One-step conversion of 2-Amino- N ′-arylbenzamidines into 3-aryl-4-imino-3,4-dihydroquinazoline-2-carbonitriles using 4,5-dichloro-1,2,3- dithiazolium chloride

Article abstract of DOI:10.1021/jo401648t

2-Amino-N′-arylbenzamidines react with 4,5-dichloro-1,2,3- dithiazolium chloride (Appel salt) in the presence of Huenig's base (2 equiv) to give in one step 3-aryl-4-imino-3,4-dihydroquinazoline-2-carbonitriles in 53-81% yields. Nine examples are presented along with the single-crystal X-ray structure of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile. Furthermore, the behavior of the latter toward both acid and base hydrolysis is investigated. All new compounds are fully characterized, and a mechanistic rationale for the formation of the iminoquinazolines is provided.

Full text of DOI:10.1021/jo401648t

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Article
The one-step conversion of 2-amino-N'-arylbenzamidines
into 3-aryl-4-imino-3,4-dihydroquinazoline-2-carbonitriles
using 4,5-dichloro-1,2,3-dithiazolium chloride
Styliana I Mirallai, Manolis J. Manos, and Panayiotis A. Koutentis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401648t • Publication Date (Web): 10 Sep 2013
Downloaded from http://pubs.acs.org on September 11, 2013
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The one-step conversion of 2-amino-N'-arylbenzamidines into 3-aryl-4-imino-
3,4-dihydroquinazoline-2-carbonitriles using 4,5-dichloro-1,2,3-dithiazolium
chloride
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Styliana I. Mirallai, Manolis J. Manos and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia,
Cyprus, koutenti@ucy.ac.cy
2-Amino-N'-arylbenzamidines react with 4,5-dichloro-1,2,3-dithiazolium chloride
(Appel salt) in the presence of Hünig’s base (2 equiv) to give in one-step 3-aryl-4-
imino-3,4-dihydroquinazoline-2-carbonitriles in 53-81% yields. Nine examples are
presented along with the single crystal X-ray structure of 4-imino-3-phenyl-3,4-
dihydroquinazoline-2-carbonitrile. Furthermore, the behavior of the latter towards
both acid and base hydrolysis is investigated. All new compounds are fully
characterised and mechanistic rationale for the formation of the iminoquinazolines is
provided.
1.
Introduction
Quinazoline (benzo[a]pyrimidine) is the parent heterocycle of an important group of
compounds that find application as components in pharmaceuticals, agrochemicals,
dyes, sensors, polymers, and in organic electronics. As such, there are extensive
reviews on the synthesis, chemistry and properties of quinazolines.1 The quinazoline
skeleton is found in many natural products.2
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An interesting quinazoline subclass is quinazolin-4(3H)-imine, the structure of which
is featured in biologically active compounds that behave as cholinesterase inhibitors,3
cMET kinase inhibitors,4 modulators of chemokine CCR3 activity,5 or exhibit
antiproliferative6 or cardiotonic activities.7
Recent methods for the preparation of quinazolin-4(3H)-imines include the
palladium-catalyzed three component reaction of carbodiimide, isocyanide and a
nucleophile,8 the three-step synthesis of 3-aryl-2-halo-4(3H)-quinazoliniminium
halides from readily accessible heteroenyne-allenes,9 the reaction of anthranilonitrile
with triethylorthoformate,10 the single step synthesis from simple carbonyl
compounds, primary amines or amino acid methyl esters and 2-azido-5-nitro-
benzonitrile,11 and a one-pot cyclization of 2-(dichloroisocyanido)benzonitrile with α-
aminoketones.12
Recently, we reinvestigated the reaction of 2-amino-N'-arylbenzamidines 113 with
tetracyanoethylene (TCNE)14 which affords the 4-anilinoquinazoline-2-carbonitriles 2
in moderate to good yields,15 (Scheme 1) and considered replacing expensive TCNE
with 4,5-dichloro-1,2,3-dithiazolium chloride 3 (Appel salt) that is easily prepared
from chloroacetonitrile and disulfur dichloride.16 The use of Appel salt 3 for the two
step introduction of C-C≡N via the synthesis of neutral 1,2,3-dithiazoles (step 1) and
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their subsequent ring transformation to cyanoheteroarenes (step 2) has been well
demonstrated,17 and excellent reviews on the chemistry of 1,2,3-dithiazoles have
appeared.18 While the reaction of 2-cyano-(4-chloro-5H-1,2,3-dithiazolylidenamino)-
benzenes with selected alkoxides gave 4-alkoxyquinazoline-2-carbonitriles,19 there is
only one report for an analogous two step preparation of 4-alkylaminopyrido[2,3-
d]pyrimidine-2-carbonitriles from 2-aminopyridine-3-carbonitriles.17i Furthermore, a
similar reaction between Appel salt 3 and 2-(1H-benzo[d]imidazol-2-yl)aniline 4 gave
directly cyanobenzimidazoquinazoline 5 in 50% yield20 (Scheme 1).
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Scheme 1. Preparation of 4-anilinoquinazolines 2 and the cyanobenzimidazo-
quinazoline 5
Surprisingly, the reaction between 2-amino-N'-arylbenzamidines 1 and Appel salt 3
did not result in the expected 4-anilinoquinazoline-2-carbonitrile 2 but rather afforded
the isomeric 3-aryl-4-imino-3,4-dihydroquinazoline-2-carbonitrile 6 (Scheme 2). To
the best of our knowledge this represents the first synthesis of a 2-cyano substituted
quinazolin-4(3H)-imine, which is worthy of note since nitriles can readily be
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subsequently modified into a wide variety of other functionalities.21 The results of our
discovery are presented herein.
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2.
Results and discussion
The reaction between anilines and 4,5-dichloro-1,2,3-dithiazolium chloride 3 typically
produce the neutral (4-chloro-5H-1,2,3-dithiazolylideneamino)benzenes.16a,22
However, in a few cases where an ortho nucleophilic side chain is present on the
arylamine, the product isolated arises as a result of an in situ ring transformation
affording the more stable heteroarene.20,23
Thus, treating 4,5-dichloro-1,2,3-dithiazolium chloride 3 (Appel salt) with 2-amino-
N'-phenylbenzamidine 1a proceeded to give 4-imino-3-phenyl-3,4-dihydroquinazo-
line-2-carbonitrile (6a) and not the expected 4-anilinoquinazoline-2-carbonitrile (2)
(Scheme 2) directly as a one-pot process. Analysis of the reaction mixture by TLC
failed to detect the presence of any intermediate.
Scheme 2. Preparation of 4-iminoquinazoline-2-carbonitrile 6a
4-Imino-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile (6a) was isolated as colorless
needles, mp 141-142 oC (from cyclohexane) [mp (DSC) onset 143.9 oC, peak max.
146.2 oC] which differed considerably from that of 4-anilinoquinazoline-2-
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carbonitrile (2) mp (DSC) onset 211.7 oC, peak max 212.5 C (from CHCl3).
Interestingly, our melting point for the anilinoquinazoline 2 was also significantly
different from that reported in the literature (lit.,15 mp 84-85 oC), despite matching
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closely with the reported H, 13C NMR and IR spectra. Furthermore, mass
spectrometry of the iminoquinazoline 6a gave a parent ion at m/z (EI) 246 Da (M+,
34%), which in combination with elemental analysis gave a molecular formula of
C15H10N4, supporting a compound that was isomeric with the anilinoquinazoline 2.
Further observed differences between the two isomers could be seen in the IR and
NMR spectra: 4-anilinoquinazoline-2-carbonitrile (2) gave a nitrile stretching
frequency of v(C≡N) 2247 cm-1 while 4-imino-3-phenyl-3,4-dihydroquinazoline-2-
carbonitrile (6a) gave a nitrile stretching frequency of v(C≡N) 2239 cm-1. The 13C
NMR spectrum showed 13 separate signals for both isomers, 7 of which were CH (by
DEPT-135 NMR). However, the most down field and up field signals for the
iminoquinazoline 6a appeared at 153.3 and 111.3 ppm, respectively while those for
anilinoquinazoline 2 appeared at 157.5 and 115.1 ppm. Both compounds also had
different Rf values of silica gel TLC plates Rf 6a (DCM/t-BuOMe, 9:1) 0.48 vs Rf 2
(DCM/t-BuOMe, 9:1) 0.52 indicating the iminoquinazoline 6a was the more polar of
the two. Any ambiguity in the structural assignment was addressed by solving the
single crystal X-ray structure for 4-imino-3-phenyl-3,4-dihydroquinazoline-2-
carbonitrile (6a) (Figure S1).
