Condensation of 2-aminomethylaniline with aldehydes and ketones for the fast one-pot synthesis of a library of 1,2,3,4-tetrahydroquinazolines under flow conditions

Article abstract of DOI:10.1007/s10593-018-2292-0

[Figure not available: see fulltext.] A new eco-friendly and reliable methodology for the synthesis of 1,2,3,4-tetrahydroquinazolines is proposed. This simple protocol was tested for the continuous synthesis of a small library of 1,2,3,4-tetrahydroquinazo

Full text of DOI:10.1007/s10593-018-2292-0

DOI 10.1007/s10593-018-2292-0
Chemistry of Heterocyclic Compounds 2018, 54(4), 478–481
Condensation of 2-aminomethylaniline with aldehydes and ketones
for the fast one-pot synthesis of a library of 1,2,3,4-tetrahydroquinazolines
under flow conditions
Francesca Mangiavacchi1, Leonardo Mollari1, Luana Bagnoli1,
Francesca Marini1, Claudio Santi1*
1
Department of Pharmaceutical Sciences,
Group of Catalysis and Organic Green Chemistry, University of Perugia,
1 Via del Liceo, Perugia 06100, Italy; e-mail: claudio.santi@unipg.it
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 478–481
Submitted February 12, 2018
Accepted March 28, 2018
A new eco-friendly and reliable methodology for the synthesis of 1,2,3,4-tetrahydroquinazolines is proposed. This simple protocol was
tested for the continuous synthesis of a small library of 1,2,3,4-tetrahydroquinazoline derivatives demonstrating good versatility and
applicability.
Keywords: aldehydes, alumina, tetrahydroquinazoline, flow chemistry, green chemistry.
Nitrogen-containing heterocycles represent a significant
structural motif widely distributed in biologically active
natural and synthetic compounds.1 Among the others,
quinazolines and 1,2,3,4-tetrahydroquinazolines have attracted
a large interest from both the synthetic and pharmaceutical
points of view. In fact, the quinazoline scaffold is a part of
numerous pharmaceutically active compounds (Fig. 1), and
in particular, 1,2,3,4-tetrahydro derivatives display anti-
inflammatory and analgesic properties.2
techniques8 with interesting applications in combinatorial
chemistry and library synthesis.9
As an extension of our interest in the synthesis of
heterocycles,10 including flow techniques,11 we optimized
the conditions for the fast preparation of a library of
substituted 1,2,3,4-tetrahydroquinazoline derivatives using
a flow setup.
The quinazoline moiety is easily prepared by 1,2,3,4-tetra-
hydroquinazoline oxidation,3 that, in turn, can be obtained
in the condensation reaction between 2-aminobenzylamine
and aldehydes or ketones. This reaction has been explored
by several research groups, the desired product has been
obtained for the first time by refluxing the reagents in
benzene or xylene with azeotropic removal of water.4 In
order to improve the green aspect of the synthesis, ionic
liquids have been explored as reaction medium,5 and more
recently, Scott et al. proposed a protocol which involves
''water slurry'' or ''solvent-free'' conditions.6 It was also
demonstrated that 2-aryl-substituted derivatives can exhibit
a ring-chain tautomeric equilibrium depending on the
nature of the substituent and the solvent.7 Flow chemistry
in the past decades has received a growing attention
because of a number of benefits over traditional batch
Figure 1. Biologically active quinazoline derivatives.
0009-3122/18/54(4)-0478©2018 Springer Science+Business Media, LLC
478

Chemistry of Heterocyclic Compounds 2018, 54(4), 478–481
NH2
NH2
Flow rate
0.670 ml/min
1
NH
(0.6 mmol/ml)
Additive
2 ml
N
H
O
3a
F
H
F
2a
(0.6 mmol/ml)
Figure 2. Preliminary reaction condition investigations for the
synthesis of compound 3a.
Table 1. Yield of compound 3a under different reaction conditions
Entry
Solvent
Additive
Yield*, %
Figure 3. General setup of the experiment for the synthesis of
compounds 3a–i.
1
2
3
4
EtOAc
MeOH
Na2SO4
Na2SO4
23
28
–
THF
Na2SO4
Considering that alumina and water are not consumed
during the reaction and that the starting materials were not
adsorbed by the column and quantitatively converted into
final products we envisioned the possibility to flux
sequentially freshly prepared mixture of diamine 1 with
different aldehydes 2a–g and ketones 2h,i to prepare a
library of 1,2,3,4-tetrahydroquinazolines 3a–i variously
substituted at the C-2 atom with aromatic and aliphatic
substituents. Instantaneously prepared solutions of
equimolar amounts of compounds 1 and 2a–i in MeOH
were injected every 6 min via a T-junction in a stream of
EtOAc generated with a variable speed FMI-LAB pump
and fluxed through a 2-ml tubular reactor filled with
alumina grade V collecting 30 ml of solvent after each
injection (Fig. 3).
