Palladium-Catalyzed Cascade Intramolecular Cyclization and Allylation of Enynoates with Allylic Alcohols

Article abstract of DOI:10.1021/acs.joc.9b00461

A Pd(II)-catalyzed mild and highly regioselective 6-endo cyclization/allylation reaction of enynoates with simple allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization could insert C-C double bond of allylic alcohol through cross-coupling reaction and lead to the formation of allyl pyrone via β-OH elimination. This cascade cross-coupling reaction represents a direct and atom economic methodology for the construction of novel allyl pyrones in moderate to good yields.

Full text of DOI:10.1021/acs.joc.9b00461

Subscriber access provided by University of Rochester | River Campus & Miner Libraries
Article
Palladium-Catalyzed Cascade Intramolecular Cyclization
and Allylation of Enynoates with Allylic Alcohols
Sheng-Qi Qiu, Tanveer Ahmad, Yun-He Xu, and Teck-Peng Loh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00461 • Publication Date (Web): 13 May 2019
Downloaded from http://pubs.acs.org on May 13, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Cascade Intramolecular Cyclization and
Allylation of Enynoates with Allylic Alcohols
Sheng-Qi Qiu,† Tanveer Ahmad,† Yun-He Xu*,† and Teck-Peng Loh*,†,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371.
Supporting Information
ABSTRACT: A Pd(II)-catalyzed mild and highly regioselective 6-endo cyclization/allylation reactions of enynoates with simple
allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization
could insert C-C double bond of allylic alcohol through cross-coupling reaction and lead to the formation of allyl pyrone via β-OH
elimination. This cascade cross coupling reaction represents a direct and atom economic methodology for the construction of novel
allyl pyrones in moderate to good yields.
R2
R3 OH
R3
[Pd]
R2
R1
CO2Et
OH
R1
R2
[Pd]
R1
+
-OH elimination
O
O
R3
O
O
Larock et al. (2003)
E
INTRODUCTION
R'
R
R'
[E+]
Pyrone is one of the significant structural subunit in numerous
bioactive natural products and pharmaceutically relevant
compounds.1 They are also prevalent building blocks in some
total synthetic routes.2 Consequently, forerunners have made a
lot of attempts to prepare compounds containing pyrone as a
core moiety.3 However, regardless of prior approaches, more
efficient and convenient synthesis was still desirable for
functionalized pyrones.4 Therefore, for the cyclization
reactions of enynoates, several strategies have been developed
by Burton5, Larock6, Rossi7 et al. by using different
electrophiles during the past few decades. There are still some
unresolved problems such as chemoselectivity between 6-endo
and 5-exo products and limited scope of substrates have
remained challenging. At the same time, transition-metal-
catalyzed cyclization reactions of enynoates to achieve
pyrones have been studied, as an effective route to prepare the
multi-substituted pyrones.8 Owing to the limitation of
conventional approaches and organometallic methods, very
recently our group and other researchers reported the
palladium-catalyzed intramolecular alkyne addition reactions
through an oxygen atom of an enynoate or enynoic acid.9
Although remarkable progress in this field has been made, but
still, it is challenging to develop highly efficient catalytic
system for the synthesis of diversely functionalized pyrones.10
Moreover, in the aforementioned examples, the coupling
partners in cascade reactions were limited to electron-deficient
olefins and styrene analogous. In last few decades, allylic
alcohol was reported as an allyl provider to attach directly
with interval dienes.11 Allylic alcohols have many advantages
like abundant in nature, easy to prepare and environmentally
friendly. Fortunately, there are already some methods to
control the allylic alcohol as an allyl provider or an alkyl
reagent with the -elimination step.12
R''
(1)
O
R''
R
CO2Me
O
R = Ph, nC4H9; R' = H, Ph; R'' = H, Me, Ph
E = I, p-O2NC6H4S, PhSe
EWG
R'
Loh and Xu et al. (2015, 2018)
R'
R
[Pd]
+
EWG
(2)
-H elimination

R
COOR''
O
R = Aryl, Alkyl; R' = H, Me, Ph; R'' = Me, Et, nBu
EWG = CO2Me, CO2Et, CO2nBu, CO2tBu, CO2Bn, CHO, CONHPh, Ph
O
R'
O
R''
R''
R
CO2Et
OH
[Pd]
[Pd]
R
R'
R
R'
+
(3)
-OH elimination

-H elimination

O
O
Ref: 8f
R''
O
O
R = Aryl, Alkyl, Cycloalkenyl
R' = H, Me, nPr, Ph
R'' = H, Me, Et, iPr, nBu
R = Aryl, Alkyl
R' = H, Me, Ph
R'' = H, Me, Ph, Bn, Ph-4-Br
Ph, CH2-Ph, Ph-4-Br
Scheme 1. Palladium-catalyzed cyclization reactions to
synthesize pyrones.
RESULTS AND DISCUSSION
In this work, we achieved our goal by using palladium
catalyzed tandem cyclization and cross-coupling reaction of
enynoates with allylic alcohols (Scheme 1). A model substrate
(Z)-enynoate 1h and allylic alcohol 2a was used for reaction
parameters optimization (Table 1). From the earlier work in
our group, we found that such type of tandem reaction was
efficiently catalyzed by Pd(II) salts. The anion species also
plays an important role in elimination step. Moreover, carbon-
carbon triple bond could be well activated with Lewis acid.
Thus, we first tried palladium chloride along with 1,2-
bis(benzylsulfinyl)ethane as a ligand.13 Only trace desire
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 8
1
2
3
4
5
6
7
8
9
product observed after stirring for 24 hours with 59 % starting
When we started to expand the scope of different
enynoates, it was found that the standard condition was not
compatible to aryl-substituted enynoates. Ethyl (Z)-5-
phenylpent-2-en-4-ynoate gave a 60 % isolated yield only. So,
the catalyst loading was adjusted to 5 % and the ligand loading
was raised to 7 %. This adjustment improved the reaction
universality a lot with getting an 81 % yield for ethyl (Z)-5-
phenylpent-2-en-4-ynoate (3a). Therefore, this condition was
then used to expand enynoate substrates scope.
material recovered (Table 1, entry 1). Anhydrous copper
chloride was tested as a Lewis acid, which could access to
easy hydroxyl elimination and increased the yield of product
up to 41 % (Table 1, entry 2). After employing these reaction
conditions, a side reaction of polymerization happened during
the reaction which was speculated by the disappearance of
enynoate in crude 1H NMR. Therefore, 4 % addition of
benzoquinone as polymerization inhibitor helps to increase the
yield to 49 % (Table 1, entry 3). A higher CuCl2 concentration
increased the yield up to 61 % (Table 1, entry 5). When the
reaction was performed under oxygen atmosphere, the yield of
the product was decreased (Table 1, entry 6). The suitable
ratio of ligand and palladium chloride was 1.4:1 with a 73 %
isolated yield of the desired product (Table 1, entry 7). A
higher ratio of ligand reduced the yield to 65 % (Table 1, entry
8). After screening various solvents, toluene is the best one for
reaction (Table 1, entry 7). When the loading of palladium
chloride was increased to 5 mol %, only little effect on yield
was observed. With the ligand being changed to White ligand,
the yield was decreased to 50 %. Only trace amount of product
was obtained without copper chloride (Table 1, entry 13), and
a 35 % yield of the desired product without ligand (Table 1,
entry 14). These results prove that an optimized ratio of
copper chloride and ligand is required for a good product
yield. Attempt for many kinds of palladium salts confirms that
the use of different anion in the catalyst was also important
(Table 1, entry 15-18). There was no product observed and the
starting material was recovered in the absence of palladium
catalyst (Table 1, entry 19).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Here is a generality of the cascade reaction between
enynoates and allylic alcohol (Table 2). All of the substrates
with a weak electron-withdrawing group or electron-donating
group on the phenyl ring could give a good yield (Table 2,
entries 3b-3g). Also, aliphatic enynoates afford a moderate to
good yield at all (Table 2, entries 3h-3l). Substrates with a
methyl or a phenyl group at the β-position of enynoates all
afford the corresponding products in good to high yields
(Table 2, entries 3n-3q).
