Access to functionalized bicyclo[4,3,0]nonenes via palladium-catalyzed oxidative cyclization of 2-allylcyclohexyl oximes

Article abstract of DOI:10.1021/jo5005422

A new palladium-catalyzed oxidative cyclization process leading to the functionalized bicyclo[4,3,0]nonenes is serendipitously discovered during attempts to form aza-heterocycle by the amino-Heck reaction of trans-2-vinylclohexyl phosphinyloxime. Under the influence of Pd(dba) ₂/Et₃N/1:1 N₂-O₂ (1:1, v/v) (Method A) or Pd(OAc)₂/Et₃N/O₂ (Method B), the reactions afford the substituted cis-1-hydroxyl-8-formyl-bicyclo[4,3,0]non-8(9)- enes or bicycle[4,3,0]non-1(9)-en-8-ones in varying yields with the incorporation of molecular oxygen into the structures. The 5,6-bicyclic scaffold of these products is presumably derived from tandem double intramolecular cyclization followed by the ring-opening of an aza-palladium(II) tricyclic intermediate.

Full text of DOI:10.1021/jo5005422

Article
pubs.acs.org/joc
Access to Functionalized Bicyclo[4,3,0]nonenes via Palladium-
Catalyzed Oxidative Cyclization of 2‑Allylcyclohexyl Oximes
Jia-Liang Zhu,* Sih-Ting Wu, and Jr-Yun Shie
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan
S
* Supporting Information
ABSTRACT: A new palladium-catalyzed oxidative cyclization
process leading to the functionalized bicyclo[4,3,0]nonenes is
serendipitously discovered during attempts to form aza-
heterocycle by the amino-Heck reaction of trans-2-vinyl-
clohexyl phosphinyloxime. Under the influence of Pd(dba)2/
Et3N/1:1 N2−O2 (1:1, v/v) (Method A) or Pd(OAc)2/Et3N/
O2 (Method B), the reactions afford the substituted cis-1-
hydroxyl-8-formyl-bicyclo[4,3,0]non-8(9)-enes or bicycle-
[4,3,0]non-1(9)-en-8-ones in varying yields with the incorporation of molecular oxygen into the structures. The 5,6-bicyclic
scaffold of these products is presumably derived from tandem double intramolecular cyclization followed by the ring-opening of
an aza-palladium(II) tricyclic intermediate.
After the aforementioned studies, we intended to extend the
protocol to 2-allylcyclohexyl oxime system, whose cyclization
reaction, as far as we know, has never been reported. For the
analogous but more-rigid ortho-allylacetophenone acyloximes,
Narasaka and co-workers9 have shown the Pd(0)-catalyzed
cyclization occurred in an 6-exo mode to give isoquinolines
(Scheme 2). According to this report and our experience,7,8 we
had originally envisaged that the cyclization of allylcyclohexyl
oximes would lead to either 3-methyl tetrahydroisoquinolines
(6-exo) or tetrahydrobenzoazepines (7-endo). However, during
the investigation, it was found that most attempted reactions
did not give the products as we expected. Herein, we wish to
report the preliminary results from this study together with a
novel Pd-catalyzed oxidative cyclization process allowing the
rapid construction of the highly functionalized bicyclo[4,3,0]-
nonene scaffold.
INTRODUCTION
■
Palladium(0)-catalyzed intramolecular cyclization of unsatu-
rated oximes (amino-Heck reaction) is an important synthetic
strategy for preparing various aza-heterocycles.1,2 Pioneering
works by Narasaka and Kitamura2i have established that these
types of reactions are initiated by the oxidative addition of the
N−O bond to Pd(0) species, and the resulting aza-Pd (II)
complex then engages in the cyclization with internal olefins to
give cyclic products. To date, the most widely employed
precursors for amino-Heck reactions are O-pentafluorobenzoyl-
oximes,2,3 which are proved to be superior to many other kinds
of oximes, such as sulfonyl-, acetyl-, and benzoyloximes, in
terms of reactivity, stability, and production of fewer undesired
byproducts.4 In our continuation study on the cyclization
reactions of phosphonyl compounds,5−8 we previously
demonstrated that a range of γ,δ-unsaturated diethyl-
phosphinyloximes could cyclize smoothly in a 5-exo fashion
under the catalysis of Pd(PPh3)4 in refluxing CH3CN with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), to afford substituted
pyrroles or indoles in good to high yields.6 As compared with
the acyloxime counterparts,4 these substrates also exhibited the
unique regioselectivity in adopting a 6-endo pathway to produce
pyridines under the different catalytic conditions.7 More
recently, we further applied the cyclization reaction to 2-
vinylclohexyl phosphinyloximes.8 During the process, the
selected substrates underwent the 6-endo cyclization exclusively
upon treating with Pd(PPh3)4 (0.2 equiv)/Et3N (5 equiv) in
DMF at 80 °C, to provide tetrahedroisoquinilines after the in
situ aromatization (Scheme 1). Additionally, we observed that
the trans-oxime precursor cyclized more easily than the
corresponding cis-isomer, as a result of the closer proximity
of the Pd−N complex to the CC double bond (equatorial−
equatorial versus equatorial−axial).
RESULTS AND DISCUSSION
■
A trans methyl-substituted oxime was first prepared for the
initial model studies. As shown in Scheme 3, reaction of trans-1-
(2-allylcyclohexyl)-ethanone (1a)10 with hydroxylamine hydro-
chloride, in the presence of sodium acetate, gave the hydroxyl
oxime 2a. Treatment of 2a with diethyl cholorophosphate and
triethyl amine in CH2Cl2 for 6 h furnished the oxime precursor
3a in 77% yield solely as the (E)-isomer.11 With 3a in hand, we
submitted it to the catalytic conditions in Scheme 1. It came as
a surprise to us when the reaction did not yield any expected
hetereocycles but rather gave the bicyclic hydroxyaldehyde 4a
(12%) along with enone 5a (5%) upon losing a carbon unit.
Besides, a large amount of ketone (52%, trans/cis = 57:43)
arising from hydrolysis4 and epimerization was isolated, which
Received: March 7, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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Scheme 1. Pd(PPh3)4-Catalyzed Cyclization of trans-2-Vinylclohexyl Phosphinyloximes
For the generation of 4a, we were particularly interested in
the hydroxylation at C-1. So far, the documented Pd-catalyzed
C−H hydroxylation reactions17 have been mostly limited to the
aromatic (sp2 C−H, aryl hydroxylation)18 or carbonyl (sp3 C−
H, α-hydroxylation)19 precursors, and usually employ gaseous
Scheme 2. Pd(0)-Catalyzed Cyclization of ortho-
Allylacetophenone Oximes
18
O2 or other oxidants (e.g., Oxone)20 as the oxygen sources.
At the beginning, we were curious about how the C-1
hydroxylation could occur without a specific source of oxygen,
regarding that the catalytic reaction in Scheme 3 was virtually
conducted under N2 protection in dry DMF. Nevertheless,
closer TLC inspection of the reaction revealed that there was a
transient intermediate formed after heating for 10 min, which
almost vanished in about 1 h (see the Supporting Information).
We then managed to isolate this intermediate after allowing the
reaction to proceed for 30 min (Scheme 5). The spectroscopic
analysis determined it as the hydroperoxide 7,21 whose
structure was further validated by the chemical correlation via
converting into 4a under treatment with PPh3.22 The
identification of 7, the on-pathway precursor to 4a, is
important, because it implies that an O2-mediated process should
be involved in the C-1 hydroxylation,19,23 and the air residue in
the nondegassed reaction media was likely to serve as the
aerobic source. On this basis, we further evaluated a series of
catalytic conditions with Pd(PPh3)4. The experimental results
are compiled in Table 1.
We first noted that neither 4a nor 5a could be formed under
the strictly O2-free conditions (Table 1, entry 1). This
observation demonstrates that oxygen is necessary not only for
the generation of 4a as reflected in the C-1 hydroxylation but also
for the formation of 5a. However, when the reaction was
conducted under a balloon pressure of pure O2, the diminished
depletion of 3a after the initial few minutes was seen even after
heating for a prolonged time at the higher temperature, to
afford only a trace amount of 4a (<3%) and no detectable 5a
(entry 2). The nonproductivity in this case should be ascribed
to the oxidation of Pd(0) into inactive Pd(II) by O2.24 Hence,
could be quantitatively reconverted to 1a by treating with a
base.10
Compound 5a is well-known,12 and the structure of 4a has
been fully established by spectroscopic methods (1H and 13C
NMR, DEPT, HRMS, and IR). Interestingly, 4a was formed as
a single diastereomer. To elucidate the steric relationship at the
C1−C6 ring-junction positions, we further transferred it into
diol 613 (83:17) through hydrogenation and NaBH4 reduction
(Scheme 4). The X-ray crystallographic analysis of the major
isomer of 6 unambiguously confirmed the cis-stereochemistry of
4a. The exclusive formation of the cis-isomer is presumably a
consequence of the prohibitively large amount of strain energy
associated with the trans 5,6-fused skeleton.
Albeit in low yields, we were fascinated by the unexpected
formation of 4a and 5a with the assembly of the oxygenated
bicyclic skeletons in a single step. We also observed that
respective submission of 1a and 2a to the same catalytic
conditions or heating 3a only with Et3N in DMF for more than
10 h merely resulted in recovered starting materials. These
results indicate that 4a and 5a were indeed the result of the
catalytic annulation of 3a. To the best of our knowledge, our
finding represents a yet unprecedented access to the bicyclo-
[4,3,0]nonene {or bicyclo[4,3,0]nonane} ring system that
occurs ubiquitously in natural14 and synthetic molecules15
and has always gained considerable synthetic efforts in its
construction.16 In these respects, we decided to carry out an in-
depth exploration into this reaction.
