Phenyliodine(III) Bis(trifluoroacetate) Mediated Synthesis of 6-Piperidinylpurine Homo-N-nucleosides Modified with Isoxazolines or Isoxazoles

Article abstract of DOI:10.1055/s-0035-1560704

The room temperature, 1,3-dipolar cycloaddition reactions of the nitrile oxide obtained from (6-piperidin-1-yl-9H-purin-9-yl)acetaldehyde oxime upon phenyliodine(III) bis(trifluoroacetate) treatment with excess unsaturated alcohols as solvent resulted in isoxazoline or isoxazole derivatives in almost quantitative yields. Analogous derivatives were prepared from the reactions of unsaturated phosphates. Preliminary biological tests indicated inhibition of lipid peroxidation for some of the examined compounds.

Full text of DOI:10.1055/s-0035-1560704

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 281–292
paper
281
T. Balalas et al.
Paper
Synthesis
Phenyliodine(III) Bis(trifluoroacetate) Mediated Synthesis of
6-Piperidinylpurine Homo-N-nucleosides Modified with Isoxazo-
lines or Isoxazoles1
Thomas Balalasa
R5
R4
R3
Catherine Peperidoub
Dimitra J. Hadjipavlou-Litina*b
Konstantinos E. Litinas*a
OA
R1
n
N
N
N
N
R2
(10 equiv)
N
N
N
N
AO
R5
R4
R3
N
N
R1
a Laboratory of Organic Chemistry, Department of Chemistry,
Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
b Department of Pharmaceutical Chemistry, School of Pharmacy,
Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
klitinas@chem.auth.gr
R2
n
PIFA (1.5 equiv)
r.t., 10 min
O
N
N
HO
n = 0–2
A = H, P(=O)(OEt)2
18 examples
(52–99%, mostly 99%)
Received: 31.07.2015
Accepted after revision: 18.09.2015
Published online: 04.11.2015
oxide10a and nitrile imines10b for the preparation of purine
derivatives VIIa–c and VIIIa–c, IXa–c, respectively. We have
also studied these products as potential thrombin and lipid
peroxidation inhibitors, and especially the latter derivatives
for their antiproliferative and cytotoxic activity.
The isoxazoline moiety is a valuable synthon for subse-
quent modification to a variety of compounds, such as β-
hydroxy ketones, γ-amino alcohols, α,β-unsaturated ke-
tones and β-hydroxy nitriles.7a–c,11 Isoxazolines are usually
prepared by the 1,3-cycloaddition reaction of nitrile oxides
to alkenes.7a–c,10a The nitrile oxides are prepared in situ from
aldoximes through direct oxidation12a–f or halogenation and
subsequent dehydrohalogenation in the presence of base in
two steps,12g–i or from nitroalkanes and phenyl isocyanate
through dehydration.6,11e,f However, these methods require
the use of long reaction times or a complex combination of
reagents.
DOI: 10.1055/s-0035-1560704; Art ID: ss-2015-z0452-op
Abstract The room temperature, 1,3-dipolar cycloaddition reactions
of the nitrile oxide obtained from (6-piperidin-1-yl-9H-purin-9-yl)acet-
aldehyde oxime upon phenyliodine(III) bis(trifluoroacetate) treatment
with excess unsaturated alcohols as solvent resulted in isoxazoline or
isoxazole derivatives in almost quantitative yields. Analogous deriva-
tives were prepared from the reactions of unsaturated phosphates. Pre-
liminary biological tests indicated inhibition of lipid peroxidation for
some of the examined compounds.
Key words modified homo-N-nucleosides, isoxazolines, isoxazoles,
1,3-dipolar cycloaddition reactions, phenyliodine(III) bis(trifluoroace-
tate), PIFA
Nucleosides and modified nucleosides represent classes
of compounds that possess very interesting biological activ-
ities,2 especially antiviral, anticancer and antimetabolic ac-
tivities. Adenosine (I) (Figure 1), which is generated at an
inflamed site, is receiving increasing interest as an endoge-
nous anti-inflammatory agent. Thus, agents influencing the
level of adenosine could act as possible drugs.3 The modi-
fied derivative aristeromycin (II) is a natural product with
antibiotic and antioncogenic activities,4 whereas the syn-
thetic derivative abacavir (III) is an HIV inhibitor.5 Modified
nucleosides with heterocyclic rings,6 such as isoxazoline de-
rivatives7 IVa, b, have been studied for their anti-HIV and
anticancer activities.
The homo-N-nucleosides, with a CH2 group between
adenine and a carbocyclic or heterocyclic ring, possess
higher conformational flexibility8 to combine with the bas-
es DNA/RNA by a lowering of the electrostatic repulsion.8b
Derivative V was prepared9 in the search for agents active
against the HIV and hepatitis B viruses. Isoxazolidinyl de-
rivative VI8b is a special glucosidase inhibitor. Recently, we
have reported reactions of 9-allyl-9H-purines with a nitrile
Recently, hypervalent iodine reagents,12a–d,13a hypoiodite
reagents13b,c or iodosobenzene12e has been employed for the
one-pot synthesis of isoxazolines via the direct oxidation of
aldoximes, and the 1,3-dipolar cycloaddition reactions of
the resulting nitrile oxides to alkenes under mild condi-
tions. In continuation of our studies on modified nucleo-
sides,10,14 we describe here the use of some hypervalent io-
dine reagents for the one-pot synthesis of modified homo-
N-nucleosides, with isoxazoline or isoxazole moieties, via
the in situ generation of the corresponding nitrile oxide.
This nitrile oxide has been obtained for the first time, ac-
cording to our knowledge, from the oxidation of (6-piperi-
din-1-yl-9H-purin-9-yl)acetaldehyde oxime. The reactions
studied and the products obtained are outlined in Schemes
1–3.
The reaction of 6-piperidin-1-yl-9H-purine14c with 2-
bromoacetaldehyde diethyl acetal and anhydrous potassi-
um carbonate in anhydrous N,N-dimethylformamide at
140 °C under microwave irradiation for 45 minutes resulted
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Synthesis
Table 1 Optimization of the Conditions for the 1,3-Dipolar Cycloaddition Reaction of Allyl Alcohol (3a) with the Nitrile Oxide Generated in situ from
Oxime 2
Entry
3a (equiv)
Methoda
Conditions
Yield (%) of products
1
2
1
1
A
B
DMF, N2, r.t., 22 h
MeOH, 0 °C, 1 h
MeOH, r.t., 1 h
4a (18), 5 (8), 2 (52)
4a (10), 5 (34), 6 (4), 2 (15)
4a (43), 5 (21), 6 (5), 2 (10)
4a (50), 5 (24)
3
1
B
4
1
B
CH2Cl2, r.t., 1 h
5
1
B
MeOH, reflux, 1 h
CH2Cl2, reflux, 1 h
CH2Cl2, MW, 100 °C, 2 min
MeOH, reflux, 1 h
CH2Cl2, reflux, 1 h
MeOH, reflux, 1 h
CH2Cl2, reflux, 1 h
CH2Cl2, r.t., 5 min
CH2Cl2, r.t., 5 min
r.t., 5 min
4a (58), 5 (12), 6 (5), 2 (12)
4a (62), 5 (17)
6
1
B
7
1
Bb
C
C
B
4a (50), 5 (25)
8
1
4a (40), 5 (24), 6 (5)
4a (41), 5 (29)
9
1
10
11
12
13
14
2
4a (63), 5 (15), 6 (5)
4a (67), 5 (15)
2
B
1
D
D
D
4a (50), 5 (25)
2
4a (71), 5 (14)
10
4a (99)
a Method A: NCS (1-h addition), 1 h, then Et3N; method B: PIDA (1.1 equiv), TFA (47 mol%) (2-h addition); method C: PIDA (1.1 equiv) (2-h addition); method D:
PIFA (1.5 equiv) (5-min addition).
b In two parts, every 1 min.
in the formation of 9-(2,2-diethoxyethyl)-6-piperidin-1-yl-
9H-purine in 83% yield, better than our former synthesis.14c
Heating this acetal with hydrochloric acid led to (6-piperi-
din-1-yl-9H-purin-9-yl)acetaldehyde (1).14c Treatment of a
solution of aldehyde 1 in aqueous ethanol with hydroxyl-
amine hydrochloride in the presence of sodium acetate at
NH2
NH2
N
HN
N
N
N
N
N
N
N
N
N
HO
HO
O
N
HO
N
NH2
HO
OH
HO
OH
III
II
I
R
NH2
NH2
N
N
N
N
N
N
N
HO
N
N
HO
N
N
N
HO
N
O
N
O
Me
VI
IVa R = Cl
IVb R = NH2
V
R
R
VII–IX
R
N
N
N
N
N
N
N
N
N
a R =
b R =
N
Ar
Ar
N
N
O
N
N
N
N
N
Me
O
N
N
N
Ph
Ph
VIIIa–c
c R =
Me
Me
IXa–c
VIIa–c
Figure 1 Nucleosides and modified nucleosides with important biological activities
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Synthesis
80 °C for 2 hours resulted in the formation of oxime 2
(Scheme 1) in 86% yield as a 1:1 mixture of E- and Z-iso-
mers, as indicated by 1H NMR spectroscopy.
