Sequential azomethine imine cycloaddition-palladium catalysed cyclisation processes

Article abstract of DOI:10.1016/S0040-4020(03)00517-9

In situ generation of azomethine imines from aryl/heteroaryl aldehydes and N,N′-disubstituted hydrazines followed by cycloaddition to N-methylmaleimide generates pyrazolidines, which undergo Pd(0) catalysed cyclisation involving the aldehyde and hydrazine

Full text of DOI:10.1016/S0040-4020(03)00517-9

Tetrahedron 59 (2003) 4451–4468
Sequential azomethine imine cycloaddition–palladium catalysed
cyclisation processes
*
Colin. W. G. Fishwick, Ronald Grigg, Visuvanathar Sridharan and Julia Virica
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
Received 19 July 2002; revised 3 March 2003; accepted 27 March 2003
Abstract—In situ generation of azomethine imines from aryl/heteroaryl aldehydes and N,N0-disubstituted hydrazines followed by
cycloaddition to N-methylmaleimide generates pyrazolidines, which undergo Pd(0) catalysed cyclisation involving the aldehyde and
hydrazine substituents, with formation of 6–8 membered rings in good yield. AMI calculations indicate the preferred configuration of the
azomethine imines involved and identify the most likely cycloaddition transition states. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
prototropy route.9,10 Our strategy in the current studies was
to react azomethine imines, generated in situ by the
aldehyde condensation route, and containing the requisite
functionality for subsequent palladium catalysed Heck or
Friedel–Crafts reactions, with N-methylmaleimide. Sub-
sequent palladium catalysed cyclisation processes then
allow access to novel fused ring heterocycles.
We have developed a number of one-pot sequential or
cascade protocols which employ several types of 1,3-
dipoles and palladium catalysed cyclisation processes. Such
tactical combinations include azomethine ylide cyclo-
addition cascades with palladium catalysed cyclisation
processes1,2 and/or carbonylation processes,3 sequential
oxypyridinium betaine cycloaddition/palladium catalysed
cyclisation–anion capture processes,4 and cascade
palladium catalysed tetramolecular queuing processes
involving carbon monoxide and/or allene as relay switches
followed by 1,3-dipolar cycloaddition or Diels–Alder
reactions.5,6 The above processes result in molecules
possessing a high degree of complexity which would
otherwise require tedious and/or technically demanding
multistep syntheses. Tactical combinations of this general
type can adopt two broad strategies in which the palladium
catalysed cascade either precedes or follows the cyclo-
addition step. This paper is concerned with the latter
strategy.
1.1. Formation of 6-membered rings
Cyclic11 and acyclic12 N,N0-disubstituted hydrazines with a
variety of substituents have been used as precursors of
azomethine imines and a range of inter- and intra-molecular
dipolarophiles have0been employed. We initially focused on
N-(2-iodobenzyl)-N -carbomethoxy hydrazine 1, which was
prepared from 2-iodobenzaldehyde and methyl carbazate
via condensation followed by the reduction of the hydrazone
with NaCNBH3. Initially we studied the cycloaddition of the
azomethine imine generated from cinnamaldehyde and 1.
Thus cinnamaldehyde was reacted with 1 and N-methyl-
maleimide (NMM) in xylene 1408C for 10 h to afford a 4:1
mixture of cycloadducts 2 and 3 in 67% yield. The
stereochemistry of 2 and 3 were established by n.O.e
studies (see Section 2).
As a part of our ongoing interest in developing tactical
combinations of cycloaddition reactions with palladium
catalysed cyclisation processes we explored the sequential
combination of azomethine imine cycloaddition with
palladium catalysed cyclisation processes (Scheme 1) with
in situ generation of the azomethine imine.
Condensation of aldehydes with 1,2-disubstituted hydra-
zines as a route to azomethine imines was described by
Huisgen in 19637,8 and we later reported a novel 1,2-
Keywords: azomethine imine; cycloaddition; palladium; cyclisation.
*
1,3-Dipolar cycloadditions often exhibit a preference for an
endo- over an exo-transition state in the absence of
Corresponding author. Tel.: þ44-113-343-6501; fax: þ44-113-343-6530;
e-mail: r.grigg@chem.leeds.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00517-9

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C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
Scheme 1.
overriding steric factors.13–15 The pyrazolidine products 2
and 3 fail to accurately reflect the azomethine imine
stereochemistry or the exo/endo-nature of the cycloaddition
transition states since this stereochemical information is lost
due to the presence of a lone pair on each of the two
N-atoms in the pyrazolidine products. However, it is
instructive to consider the possible dipoles and their
transition states. Condensation of cinnamaldehyde with 1
could give rise to four dipoles (Scheme 2).
Table 1. Calculated heats of formation for 1,3-dipoles and their
cycloaddition transition states
Structure
Hfa
nib
4
5
6
7
TS1
TS2
TS3
TS4
TS5
TS6
TS7
TS8
73.45
73.04
71.48
70.26
66.38
67.06
59.59
65.51
68.62
62.91
57.82
66.57
–
–
–
–
544.48
616.97
606.96
578.37
573.88
592.57
613.17
553.17
In principal, each of these can undergo cycloaddition with
NMM via either an exo or an endo transition state to yield
either 2 or 3, respectively. The calculated heats of formation
(Hf) of dipoles 4–7 together with those for all possible
transition states TS1–TS8 are given in Table 1 whilst the
corresponding calculated cycloaddition activation energies
and the estimated barriers for interconversion of the dipoles
are given in Table 2.
a
Heats of formation in kcal mol21, obtained using AM1 Hamiltonian after
full geometry optimisation.
All transition structures were characterized by observing them to have a
single negative vibrational frequency corresponding to the reaction
coordinate following a normal mode analysis (expressed in cm21).
b
These data indicate that all dipoles have similar heats of
formation with 6 and 7 being the most thermodynamically
stable (Table 1). Additionally, it appears that the barriers to
interconversion between dipoles, 4O6 and 5O7, respect-
ively, are small and interconversion can readily occur via
Table 2. Calculated cycloaddition activation energies and dipole
interconversion barriers
Conversion
DHa
4!2
4!3
4!6
4!7
5!2
5!3
5!6
5!7
6!2
6!3
6!4
6!5
7!2
7!3
7!4
7!5
22.00
21.81
4.68b
24.58c
22.90
15.43
28.52c
3.47b
15.22
20.31
6.65b
30.08c
27.24
24.13
26.98c
5.46b
a
Energies in kcal mol21. For cycloadditions, the energy is the difference
between the sum of the heats of formation of dipoleþNMM
(Hf¼228.88 kcal mol21) and the heat of formation of the corresponding
transition state.
b
c
Barrier to rotation around the dipole N–N bond.
Barrier to rotation around the dipole C–C bond.
Scheme 2.

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4453
rotation about the N–N dipole bonds. In contrast, dipole
interconversions involving rotation about the C–C bonds as
in 4O7 and 5O6 have relatively high energy barriers and
should be much slower (Table 2). Inspection of the data in
Table 2 also reveals the stereochemical preferences for the
cycloadditions of dipoles 4–7 with NMM. The energy
differences between the dipoles reflect, in the main, steric
effects. Assuming these are the major influences in the
dipole forming transition states we would expect 6 and 5 to
be the favoured dipoles. The most important reaction
pathway thus corresponds to cycloaddition of thermo-
dynamically favoured dipole 6 via endo transition state
TS7 to yield adduct 2. The unfavourable exo cycloaddition
of this dipole via TS6 is due to the presence of both an
appreciable parallel component in the alignment of the
electronic dipole moments of dipole 6 and NMM, and the
presence of an antibonding interaction between coefficients
on the carbonyl groups within the dipole HOMO and NMM
LUMO orbitals, respectively (Scheme 3). Although endo
addition of dipole 5 to yield 3 is also highly favourable,
overall this represents a less prominent pathway due to the
lower thermodynamic stability of dipole 5, in keeping with
the experimentally observed stereoisomeric preference.
Scheme 4.
The product 10 was obtained exclusively as the (Z)-isomer
as expected for cis-addition of ArPdI to the styryl moiety
followed by cis-b-hydride elimination. In contrast isomer 3
failed to cyclise under essentially similar conditions to those
used for the cyclisation of 2. Carrying out the reaction in
xylene at 1308C also failed to give any cyclised product. It is
not immediately obvious why (3) fails to cyclise. A possible
explanation is that the conformational differences in the
pyrazolidine moiety of the chelated oxidative addition
product (A) may preferentially destabilize/stabilize this
species in the case of (3) to the extent that the cyclisation is
disfavored.
Following the mixed results of the above sequential process,
we modified our strategy and transposed the iodide and
alkene moieties. Thus 1,2-disubstituted hydrazine 11 was
prepared by reductive amination from cinnamaldehyde and
tert-butyl carbazate.
Cycloadditions of dipoles 4 and 7 require appreciably higher
activation energies and represent less prominent reaction
pathways. This would appear to be a consequence of the Z
geometry of the N–CO2Me group within these dipoles and
reflects the increase in steric repulsion between the ester and
(o-iodo)benzyl moieties as the terminal nitrogen of the
dipole starts to re-hybridise upon proceeding into the
transition state. The particularly unfavourable exo cyclo-
additions of dipoles 7 and 5 may reflect the importance of
electronic factors on the stereochemical outcome of these
types of 1,3-dipolar cycloaddition reactions. Both exo
transition states TS2 and TS5 possess appreciable anti-
bonding interactions involving HOMO coefficients within
the vinyl groups of the dipoles and LUMO coefficients of
the NMM carbonyl moiety, respectively (Scheme 3). The
exo transition state TS2 of dipole 5 is further disfavoured
relative to the alternative endo pathway via TS3 due to an
almost parallel alignment of electronic dipoles of the
reactants in TS2 (Scheme 3).
2-Iodobenzaldehyde was reacted with 11 and NMM (xylene
1108C, 29 h) to give a 1.5:1 mixture of 12 and 13 in 76%
yield.
Next we studied the palladium catalysed 6-exo trig
cyclisation processes of 2 and 3. Treatment of 2 with a
catalyst system comprising 10 mol% Pd(OAc)2, 20 mol%
PPh3, Et4NCl (1 mol equiv.) and K2CO3 (2 mol equiv.)
(catalyst system A) in boiling acetonitrile for 4 h effected
clean cyclisation to the Heck product 10 in 81% yield
(Scheme 4).
The stereochemistry of 12 and 13 was assigned on the basis
of their 1H NMR spectra. In particular 12 exhibited methine
proton doublets at d 5.02 (J¼8.1 Hz, 1-H) and d 4.92
(J¼9.2 Hz, 4-H) and a methine proton multiplet at d 3.88
(J¼8.1 and 9.2 Hz, 5-H). Cycloadduct 13 exhibited a
broadened methine proton doublet at d 5.04 (1-H), a
methine proton singlet at d 4.93 (4-H) and a methine proton
doublet at d 3.81 (J¼8.2 Hz, 5-H).
When treated with catalyst system A cycloadduct 12
cyclised over 24 h to the Heck reaction product 14 in 53%
yield. No 7-endo trig cyclisation product was detected.
Scheme 3.

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C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
When the cyclisation was repeated with a catalyst system
comprising 10 mol% Pd(OAc)2, 20 mol% PPh3 and TlOAc
(1.2 mol equiv.) (catalyst system B) in xylene (110–1208C)
the reaction time was reduced to 2 h and the yield increased
to 89%. Similarly cycloadduct 13 cyclised cleanly (catalyst
system B) to 15 (xylene 120–1308C, 5 h) in 87% yield. We
introduced Tl (I) salts into the Heck reaction to suppress
double bond isomerisation of the Heck products.16 and they
have also been shown to accelerate some palladium
catalysed processes.17 The stereochemistry of the styryl
moieties in 14 and 15 conforms to that expected for cis-
addition of ArPdI to the alkene moiety in 12 and 13,
followed by cis-b-hydride elimination.
1.2. Formation of 7-membered rings
In order to investigate 7-membered ring formation cyclo-
adducts 23a,b and 24a,b were prepared by the reaction of
3-thiophene carboxaldehyde or 3-furan carboxaldehyde,
hydrazine 1 and NMM in boiling xylene. Thus the former
aldehyde afforded a 2.8:1 mixture of 23a and 24a in 67%
yield whilst the latter afforded a 2.5:1 mixture of 23b and
24b in 46% yield. The stereochemistry of the cycloadducts
was established by n.O.e studies (see Section 2).
Next we incorporated a vinyl bromide into the hydrazine.
Thus hydrazine 16 was prepared by alkylation of methyl
carbazate with 2,3-dibromo propene.
Reaction of hydrazine 16 with benzaldehyde and NMM
(xylene, 1408C, 14 h) gave a 1.7:1 mixture of 17a and 18a in
51% yield. An analogous reaction with thiophene-2-
carboxaldehyde (xylene, 1408C, 16 h) gave a 1:1 mixture
of 17b and 18b in 44% yield.
Cyclisation of 23a with catalyst system B (xylene, 1108C,
19 h) afforded 25 in 80% yield. Similarly 24a cyclised to 26
in 80% yield while 23b gave 27 in 73% yield. Cyclisation of
24b was not attempted.
Treatment of 17a with catalyst system B (MeCN, 808C,
16 h) gave cyclised product 19 in 49% yield. Cyclisation of
18a under the same conditions over 24 h gave 20 in 47%
yield. Similarly 21 was obtained in 54% yield from 17b
upon treatment with catalyst system B (MeCN, 808C, 16 h)
while cyclisation of 18b gave 22 in 50% yield. No
double bond isomeric products were isolated under these
conditions.

