A cascade thermal isomerisation of cyclobutane di-(carbomethoxy) Δ2-1,2,3-triazolines with intramolecular 1,3-dipolar cycloreversion as the key step

Article abstract of DOI:10.1016/j.tet.2012.02.073

Unprecedented thermal isomerisation of the strained Δ²-1, 2,3-triazolines led to the formation of products possessing a novel 1,2,7-triaza-[3.3.0]octa-2-ene ring system incorporated in a norbornane framework. Experimental evidence and quantum c

Full text of DOI:10.1016/j.tet.2012.02.073

Tetrahedron 68 (2012) 3306e3318
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A cascade thermal isomerisation of cyclobutane di-(carbomethoxy)
D
2-1,2,
3-triazolines with intramolecular 1,3-dipolar cycloreversion as the key step
,
b
b
b
ꢀ a
*
Davor Margetic , Ronald N. Warrener , Douglas N. Butler , Chuan-Ming Jin
a
ꢁ
ꢀ
ꢁ
Division of Organic Chemistry and Biochemistry, RuCer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
b Centre for Molecular Architecture, Central Queensland University, Rockhampton, Queensland 4702, Australia
a r t i c l e i n f o
a b s t r a c t
Unprecedented thermal isomerisation of the strained
D
2-1,2,3-triazolines led to the formation of prod-
Article history:
Received 28 October 2011
Received in revised form 10 February 2012
Accepted 27 February 2012
Available online 6 March 2012
ucts possessing a novel 1,2,7-triaza-[3.3.0]octa-2-ene ring system incorporated in a norbornane frame-
work. Experimental evidence and quantum chemical calculations have been used to support a postulated
reaction mechanism involving as the first step, a rare example of intramolecular 1,3-dipolar cyclo-
reversion. Subsequently, several steps involving 1,3-dipolar ring closure, hydrogen shifts and an intra-
molecular addition are postulated leading to the observed product of this deep-seated isomerisation. The
influence of changing substituents on the product outcome of this novel reaction cascade was also
studied.
Keywords:
Rearrangement
Dipolar cycloaddition
Reaction mechanism
Nitrogen heterocycles
Cycloreversion
Ó 2012 Elsevier Ltd. All rights reserved.
Computational chemistry
1. Introduction
gives an imine entity, which is involved in further molecular
rearrangements.
Standard
D
2-1,2,3-triazoline chemistry involves formation of
Preparation of norbornene fused 2,3,4-triazabicyclo[3.2.0]hept-
2-ene substrates required for our research was achieved employing
the standard synthetic procedures developed in our laboratories.
The first step was a ruthenium catalysed [2þ2] cycloaddition re-
action of norbornenes 1 and dimethylacetylene dicarboxylate
(Mitsudo reaction)8 to form the corresponding cyclobutene diesters
2 in high yields (Scheme 2).9 These cyclobutene diesters were fur-
ther subjected to high pressure azide additions10 in dichloro-
methane to form 2,3,4-triazabicyclo[3.2.0]hept-2-enes 3.11
1,2,3-triazolines by 1,3-dipolar addition of azides to alkenes. This
reaction works best with electron-rich olefins (Scheme 1).1 Ther-
molysis of 1,2,3-triazolines and imine formation with concomitant
dinitrogen elimination is the standard chemical behaviour of this
class of compounds.2,3 However, unusual reaction products were
formed in some cases, especially with substituted molecules.4
N
N
[3+2]
Δ
[1,2]H
N
N
+
N
E
X
X
X
- N2
NH
R
N
E
E
E
NH
R
N
N
RuH2CO(Ph3)3
8-14 kbar
+
+
N
R
N
N
R
R
E
benzene
CH2Cl2
R.T.
3-7 days
N
Scheme 1. Thermal rearrangement of
D
2-1,2,3-triazolines.
E
80 o
C
N
R
2
3
R
1
1-7 days
In particular, fused-ring
D
2-1,2,3-triazolines, readily cyclo-
X =CH2 , O , NCbz , C=CMe 2
,
E=COOCH3
R = Alkyl or Aryl
reverse when a small ring is annulated to the CeC subunit such as
Dewar thiophene,5 Dewar benzene6 or 3,3-dimethylcyclopropene,7
with molecular strain being a driving force for ring opening. This
Scheme 2. Preparation of 2,3,4-triazabicyclo[3.2.0]hept-2-enes.
This reaction sequence was used in our previous work to syn-
thesise the corresponding aziridines and finally fused 7-
azanorbornanes.12,13 It was found during the work-up and han-
dling that norbornene fused 2,3,4-triazabicyclo[3.2.0]hept-2-enes
3 are thermally unstable systems where substituents weaken the
1,3-dipolar cycloreversion of D
2-1,2,3-triazolines to a diazomethane
* Corresponding author. Tel.: þ385 1 456 1008; fax: þ385 1 468 0195; e-mail
ꢀ
addresses: margetid@irb.hr, margetid@emma.irb.hr (D. Margetic).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.073

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3307
central cyclobutane CeC bond. These strained bicyclic systems
2.2. Thermal isomerisations
possess several functionalities, which enhance their reactivity. The
aim of this paper is to give detailed synthetic and mechanistic study
in light of experimental evidence supporting the novel reaction
cascade.14
Results of thermal isomerisation experiments of 2,3,4-
triazabicyclo[3.2.0]hept-2-enes 4e21 are summarized in Tables 2
and 3. The effects of substitution changes and reaction conditions
(at elevated temperature 140 ꢀC, without the presence of solvent,
Table 2, and at low temperature 60e80 ꢀC in solvent, Table 3) on
reaction outcomes were studied.
2. Results and discussion
Table 2
2.1. Preparation of triazolines
Thermal isomerisations of triazolines 4e21 at 140 ꢀC (isolated yields in %)
E
X
E
X
X
E
X
The 2,3,4-triazabicyclo[3.2.0]hept-2-enes 4e21 required for this
study were prepared by high pressure azide additions10 in
dichloromethane (method B) or by stirring at room temperature
without the presence of solvent (method A) (Table 1).
N
140 o
C
E
N
+
N
+
N
N
N
N
neat
2h
N
E
E
R
N
E
H
N
R
N
endo-A
H
N
H
R
H
exo-A
D
E = CO2
Me
R
Table 1
Triazoline
X
R
t (h) exo-A
endo-A
D
Preparation of triazolines 4e21
4
5
6
11
12
13
18
21
CH2
CH2
CH2
NCBz Ph
O
O
CH2
CH2
Ph
1
6
1
1
1
1
1
1
exo-22 (24) endo-22 (18) 23 (14)
exo-24 (24) endo-24 (13) 26 (23)
exo-27 (11) endo-27 (16) 28 (11)
Triazoline
X
R
Methoda
p
t
Yield
4-OMeC6H4
4-NO2C6H4
(kbar) (d) (%)
a
E
X
a
a
E
Ph
N
N
4-OMeC6H4
Ph
Ph
exo-29 (23) endo-29b
30 (8)
N
0c
R
4
5
6
7
8
9
10
11
12
13
CH2
CH2
CH2
CH2
CH2
Dc
Bn
A
B
B
B
B
A
A
A
B
B
15 9913
a
Other products isolated.
Not isolated.
At 100 ꢀC, 2 h, or at 120 ꢀC, 1 h no reaction, at 140 ꢀC, 1 h decomposition.
CH2e4-OMeC6H4
CH2e4-NO2C6H4
CH2COOCH3
CH2CH]CH2
Bn
14
8
3
3
3
3
61
67
b
c
8
8
5215
66
23 9813
12 5913
12 8016
Table 3
Thermal isomerisations of triazolines 4e20 at 80 ꢀC (isolated yields in %)e
C]CMe2 Bn
NCBzb
Bn
Bn
E
E
X
E
O
O
7813
55
X
X
X
8
3
3
N
E
o
H
80
C
N
N
CH2e4-OMeC6H4
14
N
N
N
N
N
N
H
+
+
CHCl
E
3
N
E
E
R
R
2 h
N
R
R
N
E
E
X
C
Product type B
D
N
N
N
R
Triazoline
X
R
t (h)
B
C
D
14
15
16
17
CH2
CH2
CH2
CH2
CH2e4-OMeC6H4
CH2e4-SMeC6H4
4-Py
B
B
B
B
8
8
8
8
7
7
7
7
80
62
93
85
4
5
7
8
CH2
CH2
CH2
CH2
Df
Bn
2
12
2a
12
2
31 (94)
CH2e4-OMeC6H4
CH2COOCH3
CH2CH]CH2
Bn
32 (53) 33 (35) 26 (12)
34 (96)
35 (87)
3-Py
9
36 (95)
E
37 (5)c
X
MeO
10
20
14
15
16
17
19
C]CMe2 Bn
2
2
E
CH2
CH2
CH2
CH2
CH2
CH2
Bn
38 (93)
N
CH2e4-OMeC6H4 12b
CH2e4-SMeC6H4 12b
39 (90)
40 (80)
N
MeO
N
R
4-Py
3-Py
Ph
72b
24b
41 (85)
42 (60)
18
CH2
CH2
CH2
CH2
Bn
Ph
Bn
Bn
A
A
B
B
3
74
0.3d 43 (58)
c
E
X
OAc
E
a
100 ꢀC.
60 ꢀC.
N
N
b
c
N
Other products isolated.
140 ꢀC, no solvent.
E¼CO2Me.
OAc
R
d
e
f
19
10 6611
D
¼cyclopropylidene.
X
Py
E
N
N
N
N
Our first observed thermal isomerisation of triazoline 4 (by
N
Py
heating at 140 ꢀC for 2 h, without the presence of solvent in an open
flask) led to the formation of mixture of isomeric polycycles (exo/
endo)-22 possessing a novel 1,2,7-triazabicyclo[3.3.0]octa-2-ene
ring system, which is highlighted in bold (Scheme 3, product type
A). In addition, a smaller amount of triazoline 23 (14%) was
obtained (product type D).
R
20
8
8
5
3
8617
CF3
X
Py
CF3
N
N
N
N
N
Py
NMR spectroscopy was employed for structural study of all new
products and results obtained from 13C and 1H spectra, as well as 2D
COSY and NOESY correlations were combined. For this purpose the
1H NMR spectra were the most informative and show some in-
teresting features. For instance, the 1H NMR spectrum of exo-22
R
21
77
a
Method A: neat, rt; method B: high pressure, CH2Cl2, rt.
b
c
CBz¼CO2Bn; E¼CO2Me.
D
¼cyclopropylidene.

ꢀ
D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3308
Scheme 3. Thermal rearrangement of triazoline 4 at 140 ꢀC.
consists of 7 singlets (d 2.84, 3.09, 3.13, 3.62, 3.74, 3.89 and 6.00), 3
doublets (
d
1.92, 2.07 and 7.72), and 2 aromatic multiplets (d 7.04
and 7.38), while the 13C NMR spectrum contains 22 carbon reso-
nances. The key spectroscopic evidence for the product exo-22 is
a benzylic (C6), two methyl and two bridgehead proton resonances
and the molecular ion (1H NMR:
d benzylic 6.00, d OMe 3.13, 3.89,
Fig. 2. 300 MHz 1H NMR spectra of isomeric products exo-22 and endo-22 in CDCl3.
d
bridgehead 2.84, 3.74, HRMS-ESI: m/z¼417.1685). Particularly
indicative is the proton resonance of the C8 methyl ester group
as the major isomer. It was found that in all compounds in-
vestigated, the formation of the exo-isomer is favoured over the
endo-isomer, p-methoxybenzyl substitution in 5 gave the highest
exo/endo-ratio (10:1), which may be attributed to steric factors. This
conclusion is supported by density functional theory calculations at
positioned under the benzene ring, which is significantly affected
by the aromatic ring current and shifted at higher magnetic field (
d
3.13). The strong NOESY correlation between the benzylic proton H6
and the endo proton H2 defines the outward orientation of the C6
phenyl substituent (i.e., the S-configuration), whereas a NOESY
correlation between proton H8 and bridgehead proton H10 addi-
tionally supports the inward orientation of the C8 ester group. At
the highest magnetic field are the CH2 bridge protons (H17a,b) dis-
the B3LYP/6-31G level, which indicated that the exo-isomer, with
*
inward positioned aryl substituent is thermodynamically less sta-
ble (exo/endo-difference is 4.2 kcal/mol).
playing a characteristic two-spin AB system18 centred at
d 2.01. The
structure of this novel compound was unambiguously confirmed
by X-ray structural analysis (Fig. 1).
It was found that the mixture of products formed by thermal
reaction of cyclobutene triazolines 4e21 are highly influenced by
reaction temperature. Entirely different products were formed
when thermolysis experiments were carried at lower temperatures
(Table 3). For instance, heating of p-methoxybenzyl triazoline 5 at
80 ꢀC in chloroform gave as a main product dihydropyrazole p-
methoxybenzylimine 32 (product type B). In addition, smaller
amounts of products 33 and 26 were formed (products type C and
D), which will be discussed in the following sections (Scheme 4).
Structural elucidation of products (type B and C) was crucial for the
mechanistic rationalization of the thermolysis process.
Product type B
Product type C
Product type D
14
COOCH
3
COOCH
3
80 o
C
1
N
12
13
H
N
N
+
N
5
+
N
N
H
8
N
E
CHCl3
12 h
H COOC
3
Fig. 1. An ORTEP view of the molecular structure of exo-22 (top and side-view).
H COOC
3
N
N
Thermal ellipsoids are drawn at the 50% probability level.
MeO
26 (12%)
33 (35%)
OMe
32 (53%)
OMe
The structure of the minor isomer endo-22 was elucidated by
the comparison of spectroscopic data with isomer exo-22. There are
certain similarities with H NMR spectra of two isomeric products
Scheme 4. Thermolysis of triazoline 5.
1
The structural assignment of product 32 was based on the NMR
spectroscopic evidence. For instance, the 1H NMR of 32 contained
(Fig. 2). In both isomers, one of the unsymmetrical C8 ester signals
is shielded by an aromatic ring and shifted towards higher mag-
netic field by ca. 1 ppm. Two bridgehead proton singlets are present
in both structures indicating an unsymmetrical norbornane system.
There is a significant difference in the chemical shifts of bridgehead
protons H10, mainly due to the orientation of the phenyl sub-
stituent. In the case of endo-22 product, proton H10 is de-shielded
as the phenyl ring is positioned inward (under the polycyclic
framework). Finally, the change of configuration of C6 causes the
benzylic protons H6 to be found at significantly different positions.
Positive NOESY correlation between protons H6 and H8 in endo-22
coupled with the lack of correlation between protons H6 and H2
defines without a doubt the inward orientation of the C6 phenyl
substituent (i.e., the R-configuration).
a series of proton resonances, the most distinctive being a methy-
lene bridge (AB spin system)
bridgehead (two lines) 3.27, 3.67, methoxy (three lines)
3.74, 3.83, and benzylic methylene (AB spin system) 4.61, 4.75
d
1.79, 2.18, endo-
d
2.96, the H12 d 3.25,
d
d
3.68,
d
(J¼14.9 Hz), which is completely consistent with the assigned
structure, and further supported by the 23-signal 13C NMR spec-
trum, and high-resolution mass spectrometry (m/z¼447.1802). Of
particular importance are COSY and positive NOESY correlations
between protons H12 and endo-H13, which indicate their coupling,
both signals appearing as doublets with coupling constant
J¼8.7 Hz.
Furthermore, thermal rearrangement of triazoline 14 at 60 ꢀC in
chloroform yielded rearranged dihydropyrazole benzylimine 39 (as
a single product in 90% yield), product type C (Scheme 5). Identical
products were formed by heating of other triazolines at 60e80 ꢀC
(Table 3). The 1H NMR spectrum of 39 shows 6 singlets, 6 aliphatic
doublets, 2 aromatic doublets and 2 aromatic multiplets, while
The thermolysis of triazolines 4e6 follows identical pattern. The
S/R isomers were carefully separated for phenyl, p-methoxy and p-
nitro substituted triazolines and experimental 1H NMR ratios were
determined: (exo/endo)-22 (5:1), (exo/endo)-24 (10:1), and (exo/
endo)-27 (6:1). In addition, thermolysis of triazoline 18 gave exo-29
a
13C NMR spectrum contains 33 carbon resonances, HRMS m/

