A concise route to 4-aminomethylpyrazoles and 4-aminomethylisoxazoles from acetylacetone-derived hexahydropyrimidines under mild conditions

Article abstract of DOI:10.1515/chempap-2015-0018

Acetylacetone was successfully used as a precursor of 4-aminomethylpyrazoles and 4-aminomethylisoxazoles in a two step process at ambient temperature. In the first step, acetylacetone was transformed to the corresponding hexahydropyrimidines (1,3-diazinanes) via two consecutive one-pot Mannich aminomethylations. Hexahydropyrimidines were then treated with hydrazine, phenylhydrazine, and hydroxylamine, respectively, to obtain the corresponding 4-aminomethylpyrazoles and 4-aminomethylisoxazoles in good yields. The hexahydropyrimidine ring decomposed providing the title compounds and a reasonable mechanism has been proposed.

Full text of DOI:10.1515/chempap-2015-0018

Chemical Papers 69 (5) 729–736 (2015)
DOI: 10.1515/chempap-2015-0018
ORIGINAL PAPER
A concise route to 4-aminomethylpyrazoles and
4-aminomethylisoxazoles from acetylacetone-derived
hexahydropyrimidines under mild conditions
Abdullah I. Saleh*, Kayed A. Abu-Safieh, Bader A. Salameh
Department of Chemistry, Hashemite University, Zarqa 13115, Jordan
Received 24 May 2014; Revised 17 October 2014; Accepted 31 October 2014
Acetylacetone was successfully used as a precursor of 4-aminomethylpyrazoles and 4-aminomethyl-
isoxazoles in a two step process at ambient temperature. In the first step, acetylacetone was trans-
formed to the corresponding hexahydropyrimidines (1,3-diazinanes) via two consecutive one-pot
Mannich aminomethylations. Hexahydropyrimidines were then treated with hydrazine, phenylhy-
drazine, and hydroxylamine, respectively, to obtain the corresponding 4-aminomethylpyrazoles and
4-aminomethylisoxazoles in good yields. The hexahydropyrimidine ring decomposed providing the
title compounds and a reasonable mechanism has been proposed.
c
ꢀ 2014 Institute of Chemistry, Slovak Academy of Sciences
Keywords: 4-aminomethylpyrazoles, 4-aminomethylisoxazoles, hexahydropyrimidines, 1,3-diazi-
nanes, pyrazolone, aminomethylations, geminal diamines
Introduction
2002), rimonabant (Fong & Heymsfield, 2009), fomepi-
zole (WHO, 2013), oxacillin (Greenwood, 2008), and
ibotenic acid (Becker et al., 1999) are also examples
of approved drugs in which either the pyrazole or
the isoxazole ring system is the key structural fea-
ture.
Development of the building blocks of biologically
active heterocyclic compounds is still an active area
in the organic synthesis research. Most notably, pyra-
zole and isoxazole units are usually associated with
potent pharmaceutical agents. Several of these five-
membered heterocyclic compounds have been found
to possess valuable biological activity against various
diseases (Jamwal et al., 2013). It has been reported
that derivatives containing these units have interest-
ing properties including anti-inflammatory (Shehata
& Glennon, 1987), anticonvulsant (Uno et al., 1979),
herbicidal (Jamwal et al., 2013), antibacterial (Gaik-
wad et al., 2013), anticancer (Nishida et al., 2012),
antifungal (Brahmayya et al., 2013), anxiolytic (Wag-
ner et al., 2004), and anti-HIV activities (Sechi et
al., 2005). For example, the pyrazole derivative, cele-
coxib, and the isoxazole derivative, valdecoxib are ap-
proved and marketed drugs as selective inhibitors of
cyclooxygenase-2 (COX-2), and they are prescribed
for the treatment of arthritis and inflammatory dis-
eases (Talley et al., 2000). Muscimol (Frølund et al.,
1,3-Dicarbonyl compounds are usually transformed
to pyrazoles and isoxazoles through their treatment
with hydrazines, arylhydrazines, hydroxylamine, and
oximes (Katritzky et al., 1987; Heller & Natara-
jan, 2006; Gosselin et al., 2006; Nasu et al., 1998).
