Conformationally constrained adamantaneoxazolines of pharmacological interest

Article abstract of DOI:10.3987/COM-08-11377

New conformationally constrained adamantane 2-oxazoline building blocks 1-4 were synthesized and their antimicrotubule and antitrypanosomal potency was investigated. Although most of the new compounds affect tubulin polymerization, this does not make a major contribution to trypanocidal activity.

Full text of DOI:10.3987/COM-08-11377

HETEROCYCLES, Vol. 75, No. 8, 2008, pp. 2043 - 2061. © The Japan Institute of Heterocyclic Chemistry
Received, 29th February, 2008, Accepted, 11th April, 2008, Published online, 14th April, 2008. COM-08-11377
CONFORMATIONALLY
CONSTRAINED
ADAMANTANE-
OXAZOLINES OF PHARMACOLOGICAL INTEREST
Ioannis Papanastasiou,a George B. Foscolos,a* Andrew Tsotinis,a Judit Oláh,b
Judit Ovádi,b S. Radhika Prathalingam,c and John M. Kelly c
aFaculty of Pharmacy, Department of Pharmaceutical Chemistry, University of
Athens,
Panepistimioupoli-Zografou,
15771
Athens,
Greece
tsotinis@pharm.uoa.gr
bInstitute of Enzymology, Biological Research Center, Hungarian Academy of
Sciences, H-1113 Budapest, Hungary
cDepartment of Infectious and Tropical Diseases, London School of Hygiene and
Tropical Medicine, London WC1E 7HT, U.K.
Abstract – New conformationally constrained adamantane 2-oxazoline building
blocks 1-4 were synthesized and their antimicrotubule and antitrypanosomal
potency was investigated. Although most of the new compounds affect tubulin
polymerization, this does not make a major contribution to trypanocidal activity.
The bulk and lipophilicity of the adamantane skeleton confers interesting biological features to its
derivatives. Thus aminoadamantanes, such as amantadine and rimantadine,1 have a significant activity
against influenza A virus, inhibiting virus replication by blocking the ion channel of the small virus
membrane protein M2. Previously, our laboratory has synthesized many aminoadamantanes,2 which have
a greatly increased potency compared to amantadine and rimantadine. Recently, we and others have
shown that aminoadamantanes3 also exhibit activity against the protozoan parasite Trypanosoma brucei,
the causative agent of African trypanosomiasis.
Oxazoline bearing agents, such as rhizoxin4 and 2-indolyloxazolines,5 display anticancer activity that has
been linked to their ability to block mitosis via inhibition of tubulin polymerization. Reports that rhizoxin
also exhibits trypanocidal activity4 has led us to synthesise conformationally constrained adamantane

2-oxazoline derivatives 1-4 (Figure 1) and investigate their antimicrotubule and antitrypanosomal
potency.
Figure 1
H
N
N
N
R
NH2
N
O
R
R
O
R
O
Me
O
R
1
2
4
3
The synthetic route leading to spiroadamantaneoxazolines 1 is depicted in Scheme 1. Reaction of
adamantanone 5 with KCN and ammonium chloride gave cyanohydrin 6,6 which was then reduced to the
aminoalcohol 7 with LiAlH4. 2-Adamantanol was formed as a by-product of the reduction because of
displacement of the "cyanohydrin-ketone equilibrium" towards the ketone owing to the basicity of LiAlH4.
The formation of this by-product could be minimized by using ether rather than THF as a solvent and
conducting the reaction at ambient temperature.
Addition of excess formic acid7 to aminoalcohol 7 followed by removal of formic acid in vacuo gave the
formate 8, which, when azeotropically distilled with a mixture of toluene-water, gave the formamide 9a
that on heating ring-closed to the spirooxazoline 1a. The 2-substituted spirooxazolines 1b-d were
prepared from 7 by acylation with the appropriate anhydride or acid chloride to give the intermediates
9b-d which were then cyclised with sulphuric acid.8 The 2-aminospirooxazoline 1e was prepared from the
hydrochloride 7 by treatment with potassium cyanate9 to give 10, which was then cyclised with
concentrated H2SO4 (Scheme 1).
Scheme 2 illustrates the synthetic route followed for the preparation of exocyclic adamantane oxazolines
2, from 1-adamantyl methyl ketone 11.10 The reaction of the aminoalcohol 13 with acyl chlorides and
triethylamine gave a mixture of the desired amides 15b-d together with some N,O-bisacyl derivatives.
Treatment of the reaction mixture with 1M NaOH at room temperature afforded the desired amides. The
exocyclic 2-aminoxazoline 2e was prepared from the hydrochloride 13 in a similar way to the
spirooxazoline 1e.

Scheme 1
CH2NH2
OH
O
CN
OH
a
b
6
7
5
c
e
+
-
CH2NH3, HCO2
CH2NHCOR
OH
OH
8
d
9b-d
f
CH2NHCH=O
OH
3
N
4
1'
5
8'
7'
R
2'
2
9'
10'
3' O
1
9a
6'
5'
4'
d
1b-d
N
O
a: R=H
b: R=Me
c: R=Et
d: R=Ph
1a
+
-
N
CH2NH
CH2NHCONH2
3 Cl
g
NH2
f
OH
OH
O
1e
7, HCl
10
Reagents and conditions: (a) KCN-NH4Cl/EtOH-H2O, rt. (b) LiAlH4/Et2O and then H2O/NaOH. (c)
HCO2H (98%), reflux, 2 h. (d) toluene/140 oC, Dean-Stark. (e) (RCO)2O/THF, rt or RCOCl/Et3N/THF, rt.
(f) i) conc. H2SO4 , 45-50 oC, ii) H2O ~0 oC, iii) NaOH (10%). (g) KOCN.

Scheme 2
a
b
Me
CN
OH
CH2NH2
OH
C
O
C
C
Me
Me
12
13
11
c
e
+
-
CH2NH3, HCO2
CH2NHCOR
OH
C
C
OH
Me
d
Me
10
15b-d
f
7'
3
N
4
8'
1'
6'
5'
CH2NHCH O
OH
10'
9'
C
5
R
2
4'
O
3'
2'
Me
15a
Me
1
2b-d
d
a: R=H
b: R=Me
c: R=Et
d: R=Ph
N
O
Me
2a
-
Cl
+
N
g
f
CH2NH3
CH2NHCONH2
OH
C
C
NH2
O
OH
Me
Me
Me
13, HCl
2e
16
Reagents and conditions: (a) KCN-NH4Cl/EtOH-H2O rt. (b) LiAlH4/Et2O and then aq NaOH (2N). (c)
HCO2H (98%), reflux 2 h. (d) toluene/140 oC – Dean Stark. (e) (RCO)2O/THF, rt or RCOCl/Et3N/THF, rt.
(f) i) conc. H2SO4 , 45-50 oC, ii) H2O ~0 oC, iii) NaOH (10%). (g) KOCN.

