Uncommon aqueous media for nitrilimine cycloadditions. I. Synthetic and mechanistic aspects in the formation of 1-aryl-5-substituted-4,5-dihydropyrazoles

Article abstract of DOI:10.1039/b205063c

A number of 1-aryl-5-substituted-4,5-dihydropyrazoles 4 have been synthesised by 1,3-dipolar cycloaddition of variously substituted nitrilimines 2 onto the appropriate alkenyl dipolarophiles 3 in aqueous media and in the presence of a surfactant. Under these conditions, uncommon for the large majority of [3 + 2] cycloadditions, the electronic features of both the cycloaddends strongly dictate the reaction outcome. Clean and fast cycloadditions were observed between electron-rich nitrilimines and electron-poor dipolarophiles, while the reversal of the electronic features of the reactants gave poor results. Changes in surfactant concentration leads to some novel mechanistic insights.

Full text of DOI:10.1039/b205063c

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Uncommon aqueous media for nitrilimine cycloadditions.
I. Synthetic and mechanistic aspects in the formation of
1-aryl-5-substituted-4,5-dihydropyrazoles
Giorgio Molteni,*a Alessandro Pontib and Marco Orlandic
a
`
Universita di Milano, Dipartimento di Chimica Organica e Industriale, via Golgi 19,
20133, Milano, Italy. E-mail: giorgio.molteni@unimi.it; Fax: 02-50314139; Tel: 02-50314141
Consiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, via Golgi 19,
20133, Milano, Italy
`
Universita di Milano-Bicocca, Dipartimento di Scienze dell’Ambiente e del Territorio,
Piazza della Scienza 1, 20126, Milano, Italy
b
c
Received (in London, UK) 24th May 2002, Accepted 25th July 2002
First published as an Advance Article on the web 5th September 2002
A number of 1-aryl-5-substituted-4,5-dihydropyrazoles 4 have been synthesised by 1,3-dipolar cycloaddition of
variously substituted nitrilimines 2 onto the appropriate alkenyl dipolarophiles 3 in aqueous media and in the
presence of a surfactant. Under these conditions, uncommon for the large majority of [3 + 2] cycloadditions, the
electronic features of both the cycloaddends strongly dictate the reaction outcome. Clean and fast
cycloadditions were observed between electron-rich nitrilimines and electron-poor dipolarophiles, while the
reversal of the electronic features of the reactants gave poor results. Changes in surfactant concentration leads
to some novel mechanistic insights.
Introduction
As a very general rule, the large majority of organic reactions
are carried out in non-aqueous media, since a number of syn-
thetic valuable methodologies are currently developed in anhy-
drous solvents and/or under an inert atmosphere. As a
consequence of the strict exclusion of water from reaction mix-
tures, organic transformations carried out in water or in aqu-
eous media were often regarded as chemical curiosities and
their synthetic utility was almost neglected for a long time.
In recent years, however, there has been a rediscovery of
water-promoted organic reactions, as is testified by a number
of reviews.1,2 This trend reflects the fact that water itself dis-
Fig. 1
plays a number of desirable features: (i) the pH of the reaction
medium can be easily controlled, (ii) reaction rates can be sig-
nificantly increased, (iii) product separation can often be
Results
achieved by simple filtration of the crude reaction mixture,
and (iv) environmentally-friendly procedures can be success-
fully elaborated. Among the organic transformations which
appear to benefit from aqueous media, Diels–Alder and 1,3-
dipolar cycloadditions occupy a prominent place. These pro-
cesses, which were long regarded as solvent-insensitive, ‘‘no
mechanism’’ reactions,3 exhibit strong rate accelerations in
water.4 As a consequence, the Diels–Alder reaction has been
extensively studied in aqueous solutions5 as well as a number
of 1,3-dipolar species including nitrile oxides,6 azides,7 and
azomethine ylides.8 Very recently, we exploited the first study
on the feasibility of nitrilimine 1,3-dipolar cycloadditions to
alkenyl dipolarophiles in aqueous medium.9 The main pro-
ducts of such reactions, namely 1-aryl-5-substituted-4,5-dihy-
dropyrazoles, represent an attractive target in view of their
versatile biological activity.10–13 In this work, we undertook
the first systematic investigation on the behaviour of variously
substituted nitrilimines 2 onto alkenyl dipolarophiles 3 in aqu-
eous media (Fig. 1) according to the electronic features of both
the cycloaddends.
