Tetrahydroquinazoline derivatives by aza diels-alder reaction

Article abstract of DOI:10.3987/COM-09-S(S)72

The reaction of N-(2-Chloromethylphenyl)benzenesulfonamides (1) with N-benzylideneamines (2) gives 1,2,3,4-tetrahydroquinazoline derivatives (3) via the highly reactive o-azaxylylene intermediates. The structure of (3) is fully assigned on the basis of an

Full text of DOI:10.3987/COM-09-S(S)72

HETEROCYCLES, Vol. 80, No. 2, 2010
1457
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1457 - 1461. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd July, 2009, Accepted, 11th September, 2009, Published online, 15th September, 2009
DOI: 10.3987/COM-09-S(S)72
TETRAHYDROQUINAZOLINE DERIVATIVES BY AZA DIELS-ALDER
REACTION §
Giuseppe Cremonesi,a Piero Dalla Croce,b* Maddalena Gallanti,b and
Concetta La Rosaa
Università degli Studi di Milano
a DISMAB – Section of Organic Chemistry “A. Marchesini”, Via Venezian 21, I-
20133 Milano, Italy
b
Department of Organic and Industrial Chemistry, Via Venezian 21, I-20133
Milano, Italy
Abstract – The reaction of N-(2-Chloromethylphenyl)benzenesulfonamides (1)
with N-benzylideneamines (2) gives 1,2,3,4-tetrahydroquinazoline derivatives (3)
via the highly reactive o-azaxylylene intermediates. The structure of (3) is fully
assigned on the basis of analytical and spectroscopic data. The chemical
behaviour of (3) has been studied.
Some our previous results concerned the reaction of 1 with enol ethers, enamines and enolates to obtain
different classes of heterocyclic systems.1,2 To explain the formation of heterocyclic derivatives we
suggested the transformation of 1 into o-azaxylylenes,3 a particular class of 1-aza-buta-1,3-dienes whose
use on hetero Diels-Alder reactions is well known.4 In continuation of our interest on reactivity of 1
towards dienophiles, we report a new approach to tetrahydroquinazoline ring system by reaction of 1 with
N-benzylideneamines (2). Among the remarkable number of quinazoline synthesis5 none deals with the
direct preparation of its 1,2,3,4-tetrahydro-derivatives. The reported methods are based on the reduction
of entirely or partly oxidized substrates.5 Recent advances in quinazoline chemistry are concerned with
the presence of this ring system in alkaloids6 and in neuroprotective compounds, such as Dictyoquinazol
B7 with biological activity in neurodegeneration deseases.
The treatment of benzyl halides 1 with N-benzylideneamines (2), in dichloromethane solution in presence
of cesium carbonate at -20 °C, leads to the formation of cycloadducts 3 in good to fair yields (Scheme 1).
The structure of products 3 was assigned by means of analytical and spectroscopic data.
§ This paper is dedicated to Prof. Emeritus Akira Suzuki in the occasion of his 80th birthday.
* Corresponding author: piero.dallacroce@unimi.it

