Diastereoselective intramolecular hetero Diels-Alder approach towards polycyclic heterocycles

Article abstract of DOI:10.1016/S0040-4020(01)01153-X

Several different heterocyclic aldehydes, derived from pyrazole, pyrimidine, pyridine, indole and thiazole, were converted to polyheterocyclic compounds containing four to seven rings. The key steps in the sequence were a Knoevenagel condensation of the aldehyde and a heterocyclic carbonyl compound, such as pyrazolone and isoxazolone, followed by an intramolecular hetero Diels-Alder reaction. Most final products were isolated with high yield and diastereoselecivity. The isoxazolo fused cycloadducts formed interesting spiro-adducts upon heating. The cis nature of the bridging hydrogens of the heterocycles was evidenced by X-ray diffraction analysis.

Full text of DOI:10.1016/S0040-4020(01)01153-X

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 531±544
Diastereoselective intramolecular hetero Diels±Alder approach
towards polycyclic heterocycles
Erik Ceulemans, Marieke Voets, Sabine Emmers, Koen Uytterhoeven, Luc Van Meervelt
and Wim Dehaenp
Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Received 31 August 2001; revised 14 November 2001; accepted 19 November 2001
AbstractÐSeveral different heterocyclic aldehydes, derived from pyrazole, pyrimidine, pyridine, indole and thiazole, were converted to
polyheterocyclic compounds containing four to seven rings. The key steps in the sequence were a Knoevenagel condensation of the aldehyde
and a heterocyclic carbonyl compound, such as pyrazolone and isoxazolone, followed by an intramolecular hetero Diels±Alder reaction.
Most ®nal products were isolated with high yield and diastereoselecivity. The isoxazolo fused cycloadducts formed interesting spiro-adducts
²
upon heating. The cis nature of the bridging hydrogens of the heterocycles was evidenced by X-ray diffraction analysis. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
introduced by substitution of 5-chloro-4-formyl-1-phenyl-
pyrazoles 1a,b with prenyl thiolate. The latter have been
prepared by chloroformylation of the appropriate pyrazo-
lone.7 The resulting aldehydes 2a,b and their analogs have
been previously used by us as a starting point for intra-
molecular 1,3-dipolar cycloadditions, affording several
new polyheterocyclic systems.6
In a series of publications by Tietze et al.,1 the use of the
intramolecular hetero Diels±Alder reaction was described
to construct fused heterocycles, which in many cases are
formed with high diastereoselectivity. Furthermore, the
hetero Diels±Alder reaction has been established by Tietze2
and others3 as a powerful tool in natural product synthesis.
We recently communicated4 an application of this reaction,
starting from 5-chloropyrazole-4-aldehydes and leading to
tetracyclic pyrazoles. We will now prove the generality of
this reaction sequence by varying the heterocyclic building
blocks, which will result in a number of unprecedented new
polyheterocycles.
Following the Tietze protocol of domino Knoevenagel
condensation/intramolecular hetero Diels±Alder cyclo-
addition, we condensed pyrazoles 2a and 2b with pyrazo-
lones 5a±d. The intermediate Knoevenagel adducts 3a±f
could be observed by TLC control and the appearance of
an orange±yellow color. They were not isolated but cyclized
upon re¯ux in acetonitrile to the cis-fused tetracyclic bis-
pyrazoles 4a±e with high yield (80±90%) and diastereo-
selectivity (.99%) (Scheme 1). The yield for 4f was
signi®cantly lower (32%) which is probably due to steric
hindrance between the two phenyl groups at the 3-positions
of the pyrazole rings. The cis nature of the bridging hydro-
gens of the tetracycles 4a±f was strongly supported by their
2. Results
Heterocyclic b-chloro aldehydes are interesting synthons,
which can be transformed in a number of ways to fused
heterocycles by using the reactivity of the chlorine for
nucleophilic substitution in combination with the multitude
of transformations possible starting from the aldehyde func-
tion.5 Thus, an unsaturated side chain can be smoothly
1
coupling constant of 4 Hz in the H NMR spectrum. This
agrees well with the results found for similar benzo fused
systems described by Tietze and coworkers.1
Keywords: hetero Diels±Alder reaction; cycloaddition; diastereoselec-
tivity; selectivity; 1-oxa-1,3-buta-dienes; X-ray diffraction analysis.
To get con®rmation of the cis-fused structure of these poly-
heterocyclic compounds, X-ray analysis was carried out.
The molecular structure of 4a is depicted in Fig. 1and is
largely determined by the conformation of the central ring
system. Both pyrazole rings are planar and make an angle of
67.9(3)8 to each other, while the six-membered rings adopt a
half-chair conformation. In order to reduce the steric
hindrance with the central ring system, both phenyl rings
are rotated by about 358 out of the plane of the pyrazole
p
Corresponding author. Tel.: 132-16-32-74-39; fax: 132-16-32-79-90;
e-mail: wim.dehaen@chem.kuleuven.ac.be
Crystallographic data (excluding structure factors) ending pages for the
²
structures in this paper, have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication numbers CCDC
169436, CCDC 169437 and CCDC 169438. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: 144(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01153-X

532
E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
Scheme 1. (i) 4-Bromo-2-methyl-2-butene, thiourea, EtOH, re¯ux, (ii) NaOH, EtOH, re¯ux, (iii) pyrazolone 5a±d, EDDA, CH3CN, 300 rt, (iv) hours re¯ux as
indicated in Section 3.
rings. Due to the steric hindrance between the CF3 and
methyl groups in compound 4d, the angle between both
pyrazole rings is increased to 83.7(4)8 (Fig. 2). The unit
7 was completely transformed in a mixture of isomers 8a,b
(Scheme 2). The two products 8a and 8b (ratio 9:11) could
be separated without problems by column chromatography,
giving a combined yield of 93%. The examination of the
NMR spectra showed that a ring contraction of the isoxazole
Ê 3
cell of 4d (Fig. 2) contains three large voids (534 A each)
which are surrounded by the phenyl substituents, and are
possible solvent areas. Indeed, the maxima in the ®nal
difference density suggest the occurrence of disordered
solvent molecules in this region. In 4a (Fig. 1), the asym-
metric unit contains a molecule of water which forms an
in®nite chain of water through the whole crystal.
1
7 to the (2H)azirines 8a,b had occurred. The H NMR
spectra of 7, 8a,b again were in accordance with a cis fusion
of the pyran and thiopyran rings. The 13C NMR spectra of 8a
and 8b displayed typical signals for the azirine sp3 carbon at
37.1and 40.5 ppm, and the azirine sp 2 carbon at 171.1 and
172.0 ppm, respectively. The IR spectra of 8a and 8b show
the ester CvO stretching at 1722 and 1716 cm21, respec-
tively. 2D-HETCOR spectra were needed to assign the
structure of 8a or 8b and we concluded the following. The
methyl group of pyrazole 8a resonates at rather high ®eld,
with d 1.60 ppm, while the corresponding methyl peak for
8b was found back at d 2.02 ppm, which is a normal value
In the same way, N,N0-dimethylbarbituric acid 5e was
condensed with 2a to give tetracyclic pyrimidine 6 in
excellent yield (92%) (Scheme 2). The reaction of 2a with
oxazolone 5f took a slightly different course. The expected
adduct 7 was indeed formed and could be isolated, but on
prolonged re¯ux in acetonitrile (5 days) or toluene (3 days)
Figure 1. (a) Molecular structure of compound 4a. (b) Crystal packing of compound 4a.

E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
533
Figure 2. (a) Molecular structure of compound 4d. (b) Crystal packing of compound 4d.
for 3-methylpyrazoles. The methyl group in isomer 8a
clearly is much more in¯uenced by the anisotropic effect
of the neighbouring azirine 3-phenyl group.
and 9b, which could not be brought to transform in the
corresponding cycloadducts 10a and 10b, even on heating
at 1908C. The products 9a,b had the E-con®guration as
1
3
could be inferred from their H NMR spectra. The JCH
coupling constant between the carbonyl carbon and the
alkylidene hydrogen had a typical value of 7 Hz. It can be
argued that the indole or benzofuran rings that would be
formed in 10a,b have not suf®cient aromatic stabilization
to offset the amide or ester stabilization present in the
Knoevenagel adducts 9a,b, respectively. Recently, the
cycloadduct 11 was formed at 1908C from a 3-indolone
derivative, where the amide resonance is absent11
(Scheme 3).
It is interesting to remark that similar reactions of the isoxa-
zolone 5f with the benzene analogues were reported by
Tietze et al.8 to yield the unrearranged products. Thermal
or photochemical ring contractions of isoxazoles to
(2H)azirines are well known in the literature, with the reac-
tion proceeding in most cases to the thermodynamically
stable oxazoles.9 However, we found no trace of an oxazolo
fused isomer of 7, 8a,b. In fact, the ring contraction of 7
occurs at relatively low temperatures and may be a way to
alleviate ring strain or steric hindrance.
So far we have always started from a 5-chloro-4-formyl-
pyrazole 2. A number of other heterocycles with similar
functionalities are found in the literature. The commercial
Pyrazole 2a was condensed with 2-indolone 5g10 or
2-coumaranone 5h to afford the Knoevenagel adducts 9a
Scheme 2. (i) Barbituric acid 5e, CH3CN, re¯ux, (ii) pyrazolone 5f, CH3CN, re¯ux, (iii) CH3CN or toluene, re¯ux.

534
E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
Scheme 3.
4,6-dihydroxypyrimidine 12 was smoothly transformed
with an excess Vilsmeier reagent to afford the highly reac-
tive 4,6-dichloropyrimidine-5-aldehyde 13 according to a
published procedure.12 Mono- and disubstitution of the
two chlorine functions by nucleophiles are possible. Thus,
the use of prenylthiolate gave only the disubstituted pyrimi-
dine 14. With diallylamine either the monosubstituted 15 or
the disubstituted 16 could be obtained in good yield. Earlier
we found that pyrazoles 2a do not react with amines6
(Scheme 4).
tetracyclic pyrazoles 17 (from 14 and 5b) and 19 (from 15
and 5b), and the (2H)azirine isomers 18a,b (from 14 and 5f),
and 20a,b (from 15 and 5f). In the latter two cases the
isoxazolo fused intermediates were not detected, but
rearranged directy to the azirines 18 and 20, even in aceto-
nitrile solution. This showed that the structure of the fused
isoxazole has an in¯uence on the rate of the ring contraction.
The NMR data of 17±20 were similar to those found for the
pyrazole analogs, and again the same high selectivity for cis
fusion was found (Fig. 3). A reaction of the disubstituted
pyrimidine 16 with pyrazolone 5b in acetonitrile solution
did not give the expected ring closed product. Instead, only
starting material was isolated even on re¯uxing in toluene
for ®ve days. Probably due to steric hindrance of the allyl
groups, the pyrazolone cannot react with the aldehyde to
We were now able to use the aldehydes 14±16 in analogous
hetero Diels±Alder reactions by condensation reactions
with pyrazolone 5b and oxazolone 5f. The reaction outcome
was completely analogous, with the formation of the
Scheme 4. (i) 4-Bromo-2-methyl-2-butene, thiourea, EtOH, re¯ux, (ii) NaOH, EtOH, re¯ux, (iii) 1equiv. diallylamine, Et 3N, THF, re¯ux, (iv) 2 equiv.
diallylamine, Et3N, THF, re¯ux.