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4455
The formal Friedel–Crafts cyclisation of 23a,b and 24a is
regioselective for the C-2 position as opposed to the C-4
position in the furan and thiophene moieties. This suggests
an electrophilic component to the cyclisation as summarised
in Scheme 5.
1.3. Formation of 8-membered rings
Reaction of 28, 3-thiophene carboxaldehyde and NMM in
xylene (1408C, 22 h) gave a 1.6:1 mixture of cycloadducts
33 and 34a in 68% yield. Column chromatography afforded
individual isomers.
Palladium catalysed cyclisation of 33 employing catalyst
system B (xylene, 130–1408C, 24 h) afforded 35 in 68%
yield. Treatment of 34a with the same catalyst system
(xylene, 130–1408C, 24 h) gave a 3:1 mixture of cyclised
product 36 and deiodinated product 34b in 60% combined
yield.
Scheme 5.
There is growing support for the palladium catalysed
cyclisation of organopalladium (II) species onto a proximate
aryl/heteroaryl system proceeding via a Pd(IV) inter-
mediate.18 We have also carried out the above reaction as
a sequential one-pot process. Thus 1,3-DC reaction of
thiophene carboxaldehyde with 1 and NMM was allowed to
proceed as before (xylene, 1408C, 24 h) then catalyst system
B was added, and heating continued at 1208C for 48 h to
furnish a 3:1 mixture of 25 and 26 in 52% yield.
1,2-Disubstituted hydrazine 28 was prepared from methyl
N-carbazate and (2-iodophenyl)-acetaldehyde to explore an
alternative strategy for 7-membered ring formation.
Reaction of 28, cinnamaldehyde and NMM in xylene
(1408C, 14 h) gave a 3:1 mixture of 29 and 30 in 52%
yield. The stereochemistry of the cycloadducts was
1
determined by correlation with H NMR chemical shifts
and coupling constants with those of 2 and 3. Both
cycloadducts 29 and 30 were cleanly cyclised by catalyst
system B (xylene, 1108C, 18 h) to give 31 and 32 in 88 and
89% yield, respectively. Again only the (Z)-isomers were
observed.
Encouraged by these results, we prepared two further
hydrazines 37a,b from 2-iodobenzoic hydrazide and

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C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
3-thiophene carboxaldehyde or 3-furaldehyde, respectively,
via reductive amination.
The stereochemistry of the cycloadducts in Table 3 was
established by n.O.e studies (see Section 2). Clearly the
presence of an ortho-iodo substituent on the phenyl ring has
a profound effect on the stereochemical outcome of the
cycloaddition reactions. The iodo-substituent affects the
relative energies of the dipole 52 and 53, and also the endo-
or exo-cycloadduct transition state energies.
Initially we explored the reaction of para-formaldehyde,
hydrazine 37a and styrene in boiling xylene (1408C, 9 h).
Cycloadduct 38 was isolated in 94% yield. The attraction of
38 is the presence of two potential cyclisation pathways
involving either the thiophene moiety or the 3-phenyl
substituent. The former would give rise to an 8-membered
product whilst the latter would result in a 7-membered ring.
Cyclisation of 38 proceeded smoothly using catalyst system
B (toluene, 1108C, 16 h) to give 39 as the sole product in
85% yield. Thus the formation of the 8-membered ring is
kinetically favoured and no cyclisation onto the 3-phenyl
ring to give the seven membered ring product 40 was
observed. The high reactivity of 5- or 6-membered
heterocycles in palladium catalysed formal Friedel–Crafts
processes has been noted by us previously.19
There is a general trend discernable in Table 3 in that
mesomeric (Table 3, entries 3 and 4) or inductively
withdrawing (Table 3, entries 5, 8, 9) substituents favour
the 3, 5-cis isomer whilst mesomeric donors favour the 3, 5-
trans isomer (Table 3, entries 6 and 7). The inductive effect
of the 3-methoxy group (Table 3, entries 10 and 11) is
essentially negligible.
Cyclisation to form 8-membered ring products (54a,b–
61a,b) was found to be extraordinary facile. These products
(Table 4) were obtained in excellent yield upon treatment of
the corresponding cycloadducts with catalyst system B
(toluene, 1108 c, 6 h). The structure of the cyclised
products were established by 2D-TOCSY experiments
(see Section 2).
The structure of 39 was assigned from 2D-nmr experiments.
However, when the cycloaddition reaction was repeated
using aryl aldehydes mixtures of cycloadducts 41a, 41b and
42a, 42b were formed. The results are collected in Table 3.
Table 3. Cycloadducts from the reaction of 37a,b with arylaldehydes and
styrene
Entry
R
X
Products Ratio Yield (%)
1
2
3
4
5
6
7
8
Phenyl
Phenyl
4-Nitrophenyl
4-Nitrophenyl
2-Fluorophenyl
4-(Dimethylamino)-phenyl
4-(Dimethylamino)-phenyl
3-(Trifluoromethyl)-phenyl
3-(Trifluoromethyl)-phenyl
3-Methoxy phenyl
S
O
S
O
O
S
O
S
41a,b
42a,b
43a,b
44a,b
45a,b
46a,b
47a,b
48a,ba
49a,ba
50a,ba
51a,ba
1.3:1
1.2:1
3.5:1
3.2:1
2.8:1
1:1.5
1:1.8
2.5:1
2.5:1
1.5:1
1.3:1
68
73
57
60
48
62
64
77
76
76
74
9
10
11
O
S
O
3-Methoxy phenyl
In conclusion we have successfully demonstrated regio-
selective sequential azomethine imine 1,3-DC-palladium
catalysed cyclisation processes for the synthesis of fused
6–8-membered heterocycles.
All reactions were carried out in toluene (1108C, 16 h) with equimolar
amounts of 37a,b, arylaldehyde and styrene.
Diastereoisomers obtained as an inseparable mixture.
a

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4457
Table 4. Palladium catalysed cyclisation of 41a,b–51a,b
The solvent was evaporated in vacuo and the residue
purified by flash chromatography and/or crystallisation.
R
X
Products
Yield(%)
For N-alkyl-N0-phenyl hydrazines, the work up procedure
was modified due to the instability of these compounds to
chromatographic purification. After acidification with conc.
HCl as above, the solvent was removed in vacuo, and the
residue suspended in water (200 ml). The mixture was
washed with CH2Cl2 (3£25 ml) and the aqueous layer
basified to pH 14 (solid NaOH). The solution was extracted
with ether (4£50 ml), and the combined ether extracts dried
(MgSO4) and the solvent removed in vacuo to afford
product of sufficient purity for subsequent cycloaddition.
Phenyl
Phenyl
4-Nitrophenyl
4-Nitrophenyl
2-Fluorophenyl
4-(Dimethylamino)-phenyl
4-(Dimethylamino)-phenyl
3-(Trifluoromethyl)-phenyl
3-(Trifluoromethyl)-phenyl
3-Methoxy phenyl
3-Methoxy phenyl
3-Methoxy phenyl
3-Methoxy phenyl
S
S
O
O
O
S
S
S
O
S
S
54a
54b
55a
55b
56a
57a
57b
58aþ58b
59aþ59b
60a
60b
61a
82
84
72
69
71
81
77
79a
73b
85c
83c
70d
70d
O
O
61b
(B) Alkylation. A mixture of the monosubstituted hydrazine
(0.08 mol), a primary alkyl halide (0.04 mol) and potassium
carbonate (0.04 mol) in acetonitrile (80 ml) was stirred at
room temperature for 24–48 h. The reaction mixture was
then poured into water (200 ml) and extracted with
dichloromethane (4£50 ml). The combined organic layers
were dried (MgSO4) and the solvent removed in vacuo to
afford the crude product which was purified by flash
chromatography.
Catalyst system B, toluene, 1108C, 16 h.
Obtained as a 2.5:1 mixture of 58a and 58b from a 2.5:1 mixture of 48a
and 48b.
a
b
Obtained as a 2.5:1 mixture of 59a and 59b from a 2.5:1 mixture of 49a
and 49b.
Obtained from a 1.5:1 mixture of 50a and 50b.
Obtained from a 1.3:1 mixture of 51a and 51b.
c
d
2. Experimental
2.1.1. N-(2-Iodobenzyl)-N0-carbomethoxy hydrazine 1.
Prepared via method A from 2-iodobenzaldehyde and
methyl carbazate. Hydrazone formation was complete
after 1 h. Purification by flash chromatography, eluting
with 4:1 v/v hexane–ethyl acetate gave the product (97%)
which crystallised from ethanol as colourless needles, mp
53–558C; Found: C, 35.40; H, 3.75; N, 9.15; I, 41.20.
C9H11IN2O2 requires C, 35.31; H, 3.62; N, 9.15; I, 41.46%;
dH 7.83 (d, 1H, J¼7.9 Hz, ArH), 7.37–7.25 (m, 2H, ArH),
6.98 (t, 1H, J¼7.5 Hz, ArH), 6.52 (s, br, 1H, NH), 4.32 (s,
br, 1H, NH), 4.06 (s, 2H, CH2) and 3.71 (s, 3H, CH3); m/z
(%): 306 (Mþ, 23), 232 (72), 217 (100), 104 (12), 90 (40),
76 (8) and 59 (8).
Melting points were determined using a Reichert apparatus
and are uncorrected. Mass spectral data was obtained from a
VG Autospec mass spectrometer operating at 70 eV at the
National MS Service, Swansea. Nuclear magnetic
resonance spectra were recorded on Bruker 250, 300, 400
and 500 MHz machines. Unless otherwise specified
deutero-chloroform was used as solvent with tetramethyl-
silane as internal standard. Microanalyses were obtained
using a Carlo Erba MOD 11016 instrument. Thin layer
chromatography was carried out on Whatmann PGSIL
G/UV polyester Plate coated with a 0.2 mm layer of silica
gel 60 (Merck 9385). Column chromatography was
performed with silica gel 60 (Merck 9385). Petroleum
ether refers to the fraction with bp 40–608 C. Anhydrous
toluene and xylene was commercially available (Aldrich).
MeCN was distilled from calcium hydride. THF was
distilled from sodium.
2.1.2. N-(3-Phenyl)-prop-2-enyl-N0-tbutoxycarbonyl
t
hydrazine 11. Prepared from cinnamaldehyde and butyl
carbazate according to procedure A. Hydrazone formation
was complete after 10 min. Purification by flash chroma-
tography, eluting with 4:1 hexane–ethyl acetate gave the
product (62%) as colourless prisms from hexane–ether, mp
52–548C; Found: C, 67.90; H, 8.25; N, 11.10. C14H20N2O2
requires C, 67.72; H, 8.16; N, 11.28%; dH 7.37–7.21 (m,
5H, ArH), 6.55 (d, 1H, J¼15.7 Hz, ArCHv), 6.36 (s, br,
1H, NH), 6.23 (dt, 1H, J¼15.7 and 6.5 Hz, vCH), 4.16 (s,
br, 1H, NH), 3.61 (d, 2H, J¼6.5 Hz, CH2) and 1.45 (s, 9H,
3CH3); m/z (%): 248 (Mþ, 3), 117 (1000, 91 (23), 57 (53)
and 41 (17).
2.1. Preparation of 1,2-disubstituted hydrazines
These were prepared by one of two general procedures:
(A) Modified reductive amination.20 A mixture of the
aldehyde (15 mmol) and monosubstituted hydrazine
(15 mmol) in methanol (25 ml) was heated under gentle
reflux for 10 min to 2 h. The solution was cooled to 08C, and
dry THF (25 ml), sodium cyanoborohydride (15 mmol) and
glacial acetic acid (15 mmol) added with stirring. The
solution was then allowed to warm to room temperature and
stirred for 10 h. A further portion of sodium cyanoboro-
hydride (15 mmol) was then added at 08C, followed by
glacial acetic acid (15 mmol) and stirring continued at room
temperature for 16 h.
2.1.3. N-(2-Bromo)-prop-2-en-1-yl-N0-acetyl hydrazine
16. Prepared from 2,3-dibromopropene and acetic hydrazide
according to procedure B. Purification by flash chromato-
graphy, eluting with 7:3 v/v hexane–ethyl acetate gave the
product (31%) as colourless needles from methanol, mp
46–488C; Found: C, 31.30; H, 4.75; N, 14.25. C5H9BrN2O
requires C, 31.10; H, 4.70; N, 14.50%; dH 8.65 (s, br, 1H,
NH), 5.87 and 5.59 (2£s, 2£1H, vCH2), 4.95 (s, br, 1H,
NH), 3.67 (s, 2H, CH2) and 1.99 (s, 3H, CH3); m/z (%): 194
(Mþ, 7)/192 (Mþ, 7), 152 (56), 150 (57), 136 (52), 134 (52),
113 (24), 71 (31), 60 (29), 43 (100) and 39 (73).
The solution was acidified to pH 1 with conc. HCl, and then
basified to pH 14 with solid sodium hydroxide. Water
(100 ml) was added and the organic solvents removed in
vacuo. The basic aqueous layer was extracted with ether
(4£50 ml) and the combined ether layers dried (MgSO4).

