Application of 2-(2-chloroaroyl)methyleneimidazolidines in domino and multicomponent reaction: New entries to imidazo[1,2-a]pyridines and benzo[b]imidazo[1,2,3-ij][1,8]naphthyridines

Article abstract of DOI:10.1016/j.tet.2010.11.049

A new strategy for the synthesis of tetrahydroimidazo[1,2-a]pyridines and unusual tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridines has been successfully developed by cascade reactions including Knoevenagel condensation, aza-ene reaction, imine-enami

Full text of DOI:10.1016/j.tet.2010.11.049

Tetrahedron 67 (2011) 293e302
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of 2-(2-chloroaroyl)methyleneimidazolidines in domino
and multicomponent reaction: new entries to imidazo[1,2-a]pyridines
and benzo[b]imidazo[1,2,3-ij][1,8]naphthyridines
*
Li-Rong Wen, Cui-Yu Jiang, Ming Li , Li-Juan Wang
State Key Laboratory Base of Eco-chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 August 2010
Received in revised form 4 November 2010
Accepted 12 November 2010
Available online 18 November 2010
A new strategy for the synthesis of tetrahydroimidazo[1,2-a]pyridines and unusual tetrahydrobenzo[b]
imidazo[1,2,3-ij][1,8]naphthyridines has been successfully developed by cascade reactions including
Knoevenagel condensation, azaeene reaction, imineeenamine tautomerization, cyclocondensation/oxi-
dation, and intramolecular SNAr of precursors 2-(2-chloroaroyl)methyleneimidazolidines as new het-
erocyclic ketene aminals (HKA), which represent a class of polyfunctional scaffolds with four active
reaction sites with aromatic aldehydes and malononitrile or ethyl 2-cyanoacetate under mild conditions.
In this domino reaction, nine different active sites are involved, and two CeC bonds, two CeN bonds, and
two new rings are constructed with all reactants efficiently utilized in the chemical transformation.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-(2-Chloroaroyl)methyleneimidazolidines
Heterocyclic ketene aminals (HKAs)
Tetrahydroimidazo[1,2-a]pyridines
Benzo[b]imidazo[1,2,3-ij][1,8]naphthyridines
Multicomponent reaction
1. Introduction
n
n
HN
HN
O
O
Heterocyclic ketene aminals (HKAs) are powerful and versatile
intermediates in heterocyclic synthesis. Reactions of cyclic ketene
aminals of the general formula 1 with a number of biselectrophilic
N
H
N
H
R
R
Cl
reagents, such as
b
-keto ester enol tosylates,1 polyhalo iso-
n =1, 2
2
n =1, 2
1
phthalonitrile,2 propiolic acid ester,3 aryl azides,4 Meldrum’s acid
and aldehydes,5 bis(methylthio)methylene malononitrile,6 itaconic
anhydride,7
a
-bromoketones,8 ethyl 2-(bromomethyl)benzoate,9
Fig. 1. Functionalized ketene acetals.
BayliseHillman acetates,10 diethyl azodicarboxylate,11 1,3-dibro-
mopropane12 have so far been successfully adopted to give
five-, six-membered and fused heterocycles during the past years.
2-(2-Chloroaroyl)methyleneimidazolidines 2, as a novel class of HKA
with four active sites, show promising structural feature as versatile
building blocks for (1) two nucleophilic centers localized on the
heteroatoms (two nitrogen atoms); (2) a potential third nucleophilic
multistep synthesis. The notable feature of MCRs is that new bonds
and new functionalities are constructed during the cascade, which,
in turn, reacts further in subsequent steps to form new bonds and
functionalities until termination leads to desirable molecules. In
addition, MCRs are more environmentally benign and atom eco-
nomic as they avoid time-consuming and costly purification pro-
cesses, as well as protection-deprotection steps. In this regard, the
development of new MCRs is very important in the fields of organic
and medicinal chemistry.13
center of the a-carbon; (3) halogen atom as potential leaving group
on the aromatic ring, which subjected to an intramolecular SNAr
reaction. To the best of our knowledge, 2-(2-chloroaroyl)methyl-
eneimidazolidines 2 have never been explored (Fig. 1).
In recent years, MCRs have received considerable attention from
the organic community due to their advantages over conventional
Carbonecarbon and carboneheteroatom bond-forming re-
actions are central to organic synthesis. The synthesis of hetero-
cycles often involves ene reaction. In 1943, Aider14 systematically
described a s-bond formation from the reaction between an ene
component and an enophile with a concomitant 1,5-hydrogen shift
and migration of the double bond. Due to its synthetic potential in
organic chemistry, since then, the ene reaction has received much
attention and great development has been achieved particularly in
* Corresponding author. Tel.: þ86 0532 84022990; fax: þ86 0532 84029327;
e-mail address: liming928@qust.edu.cn (M. Li).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.049

294
L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
the past three decades.15 It has recently been extended by Huang16
who has explored the azaeene reactions of heterocyclic ketene
aminals utilizing a wide range of enophiles.
Table 1
Optimization of reaction conditions for compound 5a
Cl
N
Among the nitrogen heterocycles, functionalized naphthyridines
represent an important class of organic molecules that attract the
interest of both synthetic and medicinal chemists. More than 1000
patents were located claiming potential pharmaceutical applica-
tions.17 They have been found in the applications as antibacterial,18
anti-HIV,19 antischizophrenia,20 antiasthma,21 anti-inflammatory,22
antihypertensive,23 anticancer activities.24 Therefore, the synthesis
of imidazo[3,2,1-ij][1,8]naphthyridine derivatives may be of great
significance.
CHO
O
O
HN
CN
CN
CN
base
Solv.
+
N
H
NH2
Cl
Cl
Cl
Cl
HN
5a
Cl
3a
4
2a
Entry
Base (equiv)
db
db
Solv.
Temp (ꢀC)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
rt
24
24
3
10
10
5
5
5
5
3
3
3
3
10
10
10
10
Nil
27
55
38
35
37
40
35
30
51
80
74
67
55
35
38
40
As a continuation of our interest in the development of MCRs,25
herein, by simply incorporating an ortho-halo group into the aryl
ring of 2-benzoylmethyleneimidazolidine, we report the first pre-
cursors 2 and their application as highly efficient reagents to de-
velop a new strategy for the synthesis of imidazo[1,2-a]pyridine
and benzo[b]imidazo[1,2,3-ij][1,8]naphthyridine derivatives in
good yields. As far as we know, these compounds are scarcely
studied and only two similar examples were reported in the liter-
atures.16,26 In contrast to these previous approaches, which lack
scope and flexibility, our serendipitous route to this class of het-
erocyclic system is efficient and fairly general.
80
80
80
80
80
80
80
80
80
80
80
80
78
66
66
100
Et3N (0.5)
K2CO3(0.5)
KOH (0.5)
Pyridine (0.5)
Piperidine (0.5)
DABCO (0.5)
DMAP (0.5)
Et3N (0.1)
Et3N (0.2)
Et3N (0.3)
Et3N (0.4)
Et3N (0.2)
Et3N (0.2)
Et3N (0.2)
Et3N (0.2)
9
10
11
12
13
14
15
16
17
CH3OH
THF
DMF
2. Results and discussion
a
Isolated yield.
No base.
The azaeene type reaction was initiated by three-
component reaction of the precursor 2-(2,4-dichlorophenyl)
methyleneimidazolidine 2a with 4-chlorobenzaldehyde 3a and
malononitrile 4 leading to tetrahydroimidazo[1,2-a]pyridine 5a.
Tetrahydroimidazo[1,2-a]pyridines motifs are of general interest
within medicinal chemistry with therapeutic properties, and a se-
ries of substituted variants of 1 (n¼1, 2) have been reported as a basis
for anticancer,2 analgesics, and anti-inflammatory agents.27 As
a result of the utility of this kind of compounds, the development of
new synthetic methods for the efficient preparation of tetrahy-
droimidazo[1,2-a]pyridine motifs is an interesting challenge. Thus
we first focused our attention on the optimization of this multi-
component reaction.