It is well known that the in situ generation of nitrilimines from
the corresponding hydrazonoyl chlorides occurs in homoge-
neous phase by base treatment of the latter.14 In our previous
paper,9 we described that dipolar cycloadditions between nitri-
limines and dipolarophilic alkenes were best performed by
shaking a heterogeneous mixture of the reactants in aqueous
0.1 M sodium hydroxide as the base and in the presence of tet-
rahexylammonium chloride (THAC) as the catalyst. However,
since sizeable amounts of tetrazine by-product 5 (Scheme 1)
were obtained in some cases, the first stage of the present work
was concerned with the refinement of the above mentioned
method. The search for the suitable basic agent, catalyst and
catalyst concentration was achieved through the standard
reactions depicted in Tables 1 and 2, respectively. Since the
best results were obtained by mechanical shaking of a hetero-
geneous mixture of the reactants with sodium carbonate in the
presence of THAC (8 mM) at room temperature, we decided
to investigate the reactions of nitrilimines 2 with alkenyl di-
polarophiles 3 in such conditions. Reaction times, products
1340
New J. Chem., 2002, 26, 1340–1345
DOI: 10.1039/b205063c
This journal is # The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2002

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Table 2 Reaction between hydrazonoyl chloride 1b and acrylonitrile
3b in aqueous media
Products
and Yields (%)
Catalyst
concentration/
mM
Time/
min
Entry Catalyst
1b
4bb
1
n-Bu4N+ Clꢀ
8
8
360
420
450
240
420
420
420
420
420
420
120
120
120
120
120
120
17
—
15
—
—
—
—
—
—
—
12
10
—
—
—
—
70
81
71
86
75
76
80
84
87
88
62
65
78
81
92
94
2
Et3BnN+ Clꢀ
3
Cetyl (Me)2(Bn)N+ Clꢀ
Cetyl (n-Bu)3P+ꢀ Clꢀ
n-C12H25OSO3ꢀ Na+
n-C12H25OSO3ꢀ Na+
n-C12H25OSO3ꢀ Na+
n-C12H25OSO3ꢀ Na+
n-C12H25OSO3ꢀ Na+
n-C12H25OSO3 Na+
Hex4N+ Clꢀ
8
4
8
5
2
6
5
7
8
8
10
12
14
1
9
10
11
12
13
14
15
16
Hex4N+ Clꢀ
5
Hex4N+ Clꢀ
8
Scheme 1
Hex4N+ Clꢀ
10
14
17
Hex4N+ Clꢀ
Hex4N+ Clꢀ
and yields are collected in Table 3. 1-Aryl-5-substituted-4,5-
dihydropyrazoles 4, which were formed as the only regioi-
somers, 1,2,4,5-tetrazines 5 and pyrazoles 6 were fully charac-
terised by analytical and spectroscopic methods. The 1H NMR
spectra of cycloadducts 4 are in full agreement with those
reported in the literature for similar 1-aryl-3-alkoxycarbonyl-
5-substituted-4,5-dihydropyrazoles.15 In particular, the hydro-
gens bonded to the C-4 and C-5 positions of the 4,5-dihydro-
pyrazole ring appear as the ABX set of signals typical of these
compounds, thus accounting for the depicted regiochemistry
of the cycloaddition. It can be added that pyrazoles 6 arise
from the corresponding 5-butoxy substituted 4,5-dihydropyra-
zoles. The driving force responsible for this oxidation/elimina-
tion is probably related to the extrusion of the stable butanol
molecule; this behaviour has been reported for similar 5-
ethoxy-4,5-dihydropyrazoles.15a
yields were observed and some tetrazine by-product and/or
unreacted hydrazonoyl chloride 1 were recovered. 1-Hexene
3c (Table 3, entries 3, 7, 11) and butyl vinyl ether 3d (Table
3, entries 4, 8, 12) well illustrate this behaviour towards nitri-
limines 2a–c. Although acrylonitrile 3b belongs to the class
of electron-poor dipolarophiles, it shows an intermediate beha-
viour (Table 3, entries 2, 6, 10). The cycloaddition extent was
less satisfactory with electron-poor nitrilimines 2d,e. In parti-
cular, the presence of the strong electron-withdrawing nitro
group of 2e precluded the cycloaddition process, irrespective
of the dipolarophile R1 (Table 3, entries 17–20). To complete
this picture, it can be added that in the absence of catalyst
no reaction occurred between hydrazonoyl chloride 1b and
As can be inferred from Table 3, the extent of the cycloaddi-
tion was strongly dependent on the electronic features of both
nitrilimines 2 and alkenyl dipolarophiles 3. For a given nitrili-
mine, the cycloaddition outcome was usually satisfactory with
electron-poor dipolarophiles. For example, very short reaction
times and nearly quantitative yields of 4,5-dihydropyrazoles
4aa, 4ba and 4ca were achieved from the cycloaddition
between nitrilimines 2a–c and ethyl acrylate 3a (Table 3,
entries 1, 5, 9). Conversely, in the presence of electron-rich
alkenes longer reaction times were required, lower cycloadduct
Table 3 Reaction between hydrazonoyl chlorides 1 and dipolaro-
philes 3 in aqueous medium
Products and yields (%)a
Time/
Entry
R
R1
min
1
4
5
6
1
H
COOEt
CN
10
70
—
10
5
95
56
17
—
95
78
31
24
93
80
52
27
68
30
—
25
3
—
26
42
—
—
—
25
21
—
—
33
15
17
43
67
27
—
—
—
—
—
—
—
15
—
—
—
15
—
—
—
28
—
—
—
29
—
—
—
10
2
H
3
H
n-Bu
OBu
90
4
H
150
10
—
—
—
9
5
Me
Me
Me
Me
COOEt
CN
Table 1 Reaction between hydrazonoyl chloride 1b and 1-hexene 3c
in aqueous media
6
60
90
7
n-Bu
OBu
8
105
10
—
—
—
—
—
—
8
9
MeO COOEt
MeO CN
10
11
12
13
14
15
16
17
18
19
20
45
MeO n-Bu
MeO OBu
120
180
70
Products and yields (%)
Br
Br
Br
Br
COOEt
CN
105
105
90
Entry
Base
1b
4bc
5b
n-Bu
OBu
—
—
—
—
12
—
1
2
3
4
5
6
Na2CO3
K2CO3
Li2CO3
Cs2CO3
NaHCO3
NaOH
9
10
27
11
20
—
31
30
18
20
22
—
25
25
29
50
14
92
NO2 COOEt 100
NO2 CN
NO2 n-Bu
NO2 OBu
180
360
360
—
—
10
a
Isolation yields.
New J. Chem., 2002, 26, 1340–1345
1341

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ethyl acrylate, since starting materials were recovered
unchanged (see Experimental section).
and 13C NMR (75 MHz) spectra were taken with a Bruker AC
300 or a Bruker AMX 300 instrument (in CDCl3 solutions at
room temperature). Chemical shifts are given as ppm from
tetramethylsilane and J values are given in Hz.
Hydrazonoyl chlorides 1 were synthesised according to lit-
erature procedures.18
Discussion
Some of the nitrilimine-alkene cycloadditions carried out in
aqueous media are subjected to abnormal rate acceleration
in comparison with similar water-free cycloadditions. The best
results were obtained with electron-poor dipolarophiles and
electron-rich nitrilimines, and reflects the usual HOMO-dipole
(LUMO-dipolarophile) controlled nature of nitrilimine
cycloadditions, as demonstrated from early reports.16 On the
other hand, literature calculations are generally performed in
vacuo and/or at low level of theory. It is not surprising that
such calculations are not well suited to account for reactive
processes which occur in water. In order to provide an ade-
quate level of theory for the cycloadditions under investiga-
tion, we undertake a computational effort (HF/IPCM and
DFT/B3LYP/IPCM) also taking into account explicit water
molecules. Full discussion of these calculations appears in
the paper which immediately follows the present one in this
issue. Our calculations generally predict rate accelerations for
both electron-rich and electron-poor dipolarophiles, but the
extent of the predicted enhancements is much smaller than that
experimentally observed. It may be that, due to the very low
solubility of both reactants 1 and 3 in water and to the pre-
sence of a catalyst, cycloadditions could be driven through
pathways whose full evaluation escapes theoretical models.
