The reaction of tetralones with nitriles: A simple approach to the synthesis of new substituted benzo[h]quinazolines, benzo[f]quinazolines and dibenzo[a,i]phenanthridines

Article abstract of DOI:10.1016/j.tet.2006.01.010

The one-pot reaction of 1-tetralone with nitriles in the presence of triflic anhydride affords in good yields 2,4-disubstituted 5,6-dihydrobenzo[h] quinazolines, which oxidation with DDQ leads to the corresponding benzo[h]quinazolines. 2-Tetralone undergo

Full text of DOI:10.1016/j.tet.2006.01.010

Tetrahedron 62 (2006) 2799–2811
The reaction of tetralones with nitriles: a simple approach
to the synthesis of new substituted benzo[h]quinazolines,
benzo[f]quinazolines and dibenzo[a,i]phenanthridines
a
Antonio Herrera, Roberto Martınez-Alvarez, Mourad Chioua, Rachid Chatt,
a,
a
a
*
´
b
c
Rachid Chioua, Angel Sanchez and John Almy
d
´
a
´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, Universidad Complutense, E-28040 Madrid, Spain
b
´ ´ ´ ˆ ´
Departement de Chimie, Faculte des Sciences, Universite Abdelmalek Essaadi, Tetouan, BP 2121, Morocco
c
´
´
CAI de Resonancia Magnetica Nuclear, Facultad de Ciencias Quımicas, UCM, E-28040 Madrid, Spain
dDepartment of Chemistry, California State University, Stanislaus, Turlock, CA 95382, USA
Received 15 December 2005; accepted 5 January 2006
Available online 26 January 2006
Abstract—The one-pot reaction of 1-tetralone with nitriles in the presence of triflic anhydride affords in good yields 2,4-disubstituted
5,6-dihydrobenzo[h]quinazolines, which oxidation with DDQ leads to the corresponding benzo[h]quinazolines. 2-Tetralone undergoes
identical process forming 1,3-disubstituted 5,6-dihydrobenzo[f]quinazolines. However, when the reaction of 2-tetralone is carried out with
methylthiocyanate as nitrile, 5-methylthiotetrahydrodibenzo[a,i]phenanthridines are isolated in good yields. Easy transformations of the
methylthio group offer possible access to a variety of substituted dibenzo[a,i]phenanthridines.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
skeleton.11 Phenanthridine derivatives exhibit interesting
pharmacological properties related to the planarity of the
system. Consequently, these compounds present a DNA-
chain intercalating ability12 and benzophenanthridines are
reported as compounds with topoisomerase I-targeting
activity and cytotoxicity.13 Moreover, this heterocyclic
system posesses important photoconducting, opto-electrical
switching and photovoltaic properties14 with many appli-
cations in the field of dye-lasers and electroluminiscence.15
Among the pyrimidine derivatives, one of the prominent
compounds are the benzoquinazolines. They constitute the
core of naturally ocurring products such as the cytotoxic
alkaloid samoquasine A.1 The benzoquinazoline skeleton is
commonly found in substances exhibiting a wide range of
biological properties. 1,3-Diaminobenzoquinazolines were
evaluted many years ago as antifolate and antimalarial
agents.2 Other benzoquinazoline derivatives are used as
substitutes for thymine in nucleic acid complexes,3 while
anilinoquinazolines are potent and selective inhibitors of
erbB2 receptor tyrosine kinase.4 Quinazolinones present
inhibitory activity of thymidate synthase.5–8 Recently,
4-(dimethylamino)quinazolines are described as antagonist
for the melanin-concentrating hormone receptor 19 and
pyrazoloquinazolines are reported as novel Gly/NMDA
receptor antagonist.10
The construction of the quinazoline moiety involves
cyclization of appropriate substituted benzenes whose
preparations are not always easy. Other approaches are
based on the reaction of 1,3-dicarbonyl compounds with a
suitable N–C–N fragment.16,17 Modern methods employ
either catalyst- and solvent free conditions 18 or supercritical
carbon dioxide19 to prepare quinazoline derivatives. The
preparation of the phenanthridine ring also requires the
selection of suitable precursors that are not easy to
synthesize. Some methods make use of appropriately
substituted isoquinolines.20 Other methods employing
simple starting compounds are limited by numerous steps
and poor yields. The four-step preparation of benzo[c]phe-
nanthridine from formaldehyde and 2-methylbenzonitrile
has a 6% yield overall.21 Many methods to prepare
quinazolines and phenanthridines are reported in the
Phenanthro fused heterocycles are also of interest in many
aspects. Natural products such as tylophorine, antofine and
cryptoleurine posess the phenanthro fused heterocycle
Keywords: Pyrimidines; Benzoquinazolines; Benzophenanthridines.
*
Corresponding author. Tel.: C34 913944325; fax: C34 913944103;
e-mail: rma@quim.ucm.es
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.010

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A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
literature. In spite of their importance, only very few of
them involve less than a few steps.22
The reaction can be checked using 13C NMR. Compound 6a
exhibits two methylene carbon signals at 41.36 and
45.84 ppm corresponding to both benzyl groups. Using 1D
and 2D techniques, the signal at 45.84 ppm was unequi-
vocally assigned to the CH2 group attached at the C2
position. The reaction of 6a in boiling toluene affords 7a
whose 13C NMR spectra reveals a new signal at 193.64 ppm
representing a new carbonyl group and only one methylene
group at 45.79 ppm representing the unreacted benzyl group
at the C2 position. In contrast, when the reaction is carried
out in o-DCB at 130 8C two new carbonyl signals appear at
191.03 and 192.95 ppm, respectively, and both signals of
the CH2 dissapear.
Herein, we wish to report that the one-pot reaction of 1- and
2-tetralone with nitriles in the presence of triflic anhydride
(Tf2O) affords substituted dihydrobenzo[h]quinazolines (1),
dihydrobenzo[f]quinazolines (2) and tetrahydro[a,i]dibenzo-
phenanthridines(3) (Fig. 1)ingoodyields, which canbeeasily
oxidized to their aromatic counterparts.
9
9
10
10a
10
10a
8
7
8
7
R
1
1
N
2
N
2
R
R
6a
6
6a
6
3
3
R
N
N
R
O
4a
4a
4
R
4
5
5
N
R
R
N
R
R
DDQ
R-CN
Tf2O
1
2
N
N
6
N
7
5
6a
R
8
8a
12b
4
12a
12c
12
1 (65–83%)
5 (70–92%)
4a
4
3
2
9
4b
14
a) R = C6H5
CN
R
R
10
b) R = 4-CH3C6H4
c) R = 4-ClC6H4
d) R = SCH3
13
14a
Tf2O
11
1
3
N
N
R
DDQ
Figure 1. General structure of prepared compounds.
Toluene, 110 °C
O
N
2. Results and discussion
N
R
R
7 (40–50%)
In previous papers we have reported the synthesis of a
variety of heterocyclic systems based on the reaction of
carbonyl compounds with nitriles in the presence of triflic
anhydride.23–27 The reaction of 1-tetralone (4) with various
nitriles and Tf2O under mild conditions (see Section 3)
affords 2,4-disubstituted 5,6-dihydrobenzo[h]benzoquina-
zolines (1) in good yield (Scheme 1). The well-known
mechanism involves the formation of a trifliloxycarbenium
ion, which is trapped by the nitrile forming a nitrilium ion. A
second molecule of nitrile reacts with the intermediate to
give the corresponding quinazoline after elimination of
TfOH and loss of a proton.23 Minor amounts of the vinyl
triflate from 1-tetralone (3,4-dihydronaphthalen-1-yl tri-
flate) were detected as side product of the reaction (see
Section 3). Its formation is a consequence of a competitive
reaction involving the trifliloxycarbenium ion intermediate,
which eliminates a proton before it undergoes nucleophilic
attack by the nitrile. The oxidation of compounds 1 by
means of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in
o-DCB at 130 8C affords benzoquinazolines 5. Employing
toluene as solvent and hence a lower reaction temperature
produces an undesirable mixture of compounds that reduces
the yield of this reaction. The use of benzyl nitriles in the
reaction with 1-tetralone allows the preparation of 2,4-
dibenzyl substituted dihydrobenzoquinazolines 6. The
oxidation of these benzyl derivatives with DDQ can be
controlled by the temperature and hence by the choice of the
reaction solvent. Thus, when the reaction is carried out in
boiling toluene only the methylene group attached at the C4
position reacts to form monocarbonyl compounds 7. If the
reaction is carried out in o-DCB at 130 8C both methylene
groups are oxidized affording the dicarbonyl compounds 8.
DDQ
o-DCB, 130 °C
R
N
O
6 (70–77%)
N
O
a) R = H
b) R = 2-CH3
c) R = 4-CH3
R
8 (45–60%)
Scheme 1.
The reaction of 1-tetralone (4) with methylthiocyanate
affords the 2,4-bis(thiomethyl)-5,6-dihydrobenzo[h]quina-
zoline 1d, which reacts with DDQ to form 5d.
The easy conversion of the thiomethyl group via nucleo-
philic displacements into other interesting groups opens a
new synthetic route to other quinazoline derivatives
otherwise not easy to prepare. Thus, the reaction of 5d
with m-CPBA produces the corresponding 2,4-bis(methyl-
sulfonyl) derivative 9d (Scheme 2). The nucleophilic
substitution of the methylsulfonyl group using sodium
methoxide affords the dimethoxy derivative 10d. The
reaction of 9d with ammonia at room temperature permits
only the substitution of the methylsulfonyl group at C4
(11d) and the subsequent reaction with sodium methoxide
leads to the formation of the aminomethoxy derivative 12d.
The hydrolysis of 9d carried out with boiling aqueous
sodium hydroxide forms the uracil 13d. This compound is
also available from the acid hydrolysis of 10d.