In the initial experiment, the azaeene type reaction of 2-(2,4-
dichlorophenyl)methyleneimidazolidine 2a with 4-chloro-
benzaldehyde 3a and malononitrile 4 was chosen as the model
reaction for the optimum reaction conditions in different catalysts
and solvents, and the results are listed in Table 1. As can be seen
from Table 1, there was no reaction without addition of any catalyst
at room temperature (Table 1, entry 1), and under reflux temper-
ature only 27% yield was obtained (Table 1, entry 2), while with
Et3N (0.5 equiv) in refluxing CH3CN for 3 h the yield of 5a can reach
55% (Table 1, entry 3). So we investigated other bases and found
that in the presence of K2CO3, KOH, pyridine, piperidine, DABCO or
DMAP, the reactions became sluggish and the yields of the corre-
sponding products were lower than with Et3N (Table 1, entries
4e9). Then, the amount of Et3N was tested (Table 1, entries 10e13).
It was found that, with Et3N (0.2 equiv) as the catalyst, 5a could be
produced in 80% yield in refluxing MeCN for 3 h (Table 1, entry 11).
However, with the increase of the catalytic amount, the yields of 5a
were not further improved. Next, the model reaction was per-
formed in other solvents, such as EtOH, CH3OH, THF or DMF, the
corresponding products were obtained in only 55%, 35%, 38%, and
40% yields, respectively, even if the reaction time was prolonged to
10 h (Table 1, entries 14e17). Thus, it was clear from the experi-
ments that the best conditions for 5a should be Et3N (0.2 equiv) as
base and MeCN as solvent at 80 ꢀC for 3 h (Table 1, entry 11).
Having established the optimal conditions, we then examined
the efficiency of the protocol to other substrates. Three 2-(2-
chloroaroyl)methyleneimidazolidines 2aec were then examined
b
for their reactions with 10 aromatic aldehydes 3aej and malono-
nitrile 4 under the optimized conditions (Table 2).
For precursors 3 bearing either electron-donating or electron-
withdrawing substituents, the reactions proceeded very smoothly
and gave the corresponding products 5aep in good yields in all
cases. This reaction unveils a new reactivity pattern of the pre-
cursors 2 with 3 and malononitrile 4, and provides an efficient
route to tetrahydroimidazo[1,2-a]pyridines 5.
The subsequent SNAr cyclization requires a suitable base to en-
hance the nucleophilicity of heterocyclic nitrogen atom by depro-
tonation and capture of the HCl released during the reaction. We
directly explored the use of various 5 in the presence of K2CO3 in
DMF at 100 ꢀC under atmospheric oxygen via cyclization/oxidation
step for about 4 h, the solvent being evaporated and then water
added, finally the residue being washed with ethanol. To our sur-
prise, the reaction conditions did not require any optimization, and
led to the formation of the corresponding tetrahydrobenzo[b]imi-
dazo[1,2,3-ij][1,8]naphthyridines 6 in almost quantitative yields
(Table 2). Interestingly, workup of the reaction mixture did not
afford the expected compounds 60, and the isolated products were
unexpectedly found to be compounds 6, which are more stable by
aerobic oxidation/dehydrogenation (Scheme 1). In the 1H NMR
spectrum of 6j, apart from the aromatic protons and four CH2
protons in imidazole moiety, only one NH is present (
appeared after addition of D2O). Compared to 5, the absence of CH
proton ( 3.8e4.8) in pyridine moiety indicates that 6 electron
system exists in 6.
d 7.21, dis-
d
p
Azaeene reaction and nucleophilic substitution are two major
reactions in organic chemistry. Encouraged by this successful
transformation, we replaced 4 with ethyl 2-cyanoacetate 7 and
came to investigate this reaction. 4-Chlorobenzaldehyde 3a reacted
with 2-(2,4-dichlorophenyl)methyleneimidazolidine 2a and 7 un-
der the same conditions as described above. It is noteworthy that
the reaction proceeded without the formation of product 800a but an
unexpected white solid of 8a (Scheme 2).
Comparing this azaeene reaction with our early reported three-
component reactions25a of
b-(2-chloroaroyl)thioacetanilides with

L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
295
Table 2
The synthesis of compounds 5aep and 6aep
R1CHO
3
O
N
R1
N
R1
O
CN
NH
CN
aza-ene reaction
Et3N
O
HN
+
SNAr
R
R
K2CO3
air
CN
CN
N
H
R
NH2
Cl
N
HN
+
Cl
5
6
4
Entry
R
R1
Time (h)
azaeene product
Yielda (%)
Time (h)
SNAr-product
Yieldb (%)
1
2
3
4
5
6
7
8
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl-5-F
5-Cl
4-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
2-BrC6H4
4-FC6H4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
80
78
76
74
78
77
74
82
75
72
70
67
65
61
72
74
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
98
99
98
98
99
98
99
98
99
99
98
98
98
97
99
98
2-FC6H4
3-FC6H4
4-NO2C6H4
3-NO2C6H4
C6H5
4-CH3C6H4
4-MeOC6H4
3-CH3C6H4
3-MeOC6H4
4-ClC6H4
4-ClC6H4
9
10
11
12
13
14
15
16
a
Yield of pure, isolated product based on 2.
Yield of pure, isolated product based on 5.
b
R1
N
O
N
R1
O
R1
O
CN
CN
NH
CN
K2CO3
DMF, air
R
R
R
not
N
NH2
N
NH2
Cl
N
HN
6
6'
5
Scheme 1.
Cl
N
Cl
N
O
O
CHO
CN
O
CN
O
SNAr
K2CO3
N
Cl
Cl
HN
Cl
+
9a
Cl
8a
Cl
O
HN
3a
N
H
Cl
Cl
CN
O
2a
+
COOEt
NH2
COOEt
7
Cl
N
Cl
HN
8 a
Scheme 2.
aromatic aldehydes and ethyl 2-cyanoacetate, it is worth men-
tioning that there is a big difference in regioselectivity. According to
the latter reaction mechanism, the reaction of 2a with 3a and 7
would generate the product 800a, in which the C(O)OEt group would
remain after the intramolecular addition/cyclization of one of NH to
cyano carbon atom. But, in our present experiment, 8a was formed
by intramolecular nucleophilic addition of one of NH group in 2a to
carbonyl carbon atom, which was followed by intramolecular SNAr
to obtain corresponding compound 9a in nearly quantitative con-
version (Scheme 2).
The structure of 8a was conformed by IR in combination with
NMR and HRMS spectroscopic data. The IR spectrum of 8a shows
a strong absorption at 2223 cmꢁ1 because of the C^N group. The
absence of C(O)OEt absorption at 1740 cmꢁ1 confirms that the

296
L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
cyclization/oxidation of the initially formed azaeene adduct occurs
with participation of ethyoxy carbonyl group resulting in the for-
mation of 8a. In the 1H NMR spectrum of 8a, apart from the aro-
It should be noted that atmospheric oxygen is important for this
reaction. In order to gain more insight into the reaction mechanism,
we performed the three-component reaction with 2-(2,4-dichlor-
ophenyl)methyleneimidazolidine 2a with 7 and 3c under dry N2. To
our delight, the unaromatized intermediate 80c was isolated, sub-
sequently treatment of the intermediate in the presence of K2CO3 in
DMF at 100 ꢀC under atmospheric oxygen gave the corresponding
aromatized compound 9c. The monocrystal structure of 80c was
unequivocally established by X-ray diffraction analysis (Fig. 2).28
The structural determination of all products 9aeh was achieved
following their analytical and spectral data and unequivocally
confirmed by X-ray diffraction analysis of monocrystal of 9a
(Fig. 3).28
It is worthy of noting that all the isolated products only need
recrystallization or washing rather than column chromatography.
This ease of purification makes this methodology facile, practical,
and rapid to execute.
On the basis of the above experimental results together with the
related reports, a possible mechanism for the formation of tetra-
hedroimidazo[1,2-a]pyridines and tetrahydrobenzo[b]imidazo
[1,2,3-ij][1,8]naphthyridines is proposed and depicted in Scheme 3.
