Sequential one-pot method for oxy-Michael addition, Heck coupling, and degradation followed by condensation: Facile synthesis of 2-benzoxepin-3(1H)- ones Dedicated to the memory of my teacher Professor P.V. Subba Rao, Department of Chemistry, Andhra University, Visakhapatnam

Article abstract of DOI:10.1016/j.tet.2013.09.050

A sequential one-pot intermolecular oxy-Michael addition, intermolecular Heck coupling, and intramolecular degradation (retro-oxy-Michael addition) followed by condensation method has been developed for the synthesis of interesting 2-benzoxepin-3(1H)-ones. Significantly, the 2-benzoxepin-3(1H)-ones form the core quantum of biologically vital natural products. The initial oxy-Michael addition and Heck coupling steps involve a straight forward construction of C-O and C-C bonds, whereas, the final condensation step follows a novel mechanistic path via intramolecular degradation, double bond isomerization, and intramolecular condensation. Notably, a remarkable solvent effect has been observed in-order to promote the final intramolecular condensation.

Full text of DOI:10.1016/j.tet.2013.09.050

Tetrahedron 69 (2013) 10098e10107
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sequential one-pot method for oxy-Michael addition, Heck coupling,
and degradation followed by condensation: facile synthesis of
2-benzoxepin-3(1H)-ones
*
A. Gopi Krishna Reddy, J. Krishna, G. Satyanarayana
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram, Medak District,
502 205 Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 March 2013
Received in revised form 13 September 2013
Accepted 17 September 2013
Available online 24 September 2013
A sequential one-pot intermolecular oxy-Michael addition, intermolecular Heck coupling, and intra-
molecular degradation (retro-oxy-Michael addition) followed by condensation method has been de-
veloped for the synthesis of interesting 2-benzoxepin-3(1H)-ones. Significantly, the 2-benzoxepin-3(1H)-
ones form the core quantum of biologically vital natural products. The initial oxy-Michael addition and
Heck coupling steps involve a straight forward construction of CeO and CeC bonds, whereas, the final
condensation step follows a novel mechanistic path via intramolecular degradation, double bond
isomerization, and intramolecular condensation. Notably, a remarkable solvent effect has been observed
in-order to promote the final intramolecular condensation.
Dedicated to the memory of my teacher
Professor P.V. Subba Rao, Department of
Chemistry, Andhra University,
Visakhapatnam
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Oxy-Michael addition
Heck coupling
Pd-catalysis
retro-Oxy-Michael addition
Condensation
2-Benzoxepin-3(1H)-ones
1. Introduction
Among them, the Heck type of reaction is of particular importance,
especially the Pd-catalyzed domino Heck reactions are well doc-
Synthetic practices like one-pot/sequential one-pot are treated as
the most useful techniques/methods for synthesizing organic com-
pounds as they do not involve the intermediate isolation.1 These one-
pot processes involve multiple reactions to be catalyzed sequentially
by a metal complex or sequential addition of reagents to drive a set of
reactions.2 Such processes can be categorized as pseudo domino
strategies, cascade reactions,3 and tandem catalysis and they are
advantageous over the conventional methods, like in, less waste
generation, saving time, energy, resources, and eventually resulting
in more efficiency.4 Also, it has been noticed that, generally, the
overall yields of one-pot processes are higher than those obtained
from the corresponding step-wise reactions. Therefore, one-pot
processes that involve construction of multiple bonds, particularly
cyclic structures are of utmost importance, as this form the significant
core/part-structures in many biologically active natural products.
The transition metal mediated one-pot methods have gained
much recognition lately, because of their procedural advantages.5,6
umented.1g,7e9 Though reports on Heck coupling followed by a con-
sequent cyclization (e.g., Michael addition) are limited. Pd-catalyzed
HeckeMichael,11 Heck-aza-Michael,12 and Heck-aldol condensation
are some of the notable reactions in one-pot processes. Since most of
the Pd-catalyzed reactions administer a base; it is advantageous to
perform such one-pot processes where both base and palladium
would involve individually and affect each reaction of the proc-
ess.10e12 As continuation of our contemporary interest in the de-
velopment of synthetic methods by palladium-catalysis,13 recently
we reported a sequential one-pot intermolecular oxy-Michael ad-
dition and subsequent intermolecular Heck reaction with the Mi-
chael acceptor for the synthesis of functionalized cinnamates.14
Herein, we report a successful application involving a sequential
one-pot intermolecular oxy-Michael addition, subsequent in-
termolecular Heck coupling with the Michael acceptor followed by
intramolecular lactonization for the synthesis of 2-benzoxepin-
3(1H)-ones. Most significantly, the 2-benzoxepin-3(1H)-ones are not
only present as major skeletal structure in antibiotics xylarinol (A)
and xylarinol (B),15 but also as the part structure of new tyrosine
kinase (p56lck) inhibitor ulocladol16 and cytotoxic alterlactone17
* Corresponding author. Tel.: þ91 (40) 2301 6054; fax: þ91 (40) 2301 6032;
e-mail address: gvsatya@iith.ac.in (G. Satyanarayana).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.050

A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
10099
intermediate followed by Pd-catalyzed transformation to B is jus-
tified based on the reaction of a strong base with the diester 2ag
at low temperature, which has yielded alcohol enoate 3ag as shown
in Scheme 3 (this reaction of the diester 2ag with strong base has
Scheme 3. Degradation of 2ag to 3ag via retro-oxy-Michael addition.
been suggested by one of the reviewer to observe the possible
formation of five membered cyclic ether via intramolecular
cyclization).
Fig. 1. 2-Benzoxepin-3(1H)-one is present as core/part-structure of natural products.
Nevertheless, this interesting observation inspired us to explore
different conditions promoted by base, for intramolecular cycliza-
tions for the formation of isobenzofuran cyclic systems.19 Since the
alcohol enoate 3ag was the exclusive product in the presence of
strong base NaHMDS at the low temperature range (Scheme 3,
Table 1, entry 1), the diester 2ag was treated with the same base but
at 50 ꢀC in order to form isobenzofuran via an intramolecular oxy-
Michael addition. However, the reaction was found to be unclear
under these conditions (Table 1, entry 2). The diester 2ag was
subjected for the same kind of degradation under previous condi-
tions14 with base Cs2CO3 at 80 ꢀC in toluene in order to check the
stability of the diester 2ag. As expected, there was no progress in
the reaction with base Cs2CO3 at 80 ꢀC (Table 1 entry 3), which is
obvious otherwise the diester 2ag would not have been yielded
at all in our previous report. We thought that the temperature
change might activate the diester towards degradation (retro-oxy-
Michael addition) followed by cyclization under the same condi-
tions. As expected, it gave the cyclic ether 4ag albeit in poor yield
along with the unexpected lactenone 5ag (Table 1, entry 4). The
possible reaction mechanism for the formation of 5ag is described
in Scheme 4. Fortunately, changing the solvent proved beneficial
to generate exclusively the lactenone product 5ag, in good yield
(Table 1, entries 5 & 6).
(Fig.1). Moreover, analogues of 2-benzoxepin-3(1H)-ones have been
identified to exhibit good analgesic activities.18
2. Results and discussion
In our initial studies we have come across with an interesting
observation that the bromoester A in the presence of Pd-catalyst
and a base gave back the very first starting material benzalde-
hyde B as depicted in Scheme 1. This interesting reaction takes
Scheme 1. Oxidative degradation of A to B under Pd-catalysis.
place particularly in the presence of polar solvents, such as DMF
and CH3CN (for details see Ref. 14). The formation of B can be jus-
tified via base triggering retro-oxy-Michael addition on bromoester
A to set-up an equilibration with the starting ortho-bromobenzyl
alcohol C, which in turn in the presence of Pd-catalyst turned back
to the very first starting material benzaldehyde B as depicted
in Scheme 2.13c The formation of benzyl alcohol
C as an
After successful formation of interesting cyclic ester 5ag by
performing the reaction on an isolated diester 2ag, we aimed to
make the method more efficient by synthesizing target lactenone
5 in a sequential one-pot fashion by directly starting from ortho-
bromobenzyl alcohols 1 [i.e., a sequential one-pot intermolecular
oxy-Michael addition, intermolecular Heck coupling, and intra-
molecular degradation (retro-oxy-Michael addition) followed by
condensation]. Toluene, reported as suitable solvent for oxy-
Michael addition and subsequent Heck coupling,14 however, was
not suitable for the final cyclization. Instead, DMF was observed
to be an ideal solvent for the cyclization to give the lactenone
5ag (entries 5 & 6, Table 1) while it impedes the formation of
diester 2ag.14 Therefore, we decided to play safe in a way by
Scheme 2. Plausible routes for the oxidative degradation of A to B.