E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
535
Figure 3.
form the Knoevenagel adduct. Fig. 4 shows the molecular
structure of 18b (only the prenyl thiolate group with the
highest occupancy is shown, see Section 3). The pyrimidine
ring is planar, while the oxane and thiane rings adopt an
envelope conformation. The pyrimidine and thiane rings are
lying almost in the same plane (the angle between the best
planes through both rings is 13.1(2)8). The thiane and oxane
rings make an angle of 69.9(2)8. The azirine nitrogen atom
is situated at the same side of the fused rings as the bridging
hydrogens at atoms C4 and C5. The angle between the
Figure 4. Molecular structure of compound 18b.
Figure 5.

536
E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
Scheme 5.
prenyl thiolate substituent and the pyrimidine ring is
73.7(3)8.
Finally, the known 2,6-dichloropyridine-3,5-dialdehyde 31,
which has two b chloro aldehyde moieties, was prepared
from glutarimide following a literature procedure.15 Substi-
tution with diallylamine yielded the di-aldehyde 32, which
was treated with pyrazolone 5b under the usual conditions.
An oil was formed from acetonitrile solution which corre-
sponded to a compound 33 which was only ringclosed (as
a cis compound) to one side. The other side was the
Knoevenageladduct with a Z-con®guration (3JCHˆ10 Hz).
Further heating of 33 in toluene afforded a mixture of the
remarkable heptacyclic cycloadducts 34a,b, which could be
To extend the scope of this domino procedure for poly-
heterocyclic compounds, this method was applied to
b-halo aldehydes 21,10 2213 and 23.14 Substitution with
prenyl thiolate again gave the sul®des 24±26 (Fig. 5),
which were transformed with 5b, respectively to the tetra-
cyclic indole 27 and the tetracyclic thiazole regioisomers
29 and 30. In the case of the thiazole derivative 26 the
Knoevenagel adduct 28 was slow to cyclize in re¯uxing
acetonitrile and could be isolated. However 28 cyclized in
re¯uxing toluene to afford tetracyclic 29. Therefore, the
isomeric compound 30 was immediately prepared from 25
in re¯uxing toluene (Scheme 5).
1
separated by chromatography. The H NMR showed for
both compounds the typical values for the bridged protons
and the coupling constants of approximately 4 Hz for
coupling of proton Ha and Hb (Scheme 6).
Scheme 6. (i) 2 equiv. diallylamine, Et3N, THF, re¯ux, (ii) pyrazolone 5b, CH3CN, re¯ux, (iii) toluene, re¯ux.

E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
537
3. Experimental
3.3.2. Compound 2b. Light yellow powder from ethanol
(31%), mp: 78±798C; IR (KBr, cm21, 1600 FT) 1592 (w,
phenyl), 1681 (s, CO), 2973 (w, alkyl) and 3072 (w, phenyl);
1H NMR (400 MHz, CDCl3, d) 7.85±7.88 (d, 2H, ortho
N-phenyl), 7.61±7.63 (d, 2H, ortho), 7.43±7.55 (m, 6H,
meta and para phenyl and N-phenyl), 5.07 (t£m, 1H,
vinyl H), 3.37 (d, 2H, CH2), 1.62 (s, 3H, CH3) and 1.35
(s, 3H, CH3); 13C NMR (100 MHz, CDCl3, d) 17.3 and
25.6 (2£s, 2 CH3), 34.8 (S±CH2), 118.1 (CHv), 122.8
(C-4), 126.2, 128.3, 128.9, 129.0, 129.0 and 129.2 (ortho,
meta and para, phenyl and N-phenyl), 131.4 (C-1, phenyl),
138.6 (C(CH3)2), 138.6 (C-1, N-phenyl), 141.8 (C-5), 154.0
(C-2) and 186.0 (CHO); MS (m/z, %) 348 (M1z, 54), 315
(M1z2SH, 75), 280 (M1z2C5H8, 100), 251 (M1z2C5H8±
CHO, 26), 154 (34), 77 (C6H51, 52), 69 (C4H91, 94) and
3.1. General
Mps were determined using a Reichert Thermovar appa-
ratus. IR spectra were recorded on a Perkin±Elmer 1720
FT spectrometer, and NMR spectra on either a Bruker
AMX-400 or a Bruker WM-250 instrument. The NMR
spectra were measured with deuteriochloroform solutions
unless otherwise speci®ed. The J values are recorded in
Hz. Low resolution mass spectra were measured with a
Hewlett Packard 5989 A instrument, at 70 eV for EI spectra,
and with methane as reagent gas for CI spectra. The high
resolution mass spectra were recorded with a Kratos MS 50
TC machine. Cell constants and re¯ections were measured
with a Siemens P4±PC four-circle diffractometer (graphite
41(C H51, 72).
3
Ê
monochromator, l(Mo Ka)ˆ0.71073 A). Lattice para-
meters were obtained from least-squares of 25 re¯ections
(for 4d: 1 6,2u,218; for 18b: 23,2u,258) and 32 re¯ec-
tions (for 4a: 1 9,2u,258). The structures were solved by
direct methods and re®ned by full-matrix least-squares
on F2. Hydrogen atoms were re®ned in the riding mode
allowing the X±H distances to re®ne. Non-hydrogen
atoms were re®ned anisotropic; hydrogen atoms with U
1.2 times Ueq of the parent atom. The program package
SHELXTL-PC16 was used for all calculations and
PLATON17 for drawings.
3.3.3. Compound 14. Two equivalents of 4-bromo-2-methyl-
2-bytene, thiourea and sodiumhydroxide were used.
Chromatography with dichloormethane±n-hexane 4/1,
light yellow needles from n-hexane (45%), mp: 32.5±
33.58C; IR (KBr, cm21, 1600 FT) 1485 (s), 1515 (s, phenyl),
1680 (s, CO), 2911±2968 (w, alkyl) and 3029 (w, arom); 1H
NMR (400 MHz, CDCl3, d) 10.43 (s, 1H, CHO), 8.63 (s,1H,
3
H-2 pyrimidine), 5.34 (tr, 2H, CHv, Jˆ7.8 Hz), 3.88 (d,
3
4H, CH2, Jˆ7.8 Hz) and 1.74 (2£s, 2£6H, 4CH3); 13C
1
NMR (100 MHz, CDCl3, d) 17.6 (q£d, CH3, Jˆ126 Hz,
3Jˆ4 Hz), 25.4 (CH3, 1Jˆ126 Hz), 28.2 (CH2, 1Jˆ144 Hz),
2
1
137.4 (m, C(CH3)2, Jˆ6 Hz), 117.6 (tr£m, CHv, Jˆ
3.2. Synthesis
158 Hz, 2Jˆ6 Hz), 121.5 (d, C-5, 2Jˆ25 Hz), 156.4 (d,
1
3
C-2, Jˆ200 Hz), 172.4 (d, C-4 and C-6, Jˆ11 Hz) and
All the carbonyl compounds were produced by literature
methods (5a (Ref. 16), 5c,d (Ref. 6) and 5g (Ref. 10)) or
were commercially available (5b, 5e, 5f and 5h).
186.4 (d, CHO, Jˆ179 Hz); MS (m/z, %) 308 (M1z, 47),
1
239 (M1z2C5H9), 207 (38), 271(M 239 2C5H8, 57), 144
(22), 69 (C5H91, 99), 53 (17), 41 (100) and 39 (23).
3.3. General procedure for the synthesis of the aldehydes
2a, 2b, 14, 24, 25 and 26
3.3.4. Compound 24. Light red needles from ethanol
(30%), mp: 89.9±90.58C; IR (KBr, cm21, 1600 FT) 1594
(w, phenyl), 1658 (s, alkyl), 2961 (w, alkyl) and 3052 (w,
phenyl); 1H NMR (400 MHz, CDCl3, d) 10.29 (s, 1H,
CHO), 8.42 (d, 1H, H-4 indole), 7.60±7.55 (m, 3H, meta
and para N-phenyl), 7.43 (d, 2H, ortho N-phenyl), 7.30 (m,
1H, H-5 indole), 7.26 (m, 1H, H-6 indole), 7.12 d, 1H, H-7
indole) 5.05 (t£m, 1H, CHv), 3.14 (d, 2H, S±CH2) and
1.61 and 1.21 (2£s, 2£3H, 2CH3); 13C NMR (100 MHz,
CDCl3, d) 17.2 and 25.5 (2CH3), 35.3 (S±CH2), 110.8
(C-7, indole), 118.0 (CHv), 121.8 (C-3, indole), 121.7,
123.4, 124.8 (C-4, C-5, C-6, indole), 124.8 (C-3a), 128.5
(C-4, phenyl), 129.0 (C-2, phenyl), 129.4 (C-3, phenyl),
136.2 (C-1, phenyl), 138.5 (C(CH3)2), 139.0 (C-7a), 142.5
(C-2 indole) and 187.6 (CHO); MS (m/z, %) 321(M 1z, 43),
288 (M12SH, 50), 254 (M1z2C5H7), 253 (M1z2C5H8,
A solution of 4-bromo-2-methyl-2-butene (1mmol) and
thiourea (1mmol) in ethanol (10 ml) was re¯uxed for 1h.
After addition of sodiumhydroxide (2 mmol) in ethanol
(5 ml) re¯ux was continued for an additional hour and
then the appropriate carbaldehyde (0.7 mmol) was added.
The mixture was re¯uxed for half an hour, water (10 ml)
was added and the mixture extracted with dichloromethane
(3£50 ml). The combined extracts were dried over mag-
nesium sulfate, the solvent evaporated and the residue was
puri®ed by chromatography on silica gel with dichloro-
methane (unless otherwise speci®ed) as the eluent. Further
puri®cation was done by crystallization.
3.3.1. Compound 2a. Colorless needles from ethanol
(73%), mp: 71±728C; IR (KBr, cm21, 1600 FT) 1675 (s,
CO); H NMR (400 MHz, CDCl3, d) 10.02 (s, 1H, CHO),
100), 252 (M1z2C5H9, 82), 224 (M1z2C5H9S, 34), 233
(M1z2C5H92CHO, 41), 69 (C4H91, 53) and 41(C H5
51).
,
1
1
3
7.58 (d, 2H, ortho phenyl), 7.51and 7.45 (2 £t, 2H and 1H,
meta and para phenyl), 5.03 (t£m, 1H, CHv), 3.18 (d, 2H,
S±CH2), 2.56 (s, 3H, CH3 pyrazole) and 1.60 and 1.24 (2£s,
2£3H, CH3); 13C NMR (100 MHz, CDCl3, d) 13.6 (CH3,
pyrazole), 17.2 and 25.6 (2£CH3), 34.7 (S±CH2), 117.8
(CHv), 124.4 (C-4), 125.8, 128.7, 128.9 (C-2, C-3, C-4,
phenyl), 138.4 (C-1, phenyl), 138.6 (C(CH3)2), 140.8 (C-5),
151.3 (C-3) and 186.7 (CHO); MS (m/z, %) 286 (M1z, 5),
253 (M1z2SH, 14), 218 (M1z2C5H8, 33), 77 (C6H51, 27)
and 69 (C5H91, 100).
3.3.5. Compound 25. Previous to the addition of the appro-
priate thiazolecarbaldehyde, the mixture was cooled to
room temperature. After the addition of the carbaldehyde,
the mixture was re¯uxed for 1h. A dark red oil was formed
after chromatography with dichloromethane (79%); IR
(CCl4, cm21, 1600 FT) 1549 (s, phenyl), 1664 (m, CO),
2856 (w, alkyl), 2923 (alkyl) and 3036 (arom H); 1H NMR
(400 MHz, CDCl3, d) 10.03 (s, 1H, CHO), 8.02±7.99 (d£m,