ꢀ
D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3309
z¼575.2420 calcd 575.2435. For 39 three methyl and four bridge-
head resonances were found (1H NMR:
OMe 3.76, 3.77, 3.92,
bridgehead 2.36, 2.44 (bicyclo[2.2.1] system) and 4.12, 4.27
(bicyclo[2.2.2] system). Methylene protons are distinctively shifted
by aromatic ring current towards higher magnetic field (
rearrangement starts with breaking of the weakened central
cyclobutane bond.
d
d
start
E
d
ꢁ0.21,
E
E
1
E
E
0.81), defining the spatial orientation of the bicyclo[2.2.2] system
relative to the bicyclo[2.2.1] moiety. While endo protons H2/H10
Δ
N
N
N
N
1
2
2
N
5
N
N
E
H
N
H
4
3
H
3
appear as an AB system (
3.71. The most characteristic feature of 39 was the proton reso-
nance of the amino proton H7 positioned at 6.52 (br s). The X-ray
d 2.03, 2.08), the endo proton H4 is singlet,
H
N
4
H
d
H
5
H
d
E = CO2Me
bonds broken
bonds formed
structure of this compound is given in Fig. 3.
Scheme 6. An overall mechanistic picture of the rearrangement.
The proposed reaction mechanism starts with an intramolecular
1,3-dipolar cycloreversion and formation of the corresponding
diazoimine 44 (Scheme 7).19e21 The reaction mechanism proposed
in Scheme 7 shows a series of highly stereoselective steps. This
mechanistic proposal is based on the 1,3-dipolar cycloreversion of
Product type C
24
3
E
E
E
60 o
C
1
4
8
2
N
N
9
CHCl3
12 h
11
N
7
H
N
10
D
2-1,2,3-triazolines to diazomethane and imine entities, in partic-
N
E
N
ular when triazolines are annulated to the strained small ring
systems.5,6,7 In the next step, diazoimine 44 undergoes hydrogen
migration and formation of zwitterion 45, which is thermody-
namically more stable 2-norbornenyl anion (by 26.2 kcal/mol, at
the B3LYP level). Migration of the endo-C2 hydrogen takes place
from the endo-side resulting in the S-configuration on the ester/
diazo substituted carbon. Intramolecular [1,5]-ring closure leads to
benzylimino 4,5-dihydro-3H-pyrazole 46 (i.e., product type B), with
norbornene C2 possessing R-configuration. Selective formation of
46 results from the preferred exo attack of the terminal electro-
philic diazo nitrogen onto the 2-norbornenyl anion.22e24 After H-
shift on the 4,5-dihydro-3H-pyrazole ring, a conjugated benzyli-
mine 4,5-dihydro-1H-pyrazole 47 (product type C) is formed.
Conjugation of the C]N bond with the carbonyl group makes 47
thermodynamically more stable than intermediate 46 (by
MeO
14
39 (90%)
E = COOCH3
OMe
Scheme 5. Thermolysis of triazoline 14.
4.83 kcal/mol, as assessed by the B3LYP/6-31G calculations). Con-
*
secutive H-shift within a benzylimine moiety gave an intermediate
benzylideneimine 48. This process is thermodynamically driven,
since the conjugation with the aromatic p-system is more effective
than conjugation of the C]N bond with the carbonyl group in 47,
making benzylideneimine 48 energetically more stable (by
Fig. 3. An ORTEP view of the molecular structure of 39 (top and side-view). Thermal
ellipsoids are drawn at the 50% probability level.
5.70 kcal/mol, at the B3LYP/6-31G level). Internal addition of the
*
nitrogen lone pair to double bond and ring closure gave a final ring
structure and a formal [1,3]-hydrogen shift completes the forma-
tion of 49 (product type A).
Structures of products type B (32) and type C (33) could be easily
distinguished on the basis of their characteristic 1H NMR chemical
shifts and their coupling patterns. Therefore, protons H12 and endo-
H13 are coupled in the case of 4,5-dihydro-3H-pyrazole (32), while
this coupling is absent in 4,5-dihydro-1H-pyrazole (33). Further-
E
E
H
E
E
E
N
more, proton H12 appears at
present in 4,5-dihydro-1H-pyrazole 33, instead, a new resonance
for H10 appears at the lower field ( 6.69). Accordingly, the change
of magnetic environment around the endo protons H13 causes their
appearance at different positions in the 1H NMR spectra at
3.20
and 4.34 (in 32 and 33, respectively). The resonances of the benzylic
protons are much less affected.
The results summarized in Table 3 indicate that shorter heating
times at lower temperatures led to the formation of product type B,
which upon prolonged heating or temperature increases lead to the
formation of product type C and other products.
d 2.95 in the case of 32, while it is not
N
N
N
N
N
N
N
N
intramolecular
ring closure
[1,3]-H internal
abstraction
H
1,3-dipolar
R
d
R
E
E
R
cycloreversion
45
Diazoimine
44
exo- attack
E
E
E
d
H
[1,3]-H shift
[1,3]-H shift
48
N
N
N
N
N
N
N
H
N
N
N
dihydro
pyrazole
H
E
H
E
N
H
H
E
N
E
R
H
47
H
benzylimine
46
internal addition
49
E
to double bond, H shift
E
benzylideneimine
E
H
N
N
N
N
H
R = Bn
E = CO2CH3
N
N
E
H
E
E
N
H
N
H
exo-22
2.3. Mechanistic considerations
N
31
39
TYPE C
PRODUCT TYPE A
Scheme 7. Proposed reaction mechanism.
TYPE B
Elucidation of the structures of two key-intermediates, and of
the final product (products of type AeC) was critical for completion
of the overall reaction mechanism picture. An overall mechanistic
picture of deep-seated rearrangement involving three H-shifts is
depicted in Scheme 6. It involves five bonds to break, and also five
new bonds to be formed in the process. We assume that
The alternative reaction path in which dihydropyrazole 46 firstly
experiences H-shift within a benzylimine moiety to afford benzy-
lideneimine intermediate is less likely to take place, since

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3310
spectroscopic evidence gathered so far supports the reaction path
shown in Scheme 7 (i.e., the existence of intermediates 46 and 47),
while intermediate products for alternative reaction paths were not
detected.
The nature of the formal [1,3]hydrogen shifts depicted in
Scheme 7 deserves some comment. The most direct pathway for
this reaction in 4,5-dihydro-3H-pyrazole 46 is a concerted sigma-
tropic [1,3]-H shift, occurring with suprafacial stereochemistry.
According to WoodwardeHoffman selection rules, it is a thermally
forbidden process and requires insurmountable Ea (which is further
increased by locking of the allylic system in small five-membered
and two sets of bridgehead singlets d 3.66, 4.50 and 5.14, 5.22 in the
1H NMR spectrum and molecular ion (HRMS m/z¼561.2259). The
most diagnostic peaks in the 1H NMR spectrum of cycloadduct 53
are four methyl singlets
singlets 3.42, 3.76, as well as molecular ion in HRMS m/
z¼559.1957.
d 3.78, 3.87, 3.94, 3.95 and two bridgehead
d
Intramolecular 1,3-dipole trapping31 of the intermediate diaz-
oalkane was also attempted with allyl triazoline 8 (Scheme 9). By
thermal reaction conducted in chloroform at 80 ꢀC for 12 h, in-
termediate diazoalkene 54 went through path A (following the
general cascade mechanism outlined in Scheme 7) and formed
dihydropyrazole 35 in 87% yield. Formation of product 57 arising
from intramolecular 1,3-dipolar cycloaddition of the diazo group
onto the C]C bond was not detected spectroscopically. When the
experiment was conducted at higher temperature (solvent free,
140 ꢀC, 2 h), only polymerized material was obtained. These results
could be rationalized by the thermal instability of the intermediate
dipole 54 and low dipolarophilicity of the alkene substituent. A
comparison to the literature precedented rearrangement of tri-
azolines to bicyclic systems involving intramolecular trapping of
diazoalkene provides some information for the low reactivity of 8
towards intramolecular 1,3-cycloaddition.32 Literature molecular
systems are conformationally more flexible, as compared to sub-
strate 8, which induces larger molecular strain and steric conges-
tion preventing reaction cascade to proceed via path B (this
rationale is also indicated by molecular modelling).
ring). We carried out B3LYP/6-31G calculations, which indicate
*
that Ea for this process is 120.1 kcal/mol, thereby eliminating this
possibility. Other reasonable mechanism involving unimolecular
hydrogen shift would be a two-step process, consisting of intra-
molecular protonation of benzylimine nitrogen, and subsequent
proton migration to 4,5-dihydro-1H-pyrazole. High basicity of the
imino nitrogen25 could serve as driving force for this pathway. For
this process, B3LYP/6-31G
*
calculations predict significantly
smaller Ea (41.2 kcal/mol). Recent calculations on the [1,3]-, [1,5]-
and [1,7]-prototropic migrations indicate that a bimolecular mul-
tistep mechanism is often energetically more viable.26e29 Calcu-
lated activation energy for prototropic migration in 46 by
bimolecular mechanism is further reduced (Ea¼34.9 kcal/mol),
which indicates that a bimolecular mechanism of intermolecular
[1,3]-H shift30 is likely to be involved.
There is some experimental evidence in support of the proposed
reaction mechanism shown in Scheme 7. Firstly, spectroscopic data
for stable and isolated products type AeC. Secondly, heating of the
intermediate dihydropyrazole 31 (product type B) at higher tem-
perature (140 ꢀC, solvent free, 2 h) led to its transformation into
products (S/R)-22 (product type A) in high yield. Furthermore, 1,3-
dipole trapping experiments were conducted in order to prove the
existence of initially formed diazoimine 50 (Scheme 8). Product 31
was obtained when trapping experiments were conducted using
diluted samples of triazoline and trapping reagent (in chloroform).
However, when trapping experiments were carried out in more
concentrated solutions, in neat dipolarophile as solvent (7-
oxabenzonorbornadiene and dimethylacetylene dicarboxylate), at
80 ꢀC trapping products dihydropyrazoles 52 and 53 were formed
in 10 and 19% yield, respectively. Even under these reaction con-
ditions, major product was 31, indicating a very low energy barrier
of initial intramolecular hydrogen migration. Adduct 52 actually
consisted of two isomeric products 52a and 52b, which were not
separated and were not distinguishable by NMR spectroscopy.
Spectral data are consistent with the structure of cycloadduct 52
E
E
H
E
o
N
N
N
N
80
C
Path A
H shift
N
N
N
N
CHCl
12 h
N
3
E
E
E
8
54
55
Path B
N
E
N
N
E
H
N
N
E
E
intramolecular
N
N
N
1,3-dipolar
cycloaddition
N
N
E
N
N
H
E
E
E
H
57
TS 56
35 (87%)
product TYPE B
58
TYPE A
not detected
experimentally
not detected
experimentally
E = CO CH
2
3
Scheme 9. Intramolecular 1,3-dipole trapping experiments of triazoline 8.
showing, as the most informative, two methyl singlets
d
3.27, 4.00
2.4. Other thermolysis products
While the products type AeC described in previous sections are
the major isolated products, thermal decomposition of certain
cyclobutane diester triazolines led to the formation of new and
unprecedented products. For instance, thermolysis of triazolines
4e6 and 18 at 140 ꢀC besides products of type A yields significant
amounts of triazoles 23, 26, 28 and 30 (product type D, Table 2,
Scheme 10). High thermolysis temperature enhances the formation
of product type D, while the experiments carried out at lower
temperatures (60e80 ꢀC) significantly reduce their formation
(Table 3). It was not possible to determine by NMR spectroscopy,
which of these two isomeric products has been formed. The 1H
NMR chemical shifts, the multiplicity of signals and the coupling
constants with adjacent nuclei are consistent with proposed
structure. The 1H NMR spectrum of 23 is characterized by the
o
E
80 C, 2 h
E
N
N
E
E
N
N
CHCl
N
3
N
N
H
N
Ph
50
1,3-dipole
4
E
DMAD or 51
E
N
Ph
31 (94%)
Ph
E = CO CH
2
3
O
melt neat
80 C, 2 h
DMAD as solvent
o
o
80 C, 2 h
51
E
E
E
O
N
N
O
or
E
E
N
N
N
N
N
N
N
E
Ph
presence of single methyl resonance
glets, which are shifted towards lower field,
olefinic singlet
6.66. In addition, the 13C NMR spectrum consists of
20 carbons, while HRMS showed molecular ion (m/z): 386.1511.
d
3.84, two bridgehead sin-
53 (19%)
E
d
4.21, 4.31, and an
Ph
E
52a
Ph
(10 %) 52b
d
Scheme 8. 1,3-Dipole trapping experiments.

