One-Pot Synthesis of α-Ylidene δ-Lactones from Functionalized Allylic Bromides in a Water-Isopropanol Medium

Article abstract of DOI:10.1055/s-0036-1588078

The one-pot microwave-assisted synthesis of a series of α-ylidene δ-lactones from (Z)-2-(bromomethyl)-2-alkenoates (derived from Morita-Baylis-Hillman reaction) in an aqueous environment is reported. The protocol includes regioselective base-mediated allylation of ethyl acetoacetate with (Z)-2-(bromomethyl)-2-alkenoates followed by decarboxylative hydrolysis, carbonyl reduction of the keto carboxylate intermediate, and acid-mediated cyclization of the resulting δ-hydroxy acid to furnish the α-ylidene δ-lactones with good overall yields. The synthesis was also performed in the stepwise mode, which allowed the isolation and full characterization of each intermediate involved in the one-pot method. The main features of this efficient transformation include the fast reaction rates, the use of a benign aqueous medium, the use of inexpensive and readily available reagents, the production of nearly innocuous residues, and the requirement for a single work-up and purification stage at the end of the process.

Full text of DOI:10.1055/s-0036-1588078

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
M. Ferreira et al.
Paper
Synthesis
One-Pot Synthesis of α-Ylidene δ-Lactones from Functionalized
Allylic Bromides in a Water–Isopropanol Medium
Misael Ferreiraa
Tula B. Bisolb
Henrique P. da Conceiçãoa
Theo V. C. Russoa
Adailton J. Bortoluzzia
Marcus M. Sá*a
one-pot, mw-assisted
O
O
1. NaOH, iPrOH–H2O
2. NaOH (exc.)
3. NaBH4
R
OMe
O
R
Br
O
+
R = aryl, alkyl
11 examples
up to 62% yield
4. HCl
O
OEt
a Departamento de Química, Universidade Federal de Santa Catarina,
Florianópolis, SC 88040-900, Brazil
marcus.sa@ufsc.br
b Instituto Federal de Santa Catarina, Campus Florianópolis,
Florianópolis, SC 88020-300, Brazil
Received: 26.07.2016
Accepted after revision: 06.09.2016
Published online: 13.10.2016
lectivity through the direct interaction of microwave ener-
gy with the reaction mixture increases the process
efficiency, not only because of the reduced energy con-
sumption but also because of the associated time savings.
Moreover, the use of microwave heating enables the re-
placement of many organic solvents with water or can even
allow the use of solvent-free protocols.3
The reduction of wastes and the use of environmentally
friendly reagents and catalysts are also important parame-
ters to achieve more sustainable processes. Minimizing the
number of synthetic steps is mandatory to attain overall
process efficiency. A one-pot process is an economically fa-
vorable method in which a number of bond-formation
steps are performed in a single reaction flask and without
the need for the separation and isolation of intermediates.
In this context, synthetic chemists save time, energy and
resources by avoiding purification stages between individu-
al steps within a multistep synthesis.4 The development of
one-pot procedures allows the reduction of not only energy
and time but also the amount of solvents, silica gel and re-
lated substances involved in the work-up and/or product
isolation and purification. It also decreases the amount of
contaminated aqueous waste generated in the clean-up
stages.
α-Alkylidene γ-lactones are present as subunits in sev-
eral biologically active compounds. In recent years, α-
ylidene δ-lactones and related cyclic systems have become
common targets of biological and synthetic studies.5 All of
these structures have in common an exo-ylidene moiety
conjugated with a cyclic carboxyl group, which is believed
to be essential for their biological activities, such as antitu-
mor,6a–d antibiotic,6d and antimalarial6e properties. It has
been shown that the olefin conjugated to the carbonyl
group can act as a Michael acceptor and behave as a potent
alkylating agent reacting with physiological nucleophiles.6f
DOI: 10.1055/s-0036-1588078; Art ID: ss-2016-m0524-op
Abstract The one-pot microwave-assisted synthesis of a series of α-
ylidene δ-lactones from (Z)-2-(bromomethyl)-2-alkenoates (derived
from Morita–Baylis–Hillman reaction) in an aqueous environment is re-
ported. The protocol includes regioselective base-mediated allylation of
ethyl acetoacetate with (Z)-2-(bromomethyl)-2-alkenoates followed by
decarboxylative hydrolysis, carbonyl reduction of the keto carboxylate
intermediate, and acid-mediated cyclization of the resulting δ-hydroxy
acid to furnish the α-ylidene δ-lactones with good overall yields. The
synthesis was also performed in the stepwise mode, which allowed the
isolation and full characterization of each intermediate involved in the
one-pot method. The main features of this efficient transformation in-
clude the fast reaction rates, the use of a benign aqueous medium, the
use of inexpensive and readily available reagents, the production of
nearly innocuous residues, and the requirement for a single work-up
and purification stage at the end of the process.
Key words allylic bromide, δ-lactone, green chemistry, microwave,
one-pot, Morita–Baylis–Hillman
The increasing demand for sustainable synthetic meth-
ods that fulfill the green chemistry principles brings signif-
icant challenges for the scientific community.1 Synthetic
chemists are adopting a new paradigm that supports the
development of chemical processes that are not only highly
productive and selective but also environmentally benign.
These goals can be accomplished with the proper choice of
starting materials and reaction conditions, and through a
re-evaluation of the work-up procedures and separa-
tion/purification steps.
The use of microwave energy to assist chemical reac-
tions has become an increasingly accepted technique in the
scientific community and is responsible for many import-
ant achievements in drug discovery.2 The possibility of per-
forming reactions with very short times and with high se-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
M. Ferreira et al.
Paper
Synthesis
The growing interest in the biological activities of α-
ylidene δ-lactones and similar structures has led to the de-
velopment of several synthetic approaches.7,8 However,
these methods are associated with drawbacks such as the
need for several steps and the use of harsh reaction condi-
tions or expensive reagents. Moreover, the majority of the
procedures targeted α-methylene δ-lactones, whereas the
synthesis of α-alkylidene or α-arylidene δ-lactones is limit-
ed to a few examples.6b,6c,9
The synthesis of α-ylidene δ-lactones commenced with
the development of a mild base-mediated regioselective al-
lylation of β-keto ester 2 with allylic bromides 1, which
were obtained in high yields by treating the corresponding
α-methylene-β-hydroxy esters12 with LiBr/H2SO4 in aceto-
nitrile at ambient temperature.14 From the bases tested,
those associated with a nucleophilic character [such as
DABCO, DMAP, hexamethylenetetramine (HMTA) and Et3N]
led to the formation of stable ammonium salts, which were
either eliminated after the aqueous work-up or, in the par-
ticular case of the DABCO-derived salt 3, were slowly con-
verted into the SN2′-type product 4 under the reaction con-
ditions (Scheme 2). On the other hand, the use of DBU as
the base in acetone as the solvent gave the expected allylat-
ed diesters 5 in good isolated yields (Scheme 2 and Table 1,
entries 1–3). Inorganic bases such as K2CO3 and NaOH were
also useful as promoters (entries 4 and 5), whereas the sim-
ple combination of a slight excess of NaOH in aqueous iso-
propyl alcohol worked well for the synthesis of a represen-
tative group of allylated keto diesters 5 (entries 6–9).
Ten years ago, Singh and Batra10 described the synthesis
of α-methylene δ-lactones I starting from the base-mediat-
ed allylation11 of 2,4-pentanodione with allylic acetates II
derived from the Morita–Baylis–Hillman (MBH) reaction,12
followed by cleavage of the acyl group in III, reduction of
the remaining keto function in IV and subsequent acid-cat-
alyzed cyclization (Scheme 1). We thus envisaged that the
related α-alkylidene and α-arylidene δ-lactones V could, in
principle, be obtained from allylic bromides 1 by adjusting
the allylation step to selectively produce the isomeric un-
saturated ester VI instead of III. Further acyl cleavage of VI
followed by reductive cyclization of the resulting keto acid
VII could lead to the target δ-lactones V (Scheme 1). For
this method to be considered robust, it should be possible
to design a one-pot procedure wherein each step is carried
out sequentially from 1 through the suitable choice of com-
patible reaction conditions. Based on a review of the rele-
vant literature, it appears that the synthesis of α-alkylidene
and α-arylidene δ-lactones V by employing this strategy
has not been reported to date.
