Self-Assembled Nanoliposomes of Phosphatidylcholine: Bridging the Gap between Organic and Aqueous Media for a Green Synthesis of Hydroquinazolinones

Article abstract of DOI:10.1055/s-0035-1562604

Self-assembly of phosphatidylcholine in water creates liposomal nanoreactors for environmentally friendly synthesis of hydroquinazolinones by two- or three-component reactions, without the use of an extra catalyst or solvent. Recycling of the reaction medium and the absence of a need for other organic reagents are further advantages of this protocol.

Full text of DOI:10.1055/s-0035-1562604

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
A
letter
Synlett
F. Tamaddon et al.
Letter
Self-Assembled Nanoliposomes of Phosphatidylcholine: Bridging
the Gap between Organic and Aqueous Media for a Green Synthe-
sis of Hydroquinazolinones
Fatemeh Tamaddon*
Mohammad Taghi
Kazemi Varnamkhasti
Department of Chemistry, Yazd University, Yazd 89195-741,
Iran
ftamaddon@yazduni.ac.ir
Received: 15.06.2016
Accepted after revision: 06.07.2016
Published online: 27.07.2016
of the high diffusion power and large surface area of nano-
catalysts, various nanoscale flakes, fibers, fluids, sheets,
powders, and particles4 have been efficiently used to pro-
–7
DOI: 10.1055/s-0035-1562604; Art ID: st-2016-d0391-l
8
mote organic reactions. However, despite well-developed
Abstract Self-assembly of phosphatidylcholine in water creates liposo-
mal nanoreactors for environmentally friendly synthesis of hydro-
quinazolinones by two- or three-component reactions, without the use
of an extra catalyst or solvent. Recycling of the reaction medium and
the absence of a need for other organic reagents are further advantag-
es of this protocol.
techniques for preparing nanomaterials, their generation in
situ by self-assembly in water remains the simplest ap-
proach. Since the discovery of liposomes by Bangham and
Horne, these biomimetic nanomaterials have been devel-
oped as layered microvesicles and as carriers for delivery
9
and encapsulation of medicines, genes, cosmetics, agri-
Key words liposomes, self-assembly, nanoreactors, phosphatidylcho-
line, hydroquinazolinones, green chemistry
chemicals, or foods.1
0–12
Nanoliposomes, which consist of
three-dimensional hollow vesicles, have the advantages of
versatility, biocompatibility, and an adjustable chain
length.13 In water, nanoliposomes are usually formed from
bilayer phospholipids with their lipophilic tails oriented to
form stable uni- or multilamellar spheres with a hydrophil-
ic shell and a water-filled cavity. The thickness of the bilay-
er is typically 3–6 nm, whereas the diameter of the nanoli-
The development of chemical transformations that pro-
ceed under biocompatible water-based conditions is one of
the essential goals of green chemistry. The benefits of
such water-based transformations would be accentuated if
1,2
these transformations were multicomponent reactions
3
14
(
MCRs) and subject to catalysis by nanoliposomes. Because
posome is generally in the range 80–300 nm (Figure 1).
80–300 nm
3–6 nm
Water
Water
Aqueous
core
Lipophilic tails
Hydrophilic shell
Nanovesicle or nanoliposome
Figure 1 Bilayer phospholipids in cell membranes, nanovesicles, or nanoliposomes
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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Synlett
F. Tamaddon et al.
Letter
Phosphatidylcholine (PC) is a phospholipid with a nega-
tively charged phosphate group and a positively charged
choline moiety in its hydrophilic head (Figure 2). In aque-
ous solutions, PC spontaneously forms bilayer semi-perme-
able micelles with a thickness of 4 nm and a diameter of
In an initial study of the synthesis of 2-phenyl-2,3-dihy-
droquinazoline-4(1H)-one (3a) in a vesicular medium, we
screened the one-pot three-component reaction of isatoic
anhydride (1), ammonium acetate, and benzaldehyde (2) in
water using various amounts of phosphatidylcholine (PC),
phosphatidylethanolamine (PEA), or phosphatidylinositol
(PI) (Table 1, entries 1–14).
15,16
50–100 nm.
In vitro mimicking of organic reactions
with biocatalysts in water can help in understanding in vivo
biotransformations and in developing greener organic reac-
17,18
Table 1 Optimization of the Reaction with Phospholipids as Catalystsa
tions.