Scheme 3. Preparation and Pd(PPh3)4-Catalyzed Cyclization of 3a
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Scheme 4. Preparation of Diol Derivative 6
Scheme 5. Preparation of 7 and Its Chemical Correlation with 4a
Table 1. Evaluation of Catalytic Conditions with Pd(PPh4)3
b
yield (%)
a
c
d
entry
catalytic conditions
time (h)
4a
5a
ketone
3a
e
1
Pd(PPh3)4/Et3N/DMF/O2-free/80 °C
Pd(PPh3)4/Et3N/DMF/O2/80→95 °C
Pd(PPh3)4/Et3N/DMF/air/80→95 °C
Pd(PPh3)4/Et3N/DMF/N2:O2 (30:1)/80 °C
Pd(PPh3)4/Et3N/DMF/N2:O2 (20:1)/80 °C
Pd(PPh3)4/Et3N/DMF/N2:O2 (10:1)/80 °C
Pd(PPh3)4/Et3N/DMF/N2:O2 (7:1)/80 °C
Pd(PPh3)4/PPh3/Et3N/DMF/air/80 °C
Pd(PPh3)4/P(t-Bu)3/Et3N/DMF/air/80 °C
Pd(PPh3)4/Xantphos/Et3N/DMF/air/80 °C
Pd(PPh3)4/TFP/Et3N/DMF/air/80 °C
Pd(PPh3)4/Et3N/CH3CN/N2−O2/reflux
Pd(PPh3)4/Et3N/DMSO/N2−O2/120 °C
Pd(PPh3)4/Et3N/DMA/N2−O2/120 °C
Pd(PPh3)4/Et3N/toluene/N2−O2/reflux
Pd(PPh3)4/Et3N/1,4-dioxane/N2−O2/reflux
Pd(PPh3)4/py/DMF/N2−O2/80 °C
12
12
12
5
44
27
2
3
4
5
trace
trace
trace
6
trace
16
55
41
5
8
31
5
10
49
f
6
5
13
14
28
g
7
5
trace
trace
trace
trace
trace
5
17
24
h
8
12
12
12
12
12
12
12
2
10
19
33
h
9
trace
15
13
51
h
10
42
h
11
trace
55
34
i
12
quant.
70
i
13
i
14
trace
8
trace
50
i
15
quant.
50
i
16
12
12
12
12
12
12
40
i
17
12
14
10
i
18
Pd(PPh3)4/DBU/DMF/N2−O2/80 °C
Pd(PPh3)4/Na2CO3/DMF/N2−O2/80 °C
Pd(PPh3)4/t-BuO−K+/DMF/N2−O2/80 °C
Pd(PPh3)4/DMF/N2−O2/80 °C
quant.
i
19
i
20
i
21
13
18
a
b
0.04 M solution of 3a, 0.2 equiv of Pd(PPh3)4, 5 equiv of base, and a balloon pressure of indicated gas were used if necessary. Isolated yield.
Ketone was obtained as a trans/cis mixture. Recovered. The O2-free conditions were achieved by purging the reaction mixture with highly pure N2
(>99.9999%) prior to heating under N2. 19% of 5,6,7,8-tetrahydro-1,3-dimethylisoquinoline (8) was isolated. 14% of 8 was isolated. A 2:1 ratio of
P/Pd was used. N2/O2 10:1 gas system was used.
c
d
e
f
g
h
i
we were seemingly confronted with a dilemma between
requiring oxygen for the elaboration of the products and
meanwhile avoiding the O2-induced palladium oxidation.
Nonetheless, a slightly better conversion of 5a (5%) obtained
under air (entry 3) suggested that a decreased concentration of
O2 might be tolerated with Pd(0). In this regard, we evaluated
several N2/O2 mixed gases with the increased proportions of
oxygen (N2/O2 = 30:1, 20:1, 10:1 and 7:1, v/v) (entries 4−7).
Among which, the best results were gained from the 10:1 N2/
O2 system in giving 4a and 5a in 13% and 14% yields,
respectively (entry 6). With increasing the N2/O2 ratio to 7:1,
the palladium oxidation began to dominate as showcased by the
dramatically decreased formation of 4a and 5a and the
incomplete consumption of 3a (entry 7). It is noteworthy
that the reactions conducted under 10:1 and 7:1 mixed gases
also produced considerable amounts of 5,6,7,8-tetrahydro-1,3-
dimethylisoquinoline (8).25 Hoping that the palladium
oxidation could be circumvented by introducing phosphine
ligands to allow the regeneration of Pd(0) from Pd(II), we
further conducted several experiments under the conditions of
Pd(PPh3)4/Et3N/DMF/80 °C/air combined with a few
commonly employed ligands [PPh3,26 P(t-Bu)3,27 Xantphos26
or tri-2-furylphosphine (TFP)28]. However, these reactions all
gave the unsatisfying yields of 4a and 5a (entries 8−11). We
also screened a few solvents [CH3CN, DMSO, dimethylaceta-
mide (DMA), toluene and 1,4-dioxane] and bases (pyridine,
DBU, Na2CO3, and t-BuO−K+) under the 10:1 N2/O2 mixed
gas (entries 12−20). Among the tested solvents, only DMA
delivered a trace amount of 4a (entry 14), whereas other
solvents failed to offer either of the products. Besides, the
replacement of Et3N with the bases merely caused the lower
yields of 4a and 5a (entry 17) or the recovery or decomposition
of 3a (entries 18−20). Notably, when base was omitted from
the conditions, the reaction still provided 14% of 5a but
without giving any trace of 4a (entry 21), suggesting that the
participation of a base is crucial for the formation of 4a but may
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Table 2. Evaluation of Catalytic Conditions with Pd(dba)2 and Pd(PPh3)2Cl2
b
yield (%)
a
c
d
entry
catalytic conditions
time (h)
4a
5a
14
ketone
3a
1
2
3
4
Pd(dba)2/Et3N/DMF-H2O (9:1)/N2−O2 (10:1)/110 °C
Pd(dba)2/Et3N/DMF-H2O (9:1)/O2/110 °C
Pd(dba)2/Et3N/DMF-H2O (9:1)/N2−O2 (1:1)/110 °C
Pd(PPh3)2Cl2/Et3N/DMF/N2−O2 (10:1)/80 °C
6
12
6
9
7
36
24
27
51
5
29
12
16
trace
12
a
b
c
0.04 M solution of 3a, 0.2 equiv of catalyst, 5 equiv of Et3N, and a balloon pressure of indicated gas were employed. Isolated yield. Ketone was
d
obtained as a trans/cis mixture. Recovered.
not be for 5a. To suppress the ketone’s formation, we also
introduced a molecular sieve (3 Å)2a to the reaction conditions
in entry 6. But this effort did not lead to the improved yields
(4a: 5%; 5a: 7%).
The attempts with Pd(PPh3)4 did not lead to a significant
improvement on the formation of the desired products. Despite
this, some experimental results provided us with a mechanistic
insight into the cyclization and also established some reaction
parameters (e.g., solvent and base) for the following
investigations.
Table 3. Evaluation of Catalytic Conditions with Pd(OAc)2
b
yield (%)
time
a
c
d
entry
catalytic conditions
(h)
4a
5a
25
ketone
3a
1
Pd(OAc)2/Et3N/DMF/
8
17
trace
O2/120 °C
2
3
4
5
6
7
Pd(OAc)2/Et3N/DMF/
8
13
11
7
24
18
23
14
18
13
N2−O2 (1:1)/120 °C
Pd(OAc)2/Et3N/DMF/
N2−O2 (3:1)/120 °C
Pd(OAc)2/Et3N/DMF/
N2−O2 (5:1)/120 °C
Pd(OAc)2/DMF/O2/
120 °C
Pd(OAc)2/pyridine/
DMF/O2/120 °C
8
trace
trace
16
8
31
The tedious air-sensitivity of Pd(PPh3)4 drove us to seek
more robust Pd(0) catalysts. As a specific example, Larock and
co-workers29 once described a procedure of using Pd(dba)2/
Et3N in aqueous DMF solvent (9:1 DMF-H2O) to promote the
annulation between 2-iodobenzonitrile and acetylenes for
preparing indenones. Drawing on this report and our findings
with Pd(PPh3)4 (Table 1, entry 6), we then attempted the
conditions of Pd(dba)2/Et3N/DMF-H2O (9:1, v/v)/N2/O2
(10:1, v/v) to 3a (Table 2, entry 1). This procedure led to
9% of 4a and 14% of 5a. Furthermore, when the reaction was
performed under a pure O2 atmosphere, the formation of 4a
(7%) and 5a (5%) was still detectable (entry 2), thus
demonstrating the better air-stability of Pd(dba)2 than that of
Pd(PPh3)4. In the range of 10:1 N2/O2 to pure O2, we further
screened several N2/O2 mixed gases (7:1, 5:1, 3:1, 1:1, v/v).
These reactions afforded 4a and 5a in up to 16% and 11% yield,
respectively, and the best conversion of 4a was received from
the 1:1 N2/O2 system (entry 3). Besides, the preferential
generation of 4a over 5a (<2%) was attended under these
conditions. The catalytic system in entry 3 was consequently
chosen as an option for the selective formation of the aldehyde
(Method A). Apart from Pd(dba)2, we also examined
12
12
12
5
32
trace
5
29
Pd(OAc)2/DBU/
DMF/O2/120 °C
trace
77
a
0.04 M solution of 3a, 0.2 equiv of Pd(OAc)2, 5 equiv of base, and a
b
balloon pressure of indicated gas were employed. Isolated yield.
c
d
Ketone was obtained as a trans/cis mixture. Recovered.
replace Et3N (entries 5−7). The dropped yields of 5a in these
reactions seem to support our hypothesis. In view of the
dominating generation of 5a, the catalytic system in entry 1 was
designated as Method B for producing the enone.
