Palladium-catalyzed β-arylation of cyclic α,β-unsaturated o-methyl oximes with aryl iodides

Article abstract of DOI:10.1248/cpb.c19-01012

We report a Pd-catalyzed β-arylation of cyclic α,β-unsaturated O-methyl oximes with aryl iodides. This reaction shows complete regioselectivity and excellent functional group tolerance. β-Arylation of 2-cyclohexen-1-one O-methyl oxime (existing as 2:1 E/Z

Full text of DOI:10.1248/cpb.c19-01012

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Chem. Pharm. Bull. 68, 288–291 (2020)
Vol. 68, No. 3
Note
Palladium-Catalyzed β-Arylation of Cyclic α,β-Unsaturated O-Methyl
Oximes with Aryl Iodides
Yusuke Akagi,* Shiori Fukuyama, and Toshiya Komatsu
Faculty of Pharmaceutical Sciences, Teikyo Heisei University; 4–21–2 Nakano, Nakano-ku, Tokyo 164–8530, Japan.
Received November 14, 2019; accepted December 13, 2019
We report a Pd-catalyzed β-arylation of cyclic α,β-unsaturated O-methyl oximes with aryl iodides. This
reaction shows complete regioselectivity and excellent functional group tolerance. β-Arylation of 2-cyclohexen-
1-one O-methyl oxime (existing as 2:1 E/Z mixture) with certain aryl iodides such as 4-iodoanisole affords
only β-arylated (E)-O-methyl oximes.
Key words O-methyl oxime; β-arylation; palladium; aryl iodide; Fujiwara–Moritani reaction
cies such as 2-cyclohexen-1-one oxime, whose oxime group is
Introduction
Carbonyl compounds are very important in organic and not effective as a directing N-coordinating functionality, has
organometallic chemistry. Functionalization of carbonyl not been reported yet (Chart 1C). Thus, we focused on the
compounds using metal catalysts has been widely and ener- β-functionalization of cyclic α,β-unsaturated oxime species.
getically researched.1–5) Recently, numerous reports on the This paper describes the Pd-catalyzed β-arylation of cyclic
direct β-functionalization of carbonyl compounds have been α,β-unsaturated O-methyl oximes with aryl iodides.
published, using simple saturated and α,β-unsaturated car-
bonyl compounds6–15) (Chart 1A). Similarly, acyclic oxime
Results and Discussion
As a model study, we first examined the β-arylation of
species have also been investigated.16–23) Oxime species
are easily prepared from carbonyl compounds, and play an 2-cyclohexen-1-one (1) with aryl iodide according to the
important and versatile role in organic synthesis.16–30) In procedures described by Huang and Dong.10) This was fol-
metal-promoted direct β-functionalization of acyclic oxime lowed by oximation of the resulting β-arylated ketone
species, the oxime group usually behaves as a directing N- to yield the desired β-arylated oxime species (Chart 2).
coordinating functionality16–23) (Chart 1B). On the other hand, Pd-catalyzed β-arylation of 2-cyclohexen-1-one (1) with
metal-promoted direct β-functionalization of cyclic oxime spe- 4-iodoanisole afforded 3-(4-methoxyphenyl)cyclohexanone.
Subsequent oximation of the resulting ketone gave the desired
3-(4-methoxyphenyl)cyclohexanone O-methyl oxime (2) in
54% yield (2 steps). The obtained product (2) was a 1:1 mix-
ture of E- and Z-isomers.
Next, we attempted the β-arylation of O-methyl oxime (3)31)
(existing as a 2:1 E/Z mixture), prepared from 2-cyclohexen-
1-one (1), with 4-iodoanisole. This reaction proceeded to af-
ford 3-(4-methoxyphenyl)-2-cyclohexen-1-one O-methyl oxime
(4a) instead of 3-(4-methoxyphenyl)cyclohexanone O-methyl
Chart 1. β-Functionalization of Ketones and Oxime Species
Chart 2. Synthesis of O-Methyl Oximes (2) and (4a)
*To whom correspondence should be addressed. e-mail: y.akagi@thu.ac.jp
© 2020 The Pharmaceutical Society of Japan