Table 2. Substrate Scope of Enynoates.a,b
5 mol % PdCl2
7 mol % L
20 mol % CuCl2
R
OH
+
R
CO2Et
Me
4 mol % BQ
toluene (0.2 M)
30 C, air
O
1
2a
3
O
Me
O
O
O
O
O
O
O
O
3a
81 % (18 h)
3b
70 % (18 h)
3c
3dc
71 % (12 h)
80 % (12 h)
Cl
MeO
nBu
O
MeO2C
Table 1. Optimization of the Reaction Conditions.a
O
O
O
O
O
O
O
[Pd]/L
CuCl2
nBu
3e
3f
3g
3h
OH
+
74 % (18 h)
72 % (18 h)
81 % (18 h)
72 % (12 h)
nBu
CO2Et
4 mol % BQ
O
solvent (0.2 M),
30 C, air, time
1h
2a
3h
AcO
O
Cl
NC
time (h) yield (%)b
O
O
O
O
Entry
[Pd] (mol %)
L (mol %)
solvent
CuCl2 (mol %)
O
3i
O
O
O
1d
2d
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (4)
PdCl2 (5)
4
4
4
4
4
0
24 h
24 h
24 h
24 h
24 h
24 h
12 h
24 h
trace
41
49
40
61
3j
3k
3l
10
10
10
20
20
20
20
20
20
20
71 % (18 h)
61 % (18 h)
72 % (18 h)
63 % (18 h)
MeO
4e
5
Ph
Ph
nBu
Ph
Ph
Me
O
O
O
O
6f
7
8
9
10
11
12g
13
14
15
16
17
18
19
4
47
74 (73c)
65
O
O
O
3o
O
3p
5.6
6.4
5.6
5.6
7
7
4
0
3m
3n
52 % (18 h)
66 % (36 h)
74 % (72 h)
63 % (60 h)
cyclohexane 24 h
DMF
toluene
68
12 h
12 h
0
nBu
Me
73 (72c)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PdCl2 (5)
PdCl2 (4)
PdCl2 (4)
Pd(OAc)2 (10)
20
0
24 h
24 h
24 h
24 h
24 h
24 h
14 h
24 h
50
trace
35
0
0
0
36
N.R.
O
O
3q
10
20
20
20
20
30
80 % (18 h)
12
Pd(MeCN)4(BF4)2 (10) 12
a
Reaction conditions: The reactions were carried out under the
Pd(dba)2 (10)
White Catalyst (5)
No [Pd]
12
0
6.4
standard conditions: 1 (0.3 mmol), 2a (0.9 mmol, 3 equiv),
palladium chloride (0.015 mmol, 0.05 equiv), 1,2-
bis(benzylsulfinyl)ethane (0.021 mmol, 0.07 equiv), copper
chloride (0.06 mmol, 0.2 equiv), BQ (0.012 mmol, 0.04 equiv) in
1.5mL toluene were stirred at 30 oC for corresponding hours
shown in parentheses. b Isolated yield. c 5 eq. allylic alcohol was
added.
O
O
S
Ph
S
S
Ph
S
Bn
Ph
Bn
S
Pd
Ph
S
O
O
O
AcO OAc
O
L
White ligand
White Catalyst
a Unless noted otherwise, reactions were carried out on a 0.3
mmol scale of 1h with 3 equiv of 2a in 1.5 mL of solvent.
b NMR yield with 1,3,5-trimethylbenzene as internal standard.
Different allylic alcohols were next examined as coupling
partners, which showed the steric effect was very significant
(Table 3). Only 1-methylallyl alcohol could give a moderate
yield of 65 %. When the methyl group was replaced by phenyl
rings, the yield was decreased to 39 % (4c) and 58 % (4d)
isolated yields or a benzyl group with 48 % (4a) isolated yield.
c
d
e
Isolated yield. No BQ added. Nitrogen atmosphere.
f Oxygen atmosphere. g White ligand used as ligand.
ACS Paragon Plus Environment

Page 3 of 8
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Judging from a 1D NOESY spectra of 4b, the (E)-isomer was
release the final product as a 5-allyl pyrone structure and
release the palladium salt. The Pd(II) catalyst was then
regenerate to attempt next catalytic cycle.
confirmed as the major composition of the isolated mixture. It
was shown that the geometric selectivity was excellent for 1-
aryl alcohols, but a little worse for 1-aliphatic alcohols.
R
R
Table 3. Substrate Scope of Different Allylic Alcohols.a,b
+ Cu(OH)X
EtOOC
1
R1
O
5 mol % PdCl2
PdX2
7 mol % L
20 mol % CuCl2
3
R2
O
Ph
OH
R2
+
Ph
CO2Et
4 mol % BQ
toluene (0.2 M)
30 C, air
PdX2
O
O
R1
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1a
4
O
R
H
O
R'
Ph
Bn
Me
XCu
X
O
Et
Ph
Ph
Ph
PdX
R
O
O
O
O
O
H
H
O
O
O
4bc
4a
48 % (72 h)
E : Z = 70 : 30d
4c
O
C
39 % (48 h)
E : Z > 95 : 5d
65 % (24 h)
E : Z = 84 : 16d
OH
+
HX
Br
PdX
O
Me
Me
R
R'
Ph
Ph
OH
O
Ph
O
O
O
PdX
R
CuX2
A
R'
O
O
O
OH
4d
4f
trace (96 h)
4e
tracec (48 h)
O
2
58 % (48 h)
E : Z = 94 : 6d
O
B
a Reaction conditions: The reactions were carried out under the
standard conditions: 1a (0.3 mmol), 2 (0.9 mmol, 3 equiv),
palladium chloride (0.015 mmol, 0.05 equiv), 1,2-
bis(benzylsulfinyl)ethane (0.021 mmol, 0.07 equiv), copper
chloride (0.06 mmol, 0.2 equiv), BQ (0.012 mmol, 0.04 equiv)
Scheme 3. Proposed Mechanism.
CONCLUSION
In summary, we have developed a palladium catalyzed
tandem regioselective 6-endo cyclization and allylation
o
in 1.5 mL toluene were stirred at 30 C for corresponding
reaction. Under mild reaction conditions,
a series of
b
c
hours shown in parentheses. Isolated yield. 5 eq. allylic
alcohol was added. d Isomer ratio was determined from crude
NMR.
multifunctionalized pyrones were synthesized with one-pot
reactions of enynoate and allylic alcohol. This cascade
reaction provides a simple, easy cost-effective route for the
regioselective synthesis of allyl pyrones. The applications of
these reactions with synthesis point of view are continuing in
our group.
To preclude the possibility that a pi-allyl complex might
be formed to start the catalytic cycle, equivalent bis(pi-
allyl)dichlorodipalladium was tried as the catalyst without
allylic alcohol adjunction (Scheme 2). No desire product was
observed and 80 % of enynoate was recovered after 24 hours.
EXPERIMENTAL SECTION
General Information
5 mol % [Pd(allyl)Cl]2
7 mol % L
20 mol % CuCl2
PdCl2, CuCl2 and allylic alcohols were purchased from
commercial suppliers and used as received unless otherwise
noted. All reactions were performed in air unless otherwise
specified. All commercial solvents and reagents were
employed without further purification. Reactions were
monitored through analytical thin layer chromatography (SiO2
60 F-254 plates). The spots visualization were performed
under UV radiation (254 nm), further visualization was
possible using basic solution of potassium permanganate.