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C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
2.1.4. N-2-(20-Iodophenyl)-ethyl-N0-carbomethoxy
hydrazine 28. Prepared from methyl carbazate and
(2-iodophenyl)-acetaldehyde. Hydrazone formation was
complete after 1 h. Purification by flash chromatography
eluting with 7:3 v/v hexane–ethyl acetate gave the product
(3.7 g, 77%) as colourless prisms, mp 71–738C, from
hexane–ether; Found: C, 37.65; H, 4.30; N, 8.85; I, 39.50.
C10H13IN2O2 requires C, 37.52; H, 4.09; N, 8.75; I, 39.64%;
dH 7.78 (d, 1H, J¼7.9 Hz, ArH), 7.27–7.22 (m, 2H, ArH),
6.91 (s, br, 1H, NH), 6.88 (d, 1H, J¼8.7 Hz, ArH), 4.17 (s,
br, 1H, NH), 3.70 (s, 3H, OCH3), 3.10 and 2.89 (2£t, 2£2H,
J¼7.4 Hz, 2£CH2); m/z (%): 320 (Mþ, 1), 103 (100), 90
(13), 71 (58) and 44 (14).
2.4. General procedure for palladium catalysed
cyclisation reactions using catalyst system B
A mixture of the cycloadduct (0.4 mmol), Pd(OAc)2 (9 mg,
0.04 mmol), PPh3 (21 mg, 0.08 mmol) and TlOAc (0.126 g,
0.48 mmol) in dry solvent (20 ml) was heated under a dry
1
nitrogen atmosphere until tlc or H NMR analysis showed
complete reaction. The mixture was cooled, filtered through
florisil, the solvent removed in vacuo and the crude product
purified by flash chromatography.
2.4.1. 2-Carbomethoxy-6,8-dioxo-3-(20-iodobenzyl)-7-
methyl-4-styryl-2,3,7-triazabicyclo [3.3.0] octane 2 and
3. Prepared from cinnamaldehyde (0.264 g, 2 mmol), N-(2-
2.1.5. N-(3-Thienyl)-ethyl-N0-(2-iodobenzoyl) hydrazine
37a. Prepared from thiophene-3-carboxaldehyde and
2-iodobenzoic hydrazide via method A. The product
(4.62 g, 86%) crystallized from ethanol as colourless
needles, mp 131–1338C; Found: C, 40.35; H, 3.15; N,
8.00; I, 35.30; S, 8.65. C12H11IN2OS requires C, 40.25; H,
3.10; N, 7.80; I, 35.45; S, 8.95%; dH 7.87 (d, 1H, J¼7.9 Hz,
ArH), 7.42–7.28 (m, 4H, ArH), 7.17–7.06 (m, 2H, ArH)
and 4.21 (s, 2H, CH2). The two NH protons were not
detected; m/z (%): 358 (Mþ, 1), 248 (43), 231 (97), 203 (40),
112 (56), 97 (100) and 76 (50).
iodobenzyl)-N0-carbomethoxy hydrazine
1
(0.612 g,
2 mmol) and NMM (0.22 g, 2 mmol). Reaction was
complete after 10 h in boiling m-xylene. The product
comprised a 4:1 mixture of 2 and 3 which was separated
by flash chromatography, eluting with 7:3 v/v hexane–ethyl
acetate.
2 (0.56 g, 54%) crystallized from hexane–diethyl ether as
colourless prisms, mp 158–1608C.
Found: C, 52.15; H, 4.05; N, 7.85; I, 24.00. C23H22IN3O4
requires C, 52.00; H, 4.15; N, 7.90; I, 23.90%; dH(400 MHz)
7.71 (d, 1H, J¼7.9 Hz, ArH), 7.46 (d, 1H, J¼7.7 Hz, ArH),
7.32–7.22 (m, 6H, ArH), 6.85 (t, 1H, J¼7.7 Hz, ArH), 6.79
(d, 1H, J¼15.6 Hz, vCHPh), 6.27 (dd, 1H, J¼15.6 and
8.9 Hz, vCH), 5.30 (d, 1H, J¼8.3 Hz, 1-H), 4.26 (t, 1H,
J¼8.5 Hz, 5-H), 4.22 and 3.61 (2£d, 2£1H, J¼13.5 Hz,
NCH2), 3.70 (t, 1H, J¼8.2 Hz, 5H), 3.62 (s, 3H, CO2CH3)
and 3.11 (s, 3H, NCH3); m/z (%) 531 (Mþ, 58), 314 (11),
242 (23), 217 (100), 185 (18), 169 913), 141 (48), 128 (110,
115 (40), 90 947), 59 (31) and 32 (22).
2.1.6. N-(3-Furyl)-ethyl-N0-(2-iodobenzoyl) hydrazine
37b. Prepared from 3-furaldehyde and 2-iodobenzoic
hydrazide via method A. Purification by crystallization
from ethanol gave the product (3.64 g, 71%) as colourless
needles, mp 120–1228C; Found: C, 42.15; H, 3.05; N, 8.35;
I, 37.20. C12H11IN2O2 requires C, 42.15; H, 3.25; N, 8.20; I,
37.10%; dH 7.86 (d, 1H, J¼8.0 Hz, ArH), 7.46–7.30 (m,
5H, ArH and 1£NH), 7.11 (t, 1H, J¼7.3 Hz, ArH), 6.47 (s,
1H, ArH), 5.03 (s, br, 1H, NH) and 4.02 (s, 2H, CH2); m/z
(%): 342 (Mþ, 2), 247 (57), 231 (100), 203 (51), 105 (26),
96 (57), 81 (75), 76 (58) and 53 (35).
n.O.e. data
Enhancement (%)
4-H
2.2. General procedure for cycloaddition reactions of
aldehydes with N,N0-disubstituted hydrazines and
N-methyl maleimide (NMM) and styrene
Proton irradiated
1-H
–
5-H
9
10
1-H
4-H
5-H
–
12
A solution of the aldehyde (2 mmol), N,N0-disubstituted
hydrazine (2 mmol), and the dipolarophile (2 mol) in
anhydrous m-xylene or toluene (10 ml) was boiled under
an atmosphere of dry nitrogen until TLC or 1H NMR
analysis showed the reaction to be complete. The solvent
was removed in vacuo and the residue purified by flash
chromatography or fractional crystallization to afford the
cycloadducts.
16
3 (0.14 g, 13%) obtained as a pale yellow foam. HRMS
531.0634. C23H22IN3O4 requires 531.0655; dH(400 MHz)
7.81 (d, 1H, J¼7.9 Hz, ArH), 7.52 (d, br, 1H, J¼7.3 Hz,
ArH), 7.33–7.25 (m, 6H, ArH), 6.96 (t, 1H, J¼7.6 Hz,
ArH), 6.88 (d, 1H, J¼15.8 Hz, vCHPh), 5.96 (dd, 1H,
J¼15.7 and 4.3 Hz, vCH), 5.28 (d, 1H, J¼8.2 Hz, 1-H),
4.37 (d, 1H, J¼4.2 Hz, 4-H), 3.96 (s, 2H, NCH2), 3.71 (s,
3H, CO2CH3), 3.59 (d, 1H, J¼8.2 Hz, 5-H) and 3.15 (s, 3H,
NCH3); m/z (%) 531 (Mþ, 45), 242 (220, 217 (1000, 185
922), 141 (470, 115 (47), 90 (61) and 59 (40).
2.3. General procedure for palladium catalysed
cyclisation reactions using catalysts system A
A mixture of the cycloadduct (0.4 mmol), Pd(OAc)2 (9 mg,
0.04 mmol), PPh3 (21 mg, 0.08 mmol), NEt4Cl (0.066 g,
0.4 mmol) and K2CO3 (0.111 g, 0.8 mmol) in dry solvent
(20 ml) was heated under a dry nitrogen atmosphere until
n.O.e. data
Enhancement (%)
4-H
1
TLC or H NMR analysis showed complete reaction. The
Proton irradiated
1-H
–
5-H
10
6
mixture was cooled, poured into water (100 ml), and
extracted with dichloromethane (3£50 ml). The combined
organic extracts were dried (MgSO4), the solvent removed
in vacuo and the residue purified by flash chromatography.
1-H
4-H
5-H
–

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4459
2.4.2. Cyclisation product 10. A mixture of 2 (0.213 g,
0.4 mmol) and catalyst system A in dry acetonitrile (20 ml)
was boiled under a dry nitrogen atmosphere for 48 h. Work
up by the general procedure followed by flash chromato-
graphy of the residue, eluting with 3:2 v/v hexane–ethyl
acetate gave the product (0.131 g, 81%), which crystallized
from ethanol as colourless needles, mp 201.5–203.58C.
m-xylene for 2 h at 120–1308C according to the general
procedure. Work up followed by flash chromatography of
the residue, eluting with 7:3 v/v hexane–ethyl acetate gave
the product (0.158 g, 89%) which crystallized from ethanol
as colourless prisms, mp &greater;2308C (dec.); Found: C,
70.15; H, 6.15; N, 9.6. C26H27N3O4 requires C, 70.1; H, 6.1;
N, 9.45%; dH(400 MHz) 7.62 (d, 1H, J¼6.6 Hz, ArH),
7.39–7.25 (m, 8H, ArH), 7.15 (s, 1H, vCH), 5.24 (d, 1H,
J¼8.4 Hz, 1-H), 4.84 (d, 1H, J¼8.4 Hz, 4-H), 4.37 and 3.09
(2£d, 2£1H, J¼11.7 Hz, CH2), 3.94 (t, 1H, J¼8.4 Hz, 5-H),
2.87 (s, 3H, NCH3) and 1.42 (s, 9H, 3£CH3).
The reaction was also performed in m-xylene (24 h,
110–1208C) according to the general procedure which
gave the product in 89% yield.
Found: C, 68.55; H, 5.45; N, 10.35. C23H21N3O4 requires C,
68.45; H, 5.25; N, 10.40%; dH(400 MHz) 7.55 (d, 1H,
J¼7.6 Hz, ArH), 7.41–7.22 (m, 8H, ArH), 7.05 (d, 1H,
J¼7.3 Hz, ArH), 5.14 (d, 1H, J¼8.6 Hz, 1-H), 4.99 (d, 1H,
J¼9.4 Hz, 4-H), 4.20 and 3.74 (2£d, 2£1H, J¼15.3 Hz,
NCH2), 3.83 (s, 3H, CO2CH3), 3.53 (t, 1H, J¼9.0 Hz, 5-H)
and 2.52 (s, 3H, NCH3); m/z (%) 403 (Mþ, 50), 344 (8), 292
(15), 218 (1000, 203 (8), 191 (13), 115 (7) and 59 (15).
n.O.e. data
Enhancement (%)
4-H
Proton irradiated
1-H
–
5-H
9
8
1-H
4-H
5-H
–
18
21
–
m/z (%) 445 (Mþ, 1), 345 (95), 234 (62), 218 (92), 205 (43),
115 (23), 91 (29), 57 (100) and 44 (20).
n.O.e. data
Enhancement (%)
4-H
2.4.5. Cyclisation product 15. A mixture of 13 (0.23 g,
0.40 mmol) and catalyst system B was heated in dry
m-xylene for 5 h at 120–1308C according to the general
procedure. After work up, flash chromatography of the
residue, eluting with 7:3 v/v hexane–ethyl acetate gave the
product (0.155 g, 87%) which crystallized from hexane–
ethyl acetate as colourless needles, mp 240–2428C; Found:
C, 70.00; H, 6.25; N, 9.59. C26H27N3O4 requires C, 70.10;
H, 6.10; N, 9.45%; dH(400 MHz) 7.66–7.28 (m, 9H, ArH),
7.24 (s, 1H, vCH), 5.06 (d, 1H, J¼8.4 Hz, 1-H), 4.45 and
3.36 (2£d, 2£1H, J¼10.4 Hz, CH2), 4.43 (d, 1H, J¼8.4 Hz,
4-H), 3.73 (t, 1H, J¼8.4 Hz, 5-H), 3.06 (s, 3H, NCH3) and
1.12 (s, 9H, 3£CH3).
Proton irradiated
1-H
–
5-H
11
15
–
1-H
4-H
5-H
–
17
17
2.4.3. 2-tButoxycarbonyl-6,8-dioxo-3-(30-phenyl)-prop-
20-enyl-7-methyl-4-(20-iodo)-phenyl-2,3,4-triazabicyclo
[3.3.0] octane 12 and 13. Prepared from 2-iodobenzalde-
hyde (0.464 g, 2 mmol), hydrazine 11 (0.546 g, 2 mmol)
and NMM (0.222 g, 2 mol). Reaction was complete after
24 h in boiling m-xylene and afforded a 1.5:1 mixture of 12
and 13 which was separated by flash chromatography,
eluting with 4:1 v/v hexane–ethyl acetate.
n.O.e. data
12 (0.522 g, 46%) obtained as a pale yellow foam. Found:
C, 54.70; H, 4.75; N, 7.35; I, 22.35. C26H28IN3O4 requires
C, 54.45; H, 4.90; N, 7.35; I, 22.15%.
Enhancement (%)
4-H
Proton irradiated
1-H
–
5-H
1
1-H
4-H
5-H
dH 7.80 (d, 1H, J¼7.8 Hz, ArH), 7.33–7.23 (m, 7H, ArH),
6.98 (m, 1H, ArH), 6.51 (d, 1H, J¼16.2 Hz, vCHPh), 6.22
(dt, 1H, J¼16.2 and 6.9 Hz, vCH), 5.02 (d, 1H, J¼8.1 Hz,
1-H), 4.92 (d, 1H, J¼9.2 Hz, 4-H), 4.12 and 3.63 (2£dd,
2£1H, J¼13.6 and 6.9 Hz, CH2), 3.88 (t, 1H, J¼8.8 Hz,
5-H), 2.63 (s, 3H, NCH3) and 1.60 (s, 9H, 3£CH3); m/z (%)
573 (Mþ, 1), 356 (47), 328 (22), 144 (23), 117 (1000, 91
(28) and 57 (28).
–
3
–
m/z (%) 445 (Mþ, 1), 345 (87), 234 (50), 218 (94), 205 (39),
91 (33) and 57 (100).
2.4.6. 3-(20-Bromoprop-20-en-10-yl)-2-carbomethoxy-6,8-
dioxo-7-methyl-4-phenyl-2,3,7-triazabicyclo[3.3.0]
octane 17a and 18a. Prepared from benzaldehyde (0.21 g,
2.0 mmol), hydrazine 16 (0.43 g, 2.0 mmol) and NMM
(0.22 g, 2.0 mmol). Reaction was complete after 14 h in
boiling m-xylene and afforded a 1.7:1 mixture of 17a and
18a which was separated by flash chromatography, eluting
with 4:1 v/v hexane–ethyl acetate.
13 (0.348 g, 30%) obtained as a yellow foam. Found: C,
54.40; H, 4.65; N, 7.40; I, 21.95; dH 7.87 (d, 1H, J¼7.8 Hz,
ArH), 7.41–7.18 (m, 7H, ArH), 6.96 (t, 1H, J¼7.5 Hz,
ArH), 6.42 (d, 1H, J¼15.9 Hz, vCHPh), 6.24 (dt, 1H,
J¼15.9 and 6.6 Hz, vCH), 5.04 (d, br, 1H, 1-H), 4.93 (s,
1H, 4-H), 3.81 (d, 1H, J¼8.2 Hz, 5-H), 3.63–3.49 (m, br,
2H, CH2), 3.01 (s, 3H, NCH3) and 1.43 (s, 9H, 3£CH3); m/z
(%) 573 (Mþ, 9), 517 (35), 473 (32), 370 (22), 356 (28), 117
91000, 91 928), 57 (69) and 41 (23).
17a (0.277 g, 34%) crystallized from ethanol as colourless
needles, mp 161–1638C; Found: C, 50.15; H, 4.35; N,
10.35; Br, 19.75. C17H18BrN3O4 requires C, 50.00; H, 4.45;
N, 10.30; Br, 19.55%; dH 7.33–7.24 (m, 5H, ArH), 5.96 and
5.64 (2£s, 2£1H, vCH2), 5.16 (d, 1H, J¼8.9 Hz, 1-H), 4.68
2.4.4. Cyclisation product 14. A mixture of 12 (0.23 g,
0.40 mmol) and catalyst system B was heated in dry

