Three-dimensional heterocycles: New uracil-based structures obtained by nucleophilic substitution at the sp2 carbon of bromoisoxazoline

Article abstract of DOI:10.3390/molecules19068661

The regioisomeric cycloadducts of bromonitrile oxide and N-benzoyl-2,3-oxazanorborn- 5-ene were easily prepared and elaborated into a novel class of uracil-based scaffolds. The key-synthetic step is the nucleophilic substitution at the sp² carbon atom of the bromoisoxazoline three-dimensional heterocycles. The protocol to perform the nucleophilic substitution of uracil anions was optimized and adapted to the steric requirements of the substrates. A library of pyrimidine derivatives was prepared in very good yields and the products were fully characterized. They are proposed as nucleoside analogues and as synthons for β-turn motifs within PNA structures.

Full text of DOI:10.3390/molecules19068661

Molecules 2014, 19, 8661-8678; doi:10.3390/molecules19068661
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Three-Dimensional Heterocycles: New Uracil-Based Structures
2
Obtained by Nucleophilic Substitution at the sp Carbon of
Bromoisoxazoline
Misal Giuseppe Memeo, Francesco Lapolla, Bruna Bovio and Paolo Quadrelli *
Dipartimento di Chimica, Univesità degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed; E-Mail: paolo.quadrelli@unipv.it;
Tel.: +39-0382-987-315; Fax: +39-0382-987-323.
Received: 7 May 2014; in revised form: 4 June 2014 / Accepted: 13 June 2014 /
Published: 24 June 2014
Abstract: The regioisomeric cycloadducts of bromonitrile oxide and N-benzoyl-2,3-oxaza-
norborn-5-ene were easily prepared and elaborated into a novel class of uracil-based
2
scaffolds. The key-synthetic step is the nucleophilic substitution at the sp carbon atom of
the bromoisoxazoline three-dimensional heterocycles. The protocol to perform the
nucleophilic substitution of uracil anions was optimized and adapted to the steric
requirements of the substrates. A library of pyrimidine derivatives was prepared in very
good yields and the products were fully characterized. They are proposed as nucleoside
analogues and as synthons for β-turn motifs within PNA structures.
Keywords: nitrosocarbonyl intermediates; 1,3-dipolar cycloadditions; bromonitrile oxide;
2
nucleophilic substitution at sp carbon; uracils; thymine; X-ray analysis; nucleosides;
β-turn inducers
1
. Introduction
A novel approach to useful precursors for the synthesis of isoxazoline-carbocyclic nucleosides
was recently detailed starting from the readily available N-benzoyl-2,3-oxazanorborn-5-ene (1) and
introducing a versatile functional group via a condensed bromoisoxazoline ring. These structures can
be prepared through the efficient and exo-selective 1,3-dipolar cycloaddition reaction of bromonitrile
oxide 3 (in-situ generated from the corresponding bromoxime 2) to the 2,3-oxazanorbornene (1)
affording the regioisomeric cycloadducts 4a,b in good yields (Scheme 1) [1].

Molecules 2014, 19
Scheme 1. Cycloaddition reaction of bromonitrile oxide (3) to the N-benzoyl-2,3-
8662
oxazanorborn-5-ene (1).
Br
N
OH
Br
2
NaHCO3
AcOEt
Br
Br
N
_
O
COPh
N
N
O
+
3
N
O
COPh
+
Br
COPh
r.t., 48h
O
N
N
1
4a (45%)
O
4b (44%)
O
In previous studies the regioisomeric cycloadducts 4 were used as starting materials for
the synthesis of aminols containing the β-hydroxynitrile functionalities derived from the isoxazoline
ring opening [2]. They served as intermediates in the linear construction of uracil-substituted
nucleosidic structures [3,4].
Nitrosocarbonyl (R-CONO) chemistry represents the key strategy of the reported syntheses because
of the high dienophilic power of these fleeting intermediates and the synthetic potential of their hetero-
Diels-Alder (HDA) cycloadducts of type 1. Traditionally, nitrosocarbonyls are generated through
periodate oxidation of hydroxamic acids and instantly trapped by dienes as reported by Kirby [5].
Recently, we developed two alternative entries to nitrosocarbonyls through the mild oxidation of nitrile
oxides with N-methylmorpholine-N-oxide (NMO) [6–10].
In the planned efforts to expand upon the versatility of 1 [1–10], we were interested in varying the
synthetic applications of the regioisomeric three-dimensional cycloadducts of the bromonitrile oxide to
the oxazanorbornene 1. The presence of the bromine atom on the nitrile oxide moiety suggests the
2
exploration of the nucleophilic substitution (S
N
) reaction on a sp carbon atom [11]. We wish to report
here a study regarding the reactivity of the regioisomeric cycloadducts 4a,b in the presence of the
in-situ generated anions of uracil bases (Scheme 2). The methodologies applied are discussed in the
light of the reaction mechanism
Scheme 2. Synthetic strategy towards uracil derivatives.
O
O
O
NH
X
NH
NH
X
O
Br
X
O
c
N
b
b
N
b
N
H
O
c
a
COPh
c
N
Base
a
a
COPh
Synthetic
Elaboration
NH
2
O
2
sp Nucleophilic
substition
N
OH
O
4
X = H, Me, Halogens

Molecules 2014, 19
8663
The study also aimed to ascertain the scope and eventual limitations of this type of chemistry
upon variation of the experimental conditions and the feasibility of the planned synthetic elaborations
towards the preparation of novel β-turn inducers containing nucleobases for their insertion in Peptide
Nucleic Acids (PNA) as well as the synthesis of new nucleoside analogues [12,13].
Scheme 3. Synthesis of uracil compounds (5a,b).
Br
N
OH
Br
2
NaHCO3
AcOEt
Br
+
N
_
O
3
COPh
O
r.t., 48h
N
1
O
Br
N
N
O
COPh
Br
COPh
N
N
4a (45%)
O
4b (44%)
O
O
Base
Solvent T (°C) t (h)
NH
NaH 95% dry DMF 95
24
N
H
O
O
HN
N
O
O
HN
O
N
O
N
COPh
N
N
O
COPh
O
N
5a (64%)
O
5b (50%)

