A catalyst- and solvent-free selective approach to biologically important quinazolines and benzo[g]quinazoline

Article abstract of DOI:10.1016/j.tet.2005.01.118

A solvent-free and catalyst-free approach towards the selective synthesis of quinazolines and benzo[g] quinazolines has been developed using conventional microwave oven with excellent yields and reproducibilty.

Full text of DOI:10.1016/j.tet.2005.01.118

Tetrahedron 61 (2005) 3533–3538
A catalyst- and solvent-free selective approach to biologically
important quinazolines and benzo[g]quinazoline
*
Vipan Kumar, Chander Mohan, Manish Gupta and Mohinder P. Mahajan
Department of Applied Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
Received 13 October 2004; revised 13 January 2005; accepted 28 January 2005
Abstract—A solvent-free and catalyst-free approach towards the selective synthesis of quinazolines and benzo[g] quinazolines has been
developed using conventional microwave oven with excellent yields and reproducibilty.
q 2005 Elsevier Ltd. All rights reserved.
8
1
. Introduction
magnitude for the inhibition of cellular phosphorylation.
They have shown remarkable activity as antitubercular,
9
1
0
11
antiviral and anticancer agents. These have been used as
Numerous research papers and several review articles have
appeared in literature describing in detail the utilization of
iminophosphoranes as reagents and intermediates in organic
1
DNA ligands and also have shown binding to benzo-
2
1
diazepines and adenosine receptors. Recent disclosures
3
1
14
from our laboratory has shown quinazolines with
synthesis. The use of iminophosphoranes has now become
a powerful gear in organic synthetic strategies directed
towards the construction of nitrogen containing hetero-
cycles. The reactions of iminophosphoranes with carbonyl
compounds provide an excellent method for the construc-
substituents at second and fourth positions to be potent
antibacterial agents and further studies are in progress to
explore their medicinal and biological use. The growing
medicinal importance of these heterocycles perpetuates to
provide strong rationale for the development of synthetic
methods for their preparation. These efforts have led to
2
tion of carbon–nitrogen double bonds via inter and intra
molecular aza-Wittig reaction. Their application in the
preparation of various heterocycles including pyridine
derivatives, polycyclic compounds, benzodiazepines
1
5
several reviews emphasising the synthesis and biological
evaluation of quinazolines. The reactions of N-imidoyl-
iminophosphoranes with various aldehydes have been
shown to result in a mixture of quinazoline and dihydro-
quinazoline derivatives in a variable ratio depending upon
the nature of aldehydes as well as the employed reaction
2
3
4
5
and pharmacologically active alkaloids has also been
well archived. On the other hand aza-Wittig type reactions
of iminophosphoranes with carbon dioxides, carbon
disulphides, isocyanates, isothiocyanates and ketenes render
access to functionalised heterocumulenes as highly reactive
intermediates able to undergo a pleothera of heterocycliza-
16
conditions. The reaction apparently suffers from dis-
advantages such as longer reaction periods (25–90 h), lower
yields, lack of selectivity often leading to a mixture of
products and cumbersome workup procedure. As part of our
6
7
tion reactions. Recent work in our laboratory has shown
the reactions of N-imidoyliminophosphoranes with mono-
substituted ketenes and diphenyl ketene resulting
exclusively in the formation of pyrimidinones via a [4C2]
cycloaddition of the initially formed 1,3-diaza-1,3,5-penta-
triene and quinazolines via electrocyclic ring closure,
respectively.
17
continued interest in the chemistry of azadienes, in a
recent communication we have developed a simple and
advantageous route for the synthesis of quinazoline
18
derivatives using a domestic microwave oven. Several
experiments were performed at various power levels in
order to establish the optimum reaction conditions. It was
assumed that the initially formed 1,3-diazabuta-1,3-dienes 4
underwent electrocyclic ring closure to dihydroquinazoline
as intermediates which on aromatisation led to the quinazo-
line derivatives 3 (Scheme 1). The products were identified
as quinazolines 3 on the basis of analytical data and spectral
evidences and by comparison of these with reported melting
points in literature.
Quinazolines have demonstrated an increase in potency
over other Tyrosine Kinase inhibitors of 4–5 orders of
magnitude for the inhibition of isolated Epidermal Growth
Factor (EGF) receptor Tyrosine Kinase and 3–4 orders of
Keywords: Quinazolines; Benzo[g]quinazoline; Catalyst-free; Microwave.
*
Corresponding author. Tel.: C91 0183 2258802 09x3320; fax: C91 0183
258819 20; e-mail: mahajanmohinderp@yahoo.co.in
2
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.118

3534
V. Kumar et al. / Tetrahedron 61 (2005) 3533–3538
Scheme 2.
