Nitrilimine cycloadditions to MeOPEG-bounded alkenyl dipolarophiles

Article abstract of DOI:10.1039/b206629g

Base treatment of hydrazonoyl chloride 2 with MeOPEG-supported acrylates 1 and acrylamides 5 gave the corresponding MeOPEG-supported 4,5-dihydropyrazoles 3 and 6. Basic hydrolysis of the cycloadducts caused the removal of the MeOPEG pendant giving 5-carbo

Full text of DOI:10.1039/b206629g

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Nitrilimine cycloadditions to MeOPEG-bounded alkenyl
dipolarophiles
Luisa Garanti,* Giorgio Molteni and Pietro Casati
1
Dipartimento di Chimica Organica e Industriale, Università di Milano, via Golgi 19, 20133
Milano, Italy
Received (in Cambridge, UK) 10th July 2002, Accepted 9th September 2002
First published as an Advance Article on the web 24th October 2002
Base treatment of hydrazonoyl chloride 2 with MeOPEG-supported acrylates 1 and acrylamides 5 gave the
corresponding MeOPEG-supported 4,5-dihydropyrazoles 3 and 6. Basic hydrolysis of the cycloadducts caused
the removal of the MeOPEG pendant giving 5-carboxy- or 5-aminocarbonyl-4,5-dihydropyrazoles 7 and 8,
respectively. Cycloaddition between 2 and enantiopure MeOPEG-supported acrylamide 10 gave a mixture of
MeOPEG-supported cycloadducts 11 and 12 with low diastereoselectivity.
Introduction
According to the Huisgen 1,3-dipolar cycloaddition protocol,
the behaviour of nitrilimines towards alkenyl dipolarophiles
represents a versatile method for the direct synthesis of vari-
ously substituted 4,5-dihydropyrazoles.1 Due to their biological
activity as anti-inflammatory2 or anti-coagulating3 agents,
new methods for the regio- and/or stereoselective synthesis of
these compounds should be highly valuable. In this context, the
two following points should be considered: (i) the polymer-
supported synthesis of small heterocyclic molecules is the sub-
ject of intense research activity,4 since it represents one of the
most promising ways to generate small molecular libraries in
the field of combinatorial chemistry,5 (ii) only one example
of nitrilimine cycloaddition to resin-bound dipolarophiles
(enamines) has been recently reported.6 In the above-mentioned
paper, however, the dipolarophilic enamine was prepared from
Merrifield’s resin,7 and was therefor completely insoluble
in organic media. Recently, soluble polymers have gained popu-
larity among organic chemists due to a number of advanta-
geous features. Analytical simplicity, high reactivity and low
price of the starting materials usually compete with that of
solution chemistry,8 while the easy reaction workup parallels
one of the most appreciated features of solid-supported syn-
thesis. Thus, we decided to undertake the first study on the
feasibility of nitrilimine cycloadditions onto soluble-polymer-
supported alkenyl dipolarophiles.
Scheme 1 Reagents and conditions : i, trioctylamine–CH2Cl2, room
temp.; ii, trioctylamine–CH2Cl2, ∆.
Results and discussion
First of all, we devised the monomethyl ether of poly(ethylene
glycol) with a Mw of 5000 (MeOPEG) as a suitable soluble
support for our purposes. MeOPEG-supported acryloyl esters
1 were easily obtained as illustrated in Scheme 1, while acryla-
mide 5 was synthesised from MeOPEG-mesylate9 by the two
different sequences i and ii, iii depicted in Scheme 2. Both sup-
ported dipolarophiles 1 and 5 were reacted with hydrazonoyl
chloride 210 in the presence of trioctylamine. 5-MeOPEG-
supported-4,5-dihydropyrazoles 3 and 6 were obtained as white
solids, in nearly quantitative yields, simply by addition of
diethyl ether to the crude reaction mixtures. Structural assign-
ments of the cycloadducts rely upon 1H NMR analyses and are
fully consistent with those of similar 1-aryl-3-alkoxycarbonyl-
5-substituted-4,5-dihydropyrazoles reported in the literature.11
In particular, the proton on C5 of the 4,5-dihydropyrazole ring
of 3a resonates at 4.93 δ as a doublet of doublets, thus account-
ing for the depicted regiochemistry of the cycloaddition.