Molecules 2014, 19
. Results and Discussion
The bromonitrile oxide 3 is generated in situ in an AcOEt/NaHCO solution from the corresponding
8664
2
3
bromoxime 2 [14], which is easily prepared by treating glyoxylic acid with hydroxylamine hydrochloride
in the presence of bromine at 5 °C in dichloromethane [15]. Using N-benzoyl-2,3-oxazanorborn-5-ene
(1) as dipolarophile, the 1,3-dipolar cycloaddition reaction smoothly occurs affording the regioisomeric
compounds 4a,b in 45% and 44% yields, respectively, which are easily isolated upon chromatographic
separation (Scheme 3).
The structures of cycloadducts 4a,b were assigned based on their analytical and spectroscopic data
as well as upon comparison with previously prepared authentic samples [1]. The known exceptionally
high reactivity and exclusive exo-selectivity of the cycloaddition reaction of 1 with the bromonitrile
oxide 3 is akin to that of the related parent carbocyclic norbornene, which adds all types of reactants
only on the exo face [16]. The origin of the norbornene selectivity is usually attributed to the relief of
strain [17], geometric deformation of the double bond (pyramidalization due to torsional [18] and
hyperconjugative effects [19]) as well as favourable staggering effects in the exo attack [20]. This fact
pushed us to explore the insertion of a heterobase of choice anti-related to the oxaza-moiety of the
2
cycloadducts 4a,b through an sp S reaction as pivotal synthetic step of our strategy towards
N
nucleoside analogues and β-turn motifs.
2
The sp S
N
reaction conditions and the synthetic method were first optimized using as benchmark
reaction that between the two regioisomeric cycloadducts 4a,b and to uracil as heterobase (Scheme 4).
In the search for the best reaction conditions, we took advantage of previously reported results on
2
an sp S
N
reaction conducted on a bromoisoxazoline [21]. Upon addition of the regioisomeric
cycloadducts 4a,b to an anhydrous DMF suspension of the uracil anion, generated by treatment with
NaH, under stirring at 95 °C, poor results were obtained in terms of final products 5a,b (10%–12%
yields, respectively) after 3 days of reaction. Moreover, great difficulties were encountered in the
work-up procedures (emulsions) for the isolation of the products.
The reference authors themselves report the various efforts done to find the proper experimental
2
conditions to perform the sp S
N
reaction. However they did not detail the experimental procedure but
indicated DMF as the best solvent to run the reactions along with the temperature and reaction time
employed [21]. The choice of different solvents such as anhydrous THF or MeCN was soon abandoned
since just the starting materials were recovered after the work-up and no reaction occurred. Then we
2
tried to change base, temperature and reaction time. The sp S
N
reaction failed when NaOH was used
as well as running the reactions both at room temperature or upon heating, even after several days
under stirring. Decomposition of the starting materials was also observed under microwave heating
(
MW) (DMF/NaH at 160 °C for 30 min).
We attributed the low yields of the adducts 5a,b to the low concentration of the nucleophile.
In order to have a high conversion of the uracil base into the corresponding anion, we used NaH 95%
instead of the standard 70%–80% and performed the nucleophile in-situ generation under vacuum in a
Schlenk tube. In an anhydrous Schlenk tube an excess of NaH 95% (2.1 equivalents) is suspended in
anhydrous DMF (20 mg/mL) and vacuum is applied to get rid of the air. The uracil base is added
portionwise and the suspension is left under stirring at room temperature for 30 min.

Molecules 2014, 19
Scheme 4. Synthesis of uracil derivatives (6a,b) and thymine compounds (7a,b).
8665
Br
O
N
N
O
COPh
Br
COPh
N
N
4a
O
X
4b
O
O
X
A
F
NH
B
C
D
Cl
Br
I
+
NaH 95% / DMF
N
H
O
Me
O
9
5 °C
4h
2
HN
O
O
X
HN
O
N
N
O
N
COPh
N
N
O
COPh
O
N
X
O
6
a(A-D)
6b (A-D)
7b
X = Me, 7a
Finally, 0.8 equivalents of the regioisomeric cycloadducts 4a,b were added and the mixture was
heated at 95 °C under stirring for 24 h. The reaction was quenched by adjusting the pH to 7 by means
4
of addition of aqueous 3:1 NH Cl/NaCl and the water phase was extracted with dichloromethane
(DCM). The adducts 5a,b were purified by column chromatography under medium pressure (MPLC)
and the yields were 64% and 50% for 5a and 5b, respectively (yields determined by HPLC-RP C-18
analysis on crude extracted solutions). The isolated yields were 44% and 30% for 5a and 5b of 98.5%
purity after recrystallization, respectively.
The assigned structures of adducts 5a,b rely upon the corresponding analytical and spectroscopic data.
In particular, the vinyl protons of the uracil moiety in 5a are found at δ 5.79 (d, J = 8 Hz, =CH-C=O) and
at δ 7.83 (d, J = 8 Hz, N-CH=) while the singlet corresponding to the NH group is found at δ 11.70.
Similarly, in compound 5b, the vinyl protons of the uracil moiety are found at δ 5.79 (d, J = 8 Hz,
=
CH-C=O) and at δ 7.85 (d, J = 8 Hz, N-CH=) while the NH group singlet is found at
δ 11.72. All the other signals of the three-dimensional isoxazoline-norbornane moieties are in
the expected range and clearly support the reported structures (Scheme 3). A definitive confirmation of
the structural assignments given above came from the X-ray structure of compound 5a whose ORTEP
view is shown in Figure 1. In the oxazanorbornane ring of the compound 5a the sum of the angles at
3
N8 345.0(2)° is consistent with the sp hybridization; the 2pz lone pair takes no part in π–bonding with
the C=O group, indeed the bond distance N8-C18, 1.376(3) Å is longer than the shortened partial

