Substrate specific silver(I)-catalyzed cycloisomerization of diene involving alkyl rearrangements: Syntheses of 1,2,5,6-tetrahydrocuminic acid, p-menth-3-en-7-ol, and p-menth-3-en-7-al

Article abstract of DOI:10.1248/cpb.c17-00433

The novel cationic Ag(I)-catalyzed cycloisomerization, which is associated with alkyl rearrangements, from dimethyl 2-allyl-2-prenylmalonate (1) to dimethyl 4-isopropylcyclohex-3-ene-1,1-dicarboxylate (2) has been developed. Derivatization from the dieste

Full text of DOI:10.1248/cpb.c17-00433

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Chem. Pharm. Bull. 65, 822–825 (2017)
Vol. 65, No. 9
Communication to the Editor
Table 1. Ag(I)-Catalyzed Cycloisomerization of Diene 3
Substrate Specific Silver(I)-Catalyzed
Cycloisomerization of Diene Involving
Alkyl Rearrangements: Syntheses
of 1,2,5,6-Tetrahydrocuminic
Acid, p-Menth-3-en-7-ol, and p-Menth-
3-en-7-al
AgSbF6
(mol%)
Entry
Solvent
Temp. (°C) Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
20
5
DCM
DCM
DCE
100
100
120
150
150
150
150
170
150
30
120
120
10
52
59
Fuyuhiko Inagaki,* Mizuki Matsumoto,
Shisen Hira, and Chisato Mukai
5
54
5
DCE
65
Division of Pharmaceutical Sciences, Graduate School of Medical
Sciences, Kanazawa University; Kakuma-machi, Kanazawa 920–
1192, Japan.
5
Toluene
Xylene
THF
10
NR
NR
Trace
NR
50a)
5
10
5
10
Received May 29, 2017; accepted June 16, 2017
5
ODCB
DCE
10
5
10
The novel cationic Ag(I)-catalyzed cycloisomerization,
which is associated with alkyl rearrangements, from dimethyl
2-allyl-2-prenylmalonate (1) to dimethyl 4-isopropylcyclohex-
3-ene-1,1-dicarboxylate (2) has been developed. Derivatization
from the diester 2 into the diol 3 and its X-ray crystallo-
graphic analysis determined the structure. The mechanisms
of the novel reaction were investigated by isotopic experi-
ments, which supported the unusual alkyl shifts. In addi-
tion, the product 2 was used for the total syntheses of three
natural products, 1,2,5,6-tetrahydrocuminic acid (12),
p-menth-3-en-7-ol (13), and p-menth-3-en-7-al (14) in short
steps.
a) 1eq of BHT was added.
Key words silver; catalytic reaction; cycloisomerization;
diene; alkyl transfer
Chart 1. Treatment of Diene 1 with Several Catalysts
Coinage metal-catalyzed cyclizations of alkynes and other
functionalities have been well developed.1–5) In most cases,
the alkynophilicities of metal elements, such as gold,6–30)
silver,31,32) and copper,33,34) have led to various types of reac-
tions. In comparison with the catalytic reaction using a triple
bond, the silver catalyzed reactions of simple alkene moieties
are limited.35–42) However, for example, the silver cation is
often used in ion chromatography to separate a mixture of
unsaturated fatty acids containing similar multiple double
bond units.43–50) Thus, we hypothesized that the coordination
of the silver ion with two intramolecular alkenes might cause
a novel cyclization under high temperature. We now report the
novel silver-catalyzed cyclization of a diene, which is associ-
ated with alkyl rearrangement, and its application to natural
product syntheses.
Chart 2. Derivatization for X-Ray Crystallographic Analysis
Initially, allyl prenyl malonate 151–53) was used as the start-
ing material. After several screenings using silver salts, we
found that the condition with 20mol% of AgSbF6 in CH2Cl2
under microwave irradiation for 30min afforded the dimethyl
4-isopropyl-3-cyclohexene-1,1-dicarboxylate (2) in 52% yield
(Table 1, entry 1). Five mol% of AgSbF6 also provided 2 in
59% yield (entry 2). Changing the solvent to 1,2-dichloroeth-
ane (DCE) gave 2 in 54% yield after 120min at 120°C (entry
3), and increasing the temperature to 150°C led to the better
yield (65%) and shorter reaction time (10min) (entry 4). Other
solvents like toluene, xylene, tetrahydrofuran (THF), and
ortho-dichlorobenzene (ODCB) did not work for this reaction
Chart 3. Isotope Labeling Experiments
*ꢀToꢀwhomꢀcorrespondenceꢀshouldꢀbeꢀaddressed.ꢀ e-mail:ꢀfinagaki@p.kanazawa-u.ac.jp
© 2017 The Pharmaceutical Society of Japan

