A new course of the Perkin cyclization of 2-(2-formyl-6-methoxyphenoxy)alkanoic acids. Synthesis of 2-alkyl-7-methoxy-5-nitrobenzo[b]furans

Article abstract of DOI:10.1016/j.tet.2008.03.067

2-Alkyl-7-methoxy-5-nitrobenzo[b]furan, 2-alkyl-9-methoxy-7-nitro-3-oxo-2,3-dihydro-5H-benzo[e][1,4]-dioxepin-5-yl acetate and 2-alkyl-5-hydroxy-9-methoxy-7-nitro-5H-benzo[e][1,4]-dioxepin-3-one were formed as a result of the cyclization of 2-(2-formyl-6-

Full text of DOI:10.1016/j.tet.2008.03.067

Tetrahedron 64 (2008) 5085–5090
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Tetrahedron
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A new course of the Perkin cyclization of 2-(2-formyl-6-methoxyphenoxy)-
alkanoic acids. Synthesis of 2-alkyl-7-methoxy-5-nitrobenzo[b]furans
*
´
Monika Kowalewska, Halina Kwiecien
Department of Organic Synthesis and Drug Technology, Szczecin University of Technology, Al. Piasto´w 42, 71-065 Szczecin, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Alkyl-7-methoxy-5-nitrobenzo[b]furan,2-alkyl-9-methoxy-7-nitro-3-oxo-2,3-dihydro-5H-benzo[e][1,4]-
dioxepin-5-yl acetate and 2-alkyl-5-hydroxy-9-methoxy-7-nitro-5H-benzo[e][1,4]-dioxepin-3-one were
formedasa resultof thecyclizationof2-(2-formyl-6-methoxy-4-nitrophenoxy)alkanoicacidsunderclassical
Perkinreactionconditions. Theproductswerecharacterizedbyspectroscopicmethodsand themechanismof
the cyclization is discussed.
Received 16 October 2007
Received in revised form 6 March 2008
Accepted 19 March 2008
Available online 22 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2-Formylphenoxy alkanoic acids and their derivatives are well
known as bifunctional compounds, which are used in syntheses
of heterocyclic structures such as benzo[b]furan1 and 1,4-
benzoxazepine.2
2-(2-Formyl-6-methoxy-4-nitrophenoxy)alkanoic acids 1a–c
desired for cyclization were prepared by a known method starting
from 2-hydroxy-3-methoxy-5-nitrobenzaldehyde and the corre-
sponding methyl 2-bromo alkanoates. 2-Hydroxy-3-methoxy-5-
nitrobenzaldehyde was prepared in our laboratory by nitration of
o-vanillin with concentrated nitric acid in acetic acid solution. The
reaction time and temperature were so matched that the desired
2-hydroxy-3-methoxy-5-nitrobenzaldehyde was formed in a yield
of 80%. Methyl 2-bromobutanoate, -pentanoate and -hexanoate
were obtained by the method described,6 starting from a suitable
carboxylic acid by chlorination with thionyl chloride, followed by
bromination with bromine and esterification with methanol. All
these reactions were carried out as a continuous, one-pot process
and the yield of esters was over 90%. O-Alkylation of 2-hydroxy-3-
methoxy-5-nitrobenzaldehyde with 2-bromoesters was made in
DMF solution in the presence of potassium carbonate to give
methyl 2-(2-formyl-6-methoxy-4-nitrophenoxy)alkanoate practi-
cally in quantitative yields (Scheme 1). The key problem, effectively
solved, was the hydrolysis of the esters to the corresponding acids.
When hydrolysis of the esters was carried out with 5% sodium
hydroxide at room temperature, it gave the corresponding acid and
the product of ether bond cleavage. It has been found that the
unfavourable bond cleavage can be considerably restricted pro-
vided the ester hydrolysis is carried out at a temperature not
exceeding 10 ꢀC. In these conditions suitable acids 1a–c were
obtained in good yields as colourless crystals.
A number of methods exist for the synthesis of benzo[b]furans,
and they vary in complexity and starting materials. In almost all
cases, the benzo[b]furan synthesis is based on the cyclization of
various acyclic precursors.3 The most famous method is developed
via 2-ethynylphenols.4 On the other hand, the method via 2-(2-
formylphenoxy)alkanoic acids appears practical and general for the
synthesis of 2-alkylbenzo[b]furans using starting materials that are
commercially available, and involves simple procedures. This
process has been the subject of recent patents.5 Although the
synthesis of 2-benzo[b]furans via cyclization of 2-formylphenoxy-
acetic acid has been known for a long time, there is in the literature
only one attempt to explain the mechanism of the cyclization.1f The
proposed mechanism, involving a series of rearrangements, de-
pends upon intramolecular [2þ2] ketene cycloaddition with an
aldehyde.
This work presents the results of our studies on the cyclization
of 2-(2-formyl-6-methoxy-4-nitrophenoxy)alkanoic acids to 2-al-
kyl-7-methoxy-5-nitrobenzo[b]furans, the latter compounds being
intermediates in the synthesis of 2-alkyl-5-amino-7-methoxy-
benzo[b]furans. Bis-N,N-dichloroethyl derivatives of such amino-
benzofurans may be potential antitumour agents.