As a work hypothesis we suggested, in our previous paper, that
the role played by THAC should be related to some kind of
micellar catalysis.9 To gain better insights about this point,
let us examine closer the data summarised in Table 2 for the
reaction between hydrazonoyl chloride 1b and acrylonitrile
in aqueous 0.1 M sodium carbonate. The concentrations of
two catalysts, namely sodium dodecyl sulfate (SDS) and
THAC, were varied in the range between 2–14 mM (entries
5–10) and 1–17 mM (entries 11–16), respectively. It is apparent
that, for a fixed reaction time, the conversion degree of 1b is
roughly the same irrespective of the catalyst concentration.
To this point, it is helpful to recall that: (i) the definition of
the critical micellar concentration (CMC) states that ‘‘it is
the concentration above which molecular aggregates, or
micelles, are formed in solution’’;17 and (ii) the CMC value
for SDS is known to be 8.2 mM.6f On the basis of the latter
datum, the findings outlined in Table 2 are in contrast with
the picture of micellar catalysis, since the cycloaddition
between 1b and 3b works well even far below the CMC value
for SDS. Unfortunately, the CMC value for THAC is not
known but, from the qualitative point of view, the results
obtained with the latter catalyst are quite similar to those
obtained with SDS. It is reasonable to think that the hydro-
phobic effect causes the close association of organic reactants,
and the catalyst acts as a genuine phase transfer catalyst driv-
ing the basic agent from the bulk aqueous medium into the
organic aggregate. The generation of the labile nitrilimine
intermediate would then occur into the organic aggregate,
which is characterised by a high local concentration of the
dipolarophile. This kind of mechanism can justify the abnor-
mal rate acceleration found for some nitrilimine-alkene
cycloadditions carried out in aqueous media compared with
similar water-free cycloadditions.
Reaction between hydrazonoyl chlorides 1 and alkenyl
dipolarophiles 3 in aqueous medium
A mixture of 1 (2.0 mmol), 3 (8.0 mmol), n-Hex4N+Clꢀ (75
mg, 0.2 mmol) and aqueous 0.1 M Na2CO3 (25 cm3), was
mechanically shaken at room temperature for the time indi-
cated in Table 3.
In the case of entries 1, 5, 9, 10 and 15, the mixture was fil-
tered; the solid material was washed with water (70 cm3) and
dried giving pure 4aa, 4ba, 4ca, 4cb, or 5d, respectively.
1-Phenyl-3-methoxycarbonyl-5-ethoxycarbonyl-4,5-dihydro-
pyrazole 4aa (0.52 g, 95%) was a pale yellow solid, mp 90 ꢁC
(Found: C, 60.90; H, 5.83; N, 10.22. C14H16N2O4 requires C,
60.86; H, 5.84; N, 10.14%); nmax (Nujol)/cmꢀ1 1730, 1720;
dH (CDCl3) 1.20 (3H, t, J ¼ 7.2), 3.30 (1H, dd, J ¼ 18.1,
6.9), 3.52 (1H, dd, J ¼ 18.1, 13.4), 3.88 (3H, s), 4.20 (2H, q,
J ¼ 7.2), 4.94 (1H, dd, J ¼ 13.4, 6.9), 6.90–7.20 (5H, m); dC
(CDCl3) 23.36 (q), 34.96 (t), 52.16 (q), 55.66 (t), 66.30 (d),
113.70 (d), 130.45 (d), 133.11 (d), 134.33 (s), 140.54 (s),
169.16 (s), 169.62 (s); m/z (EI) 276 (M+).
1-(4-Methylphenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-
4,5-dihydropyrazole 4ba9 (0.55 g, 95%).
1-(4-Methoxyphenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-
4,5-dihydropyrazole 4ca (0.57 g, 93%) was a yellow solid, mp
78 ꢁC (Found: C, 58.86; H, 5.96; N, 9.21. C15H18N2O4 requires
C, 58.82; H, 5.92; N, 9.15%); nmax IR (Nujol)/cmꢀ1 1735, 1720;
dH (CDCl3) 1.19 (3H, t, J ¼ 7.0), 3.30 (1H, dd, J ¼ 18.0, 7.2),
3.51 (1H, dd, J ¼ 18.0, 13.4), 3.76 (3H, s), 3.88 (3H, s), 4.18
(2H, q, J ¼ 7.0), 4.90 (1H, dd, J ¼ 13.4, 7.2), 6.80–7.10
(4H, m); dC (CDCl3) 23.80 (q), 35.11 (t), 51.78 (q), 53.28
(q), 55.66 (t), 66.19 (d), 113.90 (d), 128.85–129.12, 133.30
(s), 134.33 (s), 139.40 (s), 169.23 (s), 169.67 (s); m/z (EI)
306 (M+).
1-(4-Methoxyphenyl)-3-methoxycarbonyl-5-cyano-4,5-dihy-
dropyrazole 4cb (0.41 g, 80%) was a white solid, mp 122 ꢁC
(Found: C, 60.29; H, 5.01; N, 16.18 C13H13N3O3 requires C,
60.23; H, 5.05; N, 16.21%); nmax (Nujol)/cmꢀ1 1720; dH
(CDCl3) 3.52 (1H, dd, J ¼ 18.1, 8.6), 3.59 (1H, dd, J ¼ 18.1,
8.6), 3.80 (3H, s), 3.89 (3H, s), 5.04 (1H, t, J ¼ 8.6), 6.90–
7.20 (4H, m); dC (CDCl3) 34.80 (t), 52.78 (q), 55.36 (q),
65.13 (d), 114.89 (d), 125.39 (s), 130.16–130.95, 131.68 (s),
134.65 (s), 139.46 (s), 168.55 (s); m/z (EI) 259 (M+).