Optimisation of iminoquinazoline formation
By screening the type and equivalents of the organic base used the reaction of Appel
salt 3 and 2-amino-N'-phenylbenzamidine (1a) was partially optimised. Typically,
4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol) was treated with 2-
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amino-N'-phenylbenzamidine (1a) (51 mg, 0.24 mmol) in DCM (4 mL) at ca. 20 C
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6
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for 4 h followed by the addition of base at ca. 20 C and an additional 2 h stirring,
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protected from moisture with CaCl2 drying tube. When pyridine (2-4 equiv) was used
as base only traces of the iminoquinazoline 6a were obtained, while more basic
trialkylamines such as Et3N (2-4 equiv) or Hünig’s base (i-Pr2NEt) (2-4 equiv) gave
55-61 and 72-75% yields, respectively. Interestingly, increasing the base strength
further by using the bicyclic amidine DBU (2-3 equiv) led to low product yields (32-
36%). With this data in mind we reacted 4,5-dichloro-1,2,3-dithiazolium chloride (3)
with various substituted 2-amino-N'-arylbenzamidines 1b-i in the presence of Hünig’s
base (2 equiv) and obtained the iminoquinazolines 6b-i, respectively (Table 1).
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Table 1 Reaction of 4,5-dichloro-1,2,3-dithiazolium chloride 3 (50 mg,
0.24 mmol) with 2-amino-N'-arylbenzamidines 1 (0.24 mmol) in DCM (4
mL) at ca. 20 oC for 4 h followed by the addition of i-Pr2NEt (2 equiv) at
ca. 20 oC and an additional 2 h stirring, protected from moisture with a
CaCl2 drying tube.
Ar
N
NH
Cl
+
Cl
R
R
Ar
NH2
NH2
N
+
S
N
N
S
CN
_
Cl
1a-i
3
6a-i
6a-i
entry
Ar
R
Yields
(%)
6a
(75)
6b (81)
6c (74)
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3
4
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6
7
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9
Ph
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3,4-Cl2C6H3
Ph
H
H
H
H
H
H
H
6d
(57)
6e (65)
6f (63)
6g
(65)
4,5-(MeO)2
4,5-(MeO)2
6h (53)
6i (61)
4-MeOC6H4
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As is seen from Table 1, reaction yields range between 53 and 81%. For the
unsubstituted benzamidines (R = H) the yields were affected by the nature of the
N-aryl group; neutral or electron rich Ar groups (Ar = Ph, 4-Tol, and 4-MeOC6H4,
entries 1-3) gave higher yields (74-81%), however, where the Ar group was less
electron rich (Ar = 4-FC6H4, 4-ClC6H4, 4-BrC6H4, and 3,4-Cl2C6H4, entries 4-7) the
yields dropped (57-65%). The reaction also tolerated electron rich dimethoxy
substituted benzamidines which gave the expected iminoquinazolines 6h and 6i in
moderate yields, 53 and 61%, respectively (entries 8 and 9).
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Some chemistry of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile (6a)
On close inspection, the two quinazoline isomers 2 and 6a can in theory be isomerised
into each other via a Dimroth rearrangement.24 Furthermore, treatment of 3-alkyl- or
3-benzyl-4-imino-3,4-dihydroquinazolines with NaOH was known to afford products
of the Dimroth rearrangement: the 4-alkylamino- and 4-benzylaminoquinazoline
isomers.11 The isomerisation of the iminoquinazoline 6a into the 4-anilinoquinazoline
2 via acid of base catalysis was therefore investigated.
Initially, solutions of the iminoquinazoline 6a in either dry toluene, toluene in the
o
presence of Hünig’s base, or in neat Hünig’s base heated to ca. 110 C indicated that
the iminoquinazoline 6a was stable to these conditions. However, reaction of 4-imino-
3-phenyl-3,4-dihydroquinazoline-2-carbonitrile (6a) in the presence of NaOH (1
o
equiv) in MeOH at ca. 67 C for 3 h, gave 2-methoxy-3-phenylquinazolin-4(3H)-
imine (7) in quantitative yield (99%). The use of milder bases such as, K2CO3 and
Na2CO3 led to lower yields (70%), while the use of amine bases such as, Hünig’s
base, pyridine or DMAP in MeOH led to complex reaction mixtures. Interestingly,
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further treatment of 2-methoxy-3-phenylquinazolin-4(3H)-imine (7) with HCl (10%)
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at ca. 67 C for 30 min led to the quantitative formation of 4-imino-3-phenyl-3,4-
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dihydroquinazolin-2(1H)-one (8)25 (99%). Furthermore, the quantitative conversion of
the iminoquinazoline 6a into 4-imino-3-phenyl-3,4-dihydroquinazolin-2(1H)-one (8)
could also be achieved as a one pot process. Finally, hydrolysis of the
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iminoquinazolinone 8 with 1N NaOH at ca. 20 C for 7 d gave the known
3-phenylquinazoline-2,4(1H,3H)-dione (9)26 in 90% yield (Scheme 3).
Interestingly, similar treatment of 4-anilinoquinazoline-2-carbonitrile (2) with NaOH
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(1 equiv) in MeOH at ca. 67 C for 4 d led to substitution of the nitrile to afford the
known 4-anilino-2-methoxyquinazoline (10)27 in good yield (71%) (Scheme 4).
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Scheme 4. Preparation of 4-anilino-2-methoxyquinazoline (10)
In contrast, direct treatment of the iminoquinazoline 6a with either TFA (1 equiv) in
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DMSO, DMF or DMA at ca. 20 C or at ca. 100 C or in the presence of HCl (1
equiv) in THF/water (1:1) also failed to give the Dimroth rearranged product but did
afford the known 4-oxo-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile (11)28 in high
yield. When 2 or more equiv of HCl were used, 3-phenylquinazoline-2,4(1H,3H)-
dione (9) was obtained in 92-99% yields. Interestingly, heating the dihydroquinazolin-
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one 11 in the presence of HCl (1 equiv) in THF/water (1:1) at ca. 65 C gave no
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reaction, but treatment with HCl (2 equiv) after 3 d at ca. 65 C afforded
3-phenylquinazoline-2,4(1H,3H)-dione (9)26 in 96% yield (Scheme 5).
In contrast to the above, similar treatment of the isomer anilinoquinazoline 2 with HCl
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(1 equiv) in THF/water (1:1) at ca. 65 C for 24 h gave no hydration, hydrolysis or
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isomerization and the compound was recovered unchanged. Nevertheless, in the
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presence of neat conc. HCl at ca. 65 C for 16 h gave 4-anilinoquinazoline-2-
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carboxamide (12) in 69% yield (Scheme 6). These studies provided support for the
fact that the iminoquinazoline 6a and the anilinoquinazoline 2 were not
interconvertable under acid conditions.
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Scheme 6. Preparation of 4-anilinoquinazoline-2-carboxamide (12)
Mechanistic rationale for the formation of the iminoquinazolines 6
There are two possible routes to the iminoquinazolines 6: the Appel salt 3 condenses
with 2-amino-N'-arylbenzamidines at the primary aniline amine to give adduct 13 or,
alternatively, condensation at the amidino secondary amine provided adduct 14. These
can then undergo intramolecular cyclizations via a common spirocyclic intermediate
15 which undergoes cleavage affording the observed iminoquinazoline 6 (Scheme 7).
Scheme 7. Mechanistic rationale for the formation of the quinazolinimine 6a
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Unfortunately, we were unable to isolate any intermediates that could provide support
for either proposal. However, we note that amidines typically undergo alkylation to
give the more basic amine which is typically the secondary amine29 and this may
explain why formation of the 4-anilinoquinazoline-2-carbonitrile (2) was not observed.
Studies to further understand this transformation are presently underway.
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3
Conclusions
Treatment of 4,5-dichloro-1,2,3-dithiazolium chloride 3 with 2-amino-N'-arylbenz-
amidines 1a-i directly affords 3-aryl-4-imino-3,4-dihydro-quinazoline-2-carbonitriles
6a-i in moderate to good yields (53-81%). The reaction provides a convenient route to
C-2 cyano substituted quinazolin-4(3H)-imines.