We investigated suitable conditions for the 1,3-dipolar
cycloaddition reaction of the nitrile oxide, generated from
oxime 2, with unsaturated alcohols by using allyl alcohol
(3a) as the representative reactant. Different oxidants and
solvents were screened under different temperature condi-
tions (Table 1).
First, the classical7a,b method by chlorination of oxime 2
with N-chlorosuccinimide in N,N-dimethylformamide solu-
tion, followed by addition of alkene 3a and triethylamine
(method A; Table 1, entry 1), in a one-pot procedure result-
ed in the new isoxazoline derivative 4a (Scheme 1) in only
18% yield. The dimerization product, furoxan 5 (8%), was
also obtained, along with recovered starting oxime 2 (52%).
Isoxazoline 4a had the expected15 regiochemistry, as indi-
cated by HMBC measurements. Thus, the protons of the
N
N
N
N
OH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
R1
R3
R2
HO
N
N
+
+
N
N
N
R2
R1
N
N
O
R3
O
O
N
8a–d
N
N
N
O
1
9c–e
O
5
(iii)
R3
(i)
R1
OH
N
N
R2
N
N
N
N
N
OH
7a–e
N
N
N
N
n
N
N
3a–c
HO
OH
R2
N
(ii)
N
n
NOH
R1
O
N
MeO
N
6
HO
10a,b
(ii)
2
R
OH
13a–c
(iv)
N
N
N
N
N
N
N
N
N
N
O
HO
R1
+
N
N
N
N
N
N
N
R2
N
R
HO
O
O
+
+ 5
N
N
N
N
O
12
11a,b
O
N
N
OH
14a,b
Me
15
7, 8, 9a R1 = R2 = H, R3 = Me
10, 11a R1 = H, R2 = Me
b R1 = R2 = Me
3, 4a n = 1
b n = 2
13, 14a R = H
b R = CH2OH
c R = Me
b R1 = R3 = H, R2 = CH2OH
c R1 = Ph, R2 = R3 = H
d R1 = Me, R2 = R3 = H
e R1 = R2 = Me, R3 = H
c n = 3
Scheme 1 Reagents and conditions: (i) NH2OH·HCl (1.5 equiv), NaOAc (2 equiv), H2O, EtOH, 80 °C, 2 h; (ii) 3a–c (10 equiv) (for 4a–c) or 10a, b (10
equiv) (for 11a, b, 12), PIFA (1.5 equiv), r.t., 10 min; (iii) 7a–e (10 equiv), PIFA (1.5 equiv), r.t. (40 °C for 7c), 10 min; (iv) 13a–c (10 equiv), PIFA (1.5
equiv), r.t. (60 °C for 13b), 10 min.
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NCH2 group [5.07 ppm (s, 2 H)] correlate to 4-CH2 (40.0
ppm in the 13C NMR spectrum) and not to 5-CH (81.8 ppm)
of the isoxazoline.
under method B, in boiling methanol or dichloromethane,
isoxazoline 4a was obtained in 63% or 67% yield, respective-
ly (Table 1, entries 10 and 11). It seemed from these results
that increasing the amount of allyl alcohol in boiling di-
chloromethane resulted in a relatively better yield of isox-
azoline 4a and a lower yield of furoxan 5.
Then, oxidation of oxime 2 with phenyliodine(III) diace-
tate (PIDA) in the presence of a catalytic amount (47 mol%)
of trifluoroacetic acid in methanol was performed at 0 °C
(method B; Table 1, entry 2). This reaction led only to a 10%
yield of isoxazoline 4a and a higher amount of furoxan
(34%), while the methoxy oxime derivative 6 (4%) was iso-
lated. Increasing the temperature to room temperature or
reflux provided a 43% or 58% yield of 4a (Table 1, entries 3
and 5) and a decreased amount of furoxan 5 (21% or 12%,
respectively). When dichloromethane was used as a solvent
at room temperature or at 40 °C, 4a was isolated in slightly
better yields (50% or 62%, respectively) (Table 1, entries 4
and 6). The use of microwave irradiation with dichloro-
methane as solvent did not improve the yield of 4a (50%)
(Table 1, entry 7). Without catalysis by trifluoroacetic acid
(method C; Table 1, entries 8 and 9), the yield of 4a in meth-
anol or dichloromethane decreased to 40% or 41%, respec-
tively, while the furoxan yield increased (24% or 29%) (Table
1, entries 8 and 9). With 2 equivalents of allyl alcohol (3a),
When phenyliodine(III) bis(trifluoroacetate) (PIFA,
method D; Table 1, entry 12) in dichloromethane was used
at room temperature, isoxazoline 4a was obtained in 50%
yield in a total time of 10 minutes (5-min addition, 5-min
stirring). The dimerization product 5 was obtained in 25%
yield. When 2 equivalents of 3a in dichloromethane was
used, the yield of 4a increased to 71% while the yield of
furoxan 5 decreased to 14% (Table 1, entry 13). Use of 10
equivalents of 3a, as a solvent, afforded isoxazoline 4a al-
most quantitatively at room temperature in only 10 min-
utes total time (Table 1, entry 14), while furoxan 5 was not
isolated. Crucially, the oxidation of oxime 2,12c followed by
trapping of the nitrile oxide formed with the excess alkene
3a used, is so fast that the side reaction can no longer com-
pete.
Table 2 1,3-Dipolar Cycloaddition Reactions of Unsaturated Alcohols with the Nitrile Oxide Generated from Oxime 2
Entry
Alcohol
Methoda
Conditions
Yield (%) of products
1
2
3b
3b
B
CH2Cl2, reflux, 1 h
r.t., 5 min
4b (48), 5 (22), 2 (8)
4b (99)
D
B
3
3c
MeOH, reflux, 1 h
CH2Cl2, reflux, 1 h
r.t., 5 min
4c (50), 5 (18), 6 (5), 2 (8)
4c (53), 5 (26), 2 (5)
4c (99)
4
3c
B
5
3c
D
B
6
7a
MeOH, reflux, 1 h
CH2Cl2, reflux, 1 h
r.t., 5 min
8a (11), 5 (32), 6 (5), 2 (20)
8a (12), 5 (38), 2 (12)
8a (99)
7
7a
B
8
7a
D
B
9
7b
MeOH, reflux, 1 h
r.t., 5 min
8b (6), 5 (27), 6 (5), 2 (35)
8b (99)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
7b
D
B
7c
MeOH, reflux, 1 h
40 °C, 5 min
5 (32), 6 (5), 2 (30)
8c (21), 9c (42), 5 (15)
5 (22), 6 (5), 2 (50)
8d (33), 9d (66)
5 (26), 6 (5), 2 (42)
9e (52), 5 (18), 2 (12)
11a (70), 12 (30)
11b (99)
7c
D
B
7d
MeOH, reflux, 1 h
r.t., 5 min
7d
D
B
7e
MeOH, reflux, 1 h
r.t., 5 min
7e
D
D
D
B
10a
10b
13a
13a
13a
13b
13c
r.t., 5 min
r.t., 5 min
MeOH, reflux, 1 h
CH2Cl2, reflux, 1 h
r.t., 5 min
14a (50), 5 (16), 6 (5), 2 (12)
14a (75), 5 (12)
14a (99)
B
D
D
D
60 °C, 5 min
14b (56), 5 (22)
15 (48), 5 (12)
r.t., 5 min
a Method B: PIDA (1.1 equiv), TFA (47 mol%) (2-h addition); method D: alcohol (10 equiv), PIFA (1.5 equiv) (5-min addition).