Table 1
Screening reaction conditions for the synthesis of 5ag starting from 2ag
Entry
Base [2 equiv]
Solvent [2 mL]
Temp [ꢀC]
Time [h]
Yield 3ag [%]a
Yield 4ag [%]a
Yield 5ag [%]a
1
2
3
4
5
6
NaHMDS
NaHMDS
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
toluene
toluene
toluene
toluene
DMF
ꢁ78 to ꢁ10
12
12
48
24
12
24
69
0
0
0
0
0
0
0
16
0
0
0
0
0
23
77
78
50
80
120
120
80
DMF
0
a
Yields of chromatographically isolated pure products.

10100
A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
Table 1), the final cyclization was also performed at the same
temperature after addition of DMF to the diester 2. Delightfully, the
reaction was successful and furnished cyclic lactenone in moderate
yields (Table 2). Though the yield is moderate, but the overall yield
is still in an acceptable range after three individual transformations
(i.e., each individual step approximately accounts for 75%), since
such systems have been achieved in not less than three individual
transformations. It is noteworthy that, when the reaction carried
out on the 2-bromobenzyl alcohol 1g, in a mixture of solvents, such
as DMF and toluene (1:1 mixture), the initial Michael addition
followed by Heck coupling itself was found unclear along with the
formation of unwanted degradative aldehyde B (8%). Indeed, this is
in good agreement to that of our previous results reported for the
synthesis of diesters where DMF was not a suitable solvent.14
Since it was well established that the sequential one-pot
method was quite successful to produce the diester 2 in excellent
yields with the bulky tertiarybutyl acrylate as the Michael acceptor,
we anticipated the subsequent intramolecular cyclization in se-
quential one-pot would also be amenable to give the lactenone 5 in
the similar fashion. However, under optimized conditions, in
Scheme 4. Formation of lactenone 5ag from isolated retro-Michael precursors 3ag and
3bg.
choosing toluene as the first solvent up-to the formation of diester
2 and then DMF as the second solvent system to promote the final
cyclization of the diester 2 to yield the lactenone 5. Since, the lac-
tenone 5ag formation was initiated at 120 ꢀC in toluene (entry 4,
Table 2
Sequential one-pot formation of lactenones 5aaeah starting from ortho-bromobenzyl alcohols 1aeh
Yields of chromatographically isolated pure products.

A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
10101
sequential one-pot, the reaction was unaffected and led to isolation
of the diester 2bg. While, the reaction on isolated diester 2bg,
particularly, at slightly higher temperature, was also unable to
produce the lactenone 5ag as an exclusive product, rather un-
expectedly furnished three possible products (Table 3). This can be
to give 2ag, the base may trigger retro-oxy-Michael addition (E2-
elimination) of 2ag and an intramolecular oxy-Michael addition of
the resulted alkoxide would lead to cyclic enolate H. Now, the cyclic
enolate H can equilibrate back to acyclic alkoxide I through possible
E
to Z-isomerization of cinnamate double bond. Finally, an
Table 3
Screening reaction conditions, for the synthesis of 5ag starting from 2bg
Entry
Base [equiv]
Solvent [mL]
Temp [ꢀC]
Time [h]
Recovery of 2bg [%]
Yield 3bg [%]a
Yield 4bg [%]a
Yield 5ag [%]a
1
2
3
4
Cs2CO3 [2]
Cs2CO3 [2]
Cs2CO3 [3]
Cs2CO3 [3]
Cs2CO3 [3]
Cs2CO3 [3]
Cs2CO3 [1.5]
Cs2CO3 [3]
Cs2CO3 [3]
NaHMDS [4]
toluene [2]
toluene [2]
DMF [2]
CH3CN [3]
DMF [2]
DMF [2]
xylene [2]
DMA [2]
80
100
80
48
48
24
24
3
48
48
12
12
12
93
83
d
0
0
0
0
0
0
9b
0
28
20
23
d
24
0
18b
16
40b
73
10
0
80
d
5
140
120
130
160
160
50
d
15b
d
0
0
0
6
d
7c
8
30
dd
dd
dd
9
10
DMSO [2]
toluene [2]
0
0
0
0
0
a
Yields of chromatographically isolated pure products.
Yields of the products based on 1H NMR.
Yields based on the recovery of the starting material (30%).
Reaction was not clean.
b
c
d
explained as, it might release of strong base CsOtBu, after the for-
mation of lactenone 5ag, might revert back the cyclic ether 4bg
intermediate to the acyclic alcohol enoate 3bg. In an alternative
way, it may be due to the bulky tertiarybutyl group might impede
final cyclization, after initial cyclization and ring opening through
the isomerization of the double bond. Delightfully, longer reaction
times in DMF forced the reaction to furnish 5ag as an exclusive
product in good yield (entry 6, Table 3).
Table 4
Step-wise conversion of diesters 2 to lactenones 5
Nevertheless, these step-wise optimized conditions (entry 6,
Table 3), particularly in case of ditertiarybutyl diester 2bg, failed to
furnish the lactenone 5ag, when applied to the optimized se-
quential one-pot method as in the case of diethyl diesters 2 (Table
2). Similar problem has been encountered with the diethyl/diter-
tiarybutyl diesters 2aj, 2ak, 2bi, and 2bl; those have been origi-
nated from the corresponding secondary alcohols 2iel. Therefore,
separate base induced (entry 6, Table 3) cyclization was applied to
these diesters (2aj, 2ak, 2bi, and 2bl). As a result, the corresponding
lactenones 5 have been obtained in fair yields (Table 4). However,
the reaction of diester 2bm with electron withdrawing group on
the aromatic ring was found unclear.
On the other hand, in order to well understand the reaction
mechanism for the lactenones formation 5, we have separately
treated the isolated alcohol esters 3ag & 3bg for cyclization. In
parallel to our expectation, the lactenone 5ag was obtained in good
yields (Scheme 4).
To further confirm the path of the reaction, it was also per-
formed on the isolated cyclic ether 4ag (i.e., employed the reaction
conditions of entry 4 in Table 1). Similarly, the reaction furnished
cyclic lactenone 5ag (Scheme 5).
Also, 2bg was subjected to base mediated cyclization (Table 3,
entry 3). And when the isolated cyclic ether 4bg (i.e., employed the
reaction conditions of entry 3 in Table 3) and an inseparable mix-
ture of 3bg & 5ag were separately treated with the base under the
same reaction conditions, gave the lactenone 5ag as expected
(Scheme 6).
Based on the above studies, the possible reaction mechanism for
the formation of 5ag from 2ag is as depicted in Scheme 7. After the
formation of oxy-Michael product A and subsequent Heck coupling
Yields of chromatographically isolated pure products.
Unclear reaction that niether yield any product nor the recovery of 2bm.

10102
A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
Fig. 2. X-ray crystal structure of 5ac. Thermal ellipsoids are drawn at 50% probability
level.20
Scheme 5. Conversion of isolated cyclic ether 4ag to the lactenone 5ag.
ones via an intermolecular oxy-Michael addition, intermolecular
Heck coupling, and intramolecular degradation (retro-oxy-Michael
addition) followed by condensation. Notably, a remarkable solvent
effect has been observed in-order to promote the final intra-
molecular degradation followed by condensation. Initial two steps
involve a straight forward construction of CeO and CeC bonds,
whereas the final cyclization involves a novel base promoted
intramolecular degradation, double bond isomerization and con-
densation mechanistic path.