First, compounds 3 proceed through Knoevenagel condensation
with 4 or 7 to give intermediates A or E. Then, the heterocyclic
ketene aminal 2, acted as hetero-ene components due to the strong
matic protons and four CH2 protons (
d
3.90e4.19) in imidazole
moiety, only one NH is present (
d
9.67, disappeared after addition of
D2O). The 13C NMR spectrum of 8a shows 20 distinct resonances in
agreement with the proposed structure. The HRMS spectrum of 8a
displays a molecular ion peak at the appropriate m/z value
(444.0065 [MþH]þ).
Encouraged by the efficiency of the two consecutive domino
processes of the azaeene reaction and nucleophilic substitution, we
set out to explore reaction conditions that would enable its combi-
nation with three-component synthesis of 9 to be performed in
one-pot procedure. We performed azaeene type reaction of 2a with
4-chlorobenzaldehyde 3a and ethyl 2-cyanoacetate 7 by simply
combining three components in MeCN and Et3N as base. Stirring the
mixture at 80 ꢀC readily gave the expected azaeene type adduct 8a,
which was not isolated. After removal of the solvent, the residue was
mixed with 1 equiv of K2CO3 in DMF, and the mixture was heated to
100 ꢀC. After completion of the reaction as monitored by TLC, the
mixture was added into an amount of ice-water to precipitate the
product, which was then collected by filtration, and washed with
ethanol to afford the expected product 9a in total yield of 81%.
Several other aldehydes 3beh also reacted with 2a and ethyl
2-cyanoacetate 7 under above conditions via azaeene reaction,
imineeenamine tautomerization, intramolecular cyclization, and
oxidation/intramolecular SNAr to afford corresponding products
9beh in good yields (Table 3).
nucleophilicity at the a-position of the ketene N,N-acetals, reacts
with A or E to form the intermediates B or F,16 which undergo
a rapid imineeenamine tautomerization to give C or G. Next,
intramolecular cyclization of C or G lead to the formation of fused
Table 3
Synthesis of 9aeh
O
R1
N
O
HN
CN
O
CN
1.Et3N
N
H
R1CHO
+
+
Cl
Cl
N
2. K2CO3
Cl
COOEt
2a
3
9
7
Entry
R1
Time (h)
SNAr-product
Yielda (%)
1
2
3
4
5
6
7
8
4-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
2-BrC6H4
4-FC6H4
3-FC6H4
C6H5
4-MeOC6H4
4
4
4
4
4
4
4
4
9a
9b
9c
9d
9e
9f
81
79
76
72
83
79
74
67
9g
9h
a
Total isolated yield.
Fig. 2. The X-ray crystal structure of 80c.

L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
297
3. Conclusion
In summary, we have successfully demonstrated the application
of 2-(2-chloroaroyl)methyleneimidazolidines 2 to synthesize tet-
rahydroimidazo[1,2-a]pyridines and tetrahydrobenzo[b]imidazo
[1,2,3-ij][1,8]naphthyridines. These studies highlighted the concept
of a substrate-design to the development of novel multicomponent
reactions by simply incorporating an ortho-halo group into the aryl
ring of 2-benzoylmethyleneimidazolidine as new synthons, which
show structural features of highly polarized pushepull interaction
C]C double bond and Cl atom as leaving group subjecting to
intramolecular SNAr. Undoubtedly, this domino synthetic strategy
presented provides a convenient and general way to construct the
target molecules from readily available starting materials under
mild conditions. A possible mechanism involved in the ring closure
cascade reaction including Knoevenagel condensation, azaeene
reaction, intramolecular imineeenamine tautomerization, fol-
lowed by cyclocondensation, oxidation and intramolecular SNAr
was proposed. In this domino reaction, nine different active sites
are involved, two CeC bonds, two CeN bonds, and two new rings
are constructed in the chemical transformation. Further
Fig. 3. The X-ray crystal structure of 9a.
heterocyclic imidazo[1,2-a]pyridine motifs 5 or 8. Finally, an
intramolecular nucleophilic aryl substitution of the o-chloro of aryl
group (SNAr) by attack of NH group leads to new and highly func-
tionalized 6 or 929 with elimination of HCl.
R1CHO
3
R1CHO
CN
3
CN
Kn
oev
ena
gel
CN
4
Kn
oe
ven
age
l
COOEt
7
R1
CN
CN
aza-ene reaction
R1
COOEt
CN
O
HN
A
E
N
H
aza-ene reaction
Cl
Cl
R1
CN
2
R1
CN
CN
O
O
COOEt
H
N
Cl
ClHN
R1
H
N
Cl
ClHN
O
R1
O
O
imine-enamine
tautomerization
CN
O
CN
R1
O
CN
CN
HN NH
Cl
Cl
HN
Cl
N
Cl
OEt
OEt
G
F
Cl
ClHN
N
R1
B
O
R1
N
O
CN
CN
O
imine-enamine
tautomerization
air
N2
N
R1
N-cyclization
-EtOH
O
Cl
HN
Cl
Cl
Cl
HN
O
CN
8
••
8
N
Cl
HN
N
Cl
SNAr
O
K2CO3
H
C
R1
N
CN
O
air
N-cyclization
SNAr
K2CO3
Cl
N
9
R1
H
R1
N
O
O
O
N
R1
CN
CN
CN
NH
K2CO , air
3
NH
oxidation/
SNAr
Cl
HN
N
NH2
Cl
Cl
HN
Cl
Cl
N
D
5
6
Scheme 3. Plausible mechanism for the formation of benzo[b]imidazo[1,2,3-ij][1,8]naphthyridines 6 and 9.

298
L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
investigations to expand the scope of the diversity oriented syn-
thesis of 2-(2-chloroaroyl)methyleneimidazolidines as versatile
building blocks by the combined use of domino and MCRs are in
progress and will be reported elsewhere in due course.
132.6, 133.6, 140.2, 145.2, 150.6, 155.9, 186.8; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H15Cl4N4O, 479.0000; found, 478.9995.
4.2.4. 10-Chloro-6-(2,4-dichlorophenyl)-4-imino-7-oxo-1,2,4,7-tet-
rahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(6b). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3292, 2216,
1629, 1594, 1564, 1538, 1470; dH (DMSO-d6) 4.36 (t, J¼9.5 Hz, 2H,
CH2), 4.57 (t, J¼9.0 Hz, 2H, CH2), 7.36e7.92 (m, 7H, NH, ArH); dC
(DMSO-d6) 45.5, 46.2, 98.2, 115.7, 122.8, 124.4, 127.9, 129.0, 130.7,
132.6, 134.5, 135.1, 138.5, 150.9, 151.4, 157.1, 158.3, 171.3; HRMS
(ESI-TOF, [MþH]þ): calcd for C21H12Cl3N4O, 441.0077; found,
441.0085.
4. Experimental section
4.1. General
All the reagents were purchased from local suppliers and used
without purification. The starting materials 2 were prepared fol-
lowing the published literature procedure.30 Chromatography re-
fers to open column chromatography on silica gel (100e200 mesh).
Melting points were recorded on a RY-1 microscopic melting
apparatus and uncorrected. 1H NMR spectra were recorded on
500 MHz and 13C NMR spectra were recorded on 125 MHz in DMSO-
d6 or acetone-d6 by using a Bruker Avance 500 spectrometer.
4.2.5. 5-Amino-7-(4-bromophenyl)-8-(2,4-dichlorobenzoyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5c). Yellow pow-
der; mp 278e280 ꢀC; IR (KBr, cmꢁ1): 3463, 3264, 2180, 1660, 1634,
1442, 1375, 1297; dH (DMSO-d6) 3.78e3.94 (m, 5H, 2ꢂCH2, CH),
6.25e7.73 (m, 9H, ArH, NH2), 9.45 (s, 1H, NH); dC (DMSO-d6) 43.3,
44.1, 59.4, 87.1, 119.3, 122.0, 127.4, 129.1, 129.8, 131.2, 132.3, 133.4,
140.2, 140.1, 148.0, 150.2, 155.7, 186.7; HRMS (ESI-TOF, [MþH]þ):
calcd for C21H16BrCl2N4O, 488.9885; found, 488.9875.
Chemical shifts are reported in d (ppm) relative to TMS or solvent as
internal standards. IR spectra were recorded on a Nicolet 510P FT-IR
spectrometer and only major peaks are reported in cmꢁ1. Mass
spectra were performed on an Ultima Global spectrometer with an
ESI source. The X-ray single-crystal diffraction was performed on
SMART APEX II instrument.