538
E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
2
3
2H, ortho phenyl), 7.52±7.44 (m, 3H, meta and para
CHvCH2 cis, Jgemˆ1.3 Hz, Jcisˆ10.4 Hz), 5.21 (d£d,
3
4
3
phenyl), 5.39 (t, 1H, CHv, Jˆ7.9 Hz, Jˆ1.4 Hz), 4.00
4H, CHvCH2 trans, Jtransˆ16.8 Hz) and 4.22 (d£d,
3
(d, 2H, CH2, Jˆ8 Hz), 1.73 (s, 3H, CH3) and 1.69 (s, 3H,
4H, 3Jˆ5.8 Hz); 13C NMR (100 MHz, CDCl3, d) 52.8
(N±CH2), 97.1 (C-5), 118.2 (vCH2), 133.4 (CHv), 158.4
(C-2), 165.5 (C-4) and 181.9 (CO); MS (m/z, %) 297.
(M1z2H, 6).
CH3); 13C NMR (100 MHz, CDCl3, d) 17.8 (CH3), 25.7
(CH3), 31.4 (CH2), 118.9 (CHv), 127.1 (C-2, phenyl),
129.1 (C-3, phenyl), 130.7 (C-5), 131.9 (C-4, phenyl),
132.4 (C-1, phenyl), 137.6 (C(CH3)2), 160.8 (C-4), 173.5
(C-2) and 181.4 (CHO); MS (m/z, %) 289 (M1z, 49), 256
(100), 221 (M1z2C5H8, 41), 193 (M1z2C5H82CO, 64), 69
3.4.3. Compound 32. Two equivalents of diallylamine and
triethylamine were used. The mixture was re¯uxed for 6 h.
Chromatography with dichloromethane±diethyl ether 5/1
gives a yellow oil (73%); IR (CCl4, cm21, 1600 FT) 1525
(s, phenyl), 1548 (s, phenyl), 1657 (s, CHO), 2931 (w, aliph
H) and 3081(w, pyridine H); 1H NMR (400 MHz, CDCl3,
d) 9.67 (s, 2H, 2 CHO), 8.32 (s, 1H, pyridine H), 5.92±5.86
(m, 4H, CHv), 5.24±5.17 (2d£d, 8H, CHvCH2) and 4.16±
4.14 (d, 8H, N±CH2); 13C NMR (100 MHz, CDCl3, d) 52.8
(d, N±CH2, 1Jˆ138 Hz), 110.6 (d, C-3 pyridine, 2Jˆ25 Hz),
(C5H91, 64) and 41(C H51, 40); HRMS (m/z) calcd for
3
C15H15NOS2 289.0595, found 289.0597.
3.3.6. Compound 26. Previous to the addition of the appro-
priate thiazolecarbaldehyde, the mixture was cooled to
room temperature. After the addition of the carbaldehyde,
the mixture was re¯uxed for 1h. Chromatography with
dichloromethane±diethyl ether 20/1gives a yellow oil
(72%); IR (KBr, cm21, 1600 FT) 1551 (s, phenyl), 1680(s,
CO), 2835 (w), 2916 (w), 2977 (w, alkyl) and 3068 (w, arom
1
1
118.0 (t, CHvCH2, Jˆ154 Hz), 133.3 (d, CHvCH2, Jˆ
1
3
156 Hz), 152.5 (d£t, C-4 pyridine, Jˆ157 Hz, Jˆ3 Hz)
1
1
H); H NMR (400 MHz, CDCl3, d) 10.13 (s, 1H, CHO),
7.92±7.89 (m, 2H, ortho phenyl), 7.46±7.44 (m, 3H, meta
and 186.2 (d, CHO, Jˆ173 Hz); MS (m/z, %) 325 (M1z,
13); HRMS (m/z) calcd for C19H23N3O2 325.1790, found
325.1785.
3
4
and para phenyl), 5.36 (t£m, 1H, CHv, Jˆ7.8 Hz, Jˆ
3
0.7 Hz), 3.68 (d, 2H, CH2, Jˆ7.8 Hz), 1.76 (d, 3H, CH3,
4
4Jˆ0.7 Hz) and 1.68 (d, 3H, CH3, Jˆ0.7 Hz); 13C NMR
3.5. General procedure for the synthesis of the polycyclic
compounds
(100 MHz, CDCl3, d) 17.9 (CH3), 25.7 (CH3), 35.6 (CH2),
117.2 (CHv), 126.4 (C-2, phenyl), 129.1 (C-3, phenyl),
130.6 (C-4, phenyl), 132.7 (C-1, phenyl), 139.8 (C(CH3)2),
147.3 (C-4), 149.5 (C-5), 165.3 (C-2) and 184.6 (CO); MS
A solution of aldehyde (2.1mmol), carbonyl compound
(2.0 mmol) and ethylenediammonium diacetate in aceto-
nitrile (100 ml) was left for 30 min at room temperature.
The yellow±orange color reveals the presence of the
Knoevenagel condensation product. This mixture was then
re¯uxed for several hours (indicated for each compound).
Evaporation of the solvent leaves a residue, which was
chromatographed on silica gel with a mixture of dichloro-
methane±diethyl ether (unless otherwise speci®ed) as the
eluent to give the ring closed compound. Further puri®-
cation was done by crystallization.
(m/z, %) 289 (M1z, 27), 256 (44), 221(M 1z2C5H8, 100),
193 (M1z2C5H8±CO, 69), 69 (C5H91, 91) and 41 (C3H5
43).
,
1
3.4. General procedure for the synthesis of the diallylic
compounds 15, 16and 32
A solution of the appropriate aldehyde (1mmol), diallyl-
amine (1mmol) and triethylamine (1mmol) in tetrahydro-
furan (25 ml) was re¯uxed. After cooling the mixture to
room temperature, the precipitate was ®ltered and the ®ltrate
evaporated. Puri®cation was carried out by chromatography
on silica gel with dichloromethane±diethyl ether as the
eluent.
3.5.1. Compound 4a. Re¯ux of compound 2a with pyrazo-
lone 5a for 36 h. Chromatography with dichloromethane±
diethyl ether 5/1. White small needles from chloroform±
diethyl ether (81%), mp: 2378C; IR (KBr, cm21, 1720 FT)
1502 (s, phenyl), 1592 (s, phenyl), 1701 (s, CO), 2985 (w,
alkyl) and 3043 (w, phenyl); 1H NMR (400 MHz, CDCl3, d)
7.77±7.58 (2 d, 4H, ortho phenyl), 7.45±7.39 (m, 4H, meta
phenyl), 7.37 (s, 1H, H-3 pyrazole, 7.29±7.24 (2t, 2H, para
3.4.1. Compound 15. The mixture was re¯uxed for 3 h.
Chromatography with dichloromethane±diethyl ether 20/1
(67%), mp: 47.58C; IR (KBr, cm21, 1600 FT) 1681 (s CO),
2932 (w, alkyl) and 3062 (w, arom H); 1H NMR (400 MHz,
CDCl3, d) 10.28 (s, 1H, CHO), 8.37 (s, 1H, pyrimidine H),
5.75 (d£d£tr, 2H, CHv), 5.26 (d£d, 2H, CHvCH2 cis,
3
phenyl), 4.19 (br d, 1H, Ha Jaeˆ3.9 Hz), 3.00 (d£d£d, 1H,
3
3
2
Hc, Jaeˆ2.4 Hz), 2.88 (d£d, 1H, Hd, Jaaˆ12.6 Hz, Jgem
ˆ
12.5 Hz), 2.51 (s, 3H, CH3 pyrazole), 2.09 (d£d£d, 1H, Hb)
and 1.79 and 1.58 (2s, 2£3H, 2CH3); 13C NMR (100 MHz,
3
2Jgemˆ1.3 Hz, Jcisˆ10.3 Hz), 5.19 (d£d, 2H, CHvCH2
3
2
CDCl3, d) 12.8 (CH3 pyrazole), 24.1(S±CH ), 25.9 (Cb),
2
trans, Jtransˆ16.9 Hz) and 4.15 (d£d, 4H, Jgemˆ1.3 Hz,
3Jˆ4.7 Hz); 13C NMR (100 MHz, CDCl3, d) 53.0 (N±
CH2), 110.7 (C-5), 119.3 (vCH2), 131.7 (CHv), 157.5
(C-2), 160.4 (C-6), 163.8 (C-4) and 187.2 (CO); MS (m/z,
%) 238 (M1z1H, 2).
26.1and 26.7 (2CH ), 40.7 (Ca), 82.2 (O±C(CH3)2), 99.4
3
(Ca±C±CH), 115.3 (Ca±C±CCH3), 120.5 and 122.6 (2C-2,
phenyl), 125.9 and 127.0 (2C-4, phenyl), 129.0 and 129.2
(2C-3, phenyl), 130.4 (N±C±S), 138.5 (C±H pyrazole),
138.8 and 139.7 (2C-1, phenyl), 147.1 (N±C±O)
and 148.3 (C±CH3 pyrazole); MS (m/z, %) 428 (M1z, 1 3),
360 (M1z2C5H8, 11), 327 (M1z2C5H9S, 100), 225 (M1z
1-phenyl-5(4H)-pyrazolon-propane, 24), 128 (C6H5±NuC±
3.4.2. Compound 16. Two equivalents of diallylamine and
triethylamine were used. The mixture was re¯uxed for 24 h.
Chromatography with dichloromethane±diethyl ether 10/1
gives a yellow oil (44%); IR (CCl4, cm21, 1600 FT) 1680 (s
1
1
CuCH1, 11), 77 (C6H5 , 48), 69 (C5H9 , 30) and 41
(CH3CN1z, 41); HRMS (m/z) calcd for C25H24N4OS
428.1671, found 428.1673; X-ray structural analysis:
C25H24N4OS, MWˆ428.55, a white transparent crystal of
1
CO), 2945 (w, alkyl) and 3055 (w, arom H); H NMR
(400 MHz, CDCl3, d) 9.44 (s, 1H, CHO), 8.08 (s, 1H, pyri-
midine H), 5.89 (d£d£tr, 4H, CHv), 5.25 (d£d, 4H,