O
O
O
O
2
OEt
R
OMe
R
OMe
base
COOEt
1
Br
base = DBU,
5
O
DABCO
R
K2CO3, NaOH
O
N
O
O
2
O
R
O
OEt
OMe
N
OEt
COOMe
3
O
O
O
O
O
4
Batra
Br
(ref 10)
O
Scheme 2 Base-dependent regioselectivity in the allylation step
1.
2.
AcO
O
+
COOMe
R
R
OH
R
OMe
III
IV
II
Table 1 Base-Mediated Allylation of β-Keto Ester 2 with Allylic Bro-
mides 1a
3.
1. alkylation; 2. acyl cleavage; 3. reductive cyclization
O
R
O
Yield (%)b
O
O
Entry
R
Base
DBU
Solvent
Product
I
+
R
OMe
R'
1
2
3
4
5
6
7
8
9
C6H5
acetone
5a
5c
5i
80
70
76
69
73
68
70
78
80
1
O
Br
4-ClC6H4
4-MeOC6H4
C6H5
DBU
acetone
1.
this work
DBU
acetone
O
O
R
O
K2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
acetone
5a
5a
5b
5c
5i
2.
3.
R
OMe
R
OH
C6H5
i-PrOH–H2Oc
i-PrOH–H2Oc
i-PrOH–H2Oc
i-PrOH–H2Oc
i-PrOH–H2Oc
COR'
O
4-MeC6H4
4-ClC6H4
4-MeOC6H4
n-Pr
VI
VII
V
O
O
Scheme 1 Synthetic approaches to δ-lactones
5k
As a continuation of our recent research on the synthet-
ic transformations of allylic bromides 1 derived from the
MBH reaction,13 in this article we report the results of re-
search toward the straightforward one-pot synthesis of α-
ylidene δ-lactones V under microwave-assisted conditions.
a Reaction conditions: 1 (1.0 mmol), 2 (1.3 mmol), base (2.0 mmol for DBU
and K2CO3; 1.2 mmol for NaOH), solvent (2.0 mL), 30 min, 25 °C.
b Isolated yield after column chromatography.
c 1:1 (v/v) mixture.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
M. Ferreira et al.
Paper
Synthesis
1
During the studies involving the allylation of keto ester
2 with allylic bromides 1, it soon became clear that the re-
action outcome was dependent on both the amount of
NaOH used and the reaction temperature. This observation
was based on the propensity of the preformed allylated di-
ester 5 to undergo decarboxylative hydrolysis, yielding the
keto carboxylate 6 when the transformation was conducted
under reflux in the presence of a large excess of NaOH
(Scheme 3). In fact, the high-yield synthesis of keto acid 7
was performed either by previously isolating the allylated
diester 5 and then treating it with excess NaOH under re-
flux (followed by acidic work-up) or through the more
practical one-pot procedure directly from bromide 1 with-
out the isolation of the preformed allylated intermediate 5.
These conditions were extended to other representative
aryl- and alkyl-substituted bromides 1, thus giving the cor-
responding keto acids 7 in good isolated yields irrespective
of the substitution pattern on the R group (Table 2).
way. In all cases, examination of the H NMR spectrum re-
vealed a typical chemical shift of ca. 7.8–7.9 ppm for the
olefinic hydrogen, thereby supporting the proposed (E)-ste-
reochemistry for the exocyclic olefin.13,14
O
O
O
NaBH4
NaOH
HClaq
R
OH
R
ONa
R
O
120 °C
6
i-PrOH–H2O
90 °C
– NaCl
– H2O
8
7
9
O
L3BO
R = C6H5 (a), 4-ClC6H4 (c), 4-MeOC6H4 (i)
Scheme 4 Construction of the δ-lactone ring of 9 through reductive
cyclization of keto acids 7
The structural elucidation of α-ylidene δ-lactones 9, to-
gether with the unequivocal determination of the stereo-
chemistry of the double bond, was further achieved by X-
ray crystallographic analysis after the crystallization of δ-
lactone 9i as a single crystal from ethyl acetate (Figure 1
and the Supporting Information).15
O
O
1. 2, NaOH (1.2 equiv)
i-PrOH–H2O, 25 °C
R
OH
R
OMe
2. NaOH (5 equiv)
reflux; then HClaq
1
7
Br
– NaBr
– H2O
O
– NaCl
O
O
R
OMe
COOEt
R
ONa
– MeOH
– EtOH
– CO2
6
5
Figure 1 ORTEP plot of δ-lactone 9i; ellipsoids are drawn at the 40%
O
O
probability level
Scheme 3 Preparation of keto acids 7 from allylic bromides 1
Table 2 One-Pot Preparation of Keto Acids 7 from Allylic Bromides 1a
Based on the success of the approach to synthesizing α-
ylidene δ-lactones 9 from allylic bromides 1 through a sim-
ple multistep sequence, and given that each step can be car-
ried out in aqueous medium, the development of a simple
one-pot process seemed promising. The combination of
NaOH as the base and aqueous isopropyl alcohol as the sol-
vent system in this route is particularly advantageous, not
only for safety and economic reasons but also because these
reagents are compatible with the functionalities present in
the starting materials, intermediates and products, as well
as with chemicals, such as the reducing agent NaBH4.
At the onset of this strategy, the possibility of adapting
the four-step route (allylation, decarboxylative hydrolysis,
reduction, and acid-mediated lactonization) to include the
use of a microwave reactor was highly attractive because of
the preliminary observation that microwave-assisted reac-
tions are much faster than the similar transformations car-
ried out at room temperature or under conventional heat-
ing. Therefore, each step was consecutively performed in a
microwave vial without the isolation of intermediates
(Scheme 5). As a possible additional feature of this one-pot
procedure, the keto-carboxylate intermediate 6 generated
from the decarboxylative hydrolysis of 5 could be directly
Entry
R
Product
Yield from 1 (%)b
1
2
3
4
5
6
C6H5
7a
7b
7c
7e
7i
78
84
89
88
80
77
4-MeC6H4
4-ClC6H4
2,4-Cl2C6H3
4-MeOC6H4
n-Pr
7k
a Reaction conditions: (i) Bromide 1 (2.0 mmol), keto ester 2 (2.6 mmol),
NaOH (2.4 mmol), i-PrOH (2.0 mL), H2O (2.0 mL), 30 min, 25 °C; (ii) NaOH
(10 mmol), reflux, 0.5–1 h; (iii) HCl.
b Isolated yield after column chromatography.
With the keto acids 7 in hand, the next step to be inves-
tigated was the reductive cyclization to the corresponding
α-ylidene δ-lactones 9. The chemoselective hydride reduc-
tion of the keto carbonyl group of 6a (obtained in situ from
7a in basic medium) followed by acid-mediated cyclization
of the resulting intermediate 8a gave the expected9a δ-lac-
tone 9a in good yield (Scheme 4). The related aryl-substi-
tuted lactones 9c and 9i were also prepared in a similar
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
M. Ferreira et al.
Paper
Synthesis
reduced to intermediate 8 without the need for the acidic
work-up required to isolate the keto acid 7 (see Scheme 3
and Scheme 4).
dicated that the nucleophilic ring-opening of lactone 9a by
i-PrOH under neutral or slightly basic medium gave the hy-
droxy ester 11a, whereas the equilibrium shifted to the cy-
clized product 9a under strongly acidic conditions. As ex-
pected, switching to a more nucleophilic solvent such as
EtOH enhanced the formation of the corresponding ethyl
ester 11b as the byproduct. Conversely, the use of the less
nucleophilic t-BuOH avoided the generation of the related
hydroxy ester, but the reaction outcome, besides being
slower, led to the competitive formation of other non-iden-
tifiable byproducts. After careful fine tuning of the i-PrOH–
H2O ratio and the relative amount of NaOH versus HCl used,
as well as the temperature and the reaction time in each
step, it was possible to almost completely suppress the for-
mation of isopropyl ester 11a (up to 5%), thus facilitating its
separation by column chromatography to give pure lactone
9a.