Scheme 2 Reagents and conditions : i, NaOH–Na2CO3–n-Bu4NBr–
CH2Cl2, ∆; ii, CH2Cl2, room temp; iii, trioctylamine–CH2Cl2, room
temp; iv, trioctylamine–CH2Cl2, ∆.
The removal of the MeOPEG pendant from the 4,5-
dihydropyrazoles 3 and 6 was accomplished under particularly
mild conditions (see Scheme 3) giving 5-carboxy- or 5-carboxy-
2504
J. Chem. Soc., Perkin Trans. 1, 2002, 2504–2508
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b206629g

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supported 4,5-dihydropyrazoles were obtained with satisfactory
overall yield (96%), cycloaddition stereoselectivity was dis-
appointing, being the ratio 11 : 12 = 57 :43. Due to the good
hydrolysis yield (87%), however, it was possible to perform
the 10
13 ϩ 14 “MeOPEG-supported” sequence with an
overall yield of 84%. For the sake of comparison, N-[(S )-1-
phenylethyl]acrylamide was reacted with 2 in the presence of
a large excess of triethylamine in boiling toluene (see Scheme 4),
thus following the classic nitrilimine cycloaddition protocol.1
This genuine example of homogeneous phase synthesis allowed
us to perform the sequence N-[(S )-1-phenylethyl]acrylamide
13 ϩ 14 with a 69% overall yield and a stereoselectivity out-
come 13 : 14 = 53 : 47.
Scheme 3 Reagents and conditions: i, 1 M NaOH–THF 1 : 1, room
temp.; ii, aq. 1 M HCl, room temp.; iii, 5% aq. NaHCO3–THF 1 : 1,
room temp.
Conclusions
This first example of the behaviour of MeOPEG-supported
acrylates or acrylamides towards nitrilimines reflects all the
advantages concerned with soluble polymer-supported syn-
thesis. In fact, all cycloadditions were fully satisfactory in terms
of product yield, easy workup and facile removal of the PEG
pendant. As far as stereoselectivity is concerned, the cyclo-
addition outcome for enantiopure MeOPEG-supported 10 is
identical to that of N-[(S )-1-phenylethyl]acrylamide, showing
that the MeOPEG pendant has little or no influence on
cycloaddition stereoselectivity.
amino-4,5-dihydropyrazoles 7 and 8, respectively. In the next
stage of our work we developed the first example of stereo-
selective cycloaddition between nitrilimines and enantiopure
MeOPEG-supported acrylamide 10. The latter compound
was synthesised starting from MeOPEG-mesylate and (S )-1-
phenylethylamine as the chiral building block. We followed two
different synthetic sequences i, iii [(S )-1-phenylethylamine
route] and ii [N-[(S )-1-phenylethyl]acrylamide12 route] as
depicted in Scheme 4. Clean nitrilimine cycloaddition to
enantiopure 10 was performed by treatment with hydrazonoyl
chloride 2 in the presence of trioctylamine. The usual reaction
workup gave a mixture of inseparable 5-MeOPEG-supported
4,5-dihydropyrazoles 11 and 12, the former of which was
Experimental
1
recognised as the major cycloadduct on the basis of H NMR
Mps were measured with a Büchi apparatus in open capillary
tubes and are uncorrected. IR Spectra were recorded with a
Perkin-Elmer 1725X spectrophotometer. Mass spectra were
determined with a VG-70EQ apparatus. 1H-NMR and 13C-
NMR Spectra were taken with a Bruker AC 200 or AC 300
instruments in CDCl3 solutions at room temperature unless
otherwise stated. Chemical shifts are given as ppm from tetra-
methylsilane, J values are given in Hz. Optical rotations,
[α]2D5, were recorded on a Perkin-Elmer Model 241 polarimeter
at the sodium D line.
analysis (see Experimental). The assignement of the absolute
configuration to C5 of the 4,5-dihydropyrazole ring of both 11
and 12 was performed as follows. First, mild basic hydrolysis
of the mixture 11 ϩ 12 gave 5-{N-[(S )-1-phenylethyl]amino-
carbonyl}-4,5-dihydropyrazoles 13 and 14, respectively, which
were separated by column chromatography. Then, the latter
products were further hydrolysed (see Experimental) giving,
respectively,
(S )-1-(4-methylphenyl)-3,5-dicarboxy-4,5-di-
hydropyrazole and (R)-1-(4-methylphenyl)-3,5-dicarboxy-4,5-
dihydropyrazole which are known in the literature.13 At this
point, it can be noted that, although the latter 5-MeOPEG-
Before use, all MeOPEG-bounded materials were melted at
90 ЊC at 1 mmHg for 1 h to remove moisture.
