Unusual reaction of N-aroyldihydrocyclopenta-pyrazolidinol with ketenes: Formation of 1,3,4-oxadiazoles

Article abstract of DOI:10.1016/S0040-4020(03)00633-1

1-Benzoyl-5-hydroxy-pyrazoline 1 was prepared and its reactions with ketenes, prepared in situ from the corresponding acid chlorides 3a-3d and the mixed anhydride 4, were studied. In all cases the 1,3,4-oxadiazoles 5 were isolated. In the case of compounds 3c and 3d a second diastereomeric oxadiazole 6 was obtained. In the case of 3a,3b and 4, an interesting aroyl migration product 7 was isolated. Structural assignments of the derived compounds were established by analysis of their IR, MS and NMR spectra (¹H, ¹³C, COSY, NOESY, HETCOR and COLOC). The proposed reaction mechanism is supported by semi-empirical (AM1) MO calculations.

Full text of DOI:10.1016/S0040-4020(03)00633-1

Tetrahedron 59 (2003) 4591–4601
Unusual reaction of N-aroyldihydrocyclopenta-pyrazolidinol with
ketenes: formation of 1,3,4-oxadiazoles
*
*
Constantinos A. Tsoleridis, Julia Stephanidou-Stephanatou, Petros Gounaridis, Hara Zika
and Minodora Pozarentzi
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Received 18 February 2003; revised 28 March 2003; accepted 16 April 2003
Abstract—1-Benzoyl-5-hydroxy-pyrazoline 1 was prepared and its reactions with ketenes, prepared in situ from the corresponding acid
chlorides 3a–3d and the mixed anhydride 4, were studied. In all cases the 1,3,4-oxadiazoles 5 were isolated. In the case of compounds 3c and
3d a second diastereomeric oxadiazole 6 was obtained. In the case of 3a,3b and 4, an interesting aroyl migration product 7 was isolated.
Structural assignments of the derived compounds were established by analysis of their IR, MS and NMR spectra (1H, 13C, COSY, NOESY,
HETCOR and COLOC). The proposed reaction mechanism is supported by semi-empirical (AM1) MO calculations. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
corresponding acid chlorides 3a–3d using triethylamine) in
refluxing benzene was undertaken. Compound 1 was
reacted with dimethylketene to provide four products
(Table 1), namely the 1-benzoylcyclopentapyrazole 2, the
1,3,4-oxadiazole 5a, the aroyl migration product 7a, and a
3:1 mixture of the regioisomeric N-aroylsubstitution
derivatives 8a1 and 8a2. From the reaction of 1 with
diphenylketene compound 2 along with the oxadiazole 5b
and the aroyl migration derivative 7b were isolated, whereas
in the case of dichloro- and chloroketene the dehydration
product 2 and the 1,3,4-oxadiazoles 5c and 5d, respectively,
were accompanied by a second diastereomeric oxadiazole
derivative 6c and 6d. In addition, from the reaction of the
more reactive dichloroketene the pyrazolylpropanodione
derivative 9c was obtained. In all cases an amount of
polymeric material was also formed.
Pyrazoles are widely used five-membered heterocyclic
compounds which have been studied extensively.1,2
Promising pharmacological and agrochemical appli-
cations1,2 have prompted their studies. In addition, the use
of some pyrazole derivatives as ultraviolet stabilizers3 and
photosensitizers,4 as well as analytical reagents in the
complexation of transition metal ions,5 has been described.
Moreover, pyrazoles and pyrazolones fused to carbocyclic
rings are of interest in the chemical and pharmaceutical
industry as herbicides,6 analgesics7 and cytotoxic agents.8
These applications and our interest in the chemistry of
pyrazoles9,10 prompted us to study the reaction of
cyclopentapyrazoles with ketenes, because ketenes exhibit
very rich cycloaddition chemistry, due to their unique
structural and electronic properties.11
Furthermore, the reaction of 1 with the mixed anhydride 4
was studied. The anhydride, a synthetic equivalent of acid
chlorides, was prepared from phenoxyacetic acid and
p-toluenesulphonyl chloride in the presence of triethylamine
in dichloromethane at room temperature. Under the mild
reaction conditions employed, compound 5e was isolated in
20% yield, along with a 3:2 regioisomeric mixture of
compounds 8e1 and 8e2 (24% yield). The aroyl migration
product 7e was formed as a minor product (ca. 3% yield)
detectable only by its 1H NMR by comparison with the ones
of 7a and 7b.
2. Results and discussion
The fused cyclopentapyrazolidinol 1 was synthesized
(Scheme 1) by condensation of 2-acetylcyclopentanone
with benzohydrazide in 76% yield.12 All attempts to protect
the hydroxyl group of 1 either by alkylation or acetylation
failed, due to the formation of the favored aromatic pyrazole
derivative 2. Therefore, the reaction of 1 with excess of
ketenes (generated in situ by the dehydrochlorination of the
Finally, the reaction of 2 with dimethylketene was studied,
in order to support the proposed mechanism (Scheme 3) for
the formation of compounds 8 and 9. The expected
pyrazolylpropanodione derivative 9a and the regioisomeric
Keywords: ketenes; pyrazole derivatives; regioisomeric mixture.
*
Corresponding authors. Tel.: þ30-2310-997831; fax: þ30-2310-997679;
e-mail: tsolerid@chem.auth.gr; ioulia@chem.auth.gr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00633-1

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C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
Scheme 1. Reaction of cyclopentapyrazolidinol 1 with ketenes.
mixture of 8a1–8a2 were formed in 30 and 9% yield,
respectively.
