Cycloaddition Reactions of Benzonorbornadiene and Homonorbornadiene: New Isoxazoline and Pyridazine Derivatives

Article abstract of DOI:10.1002/jhet.3229

Ten new isoxazoline derivatives were synthesized from the reactions of benzonorbornadiene and homonorbornadiene derivatives with nitrile oxides formed from benzaldehyde and 4-substituted benzaldehyde. Two new pyridazine derivatives were also synthesized from the reaction of the homonorbornadiene derivatives with 3,6-di (2-pyridyl)-s-tetrazine. It was seen that all cycloaddition reactions were realized as exo selectivity. Finally, γ-Gauche effect in the isoxazoline derivatives was discussed.

Full text of DOI:10.1002/jhet.3229

August 2018 Cycloaddition Reactions of Benzonorbornadiene and Homonorbornadiene:
New Isoxazoline and Pyridazine Derivatives
1917
a
b
a
and Abdullah Menzekb*
Yadigar Adiloğlu, Ertan Şahin,
Ahmet Tutar, *
a
Faculty of Science, Department of Chemistry, Sakarya University, Sakarya 54187, Turkey
Faculty of Science, Department of Chemistry, Atatürk University, Erzurum 25240, Turkey
b
*
E-mail: atutar@sakarya.edu.tr; amenzek@atauni.edu.tr
Received February 18, 2018
DOI 10.1002/jhet.3229
Published online 2 July 2018 in Wiley Online Library (wileyonlinelibrary.com).
Ten new isoxazoline derivatives were synthesized from the reactions of benzonorbornadiene and
homonorbornadiene derivatives with nitrile oxides formed from benzaldehyde and 4-substituted benzalde-
hyde. Two new pyridazine derivatives were also synthesized from the reaction of the homonorbornadiene
derivatives with 3,6-di (2-pyridyl)-s-tetrazine. It was seen that all cycloaddition reactions were realized as
exo selectivity. Finally, γ-Gauche effect in the isoxazoline derivatives was discussed.
J. Heterocyclic Chem., 55, 1917 (2018).
INTRODUCTION
[22–25]. Afterward, the corresponding nitrile oxides were
synthesized as intermediate by one-pot reaction method
with the aldoximes 6a–d and NaOCl. Therefore, the
reaction of benzonorbornadiene (4) with each aldoxime
was carried out in the presence of NaOCl at low
temperatures [between À6 ± 4°C and room temperature
(RT)] in approximately 15 h (Scheme 1). It was seen that
adducts 7a–d obtained one isomer only in each reaction
(Scheme 1).
CHO and CHC vicinal hydrogens in the isoxazoline rings
of adducts 7a–d resonate at 4.91–5.04 and 3.73–3.79 ppm as
the doublet (J = 8.1 Hz), respectively. COSY spectra of the
adducts 7a–b were also taken, and “W” interactions of Hc
and He with the bridge Ha was observed (Fig. 3).
Cycloadditions to the double bond of the compounds such
as norbornadiene derivatives were occurred form exo faces
because of electron density [5–18,26,27]. The electron
density of isolated double bond belongs to
benzonorbornadiene (4), and data (NMR and HRMS) of
adducts 7a–d are consistent with the proposed structures.
X-ray crystallographic analysis (Fig. 2) of adduct 7a
confirmed the proposed structures of adducts 7a–d.
Isoxazolines, containing nitrogen and oxygen and
likewise pyridazine, containing two nitrogen atoms are
important classes of heterocycles because they are
targeted compounds or intermediates. For example,
afoxolaner (1) used as insecticide agent, (À)-
subereamolline A (2) exhibiting breast cancer inhibitor,
and azemerone (3) are natural products (Fig. 1) [1–4].
Benzonorbornadiene (4) and homonorbornadiene (5) are
norbornadiene derivatives and can be rearranged with
reagents such as bromine because of their strained
structure [5–12]. Norbornadiene derivatives including
nitrogen–oxygen atoms and their rearrangement products
may be important. Cycloaddition reactions of some
strained compounds such as norbornadiene and
norbornadiene derivatives with nitrile oxides and tetrazines
were reported [12–21]. To the best of our knowledge,
cycloaddition reactions of homonorbornadienes (5) with
nitrile oxides and tetrazine have not been investigated.
Besides, cycloaddition reactions of benzonorbornadiene (4)
with nitrile oxides have not been also investigated. These
adducts, isoxazoline and pyridazine derivatives, will be
important because adducts are new and strained. In these
products, γ-Gauche effect may be interesting. Therefore,
the corresponding adducts were synthesized in this work.
To synthesize homonorbornadiene derivatives including
cyclopropane ring, reaction of norbornadiene (8) with ethyl
diazoacetate was performed in the presence of Pd (OAc)2
in CH Cl solution. Two homonorbornadiene derivatives
2
2
with a double bond were found in the reaction mixture.
We tried to isolate them, but could not isolate in the
1
RESULT AND DISCUSSION
current conditions. According to H-NMR spectrum of
reaction mixture, the ratio of main product to the other is
3.8:1.0 (as mol). Two homonorbornadiene derivatives
may be conceived as one of the four stereoisomeric
The benzonorbornadiene (4) and aldoximes 6a–d were
synthesized by the known method given in the literature
©
2018 Wiley Periodicals, Inc.

1918
Y. Adiloğlu, E. Şahin, A. Tutar, and A. Menzek
Vol 55
Figure 1. Some important natural products and norbornadiene derivatives.