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3311
E
Regioisomeric assignment of product 23 depicted in Scheme 10 was
supported by HMBC correlations. Two three-bond HMBC correla-
X
E
E
E
N
N
-N2
Δ
N
N
N
N-R
X
+
00
0
tions from H9 and H1 to a common quaternary C5 are the most
supportive. The tentative reaction mechanism is also proposed,
involving cyclobutane carbonecarbon bond breaking, and forma-
tion of diradical 59, followed by an eight-electron reorganization
with concomitant loss of CO2 and CH4.
80-140 o C
N
E
E
R
R
71a,b
67 X = C=CMe2
68 X = NCBz
69 X = O
70a R = Bn
70b R = CH2-4-OMeC6H4
10 X = C=CMe2, R = Bn
11 X = NCBz, R = Bn
12 X = O, R = Bn
13 X = O, R = CH2-4-OMeC6H4
Product type D
Product type A
COOCH3
E
H
H
exo-A
+
o
72 (70%)
67
140
neat
2 h
C
COOCH3
OAc
9
N
N
140 o
neat
C
endo-A
N
N
N
5'
19
N
R
20 min
H 1''
4 R = H
5 R = OCH3
6 R = NO2
R
23 R = H (14%)
26 R = OCH3 (23%)
28 R = NO2 (11%)
OAc
61 (5%)
E = COOCH3
- CO2
- CH4
Scheme 13. Thermal [8þ4] cycloreversion of triazolines 10e13 and 19.
H
COOCH3
H3C
H
N
O
N
N
O
59
Scheme 10. Thermolysis of triazolines 4e6.
An unprecedented thermolysis product was formed (23% yield)
by heating phenyl substituted triazoline 19 in the standard manner
(Scheme 11). The major product is 43 (product type B). Small
amount of 4,7-diacetyloxyindene indene 61 was also isolated, as
the result of a retro DielseAlder reaction (details on this frag-
mentation are given in a further section and in Scheme 13). In-
dicative evidence for the formation of 60 is the presence of vinylic
proton resonance in the 1H NMR spectrum (Ha,
bridgehead proton resonances (singlets, 3.74, 5.16). The bridge
protons appear as AB systems (Hb, 2.23, and the less shielded Hc,
2.71), and three methyl proton resonances appear at 2.32, 2.35
d 6.42) and two
Fig. 4. An ORTEP view of the molecular structure of 60 (top and side-view). Thermal
ellipsoids are drawn at the 50% probability level.
d
d
d
d
and 3.77. The assigned structure is further supported by the 17-
signal 13C NMR spectrum and high-resolution mass spectrometry
(m/z¼368.0896, calcd 368.0891). In addition, the structure of this
novel product was unequivocally determined as ketone 60 by single
crystal X-ray analysis (Fig. 4).
homolytic bond cleavage is analogous to the one proposed for the
thermolysis of triazolines 4e6 in Scheme 10. Ketone functionality is
introduced by the air oxidation via an alkoxy radical intermediate
63. The ethylene moiety of product 60 could be subsequently
formed from ketone 64 by the 1,3-dipolar cycloreversion of the
triazoline moiety, followed by dinitrogen elimination from 1,3-
dipole 65 via carbene-like intermediate 66 and the subsequent
formal [1,2]-hydrogen shift. The proposed 65/60 reaction se-
quence is well established in the literature on the thermolysis of
diazo compounds,33 especially those bearing electron-withdrawing
substituents.34
Hb
OAc
Hc
OAc
E
E
OAc
E
E
140 o C
OAc
H
N
+
N
N
+
Ha
neat
20 min
N
OAc
O
N
OAc
OAc
OAc
E
N
Ph
Ph
61 (5%)
43 (58%)
60 (23%)
19
E = CO2CH3
Scheme 11. Thermolysis of triazoline 19.
A different cycloreversion mechanism from that outlined in
Scheme
7 operates in the case of 7-oxa, 7-aza- and 7-
isopropylidene benzonorbornene triazolines 10e13 (as well as 19
to a smaller extent). Their thermal fragmentation at 80e140 ꢀC via
[8þ4] cycloreversion forms reactive isobenzo species 67e69 and 1-
substituted triazoles 70a,b, which further decompose presumably
via the corresponding pyrroles 71a,b (Scheme 13). Within reaction
conditions applied, isoindole 68 and isobenzofuran 69 quickly de-
compose, while the 2-(isopropylidene)isoindene 67 rearranges to
the stable substituted indene 72, by [1,11]-hydrogen shift through
either a unimolecular or a bimolecular process.26 This fragmenta-
tion pattern has been observed by us in related triazoline photo-
chemistry16 and aziridine cycloaddition chemistry.35
A small
Scheme 12. Thermolysis of triazoline 19.
amount of 37 (5%), product type D was also isolated from ther-
molysis of 10 at 80 ꢀC.
A plausible reaction mechanism leading to product 60 has been
proposed involving cyclobutane C2eC3 bond cleavage as a first re-
action step and formation of diradical 62 (Scheme 12). This
It was found that variation of substituents could influence the
reaction outcome (Tables 2 and 3). For instance, thermolysis of
triazoline 20 possessing only one methyl ester group gave 38 as the

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3312
single product (product type C, Scheme 14), while, thermal cascade
reaction of 19 stopped at the product type B stage.
4. Experimental section
4.1. General
Reagents were supplied by Aldrich and solvents were used
without further purification. For chromatography petroleum ether
fraction bp 40e60 ꢀC was used. Thin layer chromatography (TLC)
was performed on plastic sheets coated with Merck Kieselgel 60
F254. Column chromatography on silica was carried out using Merck
Silica Gel 60 (230e400 mesh). Preparative plates for the chroma-
totron were produced with Merck Silica Gel 60 PF254 containing
gypsum. Melting points were determined on a Gallenkamp melting
point apparatus and were uncorrected. The 1H and 13C NMR spectra
were acquired using Bruker AMX300 (300 MHz for 1H NMR and
75 MHz for 13C NMR) or Bruker Avance DPX400 (400 for 1H NMR
and 7100 MHz for 13C NMR) spectrometers at 303 K. Chemical
H
E
N
N
80 o
C
N
N
N
N
N
N
N
CHCl3
30 min
N
H
N
N
N
E
N
Ph
Ph
20
38 (93%)
E=COOCH3
Scheme 14. Thermolysis of triazoline 20.
On the other hand, the replacement of the methyl ester sub-
stituents with trifluoromethyl in triazoline 21 does not sufficiently
activate the cyclobutane ring to start cascade reaction in Scheme 7.
Heating at lower temperatures (100e120 ꢀC) showed no reaction,
while thermolysis at 140 ꢀC caused decomposition of substrate/
products. While the variations of benzyl substituents at triazoline
nitrogen does not influence reaction outcomes, preliminary results
with N-phthalimidoethyl triazoline indicate that after the forma-
tion of product type B, elimination of N-phthalimidoethyl sub-
stituent takes place, which leads to further rearrangements.
shifts (d) are reported in parts per million relative to internal tet-
ramethylsilane (TMS). 13C spectra were referenced against residual
solvent peaks. COSY and NOESY two-dimensional correlation NMR
experiments employed the standard BRUKER parameters. FI-IR
spectra were recorded on a PerkineElmer 1600 FT-IR spectrome-
ter. The high-resolution mass spectra were obtained by ESMS
(electrospray mass spectrometry) on a Micromass Platform II single
quadrupole mass spectrometer by Mr. Tom Frey. X-ray crystal
structure determinations were carried out by Dr. John Fawcett at
the University of Leicester. Microwave assisted reactions were
conducted in CEM DiscoverÒLabmateTH/ExplorerPLSÒ single mode
microwave reactor using closed reaction vessel technique
(power¼125 W).
2.5. Microwave reactions
It is known that rates of 1,3-dipolar cycloadditions and 1,3-
dipolar cycloreversions are accelerated under microwave condi-
tions.36 Recent literature showed that classical thermal heating
could be successfully replaced by microwave conditions for ther-
mally promoted molecular rearrangements leading to un-
precedented products.37 Of particular interest is the example given
by Wilson, where the initially formed triazoline intermediates
4.2. Synthesis of cyclobutene triazolines
General method. Mixture of corresponding cyclobutene diester
(100 mg, 0.3e0.7 mmol) and an azide (5e10 equiv) in CH2Cl2
(1 mL) was pressurized at 14 kbar for 3 days. Products were isolated
by radial chromatography (petroleum ether/ethyl acetate), or by
treatment with cold methanol and filtration.
undergo
a thermal rearrangement and intermolecular cyclo-
condensation.38 Therefore, we anticipated that both reactions (1,3-
dipolar cycloadditions and 1,3-dipolar cycloreversions) involved in
rearrangement of cyclobutane di-(carbomethoxy) triazolines will
benefit from the rate enhancement by microwave irradiation, or
even afford different products. Thus, the triazoline 4 was subjected
to microwave heating in order to compare microwave and classical
conditions. It was found that microwave induced rearrangements
follow the same reaction mechanism as classical reaction leading to
identical products. By heating of 4 in a closed-vial single mode
microwave reactor at 50 ꢀC for 30 min in chloroform (irradiation
power 150 W), clean conversion (86% isolated yield) to 31, product
type C was achieved. When triazoline 4 was heated without the
presence of solvent (70 ꢀC, 5 min) full conversion to single product
23 was achieved (76% isolated yield), while increasing the tem-
perature to 120 ꢀC (solvent free, 20 min) yielded decomposition
products.
4.2.1. Dimethyl-4-(p-methoxybenzyl)-4,5,6-triaza-1a,2b,8b,9a-pen-
tacyclo[7.6.1.02,803,7010,15]hexadeca-6,10,12,14-tetraene-3,7-
dicarboxylate (5). Mixture of corresponding cyclobutene diester
(100 mg, 0.352 mmol) and p-methoxybenzyl azide (200 mg,
1.23 mmol) in CH2Cl2 (1 mL) was pressurized at 14 kbar for 3 days.
Radial chromatography (petroleum ether/ethyl acetate 20:1,
Rf¼0.45), followed by treatment with cold methanol afforded tri-
azoline as yellow oil (96 mg, 61%); 1H NMR (300 MHz, CDCl3)
d/
ppm 1.69 (td, J¼11.1, 1.6 Hz, 1H, H16a), 2.00 (d, J¼11.1 Hz, 1H, H16b),
2.03 (d, J¼6.9 Hz, 1H, H2), 2.29 (d, J¼6.9 Hz, 1H, H8), 3.45 (s, 3H,
OCH3), 3.67 (s, 1H, H1), 3.79 (3H, s, OCH3), 3.82 (s, 1H, H9), 3.86 (3H,
s, COOCH3), 4.69 (d, J¼15.0 Hz, 1H, NCH2Ph), 4.86 (d, J¼15.0 Hz, 1H,
NCH2Ph), 6.85e6.86 (m, 2H, Ar), 7.05e7.08 (m, 2H, Ar), 7.19 (d,
J¼9.5 Hz, 2H, Ar), 7.27 (d, J¼9.5 Hz, 2H, Ar); 13C NMR (75 MHz,
CDCl3) d/ppm 43.9, 44.6, 48.4, 50.2, 50.5, 51.9, 52.2, 55.3, 64.7, 66.0,
3. Conclusion
91.9, 113.9, 114.0, 121.1, 121.3, 126.3, 126.4, 130.0, 145.8, 145.9, 159.0,
166.2, 166.8; HRMS (ES): Mþ, found 447.1798. C25H27N3O5 requires
447.1798. Anal. Calcd for C25H27N3O5: C, 66.80; H, 6.05; N, 9.35.
Found: C, 66.82; H, 6.09; N, 9.31%.
In this study, unprecedented cascade thermal rearrangement of
a series of cyclobutane di-(carbomethoxy) triazolines has been
described. It was found that intramolecular 1,3-dipolar cyclo-
reversion is a key step in isomerisation, followed by a series of
hydrogen migrations and intramolecular cyclisations. The postu-
lated reaction mechanism is in full accord with the experimental
results and quantum chemical calculations. Although this reaction
pattern is general in the series of cyclobutane triazolines, variations
of reaction conditions and substituents of triazoline and cyclo-
butane rings lead in some cases to formation of unexpected prod-
ucts and various compositions of reaction mixtures.
4.2.2. Dimethyl-4-(p-nitrobenzyl)-4,5,6-triaza-1a,2b,8b,9a-pentacy-
clo[7.6.1.02,803,7010,15]hexadeca-6,10,12,14-tetraene-3,7-dicarboxylate
(6). A solution of corresponding cyclobutene diester (200 mg,
0.700 mmol) and p-nitrobenzyl azide (500 mg, 2.65 mmol) in
CH2Cl2 (1 mL) was pressurized at 8 kbar for 3 days. Solvent was
removed in vacuo at room temperature and the residue was treated
with cold methanol to afford a yellow oil. It was taken up in CHCl3,
washed with H2O, dried (MgSO4) and evaporated in vacuo at room

