Thioether ligand-enabled cationic palladium (II)-catalyzed electrophilic C-H arylation of α,β-unsaturated oxime ethers

Article abstract of DOI:10.1021/acs.joc.0c01570

The use of the cationic palladium(II) catalyst realized electrophilic C-H arylation of α,β-unsaturated O-SEM oximes with arylboronic acids. This Pd-catalyzed electrophilic C-H arylation is facilitated by employing alkyl aryl thioether ligands, and optimization of the ligand structure greatly improves the yield. The resulting α,β-unsaturated oximes would provide access to multisubstituted heterocyclic compounds.

Full text of DOI:10.1021/acs.joc.0c01570

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Article
Thioether Ligand-Enabled Cationic Palladium(#)-Catalyzed
Electrophilic C-H Arylation of #,#-Unsaturated Oxime Ethers
Takahiro Yamada, Yoshimitsu Hashimoto, Kosaku Tanaka, #, Nobuyoshi Morita, and Osamu Tamura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01570 • Publication Date (Web): 26 Aug 2020
Downloaded from pubs.acs.org on August 26, 2020
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Page 1 of 16
The Journal of Organic Chemistry
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ꢀ
Thioether Ligand-Enabled Cationic Palladium( )-Catalyzed Elec-
trophilic C-H Arylation of α,β-Unsaturated Oxime Ethers
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Takahiro Yamada, Yoshimitsu Hashimoto, Kosaku Tanaka, III, Nobuyoshi Morita, and Osamu Tamura*
Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
Supporting Information Placeholder
B(OH)2
R
OSEM
OSEM
OSEM
H
N
N
H H
Pd(TFA)2, L
DMBQ, [Ag]
H
N
+
H
R
R
Me
・R = alkyl, EDG, EWG
・23 examples
・up to 97% yield
L =
S
O
O
Cl
Me
DMBQ
Thioether Ligand
ABSTRACT: We show that cationic palladium(ꢀ) catalyst realized electrophilic C-H arylation of α,β-unsaturated O-SEM oximes
with arylboronic acids. This Pd-catalyed electrophilic C-H aryation is facilitated by the use of alkyl aryl thioether ligands, and opti-
mization of the ligand structure greatly improves the yield. The resulting α,β-unsaturated oximes would provide access to multi-
substituted heterocyclic compounds.
Scheme 1. Conceptional Design of This Work; Pd-catalyzed
Electrophilic C-H Arylation of α,β-Unsaturated Oximes.
INTRODUCTION
α,β-Unsaturated oximes, easily prepared by the reaction of hy-
droxyl amine derivatives and α,β-unsaturated carbonyl com-
pounds, have many applications in organic synthesis and related
fields, and studies on the properties and reactivity of oxime de-
rivatives have developed rapidly in the last few decades.1 In par-
ticular, oxime is an excellent directing group, and various tran-
sition-metal-catalyzed transformations have been reported,2 es-
pecially in the field of oxime-directed C-H activation, which
can provide access to heterocyclic compounds.2a Examples in-
clude Rh-catalyzed pyridine synthesis,3 Rh-catalyzed 2,3-dihy-
dropyridine synthesis4 and Rh- or Co-catalyzed furan and pyr-
role synthesis.5 Another notable property of oxime is its car-
bonyl umpolung (polarity reversal) reactivity.6 Because of the
electron-donating effect of the oxygen atom on the imine func-
tionality, the HOMO level of the α,β-unsaturated oxime be-
comes higher, and hence its conjugated system shows a more
electron-rich and more nucleophilic character as compared with
the corresponding α,β-unsaturated carbonyl compounds.6b
OR
OR
H
N
H
N
Pd(TFA)2
Ar B(OH)2
+
H
Ar
electrophilic
C-H activation
Suzuki coupling
Pd(TFA)2
Ar B(OH)2
OR
OR
N
O+
N
R
N
L
TFA
Pd
L
Pd
L
L
+
TFA
TFA
Pd
L
-H
L
A
B
β-palladated complex
cationic intermediate
followed by Suzuki-type coupling reaction with arylboronic
acid to give β-arylated product. To our knowledge, there are no
examples of Pd-catalyzed electrophilic C-H functionalization of
α,β-unsaturated oximes. Herein, we report the Pd-catalyzed
electrophilic C-H arylation of α,β-unsaturated oxime with aryl
boronic acid, featuring the use of alkyl aryl thioether ligands.
This method would furnish β-selective C(alkenyl)-H arylation
of α,β-unsaturated oximes.
Based upon its unique electronic properties, we assumed that
α,β-unsaturated oximes react with cationic palladium species,
such as Pd(TFA)2, by electrophilic β-palladation to generate
resonance-stabilized cationic intermediate A (Scheme 1).6c-e As
a consequence, we envisioned that cationic palladated complex
A should release β-proton to give β-palladated complex B,
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Page 2 of 16
Next, we tested mono-N-protected amino acid (MPAA) ligands
RESULTS AND DISCUSSION
1
L1-L3, known as useful ligands for C-H activation of tethered
arenes (Table 1).8 Although none of them did not improve the
yield, methionine derivative L3 changed the ratio of the prod-
ucts (3aa and 4aa). This finding suggests that the sulfur atom
of L3 could influence the reaction mode via coordination to the
Pd catalyst. To further examine the effect of sulfur-containing
ligands, we prepared acetyl-protected aminoethyl thioether L4,
recently reported by Yu and co-workers.9 Fortunately, L4 im-
proved the reactivity and afforded the desired products in 58%
yield. Surprisingly, the reaction employing ligand L5 lacking
an acetylamino group increased the yield of products to 71%,
including 5aa, which was probably produced by further aryla-
tion of 4aa.10 Thus, the use of L5 significantly improved the
reactivity. Recently, Carrow and co-workers have reported that
thioether ligands affect the kinetics of Pd-catalyzed undirected
C-H alkenylation of heteroarenes.11 Thus, thioether ligands may
dissociate aggregated states of Pd, leading to the generation of
highly electrophilic reactive species, i.e., the monomeric thi-
oether-Pd complex. To investigate the effect of ligand structure
on the reaction efficiency, we carried out systematic ligand
modification of L5. Thus, L6, with reduced steric hindrance
around the sulfur atom, gave a poor product yield. Ligands with
bulkier side chains, n-butyl (L7) and cyclohexyl (L8) groups,
were also examined. Notably, cyclohexyl phenyl thioether L8
significantly increased the reactivity and afforded 81% yield.
On the other hand, replacement of the cyclohexyl group of L8
with a phenyl group (L9) reduced the yield, suggesting the im-
portance of the alkyl aryl thioether structure. Next, we focused
on modification of the phenyl group (L10-L13). Among them,
L12 gave the best result, increasing the yield to 84%. Replacing
the thioether with sulfoxide (L14) or ether (L15) led to loss of
reactivity.
Initially, we examined the reaction of α,β-unsaturated O-n-bu-
tyl oxime 1a with 4-methoxyphenylboronic acid (2a) as a cou-
pling partner by employing 10 mol % of Pd(OAc)2 as a catalyst,
Ag2CO3 as an oxidant, Na2HPO4·12H2O as a base and AgTFA
as an additive in dioxane at 90 ꢁ for 2 h. To our delight, the
desired arylated products 3aa and its double-bond isomer 4aa
were obtained as a 1.1:1 mixture in 21% yield. Encouraged this
result, we conducted an extensive survey of Pd sources, oxi-
dants, silver additives, and solvents. We found that the yield de-
creased to less than 5% in the absence of AgTFA, which sug-
gests that in situ-generated cationic palladium trifluoroacetate
is the active species for this C-H arylation. Next, we focused on
a report that the addition of 1,4-benzoquinone (BQ) promotes
the reductive elimination process in transition-metal-catalyzed
couplings with aryl boronic acid,7 and we examined the effect
of adding BQ derivatives. However, the addition of BQ was not
so effective and the product yield increased only to 25%, ac-
companied with troublesome substrate decomposition. Since
2,6-dimethyl-1,4-benzoquinone did not act as an oxidant, the
decomposition of the substrate was suppressed, and the product
yield improved to 33% (Table 1).
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Table 1. Ligand Optimizationa
B(OH)2
MeO
2a
Pd(OAc)2 (10 mol%)
ligand, DMBQ
AgTFA, Ag2CO3
O
O
N
N
O
N
+
Na2HPO4·12H2O
dioxane, 90 ℃, 2 h
MeO
R
MeO
1a
3aa
4aa : R = H
5aa : R = 4-methoxyphenyl
ligand
Table 2. Oxime Ether Optimizationa
S
Ac
N
H
OH
Ac
OH
Ac
OH
N
H
none
B(OH)2
N
H
O
O
O
L1
L2
46%
L3
MeO
OR
2a
33%
3aa:4aa = 57:43
32%
3aa:4aa = 55:45
43%
3aa:4aa= 38:62
OR
N
Pd(OAc)2 (10 mol%)
N
3aa:4aa = 55:45
L12 (30 mol%), DMBQ
AgTFA, Ag2CO3
S
S
S
S
NHAc
Na2HPO4·12H2O
dioxane, 90 ℃, 2 h
MeO
MeO
OMe
1b-h
3ba-ha
L4
L5
L6
L7
58%
3aa:4aa= 55:45
71%
3aa:4aa:5aa = 33:43:23 3aa:4aa:5aa = 36:50:14 3aa:4aa:5aa = 38:50:12
33%
73%
OR
S
S
S
S
Si
O
MeO
O
Si
O
L8
L9
45%
L10
L11
56%
O
O
81%
66%
O
O
O
O
O
3aa:4aa:5aa = 38:42:19 3aa:4aa:5aa = 45:45:9 3aa:4aa:5aa = 37:44:19 3aa:4aa:5aa = 30:42:27
O
O
O
S
3ba, 70% 3ca, 79% 3da, 48% 3ea, 46% 3fa, 97% 3ga, 56% 3ha, 14%
S
S
O
(92%)b
Cl
F3C
Cl
[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2a (3.0
equiv.), Pd(OAc)2 (10 mol%), L12 (30 mol%), Ag2CO3 (2.0
equiv.), AgTFA (40 mol%), Na2HPO4·12H2O (1.5 equiv.), 2,6-
dimethyl-1,4-benzoquinone (30 mol%), dioxane (2.0 mL),
90 ꢁ, 2 h. Isolated yield. [b] Reaction conditions: 1 (0.1 mmol,
1.0 equiv.), 2a (3.0 equiv.), Pd(TFA)2 (10 mol%), L12 (30
mol%), Ag2CO3 (2.0 equiv.), Na2HPO4·12H2O (1.5 equiv.), 2,6-
dimethyl-1,4-benzoquinone (30 mol%), dioxane (2.0 mL),
90 ꢁ, 2 h. Isolated yield.
L12
84%
L13
70%
L14
17%
L15
19%
3aa:4aa = 53:47
3aa:4aa:5aa = 32:48:19 3aa:4aa:5aa = 36:46:18
3aa:4aa = 48:52
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (3.0
equiv.), Pd(OAc)2 (10 mol%), ligand (30 mol%), Ag2CO3 (2.0
equiv.), AgTFA (40 mol%), Na2HPO4·12H2O (1.5 equiv.), 2,6-
dimethyl-1,4-benzoquinone (1.0 equiv.), dioxane (2.0 mL),
90 ꢁ, 2 h. Isolated yield.
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The Journal of Organic Chemistry
With the electrophilic nature of the palladium species in mind, Having identified an effective catalyst system and reaction con-
1
2
3
4
5
6
7
8
we turned our attention to modifying the oxime ether moiety.
Since α,β-unsaturated oximes show reversed polarity compared
to the carbonyl group, we thought it might be possible to change
the electronic state of the conjugated system by tuning the struc-
ture of the oxime ether moiety. Using oxime derivative 1 as a
pilot substrate, the structure-reactivity relationship of the oxime
ether moiety was examined (Table 2). With O-methyl 1b or O-
n-butyl oxime 1c, the arylated product 3ba or 3ca was obtained
in 70% or 79% yield, respectively. O-Methoxymethyl oxime 1d
or O-methyl trimethylsilyl oxime 1e, with a hetero atom-con-
taining ether moiety did not improve the reactivity. However,
with O-SEM oxime 1f, the yield increased dramatically to 97%.
On the other hand, the O-MEM oxime 1g, in which the TMS
group in the SEM group is replaced by the MeO group, was
ineffective, suggesting that the structure of the SEM group is
essential for high reactivity. This increased reactivity of 1f may
be due to the more electron-rich and more nucleophilic charac-
ter of the conjugated system arising from the stronger electron-
donating effect of the SEM oxy group in the imino functionality.
As expected, O-pivaloyl derivative 1h was significantly less re-
active, presumably due to its electron-withdrawing character.
ditions, we next explored the substrate scope, using a range of
α,β-unsaturated oximes (Table 3). Oxime 1i lacking the R2 sub-
stituent gave the arylation products in good yield (3ia, 4ia, 3fa).
Formation of di-4-methoxyphenyl-substituted product 3fa
shows that aryl-substituted oximes are well tolerated. In the
case of phenyl-substituted oxime 1k, the arylated products 3ka
and 4ka were obtained in 96% yield as a 49:51 mixture. This
transformation of R1-substituted oxime 1j proceeded smoothly
to give desired product 3ja in excellent yield. Oximes 1l and
1m with linear alkyl substituents on R2 were acceptable. Thus,
arylation of n-butyl-substituted substrate 1l gave the desired
products (3la and 4la) in 53% yield as a 91:9 mixture. Interest-
ingly, reaction of substrate 1m containing benzyl ether at the β-
position proceeded smoothly and afforded the desired products
(3ma and 4ma) in 87% yield. The more sterically hindered α-
isopropyl-substituted oxime 1n gave 25% yield of Z-isomer
(3na), presumably due to steric repulsion. The substrate cy-
clized at R1 and R2 1o was tolerated, and the desired product
3oa was obtained in 39% yield as a single isomer.
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Table 4. α-Phenyl Substituted Oxime Ether Scopea
Ultimately, we discovered that the use of 10 mol % palladium
trifluoroacetate as a catalyst, instead of the Pd(OAc)2 / AgTFA
system, along with 30 mol % DMBQ also worked well to afford
the arylated product. Interestingly, in the absence of DMBQ,
unexpected byproducts12,13 presumably generated by the
decomposition of L12 were isolated, indicating that DMBQ as
an additive not only promotes the reductive elimination process
in the Pd-catalyzed arylation, but also suppresses the
decomposition of the thioether ligand L12.
OSEM
OSEM
Pd(TFA)2 (10 mol%)
L12 (30 mol%)
B(OH)2 DMBQ, Ag2CO3
N
N
+
MeO
Na2HPO4·12H2O
dioxane, 90 ℃, 1 h
MeO
R
R
1p-1t
2a
3pa-ta
OSEM
OSEM
N
OSEM
N
N
MeO
MeO
MeO
Table 3. α,β-Unsaturated Oxime Ether Scopea
OMe
F
Cl
Pd(TFA)2 (10 mol%)
L12 (30 mol%)
DMBQ, Ag2CO3
3pa, 90%
(E:Z = 1.3:1)
3qa, 85%
(E:Z = 1.6:1)
3ra, 88%
(E:Z = 2.0:1)
OSEM
OSEM
OSEM
R1
N
N
N
B(OH)2
+
+
R1
R1
OSEM
Na2HPO4·12H2O
dioxane, 90 ℃, 1 h
MeO
OSEM
N
R2
R2
3ia-oa
R2
4ia-ma
N
MeO
MeO
1i-o
2a
MeO
MeO
OSEM
OSEM
OSEM
N
N
N
F3C
R
+
Br
MeO
3sa, 72%
(E:Z = 2.1:1)
3ta, 72%
(E:Z = 1.9:1)
MeO
MeO
R
OMe
R = CH3: 3fa, 92%
R = CH2CH2C6H4(p-OMe): 3ja, 96%
3ia
4ia: R = H
3fa: R = 4-methoxyphenyl
88%
[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2a (3.0
equiv.), Pd(TFA)2 (10 mol%), L12 (30 mol%), Ag2CO3 (2.0
equiv.), Na2HPO4·12H2O (1.5 equiv.), 2,6-dimethyl-1,4-benzo-
quinone (30 mol%), dioxane (2.0 mL), 90 ꢁ, 1 h. Isolated yield.
(3ia:4ia:3fa = 30:36:33)
OMe
OSEM
OSEM
OSEM
N
N
N
OSEM
N
+
+
MeO
MeO
MeO
3ka
4ka
3la
4la
This reaction also worked well with α-phenyl-substituted ox-
imes (Table 4), giving the arylated products in excellent yields
as mixtures of E/Z isomers. Varying the substituents on the phe-
nyl group of 1 showed that a wide range of substituents such as
an electron-donating group (1p), halogens (1q-1s), and an elec-
tron-withdrawing group (1t) were well tolerated and afforded
the desired products in good yield.
