Cycloisomerization of acetylenic acids to γ-alkylidene lactones using a palladium(II) catalyst supported on amino-functionalized siliceous mesocellular foam

Article abstract of DOI:10.1021/jo4028006

Cycloisomerization of various γ-acetylenic acids to their corresponding γ-alkylidene lactones by the use of a heterogeneous Pd(II) catalyst supported on amino-functionalized siliceous mesocellular foam is described. Substrates containing terminal as well

Full text of DOI:10.1021/jo4028006

Article
pubs.acs.org/joc
Cycloisomerization of Acetylenic Acids to γ‑Alkylidene Lactones
using a Palladium(II) Catalyst Supported on Amino-Functionalized
Siliceous Mesocellular Foam
Anuja Nagendiran, Oscar Verho, Clemence Haller, Eric V. Johnston,* and Jan-E. Backvall*
́
̈
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Cycloisomerization of various γ-acetylenic acids to their
corresponding γ-alkylidene lactones by the use of a heterogeneous Pd(II)
catalyst supported on amino-functionalized siliceous mesocellular foam is
described. Substrates containing terminal as well as internal alkynes were
cyclized in high to excellent yields within 2−24 h under mild reaction
conditions. The protocol exhibited high regio- and stereoselectivity, favoring the
exo-dig product with high Z selectivity. Moreover, the catalyst displayed
excellent stability under the employed reaction conditions, as demonstrated by
its good recyclability and low leaching.
amounts of metal impurities from the final product.
INTRODUCTION
■
Heterogeneous catalysis, on the other hand, offers a simple
solution to these problems and constitutes a green and
environmentally benign alternative. To the best of our
knowledge, only a handful of examples of heterogeneous
protocols for the cycloisomerization of alkynoic acids to the
corresponding lactones exist to this date.24,25,29
The transition-metal-catalyzed intramolecular addition of a
carboxylic acid to a terminal alkyne is an important trans-
formation in organic synthesis, as it provides access to the γ-
alkylidene lactone motif, which is present in a vast number of
biologically active natural products.1−5 To obtain the desired
five-membered cyclic lactones arising from exo-dig ring closure
instead of the isomeric six-membered endo-dig products (Figure
1), control of regioselectivity in the cyclization step is required.
We have recently reported on the preparation of a
heterogeneous catalyst based on Pd nanoparticles immobilized
on amino-functionalized siliceous mesocellular foam (Pd0-
AmP-MCF).30,31 Mesocellular foam (MCF) is a mesoporous
material that has proven to be an excellent support for both
chemical as well as biological catalysts, mainly due to its high
surface area, large pore volume, and adjustable pore size.32−34
Several organic transformations have successfully been
accomplished with our novel Pd(0) catalyst, such as aerobic
oxidation of primary and secondary alcohols,31 transfer
hydrogenation of alkenes35 and nitroarenes,36 racemization
and dynamic kinetic resolution of amines,30 and Suzuki-cross
couplings.35 However, the catalytic activity of the correspond-
ing heterogeneous Pd(II) precatalyst is not as well-explored
and has so far only been used together with an amino catalyst
for cascade Michael/carbocyclization reactions.37 Herein, we
report on the cycloisomerization of various γ-acetylenic acids to
alkylidene lactones catalyzed by PdII-AmP-MCF.
Figure 1. Cycloisomerization occurring in either an exo-dig or endo-dig
manner, both of which are favored according to Baldwin’s rules.
Generally, this selectivity can be controlled by the choice of
metal catalyst, as well as by careful design of the reaction
conditions. Over the past years, numerous protocols based on
transition metals such as Rh,6,7 Hg,8−11 Ru,12 Ag,13−15 Au,16−19
Cu,20,21 and Pd6,14,22−28 have been explored to allow for the
synthesis of γ-alkylidene lactones. Unfortunately, most of these
protocols require high catalyst loadings, prolonged reaction
times, and/or elevated temperatures. In addition, the majority
of the reports involve the use of homogeneous catalysis, which
is generally associated with difficulties in recycling of the
catalyst and additional purification steps to remove trace
Received: December 17, 2013
© XXXX American Chemical Society
A
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a
RESULTS AND DISCUSSION
Table 2. Screening of Solvent and Catalyst Loading
■
The cycloisomerization of 4-pentynoic acid (1) into 5-
methylenedihydrofuran-2(3H)-one (2) was chosen as the
model reaction for the screening of reaction conditions, in
which the effects of base, solvent, catalyst loading, and reaction
temperature were investigated. In order to clearly assess the
effect of the change in the different reaction parameters, the
reaction time for the screen was chosen to be 1 h. The
optimization of the reaction conditions commenced with a
screening of a series of bases. Employing Cs2CO3 (0.5 equiv) as
the base gave a 35% yield of product 2, while pyridine was
shown to be completely incompatible with this protocol (Table
1, entries 1 and 2). The most effective bases proved to be DBU,
b
entry
solvent
catalyst loading (mol %)
yield (%)
1
2
3
4
5
6
7
8
EtOH
0.3
0.3
0.3
0.3
0.3
0
12
16
23
49
66
0
THF
CH3CN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.6
0.9
0.3
76
93
97
c
9
Table 1. Screening the Type of Base and Base Loading for
the Cycloisomerization of 1 to 2
a
Conditions: 1 (0.4 mmol), Et3N (0.25 equiv), PdII-AmP-MCF (0.3
b
mol % Pd), solvent (1 mL), room temperature, 1 h. Determined by
c
1H NMR using 1,3,5-trimethoxybenzene as internal standard. Run at
40 °C for 2 h.
a
experiment it was found that the reaction does not proceed in
the absence of the Pd(II) catalyst (Table 2, entry 6).
entry
base
loading (equiv)
yield of 2 (%)
1
2
3
4
5
6
7
8
Cs2CO3
pyridine
DBU
0.5
0.5
0.5
0.5
0.5
1
35
0
The reaction proved to be highly regioselective for all of the
4-acetylenic acids that were investigated, yielding the 5-exo-dig
lactone. For disubstituted acetylenes the reaction was also
highly stereoselective, affording only the Z olefinic product. As
depicted in Table 3, the catalyst worked well for the
cycloisomerization of a variety of acetylenic acids. Both 4-
pentynoic acid (1) and 2,2-dimethylpent-4-ynoic acid (3) were
cyclized to afford the corresponding lactones, 2 and 4, in high
yields under the standard conditions (Table 3, entries 1 and 2).
