Isoxazoline-carbocyclic aminols for nucleoside synthesis through aza-Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2006.05.029

A novel approach to useful aminols for the synthesis of carbocyclic nucleosides is reported starting from a convenient source, the 2-azanorborn-5-enes. These are readily available through the Grieco cycloaddition of cyclopentadiene with iminium salts and

Full text of DOI:10.1016/j.tet.2006.05.029

Tetrahedron 62 (2006) 7370–7379
Isoxazoline-carbocyclic aminols for nucleoside synthesis
through aza-Diels–Alder reactions
a
a
b
Paolo Quadrelli,a, Andrea Piccanello, Naiara Vazquez Martinez, Bruna Bovio,
*
Mariella Mellaa and Pierluigi Caramellaa
a
`
Dipartimento di Chimica Organica, Universita degli Studi di Pavia, Viale Taramelli 10, 27100—Pavia, Italy
b
`
Dipartimento di Chimica Generale, Universita degli Studi di Pavia, Viale Taramelli 12, 27100—Pavia, Italy
Received 10 March 2006; revised 26 April 2006; accepted 11 May 2006
Available online 12 June 2006
Abstract—A novel approach to useful aminols for the synthesis of carbocyclic nucleosides is reported starting from a convenient source, the
2-azanorborn-5-enes. These are readily available through the Grieco cycloaddition of cyclopentadiene with iminium salts and are reactive
dipolarophiles toward nitrile oxides. The prolific elaboration of the isoxazoline cycloadducts allowed preparation of the target aminols
through the unmasking of the hydroxymethylene group at the C3 level of the azanorbornene structure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
cleavage of the N–O bond into the stereodefined anti ami-
nols 4.7 Starting from these, by the linear construction of
the heterobases, we have detailed the first synthesis of a class
of racemic purine- and pyrimidine-carbocyclic nucleosides
5 containing a fused isoxazolinic ring and lacking a methyl-
ene group in the side chain in the carbocyclic unit.4
The preparation of carbocyclic and heterocyclic nucleoside
analogues has been extensively pursued due to the impor-
tance in the development of new anti-viral drugs.1 Most of
the nucleoside analogues refer to a general structure defined
by the presence of a five-membered ring (furanose ring in
natural compounds) of a carbocyclic or heterocyclic nature,
which holds a hydroxymethylene group cis-related to the
heterobase needed for enzyme or nucleic acid recognition.2
Great interest has also risen in the so-called nor-derivatives
where the hydroxymethylene substituent is replaced by an
OH function.3
[R-CONO]
HDA
1,3-Dipolar
Cycloaddition
COR
N
O
Cycloaddition
1
2
N
HO
NH2
HO
c
b
N-O Bond
a
COR
Cleavage
N
a
c
a
c
b
b
In this context, we have recently developed a synthesis of the
isoxazoline-carbocyclic nucleosides 5 by the linear con-
struction of the desired purine and pyrimidine bases on the
regioisomeric aminols 4 (Scheme 1) obtained through elab-
oration of the hetero-Diels–Alder (HDA) cycloadducts 2 of
cyclopentadiene 1 with the nitrosocarbonyl intermediates
(RCONO).4 These fleeting intermediates are generated
traditionally by periodate oxidation of hydroxamic acids5
or by oxidation of nitrile oxides with N-methylmorpholine
N-oxide (NMO),6 and are promptly trapped with dienes to
afford HDA cycloadducts in high yields. The HDA cyclo-
pentadiene cycloadducts 2 have proved to be highly reactive
dipolarophiles toward nitrile oxides, affording the 1,3-di-
polar cycloadducts of type 3, which are converted quantita-
tively by detachment of the acyl moiety and reductive
O
3
4
5
Scheme 1.
For direct access to the nucleoside analogues carrying the
hydroxymethylene moiety on the carbocyclic unit, in order
to compare the role of the elongation of the side chain on
the biological activity of isoxazoline-nucleosides, the 2-aza-
bicyclo[2.2.1]hept-5-en-3-one 6 looked promising for this
purpose (Fig. 1). This lactam 6 has found wide applications
in carbocyclic nucleoside synthesis2,8 because of the easy
access to the required aminols by easy cleavage of the lactam
moiety. The preparation of the starting azaheptenone 6 is
however affected by some problems; it can be prepared
through cycloaddition of cyclopentadiene to tosyl cyanide
or methanesulfonyl cyanide, whose preparations require
a potentially hazardous starting material (cyanogen chlo-
ride).9 Although available from various chemical suppliers,
* Corresponding author. Tel.: +39 0382 987315; fax: +39 0382 987323;
e-mail: paolo.quadrelli@unipv.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.029

P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
7371
formaldehyde in an ADA reaction according to the well-
known procedure.12 The 1,3-dipolar cycloaddition of benzo-
nitrile oxide (BNO) with 8 was performed with the in situ
procedure,13 by adding the benzhydroximoyl chloride 9 to
a dichloromethane (DCM) solution of a slight excess of
N-benzyl-2-azanorborn-5-ene 8 (1.2 equiv) and a slight
excess of Et3N (1.1 equiv) (Scheme 2).
R
H
N
N
6
7
O
Figure 1.
the cost of the racemic compound is too high for large-scale
synthesis, and even more is that of the enantiomerically pure
forms.10
After stirring at room temperature for 48 h, the two regioiso-
meric isoxazoline cycloadducts 10a and 10b were isolated in
49% and 43% yields, respectively.
Structurally similar to lactam 6 are Grieco’s 2-azanor-
bornenes 7 that are derived from the cycloaddition of cyclo-
pentadiene with iminium salts generated in situ under
Mannich-like conditions, in a mild and convenient aqueous
aza-Diels–Alder (ADA) reaction.11 Despite their easy avail-
ability, no attempts have been made for their use in nucleo-
sidic syntheses. To this purpose the aza-methylene bridge
has to be modified, precisely the carbon C3 must be oxidized
by appropriate unmasking procedures. Here we report the
synthetic approach to novel isoxazoline-carbocyclic aminols
bearing an hydroxymethylene functionality starting from the
easy available 2-azanorbornenes of type 7.
The structures rely upon their analytical and spectroscopic
data. The 1H NMR spectrum of 10a showed the isoxazoline
protons as doublets (J¼8 Hz) at d 4.03 and 4.83, while in
regioisomer 10b the isoxazoline doublets (J¼8 Hz) were
found at d 3.74 and 4.94. The absence of appreciable
coupling between the isoxazoline and bridge-head protons
fully support the exo structures7a,14 and is in line with the
exo-selective addition to these dipolarophiles reported in
literature for the dihydroxylation reactions of 8.15 The regio-
chemistry is however not clearly indicated by the spectra and
an X-ray analysis of single crystal of 10b allowed us to
unequivocally attribute the correct regioisomeric structure.
Figure 2 reports the ORTEP view of 10b.