4.2.6. 6-(4-Bromophenyl)-10-chloro-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(6c). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3300, 2213,
1628, 1595, 1566, 1538, 1469; dH (DMSO-d6) 4.34 (t, J¼8.5 Hz, 2H,
CH2), 4.57 (t, J¼8.5 Hz, 2H, CH2), 7.25e7.95 (m, 8H, ArH, NH); dC
(DMSO-d6) 45.8, 46.4, 98.1, 98.4, 116.1, 116.5, 122.9, 123.6, 124.7,
129.4, 130.5, 131.7, 136.5, 138.7, 138.9, 151.8, 152.1, 156.5, 171.9;
HRMS (ESI-TOF, [MþH]þ): calcd for C21H13BrClN4O, 450.9961;
found, 450.9971.
4.2. General procedure for the preparation of products 5aep
and 6aep
A
solution of 2-(2-chloroaroyl)methyleneimidazolidines
2
(2.0 mmol), aldehydes 3 (2.4 mmol), and malononitrile 4 (2.4 mmol)
was refluxed for a certain period of time in dry MeCN (20 mL) con-
taining Et3N (0.4 mmol, 0.2 equiv). After completion of the reaction as
indicated by TLC (petroleum ethereEtOAc, 2:1, v/v), the solvent was
removed under vacuum and the residue was recrystallized from
EtOAc to afford the products 5. A mixture of corresponding 5
(1.0 mmol) and K2CO3 (1 mmol) was heated to 100 ꢀC in DMF (15 mL).
After completion of the reaction as indicated by TLC (petroleum
ethereEtOAc, 2:3, v/v), the mixture was cooled to room temperature.
An amount of ice-water was added to precipitate the product, which
was then filteredandwashedwithethanoltogivethepureproducts6.
4.2.7. 5-Amino-7-(2-bromophenyl)-8-(2,4-dichlorobenzoyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5d). Yellow pow-
der; mp 147e149 ꢀC; IR (KBr, cmꢁ1): 3426, 3327, 2171, 1654, 1636,
1520,1450,1371,1293; dH (DMSO-d6) 3.79e4.62 (m, 5H, 2ꢂCH2, CH),
5.98e7.56 (m, 9H, ArH, NH2), 9.48 (s, 1H, NH); dC (DMSO-d6) 43.6,
44.3, 58.7, 88.1, 121.7, 123.0, 127.6, 128.5, 128.8, 129.4, 129.6, 130.3,
132.4, 133.7, 140.6, 148.0, 150.8, 156.1, 187.1; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H16BrCl2N4O, 488.9885; found, 488.9883.
4.2.8. 6-(2-Bromophenyl)-10-chloro-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(6d). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3298, 2216,
1627, 1595, 1564, 1536, 1470; dH (DMSO-d6) 4.32 (m, 2H, CH2), 4.53
(m, 2H, CH2), 7.21e7.86 (m, 8H, ArH, NH); dC (DMSO-d6) 45.6, 46.3,
98.5, 115.9, 116.0, 121.4, 123.3, 124.6, 128.4, 129.3, 129.4, 130.9, 132.8,
138.5, 138.8, 151.3, 151.4, 156.1, 171.4; HRMS (ESI-TOF, [MþH]þ):
calcd for C21H13BrClN4O, 450.9961; found, 450.9954.
4.2.1. 5-Amino-7-(4-chlorophenyl)-8-(2,4-dichlorobenzoyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5a). Yellow pow-
der; mp 297e299 ꢀC; IR (KBr, cmꢁ1): 3469, 3265, 2180, 1660, 1634,
1443, 1377, 1298; dH (DMSO-d6) 3.79e3.95 (m, 5H, 2ꢂCH2, CH),
6.25e7.60 (m, 9H, ArH, NH2), 9.45 (s, 1H, NH); dC (DMSO-d6) 43.5,
44.3, 59.9, 87.6, 122.4, 127.8, 128.7, 129.0, 129.1, 129.2, 129.7, 131.3,
133.9, 140.4, 147.7, 150.4, 156.0, 187.2; HRMS (ESI-TOF, [MþH]þ):
calcd for C21H16Cl3N4O, 445.0390; found, 445.0383.
4.2.9. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(4-fluorophenyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5e). Yellow pow-
der; mp 222e224 ꢀC; IR (KBr, cmꢁ1): 3474, 3264, 2179, 1661, 1635,
1506, 1444, 1375, 1296； dH (DMSO-d6) 3.78e4.30 (m, 5H, 2ꢂCH2,
CH), 6.23e7.62 (m, 9H, ArH, NH2), 9.43 (s, 1H, NH); dC (DMSO-d6)
43.3, 44.0, 59.8, 87.5, 114.9, 115.1, 122.1, 127.3, 128.6, 129.5, 130.1,
133.3, 140.3, 145.4, 150.0, 155.6, 160.0, 161.9, 186.8; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H16Cl2FN4O, 429.0685; found, 429.0665.
4.2.2. 10-Chloro-6-(4-chlorophenyl)-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile (6a).
Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3204, 2212, 1627,
1595, 1563, 1540, 1470; dH (DMSO-d6) 4.30 (t, J¼9.0 Hz, 2H, CH2),
4.53 (t, J¼9.0 Hz, 2H, CH2), 7.28e7.89 (m, 8H, NH, ArH); dC (DMSO-
d6) 45.2, 45.9, 97.6, 115.7, 116.1, 123.3, 124.3, 128.4, 129.0, 129.9,
133.8, 135.7, 138.2, 138.5, 151.5, 156.3, 171.5; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H13Cl2N4O, 407.0466; found, 407.0459.
4.2.10. 10-Chloro-6-(4-fluorophenyl)-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile (6e).
Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3296, 2218, 1623,
1594, 1564, 1539, 1469； dH (acetone-d6) 4.50 (t, J¼8.5 Hz, 2H, CH2),
4.76 (t, J¼8.50 Hz, 2H, CH2), 7.14e7.98 (m, 8H, ArH, NH); dC (DMSO-
d6) 43.3, 44.0, 87.5,114.9,115.1,122.1,127.3,128.7,133.4,139.6, 140.0,
4.2.3. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(2,4-dichlorophenyl)-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5b). Yellow
powder; mp 231e233 ꢀC; IR (KBr, cmꢁ1): 3450, 3222, 2177, 1659,
1585, 1447, 1375, 1296; dH (DMSO-d6) 3.80e4.62 (m, 5H, 2ꢂCH2,
CH), 6.14e7.57 (m, 8H, ArH, NH2), 9.46 (s, 1H, NH); dC (DMSO-d6)
43.4, 44.1, 57.7, 87.2, 121.5, 127.5, 128.1, 129.5, 129.9, 131.4, 132.0,

L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
299
145.2, 145.9, 150.0, 155.7, 160.0, 161.9, 186.7; HRMS (ESI-TOF,
139.7, 147.7, 150.4, 155.7, 186.8; HRMS (ESI-TOF, [MþH]þ): calcd for
[MþH]þ): calcd for C21H13ClFN4O, 391.0762; found, 391.0756.
C21H16Cl2N5O3, 456.0630; found, 456.0627.
4.2.11. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(2-fluorophenyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5f). Yellow pow-
der; mp 149e151 ꢀC; IR (KBr, cmꢁ1): 3471, 3294, 2177, 1657, 1587,
1509, 1445, 1373, 1296; dH (DMSO-d6) 3.79e4.40 (m, 5H, 2ꢂCH2,
CH), 6.12e7.60 (m, 9H, ArH, NH2), 9.44 (s, 1H, NH); dC (DMSO-d6)
33.8, 43.6, 44.3, 58.3, 87.1, 115.3, 122.2, 124.9, 127.6, 128.6, 129.0,
129.9, 132.6, 133.6, 135.5, 136.4, 139.8, 140.3, 150.8, 156.1, 159.2,
161.0, 186.8; HRMS (ESI-TOF, [MþH]þ): calcd for C21H16N4OFCl2,
429.0685; found, 429.0680.