4.
Experimental
4.1.
General methods and materials
Reactions were protected from atmospheric moisture by CaCl2 drying tubes. All
volatiles were removed under reduced pressure. All reaction mixtures and column
eluents were monitored by TLC using commercial glass backed thin layer
chromatography (TLC) plates (Kieselgel 60 F254). The plates were observed under UV
light at 254 and 365 nm. The technique of dry flash chromatography30 was used
throughout for all non-TLC scale chromatographic separations using Silica Gel 60
(less than 0.063 mm). Melting points were determined using a hotstage microscope
apparatus. Solvents used for recrystallization are indicated after the melting point. UV
spectra were obtained using a UV/vis spectrophotometer and inflections are identified
by the abbreviation “inf”. IR spectra were recorded on a FTIR spectrometer with a Ge
ATR accessory and strong, medium and weak peaks are represented by s, m and w
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13
respectively. H and C NMR spectra were recorded either on a 300 MHz machine
(at 300 and 75 MHz, respectively) or on a 500 MHz machine (at 500 and 125 MHz,
respectively). 13C NMR multiplicity assignments were determined using APT of
DEPT NMR experiments. Deuterated solvents were used for homonuclear lock and
the signals are referenced to the deuterated solvent peaks. Low resolution (EI) mass
spectra were recorded on a GCMS with direct inlet probe. 4,5-Dichloro-1,2,3-
dithiazolium chloride (3),16 2-amino-N'-arylbenzamidines 1a-g,13 and TCNE14b were
prepared according to the literature.
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4.2.
Preparation of 2-amino-N'-arylbenzamidines 1h and 1i.
4.2.1. (Z)-2-Amino-4,5-dimethoxy-N'-phenylbenzamidine (1h). (Typical procedure)
To stirred 4,5-dimethoxyanthranilonitrile (957 mg, 5.36 mmol) at ca. 20 oC was added
portion-wise powdered anhydrous AlCl3 (706 mg, 5.36 mmol). The reaction mixture
o
was then heated (ca. 100 C) until a homogenous melt formed. To this was added
aniline (489 µL, 5.36 mmol) and the mixture was heated for 4 h and then allowed to
o
cool to ca. 20 C. The resultant solid mass was then crushed and slurried in 12.5%
NaOH (40 mL). The resulting mixture was extracted (DCM), washed (H2O) and dried
(Na2SO4). Removal of the volatiles followed by chromatography (t-BuOMe/EtOH,
9:1) of the residue gave the title compound 1h (178 mg, 12%) as colorless needles,
mp 172-173 oC; (from cyclohexane/EtOH); (found: C, 66.51; H, 6.26; N, 15.40.
C15H17N3O2 requires C, 66.40; H, 6.32; N, 15.49%); Rf 0.40 (t-BuOMe/EtOH, 90:10);
λmax(DCM)/nm 234 (log ε 4.56), 267 (4.30), 337 (4.04); νmax/cm-1 3435w and 3343w
(NH2), 3279w, 3117w, 3009w, 2961w, 2934w, 2911w, 2905w, 2858w, 2830w (Ar
CH), 1632m, 1587w, 1562m, 1514m, 1483m, 1458w, 1446w, 1412w, 1391m, 1285w,
1265w, 1223s, 1174w, 1113w, 1069w, 1024w, 1001w, 964w, 912w, 876w, 843m,
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777w; δH(300 MHz; CDCl3) 7.36 (2H, dd, J 7.7, 7.7), 7.07 (1H, dd, J 7.5, 7.5), 7.00-
6.95 (3H, m), 6.26 (1H, s), 5.81 (2H, br s), 4.70 (2H, br s), 3.87 (3H, s), 3.83 (3H, s);
δC(75 MHz; CDCl3) 155.7 (s), 152.1 (s), 148.9 (s), 143.6 (s), 140.7 (s), 129.5 (d),
122.9 (d), 121.9 (d), 111.6 (d), 107.9 (s), 100.7 (d), 57.0 (q), 55.7 (q); m/z (EI) 271
(M+, 100%), 254 (37), 239 (50), 211 (6), 193 (7), 179 (41), 163 (36), 147 (6), 135
(14), 120 (7), 93 (30), 77 (33), 65 (9), 51 (11).
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4.2.2. (Z)-2-Amino-4,5-dimethoxy-N'-(4-methoxyphenyl)benzamidine (1i). Similar
treatment of 4,5-dimethoxyanthranilonitrile (723 mg, 4.06 mmol), powdered
anhydrous AlCl3 (535 mg, 4.06 mmol) and p-anisidine (500 mg, 4.06 mmol) at ca. 20
oC gave the title compound 1i (151 mg, 12%) as colorless plates, mp 174-175 oC;
(from EtOH); (found: C, 63.82; H, 6.35; N, 13.86. C16H19N3O3 requires C, 63.77; H,
6.36; N, 13.94%); Rf 0.47 (t-BuOMe/EtOH, 60:40); λmax(DCM)/nm 234 (log ε 4.52),
266 (4.21), 336 (3.99); νmax/cm-1 3458w, 3433w and 3348w (NH2), 3308w, 3011w
(Ar CH), 2994w, 2957w, 2936w, 2837w, 1635s, 1603m, 1587m, 1558m, 1518m,
1501s, 1466m, 1447m, 1414w, 1385m, 1346w, 1271m, 1215s, 1184m, 1171m,
1103m, 1067w, 1038w, 1018m, 999m, 964w, 854m, 835m, 814w, 777m; δH(300
MHz; CDCl3) 6.95 (1H, s), 6.92 (4H, m), 6.26 (1H, s), 5.82 (2H, br s), 4.74 (2H, br s),
3.86 (3H, s), 3.83 (3H, s), 3.81 (3H, s); δC(75 MHz; CDCl3) 156.2 (s), 155.6 (s), 152.0
(s), 143.5 (s), 141.8 (s), 140.7 (s), 122.8 (d), 114.8 (d), 111.6 (d), 108.1 (s), 100.7 (d),
57.0 (q), 55.7 (q), 55.5 (q); m/z (EI) 301 (M+, 83%), 284 (19), 269 (18), 241 (3), 226
(3), 179 (38), 163 (13), 148 (5), 135 (10), 123 (100), 108 (63), 92 (7), 80 (9), 77 (6),
64 (4), 52 (5).
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4.3. Preparation of 3-aryl-3,4-dihydro-4-iminoquinazoline-2-carbonitriles 6a-i.
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4.3.1. 4-Imino-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile
(6a).
(Typical
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procedure): To a stirred solution of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50
mg, 0.24 mmol) in DCM (4 mL) at ca. 20 oC was added 2-amino-N'-phenyl-
benzamidine (1a) (51 mg, 0.24 mmol). After 4 h, to the reaction mixture was added
Hünig’s base (83.5 µL, 0.48 mmol) and left to stir at ca. 20 oC for an additional 2 h.
The reaction mixture was then adsorbed onto silica and chromatography (n-hexane)
gave traces of S8, followed (n-hexane/DCM, 80:20) by 4-chloro-5H-1,2,3-dithiazol-5-
one (8 mg, 20%). Further elution (DCM/t-BuOMe, 90:10) gave the title compound 6a
(43 mg, 73%) as colorless needles, mp 141-142 oC (from cyclohexane), mp (DSC)
onset 143.9 oC, peak max. 146.2 oC (from cyclohexane); (found: C, 73.02; H, 3.95; N,
22.67. C15H10N4 requires C, 73.16; H, 4.09; N, 22.75%); Rf 0.48 (DCM/t-BuOMe,
90:10); λmax(DCM)/nm 237 inf (log ε 4.25), 245 inf (4.18), 255 (4.13), 265 (4.19), 274
(4.11), 298 inf (3.77), 311 (3.94), 324 (3.99), 340 inf (3.85); νmax/cm-1 3341w, 3308w
(NH), 3071w (Ar CH), 2239w (C≡N), 1643m, 1605w, 1574w, 1560m, 1491w,
1472w, 1462m, 1348m, 1302m, 1283m, 1227w, 1217w, 1167m, 1138m, 1030w,
1007w, 997w, 876w, 827w, 800w, 760s; δH(300 MHz; CDCl3) 8.25 (1H, d, J 6.9),
7.69–7.63 (5H, m), 7.54 (1H, ddd, J 7.4, 7.4, 1.8), 7.44-7.40 (2H, m), 6.71 (1H, br s);
δC(125 MHz; CDCl3) 153.3 (s), 143.2 (s), 135.0 (s), 133.4 (d), 131.3 (d), 131.2 (s),
131.0 (d), 129.9 (d), 129.0 (d), 128.4 (d), 125.6 (d), 122.5 (s), 111.3 (s); m/z (EI) 246
(M+, 34%), 245 (M+-H, 100), 236 (7), 219 (17), 192 (11), 160 (8), 141 (7), 129 (7),
118 (12), 113 (11), 111 (12), 102 (25), 97 (17), 91 (20), 85 (19), 83 (17), 77 (64), 71
(25), 69 (26), 64 (46), 57 (48).
