Synthesis of 7-Membered Ring Carbocycles via a Palladium-Catalyzed Intramolecular Allylic Alkylation–Isomerization–Cope Rearrangement Cascade

Article abstract of DOI:10.1002/ejoc.201800230

We developed a novel method for synthesizing seven-membered ring carbocycles via a palladium-catalyzed intramolecular allylic alkylation–isomerization–Cope rearrangement cascade. Using easily available lactone derivatives as substrates, the target cascade

Full text of DOI:10.1002/ejoc.201800230

A Journal of
Accepted Article
Title: Synthesis of 7-Membered Ring Carbocycles via a Palladium-
Catalyzed Intramolecular Allylic Alkylation-Isomerization-Cope
Rearrangement Cascade
Authors: Kazuki Tsuruda, Takahisa Tokumoto, Naoya Inoue, Masaya
Nakajima, and Tetsuhiro Nemoto
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800230
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800230
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10.1002/ejoc.201800230
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of 7-Membered Ring Carbocycles via a Palladium-
Catalyzed Intramolecular Allylic Alkylation–Isomerization–Cope
Rearrangement Cascade
Kazuki Tsuruda,[a] Takahisa Tokumoto,[a] Naoya Inoue, [a] Masaya Nakajima, [a] and Tetsuhiro
Nemoto*[a,b]
Abstract: We developed a novel method for synthesizing 7-
membered ring carbocycles via palladium-catalyzed
intramolecular allylic alkylation and subsequent isomerization
of cyclopropane derivative B would proceed to form compound
C. Cis-configuration of the divinyl substituents in C would
facilitate the sequential Cope rearrangement, producing a
functionalized seven-membered ring carbocycle D.[4] Herein we
report a novel method of synthesizing 7-membered ring
carbocycles via a palladium-catalyzed intramolecular allylic
alkylation–isomerization–Cope rearrangement cascade.
a
intramolecular allylic alkylation–isomerization–Cope rearrangement
cascade. Using easily available lactone derivatives as substrates,
the target cascade reaction proceeded in the presence of 5 mol %
of Pd(dba)2 and 6 mol % of 1,3-diphenylphosphinopropane (dppp)
in THF, affording a series of 7-membered ring carbocycles in 59–
88% yield (11 examples). DFT calculations suggested that, in
addition to the reaction cascade including the cis-
divinylcyclopropane Cope rearrangement, there is another possible
pathway based on the palladium-catalyzed intramolecular allylic
substitution to construct the seven-membered ring through a retro-
cyclopropanation-mediated oxidative addition.
(a) Background
Ph
O
Pd(dba)2 (5 mol %)
PPh3 (6 mol %)
MeOOC
MeOOC
Ph
2
O
+
THF, 30 °C
MeOOC
Ph
91% yield
2:3 = 12.0:1
1 (dr = 1.7:1)
Introduction
3
Pd(dba)2
(5 mol %)
Ligand
Seven-membered ring carbocyclic frameworks are present in
various bioactive natural products and pharmaceuticals.
Therefore, the development of an efficient method of
constructing such molecular skeletons is an attractive research
topic in the field of synthetic organic and medicinal chemistry.
Considerable efforts have focused on this aim.[1]
Ligand = dppe (6 mol %):
87% recovery (2:3 = 4.4:1)
Ph
MeOOC
(2:3 = 12.0:1)
Ligand = PPh3 (12 mol %):
80% recovery (2:3 = 9.8:1)
THF, 30 °C
Pd-catalyzed isomerization
(b) Cascade Reaction Design
O
We recently developed
a diastereoselective synthetic
method of trisubstituted cyclopropanes using palladium-
Pd catalyst
Ar
MeOOC
catalyzed intramolecular allylic alkylation of a-aryl esters
B
O
Intramolecular
allylic alkylation
(Scheme 1).[2] After preparing lactone derivative
1
by
MeOOC
Yb(OTf)3/BF3·OEt2-catalyzed
intramolecular
allylic
Ar
Pd
A
Isomerization
carboxylation of a simple linear malonate derivative, compound
1 was treated with 5 mol % of Pd(dba)2 and 6 mol % of PPh3 in
THF at 30 °C, providing trisubstituted cyclopropane derivative 2
with high diastereoselectivity (2:3 = 12.0:1) (Scheme 1a).[3] Our
mechanistic investigations revealed that 2 was isomerized into
3 upon treatment with 5 mol % of Pd(dba)2 and 6 mol % of 1,3-
diphenylphosphinoethane (dppe), which significantly decreased
the diastereoselectivity (2:3 = 4.4:1). This finding led us to
design a new cascade reaction (Scheme 1b). We hypothesized
that when lactone derivative A bearing a styryl substituent in
the a-position was reacted with Pd(0) catalyst in the presence
catalyst
MeOOC
MeOOC
Cope rearrangement of
cis-divinylcyclopropane
C
Ar
Ar
D
Scheme 1. Background and Plan of This Work.
