An expedient synthesis of 5-substituted imidazo[1,2-c]quinazolines

Article abstract of DOI:10.1055/s-0032-1316802

An efficient three-step synthesis of 5-substituted 2,3-dihydroimidazo[1,2- c]quinazolines and imidazo[1,2-c]quinazolines was elaborated. 2-(2-Aminophenyl)-4,5-dihydro-1H-imidazole, prepared by phosphorus pentasulfide catalyzed condensation of 2-aminobenzonitrile with ethylenediamine, smoothly reacted with aldehydes to give the corresponding 2,3,5,6-tetrahydroimidazo[1,2- c]quinazolines. The CH-NH fragments of the latter were subjected to selective oxidative dehydrogenation with one equivalent of potassium permanganate on silica gel to give 2,3-dihydroimidazo[1,2-c]quinazolines. With two equivalents of potassium permanganate on silica gel, a one-pot exhaustive dehydrogenation to imidazo[1,2-c]quinazolines was accomplished. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316802

3512▌
PAPER
paper
An Expedient Synthesis of 5-Substituted Imidazo[1,2-c]quinazolines
5-Substituted Imidazo[1,2-c]quinazolines
Edward E. Korshin,*a,b Leila A. Sabirova,b Yakov A. Levinb
a
Department of Organic Chemistry, the Weizmann Institute of Science, Rehovot 76100, Israel
Fax +972(8)9344142; E-mail: edward.korshin@weizmann.ac.il
b
Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, 8 Arbuzov Str., Kazan 420088, Russian Federation
Received: 02.08.2012; Accepted after revision: 21.09.2012
roethylamine,2a or through amination with aminoethanol
Abstract: An efficient three-step synthesis of 5-substituted 2,3-di-
followed by phosphoryl chloride or thionyl chloride in-
hydroimidazo[1,2-c]quinazolines and imidazo[1,2-c]quinazolines
duced ring closure.3a,11,13 The reaction of 4-chloroquinaz-
oline with aminoacetaldehyde dimethyl acetal followed
was elaborated. 2-(2-Aminophenyl)-4,5-dihydro-1H-imidazole,
prepared by phosphorus pentasulfide catalyzed condensation of 2-
aminobenzonitrile with ethylenediamine, smoothly reacted with al- by acid-catalyzed cyclization of the intermediate afforded
the parent imidazo[1,2-c]quinazoline.14 In a supplementa-
ry vein, condensation of 4-aminoquinazoline with bromo-
dehydes to give the corresponding 2,3,5,6-tetrahydroimidazo[1,2-
c]quinazolines. The CH–NH fragments of the latter were subjected
to selective oxidative dehydrogenation with one equivalent of po-
acetaldehyde provided an efficient formation of the
tassium permanganate on silica gel to give 2,3-dihydroimidazo[1,2-
c]quinazolines. With two equivalents of potassium permanganate
imidazole ring to give the imidazo[1,2-c]quinazoline.15
on silica gel, a one-pot exhaustive dehydrogenation to imidazo[1,2-
c]quinazolines was accomplished.
Some more complex transformations, which include the
formation of both imidazole and quinazoline fragments of
the imidazo[1,2-c]quinazoline system, have been also re-
ported.5b,16 Indeed, heating 2-substituted 4H-3,1-benzo-
thiazine-4-thiones with ethylenediamine directly led to 5-
substituted 2,3-dihydroimidazo[1,2-c]quinazolines in low
to moderate yields.16 In a similar single example, ring
opening of 2-aryl-4H-3,1-benzoxazin-4-one by ethylene-
diamine and subsequent dehydrative recyclization of the
amino-amide-type intermediate afforded the correspond-
ing 5-aryl-2,3-dihydroimidazo[1,2-c]quinazoline.5b
Key words: nitrogen heterocycles, imidazole, cyclization, oxida-
tion, dehydrogenation, heterogeneous catalysis
Imidazo[1,2-c]quinazolines exhibit a tricyclic angularly
fused ring system, which combines the biologically valu-
able imidazole and quinazoline moieties. Some represen-
tative examples substituted in the benzene ring 5-(2-
oxoalkyl)-1a and a number of 5-(acylamino)-2,3-dihydro-
imidazo[1,2-c]quinazolines have been recently patented
as potent anticancer agents.1 Variously hydrogenated 5-
alkyl- and 5-arylimidazo[1,2-c]quinazolines have shown
a range of attractive pharmacological activity2–8 and in-
secticidal properties.9 Cyclometalated late-transition-
metal complexes (Ir or Pt) of imidazo[1,2-c]quinazolines
have been patented as efficient dopants for organic elec-
troluminescent layers in OLEDs.10 However, in spite of
significant interest in the field, there is still a shortage of
mild and reliable synthetic methods for the preparation of
selected imidazo[1,2-c]quinazoline derivatives. The re-
ported methods are usually indirect, often require the use
of drastic conditions, moisture-sensitive poisonous re-
agents, and/or poorly available precursors, which can lim-
it the overall utility of the process.
Perhaps the most rational and straightforward method for
the construction of imidazo[1,2-c]quinazolines consists of
cyclocondensation of one-carbon electrophiles with 1,5-
N,N′-bis-nucleophiles, bearing the appropriately prear-
ranged imidazole ring and amino group. However, this di-
rect route is still under-explored and suffers from
considerable limitations. Thus, condensations of 2-(2-
aminophenyl)imidazole5a and 2-(2-aminophenyl)-4,5-
diarylimidazoles17 with various benzaldehydes and dial-
kyl ketones provided a feasible access to the correspond-
ing 5-aryl- and 5,5-dialkyl-5,6-dihydroimidazo[1,2-
c]quinazolines.5a,17 Additionally, condensations of the
same bis-nucleophiles with trialkyl orthoformates or orth-
oacetates gave the 5-unsubstituted and 5-methylimid-
azo[1,2-c]quinazolines in moderate to good yield.6,17b
Unfortunately, synthetic applications of 4,5-unsubstituted
2-(2-aminophenyl)imidazole are restricted by the modest
availability of its best immediate precursor, namely 2-(2-
nitrophenyl)imidazole.5a,6,18 Moreover, 2-(2-aminophe-
nyl)imidazoles are not applicable for the preparation of
2,3-dihydro- and 2,3,5,6-tetrahydroimidazo[1,2-c]quin-
azolines of biological interest.1–7
Currently, the most common approach to the synthesis of
imidazo[1,2-c]quinazolines relies on a two-step assembly
of the imidazole ring onto a quinazoline scaffold.2a,3a,5a,11–15
For example, treatment of 4-chloroquinazolines with
aziridines followed by I–-catalyzed rearrangement of the
isolated 4-(aziridin-1-yl)quinazoline intermediates gave
the corresponding 2,3-dihydroimidazo[1,2-c]quinazo-
lines in good yields.5a,11,12 The latter compounds were also
prepared by amination of 4-chloroquinazolines with chlo-
2-(2-Aminophenyl)-4,5-dihydro-1H-imidazole (1), bear-
ing a highly nucleophilic cyclic amidine moiety,19 might
serve as a preferential 1,5-N,N′ bis-nucleophile for the di-
rect construction of the imidazo[1,2-c]quinazoline sys-
tem. So far, only a few brief reports on excess hydrogen
chloride mediated condensations of 1 with aldehydes,
SYNTHESIS 2012, 44, 3512–3522
Advanced online publication: 17.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316802; Art ID: SS-2012-T0634-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-Substituted Imidazo[1,2-c]quinazolines
3513
leading to the 2,3,5,6-tetrahydroimidazo[1,2-c]quinazo- The condensation with ethyl glyoxalate (1.1 equiv), bear-
line hydrochlorides in poor to moderate yield, are avail- ing a highly reactive carbonyl function, proceeded consid-
able.3b,4,20 From our point of view, the optimized version erably faster compared to the other tested aldehydes and
of this condensation and subsequent appropriate dehydro- took only eight hours at room temperature (Table 1, entry
genation steps could open a general way to a variety of 1). For a high-yielding preparation of 2-alkyl derivatives
imidazo[1,2-c]quinazolines. Herein, we report an experi- 3c,d under similar conditions, the aliphatic aldehydes
mentally convenient and high yielding synthesis of 5-sub- were used in a large excess (ca. 5 equiv), and a prolonged
stituted 2,3,5,6-tetrahydroimidazo[1,2-c]quinazolines 3, reaction time was required (entries 2 and 3). A Teflon
2,3-dihydroimidazo[1,2-c]quinazolines 4, and imid- screw-cap sealed reactor was used for a slow condensa-
azo[1,2-c]quinazolines 5 from 2-(2-aminophenyl)-4,5-di- tion of highly volatile acetaldehyde (entry 2). The activat-
hydro-1H-imidazole (1) as the sole precursor.
ed pentafluorobenzaldehyde (entry 7) and 4-
nitrobenzaldehyde (entries 8 and 9) reacted slightly faster
than benzaldehyde itself (entries 4 and 5), whereas the
condensation of 2-bromobenzaldehyde, the carbonyl
function of which is significantly shielded by a large bro-
mine atom, was considerably slower (entry 10). In few
comparable examples (entries 4 vs. 5 and 8 vs. 9), both
procedures A2 and A3 resulted in very similar high yields.
According to the data in Table 1, the synthesis of 5-substi-
Although a number of established methods for the synthe-
sis of 2-substituted 4,5-dihydro-1H-imidazoles (2-imidaz-
olines) are available,21 only a couple of conventional acid-
catalyzed condensations of ethylenediamine with methyl
anthranilate22 or with anthranilonitrile (2) afforded the de-
sired 2-(2-aminophenyl)-4,5-dihydro-1H-imidazole (1) in
moderate yield (20–55%).3a,5a,20 This prompted us to turn
our attention to the rarely applied preparation of 2-imidaz-
olines by phosphorus pentasulfide catalyzed condensation
of ethylenediamine and nitriles.23 Indeed, refluxing a tol-
uene solution of anthranilonitrile (2) and excess ethylene-
diamine (6 equiv) in the presence of a catalytic amount
phosphorus pentasulfide for 120 hours gave 1 in 54%
yield.24 After overnight heating of 2, excess ethylenedi-
amine and phosphorus pentasulfide (0.02 equiv) at 100–
110 °C without extra solvent, dihydroimidazole 1 was ob-
tained in 81% yield.2b In this work, we found that reflux-
tuted 2,3,5,6-tetrahydroimidazo[1,2-c]quinazolines
3
does not require the previously suggested addition of
aqueous acids.3b,4,20 However, all our attempt to prepare 5-
unsubstituted 2,3,5,6-tetrahydroimidazo[1,2-c]quinazo-
line 3b, either using an aqueous solution of formaldehyde
under conditions similar to procedures A1/A3, or from
1,3,5-trioxane as a potential source of formaldehyde in
boiling tetrahydrofuran, acetonitrile, or 1,4-dioxane (con-
ditions similar to A2), failed.
ing 2, ethylenediamine (6 equiv), and phosphorus In contrast to the failure of the synthesis of 3b, heating
pentasulfide (0.02 equiv) in xylene for 40 hours followed aminoimidazoline 1 and excess trimethyl orthoformate
by vacuum distillation led to the desired 2-(2-aminophe- for 12 hours at 120 °C gave the parent 5-unsubstituted 2,3-
nyl)-4,5-dihydro-1H-imidazole (1) in 93% yield (Scheme dihydroimidazo[1,2-c]quinazoline 4b almost quantita-
1).
tively (Scheme 2, procedure B1). Under the same reaction
conditions, condensation of 1 with trimethyl orthoacetate
afforded 5-methyl-substituted 4c (Scheme 2) in 73%
yield, which was an improvement over the 48% yield ob-
tained in the condensation of 1 with acetic anhydride.3a
Considering further possibilities for the direct synthesis of
2,3-dihydroimidazo[1,2-c]quinazolines 4, reactions of 1
with readily available and commonly reactive iminoesters
as one-carbon electrophiles were tested.25 Initial attempts
to condense 1 with methyl acetimidate and benzimidate
hydrochlorides in boiling methanol were unsuccessful,
perhaps because of deactivation of the imidazoline 1 due
to its complete protonation. Nevertheless, upon prolonged
heating of 1 with excess methyl acetimidate or benzimi-
date as the free base in boiling toluene, the desired 5-
methyl- 4c and 5-phenyl-2,3-dihydroimidazo[1,2-c]quin-
azoline (4e) were obtained, albeit in modest yields
(Scheme 2, procedure B2).