Scheme 4 Reagents and conditions: i, NaH–toluene, ∆; ii, NaOH–Na2CO3–n-Bu4NBr–toluene, 80 ЊC; iii, trioctylamine–toluene, 80 ЊC;
iv, trioctylamine–CH2Cl2, ∆; v, 5% aq. NaHCO3–THF 1 : 1, room temp.; vi, Et3N–toluene, ∆.
J. Chem. Soc., Perkin Trans. 1, 2002, 2504–2508
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MeOPEG-methanesulfonate,9 N-[(S )-1-phenylethyl]acryl-
amide,12 and N-benzylacrylamide14 were synthesised according
to literature procedures.
-CH2CH2O-), 4.33 (2H, t, J 7.2, -CH2CH2NH-), 7.35–7.45 (5H,
m, aromatics).
MeOPEG-Supported N-benzylacrylamide 5
Yields and 1H-NMR purity determination of MeOPEG-bounded
compounds
Method A.
A solution of MeOPEG-methanesulfonate
(5.08 g, 1.0 mmol) and N-benzylacrylamide (0.18 g, 1.1 mmol)
in dry CH2Cl2 (25 cm3) was treated with NaOH (0.16 g,
4.0 mmol), Na2CO3 (0.13 g, 1.2 mmol) and tetrabutyl-
ammoniun bromide (0.16 g, 0.5 mmol). The mixture was
refluxed for 16 h. The undissolved material was filtered off, the
solvent was partly removed under reduced pressure and Et2O
(15 cm3) was added. The white solid was collected by filtration
giving pure 5 (4.42 g, 86%) δH (CDCl3) 3.02 (2H, s, NCH2Ph),
3.25 (2H, t, J 7.0, CH3OCH2-), 3.34 (3H, s, CH3OCH2-), 3.95
(2H, t, J 7.0, -CH2CH2N ), 4.34 (2H, t, J 7.0, -CH2CH2N ), 5.67
The yields of MeOPEG-bounded materials were determined
from the weight of the pure compounds. It was assumed that
the average Mw of MeOPEG monomethyl ether residue is 5000
Da, while the Mw actually encompasses the range between 4500
and 5500 Da. The purity of MeOPEG-bounded compounds
1
was determined by H-NMR analyses with pre-saturation of
the MeOPEG methylene signals at 3.64 δ. In order to ensure
complete relaxation of the proton nuclei and integration
accuracy, we set relaxation delay (RD) to 6 s and aquisition
time (AQ) to 4 s. The integrations of the PEG fragment
CH3OCH2, which were found between 3.30 and 3.37 δ, were
used as internal standards with an estimated integration error
of 4%.
In the case of compound 3a the signals due to the AB part of
the ABX system (pyrazoline C4-H, 2H) are lacking, probably
because they fall under the PEG signal at 3.64 δ. The same
argument applies to compounds 3b (pyrazoline C4-H, 2H and
CH3OCO, 3H) and 6 (CH3OCO, 3H).
(1H, dd, J 10.5, 1.8, CH ᎐), 6.10 (1H, dd, J 17.6, 10.5, -CH᎐),
᎐
᎐
2
6.28 (1H, dd, J 17.6, 1.8, CH ᎐), 7.20–7.30 (5H, m, aromatics).
᎐
2
Method B. A solution of MeOPEG-supported benzylamine 4
(5.09 g, 1.0 mmol) and trioctylamine (0.53 g, 1.5 mmol) in
dry CH2Cl2 (25 cm3) was added to acryloyl chloride (0.11 g,
1.2 mmol) and stirred at room temperature for 10 h. The
solvent was partly removed under reduced pressure and Et2O
(20 cm3) was added. The white solid was collected by filtration
giving pure 5 (4.78 g, 93%).