Results and Discussion
of
a bidentate phosphorus ligand, a palladium-catalyzed
We began our investigation by preparing the model substrate
(Scheme 2). a-Styryl malonate derivative 4a was prepared
using the synthetic method reported by Melnikov et al.[5]
A
[a]
K. Tsuruda, T. Tokumoto, N. Inoue, Dr. M. Nakajima, Prof. Dr. T.
Nemoto
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1, Inohana, Chuo-ku, Chiba 260-8675 (Japan)
E-mail: tnemoto@faculty.chiba-u.jp
URL: http://www.p.chiba-u.jp/lab/yakka/reserch,eng.html
Prof. Dr. T. Nemoto
Molecular Chirality Research Center, Chiba University
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
condensation reaction between 4a and 5 proceeded in the
presence of 1 equiv of NaH to give compound 6a in 79% yield.
Intramolecular allylic carboxylation was then performed in the
presence of 20 mol % of Yb(OTf)3 and 5 mol % of BF3·OEt2 in
nitromethane at 30 °C, providing compound 7a in 68% yield as
an inseparable nearly 1:1 diastereomeric mixture. With the
model substrate in hand, the reaction conditions were
[b]
optimized for
a palladium-catalyzed intramolecular allylic
Supporting information for this article is given via a link at the end of
the document.
alkylation–isomerization–Cope rearrangement cascade using 5
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10.1002/ejoc.201800230
European Journal of Organic Chemistry
COMMUNICATION
mol % of Pd(dba)2 complex (Table 1). We first screened
phosphorus ligands in THF at 50 °C. Among the examined
6
dppp (6)
dppp (6)
dppp (6)
dppp (6)
dppp (6)
–
toluene
82
7
1,4-dioxane
CH3CN
DMF
81
81
63
0
bidentate
phosphorus
ligands
(entries
1–3),
1,3-
diphenylphosphinopropane (dppp) was found to be optimal and
compound 8a was obtained in 88% yield. The target
transformation was also promoted when using 12 mol % of
PPh3 (Entry 4). The solvent effect was next examined using
dppp as a ligand (Entries 2, 5–9). The reaction media did not
affect the chemical yield and THF was determined to be the
best solvent. No reaction occurred when the reaction was
performed in the absence of the palladium catalyst (Entries 10
and 11), indicating the requirement of palladium catalysis in
this cascade process. Thus, we selected the reaction
conditions in entry 2 as the optimum conditions.
8
9
10[b]
11[b]
THF
THF
0
[a] Isolated yield. [b] The reaction was performed in the absence of Pd
catalyst.
We next examined the scope and limitations of the reaction
under the optimized conditions (Table 2). Intramolecular allylic
carboxylation of malonate derivatives 6a–k[6] was examined
using 20 mol % of Yb(OTf)3 and 5 mol % of BF3·OEt2 in
nitromethane at 30 °C. When malonate derivatives with an alkyl
group-substituted styryl group were utilized as substrates, the
corresponding lactone derivatives were obtained in 38–56%
yield (entries 2, 3, 7, and 9). In contrast, the lactone derivative
was obtained in good to excellent yield when substrates with a
halide-substituted styryl group were used (65–99% yield)
(entries 4–6, and 8). TLC analysis of the reaction mixture
revealed that when malonate derivatives with an alkyl group-
substituted styryl group were used, the starting material was
consumed and several by-products formed. Thus, we
speculated that the lower chemical yield in this case was due to
polymerization of the electron-rich styrene units. Although the
yield was moderate, this lactonization was also effective for
naphthyl-type substrates (entries 10 and 11). All substrates
were obtained as nearly 1:1 mixtures of diastereomers.
COOMe
NaH (1 equiv)
OAc
+
Br
Ph
COOMe
THF, 0 °C to rt
86% yield
5
4a
O
Yb(OTf)3 (20 mol %)
BF3·OEt2 (5 mol %)
MeOOC
MeOOC COOMe
Ph
O
CH3NO2 (0.05 M)
30 °C, 14 h
OAc
6a
Ph
7a
(dr = ca. 1:1)
68% yield
Scheme 2. Preparation of Model Substrate 7a
Table 1. Optimization of the Reaction Conditions.