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Synthesis
R3
O
R3
R1
OH
O
OH
OP(OEt)2
4a
(i)
R1
OP(OEt)2
n
n
R2
7a,c
3a–c
R2
17a n = 1 (89%)
17b n = 2 (81%)
17c n = 3 (90%)
(i)
(i)
18a R1 = R2 = H, R3 = Me (90%)
18b R1 = Ph, R2 = R3 = H (73%)
P(OEt)3
16
OH
OH
13a
O
10a
O
(i)
(i)
OP(OEt)2
OP(OEt)2
20 (90%)
19 (71%)
Scheme 2 Reagents and conditions: (i) I2 (5-min addition), anhydrous CH2Cl2, 0 °C, then r.t., 5 min; unsaturated alcohol, pyridine (excess), anhydrous
CH2Cl2, 0 °C (5-min addition), then r.t., 5 min.
After the examination of suitable reaction conditions,
different alkenols, substituted allyl alcohols and substituted
propargyl alcohols were reacted with the nitrile oxide gen-
erated from oxime 2 (Scheme 1 and Table 2). Most of the
alkenols and allyl alcohols reacted almost quantitatively in
the presence of PIFA (method D; Table 2, entries 2, 5, 8, 10
and 18), while in the presence of PIDA and trifluoroacetic
acid the yields of isoxazolines were moderate (method B;
Table 2, entries 1, 3 and 4) or low (Table 2, entries 6, 7 and
9) with increased amounts of furoxan 5.
In the case of cinnamyl alcohol (7c), crotyl alcohol (7d)
and 3-methyl-2-buten-1-ol (7e), method B gave only furox-
an 5, along with some methoxy oxime 6, while oxime 2 was
recovered (Table 2, entries 11, 13 and 15). Oxidation of 2 in
the presence of 7c with PIFA (method D) resulted in the re-
gioisomers 8c and 9c (Table 2, entry 12) without regioselec-
tivity.16 HMBC experiments with 8c revealed correlation of
the NCH2 group [4.91 (d, J = 16.0 Hz, 1 H) and 4.99 ppm (d,
J = 16.0 Hz, 1 H)] with 4-CH–Ph of the isoxazoline [55.9
ppm in the 13C NMR spectrum and 4.19 ppm (d, J = 6.2 Hz, 1
Table 3 Summarized Biological Resultsa
Entry
Compound
RA (%) 100 μM
LOX (%) 100 μM
AAPH (%) 100 μM
20 min
60 min
1
2
4a
4b
3
56
No
No
No
17
Nt
Nt
12
No
Nt
Nt
Nt
Nt
Nt
Nt
95
–
8
44
30
43
9
91
34
92
32
47
No
No
30
No
1
No
9
3
4c
4
8a
62
No
Nt
Nt
1
5
8b
6
11a
11b
14a
15
No
No
44
0.2
5
7
8
9
No
Nt
Nt
Nt
Nt
Nt
Nt
86
–
10
11
12
13
14
15
16
17
21a
21b
21c
22a
24
No
2
14
38
4
No
4
2.5
68
–
25
41
84
–
NDGA
Trolox
63
a RA (%): % interaction with DPPH (reducing ability); LOX (%): % in vitro inhibition of soybean lipoxygenase; LOX: lipoxygenase; AAPH (%): % inhibition of lipid
peroxidation; NDGA: nordihydroguaiaretic acid; No: no activity under the experimental conditions; Nt: not tested.
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1
H) for the corresponding proton in the H NMR spectrum].
The analogous HMBC experiments with 9c indicated cor-
relation of the NCH2 group [5.13 (d, J = 16.4 Hz, 1 H) and
5.17 ppm (d, J = 16.4 Hz, 1 H)] with 4-CH–CH2OH of the
isoxazoline [59.4 ppm in the 13C NMR spectrum and 3.33
ppm (ddd, J = 4.1, 7.2, 7.4 Hz, 1 H) for the corresponding
proton in the 1H NMR spectrum]. Reaction of crotyl alcohol
(7d) under method D led to a mixture (1:2) of the regioiso-
mers 8d and 9d (Table 2, entry 14). HMBC correlation of the
NCH2 group for 8d and 9d was analogous to that described
for 8c and 9c. Reaction of alkenol 7e under PIFA conditions
gave only regioisomer 9e (Table 2, entry 16), probably due
to steric reasons; the isoxazolines 9c, d were also obtained
in higher yield than their regioisomers 8c, d.
(ddd, J = 5.0, 7.6, 10.9 Hz, 1 H) for one diastereomer, 4.52
ppm (ddd, J = 3.2, 8.6, 11.5 Hz, 1 H) for the other]. The reac-
tion of 1,1-dimethyl-2-propen-1-ol (10b) gave isoxazoline
11b quantitatively (Table 2, entry 18).
1,3-Dipolar cycloaddition reactions with propargyl al-
cohols 13a–c were tested next. Isoxazole 14a was isolated
quantitatively upon in situ trapping of the nitrile oxide gen-
erated from PIFA oxidation of oxime 2 with propargyl alco-
hol (13a) (Table 2, entry 21). Oxidation with PIDA and tri-
fluoroacetic acid gave lower yields (Table 2, entries 19 and
20). 2-Butyne-1,4-diol (13b) reacted at its melting point to
give isoxazole 14b, along with furoxan 5 (Table 2, entry 22).
Reaction of 2-butyn-1-ol (13c) only led to the oxime deriv-
ative 15 (Table 2, entry 23), analogous to the formation of
methoxy derivative 6.
Nucleosides or modified nucleosides containing a phos-
phate group present very interesting antiviral activities.2,17
Taking this into consideration, we tried to prepare phos-
phate derivatives of the above hydroxy-substituted isoxazo-
lines and isoxazoles. Efforts for the phosphorylation of 4a
proved unsuccessful (Scheme 2). For that reason, the unsat-
1-Methyl-2-propen-1-ol (10a) reacted under the opti-
mized conditions to give isoxazoline 11a, along with the
oxidation product 12 (Table 2, entry 17). Isoxazoline 11a
was obtained as a mixture (1:1) of diastereomers, as indi-
cated by HSQC and HMBC experiments. The ethanol group
of 11a is in a pseudoequatorial position, while the 5-H of
the isoxazoline ring is in a pseudoaxial position [4.45 ppm
O
N
N
N
N
(EtO)2PO
O
N
N
N
N
N
N
R1
R2
(EtO)2PO
+
R3
Ph
O
O
N
N
22a R1 = R2 = H, R3 = Me (99%)
22b R1 = Ph, R2 = R3 = H (28%)
23 (70%)
N
O
OP(OEt)2
R3
O
O
(EtO)2PO
N
R1
OP(OEt)2
N
n
N
N
R2
17a–c
18a,b
n
(i)
O
N
(i)
21a n = 1 (99%)
21b n = 2 (99%)
21c n = 3 (99%)
N
O
N
N
O
N
OP(OEt)2
OP(OEt)2
N
20
19
(i)
N
N
N
HO
N
2
(i)
O
N
N
O
(EtO)2PO
N
N
(EtO)2PO
N
N
N
O
N
O
N
25 (99%)
24 (99%)
Scheme 3 Reagents and conditions: (i) unsaturated phosphate (10 equiv), PIFA (1.5 equiv), r.t., 10 min.
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urated diethyl phosphates were prepared first by extending
the mild, rapid and easy method18a for the synthesis of
phosphates from phenols or primary and secondary alco-
hols. Thus, treatment of triethyl phosphite (16) with iodine
and unsaturated alcohols and pyridine in dichloromethane
at 0 °C resulted in 17a–c, 18a, b, 19 and 20 in very good
yields (Scheme 2), comparable or better than the yields ob-
tained from preparations with diethyl chlorophosphate18b–f
as starting material.
The above-prepared unsaturated phosphates 17a–c,
18a, b, 19 and 20 trapped the in situ formed nitrile oxide
from oxime 2 in the presence of PIFA (Scheme 3). The prod-
uct isoxazolines 21a–c, 22a, 24 and the isoxazole 25 were
isolated almost quantitatively. Isoxazoline 24 was obtained
as a mixture (1:1) of diastereomers, as indicated by 1H NMR
spectroscopy. With phosphate 18b derived from cinnamyl
alcohol, the regioisomers 22b and 23 were obtained as a
mixture after PTLC in 28% and 70% yield, respectively (as in-
dicated by 1H NMR spectroscopy).
9-(2,2-Diethoxyethyl)-6-piperidin-1-yl-9H-purine14c
6-Piperidin-1-yl-9H-purine (0.5 g, 2.46 mmol), anhydrous DMF (10
mL), anhydrous K2CO3 (0.374 g, 2.71 mmol) and 2-bromoacetalde-
hyde diethyl acetal (0.42 mL, 0.55 g, 2.71 mmol) were added with a
magnetic stirrer bar to a vial suitable for microwave irradiation. The
mixture was irradiated (45–55 W) at 140 °C for 45 min, and then was
filtered. The filtrate was concentrated (heptane was added to remove
the DMF as an azeotropic mixture). The residue was chromato-
graphed (silica gel; EtOAc–hexane, 1:1) to give the 9-(2,2-
diethoxyethyl)-6-piperidin-1-yl-9H-purine; yield: 0.651 g (83%); mp
46–48 °C (hexane) (Lit.14c 46–48 °C).