1,4-Bis(4-bromophenyl)-3,6-bis(methoxycarbonyl)-1,4-dihy-
dro-1,2,4,5-tetrazine 5d (0.34 g, 67%) was a dark red solid, mp
163 ꢁC (Found: C, 42.42; H, 2.80; N, 11.03. C18H14Br2N4O4
requires C, 42.38; H, 2.77; N, 10.98%); nmax (Nujol)/cmꢀ1
1740; dH (CDCl3) 3.74 (6H, s), 7.10–7.50 (8H, m); dC (CDCl3)
55.45 (q), 114.25 (d), 121.01 (d), 124.13 (s), 156.16 (s), 169.32
(s); m/z (EI) 510 (M+).
In the case of entries 6, 11 and 13 the mixture was filtered;
the solid material was washed with water (75 cm3) and dried.
Crystallisation from iPrOH gave pure 4bb, 4cc, or 4da, respec-
tively. Evaporation of the mother liquor and subsequent crys-
tallisation from hexane–benzene gave tetrazines 5c and 5d,
respectively.
1-(4-Methylphenyl)-3-methoxycarbonyl-5-cyano-4,5-dihydro-
pyrazole 4bb9 (0.36 g, 74%).
1-(4-Methoxyphenyl)-3-methoxycarbonyl-5-butyl-4,5-dihy-
dropyrazole 4cc (0.38 g, 52%) was a white solid, mp 62 ꢁC
(Found: C, 66.12; H, 7.68; N, 9.70. C16H22N2O3 requires C,
66.18; H, 7.64; N, 9.65); nmax (Nujol)/cmꢀ1 1730; dH (CDCl3)
0.86 (3H, t, J ¼ 6.1), 1.20–1.60 (6H, m), 2.86 (1H, dd,
J ¼ 17.9, 6.6), 3.23 (1H, dd, J ¼ 17.9, 12.5), 3.74 (3H, s),
Experimental
Melting points were determined with a Buchi apparatus in
¨
open tubes and are uncorrected. IR spectra were recorded with
a Perkin-Elmer 1725 X spectrophotometer. Mass spectra were
1
determined with a VG-70EQ apparatus. H NMR (300 MHz)
1342
New J. Chem., 2002, 26, 1340–1345

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3.83 (3H, s), 4.48 (1H, dddd, J ¼ 12.5, 6.6, 5.8, 5.2), 6.80–7.10
(4H, m); dC (CDCl3) 13.88 (q), 22.36 (t), 26.50 (t), 31.46 (t),
35.38 (t), 52.13 (q), 55.40 (q), 66.27 (d), 113.90–115.10,
130.70 (s), 137.31 (s), 139.65 (s), 168.53 (s); m/z (EI) 290 (M+).
1-(4-Bromophenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-
4,5-dihydropyrazole 4da (0.48 g, 68%) was a yellow solid, mp
89 ꢁC (Found: C, 47.40; H, 4.22; N, 7.94 C14H15BrN2O4
requires C, 47.34; H, 4.26; N, 7.89%); nmax (Nujol)/cmꢀ1
1735, 1720; dH (CDCl3) 1.16 (3H, t, J ¼ 7.1), 3.26 (1H, dd,
J ¼ 18.0, 6.7), 3.45 (1H, dd, J ¼ 18.0, 13.5), 3.81 (3H, s),
4.18 (2H, q, J ¼ 7.1), 4.91 (1H, dd, J ¼ 13.5, 6.7), 7.00–7.35
(4H, m); dC (CDCl3) 35.22 (t), 52.80 (q), 53.19 (q), 54.78 (t),
66.37 (d), 115.70 (d), 128.45–130.16, 133.43 (s), 134.70 (s),
140.10 (s), 169.11 (s), 169.80 (s); m/z (EI) 355 (M+).
1,4-Bis(4-methoxyphenyl)-3,6-bis(methoxycarbonyl)-1,4-di-
hydro-1,2,4,5-tetrazine 5c (0.14 g, 33%) was a dark red solid,
mp 160 ꢁC (Found: C, 58.28; H, 4.92; N, 13.63 C20H20N4O6
requires C, 58.25; H, 4.89; N, 13.59%); nH (Nujol)/cmꢀ1
1740; dH (CDCl3) 3.64 (6H, s), 3.78 (6H, s), 6.85–7.20 (8H,
m); dC (CDCl3) 53.28 (q), 55.45 (q), 114.25 (d), 121.10 (d),
125.03 (s), 155.92 (s), 168.90 (s); m/z (EI) 412 (M+).
Et2O–CH2Cl2 10:1. Tetrazine 5b, 5c or 5d was eluted first,
followed by the corresponding pyrazoles 6b, 6c and 6d.
Further elution gave 4bd, 4cd and 4dd, respectively.
1-(4-Methylphenyl)-3-methoxycarbonylpyrazole 6b (65 mg,
15%) was a white solid, mp 115 ꢁC (from hexane–benzene)
(Found: C, 63.64; H, 9.84; N, 12.44. C12H12N2O2 requires C,
63.69; H, 9.80; N, 12.38%); nmax (Nujol)/cmꢀ1 1730; dH
(CDCl3) 2.32 (3H, s), 3.95 (3H, s), 6.95 (1H, d, J ¼ 2.7),
7.14–7.60 (4H, m), 7.88 (1H, d, J ¼ 2.7); dC (CDCl3) 21.12
(q), 52.56 (q), 105.31 (d), 115.86 (d), 128.58–130.59, 133.15
(s), 139.18 (s), 169.16 (s); m/z (EI) 216 (M+).
1-(4-Methoxyphenyl)-3-methoxycarbonylpyrazole 6c (0.13
g, 28%) was a white solid, mp 73 ꢁC (from hexane–benzene)
(Found: C, 62.10; H, 5.17; N, 12.12. C12H12N2O3 requires C,
62.06; H, 5.21; N, 12.06%); nmax (Nujol)/cmꢀ1 1735; dH
(CDCl3) 3.80 (3H, s), 3.91 (3H, s), 6.92 (1H, d, J ¼ 3.0),
7.00–7.60 (4H, m), 7.86 (1H, d, J ¼ 3.0); dC (CDCl3) 52.38
(q), 55.72 (q), 105.84 (d), 115.50 (d), 127.60–130.00, 135.12
(s), 140.31 (s), 168.18 (s); m/z (EI) 232 (M+).