O
C
O
O
O
H2C
O
O
O
Ph
H
O
2
catalyst (0.001–0.5 g)
H2O, 80 °C
NH
O
C
+
N
H
O
HC
NH4OAc
N
H
Ph
1
3a
O
P
Me
Me
Me
H2C
O
N
Entry Catalyst (g)
Solvent
Temp (°C) Time (min) Yieldb
O
(
%)
Figure 2 Phosphatidylcholine
1
2
–
H
2
2
2
2
O
O
O
O
80
80
80
80
80
80
70
100
80
80
4800
120
90
40
80
81
87
90
97
92
96
97
91
PC (0.001)
PC (0.002)
PC (0.003)
PC (0.004)
PC (0.005)
PC (0.005)
PC (0.005)
PC (0.01)
PC (0.005)
H
H
H
Quinazolinones are basic fragment of natural products
19
20
21
3
such as luotonin A, glycosaminine, and rutaecarpine,
and of pharmaceuticals with antimalarial, antidiabetic, an-
ticancer, anticonvulsant, or antilipedimic properties.22,23 As
a result, various protocols for their synthesis have been de-
veloped that use a range of starting materials and acid cata-
4
45
5
H O
2
25
6
H
H
H
H
2
2
2
2
O
O
O
O
15
7
35
24
lysts under various reaction conditions.
-Aminobenzamide and isatoic anhydride [2H-3,1-ben-
8
15
2
9
15
zoxazine-2,4(1H)-dione] are common precursors for the
acid-catalyzed synthesis of hydroquinazolinones (HQs).2
We recently developed a heterogeneous base-catalyzed
synthesis of dihydroquinazolinones (DHQs) from 2-amino-
benzonitrile in water.27 In continuation of our recent work
on water-based organic reactions, we describe a synthetic
protocol that uses nanoliposomes formed in vitro for the
rapid synthesis of HQs from 2-aminobenzamide or isatoic
anhydride in water without use of additional reagents or
organic solvent (Figure 3).
5,26
10
50:50
O–EtOH
25
H
2
11
PC (0.005)
EtOH
80
80
80
80
80
80
80
45
45
81
76
72
78
83
96
67
12
PEA (0.005)
PI (0.005)
PI (0.05)
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
28
13
14
15
16
17
70
90
c
PPA (0.005)
50
PCd (0.005)
20
choline chloride
180
(
0.005)
1
8
9
stearic acid (0.005)
H
2
O
80
80
180
20
67
95
1
reused reaction medium from
entry 16
a
Reaction conditions: isatoic anhydride (1; 1 mmol), PhCHO (2; 1 mmol),
OAc (1 mmol), solvent (2 mL).
Isolated yield. The pure precipitated product was isolated simply by addi-
NH
4
b
tion of crushed ice and subsequent filtration.
c
(
2R)-2,3-Bis(octanoyloxy)propyl dihydrogen phosphate.
d
The reaction was carried out at 50 mmol scale.
In the absence of PC, the reaction in water was incom-
plete even after an extended reaction time (Table 1, entry
), but a maximum 97% yield of product 3 was obtained in
1
just 15 minutes by using 0.005 g of PC in 2 mL of water (en-
try 5). Given that the molecular weight of PC is 768, its con-
centration in this experiment was 0.0025 g/L or 3.26 mM,
close to the range of 5–10 mM for the critical liposome con-
centration of PC,29 the appropriate concentration for the
Figure 3 Synthesis of hydroquinazolinones in nanoliposomes assem-
bled from phosphatidylcholine in water
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
Synlett
F. Tamaddon et al.
Letter
production of liposomes with a diameter of 100 nm. The
lower yield of product with smaller amounts of PC (entries
Table 2 The Relative Catalytic Performance of PC Nanoliposomes in
the Synthesis of 3a
2
–5) might be attributed to lower numbers of micelles. A
Entry Catalyst
g)
Solvent
(4 mL)
Temp
(°C)
Time Yielda
(min) (%)
reduction in the yield of 3 with EtOH as co-solvent can be
attributed to the depression of the surface tension of the
solvent and the breakup of the nanoliposomes (entry 10).
The superior catalytic performance of PC to that of PEA (en-
try 12) or PI (entry 13) highlights the reactivity–structure
relationship of the surfactants.
