Synthesis of N-containing heterocycles via mechanochemical grinding and conventional techniques

Article abstract of DOI:10.14233/ajchem.2017.20798

Mechano heterocyclic chemistry is a recent quickly growing technique draws the attention of hetrocyclic chemists towards the use of grindstone technique in a solvent free green efficient clean synthesis of many heterocyclic systems. α,β-Epoxy ketones were used as a unique scaffold for synthesis of stable hydroxyazoles. The key advantage of grinding technique over the conventional thermal technique includes its simple, solvent free conditions, as well as facile work up with high yield economy. It is also successful in achieving three of the green chemistry objectives of a solvent free, high atom economy, save energy thus combining the features of both economic and environmental advantages.

Full text of DOI:10.14233/ajchem.2017.20798

Asian Journal of Chemistry; Vol. 29, No. 12 (2017), 2679-2686
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20798
Synthesis of N-Containing Heterocycles via Mechanochemical
Grinding and Conventional Techniques
1
1,*
1
1
2,3
AMIN F.M. FAHMY , AMIRA A. EL-SAYED , MAGDY M. HEMDAN , AYA I. HASSABALLAH and AHMED F. MABIED
1
2
3
Department of Chemistry, Faculty of Science, Ain Shams University, 11566, Abbasia, Cairo Egypt
X-ray Crystallography Lab., Solid State Physics Department, National Research Center, Dokki, Cairo, Egypt
Department of Basic Sciences, October High Institute for Engineering and Technology, 3rd District, 2nd Zone, 6th of October City, Egypt
Corresponding author: E-mail: amira_aa47@hotmail.com
Received: 22 May 2017; Accepted: 25 July 2017;
*
Published online: 30 October 2017;
AJC-18615
Mechano heterocyclic chemistry is a recent quickly growing technique draws the attention of hetrocyclic chemists towards the use of
grindstone technique in a solvent free green efficient clean synthesis of many heterocyclic systems. α,β-Epoxy ketones were used as a
unique scaffold for synthesis of stable hydroxyazoles. The key advantage of grinding technique over the conventional thermal technique
includes its simple, solvent free conditions, as well as facile work up with high yield economy. It is also successful in achieving three of
the green chemistry objectives of a solvent free, high atom economy, save energy thus combining the features of both economic and
environmental advantages.
Keywords: Green chemistry, Pyrazoles, Oxazoles, Imidazolidines, Oxazolidines.
mechano (grindstone) and conventional (thermal) techniques
for the synthesis of the target heterocyclic compounds from
the reaction of α,β-keto-oxarines with different nucleophiles.
INTRODUCTION
Oxazoles, pyrazoles and imidazoles derivatives are impor-
tant biological agents. Oxazoles have a broad spectrum of
biological and pharmacological activities such as antibacterial,
antifungal, pesticidal, insecticidal, anti-inflammatory and
antitumor [1]. Isoxazole derivatives exhibit various biological
activities such as, antibacterial, anticonvulsant, anticholes-
termic, anticancer, anthelmintics.Antiinflammatory, adenosine
antagonist, fungicidal, herbicidal, hypoglycemic, muscle
relaxant, nematocidal, insecticidal, antiviral and antimicrobial
2]. Pyrazoles used as antitumor, antibacterial and antifungal,
antiviral, antiparasitic, antitubercular, insecticidal agents, anti-
inflammatory, antidiabetic, aesthetic and analgesic properties
3]. Imidazole possess extensive spectrum of biological acti-
vities such as antibacterial, anticancer, antitubercular, anti-
fungal, analgesic and anti-HIV activities [4].
Recently, mechanochemistry offers a cleaner, more effi-
cient alternative to a majority of conventional transformations
5], however, mechano heterocyclic chemistry (MHC) [5,6]
draws the attention of heterocyclic chemists towards the uses
of grindstone technique in green efficient synthesis of many
heterocyclic systems [7-12].
In continuation of our work on uses of green mechano-
chemical synthesis of heterocyclic systems [13,14], we present
herein a comparative study between the efficient green
1
Different characterization methods were used; FTIR, H NMR,
13
C NMR, MS, in addition Single crystal X-ray study for iden-
tifying the stereo chemical structure of 1,3,5-triphenyl-4,5-
dihydro-1H-pyrazol-4-ol (2c).
EXPERIMENTAL
All the reagents and solvents were purchased from Merck
(Germany) and were used as received; commercially available
solvents were used without further purifications for crysta-
llizations of the obtained products (Adwek-Egypt). Melting
points were measured on an electro-thermal melting point
apparatus and were uncorrected. The elemental analyses were
done on a Vario El Elementar. The IR spectra were recorded
on FTIR Maltson (infinity series) spectrophotometer as KBr
[
[
1
13
discs. The H NMR and C NMR spectra were measured on
Varian Gemini 300 MHz spectrometer, with chemical shift
(δ) expressed in ppm downfield from TMS as internal standard,
[
in CDCl
3
or DMSO-d . Mass spectra were determined on
6
Shimadzu GC-MSQP 1000 EX instrument operating at 70 eV.
TLC was run using TLC aluminum sheets silica gel F254 (Merck).
It was carried out the monitoring of the progress of all reactions
and homogeneity of the synthesized compounds. X-ray study

2
680 Fahmy et al.
Asian J. Chem.
was performed at X-ray Crystallography Laboratory, Physics
Division, National Research Center (NRC), Egypt. Single
crystal diffractometer equipped with a CCD detector and a
liquid-nitrogen low-temperature device, on a Bruker-Nonius
FR590 X-ray generator with a molybdenum sealed tube. The
Kappa CCD, includes the state-of-the-art technologies for rapid,
precise and accurate data collection even with small crystals.A
charge-coupled device (CCD) detector allows many diffraction
spots to be collected.
General procedure for synthesis of compounds 1a,b:
Hydrogen peroxide (8 mL, 30 %) was added portion wise to
aryl-1-phenylprop-2-en-1-ones (0.01 mol) in acetone (30 mL),
methanol (10 mL) containing KOH (1 g) at 0 °C in an ice bath
with stirring for (75-120 min). The solid product was obtained,
filtered off and recrystallized from light petroleum ether (60/
calcd. (found) for C19
N, 9.72 (9.66).