1-(4-Bromophenyl)-3-methoxycarbonylpyrazole 6d (0.16
mg, 29%) was a white solid, mp 144 ꢁC (from hexane–benzene)
(Found: C, 46.94; H, 3.26; N, 10.04. C11H9BrN2O2 requires C,
47.00; H, 3.23; N, 9.97%); nmax (Nujol)/cmꢀ1 1735; dH
(CDCl3) 3.90 (3H, s), 6.90 (1H, d, J ¼ 3.0), 7.50–7.70 (4H,
m), 7.90 (1H, d, J ¼ 3.0); dC (CDCl3) 51.80 (q), 104.28 (d),
117.21 (d), 128.90–131.20, 132.83 (s), 140.76 (s), 168.31 (s);
m/z (EI) 2816 (M+).
In the case of entries 2, 3, 7 and 14 the mixture was taken up
with CH2Cl2 (75 cm3). The organic layer was washed with
water (100 cm3), dried over Na2SO4 and evaporated. The resi-
due was chromatographed on a silica gel column with AcOEt–
Hexane 3:1. Unreacted 1a, 1b or 1d was eluted first, followed
by the corresponding tetrazine 5.19
Further elution gave 4ab, 4ac, 4bc and 4db, respectively.
1-Phenyl-3-methoxycarbonyl-5-cyano-4,5-dihydropyrazole
4ab (0.26 g, 56%) was a pale yellow solid, mp 109 ꢁC (from
iPrOH/iPr2O) (Found: C, 62.93; H, 4.81; N, 18.28.
C12H11N3O2 requires C, 62.87; H, 4.84; N, 18.33%); nmax
(Nujol)/cmꢀ1 1725; dH (CDCl3) 3.54 (1H, dd, J ¼ 18.0, 8.8),
3.59 (1H, dd, J ¼ 18.0, 8.8), 3.92 (3H, s), 5.06 (1H, t,
J ¼ 8.8), 7.05–7.30 (5H, m); dC (CDCl3) 34.88 (t), 52.56 (q),
65.16 (d), 115.12 (d), 125.17 (s), 128.38–130.63, 131.20 (s),
140.31 (s), 169.16 (s); m/z (EI) 229 (M+).
1-Phenyl-3-methoxycarbonyl-5-butyl-4,5-dihydropyrazole
4ac (88 mg, 17%) was a white solid, mp 59 ꢁC (from iPr2O)
(Found: C, 69.24; H, 7.68; N, 10.82. C15H20N2O2 requires C,
69.20; H, 7.74; N, 10.76%); nmax (Nujol)/cmꢀ1 1730; dH
(CDCl3) 0.85 (3H, t, J ¼ 6.3), 1.20–1.56 (6H, m), 2.85 (1H,
dd, J ¼ 17.8, 6.5), 3.25 (1H, dd, J ¼ 17.8, 12.4), 3.76 (3H,
s), 4.52 (1H, dddd, J ¼ 12.4, 6.6, 6.5, 5.8), 6.90–7.10 (5H,
m); dC (CDCl3) 13.85 (q), 22.34 (t), 26.49 (t), 30.90 (t), 34.85
(t), 52.38 (q), 66.54 (d), 113.60–116.40, 131.20 (s), 139.93 (s),
168.19 (s); m/z (EI) 260 (M+).
1-(4-Methylphenyl)-3-methoxycarbonyl-5-butyl-4,5-dihy-
dropyrazole 4bc (0.16 g, 30%) was a dark yellow oil (Found:
C, 70.10; H, 8.05; N, 10.29. C16H22N2O2 requires C, 70.04;
H, 8.08; N, 10.21%); nmax (Nujol)/cmꢀ1 1730; dH (CDCl3)
0.86 (3H, t, J ¼ 5.9), 1.20–1.80 (6H, m), 2.29 (3H, s), 2.86
(1H, dd, J ¼ 17.6, 6.4), 3.23 (1H, dd, J ¼ 17.6, 12.3), 3.86
(3H, s), 4.50 (1H, dddd, J ¼ 12.3, 6.4, 5.8, 5.2), 7.05–7.15
(4H, m); dC (CDCl3) 13.96 (q), 20.59 (q), 22.45 (t), 26.55 (t),
31.55 (t), 36.50 (t), 52.02 (q), 61.41 (d), 113.90–115.10,
130.84 (s), 137.24 (s), 139.72 (s), 167.58 (s); m/z (EI) 274 (M+).
1-(4-Bromophenyl)-3-methoxycarbonyl-5-cyano-4,5-dihy-
dropyrazole 4db (0.18 g, 30%) was a yellow solid, mp 105 ꢁC
(from iPrOH/iPr2O) (Found: C, 46.81; H, 3.24; N, 13.70.
C12H10BrN3O2 requires C, 46.78; H, 3.27; N, 13.64%); nmax
(Nujol)/cmꢀ1 1730; dH (CDCl3) 3.57 (1H, dd, J ¼ 17.8, 8.7),
3.63 (1H, dd, J ¼ 17.8, 8.7), 3.92 (3H, s), 5.08 (1H, t,
J ¼ 8.7), 7.10–7.50 (4H, m); dC (CDCl3) 35.28 (t), 51.06 (q),
65.90 (d), 116.38 (d), 125.95 (s), 127.80–130.16, 132.40 (s),
133.84 (s), 140.76 (s), 168.88 (s); m/z (EI) 308 (M+).
1-(4-Methylphenyl)-3-methoxycarbonyl-5-butoxy-4,5-dihy-
dropyrazole 4bd (0.14 g, 24%) was a pale yellow solid, mp
68 ꢁC (from iPrOH/iPr2O) (Found: C, 66.22; H, 7.70; N,
9.71. C16H22N2O3 requires C, 66.18; H, 7.64; N, 9.65%); nmax
(Nujol)/cmꢀ1 1730; dH (CDCl3) 0.90 (3H, t, J ¼ 6.0), 1.20–
1.60 (4H, m), 2.28 (3H, s), 2.90 (1H, dd, J ¼ 18.0, 6.6), 3.20
(1H, dd, J ¼ 18.0, 12.4), 3.45 (2H, t, J ¼ 6.3), 3.88 (3H, s),
5.84 (1H, dd, J ¼ 12.4, 6.3), 7.10–7.30 (4H, m); dC (CDCl3)
16.03 (q), 20.37 (q), 22.30 (t), 27.53 (t), 35.38 (t), 51.85 (q),
55.30 (t), 67.28 (d), 116.36 (d), 128.80–130.70, 132.40 (s),
133.21 (s), 140.21 (s), 168.90 (s); m/z (EI) 290 (M+).
