Synthesis of 3-Aryl-3,4-dihydro-4-hydroxy-4-phenylquinazoline-2-carbonitrile via 2-(Benzoyl)arylimino-4-chloro-5H-1,2,3-dithiazoles

Article abstract of DOI:10.1055/s-2002-33520

Treatment of methyl N-(4-chloro-5H-1,2,3-dithiazole-5-ylidene)anthranilate 1 with TiCl₄ (1.5 equiv.) in CH₂Cl₂ at r.t., followed by addition of arylamines gave quinazolin-4-ones 2 bearing an aryl group at position 3 in moderate yields. Similarly 4-hydroxy-4-phenylquinazolines 6 bearing an aryl group at position 3 were prepared in good to moderate yields from 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)]benzophenones, 5, TiCl₄, and arylamines under the same conditions. The ¹H NMR spectra of 6 in CDCl₃ indicate that the compounds exist as an equilibrium mixture of 6 and the corresponding ring-opened compound, N-(2-benzoylaryl)-2-cyanoamidines 7. However, it is envisaged that compounds 6 exist as a single compound in a solid state in view of IR spectra showing no peak corresponding to a carbonyl absorption.

Full text of DOI:10.1055/s-2002-33520

LETTER
1423
Synthesis of 3-Aryl-3,4-dihydro-4-hydroxy-4-phenylquinazoline-2-
carbonitrile via 2-(Benzoyl)arylimino-4-chloro-5H-1,2,3-dithiazoles
S
ynthesis of 3-Ary
o
l-3,4-dihydro
n
-4-hydroxy-
g
4-phenylquin
-
azoline-
G
2-carbonitrile oo Chang, Kyongtae Kim*
School of chemistry and molecular engineering, Seoul National University, Seoul 151-742, Korea
Fax +82(2)8748858; E-mail: kkim@plaza.snu.ac.kr
Received 15 May 2002
hydroxyquinazolines.13 There are other methods which
lack general applicability. For example, 5-hydroxy-1-me-
thyl-5-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazo-
line was prepared by the reaction of 1-methyl-5-phenyl-
Abstract: Treatment of methyl N-(4-chloro-5H-1,2,3-dithiazole-5-
ylidene)anthranilate 1 with TiCl4 (1.5 equiv.) in CH2Cl2 at r.t., fol-
lowed by addition of arylamines gave quinazolin-4-ones 2 bearing
an aryl group at position 3 in moderate yields. Similarly 4-hydroxy-
4-phenylquinazolines 6 bearing an aryl group at position 3 were 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline with ben-
zoyl peroxide in CHCl3.8 Treatment of 1-methyl-
prepared in good to moderate yields from 2-[N-(4-chloro-5H-1,2,3-
carbamoylisatin with urea and thiourea14 was reported to
dithiazol-5-ylidene)]benzophenones, 5, TiCl4, and arylamines un-
der the same conditions. The 1H NMR spectra of 6 in CDCl3 indi-
give 3,4-dihydro-4-hydroxy-3-methyl-4-ureidocarbonyl-
cate that the compounds exist as an equilibrium mixture of 6 and the
2(1H)-quinazolinone and the corresponding sulfur ana-
corresponding ring-opened compound, N-(2-benzoylaryl)-2-cyano-
log, respectively. Dimerization of N-arylbenzimidoyl
chloride in the presence of ZnCl2, followed by addition of
HCl afforded 3-aryl-3,4-dihydro-4-hydroxy-2,4-diphe-
nylquinazolines.15
amidines 7. However, it is envisaged that compounds 6 exist as a
single compound in a solid state in view of IR spectra showing no
peak corresponding to a carbonyl absorption.
Key words: 1,2,3-dithiazoles, heterocycles, Lewis acid, quinazo-
lines, titanium tetrachloride
In connection with an ongoing project for exploring the
synthetic utility of 5-arylimino-4-chloro-5H-1,2,3-dithia-
zoles,16 we reported previously the synthesis of 3-alkyl-2-
cyanoquinazolin-4(3H)-ones 2a and 3-alkyl-2-cyano-
thieno[3,2-d]pyrimidin-4(3H)-ones 4 by the reactions of
methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthra-
nilate 1 and methyl 3-[N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)]-2-thiophenecarboxylate 3, respectively with
sterically less hindered primary alkylamines in THF at r.t.
