Cyclocondensations of (+)-camphor derived enaminones with hydrazine derivatives

Article abstract of DOI:10.1016/j.tet.2005.02.048

Reactions of 3-[(E)-(dimethylamino)methylidene]-(+)-camphor and (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1] octan-3-one with hydrazine derivatives were studied. Treatment of 3-[(E)-(dimethylamino)methylidene]-(+)-camphor

Full text of DOI:10.1016/j.tet.2005.02.048

Tetrahedron 61 (2005) 3991–3998
Cyclocondensations of (C)-camphor derived enaminones with
hydrazine derivatives
Uro sˇ Gro sˇ elj, David Bevk, Renata Jak sˇ e, Simon Re cˇ nik, Anton Meden,
*
Branko Stanovnik and Jurij Svete
Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sˇ ker cˇ eva 5, PO Box 537, 1000 Ljubljana, Slovenia
Received 2 November 2004; revised 4 February 2005; accepted 18 February 2005
Dedicated to Professor Lubor Fi sˇ era, Slovak University of Technology, Bratislava, on the occasion of his 60th anniversary
Abstract—Reactions of 3-[(E)-(dimethylamino)methylidene]-(C)-camphor and (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-tri-
methyl-2-oxabicyclo[3.2.1]octan-3-one with hydrazine derivatives were studied. Treatment of 3-[(E)-(dimethylamino)methylidene]-(C)-
camphor with hydrazines afforded the corresponding fused pyrazoles. Similarly, fused pyrazoles were obtained upon reaction of (1R,5S)-4-
[
(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with ortho-unsubstituted phenylhydrazines, while reac-
tions with ortho-substituted phenylhydrazines and with hydrazine hydrochloride resulted in ‘ring switching’ type of transformation to furnish
-aryl-4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones.
q 2005 Elsevier Ltd. All rights reserved.
2
1
. Introduction
various heterocyclic systems, including pyrazole deriva-
tives. Various chiral analogs of 3-dimethylaminopropeno-
ates were also prepared from commercially available
enantiopure starting materials, such as a-amino acids and
(C)-camphor (1). The a-amino acid derived chiral
enaminones were employed as the key-intermediates and
reagents in the synthesis of functionalized heterocycles, for
example, in the ‘ring switching’ synthesis of 3-heteroar-
ylalanine derivatives and related compounds and in the
Naturally occurring and synthetic pyrazole derivatives have
1
found widespread use in various applications. Similarly,
C)-camphor (1) and its derivatives, are among the most
frequently employed types of ex-chiral pool starting
materials and building blocks, resolving agents, chiral
shift reagents in NMR spectroscopy, and ligands in various
asymmetric applications. Camphor-functionalized pyra-
zoles, N-substituted (1R,7S)-1,10,10-trimethyl-3,4-diazatri-
(
2
5
,6
synthesis of heterocyclic analogs of dipeptides. Recently,
utilization of 3-(dimethylamino)propenoates in combinatorial
2
,6
cyclo[5.2.1.0 ]deca-2(6),4-dienes (or N-substituted
4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methyno-
H-indazoles) 2 have been synthesized from 3-formylcam-
7
synthesis has also been reported. In connection with (C)-
(
1
camphor (1) derived enaminones 4 and 5, we have previously
reported stereoselective synthesis of (1R,3R,4R)-3-(1,2,4-
triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]hep-
3
phor and hydrazine derivatives. Kotsuki and co-workers
prepared various N-(b-hydroxyethyl) substituted (1R,7S)-
2
,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0 ]deca-2(6),4-
,6
8
1
dienes 2k–m and 3k–m, which were successfully employed
tan-2-ones, and N-substituted (1R,5S)-3-aminomethyli-
9
dene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones.
as chiral ligands for enantioselective addition of diethylzinc
4
to benzaldehyde (Fig. 1).
Recently, a series of alkyl 2-substituted 3-(dimethylami-
no)propenoates and related enaminones, synthetic equiva-
lents of 1,3-dicarbonyl compounds, have been prepared and
used for the preparation of dehydroalanine esters and
Keywords: Camphor; Enaminones; Terpenes; Hydrazines; Condensations.
*
Corresponding author. Tel.: C386 1 2419 100; fax: C386 1 2419 220;
e-mail: jurij.svete@uni-lj.si
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.048

3992
U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
In continuation of our work in the field of (C)-camphor (1)
derived enaminones, we now report cyclocondensations
of (1R,4S)-3-[(E)-(dimethylamino)methylidene]-1,7,7-tri-
methylbicyclo[2.2.1]heptan-2-one (4) and (1R,5S)-4-[(E)-
of 5 with hydrazine hydrochloride (6a), which gave 4-
[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1H-pyra-
zol-3-ol (9a) in 81% yield (Scheme 1, Table 1).
(
dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicy-
Formation of pyrazole derivatives 2, 7–9 can be explained
according to the formation of pyrazoles from hydrazine
derivatives and 1,3-dicarbonyl compounds and their enam-
clo[3.2.1]octan-3-one (5) with hydrazine derivatives 6a–i
leading to, either fused pyrazole systems 2 and 7, or to 4-
[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl] substituted
pyrazole derivatives 8 and 9, as products of a ‘ring
switching’ type transformation.