2. Results and discussion
We previously found that 2-oxa-3-azanorbornenes of type 2
add BNO exo-selectively, and were 1.7 times more reactive
than norbornene as a consequence of the higher relief of
strain.7,16 Similarly, we have performed a few competition
experiments with N-benzyl-2-azanorbornene 8 and norborn-
ene 11 in the cycloaddition with BNO. Table 1 gives the
product distributions for the reactions conducted in a few
representative solvents. These results show that the 2-aza-
norbornene 8 still remains a highly reactive dipolarophile
but less than norbornene 11. As an average, the reactivity
of the 2-azanorbornene 8 is half that of norbornene 11 in
apolar solvents (entries 1 and 2) and decreases to one third
in more polar (entry 8) or polarizable (entries 5 and 6) sol-
vents or in alcohols (entries 9 and 10). The lesser reactivity
of the 2-azanorbornene 8 with respect to norbornene 11
could be attributed to the reduced strain in 8. Replacement
of the eclipsed dimethylene bridge of norbornene with the
aminomethylene moiety causes a decrease in strain, in
keeping with the reduced torsional barriers of amines with
respect to alkanes.17 The further decrease in reactivity in
2.1. The N-benzyl-2-azanorborn-5-ene 8 as dipolaro-
phile
The N-benzyl-2-azanorborn-5-ene 8 was prepared by addi-
tion of freshly distilled cyclopentadiene to an aqueous
solution of benzylamine hydrochloride and 37% aqueous
Ph
O
N
N
O
Et3N
Ph
+
Ph
C
N
OH
+
DCM
N
N
N
10b
Cl
r.t., 48h
8
9
10a
CH2Ph
CH2Ph
CH2Ph
O
N
BNO
Ph
11
12
Scheme 2.
Figure 2. ORTEP plot of cycloadduct 10b with atom labeling (ellipsoid at 25% probability). Hydrogen atoms are omitted for clarity with exception of C1, C2,
C6, and C7.

7372
P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
Table 1. Competition experiments with N-benzyl-2-azanorbornene 8 and
norbornene 11 in the cycloaddition to BNO and regioisomeric distributiona,b
position of the N–O bond was inferred by significative shifts
of various signals due to the deshielding effect produced by
the N-oxide group. In particular, the C3-Hexo, cis-related to
the oxygen, is deshielded and occurs at d 3.79 (dd, J¼12,
5 Hz) in 13a and at d 3.75 (dd, J¼12, 4 Hz) in 13b, a typical
behavior of N-oxides as reported in literature.20
No. Solvent
12 (%) 10a (%) 10b (%) 10a+10b/12 10a/10b
1
2
3
4
5
6
7
8
9
n-Hexane 66
Cyclohexane 65
19
17
14
13
13
11
11
10
13
13
13
12
12
11
10
10
9
8
8
8
0.48
0.45
0.38
0.33
0.31
0.28
0.26
0.24
0.28
0.28
59/41
59/41
54/46
54/46
57/43
52/48
55/45
56/44
62/38
62/38
THF
68
73
74
76
78
76
76
75
Acetone
C6H6
DCM
The Polonovski rearrangement of the N-oxides 13a and 13b
was performed by dissolving the oxidized compounds in
Ac2O and leaving to react at room temperature for 48 h.
The excess of Ac2O was then decomposed with water over-
night and, after adjustment of pH to 8, the water solutions
were extracted with DCM. From the dried organic phase
the N-acetyl derivatives 14a and 14b were isolated upon
evaporation of the solvent as solid compounds in 94% and
85% yields, respectively. The structures rely upon the
collected analytical and spectroscopic data. Besides little
differences in the chemical shifts relative to the isoxazoline
protons and those of the azanorbornene structure, the most
relevant changes referred to the presence of the acetyl groups
at d 2.04 and 2.16, respectively for 14a and 14b.
AcOEt
MeCN
MeOH
10 EtOH
a
BNO generated in situ in the presence of a mixture of dipolarophiles 8
and 11, 5 equiv each.
Quantitative data are the average of HPLC analyses performed in dupli-
cate from independent experiments.
b
polar or alcoholic solvents may be attributed to some com-
plexation or hydrogen-bonding involving the nitrogen lone
pair that increases the electron attracting power of the nitro-
gen and lowers the p orbital of the nearby C]C double
bond. A decrease in reactivity in the cycloadditions of the
mildly electrophilic nitrile oxides is then expected.13
Starting from the amides 14a and 14b we planned the oxida-
tive strategy shown schematically in Scheme 4 for unmask-
ing a hydroxymethylene group at the C3 of the amides.
The slight regiochemical preference of cycloadduct 10a over
10b compares well with previous results on the cycloaddi-
tions of BNO with 3-substituted cyclopentenes and can be
attributed to the polarization of the double bond caused by
the electronegative nitrogen allylic substitution.13 Solvents
affect slightly only the regiochemistry, which increases in
alcohols but unexpectedly decreases in polar and polarizable
solvents.
c
c
b
a
c
b
a
OH
3
3
N
N
14a,b
COCH3
COCH3
HO
b
3
NH2
a
2.2. Synthesis of stereoisomeric aminols
3
CHO
NH
COCH3
a
c
b
Before attempting the cleavage step we have transformed the
adducts into more convenient derivatives. Since the hydro-
genolytic detachment of the N-benzyl moiety performed
poorly, we found a convenient and high yielding alternative.
The first step was the oxidation of 10a and 10b, which were
converted into the corresponding N-oxides 13a and 13b by
treating with 1.2 equiv of mCPBA in DCM at room temper-
ature.18 Conversion of the N-oxides into the amides 14a and
14b was achieved through the mild Polonovski rearrange-
ment19 of the amine N-oxides promoted by Ac2O to afford
the N-acetyl derivatives (Scheme 3).
AM
Scheme 4.
After a few attempts at a direct conversion of the C3 into
a carbonyl function,21 we found a convenient procedure
for the oxidation of the regioisomeric N-acetyl derivatives
14a and 14b through NBS/AIBN bromination reaction
(Scheme 5). Bromination of the cycloadducts 14a and 14b
takes place easily in refluxing CCl4 for 1–2 h. After filtration
of succinimide and evaporation of the solvent, the residues
were submitted to column chromatography on silica gel elut-
ing with CHCl3. The chromatographic separations afforded
the expected exo-bromo derivatives 15a and 15b as the
The N-oxides 13a and 13b were isolated in quantitative
yields and fully characterized spectroscopically. The exo
O
O
O
N
N
N
Ph
Ph
Ph
Ac2O
mCPBA
O
N
N
N
14a
r.t., 48h
DCM, r.t.
10a
13a
CH2Ph
CH2Ph
Ac
Ph
Ph
Ph
N
N
N
O
O
O
Ac2O
mCPBA
O
CH2Ph
N
N
r.t., 48h
N
14b
DCM, r.t.
10b
13b
CH2Ph
Ac
Scheme 3.

