Synthesis of new β-hydroxy nitrate esters as potential glycomimetics or vasodilators

Article abstract of DOI:10.1002/ejoc.200800481

New β-hydroxy nitrates have been synthesized by the ringopening reaction of epoxides with Bi(NO₃)₃·5H₂O, which was used both as a catalyst and reagent. The synthesized molecules are both potential cyclitol mimetics and vasodilators as a result of their hydroxy groups and nitrate esters. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800481

FULL PAPER
DOI: 10.1002/ejoc.200800481
Synthesis of New β-Hydroxy Nitrate Esters as Potential Glycomimetics or
Vasodilators
Huseyin Cavdar[a] and Nurullah Saracoglu*[a]
Keywords: Cyclitols / Epoxidation / Nucleophilic addition / Ring expansion / Lewis acids
New β-hydroxy nitrates have been synthesized by the ring-
opening reaction of epoxides with Bi(NO3)3·5H2O, which was
used both as a catalyst and reagent. The synthesized mole-
cules are both potential cyclitol mimetics and vasodilators as
a result of their hydroxy groups and nitrate esters.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Highly hydroxylated cycloalkanes are often referred to as
cyclitols. Cyclitols are important compounds due to their
potential use as glycosidase inhibitors, which are receiving
considerable attention for their chemotherapeutic applica-
tions against diabetes, cancer, and viral infections.[1] For in-
stance, inositols and, in particular, myo-inositol (1) deriva-
tives play a central role in the cellular signal of various gly-
cosidase enzymes and may have therapeutic applications.[2]
Owing to the fundamental importance of cyclitols, there
has been considerable interest in recent years in the design
of new-generation cyclitol mimetics containing multiple hy-
droxy groups.[3] Organic nitrates[4] (RONO2) are an impor-
tant class of compounds that are widely used to treat a
number of cardiovascular diseases,[5] including congestive
and coronary heart failure, and are also of particular bene-
fit in the treatment of angina pectoris attacks,[6] unstable
angina[6a,7] and acute myocardial infection.[6a,8] Because the
use of glyceryl trinitrate[9] (2, GTN) in the treatment of
Angina pectoris has been shown to cause several adverse
effects, the search for new organic nitrates with reduced
side-effects and improved oral bioavailability has greatly in-
creased in recent years. Isosorbide dinitrate (3, ISDN) and
mononitrate are clinically used as vasodilators.[10] The syn-
thesis of four selectively nitrated derivatives 4–7[11] of myo-
inositol has been reported in studies of hypotensive and car-
diovascular activity.
Epoxides are versatile organic synthetic intermediates.
For instance, 1,2-substituted β-hydroxy nitrates can be pre-
pared through the facile ring-opening of epoxides. As a first
approach to the synthesis of hydroxy nitrates, the classic
methods used involve either the reaction of epoxides in ni-
tric acid[12] or the nitration of halohydrins with AgNO3.[13]
These methods require highly acidic conditions and the
use of an expensive silver salt, respectively. A second ap-
proach involves the ring-opening of the epoxides by the ni-
trate ion prepared from NH4NO3, Bu4NNO3 or NaNO3 in
the presence of Lewis acids.[14] The use of NO in air,[15]
[16]
[17]
(NH4)2Ce(NO3)6
and ZrO(NO3)2
in equivalent
amounts has also been reported for the direct preparation
of hydroxy nitrates from epoxides. Recently, the ring-open-
ing of various epoxides using Bi(NO3)3·5H2O to give β-hy-
droxy nitrates has been accomplished by Das et al.[18] and
Salvador and co-workers.[19]
Functionalized organic nitrates are also intermediates in
organic transformations. In fact, nitrates are the protected
form of hydroxy groups and can be reduced to the corre-
sponding alcohols by using catalytic hydrogenation[20] or re-
duction reagents.[21] Herein, we report the formation of new
nitrate esters as possible glycomimetics and vasodilators by
[a] Department of Chemistry, Atatürk University,
Erzurum 25240, Turkey
Fax: +9-442-236-0948
E-mail: nsarac@atauni.edu.tr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 4615–4621
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. Cavdar, N. Saracoglu
FULL PAPER
bismuth(III) nitrate mediated ring-opening of various bromonium ion 13 produces 10. The addition of bromine
mono- and diepoxides under mild reaction conditions. We to intermediate 13 yields 14. Substitution of the hydroxy
selected bismuth nitrate pentahydrate, Bi(NO3)3·5H2O, as it and nitrate groups of 14 by HBr results in the formation of
is relatively non-toxic, readily available at low cost, insensi- 11.