Molecules 2014, 19
8666
double bond (1.352(5) Å). The height of the pyramid with the nitrogen atom at the apex and the three
atoms connected to it at the base is 0.230(3) Å. The atoms N8 C18 O18 C19 are almost coplanar: the
maximum deviation from least–squares plane is 0.028(2) Å; the angle between the carbonyl group
and the moiety C1 O9 N8 C7 is 36.1(2)°. Bond lengths in oxazanorbornane ring C-C (range
1
.523(4)–1.534.1(3) Å) and N-C 1.477(3) Å are comparable with the values of the literature [22]. The
six-membered ring of the oxazanorbornane is puckered with deviations from the least-squares plane in the
range −0.569(3) + 0.305(2) Å. These ring exhibit a boat conformation with the parameters [23]
Q = 0.985(2), φ = 60.4(1)°, θ = 90.3(1)°, (ideal conformation: φ = 60.0°, θ = 90°, respectively).
Figure 1. ORTEP plot of compound 5a with atom labeling (ellipsoid at 20% probability).
O
N
1
9
1
2
7
2
O
N8
N11
N4
O
18
5
6
1
O9
O3
2
In the isoxazoline rings of compound 5a the angle at N4 109.1(2)° is consistent with the sp
hybridization of N4, whereby the 2pz lone pair takes part in the π–bonding within a part of the
heterocyclic ring; indeed the bond distance N4-C5 1.270(3) Å shows a double–bond character. The
internal angles at the nitrogen atoms O3-N4-C5 109.1(2)° in 5a differ by 3.9°, justified by the different
type of nitrogen. The deviation of atoms from the least–squares plane of isoxazoline rings
are in the ranges −0.013(2) + 0.012(2) Å with a T conformations; the puckering parameters are
Q = 0.020(3), φ = 132.2(2)° in 5a (ideal value φ = 126°).
The pyrimidine ring in compound 5a attached to the isoxazoline is nearly planar with a maximum
deviation of −0.016(3) Å. This ring is tilted (with respect to the isoxazoline ring) by 5.3(1)° implying
only a small conjugation. The orientation of the pyrimidine ring, due to the steric crowding the
attached atoms is confirmed by the torsion angles N4-C5-N11-C12 −7.3(3)°, 12.2(4)°.
In order to ascertain the eventual limitations of this chemistry we extended the functionalization
to the entire family of the halogenated uracils and thymine. Scheme 4 reports the reactions and the
structures of the halogenated-uracil adducts 6a,b (A–D) and the thymine adducts 7a,b obtained by
2
applying the above reported sp S
N
reaction protocol. The positive results indicate that the
methodology set-up for the uracil base can be easily transported to the other pyrimidine-type
heterobases without any variation or adjustment when other derivatives are employed. In fact, as we
can see from the data of Table 1, the overall yields are good, with small variations when moving from
one substituent to another.

Molecules 2014, 19
8667
1
Table 1. Yields, physical data, relevant IR bands and diagnostic H-NMR signals of
compounds 6a, b (A–D) and 7a,b.
1
H-NMR
N-CH=CX
8.24 (d)
6
(δ, DMSO-d )
#
−1
Entry
Adduct 6a
Yield (%)
m.p. (°C)
IR (cm ) νNH
ν
C=O
J (Hz)
1
2
3
4
A
B
C
D
46
53
56
57
193–198
180–189
96–100
3394
3360
3200
3394
1733
1734
1734
1632
7
8.23 (s)
8.27 (s)
110–115
8.23 (s)
6
b
5
6
7
8
9
A
64
76
49
57
45
55
95–100
98–105
3157
3178
3121
3160
3176
3149
1723
1732
1732
1720
1715
1710
8.24 (d)
8.24 (s)
8.29 (s)
8.24 (s)
7.69 (d)
7.69 (d)
7
B
C
104–106
162–164
215–217
D
7a
7b
1.81 (Me)
1.82 (Me)
1
0
220–222
#
From diisopropyl ether/ethanol.
The structures of the adducts 6a,b (A–D) and 7a,b rely upon the corresponding analytical and
spectroscopic data. Table 1 also reports the physical data (mps) and the frequencies of the IR bands
2
1
N
corresponding to the uracil moieties inserted upon sp S reactions as well as the diagnostic H-NMR
signals confirming the insertion of the uracil rings onto the tricyclic structures.
Belonging the heterobases to the same family of the pyrimidine heterocycles, the changes in the
NMR signals relative to the isoxazoline-norbornane moiety are negligible while the presence of the
attached uracil units is clearly indicated by the vinylic protons as well as the NH groups found in the δ
1
2.05–12.25 range. A definitive confirmation of the structural assignments given above came from the
X-ray structure of compound 7a whose ORTEP view is shown in Figure 2.
Figure 2. ORTEP plot of compound 7a with atom labeling (ellipsoid at 20% probability).
O
N
1
2
N
O
7
1
9
5
N11
6
1
8
N4
N8
O9
1
O
O3
2
In the oxazanorbornane ring of the compound 7a the sum of the angles at N8 339.4(3)° is consistent
3
with the sp hybridization; the 2pz lone pair takes no part in π–bonding with the C=O group, indeed the
bond distance N8-C18 1.377(5) Å is longer than the shortened partial double bond (1.352(5) Å). The
height of the pyramid with the nitrogen atom at the apex and the three atoms connected to it at the base
is 0.249(3) Å. The atoms N8 C18 O18 C19 are almost coplanar: the maximum deviation from