1,3,5-Triphenyl-4,5-dihydro-1H-pyrazol-4-ol (2c):
Yellow crystals (EtOH), m.p. = 140-141 °C, H NMR (DMSO-
H
16
N
2
O: C, 79.14 (78.93); H, 5.59 (5.23);
1
d ) δ: 4.98 (d, 1H, J = 2.7 Hz), 5.13 (d, 1H, J = 2.7 Hz), 6.41
6
(br. s, 1H, OH, exchangeable), 6.71 (t, 1H, J = 7.2 Hz), 7.05
(d, 2H, J = 7.5 Hz), 7.15-7.43 (m, 10H, Ar-H), 7.84 (d, 2H, J
–1
= 7.2 Hz). IR (KBr, νmax, cm ): 3261 (OH), 3060, 3027 (C–
arom), 2929 (C–Halkyl), 1597(C=N), 691, 750 δ5H. MS (70 eV)
H
+
·
+·
+·
m/z (%): 297 (M -OH, 14), 296 (M -H
2
O, 62), 295(M -
(H O+H), 38), 181 (23), 180 (20), 133 (7), 91 (53), 77 (100).
2
Anal. calcd. (found) for C21
(5.63); N, 8.91 (9.12).
H
18
2
N O: C, 80.23 (79.96); H, 5.77
3-(Naphthalen-2-yl)-1,5-diphenyl-4,5-dihydro-1H-
pyrazol-4-ol (2d): Orange crystals (light petroleum 60/80 °C),
1
80 °C) [15,16].
m.p. = 184-185 °C, H NMR (CDCl
3
) δ: 5.22 (m, 1H), 5.30
(
m, 1H), 8.09 (br. s, 1H, OH, exchangeable), 6.71 (t, 2H, J =
Reaction of α,β-epoxy ketones 1a and 1b with hydrazine
hydrate and phenylhydrazine:
7
8
8
.5 Hz), 7.15-7.48 (m, 10H, Ar-H), 7.80-7.87 (m, 4H, Ar-H),
.18 (d, 1H, J = 9.0 Hz). C NMR (CDCl
3.67 (1C-OH), ar-C [113.34 (2CH), 120.09 (1CH), 123.77
13
3
) δ: 45.96 (1C-NH),
Under green solvent free grinding: A mixture of equiva-
lent amounts of α,β-epoxy ketones 1a/or 1b (3 mmol) with
hydrazine hydrate/or phenyl hydrazine (6 mmol) was mixed
for 5-7 min in a porcelain mortar and pestle in the presence of
a few drops of acetic anhydride (Table-1). Upon completion
of the reaction as monitored by TLC, the reaction mixture
turned coloured solid mass, washed with cold water and recrys-
tallized from suitable solvents to give compounds 2a-2d.
Under conventional thermal method: A solution of α,β-
epoxy ketones 1a or 1b (3 mmol) in ethanol (30 mL) was
refluxed for 6-14 h with hydrazine hydrate and/or phenyl
hydrazine (6 mmol) (monitored by TLC), then the reaction
mixture was vacuum-distilled to about half volume. The solid
product was obtained after cooling, filtered off and recrysta-
llized from the proper solvent to give same compounds 2a
and 2b.
(
(
3CH), 125.19 (2CH), 125.79 (2CH), 126.29 (2CH), 128.65
2CH), 129.29 (3CH), 133.46 (1C), 135.79 (1C), 136.09 (1C),
–1
1
3
7
3
36.40 (1C), 138.10 (1C)], 147.04 (C=N). IR (KBr, νmax, cm ):
539 (OH), 3045 (C–Harom), 2920 (C–Halkyl), 1596 (C=N), 695,
+.
+.
48 δ5H. MS (70 eV) m/z (%): 364 (M , 90), 365 (M + 1, 33),
+·
+·
47(M -OH, 9), 346 (M -H O, 13), 181 (100), 180 (20), 155
2
(
C
17), 104 (11), 91 (45), 77 (27). Anal. calcd. (found) for
O: C, 82.39 (82.41); H, 5.53 (5.33); N, 7.69 (7.55).
25
H
20
N
2
Reaction of α,β-epoxy ketones 1a and 1b with hydroxyl-
amine hydrochloride:
Under conventional thermal method: A solution of 1a
or 1b (3 mmol) in benzene (30 mL) and few drops of triethyl-
amine was refluxed for 12-24 h with an equivalent amount of
hydroxylamine hydrochloride (6 mmol), (TLC monitoring).
A solid product was obtained after cooling, was filtered off
and recrystallized from suitable solvents to give 3a or 3b. The
reaction failed under grinding conditions,
3
,5-Diphenyl-4,5-dihydro-1H-pyrazol-4-ol (2a): Yellow
1
crystals (EtOH), m.p. = 200-202 °C, H NMR (DMSO-d
.54 (d, 1H, J = 6.6 Hz), 4.98 (d, 1H, J = 6.3 Hz), 5.93 (br. s,
H, OH, exchangeable), 7.24-7.39 (m, 8H, Ar-H), 7.60 (br. s,
H, NH, exchangeable), 7.73 (d, 2H, J = 7.8 Hz). IR (KBr,
max, cm ): 3490 (OH), 3288, 3135 (NH), 3086 (C–Harom),
920, 2841 (C–Halkyl), 1584 (C=N), 694, 754 δ5H. MS (70 eV)
m/z (%): 221 (M -OH, 14), 220 (M -H
6
) δ:
4
1
1
ν
2
3,5-Diphenyl-4,5-dihydroisoxazol-4-ol (3a) (conven.):
Pale yellow crystals (EtOH), m.p. = 158-160 °C, H NMR
1
–1
(DMSO-d ) δ: 5.32-5.41 (m, 2H), 6.49 (br. s, 1H, OH,
6
exchangeable), 7.33-7.45 (m, 8H, Ar-H), 7.78 (d, 2H, J = 7.8
+
·
+·
+·
–1
2
O, 66), 219 (M -
Hz). IR (KBr, νmax, cm ): 3313 (OH), 3065, 3026 (C–Harom),
(
7
(
H
2
O+H), 5), 191 (13), 165 (6), 134 (99), 106 (100), 105 (12),
8 (17), 77 (90). Anal. calcd. (found) for C15 O: C, 75.61
75.34); H, 5.92 (5.85); N, 11.76 (11.59).