Scheme 1. Adducts 7a–d obtained one isomer only.
Figure 2. Molecular structure of the compounds 7a. Thermal ellipsoids are drawn at the 40% probability level. [Color figure can be viewed at
wileyonlinelibrary.com]
structures such as exo-anti (9), exo-syn (10), endo-anti
11), and endo-syn. The endo-syn structure should not be
a reaction product because it will be highly unstable than
Cycloaddition reactions of two homonorbornadiene
derivatives (as mixture) with each aldoxime were carried
out in the presence of NaOCl at low temperatures
(between À6 ± 4°C and RT) for approximately 15 h
(Scheme 3). Two isomeric cyclopropane adducts were
isolated by column chromatography from each reaction
mixture and crystallized from ether/n-hexane solution
(
the others. It was reported that PdCl , Cu, and CuCN-
2
catalyzed reactions of norbornadiene (8) with
N CHCO Et give two (9 and 10), three (9, 10, and 11),
2
2
and two (9 and 11) products, respectively (Scheme 2)
28–30]. It may be accepted that the main product is the
[
(Scheme 3).
3
homonorbornadiene derivative 9 because it is occurred in
Coupling constants ( J) of hydrogens H that is geminal
c
the three reactions.
with ester group in cyclopropane rings of the major and the
Scheme 2. The carbene adducts (9, 10, and 11).
Journal of Heterocyclic Chemistry
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August 2018
Cycloadditions to Norbornadiene Derivatives
1919
minor products are 2.4 and 7.2–7.7 Hz, respectively (Fig. 3
and Table 1). Coupling constants ( J) of hydrogens in
between the six hydrogen rings (between cyclopropane
hydrogens and H and H hydrogens).
3
d
e
cyclopropane rings are important to determine the
The chemical shifts of hydrogen atoms are at the lower
fields while the chemical shifts of carbon atoms bounded
to these hydrogen atoms are at the higher fields because
of γ-Gauche effects [34–36]. As seen in Table 1 and
3
3
structure of compounds because J is higher than J
cis
trans
3
in it [31–33]. Higher and smaller coupling constants ( J)
3
3
should be Jcis and Jtrans, respectively. The minor
product should be 13 because H is in cis position with
Figure 3, the chemical shifts of H in 12 is at the higher
c
c
other hydrogene in the cyclopropane rings. The other
product should also be 12. In addition to these, it was
observed that there was γ-Gauche effects in the adducts
fields than that of H in 13 and the chemical shifts of
c
bridge H in 12 is at the lower fields than that of bridge
a
H in 13. We can say that γ-Gauche effects in 13 are
a
12 and 13 because of their steric repulsion. As seen in
higher than that of γ-Gauche effects in 12. We also say
Table 1 and Figure 3, these repulsions are that (a) between
H in the cyclopropane rings and bridge hydrogens H ; (b)
that small changes in the chemical shifts of H and H in
the products 12 and 13 can be caused by this effect.
d
e
c
a
Figure 3. Effects (W interactions or γ-Gauche) in the structures of adducts 7, 12, and 13. [Color figure can be viewed at wileyonlinelibrary.com]
Table 1
Some NMR data of adducts 12a–c and 13a–c.
3
Compounds
H
d
(ppm)
H
e
(ppm)
H
c
(ppm), J
B (ppm)
CO (ppm)
12a
13a
12b
13b
12c
13c
4.85
4.85
4.83
4.80
4.94
3.78
3.73
3.76
3.72
3.79
3.74
1.95 (t, J = 2.4 Hz)
1.74 (t, J = 7.7 Hz)
1.95 (bt, J = 2.4 Hz)
1.73–1.66 (m)
2.00–1.95 (m)
1.74 (bt, J = 7.2 Hz)
1.06–0.88
Not obvious (m)
1.07–0.88
175.8
174.5
172.9
171.5
172.6
171.7
1.23–0.74
1.02–0.94
1.05–0.81
4.95–4.91 (m)
3
H
d
and H
e
are chemical shifts of OCH and CCH in the isoxaline rings, respectively. H
c
is chemical shift and coupling constant ( J) CH that is geminal
) and carbonyl carbons (CO).
with ester group in cyclopropane rings. B are chemical shifts of bridge hydrogens (H
a
and H
c
Figure 4. γ-Gauche effects in some compounds 14–17 including cyclopropane ring. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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1920
Y. Adiloğlu, E. Şahin, A. Tutar, and A. Menzek
Vol 55
We reported γ-Gauche effects in some products 14–17
by steric repulsion [37]. Similar events were also
observed in the compounds 12 and 13 (Table 1).
including cyclopropane rings (Fig. 4) [15,37,38]. γ-
Gauche effect in the cyclopropane rings of 14 and 15 is
higher in the cis-compound 15 than that of trans-
compound 14 [37]. It may be said that the γ-Gauche effect
in 17 is higher than that of 16. Because the chemical
To ensure the structure of adducts 12 and 13, X-ray
analyses of 12b and 13b were taken. X-ray spectra
(Fig. 5) of them are very important because they also
explain the structures of carbene adducts 9 and 10 as
well. The adducts 12b and 13b should be obtained from
cycloaddition reactions of the corresponding nitrile oxide
with carbene adducts 9 and 10, respectively (Scheme 3).