Molecules 2014, 19
8668
least–squares plane is 0.039(4) Å; the angle between the carbonyl group and the moiety C1 O9 N8 C7
is 40.9(2)° in compounds 7a. Bond lengths in oxazanorbornane rings C-C (range 1.507(5)–1.540(5) Å)
and N—C 1.487(4) Å in compound 7a, are comparable with the values of the literature [22]. The
six–membered ring of the oxazanorbornane is puckered with deviations from the least–squares plane
in the range −0.306(5) +0.575(5) Å. This ring exhibits a boat conformation with the parameters [23]
Q = 0.982(3)°, φ = 60.8(3)° and θ = 90.0(3)° (ideal conformation: φ = 60.0°, θ = 90°, respectively).
2
In the isoxazoline rings of the compounds 7a the angles at N4 109.9(3)° is consistent with the sp
hybridization of N4, whereby the 2pz lone pair takes part in the π–bonding within a part of the
heterocyclic ring; indeed the bond distances N4-C5 1.272(4) Å shows a double–bond character. The
internal angles at the nitrogen atoms O3-N4-C5 109.9(3)° and C7-N8-O9 105.3(3)° in 7a differ by
4
.6°, justified by the different type of nitrogen. The deviation of atoms from the least–squares plane of
isoxazoline ring is in the ranges −0.032(3) + 0.031(3) Å, with a T conformations; the puckering
parameters are Q = 0.055(4), φ = 126.9(3)° (ideal value φ = 126°).
The pyrimidine ring in compound 7a attached to the isoxazoline is nearly planar with a maximum
deviations of −0.061(4) Å; this rings is tilted (with respect to the isoxazoline rings) by 22.1(2)° respectively
implying only a small conjugation. The orientation of the pyrimidine ring, due to the steric crowding of the
attached atoms is confirmed by the torsion angles N4-C5-N11-C16 175.8(2)°, −165.0(4)°.
Finally, we have also scaled-up the protocol (from 250 mg to 2.5 g) performing the reactions with
a larger amount of starting materials in order to have the required quantities of all the reported
compounds to carry on with the synthetic elaborations towards the final targets. Yields did not change
significantly (±2%) remaining in the reported range and the work-up procedures worked nicely,
allowing for the easy isolation of the desired compounds.
The synthetic pathway shown in the Schemes 3 and 4 represent the pivotal step as well as the most
delicate and somewhat difficult in the approach to our final goals. In fact, the first attempts to perform
2
the sp S
N
reaction failed and the method had to be properly set-up to be adapted to our tricyclic substrates.
2
The S
N
reaction on a sp carbon atom is a transformation of relevance to organic synthesis,
industrial applications as well as biochemistry [24]. Recent computational studies shed some light
2
on the sp S
N
reaction in comparison with the mechanism followed by the nucleophilic aromatic
substitution, S
N
Ar, and the nucleophilic aliphatic substitution, S
N
2 [25].
2
Contrary to the aliphatic version of the S reaction, the sp S reaction on vinyl (V) carbons
N
N
can follow different pathways. A common one is the Addition-Elimination route (A-ER); if
electron-withdrawing groups are located on the α-carbon atom, a stable anion represents the
intermediate of the reaction and the successive elimination affords the substitution product.
The presence of a nitrogen atom, belonging to the isoxazoline moiety, in the α position with respect
2
to the =C-Br sp carbon centre can suggest the A-ER as the operating mechanism. The nitrogen atom
helps the addition step allowing to stabilize the negative charge generated in the intermediate that
however suffers somewhat of the increased steric requirements determined by the hybridation change
of the C-Br carbon atom (Scheme 5) [26].
We believe that stereochemical requirements and nucleophile concentration have a consequence in
the experimental conditions we have previously detailed. For this reason the generation under vacuum
of the anion of the uracil bases can be considered a success from the experimental point of view.

Molecules 2014, 19
8669
Temperature is also important; lower temperatures do not allowed for obtaining the products in good
yields while higher temperature resulted in the decomposition of the reagents.
Scheme 5. Nucleophile addition orientation.
As final remark, we wish to point out that we have detailed the methodology to promote a
high yield process to substitute the bromine in regioisomeric bromoisoxazoline derivatives to insert
pyrimidine heterobases on a three-dimensional heterocyclic system. The protocol has to be adapted
and properly tuned for the purine-type heterobases, which suffer from the known possibility to give
regioisomeric adducts at the N7 and N9 nitrogen atoms. Preliminary results indicate that mixtures of
compounds are obtained although in lower yields and for this reason some changes in the method had
to be done to make the protocol of general application.
3. Experimental
3.1. General Information
All melting points are uncorrected. Elemental analyses were done on a C. Erba 1106 elemental
analyzer available in our Department. IR spectra (nujol mulls) were recorded on an FT-IR
1
13
Perkin-Elmer RX-1. H- and C-NMR spectra were recorded on a Bruker AVANCE 300 in
DMSO-d . Chemical shifts are expressed in ppm (δ) from internal tetramethylsilane. Column
6
chromatography: silica gel 60 (0.063–0.200 mm; Merck, Darmstadt, Germany); eluant was a
cyclohexane/ethyl acetate gradient from 9:1 to 5:5. For MPLC a Biotage FMP apparatus equipped with
KP-SIL columns, eluant cyclohexane/ethyl acetate from 9:1 to 7:3 was used. TLC was performed on
Merck silica gel F254 plates. The identification of samples from different experiments was secured by
mixed mps and superimposable IR spectra. Glyoxylic acid (Sigma-Aldrich, St. Louis, MO, USA) was
used to prepare the bromoxime 2 according to the reported method [15]. N-Benzoyl-2-oxa-3-
azanorborn-5-ene (1) was prepared according to the reported method [1–10]. Anhydrous DMF was
purchased from Sigma-Aldrich. Other chemicals and solvents were purchased from Sigma-Aldrich and
Carlo Erba Reagenti (Rodano - MI, Italy) and used without any further purification.