Recently Godde et al. have reported new fluorescent analogs
of thymine and cytosine namely benzo[g]quinazoline-2,4-
1H,3H)-dione and (4-amino-1H-benzo[g]quinazoline-2-
(
2
4
one) to probe triple helix formation. When introduced
into triplex forming oligonucleotides, this new nucleoside
can be used to reveal the protonation state of triplets in
triple-stranded structures and thus targets double-stranded
DNA through the binding of a short oligonucleotide to
homo-purine–homopyrimidine sequences via Hoogsteen (or
Scheme 1.
The spectral evidence involved the absence of a character-
istic singlet corresponding to the iminic proton of acyclic
2
5,26
1
,3-diazabuta-1,3-diene at dw8.2 and the absence of
characteristic pattern of doublet of doublet of uncyclised
reverse Hoogsteen) hydrogen bonding.
Taking this into
account, the above methodology has been succesfully
extended to the synthesis of benzo[g]quinazoline deriva-
tives by carrying out the condensation reactions of
1
p-tolyl protons in the H NMR spectrum. Interestingly, the
formation of dihydroquinazoline derivatives was not
observed in reactions of 1 with para substituted aromatic
aldehydes possessing strong electron donating groups viz.
†
N-Naphthalen-1-yl-benzamidine with various aldehydes
(Scheme 3).
–
OCH and –N(CH ) . This is in contrast to the earlier
3 3 2
reports wherein the formation of dihydroquinazoline and
their aromatisation was shown to depend on electronic
1
1
factors. The observed absence of dihydroquinazolines in
the present case suggests that the thermal conditions perhaps
also play an important role in aromatisation of dihydro-
quinazolines to quinazolines. The isolation of quinazolines
in these reactions still involved their chromatographic
separation from triphenylphosphine oxide, resulting in a
considerable loss of time and yield.
It was envisaged that this problem may be circumvented by
the direct condensation of aldehydes with N-arylamidines,
without their prior conversion to iminophosphoranes. The
reported condensation reactions of N-alkylamidines with
aldehydes to form 1,3-diazabuta-1,3-dienes invariably
employed a Lewis acid catalysts, for example, zinc (II)
Scheme 3.
Quinazoline derivatives having a secondary amino func-
tionality at C-2 constitute an important class of medicinal
entities acting as a receptor antagonists and antihyperten-
sive agents and the important members include Prazosin
and Doxazosin. Prazosin is a prototype of an a receptor
antagonist which selectively blocks post synaptic
a1-receptors while having no effects on presynaptic a2
receptors responsible for the inhibition of norepinephrine
release from sympathetic nerve terminals. The compound
has been shown to function as a multidrug resistance (MDR)
reversal agent and binds to p-glycoprotein, a transmembrane
transport protein. In view of the above, the present
methodology was further extended to the condensation
reactions of guanidines 8 with aldehydes resulting once
1
9
20
21
chloride, titanium(IV) chloride, tin (IV) chloride etc.,
drastic reaction conditions and cumbersome work up
procedures. The stringent reaction conditions employed in
these condensation reactions often leading to their
1
27
1
2
2
irreproducibility and limiting their applicability in organic
synthesis. However, there are no literary reports regarding
such condensation reactions with N-arylamidines even
under such adverse reaction conditions.
2
3
The reported advantages of microwave assisted reactions
prompted us to scrutinize these reactions using a domestic
microwave oven and we report herein the solvent-free
condensation reactions of N-arylamidines 5 with various
aldehydes in the absence of any Lewis acid catalyst.
Interestingly, these attempts have once again led to the
exclusive formation of the desired quinazolines 3 in
excellent yields (Scheme 2).
†
The preparations should be carried out in an efficient fume cupboard
because of highly carcinogenic nature of napthylamine.

V. Kumar et al. / Tetrahedron 61 (2005) 3533–3538
3535
again in the exclusive formation of the corresponding 2-sec-
amino substituted quinazoline derivatives 9 (Scheme 4).
CHN-O-Rapid Elemental Analyzer. Column chromato-
graphy was performed on a silica gel (60–120) mesh or
Harrison Research Chromatotron using 2 mm plates (Silica
gel 60 PF254).
2.1. Procedure for the condensation reactions of
N-imidoyliminophosphoranes with aldehydes
In a typical experiment, N-imidoyliminophosphorane 1 was
mixed with 1.5 equiv of aldehyde 2 and the mixture was
exposed to microwave radiation at a power of 300 W for a
period of 3–4 min. The purification of the reaction mixture
by flash chromatography resulted in the exclusive isolation
of quinazolines 3 in good yields (65–80%).
2.2. Procedure for the condensation reactions of
N-arylbenzamidine/N-naphthylamidines/guanidines
with aldehydes
The procedure employed the exposure of microwave
radiations to a mixture of N-arylbenzamidine/N-naphthyl-
amidine/guanidines 5/8/6 and aldehyde 2 (power of 200 W
for 13–15 min in 6–7 cycles of 2 min each). The progress of
the reaction was monitored by thin layer chromatography
(TLC). The isolated product in each case was recrystallized
using (1:5) dichloromethane–hexane mixture and charac-
terized as quinazoline 3/9 and benzo[g]quinazolines 7 on the
basis of spectral evidences.