4460
C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
(d, 1H, J¼8.5 Hz, 4-H), 4.07 and 3.69 (2£d, 2£1H,
J¼13.9 Hz, NCH2), 4.01 (t, 1H, J¼8.5 Hz, 5-H), 3.93 (s,
3H, OCH3) and 2.57 (s, 3H, NCH3); m/z (%) 409 (Mþ, 12),
407 (Mþ, 12), 350 (25), 348 (25), 216 (92), 159 (43), 144
(57), 115 (100), 59 (43) and 39 (40).
2.84 (s, 3H, NCH3); m/z (%) 327 (Mþ, 54), 268 (10), 216
(17), 142 (100) and 59 (18).
2.4.9. Cyclisation product 20. A mixture of 18a (0.16 g,
0.40 mmol) and catalyst system B was boiled under reflux
in dry MeCN for 24 h. After work up, flash chromatog-
raphy of the residue, eluting with 7:3 v/v hexane–ethyl
acetate gave the product (61 mg, 47%) which crystallized
from ethanol as colourless needles, mp 180–1828C;
Found: C, 62.45; H, 5.35; N, 12.60. C17H17N3O4 requires
C, 62.40; H, 5.25; N, 12.85%; dH 7.37–7.21 (m, 4H,
ArH), 5.93 and 5.47 (2£s, 2£1H, vCH2), 5.08 (d, 1H,
J¼8.4 Hz, 1-H), 4.47 (d, 1H, J¼8.4 Hz, 4-H), 4.29 and
3.11 (2£d, 2£1H, J¼11.8 Hz, NCH2), 3.87 (s, 3H,
OCH3), 3.68 (t, 1H, J¼8.4 Hz, 5-H) and 3.00 (s, 3H,
NCH3); m/z (%) 327 (Mþ, 58), 268 (19), 216 (31), 184
(42), 142 (100) and 59 (34).
18a (0.155 g, 19%) obtained as colourless needles, mp 145–
1478C, from ethanol; Found: C, 50.05; H, 4.50; N, 10.45;
Br, 19.40; dH 7.48–7.25 (m, 5H, ArH), 5.87 and 5.59 (2£s,
2£1H, vCH2), 5.19 (d, 1H, J¼8.4 Hz, 1-H), 4.87 (s, 1H,
4-H), 3.86 (d, 1H, J¼8.4 Hz, 5-H), 3.80 (s, 3H, OCH3), 3.77
and 3.45 (2£d, 2£1H, J¼13.8 Hz, NCH2) and 3.11 (s, 3H,
NCH3); m/z (%) 409 (Mþ, 7), 407 (Mþ, 7), 350 (28), 348
(29), 328 (16), 265 (17), 263 (17), 216 (89), 183 (15), 159
(37), 144 (48), 115 (100), 91 (20), 77 (22), 59 (41) and 39
(37).
2.4.7. 3-(20-Bromoprop-20-en-10-yl)-2-carbomethoxy-6,8-
dioxo-7-methyl-4-(20-thienyl)-2,3,7-triazabicyclo[3.3.0]
octane 17b and 18b. Prepared from thiophene-2-car-
boxaldehyde (0.22 g, 2.0 mmol), hydrazine 16 (0.42 g,
2.0 mmol) and NMM (0.22 g, 2.0 mmol). Reaction was
complete after 16 h in boiling m-xylene and afforded a 1:1
mixture of 17b and 18b which was separated by flash
chromatography, eluting with 4:1 v/v hexane–ethyl
acetate.
2.4.10. Cyclisation product 21. A mixture of 17b (0.16 g,
0.40 mmol) and catalyst system B was boiled under reflux
in dry MeCN for 16 h. After work up, flash chromato-
graphy of the residue, eluting with 7:3 v/v hexane–ethyl
acetate gave the product (72 mg, 54%) which crystallized
from ethanol as colourless needles, mp 185–1878 C;
Found: C, 54.10; H, 4.75; N, 12.35; S, 9.55.
C15H15N3O4S requires C, 54.05; H, 4.55; N, 12.60; S,
9.60%; dH 7.24 (d, 1H, J¼5.1 Hz, ArH), 6.99 (d, 1H,
J¼5.1 Hz, ArH), 5.94 and 5.62 (2£s, 2£1H, vCH2), 5.13
(d, 1H, J¼8.4 Hz, 1–H), 4.72 (d, 1H, J¼8.4 Hz, 4-H),
3.92 and 3.29 (2£d, 2£1H, J¼12.4 Hz, NCH2), 3.75 (s,
3H, OCH3), 3.76 (t, 1H, J¼8.4 Hz, 5-H) and 2.96 (s, 3H,
NCH3); m/z (%) 333 (Mþ, 61), 274 (18), 222 (21), 148
(100) and 59 (34).
17b (0.190 g, 23%) crystallized from ethanol as colourless
needles, mp 166–1688C; Found: C, 43.45; H, 3.75; N,
10.05; Br, 19.40; S, 7.50. C15H16BrN3O4S requires C,
43.50; H, 3.90; N, 10.15; Br, 19.30; S, 7.75%; dH 7.22 (d,
1H, J¼4.8 Hz, ArH), 7.00–6.97 (m, 2H, ArH), 5.82 and
5.58 (2£s, 2£1H, vCH2), 5.16 (d, 1H, J¼8.8 Hz, 1-H), 4.76
(d, 1H, J¼8.0 Hz, 4-H), 4.03 and 3.74 (2£d, 2£1H,
J¼13.6 Hz, NCH2), 4.09 (2£t, 1H, J¼8.0 and 8.8 Hz,
5-H), 3.88 (s, 3H, OCH3) and 2.62 (s, 3H, NCH3).
2.4.11. Cyclisation product 22. A mixture of 18b (0.16 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry MeCN for 24 h. After work up, flash chromatography of
the residue, eluting with 7:3 v/v hexane–ethyl acetate gave
the product (67 mg, 50%) which crystallized from ethanol
as colourless needles, mp 192–1948C; Found: C, 54.15; H,
4.35; N, 12.70; S, 9.75. C15H15N3O4S requires C, 54.05; H,
4.55; N, 12.60; S, 9.60%; dH 7.19 (d, 1H, J¼5.0 Hz, ArH),
6.98 (d, 1H, J¼5.0 Hz, ArH), 6.02 and 5.56 (2£s, 2£1H,
vCH2), 5.24 (d, 1H, J¼8.2 Hz, 1-H), 4.81 (d, 1H,
J¼8.2 Hz, 4-H), 4.17 and 3.32 (2£d, 2£1H, J¼12.0 Hz,
NCH2), 3.85 (s, 3H, OCH3), 3.74 (t, 1H, J¼8.2 Hz, 5-H) and
2.79 (s, 3H, NCH3); m/z (%) 333 (Mþ, 48), 274 (23), 222
(34), 148 (100) and 59 (39).
m/z (%) 415 (Mþ, 10), 413 (Mþ, 10), 356 (37), 354 (37), 271
(26), 269 (26), 222 (84), 165 (39), 150 (40), 121 (100) and
59 (36).
18b (0.190 g, 23%) crystallized from ethanol as colourless
needles, mp 154–1568C; Found: C, 43.65; H, 4.15; N,
10.15; Br, 19.15; S, 7.70%; dH 7.24 (d, 1H, J¼4.7 Hz, ArH),
7.01–6.97 (m, 2H, ArH), 5.75 and 5.58 (2£s, 2£1H,
vCH2), 5.24 (d, 1H, J¼8.6 Hz, 1-H), 4.90 (s, 1H, 4-H),
3.89 (d, 1H, J¼8.6 Hz, 5-H), 3.72 (s, 3H, OCH3), 3.84 and
3.50 (2£d, 2£1H, J¼13.2 Hz, NCH2) and 3.16 (s, 3H,
NCH3); m/z (%) 415 (Mþ, 8), 413 (Mþ, 8), 356 (34), 354
(34), 271 (22), 269 (22), 222 (75), 165 (32), 150 (41), 121
(100) and 59 (38).
2.4.12. 2-Carbomethoxy-6,8-dioxo-3-(20-iodophenyl)-7-
methyl-4-(30-thienyl)-2,3,7-triazabicyclo [3.3.0] octane
23a and 24a. Prepared from thiophene-3-carboxaldehyde
(0.22 g, 2.0 mmol), hydrazine 1 (0.61 g, 2 mmol) and NMM
(0.22 g, 2.0 mmol). Reaction was complete after 28 h in
boiling m-xylene and afforded a 2.8:1 mixture of 23a and
24a which was separated by flash chromatography, eluting
with 7:3 v/v hexane–ethyl acetate.
2.4.8. Cyclisation product 19. A mixture of 17a (0.16 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry MeCN for 16 h. After work up, flash chromatography of
the residue, eluting with 7:3 v/v hexane–ethyl acetate gave
the product (64 mg, 49%) which crystallized from ethanol
as colourless needles, mp 192.5–194.58C; Found: C, 62.65;
H, 5.15; N, 12.80. C17H17N3O4 requires C, 62.40; H, 5.25;
N, 12.85%; dH 7.34–7.20 (m, 4H, ArH), 5.99 and 5.51 (2£s,
2£1H, vCH2), 5.15 (d, 1H, J¼8.5 Hz, 1-H), 4.79 (d, 1H,
J¼8.5 Hz, 4-H), 4.36 and 3.24 (2£d, 2£1H, J¼12.1 Hz,
NCH2), 3.91 (s, 3H, OCH3), 3.82 (t, 1H, J¼8.5 Hz, 5-H) and
23a (0.51 g, 50%) crystallized from ethanol as colourless
prisms, mp 155–1578C; Found: C, 44.6; H, 3.55; N, 8.15; I,
24.90; S, 6.30. C19H18IN3O4S requires C, 44.65; H, 3.55; N,
8.20; I, 24.80; S, 6.25%; dH 7.80 (d, 1H, J¼7.5 Hz, ArH),
7.56 (d, 1H, J¼7.5 Hz, ArH), 7.37–7.18 (m, 3H, ArH), 6.96

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4461
(t, 1H, J¼7.5 Hz, ArH), 6.90 (d, 1H, J¼5.1 Hz, ArH), 5.18
n.O.e. data
(d, 1H, J¼8.3 Hz, 1-H), 4.69 (d, 1H, J¼7.6 Hz, 4-H), 4.23
and 3.96 (2£d, 2£1H, J¼13.6 Hz, NCH2), 4.10 (2£t, 1H,
J¼7.6 and 8.3 Hz, 5-H), 3.86 (s, 3H, OCH3) and 2.60 (s, 3H,
NCH3).
Enhancement (%)
4-H
Proton irradiated
1-H
–
5-H
14
10
–
1-H
4-H
5-H
–
14
17
24a (0.17 g, 17%) obtained as colourless prisms from
ethanol, mp 143–1458C; Found: C, 44.85; H, 3.50; N, 8.25;
I, 24.85; S, 6.30%; dH 7.79 (d, 1H, J¼7.7 Hz, ArH), 7.47 (s,
br, 1H, ArH), 7.39 (s, br, 1H, ArH), 7.32–7.25 (m, 2H,
ArH), 7.02–6.92 (m, 2H, ArH), 5.25 (d, br, 1H, J¼8.4 Hz,
1-H), 4.77 (s, 1H, 4-H), 4.02 and 3.95 (2£d, 2£1H,
J¼13.5 Hz, NCH2), 3.82 (d, 1H, J¼8.4 Hz, 5-H), 3.66 (s,
br, 3H, OCH3) and 3.16 (s, 3H, NCH3).
m/z (%) 383 (Mþ, 77), 324 (55), 308 (49), 272 (37), 239
(42), 198 (100), 184 (51) and 171 (41).
2.4.15. Cyclisation product 26. Reaction of 24a (0.20 g,
0.40 mmol) in the presence of catalyst system B in dry
m-xylene at 110–1208C for 14 h according to the general
procedure followed by flash chromatography, eluting with
1:1 v/v hexane–ethyl acetate gave the product (0.123 g,
80%) which crystallized from ethanol as colourless needles,
mp 199–2028C; Found: C, 59.45; H, 4.70; N, 11.10; S, 8.40.
C19H17N3O4S requires C, 59.50; H, 4.45; N, 10.95; S,
8.35%; dH (400 MHz) 7.55 (d, 1H, J¼7.5 Hz, ArH), 7.44–
7.32 (m, 4H, ArH), 7.18 (d, 1H, J¼5.1 Hz, ArH), 4.64 (d,
1H, J¼8.5 Hz, 4-H), 4.55 (d, 1H, J¼8.5 Hz, 1-H), 4.09 and
3.80 (2£d, 2£1H, J¼14.9 Hz, NCH2), 3.95 (s, 3H, OCH3),
3.02 (t, 1H, J¼8.5 Hz, 5-H) and 2.92 (s, 3H, NCH3).
m/z (%) 511 (Mþ, 39), 294 (19), 222 (61), 217 (100), 165
(34), 121 (37), 90 (59) and 59 (26).
2.4.13. 2-Carbomethoxy-6,8-dioxo-4-(30-furyl)-3-(20-
iodobenzyl)-7-methyl-2,3,7-triazabicyclo [3.3.0] octane
23b and 24b. Prepared from 3-furaldehyde (0.19 g,
2.0 mmol), hydrazine 1 (0.61 g, 2.0 mmol) and NMM
(0.22 g, 2.0 mmol). Reaction was complete after 20 h in
boiling m-xylene and afforded a 2.5:1 mixture of 23b and
24b which was separated by flash chromatography, eluting
with 7:3 v/v hexane–ethyl acetate.
n.O.e. data
23b (0.37 g, 37%) crystallized from ethanol as colourless
prisms, mp 155–1578C; Found: C, 46.10; H, 3.60; N, 8.65.
C19H18IN3O4 requires C, 46.10; H, 3.65; N, 8.5%; dH 7.76
(d, 1H, J¼7.8 Hz, ArH), 7.64 (s, 1H, ArH), 7.52 (d, 1H,
J¼7.6 Hz, ArH), 7.29 (s, 2H, ArH), 6.93 (t, 1H, J¼7.6 Hz,
ArH), 6.27 (s, 1H, ArH), 5.24 (d, 1H, J¼8.4 Hz, 1-H), 4.55
(d. 1H, J¼7.6 Hz, 4-H), 4.12 and 3.77 (2£d, 2£1H,
J¼13.7 Hz, NCH2), 4.03 (2£t, 1H, J¼8.4 and 7.6 Hz, 5-
H), 3.73 (s, 3H, OCH3) and 2.82 (s, 3H, NCH3); m/z (%) 495
(Mþ, 43), 217 (100), 206 (56), 165 (15), 149 (16), 121 (15),
90 (58), 78 (22) and 59 (35).
Enhancement (%)
4-H
Proton irradiated
1-H
–
5-H
14
4
1-H
4-H
5-H
–
5
19
–
m/z (%) 383 (Mþ, 45), 324 (35), 308 (100), 239 (54), 198
(87), 184 (44), 171 (42) and 40 (20).
2.4.16. Cyclisation product 27. Reaction of 23b (0.20 g,
0.40 mmol) in the presence of catalyst system B in dry
m-xylene at 110–1208C for 14 h according to the general
procedure followed by flash chromatography, eluting with
1:1 v/v hexane–ethyl acetate gave the product (0.107 g,
73%) which crystallized from ethanol as colourless needles,
mp 212.5–214.58C; Found: C, 62.10; H, 4.60; N, 11.65.
C19H17N3O5 requires C, 62.10; H, 4.65; N, 11.45%; dH
7.47–7.26 (m, 5H, ArH), 6.63 (d, 1H, J¼1.8 Hz, ArH), 5.29
(d, 1H, J¼10.0 Hz, 1-H), 4.76 (d, 1H, J¼9.2 Hz, 4-H), 3.91
(s, 2H, NCH2), 3.86 (s, 3H, OCH3), 3.78 (2£t, 1H, J¼9.2
and 10.0 Hz, 5-H) and 2.77 (s, br, 3H, NCH3); m/z (%) 367
(Mþ, 68), 308 (45), 292 (50), 256 (34), 223 (40), 182 (100),
168 (48) and 155 (30).
24b (0.89 g, 9%) obtained as colourless prisms, mp 138–
1408C from ethanol; Found: C, 46.25; H, 3.70; N, 8.60%; dH
7.79 (d, 1H, J¼7.9 Hz, ArH), 7.48–7.28 (m, 4H, ArH), 6.96
(t, 1H, J¼7.6 Hz, ArH), 6.30 (s, 1H, ArH), 5.27 (d, br, 1H,
J¼8.3 Hz, 1-H), 4.65 (s, 1H, 4-H), 3.98 and 3.59 (2£d,
2£1H, J¼13.4 Hz, NCH2), 3.76 (d, 1H, J¼8.3 Hz, 5-H),
3.66 (s, br, 3H, OCH3) and 3.16 (s, 3H, NCH3); m/z (%) 495
(Mþ, 7), 217 (100), 206 (21), 128 (22), 119 (34), 90 (44) and
59 (19).
2.4.14. Cyclisation product 25. Reaction of 23a (0.20 g,
0.40 mmol) in the presence of catalyst system B in dry
m-xylene at 110–1208C for 14 h according to the general
procedure followed by flash chromatography, eluting with
1:1 v/v hexane–ethyl acetate gave the product (0.126 g,
82%) which crystallized from ethanol as colourless needles,
mp 214–2168C; Found: C, 59.80; H, 4.55; N, 11.20; S, 8.40.
C19H17N3O4S requires C, 59.50; H, 4.45; N, 10.95; S,
8.35%; dH (400 MHz) 7.50 (d, 1H, J¼7.7 Hz, ArH), 7.38–
7.23 (m, 4H, ArH), 7.12 (d, 1H, J¼5.1 Hz, ArH), 5.21 (d,
1H, J¼10.2 Hz, 1-H), 5.13 (d, 1H, J¼9.3 Hz, 4-H), 4.04 and
3.96 (2£d, 2£1H, J¼15.1 Hz, NCH2), 3.59 (2£t, 1H, J¼9.3
and 10.2 Hz, 5-H), 3.91 (s, 3H, OCH3) and 2.31 (s, br, 3H,
NCH3).
2.4.17. 2-Carbomethoxy-6,8-dioxo-3-[20-(o-iodophenyl)-
ethyl]-7-methyl-4-styryl-2,3,7-triazabicyclo [3.3.0]-
octane 29 and 30. Prepared from cinnamaldehyde (0.26 g,
2.0 mmol), hydrazine 28 (0.64 g, 2.0 mmol) and NMM
(0.22 g, 2.0 mol). Reaction was completed after 10 h in
boiling m-xylene. The product comprised a 3:1 mixture of
29 and 30 which was separated by flash chromatography,
eluting with 4:1 v/v hexane–ethyl acetate.
29 (0.593 g, 52%), crystallised from hexane–ethyl acetate
as colourless needles mp 181.5–183.58C; Found: C, 52.75;

