A new access to quinazolines from simple anilines

Article abstract of DOI:10.1016/j.tet.2006.09.103

A new synthetic pathway to quinazolines is described. This new method uses hexamethylenetetramine in TFA and potassium ferricyanide in aqueous ethanolic KOH, starting from simple N-protected anilines. The method affords substituted quinazolines with high

Full text of DOI:10.1016/j.tet.2006.09.103

Tetrahedron 62 (2006) 12351–12356
A new access to quinazolines from simple anilines
a
a
a
b
Adriana Chilin,a, Giovanni Marzaro, Samuele Zanatta, Vera Barbieri, Giovanni Pastorini,
*
Paolo Manzinia and Adriano Guiottoa
aDepartment of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
bICB-CNR, Sezione di Padova, Via Marzolo 1, 35131 Padova, Italy
Received 21 July 2006; revised 5 September 2006; accepted 28 September 2006
Available online 25 October 2006
Abstract—A new synthetic pathway to quinazolines is described. This new method uses hexamethylenetetramine in TFA and potassium
ferricyanide in aqueous ethanolic KOH, starting from simple N-protected anilines. The method affords substituted quinazolines with high
selectivities and good yields, reducing reaction-time and work-up operations.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
quinazolines. Particular attention was paid to study the var-
ious parameters of this new synthetic strategy in order to
standardize the reaction conditions.
In the last few years, we have been interested in synthesizing
benzoquinazolinic derivatives in search of new antiprolifer-
ative drugs. The interest in the quinazolinic structure, due to
its wide range of biological activities,1 led to a number of
different synthetic pathways to access this nucleus (e.g.,
Niementowski’s synthesis,2 Bischler’s synthesis,3 and
Riedel’s synthesis).4 However, all these methods suffer from
the disadvantage that the starting naphthylamines need an
appropriate ortho functional group in order to cyclize to the
pyrimidine ring of the quinazoline nucleus.
2. Results and discussion
To verify if the HMTA/TFA/K3Fe(CN)6 method could have
widespread application and to set up standard reaction
conditions, N-protected anilines were chosen as starting
products. The protection of the amino group is necessary be-
cause it is well known that aromatic amines treated with
€
6
HMTA in TFA gave only Troger’s bases. As a general pro-
During ourstudieswe founda novel ringclosure of thebenzo-
quinazoline system starting from simple naphthylamines.5
This new synthetic approach consisted in reacting the appro-
priate N-protected a-naphthylamines or b-naphthylamines
with hexamethylenetetramine (HMTA) in trifluoroacetic
acid (TFA), followed by treatment with potassium ferri-
cyanide in aqueous ethanolic potassium hydroxide to give,
respectively, benzo[f]quinazoline or benzo[h]quinazoline in
good yield. The final products were achieved via the cor-
responding dihydrobenzoquinazoline intermediates, which
were directly reacted with the oxidizing agent without inter-
mediate isolation.
cedure, the N-protected aniline was treated with HMTA in
TFA, and then directly refluxed in aqueous ethanolic potas-
sium hydroxide with potassium ferricyanide.
In order to investigate reaction conditions avoiding para
formylation, 4-methylaniline was chosen as reference
compound: in fact, as reported in the literature,7 aniline itself
undergoes only para formylation. Even the HMTA/TFA/
K3Fe(CN)6 method runs through an initial formylation
step,5 but this must occur at the ortho-position in order
to achieve the desired pyrimidine annulation. In fact the
reaction mechanism involves aminomethylation at both the
ortho-position and the nitrogen atom of the carbamoyl group.
The successive dehydrogenation of ortho-aminomethyl to
aldimino group promotes an intramolecular cyclization to
dihydropyrimidine ring. Finally oxidative dehydrogenation
of the dihydropyrimidine derivative affords the desired
quinazoline (Scheme 1).
This method represents a new improved and straightforward
route to the benzoquinazoline nucleus. To expand the scope
of this method in order to access new heterocyclic scaffolds,
in this paper we also describe further investigations on
simple anilines to find an efficient synthetic route to
To constrain ortho formylation and then pyrimidine ring clo-
sure, 4-methylaniline (1a) was first tested with the amino
Keywords: Quinazoline; Synthesis; Substituent effects.
* Corresponding author. E-mail: adriana.chilin@unipd.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.103

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A. Chilin et al. / Tetrahedron 62 (2006) 12351–12356
_
was hydrolyzed in alkaline medium to dihydroquinazoline 6,
immediately isolated from the reaction mixture and kept in
toluene solution, due to its high instability (Scheme 4).