By using Pd(dba)2 and Pd(OAc)2, two catalytic procedures
have been developed for the selective production of the
aldehyde (Methods A) or enone (Method B). For the
Pd(dba)2-catalyzed system, deliberate control of the amount
of reagent O2 is obviously required in order to maintain the
activity of Pd(0). It should be noted that using less than 20 mol
% catalysts (e.g., 15 mol %) with these methods unexception-
ally led to the poorer or inconsistent generation of 4a and/or
5a. On the other hand, increasing the loading to 25 mol % also
had no effect on improving the yields.
24c
Pd(PPh3)2Cl2 as indicated in entry 4, but the reaction did
not yield any desired products.
We next probed the possibility of applying palladium(II)
acetate to the reaction. Initial efforts were directed to forming
catalytically active Pd(0) complexes from Pd(II).30 To this end,
a series of combinations of Pd(OAc)2 with phosphine
ligands26−28,31 or n-Bu4NCl32 were examined (see the
Supporting Information). However, little success was achieved
in such a manner. After considerable experimentation, we found
that the reaction performed with Pd(OAc)2/Et3N under a pure
O2 atmosphere could afford 25% of 5a and a scarcely detectable
amount of 4a (Table 3, entry 1). In comparison with this, the
use of 1:1, 3:1, and 5:1 N2:O2 (v/v) mixed gases caused a
steady yielding decline (entries 2−4). Because there was no
actual Pd(0) catalyst introduced to the reactions, we assumed
that triethylamine employed herein might serve as a reducing
agent to convert Pd(II) into Pd(0),29,33 and the mechanism for
this reduction has been well-proposed in the literature.33,34 To
clarify the role of Et3N in our case, we further conducted a few
experiments without a base35 or using pyridine or DBU to
On the basis of the experimental results, a mechanism is
tentatively proposed in Scheme 6. A few cyclization products
including 4a, 5a, and 8 were observed during the studies. We
assume they all originate from the oxidative addition of the N−
O bond to Pd(0) species of the catalysts or generated in situ
from Pd(II),33,34 yielding a Pd(II)-imino intermediate A. The
6-exo cyclization of A leads to the formation of 8, as spotted in
some cases (Table 1, entries 6 and 7). According to previous
examples,7,8,36 it is highly possible that A can also undergo a 7-
endo cyclization to afford a 6,7-bicyclic intermediate B. The
relatively high structural flexibility of B should permit a second
intramolecular cyclization between the C−Pd(II) complex and
the CN bond37 to occur rapidly to produce a rigid tricyclic
complex C in either endo or exo-orientation. To release the ring
strain, the azetidine ring of C then immediately opens
accompanied by the concomitant formation of the CC
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Scheme 6. Proposed Mechanism for the Formation of Cyclization Products
bond to give intermediate D with the creation of the
bicyclo[4,3,0]nonene core.
mediate F. Subsequent reductive elimination gives the
formation of a hydroperoxide G. Reduction of G39 followed
by an aqueous workup furnishes 4a (G→H→4a). This
proposed pathway is consistent with the observed base-
dependent formation of 4a (Table 1, entry 21) as well as the
isolation of 7.
Without the participation of a base, the formation of 5a is
supposed to start from the β-carbon elimination40 of D with
losing an imine unit, to give a complex E′ (Pathway B). After
this, the O2−Pd coordination38 combined with the elimination
and hydroperoxide reduction39 lead to the generation of an
There are two putative pathways (Pathways A and B),
respectively, leading to 4a and 5a from D. In Pathway A, D first
undergoes a base-induced β-elimination to afford an unsatu-
rated imine E. Meanwhile, the coexistence of Pd(0)/Pd(II) in
the reaction media is possible upon a synergistic action of
diluted O2 atmosphere24 and Et3N.33,34 In accordance with this
hypothesis, the complexation of the CC bond to Pd(II)
coupled with the double bond migration and O2−Pd
coordination18,38 convert E into a Pd-hydroperoxide inter-
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Scheme 7. 18O-Labeling Isotopic Experiment of 3a
allylic alcohol H′ (E′→F′→G′→H′). Finally, the oxidation of
H′ by Pd(II)41 completes the formation of 5a. Although there
was no hydroperoxide intermediate detected, the NMR analysis
of the crude mixture of a 1 h reaction of Method C indicated
the presence of trace allylic alcohol [δ: 4.05 (m), 1.71 (s) ppm]
to possibly support the Pathway B. Furthermore, the proposed
oxygen source can be validated by the isotopic labeling
experiment with 18O2 (97% and 87% 18O-enriched) affording
the 18O-isotopologues in 96% and 87% isotopic purities
(Scheme 7) as determined by mass spectrometry (see the
Supporting Information).
conditions to them. As illustrated in Table 4, the reactions all
led to the lower conversions of 4a and 5a than those received
from 3a. Besides, the 6-exo pathway was shown to prevail for
the cyclization of 9 to afford 8 as the major product. These
results ruled out the necessity to further explore these types of
substrates.
Focusing on phosphinyloximes, we subsequently synthesized
precursors 3b−d43 through the alkylation of 1a followed by the
oximination and phosphonylation (1a → 1b−d → 2b−d →
3b−d) (Scheme 9). In the sequence, oximes 2b−d and 3b−d
were all formed as the inseparable mixtures of (E/Z)-isomers.44
When 3b−d were subjected to the Pd(dba)2-catalyzed
conditions (Method A), we were pleased to find that the
reactions could afford aldehydes 4b−d in much higher yields
than 4a and no detectable enones (Scheme 10). Besides, these
To probe the effect of N-substitution on the annulation, we
synthesized the acetyl42 and O-pentafluorobenzoyl2,3 oxime
analogues 9 and 10 (Scheme 8), and we applied the developed
Scheme 8. Preparation of Acetyloxime 9 and O-
Pentafluorobenzoyloxime 10
Scheme 10. Pd(dba)2-Catalyzed Cyclization of 3b−d
Table 4. Pd-Catalyzed Reactions of 9 and 10
products were uniformly produced as the single diastereomers,
and their cis-stereochemistry was assigned on the basis of the
similar coupling patterns of proton signals to those of 4a. On
the other hand, application of Method B to 3b−d led to the
generation of enones 5b−d45 as the only isolated cyclization
products in moderate yields (Scheme 11). Apparently, the
oxime precursors bearing the bulkier alkyl substituents are more
suited for the cyclization than 3a, which is probably attributed
to the increased steric hindrance between the alkyl appendages
and the allyl group to thus bring the N−Pd(II) center and the
b
yield (%)
a
entry substrate catalytic method
time (h)
4a
5a
8
c
1
2
3
4
9
method A
method B
method A
method B
6
6
6
6
27
9
13
40
d
10
10
14
trace
11
trace
8
a
b
c
0.04 M solution of 9 or 10 was used. Isolated. 19% of the ketone
d
was obtained. 27% of the ketone was isolated.
Scheme 9. Preparation of Phosphinyloximes 3b−d
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Article
chromatographic purification (hexane/EtOAc 40:1, 30:1, 20:1, 15:1)
to afford 2a as a white solid (2.25 g, 47%). mp: 79−81 °C; IR (neat):
Scheme 11. Pd(OAc)2-Catalyzed Cyclization of 3b−d
1
3333, 3075, 1639, 992, 908 cm−1; H NMR (400 MHz, CDCl3): δ
7.95 (br s, 1H), 5.74 (dddd, J = 16.2, 9.6, 8.1, 6.6 Hz, 1H), 4.97 (dm, J
= 9.6 Hz, 1H), 4.96 (dm, J = 16.2 Hz, 1H), 2.12−2.04 (m, 1H), 2.00
(ddd, J = 11.3, 11.3, 3.4 Hz, 1H), 1.90−1.64 (m, 5H), 1.81 (s, 3H),
1.54−1.41 (m, 1H), 1.41−1.29 (m, 1H), 1.29−1.16 (m, 2H), 1.01−
0.89 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 161.6, 136.6, 116.1,
49.4, 38.8, 38.7, 31.4, 30.8, 26.1, 25.8, 10.4; HRMS-EI: m/z [M]+ calcd
for C11H19NO, 181.1467; found, 181.1455.
Preparation of trans-(E)-Diethyl-1-(2-allylcyclohexyl)-
ethylideneaminooxyphosphonate (3a). Et3N (2.27 mL, 16.27
mmol) was added to a solution of 2a (1.18 g, 6.51 mmol) in dry
CH2Cl2 (70 mL) under N2. The solution was stirred at 0 °C for 30
min prior to addition of (EtO)2POCl (2.36 mL, 16.27 mmol). The
reaction mixture continued to stir at rt for 6 h, then diluted by CH2Cl2
(150 mL), washed with H2O (50 mL × 2) and brine (50 mL), dried
over Na2SO4, filtrated and concentrated under reduced pressure. The
crude mixture was purified by flash chromatography (hexane/EtOAc
5:1, 2:1, 1:1, 1:2) to give 3a as a pale yellow oil (1.59 g, 77%). IR
(neat): 3076, 2982, 1640, 1275, 1166, 1038, 838, 813 cm−1; 1H NMR
(400 MHz, CDCl3) δ 5.78−5.66 (m, 1H), 4.97 (dm, J = 10.8 Hz, 1H),
4.96 (dm, J = 16.4 Hz, 1H), 4.27−4.11 (m, 4H), 2.20 (ddd, J = 11.4,
11.4, 3.3 Hz, 1H), 2.07−1.96 (m, 1H), 1.90 (s, 3H), 1.89−1.60 (m,
6H), 1.54−1.44 (m, 1H), 1.34 (td, J = 7.1, 3.5 Hz, 6H), 1.31−1.16 (m,
2H), 1.03−0.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.0 (d,
Figure 1. Possible steric influence of bulkier alkyl groups on
cyclization.