O
MeOOC
MeOOC
Pd(dba)2 (5 mol %)
Ligand
O
The palladium-catalyzed intramolecular allylic alkylation–
isomerization–Cope rearrangement cascade was then
examined using lactone derivatives 7a–k under the optimized
reaction conditions. In addition to the model substrate 7a (entry
1), substrates with a para-substituted styryl group 7b–f were
applicable to this cascade reaction, affording the corresponding
7-membered ring carbocycles 8b–f in 69–83% yield (entries 2–
6). Meta-substituted styryl-type substrates 7g and 7h, as well
as an ortho-substituted styryl-type substrate 7i, were suitable
for this cascade process, providing the corresponding product
in 59–78% yield (entries 7–9). Moreover, when 1-naphthyl-type
lactone 7j and 2-naphthyl-type lactone 7k were used as
substrates, products 8j and 8k were obtained in 67% yield and
64% yield, respectively (entries 10 and 11).
solvent (0.2 M)
50 °C, 14 h
Ph
Ph
8a
7a
(dr = ca. 1:1)
Entry
Ligand (mol %)
Solvent
Yield (%)[a]
1
2
3
4
5
dppe (6)
dppp (6)
dppb (6)
PPh3 (12)
dppp (6)
THF
THF
THF
THF
71
88
85
79
83
1,2-dichloroethane
Table 2. Scope and Limitations.
O
MeOOC
MeOOC
Yb(OTf)3 (20 mol %)
BF3·OEt2 (5 mol %)
Pd(dba)2 (5 mol %)
dppp (6 mol %)
O
MeOOC COOMe
Ar
CH3NO2 (0.05 M)
30 °C, Time 1
THF (0.2 M)
50 °C, Time 2
OAc
Ar
Ar
8a–k
6a–k
7a–k
(dr = ca. 1:1)
Entry
1
Substrate
Time 1
14 h
Yield of 7[a]
Time 2
14 h
Yield of 8[a]
8a: 88%
6a (Ar = Ph)
7a: 68%
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10.1002/ejoc.201800230
European Journal of Organic Chemistry
COMMUNICATION
2
6b (Ar = 4-CH3-C6H4)
6c (Ar = 4-t-Bu-C6H4)
6d (Ar = 4-F-C6H4)
6e (Ar = 4-Cl-C6H4)
6f (Ar = 4-Br-C6H4)
6g (Ar = 3-CH3-C6H4)
6h (Ar = 3-F-C6H4)
6i (Ar = 2-CH3-C6H4)
6j (Ar = 1-naphthyl)
6k (Ar = 2-naphthyl)
40 h
22 h
40 h
19 h
50 h
22 h
19 h
22 h
20 h
19 h
7b: 56%
7c: 38%
7d: 99%
7e: 95%
7f: 82%
7g: 47%
7h: 65%
7i: 56%
7j: 33%
7k: 54%
22 h
18 h
16 h
15 h
24 h
17 h
19 h
20 h
21 h
21 h
8b: 83%
8c: 76%
8d: 69%
8e: 69%
8f: 78%
8g: 59%
8h: 75%
8i: 69%
8j: 67%
8k: 64%
3
4
5
6
7
8
9
10
11
[a] Isolated yield.
To elucidate the reaction pathway through a palladium-
catalyzed intramolecular allylic alkylation-isomerization-Cope
rearrangement cascade, we first attempted to isolate the
trisubstituted cyclopropane intermediate. The postulated
trisubstituted cyclopropane intermediate, however, could not be
isomerization and the Cope rearrangement should proceed
spontaneously with low activation barrier.[7] We therefore
performed a computational analysis to gain insight into the
reaction mechanism.
isolated in this reaction, indicating that the trans to cis
Ph
Ph
MeOOC
COOMe
Pd(II)
COOMe
MeOOC
Path A
Path B
∆G
(kcal/mol)
Pd
L
L
: dppp
Path B
Path A
Pd
Ph
L
L
Ph
TS_REcis
2.5
TS_REtrans
L
L
(II)Pd
4.3
IM1
IM2
IM2
0.1
MeOOC
Ph
MeOOC
IM1
0.0
Pd
L
IM5cis
L
Ph
Pd
L
L
–5.7
IM4trans
MeOOC
IM5trans
MeOOC
Ph
–9.2
IM4cis
–10.5
MeOOC
–12.2
Ph
Pd
IM3cis
MeOOC
Ph
Ph
L
MeOOC
Ph
L
CPtrans
IM3trans
MeOOC
Ph
CPcis
–17.9
Pd
L
–15.9
L
L
–17.7
–17.8
Pd
L
Pd
L
L
cis form cyclopropanation
trans form cyclopropanation
Scheme 3. DFT-Computed Pathways for the Cyclopropanations. Optimization of geometries and frequencies are computed at the M06/LANL2DZ-6-31+G* level.