-(Naphthalen-2-yl-5-phenyl-4,5-dihydro-1H-pyrazol-
-ol (2b): Pale yellow crystals (benzene), m.p. = 200-201 °C,
2922, 2851 (C–Halkyl), 1595 (C=N), 687, 758 δ5H. MS (70 eV)
+·
+·
+·
H
14
N
2
m/z (%): 239 (M , 9), 222 (M -OH, 3), 221 (M -H O, 4), 193
2
(17), 165 (7), 133 (52), 120 (60), 104 (83), 85 (89), 77 (74),
71 (100). Anal. calcd. (found) for C15
H, 5.48 (5.22); N, 5.85 (5.50).
3-(Naphthalen-2-yl)-5-phenyl-4,5-dihydroisoxazol-4-ol
(3b) (conven.): Pale yellow crystals (light petroleum ether 60/
80 °C), m.p. = 168-170 °C, H NMR (DMSO-d
(m, 2H), 6.62 (br. s, 1H, OH, exchangeable), 7.37-7.57 (m,
3
H
13NO : C, 75.30 (75.18);
2
4
1
H NMR (CDCl
3
) δ: 4.41 (m, 2H), 5.52 (br. s, 1H, OH, exchan-
geable), 7.20-7.39 (m, 4H, Ar-H), 7.55-7.57 (m, 2H, Ar-H),
1
7
1
8
.85-7.93 (m, 2H, Ar-H), 8.14 (d, 4H, J = 8.4 Hz), 8.50 (br. s,
6
) δ: 5.47-5.54
13
H, NH, exchangeable). C NMR (CDCl
3
) δ: 45.88 (1C-NH),
13
1.51 (1C-OH), ar-C [123.85 (3CH), 128.70 (4CH), 135.33
7H, Ar-H), 7.92-7.96 (m, 4H, Ar-H), 8.30 (m, 1H, Ar-H). C
NMR (DMSO-d ) δ: 82.86 (1C-OH), 89.42 (1C-O), ar-C
(
1
(
5CH), 135.88 (1C), 135.99 (1C), 136.17 (1C), 136.25 (1C)],
6
–1
45.32 (C=N). IR (KBr, νmax, cm ): 3420 (OH), 3266, 3135
[123.72 (2CH), 125.75 (3CH), 127.29 (2CH), 127.70
(2CH+1C), 128.40 (3CH), 132.60 (1C), 133.39 (1C), 138.67
NH), 3085, 3062 (C–Harom), 2923, 2842 (C–Halkyl), 1598
+·
–1
(C=N), 698, 754 δ5H. MS (70 eV) m/z (%): 289 (M + 1, 24),
(1C)], 157.65 (C=N). IR (KBr, νmax, cm ): 3370 (OH), 3048
+
+·
+·
2
1
88 (M , 100), 271 (M -OH, 10), 270 (M -H
2
O, 42), 241 (8),
(C–Harom), 2923, 2852 (C–Halkyl), 1613(C=N), 691, 749 δ5H.
+.
65 (6), 184 (47), 154 (90), 127 (50), 106 (40), 77 (19). Anal.
MS (70 eV) m/z (%): 289 (M , 0.3), 274 (6), 269 (13), 228

Vol. 29, No. 12 (2017)
Synthesis of N-Containing Heterocycles via Mechanochemical Grinding and Conventional Techniques 2681
+
·.
(
12), 194 (7), 155 (30), 127 (32), 108 (100), 91 (15). Anal.
(C=S), 693, 747 δ5H. MS(EI): (70 eV) m/z (%): 282 (M , 2),
calcd. (found) for C19
N, 4.84 (5.02).
H15NO
2
: C, 78.87 (78.69); H, 5.23 (5.18);
249 (5), 191 (4), 177 (5), 105 (93), 91 (52), 85 (85), 77 (79),
71 (100).Anal. calcd. (found) for C16
H, 5.00 (5.21); N, 9.92 (9.84).
H
14
N OS: C, 68.06 (67.77);
2
Reaction of α,β-epoxy ketones 1a and 1b with urea,
thiourea, guanidine hydrochloride and semicarbazide
4
-(2-Naphthoyl)-5-phenylimidazolidin-2-thione (4d):
Pale yellow crystals (EtOH), m.p. = 186-188 °C, H NMR
(CDCl ) δ: 3.52 (d, 1H, J = 13.8 Hz), 3.60 (d, 1H, J = 14.1
Hz), 7.06-7.20 (m, 2H, Ar-H), 7.23-7.25 (m, 2H, Ar-H), 7.53-
7.55 (m, 3H, Ar-H), 7.70 (d, 1H, J = 8.1 Hz), 7.82-7.87 (m,
3H,Ar-H), 7.93 (d, 1H, J = 8.7 Hz), 8.03 (br. s, 1H, NH, exchan-
1
Under green solvent free grinding; A mixture of equiva-
lent amounts of α,β-epoxy ketones 1a or 1b (3 mmol) with
urea (3 mmol) was mixed for 2-3 min in a porcelain mortar and
pestle in the presence of a few drops of acetic anhydride (Table-
3
1
). Upon completion of the reaction as monitored by TLC, the
geable), 8.68 (br. s, 1H, NH, exchangeable). IR (KBr, νmax,
–1
reaction mixture turned coloured solid mass, washed with cold
water and recrystallized from suitable solvents to give compounds
cm ): 3340, 3187 (NH), 3060, 3029 (C–Harom), 2920, 2952
(C–Halkyl), 1725 (C=O), 1384 (C=S), 698, 746 δ5H. MS(EI):
+·.
+·.
+·
4a,b. Similar treatment was carried out in case thiourea with
(70 eV) m/z (%): 332 (M , 4), 333 (M +1, 1), 334 (M +2,
time 4-10 min to give 4c,d and semicarbazide within 8 min to
give 6 and 7, while the reaction was failed with guanidine.
Under conventional thermal method: A solution of com-
pounds 1a or 1b (3 mmol) in ethanol (30 mL) was refluxed for
0.33), 241 (13), 225 (3), 154 (100), 127 (42), 91 (48), 127
(41), 91 (18), 77 (11). Anal. calcd. (found) for C20
H
16
N OS:
2
C, 72.26 (72.11); H, 4.85 (4.62); N, 8.43 (8.17).