MeOPEG-Supported acrylates 1
MeOPEG-Supported 5-aminocarbonyl-4,5-dihydropyrazole 6
A solution of MeOPEG-monomethyl ether (5.00 g, 1.0 mmol)
and trioctylamine (5.30 g, 15.0 mmol) in dry CH2Cl2 (35 cm3)
was added to acryloyl chloride (0.9 g, 10.0 mmol) or
methacryloyl chloride (1.04 g, 10.0 mmol) and stirred at room
temperature for 4 h. The solvent was partly removed under
reduced pressure and Et2O (30 cm3) was added. The white solid
was collected by filtration giving pure 1.
A solution of MeOPEG-supported N-benzylacrylamide 5 (4.11
g, 0.8 mmol), hydrazonoyl chloride 2 (0.36 g, 1.6 mmol) and
trioctylamine (1.42 g, 4.0 mmol) in dry CH2Cl2 (22 cm3) was
refluxed with stirring for 28 h. The solvent was partly removed
under reduced pressure and Et2O (15 cm3) was added. The
white solid was collected by filtration giving pure 6 (3.80 g,
92%) δH (CDCl3) 2.24 (3H, s, CH3C6H4-), 2.80–2.95 (2H,
m, pyrazoline C4-H), 3.02 (2H, s, N-CH2Ph), 3.30 (3H, s,
CH3OCH2-), 3.37 (2H, t, J 7.0, CH3OCH2-), 3.75–3.82 (2H, m,
-CH2-CH2-N ), 4.30 (2H, t, J 7.2, -CH2-CH2-N ), 4.88 (1H, dd,
J 11.6, 7.8, pyrazoline C5-H), 6.95–7.05 (4H, m, -C6H4-), 7.10–
7.20 (5H, m, Ph-).
1a (4.80 g, 95%) δH (CDCl3) 3.34 (3H, s, CH3OCH2-), 3.37
(2H, t, J 7.0, CH3OCH2-), 3.85 (3H, t, J 7.0, -CH2CH2O-), 4.30
(2H, t, J 7.2, -CH OCO-) 5.82 (1H, dd, J 10.3, 1.7, CH ᎐), 6.13
᎐
2
2
(1H, dd, J 17.3, 10.3, -CO-CH᎐), 6.42 (1H, dd, J 17.3, 1.7,
᎐
CH ᎐).
᎐
2
1b (4.86 g, 96%) δH (CDCl3) 1.95 (3H, s, CH3-C), 3.30 (3H,
s, CH3OCH2-), 3.37 (2H, t, J 7.0, CH3OCH2-), 3.85 (3H, t,
J 7.0, -CH2CH2O-), 4.30 (2H, t, J 7.2, -CH2OCO-), 5.54 (1H,
1-(4-Methylphenyl)-3,5-dicarboxy-4,5-dihydropyrazole 7a and
1-(4-methylphenyl)-3,5-dicarboxy-5-methyl-4,5-dihydro
pyrazole 7b
s, CH ᎐), 6.11 (1H, s, CH ᎐).
᎐
᎐
2
2
MeOPEG-Supported 4,5-dihydropyrazoles 3
A solution of 3 (0.7 mmol) in tetrahydrofuran (15 cm3) and 1 M
NaOH (15 cm3) was stirred at room temperature for 4 h. 1 M
HCl was added until the pH reached 2 and AcOEt (150 cm3)
was added. The organic layer was washed with water (30 cm3),
dried over Na2SO4 and evaporated under reduced pressure. The
residue was crystallised from MeOH giving pure 7.
A solution of MeOPEG-acrylate 1 (0.9 mmol), hydrazonoyl
chloride 2 (0.32 g, 1.4 mmol) and trioctylamine (1.59 g,
4.5 mmol) in dry CH2Cl2 (18 cm3) was refluxed with stirring for
36 h. The solvent was partly removed under reduced pressure
and Et2O (15 cm3) was added. The white solid was collected by
filtration giving pure 3.
7a (0.13 g, 76%).13
3a (4.39 g, 93%) δH (CDCl3) 2.28 (3H, s, CH3-C6H4-), 3.30
(2H, t, J 7.0, CH3OCH2-), 3.37 (3H, s, CH3OCH2-), 3.83
(3H, s, CH3OCO-), 4.00 (3H, t, J 7.0, -CH2CH2O-), 4.30 (2H, t,
J 7.2, -CH2OCO-), 4.93 (1H, dd, J 12.6, 8.1, pyrazole C5-H),
6.95–7.10 (4H, m, aromatics).