Therefore, the carbene adducts are 9 and 10 (Scheme 2).
shifts of H in 16 (2.74 ppm) are smaller than that of 17
c
(
3.37 ppm) [15,38]. We explained that resonance at higher
field (173.2 ppm) of CO groups in the cis-compound 15
than that (174.3 ppm) of the trans-compound 14 is caused
Figure 5. Molecular structure of the compounds (a) 12b and (b) 13b. Thermal ellipsoids are drawn at the 40% probability level. [Color figure can be
viewed at wileyonlinelibrary.com]
Scheme 3. Isomeric adducts 12 and 13 isolated and crystallized from ether/n-hexane.
Journal of Heterocyclic Chemistry
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August 2018
Cycloadditions to Norbornadiene Derivatives
1921
Scheme 4. Isomeric adducts 19 and 20 as aromatic products.
Crystal structures of the molecules with the atom label
are shown in Figure 2 and 5. Compounds 7a, 12b, and
3b crystallize in the centrosymmetric space groups
EXPERIMENTAL
Column chromatography: silica gel 60
1
General.
Pbca, P-1, and P2 /c, respectively. C═N (oxazole)
distances are in the range of typical double bond range
1
(Merck). Thin-layer chromatography: silica gel precoated
(0.2 mm layer) aluminum sheets (Merck). mp:
[
1.282(3)-1.285(3) Å]. Structure 7a contains four
Gallenkamp melting point apparatus; uncorrected.
À1
asymmetric carbon atoms and all have R-configuration.
For the structures 12b and 13b, there are seven
stereogenic centers and these are as follows; C8(R),
C9(R), C10(R), C12(S), C13(S), C15(R), C14(S) [C14(R)
for 13b].
To synthesis pyridazine derivatives including
homonorbornadien derivatives 9 and 10, a solution of 9 and
1
for overnight. After the purification of the resulting adducts
in silica gel column, only 19 and 20 aromatic products were
obtained (Scheme 4). It was accepted that 19 and 20 were
formed by loss of N2 and oxidation of intermediate,
respectively. NMR data of all the products 12, 13, 19, and
Perkin–Elmer FT-IR spectrometer; KBr pellets; in cm
.
NMR Spectra: Varian Inova (300 MHz) and Bruker
(400 MHz) spectrometers; CDCl sols.; δ in ppm rel. to
3
tetramethylsilane as internal standard, J in Hz. HRMS
data were obtained by LC–MS-TOF electrospray
ionization technique (1200/6210, Agilent).
Benzonorbornadiene [22] and benzaldoximes [23–25]
(benzaldehyde oxime, 4-methoxybenzaldehyde oxime, 4-
nitrobenzaldehyde oxime, and 4-bromobenzaldehyde
oxime) were synthesized by known method.
0 in CHCl was refluxed with 3,6-di (2-pyridyl)-s-tetrazine
3
General procedure for 1,3-dipolar cycloaddition reaction
of benzonorbornadiene with benzaldoximes.
To a
solution of benzaldoximes (1.3 mmol) in methylene
chloride (4 mL) added a solution of benzonorbornadiene
2
0 are consistent with the proposed structures. Also, γ-
Gauche effect was observed in the adducts 19 and 20.
(1.0 mmol) in methylene chloride (4 mL) at RT. The
stirred solution was cooled to À6 ± 4°C, and aqueous
sodium hypochlorite (5.25%, 3.5 g, 2.5 mmol) solution
was added dropwise to the reaction medium with the help
of a syringe over 30 min. Then, the mixture was then
stirred overnight (approximately 15 h) without cooling
CONCLUSION
After the benzaldoximes were obtained from benzaldehyde,
-methoxybenzaldehyde, 4-nitrobenzaldehyde, and 4-
4
bath.
dichloromethane (3 × 10 mL) and diethyl ether
1 × 10 mL). The combined organic phase was dried with
The
reaction
mixture
extracted
with
bromobenzaldehyde, their nitrile oxides were obtained via
one-pot reactions of the corresponding aldoximes with
NaOCl. The cycloaddition reactions of benzonorbornadiene
and the mixtures of 9 and 10 with nitrile oxides were
performed, respectively. From these reactions, isoxazoline
derivatives 7, 12, and 13 were obtained. In addition to
these isoxazoline derivatives, only pyridazine derivatives
(
Na SO4 and filtered. The solvent was removed under
2
vacuum. By crystallization, the adducts 7 was purified
from mixture of ethylacetate and hexane.
(3aS*,4S*,9S*,9aS*)-3-Phenyl-3a,4,9,9a-tetrahydro-4,9-
methanonaphtho[2,3-d] isoxazole (7a). Colorless crystals,
1
9 and 20 were obtained from the reaction of the
mixtures of 9 and 10 with 3,6-di (2-pyridyl)-s-tetrazine
Scheme 4). It was observed that γ-Gauche effects are
54% yield; mp 173–175°C; R = 0.50, CH Cl /hexane
(3:2); FTIR (cm ): 3079, 3050 (aromatic, C─H), 1589
f
2
2
À1
1
(
(ÀC═N); H-NMR (400 MHz, CDCl ): δ = 7.79 (d,
3
present in adducts 12a–c, 13a–c, 19, and 20. The
structures of the products and γ-Gauche effects were
discussed. It was seen that all synthesized adducts 7, 12,
J = 6.7 Hz, A part of AB system, aromatic, 2H), 7.48–
7.42 (m, aromatic, 3H), 7.30–7.25 (m, aromatic, 2H),
7.18–7.12 (m, aromatic, 2H), 4.96 (bd, J = 8.1 Hz, OCH,
1H), 3.81 (bd, J = 8.1 Hz, 1H), 3.74 (bs, bridgeahead,
1H), 3.59 (bs, bridgeahead, 1H), 2.05 (bd, J = 9.9 Hz, A
part of AB system, bridge, 1H), 1.94 (bd, J = 9.9 Hz, B
13, 19, and 20 were occurred by exo selectivity. In this
work, 10 isoxazoline and two pyridazine derivatives were
obtained as new products.