40.07 ppm, of a methyl group at 22.24 ppm and of two
methine groups at 53.96 and 54.51 ppm was established
(Tables 2 and 3). By combining these data with the COSY
1H–1H correlations observed in the saturated region, the
presence of group (A) was confirmed (Fig. 1) with the
carbon at 40.07 ppm being next to the carbonyl.
2.1. Structure assignments
The assigned molecular structures of all new compounds
5–9 are based on rigorous spectroscopic analysis including
IR, NMR (1H, 13C, COSY, NOESY, HETCOR and
COLOC), MS and elemental analysis data.
In addition, from the COLOC correlations between the
carbonyl at 215.01 ppm with the protons at d 2.25–2.40 and
1.90–2.02, it was deduced that the last proton has a pseudo-
equatorial configuration, whereas from the COLOC corre-
lations of the methyl protons with carbons at 101.82 (2J) and
53.96 ppm (3J) the molecular fragment (B) could be
extracted. Moreover, the presence of the cyclopentanone
ring (m/z 83) was confirmed from the mass spectrum, where
the molecular fragment at m/z 355 [M283]þ was observed.
The same ion [M283]þ was also present in the mass spectra
of all oxadiazole derivatives 5 and 6.
Regarding the structure of oxadiazoles 5 the assignment of
5b is described. From the molecular ion at m/z 438 the
conclusion could be drawn that 5b is produced from the
reaction of one molecule of 1 with one molecule of
diphenylketene, a fact that was also confirmed from the 13C
NMR spectrum, where 22 different signals were observed.
The IR absorption at 1730 cm21 and the 13C NMR
resonance at 215.01 ppm were consistent with the existence
of a ketone carbonyl.
In the aromatic region, the two protons showing a multiplet
at d 7.74–7.79 belong to C-7 being the most deshielded
protons of the molecule. These protons show COLOC
correlations with the quaternary carbon at 154.29 ppm and
the methine carbon at 131.61 ppm across 3J bond con-
nectivities. In addition, the protons at d 7.40–7.45 correlate
(3J) with the quaternary carbon at 124.41 ppm. These data
indicate that the former benzoyl group of 1 has been
transformed to the group (C). The proton at d 5.93 correlates
with an amide carbonyl at 167.96 ppm and also with the
aromatic quaternary carbons at 139.25 and 139.13 ppm and
with the methine carbons at 129.21 and 128.85 ppm.
Therefore, it could be concluded that this group consists
Furthermore, from the C–H correlated spectra in the
saturated region, the presence of three methylene groups
with their carbons resonating at 19.67, 25.00 and
Table 1. Reaction products and yields (%) of compound 1 with ketenes
R1
R2
2
5
6
7
8
9
Me
Ph
Cl
Me
Ph
Cl
H
(10)
(14)
(2)
5a (25)
5b (20)
5c (25)
5d (29)
7a (22)
7b (28)
8a (12)
6c (19)
6d (6)
9c (20)
Cl
(14)

C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
4593
the former diphenylketene moiety connected to nitrogen
(D). Finally, the chemical shift at 101.82 ppm for the
quaternary carbon of fragment (B) suggests that this carbon
most probably is connected both to nitrogen and oxygen by
analogy with the C-6a carbon of structure 1, which resonates
at 103.04 ppm.13 By combination of all the above data the
oxadiazole structure 5b can be proposed.
Concerning compounds 6c and 6d, they have been
characterized as regioisomeric to 5c and 5d, respectively,
on account of their very similar spectral and analytical data.
The configuration on C-2 of the oxadiazoline ring has been
deduced from the NOESY data of compounds 5c–5d and
6c–6d, where correlation spots between methyl protons and
H-10a are present only in compounds 5 (see Section 2.2).
Concerning compound 7b the molecular ion at m/z 438
indicated that, this derivative was also produced by reaction
of one molecule of 1 with one molecule of diphenylketene
without any loss. However, in this case the hydroxyl
group of 1 remained unaffected and its presence was
unambiguously confirmed in the IR (3400 cm21) and in the
1H NMR (d 5.03) spectra. Moreover, from the similar NMR
chemical shifts of 7b to those of the starting material13 1 it
could be assumed that the fused cyclopentapyrazolidinol
system remained unaffected. In the saturated region of the
13C NMR spectrum one methyl carbon at 14.00 ppm, three
methylene carbons at 23.01, 33.44 and 41.88 ppm, a
methine carbon at 54.59 ppm and two quaternary carbons
at 75.87 and 104.18 ppm were observed (Table 4).
In addition, the carbonyl carbons at 194.54 and 170.87 in
conjunction with their IR absorptions at 1680 and
1635 cm21 could be attributed to a benzoyl and an amide
carbonyl, respectively. The methyl protons give COLOC
correlations with the quaternary carbons at 158.48 and
75.87 ppm, whereas the hydroxyl hydrogen correlates with
the same quaternary carbon at 75.87 ppm and also with the
quaternary carbon at 104.18 ppm. From these data the signal
at 75.87 ppm could be assigned to C-3a, the signal at
158.48 ppm to C-3 and the signal at 104.18 ppm to the
1
hydroxylated carbon C-6a. From the H–1H and 13C–1H
COSY of the aromatic region the benzoyl group could be
assigned. The multiplet at d 7.53–7.62 belongs to the
protons of C-9 and correlates with the carbonyl carbon at
194.54 ppm but also with the methine carbon at
132.62 ppm. In addition, the proton at d 5.99 correlates
with the amide carbonyl at 170.87 ppm, with the aromatic
quaternary carbons at 139.14 and 139.06 ppm but also with
the methine carbons at 129.14 and 128.94 ppm. These data
indicate that this group consists the former diphenylketene
moiety connected to N-1. The absence of the bridge H-3a in
connection with the substantial chemical shift change of
C-3a and H-4a compared to the parent compound 1, from
59.67 to 75.87 ppm, and from d 2.11 to 2.977, respectively,
shows the position of the benzoyl attachment.