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3313
temperature to afford a brown coloured oil (215 mg, 67%); Rf¼0.6
(petroleum ether/ethyl acetate 10:1); 1H NMR (300 MHz, CDCl3)
3H, COOCH3), 4.63 (d, J¼15.0 Hz, 1H, NCH2Ph), 4.98 (d, J¼15.0 Hz,
1H, NCH2Ph), 5.75 (s, 1H, H1), 5.96 (s, 1H, H9), 6.85 (d, J¼8.6 Hz, 2H,
Ar), 7.24e7.26 (m, 4H, Ar), 7.28e7.30 (d, J¼8.6 Hz, 2H, Ar); 13C NMR
d/
ppm 1.75 (d, J¼10.4 Hz, 1H, H16a), 2.03 (d, J¼10.4 Hz, 1H, H16b),
2.12 (d, J¼6.7 Hz, 1H, H2), 2.36 (d, J¼6.7 Hz, 1H, H8), 3.58 (s, 3H,
OCH3), 3.75 (s, 1H, H1), 3.82 (s, 1H, H9), 3.84 (s, 3H, OCH3), 4.81 (s,
2H, NCH2Ph), 7.07e7.18 (m, 4H, Ar), 7.50 (d, J¼8.7 Hz, 2H, Ar), 8.20
(75 MHz, CDCl3) d/ppm 47.5, 49.5, 50.9, 52.4, 52.6, 53.3, 66.2, 78.6,
78.7, 91.0, 114.1, 119.6, 119.8, 127.3, 127.4, 127.7, 129.9, 142.5, 143.2,
159.6, 165.6, 166.4; HRMS (ES): Mþ, found 449.1596. C24H23N3O6
requires 449.1586. Anal. Calcd for C24H23N3O6: C, 64.13; H, 5.16; N,
9.35. Found: C, 64.17; H, 5.01; N, 9.31%.
(d, J¼8.7 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3),
d/ppm 44.0, 44.6,
45.1, 48.4, 49.8, 49.9, 52.4, 52.7, 66.6, 91.7, 121.2, 121.4, 123.7, 126.5,
129.0, 145.6, 143.7, 145.6, 147.6, 143.7, 165.9, 166.5; HRMS (ES): Mþ,
found 462.1533. C24H22N4O6 requires 462.1539. Anal. Calcd for
C24H22N4O6: C, 62.33; H, 4.79; N, 12.12. Found: C, 62.29; H, 4.78; N,
12.14%.
4.2.6. Dimethyl-6,7,8-triaza-8-(p-methoxybenzyl)-1
,11 ,12 ,13
-octatacyclo[11.6.6.13,1102,1204,1005,9014,19020,25]-hex-
acosa-6,14,16,18,20,22,24-heptaene-5,9-dicarboxylate (14). To
a,2b,3a,4b,10-
b
a
b
a
a
solution of corresponding cyclobutene diester (100 mg,
0.240 mmol) in CH2Cl2 (1 mL) was added p-methoxylbenzyl azide
(200 mg, 1.22 mmol), and pressurized at 8 kbar for 1 week. The
solution was evaporated to give a yellow oil, which was subjected to
column chromatography (CH2Cl2/petroleum ether¼1:1; Rf¼0.55)
to afford product 14 as a white powder (110 mg, 80%); mp
4.2.3. Dimethyl-4-carbmethoxymethyl-4,5,6-triaza-1a,2b,8b,9a-
pentacyclo[7.6.1.02,803,7010,15]hexadeca-6,10,12,14-tetraene-3,7-
dicarboxylate (7). To a solution of corresponding cyclobutene di-
ester (200 mg, 0.704 mmol) in CH2Cl2 (1 mL) was added carbme-
thoxymethyl azide (300 mg, 260 mmol), and pressurized at 8 kbar
for 3 days. Evaporation of the solution gave a yellow oil, which was
subjected to radial chromatography (eluent 10:1 petroleum ether/
methanol) to afford triazoline 7 as yellow oil (146 mg, 52%); Rf¼0.5
96e98 ꢀC; 1H NMR (300 MHz, CDCl3)
d/ppm ꢁ0.22 (d, J¼12.6 Hz,
1H, H25a), 0.93 (d, J¼12.6 Hz, 1H, H25b), 1.43 (d, J¼2.2 Hz, 1H, H2),
1.55 (d, J¼2.2 Hz, 1H, H12), 1.97 (d, J¼2.5 Hz, 1H, H4), 2.20 (d,
J¼2.5 Hz, 1H, H10), 2.51 (s, 1H, H3), 2.30 (s, 1H, H11), 3.63 (s, 3H,
OCH3), 3.69 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.13 (d, J¼2.7 Hz, 1H,
H13), 4.15 (d, J¼2.7 Hz, 1H, H1), 4.54 (d, J¼15.1 Hz, 1H, NCH2Ph),
4.79 (d, J¼15.1 Hz, 1H, NCH2Ph), 6.81 (d, J¼8.6 Hz, 2H, Ar),
7.02e7.06 (m, 4H, Ar), 7.13e7.18 (m, 6H, Ar); 13C NMR (75 MHz,
(petroleum ether/ethyl acetate 20:1); 1H NMR (300 MHz, CDCl3)
d/
ppm 1.77 (td, J¼10.8, 1.3 Hz, 1H, H16a), 2.09 (td, J¼10.8, 1.3 Hz, 1H,
H16b), 2.39 (td, J¼6.9, 1.1 Hz,1H, H2), 2.48 (td, J¼6.9,1.1 Hz, 1H, H8),
3.74 (s, 3H, OCH3), 3.78 (s, 1H, H1), 3.80 (s, 3H, OCH3), 3.84 (s, 1H,
H9), 3.85 (s, 3H, OCH3), 4.33 (d, J¼17.9 Hz, 1H, NCH2Ph), 4.66 (d,
J¼17.9 Hz, 1H, NCH2Ph), 7.07 (dd, J¼5.3, 3.1 Hz, 2H, Ar), 7.16e7.19
CDCl3) d/ppm 29.7, 40.9, 41.2, 47.6, 47.7, 48.1, 48.2, 48.7, 50.7, 52.4,
(m, 2H, Ar); 13C NMR (75 MHz, CDCl3)
d
/ppm 44.1, 44.7, 45.1, 48.2,
52.7, 52.8, 54.8, 55.6, 67.2, 92.8, 114.4, 123.4, 123.7, 124.8, 126.0,
126.1, 126.6, 128.4, 130.2, 142.0 (overlap two carbons), 144.6, 144.7
(overlap two carbons), 159.8, 166.4, 166.9; HRMS (ES): Mþ, found
575.2436. C35H33N3O5 requires 575.2420. Anal. Calcd for
C35H33N3O5: C, 73.03; H, 5.78; N, 7.30. Found: C, 73.12; H, 5.77; N,
7.24%.
48.3, 50.7, 52.4, 52.6, 54.8, 66.9, 92.1, 121.0, 121.4, 126.1, 126.4, 146.1,
146.3, 166.5, 166.8, 169.4; HRMS (ES): Mþ, found 399.1432.
C20H21N3O6 requires 399.1430. Anal. Calcd for C20H21N3O6: C, 60.14;
H, 5.30; N, 10.52. Found: C, 60.18; H, 5.31; N, 10.49%.
4.2.4. Dimethyl-4-allyl-4,5,6-triaza-1a,2b,8b,9a-pentacyclo
[7.6.1.02,803,7010,15]hexadeca-6,10,12,14-tetraene-3,7-dicarboxylate
(8). To a solution of corresponding cyclobutene diester (200 mg,
0.704 mmol) in CH2Cl2 (1 mL) was added allyl azide (400 mg,
4.80 mmol), and pressurized at 8 kbar for 3 days. Evaporation of the
solution gave a yellow oil, which was treated with cold methanol.
The solid was collected by filtration and washed with a small
amount of cold methanol to afford triazoline 8 as colourless solid
(170 mg, 66%); mp 116e118 ꢀC; Rf¼0.35 (petroleum ether/ethyl
4.2.7. Dimethyl-6,7,8-triaza-8-(p-methylthiobenzyl)-1
,11 ,12 ,13
-octatacyclo[11.6.6.13,1102,1204,1005,9014,19020,25]-hex-
acosa-6,14,16,18,20,22,24-heptaene-5,9-dicarboxylate (15). To
solution of corresponding cyclobutene diester (150 mg,
a,2b,3a,4b,10-
b
a
b
a
a
0.360 mmol) in CH2Cl2 (1 mL) was added p-methylthiobenzyl azide
(300 mg, 1.67 mmol), and pressurized at 8 kbar for 1 week. Evap-
oration of the solution gave a yellow oil, which was subjected to
radial chromatography (ethyl acetate/petroleum ether¼1:5;
Rf¼0.4) to afford triazoline 15 as white powder (130 mg, 62%); mp
acetate 10:1); 1H NMR (300 MHz, CDCl3)
d/ppm 1.70 (td, J¼10.7,
1.6 Hz, 1H, H16a), 2.05 (td, J¼10.7, 1.6 Hz, 1H, H16b), 2.21 (td, J¼6.7,
1.3 Hz, 1H, H2), 2.34 (td, J¼6.7, 1.3 Hz, 1H, H8), 3.67 (s, 1H, H1), 3.78
(s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.95 (s, 1H, H9), 4.15 (ddd, J¼10.2,
7.5, 1.3 Hz, 1H), 4.36 (ddd, J¼10.2, 7.5, 1.3 Hz, 1H), 5.21 (td, J¼16.9,
1.3 Hz, 1H, NCH2Ph), 5.24 (td, J¼16.9, 1.3 Hz, 1H, NCH2Ph),
5.92e5.94 (m, 1H), 5.89e5.91 (m, 1H, Ar), 5.94e5.95 (m, 1H, Ar),
7.07e7.10 (m, 1H, Ar), 7.15e7.19 (m, 1H, Ar); 13C NMR (75 MHz,
104e106 ꢀC; 1H NMR (300 MHz, CDCl3)
d
/ppm ꢁ0.19 (d, J¼12.6 Hz,
1H, H25a), 0.94 (d, J¼12.6 Hz, 1H, H25b), 1.47 (dd, J¼2.3, 6.4 Hz, 1H,
H2), 1.64 (dd, J¼2.3, 6.4 Hz, 1H, H12), 1.99 (d, J¼6.4 Hz, 1H, H4), 2.25
(d, J¼6.4 Hz, 1H, H10), 2.26 (s, 1H, H3), 2.45 (s, 1H, H11), 2.47 (s, 3H,
SCH3), 3.48 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 4.18 (d, J¼2.6 Hz, 1H,
H1), 4.20 (d, J¼2.6 Hz, 1H, H13), 4.58 (d, J¼15.2 Hz, 1H, NCH2Ph),
4.82 (d, J¼15.2 Hz, 1H, NCH2Ph), 7.04e7.07 (m, 2H, Ar), 7.08e7.11
CDCl3)
d
/ppm 44.4, 44.7, 45.1, 49.0, 50.4, 51.2, 52.7, 52.8, 66.5, 92.4,
(m, 2H, Ar), 7.18e7.24 (m, 8H, Ar); 13C NMR (75 MHz, CDCl3)
d/ppm
119.4, 121.6, 121.7, 126.8 (2C), 133.1, 146.1, 146.3, 166.7, 167.3; IR
(KBr): 1450, 1720, 1742 cmꢁ1; HRMS (ES): Mþ, found 367.1537.
C20H21N3O4 requires 367.1532. Anal. Calcd for C20H21N3O4: C, 65.38;
H, 5.76; N, 11.44. Found: C, 65.35; H, 5.81; N, 11.37%.
16.5, 30.0, 41.2, 41.5, 47.9, 48.0, 48.5, 48.5, 48.6, 51.0, 52.7, 53.0, 53.1,
55.1, 67.6, 93.1, 123.8, 123.9, 125.0, 125.1, 126.3, 126.8, 126.9, 127.4,
127.5, 128.5, 129.5, 133.5, 139.1, 142.3, 144.9, 166.6, 167.1; HRMS
(ES): Mþ, found 591.2196. C35H33N3O4S requires 591.2192. Anal.
Calcd for C35H33N3O4S: C, 71.04; H, 5.62; N, 7.10. Found: C, 71.01; H,
5.60; N, 7.02%.
4.2.5. Dimethyl-4-(p-methoxybenzyl)-16-oxa-4,5,6-triaza-
1a,2b,8b,9a
-pentacyclo[7.6.1.02,803,7010,15]hexadeca-6,10,12,14-
tetraene-3,7-dicarboxylate (13). A solution of corresponding cyclo-
butene diester (100 mg, 0.349 mmol) and p-methoxybenzyl azide
(200 mg, 1.23 mmol) in CH2Cl2 (1 mL) was pressurized at 14 kbar
for 3 days. Radial chromatography (petroleum ether/ethyl acetate
20:1; Rf¼0.35), followed by treatment with cold methanol afforded
triazoline 13 as colourless solid (86 mg, 55%); mp 117e118 ꢀC; 1H
4.2.8. Dimethyl-6,7,8-triaza-8-(40-pyridyl)-1
,11 ,12 ,13
-octatacyclo[11.6.6.13,1102,1204,1005,9014,19020,25]-hex-
acosa-6,14,16,18,20,22,24-heptaene-5,9-dicarboxylate (16). To
solution of corresponding cyclobutene diester (100 mg,
0.240 mmol) in CH2Cl2 (1 mL) was added 4-pyridyl azide (200 mg,
1.70 mmol), and pressurized at 8 kbar for 1 week. Evaporation of
the solution gave yellow oil, which was subjected to radial chro-
matography (ethyl acetate and CH2Cl2 1:4; Rf¼0.2), to afford
a,2b,3a,4b,10-
b
a
b
a
a
NMR (300 MHz, CDCl3)
d
/ppm 2.07 (d, J¼6.4 Hz, 1H, H2), 2.48 (d,
J¼6.4 Hz, 1H, H8), 3.65 (s, 3H, COOCH3), 3.74 (s, 3H, OCH3), 3,82 (s,