1-(4-Methoxyphenyl)-3-methoxycarbonyl-5-butoxy-4,5-di-
hydropyrazole 4cd (0.17 g, 27%) was a white solid, mp 58 ꢁC
(from iPrOH) (Found: C, 62.77; H, 7.27; N, 9.21.
C16H22N2O4 requires C, 62.73; H, 7.24; N, 9.14%); nmax
(Nujol)/cmꢀ1 1730; dH (CDCl3) 0.85 (3H, t, J ¼ 6.0), 1.20–
1.40 (4H, m), 3.05 (1H, dd, J ¼ 18.0, 6.7), 3.18 (1H, dd,
J ¼ 18.0, 12.1), 3.40 (2H, t, J ¼ 6.4), 3.75 (3H, s), 3.84 (3H,
s), 5.80 (1H, dd, J ¼ 12.1, 6.7), 6.80–7.30 (4H, m); dC (CDCl3)
17.11 (q), 21.70 (t), 25.14 (t), 36.18 (t), 52.31 (q), 55.20 (t),
55.95 (q), 66.58 (d), 115.19 (d), 128.10–130.20, 131.94 (s),
135.16 (s), 140.38 (s), 169.25 (s); m/z (EI) 306 (M+).
1-(4-Bromophenyl)-3-methoxycarbonyl-5-butoxy-4,5-di-
hydropyrazole 4dd (0.18 g, 25%) was a yellow solid, mp 74 ꢁC
(from iPrOH/iPr2O) (Found: C, 50.76; H, 5.43; N, 7.95.
C15H19BrN2O3 requires C, 50.72; H, 5.39; N, 7.89%); nmax
(Nujol)/cmꢀ1 1730; dH (CDCl3) 0.80 (3H, t, J ¼ 6.2), 1.20–
1.45 (4H, m), 3.10 (1H, dd, J ¼ 18.0, 6.7), 3.18 (1H, dd,
J ¼ 18.0, 12.2), 3.40 (2H, t, J ¼ 6.7), 3.88 (3H, s), 5.83 (1H,
dd, J ¼ 12.2, 6.7), 7.20–7.50 (4H, m); dC (CDCl3) 16.74 (q),
20.90 (t), 26.18 (t), 36.16 (t), 52.73 (q), 55.24 (t), 67.15 (d),
116.16 (d), 128.40–130.12, 130.76 (s), 134.08 (s), 139.85 (s),
168.94 (s); m/z (EI) 355 (M+).
In the case of entries 4, 17, 19 and 20 the mixture was taken
up with CH2Cl2 (75 cm3). The organic layer was washed with
water (100 cm3), dried over Na2SO4 and evaporated. The resi-
due was chromatographed on a silica gel column with Et2O.
1-Phenyl-3-methoxycarbonyl-pyrazole 6a (61 mg, 15%) was
obtained (entry 4) as a white solid, mp 76 ꢁC (from hexane–
benzene) (Found: C, 65.38; H, 5.02; N, 13.92. C11H10N2O2
requires C, 65.34; H, 4.98; N, 13.85%); nmax (Nujol)/cmꢀ1
1730; dH (CDCl3) 3.92 (3H, s), 7.00 (1H, d, J ¼ 2.8), 7.05–
7.40 (5H, m), 7.90 (1H, d, J ¼ 2.8); dC (CDCl3) 52.28 (q),
In the case of entries 8, 12 and 16 the mixture was taken
up with CH2Cl2 (75 cm3). The organic layer was washed with
water (100 cm3), dried over Na2SO4 and evaporated. The
residue was chromatographed on a silica gel column with
New J. Chem., 2002, 26, 1340–1345
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105.27 (d), 116.12 (d), 128.60–130.86, 133.15 (s), 140.21 (s),
168.18 (s); m/z (EI) 202 (M+).
In the case of entries 1, 3 and 11, 12, the mixture was taken
up with CH2Cl2 (100 cm3). The organic layer was washed with
water (2 ꢂ 50 cm3), dried over Na2SO4 and evaporated. The
residue was chromatographed on a silica gel column with
AcOEt–light petroleum 2:1. Unreacted 1b was eluted first,
followed by the pyrazoline 4bb.
1-(4-Nitrophenyl)-3-methoxycarbonyl-5-ethoxycarbonyl-4,5-
dihydropyrazole 4ea (19 mg, 3%) was obtained (entry 17) as a
white solid, mp 97 ꢁC (from MeOH) (Found: C, 52.30; H, 4.67;
N, 13.13. C14H15N3O6 requires C, 52.34; H, 4.71; N, 13.08%);
nmax (Nujol)/cmꢀ1 1740, 1725; dH (CDCl3) 1.24 (3H, t,
J ¼ 7.2), 3.34 (1H, dd, J ¼ 17.8, 6.8), 3.61 (1H, dd,
J ¼ 17.8, 12.5), 3.95 (3H, s), 4.25 (2H, q, J ¼ 7.2), 5.02 (1H,
dd, J ¼ 12.5, 6.8), 7.30–8.30 (4H, m); dC (CDCl3) 23.70 (q),
36.16 (t), 51.05 (t), 52.66 (q), 67.32 (d), 118.28 (d), 131.80
(d), 134.15 (s), 138.80 (s), 140.89 (s), 169.58 (s), 170.07 (s);
m/z (EI) 321 (M+).