Oxazolines 3a,b were synthesized from 2-amino-2-adamantanemethanol 172(b) as illustrated in Scheme 3.
Again N,O-bisacyl derivatives (18a,b) were formed. These were hydrolysed with NaOH to the amides
19a,b which were cyclised to the oxazolines 3a,b (Scheme 3).
During the reaction of acylchlorides to aminoalcohol 17, N,O-bisacyl derivatives 18a,b were again
formed, which were hydrolyzed to amides 19a,b. The latter molecules were cyclized to their respective
oxazolines 3a,b with tosyl chloride11 in pyridine.
Scheme 3
5'
6'
7'
4'
a
c
b
9'
10'
2'
3'
N3
NH2
NHCOR
NHCOR
CH2OH
19a,b
1'
8'
4
1'
5
CH2OCOR
CH2OH
R
1
O
2
17
18a,b
a: R=Me
b: R=Ph
3a,b
Reagents and conditions: (a) RCOCl/Et3N/THF, rt. (b) NaOH (1N), rt, 12 h. (c) TsCl/Py, 115-120 oC,
15 h.
The synthesis of trimethyl derivative 3c from 2-amino-2-adamantanecarboxylic acid 2012 as starting
material is shown in Scheme 4. The amino acid 20 was acylated to acetamido acid 21, which was then
converted into methyl ester 22. Addition of excess methylmagnesium iodide to the amidoester 22 gave a
mixture of aminoalcohol 23 and aminoketone 24, which was cyclized without further purification with
sulphuric acid to trimethyloxazoline 3c and the methylene derivative 25.
Finally, the fused system 4 was prepared by reaction of potassium cyanate with the hydrochloride 2613
followed by cyclisation with concentrated HCl (Scheme 5).
A preliminary pharmacological investigation with selected compounds was carried out on Microtubule
Associated Protein-depleted tubulin, which was purified from bovine brain.14 The tubulin polymerization
was initiated by addition of paclitaxel and then the effect of the compounds on polymerization was
evaluated. Some of the adamantaneoxazolines inhibit tubulin polymerization and the results for the active
compounds are presented in Table 1.

Scheme 4
a
c
b
+
NH2
CO2H
NHAc
CO2H
NHAc
CO2Me
NHAc
OH
NHAc
Me
Me
C
Ac
24
23
21
22
20
d
+
N
N
Me
Me
Me
H2C
Me
O
O
3c
25
o
Reagents and conditions: (a) (CH3CO)2O/CHCl3, 60 C, 18 h. (b) gas HCl/CH3OH, rt. (c) CH3MgI/Et2O
and then NH4Cl/H2O. (d) i) conc. H2SO4, rt, 15 min, ii) H2O ~0 oC, iii) NaOH (10%).
Scheme 5
H
H
H
6
N
NH3 , Cl
a
NH C NH2
O
8
9
7
b
12
13
NH2
5
10
3
O
OH
OH
2
11
1
4
27
26, HCl
4
Reagents and conditions: (a) KOCN. (b) i) conc. HCl, 40-50 oC, 6 h, ii) H2O ~0 oC, iii) NaOH (10%).
To investigate if the new adamantane derivatives also had trypanocidal properties, they were tested3(a),15
against the bloodstream form of T. brucei. None of the spiroadamantaneoxazolines (1a-d), the exocyclic
adamantine oxazolines 2a-d, or 4-oxa-6-azatetracyclo[6.3.1.1.3,10.03,7]tridec-5-en-5-amine (4) displayed
any activity at 5 μg mL-1. Oxazolines 3a-c had a slight effect, inhibiting parasite growth in the range of
25-50% under the conditions tested. The only compound to show significant activity was the
aminoxazoline 2e, which caused 100% cell death at 5 μg mL-1. Further investigation, carried out in
triplicate, demonstrated that this compound was about 6-fold more effective than rimantadine against
bloodstream form T. brucei, with an IC50 of 0.89 + 0.23 μM and an IC90 of 2.40 + 0.11 μM.

Table 1. Effects of compounds on paclitaxel-induced tubulin polymerization
Compound
Inhibition of tubulin polymerization
Inhibition of tubulin polymerization
at 50 μM drug concentration (%)
at 100 μM drug concentration (%)
1a
1c
1d
2c
2d
3f
4
45
20
60
0
50
45
80
0
70
0
86
10
64
59
There was no obvious correlation between inhibition of tubulin polymerization and the activity of the
derivatives against bloodstream form T. brucei. Compounds 1a, 1c, 1d and 2d and 4 resulted in moderate
to significant inhibition of tubulin polymerization (Table 1), but had no effect on trypanosomes.
Interestingly, the only derivative which had a high level of activity was the aminoxazoline 2e. Previously,
we have shown that trypanocidal adamantanes derivatives require an amino group.3 This can be attached
directly to the adamantane ring, or via a side group, and can be substituted or non-substituted. It is a
reasonable assumption therefore, that the enhanced activity displayed by 2e, compared to the other
oxazoline derivatives, can be attributed to the amino group. Furthermore, it can be inferred that the
primary target in the trypanosome is probably the same as that of the other aminoadamantane derivatives
we have previously tested.3 The mechanism of action of these derivatives in the case of T. brucei is
unknown, but in other systems, such as influenza A virus infected cells, the therapeutic effect is mediated
by channel blocking activity.3 Although we cannot exclude the possibility that oxazoline derivatives may
affect tubulin polymerization in trypanosomes, our results suggest that this does not make a major
contribution to trypanocidal activity.
EXPERIMENTAL
Melting points were determined using a Büchi capillary apparatus and an uncorrected. Infrared (IR)
1
spectra were recorded on a Perkin-Elmer 833 spectrophotometer. H NMR spectra were recorded on
Bruker AC 200 and MSL 400 spectrometers operating at 200 and 400 MHz, respectively, using CDCl3 as
solvent and TMS as internal standard. 13C proton decoupled NMR spectra were recorded on a Bruker AC
200 at 50 MHz using CDCl3 or DMSO as solvent. 2D NMR experiments (HMQC and COSY) were used
for the elucidation of the structures of selected compounds. Service Central de Microanalyse (CNRS) in

France carried out microanalyses and the results obtained had a maximum deviation of ± 0.4% from the
theoretical value.
2-Hydroxy-2-tricyclo[3.3.1.1.3,7]decanecarbonitrile (6)
To a solution of adamantanone 5 (2.00 g, 13.3 mmol) in EtOH (30 mL) was added a solution of
ammonium chloride (2.13 g, 39.9 mmol) in water (10 mL) and a solution of potassium cyanide (2.60 g,
39.9 mml) in water (10 mL). The mixture of reaction was stirred overnight at rt. Then the solvent was
evaporated under vacuum and water was poured into the residue. The mixture was extacted with Et2O and
the organic phase was washed with water, dried over sodium sulfate and evaporated to give 2.30 g (98%)
o
of 6, mp 232-233 C. The IR spectrum has shown the existence of ketone 5 as by product. Compound 6
was used without further purification for the preparation of amine 7.
2-Hydroxy-2-tricyclo[3.3.1.1.3,7]decane-2-methanamine (7)
To a stirred suspension of LiAlH4 (1.97 g, 52.0 mmol) in dry Et2O (50 mL) was added dropwise a
solution of cyanohydrin 6 (2.30 g, 13.0 mmol) in dry ether (20 mL). The reaction mixture was stirred at rt
for 4 h and then left standing overnight. Afterwards, it was hydrolyzed with aqueous sodium hydroxide
(10%) under ice cooling. The inorganic precipitate formed was filtered off, washed with hot THF, and the
filtrate was concentrated in vacuo. Water was poured into the residue followed by the addition of
hydrochloric acid (3%). The aqueous layer was washed with Et2O, made alkaline with solid sodium
carbonate and extracted with CH2Cl2. The organic layer was dried over sodium sulfate and evaporated to
o
1
give 1.27 g (54%) of 7, mp (hydrochloride) > 250 C; H NMR (CDCl3) δ 1.50-1.54 (brd, 2H, 4΄eq, 9΄eq
-H ), 1.65-1.84 (complex m, 13H, 1, 3, 5, 6, 7, 8, 10-H, OH, NH2), 2.18-2.21 (brd, 2H, 4΄ax, 9΄ax-H), 2.82
(s, 2H, CH2N).
N-(2-Hydroxy-2-tricyclo[3.3.1.1.3,7]decylmethyl)acetamide (9b)
To a stirred suspension of aminoalcohol 7 (1.0 g, 5.5 mmol) in dry THF (10 mL) was added dropwise
under ice cooling acetic anhydride (3.0 mL, 33.0 mmol). A white precipitate was immediately formed and
the mixture was stirred overnight at ambient temperature. Afterwards, it was poured onto chilled water
and extracted with EtOAc. The organic layer was washed with water, hydrochloric acid (5%), a solution
of aqueous sodium carbonate and dried over sodium sulfate. The solvent was evaporated under vacuum to
o
give 1.06 g (86%) of 9b in crystalline form, mp 191-193 C. The product was used without further
purification for the preparation of the spiro compound 1b. IR (Nujol) ν 3334 (ΟΗ), 1643 (C=O) cm-1; 1H
NMR (DMSO-d6) δ 1.34-1.37 (brd, 2H, 4eq, 9eq-H), 1.52-1.56 (m, 6H, 6, 8, 10-H), 1.69 (brs, 2H, 5,7-H),
1.76 (brs, 2H, 1, 3-H), 1.80 (s, 3H, CH3), 2.10-2.13 (brd, 2H, 4ax, 9ax-H), 3.26-3.28 (d, J ~ 6 Hz, 2H,
CH2N), 7.55 (brs, 1H, NH); 13C NMR (DMSO-d6) δ 22.8 (CH3), 26.9 (5-C), 27.3 (7-C), 32.4 (4, 9-C),
34.2 (8, 10-C), 34.8 (1, 3-C), 38.2 (6-C), 46.1 (CH2N), 73.7 (2-C), 170.2 (C=O).