4462
C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
H, 4.60; N, 7.65; I, 23.45. C24H24IN3O4 requires C, 52.86;
H, 4.44; N, 7.70; I, 23.27%; dH 7.71 (d, 1H, J¼8.0 Hz,
ArH), 7.43–7.14 (m, 7H, ArH), 6.82 (d, 1H, J¼6.9 Hz,
ArH), 6.81 (d, 1H, J¼15.6 Hz, vCHPh), 6.32 (dd, 1H,
J¼15.6 and 9.5 Hz, vCH), 5.37 (d, 1H, J¼8.4 Hz, 1-H),
4.23 (t, 1H, J¼8.7 Hz, 4-H), 3.80 (s, 3H, OCH3), 3.63 (2£t,
1H, J¼8.7 and 8.4 Hz, 5-H), 2.98 and 2.51 (2£m, 2£2H,
2£CH2) and 3.00 (s, 3H, NCH3); m/z (%) 545 (Mþ, 2), 328
(100), 231 (30), 217 (32), 141 (28), 115 (38), 104 (43), 91
(25), 77 (27), 57 (32) and 43 (38).
33 (0.452 g, 43%) obtained as a colourless foam; Found: C,
45.55; H, 3.80; N, 7.95; I, 24.40; S, 6.05. C20H20IN3O4S
requires C, 45.70; H, 3.85; N, 8.00; I, 24.15; S, 6.10%.
dH 7.74 (d, 1H, J¼7.9 Hz, ArH), 7.44 (d, 1H, J¼1.8 Hz, ArH),
7.24–7.18 (m. 3H, ArH), 6.93–6.86 (m, 2H, ArH), 5.21 (d,
1H, J¼8.3 Hz, 1-H), 4.75 (d, 1H, J¼7.7 Hz, 4-H), 4.00 (2£t,
1H, J¼8.3 and 7.7 Hz, 5-H), 3.87 (s., 3H, OCH3), 3.11–2.90
(m, 4H, 2£CH2) and 2.69 (s, 3H, NCH3); m/z (%) 525 (Mþ, 1),
308 (100), 231 (18), 197 (17), 104 (31), 84 (40) and 49 (51).
30 (0.196 g, 17%), colourless needles, mp 196–1988C, from
hexane–ethyl acetate; Found: C, 52.60; H, 4.70; N, 7.45; I,
23.50; dH 7.77 (d, 1H, J¼7.8 Hz, ArH), 7.38–7.19 (m, 7H,
ArH), 6.88 (t, 1H, J¼.9 Hz, ArH), 6.77 (d, 1H, J¼15.7 Hz,
vCHPh), 5.99 (dd, 1H, J¼15.7 and 4.4 Hz, vCH), 5.28 (d,
1H, J¼8.1 Hz, 1-H), 4.42 (s, 1H, 4-H), 3.83 (s, 3H, OCH3),
3.56 (d, 1H, J¼8.1 Hz, 5-H), 3.02–2.75 (m, 4H, 2£CH2)
and 3.03 (s, 3H, NCH3); m/z (%) 545 (Mþ, 2), 328 (100),
231 (17), 141 (24), 128 (11), 115 918), 104 (28), 91 (11) and
77 (11).
34a (0.263 g, 25%) obtained as a colourless foam; Found: C,
45.75; H, 3.95; N, 7.90; I, 24.30; S, 5.95. C20H20IN3O4
requires C, 45.70; H, 3.85; N, 8.00; I, 24.5; S, 6.10%; dH
7.76 (d, 1H, J¼7.9 Hz, ArH), 7.38–7.24 (m, 4H, ArH), 7.01
(d, 1H, J¼4.5 Hz, ArH), 6.88 (t, 1H, J¼7.7 Hz, ArH), 5.26
(d, br, 1H, J¼8.3 Hz, 1-H), 4.85 (s, 1H, 4-H), 3.78 (s, 3H,
OCH3), 3.74 (d, 1H, J¼8.3 Hz, 5-H), 3.03 (s, 3H, NCH3)
and 3.01–2.82 (m, 4H, 2£CH2).
2.4.21. Cyclisation product 35. A mixture of 33 (0.21 g,
0.40 mmol) and catalyst system B was heated in m-xylene at
130–1408C for 24 h according to the general procedure.
Flash chromatography, eluting with 2:1 v/v hexane–ethyl
acetate gave the product (0.108 g, 68%) which crystallized
from ethanol as colourless needles, mp 232–2348C; Found:
C, 60.65; H, 4.70; N, 10.60; S, 8.00. C20H19N3O4S requires
C, 60.45; H, 4.80; N, 10.55; S, 8.05%; dH 7.37 (d, 1H,
J¼4.9 Hz, ArH), 7.27–7.16 (m, 4H, ArH), 7.00 (d, 1H,
J¼4.9 Hz, ArH), 4.81 (d, 1H, J¼7.4 Hz, 1-H), 4.67 (d, 1H,
J¼7.7 Hz, 4-H), 3.77 (s, 3H, OCH3), 3.48–2.78 (m, 4H,
2£CH2), 3.42 (2£t, 1H, J¼7.4 and 7.7 Hz, 5-H) and 2.62 (s,
3H, NCH3); m/z (%) 397 (Mþ, 48), 338 (1000, 253 (69), 197
(21), 184 (43), 91 (30) and 59 (29).
2.4.18. Cyclisation product 31. A mixture of 29 (0.22 g,
0.40 mmol) and catalyst system B was heated in dry
m-xylene for 5 h at 120–1308C according to the general
procedure. After work up by the general procedure, flash
chromatography of the residue, eluting with 1:1 v/v
hexane–ethyl acetate gave the product (0.147 g, 88%),
which crystallized from ethanol as colourless needles, mp
233–2358C; Found: C, 69.15; H, 5.50; N, 10.20.
C24H23N3O4 requires C, 69.05; H, 5.55; N, 10.05%; dH
7.41–7.17 (m, 8H, ArH), 7.04 (d, 1H, J¼7.1 Hz, ArH), 6.98
(s, 1H, vCH), 5.16 (d, 1H., J¼8.8 Hz, 1-H), 5.04 (d, 1H,
J¼9.8 Hz, 4-H), 3.82 (s, 3H, OCH3), 3.66–2.93 (m, 4H,
2£CH2), 3.53 (2£t, 1H, J¼8.8 and 9.8 Hz, 5-H) and 2.40 (s,
3H, NCH3); m/z (%) 417 (Mþ, 82), 358 (1000, 273 (45), 232
(68), 217 (20), 205 (42), 128 (16), 115 (22), 91 (31) and 40
(17).
2.4.22. Cyclisation product 36 and 2-carbomethoxy-6,8-
dioxo-3-(30-phenyl)-ethyl-7-methyl-4-(30-thienyl)-2,3,7-
triazabicyclo[3.3.0]octane 34b. A mixture of 34a (0.21 g,
0.40 mmol) and catalyst system B was heated in m-xylene at
130–1408C for 24 h according to the general procedure.
Flash chromatography, eluting with 2:1 v/v hexane–ethyl
acetate gave 36 (0.76 mg, 46%) which crystallized from
ethanol as colourless needles, mp 217–2198C; Found: C,
60.3; H, 4.75; N, 10.55; S, 8.05%; C20H19N3O4S requires C,
60.45; H, 4.8; N, 10.55; S, 8.05%; dH 7.33–7.21 (m, 5H,
ArH), 6.96 (d, 1H, J¼4.8 Hz, ArH), 5.22 (, 1H, J¼8.7 Hz,
1-H), 4.46 (d, 1H, J¼8.7 Hz, 4-H), 3.39 (s, 3H, OCH3), 3.66
(t, 1H, J¼8.7 Hz, 5-H), 3.17–2.63 (m, 4H, 2£CH2) and 3.04
(s, 3H, NCH3); m/z (%) 397 (Mþ,56), 338 (100), 253 (48),
212 (22), 184 (58), 171 (18), 91 (34) and 59 (21).
2.4.19. Cyclisation product 32. A mixture of 30 (0.22 g,
0.40 mmol) and catalyst system B was heated in dry
m-xylene for 12 h at 120–1308C according to the general
procedure. After work up, flash chromatography of the
residue, eluting with 3:2 v/v hexane–ethyl acetate gave the
product (0.140 g, 84%) as colourless prisms, mp 100–
1028C, from hexane–ether; Found: C, 69.30; H, 5.40; N,
9.90. C24H23N3O4 requires C, 69.05; H, 5.55; N, 10.05%; dH
7.57 (d, 1H, J¼7.3 Hz, ArH), 7.44–7.25 (m, 7H, ArH), 7.13
(d, 1H, J¼7.3 Hz, ArH), 7.01 (s, 1H, vCH), 4.95 (d, 1H,
J¼8.4 Hz, 1-H), 4.45 (d, 1H, J¼10.1 Hz, 4-H), 3.87 (s, 3H,
OCH3), 3.65–2.76 (m, 4H, 2£CH2), 3.36 (2£t, 1H, J¼8.4
and 10.1 Hz, 5-H) and 2.81 (s, 3H, NCH3); m/z (%) 417
(Mþ, 59), 358 (100), 273 (43), 232 (49), 217 (14), 203 (21),
128 (12), 115 (17), 91 (28) and 59 (10).
2.4.23. Deiodination product 34b. (24 mg, 15%) obtained
as colourless needles mp 166–1688C from ethanol; Found:
C, 60.2; H, 5.05; N, 10.7; S, 8.0%. C20H21N3O4S requires C,
60.14; H, 5.3; N, 10.5; S, 8.03%; dH 7.31–7.19 (m, 7H,
ArH), 7.03 (d, 1H, J¼4.8 Hz, ArH), 5.29 (d, 1H, J¼8.5 Hz,
1-H), 4.96 (s, 1H, 4-H), 3.79 (s, 3H, OCH3), 3.69 (t, 1H,
J¼8.5 Hz, 5-H), 2.99–2.74 (m, 4H, 2£CH2) and 2.87 (s,
3H, NCH3); m/z (%) 399 (Mþ, 2) 308 (100), 105 (37), 97
(15), 91 (23), 77 (18) and 59 (17).
2.4.20. 2-Carbomethoxy-6,8-dioxo-3-[20-(o-iodophenyl)-
ethyl]-7-methyl-4-(30-thienyl)-2,3,7-triazabicyclo[3.3.0]-
octane 33 and 34a. Prepared from thiophene-3-carbox-
aldehyde (0.22 g, 2.0 mmol), hydrazine 28 (0.64 g,
2.0 mmol) and NMM (0.22 g, 2.0 mmol). Reaction was
complete after 22 h in boiling m-xylene and afforded a 1.6:1
mixture of 33 and 34a which was separated by flash
chromatography, eluting with 3:1 v/v hexane–ethyl acetate.
2.4.24. 1-(20-Iodobenzoyl)-5-phenyl-2-(30-thienyl)-ethyl-
pyrazolidine 38. Reaction of paraformaldehyde (90.0 mg,