96%
(3ka:4ka = 49:51)
53%
(3la:4la = 91:9)
OMe
OSEM
N
OSEM
N
OSEM
N
+
OSEM
N
MeO
MeO
O
O
MeO
Ph
Ph
3ma
4ma
87%
3na, 25%
3oa, 39%
(3ma:4ma = 93:7)
Next, we explored the scope of boronic acids (Table 5). The
coupling of 1f with electron-donating or electron-neutral bo-
ronic acids gave the desired products in good yield (3fa-3fe and
4fb-4fe), and the products were obtained as a mixture of two
isomers. Furthermore, this reaction worked well with a variety
of electron-withdrawing arylboronic acids (2f-2h), affording
moderate to good yields.
[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2a (3.0
equiv.), Pd(TFA)2 (10 mol%), L12 (30 mol%), Ag2CO3 (2.0
equiv.), Na2HPO4·12H2O (1.5 equiv.), 2,6-dimethyl-1,4-benzo-
quinone (30 mol%), dioxane (2.0 mL), 90 ꢁ, 1 h. Isolated yield.
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Table 5. Boronic Acid Scopea
1
R
2
3
4
5
6
7
8
9
OSEM
OSEM
N
N
Pd(TFA)2 (10 mol%)
L12 (30 mol%)
DMBQ, Ag2CO3
OSEM
N
+
+
B(OH)2
R
Na2HPO4·12H2O
dioxane, 90 ℃, 1 h
R
MeO
OMe
MeO
R
1f
2a-k
3fa-fk
4fb-fk
OMe
MeO
OMe
OSEM
OSEM
OSEM
N
N
N
R = Me: 92% (3fc:4fc = 50:50)
10
11
12
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18
19
20
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22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OSEM
OSEM
MeO
MeO
N
N
R = H: 78% (3fd:4fd = 45:55)
R = Ph: 74% (3fe:4fe = 42:58)
R = Cl: 87% (3ff:4ff = 42:58)
R = Br: 45% (3fg:4fg = 45:55)
+
+
MeO
R
OMe
OMe
OMe
MeO
OMe
MeO
R = CF3: 63% (3fh:4fh = 33:67)
3fa
92%
3fb
4fb
3fc-3fh
4fc-4fh
79%
(3fb:4fb = 45:55)
Cl
F
OSEM
OSEM
Cl
OSEM
N
OSEM
N
Cl
N
N
N
N
OSEM
OSEM
N
N
+
+
+
Cl
MeO
Cl
N
F
N
OMe
OMe
OMe
Cl
MeO
24%
(3fj:4fj = 26:74)
MeO
51%
(3fk:4fk = 25:75)
4fj
4fk
3fi
4fi
3fj
3fk
42%
(3fi:4fi = 83:17)
[a] Reaction conditions: 1f (0.1 mmol, 1.0 equiv.), 2 (3.0 equiv.), Pd(TFA)2 (10 mol%), L12 (30 mol%), Ag2CO3 (2.0 equiv.),
Na2HPO4·12H2O (1.5 equiv.), 2,6-dimethyl-1,4-benzoquinone (30 mol%), dioxane (2.0 mL), 90 ꢁ, 1 h. Isolated yield.
Thus, 4-chlorophenyl and 4-trifluoromethylphenyl boronic ac-
ids 2f and 2h coupled well with oxime 1f to give the corre-
sponding arylated products in 87% (3ff and 4ff) and 62% (3fh
and 4fh) yield, respectively. Even labile 4-bromophenyl bo-
ronic acid 2g gave the arylated products 3fg and 4fg in moderate
yield. Pleasingly, sterically hindered 2,6-dichlorophenyl bo-
ronic acid 2i was also acceptable, although the yield was only
moderate (3fi and 4fi). In general, heteroaryl compounds having
strong coordination ability often deactivate Pd catalysts. Even
so, less Lewis-basic pyridines, such as 2-chloro- and 2-fluoro-
pyridines afforded the heteroarylated products (3fj, 4fj and 3fk,
4fk), suggesting that substrates with weak coordination ability
could be used in this arylation reaction.
Scheme 2. Mechanistic Experiment
MeO
N
MeO
N
Pd(TFA)2 (10 mol%)
B(OH)2
L12 (30 mol%)
DMBQ, Ag2CO3
+
(1)
OMe
MeO
MeO
Na2HPO4·12H2O
dioxane, 90 ℃, 1 h
(3.0 eq.)
OMe
1u
2a
3ua
67%
B(OH)2
(3.0 eq.)
2d
OSEM
CD3
OSEM
CD3
D
N
Pd(TFA)2 (10 mol%)
L12 (30 mol%)
DMBQ, Ag2CO3
D
N
OSEM
N
D
D
D
CD3
+
(2)
Na2HPO4·12H2O
dioxane, 90 ℃, 1 h
OMe
OMe
MeO
67%
1f-d5
Some additional experiments were conducted to gain insight
into the reaction mechanism (Scheme 2). Initially, we assumed
that the reaction was an oxime-directed C-H activation that was
triggered by coordination of the Pd catalyst to the nitrogen atom
of the α,β-unsaturated oxime. However, even the Z-isomer of
O-methyl oxime 1u afforded the arylated product 3ua in 67%
yield, comparable to the yield of the E-isomer (70%), with re-
tention of Z-geometry of the oxime moiety (Scheme 2, eq. 1 vs
Table 2, 3ba). This result indicates that coordination of the Pd
catalyst to the oxime nitrogen is not essential for this C-H ary-
lation. An isotope-labeling experiment provided valuable in-
sight into the reaction mechanism (Scheme 2, eq. 2). When the
reaction was performed with β-deuterated oxime (1f-d5), the
product isomer ratio of 3fd-d4 and 4fd-d5 was 12:88, which was
drastically different from that obtained from unlabeled oxime
1f (3fd:4fd = 45:55, Table 5). This result clearly indicates that
this reaction involves a deprotonation event at the oxime β-po-
sition, and that the ease of C-H bond cleavage of the β-proton
is largely related to the product distribution of the two isomers.
3fd-d4
4fd-d5
88
:
12
Based on these observations, we propose the following catalytic
cycle involving the cationic intermediate A stabilized by the
electron-donating effect of the imine functionality (Scheme
3).6,14 Thus, the oxime 1 reacts with cationic palladium species
to generate cationic intermediate A, which kinetically releases
proton Ha or Hb to give vinyl palladium B or allyl palladium (or
π-allyl complex) C, respectively.10 Complexes B and C undergo
Suzuki-type coupling reaction with arylboronic acid to yield
products 3 and 4, and then oxidation of the Pd(0) species with
Ag oxidant regenerates the active catalyst. This step should be
rapid, since brominated products 3sa (Table 4), 3fg and 4fg (Ta-
ble 5) were obtained. The result of the deuterated labeling ex-
periment (Scheme 2) is consistent with this electrophilic meta-
lation followed by deprotonation process.
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The Journal of Organic Chemistry
(tert-butyl) phenyl)thio)ethan-1-amine (100 mg, 0.48 mmol, 1.0
Scheme 3. Proposed Reaction Mechanism
1
eq.) in CH2Cl2 (2.5 mL) and the reaction mixture was stirred at
room temperature for overnight. After completion, the reaction
mixture was concentrated in vacuo, and the resulting mixture
was purified by flash column chromatography on silica gel
(hexane : AcOEt = 3 : 1) to afford the title compound (61 mg,
50% yield) as white solid. mp 57-58 ℃; IR (KBr) 3465, 2360,
1651, 1557, 1275, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.33
(4H, s), 5.88 (1H, br), 3.45 (2H, m), 3.03 (2H, t, J = 6.0 Hz),
1.93 (3H, s), 1.30 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
170.1, 150.1, 131.2, 130.2, 126.2, 38.7, 34.5, 34.1, 31.2, 23.2;
HRMS (EI-quadrupole) m/z: [M]+ Calcd for C14H21NOS
251.1344; Found 251.1335.
2
3
4
OSEM
OSEM
N
N
L
Pd
L
TFA
Ar B(OH)2
Ar
OSEM
Ha
+
N
OSEM
R
R
- Ha
- Hb
L
Pd
L
N
TFA
TFA
B
3
Pd(TFA)2
Ag2CO
5
6
Pd(0)
3 Pd(Ⅱ)
Hb
- TFA
R
R
OSEM
1
OSEM
N
N
L
Pd
L
O+
SEM
TFA
7
8
9
N
Ar
L
Pd
L
Ar B(OH)2
R
R
C
4
R
A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In accordance with the above proposal, treatment of 1i with
acrylate 6 under the same reaction conditions afforded azatriene
7 in 12% yield, probably through Heck-type reaction via β-pal-
ladated complex B (eq. 3). Further mechanistic studies will be
required in order to confirm the mechanism of this counterintu-
itive C-H arylation reaction.
Procedure for the Synthesis of L5. 4-(tert-butyl)phenyl
ethyl sulfane (L5). To a solution of 4-tert-butyl benzenethiol
(341 mg, 2.1 mmol, 1.0 eq.) in MeOH (6 mL) were added KOH
(118 mg, 1.0 eq.) and iodoethane (0.17 mL, 1,0 eq.). After the
resulting mixture was stirred at room temperature for 12 h, the
reaction was quenched with water. The aqueous layer was ex-
tracted with AcOEt and the combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated
in vacuo to afford the title compound (400 mg, 98% yield) as
colorless oil. IR (KBr) 2963, 2868, 1497, 1458, 1362, 1267,
1121, 1013, 821, 749, 547 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.31 (2H, d, J = 9.0 Hz), 7.27 (2H, d, J = 9.0 Hz), 2.91 (2H, q,
J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.30 (9H, s); 13C{1H} NMR
(75 MHz, CDCl3) δ 149.1, 133.0, 129.3, 125.8, 34.4, 31.3, 28.1,
14.5 ; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C12H18S
194.1129; Found 194.1129.
Pd(OAc)2 (10 mol%)
L12 (30 mol%)
AgTFA, Ag2CO3
DMBQ
OSEM
OSEM
N
N
OBn
BnO
+
(3)
(1.5 eq.)
O
dioxane
O
90℃, 24 h
1i
6
7
12%
CONCLUSION
In conclusion, we have developed an efficient Pd-catalyzed
electrophilic C-H arylation of α,β-unsaturated O-SEM oximes.
Substantial effects of alkyl aryl thioether ligands and 2,6-dime-
thyl-1,4-benzoquinone were observed, and systematic ligand
modification led to L12 as the optimal structure. Since the prod-
ucts 3 and 4 still have α,β-unsaturated oxime moieties, they can
be converted into various heterocycles.15 Therefore this method
provides easy access to multi-substituted heterocyclic com-
pounds from α,β-unsaturated oximes. Current investigation is
directed to detailed mechanistic insights into the generation of
β-palladated cationic intermediate stabilized by the electron-do-
nating effect of the oxime ether moiety.
Procedure for the Synthesis of L6. 6-(tert-butyl)thiochrom-
ane (L6). To a solution of 3-((4-(tert-butyl)phenyl)thio)propa-
noic acid (100 mg, 0.42 mmol, 1.0 eq.) in CH2Cl2 (2 mL) were
added oxalyl chloride (2.0 eq.) and catalytic DMF. After the re-
sulting mixture was stirred at room temperature for 30 min, the
reaction mixture was concentrated in vacuo. The residue was
dissolved in HFIP and stirred at room temperature for overnight.
After completion, the solvent was removed in vacuo and the re-
sulting residue was purified by flash column chromatography
on silica gel (hexane : AcOEt = 5 : 1) to afford 6-(tert-butyl)thi-
1
EXPERIMENTAL SECTION
ochroman-4-one (90 mg, 98% yield) as white solid. H NMR
(300 MHz, CDCl3) δ 8.15 (1H, d, J = 2.4 Hz), 7.44 (1H, dd, J =
8.1 Hz, 2.4 Hz), 7.22 (1H, d, J = 8.1 Hz), 3.22 (2H, m), 2.98
(2H, m), 1.31 (9H, s). To a solution of 6-(tert-butyl)thiochro-
man-4-one (90 mg, 0.26 mmol, 1.0 eq.) in TFA (1.4 mL) was
added Et3SiH (350 mg, 3.0 eq.). After the resulting mixture was
stirred at 100 ℃ (silicone oil bath) for 2 h, the reaction was con-
centrated in vacuo. The resulting residue was purified by flash
column chromatography on silica gel (hexane : AcOEt = 30 : 1)
to afford the title compound (54 mg, 63% yield) as colorless oil.
IR (KBr) 2958, 1482, 1361, 1275, 1262, 1120, 1061, 815, 749
cm–1; 1H NMR (300 MHz, CDCl3) δ 7.10 (1H, dd, J = 8.4 Hz,
2.4 Hz), 7.03 (1H, s), 7.01 (1H, d, J = 8.4 Hz), 3.01 (2H, m),
2.81 (2H, m), 2.10 (2H, m), 1.28 (9H, s); 13C{1H} NMR (75
MHz, CDCl3) δ 147.0, 133.2, 129.4, 127.0, 126.2, 123.7, 34.2,
31.3, 30.0, 27.5, 23.1; HRMS (EI-quadrupole) m/z: [M]+ Calcd
for C13H18S 206.1129; Found 206.1127.
1
General Information. H and 13C NMR spectra were rec-
orded with JEOL JNM-ECZ400S or BRUKER AV300M spec-
trometer at room temperature, with tetramethylsilane (δ = 0) as
an internal standard (CDCl3 solution). Chemical shifts were ex-
pressed in ppm, and coupling constants (J) in Hz. Infrared (IR)
spectra were recorded with a Shimadzu FTIR-8200A spectrom-
eter. Mass spectra were recorded on JEOL JMS-700 and JMS-
T100LP spectrometers. Melting points were determined by us-
ing a Yanaco melting point apparatus MP-S3. Merck silica gel
60 (1.09385) and Merck silica gel 60 F254 were used for col-
umn chromatography and thin layer chromatography (TLC), re-
spectively.
Preparation of Thioether Ligands. Ligands L1, L2, L3, L9
and L15 were purchased from commercially sources and used
without further purification. Ligands L4, L5, L6, L7, L8, L10,
L11, L12, L13 and L14 were synthesized according to the ex-
perimental section.
Procedure for the Synthesis of L7. butyl-4-(tert-butyl)phe-
nyl sulfane (L7). To a solution of 4-tert-butyl benzenethiol (200
mg, 1.23 mmol, 1.0 eq.) in MeOH (4 mL) were added KOH (90
mg, 1.3 eq.) and 1-iodobutane (0.18 mL, 1,3 eq.). After the re-
sulting mixture was stirred at room temperature for 12 h, the
reaction was quenched with water. The aqueous layer was
Procedure for the Synthesis of L4. N-(2-((4-(tert-bu-
tyl)phenyl)thio)ethyl)acetamide (L4). NEt3 (0.14 mL, 2.0 eq.)
and Ac2O (80 mg, 1.6 eq.) were added to the solution of 2-((4-
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The Journal of Organic Chemistry
Page 6 of 16
extracted with AcOEt and the combined organic layers were
1.62-1.57 (1H, m), 1.40-1.21 (5H, m); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.3, 135.6, 125.0, 114.2, 55.3, 47.9, 33.3, 26.1,
25.7; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C13H18OS
222.1078; Found 222.1080.
1
2
3
4
5
6
7
8
washed with brine, dried over Na2SO4, filtered and concentrated
in vacuo to afford the title compound (270 mg, quant.) as col-
orless oil. IR (KBr) 2959, 1503, 1463, 1395, 1363, 1260, 1120,
1013, 817, 749, 551, 439 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.28 (4H, m), 2.90 (2H, t, J = 7.2 Hz), 1.61 (2H, dt, J = 7.2 Hz,
8.1 Hz), 1.44 (2H, dd, J = 7.2 Hz, 8.1 Hz), 1.30 (9H, s), 0.92
(3H, t, J = 7.2 Hz); 13C{1H} NMR (75 MHz, CDCl3) δ 148.9,
133.4, 129.1, 125.8, 34.4, 33.7, 31.34, 31.28, 21.9, 13.6; HRMS
(EI-quadrupole) m/z: [M]+ Calcd for C14H22S 222.1442; Found
222.1445.
Procedure for the Synthesis of L12. 4-chlorophenyl cyclo-
hexyl sulfane (L12). To a solution of 4-chlorobenzenthiol (200
mg, 1.38 mmol, 1.0 eq.) in DMF (4 mL) were added K2CO3
(381 mg, 2.0 eq.) and cyclohexyl bromide (338 mg, 1.5 eq.).