4. Experimental section
4.1. General
IR spectra were recorded on a Bruker Tensor 37 (FTIR) spectro-
photometer. 1H NMR spectra were recorded on Bruker Avance 400
(400 MHz) spectrometer at 295 K in CDCl3; chemical shifts (d in
parts per million) and coupling constants (J in Hertz) are reported
in standard fashion with reference to either internal standard tet-
dH¼7.25 ppm). 13
C
Scheme 6. Transformation of isolated cyclic ether 4bg to the lactenone 5ag.
ramethylsilane (TMS) (dH¼0.00 ppm) or CHCl3
(
NMR spectra were recorded on Bruker Avance 400 (100 MHz)
spectrometer at rt in CDCl3; chemical shifts (d in ppm) are reported
relative to CHCl3 [dC¼77.00 ppm (central line of triplet)]. In the 13
C
NMR, the nature of carbons (C, CH, CH2 and CH3) was determined
by recording the DEPT-135 spectra, and is given in parentheses and
noted as s¼singlet (for C), d¼doublet (for CH), t¼triplet (for CH2),
and q¼quartet (for CH3). In the 1H NMR, the following abbrevia-
tions were used throughout: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, qui¼quintet, m¼multiplet, and br s¼broad singlet. The
assignment of signals was confirmed by 1H, 13C CPD, and DEPT
spectra. High-resolution mass spectra (HR-MS) were recorded on
an Agilent 6538 UHD Q-TOF using multimode source. All small scale
dry reactions were carried out using Schlenk tube technique. Re-
actions were monitored by TLC on silica gel using a mixture of
petroleum ether and ethyl acetate as eluents. Reactions were gen-
erally run under an argon or nitrogen atmosphere. Solvents, pe-
troleum ether, ethyl acetate, and dichloromethane were distilled
prior use. Petroleum ether with a boiling range of 60e80 ꢀC was
used. Diethyl ether and toluene were dried over benzophenone/
sodium. DMF was dried over calcium hydride. 2-Bromo benzalde-
hyde and other aromatic aldehydes were purchased from local
commercial sources and used as received. Acme’s silica gel
(60e120 mesh) was used for column chromatography (approxi-
mately 20 g per one gram of crude material).
Scheme 7. Plausible mechanistic path for the conversion of 2ag into 5ag.
intramolecular degradation followed by condensation yields lac-
tenone 5ag.
In addition to the NMR spectroscopic structural elucidation, the
structure of lactenone 5 was further unambiguously confirmed by
single crystal X-ray diffraction analysis on 5ac (Fig. 2).
4.2. General procedure-1 (for the sequential one-pot
reaction)
3. Conclusion
In an oven dried Schlenk tube, were added alcohol 1 (100.0 mg,
0.31e0.53 mmol), ethyl acrylate [155.1e265.3 mg, (i.e., 1.55e2.65
mmol)], and Cs2CO3 [303.0e518.0 mg, (i.e., 0.93e1.59 mmol)] fol-
lowed by the addition of toluene (2 mL) at rt under nitrogen
In summary, we have developed a novel sequential one-pot
method for the synthesis of functionalized 2-benzoxepin-3(1H)-

A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
10103
atmosphere. The resulted reaction mixture was stirred at 50 ꢀC in
an oil bath for 48 h. After the completion of Michael addition
(monitored by TLC) and to the cooled reaction mixture at rt, were
added Pd(OAc)2 (6.9e11.9 mg, 10 mol %) and PPh3 (16.3e27.8 mg,
20 mol %) under nitrogen atmosphere. The reaction mixture was
then heated at 80 ꢀC in an oil bath for 24 h. Once after formation
intermolecular Heck coupling product, (monitored by TLC) and
then to the cooled reaction mixture at rt, was added DMF (3 mL)
and heated to 120 ꢀC, in an oil bath for 12 h (monitored by TLC). The
reaction mixture at rt was quenched by the addition of aqueous
NH4Cl and extracted with DCM (3ꢂ15 mL). The organic layers were
washed with saturated NaCl solution, dried (Na2SO4), and filtered.
Evaporation of the solvent under reduced pressure and purification
of the crude material by silica gel column chromatography (pe-
troleum ether/ethyl acetate) furnished the lactenones 5 (40e48%).
Diesters 2ag, 2bg, and 2cg and the alcohol ester 3ag are known
in the literature.14
cooled reaction mixture at rt, were added Pd(OAc)2 (19.4 mg,
10 mol %) and PPh3 (45.0 mg, 20 mol %) under nitrogen atmosphere.
The stirred reaction mixture was then heated in an oil bath at 80 ꢀC
for 24 h and monitored by TLC. Then, the mixture was cooled to rt,
treated with aqueous NH4Cl solution, and then extracted with
CH2Cl2 (3ꢂ10 mL). The organic layer was washed with saturated
NaCl solution, dried (Na2SO4), and filtered. Evaporation of the sol-
vent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl ace-
tate, 90:10 to 85:15) furnished the diester 2aj (200.0 mg, 57%) as
a yellow viscous oil. [TLC control (petroleum ether/ethyl acetate
80:20), Rf (1j)¼0.45, Rf (2aj)¼0.45, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2923, 1735, 1712, 1631, 1603, 1493, 1252,
1179, 1162, 1107, 1034, 731 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d¼7.94
(d, 1H, J¼15.6 Hz, CH]CHCOOEt), 7.50 (d, 1H, J¼8.3 Hz, AreH), 7.02
(d, 1H, J¼2.4 Hz, AreH), 6.79 (dd, 1H, J¼8.3 Hz and 2.4 Hz, AreH),
6.23 (d, 1H, J¼15.6 Hz, CH]CHCOOEt), 4.80 (q, 1H, J¼6.4 Hz,
AreCHCH3), 4.24 (q, 2H, J¼7.3 Hz, OCH2CH3), 4.12 (qd, 2H, J¼7.3 and
1.9 Hz, OCH2CH3), 3.83 (s, 3H, AreOCH3), 3.70e3.45 (m, 2H,
OCH2CH2COOEt), 2.56 (t, 2H, J¼6.8 Hz, OCH2CH2COOEt), 1.37 (d, 3H,
J¼6.4 Hz, AreCHCH3), 1.31 (t, 3H, J¼7.3 Hz, OCH2CH3), 1.23 (t, 3H,
4.3. tert-Butyl (2E)-3-{2-[1-(3-tert-butoxy-3-oxopropoxy)
ethyl]phenyl}acrylate (2bi)
In an oven dried Schlenk tube, were added alcohol 1i (200.0 mg,
0.99 mmol), tertiarybutyl acrylate (637.0 mg, 4.97 mmol), and
Cs2CO3 (972.0 mg, 2.98 mmol) followed by addition of toluene
(4 mL) at rt under nitrogen atmosphere. The stirred reaction mix-
ture was heated in an oil bath at 50 ꢀC for 48 h. Progress of the
Michael addition was monitored by TLC till the reaction is com-
pleted. To the cooled reaction mixture at rt, were added Pd(OAc)2
(22.0 mg, 10 mol %) and PPh3 (52.0 mg, 20 mol %) under nitrogen
atmosphere. The stirred reaction mixture was then heated in an oil
bath at 80 ꢀC for 24 h and monitored by TLC. Then, the mixture was
cooled to rt, treated with aqueous NH4Cl solution, and then
extracted with CH2Cl2 (3ꢂ10 mL). The organic layer was washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapo-
ration of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate, 95:5 to 90:10) furnished the diester 2bi
(220.0 mg, 59%) as yellow viscous oil. [TLC control (petroleum
ether/ethyl acetate 90:10), Rf (1i)¼0.35, Rf (2bi)¼0.45, UV de-
tection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼2922, 1730, 1709,
J¼7.3 Hz, OCH2CH3) ppm. 13C NMR (CDCl3, 100 MHz):
¼171.4 (s,
d
O]CeO), 167.1 (s, O]CeO), 161.5 (s, AreC), 145.0 (s, AreC), 140.5
(d, CH]CHCOOEt), 128.2 (d, AreCH), 124.6 (s, AreC), 117.7 (d, CH]
CHCOOEt), 113.6 (d, AreCH), 110.7 (d, AreCH), 74.7 (d, ArCHCH3),
64.3 (t, OCH2CH2COOEt), 60.4 (t, OCH2CH3), 60.3 (t, OCH2CH3), 55.3
(q, AreOCH3), 35.2 (t, OCH2CH2COOEt), 23.9 (q, ArCHCH3), 14.3 (q,
OCH2CH3), 14.1 (q, OCH2CH3) ppm. HR-MS (APCIþ) m/z calculated
for [C19H26NaO6]þ¼[MþNa]þ: 373.1622; found 373.1630.
4.5. Ethyl (2E)-3-{6-[1-(3-ethoxy-3-oxopropoxy)ethyl]-1,3-
benzodioxol-5-yl}acrylate (2ak)
In an oven dried Schlenk tube, were added alcohol 1f (200.0 mg,
0.82 mmol), ethyl acrylate (408.0 mg, 4.10 mmol), and Cs2CO3
(798.0 mg, 2.46 mmol) followed by addition of toluene (4 mL) at rt
under a nitrogen atmosphere. The stirred reaction mixture was
heated in an oil bath at 50 ꢀC for 48 h. Progress of the Michael
addition was monitored by TLC till the reaction is completed. To the
cooled reaction mixture at rt, were added Pd(OAc)2 (18.0 mg,
10 mol %) and PPh3 (42.0 mg, 20 mol %) under nitrogen atmosphere.
