An efficient three-component synthesis of 3-(1-Hydroxyalkyl)[1,2,4]- triazolo[4,3- c ]quinazolines

Article abstract of DOI:10.1055/s-0029-1219562

An efficient three-component synthesis of 3-(1-hydroxyalkyl)[1,2,4] triazolo[4,3-c]quinazolines is described. A mixture of N- isocyaniminotriphenylphosphorane, an aldehyde, and a 4(3H)-quinazolinone undergo a 1:1:1 addition reaction in refluxing THF to afford the title compounds in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219562

LETTER
921
An Efficient Three-Component Synthesis of 3-(1-Hydroxyalkyl)[1,2,4]-
triazolo[4,3-c]quinazolines
S
ynthesisof 3-(1-Hydr
e
oxyalkyl)[1
h
,2,4]triazolo
d
[4,3-
c
]quina
i
zolines Adib,*a Samira Ansari,a Shahzad Feizi,a Hamid Reza Bijanzadehb
a
School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
Received 10 November 2009
cyclization of 2-(2-aminophenyl)-1,2,4-triazoles with car-
boxylic acids or acid chlorides;10 cyclization of 4-hydrazi-
noquinazolines with one-carbon cyclizing reagents such
as carboxylic acids or acid chlorides,5b carbon disul-
fide,5a,11 or orthoesters;6,12 cyclization of quinazolin-4-yl-
hydrazones and quinazolin-4-ylhydrazides;5a,11 and
reaction of 4-chloroquinazoline with tetrazoles.13
Abstract: An efficient three-component synthesis of 3-(1-hydroxy-
alkyl)[1,2,4]triazolo[4,3-c]quinazolines is described. A mixture of
N-isocyaniminotriphenylphosphorane, an aldehyde, and a 4(3H)-
quinazolinone undergo a 1:1:1 addition reaction in refluxing THF
to afford the title compounds in good to excellent yields.
Key words: N-isocyaniminotriphenylphosphorane,
4(3H)-quin-
azolinones, aldehydes, 3-(1-hydroxyalkyl)[1,2,4]triazolo[4,3-c]quin-
azolines, multicomponent reactions, cyclizations, heterocycles
There are several reports on the use of N-isocyanimino-
triphenylphosphorane (1, CNNPPh3, Scheme 1) in the
synthesis of metal complexes.14,15 However, applications
of 1 in organic synthesis are rare. Recently, a synthesis of
1,3,4-oxadiazepines via a three-component reaction be-
tween 1, dialkyl acetylenedicarboxylates, and 1,3-diphe-
nyl-1,3-propanedione16 and a synthesis of 2-aryl-1,3,4-
oxadiazoles from 1 and benzoic acids17 were reported.
Very recently, we have reported a new synthesis of 2-aryl-
5-hydroxyalkyl-1,3,4-oxadiazoles via a one-pot and
three-component reaction between 1, aldehydes, and car-
boxylic acids.18
Multicomponent reactions (MCR) have emerged as an ef-
ficient and powerful tool in modern synthetic organic
chemistry due to their valued features such as atom econ-
omy, straightforward reaction design, and the opportunity
to construct target compounds by the introduction of sev-
eral diversity elements in a single chemical event. Typi-
cally, purification of products resulting from MCR is also
simple since all the organic reagents employed are con-
sumed and are incorporated into the target compound.1
MCR, leading to interesting heterocyclic scaffolds, are
particularly useful for the construction of diverse chemi-
cal libraries of ‘druglike’ molecules. The isocyanide-
based MCR are especially important in this area.1d,e
Knowing the pharmacological importance of the
[1,2,4]triazolo[4,3-c]quinazoline ring systems, we have
recently focused on introducing a new synthesis of this
nucleus bearing in mind previously reported synthetic
routes. As part of our current studies on the development
of efficient and simple synthesis of biologically active
heterocyclic compounds,19 herein we describe a new, one-
pot, and three-component synthesis of [1,2,4]triazolo[4,3-
c]quinazolines. Thus a mixture of N-isocyaniminotriphe-
nylphosphorane (1), an aldehyde 2, and a 4(3H)-
quinazolinone 3 undergo a 1:1:1 addition reaction in re-
fluxing THF to produce the corresponding 3-(1-hydroxy-
alkyl)[1,2,4]triazolo[4,3-c]quinazolines 4a–l in 84–97%
yields (Scheme 1, Table 1). All the reactions reached
completion within three hours. 1H NMR analysis of the re-
action mixtures clearly indicated formation of the corre-
sponding [1,2,4]triazolo[4,3-c]quinazolines 4 in good to
Fused bridgehead heterocycles, [1,2,4]triazolo[4,3-
c]quinazolines,2,3 constitute an important class of hetero-
cyclic compounds with interesting biological properties,
some of which have been shown to possess anticancer,4
anti-inflammatory,5,6 and antibacterial7 activities. Some
examples have exhibited hypotensive6 and hypertensive8
properties. Other examples are highly selective agonists
or antagonists for GABAa brain receptors and are useful
in the diagnosis and treatment of anxiety, sleep, seizure
disorders, and also enhancement of memory.9
The most common approaches for the preparation of
[1,2,4]triazolo[4,3-c]quinazolines involve condensation–
O
N
N
OH
X
X
THF
NH
N
R1CHO
+
Ph3PO
Ph3PNNC
+
+
R1
reflux, 3 h
1
2
N
R2
N
R2
4
3
Scheme 1
SYNLETT 2010, No. 6, pp 0921–0923
x
x.