A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
2801
NaOCH3
N
OCH3
N
OCH3
10d
N
SO2CH3
m-CPBA
N
SO2CH3
N
OCH3
NH3
5d
N
N
N
NaOCH3
SO2CH3
NH2
NH2
9d
11d
12d
HCl
H2O
NaOH
H2O
H
N
O
NH
O
13d
Scheme 2.
The reaction of 2-tetralone (14) with nitriles in the presence
of triflic anhydride leads to the formation of 1,3-
disubstituted 5,6-dihydrobenzo[f]quinazolines (15), which
can be oxidized using DDQ to form the corresponding
benzo[f]quinazolines (17) (Scheme 3).
program show that intermediate 20 is more stable than 19.
For example, intermediate 20 is 11.38 kJ molK1 (PM3)
more stable than the corresponding isomer 19 when
RZC6H5. This energy difference explains the formation
of quinazolines 15. To confirm the proposed structure of the
dihydrobenzo[f]quinazoline we used NOE experiments,
which were carried out on compound 15f. The irradiation
of the signal at 2.70 corresponding to the CH3 on C1 causes
a signal enhancement of the aromatic proton H10
(7.60 ppm). In contrast, a hypothetical dihydrobenzo[g]qui-
nazoline 16a should exhibit, under the same irradiation,
only a NOE effect in the aliphatic region (Scheme 5).
With two different positions alpha to the carbonyl group on
2-tetralone (14), one can envisage the formation of two
possible products, the isomeric dihydrobenzo[f]quinazo-
lines (15) and dihydrobenzo[g]quinazolines (16). In fact, the
exclusive formation of quinazolines 15 raises the question
of the regioselective advantage of the hydrogen atoms alpha
both to the carbonyl and phenyl group. The reaction of
linear aliphatic ketones with nitriles was investigated by
us28 demonstrated that the regioselectivity of this process is
controlled by the relative stabilities of the cationic
intermediates. The general proposed mechanism24 involves
the formation of an imonium intermediate (18), which
easily eliminates triflic acid (Scheme 4). Trace amounts
of 3,4-dihydronaphthalen-2-yl triflate are also formed
(see Section 3).
When 2-tetralone (14) reacts with benzyl nitriles, 1,3-
disubstituted dihydrobenzo[f]quinazolines 15c–e are
obtained (Scheme 3). However, if the benzyl nitrile bears
electron withdrawing groups, significant amounts of
pyrimidines 22 was also obtained in addition to the expected
quinazolines 21 (Scheme 6). The amounts of pyrimidines 22
increases at higher temperatures. Surprisingly, benzonitrile
also affords a pyrimidine type product 23 when the reaction
is carried out at 120 8C. Thus, the reaction of 2-tetralone and
benzonitrile was investigated under various temperature
conditions. The results show that when this reaction is
carried out at room temperature exclusively the quinazoline
The TfOH elimination leads to the formation of olefins 19
and 20. Theoretical calculations by means of molecular
mechanics (PM3 and AM1) within Hyperchem v6.03
R
N
R
DDQ
N
N
R
N
R
15 (60–86%)
17 (75–89%)
O
R-CN
Tf2O
a) R = C6H5
b) R = 4-CH3C6H4
c) R = C6H5CH2
d) R = 2-CH3C6H4CH2
e) R = 4-CH3C6H4CH2
f) R = CH3
14
N
R
N
R
16
Scheme 3.

2802
A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
OTf
OTf
R
R
C
C
O
R-CN/Tf2O
N
N
N
N
C
R
C
R
14
18
-TfOH
R
R
C
C
N
N
N
N
C
C
R
R
19
20
R
N
R
R
N
N
N
R
15
16
Scheme 4.
1
complete assignments of the H NMR signals. Irradiations
and signals enhancement are summarized in Scheme 8. The
observed results confirm the proposed structure (Scheme 8).
Experiments are in progress to determine the exact
mechanism of the pyrimidine formation.
H
CH3
N
N
CH3
N
N
CH3
H H
The reaction of 2-tetralone (14) with methylthiocyanate
(Scheme 9) leads to a mixture of the expected
dihydrobenzoquinazoline 24 and a new compound,
which was identified as tetrahydrodibenzo[a,i]phenanthri-
dine 25. The pentacyclic structure of 25 cannot be
explained by the general mechanism for the reaction
between ketones and nitriles.23 Moreover, the presence of
only one nitrogen atom in the structure of 25 indicates
that the cyclodimerisation process of the nitrile does not
take place. In contrast to the general mechanism, only
one molecule of the nitrile and two molecules of the
starting ketone participate in the reaction.
CH3
15f
16f
Scheme 5.
15a is exclusively formed while pyrimidine 23 is the main
reaction product when the temperature is raised to 120 8C
(Scheme 7).
The formation of pyrimidine 23 could not be explained by a
fragmentation process promoted by temperature. Heating
15a in o-DCB at 120 8C for several hours, even in the
presence of Tf2O and/or TfOH, does not afford pyrimidine
23. NOE experiments with compound 22c were performed
to confirm the pyrimidine structure and to achieve the
We have proposed a mechanism to explain these results.
The first step involves the aldol condensation of the
tetralone 14 induced by traces of triflic acid to form the
R
CN
R
R
H
O
N
+
N
H3C
N
Tf2O
R
N
R
a) R = 4-Cl
14
b) R = 3,4-Cl2
c) R = 4-NO2
22( 50–61%)
21 (25–30%)
Scheme 6.

A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
2803
N
CH2Cl2
RT
CN
N
15a
O
o-DCB 120 °C
Tf2O
o-DCB
120 °C
14
H
N
H3C
N
23
Scheme 7.
m-CPBA in dichloromethane affords the sulfone 32, which
reacts with a methanolic solution of sodium methoxide
leading to the methoxyphenanthridine 33 (Scheme 11).
NO2
NO2
1
The H NMR spectra of 33 shows a singlet at 4.09 ppm
H
H
H
H
H
corresponding to the CH3O group, which does not overlap
with the signals of H13 and H14. Moreover, H7 and H8
appear as a singlet at 2.29 ppm. Irradiation of the CH3O
signal produces a significant enhancement of the signal at
8.28 ppm corresponding to H4. Another small signal
enhancement is observed at 2.29 ppm, which corresponds
to H7 and H8 (Scheme 12 and Fig. 2). The structure of the
isomeric phenanthridine 34 could be discarded because an
irradiation on the methoxy signal could not produce a signal
enhancement in the aromatic region.
H
H
H
CH2
N
CH2
N
NO2
NO2
H3C
N
H3C
N
22c
Scheme 8.
hydroxyketone 26. The last step of this condensation
involves the elimination of a water molecule and affords
the two isomeric binaphthalenones 27 and 28 (Scheme
10). The reaction of the enone 27 with methylthiocyanate
followed by loss of TfOH and cyclization affords the
tetrahydrodibenzo[a,i]phenanthridine 24. In contrast, if
the enone 28 undergoes the same process, the isomeric
tetrahydrodibenzo[a,j]phenanthridine 30 should be
formed. A similar mechanism has been reported that
involves an aldol condensation of cyclobutanone and
subsequent reaction with only one nitrile molecule has
been reported.29
The reaction of 25 with DDQ affords the totally aromatic
phenanthridine 31. Unfortunately, this compound is
unreactive towards nucleophiles and the thiomethyl group
cannot be replaced in this polyaromatic system.
In summary, we report that the one-pot reaction of 1-
and 2-tetralone with nitriles affords 2,4-disubstituted
dihydrobenzo[h]quinazolines and 1,3-disubstituted dihy-
drobenzo[f]quinazolines, respectively. These compounds
can be easily converted into their corresponding
benzoquinazolines via DDQ oxidation. The reaction of
2-tetralone with nitriles is a regiospecific process and is
proposed a mechanism to explain the results. Benzoqui-
nazolines bearing thiomethyl groups can be used as
starting materials for the synthesis of several variously
substituted quinazolines. On the other hand, the reaction
of 2-tetralone with methylthiocyanate is a one-step
procedure to obtain substituted dibenzophenanthridines.
A mechanism for this reaction is postulated.
In order to distinguish between phenanthridines 25 and 30,
we used NOE experiments. Because the chemical shift of
the thiomethyl group (2.69 ppm) is close to the signals of the
methylene protons, it is very difficult to irradiate the CH3S
signal without perturbation of other nuclei. To avoid this
problem, we prepared several derivatives of 25 based on
the reactions shown in Scheme 3. The oxidation of 25 with
H3CS
N
SCH3
O
CH3SCN
+
N
N
Tf2O
SCH3
24 (40%)
25 (48%)
14
Scheme 9.