(
1
2
3
4
PC (0.005)
H O
2
80
15
97b
9327
Amberlyst A26 OH (0.2) 1:1 EtOH–H
2
O
50–60 180
c
7831
8432
Zn(PFO)
2
(0.027)
1:3 H
2
O–EtOH
reflux
80
360
180
Silica sulfuric acid (0.08)
2
H O
To clarify the catalytic role of the combination of the
choline head and hydrophobic portion of PC, we compared
the results shown in Table 1, entries 1 and 6 with those ob-
tained in the presence of choline chloride (entry 17) and
stearic acid (entry 18). The significantly lower yields for the
reaction in water alone (Table 1, entry 1) or in the presence
of choline chloride (entry 17) or stearic acid (entry 18) pro-
vide evidence for the occurrence of the reaction within the
PC nanoliposomes, rather than as the result of the action of
isolated hydrophobic chains or polar choline groups.
To provide evidence to support the formation of lipo-
somes and to evaluate their morphology, we performed
freeze-fracture transmittance electron microscopy studies
a
b
c
Isolated yield.
This work.
PFO = perfluorooctanoate.
To examine the scope of the method and the catalytic
performance of the self-assembled nanoliposomes of PC in
water, three-component reactions of isatoic anhydride with
30
various aldehydes and amines or ammonium acetate were
carried out under the optimized conditions (Table 3). In all
cases, the reaction reached completion rapidly gave and ex-
cellent yields of the precipitated HQs, isolated by simple fil-
tration. Even the enolizable ketones of cyclopentanone and
cyclohexanone gave excellent yields of the desired products
(Table 3, entries 14 and 15).
(TEM) to obtain a high-contrast image of the self-assembled
liposomes in the reaction medium (Figure 4).
Encouraged by the catalytic superiority of the PC nano-
liposomes, we extended the optimized reaction conditions
to the synthesis of 2,3-dihydro-4(1H)-quinazolinones from
2
-aminobenzamide and a range of aldehydes. Again, the de-
sired products 3a–m were isolated in good to excellent
yields (Table 4, entries 1–15). Replacement of aldehydes
with cyclopentanones, cyclohexanones, and acetone gave
the corresponding products 3n–t in 90–93% yields (entries
14–16).
In conclusion, we have developed an environmentally
benign protocol that is advantageous for the rapid and high-
yielding three- or two-component syntheses of HQs in an in
vitro vesicular medium, made by dispersal of PC as a bio-
surfactant in water. The possibility of recycling the reaction
medium and the absence of a need for other organic re-
agents are additional advantages of this protocol.
Figure 4 Transmission electron micrograph of nanoliposomes of PC in
water
The scalability and reusability of the reaction were con-
firmed by recycling of the filtrate from the model reaction
at a 50 mmol scale (Table 1, entry 16) in a subsequent run.
After the completion of the first reaction, the product was
extracted with EtOAc and the aqueous phase was reused in
a second reaction that gave pure 3a isolated in 95% yield in
the same reaction time (entry 19).
The merits of our nanoliposomal reaction are evident
from a comparison with the results of the three-component
model reaction with those for previously reported methods
in aqueous media (Table 2).
Acknowledgment
We thank the Research Council of Yazd University.
References
30
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(
1) Polshettiwar, V.; Varma, R. S. Green Chem. 2010, 12, 743.
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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F. Tamaddon et al.
Letter
Table 3 PC-Catalyzed Synthesis of Quinazolinones in Nanoliposomal
Medium
Table 4 PC-Catalyzed Synthesis of 2,3-Dihydro-4(1H)-quinazolinonesa
a
O
O
O
O
O
PC (0.005 g)
NH
NH2
NH2
1
R1 or H
+
R
R NH2
O
CH
PC (0.005 g)
O
N
H2O (4 mL), 80 °C
+
or
+
R2 CH
N
H
R
NH4OAc
H2O (4 mL), 80 °C
R2
N
H
O
N
H
a–s
3
Yieldb
(%)
Entry
R
Product
Time
mp
1
(
min)
(°C) (Lit.)