Substitution with a longer alkyl chain at the α position reduced
the reaction rate, and consequently 2-hexyl-4-pentynoic acid
(5) required an elevated temperature (50 °C) to give a high
yield of 6 (Table 3, entry 3). For the diacid 7, prolongation of
the reaction time to 3 h afforded the corresponding lactone 8 in
97% yield (Table 3, entry 4). The catalyst also proved to be
compatible with ester and allylic functionalities, and as a result
the acids 9 and 11 were cyclized to the corresponding lactones
in high yields (Table 3, entries 5 and 6). Interestingly, internal
alkynes could also be cyclized to their corresponding lactones
with high Z selectivity with this catalytic system, although at an
elevated temperature, for a prolonged reaction time, and with a
catalyst loading of 0.5 mol %. Alkyne 13 was cyclized in
excellent yield within 3 h at 50 °C with 0.5 mol % of Pd (Table
3, entry 7). For alkynes 15 and 17 the reaction time had to be
prolonged to 24 h to give comparable yields (Table 3, entries 8
and 9). As is apprent from the results in entries 7−9, the
reaction is favored by electron-withdrawing substituents on the
phenyl ring, as they increase the electrophilicity of the alkyne
moiety. Having a hydroxyl group present on the phenyl ring
made the cyclization less efficient, and alkyne 19 was cyclized to
afford a 5:1 mixture of the exo-dig and endo-dig lactone
products in 53% yield after 3 h (Table 3, entry 10).
Unfortunately, attempts to improve the outcome of the
reaction by extending the reaction time proved to be
unsuccessful, as a result of the competing decomposition of
20. The Boc-protected amino acid derivative 21, on the other
hand, could be efficiently cyclized by this catalytic system,
affording 22 in high yield within 3 h (Table 3, entry 11). In
sharp contrast to the case for 4-pentynoic acid (1), the
cyclization of 5-hexynoic acid (23) required a prolonged
reaction time (24 h), higher catalyst loading (0.5 mol %), and
50
49
47
37
66
3
NaOAc
Et3N
Et3N
Et3N
0.25
0
Et3N
1
a
Determined by H NMR using 1,3,5-trimethoxybenzene as internal
standard.
NaOAc, and Et3N, all affording yields of ∼50% (Table 1,
entries 3−5). Et3N was chosen for further studies, as it is more
cost-effective than DBU. Furthermore, an organic base such as
Et3N is more convenient for recycling studies than the
inorganic base NaOAc, as the latter requires additional washing
with water between each recycling cycle. The loading of Et3N
was therefore investigated, and it was found that an increase
from 0.5 to 1.0 equiv resulted in a decrease of the yield from
47% to 37% (Table 1, entries 5 and 6). The best result was
obtained using 0.25 equiv of Et3N, which afforded 66% yield
(Table 1, entry 7). These results suggest that elevated base
concentrations have an inhibitory effect on the reaction.
However, performing the reaction in the absence of base
resulted in negligible amounts of 2 (Table 1, entry 8),
confirming that the base is necessary for the formation of the
product.
An evaluation of the solvent effects showed that coordinating
solvents such as THF, EtOH, and CH3CN reduced the activity
of the catalyst, affording only 12%, 16%, and 23% yields of 2
(Table 2, entries 1−3). Less coordinating solvents, such as
toluene and CH2Cl2, allowed for a more efficient reaction,
giving 49% and 66% yields, respectively (Table 2, entries 4 and
5). Finally, the loading of the catalyst was investigated and the
use of 0.9 mol % of catalyst afforded the desired product in 93%
yield (Table 2, entry 8). However, increasing the reaction time
and temperature to 2 h and 40 °C, respectively, afforded an
excellent yield of 97% with a low catalyst loading of 0.3 mol %
(Table 1, entry 9). In conclusion, the best results were obtained
when performing the reaction in CH2Cl2 at 40 °C with 0.25
equiv of Et3N and 0.3 mol % of Pd(II) for 2 h. In a control
B
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a
Table 3. Cycloisomerization of Various Acetylenic Acids to Lactones Catalyzed by PdII-AmP-MCF
a
Reaction conditions: PdII-AmP-MCF (0.3 mol % Pd), acetylenic acid (0.40 mmol), Et3N (0.10 mmol), CH2Cl2 (1 mL), 40−50 °C, 2−3 h.
b
c
d
e
1
Determined by H NMR using 1,3,5-trimethoxybenzene as internal standard. The product is highly unstable. Run with 0.5 mol % Pd. The
f
1
double-bond configuration was unambiguously assigned by the H NMR shifts of the vinylic proton and by 1D and 2D NOE experiments. 24 h
reaction time.
elevated temperature (50 °C) to give comparable yields (Table
3, entry 12), which shows the significant difference in rate
between formation of five- and six-membered-ring products.