tive to air and requires no special care during its hand-
In an analogous manner, the epoxides 16[26] and 17[27]
were selected as substrates to combine the tremendous ring-
opening power of the oxiranes with bismuth nitrate. The
reactions were performed at room temperature in CH2Cl2
and these epoxides underwent stereoselective ring-opening
ling.[22]
Results and Discussion
In our focused efforts to synthesize new-generation cycli- to the corresponding products 18 and 19 as single products
tols or vasodilators through epoxide ring-opening reactions in yields of 85 and 73%, respectively (Scheme 2).
with Bi(NO3)3·5H2O, three types of epoxides were selected:
(i) carbocyclic mono-epoxides, (ii) diepoxides, and (iii) ep-
oxides with a tricyclic framework. Initially, the reaction of
cyclooctene epoxide 8 (1 equiv.) and bismuth nitrate penta-
hydrate (1 equiv.), both as a nitrating agent and as a cata-
lyst, was investigated at room temperature with dichloro-
methane as the solvent. The corresponding β-hydroxy ni-
trate 9 was obtained as the single reaction product and was
1
characterized by H and 13C NMR (Scheme 1). The cyclo-
octene epoxide 8 was selected due to its double bond which
can be easily functionalized. Then we turned our attention
to the bromination reaction of 9 to observe the behaviour
Scheme 2.
of the double bond and the free alcohol group in the mole-
cule.[23] Compound 9 was treated with bromine in dichloro-
Owing to the fundamental importance of the two organic
methane at –30 °C (Scheme 1). After purification by col- nitrates, isosorbide dinitrate (3) and polyhydroxylated cy-
umn chromatography and crystallization, two products cloalkanes, we shifted our attention to the synthesis of
were obtained. As the major product, we isolated the bicy- molecules with two nitrate functionalities. For this reason,
clic ether-bridged product 10. The structure of the second syn- and anti-diepoxides (20 and 21) were first synthesized
product was determined to be the tetrabromide 11[24] by by oxidation of 1,4-cyclohexadiene with excess m-chloro-
NMR and elemental analysis. The structure of 10 was con- perbenzoic acid (m-CPBA) and separation by silica gel col-
firmed by chemical transformation; the bromine and nitrate umn chromatography (Scheme 3).[28] As the syn-diepoxide
of 10 were eliminated with 1,8-diazabicyclo[5.4.0]undec-7- 20 has electrophilic centres, two isomeric trans-β-hydroxy
ene (DBU) to afford 9-oxabicyclo[4.2.1]nona-2,4-diene nitrates could be expected to form. To introduce two nitrate
(12).[25] For the formation of 10 and 11, we propose the groups through the ring-opening reaction of epoxides, we
mechanism depicted in Scheme 1. The formation of 10 and treated the diepoxide 20 with bismuth nitrate in dichloro-
11 from 9 might well be explained by the formation of inter- methane at room temperature. After completion of the reac-
mediate 13. The exo attack of the hydroxy group on the tion in 20 min, the spectroscopic data of the crude product
revealed that only one dinitrate ring-opened product 24 was
formed upon nitrate addition from the initially formed
mono-nitrate adduct 26 in quantitative yield (Scheme 3). In
particular, the three aliphatic carbon signals observed for
24 support the predicted symmetrical structure; the other
possible isomer 27 should have four carbon resonance sig-
nals because of its axis of symmetry. The ring-opening reac-
tion of the anti isomer 21 by a similar procedure yielded
the dinitrate product 25 as a single product. The structure
of 25 was determined by four carbon resonance signals. The
other possible isomer 29 was not observed. The regiochem-
ical outcome of the ring-opening reactions of these cyclo-
hexene oxide type systems can be understood on the basis
of the usual stereoelectronic factors that favour a trans-di-
axial ring-opening mode. Figure 1 shows the AM1-calcu-
lated optimized geometries of the mono-epoxides 26 and
28, in which both have steric effects on the axial position
due to the hydrogen atom in 26 and the hydroxy groups in
28. These could control the regioselectivity of the addition
Scheme 1.
4616
of the second nitrate.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Hydroxy Nitrate Esters Glycomimetics or Vasodilators
as a doublet (d, J = 5.6 Hz). The multiplet at δ = 5.30–
5.19 ppm relating to CHONO2 shows that these protons are
adjacent to both alkoxy and methylenic protons.
Scheme 3. Reagents and conditions: (a) Bi(NO3)3·5H2O, room
temp., 20 min, 74%; (b) Bi(NO3)3·5H2O, room temp., 20 min, 71%.
