Synthesis of functionalized polynorbornanes employing 2,5- bis(trifluoromethyl)-1,3,4-oxadiazole

Article abstract of DOI:10.1002/jhet.998

Cycloaddition reaction of 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole with strained olefinic bonds of norbornenes was used to synthetize functionalized polynorbornanes. This simple, one step procedure was more effective when reaction was carried out by clas

Full text of DOI:10.1002/jhet.998

January 2013
Synthesis of Functionalized Polynorbornanes Employing
83
2,5-Bis(trifluoromethyl)-1,3,4-oxadiazole
Pavle Troselj, Ivica Đilović, Dubravka Matković-Calogović and Davor Margetić
a
b
b
a
ꢀ
*
ꢀ
a
ꢀ
Laboratory for Physical-Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bosković Institute,
10001 Zagreb, Croatia
bLaboratory of General and Inorganic Chemistry, Department of Chemistry, Faculty of Science, University of Zagreb,
Horvatovac 102a, HR-10000 Zagreb, Croatia
*
E-mail: margetid@irb.hr
Received March 21, 2011
DOI 10.1002/jhet.998
View this article online at wileyonlinelibrary.com.
Cycloaddition reaction of 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole with strained olefinic bonds of nor-
bornenes was used to synthetize functionalized polynorbornanes. This simple, one step procedure was more
effective when reaction was carried out by classical heating, in comparison to microwave-assisted reactions.
Various functional groups were stable in the reaction conditions (ester, imide, phthalimide, piperidyl, and
carboxylic acid), whereas anhydride, N-Boc, or TMS functionalities do not withstand reaction conditions.
J. Heterocyclic Chem., 50, 83 (2013).
INTRODUCTION
The traditional conditions for OD coupling require
strong heating and are not conductive for isolation of
thermally sensitive materials [16]. High pressure facilitated
coupling (at 1.4 GPa and RT) is advantageous in these
cases, but reactions are limited to use of special high pres-
sure equipment [14]. Therefore, the improvement of the OD
coupling protocol in terms of using shorter reaction times
and less vigorous conditions remained an important syn-
thetic goal. In this respect, we investigated OD reactions
under microwave (MW) conditions [17], and found that in
the case of 7-oxanorbornene dienophiles, MW reactions were
adventitious to classical heating in terms of reaction times and
stereochemical outcomes [18]. In this article, we explore the
utility of MW irradiated and thermal OD cycloadditions on
the synthesis of functionalized polynorbornanes.
Polycyclic compounds have been found to be useful
scaffolds in chemical structure manipulation in the devel-
opment of multifunctional drugs [1]. They provide an
excellent platform to tailor molecular diversity by appending
desired substituents at selected positions around the
molecular scaffold. The utilization of organic molecular
scaffolds as a strategy for organization of polyfunctional
groups [2] was achieved, for instance, by saccharides [3],
calix[4]arenes [4], cholic acid [5], saturated polycyclic
hydrocarbon structures [6] such as the bicylic norbornane [7],
tricyclic adamantane, and tetracyclo [6.3.1.11.4.05.12] frame-
work [8]. Conformational constraints imposed by norbornene
scaffolds effectively serve as polypeptide b-sheet indu-
cers [9,10]. The advantage of using norbornene derivatives
as molecular scaffolds is that they have built-in U-shaped
architectures delivering functional groups at desired geo-
metrical positions [11,12]. Therefore, development of nor-
bornene cycloaddition coupling protocols is of the crucial
importance in the synthesis of polynorbornanes [13].
Amongst several available heterocyclic reagents, 2,5-bis
(trifluoromethyl)-1,3,4-oxadiazole 1a (OD) coupling plays
one of the leading roles, where coupling was achieved by
tandem Diels–Alder reaction/dinitrogen elimination/1,
3-dipolar cycloaddition sequence (Scheme 1) [14,15]. Isola-
tion of intermediates was precluded by their high reactivity
and nonstability.
RESULTS AND DISCUSSION
The optimization of OD reaction with norbornenes
under microwave conditions was carried out using substrate
5 as model compound. These results are collected in Table 1.
All reactions carried out with 1a were stereospecific, giving a
single linear (exo,exo-) isomer. The observed stereospecific-
ity of cycloadditions was explained previously in terms of
the norbornene p-facial selectivity [15,18]. The inspection
of results revealed that the yields of reactions are signifi-
cantly lower than for the corresponding thermal reactions.
© 2013 HeteroCorporation

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P. Troselj, I. Đilović, D. Matković-Calogović, and D. Margetić
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Scheme 1. OD coupling reaction.
undetected intermediates
oxabicyclo[2.2.1]heptane
moiety
cycloalkene
DA adduct
1,3-dipole
R1
R1
R1
-N2
O
R1
R2
N
O
O
O
N
N
N
[4+2]
[3+2]
R2
R2
4
R2
2
1a R1=R2=CF3
1b R1=CF3 R2=CO2Me
3
Table 1
Optimization of OD reaction with norbornenes under microwave conditions.