(Scheme 1).17
Quinazolin-4-ones have received considerable attention
owing to their variety of their biological activities such as
antimalarial,1 5-HT2 antagonist,2 antitumor,3 and tranquil-
izing effects,4 etc., and numerous synthetic methods for
creating the compounds have been developed.5 In con-
trast, a limited number of synthetic methods have been re-
ported for 4-hydroxyquinazolines although some 4-
hydroxyquinazolines show activities such as inhibition of
influenza virus,6 stimulation of the growth of cobalamine
requiring cultures by incorporation into the nucleotide of
vitamin B12,7 and hypoglycemic activity in normal fasted
rats.8 A survey of the literature shows that cyclization of
2-amidinobenzophenones, prepared from 2-benzoylani-
lides and hydrazine hydrate has been most widely used for
the synthesis of 4-hydroxyquinazoline derivatives.9 In ad-
dition, reactions of 2-aminobenzophenone alkylimines
with acyl chlorides,10 reactions of 2-acylaminobenzophe-
nones with primary alkylamines,10 the same reactions
with hydrazine9b or ammonia,11 and reaction of 2-(1-
alkoxyethylideneamino)benzophenones with aminoace-
taldehydes dialkyl acetals using on acid catalyst12 have
been utilized for the synthesis of 3,4-dihydro-4-hydroxy-
4-phenylquinazolines. Grignard reagents are known to
add across the carbonyl groups of N-substituted quinazoli-
nones but are not generally a useful reaction because after
addition an –carbinolamines is formed that undergoes
ring opening. However, the reaction of quinazoline-2,4-
diones with arylmagnesium halides afforded 2,4-diaryl-4-
O
R
RNH2
N
CO2Me
THF, rt
N
CN
N
Cl
2a, R = alkyl
5
4
3
S1
O
N
2
S
2b, Ar = 4-MeC6H4
2c, Ar = 4- ClC6H4
2d, Ar = 4-MeOC6H4
Ar
1
ArNH2, N2
N
TiCl4, CH2Cl2, rt
N
N
CN
CO2Me
N
O
N
S
CO2Me
S
Cl
R
S
NHR
RNH2
+
N
S
THF, rt
N
CN
CN
S
3
4
Scheme 1
However, neither compounds 1 nor 3 reacted with pri-
mary arylamines even at reflux temperature. The inertness
of arylamines is understandable since compounds 1 and 3
were prepared by treatment of 4,5-dichloro-5H-1,2,3-
dithiazolium chloride (Appel’s salt) with arylamines in
CH2Cl2 at r.t.18
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1423,1426,ftx,en;Y07502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1424
Y.-G. Chang, K. Kim
LETTER
O
We intended to prepare quinazolinones having an aryl
group at position 3 using readily available 5-arylimino-
5H-1,2,3-dithiazole such as 1 as a starting material. Since
the inertness of arylamines toward 1 was envisaged to be
due to too weak nucleophilicity of arylamines, we tried to
activate the nucleophilic center, i.e., C-5 of the 1,2,3-
dithiazole ring by using a Lewis acid, which can interact
with the non-bonding electrons on the carbonyl oxygen
and the imino nitrogen atoms by forming a six-membered
cyclic form. The results are described herein.
Z
TiCl4, N2
ArNH2
Y
N
Cl
CH2Cl2, rt
X
N
S
S
5
5a, X = Y = H, Z = Ph
5b, X = Me, Y = H, Z = Ph
5c, X = Y = H, Z = Me
5d, X = Cl, Y = H, Z = Ph
O
Treatment of 1 with a slight excess of TiCl4 (1.5 equiv),
followed by addition of excess primary arylamines (4
equiv) in CH2Cl2 under a nitrogen atmosphere at r.t. gave
Z
Z
HO
Y
X
Ar
N
Y
N
NHAr
N
CN
3-aryl-2-cyanoquinazolin-4(3H)-ones 2b (Ar
=
4-
X
NC
MeC6H4) and 2c (Ar = 4-ClC6H4) in 74% and 52% yields,
respectively.19 Application of the same methodology to 4-
or 5-substituted 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)]benzophenones 5 (Z = Ph), prepared from 4- or
5-substituted 2-aminobenzophenones and Appel’s salt,
gave white solids, which were recrystallized from a
mixture of CH2Cl2 and n-hexane to give crystals 6
whose IR spectra did not exhibit the peaks corresponding
to a carbonyl group.20 Compounds 6 exist exclusively
in this tautomeric form in the solid state. However, the
1H NMR spectra of 6a–h taken in CDCl3 as a solvent
indicate that the compounds exist as an equilibrium
mixture of 3-aryl-3,4-dihydro-4-hydroxy-4-phenyl-
quinazoline-2-carbonitriles 6 (Z = Ph) and the corre-
sponding ring-opened compound 7, N-(2-benzoylaryl)-2-
cyanoamidines (Scheme 2).