2804
A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
O
O
27
OH
O
-H2O
TfOH
2
14
26
O
28
OTf
H3CS
H3CS
N
N
O
CH3SCN
Tf2O
a) - TfOH
b) cyclization
27
25
29
CH3SCN
Tf2O
a) - TfOH
b) cyclization
N
O
28
SCH3
30
Scheme 10.
H3CS
N
DDQ
o-DCB
31 (75%)
25
H3CO
N
H3CO2S
N
NaOCH3
MCPBA
33 (22%)
32 (83%)
Scheme 11.
CH3
H7
H
O
N
7H8
H8
H4
H13
H13
N
H14
H14
O
CH3
34
33
Figure 2.
Scheme 12.

A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
2805
3. Experimental
(m, 1H), 7.50 (m, 2H), 7.70 (m, 2H), 8.60 (m, 1H), 8.66 (m,
2H) ppm; 13C NMR (CDCl3) d: 21.43 (CH3), 21.53 (CH3),
24.78 (CH2), 27.82 (CH2), 123.44, 126.04, 127.26, 127.72,
128.15, 128.29, 128.36, 129.21, 130.80, 133.38, 138.22,
139.00, 160.10, 162.14, 164.28 (arom.) ppm; m/z (EI,
70 eV): 362 (MC%, 85), 361 (100), 127 (20), 91 (C7HC7 ,
59). Anal. Calcd for C26H22N2: C 86.15, H 6.12, N 7.73%,
found C 87.97, H 6.08, N 7.66.
3.1. General
All reagents were commercial grade and were used as
received unless otherwise indicated. Triflic anhydride was
prepared from TfOH and redistilled twice prior to use.30,31
Solvents were distilled from an appropriate drying agent
before use. Reactions were monitored by thin-layer
chromatography (TLC) using silica gel plates having
60F250. Column chromatography was performed using
silica gel 60 (70–230 mesh). Melting points were
determined on a Gallenkamp apparatus in open capillary
tubes and are uncorrected. The IR spectra were measured
with a Shimadzu FTIR 8300 instrument and samples pellets
were produced with potassium bromide spectroscopic
grade. NMR spectra were recorded on a Bruker DPX 300
and Bruker Avance AV 500 at 300 MHz for 1H and
3.2.3. 2,4-Bis(4-chlorophenyl)-5,6-dihydrobenzo[h]qui-
nazoline 1c. Purification of crude product by column
chromatography gave 1.42 g (83%), mp 118–119 8C
(CHCl3/MeOH); n (KBr) 1600, 1540, 1400, 850, 770 cmK1
;
1H NMR (CDCl3) d: 2.92 (m, 2H, CH2), 3.06 (m, 2H, CH2),
7.30 (m, 1H), 7.49 (m, 6H), 7.64 (m, 2H), 8.60 (m, 3H) ppm;
13C NMR (CDCl3) d: 24.77 (CH2), 27.69 (CH2), 123.58,
126.04, 127.35, 127.80, 128.60, 129.47, 130.59, 131.07,
133.04, 135.51, 136.48, 1136.53, 136.55, 139.07, 160.41,
75.47 MHz for 13C and 500 MHz for H and 125.72 MHz
161.24, 163.14 (arom.) ppm; m/z (EI, 70 eV): 402 (MC%
,
1
for 13C, respectively. Chemical shifts are given in d units
(ppm) to residuals CHCl3 (7.26 and 77.0, respectively) and
DMSO (2.50 and 39.5, respectively). J values are in Hz.
Mass spectra were carried out on a HP 5989A quadrupole
instrument at 70 eV with a source temperature of 200 8C.
Elemental analysis was carried out with a Perkin-Elmer
2400 CHN apparatus.
63), 401 (100). Anal. Calcd for C24H16Cl2N2: C 71.47, H
4.00, Cl 17.58, N 6.95%, found C 71.39, H 3.69, Cl 17.44, N
6.79.
3.2.4. 2,4-Bis(methylthio)-5,6-dihydrobenzo[h]quinazo-
line 1d. Purification of crude product by column chroma-
tography afforded 0.82 g (70%), mp 110–111 8C (EtOH); n
(KBr) 1530, 1440, 1360 cmK1; 1H NMR (CDCl3) d: 2.61 (s,
3H, SCH3), 2.65 (s, 3H, SCH3), 2.80 (t, 2H, JZ7.2 Hz,
CH2), 2.96 (t, 2H, JZ7.2 Hz, CH2) 7.23 (m, 1H), 7.35 (m,
2H), 8.33 (m, 1H) ppm; 13C NMR (CDCl3) d: 12.73 (CH3S),
14.31 (CH3S), 22.92 (CH2), 27.11 (CH2), 125.94, 127.10,
127.85, 130.66, 132.19, 138.76, 155.78, 167.85, 168.88
(arom.) ppm; m/z (EI, 70 eV): 274 (MC%, 100), 259 (MK
CH3, 27), 241 (MKSH, 65). Anal. Calcd for C14H14N2S2: C
72.70, H 4.07, N 7.06, S 16.17%, found C 72.72, H 3.90, N
6.90, S 16.05.
3.2. Preparation of 2,4-disubstituted dehydrogenize[h]-
quinazolines 1a–d: general procedure
A mixture of 1-tetralone (4) (0.5 g, 4.3 mmol) and 9 mmol
of the corresponding nitrile dissolved in 30 mL of CH2Cl2
was cooled at 0 8C. Triflic anhydride (1.3 g, 4.5 mmol) in
15 mL of CH2Cl2 was added dropwise. The reaction mixture
was allowed to stand to room temperature and stirred at this
temperature for 24 h. The reaction can be monitored by
TLC. The reaction mixture was hydrolyzed by careful
addition of saturated aqueous solution of sodium hydrogen
carbonate until was basic. The organic layer was separated,
washed with brine and dried over MgSO4. The solvent was
removed in vacuo and the residue purified by flash
chromatography using hexane/ethyl acetate 9:1 as eluent.
The crude product was distilled or recrystallized.
3.2.5. 2,4-Dibenzyl-5,6-dihydrobenzo[h]quinazoline 6a.
Purification of crude product by column chromatography
gave 1.08 g (70%), mp 71–72 8C (EtOH); n (KBr) 1555,
1
1491, 1390, 740, 700 cmK1; H NMR (CDCl3) d: 2.84 (m,
4H, CH2), 4.21 (s, 2H, CH2), 4.36 (s, 2H, CH2), 7.28 (m,
11H), 7.50 (m, 2H), 8.37 (m, 1H) ppm; 13C NMR (CDCl3)
d: 22.91 (CH2), 27.31 (CH2), 41.36 (CH2), 45.84 (CH2),
123.68, 125.89, 126.20, 126.42, 127.17, 127.67, 128.25,
128.52, 129.29, 130.64, 132.90, 137.87, 138.80, 139.13,
159.32, 165.68, 167.17 (arom.) ppm; m/z (EI, 70 eV): 362
(MC%, 65), 361 (100). Anal. Calcd for C26H22N2: C 86.15, H
6.12, N 7.73%, found C 87.99, H 6.05, N 7.60.
3.2.1. 2,4-Diphenyl-5,6-dihydrobenzo[h]quinazoline 1a.
Purification of crude product by column chromatography
afforded 0.93 g (65%), mp 170–171 8C (EtOH); n (KBr)
1610, 1540, 1400, 770, 710 cmK1; 1H NMR (CDCl3) d: 2.91
(m, 2H, CH2), 3.10 (m, 2H, CH2), 7.45 (m, 2H), 7.28 (m,
2H), 7.46 (m, 6H), 7.70 (m, 2H), 8.58 (m, 2H) ppm; 13C
NMR (CDCl3) d: 24.78 (CH2), 27.82 (CH2), 123.44, 126.04,
127.26, 127.72, 128.15, 128.29, 128.36, 129.21, 130.80,
133.38, 138.22, 139.00, 160.10, 162.14, 164.28
(arom.) ppm; m/z (EI, 70 eV): 334 (MC%, 63), 333 (100),
127 (20), 77 (C6HC5 , 59). Anal. Calcd for C24H18N2: C
86.20, H 5.43, N 8.38%, found C 86.04, H 5.39, N 8.29.
3.2.6. 2,4-Bis(2-methylbenzyl)-5,6-dihydrobenzo[h]qui-
nazoline 6b. Purification of crude product by column
chromatography afforded 1.25 g (75%), mp 103–104 8C
(EtOH); n (KBr) 1554, 1384, 742 cmK1; 1H NMR (CDCl3)
d: 2.33 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.84 (m, 4H,
AA0BB0 system CH2), 4.15 (s, 2H, CH2), 4.34 (s, 2H, CH2),
6.88 (d, 1H, JZ7 Hz), 7.15 (m, 7H), 7.38 (m, 3H), 8.35 (m,
1H) ppm; 13C NMR (CDCl3) d: 19.98 (CH3), 20.09 (CH3),
22.92 (CH2), 27.40 (CH2), 38.88 (CH2), 43.34 (CH2),
123.84, 125.78, 125.89, 125.98, 126.39, 126.50, 127.22,
127.72, 128.42, 130.09, 130.23, 130.64, 133.01, 136.62,
137.06, 137.72, 138.84, 159.07, 165.73, 167.35
(arom.) ppm; m/z (EI, 70 eV): 390 (MC%, 87), 389 (100),
3.2.2. 2,4-Bis(4-methylphenyl)-5,6-dihydrobenzo[h]-
quinazoline 1b. Purification of crude product by column
chromatography afforded 1.08 g (70%), mp 169–170 8C
(CHCl3/MeOH); n (KBr) 1615, 1540, 1400, 810, 770 cmK1
;
1H NMR (CDCl3) d: 2.44 (s, 3H, CH3), 2.47 (s, 3H, CH3),
2.90 (m, 2H, CH2), 3.10 (m, 2H, CH2), 7.30 (m, 1H), 7.40