In order to prepare 2-alkyl-7-methoxy-5-nitrobenzo[b]furans
2a–c, thoroughly dried 2-(2-formylo-6-methoxy-4-nitrophenoxy)-
alkanoic acids 1a–c were subjected to cyclization under the same
* Corresponding author.
E-mail address: halina.kwiecien@ps.pl (H. Kwiecien).
´
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.067

5086
M. Kowalewska, H. Kwiecien´ / Tetrahedron 64 (2008) 5085–5090
O2N
CHO
O
O2N
CHO
OH
1-4
a
R
A, B
C2H5
C3H7
C4H9
b
O
OCH3
c
OCH3
R
OH
C
O
1a-1c (75-78% )
AcO
HO
OAc
OAc
OAc
O2N
O2N
O
O2N
O
O2N
R
O
+
+
O
+
O
O
OCH3
R
R
OCH3
OCH3
OCH3
2a-2c
5
3a-3c
4a-c
(16-19%)*
(41-45%)*
(20-26%)*
(23-25%)*
* based on the GC/MS chromatographic area
A: RCHBrCO CH , K CO , DMF, 93
°C, 4h B: 5% NaOH, 10 °C, 5% HCl,
-95
2
2
3
C: Ac2O, AcONa,3AcOH, reflux,
Scheme 1.
conditions applied earlier to the synthesis of 2-alkyl-5-nitro-
benzo[b]furans,7 i.e., in a mixture of acetic anhydride and acetic
acid at reflux in the presence of anhydrous sodium acetate. The
crude neutral product was analyzed by GC/MS and was found to
contain four products, i.e., 2-alkyl-7-methoxy-5-nitrobenzo[b]furans
(2a–c), 2-alkyl-9-methoxy-7-nitro-3-oxo-2,3-dihydro-5H-benzo[e]-
[1,4]-dioxepin-5-yl acetates (3a–c), 2-alkyl-5-hydroxy-9-methoxy-
7-nitro-5H-benzo[e][1,4]-dioxepin-3-ones (4a–c) and 2-hydroxy-
3-methoxy-5-nitrobenzaldehyde triacetate (5) (Scheme 1).
ease of the ethereal bond cleavage both in alkaline and acidic
media.7a
It is known that aldehydes react with anhydrides under acid
catalysis to give geminal diacetates (acylals).8a,b The formation of
the geminal diacetates from aldehydes and acetic anhydride using
strong protic acids is one of the known methods of carbonyl group
protection.8b
Next we have found that when 3a was heated in DMF with
anhydrous potassium carbonate at 145–150 ꢀC, benzo[b]furan 2a as
the main product and certain amounts of initial benzaldehyde were
formed (Scheme 3).
Products 2a–c, 3a and 4a were isolated from the mixture and
their structures were established by spectroscopic methods. The
other compounds 3b,c and 4b,c were identified by GC/MS.
The structure of 3a was determined using 1H and 13C NMR
H3C
1
spectroscopy including H–13C 2D-COSY spectra. In the 1H NMR
O
O
spectrum, a singlet with chemical shift d¼2.37, characteristic of CH3
protons was detected for the acetyl groups O–CO–CH3. A broad
strong absorption band at n¼1810 cmꢁ1 in the IR spectrum of 3a is
characteristic of valency bond vibrations of the carbonyl group in
lactones, and a strong band at 1780 cmꢁ1 corresponded to the
acetate carbonyl group. In the IR spectrum of 4a a broad band of OH
group at 3500–3350 cmꢁ1 and carbonyl group in lactones at
1810 cmꢁ1 were present.
O2N
CHO
OH
O2N
O2N
O
DMF, K2CO3
reflux
+
O
O
O
OCH3
OCH3
OCH3
90%
2a
3a
Scheme 3.
GC/MS analysis shows that the retention time and fragmen-
tation of compounds 5 correspond to the retention time and
fragmentation of the product obtained when 2-hydroxy-3-meth-
oxy-5-nitrobenzaldehyde was heated for 30 min with acetic
anhydride and anhydrous sodium acetate (Scheme 2). The structure
of triacetate 5 was confirmed by 1H and 13C NMR spectroscopy.
The presence of product 5 in the mixture after cyclization of acid
1a proves that during the reaction there takes place an undesirable
ether bond cleavage to form the starting benzaldehyde, which
then reacts with acetic anhydride to give a triacetate. The presence
of the nitro group in position 5 of the benzene ring accounts for the
In order to obtain the desired benzo[b]furans in good yield, op-
timization of the cyclization process of model 1a was performed
changing the proportions of acetic anhydride, acetic acid in relation
to acid 1a, as well as reaction time. It was found that the highest yield
of benzo[b]furan 2a with an inconsiderable amount of 1,4-benzo-
dioxepin-3-ones 3a and 4a could be achieved when kept for 3–3.5 h
in a medium of solely acetic anhydride. When the reaction was
carried out in a mixture of acetic anhydride and acetic acid, the
amounts of3a and 4a increasedwiththe concentrationof aceticacid.
Under the optimal conditions established for 1a, cyclization of
acids 1b and 1c gave the desired benzo[b]furans 2b and 2c with
62–75% GC yield (Table 1).
It is noteworthy that products 3a–c and 4a–c were formed in all
the reaction samples, even in those where acetic acid was not
added. However, such a product was not detected in any of the
2-(2-formylphenoxy)alkanoic acids, the acids being subjected to
cyclization carried out in conditions identical both for the acids
non-substituted on the benzene ring and those containing halogen
or nitro group on position 5 of the ring.7a,b
Accordingly, the outcome of cyclization tests made in this work
was decidedly affected by the presence of a spatially large methoxy
group in the position ortho to the carboxyalkylethereal grouping.
H3C
O
O
O
O2N
O
H
O2N
H
CH3
Ac2O, AcONa
reflux, 30min
O
OH
OCH3
O
CH3
OCH3
O
40%
5
Scheme 2.

M. Kowalewska, H. Kwiecien´ / Tetrahedron 64 (2008) 5085–5090
5087
Table 1
Cyclization of 2-(2-formyl-6-methoxy-4-nitrophenoxy)alkanoic acids under optimal conditions
Starting acid 1
Producta [%]
O2N
H3C
O
HO
H3C
O
O
O2N
O
O
R
O
OCH3
2
O
O2N
O
O
O2N
CH3
H
O
OCH3
4
O
R
O
CH3
O
O
OCH3
R
OCH3
O
3
5
a
b
c
64 (44)
62 (41)
75 (49)
16 (9)
28
10
11 (6)
4
9
9
6
6
Values in brackets denote isolated yields.
a
Relative percentage of the compounds based on the GC/MS chromatographic area.
In order to confirm the effect of the methoxy group in position
ortho to the ethereal linkage, some cyclization reactions of 2-(2-
formyl-6-methoxyphenoxy)butanoic acid 1d in acetic anhydride
and in the presence of sodium acetate were carried out. The
reaction gave a mixture in which 2-ethyl-7-methoxybenzo[b]furan
2d (41%) and 1,4-benzodioxapin-3-one 3d (50%) were detected
with the aid of GC/MS analysis (Scheme 4).
conditions, i.e., in boiling acetic anhydride in the presence of
sodium carbonate, it is accompanied by two concurrent processes
giving rise to the formation of products 2 and 3.
According to the mechanism proposed by the authors,1f the
course of the first stage of 2-(2-formylphenoxy)alkanoic acid cy-
clization depends on reaction of the acid with acetic anhydride to
give a mixed anhydride and then phenoxyketene. The above re-
action is followed by a two-step intramolecular [2þ2] cycloaddition
via a dipolar intermediate, which undergoes ring closure to the
b-lactone. Subsequent decarboxylation in acetic anhydride at reflux
yields the substituted benzo[b]furan 2.1f
O
O
O
O
HO
O
A competitive process leading to product 3 is an intermolecular
acylation of the aldehyde group, similar to the formation of acylals
using anhydrides or acids.8a An intermolecular acylation first forms
a hemiacylal, which enters into reaction with acetic anhydride and
brings about a mixed diacylal 3 (Scheme 5). This process is favoured
by the presence of a spatially large methoxy group placed in a po-
sition ortho to alkoxyalkylcarboxyl chain of acids 1a–c. This fact
makes most of the atoms exist in a conformation where the alde-
hyde and acid groups are neighbouring, which may give effect to
intermolecular acylation and the consequent production of
a hemiacylal.
Ac2O
+
O
O
AcONa
O
O
OCH3
OCH3
OCH3
2d
3d
1d
Scheme 4.
In this case, according to our expectations, the reaction mixture
did not contain any product corresponding to 5, as the cleavage of
ethereal bond takes place in the presence of the electron-accepting
nitro group.
The results achieved in this work give indication that cyclization
of acids 1a–c, when carried out under typical Perkin reaction
One can assume an optional formation of 7-member acetate 3a–c,
formed from a mixed anhydride brought about by the reaction of
starting acids 1a–c with acetic acid, followed by intermolecular
O
HO
O
O
O
O
Ac2O
Ac2O
O2N
HO
R
O2N
O2N
O
O
O
AcOH,
AcONa
O
O
OCH3
O
OCH3
O
OCH3
R
R
3
AcOH,
AcONa
Ac2O
O2N
O2N
O
O
R
O
O2N
OAc
O
O
O
OCH3
O
R
O
OCH3
OCH3
R
O
O
O2N
O2N
O
-CO2
R
O
O
OCH3
O
R
OCH3
2
Scheme 5.

5088
M. Kowalewska, H. Kwiecien´ / Tetrahedron 64 (2008) 5085–5090
O
OH
-H2O
-CO2
R
O2N
O2N
Ac2O
H
COOH
R
O
R
AcONa
O
O
O
R
OH
OCH3
OCH3
OCH3
Scheme 6.
cyclization. Considering the results achieved by Kochhar,8a the
mechanism of conversion of aldehydes into geminal diacetates
involves an intermolecular transfer of the second acetate group
after the initial attack by acetic anhydride. Such a mechanism
seems probable, since there first takes place an intermolecular re-
action of the carboxyl group with the aldehyde, leading to a hemi-
acylal and afterwards by acetylation to product 3. The deposition of
hemiacylal failed, but its presence was found in almost all reactions
by GC/MS analysis.
Regarding the cyclization results achieved in this work, the
mechanism of benzo[b]furan formation through formation of
a mixed anhydride in the first stage is more probable than its al-
ternative depending on cyclization by intramolecular aldolization
(Scheme 6).3b The methoxyl group in position ortho to ethereal
bond in formyl acid should then affect the aldolization to the same
extent and cause increase in the yield of benzo[b]furan and
formation of product 3.
potassium carbonate (6.9 g, 0.05 mol) and dry DMF (90 mL) was
heated at 93–95 ꢀC with stirring for 4 h. Then the solution was
poured into ice-water, the precipitate was filtered off, washed with
water and dried in air. The crude ester was recrystallized from
methanol/water 2:1 to give pale beige crystals, mp 103–105 ꢀC
(lit.2c 103–105 ꢀC). The mixture of the ester and 5% sodium hydr-
oxide was stirred magnetically at 10 ꢀC for 2 h. The solution was
filtered through Celite, the filtrate was acidified with 5% hydro-
chloric acid and the precipitate was isolated. The crude product was
recrystallized from 2:1 methanol/water, to give 1a as colourless
crystal (11.1 g, 78%), mp 149–151 ꢀC.
GC/MS (MeOH), 1a methyl ester, MS m/z: 297 (Mþ, 32%), 280
(1%), 265 (16%), 251 (1%), 238 (77%), 225 (3%), 212 (20%),196 (100%),
181 (16%), 167 (12%), 151 (56%), 136 (13%), 122 (14%), 101 (22%), 79
(7%), 59 (45%). 1H NMR d 10.53 (s, 1H, CHO), 10.40 (s, 1H, COOH),
8.30 (d, J¼2.6, 1H, Ar), 7.94 (d, J¼2.6, 1H, Ar), 5.31–5.28 (m, 1H, CH),
3.98 (s, 3H, OCH3), 2.19–2.04 (m, 2H, CH2), 1.15 (t, J¼7.4, 3H, CH3);
13C NMR d 188.8, 176.3, 153.9, 151.8, 143.5, 128.9, 115.7, 111.8, 80.5,
The presence of acetic acid in the reaction mixture hinders the
production of the mixed anhydride, therefore in the cyclization tests
made in the presence of acetic acid, there appears to be a higher
competitive process of seven-member ring formation, and for the
acids with a nitro group, also a higher participation of the product in
the decomposition of the ethereal bond 5 can be observed.
56.7, 26.3, 9.3. IR (KBr) n: 3550–3350, 1740–1720, 1695, 1530 cmꢁ1
.
Anal. Calcd for C12H13NO7 (283.07): C, 50.89; H, 4.63; N, 4.95.
Found: C, 50.77; H, 4.71; N, 5.01.
4.2. Synthesis of 2-(2-formyl-6-methoxy-4-nitrophenoxy)-
pentanoic acid (1b)
3. Summary
Starting
from
2-hydroxy-3-methoxy-5-nitrobenzaldehyde
We have found a new course of cyclization of 2-(2-formyl-
6-methoxy-4-nitrophenoxy)alkanoic acids under typical Perkin
reaction conditions. The cyclization brings about, beside benzo[b]-
furan, a seven-member lactone ring of 1,4-benzodioxepin-3-one.
Optimal conditions of the cyclization have been determined, giving
rise to benzo[b]furan with good yield.
(9.9 g, 0.05 mol), methyl 2-bromopentanoate (9.8 g, 0.05 mol), po-
tassium carbonate (6.9 g, 0.05 mol) and DMF (90 mL) the same
procedure was followed as described for compound 1a, to give 1b
as colourless crystals (11.3 g, 76%), mp 125–127 ꢀC.
GC/MS (MeOH), 1b methyl ester, MS m/z: 311 (Mþ, 18%), 267
(24%), 252 (11%), 238 (41%), 221 (6%), 206 (100%), 192 (10%), 177
(7%), 160 (12%), 135 (11%), 119 (9%), 106 (4%), 91 (3%), 77 (5%), 55
(7%). 1H NMR d 10.52 (s, 1H, CHO), 9.10 (s, 1H, COOH), 8.30 (d, J¼2.6,
1H, Ar), 7.93 (d, J¼2.6, 1H, Ar), 5.33 (t, J¼5.9, 1H, CH), 3.98 (s, 3H,
OCH3), 2.06–2.01 (m, 2H, CH2), 1.67–1.57 (m, 2H, CH2), 1.02 (t, J¼7.4,
3H, CH3); 13C NMR d 188.8, 176.4, 153.9, 151.8, 143.5, 128.9, 115.6,
111.7, 79.4, 56.6, 34.9, 18.2, 13.7. IR (KBr) n: 3500–3350, 1740–1725,
1700, 1530 cmꢁ1. Anal. Calcd for C13H15NO7 (297.08): C, 52.53; H,
5.09; N, 4.71. Found: C, 52.45; H, 5.19; N, 4.75.
4. Experimental section
1H and 13C NMR spectra were recorded on a TM Bruker DPX 400
instrument as solutions in CDCl3. Chemical shifts (d) are given from
TMS (0 ppm) as internal standard for 1H NMR, and CDCl3
(77.0 ppm) for 13C NMR. Mass spectra were obtained on an Agilent
Technologies 6890 N apparatus, equipped with mass detector 5973
Network and 30 mꢂ0.2 mm capillary column filled up with
0.25 mm film of a 5% MePh silicate. IR spectra were recorded on
a Specord M 80 Carl Zeiss spectrophotometer. All melting points
were determined using a Boetius apparatus and are uncorrected.
2-Hydroxy-3-methoxy-5-nitrobenzaldehyde (mp 140–142 ꢀC)
was obtained by nitration of 2-hydroxy-3-methoxybenzaldehyde
(o-vanilin), with 100% nitric acid in acetic solution, although it is
commercially available. Methyl 2-bromoalkanoates, -butanoate,
-pentanoate and -hexanoate, were obtained according to the lit-
erature.6 All other reagents and solvents were commercially avail-
able, >98% purity, and used without further purification.
4.3. Synthesis of 2-(2-formyl-6-methoxy-4-nitrophenoxy)-
hexanoic acid (1c)
Starting
from
2-hydroxy-3-methoxy-5-nitrobenzaldehyde
(9.9 g, 0.05 mol), methyl 2-bromohexanoate (10.5 g, 0.05 mol),
potassium carbonate (6.9 g, 0.05 mol) and DMF (90 mL) the same
procedure was followed as described for compound 1a, to give 1c as
beige crystals (11.7 g, 75%), mp 128–130 ꢀC.
GC/MS (MeOH), 1c methyl ester, MS m/z: 325 (Mþ, 13%), 281
(18%), 266 (7%), 252 (9%), 238 (27%), 221 (4%), 206 (100%), 182 (9%),
160 (8%), 135 (9%), 119 (6%), 106 (2%), 91 (2%), 69 (3%), 55 (4%). 1H
NMR d 10.53 (s, 1H, CHO), 8.32 (d, J¼2.6, 1H, Ar), 8.11 (br band, 1H,
COOH), 7.94 (s, 1H, Ar), 5.32 (t, J¼5.1, 1H, CH), 3.98 (s, 3H, OCH3),
2.04 (t, J¼6.2, 2H, CH2), 1.52–1.59 (m, 2H, CH2), 1.42 (t, J¼6.5, 2H,
CH2), 0.95 (t, J¼7.1, 3H, CH3); 13C NMR d 188.8, 176.1, 153.9, 151.8,
143.5, 128.9, 115.8, 111.7, 79.6, 56.6, 32.7, 26.9, 22.3, 13.9. IR (KBr)
4.1. Synthesis of 2-(2-formyl-6-methoxy-4-nitrophenoxy)-
butanoic acid (1a)
A mixture of 2-hydroxy-3-methoxy-5-nitrobenzaldehyde (9.9 g,
0.05 mol), methyl 2-bromobutanoate (9.1 g, 0.05 mol), anhydrous

M. Kowalewska, H. Kwiecien´ / Tetrahedron 64 (2008) 5085–5090
5089
n: 3500–3300,1740–1720,1700,1530 cmꢁ1. Anal. Calcd for C14H17NO7
(311.10): C, 54.02; H, 5.50; N, 4.50. Found: C, 53.91; H, 5.63; N, 4.57.
1540, 1170 cmꢁ1. Anal. Calcd for C12H13NO7 (283.07): C, 50.89; H,
4.63; N, 4.95. Found: C, 50.75; H, 4.69; N, 5.03.
4.4. Synthesis of 2-(2-formyl-6-methoxyphenoxy)butanoic
acid (1d)
4.6. Cyclization of 2-(2-formyl-6-methoxy-4-nitrophenoxy)-
pentanoic acid (1b)
Starting from 2-hydroxy-3-methoxybenzaldehyde (7.6 g,
0.05 mol), methyl 2-bromobutanoate (9.1 g, 0.05 mol), potassium
carbonate(6.9 g, 0.05 mol)andDMF(90 mL)thesameprocedurewas
followed as described for compound 1a. The ester was hydrolyzed by
heating with 5% KOH on a boiling water bath for 2.5 h, to give 1d as
pale beige crystals (8.9 g, 75%), mp 112–113 ꢀC (lit.1f 113–114.5 ꢀC).
GC/MS, MS m/z: 238 (Mþ, 21%), 220 (1%), 207 (2%),194 (14%),179
(2%), 165 (8%), 152 (100%), 137 (11%), 122 (18%), 106 (68%), 93 (8%),
77 (9%), 52 (6%). 1H NMR d 10.62 (s, 1H, COOH), 10.48 (s, 1H, CHO),
7.41 (t, J¼4.4, 1H, Ar), 7.14 (d, J¼3.9, 2H, Ar), 5.03 (t, J¼5.5, 1H, CH),
3.86 (s, 3H, OCH3), 2.10–2.01 (m, 2H, CH2), 1.11 (t, J¼7.4, 3H, CH3).
Starting from acid 1b (2.08 g, 0.007 mol), acetic anhydride
(35 mL) and sodium acetate (5.7 g, 0.07 mol) following a similar
procedure to that described for 1a yielded pure 2b as a beige solid
(0.68 g, 41%). Compounds 3b and 4b were identified in the crude
reaction mixture by GC/MS analysis.
4.6.1. 2-Propyl-7-methoxy-5-nitrobenzo[b]fuþran (2b)
Mp 72–74 ꢀC, GC/MS, MS m/z: 235 (M , 87%), 220 (1%), 206
(100%), 189 (17%), 174 (3%), 160 (49%), 145 (5%), 131 (3%), 117 (17%),
103 (3%), 89 (7%), 76 (3%), 63 (4%), 50 (1%). 1H NMR d 8.07 (s, 1H, Ar),
7.66 (s, 1H, Ar), 6.51 (s, 1H, Ar), 4.08 (s, 3H, OCH3), 2.79 (t, J¼7.4, 2H,
CH2), 1.83–1.78 (m, 2H, CH2), 1.02 (t, J¼7.3, 3H, CH3); 13C NMR
d 162.8, 146.9, 144.5, 144.5, 129.9, 109.8, 103.2, 101.2, 56.5, 30.3, 20.9,
4.5. Cyclization of 2-(2-formyl-6-methoxy-4-nitrophenoxy)-
butanoic acid (1a)
13.7. IR (KBr) n: 3110–2920, 1600, 1590, 1530, 1425, 1340, 1320 cmꢁ1
.
Anal. Calcd for C12H13NO4 (235.08): C, 61.27; H, 5.57; N, 5.95.
Found: C, 61.18; H, 5.63; N, 5.99.
To a mixture of acetic anhydride (35 mL) and sodium acetate
(5.7 g, 0.07 mol), acid 1a (1.98 g, 0.007 mol) was added. The mix-
ture was stirred and heated at reflux for 3.5 h. After it was poured
into ice-water the precipitate was filtered. The crude product was
dissolved in methylene chloride, treated with 5% sodium bi-
carbonate and water. The organic layer was dried, evaporated and
the residue crude analyzed by GC/MS. The brown solid was
recrystallized from methanol to yield pure 2a (0.66 g, 44%) as
a beige solid. After methanol was removed from the filtrate on
a rotary evaporator, the residue was recrystallized from chloro-
form/hexane 1:3 to first yield colourless crystals, identified as 3a
(0.21 g, 9%) and secondly a pale yellow semisolid 4a (0.12 g, 6%).
4.6.2. 2-Propyl-3,5-dihydro-9-methoxy-7-nitro-3-oxo-2H-
benzo[e][1,4]dioxepin-5-yl acetate (3b)
GC/MS, MS m/z: 339 (Mþ, 1%), 311 (2%), 297 (19%), 252 (2%), 239
(5%), 224 (1%), 197 (100%), 180 (5%), 167 (3%), 151 (10%), 136 (3%),
122 (2%), 101 (2%), 83 (2%), 69 (1%), 55 (4%).
4.6.3. 2-Propyl-5-hydroxy-9-methoxy-7-nitro-5H-
benzo[e][1,4]dioxepin-3-one (4b)
GC/MS, MS m/z: 297 (Mþ, 19%), 252 (2%), 239 (5%), 224 (1%), 197
(100%), 180 (5%), 167 (3%), 151 (10%), 136 (3%), 122 (2%), 101 (2%), 83
(2%), 69 (1%), 55 (4%).
4.5.1. 2-Ethyl-7-methoxy-5-nitrobenzo[b]furþan (2a)
Mp 98–100 ꢀC, GC/MS, MS m/z: 221 (M , 100%), 206 (36%), 191
(5%), 175 (45%), 160 (19%), 145 (4%), 131 (5%), 115 (14%), 91 (7%), 77
(6%), 63 (4%), 50 (2%). 1H NMR d 8.07 (d, J¼2.0,1H, Ar), 7.66 (d, J¼2.0,
1H, Ar), 6.51 (s, 1H, Ar), 4.08 (s, 3H, OCH3), 2.87–2.85 (m, 2H, CH2),
1.39–1.35 (m, 3H, CH3); 13C NMR d 164.3, 146.9, 144.5, 144.5, 129.9,
109.8, 102.4, 101.2, 56.5, 21.8, 11.7. IR (KBr) n: 3110, 2980, 2930, 1600,
1590, 1530, 1430, 1335, 1325 cmꢁ1. Anal. Calcd for C11H11NO4
(221.07): C, 59.73; H, 5.01; N, 6.33. Found: C, 59.61; H, 5.13; N, 6.37.
4.7. Cyclization of 2-(2-formyl-6-methoxy-4-nitrophenoxy)-
hexanoic acid (1c)
Starting from acid 1c (2.18 g, 0.007 mol), acetic anhydride
(35 mL) and sodium acetate (5.7 g, 0.07 mol) following a similar
procedure to that described for 1a yielded pure 2c as a beige solid
(0.83 g, 49%). Compounds 3c and 4c were identified in the crude
reaction mixture by GC/MS analysis.
4.5.2. 2-Ethyl-3,5-dihydro-9-methoxy-7-nitro-3-oxo-2H-
benzo[e][1,4]dioxepin-5-yl acetate (3a)
4.7.1. 2-Butyl-7-methoxy-5-nitrobenzo[b]furan (2c)
Mp 45–47 ꢀC, GC/MS, 249 (Mþ, 78%), 234 (3%), 220 (2%), 206
(100%), 190 (9%), 174 (4%), 160 (50%), 145 (4%), 131 (3%), 117 (12%),
103 (4%), 89 (7%), 76 (3%), 63 (3%), 50 (1%). 1H NMR d 7.99 (s, 1H, Ar),
7.59 (s, 1H, Ar), 6.43 (s, 1H, Ar), 4.00 (s, 3H, OCH3), 2.75 (d, J¼6.6, 2H,
CH2), 1.68 (t, J¼6.5, 2H, CH2), 1.35 (d, J¼6.8, 2H, CH2), 0.89 (d, J¼6.6,
3H, CH3); 13C NMR d 163.1, 146.9, 144.5, 129.9, 109.8, 103.1, 101.2,
56.5, 29.6, 28.1, 22.3, 13.8. IR (KBr) n: 3120–2890, 1600, 1590, 1530,
1425, 1335, 1325 cmꢁ1. Anal. Calcd for C13H15NO4 (249.10): C, 62.64;
H, 6.07; N, 5.62. Found: C, 62.53; H, 6.15; N, 5.69.
Mp 107–107.5 ꢀC, GC/MS, MS m/z: 325 (Mþ, 1%), 297 (2%), 283
(27%), 239 (5%), 222 (2%), 197 (100%), 180 (5%), 167 (3%), 151 (12%),
136 (3%), 122 (3%), 108 (2%), 92 (1%), 79 (2%), 63 (2%), 50 (1%). 1H
NMR d 8.11 (s, 1H, Ar), 7.92 (s, 1H, Ar), 6.53 (s, 1H, CH), 4.43 (br s, 1H,
CH), 3.96 (s, 3H, OCH3), 2.37 (s, 3H, CH3), 2.07–2.04 (m, 1H, CH2),
1.94–1.88 (m, 1H, CH2), 1.10 (t, J¼7.4, 3H, CH3); 13C NMR d 171.8,
167.1, 152.2, 146.1, 143.7, 129.5, 114.1, 108.9, 97.6, 76.0, 56.8, 24.1,
20.4, 9.2. IR (KBr) n: 3000–2900, 1810, 1780, 1545, 1200–1180 cmꢁ1
.
Anal. Calcd for C14H15NO8 (325.08): C, 51.70; H, 4.65; N, 4.31. Found:
C, 51.40; H, 4.40; N, 4.21.
4.7.2. 2-Butyl-3,5-dihydro-9-methoxy-7-nitro-3-oxo-2H-
benzo[e][1,4]dioxepin-5-yl acetate (3c)
4.5.3. 2-Ethyl-5-hydroxy-9-methoxy-7-nitro-5H-benzo[e][1,4]-
dioxepin-3-one (4a)
GC/MS, MS m/z: 353 (Mþ, 1%), 325 (2%), 311 (14%), 281 (1%), 266
(2%), 252 (1%), 239 (5%), 197 (100%), 181 (4%), 167 (3%), 151 (8%), 136
(2%), 115 (2%), 97 (2%), 83 (1%), 69 (4%), 55 (2%).
GC/MS, MS m/z: 283 (Mþ, 27%), 239 (5%), 222 (2%), 197 (100%),
180 (5%), 167 (3%), 151 (12%),136 (3%), 122 (3%),108 (2%), 93 (1%), 79
(2%), 59 (2%). 1H NMR d 8.04 (s, 1H, Ar), 7.90 (s, 1H, Ar), 6.65 (d, J¼
5.2, 1H, CH), 4.10 (br s, 1H, CH), 3.97 (s, 3H, OCH3), 2.92 (br s, 1H,
OH), 2.06–2.03 (m, 1H, CH2), 1.92–1.88 (m, 1H, CH2), 1.11 (t, J¼7.4,
3H, CH3); 13C NMR d 171.3, 152.0, 146.0, 143.4, 129.1, 114.0, 108.8,
94.8, 78.2, 56.4, 24.0, 9.0. IR (KBr) n: 3550–3350, 3000–2850, 1810,
4.7.3. 2-Butyl-5-hydroxy-9-methoxy-7-nitro-5H-benzo[e][1,4]-
dioxepin-3-one (4c)
GC/MS, MS m/z: 311 (Mþ, 14%), 281 (1%), 266 (2%), 252 (1%), 239
(5%), 197 (100%), 181 (4%), 167 (3%), 151 (8%), 136 (2%), 122 (2%), 97
(2%), 83 (1%), 69 (4%), 55 (2%).

5090
M. Kowalewska, H. Kwiecien´ / Tetrahedron 64 (2008) 5085–5090
4.8. Cyclization of 2-(2-formyl-6-methoxyphenoxy)butanoic
acid (1d)
References and notes
1. (a) Burgstahler, A. W.; Worden, L. R. Org. Synth. 1966, 46, 28; (b) Bordin, F.;
Bevilacqua, R.; Dabbeni-Sala, F. Gazz. Chim. Ital. 1969, 99, 1177; Chem. Abstr.
1970, 72, 90167; (c) Suzuki, T.; Horaguchi, T.; Shimizu, T.; Abe, T. Bull. Chem.
Soc. Jpn. 1983, 56, 2762; (d) Einhorn, J.; Demerseman, P.; Royer, R. Can. J. Chem.
1983, 61, 2287; (e) Brady, W. T.; Giang, Y. F. J. Org. Chem. 1986, 51, 2147; (f)
Brady, W. T.; Giang, Y. F.; Marchand, A. P.; Wu, A. J. Org. Chem. 1987, 52, 3457;
Startingfromacid1d(1.67 g, 0.007 mol), aceticanhydride(35 mL)
and sodium acetate (5.7 g, 0.07 mol) following a similar procedure to
that described for 1a yielded a mixture of 2d (41%) and 3d (50%).
´
(g) Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969; (h) Kwiecien, H.
4.8.1. 2-Ethyl-7-methoxybenzo[b]furan (2d)
Pol. J. Chem. 1993, 67, 661; (i) Kakigami, T.; Baba, K.; Usui, T. Heterocycles 1998,
48, 2611.
2. (a) Kwiecien´ , H. Pol. J. Chem. 1998, 72, 2254; (b) Zhang, J.; Jacobson, A.; Rusche, J.
R.; Herlihy, W. J. Org. Chem. 1999, 64, 1074; (c) Kwiecien´ , H.; Szychowska, M.
Synth. Commun. 2007, 37, 3599.
GC/MS, MS m/z: 176 (Mþ, 100%), 161 (99%), 146 (19%), 131 (6%),
118 (15%), 103 (8%), 90 (7%), 77 (10%), 63 (5%), 50 (3%).
3. (a) March, J. Advanced Organic Chemistry: Reaction, Mechanisms, and Structure,
4th ed.; John Wiley and Sons: New York, NY, 1992; pp 522–524; (b) Katritzky, A.
R.; Rees, Ch. W. Comprehensive Heterocyclic Chemistry: The Structure, Reactions,
Synthesis and Uses of Heterocyclic Compounds; Bird, C. W., Cheeseman, G. W.,
Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 678–710; (c) Stroermer, K.; Schaeffer,
M. Chem. Ber. 1903, 36, 2864; (d) Takagi, K.; Ueda, T. Chem. Pharm. Bull.
1975, 23, 2427; (e) Alemagna, A.; Baldoli, C.; Del Buttero, P.; Licandro, E.;
Maiorana, S. Synthesis 1987, 2, 192; (f) Herconet, A.; Le Corre, M. Tetrahedron
1981, 37, 2867; (g) Ro¨hrkasten, R.; Konrad, M. Methoden der Organischen
Chemie (Houben–Weyl); Thieme: Stuttgart, 1994; Vol. E 6b, p 94; (h) Cher-
kaoui, O.; Nebois, P.; Filion, H. Tetrahedron 1996, 52, 9499; (i) Kwiecien´ , H.;
4.8.2. 2-Ethyl-3,5-dihydro-9-methoxy-3-oxo-2H-
benzo[e][1,4]dioxepin-5-yl acetate (3d)
GC/MS, MS m/z: 280 (Mþ, 59%), 238 (1%), 220 (2%), 207 (1%), 193
(23%),176 (42%), 152 (100%), 137 (42%), 121 (11%),106 (19%), 93 (6%),
77 (8%), 55 (4%).
4.9. Synthesis of acetic acid acetoxy-(2-acetoxy-3-methoxy-5-
nitrophenyl)methyl ester (5)
´
Witczak, M.; Rosiak, A. Pol. J. Chem. 2004, 78, 249; (j) Witczak, M.; Kwiecien,
A mixture of 2-hydroxy-3-methoxy-5-nitrobenzaldehyde (0.6 g,
0.003 mol), acetic anhydride (12 mL) and sodium acetate (2.5 g,
0.03 mol) was heated at reflux for 30 min. After it was poured into
ice-water, the precipitate was filtered, washed with water and
dried. Purification was achieved by recrystallization from methanol
to yield 5 (0.35 g, 40%) as beige crystals, mp 114–116 ꢀC.
H. Synth. Commun. 2005, 35, 2223; (k) Mohamadi, F.; Spees, M. M. J. Med.
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Severino, D.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2311; (g) Dai, W. M.; Lai, K.
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59, 9571.
GC/MS, MS m/z: 341 (Mþ, 1%), 282 (2%), 239 (9%), 221 (3%), 197
(100%), 181 (4%), 167 (3%), 145 (8%), 122 (1%), 103 (8%), 79 (1%), 65
(1%), 51 (1%). 1H NMR d 8.14 (d, J¼2.5, 1H, CH), 7.92 (s, 1H, Ar), 7.86
(d, J¼2.5, 1H, Ar), 3.94 (s, 3H, OCH3), 2.37 (s, 3H, OCH3), 2.13 (s, 6H,
OCH3); 13C NMR d 168.2, 167.6, 152.2, 146.1, 142.9, 130.5, 114.7, 108.2,
83.9, 56.8, 20.7, 20.4. IR (KBr) n: 1790–1770, 1545, 1370, 1345, 1235,
1200, 1170 cmꢁ1. Anal. Calcd for C14H15NO9 (341.07): C, 49.27; H,
4.43; N, 4.10. Found: C, 49.11; H, 4.53; N, 4.17.