The PhCO-3a and HO-6a substituents offer an additional
rigidity to the fused molecule, so that the combined
influence of all substituents on the chemical shifts of the
cyclopentane-ring methylene protons results to well
resolved individual multiplets for each proton. From the
1H–1H and 13C–1H COSY of the aliphatic region the

4594
C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
Table 3. 13C NMR data for compounds 5a–5e and 6c–6d
Position
5a
101.53
5b
5c
5d
5e
6c
6d
2
101.82
22.24
102.28
22.07
102.00
22.29
101.97
22.43
101.55
22.81
101.32
23.46
2-Me
5
6
7
8
22.53
154.17
124.71
126.80
128.68
131.49
53.43
215.18
40.18
19.73
154.29
124.41
126.85
128.65
131.61
53.96
215.01
40.07
19.67
156.09
123.52
127.24
128.86
132.41
53.47
214.24
39.92
19.63
155.40
123.91
127.03
128.78
132.03
53.66
210.65
40.00
19.66
155.42
124.06
127.00
128.78
131.97
53.89
214.61
40.03
19.67
25.30
163.85
65.61
158.21
114.73
129.53
121.51
155.36
123.85
127.14
128.70
132.10
51.11
213.16
38.96
19.89
154.57
124.26
126.90
128.64
131.72
50.71
213.70
39.14
19.93
9
10
11
12
13
14
15
16
17
18
19
20
25.23
25.00
167.96
54.51
24.91
158.94
64.38
25.12
162.04
42.00
25.94
159.57
64.42
25.98
162.86
42.57
173.52
54.06
18.79, 18.37
139.25,a 139.13a
129.21,b 128.85b
128.51,c 128.43c
127.05,d 126.97d
a,b,c,dValues are interchangeable between the two phenyls.
Figure 1. Molecular fragments extracted from the compilation of spectral data of 5b.
sequence for the three CH2 groups of cyclopentane could be
assigned. To determine the exact values of chemical shifts
and coupling constants of these protons the corresponding
part of 1H NMR spectra of both compounds 7a and 7b was
reproduced by simulation (Table 5). On the basis of our
previous work13 on compound 1 and in conjunction with
molecular modeling on compounds 7 (AM1), it was
concluded that the conformation of the cyclopentane ring
is similar to the one of 1. From the model of 7a depicted in
Figure 2 the torsion angles between the methylene protons
and the carbons C-3a and C-6a, being three bonds away,
could be extracted. These angles for the protons H-4b, H-5a
and H-6b vary from 132 to 1468 and for the protons H-4a,
H-5b and H-6a from 95 to 1098. The COSY correlation
between H-4b and H-6b (4J¼1.7 Hz) is in accordance with
the proposed ‘W’ configuration resulted from a pseudo-
equatorial conformation of protons H-4b, H-5a and H-6b.
This configuration is also supported by the COLOC
correlations between the protons H-4b at 1.723 and H-5a
at 1.897 with carbon C-6a and between the protons H-5a and
H-6b (at 2.743) with carbon C-3a via 3J(C–H). On the other
hand, the chemical shift difference between the protons at
the same methylene carbon (DdC-4¼1.223, DdC-5¼0.478,
DdC-6¼0.510) can be explained by the downfield influence
of the benzoyl group at C-3a on proton H-4a and of the
amide carbonyl on H-6b, and by the upfield influence of
NvC bond on H-5b.
Compounds 8 were assigned utilizing their similarity12 with
compounds 2a,b (Table 6).
Finally, concerning compound 9c it was confirmed that the
carbonyl substituent was on N-2 on account of its spectro-
scopic data (Table 7). Analytically, the methyl protons show
COLOC correlations with the quaternary carbons resonating
at 130.10 and 136.67 ppm, whereas the methylene protons
at d 2.46 correlate with the quaternary carbon at
167.41 ppm. This signal is attributed to the C-6a forming
a double bond with N-1, whereas the amide carbonyl carbon
resonates at 161.86 ppm. Analogous chemical shift for C-6a
was observed in the case of 9a.
It is worth mentioning that from our studies on fused
pyrazole derivatives the conclusion can be drawn that the
value for the chemical shift of C-6a ranging from ca. 160–
168 ppm can be used as a diagnostic tool for the
identification of N-2 substituted pyrazole derivatives,
whereas in the analogous N-1 substituted pyrazole deriva-
tives the corresponding value is ranging ca.150–155 ppm.