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4463
3.0 mmol) and hydrazine 37a (0.72 g, 2.0 mmol) with
excess styrene in boiling toluene for 9 h, according to the
general procedure afforded, after flash chromatography
eluting with 4:1 v/v hexane–ethyl acetate, the product
(0.89 g, 94%) as colourless prisms from hexane–ether, mp
117–1198C; Found: C, 53.2; H, 4.1; N, 6.0; I, 26.75; S, 6.8.
C21H19IN2OS requires C, 53.15; H, 4.05; N, 5.9; I, 26.75; S,
6.75%; dH 7.88 (d, 1H, J¼7.5 Hz, ArH), 7.50–7.24 (m, 7H,
ArH), 7.13–7.08 (m, 2H, ArH), 6.72 (d, 1H, J¼1.2 Hz,
ArH), 6.21 (d, 1H, J¼5.0 Hz, ArH), 5..51 (t, 1H, J¼8.7 Hz,
CH), 3.87 and 3.80 (2£d, 2£1H, J¼12.7 Hz, NCH2–
thienyl), 3.22 and 2.97 (2£m, 2£1H, NCH2) and 2.74 and
2.41 (2£m, 2£1H, CH2); m/z (%) 474 (Mþ, 1), 243 (59), 231
(27), 203 (14), 97 (100) and 76 (19).
mixture of 42a and 42b (0.78 g, 73%) which proved
inseparable by flash chromatography, eluting with 4:1 v/v
hexane–ethyl acetate. Fractional crystallization from
ethanol gave 42a as colourless prisms, mp 148–1508C;
Found: C, 60.8; H, 4.45; N, 5.2; I, 23.55. C27H23IN2O2
requires C, 60.7; H, 4.35; N, 5.25; I, 23.75%; dH 7.79 (d, 1H,
J¼7.8 Hz, ArH), 7.62 (d, 1H, J¼7.8 Hz, ArH), 7.52–7.05
(m, 12H, ArH), 6.85 (s, 1H, ArH), 6.46 (s, 1H, ArH), 5.76 (t,
1H, J¼8.8 Hz, Ha), 5.23 (s, 1H, ArH), 5.03 (dd, 1H, J¼4.9
and 11.7 Hz, Hb), 3.52 and 3.38 (2£d, 2£1H, J¼13.7 Hz,
NCH2), 3.11 (m, 1H, Hc) and 2.87 (m, 1H, Hd); m/z (%) 534
(Mþ, 1), 303 (74), 231 (46), 203 (17), 81 (100) and 76 (16).
42b obtained as colourless prisms, mp 181–1838C, from
ethanol; Found: C, 60.75; H, 4.5; N, 5.25; I, 23.85; dH 7.77
(d, 1H, J¼7.8 Hz, ArH), 7.61–7.04 (m, 13H, ArH), 6.17 (d,
1H, J¼7.6 Hz, ArH), 5.84 (t, 1H, J¼8.6 Hz, Ha), 5.52 (s,
1H, ArH), 4.29 and 3.92 (2£d, 2£1H, J¼12.6 Hz, NCH2),
4.18 (d, 1H, J¼7.4 Hz, Hb), 3.23 (dd, 1H, J¼13.4 and
8.6 Hz, Hc) and 2.76 (m, 1H, Hd); m/z (%) 534 (Mþ, 2), 303
(100), 231 (39), 203 (14), 105 (12), 91 (14), 81 (82), and 76
(15).
2.4.25. Cyclisation product 39. A mixture of 38 (0.19 g,
0.40 mmol) and catalyst system B was heated under reflux
in dry toluene for 16 h according to the general procedure.
Flash chromatography, eluting with 7:3 v/v hexane–ethyl
acetate afforded the product (0.12 g, 85%) as a colourless
gum; Found: 72.95; H, 5.2; N, 7.95; S, 9.2. C21H18N2OS
requires C, 72.8; H, 5.25; N, 8.1; S, 9.25%; dH 7.63 (d, 1H,
J¼7.4 Hz, ArH), 7.47–7.17 (m, 7H, ArH), 7.04–7.01 (m,
2H, ArH), 6.72 (d, 1H, J¼5.2 Hz, ArH), 5.56 (t, 1H,
J¼9.0 Hz, CH), 4.21 and 4.00 (2£d, 2£1H, J¼14.3 Hz,
NCH2–thienyl), 3.13–3.08 (m, 2H, NCH2) and 2.78 and
2.49 (2£m, 2£1H, CH2); m/z (%) 346 (Mþ, 70), 200 (100),
186 (16), 171 (91), 127 (13) 117 (37), 91 (13) 40 (19).
2.4.28. cis-1-(20-Iodobenzoyl)-3-(40-nitrophenyl)-5-phe-
nyl-2-(30-thienyl)-ethyl-pyrazolidine 43a and trans-43b.
Reaction of 4-nitrobenzaldehyde (0.30 g, 2.0 mmol) and
hydrazine 37a (0.72 g, 2.0 mmol) with excess styrene in
boiling toluene for 20 h according to the general procedure
afforded a 3.5:1 mixture of 43a and 43b which was
separated by flash chromatography eluting with 7:3 v/v
hexane–ethyl acetate. 43a (0.52 g, 44%), crystallized from
ethanol as colourless prisms, mp 177.5–179.58C; Found: C,
54.4; H, 3.75; N, 6.85; I, 21.45; S, 5.35. C27H22IN3O3S
requires C, 54.45; H, 3.7; N, 7.05; I, 21.3; S, 5.4%; dH 8.03–
7.92 (m, 3H, ArH), 7.51–7.11 (m, 10H, ArH), 6.81 (d, 1H,
J¼4.8 Hz, ArH), 6.24 (s, 1H, ArH), 5.83 (d, 1H, J¼4.8 Hz,
ArH), 5.76 (t, 1H, J¼8.6 Hz, Ha), 5.08 (dd, 1H, J¼4.9 and
11.9 Hz, Hb), 3.56 (s, 2H, NCH2), 3.14 (m, 1H, Hc) and 2.89
(m, 1H, Hd); m/z (%) 595 (Mþ, 1), 364 (52), 231 (100), 203
(31), 97 (66) and 76 (39).
2.4.26. cis-3,5-Diphenyl-1-(20-iodobenzoyl)-2-(30-thienyl)-
ethyl-pyrazolidine 41a and trans-41b. Reaction of benzal-
dehyde (0.21 g, 2.0 mmol) and hydrazine 37a (0.18 g,
2.0 mmol) with excess styrene in boiling toluene for 12 h,
according to the general procedure afforded a 1.3:1 mixture of
42a and 42b (0.748 g, 68%)which proved inseparable byflash
chromatography, eluting with 4:1 v/v hexane–ethyl acetate.
Fractional crystallization from ethanol gave 42a as colourless
prisms, mp 154–1568C; Found: C, 58.95; H, 4.4; N, 5.05; I,
23.0; S, 5.65. C27H23IN2OS requires C, 58.9; H, 4.2; N, 5.1; I,
23.05; S, 5.8%; dH 7.84 (d, 1H, J¼7.8 Hz, ArH), 7.54–7.04
(m, 13H, ArH), 6.77 (d, 1H, J¼5.0 Hz, ArH), 6.18 (d, 1H,
J¼1.2 Hz, ArH), 5.88 (d, 1H, J¼5.0 Hz, ArH), 5.75 (t, 1H,
J¼8.8 Hz, Ha), 5.05(dd, 1H, J¼4.9 and 11.7 Hz, Hb), 3.63and
3.52 (2£d, 2£1H, J¼13.7 Hz, NCH2), 3.08 (m, 1H, Hc) and
2.84 (m, 1H, Hd); m/z (%) 550 (Mþ,1), 319 (88), 231 (41), 203
(14), 97 (100), 91 (12) and 76 (13).
43b (0.16 g, 13%) obtained as colourless prisms, mp 203–
2058C, from ethanol; Found: C, 54.6; H, 3.8; N, 7.0; I,
21.15; S, 5.4%; dH 8.12 (d, 2H, J¼8.4 Hz, ArH), 7.84 (d,
1H, J¼7.8 Hz, ArH), 7.61–7.04 (m, 11H, ArH), 6.83 (s, 1H,
ArH), 6.26 (d, 1H, J¼5.1 Hz, ArH), 5.80 (t, 1H, J¼8.4 Hz,
Ha), 4.32 (d, 1H, J¼7.2 Hz, Hb), 4.27 and 3.89 (2£d, 2£1H,
J¼12.8 Hz, NCH2), 3.17 (dd, 1H, J¼13.2 and 8.4 Hz, Hc)
and 2.85 (m, 1H, Hd); m/z (%) 595 (Mþ, 1) 364 (53), 231
(42), 203 (17), 97 (100) and 76 (14).
41b obtained as colourless prisms, mp 188–1908C, from
ethanol; Found: C, 58.75; H, 4.25; N, 4.95; I, 23.25; S, 5.75;
dH 7.79 (d, 1H, J¼7.3 Hz, ArH), 7.66 (d, 2H, J¼7.5 Hz,
ArH), 7.44 (t, 2H, J¼7.6 Hz, ArH), 7.35–7.02 (m, 10H,
ArH), 6.79 (d, 1H, J¼1.1 Hz, ArH), 6.24 (d, 1H, J¼5.1 Hz,
ArH), 5.87 (t, 1H, J¼8.6 Hz, Ha), 4.33 and 3.95 (2£d,
2£1H, J¼12.8 Hz, NCH2), 4.21 (d, 1H, J¼7.4 Hz, Hb), 3.22
(dd, 1H, J¼13.4 and 8.6 Hz, Hc) and 2.79 (m, 1H, Hd); m/z
(%) 550 (Mþ, 1), 319 (79), 231 (36), 203 (11), 97 (100), 91
(16) and 76 (22).
2.4.29. cis-2-(30-Furyl-ethyl-1-(20-iodobenzoyl)-3-(40-
nitrophenyl)-5-phenyl-pyrazolidine 44a and trans-44b.
Reaction of 4-nitrobenzaldehyde (0.30 g, 2.0 mmol) and
hydrazine 37b (0.69 g, 2.0 mmol) with excess styrene in
boiling toluene for 20 h, according to the general procedure
afforded a 3.2:1 mixture of 44a and 44b which was
separated by flash chromatography eluting with 7:3 v/v
hexane–ethyl acetate.
2.4.27. cis-2-(30-Furyl)-ethyl-1-(20-iodobenzoyl)-3,5-
diphenyl-pyrazolidine 42a and trans-42b. Reaction of
benzaldehyde (0.21 g, 2.0 mmol) and hydrazine 37b
(0.68 g, 2 mmol) with excess styrene in boiling toluene for
12 h, according to the general procedure afforded a 1.2:1
44a (0.53 g, 46%), crystallized from ethanol as colourless
prisms, mp 176–178; Found: C, 56.1; H, 3.95; N, 7.25; I,
21.8. C27H22IN3O4 requires C, 55.95; H, 3.85; N, 7.25; I,

4464
C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
21.9%; dH (400 MHz) 8.04 (d, 2H, J¼8.3 Hz, ArH), 7.90 (d,
1H, J¼8.3 Hz, ArH), 7.47–7.10 (m, 10H, ArH), 6.96 (s, 1H,
ArH), 6.37 (s, 1H, ArH), 5.73 (t, 1H, J¼8.6 Hz, Ha), 5.18 (s,
1H, ArH), 5.07 (dd, br, 1H, Hb), 3.52 (s, 2H, NCH2), 3.15
(m, 1H, Hc) and 2.87 (m, 1H, Hd).
(Mþ, 1), 321 (78), 231 (34), 203 (16), 81 (100), 76 (23) and
53 (16).
2.4.31. cis-3-[40-(Dimethylamino)-phenyl]-1-(20-iodoben-
zoyl)-5-phenyl-2-(30-thienyl)-ethyl-pyrazolidine 46a and
trans-46b. Reaction of 4-(dimethylamino)-benzaldehyde
(0.30 g, 2.0 mmol) and hydrazine 37a (0.72 g, 2.0 mmol)
with excess styrene in boiling toluene for 18 h afforded a
1:1.5 mixture of 46a and 46b which was separated by flash
chromatography eluting with 9:1 v/v hexane–ethyl acetate.
n.O.e. data
Enhancement (%)
Proton irradiated
Ha
Hb
-
Hc
5
5
Hd
–
–
15
Ha
Hb
Hc
Hd
–
8
–
46b (0.297 g, 25%), crystallised from ethanol as colourless
prisms, mp 180–1828C; Found: C, 58.85; H, 4.9; N, 7.05; I,
21d.2; S5.35%. C29H28IN3OS requires C, 58.7; H, 4.75; N,
7.1; I, 21.4; S, 5.4%; dH 7.80 (d, 1H, J¼7.8 Hz, ArH), 7.61
(d, 1H, J¼7.8 Hz, ArH), 7.50–6.97 (m, 10H, ArH), 6.77 (d,
1H, J¼4.8 Hz, ArH), 6.63 (s, 2H, J¼7.8 Hz, ArH), 6.19 (s,
1H, ArH), 5.83 (d, 1H, J¼4.8 Hz, ArH), 5.73 (t, 1H,
J¼8.6 Hz, Ha), 4.90 (dd, 1H, J¼12.1 and 4.8 Hz, Hb), 3.55
and 3.40 (2£d, 2£1H, J¼13.2 Hz, NCH2), 2.98 (s, 6H,
2£CH3) and 3.05–2.90 (m, 2H, Hc and Hd); m/z (%) 593
(Mþ, 1), 362 (48), 231 (100), 203 (30), 115 (17), 97 (74) and
76 (35).
7
–
12
m/z (%) 579 (Mþ, 1), 348 (41), 231 (38), 203 (13), 81 (100)
and 76 (22).
44b (0.16 g, 14%), crystallized from hexane–ethyl acetate
as colourless prisms, mp 191–1938C; Found: C, 56.0; H,
4.05; N, 7.1; I21.95%; dH 8.15 (d, 2H, J¼8.5 Hz, ArH), 7.86
(d, 1H, J¼7.8 Hz, ArH), 7.63 (d, 2H, J¼7.5 Hz, ArH),
7.58–7.08 (m, 9H, ArH), 6.39 (d, 1H, J¼7.5 Hz, ArH), 5.82
(t, 1H, J¼8.0 Hz, Ha), 5.47 (s, 1H, ArH), 4.31 (d, 1H,
J¼7.2 Hz, Hb), 4.21 and 3.83 (2£d, 2£1H, J¼12.7 Hz,
NCH2), 3.14 (m, 1H, Hc) and 2.88 (m, 1H, Hd).
46b (0.439 g, 37%), obtained as colourless prisms mp 202–
2048C, from ethanol; Found: C, 58.65; H, 4.85; N, 7.15; I,
21.6; S, 5.35%; dH 7.79 (d, 1H, J¼7.8 Hz, ArH), 7.60 (d,
1H, J¼7.7 Hz, ArH), 7.48–7.24 (m, 5H, ArH), 7.11–6.96
(m, 5H, ArH), 6.81 (s, 1H, ArH), 6.65 (d, 2H, J¼7.8 Hz,
ArH), 6.22 (d, 1H, J¼4.9 Hz, ArH), 5.84 (t, 1H, J¼8.4 Hz,
Ha), 4.22 (d, 1H, J¼7.3 Hz, Hb), 4.19 and 3.84 (2£d, 2£1H,
J¼12.8, NCH2), 3.22 (dd, 1H, J¼13.3 and 8.4 Hz, Hc), 3.02
(s, 6H, 2£CH3) and 2.76 (m, 1H, Hd); m/z (%) 593 (Mþ, 1),
362 (29), 231 (76), 203 (42), 115 (15), 97 (100) and 76 (46).
n.O.e. data
Enhancement (%)
Proton irradiated
Ha
Hb
Ha
–
Hb
–
Hc
6
–
Hd
–
8
2.4.32. cis-3-[40-Dimethylamino)-phenyl]-2-(30-furyl)-
ethyl-1-(20-iodobenzoyl)-5-phenyl-pyrazolidine 47a and
trans-47b. Reaction of 4-(dimethylamino)-benzaldehyde
(0.30 g, 2.0 mmol) and hydrazine 37b (0.69, 2.0 mmol) with
excess styrene in boiling toluene for 18 h afforded a 1:1.8
mixture of 47a and 47b which was separated by flash
chromatography eluting with 9:1 v/v hexane–ethyl acetate.
m/z (%) 579 (Mþ, 1), 348 (62), 231 (36), 203 (14), 81 (100),
76 (14) and 53 (12).
2.4.30. cis-3-(20-Fluorophenyl)-2-(30-furyl)-ethyl-1-(20-
iodobenzoyl)-5-phenyl-pyrazolidine 45a and trans-45b.
Reaction of 2-fluorobenzaldehyde (0.25 g, 2.0 mmol) and
hydrazine 37b (0.68 g, 2.0 mmol) with excess styrene in
boiling toluene for 30 h afforded a 2.8:1 mixture of 45a and
45b (0.53 g, 48%) which proved inseparable by flash
chromatography eluting with 4:1 v/v hexane–ethyl acetate.
Fractional crystallization from ethanol gave 45a as colour-
less prisms, mp 166–1688C; Found: C, 58.95; H, 3.8; N,
5.15; I, 22.75; F, 3.45%. C27H22IN2O2F requires C, 58.7; H,
4.0; N, 5.05; I, 22.95; F, 3.45%; dH 7.85 (d, 1H, J¼7.9 Hz,
ArH), 7.58–7.03 (m, 11H, ArH), 6.89 (s, 1H, ArH), 6.84 (d,
1H, J¼7.8 Hz, ArH), 6.32 (s, 1H, ArH), 5.67 (t, 1H,
J¼8.4 Hz, Ha), 5.14 (s, 1H, ArH), 4.96 (dd, 1H, J¼12.0 and
5.3 Hz, Hb), 3.53 (s, 2H, NCH2) and 3.02–2.89 (m, 2H, Hc,
and Hd); m/z (%) 552 (Mþ, 1), 321 (100), 231 (38), 203 (21),
81 (95), 76 (19) and 53 (13).
47a (0.27 g, 23%), crystallized from ethanol as colourless
prisms, mp 171–1738C; Found: C, 60.2; H, 4.85; N, 7.4; I,
22.05. C29H28IN3O2 requires C, 60.3; H, 4.9; N, 7.3; I,
22.0%; dH 7.82 (d, 1H, J¼7.8 Hz, ArH), 7.64 (d, 1H,
J¼7.8 Hz, ArH), 7.52–7.21 (m, 5H, ArH), 7.14–6.90 (m,
5H, ArH), 6.60 (d, 2H, J¼7.8 Hz, ArH), 6.52 (s, 1H, ArH),
5.77 (t, 1H, J¼8.6 Hz, Ha), 5.26 (s, 1H, ArH), 4.95 (dd, 1H,
J¼12.1 and 4.8 Hz, Hb), 3.48 and 3.32 (2£d, 2£1H,
J¼13.1 Hz, NCH2), 2.95 (s, 6H, 2£CH3) and 3.03–2.91
(m, 2H, Hc and Hd).
n.O.e. data
Enhancement (%)
45b obtained as colourless prisms mp 195–1978C, from
ethanol; Found: C, 58.75; H, 4.2; N, 4.95; I, 22.95; F, 3.4%;
dH 7.81 (d, 1H, J¼8.0 Hz, ArH), 7.66 (d, 1H, J¼7.8 Hz,
ArH), 7.54–7.04 (m, 12H, ArH), 6.06 (d, 1H, 7.8 Hz, ArH),
5.97 (t, 1H, J¼8.0 Hz, Ha), 5.47 (s, 1H, ArH), 4.57 (d, 1H,
J¼7.1 Hz, Hb), 4.14 and 3.72 (2£d, 2£1H, J¼12.6 Hz,
NCH2) and 3.04–2.93 (m, 2H, Hc and Hd); m/z (%) 552
Proton irradiated
Ha
Hb
Ha
–
Hb
–
Hc
4
Hd
–
5
m/z (%) 577 (Mþ, 2), 346 (54), 231 (100), 203 (40), 146
(23), 134 (24), 81 (58), 76 (46) and 53 (27).