CC bond closer with the rotation of the C1-CN single bond
(Figure 1).
In summary, our preliminary studies on the Pd(0)-catalyzed
cyclization of 2-vinylclohexyl phosphinyloxime system has led
to the discovery of a novel cyclization process into the
functionalized bicycle[4,3,0]nonenes. Through optimization,
two catalytic procedures have been developed for the selective
generation of the bicyclic hydroxyaldehydes or enones. A
tandem process involving double 7-endo/imine cyclization
followed by the ring-opening of the resulting tricyclic complex
is proposed for the assembly of the core structure. The detailed
mechanistic rationalization and the more efficient catalytic
system are currently under active investigation, as is the
evaluation of the scope of the process because it might pertain
to other bicyclic systems and/or interesting target molecules.
JC−P = 12.2 Hz), 136.1, 116.5, 64.3 (d, JC−P = 5.5 Hz), 64.2 (d, JC−P
=
5.7 Hz), 48.7, 38.7, 38.6, 31.3, 30.6, 25.9, 25.6, 16.2 (d, JC−P = 6.6 Hz),
11.9; HRMS-EI: m/z [M]+ calcd for C15H28NO4P, 317.1756; found,
317.1760; Anal. Calcd for C15H28NO4P: C, 56.77; H, 8.89. Found: C,
56.72; H, 8.83.
Formation of 4a and 5a under Pd(PPh3)4-Catalyzed
Conditions (Table 1, entry 6). Under N2 protection, Pd(PPh3)4
(106.8 mg, 99%, 0.092 mmol) was added to a DMF (11.4 mL)
solution of 3a (145.2 mg, 0.458 mmol, 0.04 M) in a 25 mL round-
bottom flask. The solution was stirred at rt for 5 min prior to addition
of Et3N (0.32 mL, 2.29 mmol). The resulting yellow suspension was
degassed with N2 for 3 min. The flask was then attached to a
condenser equipped with a joint fitted with a balloon of N2/O2 (10:1,
v/v, 1 L) and placed into an oil bath at 80 °C. The reaction mixture
was stirred vigorously at 80 °C for 5 h, cooled to rt, quenched with
H2O (11 mL) and extracted with EtOAc (30 mL × 3). The organic
layers were combined and washed with H2O (10 mL × 2) and brine
(10 mL). After concentration, the crude products were subjected to
chromatographic purification (hexane/EtOAc 20:1, 5:1, 2:1, 3:1 1:1)
to give 1-(2-allyl-cyclohexyl)-ethanone10 (trans/cis = 57/43, 21.3 mg,
28%), 4a (10.7 mg, 13%), 5a (9.9 mg, 14%) and 8 (14 mg, 19%).
cis-1-Hydroxyl-8-formyl-9-methyl-bicyclo[4,3,0]non-8(9)-ene
EXPERIMENTAL SECTION
■
General Remarks. All of the reagents and gases were purchased
from commercial suppliers and used without further purification. All of
the solvents for the reactions were properly dried and freshly distilled
before each use. Flash chromatography was performed using silica gel
(70−230 mesh) with the indicated solvents. All of the reactions were
monitored by thin-layer chromatography on 0.25 mm silica plates
(60F-254) and visualized with UV light, ethanolic solution of vanillin
(5%), or aqueous KMnO4 solution (10%). The NMR spectra (1H, 19F,
13C, DEPT, and 2D-NOESY) were recorded on 400 or 600 MHz
spectrometers using deuteriochloroform (CDCl3) or deuteriobezene
(C6D6) as the solvents. The 1H NMR data are reported as the
chemical shift in parts per million, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m. multiplet), coupling constants (J) in Hertz, and
number of protons. The resonances of infrared (IR) spectra are
reported in wave numbers (cm−1). High-resolution and low-resolution
mass spectra (HRMS and LRMS) were performed with electron
impact (EI) ionization and a magnetic sector analyzer.
Preparation of trans-1-(2-Allyl-cyclohexyl)-ethanone (1a).
According to the literature precedure,10 1a was synthesized from 1-
acetylcyclohexene (1.4 g, 11.27 mol) in 90% yield (1.69 g) over two
steps. 1H NMR (400 MHz, CDCl3): δ 5.73 (dddd, J = 16.7, 10.0, 7.9,
6.4 Hz, 1H), 4.99 (dm, J = 10.0 Hz, 1H), 4.95 (dm, J = 16.7 Hz, 1H),
2.21 (ddd, J = 11.3, 11.2, 3.4 Hz, 1H), 2.13 (s, 3H), 2.08−2.01 (m,
1H), 1.89−1.66 (m, 6H), 1.32−1.15 (m, 3H), 1.01−0.89 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 212.9, 136.4, 116.3, 56.8, 39.2, 38.0, 30.8,
29.8, 29.3, 25.7, 25.6.
Typical Procedure for Oximination; trans-(E)-1-(2-Allyl-
cyclohexyl)-ethanone Oxime (2a). To a solution of 1a (4.39 g,
26.4 mmol) in methanol (90 mL) at 20 °C, NaOAc (4.33 g, 52.8
mmol) and NH2OH·HCl (3.67 g, 52.8 mmol) were successively
added. The resulting suspension was stirred at rt for 3 h, then diluted
by CH2Cl2 (200 mL), washed with H2O (50 mL × 3), and brine (50
mL) and concentrated in vacuo. The crude mixture was subjected to
1
(4a). IR (neat): 3418, 2854, 2742, 1668, 1632, 1203, 1106 cm−1; H
NMR (400 MHz, CDCl3): δ 10.02 (s, 1H), 2.55 (dd, J = 15.0, 7.7 Hz,
1H), 2.19−2.11 (m, 1H), 2.10 (s, 3H), 2.09−1.98 (m, 1H), 1.82−1.69
(m, 2H), 1.68−1.44 (m, 4H), 1.44−1.32 (m, 3H); 13C NMR (100
MHz, CDCl3): δ 189.5 (CH), 165.5 (C), 136.1 (C), 83.8 (C), 44.9
(CH), 32.7 (CH2), 30.8 (CH2), 25.5 (CH2), 21.8 (CH2), 20.7 (CH2),
9.5 (CH3); HRMS-EI: m/z [M]+ calcd for C11H16O2, 180.1150; found,
180.1156; Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C,
73.27; H, 8.97.
9-Methyl-bicycle[4,3,0]non-1(9)-en-8-one12 (5a). H NMR (400
1
MHz, CDCl3): δ 2.84 (dd, J = 13.8, 1.8 Hz, 1H), 2.60−2.49 (m, 1H),
2.54 (br d, J = 13.8 Hz, 1H), 2.19−2.05 (m, 2H), 2.05−1.96 (m, 1H),
1.93 (d, J = 16.4 Hz, 1H), 1.83 (dm, J = 13.5 Hz, 1H), 1.68 (s, 3H),
1.50 (qt, J = 13.2, 3.4 Hz, 1H), 1.32 (qt, J = 13.1, 3.7 Hz, 1H), 1.04
(ddd, J = 14.1, 11.0, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
209.3, 176.0, 132.8, 41.3, 40.3, 35.0, 28.6, 26.6, 25.6, 7.6; HRMS-EI:
m/z [M]+ cacld. for C10H14O, 150.1045; found, 150.1049.
5,6,7,8-Tetrahydro-1,3-dimethylisoquinoline25 (8). H NMR (400
1
MHz, CDCl3): δ 6.70 (s, 1H), 2.68 (br t, J = 6.32 Hz, 2H), 2.58 (br t, J
= 6.16 Hz, 2H), 2.43 (s, 3H), 2.40 (s, 3H), 1.87−1.79 (m, 2H), 1.79−
1.71 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 156.2, 153.4, 146.2,
127.7, 121.3, 29.4, 25.7, 23.8, 23.2, 22.2, 22.0.
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Synthesis of Octahydro-2-(hydroxymethyl)-3-methyl-1H-
inden-3a-ol (6). Palladium on activated carbon (10 mg, 5%) was
added to a solution of 4a (51 mg, 0.28 mmol) in EtOAc (10 mL). The
suspension was stirred under H2 (balloon) for 1 h and filtrated
through a Celite pad. The filtrate was concentrated, and the crude
saturated hydroxyl aldehyde was dissolved in 3 mL of CH3OH. After
stirring at 0 °C for 10 min, NaBH4 (53.5 mg, 1.41 mmol) was added to
the solution. The reaction mixture was stirred at 0 °C for an additional
90 min, poured into EtOAc (40 mL), washed with H2O (10 mL) and
brine (10 mL), and concentrated in vacuo. The crude residue was
subjected to chromatographic purification (hexane/EtOAc 3:1, 1:1) to
give 6 as a mixture of two isomers (83:17) in 37% yield over two steps
bottom flask. The mixture was degassed with N2 for 3 min. The flask
was then attached to a condenser equipped with a joint fitted with a
balloon of oxygen (1 L), and placed into an oil bath at 120 °C. After
stirring for 8 h, the reaction mixture was cooled to rt, diluted by H2O
(11 mL), and extracted with EtOAc (30 mL × 3). The organic layers
were combined and washed with H2O (30 mL × 2) and brine (30
mL). After concentration, the crude mixture was purified by flash
chromatography (hexane/EtOAc 20:1, 5:1, 2:1) to afford 13.7 mg the
ketone10 (17%), 18.5 mg of 5a (25%), and a trace amount of
recovered 3a (∼1 mg) .