We first performed DFT calculations on the reaction
mechanism of cyclopropanation (Scheme 3). There are two
possible pathways for this step: nucleophilic addition to the p-
allylpalladium (II) complexes IM1 or IM2 (Path A), or reductive
elimination from the four-membered palladacycle intermediates
IM4cis or IM4trans (Path B). In the DFT calculation for Path A, we
found no transition structure in either the transformation from
IM1 to IM3cis or that from IM2 to IM3trans, and no maximum
point was confirmed in the potential energy curve related to the
newly formed C–C bond length, indicating that the three-
membered ring formation via Path A is a barrierless reaction
with very low activation energy. On the other hand, in the DFT
calculation for Path B, the activation energies of either reaction
for TS_RE was less than 14.8 kcal/mol, leading to a cis-form
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10.1002/ejoc.201800230
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COMMUNICATION
product CPcis or trans-form product CPtrans. These calculation
data suggested that the cyclopropanation/ring-opening
reactions were reversible in the presence of a palladium
catalyst, leading us to conclude that isomerization from CPtrans
to CPcis is a reasonable process.
step. On the other hand, contrary to our expectation, the
activation energy of the intramolecular allylic substitution from
IM3cis to TS2 was calculated to be 20.2 kcal/mol, despite being
mediated by the thermodynamically unfavorable anti-p-
allylpalladium (II) complex. We expect that the conformational
similarity between IM3cis and TS2 affects the activation energy,
facilitating the seven-membered ring formation. Although the
activation energy of the reductive elimination from IM6 to TS3
is 17.6 kcal/mol, Path E would not be a plausible route because
the potential energy of IM6 is significantly larger than those of
CPcis and IM3cis. These computational studies suggest that, in
addition to the reaction cascade including the cis-
divinylcyclopropane Cope rearrangement, there is another
possible pathway based on the palladium-catalyzed
intramolecular allylic substitution to construct the seven-
We next performed DFT calculations for the seven-
membered ring formation (Scheme 4). There are three possible
pathways for this step, including Cope rearrangement via TS1
(Path C), nucleophilic addition of a benzylic anion to p-
allylpalladium (II) complex via TS2 (Path D), and reductive
elimination of eight-membered palladacycle IM6 via TS3 (Path
E). DFT calculations for Path C revealed that the activation
energy of the Cope rearrangement from CPcis to TS1 was 20.1
kcal/mol, forming thermodynamically significantly stabilized
product PD. This energy profile reasonably supported the
reaction cascade including a conventional Cope rearrangement
membered ring through
oxidative addition.
a
retro-cyclopropanation-mediated
E
TS1 (27.3)
E
Pd
L
Ph
L
L
L
L
Pd
L
Path E
Pd
Ph
IM6 (9.7)
Ph
E
TS2 (4.3)
E
L
L
Pd
TS2
TS3 (2.2)
Path D
+ PdL-L
Ph
Ph
E
Ph
Path C
E
PD’ (–16.0)
IM3cis (–15.9)
CPcis (–17.9)
PD’’ (–29.7)
Ph
E
PD (–31.8)
E
IM3cis
Ph
Scheme 4. DFT Calculation for Seven-Membered Ring Formations.
Conclusions
In conclusion, we developed a novel method for synthesizing 7-
membered ring carbocycles via palladium-catalyzed
Experimental Section
a
General Procedure for the 7-membered ring carbocycles via
palladium-catalyzed intramolecular allylic alkylation–
intramolecular
rearrangement cascade.
allylic
alkylation–isomerization–Cope
series of 7-membered ring
A
isomerization–Cope rearrangement cascade (Table 2, entry 2): A
solution of 6a (175.7 mg, 0.507 mmol), Yb(OTf)3 (62.6 mg, 0.101 mmol),
BF3･OEt2 (3 μL, 0.025 mmol) in CH3NO2 (10 mL) was stirred at 30 °C.
