The one pot quinazoline synthesis by the intramolecular
cycloaddition reaction of N-substituted N-(2cyanophenyl)benzimidoyl thiourea
Fathalla, W. and Pazdera, P.a
Department of organic chemistry, Faculty of natural Science, Masaryk university, Brno, Czech republic.;
e-maila pazdera@chemi.muni.cz
Benzodiazocines1 and quinazolines2,3 demonstrated two heterocyclic class of
compounds with diverse physiological activities. Acting as central nervous system depressant
and calcium sensitizing agents etc.. These derivatives are used as intermediate for
pharmaceutical agents, consequently many researchers tended to synthesize these compounds.
Some others tended to change their structure by changing the size of the ring or by changing
the heteroatoms. Stankovsky’s group4-6 described the synthesis of eight member 2,4disubstituted 6H-5,1,3-benzothiadiazocine by the intramolecular substitution of the N-(2chloromethylphenyl)-N’,N’-(3oxapentamethylene)formamidinoyl thioureas. In this paper we
are studying the intramolecular cycloaddition reaction of product formed in situ after addition
of secondary amines to N-(2-cyanophenyl) benzimidoyl isothiocyanate 3. This very reactive
product was easily prepared from N1-(2-cyanophenyl) benzamide 1. The amide 1 was
transformed by the phosphorous pentachloride action to afford the benzimidoyl chloride 2
which subsequently reacts with potassium thiocyanate to give the desired isothiocyanate
derivative 3. Structure of compound 3 was supported by IR spectra that showed the existence
of isothiocyanato group (cm-1), and the cyano group (cm-1). The
isothiocyanate 3 reacts with secondary amine namely morpholine, piperidine, pyrrolidine, Nmethylpiperazine to directly give the cyclic product. The possible structure of the cyclisation
product could be explained if we consider the formation of the thiourea derivative 4a-d
scheme 1.
1
C
N
C
a
N
Cl
O
N
NH
(1)
(2)
b
C
S
N
C
NH
C
c
S
N
C
N
N
N
N
X
(4a-d)
(3)
HN
X
S
S
NH
C
N
N
N
X
N
N
N
(5a-d)
(6a-d)
6
a
b
c
d
a: PCl5, toluene, 110C; b: KSCN, acetone, -5C; c: NHR2, acetone, 25C
Scheme 1
2
X
O
CH2
(CH2)0
NCH3
This intermediate contains in molecule two active nucleophillic sites which compete to attack
the nitrile group and finally give the cyclic product. These active sites are the sulphur and the
nitrogen atoms present in the thioamide group of the thiourea derivative 4. The intramolecular
reaction would be given one or both of the following cyclic products: The thiadiazocine
derivative 5 via sulphur attack4-6, or the quinazoline derivative 6 via nitrogen attack.
The product formed was the quinazoline derivative 6 giving the more thermodynamically
stable six membered ring in which the N atom takes part in the cyclisation process and this
agrees with the regioselectivity of thioamide derivatives when treated with unsaturated
compounds take part on the nitrogen atom6,7. The previous result could be proved by the
spectral data as follows:
1. I.R
The infra red spectra show the disappearance of NCS and CN bands present in case of the
isothiocyanate 3 and the existence of
NH and C=N bands at 3220, and 1613 cm-1,
respectively in 6.
2. 1H NMR
The proton nuclear magnetic resonance spectra show the introduction of the CH2 groups
from the amino group when reacting with isothiocyanate 3. It was a surprise to find that the
two CH2 groups adjacent to the nitrogen atom from amines are identical in all cases except for
the case of pyrrolidine which gave two chemical shifts at 4.01 [t, 2H, 2-CH2] and 3.87 [t, 2H,
5-CH2] ppm, respectively. Aromatic protons are present due to a benzene ring fused with the
pyrimidine moiety which consists of four different proton types corresponding to four
aromatic protons at 8.42 (d), 7.94 (d), 7.82 (t), 7.52 (t) ppm. Also another benzene ring at
position 2 of the quinazoline at 7.56 and 8.32 ppm.
3.
13
C NMR
The most important peak shown by the
13
C NMR is the peak corresponding to C=S at
chemical shift 183-184 ppm which plays an important role in the identification of the
structure .