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3314
product 16 as a white powder (120 mg, 93%); mp 128e130 ꢀC; 1H
NMR (300 MHz, CDCl3)
(d, J¼12.9 Hz, 1H, H25b), 1.62 (dd, J¼8.6, 2.5 Hz, 1H, H2), 1.67 (dd,
J¼8.6, 1.9 Hz, 1H, H12), 2.28 (d, J¼6.8 Hz, 1H, H4), 2.33 (s, 1H, H3),
2.34 (d, J¼6.8 Hz, 1H, H10), 2.96 (s, 1H, H11), 3.55 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 4.17 (s,1H, H1), 4.21 (s,1H, H13), 6.96 (d, J¼6.3 Hz, 2H,
Ar), 7.03e7.07 (m, 2H, Ar), 7.12e7.14 (m, 2H, Ar), 7.19e7.22 (m, 4H,
The solvent was removed in vacuo at room temperature and the
residue treated with cold methanol. The precipitate was collected
by filtration as colourless crystals (149 mg, 77%); mp 223e224 ꢀC;
%); Rf¼0.4 (petroleum ether/ethyl acetate 10:1); 1H NMR (300 MHz,
d
/ppm ꢁ0.03 (d, J¼12.9 Hz, 1H, H25a), 1.08
CDCl3)
d
/ppm 1.76 (d, J¼12.4 Hz, 1H, H16a), 2.30 (d, J¼7.1 Hz, 1H,
H8), 2.52 (d, J¼7.1 Hz, 1H, H2), 2.74 (d, J¼12.4 Hz, 1H, H16b), 4.68 (d,
J¼15.5 Hz, 1H, NCH2Ph), 4.88 (s, 1H, H1), 4.97 (s, 1H, H9), 5.09 (d,
J¼15.5 Hz, 1H, NCH2Ph), 7.05e7.09 (m, 3H, Ar), 7.29e7.32 (m, 2H,
Ar), 7.43e7.44 (m, 2H, Ar), 7.91e7.95 (m, 2H, Ar), 8.60 (t, J¼6.6 Hz,
Ar), 8.46 (d, J¼5.4 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm
30.2, 41.3, 41.4, 47.8, 48.0, 48.4, 48.5, 52.5, 53.4, 53.6, 53.8, 54.3,
63.8, 96.1, 109.6, 123.9, 125.0, 125.2, 126.4, 126.5, 127.0, 127.1, 142.1,
142.2, 144.5, 144.6, 144.7, 151.5, 165.5, 167.0; HRMS (ES): Mþ, found
532.2107. C32H28N4O4 requires 532.2111. Anal. Calcd for
C32H28N4O4: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.11; H, 5.33; N,
10.56%.
2H, Ar), 8.77 (t, J¼4.2 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3)
d/ppm
40.2, 42.2, 44.6, 45.5, 47.0, 51.5, 67.4 (q, J¼31.2 Hz), 88.7 (q,
J¼29.8 Hz), 122.1, 122.9 (q, J¼276.7 Hz), 124.9 (q, J¼284.6 Hz), 123.3,
123.9, 128.6, 129.0, 135.8, 137.8, 146.7, 149.5, 149.7, 152.2, 152.7,
154.7, 154.8; HRMS (ES): Mþ, found 593.1770. C30H21N7F6 requires
593.1763. Anal. Calcd for C30H21N7F6: C, 60.71; H, 3.57; N, 16.52.
Found: C, 60.77; H, 3.51; N, 16.45%.
4.2.9. Dimethyl-6,7,8-triaza-8-(30-pyridyl)-1
,11 ,12 ,13
-octatacyclo[11.6.6.13,1102,1204,1005,9014,19020,25]-hex-
acosa-6,14,16,18,20,22,24-heptaene-5,9-dicarboxylate (17). To
a,2b,3a,4b,10-
b
a
b
a
4.3. Thermal rearrangement of triazolines
a solution of cyclobutene diester 14p (100 mg, 0.240 mmol) in
CH2Cl2 (1 mL) was added 3-pyridyl azide (200 mg, 1.70 mmol), and
pressurized at 8 kbar for 1 week. Evaporation of the solution gave
a yellow oil, which was subjected to radial chromatography (ethyl
acetate/petroleum ether¼1:2; Rf¼0.4). Purified material was then
recrystallized from CH2Cl2/petroleum ether to afford product 17 as
a white powder (110 mg, 85%); mp 120e122 ꢀC; 1H NMR (300 MHz,
General method A: sample of triazoline (100e200 mg) in
a round-bottomed flask was heated at 140 ꢀC for 1 h. After cooling,
reaction mixture was separated by radial chromatography and all
new products fully characterized by 1H, 13C NMR spectroscopy and
high-resolution mass spectrometry.
General method B: sample of triazoline (100e200 mg) was dis-
solved in CDCl3 (0.5 mL) in an NMR tube and heated at 80 ꢀC for
2e12 h, the products were separated by radial chromatography.
CDCl3)
d
/ppm ꢁ0.05 (d, J¼12.8 Hz, 1H, H25a), 1.09 (d, J¼12.8 Hz, 1H,
H25b), 1.59 (d, J¼8.4 Hz, 1H, H2), 1.64 (d, J¼8.4 Hz, 1H, H12), 2.33 (s,
3H, H3, H4, H10), 2.93 (s, 1H, H3), 3.54 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 4.21 (s, 1H, H1), 4.25 (s, 1H, H13), 7.03e7.08 (m, 2H, Ar),
7.13e7.15 (m, 2H, Ar), 7.19e7.22 (m, 4H, Ar), 7.28e7.31 (m, 1H, Ar),
7.55e7.59 (m, 1H, Ar), 8.33e8.34 (m, 1H, Ar), 8.35e8.38 (m, 1H, Ar);
4.3.1. (6S,8S,9R)-Dimethyl-6-phenyl-4,5,7-triaza-1a,2b,10a-hex-
acyclo[8.6.1.02,905,9011,16]heptadeca-3,11,13,15-tetraene-3,8-
dicarboxylate (exo-22), (6R,8S,9R)-dimethyl-6-phenyl-4,5,7-triaza-
13C NMR (75 MHz, CDCl3)
d/ppm 30.1, 41.2, 41.3, 47.7, 47.8, 48.4,
1a b,10a
-hexacyclo[8.6.1.02,905,9011,16]heptadeca-3,11,13,15-tetraene-
,2
3,8-dicarboxylate (endo-22) and
48.5, 52.6, 54.4, 53.6, 53.2, 64.4, 95.6, 122.5, 123.8, 123.9, 124.9,
125.1, 126.2, 126.3, 126.8, 127.0, 136.4, 142.0, 142.1, 144.5, 144.7,
145.0, 165.7, 167.0; HRMS (ES): Mþ, found 532.2108. C32H28N4O4
requires 532.2111. Anal. Calcd for C32H28N4O4: C, 72.17; H, 5.30; N,
10.52. Found: C, 72.11; H, 5.36; N, 10.56%.
1a,8a
-10-(30-benzyl-40-carbme-
thoxy-1,2,3-triazolyl)bicyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene
(23). A sample of triazoline 4 (200 mg, 0.479 mmol) was heated at
140 ꢀC for 1 h in round-bottomed flask. Resulting brown coloured
oil was subjected to radial chromatography (petroleum ether/ethyl
acetate 10:1, then the solvent polarity was gradually increased to
ethyl acetate) to afford several products. Single crystals suitable for
X-ray analysis were obtained by slow diffusion of petroleum ether
in dichloromethane solution of compound exo-22.
4.2.10. Dimethyl-17-benzyl-3,10-dimethoxy-15,16,17-triaza-1
a,12a,
13 ,19
b
b
-hexacyclo[10.7.1.02,1104,9013,19014,18]dodeca-2,4,6,8,10,15-
heptaene-14,18-dicarboxylate (18). To a solution of corresponding
cyclobutene diester (200 mg, 0.500 mmol) in CH2Cl2 (1 mL) was
added benzyl azide (300 mg, 1.67 mmol), and pressurized at 8 kbar
for 3 days. Evaporation of the solution gave a brownish coloured oil,
which was treated with cold methanol. The solid was collected by
filtration and washed with a small amount of cold methanol to
Compound exo-22 (colourless solid, 48 mg, 24%); mp
164e166 ꢀC; %); Rf¼0.8; 1H NMR (300 MHz, CDCl3)
d/ppm 1.92 (d,
J¼9.6 Hz, 1H, H17a), 2.07 (d, J¼9.6 Hz, 1H, H17b), 2.84 (s, 1H, H10),
3.09 (s, 1H, H2), 3.13 (s, 3H, OCH3), 3.62 (br s, 1H, H1), 3.74 (s, 1H,
H8), 3.89 (s, 3H, OCH3), 6.00 (s, 1H, NH), 7.04e7.06 (m, 4H, Ar),
7.38e7.41 (m, 3H, Ar), 7.72 (d, J¼7.5 Hz, 2H, Ar); 13C NMR (100 MHz,
afford triazoline 18 as
a white powder (190 mg, 74%); mp
104e106 ꢀC; %); Rf¼0.7 (petroleum ether/ethyl acetate 10:1); 1H
CDCl3) d/ppm 47.0, 49.0, 52.2, 52.4, 55.9, 61.4, 65.6, 81.5, 88.5, 121.7,
NMR (300 MHz, CDCl3)
d
/ppm 1.74 (d, J¼6.1 Hz, 1H, H20a), 2.18 (d,
124.4, 126.8, 127.4, 127.5, 128.5, 128.8, 139.3, 143.4, 146.4, 148.3,
162.9, 171.7; HRMS (ES): Mþ, found 417.1685. C24H23N3O4 requires
417.1689. Anal. Calcd for C24H23N3O4: C, 69.05; H, 5.55; N, 10.07.
Found: C, 69.01; H, 5.49; N, 10.01%.
J¼6.1 Hz, 1H, H20b), 2.20 (d, J¼6.7 Hz, 1H, H13), 2.56 (d, J¼6.7 Hz,
1H, H19), 3.66 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
3.96 (s, 3H, OCH3), 4.04 (s, 1H, H1), 4.20 (s, 1H, H12), 4.64 (d,
J¼15.0 Hz, 1H, NCH2Ph), 5.14 (d, J¼15.0 Hz, 1H, NCH2Ph), 7.26e7.31
(m, 5H, Ar), 7.42e7.45 (m, 2H, Ar), 8.02e8.04 (m, 2H, Ar); 13C NMR
Compound endo-22 (colourless solid, 31 mg, 18%); mp
156e159 ꢀC; Rf¼0.75; 1H NMR (300 MHz, CDCl3)
d/ppm 1.99 (dt,
(75 MHz, CDCl3),
d
/ppm 29.7, 42.1, 42.4, 43.5, 49.7, 52.0, 53.2, 54.3,
J¼9.6, 1.4 Hz, 1H, H17a), 2.23 (dt, J¼9.6, 1.4 Hz, 1H, H17b), 2.89 (t,
J¼11.5 Hz, 1H, H7), 3.13 (s, 3H, OCH3), 3.48 (s, 1H, H2), 3.51 (d,
J¼1.4 Hz, 1H, H10), 3.69 (d, J¼11.5 Hz, 1H, H8), 3.72 (s, 1H, H1), 3.90
(s, 3H, OCH3), 5.39 (d, J¼11.5 Hz, 1H, H6), 7.04e7.06 (m, 4H, Ar),
7.24e7.25 (m, 1H, Ar), 7.38e7.41 (m, 2H, Ar), 7.57 (d, J¼6.5 Hz, 2H,
56.5, 65.8, 79.1, 93.3, 122.5, 122.6, 125.9, 126.0, 127.6, 128.6, 128.7,
128.8, 129.3, 132.7, 133.1, 137.7, 145.3, 145.4, 166.3, 167.1; IR (KBr):
;
1456, 1732, 1749 cmꢁ1 HRMS (ES): Mþ, found 527.2056.
C30H29N3O6 requires 527.2062. Anal. Calcd for C30H29N3O6: C,
68.30; H, 5.54; N, 7.96. Found: C, 68.45; H, 5.61; N, 7.65 %.
Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 44.7, 45.4, 51.4, 52.7, 52.8,
58.2, 62.5, 81.6, 87.9, 121.5, 125.9, 126.9, 127.1, 129.0, 129.1, 125.5,
139.2, 143.4, 146.8, 148.6, 162.9, 169.1; HRMS (ES): Mþ, found
417.1694. C24H23N3O4 requires 417.1689.
4.2.11. 4-Benzyl-11,14-di(20-pyridyl)-3,7-di(trifluoromethyl)-4,5,6,12,
13-pentaaza-1
10,12,14-tetraene (21). Solution of cyclobutene 21p (Supplementary
data) (150 mg, 0.326 mmol) and benzyl azide (200 mg,
1.304 mmol) in CH2Cl2 (1 mL) was pressurized for 3 days at 8 kbar.
a ,2b,8b,9a
-pentacyclo[7.6.1.02,803,7010,15]hexadeca-6,
Compound 23 (colourless solid, 21 mg, 14%); mp 124e126 ꢀC;
Rf¼0.4; 1H NMR (400 MHz, CDCl3)
/ppm 2.33 (d, J¼8.7 Hz, 1H,
d
H11a), 2.39 (d, J¼8.7 Hz, 1H, H11b), 3.81 (s, 3H, OCH3), 3.98 (s, 1H,