1
ino analogs. Compound 4, an enamino masked b-keto
aldehyde, reacts via initial substitution of the dimethyla-
0
The (Z)-isomer 10 then cyclizes into dihydropyrazole 11,
mino group to give the isomeric enehydrazines 10 and 10 .
0
followed by elimination of water to give fused pyrazole 2.
Similarly, compound 5 as an enamino masked b-keto ester
is first transformed into a mixture of isomeric enehydrazines
2
. Results and discussion
8
9
0
0
1
2 and 12 . The (Z)-isomer 12 then cyclizes into the
Starting compounds 4 and 5 were prepared from (C)-
camphor (1) according to literature procedures. Reaction
of 4 with hydrazine hydrochloride (6a) in methanol at rt
gave (1R,7S)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0 ]-
deca-2(6),4-diene (2a) in 81% yield. Similarly, treatment of
bicyclic intermediate 13. From this point on, further
reaction can take place in two ways: (a) elimination of
water leads to pyrazolo fused lactones 7 (Path A) and (b)
elimination of the alcohol moiety leads to ‘ring switched’
pyrazolones of type 8 (Path B) (Scheme 2).
2
,6
4
with benzylhydazine dihydrochloride (6b) and 6-chloro-3-
hydrazinopyridazine (6c) in acetic acid under reflux
afforded (1R,7S)-3-benzyl-1,10,10-trimethyl-3,4-diazatri-
cyclo[5.2.1.0 ]deca-2(6),4-diene (2b) and 6-[(1R,7S)-
So far, we do not have an explanation for chemoselectivity
of reactions of 5 with hydrazine derivatives 6a,d–j. In the
literature, there are several examples, where treatment of b-
keto esters with arylhydrazines under acidic conditions
2
,6
2
,6
1
,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0 ]deca-2(6),4-
dien-3-yl]pyridazin-3(2H)-one (2c) in 63% and 83% yield,
respectively. On the other hand, upon reaction of 5 with
phenylhydrazine derivatives 6d–j in refluxing n-propanol,
two different types of products were formed, either fused
pyrazoles 7, or cyclopentyl substituted pyrazolones 8. Thus,
treatment of 5 with ortho-unsubstituted phenylhydrazines
1
afforded 5-alkoxy- and/or 5-hydroxypyrazoles. Since
elimination of water is generally facilitated by the
protonation of the hydroxy group, while elimination of
alcohol can be, either acid-catalysed or base-catalysed,
steric factors might control selectivity of cyclisation of
bicyclic intermediates 13a,d–j into pyrazole derivatives 7d–f,
8g–j, and 9a. Thus, in the case of intermediates 13d–f
without ortho-substituent attached to the aromatic ring, the
hydroxy group can undergo protonation and, consequently,
elimination of water can take place to give fused pyrazoles
7d–f. On the other hand, in intermediates 13g–j, the
hydroxy group is hindered by the ortho-substituent attached
6
4
7
d–f afforded (1S,8R)-5-aryl-8,11,11-trimethyl-7-oxa-
,5-diazatricyclo[6.2.1.0 ]undeca-2(6),3-dienes 7d–f in
4–91% yields, while treatment of 5 with ortho-substituted
2
,6
phenylhydrazines 6g–j furnished 2-aryl-4-[(1S,3R)-3-
hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyra-
zol-3-ones 8g–j in 56–70% yields. ‘Ring switching’
transformation also took place in the case of the reaction
Scheme 1. Reaction conditions: (i) NH
$HCl (6a,d–i) or C
2
NH
1
2
$HCl (6a) MeOH, rt; (ii) PhCH
SO (6j), n-PrOH, reflux.
4
2 2
NHNH $2HCl (6b) or 6-chloro-3-hydrazinopyridazine (6c), AcOH, reflux; (iii) R-
NHNH
2
6
F
5
NHNH
2
$ ⁄
2
H
2

U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
3993
Table 1. Experimental data for compounds 2, 7–9
Compound
R
Yield (%)
2
7
8
9
2
2
6
2
6
6
6
6
6
6
6
a, 6a, 9a
b, 6b
c
H
Benzyl
81
63
83
6-Chloropyridazin-3-yl
6-Oxo-1,6-dihydropyridazin-3-yl
Phenyl
3-Methylphenyl
4-Methylphenyl
2-Methylphenyl
2-Chlorophenyl
2-Bromophenyl
Pentafluorophenyl
c
83
d, 7d
e, 7e
f, 7f
g, 8g
h, 8h
i, 8i
91
74
85
70
61
63
56
j, 8j
to the aromatic ring. Consequently, protonation of the
hydroxy group is disfavoured and elimination of alcohol,
that is, opening of the lactone ring, takes place to give the
hydroxypyrazoles 9g–j, which then tautomerise into the
pyrazolones 8g–j. In the case of transformation of 5 into 9a,
which took place upon reaction of 5 with sterically
unhindered hydrazine hydrochloride (6a), opening of the
lactone ring is favoured due to stronger basicity of the
Scheme 2.

3994
U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
Scheme 3.
primary amino group with respect to the arylamino group
Scheme 3).
the ortho-methyl group in the aryl residue was in agreement
with (1S,3R)-configuration (Fig. 2).
(
The structure of compound 7d was determined by X-ray
diffraction (Fig. 3).