Entry
1
Substrate
Product
T/ꢀC
150
t/min
30
Solvent
Yields/%a
—
10
2
3
4
5
6
7
8
9
10
150
170
120
150
150
150
150
150
150
150
120
30
30
30
30
30
30
30
24h
30
—
—
—
15
15
8
8
5
8
9
12
95b
24
CH2Cl2
CH3CN
THF
dioxane
H2O
THF
THF
11
12
13
150
150
150
30
30
30
THF
THF
THF
21
15
15
14
150
30
98
15c
16c
5
150
48h
THF
96b
c
aEstimated from 1H-NMR analysis; bclassical thermal conditions; 2-carbmethoxy-5-trifluoromethyl-1,3,4-oxadiazole 1b.
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Synthesis of Functionalized Polynorbornanes Employing
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2,5-Bis(trifluoromethyl)-1,3,4-oxadiazole
The best reaction yields were obtained in reactions carried
out without solvent (in neat 1a, Entries 1–4), whereas the
presence of solvent decreases yields (Entries 5–9). The
optimal reaction conditions were heating at 150ꢀC, for
120 min (Entry 2). Similarly, low yields were obtained in
OD reactions with model norbornenes 6–9 (Entries 11–14),
which could be connected to the reaction times considerably
shorter than used in classical thermal reactions (Entries 10
and 16). Observed lower reactivities compared with the
7-oxanorbornene dienophiles could be also explained in
terms of stereoelectronic effects. Here, s-p hyperconjugative
orbital interactions with methylene bridge lower alkene
frontier molecular orbitals, whereas oxygen bridge has
smaller repulsive and steric interactions with incoming
OD reagent [19].
The best reaction yield (98%) was obtained for the reaction
of dimethoxynaphthalene substrate 5 with 2-carbmethoxy-5-
trifluoromethyl-1,3,4-oxadiazole (Entry 15). In this case, MW
reaction at 150ꢀC gave quantitative conversion to cycloadduct
12 within 30 min. Comparable yield could be achieved by
classical heating at 150ꢀC for 48 h (Entry 16). This result
indicates identical cycloaddition reactivity of methyl ester
substituted OD as compared with the bistrifluoromethyl
substituted OD. From this experimental observation, it is
obvious that the presence of solid 1,3,4-oxadiazole reagent
(compared with low-boiling point liquid OD), and the
absence of solvent are highly advantageous. This solid
state reaction is of particular interest for development of
environmentally benign synthetic protocols [20].
78% yield) by N-alkylation with N-(2-bromoethyl)phthalimide
employing procedure analogous to literature (DMF, K2CO3)
[21]. The COC-[3]polynorbornane bis-imide 17 was obtained
according to literature starting from 16 [22]. Other substrates
used in this study are known from literature (21 and 22) [23]
and were prepared accordingly, whereas norbornenes 23 and
24 were synthetized for the first time. Thus, substrate 23 was
prepared in 46% yield from 4-aminoethylnorbornene 22 and
benzyl chloroformate, whereas 24 was prepared by microwave
or classical heating of the mixture of endo-norborn-5-ene-2,
3-dicarboxylic anhydride and (1-aminoethyl)piperidine
in 93% and 88% yield, respectively. Similarly, the heating of
the mixture of endo-norborn-5-ene-2,3-dicarboxylic anhydride
and b-alanine afforded substrate 25 [24]. Functionalities
could be incorporated into the macrocylic ring either
by their positioning onto norbornene substrate prior
OD reaction, or by the post-cycloaddition functionaliza-
tion. Hence, thermal cycloaddition reaction of phthalimide
19 with oxadiazole 1a yielded bis-N-(2-ethyl)phthalimido
COC-[3]polynorbornane 20 in 40% yield. In this product,
two phthalimido functionalities are positioned on the same
side of rigid polycyclic scaffold and their position locked.
Adduct 20 could be also obtained by bis-N-alkylation of
17, and its structure was deduced from NMR spectra. The
1
most indicative signals in H-NMR spectrum are those of
the methylene bridge protons Ha and Hb. The close presence
of the oxygen bridge atom causes their splitting to two
doublets that are positioned at d 1.23 and d 2.26 (steric
compression effect). 1H-1H COSY and NOESY correlations
and C2v symmetry of 13C-NMR spectrum further support
structure assignment, in particular indicative are strong
NOESY correlations of endo-protons Hc and Hd. Coupling
of phthalimide 19 with 2-carbmethoxy-5-trifluoromethyl-
Optimized MW reaction conditions were employed in
subsequent synthesis of functionalized polynorbornanes
(Scheme 2). For this purpose, ethylphthalimido protected
substrate 19 was prepared in one step from the imide 16 (in
Scheme 2. Reagents and conditions: (i) K2CO3, DMF, 65ꢀC, 2d; (ii) THF 150ꢀC, 2d; (iii) TFA, CH2Cl2.