Considering that in these conditions the reaction is very
fast, a flow rate of 10 ml/min (corresponding to 0.2 min
residence time) was applied enabling a very rapid
preparation of the desired library of compounds 3a–i.
The results obtained exploring the scope of the reaction
are collected in Table 2 evidencing an excellent efficiency
of the protocol with aldehydes containing both electron-
withdrawing and electron-donating groups (entries 1–7).
Moderate to good results were obtained using ketones
(entries 8, 9), as a consequence of the reduced reactivity of
the carbonyl derivative affording lower conversion yields.
In comparison to the results reported in literature,6 the
reaction promoted by alumina grade V in our flow
conditions is considerably faster than the same reaction
performed under ''water slurry'' or ''solvent-free'' condi-
tions. This is particularly evident in substrates having
strong and weak electron-withdrawing group. As an
example, compounds 3c,g can be prepared under ''water
slurry'' conditions with 99 and 90% conversion but in 3 and
18 h, respectively.6,7
MeOH–EtOAc, 4:1
* Determined from 1H NMR integrated values and based on the consump-
tion of the aldehyde.
Alumina**
>99
** Grade V (by addition of 15% w/w of water).
The results of a preliminary screening of the reaction
conditions, using as model the reaction between diamine 1
and p-fluorobenzaldehyde (2a) in a 2-ml tubular reactor
filled with the promoter of the reaction are summarized in
Figure 2 and Table 1.
Considering that the cyclization proceeds as
a
condensation of the Schiff base intermediate (not shown)
we attempted to promote the reaction by removing the
water from the passage by a drying agent like sodium
sulfate (entries 1–3). It was observed that, in these cases,
the solvent used as carrier influenced the outcome of the
reaction and the best conversion was obtained in MeOH
(28%), in comparison to EtOAc (23%), whereas in THF the
1H NMR of the crude showed the presence of a complex
reaction mixture. Despite the very low solubility of the
reagents it was reported that the reaction can be con-
veniently carried out in water and that the reaction times
under ''water slurry'' conditions are, in some cases and
depending on the nature of the substituents on the aromatic
ring of the aldehydes, similar to those observed in ''solvent-
free'' conditions under gentle heating.6 Suggesting that,
most probably, hydrophobic effects and/or hydrogen
bonding could facilitate the reaction affording the desired
product in good yield and short reaction time. Entry 4
reports the results obtained when the reactor was filled with
alumina grade V, obtained by the addition of 15% w/w
of water to neutral alumina. Using these conditions,
diamine 1 was converted into 1,2,3,4-tetrahydroquinazoline
3a in 99% yield after a 3 min residence time and it was
demonstrated that flow rate can be increased till obtaining
the same conversion yield with a 0.2 min residence time.
To reduce the absorption of the products on alumina a polar
solvent mixture was used (MeOH–EtOAc, 4:1).
This indicates that alumina has an active role in the
catalysis of the reaction probably in both steps of the
known mechanism: activating the C=O bond and removing
water during the formation of the Schiff base and
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Chemistry of Heterocyclic Compounds 2018, 54(4), 478–481
facilitating the tautomerism toward the formation of the
cyclic form.
Table 2. Yields of compounds 3a–i in the continuous flow experi-
ment
In conclusion, we have demonstrated that simple flow
setup allows preparation of the library of 2-substituted
1,2,3,4-tetrahydroquinazolines in a fast, clean, and efficient
manner. The methodology is suitable for the combinatorial
approach in the synthesis of biologically active compounds
and can be, in theory, further improved by the automati-
zation of the entire process. This will be the subject for the
future investigations.
Entry
Product
Yield*, %
>99
1
2
3
4
5
6
7
8
9
Experimental
1H and 13C NMR spectra were recorded on Bruker DPX
200 (200 and 50 MHz, respectively) and Bruker DRX
spectrometers (400 and 101 MHz, respectively) at 25°C in
CDCl3, using TMS as internal standard. Melting points
were measured on a Reichert Kofler Hot Bench apparatus
and are uncorrected.
>99
>99
>99
>99
>99
>99
31
All the starting materials were commercially available.
Solvents and reagents were used as received unless
otherwise noted.