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4.3.2. 4-Imino-3-p-tolyl-3,4-dihydroquinazoline-2-carbonitrile
(6b).
Similar
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treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol) with
(Z)-2-amino-N'-p-tolylbenzamidine (1b) (54 mg, 0.24 mmol) at ca. 20 oC gave the
title compound 6b (51 mg, 81%) as beige needles, mp 155-156 οC (from
n-hexane/DCM), mp (DSC) onset 158.6 oC, peak max. 160.9 oC (from
n-hexane/DCM); (found: C, 73.69; H, 4.54; N, 21.58. C16H12N4 requires C, 73.83; H,
4.65; N, 21.52%); Rf 0.60 (DCM/t-BuOMe, 90:10); λmax(DCM)/nm 231 (log ε 4.27),
255 (4.08), 264 (4.14), 274 (4.07), 298 inf (3.72), 310 (3.89), 323 (3.94), 342 inf
(3.79); νmax/cm-1 3292w (NH), 3040w, 3009w (Ar CH), 2924w, 2907w, 2887w,
2874w, 2243w (C≡N), 1641s, 1603w, 1578m, 1566w, 1510m, 1464m, 1352m, 1323s,
1308m, 1292w, 1240w, 1225w, 1186m, 1180m, 1146m, 1111w, 1026w, 1002w,
956w, 839m, 814w, 789m, 768s; δH(300 MHz; CDCl3) 8.26 (1H, d, J 8.1), 7.70–7.6
(2H, m), 7.52 (1H, ddd, J 7.4, 7.4, 1.8), 7.44 (2H, d, J 8.1), 7.28 (2H, d, J 8.4), 6.34
(1H, br s), 2.47 (3H, s); δC(75 MHz; CDCl3) 153.5 (s), 143.3 (s), 141.7 (s), 133.4 (d),
132.2 (s), 131.7 (d), 131.3 (s), 129.8 (d), 128.6 (d), 128.3 (d), 125.7 (d), 122.4 (s),
111.3 (s), 21.4 (q); m/z (EI) 260 (M+, 12%), 259 (M+-H, 49), 239 (9), 224 (8), 207
(31), 179 (8), 169 (11), 163 (44), 149 (12), 133 (25), 119 (10), 113 (28), 106 (20), 97
(29), 91 (67), 77 (22), 69 (37), 65 (31), 57 (30).
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4.3.3. 4-Imino-3-(4-methoxyphenyl)-3,4-dihydroquinazoline-2-carbonitrile
(6c).
Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol)
with 2-amino-N'-(4-methoxyphenyl)benzamidine (1c) (58 mg, 0.24 mmol) at ca.
20 oC gave the title compound 6c (49 mg, 74%) as orange needles, mp 140-141 οC
(from n-hexane/DCM), mp (DSC) onset 142.8 oC, peak max. 144.3 oC (from
n-hexane/DCM); (found: C, 69.61; H, 4.28; N, 20.14. C16H12N4O requires C, 69.55;
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H, 4.38; N, 20.28%); Rf 0.42 (DCM/t-BuOMe, 90:10); λmax(DCM)/nm 232 (log ε
4.26), 255 (4.09), 265 (4.14), 273 (4.07), 298 inf (3.73), 310 (3.90), 324 (3.95), 342
inf (3.80); νmax/cm-1 3312w, 3281w, 3262w (NH), 3075w, 3057w, 3011w (Ar CH),
2963w, 2934w, 2909w, 2835w, 2243w (C≡N), 1634s, 1607m, 1587m, 1576w,
1560m, 1510s, 1472m, 1462m, 1437w, 1354m, 1344w, 1321s, 1306s, 1283m, 1250s,
1234s, 1182s, 1167m, 1148m, 1136w, 1115w, 1057w, 1032m, 999w, 968w, 951w,
891w, 879w, 858m, 841s, 824m, 779m, 770s; δH(300 MHz; CDCl3) 8.27 (1H, d, J
7.8), 7.72–7.62 (2H, m), 7.52 (1H, ddd, J 7.4, 7.4, 1.7), 7.32 (2H, d, J 9.0), 7.14 (2H,
d, J 9.0), 6.89 (1H, br s), 3.91 (3H, s); δC(75 MHz; CDCl3) 161.3 (s), 153.5 (s), 143.2
(s), 133.3 (d), 131.6 (s), 130.1 (d), 129.7 (d), 128.6 (d), 128.2 (d) 127.0 (s), 125.6 (d),
122.5 (s), 116.1 (d), 111.4 (s), 55.6 (q); m/z (EI) 276 (M+, 92%), 275 (M+-H, 100),
261 (54), 259 (43), 250 (7), 234 (11), 210 (24), 181 (9), 159 (12), 154 (28), 149 (13),
129 (14), 122 (16), 102 (52), 97 (26), 95 (30), 91 (21), 83 (27), 77 (31), 71 (28), 69
(39), 64 (22), 59 (33), 57 (57).
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4.3.4. 3-(4-Fluorophenyl)-4-imino-3,4-dihydroquinazoline-2-carbonitrile
(6d).
Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol)
with 2-amino-N'-(4-fluorophenyl)benzamidine (1d) (55 mg, 0.24 mmol) at ca. 20 oC
gave the title compound 6d (36 mg, 57%) as beige needles, mp 163-163.5 οC (from
n-hexane/DCM), mp (DSC) onset 167.9 oC, peak max. 169.2 oC (from
n-hexane/DCM); (found: C, 68.29; H, 3.30; N, 21.12. C15H9FN4 requires C, 68.18; H,
3.43; N, 21.20%); Rf 0.52 (DCM/t-BuOMe, 90:10); λmax(DCM)/nm 235 inf (log ε
4.19), 255 (4.09), 263 (4.14), 273 (4.08), 299 inf (3.75), 310 (3.90), 323 (3.95), 339
inf (3.81); νmax/cm-1 3304w, 3285w (NH), 3075w, 3048w, 3009w (Ar CH), 2241w
(C≡N), 1638s, 1599m, 1578m, 1564w, 1508s, 1462m, 1418w, 1372w, 1346m, 1317s,
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1288m, 1244w, 1227m, 1177m, 1150m, 1096w, 1026w, 1003w, 881w, 851m, 839m,
831m, 822m, 789w, 764s; δH(300 MHz; CDCl3) 8.21 (1H, d, J 7.5), 7.74-7.64 (2H,
m), 7.55 (1H, ddd, J 7.4, 7.4, 1.5), 7.45-7.32 (4H, m); δC(75 MHz; CDCl3) 165.4 (s),
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162.0 (d, JCF 252.9), 153.8 (s), 143.0 (s), 133.5 (d), 131.1 (d, JCF 9.1), 130.0 (d),
128.5 (d), 125.4 (d), 122.2 (s), 118.2 (d, 2JCF 22.7), 111.2 (s); m/z (EI) 264 (M+, 26%),
263 (M+-H, 100), 245 (12), 236 (3), 209 (1), 154 (6), 147 (7), 132 (3), 102 (27), 95
(32), 90 (7), 75 (29), 63 (7).
4.3.5. 3-(4-Chlorophenyl)-4-imino-3,4-dihydroquinazoline-2-carbonitrile
(6e).
Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol)
with 2-amino-N'-(4-chlorophenyl)benzamidine (1e) (59 mg, 0.24 mmol) at ca. 20 oC
gave the title compound 6e (44 mg, 65%) as colorless needles, mp 209-210 οC (from
n-hexane/DCM), mp (DSC) onset 198.9 oC, peak max. 200.6 oC (from
n-hexane/DCM); (found: C, 64.34; H, 3.10; N, 19.92. C15H9ClN4 requires C, 64.18;
H, 3.2; N, 19.96%); Rf 0.61 (DCM/t-BuOMe, 90:10); λmax(DCM)/nm 228 (log ε 4.41),
253 inf (4.17), 264 (4.18), 273 (4.11), 298 inf (3.79), 310 (3.94), 323 (3.99), 340 inf
(3.85); νmax/cm-1 3304w (NH), 3053w (Ar CH), 2241w (C≡N), 1643s, 1597w, 1574w,
1566w, 1493m, 1466m, 1406w, 1350m, 1315s, 1292m, 1246w, 1223w, 1172m,
1155w, 1090m, 1067w, 1049w, 1022w, 1001w, 970w, 948w, 879w, 841m, 812w,
785w, 775s; δH(300 MHz; CDCl3) 8.21 (1H, d, J 8.1), 7.71–7.64 (2H, m), 7.65 (2H, d,
J 8.4), 7.56 (1H, ddd, J 7.4, 7.4, 1.4), 7.38 (2H, d, J 8.7), 5.70 (1H, br s); δC(75 MHz;
CDCl3) 153.8 (s), 143.0 (s), 137.5 (s), 133.7 (s), 133.6 (d), 131.3 (d), 130.9 (s), 130.4
(d), 130.1 (d), 128.6 (d), 125.4 (d), 122.1 (s), 111.2 (s); m/z (EI) 282 (M++2, 10%),
281 (M++1, 36), 280 (M+, 31), 279 (M+-H, 100), 244 (12), 154 (8), 149 (4), 113 (7),
111 (21), 102 (30), 90 (10), 75 (26), 63 (8).
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4.3.6. 3-(4-Bromophenyl)-4-imino-3,4-dihydroquinazoline-2-carbonitrile
(6f).
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Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol)
with 2-amino-N'-(4-bromophenyl)benzamidine (1f) (69 mg, 0.24 mmol) at ca. 20 oC
gave the title compound 6f (49 mg, 63%) as orange needles, mp 191-192 οC (from
n-hexane/DCM), mp (DSC) onset 191.7 oC, peak max. 193.6 oC (from
n-hexane/DCM); (found: C, 55.41; H, 2.70; N, 17.15. C15H9BrN4 requires C, 55.41;
H, 2.79; N, 17.23%); Rf 0.75 (DCM/t-BuOMe, 90:10); λmax(DCM)/nm 231 (log ε
4.54), 253 inf (4.25), 263 (4.23), 273 (4.15), 299 inf (3.85), 311 (4.00), 323 (4.06),
339 inf (3.94); νmax/cm-1 3298w (NH), 3086w, 3049w, 3028w, 3011w (Ar CH),
2243w (C≡N), 1688w, 1641s, 1593m, 1564m, 1489m, 1400w, 1348m, 1319m,
1290m, 1244w, 1223w, 1175m, 1155w, 1070w, 1018m, 1001m, 970w, 880w, 839m,
808m, 785m, 775s; δH(300 MHz; CDCl3) 8.18 (1H, d, J 7.8), 7.79 (2H, d, J 8.7), 7.70-
7.64 (2H, m), 7.55 (1H, ddd, J 7.4, 7.4, 1.8), 7.31 (2H, d, J 8.7), 6.86 (1H, br s);
δC(125 MHz; CDCl3) 153.7 (s), 143.0 (s), 134.3 (d), 133.6 (d), 130.8 (s), 130.6 (d),
130.1 (d), 128.6 (d), 125.6 (s), 125. (d), 122.1 (s), 111.2 (s); m/z (EI) 326 (M++2,
29%), 325 (M++1, 98), 324 (M+, 30), 323 (M+-H, 100), 259 (3), 244 (32), 209 (5), 207
(5), 192 (5), 155 (14), 122 (18), 102 (42), 90 (23), 76 (33), 63 (16), 50 (17).
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4.3.7. 3-(3,4-Dichlorophenyl)-4-imino-3,4-dihydroquinazoline-2-carbonitrile (6g).
Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol)
with 2-amino-N'-(3,4-dichlorophenyl)benzamidine (1g) (67 mg, 0.24 mmol) at ca.
20 oC gave the title compound 6g (49 mg, 65%) as beige plates, mp 175-176 οC (from
n-pentane/DCM), mp (DSC) onset 176.6 oC, peak max. 180.5 oC (from
n-pentane/DCM); (found: C, 57.24; H, 2.5; N, 17.69. C15H8Cl2N4 requires C, 57.17;
H, 2.56; N, 17.78%); Rf 0.77 (DCM/t-BuOMe, 90:10); λmax(DCM)/nm 230 (log ε
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4.41), 252 inf (4.19), 264 (4.17), 273 (4.08), 299 inf (3.79), 310 (3.93), 323 (3.97),
339 inf (3.85); νmax/cm-1 3265w (NH), 3092w, 3044w, 3019w, 3007w (Ar CH),
2953w, 2924w, 2853w, 2241w (C≡N), 1620s, 1601m, 1574m, 1562m, 1472m,
1462m, 1389w, 1354m, 1337m, 1256w, 1231m, 1182w, 1132m, 1119w, 1055m,
1034m, 1022w, 970w, 928w, 876m, 854w, 827m, 770s; δH(300 MHz; CDCl3) 8.12
(1H, d, J 7.2), 7.73 (1H, d, J 8.7), 7.70-7.65 (2H, m), 7.60-7.54 (2H, m), 7.30 (1H, dd,
J 8.4, 2.4); δC(125 MHz; CDCl3) 154.1 (s), 142.8 (s), 135.9 (s), 133.9 (s), 134.8 (s)
133.7 (d), 132.5 (s), 131.1 (d), 130.5 (s), 130.2 (d), 128.8 (d), 128. (d), 125.1 (d),
121.7 (s), 111.1 (s); m/z (EI) 317 (M++2, 43%), 315 (M+, 100), 313 (M+-2, 21), 304
(6), 285 (18), 280 (43), 272 (10), 270 (10), 260 (25), 258 (56), 244 (8), 230 (14), 223
(28), 216 (85), 186 (29), 136 (19), 109 (26), 103 (64), 96 (27), 90 (20), 76 (40), 64
(81), 57 (38).
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4.3.8. 4-Imino-6,7-dimethoxy-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile (6h).
Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50 mg, 0.24 mmol)
with 2-amino-4,5-dimethoxy-N'-(phenyl)benzamidine (1h) (64 mg, 0.24 mmol) at ca.
20 oC gave the title compound 6h (38 mg, 53%) as colorless needles, mp 230 οC
(sub.) (from acetone), mp (DSC) onset 260.8 oC, peak max. 263.2 oC (from acetone);
(found: C, 66.55; H, 4.42; N, 18.38. C17H14N4O2 requires C, 66.66; H, 4.61; N,
18.29%); Rf (t-BuOMe/EtOH, 60:40) 0.59; λmax(DCM)/nm 229 (log ε 4.58), 249 inf
(4.56), 257 inf (4.61), 266 (4.66), 275 inf (4.62), 314 (3.98), 329 (4.05), 355 (4.05),
372 inf (4.00), 393 inf (3.67); νmax/cm-1 3304w, 3287w (NH), 3100w, 3073w, 3013w
(Ar CH), 2976w, 2940w, 2870w, 2830w, 2237w (C≡N), 1628m, 1609s, 1570m,
1512s, 1493m, 1470m, 1454m, 1433w, 1381m, 1348m, 1304m, 1277m, 1229m,
1204m, 1182w, 1125m, 1055m, 1038w, 1003m, 995m, 934w, 876w, 856m, 841m,
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822m, 793m, 781m, 765m; δH(300 MHz; CDCl3) 7.72-7.66 (4H, m), 7.44–7.41 (2H,
m), 7.08 (1H, s), 6.34 (1H, br s), 4.01 (3H, s), 4.00 (3H, s); δC(75 MHz; CDCl3) 153.6
(s), 152.7 (s), 151.1 (s), 138.7 (s), 134.9 (s), 131.3 (d), 131.1 (d), 129.5 (s), 129.1 (d),
116.2 (s), 111.5 (s), 109.0 (d), 105.6 (d), 56.5 (q), 56.3 (q); m/z (EI) 306 (M+, 31%),
305 (83), 289 (11), 261 (5), 236 (3), 193 (2), 149 (8), 129 (10), 111 (7), 97 (13), 83
(13), 77 (37), 71 (15), 69 (27), 57 (26), 51 (10).