(6-Piperidin-1-yl-9H-purin-9-yl)acetaldehyde Oxime (2)
A solution of aldehyde 1 (0.457 g, 1.87 mmol) in H2O (10 mL) and
EtOH (4 mL) was heated at 80 °C. NH2OH·HCl (0.13 g, 1.87 mmol) and
NaOAc (0.205 g, 2.5 mmol) were added and the mixture was heated
for 1 h. Then, NH2OH·HCl (65 mg, 0.93 mmol) and NaOAc (0.102 g,
1.24 mmol) were added again, and the mixture was heated for a fur-
ther 1 h. After cooling, the aqueous solution was extracted with EtOAc
(10 × 20 mL). The organic layer was dried with anhydrous MgSO4, fil-
tered and concentrated to give 2 (E/Z = 1:1) as a white solid; yield:
0.417 g (86%); mp 168–170 °C (EtOAc).
Preliminary biological tests have revealed that the anti-
oxidant activity of the examined isoxazolines and isoxaz-
oles is low to moderate (12–62%), as measured by interac-
tion with the stable free radical 1,1-diphenyl-2-picrylhy-
drazyl (DPPH) (Table 3). Compounds 4a, 4c and 25
displayed 91%, 92% and 68% inhibition respectively (better
results than the standard) of lipid peroxidation at 0.1 mM,
as tested by the 2,2′-azobis(2-amidinopropane) dihydro-
chloride (AAPH) protocol (Table 3). Compounds 4b, 8a, 14a
and 25 gave 41–44% inhibition of soybean lipoxygenase (Ta-
ble 3). None of the compounds exhibited significant antivi-
ral effects in tests for anti-herpes simplex virus (anti-HSV)
activity.
IR (KBr): 3431, 3084, 2928, 2851, 1598, 1569, 1481 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.60–1.91 (m, 12 H), 4.17–4.45 (m, 8
H), 4.95 (d, J = 8.7 Hz, 2 H), 5.10 (d, J = 7.5 Hz, 2 H), 6.88 (t, J = 7.5 Hz, 1
H), 7.58 (t, J = 8.7 Hz, 1 H), 7.82 (s, 1 H), 7.86 (s, 1 H), 8.34 (s, 1 H), 8.35
(s, 1 H), 10.8 (br s, 1 H), 11.2 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.3, 25.9, 41.8, 42.1, 46.7, 119.2,
138.1, 138.5, 143.4, 144.0, 150.1, 150.2, 151.0, 151.1, 152.4, 152.5.
MS (ESI): m/z = 261 [M + H]+..
Anal. Calcd for C12H16N6O: C, 55.37; H, 6.20; N, 32.29. Found: C, 55.26;
H, 6.44; N, 32.07.
{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxazol-
5-yl}methanol (4a); Typical Procedures
In conclusion, an efficient synthesis of 6-piperidinylpu-
rine homo-N-nucleosides modified with isoxazolines or
isoxazoles in excellent yields is reported. This method in-
volves the 1,3-cycloaddition reaction of unsaturated alco-
hols or phosphates with the nitrile oxide resulting from ox-
idation of (6-piperidin-1-yl-9H-purin-9-yl)acetaldehyde
oxime with PIFA at room temperature. Some compounds
display interesting inhibition of lipid peroxidation.
Method A
NCS (0.348 g, 2.6 mmol) was added gradually over 1 h to a solution of
oxime 2 (0.378 g, 1.45 mmol) in DMF (5 mL) at r.t. under N2. Stirring
was continued for a further 1 h. Allyl alcohol (3a) (0.11 mL, 94 mg, 1.6
mmol) and Et3N (0.28 mL, 0.2 g, 2.03 mmol) were then added, and
stirring was continued for 22 h. After filtration, the filtrate was con-
centrated and the residue was separated by column chromatography
(silica gel; EtOAc–hexane, 1:1, then EtOAc, and finally EtOAc–MeOH,
9:1) to give at first furoxan 5 (40 mg, 8%), followed by recovered ox-
ime 2 (0.197 g, 52%) and isoxazoline 4a (0.106 g, 18%).
All chemicals were procured from either Sigma-Aldrich or Merck.
Melting points were determined on a Kofler hot-stage apparatus and
are uncorrected. IR spectra were obtained as Nujol mulls with a Per-
kin Elmer 1310 spectrophotometer. NMR spectra were recorded on
an Agilent 500/54 (DD2) spectrometer (500 MHz for 1H NMR, 125
MHz for 13C NMR, 202 MHz for 31P NMR) using CDCl3 as solvent and
TMS as an internal standard; J values are reported in Hz. Mass spectra
were determined on a Shimadzu LCMS-2010 EV instrument under
electrospray ionization (ESI) conditions. Microanalyses were per-
formed on a Perkin Elmer 2400-II elemental analyzer. Silica gel 60
(Merck) was used for column chromatography. Microwave experi-
ments were performed in a scientific focused microwave reactor (Bio-
tage Initiator 2.0). (6-Piperidin-1-yl-9H-purin-9-yl)acetaldehyde (1)
has been reported previously.14c
Method B
A solution of oxime 2 (50 mg, 0.19 mmol) in MeOH (10 mL) was add-
ed dropwise at r.t. over 2 h to a solution of PIDA (68 mg, 0.21 mmol) in
MeOH (1 mL), in which allyl alcohol (3a) (14 μL, 12 mg, 0.21 mmol)
and TFA (7 μL, 10.4 mg, 0.09 mmol) had been added. The mixture was
stirred for a further 1 h, then concentrated, and the residue was sepa-
rated by column chromatography (silica gel; EtOAc, then EtOAc–
MeOH, 9:1) to give furoxan 5 (11 mg, 21%), followed by recovered ox-
ime 2 (5 mg, 10%), oxime 6 (3 mg, 5%) and isoxazoline 4a (26 mg,
43%).
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Method C
2-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxaz-
ol-5-yl}ethanol (4b)
A solution of oxime 2 (50 mg, 0.19 mmol) in CH2Cl2 (10 mL) was add-
ed dropwise over 2 h to a solution of PIDA (68 mg, 0.21 mmol) in
CH2Cl2 (1 mL) under reflux, in which allyl alcohol (3a) (14 μL, 12 mg,
0.21 mmol) had been added. The mixture was stirred for a further 1 h,
then cooled and concentrated, and the residue was separated by col-
umn chromatography (silica gel; EtOAc, then EtOAc–MeOH, 9:1) to
give furoxan 5 (15 mg, 29%), followed by isoxazoline 4a (24.5 mg,
41%).
Yield: 62 mg (99%) (method D); light yellow oil.
IR (KBr): 3240, 3028, 2936, 2851, 1592 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.68–1.81 (m, 7 H), 1.89 (dt, J = 6.4,
13.1 Hz, 1 H), 2.72 (dd, J = 7.7, 17.2 Hz, 1 H), 3.04 (dd, J = 10.6, 17.2 Hz,
1 H), 3.69 (t, J = 6.4 Hz, 2 H), 4.14–4.29 (m, 4 H), 4.76–4.85 (m, 1 H),
5.10 (s, 2 H), 7.84 (s, 1 H), 8.28 (s, 1 H).
.
13C NMR (125 MHz, CDCl3): δ = 24.6, 26.0, 37.3, 40.1, 40.4, 46.5, 58.4,
79.4, 119.3, 137.9, 150.2, 152.4, 153.8, 154.8.
MS (ESI): m/z = 331 [M + H]+., 353 [M + Na]+., 369 [M + K]+..
Method D
Oxime 2 (25 mg, 0.095 mmol) was added gradually at r.t. to a solution
of PIFA (81.7 mg, 0.19 mmol) in allyl alcohol (3a) (0.129 mL, 0.11 g,
1.9 mmol). Then, further PIFA (40.8 mg, 0.095 mmol) was added, fol-
lowed by the gradual addition of oxime 2 (25 mg, 0.095 mmol). All of
the above additions lasted 5 min in total. Stirring was continued for 5
min. Then, hexane was added for the removal of 3a by evaporation (5
cycles). The residue was purified by column chromatography (silica
gel; EtOAc, then EtOAc–MeOH, 9:1) to give 4a as a white solid; yield:
59.5 mg (99%); mp 127–129 °C (EtOAc).