x
x.
2
0
1
0
Advanced online publication: 02.03.2010
DOI: 10.1055/s-0029-1219562; Art ID: D32309ST
© Georg Thieme Verlag Stuttgart · New York

922
M. Adib et al.
LETTER
excellent yields. Any product other than 4 and triphe-
nylphosphine oxide could not be detected by NMR spec-
troscopy.20
Table 1 Synthesis of 3-(1-Hydroxyalkyl)[1,2,4]triazolo[4,3-c]-
quinazolines 4a–l
4
X
H
H
H
H
H
H
H
H
H
H
H
Cl
R1
R2
Yield (%)a
The structures of the isolated products were deduced on
1
the basis of IR, H NMR and 13C NMR spectroscopy,
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
92
93
93
94
88
97
90
96
95
91
84
90
mass spectrometry, and elemental analysis. The mass
spectrum of 4f displayed the molecular ion [M+] peak at
m/z = 411 which was consistent with the 1:1:1 adduct of
N-isocyaniminotriphenylphosphorane, 2-(4-methylphe-
nyl)-4(3H)-quinazolinone, and 4-nitrobenzaldehyde los-
ing triphenylphosphine oxide. The IR spectrum of 4f
showed an absorption at 3344 cm–1 indicating the pres-
ence of a hydroxy group. The 1H NMR spectrum of 4f ex-
hibited a sharp singlet at d = 2.42 ppm due to the methyl
group. Two doublets were seen for the mutually coupled
aliphatic methine H atom (d = 5.52 ppm, J = 5.8 Hz) and
the adjacent hydroxy group (d = 6.25 ppm, J = 5.8 Hz).
The characteristic multiplets for the twelve H atoms of the
two aryl substituents and the phenylene moiety were seen
with appropriate chemical shifts and coupling constants.
The 1H-decoupled 13C NMR spectrum of 4f showed char-
acteristic signals at d = 21.12 (due to CH3), 65.77 ppm
(arising from CH), along with other 17 distinct resonances
(8 CH and 9 C) in agreement with the proposed struc-
ture.20
Ph
4-MeC6H4
4-FC6H4
3-ClC6H4
4-MeOC6H4
4-O2NC6H4
4-MeC6H4
4-O2NC6H4
4-FC6H4
4-O2NC6H4
n-Pr
Ph
Ph
Ph
4-MeC6H4
Ph
Bn
Bn
4j
4k
4l
PhCH2CH2
Ph
Ph
Ph
a Isolated yield.
In conclusion, we have developed a new, one-pot, and
three-component reaction between N-isocyaniminotriphe-
nylphosphorane, aldehydes, and 4(3H)-quinazolinones
for the efficient synthesis of 3-(1-hydroxyalkyl)[1,2,4]tri-
azolo[4,3-c]quinazolines, which are of potential synthetic
and pharmacological interest. The reactions were per-
formed under neutral conditions. The simplicity of this
method makes it an interesting alternative to other
[1,2,4]triazolo[4,3-c]quinazoline syntheses. 3-(1-Hy-
droxyalkyl)[1,2,4]triazolo[4,3-c]quinazolines prepared in
the present study may find useful applications in synthetic
organic, bioorganic, and medicinal chemistry.
A plausible mechanism for the reaction is provided in
Scheme 2. On the basis of the well-established chemistry
of isocyanides,1d,e,21–23 it is reasonable to assume that the
first step could involve nucleophilic addition of the isocy-
anide 1 on the aldehyde 2 and subsequent protonation of
the alkoxide intermediate 5 by the NH-acid 3, leading to
the nitrilium intermediate 6. This positively charged inter-
mediate may be attacked by the conjugate base of the acid
7 to form the adduct 8. This adduct may undergo intramo-
lecular aza-Wittig reaction of the iminophosphorane moi-
ety with the amide carbonyl to afford the isolated 3-(1-
hydroxyalkyl)[1,2,4]triazolo[4,3-c]quinazolines 4 by re-
moval of triphenylphosphine oxide from betaine interme-
diate 9.
Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
O
OH
+
PPh3N
N
R1
H
R1
R2
O–
R1
6
2
_
C
3
+
+
_
N
Ph3P
N
PPh3N
N
N
O
N
5
1
7
Ph3P
+
Ph3P
–O
OH
N
N
N
N
N
N
O
OH
R1
OH
R1
R1
R2
N
N
N
+
Ph3P=O
N
R2
N
R2
N
8
9
4
Scheme 2
Synlett 2010, No. 6, 921–923 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-(1-Hydroxyalkyl)[1,2,4]triazolo[4,3-c]quinolines
S.; Abbasi, A.; Bijanzadeh, H. R. Synthesis 2007, 3056.
923
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(20) General Procedure for the Preparation of Compounds
4a–l
A mixture of N-isocyaniminotriphenylphosphorane (1
mmol) and the appropriate aldehyde (1 mmol) was dissolved
in hot THF (5 mL). Then the appropriate 4 (3H)-quinazo-
linone (1 mmol) was added to the reaction mixture which
was refluxed for 3 h. Then, the solvent was removed under
the reduced pressure, and the residue was purified by TLC
using CHCl3–EtOAc (3:1) as eluent. The solvent was
removed, and the product was obtained as colorless crystals.
3-[1-Hydroxy-1-(4-fluorophenyl)methyl]-5-phenyl-
[1,2,4]triazolo[4,3-c]quinazoline (4c)
Yield 0.34 g (93%); colorless crystals; mp 192–193 °C. IR
(KBr): 3266 (OH), 1609, 1515, 1374, 1332, 1264, 1211,
1187, 1156, 1106, 1056, 1019, 947, 863, 794, 769, 680 cm–1.
1H NMR (500.1 MHz, DMSO-d6): d = 5.35 (br s, 1 H, CH),
6.02 (d, J = 4.6 Hz, 1 H, OH), 7.08 (dd, J = 8.8, 8.9 Hz, 2 H,
2 × CH), 7.11–7.19 (m, 2 H, 2 × CH), 7.56–7.66 (m, 4 H, 4
× CH), 7.78 (dd, J = 6.8, 7.4 Hz, 2 H, 2 × CH), 7.86 (dd,
J = 7.3, 8.1 Hz, 1 H, CH), 7.96 (d, J = 8.1 Hz, 1 H, CH), 8.54
(d, J = 7.9 Hz, 1 H, CH). 13C NMR (125.8 MHz, DMSO-d6):
d = 65.94 (CH), 114.46 (d, 2JFC = 21.4 Hz, CH), 115.94 (C),
122.56, 127.89, 128.28 and 128.73 (4 × CH), 128.87 (d,
3JFC = 8.1 Hz, CH), 129.25, 130.63 and 131.83 (3 × CH),
133.48 (C), 137.16 (d, 4JFC = 2.7 Hz, C), 140.33, 145.65,
148.88 and 150.75 (4 × C), 161.45 (d, 1JCF = 243.2 Hz, CF).
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167 (23), 149 (100), 113 (10), 104 (9), 83 (9), 71 (18), 57
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3-[1-Hydroxy-1-(4-nitrophenyl)methyl]-5-(4-methyl-
phenyl)[1,2,4]triazolo[4,3-c]quinazoline (4f)
Yield 0.40 g (97%); colorless crystals; mp 228 °C. IR (KBr):
3344 (OH), 1614, 1511, 1466, 1335, 1181, 1105, 1069,
1039, 986, 948, 818, 769, 696 cm–1. 1H NMR (500.1 MHz,
DMSO-d6): d = 2.42 (s, 3 H, CH3), 5.52 (d, J = 5.8 Hz, 1 H,
CH), 6.25 (d, J = 5.8 Hz, 1 H, OH), 7.37 (d, J = 7.2 Hz, 2 H,
2 × CH), 7.49 (d, J = 8.7 Hz, 2 H, 2 × CH), 7.73 (d, J = 7.8
Hz, 2 H, 2 × CH), 7.79 (dd, J = 7.4, 7.7 Hz, 1 H, CH), 7.88
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8.16 (d, J = 8.7 Hz, 2 H, 2 × CH), 8.53 (d, J = 7.4 Hz, 1 H,
CH). 13C NMR (125.8 MHz, DMSO-d6): d = 21.12 (CH3),
65.77 (CH), 115.83 (C), 122.61, 122.92, 127.93, 127.96,
128.75, 128.85, 129.26 (7 × CH), 130.59 (C), 131.98 (CH),
140.48, 140.52, 145.81, 146.79, 148.70, 149.08 and 150.11
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Synlett 2010, No. 6, 921–923 © Thieme Stuttgart · New York