H2N
NHCO2Et
NH2
HN
NH2
N
N
N
CO2Et
CO2Et
CO2Et
R
R
R
R
NHCO2Et
N
H
H
N
a
N
H3C
H3C
N
N
H2N
R
1b
5
b
N
N
H
N
CO2Et
CO2Et
R
N
H3C
6
c
Scheme 1. Proposed reaction mechanism.
H
N
NH
+
N
group protected as an ethyl carbamate. Thus, the N-protected
4-methylaniline (1b) gave 6-methylquinazoline (1c) in good
yield (49%) (Scheme 2).
N
H3C
H3C
CHO
7
1c
Scheme 4. Influence of N-protection on reaction products (B). Reagents and
conditions: (a) HMTA, TFA, 80%; (b) KOH aqueous, 92%; and (c) AcOH,
13% (7) and 13% (1c).
NH2
N
NHCO2Et
b
a
N
H3C
H3C
H3C
Compound 6 in acid solution was converted into a mixture of
the quinazoline 1c and formamidine 7: compound 1c derived
from spontaneous oxidation of 6,8 while compound 7 de-
rived from the hydrolysis of the imine bond of dihydropyr-
imidine ring.9 Therefore, to avoid undesired side reactions,
it is essential that the amino group of the starting anilines re-
mained protected until the aromatization step: this condition
is satisfied only when ethyl carbamate, stable in the strong
acid conditions needed for the initial cyclization step, is
used.
1a
1b
1c
Scheme 2. Reagents and conditions: (a) ClCO2Et, THF, 98% and (b) (1)
HMTA, TFA and (2) KOH aqueous EtOH, K3Fe(CN)6, 49%.
The reaction was even attempted with different protecting
groups on the amino function and different acid conditions
to evaluate their influence on the reaction course.
If the amino group was protected as an acetyl or trifluoro-
acetyl (2 and 3), the HMTA/TFA/K3Fe(CN)6 reaction
afforded a complex mixture, in which the quinazoline 1c
The influence of different acid conditions on the HMTA/
TFA/K3Fe(CN)6 reaction was also studied. Performing the
reaction in acetic acid or in a mixture of formic and acetic
acids, no reaction occurred, while in methanesulfonic acid,
the reaction afforded the same complex mixture as observed
with acyl as the protecting group (Scheme 3). This fact was
ascribed to the strength of the acid medium, which causes
partial hydrolysis of the amino protection. Even diluting
methanesulfonic acid with another acid (e.g., acetic acid),
a complex mixture was obtained, while dilution with a
solvent (e.g., THF) led to no reaction.
€
was present in low concentration together with the Troger’s
base 4 and other unidentified by-products (Scheme 3). In this
case, the acid hydrolysis of the protecting groups became
competitive with cyclization: the portion of still protected
molecules yielded the final quinazoline, while the portion
€
of deprotected molecules gave rise to the Troger’s base
and other unidentified by-products.
NHR
2:R = COCH3
3:R = COCF3
H3C
Using TFA in lower quantity, the reaction did not reach com-
pletion, while dilution with solvent led to no reaction.
a
N
CH3
+
N
CH2
N
+ by-products
Finally, the reaction was attempted even on compound 1a,
€
N
6
H3C
H3C
but, as expected, in TFA only the Troger’s base 4 was
4
1c
isolated, while in acetic acid a mixture of the quinazoline
1c and formamidine 7 was obtained, demonstrating that
intermediate 6 could be formed but is not stable in acid
conditions.
Scheme 3. Influence of N-protection on reaction products (A). Reagents and
conditions: (a) (1) HMTA, TFA and (2) KOH aqueous EtOH, K3Fe(CN)6.
On the other hand, the ethyl carbamate group is stable in
TFA in such a way to afford the N-protected dihydroquinazo-
line intermediate from which the final quinazoline is derived.
Hence, the stability of the N-protected intermediate is crucial
for the quinazoline formation: in our hypothesis, the inter-
mediate arising from N-deprotection is not stable in acid
conditions, owing to the hydrolysis of the imine bond, and
does not survive long enough to be aromatized to the quin-
azoline nucleus. To prove this hypothesis, compound 1b was
reacted with HMTA in TFA and the stable intermediate 5
Various N-carbethoxy anilines were submitted as starting
materials to the HMTA/TFA/K3Fe(CN)6 synthetic pathway
to test its applicability.