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3315
H1), 4.22 (s, 1H, H8), 5.32 (d, J¼15.0 Hz, 1H, NCH2Ph), 5.43 (d,
NMR (100 MHz, CDCl3)
d
/ppm 47.6, 49.1, 52.7, 52.9, 55.3, 62.3, 65.6,
J¼15.0 Hz, 1H, NCH2Ph), 6.68 (s, 1H, C¼CH), 7.06e7.11 (m, 4H, Ar),
79.6, 91.2, 121.7, 124.3, 124.5, 126.6, 127.3, 128.1, 136.9, 149.0, 149.2,
149.3, 149.9, 162.2, 171.5; HRMS (ES): Mþ, found C24H22N4O6:
462.1529, requires 462.1539.
7.21e7.24 (m, 4H, Ar), 7.30e7.33 (m, 1H, Ar); 13C NMR (100 MHz,
CDCl3) d/ppm 47.4, 48.9, 50.9, 52.9, 60.2, 115.9, 122.3, 122.8, 126.7,
126.9, 127.6, 127.9, 128.8, 132.6, 137.9, 146.7, 147.6, 160.9, 162.4,
163.2; IR (KBr): 1440, 1606, 1734 cmꢁ1; HRMS (ES): Mþ, found
357.1476. C22H19N3O2 requires 357.1477.
Compound endo-27 (colourless solid, 16 mg, 16%); mp
161e162 ꢀC; Rf¼0.65; 1H NMR (300 MHz, CDCl3)
d/ppm 2.04 (d,
J¼9.7 Hz, 1H, H17a), 2.19 (d, J¼9.7 Hz, 1H, H17b), 2.88 (t, J¼2.1 Hz,
1H, NH), 3.17 (s, 3H, OCH3), 3.42 (s, 1H, H10), 3.54 (d, J¼1.6 Hz, 1H,
H2), 3.73 (d, J¼1.6 Hz, 1H, H1), 3.74 (s, 1H, H8), 4.01 (s, 3H, OCH3),
5.43 (d, J¼9.1 Hz, 1H, H6), 7.04e7.11 (m, 4H, Ar), 7.81 (d, J¼8.4 Hz,
2H, p-NO2eC6H4), 8.28 (d, J¼8.4 Hz, 2H, p-NO2eC6H4); 13C NMR
4.3.2. (6S,8S,9R)-Dimethyl-6-(p-methoxyphenyl)-4,5,7-triaza-
1
a b,10a
-hexacyclo[8.6.1.02,905,9011,16]heptadeca-3,11,13,15-tetraene-
,2
3,8-dicarboxylate
yphenyl)-4,5,7-triaza-1
(exo-24),
,2 ,10
(6R,8S,9R)-dimethyl-6-(p-methox-
a
b
a
-hexacyclo[8.6.1.02,905,9011,16]hepta-
(100 MHz, CDCl3) d/ppm 49.2, 49.4, 51.1, 52.8, 53.0, 58.6, 60.8, 62.7,
deca-3,11,13,15-tetraene-3,8-dicarboxylate (endo-24) and 1
a
,8
a
-10-
80.8, 88.2, 121.6, 124.4, 126.1, 127.3, 128.0, 143.1, 146.1, 148.0, 148.4,
148.6, 162.6, 168.9; HRMS (ES): Mþ, found 462.1531. C24H22N4O6
requires 462.1534.
(10-p-methoxybenzyl-40-carbmethoxy-1,2,3-triazolyl)bicyclo
[6.2.1.02,7]undeca-2,4,6,9-tetraene (26). A sample of triazoline 5
(38 mg, 0.100 mmol) was heated in a test tube at 140 ꢀC for 6 h. The
yellow coloured oily residue was subjected to radial chromatogra-
phy (starting with petroleum ether/ethyl acetate 20:1, then the
solvent polarity was gradually increased to ethyl acetate) to afford
three products, in order of elution: exo-24 (yellow solid, 11 mg,
Compound 28 (yellow solid, 11 mg, 11%); mp 203e205 ꢀC;
Rf¼0.5; 1H NMR (300 MHz, CDCl3)
/ppm 2.14 (td, J¼8.3, 1.5 Hz, 1H,
d
H11a), 2.16 (td, J¼8.2, 1.5 Hz, 1H, H11b), 3.55 (s, 3H, OCH3), 3.74 (s,
3H, OCH3), 4.12 (s, 1H, H1), 4.13 (s, 1H, H8), 5.20 (d, J¼15.2 Hz, 1H,
NCH2Ph), 5.31 (d, J¼15.2 Hz, 1H, NCH2Ph), 6.46 (s, 1H, C]CH),
6.77e7.31 (m, 4H, Ar), 7.95 (d, J¼8.9 Hz, 2H, Ar), 8.27 (d, J¼8.9 Hz,
25%); mp 262e263 ꢀC; Rf¼0.75; 1H NMR (300 MHz, CDCl3)
d/ppm
1.95 (d, J¼9.8 Hz, 1H, H17a), 2.06 (d, J¼9.8 Hz, 1H, H17b), 2.86 (s, 1H,
H10), 3.08 (s, 1H, H2), 3.14 (s, 3H, OCH3), 3.74 (s, 1H, H1), 3.81 (s, 1H,
H8), 3.90 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 5.97 (s, 1H, NH), 6.93 (d,
J¼8.8 Hz, 2H, Ar), 7.05e7.24 (m, 4H, Ar), 7.63 (d, J¼8.8 Hz, 2H, Ar);
2H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 33.1, 46.9, 47.9, 52.6, 57.6,
60.7, 109.2, 116.6, 122.5, 122.9, 127.5, 127.6, 128.8, 130.1, 131.4, 143.4,
145.5, 146.6, 158.1, 161.1, 162.1; HRMS (ES): Mþ, found 402.1329.
C22H18N4O4 requires 402.1327.
13C NMR (100 MHz, CDCl3)
d/ppm 47.0, 47.7, 49.3, 55.2, 61.8, 65.6,
75.3, 84.9, 88.5, 113.5, 121.6, 124.5, 126.5, 127.4, 130.2, 132.6, 143.4,
146.3, 148.1, 159.9, 162.5, 171.8; HRMS (ES): Mþ, found 447.1791.
C25H25N3O5 requires 447.1794.
4.3.4. (6S,8S,9R)-Dimethyl-12,19-dimethoxy-6-phenyl-4,5,7-triaza-
1
a b,10a
-heptacyclo[10.8.1.02,905,9011,20]henicosa-3,11,13,15,17,19-
,2
hexaene-3,8-dicarboxylate (exo-29), 6R,8S,9R-dimethyl-12,19-
dimethoxy-6-phenyl-4,5,7-triaza-1 ,2 ,10 -heptacyclo
[10.8.1.02,905,9011,20]henicosa-3,11,13,15,17,19-hexaene-3,8-
dicarboxylate (endo-29) and 1 ,12
-3,10-dimethoxy-13-(30-benzyl-
Compound endo-24 (yellow solid, 6 mg, 13%); mp 242e243 ꢀC;
a
b
a
Rf¼0.7; 1H NMR (300 MHz, CDCl3)
/ppm 1.93 (d, J¼9.8 Hz, 1H,
d
H17a), 2.04 (d, J¼9.8 Hz, 1H, H17b), 2.84 (s, 1H, H7), 3.07 (s, 1H, H2),
3.11 (s, 3H, OCH3), 3.77 (s, 1H, H1), 3.78 (s, 1H, H8), 3.91 (s, 3H,
OCH3), 3.94 (s, 3H, OCH3), 5.45 (s,1H, NH), 6.91 (d, J¼8.8 Hz, 2H, Ar),
7.07e7.22 (m, 4H, Ar), 7.64 (d, J¼8.8 Hz, 2H, Ar); 13C NMR (100 MHz,
a
a
40-carbmethoxy-1,2,3-triazolyl)bicyclo[10.2.1.02,1104,9]pentadeca-
2,4,6,8,10,13-hexaene (30). A sample of triazoline 18 (100 mg,
0.190 mmol) was heated at 140 ꢀC for 1 h. The brown coloured oily
residue was subjected to radial chromatography (starting with
petroleum ether/ethyl acetate 10:1, then solvent polarity was
gradually increased to ethyl acetate) to afford three products: exo-
29 (colourless solid, 23 mg, 23%); mp 141e143 ꢀC; Rf¼0.7; 1H NMR
CDCl3) d/ppm 44.9, 45.7, 52.4, 52.7, 52.8, 57.2, 61.5, 82.6, 87.9, 122.5,
125.9, 126.7, 127.3, 128.0, 129.4, 135.5, 137.2, 143.7, 144.8, 148.6,
163.9, 168.5; HRMS (ES): Mþ, found 447.1788. C25H25N3O5 requires
447.1794.
Compound 26 (yellow oil, 9 mg, 23%); Rf¼0.6; 1H NMR
(300 MHz, CDCl3)
d
/ppm 1.97 (dt, J¼1.6, 9.8 Hz, 1H, H21a), 2.13 (dt,
(300 MHz, CDCl3)
d
/ppm 2.31 (td, J¼8.6, 1.6 Hz, 1H, H11a), 2.36 (td,
J¼16.0, 9.8 Hz, 1H, H21b), 2.61 (s, 3H, OCH3), 3.09 (br s, 1H, H10),
3.15 (s, 1H, H2), 3.21 (s, 1H, H1), 3.67 (s, 3H, OCH3), 3.86 (s, 1H, H8),
3.93 (s, 3H, OCH3), 3.93 (s, 1H), 4.06 (s, 3H, OCH3), 4.21 (s, 1H), 6.07
(s,1H, NH), 7.42e7.47 (m, 3H, Ar), 7.80 (d, J¼7.2 Hz, 2H, Ar), 8.02 (dd,
J¼3.4, 5.2 Hz, 2H, Ar), 8.10 (dd, J¼3.4, 5.2 Hz, 2H, Ar); 13C NMR
J¼8.6, 1.6 Hz, 1H, H11b), 3.75 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.21
(s, 1H, H1), 4.31 (s, 1H, H8), 5.26 (d, J¼14.8 Hz, 1H, NCH2Ph), 5.34 (d,
J¼14.8 Hz, 1H, NCH2Ph), 6.66 (s, 1H, C]CH), 7.07 (d, J¼8.6 Hz, 4H,
Ar), 6.77e7.31 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 30.1,
46.9, 48.9, 51.6, 55.6, 60.2, 114.2, 115.9, 122.3, 122.8, 126.5, 126.6,
129.6, 130.0, 130.4, 146.6, 146.7, 147.6, 159.2, 160.8, 162.4; HRMS
(ES): Mþ, found 387.1580. C23H21N3O3 requires 387.1583.
(100 MHz, CDCl3) d/ppm 45.2, 46.5, 51.7, 52.1, 52.9, 61.7, 61.9, 62.2,
65.4, 81.4, 88.9, 122.4, 122.5, 126.0, 126.2, 127.7, 128.5, 128.8, 128.9,
129.1, 130.1, 133.9, 138.5, 145.1, 145.9, 147.9, 162.4, 171.7; HRMS (ES):
Mþ, found 527.2057. C30H29N3O6 requires 527.2056.
4.3.3. (6S,8S,9R)-Dimethyl-6-(p-nitrophenyl)-4,5,7-triaza-1
a
,2b
,10
a-
Compound endo-29 (obtained from crude spectrum); Rf¼0.68;
hexacyclo[8.6.1.02,905,9011,16]heptadeca-3,11,13,15-tetraene-3,8-
1H NMR (CDCl3)
d/ppm 5.56 (s, 1H, NH); HRMS (m/z): calcd for
dicarboxylate (exo-27), (6R,8S,9R)-dimethyl-6-(p-nitrophenyl)-4,5,7-
C30H29N3O6: 527.2056, found: 527.2059.
triaza-1
tetraene-3,8-dicarboxylate (endo-27) and
benzyl-40-carbmethoxy-1,2,3-triazolyl)bicyclo[6.2.1.02,7]undeca-
2,4,6,9-tetraene (28). A sample of triazoline (100 mg,
a
,2
b
,10
a
-hexacyclo[8.6.1.02,905,9011,16]heptadeca-3,11,13,15-
Compound 30 (colourless solid, 7 mg, 8%); mp 166e167 ꢀC;
1
a,8a
-10-(10-p-nitro-
Rf¼0.45; 1H NMR (400 MHz, CDCl3)
/ppm 2.37 (d, J¼8.9 Hz, 1H,
d
H13a), 2.39 (d, J¼8.9 Hz, 1H, H13b), 3.81 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3), 4.01 (s, 3H, OCH3), 4.66 (s, 1H, H1), 4.82 (s, 1H, H22), 5.22 (d,
J¼15.2 Hz,1H, NCH2Ph), 5.59 (d, J¼15.2 Hz,1H, NCH2Ph), 6.78 (s,1H,
H14), 7.12e7.13 (m, 2H), 7.22e7.25 (m, 3H, Ar), 7.48 (dd, J¼3.3, 6.4 Hz,
2H, Ar), 8.03 (dd, J¼3.3, 6.4 Hz, 1H, Ar), 8.06 (dd, J¼3.3, 6.4 Hz, 1H,
6
0.216 mmol) was heated at 140 ꢀC for 1 h. The brown coloured oily
residue was subjected to radial chromatography (starting with
petroleum ether/ethyl acetate 10:1, then solvent polarity was
gradually increased to ethyl acetate) to afford several products: exo-
27 (colourless solid, 11 mg, 11%); mp 163e164 ꢀC; Rf¼0.7; 1H NMR
Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 45.3, 47.6, 47.7, 52.9, 57.9, 62.4,
62.5, 115.7, 122.6, 122.7, 126.4, 126.5, 127.8, 128.1, 128.8, 128.7, 129.3,
131.2, 131.8, 132.9, 137.7, 145.9, 146.7, 159.9, 162.4, 163.1; HRMS (ES):
Mþ, found 467.1833. C28H25N3O4 requires 467.1845.
(300 MHz, CDCl3)
d
/ppm 1.98 (dq, J¼9.7, 1.8 Hz, 1H, H17a), 2.06 (dt,
J¼9.7, 1.3 Hz, 1H, H17b), 2.76 (s, 1H, H1), 3.06 (s, 1H, H2), 3.15 (s, 3H,
OCH3), 3.23 (br s, 1H, NH), 3.57 (br s, 1H, H8), 3.76 (s, 1H, H10), 3.93
(s, 3H, OCH3), 6.03 (s, 1H, H6), 7.08e7.20 (m, 4H, Ar), 7.95 (d,
4.3.5. (9R)-Methyl-10,11-diaza-9-(imino-10-carbmethoxy-20-ben-
J¼8.9 Hz, 2H, p-NO2eC6H4), 8.27 (d, J¼8.9 Hz, 2H, p-NO2eC6H4); 13
C
zyl)-1a,8a,9b,13b
-tetracyclo[6.5.1.02,709,13]tetradeca-2,4,6,11-

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3316
tetraene-12-carboxylate (31). A solution of triazoline 4 (70 mg,
0.168 mmol) was heated in CDCl3 (0.5 mL) at 80 ꢀC for 2 h. The
solvent was removed in vacuo to afford the product as a yellow
coloured oil (66 mg, 94%); Rf¼0.35 (petroleum ether/ethyl acetate
carboxylate (35). A sample of triazoline 8 (100 mg, 0.272 mmol)
was heated in a test tube at 80 ꢀC overnight. Radial chromatography
(starting with petroleum ether/ethyl acetate 10:1, then solvent
polarity was gradually increased to ethyl acetate) afforded 35 as
yellow coloured oil (87 mg, 87%); Rf¼0.6; 1H NMR (400 MHz, CDCl3)
20:1); 1H NMR (300 MHz, CDCl3)
d
/ppm 1.97 (td, J¼9.8, 1.4 Hz, 1H,
H14a), 2.08 (td, J¼9.8, 1.4 Hz, 1H, H14b), 3.81 (s, 1H, H13), 3.86 (s,
3H, OCH3), 3.93 (s, 3H, OCH3), 3.98 (s, 1H, H8), 4.09 (s, 1H, H1), 4.42
(q, J¼8.9 Hz,1H, NCH2Ph), 4.47 (q, J¼8.9 Hz,1H, NCH2Ph), 6.82e7.39
d
/ppm 1.85 (td, J¼9.8, 1.5 Hz, 1H, H14a), 2.17 (td, J¼9.8, 1.5 Hz, 1H,
H14b), 2.95 (d, J¼8.7 Hz, 1H, H13), 3.17 (d, J¼8.7 Hz, 1H, H12), 3.29
(s, 1H, H1), 3.71 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.84 (s, 1H, H8),
4.17 (dd, J¼15.6, 5.1 Hz, 1H, NCH2Ph), 4.23 (dd, J¼15.6, 5.1 Hz, 1H,
NCH2Ph), 5.14 (td, J¼10.4, 1.6 Hz, 1H, CH2CH]CH2), 5.27 (td, J¼10.4,
1.6 Hz, 1H, CH2CH]CH2), 5.93e6.08 (m, 1H, CH2CH]CH2),
7.09e7.11 (m, 2H, Ar), 7.21e7.26 (m, 2H, Ar); 13C NMR (100 MHz,
(m, 9H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 40.7, 40.8, 48.2, 52.4,
56.2, 56.7, 57.7, 84.3, 121.5, 122.8, 126.4, 127.2, 127.5, 127.8, 128.4,
138.5, 142.9, 143.0, 147.5, 158.9, 163.4, 163.8; IR (KBr): 1458, 1674,
;
1728, 1732, 2952 cmꢁ1 HRMS (ES): Mþ, found 417.1686.
C24H23N3O4 requires 417.1689.
CDCl3) d/ppm 38.8, 46.2, 47.5, 47.9, 49.1, 52.1, 52.4, 57.2, 98.4, 116.3,
121.4, 121.6, 126.5, 126.8, 135.9, 148.4, 148.9, 162.1, 163.9, 168.1;
4.3.6. (9R,12R)-Methyl-11,12-diaza-9-(imino-10-carbmethoxy-20-(p-
HRMS (ES): Mþ, found 367.1537. C20H21N3O4 requires 367.1532.
methoxybenzyl))-1
2,4,6,10-tetraene-12-carboxylate (32), (9R)-methyl-11,12-diaza-9-
(imino-10-carbmethoxy-20-(p-methoxybenzyl))-1
,8 ,13 -tetracyclo
[6.5.1.02,709,13]tetradeca-2,4,6,11-tetraene-12-carboxylate (33) and
,8
-10-(10-p-methoxybenzyl-40-carbmethoxy-1,2,3-triazolyl)bicy-
a,8
a,
13b
-tetracyclo[6.5.1.02,709,13]tetradeca-
4.3.9. (9R)-Methyl-10,11-diaza-9-(imino-10-carbmethoxy-20-ben-
a
a
b
zyl)-1a,8a,13b
-tetracyclo[6.5.1.02,709,13]tetradeca-spiro(14:10-cyclo-
propane)-2,4,6,11-tetraene-12-carboxylate (36). A solution of
triazoline 9 (79 mg, 0.183 mmol) was heated in CDCl3 (0.5 mL) at
80 ꢀC for 2 h. The solvent was removed in vacuo to afford product
36 as yellow coloured solid (75 mg, 95%); mp 101e104 ꢀC); Rf¼0.55
1
a a
clo[6.2.1.02,7]undeca-2,4,6,9-tetraene (26). A solution of triazoline 5
(49 mg, 0.109 mmol) was heated in CDCl3 (0.5 mL) at 80 ꢀC over-
night. The solvent was removed in vacuo to afford yellow coloured
oily residue. Radial chromatography (starting with petroleum
ether/ethyl acetate 20:1, then solvent polarity was gradually in-
creased to ethyl acetate) afforded three products in order of elution:
Compound 32 (yellow oil, 26 mg, 53%); Rf¼0.8; 1H NMR
(petroleum ether/ethyl acetate 10:1); 1H NMR (300 MHz, CDCl3)
d/
ppm 0.29 (t, J¼7.7 Hz, 2H, H16), 0.81 (dt, J¼7.9, 2.9 Hz, 1H, H15a),
1.00 (dt, J¼7.9, 1.9 Hz, 1H, H15b), 3.13 (s, 1H, H13), 3.21 (s, 1H, H1),
3.84 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.96 (s, 1H, H8), 4.43 (d,
J¼15.5 Hz, 1H, NCH2Ph), 4.47 (d, J¼15.5 Hz, 1H, NCH2Ph), 6.79 (dd,
J¼7.3, 3.5 Hz, 2H, Ar), 6.98e7.35 (m, 7H, Ar); 13C NMR (100 MHz,
(300 MHz, CDCl3)
d
/ppm 1.79 (td, J¼9.6, 1.5 Hz, 1H, H14a), 2.18 (d,
J¼9.6 Hz, 1H, H14b), 2.96 (d, J¼8.7 Hz, 1H, H13), 3.25 (d, J¼8.7 Hz,
1H, H1), 3.27 (s, 1H, H12), 3.67 (s, 1H, H8), 3.68 (s, 3H, OCH3), 3.74 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 4.61 (d, J¼14.9 Hz, 1H, NCH2Ph), 4.75
(d, J¼14.9 Hz, 1H, NCH2Ph), 6.89 (d, J¼8.5 Hz, 2H, Ar), 7.10e7.12 (m,
2H, Ar), 7.21e7.22 (m, 2H, Ar), 7.29 (d, J¼8.5 Hz, 2H, Ar); 13C NMR
CDCl3) d/ppm 2.1, 9.2, 43.6, 51.9, 52.1, 53.2, 57.3, 58.6, 59.5, 84.6,
121.7, 123.6, 125.7, 126.7, 126.8, 128.0, 128.5, 138.2, 140.4, 143.4,
147.4, 158.4, 163.2, 163.4; HRMS (ES): Mþ, found 443.1841.
C26H25N3O4 requires 443.1845.
(100 MHz, CDCl3)
d/ppm 38.9, 45.3, 47.6, 48.7, 49.1, 51.2, 52.2, 52.4,
4.3.10. 1a
,8-10-(10-Benzyl-40-carbmethoxy-1,2,3-triazolyl)-11-
55.7, 57.9, 114.2, 121.4, 126.8, 127.2, 129.9, 131.9, 148.4, 148.9, 159.0,
161.9, 163.9, 165.4, 168.1; HRMS (ES): Mþ, found 447.1802.
C25H25N3O5 requires 447.1794.
isopropylidene-bicyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene (37) and 2-
isopropylidylene-indene (72). A solution of triazoline 10 (71 mg,
0.156 mmol) was heated in CDCl3 (0.5 mL) at 80 ꢀC for 2 h. The
solvent was removed in vacuo to give yellow coloured oil. Radial
chromatography (starting with petroleum ether/ethyl acetate 20:1,
then solvent polarity was gradually increased to 5:1) afforded
products 37 and 72.
Compound 33 (yellow oil, 17 mg, 35%); Rf¼0.75; 1H NMR
(300 MHz, CDCl3)
d
/ppm 1.97 (qd, J¼10.3,1.2 Hz,1H, H14a), 2.05 (td,
J¼10.3, 1.2 Hz, 1H, H14b), 3.67 (s, 1H, H13), 3.75 (s, 1H, H8), 3.78 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.05 (s, 1H, H1),
4.38 (d, J¼14.3 Hz, 1H, NCH2Ph), 4.41 (d, J¼14.3 Hz, 1H, NCH2Ph),
Compound 72 (colourless oil, 17 mg, 70%); Rf¼0.95; 1H NMR
6.74 (s, 2H, Ar), 7.01e7.26 (m, 6H, Ar); 13C NMR (100 MHz, CDCl3)
d/
(300 MHz, CDCl3) d/ppm 2.05 (s, 3H, CH3), 3.54 (s, 2H, CH2), 5.02 (s,
ppm 46.2, 46.7, 47.7, 51.6, 52.4, 55.7, 56.0, 57.9, 58.0, 84.2, 114.1,
121.6, 122.9, 124.2, 127.1, 128.4, 130.2, 130.7, 142.9, 143.0, 147.6,
158.8, 158.9, 163.4, 163.9; HRMS (ES): Mþ, found 447.1799.
C25H25N3O5 requires 447.1794. Compound 26 (yellow oil, 5 mg,
12%); Rf¼0.6.
1H, C]CH), 5.26 (s,1H, C]CH), 6.78 (s,1H, H1), 7.16 (t, J¼7.3 Hz, 2H,
AreH), 7.21 (d, J¼7.3 Hz,1H, AreH), 7.40 (d, J¼7.3 Hz,1H, AreH); 13C
NMR (100 MHz, CDCl3) d/ppm 20.8, 38.7, 113.3, 121.4, 123.9, 125.3,
126.8, 128.2, 128.3, 140.0, 143.4, 145.7, 148.7; HRMS (ES): Mþ, found
156.0935. C12H12 requires 156.0939.
Compound 37 (colourless oil, 4 mg, 5%, obtained from crude
4.3.7. (9R)-Methyl-11,12-diaza-9-(imino-10,30-dicarbmethoxy)-
spectrum); Rf¼0.6; 1H NMR (CDCl3)
d/ppm 1.55 (s, 6H, CH3), 3.82 (s,
1
a
,8
a
,13
b
-tetracyclo[6.5.1.02,709,13]tetradeca-2,4,6,11-tetraene-12-
3H, OCH3), 4.70 (s, 1H), 4.77 (s, 1H), 5.38 (d, J¼14.1 Hz, 1H, NCH2Ph),
5.39 (d, J¼14.1 Hz, 1H, NCH2Ph), 6.76 (s, 1H, C]CH), 7.07e7.34 (m,
9H, Ar); HRMS (ES): Mþ, found 397.17833. C25H23N3O2 requires
397.1790.
carboxylate (34). A solution of triazoline 7 (98 mg, 0.241 mmol) in
CDCl3 (0.5 mL) was heated at 100 ꢀC for 2 h in a sealed glass tube.
Solvent was removed in vacuo to afford product 34 as yellow solid
(94 mg, 96%); mp 128e129 ꢀC). Rf¼0.3 (petroleum ether/ethyl ac-
etate 20:1); 1H NMR (400 MHz, CDCl3)
d
/ppm 1.85 (qd, J¼10.2,
4.3.11. (9R)-3,6-Di(20-pyridyl)-9-(imino-10-carbmethoxy-20-benzyl)-
1.8 Hz, 1H, H14a), 2.18 (td, J¼10.2, 1.8 Hz, 1H, H14b), 2.98 (dd, J¼8.9,
1.6 Hz, 1H, NCH2E), 3.29 (s, 1H, H13), 3.32 (d, J¼9.0 Hz, 1H, NCH2E),
3.69 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.75 (s, 1H, H1), 3.77 (s, 3H,
OCH3), 3.80 (s, 1H, H8), 7.09e7.23 (m, 4H, Ar); 13C NMR (100 MHz,
4,5,10,11-tetraaza-1a,8a,9b,13b
-tetracyclo[6.5.1.02,709,13]tetradeca-
2,4,6,11-tetraene (38). A solution of triazoline 20 (92 mg,
0.173 mmol) in CDCl3 (0.5 mL) was heated in NMR tube at 80 ꢀC for
2 h. Radial chromatography (starting with petroleum ether/ethyl
acetate 10:1, then solvent polarity was gradually increased to ethyl
acetate) afforded 38 as yellow coloured solid (85 mg, 93%); mp
CDCl3) d/ppm 38.9, 46.7, 47.5, 49.2, 50.6, 51.5, 52.7, 54.8, 55.7, 58.4,
122.1, 122.5, 127.1, 127.9, 148.3, 148.9, 162.4, 165.2, 167.9, 170.5;
HRMS (ES): Mþ, found 399.1428. C20H21N3O6 requires 399.1430.
175e176 ꢀC); Rf¼0.35; 1H NMR (300 MHz, CDCl3)
d/ppm 2.02 (dt,
J¼10.6, 1.6 Hz, 1H, H14a), 2.16 (dt, J¼10.6, 1.6 Hz, 1H, H14b), 3.73 (s,
1H, H13), 3.93 (s, 3H, OCH3), 4.25 (d, J¼13.9 Hz, 1H, NCH2Ph), 4.37
(d, J¼13.9 Hz, 1H, NCH2Ph), 4.69 (s, 1H, H1), 4.97 (s, 1H, H8),
4.3.8. (9R)-Methyl-10,11-diaza-9-(imino-10-carbmethoxy-20-allyl)-
1a,8a,13b
-tetracyclo[6.5.1.02,709,13]tetradeca-2,4,6,10-tetraene-12-