However, the role of the ring size did not affect the exo-dig
was circumvented by carrying out the recycling experiments in
the presence of benzoquinone (1 mol %). With this
modification, a yield of 97% was repeatedly obtained in four
subsequent cycles without any sign of deactivation. This
intriguing result demonstrates that the observed deactivation is
not a result of catalyst decomposition but is rather caused by
reduction of some of the supported Pd(II) species to less active
Pd(0). In the presence of benzoquinone the Pd(0) species
formed in situ is efficiently reoxidized to active Pd(II), and the
recovered heterogeneous catalyst maintains its high catalytic
activity and can be reused four times without detectable
deactivation. In a control experiment, we found that in the
1
selectivity and 24 was the only product detected by H NMR.
A key aspect of heterogeneous catalysis is the possibility to
recycle the catalyst, and therefore we were interested in
investigating the recyclability of PdII-AmP-MCF. In the reaction
of 4-pentynoic acid to give lactone 2, the catalyst was active in
five subsequent recycling experiments, although a gradual
decrease in activity was observed for each cycle (97%, 91%,
80%, 71%, and 62%, respectively).38 However, this deactivation
C
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presence of benzoquinone also Pd0-AmP-MCF30,31 was
activated and shown to catalyze the lactonization of 4-
pentynoic acid in good yield.
temperature for an appropriate time. After the reaction was complete,
1,3,5-trimethoxybenzene (67.2 mg, 0.40 mmol) in CDCl3 (1 mL) was
added as internal standard, and the reaction vessel was subsequently
centrifuged for 10 min. An aliquot of 0.2−0.3 mL was withdrawn,
further diluted with CDCl3 (0.3 mL), and analyzed by 1H NMR
against the internal standard for yield determination.
Gratifyingly, analysis of the solid-free filtrates of the reaction
solution by ICP-OES showed a very low leaching of only 4
ppm. However, to ensure that the reaction was catalyzed
primarily by our heterogeneous Pd(II) catalyst and not by these
homogeneous Pd species, the cyclization of acid 1 was
performed using corresponding amounts of Pd(OAc)2 (4
ppm). Under the standard conditions a low yield of 18% of 2
was obtained after 2 h of reaction time. Although these results
indicate that the homogeneous Pd species participate in the
reaction, it is possible to state that it is the heterogeneous
Pd(II) catalyst that is responsible for the majority of the
product formation.
General Procedure B for Cycloisomerization. The pentynoic
acid (0.80 mmol), triethylamine (0.20 mmol, 20.2 mg), PdII-Amp-
MCF (0.30 mol %, 5.12 mg), and CH2Cl2 (2 mL) were placed in a
microwave vial, which was sealed and heated in an oil bath at the
indicated temperature for an appropriate time. The reaction mixture
was subsequently filtered through a short plug of silica gel with
pentane/EtOAc (3/2) as the eluent, and the solvents were removed in
vacuo to afford the desired product.
5-Methylenedihydrofuran-2(3H)-one (2).19 The general procedure
B for cycloisomerization was followed, and the reaction mixture was
heated at 40 °C for 2 h. Compound 2 was obtained as a colorless oil
(60.6 mg, 77%). 1H NMR (500 MHz, CDCl3): δ 4.77−4.74 (m, 1H),
4.33−4.30 (m, 1H), 2.92−2.84 (m, 2H), 2.71−2.64 (m, 2H). 13C
NMR (125 MHz, CDCl3): δ 175.0, 155.8, 88.9, 28.2, 25.3.
CONCLUSION
■
An efficient route for the cycloisomerization of acetylenic acids
to their corresponding lactones under relatively mild reaction
conditions, using a heterogeneous Pd(II) catalyst, has been
developed. The protocol tolerates the presence of different
functional groups on both the α and γ positions of the
acetylenic acids. Moreover, the reactions were found to be
highly regio- and stereoselective, resulting in selective formation
of the exo-dig products and, for internal alkynes, selective
formation of the Z configuration product. Several 4-pentynoic
acid derivatives were efficiently cyclized in excellent yields
within 2−3 h, while internal alkyne substrates as well as 5-
hexynoic acid required elevated temperature, higher catalyst
loading, and prolonged reaction times for obtaining comparable
yields. Furthermore, the heterogeneous Pd(II) catalyst showed
high recyclability and a low leaching, making it an attractive
option to previously developed homogeneous protocols. The
present catalytic system with its mild reaction conditions makes
it a promising method for the synthesis of lactones of biological
activity.
3,3-Dimethyl-5-methylenedihydrofuran-2(3H)-one (4).40 The
general procedure B for cycloisomerization was followed, and the
reaction mixture was heated at 40 °C for 2 h. Compound 4 was
obtained as a yellow oil (81.0 mg, 81%). 1H NMR (500 MHz,
CDCl3): δ 4.77−4.74 (m, 1H), 4.34−4.31 (m, 1H), 2.70−2.68 (m,
2H), 1.30 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 180.3, 153.5, 89.5,
41.0, 40.5, 24.8.
3-Hexyl-5-methylenedihydrofuran-2(3H)-one (6).41 The general
procedure B for cycloisomerization with 0.8 mmol of substrate was
followed, and the reaction mixture was heated at 50 °C for 2 h. 3-
Hexyl-5-methylenedihydrofuran-2(3H)-one was obtained as a color-
less oil (130 mg, 89%). 1H NMR (500 MHz, CDCl3): δ 4.74−4.71 (m,
1H), 4.32−4.28 (m, 1H), 3.04−2.95 (app ddt, J = 16.1 Hz, J = 9.7 Hz,
J = 1.6 Hz, 1H), 2.80−2.70 (m, 1H), 2.60−2.51 (ddt, J = 16.1 Hz,, J =
7.8 Hz, J = 2.2 Hz, 1H), 1.93−1.81 (m, 1H), 1.58−1.46 (m, 1H),
1.43−1.22 (m, 8H), 0.91−0.85 (m, 3H). 13C NMR (125 MHz,
CDCl3): δ 177.4, 154.7, 88.8, 40.1, 31.8, 31.7, 31.0, 29.0, 27.1, 22.7,
14.2.