Anal. Calcd for C16H22N6O2: C, 58.17; H, 6.71; N, 25.44. Found: C,
58.31; H, 6.53; N, 25.35.
3-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxaz-
ol-5-yl}propan-1-ol (4c)
Yield: 65 mg (99%) (method D); light yellow oil.
IR (KBr): 3241, 3029, 2937, 2857, 1590, 1568 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.53–1.67 (m, 2 H), 1.67–1.80 (m, 8 H),
2.56 (dd, J = 8.3, 17.4 Hz, 1 H), 2.97 (dd, J = 10.4, 17.4 Hz, 1 H), 3.64 (t,
J = 5.9 Hz, 2 H), 4.18–4.30 (m, 4 H), 4.60–4.69 (m, 1 H), 5.10 (s, 2 H),
7.78 (s, 1 H), 8.32 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.8, 26.2, 28.6, 31.6, 40.0, 40.4, 46.5,
62.2, 81.7, 119.5, 137.6, 150.6, 152.7, 153.9, 154.4.
IR (KBr): 3350, 3104, 2938, 2853, 1586, 1564, 1480 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.62–1.80 (m, 6 H), 2.87 (dd, J = 7.8,
17.4 Hz, 1 H), 2.95 (dd, J = 10.9, 17.4 Hz, 1 H), 3.23 (br s, 1 H), 3.54 (dd,
J = 4.1, 12.3 Hz, 1 H), 3.77 (dd, J = 2.8, 12.3 Hz, 1 H), 4.09–4.39 (m, 4
H), 4.66–4.76 (m, 1 H), 5.10 (s, 2 H), 7.80 (s, 1 H), 8.31 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.8, 26.2, 36.6, 39.9, 46.5, 63.3, 81.8,
119.5, 137.7, 150.6, 152.7, 153.9, 154.8.
MS (ESI): m/z = 345 [M + H]+., 367 [M + Na]+., 383 [M + K]+..
MS (ESI): m/z = 317 [M + H]+., 339 [M + Na]+., 355 [M + K]+..
Anal. Calcd for C17H24N6O2: C, 59.28; H, 7.02; N, 24.40. Found: C,
59.20; H, 6.86; N, 24.29.
Anal. Calcd for C15H20N6O2: C, 56.95; H, 6.37; N, 26.56. Found: C,
56.86; H, 6.42; N, 26.45.
{5-Methyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-5-yl}methanol (8a)
3,4-Bis[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-1,2,5-oxadiazole
2-Oxide (5)
Yield: 62 mg (99%) (method D); white solid; mp 183–185 °C (EtOAc).
IR (KBr): 3234, 3017, 2925, 2853, 1592, 1562 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.30 (s, 3 H), 1.68–1.78 (m, 6 H), 2.57
(d, J = 17.4 Hz, 1 H), 3.03 (d, J = 17.4 Hz, 1 H), 3.42 (d, J = 12.1 Hz, 1 H),
3.63 (d, J = 12.1 Hz, 1 H), 4.15–4.30 (m, 4 H), 5.07 (s, 2 H), 7.79 (s, 1 H),
8.31 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 22.5, 24.8, 26.2, 40.2, 42.2, 46.4, 67.2,
88.3, 119.5, 137.6, 150.6, 152.8, 153.9, 154.9.
MS (ESI): m/z = 331 [M + H]+., 353 [M + Na]+., 369 [M + K]+..
.
Yield: 40 mg (8%) (method A); white solid; mp 60–62 °C (EtOAc–
hexane).
IR (KBr): 3018, 2926, 2854, 1590 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.71–1.85 (m, 12 H), 4.24–4.43 (m, 8
H), 5.55 (s, 2 H), 6.01 (s, 2 H), 7.95 (s, 1 H), 8.03 (s, 1 H), 8.31 (s, 1 H),
8.34 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.6, 24.7, 26.2, 35.5, 38.7, 47.0, 47.1,
111.9, 119.5, 119.6, 138.0, 138.1, 150.2, 151.8, 152.2, 152.3, 153.3.
MS (ESI): m/z = 517 [M + H]+., 539 [M + Na]+..
Anal. Calcd for C16H22N6O2: C, 58.17; H, 6.71; N, 25.44. Found: C,
58.11; H, 6.65; N, 25.38.
Anal. Calcd for C24H28N12O2: C, 55.80; H, 5.46; N, 32.54. Found: C,
55.71; H, 5.53; N, 32.39.
{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxaz-
ole-4,5-diyl}dimethanol (8b)
Methyl N-Hydroxy-2-(6-piperidin-1-yl-9H-purin-9-yl)ethanimido-
ate (6)
Yield: 65 mg (99%) (method D); yellow oil.
IR (KBr): 3239, 3031, 2935, 2854, 1591, 1567, 1482 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.66–1.77 (m, 6 H), 3.41 (dt, J = 4.3,
11.0 Hz, 1 H), 3.84–4.04 (m, 4 H), 4.17–4.29 (m, 4 H), 4.65 (dt, J = 3.5,
11.0 Hz, 1 H), 5.11 (d, J = 16.1 Hz, 1 H), 5.19 (d, J = 16.1 Hz, 1 H), 7.85
(s, 1 H), 8.28 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.8, 26.2, 39.6, 46.5, 51.7, 57.7, 59.7,
83.4, 119.5, 138.3, 150.0, 152.3, 153.8, 156.6.
MS (ESI): m/z = 347 [M + H]+., 369 [M + Na]+., 385 [M + K]+..
.
Yield: 3 mg (5%) (method B); white solid; mp 102–104 °C (EtOAc–
hexane).
IR (KBr): 3420, 3026, 2927, 2854, 1637, 1587, 1567 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.67–1.79 (m, 6 H), 3.80 (s, 3 H), 4.21–
4.33 (m, 4 H), 4.98 (s, 2 H), 7.79 (s, 1 H), 8.34 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.8, 26.2, 44.1, 46.7, 53.0, 119.2,
138.3, 150.7, 152.4, 153.2, 167.9.
MS (ESI): m/z = 291 [M + H]+..
Anal. Calcd for C16H22N6O3: C, 55.48; H, 6.40; N, 24.26. Found: C,
55.43; H, 6.49; N, 24.18.
Anal. Calcd for C13H18N6O2: C, 53.78; H, 6.25; N, 28.95. Found: C,
54.03; H, 6.35; N, 28.76.
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{4-Phenyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-5-yl}methanol (8c)
1H NMR (500 MHz, CDCl3): δ = 1.23 (s, 3 H), 1.30 (s, 3 H), 1.64–1.77
(m, 6 H), 2.90 (dd, J = 4.7, 9.1 Hz, 1 H), 3.76 (dd, J = 9.1, 11.4 Hz, 1 H),
3.89 (dd, J = 4.7, 11.4 Hz, 1 H), 4.15–4.34 (m, 4 H), 5.16 (d, J = 15.7 Hz,
1 H), 5.24 (d, J = 15.7 Hz, 1 H), 7.83 (s, 1 H), 8.28 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 20.3, 24.8, 26.2, 28.1, 40.9, 46.5, 57.2,
60.1, 86.8, 119.8, 138.1, 149.9, 152.3, 154.0, 157.4.
Yield: 16 mg (21%) (method D); white oil.
IR (KBr): 3227, 3015, 2923, 2854, 1590, 1566 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.65–1.76 (m, 6 H), 3.61 (dd, J = 4.0,
12.4 Hz, 1 H), 3.81 (dd, J = 5.2, 12.4 Hz, 1 H), 4.19 (d, J = 6.2 Hz, 1 H),
4.15–4.28 (m, 5 H), 4.59 (ddd, J = 4.0, 5.2, 6.2 Hz, 1 H), 4.91 (d, J = 16.0
Hz, 1 H), 4.99 (d, J = 16.0 Hz, 1 H), 7.18–7.35 (m, 5 H), 7.54 (s, 1 H),
8.22 (s, 1 H).
MS (ESI): m/z = 345 [M + H]+., 383 [M + K]+..
Anal. Calcd for C17H24N6O2: C, 59.28; H, 7.02; N, 24.40. Found: C,
59.35; H, 6.96; N, 24.29.
13C NMR (125 MHz, CDCl3): δ = 24.8, 26.2, 39.0, 46.5, 55.8, 62.9, 90.5,
119.3, 127.4, 128.5, 129.1, 136.8, 140.0, 150.3, 152.3, 153.6, 156.6.
1-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxaz-
ol-5-yl}ethanol (11a)
MS (ESI): m/z = 393 [M + H]+., 415 [M + Na]+., 431 [M + K]+..