The course of the reaction and the obtained products depend
on the starting aniline: in fact, in this study we worked with
anilines substituted with activating and deactivating groups
in order to understand their influence on reactivity and
orientation.

A. Chilin et al. / Tetrahedron 62 (2006) 12351–12356
12353
If starting anilines have position 4 substituted with ortho/
para-directing groups (such as methyl, methoxy, chloro,
and amino groups), the quinazoline nucleus was obtained
in moderate to good yields. For example, the N-protected
4-methylaniline (1b), 4-chloroaniline (8b), 4-methoxy-
aniline (9b), and 4-O-carbethoxyaniline (10b) gave, respec-
tively, 6-methyl (1c), 6-chloro (8c), 6-methoxy (9c), and
6-hydroxyquinazoline (10c) (Scheme 2 and Table 1, entries
1–3). In particular compound 10b, in which both amino and
hydroxyl groups were protected with ethyl chloroformiate,
gave only 6-hydroxyquinazoline with deprotection of the
hydroxyl function during the oxidative step (entry 3), while
compound 11b carrying only N-protection led to a complex
reaction mixture (entry 4). Moreover, it was observed that in
the case of 1,4-phenylendiamine (12a), despite the presence
of two amino functions, only one pyrimidine ring was
formed to give 6-aminoquinazoline (12c) (Table 1, entry 5).
entries 11 and 12). This last observation demonstrates the
selectivity of the reaction toward the para position with
respect to the second amino group, and/or a steric hindrance
exerted by the meta substituent.
The effect of aniline substituents on the reaction course is
summarized in Scheme 5.
R
R
N
N
R
R
NHCO2Et
NHCO2Et
N
N
= stronger activation
= weaker activation
As expected, if starting anilines have position 4 substituted
with deactivating groups, such as nitro or carboxylic groups,
no reaction was observed (Table 1, entries 6 and 7).
R = CH3, Cl, OH, OCO2Et, NHCO2Et
Scheme 5. Effect of aniline substituents.
The influence of methoxy or amino substitution on position 3
of aniline was also tested: even if the para position was free,
only quinazoline formation was observed, probably due
to the activation of the para position in the respect of the
3-substituent. From N-protected 3-methoxyaniline (15b),
N,N0-diprotected 1,3-phenylenediamine (16b), and N,N0-di-
protected 2-methyl-1,3-phenylenediamine (17b), respec-
tively, 7-methoxy (15c), 7-aminoquinazoline (16c), and
7-amino-8-methylquinazoline (17c) were obtained (Table 1,
entries 8–11). In particular, no trace of the isomeric 5-amino-
quinazoline was recovered in the reaction mixture of entry 9,
so proving the regioselectivity of pyrimidine annulation.
This high regioselectivity was again observed in the presence
of further substituents: when the reaction was carried out on
N,N0-diprotected 1,3-phenylenediamines susbstituted in 4
position with methyl group (18b), and methoxy group
(19b), only 7-amino-6-methylquinazoline (18c), and 7-ami-
no-6-methoyquinazoline (19c) were achieved without traces
of the other two possible quinazoline isomers (Table 1,
3. Conclusions
We report further investigations on a versatile and improved
method5 for the synthesis of substituted quinazoline deriva-
tives to verify its general applicability. This new method uses
HMTA in TFA and potassium ferricyanide in aqueous
ethanolic KOH, starting from anilines with the amino group
protected as an ethyl carbamate, without isolating reaction
intermediates. Both N-ethoxycarbonyl protection and TFA
are crucial to the success of the reaction. Various 6- and
7-substituted quinazolines were obtained in yields higher
than that previously reported:10–14 even when the yields
were comparable, the old methods were time and solvent-
consuming, running through almost 4–5 steps. Moreover,
our method starts from cheaper and easily available starting
materials. Finally, three new methyl- or methoxy-7-amino-
quinazoline was synthesized. This novel method afforded
Table 1. Reaction productsa
R1
R1
R2
R3
R2
R3
N
NH2
NHCO2Et
R
b
a
N
8-19a
8-19b
8-19c
Entry
Starting amine
R3
Intermediate carbamate
R2
Product
Yield
R1
R2
R1
R3
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
NH2
NH2
NH2
NH2
Cl
8a
9a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
8b
9b
6-Chloroquinazoline
6-Methoxyquinazoline
6-Hydroxyquinazoline
Complex mixture
6-Aminoquinazoline
No reaction
No reaction
7-Methoxyquinazoline
7-Aminoquinazoline
7-Amino-8-methylquinazoline
7-Amino-6-methylquinazoline
7-Amino-6-methoxyquinazoline
8c
9c
10c
15
19
24
OCH3
OH
OH
NH2
NO2
COOH
H
H
H
CH3
OCH3
OCH3
OCO2Et
OH
NHCO2Et
NO2
COOH
H
H
H
CH3
OCH3
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
12c
54
OCH3
NHCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
15c
16c
17c
18c
19c
22
45
38
44
43
9
H
CH3
H
H
CH3
H
10
11
12
H
H
a
Reagents and conditions: (a) ClCO2Et, THF; (b) (1) HMTA, TFA and (2) KOH aqueous EtOH, K3Fe(CN)6.