5-Methylene-2-oxotetrahydrofuran-3-carboxylic Acid (8). 2-
(Prop-2-yn-1-yl)malonic acid (113.6 mg, 0.80 mmol), triethylamine
(20.2 mg, 0.20 mmol), PdII-Amp-MCF (5.12 mg, 0.30 mol %), and
CH2Cl2 (2 mL) were placed in a microwave vial, which was sealed and
heated in an oil bath at the 40 °C for 3 h. The reaction mixture was
filtered through Celite and eluted with CH2Cl2. The solvent was
removed to afford a yellow oil (99 mg, 87%).42 For isolation without
triethylamine, the crude yellow oil was dissolved in EtOAc (10 mL)
and washed with water (pH 3; 3 × 10 mL). The organic layer was
dried over MgSO4, filtered, and evaporated to afford a pale yellow oil
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all materials were
obtained from commercial suppliers and used without further
purification. THF was purchased as the dry solvent and was
column-dried before use. MeOH was purchased as the dry solvent
and dried over molecular sieves (4 Å) before use. H NMR and 13C
1
NMR were recorded on a 400 MHz instrument. Chemical shifts are
reported in ppm, relative to TMS (1H, internal standard, δ(H) 0.00)
or solvent residual peaks (1H, δ(H) CDCl3 7.26; 13C, δ(C) CDCl3
77.0) with multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, app = apparent), coupling constants (in Hz), and
integration. The stereoselectivites of the cyclized products of internal
1
(61 mg, 54%) of product. H NMR (500 MHz, CDCl3): δ 4.88 (m,
1H), 4.48 (m, 1H), 3.82 (m, 1H), 3.34 (m, 1H), 3.17 (m, 1H). 13C
NMR (125 MHz, CDCl3): δ 170.6, 169.6, 152.9, 90.5, 46.2, 29.3.
HRMS (ESI): calcd for C6H6O4Na [M + Na+], 165.0158; found,
165.0166.
Methyl 5-Methylene-2-oxotetrahydrofuran-3-carboxylate (10).43
The general procedure B for cycloisomerization was followed, and the
reaction mixture was heated at 40 °C for 2 h. Compound 10 was
obtained as a yellow oil (99.8 mg, 80%). 1H NMR (500 MHz,
CDCl3): δ 4.83−4.80 (m, 1H), 4.43−4.40 (m, 1H), 3.82 (s, 3H), 3.76
(dd, J = 10.4 Hz, J = 7.6 Hz, 1H), 3.30 (app ddt, J = 16.6 Hz, J = 7.6
Hz, J = 2.2 Hz, 1H), 3.01 (app ddt, J = 16.6 Hz, J = 10.4 Hz, J = 1.7
Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 169.6, 167.4, 153.3, 90.0,
53.5, 46.4, 29.5.
1
alkynes were determined by H NMR shifts of the vinylic proton and
by 1D and 2D NOE experiments. The PdII-AmP-MCF catalyst was
characterized for palladium content and leaching by inductively
coupled plasma (ICP-OES). Flash chromatography was performed on
an automated flash chromatography instrument using silica-based
cartridges with UV detection for fraction collection. HRMS data were
recorded using TOF ESI detection. Acids 1, 5, and 23 are
commercially available and were used without further purification. 5-
(4-Methoxyphenyl)pent-4-ynoic acid (17) was prepared according to
a reported procedures.39 Acids 3, 7, 9, 11, 13, 15, 19, and 21 were
synthesized according to procedures described below.
Methyl 3-Allyl-5-methylene-2-oxotetrahydrofuran-3-carboxylate
(12).18 The general procedure B for cycloisomerization was followed
and the reaction mixture was heated at 40 °C for 2 h. Compound 12
General Procedure A for Cycloisomerization for Yield
Determination by 1H NMR. The pentynoic acid (0.40 mmol),
triethylamine (0.10 mmol, 10.1 mg), PdII-Amp-MCF (0.30−0.50 mol
% Pd, 2.56−4.26 mg), and CH2Cl2 (1 mL) were placed in a microwave
vial, which was sealed and heated in an oil bath at the indicated
1
was obtained as a white solid (146.3 mg, 93%). H NMR (500 MHz,
CDCl3): 5.75−5.64 (m, 1H), 5.25−5.22 (m, 1H), 5.21−5.17 (m, 1H),
4.82−4.77 (m, 1H), 4.40−4.35 (m, 1H), 3.80 (s, 3H), 3.29 (dt, J =
16.7 Hz, J = 1.8 Hz, 1H), 2.90 (dt, J = 16.7 Hz, J = 2.0 Hz, 1H), 2.77
D
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(dd, J = 14.0 Hz, J = 7.6 Hz, 1H), 2.67 (dd, J = 14.0 Hz, J = 7.1 Hz,
1H).
as well as a clear positive difference peak in 1D NOE for CH2 protons
when the vinylic proton was irradiated at 5.48 ppm.