Molecules 2014, 19
.2. Cycloaddition of Bromonitrile Oxide 3 to N-Benzoyl-2,3-oxazanorborn-5-ene (1)
To a stirred solution of N-benzoyl-2,3-oxazanorborn-5-ene (1, 5.28 g, 26.24 mmol) in EtOAc (200 mL)
8670
3
NaHCO (3.93 g, 47.2 mmol) was added. To this suspension bromoxime 2 (7.98 g, 39.4 mmol) dissolved
3
in EtOAc (50 mL) were added dropwise. The reaction proceeded under stirring for 48 h at room
temperature. Upon filtration and evaporation of the solvent, an oily residue is obtained and submitted to
chromatographic separation, allowing for the isolation of the regioisomeric cycloadducts 4a,b. The
compounds were found to be identical to previously prepared authentic samples [1].
3
.3. General Procedure for the Synthesis of Compounds 5a,b, 6a,b (A–D) and 7a,b
In a dry Schlenk tube an excess of 95% NaH (2.1 equivalents) is suspended in anhydrous DMF
(
20 mg/mL) and vacuum is applied to get rid of the air inside the suspension. The dry uracil bases are
added portionwise and vacuum is applied after every addition keeping watch on the gas evolution. The
suspension is left under stirring at room temperature for 30 min to complete the nucleophile
generation. Finally, 0.8 equivalents of the regioisomeric cycloadducts 4a,b were added in one portion
and again vacuum applied. The mixtures were heated at 95 °C under vigorous stirring for 24 h. After
this period of time, the reactions were quenched by pouring the solution in the minimum amount of ice
(
50 g/0.8 equivs. of 4a,b), adjusting the pH to 7 by means of solid NH Cl/NaCl 3:1 and the water
4
phase extracted with dichloromethane (DCM, 3 × 50 mL). The desired adducts 5a,b, 6a,b (A–D) and
7
a,b were purified by column chromatography under medium pressure (MPLC).
1
2
-(5-Benzoyl-4,5,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[4,5-d][1,2]oxazin-3-yl)pyrimidine-
,4(1H,3H)-dione (5a): 0.35 g (64%), m.p. 225 °C (dec.), colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3248 cm , νC=O 1731 cm , νC=N 1694 cm . H-NMR (δ): 3.47 (m, 2H, CH
.55 (d, 1H J = 8 Hz, H4isox), 5.06 (s, 1H, CH-N), 5.13 (d, 1H, J = 8 Hz, H5isox), 5.31 (s, 1H, HC-O), 5.79
d, 1H, J = 8 Hz, =CH-C=O), 7.44 (m, 2H, arom.) 7.57 (m, 1H, arom.), 7.69 (m, 2H, arom.). 7.83 (d,
2
),
4
(
1
3
1
H, J = 8 Hz, N-CH=), 11.70 (s, 1H, NH). C-NMR (δ): 30.7, 32.8, 53.8, 79.6, 84.6, 103.9, 128.3,
28.6, 131.9, 132.7, 141.6, 148.8, 153.2, 163.1, 169.9. Elemental analysis: cald. for C17
1
14 4 5
H N O
(
MW = 354.32) C 57.63, H 3.98, N 15.81. Found C C 57.60, H 3.97, N 15.80.
1
2
-(6-Benzoyl-4,6,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[5,4-d][1,2]oxazin-3-yl)pyrimidine-
,4(1H,3H)-dione (5b): 0.27 g (50%), m.p. > 240 °C (dec.), colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3200 cm , νC=O 1716 cm , νC=N 1646 cm . H-NMR (δ): 2.04 (m, 2H, CH
.39 (d, 1H J = 8 Hz, H4isox), 5.00 (s, 1H, CH-N), 5.28 (m, 1H + 1H, H5isox and HC-O), 5.79 (d, 1H,
J 8 Hz, =CH-C=O), 7.49 (m, 2H, arom.), 7.57 (m, 1H, arom.), 7.69 (m, 2H, arom.), 7.85 (d, 1H, J = 8
2
),
4
1
3
Hz, N-CH=), 11.72 (s, 1H, NH). C-NMR (δ): 32.6, 55.0, 60.9, 61.2, 80.1, 83.9, 103.9, 121.4, 128.3,
28.5, 131.8, 133.0, 141.2, 141.5, 148.8, 152.9, 163.0. Elemental analysis: cald. for C H N O
1
1
7
14
4
5
(
MW = 354.32) C 57.63, H 3.98, N 15.81. Found C C 57.64, H 4.00, N 15.81.
1
-(5-Benzoyl-4,5,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[4,5-d][1,2]oxazin-3-yl)-5-fluoropyrimidine-
,4(1H,3H)-dione (6aA): 0.27 g (46%), m.p. 193–198 °C, colorless crystals from diisopropyl
2
−1
−1
−1 1
ether/ethanol. IR: νNH 3394 cm , ν
C=N 2
1733 cm , ν 1654 cm . H-NMR (δ): 1.97 (m, 2H, CH ),
C=O