After the resulting mixture was stirred at 100 ℃ (silicone oil
bath) for 24 h, the reaction was quenched with water. The aque-
ous layer was extracted with AcOEt and the combined organic
layers were washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (hexane : AcOEt = 30 : 1)
to afford the title compound (283 mg, 91% yield) as colorless
oil. IR (KBr) 2930, 2852, 1475, 1448, 1388, 1263, 1201, 1094,
1012, 997, 886, 819, 746, 550, 495 cm–1; 1H NMR (300 MHz,
CDCl3) δ 7.31 (2H, d, J = 8.7 Hz), δ 7.24 (2H, d, J = 8.7 Hz),
3.08 (1H, m), δ 2.00-1.90 (2H, m), δ 1.80-1.70 (2H, m), δ 1.65-
1.55 (1H, m), δ 1.38-1.30 (5H, m); 13C{1H} NMR (75 MHz,
CDCl3) δ 133.6, 133.2, 132.7, 128.9, 46.9, 33.2, 26.0, 25.7;
HRMS (EI-quadrupole) m/z: [M]+ Calcd for C12H15ClS
226.0583; Found 226.0580.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure for the Synthesis of L8. 4-(tert-butyl)phenyl cy-
clohexyl sulfane (L8). To a solution of 4-tert-butyl benzenethiol
(200 mg, 1.23 mmol, 1.0 eq.) in DMF (5 mL) were added
K2CO3 (340 mg, 2.0 eq.) and cyclohexyl bromide (300 mg, 1.5
eq.). After the resulting mixture was stirred at 100 ℃ (silicone
oil bath) for 18 h, the reaction was quenched with water. The
aqueous layer was extracted with AcOEt and the combined or-
ganic layers were washed with brine, dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (hexane : AcOEt
= 30 : 1) to afford the title compound (287 mg, 66% yield) as
colorless oil. IR (KBr) 2929, 2852, 2489, 1448, 1266, 1120,
1013, 827, 749, 557 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.28-
7.20 (4H, m), 2.98 (1H, m), 1.92-1.88 (2H, m), 1.71-1.66 (2H,
m), 1.55-1.52 (1H, m), 1.30-1.16 (5H, m), 1.30 (9H, s); 13C{1H}
NMR (75 MHz, CDCl3) δ 149.9, 132.1, 131.4, 125.7, 46.8, 34.5,
33.4, 31.3, 26.1, 25.8; HRMS (EI-quadrupole) m/z: [M]+ Calcd
for C16H24S 248.1599; Found 248.1598.
Procedure for the Synthesis of L13. Cyclohexyl-4-trifluo-
romethylphenyl sulfane (L13). To a solution of 4-trifluoro-
methylbenzenethiol (200 mg, 1.12 mmol, 1.0 eq.) in DMF (3
mL) were added K2CO3 (310 mg, 2.0 eq.) and cyclohexyl bro-
mide (274 mg, 1.5 eq.). After the resulting mixture was stirred
at 100 ℃ (silicone oil bath) for 24 h, the reaction was quenched
with water. The aqueous layer was extracted with AcOEt and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography on silica gel
(hexane : AcOEt = 30 : 1) to afford the title compound (258 mg,
88% yield) as colorless oil. IR (KBr) 2933, 2855, 1606, 1449,
1401, 1325, 1263, 1163, 1124, 1095, 1063, 1013, 824, 749 cm–
1; 1H NMR (300 MHz, CDCl3) δ 7.51 (2H, d, J = 8.1 Hz), 7.41
(2H, d, J = 8.1 Hz), 3.26 (1H, m), 2.10-1.98 (2H, m), 1.81-1.77
(2H, m), 1.67-1.63 (1H, m), 1.50-1.30 (5H, m); 13C{1H} NMR
(75 MHz, CDCl3) δ 141.2, 129.7, 125.6, 125.5, 45.6, 33.1, 25.9,
25.7; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C13H15F3S
260.0847; Found 260.0844.
Procedure for the Synthesis of L10. Cyclohexyl phenyl sul-
fane (L10). To a solution of benzenethiol (100 mg, 0.91 mmol,
1.0 eq.) in DMF (4 mL) were added K2CO3 (252 mg, 2.0 eq.)
and cyclohexyl bromide (223 mg, 1.5 eq.). After the resulting
mixture was stirred at 100 ℃ (silicone oil bath) for 21 h, the
reaction was quenched with water. The aqueous layer was ex-
tracted with AcOEt and the combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated
in vacuo. The crude product was purified by flash column chro-
matography on silica gel (hexane : AcOEt = 30 : 1) to afford the
title compound (121 mg, 69% yield) as colorless oil. IR (KBr)
2929, 2852, 1583, 1479, 1447, 1263, 1090, 1024, 997, 749, 691,
497 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.40 (2H, d, J = 8.1
Hz), 7.38-7.20 (3H, m), 3.10 (1H, m), 2.02-1.95 (2H, m), 1.79-
1.74 (2H, m), 1.64-1.60 (1H, m), 1.43-1.25 (5H, m); 13C{1H}
NMR (75 MHz, CDCl3) δ 135.2, 131.8, 128.7, 126.5, 46.5, 33.3,
26.0, 25.7; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C12H16S
192.0973; Found 192.0970.
Procedure for the Synthesis of L14. 1-chloro-4-(cyclohex-
ylsulfinyl)benzene (L14). To a solution of (4-chlorophenyl)(cy-
clohexyl)sulfane (100 mg, 0.44 mmol) in CH2Cl2 (4.5 mL) was
added mCPBA (76 mg, 1.0 eq.) at 0 ℃. After the resulting mix-
ture was stirred at 0 ℃ for 15 min, the reaction was quenched
with saturated NaHCO3 aq. The aqueous layer was extracted
with CHCl3 and the combined organic layers were washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by flash column chromatog-
raphy on silica gel (hexane : AcOEt = 1 : 1) to afford the title
compound (97 mg, 91% yield) as white solid. mp 94-96 ℃; IR
(KBr) 3463, 2932, 2855, 1644, 1474, 1450, 1390, 1275, 1078,
1041, 1010, 825, 749, 527 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.50 (4H, m), 2.55 (1H, m), 1.90-1.76 (4H, m), 1.70-1.60 (1H,
m), 1.50-1.17 (5H, m); 13C{1H} NMR (75 MHz, CDCl3) δ 140.4,
137.0, 129.2, 126.3, 63.2, 26.2, 25.5, 25.3, 23.8; HRMS (EI-
quadrupole) m/z: [M]+ Calcd for C12H15ClOS 242.0532; Found
242.0536.
Procedure for the Synthesis of L11. Cyclohexyl 4-methox-
yphenyl sulfane (L11). To a solution of 4-methoxybenzenethiol
(200 mg, 1.43 mmol, 1.0 eq.) in DMF (6 mL) were added
K2CO3 (395 mg, 2.0 eq.) and cyclohexyl bromide (350 mg, 1.5
eq.). After the resulting mixture was stirred at 100 ℃ (silicone
oil bath) for 24 h, the reaction was quenched with water. The
aqueous layer was extracted with AcOEt and the combined or-
ganic layers were washed with brine, dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (hexane : AcOEt
= 20 : 1) to afford the title compound (228 mg, 72% yield) as
colorless oil. IR (KBr) 2929, 2852, 1591, 1492, 1448, 1284,
1243, 1171, 1032, 827, 748, 641, 529 cm–1; 1H NMR (300 MHz,
CDCl3) δ 7.38 (2H, d, J = 6.6 Hz), 6.83 (2H, d, J = 6.6 Hz), 3.80
(3H, s), 2.89 (1H, m), 1.96-1.90 (2H, m), 1.76-1.71 (2H, m),
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The Journal of Organic Chemistry
1
Procedure for the Synthesis of 1b and 1u. 3-(4-methox-
ybenzyl)but-3-en-2-one O-methyl oxime (1b, 1u). To a solution
of 3-(4-methoxybenzyl)but-3-en-2-one (120 mg, 0.63 mmol,
1.0 eq.) in MeOH (3 mL) and H2O (0.3 mL) were added O-
methyl hydroxylamine hydrochloride (68 mg, 1.3 eq.) and
NaOAc (52 mg, 1.0 eq.). After the reaction mixture was stirred
at 80 ℃ (silicone oil bath) for 30 min, the reaction was quenched
with water. The aqueous layer was extracted with AcOEt and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography on silica gel
(hexane : AcOEt = 10 : 1) to afford the title compound (1b, col-
orless oil, 121 mg, 87% yield) with a small amount of Z-isomer
(1u, colorless oil, 16 mg, 12%). 1b: IR (KBr) 2936, 2833, 1611,
1584, 1510, 1463, 1440, 1299, 1246, 1176, 1125, 1051, 900,
820, 749, 641, 522 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.14
(2H, d, J = 8.7 Hz), 6.81 (2H, d, J = 8.7 Hz), 5.40 (1H, s), 5.08
(1H, s), 3.91 (3H, s), 3.78 (3H, s), 3.62 (2H, s), 1.95 (3H, s);
13C{1H} NMR (75 MHz, CDCl3) δ 157.8, 154.5, 145.6, 132.3,
130.3, 117.0, 113.5, 61.8, 55.2, 37.3, 10.8; HRMS (EI-
quadrupole) m/z: [M]+ Calcd for C13H17NO2 219.1259; Found
219.1251. 1u: IR (KBr) 2952, 1606, 1505, 1248, 1105, 997, 835,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.09 (2H, d, J = 8.7
Hz), 6.82 (2H, d, J = 8.7 Hz), 5.09 (1H, s), 5.03 (1H, s), 3.84
(3H, s), 3.79 (3H, s), 3.57 (2H, s), 1.78 (3H, s); 13C{1H} NMR
(75 MHz, CDCl3) δ 158.2, 156.2, 145.7, 130.6, 130.0, 115.1,
113.7, 61.5, 55.2, 40.1, 21.7; HRMS (EI-quadrupole) m/z: [M]+
Calcd for C13H17NO2 219.1259; Found 219.1251.
colorless oil. IR (KBr) 2991, 1275, 750 cm–1; H NMR (300
MHz, CDCl3) δ 5.30 (1H, s), δ 5.20 (1H, s), δ 4.11 (2H, t, J =
6.6 Hz), δ 1.98 (3H, s), δ 1.94 (3H, s), δ 1.65 (2H, m), δ 1.41
(2H, m), δ 0.94 (3H, t, J = 7.2 Hz); 13C{1H} NMR (75 MHz,
CDCl3) δ 155.2, 141.7, 115.9, 73.8, 31.3, 19.2, 19.1, 13.9, 10.4;
HRMS (EI-quadrupole) m/z: [M]+ Calcd for C9H17NO
155.1310; Found 155.1302.
1
2
3
4
5
6
7
8
(E)-3-(4-methoxybenzyl)but-3-en-2-one O-butyl oxime (1c or
4aa). The compound was prepared according to the general pro-
cedure for the synthesis of O-substituted α,β-unsaturated ox-
imes, purified by flash column chromatography on silica gel
(hexane : AcOEt = 20 :1) to afford the title compound (124 mg,
98% yield) as colorless oil.IR (KBr) 2957, 1612, 1510, 1463,
1246, 1176, 1039, 901, 750 cm–1; 1H NMR (300 MHz, CDCl3)
δ 7.13 (2H, d, J = 8.7 Hz), 6.81 (2H, d, J = 8.7 Hz), 5.39 (1H,
s), 5.09 (1H, s), 4.10 (2H, t, J = 6.6 Hz), 3.77 (3H, s), 3.62 (2H,
s), 1.96 (3H, s), 1.62 (2H, m), 1.36 (2H, m), 0.92 (3H, t, J = 7.2
Hz); 13C{1H} NMR (75 MHz, CDCl3) δ 157.8, 154.0, 145.8,
132.4, 130.2, 116.6, 113.5, 73.9, 55.2, 37.4, 31.3, 19.2, 13.9,
10.9; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C16H23NO2
261.1729; Found 261.1715.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-(4-methoxybenzyl)but-3-en-2-one O-methoxymethyl
oxime (1d). The compound was prepared according to the gen-
eral procedure for the synthesis of O-substituted α,β-unsatu-
rated oximes, purified by flash column chromatography on sil-
ica gel (hexane : AcOEt = 10 :1) to afford the title compound
(84 mg, 69% yield) as colorless oil. IR (KBr) 2937, 1510, 1246,
1158, 1001, 891, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.13
(2H, d, J = 8.7 Hz), 6.81 (2H, d, J = 8.7 Hz), 5.47 (1H, s), 5.15
(2H, s), 5.13 (1H, s), 3.77 (3H, s), 3.64 (2H, s), 3.40 (3H, s),
2.03 (3H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 157.8, 156.1,
145.4, 132.0, 130.2, 117.8, 113.5, 98.7, 56.5, 55.2, 37.3, 11.2;
HRMS (EI-quadrupole) m/z: [M]+ Calcd for C14H19NO3
249.1365; Found 249.1361.
Procedure for the Synthesis of 1h. (E)-3-(4-methoxyben-
zyl)but-3-en-2-one O-pivaloyl oxime (1h). To a solution of (E)-
3-(4-methoxybenzyl)but-3-en-2-one oxime (40 mg, 0.16 mmol,
1.0 eq.) in CH2Cl2 (3.2 mL) were added PivCl (25 mg, 1.3 eq.)
and NEt3 (32 mg, 2.0 eq.). After the reaction mixture was stirred
at 0 ℃ for 30 min, the reaction was quenched with water. The
aqueous layer was extracted with AcOEt and the combined or-
ganic layers were washed with brine, dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (hexane : AcOEt
= 10/1) to afford the title compound (32 mg, 69%) as colorless
oil. IR (KBr) 2968, 1758, 1511, 1275, 1105, 750 cm–1; 1H NMR
(300 MHz, CDCl3) δ 7.19 (2H, d, J = 8.7 Hz), 6.83 (2H, d, J =
8.7 Hz), 5.62 (1H, s), 5.26 (1H, s), 3.78 (3H, s), 3.72 (2H, s),
2.12 (3H, s), 1.31 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
174.9, 162.6, 158.0, 145.3, 131.2, 130.6, 120.7, 113.6, 55.1,
38.8, 37.3, 27.2, 12.6; HRMS (EI-quadrupole) m/z: [M]+ Calcd
for C17H23NO3 289.1678; Found 289.1682.
(E)-3-(4-methoxybenzyl)but-3-en-2-one
O-((trimethylsi-
lyl)methyl) oxime (1e). The compound was prepared according
to the general procedure for the synthesis of O-substituted α,β-
unsaturated oximes, purified by flash column chromatography
on silica gel (hexane : AcOEt = 20 :1) to afford the title com-
pound (138 mg, 96% yield) as colorless oil. IR (KBr) 2955,
1612, 1510, 1437, 1246, 1176, 1037, 932, 859, 763, 701 cm–1;
1H NMR (300 MHz, CDCl3) δ 7.14 (2H, d, J = 8.7 Hz), 6.82
(2H, d, J = 8.7 Hz), 5.39 (1H, s), 5.03 (1H, s), 3.89 (2H, s), 3.78
(3H, s), 3.62 (2H, s), 1.96 (3H, s), 0.09 (9H, s); 13C{1H} NMR
(75 MHz, CDCl3) δ 157.8, 154.3, 145.7, 132.3, 130.3, 116.6,
113.5, 68.3, 55.2, 37.2, 10.7, -2.75; HRMS (EI-quadrupole)
m/z: [M]+ Calcd for C16H25NO2Si 291.1655; Found 291.1648.
General Procedure for the Synthesis of O-substituted α,β-
unsaturated oximes 1a,c-g. To a solution of α,β-unsaturated
oxime (1.0 eq.) in DMF (1.0 M) were added NaH (63% disper-
sion in mineral oil, 1.5 eq.) and alkyl halide (1.3 eq.). After the
reaction mixture was stirred at room temperature for 1 h, the
reaction was quenched with water. The aqueous layer was ex-
tracted with AcOEt and the combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated
in vacuo. The crude product was purified by flash column chro-
matography on silica gel to afford the desired O-substituted α,β-
unsaturated oxime ether.