(Z)-5-(4-(Trifluoromethyl)benzylidene)dihydrofuran-2(3H)-one
(14). 5-(4-(Trifluoromethyl)phenyl)pent-4-ynoic acid (96.8 mg, 0.40
mmol), triethylamine (10.1 mg, 0.10 mmol), PdII-Amp-MCF (4.26
mg, 0.50 mol % Pd), and CH2Cl2 (1 mL) were placed in a microwave
vial, which was sealed and heated in an oil bath at 50 °C for 3 h. The
crude material was filtered through a plug of silica and the plug eluted
with CH2Cl2; removal of solvents afforded the pure product as a white
solid (79.9 mg, 83%). 1H NMR (500 MHz, CDCl3): δ 7.64 (app d, J =
8.4 Hz, 2H), 7.56 (app d, J = 8.4 Hz, 2H), 5.60−5.57 (m, 1H), 3.11−
3.04 (m, 2H), 2.77−2.71 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
tert-Butyl(5-methylene-2-oxotetrahydrofuran-3-yl)carbamate
(22).20 The general procedure B for cycloisomerization was followed,
and the reaction mixture was heated at 40 °C for 3 h. Compound 22
1
was obtained as an off-white solid (136 mg, 80%). H NMR (500
MHz, CDCl3): δ 5.10 (br s, 1H), 4.83−4.79 (m, 1H), 4.42−4.38 (m,
1H), 3.35−3.17 (m, 1H), 2.94−2.79 (m, 1H), 1.46 (s, 9H). 13C NMR
(125 MHz, CDCl3): δ 173.1, 152.4, 90.6, 81.2, 50.7, 33.7, 28.4.
6-Methylenetetrahydro-2H-pyran-2-one (24).19 The general
procedure B for cycloisomerization was followed, and the reaction
mixture was heated at 50 °C for 24 h with a catalyst loading of 0.5 mol
174.5, 150.3, 137.6, 128.5, 128.5 (q, 2JC−F = 32.3 Hz), 125.5 (q, 3JC−F
=
1
%. Compound 24 was obtained as a colorless oil (69.1 mg, 77%). H
1
4.5 Hz), 124.4 (q, JC−F = 272.7 Hz), 103.9, 26.9, 26.6. HRMS (ESI):
calcd for C12H9F3O2Na [M + Na+], 265.0447; found, 265.0454. A
clear cross-peak between the vinylic proton and CH2 protons was
observed in a 2D NOE experiment as well as a clear positive difference
peak in 1D NOE for CH2 protons when the vinylic proton was
irradiated at 5.59 ppm.
NMR (500 MHz, CDCl3): 4.65−4.62 (m, 1H), 4.30−4.27 (m, 1H),
2.62 (t, J = 6.8 Hz, 2H), 2.48 (app d, J = 6.5 Hz, 2H), 1.92−1.83 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 168.2, 155.4, 93.9, 30.4, 26.9,
18.7.
Recycling Study. A microwave vial was charged with 4-pentynoic
acid (39.2 mg, 0.40 mmol), triethylamine (10.1 mg, 0.10 mmol), PdII-
Amp-MCF (2.56 mg, 0.30 mol % Pd), 1,4-benzoquinone (0.5 mg, 1
mol %), 1,3,5-trimethoxybenzene (67.2 mg, 0.40 mmol), and CH2Cl2
(1 mL). The microwave vial was sealed and heated for 2 h at 40 °C.
The reaction vessel was subsequently centrifuged for 10 min. A 0.2−
0.3 mL aliquot was withdrawn, further diluted with CDCl3 (0.3 mL),
(Z)-5-Benzylidenedihydrofuran-2(3H)-one (16).19 5-Phenylpent-4-
ynoic acid (69.6 mg, 0.40 mmol), triethylamine (10.1 mg, 0.10 mmol),
PdII-Amp-MCF (4.26 mg, 0.50 mol %), and CH2Cl2 (1 mL) were
placed in a microwave vial, which was sealed and heated in an oil bath
at the 50 °C for 3 h. The crude material was filtered through a plug of
silica and eluted with pentane/EtOAc (3/2, 3 mL); removal of
solvents afforded the pure product as a white solid (60.5 mg, 87%). 1H
NMR (500 MHz, CDCl3): δ 7.55 (app d, J = 7.3 Hz, 2H), 7.32 (app t,
J = 7.7 Hz, 2H), 7.23−7.18 8 (m, 1H), 5.56 (t, J = 1.7 Hz, 1H), 3.07−
3.01 (m, 2H), 2.75−2.68 (m, 2H). 13C NMR (125 MHz, CDCl3): δ
175.04, 148.2, 134.0, 128.6, 128.4, 126.9, 105.1, 27.1, 26.5. A clear
cross-peak between the vinylic proton and CH2 protons was observed
in a 2D NOE experiment, as well as a clear positive difference peak in
1D NOE for CH2 protons when the vinylic proton was irradiated at
5.56 ppm. The shift of the vinylic proton was in agreement with
literature data.19
1
and analyzed by H NMR to determine the ratio of starting material
and product. The catalyst was washed twice with CH2Cl2 (2 × 3 mL).
This procedure was repeated in three subsequent cycles.