Molecules 2014, 19
8671
4
.57 (d, 1H J = 8 Hz, H4isox), 5.07 (s, 1H, CH-N), 5.15 (d, 1H, J = 8 Hz, H5isox), 5.34 (s, 1H, HC-O),
.47 (m, 2H, arom.), 7.57 (m, 1H, arom.), 7.69 (m, 2H, arom.), 8.24 (d, 1H, J = 7 Hz, N-CH=), 12.22
7
1
3
(s, 1H, NH). C-NMR (δ): 32.7, 39.8, 53.6, 79.6, 84.7, 90.0, 127.4, 128.2, 128.3, 128.7, 131.2, 131.8,
1
32.8, 147.6, 152.9, 157.4, 170.0. Elemental analysis: cald. for C H FN O (MW = 372.31) C 54.84,
17 13 4 5
H 3.52, N 15.05. Found C 54.85, H 3.50, N 15.06.
1
-(6-Benzoyl-4,6,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[5,4-d][1,2]oxazin-3-yl)-5-fluoropyrimidine-
,4(1H,3H)-dione (6bA): 0.37 g (64%), m.p. 95–100 °C, colorless crystals from diisopropyl
2
−1
−1
−1 1
ether/ethanol. IR: νNH 3157 cm , ν
1723 cm , ν
C=N 2
1648 cm . H-NMR (δ): 2.04 (s, 2H, CH ),
C=O
1
1
4
.39 (d, 1H J = 8 Hz, H4isox), 5.00 (s, 1H, CH-N), 5.28 (m, H + H, H5isox and HC-O), 7.47 (m, 2H,
arom.), 7.56 (m, 1H, arom.), 7.71 (m, 2H, arom.), 8.24 (d, 1H, J = 7 Hz, N-CH=), 12.25 (s, 1H, NH).
1
3
C-NMR (δ): 32.6, 54.8, 56.6, 80.0, 84.0, 125.8, 127.0, 127.4, 128.2, 128.3, 128.5, 131.2, 131.8,
1
3
33.0, 147.6, 152.5, 168.9. Elemental analysis: cald. for C H FN O (MW = 372.31) C 54.84, H
1
7
13
4
5
.52, N 15.05. Found C 54.83, H 3.51, N 15.02.
1-(5-Benzoyl-4,5,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[4,5-d][1,2]oxazin-3-yl)-5-chloropyrimidine-
2
,4(1H,3H)-dione (6aB): 0.32 g (53%), m.p. 189–196 °C, colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3360 cm , νC=O 1734 cm , νC=N 1703 cm . H-NMR (δ): 1.96 (m, 2H, CH
2
),
.55 (d, 1H J = 8 Hz, H4isox), 5.08 (s, 1H, CH-N), 5.17 (d, 1H, J = 8 Hz, H5isox), 5.36 ( s, 1H, HC-O),
.45 (m, 2H, arom.), 7.57 (m, 1H, arom.), 7.73 (m, 2H, arom.), 8.23 (s, 1H, N-CH=), 12.23 (s, 1H,
4
7
1
3
NH). C-NMR (δ): 32.8, 41.2, 53.4, 56.3, 84.8, 109.8, 127.4, 128.2, 128.7, 131.9, 132.7, 138.7, 148.2,
59.0, 172.4. Elemental analysis: cald. for C17 (MW = 388.76) C 52.52, H 3.37, N 14.41.
Found C 52.54, H 3.35, N 14.40.
1
4 5
H13ClN O
1-(6-Benzoyl-4,6,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[5,4-d][1,2]oxazin-3-yl)-5-chloropyrimidine-
2
,4(1H,3H)-dione (6bB): 0.46 g (76%), m.p. 98–105 °C, colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3178 cm , νC=O 1732 cm , νC=N 1708 cm . H-NMR (δ): 2.07 (m, 2H, CH
2
),
.38 (d, 1H J = 9 Hz, H4isox), 5.00 (s, 1H, CH-N), 5.28 ( s, 1H, HC-O), 5.32 (d, 1H, J = 9 Hz, H5isox),
.46 (m, 2H, arom.), 7.58 (m, 1H, arom.), 7.70 (m, 2H, arom.), 8.24 (s, 1H, N-CH=), 12.25 (s, 1H,
4
7
1
3
NH). C-NMR (δ): 32.7, 35.8, 54.6, 79.8, 84.1, 109.8, 127.4, 128.2, 128.3, 128.5, 131.8, 133.0, 138.6,
1
4 5
48.2, 152.5, 159.0, 162.3, 168.9. Elemental analysis: cald. for C17H13ClN O (MW = 388.76) C
52.52, H 3.37, N 14.41. Found C 52.50, H 3.36, N 14.42.
1-(5-Benzoyl-4,5,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[4,5-d][1,2]oxazin-3-yl)-5-bromopyrimidine-
2
,4(1H,3H)-dione (6aC): 0.38 g (56%), m.p. 96–100 °C, colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3200 cm , ν
C=N 2
1734 cm , ν 1621 cm . H-NMR (δ): 1.95 (m, 2H, CH ),
C=O
4
.54 (d, 1H J = 10 Hz, H4isox), 5.08 (s, 1H, CH-N), 5.16 (d, 1H, J = 10 Hz, H5isox), 5.36 (s, 1H, HC-O),
7
.47 (m, 2H, arom.), 7.57 (m, 1H, arom.), 7.68 (m, 2H, arom.), 8.27 (s, 1H, N-CH=), 12.18 (s, 1H,
1
3
NH). C-NMR (δ): 30.7, 32.8, 53.4, 79.6, 84.8, 98.6, 128.2, 128.7, 131.8, 132.8, 140.9, 148.4, 152.7,
1
59.2. Elemental analysis: cald. for C17
7.10, H 3.01, N 12.95.
4 5
H13BrN O (MW = 433.21) C 47.13, H 3.02, N 12.93. Found C
4

Molecules 2014, 19
8672
1
-(6-Benzoyl-4,6,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[5,4-d][1,2]oxazin-3-yl)-5-bromopyrimidine-
,4(1H,3H)-dione (6bC): 0.33 g (49%), m.p. 104–106 °C, colorless crystals from diisopropyl
2
−1
−1
−1 1
ether/ethanol. IR: νNH 3121 cm , ν
C=N 2
1732 cm , ν 1702 cm . H-NMR (δ): 2.07 (m, 2H, CH ),
C=O
4
.37 (d, 1H J = 9 Hz, H4isox), 5.00 (s, 1H, CH-N), 5.28 (s, 1H, HC-O), 5.31 (d, 1H, J = 9 Hz, H5isox),
7
.49 (m, 2H, arom.), 7.57 (m, 1H, arom.), 7.69 (m, 2H, arom.), 8.29 (s, 1H, N-CH=), 12.20 (s, 1H,
1
3
NH). C-NMR (δ): 26.3, 32.7, 54.6, 79.8, 84.1, 98.6, 128.3, 128.5, 131.7, 132.4, 133.0, 140.9, 148.4,
1
3
52.4, 159.1, 165.7, 168.9. Elemental analysis: cald. for C H BrN O (MW = 433.21) C 47.13, H
17 13 4 5
.02, N 12.93. Found C 47.14, H 3.03, N 12.95.
1-(5-Benzoyl-4,5,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[4,5-d][1,2]oxazin-3-yl)-5-iodopyrimidine-
2
,4(1H,3H)-dione (6aD): 0.42 g (57%), m.p. 110–115 °C, colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3394 cm , νC=O 1732 cm , νC=N 1654 cm . H-NMR (δ): 1.95 (m, 2H, CH
2
),
.53 (d, 1H J = 9 Hz, H4 isox), 5.07 (s, 1H, CH-N), 5.15 (d, 1H, J = 9 Hz, H5 isox), 5.34 (s, 1H, HC-O),
.46 (m, 2H, arom.), 7.57 (m, 1H, arom.), 7.67 (m, 2H, arom.), 8.23 (s, 1H, N-CH=), 12.04 (s, 1H,
4
7
1
3
NH). C-NMR (δ): 26.3, 32.8, 53.4, 73.0, 79.6, 74.7, 127.4 128.2, 128.6, 128.7, 131.8, 132.8, 145.3,
1
1
48.8, 152.6, 166.0. Elemental analysis: cald. for C H IN O (MW = 480.21) C 42.52, H 2.73, N
17 13 4 5
1.67. Found C 42.50, H 2.75, N 11.66.
1-(6-Benzoyl-4,6,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[5,4-d][1,2]oxazin-3-yl)-5-iodopyrimidine-
2
,4(1H,3H)-dione (6bD): 0.42 g (57%), m.p. 162–164 °C, colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3160 cm , νC=O 1720 cm , νC=N 1654 cm . H-NMR (δ): 2.05 (m, 2H, CH
2
),
4
7
3
.35 (d, 1H J = 9 Hz, H4isox), 4.98 (s, 1H, CH-N), 5.26 ( s, 1H, HC-O), 5.28 (d, 1H, J = 9 Hz, H5isox),
1
3
.52 (m, 3H, arom.), 7.68 (m, 2H, arom.), 8.24 (s, 1H, N-CH=), 12.05 (s, 1H, NH). C-NMR (δ): 32.7,
9.8, 54.7, 73.0, 79.9, 84.2, 127.4, 128.3, 128.4, 129.2, 131.7, 132.7, 142.1, 145.3, 148.8, 152.4, 160.7.
Elemental analysis: cald. for C17
H 2.76, N 11.68.
4 5
H13IN O (MW = 480.21) C 42.52, H 2.73, N 11.67. Found C 42.51,
1
-(5-Benzoyl-4,5,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[4,5-d][1,2]oxazin-3-yl)-5-methylpyrimidine-
,4(1H,3H)-dione (7a): 0.26 g (45%), m.p. 215–217 °C, colorless crystals from diisopropyl
2
−1
−1
−1 1
ether/ethanol. IR: νNH 3176 cm , νC=O 1715 cm , νC=N 1674 cm . H-NMR (δ): 1.81 (d, 3H, J = 1 Hz,
CH ), 1.92 (s, 2H, CH ), 4.58 (d, 1H J = 8 Hz, H4isox), 5.07 (s, 1H, CH-N), 5.12 (d, 1H, J = 8 Hz,
5isox), 5.30 (s, 1H, HC-O), 7.51 (m, 3H, arom.), 7.69 (d, 1H, J = 1 Hz, N-CH=), 7.73 (m, 2H, arom.),
3
2
H
1
3
1
1
1.70 (s, 1H, NH). C-NMR (δ): 11.9, 32.9, 54.1, 60.1, 79.8, 84.6, 111.8, 128.3, 128.8, 131.9, 133.1,
37.0, 148.9, 153.3, 163.8, 170.0. Elemental analysis: cald. for C18 (MW = 368.34) C 58.69,
16 4 5
H N O
H 4.38, N 15.21. Found C 58.70, H 4.39, N 15.19.
1-(6-Benzoyl-4,6,7,7a-tetrahydro-3aH-4,7-methanoisoxazolo[5,4-d][1,2]oxazin-3-yl)-5-methylpyrimidine-
2
,4(1H,3H)-dione (7b): 0.31 g (55%), m.p. 220–222 °C, colorless crystals from diisopropyl
−1
−1
−1 1
ether/ethanol. IR: νNH 3149 cm , ν
C=N
1710 cm , ν 1698 cm . H-NMR (δ): 1.82 (d, 3H, J = 1 Hz,
C=O
3 2
CH ), 2.04 (m, 2H, CH ), 4.41 (d, 1H J = 8 Hz, H4isox), 4.99 (s, 1H, CH-N), 5.25 (d, 1H, J = 8 Hz,
H5isox), 5.27 (s, 1H, HC-O), 7.51 (m, 3H, arom.), 7.69 (d, 1H, J = 1 Hz, N-CH=), 7.73 (m, 2H, arom.),
1
3
1
1.63 (s, 1H, NH). C-NMR (δ): 11.9, 32.6, 55.1, 61.2, 80.1, 83.7, 111.7, 128.3, 128.5, 131.8, 130.0,