Synthesis of trans-(E)-Diethyl-1-(2-allylcyclohexyl)-
ethylideneaminooxyacetate (9). Et3N (0.92 mL, 6.6 mmol) was
added to a solution of 2a (299 mg, 1.65 mmol) in dry CH2Cl2 (10
mL) under N2 protection. After stirring in an ice-bath for 15 min, a
solution of acetyl chloride (0.29 mL, 98%, 3.96 mmol) in dry CH2Cl2
(2 mL) was dropwise added via a syringe in 2 min. The resulting
yellow suspension was continued to stir at rt for 2.5 h, then diluted by
CH2Cl2 (70 mL), and successively washed with saturated NaHCO3
aqueous solution (15 mL), water (15 mL × 2), and brine (15 mL).
After concentration, the crude mixture was purified by flash
chromatography (hexane/EtOAc 30:1, 10:1, 5:1, 3:1, 1:1) to give 3b
as a colorless oil (147 mg, 40%). IR (neat) 3075, 2928, 1766, 1639,
1202 cm−1; 1H NMR (400 MHz, CDCl3): δ 5.78−5.67 (m, 1H), 4.97
(dm, J = 10.7 Hz, 1H), 4.96 (dm, J = 15.4 Hz, 1H), 2.28 (ddd, J =
11.3, 11.3, 3.0 Hz, 1H), 2.16 (s, 3H), 2.05−1.99 (m, 1 H), 1.90 (s,
3H), 1.88−1.68 (m, 5H), 1.54−1.43 (m, 1H), 1.41−1.31 (m, 1H),
1.29−1.18 (m, 2H), (qd, J = 12.7, 1.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.9, 168.8, 136.3, 116.5, 49.1, 38.9, 38.6, 31.3, 30.6, 25.9,
25.6, 19.8, 12.1; HRMS-EI: m/z [M]+ calcd for C13H21NO2, 223.1572;
found, 223.1564.
1
(19.3 mg). IR (neat): 3367, 2927, 1133, 1026 cm−1; H NMR (400
MHz, CDCl3) major isomer: δ 3.72 (dd, J = 10.4, 6.3, 1H), 3.47 (dd, J
= 10.4, 8.0 Hz, 1H), 2.36−2.24 (m, 1H), 2.12−2.00 (m, 1H), 1.95−
1.85 (m, 1H), 1.85−1.75 (m, 1H), 1.75−1.66 (m, 1H), 1.62−1.21 (m,
10H), 0.92 (d, J = 7.52 Hz, 3H); minor isomer: δ 3.65 (dd, J = 10.2,
4.76, 1H), 3.52 (dd, J = 10.2, 6.68 Hz, 1H); 2.45−2.35 (m, 1H), 2.12−
2.00 (m, 1H), 1.95−1.85 (m, 1H), 1.85−1.75 (m, 1H), 1.75−1.66 (m,
1H), 1.62−1.21 (m, 10H), 0.92 (d, J = 7.52 Hz, 3H); 13C NMR (100
MHz, CDCl3) major isomer: δ 78.6, 65.6, 46.4, 44.3, 33.7, 30.5, 29.2,
23.8, 21.5, 20.3, 8.5; minor isomer: δ 78.6, 65.6, 43.8, 43.7, 33.7, 28.5,
28.0, 23.8, 21.1, 20.3, 8.5; HRMS-EI: m/z [M]+ calcd for C11H20O2,
184.1463; found, 184.1466. The major isomer was crystallized from
CH2Cl2-EtOAc (3/1, v/v) and used for the X-ray analysis.
Preparation of cis-1-Hydroperoxy-8-formyl-9-methyl-
bicyclo[4,3,0]non-8(9)-ene (7); Conversion of 7 into 4a.
Pd(PPh3)4 (211.5 mg, 99%, 0.18 mmol) was added to a solution of
3a (287.5 mg, 0.906 mmol) in dry DMF (22.6 mL) under N2. The
mixture was stirred at rt for 5 min followed by the addition of Et3N
(0.64 mL, 4.53 mmol). The reaction mixture was continued to stir at
80 °C for 30 min under N2, then quenched with H2O (20 mL) and
extracted with EtOAc (40 mL × 3). The organic layers were
combined, washed with H2O (30 mL × 2) and brine (30 mL), and
concentrated in vacuo. The light-proof chromatographic purification of
the crude mixture (hexane/EtOAc 20:1, 5:1, 3:1, 2:1, 1:1) afforded 7
in 6% yield as a colorless oil (10.7 mg) together with the ketone10
(51.2 mg, 34%), 4a (11.4 mg, 7%) and 5a (8.2 mg, 6%). 7: IR (neat):
3388, 2938, 2863, 2821, 1671, 1606, 1162, 1051 cm−1; 1H NMR (400
MHz, C6D6): δ 9.88 (s, 1H), 2.63 (ddd, J = 14.9, 7.4, 1.4 Hz, 1H),
2.42−2.33 (m, 1H), 2.04 (ddm, J = 14.9, 8.4 Hz, 1H), 1.69 (s, 3H),
1.58 (dm, J = 14.2 Hz, 1H), 1.52−1.41 (m, 1H), 1.30−1.16 (m, 3H),
1.13−1.03 (m, 2H), 0.96 (ddd, J = 14.2, 11.1, 3.9 Hz, 1H); 13C NMR
(100 MHz, C6D6): δ 187.9, 161.3, 137.5, 94.6, 36.9, 31.2, 29.3, 25.2,
21.3, 20.6, 9.5; HRMS-EI: m/z [M]+ calcd for C11H16O3, 196.1099;
found, 196.1106.
Synthesis of trans-(E)-Diethyl-1-(2-allylcyclohexyl)-
ethylideneaminooxypentafluorobenzonate (10). Et3N (0.14
mL, 0.99 mmol) was added to a solution of 2a (71.5 mg, 0.39
mmol) in dry CH2Cl2 (5 mL) under N2 protection. After stirring at 0
°C for 20 min, a solution of pentafluorobenzoyl chloride (0.14 mL,
99%, 0.99 mmol) in dry CH2Cl2 (1 mL) was added. The reaction
mixture was continued to stir at 0 °C for 2 h, then diluted by CH2Cl2
(50 mL) and successively washed with saturated NaHCO3 aqueous
solution (10 mL), water (10 mL × 2) and brine (10 mL). After
concentration, the crude mixture was subjected to chromatographic
purification (hexane/EtOAc 50:1, 40:1, 20:1, 8:1) to afford 3c as a pale
yellow oil (142 mg, 96%). IR (neat): 3100, 2931, 1762, 1651, 1523,
1195, 857 cm−1; 19F NMR (400 MHz, CDCl3): δ −137.2, −148.1,
1
−160.1; H NMR (400 MHz, CDCl3): δ 5.79−5.68 (m, 1H), 5.00
(dm, J = 11.4 Hz, 1H), 4.99 (dm, J = 15.7 Hz, 1H), 2,34 (ddd, J =
11.3, 11.3, 3.2 Hz, 1H), 2.09−2.03 (m, 1H), 1.97 (s, 3H), 1.92−1.74
(m, 5H), 1.57−1.49 (m, 1H), 1.45−1.33 (m, 1H), 1.32−1.21 (m, 2H),
1.01 (qd, J = 12.4, 1.2 Hz, 1H); 13C NMR: (100 MHz, CDCl3) δ
171.7, 156.6, 145.4 (d, JC−F = 260.5 Hz), 145.3 (d, JC−F = 260.5 Hz),
142.9 (d, JC−F = 260.5 Hz), 137.9, 136.0, 116.7, 49.1, 38.9, 38.6, 31.4,
30.6, 25.9, 25.5, 12.7; HRMS-EI: m/z [M]+ calcd. for C18H18F5NO2,
375.1258; found, 375.1260.
To a solution of 7 (12 mg, 0.061 mmol) in CH2Cl2 (3 mL), PPh3
(80.2 mg, 0.31 mmol) was added in one portion. The reaction mixture
was stirred at rt for 5 h and concentrated in vacuo. The crude products
were purified by flash chromatography (hexane/EtOAc 60:1, 2:1) to
afford 4a in 90% yield (9.9 mg).
Typical Procedure for the Pd(dba)2-Catalyzed Cyclization
(Method A). To a 25 mL round-bottom flask containing a solution of
3a (127.4 mg, 0.401 mmol, 0.04 M) in a 9:1 (v/v) DMF-H2O mixed
solvent (10 mL), palladium bis(dibenzylideneacetone) (46.2 mg, 0.08
mmol) and Et3N (0.28 mL, 2.0 mmol) were successively added. The
resulting dark brown suspension was degassed with N2 for 3 min. The
flask was then attached to a condenser equipped with a joint fitted with
a balloon of N2/O2 (1:1, v/v, 1.2 L), and placed into an oil bath at 110
°C. The reaction mixture was stirred vigorously for 6 h, cooled to rt,
diluted by H2O (8 mL) and extracted with EtOAc (30 mL × 3). The
organic layers were combined and washed with H2O (10 mL × 2) and
brine (10 mL). After concentration, the crude mixture was purified by
flash chromatography (hexane/EtOAc 20:1, 5:1, 2:1) to afford the
ketone10 (17.9 mg, 27%), 4a (11.6 mg, 16%) ,and a trace amount of 5a
(∼1 mg).