Synthesis of Starting Material. Synthesis of 2,2-Dimethylpent-
4-ynoic acid (3). A 2 M solution of LDA in toluene (24 mL, 48 mmol)
was added to dry THF (80 mL) at −50 °C and was stirred for 30 min
under an argon atmosphere. It was then warmed to −5 °C and was
stirred for 10 min, followed by dropwise addition of methyl isobutyrate
(4.0 g, 40 mmol). The reaction mixture was cooled to −50 °C, and
propargyl bromide (5.7 g, 48 mmol) was added. The reaction mixture
was then warmed to room temperature and was stirred for an
additional 18 h. The reaction mixture was quenched with saturated
aqueous NH4Cl at 0 °C and extracted with Et2O (2 × 200 mL). The
combined organic layers were dried over MgSO4, filtered, and
evaporated in vacuo to afford crude methyl 2,2-dimethyl-4-pentynoate
as an orange oil, which was subsequently hydrolyzed by treatment of 2
M aqueous NaOH (80 mL, H2O/EtOH (1/1)) at reflux for 3 h. The
reaction mixture was then acidified to pH 1 using 1 M aqueous HCl
and extracted with Et2O (3 × 30 mL). The combined ether layers were
concentrated in vacuo and extracted with 3 M aqueous NaOH (3 × 30
mL). The combined aqueous layers were acidified to pH 1 using 6 M
aqueous HCl and extracted with CH2Cl2 (3 × 30 mL). The combined
CH2Cl2 layers were dried over MgSO4 and filtered, and the solvents
were removed in vacuo to afford the pure product as an orange oil (2.3
g, 45%). 1H NMR data were in accordance with those previously
reported.44
Synthesis of 2-(Prop-2-yn-1-yl)malonic Acid (7). Sodium (0.48 g,
20.9 mmol) was dissolved in dry MeOH under an inert atmosphere,
followed by addition of dimethyl malonate (1.94 g, 14.7 mmol). The
reaction mixture was stirred at room temperature for 15 min, after
which propargyl bromide (2.18 g, 14.5 mmol) was slowly added. The
reaction mixture was then stirred at room temperature for an
additional 5 h. The reaction mixture was quenched with 1 M aqueous
HCl, concentrated, and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried over MgSO4 and filtered, and the
solvent was removed in vacuo to afford the crude alkylated ester as a
colorless oil.
(Z)-5-(4-Methoxybenzylidene)dihydrofuran-2(3H)-one (18). 5-(4-
Methoxyphenyl)pent-4-ynoic acid (81.6 mg, 0.40 mmol), triethyl-
amine (10.1 mg, 0.10 mmol), PdII-Amp-MCF (4.26 mg, 0.50 mol %),
and CH2Cl2 (1 mL) were placed in a microwave vial, which was sealed
and heated in an oil bath at 50 °C for 24 h. The crude material was
filtered through a plug of silica and diluted with EtOAc (20 mL). The
organic layer was washed with saturated aqueous NaHCO3 (3 × 20
mL), dried over MgSO4, and filtered, and the solvent was removed to
1
afford the pure product as a white solid (54.6 mg, 67%). H NMR
(500 MHz, CDCl3): δ 7.51−7.47 (m, 2H), 6.89−6.84 (m, 2H), 5.51−
5.48 (m, 1H), 3.81 (s, 3H), 3.05−2.98 (m, 2H), 2.73−2.67 (m, 2H).
13C NMR (125 MHz, CDCl3): δ 175.2, 158.5, 146.5, 129.7, 126.8,
114.1, 104.6, 55.4, 27.3, 26.4. HRMS (ESI): calcd for C12H12O3Na [M
+ Na+], 227.0679; found, 227.0677. A clear cross-peak between the
vinylic proton and CH2 protons was observed in a 2D NOE
experiment, as well as a clear positive difference peak in 1D NOE for
CH2 protons when the vinylic proton was irradiated at 5.49 ppm.
(Z)-5-(4-Hydroxybenzylidene)dihydrofuran-2(3H)-one (20). 5-(4-
Hydroxyphenyl)pent-4-ynoic acid (76.1 mg, 0.40 mmol), triethyl-
amine (10.1 mg, 0.10 mmol), PdII-Amp-MCF (4.26 mg, 0.50 mol %),
and CH2Cl2 (1 mL) were placed in a microwave vial, which was sealed
and heated in an oil bath at the 50 °C for 3 h. The reaction mixture
was filtered through a plug of silica and eluted with pentane/EtOAc
(60/40). The organic phase was washed with NaHCO3 (3 × 3 mL),
dried over MgSO4, and filtered, and the solvents were removed to
afford a 5/1 mixture of exo-dig and endo-dig isomers 20 and 20′,
respectively, as a white solid (38.2 mg, 50%). 20: 1H NMR (500 MHz,
CDCl3) δ 7.45 (app d, J = 8.7 Hz, 2H), 6.81 (app d, J = 8.7 Hz, 2H),
5.48 (t, J = 1.7 Hz, 1H), 4.79 (br s, 1H), 3.07−2.97 (m, 2H), 2.75−
2.66 (m, 2H). The endo-dig isomer 20′ is distinguishable at δ 5.68 (t, J
= 4.7 Hz, 1H), 4.93 (br s, 1H), 2.95−2.88 (m, 2H), 2.55−2.48 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 175.2, 154.3, 146.4, 129.8,
115.4, 104.5, 98.3, 27.1, 26.2. HRMS (ESI): calcd for C11H9O3 [M−],
189.0557; found, 189.0548. A clear cross-peak between the vinylic
proton and CH2 protons in 20 was observed in a 2D NOE experiment,
To a solution of NaOH (1.2 g, 29.4 mmol) in H2O/MeOH (1/7,
80 mL) was added the crude ester, and the reaction mixture was
refluxed overnight. After it was warmed to room temperature, the
reaction mixture was acidified to pH 1 with 6 M aqueous HCl and
extracted with EtOAc (3 × 100 mL). The combined organic layers
were extracted with saturated aqueous NaHCO3 (3 × 100 mL) and
washed with EtOAc (50 mL). The combined aqueous layers were
acidified to pH 1 with 6 M aqueous HCl followed by extraction with
EtOAc (3 × 200 mL). The combined organic layers were washed with
E
dx.doi.org/10.1021/jo4028006 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
water (100 mL) and brine (100 mL), dried over MgSO4,and filtered,
and solvents were removed in vacuo. Purification by column
chromatography with a gradient starting at 0% of solvent A and
ending at 100% solvent A (solvent A, EtOAc/AcOH (96/4); solvent
B, pentane) gave pure 2-(prop-2-yn-1-yl)malonic acid as a white solid
(0.57 g, 24%). 1H NMR data were in accordance with those previously
reported.45
Synthesis of 2-(Methoxycarbonyl)pent-4-ynoic Acid (9). Sodium
(0.48 g, 20.9 mmol) was dissolved in dry MeOH under an inert
atmosphere, followed by addition of dimethyl malonate (1.9 g, 14.7
mmol). The reaction mixture was stirred at room temperature for 15
min, after which propargyl bromide (2.2 g, 14.5 mmol) was slowly
added. The reaction mixture was then stirred at room temperature for
an additional 5 h. The reaction mixture was quenched with 1 M
aqueous HCl, concentrated, and extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were dried over MgSO4 and filtered, and
the solvent was removed in vacuo to afford the crude alkylated ester as
a colorless oil.