2.2.1. 6-Methyl-2,4-diphenylquinazoline (3a). Mp 226–
227 8C, d (200 MHz): 2.52 (s, 3H, –CH ); 7.58 (m, 11H,
ArH): 8.2 (m, 2H, ArH). d (50.4 MHz): 20.8, 120.8, 121.2,
H
3
c
1
1
22.5, 122.9, 123.8, 124.0, 125.7, 126.2, 127.0, 128.3,
29.1, 131.0, 135.0, 155.4, 157.8 m/z 296 (M ).
C
0
(3b). Lit. mp (189–190 8C)
2
.2.2. 6-Methyl-4-(4 -nitrophenyl)-2-phenylquinazoline
mp 189–190 8C, dH
1
7b
Scheme 4.
(
7
200 MHz): 2.58 (s, 3H, –CH ); 7.50–7.53 (m, 3H, ArH);
3
.74–7.78 (d, 2H, JZ8.1 Hz, ArH); 8.02–8.08 (m, 3H,
Though the reactions reported herein were carried out in a
conventional microwave oven, the results were reproducible
with excellent yields. Thus, a very simple, convenient,
accelerated, less expensive, generalised and high yielding
protocol for the selective synthesis of quinazolines and
benzo[g]quinazolines has been developed.
ArH); 8.44–8.48 (d, 2H, JZ8.1 Hz, ArH); 8.61–8.66 (m,
2
1
1
H, ArH): d (50.4 MHz) 21.9, 121.2, 123.7, 124.2, 128.4,
28.5, 129.2, 130.4, 130.6, 131.0, 136.3, 137.7, 137.9,
43.9, 148.5, 159.5, 165.0. m/z 341 (M ).
c
C
0
line (3c). Lit. mp (160–165 8C)
2
.2.3. 6-Methyl-4-(4 -methoxyphenyl)-2-phenylquinazo-
1
7b
mp 160–161 8C, dH
200 MHz): 2.51 (s, 3H, –CH ); 3.92 (s, 3H, –OCH ); 7.09–
(
2
. Experimental
3 3
7
7
.13 (d, 2H, JZ8.7 Hz, ArH); 7.46–7.54 (m, 3H, ArH);
.66–7.71 (d, 1H, JZ10.0 Hz, ArH); 7.85–7.90 (m, 3H,
Melting points were determined by open capillary using
Veego Precision Digital Melting Point apparatus (MP-D)
and are uncorrected. IR spectra were recorded on a
Shimadzu D-8001 spectrophotometer. H NMR spectra
were recorded in deuterochloroform with Bruker AC-E 200
ArH); 8.00–8.05 (d, 1H, JZ10.2 Hz, ArH) 8.64–8.68 (m,
2H, ArH): d (50.4 MHz) 21.8, 55.3, 113.9, 115.5, 121.5,
123.9, 125.6, 126.6, 127.2, 128.4, 128.8, 130.1, 130.5,
135.4, 136.8, 150.6, 159.4, 160.9. m/z 326 (M ).
c
1
C
(
200 MHz) spectrometers using TMS as internal standard.
0
Chemical shift values are expressed as ppm downfield from
TMS and J values are in Hz. Splitting patterns are indicated
as s: singlet, d: doublet, t: triplet, m: multiplet, q: quartet and
br: broad peak. C NMR spectra were also recorded on a
Bruker AC-200E (50.4 MHz) spectrometers in deutero-
chloroform using TMS as internal standard. Mass spectra
were recorded on Shimadzu GCMS-QP-2000 mass spec-
trometer. Elemental analyses were performed on Heraus
2.2.4. 6-Methyl-4-(4 -N-N-dimethylaminophenyl)-2-
phenylquinazoline (3d). Mp 212–213 8C. Anal. Calcd for
C H N : C, 81.38; H, 6.24; N, 12.38. Found C, 81.52; H,
2
3 21 3
1
3
6.35; N, 12.13%: d (200 MHz): 2.58 (s, 3H, –CH ); 3.33 (s,
H 3
6H, –(NCH ) ); 6.91–6.96 (d, 2H, JZ10.0 Hz, ArH); 7.55
(m, 3H, ArH); 7.74–7.78 (d, 1H, JZ8.5 Hz, ArH); 7.90–
7.95 (d, 2H, JZ10.0 Hz, ArH); 8.07( m, 2H, ArH); 8.69 (m,
2H, ArH): d (50.4 MHz): 21.2, 40.3, 120.2, 121.0, 122.7,
3
2
c

3536
V. Kumar et al. / Tetrahedron 61 (2005) 3533–3538
1
1
23.0, 124.5, 125.2, 126.1, 128.2, 128.8, 130.0, 130.5,
32.3, 132.7, 144.5, 150.8, 154.6. m/z 339 (M ).
dc (50.4 MHz): 118.4, 124.3, 124.0, 124.5, 125.2, 125.5,
126.3, 127.0, 127.4, 128.1, 128.3, 129.0, 129.6, 130.5,
1
C
C
33.2, 135.4, 137.0, 145.3, 153.0, 155.3. m/z 366.5 (M ).