Yield: 44 mg (70%) (method D); yellow oil.
IR (KBr): 3244, 3104, 2940, 2854, 1592, 1567 cm–1
Anal. Calcd for C21H24N6O2: C, 64.27; H, 6.16; N, 21.41. Found: C,
64.32; H, 6.22; N, 21.34.
.
1H NMR (500 MHz, CDCl3): δ = 1.09 (d, J = 6.5 Hz, 3 H), 1.19 (d, J = 6.5
Hz, 3 H), 1.67–1.78 (m, 12 H), 2.76 (dd, J = 7.6, 17.6 Hz, 1 H), 2.80 (dd,
J = 11.5, 17.3 Hz, 1 H), 2.94 (dd, J = 10.9, 17.6 Hz, 1 H), 2.97 (dd, J = 8.6,
17.3 Hz, 1 H), 3.66 (dq, J = 5.0, 6.5 Hz, 1 H), 4.03 (dq, J = 3.2, 6.5 Hz, 1
H), 4.17–4.34 (m, 8 H), 4.46 (ddd, J = 5.0, 7.6, 10.9 Hz, 1 H), 4.53 (ddd,
J = 3.2, 8.6, 11.5 Hz, 1 H), 5.10 (s, 4 H), 7.78 (s, 2 H), 8.33 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 18.0, 19.1, 24.8, 26.2, 34.5, 37.5, 39.9,
40.0, 46.4, 67.0, 69.2, 85.1, 85.6, 119.5, 137.6, 137.7, 150.6, 152.8,
152.9, 153.9, 154.9, 155.0.
{5-Phenyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-4-yl}methanol (9c)
Yield: 32 mg (42%) (method D); white solid; mp 158–159 °C (MeOH).
IR (KBr): 3227, 3085, 3015, 2923, 2854, 1590, 1566, 1478 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.65–1.76 (m, 6 H), 3.33 (ddd, J = 4.5,
7.1, 7.4 Hz, 1 H), 3.83 (dd, J = 7.1, 11.6 Hz, 1 H), 4.09 (dd, J = 4.5, 11.6
Hz, 1 H), 4.15–4.29 (m, 5 H), 5.13 (d, J = 16.4 Hz, 1 H), 5.17 (d, J = 16.4
Hz, 1 H), 5.34 (d, J = 7.4 Hz, 1 H), 7.18–7.37 (m, 5 H), 7.84 (s, 1 H), 8.25
(s, 1 H).
MS (ESI): m/z = 331 [M + H]+., 353 [M + Na]+..
13C NMR (125 MHz, CDCl3): δ = 24.7, 26.2, 39.7, 46.4, 59.4, 61.7, 85.6,
119.6, 125.5, 128.4, 128.9, 137.7, 138.1, 149.7, 152.2, 153.8, 155.4.
Anal. Calcd for C16H22N6O2: C, 58.17; H, 6.71; N, 25.44. Found: C,
58.13; H, 6.64; N, 25.31.
MS (ESI): m/z = 393 [M + H]+., 415 [M + Na]+., 431 [M + K]+..
1-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxaz-
ol-5-yl}ethanone (12)
Anal. Calcd for C21H24N6O2: C, 64.27; H, 6.16; N, 21.41. Found: C,
64.16; H, 6.11; N, 21.28.
Yield: 19 mg (30%) (method D); yellow oil.
IR (KBr): 3229, 3019, 2925, 2854, 1723, 1589 cm–1
.
{4-Methyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-5-yl}methanol (8d) and {5-Methyl-3-[(6-piperidin-1-
yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxazol-4-yl}methanol (9d)
1H NMR (500 MHz, CDCl3): δ = 1.66–1.78 (m, 6 H), 2.28 (s, 3 H), 3.08
(dd, J = 12.0, 17.8 Hz, 1 H), 3.20 (dd, J = 6.7, 17.8 Hz, 1 H), 4.17–4.31
(m, 4 H), 4.90 (dd, J = 6.7, 12.0 Hz, 1 H), 5.11 (s, 2 H), 7.75 (s, 1 H), 8.32
(s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.9, 26.2, 26.5, 37.5, 39.6, 46.5, 84.5,
119.5, 137.3, 150.7, 153.0, 154.0, 154.7, 206.1.
Yield of 8d + 9d: 21 mg (33%) + 42 mg (66%) (method D); yellow oil.
IR (KBr): 3240, 3028, 2936, 2854, 1593, 1568 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.21 (d, J = 7.2 Hz, 1.5 H), 1.27 (d,
J = 6.4 Hz, 3 H), 1.64–1.77 (m, 9 H), 2.98 (ddd, J = 4.7, 8.2, 12.8 Hz, 1
H), 3.08 (ddd, J = 3.2, 4.4, 7.2 Hz, 0.5 H), 3.55 (dd, J = 4.4, 12.3 Hz, 0.5
H), 3.72 (dd, J = 8.2, 11.4 Hz, 1 H), 3.76 (dd, J = 3.2, 12.3 Hz, 0.5 H), 3.93
(dd, J = 4.7, 11.4 Hz, 1 H), 4.16–4.32 (m, 7.5 H), 4.43 (dq, J = 6.4, 12.8
Hz, 1 H), 5.03 (d, J = 15.7 Hz, 0.5 H), 5.14 (d, J = 15.7 Hz, 1 H), 5.15 (d,
J = 15.7 Hz, 0.5 H), 5.19 (d, J = 15.7 Hz, 1 H), 7.80 (s, 0.5 H), 7.83 (s, 1
H), 8.27 (s, 1 H), 8.33 (s, 0.5 H).
MS (ESI): m/z = 329 [M + H]+., 351 [M + Na]+..
Anal. Calcd for C16H20N6O2: C, 58.52; H, 6.14; N, 25.59. Found: C,
58.47; H, 6.11; N, 25.45.
2-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisoxaz-
ol-5-yl}propan-2-ol (11b)
13C NMR (125 MHz, CDCl3): δ = 16.1, 20.3, 24.8, 24.9, 26.2, 38.3, 40.1,
43.6, 46.5, 57.3, 62.2, 62.7, 80.7, 89.0, 119.4, 119.7, 137.6, 138.1,
149.8, 150.6, 152.3, 152.8, 153.9, 156.0, 158.5.
Yield: 65 mg (99%) (method D); yellow oil.
IR (KBr): 3243, 3031, 2939, 2854, 1592 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.08 (s, 3 H), 1.26 (s, 3 H), 1.67–1.79
(m, 6 H), 2.83 (dd, J = 11.0, 17.5 Hz, 1 H), 2.93 (dd, J = 9.0, 17.5 Hz, 1
H), 4.20–4.28 (m, 4 H), 4.44 (dd, J = 9.0, 11.0 Hz, 1 H), 5.09 (s, 2 H),
7.77 (s, 1 H), 8.33 (s, 1 H).
MS (ESI): m/z = 331 [M + H]+., 353 [M + Na]+., 369 [M + K]+..
Anal. Calcd for C16H22N6O2: C, 58.17; H, 6.71; N, 25.44. Found: C,
58.06; H, 6.63; N, 25.40.
13C NMR (125 MHz, CDCl3): δ = 24.6, 24.9, 26.2, 26.3, 35.9, 39.9, 46.5,
71.1, 88.1, 119.5, 137.5, 150.7, 152.9, 154.0, 155.2.
MS (ESI): m/z = 345 [M + H]+., 367 [M + Na]+..
{5,5-Dimethyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-di-
hydroisoxazol-4-yl}methanol (9e)
Yield: 35 mg (52%) (method D); yellow oil.
Anal. Calcd for C17H24N6O2: C, 59.28; H, 7.02; N, 24.40. Found: C,
59.36; H, 6.92; N, 24.32.
IR (KBr): 3229, 3025, 2925, 2854, 1589 cm–1
.
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{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]isoxazol-5-yl}metha-
nol (14a)
1H NMR (500 MHz, CDCl3): δ = 1.34 (t, J = 7.1 Hz, 6 H), 1.78 (quint,
J = 6.6 Hz, 2 H), 2.16 (q, J = 6.6 Hz, 2 H), 3.99–4.16 (m, 6 H), 4.99 (d,
J = 10.2 Hz, 1 H), 5.04 (d, J = 16.9 Hz, 1 H), 5.80 (ddt, J = 6.6, 10.2, 16.9
Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 16.1 (d, J = 6.0 Hz), 29.5, 29.6 (d, J = 5.7
Hz), 63.7 (d, J = 5.9 Hz), 66.9 (d, J = 6.0 Hz), 115.5, 137.3.