O
Br
N
O
CF
3
O
O
18
O
O
CF
O
3
O
O
N
N
O
(i)
78%
N
N
O
19
O
N
H
27 R=NHCO Bn
28 R=piperidyl
2
O
R
R
16
29 R=COOH
CF
O
23-25
OD 1a
3
CF
(ii)
3
(ii)
60%
OD 1a
(ii)
N
N
1a
40%
δ 2.26
δ 1.23
a
18 or 19
OD 1a
H
b
H
O
CF
O
CF
3
3
O
O
5
(ii)
O
O
H
O
O
O
N
N
O
(i)
CF
3
CF
3
H
d
c
O
O
N
N
O
26
O
N
H
N
H
40%
O
R
N
CF
CF
3
3
17
N
N
21 R=NHBoc
22 R=NH
O
O
O
(iii)
TFA
N
N
2
23 R=NHCO Bn
24 R=piperidyl
25 R=COOH
2
20
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P. Troselj, I. Đilović, D. Matković-Calogović, and D. Margetić
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(a)
(b)
Figure 1. X-ray structures of (a) 20 and (b) 26.
1,3,4-oxadiazole 1b (at 150ꢀC, MW, 2 h, no solvent) was
less effective, just partial conversion to product was obtained
(75% conversion, as deduced from the crude NMR spectra).
The assigned U-shaped structure of 20 was fully sup-
ported by the single crystal structural analysis, and its shape
was presented in Figure 1(a). Of particular interest in this
structure are the functionalities positioned at the endo-side
of polynorbornene, whereas two trifluoromethyl substituents
of polycyclic framework are pointed into exo-direction.
Molecular modeling (AM1 method) of these alicyclophanes
indicated that the N—N separation of the succinimide
nitrogens in 17 is 6.30 Å, and that this distance expands
to 6.63 Å upon conversion to the alicyclophane 20.
This calculated N—N distance agrees well with the
value obtained from the X-ray structure of 20 (6.68 Å).
Another structural point of interest is U-shaped curvature
of COC-[3]polynorbornane, which is small, but evident.
The choice of substituents on the maleimide is limited
because of their possible reactions with OD. It was found
that much less effective were OD coupling reactions of
N-Cbz, N-piperidyl, and carboxylic acid substrates 23–25,
where inseparable mixtures of adducts 27, 28, and 29 were
obtained by heating at 150ꢀC in THF. Equally inefficient
were OD reactions with N-Boc substrate 21 and free amine
22 (Scheme 1). In these reactions, single product was
isolated in high yield, whose 1H-NMR spectra showed that
norbornene C═C bond remained unchanged. Detailed
spectral analysis showed that the 1,3,5-triazole derivative
26 was obtained in both cases as a sole product (in 86%
and 90% yields, respectively). Even the high pressure
reaction of 22 and OD conducted at lower temperature
(THF, 100ꢀC, 24 h, 4 kbar) produced 26 in 95% yield.
Addition of bases such as triethylamine or crude K2CO3
into reaction vessel did not supress Boc deprotection. The
structure of product 26 was unequivocally confirmed by
the single crystal X-ray analysis (Figure 1(b)). Formation of
triazoles by reaction of amines with oxadiazoles is a known
process [25], and in the case of substrate 21 presumably takes
place by the in situ deprotection of amine.
Alternative synthetic route to the end-functionalized
U-shaped cavities presents OD cycloaddition with pentacyclic
alkenes 32 and 33, derived from 7-oxabenzonorbornenes
30 and 31, by addition of cyclopentadiene (Scheme 3).
Reactions proceed smoothly in high yield by heating at
140ꢀC, for 2 days giving single isomers 34 and 35 (89%
and 66%, respectively). Molecular modeling by AM1
method shows that the polycyclic skeleton of COCOC-[5]poly-
norbornane 34 and 35 positions substituents in more divergent
manner than obtained by COC-[3]polynorbornane skeleton 20.
Anhydride 36 [26] represents an experimental testing
ground for establishing the site-selectivity and reactivity
of olefinic bond in Diels–Alder reactions. Although in
Scheme 3. (i) CHCl3, 80ꢀC, 12 h, (ii) THF, 140ꢀC, 2d, ampoule.
O
O
R
R
R
R
AM1
(i)
32 R=H
33 R=Br
30 R=H
31 R=Br
140oC
OD 1a
(ii)
34
OCF3
CF3
O
R
R
O
34 R=H
35 R=Br
R
R
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Synthesis of Functionalized Polynorbornanes Employing
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2,5-Bis(trifluoromethyl)-1,3,4-oxadiazole
Scheme 4. (i) THF 140ꢀC, 1d, (ii) THF 140ꢀC, 2d, (iii) KOH/MeOH, RT, 18 h, (iv) Ac2O, furan, 60ꢀC, 3 h, (v) Ac2O, NaOAc, methoxyethylamine,
60ꢀC, 24 h.