13
C NMR spectra gave four different peaks corresponding to the -CH2- from the
amines, although we expected to have only two peaks. This is clearly due to the geometry of
the product in which one -NCH2- group from the amine (this group have almost the same
environment with respect to the other -NCH2-) is effected by anisotropy of the C=S group.
This fact is maximized in the 1HNMR spectrum when using pyrrolidine as amine.
3
4. Mass spectra
Mass spectra gave the molecular ion for all the products 6a-d, next it gave molecular
fragment which corresponds to the thioamide moiety at 131 (morpholine), 128
(piperidine),114 (pyrrolidine), and 142 (N-methyl piperazine) and the molecular fragment at
221 corresponding to the residue of the compound (2-phenyl-4-quinazoilinimine moiety).
On the basis of the above spectral data, reference data from the computer simulated spectra
and from the chemistry of the thiourea derivatives7,8 we confirmed that these compounds 6a-d
are 4-imino-2-phenyl-3,4-dihydro-3-quinazolinyl(2-N,N-diR-amino) methane thiones.
These type of compounds are of a very interesting structure and could give several products
through Dimmorth rearrangement which will be our aim in the future research, also this
structure together with the other Dimmorth rearrangement products could be of a very
valuable biological activities.
6
H5
H6
H7
H8
a
8.41
7.82
7.52
7.95
(d,1H)
(t,1H)
(t,1H)
(d,1H)
8.41
7.78
7.49
7.84
(d,1H)
(t,1H)
(t,1H)
(d,1H)
8.45
7.77
7.46
7.77
(d,1H)
(t,1H)
(t,1H)
(d,1H)
b
c
H2’,6’
H3’,4’,5’
8.33-8.35 7.59-7.60
(m,2H)
(m,3H)
8.31-8.33 7.55-7.56
(m,2H)
(m,3H)
8.31-8.33 7.56-7.57
(m,2H)
(d,3H)
others
4.33-4.38 [ m,4H,2NCH2 ]
3.80-3.84 [ m,4H,2OCH2 ]
4.26-4.29 [ m,4H,2NCH2 ]
1.70-1.75 [ m,6H,3CH2 ]
4.01 [ t,2H,NCH2 ]
3.87 [ t,2H,NCH2 ]
1.99-2.07 [ m,4H,2CH2 ]
d
8.41
7.80
7.50
7.81
(d,1H)
(t,1H)
(t,1H)
(d,1H)
8.30-8.32 7.58-7.56
(m,2H)
(m,3H)
4.37-4.41 [ m,4H,2NCH2 ]
2.57-2.60 [ m,4H,2NCH2 ]
2.39 [ s,3H,N-CH3 ]
Table 1
1
HNMR (, ppm) spectral data of quinazoline derivative 6
4
6
C=S
C2
C4
NCH2
XCH2
XCH2
NCH2
Others
a
184.70
154.98
149.60
47.95
66.82
66.82
47.79
-
b
183.35
154.28
149.70
49.06
26.53
25.92
48.55
24.82 (X=CH2)
c
183.19
155.66
151.04
52.21
27.05*
26.31*
51.69
-
d
184.38
154.85
149.51
55.06
47.21
46.78
54.71
45.53 – NCH3
* XCH2 in case of pyrrolidine represents the C3 and C4, respectively of the amine (2NCH2CH2.groups)
Table 2
13
CNMR (, ppm) spectral data of quinazoline derivative 6
Experimental
General details
Melting points of the prepared compounds were measured on a Boetius Rapido
PHMK 79/2106 (Wägetechnik) instrument. TLC was carried out on Silufol UV 254 plates
(Kavalier, Votice). The detection with Fluotes universal (Quarzlampen, Hanau ) and iodine
vapours. Eluent used was acetone : benzene 20 : 80. FTIR spectra were taken on a
spectrometer Genesis (Unicam ) in potassium bromide pellets. NMR spectra were measured
on a Bruker Avance DRX-500 spectrometer. 1H,
13
C NMR spectra were measured with
CDCl3 as a solvent and tetramethylsilane as an internal standard. Mass spectrometry (electron
impact, 70eV with a Fisons instruments TRIO 1000 and GC 8000 series. The reference data
from the computer simulated spectra were made by the Advanced Chemistry Development
Inc. ACD/NMR DB programs .