Entry R1
R2
Product Time Yield Mp
min) (%) (°C) (Lit.)
b
1
2
3
4
5
Ph
3a
20
95
93
92
91
95
220–222
(219–222)27
(
Hc
4-Tol
3b
3c
3d
3e
50
75
60
90
230–232
1
2
3
4
5
Ph
3a
3b
3c
3d
3e
15 97
45 96
60 95
90 92
75 92
221–223
219–222)27
(
232–235)27
(
Hc
Hc
Hc
Hc
6 4
4-MeOC H
193–195
4-Tol
231–233
232–235)27
(
194–195)32
(
6 4
4-HOC H
277–279
4-MeOC
4-HOC
6
H
4
195–197
194–195)27
(
278–282)27
(
3,4-(MeO)
3,5-(MeO)
2
C
6
H
3
213–215
6
H
4
276–278
278–282)27
(
211–214)27
(
6
7
2
C
6
H
3
3f
80
60
91
98
144–146
3,4-(MeO)
2
C
6
6
H
3
3
213–215
211–214)27
(
4-i-PrC
6
H
4
3g
163–165
(162–164)22
Hc
Hc
6
7
3,5-(MeO)
2
C
H
3f
60 94
60 97
146–148
8
9
4-(Me
­2-Naph
4-ClC
2
N)C
6
H
4
3h
3i
75
270
75
94
85
95
92
89
91
91
90
93
201–203
4-i-PrC
6
H
4
3g
161–163
(
202–204)33
(
162–164)22
Hc
Hc
Hc
Hc
Hc
Hc
Hc
Hc
170–172
8
9
4-Me
2-Naph
4-ClC
2
NC
6
H
4
3h
3i
45 94
120 83
45 93
30 91
90 87
90 90
120 91
180 91
90 94
60 91
75 92
201–203
(
172–174)22
(
202–204)33
10
11
12
13
14
15
6
H
4
3j
205–207
171–173
(
206–208)27
(
172–174)22
3-BrC
2-BrC
6
6
H
4
4
3k
3l
60
220–222
1
0
1
2
3
4
5
6
7
8
9
6
H
4
3j
205–207
(
>220)33
(
206–208)27
H
180
150
210
240
90
182–184
1
1
1
1
1
1
1
1
3-BrC
2-BrC
6
6
H
4
4
3k
3l
223–225
(
183–185)33
(
>220)30
2-ClC
6
H
4
3m
3n
3o
3t
201–203
H
180–182
(
200–202)33
(
183–185)33
cyclopentanone
cyclohexanone
[acetone]
255–257
2-ClC
6
H
4
3m
199–201
(
258–259)24
(
200–202)33
225–227
cyclopentanone 3n
cyclohexanone 3o
257–259
(
225–227)27
(
258–259)24
16
183–184
224–226
(
184–185)27
(
225–227)27
a
Reactions were performed with 2-aminobenzamide (2 mmol), aldehyde or
acetone (2 mmol), PC (0.01 g), H
Isolated yield.
Ph
4-MeOC
Ph
6
H
4
3p
3q
3r
202–205
2
O (4 mL).
(
204–205)33
b
6 4
4-MeOC H
208–210
(
209–211)33
4-MeC
6
H
4
Ph
196–198
(
9) Bangham, A. D.; Horne, R. W. Nature 1962, 196, 952.
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(
197–198)33
(
(
1
4-PhOC
6
H
4
Ph
3s
90 93
208–210
(
209–211)33
a
2
Reaction conditions: isatoic anhydride (1; 2 mmol), R CHO (2 mmol),
1
NH
4
OAc or R NH
2 2
(2 mmol), PC (0.01 g), H O (4 mL), 80 °C.
(
(
b
Isolated yield.
c
4
NH OAc was used.
2
2
007, 2, 85. (b) Hallaj-Nezhadi, S.; Hassan, M. Drug Delivery
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Synlett
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Letter
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and PC (0.01 g) at ~80 °C. When the reaction was complete
(TLC), the product was isolated either by simple filtration or by
extraction with EtOAc. In some cases, the crude product was
(
(
(
crystallized from 70:30 EtOH–H O.
2
2,3-Dihydroquinazolinones
General Procedure
from
2-Aminobenzamide;
301.
(
(
(
(
(
19) Li, B.; Samp, L.; Sagal, J.; Hayward, C. M.; Yang, C.; Zhang, Z.