6
7
Scheme 2
It was possible to determine which compound exists pre-
dominantly in CDCl3 based on the absorptions corre-
sponding to the OH protons of 6 and the NH protons of 7
exhibited at 4.78–6.79 and 11.23–11.47 ppm, respective-
ly. In addition, the ratio of two compounds 6 and 7 could
be determined based on the intensities of the proton sig-
nals of the group designated. Reaction time, yields and mp
of the crystals and the ratios of 6 to 7 are summarized in
the Table.
The Table shows that when the aryl group at position 3 has
a substituent at the para position (entries 1, 2, 5, 7, and 8),
6 is predominantly formed except in the case of 6f, which
has a strong electron-withdrawing group, i.e., NO2 (entry
Table Reaction Time, Yields, and Melting Points of Compounds 6, and the Ratios of 6 to 7
Entry
X
Y
Z
Ar
Time (h) Yielda Mpb (dec.) (oC) Ratios in CDCl3 1H NMR (ppm)c
Basis
(6 : 7)
6
7
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-ClC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-O2NC6H4
4-MeC6H4
0.5
2
82
63
70
83
71
74
58
179–182
166–168
176–178
176–178
176–178
138–140
191–193
a
b
c
d
e
f
16.5:1.0
1.6:1.0
1.0:2.6
1.0:1.3
1.3:1.0
1.0:3.7
4.1:1.0
3.73 (s)
7.73 (d)
2.20 (s)
2.23 (s)
2.23 (s)
8.27 (d)
2.24 (s)
3.84 (s)
7.67 (d)
2.45 (s)
2.43 (s)
2.44 (s)
8.07 (d)
OCH3
ArH
CH3
CH3
CH3
ArH
H
Me
Me
Me
H
13
4
4
20
d
Me
0.5
g
2.39 (s)
2.45 (s)
CH3
8
Me
H
Ph
4-MeOC6H4
1
71
189–190
h
14.4:1.0 2.21 (s)
2.46 (s)
CH3
a Isolated yields.
b Recrystallized from a mixture of CH2Cl2 and n-hexane.
c The spectra (300 MHz) were taken in CDCl3 except for 6b and 6e (500 MHz) because of sparing solubilities of 6b and 6e in CDCl3, s: singlet;
d: doublet; m: multiplet.
d Two CH3 groups of 6g have identical chemical shift. In the case of 7g, it was difficult to assign the chemical shifts of each methyl group
because of their too close values.
Synlett 2002, No. 9, 1423–1426 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Aryl-3,4-dihydro-4-hydroxy-4-phenylquinazoline-2-carbonitrile
1425
6). In contrast, it appears that compound 7 is predominant- underwent slow oxidation in the air to give 2b19 in 36%
ly formed when the aryl group at position 3 has an ortho yield. On the other hand, the reaction with p-anisidine un-
substituent (entry 3). The same trend is observed in the der similar conditions for 2 h, which is a shorter time than
case of an m-substituted aryl group (entry 4). The predom- that for the reaction with p-toluidine gave 2d in 58%
inant formation of 7c over 6c may be attributable to the yield. No 9b analogous to 9a was detected. The results
steric effect by the presence of an ortho substituent in the suggest that compound 6 (X = Y = H, Z = Me) is formed
Ar group, which hinders the intramolecular cyclization of as an intermediate, which eliminates rapidly a water mol-
7 to give 6. The slightly greater ratios of 7d to 6d (1.3:1.0, ecule to give 9. The methylene group of compound 9 is
entry 4) might indicate the involvement of some kind of susceptible to air oxidation to give 2. The result indicates
steric and electronic effects associated with meta substit- that 9 is isolable depending on the substituent at position
uent. The steric effects are expected to be completely free 3. Analogous air oxidation of the methylene group has
for a para substituted aryl group so that 6e is predomi- been reported.21
nantly formed (entry 5).