(E)-3-(4-methoxybenzyl)but-3-en-2-one O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (1f). The compound was prepared ac-
cording to the general procedure for the synthesis of O-substi-
tuted α,β-unsaturated oximes, purified by flash column chroma-
tography on silica gel (hexane : AcOEt = 20 :1) to afford the
title compound (430 mg, 94% yield) as colorless oil. IR (KBr)
2952, 1612, 1510, 1463, 1246, 1176, 1105, 1038, 999, 893, 857,
835, 751 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.14 (2H, d, J =
8.7 Hz), 6.82 (2H, d, J = 8.7 Hz), 5.46 (1H, s), 5.22 (2H, s), 5.12
(1H, s), 3.78 (3H, s), 3.70 (2H, m), 3.65 (2H, s), 2.02 (3H, s),
0.95 (2H, m), 0.02 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
157.8, 155.7, 145.5, 132.1, 130.2, 117.6, 113.5, 97.2, 66.4, 55.1,
37.3, 18.1, 11.2, -1.44; HRMS (EI-quadrupole) m/z: [M]+ Calcd
for C18H29NO3Si 335.1917; Found 335.1911.
(E)-3-methylbut-3-en-2-one O-butyl oxime (1a). The com-
pound was prepared according to the general procedure for the
synthesis of O-substituted α,β-unsaturated oximes, purified by
flash column chromatography on silica gel (hexane : AcOEt =
30 : 1) to afford the title compound (577 mg, 31% yield) as
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The Journal of Organic Chemistry
Page 8 of 16
1
(E)-3-(4-methoxybenzyl)but-3-en-2-one O-((2-methoxyeth-
408 cm–1; H NMR (300 MHz, CDCl3) δ 7.28-7.16 (5H, m),
1
2
3
4
5
6
7
8
oxy)methyl) oxime (1g). The compound was prepared according
to the general procedure for the synthesis of O-substituted α,β-
unsaturated oximes, purified by flash column chromatography
on silica gel (hexane : AcOEt = 5 :1) to afford the title com-
pound (72 mg, 83% yield) as colorless oil. IR (KBr) 2930, 1661,
1510, 1462, 1246, 1175, 1107, 1000, 893, 851, 750, 515 cm–1;
1H NMR (300 MHz, CDCl3) δ 7.12 (2H, d, J = 8.7 Hz), 6.80
(2H, d, J = 8.7 Hz), 5.47 (1H, s), 5.25 (2H, s), 5.17 (1H, s), 3.78
(3H, s), 3.66 (2H, m), 3.48 (2H, m), 3.37 (3H, s), 2.02 (3H, s);
13C{1H} NMR (75 MHz, CDCl3) δ 157.8, 155.8, 145.2, 132.1,
130.0, 118.0, 113.5, 97.9, 71.7, 68.4, 59.0, 55.1, 37.5, 11.2;
HRMS (EI-quadrupole) m/z: [M]+ Calcd for C16H23NO4
293.1627; Found 293.1624.
5.47 (1H, s), 5.19 (2H, s), 5.12 (1H, s), 3.69 (2H, s), 3.67 (2H,
m), 2.01 (3H, s), 0.93 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75
MHz, CDCl3) δ 155.7, 145.2, 140.1, 129.3, 128.1, 125.8, 117.9,
97.2, 66.4, 38.2, 18.1, 11.2, -1.42; HRMS (EI-quadrupole) m/z:
[M]+ Calcd for C17H27NO2Si 305.1811; Found 305.1806.
(E)-3-methyleneheptan-2-one
O-((2-(trimethylsilyl)eth-
oxy)methyl) oxime (1l). Following the general procedure for
α,β-unsaturated oxime SEM ether synthesis, (E)-3-methylene-
heptan-2-one oxime (165 mg, 1.17 mmol) was converted to the
title compound (colorless oil, 257 mg, 81% yield), and purified
by flash column chromatography on silica gel (hexane : AcOEt
= 30 : 1). IR (KBr) 2955, 1260, 1105, 1001, 835, 750, 442, 417
cm–1; 1H NMR (300 MHz, CDCl3) δ 5.35 (1H, s), 5.22 (1H, s),
5.21 (2H, s), 3.72 (2H, m), 2.35 (2H, td, J = 7.2 Hz, 0.9 Hz),
2.00 (3H, s), 1.44 (2H, m), 1.32 (2H, m), 0.98 (2H, m), 0.95 (3H,
t, J = 8.4 Hz), 0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
156.1, 146.0, 115.8, 97.1, 66.6, 32.0, 30.9, 22.5, 18.2, 14.0, 11.2,
-1.46; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C14H29NNaO2Si 294.1865; Found 294.1857.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Synthesis of α,β-unsaturated
O-SEM oximes 1i-t. To a solution of α,β-unsaturated oxime
(1.0 eq.) in DMF (1.0 M) were added NaH (63% dispersion in
mineral oil, 1.5 eq.) and SEMCl (1.3 eq.). After the reaction
mixture was stirred at room temperature for 30 min, the reaction
was quenched with water. The aqueous layer was extracted with
AcOEt and the combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash column chromatography on
silica gel to afford the desired α,β-unsaturated oxime SEM
ethers.
(E)-5-(benzyloxy)-3-methylenepentan-2-one O-((2-(trime-
thylsilyl)ethoxy)methyl) oxime (1m). Following the general pro-
cedure for α,β-unsaturated oxime SEM ether synthesis, (E)-5-
(benzyloxy)-3-methylenepentan-2-one oxime (30 mg, 0.14
mmol) was converted to the title compound (colorless oil, 40
mg, 79% yield), and purified by flash column chromatography
on silica gel (hexane : AcOEt = 30 : 1). IR (KBr) 2953, 1722,
1275, 1107, 994, 835, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.33-7.24 (5H, m), 5.45 (1H, s), 5.34 (1H, s), 5.18 (2H, s), 4.51
(2H, s), 3.69 (2H, m), 3.63 (2H, t, J = 6.9 Hz), 2.71 (2H, td, J =
6.9 Hz, 0.9 Hz), 2.00 (3H, s), 0.93 (2H, m), 0.00 (9H, s);
13C{1H} NMR (75 MHz, CDCl3) δ 155.8, 142.3, 138.6, 128.3,
127.5, 127.4, 117.9, 97.2, 72.6, 69.3, 66.5, 32.8, 18.1, 11.0, -
(E)-3-methylbut-3-en-2-one O-((2-(trimethylsilyl)ethoxy)me-
thyl) oxime (1i). The compound was prepared according to the
general procedure for the synthesis of α,β-unsaturated O-SEM
oximes, purified by flash column chromatography on silica gel
(hexane : AcOEt = 20 : 1) to afford the title compound (848 mg,
3.70 mmol, 62% yield) as colorless oil. IR (KBr) 2984, 1275,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 5.34 (1H, s), δ 5.24
(1H, m), δ 5.21 (2H, s), δ 3.73 (2H, m), δ 2.01 (3H, s), δ 1.94
(3H, s), δ 0.95 (2H, m), δ 0.00 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 156.7, 141.4, 116.8, 97.1, 66.5, 19.1, 18.1, 10.7, -1.48;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H23NNaO2Si
252.1396; Found 252.1393.
1.42; HRMS (ESI-TOF) m/z: [M
+
Na]+ Calcd for
C19H31NNaO3Si 372.1971; Found 372.1969.
(E)-4-methyl-3-methylenepentan-2-one O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (1n). Following the general procedure
for α,β-unsaturated oxime SEM ether synthesis, (E)-4-methyl-
3-methylenepentan-2-one oxime (50 mg, 0.39 mmol) was con-
verted to the title compound (colorless oil, 82 mg, 82% yield),
and purified by flash column chromatography on silica gel (hex-
ane : AcOEt = 30 : 1). IR (KBr) 2957, 1260, 1104, 1000, 898,
836, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ 5.33 (1H, s), 5.22
(1H, s), 5.21 (2H, s), 3.72 (2H, m), 3.02 (1H, m), 2.01 (3H, s),
1.07 (6H, d, J = 6.6 Hz), 0.95 (2H, m), 0.00 (9H, s); 13C{1H}
NMR (75 MHz, CDCl3) δ 156.1, 152.4, 113.1, 97.1, 66.5, 28.6,
22.3, 18.2, 11.9, -1.47; HRMS (EI-quadrupole) m/z: [M]+ Calcd
for C13H27NO2Si 257.1811; Found 257.1820.
(E)-2-(4-methoxybenzyl)-5-(4-methoxyphenyl)pent-1-en-3-
oneO-((2-(trimethylsilyl) ethoxy) methyl) oxime (1j). Following
the general procedure for α,β-unsaturated oxime SEM ether
synthesis, (E)-2-(4-methoxybenzyl)-5-(4-methoxyphenyl)pent-
1-en-3-one oxime (65 mg, 0.20 mmol) was converted to the title
compound (colorless oil, 90 mg, quant.), and purified by flash
column chromatography on silica gel (hexane : AcOEt = 10 : 1).
IR (KBr) 2951, 1612, 1511, 1246, 1176, 1105, 1037, 997, 835,
750, 518 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.12 (2H, d, J =
8.7 Hz), 7.09 (2H, d, J = 9.0 Hz), 6.81 (2H, d, J = 8.7 Hz), 6.80
(2H, d, J = 9.0 Hz), 5.45 (1H, s), 5.21 (2H, s), 5.13 (1H, s), 3.79
(6H, s), 3.69 (2H, m), 3.62 (2H, s), 2.81-2.65 (4H, m), 0.96 (2H,
m), 0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 158.8,
157.9, 157.8, 144.4, 133.7, 132.1, 130.3, 129.2, 117.6, 113.8,
113.5, 97.3, 66.4, 55.3, 55.2, 37.5, 31.9, 27.8, 18.1, -1.40;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H37NNaO4Si
478.2389; Found 478.2377.
(E)-2-methylenecycloheptan-1-one O-((2-(trimethylsilyl)eth-
oxy)methyl) oxime (1o). Following the general procedure for
α,β-unsaturated oxime SEM ether synthesis, (E)-2-methylene-
cycloheptan-1-one oxime (130 mg, 0.93 mmol) was converted
to the title compound (colorless oil, 183 mg, 73% yield), and
purified by flash column chromatography on silica gel (hexane :
AcOEt = 30 : 1). IR (KBr) 2926, 1451,1248, 1142, 1101, 1001,
(E)-3-benzylbut-3-en-2-one O-((2-(trimethylsilyl)ethoxy)me-
thyl) oxime (1k). Following the general procedure for α,β-un-
saturated oxime SEM ether synthesis, (E)-3-benzylbut-3-en-2-
one oxime (50 mg, 0.29 mmol) was converted to the title com-
pound (colorless oil, 85 mg, 97% yield), and purified by flash
column chromatography on silica gel (hexane : AcOEt = 30 : 1).
IR (KBr) 2988, 2956, 1275, 1105, 1005, 862, 837, 750, 702,
1
890, 859, 835, 750, 420 cm–1; H NMR (300 MHz, CDCl3) δ
5.31 (1H, s), 5.18 (2H, s), 4.93 (1H, s), 3.71 (2H, m), 2.58 (2H,
m), 2.34 (2H, m), 1.61 (6H, m), 0.95 (2H, m), 0.00 (9H, s);
13C{1H} NMR (75 MHz, CDCl3) δ 163.8, 146.0, 114.5, 96.8,
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66.2, 35.3, 31.0, 29.8, 27.7, 25.6, 18.1, -1.45; HRMS (ESI-
(E)-3-(3-(trifluoromethyl)phenyl)but-3-en-2-one O-((2-(tri-
TOF) m/z: [M + Na]+ Calcd for C14H27NNaO2Si 292.1708;
methylsilyl)ethoxy)methyl) oxime (1t). Following the general
procedure for α,β-unsaturated oxime SEM ether synthesis, (E)-
3-(3-(trifluoromethyl)phenyl)but-3-en-2-one oxime (150 mg,
0.65 mmol) was converted to the title compound (colorless oil,
220 mg, 94% yield), and purified by flash column chromatog-
raphy on silica gel (hexane : AcOEt = 10 : 1). IR (KBr) 2954,
1671, 1437, 1329, 1275, 1250, 1167, 1128, 1073, 996, 912, 859,
1
2
3
4
5
6
7
8
Found 292.1699.
(E)-3-(4-methoxyphenyl)but-3-en-2-one O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (1p). Following the general procedure
for α,β-unsaturated oxime SEM ether synthesis, (E)-3-(4-meth-
oxyphenyl)but-3-en-2-one oxime (90 mg, 0.51 mmol) was con-
verted to the title compound (colorless oil, 128 mg, 78% yield),
and purified by flash column chromatography on silica gel (hex-
ane : AcOEt = 20 : 1). IR (KBr) 2952, 1608, 1510, 1248, 1176,
1102, 998, 902, 834, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.25 (2H, d, J = 8.7Hz), 6.83 (2H, d, J = 8.7Hz), 5.44 (1H, s),
5.38 (1H, s), 5.20 (2H, s), 3.79 (3H, s), 3.69 (2H, m), 2.02 (3H,
s), 0.94 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3)
δ 159.3, 157.7, 145.8, 131.0, 129.2, 116.1, 113.4, 97.1, 66.5,
55.2, 18.2, 13.8, -1.44; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C17H27NNaO3Si 344.1658; Found 344.1653.
1
935, 801, 749, 700, 417 cm–1; H NMR (300 MHz, CDCl3) δ
7.61-7.40 (4H, m), 5.68 (1H, s), 5.53 (1H, s), 5.18 (2H, s), 3.67
(2H, m), 2.11 (3H, s,), 0.94 (2H, m), 0.00 (9H, s); 13C{1H}
NMR (75 MHz, CDCl3) δ 156.4, 145.5, 139.8, 131.8, 130.5,
130.1, 128.3, 125.4, 124.3, 119.2, 97.3, 66.7, 18.1, 12.8, -1.50;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H24F3NNaO2Si
382.1426; Found 382.1410.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for Pd-catalyzed β-Arylation of α,β-
unsaturated oximes. General Procedure A: To a solution of
α,β-unsaturated oxime 1 (0.1 mmol), arylboronic acid 2 (3.0
eq.), Ag2CO3 (2.0 eq.), AgTFA (0.4 eq.), Na2HPO4ꢂ12 H2O (1.5
eq.), L12 (30 mol%), 2,6-dimethyl-1,4-benzoquinone (30
mol%) in dioxane (2.0 mL) was added Pd(OAc)2 (10 mol%).
After stirring at 90 ℃ (silicone oil bath) for 2 h, the reaction
mixture was diluted with AcOEt and filtered through a Celite®
pad (rinsed with AcOEt). The filtrate was concentrated in vacuo,
and the crude product was purified by flash column chromatog-
raphy on silica gel. General Procedure B: To a solution of α,β-
unsaturated oxime 1 (0.1 mmol), arylboronic acid 2 (3.0 eq.),
Ag2CO3 (2.0 eq.), Na2HPO4ꢂ12 H2O (1.5 eq.), L12 (30 mol%),
2,6-dimethyl-1,4-benzoquinone (30 mol%) in dioxane (2.0 mL)
was added Pd(TFA)2 (10 mol%). After stirring at 90 ℃ (silicone
oil bath) for 1 h, the reaction mixture was diluted with AcOEt
and filtered through a Celite® pad (rinsed with AcOEt). The fil-
trate was concentrated in vacuo, and the crude product was pu-
rified by flash column chromatography on silica gel.
(E)-3-(4-fluorophenyl)but-3-en-2-one
O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (1q). Following the general procedure
for α,β-unsaturated oxime SEM ether synthesis, (E)-3-(4-fluor-
ophenyl)but-3-en-2-one oxime (80 mg, 0.45 mmol) was con-
verted to the title compound (colorless oil, 142 mg, quant.), and
purified by flash column chromatography on silica gel (hexane :
AcOEt = 20 : 1). IR (KBr) 2953, 1509, 1260, 1104, 997, 835,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.29 (2H, dd, J = 8.7
Hz, 5.4Hz), 6.98 (2H, dd, J = 9.0 Hz, 8.7Hz, ), 5.54 (1H, s), 5.42
(1H, s), 5.18 (2H, s), 3.68 (2H, m), 2.05 (3H, s,), 0.94 (2H, m),
0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 164.1, 160.8,
157.1, 145.5, 134.8, 129.9, 117.8, 115.0, 114.7, 97.2, 66.6, 18.1,
13.3, -1.46; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C16H24FNNaO2Si 332.1458; Found 332.1448.
(E)-3-(4-chlorophenyl)but-3-en-2-one
O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (1r). Following the general procedure
for α,β-unsaturated oxime SEM ether synthesis, (E)-3-(4-chlo-
rophenyl)but-3-en-2-one oxime (300 mg, 1.53 mmol) was con-
verted to the title compound (colorless oil, 425 mg, 85% yield),
and purified by flash column chromatography on silica gel (hex-
ane : AcOEt = 10 : 1). IR (KBr) 2952, 1490, 1248, 1094, 997,
Representative Procedure for Ligand Optimization using
α,β-unsaturated oxime 1a. (2E,3E)-4-(4-methoxyphenyl)-3-
methylbut-3-en-2-one O-butyl oxime (3aa). To a solution of
(E)-3-methylbut-3-en-2-one O-butyl oxime 1a (31 mg, 0.2
mmol, 1.0 eq.), 4-methoxyphenyl boronic acid 2a (0.6 mmol.