2
line (3e). Lit. mp (181–183 8C)
.2.5. 4-(4-Chloro-phenyl)-6-methyl-2-phenyl-quinazo-
mp181–183 8C, dH
1
7b
2.2.11. 6-Methyl-4-phenyl-2-morpholino-4-yl-quinazo-
line (9a). Mp 147–148 8C. Anal. Calcd for C H N O: C,
(
200 MHz): 2.53 (s, 3H, –CH ); 7.05–7.09 (d, 2H, JZ
3
19 19 3
8
.4 Hz, ArH); 7.41–7.47 (m, 3H, ArH); 7.65–7.70 (d, 1H,
74.73; H, 6.27; N, 13.76. Found C, 74.97; H, 6.38; N,
13.48% d (200 MHz): 2.41 (s, 3H, –CH ); 3.81–3.86 (m,
JZ10 Hz, ArH); 7.84–7.88 (m, 3H, ArH); 8.02–8.06 (d, 1H,
H
3
JZ10 Hz, ArH); 8.60–8.64 (m, 2H, ArH): d (50.4 MHz):
4H, –CH –N–CH –); 3.98–4.02 (m, 4H, –CH –O–CH –);
2 2 2 2
c
2
1
3
1.2, 120.5, 121.7, 122.2, 123.8, 124.6, 125.0, 125.8, 128.3,
28.8, 130.2, 131.1, 133.2, 135.0, 136.7, 156.8, 160.0. m/z
7.54–7.62 (m, 6H, ArH); 7.74–7.76 (m, 2H, ArH): dc
(50.4 MHz) 21.37 (–CH ); 44.56 (–CH –N–CH –); 66.97
3
2
2
C
30.5 (M ).
(–CH –O–CH –); 117.7, 126.0, 128.3, 128.5, 129.5, 129.7,
2 2
C
30.0, 131.3, 135.7, 137.9, 160.9, 168.7. m/z 305 (M ).
1
2
1
8
6
.2.6. 2,4-Diphenyl-benzo[g]quinazoline (7a). Mp 180–
81 8C. Anal. Calcd for C H N : C, 86.72; H, 4.85; N,
.43. Found C, 86.93; H, 4.57; N, 8.50%: d (200 MHz):
H
2.2.12. 6-Methyl-2-morpholin-4-yl-4-(4-nitro-phenyl)-
quinazoline (9b). Mp 188–189 8C. Anal. Calcd for
C H N O : C, 65.13; H, 5.18; N, 15.99. Found C,
2
4 16 2
.88–6.92 (d, 1H, JZ8.4 Hz, ArH); 7.27–7.59 (m, 11H,
1
9 18 4 3
ArH); 7.69–7.73 (d, 1H, JZ8.4 Hz, ArH); 7.95–8.00 (m,
H, ArH); 8.91–8.95 (d, 1H, JZ8.4 Hz, ArH): dc
50.4 MHz): 118.7, 124.3, 124.4, 124.5, 125.7, 126.0,
65.32; H, 5.27; N, 15.79%: dH (200 MHz): 2.40 (s, 3H,
–CH ); 3.78–3.84 (m, 4H, –CH –N–CH –); 3.92–3.97 (m,
2
(
3
2
2
4H, –CH –O–CH –); 7.70–7.74 (d, 2H, JZ8.1 Hz, ArH);
2 2
1
1
26.7, 127.2, 127.4, 128.2, 128.6, 129.0, 129.8, 130.6,
33.7, 135.4, 137.7, 145.6, 152.8, 155.0. m/z 332 (M ).
8.07–8.12 (m, 3H, ArH); 8.44–8.48 (d, 2H, JZ8.1 Hz,
ArH); d (50.4 MHz): 22.0 (–CH ); 43.6 (–CH –N–CH –);
C
c
3
2
2
6
130.3, 132.7, 133.8, 134.0, 148.7, 157.5, 163.2. m/z 350
3.7 (–CH –O–CH ); 118.2, 123.5, 124.7, 128.5, 129.3,
2 2
2
(
.2.7. 4-(4-Nitro-phenyl)-2-phenyl-benzo[g]quinazoline
7b). Mp 155–156 8C. Anal. Calcd for C H N O : C,
C
(M ).
