Nucleo-Palladation-Triggering Alkene Functionalization: A Route to γ-Lactones

Article abstract of DOI:10.1021/acs.orglett.7b02688

An unprecedented strategy for the highly effective synthesis of γ-lactones from homoallylic alcohols was achieved by palladium catalysis in one step. The protocol affords aryl, alkyl, and spiro γ-lactones directly from readily available homoallylic alcohols in good yields with excellent functional group tolerance and high chemoselectivity under mild conditions.

Full text of DOI:10.1021/acs.orglett.7b02688

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Nucleo-Palladation-Triggering Alkene Functionalization: A Route to
γ‑Lactones
Meifang Zheng, Pengquan Chen, Liangbin Huang, Wanqing Wu,* and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: An unprecedented strategy for the highly effective
synthesis of γ-lactones from homoallylic alcohols was achieved by
palladium catalysis in one step. The protocol affords aryl, alkyl,
and spiro γ-lactones directly from readily available homoallylic
alcohols in good yields with excellent functional group tolerance
and high chemoselectivity under mild conditions.
alladium-catalyzed reactions have a profound impact in
ygenase oxidation of cyclic ketones.6 However, the substrate
Porganic synthesis, due to their ability to form C−C, C−N, scope accessed by this strategy tends to be limited due to the
use of a strong acid. Besides, ring-closure techniques starting
from the hydroxy ester precursors7 and the alcohol
dehydrogenase oxidation of diols8 have been reported.
However, they required the preparation of diols or acidic
derivatives. Additionally, the chemical synthesis of lactones
from the cyclization of Ω-hydroxycarboxylic acids, esters, or
their activated derivatives play a dominant role.9 The insertion
of CO to allylic alcohols also provides a new avenue for lactone
synthesis.10 Yang’s group reported a gold-catalyzed method
from alkynyl acid.11 Moreover, we have previously developed a
Cu-catalyzed [3 + 2] cycloaddition of styrene for the
construction of γ-lactone skeletons.12 Although several
synthetic methods for γ-butyrolactones have been reported,
in view of the significance of the lactone derivatives, the
development of more direct, simple, and efficient routes to
access γ-butyrolactones is always in high demand. Therefore,
we envisioned that a direct route would be possible from β-
hydroxyalkenes via a novel Pd-catalyzed oxidative cyclization to
lactones.
and C−O bonds with high efficiency in a highly designated
fashion. Well-known Pd-catalyzed reactions, such as Suzuki
coupling, Wacker oxidation, and Hartwig−Buchwald reaction,
have extensive applications in industry productions.1 For
example, palladium catalysis has been applied to intermolecular
C−O bond formation with γ-hydroxyalkenes as a substrate by
Wolfe’s group.2 For a long time, our group has been dedicated
to constructing various C−C, C−N, and C−O bonds via
nucleopalladation processes. Halopalladation, aminopalladation,
and oxypalladation designed with high efficiency and easy
operation have been reported.3
The γ-lactone core and its derivatives exist in more than
15 000 natural products, including antibiotic and antitumor
reagents.4 Stemming from the medicinal importance of
molecules such as those described above, there has been a
longstanding interest in the synthesis of this moiety for organic
chemists.5 At present, many elegant strategies have been
designed to prepare γ-lactones (Scheme 1). One general
method for these substructures is Baeyer−Villiger monoox-
As a start, we selected 1-phenylbut-3-en-1-ol (1a) as the
model substrate, which was easily prepared from benzaldehyde
and allylmagnesium bromide (Table 1). As expected, when
TBHP (tert-Butyl hydroperoxide) was used as an oxidant, an
11% yield of the expected product 2a was obtained (Table 1,
entry 1). To our delight, altering the solvent from CH3CN to
CH3NO2 led to the corresponding product 2a in 74% yield
(Table 1, entry 3). Screening of the solvents showed the
efficiency of CH3NO2 was higher than other solvents (see the
Supporting Information, Table S1). Further investigation
indicated that the addition of TBHP as the oxidant led to a
higher yield of 2a than other oxidants (Table 1, entries 4−9).