N-(2-Hydroxy-2-tricyclo[3.3.1.1.3,7]decylmethyl)propanamide (9c)
To a stirred suspension of aminoalcohol 7 (1.27 g, 7.0 mmol) in dry THF (20 mL) was added dropwise
under ice cooling propionic anhydride (1.97 g, 21.0 mmol). The mixture was stirred overnight at rt and
then filtered off. The precipitate was washed with water, hydrochloric acid (5%) and water, and dried to
o
give 0.92 g (55%) of 9c in crystalline form, mp 134-135 C. The product was used without further
purification for the preparation of the spiro derivative 1c. 1H NMR (CDCl3) δ 1.10-1.14 (t, JAX = 7.5 Hz,
3H, A3X2, CH3CH2CO), 1.52-1.55 (brd, 2H, 4eq, 9eq -H ), 1.64-1.69 (m, 6H, 1, 3, 6, 7, 8eq, 10eq-H), 1.79
(brs, 2H, 5, 7-H), 1.84-1.87 (brd, 2H, 8ax, 10ax-H), 2.07-2.10 (brd, 2H, 4ax, 9ax-H), 2.18-2.24 (q, JAX = 7.5
Hz, 2H, A3X2, CH3CH2CO), 2.80 (brs, 1H, OH), 3.49-3.51(d, J = 6.0 Hz, 2H, CH2N), 6.15 (brs, 1H, NH);
13C NMR (CDCl3) δ 10.0 (CH3CH2CO), 27.0 (5-C), 27.3 (7-C), 29.6 (CH3CH2CO), 32.6 (4, 9-C), 34.4 (8,
10-C), 35.3 (1, 3-C), 38.0 (6-C), 46.3 (CH2N), 75.1 (2-C), 174.8 (C=O).
N-(2-Hydroxy-2-tricyclo[3.3.1.1.3,7]decylmethyl)benzamide (9d)
To a stirred suspension of aminoalcohol 7 (1.0 g, 5.5 mmol) in dry THF (10 mL) was added triethylamine
(734 mg, 7.2 mmol) and then dropwise a solution of benzoyl chloride (928 mg, 6.6 mmol) in dry THF (10
mL) at 0 oC. Following the work up used for 9b the title compound was obtained in 80% yield (1.25 g) in
crystalline form, mp 179-181 oC. The product was used without further purification for the preparation of
1
the spiro derivative 1d. H-NMR (CDCl3) δ 1.56-1.59 (d, 2H, 4eq, 9eq -H), 1.67 (brs, 2H, 6-H), 1.69-1.81
(m, 6H, 1, 3, 5, 7, 8eq, 10eq-H), 1.92-1.95 (d, 2H, 8ax, 10ax-H), 2.08-2.11 (d, 2H, 4ax, 9ax-H), 2.56 (brs, 1H,
OH), 3.71-3.72 (d, J = 6.0 Hz, 2H, CH2N), 6.74 (brs, 1H, NH), 7.35-7.39 (m, 2H, 3, 5-Ηarom), 7.43-7.47
(m, 1H, 4-Ηarom), 7.75-7.77 (m, 2H, 2, 6-Ηarom); 13C-NMR (CDCl3) δ 27.0 (5-C), 27.3 (7-C), 32.6 (4, 9-C),
34.4 (8, 10-C), 35.4 (1, 3-C), 38.0 (6-C), 46.7 (CH2N), 75.5 (2-C), 127.0 (2, 6-Carom), 128.4 (3, 5-Carom),
131.4 (4-Carom), 134.4 (1-Carom), 168.1 (C=O).
Spiro[oxazol-5(4Η),2΄-tricyclo[3.3.1.1.3,7]decane] (1a)
Aminoalcohol 7 (850 mg, 4.7 mmol) was dissolved in formic acid (98%, 10 mL) and then refluxed for 2 h.
The excess of formic acid was removed in vacuo under heating, and dry toluene (20 mL) was added to the
o
mixture, which was heated at 140 C in a Dean-Stark apparatus for 2 h after the start of azeotropic
distillation of toluene-water. The gluey residue was crystallized with Et2O and n-pentane, and then
o
filtered and dried to give 470 mg of formamide 9a in crystalline form, mp 117 C. The filtrate was
evaporated to give 300 mg of a ropy residue, which was purified by flash column chromatography (Et2O)
to give 90 mg of 1a. Formamide 9a (470 mg) was re-dissolved in dry toluene and heated with formic acid
(98%, 5 mL) in a Dean-Stark apparatus for 3 h after the start of azeotropic distillation of toluene-water.
The solvent was evaporated under vacuum and the residue was purified by flash chromatography (Et2O)
to give 172 mg of 1a. Total yield of 1a 29% (262 mg); 1H NMR (CDCl3) δ 1.56-1.79 (m, 12H, 1΄, 3΄, 4΄eq,
5΄, 6΄, 7΄, 8΄, 9΄eq, 10΄-H), 2.03-2.06 (brd, 2H, 4΄ax, 9΄ax-H), 3.54-3.55(d, J = 2.0 Hz, 2H, 4-H), 6.75 (s, 1H,