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4.3.9. 4-Imino-6,7-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroquinazoline-2-
carbonitrile (6i). Similar treatment of 4,5-dichloro-1,2,3-dithiazolium chloride (3) (50
mg, 0.24 mmol) with 2-amino-4,5-dimethoxy-N'-(4-methoxyphenyl)benzamidine (1i)
(71 mg, 0.24 mmol) at ca. 20 oC gave the title compound 6i (49 mg, 61%) as pale
yellow needles, mp 234-235 οC (from acetone), mp (DSC) onset 254.5 oC, peak max.
255.4 oC (from acetone); (found: C, 64.44; H, 4.84; N, 16.60. C18H16N4O3 requires C,
64.28; H, 4.79; N, 16.66%); Rf 0.73 (t-BuOMe/EtOH, 90:10); λmax(DCM)/nm 232
(log ε 4.68), 248 (4.62), 255 inf (4.61), 268 (4.61), 276 inf (4.55), 316 (4.01), 330
(4.10), 358 (4.10), 392 (3.73); νmax/cm-1 3289w (NH), 3100w, 3055w, 3024w and
3015w (Ar CH), 2984w, 2963w, 2943w, 2914w, 2866w, 2827w, 2237w (C≡N),
1640m, 1632m, 1607m, 1587w, 1578w, 1512s, 1458m, 1429w, 1414w, 1377m,
1339w, 1318w, 1308w, 1298m, 1275s, 1252s, 1221w, 1198m, 1186w, 1167m, 1121s,
1107m, 1063w, 1032m, 1017w, 995m, 953w, 882m, 868m, 837s; δH(300 MHz;
CDCl3) 7.66 (1H, s), 7.32 (2H, d, J 8.7), 7.13 (2H, d, J 8.7), 7.05 (1H, s), 6.51 (1H, br
s), 4.00 (3H, s), 3.99 (3H, s), 3.91 (3H, s); δC(75 MHz; CDCl3) 161.5 (s), 153.7 (s),
153.1 (s), 151.2 (s), 138.8 (s), 130.3 (d), 130.2 (s), 127.2 (s), 116.3 (s), 116.3 (d),
111.7 (s), 109.1 (d), 105.8 (d), 56.5 (q), 56.3 (q), 55.7 (q); m/z (EI) 336 (M+, 89%),
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335 (100), 321 (41), 305 (8), 245 (42), 159 (14), 122 (5), 107 (15), 92 (14), 77 (32),
64 (12), 51 (10).
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4.4.
Base hydrolysis of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-carbo-
nitrile (6a) (Scheme 2).
4.4.1. 2-Methoxy-3-phenylquinazolin-4(3H)-imine (7) from the iminoquinazoline 6a
(reaction conditions i). To solution of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-
carbonitrile (6a) (24.6 mg, 0.1 mmol) in MeOH (0.5 mL) was added a solution of
NaOH (4 mg, 0.1 mmol) in MeOH (0.5 mL) and the stirred mixture was heated at ca.
67 oC for 3 h and then allowed to cool to ca. 20 C. The reaction mixture was then
o
diluted (H2O), neutralised (10% HCl) and extracted (t-BuOMe). The organic extracts
were then washed (H2O) and dried (Na2SO4). Removal of the volatiles gave the title
compound 7 (25 mg, 99%) as pale yellow plates, mp (DSC) onset 126.3 oC, peak max.
128.4 oC (from DCM/n-pentane, 60:40); (found: C, 71.63; H, 5.27; N, 16.82.
C15H13N3O requires C, 71.70; H, 5.21; N, 16.72%); Rf 0.40 (t-BuOMe/DCM, 20:80);
λmax(DCM)/nm 234 (log ε 4.35), 240 inf (4.32), 247 inf (4.22), 265 inf (3.94), 275
(3.98), 284 inf (3.91), 305 inf (3.69), 316 (3.81), 329 (3.69); νmax/cm-1 3310w, 3277w
(NH), 3260w, 3061w, 2951w, 2924w, 2853w, 1643s, 1634m, 1605s, 1582s, 1481m,
1472m, 1454w, 1437m, 1371m, 1360m, 1323s, 1308m, 1298m, 1261w, 1242w,
1233w, 1184m, 1171m, 1144m, 1119w, 1074w, 1049m, 1030m, 976m, 962m, 905w,
870w, 833w, 806m, 764s; δH(500 MHz; CDCl3) 8.20 (1H, d, J 7.5), 7.61-7.57 (3H,
m), 7.54-7.51 (1H, m), 7.44 (1H, dd, J 0.5, 0.5), 7.30-7.27 (3H, m), 3.92 (3H, s);
δC(125 MHz; CDCl3) 156.6 (s), 152.0 (s), 144.7 (s), 135.1 (s), 132.9 (d), 130.1 (d),
129.3 (d), 129.0 (d), 125.7 (d), 125.4 (d), 124.5 (d), 119.5 (s), 55.1 (q); m/z (EI) 251
(M+, 22%), 250 (100), 235 (11), 119 (6), 91 (6), 77 (8).
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4.4.2. 4-Imino-3-phenyl-3,4-dihydroquinazolin-2(1H)-one (8) from the quinazolin-
imine 7 (reaction conditions ii). To solution of 2-methoxy-3-phenylquinazolin-4(3H)-
imine (7) (25.1 mg, 0.1 mmol) in MeOH (0.5 mL) was added a solution of 10% HCl
(0.5 mL) and the stirred mixture was heated at ca. 67 oC for 30 min and then allowed
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to cool to ca. 20 C. The reaction mixture was then neutralised (10% K2CO3) and
extracted (t-BuOMe). The organic extracts were then washed (H2O) and dried
(Na2SO4). Removal of the volatiles gave the title compound 8 (23.5 mg, 99%) as
colorless plates, mp (DSC) onset 218.4 oC, peak max. 223.7 oC (from MeOH) (lit.,25
o
214-218 C); (found: C, 70.93; H, 4.54; N, 17.61. C14H11N3O requires C, 70.87; H,
4.67; N, 17.71%); Rf (DCM/t-BuOMe, 70:30) 0.32; λmax(DCM)/nm 234 (log ε 4.58),
246 inf (4.37), 294 inf (3.88), 306 (4.07), 318 (4.01); νmax/cm-1 3294w, 3206w, 3152w
and (NH), 3090w and 3065w (Ar CH), 2997w, 2934w, 2891w, 2852w, 1688s (C=O),
1614s, 1491m, 1447m, 1406m, 1294s, 1267m, 1171m, 1157m, 1142m, 1117w,
1069w, 1042w, 962w, 907w, 864w, 839w, 829w, 791s, 775m, 756s; δH(500 MHz;
CD2Cl2) 9.00 (1H, br s), 8.15 (1H, br s), 7.60 (2H, dd, J 6.8, 6.8), 7.54 (1H, dd, J 7.3,
7.3), 7.46 (1H, dd, J 7.6, 7.6), 7.32 (2H, d, J 7.5), 7.16 (1H, dd, J 7.5, 7.5), 6.87 (1H,
d, J 8.0), 6.78 (1H, br s); δC(125 MHz; CD2Cl2) one quaternary carbon missing 150.9
(s), 137.4 (s), 135.5 (s), 133.5 (d), 130.5 (d), 129.9 (d), 129.6 (d), 127.3 (d), 123.4 (d),
116.0 (s), 115.2 (d); m/z (EI) 238 (3), 237 (M+, 20%), 236 (100), 195 (1), 145 (1), 118
(14), 104 (2), 91 (14), 77 (6), 65 (6).
4.4.3. 4-Imino-3-phenyl-3,4-dihydroquinazolin-2(1H)-one (8) from the quinazolin-
imine 6a (reaction conditions iii). To solution of 4-imino-3-phenyl-3,4-dihydro-
quinazoline-2-carbonitrile (6a) (24.6 mg, 0.1 mmol) in MeOH (0.5 mL) was added a
solution of NaOH (4 mg, 0.1 mmol) in MeOH (0.5 mL) and the stirred mixture was
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heated at ca. 67 oC for 3 h and then allowed to cool to ca. 20 oC. The reaction mixture
was then acidified (10% HCl) and the volatiles evaporated under reduced pressure.