Flash chromatography was carried out using 200-300 mesh
silica gel (SiO2 60) with distilled solvents. Proton nuclear
magnetic resonance (1H NMR) and carbon nuclear magnetic
resonance (13C{1H} NMR) spectra were recorded on Bruker
Advance 400M NMR spectrometers. Chloroform-d was used
as the solvent and SiMe4 (TMS) as internal standard. Chemical
N.D.P.
nBu
CO2Et
4 mol % BQ
toluene (0.2 M), 30 C, air
1h
Scheme 2. Controlled Experiment with Bis(pi-
allyl)dichlorodipalladium as Catalyst.
The proposed mechanism for the Pd(II)-catalyzed 6-endo
cyclization and allylation of enynoates was shown in Scheme
3. First, a 6-endo cyclization reaction of enynoates was
occurred catalyzed by Pd(II) and an active vinylpalladium
species (A) was formed. This species easily attracts an allylic
alcohol to construct species B. The ethyl was also removed
and converted to ethanol, which was detected by crude NMR.
This may prove that the ethyl departs the substrate with a
substitution reaction rather than a fragmentation from one
side. After an olefin insertion from the less hindered side, an
alkylpalladium species(C) was formed followed by an anti-
palladium β-hydroxyl elimination assisted with copper(II) to
1
shifts for H NMR spectra are reported as δ in units of parts
per million (ppm) downfield from TMS (δ 0.00 ppm) and
relative to the signal of chloroform-d (δ 7.260 ppm, singlet).
Multiplicities are recorded as: s (singlet); d (doublet); t
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 8
1
2
3
4
5
6
7
8
9
(triplet); q (quartet); dd (doublets of doublet); m (multiplets).
1H), 5.21 (dd, J = 10.2, 1.4 Hz, 1H), 5.11 (dd, J = 17.1, 1.5
Hz, 1H), 3.20 (dt, J = 5.6, 1.5 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ 162.1, 158.7, 147.4, 135.4, 132.1, 130.1,
128.5, 128.4, 117.4, 114.7, 113.1, 33.9; HRMS (EI): m/z
Calcd. for C14H13O2 [M+H]+: 213.0911, found: 213.0910.
5-allyl-6-(p-tolyl)-2H-pyran-2-one (3b). Colorless solid;
Coupling constants are expressed as a J value in Hz. 13C{1H}
NMR are reported as δ in units of parts per million (ppm)
downfield from TMS (δ 0.00 ppm) and relative to the signal of
chloroform-d (δ 77.03 ppm, triplet). Notable, splitting signals
of 13C nucleus was difficult to differentiate and 13C{1H} NMR
signals were reported as singlet. HRMS spectra were recorded
on Water XEVO-G2 Q-TOF (Waters Corporation).
1
47.4 mg, 0.210 mmol, yield: 70 %; H NMR (400 MHz,
CDCl3) δ 7.46 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 9.4 Hz, 1H),
7.24 (d, J = 7.9 Hz, 2H), 6.29 (d, J = 9.4 Hz, 1H), 5.93 (ddt, J
= 17.2, 10.2, 5.6 Hz, 1H), 5.21 (d, J = 10.2 Hz, 1H), 5.10 (d, J
= 17.2 Hz, 1H), 3.20 (d, J = 5.6 Hz, 2H), 2.40 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 162.3, 158.9, 147.5, 140.4, 135.5,
129.3, 129.1, 128.4, 117.4, 114.3, 112.8, 34.0, 21.4; HRMS
(EI): m/z Calcd. for C15H15O2 [M+H]+: 227.1067, found:
227.1071.
Preparation of Terminal alkynes and (Z)-Enynoates
Synthesis of terminal alkynes according to the following
procedures.14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In a dry round bottle flask, a solution of CuI (380.9 mg, 2.0
mmol, 5.0 mol%), Pd(PPh3)2Cl2 (701.9 mg, 1.0 mmol, 2.5
mol%) and alkyl iodide (40.0 mmol, 1.0 equiv.) in 300 mL of
Et3N was added trimethylsilylacetylene (40.0 mmol, 1.0
equiv.) dropwise under argon atmosphere. The mixture was
stirred at room temperature until the starting materials were
completely consumed. The reaction mixture was then filtered
with a short diatomite column and removed the solvent in
vacuum. The resulting crude product was dissolved in 150 mL
of methanol and added K2CO3 (11.06 g, 80.0 mmol, 2.0
equiv.). The reaction mixture was diluted with Et2O (200 mL)
after stirred at room temperature for 2 hours. After washing
with water (150 mL) and drying over anhydrous Na2SO4, the
residue was concentrated under reduced pressure and purified
by flash column chromatography (petroleum ether/ethyl
acetate = 50/1 as eluting solvent) to afford the corresponding
alkyne.15 2-Ethynylnaphthalene and 2-Ethynyl-1-methyl-1H-
indole were synthesized according to the reported
conditions.16, 17
5-allyl-6-(m-tolyl)-2H-pyran-2-one (3c). Yellow oil; 47.9
1
mg, 0.213 mmol, yield: 71 %; H NMR (400 MHz, CDCl3) δ
7.40 (s, 1H), 7.36-7.23 (m, 4H), 6.30 (d, J = 9.4 Hz, 1H), 5.92
(ddt, J = 17.0, 10.4, 4.7 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H),
5.10 (d, J = 17.1 Hz, 1H), 3.19 (d, J = 4.7 Hz, 2H), 2.39 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.2, 158.8, 147.4,
138.3, 135.4, 132.0, 130.9, 129.1, 128.2, 125.5, 117.4, 114.4,
113.1, 33.9, 21.4; HRMS (EI): m/z Calcd. for C15H15O2
[M+H]+: 227.1067, found: 227.1069.
5-allyl-6-(9H-fluoren-2-yl)-2H-pyran-2-one (3d). Colorless
solid; 72.4 mg, 0.240 mmol, yield: 80 %; 1H NMR (400 MHz,
CDCl3) δ 7.83-7.73 (m, 3H), 7.56 (d, J = 7.9 Hz, 2H), 7.42-
7.29 (m, 3H), 6.31 (d, J = 9.4 Hz, 1H), 5.96 (ddt, J = 17.2,
10.8, 5.6 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 17.2
Hz, 1H), 3.92 (s, 2H), 3.25 (d, J = 5.6 Hz, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 162.3, 159.2, 147.6, 143.8, 143.6, 143.3,
140.7, 135.5, 130.3, 127.6, 127.4, 127.0, 125.2, 125.2, 120.5,
119.6, 117.5, 114.3, 113.0, 36.9, 34.1; HRMS (EI): m/z Calcd.
for C21H17O2 [M+H]+: 301.1224, found: 301.1220.
5-allyl-6-(4-chlorophenyl)-2H-pyran-2-one (3e). Yellow
solid; 54.6 mg, 0.222 mmol, yield: 74 %; 1H NMR (400 MHz,
CDCl3) δ 7.52 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H),
7.30 (d, J = 9.5 Hz, 1H), 6.33 (d, J = 9.5 Hz, 1H), 5.94 (ddt, J
= 17.2, 10.7, 5.6 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 5.10 (d, J
= 17.2 Hz, 1H), 3.18 (d, J = 5.5 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ 161.8, 157.4, 147.3, 136.3, 135.1, 130.4,
129.8, 128.8, 117.6, 115.0, 113.4, 33.9; HRMS (EI): m/z
Calcd. for C14H12ClO2 [M+H]+: 247.0521, found: 247.0522.
All (Z)-configuration enynoates were prepared according to
the reported literatures. 18, 9, 7a
The (Z)-ethyl-3-iodoacryate18, enynoates except β-substituted
(Z)-enynoates (1a-1m)9, and the β-substituted (Z)-enynoates
(1n-1q)7a were prepared according to the reported literatures,
respectively. The crude product of β-substituted (Z)-enynoates
were purified by flash column chromatography (petroleum
ether/ethyl acetate = 20/1 as eluting solvent).