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4465
47b (0.47 g, 41%), obtained as colourless prisms mp 196–
1988C, from ethanol; Found: C, 60.25; H, 4.9; N, 7.5; I,
21.9%; dH 7.79 (d, 1H, J¼7.8 Hz, ArH), 7.62 (d, 1H,
J¼7.7 Hz, ArH), 7.46–7.25 (m, 5H, ArH), 7.08–6.92 (m,
5H, ArH), 6.69 (d, 2H, J¼7.8 Hz, ArH), 5.92 (d, 1H, 7.6 Hz,
ArH), 5.86 (t, 1H, J¼8.4 Hz, Ha), 5.57 (s, 1H, ArH), 4.20 (d,
1H, J¼7.5 Hz, Hb), 4.13 and 3.78 (2£d, 2£1H, J¼12.7 Hz,
NCH2), 3.19 (dd, 1H, J¼13.3 and 8.4 Hz, Hc), 2.99 (s, 6H,
2£CH3) and 2.77 (m, 1H, Hd).
49a dH 7.80–7.09 (m, 13H, ArH), 6.92 (s, 1H, ArH), 6.31 (s,
1H, ArH), 5.75 (t, 1H, J¼8.6 Hz, Ha), 5.14 (s, 1H, ArH),
5.02 (dd, 1H, J¼12.0 and 4.9 Hz, Hb), 3.52 (s, 2H, NCH2),
3.02 (m, 1H, Hc) and 2.85 (m, 1H, Hd).
49b dH 7.83–7.09 (m, 14H, ArH), 6.20 (d, 1H, 7.6 Hz,
ArH), 5.75 (t, 1H, J¼8.6 Hz, Ha), 5.46 (s, 1H, ArH), 4.29 (d,
1H, J¼7.2 Hz, Hb), 4.22 and 3.85 (2£d, 2£1H, J¼12.6 Hz,
NCH2), 3.02 (m, 1H, Hc) and 2.85 (m, 1H, Hd).
n.O.e. data
m/z (%) (mixed isomers) 602 (Mþ, 1), 371 (53), 231 (30),
203 (9) 81 (100), 76 (11) and 53 (9).
Enhancement (%)
2.4.35. cis-1-(20-Iodobenzoyl)-3-(30-methoxyphenyl)-5-
phenyl-2-(30-thienyl)-ethyl-pyrazolidine 50a and trans-
50b. Reaction of m-anisaldehyde (0.27 g, 2.0 mmol)
hydrazine 37a (0.72 g, 2.0 mmol) with excess styrene in
boiling toluene for 10 h afforded a 1.5:1 mixture of 50a and
50b (0.882 g, 76%), obtained as a colourless foam which
proved inseparable by flash chromatography eluting with
4:1 v/v hexane–ethyl acetate.
Proton irradiated
Ha
Hb
–
–
6
14
Hc
2
–
Hd
–
4
16
–
Ha
Hb
Hc
Hd
16
5
11
m/z (%) 577 (Mþ, 2), 346 (28), 231 (85), 203 (33), 81 (100),
76 (42) and 53 (36).
2.4.33. cis-1-(20-Iodobenzoyl)-5-phenyl-2-(30-thienyl)-
ethyl-3-[30-(trifluoromethyl)-phenyl]-pyrazolidine 48a
and trans-48b. Reaction of 3-(trifluoromethyl)-benzal-
dehyde (0.35 g, 2.0 mmol) and hydrazine 37a (0.72 g,
2.0 mmol) with excess styrene in boiling toluene for 12 h
afforded a 2.5:1 mixture of 48a and 48b (0.95 g, 77%) as a
colourless foam which proved inseparable by flash chro-
matography eluting with 4:1 v/v hexane–ethyl acetate.
Found: (mixed isomers) C, 57.95; H, 4.5; N, 4.75; I, 22.05;
S, 5.35. C28H25IN2O2S requires C, 57.95; H, 4.35; N, 4.85;
I, 21.85; S, 5.5%. The H NMR spectra of the individual
isomers were assigned from the mixture.
1
50a dH 7.80 (d, 1H, J¼7.8 Hz, ArH), 7.59 (d, 1H, J¼7.6 Hz,
ArH), 7.47–6.77 (m, 12H, Arh), 6.17 (s, 1H, ArH), 5.78 (d,
1H, J¼5.1 Hz, ArH), 5.74 (t, 1H, J¼8.6 Hz, Ha), 4.92 (dd,
1H, J¼12.0 and 4.7 Hz, Hb), 3.67 (s, 3H, OCH3), 3.66 and
3.52 (2£d, 2£1H, J¼13.2 Hz, NCH2), 3.12 (m, 1H, Hc), and
2.87 (m, 1H, Hd).
Found: (mixed isomers) C, 54.65; H, 3.7; F, 9.15; N, 4.4; I,
20.4; S, 5.1. C29H28F3IN3OS requires C, 54.4; H, 3.6; F, 9.2;
N, 4.55; I, 20.5; S, 5.2%; m/z (%) (mixed isomers) 618 (Mþ,
1), 387 (62), 231 (37), 203 (12), 105 (10), 97 (100) and 76
50b dH 7.77 (d, 1H, J¼7.8 Hz, ArH), 7.64 (d, 1H, J 7.7 Hz,
ArH), 7.50–6.78 (m, 13H, ArH), 6.28 (d, 1H, 5.0 Hz, ArH),
5.77 (t, 1H, J¼8.6 Hz, Ha), 4.19 (d, 1H, J¼7.2 Hz, Hb), 4.14
and3.80(2£d, 2£1H, J¼12.7 Hz, NCH2), 3.67(s, 3H, OCH3),
3.16 (dd, 1 h, J¼13.4 and 8.6 Hz, Hc) and 2.71 (m, 1H, Hd).
1
(14). The H NMR spectra of the individual isomers were
assigned from the mixture.
48a dH 7.81–7.80 (m, 13H, ArH), 6.74 (d, 1H, J¼5.0 Hz,
ArH), 6.23 (d, 1H, J¼1.2 Hz, ArH), 5.89 (d, 1H, J¼5.0 Hz,
ArH), 5.75 (t, 1H, J¼8.6 Hz, Ha), 5.01 (dd, 1H, J¼4.9 and
12.1 Hz, Hb), 3.68 and 3.54 (2£d, 2£1H, J¼13.6 Hz,
NCH2), 3.06 (m, 1H, Hc) and 2.87 (m, 1H, Hd).
m/z (%) (mixed isomers) 580 (Mþ, 1), 349 (72), 231 (44),
203 (15), 105 (12), 97 (100) and 76 (16).
2.4.36. cis-2-(30-Furyl)-ethyl-1-(20-iodobenzoyl)-3-(30-
methoxyphenyl)-5-phenyl-pyrazolidine 51a and trans-
51b. Reaction of m-anisaldehyde (0.27 g, 2.0 mmol) and
hydrazine 37b (0.69 g, 2.0 mmol) with excess styrene in
boiling toluene for 10 h afforded a 1.3:1 mixture of 51a and
51b (0.84 g, 74%) obtained as a colourless foam which
proved inseparable by flash chromatography eluting with
4:1 v/v hexane–ethyl acetate.
48b dH 7.81–7.08 (m, 14H, ArH), 6.82 (s, 1H, ArH), 6.19
(d, 1H, J¼5.0 Hz, ArH), 5.79 (t, 1H, J¼8.6 Hz, Hb), 4.29
and 3.91 (2£d, 2£1H, J¼12.8 Hz, NCH2), 4.26 (d, 1H,
J¼7.4 Hz, Hb), 3.06 (m, 1H, Hc) and 2.87 (m, 1H, Hd).
2.4.34. cis-2-(30-Furyl)-ethyl-1-(20-iodobenzoyl)-5-phe-
nyl-3-[30 (trifluoromethyl)-phenyl]-pyrazolidine 49a
and trans-49b. Reaction of 3-(trifluoromethyl)-benzal-
dehyde (0.35 g, 2.0 mmol) and hydrazine 37b (0.68 g,
2.0 mmol) with excess styrene in boiling toluene for 12 h
afforded a 2.5:1 mixture of 49a and 49b (0.92 g, 76%)
obtained as a colourless foam which proved inseparable by
flash chromatography eluting with 4:1 v/v hexane–ethyl
acetate.
Found: (mixed isomers) C, 59.7; H, 4.6; N, 4.85; I, 22.45%.
C28H25IN2O3 requires C, 59.6; H, 4.45; N, 4.95; I, 22.5%.
The 1H NMR spectra of the individual isomers were
assigned from the mixture.
51a dH 7.84 (d, 1H, J¼7.8 Hz, ArH), 7.63 (d, 1H, J¼7.7 Hz,
ArH), 7.52–6.78 (m, 12H, ArH), 6.56 (s, 1H, ArH), 6.51 (s,
1H, ArH), 5.72 (t, 1H, J¼8.5 Hz, Ha), 5.24 (s, 1H, ArH),
4.93 (dd, 1H, J¼12.2 and 4.7 Hz, Hb), 3.69 (s, 3H, OCH3),
3.49 and 3.36 (2£d, 2£1H, J¼13.4 Hz, NCH2), 3.04 (m, 1H,
Hc) and 2.80 (m, 1H, Hd).
Found: (mixed isomers) C, 55.95; H, 3.8; F, 9.4; N, 4.6; I,
20.85. C28H22F3IN2O2 requires C, 55.85; H, 3.7; F, 9.45; N,
1
4.65; I, 21.05% The H NMR spectra of the individual
isomers were assigned from the mixture.

4466
C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
51b dH 7.81 (d, 1H, J¼7.8 Hz, ArH), 7.63 (d, 1H, J¼7.7 Hz,
ArH), 7.52–6.78 (m, 12H, ArH), 5.97 (d, 1H, 7.6 Hz, ArH),
5.75 (t, 1H, J¼8.6 Hz, Ha), 5.50 (s, 1H, ArH), 4.21 (d, 1H,
J¼7.2 Hz, Hb), 4.16 and 3.77 (2£d, 2£1H, J¼12.8 Hz,
NCH2), 3.69 (s, 3H, OCH3), 3.18 (dd, 1H, J¼13.2 and
8.6 Hz, Hc) and 2.72 (m, 1H, Hd).
Flash chromatography, eluting with 1:1 v/v hexane–ethyl
acetate afforded the product (0.13 g, 72%), which crystal-
lized from ethanol as colouless needles, mp 185–1878C.
Found: C, 71.9; H, 4.75; N, 9.15; C27H21N3O4 requires C,
71.85; H, 4.7; N, 9.3%; dH 8.15 (2£d, 2£1H, J¼8.6 Hz,
ArH), 7.99 (2£d, 2£1H, J¼8.5 Hz, ArH), 7.72 (d, 1H,
J¼7.4 Hz, ArH), 7.59–7.19 (m, 9H, ArH), 6.14 (d, 1H,
J¼1.6 Hz, ArH), 5.87 (t, 1H, J¼9.0 Hz, Ha), 4.59 (dd, 1H,
J¼12.7, and 5.0 Hz, Hb), 3.40 and 3.65 (2£d, 2£1H,
J¼14.6 Hz, NCH2), 3.09 (m, 1H, Hc) and 2.81 (m, 1H, Hd);
m/z (%) 451 (Mþ, 9), 346 (75), 241 (25), 184 (60), 128 (56),
115 (16), 105 (91), 91 (48), 77 (100) and 51 (29).
m/z (%) (mixed isomers) 564 (Mþ, 2), 333 (100), 231 (41),
203 (12), 105 (11), 81 (87) 77 (12).
2.4.37. Cyclisation product 54a. A mixture of 41a (0.22 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry toluene for 16 h according to the general procedure.
Flash chromatography, eluting with 3:2 v/v hexane–ethyl
acetate afforded the product (0.14 g, 82%) as a colourless
gum; Found: C, 76.65; H, 5.3; N, 6.75; S, 7.45. C27H22N2OS
requires C, 76.75; H, 5.25; N, 6.65; S, 7.6%; dH (400 MHz)
7.70 (d, 1H, J¼7.4 Hz, ArH), 7.51–7.41 (m, 3H, ArH),
7.32–7.20 (m, 9H, ArH), 7.13–7.11 (m, 2 h, ArH), 6.63 (d,
1H, J¼5.2 Hz, ArH), 5.78 (t, 1H, J¼8.9 Hz, Ha), 4.51 (dd,
1H, J¼12.6 and 5.4 Hz, Hb), 3.82 and 3.59 (2£d, 2£1H,
J¼14.6 Hz, NCH2), 3.80 (m, 1H, Hc) and 2.83 (m, 1H, Hd).
2.4.40. Cyclisation product 55b. A mixture of 44b (0.23 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry toluene for 16 h according to the general procedure.
Flash chromatography, eluting with 1:1 v/v hexane–ethyl
acetate afforded the product (0.12 g, 69%) which crystal-
lized from ethanol as colourless needles, mp 214–2168C.
Found: C, 71.7; H, 4.65; N, 9.3%; C27H21N3O4 requires C,
71.85; H, 4.7; N, 9.3% dH (400 MHz) 8.05 (m, 2H, ArH),
7.62–7.17 (m, 12H, ArH), 6.32 (d, 1H, J¼1.8 Hz, ArH),
5.43 (t, J¼8.8 Hz, Ha), 4.54 (d, 1H, J¼7.2 Hz, Hb), 4.28 and
4.11 (2£d, 2£1H, J¼14.5 Hz, NCH2), 3.14 (dd, 1H, J¼13.2
and 8.8 Hz, Hc) and 3.01 (m, 1H, Hd).
n.O.e. data
Enhancement (%)
Proton irradiated
Ha
Hb
2
Hc
6
4
Hc
22
Ha
Hb
Hc
Hd
n.O.e. data
2
–
13
–
26
Enhancement (%)
Proton irradiated
Ha
Hb
Ha
–
Hb
–
Hc
2
–
Hd
–
2
m/z (%) 422 (Mþ, 72), 317 (35), 289 (22), 200 (88), 193
(55), 171 (100), 115 (29), 91 (35), 77 (20).
2.4.38. Cyclisation product 54b. A mixture of 41b (0.22 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry toluene for 16 h according to the general procedure.
Flash chromatography, eluting with 3:2 v/v hexane–ethyl
acetate afforded the product (0.14 g, 84%) as a colourless
gum; Found: C, 76.8; H, 5.45; N, 6.6; S, 7.6%; dH
(400 MHz, C6 D6) 7.70 (d, 1H, J¼7.4 Hz, ArH), 6.45 (d,
1H, J¼5.2 Hz, ArH), 7.14–6.98 (m, 12H, ArH), 6.92 (d,
1H, J¼5.2 Hz, ArH), 6.45 (d, 1H, J¼5.2 Hz, ArH), 5.58 (t,
1H, J¼8.6 Hz, Ha), 3.90 and 3.62 (2£d, 2£1H, J¼14.4 Hz,
NCH2), 3.73 (d, 1H, J¼7.2 Hz, Hb), 2.58 (m, 1H, Hc), and
2.43 (m, 1H, Hd).
m/z (%) 451 (Mþ, 17), 346 (38), 241 (26), 184 (100), 128
(57), 105 (44), 91 (28), 77 (40) and 57 (25).
2.4.41. Cyclisation product 56a. A mixture of 45a (0.22 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry toluene for 16 h according to the general procedure.
Flash chromatography, eluting with 3:2 v/v hexane–ethyl
acetate afforded the product (0.12 g, 71%) as a colourless
gum.
Found: C, 76.55; H, 5.05; F, 4.5; N, 6.6%; dH (400 MHz)
7.73 (d, 1H, J¼7.8 Hz, ArH), 7.54–7.40 (m, 4H, ArH),
7.32–7.21 (m, 7H, ArH), 7.10 (t, 1H, J¼7.3 Hz, ArH), 7.00
(t, 1H, J¼9.6 Hz, ArH), 6.18 (d, 1H, J¼1.8 Hz, ArH), 5.81
(t, 1H, J¼8.9 Hz, Ha), 4.65 (dd, 1H, J¼12.7 and 5.7 Hz, Hb),
3.78 and 3.44 (2£d, 2£1H, J¼14.6 Hz, NCH2), 3.03 (m, 1H,
Hc) and 2.92 (m, 1H, Hd).
n.O.e. data
Enhancement (%)
Proton irradiated
Ha
Hb
–
Hc
7
–
Hd
–1
5
Ha
Hb
Hc
–
23
n.O.e. data
4
14
Enhancement (%)
Proton irradiated
Ha
Hb
Ha
5
Hb
3
Hc
6
4
Hd
–
–
m/z (%) 422 (Mþ, 100), 318 (18), 289 (20), 214 (29), 200
(71), 193 (49), 171 (87), 115 (27) and 91 (16).
2.4.39. Cyclisation product 55a. A mixture of 44a (0.23 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry toluene for 16 h according to the general procedure.
m/z (%) 424 (Mþ, 100), 319 (26), 211 (28), 184 (85), 156
(27), 128 (81), 115 (20), 102 (18) and 77 (25).