Acetylacetone (ACAC) has been utilized as a precur-
sor of biologically interested pyrazoles and isoxazoles
(Bakharev et al., 2009). However, there is a lack of re-
ports regarding the reaction of hexahydropyrimidines
(1,3-diazinanes) (HHP) with hydrazines and hydrox-
ylamines. It was our main objective to shed light on
the reaction of hexahydropyrimidine–dicarbonyl con-
jugates obtained from acetylacetone (HHP–ACAC)
with classical reagents used to produce pyrazoles and
isoxazoles. Replication of the procedure established
for ACAC on other β-dicarbonyl compounds, namely,
hexahydropyrimidine conjugates with ethyl acetoac-
*Corresponding author, e-mail: a-saleh@hu.edu.jo
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A. I. Saleh et al./Chemical Papers 69 (5) 729–736 (2015)
etate (HHP–ETAA), resulted in different and inter-
esting spiro-products.
7,9-bis(4-chlorophenyl)-4-methyl-2,3,7,9-
tetraazaspiro[4.5]dec-3-en-1-one (XIX),
7,9-bis(4-bromophenyl)-4-methyl-2,3,7,9-
tetraazaspiro[4.5]dec-3-en-1-one (XX)
Experimental
Column chromatography was performed on 230–
400 mesh silica gel (Merck) and TLC plates with sil-
ica gel 60 F254 (Merck) were used. IR spectra of the
samples as thin films were recorded on a Magna-IR
560 Nicolet FTIR spectrometer. 1H (400 MHz) and
13C (125 MHz) NMR spectra were recorded at ambi-
ent temperature on a Bruker Avance III spectrometer
using CDCl3 as the solvent and TMS as the internal
standard. Elemental analyses were performed on a Eu-
roEA3000 CHNS–O analyzer (EuroVector, Italy).
A mixture of either HHP–ACAC conjugate (I–VI,
1.0 mmol) (for the preparation of VII–XVIII), HHP–
ETAA conjugate (1 mmol) (for the preparation of
XIX and XX), hydrazine (1.2 mmol) (for the prepa-
ration of VII–XII, XIX and XX), phenylhydrazine
(1.2 mmol) (for the preparation XIII) or hydroxy-
lamine (for the preparation of XIV–XVIII) and ab-
solute EtOH (15 mL) was stirred at ambient tem-
perature for 24 h. The solvent was evaporated un-
der reduced pressure and the resulting residue was
purified on a silica gel column using CH2Cl2 and
CH2Cl2/EtOAc acetate (ϕr = 1 : 1) as the gradient
elution solvents.
General method for preparation of HHP–
ACAC conjugates: 1-(5-acetyl-1,3-dicyclo-
hexyl-1,3-diazinan-5-yl)ethan-1-one (I), 1-[5-
acetyl-1,3-bis(4-chlorophenyl)-1,3-diazinan-
5-yl]ethan-1-one (II), 1-[5-acetyl-1,3-bis(4-
bromophenyl)-1,3-diazinan-5-yl]ethan-1-one
(III), 1-(5-acetyl-1,3-diphenyl-1,3-diazinan-
5-yl)ethan-1-one (IV), 1-[5-acetyl-1,3-bis(4-
methoxyphenyl)-1,3-diazinan-5-yl]ethan-1-one
(V), 1-[5-acetyl-1,3-bis(4-methylphenyl)-1,3-
diazinan-5-yl]ethan-1-one (VI)
Results and discussion
HHP derivatives I–VI were synthesized from
ACAC employing the double-Mannich annulations
protocol (Mukhopadhyay et al., 2011). Their struc-
tures and spectral data are given in Fig. 1 and Table 1,
respectively.
Both aliphatic and aromatic amines were applied
as starting reaction components in the above synthe-
sis. The resulting 1,3-dicarbonyl system in I–VI was
used to provide heteroclycles using reagents with dou-
ble nucleophilic centers such as hydrazine and hy-
droxylamine. Spiro products would be straightforward
products of such strategy (Feng et al., 2014). From
the pharmaceutical point of view, the newly prepared
five-membered ring adds a favorable conformational
restriction to the molecule.
A mixture of ACAC (1.0 mmol), primary amine
(R—NH2, 2.0 mmol), formaldehyde (37–41 % aque-
ous solution, 3 equiv,) and FeCl3 (5 mole %) in
dichloromethane (20 mL) was stirred at ambient tem-
perature for 24 h. The solvent was evaporated un-
der reduced pressure and the crude product was puri-
fied by column chromatography using EtOAc/hexane
(ϕr = 1 : 3) as the solvent to afford the corresponding
HHP–ACAC conjugate (Mukhopadhyay et al., 2011).