N
P2S5 (0.02 equiv)
xylene, reflux
CN
H2N
H2N
N
+
H
93%
NH2
NH2
2
1
Scheme 1 Preparation of 2-(2-aminophenyl)-4,5-dihydro-1H-imid-
azole (1)
A number of 5-substituted 2,3,5,6-tetrahydroimidazo[1,2-
c]quinazolines 3 were prepared in good to excellent yield
by cyclocondensation of 2-(2-aminophenyl)-4,5-dihydro-
1H-imidazole (1) with aldehydes without addition of acid
(Table 1). The reactions proceeded smoothly at ambient
temperature in dry tetrahydrofuran in the presence of
anhydrous magnesium sulfate as a water scavenger (pro-
cedure A1). To accelerate the process, the cyclocondensa-
tions could be carried out in boiling tetrahydrofuran
(procedure A2). Taking into account the poor solubility of
5-aryl-substituted 3 in acetonitrile, the reactions with
benzaldehydes were also performed in acetonitrile at
room temperature without magnesium sulfate (procedure
A3), and considerable amounts of 3e,g,h precipitated di-
rectly from the reaction mixture.
N
N
RC(OMe)3, procedure B1
(R = H, Me); or
N
N
H
RC(=NH)OMe, procedure B2
(R = Me, Ph)
N
R
NH2
4b,c,e
1
Scheme 2 Synthesis of 2,3-dihydroimidazo[1,2-c]quinazolines 4
from 2-(2-aminophenyl)-4,5-dihydro-1H-imidazole (1)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3512–3522

3514
E. E. Korshin et al.
PAPER
dehydrogenations were accomplished.5a,11,36 Namely, oxi-
dation of the CH–NH bonds in 5,6-dihydroimidazo[1,2-
c]quinazolines with large excess of activated manganese
dioxide led to the corresponding imidazo[1,2-c]quinazo-
lines 5b,c in poor to moderate yield.36 Also, when unsub-
stituted 4b or 5-phenyl-2,3-dihydroimidazo[1,2-
c]quinazoline (4e) were treated with two equivalents
chloranil in boiling xylene, a clean dehydrogenation of the
CH–CH bond to give the imidazo[1,2-c]quinazolines 5b,e
took place.5a,11
Table 1 Synthesis of 2,3,5,6-Tetrahydroimidazo[1,2-c]quinazolines
3a
N
N
RCHO
N
N
H
procedures A1–A3
N
R
NH2
H
1
3a,c–i
Entry
R
Conditionsb Time
(h)
Product Yieldc
(%)
1
CO2Et
Me
A1d
A1e
A1e
A2
8
3a
3c
3d
3e
3e
3f
93
87
64
90
91
89
78
92
96
74
Being interested in selective or exhaustive dehydrogena-
tion of the CH–NH and CH2–CH2 fragments in 2,3,5,6-
tetrahydroimidazo[1,2-c]quinazolines 3, comparative de-
hydrogenations under catalytic anaerobic and stoichio-
metric oxidative conditions were studied. The anaerobic
catalytic dehydrogenations of 3 to give the corresponding
2,3-dihydroimidazo[1,2-c]quinazolines 4 were carried out
over 5% palladium on carbon in boiling toluene under ar-
gon (Table 2, procedure C1). As for selective oxidative
dehydrogenation to 4, the chosen procedure D1 consisted
of treatment of 3 with potassium permanganate (1.05
equiv) in the presence of silica gel in acetonitrile at 0 °C
(Table 2).
2
72
72
15
72
18
48
12
36
40
3
(CH2)6Me
Ph
4
5
Ph
A3
6
4-MeOC6H4 A2
7
C6F5
A3
A2
A3
A2
3g
3h
3h
3i
8
4-O2NC6H4
4-O2NC6H4
2-BrC6H4
9
A high-yielding formation of 2,3-dihydroimidazo[1,2-
c]quinazolines 4 from 2,3,5,6-tetrahydroimidazo[1,2-
c]quinazolines 3 is testimony to the more facile dehydro-
genation of the CH–NH bonds compared to CH–CH
bonds (Table 2). The rate of the catalytic dehydrogenation
of the CH–NH fragments apparently depends on the na-
ture of the substituent R at C5 of the ring system (Table 2,
procedure C1). According to the 1H NMR spectra, catalyt-
ic dehydrogenation of 5-ethoxycarbonyl derivative 3a for
12 hours (entry 1) resulted in the complete consumption
of 3a and formation of the 2,3-dihydro derivative 4a (ca.
90%) accompanied by the completely dehydrogenated
imidazo[1,2-c]quinazoline 5a (7%). After the same reac-
tion time, 5-phenyl-substituted 3e was dehydrogenated to
ca. 85% completion, giving a mixture of 3e, 4e, and 5e in
a ratio of 2:9:1. Complete consumption of 3e was ob-
served after 18 hours of catalytic dehydrogenation (entry
7). Similarly catalytic dehydrogenation of 5-methyl-sub-
stituted 3c for 12 hours afforded a mixture of 3c, 4c, and
5c in a ratio of ca. 4:5:1. Traces of the starting 3c were still
10
a Reactions were performed on 1.0-mmol scale.
b Procedure A1: 1 (1 equiv), aldehyde (1.1–5.0 equiv), anhyd MgSO4
(4–5 equiv), anhyd THF, r.t. Procedure A2: 1 (1 equiv), aldehyde
(1.1–1.15 equiv), MgSO4 (4–5 equiv), THF, reflux. Procedure A3: 1
(1 equiv), aldehyde (1.1–1.15 equiv), anhyd MeCN, r.t.
c Yield of isolated product.
d Aldehyde (1.1 equiv) was used.
e Aldehyde (5.0 equiv) was used.
As an alternative general route to 5-substituted 2,3-dihy-
droimidazo[1,2-c]quinazolines 4 and to imidazo[1,2-
c]quinazolines 5, the dehydrogenation of 2,3,5,6-tetrahy-
droimidazo[1,2-c]quinazolines 3 was examined. Current-
ly, there are numerous methods for the dehydrogenation
of nitrogen heterocycles. For example, classical oxidizing
reagents, such as potassium permanganate,26a–c activated
manganese dioxide2a and sodium hypochlorite, have been
applied to the oxidative dehydrogenation of 1,2-dihydro-
quinazolines to quinazolines.26d Even a wider number of
oxidants, like activated manganese dioxide,27 barium per-
manganate,28 potassium permanganate alone,29 potassium
permanganate supported on silica gel30a,b or on aluminum
oxide,30c,d sodium periodate with a catalytic amount of
1
detected in the H NMR spectrum of the crude reaction
mixture even after 24 hours of catalytic dehydrogenation,
and the major product 5-methyl-2,3-dihydroimidazo[1,2-
c]quinazoline (4c) (58%) was isolated along with 18% of
the minor product 5-methylimidazo[1,2-c]quinazoline
(5c) (entry 3). The data indicates a considerable decelera-
tion of the CH–NH bond catalytic dehydrogenation in 5-
substituted 2,3,5,6-tetrahydroimidazo[1,2-c]quinazolines
3 in the following order of the adjacent C5-substituents:
EtO2C > aryl > alkyl. With such a deceleration of the CH–
NH bond catalytic dehydrogenation for 5-alkyl-substitut-
ed derivatives 3c,d, dehydrogenation of the CH–CH bond
begins to compete. The competition led to the substantial
formation of the exhaustively dehydrogenated byproducts
manganese(III)–porphyrin,31
o-iodoxybenzoic
acid
(IBX),32a–c and (diacetoxyiodo)benzene, have been used
to convert 2-imidazolines into imidazoles.32d–g Recently,
catalytic aerobic dehydrogenation of 2-imidazolines to
imidazoles was realized in the presence of activated
carbon33 or cationic tripyridylruthenium(II) complexes.34
Complementary to the most popular oxidative methods,
anaerobic catalytic dehydrogenation of imidazolines over
palladium on carbon has frequently been used for the syn-
thesis of imidazoles.23a,35 However, within the imid-
azo[1,2-c]quinazoline system only few unselective
Synthesis 2012, 44, 3512–3522
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-Substituted Imidazo[1,2-c]quinazolines
3515
and nitroaryls on the palladium on carbon catalyzed dehy-
drogenation could result from catalyst poisoning rather
than from the suggested electron-withdrawing nature of
the substituents.23b
Table 2 Synthesis of 2,3-Dihydroimidazo[1,2-c]quinazolines 4 by
Selective Dehydrogenation of 2,3,5,6-Tetrahydroimidazo[1,2-c]quin-
azolines 3a
N
N
With the feasibility of the selective dehydrogenation es-
tablished, we tested the possibility of the one-pot exhaus-
tive dehydrogenation of 2,3,5,6-tetrahydroimidazo[1,2-
c]quinazolines 3 to imidazo[1,2-c]quinazolines 5 (Table
3). In fact, a complete dehydrogenation of 3 to 5 could be
achieved applying the same reagents, but under more
forcing conditions. Indeed, in the palladium on carbon
catalyzed dehydrogenations of 2,3,5,6-tetrahydro deriva-
tives 3a and 3f in boiling toluene for 120 hours the corre-
sponding imidazo[1,2-c]quinazolines 5a and 5f were
isolated in ~60% yield (Table 3, procedure C1, entries 1
and 14). Upon conducting the catalytic dehydrogenations
in boiling m-xylene at 135–140 °C, the transformation of
3 to 5 was accelerated and completed within 36 hours
without affecting the productivity (Table 3, procedure
C2). Likewise, the 2,3-dihydro derivatives 4b,c,e were ef-
ficiently dehydrogenated to 5b,c,e respectively under the
conditions of procedure C2 (entries 4, 7, and 12).
N
N
procedures C1 or D1
N
R
N
R
H
3a,c–i
4a,c–i
Entry
R
Conditionsb Time
(h)
Product Yieldc
(%)
1
CO2Et
CO2Et
Me
C1
D1
C1
D1
C1
D1
C1
D1
12
4a
4a
4c
4c
4d
4d
4e
4e
4f
80d
94
2
2.5
24
3
58d
86
4
Me
2.5
24
5
(CH2)6Me
(CH2)6Me
Ph
62d
90
6
2.5
18
7
74d
92
8
Ph
2.5
18
Treatment of 2,3,5,6-tetrahydroimidazo[1,2-c]quinazo-
lines 3 with potassium permanganate (2.05 equiv) and sil-
ica gel in acetonitrile at room temperature resulted in
smooth oxidative dehydrogenation of both CH–NH and
CH2–CH2 fragments and led to the formation of imid-
azo[1,2-c]quinazolines 5 in high to excellent yield (Table
3, procedure D2). In practice, one equivalent of potassium
permanganate can dehydrogenate one CH–NH or one
CH–CH bond. Indeed, 2,3-dihydro derivative 4b on expo-
sure to 1.05 equivalents of potassium permanganate/silica
gel at room temperature afforded 5b in 92% yield (entry
5). Attempts to accelerate oxidative dehydrogenations by
using excess potassium permanganate or elevated temper-
ature were found to be counterproductive.
9
4-MeOC6H4 C1
4-MeOC6H4 D1
72
10
11
12
13
2.5
2.5
2.5
2.5
4f
88
C6F5
D1
D1
D1
4g
4h
4i
92
4-O2NC6H4
2-BrC6H4
94
90
a Reactions were performed on 0.20-mmol scale.
b Procedure C1: 3 (1 equiv), 5% Pd/C (0.1 equiv Pd), toluene, reflux
(110–115 °C) under argon. Procedure D1: 3 (1 equiv), KMnO4 (1.05
equiv), silica gel (200–250 mg), MeCN, 0 °C (2 h), r.t. (30 min).
c Yield of isolated product after flash chromatography on Florisil.
d The corresponding compound 5 was also isolated (5a: 6%; 5c: 18%;
5d: 15%; 5e: 11%).