Synthesis of compounds 3a–i (General flow experi-
ment setup). In a continuous system equipped with a FMI
Lab-Pump model RP-SY pump and a 2-ml tubular reactor
charged with deactivated alumina (15% w/w H2O), EtOAc
is fluxed with a rate of 10 ml/min. Freshly prepared solutions
of (2-aminobenzyl)amine 1 (0.061 g, 0.5 mmol) and aldehydes
2a–g or ketones 2h,i (0.48 mmol) in MeOH (1 ml) were
sequentially injected by a syringe in the EtOAc stream
through a septum of a three-way connector. The products
were collected sequentially in test tubes and evaporated
under reduced pressure affording the corresponding
quinazolines 3a–i. Physical properties of the compounds
are in good correlation with the literature data.6,7,12
2-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinazoline (3a).7
Yield 93 mg (85%), white crystals, mp 93–96°C (mp 95–
1
97°C7). H NMR spectrum (200 MHz), δ, ppm (J, Hz):
7.55–7.48 (2H, m, H Ar); 7.14–7.05 (3H, m, H Ar); 6.97
(1H, d, J = 7.3, H Ar); 6.76 (1H, t, J = 7.1, H Ar); 6.61 (1H, d,
J = 7.9, H Ar); 5.24 (1H, s, CH); 4.27 (1H, d, J = 16.7,
CH2); 4.25 (1H, br. s, NH); 3.98 (1H, d, J = 16.7, CH2);
2.00 (1H, br. s, NH). 13C NMR spectrum (50 MHz), δ, ppm
(J, Hz): 162.7 (d, J = 246); 143.6; 137.5; 128.4 (d, J = 8);
127.4; 126.3; 121.2; 118.4; 115.6 (d, J = 20); 115.1; 68.9; 46.3.
2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinazoline (3b).7
Yield 62 mg (53%), pale-yellow crystals, mp 89–91°C (mp
1
88–90°C7). H NMR spectrum (200 MHz), δ, ppm (J, Hz):
7.49 (2H, d, J = 8.4, H Ar); 7.38 (2H, d, J = 8.5, H Ar);
7.08 (1H, dd, J = 7.9, J = 7.3, H Ar); 6.96 (1H, d, J = 7.3,
H Ar); 6.75 (1H, t, J = 7.3, H Ar); 6.62 (1H, d, J = 7.9,
H Ar); 5.26 (1H, s, CH); 4.25 (1H, d, J = 16.7, CH2); 4.24
(1H, br. s, NH); 3.98 (1H, d, J = 16.7, CH2); 3.97 (1H,
br. s, NH). 13C NMR spectrum (50 MHz), δ, ppm: 143.8;
140.5; 134.6; 128.7; 128.5; 127.8; 126.7; 121.7; 118.8;
115.6; 69.3; 46.6.
89
2-(4-Bromophenyl)-1,2,3,4-tetrahydroquinazoline (3c).6
Yield 86 mg (62%), pale-yellow crystals, mp 82–84°C
* Determined from 1H NMR integrated values and based on consumption
of compounds 2a–i or 1 (entries 8 and 9). The NMR analysis evidenced a
tautomeric equilibrium as reported in the literature.7
1
(mp 82.2–84.9°C6) H NMR spectrum (200 MHz), δ, ppm
(J, Hz): 7.54 (2H, d, J = 8.3, H Ar); 7.42 (2H, d, J = 8.4,
480

Chemistry of Heterocyclic Compounds 2018, 54(4), 478–481
H Ar); 7.08 (1H, t, J = 7.5, H Ar); 6.96 (1H, d, J = 7.4,
(1H, t, J = 7.1, H Ar); 7.14–7.06 (1H, m, H Ar); 6.74–6.65
(2H, m, H Ar); 3.79 (1H, d, J = 16.8, CH2); 3.57 (1H, d,
J = 16.8, CH2); 1.65 (3H, s, CH3); 2NH signals were not
detected. 13C NMR spectrum (50 MHz), δ, ppm: 145.6;
142.3; 128.4; 127.3; 127.2; 126.5; 126.1; 120.8; 117.3;
114.3; 69.7; 43.0; 32.4.
H Ar); 6.75 (1H, t, J = 7.3, H Ar); 6.61 (1H, d, J = 7.9,
H Ar); 5.23 (1H, s, CH); 4.24 (1H, d, J = 16.8, CH2); 4.19
(1H, br. s, NH); 3.96 (1H, d, J = 16.7, CH2); 2.0 (1H, br. s,
NH). 13C NMR spectrum (50 MHz), δ, ppm: 143.3; 140.6;
131.8; 128.4; 127.4; 126.2; 122.4; 121.3; 118.4; 115.1;
68.9; 46.1.
2,2-Dimethyl-1,2,3,4-tetrahydroquinazoline (3i).7 Color-
less oil. The pure compound was not isolated, compound
2-Phenyl-1,2,3,4-tetrahydroquinazoline (3d).7 Yield
42 mg (42%), pale-yellow crystals, mp 99–101°C (mp 98–
1
signals indicated from the spectra of the crude. H NMR
1
101°C7). H NMR spectrum (400 MHz), δ, ppm (J, Hz):
spectrum (200 MHz), δ, ppm (J, Hz): 7.15 (1H, dd, J = 8.0,
J = 7.4, H Ar); 6.95 (1H, d, J = 7.4, H Ar); 6.70 (1H, t,
J = 7.4, H Ar); 6.49 (1H, d, J = 8.0, H Ar); 4.02 (2H, s,
CH2); 1.40 (6H, s, CH3); 2NH signals were not detected.