Treatment of hydrazonoyl chloride 1b with ethyl acrylate 3a
in aqueous media
A mixture of methyl 2-chloro-2-(4-methylphenyl-hydrazono)
acetate 1b (0.30 g, 1.3 mmol), ethyl acrylate 3a (0.53 g, 5.3
mmol) and aqueous 0.1 M Na2CO3 (16 cm3), was mechanically
shaken at room temperature for 24 h. The mixture was filtered;
the solid material was washed firstly with water (40 mL), then
with hexane (40 mL) and dried giving unreacted 1b (0.28 g,
94%).
In the case of entry 19, unreacted 1e was obtained.
In the case of entry 20, first fractions the pyrazole 6e; further
elution gave 4ed.
1-(4-Nitrophenyl)-3-methoxycarbonylpyrazole 6e (50 mg,
10%) was a dark yellow solid, mp 153 ꢁC (from hexane–ben-
zene) (Found: C, 53.39; H, 3.63; N, 16.63. C11H9N3O4 requires
C, 53.44; H, 3.67; N, 17.00%); nmax (Nujol)/cmꢀ1 1740; dH
(CDCl3) 3.88 (3H, s), 6.94 (1H, d, J ¼ 2.8), 7.30–7.40 (2H,
m), 7.96 (1H, d, J ¼ 2.8), 8.00–8.20 (2H, m); dC (CDCl3)
52.13 (q), 105.68 (d), 118.31 (d), 123.35 (d), 131.18 (d),
133.16 (s), 138.57 (s), 140.51 (s), 168.90 (s); m/z (EI) 247 (M+).
1-(4-Nitrophenyl)-3-methoxycarbonyl-5-butoxy-4,5-dihydro-
pyrazole 4ed (65 mg, 10%) was a yellow solid, mp 67 ꢁC (from
iPrOH) (Found: C, 56.11; H, 6.00; N, 13.14. C15H19N3O5
requires C, 56.07; H, 5.96; N, 13.08%); nmax (Nujol)/cmꢀ1
1740; dH (CDCl3) 0.85 (3H, t, J ¼ 6.3), 1.20–1.50 (4H, m),
3.10 (1H, dd, J ¼ 18.0, 6.7), 3.20 (1H, dd, J ¼ 18.0, 12.4),
3.36 (2H, t, J ¼ 6.7), 3.92 (3H, s), 5.96 (1H, dd, J ¼ 12.4,
6.7), 7.30–8.20 (4H, m); dC (CDCl3) 16.80 (q), 21.38 (t),
27.03 (t), 36.58 (t), 52.12 (q), 55.38 (t), 67.98 (d), 119.25 (d),
132.14 (d), 133.20 (s), 138.96 (s), 140.71 (s), 169.85 (s); m/z
(EI) 321 (M+).
Acknowledgements
Thanks are due to MURST and CNR for financial support.
The authors are grateful to Prof. Luisa Garanti for helpful
suggestions.
References
1
2
For a monograph: Organic Synthesis in Water, ed. P. A Grieco,
Blackie, Glasgow, 1998.
For reviews(a) J. B. F. N. Engberts and M. J. Blandamer, Chem.
Commun., 2001, 1701; (b) A. R. Katritzky and D. A. Nichols,
Chem. Rev., 2001, 101, 825; (c) A. R. Katritzky, D. A. Nichols,
M. Siskin, R. Murugan and M. Balasubramanian, Chem. Rev.,
2001, 101, 837; (d ) S. Ribe and P. Wipf, J. Chem. Soc., Chem.
Commun., 2001, 299; (e) A. Lubineau, J. Auge´ and Y. Queneau,
Synthesis, 1994, 741; ( f ) C.-J. Li, Chem. Rev, 1993, 93, 2023;
(g) R. Breslow, Acc. Chem. Res., 1991, 24, 159; (h) P. A. Grieco,
Aldrichimica Acta, 1991, 24, 59.
In the case of entry 18 the mixture was taken up with
CH2Cl2 (75 cm3). The organic layer was washed with water
(100 cm3), dried over Na2SO4 and evaporated giving untract-
able tarry material.
3
4
W. E. Doering and W. R. Roth, Tetrahedron, 1962, 18, 67.
D. C. Rideout and R. Breslow, J. Am. Chem. Soc., 1980, 102,
7816.
5
(a) R. Breslow, U. Maitra and D. C. Rideout, Tetrahedron Lett.,
1983, 24, 1901; (b) L. A. Van Royen, R. Mijngheer and P. J. De
Clercq, Tetrahedron, 1985, 41, 4667; (c) H. Waldmann, Angew.
Chem., Int. Ed. Engl., 1988, 27, 274; (d ) H. Waldmann and M.
Braun, Liebigs Ann. Chem., 1991, 1045; (e) W. Blokzijl, M. J.
Blandamer and J. B. F. N. Engberts, J. Am. Chem. Soc., 1991,
113, 4241; ( f ) J. W. Wijnen and J. B. F. N. Engberts, J. Org.
Chem., 1997, 62, 2039; (g) F. Fringuelli, O. Piermatti and F. Pizzo,
Targets Heterocycl. Syst., 1997, 1, 57; (h) D. Amantini, F. Frin-
guelli, O. Piermatti, F. Pizzo and L. Vaccaro, Green Chem.,
2001, 229; (i) F. Fringuelli, O. Piermatti, F. Pizzo and L. Vaccaro,
Eur. J. Org. Chem., 2001, 439.
Reaction between hydrazonoyl chloride 1b and 1-hexene 3c
in aqueous media
A mixture of methyl 2-chloro-2-(4-methylphenyl-hydrazono)
acetate 1b (0.45 g, 2.0 mmol), 1-hexene 3c (0.67 g, 8.0 mmol),
n-Hex4N+Clꢀ (75 mg, 0.2 mmol) and aqueous 0.1 M base (25
cm3), (see Table 1) was mechanically shaken at room tempera-
ture for 90 min.
In the case of entries 1–5, the mixture was taken up with
CH2Cl2 (100 cm3). The organic layer was washed with water
(2 ꢂ 50 cm3), dried over Na2SO4 and evaporated. The residue
was chromatographed on a silica gel column with AcOEt–
CH2Cl2 1:5. Unreacted 1b was eluted first, followed by the cor-
responding tetrazine 5b. Further elution gave pyrazoline 4bc.
In the case of entry 6 the mixture was filtered; the solid mate-
rial was washed with water (100 cm3) and dried giving tetrazine
5b.