O
O
O
O CF3
O CF3
CF3
37
O
O
1a
HOOC
HOOC
COOH
COOH
(ii)
O
O
Ac2O
(iv)
CF3
40
(iii)
O
O
O
O
O
O
36
v
1a
O
(i)
O CF3
1a
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
O
(i)
CF3
39
CO2Me
O
N
OMe
38
41
2,5-trifluoromethyl-1,3,4-oxadiazole [28], 2-carbmethoxy-5-trifluor-
omethyl-1,3,4-oxadiazole [29] and 25 [24]. All new com-
the Diels–Alder reactions with normal electron demand 7-
oxanorbornene (or 7-aza) [27] p-bond is preferred reaction
site, in the Diels–Alder reactions with reverse electron
demand, such as OD addition, norbornene p-bond is the
preferred reaction site. Simple frontier molecular orbital the-
ory (FMO ) analysis of 36 indicated that the HOMO is mostly
located on the 7-oxanorbornene p-bond, and LUMO is on the
norbornene p-bond. It was anticipated that selectivity will lead
to the preferential formation of OCOCO[5]polynorbornene 37
(Scheme 4). However, it was found that anhydride 36 was not
stable in the OD cycloaddition conditions. Instead, product 37
was prepared by three synthetic step procedure, starting with
norbornadiene diester 38. Its reaction with oxadiazole produced
COC[3]polynorbornene 39 in 33% yield. KOH hydrolysis and
the in situ formation of bis-anhydride of the tetraacid 40 was fol-
lowed by trapping with furan to afford 37 (67%). Functionaliza-
tion of anhydride 36 with methoxyethylamine gave imide 41,
which was subjected to OD reaction. It was found that synthesis
of cycloadduct structurally related to 37 from 41 was not suc-
cessful, because of the decomposition of substrate.
1
pounds gave H-NMR and 13C-NMR spectra and high-resolution
mass spectra corresponding to their assigned structures.
4-(20-Ethylphthalimido)-1a,2a,6a,7a-4-azatricyclo[5.2.1.02,6
]
deca-8-ene-3,5-dione (19). Mixture of imide 16 (1.0 g, 6.13 mmol), N-
(2-bromoethyl)phthalimide 18 (1.56 g, 6.13 mmol), and potassium
carbonate (4.24 g, 30.6 mmol) in DMF (20 mL) was heated at
65ꢀC for 48h. Solvent was removed in vacuo, residue dissolved
in dichloromethane and washed with water. Organic layers were
separated, dried (MgSO4), and solvent removed in vacuo to afford
colorless solid. (1.60 g, 78%, mp 177–178ꢀC). 1H-NMR (CDCl3),
d/ppm: 1.42 (1H, dd, J = 8.9 Hz, J = 2.1 Hz), 1.61 (1H, dd,
J = 8.9Hz, J = 2.1 Hz), 3.16 (2H, br s), 3.22 (2H, s), 3.61 (2H,
t, J = 4.8Hz), 3.69 (2H, t, J = 4.8 Hz), 5.95 (2H, s), 7.62–7.69
(2H, m), 7.72–7.80 (2H, m); 13C-NMR (CDCl3), d/ppm:,
HRMS (m/z): Calcd for C19H16O4N2: 336.1110 found: 336.1117.
4-(20-Benzyloxycarbonylaminoethyl)-(1a,2a,6a,7a)-4-
azatricyclo[5.2.1.02,6]deca-8-ene-3,5-dione (23). Mixture of 4-
aminoethyl-4-aza-1a,2a,6a,7a-tricyclo[5.2.1.02,6]deca-8-ene-3,
5-dione 22 [23] (1.00 g, 5 mmol), aqueous Na2CO3 (0.4 M,
25 mL) in dichloromethane (25 mL) was treated with benzyl
chloroformate (1.5 mL, 7.5 mmol) at 0ꢀC. Reaction mixture
was stirred for 16 h at RT, then diluted with dichloromethane,
washed with water, and solvent was removed in vacuo. Residue
was subjected to column chromatography (petroleum ether/ethyl
acetate 2:1, then solvent polarity was gradually increased to EtOAc)
CONCLUSION
1
to afford colorless solid (780 mg, 46%, mp 144–146ꢀC). H-NMR
Inverse electron demand Diels–Alder reactions of 2,5-bis
(trifluoromethyl)-1,3,4-oxadiazole with norbornenes were
proven to be of synthetic value for the preparation of functio-
nalized polynorbornanes. For this particular cycloaddition re-
action and substrates, classical heating for prolonged time
was more successful than microwave-assisted heating.
(CDCl3), d/ppm: 1.46 (1H, dd, J=6.9Hz, J= 2.2 Hz), 1.67 (1H, dd,
J=6.9Hz, J= 2.2 Hz), 3.15 (2H, s), 3.26 (2H, t, J= 6.9 Hz), 3.31
(2H, s), 3.47 (2H, t, J= 6.9 Hz), 5.03 (2H, s), 6.02 (2H, s),
7.24–7.33 (2H, m); 13C-NMR (CDCl3), d/ppm: 37.7, 39.6, 44.8,
45.9, 52.2, 60.4, 66.7, 128.1, 128.2, 134.4, 136.5, 156.3, 177.6;
HRMS (m/z): Calcd for C19H20O4N2: 340.1423 found: 340.1427.