12354
A. Chilin et al. / Tetrahedron 62 (2006) 12351–12356
substituted quinazolines with high selectivities and good
yields, reducing reaction-time and work-up operations.
(CDCl3): d 9.36 (s, 1H, 4-H), 9.34 (s, 1H, 2-H), 8.02 (d,
J¼9.0 Hz, 1H, 8-H), 7.94 (d, J¼2.2 Hz, 1H, 5-H), 7.87
(dd, J¼9.0, 2.2 Hz, 1H, 7-H); HRMS (ESI-TOF) for
C8H635ClN2 (M++1): calcd: 165.0214, found: 165.0197.
Anal. Calcd for C8H5ClN2: C, 58.38; H, 3.06; Cl, 21.54;
N, 17.02. Found: C, 58.34; H, 3.09; Cl, 21.51; N, 17.06.
4. Experimental
4.1. General
4.2.3. 6-Methoxyquinazoline (9c). Extraction solvent: cy-
clohexane; yield: 19%; mp: 71 ꢀC (lit.10 71–72 ꢀC); 1H
NMR (CDCl3): d 9.29 (s, 1H, 4-H), 9.20 (s, 1H, 2-H), 7.94
(d, J¼9.2 Hz, 1H, 8-H), 7.56 (dd, J¼9.2, 2.8 Hz, 1H, 7-H),
7.13 (d, J¼2.5 Hz, 1H, 5-H), 3.95 (s, 3H, OCH3); HRMS
(ESI-TOF) for C9H9N2O (M++1): calcd: 161.0709, found:
161.0622. Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N,
17.49. Found: C, 67.44; H, 5.06; N, 17.52.
Melting points were determined on a Gallenkamp MFB-595-
010M melting point apparatus and are uncorrected. Analyti-
cal TLC was performed on pre-coated 60 F254 silica gel plates
(0.25 mm; Merck) developing with a CHCl3/MeOH mixture
(9:1). Preparative column chromatography was performed
using silica gel 60 (0.063–0.100 mm; Merck), eluting with
CHCl3. 1H NMR spectra were recorded on a Bruker
AMX300 spectrometer with TMS as an internal standard.
Chemical shift values are reported in parts per million and
coupling constants are reported in hertz. IR spectra were re-
corded on a Perkin–Elmer 1600 FT-IR spectrometer. HRMS
spectra were obtained using an ESI-TOF Mariner 5220 (Ap-
plied Biosystem) mass spectrometer with direct injection of
the sample and collecting data in the positive ion mode.
GC–MS analysis of samples were carried out using a Varian
CP-3800 gas chromatograph with a Mass Selective Detector
(EI), equipped with an Agilent HP-INNOWax column (30 m
length, 0.25 mm I.D., and 0.25 mm film thickness) using
helium as carrier gas (1 mL/min) and a temperature program
from 100 ꢀC (3 min) to 300 ꢀC (10 ꢀC/min) for a total run
length of 28 min. Elemental analyses were performed on
a Perkin–Elmer 2400 Analyser and are within ꢁ0.4% of
theoretical values.