E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
539
0.4£0.3£0.2 mm3 size, space group P-1, Zˆ2, triclinic,
(s, phenyl), 1595 (s, phenyl), 2981 (w, alkyl) and 3066 (w,
phenyl); 1H NMR (400 MHz, CDCl3, d) 7.77±7.59 (2 d, 4H,
ortho phenyl), 7.48±7.40 (m, 4H, meta phenyl), 7.35±7.25
Ê
aˆ9.952(1), bˆ10.245(1), cˆ11.852(2) A, aˆ104.55(1),
Ê 3
bˆ94.89(1),
gˆ92.40(1)8,
Vˆ1162.9(4) A ,
dcalcˆ
1.224 g cm23, F(000)ˆ452, Tˆ289 K, v-scan, Dvˆ0.608,
2.0,v,60.08 min21, 3435 collected re¯ections ((sin u/
l)maxˆ0.53), 2830 unique re¯ections (Rintˆ2.5%). Final
R-values: R1ˆ0.0850 for 2414 re¯ections with I.2s(I) and
R1ˆ0.0942, wR2ˆ 0.2955 for all re¯ections. The asymmetric
unit contains a water molecule forming an in®nite water chain
through the crystal.
(2£t, 2H, para phenyl), 4.32 (br d, 1H, Ha, Jaeˆ4.0 Hz),
3
3
3.04 (d£d£d, 1H, Hc, Jaeˆ2.4 Hz), 2.98 (d£d, 1H, Hd,
2
3Jaaˆ12.7 Hz, Jgemˆ12.8 Hz), 2.40 (s, 3H, CH3 pyrazole),
2.05 (d£t, 1H, Hb) and 1.61 and 1.59 (2£s, 2£3H, 2CH3);
13C NMR (100 MHz, CDCl3, d) 15.3 (CH3 pyrazole), 23.7
(S±CH2), 26.3 (Cb), 26.7 (2 CH3), 40.7 (Ca), 82.8
(O±C(CH3)2), 96.7 (Ca±C±CCF3), 113.6 (Ca±C±CCH3),
121.0 (CF3), 121.6 and 122.5 (2C-2, phenyl), 126.9 and
127.2 (2C-4, phenyl), 129.1 and 129.2 (2C-3, phenyl),
130.6 (N±C±S), 137.8 and 139.7 (2C-1, phenyl), 138.5
(C±CF3), 148.7 (N±C±O) and 149.1 (C±CH3 pyrazole);
MS (m/z, %) 496 (M1z, 13), 395 (M1z2C5H9S, 66), 359
(M1z2CF32C5H8, 20), 225 (M1z21-phenyl-tri¯uoro-
methyl-5(4H)-pyrazolon-propane, 28), 128 (C6H5±NuC±
CuCH1, 14), 77 (C6H51, 88), 69 (C5H91, 100) and 41
(CH3CN1, 77); X-ray structural analysis: C26H23F3N4OS,
MWˆ496.54, a white transparent crystal of 0.4£0.4£
3.5.2. Compound 4b. Re¯ux of compound 2a with pyrazo-
lone 5b for 36 h. Product 4b precipitated from the mixture.
Yellow±white powder from diethyl ether (87%), mp:
2198C; IR (KBr, cm21, 1600 FT) 1514 (s, phenyl), 1594
(s, phenyl), 2958 (m, alkyl) and 3058 (w, phenyl); 1H
NMR (400 MHz, CDCl3, d) 7.74±7.63 (2 d, 4H, ortho
phenyl), 7.46±7.38 (m, 4H, meta phenyl), 7.30±7.21(2t,
3
2H, para phenyl), 4.21(br d, 1H, H a, Jaeˆ4.0 Hz), 3.07
3
2
(d£d, 1H, Hd, Jaaˆ12.5 Hz, Jgemˆ12.4 Hz), 2.98 (d£d£d,
1H, Hc, 3Jaeˆ2.3 Hz), 2.46 (s, 3H, CH3), 2.12 (s, 3H, CH3),
1.95 (d£t, 1H, Hb), 1.63 and 1.56 (2 s, 2£3H, 2CH3); 13C
NMR (100 MHz, CDCl3, d) 12.6 and 13.7 (2CH3 pyrazole),
0.4 mm3 size, space group R-3, Zˆ18, hexagonal, aˆ
3
Ê
Ê
30.749(4), cˆ14.487(3) A, Vˆ11862(3) A , dcalc
ˆ
1.251 g cm23, F(000)ˆ4644, Tˆ289 K, v-scan, Dvˆ
0.608, 3.0,v,60.08 min21, 3990 collected re¯ections
((sin u/l)maxˆ0.53), 3189 unique re¯ections (Rintˆ
3.3%). Final R-values: R1ˆ0.0852 for 2322 re¯ections
with I.2s(I) and R1ˆ0.1113, wR2ˆ0.2834 for all
re¯ections.
23.2 (S±CH2), 26.4 (Cb), 26.4 and 26.6 (2CH3), 40.1(C ),
a
81.6 (O±C(CH3)2), 96.6 (Ca±C±CCH3 furanring), 113.0
(Ca±C±CCH3), 120.4 and 122.4 (2C-2, phenyl), 125.4 and
126.9 (2C-4, phenyl), 128.9 and 129.2 (2C-3, phenyl), 130.7
(N±C±S), 138.7 and 139.8 (2C-1, phenyl), 147.0 and 147.6
(2C±CH3 pyrazole), 148.9 (N±C±O); MS (m/z, %) 442
(M1z, 8), 341(M 1z2C5H9S, 100), 225 (M1z23-methyl-1-
phenyl-5(4H)-pyrazolon-propane, 35), 128 (C6H5±NuC±
CuCH1, 18) and 77 (C6H51, 52); HRMS (m/z) calcd for
C26H26N4OS 442.1827, found 442.1830.
3.5.5. Compound 4e. Re¯ux of compound 2b with pyrazo-
lone 5b for 30 h. Chromatography with dichloromethane±
diethyl ether 10/1. White powder from ethanol (83%), mp:
250.18C; IR (CCl4, cm21, 1600 FT) 2961 (w, alkyl) and
1
3065 (w, phenyl); H NMR (400 MHz, CDCl3, d) 7.97±
7.95 (d£t, 2H, meta phenyl), 7.76±7.71(2 d £t, 4H, meta
3.5.3. Compound 4c. Re¯ux of compound 2a with pyrazo-
lone 5c for 36 h. Chromatography with dichloromethane±
diethyl ether 8/1. White powder from chloroform±diethyl
ether (87%), mp: 221.58C; IR (KBr, cm21, 1600 FT) 1503
(s, phenyl), 1515 (s, phenyl), 1599 (m, phenyl), 2979 (w,
alkyl) and 3063 (w, phenyl); 1H NMR (400 MHz, CDCl3, d)
7.90±7.70 (2d, 4H, ortho phenyl), 7.55±7.10 (m, 11H,
phenyl), 7.50±7.34 (m, 8H, ortho and para phenyl), 7.23±
3
7.20 (t£t, 1H, para phenyl), 4.74 (d, 1H, Ha, Jaeˆ3.6 Hz),
3
2
3.08 (d£d, 1H, Hd, Jaaˆ12.7 Hz, Jgemˆ11.8 Hz), 3.03
3
(d£d, H, Hc, Jaeˆ2.8 Hz), 2.04 (d£t, 1H, Hb), 1.88 (s, 3H,
CH3), 1.65 and 1.61 (2s, 2£3H, 2CH3); 13C NMR (100 MHz,
CDCl3, d) 13.9 (CH3 pyrazole), 23.0 (S±CH2), 26.6 and
26.8 (2CH3), 27.5 (Cb), 40.2 (Ca), 81.8 (O±C(CH3)2), 96.4
(Ca±C±CCH3), 112.1 (Ca±C±C phenyl), 120.4, 121.1,
123.0, 125.5, 127.2, 127.4, 128.0, 128.8 and 128.9 (phenyl),
129.2 (C-1, phenyl), 131.6 (N±C±S), 138.6 and 139.7
(2C-1, phenyl), 147.5 and 147.8 (C±CH3 and C-phenyl),
150.6 (N±C±O); MS (m/z, %) 504 (M1z, 36), 403
(M1z2C5H9S, 100), 287 (M1z21,3-diphenyl-5(4H)-pyrazo-
lon-propane, 24), 128 (C6H5±NuC±CuCH1, 12), 77
(C6H51, 25), 69 (C5H91, 16), 49 ((12) and 41 (CH3CN1,
21); HRMS (m/z) calcd for C31H28N4OS 504.1984, found
504.1989.
3
phenyl), 4.19 (d, 1H, Ha, Jaeˆ3.9 Hz), 3.24 (d£d, 1H, Hd,
2
3
3Jaaˆ12.5 Hz, Jgemˆ12.6 Hz), 3.08 (d£d, 1H, Hc, Jaeˆ
2.3 Hz), 2.02 (d£t, 1H, Hb), 1.68 and 1.60 (2s, 2£3H,
2CH3) and 1.40 (s, 3H, CH3 pyrazole); 13C NMR (100
MHz, CDCl3, d) 10.8 (CH3 pyrazole), 24.1(S±CH ), 26.3
2
and 26.9 (2CH3), 27.0 (Cb), 40.8 (Ca), 81.9 (O±C(CH3)2),
96.8 (Ca±C±C phenyl), 114.8 (Ca±C±CCH3), 120.9, 122.5,
125.8, 126.8, 127.8, 128.1, 128.9, 129.2, and 129.7 (C-2,
C-3 and C-4, phenyl), 130.2 (N±C±S), 138.5 (C±H
pyrazole), 134.1, 138.7 and 139.9 (C-1, phenyl),
147.7 (C±CH3 pyrazole) and 150.2 and 150.3 (C-phenyl
pyrazole and N±C±O); MS (m/z, %) 504 (M1z, 8), 403
(M1z2C5H9S, 68), 225 (M1z21,3-diphenyl-5(4H)-pyrazo-
lon-propane, 42), 128 (C6H5±NuC±CuCH1, 30), 77
(C6H51, 91), 69 (C5H91, 66) and 41(CH 3CN1z, 100);
HRMS (m/z) calcd for C31H28N4OS 504.1984, found
504.1978.
3.5.6. Compound 4f. Re¯ux of compound 2b with pyrazo-
lone 5c for 72 h. Chromatography with dichloromethane±
diethyl ether 20/1. White powder from ethanol (32%), mp:
127.88C; IR (KBr, cm21 1600 FT) 1500 (m, phenyl), 1596
1
(m, phenyl), 2981(w, alkyl) and 3058 (w, phenyl); H NMR
(400 MHz, CDCl3, d) 7.87±7.85 and 7.74±7.72 (d£d, 4H,
ortho N-phenyl), 7.51±7.35 (m, 7H, phenyl), 7.23 (t£t, 1H,
para phenyl), 7.17±7.15 (m, 3H, phenyl), 6.98±6.95 (m,
3.5.4. Compound 4d. Re¯ux of compound 2a with pyrazo-
lone 5d for 36 h. Chromatography with dichloromethane±
diethyl ether 10/1. White powder from chloroform±diethyl
ether (83%), mp: 141.58C; IR (KBr, cm21, 1600 FT) 1504
3
5H, phenyl), 4.64 (d, 1H, Ha, Jaeˆ3.3 Hz), 3.29 (d£d, 1H,
Hd, 3Jaaˆ12.1 Hz, 2Jgemˆ12.1 Hz), 3.11 (d£d, 1H, Hc, 3Jaeˆ