Allylic alcohols (2b and 2d-2g) were prepared according to
the reported literatures.19, 20
Procedure for the Synthesis of Products (3a-3q), (4a-4d). In
an oven dried 15 mL glass tube charged with a stir bar, toluene
(1.5 mL) was added to a mixture of PdCl2 (2.7 mg, 0.015
mmol, 5 mol%), 1,2-bis(benzylsulfinyl)ethane (6.4 mg, 0.021
mmol, 7 mol%), CuCl2 (8.1 mg, 0.06 mmol, 20 mol%) and
benzoquinone (1.3 mg, 0.012 mmol, 4 mol%) under air. The
mixture was stirred for 5 minute and then the enynoate (0.3
mmol, 1.0 equiv.) with corresponding allylic alcohol (0.9
mmol, 3.0 equiv.) were subsequently added to the mixture.
The reaction mixture was stirred at 30 °C until the starting
material enynoate was completely consumed (Monitored by
TLC). The reaction mixture was diluted with ethyl acetate and
then washed with water twice (10 mL x 2) and brine (5 mL).
The organic layer was dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate = 20/1 as eluting solvent) to afford the product.
5-allyl-6-phenyl-2H-pyran-2-one (3a). Colorless solid; 51.6
mg, 0.243 mmol, yield: 81 %;. 1H NMR (400 MHz, CDCl3) δ
7.60-7.53 (m, 2H), 7.48-7.42 (m, 3H), 7.31 (d, J = 9.5 Hz,
1H), 6.32 (d, J = 9.5 Hz, 1H), 5.93 (ddt, J = 17.1, 10.3, 5.7 Hz,
Methyl
3-(5-allyl-2-oxo-2H-pyran-6-yl)benzoate
(3f).
1
Yellow oil; 58.2 mg, 0.216 mmol, yield: 72 %; H NMR (400
MHz, CDCl3) δ 8.26 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.77 (d,
J = 7.8 Hz, 1H), 7.54 (dd, J = 7.8, 7.8 Hz, 1H), 7.33 (d, J = 9.5
Hz, 1H), 6.35 (d, J = 9.5 Hz, 1H), 5.94 (ddt, J = 17.1, 9.9, 5.6
Hz, 1H), 5.25 (d, J = 9.9 Hz, 1H), 5.13 (d, J = 17.1 Hz, 1H),
3.94 (s, 3H), 3.20 (d, J = 5.6 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ 166.3, 161.8, 157.4, 147.2, 135.0, 132.7,
132.4, 131.1, 130.6, 129.7, 128.7, 117.7, 115.2, 113.7, 52.4,
33.9; HRMS (EI): m/z Calcd. for C16H15O4 [M+H]+: 271.0965,
found: 271.0969.
5-allyl-6-(4-methoxyphenyl)-2H-pyran-2-one
(3g).
1
Colorless oil; 58.8 mg, 0.243 mmol, yield: 81 %; H NMR
(400 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.29 (d, J = 9.4 Hz,
1H), 6.98-6.92 (m, 2H), 6.27 (d, J = 9.4 Hz, 1H), 5.95 (ddt, J =
17.0, 10.2, 5.6 Hz, 1H), 5.21 (dq, J = 10.2, 1.4 Hz, 1H), 5.10
(dq, J = 17.1, 1.6 Hz, 1H), 3.85 (s, 3H), 3.20 (dt, J = 5.7, 1.8
Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.3, 161.0,
ACS Paragon Plus Environment

Page 5 of 8
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
158.7, 147.7, 135.5, 130.0, 124.5, 117.3, 113.8, 113.8, 112.3,
33.6, 33.1, 32.9; HRMS (EI): m/z Calcd. for C16H17O2
[M+H]+: 241.1224, found: 241.1230.
55.4, 34.0; HRMS (EI): m/z Calcd. for C15H15O3 [M+H]+:
243.1016, found: 243.1014.
5-allyl-6-(4-methoxyphenyl)-4-phenyl-2H-pyran-2-one
(3n). Colorless oil; 62.6 mg, 0.198 mmol, yield: 66 %; H
1
5-allyl-6-butyl-2H-pyran-2-one (3h). Colorless oil; 41.6 mg,
0.216 mmol, yield: 72 %; 140.4 mg, 0.730 mmol, yield: 73 %
for 1 mmol scale reaction. 1H NMR (400 MHz, CDCl3) δ 7.16
(d, J = 9.4 Hz, 1H), 6.16 (d, J = 9.4 Hz, 1H), 5.81 (ddt, J =
17.1, 10.2, 6.1 Hz, 1H), 5.12 (dd, J = 10.1, 1.1 Hz, 1H), 5.04
(dd, J = 17.1, 1.2 Hz, 1H), 3.07 (d, J = 6.0 Hz, 2H), 2.49 (t, J
= 7.7 Hz, 2H), 1.64 (tt, J = 7.7, 7.6 Hz, 2H), 1.36 (tq, J = 7.6,
7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 162.8, 162.7, 147.1, 135.0, 116.8, 113.4,
112.4, 33.3, 30.6, 29.6, 22.4, 13.8; HRMS (EI): m/z Calcd. for
C12H17O2 [M+H]+: 193.1294, found: 193.1290.
NMR (400 MHz, CDCl3) δ 7.62-7.57 (m, 2H), 7.44-7.39 (m,
3H), 7.32-7.28 (m, 2H), 6.97-6.92 (m, 2H), 6.19 (s, 1H), 5.63
(ddt, J = 17.3, 10.3, 5.1 Hz, 1H), 5.00 (dq, J = 10.3, 1.7 Hz,
1H), 4.79 (dq, J = 17.2, 1.8 Hz, 1H), 3.86 (s, 3H), 3.13 (dt, J =
5.2, 1.9 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.1,
160.9, 160.8, 159.4, 137.4, 136.1, 130.3, 128.8, 128.2, 127.7,
125.2, 116.7, 113.8, 113.7, 112.6, 55.4, 31.6; HRMS (EI): m/z
Calcd. for C21H19O3 [M+H]+: 319.1329, found: 319.1328.
5-allyl-6-butyl-4-phenyl-2H-pyran-2-one (3o). Light yellow
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
oil; 59.2 mg, 0.222 mmol, yield: 74 %; H NMR (400 MHz,
5-allyl-6-cyclopropyl-2H-pyran-2-one (3i). Yellow oil; 33.5
CDCl3) δ 7.44-7,36 (m, 3H), 7.28-7.22 (m, 2H), 6.08 (s, 1H),
5.71 (ddt, J = 17.1, 10.3, 5.2 Hz, 1H), 5.04 (d, J = 10.2 Hz,
1H), 4.85 (d, J = 17.2 Hz, 1H), 3.00 (d, J = 5.0 Hz, 2H), 2.54
(t, J = 7.4 Hz, 2H), 1.76-1.67 (m, 2H), 1.46-1.34 (m, 2H), 0.94
(t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.7,
162.6, 160.4, 137.3, 135.4, 128.9, 128.4, 127.5, 116.1, 112.7,
111.7, 31.2, 30.7, 29.6, 22.6, 13.8; HRMS (EI): m/z Calcd. for
C18H21O2 [M+H]+: 269.1537, found: 269.1541.
5-allyl-4-methyl-6-phenyl-2H-pyran-2-one (3p). Colorless
solid; 42.7 mg, 0.189 mmol, yield: 63 %; 1H NMR (400 MHz,
CDCl3) δ 7.60-7.50 (m, 2H), 7.47-7.38 (m, 3H), 6.19 (s, 1H),
6.01 (ddt, J = 17.1, 9.8, 3.4 Hz, 1H), 5.23 (d, J = 10.1 Hz, 1H),
5.04 (d, J = 17.3 Hz, 1H), 3.18 (d, J = 3.4 Hz, 2H), 2.21 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.1, 158.6, 157.7,
135.8, 132.6, 130.0, 128.4, 128.3, 116.6, 113.7, 113.4, 31.4,
19.9; HRMS (EI): m/z Calcd. for C15H15O2 [M+H]+: 227.1067,
found: 227.1072.