4.2.4. 6-Hydroxyquinazoline (10c). After washing with
chloroform (3ꢂ100 mL), the aqueous solution was neutral-
ized with 1 M HCl, extracted with EtOAc (3ꢂ100 mL),
and evaporated under reduced pressure. Yield: 24%; mp:
1
235 ꢀC (lit.12 239 ꢀC); H NMR (CDCl3): d 9.28 (s, 1H,
4-H), 9.18 (s, 1H, 2-H), 8.14 (d, J¼2.5 Hz, 1H, 5-H), 7.99
(d, J¼9.1 Hz, 1H, 8-H), 7.61 (dd, J¼9.1, 2.5 Hz, 1H, 7-H);
HRMS (ESI-TOF) for C8H7N2O (M++1): calcd: 147.0553,
found: 147.0693. Anal. Calcd for C8H6N2O: C, 65.75; H,
4.14; N, 19.17. Found: C, 65.68; H, 4.17; N, 19.17.
4.2.5. 6-Aminoquinazoline (12c). Extraction solvent: tolu-
ene; yield: 54%; mp: 212 ꢀC (lit.13 213 ꢀC); 1H NMR
(CDCl3): d 9.20 (s, 1H, 4-H), 9.13 (s, 1H, 2-H), 7.90 (d,
J¼9.1 Hz, 1H, 8-H), 7.35 (dd, J¼9.1, 2.6 Hz, 1H, 7-H),
6.95 (d, J¼2.6 Hz, 1H, 5-H); HRMS (ESI-TOF) for
C8H8N3 (M++1): calcd: 146.0713, found: 146.0693. Anal.
Calcd for C8H7N3: C, 66.19; H, 4.86; N, 28.95. Found: C,
66.23; H, 4.80; N, 28.97.
Analytical data for compounds 1c,10 8c,11 9c,10 10c,12 12c,13
15c,10 and 16c14 were compared with literature data.
For the synthesis of carbamates 1b and 8–19b, and for exper-
iments with different acids, see the Supplementary data.
4.2.6. 7-Methoxyquinazoline (15c). Extraction solvent: cy-
1
clohexane; yield: 22%; mp: 90 ꢀC (lit.10 87 ꢀC); H NMR
4.2. General procedures for quinazolines
(MeOD-d4): d 9.30 (s, 1H, 4-H), 9.10 (s, 1H, 2-H), 7.97 (d,
J¼9.0 Hz, 1H, 5-H), 7.53 (dd, J¼9.0, 2.5 Hz, 1H, 6-H),
7.31 (d, J¼2.5 Hz, 1H, 8-H), 4.01 (s, 3H, OCH3); HRMS
(ESI-TOF) for C9H9N2O (M++1): calcd: 161.0709, found:
161.0699. Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N,
17.49. Found: C, 67.53; H, 5.00; N, 17.50.
A mixture of carbamate 1b or 8–19b (5 mmol) and HMTA
(35 mmol) in TFA (35 mL) was refluxed for 1 h. After cool-
ing, the mixture was diluted with 4 M HCl (200 mL). The
undissolved residue was filtered off and the solution was
evaporated under reduced pressure. The residue was dis-
solved in aqueous ethanolic (water/EtOH, 1/1) 10% KOH
(300 mL), added of K3Fe(CN)6 (12.5 g, 38 mmol) and re-
fluxed for 4 h. After cooling, the mixture was diluted with
water (300 mL), extracted with organic solvent (see below)
(5ꢂ100 mL), and the organic phase was evaporated under
reduced pressure.
4.2.7. 7-Aminoquinazoline (16c). Extraction solvent: tolu-
ene; yield: 45%; mp: 190 ꢀC (lit.14 190.5–191 ꢀC); 1H
NMR (MeOD-d4): d 9.01 (s, 1H, 4-H), 8.84 (s, 1H, 2-H),
7.79 (d, J¼8.9 Hz, 1H, 5-H), 7.16 (dd, J¼8.9, 2.0 Hz, 1H,
6-H), 6.90 (d, J¼2.0 Hz, 1H, 8-H); HRMS (ESI-TOF) for
C8H8N3 (M++1): calcd: 146.0713, found: 146.0589. Anal.
Calcd for C8H7N3: C, 66.19; H, 4.86; N, 28.95. Found: C,
66.23; H, 4.85; N, 28.92.
4.2.1. 6-Methylquinazoline (1c). Extraction solvent: tolu-
ene; yield: 49%; mp: 62 ꢀC (lit.10 62–63 ꢀC); 1H NMR
(CDCl3): d 9.32 (s, 1H, 4-H), 9.27 (s, 1H, 2-H), 7.95 (d,
J¼8.6 Hz, 1H, 8-H), 7.76 (dd, J¼8.6, 1.8 Hz, 1H, 7-H),
7.69 (d, J¼1.8 Hz, 1H, 5-H), 2.58 (s, 3H, CH3); HRMS
(ESI-TOF) for C9H9N2 (M++1): calcd: 145.0760, found:
145.0674. Anal. Calcd for C9H8N2: C, 74.98; H, 5.59; N,
19.43. Found: C, 75.00; H, 5.50; N, 19.50.
4.2.8. 7-Amino-8-methylquinazoline (17c). Extraction sol-
1
vent: toluene; yield: 38%; mp: 163 ꢀC; H NMR (MeOD-
d4): d 8.96 (s, 1H, 4-H), 8.90 (s, 1H, 2-H), 7.65 (d,
J¼8.8 Hz, 1H, 5-H or 6-H), 7.16 (d, J¼8.8 Hz, 1H, 5-H or
6-H), 2.43 (s, 3H, CH3); IR (KBr) 3450, 3370, 3025, 2930,
2865, 1620, 1520, 1490, 1375, 1270, 1145, 1035, 940,
825 cmꢃ1; HRMS (ESI-TOF) for C9H10N3 (M++1): calcd:
160.0869, found: 160.0781. Anal. Calcd for C9H9N3: C,
67.90; H, 5.70; N, 26.40. Found: C, 67.94; H, 5.68; N, 26.38.
4.2.2. 6-Chloroquinazoline (8c). Extraction solvent: tolu-
ene; yield: 15%; mp: 137 ꢀC (lit.11 143 ꢀC); 1H NMR

A. Chilin et al. / Tetrahedron 62 (2006) 12351–12356
12355
4.2.9. 7-Amino-6-methylquinazoline (18c). Extraction sol-
4.5. 6-Methyl-1,2-dihydroquinazoline (6)
1
vent: toluene; yield: 44%; mp: 175 ꢀC; H NMR (DMSO-
d6): d 9.01 (s, 1H, 4-H), 8.91 (s, 1H, 2-H), 7.64 (s, 1H,
5-H or 8-H), 7.38 (s, 1H, 5-H or 8-H), 2.30 (s, 3H, CH3);
IR (KBr) 3430, 3345, 3030, 2930, 2865, 1625, 1530, 1345,
1235, 1145, 1100, 1015, 950, 845 cmꢃ1; HRMS (ESI-
TOF) for C9H10N3 (M++1): calcd: 160.0869; found:
160.0912. Anal. Calcd for C9H9N3: C, 67.90; H, 5.70; N,
26.40. Found: C, 68.01; H, 5.67; N, 26.32.
A solution of 5 (0.95 g, 4.3 mmol) in 10% KOH (200 mL)
was refluxed for 2 h. After cooling, the mixture was ex-
tracted with toluene (3ꢂ100 mL) and the organic phase
was evaporated under reduced pressure to give 6 (0.58 g,
92%). 1H NMR (DMSO-d6): d 7.95 (t, J¼1.6 Hz, 1H,
4-H), 6.96 (dd, J¼8.1, 1.5 Hz, 1H, 7-H), 6.92 (d, J¼
1.5 Hz, 1H, 5-H), 6.45 (d, J¼8.1 Hz, 1H, 8-H), 5.86 (d,
J¼1.6 Hz, 1H, NH), 4.77 (d, J¼1.6 Hz, 2H, 2-H), 2.14 (s,
3H, CH3). Anal. Calcd for C9H10N2: C, 73.94; H, 6.89;
N, 19.16. Found: C, 74.00; H, 6.86; N, 19.14. Compound 6
easily decomposed if not kept in aprotic or non-polar sol-
vent, such as toluene.
4.2.10. 7-Amino-6-methoxyquinazoline (19c). Extraction
solvent: EtOAc; yield: 43%; mp: 163 ꢀC; 1H NMR
(CDCl3): d 9.01 (s, 1H, 4-H), 9.00 (s, 1H, 2-H), 7.07 (s,
1H, 5-H or 8-H), 7.00 (s, 1H, 5-H or 8-H), 4.02 (s, 3H,
OCH3); IR (KBr) 3420, 3395, 3040, 2930, 2865, 1690,
1575, 1490, 1380, 1320, 1235, 1215, 1170, 1025, 905,
835 cmꢃ1; HRMS (ESI-TOF) for C9H10N3O (M++1): calcd:
176.0818, found: 176.0685. Anal. Calcd for C9H9N3O: C,
61.70; H, 5.18; N, 23.99. Found: C, 61.68; H, 5.22; N, 24.02.