Thus, when the HHP–ACAC conjugate I was
stirred overnight with hydrazine in absolute ethanol
at ambient temperature, unexpected decomposition of
the hexahydropyrimidine ring took place with simulta-
neous formation of the 4-aminomethylpyrazole deriva-
tive VII in good yields. Analogously, 4-aminomethyl-
pyrazole derivatives VIII–XIII were obtained start-
ing from the HPP–ACC conjugates II–VI (Fig. 1).
A similar reaction of I–VI with hydroxylamine un-
der the same conditions afforded the corresponding
4-aminomethylisoxazoles XIV–XVIII (Fig. 1) in com-
parable yields. Spectral and analytical data of the pre-
pared compounds are summarized in Tables 2 and 3.
The structure of all products was confirmed by
NMR spectral data. As an example, the results
for 4-aminomethylpyrazole derivative VII and 4-
aminomethylisoxazole derivative XIV are discussed.
For VII, the disappearance of the signal for the car-
bonyl carbon (δC = 204.8) of the starting compound
(I, Fig. 1) and the appearance of two new quaternary
carbons (δC = 114.0 and δC = 142.3) (pyrazole car-
bons) are direct evidence of a pyrazole ring system
General method for preparation of pyrazoles
VII–XIII, isoxazoles XIV–XVIII and pyrazol-
3-ones XIX and XX: 4-(cyclohexylmethyl)-
3,5-dimethyl-1H-pyrazole (VII), 4-chloro-N-
[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]aniline
(VIII), 4-bromo-N-[(3,5-dimethyl-1H-pyrazol-
4-yl)methyl]aniline (IX), N-[(3,5-dimethyl-
1H-pyrazol-4-yl)methyl]aniline (X), N-
[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-
methoxyaniline (XI), N-[(3,5-dimethyl-1H-
pyrazol-4-yl)methyl]-4-methylaniline (XII),
4-chloro-N-[(3,5-dimethyl-1-phenyl-1H-
pyrazol-4-yl)methyl]aniline (XIII), 4-chloro-
N-[(dimethyl-1,2-oxazol-4-yl)methyl]aniline
(XIV), 4-bromo-N-[(dimethyl-1,2-oxazol-
4-yl)methyl]aniline (XV), N-[(dimethyl-
1,2-oxazol-4-yl)methyl]aniline (XVI),
N-[(dimethyl-1,2-oxazol-4-yl)methyl]-4-
methoxyaniline (XVII), N-[(dimethyl-1,2-
oxazol-4-yl)methyl]-4-methylaniline (XVIII),
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Table 1. Characterization data of compounds I–VI
731
Compound
R
Yield Spectral data
IR, ν˜/cm−1: 1671 (C O), 2950 (CH
—
—
I
Cyclohexyl
85
86
83
87
88
91
)
aliphatic
1H NMR (CDCl3), δ: 1.02–1.26, 1.54–1.57, 1.71–1.78 (m, 22H, Hcyclohexyl), 2.12 (s,
6H, CH3), 2.32 (m, 2H, CH2, Hcyclohexyl), 2.96 (s, 4H, CH2), 3.26 (s, 2H, CH2)
13C NMR (CDCl3), δ: 25.9, 26.1 (CH2), 26.6 (CH3), 28.8, 51.7 (CH2), 62.1 (CH),
67.4 (C), 70.9 (CH2), 204.8 (C)
—
II
III
IV
V
4-Chlorophenyl
4-Bromophenyl
Phenyl
IR, ν˜/cm−1: 1669 (C O), 2992 (CH), 3088 (CH