Typical Procedure for Alkylation of 1a; trans-1-(2-
allylcyclohexyl)propan-1-one (1b). Under a N2 atmosphere, a
solution of n-BuLi (1.75 mL, 1.6 M in hexane, 2.80 mmol) was slowly
added to a stirred solution of diisopropylamine (0.393 mL, 2.8 mmol)
in dry THF (7.9 mL) precooled to 0 °C via a syringe in 5 min. The
mixture was then cooled at −78 °C and stirred for 30 min. After this, a
solution of 1a (332.8 mg, 2.0 mmol) in dry THF (4.4 mL) was added
dropwise via a syringe in 10 min, and stirring was continued for an
additional 30 min at −78 °C before the quick addition of iodomethane
(0.3 mL, 99%, 4.72 mmol). The mixture was allowed to stir at room
temperature for 21 h, then diluted with saturated aqueous NH4Cl
solution (10 mL) and extracted with diethyl ether (100 mL). The
organic layer was separated and washed with water (20 mL × 2) and
brine (20 mL). The combined aqueous layers were re-extracted with
another portion of diethyl ether (100 mL) and the organic layer was
washed with water and brine. The combined organic layers were
concentrated under reduced pressure, and the crude reside was
purified by flash chromatography (hexane/EtOAc 150:1, 120:1, 100:1,
Typical Procedure for the Pd(OAc)2-Catalyzed Cyclization
(Method B). Palladium acetate (21.8 mg, 0.097 mmol) and Et3N
(0.39 mL, 2.42 mmol) were successively added to a DMF (11.9 mL)
solution of 3a (154 mg, 0.485 mmol, 0.04 M) in a 25 mL round-
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80:1) to give 1b in 42% yield (151.6 mg) as a colorless oil. IR (neat):
115.9, 49.2, 39.1, 38.9, 31.5, 29.2, 26.1, 26.0, 19.5, 14.9; HRMS-EI: m/
z [M]+ calcd for C13H23NO, 209.178; found, 209.1778.
1
3075, 1710, 1640, 996, 948 cm−1; H NMR (400 MHz, CDCl3): δ
trans-1-(2-Allylcyclohexyl)pentan-1-one Oxime (2d). From
1d (556.4 mg, 2.67 mmol), the title compound was similarly prepared
as 2a. The reaction proceeded for 22 h at rt. After chromatographic
purification (hexane/EtOAc 30:1, 20:1, 10:1, 5:1), 198 mg of 2d was
obtained (33%) as an isomeric mixture (E/Z = 16/84). IR (neat):
5.76−5.65 (m, 1H), 4.95 (dm, J = 9.4 Hz, 1H), 4.94 (dm, J = 17.8 Hz,
1H), 2.52 (dq, J = 17.9, 7.3 Hz, 1H), 2.36 (dq, J = 17.9, 7.3 Hz, 1H),
2.22 (td, J = 10.7, 2.4 Hz, 1 H), 2.03−1.99 (m, 1H), 1.93−1.65 (m,
7H), 1.32−1.15 (m, 3 H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 215.3, 136.6, 116.1, 55.9, 39.4, 38.1, 35.7, 30.9, 30.2,
25.9, 25.7, 7.6; HRMS-EI: m/z [M]+ calcd for C12H20O, 180.1514;
found, 180.1521.
trans-1-(2-Allylcyclohexyl)butan-1-one (1c). The title com-
pound was similarly prepared as 1b from 1a (791.9 mg, 4.76 mmol) by
using iodoethane as the alkylating reagent. The reaction proceeded for
16 h at rt. After chromatographic purification (hexane/EtOAc 250:1,
200:1, 100:1), 509 mg of 1c was obtained (55%) as a yellow oil. IR
(neat): 3075, 1708, 1665, 910, 995 cm−1; 1H NMR (400 MHz,
CDCl3): δ 5.76−5.67 (m, 1H), 4.96 (dm, J = 8.6 Hz, 1H), 4.95 (dm, J
= 17.3 Hz, 1H), 2.46 (dt, J = 17.2, 7.4 Hz, 1H), 2.34 (dt, J = 17.2, 7.2
Hz, 1H), 2.20 (tm, J = 10.1 Hz, 1H), 2.05−2.00 (m, 1H), 1.84−1.67
(m, 6 H), 1.60 (sextet, J = 7.4 Hz, 2H), 1.31−1.13 (m, 3H), 1.02−0.94
(m, 1 H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
214.8, 136.6, 116.2, 56.1, 44.5, 39.3, 37.9, 30.9, 30.0, 25.9, 25.7, 16.8,
13.8; HRMS-EI: m/z [M]+ calcd for C13H22O, 194.1671; found,
194.1668.
trans-1-(2-Allylcyclohexyl)pentan-1-one (1d). The title com-
pound was similarly prepared as 1b from 1a (716.6 mg, 4.31 mmol) by
using iodopropane as the alkylating reagent. The reaction proceeded
for 21 h at rt. After chromatographic purification (hexane/EtOAc
100:1), 514 mg of 1d was obtained (57%) as a yellow oil. IR (neat):
3074, 1707, 1642, 995, 968, 911 cm−1; 1H NMR (400 MHz, CDCl3):
δ 5.80−5.65 (m, 1H), 4.96 (br d, J = 9.2 Hz, 1H), 4.95 (br d, J = 17.9
Hz, 1H), 2.48 (dt, J = 17.1, 7.5 Hz, 1H), 2.36 (dt, J = 17.1, 7.3 Hz,
1H), 2.21 (tm, J = 10.9 Hz, 1H), 2.05−2.01 (m, 1H), 1.83−1.70 (m,
5H), 1.57−1.49 (m, 2H), 1.35−1.20 (m, 6 H), 0.99−0.94 (m, 1H),
0.90 (t, J = 7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 214.9,
136.6, 116.2, 56.1, 42.3, 39.3, 37.9, 30.9, 30.1, 25.9, 25.7, 25.5, 22.4,
13.9; HRMS-EI: m/z [M]+ calcd for C14H24O, 208.1827; found,
208.1832.
1
3266, 1642, 1448, 1101, 993, 951, 911 cm−1; H NMR (400 MHz,
CDCl3) δ E-form: 9.39 (br s, 1H), 5.83−5.61 (m, 1H), 4.99 (dm, J =
10.9 Hz, 2H), 2.38 (dt, J = 17.8, 5.2 Hz, 1H), 2.36−2.31 (m, 1H),
2.24−2.02 (m, 1H), 2.00−1.82 (m, 2H), 1.80−1.61 (m, 4H), 1.60−
1.44 (m, 3H), 1.43−1.31 (m, 3H), 1.30−1.15 (2H), 1.01−0.85 (m,
1H), 0.92 (t, J = 8.0 Hz, 3H); Z-form: 8.96 (br s,, 1H), 5.83−5.61 (m,
1H), 4.96 (dm, J = 11.8 Hz, 2H), 2.15 (dt, J = 21.9, 8.6 Hz, 1H),
2.23−2.02 (m, 2H), 1.99−1.83 (m, 2H), 1.80−1.69 (m, 4H), 1.60−
1.45 (m, 3H), 1.44−1.30 (m, 3H), 1.29−1.15 (m, 2H), 1.01−0.83 (m,
1H), 0.93 (t, J = 7.04 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ E-
form:163.1, 137.0, 115.8, 49.2, 39.1, 38.4, 31.6, 31.6, 29.2, 26.9, 26.2,
25.8, 22.7, 13.9; Z-form: 164.2, 136.9 115.9, 49.2, 39.1, 38.9, 31.6, 31.6,
28.3, 28.1, 26.1, 26.0, 23.5, 13.8; HRMS-EI: m/z [M]+ calcd for
C14H25NO, 223.1936; found, 223.1936.