4.2.18. 10-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyr-
idine-4-imino-5-carbonitrile-6-(3-nitrophenyl)-7-one (6i). Yellow
powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3440, 2211, 1628, 1597, 1565,
1541,1472,1348; dH (TFA-d) 5.86e5.95 (m, 4H, 2ꢂCH2), 8.33e9.32 (m,
8H, ArH, NH); dC (TFA-d) 49.1, 50.3, 95.0, 106.7, 125.0, 125.4, 128.5,
130.7, 132.5, 133.4, 136.2, 137.2, 139.9, 147.6, 150.9, 151.6, 156.2, 166.1,
178.0; HRMS (ESI-TOF, [MþH]þ): calcd for C21H13ClN5O3, 418.0707;
found, 418.0708.
4.2.19. 5-Amino-8-(2,4-dichlorobenzoyl)-7-phenyl-1,2,3,7-tetrahy-
droimidazo[1,2-a]pyridine-6-carbonitrile (5j). Yellow powder; mp
245e247 ꢀC; IR (KBr, cmꢁ1): 3436, 3348, 2177, 1657, 1446, 1373,
1295; dH (DMSO-d6) 3.79e3.97 (m, 5H, 2ꢂCH2, CH), 6.15e7.60 (m,
10H, ArH, NH2), 9.43 (s, 1H, NH); dC (DMSO-d6) 41.2, 43.3, 44.1, 59.9,
87.6,122.2, 126.4, 126.9,127.2,128.4,129.2, 129.8, 130.2,133.3,140.2,
148.7, 150.1, 155.8, 186.8; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H17Cl2N4O, 411.0779; found, 411.0768.
4.2.12. 10-Chloro-6-(2-fluorophenyl)-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8] naphthyridine-5-carbonitrile (6f).
Yellow powder; decompose, >250 ꢀC; IR (KBr, cmꢁ1): 3290, 2212,
1659, 1597, 1560, 1539, 1470; dH (DMSO-d6) 4.32 (t, J¼8.5 Hz, 2H,
CH2), 4.53 (t, J¼8.5 Hz, 2H, CH2), 6.85e7.93 (m, 8H, ArH, NH); dC
(DMSO-d6) 45.1, 45.7, 98.5, 115.4, 115.6, 118.9, 123.0, 124.0, 124.3,
124.6, 128.7, 129.0, 129.9, 130.5, 131.4, 138.3, 138.5, 151.5, 154.4,
156.4, 158.1, 171.7; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H13N4OFCl, 391.0762; found, 391.0753.
4.2.20. 10-Chloro-4-imino-7-oxo-6-phenyl-1,2,4,7-tetrahydrobenzo[b]
imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile (6j). Yellow pow-
der; mp >300 ꢀC; IR (KBr, cmꢁ1): 3296, 2216,1628,1595,1564,1537,
1471; dH (acetone-d6) 4.55 (t, J¼8.5 Hz, 2H, CH2), 4.81 (t, J¼8.5 Hz,
2H, CH2), 7.21 (s, 1H, NH), 7.32e8.02 (m, 8H, ArH); dC (DMSO-d6)
45.4, 46.0, 98.1, 115.6, 116.3, 123.4, 124.2, 127.8, 128.3, 128.9, 129.2,
136.8, 138.3, 138.5, 151.2, 152.0, 157.4, 171.5; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H14ClN4O, 373.0856; found, 373.0852.
4.2.13. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(3-fluorophenyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5g). Yellow pow-
der; mp 207e209 ꢀC; IR (KBr, cmꢁ1): 3421, 3267, 2179, 1659, 1447,
1371, 1295; dH (DMSO-d6) 3.79e3.94 (m, 5H, 2ꢂCH2, CH), 6.24e7.65
(m, 9H, ArH, NH2), 9.43 (s, 1H, NH); dC (DMSO-d6) 43.4, 44.1, 59.2,
87.2, 113.3, 115.1, 118.6, 122.1, 123.1, 127.4, 129.1, 130.1, 133.4, 140.4,
150.3, 152.3, 155.7, 161.5, 163.4, 186.7; HRMS (ESI-TOF, [MþH]þ):
calcd for C21H16Cl2FN4O, 429.0685; found, 429.0673.
4.2.21. 5-Amino-8-(2,4-dichlorobenzoyl)-7-p-tolyl-1,2,3,7-tetrahy-
droimidazo[1,2-a]pyridine-6-carbonitrile (5k). Yellow powder; mp
203e205 ꢀC; IR (KBr, cmꢁ1): 3473, 3263, 2184, 1662, 1633, 1441,
1376, 1298; dH (DMSO-d6) 2.20 (s, 3H, CH3), 3.78e3.94 (m, 5H,
2ꢂCH2, CH), 6.27e7.70 (m, 9H, ArH, NH2), 9.40 (s, 1H, NH); dC
(DMSO-d6) 21.1, 43.3, 44.1, 60.2, 87.7, 114.2, 122.2, 126.8, 127.3,
128.3, 128.9, 133.3, 135.3, 140.2, 145.5, 150.1, 155.8, 186.7; HRMS
(ESI-TOF, [MþH]þ): calcd for C22H19Cl2N4O, 425.0936; found,
425.0938.
4.2.14. 10-Chloro-6-(3-fluorophenyl)-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile (6g).
Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3311, 2214, 1630, 1595,
1564, 1533, 1469; dH (DMSO-d6) 4.32 (t, J¼8.5 Hz, 2H, CH2), 4.55 (t,
J¼8.5 Hz, 2H, CH2), 7.08e7.92 (m, 8H, ArH, NH); dC (DMSO-d6) 45.5,
46.0, 98.1, 114.9, 115.1, 115.7, 123.3, 124.1, 124.4, 129.2, 130.6, 138.2,
138.7, 139.3, 145.2, 149.4, 152.1, 152.5, 156.0, 161.2, 171.8; HRMS (ESI-
TOF, [MþH]þ): calcd for C21H13ClFN4O, 391.0762; found, 391.0762.
4.2.22. 10-Chloro-4-imino-7-oxo-6-(p-tolyl)-1,2,4,7-tetrahydrobenzo
[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(6k). Yellow
powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3305, 2209, 1670,1645, 1622,
1595, 1562, 1539, 1472； dH (DMSO-d6) 2.40 (s, 3H, CH3), 4.34 (t,
J¼8.5 Hz, 2H, CH2), 4.56 (t, J¼8.5 Hz, 2H, CH2), 7.17e7.92 (m, 8H,
ArH, NH); dC (DMSO-d6) 21.5, 45.4, 46.1, 98.1, 115.6, 116.4, 116.8,
123.4, 124.4, 127.9, 128.8, 129.1, 133.9, 138.7, 139.5, 148.4, 151.5,
152.2, 197.9; HRMS (ESI-TOF, [MþH]þ): calcd for C22H16ClN4O,
387.1013; found, 387.1021.
4.2.15. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(4-nitrophenyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5h). Yellow pow-
der; mp 283e286 ꢀC; IR (KBr, cmꢁ1): 3460, 2923, 2178, 1660, 1636,
1515, 1446, 1346, 1298; dH (DMSO-d6) 3.80e4.04 (m, 5H, 2ꢂCH2,
CH), 6.48 (s, 2H, NH2), 6.88e7.99 (m, 7H, ArH), 9.51 (s, 1H, NH); dC
(DMSO-d6) 41.5, 43.5, 44.1, 58.6, 86.7, 121.7, 123.9, 127.6, 128.2,
129.2, 133.7, 139.9, 146.3, 150.5, 155.8, 186.7; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H16Cl2N5O3, 456.0630; found, 456.0634.
4.2.23. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(4-methoxyphenyl)-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5l). Yellow
powder; mp 274e276 ꢀC; IR (KBr, cmꢁ1): 3433, 3206, 2179, 1664,
1636, 1443, 1378, 1299; dH (DMSO-d6) 3.67 (s, 3H, OCH3), 3.78e3.94
(m, 5H, 2ꢂCH2, CH), 6.26 (s, 2H, NH2), 6.52e7.60 (m, 7H, ArH), 9.39
(s, 1H, NH); dC (DMSO-d6) 43.3, 44.0, 55.4, 60.3, 87.8, 113.8, 122.3,
127.3, 127.8, 127.9, 128.8, 128.9, 129.5, 133.2, 140.3, 149.9, 155.7,
157.9, 186.8; HRMS (ESI-TOF, [MþH]þ): calcd for C22H19Cl2N4O2,
441.0885; found, 441.0879.