O
O
2, NaOH, i-PrOH–H2O, μw
NaOH (excess), μw
1
2
Ph
OMe
Ph
O
3
NaBH4, μw
HClaq, μw
9a
1a
Br
4
1
4
O
O
O
2
3
Ph
8a
L3BO
ONa
Ph
OMe
Ph
ONa
COOEt
6a
5a
O
O
Scheme 5 Microwave-assisted one-pot synthesis of α-ylidene δ-lac-
tones 9 from allylic bromides 1
With the adjustment of the reaction parameters for the
one-pot transformation, the microwave-assisted methodol-
ogy was extended to a representative series of aryl-substi-
tuted lactones 9b–j as well as an alkyl analogue 9k (Table
3). Based on the 11 examples listed in Table 3, one can con-
clude that the method is quite general and no considerable
influence of the R group is evidenced. However, the prepa-
ration of alkyl-substituted lactone 9k required a few adjust-
ments in the acid-mediated cyclization due to the preferen-
tial formation of hydroxy acid 12 as a ring-opening byprod-
uct under the original conditions. This difficulty could be
circumvented by raising the concentration of HCl added in
the forth step (6 M instead of 1.5 M), which caused a shift in
the hydroxy acid–lactone equilibrium toward the cyclic
form.
The few cases where the isolated yield did not reach 50%
(Table 3, entries 8–11) could be related to the non-opti-
mized chromatography method applied in the purification
stage, because the crude reaction product was reasonably
pure (by NMR analysis) and the recovered mass was in the
range of 80–90%. Although efforts to optimize the purifica-
tion step were not undertaken, preliminary studies em-
ploying alternative methods of purification, such as recrys-
tallization, led to comparable results, apparently without
the significant formation of ring-opening byproducts
during the process.
Allylic bromide 1a was chosen as the model substrate to
adjust the one-pot conditions to selectively produce δ-lac-
tone 9a under microwave conditions. In fact, initial studies
indicated the presence of two distinct byproducts, 10a and
11a (Scheme 6), together with the expected δ-lactone 9a, as
1
evidenced from analysis of the crude product by H NMR
spectroscopy.
Taking into account that the formation of the carboxyl-
substituted lactone 10a should be related to an incomplete
decarboxylative hydrolysis of the starting allylated inter-
mediate 5a (Scheme 6), this shortcoming was readily by-
passed by simply increasing the temperature, time or
amount of base in the second step, thus allowing the com-
plete conversion of 5a into the keto carboxylate intermedi-
ate 6a.
O
O
O
1. NaBH4
2. HCl
Ph
5a
OMe
Ph
ONa
Ph
OH
NaOH
COOEt
μw
μw
6a
12a
O
O
HO
1. NaBH4, μw
R'OH
2. HCl
μw
9a
μw
R'OH
O
O
O
Ph
OR'
In conclusion, we have developed a fast and efficient
one-pot method for the synthesis of a series of α-ylidene δ-
lactones in aqueous medium, starting from (Z)-2-(bro-
momethyl)-2-alkenoates 1 derived from Morita–Baylis–
Hillman adducts. The key steps involve the regioselective
base-mediated allylation of ethyl acetoacetate with 1,
which allows direct access to the allylated diesters 5. Subse-
quent decarboxylative hydrolysis of the diesters gave the
corresponding keto carboxylates 6 which, after carbonyl re-
duction to 8 followed by acid-mediated lactonization, fur-
nished the corresponding α-ylidene δ-lactones in good iso-
Ph
OMe
Ph
O
COOEt
11a R' = i-Pr
11b R' = Et
10a
COOEt
HO
HO
Scheme 6 Plausible formation of side products 10a and 11a,b
On the other hand, the formation of the hydroxyl ester
byproduct 11a (5–10% according to the H NMR analysis)
under microwave-assisted conditions could be related to
the direct esterification of hydroxy acid intermediate 12a
or to the alcoholysis of the preformed lactone 9a with i-
PrOH, present as the cosolvent. In fact, control reactions in-
1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
M. Ferreira et al.
Paper
Synthesis
Table 3 Microwave-Assisted One-Pot Synthesis of α-Ylidene δ-Lac-
tones 9 from Allylic Bromides 1a
(apparent triplet), q (quartet), sext (sextet), m (multiplet). Coupling
constants (J) are measured in hertz (Hz). Chemical shifts were record-
ed in parts per million (ppm, δ) relative to CDCl3 (at δ = 7.26 ppm for
1H NMR, and at δ = 77.16 ppm for 13C NMR) as the internal standard.
Column chromatography was performed using silica gel (70–230
mesh) and hexane–EtOAc as the eluent. TLC analysis was performed
in silica gel plates. The ESI-QTOF mass spectrometer was operated in
the positive ion mode at 4.5 kV and at a desolvation temperature of
180 °C. The standard electrospray ion (ESI) source was used to gener-
ate the ions. The instrument was calibrated in the range m/z 50–3000
by using a calibration standard (low concentration tuning mix solu-
tion) and data were processed with the aid of computer software. Mi-
crowave-assisted reactions were performed in 10 mL sealed tubes in
a monomode microwave CEM Explorer reactor instrument with in-
frared temperature monitoring and a noninvasive pressure transduc-
er. Allylic bromides 1 were prepared from Morita–Baylis–Hillman ad-
ducts according to the described methods,13a,14 and showed physical
and spectral data that were consistent with their expected structure
and by comparison with reported spectral data.
O
1. 2, NaOH, i-PrOH–H2O, 90 °C, 10 min
O
2. NaOH (excess), 120 °C, 20 min
R
OMe
R
O
3. NaBH4, 90 °C, 10 min
4. HClaq, 120 °C, 10 min
μw (200 W)
Br
1
9
Entry
R
Product
Yield (%)b
1
2
C6H5
9a
9b
9c
9d
9e
9f
53
52
54
58
55
56
62
34
35
41
46
4-MeC6H4
4-ClC6H4
3
4
2-ClC6H4
5
2,4-Cl2C6H3
4-BrC6H4
6
7
2-BrC6H4
9g
9h
9i
8
4-FC6H4
Allylation of β-Ketoester 2; Typical Procedure
9
4-MeOC6H4
3,4-(OCH2O)C6H3
n-Pr
To a stirred solution of ethyl acetoacetate (1.3 mmol) in isopropyl al-
cohol–H2O (2.0 mL, 1:1 v/v) was added NaOH (1.2 mmol) and the
mixture was stirred for 10 min at 25 °C. The solution was transferred
to a round-bottom flask containing (Z)-2-(bromomethyl)-2-alkenoate
1 (1.0 mmol) and the mixture was stirred for 30 min at 25 °C. The fi-
nal mixture was diluted with CH2Cl2 and the organic solution was
washed with H2O, 1 M HCl, and brine, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The resulting resi-
due was purified by column chromatography (hexane–EtOAc, 9:1) to
give the corresponding allylated product 5.
10
11
9j
9k
a For reaction conditions, see the experimental section.
b Isolated yield after column chromatography.
lated yields (50–60%). This four-step transformation could
be readily performed under microwave irradiation in a sin-
gle reaction vessel or, alternatively, in a stepwise manner,
which allowed the isolation and characterization of each in-
termediate involved in the one-pot process.
Ethyl (E)-2-Acetyl-4-carbomethoxy-5-phenylpent-4-enoate (5a)
Yield: 73% (222 mg); pale-yellow oil.
IR (neat): 2984, 2953, 1715, 1634, 1436, 1260, 1097, 773, 700 cm–1
.
The synthetic protocol outlined herein offers efficiency
and simplicity, with the use of a benign alcohol–water me-
dium, the involvement of readily available and inexpensive
chemicals, the production of nearly innocuous byproducts
(water, carbon dioxide, low molecular weight alcohols and
sodium salts), and the requirement of only a single work-up
and chromatography step at the end of the process. Thus, it
should be applicable to the preparation of a wide variety of
α-methylene, α-alkylidene and α-arylidene δ-lactones and
could also be adapted for scaling-up procedures.