P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
7373
HO
NHAc
HO
d
O
O
N
N
NH2
H
e
c
O
N
O
N
OEt
OEt
Ph
Ph
CHO
a
b
NHAc
Ph
16a
17a NHAc
Ph
Br
O
O
N
18a
N
19a
Ph
NHAc
Ph
NH2
c
N
N
O
O
N
N
14a
15a
CH(OEt)2
H
CHO
H
H
H
e
d
Ac
Ac
c
Ph
Ph
a. NBS, AIBN, CCl4, ∆
HO
HO
Ph
b. NaHCO3/EtOH, ∆, 10d
c. AcOH/H2O 3/7, r.t., 48h
d. NaBH4/MeOH, r.t., 24h
e. HCl 3M, MeOH, ∆, 18h
H
16a'
O
O
H
17a'
NHAc
N
18a'
N
19a'
Ph
NHAc
Ph
N
Ph
Ph
Ph
HO
HO
N
NHAc
e
NH2
N
N
H
d
O
a
O
c
b
O
Br
O
OEt
OEt
CHO
NHAc
N
N
O
O
NHAc
N
18b
N
19b
Ph
Ph
14b
15b
16b
17b
Ac
Ac
Scheme 5.
major constituents, both obtained in 47% yield. Their struc-
tures rely upon the 1H NMR spectra, which show the CH–Br
signals as singlets at d 5.37 and 5.45, respectively, for 15a
and 15b. The lack of coupling with the bridge-head protons
is consistent with the exo stereochemistry of bromine
atom.14
be converted into the aldehyde 17b. From the chromato-
graphic separation an oily fraction was isolated containing
presumably the acetal 16b and related hemiacetal structures.
The oil could not be purified but was directly hydrolyzed to
the aldehyde. The formation of a single aldehyde 17b in
this case is probably due to the severe steric hindrance for
substituents cis-located to the phenyl isoxazoline moiety,
which offsets the epimerization.
In the case of the bromination of 14a, chromatographic sep-
aration of the reaction mixtures also afforded more advanced
intermediates toward the final aminol targets. Two epimeric
diethoxy acetals 16a and 16a0 and the corresponding alde-
hydes 17a and 17a0 could be isolated, while in the case of
the bromination of 14b only the aldehyde 17b was character-
ized. The formation of the acetals and the aldehydes can be
attributed to the silica gel-promoted transformation of the
bromo derivatives 15 due to the presence of ethanol as stabi-
lizing agent in the chloroform used for the chromatographic
separation. From 14a in particular, two epimeric acetals 16a
(mp 140–142 ꢀC) and 16a0 (mp 110–112 ꢀC) were isolated
as white solids in fair yields (16% and 12%, respectively).
The structures rely upon careful spectroscopic analyses.
The ring opening of the azanorbornene skeleton was indi-
cated by the presence of a neat NH–Ac absorption in the
FTIR spectrum (in 16a, band at 3260 cmꢁ1; in 16a0, band
The last compounds eluted are the aldehydes 17. From 14a,
the two epimeric aldehydes 17a and 17a0 were isolated as an
oily mixture in comparable amounts in a combined yield of
1
18%. In the H NMR spectrum of the mixture two singlets
corresponding to the aldehyde groups were detected at
d 9.97 and 10.01, while the signal at d 6.25 corresponded
to the NH group, as the FTIR spectrum confirmed (NH
band at 3297 cmꢁ1 and the prominent aldehyde absorption).
Since chromatographic separation of the two aldehydes was
unsatisfactory, the mixture was submitted to the subsequent
reductive step. From 14b a single aldehyde 17b was obtained
as a crystalline compound (20% yield). It shows a neat NH
absorption at 3520 cmꢁ1 and the C]O band at 1716 cmꢁ1
in the FTIR spectrum. In the 1H NMR spectrum the aldehyde
signal occurs as a sharp singlet at d 9.79 while the NH is
a broad singlet at d 7.07.
1
at 3271 cmꢁ1) and in the H NMR spectra by the signals
of two different OEt groups attributable to diastereotopic
diethylacetal moieties. Moreover in these cleavage products,
the flexible cyclopentane moiety allows couplings between
the isoxazoline protons and the adjacent methines. In the
retained product 16a the H5-isoxazolinic proton occurs as
a double doublet at d 5.16 because of coupling with the
H4-isoxazolinic proton at d 4.09 (J¼10 Hz) and the adjacent
trans methine (Jtrans¼3 Hz) while in the epimeric product
16a0 the H5-isoxazolinic proton is a double doublet at
d 5.12 owing to the coupling with the H4-isoxazolinic proton
at d 4.23 (J¼9 Hz) and the adjacent cis methine (Jcis¼6 Hz).
The transformation of the bromides 15 into the acetals 16
and then into the aldehyde 17 could be optimized by adapt-
ing reported procedures. Thus refluxing the bromide 15a in
22
ethanol in the presence of an excess of NaHCO3 allowed
the complete conversion of 15a into a 1:1 mixture of the
two epimeric acetals 16a and 16a0, which were quantita-
tively hydrolyzed to the corresponding aldehydes 17a and
17a0 upon treatment with AcOH/H2O 3:7 at room tempera-
ture for 48 h.23 Noteworthy and in accordance with expected
enolization in acidic medium, from any single epimeric
acetal 16a or 16a0 the two epimeric aldehydes were obtained
in a nearly 1:1 ratio and, as before, not separated but submit-
ted to subsequent reduction. By applying the same procedure
to the bromide 15b a single aldehyde 17b was obtained.
NOESY experiments support the attributions showing diag-
nostic cross-peaks between the acetal proton and the H5-
isoxazoline one in isomer 16a. In the epimer 16a0 the
NOESY cross-peaks occur between the acetal proton and
one of the two different cyclopentane methylene protons
and between the other methylene protons with the amide
NH. By adapting the same procedure the bromide 15b could
The reduction of the aldehydes 17 to the desired primary
alcohols 18 was performed with NaBH4 in MeOH solution.
From the diastereomeric aldehydes 17a and 17a0, the

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P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
corresponding alcohols 18a and 18a0 were obtained in quan-
titative yields and could be easily separated by column chro-
matography as colorless solids. The structures rely upon
their analytical and spectroscopic data. Besides the signals
underwent 1,3-dipolar cycloaddition with BNO to afford
the regioisomeric cycloadducts 10a and 10b in good yields.
Replacement of the benzyl group was easily achieved
through N-oxidation and a successive Polonovski rearrange-
ment leading to the N-acetyl derivatives, which proved to be
convenient intermediates for the activation of the C3 posi-
tion of the azanorbornene structure. Upon treatment with
NBS and solvolysis24 of the bromo derivatives 15a and
15b, the aldehydes 17a and 17b were obtained. The straight-
forward reduction of the latters gave the target aminols.
1
attributable to the cyclopenta-isoxazoline skeleton, the H
NMR spectrum of the alcohols 18 showed the significant
presence of the OH and the diastereotopic protons of the
hydroxymethylene group as multiplets at d 3.73 and 3.84
in 18a and at d 3.71 and 3.86 in 18a0. The stereochemistry
relies upon the vicinal coupling of the H5-isoxazolinic pro-
tons and the methines. In the retained product 18a the
H5-isoxazolinic proton at d 5.13 (dd, J¼9.6, 4 Hz) is cou-
pled with the smaller Jtrans with the adjacent trans methine
while in the epimeric product 18a0 the H5-isoxazolinic
proton at d 5.20 (dd, J¼9, 5 Hz) is coupled with the larger
Jcis with the analogous type of proton.
In conclusion, we have proposed a novel approach to useful
aminols for the synthesis of carbocyclic nucleosides starting
from the readily available 2-azanorbornenes and unmasking
the hydroxymethylene group at the C3 level of the azanor-
bornene structure.