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A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
375 (MKCH3, 10). Anal. Calcd for C28H26N2: C 86.12, H
6.71, N 7.17%, found C 86.00, H 6.66, N 7.09.
3.3.3. 2,4-Bis(methylthio)benzo[h]quinazoline 5d. Purifi-
cation of crude product by column chromatography gave
0.23 g (93%), mp 103–104 8C (EtOH); n (KBr) 1560, 1490,
800, 750 cmK1; 1H NMR (CDCl3) d: 2.71 (s, 3H, CH3), 2.77
(s, 3H, CH3), 7.77 (m, 5H), 9.16 (m, 1H) ppm; 13C NMR
(CDCl3) d: 12.74 (CH3), 14.44 (CH3), 118.18, 120.06,
125.28, 126.29, 127.08, 127.75, 129.55, 129.64, 135.41,
148.15, 167.26, 169.81 (arom.) ppm; m/z (EI, 70 eV): 272
(MC%, 100), 257 (MKCH3, 38), 239 (MKSH, 51), 225
(MKSCH3, 13). Anal. Calcd for C14H12N2S2: C 61.73, H
4.44, N 10.28, S 23.54%, found C 61.66, H 4.40, N 10.11, S
23.44.
3.2.7. 2,4-Bis(4-methylbenzyl)-5,6-dihydrobenzo[h]-
quinazoline 6c. Purification of crude product by column
chromatography afforded 1.30 g (77%), mp 108–109 8C
1
(EtOH); n (KBr) 1556, 1388, 808, 744 cmK1; H NMR
(CDCl3) d: 2.30 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.81 (m,
4H, AA0BB0 system CH2), 4.16 (s, 2H, CH2), 4.30 (s, 2H,
CH2), 7.12 (m, 7H), 7.39 (m, 4H), 8.35 (m, 1H) ppm; 13C
NMR (CDCl3) d: 20.99 (CH3), 21.06 (CH3), 22.88 (CH2),
27.30 (CH2), 40.95 (CH2), 45.36 (CH2), 123.65, 125.89,
127.14, 127.64, 128.51, 128.96, 128.13, 129.20, 130.60,
132.91, 134.72, 135.65, 136.03, 138.81, 159.31, 165.82,
167.28 (arom.) ppm; m/z (EI, 70 eV): 390 (MC%, 100), 389
(100). Anal. Calcd for C28H26N2: C 86.12, H 6.71, N 7.17%,
found C 85.99, H 6.61, N 7.15.
3.4. Preparation of monobenzoyldihydrobenzo[h]quina-
zolines 7: general procedure
A mixture of 0.55 mmol of the corresponding dihydroqui-
nazoline 6 and DDQ (0.25 g, 1.1 mmol) in 20 mL of toluene
was heated at 100 8C during 3 h. The solvent was removed
under reduced pressure and the residue was purified by flash
chromatography using hexane/ethyl acetate 9:1 as eluent.
3.2.8. 3,4-Dihydronaphthalen-1-yl triflate. This product
was isolated from the reaction mixtures in 3–6% yield,
bpZ50 8C (0.5 Torr, kugelrohr); IR (film)Z1420, 1247,
1
1142 cmK1; H NMR (CDCl3) d: 2.52 (m, 2H, CH2), 2.88
(m, 2H, CH2), 6.03 (t, 1H, JZ5.0 Hz, ]CH), 7.29 (m,
4H) ppm; 13C NMR (CDCl3) d: 22.30 (C3), 26.82 (C4),
117.69 (C]), 118.64 (q, CF3, JZ318 Hz), 121.22, 126.91,
127.73, 128.67, 129.16, 136.23 (arom.), 146.38 (]C) ppm;
m/z (EI, 70 eV): 278 (MC%, 20), 145 (MKTf, 100), 129
(MKOTf, 21).
3.4.1. 4-Benzoyl-2-benzyl-5,6-dihydrobenzo[h]quinazo-
line 7a. Purification of crude product by column chroma-
tography afforded 0.1 g (50%) of an undistillable oil; n
(film) 1676 (C]O), 1569, 1450 cmK1; 1H NMR (CDCl3) d:
2.9 (m, 4H, CH2), 4.35 (s, 2H, CH2), 7.35 (m, 11H), 7.90 (m,
2H), 8.42 (m, 1H) ppm; 13C NMR (CDCl3) d: 22.85 (CH2),
27.16 (CH2), 45.79 (CH2), 123.42, 125.99, 126.41, 127.36,
128.01, 128.36, 128.58, 129.32, 130.62, 131.41, 132.33,
134.06, 135.25, 138.63, 139.37, 160.83, 161.16. 167.21
3.3. Preparation of benzo[h]quinazolines 5: general
procedure
(arom.), 193.64 (CO) ppm; m/z (EI, 70 eV): 376 (MC%
,
100), 375 (38), 271 (MKC6H5CO, 25). Anal. Calcd for
C26H20N2O: C 82.95, H 5.35, N 7.44%, found C 82.92, H
5.29, N 7.32.
A mixture of 0.9 mmol of the corresponding dihydrobenzo-
quinazoline 1 and DDQ (0.4 g, 1.8 mmol) in 10 mL of
o-DCB was heated at 120 8C during 3 h. The solvent was
removed under reduced pressure and the residue was
purified by flash chromatography using hexane/ethyl acetate
9:1 as eluent.
3.4.2. 4-(4-Methylbenzoyl)-2-(4-methylbenzyl)-5,6-dihy-
drobenzo[h]quinazoline 7c. Purification of crude product
by column chromatography afforded 0.09 g (40%), mp 113–
114 8C (hexane); n (KBr) 1672 (C]O), 1604, 1555,
3.3.1. 1,3-Diphenylbenzo[h]quinazoline 5a. Purification of
crude product by column chromatography afforded 0.24 g
(80%), mp 152–153 8C (EtOH); n (KBr) 1566, 1490, 804,
1
777 cmK1; H NMR (CDCl3) d: 2.32 (s, 3H, CH3), 2.44
(s, 3H, CH3), 2.87 (m, 4H, CH2), 4.30 (s, 2H, CH2), 7.11 (m,
2H), 7.24 (m, 4H), 7.38 (m, 3H), 7.80 (m, 2H), 8.40 (m,
1H) ppm; 13C NMR (CDCl3) d: 21.05 (CH3), 21.85 (CH3),
22.87 (CH2), 27.19 (CH2), 45.38 (CH2), 123.14, 125.98,
127.31, 129.96, 129.04, 129.16, 129.33, 130.72, 131.31,
132.42, 132.82, 135.63, 135.85, 139.35, 145.21, 161.01,
161.18, 167.41 (arom.), 193.37 (CO) ppm; m/z (EI, 70 eV):
404 (MC%, 100), 403 (54). Anal. Calcd for C28H24N2O: C
83.14, H 5.98, N 6.93%, found C 83.01, H 5.87, N 6.82.
1
690 cmK1; H NMR (CDCl3) d: 7.72 (m, 13H), 8.86 (m,
2H), 9.55 (m, 1H) ppm; 13C NMR (CDCl3) d: 119.26,
122.82, 125.34, 127.32, 127.82, 128.51, 128.70, 129.65,
130.04, 130.31, 130.48, 135.09, 138.07, 138.47, 151.92,
162.13, 166.76 (arom.) ppm; m/z (EI, 70 eV): 332 (MC%
,
63), 331 (100), 253 (11). Anal. Calcd for C24H16N2: C
86.72, H 4.85, N 8.43%, found C 86.59, H 4.88, N 8.38.
3.3.2. 2,4-Bis(4-methlphenyl)benzo[h]quinazoline 5b.
Purification of crude product by column chromatography
afforded 0.25 g (86%), mp 151–152 8C (EtOH); n (KBr)
1560, 1439, 1095, 761 cmK1; 1H NMR (CDCl3) d: 2.47 (s,
3H, CH3), 2.51 (s, 3H, CH3), 7.35 (m, 4H), 7.85 (m, 7H),
8.75 (d, 2H, JZ8 Hz) 9.54 (m, 1H) ppm; 13C NMR (CDCl3)
d: 21.47 (CH3), 21.56 (CH3), 119.09, 122.99, 125.34,
127.16, 127.37, 127.68, 128.66, 129.25, 129.88, 130.30
130.82, 135.07, 135.34, 135.88, 139.75, 140.59, 151.85,
3.5. Preparation of dibenzoyldihydrobenzo[h]quinazo-
lines 8: general procedure
A mixture of 0.70 mmol of the corresponding dihydroqui-
nazoline 6 and DDQ (0.31 g, 1.65 mmol) in 20 mL of
o-DCB was heated at 150 8C during 3 h. The solvent was
removed under reduced pressure and the residue was
purified by flash chromatography using hexane/ethyl acetate
9:1 as eluent.
160.23, 166.66 (arom.) ppm; m/z (EI, 70 eV): 360 (MC%
,
85), 359 (100), 345 (MKCH3, 20). Anal. Calcd for
C26H20N2: C 86.64, H 5.59, N 7.77, found C 86.50, H
5.44, N 7.69.
3.5.1. 2,4-Bis(benzoyl)-5,6-dihydrobenzo[h]quinazoline
8a. Purification of crude product by column