Journal of Heterocyclic Chemistry
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1922
Y. Adiloğlu, E. Şahin, A. Tutar, and A. Menzek
Vol 55
1
3
part of AB system, bridge, 1H); C-NMR (100 MHz,
(C), 132.3 (CH), 128.5 (CH), 128.2 (C), 127.2 (CH),
127.0 (CH), 124.5 (C), 123.2 (CH), 121.8 (CH), 89.7
(OCH), 58.6, 51.7, 47.0, 43.7; HRMS (APCI–Tof)
calcd for [C H BrNO + H] : m/z = 340.0337; found:
18 14
340.0323.
CDCl ): δ = 155.9 (C), 147.5 (C), 143.6 (C), 130.0 (CH),
3
1
(
29.1 (C), 128.8 (CH), 126.9 (CH), 126.8 (CH), 126.6
CH), 122.9 (CH), 121.5 (CH), 89.1 (OCH), 58.7, 51.49,
6.9, 43.5; HRMS (APCI–Tof) calcd for
C H NO + H] : m/z = 262.1232; found: 262.1223.
3aS*,4S*,9S*,9aS*)-3-(4-Methoxyphenyl)-3a,4,9,9a-
tetrahydro-4,9-methanonaphtho[2,3-d] isoxazole (7b).
7
9
+
4
[
+
1
(
8
15
Reaction of norbornadiene with ethyl diazoacetate. To a
mixture of norbornadiene (1.8 g, 2 mL, 19.5 mmol), Pd
(
OAc)2 (110 mg, 0.5 mmol, 2.5 mol%) and dry
dichloromethane (10 mL) was added ethyl diazoacetate
15% in toluene, 2 mL) under N atmosphere at RT. The
Colorless crystals, 59% yield; mp 132–134°C; R = 0.53,
f
À1
CH Cl /hexane (4:1); FTIR (cm ): 3070, 3040
2
2
(
1
2
(
aromatic, C─H), 1607 (ÀC═N); H-NMR (400 MHz,
mixture was then stirred overnight (approximately 15 h)
at RT. The solvent was removed under vacuum, then the
CDCl ): δ = 7.73 (d, J = 8.7 Hz, A part of AB system,
3
aromatic, 2H), 7.29–7.24 (m, aromatic, 2H), 7.16–7.12
residue extracted with Et O (2 × 25 mL). The combined
2
(
m, aromatic, 2H), 6.98 (d, J = 8.7 Hz, B part of AB
system, aromatic, 2H), 4.91 (bd, J = 8.1 Hz, OCH, 1H),
.86 (s. OMe), 3.79 (bd, J = 8.1 Hz, 1H), 3.72 (bs,
bridgeahead, 1H), 3.57 (bs, bridgeahead, 1H), 2.05 (bd,
J = 9.9 Hz, A part of AB system, bridge, 1H), 1.93 (bd,
J = 9.9 Hz, B part of AB system, bridge, 1H); C-NMR
100 MHz, CDCl ): δ = 161.0 (C), 155.4 (C), 147.6 (C),
43.7 (C), 128.3 (CH), 126.8 (CH), 126.6 (CH), 122.9
CH), 121.6 (C), 121.5 (CH), 114.3 (CH), 88.8 (OCH),
9.0, 55.4, 51.5, 46.9, 43.5; HRMS (APCI–Tof) calcd for
organic phase was dried with Na SO and filtered. The
2
4
solvent was removed under vacuum. The organic was
washed with excess water (20 mL) and brine (15 mL).
3
After it was dried over Na SO4 and the solvent was
2
removed under vacuum, a mixture of products 9 and 10
1
3
1
(
14%, 0.47 g) was obtained. According to H-NMR
(
3
spectrum of products, ratio is 9 to 10 is 3.8 (as mol).
Therefore, amounts of 9 and 10 should be 364 mg, (77%)
and 96 mg, (21%), respectively.
1
(
5
[
+
1,3-Dipolar cycloaddition reactions of mixtures of the
C H NO + H] : m/z = 292.1338; found: 292.1325.
3aS*,4S*,9S*,9aS*)-3-(4-Nitrophenyl)-3a,4,9,9a-
tetrahydro-4,9-methanonaphtho[2,3-d] isoxazole (7c).
Yellow crystals, 66% yield; mp 233–235°C; R = 0.50,
19 17 2
products
9
and 10 (182 mg), with benzaldoximes
(
(
1.0 mmol). The general procedure where the mixture of
products 9 (140 mg, 0.79 mmol) and 10 (38 mg,
0.21 mmol) is found instead of benzonorbornadiene was
used for synthesis of these adducts 12 and 13. The
resulting adducts were purified on silica gel column
chromatography (66 g) with ether/hexane (1/10) elution.