The NOESY experiment carried out on 18a confirmed the
stereochemistry due to the existence of cross-peaks correlat-
ing the hydroxymethylene protons with the H5-isoxazoline
proton at d 5.13 and the NH proton with the H4-isoxazoline
one at d 4.11. In the epimer 18a0 the NOESY experiment
confirmed the anti relationship between the alcoholic func-
tion and the acetamide group because of the sole presence
of a cross-peak correlating the H5-isoxazoline proton at
d 5.20 and the CH–CH2OH proton, while the CH2OH shows
no NOE cross-peaks. The spectra of the regioisomeric alco-
hol 18b show the hydroxymethylene protons at d 3.74 and
3.83; the H5-isoxazolinic proton at d 4.99 (dd, J¼9 Hz
with the H4-isoxazolinic proton at d 4.18) is trans coupled
with the CH–NHAc (J¼2 Hz) at d 4.39.
The aminols will be used for the linear construction of purine
and pyrimidine carbocyclic nucleosides whose activities as
anti-viral agents will be compared with those of the previ-
ously synthesized compounds.
4. Crystal structure analyses
The ORTEP view of compound 10b with the atomic num-
bering is shown in Figure 2. The crystal and collection
data as well as the structure refinements of the cycloadduct
are given in Table 3. Table 4 reports the bond lengths and
angles while Table 5 the torsion angles.
Table 3. Crystal data, collection data, and structure refinements of cyclo-
adduct 10b
Finally, the three regio- and stereoisomeric alcohols 18 were
definitively and quantitatively hydrolyzed to the correspond-
ing aminols 19 by boiling a methanolic solution with HCl
3 M overnight (Scheme 5). Table 2 summarizes the main
physical and spectroscopic data of the target compounds.
Very sharp bands were found in the FTIR spectra between
3250–3370 cmꢁ1 corresponding to the NH2 groups while
the OH bands are somewhat broad and at lower frequencies
because of strong intra- and inter-molecular hydrogen
bonds. In the 1H NMR spectra the hydroxymethylene groups
gave AB systems at the expected chemical shifts and the
isoxazoline protons were also in their typical range.
10b
Formula
CCD deposit no.
MW
C20H20N2O
291,467
304.38
0.52ꢂ0.42ꢂ0.28
Crystal size, mm
Temperature, K
Crystal system
Space group
293(2)
Monoclinic
P21/n
12.622(2)
9.687(1)
13.348(1)
˚
a, A
˚
b, A
˚
c, A
b
V, A
96.01(1)
1623.1(3)
3
˚
Z
4
1.246
0.774
Mo Ka
Dcalcd, g/cm3
Abs coeff., m, cmꢁ1
Radiation
Table 2. Physical and spectroscopic data of the aminols 19
Entry 19 Mp ꢀCa
FTIR (cmꢁ1
)
1H NMR (d)
l
F(000)
0.071073
648
nOH nNH
CH2OH
H4- H5-
isoxaz. isoxaz.
2
Range (ꢀ) for data coll.
Index range
2.1ꢃqꢃ30.0
1
2
3
a
116–118 3176 3334, 3266 3.70
a0 154–156 3158 3330, 3257 3.67, 3.87 4.03
130–131 3176 3370, 3291 3.70 4.26
4.02
5.21
5.28
4.79
ꢁ17<h<17, 0<k<13, 0<l<18
4723
4656
Reflection no.
Unique refl.
b
Correction applied
Absorption correction
Absorption factors T
No. of obsd refl. I>2s(I)
Refinement method
Variables no.
Weights
Lorentz polarization
Semi-empirical from psi-scan
0.998, 0.973
a
White solids from benzene/ethanol.
1610
Full-matrix least-squares on F2
288
3. Conclusions
0.0474, 0.003
0.923 (No refl. 4656)
0.064 (No refl. 1610)
0.143 (No refl. 4656)
0.220, ꢁ0.110
In the search of a new and convenient synthetic route to isox-
azoline-carbocyclic aminols with a primary hydroxy group
useful for nucleoside preparations, we took advantage of
the easily available N-benzyl-2-azanorbornene, which
Goodness-of-fit
R1
wR2
ꢁ3
˚
(Dr) max, min, eA

P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
7375
ꢀ
˚
Table 4. Bond lengths (A) and angles ( ) with Esd’s in parentheses of cyclo-
adducts 10b
implying only a small conjugation between the double
bond N4–C5 and the phenyl. The orientation is expressed
by torsion angles given in Table 5. The deviations of atoms
from the least-squares plane of the isoxazoline rings are in
10b
Bond lengths
˚
˚
the range from ꢁ0.005(2) A to 0.006(2) A consistent with
C1–C2
C1–N9
C1–C10
C2–O3
C2–C6
O3–N4
N4–C5
C5–C6
C5–C11
C6–C7
C7–C8
C7–C10
C8–N9
N9–C17
1.521(3)
1.481(3)
1.526(4)
1.454(3)
1.534(4)
1.420(3)
1.278(3)
1.496(3)
1.464(3)
1.542(3)
1.524(4)
1.522(4)
1.493(4)
1.430(4)
conformation
E
puckering parameters:26 Q¼0.010,
f¼144.8ꢀ (ideal value 144ꢀ). The interplanar angle between
the isoxazoline and the moiety C1–C2–C6–C7 is 117.98(9)ꢀ.
The six-membered ring of the azanorbornane is puckered
with deviations by least-squares plane in the range
˚
˚
ꢁ0.614(2) A to 0.342(3) A. These rings adopt boat confor-
mation with parameters: Q¼0.979, f¼62.4ꢀ, and q¼88.5ꢀ
(ideal conformation f¼60ꢀ and q¼90ꢀ). The four chiral
atoms C1, C2, C6, and C7 have the following configuration
specified by the sequence rule:27 S, S, R, R or R, R, S, S
because of the centric space group. The molecular packing
in the crystal is determined by van der Waal’s contacts.
Bond angles
C2–C1–N9
C2–C1–C10
N9–C1–C10
C1–C2–O3
C1–C2–C6
O3–C2–C6
C2–O3–N4
O3–N4–C5
N4–C5–C6
N4–C5–C11
C6–C5–C11
C2–C6–C5
C2–C6–C7
C5–C6–C7
C6–C7–C8
C6–C7–C10
C8–C7–C10
C7–C8–N9
C1–N9–C8
C1–N9–C17
C8–N9–C17
C1–C10–C7
103.9(2)
102.8(2)
104.6(2)
112.5(2)
102.7(2)
105.2(2)
109.5(2)
109.6(2)
114.5(2)
120.0(2)
125.5(2)
101.2(2)
102.9(2)
114.4(2)
107.1(2)
101.9(2)
100.8(2)
103.4(2)
104.0(2)
116.1(2)
111.7(1)
93.0(2)
5. Experimental
All melting points are uncorrected. Elemental analyses were
done on a C. Erba 1106 elemental analyzer. IR spectra
(Nujol mulls) were recorded on an FTIR Perkin–Elmer
1
RX-1. H and 13C NMR spectra and NOESY experiments
were recorded on a Bruker AVANCE 300 in the specified
deuterated solvents. Chemical shifts are expressed in parts
per million from internal tetramethylsilane (d). UV–vis
spectra were recorded on an UV Perkin–Elmer LAMBDA
16 spectrophotometer using acetonitrile as solvent. HPLC
analyses were carried out by means of a WATERS 1525 in-
strument equipped with an UV 2487 detector (l¼263 nm)
both controlled by BreezeÔ software and a RP C-18 Intersil
ODS-2 column; a mixture of H2O/CH3CN 60:40 (1.0 mL/
min) was used as an eluant. Column chromatography and
TLC: silica gel 60 (0.063–0.200 mm) (Merck), eluants as
specified. The identification of samples from different exper-
iments was secured by mixed mps and superimposable IR
spectra.