Other additives, such as CuCl, In(OTf)3, and FeCl3, gave an
inferior yield compared with that of CuCl2 (Table 1, entries
Scheme 1. Previous Synthetic Methods for Lactones
Received: August 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02688
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
a
b
entry
catalyst
PdCl2
additive
oxidant
TBHP
solvent
yield (%)
1
2
3
4
5
6
7
8
9
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl
CH3CN
11
50
74
60
21
7
PdCl2
DTBP
TBHP
DTBP
PhI(OAc)2
DDQ
CH3CN
PdCl2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
PdCl2
PdCl2
PdCl2
PdCl2
H2O2
15
13
12
57
34
10
17
14
46
57
n.d.
68
10
25
PdCl2
O2
PdCl2
BQ
c
10
PdCl2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
11
12
13
14
15
PdCl2
PdCl2
In(OTf)3
FeCl3
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
−
PdCl2
Pd(OAc)2
Pd(CH3CN)2Cl2
PdCl2
d
16
17
−
PdCl2
e
18
19
PdCl2
f
20
PdCl2
CuCl2
a
b
Reaction conditions: unless otherwise noted, the reaction was carried out with 0.5 mmol of 1a and in solvent (1 mL) at 80 °C for 24 h. Yield
c
d
determined by GC-MS with dodecane as internal standard. n.d. = not detected. 2 equiv of NaHCO3 were added. The reaction was carried out with
5 mol % of PdCl2. The reaction was carried out with 10 mol % of CuCl2. The reaction was carried out at 50 °C for 24 h.
e
f
11−13). Other palladium loadings, such as Pd(OTf)2 and
Pd(CH3CN)2Cl2, showed lower efficiency compared with
PdCl2 (Table 1, entries 14−16). No reaction was observed in
the absence of a palladium catalyst (Table 1, entry 17), while in
the absence of CuCl2, a 10% yield of product 2a was detected
(Table 1, entry 19). Also, lower temperature was tested for this
reaction in which a 25% yield of the desired lactone 2a was
obtained (Table 1, entry 20).
Table 2. Screening of Ligands for the Optimal Reaction
Conditions
a
a
b
entry
ligand
yield (%)
Major efforts were then made to further optimize the
intramolecular alkene functionalization in order to extend its
methodology scope. Several bidentate ligands were examined
using homoallylic alcohol 1a as the benchmark testing substrate
(Table 2). The screening of the ligands revealed L5 leading to a
remarkable yield of 2a up to 86% (85% isolated yield).
However, the use of L3 was found to be inactive (Table 2, entry
3), and the use of L2 together with PdCl2 led to a sharp
decrease in the yield of 2a to 5% (Table 2, entry 4). Employing
L4 in the coupling reaction afforded 2a in 75% yield (Table 2,
entry 5). Thus, we choose the conditions in Table 2, entry 5 as
the standard conditions.
Having established the optimal conditions, we next
investigated the substrate scope of the reaction with various
homoallylic alcohols (Scheme 2). Alcohols with a 4-Me, 3-Me,
or 2-Me substituent offered the corresponding products 2b−2d
in 83%, 79%, and 65% yields, respectively. We also examined a
tert-butyl substituted substrate, which went through the process
smoothly and gave a 45% yield of compound 2f. Halogen-
substituted substrates worked well with good group tolerance,
producing the desired lactones 2h−2j in the yields of 62%,
87%, and 77%, respectively. The transformation of a naphthyl
substituted substrate (1k) could also proceed well under the
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
L5
10
5
n.d.
75
86 (85)
66
c
7
77
a
Reaction conditions: unless otherwise noted, the reaction was carried
out with 1a (0.5 mmol), PdCl2 (10 mol %), L (12 mol %), CuCl2 (20
mol %), TBHP (1 mmol), and H2O (1 mmol) in CH3NO2 (1 mL) at
80 °C for 24 h. Yield determined by GC with dodecane as internal
standard, and isolated yield is in the parentheses. n.d. = not detected.