TiCl4, N2
ArNH2
It is interesting to note that the ratios of 6 to 7 were de-
6 (X = Y = H, Z= Me)
5c
CH2Cl2, rt
creased somewhat by the presence of a methyl group (X =
Me) on the arylimino moiety despite Ar group being the
same. For instance, the ratios of 6a to 7a which is 16.5:1.0
(entry 1) changed into 14.4:1.0 of 6h to 7h (entry 8) when
Ar = 4-MeOC6H4. The same trend was observed in the
case of Ar = 4-ClC6H4 (entries 2 and 5) despite triviality.
This may be attributable to the high electron density on
the carbonyl carbon due to the electron-donating effect of
a methyl group so that nucleophilic attack by an arylami-
no group of 7 may be less favorable.
Me
CH2
N
Ar = 4-MeC6H4
- H2O
O2
2b
N
9a
CN
CN
OMe
CH2
N
O2
Ar = 4-MeOC6H4
- H2O
2d
N
The mechanism for the formation of 6 may be rationalized
based on the formation of the complex 8 in which TiCl4
interacts with the nonbonding electrons on the carbonyl
oxygen and the imino nitrogen at C-5 of 1,2,3-dithiazole
moiety so that the imino carbon becomes a good nucleo-
philic center to react with arylamines, yielding eventually
N-(2-benzoylaryl)-2-cyanoamidines 7. Intramolecular
cyclization of 7 in the presence of TiCl4 affords 6
(Scheme 3).
9b
Scheme 4
In conclusion, a synthetic method for quinazolin-4-ones 2
and 4-hydroxy-4-phenylquinazolines 6 bearing an aryl
group at position 3 has been developed by treatment of
methyl
N-(4-chloro-5H-1,2,3-dithiazole-5-ylidene)an-
thranilate 1 and 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)]benzo- or acetophenones 5, respectively, with
TiCl4 in CH2Cl2 under a nitrogen atmosphere at r.t., fol-
lowed by addition of arylamines.
Cl
TiCl4
N
δ−
O
N
δ+
S
S
ArNH2
TiCl4
5
Acknowledgement
(Z = Ph)
X
We are grateful to the Brain Korea 21 program for financial support
of this work.
Y
8
+
H2NAr
Cl
References
NHAr
CN
Cl4Ti
δ−
O
TiCl4
N
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O
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S
δ+
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- S2
6
X
X
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Y
7
Scheme 3
Similar treatment of 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)]acetophenone 5c with p-toluidine (3.5 equiv) in
the presence of TiCl4 (1.1 equiv) under the foregoing con-
ditions for 11 h afforded, however, 4-methylenequinazo-
line 9a19 in 53% yield (Scheme 4). Compound 9a
Synlett 2002, No. 9, 1423–1426 ISSN 0936-5214 © Thieme Stuttgart · New York

1426
Y.-G. Chang, K. Kim
LETTER
mL) was added TiCl4 (0.55–0.64 mmol) by using a
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hypodermic syringe under nitrogen atmosphere.
Subsequently arylamines were added. When p-toluidine was
added, the reaction mixture showed a yellow spot (Rf = 0.7,
EtOAc–n-hexane = 1:3), assignable to be 3,4-dihydro-4-
methylene-3-(4-tolyl)quinazoline-2-carbonitrile (9a). IR
(neat): 2240, 1635, 1603, 1581, 1555, 1504, 1469, 1344,
1322, 1226, 1206, 1110, 816, 762 cm–1. 1H NMR (CDCl3,
300 MHz): = 2.47 (s, 3 H, CH3), 3.61 (d, 1 H, J = 2.5 Hz,
=CH), 4.65 (d, 1 H, J = 2.5 Hz, =CH), 7.26–7.32 (m, 3 H,
ArH), 7.36–7.52 (m, 4 H, ArH), 7.53 (d, 1 H, J = 7.8 Hz,
ArH). 13C NMR (CDCl3, 75 MHz): = 21.8, 85.0, 112.1,
123.4, 123.7, 128.2, 128.9, 129.4, 131.1, 131.9, 133.1,
135.9, 140.8, 141.0, 142.8. Anal. Calcd for C17H13N3: C,
78.74; H, 5.05; N, 16.20. Found: C, 78.62; H, 5.09; N, 16.35.