As discussed, nitrophenyl-substituted 3h and halogenated
substrates 3g and 3i, when subjected to catalytic dehydro-
genation under the conditions of procedure C2 for 24–36
hours, afforded the corresponding imidazo[1,2-c]quinaz-
olines 5 in very low yields (<10% in each case). Apparent-
ly, the nitroaryls and haloaryls do not tolerate slow
dehydrogenation over palladium on carbon, and catalytic
dehydrogenations of these substrates have no preparative
value. On the other hand, all the presented data demon-
strate a good chemoselectivity and broad feasibility for
the oxidative dehydrogenation with potassium permanga-
nate/silica gel leading to 2,3-dihydroimidazo[1,2-c]quin-
azolines 4 (Table 2, procedure D1) and imidazo[1,2-
c]quinazolines 5 (Table 3, procedure D2).
5c,d (15–18% isolated yield) at the expense of the selec-
tively dehydrogenated product 4c,d (entries 3 and 5).
The data of Table 2 witness the viability of both catalytic
(procedure C1) and oxidative (procedure D1) methods for
selective dehydrogenation of the halo- and nitro-group-
free 2,3,5,6-tetrahydroimidazo[1,2-c]quinazolines 3a,c–f
to the corresponding 2,3-dihydroimidazo[1,2-c]quinazo-
lines 4a,c–f (entries 1–10). In contrast, the palladium on
carbon catalyzed dehydrogenations of 5-(pentafluorophe-
nyl) 3g, 5-(4-nitrophenyl) 3h, and 5-(2-bromophenyl) de-
rivatives 3i according to procedure C1 afforded complex
mixtures of products, containing less than 30% of the de-
sired 4. This result is in agreement with the earlier obser-
vations on a poor productivity of the palladium on carbon
catalyzed dehydrogenation of 2-chlorophenyl- and 2-(tri-
fluoromethyl)phenyl-substituted imidazolines to the cor-
responding 2-arylimidazoles.23b In view of the capable
catalytic dehydrogenations of the 5-ethoxycarbonyl- 3a
(entry 1) and 5-aryl-substituted derivatives 3e,f (entries 7
and 9), the adverse effect of the halogen-containing aryls
In summary, we have developed a convenient preparative
route to 2,3-dihydroimidazo[1,2-c]quinazolines 4 and im-
idazo[1,2-c]quinazolines 5 from commercially available
2-aminobenzonitrile (2), ethylenediamine, and aldehydes.
The entire sequence consists of three high-yielding steps:
(i) phosphorus pentasulfide catalyzed condensation of 2
and ethylenediamine leading to 2-(2-aminophenyl)-4,5-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3512–3522

3516
E. E. Korshin et al.
PAPER
1H and 13C NMR spectra were recorded on a Bruker Avance-500,
Bruker AMX-400 or Bruker Avance-300 spectrometers at r.t. refer-
enced to Me4Si (δ = 0). 19F NMR spectra were recorded on a Bruker
Avance-300 spectrometer; chemical shifts are referenced to C6F6
external standard (δ = –162.0). IR spectra were obtained with a Ni-
colet-6700 FT-IR instrument in CHCl3 or in Nujol films. HRMS
(ESI and FD) was performed using Micromass Platform LCZ-4000.
Melting points were measured with a Büchi 510 micro melting
point apparatus and are uncorrected. Kugelrohr distillation was car-
ried out using a Büchi GKR-51 apparatus. TLC analysis was per-
formed on Merck silica gel 60 F254 plates followed by charring with
alkaline KMnO4 soln or with I2/silica gel. Column flash chromatog-
raphy (FC) was performed on silica gel 60 (230–400 mesh ASTM)
from Merck or on Florisil (100–200 mesh) from Fluka. THF, tolu-
ene and m-xylene were distilled over Na/benzophenone, MeCN was
distilled over CaH2, and ethylenediamine was dried over KOH pel-
lets followed by distillation from CaH2 under N2. Liquid aldehydes
were freshly distilled prior to use. Other commercially available re-
agents were used as received. Methyl acetimidate hydrochloride
and methyl benzimidate hydrochloride were prepared according to
the literature procedure.37
Table 3 Synthesis of Imidazo[1,2-c]quinazolines 5 through Exhaus-
tive Dehydrogenation of 2,3,5,6-Tetrahydroimidazo[1,2-c]quinazo-
lines 3 and 2,3-Dihydroimidazo[1,2-c]quinazolines 4a
N
N
N
proce-
dure
C2 or D2
proce-
dure
C2 or D2
N
N
N
N
R
N
R
N
R
H
3a,c–i
5a–i
4b,c,e
Entry Substrate
R
Conditionsb Time Product Yieldc
(h)
(%)
1
3a
3a
3a
4b
4b
3c
4c
3c
3d
3d
3e
4e
3e
3f
CO2Et
CO2Et
CO2Et
H
C1
C2
D2
C2
D2d
C2
C2
D2
C2
D2
C2
C2
D2
120 5a
58
67
88
80
92
75
82
90
64
76
84
86
96
60
82
88
94
95
85
2
36
12
28
14
36
24
12
36
14
36
24
12
5a
5a
5b
5b
5c
5c
5c
5d
5d
5e
5e
5e
3
4
5
H
6
Me
2-(2-Aminophenyl)-4,5-dihydro-1H-imidazole (1)
A mixture of 2-aminobenzonitrile (2, 6.135 g, 51.815 mmol), ethyl-
enediamine (18.70 g, 310 mmol, 6 equiv), and P2S5 (365 mg, 1.13
mmol, 0.022 equiv) in anhyd m-xylene (50 mL) was refluxed for 40
h in atmosphere of dry N2. After cooling to r.t. and sedimentation of
the yellow paste, a clear yellow soln was formed. The soln was de-
canted, and the reaction flask was thoroughly rinsed with additional
xylene. After evaporation of the solvent and excess ethylenedi-
amine, Kugelrohr distillation of the residue (175–180 °C/1.33
mbar) gave the product 1 as a colorless hard solid; yield: 7.75 g
(93%); mp 59–60 °C (Lit.3a 46 °C, Lit.22 50 °C).
7
Me
8
Me
9
(CH2)6Me
10
11
12
13
14
15
16
17
18
19
(CH2)6Me
Ph
Ph
Ph
IR (Nujol): 3420, 3240 (N–H), 1619 (C=N), 1585, 1565, 1511 cm–1.
1H NMR (400 MHz, C6D6): δ = 7.09–7.02 (m, 2 H), 6.56 (br ddd,
J = 8.2, 8.2, 1.0 Hz, 1 H), 6.36 (dd, J = 8.2, 0.9 Hz, 1 H), 6.27 (br s,
1 H, NH), 3.80 (br s, 4 H, CH2CH2), 2.70 (br s, 2 H, NH2).
13C NMR (101 MHz, C6D6): δ = 165.4 (N=C–N), 149.4 (C), 131.0
(CH), 127.9 (CH), 116.2 (CH), 115.3 (CH), 111.8 (C), 56.1 (br,
CH2N=), 43.4 (br, CH2N).
4-MeOC6H4 C1
4-MeOC6H4 C2
4-MeOC6H4 D2
120 5f
3f
36
12
16
16
12
5f
5f
5g
5h
5i
3f
HRMS (ESI): m/z [M + H]+ calcd for C9H12N3: 162.1026; found:
162.1029.
3g
3h
3i
C6F5
4-O2NC6H4 D2
2-BrC6H4 D2
D2
Anal. Calcd for C9H11N3: C, 67.05; H, 6.88; N, 26.07. Found: C,
66.92; H, 6.50; N, 26.12.
a Reactions were performed on a 0.20-mmol scale.
2,3,5,6-Tetrahydroimidazo[1,2-c]quinazolines 3;
b Procedure C1: 3 (1 equiv), 5% Pd/C (0.1 equiv Pd), toluene, reflux
(110–115 °C), under argon. Procedure C2: 3 (1 equiv), 5% Pd/C (0.1
equiv Pd), xylene, reflux (135–140 °C), under argon. Procedure D2:
3 (1 equiv), KMnO4 (2.05 equiv), silica gel (400 mg), MeCN, r.t.
c Yield of isolated product after flash chromatography (silica gel).
d KMnO4 (1.05 equiv).
General Procedures A1–A3
Procedure A1: To a cold (0 °C) suspension of 1 (161 mg, 1.0 mmol)
and anhyd MgSO4 (480–600 mg, 4–5 mmol) in anhyd THF (6 mL)
a soln of ethyl glyoxalate (112 mg, 1.1 mmol) or aliphatic aldehyde
(5 mmol) in toluene (2 mL) was added. The mixture was stirred un-
der N2 at r.t. for 8 h (ethyl glyoxalate) or for 3 d (aliphatic alde-
hydes), filtered via a short plug of Celite, the reaction vessel and the
filter were rinsed with CH2Cl2. The combined filtrate was evaporat-
ed. (1) In the case of ethyl glyoxalate, the residue was dissolved in
warm CH2Cl2 (25 mL) and filtered, and the filtrate was concentrated
to 2–3 mL and diluted with toluene (5 mL) to induce an intensive
crystallization of 3a. Solid 3a was collected by filtration, thorough-
ly washed with Et2O, and dried in vacuo. (2) In the case of acetal-
dehyde, the residue was treated with Et2O to induce the formation
of pure solid 3c, which was collected by filtration. (3) In the case of
octanal, the residue was subjected to FC (silica gel, EtOAc) to give
3d as a pure solid.
dihydro-1H-imidazole (1); (ii) acid-free condensation of 1
with aldehydes to give 2,3,5,6-tetrahydroimidazo[1,2-
c]quinazolines 3 or with orthoesters (or imidates) to give
2,3-dihydroimidazo[1,2-c]quinazolines 4; (iii) oxidative
selective or exhaustive dehydrogenation of 3 with potas-
sium permanganate/silica gel to 4 or 5, respectively.
Within the studied set of substrates, the oxidative dehy-
drogenations are more efficient compared to catalytic de-
hydrogenations over palladium on carbon.
Procedure A2: A suspension of the 1 (161 mg, 1.0 mmol), aromatic
aldehyde (1.1–1.15 mmol), and anhyd MgSO4 (480–600 mg, 4–5
mmol) in anhyd THF (8 mL) was refluxed under N2 for 12–40 h
(Table 1). The mixture was filtered through Celite and evaporated,
Synthesis 2012, 44, 3512–3522
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-Substituted Imidazo[1,2-c]quinazolines
3517
and the residue was treated with Et2O. The precipitate 3 was collect-
ed by filtration, thoroughly washed with Et2O, and dried in vacuo.
HRMS (ESI): m/z [M + H]+ calcd for C17H26N3: 272.2121; found:
272.2127.
Procedure A3: A mixture of the 1 (161 mg, 1.0 mmol) and aromatic
aldehyde (1.05–1.2 mmol) in anhyd MeCN (6 mL) was stirred at r.t.
under N2 for 2–3 d (Table 1). The first portion of pure solid 3 crys-
tallized directly from the mixture. It was collected by filtration,
washed with small volume of cold MeCN, toluene, and Et2O. The
combined filtrate was evaporated, the residue was dissolved in a
minimal volume of CH2Cl2 (0.5–1 mL) and diluted with Et2O (5–10
mL) to induce precipitation of an additional portion of 3.
5-Phenyl-2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline (3e)
Colorless solid; yield: 224 mg (90%, A2), 227 mg (91%, A3); mp
193–194 °C (Lit.3b 191–197 °C).
IR (CHCl3): 3416 (N–H), 1620 (C=N), 1482 cm–1.
1H NMR (400 MHz, CD2Cl2): δ = 7.86 (dd, J = 7.8, 1.3 Hz, 1 H),
7.60–7.55 (m, 2 H), 7.46–7.41 (m, 3 H), 7.25 (ddd, J = 7.8, 7.8, 1.5
Hz, 1 H), 6.81 (br ddd, J = 7.8, 7.8, 0.9 Hz, 1 H), 6.66 (br d, J = 8.5
Hz, 1 H), 5.13 (s, 1 H, H5), 4.48 (br s, 1 H, H6), 3.88 (ddd, J = 13.8,
10.0, 2.6 Hz, 1 H, HH′CN=), 3.60 (ddd, J = 13.8, 13.8, 9.0 Hz, 1 H,
H′HCN=), 3.05 (ddd, J = 9.0, 9.0, 2.6 Hz, 1 H, HH′CN), 2.83 (ddd,
J = 13.8, 10.0, 9.0 Hz, 1 H, H′HCN).
13C NMR (101 MHz, CD2Cl2): δ = 160.8 (N=C–N), 145.5 (C),
139.6 (C), 132.4 (CH), 129.9 (2 CH), 129.1 (2 CH), 128.3 (CH),
127.1 (CH), 119.2 (CH), 114.8 (CH), 113.1 (C), 74. 7 (CH-5), 53.6
(CH2N=), 50.3 (CH2N).
Ethyl 2,3,5,6-Tetrahydroimidazo[1,2-c]quinazoline-5-carboxyl-
ate (3a)
Pale yellow solid; yield: 228 mg (93%, A1); mp 243–245 °C (dec.).
IR (CHCl3): 3430 (N–H), 1696 (C=O), 1644 cm–1 (C=N).
1H NMR (500 MHz, CDCl3): δ = 7.87 (dd, J = 7.8, 1.4 Hz, 1 H),
7.23 (ddd, J = 8.0, 8.0, 1.5 Hz, 1 H), 6.83 (ddd, J = 7.8, 7.8, 1.0 Hz,
1 H), 6.70 (br d, J = 8.0 Hz, 1 H), 4.96 (br s, 1 H, H6), 4.88 (d,
J = 2.1 Hz, 1 H, H5), 4.21 (q, J = 7.1 Hz, 2 H, CH2O), 4.00–3.88
(sym m, 2 H, HH′CN=), 3.56 (ddd, J = 10.2, 8.2, 8.2 Hz, 1 H,
HH′CN), 3.39 (ddd, J = 10.0, 8.2, 8.2 Hz, 1 H, H′HCN), 1.24 (t,
J = 7.1 Hz, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 168.9 (O–C=O), 158.6 (N=C–N),
142.7 (C), 132.3 (CH), 126.8 (CH), 119.8 (CH), 115.1 (CH), 112.8
(C), 68.4 (CH-5), 61.9 (CH2O), 53.4 (CH2N=), 49.3 (CH2N), 14.1
(CH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3: 250.1339; found:
250.1345.
5-(4-Methoxyphenyl)-2,3,5,6-tetrahydroimidazo[1,2-c]quinaz-
oline (3f)
Colorless solid; yield: 248 mg (89%, A2); mp 184–185 °C.
IR (CHCl3): 3417 (N–H), 1618 (C=N), 1482, 1253 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.92 (dd, J = 7.8, 1.0 Hz, 1 H),
7.49 (d sym m, J = 8.6 Hz, 2 H), 7.25 (br ddd, J = 7.8, 7.8, 1.5 Hz,
1 H), 6.94 (d sym m, J = 8.6 Hz, 2 H), 6.83 (br ddd, J = 7.8, 7.8, 1.0
Hz, 1 H), 6.63 (br d, J = 8.0 Hz, 1 H), 5.10 (s, 1 H, H5), 4.34 (br s,
1 H, H6), 3.93 (ddd, J = 13.9, 10.1, 2.4 Hz, 1 H, HH′CN=), 3.84 (s,
3 H, CH3O), 3.65 (ddd, J = 13.9, 13.9, 9.0 Hz, 1 H, H′HCN=), 3.09
(ddd, J = 9.0, 9.0, 2.4 Hz, 1 H, HH′CN), 2.83 (ddd, J = 13.9, 10.1,
9.0 Hz, 1 H, H′HCN).
HRMS (ESI): m/z [M + H]+ calcd for C13H16N3O2: 246.1237; found:
246.1242.
Anal. Calcd for C13H15N3O2: C, 63.66; H, 6.16; N, 17.13. Found: C,
63.41; H, 6.38; N, 17.02.
5-Methyl-2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline (3c)
Colorless solid; yield: 163 mg (87%, A1); mp 210–212 °C (dec.).
IR (CHCl3): 3417 (N–H), 1618 (C=N), 1483 cm–1.
13C NMR (101 MHz, CDCl3): δ = 161.2 (CAr-OMe), 160.5 (N=C–
N), 145.0 (C), 132.3 (CH), 131.1 (C), 129.1 (2 CH), 127.0 (CH),
119.2 (CH), 114.5 (CH), 114.1 (2 CH), 112.5 (C), 73.7 (CH-5), 55.3
(CH3O), 53.0 (CH2N=), 49.9 (CH2N).
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O: 280.1444; found:
280.1439.
1H NMR (300 MHz, CDCl3): δ = 7.87 (dd, J = 7.8, 1.5 Hz, 1 H),
7.22 (br ddd, J = 7.8, 7.8, 1.5 Hz, 1 H), 6.80 (ddd, J = 7.8, 7.8, 0.9
Hz, 1 H), 6.69 (dd, J = 8.0, 0.9 Hz, 1 H), 4.32 (q, J = 5.7 Hz, 1 H,
H5), 4.26 (br s, 1 H, H6), 3.99 (ddd, J = 13.6, 10.1, 2.5 Hz, 1 H,
HH′CN=), 3.74 (ddd, J = 13.6, 13.6, 9.1 Hz, 1 H, H′HCN=), 3.57
(ddd, J = 9.1, 8.2, 2.5 Hz, 1 H, HH′CN), 2.95 (ddd, J = 13.6, 10.1,
8.2 Hz, 1 H, H′HCN), 1.44 (d, J = 5.7 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.5 (N=C–N), 145.1 (C), 132.2
(CH), 127.0 (CH), 119.2 (CH), 114.7 (CH), 112.8 (C), 66.4 (CH-5),
53.2 (CH2N=), 49.2 (CH2N), 21.3 (CH3).
5-(Pentafluorophenyl)-2,3,5,6-tetrahydroimidazo[1,2-c]quinaz-
oline (3g)
Yellow solid; yield: 265 mg (78%, A3); mp 148–150 °C (dec.).
IR (CHCl3): 3440 (sh) and 3410 (N–H), 1619 (C=N), 1508 cm–1 (C–
F).
1H NMR (500 MHz, CDCl3): δ = 7.92 (dd, J = 7.8, 1.4 Hz, 1 H),
7.28 (br ddd, J = 7.7, 7.7, 1.5 Hz, 1 H), 6.88 (ddd, J = 7.7, 7.7, 0.9
Hz, 1 H), 6.69 (d, J = 8.1 Hz, 1 H), 5.90 (s, 1 H, H5), 4.70 (br s, 1
H, H6), 3.98 (ddd, J = 14.0, 10.2, 4.8 Hz, 1 H, HH′CN=), 3.81 (ddd,
J = 14.0, 11.2, 9.8 Hz, 1 H, H′HCN=), 3.21–3.09 (m, 2 H, HH′CN).
HRMS (ESI): m/z [M + H]+ calcd for C11H14N3: 188.1182; found:
188.1178.
Anal. Calcd for C11H13N3: C, 70.56; H, 7.00; N, 22.44. Found: C,
70.30; H, 7.19; N, 22.38.
5-Heptyl-2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline (3d)
Colorless solid; yield: 173 mg (64%, A1); mp 109–111 °C.
IR (CHCl3): 3420 (N–H), 1618 (C=N), 1483 cm–1.
13C NMR (126 MHz, CDCl3): δ = 159.2 (N=C–N), 145.6 (d sym m,
J
C-F = 250 Hz, 2 CF), 143.6 (C), 141.8 (d sym m, JC-F = 257 Hz,
CF), 137.7 (d sym m, JC-F = 254 Hz, 2 CF), 132.7 (CH), 127.1 (CH),
120.0 (CH), 115.0 (CH, C), 112.2 (t sym m, JC-F = 13.8 Hz, C), 64.2
(CH-5), 52.6 (CH2N=), 49.1 (CH2N).
19F NMR (282 MHz, CDCl3): δ = –141.6 (br d, JF-F = 14.5 Hz, 2 F,
FCortho), –152.0 (t, JF-F = 20.9 Hz, 1 F, FCpara), –160.9 (sym m, 2 F,
FCmeta).
1H NMR (500 MHz, CDCl3): δ = 7.88 (dd, J = 7.8, 1.3 Hz, 1 H),
7.23 (ddd, J = 8.0, 8.0, 1.3 Hz, 1 H), 6.80 (dd, J = 7.8, 7.8 Hz, 1 H),
6.66 (d, J = 8.0 Hz, 1 H), 4.26 (t, J = 4.8 Hz, 1 H, H5), 4.19 (br s, 1
H, H6), 4.00 (ddd, J = 13.6, 10.1, 2.6 Hz, 1 H, HH′CN=), 3.74 (ddd,
J = 13.6, 13.6, 8.8 Hz, 1 H, H′HCN=), 3.55 (ddd, J = 8.8, 8.8, 2.6
Hz, 1 H, HH′CN), 2.98 (ddd, J = 13.6, 10.1, 8.8 Hz, 1 H, H′HCN),
1.75–1.70 (m, 2 H, CH2C-5), 1.57–1.45 (m, 2 H, CH2), 1.41–1.23
(m, 8 H, 4 CH2), 0.89 (t, J = 6.8 Hz, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H11F5N3: 340.0868; found:
340.0861.
13C NMR (126 MHz, CDCl3): δ = 161.5 (N=C–N), 145.1 (C), 132.1
(CH), 127.0 (CH), 119.1 (CH), 114.7 (CH), 112.7 (C), 70.0 (CH),
53.3 (CH2N=), 49.1 (CH2N), 34.3 (CH2), 31.7 (CH2), 29.6 (CH2),
29.2 (CH2), 23.3 (CH2), 22.6 (CH2), 14.1 (CH3).
5-(4-Nitrophenyl)-2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline
(3h)
Yellow-orange solid; yield: 271 mg (92%, A2), 283 mg (96%, A3);
mp 200–202 °C (dec.).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3512–3522

3518
E. E. Korshin et al.
PAPER
IR (CHCl3): 3412 (N–H), 1621 (C=N), 1527 (asym NO2), 1456,
1437, 1350 cm–1 (sym NO2).
evaporated, and the residue was subjected to FC (Florisil, gradient
5% to 70% EtOAc–hexane) to give the 2,3-dihydroimidazo[1,2-
c]quinazoline 4.
1H NMR (500 MHz, CD2Cl2): δ = 8.27 (d sym m, J = 8.8 Hz, 2 H),
7.87 (br d, J = 7.8 Hz, 1 H), 7.78 (d sym m, J = 8.8 Hz, 2 H), 7.28
(br ddd, J = 7.8, 7.8, 1.4 Hz, 1 H), 6.85 (br dd, J = 7.7, 7.7 Hz, 1 H),
6.70 (d, J = 8.1 Hz, 1 H), 5.27 (s, 1 H, H5), 4.56 (br s, 1 H, H6), 3.91
(ddd, J = 13.5, 10.0, 2.6 Hz, 1 H, HH′CN=), 3.63 (ddd, J = 13.5,
13.5, 9.2 Hz, 1 H, H′HCN=), 3.02 (ddd, J = 9.2, 9.2, 2.6 Hz, 1 H,
HH′CN), 2.85 (ddd, J = 13.5, 10.0, 9.2 Hz, 1 H, H′HCN).
13C NMR (126 MHz, CD2Cl2): δ = 160.1 (N=C–N), 149.2 (CAr-
NO2), 146.4 (C), 145.0 (C), 132.7 (CH), 129.5 (2 CH), 127.2 (CH),
124.4 (2 CH), 119.8 (CH), 115.0 (CH), 112.9 (C), 73.8 (CH-5), 54.0
(CH2N=), 50.2 (CH2N).
2,3-Dihydroimidazo[1,2-c]quinazolines 4 by Selective Oxidative
Dehydrogenation of 2,3,5,6-tetrahydroimidazo[1,2-c]quinazo-
lines 3; General Procedure D1
To a cold (0 °C) well stirred suspension of 3 (0.20 mmol) and silica
gel Si 60 (200–250 mg) in anhyd MeCN (3 mL), a soln of KMnO4
(33 mg, 0.21 mmol, 1.05 equiv) in MeCN (2mL) was added. The
mixture was stirred for 2 h at 0 °C and for 30 min at r.t., after this
time, the original deep-purple mixture had changed to pink. The re-
action was quenched by addition of EtOH (1 mL), stirred for 1 h,
and filtered through a plug of Celite. The reaction flask and the filter
were thoroughly rinsed with CH2Cl2, the combined filtrates were
evaporated. The residue was subjected to FC (Florisil) to give the
products 4.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N4O2: 295.1190; found:
295.1187.
Anal. Calcd for C16H14N4O2: C, 65.30; H, 4.79; N, 19.04. Found: C,
65.18; H, 4.90; N, 18.85.
Ethyl 2,3-Dihydroimidazo[1,2-c]quinazoline-5-carboxylate (4a)
Lemon-yellow solid; yield: 39.0 mg (80%, C1), 46.2 mg (94%, D1);
mp 120–122 °C, Rf = 0.34 (Et3N–EtOAc, 1:15).
IR (CHCl3): 1731 (C=O), 1648 (C=N), 1293, 1243 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.03 (dd, J = 7.8, 1.2 Hz, 1 H),
7.65 (br d, J = 7.8 Hz, 1 H), 7.59 (ddd, J = 7.8, 7.8, 1.4 Hz, 1 H),
7.40 (br ddd, J = 7.8, 7.8, 1.2 Hz, 1 H), 4.48 (q, J = 7.1 Hz, 2 H,
CH2O), 4.45 (t, J = 9.8 Hz, 2 H, CH2N), 4.13 (t, J = 9.8 Hz, 2 H,
CH2N), 1.45 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 161.2 (O–C=O), 154.8 (C), 145.1
(C), 142.6 (C), 133.2 (CH), 128.4 (CH), 128.2 (CH), 125.3 (CH),
119.2 (C), 63.2 (CH2O), 54.1 (CH2N=), 48.9 (CH2N), 14.1 (CH3).
5-(2-Bromophenyl)-2,3,5,6-tetrahydroimidazo[1,2-c]quinazo-
line (3i)
Yellowish solid; yield: 244 mg (74%, A2); mp 186–188 °C.
IR (CHCl3): 3410 (N–H), 1618 (C=N), 1482 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.93 (dd, J = 7.8, 1.4 Hz, 1 H),
7.80 (dd, J = 7.8, 1.7 Hz, 1 H), 7.58 (dd, J = 8.0, 1.2 Hz, 1 H), 7.40
(br ddd, J = 7.6, 7.6, 1.2 Hz, 1 H), 7.28–7.23 (m, 2 H), 6.84 (br ddd,
J = 7.8, 7.8, 1.0 Hz, 1 H), 6.64 (br d, J = 7.8 Hz, 1 H), 5.81 (s, 1 H,
H5), 4.48 (br s, 1 H, H6), 3.96 (ddd, J = 14.0, 10.2, 3.6 Hz, 1 H,
HH′CN=), 3.75 (ddd, J = 14.0, 12.6, 9.1 Hz, 1 H, H′HCN=), 3.17
(ddd, J = 9.1, 9.1, 3.6 Hz, 1 H, HH′CN), 2.90 (ddd, J = 12.6, 10.2,
8.9 Hz, 1 H, H′HCN).
13C NMR (126 MHz, CDCl3): δ = 160.6 (N=C–N), 144.4 (C), 137.4
(C), 133.0 (CH), 132.4 (CH), 130.7 (CH), 130.0 (CH), 128.3 (CH),
127.0 (CH), 123.2 (C), 119.4 (CH), 114.6 (CH), 112.3 (C), 71.5
(CH-5), 53.0 (CH2N=), 49.6 (CH2N).
HRMS (ESI): m/z [M + H]+ calcd for C13H14N3O2: 244.1081; found:
244.1078.
Anal. Calcd for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C,
63.91; H, 5.55; N, 17.08.
2,3-Dihydroimidazo[1,2-c]quinazoline (4b)
HRMS (FD): m/z [M]+ calcd for C16H1479BrN3: 327.0371; found:
327.0374.
Colorless solid; yield: 245 mg (96%, B1); mp 126–127 °C (Lit.11
121–122 °C, Lit.13b 124–127 °C, Lit.12 128–129 °C, Lit.13a 128–130
°C); Rf = 0.23 (Et3N–CH2Cl2, 1:20).
2,3-Dihydroimidazo[1,2-c]quinazolines 4; General Procedures
B1–D1
IR (CHCl3): 1646 (C=N), 1470, 1374 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.97 (br dd, 3J = 7.8, 1.5 Hz, 1 H),
7.72 (d, J = 2.1 Hz, 1 H), 7.54 (dddd, J = 7.8, 7.8, 1.5, 1.5 Hz, 1 H),
7.46 (br d, J = 7.8 Hz, 1 H), 7.30 (dddd, J = 7.8, 7.8, 1.5, 1.5 Hz, 1
H), 4.12–4.06 (m, 4 H, NCH2CH2N=).
13C NMR (75 MHz, CDCl3): δ = 154.1 (N=C–N), 146.2 (C), 143.2
(HC=N), 132.9 (CH), 127.0 (CH), 126.7 (CH), 124.9 (CH), 118.8
(C), 53.4 (CH2N=), 46.5 (CH2N).
2,3-Dihydroimidazo[1,2-c]quinazolines 4b,c by Condensation
of 1 with Orthoesters; General Procedure B1
A mixture of 1 (242 mg, 1.5 mmol) and methyl orthoformate or or-
thoacetate (5 mL in each case) was heated at 115–120 °C for 12 h
under N2. All the volatiles were distilled off in vacuo, the residue
was washed with hexane and recrystallized (EtOAc–hexane) to give
2,3-dihydroimidazo[1,2-c]quinazoline (4b) (245 mg, 96%) or 5-
methyl-2,3-dihydroimidazo[1,2-c]quinazoline (4c) (202 mg, 73%).
HRMS (ESI): m/z [M + H]+ calcd for C10H10N3: 172.0869; found:
172.0867.
5-Substituted 2,3-Dihydroimidazo[1,2-c]quinazolines 4c,e by
Condensation of 1 with Iminoesters; General Procedure B2
To a cold (0 °C) well stirred suspension of 1 (161 mg, 1.0 mmol)
and methyl acetimidate hydrochloride or benzimidate hydrochlo-
ride (3.0 mmol in each case) in anhyd toluene (5 mL), solid t-BuOK
(337 mg, 3.0 mmol) was added. After stirring for 1 h at r.t, the mix-
ture was refluxed for 5 d under N2. Filtration through Celite, evap-
oration followed by FC (Florisil) afforded 5-methyl-2,3-
dihydroimidazo[1,2-c]quinazoline (4c) (86 mg, 47%) or 5-phenyl-
2,3-dihydroimidazo[1,2-c]quinazoline (4e) (88 mg, 36%), respec-
tively.
5-Methyl-2,3-dihydroimidazo[1,2-c]quinazoline (4c)
Colorless solid; yield: 202 mg (73%, B1), 86 mg (47%, B2), 21.5
mg (58%, C1), 32.0 mg (86%, D1); mp 93–94 °C (Lit.3a 130 °C,
Lit.16 159 °C); Rf = 0.28 (Et3N–CH2Cl2, 1:20).
IR (CHCl3): 1650 (C=N), 1644 (C=N), 1579, 1468, 1409 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.97 (dd, J = 7.9, 1.5 Hz, 1 H),
7.52 (br ddd, J = 8.0, 8.0, 1.5 Hz, 1 H), 7.42 (br dd, J = 8.2, 1.2 Hz,
1 H), 7.25 (br ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 4.16–4.01 (sym m, 4
H, NCH2CH2N=), 2.35 (s, 3 H, CH3).
2,3-Dihydroimidazo[1,2-c]quinazolines 4 by Selective Catalytic
Dehydrogenation of 2,3,5,6-tetrahydroimidazo[1,2-c]quinazo-
lines 3 General Procedure C1
A suspension of 3 (0.20 mmol) and 5% Pd/C (42 mg, 0.020 mmol,
0.1 equiv) in anhyd de-aerated toluene (5.0 mL) was refluxed under
argon until the consumption of 3 was complete (TLC monitoring).
The mixture was filtered through a plug of Celite, the filtrate was
13C NMR (75 MHz, CDCl3): δ = 155.1 (C), 152.2 (C), 146.9 (C),
132.9 (CH), 126.3 (CH), 125.8 (CH), 125.3 (CH), 117.7 (C), 53.4
(CH2N=), 47.2 (CH2N), 21.9 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C11H12N3: 186.1026; found:
186.1031.
Synthesis 2012, 44, 3512–3522
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-Substituted Imidazo[1,2-c]quinazolines
3519
5-Heptyl-2,3-dihydroimidazo[1,2-c]quinazoline (4d)
Colorless solid; yield: 33.3 mg (62%, C1), 48.6 mg (90%, D1); mp
71–72 °C; Rf = 0.07 (EtOAc).
13C NMR (126 MHz, CDCl3): δ = 154.3 (C), 145.9 (C), 144.3 (d
sym m, JC-F = 256 Hz, 2 CF), 142.6 (d sym m, JC-F = 259 Hz, CF),
141.2 (br, C), 137.9 (d sym m, JC-F = 254 Hz, 2 CF), 133.4 (CH),
IR (CHCl3): 1646 (C=N), 1575, 1467, 1406 cm–1.
127.8 (CH), 127.5 (CH), 125.2 (CH), 118.2 (C), 109.8 (td, JC-F
18.4, 4.3 Hz, C), 53.5 (CH2N=), 47.4 (CH2N).
19F NMR (282 MHz, CDCl3): δ = –140.2 (br dd, JF-F = 23.4, 7.0 Hz,
2 F, FCortho), –150.6 (br t, JF-F = 20.8 Hz, 1 F, FCpara), –160.0 (sym
m, 2 F, FCmeta).
HRMS (FD): m/z [M]+ calcd for C16H8F5N3: 337.0638; found:
337.0644.
=
1H NMR (500 MHz, CDCl3): δ = 7.97 (dd, J = 7.8, 1.3 Hz, 1 H),
7.53 (br ddd, J = 7.8, 7.8, 1.5 Hz, 1 H), 7.44 (br d, J = 7.8 Hz, 1 H),
7.26 (br ddd, J = 7.8, 7.8, 1.1 Hz, 1 H), 4.15–4.06 (sym m, 4 H,
NCH2CH2N=), 2.53 (t, J = 7.9 Hz, 2 H, CH2C-5), 1.77 (br tt,
J = 7.6, 7.6 Hz, 2 H, CH2), 1.43 (br tt, J = 7.3, 7.3 Hz, 2 H, CH2),
1.38–1.26 (m, 6 H, 3 CH2), 0.88 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 155.5 (2 C), 146.8 (C), 132.9
(CH), 126.4 (CH), 125.8 (CH), 125.1 (CH), 117.5 (C), 53.3
(CH2N=), 46.8 (CH2N), 35.2 (CH2C-5), 31.7 (CH2), 29.4 (CH2),
29.0 (CH2), 26.7 (CH2), 22.6 (CH2), 14.0 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H24N3: 270.1965; found:
270.1970.
5-(4-Nitrophenyl)-2,3-dihydroimidazo[1,2-c]quinazoline (4h)
Lemon-yellow solid; yield: 55.2 mg (94%, D1); mp 214–216 °C
(dec.); Rf = 0.18 (Et3N–EtOAc, 1:20).
IR (CHCl3): 1647 (C=N), 1528 (asym NO2), 1351 cm–1 (sym NO2).
1H NMR (500 MHz, CDCl3): δ = 8.36 (d sym m, J = 8.8 Hz, 2 H),
8.05 (dd, J = 7.8, 1.4 Hz, 1 H), 7.85 (d sym m, J = 8.8 Hz, 2 H), 7.61
(br ddd, J = 7.8, 7.8, 1.5 Hz, 1 H), 7.54 (dd, J = 8.0, 1.4 Hz, 1 H),
7.38 (br ddd, J = 7.8, 7.8, 1.2 Hz, 1 H), 4.15–4.10 (m, 2 H,
CHH′N=), 4.04–3.99 (m, 2 H, CHH′N).
13C NMR (126 MHz, CDCl3): δ = 155.0 (C), 151.6 (C), 148.7 (C),
146.1 (C), 140.7 (C), 133.3 (CH), 129.1 (2 CH), 127.32 (CH),
127.29 (CH), 125.3 (CH), 124.0 (2 CH), 118.0 (C), 53.7 (CH2N=),
48.8 (CH2N).
Anal. Calcd for C17H23N3: C, 75.80; H, 8.61; N, 15.60. Found: C,
75.52; H, 8.67; N, 15.53.
5-Phenyl-2,3-dihydroimidazo[1,2-c]quinazoline (4e)
Colorless solid; yield: 88 mg (36%, B2), 36.5 mg (74%, C1), 48.6
mg (90%, D1); mp 109–110 °C (Lit.5a 102–104 °C, Lit.16 108 °C),
Rf = 0.10 (Et3N–EtOAc–hexane, 1:10:10).
IR (CHCl3): 1646 (C=N), 1553, 1466, 1395 cm–1.
HRMS (FD): m/z [M]+ calcd for C16H12N4O2: 292.0960; found:
292.0963.
1H NMR (500 MHz, CDCl3): δ = 8.05 (dd, J = 7.8, 0.7 Hz, 1 H),
7.65–7.61 (sym m, 2 H), 7.60–7.55 (m, 2 H), 7.51–7.46 (m, 3 H),
7.32 (br ddd, J = 7.8, 7.8, 2.0 Hz, 1 H), 4.11–4.00 (sym m, 4 H,
NCH2CH2N=).
13C NMR (126 MHz, CDCl3): δ = 155.5 (C), 153.7 (C), 146.7 (C),
135.0 (C), 133.1 (CH), 130.2 (CH), 128.7 (2 CH), 127.7 (2 CH),
127.2 (CH), 126.5 (CH), 125.2 (CH), 117.8 (C), 53.4 (CH2N=), 48.9
(CH2N).
5-(2-Bromophenyl)-2,3-dihydroimidazo[1,2-c]quinazoline (4i)
Colorless solid; yield: 58.6 mg (90%, D1); mp 152–154 °C;
Rf = 0.27 (Et3N–EtOAc, 1:20).
IR (CHCl3): 1646 (C=N), 1467, 1400 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.06 (dd, J = 7.9, 1.4 Hz, 1 H),
7.67 (d, J = 8.0 Hz, 1 H), 7.60 (br ddd, J = 7.8, 7.0, 1.4 Hz, 1 H),
7.57 (br dd, J = 8.1, 1.4 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.39–7.34 (m,
2 H), 4.13–4.06 (m, 2 H, CHH′N=), 4.03–3.94 (br m, 1 H, CHH′N),
3.73–3.63 (br m, 1 H, CHH′N).
13C NMR (126 MHz, CDCl3): δ = 154.8 (C), 152.2 (C), 146.5 (C),
136.2 (C), 133.2 (CH), 133.1 (CH), 131.3 (CH), 129.4 (CH), 128.1
(CH), 127.3 (CH), 126.8 (CH), 125.2 (CH), 121.0 (CBr), 118.0 (C),
53.4 (CH2N=), 47.6 (CH2N).
HRMS (ESI): m/z [M + H]+ calcd for C16H14N3: 248.1182; found:
248.1190.
5-(4-Methoxyphenyl)-2,3-dihydroimidazo[1,2-c]quinazoline
(4f)
Colorless solid; yield: 39.8 mg (72%, C1), 49.0 mg (88%, D1); mp
149–150 °C; Rf = 0.18 (Et3N–MeOH–EtOAc–hexane, 1:1:10:10).
IR (CHCl3): 1643 (C=N), 1608, 1515, 1466, 1392, 1255, 1174 cm–1.
HRMS (FD): m/z [M]+ calcd for C16H1279BrN3: 325.0215; found:
325.0212.
1H NMR (500 MHz, CDCl3): δ = 8.03 (dd, J = 7.8, 0.7 Hz, 1 H),
7.61 (d sym m, J = 8.7 Hz, 2 H), 7.59–7.53 (m, 2 H), 7.32 (br ddd,
J = 7.8, 7.8, 1.8 Hz, 1 H), 6.99 (d sym m, J = 8.7 Hz, 2 H), 4.12–
4.03 (sym m, 4 H, NCH2CH2N=), 3.86 (s, 3 H, CH3O).
Anal. Calcd for C16H12BrN3: C, 58.91; H, 3.71; N, 12.88. Found: C,
58.69; H, 3.95; N, 12.70.
13C NMR (126 MHz, CDCl3): δ = 161.1 (C-OMe), 155.7 (C), 153.6
(C), 146.8 (C), 133.0 (CH), 129.4 (2 CH), 127.5 (C), 127.1 (CH),
126.3 (CH), 125.1 (CH), 117.7 (C), 114.0 (2 CH), 55.4 (CH3O),
53.5 (CH2N=), 49.1 (CH2N).
HRMS (ESI): m/z [M + H]+ calcd for C17H16N3O: 278.1288; found:
278.1295.
Imidazo[1,2-c]quinazolines 5; General Procedures C2, D2
Imidazo[1,2-c]quinazolines 5 by Catalytic Dehydrogenation of
2,3,5,6-Tetrahydroimidazo[1,2-c]quinazolines 3 and 2,3-Dihy-
droimidazo[1,2-c]quinazolines 4; General Procedure C2
A suspension of 3 (0.20 mmol) and 5% Pd/C (42 mg, 0.020 mmol
Pd, 0.1 equiv) in anhyd de-aerated m-xylene (5.0 mL) was refluxed
under argon until complete consumption of 3 and more polar inter-
mediate 4 (TLC monitoring). The mixture was filtered through a
plug of Celite, rinsed with CH2Cl2, and the combined filtrates were
evaporated. The residue was subjected to FC (silica gel, gradient
10% to 60% EtOAc–hexane) to give imidazo[1,2-c]quinazoline 5.
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.45; H, 5.64; N, 15.09.
5-(Pentafluorophenyl)-2,3-dihydroimidazo[1,2-c]quinazoline
(4g)
Colorless solid; yield: 62.0 mg (92%, D1); mp 131–132 °C,
Rf = 0.25 (Et3N–EtOAc–hexane, 1:10:10).
Imidazo[1,2-c]quinazolines 5 by Oxidative Dehydrogenation of
2,3,5,6-Tetrahydroimidazo[1,2-c]quinazolines 3; General Pro-
cedure D2
To a stirred suspension of 3 (0.20 mmol) and silica gel Si 60 (400
mg) in anhyd MeCN (5 mL), well grinded solid KMnO4 (65 mg,
0.41 mmol, 2.05 equiv) was added. The mixture was stirred at r.t.
overnight (12–16 h) and quenched by addition of EtOH (1 mL). Af-
ter 1 h stirring at r.t., the mixture was filtered through a plug of
IR (CHCl3): 1657 (sh), 1648 (C=N), 1522, 1503 (C–F), 996, 883
cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.05 (dd, J = 7.9, 1.4 Hz, 1 H),
7.61 (br ddd, J = 7.9, 7.9, 1.5 Hz, 1 H), 7.52 (br dd, J = 7.9, 1.1 Hz,
1 H), 7.41 (ddd, J = 7.9, 7.9, 1.1 Hz, 1 H), 4.14 (t, J = 9.7 Hz, 2 H,
CH2N=), 3.90 (t, J = 9.7 Hz, 2 H, CH2N).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3512–3522

3520
E. E. Korshin et al.
PAPER
Celite and rinsed well with CH2Cl2. Evaporation followed by FC
(silica gel) afforded the products 5.
13C NMR (126 MHz, CDCl3): δ = 145.8 (C), 144.2 (C), 141.2 (C),
132.7 (CH), 129.8 (CH), 127.9 (CH), 127.6 (CH), 122.7 (CH),
118.7 (C), 111.1 (CH), 34.3 (CH2C-5), 31.7 (CH2), 29.4 (CH2), 29.0
(CH2), 25.9 (CH2), 22.6 (CH2), 13.9 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H22N3: 268.1808; found:
268.1813.
Ethyl Imidazo[1,2-c]quinazoline-5-carboxylate (5a)
Lemon-yellow solid; yield: 28.0 mg (58%, C1), 32.2 mg (67%, C2),
42.5 mg (88%, D2); mp 147–149 °C; Rf = 0.58 (Et3N–EtOAc,
1:15).
Anal. Calcd for C17H21N3: C, 76.37; H, 7.92; N, 15.72. Found: C,
76.18; H, 7.95; N, 15.55.
IR (CHCl3): 1731 (C=O), 1606 (C=N), 1311, 1285, 1248, 1096,
1069 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.65 (d, J = 1.5 Hz, 1 H), 8.62–
8.59 (sym m, 1 H), 8.16–8.11 (sym m, 1 H), 7.78–7.73 (m, 2 H),
7.70 (d, J = 1.5 Hz, 1 H), 4.64 (q, J = 7.1 Hz, 2 H, CH2O), 1.55 (t,
J = 7.1 Hz, 3 H, CH3).
5-Phenylimidazo[1,2-c]quinazoline (5e)
Colorless solid; yield: 41.0 mg (84% from 3e, C2), 42.3 mg (86%
from 4e, C2), 47.0 mg (96%, D2); mp 143–144 °C (Lit.38 127–129
°C, Lit.5a 144–146 °C); Rf = 0.21 (EtOAc–hexane, 1:1).
13C NMR (126 MHz, CDCl3): δ = 160.8 (O–C=O), 144.3 (C), 139.3
(C), 135.2 (C), 133.1 (CH), 130.6 (CH), 130.3 (CH), 129.5 (CH),
122.7 (CH), 120.2 (C), 114.9 (CH), 63.6 (CH2O), 14.2 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H12N3O2: 242.0924; found:
242.0921.
IR (CHCl3): 1618 (br) (C=N), 1528, 1473, 1379, 1355, 1310, 1302,
1103 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.57 (ddd, J = 7.7, 1.5, 0.4 Hz, 1
H), 8.01 (ddd, J = 7.8, 1.3, 0.5 Hz, 1 H), 7.94–7.90 (m, 2 H), 7.73
(d, J = 1.5 Hz, 1 H), 7.71 (br ddd, J = 7.7, 7.7, 1.5 Hz, 1 H), 7.66 (br
ddd, J = 7.6, 7.6, 1.4 Hz, 1 H), 7.63–7.60 (m, 3 H), 7.61 (d, J = 1.5
Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 146.8 (C), 144.4 (C), 141.2 (C),
133.6 (C), 132.5 (CH), 131.1 (CH), 130.2 (CH), 129.1 (2 CH),
128.5 (2 CH), 128.4 (CH), 128.3 (CH), 122.6 (CH), 118.7 (C),
113.1 (CH).
Anal. Calcd for C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C,
64.90; H, 4.85; N, 17.29.
Imidazo[1,2-c]quinazoline (5b)
Colorless solid; yield: 27.0 mg (80%, C2), 31.2 mg (92%, D2); mp
137–138 °C (Lit.6 126–127 °C, Lit.36 127–129 °C, Lit.15 135–137
°C, Lit.14 140–140.5 °C); Rf = 0.15 (Et2O).
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3: 246.1026; found:
246.1027.
IR (CHCl3): 1622 (C=N), 1612 (C=N), 1477, 1317 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.90 (s, 1 H, H5), 8.54 (br dd,
J = 7.9, 1.5 Hz, 1 H), 7.95 (br d, J = 7.8 Hz, 1 H), 7.71 (br dddd,
J = 7.8, 7.8, 1.5, 1.5 Hz, 1 H), 7.67 (br dddd, J = 7.8, 7.8, 1.4, 1.4
Hz, 1 H), 7.66 (br d, J = 1.4 Hz, 1 H), 7.64 (br d, J = 1.4 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 143.1 (C), 140.8 (C), 136.8 (CH),
133.0 (CH), 130.1 (CH), 128.7 (CH), 128.4 (CH), 122.6 (CH),
119.7 (C), 112.0 (CH).
5-(4-Methoxyphenyl)imidazo[1,2-c]quinazoline (5f)
Colorless solid; yield: 33.2 mg (60%, C1), 45.0 mg (82%, C2), 48.6
mg (88%, D2); mp 134–135 °C; Rf = 0.46 (EtOAc).
IR (CHCl3): 1609 (C=N), 1511, 1306, 1257 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.54 (br dd, J = 7.9, 1.5 Hz, 1 H),
7.97 (br dd, J = 8.1, 0.6 Hz, 1 H), 7.89 (d sym m, J = 8.8 Hz, 2 H),
7.75 (d, J = 1.5 Hz, 1 H), 7.68 (br ddd, J = 8.0, 8.0, 1.6 Hz, 1 H),
7.63 (br ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 7.60 (br d, J = 1.5 Hz, 1 H),
7.10 (d sym m, J = 8.8 Hz, 2 H), 3.91 (s, 3 H, CH3O).
HRMS (ESI): m/z [M + H]+ calcd for C10H8N3: 170.0713; found:
170.0709.
13C NMR (126 MHz, CDCl3): δ = 161.7 (C-OMe), 146.6 (C), 144.5
(C), 141.3 (C), 132.3 (CH), 130.14 (2 CH), 130.07 (CH), 128.2
(CH), 128.0 (CH), 125.9 (C), 122.6 (CH), 118.5 (C), 114.4 (2 CH),
113.1 (CH), 55.5 (CH3O).
5-Methylimidazo[1,2-c]quinazoline (5c)
Colorless solid; yield: 27.3 mg (75% from 3c, C2), 30.2 mg (82%
from 4c, C2), 33.0 mg (90%, D2); mp 131–132 °C (Lit.15 118–120
°C, Lit.36 124–126 °C); Rf = 0.20 (EtOAc).
IR (CHCl3): 1625 (C=N), 1617 (C=N), 1475, 1389, 1318, 1310 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C17H14N3O: 276.1131; found:
1H NMR (500 MHz, CDCl3): δ = 8.51 (dd, J = 7.9, 1.5 Hz, 1 H),
7.88 (br d, J = 7.8 Hz, 1 H), 7.68 (br ddd, J = 7.8, 7.8, 1.5 Hz, 1 H),
7.64 (d, J = 1.4 Hz, 1 H), 7.61 (br ddd, J = 7.8, 7.8, 1.1 Hz, 1 H),
7.57 (d, J = 1.4 Hz, 1 H), 2.87 (s, 3 H, CH3).
276.1126.
Anal. Calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
73.95; H, 4.79; N, 15.20.
13C NMR (126 MHz, CDCl3): δ = 145.3 (C), 143.7 (C), 140.9 (C),
132.8 (CH), 130.0 (CH), 127.8 (CH), 127.6 (CH), 122.6 (CH),
118.5 (C), 111.4 (CH), 21.2 (CH3).
5-(Pentafluorophenyl)imidazo[1,2-c]quinazoline (5g)
Colorless solid; yield: 63.0 mg (94%, D2); mp 151–152 °C;
Rf = 0.37 (EtOAc–hexane, 1:1).
IR (CHCl3): 1615 (br, C=N), 1518, 1506, 1501 (all C–F), 1388, 995
cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.65–8.60 (sym m, 1 H), 8.03–
7.99 (sym m, 1 H), 7.80–7.75 (m, 2 H), 7.67 (d, J = 1.5 Hz, 1 H),
7.32 (br d, J = 1.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 145.2 (d sym m, JC-F = 243 Hz, 2
CF), 143. 9 (C), 143.1 (d sym m, JC-F = 256 Hz, CF), 140.5 (C),
138.1 (d sym m, JC-F = 248 Hz, 2 CF), 134.5 (br s, C), 133.3 (CH),
130.6 (CH), 129.8 (CH), 128.7 (CH), 122.8 (CH), 119.1 (C), 112.1
(CH), 108.5 (sym m, C).
19F NMR (282 MHz, CDCl3): δ = –138.6 (br dd, JF-F = 17.7, 7.0 Hz,
2 F, FCortho), –149.0 (br t, JF-F = 21.0 Hz, 1 F, FCpara), –159.5 (sym
m, 2 F, FCmeta).
HRMS (ESI): m/z [M + H]+ calcd for C11H10N3: 184.0869; found:
184.0875.
5-Heptylimidazo[1,2-c]quinazoline (5d)
Colorless solid; yield: 34.0 mg (64%, C2), 40.7 mg (76%, D2); mp
85–86 °C; Rf = 0.24 (EtOAc–hexane, 1:2).
IR (CHCl3): 1624 (C=N), 1616 (C=N), 1474, 1386, 1315 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.53 (dd, J = 8.0, 1.5 Hz, 1 H),
7.91 (dd, J = 8.1, 1.0 Hz, 1 H), 7.66 (br ddd, J = 8.0, 8.0, 1.5 Hz, 1
H), 7.63 (br d, J = 1.4 Hz, 1 H), 7.61 (d, J = 1.4 Hz, 1 H), 7.60 (br
ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 3.11 (t, J = 7.7 Hz, 2 H, CH2C-5),
2.01 (tt, J = 7.6, 7.6 Hz, 2 H, CH2), 1.56–1.50 (m, 4 H, 2 CH2),
1.45–1.39 (sym m, 2 H, CH2), 1.35–1.1.30 (m, 2 H, CH2), 0.91 (t,
J = 7.0 Hz, 3 H, CH3).
HRMS (FD): m/z [M]+ calcd for C16H6F5N3: 335.0482; found:
335.0479.
Synthesis 2012, 44, 3512–3522
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-Substituted Imidazo[1,2-c]quinazolines
3521
5-(4-Nitrophenyl)imidazo[1,2-c]quinazoline (5h)
Yellow solid; yield: 55.3 mg (95%, D2); mp 205–206 °C (dec.);
Rf = 0.25 (hexane–EtOAc, 1:2).
Bacon, K. WO 2004029055 2004; Chem. Abstr. 2004, 140,
321374.
(3) For activity of 2,3-dihydro- and 2,3,5,6-tetrahydro-
imidazo[1,2-c]quinazolines as bronchodilators, see:
(a) Bahekar, R. H.; Rao, A. R. R. Arzneim. Forsch. 2001, 51,
284. (b) Schindler, O. US 3309369 1967; Chem. Abstr.
1967, 67, 73617.
(4) For hypoglycemic and antidiabetic properties of 2,3,5,6-
tetrahydroimidazo[1,2-c]quinazolines, refer to: Frei, J.;
Schweizer, E. EP 46446 1982; Chem. Abstr. 1982, 96,
217872.
(5) Platelet activating factor (PAF-receptor) potent antagonists:
(a) Cardellini, M.; Franchetti, P.; Grifantini, M.; Martelli, S.;
Petrelli, F. Farmaco 1975, 30, 536. (b) Houlihan, W. J.;
Cheon, S. H.; Parrino, V. A.; Handley, D. A.; Larson, D. A.
J. Med. Chem. 1993, 36, 3098.
IR (CHCl3): 1620 and 1597 (C=N), 1528 (asym NO2), 1348 (sym
NO2), 1305, 856 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.59 (ddd, J = 7.5, 1.7, 0.8 Hz, 1
H), 8.48 (d sym m, J = 8.8 Hz, 2 H), 8.15 (d sym m, J = 8.8 Hz, 2
H), 8.01 (ddd, J = 7.8, 1.4, 0.6 Hz, 1 H), 7.75 (br ddd, J = 7.7, 7.7,
1.6 Hz, 1 H), 7.71 (br ddd, J = 7.6, 7.6, 1.4 Hz, 1 H), 7.67 and 7.66
(AB q, J = 1.5 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 149.2 (C–NO2), 144.5 (C), 144.4
(C), 140.9 (C), 139.3 (C), 133.1 (CH), 130.5 (CH), 129.8 (2 CH),
129.1 (CH), 128.6 (CH), 124.3 (2 CH), 122.8 (CH), 118.8 (C),
112.4 (CH).
HRMS (ESI): m/z [M + H]+ calcd for C16H11N4O2: 291.0877; found:
(6) For a potency of imidazo[1,2-c]quinazolines and 5,6-di-
hydroimidazo[1,2-c]quinazolines as lipid peroxidation
inhibitors, see: Domany, G.; Gizur, T.; Gere, A.; Takacs-
Novak, K.; Farsang, G.; Ferenczy, G. G.; Tarkanyi, G.;
Demeter, M. Eur. J. Med. Chem. 1998, 33, 181.
(7) For antiarrhythmic properties of tetracyclic 2,3,5,6-tetra-
hydroimidazo[1,2-c]quinazolines, see: Franke, A.;
Ostersehlt, B.; Schlecker, R.; Randenbach, B.; von
Philipsborn, G. DE 3730718 1989; Chem. Abstr. 1989, 111,
115199.
(8) For HIV-1 antiviral activity of imidazo[1,2-c]quinazolines,
refer to: Krikorian, D.; Parushev, S.; Tarpanov, V.;
Mechkarova, P.; Mikhova, B.; Botta, M.; Corelli, F.; Maga,
G.; Spadari, S. Med. Chem. Res. 1997, 7, 546.
(9) Selby, T. P. WO 2003032731 2003; Chem. Abstr. 2003, 138,
316207.
291.0874.
Anal. Calcd for C16H10N4O2: C, 66.20; H, 3.47; N, 19.30. Found: C,
65.99; H, 3.65; N, 19.18.
5-(2-Bromophenyl)imidazo[1,2-c]quinazoline (5i)
Colorless solid; yield: 55.3 mg (85%, D2); mp 145–147 °C;
Rf = 0.28 (hexane–EtOAc, 1:1).
IR (CHCl3): 1621 (C=N), 1475, 1383, 1311, 938 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.61 (br dd, J = 7.3, 1.9 Hz, 1 H),
8.03 (br dd, 3J = 7.6, 1.5 Hz, 1 H), 7.79 (dd, J = 7.8, 1.1 Hz, 1 H),
7.75 (ddd, J = 7.2, 7.2, 1.8 Hz, 1 H), 7.72 (ddd, J = 7.2, 7.2, 1.4 Hz,
1 H), 7.62 (dd, J = 7.5, 1.7 Hz, 1 H), 7.59 (d, J = 1.5 Hz, 1 H), 7.56
(ddd, J = 7.5, 7.5, 1.2 Hz, 1 H), 7.49 (ddd, J = 7.8, 7.8, 1.8 Hz, 1 H),
7.20 (d, J = 1.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 145.7 (C), 143.6 (C), 140.8 (C),
134.6 (C), 133.5 (CH), 132.6 (CH), 132.0 (CH), 130.8 (CH), 130.2
(CH), 128.8 (CH), 128.5 (CH), 128.2 (CH), 122.7 (CH), 122.0 (C),
118.9 (C), 113.0 (CH).
(10) Stoessel, P.; Heil, H.; Jooseten, D.; Pfumm, C.; Gerhard, A.;
Breuning, E. WO 2010086089 2010; Chem. Abstr. 2010,
153, 287153.
(11) Claudi, F.; Franchetti, P.; Grifantini, M.; Martelli, S. J. Org.
Chem. 1974, 39, 3508.
HRMS (FD): m/z [M]+ calcd for C16H1079BrN3: 323.0058; found:
323.0064.
(12) Hardtmann, G. E.; Ott, H. J. Org. Chem. 1974, 39, 3599.
(13) (a) Vlasenko, A. F.; Mandrichenko, B. E.; Rogul’chenko, G.
K.; Sinyak, R. S.; Mazur, I. A.; Kochergin, P. M. Chem.
Heterocycl. Compd. 1976, 12, 696. (b) Wagner, G.; Bunk, E.
Pharmazie 1979, 34, 209.
(14) Petric, A.; Tisler, M.; Stanovnik, B. Monatsh. Chem. 1983,
114, 615.