1H NMR (200 MHz, CDCl3): δ = 1.13 (t, J = 7.5 Hz, 3 H, CH3), 2.14 (s,
3 H, CH3), 3.07 (dd, J = 6.5, 14.7 Hz, 1 H, CH2), 3.23 (dd, J = 8.0, 14.7 Hz,
1 H, CH2), 3.80 (s, 3 H, OCH3), 3.84 (dd, J = 6.5, 8.0 Hz, 1 H, CH), 3.96
(dq, J = 7.5, 14.5 Hz, 1 H, CH2), 4.12 (dq, J = 7.5, 14.5 Hz, 1 H, CH2),
7.33–7.42 (m, 5 H, CHAr), 7.77 (s, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 25.5 (CH2), 28.8 (CH3), 52.2
(CH3), 58.3 (CH), 61.5 (OCH2), 128.7 (2 × CH), 128.8 (CH), 129.1 (C),
129.2 (2 × CH), 135.0 (C), 141.9 (=CH), 168.1 (C=O), 169.4 (C=O), 202.3
(C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C17H20O5Na: 327.1203; found:
327.1208.
Ethyl (E)-2-Acetyl-4-carbomethoxy-5-(4-methylphenyl)pent-4-
enoate (5b)
All chemicals were of reagent grade and were used as received. Melt-
ing points were determined with a hot-plate apparatus and are un-
corrected. Infrared spectra were acquired with a FTIR spectrometer
(range 4000–400 cm–1) using KBr for solids and film for liquid sam-
ples. Elemental analysis for keto acid 7c was conducted with a CHNS
microanalyzer and the analytical results were within ±0.4% of the
theoretical values. 1H NMR spectra were recorded at 400 MHz or at
200 MHz, and 13C NMR spectra (fully decoupled) were recorded at
100 MHz or at 50 MHz. Splitting patterns are designated as s (singlet),
br s (broad singlet), d (doublet), dd (doublet of doublet), dddd (dou-
blet of doublet of doublet of doublet), dq (doublet of quartet), ddq
(doublet of doublet of quartet), t (triplet), tt (triplet of triplet), app t
Yield: 68% (216 mg); pale-yellow oil.
IR (neat): 2984, 2953, 1715, 1632, 1511, 1436, 1365, 1258, 1095,
814 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.14 (t, J = 7.5 Hz, 3 H, CH3), 2.15 (s,
3 H, CH3), 2.34 (s, 3 H, CH3), 3.08 (dd, J = 6.8, 14.5 Hz, 1 H, CH2), 3.24
(dd, J = 8.0, 14.5 Hz, 1 H, CH2), 3.80–3.87 (m, 4 H, CH+OCH3), 3.92–
4.18 (m, 2 H, CH2), 7.18 (d, J = 8.0 Hz, 2 H, CHAr), 7.29 (d, J = 8.0 Hz,
2 H, CHAr), 7.74 (s, 1 H, =CH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
M. Ferreira et al.
Paper
Synthesis
13C NMR (50 MHz, CDCl3): δ = 13.7 (CH3), 21.1 (CH3), 25.4 (CH2), 28.6
(CH3), 51.8 (OCH3), 58.1 (CH), 61.2 (OCH2), 128.0 (C), 129.1 (2 × CH),
129.2 (2 × CH), 131.9 (C), 138.7 (C), 141.6 (=CH), 168.0 (C=O), 169.2
(C=O), 202.0 (C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H22O5Na: 341.1359; found:
341.1355.
Synthesis of Ketoacids 7; Typical Procedures
From allylated diesters 5: To a stirred suspension of allylated product 5
(1.0 mmol) in isopropyl alcohol–H2O (2.0 mL, 1:1 v/v) was added
NaOH (5.0 mmol) and the mixture was stirred under reflux for 1–
1.5 h. After the final mixture had cooled to r.t., it was diluted with
CH2Cl2 and the organic solution was washed with 0.5 M HCl, H2O and
brine, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The resulting residue was purified by column chro-
matography (hexane–EtOAc, 6:4) to give the corresponding keto acid
7 in 75–85% yield.
Ethyl (E)-2-Acetyl-4-carbomethoxy-5-(4-chlorophenyl)pent-4-
enoate (5c)
Yield: 70% (237 mg); pale-yellow oil.
Two-step synthesis from allylic bromides 1: To a stirred solution of eth-
yl acetoacetate (2.6 mmol) in isopropyl alcohol–H2O (4.0 mL, 1:1 v/v)
was added NaOH (2.4 mmol) and the mixture was stirred for 10 min
at 25 °C. The solution was transferred to a round-bottom flask con-
taining (Z)-2-(bromomethyl)-2-alkenoate 1 (2.0 mmol) and the mix-
ture was stirred for 30 min at 25 °C. Another portion of NaOH (10
mmol) was then added and the resulting mixture was stirred and
heated to reflux for 0.5–1 h. After the final mixture had cooled to r.t.,
it was diluted with CH2Cl2 and the organic solution was washed with
0.5 M HCl, H2O and brine, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The resulting residue was puri-
fied by column chromatography (hexane–EtOAc, 6:4) to give the cor-
responding keto acid 7. The yields below refer to this two-step pro-
cess (overall yields from bromides 1).
IR (neat): 2984, 2953, 1715, 1634, 1593, 1491, 1436, 1256, 1091,
1014, 840 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.16 (t, J = 7.0 Hz, 3 H, CH3), 2.17 (s,
3 H, CH3), 3.03 (dd, J = 6.6, 14.2 Hz, 1 H, CH2), 3.17 (dd, J = 7.6, 14.2 Hz,
1 H, CH2), 3.81 (s, 3 H, OCH3), 3.86 (dd, J = 6.6, 7.6 Hz, CH), 3.94–4.25
(m, 2 H, CH2), 7.35 (br s, 4 H, CHAr), 7.70 (s, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 25.4 (CH2), 28.9 (CH3), 52.2
(CH3), 58.0 (CH), 61.5 (OCH2), 128.8 (2 × CH), 129.6 (C), 130.5 (2 × CH),
133.4 (C), 134.7 (C), 140.4 (=CH), 167.8 (C=O), 169.2 (C=O), 202.0
(C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C17H19ClO5Na: 361.0813; found:
361.0815.
Ethyl (E)-2-Acetyl-4-carbomethoxy-5-(4-methoxyphenyl)pent-4-
enoate (5i)
(E)-2-Benzylidene-5-oxohexanoic Acid (7a)
Yield: 78% (170 mg); white solid; mp 130.5–131.2 °C.
Yield: 78% (261 mg); pale-yellow oil.
IR (KBr): 3398, 2972, 2931, 2900–2500, 1707, 1679, 1621, 1426,
IR (neat): 2982, 2953, 2839, 1715, 1605, 1513, 1438, 1256, 1179,
1281, 1163, 773 cm–1
.
1095, 838 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 3 H, CH3), 2.72–2.77 (m, 2 H,
CH2), 2.81–2.86 (m, 2 H, CH2), 7.34–7.43 (m, 5 H, CHAr), 7.86 (s, 1 H,
=CH).
13C NMR (100 MHz, CDCl3): δ = 21.7 (CH2), 30.0 (CH3), 42.8 (CH2),
128.9 (2 × CH), 129.2 (CH), 129.4 (2 × CH), 130.8 (C), 135.1 (C), 142.5
(=CH), 173.6 (C=O), 207.9 (C=O).
1H NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.2 Hz, 3 H, CH3), 2.15 (s,
3 H, CH3), 3.08 (dd, J = 6.8, 14.4 Hz, 1 H, CH2), 3.22 (dd, J = 8.0, 14.4 Hz,
1 H, CH2), 3.78 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.84 (dd, J = 6.8,
8.0 Hz, 1 H, CH), 4.00 (dq, J = 7.2, 14.4 Hz, 1 H, CH2), 4.08 (dq, J = 7.2,
14.4 Hz, 1 H, CH2), 6.89 (d, J = 8.8 Hz, 2 H, CHAr), 7.36 (d, J = 8.8 Hz,
2 H, CHAr), 7.69 (s, 1 H, =CH).
HRMS (ESI+): m/z [M + Na]+ calcd for C13H14O3Na: 241.0835; found:
241.0836.