3b (4.26 g, 90%) δH (CDCl3) 1.62 (3H, s, CH3-C), 2.27 (3H, s,
CH3-C6H4-), 3.34 (3H, s, CH3OCH2-), 3.37 (2H, t, J 7.0,
CH3OCH2-), 3.85 (2H, t, J 7.0, -CH2CH2O-), 4.27–4.32 (2H,
m, -CH2OCO-), 6.95–7.05 (4H, m, aromatics).
7b (0.14 g, 77%) was a white solid. Mp 190 ЊC (Found: C,
59.58; H, 5.42; N, 10.73; C13H14N2O4 requires C, 59.54; H, 5.38;
N, 10.68%); νmax (Nujol)/cmϪ1 3400, 1750, 1665; δH (CDCl3)
1.48 (3H, s), 2.23 (3H, s), 3.18 (1H, d, J 17.8), 3.42 (1H, d,
J 17.8), 6.90–7.10 (4H, m), 13.20 (2H, br s); δC (CDCl3) 20.1 (q),
22.8 (q), 37.4 (t), 62.6 (s), 112.4 (d), 130.1 (d), 137.8 (s), 140.1
(s), 140.9 (s), 165.7 (s), 167.6 (s); m/z (EI) 351 (Mϩ).
1-(4-Methylphenyl)-3-methoxycarbonyl-5-(N-benzyl)amino-
carbonyl-4,5-dihydropyrazole 8
MeOPEG-Supported benzylamine 4
A solution of 6 (3.80 g, 0.7 mmol) in tetrahydrofuran (15 cm3)
and 5% aqueous NaHCO3 (15 cm3) was stirred at room
temperature for 6 h. Et2O (100 cm3) was added, the organic
layer was washed with water (2 × 50 cm3), dried over Na2SO4
and evaporated under reduced pressure. The residue was
crystallised from i-Pr2O giving pure 8 (0.80 g, 74%) as a white
solid. Mp 188 ЊC (Found: C, 68.41; H, 6.06; N, 12.02; C20H21-
N3O3 requires C, 68.36; H, 6.02; N, 11.96%); νmax (Nujol)/cmϪ1
A solution of MeOPEG-methanesulfonate (5.08 g, 1.0 mmol)
and benzylamine (1.07 g, 10.0 mmol) in dry CH2Cl2 (25 cm3)
was stirred at room temperature for 18 h. The solvent was
partly removed under reduced pressure and Et2O (15 cm3) was
added. The white solid was collected by filtration giving pure 4
(5.04 g, 99%) δH (CDCl3) 3.04 (2H, s, -NHCH2Ph), 3.35 (3H, s,
CH3OCH2-), 3.38 (2H, t, J 7.0, CH3OCH2-), 3.85 (2H, t, J 7.0,
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3280, 1720, 1660; δH (CDCl3) 2.23 (3H, s), 3.20 (1H, dd, J 18.4,
9.3), 3.60 (1H, dd, J 18.6, 13.8), 3.78 (3H, s), 4.30 (1H, dd,
J 15.2, 6.7), 4.36 (1H, dd, J 15.2, 6.7), 4.70 (1H, dd, J 13.8, 9.3),
6.20 (1H, br t, J 6.7), 6.95–7.10 (9H, m); δC (CDCl3) 20.1 (q),
27.7 (t), 38.6 (t), 53.3 (q), 59.0 (d), 116.7 (d), 128.0–131.3, 132.3
(s), 136.6 (s), 140.0 (s), 162.2 (s), 166.3 (s), 167.9 (s); m/z (EI)
351 (Mϩ).
was washed with water (2 × 50 cm3), dried over Na2SO4 and
evaporated under reduced pressure. The residue was chromato-
graphed on a silica gel column with AcOEt–hexane–CH2Cl2
3 : 6 : 1. The major isomer (5S )-1-(4-methylphenyl)-3-methoxy-
carbonyl-5-{N-[(S )-1-phenylethyl]amino}carbonyl-4,5-dihydro-
pyrazole 13 was eluted first, followed by the minor isomer (5R)-
1-(4-methylphenyl)-3-methoxycarbonyl-5-{N-[(S )-1-phenyl-
ethyl]amino}carbonyl-4,5-dihydropyrazole 14.