In the azanorbornane ring the sum of the angles at N9
[331.8(2)ꢀ] is consistent with sp3 hybridization. The heights
of the pyramids with the nitrogen atom at the apex and the
˚
three atoms connected to it at the base is 0.459(2) A. In
the isoxazoline rings the angle at N4 of 10b is consistent
with sp2 hybridization of N4 whereby the 2pz lone pair takes
part in p-bonding within a part of the heterocyclic rings.
Indeed the bond distances N4–C5 show a double bond char-
Materials. Benzhydroximoyl chloride 9 was prepared
according to the well-known procedures.28
5.1. Cycloaddition of BNO with N-benzyl-2-
azanorbornene
˚
acter: 1.278(3) A. The internal angles at the nitrogen atoms,
O3–N4–C5 109.6(2)ꢀ, C1–N9–C8 104.0(2)ꢀ differ by 5.6ꢀ,
justified by the different types of nitrogen; the narrower
angle C1–N9–C8 is caused by the lone pair.
To N-benzyl-2-azanorbornene 8 (61.0 g, 327 mmol) dis-
solved in DCM (130 mL), Et3N (42 mL, 300 mmol) was
added and a solution of benzhydroximoyl chloride 9
(42.4 g, 273 mmol) in 150 mL of DCM was added dropwise
under stirring at 0 ꢀC. The reaction was continued for 48 h.
The organic solution was washed with water and dried over
anhydrous Na2SO4. The crude residue was then submitted to
column chromatography to separate the cycloadducts 10a
and 10b, which were isolated in 49% and 43% yields,
respectively.
Bond lengths and angles in the condensed phenyl rings are
reasonable, on weighted average,25 1.374(3) A and
˚
119.9(4)ꢀ. The phenyl ring attached to isoxazoline is nearly
˚
planar with maximum deviation 0.008(3) A; this ring is
tilted with respect to the isoxazoline moiety by 26.2(1)ꢀ,
Table 5. Torsion angles (ꢀ) in compound 10b with Esd’s in parentheses
10b
10a (33.8 g, 49%): As straw colored crystals from ethanol,
mp 116–118 ꢀC; [Found C, 78.9; H, 6.6; N, 9.1.
C20H20N2O (MW¼304.38) requires C, 78.92; H, 6.62; N,
9.20%]; nmax (Nujol) 1590 cmꢁ1; dH (300 MHz, CDCl3)
7.25–7.56 (10H, m, Ph), 4.83 (1H, dt, J 8, 1 Hz, H5-isoxaz.),
N4–C5–C11–C12
N4–C5–C11–C16
C6–C5–C11–C12
C6–C5–C11–C16
24.8(3)
ꢁ154.0(2)
ꢁ153.9(2)
27.3(3)

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P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
4.03 (1H, d, J 8 Hz, H4-isoxaz.), 3.79 (2H, AB syst., J 13 Hz,
CH2–Ph), 3.51 (1H, s, CH–N), 2.94 (1H, dd, J 10, 4 Hz, H3-
exo), 2.78 (1H, br s, CH), 2.12 (1H, d, J 10 Hz, H3-endo),
1.64 (2H, m, CH2); dC (75 MHz, CDCl3) 156.4, 138.8,
129.7, 128.8, 128.6, 128.5, 128.4, 127.1, 126.6, 86.2, 61.8,
58.0, 53.3, 52.3, 44.4, 30.4.
13b: White solid from ethanol, mp 144–146 ꢀC; [Found C,
74.8; H, 6.2; N, 8.6. C20H20N2O2 (MW¼320.38) requires
C, 74.97; H, 6.29; N, 8.74%]; nmax (Nujol) 1654 cmꢁ1; dH
(300 MHz, CDCl3) 7.62 (4H, m, Ph), 7.35 (6H, m, Ph),
5.83 (1H, d, J 8 Hz, H5-isoxaz.), 4.64 (1H, d, J 12 Hz,
CH2–Ph), 4.37 (1H, d, J 12 Hz, CH2–Ph), 4.12 (1H, d,
J 8 Hz, H4-isoxaz.), 3.86 (1H, s, CH–N), 3.75 (1H, dd,
J 12, 4 Hz, H3-exo), 3.30 (1H, d, J 12 Hz, H3-endo), 2.80
(1H, d, J 14 Hz, CH), 2.78 (1H, d, J 12 Hz, CH2), 1.69
(1H, d, J 12 Hz, CH2); dC (75 MHz, CDCl3) 156.8, 132.0,
130.6, 130.4, 129.4, 128.9, 128.4, 127.7, 126.8, 81.8, 76.0,
73.0, 67.8, 54.4, 40.3, 31.4.
10b (29.7 g, 43%): As straw colored crystals from ethanol,
mp 119–121 ꢀC; [Found C, 78.9; H, 6.7; N, 9.2.
C20H20N2O (MW¼304.38) requires C, 78.92; H, 6.62; N,
9.20%]; nmax (Nujol) 1592 cmꢁ1; dH (300 MHz, CDCl3)
7.74 (4H, m, Ph), 7.25–7.56 (6H, m, Ph), 4.94 (1H, dt, J 8,
1.4 Hz, H5-isoxaz.), 3.78 (2H, s, CH2–Ph), 3.74 (1H, d,
J 8 Hz, H4-isoxaz.), 3.50 (1H, s, CH–N), 2.69 (1H, br s,
CH); 2.63 (2H, m, H3); 1.58 (2H, m, CH2); dC (75 MHz,
CDCl3) 156.7, 139.2, 129.8, 128.9, 128.7, 128.3, 127.0,
126.7, 85.8, 64.4, 59.5, 57.3, 55.7, 40.6, 28.8.
5.4. Polonovski rearrangement
N-Oxides 13a and 13b were dissolved in pure Ac2O
(2.5 equiv) by controlling the temperature with an ice-
bath. Stirring was continued at room temperature for 48 h.
After this period of time, excess Ac2O was decomposed by
addition of water (leaving the mixtures overnight). To the
solutions NaHCO3 was added up to pH¼8 and the solutions
extracted with DCM. The organic phases were dried over
anhydrous Na2SO4 and evaporation of the solvent afforded
the crude N-acetyl derivatives 14a and 14b in nearly quanti-
tative yields.
5.2. Competition experiments between norbornenes 8
and 11, and regioisomeric distribution of cycloadducts
10a and 10b
For the competition experiments, benzhydroximoyl chloride
9 (15 mg, 9.6 mmol) was added to a solution of N-benzyl-2-
azanorbornene 8 and norbornene 11 in equimolecular
amounts in 25 mL of the desired solvent along with
1.1 equiv of Et3N. The mixtures were allowed to react at
room temperature for 48 h. The solvents were evaporated
and the crude residue was taken up in 25 mL of acetonitrile
to be submitted to HPLC analyses.