1
mg, 0.189 mmol, yield: 63 %; H NMR (400 MHz, CDCl3) δ
7.14 (d, J = 9.4 Hz, 1H), 6.07 (d, J = 9.4 Hz, 1H), 5.87 (ddt, J
= 17.1, 10.4, 6.0 Hz, 1H), 5.13 (dd, J = 10.2, 1.8 Hz, 1H), 5.07
(dd, J = 17.1, 1.7 Hz, 1H), 3.19 (d, J = 6.0 Hz, 2H), 1.91-1.82
(m, 1H), 1.22-1.15 (m, 2H), 1.00-0.93 (m, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 162.6, 162.3, 147.3, 135.0, 116.6, 112.0,
111.7, 33.2, 11.3, 8.3; HRMS (EI): m/z Calcd. for C11H13O2
[M+H]+: 177.0911, found: 177.0905.
5-allyl-6-(3-chloropropyl)-2H-pyran-2-one (3j). Colorless
1
oil; 45.1 mg, 0.213 mmol, yield: 71 %; H NMR (400 MHz,
CDCl3) δ 7.18 (d, J = 9.5 Hz, 1H), 6.19 (d, J = 9.5 Hz, 1H),
5.83 (ddt, J = 17.0, 10.1, 6.1 Hz, 1H), 5.13 (dq, J = 10.1, 1.5
Hz, 1H), 5.06 (dq, J = 17.1, 1.7 Hz, 1H), 3.60-3.55 (m, 2H),
3.11 (dt, J = 6.1, 1.6 Hz, 2H), 2.70 (dd, J = 7.1 Hz, 2H), 2.20-
2.10 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.4,
160.5, 147.0, 134.8, 117.0, 114.0, 113.4, 44.0, 33.2, 29.8,
27.8; HRMS (EI): m/z Calcd. for C11H14ClO2 [M+H]+:
213.0677, found: 213.0674.
5-allyl-6-butyl-4-methyl-2H-pyran-2-one (3q). Colorless
1
oil; 49.6 mg, 0.240 mmol, yield: 80 %; H NMR (400 MHz,
4-(5-allyl-2-oxo-2H-pyran-6-yl)butanenitrile (3k). Colorless
CDCl3) δ 6.02 (s, 1H), 5.86 (ddt, J = 17.1, 10.3, 5.2 Hz, 1H),
5.09 (d, J = 10.2 Hz, 1H), 4.94 (d, J = 17.2 Hz, 1H), 3.11 (d, J
= 4.9 Hz, 2H), 2.54-2.44 (m, 2H), 2.12 (s, 3H), 1.69-1.58 (m,
2H), 1.42-1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 162.7, 162.2, 157.4, 134.8, 116.0,
112.8, 112.0, 30.7, 30.1, 29.7, 22.4, 20.0, 13.8; HRMS (EI):
m/z Calcd. for C13H19O2 [M+H]+: 207.1380, found: 207.1377.
6-phenyl-5-(4-phenylbut-2-en-1-yl)-2H-pyran-2-one (4a).
Colorless solid; 44.1 mg, 0.144 mmol, yield: 48 %. The E : Z
ratio was determined after purification by flash
1
oil; 37.0 mg, 0.183 mmol, yield: 61 %; H NMR (400 MHz,
CDCl3) δ 7.18 (d, J = 9.5 Hz, 1H), 6.22 (d, J = 9.5 Hz, 1H),
5.83 (ddt, J = 17.0, 10.1, 6.0 Hz, 1H), 5.15 (dq, J = 10.1, 1.5
Hz, 1H), 5.06 (dq, J = 17.1, 1.7 Hz, 1H), 3.11 (dt, J = 6.0, 1.6
Hz, 2H), 2.72-2.66 (m, 2H), 2.42 (t, J = 6.9 Hz, 2H), 2.06 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.1, 159.3, 147.0,
134.6, 118.8, 117.2, 114.4, 113.6, 33.2, 29.2, 22.9, 16.7;
HRMS (EI): m/z Calcd. for C12H14NO2 [M+H]+: 204.1020,
found: 204.1023.
1
1
2-(5-allyl-2-oxo-2H-pyran-6-yl)ethyl acetate (3l). Yellow
chromatography to be approximately 82 : 18 by H NMR. H
NMR (400 MHz, CDCl3) δ 7.58-7.52 (m, 2H), 7.47-7.39 (m,
3H), 7.33-7.27 (m, 3H), 7.24-7.13 (m, 3H), 6.30 (d, J = 9.5
Hz, 1H), 5.80 (Z isomer) (dt, J = 9.0, 8.4 Hz, 1H × 0.18H),
5.73-5.49 (m, 1H × 0.18 + 2H × 0.82), 3.40 (d, J = 6.5 Hz,
2H), 3.32 (Z isomer) (d, J = 6.9 Hz, 2H × 0.18), 3.18 (E
isomer) (dq, J = 5.5, 1.5 Hz, 2H × 0.82); 13C{1H} NMR (101
MHz, CDCl3) δ 162.2, 158.4, 147.4, 146.9, 140.05, 140.02,
132.3, 132.2, 132.1, 131.0, 130.1, 128.8, 128.62, 128.57,
128.53, 128.50, 128.45, 128.43, 128.25, 128.21, 127.2, 126.2,
114.9, 114.7, 113.9, 77.4, 77.0, 76.7, 38.9, 33.5, 32.8, 27.81;
HRMS (EI): m/z Calcd. for C21H19O2 [M+H]+: 303.1380,
found: 303.1384.
1
oil; 47.9 mg, 0.216 mmol, yield: 72 %; H NMR (400 MHz,
CDCl3) δ 7.17 (d, J = 9.5 Hz, 1H), 6.22 (d, J = 9.5 Hz, 1H),
5.82 (ddt, J = 17.0, 10.3, 6.0 Hz, 1H), 5.14 (dd, J = 10.2, 1.5
Hz, 1H), 5.05 (dd, J = 17.1, 1.6 Hz, 1H), 4.35 (t, J = 6.5 Hz,
2H), 3.09 (d, J = 6.0 Hz, 2H), 2.84 (t, J = 6.5 Hz, 2H), 2.04 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.7, 162.1, 157.9,
146.7, 134.6, 117.2, 114.5, 114.1, 61.2, 33.1, 30.4, 20.9;
HRMS (EI): m/z Calcd. for C12H15O4 [M+H]+: 223.0965,
found: 223.0968.
5-allyl-6-phenethyl-2H-pyran-2-one (3m). Colorless oil;
1
37.4 mg, 0.156 mmol, yield: 52 %; H NMR (400 MHz,
CDCl3) δ 7.30-7.13 (m, 5H), 7.11 (d, J = 9.4 Hz, 1H), 6.17 (d,
J = 9.4 Hz, 1H), 5.59 (ddt, J = 17.0, 10.3, 6.1 Hz, 1H), 5.05
(dd, J = 10.2, 1.8 Hz, 1H), 4.95 (dt, J = 17.0, 1.6 Hz, 1H), 2.97
(t, J = 7.7 Hz, 2H), 2.87 (d, J = 6.0 Hz, 2H), 2.78 (t, J = 7.7
Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 161.0,
147.0, 140.1, 134.8, 128.6, 128.4, 126.4, 116.9, 113.7, 113.2,
5-(but-2-en-1-yl)-6-phenyl-2H-pyran-2-one (4b). Colorless
solid; 41.7 mg, 0.195 mmol, yield: 65 %. The E : Z ratio was
determined after purification by flash chromatography to be
1
1
approximately 82 : 18 by H NMR. H NMR (400 MHz,
CDCl3) δ 7.60-7.52 (m, 2H), 7.49-7.41 (m, 3H), 7.32 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 8
1
2
3
4
5
6
7
8
stereocontrolled synthesis of unsaturated, bridged, bicyclic lactones.
9.5 Hz, 1H), 6.31 (d, J = 9.5 Hz, 1H), 5.71-5.36 (m, 2H), 3.20
(Z isomer) (d, J = 7.0 Hz, 2H × 0.18), 3.12 (E isomer) (s, 2H ×
0.82), 1.73 (E isomer) (s, 3H × 0.82), 1.64 (Z isomer) (d, J =
6.6 Hz, 3H × 0.18); 13C{1H} NMR (101 MHz, CDCl3) δ 162.2,
162.1, 158.2, 158.1, 147.6, 147.1, 132.25, 132.17, 130.02,
129.99, 128.8, 128.6, 128.43, 128.40, 128.2, 127.9, 127.0,
126.8, 114.9, 114.8, 114.6, 114.1, 32.8, 27.4, 18.0, 13.0;
HRMS (EI): m/z Calcd. for C15H15O2 [M+H]+: 227.1067,
found: 227.1073.
J. Org. Chem. 1992, 57, 4083. (e) Vara Prasad, J. V. N.; Para, K. S.;
Lunney, E. A.; Ortwine, D. F.; Dunbar, J. B., Jr.; Ferguson, D.;
Tummino, P. J.; Hupe, D.; Tait, B. D.; Domagala, J. M.; Humblet, C.;
Bhat, T. N.; Liu, B.; Guerin, D. M. A.; Baldwin, E. T.; Erickson, J.
W.; Sawyer, T. K. Novel series of achiral, low molecular weight, and
potent HIV-1 protease inhibitors. J. Am. Chem. Soc. 1994, 116, 6989.
(f) Schlingmann, G.; Milne, L.; Carter, G. T. New α-pyrones
produced by fungal culture LL-11G219 function as androgen receptor
ligands. Tetrahedron 1998, 54, 13013. (g) Matsuda, H.; Shimoda, H.;
Yoshikawa, M. Structure-requirements of isocoumarins, phthalides,
and stilbenes from hydrangeae dulcis folium for inhibitory activity on
histamine release from rat peritoneal mast cells. Bioorg. Med. Chem.
Lett. 1999, 7, 1445. (h) Wijeratne, E. M. K.; Paranagama, P. A.;
Gunatilaka, A. A. L. Five new isocoumarins from Sonoran desert
plant-associated fungal strains paraphaeosphaeria quadriseptata and
chaetomium chiversii. Tetrahedron 2006, 62, 8439. (i) Yokoe, H.;
Mitsuhashi, C.; Matsuoka, Y.; Yoshimura, T.; Yoshida, M.; Shishido,
K. Enantiocontrolled total syntheses of breviones A, B, and C. J. Am.
Chem. Soc. 2011, 133, 8854.
(2) (a) Kozytska, M. V.; Dudley, G. B. On the intramolecular
pyrone Diels–Alder approach to basiliolide B. Tetrahedron Lett.
2008, 49, 2899. (b) Larsson, R.; Sterner, O.; Johansson, M.
Biomimetic synthesis toward the transtaganolides/basiliolides. Org.
Lett. 2009, 11, 657. (c) Nelson, H. M.; Stoltz, B. M. Progress toward
the synthesis of the transtaganolide/basiliolide natural products: an
Ireland–Claisen approach. Tetrahedon Lett. 2009, 50, 1699. (d)
Nelson, H. M.; Gordon, J. R.; Virgil, S. C.; Stoltz, B. M. Total
syntheses of (−)-transtaganolideꢀA, (+)-transtaganolideꢀB, (+)-
transtaganolideꢀC, and (−)-transtaganolideꢀD and biosynthetic
implications. Angew. Chem., Int. Ed. 2013, 52, 6699. (e) Zhuo, C.-X.;
Fürstner, A. Concise synthesis of a pateamineꢀA analogue with in
vivo anticancer activity based on an iron-catalyzed pyrone ring
opening/cross-coupling. Angew. Chem., Int. Ed. 2016, 55, 6051.
(3) (a) Gogte, C. R. Chemistry of β-aryl-glutaconic acids. Proc.
Indian Acad. Sci. 1938, 7A, 214. (b) Ishibe, N.; Yutaka, S. Heavy-
atom effect in photoisomerization of 4-pyrones and 4-pyridones. J.
Org. Chem. 1978, 43, 2138.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-phenyl-5-(3-phenylallyl)-2H-pyran-2-one (4c). Colorless
1
solid; 33.8 mg, 0.117 mmol, yield: 39 %, E : Z > 95 : 5; H
NMR (400 MHz, CDCl3) δ 7.63-7.58 (m, 2H), 7.48-7.44 (m,
3H), 7.39-7.31 (m, 5H), 7.28-7.22 (m, 1H), 6.46-6.40 (m, 1H),
6.36-6.25 (m, 2H), 3.37 (dd, J = 5.9, 1.5 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 162.1, 158.7, 147.4, 136.7, 132.4,
132.1, 130.2, 128.7, 128.6, 128.5, 127.7, 126.9, 126.2, 114.8,
113.4, 33.2; HRMS (EI): m/z Calcd. for C20H17O2 [M+H]+:
289.1223, found: 289.1221.
5-(3-(4-bromophenyl)allyl)-6-phenyl-2H-pyran-2-one (4d).
Yellow solid; 63.4 mg, 0.174 mmol, yield: 58 %. The E : Z
ratio was determined after purification by flash
1
1
chromatography to be approximately 95 : 5 by H NMR. H
NMR (400 MHz, CDCl3) δ 7.61-7.54 (E isomer) (m, 2H ×
0.95), 7.49-7.41 (m, 5H), 7.35 (E isomer) (d, J = 9.4 Hz, 1H ×
0.95), 7.30 (Z isomer) (d, J = 9.7 Hz, 1H × 0.05), 7.25-7.21 (E
isomer) (m, 2H × 0.95), 7.06 (Z isomer) (d, J = 8.3 Hz, 2H ×
0.05), 6.56 (Z isomer) (d, J = 10.8 Hz, 1H × 0.05), 6.40-6.23
(m, 3H), 5.71 (Z isomer) (dt, J = 11.5, 7.2 Hz, 2H × 0.05),3.45
(Z isomer) (dd, J = 7.2, 2.0 Hz, 2H × 0.05), 3.35 (E isomer)
(dd, J = 5.5, 1.1 Hz, 2H × 0.95); 13C{1H} NMR (101 MHz,
CDCl3) δ 162.0, 158.8, 147.2, 135.6, 132.0, 131.8, 131.5,
131.3, 130.3, 129.3, 128.65, 128.56, 128.54, 128.4, 127.8,
121.5, 115.0, 114.9, 113.1, 33.2, 29.7; HRMS (EI): m/z Calcd.
for C20H16BrO2 [M+H]+: 367.0328, found: 367.0331.
(4) (a) Dombray, T.; Blanc, A.; Weibel, J.-M.; Pale, P. Gold(I)-
catalyzed cycloisomerization of β-alkynylpropiolactones to
substituted α-pyrones. Org. Lett. 2010, 12, 5362-5365. (b) Frébault,
F.; Oliveira, M. T.; Wöstefeld, E.; Maulide, N. A concise access to 3-
substituted 2-pyrones. J. Org. Chem. 2010, 75, 7962. (c) Luo, T.; Dai,
M.; Zheng, S.-L.; Schreiber, S. L. Syntheses of α-pyrones using gold-
catalyzed coupling reactions. Org. Lett. 2011, 13, 2834. (d) Miura, T.;
Fujioka, S.; Takemura, N.; Iwasaki, H.; Ozeki, M.; Kojima, N.;
Yamashita, M. Synthesis of 6-substituted 3-(alkoxycarbonyl)-5-aryl-
α-pyrones. Synthesis 2014, 46, 496. (e) Manikandan, R.; Jeganmohan,
M. Ruthenium-catalyzed dimerization of propiolates: a simple route
to α-pyrones. Org. Lett. 2014, 16, 652. (f) Grigalunas, M.; Wiest, O.;
Helquist, P. Single-flask multicomponent synthesis of highly
SUPPORTING INFORMATION
Spectral data for all novel compounds (1H NMR, 13C NMR).