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289
oxime (2). Conjugate addition to the α,β-unsaturated ketone 12 and 13). However, toluene afforded not only the desired
and subsequent protonation of the resulting Pd(II) enolate 3-(4-methoxyphenyl)-2-cyclohexen-1-one O-methyl oxime (4a)
typically occurs.10,14,15) However, in the O-methyl oxime, it is but also a mixture of undesired β-arylated O-methyl oximes,
thought that β-hydrogen elimination occurred (Chart 3). The 3-tolyl-2-cyclohexen-1-one O-methyl oximes (4e–g),32) result-
reaction yield was low (11% yield), but this series of reac- ing from starting O-methyl oxime (3) and toluene instead of
tions, oximation of ketone (1) followed by β-arylation of O- 4-iodoanisole. Finally, Pd catalysts were investigated (entries
methyl oxime (3), had the synthetic advantage of giving α,β- 14 and 15). As a result, replacing Pd(OAc)2 with Pd(PPh3)2Cl2
unsaturated O-methyl oxime (4a) which could not be obtained afforded the desired product (4a) in 48% yield (entry 15).
by β-arylation of the ketone (1) and subsequent oximation.
The resulting product (4a) was only the E-isomer, which was
To improve the yield of the resulting O-methyl oxime (4a), determined by a 2D nuclear Overhauser effect spectroscopy
we examined the reaction conditions (Table 1). Using Pd(OAc)2 (NOESY) NMR experiment. Along with the product (4a), only
and AgOAc, the yield was twice as much as that using the tri- the starting O-methyl oxime (3) was recovered (46% recov-
fluoroacetate counterion (entry 2). Cu(OAc)2, AgTFA, Cs2CO3 ery). O-Methyl oxime (2) was not observed. From the ratio
and NaOtBu were less effective as additives (entries 3–6). It of E- and Z-isomers of recovered starting O-methyl oxime
was thought that the less electron-rich PPh3 would be more (3) (existing as approx. 2:3 E/Z mixture), it was considered
suitable as the phosphine ligand (entries 8 and 9), but the pres- that there was no possibility of isomerization of the O-methyl
ence or absence of PPh3 was not crucial in this reaction (entry oxime under this reaction conditions.33)
9 vs. entry 10). In contrast to the phosphine ligands, AgOAc
With the optimized conditions in hand, the substrate scope
was essential (entry 11). Solvent effects were also surveyed. of the aryl iodides was investigated (Table 2). Substitutions
Only 1,4-dioxane without 1,1,1,3,3,3-hexafluoro-2-propanol on the aryl group at the ortho, meta, or para positions were
(HFIP) resulted in a decreased yield (entry 7), thus HFIP all tolerated (4a–c, 4e–h). Aryl iodides with both electron-
was important. Toluene also proved to be efficient (entries donating and electron-withdrawing groups participated to give
the corresponding β-arylated O-methyl oximes (4i–l). Under
this reaction conditions, a variety of functional groups were
tolerated, including nitriles (4i), esters (4k), and nitro groups
(4l). In all cases, E-isomers were obtained preferentially over
Z-isomers.34) The E- and Z-isomers were easily separable by
silica gel column chromatography. The exact reason for the
different ratios of resulting E- and Z-isomers based on the
Chart 3. Proposed Mechanism for β-Arylation of O-Methyl Oxime (3)
Table 2. Substrate Scope of Aryl Iodidesa)
Table 1. Optimization of Reaction Conditionsa)
Pd catalyst
(10mol%)
Ligand
(20mol%)
Additive
(2 equiv.)
Yield
(%)
Entry
1
2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dppf)Cl2
Pd(PPh3)2Cl2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
P(iPr)3
PPh3
None
PPh3
PPh3
None
None
None
AgTFA
AgOAc
Cu(OAc)2
AgTFA
Cs2CO3
NaOtBu
AgOAc
AgOAc
AgOAc
AgOAc
None
11
22
6
3
4
2
5b)
6b)
7b)
8
8
7
9
28
34
30
0
9
10
11
12c)
13c)
14
15
AgOAc
AgOAc
AgOAc
AgOAc
37
32
36
48
a) All the reactions were run with 3 (0.2mmol) and 4-iodoanisole (0.2mmol) in
1.0mL solvent for 18h. b) HFIP was not added. c) Toluene was used instead of
1,4-dioxane.
a) All the reactions were run with 3 (0.2mmol) and aryl iodide (0.2mmol) in
1.0mL solvent for 18h.

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Table 3. Substrate Scope of O-Methyl Oximesa)
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Conclusion
In summary, we have developed a novel method for the
Pd-catalyzed β-arylation of O-methyl oximes, which can
be prepared from cyclic α,β-unsaturated ketones such as
2-cyclohexen-1-one. This reaction can stand further improve-
ment with respect to the yield, but it shows complete site-
selectivity and extensive functional group tolerance. Using
certain aryl iodides, only the E-isomer was obtained from the
starting O-methyl oxime which existed as a mixture of E- and
Z-isomers. In addition, not only aryl iodides but also arenes
(e.g., p-xylene and toluene) can be used as the aryl sources.
Efforts on direct β-arylation of cyclic saturated O-methyl ox-
imes with aryl halides and arenes are ongoing.
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supplementary materials.
Conflict of Interest The authors declare no conflict of
interest.
37) 2-Cyclohepten-1-one O-methyl oxime was a 1:1 mixture of E- and
Z-isomers, see supplementary materials.
Supplementary Materials The online version of this ar-
ticle contains supplementary materials.

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