2
4 15 3 2
7
1
7
6.38; H, 4.01; N, 11.13. Found: C, 76.28; H, 3.83; N,
1.41%: d (200 MHz): 6.92–6.96 (d, 1H, JZ8.4 Hz, ArH);
.36–7.62 (m, 10H, ArH); 7.69–7.73 (d, 1H, JZ8.4 Hz,
2.2.13. 4-(4-Methoxy-phenyl)-6-methyl-2-morpholin-4-
yl-quinazoline (9c). Mp 182–183 8C. Anal. Calcd for
C H N O : C, 71.62; H, 6.31; N, 12.53. Found C,
H
ArH); 7.97–8.02 (m, 2H, ArH); 8.93–8.97 (d, 1H, JZ
2
0 21 3 2
8
1
1
3
.4 Hz, ArH) d (50.4 MHz): 117.9, 124.0, 124.7, 125.5,
26.0, 126.3, 126.6, 127.2, 127.4, 128.0, 128.6, 129.9,
30.1, 133.4, 134.4, 137.0, 140.7, 145.6, 152.0, 155.7. m/z
71.76; H, 6.48; N, 12.26%: dH (200 MHz): 2.41 (s, 3H,
–CH ); 3.81–3.86 (m, 4H, –CH –N–CH ); 3.92 (s, 3H,
–OCH ); 3.98–4.02 (m, 4H, –CH –O–CH –); 7.08–7.12 (d,
3 2 2
c
3
2
2
C
77 (M ).
2H, JZ8.2 Hz, ArH); 7.66–7.71 (d, 1H, JZ10.2 Hz, ArH);
.85–7.90 (m, 3H, ArH); 8.01–8.06 (d, 1H, JZ10.3 Hz,
ArH): d (50.4 MHz): 20.8 (–CH ); 42.8 (–CH –N–CH –);
7
2.2.8. 4-(4-Methoxy-phenyl)-2-phenyl-benzo[g]quinazo-
line (7c). Mp 167–168 8C. Anal. Calcd for C H N O: C,
c
3
2
2
55.0 (–OCH ); 66.9(–CH –O–CH –); 118.0, 119.2, 120.8,
3 2 2
2
5
18
2
8
2.85; H, 5.01; N, 7.73. Found C,83.05; H, 4.82; N, 7.64%:
121.4, 123.5, 124.7, 125.0, 128.5, 133.0, 144.7, 152.7,
155.8. m/z 335 (M ).
C
d (200 MHz): 3.95 (s, 3H, –OCH ); 6.90–6.94 (d, 1H, JZ
H
3
8
.4 Hz, ArH); 7.36–7.62 (m, 10H, ArH); 7.70–7.74 (d, 1H,
0
morpholin-4-yl-quinazoline (9d). Mp 198–199 8C. Anal.
JZ8.4 Hz, ArH); 7.97–8.02 (m, 2H, ArH); 8.92–8.96 (d,
2.2.14. 6-Methyl-4-(4 -N-N-dimethylaminophenyl)-2-
1
1
1
1
H, JZ8.4 Hz, ArH) d (50.4 MHz): 55.3 (–OCH ), 118.0,
c
3
22.8, 124.0, 125.4, 126.6, 126.9, 127.6, 127.9, 128.4,
28.6, 129.0, 129.9, 130.4, 133.8, 134.6, 137.0, 140.8,
Calcd for C H N O: C, 72.39; H, 6.94; N, 16.08. Found C,
2
1 24 4
72.79; H, 6.48; N, 16.18%: dH (200 MHz): 2.45 (s, 3H,
–CH ); 2.98 (s, 6H, –N(CH ) ); 3.80–3.85 (m, 4H, –CH –
C
45.3, 153.0, 156.7. m/z 362 (M ).
3
3 2
2
N–CH –); 3.99–4.03 (m, 4H, –CH –O–CH –); 6.84–6.88
2
2
2
2.2.9. Dimethyl-[4-(2-phenyl-benzo[g]quinazolin-4-yl)-
phenyl]-amine (7d). Mp 198–199 8C. Anal. Calcd for
(d, 2H, JZ8.5 Hz, ArH); 7.43–7.48 (d, 1H, JZ10.0 Hz,
ArH); 7.53–7.58 (d, 1H, JZ10.0 Hz); 7.74–7.78 (m, 3H,
ArH): d (50.4 MHz): 21.2 (–CH ); 40.3 (–N(CH ) ); 43.6
C H N :C, 83.17; H, 5.64; N, 11.19. Found C, 83.37; H,
2
6
21
3
c
3
3 2
5
6
.51; N, 11.12%: dH (200 MHz): 2.90 (s, 6H, –(NCH3)2);
.88–6.92 (d, 1H, JZ8.2 Hz, ArH); 7.42–7.70 (m, 10H,
(–CH –N–CH –); 54.0 (–CH –O–CH –); 120.2, 121.9,
2 2 2 2
122.0, 123.5, 124.8, 125.7, 128.2, 130.2, 131.7, 142.7,
153.5, 157.5. m/z 348 (M ).