3.0 eq.), Ag2CO3 (0.4 mmol. 2.0 eq.), AgTFA (0.08 mmol, 0.4
eq.), Na2HPO4ꢂ12H2O (0.3 mmol, 1.5 eq.), 2,6-dimethyl-1,4-
benzoquinone (0.2 mmol, 1.0 eq.), L12 (0.06 mmol, 30 mol%)
in dioxane 2 mL was added Pd(OAc)2 (0.02 mmol, 10 mol%) at
room temperature. After resulting mixture was stirred at 90 °C
(silicone oil bath) for 2 h, the reaction mixture was filtered
through a Celite® pad (rinsed with AcOEt) and the filtrate was
concentrated in vacuo. The crude product was purified by col-
umn chromatography on silica gel (hexane : AcOEt = 30 : 1) to
afford the desired arylated compounds 3aa (14.1 mg, 27%), 4aa
(21.4 mg, 41%), and 5aa (11.8 mg, 16%). 3aa: Colorless oil. IR
(KBr) 2958, 1606, 1509, 1275, 1258, 1037, 750 cm–1; 1H NMR
(300 MHz, CDCl3) δ 7.27 (2H, d, J = 8.7 Hz), 6.90 (2H, d, J =
8.7 Hz), 6.78 (1H, s), 4.14 (2H, t, J = 6.6 Hz), 3.83 (3H, s), 2.09
(3H, s), 2.08 (3H, s), 1.69 (2H, m), 1.42 (2H, m), 0.96 (3H, t, J
= 7.2 Hz); 13C{1H} NMR (75 MHz, CDCl3) δ 158.5, 156.7,
133.8, 130.7, 130.1, 129.5, 113.6, 73.9, 55.3, 31.4, 19.3, 14.3,
14.0, 10.9; HRMS (EI-quadrupole) m/z: [M]+ Calcd for
C16H22NO2 260.1651; Found 260.1655.
1
907, 833, 750 cm–1; H NMR (300 MHz, CDCl3) δ 7.27-7.25
(4H, m), 5.57 (1H, s), 5.44 (1H, s), 5.18 (2H, s), 3.67 (2H, m),
2.05 (3H, s,), 0.93 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75
MHz, CDCl3) δ 156.8, 145.5, 137.3, 133.6, 129.6, 128.1, 118.2,
97.2, 66.7, 18.1, 13.2, -1.46; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C16H24ClNNaO2Si 348.1163; Found 348.1150.
(E)-3-(4-bromophenyl)but-3-en-2-one
O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (1s). Following the general procedure
for α,β-unsaturated oxime SEM ether synthesis, (E)-3-(4-bro-
mophenyl)but-3-en-2-one oxime (100 mg, 0.42 mmol) was
converted to the title compound (colorless oil, 153 mg, 98%
yield), and purified by flash column chromatography on silica
gel (hexane : AcOEt = 10 : 1). IR (KBr) 2953, 1487, 1377, 1248,
1105, 996, 938, 859, 834, 750, 693 cm–1; 1H NMR (300 MHz,
CDCl3) δ 7.44 (2H, d, J = 8.7 Hz), δ 7.20 (2H, d, J = 8.7 Hz),
5.58 (1H, s), 5.46 (1H, s), 5.18 (2H, s), 3.67 (2H, m), 2.06 (3H,
s,), 0.94 (2H, m), 0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3)
δ 156.8, 145.5, 137.8, 131.1, 130.0, 121.8, 118.3, 97.2, 91.5,
66.7, 18.2, 13.2, -1.44; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C16H24BrNNaO2Si 392.0657, 394.0637; Found 392.0645,
394.0618.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-
en-2-one O-methyl oxime (3ba). Following the general
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
procedure A on 0.14 mmol scale. Purification by flash column AcOEt = 30 : 1) afforded the title compound (colorless oil, 38
1
2
3
4
5
6
7
8
chromatography on silica gel (hexane : AcOEt = 10 : 1) afforded
the title compound 3ba (colorless oil, 32 mg, 70% yield) with a
small amount of Z-isomer 3ua (E/Z isomer ratio was 2.6:1).
3ba: IR (KBr) 3466, 2358, 1608, 1509, 1275, 1259, 1176, 1044,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.24 (2H, d, J = 8.4
Hz), 7.10 (2H, d, J = 8.7 Hz), 6.98 (1H, s), 6.83 (2H, d, J = 8.4
Hz), 6.81 (2H, d, J = 8.4 Hz), 3.94 (2H, s), 3.83 (3H, s), 3.78
(3H, s), 3.77 (3H, s), 2.07 (3H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 158.8, 157.6, 155.7, 135.9, 132.7, 131.2, 130.2, 129.4,
129.1, 113.8, 113.6, 61.8, 55.20, 55.16, 32.2, 11.3; HRMS (EI-
quadrupole) m/z: [M]+ Calcd for C20H23NO3 325.1678; Found
325.1679.
mg, 97% yield). Following the general procedure B on 0.09
mmol scale. Purification by flash column chromatography on
silica gel (hexane : AcOEt = 30 : 1) afforded the title compound
(colorless oil, 36.3 mg, 92% yield). IR (KBr) 2951, 1607, 1509,
1463, 1247, 1176, 1105, 1035, 997, 894, 858, 835, 750, 539 cm–
1; H NMR (300 MHz, CDCl3, 3) δ 7.24 (2H, d, J = 8.7 Hz),
1
7.10 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 6.85 (2H, d, J = 8.7 Hz),
6.80 (2H, d, J = 8.7 Hz), 5.14 (2H, s), 3.96 (2H, s), 3.79 (3H, s),
3.78 (3H, s), 3.59 (2H, m), 2.14 (2H, s), 0.88 (2H, m), -0.01 (9H,
s); 13C{1H} NMR (75 MHz, CDCl3, contains a small amount of
Z-isomer.) δ 158.9, 157.6, 156.8, 135.7, 132.6, 131.9, 130.2,
129.3, 129.1, 113.8, 113.7, 97.2, 66.5, 55.2, 55.1, 32.2, 18.1,
11.6, -1.43; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C25H35NNaO4Si 464.2233; Found 464.2211.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-butyl oxime (3ca or 5aa). Following the general pro-
cedure A on 0.11 mmol scale. Purification by flash column
chromatography on silica gel (hexane : AcOEt = 30 : 1) afforded
the title compound (colorless oil, 32 mg, 79% yield). IR (KBr)
2956, 1606, 1509, 1247, 1176, 1035, 750, 420 cm–1; 1H NMR
(300 MHz, CDCl3) δ 7.24 (2H, d, J = 8.7 Hz), 7.09 (2H, d, J =
9.0 Hz), 6.97 (1H, s), 6.84 (2H, d, J = 8.7 Hz), 6.80 (2H, d, J =
9.0 Hz), 4.02 (2H, t, J = 6.6 Hz), 3.93 (2H, s), 3.79 (3H, s), 3.78
(3H, s), 2.08 (3H, s), 1.50 (2H, m), 1.28 (2H, m), 0.86 (3H, t, J
= 7.2 Hz); 13C{1H} NMR (75 MHz, CDCl3) δ 158.8, 157.5,
155.2, 136.3, 133.0, 131.0, 130.2, 129.6, 129.1, 113.8, 113.6,
73.8, 55.24, 55.22, 32.3, 31.3, 19.1, 13.9, 11.3; HRMS (EI-
quadrupole) m/z: [M]+ Calcd for C23H29NO3 367.2147; Found
367.2144.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-((2-methoxyethoxy)methyl) oxime (3ga). Following the
general procedure A on 0.10 mmol scale. Purification by flash
column chromatography on silica gel (hexane : AcOEt = 3 : 1)
afforded the title compound (colorless oil, 21.7 mg, 56% yield).
IR (KBr) 2930, 1606, 1509, 1462, 1247, 1176, 1107, 1032, 998,
1
894, 750, 536 cm–1; H NMR (300 MHz, CDCl3, contains a
small amount of Z-isomer.) δ 7.26 (2H, d, J = 8.7 Hz), 7.10 (1H,
s), 7.06 (2H, d, J = 6.3 Hz), 6.84 (2H, d, J = 8.7 Hz), 6.79 (2H,
d, J = 6.3 Hz), 5.17 (2H, s), 3.94 (2H, s), 3.79 (3H, s), 3.77 (3H,
s), 3.45 (2H, m), 3.36-3.33 (2H, m), 3.33 (3H, s), 2.14 (3H, s);
13C{1H} NMR (75 MHz, CDCl3, contains a small amount of Z-
isomer.) δ 159.0, 157.6, 156.7, 135.4, 132.7, 132.3, 130.2, 129.2,
129.0, 113.8, 113.6, 97.9, 71.7, 68.5, 58.9, 55.3, 55.2, 32.3,
11.6 ; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C23H29NO5
399.2046; Found 399.2046.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-methoxymethyl oxime (3da). Following the general
procedure A on 0.12 mmol scale. Purification by flash column
chromatography on silica gel (hexane : AcOEt = 5 : 1) afforded
the title compound (colorless oil, 19.5 mg, 48% yield). IR (KBr)
2932, 1606, 1509, 1462, 1246,1177, 1154, 1086, 1033, 999, 892,
749, 535 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.25 (2H, d, J =
6.6 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.04 (1H, s), 6.84 (2H, d, J =
8.7 Hz), 6.79 (2H, d, J = 8.7 Hz), 5.08 (2H, s), 3.95 (2H, s), 3.79
(3H, s), 3.77 (3H, s), 3.27 (3H, s), 2.14 (3H, s); 13C{1H} NMR
(75 MHz, CDCl3) δ 159.0, 157.6, 157.1, 135.6, 132.6, 132.1,
130.3, 129.3, 129.0, 113.8, 113.7, 98.8, 56.7, 55.3, 55.2, 32.3,
11.7; HRMS (EI-quadrupole) m/z: [M]+ Calcd for C21H25NO4
355.1784; Found 355.1775.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-pivaloyl oxime (3ha). Following the general procedure
A on 0.07 mmol scale. Purification by flash column chromatog-
raphy on silica gel (hexane : AcOEt = 5 : 1) afforded the title
compound (colorless oil, 4.3 mg, 14% yield). IR (KBr) 2917,
1752, 1604, 1509, 1245, 1176, 1105, 1028, 750 cm–1; 1H NMR
(300 MHz, CDCl3) δ 7.28 (2H, d, J = 9.0 Hz), 7.18 (1H, s), 7.15
(2H, d, J = 8.7 Hz), 6.86 (2H, d, J = 8.7 Hz), 6.82 (2H, d, J =
9.0 Hz), 4.00 (2H, s), 3.80 (3H, s), 3.77 (3H, s), 2.16 (3H, s),
1.28 (9H, s); 13C{1H} NMR (75 MHz, CDCl3, contains a small
amount of Z-isomer.) δ 174.9, 164.7, 159.3, 157.8, 134.8, 134.5,
131.5, 130.5, 130.4, 129.4, 128.7, 113.9, 113.8, 55.2, 38.8, 32.5,
29.7, 27.3, 13.4; HRMS (EI-quadrupole) m/z: [M]+ Calcd for
C24H29NO4 395.2097; Found 395.2096.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-
en-2-one O-((trimethylsilyl)methyl) oxime (3ea). Following
the general procedure A on 0.10 mmol scale. Purification by
flash column chromatography on silica gel (hexane : AcOEt =
30 : 1) afforded the title compound (colorless oil, 18.2 mg, 46%
yield). IR (KBr) 3453, 2360, 1607, 1509, 1275, 1260, 1035, 859,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.23 (2H, d, J = 8.7
Hz), 7.11 (2H, d, J = 8.7 Hz), 6.97 (1H, s), 6.83 (2H, d, J = 8.7
Hz), 6.81 (2H, d, J = 8.7 Hz), 3.94 (2H, s), 3.82 (2H, s), 3.790
(3H, s), 3.788 (3H, s), 2.07 (3H, s), 0.03 (9H, s); 13C{1H} NMR
(75 MHz, CDCl3) δ 158.8, 157.5, 155.4, 135.9, 132.7, 131.0,
130.2, 129.6, 129.1, 113.7, 113.6, 68.2, 55.2, 32.1, 11.2, -2.77;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H31NNaO3Si
420.1971; Found 420.1965.
(2E,3E)-4-(4-methoxyphenyl)-3-methylbut-3-en-2-one
O-
((2-(trimethylsilyl)ethoxy)methyl) oxime (3ia). Following the
general procedure B on 0.13 mmol scale. Purification by flash
column chromatography on silica gel (hexane : AcOEt = 30 : 1)
afforded 3ia (colorless oil, 11.7 mg, 27% yield), 4ia (colorless
oil, 14.3 mg, 32% yield) and 3fa (colorless oil, 17 mg, 29%
yield). 3ia: IR (KBr) 2953, 1607, 1509, 1466, 1250, 1178, 1104,
998, 893, 859, 835, 750, 531 cm–1; 1H NMR (300 MHz, CDCl3)
δ 7.26 (2H, d, J = 9.0 Hz), 6.88 (2H, d, J = 9.0 Hz), 6.81 (1H,
s), 5.23 (2H, s), 3.80 (3H, s), 3.74 (2H, m), 2.11 (3H, s), 2.08
(3H, s), 0.96 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 158.6, 158.2, 133.4, 130.7, 130.3, 129.8, 113.6, 97.0,
66.5, 55.2, 18.1, 14.3, 11.2, -1.45; HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C18H29NNaO3Si 358.1814; Found 358.1810.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-
en-2-one O-((2-(trimethylsilyl) ethoxy) methyl) oxime (3fa).
Following the general procedure A on 0.09 mmol scale. Puri-
fication by flash column chromatography on silica gel (hexane :
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Page 11 of 16
The Journal of Organic Chemistry
(2E,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-en-
(1H, s), 6.88 (2H, d, J = 8.7 Hz), 6.77* (2H, d, J = 8.7 Hz),
6.16* (1H, m), 5.22 (2H, s), 5.17* (2H, s), 4.52 (2H, s), 4.27*
(1H, d, J = 6.0 Hz), 3.83 (3H, s), 3.76-3.69 (4H, m), 2.96 (2H,
t, J = 7.2 Hz), 2.11 (3H, s), 2.01* (3H, s), 0.96 (2H, m), 0.02
(9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 158.8, 157.1, 138.8,
134.3, 132.3, 130.5, 129.3, 128.3, 127.5, 127.4, 113.7, 97.3,
72.6, 69.3, 66.5, 55.3, 28.0, 18.2, 11.4, -1.44; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C26H37NNaO4Si 478.2390;
Found 478.2375.
1
2
3
4
5
6
2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3ja). Fol-
lowing the general procedure B on 0.07 mmol scale. Purifica-
tion by flash column chromatography on silica gel (hexane :
AcOEt = 5 : 1) afforded 3ja (colorless oil, 39.6 mg, 96% yield).
IR (KBr) 2952, 1607, 1509, 1463, 1246, 1177, 1105, 1035, 997,
834, 750 cm–1; H NMR (300 MHz, CDCl3, contains a small
1
amount of Z-isomer.) δ 7.26-7.12 (6H, m), 6.97 (1H, s), 6.88-
6.80 (6H, m), 5.16 (2H, s), 3.94 (2H, s), 3.81 (6H, s), 3.79 (3H,
s), 3.62 (2H, m), 2.91-2.87 (2H, m), 2.81-2.77 (2H, m), 0.90
(2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3, contains
a small amount of Z-isomer.) δ 159.8, 158.9, 158.0, 157.6, 134.6,
133.7, 132.6, 132.0, 130.6, 130.3, 129.9, 129.3, 129.1, 129.0,
113.8, 113.6, 97.3, 66.4, 55.25, 55.22, 55.1, 32.2, 32.0, 27.8,
18.1, -1.40; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C33H43NNaO5Si 584.2808; Found 584.2790.
7
8
9
(E)-3-((Z)-4-methoxybenzylidene)-4-methylpentan-2-one O-
((2-(trimethylsilyl)ethoxy)methyl) oxime (3na). Following the
general procedure B on 0.12 mmol scale. Purification by flash
column chromatography on silica gel (hexane : AcOEt = 5 : 1)
afforded 3na (colorless oil, 10.5 mg, 25% yield). IR (KBr) 2957,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1607, 1509, 1254, 1177, 1103, 1002, 858, 835, 750 cm–1; H
1
NMR (300 MHz, CDCl3) δ 7.21 (2H, d, J = 8.4 Hz), 6.80 (2H,
d, J = 8.4 Hz), 6.33 (1H, s), 5.24 (2H, s), 3.79 (3H, s), 3.73 (2H,
m), 2.69 (1H, m), 1.84 (3H, s), 1.14 (6H, d, J = 6.9 Hz), 0.96
(2H, m), 0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 159.4,
158.6, 143.6, 129.8, 129.6, 125.6, 113.6, 96.8, 66.1, 55.2, 35.7,
21.5, 18.2, 16.9, -1.43; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C20H33NNaO3Si 386.2127; Found 386.2123.