13C NMR spectrum (50 MHz), δ, ppm: 142.7; 127.2; 126.1;
119.9; 117.4; 115.0; 64.5; 42.6; 28.4.
7.56–7.54 (2H, m, H Ar); 7.45–7.36 (3H, m, H Ar); 7.09
(1H, t, J = 7.6, H Ar); 6.93 (1H, d, J = 7.3, H Ar); 6.75 (1H,
t, J = 7.3, H Ar); 6.62 (1H, d, J = 7.9, H Ar); 5.25 (1H, s,
CH); 4.30 (1H, d, J = 16.7, CH2); 4.25 (1H, br. s, NH);
4.03 (1H, d, J = 16.7, CH2); 2.0 (1H, br. s, NH). 13C NMR
spectrum (101 MHz), δ, ppm: 144.2; 142.0; 129.2; 129.0;
127.7; 127.1; 126.7; 121.7; 118.6; 115.5; 70.0; 46.9.
The University of Perugia for the financial support
“Fondo Ricerca di Base 2017” is warmly acknowledged.
F.M. acknowledges National Consortium of the Italian
University C.I.N.M.P.I.S. for the fellowship.
2-(4-Methylphenyl)-1,2,3,4-tetrahydroquinazoline (3e).12
Yield 72 mg (67%), white crystals, mp 95–96°C (mp 105–
1
107°C12). H NMR spectrum (200 MHz), δ, ppm (J, Hz):
7.43 (2H, d, J = 7.8, H Ar); 7.28–7.19 (2H, m, H Ar); 7.07
(1H, t, J = 7.4, H Ar); 6.96 (1H, d, J = 7.4, H Ar); 6.74
(1H, t, J = 7.4, H Ar); 6.60 (1H, d, J = 7.4, H Ar); 5.24
(1H, s, CH); 4.28 (1H, d, J = 16.0, CH2); 4.25 (1H, br. s,
NH); 4.06 (1H, d, J = 16.0, CH2); 2.38 (3H, s, CH3); 2.20
(1H, br. s, NH). 13C NMR spectrum (50 MHz), δ, ppm:
144.3; 139.4; 138.5; 129.8; 127.7; 126.9; 126.6; 121.9;
118.5; 115.7; 69.9; 46.9; 21.5.
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2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinazoline
(3f).7 Yield 63 mg (55%), pale-yellow crystals, mp 104–
1
106°C (mp 105–107°C7) H NMR spectrum (200 MHz),
δ, ppm (J, Hz): 7.46 (2H, d, J = 8.5, H Ar); 7.11–7.02 (1H,
m, H Ar); 6.98–6.92 (3H, m, H Ar); 6.74 (1H, t, J = 7.3,
H Ar); 6.59 (1H, d, J = 7.9, H Ar); 5.21 (1H, s, CH), 4.29
(1H, d, J = 16.6, CH2); 4.15 (1H, br. s, NH); 4.00 (1H, d,
J = 16.6, CH2); 3.84 (3H, s, OCH3); 3.83 (1H, br. s, NH).
13C NMR spectrum (101 MHz), δ, ppm: 159.2; 143.3;
133.3; 127.2; 126.7; 125.7; 120.7; 117.6; 114.5; 113.5;
68.6; 54.8; 46.0.
2-(4-Nitrophenyl)-1,2,3,4-tetrahydroquinazoline (3g).7
Yield 101 mg (82%), white crystals, mp 102–105°C
1
(mp 105–107°C7) H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 8.27 (2H, d, J = 8.5, H Ar); 7.76 (2H, d, J = 8.5,
H Ar); 7.12 (1H, t, J = 7.9, H Ar); 6.97 (1H, d, J = 7.5,
H Ar); 6.79 (1H, t, J = 7.4, H Ar); 6.68 (1H, d, J = 8.0,
H Ar); 5.41 (1H, s, CH); 4.21 (1H, d, J = 16.6, CH2), 4.20
(1H, br. s, NH), 3.93 (1H, d, J = 16.7, CH2); 2.0 (1H, br. s,
NH). 13C NMR spectrum (101 MHz), δ, ppm: 149.1; 148.3;
145.1; 128.3; 127.9; 126.7; 124.3; 121.8; 119.2; 115.8;
68.8; 45.8.
2-Methyl-2-phenyl-1,2,3,4-tetrahydroquinazoline (3h).7
The pure compound was not isolated, compound signals
1
indicated from the spectra of the crude. H NMR spectrum
(400 MHz), δ, ppm (J, Hz): 7.52–7.48 (5H, m, H Ar); 7.34
481