Yield: 59 mg (99%) (method D); white solid; mp 131–133 °C (EtOAc).
IR (KBr): 3144, 3018, 2938, 2854, 1595, 1566, 1452 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.67–1.79 (m, 6 H), 4.15–4.31 (m, 4 H),
4.64 (s, 2 H), 5.42 (s, 2 H), 6.25 (s, 1 H), 7.86 (s, 1 H), 8.30 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.5, 26.0, 38.6, 46.6, 55.7, 100.9,
119.4, 138.1, 150.1, 152.2, 153.6, 159.2, 173.8.
31P NMR (202 MHz, CDCl3): δ = –0.88.
MS (ESI): m/z = 223 [M + H]+., 245 [M + Na]+..
MS (ESI): m/z = 315 [M + H]+., 337 [M + Na]+..
Diethyl 2-Methylprop-2-enyl Phosphate (18a)
Yield: 1.378 g (90%); oil.18b
Anal. Calcd for C15H18N6O2: C, 57.31; H, 5.77; N, 26.74. Found: C,
57.12; H, 5.91; N, 26.56.
Cinnamyl Diethyl Phosphate (18b)
Yield: 1.451 g (73%); oil.18f
{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]isoxazole-4,5-diyl}di-
methanol (14b)
Diethyl 1-Methylprop-2-enyl Phosphate (19)
Yield: 1.087 g (71%); oil.18b
Yield: 37 mg (56%) (method D); yellow oil.
IR (KBr): 3240, 3015, 2937, 2863, 1594, 1441 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.68–1.80 (m, 6 H), 4.16–4.33 (m, 4 H),
4.53 (s, 2 H), 4.68 (s, 2 H), 5.48 (s, 2 H), 7.86 (s, 1 H), 8.26 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.5, 26.0, 37.5, 46.7, 51.9, 54.2, 114.9,
Diethyl Propargyl Phosphate (20)
Yield: 1.272 g (90%); oil.18b
119.1, 139.3, 149.9, 151.9, 153.6, 158.3, 169.2.
MS (ESI): m/z = 345 [M + H]+..
Diethyl {3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-5-yl}methyl Phosphate (21a); Typical Procedure
Anal. Calcd for C16H20N6O3: C, 55.80; H, 5.85; N, 24.40. Found: C,
55.89; H, 5.34; N, 24.27.
The above method D was followed for the reaction of allyl diethyl
phosphate (17a) (0.184 g, 0.95 mmol) with oxime 2. After the 5 min-
utes of stirring, MeOH was added for the removal of excess 17a by
evaporation (5 cycles). The residue was separated by PTLC (EtOAc) to
give 21a as an orange oil; yield: 85 mg (99%).
But-2-ynyl N-Hydroxy-2-(6-piperidin-1-yl-9H-purin-9-
yl)ethanimidoate (15)
Yield: 30 mg (48%) (method D); pale yellow oil.
IR (KBr): 3451, 3025, 2925, 2854, 1588, 1458 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.68–1.76 (m, 6 H), 1.86 (t, J = 2.4 Hz, 3
H), 4.22–4.31 (m, 4 H), 4.76 (d, J = 2.4 Hz, 2 H), 4.99 (s, 2 H), 7.80 (s, 1
H), 8.37 (s, 1 H).
IR (KBr): 3042, 2943, 2860, 1593, 1211, 1138, 1038 cm–1
.
.
1H NMR (500 MHz, CDCl3): δ = 1.32 (dt, J = 0.9, 7.1 Hz, 3 H), 1.33 (dt,
J = 0.9, 7.1 Hz, 3 H), 1.68–1.78 (m, 6 H), 2.87 (dd, J = 7.3, 17.6 Hz, 1 H),
3.03 (dd, J = 11.1, 17.6 Hz, 1 H), 3.98–4.13 (m, 6 H), 4.20–4.30 (m, 4
H), 4.79–4.87 (m, 1 H), 5.12 (s, 2 H), 7.78 (s, 1 H), 8.33 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 3.7, 24.8, 26.2, 44.1, 46.8, 54.4, 72.3,
84.5, 119.3, 138.3, 150.7, 150.8, 152.5, 166.9.
MS (ESI): m/z = 329 [M + H]+., 351 [M + Na]+..
13C NMR (125 MHz, CDCl3): δ = 16.1 (d, J = 6.7 Hz), 24.8, 26.2, 37.2,
39.8, 46.5, 64.2 (d, J = 6.0 Hz), 67.1 (d, J = 5.5 Hz), 79.2 (d, J = 7.8 Hz),
119.5, 137.6, 150.5, 152.7, 153.9, 154.2.
31P NMR (202 MHz, CDCl3): δ = –2.0.
MS (ESI): m/z = 453 [M + H]+., 475 [M + Na]+..
Anal. Calcd for C16H20N6O2: C, 58.52; H, 6.14; N, 25.59. Found: C,
58.41; H, 6.23; N, 25.48.
Anal. Calcd for C19H29N6O5P: C, 50.44; H, 6.46; N, 18.57. Found: C,
50.32; H, 6.52; N, 18.48.
Allyl Diethyl Phosphate (17a); Typical Procedure
I2 (2.05 g, 8.07 mmol) was added gradually over 5 min to a solution of
P(OEt)3 (16) (1.51 mL, 1.463 g, 8.82 mmol) in anhydrous CH2Cl2 (2
mL) at 0 °C. This mixture was stirred at r.t. for 5 min, then added
dropwise over 5 min to a solution of allyl alcohol (3a) (0.5 mL, 0.427
g, 7.36 mmol) and pyridine (2.37 mL, 29.41 mmol) in anhydrous
CH2Cl2 (2 mL) at 0 °C. Then, the mixture was stirred at r.t. for 5 min.
Et2O (50 mL) was added and the mixture was washed with 20% v/v
NaHSO4 (3 × 20 mL) and 0.1 M Na3PO4 as buffer (2 × 10 mL). The or-
ganic layer was dried and concentrated, and the residue was separat-
ed by column chromatography (silica gel; EtOAc–hexane, 1:1) to give
17a as an oil;18b yield: 1.271 g (89%).
Diethyl 2-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-5-yl}ethyl Phosphate (21b)
Yield: 88 mg (99%); orange oil.
IR (KBr): 3079, 2930, 2857, 1642, 1591, 1210, 1138, 1039 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.32 (t, J = 7.0 Hz, 6 H), 1.68–1.83 (m, 6
H), 1.87–1.94 (m, 1 H), 1.94–2.01 (m, 1 H), 2.63 (dd, J = 7.9, 17.3 Hz, 1
H), 3.03 (dd, J = 10.5, 17.3 Hz, 1 H), 4.05–4.18 (m, 6 H), 4.18–4.28 (m,
4 H), 4.78 (ddt, J = 5.3, 7.9, 10.5 Hz, 1 H), 5.12 (s, 2 H), 7.78 (s, 1 H),
8.33 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 16.2 (d, J = 6.5 Hz), 24.8, 26.2, 35.8 (d,
J = 6.7 Hz), 40.0, 40.6, 46.7, 63.9 (d, J = 2.4 Hz), 64.0 (d, J = 2.4 Hz),
78.1, 119.5, 137.6, 150.6, 152.7, 153.9, 154.6.
But-3-enyl Diethyl Phosphate (17b)
Yield: 1.24 g (81%); oil.18c
31P NMR (202 MHz, CDCl3): δ = –1.14.
Diethyl Pent-4-enyl Phosphate (17c)
Yield: 1.471 g (90%); oil.18d
IR (KBr): 3076, 2939, 1642, 1265, 1036, 978 cm–1
MS (ESI): m/z = 467 [M + H]+., 489 [M + Na]+..
Anal. Calcd for C20H31N6O5P: C, 51.50; H, 6.70; N, 18.02. Found: C,
51.63; H, 6.75; N, 17.94.
.
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Diethyl 3-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
Diethyl 1-{3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihy-
droisoxazol-5-yl}propyl Phosphate (21c)
droisoxazol-5-yl}ethyl Phosphate (24)
Yield: 90 mg (99%); orange oil.
Yield: 88 mg (99%); orange oil.
IR (KBr): 3063, 2931, 2853, 1589, 1565, 1062, 1024, 993 cm–1
.