C
ArH); 7.73–7.77 (d, 1H, JZ8.2 Hz, ArH); 7.93–7.98 (m,
H, ArH); 8.94–8.98 (d, 1H, JZ8.4 Hz, ArH) dc
50.4 MHz): 43.2 (–(NCH ) ); 118.2, 122.5, 124.3, 125.7,
2
(
3
2
2.2.15. 4-(4-Chloro-phenyl)-6-methyl-2-morpholin-4-yl-
quinazoline (9e). Mp 180–181 8C. Anal. Calcd for
C H N OCl: C, 67.15; H, 5.34; N, 12.37. Found C,
1
1
3
26.8, 127.0, 127.4, 127.9, 128.3, 128.6, 129.3, 129.9,
30.8, 134.0, 134.7, 137.3, 140.2, 145.2, 153.7, 156.9. m/z
1
9 18 3
C
75 (M ).
67.03; H, 5.71; N, 12.21%: dH (200 MHz): 2.42 (s, 3H,
CH ); 3.80–3.85 (m, 4H, –CH –N–CH –); 3.92–3.97 (m,
–
3
2
2
2.2.10. 4-(4-Chloro-phenyl)-2-phenyl-benzo[g]quinazo-
line (7e). Mp 156–158 8C. Anal. Calcd for C H N Cl:
C, 78.58; H, 4.12; N, 7.64. Found C, 78.67; H, 4.20; N, 7.45:
dH (200 MHz): 6.88–6.92 (d, 1H, JZ8.4 Hz, ArH); 7.40–
4H, –CH –O–CH –); 7.12–7.16 (d, 2H, JZ8.4 Hz, ArH);
2 2
7.57–7.62 (m, 3H, ArH); 7.84–7.88 (d, 2H, JZ8.4 Hz,
ArH): d (50.4 MHz): 20.7 (–CH ); 43.8 (–CH –N–CH –);
2
4 15 2
c
3
2
2
64.9 (–CH –O–CH –); 119.0, 122.3, 123.4, 124.3, 126.2,
2 2
7
7
.60 (m, 10 H, ArH); 7.72–7.76 (d, 1H, JZ8.2 Hz, ArH);
.92–7.97 (m, 2H, ArH); 8.94–8.98 (d, 1H, JZ8.4 Hz, ArH)
126.8, 129.7, 130.8, 131.2, 134.8, 154.7, 157.2. m/z 339.5
(M ).
C

V. Kumar et al. / Tetrahedron 61 (2005) 3533–3538
3537
2
.2.16. 6-Methyl-4-phenyl-2-pyrrolidin-1-yl-quinazoline
9f). Mp 140–141 8C. Anal. Calcd for C H N : C, 78.86;
CH –); 7.50–7.58 (m, 6H, ArH); 7.70–7.74 (m, 2H, ArH): d
2 c
(50.4 MHz): 19.3 (–CH ); 25.2 (–CH ); 26.0 (–CH –CH –);
3 2 2 2
44.4 (–CH –N–CH –); 117.0, 118.3, 120.4, 122.7, 123.4,
2 2
(
H, 6.62; N, 14.52. Found C, 79.02; H, 6.68; N, 14.28%: dH
1
9
19
3
(
–
6
200 MHz): 2.01–2.07 (m, 4H, –CH –CH –); 2.37 (s, 3H,
2
125.2, 127.9, 130.0, 135.3, 145.3, 157.7, 166.3. m/z 303
(M ).
2
C
CH ); 3.70–3.76 (m, 4H, –CH –N–CH –); 7.50–7.58 (m,
2
3
2
H, ArH); 7.70–7.73 (m, 2H, ArH); d (50.4 MHz): 21.1
c
(
1
1
–CH ); 24.9 (–CH –CH –); 45.7 (–CH –N–CH ); 117.3,
2
2.2.22. 6-Methyl-4-(4-nitro-phenyl)-2-piperidin-1-yl-
quinazoline (9l). Mp 160–162 8C. Anal. Calcd for
C H N O : C, 68.95; H, 5.79; N, 16.08. Found C,
3
2
2
2
18.2, 120.1, 122.5, 123.3, 125.4, 127.7, 130.2, 135.6,
45.1, 157.9, 166.6. m/z 289 (M ).