The stirred reaction mixture was then heated in an oil bath at 80 ꢀC
for 24 h and monitored by TLC. Then, the mixture was cooled to rt,
treated with aqueous NH4Cl solution and then extracted with
CH2Cl2 (3ꢂ10 mL). The organic layer was washed with saturated
NaCl solution, dried (Na2SO4), and filtered. Evaporation of the sol-
vent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl ace-
tate, 90:10 to 85:15) furnished the diester 2ak (178.0 mg, 60%) as
a yellow viscous oil. [TLC control (petroleum ether/ethyl acetate
80:20), Rf (1f)¼0.50, Rf (2ak)¼0.50, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2958, 2921, 2852, 1732, 1618, 1482, 1285,
1632, 1367, 1319, 1149, 1105, 954, 762 cmꢁ1 1H NMR (CDCl3,
.
400 MHz):
d
¼7.98 (d, 1H, J¼15.6 Hz, CH]CHCOOtBu), 7.52 (d, 1H,
J¼7.3 Hz, AreH), 7.48 (d,1H, J¼7.8 Hz, AreH), 7.38 (dd,1H, J¼7.8 and
7.3 Hz, AreH), 7.25 (dd, 1H, J¼7.8 and 7.8 Hz, AreH), 6.27 (d, 1H,
J¼15.6 Hz, CH]CHCOOtBu), 4.81 (q, 1H, J¼6.4 Hz, AreCHCH3), 3.55
(t, 2H, J¼6.4 Hz, OCH2CH2COOtBu), 2.48 (td, 2H, J¼6.4 and 1.5 Hz,
OCH2CH2COOtBu), 1.55 [s, 9H, OC(CH3)3], 1.45 [s, 9H, OC(CH3)3], 1.40
(d, 3H, J¼6.4 Hz, AreCHCH3) ppm. 13C NMR (CDCl3, 100 MHz):
d
¼170.8 (s, O]CeO), 166.1 (s, O]CeO), 142.8 (s, AreC), 140.3 (d,
CH]CHCOOtBu), 132.4 (s, AreC), 130.0 (d, AreCH), 127.3 (d,
AreCH), 126.6 (d, AreCH), 126.0 (d, AreCH), 122.0 (d, CH]
CHCOOtBu), 80.5 [s, OC(CH3)3], 80.4 [s, OC(CH3)3], 74.7 (d,
AreCHCH3), 64.5 (t, OCH2CH2COOtBu), 36.4 (t, CH2CH2COOtBu),
28.1 [q, 3C, OC(CH3)3], 28.0 [q, 3C, OC(CH3)3], 23.7 (q,
AreCHCH3) ppm. HR-MS (APCIþ) m/z calculated for
[C22H31O5]þ¼[MþH]þ: 375.2166; found 375.2171.
1254, 1180, 1103, 1038, 934 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d¼7.92
(d, 1H, J¼15.6 Hz, CH]CHCOOEt), 6.99 (s, 1H, AreH), 6.97 (s, 1H,
AreH), 6.20 (d, 1H, J¼15.6 Hz, CH]CHCOOEt), 5.98 (d, 1H, J¼6.4 Hz,
OCH2O), 5.97 (d, 1H, J¼6.4 Hz, AreH), 4.79 (q, 1H, J¼6.8 Hz,
AreCHCH3), 4.24 (q, 2H, J¼7.3 Hz, OCH2CH3), 4.14 (q, 2H, J¼7.3 Hz,
OCH2CH3), 3.65e3.50 (m, 2H, OCH2CH2COOEt), 2.55 (t, 2H,
J¼6.4 Hz, OCH2CH2COOEt),1.34 (d, 3H, J¼6.8 Hz, AreCHCH3), 1.32 (t,
4.4. Ethyl (2E)-3-{2-[1-(3-ethoxy-3-oxopropoxy)ethyl]-4-
methoxyphenyl}acrylate (2aj)
3H, J¼7.3 Hz, OCH2CH3), 1.25 (t, 3H, J¼7.3 Hz, OCH2CH3) ppm. 13
C
In an oven dried Schlenk tube, were added alcohol 1j (200.0 mg,
0.86 mmol), ethyl acrylate (433.0 mg, 4.32 mmol), and Cs2CO3
(846.0 mg, 2.58 mmol) followed by addition of toluene (4 mL) at rt
under a nitrogen atmosphere. The stirred reaction mixture was
heated in an oil bath at 50 ꢀC for 48 h. Progress of the Michael
addition was monitored by TLC till the reaction is completed. To the
NMR (CDCl3, 100 MHz):
d
¼171.5 (s, O]CeO), 167.0 (s, O]CeO),
149.9 (s, AreC), 147.2 (s, AreC), 140.3 (d, CH]CHCOOEt), 138.9 (s,
AreC), 125.8 (s, AreC), 118.2 (d, CH]CHCOOEt), 106.1 (d, AreCH),
105.6 (d, AreCH), 101.4 (t, OCH2O), 74.1 (d, ArCHCH3), 64.2 (t,
OCH2CH2COOEt), 60.5 (t, OCH2CH3), 60.4 (t, OCH2CH3), 35.3 (t,
OCH2CH2COOEt), 24.0 (q, ArCHCH3), 14.3 (q, OCH2CH3), 14.2 (q,

10104
A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
OCH2CH3)
ppm.
HR-MS
(APCIþ)
m/z
calculated
for
4.8. tert-Butyl (5,6-dimethoxy-1,3-dihydro-2-benzofuran-1-
yl)acetate (4bg)
[C19H25O7]þ¼[MþH]þ: 365.1595; found 365.1603.
In an oven dried Schlenk tube, were added diester 2bg (50.0 mg,
0.12 mmol) and Cs2CO3 (117.3 mg, 0.36 mmol) followed by the
addition of CH3CN (3 mL) at rt under nitrogen atmosphere. The
resulted reaction mixture was stirred at 80 ꢀC in an oil bath for 24 h.
Progress of the reaction was monitored by TLC. The reaction mix-
ture at rt was quenched by the addition of aqueous NH4Cl and
extracted with DCM (3ꢂ15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapo-
ration of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate) furnished the ether 4bg (5.9 mg, 16%) as pale
yellow viscous liquid. [TLC control (petroleum ether/ethyl acetate
80:20), Rf (2bg)¼0.45, Rf (4bg)¼0.47, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2975, 1723, 1603, 1503, 1464, 1391, 1274,
1220, 1146, 1108, 1036, 844, 766 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
4.6. tert-Butyl (2E)-3-[2-(hydroxymethyl)-4,5-
dimethoxyphenyl]acrylate (3bg)
To a cold (ꢁ78 ꢀC), magnetically stirred solution of a diester 2bg
(100 mg, 0.24 mmol), under argon atmosphere, in dry toluene
(2 mL), was added 1 M solution of NaHMDS (0.96 mL, 0.96 mmol) in
toluene. Then the reaction mixture was allowed to stir at ꢁ78 ꢀC for
1 h and allowed to ꢁ10 ꢀC for 3 h. The reaction mixture was
quenched with aqueous NH4Cl solution and extracted with ethyl
acetate (3ꢂ15 mL). The organic layer was washed with saturated
NaCl solution, dried (Na2SO4), and filtered. Evaporation of the fil-
trate under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl ace-
tate 70:30 to 50:50) furnished the hydroxy ester 3bg (43.4 mg, 62%)
as a pale yellow viscous liquid. [TLC control (petroleum ether/ethyl
acetate 70:30), Rf (2bg)¼0.50, Rf (3bg)¼0.30, UV detection]. IR
(MIR-ATR, 4000e600 cmꢁ1): nmax¼3432, 2975, 1702, 1629, 1601,
d
¼6.71 (2ꢂ s, 2H, AreH), 5.60e5.48 (m, 1H, ArCHCH2COOtBu), 5.06
(dd, 1H, J¼11.7 and 2.9 Hz, ArCHaHbO), 4.98 (dd, 1H, J¼11.7 and
1.5 Hz, ArCHaHbO), 3.85 (s, 3H, ArOCH3), 3.84 (s, 3H, ArOCH3), 2.65
(dd, 2H, J¼6.8 and 1.5 Hz, ArCHCH2COOEt), 1.44 [s, 9H,
1514, 1457, 1274, 1146, 1104, 977, 845 cmꢁ1 1H NMR (CDCl3,
.