13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3), 25.6 (CH2), 29.0 (CH3), 52.1
(CH3), 55.4 (CH3), 58.3 (CH), 61.5 (OCH2), 114.1 (2 × CH), 126.8 (C),
127.4 (C), 131.2 (2 × CH), 141.5 (=CH), 160.1 (C), 168.4 (C=O), 169.5
(C=O), 202.5 (C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H22O6Na: 357.1309; found:
357.1312.
(E)-2-(4-Methylbenzylidene)-5-oxohexanoic Acid (7b)
Yield: 84% (195 mg); pale-yellow solid; mp 131.5–132.5 °C.
IR (KBr): 3398, 2972, 2931, 2900–2500, 1707, 1679, 1621, 1426,
1281, 1163, 774 cm–1
.
Ethyl (E)-2-Acetyl-4-(carbomethoxy)oct-4-enoate (5k)
1H NMR (400 MHz, CDCl3): δ = 2.18 (s, 3 H, CH3), 2.38 (s, 3 H, CH3),
2.71–2.77 (m, 2 H, CH2), 2.81–2.87 (m, 2 H, CH2), 7.22 (d, J = 8.0 Hz,
2 H, CHAr), 7.29 (d, J = 8.0 Hz, 2 H, CHAr), 7.83 (s, 1 H, =CH).
Yield: 80% (216 mg); pale-yellow oil.
IR (neat): 2961, 1717, 1646, 1438, 1285, 1222, 1146, 1077, 759 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 21.7 (CH2), 30.0 (CH3), 42.7
(CH2), 129.6 (4 × CH), 129.8 (C), 132.2 (C), 139.6 (C), 142.5 (=CH),
173.9 (C=O), 208.0 (C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C14H16O3Na: 255.0992; found:
255.0995.
1H NMR (200 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 3 H, CH3), 1.26 (t,
J = 7.2 Hz, 3 H, CH3), 1.35–1.55 (m, 2 H, CH2), 2.20–2.29 (m, 5 H,
CH2+CH3), 2.78 (dd, J = 7.6, 14.2 Hz, 1 H, CH2), 2.88 (dd, J = 6.2,
14.2 Hz, 1 H, CH2), 3.74 (s, 3 H, OCH3), 3.75–3.85 (m, 1 H, CH), 4.16 (q,
J = 7.2 Hz, 2 H, CH2), 6.87 (t, J = 7.4 Hz, 1 H, =CH).
13C NMR (50 MHz, CDCl3): δ = 13.6 (CH3), 13.8 (CH3), 21.8 (CH2), 25.2
(CH2), 29.1 (CH3), 30.4 (CH2), 51.5 (OCH3), 58.0 (CH), 61.1 (OCH2),
127.9 (C), 145.8 (=CH), 167.4 (C=O), 169.1 (C=O), 202.2 (C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C14H22O5Na: 293.1359; found:
293.1357.
(E)-2-(4-Chlorobenzylidene)-5-oxohexanoic Acid (7c)
Yield: 89% (225 mg); white solid; mp 135.2–136.0 °C.
IR (KBr): 3400, 3072, 2955, 2930–2500, 1709, 1681, 1617, 1491, 1422,
1281, 1093, 918, 830 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 3 H, CH3), 2.70–2.74 (m, 2 H,
CH2), 2.78–2.82 (m, 2 H, CH2), 7.31 (d, J = 8.4 Hz, 2 H, CHAr), 7.39 (d,
J = 8.4 Hz, 2 H, CHAr), 7.78 (s, 1 H, =CH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
M. Ferreira et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 21.6 (CH2), 30.0 (CH3), 42.5 (CH2),
129.2 (2 × CH), 130.7 (2 × CH), 131.3 (C), 133.4 (C), 135.2 (C), 141.1
(=CH), 173.1 (C=O), 207.7 (C=O).
transferred to a 10 mL microwave vessel containing (Z)-2-(bro-
momethyl)-2-alkenoate 1 (1.0 mmol). The vessel was sealed with a
septum, placed into the microwave cavity and irradiated (t = 10 min
hold, Tmax = 90 °C).
HRMS (ESI+): m/z [M + Na]+ calcd for C13H13ClO3Na: 275.0445; found:
275.0448.
Step 2: After the mixture had cooled to r.t., NaOH (4.5 mmol) was
added and the mixture was again irradiated (t = 20 min hold,
Tmax = 120 °C).
Anal. Calcd for C13H13ClO3: C, 61.79; H, 5.19. Found: C, 62.07; H, 5.58.
Step 3: After the mixture had cooled to r.t., NaBH4 (1.0 mmol) was
added and the mixture was again irradiated (t = 10 min hold,
Tmax = 90 °C).
(E)-2-(2,4-Dichlorobenzylidene)-5-oxohexanoic Acid (7e)
Yield: 88% (253 mg); white solid; mp 114.0–115.0 °C.
IR (KBr): 3404, 3070, 2957, 2929, 2900–2500, 1709, 1685, 1623, 1585,
Step 4: After the mixture had cooled to r.t., it was acidified with 4.0
mL of 1.5 M HCl (except for the preparation of alkyl-substituted lac-
tone 9k, which required the use of 6 M HCl) and the acidic mixture
was again irradiated (t = 10 min hold, Tmax = 120 °C). Finally, after the
mixture had cooled to r.t., it was diluted with CH2Cl2 and the organic
solution was washed with 0.1 M HCl and brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The resulting resi-
due was purified by column chromatography (hexane–EtOAc, 9:1 to
7:3) to give the corresponding δ-lactone 9.
1468, 1424, 1281, 1171, 1099, 863 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.14 (s, 3 H, CH3), 2.64–2.71 (m, 4 H,
2 × CH2), 7.23–7.33 (m, 2 H, CHAr), 7.45 (s, 1 H, CHAr), 7.83 (s, 1 H,
=CH).
13C NMR (100 MHz, CDCl3): δ = 21.7 (CH2), 29.8 (CH3), 42.4 (CH2),
127.3 (CH), 129.7 (CH), 130.6 (CH), 132.3 (C), 133.4 (C), 134.7 (C),
135.3 (C), 138.6 (=CH), 172.6 (C=O), 207.9 (C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C13H12Cl2O3Na: 309.0056; found:
309.0057.
(E)-3-Benzylidene-6-methyltetrahydropyran-2-one (9a)
Yield: 53% (107 mg); white solid; mp 65.3–66.0 °C (Lit.9a 65.5–
66.0 °C).
(E)-2-(4-Methoxybenzylidene)-5-oxohexanoic Acid (7i)
Yield: 80% (199 mg); pale-yellow solid; mp 103.4–105.0 °C.
IR (KBr): 3402, 3059, 2925, 2841, 2800–2450, 1709, 1672, 1605, 1513,
IR (KBr): 3090, 3053, 3027, 2972, 2927, 2853, 1705, 1609, 1446, 1352,
1260, 1191, 1122, 948, 779 cm–1
.
1430, 1256, 1179, 1026, 828 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.42 (d, J = 6.4 Hz, 3 H, CH3), 1.67
(dddd, J = 5.3, 10.5, 12.0, 14.0 Hz, 1 H, CH2), 2.01 (dddd, J = 2.5, 3.5,
5.7, 14.0 Hz, 1 H, CH2), 2.77 (dddd, J = 3.0, 5.7, 12.0, 16.5 Hz, 1 H, CH2),
2.97 (dddd, J = 1.8, 3.5, 5.3, 16.5 Hz, 1 H, CH2), 4.51 (ddq, J = 2.5, 6.4,
10.5 Hz, 1 H, CH), 7.34–7.46 (m, 5 H, CHAr), 7.92 (app t, J = 2.2 Hz, 1 H,
=CH).
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 25.2 (CH2), 29.7 (CH2), 75.9
(CH), 125.2 (C), 128.6 (2 × CH), 129.2 (CH), 130.2 (2 × CH), 135.1 (C),
141.4 (=CH), 167.3 (C=O).
1H NMR (400 MHz, CDCl3): δ = 2.19 (s, 3 H, CH3), 2.70–2.78 (m, 2 H,
CH2), 2.82–2.88 (m, 2 H, CH2), 3.83 (s, 3 H, OCH3), 6.93 (d, J = 8.8 Hz,
2 H, CHAr), 7.37 (d, J = 8.8 Hz, 2 H, CHAr), 7.79 (s, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 21.6 (CH2), 29.9 (CH3), 42.5 (CH2), 55.4
(OCH3), 114.3 (2 × CH), 127.4 (C), 128.2 (C), 131.5 (2 × CH), 141.9
(=CH), 160.4 (C), 173.9 (C=O), 208.3 (C=O).