AUTHOR INFORMATION
Corresponding Author
xyh0709@ustc.edu.cn; teckpeng@ntu.edu.sg;
Notes
The authors declare no competing financial interest.
substituted α-pyrones via
a sequential enolate arylation and
ACKNOWLEDGMENT
alkenylation strategy. Org. Lett. 2016, 18, 5724.
We gratefully acknowledge the funding support of Anhui
Provincial Natural Science Foundation (1708085MB29), the
National Natural Science Foundation of China (21672198) and
the State Key Program of National Natural Science Foundation of
China (21432009).
(5) Wang, Y.; J. Burton, D. A Facile, general synthesis of 3,4-
difluoro-6-substituted-2-pyrones. J. Org. Chem. 2006, 71, 3859.
(6) (a) Yao, T.; Larock, R. C. Synthesis of isocoumarins and α-
pyrones via iodocyclization. Tetrahedron Lett. 2002, 43, 7401. (b)
Yao, T.; Larock, R. C. Synthesis of isocoumarins and α-pyrones via
electrophilic cyclization. J. Org. Chem. 2003, 68, 5936.
(7) (a) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Selective
synthesis of natural and unnatural 5,6-disubstituted 2(2H)-pyranones
via iodolactonization of 5-substituted (Z)-2-en-4-ynoic acids.
Tetrahedron 2001, 57, 2857. (b) Biagetti, M.; Bellina, F.; Carpita, A.;
Viel, S.; Mannina, L.; Rossi, R. Selective synthesis of 5,6-
disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-
2(2H)-pyranones, including fusalanipyrone and gibepyrone A. Eur. J.
Org. Chem. 2002, 1063. (c) Biagetti, M.; Bellina, F.; Carpita, A.;
Stabile, P.; Rossi, R. New procedures for the selective synthesis of
REFERENCES
(1) (a) Chen, K. K.; Kovarikova, A. J. Pharmacology and
toxicology of toad venom. J. Pharm. Sci. 1967, 56, 1535. (b)
Venkataraman, H.; Cha, J. K. Total synthesis of citreomontanin and
its C18Z polyene isomer. Tetrahedron Lett. 1987, 28, 2455. (c)
Abraham, W. R.; Arfmann, H. Fusalanipyrone, a monoterpenoid from
fusarium solani. Phytochemistry 1988, 27, 3310. (d) Posner, G. H.;
Nelson, T. D.; Kinter, C. M.; Johnson, N. Diels-Alder cycloadditions
using nucleophilic 3-(p-tolylthio)-2-pyrone. Regiocontrolled and
ACS Paragon Plus Environment

Page 7 of 8
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
2(2H)-pyranone
Tetrahedron 2002, 58, 5023.
(8) For a Ag(I)-catalyzed cyclization of enyne carboxylic acids,
please see: (a) Castañer, J.; Pascual, J. Isomerisation of
phenylpropargylidenernalonic
carboxybutenolide. J. Chem. Soc. 1958, 0, 3962. (b) Yoshikawa, T.;
Shindo, M. Stereoselective synthesis of (E)-2-en-4-ynoic acids with
ynolates: catalytic conversion to tetronic acids and 2-pyrones. Org.
Lett. 2009, 11, 5378. For Cu-catalyzed cyclization and bromination
examples, see: (c) Liang, Y.; Xie, Y.-X.; Li, J.-H. Cy2NH·HX-
promoted cyclizations of o-(alk-1-ynyl)benzoates and (Z)-alk-2-en-4-
ynoate with copper halides to synthesize isocoumarins and α-pyrone.
Synthesis 2007, 400. Please see the example of a Pd-catalyzed 6-endo
cyclization and arylation reaction: (d) Rossi, R.; Bellina, F.; Biagetti,
M.; Catanese, A.; Mannina, L. Palladium-catalyzed synthesis of
derivatives
and
3-aryl-4-iodoisocoumarins.
Heterocyclic. Chem. 2004, 41, 941. (d) Zheng, M.-F.; Huang, L.-B.;
Tong, Q.-Z.; Wu, W.-Q.; Jiang, H.-F. Oxypalladation initiating the
oxid-ative Heck reaction with alkenyl -alcohols: synthesis of
isocoumarin–alkanones. Eur. J. Org. Chem. 2016, 663. For the β-OH
elimination of allylic alcohol please see: (e) Harrington, P. J.;
Hegedus, L. S.; Mcdaniel, K. F. Palladium-catalyzed reactions in the
synthesis of 3- and 4-substituted indoles. 2. Total synthesis of the N-
acetyl methyl ester of (.+-.)-clavicipitic acids. J. Am. Chem. Soc.
1987, 109, 4335. (f) Francis, J. W.; Henry, P. M. Palladium(II)-
catalyzed exchange and isomerization reactions. 14. Kinetics and
stereochemistry of the isomerization and water exchange of 2-
(methyl-d3)-4-methyl-1,1,1,5,5,5-hexafluoro-3-penten-2-ol in aqueous
solution catalyzed by PdCl42-. Two new mechanistic probes for
catalytic chemistry. Organometallics 1991, 10, 3498. (g) Saito, S.;
Hara, T.; Takahashi, N.; Hirai, M.; Moriwake, T. Synthesis of
optically active substituted dihydrofurans and dihydropyrroles via
acid
to
γ-benxylidene-α-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
stereodefined
disubstituted)methylidene]isobenzofuran-1(3H)-ones
stereodefined 5-[(1,1-unsymmetrically
3-[(1,1-unsymmetrically
and
palladium(II)-promoted
diastereoselective
dehydroxylative
heterocyclization. Synlett 1992, 237. (h) Ma, S.; Lu, X. Studies on
PdII-catalyzed cyclization of 4’-hydroxy-2’-alkenyl 2-alkynoates. J.
Organomet. Chem. 1993, 447, 305. (i) Kimura, M.; Horino, Y.;
Mukai, R.; Tanaka, S.; Tamaru, Y. Strikingly simple direct α-
allylation of aldehydes with allyl alcohols:ꢀ remarkable advance in the
Tsuji−Trost reaction. J. Am. Chem. Soc. 2001, 123, 10401. (j) Ozawa,
F.; Okamoto, H.; Kawgishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji,
M. (π-allyl)palladium complexes bearing diphosphinidenecyclobutene
ligands (DPCB):ꢀ highly active catalysts for direct conversion of
allylic alcohols. J. Am. Chem. Soc. 2002, 124, 10968. (k) Manabe, K.;
Kobayashi, S. Palladium-catalyzed, carboxylic acid-assisted allylic
substitution of carbon nucleophiles with allyl alcohols as allylating
agents in water. Org. Lett. 2003, 5, 3241. (l) Kabalka, G. W.; Dong,
G.; Venkataiah, B. Rhodium-catalyzed cross-coupling of allyl
alcohols with aryl- and vinylboronic acids in ionic liquids. Org. Lett.
2003, 5, 893. (m) Yoshida, M.; Gotou, T.; Ihara, M. Palladium-
catalysed coupling reaction of allenic alcohols with aryl- and
alkenylboronic acids. Chem. Commun. 2004, 1124. (n) Please see
reference 11d. (o) Batuecas, M.; Esteruelas, M. A.; García-Yebra, C.;
Oñate, E. Redox isomerization of allylic alcohols catalyzed by
osmium and ruthenium complexes containing a cyclopentadienyl
ligand with a pendant amine or phosphoramidite group: X-ray
structure of an η3-1-hydroxyallyl-metal-hydride intermediate.
Organometallics 2010, 29, 2166. (p) Yamaguchi, Y.; Hashimoto, M.;
Tohyama, K.; Kimura, M. Nucleophilic allylation of N,O-acetals with
allylic alcohols promoted by Pd/Et3B and Pd/Et2Zn systems.