(2E,3E)-3-benzyl-4-(4-methoxyphenyl)but-3-en-2-one O-((2-
(trimethylsilyl)ethoxy)methyl) oxime (3ka or 4fd), (2E,3E)-3-
(4-methoxybenzyl)-4-phenylbut-3-en-2-one O-((2-(trimethylsi-
lyl)ethoxy)methyl) oxime (4ka or 3fd). Following the general
procedure B on 0.10 mmol scale. Purification by flash column
chromatography on silica gel (hexane : AcOEt = 30 : 1) afforded
3ka (colorless oil, 18.9 mg, 46% yield) and 4ka (colorless oil,
20.7 mg, 50% yield) as inseparable mixture.
(E)-2-((E)-4-methoxybenzylidene)cycloheptan-1-one O-((2-
(trimethylsilyl)ethoxy)methyl) oxime (3oa). Following the gen-
eral procedure B on 0.11 mmol scale. Purification by flash col-
umn chromatography on silica gel (hexane : AcOEt = 5 : 1) af-
forded 3oa (colorless oil, 16 mg, 39% yield). IR (KBr) 2925,
(E)-3-((E)-4-methoxybenzylidene)heptan-2-one O-((2-(tri-
methylsilyl)ethoxy)methyl) oxime (3la), (2E,3E)-3-(4-methox-
ybenzyl)hept-3-en-2-one O-((2-(trimethylsilyl)ethoxy)methyl)
oxime (4la). Following the general procedure B on 0.15 mmol
scale. Purification by flash column chromatography on silica
gel (hexane : AcOEt = 30 : 1) afforded 3la (colorless oil, 27.1
mg, 48% yield) and 4la (colorless oil, 2.7 mg, 5% yield). 3la:
IR (KBr) 2956, 2363, 1509, 1250, 1176, 1105, 1000, 834, 749,
671, 428 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.25 (2H, d, J =
8.7 Hz), 6.90 (2H, d, J = 8.7 Hz), 6.75 (1H, s), 5.25 (2H, s), 3.83
(3H, s), 3.75 (2H, m), 2.55 (2H, m), 2.11 (3H, s), 1.53 (2H, m),
1.36 (2H, m), 0.98 (2H, m), 0.94 (3H, t, J = 5.7 Hz), 0.02 (9H,
s); 13C{1H} NMR (75 MHz, CDCl3) δ 158.6, 157.4, 138.7,
130.2, 129.9, 129.8, 113.7, 97.2, 66.5, 55.2, 31.5, 27.2, 23.0,
18.2, 13.9, 11.7, -1.41; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C21H35NNaO3Si 400.2284; Found 400.2275. 4la: IR (KBr)
1
1509, 1275, 1259, 1001, 835, 750 cm–1; H NMR (300 MHz,
CDCl3, contains a small amount of Z-isomer.) δ 7.29 (2H, d, J
= 8.7 Hz), 6.87 (2H, d, J = 8.7 Hz), 6.72 (1H, s), 5.23 (2H, s),
3.81 (3H, s), 3.75 (2H, m), 2.66-2.50 (4H, m), 1.70-1.60 (6H,
m), 0.99 (2H, m), 0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3)
δ 165.7, 158.5, 137.2, 130.4, 129.7, 127.9, 113.7, 113.6, 96.8,
66.2, 55.2, 30.5, 29.9, 28.3, 27.7, 25.0, 18.1, -1.39; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C21H33NNaO3Si 398.2127;
Found 398.2121.
(2E,3E)-3,4-bis(4-methoxyphenyl)but-3-en-2-one O-((2-(tri-
methylsilyl)ethoxy)methyl) oxime (E-3pa), (2E,3Z)-3,4-bis(4-
methoxyphenyl)but-3-en-2-one
O-((2-(trimethylsilyl)eth-
1
2955, 2360, 1638, 1509, 1259, 1105, 998, 835, 750 cm–1; H
oxy)methyl) oxime (Z-3pa). Following the general procedure B
on 0.09 mmol scale. Purification by flash column chromatog-
raphy on silica gel (hexane : AcOEt = 5 : 1) afforded (E)-3pa
(colorless oil, 19.2 mg, 50% yield) and (Z)-3pa (colorless oil,
15.3 mg, 40% yield). (E)-3pa: IR (KBr) 2952, 1606, 1511, 1462,
1248,1177, 1099, 1034, 998, 833, 750 cm–1; 1H NMR (300 MHz,
CDCl3) δ 7.09 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.7 Hz), 6.86
(1H, s), 6.85 (2H, d, J = 8.7 Hz), 6.66 (2H, d, J = 8.7 Hz), 5.21
(2H, s), 3.82 (3H, s), 3.74 (3H, s), 3.69 (2H, m), 1.98 (3H, s),
0.96 (2H, m), 0.03 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
159.5, 158.8, 158.7, 136.4, 131.3, 131.1, 129.8, 129.0, 114.0,
113.4, 97.1, 66.6, 55.13, 55.10, 18.2, 13.3, -1.39; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C24H33NNaO4Si 450.2077;
Found 450.2060. (Z)-3pa: IR (KBr) 2954, 1602, 1509, 1275,
NMR (300 MHz, CDCl3) δ 7.11 (2H, d, J = 8.7 Hz), 6.76 (2H,
d, J = 8.7 Hz), 5.99 (1H, t, J = 7.2 Hz), 5.15 (2H, s), 3.76 (3H,
s), 3.72 (2H, s), 3.63 (2H, m), 2.23 (2H, m), 1.99 (3H, s), 1.44
(2H, m), 0.95-0.87 (5H, m), -0.02 (9H, s); 13C{1H} NMR (75
MHz, CDCl3) δ 157.5, 156.6, 136.3, 133.9, 133.0, 129.2, 113.5,
97.1, 66.3, 55.2, 31.3, 30.8, 22.6, 18.1, 13.9, 11.4, -1.44; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C21H35NNaO3Si 400.2284;
Found 400.2294.
(E)-5-(benzyloxy)-3-((E)-4-methoxybenzylidene)pentan-2-
one O-((2-(trimethylsilyl)ethoxy)methyl) oxime (3ma), (2E,3E)-
5-(benzyloxy)-3-(4-methoxybenzyl)pent-3-en-2-one O-((2-(tri-
methylsilyl)ethoxy)methyl) oxime (4ma). Following the general
procedure B on 0.086 mmol scale. Purification by flash column
chromatography on silica gel (hexane : AcOEt = 5 : 1) afforded
3ma and 4ma (colorless oil, 34 mg, 3ma : 4ma = 93 : 7, 87%
yield) as inseparable mixture. 3ma, 4ma: IR (KBr) 2952, 1606,
1
1259, 1172, 1105, 1037, 999, 834, 750 cm–1; H NMR (300
MHz, CDCl3) δ 7.38 (2H, d, J = 8.7 Hz), 7.35 (2H, d, J = 8.7
Hz), 6.88 (2H, d, J = 8.7 Hz), 6.86 (1H, s), 6.84 (2H, d, J = 8.7
Hz), 5.25 (2H, s), 3.82 (3H, s), 3.81 (3H, s), 3.69 (2H, m), 2.02
(3H, s), 0.96 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.3, 158.9, 157.8, 135.5, 132.3, 130.2, 129.3, 128.0,
127.8, 113.9, 113.8, 97.0, 66.2, 55.3, 55.2, 18.2, 16.4, -1.42;
1
1509, 1251, 1178, 1100, 998, 835, 750 cm–1; H NMR (300
MHz, CDCl3, detectable signals from 4ma are marked with an
asterisk.) δ 7.37-7.32 (7H, m), 7.07* (2H, d, J = 8.7 Hz), 6.89
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Page 12 of 16
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H33NNaO4Si
450.2077; Found 450.2057.
one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (Z-3sa). Fol-
1
2
3
4
5
6
7
8
lowing the general procedure B on 0.11 mmol scale. Purifica-
tion by flash column chromatography on silica gel (hexane :
AcOEt = 10 : 1) afforded (E)-3sa (colorless oil, 25.4 mg, 48%
yield) and (Z)-3sa (colorless oil, 12.4 mg, 24% yield). (E)-3sa:
IR (KBr) 2952, 1605, 1509, 1275, 1257, 1178, 1102, 997, 828,
750 cm–1; 1H NMR (300 MHz, CDCl3, contains a small amount
of Z-isomer.) δ 7.44 (2H, d, J = 8.4 Hz), 7.04 (2H, d, J = 8.4
Hz), 6.93 (1H, s), 6.89 (2H, d, J = 8.7 Hz), 6.67 (2H, d, J = 8.7
Hz), 5.16 (2H, s), 3.75 (3H, s), 3.65 (2H, m), 2.03 (3H, s), 0.93
(2H, m), 0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 159.0,
158.6, 136.8, 135.8, 131.8, 131.7, 131.3, 130.9, 128.4, 121.3,
113.5, 97.2, 66.8, 55.2, 18.2, 12.8, -1.40; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C23H30BrNNaO3Si 498.1076; Found
498.1054. (Z)-3sa: IR (KBr) 2952, 1605, 1509, 1275, 1259,
(2E,3E)-3-(4-fluorophenyl)-4-(4-methoxyphenyl)but-3-en-2-
one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (E-3qa),
(2E,3Z)-3-(4-fluorophenyl)-4-(4-methoxyphenyl)but-3-en-2-
one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (Z-3qa). Fol-
lowing the general procedure B on 0.10 mmol scale. Purifica-
tion by flash column chromatography on silica gel (hexane :
AcOEt = 10 : 1) afforded (E)-3qa (colorless oil, 21.5 mg, 53%
yield) and (Z)-3qa (colorless oil, 13.1 mg, 32% yield). (E)-3qa:
IR (KBr) 2952, 1603, 1509, 1253, 1101, 997, 834, 750 cm–1; 1H
NMR (300 MHz, CDCl3, contains a small amount of Z-isomer.)
δ 7.15 (2H, dd, J = 8.7 Hz, 5.7 Hz), 7.02 (2H, dd, J = 8.7 Hz,
8.7 Hz), 6.93 (1H, s), 6.88 (2H, d, J = 8.7 Hz), 6.66 (2H, d, J =
8.7 Hz), 5.17 (2H, s), 3.74 (3H, s), 3.65 (2H, m), 2.03 (3H, s),
0.92 (2H, m), 0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ
163.7, 160.4, 158.95, 158.89, 135.9, 133.6, 131.7, 131.6, 131.3,
130.8, 128.6, 115.6, 115.4, 113.5, 97.2, 66.7, 55.1, 18.2, 12.8, -
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1174, 1102, 997, 831, 750, 474 cm–1; H NMR (300 MHz,
CDCl3, contains a small amount of E-isomer.) δ 7.44 (2H, d, J
= 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz),
6.87 (1H, s), 6.86 (2H, d, J = 8.7 Hz), 5.24 (2H, s), 3.82 (3H, s),
3.68 (2H, m), 2.01 (3H, s), 0.95 (2H, m), 0.01 (9H, s); 13C{1H}
NMR (75 MHz, CDCl3, contains a small amount of E-isomer.)
δ 159.3, 157.4, 138.9, 134.9, 131.6, 130.5, 130.2, 128.8, 128.2,
121.6, 113.9, 97.0, 66.3, 55.2, 18.2, 16.3, -1.43; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C23H30BrNNaO3Si 498.1076;
Found 498.1065.
1.41; HRMS (ESI-TOF) m/z: [M
+
Na]+ Calcd for
C23H30FNNaO3Si 438.1877; Found 438.1864. (Z)-3qa: IR
(KBr) 2953, 1603, 1509, 1275, 1258, 1179, 1102, 997, 834, 750
cm–1; 1H NMR (300 MHz, CDCl3) δ 7.41 (2H, dd, J = 9.0 Hz,
5.7 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.03 (2H, dd, J = 8.7 Hz, 8.7
Hz), 6.86 (2H, d, J = 9.0 Hz), 6.83 (1H, s), 5.24 (2H, s), 3.81
(3H, s), 3.68 (2H, m), 2.01 (3H, s), 0.95 (2H, m), 0.00 (9H, s);
13C{1H} NMR (75 MHz, CDCl3) δ 164.1, 160.8, 159.2, 157.6,
136.0, 135.0, 130.3, 129.6, 128.9, 128.3, 128.2, 115.5, 115.2,
113.8, 97.0, 66.3, 55.2, 18.2, 16.3, -1.43; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C23H30FNNaO3Si 438.1877; Found
438.1857.
(2E,3E)-4-(4-methoxyphenyl)-3-(3-(trifluoromethyl)phe-
nyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)methyl) oxime
(E-3ta),
(2E,3Z)-4-(4-methoxyphenyl)-3-(3-(trifluorome-
thyl)phenyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)me-
thyl) oxime (Z-3ta). Following the general procedure B on 0.10
mmol scale. Purification by flash column chromatography on
silica gel (hexane : AcOEt = 20 : 1) afforded (E)-3ta (colorless
oil, 25.4 mg, 47% yield) and (Z)-3ta (colorless oil, 11.5 mg,
25% yield). (E)-3ta: IR (KBr) 2954, 1605, 1509, 1325, 1275,
(2E,3E)-3-(4-chlorophenyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (E-3ra),
(2E,3Z)-3-(4-chlorophenyl)-4-(4-methoxyphenyl)but-3-en-2-
one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (Z-3ra). Fol-
lowing the general procedure B on 0.09 mmol scale. Purifica-
tion by flash column chromatography on silica gel (hexane :
AcOEt = 10 : 1) afforded (E)-3ra (colorless oil, 23.1 mg, 59%
yield) and (Z)-3ra (colorless oil, 11.4 mg, 29% yield). (E)-3ra:
IR (KBr) 2953, 1605, 1509, 1489, 1301, 1249, 1174, 1093, 997,
1
1257, 1163, 1127, 994, 835, 750 cm–1; H NMR (300 MHz,
CDCl3, contains a small amount of Z-isomer.) δ 7.54 (1H, d, J
= 7.8 Hz), 7.46-7.33 (3H, m), 6.99 (1H, s), 6.83 (2H, d, J = 7.8
Hz), 6.65 (2H, d, J = 7.8 Hz), 5.14 (2H, s), 3.74 (3H, s), 3.62
(2H, m), 2.08 (3H, s), 0.91 (2H, m), 0.00 (9H, s); 13C{1H} NMR
(75 MHz, CDCl3, contains a small amount of Z-isomer.) δ 159.2,
158.3, 138.7, 135.6, 133.6, 131.6, 131.3,128.8, 128.1, 127.1,
124.0, 113.6, 97.3, 66.8, 55.2, 18.1, 12.6, -1.43; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C24H30F3NNaO3Si 488.1845;
Found 488.1868. (Z)-3ta: IR (KBr) 2952, 1602, 1509, 1330,
1
859, 833, 749 cm–1; H NMR (300 MHz, CDCl3, contains a
small amount of Z-isomer.) δ 7.26 (2H, d, J = 8.7 Hz), 7.09 (2H,
d, J = 8.7 Hz), 6.91 (2H, d, J = 8.7 Hz), 6.86 (1H, s), 6.66 (2H,
d, J = 8.7 Hz), 5.15 (2H, s), 3.73 (3H, s), 3.63 (2H, m), 2.02 (3H,
s), 0.92 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3,
contains a small amount of Z-isomer.) δ 159.0, 158.7, 136.3,
135.8, 133.1, 131.5, 131.3, 130.9, 128.7, 128.4, 113.5, 97.2,
66.8, 55.1, 18.2, 12.8, -1.41; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C23H30ClNNaO3Si 454.1581; Found 454.1561. (Z)-
3ra: IR (KBr) 2952, 1605, 1509,1249, 1174, 1093, 997, 833,
749 cm–1; 1H NMR (300 MHz, CDCl3, contains a small amount
of E-isomer.) δ 7.40-7.28 (6H, m), 6.87 (1H, s), 6.86 (2H, d, J
= 8.7 Hz), 5.24 (2H, s), 3.81 (3H, s), 3.68 (2H, m), 2.01 (3H, s),
0.95 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3,
contains a small amount of E-isomer.) δ 159.3, 157.5, 138.4,
134.8, 133.5, 130.4, 130.1, 128.8, 128.6, 127.9, 113.8, 97.0,
66.3, 55.2, 18.2, 16.3, -1.43; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C23H30ClNNaO3Si 454.1581; Found 454.1559.