1H NMR (CDCl3), δ: 2.17 (s, 6H, CH3), 3.81 83(s, 4H, CH2), 4.33 (s, 2H, CH2), 7.01
(d, 4H, J = 8.8 Hz, Haryl), 7.28 (d, 4H, J = 8.8 Hz, Haryl
13C NMR (CDCl3), δ: 26.6 (CH3), 53.3 (CH2), 67.1 (C), 69.2 (CH2), 119.2, 126.6
)
aryl
—
)
(C), 129.3 (CH), 147.7, 203.2 (C)
IR, ν˜/cm−1: 1697 (C O), 2929 (CH), 3016 (CH
1H NMR (CDCl3), δ: 2.16 (s, 6H, CH3), 3.79 (s, 4H, CH2), 4.33 (s, 2H, CH2), 6.93
(d, 4H, J = 8.8 Hz, Haryl), 7.38 (d, 4H, J =8.8 Hz, Haryl
13C NMR (CDCl3), δ: 26.7 (CH3), 53.0 (CH2), 67.1 (C), 68.7 (CH2), 113.9 (C),
)
—
—
aryl
)
119.5, 132.3 (CH), 148.1, 203.1 (C)
IR, ν˜/cm−1: 1697 (C O), 2822 (CHaliphatic), 3026 (CHaryl
1H NMR (CDCl3), δ: 2.25 (s, 6H, CH3), 3.90 (s, 4H, CH2), 4.47 (s, 2H, CH2), 7.06–
)
—
—
7.41 (m, 10H, J = 8 Hz, Haryl
)
13C NMR (CDCl3), δ: 26.8 (CH3), 53.4 (CH2), 67.2 (C), 69.4 (CH2), 118.0, 121.6,
129.5 (CH), 149.4, 203.7 (C)
4-Methoxyphenyl
4-Tolyl
IR, ν˜/cm−1: 1695 (C O), 2833 (CHaliphatic), 3036 (CHaryl
)
—
—
1H NMR (CDCl3), δ: 2.15 (s, 6H, CH3), 3.73 (s, 6H, CH3), 3.78 (s, 4H, CH2), 4.56
(s, 2H, CH2), 6.84 (d, 4H, J = 8.8 Hz, Haryl), 7.02 (d, 4H, J = 8.8 Hz, Haryl
13C NMR (CDCl3), δ: 26.8, 55.7 (CH3), 52.7 (CH2), 67.3 (C), 69.8 (CH2), 117.0
(CH), 127.1 (C), 130.0 (CH), 149.9, 203.5 (C)
)
VI
IR, ν˜/cm−1: 1693 (C O), 2821 (CHaliphatic), 3016 (CHaryl
)
—
—
1H NMR (CDCl3), δ: 2.21 (s, 6H, CH3), 2.33 (s, 6H, CH3), 3.78 (s, 4H, CH2), 4.33
(s, 2H, CH2), 7.02 (d, 4H, J = 8.6 Hz, Haryl), 7.14 (d, 4H, J = 8.6 Hz, Haryl
)
13C NMR (CDCl3), δ: 21.7, 23.9 (CH3), 52.9 (CH2), 67.1 (C), 70.0 (CH2), 113.7 (C),
114.3, 118.4 (CH), 126.7, 203.5 (C)
Fig. 1. Synthesis of HHP–ACAC conjugates I–VI (for R, see Table 1) and their conversion into pyrazoles VII–XIII and isoxazoles
XIV–XVIII (for R, see Table 2). Reaction conditions: i) ACAC (1 equiv), formaldehyde (3 equiv), amine (2 equiv), 5
mole % FeCl3, dichloromethane, ambient temperature, 24 h; ii) hydrazine or phenylhydrazine or hydroxylamine, abs.
EtOH, ambient temperature, 24 h.
formation. Additionally, the decomposition of a hex-
ahydropyrimidine ring can be confirmed by comparing
the signals at δH = 2.96 (s, 4H) and δC = 51.7 for the
CH2—C—CH2 group and at δH = 3.26 (s, 2H) and δC
= 70.9 for the N—CH2—N group present in the start-
ing compound with those at δH = 3.52 and δC = 39.3
for the only one CH2 group in the product. Clearly,
13C DEPT-135 assignments combined with the inte-
gration associated with the NMR signals, strongly sug-
gest the pyrimidine ring decomposition (note that due
to the symmetry of methyl groups, a six-proton sin-
glet was identified in both the starting material and
the product).