So as to obtain new di-β-hydroxy nitrates as potential Scheme 4. Reagents and conditions: (a) Bi(NO3)3·5H2O, room
temp., 16 h, 70%; (b) Bi(NO3)3·5H2O, room temp., 30 min, 85%.
glycosidases or vasodilators, we also used the syn-1,5-cyclo-
octadiene diepoxide 30, prepared from m-CPBA oxidation,
as a substrate for the ring-opening reaction with bismuth
After the successful formation of the mono- and di-β-
hydroxy nitrates from the rigid carbocyclic epoxides we in-
nitrate in CH2Cl2; we isolated only one product in quantita-
vestigated the ring-opening activity of bismuth nitrate
tive yield (Scheme 4).[29] We presumed that the isolated
towards epoxides in bicyclic skeletons. Norbornene epoxide
product was the dinitrate 31. Because of the steric hin-
drance of the first added nitrate functionality, we concluded
that the second nitrate group attacks to form syn-1,5-dini-
(35)[31] was selected as a test molecule. After the reaction of
35 with bismuth nitrate in CH2Cl2, the reaction mixture was
purified by chromatography on silica gel to give two iso-
trate 31 instead of 1,4-dinitrate 32 due to axial interactions.
meric products (Scheme 5). Careful examination of the
We carried out AM1 and PM3 calculations on both pos-
reaction products revealed the formation of Wagner–
sible products and found that the isomer 31 (–133.47 and
Meerwein rearrangement products instead of the expected
trans ring-opened product 38.
–125.79 kcal/mol, by the AM1 and PM3 methods, respec-
tively) is thermodynamically more stable than the isomer
32 (125.50l and –119.61 kcal/mol for the AM1 and PM3
methods, respectively). Furthermore, we prepared syn-diep-
oxide 33 by photo-oxygenation using tetraphenylporphyrin
(TPP) as a sensitizer of 1,3-cyclohexadiene followed by the
CoTPP-catalyzed reaction (Scheme 4).[30] The diepoxide 33
prepared was submitted to the ring-opening reaction with
bismuth nitrate. Theoretically, the formation of three prod-
ucts (two symmetrical and one unsymmetrical) could be ex-
pected. However, the nitrated toxocarol derivative 34 was
obtained as the sole product (Scheme 4). Although the
three carbon signals observed for the molecule clearly indi-
cate the formation of a symmetrical product, the alkoxy
protons (CHOH) in molecule 34 resonate at δ = 4.04 ppm
Scheme 5.
The structural assignments of the products were revealed
1
by H NMR spectroscopy. For both products, the relative
configurations of the nitrate and skeleton structure of the
molecules were determined from the coupling constants of
the relevant protons. Whereas the methine proton con-
nected to the nitrate (CHONO2) in molecule 37 resonates
at δ = 4.98 ppm as a doublet of doublet of doublets (ddd,
J = 7.1, 3.6, 2.8 Hz), the corresponding resonance in 36 at
δ = 4.98 ppm is a doublet of doublets (dd, J = 7.9, 2.9 Hz).
The long-distance coupling constant (J = 2.8 Hz) in mole-
Figure 1. Optimized geometries of the mono-epoxides 26 and 28.
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4617

H. Cavdar, N. Saracoglu
FULL PAPER
cule 37 (M or W orientation; the long-range coupling be- exo face of the cation 46 is more accessible than the endo
tween 7syn-H and 2endo-H) supports the exo position of face, which is blocked by the benzene ring. Thus, the exis-
the nitrate, whereas there is no long-range coupling in the tence of a double bond (or aromatic ring) in the bicyclic
endo-nitrate structure 36. Double resonance experiments carbon skeleton affects the product number, as well as the
were also used for the characterization of 36 and 37. Irradi- reaction outcome.
ation of the bridge alkoxy proton converted the signal of
the CHONO2 proton into a doublet of doublets in 37.
However, no similar behaviour was observed for 36 due to
the endo-nitrate. Moreover, the large coupling constants (J
= 13.9 Hz for 37 and J = 14.5 Hz for 26) for the geminal 3
and 3Ј protons are in agreement with the proposed struc-
tures.
In this reaction, the products 36 and 37 are Wagner–
Meerwein rearrangement products, possibly obtained via
intermediate 39 (Scheme 6). It is not possible to explain the
products by the classic addition of nitrate to the epi ion 39.
In short, this mode of reaction shows a non-classic carbo-
cation rearrangement.
Scheme 7.
Conclusions
The present study using epoxides and bismuth nitrate
produced not only new mono- and di-β-hydroxy nitrates as
possible glycomimetics and vasodilators as well as synthetic
precursors, but also led to insights into the reaction mecha-
nisms. Monocarbocyclic oxiranes open to give products
with trans stereo- and regioselectivity, whereas the epoxides
fused to a bicyclic carbon framework are exposed to skel-
Scheme 6.
eton rearrangement through a non-classic carbocation
mechanism.
Comparison of the results obtained during the final ex-
periment with the others indicates that the structure of the
carbocycle containing the epoxide ring affects the reaction
Experimental Section
outcome. We assume that steric effects in the intermediate
General Methods: Melting points were determined with a Büchi
39 force the system to undergo a skeleton rearrangement.