14a (94%): As straw colored crystals from benzene/
n-hexane/drops of ethanol, mp 154–156 ꢀC; [Found C,
70.3; H, 6.3; N, 10.9. C15H16N2O2 (MW¼256.29) requires
C, 70.29; H, 6.29; N, 10.93%]; nmax (Nujol) 1630 cmꢁ1
;
dH (300 MHz, CDCl3) 7.85 (2H, m, Ph), 7.45 (3H, m, Ph),
4.91 (1H, m, H5-isoxaz.), 4.89 (1H, m, CH–N), 3.98 (1H,
m, H4-isoxaz.), 3.47 (1H, dd, J 10, 4 Hz, H3-endo), 3.07
(1H, dd, J 10, 2 Hz, H3-exo), 3.04 (1H, s, CH), 2.04 (3H,
s, CH3), 1.76 (2H, m, CH2); dC (75 MHz, CDCl3) 168.9,
155.3, 130.2, 129.1, 128.9, 126.8, 85.5, 57.8, 56.4, 47.6,
44.4, 30.7, 21.7.
For the determination of the regioisomeric distribution, the
same quantities and procedure were followed in the absence
of norbornene 11.
The results are reported in Table 2.
5.3. Oxidation of the cycloadducts 10a and 10b with
mCPBA
14b (92%): As straw colored crystals from benzene/
n-hexane/drops of ethanol, mp 180–182 ꢀC; [Found C,
70.2; H, 6.3; N, 11.0. C15H16N2O2 (MW¼256.29) requires
To DCM solutions of cycloadducts 10a and 10b, a slight
excess (1.1 equiv) of mCPBA was added portionwise under
stirring, cooling with a water bath the solutions if the temper-
ature rises. The reactions were continued until the starting
cycloadducts are consumed (TLC monitoring). Once the
reactions were over, the solutions were neutralized with
K2CO3 and were washed with water with final drying over
anhydrous Na2SO4. Upon evaporation of the solvent, the
crude N-oxides 13a and 13b were obtained in quantitative
yields.
C, 70.29; H, 6.29; N, 10.93%]; nmax (Nujol) 1622 cmꢁ1
;
dH (300 MHz, CDCl3) 7.73 (2H, m, Ph), 7.44 (3H, m, Ph),
4.83 (1H, d, J 8 Hz, H5-isoxaz.), 4.34 (1H, s, CH–N), 3.80
(1H, d, J 8 Hz, H4-isoxaz.), 3.27 and 3.40 (2H, AB syst.,
H3), 2.88 (1H, s, CH), 2.16 (3H, s, CH3), 1.74 (2H, m,
CH2); dC (75 MHz, CDCl3) 168.1, 156.2, 129.9, 129.7,
128.5, 126.4, 84.6, 61.2, 55.6, 49.6, 39.1, 31.8, 21.7.
5.5. Reactions with NBS/AIBN
13a: White solid from ethanol, mp 122–124 ꢀC; [Found C,
74.8; H, 6.1; N, 8.7. C20H20N2O2 (MW¼320.38) requires
C, 74.97; H, 6.29; N, 8.74%]; nmax (Nujol) 1654 cmꢁ1; dH
(300 MHz, CDCl3) 7.98 (2H, m, Ph), 7.00–7.60 (8H, m,
Ph), 5.05 (1H, d, J 13 Hz, H5-isoxaz.), 4.97 (1H, d,
J 8 Hz, CH2–Ph), 4.45 (1H, d, J 13 Hz, H4-isoxaz.), 4.23
(1H, d, J 8 Hz, CH2–Ph), 3.94 (1H, s, CH–N), 3.79 (1H,
dd, J 12, 5 Hz, H3-exo), 3.56 (1H, dd, J 12, 1 Hz, H3-
endo), 3.11 (1H, d, J 4 Hz, CH), 2.98 (1H, d, J 12 Hz,
CH2), 1.84 (1H, d, J 12 Hz, CH2); dC (75 MHz, CDCl3)
153.7, 131.2, 130.8, 130.4, 129.6, 128.9, 128.7, 127.1,
126.4, 84.5, 76.2, 74.8, 69.4, 52.9, 43.1, 29.9.
N-Acetyl derivatives 14a and 14b were dissolved in CCl4
(40 mL/g), using carefully CCl4 washed glassware. To the
suspensions 1 equiv NBS was added at room temperature
along with 10% mol of AIBN. The mixtures were refluxed
and the reaction status was monitored by TLC until the start-
ing materials have disappeared. To ensure this, an additional
half equivalent of NBS could be added. As the conversion of
14a and 14b was completed, the solutions were cooled down
to ambient and then to lower temperature with an ice-bath to
ensure the maximum separation of succinimide. From the
filtrate, solvent was removed upon evaporation and the crude
residues were submitted to chromatographic separation on

P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
7377
silica gel by eluting initially with CHCl3 and CHCl3/MeOH
9:1 afterwards. The bromo-cycloadducts 15a and 15b, the
acetals 16a and 16a0, and the aldehydes 17a, 17a0, and 17b
were collected and characterized.
84.9 [84.5], 77.1 [77.3], 60.4 [62.0], 57.8 [60.2], 54.8
[55.7], 28.6 [30.0], 22.8 [23.3].
17b (20%): White solid from benzene/n-hexane, mp 162–
164 ꢀC; [Found C, 66.1; H, 5.9; N, 10.2. C15H16N2O3
(MW¼272.29) requires C, 66.16; H, 5.92; N, 10.29%];
nmax (Nujol) 3320, 1716 cmꢁ1; dH (300 MHz, CD3COCD3)
9.79 (1H, s, CHO), 7.69 (2H, m, Ph), 7.45 (3H, m, Ph),
7.07 (1H, br s, NH), 5.09 (1H, dd, J 9, 3 Hz, H5-isoxaz.),
4.73 (1H, dd, J 9, 3 Hz, H4-isoxaz.), 4.24 (1H, m, CH–N),
3.07 (1H, m, CH), 2.29 (2H, m, CH2), 1.85 (3H, s CH3);
dC (75 MHz, CD3COCD3) 202.5, 170.6, 159.3, 131.2,
130.1, 129.5, 128.1, 91.7, 58.8, 56.8, 51.7, 32.0, 23.3.
15a (47%): White solid from benzene/n-hexane, mp 212–
215 ꢀC; [Found C, 53.7; H, 4.5; N, 8.3. C15H15N2O2Br
(MW¼335.20) requires C, 53.75; H, 4.51; N, 8.36%]; nmax
(Nujol) 1706, 1653 cmꢁ1; dH (300 MHz, CDCl3) 7.72 (2H,
m, Ph), 7.47 (3H, m, Ph), 5.37 (1H, s, CH–Br), 5.08 (1H,
d, J 8 Hz, H5-isoxaz.), 4.54 (1H, s, CH–N), 3.97 (1H, d,
J 8 Hz, H4-isoxaz.), 2.97 (1H, s, CH), 2.63 (1H, m, CH2),
2.24 (3H, s, CH3), 1.77 (1H, m, CH2); dC (75 MHz,
CDCl3) 168.5, 154.4, 130.5, 129.1, 128.1, 126.3, 84.5,
64.6, 60.3, 59.5, 49.8, 28.2, 22.2.