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HETEROCYCLES, Vol. 80, No. 2, 2010
In the case of the reaction between 1b and 2a a careful NMR analysis of crude reaction mixture indicated
the presence of two diastereomeric products 3e/3e’ in ratio 90:10. As it was not possible to separate them
by means of chromatography on silica gel or crystallization, the mixture was submitted to NOESY
analysis to determine their relative stereochemistry. The positive NOE effect observed in the minor
diastereomer between the two protons H-2 and H-4, allowed us to assign to it the relative cis
configuration, thereby the relative trans configuration was assigned to the major one.
Scheme 1
SO2Ph
Ph
SO2Ph
SO2Ph
NH
H
N
N
Ph
H
Cs2CO3
H
Ph
R1
+
+
N
N
CH2Cl2
-20 °C
N
R1
NOE
CH
R
X
Bn
R
H
R
H
1a-b
3a-e
3e'
2a-d
1a : R = H; X = Cl
1b : R = Ph, X = Br
2a : R1 = Bn
2b : R1 = C6H11
2c : R1 = Ph
3a
3b
3c
3d
: R = H; R1 = Bn
: R = H; R1 = C6H11
: R = H; R1 = Ph
(72%)
(65%)
(68%)
2d : R1 = 4-MeO-C6H4
: R = H; R1 = 4-MeO-C6H4 (78%)
(81%)
3e/3e' : R = Ph; R1 = Bn
The formation of quinazoline derivatives (3) can be explained assuming an initially base promoted
elimination of hydrogen halide from 1 giving to the highly reactive intermediate o-azaxylylenes.1,2
Successively, these intermediates are readily trapped by electron rich imines (2)8 to give
tetrahydroquinazolines (3) via aza Diels-Alder type reaction. The stereochemical results observed in the
reaction of 1b with 2a can be rationalized taking into account the two possible attacks of the E-imine to
the dienic system with a preferential formation of the more stable trans diastereoisomer 3e.
Compounds 3 can be structurally correlated to N,N-acetals therefore unstable under acid conditions and
stable in basic medium. In order to confirm this prediction we treated 3 with 15% aq. HCl solution in
THF solution and observed its complete transformation into 4 with elimination of benzaldehyde (Scheme
2). As expected no reaction occurs with potassium t-butoxide in DMF solution.
Scheme 2
SO2Ph
H
N
NH SO2Ph
CH2 NH2
Ph
15% aq.HCl
THF
Ph-CHO
+
N
Ph
Cl
H H
CH2Ph
3a
4

HETEROCYCLES, Vol. 80, No. 2, 2010
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EXPERIMENTAL
Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Elemental analyses
were performed by the Microanalytical Laboratory of the Department. 1H NMR spectra were recorded in
CDCl3 solution using a Bruker AMX 300 MHz spectrometer, and chemical shifts are given in ppm relative
to TMS. The MS spectra were determined using a VG Analytical 7070 EQ mass spectrometer with an
attached VG Analytical 11/250 data system.
N-(2-Bromophenylmethylphenyl)benzenesulfonamide (1b)9 and imines (2a-d)10,11,12 were prepared
according to the reported procedures.
N-(2-Chloromethylphenyl)benzenesulfonamide (1a). This compound was obtained following Corey’s
method,3 reported for the tosyl analogue, starting from 2-aminobenzyl-alcohol and benzenesulfonyl
1
chloride. Solid, mp 148-150 °C (toluene). Yield 98%. H NMR : 4.33 (s, 2H, CH2); 6.75 (s, 1H, NH);
7.20-7.98 (m, 9H, Ar). Anal. Calcd for C13H12ClNO2S: C, 55.42; H, 4.29; N, 4.97. Found: C, 55.31; H,
4.21; N, 4.92.
Preparation of quinazoline derivatives (3): general procedure.
To a suspension of cesium carbonate (2.0 mmol) in CH2Cl2 (20 mL) containing 2 (2.0 mmol), cooled to -
20 °C, 1 (1.0 mmol) in CH2Cl2 (20 mL) was added in 4 h and the mixture was then stirred at rt for 16 h.
Treatment with water (20 mL), separation of organic layer and evaporation of the solvent gave the crude
products. After column chromatography (Al2O3 – toluene/AcOEt : 85/15) were obtained:
1-Benzenesulfonyl-3-benzyl-2-phenyl-1,2,3,4-tetrahydroquinazoline (3a): Solid, mp 156-158 °C
(toluene). Yield 72%. 1H NMR : 3.25 (d, 1H, J = 17.2 Hz, H-4); 3.55 (d, 1H, J = 13.7 Hz, N-CH2); 3.75
(d, 1H, J = 17.2 Hz, H-4); 4.00 (d, 1H, J = 13.7 Hz, N-CH2); 6.60 (s, 1H, H-2); 6.80-8.00 (m, 19H, Ar).
13C NMR : 46.0 (C-4); 58.0 (CH2 of Bn); 78.5 (C-2); 120.0-140.6 (Ar). MS (IE) m/z = 440 [M+]. Anal.
Calcd for C27H24N2O2S: C, 73.61; H, 5.45; N, 6.36. Found: C, 73.54; H, 5.49; N, 6.34.
1-Benzenesulfonyl-3-cyclohexyl-2-phenyl-1,2,3,4-tetrahydroquinazoline (3b): Solid, mp 128-130 °C
(i-Pr2O). Yield 65%. 1H NMR : 1.10-2.50 (m, 11H, cyclohexyl); 3.50 (d, 1H, J = 17.0 Hz, H-4); 3.70 (d,
1H, J = 17.0 Hz, H-4); 6.50 (s, 1H, H-2); 6.80-7.85 (m, 14H, Ar). Anal. Calcd for C26H28N2O2S: C, 72.19;
H, 6.52; N, 6.48. Found: C, 72.08; H, 6.44; N, 6.50.