Ethyl (3aS*,4R*,4aS*,5R*,5aS*,6S*,6aS*)-3-phenyl-3a,4a,
f
À1
CH Cl /hexane (3:2); FTIR (cm ): 3109, 3084
2
2
1
(
aromatic, C─H), 1598 (ÀC═N); H-NMR (300 MHz,
CDCl ): δ = 8.31 (d, J = 8.6 Hz, A part of AB system,
3
aromatic, 2H), 7.95 (d, J = 8.6 Hz, B part of AB system,
aromatic, 2H), 7.31–7.27 (m, aromatic, 2H), 7.20–7.14
m, aromatic, 2H), 5.04 (d, J = 8.1 Hz, OCH, 1H), 3.82
d, J = 8.1 Hz, 1H), 3.78 (bs, bridgeahead, 1H), 3.57 (bs,
bridgeahead, 1H), 2.01–1.96 (m, bridge, 2H); C-NMR
75 MHz, CDCl ): δ = 154.6 (C), 148.4 (C), 147.0 (C),
43.2 (C), 135.3 (C), 127.4 (CH), 127.1 (CH), 126.9
CH), 124.1 (CH), 123.2 (CH), 121.6(CH), 90.3 (OCH),
8.0, 51.4, 46.8, 43.4; HRMS (APCI–Tof) calcd for
C H N O + H] : m/z = 307.1083; found: 307.1064.
3aS*,4S*,9S*,9aS*)-3-(4-Bromophenyl)-3a,4,9,9a-
5
,5a,6,6a-hexahydro-4H-4,6-methanocyclopropa[4,5]
(
benzo[1,2-d]isoxazole-5-carboxylate (12a).
Colorless
(
crystals (59 mg, 25%); mp 119–121°C; R = 0.30,
f
1
3
À1
ether/n-hexane (1:10); FTIR (cm ): 3066, 3052
(
1
3
(aromatic, C─H), 1720 (C═O), 1590 (ÀC═N); H-NMR
1
(
(
300 MHz, CDCl ): δ = 7.72–7.63 (m, aromatic, 2H),
3
7
1
.42–7 (m, aromatic, 3H), 4.85 (d, J = 8.3 Hz, OCH,
5
[
H), 4.08 (bq, J = 7.2 Hz, OCH , 2H), 3.78 (d,
2
+
18 14 2 3
(
J = 8.3 Hz, 1H), 2.81 (bs, bridgeahead, 1H), 2.68 (bs,
bridgeahead, 1H), 1.95 (t, J = 2.4 Hz, cyclopropane, 1H),
tetrahydro-4,9-methanonaphtho[2,3-d] isoxazole (7d).
Colorless crystals, 36% yield; mp 155–157°C;
1
.61–1.57 (m, cyclopropane, 1H), 1.40–1.34 (m,
cyclopropane, 1H), 1.24 (bt, J = 7.2 Hz, CH , 3H), 1.06
À1
3
R = 0.57, CH Cl /hexane (3:2); FTIR (cm ): 3024
f
2
2
(d, J = 12.1 MHz. A part of AB system, bridge, 1H),
1
(
aromatic, C─H), 1585 (ÀC═N); H-NMR (300 MHz,
0
.88 (d, J = 12.1 Hz, B part of AB system, bridge, 1H);
CDCl ): δ = 7.63 (d, J = 8.4 Hz, A part of AB system,
3
13
C-NMR (75 MHz, CDCl ): δ = 175.8 (CO), 156.1 (C),
3
aromatic, 2H), 7.57 (d, J = 8.4 Hz, B part of AB
system, aromatic, 2H), 7.30–7.23 (m, aromatic, 2H),
.18–7.11 (m, aromatic, 2H), 4.96 (d, J = 8.1 Hz, OCH,
H),3.78 (d, J = 8.1 Hz, 1H), 3.73 (bs, bridgeahead,
H), 3.54 (bs, bridgeahead, 1H), 1.99 (d, J = 9.6 Hz, A
1
30.2 (CH), 129.2 (C), 129.0 (CH), 126.9 (CH), 88.1
(
1
OCH), 61.0, 58.4, 43.2, 39.6, 26.2, 22.7, 22.0, 21.0,
4.5; HRMS (APCI–Tof) calcd for [C H NO + H] :
18 19 3
7
1
1
+
m/z = 298.1443; found: 298.1425.
Ethyl (3aS*,4R*,4aS*,5S*,5aS*,6S*,6aS*)-3-phenyl-3a,4a,5,
part of AB system, bridge, 1H), 1.93 (d, J = 9.6 Hz,
5a,6,6a-hexahydro-4H-4,6-methanocyclopropa[4,5]benzo[1,2-d]
1
3
B
part of AB system, bridge, 1H);
C-NMR
isoxazole-5-carboxylate (13a).