A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
2807
chromatography afforded 0.12 g (45%), mp 157–158 8C
(EtOH); n (KBr) 1679 (C]O), 1593, 1452, 740, 690 cmK1
C14H12N2O2: C 69.99, H 5.03, N 11.66%, found C 69.85,
H 4.91, N 11.59.
;
1H NMR (CDCl3) d: 3.02 (m, 4H, CH2), 7.47 (m, 9H), 8.02
(m, 4H), 8.42 (m, 1H) ppm; 13C NMR (CDCl3) d: 23.38
(CH2), 26.85 (CH2), 126.50, 127.35, 128.15, 128.32,
128.78, 130.55, 131.00, 131.57, 132.17, 133.58, 134.42,
134.94, 135.23, 160.44, 161.01, 161.47 (arom.), 191.03,
192.95 (CO) ppm; m/z (EI, 70 eV): 390 (MC%, 158), 389
(15), 284 (MKC6H5CO, 43), 77 (C6HC5 , 100). Anal. Calcd
for C26H18N2O2: C 79.98, H 4.65, N 7.17%, found C 79.87,
H 4.61, N 7.00.
3.5.5. 4-Amino-2-(methylsulfonyl)benzo[h]quinazoline
11d. A continuous stream of ammonia gas was bubbled
through a solution of 0.2 g (0.59 mmol) of 9d in 20 mL of
dichloromethane at room temperature. After 2 h, the solvent
was eliminated, the residue washed gently with water and
purified by recrystallization giving 0.12 g (74%) of 11d, mp
275 8C (EtOH, decomp.); n (KBr): 3490, 3298 (NH2), 1637,
1488, 1313 (SO2), 777 cmK1; 1H NMR (CDCl3) d: 3.44 (s,
3H, CH3), 7.77 (m, 2H), 8.05 (m, 3H), 8.53 (br s, 2H, NH2),
8.93 (m, 1H) ppm; 13C NMR (CDCl3) d: 38.39 (CH3),
110.66, 119.32, 124.25, 127.56, 127.95, 128.08, 128.95,
129.88, 134.81, 147.74, 162.04, 162.60 (arom.) ppm; m/z
(EI, 70 eV): 273 (MC%, 45), 258 (MKCH3, 15), 194 (MK
CH3SO2, 100). Anal. Calcd for C13H11N3O2S: C 57.13, H
4.06, N 15.37, S 11.73%, found C 57.03, H 3.96, N 15.25, S
11.69.
3.5.2. 2,4-Bis(4-methylbenzoyl)-5,6-dihydrobenzoquina-
zoline 8c. Purification of crude product by column
chromatography afforded 0.18 g (60%), mp 143–144 8C
(hexane); n (KBr) 1678 (C]O), 1668 (CO), 1604, 1550,
950 cmK1; 1H NMR (CDCl3) d: 2.42 (s, 6H, CH3), 2.94 (s,
2H, CH2), 7.33 (m, 7H), 7.94 (m, 2H), 8.42 (m, 2H), 9.32
(m, 1H) ppm; 13C NMR (CDCl3) d: 21.80 (CH3), 21.86
(CH3), 23.36 (CH2), 26.87 (CH2), 126.48, 126.99, 127.58,
128.12, 129.08, 129.52, 130.66, 131.16, 131.66, 132.05,
132.52, 132.70, 139.37, 144.61, 145.66, 160.75, 161.28,
161.33 (arom.), 190.77, 192.67 (CO) ppm; m/z (EI, 70 eV):
418 (MC%, 100), 417 (20), 298 (90). Anal. Calcd for
C28H22N2O2: C 80.36, H 5.30, N 6.69%, found C 80.25, H
5.28, N 6.59.
3.5.6. 4-Amino-2-(methoxy)benzo[h]quinazoline 12d.
A solution containing 0.2 g (0.59 mmol) of 11d and sodium
methoxide (0.15 g, 2.36 mmol) in 20 mL of dry methanol
was refluxed for 2 h. After addition of water and extraction
with dichloromethane, the organic layers were washed with
brine. Elimination of solvent affords a residue, which was
purified by recrystallization giving 0.14 g (85%) of 12d, mp
274–275 8C (EtOH); n (KBr): 3450, 3233 (NH2), 1355,
3.5.3. 2,4-Bis(methylsulfonyl)benzo[h]quinazoline 9d. To
a stirred solution of 2,4-bis(methylthio)benzo[h]quinazoline
5d containing 0.5 g (1.83 mmol) in 20 mL of anhydrous
dichloromethane was added slowly a solution of 1.27 g
(7.32 mmol) of m-CPBA in 20 mL of dichloromethane. The
mixture was stirred at room temperature for 4 h. An aqueous
solution of Na2S2O3 (5%) was then added and the layers
shaked and separated. The aqueous phase was extracted
with CH2Cl2 and the combined organic layers washed with
NaHCO3 aqueous solution, brine and dried over MgSO4.
The solvent was removed in vacuo and the residue was
purified by recrystallization to give 0.52 g (85%) of 9d, mp
191–192 8C (EtOH); n (KBr): 1388, 1303 (SO2), 1143, 947,
785 cmK1; 1H NMR (CDCl3) d: 3.54 (s, 3H, CH3), 3.85 (s,
3H, CH3), 7.99 (m, 5H), 9.20 (m, 1H) ppm; 13C NMR
(CDCl3) d: 39.67 (CH3), 42.39 (CH3), 115.17, 118.09,
125.38, 128.53, 128.87, 129.06, 131.91, 132.65, 135.98
(arom.) ppm; m/z (EI, 70 eV): 336 (MC%, 20), 272 (MK
SO2, 100), 195 (67). Anal. Calcd for C14H12N2O4S2: C
49.99, H 3.60, N 8.33, S 19.06%, found C 49.87, H 3.55, N
8.21, S 18.98.
1
1078, 796 cmK1; H NMR (CDCl3) d: 4.08 (s, 3H, CH3),
7.59 (m, 4H), 7.78 (m, 1H), 8.80 (br s, 2H, NH2) 8.98 (m,
1H) ppm; 13C NMR (CDCl3) d: 54.25 (CH3), 106.96,
118.49, 123.85, 124.90, 126.51, 127.54, 129.13, 129.63,
135.48, 151.21, 162.42, 163.33 (arom.) ppm; m/z (EI,
70 eV): 225 (MC%, 100), 224 (57), 195 (48). Anal. Calcd
for C13H11N3O: C 69.32, H 4.92, N 18.66%, found C 69.20,
H 4.80, N 18.55.
3.5.7. Benzo[h]quinazoline-2,4-(1H,3H)-dione 13d.
Compound 11d (0.2 g, 0.59 mmol) was suspended in
20 mL of aqueous NaOH 10% and refluxed 2 h. The
reaction mixture was acidified with HCl 10% until pH 2 and
the solid was collected by filtration and washed gently with
cold water. Recrystallization in hot water gave 0.1 g (80%)
of 13d. If the hydrolysis was carried out by reluxing 11d in
aqueous hydrochloric acid 1:1, compound 13 was obtained
in 53% yield, mp decomposition; n (KBr): 3278 (NH), 1664,
1598 (CO), 790, 756 cmK1; 1H NMR (DMSO-d6) d: 7.10 (d,
1H, JZ9.6 Hz), 7.40 (t, 1H, JZ9.6 Hz), 7.50 (t, 1H, JZ
9.6 Hz), 8.78 (d, 1H, JZ9.6 Hz) 10.05 (br s, 2H, NH2) ppm;
13C NMR (DMSO-d6) d:109.70, 116.44, 123.25, 124.52,
125.76, 127.37, 128.02, 129.04, 136.54, 153.75 (arom.),
158.64, 165.93 (CO) ppm; m/z (EI, 70 eV): 212 (MC%, 10),
78 (100). Anal. Calcd for C12H8N2O2: C 67.92, H 3.80, N
13.20%, found C 67.79, H 3.71, N 13.13.
3.5.4. 2,4-Dimethoxybenzo[h]quinazoline 10d. A solution
containing 0.2 g (0.59 mmol) of 9d and sodium methoxide
(0.15 g, 2.36 mmol) in 20 mL of dry methanol was refluxed
for 2 h. After addition of water and extraction with
dichloromethane, the organic layers were washed with
brine. Elimination of solvent affords a residue, which was
purified by recrystallization giving 0.13 g (90%) of 10d, mp
3.6. Preparation of 1,3-disubstituted 5,6-dihydrobenzo[f]-
quinazolines 15a–f: general procedure
1
101–102 8C (EtOH); n (KBr): 1267, 1195, 765 cmK1; H
NMR (CDCl3) d: 4.18 (s, 3H, CH3), 4.21 (s, 3H, CH3), 7.67
(m, 5H), 7.90 (m, 5H), 9.06 (m, 1H) ppm; 13C NMR
(CDCl3) d: 54.49 (CH3), 54.78 (CH3), 109.38, 119.53,
124.52, 124.93, 126.53, 127.75, 129.30, 135.74, 152.09,
,
47), 239 (100), 225 (MKCH3, 8). Anal. Calcd for
A mixture of 2-tetralone (14) (0.5 g, 4.3 mmol) and 9 mmol
of the corresponding nitrile dissolved in 30 mL of CH2Cl2
was cooled at 0 8C. Triflic anhydride (1.3 g, 4.5 mmol) in
15 mL of CH2Cl2 was added dropwise. The reaction mixture
was allowed to stand to room temperature and stirred at this
162.37, 169.06 (arom.) ppm; m/z (EI, 70 eV): 240 (MC%