540
E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
3.2 Hz), 2.05 (d£t, 1H, Hb), 1.65 and 1.60 (2s, 2£3H,
2CH3); 13C NMR (100 MHz, CDCl3, d) 23.3 (S±CH2),
26.4 and 27.1(2CH 3), 27.5 (Cb), 40.3 (Ca), 81.8
(O±C(CH3)2), 96.1(C a±C±C phenyl), 113.9 (Ca±C±C
phenyl), 120.6, 122.7, 125.7, 126.8, 127.1, 127.2, 127.5,
127.7, 128.7, 129.1 and 129.2 (phenyl), 133.6 (N±C±S),
130.8 and 132.2 (2C-1, phenyl), 138.5 and 139.7 (C-1,
N-phenyl), 147.9 (N±C±O), 150.9 and 151.4 (2C-phenyl
pyrazole); MS (m/z, %) 566 (M1z, 29), 465 (M1z2C5H9S,
100), 287 (M1z21,3-diphenyl-5(4H)-pyrazolon-propane,
(CH3CN1, 68) and 39 (C3H31, 14); HRMS (m/z) calcd for
C25H23N3O2S 429.1511, found 429.1506.
3.5.9. Compound 8a,b. The polycyclic compound 7
(300 mg, 0.7 mmol) was re¯uxed for 5 days in acetonitrile
or 3 days in toluene. The two formed compounds were
separated by chromatography on silica gel with dichloro-
methane as the eluent.
8a: crystallisation from chloroform±diethylether (43%),
mp: 2658C; IR (KBr, cm21, 1600 FT) 1502 (s, phenyl),
1598 (m, phenyl), 1722 (s, CO), 2933 (w, alkyl), 2980 (m,
alkyl) and 3052 (w, phenyl); 1H NMR (400 MHz, CDCl3, d)
7.87, 7.65 and 7.58 (m, 5H, ortho, para and meta phenyl on
azirine), 7.56, 7.42 and 7.29 (m, 5H, ortho, meta and para
28), 128 (C6H5±NuC±CuCH1, 24), 91(C H5N1, 90),
6
77 (C6H51, 51), 69 (C5H91, 30), 51(C 4H31, 23), 49
(C4H1, 40) and 41(CH CN1, 47); HRMS (m/z) calcd for
C36H30N4OS 566.2140, found 566.2148.
3
3
4
3.5.7. Compound 6. Re¯ux of compound 2a with barbituric
acid 5e for 36 h. Chromatography with dichloromethane±
diethyl ether 10/1. Yellow powder from chloroform±diethyl
ether (70%), mp: 1908C; IR (KBr, cm21, 1600 FT) 1610 (m,
phenyl), 1648 (m, CO), 1704 (m, CO) and 2982 (w, alkyl);
1H NMR (400 MHz, CDCl3, d) 7.59 (d, 2H, ortho phenyl),
7.40 (t, 2H, meta phenyl), 7.25 (t, 1H, para phenyl), 4.44 (d,
phenyl on pyrazole), 4.1(d £d, 1H, Ha, Jaeˆ3.8 Hz, Jeeˆ
1.4 Hz), 3.66 (t, 1H, Hd, 3Jaaˆ12.9 Hz, 2Jgemˆ12.2 Hz), 3.26
(d£d, 1H, Hc, 3Jaeˆ2.5 Hz), 2.41(d £d£d, 1H, Hb), 1.88 and
1.68 (2s, 2£3H, 2CH3) and 1.60 (s, 3H, CH3 pyrazole); 13
C
NMR (100 MHz, CDCl3, d) 12.1 (CH3 pyrazole), 23.6
(S±CH2), 27.4 and 29.1(2CH ), 30.9 (Ca), 37.1(C ±C±
3
a
CO), 42.4 (Cb), 81.6 (O±C(CH3)2), 109.6 (Ca±C±C±CH3),
121.9, 129.6, 130.3 and 134.1 (C-1, C-3, C-2 and C-4
phenyl on azirine), 122.6, 127.0, 129.1 and 139.5 (C-2,
C-4, C-3 and C-1 phenyl), 131.8 (N±C±S), 148.4 (C±CH3
pyrazole) 155.1 (NvC) and 171.0 (CO); MS (m/z, %) 429
(M1z, 11), 361 (M1z2C5H8, 26), 258 (M1z2C5H8±C6H5CN,
21), 228 (17), 105 (C6H5N21, 100), 77 (C6H51, 39), 69
(C5H91, 37), 51(C 4H31, 11) and 41 (CH3CN1, 29);
HRMS (m/z) calcd for C25H23N3O2S 429.1511, found
429.1518.
3
1H, Ha, Jaeˆ4.0 Hz), 3.36 (s, 3H, N±CH3), 3.31(s, 3H,
3
N±CH3), 3.04 (d£d£d, 1H, Hc, Jaeˆ2.4 Hz), 2.92 (d£d,
3
2
1H, Hd, Jaaˆ12.5 Hz, Jgemˆ12.6 Hz), 2.43 (s, 3H, CH3
pyrazole), 2.12 (d£t, 1H, Hb) and 1.54 (s, 6H, 2CH3); 13C
NMR (100 MHz, CDCl3, d) 13.2 (CH3 pyrazole), 24.6
(S±CH2), 25.4 (Cb), 27.0 and 27.3 (2CH3), 28.0 and 28.8
(2N±CH3), 40.7 (Ca), 82.2 (O±C(CH3)2), 87.4 (Ca±C±CO),
113.9 (Ca±C±CCH3), 122.4 (C-2, phenyl), 126.5 (C-4,
phenyl), 129.0 (C-3, phenyl), 130.1 (N±C±S), 139.7 (C-1,
phenyl), 150.9 and 151.0 (H3CN±C±O and C±CH3
pyrazole), 154.3 (CO) and 162.1 (N±CO±N); MS (m/z,
%) 424 (M1z, 12), 323 (M1z2C5H9S, 47), 269 (M1z2
C6H7N2O3, 14), 266 (M1z2C6H8N2O3, 16), 235 (M1z2
C6H7N2O3±SH, 16), 128 (C6H5±NuC±CuCH1, 18), 77
(C6H51, 35), 69 (C5H91, 73), 51(C 4H31, 13), 41
(CH3CN1, 100) and 39 (C3H31, 14); HRMS (m/z) calcd
for C22H25N4O3S 424.1569, found 424.1573.
8b: crystallisation from chloroform±diethylether (50%),
mp: 219.58C; IR (KBr, cm21 1600 FT) 1501 (m, phenyl),
1596 (w, phenyl), 1715 (s, CO), 2937 (w, alkyl), 2978 (w,
alkyl) and 3049 (w, phenyl); 1H NMR (400 MHz, CDCl3, d)
7.56, 7.48 and 7.38 (5H, ortho, para and meta phenyl on
azirine), 7.38, 7.28 and 7.23 (meta, para and ortho phenyl
on pyrazole), 3.93 (d£d, 1H, Ha, 3Jaeˆ4.3 Hz, 4Jeeˆ1.1 Hz),
3
2
3.47 (t, 1H, Hd, Jaaˆ12.0 Hz, Jgemˆ13.3 Hz), 3.36 (d£d,
3
3.5.8. Compound 7. Re¯ux of compound 2a with isoxazo-
lone 5f for 36 h. The white precipitate was puri®ed by
crystallization from acetonitrile (84%), mp: 2218C; IR
(KBr, cm21, 1600 FT) 1504 (m, phenyl), 1600 (m, phenyl),
2981(w, alkyl) and 3058 (w, phenyl); 1H NMR (400 MHz,
CDCl3, d) 7.62 (d£8.7 Hz, 2H, ortho phenyl (isoxazole),
3Jˆ), 7.47 (t, 2H, meta phenyl (pyrazole)), 7.33 (t£t, 1H,
para phenyl (pyrazole)), 7.32 (t£t, 1H, para phenyl (isoxa-
zole)), 7.25 (t, 2H, meta phenyl (isoxazole), 7.04 (d, 2H,
1H, Hc, Jaeˆ3.0 Hz), 2.43 (d£d£d, 1H, Hb), 2.02 (s, 3H,
CH3 pyrazole), 1.92 and 1.68 (2s, 2£3H, 2 CH3); 13C NMR
(100 MHz, CDCl3, d) 12.2 (CH3 pyrazole), 24.1(S±CH ),
2
27.3 and 29.0 (2CH3), 30.9 (Ca), 40.5 (Ca±C±CO), 42.0
(Cb), 81.6 (O±C(CH3)2), 111.4 (Ca±C±C±CH3), 121.6,
129.1, 129.3 and 133.5 (C-1, C-3, C-2 and C-4 phenyl on
azirine), 122.9, 127.4, 129.1 and 139.2 (C-2, C-4, C-3 and
C-1phenyl), 219.8 (N± C±S), 148.7 (C±CH3 pyrazole)
159.2 (NvC) and 170.9 (CO); MS (m/z, %) 429 (M1z, 7),
401(M 1z2C2H41, 13), 361 (M1z2C5H8, 47), 258 (M1z2
C5H8±C6H5CN, 37), 257 (M1z2C5H9±C6H5CN, 13), 228
(32), 227 (21), 128 (C6H5±NuC±CuCH1, 14), 105
(C6H5N21, 100), 77 (C6H51, 57), 69 (C5H91, 53), 51
(C4H31, 17) and 41 (CH3CN1, 38); HRMS (m/z) calcd for
C25H23N3O2S 429.1511, found 429.1512.
ortho phenyl (pyrazole), 3Jˆ7.1Hz), 4.08 (d, 1H, H , 3Jaeˆ
a
3
4 Hz), 3.10 (d, 2H, Hd and Hc, Jˆ7.6 Hz), 2.05 (t£d, 1H,
Hb), 1.67 and 1.57 (2s, 2£3H, 2CH3) and 1.35 (s, 3H, CH3
pyrazole); 13C NMR (100 MHz, CDCl3, d) 10.7 (CH3
pyrazole), 23.5 (S±CH2), 25.9 and 26.0 (2CH3), 26.8 (Cb),
40.5 (Ca), 84.2 (O±C(CH3)2), 87.9 (Ca±C±C phenyl), 113.0
(Ca±C±C±CH3), 122.5 (2C-2, phenyl), 127.0 and 129.4
(2C-4, phenyl), 128.1 and 129.2 (2C-3, phenyl), 129.5
(C-1, phenyl isoxazole), 130.3 (N±C±S), 139.7 (C-1,
phenyl pyrazole), 150.0 (C±CH3 pyrazole), 164.5 (C-phenyl)
and 167.3 (O±C±O); MS (m/z, %) 429 (M1z, 38), 414
(M1z2CH3, 11), 361 (M1z2C5H8, 33), 316 (38), 128
(C6H5±NuC±CuCH1, 13), 105 (C6H5N21, 100), 77
(C6H51, 78), 69 (C5H91, 55), 51(C 4H31, 26), 41
3.5.10. Compound 9a. Reaction of compound 2a with indo-
lone 5g, re¯ux for 30 h. Chromatography with dichloro-
methane afforded the Knoevenagel adduct 9a as a yellow
oil (74%); IR (CCl4, cm21 1600 FT) 1549 (s, phenyl), 1718
1
(m, CO), 2929 (w, alkyl) and 3063 (w, phenyl); H NMR
(400 MHz, CDCl3, d) 7.83 (s, 1H, imine), 7.70±7.61 and
7.58±7.35 (2 m, 10 H, phenyl on pyrazole and phenyl on