4.6. N-(2-Formyl-4-methylphenyl)formamidine (7)
A solution of 6 (0.55 g, 3.8 mmol) in acetic acid (30 mL)
was refluxed for 1 h. After cooling, the mixture was diluted
with water (100 mL), neutralized with NaHCO3, and ex-
tracted with toluene (3ꢂ80 mL). The organic phase was
evaporated under reduced pressure and the residue was ana-
lyzed by GC–MS, identifying 1c (tR¼12.7 min) and 7
(tR¼13.9 min) as reaction products. The residue was further
purified by column chromatography to give, in order of elu-
tion, 1c (7.1 mg, 13%); GC–MS (EI): m/z 144, 117, 89, 90,
63 (see above for other analytical data) and 7 (7.9 mg, 13%);
1H NMR (CDCl3): d 9.32 (s, 1H, CHO or CH]NH), 9.27 (s,
1H, CHO or CH]NH), 7.95 (d, J¼8.6 Hz, 1H, 6-H), 7.76
(dd, J¼8.6, 1.8 Hz, 1H, 5-H), 7.69 (d, J¼1.8 Hz, 1H, 3-H),
2.58 (s, 3H, CH3); GC–MS (EI): m/z 136, 135, 107, 106,
77; HRMS (ESI-TOF) for C9H11N2O (M++1): calcd:
163.0866, found: 163.0901. Anal. Calcd for C9H10N2O: C,
66.65; H, 6.21; N, 17.27. Found: C, 66.66; H, 6.18; N, 17.30.
4.3. Synthesis from compounds 2 and 3
A mixture of carbamate 215 or 316 (5 mmol) and HMTA
(35 mmol) in TFA (35 mL) was refluxed for 1 h. After cool-
ing, the mixture was diluted with 4 M HCl (200 mL). The un-
dissolved residue was filtered off and the solution was
evaporated under reduced pressure. The residue was dis-
solved in aqueous ethanolic (water/EtOH, 1/1) 10% KOH
(300 mL), added with K3Fe(CN)6 (12.5 g, 38 mmol) and re-
fluxed for 4 h. After cooling, the mixture was diluted with
water (300 mL), extracted with toluene (5ꢂ100 mL), and
the organic phase was evaporated under reduced pressure
€
to give a complex mixture, in which 1c and Troger’s bases
4 were detectable by NMR analysis: H NMR (CDCl3):
1
d 9.32 (s, 1H, 1c-4-H), 9.27 (s, 1H, 1c-2-H), 7.95 (d,
J¼8.6 Hz, 1H, 1c-8-H), 7.76 (dd, J¼8.6, 1.8 Hz, 1H, 1c-
7-H), 7.69 (d, J¼1.8 Hz, 1H, 1c-5-H), 7.02 (d, J¼8.8 Hz,
2H, 4-3-H and 9-H or 4-H and 10-H), 6.96 (d, J¼8.8 Hz,
2H, 4-3-H and 9-H or 4-H and 10-H), 6.70 (s, 2H, 4-1-H
and 7-H), 4.64 (d, J¼16.6 Hz, 2H, 4-6-H and 12-H), 4.30
(s, 2H, 4-N–CH2–N), 4.10 (d, J¼16.6 Hz, 2H, 4-6-H and
12-H), 2.21 (s, 6H, 2H, 4-2-CH3 and 8-CH3), 2.58 (s, 3H,
1c-CH3); peak assignment was made by comparison with
NMR spectrum of an authentic sample of 4 prepared from
literature method.6
Acknowledgements
The present work has been carried out with financial sup-
ports of the Italian Ministry for University and Research
(MIUR), Rome, Italy.
Supplementary data
Experimental details for compounds 1b and 8–19b, and
experiments with different acids can be found in the online
version. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/
j.tet.2006.09.103.
4.4. Ethyl 6-methyl-2H-quinazoline-1-carboxylate (5)
A mixture of 1b (1.0 g, 5.6 mmol) and HMTA (5.5 g,
39.1 mmol) in TFA (40 mL) was refluxed for 1 h. After
cooling, the mixture was diluted with 4 M HCl (200 mL).
The undissolved residue was filtered off and the solution
was evaporated under reduced pressure. The residue was
dissolved in water (200 mL), neutralized with NaHCO3,
and extracted with EtOAc (3ꢂ100 mL). The organic phase
was evaporated under reduced pressure, and the solid was
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1
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