539 capillary melting apparatus and are uncorrected. Infrared spec-
In this manner, to investigate the effect of the double bond
tra were recorded with a Mattson 1000 FT-IR spectrophotometer.
on the skeleton rearrangement, the exo-benzonorbornadi-
1H and 13C NMR spectra were recorded with 200 (50) and 400
ene epoxide (43)[32] was treated with bismuth nitrate in
(100) MHz Varian spectrometers and are reported in δ units with
CH2Cl2. A sole ring-opened product 44 was obtained in
quantitative yield. A reasonable mechanism for the forma-
tion of 44 is shown in Scheme 7. The reaction may well
proceed via non-classic carbocation intermediate 46. The
SiMe4 as the internal standard. Elemental analyses were carried
out with a Leco CHNS-932 instrument.
Calculation Methods: All calculations were performed by using
SPARTAN04 software for Windows, version 1.0.0.[33] Energies were
refined by using the semiempirical AM1 and PM3 methods.
1
structure of 44 was elucidated on the basis of H NMR
spectroscopic data. The coupling constants relating to the
methylenic protons (ddd, J = 13.4, 7.3, 3.3 Hz) and methine
proton (dd, J = 7.3, 3.3 Hz) adjacent to the nitrate fully
support the rearrangement product 44. Although the
methylenic protons of 44 resonate as an AB system at δ =
2.33 and 2.12 ppm, the large coupling constants show that
these protons are in an ethano bridge, not in a methano
bridge. Extensive NMR studies did not reveal the formation
Typical Procedure for the Synthesis of β-Hydroxy Nitrates: Bi(NO3)3·
5H2O (1 mmol) was added to a solution of the epoxide (1 mmol)
in CH2Cl2 (1 mL) at room temperature. The reaction was com-
pleted in 5 min–18 h as verified by TLC. Then the reaction mixture
was filtered through filter paper and the solvent was concentrated
under reduced pressure. The crude product was purified by column
chromatography or crystallization.
trans-[1S(R),8S(R),Z]-8-Hydroxycyclooct-4-enyl Nitrate (9): The
of any second product. These observations indicate that the product 9 was obtained from 8 (250 mg, 2.02 mmol) and Bi(NO3)3·
4618
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Hydroxy Nitrate Esters Glycomimetics or Vasodilators
5H2O (978 mg, 2.02 mmol) as described above by a typical pro-
cedure for 16 h. After filtration, the residue was purified by column
chromatography (silica gel, 30 g), eluting with ethyl acetate/hexane
(15:85). Elution gave the product 9 as a colourless oil (280 mg,
18 as a colourless oil (280 mg, 85%). 1H NMR (200 MHz, CDCl3):
δ = 5.65–5.49 (m, 2 H, =CH), 5.10 (ddd, J = 15.3, 8.9, 6.3 Hz, 1
H, CHONO2), 3.98 (ddd, J = 15.3, 8.9, 6.3 Hz, 1 H, CHOH), 2.78–
2.50 (m, 2 H, CH2), 2.30–2.03 (m, 2 H, CH2) ppm. 13C NMR
(50 MHz, CDCl3): δ = 126.4, 124.9, 85.2, 69.1, 35.0, 31.1 ppm. IR
1
74%). H NMR (400 MHz, CDCl3): δ = 5.71 (ddd, J = 17.3, 11.2,
7.3 Hz, 1 H, A part of AB system, =CH), 5.62 (ddd, J = 17.3, 11.2, (CH Cl ): ν = 3570, 3392, 3040, 2908, 2854, 1631, 1557, 1441, 1422,
˜
2
2
7.3 Hz, 1 H, B part of AB system, =CH), 5.18 (ddd, J = 13.0, 8.8,
1348, 1314, 1278, 1213, 1159, 1100, 1070, 1040, 997, 973, 867, 792,
3.9 Hz, 1 H, CHONO2), 3.96 (ddd, J = 13.0, 8.8, 3.9 Hz, 1 H, 755 cm–1. C6H9NO4 (159.14): calcd. C 45.28, H 5.70, N 8.80; found
CHOH), 2.48–2.37 (m, 2 H, CH2), 2.28–2.08 (m, 4 H, CH2), 1.84– C 44.93, H 5.53, N 8.70.
1.23 (m, 2 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 130.2,
trans-[2S(R),3S(R)]-3-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl
128.5, 86.0, 71.8, 33.2, 28.6, 23.0, 22.7 ppm. IR (CH Cl ): ν = 3418,
˜
2
2
Nitrate (19): The reaction was performed following the typical pro-
cedure described for 16 h starting from 17 (140 mg, 0.96 mmol) and
Bi(NO3)3·5H2O (465 mg, 0.96 mmol). The product 19 was recrys-
tallized from CH2Cl2/hexane as yellow crystals (145 mg, 73%, m.p.