C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
4467
2.4.42. Cyclisation product 57a. A mixture of 46a (0.24 g,
0.40 mmol) and catalyst system B was boiled under reflux in
dry toluene for 16 h according to the general procedure.
Flash chromatography, eluting with 3:2 v/v hexane–ethyl
acetate afforded the product (0.15 g, 81%) as a colourless
gum; Found: C, 74.85; H, 5.95; N, 8.9; S, 6.95; C29H27N3OS
requires C, 74.8; H, 5.85; N, 9.0; S, 6.9%; dH 7.76 (d, 1H,
J¼7.6 Hz, ArH), 7.48–6.98 (m, 11H, ArH), 6.65–6.59 (m,
3H, ArH), 5.77 (t, 1H, J¼8.8 Hz, Ha), 4.38 (dd, 1H, J¼12.6
and 5.4 Hz, Hb), 3.70 and 3.58 (2£d, 2£1H, J¼14.2 Hz,
NCH2), 3.06 (m, 1H, Hc), 2.88 (m, 1H, Hd), and 2.96 (s, 6H,
2£CH3); m/z (%) 465 (Mþ, 20), 360 (32), 332 (24), 200
(100), 171 (86), 115 (21) and 77 (29).
The 1H NMR spectra of the individual isomers were
assigned from the mixture.
59a dH 7.93–7.24 (m, 14H, ArH), 6.19 (d, 1H, J¼1.8 Hz,
ArH), 5.89 (t, 1H, J¼8.9 Hz, Ha), 4.60 (dd, 1H, J¼12.4 and
5.5 Hz, Hb), 3.68 and 3.41 (2£d, 2£1H, J¼14.9 Hz, NCH2),
3.16 (m, 1H, Hc) and 2.84 (m, 1H, Hd).
59b dH 7.96–7.24 (m, 14H, ArH), 6.26 (d, 1H, J¼1.8 Hz,
ArH), 5.53 (t, 1H, J¼8.8 Hz, Ha), 4.53 (d, 1H, J¼7.2 Hz,
Hb), 4.48 and 4.18 (2£d, 2£1H, J¼14.6 Hz, NCH2), 3.10
(dd, 1H, J¼13.6 and 8.8 Hz, Hc) and 2.74 (m, 1H, Hd).
m/z (%) (mixed isomers) 474 (Mþ, 18), 369 (94), 264 (35),
184 (100), 128 (76), 115 (20), 105 (63), 91 (54), 77 (77) and
51 (30).
2.4.43. Cyclisation product 57b. A mixture of 46b (0.24 g,
0.40 mmol) and catalyst system B was boiled under reflux
in dry toluene for 16 h according to the general
procedure. Flash chromatography, eluting with 3:2 v/v
hexane–ethyl acetate afforded the product (0.14 g, 77%)
as a colourless gum; Found: C, 74.9; H, 5.8; N, 8.85; S,
6.7; C29H27N3OS requires C, 74.8; H, 5.85; N, 9.0; S,
6.9%; dH 7.64–6.65 (m, 15H, ArH), 5.48 (t, 1H,
J¼8.8 Hz, Ha), 4.36 (d, 1H, J¼7.2 Hz, Hb), 4.31 and
4.07 (2£d, 2£1H, J¼14.4 Hz, NCH2), 3.11 (dd, 1H,
J¼13.3 and 8.8 Hz, Hc), 2.87 (m, 1H, Hd) and 2.98 (s,
6H, 2£CH3); m/z (%), 465 (Mþ, 18), 360 (37), 200 (100),
171 (76), 115 (22), and 77 (34).
2.4.46. Cyclisation product 60a and 60b. Treatment of a
1.5:1 mixture of 50a and 50b (0.46 g, 0.80 mmol) with
catalyst system B in boiling dry toluene for 16 h according
to the general procedure afforded a 1.5:1 mixture of 60a and
60b which was separated by flash chromatography, eluting
with 3:2 v/v hexane–ethyl acetate.
60a (0.18 g, 85%), obtained as a colourless gum; Found: C,
74.45; H, 5.3; N, 6.1; S, 7.05; C28H24N2O2S requires C,
74.3; H, 5.35; N, 6.2; S, 7.1%; dH 7.73 (d, 1H, J¼7.5 Hz,
ArH), 7.55–7.14 (m, 10H, ArH), 6.85–6.78 (m, 3H, ArH),
6.69 (d, 1H, J¼5.0 Hz, ArH), 5.81 (t, 1H, J¼8.9 Hz, Ha),
4.51 (dd, 1H, J¼12.6 and 5.5 Hz, Hb), 3.72 (s, 3H, OCH3),
3.72 and 3.55 (2£d, 2£1H, J¼14.6 Hz, NCH2), 3.06 (m, 1H,
Hc) and 2.82 (m, 1H, Hd); m/z (%) 452 (Mþ, 55), 347 (31),
200 (90), 171 (100), 115 (24) and 77 (32).
2.4.44. Cyclisation products 58a and 57b. Treatment of a
2.5:1 mixture of 48a and 48b (0.50 g, 0.80 mmol) with
catalyst system B in boiling dry toluene for 16 h according
to the general procedure afforded a 2.5:1 mixture of 58a and
58b (0.31 g, 79%), obtained as a colourless gum which was
found to be inseparable by flash chromatography, eluting
with 3:2 v/v hexane–ethyl acetate.
60b (0.12 g, 83%), obtained as a colourless gum; Found: C,
74.3; H, 5.5; N, 6.25; S, 6.95; C28H24N2O2S requires C,
74.3; H, 5.35; N, 6.2; S, 7.1%; dH 7.51–6.74 (m, 15H, ArH),
5.48 (t, 1H, J¼8.8 Hz, Ha), 4.42 (d, 1H, J¼7.2 Hz, Hb), 4.32
and 4.13 (2£d, 2£1H, J¼14.6 Hz, NCH2), 3.59 (s, 3H,
OCH3), 3.12 (dd, 1H, J¼13.4 and 8.8 Hz, Hc) and 2.91 (m,
1H, Hd); m/z (%) 452 (Mþ, 34), 347 (27), 200 (100), 171
(87), 115 (22) and 77 (27).
Found: (mixed isomers) C, 68.8; H, 4.5; F, 11.55; N, 5.55; S,
6.35; C28H21F3N2OS requires C, 68.55; H, 4.3; F, 11.6; N,
5.7; S, 6.55%. The 1H NMR spectra of the individual
isomers were assigned from the mixture.
58a dH 7.89–7.12 (m, 14H, ArH), 6.71 (d, 1H, J¼5.1 Hz,
ArH), 5.84 (t, 1H, J¼8.9 Hz, Ha), 4.58 (dd, 1H, J¼12.2 and
5.6 Hz, Hb), 3.77 and 3.48 (2£d, 2£1H, J¼14.6 Hz, NCH2),
3.14 (m, 1H, Hc) and 2.88 (m, 1H, Hd).
2.4.47. Cyclisation product 61a and 61b. Treatment of a
1.3:1 mixture of 51a and 51b (0.45 g, 0.80 mmol), with
catalyst system B in boiling dry toluene for 16 h according
to the general procedure afforded a 1.3:1 mixture of 61a and
61b, which was separated by flash chromatography, eluting
with 3:2 v/v hexane–ethyl acetate.
58b dH 7.92–7.12 (m, 14H, ArH), 6.82 (d, 1H, J¼5.0 Hz,
ArH), 5.51 (t, 1H, J¼8.8 Hz, Ha), 4.55 (d, 1H, J¼7.2 Hz,
Hb), 4.42 and 4.18 (2£d, 2£1H, J¼14.6 Hz, NCH2), 3.14
(m, 1H, Hc) and 2.88 (m, 1H, Hd); m/z (%) (mixed isomers)
490 (Mþ, 32), 386 (28), 200 (75), 171 (100), 115 (20), 91
(42) and 77 (23).
61a (0.138 g, 70%), obtained as a colourless gum; Found: C,
77.0; H, 5.45; N, 6.55; C28H24N2O3 requires C, 77.05; H,
5.55; N, 6.4%; dH 7.75 (d, 1H, J¼7.8 Hz, ArH), 7.54–7.40
(m, 4H, ArH), 7.32–7.24 (m, 6H, ArH), 6.84–6.78 (m, 3H,
ArH), 6.13 (d, 1H, J¼1.8 Hz, ArH), 5.80 (t, 1H, J¼8.9 Hz,
Ha), 4.52 (dd, 1H, J¼12.6 and 5.6 Hz, Hb), 3.77 (s, 3H,
OCH3), 3.65 and 3.48 (2£d, 2£1H, J¼14.6 Hz, NCH2), 3.05
(m, 1H, Hc) and 2.79 (m, 1H, Hd); m/z (%) 436 (Mþ, 38),
331 (28), 226 (37), 184 (100), 128 (76), 115 (22), 105 (20),
91 (22) and 77 (31).
2.4.45. Cyclisation product 59a and 59b. Treatment of a
2.5:1 mixture of 49a and 49b (0.48 g, 0.80 mmol) with
catalyst system B in boiling dry toluene for 16 h according
to the general procedure afforded a 2.5:1 mixture of 59a and
59b (0.28 g, 73%), obtained as a colourless gum which was
found to inseparable by flash chromatography, eluting with
3:2 v/v hexane–ethyl acetate.
Found: (mixed isomers) C, 70.95; H, 4.4; F11.8; N, 6.0;
C28H21F3N2O2 requires C, 70.9; H, 4.45; F, 12.0; N, 5.9%.
61b (0.108 g, 71%), obtained as a colourless gum; Found:
C, 77.2; H, 5.5; N, 6.45; C28H24N2O3 requires C, 77.05; H,

4468
C. W. G. Fishwick et al. / Tetrahedron 59 (2003) 4451–4468
Gomez-Escalonilla, M. J.; de la Hoz, A.; Langa, F.; Moreno,
A. Tetrahedron 1998, 54, 13167–13180. (b) Sun, B.; Adachi,
K.; Nogachi, M. Tetrahedron 1996, 52, 901–914. (c) Bin, S.;
Adachi, K.; Noguchi, M. Synthesis 1997, 53–56.
5.55; N, 6.4%; dH 7.52–6.75 (m, 14H, ArH), 6.30 (d, 1H,
J¼1.8 Hz, ArH), 5.51 (t, 1H, J¼8.8 Hz, Ha), 4.43 (d, 1H,
J¼7.2 Hz, Hb), 4.27 and 4.08 (2£d, 2£1H, J¼14.5 Hz,
NCH2), 3.62 (s, 3H, OCH3), 3.14 (dd, 1H, J¼13.4 and
8.8 Hz, Hc) and 2.88 (m, 1H, Hd); m/z (%) 436 (Mþ, 16),
331 (62), 226 (24), 184 (60), 128 (44), 115 (17), 105 (82), 91
(41) and 77 (100).
11. (a) Turk, C.; Svete, J.; Stanovnik, B.; Golic, L.; Golic-
Greladolnik, S.; Golobik, A.; Selic, L. Helv. Chim. Acta 2001,
84, 146–156. (b) Fuchi, N.; Doi, T.; Harada, T.; Urban, J.;
Cao, B.; Kahn, M.; Takahashi, T. Tetrahedron Lett. 2001, 42,
1305–1308. (c) Saki, N.; Funabashi, M.; Hamada, T.;
Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1999, 55,
13703–13724. (d) Roussi, F.; Bonin, M.; Chirani, A.;
Micouin, L.; Riche, C.; Husson, H.-P. Tetrahedron Lett.
1999, 40, 3727–3730. (e) Dolle, R. E.; Barden, M. C.;
Brennan, P. E.; Ahmed, G.; Tran, V.; Ho, D. M. Tetrahedron
Lett. 1999, 40, 2907–2908. (f) Huisgen, R.; Temme, R.
Heteroatom. Chem. 1999, 10, 79–88. (g) Stanovnik, B.; Jelen,
B.; Zlicer, M. Farmaco 1993, 48, 231–242.
Acknowledgements
We thank the EPSRC and Leeds University for Support.
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