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D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3317
6.99e7.00 (m, 2H, Ar), 7.01 (s, 1H, H12), 7.20e7.26 (m, 2H, Ar),
7.31e7.35 (m, 1H, Ar), 7.43 (dd, J¼4.8, 2.3 Hz, 1H, Ar), 7.61 (s, 1H, Ar),
7.86 (dt, J¼7.5, 1.7 Hz, 1H, Ar), 7.93 (dt, J¼7.5, 1.7 Hz, 1H, Ar), 8.46 (d,
J¼4.2 Hz,1H, Ar), 8.62 (d, J¼7.5 Hz,1H, Ar), 8.64 (d, J¼7.5 Hz,1H, Ar),
1H NMR (300 MHz, CDCl3)
d
/ppm ꢁ0.25 (d, J¼12.0 Hz, 1H, H24a),
1.02 (d, J¼12.0 Hz, 1H, H24b), 2.10 (d, J¼8.6 Hz, 1H, H10), 2.12 (s, 1H,
H3), 2.19 (d, J¼8.6 Hz, 1H, H2), 2.53 (s, 1H, H9), 2.87 (d, J¼8.6 Hz, 1H,
H4), 3.22 (d, J¼8.2 Hz, 1H, H5), 3.42 (s, 3H, OCH3), 3.66 (s, 3H,
OCH3), 4.29 (d, J¼2.7 Hz, 1H, H1), 4.32 (d, J¼2.7 Hz, 1H, H11), 6.49
(d, J¼4.6 Hz, 2H, Arepy), 7.10e7.12 (m, 4H, Ar), 7.19e7.20 (m, 2H,
Ar), 7.24e7.28 (m, 2H, Ar), 8.41 (br s, 2H, Arepy); 13C NMR
8.88 (d, J¼5.1 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 45.9,
49.2, 52.5, 55.3, 59.1, 63.9, 81.9, 123.0, 123.2, 124.4, 124.5, 127.4,
128.8, 128.9, 137.3, 138.9, 143.2, 145.2, 148.5, 149.4, 149.8, 153.2,
153.7, 155.1, 155.2, 152.9, 154.2, 162.9, 164.1, 164.2; HRMS (ES): Mþ,
found 515.2072. C30H25N7O2 requires 515.2070.
(100 MHz, CDCl3) d/ppm 31.7 (C24), 42.4, 44.3, 45.0, 48.8 (overlap,
C1,C11), 49.4, 50.5, 52.7 (overlap 2ꢂOCH3), 55.5, 77.9, 113.6, 124.0,
125.0, 125.2, 126.5, 127.0, 127.1, 142.2, 142.3, 144.7, 144.8, 150.8
(overlap, 2ꢂCAr), 157.8 (overlap, 2ꢂCAr), 163.4, 164.2, 168.2; HRMS
(ES): Mþ, found 532.2111. C32H28N4O4 requires 532.2111.
4.3.12. (8R)-Methyl-6,7-diaza-8-(imino-10-carbmethoxy-200-(p-me-
thoxybenzyl))-1a,2b,3a,4b,9a,10b,11a
-heptacyclo[7.6.6.13,9
02,1004,8012,17018,23]tetracosa-5,12,14,16,18,20,22-heptaene-5-
carboxylate (39). A solution of p-methoxybenzyl triazoline 14
(100 mg, 0.18 mmol) in CDCl3 (0.5 mL) was heated at 60 ꢀC for 12 h.
The reaction was followed by 1H NMR spectroscopy and stopped
upon completion. Product 39 was isolated by radial chromatogra-
phy (petroleum ether/ethyl acetate 5:1) as colourless solid (90 mg,
4.3.15. (8R)-Methyl-6,7-diaza-8-(imino-10-carbmethoxy-20-(300-pyr-
idyl))-1a,2b,3a,4b,9a,10b,11a
-heptacyclo[7.6.6.13,902,1004,8
012,17018,23]tetracosa-5,12,14,16,18,20,22-heptaene-5-carboxylate
(42). A solution of 3-pyridyl triazoline 17 (50 mg, 0.09 mmol) in
CDCl3 (0.5 mL) in an NMR tube was heated at 60 ꢀC for 24 h. The
reaction was followed by 1H NMR spectroscopy and stopped upon
completion. Product 42 was isolated by radial chromatography
(petroleum ether/ethyl acetate 4:1). Evaporation of the solvent
gave a light-yellow powder (42 mg, 84%); mp 84e86 ꢀC; Rf¼0.4; 1H
90%); mp 138e140 ꢀC; Rf¼0.8; 1H NMR (300 MHz, CDCl3)
d/ppm
ꢁ0.21 (d, J¼11.8 Hz, 1H, H24a), 0.81 (d, J¼11.8 Hz, 1H, H24b), 2.03
(dd, J¼7.8, 2.0 Hz, 1H, H2), 2.08 (dd, J¼7.8, 2.0 Hz, 1H, H10), 2.36 (m,
1H, H9), 2.44 (m, 1H, H3), 3.71 (m, 1H, H4), 3.76 (s, 3H, OCH3), 3.77
(s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.12 (m, 1H, H11), 4.27 (m, 1H, H1),
4.49 (d, J¼14.8 Hz, 1H, NCH2Ph), 4.60 (d, J¼14.8 Hz, 1H, NCH2Ph),
6.52 (br s, 1H, NH), 6.63 (d, J¼8.7 Hz, 2H, Ar), 6.89 (d, J¼8.7 Hz, 2H,
Ar), 7.09e7.11 (m, 4H, Ar), 7.16e7.18 (m, 2H, Ar), 7.25e7.27 (m, 2H,
NMR (300 MHz, CDCl3)
d
/ppm ꢁ0.24 (d, J¼12.0 Hz, 1H, H24a), 1.07
(d, J¼12.0 Hz,1H, H24b), 2.11 (dd, J¼8.7, 2.4 Hz,1H, H10), 2.13 (s, 1H,
H3), 2.19 (dd, J¼8.7, 2.4 Hz, 1H, H2), 2.56 (s, 1H, H9), 2.88 (d,
J¼8.7 Hz, 1H, H4), 3.23 (d, J¼8.3 Hz, 1H, H5), 3.45 (s, 3H, OCH3), 3.65
(s, 3H, OCH3), 4.30 (d, J¼2.7 Hz, 1H, H1), 4.33 (d, J¼2.7 Hz, 1H, H11),
7.01 (d, J¼8.8 Hz, 1H, Ar), 7.09e7.12 (m, 4H, Ar), 7.20e7.22 (m, 3H,
Ar), 7.25e7.28 (m, 2H, Ar), 7.90 (br s, 1H, Ar), 8.30 (br s, 1H, Ar); 13C
Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 30.4, 43.7, 46.3, 48.1, 48.4,
48.7, 51.2, 52.6, 53.1, 55.9, 57.8, 58.2, 83.1, 114.5, 123.9, 124.1, 124.9,
125.2, 126.4, 126.5, 126.9, 127.0, 129.2, 131.0, 137.1, 140.4, 142.6,
142.7, 144.9, 145.0, 159.2, 163.6, 165.2; HRMS (ES): Mþ, found
575.2435. C35H33N3O5 requires 575.2420. Anal. Calcd for
C35H33N3O5: C, 73.03; H, 5.78; N, 7.30. Found: C, 73.09; H, 5.73; N,
7.23%. Slow evaporation of mixed petrol ether/ethyl acetate solu-
tion gave a colourless single crystal suitable for X-ray analysis.
NMR (100 MHz, CDCl3) d/ppm 31.7, 42.4, 44.4, 45.0, 48.7, 48.8, 49.5,
50.5, 52.7, 52.9, 55.8, 77.9, 123.9, 124.0, 124.1, 125.0, 125.1, 125.2,
126.5, 126.6, 126.7, 127.0, 127.1, 134.6, 139.5, 142.2, 142.3, 144.7,
144.8, 145.9, 165.5, 165.8; HRMS (ES): Mþ, found 532.2125.
C32H28N4O4 requires 532.2111.
4.3.13. (8R)-Methyl-6,7-diaza-8-(imino-10-carbmethoxy-20-(p-meth-
4.3.16. (9R)-Methyl-10,11-diaza-3,6-diacetyloxy-9-(imino-10-carb-
ylthiobenzyl))-1a,2b
,3a
,
4b
,9a
,10
b
,11a
-heptacyclo[7.6.6.13,902,1004,8
methoxy-20-phenyl)-1 -tetracyclo[6.5.1.02,709,13]tetradeca-
a a,13b
,8
2,4,6,10-tetraene-12-carboxylate (43), 3,6-diacetyloxy-10-(methyl-
idene-10-carbmethoxy)-1 -tricyclo[6.2.1.02,7]undeca-2,4,6,10-
,8
012,17018,23]tetracosa-5,12,14,16,18,20,22-heptaene-5-carboxylate
(40). A solution of p-methylthiobenzyl triazoline 15 (50 mg,
0.09 mmol) in CDCl3 (0.5 mL) in an NMR tube was heated at 60 ꢀC
for 12 h. The reaction was followed by 1H NMR spectroscopy and
stopped upon completion. Product 40 was isolated by radial chro-
matography (petroleum ether/ethyl acetate 2:1) (40 mg, 80%); mp
a
a
triene-9-one (60) and 4,7-diacetyloxyindene (61). A sample of tri-
azoline 19 (200 mg, 0.387 mmol) was heated at 140 ꢀC for 20 min.
The product was purified by radial chromatography (petroleum
ether/ethyl acetate 10:1). The solvent was removed in vacuo to
afford the product as a yellow coloured oil, which was treated with
cold methanol to give product 43, which was collected by filtration.
Radial chromatography of other fractions (petroleum ether/ethyl
acetate 10:1) afforded two additional products, 60 and 61. Single
crystals suitable for X-ray analysis were obtained by slow diffusion
of petroleum ether in dichloromethane solution of compound 60.
Compound 43 (colourless solid, 115 mg, 58%); mp 128e129 ꢀC;
Rf¼0.65 (petroleum ether/ethyl acetate 10:1); 1H NMR (400 MHz,
106e108 ꢀC; Rf¼0.85; 1H NMR (300 MHz, CDCl3)
/ppm ꢁ0.21 (d,
d
J¼11.8 Hz, 1H, H24a), 0.81 (d, J¼11.8 Hz, 1H, H24b), 2.02 (dd, J¼8.0,
2.7 Hz, 1H, H2), 2.09 (dd, J¼8.0, 2.7 Hz, 1H, H10), 2.37 (m, 1H, H9),
2.44 (m, 1H, H3), 2.45 (s, 3H, SCH3), 3.72 (s, 1H, H4), 3.77 (s, 3H,
OCH3), 3.92 (s, 3H, OCH3), 4.12 (d, J¼2.8 Hz, 1H, NCH2Ph), 4.28 (d,
J¼2.8 Hz, 1H, NCH2Ph), 4.52 (d, J¼15.2 Hz, 1H, H11), 4.62 (d,
J¼15.2 Hz, 1H, H1), 6.55 (br s, 1H, NH), 6.89 (d, J¼8.4 Hz, 2H, Ar),
6.98 (d, J¼8.4 Hz, 2H, Ar), 7.09e7.11 (m, 4H, Ar), 7.15e7.18 (m, 2H,
Ar), 7.25e7.28 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d
/ppm 16.7,
CDCl3)
d
/ppm 1.92 (td, J¼10.3, 1.4 Hz, 1H, H14a), 2.32 (s, 3H, OAc),
30.4, 43.7, 46.3, 48.1, 48.4, 48.7, 51.3, 52.6, 53.1, 57.9, 58.2, 83.1,123.6,
123.8, 123.9, 124.6, 124.9, 126.2, 126.4, 126.6, 126.7, 126.9, 127.2,
128.2, 135.6, 137.3, 142.3, 142.4, 144.5, 144.6, 163.6, 165.0; HRMS
(ES): Mþ, found 591.2197. C35H33N3O4S requires 591.2192.
2.33 (s, 3H, OAc), 2.37 (d, J¼10.3 Hz,1H, H14b), 3.23 (d, J¼8.6 Hz,1H,
H13), 3.31 (s, 1H, H1), 3.47 (overlapped, d, J¼8.6 Hz, 1H, H12), 3.47
(s, 3H, OCH3), 3.47 (overlapped, s, 1H, H8), 3.66 (s, 3H, OCH3); 6.77
(d, J¼8.5 Hz, 2H, Ar), 6.87 (s, 2H, Ar), 7.09 (t, J¼7.6 Hz, 1H, Ar), 7.29
(d, J¼8.5 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 21.3, 38.5,
4.3.14. (8R)-Methyl-6,7-diaza-8-(imino-10-carbmethoxy-20-(400-pyr-
45.6, 45.8, 46.0, 46.2, 46.8, 49.7, 52.2, 52.5, 118.9, 121.1, 121.3, 125.0,
129.1, 141.1, 141.6, 142.0, 142.3, 142.5, 150.5, 154.3, 163.6, 169.2,
169.4; HRMS (ES): Mþ, found 517.1483. C27H25N3O8 requires
517.1486.
idyl))-1a,2b
,3a
,
4b,9a,10b,11a
-heptacyclo[7.6.6.13,902,1004,8
012,17018,23]tetracosa-6,12,14,16,18,20,22-heptaene-5-carboxylate
(41). A solution of 4-pyridyl triazoline 17 (100 mg, 0.18 mmol) in
CDCl3 (0.5 mL) in an NMR tube was heated at 60 ꢀC for 72 h. The
reaction was followed by 1H NMR spectroscopy and stopped upon
completion. Product 41 was isolated by radial chromatography
(petroleum ether/ethyl acetate 5:1). Evaporation of the solvent
gave a light-yellow powder (85 mg, 85%); mp 106e108 ꢀC; Rf¼0.25;
Compound 60 (yellow solid, 46 mg, 23%); mp 153e155 ꢀC;
Rf¼0.75 (petroleum ether/ethyl acetate 10:1); 1H NMR (400 MHz,
CDCl3)
d/ppm 2.23 (td, J¼10.2, 1.7 Hz, 1H, H11a), 2.32 (s, 3H, OAc),
2.35 (s, 3H, OAc), 2.71 (td, 1H, J¼10.2, 1.7 Hz, H11b), 3.74 (s, 1H, H1),
3.77 (s, 3H, OCH3), 5.16 (s, 1H, H8), 6.42 (s, 1H, C]CH), 6.89 (d,