General Procedure for Preparing 3b−d; trans-Diethyl-1-(2-
allylcyclohexyl)propylideneaminooxyphosphonate (3b). Under
N2 protection, sodium hydride (50.6 mg, 60%, 1.26 mmol) and diethyl
chlorophosphate (0.31 mL, 2.11 mmol) were successively added to a
solution of 2b (102.9 mg, 0.527 mmol) in THF (6.4 mL) precooled at
0 °C. The mixture was stirred at rt for 20 h, then diluted by EtOAc
(150 mL), and washed with saturated NH4Cl aqueous solution (20
mL), water (20 mL × 2) and brine (20 mL). After concentration, the
crude mixture was purified by chromatography (hexane/EtOAc 8:1,
5:1, 2:1, 1:1) to afford 3b (146 mg, 84%, E/Z = 57/43) as a colorless
oil. IR (neat): 3076, 1640, 1548, 1274, 1034, 974, 910 cm−1; 1H NMR
(400 MHz, CDCl3) δ E-form: 5.79−5.66 (m, 1H), 4.98 (dm, J = 10.0
Hz, 1H), 4.97 (dm, J = 17.2 Hz, 1H); 4.29−4.11 (m, 4H); 2.48 (dq, J
= 13.9, 7.7 Hz, 1H) 2.34−2.25 (m, 2H), 2.25−1.97 (m, 3H), 1.94−
1.82 (m, 1H), 1.82−1.48 (m, 5H), 1.35 (t, J = 7.04 Hz, 6H), 1.29−
1.18 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 1.04−0.88 (m, 1H); Z-form:
5.79−5.66 (m, 1H); 4.98 (dm, J = 10.0 Hz, 1H); 4.97 (dm, J = 17.2
Hz, 1H); 4.29−4.11 (m, 4H), 2.37−2.30 (m, 1H); 2.34−2.25 (m,
2H), 2.25−1.97 (m, 3H), 1.94−1.82 (m, 1H), 1.82−1.48 (m, 5H),
1.35 (t, J = 7.04 Hz, 6H), 1.29−1.18 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H),
1.04−0.88 (m, 1H); 13C NMR (100 MHz, CDCl3) δ E-form: 172.5 (d,
trans-1-(2-Allylcyclohexyl)propan-1-one Oxime (2b). From
1b (240.2 mg, 1.33 mmol), the title compound was similarly prepared
as 2a. The reaction proceeded for 20 h at rt. After chromatographic
purification (hexane/EtOAc 40:1, 20:1, 10:1), 106.7 mg of 2b was
obtained (41%) as an isomeric mixture (E/Z = 60:40). IR (neat):
JC−P = 12.1 Hz), 136.3, 116.3, 64.3 (d, JC−P = 3.9 Hz), 64.2 (d, JC−P
=
1
3247, 3079, 1640, 996, 914 cm−1; H NMR (400 MHz, CDCl3) δ E-
6.2 Hz), 48.8, 39.1, 38.4, 31.4, 31.3, 29.4, 25.9, 25.8, 21.0, 16.2 (d, JC−P
= 6.3 Hz), 10.6; Z-form: 173.7 (d, JC−P = 11.9 Hz), 136.2, 116.2, 64.4
(d, JC−P = 4.7 Hz), 64.3 (d, JC−P = 3.9 Hz), 48.8, 38.8, 38.6, 31.0, 30.9,
29.4, 25.8, 25.7, 21.0, 16.2 (d, JC−P = 6.3 Hz), 10.9; HRMS-EI: m/z
[M]+ calcd for C16H30NO4P, 331.1912; found, 331.1904.
form: 9.33 (br s, 1H), 5.81−5.68 (m, 1H), 4.97−4.94 (m, 2H), 2.41
(dq, J = 16.0, 8.0 Hz, 1H) 2.29−2.12 (m, 2H) 2.09−1.92 (m, 1H);
1.91−1.83 (m, 1H), 1.82−1.61 (m, 4H), 1.61−1.18 (m, 4H), 1.11 (t, J
= 7.4 Hz, 3H), 1.01−0.80 (m, 1H); Z-form: 9.60 (br s, 1H), 5.72−5.64
(m, 1H), 5.00−4.92 (m, 2H), 2.40−2.32 (m, 1H), 2.29−2.12 (m, 2H),
2.09−1.92 (m, 1H), 1.91−1.83 (m, 1H), 1.82−1.61 (m, 4H), 1.61−
1.18 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H), 1.01−0.80 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ E-form: 163.8, 137.0, 115.8, 49.2, 39.1, 38.9,
31.6, 31.4, 26.2, 26.0, 20.0, 10.5; Z-form: 165.0, 136.8, 116.0, 49.2,
38.9, 38.5, 31.6, 31.4, 26.1, 26.0, 20.0, 10.5; HRMS-EI: m/z [M]+ calcd
for C12H21NO, 195.1623; found, 195.1616.
t r a n s - D i e t h y l - 1 - ( 2 - a l l y l c y c l o h e x y l ) -
butylideneaminooxyphosphonate (3c). From 2c (37.9 mg, 0.18
mmol), the title compound was similarly synthesized as 3b. The
reaction proceeded for 18 h at rt. After chromatographic purification
(hexane/EtOAc 10:1, 5:1, 1:1), 3c (53.2 mg, 85%, E/Z = 40/60) was
obtained as a pale yellow oil. IR (neat): 3075, 1662, 1640, 1274, 1035,
979, 927 cm−1; 1H NMR (400 MHz, CDCl3) δ E-form: 5.79−5.66 (m,
1H), 4.97 (dm, J = 9.6 Hz, 1H), 4.96 (dm, J = 17.6 1H), 4.28−4.11
(m, 4H), 2.42 (dt, J = 17.9, 5.4 Hz, 1H), 2.16−2.08 (m, 2H), 2.08−
2.08−1.83 (m, 3H), 1.83−1.51 (m, 7H), 1.35 (t, J = 7.04 Hz, 6H),
1.29−1.14 (m, 1H), 0.95 (t, J = 7.32 Hz, 3H), 0.91−0.83 (m, 1H); Z-
form: 5.79−5.66 (m, 1H), 4.97 (dm, J = 9.6 Hz, 1H), 4.96 (dm, J =
17.6 1H), 4.28−4.11 (m, 4H), 2.22 (dt, J = 15.4, 7.9 Hz, 1H), 2.16−
2.08 (m, 2H), 2.08−1.83 (m, 3H), 1.83−1.51 (m, 7H), 1.35 (t, J =
7.04 Hz, 6H), 1.29−1.14 (m, 1H), 0.97 (t, J = 7.24 Hz, 3H), 0.91−
0.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ E-form: 171.4 (d, JC−P
= 12.2 Hz), 136.3, 116.3, 64.2 (d, JC−P = 5.9 Hz), 48.8, 38.7, 38.3, 31.3,
31.1, 29.2, 25.9, 25.7, 19.4, 16.1 (d, JC−P = 6.3 Hz), 14.0; Z-form: 172.7
(d, JC−P = 11.8 Hz), 136.3, 116.3; 64.3 (d, JC−P = 5.9 Hz), 48.8, 39.1,
38.8, 31.4, 31.1, 30.1, 25.8, 25.8, 19.9, 16.1 (d, JC−P = 6.3 Hz), 14.8;
HRMS-EI: m/z [M]+ calcd for C17H32NO4P, 345.2069; found,
345.2061.
trans-1-(2-Allylcyclohexyl)butan-1-one Oxime (2c). From 1c
(266.3 mg, 1.37 mmol), the title compound was similarly prepared as
2a. The reaction proceeded for 24 h at rt. After chromatographic
purification (hexane/EtOAc 30:1, 20:1, 10:1, 5:1), 117 mg of 2c was
obtained (40%) as an isomeric mixture (E/Z = 46/54). IR (neat):
1
3579, 3100, 1640, 993, 909 cm−1; H NMR (400 MHz, CDCl3) δ E-
form: 8.36 (br s, 1H), 5.81−5.68 (m, 1H), 4.97 (dm, J = 10.8 Hz, 2H),
2.36−2.32 (m, 1H), 2.22−2.01 (m, 2H), 1.98−1.83 (m, 2H), 1.83−
1.68 (m, 4H), 1.68−1.45 (m, 4H), 1.37−1.11 (m, 2H), 0.95 (t, J = 7.4
Hz, 3H), 0.95−0.85 (m, 1H); Z-form: 8.14 (br s, 1H), 5.81−5.68 (m,
1H), 4.97 (dm, J = 10.8 Hz, 2H), 2.35 (dt, J = 18.0, 6.8 Hz, 1H),
2.22−2.01 (m, 2H), 1.98−1.83 (m, 2H), 1.83−1.68 (m, 4H), 1.68−
1.45 (m, 4H), 1.37−1.11 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H), 0.95−0.85
(m, 1H); 13C NMR (100 MHz, CDCl3) δ E-form: 163.0, 137.0, 115.9,
49.2, 39.1, 38.4, 31.6, 29.2, 26.1, 25.9, 19.5,14.2; Z-form: 164.3, 136.9,
3631
dx.doi.org/10.1021/jo5005422 | J. Org. Chem. 2014, 79, 3623−3633

The Journal of Organic Chemistry
Article
trans-Diethyl-1-(2-allylcyclohexyl)pentylidene-
aminooxyphosphonate (3d). From 2d (197 mg, 0.882 mmol), the
title compound was similarly synthesized as 3b. The reaction
proceeded for 20 h at rt. The flash chromatography was performed
on silica gel [prewashed with hexane/Et3N (200:1)] and eluted with
hexane/EtOAc (20:1, 10:1, 5:1, 1:1) to give 3d44 (210 mg, 66%, E/Z =
37/63) as a colorless yellow oil. IR (neat): 3076, 1644, 1549, 1217,
9-Propyl-bicyclo[4,3,0]non-1(9)-en-8-one (5c). In Method B,
the title compound was synthesized from 3c (66.3 mg, 0.192 mmol)
after heating for 3 h. The chromatographic purification (hexane/
EtOAc 20:1, 10:1, 5:1) afforded 5c (11.3 mg, 33%) as a pale yellow oil.
1
IR (neat): 2929, 1697, 1644 cm−1; H NMR (400 MHz, CDCl3): δ
2.85 (br d, J = 14.4 Hz, 1H), 2.61−2.47 (m, 1H), 2.53 (d, J = 14.4 Hz,
1H), 2.20−2.05 (m, 2H), 2.13 (t, J = 7.4 Hz, 2H), 2.04−1.96 (m, 1H),
1.95−1.87 (m, 1H), 1.87−1.80 (m, 1H), 1.50 (qt, J = 13.2, 3.3 Hz,
1H), 1.40 (sextet, J = 7.4 Hz, 2H), 1.31 (qt, J = 13.2, 3.8 Hz, 1H),1.04
(dddd, J = 12.3, 12.3, 12.3, 3.0 Hz, 1H), 0.86 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 208.9, 176.4, 137.0, 41.5, 40.2, 35.2, 28.7,
26.9, 25.6, 24.5, 22.0, 13.9; HRMS-EI: m/z [M]+ calcd for C12H18O,
178.1358, found, 178.1364; Anal. Calcd for C12H18O: C, 80.85; H,
10.18. Found: C, 80.86 ; H, 10.16.
1
1043, 909 cm−1; H NMR (400 MHz, CDCl3) δ E-form: 5.79−5.64
(m, 1H), 4.98 (br d, J = 9.76 Hz, 1H), 4.97 (br d, J = 16.9 Hz, 1H),
4.35−4.00 (m, 4H), 2.43 (dt, J = 17.8, 6.6 Hz, 1H), 2.31−2.06 (m,
3H), 1.92−1.83 (m, 2H), 1.81−1.74 (m, 4H), 1.65−1.54 (m, 3H),
1.43−1.30 (m, 2H), 1.35 (t, J = 8.0 Hz, 6H), 1.29−1.15 (m, 2H),
1.01−0.85 (m, 1H), 0.91 (t, J = 7.52 Hz, 3H); Z-form: 5.79−5.64 (m,
1H), 4.98 (br d, J = 9.76 Hz, 1H), 4.97 (br d, J = 16.9 Hz, 1H), 4.35−
4.00 (m, 4H), 2.31−2.00 (m, 4H), 1.92−1.83 (m, 2H), 1.81−1.74 (m,
4H), 1.65−1.54 (m, 3H), 1.43−1.30 (m, 2H), 1.35 (t, J = 8.0 Hz, 6H),
1.29−1.15 (m, 2H), 1.01−0.85 (m, 1H), 0.92 (t, J = 7.28 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ E-form: 171.7 (d, JC−P = 12.3 Hz), 136.9,
116.1, 64.2 (d, JC−P = 6.2 Hz), 52.0, 39.1, 38.4, 31.3, 31.0, 28.2, 28.0,
9-Butyl-bicyclo[4,3,0]non-1(9)-en-8-one (5d). In Method B,
the title compound was synthesized from 3d (138 mg, 0.384 mmol)
after heating for 4 h. The chromatographic purification (hexane-EtOAc
20:1, 10:1, 5:1) afforded 5d45b (43.7 mg, 59%) as a yellow oil. IR
1
(neat): 2929, 1696, 1645 cm−1; H NMR (400 MHz, CDCl3): 2.84
(br d, J = 13.2 Hz, 1H), 2.58−2.45 (m, 1H), 2.53 (br d, J = 13.2 Hz,
1H), 2.21−2.05 (m, 4H), 2.04−1.95 (m, 1H), 1.91 (dd, J = 20.0, 4.2
Hz, 1H), 1.83 (br d, J = 13.3 Hz, 1H), 1.50 (qt, J = 12.8, 3.0 Hz, 1H),
1.38−1.22 (m, 5H), 1.04 (qd, J = 12.8, 2.2 Hz, 1H), 0.88 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 208.8, 176.2, 137.3, 41.5, 40.1,
35.2, 31.0, 28.7, 26.9, 25.6, 22.6, 22.3, 13.9; HRMS-EI m/z [M]+ calcd
for C13H20O, 192.1514; found, 192.1519.
25.9, 25.6, 22.4, 16.2 (d, JC−P = 6.4 Hz), 13.8; Z-form: 172.8 (d, JC−P
=
11.8 Hz), 136.3, 116.3, 64.3 (d, JC−P = 5.3 Hz), 48.9, 38.8, 38.7, 31.4,
31.2, 28.4, 27.8, 25.8, 25.7, 22.6, 16.2 (d, JC−P = 6.4 Hz), 13.7; HRMS-
EI: m/z [M]+ calcd for C18H34NO4P, 359.2225; found, 359.2219.
cis-1-Hydroxyl-8-formyl-9-ethyl-bicyclo[4,3,0]non-8(9)-ene
(4b). In Method A, the title compound was synthesized from 3b (139
mg, 0.419 mmol) after heating for 4 h. The chromatographic
purification (hexane/EtOAc 20:1, 10:1, 3:1) gave 4b (32.6 mg, 40%)
as a yellow oil. IR (neat): 3437, 2805, 1654, 1199 cm−1; 1H NMR (400
MHz, C6D6): δ 9.96 (s, 1H), 2.48 (dd, J = 15.5, 7.6 Hz, 1H), 2.27−
2.21 (m, 1H), 2.10−2.07 (m, 1H), 2.02 (dd, J = 15.5, 9.0 Hz, 1H),
1.61−1.60 (m, 1H), 1.54−1.49 (m, 2H), 1.36−1.24 (m, 3H), 1.14−
1.01 (m, 4H), 0.94 (t, J = 7.7 Hz, 3H); 13C NMR (100 MHz, C6D6): δ
188.2, 169.7, 135.9, 83.5, 45.4, 33.2, 30.5, 25.0, 21.5, 20.6, 17.6, 15.6;
HRMS-EI: m/z [M]+ calcd for C12H18O2, 194.1307; found, 194.1297.
cis-1-Hydroxyl-8-formyl-9-propyl-bicyclo[4,3,0]non-8(9)-ene
(4c). In Method A, the title compound was synthesized from 3c (115.7
mg, 0.335 mmol) after heating for 3 h. The chromatographic
purification (hexane/EtOAc 20:1, 10:1, 3:1) gave 4c (44.8 mg, 64%)
as a yellow oil. IR (neat): 3488, 2857, 1659, 1196 cm−1; 1H NMR (400
MHz, C6D6): δ 9.97 (s, 1H), 2.50 (dd, J = 15.4, 7.6 Hz, 1H), 2.29−
2.20 (m, 1H), 2.10−1.97 (m, 1H), 2.03 (dd, J = 15.4, 9.2 Hz, 1H),
1.66−1.57 (m, 1H), 1.53−1.42 (m, 2H), 1.39−1.20 (m, 5H), 1.19−
0.92 (m, 4H), 0.79 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, C6D6): δ
188.3, 167.8, 136.7, 83.4, 45.4, 33.2, 30.5, 26.5, 25.0, 23.9, 21.5, 20.6,
14.2; HRMS-EI: m/z [M]+ calcd for C13H20O2, 208.1463; found,
208.1460.
ASSOCIATED CONTENT
■
S
* Supporting Information
The NMR spectra of all compounds in this article, the ORTEP
structure and CIF file of 6, the TLC analysis of the catalytic
reaction in Scheme 3, the optimization results with Pd(OAc)2/
ligands or n-Bu4NCl, the mass spectra of 18O-isotopic
experiments, this material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*jlzhu@mail.ndhu.edu.tw
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
cis-1-Hydroxyl-8-formyl-9-butyl-bicyclo[4,3,0]non-8(9)-ene
(4d). In Method A, the title compound was synthesized from 3d (86
mg, 0.239 mmol) after heating for 4 h. The chromatographic
purification (hexane/EtOAc 20:1, 10:1, 3:1) gave 4d (39 mg, 73%) as
We thank the National Science Council of Republic of China
(Taiwan) for funding of this research and the Department of
Chemistry of National Chung Hsing University for the NMR
and HRMS analysis.
1
a yellow oil. IR (neat): 2858, 1648, 1546 cm−1; H NMR (400 MHz,
C6D6): δ 10.01 (s, 1H), 2.50 (dd, J = 15.4, 7.7 Hz, 1H), 2.32−2.25 (m,
1H), 2.15−2.08 (m, 1H), 2.04 (dd, J = 15.4, 8.5 Hz, 1H), 1.61−1.59
(m, 1H), 1.51−1.47 (m, 2H), 1.39−1.27 (m, 5H), 1.26−1.15 (m, 3H),
1.08−0.97 (m, 2H), 0.88−0.72 (m, 1H), 0.83 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, C6D6): δ 188.2, 168.2, 136.4, 83.4, 45.5, 33.2, 33.0,
30.5, 25.0, 24.4, 23.1, 21.5, 20.6, 13.8; HRMS-EI: m/z [M]+ calcd for
C14H22O2, 222.162; found, 222.1617; Anal. Calcd for C14H22O2: C,
75.63; H, 9.97. Found: C, 75.68; H, 9.94.
REFERENCES
■
(1) Tsuji, J. Palladium Reagents and Catalysts: New Perspectives for the
21st Century; Wiley and Sons: New York, 2003; pp 169−171.
(2) For examples on intramolecular amino-Heck reactions, see
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2005, 7, 609. (d) Sakoda, K.; Mihara, J.; Ichikawa, J. Chem. Commun.
9-Ethyl-bicyclo[4,3,0]non-1(9)-en-8-one (5b). In Method B,
the title compound was synthesized from 3b (40.6 mg, 0.123 mmol)
after heating for 4 h. The chromatographic purification (hexane/
EtOAc 20:1, 10:1, 5:1) afforded 5b45a (11.2 mg, 56%) as a yellow oil.
2005, 4684. (e) Furstner, A.; Radkowski, H.; Peters, H. Angew. Chem.,
̈
Int. Ed. 2005, 44, 2777. (f) Ichikawa, J.; Nadano, R.; Ito, N. Chem.
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1
IR (neat): 2931, 1698, 1645 cm−1; H NMR (400 MHz, CDCl3): δ
2.85 (dd, J = 14.4, 1.7 Hz, 1H), 2.61−2.45 (m, 1H), 2.53 (d, J = 14.4
Hz, 1H), 2.17 (q, J = 7.5 1.50 (qt, J = 13.2, 3.4 Hz, 1H), 1.32(qt, J =
13.0, 3.8 Hz, 1H), 1.11−0.99 (m, 1H), 0.97 (t, J = 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 208.7, 175.8, 138.7, 41.5, 40.1, 35.2, 28.5,
26.9, 25.6, 15.8, 13.6; HRMS-EI: m/z [M]+ calcd for C11H16O,
164.1201; found, 164.1198.
(l) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36, 1142.
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3632
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