13
2-H); C NMR δ 26.4 (5΄-C), 26.6 (7΄-C), 33.4 (4΄, 9΄-C), 34.6 (8΄, 10΄-C), 36.6 (1΄, 3΄-C), 37.1 (6΄-C),
62.6 (4-C), 89.3 (5, 2΄-C), 154.5 (2-C); mp (picrate) 166-168 oC (decomp) (MeOH-Et2O). Anal. Calcd for
C26H28N4O8 (picrate): C, 51.43; H, 4.80. Found: C, 51.19; H, 4.90.
2-Methylspiro[oxazol-5(4Η),2΄-tricyclo[3.3.1.1.3,7]decane] (1b)
Amide 9b (860 mg, 3.9 mmol) was dissolved in small portions into sulphuric acid (98%, 2mL) under ice
o
cooling. The solution formed was left for 25 min and then heated under stirring at 45-50 C for 15 min.
Chilled water was then poured onto the mixture, which was made alkaline on addition of a solution of
aqueous sodium hydroxide. The resulting mixture was extracted with Et2O and the organic layer dried
over sodium sulfate. Evaporation of Et2O in vacuo gave 750 mg (94%) of 1b in crystalline form, mp
o
1
111-113 C; H NMR (CDCl3) δ 1.57-1.82 (m, 12H, 1΄, 3΄, 4΄eq, 5΄, 6΄, 7΄, 8΄, 9΄eq, 10΄-H), 1.92(s, 3H,
13
CH3), 2.06-2.09 (brd, 2H, 4΄ax, 9΄ax-H), 3.54-3.55 (d, J = 1.0 Hz, 2H, 4-H); C NMR (CDCl3) δ 14.6
(CH3), 26.35(5΄-C), 26.6 (7΄-C), 33.4 (4΄, 9΄-C), 34.4 (8΄, 10΄-C), 36.7 (1΄, 3΄-C), 37.1 (6΄-C), 63.7 (4-C),
89.9 (5,2΄-C), 164.4 (2-C); mp (picrate) 202-204 oC (decomp) (MeOH-Et2O). Anal. Calcd for C19H22N4O8
(picrate): C, 52.53; H, 5.10. Found: C, 52.70; H, 5.10.
2-Ethylspiro[oxazol-5(4Η),2΄-tricyclo[3.3.1.1.3,7]decane] (1c)
1
Oxazoline 1c was prepared from amide 9c following the procedure used for 1b; yield 73%. H-NMR
(CDCl3) δ 1.11-1.15 (t, JAX = 7.5 Hz, 3H, A3X2, CH3), 1.57-1.76 (m, 12H, 1΄, 3΄, 4΄eq, 5΄, 6΄, 7΄, 8΄, 9΄eq,
10΄-H ), 2.06-2.09 (brd, 2H, 4΄ax, 9΄ax-H), 2.20-2.26 (q, JAX = 7.5 Hz, 2H, A3X2, CH2), 3.55 (s, 2H, 4-H);
13C NMR (CDCl3) δ 10.3 (CH3), 21.9 (CH2), 26.4 (5΄-C), 26.6 (7΄-C), 33.5 (4΄, 9΄-C), 34.5 (8΄, 10΄-C),
o
36.7 (1΄, 3΄-C), 37.2 (6΄-C), 63.5 (4-C), 89.5 (5,2΄-C), 168.4 (2-C); mp (picrate) 201-202 C (decomp)
(MeOH-Et2O). Anal. Calcd for C20H24N4O8 (picrate): C, 53.57; H, 5.39. Found: C, 53.47; H, 5.35.
2-Phenylspiro[oxazol-5(4Η),2΄-tricyclo[3.3.1.1.3,7]decane] (1d)
Oxazoline 1c was prepared from amide 9d following the procedure used for 1b; yield 70%. The solvent
used for the extraction was CHCl3; mp 118-120 oC; 1H NMR (CDCl3) δ 1.66-1.92 (m, 12H, 1΄, 3΄, 4΄eq, 5΄,
6΄, 7΄, 8΄, 9΄eq, 10΄-H ), 2.24-2.27 (brd, 2H, 4΄ax, 9΄ax-H), 3.83 (s, 2H, 4-H), 7.36-7.46(m, 3H, 3, 4, 5-
Ηarom), 7.94-7.96 (~d, 2H, 2, 6- Ηarom); 13C NMR (CDCl3) δ 26.4 (5΄-C), 26.7 (7΄-C), 33.6 (4΄, 9΄-C), 34.5
(8΄, 10΄-C), 36.8 (1΄, 3΄-C), 37.2 (6΄-C), 63.9 (4-C), 90.1 (5,2΄-C), 128.0 (2, 6-Carom), 128.2 (1, 3, 5-Carom),
o
131.0 (4-Carom), 163.2 (2-C). mp (picrate) 206-208 C (decomp) (MeOH-Et2O). Anal. Calcd for
C24H24N4O8 (picrate); C, 58.06; H, 4.87. Found C, 58.19; H, 4.88.
N-[2-Hydroxy-2-(tricyclo[3.3.1.1.3,7]decylmethyl)]urea (10)
To a stirred solution of the hydrochloride of 7 (476 mg, 2.2 mmol) in water (8 mL) was added potassium
cyanate (178 mg, 2.2 mmol). The mixture was refluxed for 4 h and then the solvent was evaporated under
vacuum to give a solid residue, which was dissolved in boiling EtOH. The solution was filtered through a
fluted filter paper and the filtrate was evaporated in vacuo to give 370 mg (75%) of crystalline 10, mp

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202-204 C. The product was used without further purification for the preparation of spiro amine 1e. H
NMR (CDCl3) δ 1.35-1.38 (brd, 2H, 4eq, 9eq -H ), 1.53-1.79 (m, 10H, 1, 3, 5, 6, 7, 8, 10-H), 1.69 (brs, 2H,
5, 7-H), 2.11-2.14 (brd, 2H, 4ax, 9ax-H), 3.18-3.20 (d, J = 5.5 Hz, 2H, CH2N), 5.52 (s, 2H, NH2), 5.93 (brs,
13
1H, NH); C NMR (CDCl3) δ 27.0 (5-C), 27.4 (7-C), 32.5 (4, 9-C), 34.1 (8, 10-C), 34.8 (1, 3-C), 38.2
(6-C), 46.5 (CH2N), 73.9 (2-C), 159.8 (C=O).
Spiro[oxazol-5(4Η),2΄-tricyclo[3.3.1.1.3,7]decane]-2-amine (1e)
Urea 10 (250 mg, 1.1 mmol) was dissolved in small portions in sulphuric acid (98%, 1 mL) under ice
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cooling. The solution was heated at 45-50 C for 2 h and then poured onto chilled water. The resulting
mixture was washed with EtOAc, made alkaline with a solution of aqueous sodium hydroxide, extracted
with EtOAc and then the organic layer was dried over sodium sulfate. The solvent was evaporated under
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reduced pressure to give 200 mg (88%) of crystalline 1e, mp 162-164 C (Et2O); H NMR (CDCl3) δ
1.58-1.80 (m, 10H, 4΄eq, 5΄, 6΄, 7΄, 8΄, 9΄eq, 10΄-H ), 1.96 (brs, 2H, 1΄, 3΄-H), 2.04-2.07 (brd, 2H, 4΄ax, 9΄ax
-H), 3.52 (s, 2H, 4-H), 4.66 (s, 2H, NH2); 13C NMR (CDCl3) δ 26.4 (5΄-C), 26.6 (7΄-C), 33.5 (4΄, 9΄-C),
34.5 (8΄, 10΄-C), 36.5 (1΄, 3΄-C), 37.2 (6΄-C), 61.1 (4-C), 91.0 (5, 2΄-C), 164.1 (2-C). Anal. Calcd for
C12H18N2O: C, 69.87; H, 8.80. Found: C, 70.11; H, 8.72.
1-Tricyclo[3.3.1.1.3,7]decylethanone (11)
A mixture of β-oxo-1-tricyclo[3.3.1.1.3,7]decanepropanoic acid ethyl ester10 (10.44 g, 41.8 mmol) in
sulphuric acid (98%, 2.4 mL) and water (12.5 mL) was refluxed for 4 h and then poured onto chilled
water, where some of the product crystallized. The mixture was taken up with ether and the organic layer
was exhaustively washed with water and a solution of aqueous sodium carbonate, dried over sodium
sulfate and evaporated under reduced pressure to give 6.26 g (84%) of 11, mp 53-54 oC.
α-Hydroxy-α-methyl-1-tricyclo[3.3.1.1.3,7]decaneacetonitrile (12)
Ketone 11 (6.26 g, 35.2 mmol), sodium cyanide (6.9 g, 140.8 mmol) and ammonium chloride (7.53 g
140.8 mmol) in a mixture of Et2O, water and THF (1:1:1, 90 mL) was vigorously stirred overnight. Then
water was poured onto the mixture, which was extracted with Et2O. The organic layer was washed with
water, hydrochloric acid (5%) and water. After drying over sodium sulfate the solvent was removed under
vacuum to give 6.45 g of the title compound, along with some amount of 11 (IR spectral data). The
product was used without further purification for the preparation of amine 13.
α-Hydroxy-α-methyl-1-tricyclo[3.3.1.1.3,7]decanemethanamine (13)
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To a chilled (0 C) stirred suspension of LiAlH4 (2.0 g, 53.3 mmol) in dry Et2O (60 mL) was added
dropwise a solution of cyanohydrin 12 (3.00 g, 14.6 mmol) in dry Et2O (40 mL). The reaction mixture
was stirred at rt for 4 h, and then hydrolyzed by adding water and a solution of aqueous sodium hydroxide
(10%) under ice cooling. The inorganic precipitate formed was filtered off, washed with hot THF, and the
filtrate was concentrated in vacuo. Water was poured onto the residue and then hydrochloric acid (3%).