5-Benzoyl-4-phenyloxazolidin-2-one (5a) (conven.):
2
-3 h with urea (3mmol) in the presence of a catalytic amount
Colourless crystals (light petroleum ether 60/80 °C), m.p. =
1
of potassium hydroxide (monitored by TLC), then the reaction
mixture was vacuum-distilled to about half volume and acidified
with dilute hydrochloric acid. A solid product was obtained,
filtered off and recrystallized from a proper solvent to give the
same compound 4a,b. Similar treatment was carried out in
case thiourea to give compounds 4c,d, guanidine hydrochloride
to give 5a,b and semicarbazide to give 6 and 7.
288-290 °C, H NMR (DMSO-d
6
) δ: 3.06 (d, 1H, J = 13.5
Hz), 3.28 (d, 1H, J = 13.5 Hz), 7.16-7.20 (m, 4H, Ar-H), 7.26
(d, 2H, J = 6.9 Hz), 7.34 (t, 2H, J = 7.2 Hz, J = 7.5 Hz), 7.53
(d, 2H, J = 7.2 Hz), 8.37 (br. s, 1H, NH, exchangeable). IR
–1
(KBr, νmax, cm ): 3373-3285 (NH), 3055, 3027 (C–Harom),
2970, (C–Halkyl), 1702 (C=O), 1658 (C=O), 699, 755 δ5H. MS
+·.
(EI): (70 eV) m/z (%): 267 (M , 4), 253 (56), 250 (3), 239
(65), 211 (37), 105 (72), 91 (100), 77 (72), 65 (28). Anal.
4
-Benzoyl-5-phenylimidazolidin-2-one (4a): Pale yellow
1
crystals (EtOH), m.p. = 180-181 °C, H NMR (DMSO-d
.96 (d, 1H, J = 13.5 Hz), 3.47 (d, 1H, J = 13.5 Hz), 7.20-7.28
m, 5H, Ar-H), 7.34-7.45 (m, 3H, Ar-H), 7.62 (d, 2H, J = 7.5
Hz), 8.67 (br. s, 1H, NH, exchangeable), 10.45 (br. s, 1H, NH,
6
) δ:
calcd. (found) for C16
N, 5.24 (5.50).
H
13NO : C, 71.90 (71.79); H, 4.90 (4.71);
3
2
(
5-(2-Naphthoyl)-4-phenyloxazolidin-2-one (5b) (conven.):
1
Colourless crystals (acetic acid), m.p. = 138-140 °C, H NMR
–1
exchangeable). IR (KBr, νmax, cm ): 3259, 3310 (NH), 3060,
(DMSO-d ) δ: 3.21 (d, 1H, J = 13.2 Hz), 3.41 (d, 1H, J = 13.2
6
3031 (C–Harom), 2976, 2925 (C–Halkyl), 1715 (C=O), 698, 760
Hz), 7.19-7.33 (m, 5H, Ar-H), 7.47-7.53 (m, 2H, Ar-H), 7.73
+·.
δ
5H. MS (EI): (70 eV) m/z (%): 266 (M , 1.4), 175 (80), 104
(d, 1H, J = 8.4 Hz), 7.88-7.92 (m, 3H, Ar-H), 8.0 (m, 1H, Ar-
13
(
100), 91 (54), 77 (35), 65 (14). Anal. calcd. (found) for
: C, 72.16 (72.33); H, 5.30 (5.41) ; N, 10.52 (11.67).
-(2-Naphthoyl)-5-phenylimidazolidin-2-one (4b): Yellow
H), 8.38 (br. s, 1H, NH, exchangeable). C NMR (DMSO-d )
6
C
16
H
14
N O
2 2
δ: 43.13 (1C-NH), 71.45 (1C-O), ar-C [123.82 (1CH), 126.24
(2CH), 127.39 (3CH), 130.31 (6CH), 131.97 (1C), 132.54
(1C), 136.09 (1C), 138.69 (1C)], 170.45 (C=O), 187.54 (C=O).
4
1
crystals (EtOH), m.p. = 229-230 °C, H NMR (DMSO-d
.10 (d, 1H, J = 13.2 Hz), 3.62 (d, 1H, J = 13.2 Hz), 7.25-7.33
m, 5H, Ar-H), 7.53-7.56 (m, 2H, Ar-H), 7.80 (d, 1H, J = 8.4
Hz), 7.92-8.00 (m, 3H, Ar-H), 8.14 (m, 1H, Ar-H), 8.74 (br. s,
H, NH, exchangeable), 10.49 (br. s, 1H, NH, exchangeable).
6
) δ:
–1
3
(
IR (KBr, νmax, cm ): 3320, 3235 (NH), 3060, 3030 (C–Harom),
2922, 2851 (C–Halkyl), 1715 (C=O), 1645 (C=O), 700, 749 δ5H.
+·.
MS(EI) (70 eV) m/z (%): 317 (M , 0.2), 281 (1), 267 (1), 149
1
(13), 127 (14), 111 (18), 91 (13), 77 (11), 60 (100). Anal.
13
C NMR (DMSO-d
C [124.30 (1CH), 126.57 (2CH), 127.43 (3CH), 128.08 (4CH),
30.49 (2CH), 132.30 (1C), 132.49 (1C), 134.82 (1C), 136.89
6
) δ: 65.49 (1C-NH), 70.36 (1C-NH), ar-
calcd. (found) for C20
N, 4.41 (4.37).
H
15NO : C, 75.70 (75.62); H, 4.76 (4.59);
3
1
6-Benzoyl-5-phenyl-1,3,4-oxadiazinan-2-one (6): Pale
–1
(
3
1C)], 155.94 (C=O), 175.31 (C=O). IR (KBr, νmax, cm ):
yellow crystals (light petroleum ether 60/80 °C), m.p. = 202-
1
285(NH), 3059, 3032 (C–Harom), 2922 (C–Halkyl), 1721 (C=O),
204 °C, H NMR (DMSO-d
6
) δ: 3.83 (d, 1H, J = 12.6 Hz),
+·.
7
00, 747 δ5H. MS (EI): (70 eV) m/z (%): 316 (M , 1), 225
3.96 (d, 1H, J = 13.2 Hz), 7.13-7.67 (m, 9H, Ar-H), 7.88 (m,
(
100), 154 (60), 91 (54), 127 (41), 91 (18), 77 (7), 65 (6).