To a H2O/MeOH mixture (1/7, 80 mL) was added the crude ester,
and the reaction mixture was basified to pH 10 using 6 M aqueous
NaOH and refluxed overnight. After it was warmed to room
temperature, the reaction mixture was acidified to pH 1 and the
product was extracted with EtOAc (3 × 100 mL), dried over MgSO4,
and filtered. Purification by column chromatography with a gradient
starting at 0% of solvent A and ending at 100% solvent A (solvent A,
EtOAc/AcOH (96/4); solvent B, pentane) gave pure 2-
(methoxycarbonyl)pent-4-ynoic acid as a white solid (0.77 g, 33%).
1H NMR data were in accordance with those previously reported.43
NaHCO3 (3 × 100 mL). The aqueous layer was washed with CH2Cl2
(50 mL) and acidified to pH 1 using 1 M aqueous HCl. The product
was extracted with CH2Cl2 (3 × 200 mL), the extract was dried over
MgSO4 and filtered, and the solvents were removed in vacuo.
Purification by column chromatography with a gradient starting at 0%
of solvent A and ending at 100% solvent A (solvent A, EtOAc/AcOH
(96/4); solvent B, pentane) afforded pure 5-(4-(trifluoromethyl)-
phenyl)pent-4-ynoic acid (13) as a white solid (1.00 g, 64%). 1H
NMR (500 MHz, CDCl3): δ 7.54 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2
Hz, 2H), 2.77 (m, 2H), 2.27 (m, 2H). 13C NMR (125 MHz, CDCl3):
δ 178.0, 132.0, 129.8 (q, 2JC−F = 32.6 Hz), 127.4, 125.3 (q, 3JC−F = 3.7
Hz), 124.35 (q, 1JC−F = 272.5 Hz), 90.4, 80.4, 33.3, 15.2. HRMS (ESI):
calcd for C12H9F3O2Na [M + Na+], 265.0447; found, 265.0457.
Synthesis of 5-Phenylpent-4-yn-1-ol. 4-Pentynol (0.94 g, 10.6
mmol) and Et3N (3.37 g, 33.3 mmol) were added to a suspension of
phenyl iodide (4.56 g, 22.3 mmol), Pd(PPh3)4 (129 mg, 0.112 mmol),
and CuI (42.5 mg, 0.220 mmol) in dry THF (6 mL). The resulting
reaction mixture was stirred at room temperature overnight under an
inert atmosphere. The reaction mixture was then filtered through silica
and purified with a gradient starting at 0% of solvent A and ending at
100% solvent A (solvent A, EtOAc/AcOH (96/4); solvent B, pentane)
1
to afford 5-phenylpent-4-yn-1-ol as a white solid (1.45 g, 78%). H
NMR data were in accordance with those previously reported.47
Synthesis of 5-Phenylpent-4-ynoic Acid (15). Jones reagent (8.4
mL, 0.5 M CrO3 in concentrated H2SO4/H2O (2/3)) was added
dropwise to a solution of 5-phenylpent-4-yn-1-ol (0.45 g, 2.8 mmol) in
acetone at 0 °C. After it was stirred overnight in an ice bath, the
reaction mixture was quenched with i-PrOH (5 mL) in vacuo. The
resulting crude mixture was acidified with 1 M aqueous HCl to pH 1
and extracted with CH2Cl2 (3 × 100 mL). The combined organic
layers were washed with water (50 mL) and extracted with saturated
aqueous NaHCO3 (3 × 100 mL). The aqueous layer was washed with
CH2Cl2 (50 mL) and acidified to pH 1 with 1 M aqueous HCl. The
product was extracted with CH2Cl2 (3 × 200 mL), the extract was
dried over MgSO4 and filtered, and the solvents were removed in
vacuo. Purification by column chromatography with a gradient starting
at 0% of solvent A and ending at 100% solvent A (solvent A, EtOAc/
AcOH (96/4), solvent B, pentane) afforded pure 5-phenylpent-4-
Synthesis of 2-(Methoxycarbonyl)-2-(prop-2-yn-1-yl)pent-4-enoic
Acid (11). To a solution of dimethyl 2-(prop-2-yn-1-yl)malonate (1.0
g, 5.88 mmol) in anhydrous THF (20 mL) under an inert atmosphere
was added (153 mg, 6.5 mmol), and the mixture was stirred at room
temperature for 5 min, after which allyl bromide (747 mg, 6.2 mmol)
was added. The resulting suspension was stirred at room temperature
overnight. Subsequently H2O (20 mL) was added and the reaction
mixture was concentrated in vacuo and extracted with CH2Cl2 (3 ×
100 mL). The combined organic layers were washed with water (50
mL), dried over MgSO4, and filtered, and the solvents were removed
in vacuo to afford an oil, which was which was subjected to selective
hydrolysis. The crude product was dissolved in MeOH (70 mL)
followed by addition of a 0.6 M aqueous solution of NaOH (10 mL),
and the mixture was refluxed overnight. The reaction mixture was
acidified to pH 2 using 2 M aqueous HCl and extracted with CH2Cl2
(3 × 75 mL). The combined organic layers were washed with water
(50 mL), dried over MgSO4, and filtered, and the solvents were
1
ynoic acid (15) as a white solid (0.29 g, 69%). H NMR data were in
accordance with those previously reported.19
Synthesis of 5-(4-Hydroxyphenyl)pent-4-ynoic Acid (19). Ethyl-4-
pentynoate was prepared following reported procedures.39 5-Phenyl-
pent-4-ynoic acid was prepared following the reported procedures for
the preparation of compound 17 to afford compound 19 as a yellow
solid (651 mg, 58%). 1H NMR (500 MHz, MeOD): δ 7.36 (app d, J =
8.3 Hz, 2H), 6.87 (app d, J = 8.3 Hz, 2H), 2.87−2.78 (m, 2H), 2.77−
2.71 (m, 2H), 2.69 (m, 1H). 13C NMR (125 MHz, MeOD): δ 175.8,
158.4, 133.9, 116.2, 115.9, 86.7, 82.0, 34.6, 16.0. HRMS (ESI): calcd
for C11H9O3 [M−], 189.0557; found, 189.0559.