5.6. Conversion of the bromo-cycloadducts 15a and 15b
into the aldehydes 17a and 17b
15b (47%): White solid from benzene/n-hexane, mp 195–
200 ꢀC; [Found C, 53.8; H, 4.4; N, 8.4. C15H15N2O2Br
(MW¼335.20) requires C, 53.75; H, 4.51; N, 8.36%]; nmax
(Nujol) 1700, 1661 cmꢁ1; dH (300 MHz, CDCl3) 7.74 (2H,
m, Ph), 7.45 (3H, m, Ph), 5.45 (1H, s, CH–Br), 4.88 (1H,
d, J 8 Hz, H5-isoxaz.), 4.51 (1H, s, CH–N), 3.97 (1H, d,
J 8 Hz, H4-isoxaz.), 2.84 (1H, s, CH), 2.50 (1H, d,
J 11 Hz, CH2), 2.18 (3H, s, CH3), 1.73 (1H, d, J 11 Hz,
CH2); dC (75 MHz, CDCl3) 169.1, 155.8, 130.4, 129.0,
127.7, 126.8, 85.1, 68.0, 62.0, 54.6, 45.7, 29.7, 22.0.
To a solution in absolute EtOH of the bromo-cycloadducts
15a and 15b, an excess of NaHCO3 was added and the mix-
tures were refluxed for several days, monitoring the evolu-
tion of the reactions by TLC until complete consumption
of the starting materials. After filtration of the solid, the sol-
vent was evaporated. The residues constituted a mixture of
the acetals 16 and/or the aldehydes 17a and 17b. Complete
transformation of the acetals into the aldehydes was secured
by hydrolysis with AcOH/H2O 3:7 at room temperature for
48 h. At the end of the reaction, the solution volumes were
doubled with water and the pH adjusted at 7.5 with NaOH
20%. The water phases were extracted with DCM three
times. The organic phases were dried over anhydrous
Na2SO4 and evaporation of the solvent afforded the crude
aldehydes 17. From 15a, the aldehydes 17a and 17a0 were
obtained as an epimeric mixture, not separated but submitted
to the reduction step, while from 15b the aldehyde 17b was
isolated and found identical to previously prepared sample.
16a (16%): White solid from benzene/n-hexane, mp 140–
142 ꢀC; [Found C, 65.8; H, 7.5; N, 8.1. C19H26N2O4
(MW¼346.41) requires C, 65.87; H, 7.57; N, 8.09%]; nmax
(Nujol) 3260, 1651 cmꢁ1; dH (300 MHz, CD3COCD3)
7.87 (2H, m, Ph), 7.44 (1H, br s, NH), 7.42 (3H, m, Ph),
5.16 (1H, dd, J 10, 3 Hz, H5-isoxaz.), 4.68 (1H, d, J 5 Hz,
O–CH–O), 4.44 (1H, m, CH–N), 4.09 (1H, dd, J 10, 3 Hz,
H4-isoxaz.), 3.64 and 3.77 (4H, m, CH2O), 2.57 (1H, m,
CH), 2.05 (1H, m, CH2), 1.91 (3H, s, CH3), 1.74 (1H, m,
CH2), 1.24 (6H, t, CH3); dC (75 MHz, CD3COCD3) 169.4,
158.5, 130.9, 130.6, 129.8, 128.4, 104.5, 89.2, 64.0, 63.5,
60.5, 55.7, 52.2, 33.9, 23.6, 16.1.
5.7. Reduction of the aldehydes 17a and 17b
To a solution in MeOH of the aldehydes 17a and 17b,
2 equiv of NaBH4 were added under stirring at room temper-
ature. The reactions were carried on until complete con-
sumption of the starting materials, monitoring by TLC.
The reactions were subsequently quenched with water and
saturated with salt. The water phases were extracted with
DCM three times. The organic phases were dried over anhy-
drous Na2SO4 and evaporation of the solvent afforded the
crude alcohols 18a and 18b in quantitative yields. Purifica-
tion of the products was secured by column chromato-
graphy: from isomer 18a the two stereoisomers 18a and
18a0 were easily separated on silica gel by eluting with
CHCl3 initially and CHCl3/MeOH 9:1 afterwards.
16a0 (12%): White solid from benzene/n-hexane, mp 110–
112 ꢀC; [Found C, 65.9; H, 7.6; N, 8.0. C19H26N2O4
(MW¼346.41) requires C, 65.87; H, 7.57; N, 8.09%]; nmax
(Nujol) 3271, 1645 cmꢁ1; dH (300 MHz, CD3COCD3)
8.12 (2H, m, Ph), 7.50 (1H, br s, NH), 7.43 (3H, m, Ph),
5.12 (1H, dd, J 9, 6 Hz, H5-isoxaz.), 4.67 (1H, d, J 8.5 Hz,
O–CH–O), 4.29 (1H, t, J 6 Hz, CH–N), 4.23 (1H, d,
J 9 Hz, H4-isoxaz.), 3.61 (4H, m, CH2O), 2.83 (1H, m,
CH), 1.94 (3H, s, CH3), 1.76 (1H, m, CH2), 1.60 (1H, m,
CH2), 1.18 (6H, t, CH3); dC (75 MHz, CD3COCD3) 170.6,
157.7, 130.9, 130.6, 129.8, 128.5, 104.5, 87.7, 63.6, 62.5,
60.8, 55.5, 50.4, 33.0, 23.3, 16.2.
18a (100%): White solid from acetone, mp 160–161 ꢀC;
[Found C, 65.6; H, 6.6; N, 10.2. C15H18N2O3 (MW¼
274.31) requires C, 65.67; H, 6.61; N, 10.21%]; nmax (Nujol)
3535, 3297, 1653 cmꢁ1; dH (300 MHz, CD3COCD3) 7.89
(2H, m, Ph), 7.70 (1H, b, NH), 7.43 (3H, m, Ph), 5.13 (1H,
dd, J 9.6, 4 Hz, H5-isoxaz.), 4.42 (1H, m, CH–N), 4.36
(1H, t, J 5 Hz, CH), 4.11 (1H, dd, J 9.6, 4 Hz, H4-isoxaz.),
3.73 and 3.84 (2H, m, CH2–O), 2.38 (1H, m, OH), 2.13
(1H, m, CH2), 1.89 (3H, s, CH3), 1.62 (1H, m, CH2); dC
(75 MHz, CD3COCD3) 170.5, 155.9, 134.9, 130.8, 129.8,
128.4, 90.5, 64.2, 60.8, 55.7, 50.8, 36.0, 23.6.