(4-Imino-2-phenyl-3,4-dihydro-3-quinazolinyl)(2-N,N-diR-amino)methane
thiones 6a-d
A mixture of N1-(2-cyanophenyl)benzamide9 (5.0 g, 22.5 mmol) 1, and phosphorous
pentachloride (5.0 g, 24 mmol) in absolute toluene were refluxed for 8 h. The solvent was
removed under reduced pressure to give a brownish coloured oil of N1-(2-cyanophenyl)-1benzenecarboximidoyl chloride10 2 which wasn’t further purified. To the solution of crude oil
in dry acetone, a solution of potassium thiocyanate (2.2 g, 22.5 mmol) in dry acetone was
added portion wise during stirring and cooling at -5C for 2 h. The precipitated potassium
chloride was filtered off and the filtrate is the acetone solution of 1-(2-cyanophenyl)-N1thioxomethylene-1-benzene carboximidamide 3. The infra red spectrum was taken for this
5
solution to give a strong peak at 2059 cm-1 referring to NCS band. The isothiocyanate was
used with out further isolation and purification (to avoid polymerisation and destruction of
this very reactive compound). To the solution of isothiocyanate 3 in acetone, the
corresponding secondary amine (22.5 mmol) was added portion wise while stirring at room
temperature over a period of 1h. Next the reaction mixture was stirred for 24h. The
precipitated quinazoline 6a-d was filtered off and crystallised from ethyl alcohol.
Charecterisation spectral data are given in tables 1-3
6
7
References
1. Grasso, S.; Zappalá, M.; Chimirri, A.: Heterocycles, 26(9), 2477-501 (1987).
2. Brown, D. J.: The chemistry of heterocyclic compounds “Quinazolines” Supplement ,
Edit.: Taylor, E. C.; Found. Edit.: Weissberger, A.; John Wiley and sons, Inc. (1998).
3. Abdel-Megeed, M.; Teniou, A.: Rev. Roum. Chim., 33, 981 (1988).
4. Bodajla, M.; Stankovský, Š.; Špirková, K.: Collect. Czech. Chem. Commun., 60, 14151417 (1995).
5. Bodajla, M.; Stankovský, Š.; Špirková, K.; Jantová, S.: Collect. Czech. Chem. Commun.,
61, 1681-1688 (1996).
6.Bodajla, M.; Stankovský, Š.; Jantová, S.; Hudecová, D.; Špirková, K.: Chem. Papers, 50(1),
28-34 (1996).
7. Pazdera, P.; Fathalla, W.: under publication.
8. Pazdera, P.; Ondráček, D.; Nováček, E.: Chem. Papers, 43(6), 771-781 (1989).
9. Osamu, K.; Shigeo, Y.: Toshiro, K.: Agric. Biol. Chem., 44(9), 2143-2148 (1980)
10. Houghton, P. G.; Pipe, D. F.; Rees, C. W.: J. Chem. Soc. Perkin Trans. I, 1471-1479
(1985 ).
8
6
Formula
M/z
M.w.
M+
Wi found %
Wi calc %
C
H
N
S
C
H
Over
N
S
M.P., C
all
IR (, cm-1)
C=N
NH
1614
3220
CH
yield*
a
C19H18N4OS 350 65.12
5.18
15.99
9.15 64.98
5.05
16.02
9.00
22 %
185
350.44
2961
2923
2859
b
C20H20N4S
348 68.94
5.78
16.08
9.20 68.79
5.70
16.10
9.09
29 %
135
1610
3180
348.47
c
C19H18N4S
2852
334 68.24
5.42
16.75
9.59 68.07
5.33
16.60
9.43
25 %
205
1611
3200
334.44
d
C20H21N5S
2926
2968
2867
363 66.09
5.82
19.27
8.82 65.90
5.70
19.07
8.69
363.48
* % yield is calculated with respect to the starting benzamide derivative 1
Table 3
Charecteristics of the quinazoline derivative 6
7
16 %
244
1610
3240
2934