HRMS (ESI+): m/z [M + Na]+ calcd for C14H16O4Na: 271.0941; found:
271.0946.
HRMS (ESI+): m/z [M + H]+ calcd for C13H15O2: 203.1067; found:
203.1069.
(E)-2-(But-1-ylidene)-5-oxohexanoic Acid (7k)
Yield: 77% (142 mg); pale-yellow oil.
IR (KBr): 3402, 2961, 2900–2500, 1709, 1683, 1642, 1428, 1285, 1167,
(E)-3-(4-Methylbenzylidene)-6-methyltetrahydropyran-2-one
(9b)
918 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.2 Hz, 3 H, CH3), 1.44–1.54
(m, 2 H, CH2), 2.17 (s, 3 H, CH3), 2.23 (q, J = 7.2 Hz, 2 H, CH2), 2.53–
2.63 (m, 4 H, 2 × CH2), 6.96 (t, J = 7.2 Hz, 1 H, =CH), 10.54 (br s, 1 H,
COOH).
13C NMR (100 MHz, CDCl3): δ = 13.8 (CH3), 20.8 (CH2), 21.9 (CH2), 29.8
(CH3), 30.6 (CH2), 42.7 (CH2), 130.2 (C), 146.6 (=CH), 172.9 (C=O),
208.4 (C=O).
Yield: 52% (113 mg); yellow solid; mp 95.0–96.8 °C.
IR (KBr): 3025, 2980, 2937, 1701, 1603, 1511, 1448, 1391, 1260, 1195,
1120, 820 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.41 (d, J = 6.5 Hz, 3 H, CH3), 1.66
(dddd, J = 5.5, 10.5, 11.7, 14.0 Hz, 1 H, CH2), 1.90–2.10 (m, 1 H, CH2),
2.37 (s, 3 H, CH3), 2.74 (dddd, J = 2.6, 5.6, 11.7, 16.8 Hz, 1 H, CH2), 2.96
(dddd, J = 2.0, 3.3, 5.5, 16.8 Hz, 1 H, CH2), 4.49 (ddq, J = 2.5, 6.5,
10.5 Hz, 1 H, CH), 7.21 (d, J = 8.0 Hz, 2 H, CHAr), 7.35 (d, J = 8.0 Hz, 2 H,
CHAr), 7.88 (br s, 1 H, =CH).
HRMS (ESI+): m/z [M + Na]+ calcd for C10H16O3Na: 207.0992; found:
207.0995.
13C NMR (100 MHz, CDCl3): δ = 21.41 (CH3), 21.45 (CH3), 25.2 (CH2),
29.7 (CH2), 75.7 (CH), 124.1 (C), 129.3 (2 × CH), 130.4 (2 × CH), 132.2
(C), 139.5 (C), 141.4 (=CH), 167.5 (C=O).
Microwave-Assisted One-Pot Synthesis of δ-Lactones 9; Typical
Procedure
The four-step synthesis of δ-lactones 9 from (Z)-2-(bromomethyl)-2-
alkenoates 1 was performed through a one-pot procedure under mi-
crowave irradiation (maximum potency = 200 W, maximum
pressure = 200 psi, t = 2 min ramp, 1 min cooling, stirring mode ‘on’
for all steps). Specific conditions for each step are described below.
HRMS (ESI+): m/z [M + H]+ calcd for C14H17O2: 217.1223; found:
217.1220.
(E)-3-(4-Chlorobenzylidene)-6-methyltetrahydropyran-2-one (9c)
Yield: 54% (128 mg); white solid; mp 69.0–70.0 °C.
Step 1: To a stirred solution of ethyl acetoacetate (1.3 mmol) in iso-
propyl alcohol–H2O (2.0 mL, 1:1 v/v) was added NaOH (1.2 mmol)
and the mixture was stirred for 10 min at 25 °C. The solution was
IR (KBr): 3076, 2976, 2931, 1707, 1617, 1489, 1344, 1256, 1189, 1118,
840 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
M. Ferreira et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.40 (d, J = 6.4 Hz, 3 H, CH3), 1.66
(dddd, J = 5.4, 10.4, 12.0, 14.0 Hz, 1 H, CH2), 2.01 (dddd, J = 2.5, 3.0,
5.6, 14.0 Hz, 1 H, CH2), 2.72 (dddd, J = 2.8, 5.6, 12.0, 17.0 Hz, 1 H, CH2),
2.91 (dddd, J = 2.0, 3.0, 5.4, 17.0 Hz, 1 H, CH2), 4.50 (ddq, J = 2.5, 6.4,
10.4 Hz, 1 H, CH), 7.36 (s, 4 H, CHAr), 7.83 (app t, J = 2.4 Hz, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 25.2 (CH2), 29.7 (CH2), 76.0
(CH), 125.8 (C), 128.9 (2 × CH), 131.5 (2 × CH), 133.5 (C), 135.2 (C),
140.0 (=CH), 167.1 (C=O).
(E)-3-(2-Bromobenzylidene)-6-methyltetrahydropyran-2-one (9g)
Yield: 62% (174 mg); yellow solid; mp 96.0–97.6 °C.
IR (KBr): 3057, 2980, 2925, 1697, 1611, 1436, 1256, 1189, 1118, 1024,
783 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.42 (d, J = 6.0 Hz, 3 H, CH3), 1.50–1.77
(m, 1 H, CH2), 1.97 (dddd, J = 2.6, 3.6, 5.6, 14.0 Hz, 1 H, CH2), 2.57
(dddd, J = 2.8, 5.6, 11.8, 16.6 Hz, 1 H, CH2), 2.76 (dddd, J = 1.8, 3.6, 5.5,
16.6 Hz, 1 H, CH2), 4.52 (ddq, J = 2.6, 6.0, 10.2 Hz, 1 H, CH), 7.15–7.37
(m, 3 H, CHAr), 7.63 (d, J = 7.6 Hz, 1 H, CHAr), 7.95 (app t, J = 2.0 Hz, 1 H,
=CH).
HRMS (ESI+): m/z [M + H]+ calcd for C13H14ClO2: 237.0677; found:
237.0676.
13C NMR (100 MHz, CDCl3): δ = 21.7 (CH3), 24.6 (CH2), 29.9 (CH2), 76.4
(CH), 124.7 (C), 127.2 (CH), 127.6 (C), 130.16 (CH), 130.20 (CH), 133.2
(CH), 135.6 (C), 140.5 (=CH), 166.5 (C=O).
(E)-3-(2-Chlorobenzylidene)-6-methyltetrahydropyran-2-one (9d)
Yield: 58% (137 mg); white solid; mp 102.8–104.6 °C.
HRMS (ESI+): m/z [M + H]+ calcd for C13H14BrO2: 281.0172; found:
281.0175.
IR (KBr): 3055, 2976, 2933, 1701, 1613, 1436, 1256, 1189, 1118,
779 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.42 (d, J = 6.4 Hz, 3 H, CH3), 1.66
(dddd, J = 5.4, 10.5, 12.0, 14.0 Hz, 1 H, CH2), 1.90–2.05 (m, 1 H, CH2),
2.62 (dddd, J = 2.8, 5.4, 12.0, 16.6 Hz, 1 H, CH2), 2.80 (dddd, J = 1.7, 3.7,
5.4, 16.6 Hz, 1 H, CH2), 4.54 (ddq, J = 2.8, 6.4, 10.5 Hz, 1 H, CH), 7.20–
7.50 (m, 4 H, CHAr), 8.02 (app t, J = 2.2 Hz, 1 H, =CH).
13C NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 24.6 (CH2), 29.8 (CH2), 76.3
(CH), 126.5 (CH), 127.7 (C), 129.9 (CH), 130.0 (CH), 130.1 (CH), 133.6
(C), 134.6 (C), 138.1 (=CH), 166.5 (C=O).
(E)-3-(4-Fluorobenzylidene)-6-methyltetrahydropyran-2-one (9h)
Yield: 34% (75 mg); yellow solid; mp 61.5–63.0 °C.