17a/a0 (18%): White solid from benzene/ethanol, mp 119–
122 ꢀC; [Found C, 66.3; H, 5.8; N, 10.3. C15H16N2O3
(MW¼272.29) requires C, 66.16; H, 5.92; N, 10.29%];
nmax (Nujol) 3297, 1717, 1653 cmꢁ1; dH (300 MHz,
CDCl3) 9.97 [10.01] (1H, s, CHO), 8.11 (2H, m, Ph), 7.46
(3H, m, Ph), 6.25 (1H, m, NH), 5.62 [5.65] (1H, d, J 8 Hz,
H5-isoxaz.), 5.51 [5.54] (1H, s, CH–N), 4.49 [4.54] (1H, s,
CH), 4.36 [4.42] (1H, d, J 8 Hz, H4-isoxaz.), 2.01 [2.06]
(3H, s, CH3), 1.89 [1.93] and 2.22 (2H, m, CH2); dC
(75 MHz, CDCl3) 170.4, 156.4, 130.3, 128.8, 127.7, 127.5,

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P. Quadrelli et al. / Tetrahedron 62 (2006) 7370–7379
18a0 (100%): White solid from acetone, mp 152–154 ꢀC;
[Found C, 65.6; H, 6.6; N, 10.1. C15H18N2O3 (MW¼
274.31) requires C, 65.67; H, 6.61; N, 10.21%]; nmax (Nujol)
3316, 1676 cmꢁ1; dH (300 MHz, CD3COCD3) 8.11 (2H, m,
Ph), 7.52 (1H, b, NH), 7.42 (3H, m, Ph), 5.20 (1H, dd, J 9,
5 Hz, H5-isoxaz.), 4.29 (2H, m, CH–N and CH), 4.27 (1H,
d, J 9 Hz, H4-isoxaz.), 3.71 and 3.86 (2H, m, OH and
CH2–O), 2.73 (1H, m, CH), 1.94 (3H, s, CH3), 1.47 (2H,
dd, J 13, 6 Hz, CH2); dC (75 MHz, CD3COCD3) 170.7,
157.7, 130.9, 130.6, 129.8, 128.5, 87.6, 62.0, 60.9, 55.7,
49.4, 33.7, 23.3.
(2H, b, NH2), 4.79 (1H, d, J 9 Hz, H5-isoxaz.), 4.26 (1H,
dd, J 9, 2 Hz, H4-isoxaz.), 4.13 (1H, d, J 6 Hz, CH–N),
3.70 (2H, AB syst., CH2–O), 2.48 (1H, m, CH), 2.11 (2H,
m, CH2) 1.51 (1H, d, J 13 Hz, CH2); dC (75 MHz,
CD3COCD3) 160.5, 130.9, 130.8, 130.0, 128.2, 95.0, 68.0,
66.2, 55.2, 49.1, 37.5.
5.9. X-ray crystallography
Unit-cell dimensions for compound 10b were obtained by
least-squares fit of 2q values for 25 reflections, using an
Enraf–Nonius CAD4 diffractometer with graphite-mono-
chromated Mo Ka radiation at the Centro Grandi Strumenti
18b (100%): White solid from acetone, mp 142–145 ꢀC;
[Found C, 65.7; H, 6.7; N, 10.3. C15H18N2O3
(MW¼274.31) requires C, 65.67; H, 6.61; N, 10.21%];
nmax (Nujol) 3378, 3318, 1653 cmꢁ1; dH (300 MHz,
CD3COCD3) 7.81 (2H, m, Ph), 7.50 (1H, b, NH), 7.45
(3H, m, Ph), 4.99 (1H, dd, J 9, 4 Hz, H5-isoxaz.), 4.53
(1H, t, J 5 Hz, OH), 4.39 (1H, m, CH–N), 4.18 (1H, dd,
J 9, 4 Hz, H4-isoxaz.), 3.74 and 3.83 (2H, m, CH2–O),
2.37 (1H, m, CH), 2.14 (2H, s, CH2), 1.87 (3H, m, CH3);
dC (75 MHz, CD3COCD3) 169.6, 160.4, 130.9, 130.0,
129.8, 128.3, 93.8, 65.7, 58.0, 54.8, 47.9, 35.0, 23.5.
`
(CGS) dell’Universita, Pavia, Italy.
A summary of crystal data, data collection, and structure re-
finement for compounds 10b is presented in Table 3. Table 4
reports the bond lengths and angles while Table 5 the torsion
angles.
An approximate absolute scale factor and a mean thermal
˚
parameters of 3.31 Awas determined by Wilson’s method.
29
The structure was solved by direct method and the E-map
correctly revealed the non-hydrogen atoms in the molecules
and refined anisotropically in subsequent three-cycle least-
squares. The positions of the hydrogen atoms were located
from a difference Fourier synthesis, and refined isotropically
in the subsequent least-squares refinement. The program
SHELXL30 was used to solve the structure. The ORTEP31
program was used for molecular graphics.
5.8. Hydrolysis of the alcohols 18a and 18b
To a solution in MeOH of the alcohols 18a, 18a0, and 18b, an
equivalent volume of HCl 3 M was added and the solutions
were heated overnight under a nitrogen atmosphere. The so-
lution volumes were doubled with water and the pH adjusted
to 8 with NaHCO3. The solutions were then saturated with
salt and extracted with DCM three times. The organic phases
were dried over anhydrous Na2SO4 and evaporation of the
solvent afforded quantitatively the crude aminols 19a,
19a0, and 19b, which were purified by crystallization.
CCDC 291,467 contains the supplementary crystallographic
data. These data can be obtained free of charge via the inter-
net web site at www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Center, 12
Union Road, Cambridge, CB21EZ, UK, or deposit@ccdc.
cam.ac.uk).
19a (100%): White solid from benzene/ethanol, mp 116–
118 ꢀC; [Found C, 67.2; H, 6.9; N, 12.1. C13H16N2O2
(MW¼232.27) requires C, 67.22; H, 6.94; N, 12.06%];
nmax (Nujol) 3334, 3266, 3176, 1604 cmꢁ1; dH (300 MHz,
CD3COCD3) 7.67 (2H, m, Ph), 7.44 (3H, m, Ph), 5.21
(1H, dd, J 9, 2 Hz, H5-isoxaz.), 5.16 (2H, b, NH2), 4.02
(2H, m, CH–N and H4-isoxaz.), 3.70 (2H, AB syst., CH2–
O), 2.52 (1H, m, CH), 2.10 (2H, m, CH2); dC (75 MHz,
CD3COCD3) 158.8, 131.0, 130.8, 129.9, 128.2, 91.7, 66.2,
64.7, 62.2, 51.2, 37.8.
Acknowledgements
Financial support by University of Pavia (FAR), MIUR
(PRIN 2004 and PRIN 2005) is gratefully acknowledged.
Thanks are due to Dr. Massimo Boiocchi (CGS) for X-ray
data collection.
References and notes
19a0 (100%): White solid from benzene/ethanol, mp 153–
158 ꢀC; [Found C, 67.3; H, 7.0; N, 12.1. C13H16N2O2
(MW¼232.27) requires C, 67.22; H, 6.94; N, 12.06%];
nmax (Nujol) 3329, 3257, 3158, 1591 cmꢁ1; dH (300 MHz,
CD3COCD3) 7.66 (2H, m, Ph), 7.45 (3H, m, Ph), 5.28
(1H, dd, J 9, 5 Hz, H5-isoxaz.), 4.03 (1H, d, J 9 Hz, H4-iso-
xaz.), 3.97 (1H, s, CH–N), 3.67 and 3.87 (2H, m, CH2–O),
2.84 (1H, m, CH), 1.58 (2H, m, CH2); dC (75 MHz,
CD3COCD3) 158.6, 131.9, 130.1, 129.6, 128.0, 89.1, 65.4,
62.2, 62.1, 49.6, 36.3.
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