6
(a) C. Grundmann and R. Richter, J. Org. Chem., 1967, 32, 2308;
(b) C. Grundmann and S. K. Datta, J. Org. Chem., 1969, 34, 2016;
(c) K. J. Dignam, A. F. Hegarty and P. L. Quain, J. Org. Chem.,
1978, 43, 388; (d ) Y. Inoue, K. Araki and S. Shiraishi, Bull. Chem.
Soc. Jpn., 1991, 64, 3079; (e) J. C. Rohloff, J. Robinson III and
J. O. Gardner, Tetrahedron Lett., 1992, 33, 3113; ( f ) D. van
Mersbergen, J. W. Wijnen and J. B. F. N. Engberts, J. Org.
Chem., 1998, 63, 8801.
(a) Z. Demko and K. B. Sharpless, J. Org. Chem., 2001, 66, 7945;
(b) J. W. Wijnen, R. A. Steiner and J. B. F. N. Engberts, Tetrahe-
dron Lett., 1995, 36, 5389.
(a) R. Grigg, T. Mongkolaussavaratana, C. A. Pounds and S.
Sivagnanam, Tetrahedron Lett., 1990, 31, 7215; (b) A. Lubineau,
G. Bouchain and Y. Queneau, J. Chem. Soc., Perkin Trans. 1,
1995, 2433.
7
8
Reaction between hydrazonoyl chloride 1b and acrylonitrile 3b
in aqueous media
A mixture of methyl 2-chloro-2-(4-methylphenyl-hydrazono)
acetate 1b (0.45 g, 2.0 mmol), acrylonitrile 3b (0.42 g, 8.0
mmol), phase-transfer catalyst (see Table 2) and aqueous 0.1
M Na2CO3 (25 cm3), was mechanically shaken at room tem-
perature for the time indicated in Table 2.
In the case of entry 2, entries 4–10 and 13–16 the mixture
was filtered; the solid material was washed with water (100
cm3) and dried giving the pyrazoline 4bb.
9
G. Broggini, G. Molteni and M. Orlandi, J. Chem. Soc., Perkin
Trans. 1, 2000, 3742.
10 S. W. Djuric, N. Y. BaMaung, A. Basha, H. Liu, J. R. Luly, D. J.
Madar, R. J. Sciotti, N. P. Tu, F. L. Wagenaar, P. E. Wiedeman,
X. Zhou, S. Ballaron, J. Bauch, Y.-W. Chen, X. G. Chiou, T. Fey,
D. Gauvin, E. Gubbins, G. C. Hsieh, K. C. Marsh, K. V. Molli-
son, M. Pong, T. K. Shaughnessy, M. P. Sheets, M. Smith, J. M.
Trevillyan, U. Warrior, C. D. Wegner and G. W. Carter, J. Med.
Chem., 2000, 43, 2975.
1344
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View Article Online
11 S. R. Stauffer, C. J. Coletta, R. Tedesco, G. Nishiguchi, K. Carl-
son, J. Sun, B. S. Katzenellenbogen and J. A. Katzenellenbogen,
J. Med. Chem., 2000, 43, 4934.
12 D. L. Selwood, D. G. Brummell, J. Budworth, G. E. Burtin, R. O.
Campbell, S. S. Chana, I. G. Charles, P. A. Fernandez, R. C.
Glen, M. C. Goggin, A. J. Hobbs, M. R. Kling, Q. Liu, D. J.
Madge, S. Meillerais, K. L. Powell, K. Reynolds, G. D. Spacey,
J. N. Stables, M. A. Tatlock, K. A. Wheeler, G. Wishart and
C.-K. Woo, J. Med. Chem., 2001, 44, 78.
Chem. Soc. Jpn., 1984, 57, 787; (c) A. S. Shawali and S. T.
Ezmirly, J. Heterocycl. Chem., 1988, 25, 257.
16 (a) K. N. Houk, J. Sims, R. E. Duke, R. W. Strozier and J. K.
George, J. Am. Chem. Soc., 1973, 95, 7287; (b) K. N. Houk, J.
Sims, C. R. Watts and L. J. Luskus, J. Am. Chem. Soc., 1973,
95, 7301; (c) K. N. Houk and P. Caramella, J. Am. Chem. Soc.,
1976, 98, 6397.
17 S. Vojutsky, Colloid Chemistry, Mir Publishers, Moscow,
1985.
13 D. J. P. Pinto, M. J. Orwat, S. Wang, J. M. Fevig, M. L. Quan,
E. Amparo, J. Cacciola, K. A. Rossi, R. S. Alexander, A. M.
Smallwood, J. M. Luettgen, L. Liang, B. J. Aungst, M. R. Wright,
R. M. Knabb, P. C. Wong, R. R. Wexler and P. Y. S. Lam,
J. Med. Chem., 2001, 44, 566.
14 (a) J. S. Clovis, A. Eckell, R. Huisgen and R. Sustmann, Chem.
Ber., 1967, 100, 60; (b) R. Huisgen, M. Seidel, G. Wallbillich
and H. Knupfer, Tetrahedron, 1962, 17, 3.
18 (a) Compound 2a: R. Fusco and R. Romani, Gazz. Chim. Ital.,
1946, 76, 419; (b) Compounds 2b,d: M. M. El-Abadelah, A. Q.
Hussein, m. R. Kamal and K. H. Al-Adhami, Heterocycles,
1988, 27, 917; (c) Compound 2c: G. Broggini and G. Molteni,
J. Chem. Soc., Perkin Trans. 1, 2000, 1685; (d ) Compound 2e:
M. T. Cocco, A. Maccioni and A. Plumitallo, Farmaco, Ed.
Sci., 1985, 40, 272.
19 (a) Compound 5a: P. Dalla Croce, M. Ioannisci and E. Licandro,
J. Chem. Soc., Perkin Trans. 1, 1979, 330; (b) Compound 5b: see
ref. 9.
15 (a) R. Paul and S. Tchelitcheff, Bull. Soc. Chim. Fr., 1967, 4179;
(b) T. Shimizu, Y. Hayashi, T. Nishio and K. Teramura, Bull.
New J. Chem., 2002, 26, 1340–1345
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