400 MHz):
d
¼7.87 (d, 1H, J¼15.6 Hz, CH]CHCOOtBu), 7.07 (s, 1H,
OC(CH3)3] ppm. 13C NMR (CDCl3, 100 MHz):
d
¼170.2 (s, O]CeO),
AreH), 6.94 (s, 1H, AreH), 6.22 (d, 1H, J¼15.6 Hz, CH]CHCOOtBu),
4.78 (s, 2H, AreCH2OH), 3.90 (s, 3H, AreOCH3), 3.89 (s, 3H,
AreOCH3), 1.89 (br s, OH), 1.52 [(s, 9H, C(CH3)3] ppm. 13C NMR
149.2 (s, AreC), 148.8 (s, AreC), 132.6 (s, AreC), 130.7 (s, AreC),
104.3 (d, AreCH), 103.9 (d, AreCH), 80.8 [s, OC(CH3)3], 80.7 (d,
ArCHCH2COOtBu), 72.8 (t, ArCH2O), 56.1 (q, AreOCH3), 56.0 (q,
AreOCH3), 42.9 (t, ArCHCH2COOEt), 28.0 [q, 3C, OC(CH3)3] ppm.
HR-MS (APCIþ) m/z calculated for [C16H20O4]þ¼[Me(H2O)]þ:
276.1356; found 276.1352.
(CDCl3, 100 MHz):
d
¼166.6 (s, O]CeO), 150.6 (s, AreC), 148.6 (s,
AreC), 139.8 (d, CH]CHCOOtBu), 133.4 (s, AreC), 125.3 (s, AreC),
119.6 (d, AreCH), 111.6 (d, AreCH), 109.0 (d, CH]CHCOOtBu), 80.5
[(s, C(CH3)3] 62.3 (t, AreCH2OH), 56.0 (q, AreOCH3), 55.9 (q,
AreOCH3), 28.2 [(q, 3C, C(CH3)3] ppm.
4.9. 2-Benzoxepin-3(1H)-one (5aa)
4.7. Ethyl (5,6-dimethoxy-1,3-dihydro-2-benzofuran-1-yl)ac-
etate (4ag)
GP-1 was carried out with alcohol 1a (100.0 mg, 0.53 mmol),
ethyl acrylate (265.3 mg, 2.65 mmol), Cs2CO3 (518.0 mg,
1.59 mmol), toluene (2 mL) for Michael addition at 50 ꢀC for 48 h,
then with Pd(OAc)2 (11.9 mg, 10 mol %), PPh3 (27.8 mg, 20 mol %) for
Heck coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at
120 ꢀC for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 95:5 to
85:15) furnished the lactenone 5aa (39.5 mg, 46%) as a pale yellow
viscous liquid. [TLC control (petroleum ether/ethyl acetate 90:10),
Rf (1a)¼0.50, Rf (5aa)¼0.38, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2921, 1707, 1602, 1457, 1273, 1209, 1157,
In an oven dried Schlenk tube, were added diester 2ag (50.0 mg,
0.14 mmol) and Cs2CO3 (133.5 mg, 0.72 mmol) followed by the
addition of toluene (2 mL) at rt under nitrogen atmosphere. The
resulted reaction mixture was stirred at 120 ꢀC in an oil bath for
24 h. Progress of the reaction was monitored by TLC. The reaction
mixture at rt was quenched by the addition of aqueous NH4Cl and
extracted with DCM (3ꢂ15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapo-
ration of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate, 90:10 to 85:15) furnished the ether 4ag
(5.6 mg, 16%), as a pale yellow viscous liquid. [TLC control (petro-
leum ether/ethyl acetate 75:25), Rf (2ag)¼0.45, Rf (4ag)¼0.46, UV
detection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼2917, 1728, 1602,
1106, 1034, 818, 741 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d¼7.55e7.30
(m, 4H, AreH), 7.21 (d, 1H, J¼11.7 Hz, CH]CHCO), 6.35 (d, 1H,
J¼11.7 Hz, CH]CHCO), 5.06 (s, 2H, ArCH2O) ppm. 13C NMR (CDCl3,
100 MHz):
d
¼167.6 (s, O]CeO), 140.6 (d, CH]CHCO), 135.4
(s, AreC), 135.1 (s, AreC), 130.2 (d, AreCH), 129.8 (d, AreCH),
129.7 (d, AreCH), 128.6 (d, AreCH), 122.7 (d, CH]CHCO), 68.6
(t, ArCH2O) ppm. HR-MS (APCIþ) m/z calculated for
[C10H7O]þ¼[(MþH)ꢁH2O]þ: 143.0491; found 143.0496.
1505, 1464, 1266, 1220, 1163, 1107, 1037, 855, 729 cmꢁ1
.
1H NMR
¼6.72 (s, 1H, AreH), 6.70 (s, 1H, AreH),
(CDCl3, 400 MHz):
d
5.65e5.55 (m, 1H, ArCHCH2COOEt), 5.08 (dd, 1H, J¼11.7 and 2.9 Hz,
ArCHaHbO), 5.00 (dd, 1H, J¼11.7 and 1.5 Hz, ArCHaHbO), 4.18 (q, 2H,
J¼7.3 Hz, OCH2CH3), 3.86 (s, 3H, ArOCH3), 3.85 (s, 3H, ArOCH3), 2.72
(dd, 2H, J¼7.3 and 6.4 Hz, ArCHCH2COOEt), 1.25 (t, 3H, J¼7.3 Hz,
4.10. 8-(Benzyloxy)-2-benzoxepin-3(1H)-one (5ab)
GP-1 was carried out with alcohol 1b (100.0 mg, 0.34 mmol),
ethyl acrylate (170.2 mg, 0.17 mmol), Cs2CO3 (332.3 mg, 1.03 mmol),
toluene (2 mL) for Michael addition at 50 ꢀC for 48 h, then with
Pd(OAc)2 (7.6 mg, 10 mol %), PPh3 (17.8 mg, 20 mol %) for Heck
coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at 120 ꢀC for
12 h. Purification of the crude material by silica gel column chro-
matography (petroleum ether/ethyl acetate, 90:10 to 85:15) fur-
nished the lactenone 5ab (36.2 mg, 40%) as a pale yellow semi-
solid. [TLC control (petroleum ether/ethyl acetate 80:20), Rf (1b)¼
0.48, Rf (5ab)¼0.41, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1):
OCH2CH3) ppm. 13C NMR (CDCl3, 100 MHz):
d¼170.9 (s, O]CeO),
149.3 (s, AreC), 148.9 (s, AreC), 132.2 (s, AreC), 130.6 (s, AreC),
104.2 (d, AreCH), 103.9 (d, AreCH), 80.6 (d, ArCHCH2COOEt), 72.8
(t, ArCH2O), 60.6 (t, OCH2CH3), 56.1 (q, AreOCH3), 56.0 (q,
AreOCH3), 41.8 (t, ArCHCH2COOEt), 14.2 (q, OCH2CH3) ppm. HR-MS
(APCIþ) m/z calculated for [C14H18NaO5]þ¼[MþNa]þ: 289.1046;
found 289.1052. Further elution of crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 85:15 to
70:30) yielded Michael addition product 5ag (10.2 mg, 23%). [TLC
control (petroleum ether/ethyl acetate 75:25), Rf (2ag)¼0.45, Rf
(5ag)¼0.30, UV detection].
nmax¼2925, 1701, 1605, 1501, 1283, 1178, 1040, 835, 737 cmꢁ1
.
1H
NMR (CDCl3, 400 MHz):
d¼7.46e7.30 (m, 6H, AreH), 7.14 (d, 1H,

A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
10105
J¼12.2 Hz, CH]CHCO), 7.03 (dd, 1H, J¼8.3 and 2.4 Hz, AreH), 7.01
(d, 1H, J¼2.4 Hz, AreH), 6.22 (d, 1H, J¼12.2 Hz, CH]CHCO), 5.12 (s,
2H, PhCH2O), 5.00 (s, 2H, ArCH2O) ppm. 13C NMR (CDCl3, 100 MHz):
then with Pd(OAc)2 (6.9 mg, 10 mol %), PPh3 (16.3 mg, 20 mol %) for
Heck coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at
120 ꢀC for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 85:15 to
75:25) furnished the lactenone 5ae (40.5 mg, 44%) as colorless
solid, recrystallized from dichloromethane/petroleum ether
(mp 160e161 ꢀC). [TLC control (petroleum ether/ethyl acetate
75:25), Rf (1e)¼0.45, Rf (5ae)¼0.38, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2925, 1694, 1602, 1517, 1453, 1354, 1275,
d¼168.0 (s, O]CeO), 160.1 (s, AreC), 140.6 (d, CH]CHCO), 137.1 (s,
AreC), 136.0 (s, AreC), 131.7 (d, AreCH), 128.7 (d, 2C, AreCH),
128.5 (s, AreC), 128.3 (d, AreCH), 127.4 (d, 2C, AreCH), 120.2 (d,
CH]CHCO), 115.7 (d, AreCH), 115.1 (d, AreCH), 70.3 (t, PhCH2O),
68.7 (t, ArCH2O) ppm. HR-MS (APCIþ) m/z calculated for
[C17H15O3]þ¼[MþH]þ: 267.1016; found 267.1020.
1164, 1106, 1031, 987, 864, 733, 698 cmꢁ1
.
1H NMR (CDCl3,
4.11. 8-Methoxy-2-benzoxepin-3(1H)-one (5ac)
400 MHz):
d
¼7.42 (d, 2H, J¼7.8 Hz, AreH), 7.37 (dd, 2H, J¼7.8 and
7.3 Hz, AreH), 7.31 (t, 1H, J¼7.3 Hz, AreH), 7.04 (d, 1H, J¼12.2 Hz,
CH]CHCO), 6.91 (s, 1H, AreH), 6.89 (s, 1H, AreH), 6.22 (d, 1H,
J¼12.2 Hz, CH]CHCO), 5.16 (s, 2H, PhCH2O), 4.97 (s, 2H, ArCH2O),
GP-1 was carried out with alcohol 1c (100.0 mg, 0.46 mmol),
ethyl acrylate (230.3 mg, 2.30 mmol), Cs2CO3 (449.6 mg,
1.38 mmol), toluene (2 mL) for Michael addition at 50 ꢀC for 48 h,
then with Pd(OAc)2 (10.3 mg,10 mol %), PPh3 (24.1 mg, 20 mol %) for
Heck coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at
120 ꢀC for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 90:10 to
80:20) furnished the lactenone 5ac (40.4 mg, 46%) as a pale brown
solid, recrystallized from dichloromethane/hexane (mp 96e98 ꢀC).
[TLC control (petroleum ether/ethyl acetate 80:20), Rf (1c)¼0.45, Rf
(5ac)¼0.40, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1):
nmax¼2926, 1699, 1605, 1503, 1453, 1284, 1251, 1160, 1034, 909, 805,
3.93 (s, 3H, AreOCH3) ppm. 13C NMR (CDCl3, 100 MHz):
d
¼168.0 (s,
O]CeO), 150.9 (s, AreC), 148.7 (s, AreC), 140.6 (d, CH]CHCO),
136.3 (s, AreC), 129.2 (s, AreC), 128.6 (d, 2C, AreCH), 128.4 (s,
AreC), 128.1 (d, AreCH), 127.2 (d, 2C, AreCH), 120.7 (d, CH]CHCO),
114.7 (d, AreCH), 111.7 (d, AreCH), 71.1 (t, PhCH2O), 68.3 (t,
ArCH2O), 56.2 (q, AreOCH3) ppm. HR-MS (APCIþ) m/z calculated for
[C18H17O4]þ¼[MþH]þ: 297.1121; found 297.1120.
4.14. [1,3]Dioxolo[4,5-h][2]benzoxepin-7(5H)-one (5af)
727 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
¼7.34 (d, 1H, J¼8.3 Hz,
GP-1 was carried out with alcohol 1f (100.0 mg, 0.43 mmol),
ethyl acrylate (215.2 mg, 2.15 mmol), Cs2CO3 (423.0 mg,1.30 mmol),
toluene (2 mL) for Michael addition at 50 ꢀC for 48 h, then
with Pd(OAc)2 (9.6 mg, 10 mol %), PPh3 (22.5 mg, 20 mol %) for
Heck coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at
120 ꢀC for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 90:10
to 80:20) furnished the lactenone 5af (38.6 mg, 44%) as colorless
solid, recrystallized from dichloromethane/petroleum ether
(mp 149e150 ꢀC). [TLC control (petroleum ether/ethyl acetate
80:20), Rf (1f)¼0.45, Rf (5af)¼0.40, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2921, 1698, 1617, 1504, 1490, 1387, 1267,
AreH), 7.14 (d, 1H, J¼12.2 Hz, CH]CHCO), 6.96 (dd, 1H, J¼8.3 and
2.4 Hz, AreH), 6.92 (d, 1H, J¼2.4 Hz, AreH), 6.21 (d, 1H, J¼12.2 Hz,
CH]CHCO), 5.01 (s, 2H, ArCH2O), 3.85 (s, 3H, AreOCH3) ppm. 13
C
NMR (CDCl3, 100 MHz):
d
¼168.1 (s, O]CeO), 161.0 (s, AreC), 140.7
(d, CH]CHCO), 137.0 (s, AreC), 131.7 (d, AreCH), 128.3 (s, AreC),
120.0 (d, CH]CHCO), 114.8 (d, AreCH), 114.2 (d, AreCH), 68.7 (t,
ArCH2O), 55.5 (q, AreOCH3) ppm. HR-MS (APCIþ) m/z calculated for
[C11H11O3]þ¼[MþH]þ: 191.0703; found 191.0704.
4.12. 8-(Benzyloxy)-7-methoxy-2-benzoxepin-3(1H)-one
(5ad)
1238, 1147, 1023, 928, 879 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
¼7.06
GP-1 was carried out with alcohol 1d (100.0 mg, 0.31 mmol),
ethyl acrylate (155.2 mg, 1.55 mmol), Cs2CO3 (303.0 mg,
0.93 mmol), toluene (2 mL) for Michael addition at 50 ꢀC for 48 h,
then with Pd(OAc)2 (6.9 mg, 10 mol %), PPh3 (16.3 mg, 20 mol %) for
Heck coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at
120 ꢀC for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 85:15 to
75:25) furnished the lactenone 5ad (38.6 mg, 42%) as white solid,
recrystallized from dichloromethane/hexane (mp 159e160 ꢀC).
[TLC control (petroleum ether/ethyl acetate 75:25), Rf (1d)¼0.45, Rf
(5ad)¼0.38, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1):
nmax¼2924, 1702, 1603, 1519, 1368, 1275, 1165, 1025, 740 cmꢁ1. 1H
(d,1H, J¼12.2 Hz, CH]CHCO), 6.86 (s, 1H, AreH), 6.83 (s, 1H, AreH),
6.24 (d, 1H, J¼12.2 Hz, CH]CHCO), 6.03 (s, 2H, OeCH2eO), 4.93 (s,
2H, ArCH2O) ppm. 13C NMR (CDCl3, 100 MHz):
d¼167.8 (s, O]CeO),
149.0 (s, AreC), 148.7 (s, AreC), 140.3 (d, CH]CHCO), 130.2 (s,
AreC), 130.0 (s, AreC), 121.0 (d, CH]CHCO), 109.3 (d, AreCH), 109.0
(d, AreCH), 101.9 (t, OeCH2eO), 68.2 (t, ArCH2O) ppm. HR-MS
(APCIþ) m/z calculated for [C11H9O4]þ¼[MþH]þ: 205.0495; found
205.0493.
4.15. 7,8-Dimethoxy-2-benzoxepin-3(1H)-one (5ag)
GP-1 was carried out with alcohol 1g (100.0 mg, 0.40 mmol),
ethyl acrylate (202.6 mg, 2.02 mmol), Cs2CO3 (395.6 mg,
1.21 mmol), toluene (2 mL) for Michael addition at 50 ꢀC for 48 h,
then with Pd(OAc)2 (9.1 mg, 10 mol %), PPh3 (21.0 mg, 20 mol %) for
Heck coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at
120 ꢀC for 12 h. Purification of the crude material by silica gel
column chromatography (petroleum ether/ethyl acetate, 85:15 to
70:30) furnished the lactenone 5ag (42.8 mg, 48%) as yellow semi-
solid. [TLC control (petroleum ether/ethyl acetate 75:25), Rf (1g)¼
0.45, Rf (5ag)¼0.30, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1):
nmax¼2924, 1693, 1603, 1519, 1463, 1356, 1274, 1247, 1164, 1107,
NMR (CDCl3, 400 MHz):
d
¼7.42 (d, 2H, J¼7.8 Hz, AreH), 7.38 (dd,
2H, J¼7.8 and 7.3 Hz, AreH), 7.32 (t, 1H, J¼7.3 Hz, AreH), 7.11 (d, 1H,
J¼12.2 Hz, CH]CHCO), 6.91 (s, 1H, AreH), 6.89 (s, 1H, AreH),
6.25 (d, 1H, J¼12.2 Hz, CH]CHCO), 5.20 (s, 2H, PhCH2O), 4.92 (s,
2H, ArCH2O), 3.91 (s, 3H, AreOCH3) ppm. 13C NMR (CDCl3,
100 MHz):
d
¼167.9 (s, O]CeO), 150.3 (s, AreC), 149.5 (s, AreC),
140.5 (d, CH]CHCO), 136.2 (s, AreC), 129.0 (s, AreC), 128.7 (d, 2C,
AreCH), 128.6 (s, AreC), 128.2 (d, AreCH), 127.2 (d, 2C, AreCH),
121.0 (d, CH]CHCO), 113.7 (d, AreCH), 112.7 (d, AreCH), 71.1 (t,
PhCH2O), 68.3 (t, ArCH2O), 56.2 (q, AreOCH3) ppm. HR-MS (APCIþ)
m/z calculated for [C18H17O4]þ¼[MþH]þ: 297.1121; found 297.1121.
1029, 988, 840, 731 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d¼7.12 (d, 1H,
J¼12.2 Hz, CH]CHCO), 6.90 (s, 1H, AreH), 6.87 (s, 1H, AreH),
6.26 (d, 1H, J¼12.2 Hz, CH]CHCO), 4.98 (s, 2H, ArCH2O), 3.93 (s,
3H, ArOCH3), 3.90 (s, 3H, ArOCH3) ppm. 13C NMR (CDCl3,
4.13. 7-(Benzyloxy)-8-methoxy-2-benzoxepin-3(1H)-one (5ae)
GP-1 was carried out with alcohol 1e (100.0 mg, 0.31 mmol),
ethyl acrylate (155.2 mg, 1.55 mmol), Cs2CO3 (303.0 mg,
0.93 mmol), toluene (2 mL) for Michael addition at 50 ꢀC for 48 h,
100 MHz):
d
¼168.0 (s, O]CeO), 150.3 (s, AreC), 149.7 (s,
AreC), 140.6 (d, CH]CHCO), 128.7 (s, AreC), 128.6 (s, AreC), 120.9
(d, CH]CHCO), 112.1 (d, AreCH), 111.3 (d, AreCH), 68.3 (t, ArCH2O),

10106
A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
56.2 (q, AreOCH3), 56.1 (q, AreOCH3) ppm. HR-MS (APCIþ) m/z
calculated for [C12H13O4]þ¼[MþH]þ: 221.0808; found 221.0804.
ether/ethyl acetate, 70:30 to 60:40) furnished the ether as yellow
oil 5bl (62.5 mg, 52%). [TLC control (petroleum ether/ethyl acetate
60:40), Rf (2bl)¼0.75, Rf (5bl)¼0.20, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2925, 2852, 1695, 1604, 1518, 1462, 1362,
1335, 1199, 1177, 1151, 1068, 1025, 957, 863, 812, 729, 612 cmꢁ1. 1H
4.16. 6,7,8-Trimethoxy-2-benzoxepin-3(1H)-one (5ah)
GP-1 was carried out with alcohol 1h (100.0 mg, 0.36 mmol),
ethyl acrylate (180.7 mg, 1.80 mmol), Cs2CO3 (351.9 mg, 1.08 mmol),
toluene (2 mL) for Michael addition at 50 ꢀC for 48 h, then with
Pd(OAc)2 (8.1 mg, 10 mol %), PPh3 (18.9 mg, 20 mol %) for Heck
coupling at 80 ꢀC for 24 h and finally with DMF (3 mL) at 120 ꢀC for
12 h. Purification of the crude material by silica gel column chro-
matography (petroleum ether/ethyl acetate, 85:15 to 75:25) fur-
nished the lactenone 5ah (42.3 mg, 47%) as yellow viscous liquid.
[TLC control (petroleum ether/ethyl acetate 80:20), Rf (1h)¼0.45, Rf
(5ah)¼0.38, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1):
nmax¼2925, 1703, 1595, 1498, 1458, 1375, 1338, 1249, 1123, 1089,
NMR (CDCl3, 400 MHz):
d
¼7.11 (d, 1H, J¼12.2 Hz, CH]CHCO), 6.96
(s,1H, AreH), 6.86 (s, 1H, AreH), 6.30 (d, 1H, J¼12.2 Hz, CH]CHCO),
5.25 [q, 1H, J¼6.4 Hz, ArCH(CH3)O], 3.95 (s, 3H, AreOCH3), 3.90 (s,
3H, AreOCH3) 1.83 [d, 3H, J¼6.4 Hz, ArCH(CH3)O] ppm. 13C NMR
(CDCl3, 100 MHz):
d
¼167.7 (s, O]CeO), 150.3 (s, AreC), 149.2 (s,
AreC), 140.2 (d, CH]CHCO), 131.9 (s, AreC), 128.3 (s, AreC),
121.4 (d, CH]CHCO), 112.3 (d, AreCH), 107.9 (d, AreCH), 72.4
[d, ArCH(CH3)O], 56.1 (q, AreOCH3), 56.0 (q, AreOCH3), 17.5
[q, ArCH(CH3)O] ppm. HR-MS (APCIþ) m/z calculated for
[C13H15O4]þ¼[MþH]þ: 235.0695; found 235.0694.
1031, 822 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d¼7.43 (d, 1H,
4.19. 8-Methoxy-1-methyl-2-benzoxepin-3(1H)-one (5aj)
J¼12.2 Hz, CH]CHCO), 6.71 (s, 1H, AreH), 6.24 (d, 1H, J¼12.2 Hz,
CH]CHCO), 4.94 (s, 2H, ArCH2O), 3.91 (s, 3H, ArOCH3), 3.90 (s, 3H,
ArOCH3), 3.87 (s, 3H, ArOCH3) ppm. 13C NMR (CDCl3, 100 MHz):
In an oven dried Schlenk tube, were added diester 2aj (150.0 mg,
0.43 mmol) and Cs2CO3 (419.0 mg, 1.29 mmol) followed by the ad-
dition of DMF (3 mL) at rt under nitrogen atmosphere. The resulted
reaction mixture was stirred at 120 ꢀC in an oil bath for 12 h. Progress
of the reaction was monitored by TLC. The reaction mixture at rt was
quenched by the addition of aqueous NH4Cl and extracted with DCM
(3ꢂ15 mL). The organic layers were washed with saturated NaCl
solution, dried (Na2SO4), and filtered. Evaporation of the solvent
under reduced pressure and purification of the crude material by
silica gel column chromatography (petroleum ether/ethyl acetate,
85:15 to 80:20) furnished the ether as yellow viscous liquid 5aj
(50.8 mg, 58%). [TLC control (petroleum ether/ethyl acetate 80:20),
Rf (2aj)¼0.60, Rf (5aj)¼0.30, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2923, 2852, 1697, 1605, 1562, 1501, 1460,
1399,1382,1236,1218,1178,1073,1035, 975, 876, 859 cmꢁ1. 1H NMR
d
¼168.2 (s, O]CeO), 155.0 (s, AreC), 152.2 (s, AreC), 142.5 (s,
AreC), 135.6 (d, CH]CHCO), 131.9 (s, AreC), 122.6 (s, AreC), 120.2
(d, CH]CHCO), 107.4 (d, AreCH), 68.7 (t, ArCH2O), 61.7 (q,
AreOCH3), 61.0 (q, AreOCH3), 56.2 (q, AreOCH3) ppm. HR-MS
(APCIþ) m/z calculated for [C13H15O5]þ¼[MþH]þ: 251.0914; found
251.0913.
4.17. 1-Methyl-2-benzoxepin-3(1H)-one (5bi)
In an oven dried Schlenk tube, were added diester 2bi
(200.0 mg, 0.53 mmol) and Cs2CO3 (520.0 mg, 1.59 mmol) followed
by the addition of DMF (4 mL) at rt under nitrogen atmosphere. The
resulted reaction mixture was stirred at 120 ꢀC in an oil bath for
12 h. Progress of the reaction was monitored by TLC. The reaction
mixture at rt was quenched by the addition of aqueous NH4Cl and
extracted with DCM (3ꢂ15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapo-
ration of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate, 90:10 to 80:20) furnished the ether as yellow
oil 5bi (50.8 mg, 55%). [TLC control (petroleum ether/ethyl acetate
80:20), Rf (2bi)¼0.50, Rf (5bi)¼0.25, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2923, 2852, 1701, 1617, 1455, 1398, 1269,
1215, 1152, 1068, 1044, 1018, 972, 823, 808, 777, 731 cmꢁ1. 1H NMR
(CDCl3, 400 MHz):
d
¼7.33 (d, 1H, J¼8.3 Hz, AreH), 7.14 (d, 1H,
J¼11.7 Hz, CH]CHCO), 7.00 (d, 1H, J¼2.4 Hz, AreH), 6.94 (dd, 1H,
J¼8.3 and 2.4 Hz, AreH), 6.25 (d, 1H, J¼11.7 Hz, CH]CHCO), 5.26 [q,
1H, J¼6.8 Hz, ArCH(CH3)O], 3.87 (s, 3H, AreOCH3) 1.82 [d, 3H,
J¼6.8 Hz, ArCH(CH3)O] ppm. 13C NMR (CDCl3, 100 MHz):
¼167.8 (s,
d
O]CeO),161.1 (s, AreC),140.5 (d, CH]CHCO),140.2 (s, AreC),131.8
(d, AreCH), 128.0 (s, AreC), 120.5 (d, CH]CHCO), 113.6 (d, AreCH),
111.4 (d, AreCH), 72.5 [d, ArCH(CH3)O], 55.5 (q, AreOCH3), 17.3 [q,
ArCH(CH3)O] ppm. HR-MS (APCIþ) m/z calculated for
[C12H13O3]þ¼[MþH]þ: 205.0859; found 205.0862.
(CDCl3, 400 MHz):
d
¼7.60e7.30 (m, 4H, AreC), 7.21 (d, 1H,
4.20. 8,9-Dihydro[1,3]dioxolo[4,5-h][2]benzoxepin-7(5H)-one
(5ak)
J¼12.2 Hz, CH]CHCO), 6.39 (d, 1H, J¼12.2 Hz, CH]CHCO), 5.31 [q,
1H, J¼6.8 Hz, ArCH(CH3)O],1.85 [d, 3H, J¼6.8 Hz, ArCH(CH3)O] ppm.
13C NMR (CDCl3, 100 MHz):
d¼167.4 (s, O]CeO), 140.4 (d, CH]
In an oven dried Schlenk tube, were added diester 2ak (80.0 mg,
0.22 mmol) and Cs2CO3 (214.0 mg, 0.66 mmol) followed by the
addition of DMF (2 mL) at rt under nitrogen atmosphere. The
resulted reaction mixture was stirred at 120 ꢀC in an oil bath for
12 h. Progress of the reaction was monitored by TLC. The reaction
mixture at rt was quenched by the addition of aqueous NH4Cl and
extracted with DCM (3ꢂ15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapo-
ration of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum
ether/ethyl acetate, 85:15 to 75:25) furnished the ether as yellow
oil 5ak (24.0 mg, 50%). [TLC control (petroleum ether/ethyl acetate
80:20), Rf (2ak)¼0.50, Rf (5ak)¼0.20, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼2921, 2851, 1694, 1505, 1489, 1385, 1261,
CHCO), 138.2 (s, AreC), 135.1 (s, AreC), 130.1 (d, AreCH), 129.9 (d,
AreCH), 129.1 (d, AreCH), 124.9 (d, AreCH), 123.0 (d, CH]CHCO),
72.7 [d, ArCH(CH3)O], 17.3 [q, ArCH(CH3)O] ppm. HR-MS (APCIþ) m/
z
calculated for [C10H9O]þ¼[(MþH)ꢁH2O]þ: 157.0648; found
157.0644.
4.18. 7,8-Dimethoxy-1-methyl-2-benzoxepin-3(1H)-one (5bl)
In an oven dried Schlenk tube, were added diester 2bl
(220.0 mg, 0.50 mmol) and Cs2CO3 (493.0 mg, 1.50 mmol) followed
by the addition of DMF (4 mL) at rt under nitrogen atmosphere. The
resulted reaction mixture was stirred at 120 ꢀC in an oil bath for
12 h. Progress of the reaction was monitored by TLC. The reaction
mixture at rt was quenched by the addition of aqueous NH4Cl and
extracted with DCM (3ꢂ15 mL). The organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered. Evapo-
ration of the solvent under reduced pressure and purification of the
crude material by silica gel column chromatography (petroleum
1156, 1036, 932 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
¼7.06 (d, 1H,
J¼12.2 Hz, CH]CHCO), 6.98 (s, 1H, AreH), 6.83 (s, 1H, AreH), 6.30
(d, 1H, J¼12.2 Hz, CH]CHCO), 6.04 (d, 1H, J¼6.3 Hz, OCHaHbO), 6.03
(d, 1H, J¼6.3 Hz, OCHaHbO), 5.20 [q, 1H, J¼6.3 Hz, ArCH(CH3)O], 1.79
[d, 3H, J¼6.3 Hz, ArCH(CH3)O] ppm. 13C NMR (CDCl3,

A.G.K. Reddy et al. / Tetrahedron 69 (2013) 10098e10107
10107
K. Org. Lett. 2010, 12, 2500e2503; (i) Satyanarayana, G.; Maier, M. E. Eur. J. Org.
Chem. 2008, 5543e5552; (j) Leogane, O.; Lebel, H. Angew. Chem. 2008, 120,
356e358; Angew. Chem., Int. Ed. 2008, 47, 350e352; (k) Barluenga, J.; Mendoza,
100 MHz):
d
¼167.6 (s, O]CeO), 149.3 (s, AreC), 148.1 (s,
AreC), 140.0 (d, CH]CHCO), 133.7 (s, AreC), 129.7 (s, AreC), 121.6
(d, CH]CHCO), 109.3 (d, AreCH), 105.6 (d, AreCH), 101.9 (t,
OCH2O), 72.3 (d, ArCHCH3), 17.6 (q, ArCHCH3) ppm. HR-MS (APCIþ)
m/z calculated for [C12H11O4]þ¼[(MþH)]þ: 219.0652; found
219.0657.
~
ꢀ
A.; Rodríguez, F.; Fananas, F. J. Angew. Chem. 2009, 121, 1672e1675; Angew.
Chem., Int. Ed. 2009, 48, 1644e1647; (l) Liang, Y.; Meng, T.; Zhang, H.-J.; Xi, Z.
Synlett 2011, 911e914; (m) Toyoshima, T.; Mikano, Y.; Miura, T.; Murakami, M.
Org. Lett. 2010, 12, 4584e4587; (n) Schweinitz, A.; Chtchemelinine, A.; Orellana,
A. Org. Lett. 2011, 13, 232e235; (o) Jafarpour, F.; Jalalimanesh, N. Tetrahedron
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C. Tetrahedron Lett. 2004, 45, 5653e5656; (q) Hashmi, A. S. K.; Ghanbari, M.;
Rudolph, M.; Rominger, F. Chem.dEur. J. 2012, 18, 8113e8119; (r) Hashmi, A. S.
Acknowledgements
€
€
K.; Lothschutz, C.; Dopp, R.; Ackermann, M.; Becker, J. D. B.; Rudolph, M.;
Scholz, C.; Rominger, F. Adv. Synth. Catal. 2012, 354, 133e137; (s) Hashmi, A. S.
Financial support by the Council of Scientific and Industrial
Research [(CSIR), 02(0018)/11/EMR-II] and Department of Science
and Technology [(DST), CHE/2010-11/006/DST/GSN], New Delhi is
gratefully acknowledged. We thank one of the reviewers for sug-
gesting this base mediated intramolecular cyclization. A.G.K. and
J.K. thank CSIR, New Delhi, for the award of research fellowship.
€
€
K.; Lothschutz, C.; Dopp, R.; Rudolph, M.; Ramamurthi, T. D.; Rominger, F. An-
gew. Chem. 2009, 121, 8392e8395; Angew. Chem., Int. Ed. 2009, 48, 8243e8246.
6. For some recent sequential one-pot Pd-catalyzed transformations, see: (a)
Song, R.-J.; Liu, Y.; Li, R.-J.; Li, J.-H. Tetrahedron Lett. 2009, 50, 3912e3916; (b)
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Supplementary data
Copies of 1H and 13C NMR spectra related to this article
are available. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.09.050.
7. For reviews on domino Heck reactions, see: (a) Negishi, E.; Copret, C.; Ma, S.;
Liou, S.-Y.; Liu, F. Chem. Rev. 1996, 96, 365e394; (b) Beletskaya, I. P.; Cheprakov,
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