2.2. Reaction mechanisms
From the isolation of products 5–7 on one hand and 8 and 9
on the other hand the reaction mechanisms depicted in
Schemes 2 and 3 can be proposed. As shown in Scheme 2,

Table 4. 13C, 1H and COLOC NMR data for compounds 7a and 7b
Position
Compound 7a
Ha
Compound 7b
C
COLOCb
C
Ha
COLOCb
3
157.87
13.97
75.90
33.59
158.48
14.00
75.87
33.44
3-Me
3a
4
1.69 (s)
157.85, 75.89
1.62 (s)
158.48, 75.87
104.18
2.93–3.04 (m),c
1.71–1.76 (m)
1.87–1.98 (m),
1.37–1.53 (m)
2.11–2.23 (m),
2.64–2.73 (m)
2.93–3.33 (m),c
1.69–1.73 (m)
1.83–1.95 (m),
1.33–1.49 (m)
2.11–2.21 (m),
2.71–2.79 (m)
5
6
23.18
41.94
23.01
41.88
104.18
104.18, 75.87
23.01, 104.18, 75.87
104.18, 75.87
6a
OH
7
8
9
10
11
12
13
14
15
16
17
104.08
5.01 (br, s)
75.89
5.03 (s)
195.16
137.73
128.84
128.24
132.64
176.63
32.10
194.54
137.31
128.78d
128.17
132.62
170.87
54.59
7.75–7.81 (m)
7.35–7.43 (m)
7.48–7.55 (m)
195.14, 132.63
137.71
7.53–7.62 (m)
7.11–7.20 (m)
7.39–7.47 (m)
194.54, 132.62
137.31
3.38 (sep, 6.9)
1.21 (d, 6.9)
1.27 (d, 6.9)
5.99 (s)
170.87, 139.14, 139.06, 129.14, 128.94
18.40
18.75
176.62, 32.10, 18.75
176.62, 18.40
139.14,e 139.06
129.14, 128.94
128.73,d 128.43
127.10, 127.09
7.30–7.44,f 7.40–7.52
7.30–7.47, 7.30–7.47
7.22–7.29, 7.33–7.40
a
Multiplicities and couplings in Hz in parentheses. For exact values of chemical shifts and coupling constants of cyclopentane-ring protons see Table 5.
3
b
c
d
e
f
Long-range (2JC–H and JC–H) correlations between the protons on the left and the carbons stated on the column.
Presented in a,b order.
May be interchanged.
For both phenyls.
Superimposed multiplets distinguished by homo- and hetero-COSY.

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C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
Table 5. Chemical shifts and nJ(H,H) coupling constants fitted to the best simulated spectra for the cyclopentane methylene protons of compounds 7a and 7b
Compound 7a
Compound 7b
H-4a
H-4b
H-5a
H-5b
1.449
12.0
5.5
H-6a
H-6b
2.686
0.0
1.7
H-4a
H-4b
H-5a
H-5b
1.411
12.0
5.7
H-6a
H-6b
2.743
0.0
1.7
2.985
H-4a
H-4b
1.762
213.6
1.927
6.0
2.5
2.176
0.0
0.0
2.977
H-4a
H-4b
1.723
213.2
1.897
6.2
2.5
2.161
0.0
0.0
H-5a
H-5b
H-6a
213.0
6.4
12.3
2.6
6.1
213.2
H-5a
H-5b
H-6a
212.7
6.3
12.1
2.3
5.7
213.0
Figure 2. Molecular model of the compound 7a (AM1).
Table 6. 1H and 13C NMR spectral data for the isomers 8a1,a2 and 8e1,e2 (multiplicities and J in Hz)
Position
8a1
8a2
8e1
8e2
8a1
8a2
8e1
8e2
3
147.81
13.05
130.85
22.14
30.33
27.17
152.32
176.21
31.68
19.11
136.00
14.15
128.81
21.85
29.55
24.53
165.23
178.42
33.03
19.26
149.13
13.52
131.37
21.74
29.63
128.42
13.03
136.12
22.09
30.31
3-Me
3a
4
5
6
6a
7
8
2.21 (s)
2.51 (s)
2.19 (s)
2.49 (s)
2.49–2.60 (m)a
2.49–2.60 (m)a
2.96–3.03 (m)
2.49–2.60 (m)a
2.49–2.60 (m)a
2.70 (t, 7.2)
2.44–2.58 (m)
2.44–2.58 (m)
2.93–3.00 (m)
2.32–2.43 (m)
2.32–2.43 (m)
2.67 (t, 7.3)
26.62
24.32
152.43
168.28
65.73
158.09
114.81
129.49
121.54
166.34
166.89
66.61
158.07
114.87
129.49
121.63
3.79 (sep, 7.0)
1.26 (d, 7.0)
3.88 (sep, 7.0)
1.26 (d, 7.0)
9
5.36 (s)
5.38 (s)
10
11
12
6.94–7.00 (m)
7.22–7.30 (m)
6.86–6.93 (m)
6.94–7.00 (m)
7.22–7.30 (m)
6.86–6.93 (m)
As a 3:1 mixture for compounds 8a1,a2 and 3:2 or compounds 8e1,e2.
Superimposed multiplets distinguished by homo- and hetero-COSY.