Anal. calcd. (found) for C20 : C, 75.93 (75.71); H, 5.10
4.85); N, 8.86 (9.05).
-Benzoyl-5-phenylimidazolidin-2-thione (4c): Yellow
1H, Ar-H), 10.53 (br. s, 1H, NH, exchangeable), 13.53 (br. s,
–1
H
16
N O
2 2
1H, NH, exchangeable). IR (KBr, νmax, cm ): 3388, 3231 (NH),
(
3061, 3028 (C–Harom), 2969, 2924 (C–Halkyl), 1689, 1631
+·.
4
(C=O), 693, 756 δ5H. MS (EI)(70 eV) m/z (%): 282 (M , 0.04),
1
crystals (EtOH), m.p. = 215-218 °C, H NMR (DMSO-d
.08 (d, 1H, J = 13.2 Hz), 3.49 (d, 1H, J = 13.8 Hz), 7.20-7.32
m, 5H, Ar-H), 7.35-7.51 (m, 3H, Ar-H), 7.58-7.59 (m, 2H,
Ar-H), 10.75 (br. s, 1H, NH, exchangeable), 11.49 (br. s, 1H,
6
) δ:
250 (1), 237 (2), 178 (8), 150 (25), 105 (20), 104 (100), 91
3
(
(93), 77 (62), 65 (16). Anal. calcd. (found) for C16
H
14
N
2
O : C,
3
68.07 (67.79); H, 5.00 (4.83); N, 9.92 (9.70).
3-(Naphthalen-2-yl)-5-phenyl-1H-pyrazole-1-carboxa-
–1
NH, exchangeable). IR (KBr, νmax, cm ): 3325, 3234 (NH),
087, 3063 (C–Harom), 2957, 2921 (C–Halkyl), 1727 (C=O), 1387
mide (7): Yellow crystals (light petroleum ether 60/80 °C),
1
3
m.p. = 119-120 °C, H NMR (DMSO-d
6
) δ: 7.09-7.19 (m, 2H,

2
682 Fahmy et al.
Asian J. Chem.
Ar-H), 7.59-7.67 (m, 4H, Ar-H), 7.94-7.99 (m, 5H, Ar-H),
.09 (d, 1H, J = 7.8 Hz), 8.60 (s, 1H), 12.97 (br. s, 2H, CONH ,
E. coli (ATCC-25923), Salmonella typhi, Staphylococcus aureus
(ATCC-25923), Candida albicans (ATCC-10231) and Asper-
gillus flavus. For the antibacterial assay, a standard inoculum
8
2
13
exchangeable). C NMR (DMSO-d
6
) δ: ar-C [125.10 (5CH),
27.55 (2CH), 127.62 (2CH), 128.01 (2CH), 128.14 (2CH),
29.22 (4C)], 132.08 (C=C), 134.87 (C=N), 167.37 (C=O).
5
1
1
(10 CFU/mL) was distributed on the surface of the agar plates
using a sterile glass spreader, whereas for the antifungal assay
a loopfull of a particular fungal isolate was transferred to (3 mL)
sterile saline to get a suspension of the corresponding species;
(0.1 mL) of the spore suspension was distributed on the surface
of sterile Sabouraud dextrose agar plates. Six millimeter diameter
wells were punched in the agar media and filled with 100 µL
of the tested chemical compound (500 µg/mL in DMSO) which
is previously sterilized through 0.45 sterile membrane filter.
The plates were kept at room temperature for 1-2 h, then incu-
bated at 37°C for 24 h for bacteria and at 30 °C for 4 days for
fungi. Commercial antibiotic discs were used as positive refe-
rence standard to determine the sensitivity of the strains [25].
Determination of the minimum inhibitory concentration
–1
IR (KBr, νmax, cm ): 3423 (NH), 3052 (C–Harom), 2921, 2849
+·
(C–Halkyl), 1699 (C=O). MS (EI) (70 eV) m/z (%): 313 (M ,
3
1
6), 270 (11), 256 (7), 240 (22), 172 (9), 155 (100), 127 (89),
05 (56), 91 (27), 77 (33).Anal. calcd. (found) for C20 O:
H
15
N
3
C, 76.66(76.49); H, 4.82(4.90); N, 13.41(13.23).
Crystal structure determination of compound 1,3,5-triphenyl-
4
,5-dihydro-1H-pyrazol-4-ol (2c):
A suitable single crystal of 2c has been selected and mounted
onto thin glass fiber. The X-ray single crystal diffraction data
were collected at the ambient temperature (298 K) on an Enraf-
Nonius 590 diffractometer with a Kappa CCD detector [17].
Reflection data has been recorded in the rotation mode using
the φ and ω scan technique. The structure was solved using
direct methods with SHELXS97 [18] and refined on F2 using
all data by full-matrix least square procedures with SHELXS97
(
MIC) of the chemical compounds: Compounds inhibiting
the growth of the above microorganisms were tested for their
MIC by the broth dilution method [26]. The nutrient broth
and the yeast extract broth media containing 1 mL of the serial
dilutions of the tested compounds (3.125, 6.25, 12.5, 25,50
µg/mL) were inoculated with the microbial strains, the bacterial
cultures were incubated at 37 °C for 24 h, whereas the fungal
ones were incubated at 30 °C for 48 h. The lowest concentration
required to arrest the microbial growth was regarded as the
MIC of the tested compounds.
[
18] implemented in maXus program suit [19]. The non-
hydrogen atoms were refined with anisotropic displacement
parameters.All hydrogen atoms were positioned geometrically
and were initially refined with soft restraints on the bond lengths
and angles to regularize their geometry (C–H in the range 0.93-
0.98, O–H = 0.82 and N–H in the range 0.86-0.89) and Uiso(H)
(
in the range 1.2-1.5 times Ueq of the parent atom). Then, the
positions were refined with riding constraints [20]. The general-
purpose crystallographic tool PLATON [21] was used for the
structure analysis and presentation of the results. The molecular
graphics were done using ORTEP-3 for Windows [22] and
DIAMOND [23] programs. Details of the data collection condi-
tions and the parameters of the refinement are given in Table-1.
The full crystallographic information can be obtained free
of charge using deposit number CCDC 1439398, via http://
www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-
mail: deposit@ccdc.cam.ac.uk.