E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
541
indole), 7.27 (d, 1H, H-7 indole), 7.17 (t, 1H, H-6 indole),
6.99 (t, 1H, H-5 indole), 6.58 (d, 1H, H-4 indole), 4.96 (t,
(C-4 pyrimidine); MS (m/z, %) 464 (M1z, 19) and 395
(M1z2C5H9, 100); HRMS (m/z) calcd for C25H28N4OS2
464.1705, found 464.1705.
3
1H, CHv), 3.13 (d, 2H, S±CH2, Jˆ7.9 Hz), 2.32 (s, 3H,
CH3 pyrazole) and 1.52 and 1.31 (2s, 2£3H, 2CH3); 13C
NMR (100 MHz, CDCl3, d) 13.7 (CH3 pyrazole), 17.3 and
25.5 (2CH3), 34.3 (CH2), 109.3 (C-7 indole), 118.4
(CH2±Cv), 121.7 (C-4 pyrazole), 122.3, 123.4 and 125.3
(C-4, C-5 and C-6 indole), 126.5 (C-3a indole), 127.8,
128.0, 128.6, 128.7, 129.3, 129.4, 129.7 and 134.6 (phenyl),
128.1 (C-3 indole), 129.5 (C imine), 137.5 (C(CH3)), 139.2
(C-5 pyrazole), 143.7 (C-7a indole) 148.5 (C-3 pyrazole)
and 167.3 (C-2 indole); MS (m/z, %) 477 (M1z, 25), 376
3.5.13. Compound 18a,b. Reaction of compound 14 with
isoxazolone 5f, re¯ux for 60 h. Chromatography with
dichloromethane±n-hexane afforded two azirine com-
pounds 19a,b.
18a: crystallization from methanol (52%), mp: 178.38C; IR
(KBr, cm21, 1600 FT) 1504 (m, phenyl), 1525 (s, phenyl),
1720 (s, vO), 1766 (W), 2922 (w, aliph H), 2984 (w, aliph
H), 3070 (w, arom H); 1H NMR (400 MHz, CDCl3, d) 8.22
(s, 1H, H pyr), 7.66 (d, 2H, ortho phenyl), 7.5 (tr, 1H, para
phenyl), 7.42 (tr, 2H, meta phenyl), 5.29 (tr,1H, CHv), 4.28
(M1z2C5H8S, 100), 408 (M1z2C5H91, 23), 393 (M1z2
1
C5H91±CH3, 18), 204 (22), 77 (C6H51, 22), 69 (C5H9
,
31) and 41 (CH3CN1, 31).
3
4
(d£d, 1H, Ha, Jaeˆ3.8 Hz, Jaaˆ1.7 Hz), 3.82/3.74 (d£m,
3
3.5.11. Compound 9b. Reaction of compound 2a with
coumaranone 5h, re¯ux for 24 h. Chromatography with
dichloromethane afforded the Knoevenagel adduct 9b as a
yellow oil (67%); IR (CCl4, cm21 1600 FT) 1548 (s,
phenyl), 1793 (s, CO), 2930 (w, alkyl), 2976 (w, alkyl)
and 3064 (w, phenyl); 1H NMR (400 MHz, CDCl3, d)
7.79 (s, 1H, imine), 7.69±7.67 (d, 2H, ortho phenyl),
7.52±7.48 (t, 2H, meta phenyl), 7.43±7.41(t, 1H, para
phenyl), 7.35±7.20 and 7.15±7.05 (2 m, 4H, coumaranone),
4.92 (t£t, 1H, CHv), 3.09 (d, 2H, S±CH2, 3Jˆ7.9 Hz), 2.28
2H, S±CH2 alkene), 3.63 (d£d, 1H, Hd, Jgemˆ12.9 Hz,
3
3Jaaˆ12.9 Hz), 3.37 (d£tr, 1H, Hc, Jaeˆ4 Hz), 2.39
(d£tr,1H, Hb), 1.9/1.62 (2£s, 2£3H, 2 CH3), 1.73 (s,
2£3H, 2CH3 alkene); 13C NMR (100 MHz, CDCl3, d)
17.9 and 25.7 (CH3 alkene), 24.0 (S±CH2), 26.8 and 29.0
(CH3 furan), 29.4 (S±CH2 alkene), 35.1(C a), 39.2 (Cb), 38.7
(Ca±C±CO), 81.7 (C(CH3) furan), 118.2 (CHv), 120.1
(C-5 pyridine), 121.1, 129.2, 129.5 and 133.7 (phenyl),
137.4 (vC±(CH3)2), 154.9 (C-2 pyridine), 156.5 (C-phenyl),
163.3 (C-6 pyridine), 169.8 (C-4 pyridine) and 170.0 (CO);
MS (m/z, %) 452 (M1z11, 100); HRMS (m/z) calcd for
C24H25N3O2S2 451.1388, found 451.1402.
(s, 3H, CH3 pyrazole), 1.49 and 1.27 (2s, 2£3H, 2CH3); 13
C
NMR (100 MHz, CDCl3, d) 13.6 (CH3 pyrazole), 17.0 and
25.2 (2CH3), 34.2 (CH2), 110.6 (C-7 coumaranone), 118.1
(CH2±Cv), 121.7 (C-4 pyrazole), 122.1, 123.2 and 124.5
(C-4, C-5 and C-6 coumaranone), 123.4 (C-3a coumara-
none), 128.0, 128.9 and 129.4 (C-2, C-3 and C-4, phenyl),
130.2 (C-3 coumaranone), 130.9 (C imine), 134.9 (C-1,
phenyl), 137.4 (C(CH3)), 138.9 (C-5 pyrazole), 148.3 (C-3
pyrazole), 154.0 (C-7a indole) and 168.1 (C-2 indole); MS
(m/z, %) 402 (M1z, 60), 336 (M1z2C5H6, 27), 335 (M1z2
C5H7, 44), 334 (M1z2C5H8, 100), 307 (M1z2C5H7±CO,
27), 306 M1z2C5H8±CO, 79), 302 (M1z2C5H7S, 28), 301
(M1z2C5H9S, 82), 145 (M1z2C9H5O1, 23), 77 (C6H51, 39),
18b: crystallization from methanol (18%), mp: 180.18C; IR
(KBr, cm21, 1600 FT) 1529 (s, phenyl), 1715 (s, vO), 1762
(w), 2924 (w,aliph H), 2974 (w, aliph H), 3036 (w, arom H);
1H NMR (400 MHz, CDCl3, d) 8.42 (s, 1H, 1H pyr), 7.82 (d,
2H, ortho phenyl), 7.57 (tr, 1H, para phenyl), 7.49 (tr, 2H,
meta phenyl), 4.70 (tr, 1H, CHv), 4.39 (d£d, 1H, Ha,
4
3Jaeˆ3.3 Hz, Jaaˆ1.8 Hz), 3.50/3.40 (d£m, 2H, S±CH2
2
3
alkene), 3.83 (d£d, 1H, Hd, Jgemˆ12.8 Hz, Jaaˆ12.8 Hz),
3.28 (d£tr, 1H, Hc, 3Jaeˆ3.5 Hz), 2.39 (d£tr, 1H, Hb), 1.85/
1.62 (2£s, 2£3H, 2CH3), 1.59/1.47 (2£s, 2£3H, 2CH3
alkene); 13C NMR (100 MHz, CDCl3, d) 17.6 and 25.6
69 (C5H91, 66), 51(C H31, 16) and 41 (CH3CN1, 55).
4
(CH3 alkene), 23.9 (S±CH2), 26.9 and 29.1(CH furan),
3
3.5.12. Compound 17. Reaction of compound 14 with
pyrazolone 5b, re¯ux for 60 h. Chromatography with
dichloromethane. Yellow crystals from chloroform±diethyl-
ether (98%), mp: 167.38C; IR (KBr, cm21, 1600 FT) 1512
(s), 1574 (m), 1596 (m), 2908 (br, aliph CH), 3063 (w, arom
CH); 1H NMR (400 MHz, CDCl33, d) 8.57 (s, 1H, H-2 pyri-
midine), 7.72 (d, 2H, ortho H, Jˆ7.5 Hz), 7.38 (tr, 2H,
28.2 (S±CH2 alkene), 33.6 (Ca), 35.9 (Ca±C±CO), 39.0
(Cb), 82.1( C(CH3) furan), 117.0 (CHv), 118.9 (C-5 pyri-
dine), 122.3, 128.8, 130.7 and 133.3 (phenyl), 137.4 (vC±
(CH3)2), 155.2 (C-2 pyridine), 156.8 (C-phenyl), 165.1 (C-6
pyridine), 168.0 (C-4 pyridine) and 170.4 (CO); MS (m/z,
%) 452 (M1z11, 100); HRMS (m/z) calcd for C24H25N3O2S2
451.1388, found 451.1392; X-ray structural analysis:
C24H25N3O2S2, MWˆ451.39, a white transparent crystal
of 0.2£0.2£0.2 mm3 size, space group P-1, Zˆ2, triclinic,
3
3
meta H, Jˆ7.5 Hz), 7.18 (tr, 1H, para H, Jˆ7.5 Hz),
3
4
5.38 (tr, CHv, Jˆ7.9 Hz, Jˆ1.4 Hz), 4.49 (d, 1H, Ha,
2
3Jaeˆ4 Hz), 3.94 (m, 2H, CH2), 3.05 (d£d, 1H, Hd, Jgem
ˆ
aˆ9.876(2), bˆ11.303(2), cˆ11.640(2) A, aˆ72.55(1),
Ê
3
3
Ê 3
12.7 Hz, Jaaˆ11.6 Hz), 2.98 (d£d£d, 1H, Hc, Jaeˆ4 Hz,
4Jaaˆ1Hz), 2.01 (d £d£d, 1H, Hb), 1.93 (s, 3H, CH3
pyrazole), 1.60±1.59 (2£s, 2£3H, CH3 pyranring), 1.76±
1.74 (2£s, 2£3H, CH3 alkene); 13C NMR (100 MHz,
CDCl3, d) 13.3 (CH3 pyrazole), 17.9 and 25.6 (2CH3
alkene), 23.5 (S±CH2), 28.5 (S±CH2 alkene), 26.0 and
bˆ81.79(1), gˆ79.03(1)8, Vˆ1211.81(4) A , dcalc
ˆ
1.237 g cm23, F(000)ˆ476, Tˆ289 K, v-scan, Dvˆ0.608,
2.0,v,60.08 min21, 3705 collected re¯ections ((sin u/
l)maxˆ0.53), 2951unique re¯ections ( Rintˆ3.4%). Final
R-values: R1ˆ0.0484 for 2090 re¯ections with I.2s(I)
and R1ˆ0.0796, wR2ˆ0.1288 for all re¯ections. The
asymmetric unit contains a disordered methanol molecule.
For the prenyl thiolate substituent two conformations
have been re®ned with population parameters 0.71and
0.29.
26.7 (2CH3 furan), 30.1(C ), 37.2 (Cb), 81.8 (C(CH3)
a
furan), 93.6 (Ca±CvCCH3), 118.1 (CH2±Cvalkene),
120.4 (C-2, phenyl), 122.1 (C-5 pyrimidine), 125.5 (C-4,
phenyl), 128.8 (C-3, phenyl), 137.3 (vC±(CH3)2), 138.6
(C-1, phenyl), 146.5 (C±CH3 pyrazole), 148.1 (N±C±O),
155.0 (C-2 pyrimidine), 163.8 (C-6 pyrimidine) and 169.4
3.5.14. Compound 19. Reaction of compound 15 with