13 (0.19 g, 50%) was a white solid. Mp 89 ЊC from i-Pr2O
(Found: C, 69.07; H, 6.30; N, 11.56; C21H23N3O3 requires C,
69.02; H, 6.34; N, 11.50%); [α]2D5 ϩ123.0 (CHCl3, c = 0.22); νmax
(Nujol)/cmϪ1 3180, 1730, 1665; δH (CDCl3) 1.26 (3H, d, J 7.2),
2.25 (3H, s), 3.16 (1H, dd, J 18.0, 13.1), 3.58 (1H, dd, J 18.0,
6.7), 3.83 (3H, s), 4.68 (1H, dd, J 13.1, 6.7), 5.16 (1H, dq, J 9.8,
7.2), 6.20 (1H, br d, J 9.8), 7.0–7.3 (9H, m) δC (CDCl3) 20.5 (q),
22.8 (q), 27.2 (t), 37.3 (d), 52.8 (q), 59.4 (d), 116.1 (d), 129.0–
131.0, 131.8 (s), 137.2 (s), 140.9 (s), 163.2 (s), 167.6 (s), 169.4 (s);
m/z (EI) 365 (Mϩ).
14 (0.15 g, 37%) was a white solid. Mp 79 ЊC from i-Pr2O
(Found: C, 69.04; H, 6.37; N, 11.44; C21H23N3O3 requires C,
69.02; H, 6.34; N, 11.50%); [α]2D5 Ϫ77.2 (CHCl3, c = 0.28); νmax
(Nujol)/cmϪ1 3180, 1720, 1660; δH (CDCl3) 1.30 (3H, d, J 7.2),
2.28 (3H, s), 3.25 (1H, dd, J 18.4, 12.7), 3.59 (1H, dd, J 18.4,
6.5), 3.86 (3H, s), 4.70 (1H, dd, J 12.7, 6.5), 5.16 (1H, dq, J 9.8,
7.2), 6.20 (1H, br d, J 9.8), 7.0–7.3 (9H, m); δC (CDCl3) 20.1 (q),
24.3 (q), 28.8 (t), 39.6 (d), 53.3 (q), 58.5 (d), 116.8 (d), 129.0–
131.0, 131.3 (s), 136.6 (s), 139.9 (s), 162.3 (s), 166.6 (s), 170.1 (s);
m/z (EI) 365 (Mϩ).
MeOPEG-Supported (S )-1-phenylethylamine 9
A solution of (S )-1-phenylethylamine (0.24 g, 2.0 mmol) in dry
toluene (40 cm3) was treated with NaH (90 mg, 3.8 mmol)
and then refluxed for 1 h. MeOPEG-methanesulfonate (5.08 g,
1.0 mmol) in hot (60 ЊC) dry toluene was added and the mixture
was refluxed for 2 h. The solvent was partly removed under
reduced pressure and Et2O (35 cm3) was added. The white
solid was collected by filtration giving pure 9 (4.92 g, 96%)
δH (CDCl3) 1.40 (3H, d, J 6.8, CH3CH ), 1.62 (1H, br s, -CH2-
NH-), 3.34 (3H, s, CH3OCH2-), 3.37 (2H, t, J 7.0, CH3OCH2–-),
3.85 (2H, t, J 7.0, -CH2CH2N ), 4.34 (2H, t, J 7.2, -CH2CH2N ),
5.12–5.22 (1H, m, CH3CH ), 7.30–7.35 (5H, m, aromatics).
MeOPEG-Supported N-[(S )-1-phenylethyl]acrylamide 10
Method A. A solution of N-[(S )-1-phenylethyl]acrylamide12
(0.14 g, 1.2 mmol) in dry toluene (50 cm3) was treated with
NaOH (0.16 g, 4.0 mmol), Na2CO3 (0.13 g, 1.2 mmol) and
tetrabutylammoniun bromide (0.16 g, 0.5 mmol). The mixture
was warmed to 80 ЊC for 0.5 h, and MeOPEG-methane-
sulfonate (5.08 g, 1.0 mmol) in hot (60 ЊC) dry toluene (20 cm3)
was added. After warming (80 ЊC) and stirring for 4 h, the
undissolved material was filtered off, the solvent was partly
removed under reduced pressure and Et2O (25 cm3) was added.