(15) Gueiffier, A.; Viols, H.; Chapat, J. P.; Chavignon, O.;
Teulade, J. C.; Dauphin, G. J. Heterocycl. Chem. 1990, 27,
421.
Anal. Calcd for C16H10BrN3: C, 59.28; H, 3.11; N, 12.96. Found: C,
59.11; H, 3.18; N, 13.03.
Acknowledgment
This research was supported by the Israel Ministry of Absorption
through the Kamea Fellowship (to E.E.K.), the Weizmann Institute
of Science (Levine Foundation), and the Arbuzov Institute of Orga-
nic and Physical Chemistry (Research Council Grant-in-Aid).
(16) Legrand, L.; Lozac’h, N. Bull. Soc. Chim. Fr. 1975, 1411.
(17) (a) Shi, D.; Wang, J.; Shi, C.; Rong, L.; Zhuang, Q.; Hu, H.
Synlett 2004, 1098. (b) Shi, D.; Shi, C.; Wang, J.; Rong, L.;
Zhuang, Q.; Wang, X. J. Heterocycl. Chem. 2005, 42, 173.
(18) Sharma, D.; Narasimhan, B.; Kumar, P.; Judge, V.; Narang,
R.; De Clercq, E.; Balzarini, J. Eur. J. Med. Chem. 2009, 44,
2347.
(19) (a) Ostrowska, K.; Kolasa, A. In Science of Synthesis; Vol.
22; Charette, A. B., Ed.; Thieme: Stuttgart, 2005, 379.
(b) Boyd, G. V. In The Chemistry of Amidines and Imidates;
Vol. 2; Patai, S.; Rapoport, Z., Eds.; Wiley: Chichester,
1991, 367. (c) Granik, V. G. Russ. Chem. Rev. 1983, 52, 669.
(20) Antonini, I.; Cristalli, G.; Franchetti, P.; Grifantini, M.;
Martelli, S. J. Heterocycl. Chem. 1980, 17, 155.
(21) For recent reviews on the synthesis of 2-imidazolines, see:
(a) Crouch, R. D. Tetrahedron 2009, 65, 2387. (b) Liu, H.;
Du, D.-M. Adv. Synth. Catal. 2009, 351, 489.
(22) Isagulyants, V. I.; Fedorova, R. I.; Adzhiev, A. Y. Chem.
Heterocycl. Compd. 1972, 8, 349.
References
(1) (a) Liu, N. WO 2011128407 2011; Chem. Abstr. 2011, 155,
580856. (b) Liu, N. WO 2010034414 2010; Chem. Abstr.
2010, 152, 398188. (c) Henteman, M. F.; Scott, W.; Wood,
J.; Johnson, J.; Redman, A.; Bullion, A.-M.; Guernon, L.
WO 2009091550 2009; Chem. Abstr. 2009, 151, 173483.
(d) Hentemann, M.; Wood, J.; Scott, W.; Michels, M.;
Campbell, A.-M.; Bullion, A.-M.; Rowley, R. B.; Redman,
A. WO 2008070150 2008; Chem. Abstr. 2008, 149, 54012.
(2) For 2,3-dihydroimidazo[1,2-c]quinazolines and
imidazo[1,2-c]quinazolines as PI3K-inhibitors for treatment
of inflammatory and immunoregulatory disorders, refer to:
(a) Balakumar, C.; Lamba, P.; Kishore, D. P.; Narayana, B.
L.; Rao, K. V.; Rajwinder, K.; Rao, A. R.; Shireesha, B.;
Narsaiah, B. Eur. J. Med. Chem. 2010, 45, 4904.
(b) Shimada, M.; Murata, T.; Fuchikami, K.; Tsujishita, H.;
Omori, N.; Kato, I.; Miura, M.; Urbahns, K.; Gantner, F.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3512–3522

3522
E. E. Korshin et al.
PAPER
(23) (a) Korshin, E. E.; Sabirova, L. I.; Akhmadullin, A. G.;
Levin, Y. A. Russ. Chem. Bull. 1994, 43, 431.
(30) (a) Mohammadpoor-Baltork, I.; Zolfigol, M. A.; Abdollahi-
Alibeik, M. Tetrahedron Lett. 2004, 45, 8687. (b) Guo, X.-
Z.; Shi, L.; Wang, R.; Liu, X.-X.; Li, B.-G.; Lu, X.-X.
Bioorg. Med. Chem. 2008, 16, 10301. (c) Abdollahi-Alibeik,
M.; Mohammadpoor-Baltork, I.; Zolfigol, M. A. Bioorg.
Med. Chem. Lett. 2004, 14, 6079. (d) Sun, M.; Wu, X.;
Chen, J.; Cai, J.; Cao, M.; Ji, M. Eur. J. Med. Chem. 2010,
45, 2299.
(31) (a) Kargar, H.; Moghadam, M.; Mirkhani, V.;
Tangestaninejad, S.; Mohammadpoor-Baltork, I.; Nameni, I.
Bioorg. Med. Chem. Lett. 2011, 21, 2146. (b) Kargar, H.;
Moghadam, M.; Mirkhani, V.; Tangestaninejad, S.;
Mohammadpoor-Baltork, I.; Maghipour, M. Polyhedron
2011, 30, 1463.
(32) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
Angew. Chem. Int. Ed. 2003, 42, 4077. (b) Nicolaou, K. C.;
Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004,
126, 5192. (c) Bakunov, S. A.; Bakunova, S. M.; Wenzler,
T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.; Tidwell, R. R.
J. Med. Chem. 2008, 51, 6927. (d) Ishihara, M.; Togo, H.
Synlett 2006, 227. (e) Büttner, A.; Seifert, K.; Cottin, T.;
Sarli, V.; Tzagkaroulaki, L.; Scholz, S.; Giannis, A. Bioorg.
Med. Chem. 2009, 17, 4943. (f) Chen, J.; Wang, Z.; Li,
C.-M.; Lu, Y.; Vaddady, P. K.; Meibohm, B.; Dalton, J. T.;
Miller, D. D.; Li, W. J. Med. Chem. 2010, 53, 7414.
(g) Goossens, K.; Wellens, S.; Van Hecke, K.; Van
Meervelt, L.; Cardinaels, T.; Binnemans, K. Chem.–Eur. J.
2011, 17, 4291.
(b) Anastassiadou, M.; Baziard-Mouysset, G.; Payard, M.
Synthesis 2000, 1814. (c) Anastassiadou, M.; Danoun, S.;
Crane, L.; Baziard-Mouysset, G.; Payard, M.; Caignard, D.-
H.; Renard, P.; Rettori, M.-C. Bioorg. Med. Chem. 2001, 9,
585. (d) Crane, L.; Anastassiadou, M.; El Hage, S.; Stigliani,
J. L.; Baziard-Mouysset, G.; Payard, M.; Leger, J. M.; Bizot-
Espiard, J.-G.; Ktorza, A.; Caignard, D.-H.; Renard, P.
Bioorg. Med. Chem. 2006, 14, 7419. (e) Moghagadam, M.;
Mohammadpoor-Baltork, I.; Mirkhani, V.; Tangestaninejad,
S.; Abdollahi-Alibeik, M.; Yousefi, B. H.; Kargar, H.
Monatsh. Chem. 2007, 138, 579. (f) Machaj, M.; Pach, M.;
Wolek, A.; Zabrzenska, A.; Ostrowska, K.; Kalinowska-
Tluscik, J.; Oleksyn, B. Monatsh. Chem. 2007, 138, 1273.
(24) (a) Korshin, E. E.; Eliseenkova, R. M.; Zakharova, L.;
Sabirova, L.; Levin, Y. A. Phosphorus, Sulfur Silicon Relat.
Elem. 1996, 111, 197. (b) Sabirova, L. I. Ph.D. Thesis;
Kazan State University: Russian Federation, 1994.
(25) (a) Nakajima, N.; Ubukata, M. In Science of Synthesis; Vol.
22; Charette, A. B., Ed.; Thieme: Stuttgart, 2005, 343.
(b) Neilson, D. G. In The Chemistry of Amidines and
Imidates; Vol. 2; Patai, S.; Rapoport, Z., Eds.; Wiley:
Chichester, 1991, 425. (c) Neilson, D. G. In The Chemistry
of Amidines and Imidates; Patai, S., Ed.; Wiley: London,
1975, 387.
(26) (a) Ozaki, K.; Yamada, Y.; Oine, T.; Ishizuka, T.; Iwasawa,
Y. J. Med. Chem. 1985, 28, 568. (b) Szczepankiewicz, W.;
Suwinski, J.; Bujok, R. Tetrahedron 2000, 56, 9343. (c) El-
Shaieb, K. M.; Hopf, H.; Jones, P. G. ARKIVOC 2010, (x),
98. (d) Maheswari, C. U.; Kumar, G. S.; Venkateshwar, M.;
Kumar, R. A.; Kantam, M. L.; Reddy, K. R. Adv. Synth.
Catal. 2010, 352, 341.
(27) (a) Martin, P. K.; Matthews, H. R.; Rapoport, H.;
Thyagarajan, G. J. Org. Chem. 1968, 33, 3758. (b) DeWald,
H. A.; Beeson, N. W.; Hershenson, F. M.; Wise, L. D.;
Downs, D. A.; Heffner, T. G.; Coughenour, L. L.; Pugsley,
T. A. J. Med. Chem. 1988, 31, 454. (c) Wiglenda, T.; Gust,
R. J. Med. Chem. 2007, 50, 1475.
(33) Haneda, S.; Okui, A.; Ueba, C.; Hayashi, M. Tetrahedron
2007, 63, 2414.
(34) Taketoshi, A.; Tsujimoto, A.; Maeda, S.; Koizumi, T.;
Kanbara, T. ChemCatChem 2010, 2, 58.
(35) (a) Stoyanov, V. M.; El’chaninov, M. M.; Simonov, A. M.;
Pozharskii, A. F. Chem. Heterocycl. Compd. 1989, 25, 1168.
(b) Amemiya, Y.; Miller, D. D.; Hsu, F. L. Synth. Commun.
1990, 20, 2483. (c) Bishop, M. J.; Barvian, K. A.; Berman,
J.; Bigham, E. C.; Garrison, D. T.; Gobel, M. J.; Hodson, S.
J.; Irving, P. E.; Liacos, J. A.; Navas, F. III; Saussy, D. L.;
Speake, J. D. Bioorg. Med. Chem. Lett. 2002, 12, 471.
(d) Parik, P.; Senauerova, S.; Liskova, V.; Handlir, K.;
Ludvig, M. J. Heterocycl. Chem. 2006, 43, 835. (e) Galley,
G.; Groebke, Z. K.; Norcross, R.; Stalder, H. WO
2007085558 2007; Chem. Abstr. 2007, 147, 235164.
(36) Franchetti, P.; Grifantini, M. J. Heterocycl. Chem. 1970, 7,
1295.
(28) (a) Highey, J. L. IV.; Knapp, S.; Schudar, H. Synthesis 1980,
489. (b) Genisson, Y.; Lauth de Viguerie, N.; André, C.;
Baltas, M.; Gorrichon, L. Tetrahedron: Asymmetry 2005,
16, 1017.
(29) (a) Yutilov, Y. M.; Khabarov, K. M. Chem. Heterocycl.
Compd. 1986, 22, 180. (b) Campos, M. E.; Jimenes, R.;
Martinez, F.; Salgado, H. Heterocycles 1995, 40, 841.
(c) Qiao, J. X.; King, S. R.; He, K.; Wong, P. C.; Rendina,
A. R.; Luettgen, J. M.; Xin, B.; Knabb, R. M.; Wexler, R. R.;
Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2009, 19, 462.
(37) Yadav, V. K.; Ganesh, Babu. K. Eur. J. Org. Chem. 2005,
452.
(38) Gueiffier, A.; Viols, H.; Blache, Y.; Chavignon, O.; Teulade,
J. C.; Aumelas, A.; Chapat, J.-P. Heterocycles 1994, 38, 551.
Synthesis 2012, 44, 3512–3522
© Georg Thieme Verlag Stuttgart · New York