The aqueous layer was washed with Et2O, made alkaline with solid sodium carbonate and extracted with
CH2Cl2. The organic layer was dried over sodium sulfate and evaporated in vacuo to give 1.2 g (39%) of
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amine 13. Melting of this material commences at 120-121oC and ceases at 126-127 C (decomp). The
1
product was used without further purification for the preparation of acetamide 15b. H NMR (CDCl3) δ
1.01 (s, 3H, CH3), 1.58-1.68 (m, 14H, 2, 4, 6, 8, 9, 10-H, NH2), 1.95 (brs, 4H, 3, 5, 7-H, OH), 2.45-2.79
13
(q, JAB = 12.6 Hz, 2H, AB, CH2N); C NMR (CDCl3) δ 19.4 (CH3), 28.5 (3, 5, 7-C), 36.3 (4, 6, 10-C),
37.2 (2, 8, 9-C), 38.4 (1-C), 44.8 (CH2N), 74.2 (C-O).
N-[2-Hydroxy-2-(1-tricyclo[3.3.1.1.3,7]decyl)propyl]acetamide (15b)
To a stirred suspension of aminoalcohol 13 (1.48 g, 7.1 mmol) in dry THF (25 mL) was added
triethylamine (1.88 g, 18.46 mmol) and then dropwise under ice cooling a solution of acetyl chloride (725
mg, 9.23 mmol) in dry THF (10 mL). The mixture was stirred at ambient temperature overnight, poured
onto chilled water and extracted with CH2Cl2. The organic layer was washed with water, hydrochloric
acid (5%), water and dried over sodium sulfate. The solvent was then evaporated under vacuum to give
1.52 g of a product, which was dissolved in EtOH (20 mL) and saponified with a solution of aqueous
sodium hydroxide (976 mg, 24.4 mmol) in water (2 mL) for 2 h. EtOH was then removed in vacuo and
water was poured onto the residue. The mixture was extracted with CH2Cl2, the organic layer dried over
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sodium sulfate and evaporated to give 1.38 g (78%) of 15b, mp 147-149 C. The product was used
without further purification for the preparation of oxazole 2b. IR (Nujol) ν 3335 (ΟΗ), 1654 (C=O) cm-1;
1H NMR (CDCl3) δ 1.01(s, 3H, CH3), 1.57-1.68 (m, 14H, 2, 4, 6, 8, 9, 10-H, NH2), 1.97 (brs, 4H, 3, 5,
7-H), 2.00 (s, 3H, CH3CO), 2.48 (brs, 1H, OH), 3.19-3.26 (m, 1H, ABX, CHAHNH), 3.33-3.38 (m, 1H,
13
ABX, CHHBNH), 6.18 (brs, 1H, NH); C NMR (CDCl3) δ 19.0 (CH3), 23.3 (CH3CO), 28.4 (3, 5, 7-C),
36.0 (4, 6, 10-C), 36.9 (2, 8, 9-C), 38.6 (1-C), 44.2 (CH2N), 76.2 (C-OH), 171.4 (C=O).
N-[2-Hydroxy-2-(1-tricyclo[3.3.1.1.3,7]decyl)propyl]propanamide (15c)
To a stirred suspension of aminoalcohol 13 (840 mg, 4.0 mmol) in dry THF (20 mL) was added
triethylamine (813 mg, 8.0 mmol) and then dropwise under ice cooling a solution of propionyl chloride
(444 mg, 4.8 mmol) in dry THF (10 mL). Amide 15c (1.0 g, 95%) was obtained in crystalline form after
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employing the same work up used for 15b; mp 112-114 C. The product was used without further
purification for the preparation of oxazole 2c. IR (Nujol) ν 3350 (ΟΗ), 3286 (ΝΗ), 1648 (C=O) cm-1; 1H
NMR (CDCl3) δ 1.01(s, 3H, CH3), 1.11-1.15 (t, JAX = 7.5 Hz, 3H, A3X2, CH3CH2CO), 1.57-1.67 (m, 14H,
2, 4, 6, 8, 9, 10-H, NH2), 1.97 (brs, 4H, 3, 5, 7-H), 2.19-2.25 (q, JAX = 7.5 Hz, 2H, A3X2, CH3CH2CO),
2.46 (brs, 1H, OH), 3.22-3.26 (m, 1H, ABX, CHAHNH), 3.33-3.38 (m, 1H, ABX, CHHBNH), 6.18 (brs,
1H, NH); 13C NMR (CDCl3) δ 10.0 (CH3CH2CO), 18.9 (CH3), 28.4 (3, 5, 7-C), 29.7 (CH3CH2CO), 36.0
(4, 6, 10-C), 36.9 (2, 8, 9-C), 38.7 (1-C), 44.0 (CH2N), 76.2 (C-OH), 175.1 (C=O).
N-[2-Hydroxy-2-(1-tricyclo[3.3.1.1.3,7]decyl)propyl]benzamide (15d)

To a stirred suspension of aminoalcohol 13 (1.12 g, 5.4 mmol) in dry THF (20 mL) was added
triethylamine (1.42 g, 13.9 mmol) and then dropwise under ice cooling a solution of benzoyl chloride
(980 mg, 6.9 mmol) in dry THF (10 mL). Benzamide 15d (1.05 g, 63%) was obtained as an off-white
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soilid after employing the same work up used for 15b. Melting of this compound commences at 135 C
and ceases at 150 oC. The product was used without further purification for the preparation of oxazole 2d.
IR (Nujol) ν 3339 (ΟΗ), 1637 (C=O) cm-1; 1H NMR (CDCl3) δ 1.09 (s, 3H, CH3), 1.59-1.70 (m, 12H, 2, 4,
6, 8, 9, 10-H,), 1.99 (s, 3H, 3, 5, 7-H), 2.47 (brs, 1H, OH), 3.39-3.43 (m, 1H, ABX, CHAHNH), 3.59-3.64
(m, 1H, ABX, CHHBNH), 6.76 (brs, 1H, NH), 7.35-7.39 (m, 2H, 3, 5-Harom), 7.43-7.47 (m, 1H, 4-Harom),
13
7.74-7.76 (d, J = 7.5 Hz, 2H, 2, 6-Harom); C NMR (CDCl3) δ 19.2 (CH3), 28.4 (3, 5, 7-C), 36.0 (4, 6,
10-C), 36.9 (2, 8, 9-C), 38.8 (1-C), 44.4 (CH2N), 76.5 (C-OH), 126.9 (2, 6-Carom), 128.5 (3, 5-Carom),
131.4 (4-Carom), 134.5 (1-Carom), 168.5 (C=O).
4,5–Dihydro-5-methyl-5-(1-tricyclo[3.3.1.1.3,7]decyl)oxazole (2a)
Oxazoline 2a was prepared by the procedure used for the synthesis of 1a, by reacting aminoalcohol 13
with formic acid; yield 35%, mp (formamide 15a) 142-143 oC; mp (oxazoline 2a) 159-161 oC (Et2O); 1H
NMR (CDCl3) (oxazoline 2a) δ 1.23 (s, 3H, 5-CH3), 1.52 (br.s, 6H, 2´, 8´, 9´-H), 1.58-1.68 (brq, 6H, 4´,
6´, 10´-H), 1.98 (brs, 3H, 3´, 5´, 7´-H), 3.20-3.83 (q, JAB = 14.5 Hz, 2H, AB, 4-H), 6.72 (s, 1H, 2-H); 13C
NMR. (CDCl3) (oxazoline 2a) δ 20.8 (CH3), 27.9 (3´, 5´, 7´-C), 35.7 (4´, 6´, 10´-C), 36.7 (2´, 8´, 9´-C),
37.5 (1´-C), 59.9 (4-C), 89.9 (5-C), 154.4 (2-C). Anal. Calcd for C20H24N4O8: C, 76.67; H, 9.65. Found:
C, 76.91; H, 9.62.
4,5–Dihydro-2,5-dimethyl-5-(1-tricyclo[3.3.1.1.3,7]decyl)oxazole (2b)
Amide 15b (640 mg, 2.6 mmol) was dissolved in small portions into sulphuric acid (98%, 2 mL) under
ice cooling. The solution was chilled for 15 min and then cold water was poured onto the mixture, which
was made alkaline by adding a solution of aqueous sodium hydroxide. The mixture was extracted with
Et2O and the organic layer dried over sodium sulfate and concentrated in vacuo to give a gluey residue,
which was purified by flash column chromatography (Et2O) to give 515 mg (87%) of 2b; mp 192-193 oC
(MeOH-Et2O). 1H NMR (CDCl3) δ 1.21 (s, 3H, 5-CH3), 1.51 (brs, 6H, 4´, 6´,10´-H), 1.57-1.68 (brq, 6H,
2´, 8´, 9´-H), 1.90 (s, 3H, 2-CH3), 1.97 (brs, 3H, 3´, 5´, 7´-H), 3.18-3.81 (q, JAB = 14.0 Hz, 2H, AB 4-H);
13C NMR (CDCl3) δ 14.2 (2-CH3), 20.8 (5-CH3), 28.1 (3´, 5´, 7´-C), 35.8 (4´, 6´, 10´-C), 36.9 (2´, 8´,
9´-C), 37.7 (1´-C), 61.1 (4-C), 90.5 (5-C), 164.4 (2-C). Anal. Calcd for C21H26N4O8 (picrate): C, 54.54; H,
5.67. Found: C, 54.53; H, 5.92.
4,5–Dihydro-2-ethyl-5-methyl-5-(1-tricyclo[3.3.1.1.3,7]decyl)oxazole (2c)
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Oxazoline 2c was prepared by the procedure used for the synthesis of 2b; mp (picrate) 148-150 C
1
(MeOH-Et2O); yield 63%; H NMR (CDCl3) δ 1.12-1.15 (t, JAX = 7.5 Hz, 3H, A3X2, CH3), 1.20 (s, 3H,
5-CH3), 1.51 (brs, 6H, 4´, 6´, 10´-H), 1.57-1.68 (brq, 6H, 2´, 8´, 9´-H), 1.90 (s, 3H, 2-CH3), 1.96 (brs, 3H,

3´, 5´, 7´-H), 2.19-2.24 (q, JAX = 7.5 Hz, 2H, A3X2, CH2), 3.19-3.82 (q, JAB = 14.0 Hz, 2H, AB, 4-H); 13C
NMR (CDCl3) δ 10.3 (CH3), 20.8 (5-CH3), 21.7 (CH2), 28.1 (3´, 5´, 7´-C), 35.8 (4´, 6´, 10´-C), 36.9 (2´,
8´, 9´-C), 37.8 (1´-C), 60.9 (4-C), 90.1 (5-C), 168.4 (2-C). Anal. Calcd for C22H28N4O8 (picrate): C, 55.45;
H, 5.92. Found: C, 55.73; H, 6.20.
4,5–Dihydro-5-methyl-2-phenyl-5-(1-tricyclo[3.3.1.1.3,7]decyl)oxazole (2d)
Oxazoline 2d was prepared by the procedure used for the synthesis of 2b, but the reaction mixture was
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stirred at rt for 15 min; yield 51%; mp (picrate) 198-200 C (MeOH-Et2O). H NMR (CDCl3) δ 1.34 (s,
3H, CH3), 1.58-1.70 (m, 12H, 2´, 4´, 6´, 8´, 9´, 10´-H), 1.99 (brs, 3H, 3´, 5´, 7´-H), 3.45-4.09 (q, JAB = 15
13
Hz, 2H, AB, 4-H), 7.36-7.43 (m, 3H, 3, 4, 5-Harom), 7.91-7.93 (m, 2H, 2, 6-Harom); C NMR (CDCl3) δ
20.9 (CH3), 28.1 (3´, 5´, 7´-C), 35.9 (4´, 6´, 10´-C), 36.9 (2´, 8´, 9´-C), 38.1 (1´-C), 61.5 (4-C), 90.7 (5-C),
128.0 (2-Carom), 128.2 (1, 4-Carom), 131.0 (3, 5-Carom), 163.3 (2-C). Anal. Calcd for C26H28N4O8: C, 59.53;
H, 5.38. Found: C, 59.31; H, 5.52.
N-[2-Hydroxy-2-(1-tricyclo[3.3.1.1.3,7]decyl)propyl]urea (16)
To a stirred suspension of hydrochloride of 13 (693 mg, 2.8 mmol) in water (15 mL) was added
potassium cyanate (229 mg, 2.8 mmol). The mixture was refluxed for 3.5 h, filtered and the residue was
washed well with water, and dried to give 525 mg (74%) of crystalline 16, mp 209-211 oC (decomp). 1H
NMR (DMSO-d6) δ 0.80 (s, 3H, CH3), 1.48-1.56 (m, 12H, 2, 4, 6, 8, 9, 10-H), 1.84 (brs, 3H, 3, 5, 7-H),
2.82-2.86 (m, 1H, CHN), 2.98-3.03 (m, 1H, CHN), 5.50 (s, 2H, NH2), 5.73 (brs, 1H, NH); 13C NMR
(DMSO-d6) δ 18.2 (CH3), 27.6 (3, 5, 7-C), 35.3 (4, 6, 10-C), 36.3 (2, 8, 9-C), 37.8 (1-C), 43.7 (CH2N),
74.5 (C-OH), 159.3 (C=O). The product was used without further purification for the preparation of
oxazolamine 2e.
4,5–Dihydro-5-methyl-5-(1-tricyclo[3.3.1.1.3,7]decyl)oxazol-2-amine (2e)
Urea 10 (250 mg, 1.1 mmol) was dissolved in small portions into sulphuric acid (98%, 1 mL) under ice
cooling. The solution was then heated at 45-50 oC for 2 h and poured onto chilled water. After following
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the work up used for 1e, oxazoline 2e was obtained in 85% yield (200 mg); mp (fumarate) 181 C
(decomp). 1H NMR (DMSO-d6) δ 1.32 (s, 3H, CH3), 1.35-1.57 (m, 12H, 2΄, 4΄, 5΄, 6΄, 7΄, 8΄, 9΄, 10΄-H ),
1.91 (s, 3´, 5´, 7´-H), 3.20-3.24 (m, 1H, 4-H), 3.78-3.82 (m, 1H, 4-H), 3.72 (brs, 4H, NH2, 2×CO2H), 6.35
(s, 2H, CH= fumarate); 13C-NMR (DMSO-d6) δ 14.7 (CH3), 26.8 (3´, 5´, 7´-C), 34.3 (4´, 6´, 10´-C), 35.6
(2´, 8´, 9´-C), 48.7 (4-C), 52.2 (1´-C), 94.7 (5-C), 134.9 (CH= fumarate), 161.6 (2-C), 168.6 (C=O
fumarate). Anal. Calcd for C18H26N2O5 (fumarate): C, 64.65; H, 7.84. Found: C, 65.01; H, 7.97.
N-(2-Hydroxymethyl-2-tricyclo[3.3.1.1.3,7]decyl)acetamide (19a)
To a stirred suspension of aminoalcohol 17 (1.5 g, 8.3 mmol) in dry THF (15 mL) was added
triethylamine (3.36 g, 33.2 mmol) and then dropwise, under ice cooling, a solution of acetyl chloride
(1.44 g, 18.3 mmol) in dry THF (10 mL). The mixture was stirred at 0 oC for 10 min and then refluxed for

6 h. The solvent was evaporated under vacuum, water was added to the residue and the mixture was
extracted with CH2Cl2. The organic layer was washed with water, hydrochloric acid (5 %), water and
dried over sodium sulfate. The solvent was removed in vacuo to give 2.04 g of 18a as an oily product; IR
(Nujol) ν 3501-3289, 1737, 1644 cm-1. The above mixture consisting of the N-acetyl and N,O-bisacetyl
derivatives (2.04 g) was dissolved in EtOH (30 mL) and saponified with a solution of sodium hydroxide
(320 mg, 8.0 mmol) in water (11 mL) for 18 h at rt. The solvent was evaporated under vacuum and water
was poured onto the residue. The resulting mixture was filtered and the precipitate was washed with water,
hydrochloric acid (5%) and water, and dried to give 1.8 g (97%) of 19a; IR (Nujol) ν 3388-3239, 1644
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cm-1. Melting of 19a commences at 187 C and ceases at 195-196 C with decomposition. H NMR
(DMSO-d6) δ 1.66-1.87 (m, 10H, 4eq, 5, 6, 7, 8, 9eq, 10-H), 1.98-2.02 (brd, 2H, 4ax, 9ax-H), 2.03 (s, 3H,
CH3), 2.20 (brs, 2H, 1, 3-H), 3.95-3.96 (s, 2H, CH2O), 4.68 (brs, 1H, OH), 5.56 (brs, 1H, NH); 13C NMR
(DMSO-d6) δ 24.1 (CH3), 26.9 (5-C), 27.2 (7-C), 30.8 (1-C), 31.0 (3-C), 32.9 (4, 9-C), 33.2 (8, 10-C),
38.3 (6-C), 62.8 (2-C), 67.4 (CH2O), 171.4 (C=O). The product was used without further purification for
the preparation of the spiro derivative 3a.
N-(2-Hydroxymethyl-2-tricyclo[3.3.1.1.3,7]decyl)benzamide (19b)
To a stirred suspension of aminoalcohol 17 (1.5 g, 8.3 mmol) in dry THF (20 mL) was added
triethylamine (3.36 g, 33.2 mmol) and then dropwise under ice cooling a solution of benzoyl chloride
(2.57 g, 18.3 mmol) in dry THF (10 mL). The mixture was reluxed for 3 h, stirred at ambient temperature
for 24 h, and then the solvent was evaporated under vacuum. Water was poured onto the residue and the
mixture was extracted with CH2Cl2. The organic layer was washed with water, hydrochloric acid (5%),
water and dried over sodium sulfate. The solvent was removed in vacuo to give 3.6 g of a product, which
was purified by flash column chromatography (EtOAc: n-hexane = 1 : 1, v/v) to give 1.94 g (82%) of 19b.
IR (Nujol) ν 3342 (NH), 3272, (OH), 1636, (C=O) cm-1. Melting of 19b commences at 148 oC and ceases
at 168-170 oC (decomp). 1H NMR (DMSO-d6) δ 1.74-2.14 (m, 12H, 4, 5, 6, 7, 8, 9,10-H ), 2.36 (s, 2H, 1,
3-H), 4.04 (s, 2H, CH2O), 4.81 (brs, 1H, OH), 6.27 (brs, 1H, NH), 7.40-7.44 (m, 2H, 3, 5-Ηarom), 7.47-7.4
13
(m, 1H, 4-Ηarom), 7.73-7.75 (m, 2H, 2, 6-Ηarom); C NMR (DMSO-d6) δ 27.1 (5-C), 27.2 (7-C), 31.0 (1,
3-C), 33.0 (4, 9-C), 33.3 (8, 10-C), 38.3 (6-C), 63.0 (2-C), 67.2 (CH2O), 126.9 (2, 6-Carom), 128.7 (3,
5-Carom), 131.6 (4-Carom), 134.9 (1-Carom), 168.3 (C=O). The product was used without further purification
for the preparation of the spiro derivative 3b.
2-Methylspiro[oxazol-4(5Η),2΄-tricyclo[3.3.1.1.3,7]decane] (3a)
To a solution of acetamidealcohol 19a (1.0 g, 4.5 mmol) in pyridine (6 mL) was added tosyl chloride
(858 mg, 4.5 mmol) in small portions under ice cooling. The reaction mixture was heated at 115-120 ºC
for 15 h and then poured onto water. The resulting mixture was extracted with CHCl3 and the organic
layer was exhaustively washed with water, dried over sodium sulfate and concentrated in vacuo to give

510 mg of a product, which was purified by flash column chromatography (Et2O) to give 380 mg (41%)
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of crystalline 3a, mp 105-107 C mp (picrate) 179-180 C (decomp) (MeOH-Et2O). H NMR (CDCl3) δ
1.56-1.85 (m, 12H, 1΄, 3΄, 4΄eq, 5΄, 6΄, 7΄, 8΄, 9΄eq, 10΄-H ), 1.96 (s, 3H, CH3), 2.31-2.33 (brd, 2H, 4΄ax,
9΄ax-H), 4.01 (s, 2H, 5-H); 13C NMR (CDCl3) δ 13.3 (CH3), 25.5 (5΄-C), 26.2 (7΄-C), 29.1 (CH3), 33.6 (4΄,
9΄-C), 35.5 (8΄, 10΄-C), 36.7 (6΄-C), 36.9 (1΄, 3΄-C), 74.6 (4, 2΄-C), 76.7 (5-C), 160.7 (2-C). Anal. Calcd
for C19H22N4O8 (picrate): C, 52.53; H, 5.10. Found: C, 52.27; H, 5.16.
2-Phenylspiro[oxazol-4(5Η),2΄-tricyclo[3.3.1.1.3,7]decane] (3b)
To a suspension of benzylamidealcohol 19b (1.0 g, 3.5 mmol) in pyridine (8 mL) was added tosyl
chloride (667 mg, 3.5 mmol) in small portions under ice cooling, and the resulting mixture was heated
for10 h. Oxazole 3b 230 mg (25%) was obtained as a crystalline solid after applying the same work up
used for the isolation of 3a, and having the residue obtained chromatographed using as eluents n-hexane :
Et2O = 1 : 1, v/v; mp 118-120 oC; mp (picrate) 205-207 oC (MeOH-Et2O) (decomp). 1H NMR (CDCl3) δ
1.66-1.92 (m, 12H, 1΄, 3΄, 4΄eq, 5΄, 6΄, 7΄, 8΄, 9΄eq, 10΄-H), 2.24-2.27 (brd, 2H, 4΄ax, 9΄ax-H), 3.83 (s, 2H,
13
5-H), 7.36-7.46 (m, 3H, 3, 4, 5-Harom), 7.94-7.96 (m, 2H, 2, 6-Harom ); C NMR (CDCl3) δ 26.4 (5΄-C),
26.7 (7΄-C), 33.6 (4΄, 9΄-C), 34.5 (8΄, 10΄-C), 36.7 (1΄, 3΄-C), 37.2 (6΄-C), 64.0 (5-C), 90.0 (4,2΄-C), 128.0
(2, 6-Carom), 128.2 (3, 5-Carom), 128.5 (1-Carom), 131.0 (4-Carom), 163.1 (2-C). Anal. Calcd for C24H24N4O8
(picrate): C, 58.06; H, 4.87. Found: C, 58.20; H, 4.91.
2-Acetamido-2-tricyclo[3.3.1.1.3,7]decanecarboxylic acid (21)
To a stirred suspension of amino acid 21 (2.12 g, 10.9 mmol) in CHCl3 (20 mL) was added dropwise at
o
60 C acetic anhydride (0.75 mL). After the mixture had been stirred for 6 h a second portion of acetic
anhydride (0.75 mL) was added and heating was continued for 12 h. The solvent was then evaporated and
water was added dropwise under ice cooling onto the residue. The resulting mixture was filtered off, and
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1
the precipitate washed with water, and dried to give 1.85 g (72%) of the title compound; mp 215 C. H
NMR (CDCl3) δ 1.62-1.65 (brd, 4H, 8eq, 4eq, 9eq, 10eq-H ), 1.75 (brs, 4H, 1, 3, 6-H), 1.92 (m, 2H, 5, 7-H),
2.18 (s, 3H, CH3), 2.31-2.35 (brd, 2H, 8ax, 10ax-H), 2.48-2.51 (brd, 2H, 4ax, 9ax-H), 2.56 (brs, 1H, NH);
13C NMR (CDCl3) δ 15.3 (CH3), 26.2 (5-C), 27.4 (7-C), 31.0 (4, 9-C), 33.5 (8,10-C), 35.0 (1, 3-C), 37.7
(6-C), 72.2 (2-C), 159.2 (CON), 179.1 (CO2H). The product was used without further purification for the
preparation of methyl ester 22.
2-Acetamido-2-tricyclo[3.3.1.1.3,7]decanecarboxylic acid methyl ester (22)
To a saturated solution of hydrogen chloride in MeOH (15 mL) was sequentially added MeOH (5 mL)
and carboxylic acid 21 (2.0 g, 8.4 mmol) in small portions under ice cooling. The mixture was stirred at rt
overnight, the solvent evaporated and water was added onto the residue The mixture was extracted with
CHCl3 and the organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo
to give 2.0 g (95%) of the title compound 22; mp 103-105 oC.

2,5,5-Trimethylspiro[oxazol-4,2΄-tricyclo[3.3.1.1.3,7]decane] (3c)
To the Grignard reagent, prepared from methyl iodide (5.79 g, 40.8 mmol) and magnesium turnings (0.99
g, 40.8 mmol) in dry Et2O (20 mL), was added dropwise under argon a solution of ester 22 (1.7 g, 6.8
mmol) in dry Et2O (20 mL). The mixture was stirred at ambient temperature overnight and then
hydrolyzed by adding a saturated aqueous ammonium chloride solution. The aqueous layer formed was
extracted with Et2O and a small quantity of THF. The combined organic layers were washed with sodium
thiosulfate, dried over sodium sulfate and concentrated under vacuum. The residue obtained was worked
up as in the procedure used for 2b to give a gluey product, which was purified by flash column
o
chromatography (Et2O : n-hexane = 1 : 1, v/v) to afford 380 mg (24%) of 3c; mp (picrate) 203-205 C
(decomp) (MeOH-Et2O); 1H NMR (CDCl3) δ 1.39 (s, 6H, 2×5-CH3), 1.49-1.53 (m, 2H, 4΄eq, 9΄eq -H), 1.67
(brs, 2H, 6-H), 1.65-1.67 (m, 4H, 6΄, 8΄eq, 10΄eq-H), 1.82-1.90 (m, 6H, 1΄, 3΄, 5΄, 7΄, 8΄ax, 10΄ax-H), 1.89 (s,
3H, 2-CH3), 2.45-2.48 (m, 2H, 4΄ax, 9΄ax-H); 13C NMR (CDCl3) δ 14.8 (2-CH3), 25.0 (2×5-CH3), 27.1
(5΄-C), 27.5 (7΄-C), 33.9 (1΄, 3΄-C), 34.2 (8΄, 10΄-C), 34.8 (4΄, 9΄-C), 38.4 (6΄-C), 75.5 (4,2΄-C), 88.6 (5-C),
159.6 (2-C). Anal. Calcd for C21H26N4O8 (picrate): C, 54.54; H, 5.67. Found: C, 54.33; H, 5.82.
Apart from 3c, a second fraction was isolated from the flash column (110 mg, 8 %), the spectral data of
which correspond to the structure of by-product 25. 1H NMR (CDCl3) δ 1.57-1.65 (m, 6H, 1΄, 3΄, 4΄eq, 8΄eq,
9΄eq, 10΄eq-H ), 1.75 (brs, 2H, 6-H), 1.87 (brs, 2H, 5΄, 7΄-H), 2.04 (s, 3H, 2-CH3), 2.18-2.21(brd, 2H, 8΄ax,
10΄ax-H), 2.40-2.43 (brd, 2H, 4΄ax, 9΄ax-H), 4.52-4.53 (d, JAX = 2.5Hz, 1H, CHA=), 4.80-4.81 (d, JAX
=
2.5Hz, 1H, CHX=); 13C NMR (CDCl3) δ 14.1 (2-CH3), 26.3 (5΄-C), 27.6 (7΄-C), 31.3 (8΄, 10΄-C), 34.0(4΄,
9΄-C), 37.0 (1΄, 3΄-C), 38.6 (6΄-C), 76.0 (4,2΄-C), 87.9 (C=), 158.7 (2-C), 165.9 (5-C).
N-[1-Hydroxy-2-(tricyclo[3.3.1.1.3,7]decyl)]urea (27)
To a stirred solution of the hydrochloride salt of 26 (750 mg, 3.7 mmol) in water (15 mL) was added
potassium cyanate (300 mg, 3.7 mmol). The mixture was refluxed for 4 h and the solvent was then
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1
evaporated under vacuum to give 660 mg (85 %) of 27; mp > 230 C (water); H NMR (DMSO-d6) δ
1.24-1.73(m, 10H, 4, 5, 6, 8, 10-H), 1.90 (m, 3H, 3, 5, 7-H), 3.38 (brs, 1H, 2-H), 5.38 (brs, 1H, ΟH), 5.52
13
(s, 2H, NH2), 6.04-6.05(m, 1H, NH); C NMR (DMSO-d6) δ 29.1 (5-C), 29.6 (7-C), 29.9 (6-C), 34.2
(3-C), 35.8 (4, 10-C), 38.9 (9-C), 45.4 (8-C), 58.7 (2-C), 67.7 (1-C), 159.6 (C=O). The product was used
without further purification for the preparation of amine 4.
4-Oxa-6-azatetracyclo[6.3.1.1.3,10.03,7]tridec-5-en-5-amine (4)
Urea 27 (230 mg, 1.1 mmol) was dissolved in small portions in sulphuric acid (98%, 1 mL) under ice
cooling. The solution was heated at 45-50 oC for 6 h and then poured onto chilled water. The mixture was
diluted with EtOAc, made alkaline with a solution of aqueous sodium hydroxide and extracted with
EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 70 mg (33%)
of crystalline 4; mp 222-223 oC (decomp) (water); 1H NMR (CDCl3) δ 1.67-1.89 (m, 6H, 2eq, 9eq, 11, 12eq,

13eq -H ), 2.08-2.88 (m, 7H, 1, 2ax, 8 , 9ax, 10, 12ax, 13ax-H), 3.18 (brs, 1H, 7-H), 7.50 (brs, 2H, NH2); 13C
NMR (CDCl3) 28.5 (1, 8, 10-C), 34.6 (11-C), 36.2 (7-C), 38.5 (9, 12-C), 44.9 (2, 13-C), 64.4 (3-C), 168.9
(5-C, amino form), 202.5 (5-C, imino form). Anal. Calcd for C11H16N2O: C, 68.72; H, 8.39. Found: C,
69.05; H, 8.52.
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