4-(20-Piperidinoaminoethyl)-(1a,2a,6a,7a)-4-azatricyclo
[5.2.1.02,6]deca-8-ene-3,5-dione (24). Mixture of endo-norborn-5-
ene-2,3-dicarboxylic anhydride (200 mg, 1.22 mmol) and
(1-aminoethyl)piperidine (156 mg, 1.22 mmol) was heated at
150ꢀC for 30 min in an open round bottomed flask. After cooling,
residue was passed through a short silica column (eluted with
ethyl acetate) to afford yellow colored oil. (88%, mp 128–131ꢀC).
Method B. Reaction mixture was heated in MW reactor for 1 h
EXPERIMENTAL
The NMR spectra were recorded in CDCl3 solutions containing
tetramethylsilane as internal standard on Bruker AMX 300 or
600 MHz instruments. Melting points were determined using a Gal-
lenkamp digital melting point apparatus and are uncorrected. The
high-resolution mass spectra were recorded on a Micromass Platform
II single quadrupole AutoSpec instrument (ESMS, electrospray mass
spectrometry in CH2Cl2). Radial chromatography was carried out
with a chromatotron, Model No. 79245T, using 1 mm thickness
plates with silica gel 60F254 as the stationary phase. Chemicals
were purchased from Aldrich (St. Louis, MO) and used without
purification. Known procedures were used to prepare
1
at 150ꢀC (93%). H-NMR (CDCl3), d/ppm: 1.31–1.32 (2H, m),
1.42–1.46 (6H, m), 1.63 (1H, dd, J = 8.8Hz, J = 1.4 Hz) 2.23 (2H,
t, J = 7.1 Hz), 3.15 (2H, s), 3.28 (2H, s), 3.36 (2H, t, J = 7.1 Hz),
5.99 (2H, t, J = 1.8 Hz); 13C-NMR (CDCl3), d/ppm: 24.2, 25.9,
35.5, 44.8, 45.7, 51.9, 54.3, 55.6, 134.3, 177.5; HRMS (m/z):
Calcd for C16H22O2N2: 274.1681 found: 274.1689.
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General procedure for OD cycloadditions. Method A -
1,11-Bis(trifluoromethyl)-6,16-diethyl-1a,2b,3a,4a,8a,9a,
10b,11a,12b,13a,14a,18a,19a,20b-6,16-diaza-22-oxaoctacyclo
[9.9.11,11.13,9.113,19.02,10.04,8.012,20.014,18]tricosa-5,7,15,17-tetraone
dicarboxylate (29). Method B (MeCN, 20%), 1H-NMR (CDCl3), d/
ppm (obtained from crude mixture): 1.39 (2H, d, J=10.5Hz), 2.23
(4H, s), 2.29 (2H, d, J= 10.5 Hz), 3.05 (4H, s), 3.09 (4H, s), 4.24
(4H, s), 7.35 (2H, br s).
microwave. Mixture of oxadiazole 1a (60 mg, 0.25 mmol) and
substrate (50–100 mg, 0.05mmol) in appropriate solvent was
subjected to microwave-assisted reaction at 140–170ꢀC. Reactions
were conducted in CEM DiscoverWLabmateTH/ExplorerPLSW
single mode microwave reactor using closed reaction vessel
technique (power= 125 W). Excess of solvent was removed in
vacuo, and products were analyzed by either by TLC or 1H-NMR
spectroscopy. Radial chromatography (with petroleum ether–ethyl
acetate) was used to isolate pure products.
1,16-Bis(trifluoromethyl)-5,12,20,27-tetramethoxy-(1a,2b,3a,
4b,5a,12a,13b,14a,15b,16a,17b,18a,19b,20a,27a,28b,29a,
30b)-33-oxadodecacyclo[14.14.1.13,141.15,12.118,29.120,27.02,15.04,13
.06,11.017,30.019,28.021,26]pentatriaconta-4,6,8,10,12,19,21,23,25,27-
decaene (10). Method A (15%), method B (95%), (mp 187–191ꢀC).
1H-NMR (CDCl3), d/ppm: 1.63 (2H, dd, J = 9.8 Hz), 2.33 (4H, s),
2.58 (2H, dd, J = 9.8Hz), 3.95 (12H, s), 4.09 (4H, s), 7.41 (4H,
dd, J = 6.0 Hz, J = 2.8 Hz), 8.01 (4H, dd, J = 6.0 Hz, J = 2.8 Hz);
General procedure for OD cycloadditions. Method B -
thermal. Mixture of oxadiazole 1a (100 mg, 0.42 mmol) and
substrate (100–150 mg, 0.05–0.1 mmol) in THF (2–3 mL) was
heated in a sealed glass tube. Upon cooling, solvent and escess
reagent were removed in vacuo, and products were purified by
radial chromatography (with petroleum ether–ethyl acetate).
1,11-Bis(20-ethylphthalimido)-6,16-bis(ethyl)-1a,2b,3a,4a,
8a,9a,10b,11a,12b, 13a,14a,18a,19a,20b-6,16-diaza-22-
oxaoctacyclo[9.9.11,11.13,9.113,19.02,10.04,8.012,20.014,18]tricosane-
5,7,15,17-tetraone (20). Method B with 16 (40%), (mp 263–264ꢀC).