3
. Structure determination
The structures of compounds 2, 7–9 were determined by
spectroscopic methods (NMR, IR, MS, HRMS) and/or by
analyses for C, H, and N. The structure of compound 9a,
which was not isolated in analytically pure form, was
1
3
confirmed by C NMR and HRMS. Physical and spectral
data of known compounds 2a,b were in agreement with the
3a,e
literature data. Spectral data for pyrazoles 2, 7–9 were in
1
agreement with the literature data for related pyrazole and
2
camphor derivatives. IR spectra of compounds 2c and 8d–f
exhibited amide C]O absoption bands at 1681 and 1682–
1
K1
673 cm , respectively, while no C]O absorption was
observed in IR spectra of compounds 2a,b, 7d–f, and 9a. In
compound 8g, NOE between the OH proton and protons of
Figure 2.

U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
3995
9
cyclo[3.2.1]octan-3-one (5), and 6-chloro-3-hydrazinopyri-
1
dazine (6c), were prepared according to the procedures
0
described in the literature.
5
[
.1.1. (1R,7S)-1,10,10-Trimethyl-3,4-diazatricyclo-
5.2.1.0 ]deca-2(6),4-diene (2a). A mixture of 4
2
,6
(0.207 g, 1 mmol), hydrazine hydrochloride (6a, 0.069 g,
1 mmol), and methanol (4 ml) was stirred at rt for 24 h.
Water (6 ml) was added and the precipitate was collected by
filtration to give 2a. Yield: 0.143 g (81%) of yellowish
3
a
23
D
crystals; mp 143–147 8C, lit. mp 149–150 8C; [a] Z
1
C35.8 (cZ0.4, CH Cl ). H NMR (DMSO-d ): d 0.56, 0.91
2
2
6
(6H, 2 s, 1:1, 2Me); 0.98–1.16 (2H, m, CH ); 1.19 (3H, s,
Me); 1.75–1.83 (1H, m, 1H of CH ); 1.98–2.07 (1H, m, 1H
2
2
of CH ); 2.73 (1H, d, JZ3.9 Hz, H–C(7)); 7.16 (1H, s, H–
2
1
C(5)); 11.62 (1H, s, H–N(3)). C NMR (DMSO-d ): d 11.2,
3
6
19.7, 20.9, 28.2, 34.1, 47.5, 50.4, 61.4, 120.4, 126.4, 166.5.
(
Found: C, 74.96; H, 9.36; N, 15.59. C H N requires: C,
1
1 16 2
7
1
1
4.96; H, 9.15; N, 15.89.); nmax (KBr): 3415, 3145, 2923,
586, 1479, 1454, 1415, 1386, 1369, 1286, 1273, 1140,
Figure 3. ORTEPviewof theasymmetric unitofcompound7d withlabeling
of nonhydrogen atoms (ellipsoids are drawn at 50% probability level).
K1
084, 1026, 972, 804 cm
.
5.2. General procedure for the preparation of
compounds 2b,c, 7d–f, 8g,h, and 9a
4. Conclusion
In conclusion, (C)-camphor derived enaminones 4 and 5
are easily available reagents, which are suitable for the
preparation of terpene-functionalized pyrazole derivatives.
Reactions of (1R,4S)-3-[(E)-(dimethylamino)methylidene]-
A mixture of enaminone 4 or 5 (1 mmol), hydrazine
derivative 6 (1 mmol), and appropriate solvent (w5 ml)
was heated under reflux for 2–6 h. Volatile components
were evaporated in vacuo and the residue was purified by
column chromatography (CC). Fractions containing the
product were combined and evaporated in vacuo to give
1
zine derivatives 6 lead to 3-substituted (1R,7S)-1,10,10-
,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4) with hydra-
2
,6
trimethyl-3,4-diazatricyclo[5.2.1.0 ]deca-2(6),4-dienes 2.
However, in the case of (1R,5S)-4-[(E)-(dimethylamino)-
methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-
one (5), the chemoselectivity was found to be dependent on
the type of hydrazine derivative 6 employed. Reactions of 5
with ortho-unsubstituted phenylhydrazines 6d–f afforded
fused pyrazole systems 7d–f, while reactions with hydrazine
hydrochloride (6a) and ortho-substituted phenylhydrazines
2b,c, 7d–f, 8g,h, and 9a.
The following compounds were prepared in this manner:
5.2.1. (1R,7S)-3-Benzyl-1,10,10-trimethyl-3,4-diazatricy-
2
,6
clo[5.2.1.0 ]deca-2(6),4-diene (2b). Prepared from 4
(0.207 g, 1 mmol), benzylhydrazine dihydrochloride (6b,
0.195 g, 1 mmol), and acetic acid (100%, 6 ml), reflux for
4 h, CC (diethyl ether–petroleum ether, 1:2). Yield: 0.168 g
6g–j led to 4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopen-
tyl] substituted pyrazole derivatives 9a and 8g–j, respect-
ively, as products of a ‘ring switching’ type transformation.
3
e
22
D
(63%) of colourless oil, lit. oil; [a]
ZK14.9 (cZ0.29,
C
1
CH Cl ). EI-MS: m/zZ266 (M ). H NMR (DMSO-d ): d
2
2
6
0.65, 0.82, 1.13 (9H, 3 s, 1:1:1, 3Me); 0.88–1.00 (2H, m,
CH ); 1.61–1.70 (1H, m, 1H of CH ); 1.93–2.01 (1H, m, 1H
2
2
5
. Experimental
of CH ); 2.73 (1H, d, JZ3.8 Hz, H–C(7)); 5.24 (1H, d, JZ
2
1
6.0 Hz, 1H of CH N); 5.32 (1H, d, JZ16.0 Hz, 1H of
2
5
.1. General
CH
7
N); 7.05–7.07 (2H, m, 2H of Ph); 7.09 (1H, s, H–C(5));
2
1
3
.22–7.34 (3H, m, 3H of Ph). C NMR (CDCl ): d 11.7,
3
Melting points were determined on a Kofler micro hot stage.
The H NMR spectra were obtained on a Bruker Avance
20.0, 20.7, 28.2, 33.8, 48.0, 52.7, 54.3, 63.2, 127.0, 127.9,
129.0, 129.5, 131.6, 138.6, 153.9. (Found: C, 80.84; H, 8.71;
1
1
13
DPX 300 at 300 MHz for H, and 75.5 MHz for C nucleus,
N, 10.51. C18
EI-HRMS: m/zZ266.1796 (M ); C18H N O requires:
22 2
H N requires: C, 81.16; H, 8.32; N, 10.52.);
22 2
C
using DMSO-d and CDCl as solvents and TMS as the
6
3
C
internal standard. Mass spectra were recorded on an
AutoSpecQ spectrometer, IR spectra on a Perkin–Elmer
Spectrum BX FTIR spectrophotometer. Microanalyses were
performed on a Perkin–Elmer CHN Analyser 2400. Column
chromatography (CC) was performed on silica gel (Fluka,
silica gel 60, 0.04–0.06 mm).
m/zZ266.1783 (M ); nmax (NaCl): 2957, 2872, 1606, 1522,
1496, 1440, 1383, 1362, 1285, 1194, 1117, 1059, 997,
K1
907 cm
.
5.2.2. 6-[(1R,7S)-1,10,10-Trimethyl-3,4-diazatricyclo-
2
,6
[5.2.1.0 ]deca-2(6),4-dien-3-yl]pyridazin-3(2H)-one
2c). Prepared from 4 (0.207 g, 1 mmol), 6-chloro-3-
(
Hydrazines 6a,b,d–j are commercially available (Fluka
AG). (1R,4S)-3-[(E)-(Dimethylamino)-methylidene]-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-one (4), (1R,5S)-4-[(E)-
hydrazinopyridazine (6c, 0.145 g, 1 mmol), and acetic
acid (100%, 6 ml), reflux for 4 h, CC (ethyl acetate). Before
chromatographic purification, the crude solid product was
crystallised from methanol. Yield: 0.124 g (83%) of white
8
(
dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabi-

3996
U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
2
D
0
crystals; mp 213–218 8C (from methanol); [a] ZC9.9
crystals; mp 146–150 8C (from chloroform–n-heptane);
21 1
[a] ZK27.2 (cZ0.23, CH Cl ). H NMR (CDCl ): d
D 2 2 3
1
(
cZ0.40, CH Cl ). H NMR (DMSO-d ): d 0.71, 0.90 (6H,
2
2
6
2
s, 1:1, 2Me); 0.95–1.03 (1H, m, 1H of CH ); 1.19–1.27
0.97, 1.08, 1.42 (9H, 3 s, 1:1:1, 3Me); 1.83–1.95 (1H, m, 1H
of CH ); 1.95–2.14 (2H, m, CH ); 2.19–2.28 (1H, m, 1H of
2
(
1H, m, 1H of CH ); 1.32 (3H, s, Me); 1.78–1.86 (1H, m, 1H
2
2
2
of CH ); 2.01–2.11 (1H, m, 1H of CH ); 2.81 (1H, d, JZ
CH ); 2.35 (3H, s, Me-Ar); 2.57 (1H, d, JZ4.4 Hz, H–
2
2
2
0
3
.6 Hz, H–C(7)); 7.05 (1H, d, JZ10.0 Hz, H–C(5 )); 7.44
C(1)); 7.19 (2H, br d, JZ8.5 Hz, 2H of Ar); 7.23 (1H, s, H–
0
1H, s, NH). C NMR (DMSO-d ): d 13.4, 20.4, 21.0, 28.1,
13
(
(
1H, s, H–C(5)); 7.92 (1H, d, JZ10.0 Hz, H–C(4 )); 12.92
C(3)); 7.66 (2H, br d, JZ8.5 Hz, 2H of Ar). C NMR
1
3
(CDCl ): d 18.7, 19.5, 21.3, 24.3, 34.0, 38.1, 43.1, 43.9,
6
3
3
1
3.5, 47.4, 54.8, 63.8, 129.6, 132.4, 133.1, 134.8, 142.2,
54.0, 160.8. (Found: C, 66.83; H, 7.09; N, 20.47.
94.0, 107.1, 120.1, 129.8, 135.4, 136.3, 137.1, 149.5.
(Found: C, 76.29; H, 8.03; N, 9.76. C H N O requires:
C, 76.56; H, 7.85; N, 9.92.); nmax (KBr): 2972, 1589, 1526,
1
8 22 2
C H N O requires: C, 66.64; H, 6.71; N, 20.73.); n
max
1
5
18
4
K1
(
1
KBr): 3446, 2961, 1681 (C]O), 1613, 1563, 1475, 1448,
380, 1308, 1242, 1007, 986, 839 cm
1458, 1428, 1076, 973, 882, 855, 818 cm
.
K1
.
5
.2.6. 4-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]-
5
.2.3. (1S,8R)-5-Phenyl-8,11,11-trimethyl-7-oxa-4,5-di-
2-(2-methylphenyl)-1,2-dihydro-3H-pyrazol-3-one (8g).
Prepared from 5 (0.223 g, 1 mmol), (2-methylphenyl)hy-
drazine hydrochloride (6g, 0.159 g, 1 mmol), and anhydrous
n-propanol (5 ml), reflux for 4 h, CC (first: ethyl acetate–
petroleum ether, 1:4, then ethyl acetate–petroleum ether,
2
,6
azatricyclo[6.2.1.0 ]undeca-2(6),3-diene (7d). Prepared
from 5 (0.223 g, 1 mmol) and phenylhydrazine hydro-
chloride (6d, 0.145 g, 1 mmol), and anhydrous n-propanol
(
1
5 ml), reflux for 2 h, CC (ethyl acetate–petroleum ether,
:3). Yield: 0.224 g (91%) of white crystals; mp 173–177 8C
1:2). Yield: 0.210 g (70%) of white crystals; mp 139–145 8C
2
5
21
(
from ethyl acetate–n-hexane); [a] ZK27.6 (cZ0.25,
(from chloroform–n-heptane); [a] ZK13.2 (cZ0.39,
D
1
D
1
C
C
CH Cl ). EI-MS: m/zZ268 (M ). H NMR (CDCl ): d
CH Cl ). EI-MS: m/zZ300 (M ). H NMR (CDCl ): d
2
2
3
2
2
3
0
of CH ); 1.96–2.14 (2H, m, CH ); 2.20–2.29 (1H, m, 1H of
.98, 1.08, 1.44 (9H, 3 s, 1:1:1, 3Me); 1.84–1.91 (1H, m, 1H
1.00, 1.01, 1.31 (9H, 3 s, 1:1:1, 3Me); 1.59–1.67 (1H, m, 1H
0
of CH ); 1.93–2.27 (4H, m, 3H of CH and H–C(1 )); 2.16
2
2
2
2
CH ); 2.58 (1H, d, JZ4.4 Hz, H–C(1)); 7.19 (1H, tt, JZ1.2,
(3H, s, Me-Ar); 5.82 (1H, br s, OH); 6.65 (1H, d, JZ
10.4 Hz, H–C(5)); 6.83 (1H, br t, JZ7.3 Hz, 1H of Ar); 6.87
(1H, br d, JZ7.6 Hz, 1H of Ar); 7.07 (1H, br d, JZ7.3 Hz,
1H of Ar); 7.14 (1H, br t, JZ7.6 Hz, 1H of Ar); 8.97 (1H, d,
2
7
2
.5 Hz, 1H of Ph); 7.25 (1H, s, H–C(3)); 7.36–7.42 (2H, m,
H of Ph); 7.79–7.81 (2H, m, 2H of Ph). C NMR (CDCl3):
1
3
d 18.7, 19.5, 24.2, 34.0, 38.1, 43.1, 43.9, 94.2, 107.3, 120.0,
25.7, 129.3, 136.6, 139.5, 149.7. (Found: C, 76.23; H, 7.64;
N, 10.35. C H N O requires: C, 76.09; H, 7.51; N,
1
3
1
JZ10.4 Hz, NH). C NMR (CDCl ): d 17.4, 18.8, 18.9,
3
23.8, 31.8, 38.0, 43.8, 50.3, 92.0, 100.0, 112.1, 120.9, 122.2,
127.5, 130.8, 146.7, 151.2, 170.1. (Found: C, 71.94; H, 8.09;
N, 9.27. C H N O requires: C, 71.97; H, 8.05; N, 9.33.);
1
7 20 2
1
0.44.); EI-HRMS: m/zZ268.1585; C H N O requires:
17 20 2
C
m/zZ268.1576 (M ). Found: n
(KBr): 2956, 1595,
max
18 24 2 2
C
1
6
516, 1492, 1455, 1418, 1377, 1088, 1057, 970, 847, 760,
90 cm
EI-HRMS: m/zZ300.1846 (M ); C H N O requires:
18 24 2 2
C
m/zZ300.1838 (M ). n
677 (C]O), 1607, 1426, 1219, 1138, 756 cm
K1
.
(KBr): 3452, 3287, 3256, 2970,
max
K1
1
.
5
.2.4. (1S,8R)-5-(3-Methylphenyl)-8,11,11-trimethyl-7-
oxa-4,5-diazatricyclo-[6.2.1.0 ]undeca-2(6),3-diene
2
,6
5.2.7. 2-(2-Chlorophenyl)-4-[(1S,3R)-3-hydroxy-2,2,3-
trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one
(8h). Prepared from 5 (0.223 g, 1 mmol), (2-chlorophenyl)-
hydrazine hydrochloride (6h, 0.179 g, 1 mmol), and anhy-
drous n-propanol (5 ml), reflux for 6 h, CC (first: ethyl
acetate–petroleum ether, 1:4). Yield: 0.196 g (61%) of
white crystals; mp 177–182 8C (from chloroform–n-hep-
(
(
7e). Prepared from enaminone 5 (0.223 g, 1 mmol) and
3-methylphenyl)hydrazine hydrochloride (6e, 0.159 g,
mmol), and anhydrous n-propanol (5 ml), reflux for 3 h,
1
CC (ethyl acetate–petroleum ether, 1:4). Yield: 0.209 g
2
1
(
(
(
(
(
74%) of light orange crystals; mp 75–79 8C; [a] ZK26.3
D
C 1
cZ0.74, CH Cl ). EI-MS: m/zZ282 (M ). H NMR
2
2
2
1
CDCl ): d 0.97, 1.08, 1.43 (9H, 3 s, 1:1:1, 3Me); 1.84–1.91
1H, m, 1H of CH ); 1.96–2.14 (2H, m, CH ); 2.20–2.29
tane); [a] ZK9.3 (cZ0.31, CH Cl ). EI-MS: m/zZ320
3
D
2
2
C
1
(M ). H NMR (CDCl ): d 1.00, 1.01, 1.31 (9H, 3 s, 1:1:1,
2
2
3
1H, m, 1H of CH ); 2.38 (3H, s, Me-Ar); 2.57 (1H, d, JZ
3Me); 1.59–1.67 (1H, m, 1H of CH ); 1.94–2.27 (4H, m, 3H
2
2
0
4
.5 Hz, H–C(1)); 7.01 (1H, br d, JZ7.5 Hz, 1H of Ar); 7.24
of CH and H–C(1 )); 6.41 (1H, br s, OH); 6.62 (1H, d, JZ
2
(
1H, s, H–C(3)); 7.27 (1H, br t, JZ7.8 Hz, 1H of Ar); 7.59
1H, br d, JZ8.3 Hz, 1H of Ar); 7.63 (1H, br s, 1H of Ar).
10.3 Hz, H–C(5)); 6.82 (1H, dt, JZ1.4, 7.8 Hz, 1H of Ar);
6.94 (1H, dd, JZ1.2, 8.0 Hz, 1H of Ar); 7.18 (1H, br t, JZ
7.8 Hz, 1H of Ar); 7.26 (1H, dd, JZ1.3, 7.9 Hz, 1H of Ar);
(
1
3
C NMR (CDCl ): d 18.7, 19.5, 21.9, 24.2, 34.0, 38.1, 43.1,
3.9, 94.1, 107.2, 117.1, 120.8, 126.5, 129.0, 136.5, 139.3,
39.4, 149.7. (Found: C, 76.28; H, 7.79; N, 10.16. C H N O
3
1
3
4
1
8.97 (1H, br d, JZ10.3 Hz, NH). C NMR (CDCl ): d 18.8,
3
18.9, 23.8, 31.7, 38.0, 43.8, 50.3, 92.2, 101.0, 113.8, 118.6,
121.4, 128.3, 129.7, 144.7, 150.6, 170.0. (Found: C, 63.62;
H, 6.71; N, 8.45. C H ClN O requires: C, 63.65; H, 6.60;
1
8 22 2
requires: C, 76.56; H, 7.85; N, 9.92.); EI-HRMS: m/zZ
2
nmax (KBr): 2960, 1611, 1597, 1516, 1489, 1460, 1414, 1392,
C
C
82.1740 (M ); C H N O requires: m/zZ282.1732 (M ).
18 22 2
17 21
2 2
C
N, 8.73.); EI-HRMS: m/zZ320.1301 (M ). C H ClN O
17 21 2 2
C
requires: 320.1292 (M ). n
682 (C]O), 1618, 1466, 1215, 1138, 748 cm
K1
1
380, 1142, 1099, 1069, 975, 884, 854 cm
.
(KBr): 3452, 3259, 2983,
max
K1
1
.
5
.2.5. (1S,8R)-5-(4-Methylphenyl)-8,11,11-trimethyl-7-
2
,6
oxa-4,5-diazatricyclo-[6.2.1.0 ]undeca-2(6),3-diene
7f). Prepared from 5 (0.223 g, 1 mmol), (4-methylphenyl)-
5.2.8. 4-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]-
1H-pyrazol-3-ol (9a). Prepared from 5 (0.223 g, 1 mmol),
hydrazine hydrochloride (6a, 0.069 g, 1 mmol), and anhy-
drous n-propanol (5 ml), reflux for 5 h, CC (chloroform–
methanol, 15:1). Yield: 0.175 g (83%) of white crystals; mp
(
hydrazine hydrochloride (6f, 0.159 g, 1 mmol), and anhy-
drous n-propanol (5 ml), reflux for 4 h, CC (ethyl acetate–
petroleum ether, 1:4). Yield: 0.240 g (85%) of white

U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
3997
11
2
D
5
2
03–210 8C; [a] ZC24.4 (cZ0.24, DMSO); C36.2 (cZ
diffractometer using the Nonius Collect Software.
C
1
12
DENZO and SCALEPACK were used for indexing and
scaling of the data. The structure was solved by means of
0
d ): d 0.60, 0.76, 1.13 (9H, 3 s, 1:1:1, 3Me); 1.58–1.81 (4H,
.12, MeOH). EI-MS m/zZ210 (M ). H NMR (DMSO-
6
0
s, OH); 7.16 (1H, s, H–C(3)); 9.65 (1H, s, NH); 11.03 (1H, s,
13
14
m, 2CH ); 2.74 (1H, br t, JZ9.0 Hz, H–C(1 )); 4.59 (1H, br
SIR97. Refinement was done using Xtal3.4 program
package and the crystallographic plot was prepared by
ORTEP III . Crystal structure was refined on F values
2
1
3
HO–C(3)). C NMR (DMSO-d ): d 19.8, 25.4, 25.6, 27.5,
15
6
3
H, 8.60; N, 12.90. C H N O requires: C, 62.83; H, 8.63;
8.5, 42.9, 47.5, 81.6, 105.7, 129.4, 159.9. (Found: C, 63.09;
using the full-matrix least-squares procedure. The non-
hydrogen atoms were refined anisotropically. The positions
of hydrogen atoms were geometrically calculated and their
positional and isotropic atomic displacement parameters
were not refined. Absorption correction was not necessary.
11 18 2 2
C
N, 13.32.); EI-HRMS: m/zZ210.1374 (M ); C H N O
1 18 2 2
1
C
requires: m/zZ210.1368 (M ). n
2
(KBr): 3481, 3200,
979, 1524, 1469, 1368, 1144, 1101, 1078, 932 cm
max
K1
.
1
6
Regina weighting scheme was used.
5
.2.9. 2-(2-Bromophenyl)-4-[(1S,3R)-3-hydroxy-2,2,3-
trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one
8i). A mixture of 5 (0.223 g, 1 mmol), (2-bromophenyl)hy-
drazine hydrochloride 6i (0.224 g, 1 mmol), and anhydrous
n-propanol (5 ml) was heated under reflux for 6 h. The
reaction mixture was cooled to rt, the precipitate was
collected by filtration, and washed with cold n-propanol
The crystallographic data for compound 7d have been
deposited with the Cambridge Crystallographic Data Center
as supplementary material with the deposition number:
CCDC 254054. These data can be obtained, free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html.
(
(
crystals; mp 186–194 8C (from chloroform–n-heptane);
0 8C, 2 ml) to give 8i. Yield: 0.230 g (63%) of white
Acknowledgements
2
1
[
(
a] ZK11.2 (cZ0.22, CH Cl ). EI-MS: m/zZ364
D 2 2
C 1
M ). H NMR (CDCl ): d 1.00, 1.01, 1.31 (9H, 3 s,
3
The financial support from the Ministry of Science and
Technology, Slovenia through grants P0-0502-0103, P1-
179, and J1-6689-0103-04 is gratefully acknowledged.
1
m, 3H of CH and H–C(1 )); 6.39 (1H, br s, OH); 6.62 (1H,
:1:1, 3Me); 1.59–1.68 (1H, m, 1H of CH ); 1.95–2.27 (4H,
0
2
2
0
d, JZ10.4 Hz, H–C(5)); 6.76 (1H, dt, JZ1.5, 7.8 Hz, 1H of
Ar); 6.93 (1H, dd, JZ1.4, 8.2 Hz, 1H of Ar); 7.22 (1H, dt,
JZ1.1, 7.8 Hz, 1H of Ar); 7.43 (1H, dd, JZ1.3, 7.9 Hz, 1H
The diffraction data for compound 7d were collected on the
Kappa CCD Nonius diffractometer in the Laboratory of
Inorganic Chemistry, Faculty of Chemistry and Chemical
Technology, University of Ljubljana, Slovenia. We
acknowledge with thanks the financial contribution of the
Ministry of Science and Technology, Republic of Slovenia
through grants X-2000 and PS-511-103, which thus made
the purchase of the apparatus possible.
1
3
of Ar); 8.99 (1H, br d, JZ10.4 Hz, NH). C NMR (CDCl3):
d 18.8, 18.9, 23.8, 31.7, 38.0, 43.9, 50.3, 92.2, 101.0, 108.1,
1
5
14.0, 121.9, 128.9, 132.9, 145.7, 150.6, 170.0. (Found: C,
5.93; H, 5.76; N, 7.38 C H BrN O requires: C, 55.90;
1
7
21
2 2
H, 5.79; N, 7.67.); EI-HRMS: m/zZ364.0799 (MC);
C
C H BrN O requires: m/zZ364.0786 (M ); nmax
1
7
21
2
2
(
1
KBr): 3436, 3256, 2943, 1679 (C]O), 1616, 1461, 1213,
134, 750 cm
K1
.
5
.2.10. 2-Pentafluorophenyl-4-[(1S,3R)-3-hydroxy-2,2,3-
References and notes
trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-one
8j). A solution of sulfuric acid in n-propanol (1 M, 0.5 ml,
.5 mmol) was added to the solution of enamino lactone 5
0.223 g, 1 mmol) and pentafluorophenylhydrazine (6j,
.198 g, 1 mmol) in anhydrous n-propanol (5 ml), and the
mixture was heated under reflux for 5 h. Volatile com-
ponents were evaporated in vacuo and the residue was
purified by CC (first: ethyl acetate–petroleum ether, 1:10,
then ethyl acetate–petroleum ether, 1:3). Fractions contain-
ing the product were combined and evaporated in vacuo to
give 8j. Yield: 0.211 g (56%) of white crystals; mp 163–
(
0
(
0
1. For an illustration see: (a) Elguero, J. In Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pyrazoles in Comprehensive
Heterocyclic Chemistry II; Elsevier Science: Oxford, 1996;
Vol. 3, pp 1–75. (b) Varvounis, G.; Fiamegos, Y.; Pilidis, G.
Adv. Heterocycl. Chem. 2001, 80, 73–156. (c) Stanovnik, B.;
Svete, J. In Neier, R., Ed.; Pyrazoles in Science of Synthesis,
Houben-Weyl Methods of Organic Transformations; Georg
Thieme Verlag: Stuttgart, 2002; Vol. 12, pp 15–225.
