 4 was obtained when 3e was
treated with DBU in THF (eqn (2)). 3-Hydroxypyridines are
important structural units found in numerous bioactive
compounds.11 Thus, the Heck-type reaction of oxime 1 provides
a complemental route to poly-substituted 3-hydroxypyridine
from readily available starting materials.12
Table 2 The results of Heck-type cyclisation of oxime ethersa
Entry
1 (R1, R2, X)
2
Yieldb (%)
ð2Þ
1
2
3
4
5
1a (H, Et, NTs)
1b (H, Ph, NTs)
1c (Bu, Et, NTs)
1d (Ph, Ph, NTs)
1e (Ph, Et, NTs)
2a
2b
2c
2d
2e
81
68
43
70
86
In summary, we have developed a new Heck-type reaction
of oxime 1 bearing a vinyl iodide moiety, which allows rapid
construction of heterocyclic oxmine. This finding demon-
strated that the vinylpalladium(II) intermediate is able to
undergo insertion of CQN bond, which complements the
work related to an arylpalladium(II) analogue and broadens
the Heck-type reaction of oxime. Furthermore, this transfor-
mation was confirmed to be effective for the synthesis of the
3-hydroxypyridine derivative. Further study on the total
synthesis of vitamin B6 by using this reaction as a key step
is ongoing and will be reported in due course.
6
7
50
37
8
9
1h (Ph, Et, O)
1i (H, Ph, O)
2h
2i
34
25
a
Conditions: substrate 1 (0.30 mmol), Pd(PPh3)2Cl2 (0.03 mmol),
Ag2O (0.3 mmol), and K2CO3 (0.30 mmol) in toluene (4 mL) under
The financial support from NSFC (No. 21002025), the
Fundamental Research Funds for the Central Universities,
Shanghai Rising-Star Program (11QA1401700), and
b
N2, 120 1C, 24 h. Isolated yield.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12206–12208 12207

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Specialized Research Fund for the Doctoral Program of
Higher Education (20100074120014) is highly appreciated.
6 H. S. Kim, S. H. Kim and J. N. Kim, Tetrahedron Lett., 2009,
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7 The insertion of the CQN bond into the Pd–C bond is generally
viewed as an unfavorable step partly due to the strong s coordination
between their nitrogen and palladium center: (a) H. Nakamura,
K. Nakamura and Y. Yamamoto, J. Am. Chem. Soc., 1998,
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c
12208 Chem. Commun., 2011, 47, 12206–12208
This journal is The Royal Society of Chemistry 2011