2808
A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
temperature for 24 h. The reaction can be monitored by
TLC. The reaction mixture was hydrolyzed by careful
addition of saturated aqueous solution of sodium hydrogen
carbonate until was basic. The organic layer was separated,
washed with brine and dried over MgSO4. The solvent was
removed in vacuo and the residue purified by flash
chromatography using hexane/ethylacetate 9:1 as eluent.
The crude product was distilled or recrystallized.
3.6.5. 1,3-Bis(4-methylbenzyl)-5,6-dihydrobenzo[f]-
quinazoline 15e. Purification of crude product by column
chromatography afforded 1.25 g (75%), mp 101–102 8C
(EtOH); n (KBr) 1550, 1394, 792 cmK1; 1H NMR (CDCl3)
d: 2.34 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.91 (m, 4H, CH2),
4.23 (s, 2H, CH2), 4.32 (s, 2H, CH2), 7.17 (m, 11H), 7.46
(m, 1H) ppm; 13C NMR (CDCl3) d: 21.06 (CH3), 28.31
(CH3), 32.20 (CH2), 41.34 (CH2), 45.17 (CH2), 125.35,
126.60, 127.68, 127.85, 128.08, 128.73, 129.01, 129.12,
129.21, 131.06, 136.65, 135.79, 138.55, 162.86, 166.49,
168.38 (arom.) ppm; m/z (EI, 70 eV): 390 (MC%, 57), 389
(100). Anal. Calcd for C28H26N2: C 86.12, H 6.71, N 7.17%,
found C 85.89, H 6.61, N 7.08.
3.6.1. 1,3-Diphenyl-5,6-dihydrobenzo[f]quinazoline 15a.
Purification of crude product by column chromatography
afforded 1.01 g (86%), mp 121–122 8C (hexane); n (KBr)
1603, 1537, 1421, 762, 692 cmK1; 1H NMR (CDCl3) d: 3.09
(m, 4H, CH2), 6.95 (m, 2H), 7.17 (m, 1H), 7.28 (m, 1H),
7.46 (m, 6H), 7.70 (m, 2H), 8.60 (m, 2H) ppm; 13C NMR
(CDCl3) d: 28.45 (CH2), 32.14 (CH2), 123.99, 126.01,
127.83, 127.88, 128.23, 128.46, 128.50, 128.84, 129.40,
129.65, 130.43, 131.14, 137.64, 138.17, 139.54, 161.54,
3.6.6. 1,3-Dimethyl-5,6-dihydrobenzo[f]quinazoline 15f.
Purification of crude product by column chromatography
afforded 0.54 g (60%), mp 87–88 8C (EtOH); n (KBr) 1552,
1
1375, 788 cmK1; H NMR (CDCl3) d: 2.62 (s, 3H, CH3),
161.98, 168.96 (arom.) ppm; m/z (EI, 70 eV): 334 (MC%
,
2.67 (s, 3H, CH3), 2.82 (m, 4H, CH2), 7.23 (m, 3H), 7.50 (m,
1H) ppm; 13C NMR (CDCl3) d: 24.65 (CH3), 25.53 (CH3),
28.23 (CH2), 31.86 (CH2), 124.33, 126.43, 127.51, 127.86,
131.17, 138.41, 161.38, 164.36, 167.24 (arom.) ppm; m/z
(EI, 70 eV): 210 (MC%, 100), 209 (40). Anal. Calcd for
C14H14N2: C 79.97, H 6.71, N 13.32%, found C 79.86, H
6.66, N 13.29.
63), 333 (100). Anal. Calcd for C24H18N2: C 86.20, H 5.43,
N 8.38%, found C 86.09, H 5.33, N 8.26.
3.6.2. 1,3-Bis(4-methylphenyl)-5,6-dihydrobenzo[f]quin-
azoline 15b. Purification of crude product by column
chromatography afforded 0.99 g (80%), mp 180–181 8C
(EtOH); n (KBr) 1539, 1423, 802 cmK1; 1H NMR (CDCl3)
d: 2.43 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.07 (m, 4H, CH2),
6.94 (m, 8H), 7.61, 8.48 (AA0XX0system, 4H) ppm; 13C
NMR (CDCl3) d: 21.47 (CH3), 21.54 (CH3), 28.50 (CH2),
32.17 (CH2), 123.54, 125.97, 127.68, 127.77, 128.20,
128.74, 129.19, 129.21, 129.62, 131.45, 135.02, 136.74,
138.09, 139.44, 140.55, 161.56, 161.91, 168.76
(arom.) ppm; m/z (EI, 70 eV): 362 (MC%, 77), 361 (100).
Anal. Calcd for C26H22N2: C 86.15, H 6.12, N 7.73%, found
C 85.98, H 6.09, N 7.65.
3.7. Synthesis of dibenzyldihydroquinazolines 21 and
dibenzylpyrimidines 22
According to the general procedure in Section 3.6, the
reaction of 2-tetralone and 4-chlorobenzylnitrile afforded a
reaction mixture, which was chromatographied giving 0.56
(30%) of 21a and 0.90 g (61%) of 22a.
3.7.1. 1,3-Bis(4-chlorobenzyl)-5,6-dihydrobenzo[f]quin-
azoline 21a. Mp 97–98 8C; n (KBr) 1541, 1394,
3.6.3. 1,3-Dibenzyl-5,6-dihydrobenzo[f]quinazoline 15c.
Purification of crude product by column chromatography
afforded 0.93 g (60%), mp 80–81 8C (EtOH); n (KBr) 1541,
1494, 1398 cmK1; 1H NMR (CDCl3) d: 2.92 (m, 4H, CH2),
4.28 (s, 2H, CH2), 4.37 (s, 2H, CH2), 7.33 (m, 14H) ppm;
13C NMR (CDCl3) d: 28.31 (CH2), 32.18 (CH2), 41.73
(CH2), 45.55 (CH2), 125.47, 126.35, 126.63, 127.65,
127.91, 128.18, 128.32, 128.54, 128.90, 129.27, 130.97,
138.58, 162.67, 166.30, 168.46 (arom.) ppm; m/z (EI,
70 eV): 362 (MC%, 52), 361 (100). Anal. Calcd for
C26H22N2: C 86.15, H 6.12, N 7.73%, found C 85.98, H
5.98, N 7.69.
1
752 cmK1; H NMR (CDCl3) d: 2.91 (m, 4H, CH2), 4.19
(s, 2H, CH2), 4.31 (s, 2H, CH2), 7.21 (m, 11H), 7.41 (m,
1H) ppm; 13C NMR (CDCl3) d: 28.23 (CH2), 32.12 (CH2),
41.05 (CH2), 44.76 (CH2), 125.48, 126.68, 127.51, 128.05,
128.39, 128.59, 130.32, 130.60, 132.28, 136.93, 137.16,
138.63, 162.26, 165.87, 168.63 (arom.) ppm; m/z (EI,
70 eV): 430 (MC%, 59), 429 (100). Anal. Calcd for
C26H20Cl2N2: C 72.39, H 4.67, Cl 16.44, N 6.49%, found
C 72.25, H 4.59, Cl 16.38, N 6.36.
3.7.2. 2,4-Bis(4-chlorobenzyl)-6-methylpyrimidine 22a.
Undistillable oil; n (film) 1587, 1545, 1373 cmK1; 1H NMR
(CDCl3) d: 2.40 (s, 3H, CH3), 3.97 (s, 2H, CH2), 4.18 (s, 2H,
CH2), 6.71 (s, 1H), 7.21 (m, 8H) ppm 13C NMR (CDCl3) d:
24.13 (CH3), 43.23 (CH2), 41.12 (CH2), 117.08, 128.39,
128.78, 130.50, 130.59, 132.22, 132.71, 136.17, 167.60,
3.6.4. 1,3-Bis(2-methylbenzyl)-5,6-dihydrobenzo[f]quin-
azoline 15d. Purification of crude product by column
chromatography afforded 0.84 g (50%), mp 110–111 8C
(EtOH); n (KBr) 1541, 1394, 760 cmK1; 1H NMR (CDCl3)
d: 2.22 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.97 (m, 4H, CH2),
4.29 (s, 2H, CH2), 4.31 (s, 2H, CH2), 6.98 (m, 1H), 7.26 (m,
11H) ppm; 13C NMR (CDCl3) d: 19.77 (CH3), 20.01 (CH3),
28.39 (CH2), 32.23 (CH2), 39.76 (CH2), 43.08 (CH2),
125.38, 125.79, 126.00, 126.46, 126.77, 127.36, 127.97,
128.16, 128.87, 130.01, 130.14, 130.16, 131.08, 136.60,
137.15, 137.23, 137.52, 138.65, 162.85, 166.54, 168.23
(arom.) ppm; m/z (EI, 70 eV): 390 (MC%, 100), 389 (26),
375 (MKCH3, 62). Anal. Calcd for C28H26N2: C 86.12, H
6.71, N 7.17%, found C 85.99, H 6.60, N 7.09.
168.68, 168.70 ppm (arom.); m/z (EI, 70 eV): 342 (MC%
,
94), 321 (100). Anal. Calcd for C19H16Cl2N2: C 66.48, H
4.70, Cl 20.66, N 8.16%, found C 66.31, H 4.65, Cl 20.58,
N 8.11.
Using the general procedure in Section 3.6, the reaction of
2-tetralone and 3,4-dichlorobenzylnitrile afforded a reaction
mixture, which was chromatographied giving 0.53 (25%) of
21b and 0.88 g (50%) of 22b.