25 mol % L5 was added.
b
c
B
DOI: 10.1021/acs.orglett.7b02688
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Synthesis of Lactones
Scheme 3. 18O-Labeling Experiment
a novel Pd(II)-catalyzed tandem process is proposed (Scheme
4). Initial coordination of the internal alkene to Pd(II) affords
Scheme 4. Possible Catalytic Cycle
intermidiate A.2a Subsequently, the π system of CC bond
inserts into the [Pd]−O bond to form palladacycle B, followed
by β-H elimination to give intermediate C. Then, the
nucleophilic addition of water to C generates the intermediate
D.15 Subsequent β-H elimination produces enol E. Con-
sequently, the keto−enol tautomerism of intermediate E
produces the target product 2a. And the Pd(II) species is
regenerated by [Cu]/TBHP to complete the catalytic cycle.17
The alternative mechanism is via the Wacker process, as shown
in Cycle B. The anti-Markovnikov selectivity of the Wacker
process of intermediate A affords intermediate F. Subsequent
keto−enol tautomerism of intermediate G produces the
aldehyde H. Then, the cyclization of intermediate H affords
the final product 2a.18 However, the mechanism is still
unresolved.19
In conclusion, a novel and useful method has been developed
to construct lactones via a Pd-catalyzed intermolecular
cyclization reaction of homoallylic alcohols. This protocol
provides an efficient route to functionalized lactones with easily
accessible substrates and mild conditions with good to excellent
yields. Ongoing research involves further investigations of the
synthetic application, and detailed mechanistic studies are
underway in our laboratory.
a
Reaction conditions: unless otherwise noted, the reaction was carried
out with 1 (0.5 mmol), PdCl2 (10 mol %), L5 (12 mol %), CuCl2 (20
mol %), TBHP (1 mmol), and H2O (1 mmol) in CH3NO2 (1 mL) at
b
80 °C for 24 h. Yields refer to the isolated yields. 1 mmol of 1a was
tested under the standard conditions. The reaction was carried out
with solvent CH3CN.
c
optimized reaction conditions to afford product 2k. Gratify-
ingly, substrates containing an α-methyl or a β-methyl
substituent were found to be a suitable substrate with high
selectivity, giving the corresponding products 2m−2p in good
yields. Aliphatic alcohols also worked well and converted to the
desired lactones 2q and 2r efficiently. Particularly, spiro
product 2q was obtained in 68% yield. Moreover, a 31%
yield of 5-styryldihydrofuran-2(3H)-one (2s) was afforded with
using 1-phenylhexa-1,5-dien-3-ol (1s) as the substrate.
However, alkynyl substituted homoallylic alcohol could not
transfer to the corresponding product 2t. Besides, when 2-
vinylphenol was subjected to the system instead of γ-
hydroxyalkenes under the standard conditions, the desired
benzofuran-2(3H)-one (2u) was obtained in 35% yield, in
which the core is shared by several biologically relevant
molecules.13
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02688.
Critical evidence was obtained in the isotope labeling
experiments by using TBHP in a H2O18 solution (Scheme
3).16 The reaction in CH3NO2 led to the formation of [18O]-2a
and 2a with a ratio of 1:1, and this result was confirmed by high
resolution mass spectrometry (see the Supporting Information
for details).
Typical experimental procedure and characterization for
all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Based on the experimental results and previous re-
*E-mail: jianghf@scut.edu.cn.
*E-mail: cewuwq@scut.edu.cn.
ports,2,14−16 a tentative mechanism for γ-lactone synthesis via
C
DOI: 10.1021/acs.orglett.7b02688
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Liangbin Huang: 0000-0001-9450-9454
Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Key Research and Develop-
ment Program of China (2016YFA0602900), the National
Natural Science Foundation of China (21672072 and
21420102003), and the Fundamental Research Funds for the
Central Universities (2015ZY001 and 2017ZD062) for
financial support.
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