IR (KBr): 3035, 2927, 2854, 1642, 1587, 1211, 1132, 1033 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.33 (t, J = 7.0 Hz, 6 H), 1.63–1.83 (m, 8
H), 1.97–2.20 (m, 2 H), 2.58 (dd, J = 8.2, 17.3 Hz, 1 H), 2.99 (dd,
J = 10.5, 17.3 Hz, 1 H), 3.97–4.21 (m, 6 H), 4.22–4.32 (m, 4 H), 4.50–
4.57 (m, 1 H), 5.13 (s, 2 H), 7.80 (s, 1 H), 8.36 (s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 1.15–1.37 (m, 18 H), 1.65–1.81 (m, 12
H), 2.92 (dd, J = 8.1, 18.4 Hz, 2 H), 2.97 (dd, J = 6.5, 18.4 Hz, 2 H), 4.01–
4.15 (m, 10 H), 4.16–4.29 (m, 8 H), 4.46–4.52 (m, 1 H), 4.52–4.67 (m, 2
H), 5.10 (s, 4 H), 7.77 (s, 1 H), 7.78 (s, 1 H), 8.33 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 16.2 (d, J = 5.8 Hz), 24.7, 26.2, 29.8,
31.3, 40.3, 40.4, 46.9, 63.9 (d, J = 6.2 Hz), 67.0 (d, J = 5.5 Hz), 81.2,
119.5, 137.9, 149.9, 151.9, 153.4, 154.3.
31P NMR (202 MHz, CDCl3): δ = –1.08.
MS (ESI): m/z = 481 [M + H]+., 503 [M + Na]+..
13C NMR (125 MHz, CDCl3): δ = 16.1 (d, J = 1.5 Hz), 16.2 (d, J = 2.2 Hz),
17.7 (d, J = 2.1 Hz), 22.7 (d, J = 2.2 Hz), 24.9, 26.2, 36.4, 36.8, 39.8, 39.9,
46.7, 63.9 (d, J = 3.6 Hz), 64.1 (d, J = 3.9 Hz), 74.7 (d, J = 6.1 Hz), 82.6
(d, J = 7.0 Hz), 83.5 (d, J = 7.5 Hz), 118.1, 119.6, 137.7, 150.6, 152.6,
153.9, 154.2, 154.3.
31P NMR (202 MHz, CDCl3): δ = –1.61, –1.80.
MS (ESI): m/z = 467 [M + H]+., 489 [M + Na]+..
Anal. Calcd for C21H33N6O5P: C, 52.49; H, 6.92; N, 17.49. Found: C,
52.41; H, 6.74; N, 17.28.
Anal. Calcd for C20H31N6O5P: C, 51.50; H, 6.70; N, 18.02. Found: C,
51.62; H, 6.74; N, 17.98.
Diethyl {5-Methyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-
dihydroisoxazol-5-yl}methyl Phosphate (22a)
Diethyl {3-[(6-Piperidin-1-yl-9H-purin-9-yl)methyl]isoxazol-5-
yl}methyl Phosphate (25)
Yield: 88 mg (99%); orange oil.
IR (KBr): 3030, 2930, 2857, 1642, 1589, 1482, 1214, 1132, 1036 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.23–1.37 (m, 6 H), 1.38 (s, 3 H), 1.60–
1.81 (m, 6 H), 2.64 (d, J = 17.6 Hz, 1 H), 3.02 (d, J = 17.6 Hz, 1 H), 3.89
(dd, J = 5.8, 10.8 Hz, 1 H), 3.98 (dd, J = 5.8, 10.8 Hz, 1 H), 4.09 (dq,
J = 6.9, 7.4 Hz, 4 H), 4.22–4.28 (m, 4 H), 5.08 (s, 2 H), 7.78 (s, 1 H), 8.33
(s, 1 H).
.
Yield: 85 mg (99%); orange oil.
IR (KBr): 3018, 2931, 2851, 1592, 1480, 1210, 1184, 1139, 1034 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.30 (dt, J = 0.9, 7.1 Hz, 6 H), 1.69–1.77
(m, 6 H), 4.04–4.15 (m, 4 H), 4.18–4.30 (m, 4 H), 5.06 (d, J = 8.9 Hz, 2
H), 5.44 (s, 2 H), 6.39 (s, 1 H), 7.79 (s, 1 H), 8.35 (s, 1 H).
.
13C NMR (125 MHz, CDCl3): δ = 16.1 (d, J = 5.9 Hz), 22.6, 24.9, 26.2,
40.1, 43.0, 46.6, 64.2 (d, J = 5.8 Hz), 70.3 (d, J = 5.3 Hz), 86.1 (d, J = 8.2
Hz), 119.7, 137.6, 150.8, 152.8, 154.1, 154.2.
13C NMR (125 MHz, CDCl3): δ = 16.1 (d, J = 6.6 Hz), 24.8, 26.2, 38.5,
46.6, 59.1 (d, J = 4.8 Hz), 64.4 (d, J = 6.0 Hz), 103.5, 119.6, 137.5, 150.6,
152.8, 153.9, 159.8, 168.1 (d, J = 7.7 Hz).
31P NMR (202 MHz, CDCl3): δ = –1.29.
31P NMR (202 MHz, CDCl3): δ = –1.40.
MS (ESI): m/z = 467 [M + H]+., 489 [M + Na]+..
MS (ESI): m/z = 451 [M + H]+., 473 [M + Na]+..
Anal. Calcd for C20H31N6O5P: C, 51.50; H, 6.70; N, 18.02. Found: C,
51.56; H, 6.57; N, 17.91.
Anal. Calcd for C19H27N6O5P: C, 50.66; H, 6.04; N, 18.66. Found: C,
50.59; H, 6.12; N, 18.57.
Diethyl {4-Phenyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-
dihydroisoxazol-5-yl}methyl Phosphate (22b) and Diethyl {5-Phe-
nyl-3-[(6-piperidin-1-yl-9H-purin-9-yl)methyl]-4,5-dihydroisox-
azol-4-yl}methyl Phosphate (23)
Biological Experiments
For the in vitro biological assays, test compounds were dissolved in
DMSO.
1) RA (%) measurements: interaction with the stable free radical
DPPH (final concentration: 0.05 mM) in absolute EtOH (final concen-
tration: 0.1 mM).14b–d
Yield of 22b + 23: 28 mg (28%) + 70 mg (70%); orange oil.
IR (KBr): 3085, 2983, 2908, 2836, 1638, 1588, 1480 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.28–1.36 (m, 8.4 H), 1.66–1.83 (m, 8.4
H), 3.28–3.34 (m, 1 H), 4.02–4.18 (m, 8.4 H), 4.18–4.33 (m, 5.6 H),
4.50 (d, J = 6.4 Hz, 0.4 H), 4.69–4.73 (m, 0.4 H), 4.95 (d, J = 15.4 Hz, 0.4
H), 5.03 (d, J = 15.4 Hz, 0.4 H), 5.17 (d, J = 15.8 Hz, 1 H), 5.27 (d,
J = 15.8 Hz, 1 H), 5.54 (d, J = 7.6 Hz, 1 H), 7.29–7.37 (m, 7 H), 7.57 (s,
0.4 H), 7.84 (s, 1 H), 8.26 (s, 0.4 H), 8.29 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 16.3 (d, J = 6.5 Hz), 16.5 (d, J = 3.9 Hz),
24.6, 24.8, 26.2, 26.3, 38.8, 38.9, 46.6, 47.2, 56.6, 57.5 (d, J = 6.8 Hz),
64.2 (d, J = 4.9 Hz), 64.5 (d, J = 3.3 Hz), 85.5, 87.7 (d, J = 2.0 Hz), 119.4,
119.5, 125.8, 127.5, 128.3, 128.7, 129.0, 129.2, 137.6, 137.8, 139.4,
139.7, 150.4, 150.6, 152.3, 152.6, 153.1, 153.2, 153.5, 153.8.
2) Lipoxygenase inhibition: the soybean lipoxygenase/linoleic sodi-
um protocol was used.14b–d
3) Antilipid peroxidation: the AAPH protocol was performed.14b–d
Acknowledgment
We are grateful to Prof. C. Panagiotidis and A. Dalli, Department of
Pharmacology and Pharmacognosy, School of Pharmacy, Aristotle
University of Thessaloniki, Greece for the tests of anti-HSV activity.
31P NMR (202 MHz, CDCl3): δ = –0.97, –1.15.
MS (ESI): m/z = 529 [M + H]+., 551 [M + Na]+..
References
(1) Preliminary communication presented at the 2nd Pharmaceuti-
cal Sciences Congress, October 9–11, 2014, Patra, Greece; Book
of Abstracts, p 13 (EA017).
Anal. Calcd for C25H33N6O5P: C, 56.81; H, 6.29; N, 15.90. Found: C,
56.65; H, 6.24; N, 15.76.
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