The remaining solid was then dissolved (H2O), neutralised (10% K2CO3) and
extracted (t-BuOMe). The organic extracts were then washed (H2O) and dried
(Na2SO4). Removal of the volatiles gave the title compound 8 (23.4 mg, 99%) as
colorless plates, mp (DSC) onset 218.4 oC, peak max. 223.7 oC (from MeOH) (lit.,25
214-218 oC) identical to the sample described above.
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4.4.4. 3-Phenylquinazoline-2,4(1H,3H)-dione (9) from the quinazolinimine 8
(reaction conditions iv). To 4-imino-3-phenyl-3,4-dihydroquinazolin-2(1H)-one (8)
(23.7 mg, 0.1 mmol) was added a solution of 1N NaOH (1 mL) and the reaction
mixture left to stir at ca. 20 oC for 7 d. The reaction mixture was then neutralised
(10% HCl) and extracted (t-BuOMe). The organic extracts were then washed (H2O)
and dried (Na2SO4). Removal of the volatiles gave the title compound 9 (21.5 mg,
90%) as colorless plates, mp (DSC) onset 281.2 oC, peak max. 281.8 oC (lit.,26 281-
282 oC) (from cyclohexane/EtOH, 1:1); Rf 0.52 (DCM/t-BuOMe, 80:20);
λmax(DCM)/nm 229 (log ε 4.17), 242 inf (3.97), 309 (3.47), 3.19 (3.39); νmax/cm-1
3213w, 3198w, 3122w, 3080w, 3057w, 3020w, 3003w (Ar CH), 2941w, 2899w,
2808w, 1726m (C=O), 1697w, 1659s (C=O), 1626m, 1611m, 1591m, 1518w, 1493m,
1445m, 1400m, 1341w, 1327w, 1288m, 1273w, 1240w, 1150m, 1072w, 1026w,
1017w, 876w, 866w, 817w, 783w, 752s; δH(300 MHz; CDCl3) 9.52 (1H, s), 8.15 (1H,
dd, J 1.5, 1.5), 7.60-7.49 (4H, m), 7.34-7.30 (2H, m), 6.94 (1H, d, J 8.1); δC(75 MHz;
CDCl3) one quaternary carbon missing 162.5 (s), 151.4 (s), 138.6 (s), 135.4 (d), 134.8
(s), 129.5 (d), 128.9 (d), 128.8 (d), 128.5 (d), 123.6 (d), 115.1 (d), 114.8 (s); m/z (EI)
238 (M+, 100%), 237 (31), 146 (51), 119 (100), 93 (48), 90 (17), 77 (8), 64 (22).
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4.5.
Base hydrolysis of 4-anilinoquinazoline-2-carbonitrile (2) (Scheme 3).
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4.5.1. 4-Anilino-2-methoxyquinazoline (10). To solution of 4-anilinoquinazoline-2-
carbonitrile (2) (24.6 mg, 0.1 mmol) in MeOH (0.5 mL) was added a solution of
NaOH (4 mg, 0.1 mmol) in MeOH (0.5 mL) and the stirred mixture was heated at ca.
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67 oC for 4 d and then allowed to cool to ca. 20 C. The reaction mixture was then
diluted (H2O), neutralised (10% HCl) and extracted (t-BuOMe). The organic extracts
were then washed (H2O) and dried (Na2SO4). Removal of the volatiles gave the title
compound 10 (17.8 mg, 71%) as pale yellow plates, mp (DSC) onset 198.4 oC, peak
max. 200.9 oC, decomp. onset 206.1 oC, peak. max. 208.9 C (lit.,27 198-200 oC)
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(from DCM/n-pentane, 60:40); Rf 0.45 (DCM/t-BuOMe, 80:20); λmax(DCM)/nm 234
(log ε 4.46), 278 (4.17), 295 inf (4.02), 322 inf (4.06), 335 (4.71), 349 inf (4.08);
νmax/cm-1 3161w, 3051w (Ar CH), 2986w, 1620m, 1599m, 1568s, 1530m, 1497s,
1470m, 1445s, 1416m, 1373s, 1323s, 1292w, 1259m, 1190w, 1177w, 1138w, 1103w,
1072m, 1030w, 991w, 912w, 879w, 871w, 853w, 841w, 800w, 766m, 754m; δH(500
MHz; CDCl3) 7.80-7.76 (3H, m), 7.74-7.69 (2H, m), 7.46 (1H, br s), 7.41 (2H, dd, J
7.5, 7.5), 7.37 (1H, ddd, J 7.3, 7.3, 2.0), 7.16 (1H, dd, J 7.5, 7.5), 4.07 (3H, s); δC(75
MHz; CDCl3) 162.6 (s), 159.5 (s), 152.1 (s), 138.1 (s), 133.2 (d), 129.1 (d), 127.5 (d),
124.4 (d), 123.8 (d), 121.5 (d), 120.5 (d), 112.3 (s), 54.5 (q); m/z (EI) 251 (M+, 46%),
250 (M+-1, 100), 235 (11), 220 (26), 207 (7), 144 (6), 116 (9), 110 (6), 90 (9), 77 (20),
65 (14), 51 (11).
4.6.
Acid hydrolysis of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-carbo-
nitrile (6a) (Scheme 4).
4.6.1. 4-Oxo-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile
(11)
(reaction
conditions i). To a stirred solution of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-
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carbonitrile (6a) (24.6 mg, 0.1 mmol) in DMSO (1 mL) was added TFA (7.7 µL, 0.1
mmol). The reaction mixture was heated at ca. 100 oC for 2 d and monitored by TLC.
When no starting quinazoline remained (by TLC) the reaction mixture was allowed to
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cool to ca. 20 C and then neutralised with 10% K2CO3, diluted in H2O (3 mL) and
extracted (t-BuOMe, 2 × 30 mL). The combined organic phases were dried (Na2SO4),
adsorbed onto silica and chromatographed to give the title compound 11 (23.5 mg,
99%), as colorless needles, mp 193-194 oC (lit.,28 196-197 oC) (from
cyclohexane/EtOH, 90:10); Rf 0.55 (DCM/t-BuOMe, 95:05); λmax(DCM)/nm 232 (log
ε 4.14), 249 inf (3.70), 260 inf (3.54), 291 inf (3.71), 303 (3.79), 312 inf (3.73), 327
(3.59); νmax/cm-1 3076w, 3052w (Ar CH), 2239w (C≡N), 1692s (C=O), 1605m,
1599m, 1584m, 1560m, 1491m, 1466m, 1462m, 1342s, 1323m, 1279s, 1236w,
1211w, 1159w, 1117w, 1107w, 1088w, 1076w, 1022w, 1009w, 972w, 893w, 885w,
847w, 799w, 777s, 768s; δH(500 MHz; CDCl3) 8.37 (1H, d, J 5.0), 7.92-7.86 (2H, m),
7.69 (1H, dd, J 7.5, 7.5), 7.63-7.60 (3H, m), 7.43-7.41 (2H, m); δC(75 MHz; CDCl3)
160.1 (s), 146.5 (s), 135.4 (d), 135.2 (s), 131.5 (s), 130.7 (d), 130.3 (d), 130.1 (d),
128.7 (d), 128.2 (d), 127.5 (d), 123.0 (s), 111.0 (s); m/z (EI) 247 (M+, 100%), 219
(51), 192 (7), 166 (6), 129 (6), 119 (48), 102 (13), 90 (12), 77 (71), 63 (8), 51 (32).