Tetrahedron Lett. 2011, 52, 913. (q) Li, J.-X.; Yang, S.-R.; Wu, W.-
Q.; Qi, C.-R.; Deng, Z.-X.; Jiang, H.-F. Synthesis of 1,4-dienes by
Pd(II)-catalyzed haloallylation of alkynes with allylic alcohols in
ionic liquids. Tetrahedron 2014, 70, 1516. (r) Ou, W.-H.; Huang, H.
Environment-friendly, mild and one-step synthesis of safrole. Asian.
J. Chem. 2015, 27, 1175. For the stereoselectivity of β-hetero
elimination please see: (s) Frost, C. G.; Howarth, J.; Williams, J. M. J.
Selectivity in palladium catalysed allylic substitution. Tetrahedron:
Asymmetry 1992, 3, 1089. (t) Daves, G. D., Jr. Acc. C-glycoside
synthesis by palladium-mediated glycal-aglycon coupling reactions.
Chem. Res. 1990, 23, 201. (u) Zhu, G.; Lu, X. Reactivity and
disubstituted)methylidene]furan-2(5H)-ones. Tetrahedron Lett. 2000,
41, 5281. Two examples of a Pd-catalyzed tandem annulation of
enyne with methyl vinyl ketone: (e) Wang, H.; Han, X.; Lu, X.
Palladium(II)-catalyzed tandem annulation reaction of o-
alkynylbenzoates with methyl vinyl ketone for the synthesis of
isocoumarins. Tetrahedron 2013, 69, 8626. Please see the example of
a Pd-catalyzed 6-endo cyclization and alkylation reaction: (f) Ahmad,
T.; Qiu, S.-Q.; Xu, Y.-H.; Loh, T.-P. Palladium-catalyzed one-pot
highly regioselective 6-endo cyclization and alkylation of enynoates:
synthesis of 2-alkanone pyrones. J. Org. Chem. 2018, 83, 13414. For
a gold-catalyzed review of pyrones please see: (g) Fürstner, A. Gold
catalysis for heterocyclic chemistry: a representative case study on
pyrone natural products. Angew. Chem. Int. Ed. 2018, 57, 4215.
(9) Tian, P.-P.; Cai, S.-H.; Liang, Q.-J.; Zhou, X.-Y.; Xu, Y.-H.;
Loh, T.-P. Palladium-catalyzed difunctionalization of internal alkynes
via highly regioselective 6-endo cyclization and alkenylation of
enynoates: synthesis of multisubstituted pyrones. Org. Lett. 2015, 17,
1636. Other examples please see references 5, 6, 7 and 8.
(10) Frebault, F.; Oliveira, M. T.; Wöstefeld, E.; Maulide, N. A
concise access to 3-substituted 2-pyrones. J. Org. Chem. 2010, 75,
7962. Other examples please see reference 7.
(11) (a) Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.;
Marinelli, F.; Pietroni, B. R. Palladium-catalyzed reaction of vinyl
triflates and vinyl/aryl halides with 4-alkynoic acids: regio- and
stereoselective
synthesis
of
(E)-γ-vinyl/aryl-γ-methylene-γ-
butyrolactones. J. Org. Chem. 1992, 57, 976. (b) Rossi, R.; Bellina,
F.; Biagetti, M.; Catanese, A.; Mannina, L. Palladium-catalyzed
synthesis
disubstituted)methylidene]isobenzofuran-1(3H)-ones
stereodefined 5-[(1,1-unsymmetrically
of
stereodefined
3-[(1,1-unsymmetrically
and
disubstituted)methylidene]furan-2(5H)-ones. Tetrahedron Lett. 2000,
41, 5281. (c) Gu, Z.; Ma, S. PdCl2-catalyzed two-component cross-
coupling cyclization of 2,3-allenoic acids with 2,3-allenols. An
efficient synthesis of 4-(1′,3′-dien-2′-yl)-2(5H)furanone derivatives. J.
Am. Chem. Soc. 2005, 127, 6182. (d) Huang, J.-M.; Zhou, L.; Jiang,
H.-F. Palladium-catalyzed allylation of alkynes with allyl alcohol in
aqueous media: highly regio- and stereoselective synthesis of 1,4-
dienes. Angew. Chem. Int. Ed. 2006, 45, 1945. (e) Please see
reference 8e. (f) Pathare, R. S.; Sharma, S.; Gopal, K.; Sawant, D. M.;
Pardasani, R. T. Palladium-catalyzed convenient one-pot synthesis of
multi-substituted 2-pyrones via transesterification and alkenylation of
enynoates. Tetrahedron Lett. 2017, 58, 1387.
(12) For the β-H elimination of allylic alcohol please see: (a)
Taylor, E. C.; Gillespie, P.; Patel, M. Novel 5-desmethylene analogs
of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid as potential anticancer
agents. J. Org. Chem. 1992, 57, 3218. (b) Taylor, E. C.; Liu, B. A
simple and concise synthesis of LY231514(MTA). Tetrahedron Lett.
1999, 40, 4023. (c) Gangjee, A.; Qiu, Y.; Kisliuk, R. L. Synthesis of
classical and nonclassical 2-amino-4-oxo-6-benzylthieno-[2,3-
d]pyrimidines as potential thymidylate synthase inhibitors. J.
stereochemistry of β-heteroatom elimination.
A detailed study
through palladium-catalyzed cyclization reaction model.
a
Organometallics 1995, 14, 4899. For the mechanism study of β-OH
elimination of allylic alcohol please see: (v) Palmes, J. A.; Paioti, P.
H. S.; de Souza, L. P.; Aponick, A. PdII-catalyzed spiroketalization of
ketoallylic diols. Chem. Eur. J. 2013, 19, 11613. (w) Ghebreghiorgis,
T.; Kirk, B. H.; Aponick, A.; Ess, D. H. Multiple mechanisms in
Pd(II)-catalyzed SN2’ reactions of allylic alcohols. J. Org. Chem.
2013, 78, 7664.
(13) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C.
Serial ligand catalysis: a highly selective allylic C-H oxidation. J. Am.
Chem. Soc. 2005, 127, 6970.
(14) Takeuchi, R.; Tanabe, T.; Tanaka, S. Stereodivergent
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 8
1
2
3
4
5
6
7
8
synthesis of (E)- and (Z)-2-alken-4-yn-1-ols from 2-propynoic acid: a
on a one-pot Ullmann coupling/Claisen rearrangement and its
application to the synthesis of a hexahydropyrrolo[2,3-b]indole
alkaloid. Tetrahedron 2013, 69, 9481.
practical route via 2-alken-4-ynoates. J. Org. Chem. 2000, 65, 1558.
(15) Yu, R. T.; Rovis, T. Enantioselective rhodium-catalyzed
[2+2+2] cycloaddition of alkenyl isocyanates and terminal alkynes:ꢀ
application to the total synthesis of (+)-lasubine II. J. Am. Chem. Soc.
2006, 128, 12370.
(16) Benanti, T. L.; Saejueng, P.; Venkataraman, D. Segregated
assemblies in bridged electron-rich and electron-poor π-conjugated
moieties. Chem. Commun. 2007, 692.
(18) Paterson, I.; Paquet, T. Total synthesis and configurational
validation of (+)-phorbaside A. Org. Lett. 2010, 12, 2158.
(19) Lin, H.; Liu, Y.; Wu. Z.-L. Highly diastereo- and enantio-
selective epoxidation of secondary allylic alcohols catalyzed by
styrene monooxygenase. Chem. Commun. 2011, 47, 2610.
(20) Lehmann, J.; Lloyd-Jones, G. C. Regiocontrol and
stereoselectivity in tungsten-bipyridine catalysed allylic alkylation.
Tetrahedron 1995, 51, 8863.
9
(17) Miyamoto, H.; Hirano, T.; Okawa, Y.; Nakazaki, A.;
Kobayashi, S. Stereoselective synthesis of spirocyclic oxindoles based
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment