Domino diels-alder reactions of N-methoxyethyl-7-oxa-norbornadiene-2,3- dicarboximide: An elusive, highly reactive dienophile

Article abstract of DOI:10.1016/j.tet.2010.12.032

Flash vacuum pyrolysis (FVP) has been used to generate the novel 7-oxa-norbornadiene-2,3-dicarboxylic imide that in situ gave an unprecedented cycloaddition reaction cascade with the imidofuran, a side-product of FVP. Stereoselectivity of cycloadditions w

Full text of DOI:10.1016/j.tet.2010.12.032

Tetrahedron 67 (2011) 1580e1588
Contents lists available at ScienceDirect
Tetrahedron
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Domino DielseAlder reactions of N-methoxyethyl-7-oxa-norbornadiene-2,
3-dicarboximide: an elusive, highly reactive dienophile
,
b
b
c
ꢀ a
*
Davor Margetic , Douglas N. Butler , Ronald N. Warrener , Yasujiro Murata
a
ꢁ
ꢀ
Laboratory for Physical-Organic Chemistry, Division of Organic Chemistry and Biochemistry, RuCer Boskovic Institute, 10001 Zagreb, Croatia
b Centre for Molecular Architecture, Central Queensland University, Rockhampton, Queensland 4702, Australia
c Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2010
Received in revised form 23 November 2010
Accepted 13 December 2010
Available online 17 December 2010
Flash vacuum pyrolysis (FVP) has been used to generate the novel 7-oxa-norbornadiene-2,3-dicarboxylic
imide that in situ gave an unprecedented cycloaddition reaction cascade with the imidofuran, a side-
product of FVP. Stereoselectivity of cycloadditions was studied with the aid of density functional cal-
culations, which fully support observed exo/endo-selectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
DielseAlder reaction
Furan
Flash vacuum pyrolysis
DFT calculations
Transition states
1. Introduction
2. Results and discussion
Norbornadiene and 7-hetero-norbornadiene-2,5-carboxylic an-
hydrides and imides are interesting for both synthetic and theo-
retical reasons. For instance, a computational study of these dienes1
Previously we have used a Zn/Ag debromination of imide 5 to
prepare 7-oxanorbornadiene imide 1b, which was trapped in situ
with various cyclic dienes.5 These conditions were too harsh to
isolate and spectroscopically detect 1b. An FVP route seemed to be
more promising for the isolation and spectroscopic characteriza-
tion of its counterpart 1a. We also expected that adducts of imide
1a would be more stable and have better chromatographic prop-
erties than those of anhydride 2 (due to anhydride susceptibility to
hydrolysis) and so embarked on its synthesis.
showed that both
substituted double bond (by 6.2ꢀ and 4.8ꢀ, respectively, using a DFT
B3LYP/6-31G calculations). These molecules are also highly reactive
1 and 2 have significantly pyramidalised
*
dienophiles, useful in the synthesis of sesquinorbornadienes.
We have previously used flash vacuum pyrolysis (FVP)2 on an-
hydride 33 to generate corresponding 7-oxanorbornadiene anhy-
dride2 (Scheme 1), butthat FVPfailed toproduceits 7-azaand 7-thia
counterparts.4 Here we report the results of FVP experiments on
corresponding imides 4aed.
2.1. FVP of 4a
O
O
O
O
O
O
O
In a series of experiments, it was found that FVP of imide 4a at
375 ꢀC (0.005 mbar) produced a mixture of products, while further
increases of temperature to 390, 400, 420, 430, 445, and 480 ꢀC
gave increasingly more of the over-cracked product 2-methox-
yethyl-1H,3H-pyrrolo[3,4-c]furan-1,3-dione 6a (Scheme 2), with its
Br
Br
O
O
NR
O
O
O
O
NMe
NR
O
O
O
O
O
O
1
4
5
2
3
Series
1c R = PMB
1d R = CH2CH2OAc
1a R = CH2CH2OMe
1b R = Me
distinctive aromatic singlet at d 7.76. This was the most volatile
product depositing furthest away from the pyrolysis oven, resulting
in the total thermal destruction of starting material.6 At 445 ꢀC
a yield of 54% of furan 6a was obtained. Even at the lowest tem-
peratures necessary to accomplish furan elimination, imide 6a was
detected, along with the substrate 4a. The results suggest that retro
DielseAlder acetylene elimination in the imide case was easier than
Scheme 1.
* Corresponding author. Tel.: þ385 1 456 1008; fax: þ385 1 468 0195; e-mail
ꢀ
address: margetid@irb.hr (D. Margetic).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.032

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D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1581
from anhydride 3 to obtain 7. However, we could not spectro-
scopically detect the desired imide 1a.
O
RN
O
H
H
O
FVP
FVP
375 o
4a
+
O
1a
+
O
O
430 oC
C
O
O
not observed
6a
7
R = CH2CH2OMe
Scheme 2. End-products of FVP of 4a.
All attempts to isolate the intermediate product 1a were un-
fruitful so we have treated the FVP products with anthracene
(CHCl3, 60 ꢀC 1 h) and were thus able to isolate four cycloadducts
9e12 by chromatographic separation (in 11, 13, 4, and 9% yields,
respectively, Scheme 3). They originate from the domino Diel-
seAlder reaction7 of N-methoxyethyl-7-oxanorbornadiene-2,3-
dicarboximide 1a, furan 6a, and anthracene. Variation of FVP
temperature causes a change in product composition (Table 1).
When anthracene was added to the FVP tube prior a pyrolysis
(excess), 1:1 cycloadduct 9 was formed exclusively (41% yield),
while 6a remained unreacted. This result suggests higher reactivity
of anthracene than 6a, probably due to the formation of less stable
intermediate alkene adduct in the case of 6a.
O
RN
O
O
O
8
FVP
+
4a
1a
375 oC
CHCl3
O
O
O
60 oC
1h
N
R
9
O
10
NR
O
O
RN
O
O
O
O
RN
O
RN
O
+
O
RN
+
O
O
O
Fig. 1. Mid-portion of 1H NMR spectra of adducts 9e12.
O
O
O
O
O
NR
NR
O
O
6a
O
O
O
O
NR
O
NR
O
11
12
R = CH2CH2OCH3
spectra showed that aromatic shielding caused the chemical shift of
the CH2 protons in product 9 from 3.36 ppm in 4a to 2.81 ppm. In
products 10e12, the shielding is only found for the methylene group,
which is adjacent to the anthracene unit. The CH2 proton signals are
shifted to even higher fields (2.52, 2.52, and 2.34 ppm, respectively),
where the methylene protons in adduct 12 experience the largest
shielding. The methoxy groups are apparently not so shielded, but
still follow the same descending order (9e12: 3.13, 2.99, and
2.96 ppm, in 4a 3.29 ppm). On the other hand, the olefinic protons in
9 were shielded to a lesser extent (6.58 ppm in 4a vs 6.41 ppm in 9).
However, these shieldings alone were not sufficient to assign the
exact stereochemistry of products. Hence, thecombined results of 2D
NMR (COSY and NOESY experiments) and molecular modeling were
used for structural elucidation of 10e12.
Scheme 3. FVP of 4a.
Table 1
Ratios of cycloadducts, anthracene added after FVPa
T/ꢀC
4a
6a
9
10
11
12
375
390
390b
400
420
430
445
480
5
4
10
0.5
2
0.1
0.8
1
1
1
d
0.1
0.5
d
1
1
d
Trace
Trace
d
1
1.5
1.5
1.5
1.1
1.5
2.01
1.1
0.7
0.1
0.7
0.5
1
1
0.2
1
0.2
0.1
0.1
d
0.4
0.1
0.4
0.1
1
d
0.1
d
Obtained by 1H NMR analysis.
Anthracene added in FVP tube before pyrolysis.
a
b
Molecular modeling (BLYP/6-31G ) of adducts with the exo,exo-
*
stereochemistry indicates that protons of the two methylene
groups positioned on neighboring imide nitrogens are separated by
Products 9e12 show increased spectral complexity, as illustrated
in Fig.1. For instance, the 1H NMR of 12 contained of series of proton
resonances, the most distinctive being vinylic 6.34, bridgehead (five
lines) 4.65, 4.69, 4.79, 4.86, 4.92, and methoxy (four lines) 3.09,
3.23 (two signals overlapped), 3.23, which is completely consistent
with the assigned structure, and further supported by the 32-line 13C
NMR, and high-resolution mass spectrometry (m/z¼984.3065, calcd
984.3065). Spectral data for all adducts supports a stereoselective
DielseAlder reaction, giving only exo,endo-adducts. exo-Structure of
cycloadduct 9 was elucidated from its spectral data, Cs symmetry and
compared with the independently prepared N-methyl derivative 9b
(by debromination of 5 and trapping with anthracene). Proton NMR
ꢂ
2.61 A, while the proximal bridgehead protons are separated by
ꢂ
d
2.52 A. For this structure, positive NOE correlations were expected.
d
d
In the case of exo,endo-stereochemistry bridgehead protons are
ꢂ
separated by 3.41 A, for which weak NOE correlation is assumed.
Therefore, the lack of NOE correlations between the ethylene
triplets on neighboring imide nitrogens, and the lack of NOE cor-
relations among bridgehead singlets were suggestive of an
exo,endo-stereochemistry.
Experimental data suggest that the initially formed imide 1a
and the imidofuran 6a reacted further in a domino manner, either
in the pyrolysis furnace, or out in the tube, since they have similar

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D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1582
volatilities and deposit together on the cooler parts of the pyrolysis
tube. Here, imidofuran 6a acts both as a diene and a masked
dienophile, whose dienophilic character is developed after initial
DielseAlder cycloaddition. This domino reaction gave at the first
instance, the 1:1 adduct 13, which was also reactive dienophile,
producing the domino 2:1 adduct 14 and the 3:1 adduct 15
(Scheme 4). It is possible that some higher domino cycloadducts
were formed and that these have not been detected. When
a chromatographic workup was applied to the mixture of products
13e15, we have been able to spectroscopically detect adducts 13
and 14 in partially purified form, as well as hydrolysis product 13b.
The key spectroscopic evidence for intermediate cycloadduct 13 are
two methyl and two bridgehead proton resonances and the
O
RN
O
O
O
8
FVP
360 o
+
4c
+
1c
O
CHCl3
60 oC
2h
O
C
O
N
R
O
17
N
16
O
R
not isolated
R = PMB
O
O
X-ray structure
O
RN
O
O
N
O
6c
18
molecular ion (1H NMR:
HRMS-ESI: m/z¼416.1223), while for 14 three methyl and three
bridgehead resonances were found (1H NMR:
NMe 3.18, 3.19, 3.29,
bridgehead 4.70, 5.03, 5.59, HRMS-ESI: m/z¼587.1754).
d
NMe 3.31, 3.32, d bridgehead 4.80, 5.57,
H
not detected
d
Scheme 5. FVP of 4c.
d
substrate: cerium(IV) ammonium nitrate was used,9 while FVP
conditions used in our work are better replicated by reflux heating
in TFA, or MW irradiation in TFA/DCM at 120 ꢀC.8
R
N
O
CONHR
Studies on related imides showed that FVP of acetate 4d
required slightly higher temperature than 4a (420 ꢀC). Imidofuran
6d is the dominant product in the mixture, as indicated by its
HOOC
O
O
FVP
375 o
O
4a
1a
+ 6a
C
O
O
distinctive aromatic singlet at
d 7.80. The presence of 6d is even
O
O
NR
O
more pronounced in the FVP experiment carried out at 460 ꢀC
(Scheme 6). Even at this temperature, significant amount of un-
cracked imide 4d is present. The detailed 1H NMR analysis of the
reaction mixture revealed that alongside 6d cycloadducts 19 and 20
were formed in approx. 1:1.5 ratio. For the formation of 19 in-
dicative is the presence of two bridgehead proton resonances
NR
13b
O
13
R
N
6a
O
O
O
O
O
RN
O
RN
O
O
6a
O
O
O
O
NR
O
(singlets,
d 4.73, 4.96), while in the case of 20 one may found three
O
NR
O
O
4.65, 4.91, 4.94). Aromatic ring shielding caused the 1H NMR
O
O
(d
O
NR
O
NR
R = CH2CH2OCH3
O
14
chemical shift of the ethylene triplets in product 30 to 2.82 and
3.32 ppm (4d: 3.47 and 4.03 ppm), while in 20 these resonances are
found at 3.13 and 3.24 ppm. Methyl proton resonances in 19 and 20
were also shifted to higher field, 1.89 and 1.77 ppm, respectively
(starting from 2.00 ppm in 4d).
15
Scheme 4. Intermediate products in FVP of 4a.
2.2. FVP of 4bed
FVP of the corresponding N-methyl imide 4b (at 395 ꢀC,
0.001 mbar) gave a similar complex mixture to 4a and no attempts
was made to separate the reaction mixture. When the temperature
was raised to 440 ꢀC furan 6b was formed as a major product. Again,
no conclusive spectroscopic evidence of formation of imide 1b was
obtained.
O
RN
O
RN
O
O
O
8
FVP
+
4d
O
1d
+
460 oC
O
O
CHCl3
60 oC
1h
O
N
R
O
N
O
O
20
6d
19
R
Inconsistent results were obtained in the case of p-methox-
ybenzyl (PMB) substituted imide 4c (Scheme 5). Thus, FVP of 4c at
360 ꢀC yielded a complex mixture of products, which was separated
by chromatography. Most notable differences in comparison with
products obtained by FVP of 4a are the lack of higher 3:1 and 4:1
adducts. In addition, imidofuran 6c was not detected, presumably
due to its instability in the reaction conditions. Experimental sup-
port for this explanation is given by the exclusive formation of 1:1
and 2:1 adducts 17 (18% yield) and 18 (10%), and the presence of
larger proportion of polymeric material as compared to FVP of 4a.
1 : 1.5
R = CH2CH2OAc
Scheme 6. FVP of 4d.
Further synthetic studies showed that 7-oxanorborneno imide
2110, a partially saturated counterpart of 7-oxanorbornadieno imide
4b showed similar chemical behavior in the pyrolysis furnace
(Scheme 7). Thus, FVP of 21 at 380 ꢀC yielded a mixture of products,
in which furanoimide 6b dominates. Reduction of FVP temperature
to 340 ꢀC gave a mixture of 21, 22, 6b, and 25 in a 0.8:3.4:0.1:0.2
ratio. While the existence of the intermediate product 1a could not
be proven by means of 1H NMR spectroscopy, it was possible to
The 1H NMR spectrum of 17 consists eight singlets (
3.99, 4.29, 4.66, 4.76, 4.91, and 5.87) and eight aromatic multiplets
6.60, 6.70, 6.74, 6.77, 6.98, 7.11, 7.12, and 7.21), while the 13C NMR
d 3.77, 3.79,
(d
detect its saturated counterpart 22 in the crude pyrolysate (d NMe
exhibited 22 resonances. Surprisingly, instead of substituted 1:1
cycloadduct 16, deprotected 1:1 adduct 18 was isolated and fully
characterized by means of 1D NMR spectroscopy and X-ray struc-
tural analysis (Scheme 4). The 1H NMR spectrum of 18 shows three
singlets and four aromatic multiplets, while 13C NMR contains
eleven carbon resonances, m/z¼341.1056 calcd 341.1052. The most
characteristic feature of 18 was the proton resonance of imide
group positioned at 6.69 ppm. Several PMB group deprotection
methods were published,8 for the specific dioxanorbornene 4c
2.96,
d
bridgehead 5.36, m/z¼179.0580). Its formation was pre-
viously indirectly proven by hydrogenation reactions of imide 5.10
In addition, the intermediate cycloadduct 25 was spectroscopi-
cally observed (d NMe 3.00, 3.02, d bridgehead 4.44, 5.59) and
confirmed by mass spectrometry (m/z¼330.0850). These reactive
intermediates could not be isolated, but were converted to the
corresponding anthracene cycloadducts 23 and 24 by heating at
70 ꢀC for 1 h in chloroform solution. Products 23 and 24 were
isolated in 35% and 5% yield, respectively.

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D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1583
O
O
O
MeN
O
NMe
O
O
O
O
O
+
FVP
33
8
O
340 oC
O
O
Me
N
O
CHCl3
+
O
NMe
N
O
35
O
N
70 o
1h
C
34
O
Me
O
Me
32
O
O
O
MeN
O
O
N
O
O
37
Me
6b
Scheme 7. FVP of 21.
2.3. Microwave reactions
6-31G method was used. In addition, two recently developed DFT
*
functionals were employed (BMK14 and M052X15), which are spe-
cifically designed for obtaining better reaction energetics. Since
flexibility of methoxyethyl substituents in 1a and 6 significantly
increases computational time, CH2CH2OCH3 groups were replaced
by an H atom. This simplified reaction system is still a valid model,
since all important structural and electronic features of studied
system remained. There are four possible modes of diene approach
It is known that rates of DielseAlder11 and retro DielseAlder re-
actions are accelerated under microwave conditions.12 Since recent
literature reports showed that FVP conditions could be successfully
replaced by MW conditions,13 we anticipated that both reactions
(conductedinsinglereactionpot)willbenefitfromrateenhancement
by microwave irradiation. Thus, the 7-oxanorborneno maleimide 4a
was subjected to microwave heating in order to compare microwave
and FVP conditions. Samples of 4a were heated in a closed-vial single
mode MW reactor for 5 min at temperatures varying from 200 to
250 ꢀC (power 250 W). At 200 ꢀC, maleimide 4a was recovered un-
changed, while at temperatures above 230 ꢀC, 1H NMR gave no
spectral support for the production of expected cycloadducts in the
crude pyrolysate, whereas 4a starts to decompose forming complex
mixture consisting mainly of polymers. Similar results were obtained
with maleimide 4c (MW at 200e220 ꢀC, 5 min).
to the p-bond of norbornadiene of type 1a: two of these are from
the top (exo-) face (exo,exo- and exo,endo-TS1 and TS2) (defined in
the respect to the norbornene moiety), and two approaches are
from the bottom (endo-) face (endo,endo- and endo,exo-TS3 and
TS4). Modes of approach of diene 6 to 1:1 and 2:1 adducts were
named accordingly. A summary of the computational results is
given in Fig. 2.
The calculated transition state geometries represent a con-
certed, synchronous cycloaddition mechanism, as illustrated in
Fig. 3 for TS1 and TS2. The most interesting aspect of the calculated
geometries is the length of the newly formed bonds between the
dipole and dipolarophile. Survey of the data reveals that the newly
2.4. Quantum-chemical calculations
ꢂ
forming C/C bonds are separated by 2.175e2.325 A, which are
The origins of the experimentally observed stereoselectivities
obtained in domino DielseAlder reactions of 1a and furan 6 and
additional support for structural assignments were sought com-
putationally. For this purpose, transition state calculations, using
density functional theory (DFT) were employed. A standard B3LYP/
slightly longer than the bond lengths calculated for a series of
hydrocarbon pericyclic reactions.30 These TS structures possess
five-membered furan moiety where the oxygen atom is tilted away
from planarity by
a
¼25.8 and 15.0ꢀ, respectively.
exo,exo-
exo,endo-
endo,exo-
endo,endo-
H
N
TS2
O
O
O
O
O
O
O
O
NH
O
NH
O
O
<
<
<
O
Reaction 1
O
NH
O
O
NH
O
O
O
O
HN
O
O
NH
NH
O
TS1
TS3
O
TS4
O
Eact
19.6/19.7/20.8
14.6/15.3/16.4
22.6/25.1/24.1
24.9/21.5/27.3
O
HN
H
N
O
O
O
O
O
O
O
O
HN
O
O
HN
O
HN
O
NH
NH
O
O
O
O
O
O
<
O
NH
Reaction 2
O
<
O
<
O
O
O
O
O
O
O
O
O
O
TS10
NH
O
TS9
NH
NH
O
NH
TS11
O
O
TS12
Eact
18.4/20.1/13.7
22.9/26.3/21.9
47.7/48.6/44.2
50.9/49.2/47.2
H
N
Reaction 3
O
O
O
O
HN
O
O
HN
O
O
O
O
O
HN
O
O
O
O
HN
O
NH
O
O
NH
O
O
O
O
O
<
O
NH
<
<
O
O
O
O
O
NH
O
O
O
O
O
O
NH
O
O
NH
O
O
O
NH
O
O
NH
NH
O
O
O
O
TS13
NH
TS14
HN
TS15
O
TS16
O
Eact
19.2/26.1/18.6
23.6/26.7/23.2
48.5/57.5/41.0
52.2/56.2/43.3
Fig. 2. B3LYP/6-31G
*
, BMK/6-31G
*
, and M052X/6-31G
activation energies (kJ molꢁ1).
*

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D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1584
to reactions 2 and 3 (TS11, TS12, TS15, and TS16). This difference
could be rationalized by a significant increase in steric interactions
of the incoming diene with the 7-oxanorbornane bridge, which
does not exist in TS3 and TS4. These predictions are in good ac-
cordance with previously published experimental and theoretical
results on norbornene
tion for preferred exo-addition to the
p
-facial selectivity.18e22 Plausible explana-
-bond of norbornadiene of
p
type 1a may be offered in terms of the non-equivalent orbital ex-
tension and double bond pyramidalization. Pyramidalization an-
gles of 6.2, 12.4, and 11.6ꢀ were calculated for norborene reactants
13 (R¼H), 14 (R¼H), and 15 (R¼H), at the B3LYP/6-31G
*
level,
respectively. Reactants 14 (R¼H) and 15 (R¼H) are norbornenes,
which are always more pyramidalized than corresponding nor-
bornadienes, due to electronic interactions.23 It could be seen that
relative activation energies are not correlated with the extent of
pyramidalization, indicating that other factors play an important
role in determining their reactivity. The other factor governing the
Fig. 3. B3LYP/6-31G optimized structures of TS1 and TS2.
*
The hybrid density functionals B3LYP, BMK, and M052X showed
verygood qualitative agreement amongst themselves. Therefore, we
may conclude with a confidence that TS2 has the smallest Ea, while
the relative activation energies increase in the following order:
Ea(TS2)<Ea(TS1)<Ea(TS4)<Ea(TS3); Ea(TS10)<Ea(TS9)<Ea(TS11)<
Ea(TS12); and Ea(TS14)<Ea(TS13)<Ea(TS16)<Ea(TS15). The DFT16
calculations clearly indicate that the approach of diene (imido-
furan) 6 from the exo-face of the dienophile is energetically pre-
ferred overendo-approach (Fig. 2). Regardless of the functional used,
preference for exo-addition were always obtained. Furthermore,
energy differences between exo,exo- and exo,endo-TSs are larger
than 4 kcal molꢁ1, which indicates that reactants could achieve
stereoselective cycloadditions.17 The addition of the second and
third molecule of 6 also favors an exo,endo-approach (in TS10 and
TS14) by4.5 kcal molꢁ1. This conclusion is in full accordancewith our
experimental data. The comparison of B3LYP with new BMK and
M052X DFT methods, showed that both methods perform well for
this particular reaction, giving relative Eas, which are very close to
those estimated by B3LYP functional.
preference to exo-addition to the p-bond of norbornadiene of type
1a was identified as non-equivalent orbital extension.
Fig. 4 depicts the LUMO of reactant 13 (R¼H), plotted on elec-
tron density isosurface. The inspection of isosurfaces reveals that
there is orbital non-equivalency between the exo- and endo-p-
faces. There is a larger electron density located on the exo-face,24
which in the combination with the steric hindrance imposed at
the endo-face contributes to the exo-face preference.25
Repulsive steric interactions are nicely visualized when
N-methoxyethyl substituents were added, such as in the product
12 (Fig. 5c). Furthermore, Fig. 5 depicts electrostatic potential
surfaces for TS13 and TS14. Here repulsive OeO lone electron pair
interactions in the case of the exo,exo-approach in TS13 are
clearly visible, indicating that exo,endo-approach (TS14) is
preferred.
An interesting observation is the dramatic increase in activation
energy for endo-addition going from the first reaction (TS3 and TS4)
3. Conclusion
Flash vacuum pyrolysis (FVP) has been used as a powerful tool to
generate the novel 7-oxa-norbornadiene-2,3-dicarboxylic imide
that in situ gave a domino DielseAlder cycloaddition reaction
cascade with over-cracked furanoimide. The furanoimide product
behaves in an unprecedented manner, firstly as 1,3-diene, and after
cycloaddition, takes place in subsequent DielseAlder reaction as
a highly potent dienophile. Exclusive formation of exo,endo-ad-
ducts in these cycloadditions was studied by the aid of density
functional calculations and rationalized by the exo-pyramidaliza-
tion of norbornene p-bond, steric and oxygen lone pair repulsions.
The 1H,3H-pyrrolo[3,4-c]furan-1,3-diones 6a and 7 are interesting
novel dienes/masked dienophiles, which, upon DielseAlder
reaction deliver highly activated dienophilic double bonds, and the
synthetic uses of these observations are currently being
investigated in our laboratories.
Fig. 4. LUMO of 13(R¼H) plotted on electron density isosurface (isovalue¼0.002
electrons/au3): (a) side-view, (b) exo-face, (b) endo-face, (c) exo-face.
Fig. 5. (a) B3LYP/6-31G
*
optimized structure of product 12 and electrostatic potential surfaces for (b) TS13, (c) TS14 (isovalue¼ꢁ20 au).26,27

ꢀ
D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1585
4. Experimental part
4.1. General
ne (7 mL) was added dropwise to an ice-cooled solution of anhydride
3 (3.00 g, 12.931 mmol) in CHCl3 (60 mL). The solution was allowed to
stir at room temperature for 12 h. To this mixture Ac2O (12 mL) was
added and stirred below 25 ꢀC for 12 h. The solution containing solid
was cooled in an ice bath, precipitate collected by filtration and
washed with cooled chloroform. Amic acid (4.0 g) was dissolved in
Ac2O (25 mL) and Et3N (4 mL), and the mixture stirred at 50e60 ꢀC for
3 days. Reaction mixture was cooled to room temperature, precipitate
collected by filtration, and washed with water to obtain 4d as colorless
crystals (2.8 g). Mother liquor was evaporated off under high vacuum,
and solid material was washed with water to obtain additional
amount of the title compound 4c (850 mg, total yield 64.6%, mp
186e188 ꢀC).
dH (400 MHz, CDCl3) 6.59 (4H, s), 5.26 (4H, s), 4.04 (2H, t,
J¼5.12 Hz), 3.48 (2H, t, J¼5.12 Hz), 2.02 (3H, s), dC (100 MHz, CDCl3)
174.4, 170.6, 139.4, 81.6, 69.7, 60.9, 37.7, 21.1; nmax (KBr) 3144, 1693,
1678,1393, 1206 cmꢁ1; HRMS (ESI): Mþ, found 347.1372, C18H21NO6
requires 347.13689.
FVP of 4a. In a typical run, FVP of 4a (30 mg, 0.104 mmol) at
420 ꢀC produced a mixture, which was dissolved in chloroform
(1e2 mL) and treated with anthracene (100 mg, 0.561 mmol) for
2 h at 60 ꢀC. Reaction mixture was subjected to radial chromatog-
raphy (petroleum ethereethyl acetate 10:1, then the solvent po-
larity was gradually increased to 1:1) to obtain products, in order of
elution: anthracene, 6a, 4a, 9, 10, 11, and 12.
The NMR spectra were recorded in CDCl3 solutions containing
tetramethylsilane as internal standard on a Bruker AMX-300 or
a Bruker Avance DPX-400 NMR spectrometer fitted with a gradient
quattro nucleus probe. Melting points were determined using
a Gallenkamp digital melting point apparatus and are uncorrected.
The high-resolution mass spectra were recorded on a Micromass
Platform II single quadrupole AutoSpec instrument (ESMS, elec-
trospray mass spectrometry in CH2Cl2). Radial chromatography was
carried out with a chromatotron, Model No. 79245 T, using 1 mm
plates with silica gel 60 F254 as the stationary phase.
Flash-vacuum experiments were conducted under vacuum
(0.001 mbar) in a 600ꢂ10 mm Pyrex tube heated by a horizontally
mounted ‘Thermolyne’ model 21100 tube furnace. Products were
collected at the end of furnace on cooler part of the tube. Volatile
products (furan and acetylene) were condensed in liquid nitrogen
trap. Allnewcompounds wereisolatedby radial chromatographyand
gave satisfactory spectroscopic and analytical data (accurate mass).
Microwave assisted reactions were conducted in CEM Discov-
erÒLabmateTH/ExplorerPLSÒ single mode microwave reactor using
closed reaction vessel technique (power¼125 W).
N-2-Methoxyethyl carboximide precursor 4a was prepared by
previously published procedure,28 by reaction of anhydride 3 with
methoxyethyl amine, followed by cyclisation with acetic anhydride.
4.1.4. 1-Methoxyethyl-1-aza-5-oxabicyclo[3.3.03,7]octa-3,6-diene-
2,8-dione (6a). Compound 6a (18 mg, 40%, mp 104e106 ꢀC); dH
(400 MHz, CDCl3) 7.76 (2H, s), 3.82 (2H, t, J¼5.6 Hz), 3.59 (2H, t,
J¼5.6 Hz), 3.34 (3H, s); dC (100 MHz, CDCl3) 69.2, 161.6, 138.7, 122.4,
58.6, 37.8; nmax (KBr) 3047, 1788, 1599, 1389, 1219 cmꢁ1; HRMS
(ESI): Mþ, found 195.0529, C9H9NO4 found 195.0531.
4.1.1. (2a,5a,7a,10a)-12-Methoxyethyl-12-aza-14,15-dioxapenta cy-
clo[4.4.3.12,5.17,10.02,7] pentadeca-3,8-diene-11,13-dione (4b)11. An aq
ueous solution of methylamine (25e30%, 3 mL) was added dropwise
to an ice-cooled solution of anhydride 3 (645 mg, 2.783 mmol) in
ethanol (5 mL). The solutionwas allowed to stirat room temperature
for 2 h. The solvent was evaporated under reduced pressure (water
bath temperature 20e30 ꢀC) to give the intermediate amic acid as
brown oil. Without further purification, this oil was treated with
Ac2O (2 mL), NaOAc (400 mg), and the mixture stirred at 50e60 ꢀC
for 1 h. The solvent was evaporated under high vacuum, residue
dissolved in CH2Cl2, washed with water, dried over MgSO4, and the
solvent was evaporated off to produce solid material, which was
recystallised from EtOAc to yield the title compound 4b as colorless
crystals (300 mg, 44%, mp 241e244 ꢀC).
4.1.5. (2a,9a,11a,14a)-16-Methoxyethyl-16-aza-18-oxahepta cyclo[8.
4.3.42,9.111,14.01,10.02,9.03,8]tetracosa-3,5,7,12,19, 21,23-heptaene-15,17-
dione (9). Compound 9 (9 mg, 11%, mp 108e111 ꢀC); dH (400 MHz,
CDCl3) 7.32 (2H, dd, J¼3.3 , 5.5 Hz), 7.24 (2H, dd, J¼3.3 , 5.5 Hz), 7.18
(2H, dd, J¼3.1 , 5.5 Hz), 7.07 (2H, dd, J¼3.1 , 5.5 Hz), 6.41 (2H, s), 4.81
(2H, s), 4.75 (2H, s), 3.11 (2H, t, J¼6.2 Hz), 3.13 (3H, s), 2.81 (2H, t,
J¼6.2 Hz); dC (100 MHz, CDCl3) 176.4, 141.5, 140.0, 137.8, 126.9,
126.7, 125.0, 124.4, 81.7, 68.0, 65.2, 58.4, 48.1, 37.2; nmax (KBr) 3019,
1766, 1426, 778 cmꢁ1; HRMS (ESI): Mþ, found 397.1318, C25H21NO4
requires 397.1314.
dH (400 MHz, CDCl3) 6.62 (2H, t, J¼0.9 Hz), 5.26 (2H, t, J¼0.9 Hz),
2.72 (3H, s); dC (100 MHz, CDCl3) 174.4, 139.2, 81.4, 69.6, 24.6; nmax
(KBr) 3129, 1726, 1226 cmꢁ1; HRMS (ESI): Mþ, found 245.0692,
C13H11NO4 requires 245.0688.
4.1.6. (2
b,4a,11a,13b,15a,18a)-20,29-Di(methoxyethyl)-20,29-diaza-
31,32-dioxaoctacyclo [12.4.3.6.4,11.33,12.12,13.115,18.01,14.03,12.05,10.022,27
]
dotriaconta-5,7,9,16,22,24,26-heptaene-19,21,28,30-tetraone
(10). Compound 10 (8 mg, 13%, mp 233e234 ꢀC); dH (400 MHz,
CDCl3) 7.22e7.31 (4H, m), 7.11e7.16 (4H, m), 6.34 (2H, s), 4.95 (2H,
s), 4.74 (2H, s), 4.70 (2H, s), 3.41 (2H, t, J¼5.8 Hz), 3.29 (2H, t,
J¼5.8 Hz), 3.21 (3H, s), 3.12 (3H, s), 3.07 (2H, t, J¼6.3 Hz), 2.52
(2H, t, J¼6.3 Hz); dC (100 MHz, CDCl3) 175.9, 175.7, 140.9, 140.4,
138.2, 127.8, 127.5, 125.8, 125.4, 84.0, 78.4, 68.7, 68.4, 58.8, 49.04,
40.0, 39.2, 37.9, 37.8; nmax (KBr) 2989, 1769, 1753, 1346,
1293 cmꢁ1; HRMS (ESI): Mþ, found 594.1994, C52H48N4O6 re-
quires 594.2002.
4.1.2. (2
a
,5
a
,7
a
,10
a
)-12-(p-Methoxybenzyl)-12-aza-14,15-dioxa pen-
tacyclo[4.4.3.12,5.17,10.02,7
]
pentadeca-3,8-diene-11,13-dione (4c)9.
p-Methoxybenzylamine (411 mg, 4 mmol) was added dropwise to
an ice-cooled solution of anhydride 3 (262 mg, 1.129 mmol) and
Et3N (1 mL) in CH2Cl2 (5 mL). The solution was allowed to stir at
room temperature for 24 h. The solvent was evaporated under re-
duced pressure (water bath temperature 20e30 ꢀC) to give the in-
termediate amic acid as brown oil. Without further purification, this
oil was treated with Ac2O (2 mL) and Et3N (1 mL), and the mixture
stirred at 50e60 ꢀC overnight. The solvent was evaporated under
high vacuum, residue dissolved in CH2Cl2, washed with water, dried
over MgSO4, and the solvent was evaporated to produce solid ma-
terial, which was recystallised from EtOAc to yield colorless crystals
of the title compound 4c (142 mg, 36%).
4.1.7. (2a,4a,11a,13a,15b,17a,20a,22b)-24,33,36-Tri(methoxy ethyl)-
24,33,36-triaza-38,39,40-trioxadodecacyclo[12.8.3.6.4,11
.33,12.316,21.12,13.115,22.117,20.01,14.03,12.05,10.016,21.026,31]tetratriaconta-
5,7,9,18,26,28,30-heptaene-23,25,32,34,35,37-hexaone
(11). Compound 11 (6 mg, 4%, mp 240e242 ꢀC); dH (400 MHz,
CDCl3) 7.19 (4H, dd, J¼3.3 , 5.3 Hz), 7.09 (2H, dd, J¼3.1 , 5.3 Hz), 7.04
(2H, dd, J¼3.1 , 5.3 Hz), 6.34 (2H, s), 4.65 (2H, s), 3.45 (2H, t,
J¼5.8 Hz), 3.36 (2H, t, J¼5.8 Hz), 3.35 (2H, t, J¼6.7 Hz), 3.23 (3H, s),
3.21 (2H, t, J¼6.7 Hz), 3.09 (3H, s), 2.99 (3H, s), 2.79 (2H, t, J¼6.9 Hz),
dH (400 MHz, CDCl3) 7.17 (2H, d, J¼8.6 Hz), 6.80 (2H, d, J¼8.6 Hz),
6.39 (4H, s), 5.21 (4H, s), 4.29 (2H, s), 3.79 (3H, s).
4.1.3. (2
a,5a,7a,10a)-12-(Acetoxyethyl)-12-aza-14,15-dioxapenta cyclo
[4.4.3.12,5.17,10.02,7] pentadeca-3,8-diene-11,13-dione (4d). Ethanolami

ꢀ
D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1586
2.52 (2H, t, J¼6.9 Hz); dC (100 MHz, CDCl3) 175.7, 174.5, 174.4, 140.2,
139.8,138.2,127.4,127.0,125.5,124.5, 87.1, 79.6, 78.1, 71.5, 69.7, 69.0,
68.6, 68.1, 64.8, 59.4, 58.7, 58.5, 51.9, 39.5, 38.6, 35.8; nmax (KBr)
3045, 1773, 1748, 1732, 1597, 1593, 1592, 1406 cmꢁ1; HRMS (ESI):
Mþ, found 789.2133, C43H39N3O12 requires 789.2533.
colored oil, which was subjected to radial chromatography (pe-
troleum ethereethyl acetate 10:1, then solvent polarity was grad-
ually increased to 1:1) to afford the title compound 9b as a colorless
solid (61 mg, 58%, mp 176e178 ꢀC).
dH (400 MHz, CDCl3) 7.33 (2H, dd, J¼3.1 , 5.3 Hz), 7.25 (2H, dd,
J¼3.1 , 5.3 Hz), 7.18 (2H, dd, J¼3.3 , 5.5 Hz), 7.05 (2H, dd, J¼3.3 ,
5.5 Hz), 6.43 (2H, s), 4.81 (2H, s), 4.75 (2H, s), 2.34 (3H, s); dC
(100 MHz, CDCl3) 176.6, 141.5, 139.9, 137.8, 126.9, 126.8, 124.9, 124.4,
81.6, 65.5, 48.2, 23.9; nmax (KBr) 3011, 1771, 1478, 1322 cmꢁ1; HRMS
(ESI): Mþ, found 355.1208, C23H17N1O3 requires 355.1208.
FVP of 4c. In a typical run, FVP of 4c (30 mg, 0.085 mmol) at
360 ꢀC produced a mixture, which was dissolved in chloroform
(1e2 mL) and treated with anthracene (100 mg, 0.561 mmol) for
2 h at 60 ꢀC. Reaction mixture was subjected to radial chromatog-
raphy (petroleum ethereethyl acetate 10:1, then the solvent po-
larity was gradually increased to 1:1) to obtain products, in order of
elution: anthracene, 18, and 17.
4.1.8. (2
oxyethyl)-28,37,40,43-tetraaza-45,46,47,48-tetraoxapenta decacyclo
[12.12.3.6.17,24.33,12.35,10.316,25.12,13.14,11.16,9.115,26.01,14.03,12.05,10.016,25
18,23.030,35]octatetraconta-7,18,20,22,30,32,34-heptaene-
a,4b,6a,9a,11b,13a,15b,17a,24a,26b)-28,37,40,43-Tetra (meth
.
0
27,29,36,38,39,41,42,44-octaone (12). Compound 12 (3 mg, 9%, mp
268e270 ꢀC); dH (400 MHz, CDCl3) 7.19 (2H, dd, J¼3.3 , 5.1 Hz), 7.15
(2H, dd, J¼3.3 , 5.3 Hz), 7.17 (2H, dd, J¼3.3 , 5.1 Hz), 7.03 (2H, dd,
J¼3.3 , 5.3 Hz), 6.34 (2H, s), 4.92 (2H, s), 4.86 (2H, s), 4.79 (2H, s),
4.69 (2H, s), 4.65 (2H, s), 3.42e3.44 (4H, m), 3.30e3.38 (4H, m), 3.23
(6H, s), 3.20 (2H, t, J¼6.8 Hz), 3.11 (2H, t, J¼6.8 Hz), 3.09 (3H, s), 2.97
(2H, t, J¼7.1 Hz), 2.96 (3H, s), 2.34 (2H, t, J¼7.1 Hz); dC (100 MHz,
CDCl3) 175.8, 174.4, 174.3, 173.7, 140.8, 140.3, 138.2, 127.8, 127.1,
125.6, 124.5, 87.7, 82.6, 79.6, 78.1, 71.4, 70.1, 68.9, 68.6, 68.5, 68.4,
64.7, 58.9, 58.7, 51.8, 39.7, 39.0, 38.8, 37.5, 33.2, 30.9, 29.8; nmax (KBr)
3040, 1786, 1766, 1751, 1720, 1578, 1443, 1374 cmꢁ1; HRMS (ESI):
Mþ, found 984.3065, C52H48N4O16 requires 984.3065.
4.1.13. (2b,8b,10a,13a)-5,15-Di(p-methoxybenzyl)-5,15-diaza-17,18-
dioxahexacyclo[7.4.3.10,13.12,8.110,13.01,9.03,7]heptadeca-3,11-diene-
4,6,14,16-tetraone (17). Compound 17 (11 mg, 18%, mp
223e225 ꢀC); dH (400 MHz, CDCl37.21 (2H, dd, J¼3.5 , 5.2 Hz), 7.12
(2H, dd, J¼3.2 , 5.5 Hz), 7.11 (2H, d, J¼8.5 Hz), 6.98 (2H, dd, J¼3.5 ,
5.2 Hz), 6.77 (2H, d, J¼8.5 Hz), 6.74 (2H, d, J¼8.6 Hz), 6.70 (2H, d,
J¼8.6 Hz), 6.60 (2H, dd, J¼3.2 , 5.5 Hz), 4.91 (2H, s), 5.87 (2H, s), 4.76
(2H, s), 4.66 (2H, s), 4.29 (2H, s), 3.99 (2H, s), 3.79 (3H, s),) 3.77 (3H,
s); dC (100 MHz, CDCl3) 175.6, 174.4, 159.3, 158.9, 140.8, 139.1, 138.8,
130.8, 130.4, 127.0, 126.9, 126.8, 126.6, 124.6, 124.1, 113.6, 113.4, 83.7,
78.2, 71.5, 63.6, 55.2, 50.9, 42.6, 42.0; nmax (KBr) 2998, 1774, 1747,
1624, 1456 cmꢁ1; HRMS (ESI): Mþ, found 718.2321, C44H34N2O8
requires 718.2315.
FVP of 4a (30 mg, 0.104 mmol) at 445 ꢀC produced a mixture,
which was subjected to radial chromatography (petroleum ether-
eethyl acetate 10:1) to obtain 6a (11 mg, 54%).
FVP of mixture of 4a (50 mg, 0.173 mmol) and anthracene
(200 mg, excess) at 390 ꢀC produced a mixture, which was sub-
jected to radial chromatography (petroleum ethereethyl acetate
10:1, then the solvent polarity was gradually increased to 1:1) to
obtain products, in order of elution: anthracene, 6a (11 mg, 33%)
and 9 (28 mg, 41%).
FVP of 4a (30 mg, 0.104 mmol) at 420 ꢀC produced a mixture,
which was subjected to radial chromatography (petroleum ether-
eethyl acetate 10:1) to obtain in order of elution: 6a, 4a, and pu-
rified 13, 14, and 13b.
4 .1.14 . ( 2 a , 9 a , 11 a , 14 a ) - 16 - A z a - 18 - o x a h e p t a c y c l o
[8.4.3.42,9.111,14.01,10.02,9.03,8]tetracosa-3,5,7,12,19,21,23-heptaene-
15,17-dione (18). Compound 18 (3 mg, 10%, mp 178e181 ꢀC); dH
(400 MHz, CDCl3) 7.20 (2H, dd, J¼3.1 , 5.5 Hz), 6.84 (2H, d, J¼8.6 Hz),
6.64 (2H, d, J¼8.6 Hz); 6.69 (1H, s), 6.55 (2H, dd, J¼3.1 , 5.5 Hz), 4.71
(2H, s), 5.81 (2H, s), 4.31 (2H, s); dC (100 MHz, CDCl3) 175.5, 142.4,
139.2, 137.1, 126.8, 126.1, 124.5, 123.4, 81.7, 65.6, 24.9; nmax (KBr)
3068, 2356, 1746, 1346 cmꢁ1; HRMS (ESI): Mþ, found 341.1056,
C22H15N1O3 requires 341.1052.
4.1.9. (2b,8b,10a,13a)-5,15-Di(methoxyethyl)-5,5-diaza-17,18-dioxa-
hexacyclo[7.4.3.12,8.110,13.01,9.03,7]octadeca-3,11-diene-4,6,14,16-tet-
raone (13). (Spectral data obtained from crude spectrum); dH
(400 MHz, CDCl3) 6.53 (2H, t, J¼0.9 Hz), 5.57 (2H, s), 4.80 (2H, t,
J¼0.9 Hz), 3.70 (2H, t, J¼5.5 Hz), 3.62 (2H, t, J¼5.5 Hz), 3.49 (2H, t,
J¼5.5 Hz), 3.46 (2H, t, J¼5.5 Hz), 3.32 (3H, s), 3.31 (3H, s); HRMS
(ESI): Mþ, found 416.1223, C20H20N2O8 requires 416.1219.
Monocrystals of 18 suitable for structural analysis were obtained
byslowcrystallization from CH2Cl2 solution. Crystal data:C22H15N1O3,
ꢂ
ꢂ
Mr¼341.35, Monoclinic, C2/c, a¼27.608(2ꢀ) A, b¼9.3019(8) A,
3
ꢂ
¼90ꢀ,
b
¼98.499(2)ꢀ,
¼90 , V¼3279.9(5) A , Z¼8,
g
ꢂ
4.1.10. 4-Carboxymethoxyethyl-(2
-aza-14,15-dioxapentacyclo[4.4.3.12,5.17,10.01,6
b
,8
b
,10
a
,13
]
a
)-12-methoxy ethyl-12
pentadeca-3,8-diene-
c¼12.9135(11) A,
a
T¼298(2)K, density¼1.383 Mg/m3, crystalsize¼0.21ꢂ0.17ꢂ0.11 mm3.
11,13-dione-3-carboxylic (13b). (Spectral data obtained from crude
spectrum); dH (400 MHz, CDCl3) 6.45 (1H, dd, J¼1.3 , 5.6 Hz), 6.44
(1H, dd, J¼1.3 , 5.6 Hz), 5.49 (1H, d, J¼2.4 Hz), 5.56 (1H, s), 5.10 (1H,
s), 4.72 (1H, d, J¼3.7 Hz), 3.42e3.73 (8H, m), 3.36 (3H, s), 3.32 (3H,
s); HRMS (ESI): Mþ, found 434.1321, C20H22N2O9 requires 434.1325.
Final R indices [I>2
s
(I)], R1¼0.0614, wR2¼0.1765. R indices (all data),
R1¼0.0723, wR2¼0.1890. Data/restraints/parameters, 2882/0/235.
Goodness-of fit on F2, 1.054.
FVP of 4d. In a typical run, FVP of 4d (30 mg, 0.103 mmol) at
420 ꢀC produced a mixture, which was dissolved in chloroform
(1e2 mL) and treated with (100 mg, 0.561 mmol) for 2 h at 60 ꢀC.
4.1.11. (2
b,4a,7a,9b,11a,17a)-14,19,22-Tri(methoxyethyl)-14,19, 22-
triaza-24,25,26-trioxaonacyclo[8.7.3.3.3,8.12,9.14,7.111,17.02,9 .04,7.011,17
]
4.1.15. (2a,9a,11a,14a)-16-Acethoxyaminoethyl-16-aza-18-oxa hep-
hexacosa-5,12-diene-13,15,18,20,21,23-hexaone (14). (Spectral data
obtained from crude spectrum); dH (400 MHz, CDCl3) 6.53 (2H, s),
5.59 (2H, s), 5.03 (H, s), 4.70 (2H, s), 3.35e3.85 (12H, s), 3.29 (3H, s),
3.19 (3H, s), 3.18 (3H, s); HRMS (ESI): Mþ, found 587.1754,
C27H29N3O12 requires 587.1751.
tacyclo[8.4.3.42,9.111,14.01,10.02,9.03,8]tetracosa-3,5,7,12,19,21, 23-hepta
ene-15,17-dione (19). (Estimated from crude reaction spectrum); dH
(400 MHz, CDCl3) 7.14 (4H, dd, J¼3.2 , 5.4 Hz); 7.23e7.26 (4H, m),
6.38 (2H, s), 4.96 (2H, s), 4.73 (2H, s), 3.24 (2H, t, J¼6.2 Hz), 3.13 (2H,
t, J¼6.2 Hz), 1.89 (3H, s).
4.1.12. (2
a
,9
a
,11
a
,14
a
)-16-Methyl-16-aza-18-oxaheptacyclo[8.4.
4.1.16. (2b,4a,11a,13b,15a,18a)-20,29-Di(acethoxyaminoethyl)-
3.42,9.111,14.01,10.02,9.03,8]tetracosa-3,5,7,12,19, 21,23-heptaene-15,17-
dione (9b). To a refluxing solution of dibromide 5 (100 mg,
0.297 mmol) and anthracene (200 mg, excess) in dry THF (10 mL) at
reflux, freshly prepared ZneAg couple (200 mg) was added and
refluxed for 1 h. Filtration and evaporation of solvent gave a brown
20,29-diaza-31,32-dioxaoctacyclo[12.4.3.6.4,11.33,12.12,13.115,18
.01,14.03,12.05,10.022,27]dotriaconta-5,7,9,16,22,24,26-heptaene-
19,21,28,30-tetraone (20). (Estimated from crude reaction spec-
trum); dH (400 MHz, CDCl3) 7.16e7.25 (4H, m), 7.13 (2H, dd, J¼3.2 ,
5.4 Hz), 6.39 (2H, s), 4.94 (2H, s), 4.91 (2H, s), 4.65 (2H, s), 3.97 (2H,

ꢀ
D. Margetic et al. / Tetrahedron 67 (2011) 1580e1588
1587
t, J¼5.3 Hz), 3.47 (2H, t, J¼5.3 Hz), 3.32 (2H, t, J¼5.6 Hz), 2.82 (2H, t,
4.3. Computational details
J¼5.6 Hz), 1.96 (3H, s), 1.77 (3H, s).
All geometrical optimizations were carried out employing B3LYP/
4.1.17. 1-Acethoxyaminoethyl-1-aza-5-oxabicyclo[3.3.03,7]octa-3,6-
diene-2,8-dione (6d). Compound 6d (6 mg, 33%, mp 126e129 ꢀC);
dH (400 MHz, CDCl3) 7.80 (2H, s), 4.29 (2H, t, J¼5.6 Hz), 3.88 (2H, t,
J¼5.6 Hz), 2.00 (3H, s); dC (100 MHz, CDCl3) 170.9, 161.5, 137.9,
6-31G
*
17, BMK/6-31G
basis set. Calculations were performed using Gaussian03 suite
*
and M052X/6-31G
*
methods employing
6-31G
*
of programs,29 implemented on dual core Opteron 240 personal
computer under Linux operating system and computer cluster Isa-
bella at the Computing centre of the University of Zagreb. Activation
energies were estimated, performing transition state (TS) calcula-
tions.30 Harmonic vibration frequencies were calculated for all
localized stationary structures to verify whether they are minima or
transition states.
122.2, 61.4, 37.6, 20.7; nmax (KBr) 3156, 1810, 1775, 1397 cmꢁ1
;
HRMS (ESI): Mþ, found 223.0483, C10H9NO5 requires 223.0481.
FVP of 21. In a typical run, FVP of 21 (20 mg, 0.081 mmol) at
340 ꢀC produced a mixture, which was dissolved in chloroform
(1e2 mL) and treated with anthracene (100 mg, 0.561 mmol) for
2 h at 60 ꢀC. Reaction mixture was subjected to radial chromatog-
raphy (petroleum ethereethyl acetate 10:1, then the solvent po-
larity was gradually increased to 1:1) to obtain products, in order of
elution 6b, 23, 24.
Acknowledgements
This research was funded by grants from the Australian Research
Council (ARC) and the Croatian ministry of science, education and
sport (No. 098-0982933-3218).
4.1.18. (2a,9a,11a,14a)-16-Methyl-16-aza-18-oxaheptacyclo[8.4.
3.42,9.111,14.01,10.02,9.03,8]tetracosa-3,5,7,19, 21,23-hexaene-15,17-dione
(23). Compound 23 (10 mg, 35%, mp 226e227 ꢀC); dH (400 MHz,
CDCl3) 0.89e0.99 (2H, m), 7.33 (2H, dd, J¼3.3 , 5.3 Hz), 7.24 (2H, dd,
J¼3.3 , 5.3 Hz), 7.11 (2H, dd, J¼3.3 , 5.3 Hz), 7.10 (2H, dd, J¼3.3 ,
5.3 Hz), 4.78 (2H, s), 4.46 (2H, dd, J¼2.4 , 3.5 Hz), 2.45 (3H, s),
1.45e1.52 (2H, m); dC (100 MHz, CDCl3) 176.9, 139.9, 139.8, 126.9,
126.7, 124.8, 124.4, 84.3, 79.9, 67.2, 48.6, 26.3; nmax (KBr) 3121, 1734,
1428, 1287 cmꢁ1; HRMS (ESI): Mþ, found 357.1357, C23H19NO3 re-
quires 357.1365.
Supplementary data
Full crystallographic data for compound 18 have been deposited
with the Cambridge Crystallographic Data Centre, deposition num-
ber CCDC 794352. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. These data include MOL files and InChIKeys of the
most important compounds described in this article.
4.1.19. (2
b
,4
a
,11
a
,13
b
,15
a
,18
a
)-20,29-Dimethyl-20,29-diaza-31,32-
do-
dioxaoctacyclo[12.4.3.6.4,11.33,12.12,13.115,18.01,14.03,12.05,10 .022,27
]
References and notes
triaconta-5,7,9,22,24,26-hexaene-19,21,28,30-tetraone
(24). Compound 24 (2 mg, 5%, mp 319e321 ꢀC); dH (400 MHz,
CDCl3) 7.25 (2H, dd, J¼3.3 , 5.5 Hz), 7.22 (2H, dd, J¼3.3 , 5.5 Hz), 7.14
(2H, dd, J¼3.1 , 5.3 Hz), 7.11 (2H, dd, J¼3.1 , 5.3 Hz), 4.79 (2H, s), 4.68
(2H, s), 4.63 (2H, dd, J¼1.1 , 5.2 Hz), 2.96 (3H, s), 2.05 (3H, s),
1.25e1.29 (2H, m), 0.84e0.90 (2H, m); dC (100 MHz, CDCl3) 175.6,
175.5, 140.3, 135.2, 127.0, 126.7, 125.0, 124.2, 84.1, 75.1, 64.2, 32.2,
29.7, 27.1; nmax (KBr) 3034, 1741, 1733, 1415, 1313 cmꢁ1; HRMS (ESI):
Mþ, found 508.1629, C30H24N2O6 requires 508.1634.
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