1
removed in vacuo to afford a colorless oil (800 mg, 68%). H NMR
data were in accordance with those previously reported.46
Synthesis of 5-(4-(Trifluoromethyl)phenyl)pent-4-yn-1-ol. Pd-
(PPh3)4 (68.6 mg, 59.4 μmol), CuI (22.8 mg, 0.12 mmol), 4-
pentyn-1-ol (500 mg, 5.95 mmol), 1-bromo-4-(trifluoromethyl)-
benzene (0.89 g, 3.96 mmol), and Et3N (0.60 g, 5.95 mmol) were
dissolved in MeCN (30 mL) under an inert atmosphere. The resulting
suspension was refluxed for 24 h. The resulting solution was filtered
through Celite and concentrated in vacuo to give 5-(4-
(trifluoromethyl)phenyl)pent-4-yn-1-ol as an orange oil (0.74 g,
Synthesis of 2-((tert-Butoxycarbonyl)amino)pent-4-ynoic Acid
(21). Boc2O (216 mg, 0.99 mmol) was added to a suspension of
propargyl glycine (100 mg, 0.88 mmol) and K2CO3 (137 mg, 0.99
mmol) in THF/H2O (1/1, 2 mL). The resulting reaction mixture was
stirred overnight at room temperature. The reaction mixture was
acidified with 1 M aqueous HCl to pH 3 and extracted with EtOAc
(3× 10 mL). The combined organic layers were washed with water
(pH 3.1 × 10 mL), dried over MgSO4, filtered, and concentrated in
1
82%). H NMR (500 MHz, CDCl3): δ 7.45 (d, J = 8.2 Hz, 2H),
7.48 (d, J = 8.2, 2H), 3.82 (t, J = 6.1 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H),
1.87 (quin, J = 6.6 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 131.9,
129.5 (q, 2JC−F = 32.7 Hz), 127.7, 125.3 (q, 3JC−F = 3.7 Hz), 124.1 (q,
1JC−F = 272.0 Hz), 92.3, 80.1, 61.7, 31.3, 16.1. HRMS (ESI): calcd for
C12H11F3ONa [M + Na+], 251.0654; found, 251.0663.
Synthesis of 5-(4-Ttrifluoromethyl)phenyl)pent-4-ynoic Acid (13).
Jones reagent (19.2 mL, 0.5 M CrO3 in concentrated H2SO4/H2O (2/
3)) was added dropwise to a solution of 5-(4-(trifluoromethyl)-
phenyl)pent-4-yn-1-ol (1.49 g, 6.4 mmol) in acetone at 0 °C. After it
was stirred overnight in an ice bath, the reaction mixture was quenched
with i-PrOH (5 mL) and concentrated in vacuo. The resulting crude
mixture was acidified with 1 M aqueous HCl to pH 1 and extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with water (50 mL) and extracted with saturated aqueous
1
vacuo to afford a white solid (154 mg, 70%). H NMR data were in
accordance with those previously reported.48
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: eric@organ.su.se (E.V.J.); jeb@organ.su.se (J.-E.B.).
F
dx.doi.org/10.1021/jo4028006 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(31) Johnston, E. V.; Verho, O.; Karkas, M. D.; Shakeri, M.; Tai, C.-
̈
̈
Notes
W.; Palmgren, P.; Eriksson, K.; Oscarsson, S.; Backvall, J.-E. Eur. J.
̈
The authors declare no competing financial interest.
Chem. 2012, 18, 12202.
(32) Ping, E. W.; Pierson, J.; Wallace, R.; Miller, J. T.; Fuller, T. F.;
Jones, C. W. Appl. Catal., A 2011, 396, 85.
(33) Ping, E. W.; Wallace, R.; Pierson, J.; Fuller, T. F.; Jones, C. W.
ACKNOWLEDGMENTS
■
The Berzelius Center EXSELENT and the Swedish Research
Council are gratefully acknowledged for financial support. We
also kindly acknowledge Dr. Cheuk-Wai Tai for valuable input
on this project.
Micropor. Mesop. Mat. 2010, 132, 174.
(34) Taguchi, A.; Schuth, F. Micropor. Mesop. Mat. 2005, 77, 1.
̈
(35) Verho, O.; Nagendiran, A.; Johnston, E. V.; Tai, C.-W.; Backvall,
̈
J.-E. ChemCatChem 2013, 5, 612.
(36) Verho, O.; Nagendiran, A.; Tai, C.-W.; Johnston, E. V.; Backvall,
̈
J.-E. ChemCatChem 2014, 6, 205.
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