4.6.2. 4-Oxo-3-phenyl-3,4-dihydroquinazoline-2-carbonitrile
(11)
(reaction
conditions ii). To a stirred solution of 4-imino-3-phenyl-3,4-dihydroquinazoline-2-
carbonitrile (6a) (24.6 mg, 0.1 mmol) in THF/H2O (1:1) (1 mL) was added conc. HCl
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(9 µL, 0.1 mmol). The reaction mixture was heated at ca. 65 C for 24 h and
monitored by TLC. When no starting quinazoline remained (by TLC) the reaction
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mixture was allowed to cool to ca. 20 C and then neutralised with 10% K2CO3 and
extracted (t-BuOMe, 2 × 30 mL). The combined organic phases were dried (Na2SO4),
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adsorbed onto silica and chromatographed to give the title compound 11 (21.5 mg,
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87%), as colorless needles, mp 193-194 oC (lit.,28 196-197 C) identical to that
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4.6.3. 3-Phenylquinazoline-2,4(1H,3H)-dione (9) from the quinazolinone 11
(reaction conditions iii). To a stirred solution of 4-oxo-3-phenyl-3,4-dihydro-
quinazoline-2-carbonitrile (11) (23.7 mg, 0.1 mmol) in THF/H2O (1:1) (1 mL) was
added conc. HCl (18 µL, 0.2 mmol). The reaction mixture was heated at ca. 65 oC for
3 d and monitored by TLC. When no starting quinazoline remained (by TLC) the
o
reaction mixture was allowed to cool to ca. 20 C and then neutralised with 10%
K2CO3 and extracted (t-BuOMe, 60 mL). The combined organic phases were dried
(Na2SO4), adsorbed onto silica and chromatographed to give the title compound 9
(22.8 mg, 96%), as colorless plates, mp (DSC) onset 281.2 oC, peak max. 281.8 oC
(lit.,26 281-282 oC)identical to authentic sample.
4.6.4. 3-Phenylquinazoline-2,4(1H,3H)-dione (9) from the quinazolinimine 6a
(Scheme 4, reaction conditions iv). To a stirred solution of 4-imino-3-phenyl-3,4-
dihydroquinazoline-2-carbonitrile (6a) (24.6 mg, 0.1 mmol) in THF/H2O (1:1) (1 mL)
was added conc. HCl (56 µL, 0.4 mmol). The reaction mixture was heated at ca. 65 oC
for 1.5 d and monitored by TLC. When no starting quinazoline remained (by TLC)
o
the reaction mixture was allowed to cool to ca. 20 C and then neutralised with 10%
K2CO3 and extracted (t-BuOMe, 60 mL). The combined organic phases were dried
(Na2SO4), adsorbed onto silica and chromatographed to give the title compound 9
(23.6 mg, 99%), as colorless plates, mp (DSC) onset 281.2 oC, peak max. 281.8 oC
(lit.,26 281-282 oC) (from cyclohexane/EtOH, 1:1) identical to an authentic sample.
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4.7.
Hydration of 4-anilinoquinazoline-2-carbonitrile (2)
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4.7.1. 4-Anilinoquinazoline-2-carboxamide (12). To 4-anilinoquinazoline-2-carbo-
nitrile (2) (24.6 mg, 0.10 mmol) was added conc. HCl (0.5 mL). The reaction mixture
9
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was heated at ca. 65 C for 16 h and monitored by TLC. When no starting material
o
remained the reaction mixture was allowed to cool to ca. 20 C and neutralised with
6M NaOH followed by precipitation and filtration of the title compound 12 (18.2 mg,
69%), as colorless needles, mp (DSC) onset 229.6 oC, peak max. 230.1 oC (from
THF/n-pentane, 60:40); (found: C, 68.26; H, 4.69; N, 20.92. C15H12N4O requires C,
68.17; H, 4.58; N, 21.20%); Rf 0.48 (THF/DCM, 50:50); λmax(DCM)/nm 339 (log ε
4.22); νmax/cm-1 3505w, 3414w, 3289w and 3186w (NH), 1680w, 1638m, 1626m,
1609w, 1566s, 1531m, 1493m, 1487s, 1447m, 1416s, 1368m, 1315w, 1302w, 1292w,
1256w, 1213w, 1157w, 1134w, 1096w, 1078w, 1030w, 989w, 910w, 883w, 870w,
847w, 796w, 768m, 758s; δH(500 MHz; CDCl3) 9.98 (1H, s), 8.61 (1H, d, J 10.0),
7.97-7.90 (4H, m), 7.88 (1H, br s), 7.70 (1H, dd, J 7.5, 7.5), 7.68 (1H, br s), 7.43 (2H,
dd, J 7.5, 7.5), 7.17 (1H, dd, J 7.5, 7.5); δC(75 MHz; CDCl3) 165.7 (s), 158.4 (s),
154.5 (s), 149.5 (s), 139.0 (s), 133.7 (d), 128.7 (d), 128.6 (d), 127.6 (d), 124.1 (d),
123.2 (d), 122.4 (d), 114.9 (s); m/z (EI) 264 (M+, 92%), 219 (100), 192 (5), 129 (5),
110 (14), 92 (13), 77 (35), 65 (8), 51 (16).
4.5.
X-Ray Crystallographic Studies
Data were collected on an Oxford-Diffraction Supernova diffractometer, equipped
with a CCD area detector utilizing Mo-Kα radiation (λ = 0.71073 Å). A suitable
crystal was attached to glass fibers using paratone-N oil and transferred to a goniostat
where they were cooled for data collection. Unit cell dimensions were determined and
refined by using 6074 (3.02≤θ≤28.90º) reflections. Empirical absorption corrections
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(multi-scan based on symmetry-related measurements) were applied using CrysAlis
RED software.31 The structure was solved by direct methods using SIR9232 and
refined on F2 using full-matrix least squares using SHELXL97.33 Software packages
used: CrysAlis CCD31 for data collection, CrysAlis RED31 for cell refinement and
data reduction, WINGX for geometric calculations,34 and DIAMOND35 for molecular
graphics. The non-H atoms were treated anisotropically. The hydrogen atom attached
to N3 was located on a difference Fourier map, whereas all other hydrogen atoms
were placed in calculated, ideal positions and refined as riding on their respective
carbon atoms.
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4.5.1. Crystal refinement data for compound 6a: C15H10N4, M = 246.27,
orthorhombic, space group Pbca, a = 16.3251(4), b = 6.7320(2), c = 21.6139(5) Å, V
= 2375.4(2) Å3, Z = 8, T = 100(2) K, ρcalcd = 1.377 g cm-3, 2θmax = 53. Refinement of
176 parameters on 2460 independent reflections out of 10391 measured reflections
(Rint = 0.0236) led to R1 = 0.0363 [I>2s(I)], wR2 = 0.1119 (all data), and S = 1.080
with the largest difference peak and hole of 0.193 and -0.206 e-3, respectively.
Crystallographic data for compound 6a has been deposited with the Cambridge
Crystallographic Data Centre with deposit number CCDC-952956. This data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +441223336033; or e-mail: deposit@ccdc.cam.ac.uk.
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Acknowledgements
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The authors wish to thank the Cyprus Research Promotion Foundation (Grant No.
NEAYPODOMH/NEKYP/0308/02) and the following organizations and companies
in Cyprus for generous donations of chemicals and glassware: the State General
Laboratory, the Agricultural Research Institute, the Ministry of Agriculture,
MedoChemie Ltd, Medisell Ltd and Biotronics Ltd. Furthermore, we thank the A.G.
Leventis Foundation for helping to establish the NMR facility in the University of
Cyprus.
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Supporting Information: Copies of 1D H and 13C NMR spectra of all new
compounds. Single crystal X-ray structure of compound 6a. This material is available
free of charge via the Internet at http://pubs.acs.org/.
References
1
(a) Rewcastle, G. W. (eds. in Chief: Katritzky, A. R.; Ramsden, C. A.; Scriven, E.
F. V.; Taylor, R. J. K.). In Comprehensive Heterocyclic Chemistry III; Aitken, R.
A., Ed.; Elsevier: Oxford, 2008; Vol. 8, Chapter 8.02, p 117-272; (b) Undheim,
K.; Benneche, T. (eds. in Chief: Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.).
In Comprehensive Heterocyclic Chemistry II; Boulton, A. J., Ed.; Pergamon:
Oxford, 1996; Vol. 6, Chapter 6.02, p 93-231; (c) Brown, D. J. (eds. in Chief:
Katritzky, A. R.; Rees, C. W.). In Comprehensive Heterocyclic Chemistry;
Boulton, A. J.; McKillop, A., Ed.; Pergamon: Oxford, 1984; Vol. 3, Chapter 2.13,
p 57-155; (d) Kikelj, D. In Quinazolines; Yamamoto, Y., Ed.; Science of
Synthesis Product Class 13: Georg Thieme Verlag: Stuttgart, 2003; Vol. 16, p
573-750.
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