Colorless crystals (11 mg,
(
75 MHz, CDCl ): δ = 155.4 (C), 147.5 (C), 143.7
17%); mp 109–111°C; R = 0.22, ether/n-hexane (1:10);
3
f
Journal of Heterocyclic Chemistry
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August 2018
Cycloadditions to Norbornadiene Derivatives
1923
À1
FTIR (cm ): 3060, 3030 (aromatic, C─H), 2971–2848
(
Ethyl (3aS*,4R*,4aS*,5R*,5aS*,6S*,6aS*)-3-(4-nitrophenyl)-
a,4a,5,5a,6,6a-hexahydro-4H-4,6-methanocyclopropa[4,5]
benzo[1,2-d]isoxazole-5-carboxylate (12c). Colorless crystals
1
3
Aliph., C─H), 1724 (C═O), 1590 (ÀC═N); H-NMR
(
300 MHz, CDCl ): δ = 7.74–7.68 (m, aromatic, 2H),
3
(
(
(
77 mg, 30%); mp 187–189°C; R = 0.31, ether/n-hexane
7
1
1
1
.42–7.38 (m, aromatic, 3H), 4.85 (bd, J = 8.3 Hz, OCH,
H), 4.16–4.06 (m, OCH , 2H), 3.74 (dd, J = 8.3, 1,5 Hz,
H), 2.94 (bs, bridgeahead, 1H), 2.85 (bs, bridgeahead,
H), 1.71 (t, J = 7.7 Hz, cyclopropane, 1H), 1.41–1.34 (m,
cyclopropane, 1H), 1.40–1.34 (m, cyclopropane, 1H), 1.32
bt, J = 7.1 Hz, CH , 3H), 1.27–1.08 (m, 2H), 0.70.71 (m,
H); C-NMR (75 MHz, CDCl ): δ = 174.45 (CO), 156.1
C), 130.2 (C), 129.2 (CH), 129.0 (CH), 127.0 (CH), 88.6
f
À1
1:10); FTIR (cm ): 3079–3028 (aromatic, C─H), 1722
2
1
C═O), 1600 (ÀC═N); H-NMR (300 MHz, CDCl3):
δ = 8.28–8.21 (m, aromatic, 2H), 7.90–7.82- (m, aromatic,
2
H), 4.94 (bd, J = 8.3 Hz, OCH, 1H), 4.15–4.05 (m,
OCH , 2H), 3.79 (bd, J = 8.3 Hz, 1H), 2.86 (bs,
(
1
2
3
13
bridgeahead, 1H), 2.68 (bs, bridgeahead, 1H), 2.00–1.95
m, cyclopropane, 1H), 1.65–1.58 (m, cyclopropane, 1H),
3
(
1
(
(
.42–1.37 (m, cyclopropane, 1H), 1.28–1.20 (m, CH3,
OCH), 61.3, 59.1, 43.4, 40.0, 25.6, 23.3, 22.6, 18.4, 14.3;
HRMS (APCI–Tof) calcd for [C H NO + H] :
m/z = 298.1443; found: 298.1426.
+
3H), 1.02 (bd, J = 12.0 Hz, A part of AB system, bridge,
H), 0.94 (bd, J = 12.0 Hz, B part of AB system, bridge,
19
21
4
1
1
3
Ethyl (3aS*,4R*,4aS*,5R*,5aS*,6S*,6aS*)-3-(4-methoxyphenyl)-
a,4a,5,5a,6,6a-hexahydro-4H-4,6-methanocyclopropa[4,5]benzo[1,2-
d]isoxazole-5-carboxylate (12b).
1H); C-NMR (75 MHz, CDCl
(C), 148.5 (C), 135.4 (C), 127.6 (CH), 124.3 (CH), 89.3
OCH), 61.1, 57.7, 43.1, 39.6, 25.9, 22.8, 21.8, 20.5,
3
): δ = 172.6 (CO), 154.8
3
Colorless crystals (73 mg,
5%); mp 173–175°C; R = 0.36, ether/n-hexane (1:10); FTIR
(
+
2
(
f
14.45; HRMS (APCI–Tof) calcd for [C18
H18NO + H] :
5
À1
cm ): 3079–3021 (aromatic, C-H), 1717 (C═O), 1607
m/z = 343.1294; found: 343.1278.
1
(
ÀC═N); H-NMR (300 MHz, CDCl ): δ = 7.63 (bd,
Ethyl (3aS*,4R*,4aS*,5S*,5aS*,6S*,6aS*)-3-(4-nitrophenyl)-
3a,4a,5,5a,6,6a-hexahydro-4H-4,6-methanocyclopropa[4,5]
benzo[1,2-d]isoxazole-5-carboxylate (13c). Colorless crystals
3
J = 9.0 Hz, A part of AB system, aromatic, 1H), 6.91 (bd,
J = 9.0 Hz, B part of AB system, aromatic, 1H), 4.83 (bd,
(
(
(
16 mg, 23%); mp 180–182°C; R = 0.28, ether/n-hexane
J = 8.3 Hz, OCH, 1H), 4.11 (bq, J = 6,9 Hz, OCH , 2H),
.83.(s, OMe, 3H) 3.76 (bd, J = 8.3 Hz, 1H), 2.81 (bs,
bridgeahead, 1H), 2.68 (bs, bridgeahead, 1H), 1.95 (bt,
f
2
À1
1:10); FTIR (cm ): 3122, 3073 (aromatic, C─H), 1713
C═O); H-NMR (300 MHz, CDCl ): δ = 8.28–8.22 (m,
3
1
3
aromatic, 2H), 7.90–7.84- (m, aromatic, 2H), 4.95–4.91
m, OCH, 1H), 4.16–4.08 (m, OCH , 2H), 3.74 (bd,
J = 2.4 Hz, cyclopropane, 1H), 1.62–1.55 (m, cyclopropane,
(
1H), 1.41–1.33 (m, cyclopropane, 1H), 1.25 (bt, J = 6.9 Hz,
2
J = 8.4 Hz, 1H), 2.99 (bs, bridgeahead, 1H), 2.83 (bs,
bridgeahead, 1H), 1.74 (bt, J = 7.2 Hz, cyclopropane, 1H),
1.42–1.36 (m, cyclopropane, 1H), 1.24–1.15 (m,
CH , 3H), 1.07 (bd, J = 12.0 Hz, A part of AB system,
3
bridge, 1H), 0.88 (bd, J = 12.0 Hz, B part of AB system,
13
bridge, 1H); C-NMR (75 MHz, CDCl ): δ = 172.9 (CO),
3
161.1 (C), 155.6 (C), 128.5 (CH), 121.7 (C), 114.4 (CH), 87.8
cyclopropane, 1H), 1.24 (bt, J = 7.1 Hz, CH , 3H), 1.05
3
(
1
OCH), 61.0, 58.7, 55.6, 43.17, 39.6, 26.2, 22.7, 22.1, 20.6,
(bd, J = 13.2 Hz, A part of AB system, bridge, 1H), 0.81
(bd, J = 12.0 Hz, B part of AB system, bridge, 1H); C-
+
13
4.5; HRMS (APCI–Tof) calcd for [C H NO + H] : m/
19
21
4
z = 328.1549; found: 328.1534.