2. For an illustration see: (a) Money, T. Nat. Prod. Rep. 1985, 2,
253–289. (b) Oppolzer, W. Tetrahedron 1987, 43, 1969–2004.
(c) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241–1250. (d)
Money, T. In Remote Functionalization of Camphor: Appli-
cation to Natural Product Synthesis in Organic Synthesis:
Theory and Applications, Vol. 3; JAI: Greenwich, 1996;
p 1–83.
1
67 8C (from chloroform–n-heptane, with previous melting
21
and solidifying at 139–145 8C); [a] ZC0.9 (cZ0.316,
D
1
CH Cl ). H NMR (CDCl ): d 0.97, 1.00, 1.29 (9H, 3 s,
2
2
3
1
m, 3H of CH and H–C(1 )); 5.92 (1H, br s, OH); 6.75 (1H,
:1:1, 3Me); 1.57–1.67 (1H, m, 1H of CH ); 1.91–2.23 (4H,
0
2
2
d, JZ10.0 Hz, H–C(5)); 9.03 (1H, d, JZ10.0 Hz, NH).
3. (a) Wallach, O. Liebigs. Ann. Chem. 1903, 329, 109–131. (b)
Jacquier, R.; Maury, G. Bull. Soc. Chim. Fr. 1967, 295–297.
(c) Nagai, S.; Oda, N.; Ito, I.; Kudo, Y. Chem. Pharm. Bull.
1979, 27, 1771–1779. (d) Nagai, S.; Ueda, T.; Oda, N.;
Sakakibara, J. Heterocycles 1983, 20, 995–1000. (e) Watson,
A. A.; House, D. A.; Steel, P. J. J. Organomet. Chem. 1986,
(
Found: 54.08; H, 4.70; N, 7.19. C H F N O requires: C,
17 17 5 2 2
5
1
4.26; H, 4.55; N, 7.44.); nmax (KBr): 3331, 3295, 2976,
.
K1
673 (C]O), 1627, 1520, 1429, 1141, 1018, 966 cm
5
.3. X-ray structure determination
311, 387–397. (f) Watson, A. A.; House, D. A.; Steel J. Org.
Chem. 1991, 56, 4072–4074.
4. (a) Kotsuki, H.; Hayakawa, H.; Wakao, M.; Shimanouchi, T.;
Single crystal X-ray diffraction data of compound 7d were
collected at room temperature on a Nonius Kappa CCD

3998
U. Gro sˇ elj et al. / Tetrahedron 61 (2005) 3991–3998
Ochi, M. Tetrahedron: Asymmetry 1995, 11, 2665–2668. (b)
9. Gro sˇ elj, U.; Bevk, D.; Jak sˇ e, R.; Meden, A.; Pirc, S.; Re cˇ nik,
S.; Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2004, 15,
2367–2383.
Kotsuki, H.; Wakao, M.; Hayakawa, H.; Shimanouchi, T.;
Shiro, M. J. Org. Chem. 1996, 61, 8915–8920.
. For recent reviews see: (a) Stanovnik, B.; Svete, J. Chem. Rev.
5
10. Druey, J.; Meier, K.; Eichenberger, K. Helv. Chim. Acta 1954,
37, 121–133.
2004, 104, 2433–2480. (b) Svete, J. Monatsh. Chem. 2004,
135, 629–647. (c) Svete, J. Heterocycl. Chem. 2002, 39,
437–454. (d) Stanovnik, B.; Svete, J. Synlett 2000, 1077–1091.
11. Collect Software. Nonius, BV, Delft, The Netherlands, 1998.
12. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307.
13. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori,
G.; Spagna, R. J. Appl. Cryst. 1999, 32, 115.
(
e) Stanovnik, B.; Svete, J. Targets Heterocycl. Syst. 2000, 4,
105–137. (f) Stanovnik, B. J. Heterocycl. Chem. 1999, 36,
1581–1593.
6
7
. Jak sˇ e, R.; Svete, J.; Stanovnik, B.; Golobi cˇ , A. Tetrahedron
004, 60, 4601–4608.
. (a) Pirc, S.; Bevk, D.; Goli cˇ Grdadolnik, S.; Svete, J.
14. Hall, S. R.; King, G. S. D.; Stewart, J. M. The Xtal3.4 User’s
Manual; University of Western Australia: Lamb, Perth, 1995.
15. Burnett, M. N.; Johnson, C. K. In ORTEP-III: Oak Ridge
Thermal Ellipsoid Plot Program for Crystal Structure
Illustrations. Oak Ridge National Laboratory Report ORNL-
6895, 1996.
2
ARKIVOC 2003 (xiv), 37–48. (b) Westman, J.; Lundin, R.
ˇ
Synthesis 2003, 1025–1030. (c) Ceba sˇ ek, P.; Wagger, J.; Bevk,
D.; Jak sˇ e, R.; Svete, J.; Stanovnik, B. J. Comb. Chem. 2004, 6,
3
56–362.
16. Wang, H.; Robertson, B. E. In Structure and Statistics in
Crystallography; Wilson, A. J. C., Ed.; Adenine: New York,
1985.
8
. Gro sˇ elj, U.; Re cˇ nik, S.; Svete, J.; Meden, A.; Stanovnik, B.
Tetrahedron: Asymmetry 2002, 13, 821–833.