Assessment of the antimicrobial activity using the agar
well diffusion technique: The chemically synthesized com-
pounds were screened for their antibacterial and antifungal
activities using the agar well diffusion technique [24]. The
microorganisms (reference and clinical isolates) used include
RESULTS AND DISCUSSION
Grinding of α,β-epoxy ketones (1a,1b)[15,16] with hydra-
zine hydrate and/or phenyl hydrazine at room temperature in
a porcelain mortar under solvent-free conditions produced
stable pyrazoline-4-ol derivatives (2a-d) in shorter reaction
time (5-7 min) and high yields (80-93 %). However, refluxing
solution of 1a,b with hydrazine hydrate and/or phenyl hydra-
zine in ethanol afforded the same compounds 2a-d in a longer
reaction time and moderate to high yields (59-83 %). The reaction
probably takes place according to the following Scheme-I.
Treating solutions of 1a and 1b with hydroxylamine hydro-
chloride in benzene and in the presence of a catalytic amount
of triethyl amine gave the isoxazoline-4-ol derivatives (3a,b)
as shown in Scheme-I. However, the reaction failed under solvent
free grinding conditions. α,β-Epoxy ketones are considered
as a unique scaffold for synthesis of stable hydroxy azoles [27].
TABLE-1
SINGLE CRYSTAL EXPERIMENTAL DETAILS OF 2c (SEE THE SUPPLEMENTARY
FILE WHICH CONTAINS 2c-REVISED.CIF AND ORT VIEW MATRIX)
Crystal data
CCDC
1,3,5-Triphenyl-4,5-dihydro-1H-pyrazol-4-ol (2c)
1439398
Chemical formula
Mr
C H N O
314.39
2
1
18
2
Crystal system, space group
Temperature (K)
a, b, c (Å)
Triclinic, P-1
298
11.9162 (4), 12.4930 (5), 13.9404 (7)
a, b, g (°)
V (Å )
Z
108.9591 (14), 113.268 (2), 95.0969 (14)
1745.84 (13)
4
3
No. of measured, independent and observed [I > 2σ(I)] reflections
8904, 8904, 1228

Vol. 29, No. 12 (2017)
Synthesis of N-Containing Heterocycles via Mechanochemical Grinding and Conventional Techniques 2683
R
Ph
H
N
N
N
2
NH (C=X)NH2
X
Ar
NH NHR
O
2
EtOH / KOH
N
H
Ph
Grinding & Conventional
3
Grinding & Conventional
2a-d
-10 min & 120-180 min
5-7 min & 420-840 min
4a) Ar = Ph,
b) Ar = 2-naphthyl, X = O
X = O
HO
Ar
4
2a) Ar = Ph,
2b) Ar = 2-naphthyl, R = H
R = H
4
c) Ar = Ph, X = S
O
O
4d) Ar = 2-naphthyl, X = S
1a,b
2
c) Ar = Ph,
R = Ph
2d) Ar = 2-naphthyl, R = Ph
Ph
H
N
Ar
1
Ph
O
N
2
NH (C=NH)NH2
O
NH OH.HCl
O
2
Ph
1
1
a) Ar = Ph
b) Ar = 2-naphthyl
EtOH / KOH
Conventional
60-840 min
O
Conventional
3
5a) Ar = Ph
b) Ar = 2-naphthyl
720-1440 min
Ar
3a) Ar = Ph
b) Ar = 2-naphthyl
Ar
5
3
OH
Scheme-I: Synthesis of pyrazoles 2a-d and 1, 2-oxazoles 3a,b
NH NH(C=O)NH2 /KOH/EtOH
2
Structures of the synthesized pyrazolin-4-ol derivatives
a-d and 1,2-oxazolin-4-ol derivatives (3a,b) was confirmed
from: (i) The data obtained from previously similar work [28].
-
H O
-
NH3
2
2
Grinding & Conventional
8 min & 270 min
Grinding & Conventional
8 min & 300 min
O
(
(
ii) Their microanalytical and spectral data. Thus, their infrared
IR) spectra showed broad bands corresponding to bonded
H
NH
2
N
O
-1
HN
OH groups in the range 3490-3313 cm and bands at 1613-
N
-1
1
N
1
3
584 cm correlated to C=N groups. Their H NMR of 2a-d,
O
Ph
a,b revealed signals due to two adjacent methine protons and
Ph
aromatic protons and in addition to OH protons that exchan-
Ar
COPh
13
6
7) Ar = 2-naphthyl
geable with D
a, 2d and 3b showed signals corresponding to their carbon
atoms skeleton
Mass spectra showed the molecular ion M, M-H
2
O shake. The C NMR spectra of compounds
Scheme-II: Synthesis of imidazolidines 4a-d, 1,3-oxazolidines 5a,b,
oxadiazine 6 and pyrazole 7 derivatives
2
2
O, M-
-1
-1
cm and bands at 1727-1631 cm due to C=O groups. Their
H NMR spectra showed absorption signals of the two adjacent
methine protons with coupling constant in the range 13.2-14.1
Hz, except compound 7 didn’t show these signals; in addition
to signals of their aromatic protons and broad signals in the
OH peaks and mass fragmentation pattern in accord with the
presence of OH group in their proposed structures.
Grinding 1a,b with urea and/or thiourea in a porcelain
mortar and pestle in the presence of a few drops of acetic anhy-
dride for 3-10 min afforded imidazolidine derivatives 4a-d
after shorter reaction time (3-10 min) with high yields (82-
1
down field region for NH protons that exchangeable with D O
2
13
shake. The C NMR spectra showed carbon chemical shift
values of compounds 4b, 5b and 7 correspond very well with
their carbon atoms. Their mass spectra showed the molecular
ion peaks and mass peaks inconsistent with their proposed
structures.
In order to compare the efficiency of green grinding [12]
and conventional (thermal) reactions leading to the target
heterocycles 2, 4, 6 and 7 and their associated economy. We
used the concept of atom economy (AE) [29] to expresses the
efficiency of the reactants to give the desired product. However,
the atom economy values were the same for the mechano-
chemical and conventional procedures because we used two
alternative reaction conditions to obtain the same target
compounds.