542
E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
pyrazolone 5b, re¯ux for 48 h. Chromatography with
dichloromethane±diethylether 10/1. Yellow powder from
chloroform±diethylether (39%), mp: 156.28C; IR (KBr,
cm21, 1600 FT) 3055 (w, pyrimidine H), 2924 and 2860
(m, aliph H), 1729 (w), 1575 (s, phenyl), 1516 (s, phenyl);
1H NMR (400 MHz, CDCl3, d) 8.28 (s, 1H, pyri H), 7.70 (d,
2H, ortho H), 7.39 (tr, 2H, meta H), 7.22 (tr, 1H, para H),
5.77 (m, 1H, CHvCH2), 5.16 (d, 1H, CHvCH2), 5.05 (d,
1H, CHvCH2), 4.55 (m, 4H, Ha, N±CH2 (1H), O±CH2),
3.92 (d£d, 1H, N±CH2,), 3.50 (d£d, 1H, Hd, 2Jgemˆ12.6 Hz,
3Jaaˆ12.6 Hz), 3.33 (d£d, 1H, Hc, 3Jaeˆ5.4), 2.35 (d£d, 1H,
106.5 (C-5 pyridine), 117.5 (CHvCH2), 121.5, 129.1, 130.5
and 133.9 (phenyl), 131.7 (CHvCH2), 156.4 (C-phenyl),
156.8 (C-2 pyridine), 157.3 and 159.3 (C-4 and C-6 pyri-
dine) and 170.1 (CO); MS (m/z, %) 381(M 1z11, 100);
HRMS (m/z) calcd for C20H17ClN4O2 380.1040, found
380.1039.
3.5.16. Compound 27. Reaction of compound 24 with
pyrazolone 5b, re¯ux for 72 h. Chromatography with
dichloromethane±diethylether 10/1. White±yellow powder
from ethanol (88%), mp: 243.88C; IR (KBr, cm21, 1600 FT)
1608 (s, phenyl), 2914 (w, alkyl), 2952 (w, alkyl) and 3058
(w, phenyl); 1H NMR (400 MHz, CDCl3, d) 7.76±7.72 and
7.66±7.24 (2 m, 10H, phenyl), 7.23±7.15 (m, 3H, H-4, H-5,
H-6 indole), 7.10 (d, 1H, H-7 indole), 4.58 (br d, 1H, Ha,
3
Hb, Jaeˆ5.2), 2.05 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3, d) 13.5 (CH3), 28.1(C ), 30.9 (Cb), 44.0 (N±
a
CH2), 50.6 (N±CH2 alkene), 69.8 (O±CH2), 95.2 (Ca±C±
CCH3), 117.3 (CHvCH2), 120.1 (C-5 pyrimidine), 120.5
(C-2, phenyl), 125.8 (C-4, phenyl), 127.0 (C-1, phenyl),
128.9 (C-3, phenyl), 131.8 (CHvCH2), 147.1 (CaC±C±
CH3), 147.6 (N±C±O), 156.5 (C-2 pyrimidine) and 158.8
and 158.2 (C-4 and C-6 pyrimidine); MS (m/z, %) 393 (M1z,
37), 378 (M1z2CH3, 12), 206 (61), 77 (C6H51, 64), 51
(C4H31, 19), 41 (C3H61, 100) and 39 (C3H31, 32); HRMS
(m/z) calcd for C21H20N5O 393.1356, found 393.1359.
3
3Jaeˆ3.7 Hz), 3.12 (d£d, 1H, Hc, Jaeˆ1.3 Hz), 3.06 (d£d,
3
2
1H, Hd, Jaaˆ12.7 Hz, Jgemˆ12.2 Hz), 2.08 (d£d£d, 1H,
Hb), 1.95 (s, 3H, CH3), 1.65 and 1.62 (2s, 2£3H, 2CH3);
13C NMR (100 MHz, CDCl3, d) 15.0 (CH3 pyrazole), 23.5
(S±CH2), 26.4 (Cb), 26.4 and 26.5 (2CH3), 40.4 (Ca), 81.7
(O±C(CH3)2), 97.9 (Ca±C±CCH3), 107.3 (Ca±C±indole),
109.5 (C-7 indole), 117.2, 120.0 and 121.0 (C-4, C-5 and
C-6 indole), 125.3 (C-3a indole), 120.4, 127.2, 128.0, 128.9,
128.5 and 1296 (phenyl), 137.0 (C-1, phenyl indole), 137.7
(C-1, phenyl pyrazole), 138.2 and 138.3 (N±C±S and C-7a
indole), 147.6 (C±CH3 pyrazole), 147.7 (N±C±O); MS
(m/z, %) 477 (M1z, 25), 376 (M1z2C5H9S, 100), 204 (13),
77 (C6H51, 26), 69 (C5H91, 19), 51 (C4H31, 10) and 41
(CH3CN1, 44); HRMS (m/z) calcd for C30H27N3OS
477.1875, found 477.1840.
3.5.15. Compound 20a,b. Reaction of compound 15 with
isoxazolone 5f, re¯ux for 70 h. Chromatography with
dichloromethane±diethylether 9/1afforded two azirine
compounds 20a,b.
20a: crystallization from chloroform±diethylether (19%),
mp: 2258C; IR (KBr, cm21, 1600 FT) 3067 (w, arom H),
2973 (w, aliph H), 2919 (w, aliph H), 1768 (s), 1579 (s,
phenyl) and 1515 (m, phenyl); 1H NMR (400 MHz,
CDCl3, d) 7.93 (s, 1H, pyridine H), 7.51 (tr, 1H, para H),
7.48 (d, 2H, ortho H), 7.40 (d, 2H, meta H), 5.83 (m, 1H,
CHvCH2), 5.30 (d£d, 2H, CHvCH2), 4.94 (d£d, 1H,
3.5.17. Compound 28. Reaction of compound 26 with
pyrazolone 5b, re¯ux for 1h. The precipitate is collected
and is characterized as the Knoevenagel adduct 28. This
powder is of satisfactory quality for further use (89%),
mp: 151.88C; IR (KBr, cm21, 1600 FT) 1696 (s, CO),
2
3
O±CH, Jgemˆ12.1 Hz, Jaaˆ2.6 Hz), 4.57 (d£d, 1H,
O±CH, 3Jaeˆ1.7 Hz), 4.37±4.18 (AB-pattern, 2H,
2962 (w, aliph H); H NMR (400 MHz, CDCl3, d) 8.03±
1
3
N±CH2), 4.26 (d£d, 1H, Ha, Jaeˆ4.4 Hz), 3.98 (d£d, 1H,
8.00 (d£d, 2H, ortho H), 7.97 (s, 1H, imine H), 7.94±7.91
(m, 2H, ortho H), 7.51±7.49 (m, 3H, meta and para H),
7.44±7.39 (d£d, 2H, meta H), 7.19±7.15 (tr, 1H, para H),
5.34 (tr£m, 1H, CHv), 3.59 (d, 2H, S±CH2), 2.79 (s, 3H,
CH3 pyrazole), 1.69 (s, 3H, CH3) and 1.52 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3, d) 17.8 (CH3), 19.5 (CH3), 25.8
(CH3), 37.3 (S±CH2), 118.6 (C±CO), 118.3, 124.6, 125.5,
126.6, 128.8, 129.3, 131.1, 131.9, 132.8, 138.5 (Phenyl),
(CH imine), 139.4 (C(CH3)2), 144.2 (C-4 thiazole),
148.9 (C±CH3 pyrazole), 151.7 (C-5 thiazole), 165.1
(C-2 thiazole) and 165.1 (CO); MS (m/z, %) 445 (M1z,
10), 377 (M1z2C5H8, 57), 344 (M1z2C5H9S, 100), 69
(C5H91, 19).
2
3
Hd, Jdcˆ12.9 Hz, Jaaˆ12.9 Hz), 3.62 (d£d, 1H, Hc,
4
3Jaeˆ5.5 Hz, Jaaˆ1.7 Hz), 2.62 (d£d, 1H, Hb); 13C NMR
(100 MHz, CDCl3, d) 29.6 (Ca), 36.9 (Cb), 39.1(C ±C±
a
CO), 44.7 (N±CH2), 51.1 (N±CH2 alkene), 68.9 (O±CH2),
107.6 (C-5 pyridine), 118.9 (CHvCH2), 121.0, 129.2, 129.3
and 133.9 (phenyl), 131.4 (CHvCH2), 156.7 (C-2
pyridine), 157.8, 158.26 and 158.32 (C-phenyl, C-4 and
C-6 pyridine) and 170.0 (CO); MS (m/z, %) 381(M 1z11,
100); HRMS (m/z) calcd for C20H17ClN4O2 380.1040, found
380.1036.
20b: crystallization from chloroform±diethylether (29%),
mp: 176.28C; IR (KBr, cm21, 1600 FT) 3026 (w, arom H),
2963 (w, aliph H), 2925 (w, aliph H), 1721 (s), 1581 (s,
phenyl) and 1514 (w, phenyl); 1H NMR (400 MHz,
CDCl3, d) 8.18 (s, 1H, pyri H), 7.85 (d, 2H, ortho phenyl),
7.58 (tr, 1H, para phenyl), 7.52 (tr, 2H, meta H), 5.85 (m,
1H, CHvCH2), 5.25 (d£d, 2H, CHvCH2 alkene), 4.89
3.5.18. Compound 29. Heating of compound 28 in xylene
afforded after 15 h the required ring-closed product 29.
Chromatography with dichloromethane±diethylether 10/1
(52%) mp: 194.58C; IR (CCl4, cm21, 1600 FT) 1549 (s,
arom H), 2289 (w), 2927 (w, aliph H), 2984 (w, aliph H)
2
3
1
(d£d, 1H, O±CH, Jgemˆ12.1 Hz, Jaaˆ3.1Hz), 4.56 (d,
and 3066 (w, arom H); H NMR (400 MHz, CDCl3, d)
7.91±7.88 (d£d, 2H, ortho H), 7.75±7.73 (d£d, 2H, ortho
3
1H, O±CH, Jaeˆ1.5 Hz), 4.39±4.26 (AB-pattern, 2H,
3
N±CH2), 4.26 (d, 1H, Ha, Jaeˆ4 Hz), 4.10 (d£d, 1H, Hd,
H), 7.46±7.36 (m, 5H, 2 meta and para H), 7.21±7.17 (t,
3
3
3
2Jgemˆ12.8 Hz, Jaaˆ12.8 Hz), 3.50 (d£d, 1H, Hc, Jaeˆ
1H, para H), 4.54 (d, 1H, Ha, Jaeˆ4.48 Hz), 3.08 (m, 2H,
5 Hz, Jaaˆ1.9 Hz), 2.60 (d£d, 1H, Hb); 13C NMR
Hc and Hd), 2.27 (s, 3H, CH3 pyrazole), 2.25±2.21(m, 1H,
Hb), 1.65 (s, 3H, CH3) and 1.53 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3, d) 15.3 (CH3 pyrazole), 24.9 (CH2±S),
4
(100 MHz, CDCl3, d) 29.7 (Ca), 35.9 (Cb), 36.0 (Ca±C±
CO), 44.7 (N±CH2), 50.9 (N±CH2 alkene), 69.3 (O±CH2),