4.2.16. 10-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyr-
idine-4-imino-5-carbonitrile-6-(4-nitrophenyl)-7-one (6h). Yellow
powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3439, 2216, 1622, 1595, 1563,
1541, 1472, 1345; dH (DMSO-d6) 4.32 (t, J¼9.0 Hz, 2H, CH2), 4.58 (t,
J¼9.0 Hz, 2H, CH2), 7.34e8.32 (m, 8H, ArH, NH); dC (TFA-d) 49.1,
50.5, 94.5, 106.7, 113.4, 127.0, 130.6, 131.0, 132.5, 139.9, 142.7, 147.5,
151.5, 151.8, 156.1, 166.4, 177.8; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H13ClN5O3, 418.0707; found, 418.0690.
4.2.17. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(3-nitrophenyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5i). Yellow pow-
der; mp 223e225 ꢀC; IR (KBr, cmꢁ1): 3447, 2176, 1660, 1636, 1526,
1448,1349,1297; dH (DMSO-d6) 3.80e4.27 (m, 5H, 2ꢂCH2, CH), 6.48
(s, 2H, NH2), 6.48e7.91 (m, 7H, ArH), 9.52 (d, 1H, NH); dC (DMSO-d6)
40.6, 41.5, 43.4, 44.1, 58.6, 86.9,121.6,121.8,127.5,129.2,130.2,133.7,
4.2.24. 10-Chloro-4-imino-6-(4-methoxyphenyl)-7-oxo-1,2,4,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8] naphthyridine-5-carbonitrile (6l).
Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3256, 2217, 1667, 1632,
1593, 1564, 1539, 1468; dH (DMSO-d6) 3.84 (s, 3H, OCH3), 4.31e4.37
(m, 2H, CH2), 4.53e4.57 (m, 2H, CH2), 6.99e7.94 (m, 8H, ArH, NH); dC
(DMSO-d6) 45.2, 45.9, 55.6, 97.8,113.5,115.5,116.6,123.5,124.4,125.9,

300
L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
129.1, 129.7, 131.7, 137.5, 138.4, 143.0, 148.2, 160.2, 171.5; HRMS (ESI-
135.5, 142.4, 151.4, 157.1, 187.2; HRMS (ESI-TOF, [MþH]þ): calcd for
TOF, [MþH]þ): calcd for C22H16N4O2Cl, 403.0962; found, 403.0957.
C21H16Cl3N4O, 445.0390; found, 445.0393.
4.2.25. 5-Amino-8-(2,4-dichlorobenzoyl)-7-m-tolyl-1,2,3,7-tetrahy-
droimidazo[1,2-a]pyridine-6-carbonitrile (5m). Yellow powder; mp
155e157 ꢀC; IR (KBr, cmꢁ1): 3327, 2178, 1654, 1636, 1586, 1448,
1374, 1295; dH (DMSO-d6) 2.12 (s, 3H, CH3), 3.76e3.97 (m, 5H,
2ꢂCH2, CH), 6.20e7.20 (m, 9H, ArH, NH2), 9.42 (s, 1H, NH); dC
(DMSO-d6) 21.5, 41.4, 43.3, 44.1, 60.1, 87.9, 122.2, 124.4, 127.0, 127.2,
127.6, 128.4, 133.3, 137.0, 150.1, 155.7, 186.9; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H19Cl2N4O, 425.0936; found, 425.0935.
4.2.32. 9-Chloro-6-(4-chlorophenyl)-4-imino-7-oxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(6p). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3214, 2216,
1654, 1623, 1596, 1563, 1540, 1471; dH (acetone-d6) 4.56 (t, J¼9.0 Hz,
2H, CH2), 4.82 (t, J¼9.0 Hz, 2H, CH2), 7.27e7.99 (m, 8H, ArH, NH); dC
(DMSO-d6) 45.5, 46.0, 97.9, 116.2, 118.3, 125.9, 126.2, 128.5, 128.8,
129.9, 133.6, 133.9,135.7, 136.1,149.3,151.2,151.8,156.1,171.1; HRMS
(ESI-TOF, [MþH]þ): calcd for C21H13Cl2N4O, 407.0466; found,
407.0478.
4.2.26. 10-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyr-
idine-4-imino-5-carbonitrile-6-m-tolyl-7-one (6m). Yellow powder;
mp>300 ꢀC; IR (KBr, cmꢁ1): 3447, 2214,1625,1593,1562,1538,1471,
1348; dH (TFA-d) 3.13 (s, 3H, CH3), 5.77e5.85 (m, 4H, 2ꢂCH2),
7.89e8.99 (m, 7H, ArH,); dC (TFA-d) 22.2, 48.9, 50.1, 94.8,106.8,116.0,
125.3,126.4,129.7,130.3,131.7,132.6,135.0,135.3,139.8,142.7,147.2,
151.5, 156.0, 170.3, 178.2; HRMS (ESI-TOF, [MþH]þ): calcd for
C22H16ClN4O, 387.1013; found, 387.1020.
4.3. General procedure for synthesis of products 9aeh
A
solution of 2-(2-chloroaroyl)methyleneimidazolidines
2
(2.0 mmol), aldehydes 3 (2.4 mmol), and ethyl 2-cyanoacetate 7
(2.4 mmol) was refluxed for a certain period of time in dry MeCN
(20 mL) containing Et3N (0.4 mmol, 0.2 equiv). After completion of
the reaction as indicated by TLC (petroleum ethereEtOAc, 2:1, v/v),
the solvent was removed under vacuum, the residue was mixed with
1 equiv of K2CO3 in DMF, and the mixture was heated to 100 ꢀC. After
completion of the reaction as monitored by TLC (petroleum ether-
eEtOAc, 2:3, v/v), the mixture was added into an amount of ice-water
to precipitate the product, which was then collected by filtration and
washed with ethanol to afford the expected products 9.
4.2.27. 5-Amino-8-(2,4-dichlorobenzoyl)-7-(3-methoxyphenyl)-
1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5n). Yellow
powder; mp 200e202 ꢀC; IR (KBr, cmꢁ1): 3439, 2177, 1656, 1586,
1446, 1371, 1295; dH (DMSO-d6) 3.57 (s, 3H, OCH3), 3.75e3.94 (m,
4H, 2ꢂCH2), 4.68 (s, 1H, CH), 5.99e7.50 (m, 9H, ArH, NH2), 9.40 (s,
1H, NH); dC (DMSO-d6) 41.4, 43.3, 44.1, 55.2, 59.9, 87.7, 111.7, 112.7,
119.4, 122.1, 127.3, 127.5, 129.4, 129.6, 133.4, 150.2, 155.8, 159.3,
186.8; HRMS (ESI-TOF, [MþH]þ): calcd for C22H19Cl2N4O2,
441.0885; found, 441.0888.
4.3.1. 10-Chloro-6-(4-chlorophenyl)-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9a). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2222, 1670,
1645, 1602, 1563, 1539, 790; dH (DMSO-d6) 4.47e4.51 (m, 2H, CH2),
4.61e4.65 (m, 2H, CH2), 7.35e7.99 (m, 7H, ArH); dC (DMSO-d6) 45.2,
46.6, 99.5, 100.5, 116.1, 116.4, 123.5, 125.1, 128.9, 129.7, 130.2, 134.5,
135.5, 138.5, 139.6, 151.3, 157.9, 160.8, 172.8; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H12Cl2N3O2, 408.0307; found, 408.0309.
4.2.28. 10-Chloro-benzo-1,2-dihydroimidazo[3,2,1-ij][1,8]naphthyr-
idine-4-imino-5-carbonitrile-6-(3-methoxyphenyl)-7-one
(6n). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3442, 2215,1626,
1595,1562,1539,1471,1345; dH (TFA-d) 4.73 (s, 3H, OCH3), 5.77e5.82
(m, 4H, 2ꢂCH2), 7.78e9.00 (m, 7H, ArH,); dC (TFA-d) 49.6, 50.7, 58.9,
95.6, 107.6, 116.8, 119.1, 119.8, 123.7, 126.0, 131.2, 133.3, 134.4, 137.7,
140.6, 148.0, 152.3, 156.8, 162.4, 169.7, 178.7; HRMS (ESI-TOF,
[MþH]þ): calcd for C22H16ClN4O2, 403.0962; found, 403.0957.