Vol. 65, No. 9 (2017)
Chem. Pharm. Bull.
823
Chart 4. Plausible Mechanisms
(entries 5–8). Thus, the conditions of entry 4 seemed to pro-
vide the best reaction. Addition of butylated hydroxytoluene
(BHT) as a radical scavenger in best condition also provided
the desired 2 in 50% yield, which suggested that the reac-
tion did not proceed via radical intermediates (entry 9). We
next examined the different types of catalysts (Ag(I), Au(I),
Au(III), Pt(II), etc.) for the same reaction (Chart 1). However,
the desired 2 was not observed under all these conditions.
The structure of 2 was unambiguously elucidated by the
reduction to form 3 and its X-ray crystallography (Chart 2).
Next, we focused on the elucidation of the reaction mecha-
nisms because production of the isopropyl moiety at the
4-position of product 2 induces an alkyl rearrangement. Thus,
a carbon-13 (13C) analysis using 1-13C was investigated. After
the reaction under the best condition described for Table 1,
entry 4, the resulting products showed two large 13C-peaks at
the C4 position (2a-13C) and isopropylmethine carbon (2b-13C)
(Chart 3). A deuterated analysis using CD2 instead of 13CH2
(1-D) was also examined. However, the resulting product indi-
cated deuterium scrambling. Based on these results, the plau-
sibleꢀmechanismsꢀareꢀshownꢀinꢀChartꢀ4.ꢀAtꢀfirst,ꢀcoordinationꢀ
of the silver cation with both double bonds of 1 would form I.
Cyclization forming the 7-membered ring intermediates II and
II′, and 1,2-H shift of II′ might then provide the intermediate
III (III′). In case of the alkyl shift via the ring contraction of
III to construct the intermediate IV, the following 1,2-H shift
and elimination of the silver cation would form product 2a,
which has a 13C at the C4 position. On the contrary, methyl
rearrangement for formation of the intermediate VI could
follow the alkyl transfer accelerated by the ring contraction
(VII). As the same process of IV to 2a, 2b having 13C at the
isopropylmethine position would be observed. The reason for
the deuterium scrambling is uncertain. However, it might have
Chart 5. Trials for Silver(I)-Catalyzed Cyclization
Our next efforts focused on the scope and limitations of
occurred due to the uncontrollable 1,2-H shift of II, II′, III, the similar cyclization associated with alkyl rearrangement.
and III′. Forꢀ thisꢀ objective,ꢀ allyl,ꢀ homoallylꢀ 3,3-dimethylallyl,ꢀ 2-meth-

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Chem. Pharm. Bull.
Vol. 65, No. 9 (2017)
Acknowledgment We are grateful for the support of
Grant-in-Aidꢀ forꢀ Scientificꢀ Researchꢀ fromꢀ theꢀ Ministryꢀ ofꢀ
Education, Culture, Sports, Science and Technology (MEXT)
of Japan.
Conflict of Interest Theꢀ authorsꢀ declareꢀ noꢀ conflictꢀ ofꢀ
interest.
Supplementary Materials The online version of this ar-
ticle contains supplementary materials (a: experimental proce-
duresꢀandꢀcharacterizations,ꢀb:ꢀcifꢀfileꢀforꢀcompoundꢀ3).
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