a
the reaction is most probably initiated by an attack of N-1 of
1 to the ketene carbonyl giving intermediate 10. This attack
is supported by semi-empirical MO calculations (AM1) on
compound 1 which gave for N-1 net charge q¼20.30
electrons and HOMO pz coefficient¼0.62, whereas the
corresponding values for N-2 are 20.001 and 20.36. When
ketene approaches N-1 from the exo side of the fused
pyrazolidine ring (path a), proton abstraction of the
hydroxyl group by the ketene moiety is favorable causing
subsequent fission of the pyrazolidine ring (intermediate 11,
Fig. 3). This fission is followed by attack at the former C-3
by the more electron-rich oxygen of the benzoyl group with

C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
Table 7. 13C, H and COLOC NMR data for compounds 9a and 9c
4597
1
Position
Compound 9a
Ha
Compound 9c
Ha
C
COLOCb
C
COLOCb
3
135.56
13.81
128.78
21.55
29.22
136.67
13.28
130.10
21.60
29.26
24.25
167.41
161.86
85.50
3-Me
3a
4
5
6
6a
7
8
2.48 (s)
135.56, 128.78
2.50 (s)
136.67, 130.10
2.39c (t, 7.0)
2.18 (qui, 7.0)
2.41c (t, 7.0)
165.72, 128.78, 29.22
21.55, 24.22
165.72, 128.78
2.44c (t, 7.0)
2.24 (qui, 7.0)
2.46c (t, 7.0)
167.41, 130.10, 29.26
21.60, 24.25
167.41, 130.10
24.22
165.72
175.35
55.23
8-Me
9
10
11
12
13
24.93
1.70
175.35, 55.23
196.98
136.79
127.80
128.12
131.54
182.72
133.13
128.97
128.40
132.83
7.76–7.81 (m)
7.27–7.34 (m)
7.34–7.41 (m)
131.54
136.79
127.80
7.87–7.91 (m)
7.34–7.41 (m)
7.45–7.51 (m)
182.72, 132.83
133.13
128.97
aMultiplicities and J in Hz in parentheses. bLong-range (2JC–H and 3JC–H) correlations between the protons on the left and the carbons stated on the column.
cSuperimposed multiplets distinguished by homo- and hetero-COSY.
Scheme 2. Plausible mechanism for the reaction of 1 with ketenes explaining the formation of 5–7.
Scheme 3. Plausible mechanism for explaining the formation of 8 and 9.

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C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
regioisomer, depicted in Figure 4, for regioisomers 5c and
6c. The methyl group is more crowded in the 2S than in the
2R configuration being between the two carbonyls. In this
way, the downfield shift of the methyl protons of
regioisomer 5c (d 2.13) over the corresponding of 6c (d
1.88) and their 13C chemical shifts 22.07 over 22.81,
respectively, could be explained. In addition, the calculated
dipole moment of the 2S isomer (3.19 D) is lower than the
corresponding value (3.96 D) of the 2R in agreement with
their column elution order and also with their mp, where the
mp of 5 is lower than the one of 6 in both isolated isomeric
pairs (see Section 4).
Formation of products 8 and 9 could be explained by
accepting a process involving initial dehydration of 1 to 2a.
Subsequent benzoyl migration from N-1 to N-2 of 2a can
occur easily in solution yielding a 3:1 equilibrium mixture12
of isomeric pairs 2a and 2b. Quaternization of the N-sp3 by
the excess of ketene yields the zwitterions 12 of both 2a and
2b (Scheme 3). Elimination of benzoic acid leads to
compounds 8 (reaction path c), whereas intramolecular
attack of the benzoyl carbonyl carbon by the carbanion of
the ketene moiety gives 9 as a single substituted isomer on
N-2 (reaction path d). An additional proof for the proposed
mechanism is the formation of benzoic acid in the case of
the reaction of 1 with 3a and 4 and the increased yield of 2 in
the case of 3b. In order to establish the initial formation of 2
and the mechanism proposed in Scheme 3 the reaction of 2
with dimethylketene was studied, whereupon the expected
pyrazolyl propanodione derivative 9a and the regioisomeric
mixture of 8a1–8a2 were formed in 30 and 9% yield,
respectively.
Figure 3. Molecular model of the intermediate 11 (R1¼R2¼CH3) (AM1).
simultaneous shift of the ketene moiety. Thus, the formation
of regioisomers 5 (2S) can be explained. To the contrary,
when the ketene molecule approaches N-1 from the endo
side (path b), proton abstraction of the hydroxyl group is
less favorable and occurs only in the case of the more
reactive chloro- and dichloroketenes giving the regio-
isomeric oxadiazoles 6 (2R). In the case of dimethyl-,
diphenyl- and phenoxyketenes of moderate reactivity,
abstraction of the hydroxyl proton is not favored and
benzoyl migration at the former C-3a occurs leading to the
formation of compound 7.
3. Conclusion
The proposed mechanisms are also supported by the yield
ratio of the chloroderivatives 5c, 6c (25%, 19%) and 5d, 6d
(29, 6%), where the more reactive dichloroketene gives
approximately the same yields for both isomers.
In conclusion, we have studied an unusual reaction of a
fused cyclopentapyrazolidinol with ketenes leading to
unexpected products. The proposed mechanisms offer a
rational explanation for the regioselectivity found. In
addition, from the above studies on fused pyrazole
derivatives the value for the chemical shift of C-6a ranging
from ca. 160–168 ppm can be used as a diagnostic tool for
In order to distinguish between the two possible regio-
isomers 5 and 6 MO calculations (AM1) have been carried
out affording the more stable conformation of each
Figure 4. Molecular models of the diastereoisomers 5c and 6c at their most stable conformation (AM1).

C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
4599
the identification of N-2 substituted pyrazole derivatives,
whereas in the analogous N-1 substituted pyrazole
derivatives the corresponding value is ranging ca. 150–
155 ppm.
4.2.2. 1-Benzoyl-1,4,5,6-tetrahydro-3-methyl-cyclo-
penta[c]pyrazole (2). White solid,12 (0.023 g, 10%), mp
44–468C, Rf¼0.70.
4.2.3. (2S)-2,3-Dihydro-2-methyl-3-(2-methyl-1-oxo-
propyl)-2-(2-oxocyclopentyl)-5-phenyl-1,3,4-oxadiazole
(5a). White solid (0.078 g, 25%), mp 102–1038C (EtOH),
4. Experimental
4.1. General
1
Rf¼0.40. H and 13C NMR: Tables 2 and 3. IR (neat) nmax
1720, 1645, 1620 cm21. EIMS m/z (%) 314 (12, Mþ), 244
(17), 231 (14), 161 (100). Anal. calcd for C18H22N2O3
(314.39): C, 68.77; H, 7.05; N, 8.91. Found: C, 68.82; H,
7.00; N, 8.80.