After 14 h, the reaction mixture was cooled down to room temperature
and then quenched with saturated aq. NaHCO3 solution. The organic
layer was separated and the aqueous layer was extracted twice with
AcOEt. The combined organic extracts were washed with water and
brine, dried over sodium sulfate. After concentration in vacuo, the
residue was purified by silica gel column chromatography (n-
hexane/AcOEt = 5/1) to give 7a (94.2 mg, dr. = 1:1, 68% yield) as an
carbocycles were obtained from easily available lactone
derivatives in 59–88% yield (11 examples). DFT calculations
suggest that, in addition to the reaction cascade including the
cis-divinylcyclopropane Cope rearrangement, there is another
possible pathway based on the palladium-catalyzed
intramolecular allylic substitution to construct the seven-
membered ring through
oxidative addition.
a retro-cyclopropanation-mediated
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10.1002/ejoc.201800230
European Journal of Organic Chemistry
COMMUNICATION
inseparable mixture of diastereomers. Ratio of the diastereomeric
mixture was determined by H-NMR analysis of the obtained mixture. A
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1
solution of 7a (50.7 mg, 0.186 mmol), Pd(dba)2 (5.3 mg, 0.00921 mmol),
dppp (4.6 mg, 0.0111 mmol) in THF (0.93 mL) in an argon atmosphere
was warmed to 50 °C. After being stirred for 14 h at the same
temperature, the reaction mixture was concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-
hexane/AcOEt = 80/1) to give methyl 3-phenylcyclohepta-1,5-diene-1-
carboxylate (8a) (37.1 mg, 88% yield) as pale yellow oil. 8a: IR (ATR) n
3026, 2365, 1711, 1435, 1242, 1195, 1074, 758, 701, 617 cm-1; 1H-
NMR (CDCl3, 400 MHz) d 2.40–2.46 (1H, m), 2.54–2.58 (1H, m), 3.30
(2H, d, J = 5.2 Hz), 3.72 (3H, s), 3.94–3.99 (1H, m), 5.69–5.80 (2H, m),
7.13 (1H, d, J = 5.6 Hz), 7.23–7.26 (3H, m), 7.32–7.35 (2H, m); 13C-
NMR (CDCl3, 100 MHz) d 25.7, 33.7, 43.9, 51.9, 126.7, 127.4 (2C),
127.4, 128.7 (2C), 129.6, 131.7, 144.5, 146.5, 168.0; HRMS (ESI-TOF)
m/z: Calcd for C15H16NaO2 [M+Na]+: 251.1043; found: 251.1046.
[5]
A. O. Chagarovsky, O. A. Ivanova, E. R. Rakhmankulov, E. M.
Budynina, I. V.Trushkov, M. Y. Melnikov, Adv. Synth. Catal. 2010, 352,
3179.
[6]
[7]
For the preparation of substrates, see Supporting Information.
The half-life of cis-divinylcyclopropane is 449 seconds at 20.4 °C,
implying that isolation of the cis-divinylcyclopropane intermediate
would be difficult. For a reference, see: J. M. Brown, B. T. Golding, J.
J. Stofko, J. Chem. Soc., Chem. Commun. 1973, 0, 319b.
Acknowledgements
This work was supported financially by JSPS KAKENHI Grant
Number 15K07850, and grant from Global and Prominent
Research, Chiba University.
Keywords: Cascade reaction • Catalysis • Palladium •
Rearrangement • Synthetic method
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10.1002/ejoc.201800230
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Cascade Reaction*
O
MeOOC
Ar
MeOOC
Kazuki Tsuruda, Takahisa Tokumoto,
Naoya Inoue, Masaya Nakajima, and
Tetsuhiro Nemoto*
Ar
MeOOC
Ar
Isomerization
Pd cat.
O
MeOOC
Ar
59–88% yield
(11 examples)
Pd-catalyzed intramolecular allylic substitution
– isomerization – Cope rearrangement cascade
Page No. – Page No.
We report a novel method for synthesizing 7-membered ring carbocycles via a
palladium-catalyzed intramolecular allylic alkylation–isomerization–Cope
rearrangement cascade. DFT calculation for the seven-membered ring formation
step suggested that, in addition to the reaction cascade including the conventional
Cope rearrangement, there is another possible pathway based on the palladium-
catalyzed intramolecular allylic substitution via retro-cyclopropanation.
Synthesis of 7-Membered Ring
Carbocycles via a Palladium-
Catalyzed Intramolecular Allylic
Alkylation–Isomerization–Cope
Rearrangement Cascade
This article is protected by copyright. All rights reserved.