1
1259, 1168, 1127, 997, 835, 750 cm–1; H NMR (300 MHz,
CDCl3, contains a small amount of E-isomer.) δ 7.70 (1H, s),
7.64-7.40 (3H, m), 7.37 (2H, d, J = 8.7 Hz), 6.93 (1H, s), 6.87
(2H, d, J = 8.7 Hz), 5.25 (2H, s), 3.83 (3H, s), 3.70 (2H, m),
2.03 (3H, s), 0.96 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3, contains a small amount of E-isomer.) δ 159.5, 157.3,
140.8, 134.7, 131.3, 130.6, 129.9, 128.9, 128.6, 124.2, 123.3,
113.9, 97.0, 66.3, 55.2, 18.2, 16.4, -1.47; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C24H30F3NNaO3Si 488.1845; Found
488.1847.
(2E,3E)-3-(4-methoxybenzyl)-4-(3,4,5-trimethoxy-
phenyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)methyl)
oxime (3fb), (2E,3E)-4-(4-methoxyphenyl)-3-(3,4,5-trimethox-
ybenzyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)methyl)
oxime (4fb). Following the general procedure B on 0.09 mmol
scale. Purification by flash column chromatography on silica
gel (hexane : AcOEt = 3 : 1) afforded 3fb (colorless oil, 16.1
(2E,3E)-3-(4-bromophenyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (E-3sa),
(2E,3Z)-3-(4-bromophenyl)-4-(4-methoxyphenyl)but-3-en-2-
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The Journal of Organic Chemistry
mg, 36% yield) and 4fb (colorless oil, 19.4 mg, 43% yield). 3fb: contains inseparable isomer 4fd.) δ 157.6, 156.7, 137.5, 136.9,
IR (KBr) 1579, 1509, 1275, 1128, 999, 835, 750 cm–1; 1H NMR
(300 MHz, CDCl3, contains a small amount of inseparable iso-
mer 4fb.) δ 7.09 (2H, d, J = 8.7 Hz), 7.03 (1H, s), 6.79 (2H, d,
J = 8.7 Hz), 6.50 (2H, s), 5.15 (2H, s), 3.99 (2H, s), 3.83 (3H,
s), 3.76 (3H, s), 3.63 (6H, s), 3.60 (2H, m), 2.17 (3H, s), 0.87
(2H, m), -0.03 (9H, s); 13C{1H} NMR (75 MHz, CDCl3, con-
tains a small amount of inseparable isomer 4fd.) δ 157.6, 156.7,
152.9, 137.4, 136.7, 132.6, 132.34, 132.25, 130.3, 128.9, 113.7,
106.1, 97.3, 66.6, 60.9, 55.8, 55.2, 32.5, 18.1, 11.6, -1.44;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H39NNaO6Si
524.2444; Found 524.2420. 4fb: IR (KBr) 2952, 1605, 1588,
1509, 1455, 1420, 1328, 1249, 1179, 1128, 999, 894, 835, 750,
529 cm–1; 1H NMR (300 MHz, CDCl3, contains a small amount
of inseparable isomer 3fb.) δ 7.28 (2H, d, J = 9.0 Hz ), 7.06 (1H,
s), 6.88 (2H, d, J = 9.0 Hz), 6.42 (2H, s), 5.18 (2H, s), 3.96 (2H,
s), 3.82 (3H, s), 3.81 (3H, s), 3.80 (6H, s), 3.65 (2H, m), 2.16
(2H, s), 0.90 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.0, 157.0, 153.0, 136.3, 135.9, 135.6, 132.2, 130.2,
129.3, 113.8, 105.1, 97.2, 66.4, 60.8, 55.9, 55.3, 33.2, 18.0, 11.7,
-1.44; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C27H39NNaO6Si 524.2444; Found 524.2421.
132.6, 132.2, 129.1, 128.8, 128.3, 127.4, 113.6, 97.2, 66.5, 55.1,
32.2, 18.1, 11.7, -1.42; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C24H33NNaO3Si 434.2127; Found 434.2115. 4fd (3ka): IR
1
2
3
4
5
6
7
8
1
(KBr) 1606, 1509, 1248, 1105, 997, 835, 750 cm–1; H NMR
(300 MHz, CDCl3) δ 7.26-7.10 (7H, m), 7.06 (1H, s), 6.84 (2H,
d, J = 9.0 Hz), 5.11 (2H, s), 4.02 (2H, s), 3.79 (3H, s), 3.55 (2H,
m), 2.14 (3H, s), 0.85 (2H, m), 0.02 (9H, s); 13C{1H} NMR (75
MHz, CDCl3) δ 158.9, 156.8, 140.7, 135.4, 132.1, 130.2, 129.3,
128.2, 128.1, 125.6, 113.8, 97.2, 66.5, 55.2, 33.2, 18.1, 11.6, -
9
1.40; HRMS (ESI-TOF) m/z: [M
C24H33NNaO3Si 434.2127; Found 434.2115.
+
Na]+ Calcd for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2E,3E)-4-([1,1'-biphenyl]-4-yl)-3-(4-methoxybenzyl)but-3-
en-2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3fe),
(2E,3E)-3-([1,1'-biphenyl]-4-ylmethyl)-4-(4-methoxy-
phenyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)methyl)
oxime (4fe). Following the general procedure B on 0.09 mmol
scale. Purification by flash column chromatography on silica
gel (hexane : AcOEt = 10 : 1) afforded 3fe (colorless oil, 14.4
mg, 33% yield) and 4fe (colorless oil, 17.8 mg, 41% yield). 3fe:
IR (KBr) 2951, 1606, 1509, 1486, 1275, 1259, 1104, 997, 835,
750 cm–1; 1H NMR (300 MHz, CDCl3,contains inseparable iso-
mer 4fe.) δ 7.62-7.24 (9H, m), 7.15-7.07 (3H, m), 6.86 (2H, d,
J = 8.7 Hz), 5.14 (2H, s), 4.07 (2H, s), 3.64 (3H, s), 3.60 (2H,
m), 2.18 (3H, s), 0.88 (2H, m), -0.04 (9H, s); 13C{1H} NMR (75
MHz, CDCl3, contains inseparable isomer 4fe.) δ 157.6, 156.7,
140.5, 140.1, 137.5, 135.8, 132.5, 131.8, 129.3, 129.1, 128.8,
127.4, 127.0, 113.4, 97.2, 66.5, 55.1, 32.4, 18.1, 11.7, -1.41;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C30H37NNaO3Si
510.2440; Found 510.2415. 4fe: IR (KBr) 1605, 1509, 1487,
1275, 1259, 1178, 1105, 997, 895, 835, 751, 698 cm–1; 1H NMR
(300 MHz, CDCl3) δ 7.58 (2H, d, J = 8.1 Hz), 7.49 (2H, d, J =
8.1 Hz), 7.42 -7.23 (7H, m), 7.08 (1H, s), 6.86 (2H, d, J = 9.0
Hz), 5.13 (2H, s), 4.06 (2H, s), 3.80 (3H, s), 3.58 (2H, m), 2.17
(3H, s,), 0.84 (2H, m), -0.05 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.0, 156.7, 141.1, 139.9, 138.4, 135.3, 132.2, 130.3,
129.3, 128.7, 128.5, 126.95, 126.90, 113.9, 97.3, 66.5, 55.3,
32.8, 18.0, 11.6, -1.42; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C30H37NNaO3Si 510.2440; Found 510.2422.
(2E,3E)-3-(4-methoxybenzyl)-4-(p-tolyl)but-3-en-2-one O-
((2-(trimethylsilyl)ethoxy)methyl) oxime (3fc), (2E,3E)-4-(4-
methoxyphenyl)-3-(4-methylbenzyl)but-3-en-2-one O-((2-(tri-
methylsilyl)ethoxy) methyl) oxime (4fc). Following the general
procedure B on 0.09 mmol scale. Purification by flash column
chromatography on silica gel (hexane : AcOEt = 30 : 1) afforded
3fc (colorless oil, 17.6 mg, 46% yield) and 4fc (colorless oil,
17.6 mg, 46% yield). 3fc: IR (KBr) 1509, 1275, 1105, 998, 835,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.21 (2H, d, J = 8.1
Hz), 7.12 (2H, d, J = 8.1 Hz), 7.10 (1H, s), 7.06 (2H, d, J = 8.7
Hz), 6.79 (2H, d, J = 8.7 Hz), 5.13 (2H, s), 3.94 (2H, s), 3.77
(3H, s), 3.59 (2H, m), 2.33 (3H, s), 2.13 (3H, s), 0.87 (2H, m),
-0.02 (9H, s) ; 13C{1H} NMR (75 MHz, CDCl3) δ 157.5, 156.8,
137.2, 136.7, 133.9, 132.7, 132.2, 129.08, 129.07, 128.8, 113.6,
97.2, 66.5, 55.1, 32.3, 21.2, 18.1, 11.7, -1.41; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C25H35NNaO3Si 448.2284;
Found 448.2270. 4fc: IR (KBr) 2952, 1606, 1509, 1275, 1257,
1
1178, 1104, 998, 895, 835, 750 cm–1; H NMR (300 MHz,
(2E,3E)-4-(4-chlorophenyl)-3-(4-methoxybenzyl)but-3-en-2-
one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3ff), (2E,3E)-
3-(4-chlorobenzyl)-4-(4-methoxyphenyl)but-3-en-2-one O-((2-
(trimethylsilyl)ethoxy) methyl) oxime (4ff). Following the gen-
eral procedure B on 0.09 mmol scale. Purification by flash col-
umn chromatography on silica gel (hexane : AcOEt = 10 : 1)
afforded 3ff (colorless oil, 13.0 mg, 32% yield) and 4ff (color-
less oil, 22.0 mg, 55% yield) as inseparable mixture. 3ff, 4ff: IR
(KBr) 1606, 1509, 1248, 1177, 1095, 997, 896, 835, 750 cm–1;
1H NMR (300 MHz, CDCl3, signals from the minor isomer 3ff
are marked with an asterisk.) δ 7.28-7.19* (4H, m), 7.21-7.18
(4H, m), 7.09 (2H, d, J = 8.4 Hz), 7.06 (1H, s), 7.05* (2H, d, J
= 8.7 Hz), 7.00* (1H, s), 6.85 (2H, d, J = 8.7 Hz), 6.79* (2H, d,
J = 8.7 Hz), 5.16* (2H, s), 5.12 (2H, s), 3.99 (2H, s), 3.92* (2H,
s), 3.81 (3H, s), 3.79* (3H, s), 3.58* (2H, m), 3.54 (2H, m), 2.16
(3H, s), 2.14* (3H, s), 0.88 (2H, m), 0.87* (2H, m), 0.00 (9H,
s), -0.00* (9H, s); 13C{1H} NMR (75 MHz, CDCl3, inseparable
mixture of 3ff and 4ff) δ 159.1, 157.7, 156.5, 156.4, 139.3,
138.1, 135.3, 135.0, 133.2, 132.5, 132.2, 131.2, 130.8, 130.2,
130.17, 130.12 129.5, 129.1, 129.0, 128.5, 128.3, 113.9, 113.7,
97.3, 66.49, 66.44, 55.2, 55.1, 32.5, 32.2, 18.0, 11.7, 11.4,-1.43;
CDCl3) δ 7.25 (2H, d, J = 8.7 Hz), δ 7.06 (4H, s), 7.04 (1H, s),
6.84 (2H, d, J = 8.7 Hz), 5.12 (2H, s), 3.98 (2H, s), 3.79 (3H, s),
3.57 (2H, m), 2.30 (3H, s), 2.13 (3H, s), 0.85 (2H, m), -0.02 (9H,
s) ; 13C{1H} NMR (75 MHz, CDCl3) δ 158.9, 156.8, 137.5,
135.6, 134.9, 131.9, 130.2, 129.4, 129.0, 128.0, 113.8, 97.2,
66.5, 55.2, 32.7, 21.0, 18.1, 11.7, -1.42; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C25H35NNaO3Si 448.2284; Found
448.2273.
(2E,3E)-3-(4-methoxybenzyl)-4-phenylbut-3-en-2-one
((2-(trimethylsilyl)ethoxy)methyl) oxime (3fd), (2E,3E)-3-ben-
zyl-4-(4-methoxyphenyl)but-3-en-2-one O-((2-(trimethylsi-
O-
lyl)ethoxy)methyl) oxime (4fd). Following the general proce-
dure B on 0.09 mmol scale. Purification by flash column chro-
matography on silica gel (hexane : AcOEt = 30 : 1) afforded 3fd
(colorless oil, 13.1 mg, 35% yield) and 4fd (colorless oil, 16.1
mg, 43% yield) as inseparable mixture. 3fd (4ka): IR (KBr)
1605, 1509, 1275, 1259, 1178, 1103, 997, 835, 764, 750 cm–1;
1H NMR (300 MHz, CDCl3, contains inseparable isomer 4fd.)
δ 7.30-7.08 (7H, m), 7.09 (1H, s), 6.81 (2H, d, J = 9.0 Hz), 5.16
(2H, s), 3.96 (2H, s), 3.79 (3H, s), 3.60 (2H, m), 2.15 (3H, s),
0.89 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz, CDCl3,
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The Journal of Organic Chemistry
Page 14 of 16
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H32ClNNaO3Si
468.1738; Found 468.1729.
30 : 1) afforded 3fi (colorless oil, 15.5 mg, 36% yield) and 4fi
1
2
3
4
5
6
7
8
(colorless oil, 2.5 mg, 6% yield). 3fi: IR (KBr) 2952, 1611, 1510,
1428, 1275, 1246, 1176, 1105, 1037, 998, 895, 857, 835, 764,
750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.34 (2H, d, J = 7.8
Hz), 7.18 (1H, m), 6.94 (2H, d, J = 8.7 Hz), 6.68 (1H, s), 6.67
(2H, d, J = 8.7 Hz), 5.19 (2H, s), 3.72 (3H, s), 3.64 (2H, m),
3.58 (2H, s), 2.12 (3H, s), 0.92 (2H, m), 0.00 (9H, s); 13C{1H}
NMR (75 MHz, CDCl3) δ 157.5, 155.4, 142.0, 135.03, 134.99,
131.9, 129.7, 129.0, 127.9, 125.9, 113.2, 97.3, 66.4, 55.1, 33.4,
18.1, 11.8, -1.41; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C24H31Cl2NNaO3Si 502.1348; found 502.1335. 4fi: IR (KBr)
(2E,3E)-4-(4-bromophenyl)-3-(4-methoxybenzyl)but-3-en-2-
one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3fg), (2E,3E)-
3-(4-bromobenzyl)-4-(4-methoxyphenyl)but-3-en-2-one O-((2-
(trimethylsilyl)ethoxy) methyl) oxime (4fg). Following the gen-
eral procedure B on 0.09 mmol scale. Purification by flash col-
umn chromatography on silica gel (hexane : AcOEt = 30 : 1)
afforded 3fg (colorless oil, 13.0 mg, 16% yield) and 4fg (color-
less oil, 12.9 mg, 29% yield) as inseparable mixture. 3fg, 4fg:
IR (KBr) 2951, 1509, 1275, 1259, 1103, 998, 897, 836, 764,
750 cm–1; 1H NMR (300 MHz, CDCl3, signals from the minor
isomer 3fg are marked with an asterisk.) δ 7.39* (2H, d, J = 8.1
Hz), 7.32 (2H, d, J = 8.7 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.15*
(2H, d, J = 8.1 Hz), 7.07 (1H, s), 7.06* (2H, d, J = 8.7 Hz), 7.05
(2H, d, J = 8.7 Hz), 6.98* (1H, s), 6.84 (2H, d, J = 9.0 Hz),
6.79* (2H, d, J = 8.7 Hz), 5.14* (2H, s), 5.10 (2H, s), 3.95 (2H,
s), 3.90* (2H, s), 3.80 (3H, s), 3.77* (3H, s), 3.56* (2H, m),
3.53 (2H, m), 2.14 (3H, s), 2.12* (3H, s), 0.87* (2H, m), 0.84
(2H, m), -0.00* (9H, s), -0.02 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3, inseparable mixture of 3fg and 4fg.) δ 159.1, 157.7,
156.5, 156.4, 139.9, 138.2, 135.7, 134.9, 132.5, 132.2, 131.5,
131.3, 130.9, 130.4, 130.2, 129.9, 129.1, 129.0, 121.4, 119.3,
113.9, 113.7, 97.3, 66.50, 66.46, 55.26, 55.16, 32.6, 32.2, 18.0,
11.7, 11.4, -1.42; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C24H32BrNNaO3Si 512.1233; Found 512.1227.