IR (KBr): 3043, 2980, 2933, 1701, 1615, 1599, 1509, 1269, 1228, 1118,
834 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.42 (d, J = 6.4 Hz, 3 H, CH3), 1.68
(dddd, J = 5.2, 10.4, 12.1, 14.1 Hz, 1 H, CH2), 2.02 (dddd, J = 2.8, 3.2,
5.6, 14.1 Hz,1 H, CH2), 2.74 (dddd, J = 2.8, 5.6, 12.1, 16.7 Hz, 1 H, CH2),
2.93 (dddd, J = 2.0, 3.2, 5.2, 16.7 Hz, 1 H, CH2), 4.51 (ddq, J = 2.8, 6.4,
10.4 Hz, 1 H, CH), 7.10 (t, J = 8.4 Hz, 2 H, CHAr), 7.43 (dd, J = 5.2, 8.4 Hz,
2 H, CHAr), 7.87 (br s, 1 H, =CH).
HRMS (ESI+): m/z [M + H]+ calcd for C13H14ClO2: 237.0677; found:
237.0673.
(E)-3-(2,4-Dichlorobenzylidene)-6-methyltetrahydropyran-2-one
(9e)
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 25.2 (CH2), 29.8 (CH2), 75.9
(CH), 115.8 (d, J = 22.0 Hz, 2 × CH), 125.0 (C), 131.4 (d, J = 3.0 Hz, C),
132.3 (d, J = 7.3 Hz, 2 × CH), 140.2 (=CH), 163.0 (d, J = 249.4 Hz, C),
167.2 (C=O).
Yield: 55% (149 mg); white solid; mp 122.0–124.0 °C.
IR (KBr): 3088, 2982, 2927, 2904, 1699, 1621, 1585, 1471, 1385, 1271,
1195, 1124, 826 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C13H14FO2: 221.0972; found:
1H NMR (200 MHz, CDCl3): δ = 1.41 (d, J = 6.6 Hz, 3 H, CH3), 1.55–1.77
(m, 1 H, CH2), 1.90–2.05 (m, 1 H, CH2), 2.58 (dddd, J = 3.0, 5.3, 11.6,
16.5 Hz, 1 H, CH2), 2.75 (dddd, J = 1.5, 3.5, 5.5, 16.5 Hz, 1 H, CH2), 4.52
(ddq, J = 2.5, 6.6, 10.2 Hz, 1 H, CH), 7.21–7.30 (m, 2 H, CHAr), 7.45 (br s,
1 H, CHAr), 7.94 (app t, J = 2.2 Hz, 1 H, =CH).
221.0975.
(E)-3-(4-Methoxybenzylidene)-6-methyltetrahydropyran-2-one
(9i)
Yield: 35% (81 mg); yellow solid; mp 105.5–106.3 °C.
13C NMR (100 MHz, CDCl3): δ = 21.6 (CH3), 24.7 (CH2), 29.8 (CH2), 76.4
(CH), 127.0 (CH), 128.3 (C), 129.9 (CH), 130.9 (CH), 132.1 (C), 135.3
(C), 135.5 (C), 136.9 (=CH), 166.2 (C=O).
HRMS (ESI+): m/z [M + H]+ calcd for C13H13Cl2O2: 271.0287; found:
271.0289.
IR (KBr): 3080, 3029, 2972, 2925, 2855, 1699, 1599, 1509, 1271, 1175,
1132, 1022, 842 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.40 (d, J = 6.0 Hz, 3 H, CH3), 1.66
(dddd, J = 5.2, 10.5, 12.0, 13.6 Hz, 1 H, CH2), 2.00 (dddd, J = 2.2, 3.2,
5.5, 13.6 Hz, 1 H, CH2), 2.74 (dddd, J = 2.8, 5.5, 12.0, 16.8 Hz, 1 H, CH2),
2.94 (dddd, J = 1.8, 3.2, 5.2, 16.8 Hz, 1 H, CH2), 3.82 (s, 3 H, OCH3), 4.47
(ddq, J = 2.2, 6.0, 10.5 Hz, 1 H, CH), 6.92 (d, J = 8.8 Hz, 2 H, CHAr), 7.41
(d, J = 8.8 Hz, 2 H, CHAr), 7.85 (app t, J = 2.0 Hz, 1 H, =CH).
(E)-3-(4-Bromobenzylidene)-6-methyltetrahydropyran-2-one (9f)
Yield: 56% (157 mg); white solid; mp 101.5–103.0 °C.
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 25.3 (CH2), 29.8 (CH2), 55.4
(OCH3), 75.7 (CH), 114.1 (2 × CH), 122.6 (C), 127.9 (C), 132.3 (2 × CH),
141.2 (=CH), 160.4 (C), 167.8 (C=O).
HRMS (ESI+): m/z [M + H]+ calcd for C14H17O3: 233.1172; found:
233.1175.
IR (KBr): 3082, 2976, 2947, 2923, 2851, 1705, 1611, 1581, 1485, 1348,
1260, 1189, 1116, 814 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.42 (d, J = 6.4 Hz, 3 H, CH3), 1.55–1.80
(m, 1 H, CH2), 1.95–2.10 (m, 1 H, CH2), 2.72 (dddd, J = 3.0, 5.6, 11.5,
16.7 Hz, 1 H, CH2), 2.92 (dddd, J = 2.0, 3.6, 5.5, 16.7 Hz, 1 H, CH2), 4.51
(ddq, J = 2.8, 6.4, 10.2 Hz, 1 H, CH), 7.30 (d, J = 8.5 Hz, 2 H, CHAr), 7.54
(d, J = 8.5 Hz, 2 H, CHAr), 7.83 (br s, 1 H, =CH).
(E)-3-(3,4-Methylenedioxybenzylidene)-6-methyltetrahydropy-
ran-2-one (9j)
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 25.2 (CH2), 29.7 (CH2), 76.0
(CH), 123.5 (C), 125.9 (C), 131.7 (2 × CH), 131.9 (2 × CH), 133.9 (C),
140.0 (=CH), 167.0 (C=O).
Yield: 41% (101 mg); yellow solid; mp 127.3–128.6 °C.
IR (KBr): 3076, 2976, 2929, 1697, 1609, 1591, 1499, 1271, 1238, 1193,
1095, 1032, 830 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C13H14BrO2: 281.0172; found:
281.0169.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
M. Ferreira et al.
Paper
Synthesis
1H NMR (200 MHz, CDCl3): δ = 1.41 (d, J = 6.1 Hz, 3 H, CH3), 1.55–1.80
(m, 1 H, CH2), 2.02 (dddd, J = 2.3, 3.5, 5.5, 14.2 Hz, 1 H, CH2), 2.73
(dddd, J = 2.8, 5.5, 11.7, 16.8 Hz, 1 H, CH2), 2.95 (dddd, J = 2.0, 3.5, 5.6,
16.8 Hz, 1 H, CH2), 4.48 (ddq, J = 2.3, 6.1, 10.4 Hz, 1 H, CH), 6.00 (s,
2 H, CH2), 6.83–7.00 (m, 3 H, CHAr), 7.82 (app t, J = 2.1 Hz, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 25.3 (CH2), 29.8 (CH2), 75.6
(CH), 101.6 (CH2), 108.6 (CHAr), 109.9 (CHAr), 123.3 (C), 126.0 (CHAr),
129.4 (C), 141.2 (=CH), 148.0 (C), 148.6 (C), 167.5 (C=O).
(4) (a) Zhao, W.; Chen, F.-E. Curr. Org. Synth. 2012, 9, 873.
(b) Climent, M. J.; Corma, A.; Iborra, S. Chem. Rev. 2011, 111,
1072. (c) Broadwater, S. J.; Roth, S. L.; Price, K. E.; Kobaslija, M.;
McQuade, D. T. Org. Biomol. Chem. 2005, 3, 2899.
(5) Albrecht, A.; Albrecht, Ł.; Janecki, T. Eur. J. Org. Chem. 2011,
2747.
(6) (a) Kupchan, S. M.; Hemingway, R. J.; Werner, D.; Karim, A.;
McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1968, 90, 3596.