3018, 2937, 2867, 1722, 1629, 1576, 1482, 1467, 1449, 1318, 1283,
1209, 1138, 1122, 1059, 1014, 973, 863, 737 cm–1. C8H13NO4
(187.19): calcd. C 51.33, H 7.00, N 7.48; found C 51.02, H 7.18, N
7.60.
1
54–55 °C). H NMR (400 MHz, CDCl3): δ = 7.26–7.20, (m, 2 H,
Bromination of trans-[1S(R),8S(R),Z]-8-Hydroxycyclooct-4-enyl Ni-
trate (9): A solution of Br2 (427 mg, 2.67 mmol) in CH2Cl2 (5 mL)
was added dropwise to a solution of 9 (500 mg, 2.67 mmol) in
CH2Cl2 (7 mL) at –30 °C and the mixture was stirred for 1 h. The
reaction mixture was warmed to room temperature and the solvent
of the mixture was removed under pressure. The residue was puri-
fied by column chromatography (silica gel, 30 g), eluting with ethyl
acetate/hexane (3:97). The first elution gave the tetrabromide 11
(350 mg, 30%) and the second fraction provided 10 (485 mg,
68%).
aryl), 7.19–7.07 (m, 2 H, aryl), 5.27 (ddd, J = 12.9, 8.3, 5.4 Hz, 1
H, CHONO2), 4.16 (ddd, J = 12.9, 8.3, 5.4 Hz, 1 H, CHOH), 3.25
(dd, J = 16.8, 5.4 Hz, 1 H, A part of AB system, CH2), 2.97 (dd,
J = 16.8, 8.3 Hz, 1 H, A part of AB system, CH2), 2.92–1.30 (m,
2 H, CH2), 2.82 (m, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 132.9, 132.0, 129.2, 129.0, 127.2, 127.0, 83.4, 67.7, 36.3,
32.4 ppm. IR (CH Cl ): ν = 3565, 3402, 3066, 3025, 2908, 2853,
˜
2
2
1717, 1635, 1585, 1496, 1455, 1440, 1423, 131, 1321, 1276, 1217,
1161, 1111, 1059, 983, 953, 871, 749 cm–1. C10H11NO4 (209.20):
calcd. C 57.41, H 5.30, N 6.70; found C 57.51, H 5.08, N 6.63.
[1S(R),2S(R),5R(S),6R(S)]-5-Bromo-9-oxabicyclo[4.2.1]nonan-2-yl Reaction of 1,4-Cyclohexadiene with m-CPBA: A mixture of 1,4-
Nitrate (10): Yield 360 mg, 51%, recrystallized from CH2Cl2/hex- cyclohexadiene (2.50 g, 31.25 mmol) and m-CPBA [15.54 g (70%),
ane as white crystals, m.p. 61–62 °C. 1H NMR (200 MHz, CDCl3): 62.50 mmol] in dichloromethane (100 mL) was cooled in a salt–ice
δ = 5.38–5.31 (m, 1 H, CHONO2), 4.83–4.75 (m, 1 H, OCH), 4.64–
4.61 (m, 1 H, CHBr), 4.20–4.10 (m, 1 H, OCH), 2.30–1.90 (m, 8
H, CH2) ppm. 13C NMR (50 MHz, CDCl3): δ = 85.10, 84.11,
bath and stirred for 2 h. Dichloromethane (50 mL) was added and
the reaction mixture was then washed with 10% NaOH
(3ϫ100 mL) and water (50 mL), dried with MgSO4, filtered and
the solvent removed under reduced pressure. The residue (3.42 g)
was subjected to silica gel chromatography using ethyl acetate/hex-
ane (10:90). The first fraction gave 21 (2.35 g, 67%). Then the col-
umn was eluted with CH2Cl2 to give 20 (850 mg, 24%).
79.34, 54.59, 31.50, 30.12, 28.22, 27.66 ppm. IR (CH Cl ): ν =
˜
2
2
2958, 1630, 1280, 1062, 936, 857 cm–1. C8H12BrNO4 (266.09):
calcd. C 36.11, H 4.55, N 5.26; found C 35.99, H 4.52, N 5.25.
[1S(R),2S(R),5S(R),6S(R)]-1,2,5,6-Tetrabromocyclooctane
(11):
Yield 260 mg, 22%, recrystallized from CH2Cl2/hexane as white
crystals, m.p. 129–130 °C. H NMR (200 MHz, CDCl3): δ = 4.78–
syn-1,4-Cyclohexadiene Diepoxide (20): Yield 625 mg, 18%, colour-
less crystals from CH2Cl2/hexane, m.p. 61–62 °C. 1H NMR
1
4.75 (m, 4 H, CHBr), 2.86–2.79 (m, 4 H, CH2), 2.15–2.08 (m, 4 H, (200 MHz, CDCl3): δ = 3.02 (d, J = 1.4 Hz, 4 H, OCH), 2.68 (d,
CH2) ppm. 13C NMR (50 MHz, CDCl3): δ = 59.2, 28.8 ppm. IR
(CH Cl ): ν = 2922, 1426, 1217, 1065, 994, 762 cm–1. C H Br
4
J = 16.5 Hz, 2 H, A part of AB system, CH2), 2.24 (dd, J = 16.5,
1.4 Hz, 2 H, B part of AB system, CH2) ppm. 13C NMR (50 MHz,
˜
2
2
8
12
(427.80): calcd. C 22.46, H 2.83; found C 22.68, H 2.59.
CDCl ): δ = 51.1, 25.5 ppm. IR (CH Cl ): ν = 3009, 2990, 2929,
˜
3 2 2
1470, 1424, 1353, 1279, 1266, 1095, 1023, 933, 897, 835, 810, 788,
771 cm–1. C6H8O2 (112.13): calcd. C 64.27, H 7.19; found C 64.01,
H 6.99.
(2Z,4Z)-9-Oxabicyclo[4.2.1]nona-2,4-diene (12): DBU (1.15 g,
7.57 mmol) was added to a solution of 10 (100 mg, 0.38 mmol) in
toluene (3 mL) and the mixture was heated at reflux for 3 h. After
cooling, H2O was added to the reaction mixture and the mixture
was extracted with diethyl ether. The organic layer was washed with
water and dried with MgSO4. After removal of the solvent in
vacuo, the residue was purified by silica gel thin-layer chromatog-
raphy. Elution with diethyl ether/hexane (25:75) gave 12 (40 mg,
anti-1,4-Cyclohexadiene Diepoxide (21): Yield 1.95 g, 56%, colour-
less crystals from CH2Cl2/hexane, m.p. 181–182 °C. 1H NMR
(200 MHz, CDCl3): δ = 3.07–3.05 (m, 4 H, OCH), 232–2.30 (m, 4
H, CH2) ppm. 13C NMR (50 MHz, CDCl3): δ = 50.9, 25.9 ppm. IR
(CH Cl ): ν = 2925, 2854, 1729, 1464, 127, 1074, 750 cm–1. C H O
˜
2
2
6
8
2
1
87%, oil at room temperature). H NMR (200 MHz, CDCl3): δ =
(112.13): calcd. C 64.27, H 7.19; found C 64.30, H 7.38.
6.14–6.06 (m, 2 H, AAЈ part of AAЈBBЈ system, =CH), 5.85–5.75
(m, 2 H, BBЈ part of AAЈBBЈ system, =CH), 4.71–4.63 (m, 2 H,
OCH), 2.24–2.12 (m, 4 H, CH2) ppm. 13C NMR (50 MHz, CDCl3):
[1R(S),2R(S),4R(S),5R(S)]-2,5-Dihydroxycyclohexane-1,4-diyl Dini-
trate (24): The product 24 was prepared following the typical pro-
cedure described above for 20 min starting from 20 (250 mg,
2.23 mmol) and Bi(NO3)3·5H2O (2.18 g, 4.46 mmol). The product
24 was recrystallized from CH2Cl2/hexane as white crystals
(395 mg, 74%, m.p. 113–114 °C). 1H NMR (200 MHz,
CD3COCD3): δ = 5.25 (ddd, J = 10.7, 7.1, 4.0 Hz, 2 H, CHONO2),
5.86 (d, J = 4.0 Hz, 2 H, OH), 4.05 (ddd, J = 10.7, 7.1, 4.0 Hz, 2
H, CHOH), 2.25 (ddd, J = 10.7, 7.1, 4.0 Hz, 2 H, A part of AB
system, CH2), 2.02 (ddd, J = 10.7, 7.1, 4.0 Hz, 2 H, B part of AB
system, CH2) ppm. 13C NMR (50 MHz, CD3COCD3): δ = 84.8,
δ = 140.6, 126.4, 80.1, 41.9 ppm. IR (CH Cl ): ν = 2925, 1732,
˜
2
2
1633, 1067, 913, 744 cm–1. C8H10O (122.16): calcd. C 78.65, H 8.25;
found C 79.01, H 8.08.
trans-[1S(R),6S(R)]-6-Hydroxycyclohex-3-enyl Nitrate (18): The re-
action was performed following the typical procedure described
above for 20 min starting from 16 (200 mg, 2.08 mmol) and
Bi(NO3)3·5H2O (1.01 g, 2.09 mmol). The mixture was filtered and
the residue purified by column chromatography (silica gel, 30 g),
eluting with ethyl acetate/hexane (5:95). Elution gave the product
68.6, 34.3 ppm. IR (CH Cl ): ν = 3398, 2925, 2856, 1716, 1635,
˜
2
2
Eur. J. Org. Chem. 2008, 4615–4621
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4619

H. Cavdar, N. Saracoglu
FULL PAPER
1442, 1276, 1181, 1067, 1015, 961, 854, 751 cm–1. C6H10N2O8
(238.15): calcd. C 30.26, H 4.23, N 11.76; found C 30.50, H 4.08,
N 11.67.
[2S(R),7R(S)]-7-Hydroxybicyclo[2.2.1]heptan-2-yl Nitrate (37):
Yield 730 mg, 58%, colourless crystals from CH2Cl2/hexane, m.p.
47–48 °C. 1H NMR (200 MHz, CDCl3): δ = 4.98 (ddd, J = 7.1,
3.6, 2.8 Hz, 1 H, CHONO2), 4.05 (br. s, 1 H, CHOH), 2.35 (d, J
= 4.4 Hz, 1 H, CH), 2.26–2.20 (m, 1 H, CH), 2.14–2.11 (m, 1 H,
CH2), 2.03 (dd, J = 13.9, 7.1 Hz, 1 H, A part of AB system, CH2),
1.98–1.54 (m, 2 H, CH2), 1.28–1.16 (m, 2 H, CH2) ppm. 13C NMR
(50 MHz, CDCl3): δ = 88.7, 81.3, 46.4, 42.6, 37.4, 26.7, 24.4 ppm.
[1S(R),3S(R),4S(R),6S(R)]-4,6-Dihydroxycyclohexane-1,3-diyl Dini-
trate (25): The product 25 was prepared following the typical pro-
cedure described above for 20 min starting from 21 (850 mg,
7.59 mmol) and Bi(NO3)3·5H2O (7.36 g, 15.18 mmol). The product
25 was recrystallized from CH2Cl2/hexane as white crystals (1.29 g,
71%, m.p. 172–173 °C). 1H NMR (200 MHz, CDCl3): δ = 5.10 (q,
J = 5.8 Hz, 2 H, CHONO2), 4.18 (q, J = 5.8 Hz, 2 H, CHOH),
2.31 (t, J = 5.8 Hz, 2 H, CH2), 2.07 (t, J = 5.8 Hz, 2 H, CH2) ppm.
13C NMR (50 MHz, CDCl3): δ = 83.1, 67.7, 37.7, 29.2 ppm. IR
IR (CH Cl ): ν = 3343, 2965, 2925, 1625, 1279, 1157, 1085, 1068,
˜
2
2
966, 865, 757 cm–1. C7H11NO4 (173.17): calcd. C 48.55, H 6.40, N
8.09; found C 48.77, H 6.35, N 8.23.
[2R(S),9R(S)]-9-Hydroxy-1,2,3,4-tetrahydro-1,4-methanonaph-
thalen-2-yl Nitrate (44): The product 44 was prepared following the
typical procedure described above for 18 h starting from 43
(400 mg, 2.53 mmol) and Bi(NO3)3·5H2O (1.23 g, 2.53 mmol). The
residue was purified by column chromatography (silica gel, 10 g),
eluting with ethyl acetate. Elution gave the product 44 (350 mg,
63%, recrystallized from CH2Cl2/hexane as white crystals, m.p.
102–103 °C). 1H NMR (400 MHz, CDCl3): δ = 7.29–7.21 (m, 1 H,
aryl), 7.20–7.15 (m, 3 H, aryl), 4.95 (dd, J = 7.3, 3.3 Hz, 1 H,
CHONO2), 4.08 (m, 1 H, CHOH), 3.53 (m, 1 H, CH), 3.36–3.35
(m, 1 H, CH), 2.35 (m, 1 H, OH), 2.33 (ddd, J = 13.4, 7.3, 3.3 Hz,
1 H, A part of AB system, CH2), 2.12 (dd, J = 13.4, 7.3 Hz, 1 H,
B part of AB system, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ
= 145.0, 139.0, 128.0, 123.3, 122.4, 85.3, 83.8, 52.4, 48.2, 32.3 ppm.
(CH Cl ): ν = 3753, 3378, 2931, 1638, 1441, 1326, 1279, 1181, 1090,
˜
2
2
1069, 1015, 950, 862, 752 cm–1. C6H10N2O8 (238.15): calcd. C
30.26, H 4.23, N 11.76; found C 30.41, H 4.20, N 11.70.
[1R(S),2R(S),5R(S),6R(S)]-2,6-Dihydroxycyclooctane-1,5-diyl Dini-
trate (31): The product 31 was prepared following the typical pro-
cedure described above for 16 h starting from 30 (600 mg,
4.29 mmol) and Bi(NO3)3·5H2O (4.16 g, 8.57 mmol). The residue
was purified by column chromatography (silica gel, 30 g), eluting
with ethyl acetate/hexane (40:60). Elution gave the product 31
(800 mg, 70%, recrystallized from CH2Cl2/hexane as white crystals,
1
m.p. 91–92 °C). H NMR (400 MHz, CD3OD): δ = 5.05 (ddd, J =
10.5, 8.0, 2.3 Hz, 2 H, CHONO2), 3.79 (ddd, J = 10.5, 8.0, 2.3 Hz,
2 H, CHOH), 2.12–2.00 (m, 4 H, CH2), 1.98–1.84 (m, 4 H,
CH2) ppm. 13C NMR (100 MHz, CD3OD): δ = 87.9, 70.8, 28.5,
IR (CH Cl ): ν = 3386, 2941, 1629, 1365, 1278, 1086, 1008, 977,
˜
2
2
860, 755 cm–1. C11H11NO4 (221.21): calcd. C 59.73, H 5.01, N 6.33;
24.3 ppm. IR (CH Cl ): ν = 3386, 2941, 1629, 1365, 1278, 1086,
˜
2
2
found C 60.03, H 4.82, N 6.25.
1008, 977, 860, 755 cm–1. C8H14N2O8 (266.21): calcd. C 36.09, H
5.30, N 10.52; found C 35.99, H 5.38, N 10.65.
[1R(S),2R(S),3S(R),4S(R)]-2,3-Dihydroxycyclohexane-1,4-diyl Dini-
trate (34): The product 34 was prepared following the typical pro-
cedure described above for 30 min starting from 33 (500 mg,
4.46 mmol) and Bi(NO3)3·5H2O (4.34 g, 8.94 mmol). The product
34 was recrystallized from CH2Cl2/hexane as white crystals
Acknowledgments
The authors are indebted to the Department of Chemistry and
Atatürk University for financial support of this work.
1
(900 mg, 85%, m.p. 88–89 °C). H NMR (200 MHz, CDCl3): δ =
5.30–5.19 (m, 2 H, CHONO2), 4.04 (d, J = 5.6 Hz, 2 H, CHOH),
3.04–2.91 (m, 2 H, OH), 2.22–2.03 (m, 2 H, AAЈ part of AAЈBBЈ
system, CH2), 1.97–1.26 (m, 2 H, BBЈ part of AAЈBBЈ system,
CH2) ppm. 13C NMR (50 MHz, CDCl3): δ = 82.4, 71.6, 24.7 ppm.
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IR (CH Cl ): ν = 3403, 2940, 1634, 1440, 1315, 1276, 1068, 996,
˜
2
2
853, 755 cm–1. C6H10N2O8 (238.04): calcd. C 30.26, H 4.23, N
11.76; found C 30.03, H 4.40, N 11.75.
Reaction of Norbornene Epoxide (35) with Bi(NO3)3·5H2O: The re-
action was performed following the typical procedure described
above for 30 min starting from 35 (800 mg, 7.27 mmol) and
Bi(NO3)3·5H2O (3.53 g, 7.27 mmol). The mixture was filtered and
the residue was purified by column chromatography (silica gel,
30 g), eluting with ethyl acetate/hexane (5:95). The first elution gave
the product 36 as a colourless oil (380 mg, 30%). Then the column
was eluted by ethyl acetate/hexane (7:93) to give 37 (850 mg,
68%).
[2R(S),7R(S)]-7-Hydroxybicyclo[2.2.1]heptan-2-yl Nitrate (36): 1H
NMR (200 MHz, CDCl3): δ = 4.78 (dd, J = 7.9, 2.9 Hz, 1 H,
CHONO2), 4.25 (m, 1 H, CHOH), 2.31–2.29 (m, 1 H, CH), 2.18–
2.13 (m, 1 H, CH), 2.05–1.95 (m, 2 H, CH2), 1.87 (dd, J = 14.5,
7.9 Hz, 1 H, A part of AB system, CH2), 1.69–1.53 (m, 1 H, CH2),
1.27–1.20 (m, 2 H, CH2) ppm. 13C NMR (50 MHz, CDCl3): δ =
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˜
2
2
2967, 2882, 1618, 1282, 1148, 1037, 1005, 935, 867, 758 cm–1.
C7H11NO4 (173.17): calcd. C 48.55, H 6.40, N 8.09; found C 48.82,
H 6.55, N 8.45.
4620
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4615–4621

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Received: May 16, 2008
Published Online: August 1, 2008
Eur. J. Org. Chem. 2008, 4615–4621
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4621