9
1
2918, 1509, 1435, 1249, 997, 835, 750 cm–1; H NMR (300
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3) δ 7.25 (2H, d, J = 9.0 Hz), 7.13 (2H, d, J = 7.8
Hz), 6.95 (1H, t, J = 7.8 Hz), 6.89 (1H, s), 6.86 (2H, d, J = 9.0
Hz), 5.04 (2H, s), 4.21 (2H, s), 3.81 (3H, s), 3.55 (2H, m), 2.04
(3H, s), 0.87 (2H, m), 0.00 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3) δ 158.6, 156.7, 136.7, 136.0, 134.7, 131.9, 130.2, 129.5,
128.0, 127.1, 113.6, 97.1, 66.0, 55.3, 31.3, 18.1, 12.3, -1.34;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H31Cl2NNaO3Si
502.1348; Found 502.1327.
(2E,3E)-4-(6-chloropyridin-3-yl)-3-(4-methoxybenzyl)but-3-
en-2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3fj),
(2E,3E)-3-((6-chloropyridin-3-yl)methyl)-4-(4-methoxy-
phenyl)but-3-en-2-one O-((2-(trimethylsilyl)ethoxy)methyl) ox-
ime (4fj). Following the general procedure B on 0.09 mmol
scale. Purification by flash column chromatography on silica
gel (hexane : AcOEt = 10 : 1) afforded 3fj (colorless oil, 2.2 mg,
5% yield) and 4fj (colorless oil, 7.8 mg, 19% yield) as insepa-
rable mixture. 3fj, 4fj: IR (KBr) 2917, 2358, 1606, 1509, 1457,
1275, 1257, 1177, 1105, 997, 896, 835, 750 cm–1; 1H NMR (300
MHz, CDCl3,signals from the minor isomer 3fj are marked with
an asterisk.) δ 8.31* (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 2.1
Hz), 7.52* (1H, dd, J = 8.4, 2.4 Hz), 7.44 (1H, dd, J = 8.4, 2.1
Hz), 7.23* (1H, s), 7.18 (1H, s), 7.17 (2H, d, J = 8.7 Hz), 7.08
(1H, s), 7.03* (2H, d, J = 8.7 Hz), 6.95* (1H, s), 6.88 (2H, d, J
= 8.7 Hz), 6.78* (2H, d, J = 8.7 Hz), 5.15* (2H, s), 5.10 (2H, s),
3.95 (2H, s), 3.90* (2H, s), 3.81 (3H, s), 3.77* (3H, s), 3.60*
(2H, m), 3.57 (2H, m), 2.13 (3H, s), 2.13* (3H, s), 0.90* (2H,
m), 0.88 (2H, m), -0.01 (9H, s), -0.02* (9H, s); 13C{1H} NMR
(75 MHz, CDCl3, inseparable mixture of 3fj and 4fj) δ 159.2,
157.9, 156.2, 156.1, 149.9, 149.7, 148.6, 140.5, 138.6, 138.4,
135.5, 134.4, 133.0, 131.5, 130.0, 128.9, 128.8, 126.8, 123.8,
123.7, 114.0, 113.9, 97.3, 66.4, 55.3, 32.3, 29.7, 18.1, 18.0, 11.7,
11.2, -1.42; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C23H31FN2NaO3Si 453.1986; Found 453.1981.
(2E,3E)-3-(4-methoxybenzyl)-4-(4-(trifluoromethyl)phe-
nyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)methyl) oxime
(3fh), (2E,3E)-4-(4-methoxyphenyl)-3-(4-(trifluoromethyl)ben-
zyl)but-3-en-2-one O-((2-(trimethylsilyl) ethoxy)methyl) oxime
(4fh). Following the general procedure B on 0.09 mmol scale.
Purification by flash column chromatography on silica gel (hex-
ane : AcOEt = 30 : 1) afforded 3fh (colorless oil, 9.0 mg, 21%
yield) and 4fh (colorless oil, 18.0 mg, 42% yield). 3fh: IR (KBr)
2953, 1614, 1509, 1323, 1275,1246, 1165, 1126, 1067, 997, 835,
764, 750 cm–1; 1H NMR (300 MHz, CDCl3, contains insepara-
ble isomer 4fh.) δ 7.56 (2H, d, J = 9.0 Hz), 7.38 (2H, d, J = 9.0
Hz), 7.07 (1H, s), 7.05 (2H, d, J = 8.7 Hz), 6.79 (2H, d, J = 8.7
Hz), 5.15 (2H, s), 3.91 (2H, s), 3.77 (3H, s), 3.59 (2H, m), 2.14
(3H, s), 0.88 (2H, m), -0.02 (9H, s); 13C{1H} NMR (75 MHz,
CDCl3,contains inseparable isomer 4fh.) δ 157.7, 156.3, 140.5,
139.4, 132.0, 130.5, 129.03, 128.98, 125.3, 125.2, 113.8, 97.3,
66.5, 55.2, 32.3, 18.1, 11.8, -1.42; HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C25H32F3NNaO3Si 502.2001; Found 502.1976.
4fh: IR (KBr) 2954, 1607, 1509, 1324, 1253, 1161, 1123, 1066,
998, 898, 835, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ 7.50
(2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 9.0 Hz), 7.20 (2H, d, J =
8.7 Hz), 7.10 (1H, s), 6.85 (2H, d, J = 9.0 Hz), 5.09 (2H, s), 4.06
(2H, s), 3.80 (3H, s), 3.53 (2H, m), 2.16 (3H, s), 0.82 (2H, m),
-0.03 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 159.1, 156.3,
145.2, 134.6, 132.8, 130.1, 129.0, 128.4, 125.2, 125.1, 113.9,
97.3, 66.4, 55.3, 33.1, 18.0, 11.3, -1.47; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C25H32F3NNaO3Si 502.2001; Found
502.1976.
(2E,3E)-4-(6-fluoropyridin-3-yl)-3-(4-methoxybenzyl)but-
3-en-2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3fk),
(2E,3E)-3-((6-fluoropyridin-3-yl)methyl)-4-(4-methoxy-
phenyl)but-3-en-2-one O-((2-(trimethylsilyl)ethoxy)methyl)
oxime (4fk). Following the general procedure B on 0.09 mmol
scale. Purification by flash column chromatography on silica
gel (hexane : AcOEt = 10 : 1) afforded 3fk (colorless oil, 5 mg,
13% yield) and 4fk (colorless oil, 14.8 mg, 38% yield) as in-
separable mixture. 3fk, 4fk: IR (KBr) 2917, 1595,1509, 1482,
1
1395, 1275, 1259, 1178, 1105, 998, 835, 764, 750 cm–1; H
(2E,3E)-4-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)but-3-
en-2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (3fi),
(2E,3E)-3-(2,6-dichlorobenzyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-((2-(trimethylsilyl)ethoxy) methyl) oxime (4fi). Follow-
ing the general procedure B on 0.09 mmol scale. Purification by
flash column chromatography on silica gel (hexane : AcOEt =
NMR (300 MHz, CDCl3,signals from the minor isomer 3fk are
marked with an asterisk.) δ 8.13* (1H, d, J = 2.1 Hz), 7.98 (1H,
d, J = 2.1 Hz), 7.66* (1H, dd, J = 8.4, 2.1 Hz), 7.56 (1H, dd, J
= 8.4, 2.1 Hz), 7.19 (2H, d, J = 8.7Hz), 7.07 (1H, s), 7.03* (2H,
d, J = 8.7 Hz), 6.97* (1H, s), 6.87 (2H, d, J = 8.7 Hz), 6.89-
6.84* (1H, m), 6.79 (1H, d, J = 8.4 Hz), 6.78* (2H, d, J = 8.7
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The Journal of Organic Chemistry
Hz), 5.15* (2H, s), 5.11 (2H, s), 3.96 (2H, s), 3.89* (2H, s), 3.81
(2H, s), 3.73 (2H, m), 2.11 (3H, s), 2.06 (3H, s), 0.96 (2H, m),
0.01 (9H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 166.8, 157.0,
142.6, 140.3, 136.1, 128.6, 128.2, 127.2, 122.5, 97.4, 66.7, 66.3,
18.1, 13.4, 10.9, -1.45; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C21H31NNaO4Si 412.1920; Found 412.1926.
1
2
3
4
5
6
7
8
(3H, s), 3.77* (3H, s), 3.58 (2H, m), 3.58* (2H, m), 2.14* (3H,
s), 2.13 (3H, s), 0.90* (2H, m), 0.88 (2H, m), -0.01 (9H, s), -
0.02* (9H, s); 13C{1H} NMR (75MHz, CDCl3,inseparable mix-
ture of 3fk and 4fk) δ 163.6, 160.5, 159.2, 157.8, 156.2, 156.1,
147.9, 147.7, 147.2, 147.0, 141.0, 140.9, 139.8, 134.7, 134.0,
133.9, 132.9, 131.6, 130.1, 128.9, 128.8, 126.9, 114.0, 113.9,
109.4, 109.0, 108.9, 108.5, 97.3, 97.2, 66.5, 66.4, 55.3, 55.2,
32.2 29.7, 29.5, 18.0, 11.7, 11.2, -1.44; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C23H31FN2NaO3Si 453.1986; Found
453.1981.
Conversion of β-Arylated α,β-unsaturated oximes to
Multi-substituted Pyridine.3a 4-(4-methoxyphenyl)-2,3-dime-
thyl-5,6-diphenylpyridine. To a solution of (2E,3E)-4-(4-meth-
oxyphenyl)-3-methylbut-3-en-2-one O-((2-(trimethylsilyl)eth-
oxy)methyl) oxime (3ia, 0.1 mmol, 1.0 eq.) and diphenylacety-
lene (1.2 eq.) in toluene was added RhCl(PPh3)3 (5 mol%) and
stirring at reflux (silicone oil bath) for 24 h. After completion,
the reaction mixture was diluted with AcOEt and filtered
through a Celite® pad (rinsed with AcOEt). The filtrate was con-
centrated in vacuo, and the crude product was purified by flash
column chromatography on silica gel (hexane : AcOEt = 5 : 1)
afforded the title compound (12 mg, 32% yield) as pale yellow
solid.
To a solution of (2E,3E)-4-(4-methoxyphenyl)-3-methylbut-3-
en-2-one oxime (0.1 mmol, 1.0 eq.) and diphenylacetylene (1.2
eq.) in toluene was added RhCl(PPh3)3 (5 mol%) and stirring at
reflux (silicone oil bath) for 3 h. After completion, the reaction
mixture was diluted with AcOEt and filtered through a Celite®
pad (rinsed with AcOEt). The filtrate was concentrated in vacuo,
and the crude product was purified by flash column chromatog-
raphy on silica gel (hexane : AcOEt = 5 : 1) afforded the title
compound (29 mg, 80% yield) as pale yellow solid. mp 116-
118 ℃; IR (KBr) 3450, 1636, 1275, 1261, 750 cm–1; 1H NMR
(300 MHz, CDCl3) δ 7.25-23 (2H, m), 7.15-7.12 (3H, m), 7.00-
6.94 (3H, m), 6.86 (2H, d, J = 8.7 Hz), 6.84-6.78 (2H, m), 6.73
(2H, d, J = 8.7 Hz), 3.75 (3H, s), 2.68 (3H, s), 2.11 (3H, s);
13C{1H} NMR (75 MHz, CDCl3) δ 158.2, 156.0, 154.3, 149.6,
141.1, 138.8, 133.2, 131.2, 131.1, 130.6, 129.9, 128.5, 127.5,
127.2, 126.9, 125.9, 113.2, 55.1, 23.6, 16.8; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C26H23NO 365.1780; Found 365.1744.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2Z,3E)-3-(4-methoxybenzyl)-4-(4-methoxyphenyl)but-3-en-
2-one O-methyl oxime (3ua). Following the general procedure
B on 0.064 mmol scale. Purification by flash column chroma-
tography on silica gel (hexane : AcOEt = 10 : 1) afforded 3ua
(colorless oil, 14 mg, 67% yield). IR (KBr) 3500, 2358, 1607,
1509, 1463, 1275, 1256, 1175, 1044, 749 cm–1; 1H NMR (300
MHz, CDCl3) δ 7.18 (2H, d, J = 9.0 Hz), 7.15 (2H, d, J = 9.0
Hz), 6.84 (2H, d, J = 9.0 Hz), 6.81 (2H, d, J = 9.0 Hz), 6.35 (1H,
s), 3.90 (3H, s), 3.793 (3H, s), 3.787 (3H, s), 3.64 (2H, s), 1.62
(3H, s); 13C{1H} NMR (75 MHz, CDCl3) δ 158.8, 158.1, 157.5,
137.4, 131.1, 130.2, 129.9, 129.4, 129.2, 113.7, 113.6, 61.6,
55.22, 55.21, 43.6, 15.9; HRMS (EI-quadrupole) m/z: [M]+
Calcd for C20H23NO3 325.1678; Found 325.1684.
1.0 mmol scale synthesis of 3fa. Following the general pro-
cedure B on 1.0 mmol scale. Purification by flash column chro-
matography on silica gel (hexane : AcOEt = 30 : 1) afforded 3fa
(colorless oil, 355 mg, 80% yield).
Preparation of deuterated α,β-unsaturated oxime . (E)-3-
(4-methoxybenzyl)but-3-en-2-one-1,1,1,4,4-d
O-((2-(trime-
5
thylsilyl) ethoxy)methyl) oxime-1,1,1,4,4-d5 (1f-d5). Following
the general procedure for α,β-unsaturated oxime SEM ether
synthesis, (E)-3-(4-methoxybenzyl)but-3-en-2-one-4,4-d2 ox-
ime-4,4-d2 (280 mg, 1.35 mmol) was converted to the title com-
ASSOCIATED CONTENT
pound (460 mg, quant.) as colorless oil. Purified by flash col-
umn chromatography on silica gel (hexane : AcOEt = 20 : 1).
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website.
Isotope Labeling Experiment. Isotope labeling experiment
was performed following the general procedure B on 0.09 mmol
scale. Purification by flash column chromatography on silica
gel (hexane : AcOEt = 10 : 1) afforded 3fd-d4 and 4fd-d5 (col-
orless oil, 25.1 mg, 67% yield) as inseparable mixture.
Characterization data for all new compounds, additional
experiments and spectral data (PDF) ꢀ
AUTHOR INFORMATION
Procedure for the Synthesis of 7. Benzyl (8E,10E,12E)-
2,2,9,10-tetramethyl-5,7-dioxa-8-aza-2-silatetradeca-8,10,12-
trien-14-oate (7). To a solution of α,β-unsaturated oxime 1i (30
mg, 0.13 mmol, 1.0 eq.), benzyl acrylate 6 (0.20 mmol, 1.5 eq.),
Ag2CO3 (0.26 mmol, 2.0 eq.), AgTFA (0.05 mmol, 0.4 eq.),
L12 (0.04 mmol, 30 mol%), 2,6-dimethyl-1,4-benzoquinone
(0.04 mmol, 30 mol%) in dioxane (2.0 mL) was added
Pd(OAc)2 (0.013 mmol, 10 mol%). After stirring at 90 ℃ (sili-
cone oil bath) for 24 h, the reaction mixture was diluted with
AcOEt and filtered through a Celite® pad (rinsed with AcOEt).
The filtrate was concentrated in vacuo, and the crude product
was purified by flash column chromatography on silica gel
(hexane : AcOEt = 5 : 1) afforded azatriene 7 (6.2 mg, 12%
yield) as colorless oil. IR (KBr) 2948, 1714, 1621, 1275, 1260,
1139, 993, 835, 763, 750 cm–1; 1H NMR (300 MHz, CDCl3) δ
7.74 (1H, dd, J = 15.3 Hz, 11.7Hz), 7.40-7.34 (5H, m), 6.53 (1H,
d, J = 11.7 Hz), 6.05 (1H, d, J = 15.3 Hz), 5.25 (2H, s), 5.22
Corresponding Author
Tamura Osamu ꢀ Showa Pharmaceutical University,
Machida, Tokyo 194-8543, Japan; E-mail:
tamura@ac.shoyaku.ac.jp.
Authors
Takahiro Yamada ꢀ Showa Pharmaceutical University,
Machida, Tokyo 194-8543, Japan
Yoshimitsu Hashimoto ꢀ Showa Pharmaceutical Univer-
sity, Machida, Tokyo 194-8543, Japan
Kosaku Tanaka, III ꢀ Showa Pharmaceutical University,
Machida, Tokyo 194-8543, Japan
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Machida, Tokyo 194-8543, Japan
Notes
The authors declare no competing financial interest.
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See the experimental section for details.
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