1H-NMR (CDCl3), d/ppm: 1.23 (2H, dd, J=7.5Hz, J= 4.9 Hz), 2.26
(2H, dd, J=7.5Hz, J= 4.9 Hz), 2.79 (4H, s), 2.92 (4H, s), 3.55
(4H, t, J= 7.1 Hz), 4.01 (4H, t, J= 7.1 Hz); 7.57–7.97 (8H, m);
13C-NMR (CDCl3), d/ppm: 28.1, 38.2, 38.7, 40.7, 48.2, 49.3, 88.5
2
13C-NMR (CDCl3), d/ppm: 41.4, 42.0, 54.8, 61.2, 87.1 (q, JC,
1
F = 31.5 Hz), 121.5, 124.9, 123.5 (q, JC,F = 276.8 Hz), 127.7,
133.5, 143.9; HRMS (m/z): Calcd for C38H32O5F6: 682.2154
found: 682.2157.
1-Methyl-16-trifluoromethyl-5,12,20,27-tetramethoxy-(1a,2b,
3a,4b,5a,12a,13b,14a,15b,16a,17b,18a,19b,20a,27a,28b,29a,
30b)-33-oxadodecacyclo[14.14.1.13,14.1.15,12.118,29.120,27.02,15.04,13
.06,11.017,30.019,28.021,26]pentatriaconta-4,6,8,10,12,19,21,23,25,27-
decaene-1-carboxylate (15). Method A (98%), method B (96%),
(mp 211–213ꢀC). 1H-NMR (CDCl3), d/ppm: 1.56 (2H, dd,
J=5Hz, J= 2 Hz), 2.31 (2H, dd, J=5Hz, J= 2 Hz), 2.42 (2H, dd,
J=5 Hz, J= 2 Hz), 2.71 (2H, dd, J=5Hz, J= 2 Hz), 3.66 (4H, s),
3.95 (6H, s), 4.1 (6H, s), 4.2 (3H, s), 4.2 (4H, s), 7.41 (2H, dd,
J=5.0Hz, J = 2.0 Hz), 8.00 (2H, dd, J = 5 Hz, J = 2 Hz); 13C-
NMR (CDCl3), d/ppm: 41.3, 42.1, 44.1, 52.0, 54.6, 54.8,
2
1
(q, JC,F = 31.3 Hz), 123.4, 124.2 (q, JC,F = 278.1 Hz), 131.8, 134.2,
168.6, 176.9, HRMS (m/z): Calcd for C42H32O9N4F6: 850.2073
found: 850.2077.
Bisalkylation method. Mixture of imide 17 (62 mg, 0.123 mmol),
N-(2-bromoethyl)phthalimide 18 (80 mg, 0.316 mmol), and potassium
carbonate (20 mg, 0.145 mmol) in DMF (1.5 mL) was heated at 65ꢀC
for 48 h. Solvent was removed in vacuo, residue dissolved in
dichloromethane and washed with water. Organic layers were
separated, dried (MgSO4), and solvent removed in vacuo to afford
colorless solid (98.3 mg, 94%).
2
60.7, 61.0, 81.1, 87.2 (q, JC,F = 31.1 Hz), 121.3, 121.4,
1
124.6, 124.8, 123.7 (q, JC,F = 277.0 Hz), 127.8, 127.9, 133.4,
133.7, 143.8, 144.0, 161.6; HRMS (m/z): Calcd for C39H35O5F3:
640.2436 found: 640.2349.
4-(20-(2,5-Bis(trifluoromethyl)-1,3,4-oxadiazolo)aminoethyl)-
(1a,2b,3b,6b,7b,8a)-15-Oxapentacyclo[6.6.1.13,6.02,7.09,14
]
1a,2a,6a,7a-4-azatricyclo[5.2.1.02,6]deca-8-ene-3,5-dione
(26). Method B with 22 (86%), method B with 23 (90%), (mp 177–
178ꢀC). 1H-NMR (CDCl3), d/ppm: 1.58 (1H, dd, J=8.6Hz,
J= 2.3 Hz), 1.93 (1H, dd, J=8.6Hz, J= 2.3 Hz), 3.30 (2H, s), 3.38
(2H, s), 3.78 (2H, t, J= 6.4 Hz), 4.33 (2H, t, J= 6.4 Hz), 6.08 (2H,
s); 13C-NMR (CDCl3), 36.9, 44.5, 44.8, 45.9, 52.2, 67.9, 117.8 (q,
tetradeca-4,9,11,13-tetraene (32). Solution of 7-oxabenzonor-
bornadiene 30 (1.00 g, 6.94 mmol) in chloroform (5mL) and
freshly cracked cyclopentadiene (2.00 g, 30.3 mmol) was heated at
70ꢀC for 18 h in sealed glass tube. Solvent was removed in vacuo,
and oily residue was separated by flash column chromatography
(silicagel, petroleum ether, then solvent polarity was increased to
2
1JC,F = 293.1 Hz), 134.6, 146.9 (q, JC,F = 41.4 Hz), 175.9; d/ppm:,
1
5% ethyl acetate) to afford colorless oil (1.30 g, 89.0%). H-NMR
HRMS (m/z): Calcd for C15H12O2N4F6: 394.0864 found: 394.0861.