The white solid was collected by filtration giving pure 10
(4.14 g, 80%) δH (CDCl3) 1.40 (3H, d, J 6.8, CH3CH ), 3.34
(3H, s, CH3OCH2-), 3.37 (2H, t, J 7.0, CH3OCH2-), 3.85 (2H, t,
J 7.0, -CH2CH2N ), 4.34 (2H, t, J 7.2, -CH2CH2N ), 5.12–5.22
Homogeneous phase synthesis of cycloadducts 13 and 14
A
solution of N-[(S )-1-phenylethyl]acrylamide (0.88 g,
5.0 mmol) and hydrazonoyl chloride 2 (1.30 g, 5.8 mmol) in
dry toluene was added to triethylamine (2.93 g, 29.0 mmol)
and then refluxed for 6 h. The solvent was evaporated and the
residue was chromatographed on a silica gel column with
AcOEt–hexane–CH2Cl2 3 : 6 : 1. The major isomer 13 (0.66 g,
36%) was eluted first, followed by the minor isomer 14 (0.60 g,
33%). Ratio 13 : 14 = 53 : 47.
(1H, m, CH CH ), 5.60 (1H, dd, J 10.3, 1.6, CH ᎐), 6.08
᎐
2
3
(1H, dd, J 17.5, 10.3, -CH᎐), 6.25 (1H, dd, J 17.5, 1.6, CH ᎐),
᎐
᎐
2
7.30–7.35 (5H, m, aromatics).
(5S)-1-(4-Methylphenyl)-3,5-dicarboxy-4,5-dihydropyrazole and
(5R)-1-(4-methylphenyl)-3,5-dicarboxy-4,5-dihydropyrazole
Method B. A solution of MeOPEG-supported (S )-1-phenyl-
ethylamine 9 (5.10 g, 1.0 mmol) and trioctylamine (0.53 g,
1.5 mmol) in hot (60 ЊC) dry toluene (30 cm3) was added to
acryloyl chloride (0.11 g, 1.2 mmol) and stirred at 80 ЊC for
6 h. The solvent was partly removed under reduced pressure
and Et2O (25 cm3) was added. The white solid was collected by
filtration giving pure 5 (4.85 g, 94%).
A solution of 13 (0.73 g, 2.0 mmol) in tetrahydrofuran (2.5 cm3)
and 2 M NaOH (2.5 cm3) was stirred at 50 ЊC for 4 h. 1 M HCl
was added until the pH 2 reached and AcOEt (50 cm3)
was added. The organic layer was washed with water (20 cm3),
dried over Na2SO4 and evaporated under reduced pressure.
The residue was crystallised from MeOH giving (5S )-1-(4-
methylphenyl)-3,5-dicarboxy-4,5-dihydropyrazole13 (0.34 g,
69%).
MeOPEG-Supported 5-{N-[(S )-1-phenylethyl]amino}carbonyl-
4,5-dihydropyrazoles 11 and 12
The same procedure applied to 14 gave (5R)-1-(4-methyl-
phenyl)-3,5-dicarboxy-4,5-dihydropyrazole13 (0.33 g, 66%).
A
solution of MeOPEG-supported N-[(S )-1-phenylethyl]-
acrylamide 10 (6.21 g, 1.2 mmol), hydrazonoyl chloride 2
(0.36 g, 1.6 mmol) and trioctylamine (1.42 g, 4.0 mmol) in dry
CH2Cl2 (25 cm3) was refluxed with stirring for 50 h. The solvent
was partly removed under reduced pressure and Et2O (25 cm3)
was added. The white solid was collected by filtration giving
a 57 : 43 mixture of cycloadducts 11 and 12 (6.18 g, 96%).
Cycloadduct ratio was deduced from integration of the 1H
NMR resonance signals due to the –COOCH3 group placed
in the 3- position of the 4,5-dihydropyrazole ring: δH (CDCl3)
3.79 (3H, s) (for 11), and 3.82 (3H, s) (for 12).
Acknowledgements
We thank MURST and CNR for financial support.
C.I.N.M.P.I.S. is gratefully acknowledged for a grant that
enabled Dr Pietro Casati to work on this project.
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J. Chem. Soc., Perkin Trans. 1, 2002, 2504–2508
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