Compound 9a gradually faded out during chromatography
to give a new spot (Rf = 0.5, EtOAc–n-hexane = 1: 3),
corresponding to 2-cyano-3-(4-tolyl)quinazolin-4(3H)-one
(2b), which was eluted with a mixture of EtOAc and n-
hexane (1:5) as an eluent to give 2b, which was
recrystallized from EtOH. Mp 175-176 °C. IR (KBr): 1677,
1581, 1501, 1456, 1328, 1312, 1274, 1104, 1082, 810, 774
cm–1. 1H NMR (CDCl3, 300 MHz): = 2.49 (s, 3 H, CH3),
7.31 (d, 2 H, J = 8.3 Hz, ArH), 7.43 (d, 2 H, J = 8.3 Hz, ArH),
7.67–7.73 (m, 1 H, ArH), 7.82–7.92 (m, 2 H, ArH), 8.38 (d,
1 H, J = 7.6 Hz, ArH). 13C NMR (CDCl3, 75 MHz): = 21.9,
111.6, 123.4, 127.9, 128.3, 129.1, 130.7, 131.2, 132.1,
132.9, 135.8, 141.5, 146.9, 160.6. Anal. Calcd for
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C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.50; H,
4.22; N, 16.21.
(20) General Procedure for the Synthesis of 3-Aryl-3,4-
dihydro-4-hydroxy-4-phenylquinazoline-4-carbonitriles
6. To a solution of 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)]benzophenone (5a) (0.29–0.41 mmol) in CH2Cl2
(15 mL) was added TiCl4 (0.46–0.91 mmol) by using a
hypodermic syringe under nitrogen atmosphere, followed by
addition of arylamines (0.61–1.03 mmol). The mixture was
worked up as described in the general procedure for the
synthesis of 2. Elution with a mixture of n-hexane and
EtOAc (3:1) gave 6a,b and 6f. 4-Hydroxy-3-(4-
methoxyphenyl)-4-phenylquinazoline-2-carbonitrile (6a),
which was recrystallized from a mixture of CH2Cl2 and n-
hexane. Mp 179–182 °C (dec.). IR (KBr): 3168, 2224, 1597,
1578, 1454, 1467, 1446, 1354, 1290, 1248, 1168, 1030, 995,
819, 765, 733 cm–1. 1H NMR (CDCl3, 300 MHz): = 3.73
(s, 3 H, OCH3 of major), 3.84 (s, 3 H, OCH3 of minor), 5.99
(s, br, 1 H, OH of major), 6.60–6.66 (m, 2 H, ArH of major),
6.80–6.82 (m, 1 H ArH of major), 6.89 (d, 1 H, J = 7.4 Hz,
ArH of major), 7.12–7.26 (m, 6 H, ArH of major), 7.39–7.53
(m, 2 H, ArH of major), 7.74–7.76 (m, 1 H, ArH of major).
13C NMR (CDCl3, 75 MHz): = 55.3, 87.6, 112.0, 113.7,
124.7, 127.6, 128.1, 128.1, 128.2, 128.3, 129.7, 129.8,
131.1, 133.1, 134.3, 139.0, 141.8, 159.7. The aromatic
proton signals of minor compound are envisaged to overlap
with those of major. Anal. Calcd for C22H17N3O2: C, 74.35;
H, 4.82; N, 11.82. Found: C, 74.49; H, 4.80; N, 11.71.
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1985, 118, 1632.
(19) General Procedure for the Synthesis of 3-Aryl-2-
cyanoquinazolin-4(3H)-ones 2. (A) To a solution of methyl
N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilate (1)
(0.42–0.94 mmol) in CH2Cl2 (20 mL) was added TiCl4
(0.82–1.37 mmol) by using a hypodermic syringe under
nitrogen atmosphere. The solution turned immediately dark
red. Arylamines (1.86–3.78 mmol) were added to the dark
red solution, which was stirred until no spot corresponding
to 1 was observed on TLC (silica gel, Rf = 0.6, EtOAc–
hexane = 1:3). Water (30 mL) was added and the mixture
was extracted with CH2Cl2 (25 mL 3). The combined
extracts were dried over MgSO4, followed by evaporation of
the solvent. The residue was chromatographed on a silica gel
(70–230 mesh, 2 10 cm). Elution with n-hexane gave
sulfur. Subsequent elution with a mixture of n-hexane and
EtOAc (5:1) gave unknown mixtures and 2. (B) To a
solution of 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)]acetophenone (5c) (0.36–0.59 mmol) in CH2Cl2 (15
Synlett 2002, No. 9, 1423–1426 ISSN 0936-5214 © Thieme Stuttgart · New York