1,11-Bis(trifluoromethyl)-6,16-bis(20-benzyloxycarbony-
laminoethyl)-1a,2b,3a,4a,8a,9a,10b,11a,12b,13a,14a,18a,
19a,20b-6,16-diaza-22-oxaoctacyclo[9.9.11,11.13,9.113,19.02,10
.04,8.012,20.014,18]tricosane-5,7,15,17-tetraone dicarboxylate
(27). Method A (50%), method B (30%), 1H-NMR (CDCl3),
d/ppm (obtained from crude mixture): 1.25 (2H, d, J = 8.6 Hz),
2.20 (4H, s), 2.30 (2H, dd, J = 8.6 Hz, J = 1.7 Hz), 2.74 (4H, s),
2.84 (4H, s), 3.25–3.27 (4H, m), 3.46 (4H, t, J = 6.0 Hz), 5.05
(4H, s), 7.25–7.39 (10H, m); HRMS (m/z): Calcd for
C42H40O9N4F6: 858.2699 found: 858.2701.
(CDCl3), d/ppm: 1.38 (1H, d, J = 8.1 Hz), 1.56 (1H, td, J= 8.1Hz,
J = 1.7 Hz), 2.38 (2H, t, J = 1.7 Hz), 2.92 (2H, t, J= 1.4Hz), 4.97
(2H, s), 6.14 (2H, t, J= 1.7Hz), 7.09 (4H, dd, J = 5.4 Hz,
J = 3.2 Hz), 7.18 (4H, dd, J = 5.4 Hz, J =3.2Hz); 13C-NMR
(CDCl3), d/ppm: 44.4, 49.4, 53.7, 80.2, 118.9, 126.5, 134.4,
148.4; HRMS (m/z): Calcd for C15H14O1: 210.1045 found:
210.1046.
11,12-Dibromo-(1a,2b,3b,6b,7b,8a)-15-oxapentacyclo[6.6.1
.13,6.02,7.09,14]tetradeca-4,9,11,13-tetraene (33). Solution of 4,5-
dibromo-7-oxabenzonorbornadiene 31 (1.00 g, 3.33 mmol) in
chloroform (5mL) and freshly cracked cyclopentadiene (2.00 g,
30.3mmol) was heated at 80ꢀC for 18h in sealed glass tube.
Solvent was removed in vacuo, and oily residue was separated
by flash column chromatography (silicagel, petroleum ether,
then solvent polarity was increased to 5% ethyl acetate) to
afford colorless solid (0.94 g, 77%, mp 213–214ꢀC). 1H-NMR
(CDCl3), d/ppm: 1.36 (1H, d, J = 8.2 Hz), 1.55 (1H, td, J = 8.2 Hz,
J = 1.6Hz), 2.36 (2H, dd, J = 2.6 Hz, J = 1.3 Hz), 2.92 (2H, t,
J = 1.6Hz), 4.92 (2H, s), 6.09 (2H, t, J = 1.5 Hz), 7.41 (4H, s);
13C-NMR (CDCl3), d/ppm: 43.9, 48.6, 53.3, 79.4, 121.8, 123.9,
1,11-Bis(trifluoromethyl)-6,16-bis(20-piperidinoaminoethyl)-
1a,2b,3a,4a,8a,9a,10b,11a,12b,13a,14a,18a,19a,20b-6,16-
diaza-22-oxaoctacyclo[9.9.11,11.13,9.113,19.02,10.04,8.012,20.014,18
]
tricosane-5,7,15,17-tetraone dicarboxylate (28). Method
B
(20%), 1H-NMR (CDCl3), d/ppm (obtained from crude mixture):
1.33 (2H, d, J = 10.5 Hz), 1.72 (4H, s), 2.21 (2H, d, J = 10.5 Hz),
2.87 (8H, t, J = 7.1 Hz), 2.89 (4H, s), 3.19 (4H, s), 3.59 (4H,
t, J = 6.6Hz), 3.66 (4H, t, J = 6.6Hz), 3.70 (4H, t, J = 7.1 Hz), 3.72
(8H, t, J = 7.1Hz).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Synthesis of Functionalized Polynorbornanes Employing
89
2,5-Bis(trifluoromethyl)-1,3,4-oxadiazole
1H-NMR (CDCl3), d/ppm: 2.20 (2H, d, J = 11.7 Hz), 2.37 (4H,
s), 2.70 (2H, d, J = 11.7 Hz), 3.24 (4H, s), 5.18 (4H, s), 6.62 (4H,
s); 13C-NMR (CDCl3), d/ppm: 34.6, 44.3, 52.1, 66.9, 83.5, 88.8
(q, JCF3 = 128.4 Hz), 125.7 (q, JCF3 = 237.8 Hz), 138.9, 170.1;
HRMS (m/z): Calcd for C30H20O9F6: 638.1012 found: 638.1018.