Molecules 2014, 19
8673
1
36.8, 148.8, 152.9, 163.7, 168.9. Elemental analysis: cald. for C H N O (MW = 368.34) C 58.69,
1
8
16
4
5
H 4.38, N 15.21. Found C 58.71, H 4.37, N 15.20.
3
.4. X-ray Crystallographic Analysis of Compounds 5a and 7a
Unit cell dimensions for compounds 5a and 7a were obtained by least-squares fitting of 2θ values for
5 reflections, with an Enraf–Nonius CAD4 diffractometer and graphite-monochromated Mo–Kα
2
radiation at the Centro Grandi Strumenti (CGS) of the University of Pavia, Italy. The structure was
solved by direct methods, and the E-map correctly revealed the non-hydrogen atoms in the molecules.
The positions of the hydrogen atoms were located by difference Fourier synthesis, compared with those
calculated from the geometry of the molecules and refined isotropically in the subsequent least-squares
refinement. The program SHELXL [27] was used to solve the structure. The ORTEP program [28] was
2
.5
used for molecular graphics. The ORTEP plots of 8-benzoyl-5-uracil-3,9-dioxa-4,8-diaza-[5.2.1.0 ]-
2
.5
dec-4-ene (5a) and 8-benzoyl-5-thymine-3,9-dioxa-4,8-diaza-[5.2.1.0 ]dec-4-ene (7a) are shown in
Figures 1 and 2 and the corresponding bond lengths and angles are given in Table 2.
A total 2,893 reflections for 5a and 1,828 for 7a was explored with the ω/2θ scan tecnique.
Correction was applied for Lorentz and polarization. An approximate scale and a mean thermal factor
2
2
of 2.867 Å and 3.417 Å were determined by Wilson statistic [29] for 5a and 7a. The structure was
solved by direct methods and E-map correctly revealed all the non-hydrogen atoms in the molecules.
The position of the hydrogen atoms was checked in a final difference Fourier-map and refined
isotropically in the subsequent least- squares refinement. The experimental crystal X-ray data are
summarized in Tables 3 and 4, respectively. CCDC deposition numbers: (5a) 987413 and (7a) 987414.
Table 2. Selected bond lengths (Å) and angles (deg) (with Esd’s in Parentheses).
Compounds 5a 7a 5a 7a.
C1—C2
C1—O9
1.523(4) 1.507(6)
1.458(3) 1.456(5)
1.501(4) 1.497(6)
1.452(3) 1.453(4)
1.534(3) 1.540(5)
1.420(2) 1.402(4)
1.270(3) 1.272(4)
C5—C6
C5—N11
C6—C7
C7—N8
C7—C10
N8—O9
N8—C18
1.499(3) 1.498(5)
1.417(3) 1.408(4)
1.538(4) 1.533(5)
1.477(3) 1.487(5)
1.517(3) 1.520(6)
1.450(2) 1.455(4)
1.376(3) 1.377(5)
C1—C10
C2—O3
C2—C6
O3—N4
N4—C5
Bond Angles (°)
C2—C1—O9
C2—C1—C10
O9—C1—C10
C1—C2—C6
O3—C2—C6
C2—O3—N4
O3—N4—C5
N4—C5—C6
N4—C5—N11
C6—C5—N11
104.8(2) 104.3(2)
103.9(2) 104.2(4)
103.3(2) 103.8(4)
102.6(2) 102.9(3)
105.8(2) 105.5(3)
109.4(2) 109.4(3)
109.1(2) 109.9(3)
115.6(2) 115.1(3)
118.1(2) 116.4(3)
126.4(2) 128.3(3)
C2—C6—C5
C2—C6—C7
C6—C7—N8
C6—C7—C10
N8—C7—C10
C7—N8—O9
C7—N8—C18
O9—N8—C18
C1—O9—N8
C1—C10—C7
100.1(2) 99.8(3)
101.9(2) 101.7(3)
104.0(2) 104.2(3)
103.2(2) 102.7(4)
101.6(2) 101.2(3)
105.2(2) 105.3(3)
126.9(2) 124.1(3)
112.9(2) 110.0(3)
103.7(2) 103.4(3)
92.7(2) 92.9(4)