NMR (75 MHz, CDCl ): δ = 171.2 (CO), 154.9 (C),
3
Ethyl (3aS*,4R*,4aS*,5S*,5aS*,6S*,6aS*)-3-(4-methoxyphenyl)-
a,4a,5,5a,6,6a-hexahydro-4H-4,6-methanocyclopropa[4,5]
benzo[1,2-d]isoxazole-5-carboxylate (13b).
1
48.5 (C), 135.4 (C), 127.6 (CH), 124.3 (CH), 89.8
3
(OCH), 61.4, 58.4, 43.3, 40.0, 25.6, 23.3, 22.5, 18.3, 14.3;
Colorless crystals
+
HRMS (APCI–Tof) calcd for [C H NO + H] : m/
z = 343.1294; found: 343.1291.
18
18
5
(
15 mg, 21%); mp 114–116°C; R = 0.17, ether/n-hexane
f
À1
(1:10); FTIR (cm ): 3082–3030 (aromatic, C─H), 1728
1
Cycloaddition reactions of mixtures of the products 9 and
0 (182 mg), with tetrazine.
(
C═O), 1606 (ÀC═N); H-NMR (300 MHz, CDCl3):
δ = 7.55 (bd, J = 9.0 Hz, A part of AB system,
aromatic, 1H), 6.90 (bd, J = 9.0 Hz, B part of AB
system, aromatic, 1H), 4.80 (bd, J = 7.8 Hz, OCH, 1H),
1
(
A mixture of products 9
140 mg, 0.79 mmol) and 10 (38 mg, 0.21 mmol) and
,6-di (2-pyridyl)-s-tetrazine (0.23 g, 1.0 mmol) in CHCl3
5 mL) was refluxed overnight, and then solvent was
3
(
4
.17–4.06 (m, OCH , 2H), 3.83.(s, OMe, 3H) 3.72 (bd,
2
removed under vacuum. Purification of resulting adducts
on silica gel column (48 g) with ether/hexane (1/10)
elution gave 19 (52 mg, 17%) and 20 (12 mg, 15%).
Exo-ethyl (5R,5aS,6aS,7S)-1,4-di (pyridin-2-yl)-5a,6,6a,7-
tetrahydro-5H-5,7-methanocyclopropa
carboxylate (19).
J = 7.8 Hz, 1H), 2.93 (bs, bridgeahead, 1H), 2.83 (bs,
bridgeahead, 1H), 1.73–1.66 (m, cyclopropane, 1H), 1.39–
1
.33 (m, cyclopropane, 1H), 1.23 (bt, J = 7.2 Hz, CH3,
H), 1.22–1.08 (m, 2H) 1.23 (bt, J = 12.0 Hz, A part of
AB system, bridge, 1H), 0.74 (bd, J = 12.2 Hz, B part
3
[g]phthalazine-6-
13
Mp 200–202°C; R = 0.21, ethyl
f
of AB system, bridge, 1H); C-NMR (75 MHz, CDCl3):
À1
acetate/n-hexane (1:10); FTIR (cm ): 3063, 3053
δ = 171.5 (CO), 161.1 (C), 155.7 (C), 128.5 (CH), 121.7
1
(aromatic, C─H), 1708 (C═O); H-NMR (300 MHz,
(C), 114.4 (CH), 88.2 (OCH), 61.3, 59.4, 55.6, 43.3,
CDCl ): δ = 8.76 (bd, J = 3.7 Hz, aromatic, 2H), 8.61
(bd, J = 8.0 Hz, aromatic, 2H), 7.97–7.85 (m, aromatic,
2H), 7.41–7.34 (m, aromatic, 2H), 4.64 (bs, bridgeahead,
4
0.0, 25.6, 23.2, 22.6, 18.4, 14.3; HRMS (APCI–Tof)
3
+
calcd for [C H NO + H] : m/z = 328.1549; found:
1
9
21
4
328.1536.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
2
924
Y. Adiloğlu, E. Şahin, A. Tutar, and A. Menzek
Vol 55
3
H), 4.10 (bq, J = 7.2 Hz, OCH , 2H), 2.79 (bs,
γ = 90°; volume: 2675.4 (6) Å ; Z = 8; calculated density:
2
3
À1
cyclopropane, 1H), 1.96 (bs, cyclopropane, 2H), 1.56
1.298 g/cm ; absorption coefficient: 0.080 mm ;
(
(
(
bd, J = 10.9 Hz, A part of AB system, bridge, 1H), 1.38
bd, J = 10.9 Hz, B part of AB system, bridge, 1H), 1.24
F(000) = 1104; θ-range for data collection 3.1–26.2°;
2
refinement method: full matrix least square on F ;
2
1
3
data/parameters: 2102/182; goodness-of-fit on F : 1.239;
bt, J = 7.2 Hz, CH , 3H); C-NMR (75 MHz, CDCl3):
3
final R-indices [I > 2σ(I)]: R = 0.0590, wR = 0.125;
1
2
δ = 171.7 (CO), 155.7 (C), 152.8 (C), 151.0 (C), 149.4
(
(
Tof) calcd for [C H N O + H] : m/z = 385.1665;
found: 385.1647.