Melting points were measured on a Kofler hot-stage and are
uncorrected. Column chromatography was carried out using
Merck silica gel. Petroleum ether refers to the fraction
boiling between 60 and 808C. NMR spectra were recorded
4.2.4. 3a-Benzoyl-4,5,6,6a-tetrahydro-6a-hydroxy-3-
methyl-1-(2,2-dimethylacetyl)-cyclopenta[c]pyrazole
(7a). White solid (0.069 g, 22%), mp 138–1398C (EtOH),
1
on a Bruker AM 300 spectrometer at 300 MHz for H and
75 MHz for 13C, respectively, using CDCl3 as solvent. The
chemical shifts are expressed in d values (ppm) relative to
TMS as internal standard for 1H and relative to TMS
(0.00 ppm) or to CDCl3 (77.05 ppm) for 13C NMR spectra.
1
Rf¼0.24. H, 13C and COLOC NMR: Table 4. IR (neat)
n
max 3360, 1675, 1635 cm21. EIMS m/z (%) 314 (10, Mþ),
244 (14), 192 (8), 171 (62), 122 (32), 105 (100). Anal. calcd
for C18H22N2O3 (314.39): C, 68.77; H, 7.05; N, 8.91.
Found: C, 68.70; H, 7.09; N, 8.83.
n
Coupling constants J are reported in Hz. The following
abbreviations are used to describe spin multiplicity: s¼
singlet, d¼doublet, t¼triplet, q¼quartet, qui¼quintet, sex¼
sextet, sep¼septet, m¼multiplet, br¼broad, dd¼double of
doublets, dt¼double of triplets. IR spectra were recorded on
a Perkin–Elmer 297 spectrometer and are reported in wave
numbers (cm21). Low-resolution electron impact mass
spectra (EIMS) were obtained on a VG TS-250 instrument
and elemental analyses performed with a Perkin–Elmer
2400-II CHN analyzer. The MO calculations for minimum
energy conformation of compounds were computed with the
AM1 method as implemented in the MOPAC package14
version 6.3. All stationary points were refined by minimiz-
ation of the gradient norm of the energy to at least
0.005 kcal/mol.
4.3. Reaction of 1 with diphenylketene
The reaction was carried out as described above with
1 mmol of 1 to afford after column chromatography
compound 2 (0.032 g, 14%).
4.3.1. (2S)-2,3-Dihydro-2-methyl-3-(2,2-diphenylacetyl)-
2-(2-oxocyclopentyl)-5-phenyl-1,3,4-oxadiazole (5b).
White solid (0.088 g, 20%), mp 145–1468C (Et2O/
1
petroleum ether). H and 13C NMR: Tables 2 and 3. IR
(nujol) nmax 1730, 1650, 1620 cm-1. EIMS m/z (%) 438
(49, Mþ), 355 (6), 244 (82), 194 (57), 192 (15), 168
(68), 167 (98), 166 (75), 165 (100), 162 (40), 161 (96), 152
(61), 115 (10), 105 (98). Anal. calcd for C28H26N2O3
(438.53): C, 76.69; H, 5.98; N, 6.39. Found: C, 76.73; H,
5.82; N, 6.36.
4.2. Reaction of pyrazolidinol 1 with dimethylketene—
general procedure
A solution of isobutyryl chloride (3a) (0.21 g, 2.0 mmol) in
dry benzene (5 mL) was added dropwise at room tempera-
ture for 2 h to a stirred solution of 1 (0.244 g, 1.0 mmol) and
Et3N (0.21 g, 2.1 mmol) in dry benzene (20 mL). The
reaction mixture was stirred under reflux for 4 h and then a
further quantity of Et3N (2.1 mmol) was added followed by
the dropwise addition of isobutyryl chloride (2.0 mmol) in
dry benzene (5 mL). The reaction mixture was stirred under
reflux for a further 4 h and then washed with a 10%
NaHCO3 aqueous solution (10 mL). The organic layer was
separated, dried (Na2SO4), and evaporated under reduced
pressure. The residue was purified by column chromato-
graphy on silica gel using petroleum ether/EtOAc as
eluent, slowly increasing the polarity to give in order of
elution.
4.3.2. 3a-Benzoyl-4,5,6,6a-tetrahydro-6a-hydroxy-3-
methyl-1-(2,2-diphenylacetyl)-cyclopenta[c]pyrazole
(7b). White solid (0.123 g, 28%), mp 192–1938C (EtOH).
1H, 13C and COLOC NMR: Table 4. IR (nujol) nmax 3400,
1680, 1635 cm-1. EIMS m/z (%) 439 (38, Mþ), 421 (4), 411
(5), 317 (19), 245 (37), 169 (44), 153 (95), 140 (50), 128
(59), 111 (69), 105 (65), 91 (55), 83 (100). Anal. calcd for
C28H26N2O3 (438.53): C, 76.69; H, 5.98; N, 6.39. Found: C,
76.49; H, 5.80; N, 6.50.
4.4. Reaction of 1 with dichloroketene
The reaction was carried out as described above with
1 mmol of 1 to give in elution order after column
chromatography compound 2 (0.005 g, 2%).
4.2.1. 1,4,5,6-Tetrahydro-3-methyl-1-(2-methyl-1-oxo-
propyl)-cyclopenta[c]pyrazole (8a1) and 2,4,5,6-tetra-
hydro-3-methyl-2-(2-methyl-1-oxopropyl)-cyclopenta[c]-
pyrazole (8a2). As a 3:1 mixture of regioisomers (0.023 g,
12%). White solid, mp 112–1158C, Rf (petr. ether/EtOAc
4.4.1. 2-(2-Benzoyl-2,2-dichloroacetyl)-2,4,5,6-tetra-
hydro-3-methylcyclopenta[c]pyrazole (9c). White solid
(0.067 g, 20%), mp 155–1568C (Et2O/petroleum ether). 1H,
13C and COLOC NMR: Table 7. IR (nujol) nmax 1730, 1670,
1620 cm21
.
EIMS m/z (%) 336/338/340 (33, Mþ),
1
10:1)¼0.82. H and 13C NMR: Table 6. IR (nujol) nmax
1705 cm-1. EIMS m/z (%) 192 (9, Mþ), 122 (100), 69 (52).
Anal. calcd for C11H16N2O (192.26): C, 68.72; H, 8.39; N,
14.57. Found: C, 68.81; H, 8.34; N, 14.41.
308/310/312 (7), 226 (8), 192 (12). Anal. calcd for
C16H14Cl2N2O2 (337.21): C, 56.99; H, 4.18; N, 8.31.
Found: C, 56.89; H, 3.99; N, 8.16.

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C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
4.4.2. (2S)-3-(2,2-Dichloroacetyl)-2,3-dihydro-2-methyl-
2-(2-oxocyclopentyl)-5-phenyl-1,3,4-oxadiazole (5c).
White solid (0.089 g, 25%), mp 97–988C (EtOH). H and
13C NMR: Tables 2 and 3. IR (nujol) nmax 1730, 1670 cm21
EIMS m/z (%) 354/356/358 (17, Mþ), 271 (90), 243 (16),
229 (37) 161 (100), 105 (99). Anal. calcd for
C16H16Cl2N2O3 (355.22): C, 54.10; H, 4.54; N, 7.89.
Found: C, 54.19; H, 4.65; N, 7.91.
methyl-2-(2-phenoxyacetyl)-cyclopenta[c]pyrazole
(8e2). As a 3:2 mixture (0.062 g, 24%), white solid, mp 88–
908C. 1H and 13C NMR: Table 6. IR (nujol) nmax
1705 cm21. EIMS m/z (%) 256 (17, Mþ), 135 (63), 122
(50), 91 (90), 77 (100). Anal. calcd for C15H16N2O2
(256.31): C, 70.29; H, 6.29; N, 10.93. Found: C, 70.35; H,
6.12; N, 10.78.
1
.
4.6.2. (2S)-2,3-Dihydro-2-methyl-2-(2-oxocyclopentyl)-3-
(2-phenoxyacetyl)-5-phenyl-1,3,4-oxadiazole (5e). White
4.4.3. (2R)-3-(2,2-Dichloroacetyl)-2,3-dihydro-2-methyl-
(6c).
1
2-(2-oxocyclopentyl)-5-phenyl-1,3,4-oxadiazole
solid (0.083 g, 22%), mp 80–818C (EtOH). H and 13C
1
White solid (0.067 g, 19%), mp 124–1258C (EtOH). H
and 13C NMR: Tables 2 and 3. IR (neat) nmax 1730, 1670,
1620 cm21. EIMS m/z (%) 354/356/358 (60, Mþ), 270 (77),
244 (65), 161 (79), 111 (100). Anal. calcd for
C16H16Cl2N2O3 (355.22): C, 54.10; H, 4.54; N, 7.89.
Found: C, 54.08; H, 4.46; N, 7.71.
NMR: Tables 2 and 3. IR (neat) nmax 1720, 1645,
1620 cm21. EIMS m/z (%) 378 (5, Mþ), 295 (7), 161
(11), 107 (66), 77 (100). Anal. calcd for C22H22N2O4
(378.43): C, 69.83; H, 5.86; N, 7.40. Found: C, 70.03; H,
5.80; N, 7.52.
4.7. Reaction of 2 with dimethylketene
4.5. Reaction of 1 with chloroketene
A solution of isobutyryl chloride (3a) (0.21 g, 2.0 mmol) in
dry C6H6 (5 mL) was added dropwise at room temperature
for 1 h to a stirred solution of 2 (0.226 g, 1.0 mmol) and
Et3N (0.21 g, 2.1 mmol) in dry benzene (20 mL). The
reaction mixture was stirred under reflux for 4 h and then the
previously described work-up procedure was undertaken to
give the following compounds in elution order.
The reaction was carried out as described above with
1 mmol of 1 to give after column chromatography
compound 2 (0.032 g, 14%).
4.5.1. (2S)-2,3-Dihydro-2-methyl-3-(2-chloroacetyl)-2-
(2-oxocyclopentyl)-5-phenyl-1,3,4-oxadiazole (5d). White
solid (0.093 g, 29%), mp 96–978C (EtOH). 1H and 13C NMR:
Tables 2 and 3. IR (nujol) nmax 1730, 1650, 1620 cm21. EIMS
m/z (%) 320/322 (15, Mþ), 245 (7), 237 (28), 161 (92), 105
(81), 77 (100). Anal. calcd for C16H17ClN2O3 (320.78): C,
59.91; H, 5.34; N, 8.73. Found: C, 59.82; H, 5.48, N, 8.57.