We consequently introduced yield economy (YE) [13,14]
as a metric to assess the conversion efficiency of these two
different approaches. The yield economy basically measures
how much yield (%) of the desired product is obtained over a
certain reaction time (i.e., yield (%)/reaction time (min)). A
higher yield economy is, therefore, indicative of a higher level
of conversion and much more efficient chemical process and
more economical reaction. The yield economy of a reaction
can be calculated using the following equation.
86 %). Treatment of solutions of epoxides 1a and 1b in ethanol
with urea and/or thiourea in the presence of catalytic amounts
of potassium hydroxide afforded same compounds 4a-d after
longer reaction time (2-3 h) with yields (71-80 %). Similar,
treatment of 1a and 1b with guanidine hydrochloride gave
oxazolidine derivatives 5a and 5b, respectively, however, the
reaction failed under grinding conditions. On the other hand,
the reactions of compounds 1a, b with semicarbazide afforded
1, 3, 4-oxadiazin derivative 6 and pyrazole derivative 7, respec-
tively under grinding and conventional techniques as shown
in Scheme-II.
Scheme-II shows that pyrazolidines 4 and oxazolidines
5
contains C=O group which means that the reaction may go
via a mechanism based on the behaviour of ureas and guanidine
as bis-nucleophiles started attack by NH group of ureas and/
2
or guanidine on the β-carbon atom of keto-oxiranes to give an
open chain non-isolable intermediate which under-goes cyclo-
dehydration or cyclo-deammoniation on α-carbon atom of
oxirane ring to give compounds 4-, 5-, respectively.
The structures of the synthesized compounds 4-7 were
supported from: (i) The data from previously similar work with
thiourea and semicarbazides [28]. (ii) Their microanalytical
and spectral data. Thus, their infrared spectra showed absorption
bands correlated with their NH groups in the range 3423-3187
Yield economy (YE) =Yield (%)/Reaction time (min) [13,14]

2
684 Fahmy et al.
Asian J. Chem.
Yield economy was used in this study to provide a decisive
conventional thermal reactions. That is due to the fact that, in
solutions, particles get the energy to react from heat. But in
grinding, energy is imparted through friction.
assessment of the yields obtained under the mechanochemical
and conventional conditions (Table-1). Assessing a chemical
reaction based entirely on its percentage yield can be misleading
13,14]. For example, the yields for compound 2a under the
mechanochemical and conventional conditions were 93 and
3 %, respectively, with a difference of only 10 %. However,
the yield economy values for the mechanochemical and conven-
tional conditions were 18.6 and 0.19, respectively, representing
a much bigger difference and highlighting the of the former
approach. Similar trends were observed for all of the other
compounds in the series. The yield economy values of 2-7 are
listed in Table-2.
It is observed from Table-2, that the mechano [Grindstone]
green synthesis of the target heterocyclic compounds takes
place under solvent free conditions in a shorter time with high
yield economies and low energy in comparison with the
Crystal structure of 2c: Single crystal X-ray diffraction
results of the compound 1, 3,5-triphenyl-4,5-dihydro-1H-pyrazol-
4-ol (2c) found it to be crystallized in a triclinic system with
space group P-1 possessing four molecules in the unit cell.
The crystal structure contains two independent molecules in the
asymmetric unit with almost identical conformation as shown
in ORTEP view (Fig. 1). The structure of 2c represents a pyrazo-
line derivative, where pyrazol-4-ol moiety attached with three
phenyl rings at the atoms C2, C4 and N6 (referring to one of
the independent molecules for simplicity), as shown in Fig. 1.
The consistency of the geometrical parameters of the
structure was performed through MOGUL software and
Cambridge Structural Database (CSD V5.36) [30]. MOGUL
search was selected to base the choice of similar fragments in
[
8
TABLE-2
PHYSICAL DATA OF THE TARGET HETEROCYCLES (2-7) UNDER GRINDING AND CONVENTIONAL (THERMAL) REACTIONS
Thermal method
Grinding method
No.
AE
YE(Th/G)
Time (min)
420
Yield (%)
83
m.p. (°C)
198-0
200-2
140-1
186-9
158-0
168-0
182-4
232-5
214-6
187-0
288-0
138-0
202-5
118-0
Time (min)
Yield (%)
m.p. (°C)
200-2
200-1
140-1
184-5
-
2a
5
7
7
6
-
93
90
85
80
-
86.92
88.89
94.57
95.29
81.14
84.15
93.66
94.61
94
94.86
83.57
85.80
94.31
89.68
0.19/18.6
0.18-12.85
0.12/12.14
0.07/13.33
-
2b
360
600
840
720
1440
120
180
150
180
840
360
270
300
65
77
59
74
57
80
81
71
80
84
90
40
2c
2d
3a
3b
-
-
-
-
4a
3
5
4
10
-
-
8
8
86
86
82
88
-
-
60
86
180-1
229-0
215-8
186-8
-
0.66/28.66
0.45/17.2
0.47/20.5
0.44/8.80
-
4b
4c
4d
5a
5b
-
-
6
7
202-4
119-0
0.14/7.50
0.13/10.75
39
NOTE: AE = atom economy, YE = yield economy
Fig. 1. A view of the structure of the two independent molecules of (2C), A left and B right; showing the atom-labeling scheme. Displacement
ellipsoids are drawn at the 30 % probability level

Vol. 29, No. 12 (2017)
Synthesis of N-Containing Heterocycles via Mechanochemical Grinding and Conventional Techniques 2685
the CSD considering that the unusual report of exact fragments
must have numbers less than 15 to bonds, angles and rings
and 40 to torsion angles. The results showed that the bond
lengths, bond angles and torsions are in good agreement with
each other and also with pre-determined structures having
similar moieties.
TABLE-3
HYDROGEN-BOND GEOMETRY (Å, °) OF 2C
D–H···A
D–H
H···A
D···A
D–H···A
114.2 (6)
110.1(2)
i
O3–H3···O29
C29–H29··· O3
0.960(6)
0.960(3)
2.19 1(7)
2.24 2(4)
2.722(6)
2.725(5)
ii
Symmetry codes: (i) 1-x, 1-y,-z; (ii) 1+X, Y, Z
However, MOGUL reported slight differences, in C2-N6
bond length (1.443 Å) where the nearest bond length in the
MOGUL distribution is 1.451 Å. Also, the torsion angles
C10C11C2N6 and C12C11C2N6 where the difference bet-
ween their values and the nearest torsion angles in the MOGUL
distribution (dmin) are 0.143° and 1.869 respectively. This
slight variation could be explained due to the effect of the
steric hindrance and crystal packing.