À3
largest diff. peak and hole: 0.210 and À0.200 e Å
.
CH), 137.0 (CH), 125.1 (CH), 123.0 (CH), 60.9
Crystal data for 12b; C H NO , crystal system, space
19
21
4
OCH ), 42.6, 38.3, 30.1, 29.7, 14.45; HRMS (APCI–
2
+
group: triclinic, P-1 (no: 2); unit cell dimensions:
a = 6.338(1), b = 10.252(2), c = 13.888(2) Å,
α = 68.164(7), β = 85.758(7), γ = 87.771(7)°; volume:
2
3 20 4 2
Endo-ethyl (5R,5aS,6aS,7S)-1,4-di (pyridin-2-yl)-5a,6,6a,7-
tetrahydro-5H-5,7-methanocyclopropa [g]phthalazine-6-
carboxylate (20).
acetate/n-hexane (1:10); FTIR (cm ): 3109, 3057
(
CDCl ): δ = 8.82–8.75 (m, aromatic, 2H), 8.59 (bd,
J = 7.6 Hz, aromatic, 2H), 7.89 (bt, J = 7.7 Hz, aromatic,
2
2
3
3
8
17.35 (25) Å ; Z = 2; calculated density: 1.33 g/cm ;
À1
absorption coefficient: 0.093 mm ; F(000) = 348; θ-
range for data collection 3.1–28.6°; refinement method:
full matrix least square on F ; data/parameters:
Mp 186–189°C; Rf = 0.18, ethyl
À1
2
1
aromatic, C─H), 1719 (C═O); H-NMR (300 MHz,
2
3
054/217; goodness-of-fit on F : 1.335; final R-indices
3
[
I > 2σ(I)]: R1 = 0.088, wR2 = 0.112; largest diff.
À3
peak and hole: 0.282 and À0.243 e Å . Crystal data
H), 7.41–7.34 (m, aromatic, 2H), 4.73 (bs, bridgeahead,
for 13b; C H NO , crystal system, space group:
19
21
4
H), 4.27 (bq, J = 6.9 Hz, OCH , 2H), 2.37 (bt,
2
monoclinic, P2 /c (no: 14); unit cell dimensions:
1
J = 7.5 Hz, cyclopropane, 1H), 1.75 (bd, J = 7.5 Hz,
a = 13.324(4), b = 10.259(3), c = 13.060(3) Å, α = 90,
cyclopropane, 2H), 1.42–1.20 (m, bridge and CH , 5H);
3
3
β = 113.870(9), γ = 90°; volume: 1632.5(8) Å ; Z = 4;
1
3
C-NMR (75 MHz, CDCl ): δ = 172.0 (CO), 155.6 (C),
3
3
calculated density: 1.33 g/cm ; absorption coefficient:
1
(
1
52.7 (C), 152.0 (C), 149.5 (CH), 137.0 (CH), 124.0
À1
0
3
.093 mm ; F(000) = 696; θ-range for data collection
.1–28.6°; refinement method: full matrix least square
CH), 122.9 (CH), 61.5 (OCH ), 43.0, 38.9, 36.5, 26.7,
2
+
4.40; HRMS (APCI–Tof) calcd for [C H N O + H] :
23 20 4 2
2
2
on F ; data/parameters: 1976/218; goodness-of-fit on F :
.320; final R-indices [I > 2σ(I)]: R1 = 0.084,
m/z = 385.1665; found: 385.1646.
1
X-ray diffraction.
For the crystal structure
determination, single crystal of compounds (a) 7a, (b)
2b, and (c) 13b was used for data collection on a four-
wR2 = 0.123; largest diff. peak and hole: 0.240 and
À3
À0.230 e Å
.
1
Crystallographic data for all the structures reported in
this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary
publication No. CCDC-1814554 (7a), 1817102 (12b),
and 1817401 (13b). Copies of these data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; FAX: (+44) 1223 336033, or
online via www.ccdc. cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc. cam.ac.uk.
circle Rigaku R-AXIS RAPID-S diffractometer (equipped
with a two-dimensional area IP detector). Graphite-
monochromated Mo-K radiation (λ = 0.71073 Å) and
oscillation scans technique with Δw = 5° for one image
were used for data collection. The lattice parameters were
determined by the least squares methods on the basis of
all reflections with F > 2σ(F ). Integration of the
intensities, correction for Lorentz, and polarization effects
and cell refinement were performed using CrystalClear
α
2
2
(Rigaku/MSC Inc., 2005) software [39]. The structures
were solved by direct methods using SHELXS-97 [40],
which allowed location of most of the heaviest atoms,
with the remaining non-hydrogen atoms being located
from difference Fourier maps calculated from successive
Acknowledgment. The authors are indebted to Sakarya
University (BAP no: FBDTEZ 2016-50-02-011) for its financial
support.
2
full-matrix least squares refinement cycles on F using
REFERENCES AND NOTES
SHELXL-97 [40]. All non-hydrogen atoms were refined
using anisotropic displacement parameters. Hydrogens
attached to carbons were located at their geometric
positions using appropriate HFIX instructions in
SHELXL. The final difference Fourier maps showed no
peaks of chemical significance. Crystal data for 7a;
C H NO, crystal system, space group: orthorhombic,
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1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet