The Conversion of 4-Anilinoquinazoline- and 3-Aryl-4-imino-3,4-dihydro-quinazoline-2-carbonitriles into Benzo[4,5]imidazo[1,2-c]quinazoline-6-carbonitriles via Oxidative and Nonoxidative C-N Couplings

Article abstract of DOI:10.1021/acs.joc.5b01514

Benzo[4,5]imidazo[1,2-c]quinazoline-6-carbonitriles are prepared in high yields via three new routes: (1) a Cu(OTf)₂ (0-5 mol %) catalyzed hypervalent iodine [PhI(OTf)₂] mediated oxidative coupling of 4-anilinoquinazoline-2-carbonitr

Full text of DOI:10.1021/acs.joc.5b01514

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The conversion of 4-anilinoquinazoline- and 3-aryl-4-imino-3,4-dihydro-
quinazoline-2-carbonitriles into benzo[4,5]imidazo[1,2-c]quinazoline-6-
carbonitriles via oxidative and non-oxidative C-N couplings
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Styliana I. Mirallai and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia,
Cyprus, koutenti@ucy.ac.cy
Benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitriles are prepared in high yields via
three new routes: 1) a Cu(OTf)2 (0ꢀ5 mol %) catalyzed hypervalent iodine [PhI(OTf)2]
mediated oxidative coupling of 4ꢀanilinoquinazolineꢀ2ꢀcarbonitriles in neat
trifluoroacetic acid (TFA); 2) a Pd(OAc)2 (10 mol %) or CuI (10 mol %) mediated
nonꢀoxidative coupling of 4ꢀ(2ꢀbromoanilino)quinazolineꢀ2ꢀcarbonitrile; and 3) a
nonꢀoxidative Pd(Ar3P)3 [Ar = 3,5ꢀ(F3C)2C6H3] [aka Superstable Pd(0) Catalyst®] (10
mol %) mediated intramolecular CꢀN cyclization of 3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀ
dihydroquinazolineꢀ2ꢀcarbonitriles. All new compounds are fully characterized.
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1.
Introduction
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Benzo[4,5]imidazo[1,2ꢀc]quinazoline (1) is a planar trinitrogen heteroacene that hosts
both benzimidazole and quinazoline structures fused together via a shared bond
(Scheme 1).1 Not surprisingly, benzo[4,5]imidazo[1,2ꢀc]quinazolines display a wide
array of biological activities. Some act as DNA interchelators and show antitumor,2
anticancer,3 antiviral,4 and antimicrobial5 activities, while others act as anticonvulsant
agents,6 or as bronchodilators.7 Metal chelates with ruthenium(II),8 tin9 and lead9 have
also been studied. Benzo[4,5]imidazo[1,2ꢀc]quinazolines also have hole transporting
properties.10
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Scheme 1. Structure and numbering scheme for benzo[4,5]imidazo[1,2ꢀc]quinazoline
(1) and two common precursors 2ꢀ(2ꢀaminophenyl)benzimidazole 2 and 4Hꢀ
benzo[d][1,3]oxazinꢀ4ꢀones 3.
Most syntheses of benzo[4,5]imidazo[1,2ꢀc]quinazolines focus on building the
pyrimidine ring starting from 2ꢀ(2ꢀaminophenyl)benzimidazoles 21,3b,4b,6,11 or via
structurally related precursors e.g., 2ꢀ(2ꢀnitrophenyl)benzimidazoles,12 Nꢀ[2ꢀ(benzꢀ
imidazolꢀ2ꢀyl)phenyl]phosphanimines,13 2ꢀ(2ꢀazidophenyl)benzimidazoles,14 Nꢀ[2ꢀ
(benzimidazolꢀ2ꢀyl)phenyl]methanimines,5c,d,15 and 2ꢀ(2ꢀhalophenyl)benzimidazꢀ
oles.16 A second major synthetic route of benzo[4,5]imidazo[1,2ꢀc]quinazolines is via
construction of the imidazole ring which has been limited to treatment of 4Hꢀ
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benzo[d][1,3]oxazinꢀ4ꢀones 3 with 1,2ꢀbenzenediamines either directly5a,b,e,7b,11i,17 or
via the isolable intermediate 3ꢀ(2ꢀaminophenyl)ꢀ3Hꢀquinazolinꢀ4ꢀones,7b,18 or
structurally related benzo[1,3]thiazinꢀ4ꢀones.20
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Scheme 2. Retrosynthetic analysis of benzo[4,5]imidazo[1,2ꢀc]quinazoline skeleton
to give either 4ꢀanilinoquinazoline (4) or 3ꢀphenylquinazolinꢀ4(3H)ꢀimine (5).
A structural analysis of both 4ꢀanilinoquinazoline (4) and 3ꢀphenylquinazolinꢀ4(3H)ꢀ
imine (5), reveals that their structures are just one CꢀN bond short of the
benzo[4,5]imidazo[1,2ꢀc]quinazoline skeleton (Scheme 2). Our ongoing studies on
the synthesis and chemistry of 2ꢀaminoꢀN'ꢀarylbenzamidines21 provided us with a
small library of 4ꢀanilinoquinazolineꢀ and 3ꢀarylꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀ
carbonitriles.22 In light of the limited number of routes to the benzo[4,5]imidazo[1,2ꢀ
c]quinazoline skeleton via construction of the imidazole ring we investigated both
oxidative and nonꢀoxidative methods for converting these readily available
quinazolineꢀ2ꢀcarbonitriles into benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitriles.
The development of synthetic routes that hosted nitriles in the final products are
worthwhile since these can readily be converted into a wide range of other
functionalities.23 Furthermore, the presence of a cyano group in this tetracycle
improved the cytotoxicity in comparison to the parent compound.3b
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2.
Results and Discussion
Oxidative and non-oxidative cyclization chemistry of 4-anilino-
2.1.
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quinazoline-2-carbonitriles 4
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The 4ꢀanilinoquinazolines 4 host a N,N'ꢀdisubstituted benzamidine motif within their
structures, cyclization of which affords the desired benzo[4,5]imidazo[1,2ꢀc]quinazolꢀ
ines. The literature on the preparation of benzoꢀ or hetarenoꢀfused imidazoles from
amidines via oxidative CꢀN coupling highlighted the use of electroꢀoxidation24 and
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the use of a variety of oxidants including H2O2,25 cerium ammonium nitrate (CAN),24a
24a,29
NaOCl,26 NCS,27 MnO2,28 Pb(OAc)4
and hypervalent iodine(III) reagents.30 In
our hands, cyclization efforts using either H2O2, CAN, NCS, MnO2 or Pb(OAc)4
failed but succeeded with hypervalent iodine(III) reagents.
PhI(OAc)2 (PIDA or DAIB) and PhI(OTf)2 (PIFA or BFIB) either alone in equimolar
or greater quantities,29c,31 or catalytically in the presence of coꢀoxidants,32 are
typically used for such cyclizations. Variations where the hypervalent iodine(III)
reagent is generated in situ have also been reported.33
The closest reported reaction to our targeted cyclization was the oxidative ring closure
of the structurally related 6ꢀanilinopurines 6 to give the benzo[4,5]imidazo[2,1ꢀi]ꢀ
purines 7, using PIDA (1.5 equiv), Cu(OTf)2 (5 mol %) in a solvent mixture of
AcOH/Ac2O (1:1) heated at reflux (Scheme 3).32b
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Scheme 3. The copper(II) mediated oxidative ring closure of 6ꢀanilinopurines 6 to
give benzo[4,5]imidazo[2,1ꢀi]purines 7.32b
In our hands these conditions worked well for converting 4ꢀanilinoquinazolineꢀ2ꢀ
carbonitrile (4a) into benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a) which
was isolated in 81% yield together with a small quantity of an unidentified side
product (see Supporting Information, Section S1, Table S1, entry 1). Side products
have also been observed by Chu et al.,31b who noted that their formation could be
avoided by using PIFA in place of PIDA. With this in mind the reaction was
reoptimized (see Supporting Information, Section S1) and found to work better when
only PIFA (1.1 equiv) was used in neat trifluoroacetic acid (TFA) at ca. 20 oC to give
the desired benzo[4,5]imidazo[1,2ꢀc]quinazoline 1a in 92% yield after only 30 min
(Table 1, entry 1 and Supporting Information, Table S1, entry 7).
Having partially optimized this oxidative ring closure the mildest conditions, PIFA
(1.1 equiv) in neat TFA at room temperature, were then applied to a range of
4ꢀanilinoquinazolineꢀ2ꢀcarbonitriles 4a-j (Table 1). These metal free conditions
worked well for the parent, the 4ꢀMe and the 4ꢀMeO substituted analogues (Table 1,
entries 1ꢀ3), however, the reactions with 4ꢀanilinoquinazolines that hosted inductively
electron withdrawing halogen substituents on the aniline moiety (Table 1, entries 6ꢀ17)
required prolonged reaction times. As such, we reꢀoptimized the reaction conditions
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for 4ꢀ(4ꢀfluoroanilino)quinazolineꢀ2ꢀcarbonitrile (4e) (Table 1, entries 6ꢀ9):
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temperatures (from 20 to 80 C) did not significantly improve the reaction (data not
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shown). Fortunately, a shorter reaction time (1.5 h) was achieved by reintroducing
Cu(OTf)2 (5 mol %), increasing the amount of PIFA (1.5 equiv) and raising the
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reaction temperature to 80 C (Table 1, entry 9). Worthy of note was that with the
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reagents in this stoichiometry the reaction worked well even at 20 C to give the
product 1f in 85% yield although the reaction required more time (6 h) to consume the
starting material (Table 1, entry 8). These Cu catalyzed conditions worked equally
well for the remaining halogen bearing analogues (Table 1, entries 11,13,15 and 17).
Tentatively, we assume that the Lewis acidity of the Cu species assists to activate the
hypervalent iodine oxidant (for a brief mechanistic discussion see Supporting
Information, Section S1.1).
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Table 1. Reactions of 4ꢀanilinoquinazolineꢀ2ꢀcarbonitriles 4a-j (0.20 mmol) with
PIFA (1.1ꢀ1.5 equiv) and Cu(OTf)2 (0ꢀ5 mol %) in neat TFA to give benzo[4,5]ꢀ
imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitriles 1a-r
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entrya
R1
R2
PIFA
(equiv)
1.1
1.1
1.1
1.1
1.5
1.1
1.1
1.5
1.5
1.1
1.5
1.1
1.5
1.1
1.5
Cu(OTf)2
(mol %)
temp
(oC)
20
20
20
20
80
20
80
20
80
20
80
20
80
20
80
20
80
20
80
time
(h)
0.5
1
1
26
3
7 d
25
6
1.50
32
4
4 d
2
7 d
0.75
32
4
16
8
yield 1
(%)
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H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
9ꢀMe
9ꢀMeO
9,10ꢀ(MeO)2
9,10ꢀ(MeO)2
9ꢀF
ꢀ
ꢀ
ꢀ
ꢀ
5
ꢀ
5
5
5
ꢀ
5
ꢀ
5
ꢀ
5
ꢀ
1a (92)
1b (80)
1c (82)
1d/e (85)b
1d/e (82)b
1f (81)c
1f (86)
9ꢀF
9ꢀF
9ꢀF
9ꢀCl
1f (85)
1f (89)
1g (86)
1g (88)
1h/i (41)d,e
1h/i (77)d
1j (77)f
1j (82)
1k (87)
1k(87)
1l (83)
9ꢀCl
9,10ꢀ(Cl)2
9,10ꢀ(Cl)2
11ꢀBr
11ꢀBr
9ꢀBr
1.1
1.5
1.1
1.5
H
9ꢀBr
H
H
5
ꢀ
5
2,3ꢀ(MeO)2
2,3ꢀ(MeO)2
1l (85)
a Substituent numbering based on major product. b Two inseparable products 1d/1e (2.6:1) by 1H NMR
c
of crude. Incomplete reaction: 4% of starting material recovered (note at 24 h there was 53% of
product). d Two inseparable products 1h/1i (2.6:1) by 1H NMR of crude. e Incomplete reaction: 35% of
f
starting material recovered. Incomplete reaction: 2% of starting material recovered (note at 24 h there
was 45% of product).
Not surprisingly, the reactions of 4ꢀanilinoquinazolines that hosted unsymmetrically
substituted anilines 4d [R2 = 3,4ꢀ(MeO)2] and 4g [R2 = 3,4ꢀ(Cl)2] gave mixtures of
two cyclization products a major and minor the ratio of ca. 2.6:1, which tentatively
reflected steric phenomena.
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With 4ꢀ(2ꢀbromoanilino)quinazolineꢀ2ꢀcarbonitrile (4h) in hand, we considered a
regioꢀcontrolled transition metalꢀcatalyzed nonꢀoxidative coupling. A number of non
oxidative cyclization protocols are known for the transformation of Nꢀalkyl or arylꢀ
substituted N'ꢀ(2ꢀhalophenyl)benzamidines to give 1ꢀalkylꢀ or 1ꢀarylꢀsubstituted 2ꢀ
arylꢀ1Hꢀbenzimidazoles; some involve transition metal catalysis (e.g., Pd,34 Cu,34d,35
or Co36), while others invoke base mediated aryne intermediates35b,37 or simply
intramolecular nucleophilic aromatic substitution.35b,38
After screening several Pd catalysts [Pd(OAc)2, Pd(dppf)Cl2.CH2Cl2, Pd(MeCN)2,
Pd(PhCN)2, PdCl2(Ph3P)2 and Pd(Ar3P)3 where Ar = 3,5ꢀ(F3C)2C6H3 (aka Superstable
Pd(0) Catalyst®)], ligands [2,2'ꢀbis(diphenylphosphino)ꢀ1,1'ꢀbinaphthyl (BINAP),
1,10ꢀphenanthroline (1,10ꢀPhen), 1,1'ꢀbis(diphenylphosphino)ferrocene (DPPF) and
N,N'ꢀdimethylethylenediamine (DMEDA)], bases [KHCO3, K3PO4, M2CO3 (M = Na,
K, Cs), KOH and DBU] and solvents (PhMe, MeCN, 1,4ꢀdioxane, THF, DMSO,
DMF, DMA and EtOH) we identified the following conditions: Pd(OAc)2 (10 mol %),
o
BINAP (10 mol %), K2CO3 (1 equiv), PhMe at ca. 160 C (sealed tube – Wood’s
metal bath temperature) that after 5 h completely consumed the starting material and
gave the target 1a in a 85% yield (Scheme 4).
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Scheme 4. Nonꢀoxidative CꢀN couplings of 4ꢀ(2ꢀbromoanilino)quinazolineꢀ2ꢀ
carbonitrile (4h) to give benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a)
o
Worthy of note was the need for high reaction temperatures (160 C): lower
o
temperatures (ca. 110 C) led to long reaction times (> 2 d) and incomplete
consumption of the starting material (up to 12% recovered). Attempts to lower the
reaction temperatures or reduce the Pd catalyst loading were unsuccessful, however,
the alternative use of CuI (10 mol %) with 1,10ꢀPhen (10 mol %) as ligand using
K2CO3 (1 equiv) as base in MeCN heated at reflux enabled the cyclization at
o
significantly lower reaction temperature (ca. 80 C) in 3 h to give the desired
tetracycle 1a in an improved 93% yield (Scheme 4). The use of less CuI (5 mol %),
alternative ligands (BINAP or DMEDA) failed to drive the reaction to completion
while the use of “ligand free” reaction conditions (CuI, DBU and DMSO)35e led to no
reaction. Interestingly, most reported reactions of this type invoked the need for 2
equiv of base, however, this led to a lower yield (80%).
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2.2.
Oxidative and non-oxidative cyclization chemistry of 3-aryl-4-imino-3,4-
5
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dihydroquinazoline-2-carbonitriles 5
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Unlike the above N,N'ꢀdisubstituted benzamidines and to the best of our knowledge,
there is only one report on the oxidative coupling of N,Nꢀdisubstituted benzamidines:
the O2/Cu(OAc)2 mediated oxidative cyclization of three NꢀarylꢀNꢀmethylbenzꢀ
amidines 8 to 1ꢀmethylꢀ2ꢀarylbenzimidazoles 9 in 54ꢀ84% yields (Scheme 5)39 and
there are no reports of nonꢀoxidative couplings.
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Scheme 5. Copper mediated oxidative CꢀN coupling of NꢀarylꢀNꢀmethylbenzamidines
8 to give 1ꢀmethylꢀ2ꢀarylbenzimidazoles 9.39
Attempted oxidative couplings of 4ꢀiminoꢀ3ꢀphenylꢀ3,4ꢀdihydroquinazolineꢀ2ꢀ
carbonitrile (5a) using either Buchwald’s conditions (Scheme 5), alternative oxidants
such as H2O2, NCS, MnO2, Pb(OAc)4, DDQ, benzoquinone and CAN, or the
Cu(OTf)2/PIFA conditions described above (Table 1) failed to give any reaction or led
to complex reaction mixtures (by TLC).
As such, we then investigated the alternative nonꢀoxidative coupling. The desired
3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5b) was prepared
via two routes: Firstly, by reaction of 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)benzamidine (10)
with 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium chloride (11) (aka Appel salt) (Conditions A)22a
which gave the product 5b in 74% yield and secondly by reaction of 2ꢀaminoꢀN'ꢀ(2ꢀ
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bromophenyl)benzamidine (10) with tetracyanoethene (TCNE) at ꢀ20 C (Conditions
B)22b which gave the product 5b in 66% yield together with the isomeric 4ꢀ(2ꢀbromoꢀ
anilino)quinazoline 4h in 25% yield (Scheme 6).
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i) Appel salt 11 (1 equiv)
DCM, 20 oC, 12 h
Br
HN
ii) i-Pr2NEt (2 equiv)
DCM, 20 oC, 3 h
N
5b (74%)
4h (25%)
NH2
N
Cl
Cl
N
CN
+
S
N
S
Br
NH2
Cl
TCNE (2 equiv)
MeCN, -20 oC, 1 d
11
10
5b (66%)
Scheme 6. Preparation of 3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀ
carbonitrile (5b) via Appel salt 11 (Conditions A)22a and TCNE (Conditions B).22b
Initially, Cu mediated nonꢀoxidative CꢀN couplings reactions of 3ꢀ(2ꢀbromophenyl)ꢀ
4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5b) were attempted, however, our
best conditions for the 4ꢀanilino analogue 4a ie CuI (10 mol %) 1,10ꢀPhen (10 mol %),
K2CO3 (1 equiv) in MeCN heated at reflux failed to give the desired cyclization. In
light of this we switched back to the Pd catalyzed conditions and identified the
following semiꢀoptimized conditions: Pd(OAc)2 (10 mol %), BINAP (10 mol %),
Cs2CO3 (1 equiv) in dry PhMe heated at reflux for 17 h under an argon atmosphere
which led to complete consumption of the starting material and gave the target
tetracycle 1a in 78% yield. By switching the Pd catalyst to Superstable Pd(0)
Catalyst® (10 mol %) and using K2CO3 (2 equiv) as base we were able to lower the
quantity of BINAP (5 mol %) and shorten the reaction time to only 5 h improving the
product yield to a satisfactory 93%. Interestingly, traces of moisture or air led to
significantly reduced product yields (62ꢀ65%) and longer reaction times, while the
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reaction with Superstable Pd(0) Catalyst® also worked in the absence of BINAP to
give benzimidazo[1,2ꢀc]quinazolineꢀ2ꢀcarbonitrile (1a) in near quantitative yield
(98%) but this reaction needed 3 days to come to completion. These conditions were
also suitable for preparing the 2,3ꢀdimethoxyꢀsubstitiuted benzimidazo[1,2ꢀc]quinꢀ
azoline 1l (Table 3, entry 4) but were unsuitable for preparing the 2ꢀCl, 2ꢀBr, 3ꢀCl,
1ꢀMe and 3ꢀMeO analogues: after 24 h the reactions failed to come to completion
(data not shown). Attempts to run these reactions at higher temperatures (140ꢀ160 oC)
using either microwave irradiation or by immersing the sealed reactions mixtures into
preheated Wood’s metal baths led to complex reaction mixtures and low to moderate
yields of the desired product (data not shown). Fortunately, in these cases, increasing
the quantity of K2CO3 to 3 equiv led to total consumption of the starting material
within 6 h (Table 3).
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12
13
14
15
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23
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Table 3. Nonꢀoxidative cyclization of 3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinꢀ
azolineꢀ2ꢀcarbonitriles 5b-h (0.2 mmol) to give benzimidazo[1,2ꢀc]quinazolineꢀ2ꢀ
carbonitriles 1a,l,m-q
entry
Ra
K2CO3
(equiv)
time
(h)
5
5
3
6
5
5
6
yields 1
(%)
1
2
3
4
5
6
7
8
9
H
H
1ꢀMe
2
3
3
3
2
3
3
3
3
1a (93)
1a (95)
1m (97)
1n (91)
1l (94)
1l (96)
1o (92)
1p (94)
1q (90)
3ꢀMeO
2,3ꢀ(MeO)2
2,3ꢀ(MeO)2
2ꢀCl
3ꢀCl
2ꢀBr
5
6
a Substituent numbering based on product.
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Interestingly, the more sterically hindered 1ꢀMe analogue 5c reacted the fastest (3 h)
(Table 3, entry 3), suggesting that steric compression at the reaction site may promote
the reaction. Furthermore, repeating the reaction of the unsubstituted analogue 5b
with 3 equiv of K2CO3 did not shorten the reaction time and gave the cyclized product
in an identical yield compared to the analogous reaction using 2 equiv of K2CO3 (data
not shown). With these improved conditions we attempted to reoptimize the reactions
by switching back to a stronger base Cs2CO3 (2 and 3 equiv) or to reduce the Pd
catalyst to 5 mol %, however, in both cases the reactions failed to come to completion.
Switching the Pd catalyst also led to a slower consumption of the starting materials.
Tentatively, we believe that increasing the equivalents of K2CO3, which was
heterogeneous in the reaction mixture, from 2 to 3 assists the reaction simply by
increasing the surface area. We note that our inorganic bases are typically powdered
and vacuum dried at 80ꢀ90 oC before use to improve the available surface area.40 This
may also explain the need for dry PhMe since traces of moisture in the solvent can
affect the dispersion of the anhydrous base. Attempts to overcome this by using a
biphasic reaction mixture or by using phase transfer catalysts (18ꢀcrownꢀ6,
BnEt3NCl),40 failed.
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3.
Conclusions
A Cu(OTf)2 catalyzed PIFA mediated oxidative cyclization of 4ꢀanilinoquinazolineꢀ2ꢀ
carbonitriles affords thirteen substituted benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀ
carbonitriles hosting electron releasing Me and MeO substituents or electron
withdrawing halogen substituents in good to excellent yields. Interestingly, in at least
two cases (the unsubstituted and the dimethoxy substituted analogues) the reactions
work equally well in the absence of the copper catalyst. Where the anilino moiety is
unsymmetrical the oxidative cyclisation suffers from regioselectivity, however, this
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can be overcome by switching to a nonꢀoxidative strategy: Pd(OAc)2 and CuI
catalyzed protocols were developed that successfully cyclized 4ꢀ(2ꢀbromoanilino)ꢀ
quinazolineꢀ2ꢀcarbonitrile (4h) to benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile
(1a) in high yields. An alternative Pd(0) catalyzed nonꢀoxidative CꢀN coupling was
also developed that enabled the cyclization of seven 3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀ
dihydroquinazolineꢀ2ꢀcarbonitriles again in high yields (90ꢀ97%). These methods
expand the synthetic routes of benzo[4,5]imidazo[1,2ꢀc]quinazolines and potentially
can find application in the synthesis of structurally related heterocycles.
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4.
Experimental Section
General procedures
4.1.
Anhydrous Na2SO4 was used for drying organic extracts and 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 chromatography41 was used throughout for all nonꢀ
TLC scale chromatographic separations using silica gel 60 (less than 0.063 mm).
Melting points were determined using a hotstage microscope apparatus or a DSC with
samples hermetically sealed in aluminum pans under an argon atmosphere, using
o
heating rates of 5 C/min. 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
FTIRꢀNIR spectrometer with a Ge ATR accessory and strong, medium and weak
1
peaks are represented by s, m and w, respectively. H and 13C NMR spectra were
recorded at 300 and 75 MHz, or at 500 and 125 MHz, respectively. Deuterated
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solvents were used for homonuclear lock, and the signals are referenced to the
deuterated solvent peaks. DEPT or APT NMR studies identified quaternary, tertiary,
secondary, and primary carbons, which are indicated by (s), (d), (t), and (q) notations,
respectively. Low resolution (EI) mass spectra were recorded on a GCMS with direct
inlet probe. MALDIꢀTOF mass spectra were conducted on a timeꢀofꢀflight (TOF)
mass spectrometer. 4,5ꢀDichloroꢀ1,2,3ꢀdithiazolium chloride (11),42 tetracyanoethene
(TCNE),43 2ꢀaminoꢀN'ꢀ(3,4ꢀdimethoxyphenyl)benzamidine,22b 2ꢀaminoꢀN'ꢀ(3,4ꢀdiꢀ
chlorophenyl)benzamidine,21 4ꢀ(arylamino)quinazolineꢀ2ꢀcarbonitriles 4a-c,e,f,i,j,22b
and 4ꢀiminoꢀ3ꢀphenylꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5a)22a were prepared
according to literature procedures.
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4.2.
Preparation of N-arylbenzamidines
4.2.1. 2ꢀAminoꢀN'ꢀ(2ꢀbromophenyl)benzamidine (10) (typical procedure). To
o
stirred anthranilonitrile (343 mg, 2.91 mmol) at ca. 20 C was added powdered
anhydrous AlCl3 (387 mg, 2.91 mmol). The reaction mixture was then heated (ca. 100
oC) until a homogenous melt formed. To this was added 2ꢀbromoaniline (500 mg,
2.91 mmol) and the mixture was heated for 6 h and then allowed to cool to ca. 20 oC.
The resultant solid mass was then crushed and slurried in 12.5% NaOH (40 mL). The
resulting mixture was extracted (DCM, 3 × 50 mL), washed (H2O, 1 × 50 mL) and
dried (Na2SO4). The organic phase adsorbed onto silica and chromatographed (tꢀ
BuOMe) to give the title compound 10 (306 mg, 36%) as colorless needles, mp
o
o
(hotstage) 125.5ꢀ126.5 C (lit.,44 127ꢀ129 C) (from cꢀhexane/EtOH, 90:10); Rf 0.74
(tꢀBuOMe); λmax(DCM)/nm 250 (log ε 4.45), 304 (3.78), 352 (3.76); νmax/cmꢀ1 3478w,
3451w and 3370w (NꢀH), 3169w and 3046w (aryl CꢀH), 1630s, 1614s, 1580m,
1562m, 1545m, 1493w, 1464m, 1433w, 1387m, 1319w, 1310w, 1271w, 1258w,
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1233w, 1161w, 1121w, 1040w, 1024m, 835m, 748m; δH(500 MHz; CDCl3) 7.64 (1H,
d, J 8.0), 7.43 (1H, d, J 8.0), 7.30 (1H, dd, J 7.5, 7.5), 7.20 (1H, dd, J 7.8, 7.8), 7.04
(1H, d, J 7.5), 6.95 (1H, dd, J 7.8, 7.8), 6.74 (1H, d, J 8.0), 6.69 (1H, dd, J 7.5, 7.5),
5.96 (2H, br s), 4.77 (2H, br s); δC(125 MHz; CDCl3) 156.1 (s), 147.9 (s), 147.4 (s),
133.3 (d), 131.4 (d), 128.5 (d), 127.5 (d), 124.5 (d), 123.2 (d), 117.2 (d), 116.6 (s),
116.5 (d), 116.4 (s); m/z (EI) 291 (M++2, 38%), 289 (M+, 39), 274 (13), 272 (14), 210
(100), 193 (23), 173 (69), 171 (71), 119 (92), 105 (34), 92 (63), 76 (16), 65 (57).
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12
13
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4.2.2. 2ꢀAminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ6ꢀmethylbenzamidine (12). Similar treatment
of 6ꢀmethylanthranilonitrile (384 mg, 2.91 mmol) with anhydrous AlCl3 (387 mg,
2.91 mmol) and 2ꢀbromoaniline (500 mg, 2.91 mmol) gave the title compound 12
(1.33 g, 43%) as colorless plates, mp (hotstage) 153.3ꢀ154.3 oC (from cꢀhexane/DCM,
90:10); Rf 0.76 (tꢀBuOMe); (found: C, 55.40; H, 4.57; N, 13.62. C14H14BrN3 requires
C, 55.28; H, 4.64; N, 13.81%); λmax(DCM)/nm 287 (log ε 3.71); νmax/cmꢀ1 3429w,
3350w and 3269w (NꢀH), 3123w (aryl CꢀH), 1626s, 1599s, 1578s, 1466m, 1433w,
1379w, 1302w, 1285w, 1169w, 1101w, 1070w, 1041w, 1026m, 783m, 754s; δH(500
MHz; CD3CN) 7.63 (1H, d, J 8.0), 7.34 (1H, dd, J 7.0, 7.0), 7.02 (2H, dd, J 9.0, 9.0),
6.97 (1H, dd, J 7.0, 7.0), 6.57 (2H, dd, J 7.8, 7.8), 5.35 (2H, br s), 4.64 (2H, br s),
2.40 (3H, s); δC(125 MHz; DMSOꢀd6) 155.7 (s), 148.6 (s), 145.9 (s), 135.6 (s), 132.9
(d), 128.8 (d), 128.6 (d), 123.7 (d), 123.0 (s), 122.5 (d), 118.0 (d), 116.5 (s), 112.8 (d),
19.9 (q); m/z (MALDIꢀTOF) 306 (MH++2, 100%), 304 (MH+, 88), 289 (34), 287 (35),
224 (27), 209 (13), 173 (8), 133 (26).
4.2.3. 2ꢀAminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ4ꢀmethoxybenzamidine (13). Similar treatment
of 4ꢀmethoxyanthranilonitrile (431 mg, 2.91 mmol) with anhydrous AlCl3 (387 mg,
2.91 mmol) and 2ꢀbromoaniline (500 mg, 2.91 mmol) gave the title compound 13
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(1.62 g, 51%) as colorless plates, mp (hotstage) 121.5ꢀ122.5 oC (from cꢀhexane/DCM,
90:10); Rf 0.58 (tꢀBuOMe); (found: C, 52.43; H, 4.35; N, 13.02. C14H14BrN3O
requires C, 52.52; H, 4.41; N, 13.12%); λmax(DCM)/nm 266 (log ε 4.15), 286 inf
(3.89), 321 (3.94); νmax/cmꢀ1 3466w and 3350w (NꢀH), 2999w (aryl CꢀH), 2965w and
2895w (alkyl CꢀH), 1618s, 1614s, 1593m, 1572m, 1553m, 1508m, 1466w, 1441w,
1427w, 1377s, 1306w, 1256m, 1231m, 1215s, 1164m, 1157w, 1092w, 1067w, 1034w,
1024m, 833s, 795m, 758s; δH(500 MHz; CDCl3) 7.63 (1H, d, J 8.0), 7.35 (1H, d, J
8.5), 7.28 (1H, dd, J 7.5, 7.5), 7.03 (1H, d, J 7.5), 6.94 (1H, dd, J 8.0, 8.0), 6.27 (1H,
dd, J 6.0, 2.5), 6.22 (1H, d, J 2.5), 6.15 (2H, br s), 4.70 (2H, br s), 3.79 (3H, s);
δC(125 MHz; CDCl3) 162.2 (s), 156.0 (s), 149.9 (s), 147.4 (s), 133.3 (d), 129.0 (d),
128.4 (d), 124.4 (d), 123.4 (d), 116.9 (s), 109.4 (s), 103.7 (d), 100.8 (d), 55.1 (q); m/z
(MALDIꢀTOF) 322 (M++2, 100%), 320 (MH+, 100), 305 (21), 303 (22), 242 (1), 149
(4).
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4.2.4. 2ꢀAminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ4,5ꢀdimethoxybenzamidine (14). Similar treatꢀ
ment of 4,5ꢀdimethoxyanthranilonitrile (518 mg, 2.91 mmol) with anhydrous AlCl3
(387 mg, 2.91 mmol) and 2ꢀbromoaniline (500 mg, 2.91 mmol) gave the title
o
compound 14 (0.71 g, 20%) as colorless needles, mp (hotstage) 151ꢀ152 C (from cꢀ
hexane/DCM, 80:20); Rf 0.44 (tꢀBuOMe); (found: C, 51.35; H, 4.54; N, 12.17.
C15H16BrN3O2 requires C, 51.44; H, 4.61; N, 12.00%); λmax(DCM)/nm 275 inf (log ε
4.05), 337 (3.94); νmax/cmꢀ1 3468w, 3370w and 3291w (NꢀH), 3138w and 3065w (aryl
CꢀH), 2934w and 2833w (alkyl CꢀH), 1626s, 1558w, 1522m, 1468w, 1440w, 1387m,
1350w, 1277w, 1246m, 1229s, 1213s, 1192w, 1179w, 1159w, 1031w, 1022w, 854m,
768m, 743s; δH(500 MHz; CDCl3) 7.63 (1H, d, J 8.0), 7.29 (1H, dd, J 7.3, 7.3), 7.04
(1H, d, J 8.0), 6.96 (1H, br s), 6.94 (1H, dd, J 8.0, 8.0), 6.27 (1H, s), 5.82 (2H, br s),
4.68 (2H, br s), 3.87 (3H, s), 3.83 (3H, s); δC(125 MHz; CDCl3) 155.9 (s), 152.5 (s),
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147.4 (s), 143.9 (s), 140.8 (s), 133.3 (d), 128.4 (d), 124.4 (d), 123.3 (d), 116.8 (s),
111.8 (d), 107.6 (s), 100.9 (d), 57.1 (q), 55.8 (q); m/z (MALDIꢀTOF) 352 (MH++2,
97%), 350 (MH+, 100), 349 (M+, 12), 339 (6), 337 (6), 335 (4), 333 (3), 272 (3).
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4.2.5. 2ꢀAminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ5ꢀchlorobenzamidine (15). Similar treatment
of 5ꢀchloroanthranilonitrile (442 mg, 2.91 mmol) with anhydrous AlCl3 (387 mg, 2.91
mmol) and 2ꢀbromoaniline (500 mg, 2.91 mmol) gave the title compound 15 (1.70 g,
52%) as colorless needles, mp (hotstage) 147ꢀ147.5 oC (from cꢀhexane/DCM, 90:10);
Rf 0.65 (tꢀBuOMe); (found: C, 48.03; H, 3.36; N, 12.87. C13H11BrClN3 requires C,
48.10; H, 3.42; N, 12.95%); λmax(DCM)/nm 243 inf (log ε 4.56), 286 inf (3.94), 343
(3.92); νmax/cmꢀ1 3428w, 3397w, 3312w and 3198w (NꢀH), 3065w (aryl CꢀH), 1630m,
1614m, 1585m, 1572w, 1541w, 1487w, 1464m, 1435w, 1375m, 1301w, 1254w,
1236w, 1161w, 1115w, 1083w, 1038w, 1024w, 819s, 747s; δH(500 MHz; CDCl3)
7.64 (1H, d, J 8.0), 7.41 (1H, br s), 7.30 (1H, dd, J 7.5, 7.5), 7.15 (1H, dd, J 9.0, 2.5),
7.02 (1H, d, J 8.0), 6.97 (1H, ddd, J 7.8, 7.8, 1.5), 6.67 (1H, d, J 9.0), 5.96 (2H, br s),
4.78 (2H, br s); δC(125 MHz; CDCl3) 155.2 (s), 146.9 (s), 146.5 (s), 133.4 (d), 131.3
(d), 128.5 (d), 127.2 (d), 124.8 (d), 123.0 (d), 120.9 (s), 118.4 (d), 117.3 (s), 116.5 (s);
m/z (MALDIꢀTOF) 328 (MH++4, 24%), 326 (MH++2, 100), 324 (MH+, 76), 312 (5),
310 (4).
4.2.6. 2ꢀAminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ4ꢀchlorobenzamidine (16). Similar treatment
of 4ꢀchloroanthranilonitrile (442 mg, 2.91 mmol) with anhydrous AlCl3 (387 mg, 2.91
mmol) and 2ꢀbromoaniline (500 mg, 2.91 mmol) gave the title compound 16 (1.84 g,
57%) as colorless needles, mp (hotstage) 130ꢀ131 oC (from cꢀhexane/DCM, 90:10); Rf
0.62 (tꢀBuOMe); (found: C, 47.97; H, 3.40; N, 12.83. C13H11BrClN3 requires C, 48.10;
H, 3.42; N, 12.95%); λmax(DCM)/nm 261 inf (log ε 4.09), 286 inf (3.82), 330 (3.81);
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νmax/cmꢀ1 3476w, 3375w and 3283w (NꢀH), 3188w and 3067w (aryl CꢀH), 1624s,
1578m, 1549m, 1491m, 1470m, 1435w, 1420w, 1375m, 1321w, 1258w, 1234w,
1113w, 1053w, 1024m, 914s, 854m, 835m, 748s; δH(500 MHz; CDCl3) 7.64 (1H, dd,
J 8.0, 1.0), 7.35 (1H, d, J 8.5), 7.30 (1H, dd, J 7.5, 7.5), 7.22 (1H, d, J 7.5), 6.96 (1H,
ddd, J 8.0, 8.0, 1.0), 6.72 (1H, d, J 2.0), 6.64 (1H, d, J 9.0, 2.0), 6.12 (2H, br s), 4.75
(2H, br s); δC(125 MHz; CDCl3) 155.5 (s), 149.0 (s), 146.9 (s), 137.1 (s), 133.4 (d),
128.8 (d), 128.5 (d), 124.7 (d), 123.1 (d), 116.6 (s), 116.5 (d), 116.4 (d), 114.6 (s); m/z
(MALDIꢀTOF) 328 (MH++4, 26%), 326 (MH++2, 100), 324 (MH+, 76), 312 (12), 310
(9), 309 (12), 307 (7).
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4.2.7. 2ꢀAminoꢀ5ꢀbromoꢀN'ꢀ(2ꢀbromophenyl)benzamidine (17). Similar treatment
of 5ꢀbromoanthranilonitrile (571 mg, 2.91 mmol) with anhydrous AlCl3 (387 mg, 2.91
mmol) and 2ꢀbromoaniline (500 mg, 2.91 mmol) gave the title compound 17 (2.15 g,
58%) as colorless plates, mp (hotstage) 136.5ꢀ137.8 oC (from cꢀhexane/DCM, 90:10);
Rf 0.60 (tꢀBuOMe); (found: C, 42.19; H, 2.92; N, 11.26. C13H11Br2N3 requires C,
42.31; H, 3.00; N, 11.39%); λmax(DCM)/nm 244 inf (log ε 4.38), 265 inf (4.21), 343
(3.70); νmax/cmꢀ1 3428w, 3393w, 3318w and 3196w (NꢀH), 3067w (aryl CꢀH), 1632s,
1611s, 1582m, 1568m, 1537m, 1485m, 1462s, 1435w, 1375s, 1304w, 1254m, 1234w,
1163m, 1119w, 1115w, 1051w, 1022w, 839m, 818s, 745s; δH(500 MHz; CDCl3) 7.64
(1H, d, J 8.0), 7.55 (1H, br s), 7.31 (1H, dd, J 7.5, 7.5), 7.27 (1H, dd, J 7.5, 2.0), 7.02
(1H, d, J 8.0), 6.97 (1H, dd, J 7.5, 7.5), 6.63 (1H, d, J 9.0), 5.99 (2H, br s), 4.76 (2H,
br s); δC(125 MHz; CDCl3) one C (s) resonance missing, 155.1 (s), 146.9 (s), 134.0
(d), 133.4 (d), 130.1 (d), 128.5 (d), 124.8 (d), 123.0 (d), 118.7 (d), 117.9 (s), 116.5 (s),
107.6 (s); m/z (MALDIꢀTOF) 372 (MH++4, 76%), 370 (MH++2, 100), 368 (MH+, 74),
358 (18), 356 (36), 351 (25), 306 (7), 304 (8), 290 (7), 174 (5), 172 (5).
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4.3.
Preparation of 4-(arylamino)quinazoline-2-carbonitriles 4d, 4g and 4h
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4.3.1. 6,7ꢀDimethoxyꢀ4ꢀ(phenylamino)quinazolineꢀ2ꢀcarbonitrile (4d) (typical
procedure). To a stirred solution of 2ꢀaminoꢀN'ꢀ(3,4ꢀdimethoxyphenyl)benzamidine22b
(271 mg, 1.00 mmol) in MeCN (10 mL) at ca. 20 oC was added glacial AcOH (57.0
ꢁL, 1.00 mmol). To that mixture, at ca. 20 oC was added dropwise a solution of
TCNE (128 mg, 1.00 mmol) in MeCN (10 mL) and left to stir for 7 h. The reaction
mixture was then adsorbed onto silica and chromatographed (DCM/tꢀBuOMe, 95:05)
to give the title compound 4d (104.8 mg, 34%) as yellow needles, mp (hotstage)
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285.9ꢀ287 C (cꢀhexane/THF, 80:20), mp (DSC) onset 286.6 oC, peak max. 287.1 oC;
Rf 0.55 (DCM/tꢀBuOMe, 95:05); (found: C, 66.60; H, 4.47; N, 18.13. C17H14N4O2
requires C, 66.66; H, 4.61; N, 18.29%); λmax(DCM)/nm 258 inf (log ε 4.16), 268 inf
(4.14), 281 inf (4.09), 332 (4.29); νmax/cmꢀ1 3401w (NꢀH), 3015w (aryl CꢀH), 2928w
and 2855w (alkyl CꢀH), 2239w (C≡N), 1611m, 1578m, 1514s, 1460s, 1425m, 1396w,
1360w, 1294w, 1273m, 1242m, 1205m, 1161m, 1074w, 1036w, 1001m, 841m, 737s;
δH(500 MHz; DMSOꢀd6) 9.93 (1H, br s), 7.91 (1H, s), 7.69 (2H, d, J 7.5), 7.45 (2H,
dd, J 7.8, 7.8), 7.30 (1H, s), 7.21 (1H, dd, J 7.5, 7.5), 3.98 (3H, s), 3.95 (3H, s);
δC(125 MHz; DMSOꢀd6) 156.9 (s), 155.1 (s), 151.0 (s), 146.1 (s), 138.4 (s), 138.1 (s),
128.8 (d), 124.8 (d), 123.3 (d), 117.3 (s), 109.7 (s), 107.6 (d), 102.2 (d), 56.6 (q), 56.3
(q); m/z (MALDIꢀTOF) 308 (MH++1, 12%), 307 (MH+, 100), 100 (5). Further elution
(DCM/tꢀBuOMe, 60:40) gave 4ꢀiminoꢀ6,7ꢀdimethoxyꢀ3ꢀphenylꢀ3,4ꢀdihydroquinazolꢀ
ineꢀ2ꢀcarbonitrile (18) (2.1 mg, 1%) as colorless needles, mp (hotstage) 230 οC (sub.)
[lit.,22a 230 οC (sub.)] (from acetone); Rf 0.59 (tꢀBuOMe/EtOH, 60:40); δH(300 MHz;
CDCl3) 7.72ꢀ7.66 (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
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(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),
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4.3.2. 4ꢀ[(3,4ꢀDichlorophenyl)amino]quinazolineꢀ2ꢀcarbonitrile (4g). Similar treatꢀ
ment of 2ꢀaminoꢀN'ꢀ(3,4ꢀdichlorophenyl)benzamidine21 with TCNE gave the title
compound 4g (138 mg, 44%) as colorless needles, mp (hotstage) 257.7ꢀ258.7 oC (cꢀ
hexane/THF, 80:20), mp (DSC) onset 258.6 oC, peak max. 259.2 oC; Rf 0.62 (DCM/tꢀ
BuOMe, 95:05); (found: C, 57.02; H, 2.53; N, 17.66. C15H8Cl2N4 requires C, 57.17; H,
2.56; N, 17.78%); λmax(DCM)/nm 248 inf (log ε 4.23), 268 (4.07), 282 inf (3.99), 336
(4.23), 396 (3.11), 424 (3.02); νmax/cmꢀ1 3366w (NꢀH), 3129w and 3032w (aryl CꢀH),
2251w (C≡N), 1618w, 1602w, 1570m, 1555w, 1522s, 1499w, 1474m, 1425m, 1366m,
1314w, 1219w, 1132w, 1092w, 1030w, 806m, 793m, 760s; δH(500 MHz; DMSOꢀd6)
10.39 (1H, br s), 8.59 (1H, d, J 8.0), 8.14 (1H, d, J 2.5), 8.01 (1H, dd, J 7.8, 7.8), 7.91
(1H, d, J 8.0), 7.85ꢀ7.82 (2H, m), 7.70 (1H, d, J 8.5); δC(125 MHz; DMSOꢀd6) 158.2
(s), 149.0 (s), 139.6 (s), 138.5 (s), 134.8 (d), 130.9 (s), 130.6 (d), 129.4 (d), 128.3 (d),
126.4 (s), 124.2 (d), 123.5 (d), 122.9 (d), 116.8 (s), 115.6 (s); m/z (MALDIꢀTOF) 317
(MH++2, 9%), 315 (MH+, 22), 266 (14), 215 (39), 153 (100), 130 (5). Further elution
(DCM/tꢀBuOMe, 90:20) gave 3ꢀ(3,4ꢀdichlorophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolꢀ
ineꢀ2ꢀcarbonitrile (19) (5.4 mg, 2%) as beige plates, mp (hotstage) 175ꢀ176 οC (lit.,22a
175ꢀ176 oC) (from nꢀpentane/DCM); Rf 0.77 (DCM/tꢀBuOMe, 90:10); δH(300 MHz;
CDCl3) 8.12 (1H, d, J 7.2), 7.73 (1H, d, J 8.7), 7.70ꢀ7.65 (2H, m), 7.60ꢀ7.54 (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); identical to an authentic sample.
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4.3.3. 4ꢀ[(2ꢀBromophenyl)amino]quinazolineꢀ2ꢀcarbonitrile (4h). Similar treatment
of 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)benzamidine (10) with TCNE gave the title compound
4h (290 mg, 89%) as colorless plates, mp (hotstage) 181ꢀ182 oC (cꢀhexane/THF,
90:10), mp (DSC) onset 181.8 oC, peak max. 182.6 oC; Rf 0.76 (DCM/tꢀBuOMe,
95:05); (found: C, 55.33; H, 2.70; N, 17.00. C15H9BrN4 requires C, 55.41; H, 2.79; N,
17.23%); λmax(DCM)/nm 258 inf (log ε 3.97), 270 inf (3.93), 283 inf (3.85), 297 inf
(3.79), 337 (4.14); νmax/cmꢀ1 3395w (NꢀH), 3062w (aryl CꢀH), 2245w (C≡N), 1614m,
1595m, 1584m, 1570m, 1558m, 1530s, 1495m, 1460m, 1441m, 1420m, 1369w,
1356m, 1319m, 1236w, 1217w, 1171w, 1130w, 1092w, 1022m, 1018m, 991m, 760s,
752s, 746s; δH(500 MHz; CDCl3) 8.78 (1H, d, J 8.5), 8.35 (1H, br s), 8.02 (2H, dd, J
9.3, 9.3), 7.95 (1H, dd, J 7.8, 7.8), 7.78 (1H, dd, J 7.5, 7.5), 7.66 (1H, d, J 8.0), 7.45
(1H, dd, J 7.5, 7.5), 7.10 (1H, dd, J 7.8, 7.8); δC(125 MHz; CDCl3) 157.1 (s), 149.6
(s), 140.4 (s), 135.1 (s), 134.3 (d), 132.4 (d), 129.8 (d), 129.7 (d), 128.8 (d), 125.8 (d),
122.9 (d), 120.4 (d), 116.5 (s), 115.6 (s), 114.8 (s); m/z (MALDIꢀTOF) 327 (MH++2,
100%), 325 (MH+, 64), 245 (19). Further elution (DCM/tꢀBuOMe, 90:10) gave 3ꢀ(2ꢀ
bromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroꢀquinazolineꢀ2ꢀcarbonitrile (5b) (3.3 mg, 1%) as
colorless needles, mp (hotstage) 183.6ꢀ185.7 οC (from cꢀhexane/DCM, 90:10), mp
(DSC) onset 183.7 oC, peak max. 186.2 oC; Rf 0.54 (DCM/tꢀBuOMe, 90:10); (found:
C, 55.56; H, 2.64; N, 17.26. C15H9BrN4 requires C, 55.41; H, 2.79; N, 17.23%);
λmax(DCM)/nm 274 (log ε 4.16), 283 (4.22), 293 (4.15), 318 inf (3.81), 330 (3.94),
343 (3.97), 360 inf (3.80); νmax/cmꢀ1 3323w (NꢀH), 3013w (aryl CꢀH), 2239 (C≡N),
1641s, 1605w, 1589m, 1564m, 1472m, 1462m, 1354s, 1337w, 1321w, 1302w, 1231w,
1182w, 1161w, 1121m, 1065m, 1024w, 1003m, 880m, 816s, 779s, 762s; δH(500 MHz;
CDCl3) 8.21 (1H, br s), 7.89 (1H, d, J 8.0), 7.73–7.68 (2H, m), 7.61 (1H, dd, J 7.8,
7.8), 7.58ꢀ7.50 (3H, m), 6.72 (1H, br s); δC(125 MHz; CDCl3) one C (d) resonance
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missing, 152.6 (s), 143.1 (s), 134.8 (d), 134.6 (s), 133.5 (d), 132.7 (d), 131.0 (d),
130.0 (d), 129.8 (d), 128.7 (d), 125.5 (s), 123.9 (s), 122.5 (s), 111.1 (s); m/z (MALDIꢀ
TOF) 326 (MH++1, 6%), 325 (MH+, 68), 324 (M+, 24), 323 (100).
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Preparation of 3-(2-bromophenyl)-4-imino-3,4-dihydroquinazoline-2-
carbonitriles 5b-h
4.4.1. 3ꢀ(2ꢀBromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5b)
4.4.1.1. Method A via TCNE (typical procedure). To a stirred solution of TCNE (256
mg, 2.00 mmol) in dry MeCN (10 mL) at ca. ꢀ20 oC was added a solution of 2ꢀaminoꢀ
N'ꢀ(2ꢀbromophenyl)benzamidine (10) (289 mg, 1.00 mmol) in dry MeCN (10 mL).
The reaction mixture was then left to stir at ca. ꢀ20 oC for 1 d, after which time it was
adsorbed onto silica and chromatographed (DCM/tꢀBuOMe, 95:05) to give the title
compound 5b (215 mg, 66%) as colorless plates, mp (hotstage) 183.6ꢀ185.7οC (from
cꢀhexane); Rf 0.54 (DCM/tꢀBuOMe, 90:10); identical to that described above.
4.4.1.2. Method B via Appel salt 11 (typical procedure). To a stirred solution of 4,5ꢀ
dichloroꢀ1,2,3ꢀdithiazolium chloride (11) (826 mg, 3.97 mmol) in DCM (40 mL) at ca.
o
20 C was added 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)benzamidine (10) (1.15 g, 3.97 mmol)
and the mixture was then left to stir at ca. 20 oC for 12 h. Then, to the reaction
mixture was added Hünig’s base (1.36 ꢁL, 7.92 mmol) and left to stir at ca. 20 oC for
an additional 3 h. The reaction mixture was then adsorbed onto silica and
chromatographed (nꢀhexane) to give traces of S8, followed by (nꢀhexane/DCM, 80:20)
4ꢀchloroꢀ5Hꢀ1,2,3ꢀdithiazolꢀ5ꢀone (65 mg, 11%). Further elution (DCM/tꢀBuOMe,
90:10) gave the title compound 5b (856 mg, 74%) as colorless plates, mp (hotstage)
ο
183.6ꢀ185.7 C (from cꢀhexane); Rf 0.54 (DCM/tꢀBuOMe, 90:10); identical to that
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4.4.2. 3ꢀ(2ꢀBromophenyl)ꢀ4ꢀiminoꢀ5ꢀmethylꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile
(5c) via Method B. Similar treatment of 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium chloride (11)
(826 mg, 3.97 mmol) with 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ6ꢀmethylbenzamidine (12)
(1.207 g, 3.97 mmol) gave the title compound 5c (338.1 mg, 74%) as colorless plates,
mp (hotstage) 122.9ꢀ124.5 οC (from cꢀhexane/DCM, 90:10); mp (DSC) onset
123.2 oC, peak max. 129.0 oC (from cꢀhexane/DCM, 90:10); Rf 0.73 (DCM/tꢀBuOMe,
90:10); (found: C, 56.19; H, 3.36; N, 16.51. C16H11BrN4 requires C, 56.66; H, 3.27; N,
16.52%); λmax(DCM)/nm 245 inf (log ε 4.09), 260 inf (3.91), 269 (3.93), 279 (3.85),
315 inf (3.78), 328 (3.84), 342 (3.80), 360 inf (3.59); νmax/cmꢀ1 3408w (NꢀH), 3055w
(aryl CꢀH), 2237 (C≡N), 1626s, 1591m, 1560m, 1516w, 1470m, 1435w, 1360s,
1325w, 1305w, 1290w, 1217w, 1173w, 1156w, 1086w, 1065w, 1047w, 1024w,
1005s, 802s, 760s, 725m; δH(500 MHz; CDCl3) NH deuterium exchanged, 7.88 (1H,
dd, J 7.8, 1.0), 7.61 (1H, ddd, J 7.8, 7.8, 1.3), 7.55ꢀ7.48 (4H, m), 7.33 (1H, dd, J 7.0,
1.3), 2.83 (3H, s); δC(75 MHz; CDCl3) two C (s) resonances missing, 145.0 (s), 139.7
(s), 134.9 (d), 133.3 (d), 132.6 (d), 132.3 (d), 131.4 (d), 129.8 (d), 128.6 (s), 126.9 (d),
124.4 (s), 121.3 (s), 111.2 (s), 31.0 (q); m/z (MALDIꢀTOF) 341 (MH++2, 97%), 339
(MH+, 100).
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4.4.3. 3ꢀ(2ꢀBromophenyl)ꢀ4ꢀiminoꢀ7ꢀmethoxyꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarboꢀ
nitrile (5d) via Method B. Similar treatment of 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium
chloride (11) (826 mg, 3.97 mmol) with 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ4ꢀmethoxyꢀ
benzamidine (13) (1.270 g, 3.97 mmol) gave the title compound 5d (275.4 mg, 77%)
as colorless plates, mp (hotstage) 158.9ꢀ161.2 οC (from cꢀhexane/DCM, 90:10), mp
(DSC) onset 160.3 oC, peak max. 162.6 oC (from cꢀhexane/DCM, 90:10); Rf 0.47
(DCM/tꢀBuOMe, 90:10); (found: C, 54.28; H, 2.98; N, 15.70. C16H11BrN4O requires
C, 54.10; H, 3.12; N, 15.77%); λmax(DCM)/nm 247 inf (log ε 4.29), 256 (4.36), 265
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(4.39), 275 (4.30), 300 inf (3.61), 313 (3.70), 327 (3.68), 354 inf (3.49); νmax/cmꢀ1
3298w (NꢀH), 3009w (aryl CꢀH), 2967w, 2940w and 2839w (alkyl CꢀH), 2237 (C≡N),
1634s, 1613s, 1592s, 1574w, 1562w, 1491s, 1472m, 1437w, 1352m, 1308s, 1283m,
1224w, 1200w, 1167s, 1130w, 1069w, 1026s, 1001w, 839m, 797m, 764s, 754s, 727m;
δH(500 MHz; CDCl3) NH deuterium exchanged, 8.10 (1H, br s), 7.88 (1H, d, J 8.3),
7.61 (1H, ddd, J 7.5, 7.5, 1.5), 7.53ꢀ7.49 (2H, m), 7.13ꢀ7.11 (2H, m), 3.93 (3H, s);
δC(125 MHz; CDCl3) one C (s) resonance missing, 163.8 (s), 144.9 (s), 134.8 (d),
132.6 (d), 131.5 (s), 131.0 (d), 129.7 (d), 127.0 (d), 124.0 (s), 118.8 (d), 115.4 (s),
111.1 (s), 110.3 (d), 55.8 (q); m/z (MALDIꢀTOF) 357 (MH++2, 100%), 355 (MH+,
89).
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4.4.4. 3ꢀ(2ꢀBromophenyl)ꢀ4ꢀiminoꢀ6,7ꢀdimethoxyꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarboꢀ
nitrile (5e) via Method B. Similar treatment of 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium
chloride (11) (826 mg, 3.97 mmol) with 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ4,5ꢀdimethoxyꢀ
benzamidine (14) (1.390 g, 3.97 mmol) gave the title compound 5e (256.3 mg, 66%)
as colorless plates, mp (hotstage) 225.9ꢀ226.6 οC (from cꢀhexane/DCM, 90:10); mp
(DSC) onset 226.7 oC, peak max. 227.4 oC, decomp. onset 232.6 oC, peak max
239.5 oC (from cꢀhexane/DCM, 90:10); Rf 0.32 (DCM/tꢀBuOMe, 90:10); (found: C,
53.10; H, 3.27; N, 14.63. C17H13BrN4O2 requires C, 53.01; H, 3.40; N, 14.54%);
λmax(DCM)/nm 258 inf (log ε 4.33), 268 (4.39), 277 inf (4.33), 304 inf (3.60), 316
(3.78), 330 (3.88), 355 (3.87), 374 inf (3.77), 396 inf (3.40); νmax/cmꢀ1 3291w (NꢀH),
3092w, 3067w and 3009w (aryl CꢀH), 2965w, 2938w and 2837w (alkyl CꢀH), 2237w
(C≡N), 1636s, 1609s, 1504s, 1472m, 1452m, 1442m, 1423w, 1379m, 1346w, 1304s,
1283m, 1265m, 1250m, 1207m, 1182w, 1126s, 1119s, 1076w, 1049w, 1024m, 997m,
885m, 864s, 851m, 831m, 775m, 760s; δH(500 MHz; CDCl3) 7.90 (1H, d, J 8.0), 7.67
(1H, br s), 7.63 (1H, dd, J 8.0, 8.0), 7.54 (1H, dd, J 8.0, 8.0), 7.51 (1H, dd, J 7.8, 1.8),
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7.11 (1H, s), 6.28 (1H, br s), 4.02 (3H, s), 4.00 (3H, s); δC(75 MHz; CDCl3) 153.8 (s),
151.2 (s), 138.6 (s), 134.9 (d), 134.4 (s), 132.8 (d), 131.1 (d), 129.9 (d), 129.2 (s),
124.2 (s), 116.1 (s), 111.3 (s), 109.3 (d), 105.7 (d), 56.5 (q), 56.4 (q); m/z (MALDIꢀ
TOF) 387 (MH++2, 83%), 385 (MH+, 100), 305 (10).
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4.4.5. 3ꢀ(2ꢀBromophenyl)ꢀ6ꢀchloroꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile
(5f) via Method B. Similar treatment of 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium chloride (11)
(826 mg, 3.97 mmol) with 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ5ꢀchlorobenzamidine (15)
(1.290 g, 3.97 mmol) gave the title compound 5f (290.1 mg, 81%) as colorless plates,
mp (hotstage) 226.5ꢀ227.8 οC (from cꢀhexane/DCM, 90:10); mp (DSC) onset
227.0 oC, peak max. 228.7 oC (from cꢀhexane/DCM, 90:10); Rf 0.70 (DCM/tꢀBuOMe,
90:10); (found: C, 49.96; H, 2.18; N, 15.47. C15H8BrClN4 requires C, 50.10; H, 2.24;
N, 15.58%); λmax(DCM)/nm 242 inf (log ε 4.05), 250 (4.04), 256 inf (4.02), 266 (4.05),
276 (3.95), 304 inf (3.74), 316 (3.91), 329 (3.96), 343 inf (3.85), 359 inf (3.68), 379
inf (3.20); νmax/cmꢀ1 3298w (NꢀH), 3055w (aryl CꢀH), 2243w (C≡N), 1643m, 1630m,
1601w, 1587w, 1570w, 1557w, 1464w, 1424m, 1344m, 1312s, 1296m, 1165m,
1121w, 1080w, 1047w, 1030w, 1003w, 837s, 771s, 729m, 721m; δH(500 MHz;
CDCl3) 8.28 (1H, br s), 7.90 (1H, d, J 8.0), 7.66 (2H, dd, J 8.5, 2.0), 7.62 (2H, dd, J
6.5, 6.5), 7.54 (1H, dd, J 7.5, 7.5), 7.49 (1H, dd, J 8.0, 1.5), 6.67 (1H, br s); δC(75
MHz; CDCl3) 3 C (s) and 1 C (d) resonances missing, 141.6 (s), 136.1 (s), 135.0 (d),
133.9 (d), 133.0 (d), 131.0 (d), 130.0 (d), 125.5 (d), 124.0 (s), 111.0 (s); m/z (MALDIꢀ
TOF) 363 (MH++4, 13%), 361 (MH++2, 100), 359 (MH+, 55), 130 (2).
4.4.6. 3ꢀ(2ꢀBromophenyl)ꢀ7ꢀchloroꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile
(5g) via Method B. Similar treatment of 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium chloride (11)
(826 mg, 3.97 mmol) with 2ꢀaminoꢀN'ꢀ(2ꢀbromophenyl)ꢀ4ꢀchlorobenzamidine (16)
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(1.290 g, 3.97 mmol) gave the title compound 5g (284.5 mg, 79%) as colorless plates,
mp (hotstage) 145.7ꢀ147.8 οC (from cꢀhexane/DCM, 90:10); mp (DSC) onset
146.1 oC, peak max. 150.7 oC (from cꢀhexane/DCM, 90:10); Rf 0.67 (DCM/tꢀBuOMe,
90:10) ; (found: C, 49.99; H, 2.17; N, 15.46. C15H8BrClN4 requires C, 50.10; H, 2.24;
N, 15.58%); λmax(DCM)/nm 245 (log ε 4.23), 254 (4.23), 264 (4.25), 274 (4.14), 302
inf (3.63), 313 (3.76), 326 (3.80), 344 inf (3.63), 362 inf (3.41), 383 inf (2.89);
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ν
max/cmꢀ1 3298w and 3273w (NꢀH), 3069w (aryl CꢀH), 2241w (C≡N), 1640s, 1585m,
1571m, 1557w, 1472w, 1462m, 1416m, 1346m, 1298s, 1155s, 1115w, 1080m, 1028w,
1003w, 920m, 835m, 824m, 760m, 727m, 718m; δH(500 MHz; CDCl3) NH deuterium
exchanged, 8.29 (1H, br s), 7.91 (1H, d, J 8.0), 7.67 (1H, d, J 1.5), 7.63 (1H, dd, J 7.5,
7.5), 7.55ꢀ7.49 (3H, m); δC(125 MHz; CDCl3) 4 C (s) and 1 C (d) resonances missing,
144.1 (s), 139.7 (s), 135.0 (d), 133.0 (d), 131.0 (d), 130.2 (d), 130.0 (d), 128.1 (d),
124.0 (s), 110.9 (s); m/z (MALDIꢀTOF) 363 (MH++4, 17%), 361 (MH++2, 100), 359
(MH+, 96), 340 (7), 338 (45), 336 (35).