4.7.1. 1,4,5,6-Tetrahydro-3-methyl-1-(2-methyl-1-oxo-
propyl)-cyclopenta[c]pyrazole (8a1) and 2,4,5,6-tetra-
hydro-3-methyl-2-(2-methyl-1-oxopropyl)-cyclopenta[c]-
pyrazole (8a2). Overall yield 0.017 g, 9% as a 3:1 mixture.
4.5.2. (2R)-2,3-Dihydro-2-methyl-3-(2-chloroacetyl)-2-
(2-oxocyclopentyl)-5-phenyl-1,3,4-oxadiazole (6d). White
4.7.2. 2-(2-Benzoyl-2,2-dimethylacetyl)-2,4,5,6-tetra-
hydro-3-methylcyclopenta[c]pyrazole (9a). White solid
(0.119 g, 30%), mp 84–858C (EtOH). 1H, 13C and COLOC
NMR: Table 7. IR (nujol) nmax 1730, 1670 cm-1. EIMS m/z
(%) 297 (23, Mþ1þ), 269 (9), 268 (55), 228 (100), 226 (70),
219 (14), 211 (14), 199 (80), 191 (14) 121 (91), 106 (77),
105 (100), 91 (28). Anal. calcd for C18H20N2O2 (396.37): C,
72.95; H, 6.80; N, 9.45. Found: C, 72.90; H, 6.69; N, 9.32.
1
solid (0.019 g, 6%), mp 106–1088C (EtOH). H and 13C
NMR:Tables2and3. EIMSm/z(%)320/322(7, Mþ),246(1),
237 (10), 161 (100), 105 (65), 77 (58). Anal. calcd for
C16H17ClN2O3 (320.78): C, 59.91; H, 5.34; N, 8.73. Found: C,
59.79; H, 5.27, N, 8.62.
4.6. Reaction of 1 with the anhydride 5 in the presence of
Et3N
A solution of phenoxyacetic acid (0.46 g, 3.0 mmol),
toluene-p-sulphonyl chloride (0.57 g, 3.0 mmol), and Et3N
(0.61 g, 6.0 mmol) in dry CH2Cl2 (15 mL) was stirred at
room temperature for 10 min. To this solution the
pyrazolidinol 1 (0.244 g, 1.0 mmol) was added in dry
CH2Cl2 (2 mL) and the solution was stirred at room
temperature for 24 h. A further quantity of phenoxyacetic
acid-toluene-p-sulphonyl chloride-Et3N solution, prepared
as above, was added and stirring was continued for 24 h.
The reaction mixture was then washed with a 10% NaHCO3
aqueous solution (10 mL), with water (20 mL) and dried.
The solvent was evaporated and the residue was chromato-
graphed on silica gel column with petroleum ether/EtOAc as
eluent with slowly increasing polarity to give the following
compounds in elution order.
References
1. Elguero, J. Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon:
Oxford, 1996; Vol. 3, p 1.
2. Silva, A. M. S.; Almeida, L. M. P. M.; Cavaleiro, J. A. S.;
Foces-Foces, C.; Llamas-Saiz, A. L.; Fontenas, C.; Jagerovic,
N.; Elguero, J. Tetrahedron 1997, 53, 11645–11658.
´
3. Catalan, J.; Fabero, F.; Claramunt, R. M.; Santa Maria, M. D.;
Foces-Foces, M. C.; Cano, F. H.; Martinez-Ripoll, M.;
Elguero, J.; Sastre, R. J. Am. Chem. Soc. 1992, 114,
5039–5048.
4. Clark A.B.; Holstead C.; Simons, J. M. UK Patent Appl. GB 2
136 980; Chem. Abstr. 1985, 102, p103656x.
5. Ahmad, R.; Ahmad, N.; Zia-Ul-Haq, M.; Wahid, A. J. Chem.
Soc. Pak. 1996, 18, 38.
Compound 2 (0.032 g, 14%).
6. Wolf A. D.; US Patent 4 124 373, 1978; Chem. Abstr. 1979,
90, P152175g.
4.6.1. 1,4,5,6-Tetrahydro-3-methyl-1-(2-phenoxyacetyl)-
cyclopenta[c]pyrazole (8e1) and 2,4,5,6-tetrahydro-3-
7. Bourdais J.; Peyroux J. M. A. Ger. Offen. 2 630 015, 1977;
Chem. Abstr. 1977, 87, P5969d.

C. A. Tsoleridis et al. / Tetrahedron 59 (2003) 4591–4601
4601
´
8. Gordaliza, M.; Miguel del Coral, J. M.; Castro, M. A.; Lopez-
11. Tidwell, T. T. Ketenes; Wiley: New York, 1995; pp 459–571.
12. Tsoleridis, C. A.; Stephanidou-Stephanatou, J.; Zika, C.;
Pozarentzi, M.; Alevizopoulos, S. Helv. Chim. Acta 2003, 86,
330–342.
´
´
´
Vazquez, M. L.; San Feliciano, A.; Garcıa-Gravalos, M. D.;
Carpy, A. Biorg. Med. Chem. 1995, 3, 1203–1210.
9. Mitkidou, S.; Papadopoulos, S.; Stephanidou-Stephanatou, J.;
Terzis, A.; Mentzafos, D. J. Chem. Soc. Perkin Trans. 1 1990,
1025–1031.
13. Tsoleridis, C. A.; Stephanidou-Stephanatou, J. Magn. Reson.
Chem. 2002, 40, 733–737.
10. Mitkidou, S.; Papadopoulos, S.; Stephanidou-Stephanatou, J.;
Terzis, A.; Mentzafos, D. J. Org. Chem. 1990, 55, 4732–4735.
14. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902–3909.