133.9, 149.0; HRMS (m/z): Calcd for C15H12O1Br2: 365.9255
found: 365.9261.
1,16-Bis-trifluoromethyl-(1a,2b,3a,4a,5b,12b,13a,14a,
15b,16a,17a,18b,19a,20b,27b,28a,29b,30a)-31,33,35-
trioxadodecacyclo[14.14.1.13,14.15,12.118,29.120,27.02,15.04,13
.06,11.017,30.019,28.021,26]pentatriaconta-6,8,10,21,23,25-hexaene
(34). Method A (70%), method B (89%), (mp 243–245ꢀC).
1H-NMR (CDCl3), d/ppm: 1.22 (2H, d, J = 11.7 Hz), 2.02 (2H,
s), 2.22 (2H, d, J = 11.7 Hz), 2.74 (4H, s), 5.13 (4H, s), 7.11–7.13
(4H, m), 7.23–7.28 (4H, m); 13C-NMR (CDCl3), d/ppm: 39.0,
2
1
X-ray structures. All XRD data was collected on an Oxford
Diffraction Xcalibur CCD diffractometer, using Mo Ka
(l = 0.71073 Å) radiation, structure solution by SHELXS97
(Sheldrick, 1997).
CCDC 813953 and 813954 contains the supplementary crys-
tallographic data for the structures 20 and 26. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/re-
trieving.html, or from the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223
336033; or e-mail: deposit@ccdc.cam.ac.uk.
2
39.1, 48.3, 50.9, 77.6, 87.2 (q, JC,F = 31.3 Hz), 118.7, 123.0 (q,
1JC,F = 276.8Hz), 126.3, 147.1; HRMS (m/z): Calcd for
C34H28O3F6: 598.1943 found: 598.1951.
1,16-Bis-trifluoromethyl-8,9,23,24-tetrabromo(1a,2b,3a,4a,
5b,12b,13a,14a,15b,16a,17a,18b,19a,20b,27b,28a,29b,30a)-
31,33,35-trioxadodecacyclo[14.14.1.13,14.15,12.118,29.120,27.02,15
.04,13.06,11.017,30.019,28.021,26]pentatriaconta-6,8,10,21,23,25-
hexaene (35). Method A (40%), method B (66%), (mp
20 Crystal data: CCDC 813953, C42H32O9N4F6, Mr = 179.4,
monoclinic, C2/c, a = 18.5522(5)Å, b = 10.5073(3) Å, c = 22.6702
(6) Å, b = 93.314(2)o, V = 103.909(2) Å3, Z = 16, T = 298 K,
density = 1.248 mg/m3, crystal size = 0.78 ꢁ 0.18 ꢁ 0.03 mm3.
1
187–188ꢀC). H-NMR (CDCl3), d/ppm: 1.19 (2H, d, J= 10.4 Hz),
2.00 (4H, dd, J=3.1Hz, J= 1.8 Hz), 2.25 (2H, d, J=10.4Hz), 2.62
(4H, s), 2.73 (4H, s), 5.15 (4H, s), 7.43 (4H, s); 13C-NMR (CDCl3),
d/ppm: 39.0, 40.0, 48.5, 50.8, 78.5, 87.8 (q, 2JC,F = 30.9 Hz), 122.3,
26 Crystal data: CCDC 813954, colorless plates, C15H12O2N4F6,
Mr = 394.29, monoclinic, P21/n, a = 13.5873(11) Å, b = 13.1008
(15) Å, c = 19.650(2) Å, b = 104.007(9)o, V = 3393.8(6)Å3, Z = 8,
T = 293(2) K, density = 1.543 mg/m3, crystal size= 0.78ꢁ 0.18
ꢁ 0.03 mm3.
1
124.4, 125.8 (q, JC,F = 280.3 Hz), 148.1; HRMS (m/z): Calcd for
C34H24O3F6Br4: 909.8363 found: 909.8358.
4,5,11,12-Tetramethyl-1,8-bis(trifluoromethyl)-(2b,3a,6a,7b,
9b,10a,13a,14b)-16-oxahexacacyclo[6.6.1.11,8.13,6.110,13.02,7.09,14
]
heptadeca-4,11-diene-4,5,11,12-tetracarboxylate (39). Solution of
diester 38 (2.20 g, 10.57 mmol) and OD (1.13 g, 5.49 mmol) in
dichloromethane (2 mL) was heated at 140ꢀC for 18 h. Solvent and
excess reagent were removed under reduced pressure to afford a
brown colored oil. Treatment of oil with cold methanol gave
colorless solid, which was collected by filtration. Recrystallization
from methanol gave colorless crystals (1.05 g, 33%, mp 201–203ꢀC).
Acknowledgments. This research was funded by the Croatian
ministry of science, education and sport (grants 098-0982933-3218
and 098-0982933-2920).
1H-NMR (CDCl3), d/ppm: 1.50 (2H, d, J = 9.8 Hz), 2.27
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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