A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
2809
3.7.3. 1,3-Bis(3,4-dichlorobenzyl)-5,6-dihydrobenzo[f]-
quinazoline 21b. Undistillable oil; n (film) 1541, 1471,
3.8. Preparation of benzo[f]quinazolines 17: general
procedure
1
1394 cmK1; H NMR (CDCl3) d: 2.92 (m, 4H, CH2), 4.16
A mixture of 0.9 mmol of the corresponding dihydrobenzo-
quinazoline 15 and DDQ (0.4 g, 1.8 mmol) in 10 mL of
o-DCB was heated at 120 8C during 3 h. The solvent was
removed under reduced pressure and the residue was
purified by flash chromatography using hexane/ethyl acetate
9:1 as eluent.
(s, 2H, CH2), 4.29 (s, 2H, CH2), 7.04 (m, 1H), 7.30 (m,
9H) ppm 13C NMR (CDCl3) d: 28.17 (CH2), 32.06 (CH2),
40.72 (CH2), 44.42 (CH2), 125.67, 126.76, 127.44, 128.16,
128.48, 128.58, 128.71, 130.23, 130.43, 130.55, 130.63,
130.94, 131.12, 132.20, 132.48, 138.45, 138.70, 161.66,
165.31, 168.86 (arom.) ppm; m/z (EI, 70 eV): 498 (MC%
,
48), 497 (100). Anal. Calcd for C26H18Cl4N2: C 62.42, H
3.63, Cl 28.35, H 5.60%, found C 62.29, H 3.59, Cl 28.22.
N 5.55.
3.8.1. 1,3-Diphenylbenzo[f]quinazoline 17a. Purification
of crude product afforded 0.23 g (80%), mp 149–150 8C
1
(EtOH); n (KBr) 1603, 1531, 1429, 775, 700 cmK1; H
NMR (CDCl3) d: 7.25 (m, 1H), 7.53 (m, 7H), 7.80 (m, 4H),
8.05 (2H, AB system, JZ9.1 Hz), 8.71 (m, 2H) ppm; 13C
NMR (CDCl3) d: 119.34, 126.42, 127.08, 127.33, 127.75,
128.54, 128.63, 128.75, 129.04, 129.14, 130.55, 132.77,
135.59, 137.73, 141.91, 154.35, 159.79, 166.22
(arom.) ppm; m/z (EI, 70 eV): 332 (MC%, 70), 331 (100).
Anal. Calcd for C24H16N2: C 86.72, H 4.85, N 8.43%, found
C 86.66, H 4.73, N 8.31.
3.7.4. 2,4-Bis(3,4-dichlorobenzyl)-6-methylpyrimidine
22b. Mp 83–84 8C (EtOH); n (film) 1583, 1472,
1
1363 cmK1; H NMR (CDCl3) d: 2.43 (s, 3H, CH3), 3.95
(s, 2H, CH2), 4.15 (s, 2H, CH2), 6.77 (s, 1H), 7.06 (m, 1H),
7.18 (m, 1H), 7.38 (m, 4H) ppm 13C NMR (CDCl3) d: 24.12
(CH3), 42.87 (CH2), 44.78 (CH2), 117.29, 128.60, 128.65,
130.17, 130.55, 131.09, 132.16, 132.60, 137.79, 138.55,
167.94, 168.26 (arom.) ppm; m/z (EI, 70 eV): 410 (MC%
,
100), 409 (92). Anal. Calcd for C19H14Cl4N2: C 55.37, H
3.42, Cl 34.41, N 6.80%, found C 55.27, H 3.39, Cl 34.43,
N 6.70.
3.8.2. 1,3-Bis(4-methylphenyl)benzo[f]quinazoline 17b.
Purification of crude product afforded 0.28 g (86%), mp
174–175 8C (EtOH); n (KBr) 1604, 1471, 831, 760 cmK1
;
1H NMR (CDCl3) d: 2.45 (s, 3H, CH3), 2.50 (s, 3H, CH3),
7.29 (m, 5H), 7.50 (m, 1H), 7.63 (d, 2H, JZ9.0 Hz), 7.88
(m, 2H), 8.05 (2H, AB system, JZ9.56 Hz), 8.59 (d, 2H,
JZ9.0 Hz) ppm; 13C NMR (CDCl3) d: 21.53 (CH3), 21.55
(CH3), 119.16, 126.28, 128.67, 127.34, 127.71, 128.57,
128.66, 129.15, 129.26, 129.68, 132.65, 135.07, 135.50,
139.12, 139.61, 140.68, 154.34, 159.84, 166.14
(arom.) ppm; m/z (EI, 70 eV): 360 (MC%, 73), 359 (100).
Anal. Calcd for C26H20N2: C 86.64, H 5.59, N 7.77%, found
C 86.54, H 5.44, N 7.71.
Using the general procedure in Section 3.6, the reaction of
2-tetralone and 4-nitrobenzylnitrile afforded a reaction
mixture, which was chromatographied giving 0.58 (30%)
of 21c and 0.78 g (50%) of 22c.
3.7.5. 1,3-Bis(4-nitrobenzyl)-5,6-dihydrobenzo[f]quin-
azoline 21c. Mp 144–145 8C (MeOH); n (film) 1543, 1346
(NO2) cmK1; 1H NMR (CDCl3) d: 2.93 (m, 4H), 4.30 (s, 2H,
CH2), 4.46 (s, 2H, CH2), 7.36 (m, 8H), 8.14 (m, 4H) ppm;
13C NMR (CDCl3) d: 28.15 (CH2), 32.09 (CH2), 41.62
(CH2), 45.13 (CH2), 123.51, 123.63, 125.88, 126.80,
127.30, 128.30, 128.76, 129.89, 130.10, 130.25, 138.75,
145.83, 146.17, 146.78, 161.34, 164.98, 169.14
(arom.) ppm; m/z (EI, 70 eV): 452 (MC%, 51), 451 (100),
422 (MKNO, 23). Anal. Calcd for C26H20N4O4: C 69.02, H
4.46, N 12.38%, found C 68.88, H 4.39, N 12.29.
3.8.3. Reaction of 2-tetralone (14) with benzonitrile in
o-DCB as solvent. The reaction was carried out following
the general procedure in Section 3.6 heating at 120 8C for
24 h. Purification of crude product afforded 0.63 g (60%) of
4-methyl-2,6-diphenylpyrimidine 23. (Lit.32), mp 101–
102 8C (EtOH); n (KBr) 1600, 1570, 1530 cmK1 1H
;
NMR (CDCl3) d: 2.65 (s, 3H, CH3), 7.47 (s, 1H), 7.53 (m,
6H), 8.22 (m, 2H), 8.60 (m, 2H) ppm; 13C NMR (CDCl3) d:
24.61 (CH3), 113.96, 127.20, 128.37, 128.44, 128.85,
130.47, 130.66, 137.29, 163.69, 164.33, 167.76
(arom.) ppm; m/z (EI, 70 eV): 246 (MC%, 100), 143 (MK
C6H5CN, 26). Anal. Calcd for C17H14N2: C 82.90, H 5.73, N
11.37%, found C 82.82, H 5.62, N 11.31.
3.7.6. 5-Methyl-2,4-bis(2-nitrobenzyl)pyrimidine 22c.
Mp 142–143 (EtOH); n (film) 1546, 1342 (NO2) cmK1
;
1H NMR (CDCl3) d: 2.93 (s, 3H, CH3), 4.04 (s, 2H, CH2),
4.23 (s, 2H, CH2), 6.75 (s, 1H), 7.38 (m, 4H), 8.08 (m,
4H) ppm; 13C NMR (CDCl3) d: 24.55 (CH3), 43.94 (CH2),
45.91 (CH2), 117.99, 123.94, 124.27, 130.45, 130.48,
145.52, 146.32, 167.91, 168.39, 168.61 (arom.) ppm; m/z
(EI, 70 eV): 364 (MC%, 100), 363 (97), 334 (MKNO, 23),
317 (MKNO2H, 20). Anal. Calcd for C19H16N4O4: C 62.63,
H 4.43, N 15.38% found C 62.55, H 4.30, N 15.22.
3.9. The reaction of 2-tetralone with methylthiocyanate:
general procedure
A mixture of 2-tetralone (14) (0.3 g, 2.05 mmol) and 0.62 g
(8.56 mmol) of methylthiocyanate dissolved in 10 mL of
o-DCB was cooled at 0 8C. Triflic anhydride (0.70 g,
2.46 mmol) in 15 mL of o-DCB was added dropwise. The
reaction mixture was allowed to stand to room temperature
and stirred at this temperature for 24 h and then at 120 8C for
3 h. The reaction can be monitored by TLC. The reaction
mixture was hydrolyzed by careful addition of saturated
aqueous solution of sodium hydrogen carbonate until was
basic. The organic layer was separated, washed with brine
3.7.7. 3,4-Dihydronaphthalen-2-yl triflate. This product
was isolated from the reaction mixtures in 4–7% yield, bpZ
50 8C (0.5 Torr, kugelrohr); IR (film)Z1420, 1247,
1
1142 cmK1; H NMR (CDCl3) d: 2.72 (t, 2H, JZ8.3 Hz,
CH2), 3.08 (t, 2H, JZ8.3 Hz, CH2), 6.51 (s, 1H, ]CH),
7.15 (m, 4H) ppm; m/z (EI, 70 eV): 278 (MC%, 30), 145
(MKTf, 22), 129 (MKOTf, 100).