(b) Dehal, S. S.; Marples, B. A.; Stretton, R. J.; Traynor, J. R. J. Med.
Chem. 1980, 23, 90. (c) Chagonda, L. S.; Lockey, P. M.; Marples, B.
A.; Traynor, J. R. Steroids 1984, 43, 283. (d) McMurry, J. E.;
Dushin, R. G. J. Am. Chem. Soc. 1990, 112, 6942. (e) Acton, N.;
Karle, J. M.; Miller, R. E. J. Med. Chem. 1993, 36, 2552.
(f) Heilmann, J.; Wasescha, M. R.; Schmidt, T. J. Bioorg. Med.
Chem. 2001, 9, 2189.
HRMS (ESI+): m/z [M + H]+ calcd for C14H15O4: 247.0965; found:
247.0965.
(E)-3-(But-1-ylidene)-6-methyltetrahydropyran-2-one (9k)
Yield: 46% (77 mg); pale-yellow oil.
IR (KBr): 2962, 2933, 1715, 1636, 1448, 1387, 1275, 1087, 940 cm–1
.
(7) (a) Albrecht, L.; Wojciechowski, J.; Albrecht, A.; Wolf, W. M.;
Janecka, A.; Studzian, K.; Krajewska, U.; Rózalski, M.; Janecki, T.;
Krawczyk, H. Eur. J. Med. Chem. 2010, 45, 710. (b) Modranka, J.;
Albrecht, A.; Janecki, T. Synlett 2010, 2867. (c) Janecki, T.;
Wasek, T. Tetrahedron 2004, 60, 1049. (d) Albrecht, L.; Richter,
B.; Krawczyk, H.; Jørgensen, K. A. J. Org. Chem. 2008, 73, 8337.
(e) Krawczyk, H.; Albrecht, L.; Wojciechowski, J.; Wolf, W. M.
Tetrahedron 2007, 63, 12583. (f) Krawczyk, H.; Sliwinski, M.;
Kedzia, J.; Wojciechowski, J.; Wolf, W. M. Tetrahedron: Asymme-
try 2007, 18, 2712. (g) Krawczyk, H.; Sliwinski, M.; Kedzia, J.;
Wojciechowski, J.; Wolf, W. M. Tetrahedron: Asymmetry 2006,
17, 908. (h) Krawczyk, H.; Sliwinski, M.; Kedzia, J. Tetrahedron:
Asymmetry 2006, 17, 2817. (i) Krawczyk, H.; Sliwinski, M. Tetra-
hedron 2003, 59, 9199.
1H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H, CH3), 1.37 (d, J =
6.4 Hz, 3 H, CH3), 1.49 (sext, J = 7.4 Hz, 2 H, CH2), 1.62 (dddd, J = 5.6,
10.4, 12.3, 14.0 Hz, 1 H, CH), 1.96 (dddd, J = 2.4, 3.2, 5.6, 14.0 Hz, 1 H,
CH), 2.08–2.15 (m, 2 H, CH2), 2.33–2.43 (m, 1 H, CH), 2.57–2.64 (m,
1 H, CH), 4.38 (ddq, J = 2.4, 6.4, 10.4 Hz, 1 H, CH), 7.04 (tt, J = 2.4,
7.4 Hz, 1 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3), 21.5 (CH3), 21.6 (CH2), 23.0
(CH2), 29.5 (CH2), 30.5 (CH2), 75.7 (CH), 125.0 (C), 146.3 (=CH), 167.1
(C=O).
HRMS (ESI+): m/z [M + H]+ calcd for C10H17O2: 169.1223; found:
169.1226.
(8) (a) Gupta, A.; Vankar, Y. D. Tetrahedron 2000, 56, 8525.
(b) Krishna, P. R.; Kannan, V.; Sharma, G. V. M. J. Org. Chem.
2004, 69, 6467. (c) Leroy, B. Tetrahedron Lett. 2005, 46, 7563.
(9) (a) Matsuda, I. J. Organomet. Chem. 1987, 321, 307.
(b) Basavaiah, D.; Satyanarayana, T. Org. Lett. 2001, 3, 3619.
(c) Kim, S. J.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48,
1069. (d) Mandal, S. K.; Paira, M.; Roy, S. C. J. Org. Chem. 2008,
73, 3823. (e) Ramachandran, P. V.; Bhattacharyya, A. Heterocy-
cles 2010, 80, 863. (f) Ramachandran, P. V.; Pratihar, D.; Garner,
G.; Raju, B. C. Tetrahedron Lett. 2011, 52, 4985.
Acknowledgment
The authors wish to thank the Central de Análises (Departamento de
Química, UFSC, Florianópolis) for spectroscopic analysis. Special
thanks to CEBIME (Laboratório Central de Biologia Molecular e Estru-
tural) for providing the mass spectra. M.F., H.P.C., and T.V.C.R. thank
CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológi-
co) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior) for fellowships. M.M.S. and A.J.B. are grateful to CNPq for re-
search fellowships. Financial support from INCT-Catalysis/CNPq (Bra-
zilian Research Council) is also gratefully acknowledged.
(10) Singh, V.; Batra, S. Synthesis 2006, 63.
(11) (a) Ameer, F.; Drewes, S. E.; Emslie, N. D.; Kaye, P. T.; Mann, R. L.
J. Chem. Soc., Perkin Trans. 1 1983, 2293. (b) Gowrisankar, S.;
Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 6241.
(c) Kim, K. H.; Lim, J. W.; Lee, J.; Go, M. J.; Kim, J. N. Adv. Synth.
Catal. 2014, 356, 3363.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588078.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(12) Recent reviews on Morita–Baylis–Hillman reaction and syn-
thetic applications: (a) Basavaiah, D.; Veeraraghavaiah, G. Chem.
Soc. Rev. 2012, 41, 68. (b) Basavaiah, D.; Reddy, B. S.; Badsara, S.
S. Chem. Rev. 2010, 110, 5447. (c) Declerck, V.; Martinez, J.;
Lamaty, F. Chem. Rev. 2009, 109, 1.
References
(1) (a) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437. (b) Anastas, P.
T. Tetrahedron 2010, 66, 1026. (c) Tucker, J. L. Org. Process Res.
Dev. 2010, 14, 328. (d) Bryan, M. C.; Dillon, B.; Hamann, L. G.;
Hughes, G. J.; Kopach, M. E.; Peterson, E. A.; Pourashraf, M.;
Raheem, I.; Richardson, P.; Richter, D.; Sneddon, H. F. J. Med.
Chem. 2013, 56, 6007.
(2) (a) Kappe, C. O.; Dallinger, D. Mol. Diversity 2009, 13, 71.
(b) Baig, R. B. N.; Varma, R. S. Chem. Soc. Rev. 2012, 41, 1559.
(3) (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563.
(b) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629.
(13) (a) Ferreira, M.; Sá, M. M. Adv. Synth. Catal. 2015, 357, 829.
(b) Ferreira, M.; Assunção, L. S.; Filippin-Monteiro, F. B.;
Creczynski-Pasa, T. B.; Sá, M. M. Eur. J. Med. Chem. 2013, 70, 411.
(c) Sá, M. M.; Ferreira, M.; Caramori, G. F.; Zaramello, L.;
Bortoluzzi, A. J.; Faggion, D. Jr.; Domingos, J. B. Eur. J. Org. Chem.
2013, 5180. (d) Sá, M. M.; Meier, L. Heteroat. Chem. 2013, 24,
384. (e) Silveira, G. P.; Ferreira, M.; Fernandes, L.; Moraski, G. C.;
Cho, S.; Hwang, C.; Franzblau, S. G.; Sá, M. M. Bioorg. Med. Chem.
Lett. 2012, 22, 6486.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
M. Ferreira et al.
Paper
Synthesis
(14) (a) Ferreira, M.; Fernandes, L.; Sá, M. M. J. Braz. Chem. Soc. 2009,
20, 564. (b) Meier, L.; Ferreira, M.; Sá, M. M. Heteroat. Chem.
2012, 23, 179. (c) Sá, M. M.; Ferreira, M.; Lima, E. S.; Santos, I.;
Orlandi, P. P.; Fernandes, L. Braz. J. Microbiol. 2014, 45, 807.
(15) CCDC 1484394 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J