4.4.7. 6ꢀBromoꢀ3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile
(5h) via Method B. Similar treatment of 4,5ꢀdichloroꢀ1,2,3ꢀdithiazolium chloride (11)
(826 mg, 3.97 mmol) with 2ꢀaminoꢀ5ꢀbromoꢀN'ꢀ(2ꢀbromophenyl)benzamidine (17)
(1.465 g, 3.97 mmol) gave the title compound 5h (306.6 mg, 76%) as colorless plates,
mp (hotstage) 239.9ꢀ245.0 οC (from cꢀhexane/DCM, 90:10); mp (DSC) onset
244.4 oC, peak max. 246.9 oC (from cꢀhexane/DCM, 90:10); Rf 0.63 (DCM/tꢀBuOMe,
90:10); (found: C, 44.42; H, 1.99; N, 13.83. C15H8Br2N4 requires C, 44.59; H, 2.00; N,
13.87%); λmax(DCM)/nm 243 (log ε 4.06), 251 (4.04), 267 (4.05), 277 (3.95), 304 inf
(3.74), 317 inf (3.91), 329 (3.98), 343 inf (3.88), 360 inf (3.70), 379 inf (3.23);
νmax/cmꢀ1 3294w (NꢀH), 3053w and 3030w (aryl CꢀH), 2243w (C≡N), 1643m, 1630m,
1585m, 1570m, 1462m, 1418w, 1346m, 1310s, 1296m, 1277w, 1163m, 1067w,
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1047w, 1030w, 1001w, 835s, 813s, 770s, 727m, 714m; δH(500 MHz; CDCl3) 8.48
(1H, br s), 7.90 (1H, d, J 8.0), 7.80 (1H, dd, J 8.8, 2.3), 7.63 (1H, dd, J 7.5, 7.5), 7.55
(2H, dd, J 7.5, 7.5), 7.49 (1H, dd, J 9.0, 1.5), 6.66 (1H, br s); δC(75 MHz; CDCl3) 4 C
(s) resonances missing, 142.0 (s), 136.8 (d), 135.0 (d), 133.0 (d), 131.0 (d), 130.1 (d),
130.0 (d), 128.6 (d), 124.1 (s), 124.0 (s), 111.0 (s); m/z (MALDIꢀTOF) 407 (MH++4,
20%), 405 (MH++2, 29), 403 (MH+, 15), 130 (100), 128 (51).
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4.4.
Preparation of Benzo[4,5]imidazo[1,2-c]quinazoline-6-carbonitriles 1a-q
4.4.1. Benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a)
4.4.1.1. Method A: via the PIFA only mediated oxidative cyclization of 4ꢀ(phenylꢀ
amino)quinazolineꢀ2ꢀcarbonitrile (4a) (typical procedure). To a stirred solution of
4ꢀ(phenylamino)quinazolineꢀ2ꢀcarbonitrile (4a) (49.2 mg, 0.20 mmol) in trifluoroꢀ
acetic acid (TFA) (1 mL) was added phenyliodine bis(trifluoroacetate) (PIFA) (94.6
mg, 0.22 mmol) at ca. 20 oC and left to stir for 30 min. The reaction mixture was then
diluted (water, 5 mL), extracted (DCM, 3× 5 mL) and dried (Na2SO4). The organic
phase was then adsorbed onto silica and chromatographed (DCM) to give benzoꢀ
[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a) (45.1 mg, 92%) as pale yellow
o
fibres, mp (hotstage) 258.1ꢀ259.0 oC (lit.,3b 252ꢀ254 C) (nꢀpentane/THF, 80:20), mp
(DSC) onset 259.0 oC, peak max. 259.5 oC; Rf 0.65 (DCM); (found: C, 73.61; H, 3.42;
N, 22.79. C15H8N4 requires C, 73.76; H, 3.30; N, 22.94%); λmax(DCM)/nm 236 (log ε
4.32), 276 inf (4.46), 286 (4.60), 296 (4.59), 317 (3.87), 331 (3.82), 346 (3.59), 390
(3.03); νmax/cmꢀ1 3048w (aryl CꢀH), 2243w (C≡N), 1620w, 1587w, 1526w, 1468w,
1449m, 1383m, 1327w, 1312w, 1261w, 1252w, 1223w, 1204w, 1159w, 1119w,
1013w, 793m, 775w, 758m, 746s; δH(500 MHz; CDCl3) 8.73 (1H, dd, J 7.5, 1.5),
8.58 (1H, d, J 8.5), 8.06 (2H, dd, J 7.0, 7.0), 7.88 (1H, ddd, J 7.5, 7.5, 1.5), 7.84 (1H,
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ddd, J 7.5, 7.5, 1.0), 7.67 (1H, ddd, J 7.5, 7.5, 1.0), 7.60 (1H, ddd, J 7.8, 7.8, 1.0);
δC(125 MHz; DMSOꢀd6) 146.0 (s), 144.1 (s), 141.2 (s), 132.4 (d), 131.3 (d), 129.3 (d),
127.4 (s), 127.1 (d), 124.44 (d), 124.38 (d), 122.2 (s), 120.6 (d), 120.0 (s), 112.4 (d),
112.2 (s); m/z (MALDIꢀTOF) 246 (MH++1, 23%), 245 (MH+, 100), 244 (M+, 29).
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4.4.1.2. Method B: via the PIFA and Cu(OTf)2 mediated oxidative cyclization of
4ꢀ(phenylamino)quinazolineꢀ2ꢀcarbonitrile (4a) (typical procedure). To a stirred
solution of 4ꢀ(phenylamino)quinazolineꢀ2ꢀcarbonitrile (4a) (49.2 mg, 0.20 mmol) in
trifluoroacetic acid (1 mL) was added phenyliodine bis(trifluoroacetate) (PIFA)
(129.0 mg, 0.30 mmol) and Cu(OTf)2 (3.6 mg, 5 mol %) at ca. 20 oC. The reaction
mixture was then immersed in a preheated oil bath at ca. 80 oC and left to stir for 30
min. The reaction mixture was then diluted (water, 5 mL), extracted (DCM, 3× 5 mL)
and dried (Na2SO4). The organic phase was then adsorbed onto silica and
chromatographed (DCM) to give benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile
(1a) (44.1 mg, 90%) as pale yellow fibres, mp (hotstage) 258.1ꢀ259.0 oC (lit.,3b 252ꢀ
254 oC) (nꢀpentane/THF, 80:20); Rf 0.65 (DCM); identical to that described above.
4.4.1.3. Method C: via the Pd(OAc)2 mediated nonꢀoxidative cyclization of 4ꢀ[(2ꢀ
bromophenyl)amino]quinazolineꢀ2ꢀcarbonitrile (4h) (typical procedure). A mixture
of 4ꢀ[(2ꢀbromophenyl)amino]quinazolineꢀ2ꢀcarbonitrile (4h) (32.5 mg, 0.10 mmol),
Pd(OAc)2 (2.2 mg, 10 mol %), BINAP (6.2 mg, 10 mol %) and powdered dry K2CO3
(13.8 mg, 0.10 mmol) was placed in a sealed tube, deaerated with argon and dissolved
in dry PhMe (1 mL) at ca. 20 oC. The reaction mixture was then immersed into a
preheated Wood’s metal bath at ca. 160 oC and left to stir for 5 h. The reaction
mixture was then cooled to ca. 20 oC and adsorbed onto silica and chromatographed
(DCM) to give benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a) (20.8 mg,
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85%) as pale yellow fibres, mp (hotstage) 258.1ꢀ259.0 oC (lit.,3b 252ꢀ254 C) (nꢀ
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pentane/THF, 80:20); Rf 0.65 (DCM); identical to that described above.
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4.4.1.4. Method D: via the CuI mediated nonꢀoxidative cyclization of 4ꢀ[(2ꢀbromoꢀ
phenyl)amino]quinazolineꢀ2ꢀcarbonitrile (4h) (typical procedure). A mixture of 4ꢀ
[(2ꢀbromophenyl)amino]quinazolineꢀ2ꢀcarbonitrile (4h) (32.5 mg, 0.10 mmol), CuI
(1.9 mg, 10 mol %), 1,10ꢀphenanthroline (2.0 mg, 10 mol %) and powdered dry
K2CO3 (13.8 mg, 0.10 mmol) dissolved in dry MeCN (1 mL) at ca. 20 oC and the
stirred reaction mixture was heated at reflux (ca. 80 oC) for 3 h, then cooled to ca.
20 oC, adsorbed onto silica and chromatographed (DCM) to give benzo[4,5]imidazoꢀ
[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a) (22.6 mg, 93%) as pale yellow fibres, mp
(hotstage) 258.1ꢀ259.0 oC (lit.,3b 252ꢀ254 oC) (nꢀpentane/THF, 80:20); Rf 0.65 (DCM);
identical to that described above.
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4.4.1.5. Method E: via the Pd(OAc)2 mediated nonꢀoxidative cyclization of 3ꢀ(2ꢀ
bromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5b) (typical procedure).
A mixture of 3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5b)
(32.5 mg, 0.10 mmol), Pd(OAc)2 (2.2 mg, 10 mol %), BINAP (6.2 mg, 10 mol %) and
Cs2CO3 (32.6 mg, 0.10 mmol) was deaerated with argon and dissolved in dry PhMe
(1 mL) at ca. 20 oC. The stirred reaction mixture was then heated at reflux (ca. 110
oC) for 17 h, then cooled to ca. 20 oC, adsorbed onto silica and chromatographed
(DCM) to give benzo[4,5]imidazo[1,2ꢀc]quinazolineꢀ6ꢀcarbonitrile (1a) (19.0 mg,
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78%) as pale yellow fibres, mp (hotstage) 258.1ꢀ259.0 oC (lit.,3b 252ꢀ254 C) (nꢀ
pentane/THF, 80:20); Rf 0.65 (DCM); identical to that described above.
4.4.1.6. Method F: via the Pd[3,5ꢀ(F3C)2C6H3]3 mediated nonꢀoxidative cyclization
of 3ꢀ(2ꢀbromophenyl)ꢀ4ꢀiminoꢀ3,4ꢀdihydroquinazolineꢀ2ꢀcarbonitrile (5b) (typical
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