2-Aminobenzamide (2 mmol) and the appropriate aldehyde (2
J. Org. Chem. 2013, 78, 1273.
20) Miller, K. L.; Clegg, D. O. Rheum. Dis. Clin. N. Am. 2011, 37, 103;
DOI: 10.1016/j.rdc.2010.11.007.
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Lee, E. S.; Jahng, Y. Chem. Pharm. Bull. 2008, 56, 607.
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Chauhan, P. M. J. Org. Chem. 2012, 77, 929.
23) (a) Rajput, R.; Mishra, A. P. Int. J. Pharm. Pharm. Sci. 2012, 4, 66;
http://www.ijppsjournal.com/Vol4Issue2/3543.pdf.
mmol) were added to a stirred mixture of PC (0.01 g) and H O (4
2
mL) at ~80 °C. When the reaction was complete (TLC), the pre-
cipitated product was isolated by filtration.
Selected Analytical Data
3-(4-Phenoxyphenyl)-2-phenyl-1,2-dihydroquinazolin-4(1H)-
one (3s)
White solid; yield (2 mmol scale): 730 mg (93%); mp 208–
–1 1
210 °C. FT-IR (KBr): 3273, 1637, 1609, 1506 cm . H NMR (400
MHz, DMSO-d ): δ = 6.27 (s, 1 H), 6.72 (t, J = 7.4 Hz, 1 H), 6.76
6
(
1
b) Alizadeh, A.; Ghanbaripour, R.; Zhu, L.-G. Synlett 2014, 25,
596.
(d, J = 8.0 Hz, 1 H), 6.94–6.98 (m, 4 H), 7.13 (t, J = 7.3 Hz, 1 H),
7.25–7.33 (m, 6 H), 7.38 (m, 4 H), 7.62 (s, 1 H, NH), 7.72 (d, J =
13
(
24) (a) Vijayakumar, B.; Prasanthi, P.; Muni Teja, K.; Kumar Reddy,
M.; Nishanthi, P.; Nagendramma, M.; Nishanthi, M. Int. J. Med.
Chem. Anal. 2013, 3, 10; http://www.ijmca.com/File_Folder/10-
7.3 Hz, 1 H). C NMR (100 MHz, DMSO-d ): δ = 115.59, 115.64,
6
116.13, 118.40, 119.45, 119.48, 124.41, 127.57, 128.83, 129.07,
129.22, 129.26, 130.92, 134.62, 136.96, 141.38, 141.42, 147.50,
147.55, 155.30, 157.43, 163.23.
2
1.pdf. (b) Chen, J.; Su, W.; Wu, H.; Liu, M.; Jin, C. Green Chem.
2
007, 9, 972. (c) Wu, J.; Du, X.; Ma, J.; Zhang, Y.; Shi, Q.; Luo, L.;
2-(3,4-Dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one
(3e)
Song, B.; Yang, S.; Hu, D. Green Chem. 2014, 16, 3210.
(
(
(
25) (a) Dabiri, M.; Salehi, P.; Otokesh, S.; Baghbanzadeh, M.;
Pale-yellow solid; yield (2 mmol scale): 540 mg (95%); mp 213–
215 °C. FT-IR (KBr): 3331, 3297, 1654, 1611, 1512, 1484, 1232,
Kozehgary, G.; Mohammadi, A. A. Tetrahedron Lett. 2005, 46,
–1 1
6123. (b) Rahman, M.; Ling, I.; Abdullah, N.; Hashim, R.; Hajra,
1263 cm . H NMR (400 MHz, DMSO-d ): δ = 3.35 (s, 1 H, NH),
6
A. RSC Adv. 2015, 5, 7755.
3.76 (s, 3 H, CH ), 3.77 (s, 3 H, CH ), 5.71 (s, 1 H, CH), 6.70 (t, J =
3
3
26) (a) Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett.
7.2, 1 H), 6.77 (d, J = 8.4, 1 H), 6.96 (d, J = 8.4, 1 H), 7.01 (d, J = 8.4,
1 H), 7.15 (d, J= 2.0, 1 H), 7.26 (dt, J = 7.6, J = 1.6, 1 H), 7.63 (dd,
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2
1
3
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6
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(
Isatoic anhydride (1; 2 mmol), the appropriate aldehyde (2
mmol), and the appropriate ammonium salt (2.5 mmol) or
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E