ꢀ
D. Margetic et al. / Tetrahedron 68 (2012) 3306e3318
3318
J¼8.9 Hz, 1H, Ar), 6.93 (d, J¼8.9 Hz, 1H, Ar); 13C NMR (100 MHz,
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data related to this article can be
found in the online version, at doi:10.1016/j.tet.2012.02.073.
CDCl3) d/ppm 21.2, 43.7, 46.8, 48.9, 52.2, 53.4, 53.5, 117.1, 122.6,
123.2, 139.8, 142.6, 143.1, 143.9, 149.7, 166.4, 169.1, 169.6, 199.6;
HRMS (ES): Mþ, found 368.0891. C18H16O7 requires 368.0896. Anal.
Calcd for C18H16O7: C, 62.79; H, 4.68; O, 32.53. Found: C, 65.14; H,
4.44; O, 30.29%.
References and notes
Compound 61 (yellow oil, 9 mg, 5%); Rf¼0.85 (petroleum ether/
1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 6th
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2. (a) Scheiner, P. J. Org. Chem. 1965, 30, 7e10; (b) Reddy, D. S.; Judd, W. R.; Aube, J.
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3. Gilchrist, T.; Alves, M. J. In Organic Azides Syntheses and Applications; Brase, S.,
ethyl acetate 10:1); 1H NMR (400 MHz, CDCl3)
d/ppm 1.75 (s, 3H,
ꢀ
OAc), 2.04 (s, 3H, OAc), 2.93 (s, 1H, H1a), 3.13 (s, 1H, H1b), 7.03e4.48
(m, 4H, Ar, C]CH); 13C NMR (100 MHz, CDCl3)
d/ppm 29.5, 55.2,
60.3, 82.3, 86.8, 118.0, 118.6, 120.1, 122.8, 127.8, 127.9, 149.9, 151.6;
HRMS (ES): Mþ, found 232.0738. C13H12O4 requires 232.0736.
Banert, K., Eds.; Wiley: Chichester, UK, 2010; p 177.
ꢂ
4. (a) Perrocheau, J.; Carrie, R.; Fleury, J.-P. Can. J. Chem. 1994, 72, 2458e2467; (b)
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Broeckx, W.; Overbergh, N.; Samyn, C.; Smets, G.; L’Abbe, G. Tetrahedron 1971,
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4.4.1. Methyl-10,11-diaza-12-(10
deca-20,40,60-triene-90-(imino-100-carbmethoxy-200-benzyl))-
,8 ,9 ,13
-14-oxatetracyclo[6.5.1.02,709,13]tetradeca-2,4,6,10-
a a b b
,80 ,90 ,100 -tricyclo[6.2.1.02,7]un-
1
a
a
b
b
6. Christl, M.; Lesch, S.; Deuerlein, S.; Stalke, D. Helv. Chim. Acta 2005, 88,
1421e1430.
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0.144 mmol) and 7-oxabenzonorbornadiene (200 mg, 1.44 mmol)
was heated in a test tube at 80 ꢀC for 2 h. Radial chromatography
(starting with petroleum ether/ethyl acetate 20:1, then solvent
polarity was gradually increased to ethyl acetate) afforded adduct
52 as brown coloured solid (8 mg, 10%); mp 139e142 ꢀC; Rf¼0.3; 1H
7. Franck-Neumann, M.; Buchecker, G. Tetrahedron Lett. 1969, 10, 2659e2662.
8. Mitsudo, T.; Kokuryo, K.; Shinsugi, T.; Nakagawa, Y.; Watanabe, Y.; Takegami, Y.
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9. Margetic, D.; Troselj, P.; Murata, Y. Synth. Commun. 2011, 41, 1239e1246.
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11. Butler, D. N.; Malpass, J. R.; Margetic, D.; Russell, R. A.; Sun, G.; Warrener, R. N.
/ppm 1.90 (d, J¼9.7 Hz, 1H, H11a0), 2.23 (d,
Synlett 1998, 588e589.
12. Warrener, R. N. Eur. J. Org. Chem. 2000, 3363e3380.
13. Butler, D. N.; Hammond, M. L. A.; Johnston, M. R.; Sun, G.; Malpass, J. R.;
Fawcett, J.; Warrener, R. N. Org. Lett. 2000, 2, 721e724.
NMR (300 MHz, CDCl3)
d
J¼6.1 Hz, 1H, H9), 2.71 (d, J¼6.1 Hz, 1H, H11b0), 2.74 (td, J¼9.1,
1.9 Hz,1H, H100), 3.23 (d, J¼6.1 Hz,1H, H13), 3.27 (s, 3H, OCH3), 3.66
(s, 1H, H10), 4.00 (s, 3H, OCH3), 4.45 (d, J¼14.4 Hz, 1H, NCH2Ph), 4.50
(d, J¼14.4 Hz, 1H, NCH2Ph), 4.59 (s, 1H, H80), 5.14 (s, 1H, H1), 5.22 (d,
J¼6.1 Hz, 1H, H90), 5.75 (s, 1H, H8), 7.08e7.38 (m, 13H, Ar); 13C NMR
14. (a) Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14323e14327; (b)
Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 105, 137e170; (c) Tietze,
L. F. Chem. Rev. 1996, 96, 115e136; (d) Wang, K. K. Chem. Rev. 1996, 96, 207e222;
(e) Wagner, G.; Pedersen, B.; Herrmann, R. Article 42. In Electronic Conference on
Organometallic Chemistry (ECTOC-3), 30 Junee31 July 1997, Rzepa, H.; Goodman,
J.; Winter, M., Eds. http://www.ch.ic.ac.uk/ectoc/ectoc-3/pub/042/.
(100 MHz, CDCl3) d/ppm 46.3, 47.1, 47.9, 49.0, 49.5, 50.1, 50.5, 51.4,
51.7, 57.8, 80.9, 81.2, 98.8, 120.2, 120.7, 121.4, 121.5, 126.2, 127.1,
127.6,127.7,127.9,128.3,128.8, 138.4,142.9,146.0, 147.2,151.3,164.2,
168.6, 171.3; HRMS (ES): Mþ, found 561.2259. C34H31N3O5 requires
561.2264.
ꢀ
15. Margetic, D.; Butler, D. N.; Warrener, R. N.; Holland, C. M. In The Second Brisbane
Biological and Organic Chemistry Symposium (BBOCS-2); The University of
Queensland: Brisbane, Australia, November 30, 2001.
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16. Warrener, R. N.; Margetic, D.; Butler, D. N.; Sun, G. Synlett 2001, 202e205.
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17. Margetic, D.; Butler, D. N.; Warrener, R. N. Aust. J. Chem. 2000, 53, 959e963.
18. Dastan, A.; Uzundumlu, E.; Balci, M.; Fabris, F.; De Lucchi, O. Eur. J. Org. Chem.
4.4.2. 9-(50-(30,40,50-Tricarbmethoxy-10,20-diazolyl))-10-(imino-100-
2004, 183e192.
carbmethoxy-200-benzyl)-1 -tricyclo[6.2.1.02,7]undeca-
a,8a,9b,10b
19. Bianchi, V. G.; De Micheli, C.; Gandolfi, R. Angew. Chem., Int. Ed. Engl. 1979, 18,
781e798.
20. (a) Mloston, G.; Huisgen, R. Tetrahedron 2001, 57, 145e151; (b) Oshima, T.;
Nagai, T. J. Chem. Soc., Chem. Commun. 1994, 2787e2788; (c) Lira, B. F.; de
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Molecules 2002, 7, 791e800.
20,40,60-triene (53). A mixture of triazoline 4 (50 mg, 0.199 mmol)
and DMAD (300 mg, 2.11 mmol, large excess) was heated in a test
tube at 80 ꢀC for 3 h. Radial chromatography (starting with petro-
leum ether/ethyl acetate 10:1, then solvent polarity was gradually
increased to ethyl acetate) afforded adduct 53 as a yellow solid
21. Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43,
478e482.
(21 mg, 19%); mp 64e65 ꢀC; Rf¼0.4; 1H NMR (300 MHz, CDCl3)
d/
€
22. Gais, H.-J.; van Gumpel, M.; Raabe, G.; Muller, J.; Braun, S.; Lindner, H. J.; Rohs,
S.; Runsink, J. Eur. J. Org. Chem. 1999, 1627e1651.
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1976, 741e747.
ppm 1.56 (d, J¼10.4 Hz,1H, H11a),1.70 (dt, J¼10.4, 1.3 Hz,1H, H11b),
3.18 (s, 2H, H9), 3.42 (s,1H, H10), 3.78 (s, 3H, OCH3), 3.84 (1H, s, H9),
3.87 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.28 (d,
J¼17.5 Hz, 1H, NCH2Ph), 4.60 (d, J¼17.5 Hz, 1H, NCH2Ph), 6.97e7.19
24. Stille, J. K.; Feld, W. A.; Freeburger, M. E. J. Am. Chem. Soc. 1972, 94, 8485e8489.
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25. Margetic, D. In Superbases for Organic Synthesis: Guanidines, Amidines, Phos-
phazenes and Related Organocatalysts; Ishikawa, T., Ed.; Wiley: Chichester, UK,
2009; pp 9e48.
(m, 9H, Ar); 13C NMR (100 MHz, CDCl3)
d/ppm 45.6, 46.9, 47.5, 48.6,
ꢀ
ꢀ
ꢀ
52.1, 52.9, 53.7, 54.1, 59.6, 84.3, 106.8, 121.7, 122.2, 126.1, 127.1, 128.2,
137.2, 147.0, 147.2, 150.4, 153.7, 157.2, 160.7, 162.4, 163.1, 165.9, 166.4;
HRMS (ES): Mþ, found 559.1957. C30H29N3O8 requires 559.1955.
26. de Cozar, A.; Millan, M. C.; Cebrian, C.; Prieto, P.; Díaz-Ortiz, A.; de la Hoz, A.;
Cossío, F. P. Org. Biomol. Chem. 2010, 8, 1000e1009.
27. Yamabe, S.; Tsuchida, N.; Yamazaki, Y. J. Chem. Theor. Comput. 2005, 1, 944e952.
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for this paper. These data can be obtained free of charge from The
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