A similar analysis revealed the same conclusion
for isoxazole XIV formation. Specifically, symmetric
methyl groups of the starting compound II (δH and
δC respectively) (δH = 2.17, s, 6H; δC = 26.6) be-
came asymmetric in the product XIV (δH = 2.28, s,
3H; δC = 10.1; δH = 2.40, s, 3H; δC = 11.1). The for-
mation of an isoxazole ring system is evident due to
the disappearance of the signal for the carbonyl car-
bon (δC = 203.2) of reactant II, and the appearance
of new three quaternary carbons (confirmed by 13C
DEPT-135 spectra) of the isoxazole ring (δC: 111.1,
159.6, 166.7) of product XIV. The hexahydropyrimi-
dine ring decomposition was also confirmed by the dis-
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A. I. Saleh et al./Chemical Papers 69 (5) 729–736 (2015)
Table 2. Characterization data of compounds VII–XX
wi(calc.)/%
wi(found)/%
Compound
R
X
Formula
Mr
Yield/%
C
H
N
VII
VIII
IX
Cyclohexyl
4-Chlorophenyl
4-Bromophenyl
Phenyl
NH
NH
NH
NH
NH
NH
NPh
O
C12H21N3
C12H14ClN3
C12H14BrN3
C12H15N3
207.32
235.71
280.16
201.16
231.29
215.29
311.81
236.70
281.15
202.25
232.28
216.28
389.28
478.18
69.52
69.77
10.21
10.24
20.27
20.35
75
86
60
66
79
81
83
87
90
64
85
81
85
87
61.15
60.91
5.99
6.01
17.83
17.89
51.44
51.64
5.04
5.06
15.00
15.05
X
71.61
71.79
7.51
7.49
20.88
20.91
XI
4-Methoxyphenyl
4-Tolyl
C13H17N3O
C13H17N3
67.51
66.87
7.41
7.59
18.17
17.95
XII
72.52
71.79
7.96
8.05
19.52
19.11
XIII
XIV
XV
4-Chlorophenyl
4-Chlorophenyl
4-Bromophenyl
Phenyl
C
18H18ClN3
69.34
69.14
5.82
5.84
13.48
13.53
C12H13ClN2O
C12H13BrN2O
C12H14N2O
60.89
60.65
5.54
5.52
11.84
11.79
O
51.26
51.11
4.66
4.67
9.96
9.98
XVI
XVII
XVIII
XIX
XX
O
71.26
71.44
6.98
7.00
13.85
13.90
4-Methoxyphenyl
4-Tolyl
O
C13H16N2O2
C13H16N2O
67.22
66.45
6.94
7.00
12.06
11.90
O
72.19
73.01
7.46
7.71
12.95
13.08
–
–
C19H18Cl2N4O
C19H18Br2N4O
58.62
59.01
4.66
4.69
14.39
14.53
–
–
47.72
48.05
3.79
3.81
11.72
11.77
Fig. 2. Proposed mechanism of the formation of products VII–XVIII (for R and X, see Table 2); i) H2NXH; ii) loss of H2CO; iii)
—
loss of RN CH2.
—
appearance of the two CH2 groups (CH2—C—CH2)
(δH = 3.81, s, 4H; δC = 53.3) and one CH2 group
(N—CH2—N) (δH = 4.33, s, 2H; δC = 69.2) present
in the starting compound and the appearance of a sig-
nal (δH = 4.00, s, 2H; δC = 37.1) for only one CH2
group (C—CH2—N) in the product.
mediate hydrazones (A, Fig. 2). Cyclization of hydra-
zones leads to the pyrazole ring system forming in-
termediates B and C. It is assumed that the spiro-
intermediate B undergoes a hexahydropyrimidine ring
opening. The cleavage of bond between the spiro car-
bon and the CH2 group at the adjacent nitrogen is
accompanied by either hydroxyl group migration or
progression through a charged intermediate leading to
the formation of the pyrazole ring system in interme-
diate C. Under these circumstances, aromatization of
the hetero-ring on the expense of the HHP ring system
degradation is the driving force of this conversion. The
subsequent loss of the formaldehyde molecule and de-
composition of the resulting geminal diamine interme-
The above conclusions are supported by the FTIR
—
spectral analysis. The characteristic C O bands of
—
the starting compounds disappeared and the corre-
sponding bands associated with the newly formed
hetero-ring systems were observed.