2810
A. Herrera et al. / Tetrahedron 62 (2006) 2799–2811
and dried over MgSO4. The solvent was removed in vacuo
and the residue purified by flash chromatography using
hexane/ethylacetate 9:1 as eluent. The crude product
afforded 0.22 g (40%) of 24 and 0.31 g (48%) of 25.
0.04 g (22%) of 33, mp 141–142 8C (EtOH); n (KBr): 1296,
1
1066, 796 cmK1; H NMR (CDCl3) d: 2.69 (m, 2H, CH2),
2.93 (s, 4H, CH2), 3.11 (m, 2H, CH2), 4.09 (s, 3H, CH3),
7.27 (m, 7H), 8.27 (m, 1H) ppm; 13C NMR (CDCl3) d: 28.45
(CH2), 29.38 (CH2), 29.40 (CH2), 32.68 (CH2), 53.37
(CH3), 116.58, 122.79, 125.97, 126.26, 126.60, 126.87,
126.91, 127.65, 128.02, 128.20, 131.57, 133.41, 137.98,
138.64, 146.59, 155.95, 158.82 (arom.) ppm; m/z (EI,
70 eV): 313 (MC%, 100), 312 (89), 296 (MKCH3, 10).
Anal. Calcd for C22H19NO: C 84.31, H 6.11, N 4.47%,
found C 84.23, H 6.05, N 4.38.
3.9.1. 1,3-Bis(methylthio)-5,6-dihydrobenzoquinazoline
24. Mp 89–90 8C (hexane); n (KBr) 1523, 1421,
1
1344 cmK1; H NMR (CDCl3) d: 2.61 (s, 3H, SCH3), 2.63
(s, 3H, SCH3), 2.85 (m, 4H, CH2), 7.29 (m, 3H), 8.11 (m,
1H) ppm; 13C NMR (CDCl3) d: 13.90 (CH3S), 14.15
(CH3S), 28.10 (CH2), 31.72 (CH2), 121.86, 126.24,
126.59, 127.85, 127.96, 130.47, 137.89, 165.31, 165.53,
168.02, (arom.) ppm; m/z (EI, 70 eV): 274 (MC%, 100), 273
(80), 259 (MKCH3, 18), 241 (MKSH, 19). Anal. Calcd for
C14H14N2S2: C 61.28, H 5.14, N 10.21, S 32.37%, found C
61.17, H 5.09, N 10.11, S 32.22.
3.9.5. 5-(Methylthio)dibenzo[a,i]phenanthridine 31. A
mixture of 0.9 mmol of 25 and DDQ (0.83 g, 3.6 mmol) in
10 mL of o-DCB was heated at 120 8C during 3 h. The
solvent was removed under reduced pressure and the residue
is purified by flash chromatography using hexane/ethyl
acetate 9:1 as eluent. The crude product afforded 0.22 g
(75%) of 31, mp 133–134 8C (EtOH); n (KBr) 1261, 1020,
800 cmK1; 1H NMR (CDCl3) d: 2.93 (s, 3H, CH3), 7.72 (m,
4H), 8.07 (m, 5H), 8.93 (m, 2H), 9.55 (m, 1H) ppm; 13C
NMR (CDCl3) d: 29.68 (CH3), 124.26, 125.22, 125.98,
126.53, 126.75, 126.88, 127.54, 127.79, 128.22, 128.83,
129.49, 130.34, 130.69, 132.48, 132.77, 134.83, 172.28
(arom.) ppm; m/z (EI, 70 eV): 325 (MC%, 61), 324 (100),
310 (MKCH3, 19), 278 (MKSCH3, 24). Anal. Calcd for
C22H15NS: C 81.20, H 4.65, N 4.30, S 9.85%, found C
81.11, H 4.50, N 4.26, S 9.77.
3.9.2. 5-(Methylthio)-7,8,13,14-tetrahydrodibenzo[a,i]-
phenanthridine 25. Mp 149–150 8C (EtOH); n (KBr)
1
1544, 1427, 1375 cmK1; H NMR (CDCl3) d: 2.66 (m,
2H, CH2), 2.69 (s, 3H, SCH3), 3.03 (m, 6H, CH2), 7.36 (m,
7H), 8.23 (m, 1H) ppm; 13C NMR (CDCl3) d: 14.60 (CH3S),
28.88 (CH2), 29.48 (CH2), 32.95 (CH2), 124.76, 125.91,
126.12, 127.03, 127.26, 127.68, 127.70, 127.84, 128.56,
129.08, 132.40, 133.18, 138.97, 139.05, 144.70, 153.34,
157.39 (arom.) ppm; m/z (EI, 70 eV): 329 (MC%, 94), 328
(100), 314 (MKCH3, 19), 296 (MKSH, 22). Anal. Calcd
for C22H19NS: C 80.20, H 5.81, N 4.25, S 9.73%, found C
80.10, H 5.77, N 4.11, S 9.65.
3.9.3. 5-(Methylsulfonyl)-7,8,13,14-tetrahydrodiben-
zo[a,i]phenanthridine 32. To a stirred solution of
5-(methylthio)-7,8,13,14-tetrahydrodibenzo[a,i]phenanthri-
dine 25 containing 0.5 g (1.52 mmol) in 20 mL of
anhydrous dichloromethane was added slowly a solution
of 1.1 g (6.54 mmol) of m-CPBA in 20 mL of dichloro-
methane. The mixture was stirred at room temperature for
4 h. An aqueous solution of Na2S2O3 (5%) was then added
and the layers shaked and separated. The aqueous phase was
extracted with CH2Cl2 and the combined organic layers
washed with NaHCO3 aqueous solution, brine and dried
over MgSO4. The solvent was removed in vacuo and the
residue was purified by recrystallization to give 0.45 g
(83%) of 28, mp 234–235 8C (EtOH); n (KBr): 1402, 1261
Acknowledgements
We gratefully acknowledge the DGESIC (Spain, grant
BQU2002-00406) and the AECI (Spain, grant PR120/00-
8980) for financial support. We also thank the CAIs of the
UCM for recording MS and NMR spectra and determining
the CHN analyses.
References and notes
1
(SO2), 1124, 764 cmK1; H NMR (CDCl3) d: 2.71 (t, 2H,
1. Morita, H.; Sato, Y.; Chang, K.-L.; Choo, C. Y.; Itokawa, H.;
Takeya, K.; Kobayashi, J. J. Nat. Prod. 2000, 63, 1707–1708.
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JZ8.5 Hz, CH2), 3.01 (m, 4H, 2H), 3.14 (d, 2H, JZ8.5 Hz,
CH2), 3.44 (s, 3H, CH3), 7.35 (m, 6H), 7.50 (m, 1H), 8.27
(m, 1H) ppm; 13C NMR (CDCl3) d: 29.15 (CH2), 29.43
(CH2), 32.60 (CH2), 41.78 (CH3), 126.38, 126.44, 126.62,
128.18, 128.92, 128.95, 129.63, 130.19, 130.96, 131.79,
138.04, 139.67, 148.12, 151.91, 156.62 (arom.) ppm; m/z
(EI, 70 eV): 361 (MC%, 100), 360 (60), 296 (MKSO2H, 17),
282 (MKCH3SO2, 72). Anal. Calcd for C22H19NO2S: C
73.10, H 5.30, N 3.88, S 8.87%, found C 72.95, H 5.25, N
3.76, S 8.77.
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nanthridine 33. A solution containing 0.3 g (0.59 mmol)
of 32 and sodium methoxide (0.15 g, 2.36 mmol) in 20 mL
of dry methanol was refluxed for 2 h. After addition of water
and extraction with dichloromethane, the organic layers
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residue, which was purified by recrystallization giving
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