E. Ceulemans et al. / Tetrahedron 58 (2002) 531±544
543
25.9 (CH3), 26.1(CH 3), 32.0 (Cb), 41.7 (Ca), 81.7 (C(CH3)2),
96.2 (Ca±C±CCH3), 124.1 (Ca±C±N), 120.4, 125.3, 125.9,
128.8, 129.0 and 129.7 (phenyl), 133.5 and 138.7 (2C-1,
Phenyl), 146.8 and 147.6 (C±CH3 and O±C±N±phenyl),
147.9 (S±C±S), 162.6 (C-2 thiazole); MS (m/z, %) 446
(M1z11, 100); HRMS (m/z) calcd for C25H23N3O2S2
445.1283, found 445.1276.
1600 FT) 1549 (s, arom H) and 3070 (w, arom H); 1H NMR
(400 MHz, CDCl3, d) 7.67±7.63 (d£m, 4H, ortho H), 7.37±
7.33 (d£d, 4H, meta H), 7.19±7.15 (tr, 2H, para H), 7.04 (s,
1H, pyridine H), 5.83 (m, 2H, CHv), 5.12 (m, 4H,
2
CH2vCH), 4.34±4.31(d £d, 2H, OCH2, Jgemˆ10.8 Hz,
3
3Jaeˆ3.0 Hz), 4.29±4.22 (m, 4H, O±CH2, Jaaˆ8.0 Hz and
N±CH2±CHv), 4.07±4.01(d £d, 2H, N±CH2±CHv), 3.97
(d, 2H, Ha, 3Jaeˆ4.8 Hz), 3.51(d £d, 2H, Hc, 2Jgemˆ12.3 Hz,
3Jaeˆ4.4 Hz), 3.29 (d£d, 2H, Hd, 3Jaaˆ6.0 Hz), 2.44 (m, 2H,
Hb) and 2.08 (s, 6H, 2 CH3); 13C NMR (100 MHz, CDCl3, d)
13.8 (CH3), 30.7 (Cb), 31.7 (Ca), 46.3 (N±CH2), 50.9
(N±CH2±CHv), 70.1(O±CH 2), 99.5 (Ca±C±CCH3),
104.2 (C-3 pyridine), 116.3 (CHvCH2), 120.6 (C-2,
phenyl), 125.5 (C-4, phenyl), 128.8 (C-3, phenyl), 134.8
(CHvCH2), 138.6 (C-1, phenyl), 141.1 (C-4 pyridine),
146.8 (C±CH3), 148.4 (CH2±O±C) and 150.7 (C-2 pyri-
dine); MS (m/z, %) 637 (M1z, 100), 622 (M1z2CH3, 33),
450 (57); HRMS (m/z) calcd for C39H39N7O2 637.3165,
found 637.3165.
3.5.19. Compound 30. Reaction of compound 25 with
pyrazolone 5b, re¯ux for 36 h. Chromatography with
dichloromethane afforded an oily product 30 (65%); IR
(KBr, cm21, 1600 FT) 1549 (s, arom H), 2289 (w), 2858
1
(w, aliph H) and 2925 (w, aliph H); H NMR (400 MHz,
CDCl3, d) 7.94±7.91(d, 2H, ortho phenyl), 7.749±7.72 (d,
2H, ortho phenyl), 7.44±7.37 (m, 5H, 2 meta and para
phenyl), 7.23±7.19 (t, 1H, para phenyl), 4.41(d, 1H, H
2
,
a
3Jaaˆ4.7 Hz), 3.3.27 (d£d, 1H, Hc, Jgemˆ13.4 Hz, Jaeˆ
3
3
3.0 Hz), 3.2±3.14 (d£d, 1H, Hd, Jaaˆ9.3 Hz), 2.36 (s, 3H,
CH3 pyrazole), 2.33±2.27 (m, 1H, Hb), 1.60 (s, 3H, CH3)
and 1.54 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3, d) 15.5
(CH3 pyrazole), 25.0 (CH2±S), 25.1(CH 3), 26.6 (CH3), 29.7
(Cb), 41.1 (Ca), 82.2 (C(CH3)2), 96.4 (Ca±C±CCH3), 128.91
(N±C±S), 120.5, 125.6, 126.4, 128.9, and 130.2 (phenyl),
133.1 and 138.6 (C-1, phenyl), 143.7 (Ca±C±S), 146.4 and
148.1 (C±CH3 and N±C±O) and 166.1 (C-2 thiazole); MS
(m/z, %) 445 (M1z, 33) and 344 (100); HRMS (m/z) calcd for
C25H23N3O2S2 445.1283, found 445.1286.
34b: mp 2458C (chloroform±diethylether); IR (KBr, cm21
,
1600 FT) 1560 (s, arom), 1599 (s, arom), 3070 (w arom H);
1H NMR (400 MHz, CDCl3, d) 7.74±7.72 (d£m, 4H, ortho
H), 7.40±7.36 (d£d, 4H, meta H), 7.21±7.16 (tr, 2H, para
H), 6.98 (s, 1H, pyridine H), 5.82 (m, 2H, CHv), 5.12 (m,
4H, CH2vCH), 4.35±4.31(d £d, 2H, OCH2, 2Jgemˆ10.6 Hz,
3
3Jaeˆ3.2 Hz), 4.29±4.22 (m, 4H, O±CH2, Jaaˆ9.2 Hz),
4.23±4.08 (AB systeem, 4H, N±CH2±CHv), 3.90 (d, 2H,
3
2
3
3.5.20. Compound 33. Reaction of compound 32 with pyra-
zolone 5b, re¯ux for 12 h. Chromatography with dichloro-
methane±diethylether 8/1afforded an oily red product
(56%); 1H NMR (400 MHz, CDCl3, d) 9.25 (s, 1H, pyridine
H), 8.02 (d£d, 2H, ortho phenyl), 7.70 (d£d, 2H, ortho H),
7.42 (s, 1H, imine H), 7.33±7.39 (m, 4H, meta phenyl),
7.18±7.08 (2 tr, 2H, para phenyl), 6.00±5.92 (m, 2H, 2
CHvCH2 chain), 5.84±5.74 (m, 1H, CHvCH2 six
membered ring), 5.31±5.11 (m, 6H, C H2vCH), 4.43±
Ha, Jaeˆ4.6 Hz), 3.57 (d£d, 2H, Hc, Jgemˆ12.4 Hz, Jaeˆ
4.2 Hz), 3.29 (d£d, 2H, Hd, 3Jaaˆ4.5 Hz), 2.39 (m, 2H, Hb)
and 2.26 (s, 6H, 2 CH3); 13C NMR (100 MHz, CDCl3, d)
13.8 (CH3), 30.7 (Cb), 31.3 (Ca), 46.7 (N±CH2), 51.0
(N±CH2±CHv), 69.8 (O±CH2), 99.9 (Ca±C±CCH3),
104.9 (C-3 pyridine), 116.3 (CHvCH2), 120.4 (C-2,
phenyl), 125.4 (C-4, phenyl), 128.9 (C-3, phenyl), 134.8
(CHvCH2), 138.8 (C-1, phenyl), 140.5 (C-4 pyridine),
147.1 (C±CH3), 148.8 (CH2±O±C) and 150.4 (C-2 pyri-
dine); MS (m/z, %) 637 (M1z, 100), 622 (M1z2CH3, 32),
450 (45); HRMS (m/z) calcd for C39H39N7O2 637.3165,
found 637.3173.
3
4.28 (m, 3H, O±CH2, Hc of Hd), 4.17 (d, 1H, Ha, Jaeˆ
4.6 Hz), 4.16±4.00 (m, 5H, Hc of Hd, N±(CH2±
CHvCH2)2), 3.55±3.46 (m, 2H, N±CH2), 2.43 (m, 1H,
Hb), 2.31(s, 3H, CH ) and 2.22 (m, 3H, CH3); 13C NMR
3
(100 MHz, CDCl3, d) 13.8 (CH3), 14.3 (CH3), 29.9 (Cb),
32.3 (Ca), 45.7 (N-CH2 six membered ring), 51.1
(N±CH2±CHvCH2), 54.2 (2N±CH2±CHvCH2), 69.7
(O±CH2), 97.6 (C±CCH3), 105.7 and 109.3 (C-3 and C-5
pyridine), 117.2 (2N±CH2±CHvCH2), 117.5 (C±CH3
imine and N±CH2±CHvCH2), 118.9 and 120.3 (C-2,
phenyl), 123.9 and 125.4 (C-4, phenyl), 128.5 and 128.8
(C-3, phenyl), 132.9 (N±CH2±CHvCH2), 134.5 (2N±
CH2±CHvCH2), 138.5 and 139.3 (C-1, phenyl), 142.9
Acknowledgements
Financial support from the FWO-Vlaanderen, the Univer-
sity of Leuven and the ministerie voor Wetenschapsbeleid is
gratefully acknowledged. This work has been accomplished
with fellowships from the FWO-Vlaanderen (for K. U.), the
University (for M. V.) and the IWT (for E. C. and S. E.).
1
(d£d, C-4 pyridine, Jˆ142 Hz), 143.3 (d£m, CH imine,
1Jˆ158 Hz), 148.0 (CH2±O±C), 148.1 (q, C±CH3), 151.1
(q£d, C±CH3 imine), 154.4 and 162.9 (C-2 and C-6 pyri-
References
3
dine) and 163.0 (CO, Jˆ10 Hz); MS (m/z, %) 637 (M1z,
100); HRMS (m/z) calcd for C39H39N7O2 637.3165, found
637.3169.
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,

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