Mechanistically, the HHP–ACAC conjugates I–VI
react with hydrazine via its nucleophilic addition to
the carbonyl group forming the corresponding inter-
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Table 3. Spectral data of compounds VII–XX
733
Compound
Spectral data
VII
IR, ν˜/cm−1: 1592 (C N), 2927 (CH), 3206 (NH)
—
—
1H NMR (CDCl3), δ: 1.02–1.20, 1.53–1.85 (m, 10H, Hcyclohexyl), 2.15 (s, 6H, CH3), 2.38–2.40 (m, 1H, CHcyclohexyl),
3.52 (s, 2H, CH2)
13C NMR (CDCl3), δ: 10.7 (CH3), 25.0, 26.0, 33.3, 39.3 (CH2), 56.0 (CH), 114.0, 142.3 (C)
—
VIII
IX
IR, ν˜/cm−1: 1638 (C N), 2926 (CH), 3419 (NH)
—
1H NMR (CDCl3), δ: 2.29 (s, 6H, CH3), 4.02 (s, 2H, CH2), 6.59 (d, 2H, J = 8.8 Hz, Haryl), 7.16 (d, 2H, J = 8.8 Hz,
Haryl
)
13C NMR (CDCl3), δ: 10.8 (CH3), 37.8 (CH2), 112.7 (C), 113.7 (CH), 122.0 (C), 129.1 (CH), 143.2, 146.8 (C)
IR, ν˜/cm−1: 1640 (C N), 2930 (CH), 3027 (CHaryl), 3448 (NH)
—
—
1H NMR (CDCl3), δ: 2.29 (s, 6H, CH3), 4.01 (s, 2H, CH2), 6.55 (d, 2H, J = 8.8 Hz, Haryl), 7.29 (d, 2H, J = 8.8 Hz,
Haryl
)
13C NMR (CDCl3), δ: 10.8 (CH3), 37.7 (CH2), 109.0, 112.6 (C), 114.2, 131.9 (CH), 143.8, 147.2 (C)
IR, ν˜/cm−1: 1638 (C N), 3445 (NH)
—
X
—
1H NMR (CDCl3), δ: 2.31 (s, 6H, CH3), 4.07 (s, 2H, CH2), 6.69–7.25 (m, 5H, Haryl
)
13C NMR (CDCl3), δ: 10.8
(CH3), 37.7 (CH2), 112.7 (CH), 113.0 (C), 117.5, 129.3 (CH), 143.3, 148.4 (C)
XI
IR, ν˜/cm−1: 1660 (C N), 3454 (NH)
—
—
1H NMR (CDCl3), δ: 2.28 (s, 6H, CH3), 3.79 (s, 3H, CH3), 4.02 (s, 2H, CH2), 6.65 (d, 2H, J = 9.2 Hz, Haryl), 6.85
(d, 2H, J = 9.2 Hz, Haryl
13C NMR (CDCl3), δ: 10.8 (CH3), 38.7 (CH2), 55.9 (CH3), 113.3, 114.0 (C), 114.6, 115.0 (CH), 142.8, 152.2 (C)
)
—
XII
XIII
XIV
IR, ν˜/cm−1: 1617 (C N), 3495 (NH)
—
1H NMR (CDCl3), δ: 2.00 (s, 3H, CH3), 2.28 (s, 6H, CH3), 4.51 (s, 2H, CH2), 6.38 (d, 2H, J = 8.8 Hz, Haryl), 6.92
(d, 2H, J = 8.8 Hz, Haryl
)
13C NMR (CDCl3), δ: 10.7 (CH3), 20.4 (CH3), 38.6 (CH2), 114.5, 115.3 (CH), 113.4, 114.0, 141.8, 152.3 (C)
IR, ν˜/cm−1: 1634 (C N), 3445 (NH)
—
—
1H NMR (CDCl3), δ: 2.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 4.08 (s, 2H, CH2), 6.61–7.40 (m, 9H, Haryl
)
13C NMR (CDCl3), δ: 10.9, 11.87 (CH3), 38.3 (CH2), 113.7 (CH), 114.9, 121.0 (C), 122.1, 124.9, 127.5, 129.1 (CH),
137.9, 139.8, 146.8, 148.3 (C)
IR, ν˜/cm−1: 1638 (C N), 3404 (NH)
—
—
1H NMR (CDCl3), δ: 2.28 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.00 (s, 2H, CH2), 6.58 (d, 2H, J = 8.6 Hz, Haryl), 7.17
(d, 2H, J = 8.6 Hz, Haryl
)
13C NMR (CDCl3), δ: 10.1, 11.1 (CH3), 37.1 (CH2), 111.1 (C), 113.0 (CH), 122.9 (C), 129.2 (CH), 146.2, 159.6,
166.7 (C)
IR, ν˜/cm−1: 1638 (C N), 3444 (NH)
—
XV
—
1H NMR (CDCl3), δ: 2.26 (s, 3H, CH3), 2.39 (s, 3H, CH3), 3.99 (s, 2H, CH2), 6.54 (d, 2H, J = 8.8 Hz, Haryl), 7.29
(d, 2H, J = 8.8 Hz, Haryl
)
13C NMR (CDCl3), δ: 10.2, 11.1 (CH3), 37.0 (CH2), 109.9, 111.1 (C), 114.4, 132.1 (CH), 146.7, 159.6, 166.7 (C)
IR, ν˜/cm−1: 1639 (C N), 3447 (NH)
—
XVI
—
1H NMR (CDCl3), δ: 2.34 (s, 3H, CH3), 2.45 (s, 3H, CH3), 4.25 (s, 2H, CH2), 6.72–7.27 (m, 5H, Haryl
)
13C NMR (CDCl3), δ: 10.1, 11.1 (CH3), 37.1 (CH2), 111.7 (C), 113.1, 118.4, 129.4 (CH), 147.7, 159.9, 166.9 (C)
IR, ν˜/cm−1: 1637 (C N), 3347 (NH)
—
XVII
—