Molecules 2014, 19
Table 3. Crystal data, data collection and structure refinement (compound 5a).
8674
Empirical Formula
17 14 4 5
C H N O
Formula weight
354.32
Crystal size, mm
0.56 × 0.42 × 0.18
Temperature, K
293
Crystal system
Orthorhombic
Space group
P bca
a, Å
b, Å
c, Å
α
9.977(4)
16.774(3)
19.649(3)
90
β
90
γ
90
3
V, Å
3288(1)
Z
8
−
3
Dcalcd, g·cm
1.431
−
1
Absorption coeff., µ, mm
Diffractometer/scan
λ, Å
0.108
Enraf–Nonius CAD–4, θ/2θ
0.71073
F(000)
1472
Range (°) for data
Index ranges
2.0 < θ > 25
0 < h > 11, 0 < k > 19, 0 < l > 23
No. of reflects. measd
No. of unique reflects
Correction applied
Refinement method
No. of variables
2893
1824
Lorentz–polarization
Full–matrix least–squares
291
Goodness–of–fit (2893)
R1 (I) > 2 σ (I), (1824)
R1 (2883)
0.900
0.0403
0.0785
−
3
(
∆ρ) max, min, eÅ
0.124, −0.151
Table 4. Crystal data, data collection and structure refinement (compound 7a).
Empirical Formula
20 22 4 6
C H N O
Formula weight
414.417
Crystal size, mm
0.50 × 0.385 × 0.14
293
Temperature, K
Crystal system
Monoclinic
Space group
P 2 /n
1
a, Å
b, Å
c, Å
α
11.991(3)
11.4437(8)
14.63(1)
90.0
β
101.34(4)
90.0
γ

Molecules 2014, 19
8675
Table 4. Cont.
Empirical Formula
20 22 4 6
C H N O
3
V, Å
1968.3(14)
Z
4
−
3
Dcalcd, g·cm
1.3985
−
1
Absorption coeff., µ, mm
Diffractometer/scan
Radiation
0.1051
Enraf–Nonius CAD–4, θ/2 θ
MoKα
λ, Å
0.71073
F(000)
872
Range (°) for data
Index ranges
2.0 < θ > 25.0
−11 < h > 11, 0 < k > 10, 0 < l > 14
No. of reflects. measd
No. of unique reflects
Correction applied
Refinement method
No. of variables
1828
1266
Lorentz–polarization
Full–matrix least–squares
359
Goodness–of–fit (1828)
R1 (I) > 2 σ (I), (1266)
R1 (1828)
1.024
0.0414
0.0728
−
3
(
∆ρ) max, min, eÅ
0.119, −0.129
4
. Conclusions
The regioisomeric cycloadducts of the bromonitrile oxide to the N-benzoyl-2,3-oxazanorborn-5-ene
were easily prepared and elaborated into a novel class of uracil-based scaffolds. The key synthetic
2
step is represented by the nucleophilic substitution at the sp carbon atom of the bromoisoxazoline
three-dimensional heterocycles. The protocol to perform the nucleophilic substitution of uracil anions
was revised, and optimized as well as adapted to the steric requirements of the substrates.
Regarding the uracil derivatives of type 5, 6 and 7 the synthetic elaboration will continue with
standard hydrolysis for the detachment of the benzoyl group and hydrogenolysis of the resulting N-O
bond to give the desired aminols. These latter represent a novel class of nucleoside analogues [21] to be
tested against a variety of viruses or used as synthons for the preparation of β-turn inducers containing
nucleobases for their insertion in PNAs [12,30,31].
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/6/8661/s1.
Acknowledgments
Financial support by the University of Pavia, MIUR (PRIN 2011, CUP: F11J12000210001)
is gratefully acknowledged. Thanks are also due to the Consorzio Interuniversitario Nazionale
Metodologie e Processi Innovativi di Sintesi (CINMPIS) for research support. We also thank the
Fondazione Banca del Monte di Lombardia (Progetto Professionalità I. Becchi 2013) for a grant to

Molecules 2014, 19
8676
MGM. COST Action CM1004 “Synthetic Probes for Chemical Proteomics and Elucidation of
Biosynthetic Pathways” is gratefully acknowledged.
Author Contributions
The listed authors contributed to this work as described in the following. Misal G. Memeo gave the
concepts of work and interpreted the results. Francesco Lapolla carried out of the synthetic work and
interpreted the results. Bruna Bovio performed the X-Ray analyses and cooperated in the preparation
of the manuscript. Paolo Quadrelli prepared the manuscript and contributed with valuable discussions
as well as scientific input and funding of Spectra for Substances. All authors read and approved the
final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
References
1
.
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molecular modeling of novel dihydroxycyclopentane-carbonitrile nor-nucleosides by bromonitrile
oxide 1,3-dipolar cycloaddition. Tetrahedron 2012, 68, 1845–1852.
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.
Quadrelli, P.; Bovio, B.; Piccinini, A.; Caramella, P.; de Sarlo, F.; Machetti, F. Conversion of a
nitrosocarbonyl hetero Diels-Alder cycloadduct to useful isoxazoline-carbocyclic aminols.
Tetrahedron 2009, 65, 10679–10686.
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.
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