C
2
0 20 4 2
68.80; H, 5.87; N, 15.96%: d (200 MHz): 1.70–1.75 (m,
H
2.2.17. 6-Methyl-4-(4-nitro-phenyl)-2-pyrrolidin-1-yl-
quinazoline (9g). Mp 154–155 8C. Anal. Calcd for
6H, –CH –CH –CH –); 2.41 (s, 3H, –CH ); 3.98–4.03 (m,
2 2 2 3
4H, –CH –N–CH –); 7.70–7.74 (d, 2H, JZ8.2 Hz, ArH);
2 2
C H N O : C, 68.25; H, 5.43; N, 16.76. Found C,
1
8.02–8.08 (m, 3H, ArH); 8.44–8.48 (d, 2H, JZ8.2 Hz,
ArH): d (50.4 MHz): 19.3 (–CH ); 25.2 (–CH ); 26.0
9 18 4 2
6
4
–
8
8.48; H, 5.20; N, 16.86%: d (200 MHz): 1.82–1.86 (m,
H
c
3
2
H, –CH –N–CH –); 2.37 (s, 3H, –CH ); 3.72–3.77 (m, 4H,
3
(–CH –CH –); 44.4 (–CH –N–CH –); 118.0, 123.5, 124.4,
2 2 2 2
2
2
CH –N–CH –); 7.70–7.74 (d, 2H, JZ8.2 Hz, ArH); 8.01–
128.7, 129.2, 130.4, 132.8, 133.9, 134.3, 148.5, 157.3,
163.0. m/z 348 (M ).
2
2
C
.07 (m, 3H, ArH); 8.44–8.48 (d, 2H, JZ8.2 Hz, ArH): dc
(
N–CH –); 118.2, 119.1, 120.0, 120.8, 123.4, 126.2, 128.5,
1
50.4 MHz): 22.0 (–CH3); 26.2 (–CH –CH –); 48.1 (–CH –
2 2 2
2
2.2.23. 4-(4-Methoxy-phenyl)-6-methyl-2-piperidin-1-yl-
quinazoline (9m). Mp 140–141 8C. Anal. Calcd for
C H N O: C, 75.65; H, 6.95; N, 12.60. Found C, 75.47;
C
30.0, 131.8, 142.7, 153.5, 156.0. m/z 334 (M ).
2
1 23 3
0
2
.2.18. 6-Methyl-4-(4 -methoxyphenyl)-2-pyrrolidino-1-
H, 6.98; N, 12.78%: dH (200 MHz): 1.70–1.75 (m, 6H,
CH –CH –CH –); 2.37 (s, 3H, –CH ); 3.90 (s, 3H,
yl-quinazoline (9h). Mp 147–148 8C. Anal. Calcd for
C H N O: C, 75.21; H, 6.63; N, 13.16. Found C, 75.03;
–
2
2
2
3
2
1
24
3
–OCH ); 3.98–4.03 (m, 4H, –CH –N–CH –); 6.88–6.92
3 2 2
H, 6.73; N, 13.12%: dH (200 MHz): 2.00–2.07 (m, 4H,
CH –CH –); 2.40 (s, 3H, –CH ); 3.73–3.79 (m, 4H, –CH –
(d, 2H, JZ8.2 Hz, ArH); 7.38–7.43 (d, 1H, JZ10.3 Hz,
ArH); 7.52–7.57 (d, 1H, JZ10.3 Hz, ArH); 7.75–7.79 (m,
3H, ArH): d (50.4 MHz): 19.7 (–CH ); 25.0 (–CH ); 25.9
–
2
2
3
2
N–CH –); 3.92 (s, 3H, –OCH ); 7.03–7.08 (d, 2H, ArH, JZ
2
3
c
3
2
8
.8 Hz); 7.49–7.64 (m, 3H, ArH); 7.71–7.76 (d, 2H, ArH,
(
119.8, 120.7, 121.2, 122.7, 123.0, 124.5, 127.8, 132.8,
–CH –CH –); 44.8 (–CH –N–CH –); 55.0 (–OCH );
2 2 2 2 3
JZ8.8 Hz): d (50.4 MHz): 21.3 (–CH ); 25.5 (–CH –CH –);
c
3
2
2
C
133.0, 145.0, 152.4, 157.4 m/z 333 (M ).
4
1
1
7.2 (–CH –N–CH ); 55.2 (–OCH ); 113.7, 117.0, 124.6,
2 2 3
26.2, 127.5, 128.7, 130.2, 131.4, 135.6, 150.1, 160.9,
68.6. m/z 319 (M ).
C
0
piperidin-1-yl-quinazoline (9n). Mp 143–144 8C. Anal.
2
.2.24. 6-Methyl-4-(4 -N-N-dimethylaminophenyl)-2-
2.2.19. Dimethyl-[4-(6-methyl-2-pyrrolidin-1-yl-quina-
zolin-4-yl)-phenyl]-amine (9i). Mp 164–165 8C. Anal.