1H NMR (CDCl3), δ: 2.28 (s, 3H, CH3), 2.39 (s, 3H, CH3), 3.78 (s, 3H, CH3), 3.99 (s, 2H, CH2), 6.65 (d, 2H, J =
8.8 Hz, Haryl), 6.83 (d, 2H, J = 8.8 Hz, Haryl
)
13C NMR (CDCl3), δ: 10.2, 11.1 (CH3), 38.1 (CH2), 111.6 (C), 114.6, 115.0 (CH), 141.8, 152.8, 159.8, 166.6 (C)
IR, ν˜/cm−1: 1618 (C N), 3457 (NH)
—
XVIII
—
1H NMR (CDCl3), δ: 2.28 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.01 (s, 2H, CH2), 6.60 (d, 2H, J =
8.4 Hz, Haryl), 7.05 (d, 2H, J = 8.4 Hz, Haryl
)
13C NMR (CDCl3), δ: 10.2, 11.1, 20.4 (CH3), 37.4 (CH2), 111.6 (C), 113.1, 129.84 (CH), 127.5, 145.5, 159.7, 166.5
(C)
—
—
XIX
XX
IR, ν˜/cm−1: 1639 (C N), 1790 (C O), 3503 (NH)
—
—
1H NMR (CDCl3), δ: 2.03 (s, 3H, CH3), 3.38 (d, 2H, J = 12.4 Hz), 3.60 (d, 2H, J = 12.4 Hz), 4.10 (d, 1H, J =
11.2 Hz), 5.12 (d, 1H, J = 11.2 Hz), 6.92 (d, 4H, J = 8.4 Hz), 7.29 (d, 4H, J = 8.4 Hz), 9.34 (brs, 1H)
13C NMR (CDCl3), δ: 17.8 (CH3), 51.3 (C), 53.1, 69.1 (CH2), 118.7, 129.6 (CH), 126.5, 147.3, 165.0, 175.4 (C)
IR, ν˜/cm−1: 1638 (C N), 1794 (C O), 3500 (NH)
—
—
—
—
1H NMR (CDCl3), δ: 2.02 (s, 3H, CH3), 3.39 (d, 2H, J = 12.6 Hz), 3.61 (d, 2H, J = 12.6 Hz), 4.10 (d, 1H, J =
11.6 Hz), 5.14 (d, 1H, J = 11.6 Hz), 6.86 (d, 4H, J = 8.8 Hz), 7.43 (d, 4H, J = 8.8 Hz), 8.70 (brs, 1H)
13C NMR (CDCl3), δ: 17.8 (CH3), 51.1 (C), 53.0, 68.6 (CH2), 113.8 (C), 119.0, 132.5 (CH), 147.6, 164.9, 175.0 (C)
diate lead to the formation of the products obtained.
The geminal diamine decomposition occurs as a result
of inherent instability of such intermediates, leading
to the formation of the respective by-product that was
confirmed by the NMR spectra. This decomposition is
a well established phenomenon and it has been found
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A. I. Saleh et al./Chemical Papers 69 (5) 729–736 (2015)
Fig. 3. Synthesis of pyrazol-3-one derivatives from HHP–ETAA conjugates (Saleh et al., 2014). Reaction conditions: i) hydrazine
hydrate, abs. EtOH, ambient temperature, 24 h (85 % and 87 % yield of XIX and XX, respectively).
to occur in both biological reactions and in certain
synthetic transformations (Moad & Benkovic, 1978).
It is clear that both the starting HHP derivative
and the intermediate C are considered to be geminal
diamines. However, HHP rings are known to be stable
and they have been found in several natural and syn-
thetic biologically active compounds, while geminal
diamines with their structure similar to that of inter-
mediate C are unstable (Moad & Benkovic, 1978).
It is highly probable that the formation of 4-
aminomethylisoxazole products by the reaction of II–
VI with hydroxylamine follows the same mechanism as
described above. The products obtained through this
route either with hydrazine or hydroxylamine forming
pyrazole and isoxazole ring systems, respectively, is
not entirely unusual. The formation of indazoles by the
reaction of azabicyclononanones with hydrazine, hy-
droxylamine, or methylhydrazine has been explained
on a similar mechanistic background (Neochoritis et
al., 2011). Also in this case, the driving force of such
transformations is the aromatization of the hetero-ring
system. Theoretical calculations performed for this
system indicate that the aromatization step is ther-
modynamically favorable.