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1-Benzenesulfonyl-2,3-diphenyl-1,2,3,4-tetrahydroquinazoline (3c): Solid, mp 164-165 °C (toluene).
1
Yield 68%. H NMR : 3.45 (d, 1H, J = 15.4 Hz, H-4); 4.05 (d, 1H, J = 15.4 H-4); 6.75 (s, 1H, H-2);
6.82-7.96 (m, 19H, Ar). MS (IE) m/z = 426 [M+]. Anal. Calcd for C26H22N2O2S: C, 73.21; H, 5.20; N,
6.57. Found: C, 73.18; H, 5.18; N, 6.49.
1-Benzenesulfonyl-3-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroquinazoline (3d): Solid, mp
168-170 °C (toluene). Yield 78%. 1H NMR : 3.50 (d, 1H, J = 13.5 Hz, H-4); 3.75 (s, 3H, OMe); 4.10 (d,
1H, J = 13.5 H-4); 6.65 (s, 1H, H-2); 6.70-7.86 (m, 18H, Ar). 13C NMR : 45.0 (C-4); 55.7 (Me-O); 71.4
(C-2); 113.8-141.6 (Ar). Anal. Calcd for C27H24N2O3S: C, 71.03; H, 5.30; N, 6.14. Found: C, 71.05; H,
5.32; N, 6.11.
1-Benzenesulfonyl-3-benzyl-2,4-diphenyl-1,2,3,4-tetrahydroquinazoline (3e/3e’): Solid, mp 143-
1
145 °C (MeOH). Yield 81%. H NMR (mixture of two diastereoisomers 3e/3e’ in ratio 90:10
respectively) : 3.20 (d, 1H, J = 13.3 Hz, N-CH2) (3e); 3.45 (d, 1H, J = 13.3 Hz, N-CH2) (3e); 3.85 (d,
1H, J = 13.2 Hz, N-CH2) (3e’); 4.03 (d, 1H, J = 13.2 Hz, N-CH2) (3e’); 4.30 (s, 1H, H-4) (3e’); 4.95 (s,
1H, H-4) (3e); 6.20 (s, 1H, H-2) (3e); 6.54 (s, 1H, H-2) (3e’); 6.70-8.00 (m, 24H, Ar). 13C NMR (mixture
of two diastereoisomers 3e/3e’) : 53.4 (CH2) (3e); 59.6 (CH2) (3e’); 63.5 (C-4) (3e’); 64.3 (C-4) (3e);
72.7 (C-2) (3e); 75.1 (C-2) (3e’); 124.2-142.7 (Ar). Anal. Calcd for C33H28N2O2S: C, 76.72; H, 5.46; N,
5.42. Found: C, 76.62; H, 5.49; N, 5.45.
N-[2-(Benzylamino-methyl)-phenyl]benzenesulfonamide hydrochloride (4).
A solution of 3a (1.0 mmol) in THF (20 mL) was treated with aq. HCl 15% solution (10 mL) and heated
at 60 °C for 6 h. The organic solvent was evaporated off and the water residue extracted with toluene. The
organic phase was separated, the aqueous layer was evaporated off and the residue treated with acetone.
1
The solid was filtered and purified by crystallisation. Solid, mp 186-188 °C (AcOEt). Yield 75%. H
NMR : 3.45 (s, 2H, CH2); 3.75 (s, 2H, CH2); 7.00-7.82 (m, 14H, Ar). Anal. Calcd for C20H21ClN2O2S:
C, 61.77; H, 5.44; N, 7.20. Found: C, 61.88; H, 5.41; N, 7.28.
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