4.3.2. 10-Chloro-6-(2,4-dichlorophenyl)-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9b). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2219,1672,1644,
1608, 1564, 1540, 1467; dH (DMSO-d6) 4.50e4.54 (m, 2H, CH2),
4.62e4.66 (m, 2H, CH2), 7.37e8.00 (m, 6H, ArH); dC (DMSO-d6) 45.2,
46.7, 99.4, 100.6, 115.4, 116.5, 123.0, 123.2, 125.1, 128.3, 129.4, 130.8,
132.5, 135.0, 138.5, 139.6, 151.1, 157.6, 157.7, 172.5; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H11Cl3N3O2, 441.9917; found, 441.9928.
4.2.29. 5-Amino-7-(4-chlorophenyl)-8-(2,4-dichloro-5-fluo-
robenzoyl)-1,2,3,7-tetrahydro-imidazo[1,2-a]pyridine-6-carbonitrile
(5o). Yellow powder; mp 254e256 ꢀC; IR (KBr, cmꢁ1): 3407, 3338,
2177,1660,1634,1509,1485,1448,1396,1294; dH (DMSO-d6) 3.79 (t,
J¼9.5 Hz, 2H, CH2), 3.87e3.96 (m, 3H, CH2, CH), 6.36 (s, 2H, NH2),
6.68e7.79 (m, 6H, ArH), 9.46 (s, 1H, NH); dC (DMSO-d6) 43.4, 44.1,
59.8, 87.0, 120.2, 120.3, 121.9, 124.5, 117.0, 128.3, 128.8, 130.9, 147.2,
142.6, 149.9, 155.3, 155.9, 157.2, 185.0； HRMS (ESI-TOF, [MþH]þ):
calcd for C21H15Cl3N4OF, 463.0295; found, 463.0276.
4.3.3. 6-(4-Bromophenyl)-10-chloro-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9c). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2224,1644,1602,
1566, 1542, 1463; dH (DMSO-d6) 4.47e4.51 (m, 2H, CH2), 4.61e4.65
(m, 2H, CH2), 7.28e7.99 (m, 7H, ArH); dC (DMSO-d6) 45.0, 46.5, 99.1,
100.2,115.7,116.3,122.8,123.4, 124.9,129.4,130.1,131.7,135.6,138.4,
139.3, 151.1, 157.6, 160.5, 172.5; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H12BrClN3O2, 451.9801; found, 451.9803.
4.2.30. 10-Chloro-6-(4-chlorophenyl)-9-fluoro-4-imino-7-oxo-
1,2,4,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8] naphthyridine-5-car-
bonitrile (6o). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 3322,
2221, 1668, 1629, 1581, 1536, 1471, 1377, 1240; dH (acetone-d6)
4.19e4.32 (m, 4H, 2ꢂCH2), 6.98e7.35 (m, 7H, ArH, NH); dC (ace-
tone-d6) 43.3, 44.6, 97.7, 115.8, 117.2, 117.4, 125.8, 127.3, 127.9,
130.4, 130.7, 134.6, 135.3, 141.2, 152.2, 154.7, 156.5, 156.8, 157.9,
186.4; HRMS (ESI-TOF, [MþH]þ): calcd for C21H12Cl2FN4O,
425.0372; found, 425.0358.
4.3.4. 6-(2-Bromophenyl)-10-chloro-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9d). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2221,1655, 1610,
1567, 1541, 1460; dH (DMSO-d6) 4.48e4.55 (m, 2H, CH2), 4.62e4.66
(m, 2H, CH2), 7.28e7.98 (m, 7H, ArH); dC (DMSO-d6) 45.1, 46.5, 99.1,
100.4, 115.2, 116.2, 120.8, 122.9, 124.9, 128.3, 129.0, 129.3, 130.9,
132.6, 137.8, 138.3, 139.3, 150.9, 157.6, 160.0, 172.1; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H12BrClN3O2, 451.9801; found, 451.9819.
4.2.31. 5-Amino-7-(4-chlorophenyl)-8-(2,5-dichlorobenzoyl)-1,2,3,7-
tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5p). Yellow pow-
der; mp 230e232 ꢀC; IR (KBr, cmꢁ1): 3470, 3246, 2179, 1667, 1634,
1440, 1377, 1295; dH (DMSO-d6) 3.92e4.08 (m, 5H, 2ꢂCH2, CH),
7.01e7.15 (m, 9H, NH2, ArH), 9.72 (s, 1H, NH); dC (DMSO-d6) 43.6,
43.9, 44.7, 90.8, 98.0, 117.1, 128.2, 128.5, 129.5, 129.7, 131.1, 134.1,
4.3.5. 10-Chloro-6-(4-fluorophenyl)-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9e). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2224,1679,1646,

L.-R. Wen et al. / Tetrahedron 67 (2011) 293e302
301
1599, 1565, 1541, 1515, 1471, 791; dH (DMSO-d6) 4.46e4.51 (m, 2H,
CH2), 4.60e4.64 (m, 2H, CH2), 7.30e8.00 (m, 7H, ArH); dC (DMSO-
d6) 45.1, 46.5, 99.6, 100.5, 115.6, 115.8, 116.1, 116.3, 123.4, 124.9,
129.6, 130.6, 132.7, 138.4, 139.4, 151.2, 157.8, 161.0, 172.7; HRMS (ESI-
TOF, [MþH]þ): calcd for C21H12ClFN3O2, 392.0602; found, 392.0621.
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
References and notes
1. Yan, S.-J.; Huang, C.; Su, C.-X.; Ni, Y.-F.; Lin, J. J. Comb. Chem. 2010, 12, 91e94.
2. Yan, S.-J.; Niu, Y.-F.; Huang, R.; Lin, J. Synlett 2009, 2821e2824.
3. Schirok, H.; Alonso-Alijia, C.; Benet-Buchnolz, J.; Goller, A. H.; Grosser, R.; Mi-
chels, M.; Paulsen, H. J. Org. Chem. 2005, 70, 9463e9469.
4.3.6. 10-Chloro-6-(3-fluorophenyl)-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9f). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2225, 1684, 1648,
1606, 1599, 1564, 1540, 1471, 790, 760; dH (DMSO-d6) 4.41e4.45 (m,
2H, CH2), 4.54e4.58 (m, 2H, CH2), 6.80e7.95 (m, 7H, ArH); dC
(DMSO-d6) 45.2, 46.6, 99.8, 100.7, 115.8, 115.9, 116.0, 116.2, 116.4,
123.1, 124.3, 124.4, 125.0, 129.5, 130.1, 132.0, 132.1, 138.4, 139.5, 151.1,
155.7, 157.8, 158.1, 160.1, 172.6; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H12ClFN3O2, 392.0602; found, 392.0607.
4. Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 1992, 57, 184e190.
5. Yu, C.-Y.; Yang, P.-H.; Zhao, M.-X.; Huang, Z.-T. Synlett 2006, 1835e1840.
6. Liao, J.-P.; Zhang, T.; Yu, C.-Y.; Huang, Z.-T. Synlett 2007, 761e764.
7. Chakrabarti, S.; Panda, K.; Misra, N. C.; Ila, H.; Junjappa, H. Synlett 2005,1437e1441.
8. Nie, X.-P.; Wang, M.-X.; Huang, Z.-T. Synthesis 2000, 10, 1439e1443.
9. Xu, Z.-H.; Jie, Y.-F.; Wang, M.-X.; Huang, Z.-T. Synthesis 2002, 4, 523e527.
10. Yaqub, M.; Yu, C.-Y.; Jia, Y. M.; Huang, Z.-T. Synlett 2008, 1357e1360.
11. Zhao, M.-X.; Wang, Z.-M.; Wang, M.-X.; Yan, C.-H.; Huang, Z.-T. Tetrahedron
2002, 58, 7791e7796.