There have been several attempts to apply the
above mechanism designed for HHP–ACAC conju-
gates to other substrates, in particular, hexahydropy-
rimidines conjugated with dibenzoylmethane (HHP–
DBM) and ethyl acetoacetate (HHP–ETAA), respec-
tively. Efforts to prepare HHP–DBM analogs under
the same conditions reported herein resulted in the
formation of monocarbonyl derivatives (5-benzoyl-1,3-
diazinans) (Saleh et al., 2014) which are unsuitable for
the current protocol.
analytical and spectral data are summarized in Ta-
bles 2 and 3. It is worth mentioning that the slightly
different chemical shift of the aromatic ring protons
observed for compounds XIX and XX might be due
to the differences in size, electronegativity, and the
degree of overlapping with aromatic π-electrons of
Cl versus Br substituents (the same phenomenon has
been observed for the corresponding anilines substi-
tuted in the para position).
The possibility of the HHP ring survival, un-
like the HHP–ACAC conjugates reported herein, can
be explained similarly. Specifically, aromatization of
the pyrazole/isoxazole ring systems causes the HHP
ring destruction, whereas the same factor is less pro-
nounced or even absent in the spiro-heterocyclic com-
pounds XIX and XX. Accordingly, the following mech-
anism can be proposed for such systems (Fig. 4) (Co-
civera et al., 1978; Katritzky et al., 1987).
In the first step, nucleophilic addition of a hy-
drazine nitrogen atom to the ketone group of the β-
ketoester proceeds to form a carbinolamine (Fig. 4,
route a) followed by the ring closure via hydrazone as
the intermediate. Alternatively, the carboxylate group
is attacked via the nucleophilic addition/elimination
mechanism (Fig. 4, route b) followed by the pyra-
zolone ring closure. For symmetrically substituted hy-
drazine, both routes ultimately produce the same
pyrazolone product. However, Cocivera et al. (1978)
demonstrated that route a is the main pathway for
HHP–ETAA conjugates.
Conclusions
A concise and good yielding procedure for the
preparation of 4-aminomethylpyrazoles and 4-amino-
methylisoxazoles from acetylacetone using reagents
with double nucleophilic centers, namely, hydrazine,
phenylhydrazine and hydroxylamine in two steps un-
der mild conditions has been proposed (Fig. 1). Ad-
ditionally, a suitable mechanism has been provided
(Fig. 2) and confirmed by a literature report consider-
ing a similar system (Neochoritis et al., 2011). A differ-
ent mechanism was observed when hexahydropyrim-
idines conjugated with ethyl acetoacetate were used
under the same conditions. This difference is, proba-
However, recent reports have introduced high-
yielding procedures for the reaction of ethyl acetoac-
etate with formaldehyde and primary amines to fur-
nish the corresponding hexahydropyrimidines in com-
parable yields (Latypova et al., 2013; Mukhopadhyay
et al., 2011). HHP–ETAA conjugates (Saleh et al.,
2014) have shown a different mechanism when treated
with hydrazine and, subsequently, different products
were obtained (Fig. 3). The products obtained in com-
parable yields were characterized as spiroheterocyclic
pyrazol-3-one compounds XIX and XX (Fig. 3). Their
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A. I. Saleh et al./Chemical Papers 69 (5) 729–736 (2015)
735
Fig. 4. Proposed mechanism for the formation of compounds XIX (R = 4-chlorophenyl) and XX (R = 4-bromophenyl).
bly, due to the presence of an ester group in the HHP–
ETAA conjugates.
cyclization steps for reaction between hydrazine and ethyl
acetoacetate. Canadian Journal of Chemistry, 56, 473–480.
DOI: 10.1139/v78-076.
Attempts to prepare the corresponding hexahy-
dropyrimidines conjugated with dibenzoylmethane
(HHP–DBM) have resulted in 5-benzoyl-1,3-diazi-
nans. Consequently, the dibenzoylmethane-system
was not studied. On the other hand, hexahydropyrim-
idines conjugated with asymmetric β-diketones (such
as 1-phenylbutane-1,3-dione) have been avoided at
this stage to focus rather on the mechanism than on
regio- or stereochemical complications possibly arising
from the reaction.
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Acknowledgements. The authors would like to thank the
Hashemite University for the support of this work. Our thanks
extend also to Fatmeh AlSoubani, Bassem Nassralla, and Hus-
sein Ghannam.
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