Calcd for C H N : C, 76.27; H, 7.56; N, 16.17. Found C,
2
2 26 4
7
6
–
6.43; H, 7.72; N, 15.93%: d (200 MHz): 1.70–1.75 (m,
H
Calcd for C H N : C, 75.87; H, 7.28; N, 16.85. Found
1 24 4
2
H, –CH –CH –CH –); 2.41 (s, 3H, –CH ); 2.93 (s, 6H,
2
2
2
3
C, 76.02; H, 7.48; N, 16.43%: d (200 MHz): 2.02–2.06 (m,
H
N(CH ) ); 3.98–4.03 (m, 4H, –CH –N–CH –); 6.84–6.88
3
2
2
2
4
–
H, –CH –CH –); 2.32 (s, 3H, –CH ); 2.98 (s, 6H,
2 2 3
(
d, 2H, JZ8.2 Hz, ArH); 7.43–7.48 (d, 1H, JZ10.3 Hz,
ArH); 7.53–7.58 (d, 1H, JZ10.3 Hz, ArH); 7.74–7.78 (m,
H, ArH) d (50.4 MHz): 21.3 (–CH ); 25.0 (–CH ); 25.7,
N(CH ) ); 3.68–3.73 (m, 4H, –CH –N–CH –); 6.94–6.98
3
2
2
2
(
d, 2H, JZ8.4 Hz, ArH); 7.52–7.57 (d, 1H, JZ10.2 Hz,
3
c
3
2
ArH); 7.64–7.69 (d, 1H, JZ10.2 Hz, ArH); 7.90–7.95 (m,
(
–CH –CH –); 39.3 (–N(CH ) ); 44.9 (CH –N–CH –);
2 2 3 2 2 2
3
3
1
1
H, ArH): d (50.4 MHz): 22.0 (–CH ); 23.8 (–CH –CH –);
9.4 (–N(CH ) ); 42.7 (–CH –N–CH –); 118.0, 119.2,
c 3 2 2
1
1
18.5, 119.3, 120.2, 125.6, 125.8, 126.3, 130.8, 131.3,
34.9, 146.3, 154.3, 158.7. m/z 346 (M ).
C
3
2
2
2
23.4, 124.5, 127.2, 128.0, 129.3, 130.1, 132.5, 143.5,
50.7, 157.2. m/z 332 (M ).
C
2.2.25. 4-(4-Chloro-phenyl)-6-methyl-2-piperidin-1-yl-
quinazoline (9o). Mp 156–157 8C. Anal. Calcd for
2.2.20. 4-(4-Chloro-phenyl)-6-methyl-2-pyrrolidin-1-yl-
quinazoline (9J). Mp 157–158 8C. Anal. Calcd for
C H N Cl: C, 71.10; H, 5.97; N, 12.44. Found C, 71.03;
2
0 20 3
H, 6.04; N, 12.51%: dH (200 MHz): 1.69–1.75 (m, 6H,
C H N Cl: C, 70.47; H, 5.60; N, 12.98. Found C, 70.86;
1
9 18 3
–
–
7
1
CH –CH –CH –); 2.41 (s, 3H, –CH ); 3.98–4.02 (m, 4H,
2 2 2 3
H, 5.39; N, 12.87%: dH (200 MHz): 2.04–2.08 (m, 4H,
CH –CH –); 2.24 (s, 3H, –CH ); 3.64–3.70 (m, 4H, –CH –
CH –N–CH –); 6.90–6.94 (d, 2H, JZ8.2 Hz, ArH); 7.43–
2
2
–
2
2
3
2
.48 (d, 1H, JZ10.3 Hz, ArH); 7.57–7.62 (d, 1H, JZ
N–CH –); 6.90–6.94 (d, 2H, JZ8.4 Hz, ArH); 7.51–7.56 (d,
2
0.3 Hz, ArH); 7.74–7.78 (m, 3H, ArH) d (50.4 MHz): 21.3
c
1
7
(
H, JZ10.2 Hz, ArH); 7.64–7.69 (d, 1H, JZ10.2 Hz, ArH);
.85–7.90 (m, 3H, ArH): d (50.4 MHz): 20.2 (–CH ); 23.4
–CH –CH –); 42.7 (–CH –N–CH –); 118.4, 119.0, 122.4,
(–CH ); 25.0 (–CH ); 25.7, (–CH –CH –); 44.2 (CH –N–
CH –); 118.0, 119.3, 120.5, 123.6, 125.8, 126.7, 130.0,
3 2 2 2 2
c
3
2
C
31.2, 133.9, 147.3, 154.3, 158.7. m/z 337.5 (M ).
2
2
2
2
1
1
1
24.7, 126.2, 128.3, 129.0, 130.1, 133.5, 143.5, 150.9,
56.2. m/z 323.5 (M ).
C
2
(
.2.21. 6-Methyl-4-phenyl-2-piperidin-1-yl-quinazoline
9k). Mp 137–138 8C. Anal. Calcd for C H N : C,
References and notes
2
0 21 3
7
1
9.17; H, 6.98; N, 13.85. Found C, 79.28; H, 6.83; N,
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2
CH –); 2.38 (s, 3H, –CH ); 3.97–4.02 (m, 4H, –CH –N–
3
2
2

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