Fig. 3. A view of the molecular packing of the compound 2C, O–H···O
interactions are shown as green dashed lines
The molecular packing explains the stability of hydroxy
azoles towards aromatization due to the strong hydrogen
bonding once it is formed.
Screening of the antimicrobial activity of the chemi-
cally synthesized compounds: The possible antimicrobial
activities of the synthesized heterocyclic compounds 2b, 2d,
3
b, 4b, 4d and 5b were investigated against five reference
microbial isolates including; Gram-negative Escherichia coli
ATCC-25922) and Salmonella typhi, Gram-positive Staphy-
lococcus aureus (ATCC-25923) and Fungi Candida albicans
(
(
ATCC-10231) and Aspergillus flavus as shown in Table-4.
Fig. 2. Molecular structure of one of the independent molecules (A) of 2C
TABLE-4
shows the atom labeling. Displacement ellipsoids are drawn at the
ANTIMICROBIAL ACTIVITY OF CHEMICALLY
SYNTHESIZED COMPOUNDS
30 % probability level
Inhibition zone diameter (mm/mg sample)
Compd.
Calculations of the least-squares plane passing through
the consisting atoms of every moiety separately in the two
independent molecules (Fig. 1) showed planar configurations
in the phenyl rings (C19→C24, C7→C12 and C14→C18) of
A and (C37→C42, C43→C48 and C31→C36) in B, with
maximum deviation of 0.012(8) Å for C12 in A and 0.012(2)
Å for atom C42 of B.
Stereochemical feature (2C) [envelop conformation]:
The crystal structure identified the most important stereo chemical
features of 2C, where the pyrazole ring has an envelope confor-
mation, the ring is twisted about the C1–C2 bond with the
flap atom C2 which lies 0.138(7) Å out of the plane of the
remaining four atoms. The same envelope feature was found
in B for the pyrazole ring, which is twisted about the C28–
C27 bond with the flap atom C28 which lies 0.113(7) Å out of
the plane of the remaining four atoms [31].
E.
S.
S.
C.
A.
flavus
No.
coli
typhi
aureus
albicans
2
2
3
4b
4d
5b
S
b
d
b
33
33
34
35
34
34
38
N
29
29
32
33
31
32
35
N
33
32
34
35
33
33
35
N
20
21
21
24
20
24
N
23
22
21
25
23
24
N
F
30
27
S = Sulfamethoxazol 10 µg/mL (antibacterial agent); F = Fluconazol
0 µg/mL (antifungal agent). The concentration of all synthesized
1
compounds were (500 µg/mL in DMSO); 0.0 = no inhibition. N = not
tested.
The tested compounds 2b, 2d, 3b, 4b, 4d and 5b are
exhibited a high activity against both Escherichia coli (ATCC-
25922) and Salmonella typhi (as examples of Gram-negtive),
Staphylococcus aureus (ATCC-25923) (as example of Gram-
positive), Candida albicans (ATCC-10231) (pathogenic yeast)
andAspergillus flavus (pathogenic mould). The tested compounds
The structure of 2C is stabilized by the intermolecular
interactions as well as a network of hydrogen bond contacts,
confirmed parallel layers O-H···O (Table-3). The packing diagram
of the compound is shown in Fig. 3.

2
686 Fahmy et al.
Asian J. Chem.
6
7
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.
R.M. Claramunt, C. López, D. Sanz and J. Elguero, Adv. Heterocycl. Chem.,
were showed a zone of inhibition diameters ranged from 33 to
1
12, 117 (2014);
3
3
5 mm against E. coli, 29 to 33 mm; against S. typhi and 32 to
5 mm against S. aureus, at 500 mg/mL of DMSO. In compa-
https://doi.org/10.1016/B978-0-12-800171-4.00003-2.
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rison with fluconazol, the tested compounds were showed a
zone of inhibition diameters ranged from 20 to 24 mm and 21
to 25 mm against C. albicans and A. flavus respectively at 500
mg/mL of DMSO. Evident MIC values on the entire set of the
tested microbial organism were determined for the chemical
agents 2b, 2d, 3b, 4b, 4d and 5b and the results are summarized
in Table-5. The MIC values are ranged from 6.25 µg to 12.5
µg in case of all chemically synthesized compounds against
all used microbial. Compounds 4b and 5b are the most potent
compounds.
8
9
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https://doi.org/10.2174/157017861101140113160517.
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https://doi.org/10.1039/C1CS15171A.
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THE CHEMICALLY SYNTHESIZED COMPOUNDS
1
3. A.F.M. Fahmy, A.A. El-Sayed and M.M. Hemdan, Chem. Cent. J., 10,
9 (2016);
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MIC values (µg/mL)
Compd.
https://doi.org/10.1186/s13065-016-0205-9.
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1
1
1
E.
S.
S.
C.
A.
flavus
No.
coli
typhi
aureus
albicans
2
2
3
4
4
5
b
d
b
b
d
b
12.5
12.5
12.5
6.25
12.5
6.25
3.125
N
12.5
12.5
12.5
12.5
12.5
6.25
3.125
N
12.5
6.25
6.25
6.25
12.5
6.25
3.125
N
12.5
12.5
6.25
6.25
6.25
6.25
N
12.5
6.25
12.5
6.25
12.5
6.25
N
6
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S
F
3.125
3.125
1
S = Sulfamethoxazol 10 µg/mL (antibacterial agent); F = Fluconazol
0 µg/mL (antifungal agent). The concentration of all synthesized
1
compounds were (500 µg/mL in DMSO); 0.0 = no inhibition. N = not
tested.
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Conculsion
2
2
2
In summary promising biologically active heterocyclic
compounds were obtained from the reaction of the α,β-epoxy
ketones as precursors originate [OH] groups in different effi-
cient synthetic strategies for building stable hydroxyl azoles
under grinding and conventional thermal conditions. The key
advantages of grinding strategy over conventional approaches
include its green [5], safe, simple, solvent-free conditions, as
well as its facile work-up, high yield economy and environ-
mental friendliness. Single crystal X-ray study identified the
stereo-chemical structure of 2C, which can be also considered
as a guide for the prepared derivatives.
2
2
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