12. Jones, R. C. F.; Patel, P.; Hirst, S. C.; Turne, I. Tetrahedron 1997, 53, 11781e11790.
13. (a) Li, D.-M.; Song, L.-P.; Li, X.-F.; Xing, C.-H.; Peng, W.-M.; Zhu, S.-Z. Eur. J. Org.
€
Chem. 2007, 3520e3525; (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
4.3.7. 10-Chloro-4,7-dioxo-6-phenyl-1,2,4,7-tetrahydrobenzo[b]imi-
dazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile (9g). Yellow powder;
mp >300 ꢀC; IR (KBr, cmꢁ1): 2224, 1644, 1602, 1566, 1542, 1463; dH
(DMSO-d6) 4.47e4.50 (m, 2H, CH2), 4.60e4.63 (m, 2H, CH2),
7.31e7.99 (m, 8H, ArH); dC (DMSO-d6) 44.8, 46.2, 99.2, 100.3, 115.9,
116.0, 123.2, 124.7, 127.8, 128.4, 129.3, 129.4, 136.3, 138.2, 139.1,
151.0, 157.7, 161.8, 172.4; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H13ClN3O2, 374.0696; found, 374.0695.
€
3168e3210; (c) Domling, A. Chem. Rev. 2006, 106, 17e89; (d) Zhang, M.; Jiang,
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H.-F.; Liu, H.-L.; Zhu, Q.-H. Org. Lett. 2007, 9, 4111e4113; (e) Zhu, J.-P.; Bienayme,
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F.; Zhou, H. Y.; Su, G. X.; Zhang, W.; Yan, B. J. Comb. Chem. 2009, 11, 1083e1093;
(g) Wan, J.-P.; Gan, S.-F.; Sun, G.-L.; Pan, Y.-J. J. Org. Chem. 2009, 74, 2862e2865;
(h) Wan, J.-P.; Pan, Y.-J. Chem. Commun. 2009, 2768e2770; (i) Ganem, B. Acc.
Chem. Res. 2009, 42, 463e472; (j) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G.-G.
J. Am. Chem. Soc. 2009, 131, 11660e11661; (k) Jiang, B.; Wang, X.; Shi, F.; Tu, S.-J.;
Ai, T.; Ballew, A.; Li, G. G. J. Org. Chem. 2009, 74, 9486e9489; (l) Jiang, B.; Li, C.;
Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. G. J. Org. Chem. 2010, 75, 2962e2965;
(m) Wei, H.-L.; Yan, Z.-Y.; Niu, Y.-L.; Li, G.-Q.; Liang, Y.-M. J. Org. Chem. 2007, 72,
8600e8603; (n) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. J. Org. Chem. 2005, 70,
2866e2869; (o) Sun, J.; Zhang, L.-L.; Xia, E.-Y.; Yan, C.-G. J. Org. Chem. 2009, 74,
3398e3401; (p) Wang, P.; Song, L.; Yi, H.; Zhang, M.; Zhu, S.; Deng, H.; Shao, M.
Tetrahedron Lett. 2010, 51, 3975e3977.
4.3.8. 10-Chloro-6-(4-methoxyphenyl)-4,7-dioxo-1,2,4,7-tetrahy-
drobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbonitrile
(9h). Yellow powder; mp >300 ꢀC; IR (KBr, cmꢁ1): 2219, 1645,
1605, 1566, 1543, 1462; dH (DMSO-d6) 3.84 (s, 3H, CH3), 4.44e4.48
(m, 2H, CH2), 4.58e4.62 (m, 2H, CH2), 7.01e7.99 (m, 7H, ArH); dC
(DMSO-d6) 44.9, 46.2, 55.9, 99.3, 100.5, 113.9, 116.2, 116.4, 123.6,
124.9, 128.3, 129.6, 130.0, 138.4, 139.3, 151.2, 158.0, 160.6, 161.9,
172.7; HRMS (ESI-TOF, [MþH]þ): calcd for C22H15ClN3O3, 404.0802;
found, 404.0798.
14. (a) Aider, K.; Pascher, F.; Schmitz, A. Chem. Ber. 1943, 76, 27; (b) Aider, K.; Noble,
T. Chem. Ber. 1943, 76, 54.
15. (a) Cossy, J.; Bouzide, A.; Pfau, M. J. Org. Chem. 1997, 62, 7106e7113; (b) Op-
polzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476e486; (c) Car-
ruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon: Oxford,
1990, pp 241e268; (d) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021e1050;
(e) Snider, B. B. Acc. Chem. Res. 1980, 13, 426e432; (f) Borzilleri, R. M.; Weinreb,
S. M. Synthesis 1995, 347e360; (g) Clarke, M. L.; France, M. B. Tetrahedron 2008,
64, 9003e9031.
4.3.9. 7-(4-Chlorophenyl)-8-(2,4-dichlorobenzoyl)-5-oxo-1,2,3,5-tet-
rahydroimidazo[1,2-a]pyridine-6-carbonitrile (8a). Yellow powder;
mp 262e264 ꢀC; IR (KBr, cmꢁ1): 3291, 2223, 1661, 1612, 1574, 1533,
1494, 1470, 1322, 1293, 824, 787; dH (DMSO-d6) 3.90e3.94 (m, 2H,
CH2), 4.15e4.19 (m, 2H, CH2), 7.07e7.23 (m, 7H, ArH), 9.67 (s, 1H,
NH); dC (DMSO-d6) 44.2, 44.3, 91.5, 100.9, 117.1, 127.4, 128.6, 129.4,
130.8, 131.5, 131.7, 134.8, 135.2, 135.3, 139.6, 157.4, 158.6, 161.4,
189.6; HRMS (ESI-TOF, [MþH]þ): calcd for C21H13Cl3N3O2,
444.0073; found, 444.0065.
16. (a) Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T. Tetrahedron 2002, 58, 1309e1316; (b)
Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc., Perkin Trans.1 1999,
2087e2094; (c) Zhang, J.-H. M.; Wang, M.-X.; Huang, Z.-T. Tetrahedron Lett.
1998, 39, 9237e9240.
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465, 2007; Chem. Abstr. 2007, 148, 33755; (b) Cosford, N.D.P.; Layton, M.E.;
Liang, J.; Lindsley, C.W.; Sanderson, P.E.; Zhao, Z. WO 091 395, 2006; Chem.
Abstr. 2006, 145, 293099; (c) Wang, Y.; Mull, E.S. WO 101 988, 2003; Chem.
Abstr. 2006, 140, 16716; (d) Shimamoto, T.; Inoue, H.; Hayashi, Y. WO 07 704,
1999; Chem. Abstr. 1999, 130, 196577; (e) Leach, C.A.; Smith, S.A. WO 086 400,
2003; Chem. Abstr. 2003, 139, 337978.
18. (a) Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; DeWolf, W. E., Jr.;
Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson, C. A.; Keller, P. M.; Manley, P. J.; Moore,
T. D.; Payne, D. J.; Pearson, S.; Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Uzinskas, I. N.;
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Chem. Abstr. 2006, 146, 441772.
4.3.10. 7-(4-Bromophenyl)-8-(2,4-dichlorobenzoyl)-5-oxo-1,2,3,5,6,7-
hexahydroimidazo[1,2-a]pyridine-6-carbonitrile (80c). White powder,
mp 265e266 ꢀC; IR (KBr, cmꢁ1): 3295, 2260, 1709, 1645, 1588, 1556,
1534, 1488, 1451, 822, 747; dH (DMSO-d6) 3.73e3.97 (m, 5H, 2ꢂCH2,
CH), 4.96 (d, J¼5.0 Hz, 1H, CH), 6.74e7.60 (m, 7H, ArH), 9.65 (s, 1H,
NH); dC (DMSO-d6) 41.2, 42.0, 42.8, 43.8, 87.3, 115.8, 121.2, 127.5,
128.9, 129.2, 129.4, 129.9, 130.1, 131.8, 133.8, 139.5, 155.2, 161.1,
186.2; HRMS (ESI-TOF, [MþH]þ): calcd for C21H15BrCl2N3O2,
489.9725; found, 489.9739.
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Supplementary data
Supplementary data associated with this article can be found in
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